PMID- 23790239 TI - Distinct subtypes of zona pellucida morphology reflect canine oocyte viability and cumulus-oocyte complex quality. AB - The aim of this study was to analyze surface morphology of the zona pellucida (ZP) and assess its relationship with oocyte viability, cumulus-oocyte complex (COC) quality, and oocyte donor age in dogs. Canine ovaries were sliced to release COCs for use in three experiments. In Experiment 1, oocytes from high quality (grade I) COCs were viewed with scanning electron microscopy to visualize the zona surface. Four zonae, classified as types I, II, III, and IV, were detectable on high-quality oocytes. Most (95.5%) dog donors had oocytes with two or three ZP types. The ZP type I had a smooth compact surface with few pores. The ZP type II was less compact with many distinct circular or elliptical pores. The ZP type III had a rough surface with folds and many irregular shaped pores and hollows. The ZP type IV also had a rough surface with folds, but in addition, stringy filaments obscured the pores and hollows. The frequency of ZP type I in the oocyte population was low (2.7%), whereas ZP types II, III, and IV each occurred in approximately one-third of the oocyte population. In Experiment 2, oocytes from high-quality COCs were stained with propidium iodide (PI) before scanning electron microscopy to investigate the relationship of oocyte viability with ZP morphology. In Experiment 3, oocytes were collected from low-quality (grade 2) and high-quality (grade 1) COCs to investigate the role of COC quality on zona structure. Zonae types I and II were characteristic of PI-positive (dead) oocytes and oocytes from low-quality COCs, whereas ZP types III and IV were prevalent on PI-negative (living) oocytes and oocytes from high-quality COCs. We concluded that the heterogeneous ZP surface underwent structural rearrangements related to oocyte viability and COC quality. This warrants further investigation into ZP structure and may be useful for canine-assisted reproduction. PMID- 23790240 TI - Sequential evolution of different phases in metastable Gd(2-x)Ce(x)Zr(2-x)Al(x)O7 (0.0 <= x <= 2.0) system: crucial role of reaction conditions. AB - The Gd(2-x)Ce(x)Zr(2-x)Al(x)O7 (0.0 <= x <= 2.0) series was synthesized by the gel combustion method. This system exhibited the presence of a fluorite-type phase, along with a narrow biphasic region, depending upon the Ce/Gd content in the sample. Thermal stability of these new compounds under oxidizing and reducing conditions has been investigated. The products obtained on decomposition of Gd(2 x)Ce(x)Zr(2-x)Al(x)O7 in oxidizing and reducing conditions were found to be entirely different. It was observed that in air the fluorite-type solid solutions of Gd(2-x)Ce(x)Zr(2-x)Al(x)O7 composition undergo phase separation into perovskite GdAlO3 and fluorite-type solid solutions of Gd-Ce-Zr-O or Ce-Zr-Al-O depending upon the extent of Ce and Al substitution. On the other hand, Gd(2 x)Ce(x)Zr(2-x)Al(x)O7 samples on heating under reducing conditions show a phase separation to CeAlO3 perovskite and a defect-fluorite of Gd2Zr2O7. The extent of metastability for a typical composition of Gd(1.2)Ce(0.8)Zr(1.2)Al(0.8)O7 (nano), Gd(1.2)Ce(0.8)Zr(1.2)Al(0.8)O(6.6) (heated under reduced conditions), Gd(1.2)Ce(0.8)Zr(1.2)Al(0.8)O7 (heated in air at 1200 degrees C) has been experimentally determined employing a high temperature Calvet calorimeter. On the basis of thermodynamic stability data, it could be inferred that the formation of a more stable compound in the presence of two competing cations (i.e., Gd(3+) and Ce(3+)) is guided by the crystallographic stability. PMID- 23790241 TI - The trade-off between the light-harvesting and photoprotective functions of fucoxanthin-chlorophyll proteins dominates light acclimation in Emiliania huxleyi (clone CCMP 1516). AB - Mechanistic understanding of the costs and benefits of photoacclimation requires knowledge of how photophysiology is affected by changes in the molecular structure of the chloroplast. We tested the hypothesis that changes in the light dependencies of photosynthesis, nonphotochemical quenching and PSII photoinactivation arises from changes in the abundances of chloroplast proteins in Emiliania huxleyi strain CCMP 1516 grown at 30 (Low Light; LL) and 1000 (High Light; HL) MUmol photons m(-2) s(-1) photon flux densities. Carbon-specific light saturated gross photosynthesis rates were not significantly different between cells acclimated to LL and HL. Acclimation to LL benefited cells by increasing biomass-specific light absorption and gross photosynthesis rates under low light, whereas acclimation to HL benefited cells by reducing the rate of photoinactivation of PSII under high light. Differences in the relative abundances of proteins assigned to light-harvesting (Lhcf), photoprotection (LI818-like), and the photosystem II (PSII) core complex accompanied differences in photophysiology: specifically, Lhcf:PSII was greater under LL, whereas LI818:PSII was greater in HL. Thus, photoacclimation in E. huxleyi involved a trade-off amongst the characteristics of light absorption and photoprotection, which could be attributed to changes in the abundance and composition of proteins in the light-harvesting antenna of PSII. PMID- 23790242 TI - Self-reactive CFTR T cells in humans: implications for gene therapy. AB - Cystic fibrosis (CF) is one of the most common autosomal recessive lethal disorders affecting white populations of northern European ancestry. To date there is no cure for CF. Life-long treatments for CF are being developed and include gene therapy and the use of small-molecule drugs designed to target specific cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations. Irrespective of the type of molecular therapy for CF, which may include gene replacement, exon skipping, nonsense suppression, or molecular correctors, because all of these modulate gene expression there is an inherent risk of activation of T cells against the wild-type version of CFTR. Here we report the validation of the human interferon-gamma enzyme-linked immunospot assay and its application for the analysis of CFTR-specific T cell responses in patients with CF and in non-CF subjects. We found non-CF subjects with low levels of self-reactive CFTR-specific T cells in the United States and several patients with CF with low to high levels of self-reactive CFTR-specific T cells in both the United States and the United Kingdom. PMID- 23790243 TI - Do prokinetics influence the completion rate in small-bowel capsule endoscopy? A systematic review and meta-analysis. AB - BACKGROUND: The use of purging for bowel cleansing prior to small-bowel capsule endoscopy (SBCE) has now been established in clinical practice. Despite that, the number of incomplete SBCEs is still around 15-20%. To date, the use of prokinetics in SBCE - aiming to improve completion rate (CR) - remains a contentious issue resulting in lack of consensus among capsule experts. METHODS: Extensive medical literature searches were conducted (to November 2012), using suitable MeSH terms and keywords, in search of studies that compared capsule ingestion with prokinetic agents vs. controls or placebo. We examined the effects of prokinetic administration on SBCE CR (primary end point), as well as on the following secondary end points: diagnostic yield (DY), gastric transit time (GTT) and small-bowel transit time (SBTT) by meta-analysis of all relevant studies. RESULTS: A total of 17 eligible studies (14 prospective, 3 retrospective) were identified, including 1028 individuals who ingested the capsule with no prokinetic vs. 876 who received a prokinetic. Overall, there was a higher CR in patients who ingested the capsule with prokinetics vs. controls (OR [95% CI]: 1.96 [1.38-2.78]). Of the two most readily available prokinetics, metoclopramide was associated with superior SBCE CR vs. control (OR [95% CI]: 2.8 [1.35-3.21]), while erythromycin showed no benefit (OR [95% CI]: 1.36 [0.61-3.03]). Where prokinetics were used alone, neither metoclopramide nor erythromycin showed any benefit on CR. There was no benefit of prokinetics (over controls) on DY. However, metoclopramide had a significant effect on GTT and SBTT. LIMITATIONS: The majority of the included studies were heterogeneous, and the effect of prokinetics on image quality and mucosal visualization was not examined. CONCLUSION: Our pooled data shows that the use of prokinetics for capsule ingestion improves CR in SBCE. This effect appears to be particularly evident with metoclopramide, when used concurrently with purging and/or use of real-time monitoring. In a small number of studies, erythromycin showed - through its gastrokinetic effect - marginal benefit. No prokinetic has a beneficial effect on SBCE DY. PMID- 23790244 TI - What do we know about the safety of corticosteroids in rheumatoid arthritis? AB - BACKGROUND: Clear information is still lacking on the safety of corticosteroids (GCs) therapy in RA despite six decades of clinical experience. SCOPE: We performed a literature search in Ovid MEDLINE from January 2000 to December 2012. Our Population Intervention Comparator Outcomes (PICO) strategy search was: rheumatoid arthritis [Population], corticosteroids or glucocorticoids [Intervention], any comparison [Comparator], adverse effects [Outcome]. Studies were selected if they reported any measure of association between GCs intake and potential adverse effects in RA patients. FINDINGS: We identified 1030 papers and selected for analysis 26 observational studies and six systematic reviews. The major side effects of GCs in RA are bone loss, risk of cardiovascular events and risk of infections as evidenced by large observational studies and not necessarily RCTs. Others associations were reported with herpes zoster, tuberculosis, hyperglycemia, cutaneous abnormalities, gastrointestinal perforation, respiratory infection and self-reported health problems such as cushingoid phenotype, ecchymosis, parchment-like skin, epistaxis, weight gain and sleep disturbance. Other potential adverse effects of GCs were studied but no association was found. These included psychological disorders, dermatophytosis, brain diseases, interstitial lung disease, memory deficit, metabolic syndrome, lymphoma, non-Hodgkin's lymphoma, renal function and cerebrovascular accidents. Most of the evidence emanates from observational researches and the inherent limitations of such data should be kept in mind. CONCLUSION: Recent observational data and systematic reviews suggest that GCs can lead to relatively alarming and burdensome side effects in RA. This is particularly true for patients who have longer term and higher dose therapies. GCs are largely used in RA and knowing their safety profile is essential to improve patients care. The design of new therapeutic strategies intended to minimize the daily dosing of GCs while conserving their beneficial effect should be encouraged. PMID- 23790245 TI - Meta-analysis of clinical outcomes of intravenous recombinant tissue plasminogen activator for acute ischemic stroke: within 3 hours versus 3-4.5 hours. AB - OBJECTIVE: This meta-analysis was to compare clinical outcomes of intravenous recombinant tissue plasminogen activator (IV rtPA) administered within 3 hours versus 3-4.5 hours after symptom onset. METHODS: We collected all interventional or observational studies that compared clinical outcomes of IV rtPA treatment within 3 hours and 3-4.5 hours after acute ischemic stroke onset by searching PubMed (up to October 2012), Embase (1966 to October 2012) and Web of Science (2003 to October 2012) as well as manually searching the references of articles retrieved. The combined effect was calculated by odds ratios (ORs) and 95% confidence intervals (CIs) to analyze favorable functional outcome, mortality and symptomatic intracranial hemorrhage (sICH) at 90 days. Publication bias was analyzed by Begg's funnel plot and Egger's regression test. RESULTS: Our initial search identified a total of 27,391 articles. After reviewing the titles, abstracts and full text, a total of six studies and more than 25,000 patients were included in the final meta-analysis. The combined analyses demonstrated significant differences in the favorable outcome (modified Rankin scale, mRS: 0 2): OR = 0.89, 95% CI = 0.81-0.98 and very favorable outcomes (mRS: 0-1): OR = 0.86, 95% CI = 0.78-0.94 between two groups, which were both in favor of the 3 4.5 hours group. When all studies reporting data on sICH were combined, the overall summary OR indicated no differences in the two groups. The combined analyses showed no significant differences in 90 day mortality and 7 day mortality between within 3 hours and 3-4.5 hours. CONCLUSIONS: This meta-analysis does not provide any evidence that treatment with rtPA within 3-4.5 hours is less safe than treatment within 3 hours. It suggests that treatment with IV rtPA may be recommended to ischemic stroke patients that present within 4.5 hours of onset, although every effort should be made to give those patients IV rtPA within 3 hours of symptom onset. PMID- 23790247 TI - Nothing is perfect! Trouble-shooting in immunological and molecular studies of cestode infections. AB - This personal review focuses on ways to approach and overcome some of the more common issues encountered while studying cestode zoonoses. The information presented here is based on the author's own experiences with immunological and molecular approaches for the detection of these parasites. There are many incongruities between immunological and molecular studies due to biased work. Nothing is perfect. Indirect approaches using either immunological, or even molecular tools, are limited without confirmation from direct evidence of infection. The dilemma of whether developing countries should develop their own diagnostic tests or rely on commercially available kits is also discussed. PMID- 23790248 TI - Evaluation and treatment of sex addiction. AB - There have been several diagnostic labels for persistent, excessive sexual behaviors, often referred in the popular media as sex addiction. Two related diagnoses, Internet addictive disorder and hypersexual disorder, were considered for, but not included in the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders. However, most clinicians, even those trained in sexual disorders or addiction medicine, have little to no training in treating sexual compulsivity and cybersex addiction. The authors present the historical context, proposed diagnostic criteria, evaluation protocols, comorbid disorders, speculations about the neuroscience, and treatment recommendations. PMID- 23790249 TI - Pemetrexed as the first-line therapy for Chinese patients with advanced non squamous non-small-cell lung cancer. AB - Non-small cell lung cancer (NSCLC) represents the most common cause of cancer mortality worldwide and counts for the greatest number of deaths from lung cancer in both men and women over age 60. Pemetrexed is a multi-targeted anti-metabolite and has shown comparable activity for Caucasian patients with advanced NSCLC. In this single-center retrospective study, we analyzed the outcome in 75 Chinese non squamous NSCLC patients treated with pemetrexed as first-line therapy and assessed its efficacy and tolerability. The overall response rate was 9.3% (7/75) with 7 partial response s and no complete response. There were 44 (58.7%) stable diseases and 24 progressive diseases (32.0%). The median progression-free survival (PFS) was 6.79 months (95% CI 5.69-7.90 months), and the median overall survival (OS) was 11.67 months (95% CI 9.98-13.36 months). Good performance status and negative smoke history predicted better PFS and OS. Most side effects were generally mild and well tolerated. Taken together, pemetrexed was safe and effective in Chinese patients with non-squamous NSCLC. Pemetrexed alone or in combination with other efficacious drugs may serve as first-line therapy for this disease. PMID- 23790250 TI - Gestational diabetes mellitus decreases placental uptake of long-chain polyunsaturated fatty acids: involvement of long-chain acyl-CoA synthetase. AB - The long-chain polyunsaturated fatty acids (LC-PUFAs) arachidonic (AA) and docosahexaenoic (DHA) acids are essential for fetal development. Gestational diabetes mellitus (GDM) is a pregnancy disorder associated with perinatal and lifelong risk complications for both the mother and the newborn. Our aim was to investigate the influence of GDM, and some of its associated conditions, upon the placental uptake of AA and DHA. Uptake of (14)C-AA and (14)C-DHA by human trophoblasts obtained from normal pregnancies (NTB cells) was mediated by both saturable (for lower substrate concentrations) and non-saturable (for higher substrate concentrations) mechanisms. Uptake of both fatty acids was inhibited by other LC-PUFAs and, markedly, by the long-chain acyl-CoA synthetase (ACSL) inhibitor, triacsin C. Human trophoblasts obtained from GDM pregnancies (DTB cells) showed a significantly lower (14)C-AA and (14)C-DHA accumulation, through a decrease in both the saturable and the non-saturable components of uptake, which was associated with a decrease in ACSL1 mRNA levels. Uptake of LC-PUFAs by NTB cells increased (by 20-25%) after short-term exposure to TNF-alpha ((14)C-AA and (14)C-DHA) and insulin ((14)C-DHA). In conclusion, GDM, distinctly from its associated conditions, markedly decreases placental uptake of LC-PUFAs, which probably contributes to the deleterious effects of this disease for the newborn. PMID- 23790251 TI - Ex vivo assessment of extravascular lung water with transpumonary thermodilution. PMID- 23790252 TI - Metabolo-proteomics to discover plant biotic stress resistance genes. AB - Plants continuously encounter various environmental stresses and use qualitative and quantitative measures to resist pathogen attack. Qualitative stress responses, based on monogenic inheritance, have been elucidated and successfully used in plant improvement. By contrast, quantitative stress responses remain largely unexplored in plant breeding, due to complex polygenic inheritance, although hundreds of quantitative trait loci for resistance have been identified. Recent advances in metabolomic and proteomic technologies now offer opportunities to overcome the hurdle of polygenic inheritance and identify candidate genes for use in plant breeding, thus improving the global food security. In this review, we describe a conceptual background to the plant-pathogen relationship and propose ten heuristic steps streamlining the application of metabolo-proteomics to improve plant resistance to biotic stress. PMID- 23790254 TI - Susceptibility to plant disease: more than a failure of host immunity. AB - Susceptibility to infectious diseases caused by pathogens affects most plants in their natural habitat and leads to yield losses in agriculture. However, plants are not helpless because their immune system can deal with the vast majority of attackers. Nevertheless, adapted pathogens are able to circumvent or avert host immunity making plants susceptible to these uninvited guests. In addition to the failure of the plant immune system, there are other host processes that contribute to plant disease susceptibility. In this review, we discuss recent studies that show the active role played by the host in supporting disease, focusing mainly on biotrophic stages of infection. Plants attract pathogens, enable their entry and accommodation, and facilitate nutrient provision. PMID- 23790253 TI - Flowering time regulation: photoperiod- and temperature-sensing in leaves. AB - Plants monitor changes in photoperiod and temperature to synchronize their flowering with seasonal changes to maximize fitness. In the Arabidopsis photoperiodic flowering pathway, the circadian clock-regulated components, such as FLAVIN-BINDING, KELCH REPEAT, F-BOX 1 and CONSTANS, both of which have light controlled functions, are crucial to induce the day-length specific expression of the FLOWERING LOCUS T (FT) gene in leaves. Recent advances indicate that FT transcriptional regulation is central for integrating the information derived from other important internal and external factors, such as developmental age, amount of gibberellic acid, and the ambient temperature. In this review, we describe how these factors interactively regulate the expression of FT, the main component of florigen, in leaves. PMID- 23790255 TI - Influence of body adiposity on structural characteristics of skeletal muscle in men and women. AB - The structure of skeletal muscle (SM) can be characterized by quantitative (size) and qualitative (composition) attributes, which are disparately reported to be influenced by body adiposity. This study tests the hypothesis that body adiposity exerts a systematic influence on these muscle characteristics and evaluates the possible functional implications for movements. Lower limb SM volume (VSM) and attenuation (ATTSM), an inverse measure of lipid infiltration in muscle, were determined with computed tomography in 21 men (BMI = 21-36 kg m(-2) ; age = 31-71 years.) and 18 women (BMI = 19-35 kg m(-2) ; age = 32-76 years.). After adjusting for age, a multivariate regression analysis revealed that body adiposity positively correlated (P<0.05-0.001) with absolute VSM and cross-sectional area (CSA) in both genders, while VSM per unit body mass (VSM/BM) decreased with adiposity (P<0.001) in women and was constant in men. ATTSM was higher in men (P<0.05) and decreased (P<0.05) with adiposity in both genders. The product of ATTSM by average muscle CSA (predictor of maximal strength) and by VSM/BM (predictor of maximal dynamic performance) was lower in women (P<0.001) and was reduced by age in both genders (P<0.05-0.01), while obesity had a negative effect (P<0.001) only on the predictor of performance. In conclusion, body adiposity significantly increases SM size and reduces ATTSM. Structural indicators accounting for both quantitative and qualitative characteristics of SM may be useful predictors of the effects of obesity on motor function at different ages. With rising body adiposity and advancing age, women appear mostly affected by the decline of SM features relevant for motor performance. PMID- 23790256 TI - A computational bioinformatics analysis of gene expression identifies candidate agents for prostate cancer. AB - Prostate cancer is the second most frequently diagnosed cancer and the sixth leading cause of cancer death in males worldwide. Although great progress has been made, the molecular mechanisms of prostate cancer are far from being fully understood and treatment of this disease remains palliative. In this study, we sought to explore the molecular mechanism of prostate cancer and then identify biologically active small molecules capable of targeting prostate cancer using a computational bioinformatics analysis of gene expression. A total of 3068 genes, involved in cell communication, development, localisation and cell proliferation, were differentially expressed in prostate cancer samples compared with normal controls. Pathways associated with signal transduction, immune response and tumorigenesis were dysfunctional. Further, we identified a group of small molecules capable of reversing prostate cancer. These candidate agents may provide the groundwork for a combination therapy approach for prostate cancer. However, further evaluation for their potential use in the treatment of prostate cancer is still needed. PMID- 23790257 TI - Lipoic acid in animal models and clinical use in diabetic retinopathy. AB - INTRODUCTION: Oxidative stress, a consequence of excessive production of reactive oxygen species (ROS), is a factor in the development of many diseases, including diabetes and its complications. Alpha-lipoic acid (ALA), a natural thiol antioxidant, has been shown to have beneficial effects on oxidative stress parameters in various tissues. This article is an up-to-date review of current thinking regarding ALA and its use in providing antioxidant (AO) drug therapy for ocular dysfunction due to diabetic retinopathy (DR). AREAS COVERED: ALA prevents micro- and macro-vascular damage through normalized pathways downstream of mitochondrial overproduction of ROS, and preserves pericyte coverage of retinal capillaries. In addition, clinical studies suggest that oral administration of ALA can improve insulin sensitivity in patients with type-2 diabetes. Moreover, ALA treatment has been shown to suppress expression of vascular endothelial growth factor (VEGF), angiopoietin 2 and erythropoietin via blockade of superoxide formation. EXPERT OPINION: The diverse beneficial effects of ALA, many of which have only recently been uncovered, suggest that it acts by multiple mechanisms on oxidative stress parameters. Consequently, ALA supplementation is an achievable adjunct therapy to help prevent vision loss in diabetic patients. Finally, further research to better understand the mechanism of ALA will be useful for the development of more effective therapies in patients affected by DR. PMID- 23790258 TI - Risk factors contributing to the difference in prognosis for papillary versus micropapillary thyroid carcinoma. AB - BACKGROUND: The aggressiveness of papillary thyroid carcinoma (PTC) was evaluated by comparing conventional PTC with papillary thyroid microcarcinoma (PTMC). Risk factors associated with differences in clinical and pathologic features were analyzed to provide appropriate surgical management. METHODS: A total of 539 patients with papillary carcinoma who underwent total thyroidectomy were retrospectively reviewed. The median follow-up period was 32 months. RESULTS: Of 539 patients, 311 (57.7%) had PTMC, and 228 (42.3%) had conventional PTC. No differences between patients with PTMC and those with PTC were observed in age, gender, and multifocality. PTMC was associated with less frequent bilaterality (P = .002), lymph node metastasis (P < .001), thyroid capsule invasion (P < .001), and disease recurrence (P < .001), and a higher rate of incidental diagnosis (P = .001). There was no statistically significant difference between the prevalence of lymph node metastasis at diagnosis and disease recurrence rate between nonincidental PTMC and conventional PTC (P > .05). CONCLUSIONS: Incidental PTMC had significantly fewer aggressive tumor features. Nonincidental PTMC presented with aggressive characteristics similar to those of conventional PTC and should be treated likewise. The authors suggest routine total thyroidectomy followed by an adequate exploration of the central neck compartment as a safe treatment. PMID- 23790260 TI - Cerebrospinal fluid neopterin is brain-derived and not associated with blood-CSF barrier dysfunction in non-inflammatory affective and schizophrenic spectrum disorders. AB - Many psychiatric patients have a minor blood-CSF barrier dysfunction and increased Cerebrospinal fluid (CSF) neopterin concentrations. The source of normal CSF neopterin, a biomarker in inflammatory and non-inflammatory neurological diseases, has never been shown explicitly, a precondition for sensitive detection of pathologically increased CSF neopterin. Neopterin concentrations (ELISA) in CSF and serum of normal controls (n = 26) are evaluated by inter-individual variation propagation. Normal CSF neopterin is brain-derived: The inter-individual variation of CSF neopterin in the control group does not depend on serum neopterin concentration variation (coefficient of variation, CV CSF = 9.7% < CV-serum = 24.5%). Additionally individual normal CSF neopterin concentrations are invariant to the variation of the albumin quotient, QAlb, i.e. CSF neopterin does not derive from leptomeninges. Subsequently CSF neopterin was interpreted with reference to its absolute concentration in CSF (cut off = 5.5 nmol/l). Patients (N = 44), retrospectively selected from a larger group with schizophrenic and affective spectrum disorder, are characterized by the absence of any clinical and neurochemical signs of inflammation. In this group 30% had an increased CSF neopterin concentration and 30% had an increased QAlb with only 7% combined pathologies. Increased CSF neopterin did not correlate with the blood CSF barrier dysfunction. In the discussion we point to possible sources of both independent pathologies, connected either with reduced CSF flow rate (QAlb) or microglial activation (neopterin). With CSF neopterin analysis earlier in vitro studies about microglia activation in schizophrenic spectrum disorders or corresponding therapeutic efforts could get a more direct, in-vivo analytical tool. PMID- 23790261 TI - What is the scale of intimate partner homicide? PMID- 23790262 TI - Balamuthia mandrillaris: in vitro interactions with selected protozoa and algae. AB - Although Balamuthia mandrillaris was identified more than two decades ago as an agent of fatal granulomatous encephalitis in humans and other animals, little is known about its ecological niche, biological behavior in the environment, food preferences and predators, if any. When infecting humans or other animals, Balamuthia feeds on tissues; and in vitro culture, it feeds on mammalian cells (monkey kidney cells, human lung fibroblasts, and human microvascular endothelial cells). According to recent reports, it is believed that Balamuthia feeds on small amebae, for example, Acanthamoeba that are present in its ecological niche. To test this hypothesis, we associated Balamuthia on a one-on-one basis with selected protozoa and algae. We videotaped the behavior of Balamuthia in the presence of a potential prey, its ability to hunt and attack its food, and the time required to eat and cause damage to the target cell by direct contact. We found that B. mandrillaris ingested trophozoites of Naegleria fowleri, Naegleria gruberi, Acanthamoeba spp., Trypanosoma cruzi epimastigotes, Toxoplasma gondii tachyzoites, and Giardia. However, it did not feed on Acanthamoeba cysts or algae. Balamuthia caused cytolysis of T. cruzi epimastigotes and T. gondii tachyzoites by direct contact. Balamuthia trophozoites and cysts were, however, eaten by Paramecium sp. PMID- 23790259 TI - Characterization of depression in prodromal Huntington disease in the neurobiological predictors of HD (PREDICT-HD) study. AB - Depression causes significant morbidity and mortality, and this also occurs in Huntington Disease (HD), an inherited neurodegenerative illness with motor, cognitive, and psychiatric symptoms. The presentation of depression in this population remains poorly understood, particularly in the prodromal period before development of significant motor symptoms. In this study, we assessed depressive symptoms in a sample of 803 individuals with the HD mutation in the prodromal stage and 223 mutation-negative participants at the time of entry in the Neurobiological Predictors of HD (PREDICT-HD) study. Clinical and biological HD variables potentially related to severity of depression were analyzed. A factor analysis was conducted to characterize the symptom domains of depression in a subset (n=168) with clinically significant depressive symptoms. Depressive symptoms were found to be more prevalent in HD mutation carriers but did not increase with proximity to HD diagnosis and were not associated with length of the HD mutation. Increased depressive symptoms were significantly associated with female gender, self-report of past history of depression, and a slight decrease in functioning, but not with time since genetic testing. The factor analysis identified symptom domains similar to prior studies in other populations. These results show that individuals with the HD mutation are at increased risk to develop depressive symptoms at any time during the HD prodrome. The clinical presentation appears to be similar to other populations. Severity and progression are not related to the HD mutation. PMID- 23790263 TI - Conization using the Shimodaira-Taniguchi procedure for adenocarcinoma in situ of the uterine cervix. PMID- 23790264 TI - Purchaser-provider splits in health care-the case of Finland. AB - The purchaser-provider split (PPS) is a service delivery model in which third party payers are kept organizationally separate from service providers. The operations of the providers are managed by contracts. One of the main aims of PPS is to create competition between providers. Competition and other incentive structures built into the contractual relationship are believed to lead to improvements in service delivery, such as improved cost containment, greater efficiency, organizational flexibility, better quality and improved responsiveness of services to patient needs. PPS was launched in Finland in the early 1990s but was not widely implemented until the early 2000s. Compared to other countries with PPS the development and implementation of PPS in Finland has been unusual. Firstly, purchasing is implemented at the level of municipalities, which means that the size of the Finnish purchasers is extremely small. Elsewhere purchasing is mostly implemented at the regional or national levels. Secondly, PPS is also applied to primary health care and A&E services while in other countries the services mainly include specialized health care and residential care for the elderly. Thirdly, PPS in health and social services is not regulated by any specific legislation, regulative mechanisms or guidelines. Instead it is regulated within the same framework as public procurement in general. PMID- 23790265 TI - Financial crisis and austerity measures in Greece: their impact on health promotion policies and public health care. AB - This review study explores the available data relating to the impact of financial crisis and subsequently applied austerity measures on the health care, social services and health promotion policies in Greece. It is evident that Greece is affected more than any other European country by the financial crisis. Unemployment, job insecurity, income reduction, poverty and increase of mental disorders are among the most serious consequences of crisis in the socioeconomic life. The health system is particularly affected by the severe austerity measures. The drastic curtailing of government spending has significantly affected the structure and functioning of public hospitals that cope with understaffing, deficits, drug shortage and basic medical supplies. Moreover, health promotion policies are constrained, inhibiting thus the relevant initiatives toward disease prevention and health promotion education practices. Overall, the current economic situation in Greece and its impact on real life and health care is quite concerning. Policy makers should not disregard the implications that austerity and fiscal policies have on the health sector. Greater attention is needed in order to ensure that individuals would continue getting public health care and having access to preventive and social support services. To face the economic hardship, policy makers are expected to implement human-centered approaches, safeguarding the human dignity and the moral values. PMID- 23790266 TI - Clinico-radiological spectrum of reversible splenial lesions in children. AB - Recently, many cases of children presenting reversible splenial lesions during febrile illness (RESLEF) have been reported; however, their overall clinico radiological features are unclear. To describe the clinico-radiological features, we retrospectively reviewed the etiology (pathogen), clinical course, laboratory data, magnetic resonance imaging and electroencephalography (EEG) findings, therapy, and prognosis of 23 episodes in 22 children (1 child recurred) who presented neurological symptoms, with RESLEF. The etiologies (pathogens) varied. Seizure occurred in 7 episodes, disturbance of consciousness (DC) in 13, and delirious behavior in 18. Serum sodium levels <136 mEq/L were observed in 18 episodes. Lesions outside the splenium were found in 4 cases. Slow waves were observed on EEG in 10 episodes. Methylprednisolone pulse therapy was given in 7 cases. No case resulted in neurological sequelae. Among 23 episodes, clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) was diagnosed in 6 episodes, whereas non-MERS was observed in 17 episodes. No difference was observed in almost all the clinico-radiological features' data between the 2 groups. The largest differences were observed in the rate of purposeless movement, DC, extension of the abnormal lesions outside the splenium, and marked slowing of background activity on EEG. RESLEF exhibit a spectrum of clinico-radiological features. These results suggest that non-MERS and MERS both are a part of a larger pathological condition, which we have termed as RESLEF spectrum syndrome. Given the view that such a syndrome exists, the clinical characteristics and position of non-MERS and MERS become clear. PMID- 23790267 TI - Lipid metabolism in mixtures of red clover (Trifolium repens) and perennial ryegrass (Lolium perenne) in lab scale silages and in vitro rumen incubations. AB - Most often, farmers consider red clover an unattractive forage because of its low ensilability. Nevertheless, several in vivo and in vitro experiments also showed advantages of red clover silages such as decreased rumen biohydrogenation of polyunsaturated fatty acids. This has been attributed to a possible protective role of protein-bound phenols, with polyphenol oxidase playing a key role in their formation. This enzyme is active in red clover, but not in other green forages, such as, for example, perennial ryegrass. Therefore, the aim was to study the lipid metabolism within red clover/ryegrass mixtures in lab scale silages and during in vitro rumen batch incubations. Ensilability of red clover increased with higher proportions of ryegrass in the silage mixture. However, the lipid-protecting mechanism of red clover does not seem to occur in the co-ensiled ryegrass as lipolysis of polar lipids linearly increased with increasing proportions of ryegrass (86.0%, 91.6%, 89.9%, 93.1% and 95.6% in 60-day-old silages with 100/0, 75/25, 50/50, 25/75 and 0/100 red clover/ryegrass, respectively). Rumen lipolysis and biohydrogenation of C18:3n-3 and C18:2n-6 were negatively related to red clover proportions in the silage mixtures. The lipid protective mechanism in red clover silages is confirmed, but it seems not to be transferred to lipids in co-ensiled forages. PMID- 23790268 TI - Simple and reliable preparation of immunodiagnostic antigens for Taenia solium cysticercosis. AB - SUMMARY Cysticercosis caused by infection with the larval stage of Taenia solium is an important cause of neurological disease worldwide and immunodiagnosis is important for the control and elimination of cysticercosis. In the present study, we established a simple and reliable preparation of immunodiagnostic low molecular-weight antigens (LMWAgs) from T. solium cyst fluids by a cation exchange chromatography (CEC). Banding patterns of LMWAgs on SDS-PAGE were different between isolates from Ecuador and China. All cysticercosis patient sera and some echinococcosis patient sera recognized both LMWAgs by enzyme-linked immunosorbent assay (ELISA), but sera from healthy persons were not positive. There was no statistical difference in immunodiagnostic performance of LMWAgs prepared from different geographical isolates. These results indicated that these novel immunodiagnostic antigen preparations could contribute the control and prevention of cysticercosis in endemic areas, especially developing countries. PMID- 23790269 TI - Arabidopsis PPP family of serine/threonine protein phosphatases: many targets but few engines. AB - The major plant serine/threonine protein phosphatases belong to the phosphoprotein phosphatase (PPP) family. Over the past few years the complement of Arabidopsis thaliana PPP family of catalytic subunits has been cataloged and many regulatory subunits identified. Specific roles for PPPs have been characterized, including roles in auxin and brassinosteroid signaling, in phototropism, in regulating the target of rapamycin pathway, and in cell stress responses. In this review, we provide a framework for understanding the PPP family by exploring the fundamental role of the phosphatase regulatory subunits that drive catalytic engine specificity. Although there are fewer plant protein phosphatases compared with their protein kinase partners, their function is now recognized to be as dynamic and as regulated as that of protein kinases. PMID- 23790270 TI - Treatment response of airway clearance assessed by single-breath washout in children with cystic fibrosis. AB - BACKGROUND: We studied the ability of 4 single-breath gas washout (SBW) tests to measure immediate effects of airway clearance in children with CF. METHODS: 25 children aged 4-16 years with CF performed pulmonary function tests to assess short-term variability at baseline and response to routine airway clearance. Tidal helium and sulfur hexafluoride (double-tracer gas: DTG) SBW, tidal capnography, tidal and vital capacity nitrogen (N2) SBW and spirometry were applied. We analyzed the gasses' phase III slope (SnIII--normalized for tidal volume) and FEV1 from spirometry. RESULTS: SnIII from tidal DTG-SBW, SnIII from vital capacity N2-SBW, and FEV1 improved significantly after airway clearance. From these tests, individual change of SnIII from tidal DTG-SBW and FEV1 exceeded short-term variability in 10 and 6 children. CONCLUSIONS: With the tidal DTG-SBW, an easy and promising test for peripheral gas mixing efficiency, immediate pulmonary function response to airway clearance can be assessed in CF children. PMID- 23790271 TI - Which came first-the chicken or the egg? the cycle of abuse, violence, and/or neglect and HIV. PMID- 23790273 TI - Exposure to crime and trauma among HIV-infected men who have sex with men: associations with HIV stigma and treatment engagement. AB - Active engagement in HIV clinical care, including uptake and adherence to antiretroviral therapy (ART), is necessary to optimize treatment benefit and can reduce the spread of HIV infection. Among a predominately minority sample of 303 HIV-infected men who have sex with men (MSM) who were either newly diagnosed with HIV or showed evidence of inconsistent engagement in HIV care, we explored rates of exposure to crime, sexual and physical trauma, and associations with factors potentially related to poor engagement in care. Two thirds of participants experienced a crime-related event, and nearly one third reported exposure to physical and/or sexual trauma. All three types of exposure were related to HIV stigma and to concerns about initiating ART. Associations between exposure and social support and HIV disclosure needs were also observed. Findings have implications for the role of trauma exposure and efforts to optimize treatment engagement for HIV-infected MSM. PMID- 23790272 TI - HIV-infected men who have sex with men and histories of childhood sexual abuse: implications for health and prevention. AB - A personal history of childhood sexual abuse (CSA) is prevalent and deleterious to health for people living with HIV (PLWH), and current statistics likely underrepresent the frequency of these experiences. In the general population, the prevalence of CSA appears to be higher in men who have sex with men (MSM) than heterosexual men, but there are limited data available for HIV-infected MSM. CSA is associated with poor mental and physical health and may contribute to high rates of HIV risk behaviors, including unprotected sex and substance abuse. CSA exposure is also associated with low engagement in care for PLWH. More information is needed regarding CSA experiences of HIV-infected MSM to optimize health and wellbeing for this population and to prevent HIV transmission. This article reviews the epidemiology, implications, and interventions for MSM who have a history of CSA. PMID- 23790274 TI - Urban adolescent girls' perspectives on multiple partners in the context of the sexual double standard and intimate partner violence. AB - This article describes the influence of abusive and nonabusive relationship dynamics on the number of sex partners among urban adolescent girls. Focus groups were conducted with 64 sexually active adolescent girls ages 14 to 17 years. General coding and content analyses identified patterns, themes, and salient beliefs. More than one third (37.5%) reported having experienced physical, intimate partner violence; 32.8% had two or more recent sex partners, and 37.5% had ever had a sexually transmitted infection (STI) or HIV. Although some girls in abusive relationships feared retribution if they had more than one partner, others sought additional partners for solace or as an act of resistance. Adolescent HIV/STI prevention programs need to address the influence of gender norms such as the sexual double standard, as well as partner pressure and partner abuse on adolescent decision-making about safer sex, and also promote healthy relationships as integral to advancing HIV/STI risk reduction. PMID- 23790275 TI - HIV risk among women from domestic violence agencies: prevalence and correlates. AB - The co-occurrence of HIV and intimate partner violence is a significant public health problem. Although these intersecting epidemics have been examined in various populations, limited data exist among recently abused women seeking services from domestic violence agencies. Our study examined sexual risk behaviors among 103 predominantly low-income, urban women receiving services from domestic violence agencies. Results showed that 42% of women engaged in risky sexual behavior (e.g., inconsistent condom use, sexually transmitted disease diagnosis, sex with more than one partner) in the previous 3 months. Multivariable analyses revealed that women who engaged in sexual risk behaviors were more likely to have never been married, experienced greater fear of abuse when negotiating condom use, used substances before sex, and had lower self esteem compared to abused women who did not engage in sexual risk behaviors. Results underscore the need to integrate sexual risk screening and risk reduction programs into domestic violence agencies for women. PMID- 23790276 TI - Intimate partner violence and antiretroviral adherence among women receiving care in an urban Southeastern Texas HIV clinic. AB - This nonexperimental, descriptive study examined relationships between recent intimate partner violence (IPV) and antiretroviral therapy (ART) adherence among women. Data from 272 HIV-infected women receiving care at a large HIV clinic were obtained through interviews and medical record abstraction. The Severity of Violence Against Women Scale was used to determine IPV experience in the previous 12 months; the prevalence of recent IPV in our sample was 52%. Mean Domestic Violence Specific Morisky Medication Adherence Scale scores among women experiencing recent IPV were significantly lower (M = 5.49, SD = 2.06) than in women without IPV experiences (M = 6.57, SD = 1.57, t[262.1] = 4.91, p < .001). A greater proportion of detectable viral loads (Fisher's exact p < .001) was found in women experiencing recent IPV compared to women who did not experience IPV. The data indicate that clinicians should screen HIV-infected women frequently for IPV when assessing ART adherence. PMID- 23790277 TI - Unique factors that place older Hispanic women at risk for HIV: intimate partner violence, machismo, and marianismo. AB - Hispanic women who are 50 years of age and older have been shown to be at increased risk of acquiring HIV infection due to age and culturally related issues. The purpose of our study was to investigate factors that increase HIV risk among older Hispanic women (OHW) as a basis for development or adaptation of an age and culturally tailored intervention designed to prevent HIV-related risk behaviors. We used a qualitative descriptive approach. Five focus groups were conducted in Miami, Florida, with 50 participants. Focus group discussions centered around eight major themes: intimate partner violence (IPV), perimenopausal-postmenopausal-related biological changes, cultural factors that interfere with HIV prevention, emotional and psychological changes, HIV knowledge, HIV risk perception, HIV risk behaviors, and HIV testing. Findings from our study stressed the importance of nurses' roles in educating OHW regarding IPV and HIV prevention. PMID- 23790278 TI - Providing sensitive care for adult HIV-infected women with a history of childhood sexual abuse. AB - Childhood sexual abuse (CSA) is a serious public health issue. Women with HIV who have a history of CSA are at increased risk for sporadic medical treatment, nonadherence to HIV medications, and HIV risk behaviors. These associations pose a challenge to providing health care for this population and are complicated by the possible psychological sequelae of CSA, such as anxiety, depression, dissociation, and posttraumatic stress disorder. This article reviews the effects of CSA on the health status of women with HIV, barriers to treatment adherence, suggested components of trauma-sensitive medical care, and mental health approaches. A trauma-informed, trauma-sensitive care model that addresses barriers associated with health care for women with a history of CSA is suggested. Specific recommendations are offered for the provision of effective clinical care for women with HIV who also have a history of CSA to help HIV care providers better recognize and appreciate the distinct needs of this patient population. PMID- 23790279 TI - From violence to sex work: agency, escaping violence, and HIV risk among establishment-based female sex workers in Tijuana, Mexico. AB - Violence experienced by female sex workers has been found to affect the HIV risk and quality of life of these women. Research on this topic has dealt with female sex workers and current experiences of violence with partners, clients, and in the workplace. In this study, we used feminist constructivist grounded theory to explore perceptions of violence among establishment-based female sex workers in Tijuana, Mexico. A key concept that emerged from 20 semi-structured in-depth interviews was "escaping violence with a romantic partner by becoming independent through sex work." The women also emphasized the negative impact of violence in the workplace but felt that achieving separation from a violent partner gave them strength to protect their lives and health. Interventions to help these women protect themselves from HIV infection and improve their quality of life should aim to build upon their strengths and the agency they have already achieved. PMID- 23790280 TI - Interventions to address HIV and intimate partner violence in Sub-Saharan Africa: a review of the literature. AB - HIV and intimate partner violence (IPV) are commonly co-occurring epidemics affecting the health of women globally and especially in sub-Saharan Africa. There is a need for interventions that address both HIV and IPV in health care settings. Our review examined recent literature for intervention studies that explored both HIV and IPV. Of the nine interventions identified, only two were set in health care settings; the remainder were community based. Large multifaceted community-based interventions showed promise in the areas of addressing social norms in order to empower women. Educational interventions have shown short-term improvements in HIV-related knowledge and behavioral intention. Further research is needed to examine brief screening, intervention, and referral for HIV and IPV services within health care settings. Health care-specific interventions such as use of preexposure and postexposure prophylaxis to prevent HIV transmission must also be studied in the context of IPV. PMID- 23790281 TI - Mechanical properties of contemporary composite resins and their interrelations. AB - OBJECTIVE: To characterize a spectrum of mechanical properties of four representative types of modern dental resin composites and to investigate possible interrelations. METHODS: Four composite resins were used, a microhybrid (Filtek Z-250), a nanofill (Filtek Ultimate), a nanohybrid (Majesty Posterior) and an ormocer (Admira). The mechanical properties investigated were Flexural Modulus and Flexural Strength (three point bending), Brinell Hardness, Impact Strength, mode I and mode II fracture toughness employing SENB and Brazilian tests and Work of Fracture. Fractographic analysis was carried out in an SEM to determine the origin of fracture for specimens subjected to SENB, Brazilian and Impact Strength testing. The results were statistically analyzed employing ANOVA and Tukey post hoc test (a=0.05) while Pearson correlation was applied among the mechanical properties. RESULTS: Significant differences were found between the mechanical properties of materials tested apart from mode I fracture toughness measured by Brazilian test. The latter significantly underestimated the mode I fracture toughness due to analytical limitations and thus its validity is questionable. Fractography revealed that the origin of fracture is located at notches for fracture toughness tests and contact surface with pendulum for Impact Strength testing. Pearson analysis illustrated a strong correlation between modulus of elasticity and hardness (r=0.87) and a weak negative correlation between Work of Fracture and Flexural Modulus (r=-0.46) and Work of Fracture and Hardness (r=-0.44). Weak correlations were also allocated between Flexural Modulus and Flexural Strength (r=0.40), Flexural Strength and Hardness (r=0.39), and Impact Strength and Hardness (r=0.40). SIGNIFICANCE: Since the four types of dental resin composite tested exhibited large differences among their mechanical properties differences in their clinical performance is also anticipated. PMID- 23790282 TI - A common structural theme in histone chaperones mimics interhistone contacts. AB - Histones are among the most conserved proteins in eukaryotes: the structural constraints of the nucleosome pose a challenge to evolving novel function. Nevertheless, confined histone surfaces have diversified, allowing the modulation of basic chromatin function through specialized histone chaperones. Recent structures of three histone-chaperone complexes, DAXX, HJURP, and Scm3, exemplify a common parsimonious solution to the restricted evolutionary space of histone recognition by their cognate histone chaperones: the reutilization of existing themes in histone structural biology. PMID- 23790283 TI - Remote magnetic navigation for mapping and ablation of right and left ventricular outflow tract arrhythmias. AB - OBJECTIVE: The aim of this study was to assess the efficacy and potential complications of a remote-controlled magnetic navigation system (Niobe II, Stereotaxis) for mapping and ablation of right or left ventricular outflow tract ventricular tachycardia or premature ventricular contractions. METHODS: We studied 32 consecutive patients, mean age 43+/-11 years, 24 female. Mapping of the arrhythmia was performed using the CARTO RMT mapping system, remotely guided by the Niobe II. Radiofrequency ablation was performed at the site of earliest ventricular activation with pacemapping of at least 11/12 leads. Acute success was defined as suppression and non-inducibility of the arrhythmia after stimulation with isoprenaline. After a minimum 3-month follow-up, we assessed clinical success (absence of symptoms and suppression of the arrhythmia on Holter recording), defined as less than 50 premature ventricular contractions/24 hours. RESULTS: The origin of the arrhythmia was in the right ventricular outflow tract in 28 patients (88%), in the left in three, and in the epicardium in one. Acute success was achieved in 26 patients (81%). Two patients underwent a second successful procedure, in one of which an epicardial approach was necessary. The overall clinical success rate, after two repeat procedures, was 88%. No complications occurred. There were two recurrences during a mean follow-up of 307+/-204 days. CONCLUSION: The Niobe II remote control system for mapping and ablation of ventricular outflow tract arrhythmias is effective and safe, and provides precise mapping and a high success rate, with no complications. PMID- 23790284 TI - A potential tool for high-resolution monitoring of ocean acidification. AB - Current anthropogenic carbon dioxide emissions generate besides global warming unprecedented acidification rates of the oceans. Recent evidence indicates the possibility that ocean acidification and low oceanic pH may be a major reason for several mass extinctions in the past. However, a major bottleneck for research on ocean acidification is long-term monitoring and the collection of consistent high resolution pH measurements. This study presents a low-power (<1 W) small sample volume (25 MUL) semiconductor based fluorescence method for real-time ship-board pH measurements at high temporal and spatial resolution (approximately 15 s and 100 m between samples). A 405 nm light emitting diode and the blue and green channels from a digital camera was used for swift detection of fluorescence from the pH sensitive dye 6,8-Dihydroxypyrene-1,3-disulfonic acid in real-time. Main principles were demonstrated by automated continuous measurements of pH in the surface water across the Baltic Sea and the Kattegat region with a large range in salinity (~3-30) and temperature (~0-25 degrees C). Ship-board precision of salinity and temperature adjusted pH measurements were estimated as low as 0.0001 pH units. PMID- 23790285 TI - Liquid phase microextraction strategies combined with total reflection X-ray spectrometry for the determination of low amounts of inorganic antimony species in waters. AB - In the present study, and taking into account the microanalytical capability of total reflection X-ray spectrometry (TXRF), we explored the possibilities of hollow fibre liquid-phase microextraction (HF-LPME) and dispersive liquid-liquid microextraction (DLLME) combined with TXRF for the determination of low amounts of inorganic Sb species in waters. For each of the LPME configurations aforementioned, experimental parameters affecting Sb extraction but specially the proper sample preparation process (deposition volume on the reflective carrier and drying mode) and measurement conditions for subsequent TXRF analysis have been carefully evaluated. The best analytical strategy for the determination of Sb(III) and Sb(V) in the low MUg L(-1) range was found to be the application of the DLLME mode before TXRF analysis. The developed methodology was successfully applied to the determination of inorganic Sb speciation in different types of spiked water samples. PMID- 23790286 TI - Electrochemical sensor based on chlorohemin modified molecularly imprinted microgel for determination of 2,4-dichlorophenol. AB - A newly designed molecularly imprinted polymer (MIP) was synthesized and successfully utilized as a recognition element of an amperometric sensor for 2,4 dichlorophenol (2,4-DCP) detection. The MIP with a well-defined structure could imitate the dehalogenative function of the natural enzyme chloroperoxidase for 2,4-DCP. Imprinted sensor was fabricated in situ on a glassy carbon electrode surface by drop-coating the 2,4-DCP imprinted microgel suspension and chitosan/Nafion mixture. Under optimized conditions, the sensor showed a linear response in the range of 5.0-100 MUmol L(-1) with a detection limit of 1.6 MUmol L(-1). Additionally, the imprinted sensor demonstrated higher affinity to target 2,4-DCP over competitive chlorophenolic compounds than non-imprinted sensor. It also exhibited good stability and acceptable repeatability. The proposed sensor could be used for the determination of 2,4-DCP in water samples with the recoveries of 96.2-111.8%, showing a promising potential in practical application. PMID- 23790287 TI - Determination of aminothiols by liquid chromatography with amperometric detection at a silver electrode: application to white wines. AB - Liquid chromatography coupled to a silver electrode based flow-through amperometric detector (LC-EC-Ag) was developed for the determination of aminothiols in white wines. The C18 reversed phase LC system operated in the isocratic mode at 0.7 mL min(-1) and used an acidic mobile phase composed of formic acid, EDTA, sodium nitrate, sodium hydroxide, and methanol 1% (v/v) at pH 4.5. The working electrode operated at 0.08 V vs Ag/AgCl, 3M KCl and its manual cleaning was realized once a month by smoothing on a polishing cloth. The analyzed aminothiols were resolved and eluted within 4 min, and all standard curves were linear in the range 2*10(-7)-2*10(-5) M. The analyzed wine samples needed no preparation other than dilution with the mobile phase. The concentration of cysteine (CYS), homocysteine (HCYS), glutathione (GSH) and N acetylcysteine (NAC) in bottled white wines, determined by the method of standard addition, was found to be in the low MUM range (0.2-2 mg L(-1)) depending on the wine type and its age. PMID- 23790288 TI - Comparative studies on zirconia and graphene composites obtained by one-step and stepwise electrodeposition for deoxyribonucleic acid sensing. AB - In this paper, the comparison of two kinds of electrochemically reduced graphene oxide (ERGNO) and zirconia composites, obtained by one-step (ZrO2-ERGNO) and stepwise (ZrO2/ERGNO) electrodeposition for DNA sensing, is systematically studied. The resulting composites were characterized by scanning electron microscopy, cyclic voltammetry, and differential pulse voltammetry. The results indicated that the ZrO2-ERGNO presented fine globular nanostructure. However, ZrO2/ERGNO presented agglomerate massive microstructure due to the absence of the oxygen-containing groups of graphene oxide, confirming the oxygen-containing groups provided a better affinity for the deposition of ZrO2. Due to the strong binding of the phosphate groups of DNA with the zirconia film, DNA probes were attached on the ZrO2-based composites. ZrO2-ERGNO/Au owning fine nanostructure presented larger surface area than microstructured ZrO2/ERGNO/Au. Moreover, compared with microstructured ZrO2/ERGNO, the nanostructured ZrO2-ERGNO provided more accessible space for immobilized DNA probe hybridization with target sequence, which consequently resulted in higher hybridization efficiency. Therefore, the ZrO2-ERGNO was chosen for fabricating DNA sensor with a limit of detection 1.21*10(-14) mol L(-1). PMID- 23790289 TI - An ultrasensitive iron(III)-complex based hydrogen peroxide electrochemical sensor based on a nonelectrocatalytic mechanism. AB - In this communication, the first nonelectrocatalysis-type hydrogen peroxide electrochemical sensor is reported. The electroactive iron(III) diethylenetriaminepentaacetic acid (DTPA-Fe(III)) complex is immobilized on the cysteamine (cys) modified nanoporous gold (NPG) films by covalent method. The immobilized DTPA-Fe(III) complex quickly communicates an electron with the electrode. Upon addition of hydrogen peroxide, however, hydrogen peroxide inhibits the direct electron transfer of the DTPA-Fe(III) complex due to the generation of nonelectroactive DTPA-Fe(III)-H2O2 complex. Based on quenching mechanism, the first hydrogen peroxide electrochemical sensor based on a nonelectrocatalytic mechanism is developed. The novel hydrogen peroxide electrochemical sensor has the ultralow detection limit (1.0*10(-14) M) and wide linear range (1.0*10(-13) to 1.0*10(-8) M) with excellent reproducibility and stability. PMID- 23790290 TI - Application of hot platinum microelectrodes for determination of flavonoids in flow injection analysis and capillary electrophoresis. AB - The determination of quercetin and rutin by flow injection analysis (FIA) and capillary electrophoresis (CE) using electrochemical detection was described. These flavonoids were determined at normal (unheated) and hot platinum microelectrodes using cyclic voltammetry. When quercetin or rutin is reaching the platinum electrode, a change of the current in the region of the platinum oxide formation is observed. Integration of the current changes in this in this region creates analytical signals in the form of peaks. An increase of temperature to about 76 degrees C in a small zone adjacent to the microelectrode causes an increase of the analytical signal by more than 6 times under FIA conditions. This method enables the use of hot microelectrodes as detectors in HPLC or CE. In CE the improvement of the analytical signal at hot microelectrodes is smaller than in FIA and increase only 1.3-3.4 times. Heated microelectrodes were used for analysis of the flavonoids in natural samples of the plant (extract of sea buckthorn) and a pharmaceutical preparation (Cerutin). PMID- 23790291 TI - Microwave-assisted extraction combined with gel permeation chromatography and silica gel cleanup followed by gas chromatography-mass spectrometry for the determination of organophosphorus flame retardants and plasticizers in biological samples. AB - An analytical method for the determination of 14 organophosphorus flame retardants (OPFRs), including halogenated OPFRs, non-halogenated OPFRs and triphenyl phosphine oxide (TPPO) in biological samples was developed using gas chromatography-mass spectrometry (GC/MS). Biological samples were extracted using microwave-assisted extraction (MAE) with hexane/acetone (1:1, v/v) as the solvent; then, a two-step clean-up technique, gel permeation chromatography (GPC) combined with solid phase extraction (SPE), was carried out before GC/MS analysis. Experimental results showed that the developed method efficiently removed the lipid compounds and co-extract interferences. Moreover, using the relatively "narrow" column (with an i.d. of 10 mm) significantly decreased the elution volume and, therefore, prevented the loss of the most volatile OPFRs, especially trimethyl phosphate (TMP) and triethyl phosphate (TEP). The method detection limits (MDLs) for OPFRs in the biological samples ranged from 0.006 to 0.021 ng g(-1) lw, and the recoveries were in the range of 70.3-111%, except for TMP (38.9-55.6%), with relative standard deviations (RSDs) of less than 14.1%. The developed method was applied to determine the amount of the target OPFRs in biological samples (i.e., fish and domestic birds) that were collected from the Pearl River Delta (PRD) region in southern China. Of the 14 OPFRs, tri-n-butyl phosphate (TnBP), tris(2-chloroethyl) phosphate (TCEP), tris(chloropropyl) phosphate (TCPP) and tributoxyethyl phosphate (TBEP) were present in all of the biological samples that were analyzed, and dominated by TnBP, TCEP and TBEP. The concentrations of OPFRs in the biological samples that were collected from the PRD region were higher than those reported in other locations. PMID- 23790292 TI - Analysis of heterocyclic amines in hair by on-line in-tube solid-phase microextraction coupled with liquid chromatography-tandem mass spectrometry. AB - Mutagenic and carcinogenic heterocyclic amines (HCAs) are formed during heating of various proteinaceous foods, but human exposure to HCAs has not yet been elucidated in detail. To assess long-term exposure to HCAs, we developed a simple and sensitive method for measuring HCAs in hair by automated on-line in-tube solid-phase microextraction (SPME) coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Using a Zorbax Eclipse XDB-C8 column, 16 HCAs were analyzed within 15 min. The optimum in-tube SPME conditions were 20 draw/eject cycles of 40 MUL sample at a flow rate of 200 MUL min(-1) using a Supel-Q PLOT capillary column as an extraction device. The extracted HCAs were easily desorbed from the column by passage of the mobile phase, with no carryover observed. This in-tube SPME LC-MS/MS method showed good linearity for HCAs in the range of 10 2000 pg mL(-1), with correlation coefficients above 0.9989 (n=18), using stable isotope-labeled HCA internal standards. The detection limits (S/N=3) of 14 HCAs except for MeAalphaC and Glu-P-1 were 0.10-0.79 pg mL(-1). This method was successfully utilized to analyze 14 HCAs in hair samples without any interference peaks, with quantitative limits (S/N=10) of about 0.17-1.32 pg mg(-1) hair. Using this method, we evaluated the exposure to HCAs in cigarette smoke and the suitability of using hair HCAs as exposure biomarkers. PMID- 23790293 TI - Evaluation and optimization of solid adsorbents for the sampling of gaseous methylated mercury species. AB - This study evaluates the suitability of commercially available adsorbents for the measurement of gaseous organic mercury species namely monomethylmercury (MMHg) and dimethylmercury (DMHg). Bond Elut ENV (BE), a new generation of divinylbenzene (DVB), is evaluated the first time for simultaneous sampling and quantification of ultra-trace levels of MMHg and DMHg in air and its performance compared against Carbotrap((r)) B (CB) and Tenax((r)) TA (TA), two commonly used adsorbents for mercury solid phase adsorption. The suitability of TA as an absorbent for MMHg (recovery 100+/-8.1%) but less so for DMHg (recovery 64+/ 17.3%) was confirmed while the reverse was observed for CB with an average recovery of 100+/-0.3% for DMHg but only 61+/-32.5% for MMHg. BE is the only adsorbent that showed excellent performance for trapping both Hg species with recoveries of 98+/-9.2% and 95+/-8.1% for MMHg and DMHg, respectively. Furthermore, BE exhibited much higher sampling capacities (>100L at 4 degrees C) and preservation of sample integrity (>1 month at -20 degrees C in the dark). Overall, BE proves to be the most suitable adsorbent for simultaneous trapping of organic Hg species with high sampling capacity and sample stability but also very good chromatographic properties which are desirable characteristics for both collection traps and analytical traps. Bond Elut ENV is proposed as an alternative to both Tenax((r)) TA and Carbotrap((r)) B with additional advantages of offering more versatility and sampling options. PMID- 23790294 TI - Determination of acetaldehyde in saliva by gas-diffusion flow injection analysis. AB - The consumption of ethanol is known to increase the likelihood of oral cancer. In addition, there has been a growing concern about possible association between long term use of ethanol-containing mouthwashes and oral cancer. Acetaldehyde, known to be a carcinogen, is the first metabolite of ethanol and it can be produced in the oral cavity after consumption or exposure to ethanol. This paper reports on the development of a gas-diffusion flow injection method for the online determination of salivary acetaldehyde by its colour reaction with 3 methyl-2-benzothiazolinone hydrazone (MBTH) and ferric chloride. Acetaldehyde samples and standards (80 MUL) were injected into the donor stream containing NaCl from which acetaldehyde diffused through the hydrophobic Teflon membrane of the gas-diffusion cell into the acceptor stream containing the two reagents mentioned above. The resultant intense green coloured dye was monitored spectrophotometrically at 600 nm. Under the optimum working conditions the method is characterized by a sampling rate of 9h(-1), a linear calibration range of 0.5 15 mg L(-1) (absorbance=5.40*10(-2) [acetaldehyde, mg L(-1)], R(2)=0.998), a relative standard deviation (RSD) of 1.90% (n=10, acetaldehyde concentration of 2.5 mg L(-1)), and a limit of detection (LOD) of 12.3 MUg L(-1). The LOD and sampling rate of the proposed method are superior to those of the conventional gas chromatographic (GC) method (LOD=93.0 MUg L(-1) and sampling rate=4 h(-1)). The reliability of the proposed method was illustrated by the fact that spiked with acetaldehyde saliva samples yielded excellent recoveries (96.6-101.9%), comparable to those obtained by GC (96.4-102.3%) and there was no statistically significant difference at the 95% confidence level between the two methods when non-spiked saliva samples were analysed. PMID- 23790295 TI - Sequential injection immunoassay for human bone morphogenic protein-7 using an immunoreactor immobilized with anti-human bone morphogenic protein-7 antibody- CdSe/ZnS quantum dot conjugates. AB - The detection of human bone morphogenic protein-7 (BMP-7) was achieved using a sequential injection immunoassay (SIIA) system. The SIIA system is based on the binding between BMP-7 and anti-human BMP-7 (AbBMP7)-CdSe/ZnS quantum dot (QD) conjugates immobilized onto a glass disk or an optical fiber, using fluorescence detection at excitation and emission wavelengths of 470 nm and 580 nm, respectively. The AbBMP7-QD conjugates were prepared by conjugating anti-human BMP-7 antibody (AbBMP7) to hydrophilic CdSe/ZnS core/shell quantum dots (QDs). The SIIA system was fully automated using software written in the LabVIEWTM development environment. The analytical performance of the SIIA system was characterized with a number of variables such as carrier flow rate and elution buffer. Under partially optimized operating conditions, the SIIA system had a linear calibration graph at up to 10.0 ng mL(-1) BMP-7 (R(2)>=0.975) and a sample frequency of two samples per hour. The SIIA system with an optical fiber immunosensor was used to detect and quantify BMP-7 in spiked real samples obtained from a biological process with recoveries in the range of 95-102%. PMID- 23790296 TI - Compressed matrix thin film (CMTF)-assisted laser desorption ionization mass spectrometric analysis. AB - The inhomogeneous re-crystallization process of matrix materials is the major concerns associated with matrix assisted laser desorption/ionization (MALDI) analysis. We describe here the approach termed compressed matrix thin film (CMTF) in order to make a uniform matrix deposition. In this approach, solid matrix particles are compressed under 10 MPa of pressure by a compressor that is regularly used in infrared spectroscopic analysis. Then aqueous samples can be deposited on the surface of the matrix film. Major advantages of the CMTF approach are summarized as follows. (1) Reproducible sample preparation procedure. Size and thickness of matrix thin films can be controlled by using a fixed mold.force and known amount of matrix materials. (2) Significantly decreased shot-to-shot variations and enhanced reproducibility. (3) Tolerance for in situ salt washing. Because matrix materials are hydrophobic, salts can be washed away while proteins or peptides are retained on the surface of matrix thin films through hydrophobic interactions. (4) Improved sensitivity. The hydrophobic coating of MALDI sample plate by matrix thin films prevents the spreading of samples across the plate and confines analytes to a small area, leading to increased local concentration. (5) A new means for tissue analysis. Tissue sections can be directly transferred to the uniform surface of matrix materials for reproducible and quantitative comparison of different molecules in different localization. The proposed CMTF should be an enabling technique for mass spectrometric analysis with improved correlations between signal intensities and sample quantities. PMID- 23790297 TI - Compound-specific stable carbon isotope ratios of phenols and nitrophenols derivatized with N,O-bis(trimethylsilyl)trifluoroacetamide. AB - We developed an analytical method for measuring compound-specific stable carbon isotope ratios (delta(13)C) of phenols and nitrophenols in filter samples of particulate organic matter. The method was tested on 13 phenols derivatized with N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA), together with four nonphenolic compounds. The data obtained by our method required two specific corrections for the determination of valid delta(13)C values: (1) for nitro compounds, the routine correction with use of m/z 46 for the contribution of (12)C(17)O(16)O molecules) to m/z 45 was modified due to impact of NO2 on the m/z 46 trace, and (2) for the derivatized phenols, measured delta(13)C values were corrected for the shift in delta(13)C due to the addition of carbon atoms from the BSTFA moiety. Analysis of standard-spiked filters showed that overall there was a small compound-dependent bias in the delta(13)C values: the average bias+/-the standard error of the mean of -0.21+/-0.10/00 for the standard compounds tested, except 3 methylcatechol, methylhydroquinone, 4-methyl-2-nitrophenol, and 2,6-dimethyl-4 nitrophenol, whereas the average biases+/-the standard errors of the mean for those were +1.2+/-0.30/00, +1.2+/-0.20/00, -1.2+/-0.20/00, and -1.4+/-0.50/00, respectively, when the injected mass of a derivatized compound exceeded 15 ngC. In situations where such small biases and uncertainties are acceptable, the method described here could be used to obtain valuable information about delta(13)C values. We also analyzed a real filter sample to demonstrate the practical applicability of the method. PMID- 23790298 TI - A matrix-assisted laser desorption/ionization tandem mass spectrometry method for direct screening of small molecule mixtures against an aminoglycoside kinase. AB - Aminoglycoside phosphotransferase 3'IIIa (APH3'IIIa) is a bacterial enzyme involved in antibiotic resistance through phosphorylation of aminoglycosides, which can potentially be overcome by co-administration of an APH3'IIIa inhibitor with the antibiotic. Current assay methods for discovery of APH3'IIIa inhibitors suffer from low specificity and high false positive/negative hit rates. Here, we describe a method for screening APH3'IIIa inhibitors based on direct detection of kanamycin A phosphorylation using MALDI-MS/MS, which is more rapid than conventional assays and does not require secondary assays or sample cleanup. The MALDI-MS/MS assay operates at an ionic strength of 45 mM and co-factors can be utilized at near-physiological levels for optimal enzyme activity. Detection via MALDI-MS/MS allowed for improved reproducibility when compared to ESI-MS/MS. Furthermore, the use of MS/MS provided better signal-to-noise ratios relative to MS alone on the MALDI instrument. The assay was validated via generation of Z' factors, with values of 0.78 and 0.56 in the absence and presence of 0.2% DMSO, respectively. The assay was used to screen a kinase directed library of >200 compounds, assayed as 21 mixtures of 10 compounds each. Five novel synthetic inhibitors were identified following mixture deconvolution. Inhibition constants were obtained for the aforementioned inhibitors using the MALDI-MS/MS assay, revealing several low to mid micromolar "hits", and highlighting the quantitative nature of the assay. PMID- 23790299 TI - Fluorescence detection of glutathione reductase activity based on deoxyribonucleic acid-templated silver nanoclusters. AB - Fluorescent silver nanoclusters stabilized by DNA (DNA-AgNCs) exhibit distinct response rates to thiol and disulfide. Glutathione reductase can catalyze the reduction of the oxidized glutathione (GSSG) quickly to reduced glutathione (GSH) in the presence of beta-nicotinamide adenine dinucleotide 2'-phosphate reduced tetrasodium salt hydrate (NADPH). Consequently, DNA-AgNCs can serve as a new fluorescent platform for assaying the glutathione reductase (GR) activity. This newly proposed assay has a high sensitivity and a good selectivity toward GR. The GR activity can be detected in the range of 0.2-2.0 mU mL(-1) with a minimum detectable concentration of 0.2 mU mL(-1). Pepsin, lysozyme, trypsin, avidin, thrombin, myoglobin, and BSA have little effect on the fluorescence intensity of DNA-AgNCs. The GR activity assay is successfully used to monitor the inhibition of GR activity by a typical inhibitor 1,3-bis(2-chloroethyl)-1-nitrosourea. PMID- 23790300 TI - Terbium fluorescence as a sensitive, inexpensive probe for UV-induced damage in nucleic acids. AB - Much effort has been focused on developing methods for detecting damaged nucleic acids. However, almost all of the proposed methods consist of multi-step procedures, are limited, require expensive instruments, or suffer from a high level of interferences. In this paper, we present a novel simple, inexpensive, mix-and-read assay that is generally applicable to nucleic acid damage and uses the enhanced luminescence due to energy transfer from nucleic acids to terbium(III) (Tb(3+)). Single-stranded oligonucleotides greatly enhance the Tb(3+) emission, but duplex DNA does not. With the use of a DNA hairpin probe complementary to the oligonucleotide of interest, the Tb(3+)/hairpin probe is applied to detect ultraviolet (UV)-induced DNA damage. The hairpin probe hybridizes only with the undamaged DNA. However, the damaged DNA remains single stranded and enhances the intrinsic fluorescence of Tb(3+), producing a detectable signal directly proportional to the amount of DNA damage. This allows the Tb(3+)/hairpin probe to be used for sensitive quantification of UV-induced DNA damage. The Tb(3+)/hairpin probe showed superior selectivity to DNA damage compared to conventional molecular beacons probes (MBs) and its sensitivity is more than 2.5 times higher than MBs with a limit of detection of 4.36+/-1.2 nM. In addition, this probe is easier to synthesize and more than eight times cheaper than MBs, which makes its use recommended for high-throughput, quantitative analysis of DNA damage. PMID- 23790301 TI - Development of a colorimetric microfluidic pH sensor for autonomous seawater measurements. AB - High quality carbonate chemistry measurements are required in order to fully understand the dynamics of the oceanic carbonate system. Seawater pH data with good spatial and temporal coverage are particularly critical to apprehend ocean acidification phenomena and their consequences. There is a growing need for autonomous in situ instruments that measure pH on remote platforms. Our aim is to develop an accurate and precise autonomous in situ pH sensor for long term deployment on remote platforms. The widely used spectrophotometric pH technique is capable of the required high-quality measurements. We report a key step towards the miniaturization of a colorimetric pH sensor with the successful implementation of a simple microfluidic design with low reagent consumption. The system is particularly adapted to shipboard deployment: high quality data was obtained over a period of more than a month during a shipboard deployment in northwest European shelf waters, and less than 30 mL of indicator was consumed. The system featured a short term precision of 0.001 pH (n=20) and an accuracy within the range of a certified Tris buffer (0.004 pH). The quality of the pH system measurements have been checked using various approaches: measurements of certified Tris buffer, measurement of certified seawater for DIC and TA, comparison of measured pH against calculated pH from pCO2, DIC and TA during the cruise in northwest European shelf waters. All showed that our measurements were of high quality. The measurements were made close to in situ temperature (+0.2 degrees C) in a sampling chamber which had a continuous flow of the ship's underway seawater supply. The optical set up was robust and relatively small due to the use of an USB mini-spectrometer, a custom made polymeric flow cell and an LED light source. The use of a three wavelength LED with detection that integrated power across the whole of each LED output spectrum indicated that low wavelength resolution detectors can be used instead of the current USB mini spectrophotometer. Artefacts due to the polychromatic light source and inhomogeneity in the absorption cell are shown to have a negligible impact on the data quality. The next step in the miniaturization of the sensor will be the incorporation of a photodiode as detector to replace the spectrophotometer. PMID- 23790302 TI - Single domain antibody-quantum dot conjugates for ricin detection by both fluoroimmunoassay and surface plasmon resonance. AB - The combination of stable biorecognition elements and robust quantum dots (QDs) has the potential to yield highly effective reporters for bioanalyses. Llama derived single domain antibodies (sdAb) provide small thermostable recognition elements that can be easily manipulated using standard DNA methods. The sdAb was self-assembled on dihydrolipoic acid (DHLA) ligand-capped CdSe-ZnS core-shell QDs made in our laboratory through the polyhistidine tail of the protein, which coordinated to zinc ions on the QD surface. The sdAb-QD bioconjugates were then applied in both fluorometric and surface plasmon resonance (SPR) immunoassays for the detection of ricin, a potential biothreat agent. The sdAb-QD conjugates functioned in fluoroimmunoassays for the detection of ricin, providing equivalent limits of detection when compared to the same anti-ricin sdAb labeled with a conventional fluorophore. In addition, the DHLA-QD-sdAb conjugates were very effective reporter elements in SPR sandwich assays, providing more sensitive detection with a signal enhancement of ~10-fold over sdAb reporters and 2-4 fold over full sized antibody reporters. Commercially prepared streptavidin-modified polymer-coated QDs also amplified the SPR signal for the detection of ricin when applied to locations where biotinylated anti-ricin sdAb was bound to target; however, we observed a 4-fold greater amplification when using the DHLA-QD-sdAb conjugates in this format. PMID- 23790303 TI - A novel ratiometric sensor for the fast detection of palladium species with large red-shift and high resolution both in aqueous solution and solid state. AB - A highly selective fluorescent probe (OHBT) was designed and synthesized by linking the ESIPT fluorophore N-(3-(benzo[d]thiazol-2-yl)-4-(hydroxyphenyl) benzamide) (HBTBC) to the palladium specificity response group, allyl group, for the detection of palladium species in aqueous solution. The allyl group can be hydrolyzed by Pd(0) species through the Pd(0)-catalyzed Tsuji-Trost reaction and thus release the fluorophore HBTBC, which shows two emission bands. The maximum emission spectra originated from the enol and keto forms at 415 and 555 nm respectively and with no overlap, which implies the high resolution of the palladium detection. The palladium species can also be detected by paper strip because of the solid-state fluorescence of probe HOBT catalyzed by palladium. This method was successfully applied in the palladium related Suzuki-Miyaura coupling reaction and the detection limit is lower than 1 MUM. PMID- 23790304 TI - Ratiometric fluorescence detection of mercuric ion based on the nanohybrid of fluorescence carbon dots and quantum dots. AB - A novel nanohybrid ratiometric fluorescence probe comprised of carbon dots (C dots) and hydrophilic CdSe@ZnS quantum dots (QDs) has been developed by simply mixing the blue-emission C-dots with red-emission carboxylmethyldithiocarbamate modified CdSe@ZnS QDs (GDTC-QDs). The nanohybrid ratiometric fluorescence probe exhibits dual emissions at 436 nm and 629 nm under a single excitation wavelength. Due to the strong chelating ability of GDTC on the surface of QDs to mercuric ion (Hg(2+)), the fluorescence of the GDTC-QDs in the nanohybrid system could be selectively quenched in the presence of Hg(2+) while the fluorescence of the C-dots remained constant, resulting in an obviously distinguishable fluorescence color evolution (from red to blue) of the nanohybrid system. The detection limit of this method was found to be as low as 0.1 MUM. Furthermore, the recovery result for Hg(2+) in real samples including tap water and lake water by this method was satisfying, suggesting its potential application for Hg(2+) sensing. PMID- 23790306 TI - A chip-type thin-layer electrochemical cell coupled with capillary electrophoresis for online separation of electrode reaction products. AB - A coupling technique of thin-layer electrolysis with high-performance capillary electrophoresis/UV-vis technique(EC/HPCE/UV-vis) is developed for online separation and determination of electrode reaction products. A chip-type thin layer electrolytic (CTE) cell was designed and fabricated, which contains a capillary channel and a background electrolyte reservoir, allowing rapid electrolysis, direct sampling and online electrophoretic separation. This chip type setup was characterized based on an electrophoresis expression of Nernst equation that was applied to the redox equilibrium of o-tolidine at different potentials. The utility of the method was demonstrated by separating and determining the electro-oxidation products of quercetin in different pH media. Two main products were always found in the studied time, potential and pH ranges. The variety of products increased not only with increasing potential but also with increasing pH value, and in total, at least 13 products were observed in the electropherograms. This work illustrates a novel example of capillary electrophoresis used online with thin-layer electrolysis to separate and detect electrode reaction products. PMID- 23790305 TI - Surface-enhanced Raman scattering molecular sentinel nanoprobes for viral infection diagnostics. AB - In this paper, we describe a surface-enhanced Raman scattering (SERS)-based detection approach, referred to as "molecular sentinel" (MS) plasmonic nanoprobes, to detect an RNA target related to viral infection. The MS method is essentially a label-free technique incorporating the SERS effect modulation scheme associated with silver nanoparticles and Raman dye-labeled DNA hairpin probes. Hybridization with target sequences opens the hairpin and spatially separates the Raman label from the silver surface thus reducing the SERS signal of the label. Herein, we have developed a MS nanoprobe to detect the human radical S-adenosyl methionine domain containing 2 (RSAD2) RNA target as a model system for method demonstration. The human RSAD2 gene has recently emerged as a novel host-response biomarker for diagnosis of respiratory infections. Our results showed that the RSAD2 MS nanoprobes exhibits high specificity and can detect as low as 1 nM target sequences. With the use of a portable Raman spectrometer and total RNA samples, we have also demonstrated for the first time the potential of the MS nanoprobe technology for detection of host-response RNA biomarkers for infectious disease diagnostics. PMID- 23790307 TI - [Hemorrhagic accidents of the new oral anticoagulants and coagulation assays]. AB - New oral anticoagulants which specifically inhibit factor Xa (FXa) or thrombin (FIIa) do not require routine laboratory monitoring. However, they induce a state of hypocoagulation and increase the risk of bleeding. In some clinical situations, such as emergency surgery, hemorrhagic episodes, or recurrent stroke, coagulation monitoring may be useful. A significant number of publications have reported uncontrollable hemorrhagic complications and deaths in patients treated with these new anticoagulants. The selection of the most appropriate clotting assay is based on the drug used and the availability of the test. The new anticoagulants influence all global clot-based tests. Prothrombin time and partial thromboplastin time measured before and after treatment are considered as qualitative tests since they are not specific. Specific anti-Xa and anti-IIa assays are available and results can be expressed in nanogram per milliliter of plasma using calibrated plasmas containing well-established amounts of drug. The fact that there is no specific antidote to reverse the anticoagulant action of the new anticoagulants can impair management of hemorrhagic complications; clinical experience is still limited. Pro-hemostatic treatment with non-activated or activated prothrombin complexes (FEIBA((r))), or as a last recourse with FVIIa concentrates (NovoSeven((r))), has been used with variable results. Some suggestions for the management of patients with bleeding have been published but there is still little clinical evidence for these interventions. PMID- 23790308 TI - Multimodal contrast agents for in vivo neuroanatomical analysis of monosynaptic connections. AB - We developed and examined the applicability of two multimodal paramagnetic contrast agents for the longitudinal in vivo investigations of the brain projections. The classical dextran based neuroanatomical tracer was conjugated with mono- and bimetal Gd(3+) complexes and an optical reporter. Relaxometric studies of both tracer molecules were performed in vitro followed by in cellulo MR and microscopy investigations. Finally, tracers were injected into the motor cortex of the rat brain; uptake and transporting properties were compared by MRI. The advantage of the multimodal approach was taken and histological studies were performed on the same animals. The histology results confirm the MRI studies demonstrating that the applied tracers labelled anterogradely the regions known for their connections with the motor cortex of the rat brain. PMID- 23790309 TI - Identification of periodontitis associated changes in the proteome of whole human saliva by mass spectrometric analysis. AB - AIM: Interest in human saliva proteomics for disease-specific biomarker screening increased in the last decade. We used whole saliva samples from periodontally healthy and diseased subjects with chronic periodontitis to screen for disease associated differences in the protein pattern. MATERIAL AND METHODS: We selected 20 periodontally healthy and 20 periodontally diseased subjects from the population-based cross-sectional Study of Health in Pomerania (SHIP-2 and SHIP Trend). Saliva collection was performed with commercially available Salivette((r)) (Sarstedt, Numbrecht, Germany). Whole saliva proteins were analysed after trichloroacetic acid (TCA) precipitation and proteolytic digestion with trypsin by LC-MS/MS. MS-data were analysed and quantified using the Rosetta Elucidator software package. RESULTS: In whole saliva we identified 344 human protein groups across all samples. For label free quantitation we only considered 152 proteins identified with more than one unique peptide. In total, 20 proteins showed 1.5-fold difference in abundance between controls and patients (p < 0.05); the majority of these proteins showed higher abundance in the periodontally diseased subjects. Functional annotation of proteins linked the periodontally diseased status with acute phase response and inflammatory processes. CONCLUSION: Label free proteomic analysis of whole saliva is a powerful tool to characterize the periodontal disease status and differentiate between healthy and periodontally diseased subjects. PMID- 23790310 TI - Phosphorescence bioimaging using cyclometalated Ir(III) complexes. AB - Recent advances in the development of the phosphorescent Ir(III) complexes have made it possible to implement the phosphorescence modality in bioimaging applications. A variety of phosphorescent Ir(III) complexes have been synthesized and assessed in the context of in vitro and in vivo imaging, especially in subcellular organelle staining and the sensing of biologically important analytes. The examples presented here demonstrate that Ir(III) complexes provide attractive alternatives to fluorescent organic compounds in the construction of biolabels and biosensors. The complexes are particularly advantageous with respect to fluorescent compounds in their compatibility with time-gated bioimaging techniques that completely eliminate background signals due to autofluorescence. PMID- 23790311 TI - Recent trends in analytical and structural glycobiology. AB - The great complexity of glycosylated biomolecules necessitates a set of powerful analytical methodologies to reveal functionally important structural features. Mass spectrometry (MS), with its different ionization techniques, mass analyzers, and detection strategies, has become the most important analytical method in glycomic and glycoproteomic investigations. In combination with MS, microscale separations (based on capillary chromatography and electrophoresis) and carbohydrate microchemistry, we feature here conceptually important applications of the recent years. This review focuses on methodological advances pertaining to disease biomarker research, immunology, developmental biology, and measurements of importance to biopharmaceuticals. High-sensitivity determinations and sample enrichment/preconcentration are particularly emphasized in glycomic and glycoproteomic profiling. PMID- 23790312 TI - Quantitation of endogenous peptides using mass spectrometry based methods. AB - The mass spectrometry-based 'omics' sub-discipline that focuses on comprehensive, often exploratory, analyses of endogenous peptides involved in cell-to-cell communication is oftentimes referred to as peptidomics. Although the progress in bioanalytical technology development for peptide discovery has been tremendous, perhaps the largest advances have involved robust quantitative mass spectrometric approaches and data mining algorithms. These efforts have accelerated the discovery and validation of biomarkers, functionally important posttranslational modifications, and unexpected molecular interactions, information that aids drug development. In this article we outline the current approaches used in quantitative peptidomics and the technical challenges that stimulate new advances in the field, while also reviewing the newest literature on functional characterizations of endogenous peptides using quantitative mass spectrometry. PMID- 23790313 TI - Ventral striatum lesions enhance stimulus and response encoding in dorsal striatum. AB - BACKGROUND: The development of addiction is thought to reflect a transition from goal-directed to stimulus-response driven behavior, functions attributed to ventral (VS) and dorsal striatum (DS), respectively. In line with this theory, neuroadaptations that occur during prolonged drug use progress from VS to DS. Here we ask if VS dysfunction alone, independent of drug use, can affect neural selectivity in DS. METHODS: To address this issue, we recorded from single neurons in DS while rats performed an odor-guided choice task for differently valued rewards in rats with and without unilateral VS lesions. In a separate group of animals, we used bilateral VS lesions to determine if VS was critical for performance on this task. RESULTS: We describe data showing that unilateral lesions of VS enhance neural representations in DS during performance of a task that is dependent on VS. Furthermore, we show that VS is critical for reward guided decision-making initially, but that rats regain function after several days. CONCLUSIONS: These results suggest that loss of VS function, independent of chronic drug use, can trigger stronger encoding in DS in a reward-guided decision making task and that the transition from VS to DS governed behavior observed in addiction might be due, in part, to initial loss of VS function. PMID- 23790314 TI - Fast test: clinical practice and interpretation. PMID- 23790315 TI - The role of epigenetics in malignant pleural mesothelioma. AB - Malignant pleural mesothelioma (MPM) is an almost invariably fatal cancer of the pleura due to asbestos exposure. Increasing evidence indicates that unresponsiveness to chemotherapy is due to epigenetic errors leading to inadequate gene expression in tumor cells. The availability of compounds that modulate epigenetic modifications, such as histone acetylation or DNA methylation, offers new prospects for treatment of MPM. Here, we review latest findings on epigenetics in mesothelioma and present novel strategies for promising epigenetic therapies. PMID- 23790316 TI - Overexpression of beclin1 induced autophagy and apoptosis in lungs of K-rasLA1 mice. AB - Beclin1, as a key molecule in controlling autophagy pathway, can activate both cell survival and cell death pathway. As a role of autophagy in cancer progression remains controversial, introduction of beclin1 to the lungs of K ras(LA1) mice was performed via inhalation. Prolonged autophagy activation was induced by repeated exposure of lentivirus-beclin1, total of 8 times (2 times/week, 4 weeks). By the time of sacrifice, lungs were collected and analyzed for the therapeutic efficacy. Total numbers of tumors on the surface and histopathological tumor progression were reduced in the lungs of K-ras(LA1) mice. Successful delivery of beclin1 induced autophagy and apoptosis in the target organ, which were confirmed by following features; increased autophagic vacuoles in the cytosol, increased number of mitochondria with decreased mitochondrial 12S RNA, and increased protein levels of mitochondria-related apoptosis. Markers for cell proliferation and angiogenesis, PCNA and VEGF, which used for prediction of cancer prognosis, were significantly reduced after introduction of beclin1. Taken together, the results indicate that autophagy regulating gene, beclin1, can be a potential target for lung cancer gene therapy. PMID- 23790317 TI - Human parainfluenza virus type 2 vector induces dendritic cell maturation without viral RNA replication/transcription. AB - The dendritic cell (DC), a most potent antigen-presenting cell, plays a key role in vaccine therapy against infectious diseases and malignant tumors. Although advantages of viral vectors for vaccine therapy have been reported, potential risks for adverse effects prevent them from being licensed for clinical use. Human parainfluenza virus type 2 (hPIV2), one of the members of the Paramyxoviridae family, is a nonsegmented and negative-stranded RNA virus. We have developed a reverse genetics system for the production of infectious hPIV2 lacking the F gene (hPIV2DeltaF), wherein various advantages for vaccine therapy exist, such as cytoplasmic replication/transcription, nontransmissible infectivity, and extremely high transduction efficacy in various types of target cells. Here we demonstrate that hPIV2DeltaF shows high transduction efficiency in human DCs, while not so high in mouse DCs. In addition, hPIV2DeltaF sufficiently induces maturation of both human and murine DCs, and the maturation state of both human and murine DCs is almost equivalent to that induced by lipopolysaccharide. Moreover, alkylating agent beta-propiolactone-inactivated hPIV2DeltaF (BPL hPIV2DeltaF) elicits DC maturation without viral replication/transcription. These results suggest that hPIV2DeltaF may be a useful tool for vaccine therapy as a novel type of paramyxoviral vector, which is single-round infectious vector and has potential adjuvant activity. PMID- 23790318 TI - Dynamic structural changes in microbial membranes in response to high hydrostatic pressure analyzed using time-resolved fluorescence anisotropy measurement. AB - High hydrostatic pressure has a profound physiological impact on lipid membranes, primarily resulting in tighter packing and restriction of acyl-chain motion. To fulfill membrane protein functions in high-pressure environments, deep-sea organisms possess specialized cell membranes. Although the effects of high pressure on model membranes have been investigated in great detail, high-pressure induced structural changes in living cell membranes remain to be elucidated. Of the spectroscopic techniques available to date, fluorescence anisotropy measurement is a common useful method that provides information on dynamic membrane properties. This mini-review focuses on pressure-induced changes in natural cell membranes, analyzed by means of high-pressure time-resolved fluorescence anisotropy measurement (HP-TRFAM). Specifically, the role of eicosapentaenoic acid in deep-sea piezophiles is described in terms of the structural integrity of the membrane under high pressure. PMID- 23790319 TI - Advantages and disadvantages of the animal models v. in vitro studies in iron metabolism: a review. AB - Iron deficiency is the most common nutritional deficiency in the world. Special molecules have evolved for iron acquisition, transport and storage in soluble, nontoxic forms. Studies about the effects of iron on health are focused on iron metabolism or nutrition to prevent or treat iron deficiency and anemia. These studies are focused in two main aspects: (1) basic studies to elucidate iron metabolism and (2) nutritional studies to evaluate the efficacy of iron supplementation to prevent or treat iron deficiency and anemia. This paper reviews the advantages and disadvantages of the experimental models commonly used as well as the methods that are more used in studies related to iron. In vitro studies have used different parts of the gut. In vivo studies are done in humans and animals such as mice, rats, pigs and monkeys. Iron metabolism is a complex process that includes interactions at the systemic level. In vitro studies, despite physiological differences to humans, are useful to increase knowledge related to this essential micronutrient. Isotopic techniques are the most recommended in studies related to iron, but their high cost and required logistic, making them difficult to use. The depletion-repletion of hemoglobin is a method commonly used in animal studies. Three depletion-repletion techniques are mostly used: hemoglobin regeneration efficiency, relative biological values (RBV) and metabolic balance, which are official methods of the association of official analytical chemists. These techniques are well-validated to be used as studies related to iron and their results can be extrapolated to humans. Knowledge about the main advantages and disadvantages of the in vitro and animal models, and methods used in these studies, could increase confidence of researchers in the experimental results with less costs. PMID- 23790320 TI - Lysophosphatidic acid increases the production of pivotal mediators of decidualization and vascularization in the rat uterus. AB - INTRODUCTION: The decidual reaction and the formation of new vessels in the uterus are two crucial processes during embryo implantation. Previously, we observed that lysophosphatidic acid (LPA) increases cyclooxygenase-2 derived - prostaglandin E2 production during implantation in the rat uterus and that it augments the expression of decidualization (IGFBP-1) and vascularization (IL-10) markers. Both cyclooxygenase and nitric oxide synthase (NOS) are known enzymes involved in these processes. Thus, we became interested in studying which factors contribute to LPA receptor-specific role during the decidual and the vascular reaction at implantation. METHODS: We adopted a pharmacological approach in vitro incubating the uterus from rats on day 5 of gestation (day of implantation) with LPA, DGPP (a highly selective antagonist of LPA3, an LPA receptor) and cyclooxygenase and NOS selective and non-selective inhibitors. We determined NOS activity, prostaglandin E2 production and IGFBP-1 and IL-10 expression to evaluate decidualization and vascularization. RESULTS: We observed that LPA augmented the activity of the inducible NOS isoform through LPA1/LPA3. Inducible NOS activity participated in the induction of cyclooxygenase-2/prostaglandin E2 increase stimulated by LPA. Also, cyclooxygenase-2 derived prostaglandins mediated LPA-stimulatory action on NOS activity. Both cyclooxygenase-2 and inducible NOS mediated LPA effect on IGFBP-1 and IL-10 expression. CONCLUSIONS: These results suggest the participation of LPA/LPA3 in the production of crucial molecules involved in vascularization and decidualization, two main processes that prepare the uterine milieu for embryo invasion during implantation. PMID- 23790322 TI - A nexus model of the temporal-parietal junction. AB - The temporal-parietal junction (TPJ) has been proposed to support either specifically social functions or non-specific processes of cognition such as memory and attention. To account for diverse prior findings, we propose a nexus model for TPJ function: overlap of basic processes produces novel secondary functions at their convergence. We present meta-analytic evidence that is consistent with the anatomical convergence of attention, memory, language, and social processing in the TPJ, leading to a higher-order role in the creation of a social context for behavior. The nexus model accounts for recent examples of TPJ contributions specifically to decision making in a social context and provides a potential reconciliation for competing claims about TPJ function. PMID- 23790323 TI - Diarrhoea in irradiated patients: a prospective multicentre observational study. AB - AIMS: To determine the incidence of cancer treatment-induced diarrhoea in patients submitted to irradiation. METHODS: Forty-five Italian radiation oncology departments took part in this prospective observational study and a total of 1020 patients were enrolled. The accrual lasted three consecutive weeks; evaluation was based on diary cards filled in daily by patients during radiotherapy and one week after cessation. Diary cards recorded both the onset and intensity of diarrhoea. RESULTS: A total of 1004 patients were eligible for this analysis. 147/1004 (14.6%) patients had diarrhoea. The median minimum number of daily events was 1 (range 1-7) with a median maximum events of 3 (range 1-23). 82/147 patients (56.2%) had a drug prescription for diarrhoea. In the evaluation of the onset of diarrhoea, in multivariate analysis, we found the following factors to be statistically significant predictors of an increased likelihood of diarrhoea: primitive tumour site, therapeutic purpose and field size. CONCLUSIONS: Patients with abdominal-pelvic cancer, treated with curative purpose and using large field sizes are at high risk of cancer treatment-induced diarrhoea. Diarrhoea was also observed in patients treated at other sites. In this population group there is the need for more stringent monitoring during the delivery of radiation therapy. PMID- 23790324 TI - The faster-X effect: integrating theory and data. AB - Population genetics theory predicts that X (or Z) chromosomes could play disproportionate roles in speciation and evolutionary divergence, and recent genome-wide analyses have identified situations in which X or Z-linked divergence exceeds that on the autosomes (the so-called 'faster-X effect'). Here, we summarize the current state of both the theory and data surrounding the study of faster-X evolution. Our survey indicates that the faster-X effect is pervasive across a taxonomically diverse array of evolutionary lineages. These patterns could be informative of the dominance or recessivity of beneficial mutations and the nature of genetic variation acted upon by natural selection. We also identify several aspects of disagreement between these empirical results and the population genetic models used to interpret them. However, there are clearly delineated aspects of the problem for which additional modeling and collection of genomic data will address these discrepancies and provide novel insights into the population genetics of adaptation. PMID- 23790325 TI - Independent calculation-based verification of IMRT plans using a 3D dose calculation engine. AB - Independent monitor unit verification of intensity-modulated radiation therapy (IMRT) plans requires detailed 3-dimensional (3D) dose verification. The aim of this study was to investigate using a 3D dose engine in a second commercial treatment planning system (TPS) for this task, facilitated by in-house software. Our department has XiO and Pinnacle TPSs, both with IMRT planning capability and modeled for an Elekta-Synergy 6MV photon beam. These systems allow the transfer of computed tomography (CT) data and RT structures between them but do not allow IMRT plans to be transferred. To provide this connectivity, an in-house computer programme was developed to convert radiation therapy prescription (RTP) files as generated by many planning systems into either XiO or Pinnacle IMRT file formats. Utilization of the technique and software was assessed by transferring 14 IMRT plans from XiO and Pinnacle onto the other system and performing 3D dose verification. The accuracy of the conversion process was checked by comparing the 3D dose matrices and dose volume histograms (DVHs) of structures for the recalculated plan on the same system. The developed software successfully transferred IMRT plans generated by 1 planning system into the other. Comparison of planning target volume (TV) DVHs for the original and recalculated plans showed good agreement; a maximum difference of 2% in mean dose, - 2.5% in D95, and 2.9% in V95 was observed. Similarly, a DVH comparison of organs at risk showed a maximum difference of +7.7% between the original and recalculated plans for structures in both high- and medium-dose regions. However, for structures in low-dose regions (less than 15% of prescription dose) a difference in mean dose up to +21.1% was observed between XiO and Pinnacle calculations. A dose matrix comparison of original and recalculated plans in XiO and Pinnacle TPSs was performed using gamma analysis with 3%/3mm criteria. The mean and standard deviation of pixels passing gamma tolerance for XiO-generated IMRT plans was 96.1 +/- 1.3, 96.6 +/- 1.2, and 96.0 +/- 1.5 in axial, coronal, and sagittal planes respectively. Corresponding results for Pinnacle-generated IMRT plans were 97.1 +/- 1.5, 96.4 +/- 1.2, and 96.5 +/- 1.3 in axial, coronal, and sagittal planes respectively. PMID- 23790326 TI - Clinical outcome of reverse total shoulder arthroplasty combined with latissimus dorsi transfer for the treatment of chronic combined pseudoparesis of elevation and external rotation of the shoulder. AB - BACKGROUND: Reverse total shoulder arthroplasty (RTSA) allows correction of pseudoparesis of elevation caused by irreparable rotator cuff tear but does not address loss of active external rotation. Latissimus dorsi transfer (LDT) is an established procedure for correction of pseudoparesis of external rotation. METHODS: Forty-one shoulders of 40 consecutive patients, who were a mean age of 70 years old (range 47-85 years), underwent RTSA combined with LDT for irreparable rotator cuff failure with severe shoulder dysfunction. RESULTS: Nine orthopedic complications occurred in 7 of the 41 shoulders. Four shoulders were lost to follow-up, and 5 were excluded from the functional analysis. The mean follow-up of the eligible 32 shoulders with the prosthesis still in place was 53 months (range, 24-105 months). The age-related Constant score increased significantly from a preoperative mean of 45% (range, 16%-80%) to 89% (range, 25% 100%). The mean subjective shoulder value increased from 33% (range, 0%-70%) to 75% (range, 30%-100%). Active external rotation significantly improved from a mean of 4 degrees (range, -30 degrees to 40 degrees ) to 27 degrees (range, 10 degrees to 70 degrees ). A preoperative external rotation lag sign could be corrected in 25 of the 32 shoulders. For the 16 shoulders with at least 5 years of follow-up, the Constant scores were 47% (range, 16%-80%) preoperatively, 92% (range, 51%-100%) at 2 years, and 94% (range, 57%-100%) at the latest follow-up, and the respective subjective shoulder values were 32% (range, 0%-70%), 73% (range, 30%-100%), and 80% (range, 60%-100%). CONCLUSION: If treated with RTSA combined with LDT, patients with pseudoparesis of elevation and pseudoparesis of external rotation can expect an excellent clinical outcome for a period beyond 5 years, provided that complications that require removal of the prosthesis can be prevented. PMID- 23790327 TI - Hemiarthroplasty of the distal humerus for acute and chronic complex intra articular injuries. AB - BACKGROUND: Comminuted intra-articular distal humeral fractures represent a challenging upper extremity injury. This study reviews clinical and radiographic results in patients with distal humeral hemiarthroplasty (DHH). METHODS: DHH with the Latitude prosthesis (Tornier, Saint-Ismier, France) was performed in 8 patients (mean age, 64 years; age range, 33-75 years) for unreconstructible fractures of the distal humerus or salvage of failed internal fixation. Clinical outcomes were assessed with the American Shoulder and Elbow Surgeons elbow instrument; Mayo Elbow Performance Index; and Disabilities of the Arm, Shoulder and Hand questionnaire at a mean of 36 months. Radiologic assessment included radiographs and computed tomography to evaluate olecranon wear and densitometry (dual-energy x-ray absorptiometry). Range of motion, pain, and elbow satisfaction were recorded, and descriptive statistics were used for analysis. RESULTS: Seven patients were available to participate in the follow-up examination. Acute cases (5 patients) scored better than salvage cases (2 patients) on the Mayo Elbow Performance Score (80 points [range, 67-95 points] and 65 points [range, 50-80 points], respectively) and Disabilities of the Arm, Shoulder and Hand score (31 points [range, 2.5-68 points] and 39 points [range, 17-62 points], respectively). The mean arc of elbow flexion and extension was 96 degrees (range, 70 degrees 130 degrees ), with mean flexion of 120 degrees (range, 90 degrees -135 degrees ) and a mean extension loss of 19 degrees (range, 5 degrees -30 degrees ). The mean arc of forearm rotation was 160 degrees (range, 140 degrees -180 degrees ). Reoperation was required in 4 patients because of painful retained hardware. Five patients reported pain with activities of daily living. CONCLUSION: DHH should be used with caution until such time as longer-term outcome studies are able to show the efficacy of this procedure. PMID- 23790328 TI - Genetic diversity of Plasmodium falciparum isolates from naturally infected children in north-central Nigeria using the merozoite surface protein-2 as molecular marker. AB - OBJECTIVE: To characterize the genetic diversity of Plasmodium falciparum (P. falciparum) field isolates in children from Lafia, North-central Nigeria, using the highly polymorphic P. falciparum merozoite surface protein 2 (MSP-2) gene as molecular marker. METHODS: Three hundred and twenty children were enrolled into the study between 2005 and 2006. These included 140 children who presented with uncomplicated malaria at the Dalhatu Araf Specialist Hospital, Lafia and another 180 children from the study area with asymptomatic infection. DNA was extracted from blood spot on filter paper and MSP-2 genes were genotyped using allele specific nested PCR in order to analyze the genetic diversity of parasite isolates. RESULTS: A total of 31 and 34 distinct MSP-2 alleles were identified in the asymptomatic and uncomplicated malaria groups respectively. No difference was found between the multiplicity of infection in the asymptomatic group and that of the uncomplicated malaria group (P>0.05). However, isolates of the FC27 allele type were dominant in the asymptomatic group whereas isolates of the 3D7 allele type were dominant in the uncomplicated malaria group. CONCLUSIONS: This study showed a high genetic diversity of P. falciparum isolates in North-central Nigeria and is comparable to reports from similar areas with high malaria transmission intensity. PMID- 23790329 TI - In-vitro scolicidal activity of Mallotus philippinensis (Lam.) Muell Arg. fruit glandular hair extract against hydatid cyst Echinococcus granulosus. AB - OBJECTIVE: To investigate new scolicidal agent from natural resources to cope with the side effects associated with synthetic drugs in Echinococcosis. METHODS: The scolicidal potential of methanolic fruit powder extract (10 and 20 mg/mL) of Mallotus philippinensis (M. philippinensis) was investigated. Viability of protoscoleces was confirmed by trypan blue exclusion method, where mortality was observed at concentration of 10 and 20 mg/mL in 60 min treatment against Echinococcus granulosus (E. granulosus), under in-vitro conditions with reference to the known standard drug Praziquantel(r). RESULTS: At concentration 10 and 20 mg/mL, the mortality rate was observed 97% and 99% respectively for 60 min treatment; while up to 93% mortality was observed with 20 mg/mL for only 10 min treatment. The concentration above 20 mg/mL for above 2 h showed 100% mortality, irrespective of further incubation. CONCLUSIONS: As compared with the standard anti-parasitic drug Praziquantel our extract has significant scolicidal activity with almost no associated side effects. PMID- 23790330 TI - Effects of Gmelina arborea extract on experimentally induced diabetes. AB - OBJECTIVE: To study the effects of aqueous extract of Gmelina arborea bark on normoglycemic levels and streptozotocin (STZ) induced diabetes in rats. METHODS: After single administration of the aqueous extract, plasma glucose level was determined up to 6 h. In subacute study, the aqueous extract was administered for 28 d and plasma glucose level was determined weekly. The diabetes was induced in rats by the intraperitoneal injection of STZ at a dose of 55 mg/kg body weight. The diabetic animals were divided into four groups containing six in each: Group I diabetic control, Group II and III treated with the aqueous extract respectively at a dose of 250 and 500 mg/kg body weight once daily and Group IV treated with glibenclamide at a dose of 0.6 mg/kg body weight once daily. In acute study, the aqueous extract and glibenclamide were administered orally to rats. Plasma glucose levels were determined at 30, 60, 120, 240 and 360 min after the administration of the test samples. To study subacute effects, test samples (the aqueous extract and glibenclamide) were administered for 28 d consecutively. The effects of each test sample on plasma glucose level, body weight as well as food and water intake were also monitored weekly. The oral glucose tolerance test and biochemical indicators were estimated on day 28. RESULTS: The aqueous extract did not significantly decrease the plasma glucose level in the normoglycemic rats as shown by the acute and subacute assays. However, after oral administration of the aqueous extract, the plasma glucose level was significantly (P<0.001) decreased in the diabetic rats in the acute study. The long-term administration of the aqueous extract significantly (P<0.001) reduced plasma glucose levels of the diabetic rats. Additionally, the aqueous extract also reduced loss of body weight and significantly decreased food and water intake in the diabetic animals. Nevertheless, no effects on biochemical indicators were observed at the selected doses. CONCLUSIONS: The aqueous extract of Gmelina arborea bark had antihyperglycemic activity against STZ induced diabetes in rats, after single and subacute oral administration. Moreover, it did not show significant glucose lowering effect in normoglycemic rats. PMID- 23790331 TI - Antioxidant, hepatoprotective and hypolipidemic effects of methanolic root extract of Cassia singueana in rats following acute and chronic carbon tetrachloride intoxication. AB - OBJECTIVE: To evaluate in vivo antioxidant and hepatoprotective activities of the methanolic extract of the root of Cassia singueana in rats following acute and chronic carbon tetrachloride intoxication. METHODS: Malondialdehyde (MDA), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin as indices of liver damage and lipid peroxidation were detected in rats after intraperitoneal administration of extract (5 mg/kg). RESULTS: The liver, kidney and heart showed significant reduction (P<0.05) in the levels of MDA from (0.18+/ 0.04), (0.23+/-0.07) and (0.26+/-0.10) nmol/mg respectively in the CCl4 control to (0.15+/-0.03), (0.17+/-0.04) and (0.17+/-0.07) nmol/mg protein in groups pre treated with the extract for three days at 5 mg/kg). Similarly, compared to the CCl4 control, significant reduction (P<0.05) in serum AST, ALT and bilirubin as well as in level of total cholesterol and MDA with concomitant increase in HDL cholesterol, superoxide dismutase and catalase levels when CCl4-intoxicated rats were treated with Cassia singueana root extract for two weeks. CONCLUSIONS: These results suggest that methanolic extract of Cassia singueana contain potent antioxidant compounds that can offer significant protection against hepatic and oxidative injuries. PMID- 23790332 TI - In vitro antibacterial and antitumor activities of some medicinal plant extracts, growing in Turkey. AB - OBJECTIVE: To investigate antibacterial and antitumor activities of 51 different extracts prepared with 3 types of solvents (water, ethanol and methanol) of 16 different plant species (Ajuga reptans (A. reptans) L., Phlomis pungens (P. pungens) Willd., Marrubium astracanicum (M. astracanicum) Jacq., Nepeta nuda (N. nuda) L., Stachys annua (S. annua) L., Genista lydia (G. lydia) Boiss., Nuphar lutea (N. lutea) L., Nymphaea alba (N. alba) L., Vinca minor (V. minor) L., Stellaria media (S. media) L., Capsella bursa-pastoris (C. bursa-pastoris) L., Galium spurium (G. spurium) L., Onosma heterophyllum (O. heterophyllum) Griseb., Reseda luteola (R. luteola) L., Viburnum lantana (V. lantana) L. and Mercurialis annua (M. annua) L.) grown in Turkey was conducted. METHODS: Antibacterial activity was evaluated with 10 bacteria including Streptococcus pyogenes (S. pyogenes), Staphylococcus aureus (S. aureus), Staphylococcus epidermidis (S. epidermidis), Escheria coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Salmonella typhimurium (S. typhimurium), Serratia marcescens (S. marcescens), Proteus vulgaris (P. vulgaris), Enterobacter cloacae (E. cloacea), and Klebsiella pneumoniae (K. pneumoniae) by using disc diffusion method. Antitumor activity was evaluated with Agrobacterium tumefaciens (A. tumefaciens)-induced potato disc tumor assay. RESULTS: Best antibacterial activity was obtained with ethanolic extract of P. pungens against S. pyogenes. Ethanolic and methanolic extract of N. alba and ethanolic extract of G. lydia also showed strong antibacterial activities. Results indicated that alcoholic extracts especially ethanolic extracts exhibited strong antibacterial activity against both gram-positive and gram-negative bacteria. Best antitumor activity was obtained with methanolic extracts of N. alba and V. lantana (100% tumor inhibition). Ethanolic extract of N. alba, alcoholic extracts of N. lutea, A. reptans and V. minor flowers, methanolic extracts of G. lydia and O. heterophyllum and ethanolic extract of V. lantana and aqueous extract of V. minor leaves exhibited strong tumor inhibitions. CONCLUSIONS: In near future works, identification of active components can be studied for plant extracts having strong bioactivity. PMID- 23790333 TI - Efficacy of larvicidal and pupicidal activity of Catharanthus roseus aqueous and solvent extracts against Anopheles stephensi Liston and Culex quinquefasciatus Say (Diptera: Culicidae). AB - OBJECTIVE: To investigate the larvicidal and pupicidal activities of aqueous, ethyl acetate and methanol extracts of Catharanthus roseus (C. roseus) against malaria and filariasis vectors. METHODS: The larvicidal and pupicidal activities of C. roseus leaf extracts were tested against the fourth instar larvae and pupae of Anopheles stephensi (An. stephensi) and Culex quinquefasciatus (Cx. quinquefasciatus). The mortality was observed after 24 and 48 h post the treatment. The data were subjected to probit analysis to determine the lethal concentrations (LC50 and LC90) at which 50% and 90% of the treated larvae or pupae of the tested species were killed. RESULTS: The larval and pupal mortality were observed after 24 and 48 h of exposure of aqueous, ethyl acetate and methanol extracts of C. roseus; no mortality was observed in the control group. The LC50 values against the fourth-instar larvae of An. stephensi were 68.62 and 72.04 mg/mL for the aqueous extract, 82.47 mg/mL for the ethyl acetate extract, and 78.80 and 86.64 mg/mL for the methanol extract, while the aqueous, ethyl acetate and methanol extracts had LC50 values of 85.21, 76.84 and 94.20 mg/mL against the fourth-instar larvae of Cx. quinquefasciatus. The aqueous, ethyl acetate and methanol extracts had LC50 values of 118.08, 182.47 and 143.80 mg/mL against the pupae of An. stephensi and 146.20, 226.84 and 156.62 mg/mL against the pupae of Cx. quinquefasciatus, respectively. CONCLUSIONS: The aqueous and methanol extracts of C. roseus leaves had an excellent potential to control the malarial vector An. stephensi and filariasis vector Cx. quinquefasciatus. PMID- 23790334 TI - Cytokine levels in patients with chikungunya virus infection. AB - OBJECTIVE: To investigate cytokine profile in patients with chikungunya virus (CHIKV) infection. METHODS: Twenty eight pairs of serum samples collected from CHIKV infected patients during the outbreak of chikungunya fever in South Thailand in 2008 were obtained. A multiple cytokine assay for detection of 17 cytokines was performed. RESULTS: In the acute stage of CHIKV infection, the patients had significantly higher levels of interleukin-6, granulocyte colony stimulating factor, granulocyte-macrophage colony-stimulating factor, monocyte chemotactic protein 1 and tumor necrosis factor alpha than the control (P<0.001, P=0.023, P=0.015, P<0.001 and P=0.024, respectively). When the disease developed to the recovery stage, the patients had significantly lower levels of interleukin 6, granulocyte-macrophage colony-stimulating factor, monocyte chemotactic protein 1 and macrophage inflammatory protein beta than in the acute stage (P<0.001). CONCLUSIONS: This study provides additional information that these cytokines could play roles in pathogenesis of CHIKV infection and could be used as disease biomarkers or drug targets. PMID- 23790335 TI - Expression and effect of TLR4 in rats with diabetic nephropathy. AB - OBJECTIVE: To observe the expression of TLR4 in kidney tissue of rats with diabetic nephropathy and discuss the role of TLR4 in the occurrence and development of the diabetic nephropathy. METHODS: A total of 60 clean male SD rats were selected and randomly divided into the modeling group and control group after 1 week of breeding, including 30 rats in each group. Biochemical indices as well as the protein expression of TLR4 were observed and compared between two groups at 2 w, 4 w, 6 w, 8 w and 12 w after the modeling, and the correlation between TLR4 and each biochemical indexes was analyzed. RESULTS: Rats in the modeling group had higher levels of blood glucose, 24-hour urine protein and blood urea nitrogen after the modeling, and showed the increase in the serum creatinine, kidney/body weight ratio, CRP and serum TNF-alpha at 4w after the modeling, with the significant difference compared to results of the control group (P<0.05). The cross-section area and mean volume of glomerulus in the modeling group at 4 w, 6 w, 8 w and 12 w were significantly higher than those in the control group, with the statistically significant difference (P<0.05). The expression of TLR4 at each time point in the control group was relatively low. Rats in the modeling group had the high expression of TLR4 in kidney's glomerular basement membrane, proximal convoluted tubule and renal interstitial area since 2 w, with the significant difference compared to the control group (P<0.05). The expression in rats of the modeling group was higher than the one of the control group since the 2nd week. As the time flied, its expression increased, with the statistically significant difference between two groups (P<0.05). There was certain correlation between the protein expression of TLR4 and the increased serum titer of 24-hour urine protein excretion, serum creatinine, CRP and TNF alpha. CONCLUSIONS: TLR4 may activate the immuno-inflammatory reactions to play a role in the occurrence and development of the diabetic nephropathy. PMID- 23790336 TI - COX-2, MMP-7 expression in oral lichen planus and oral squamous cell carcinoma. AB - OBJECTIVE: To observe cyclooxygenase (COX)-2 expression in normal oral mucosa (NOM), oral lichen planus (OLP) and oral squamous cell carcinoma (OSCC) and explore its significance in the incidence of oral cancer. METHODS: The immunohistochemical method and RT-PCR method were applied to detect the expression of COX-2 and MMP-7 in 10 cases with NOM, 33 cases of with OLP and 38 cases with OSCC. RESULTS: The expression of COX-2 mRNA in OSCC tissues (68.4%, 26/38) was significantly higher than in the OLP (24.2%, 8/33) and NOM (0.0%, 0/10) (P<0.01). The expression of MMP-7 mRNA in OSCC tissues (65.8%, 25/38) was significantly higher than in the OLP (30.3%, 10/33) and NOM (0.0%, 0/10) (P<0.01). The expression of MMP-7 in OLP was significantly higher than in the NOM (P<0.05). There was no significant expression of COX-2 protein in NOM, and the positive rate was 42.4% (14/33) and 89.5% (34/38) in OLP and OSCC group, respectively. The COX-2 expression in cancer tissues was significantly higher than in NOM and OLP (P<0.05). The MMP-7 protein expression in cancer tissues (84.2%, 32/38) was significantly higher than in NOM (10.0%, 1/10) and in OLP (42.4%, 14/33), and the positive rate in OLP was significantly higher than in NOM (P< 0.01). The COX-2 expression was associated with clinical stage (P<0.05), the MMP-7 expression was associated with clinical stage and lymph node metastasis (P<0.05). The expressions of COX-2 and MMP-7 mRNA were positively correlated with OSCC. CONCLUSIONS: The abnormal expressions of COX-2 and MMP-7 are closely related to the biological behavior of OSCC, the MMP-7 may be induced by COX-2, and further lead to the invasion and metastasis of OSCC. PMID- 23790337 TI - Trifocal distraction osteogenesis for reconstruction of skull defect. AB - OBJECTIVE: To apply trifocal distraction osteogenesis in canine model of skull segmental defects and to provide reference for clinical treatment. METHODS: Six labrador dogs were selected in this study and divided into observation group and control group randomly. Each group contained 3 dogs. Skull segmental defects models were established by surgery, and dogs in bservation group received trifocal distraction osteogenesis treatment. Bone density was observed and compared between two groups during treatment. RESULTS: There were no significant difference in bone density between two groups on th 1st day (P>0.05). The bone density of observation group on the 30th day, and 60th day were higher than that of control group (P<0.01). CONCLUSIONS: Trifocal distraction osteogenesis has significant clinical effect, and it would be widely used in clinical treatment. PMID- 23790338 TI - SIRT3 expression in hepatocellular carcinoma and its impact on proliferation and invasion of hepatoma cells. AB - OBJECTIVE: To observe expression of SIRT3 in normal liver tissue, cirrhotic tissue and hepatocellular carcinoma (HCC) tissues, and to explore the significance of SIRT3 in primary HCC. METHODS: SIRT3 expression was detected in 10 normal cases, 30 cases with, 30 HCC cases by immunohistochemical and Western blotting method. RESULTS: Immunohistochemical assay showed that the SIRT3 positive expression rates were 100.0% (10/10), 96.7% (29/30) and 60.0% (18/30), respectively in normal group, paracancer group and HCC group. And the SIRT3 expression in HCC group was significantly lower than in normal group and paracancer group (P<0.05). Western-blotting showed the SIRT3 expression in cancer tissue was 0.29+/-0.07, significantly lower than that in paracancer group and normal group (P<0.05). SIRT3 expression was related to the differentiation degree and portal vein tumor thrombus (P<0.05). CONCLUSIONS: Abnormal expression of SIRT3 is closely related to the biological behavior of primary HCC. PMID- 23790339 TI - Effect of the Haoqinqingdan decoction on damp-heat syndrome in rats with influenza viral pneumonia. AB - OBJECTIVE: To investigate the effect of Chinese medicine prescription Haoqinqingdan decoction on damp-heat syndrome in rats with influenza viral pneumonia and its influence on the immune function. METHODS: A total of 48 Wistar rats were randomly divided into the normal control group, the damp-heat syndrome model group, the Haoqinqingdan decoction group (high, medium and low dose group) and the ribavirin group. The body temperature and weight of rats in each group were recorded after modeling. After treatment for 6 d, the concentration of T lymphocyte subgroup (CD3(+)CD4(+), CD3(+)CD8(+)) was determined by flow cytometry. The OD value of IFN-gamma/IL-4 was detected by double-antibody sandwich ELISA method, and its concentration was acquired through conversion. RESULTS: After modeling, the temperature and weight of rats in each modeling group showed the increasing trend (P<0.01). From the second day of treatment, there was significant difference in the body mass between groups, and the rat weight of the control group was higher than in the modeling group (P<0.05 or 0.01). With the advances of treatment, only the temperature in the medium and high dose Haoqinqingdan decoction groups declined significantly (P<0.05). After treatment, the CD4(+)/CD8(+) ratio of the damp-heat syndrome model group decreased more significantly compared with the control group. Elevated CD3(+) CD8(+) percentages and declined CD4(+)/CD8(+) ratios can be observed in the low dose group and ribavirin group (P<0.05). Moreover, the CD3(+) CD4(+) percentage of ribavirin group was lower than in the control group (P<0.05). After treatment, the IFN-gamma and IFN-gamma/ IL-4 levels in the peripheral blood of rats in the damp-heat syndrome group were obviously higher than in the control group (P<0.05). CONCLUSIONS: Compared with ribavirin, the high dose Haoqinqingdan decoction can improve the ratio of T lymphocyte subgroup and Th1/Th2 cell balance more effectively. PMID- 23790340 TI - Effect of Chinese herbal compound on liver fibrosis in rabbits with schistosomiasis by B-ultrasound. AB - OBJECTIVE: To explore the value of B-ultrasound on the evaluation of the effects of traditional Chinese medicine compound of Radix astragali, Salvia miltiorrhiza and Angelica sinensis, and TCM + praziquantel on liver fibrosis in rabbits with schistosomiasis. METHODS: The hepatic fibrosis model in rabbits with schistosomiasis was established. The experimental animals (24 rabbits) were randomly divided into four groups (group A, B, C and D, n=6). Group A (control group) was only treated by praziquantel; Group B was treated by mixture of Radix astragali and Salvia miltiorrhiza + praziquantel; Group C was treated by mixture of Radix astragali and Angelica sinensis + praziquantel; Group D was treated by mixture of Radix astragali, Salvia miltiorrhiza and Angelica sinensis + praziquantel. Then B-ultrasonogram was used to evaluate the effects. RESULTS: Each group showed certain curative effect on liver fibrosis in rabbits with schistosomiasis. The efficacy of group B, C and D was better than group A, and that of group D was the best. The differences in long diameter, thickness diameter, transverse diameter and portal vein inner diameter of liver before and after treatment were statistically significant (P<0.05). The liver function indexes and liver fibrosis indexes were significantly improved after treatment (P<0.05). CONCLUSIONS: The mixture of Radix astragali, Salvia miltiorrhiza and Angelica sinensis combined with Western medicine treatment can obviously improve the efficacy on liver fibrosis of schistosomiasis. PMID- 23790341 TI - Peripheral blood cell variations in cirrhotic portal hypertension patients with hypersplenism. AB - OBJECTIVE: To explore peripheral blood cell variations in hepatic cirrhosis portal hypertension patients with hypersplenism. METHODS: Clinical data of 322 hypersplenism patients with decreased peripheral blood cells, admitted with cirrhotic portal hypertension, was retrospectively studied over the last 17 years. RESULTS: In 64% (206/322) of patients, more than 2 kinds of blood cell were decreased, including 89 cases of pancytopenia (43.2%), 52 cases of WBC + PLT decrease (25.2%), 29 cases of RBC + PLT decrease (14.1%), and 36 cases of WBC + RBC decrease (17.5%); in 36% (116/322) of patients, single type blood cell decrease occurred, including 31 cases of PLT decrease (26.7%), 29 cases of WBC decrease (25%) and 56 cases of RBC decrease (48.3%). Of 227 routine bone marrow examinations, bone marrow hyperplasia was observed in 118 cases (52.0%), the remainder showed no hyperplasia. For the distinct scope and extent of peripheralblood cell decreases, preoperative blood component transfusions were carried out, then treated by surgery, after whole group splenectomy, the peripheral blood cell count was significantly higher (P<0.05). CONCLUSIONS: Of portal hypertensive patients with splenomegaly and hypersplenism, 64% have simultaneous decrease in various blood cells, 36% have decrease in single type blood cells, 52% of patients have bone marrow hyperplasia. A splenectomy can significantly increase the reduction of peripheral blood cells. PMID- 23790342 TI - Cutaneous leishmaniasis in Al Hassa, Saudi Arabia: epidemiological trends from 2000 to 2010. AB - OBJECTIVE: To study epidemiological trends related to cutaneous leishmaniasis (CL) in Al Hassa, an endemic area in Saudi Arabia. METHODS: This retrospective study included the spatial/temporal analysis of the reported cases of CL using the available surveillance database for the disease at the regional Vector Control Unit, from 2000 to 2010. RESULTS: The incidence of CL was declining at a stable rate especially during the last 3 years of the study (2008-2010). An interesting finding was the percentage of expatriates affected was increasing over the last 10 years compared to that of the Saudis. CONCLUSIONS: A definite declining trend in the incidence of CL was observed in Al Hassa. Further studies are warranted to assess whether special public health measures are needed for better control of CL in expatriate populations in Saudi Arabia. PMID- 23790343 TI - Mini-midvastus versus mini-medial parapatellar approach for minimally invasive total knee arthroplasty: outcomes pendulum is at equilibrium. AB - Comparisons between mini-midvastus (mMV) and mini-medial parapatellar approach (mMPP) for total knee arthroplasty (TKA) have reported variable results. We compared two approaches with minimum two year follow up. Forty consecutive patients who underwent staged bilateral TKA were prospectively randomized for mMPP approach in one knee and mMV approach in the other. Clinical parameters (muscle strength, pain, ROM, Knee Society Score) and surgic.l parameters (duration of surgery, blood loss, lateral releases) were assessed at 2, 6, 12 weeks and 6, 12, 24 months postoperatively. Clinical outcomes revealed inconsistent pattern of differences at various intervals. Surgical outcomes were not different. There were no major differences in outcomes between the two approaches. We recommend someone use surgical approach with which they are most familiar. PMID- 23790344 TI - Exposure to particulate air pollution and long-term incidence of frailty after myocardial infarction. AB - PURPOSE: Frailty, a multidimensional syndrome of increased vulnerability, is prevalent post-myocardial infarction (MI) and predicts mortality and recurrent events. We investigated whether chronic exposure to particulate matter <=2.5 MUm in diameter (PM2.5) is associated with the development of post-MI frailty. METHODS: Participants (n = 1120) were aged 65 or less and admitted to hospital in central Israel with first MI in 1992 and 1993. Daily measures of PM2.5 recorded at air quality monitoring stations were summarized and chronic exposure was estimated individually using the geo-coded residential location. Frailty assessment was conducted via an index based on deficit accumulation, and those defined as frail (applying a threshold of >=0.25) at baseline were excluded. Remaining participants who survived to follow-up 10 to 13 years post-MI (n = 848) were reassessed for frailty. Logistic regression models were constructed to evaluate the role of PM2.5 exposure in frailty risk prediction. RESULTS: Mean exposure to PM2.5 was 24.2 MUg/m(3) (range, 16.9-28.6). A total of 301 participants (35.5%) developed frailty during follow-up. Adjusting for sociodemographic and clinical variables, PM2.5 exposure was associated with increased odds of developing frailty (odds ratio, 1.53; 95% confidence interval, 1.22-1.91, comparing the 75th vs. 25th percentiles). Addition of PM2.5 exposure to the multivariable model resulted in an integrated discrimination improvement of 1.60% (P = .005) and a net reclassification index of 6.51% (P = .02). CONCLUSIONS: An association was observed between exposure to PM2.5 and incidence of frailty, providing a potential intermediary between air pollution and post-MI outcomes. PMID- 23790345 TI - The effect of body mass index on optimal vitamin D status in U.S. adults: the National Health and Nutrition Examination Survey 2001-2006. AB - OBJECTIVES: To investigate the relationship between body mass index (BMI) and optimal vitamin D status in U.S. adults. METHODS: Data on 12,927 adults 18 years and older participating in National Health and Nutrition Examination Surveys 2001 2006 were used. Serum levels of 25-hydroxy vitamin D 30 ng/mL or greater was used as a measure of vitamin D sufficiency. Log-binomial regression was used to estimate the strength of the association between BMI categories and the prevalence of vitamin D sufficiency before and after adjusting for selected characteristics. RESULTS: After adjustment, overweight and obese individuals were 24% and 55%, respectively, less likely to have a 25-hydroxy vitamin D level of 30 ng/mL or greater compared with their normal-weight counterparts. CONCLUSIONS: Our findings call attention to the importance of identifying individuals at risk for vitamin D insufficiency and its potential adverse health outcomes because the latter may increase health disparities in the U.S. population. If vitamin D insufficiency is implicated for chronic diseases such as cardiovascular diseases and diabetes, a vitamin D supplementation regimen would need to be readdressed, especially for segments of the U.S. population with greater BMIs. PMID- 23790346 TI - Lower respiratory tract infection in the first year of life is associated with worse lung function in adult life: prospective results from the Barry Caerphilly Growth study. AB - PURPOSE: We examined the association between childhood respiratory infections and adult lung function and how this association varies depending on the age at infection. METHODS: The Barry Caerphilly Growth study collected information on childhood upper and lower respiratory tract infections (URTI, LRTI) from birth to 5 years on 14 occasions. Subjects were traced prospectively and had lung function measured at age 25 years. RESULTS: A total of 581 subjects had acceptable data for both forced expiratory volume in one second (FEV1) and forced vital capacity (FVC). Childhood LRTIs (0-5 years) but not URTIs were negatively associated with all lung function measures except FVC and showed a dose-response effect. In the first year of life, a two-fold increase in the number of LRTIs experienced was associated with a reduction in FEV1 (78 mL; 95% confidence interval [95% CI], 3 153), FEV1/FVC (1.23%; 95% CI 0.25-2.22), forced expiratory flow 25%-75% (0.25 l/sec; 95% CI 0.08-0.41), and peak expiratory flow (0.30 l/sec; 95% CI 0.11-0.49) after adjustment for confounders. Few associations were found after the first year of life. There was evidence that age at infection effect modifies the association between LRTIs and FEV1, forced expiratory flow 25%-75%, and peak expiratory flow. CONCLUSIONS: LRTIs are associated with an obstructive lung function deficit. Furthermore, the first year of life may be a sensitive period for experiencing LRTIs. PMID- 23790347 TI - Effect of advanced maternal age on perinatal outcomes in twins: the impact of chorionicity. AB - PURPOSE: In contrast to singletons, twins born to older mothers have lower rates of perinatal mortality than twins born to younger mothers. We examined whether differences in chorionicity could explain this unexpected maternal age effect. METHODS: We used population-based data on twins born to mothers aged 20-29 (n = 3702) and >=35 years (n = 1880) in the North of England, UK, 1998-2007. We calculated rate ratios (RR) and 95% confidence intervals (CIs) to estimate the effect of maternal age; adjusted RRs (ARRs) were estimated by the use of generalized estimating equations for Poisson regression controlling for chorionicity and other confounders. RESULTS: Older mothers had a lower proportion of monochorionic twins (17.6% vs. 24.3%, P < .01); lower neonatal (RR, 0.57; 95% CI, 0.34-0.95) and perinatal mortality (RR, 0.74; 95% CI, 0.53-1.04). Adjustment for chorionicity attenuated these associations (ARR, 0.59; 95% CI, 0.35-0.98 and ARR, 0.80; 95% CI, 0.57-1.12, respectively) and after further adjustment for additional factors, both associations became nonsignificant. Older mothers had greater rates of small-for-gestational-age infants (ARR, 1.59; 95% CI, 1.24 2.05), and cesarean delivery (ARR, 1.31; 95% CI, 1.16-1.48). CONCLUSIONS: Perinatal death rates were lower but not statistically different for twins born to older versus younger mothers. This association was attenuated by adjustment for chorionicity. PMID- 23790348 TI - Identifying women at risk of unintended pregnancy: a comparison of two pregnancy readiness measures. AB - PURPOSE: Recently, there has been interest in developing a predictive measure to assess pregnancy readiness/intention in clinical settings. Two such measures have been created but tested primarily in pregnant or postpartum populations. This study examined agreement between the pregnancy readiness measures in a diverse population of nonpregnant women. METHODS: Women completed short questionnaires while waiting for clinical appointments. Participants' responses to the pregnancy readiness measures were cross-tabulated to assess the level of agreement between the measures. Logistic regression was used to determine factors related to disagreement between the measures. Complete information was available for 220 women. RESULTS: Almost 55% of women had disagreement between the pregnancy readiness measures. Women with a high school education or less had 2.60 times the odds of disagreement (95% confidence interval 1.23-5.49), and women who did not use contraception had 2.40 times the odds of disagreement (95% confidence interval 1.18-4.87). CONCLUSIONS: Although both pregnancy readiness measures are promising tools that could potentially be adapted for use in public health or clinical settings, there are limitations to these measures. These measures should be further tested and refined through the use of qualitative methods to ensure that a valid measure is created for use in non-pregnant populations. PMID- 23790349 TI - Improving completeness of ascertainment and quality of information for pregnancies through linkage of administrative and clinical data records. AB - PURPOSE: Birth cohorts are a common tool used in epidemiological studies about pregnancy; yet these datasets systematically miss pregnancies that are spontaneously lost or terminated. This study examined the feasibility of linking administrative and clinical datasets from Alberta Canada to identify a pregnancy cohort that includes spontaneous and medical pregnancy losses. METHODS: Deterministic linkage was used to link data from twelve clinical and administrative datasets for women who conceived between November 2007 and February 2008. Descriptive statistics were used to characterize the relative contribution of each dataset to the overall dataset. RESULTS: Overall, 6,477 unique pregnancies were eligible for inclusion, resulting in a live birth rate of 94.1%, a stillbirth rate of 0.5%, a fetal death rate of 4.1%, and an estimated 1.3% of the cohort moving out of the study area. No single dataset could identify all pregnancies. Individual databases identified 2.0-99.1% of the cohort. Fetal deaths were most frequently identified in outpatient physician claims, emergency room visits, ultrasound data, or from the cytogenetic laboratory. CONCLUSIONS: Linkage of clinical and administrative databases to identify pregnancy is feasible and can overcome many limitations associated with the use of a single dataset; however, fetal deaths continue to be under-ascertained. PMID- 23790350 TI - Promoting innovation and creativity in epidemiology for the 21st century. PMID- 23790351 TI - Open letter to President Obama on hunger strikers in Guantanamo. PMID- 23790352 TI - Socioeconomic development to fight malaria, and beyond. PMID- 23790353 TI - Socioeconomic development as an intervention against malaria: a systematic review and meta-analysis. AB - BACKGROUND: Future progress in tackling malaria mortality will probably be hampered by the development of resistance to drugs and insecticides and by the contraction of aid budgets. Historically, control was often achieved without malaria-specific interventions. Our aim was to assess whether socioeconomic development can contribute to malaria control. METHODS: We did a systematic review and meta-analysis to assess whether the risk of malaria in children aged 0 15 years is associated with socioeconomic status. We searched Medline, Web of Science, Embase, the Cochrane Database of Systematic Reviews, the Campbell Library, the Centre for Reviews and Dissemination, Health Systems Evidence, and the Evidence for Policy and Practice Information and Co-ordinating Centre evidence library for studies published in English between Jan 1, 1980, and July 12, 2011, that measured socioeconomic status and parasitologically confirmed malaria or clinical malaria in children. Unadjusted and adjusted effect estimates were combined in fixed-effects and random-effects meta-analyses, with a subgroup analysis for different measures of socioeconomic status. We used funnel plots and Egger's linear regression to test for publication bias. FINDINGS: Of 4696 studies reviewed, 20 met the criteria for inclusion in the qualitative analysis, and 15 of these reported the necessary data for inclusion in the meta-analysis. The odds of malaria infection were higher in the poorest children than in the least poor children (unadjusted odds ratio [OR] 1.66, 95% CI 1.35-2.05, p<0.001, I(2)=68%; adjusted OR 2.06, 1.42-2.97, p<0.001, I(2)=63%), an effect that was consistent across subgroups. INTERPRETATION: Although we would not recommend discontinuation of existing malaria control efforts, we believe that increased investment in interventions to support socioeconomic development is warranted, since such interventions could prove highly effective and sustainable against malaria in the long term. FUNDING: UK Department for International Development. PMID- 23790354 TI - State of the art survey on MRI brain tumor segmentation. AB - Brain tumor segmentation consists of separating the different tumor tissues (solid or active tumor, edema, and necrosis) from normal brain tissues: gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF). In brain tumor studies, the existence of abnormal tissues may be easily detectable most of the time. However, accurate and reproducible segmentation and characterization of abnormalities are not straightforward. In the past, many researchers in the field of medical imaging and soft computing have made significant survey in the field of brain tumor segmentation. Both semiautomatic and fully automatic methods have been proposed. Clinical acceptance of segmentation techniques has depended on the simplicity of the segmentation, and the degree of user supervision. Interactive or semiautomatic methods are likely to remain dominant in practice for some time, especially in these applications where erroneous interpretations are unacceptable. This article presents an overview of the most relevant brain tumor segmentation methods, conducted after the acquisition of the image. Given the advantages of magnetic resonance imaging over other diagnostic imaging, this survey is focused on MRI brain tumor segmentation. Semiautomatic and fully automatic techniques are emphasized. PMID- 23790355 TI - Influence of equine growth hormone, insulin-like growth factor-I and its interaction with gonadotropins on in vitro maturation and cytoskeleton morphology in equine oocytes. AB - In horses, successful in vitro fertilization procedures are limited by our inability to consistently mature equine oocytes by in vitro methods. Growth hormone (GH) is an important regulator of female reproduction in mammals, playing an important role in ovarian function, follicular growth and steroidogenesis. The objectives of this research were to investigate: the effects of equine growth hormone (eGH) and insulin-like growth factor-I (IGF-I) on the in vitro maturation (IVM) of equine oocytes, and the effects of eGH in addition to estradiol (E2), gonadotropins (FSH and LH) and fetal calf serum (FCS) on IVM. We also evaluated the cytoskeleton organization of equine oocytes after IVM with eGH. Equine oocytes were aspirated from follicles <30 mm in diameter and matured for 30 h at 38.5 degrees C in air with 5% CO2. In experiment 1, selected cumulus-oocyte complexes (COCs) were randomly allocated as follows: (a) control (no additives); (b) 400 ng/ml eGH; (c) 200 ng/ml IGF-I; (d) eGH + IGF-I; and (e) eGH + IGF-I + 200 ng/ml anti-IGF-I. In addition to these treatment groups, we also added 1 MUg/ml E2, 5 IU/ml FSH, 10 IU/ml LH and 10% FCS in vitro (experiment 2). Oocytes were stained with markers for microtubules (anti-alpha-tubulin antibody), microfilaments (AlexaFluor 488 Phalloidin) and chromatin (TO-PRO3-iodide) and assessed via confocal microscopy. No difference was observed when eGH and IGF-I was added into our IVM system. However, following incubation with eGH alone (40%) and eGH, E2, gonadotropins and FCS (36.6%) oocytes were classified as mature v. 17.6% of oocytes in the control group (P < 0.05). Matured equine oocytes showed that a thin network of filaments concentrated within the oocyte cortex and microtubules at the metaphase spindle showed a symmetrical barrel-shaped structure, with chromosomes aligned along its midline. We conclude that the use of E2, gonadotropins and FCS in the presence of eGH increases the number of oocytes reaching oocyte competence. PMID- 23790356 TI - Facebook friends with (health) benefits? Exploring social network site use and perceptions of social support, stress, and well-being. AB - There is clear evidence that interpersonal social support impacts stress levels and, in turn, degree of physical illness and psychological well-being. This study examines whether mediated social networks serve the same palliative function. A survey of 401 undergraduate Facebook users revealed that, as predicted, number of Facebook friends associated with stronger perceptions of social support, which in turn associated with reduced stress, and in turn less physical illness and greater well-being. This effect was minimized when interpersonal network size was taken into consideration. However, for those who have experienced many objective life stressors, the number of Facebook friends emerged as the stronger predictor of perceived social support. The "more-friends-the-better" heuristic is proposed as the most likely explanation for these findings. PMID- 23790357 TI - The persuasion context and results in online opinion seeking: effects of message and source-the moderating role of network managers. AB - Online opinion networks are areas for social exchange, or conversational networks, made up of individuals actively involved in sharing experiences and opinions concerning matters of mutual interest between consumers or concerning their experience with a given product or service. We pinpoint a gap in the literature regarding how the persuasion process occurs when individuals seek opinions online, including the results process. In an attempt to find an answer, we draw on traditional theories related to information processing. These are mostly taken from the field of psychology and enable us to identify which signals or aspects of communication or opinions the individuals focus their attention on (message and source) and the value attached to such communications as well as how much they impact individuals' purchase decisions, bearing in mind the medium (or online opinion network) in which the opinions are located. Findings from those interviewed support the idea that the quality of information on the Internet, as well as trust in the source of said information, or in the opinion of network users, have an impact on the informational value obtained from involvement in this online opinion seeking and on purchasing decisions. Moreover, depending on the kind of network (firm or brand controlled, review Web sites, and user controlled nonofficial opinion networks), the quality of the information or trust in the users will have a different bearing in the persuasion process. PMID- 23790358 TI - Perpetration of teen dating violence in a networked society. AB - Teen dating violence (TDV) is a serious form of youth violence that youth fairly commonly experience. Although youth extensively use computer-mediated communication (CMC), the epidemiology of CMC-based TDV is largely unknown. This study examined how perpetration of psychological TDV using CMC compares and relates to perpetration using longer-standing modes of communication (LSMC; e.g., face-to-face). Data from the national Growing up with Media study involving adolescents aged 14-19 collected from October 2010 to February 2011 and analyzed May 2012 are reported. Analyses focused on adolescents with a history of dating (n=615). Forty-six percent of youth daters had perpetrated psychological TDV. Of those who perpetrated in the past 12 months, 58% used only LSMC, 17% used only CMC, and 24% used both. Use of both CMC and LSMC was more likely among perpetrators who used CMC than among perpetrators who used LSMC. In addition, communication mode and type of psychological TDV behavior were separately related to frequency of perpetration. Finally, history of sexual intercourse was the only characteristic that discriminated between youth who perpetrated using different communication modes. Results suggest that perpetration of psychological TDV using CMC is prevalent and is an extension of perpetration using LSMC. Prevention should focus on preventing perpetration of LSMC-based TDV as doing so would prevent LSMC as well as CMC-based TDV. PMID- 23790359 TI - Integrating technology readiness into the expectation-confirmation model: an empirical study of mobile services. AB - The aim of this study was to integrate technology readiness into the expectation confirmation model (ECM) for explaining individuals' continuance of mobile data service usage. After reviewing the ECM and technology readiness, an integrated model was demonstrated via empirical data. Compared with the original ECM, the findings of this study show that the integrated model may offer an ameliorated way to clarify what factors and how they influence the continuous intention toward mobile services. Finally, the major findings are summarized, and future research directions are suggested. PMID- 23790360 TI - Big five personality traits reflected in job applicants' social media postings. AB - Job applicants and incumbents often use social media for personal communications allowing for direct observation of their social communications "unfiltered" for employer consumption. As such, these data offer a glimpse of employees in settings free from the impression management pressures present during evaluations conducted for applicant screening and research purposes. This study investigated whether job applicants' (N=175) personality characteristics are reflected in the content of their social media postings. Participant self-reported social media content related to (a) photos and text-based references to alcohol and drug use and (b) criticisms of superiors and peers (so-called "badmouthing" behavior) were compared to traditional personality assessments. Results indicated that extraverted candidates were prone to postings related to alcohol and drugs. Those low in agreeableness were particularly likely to engage in online badmouthing behaviors. Evidence concerning the relationships between conscientiousness and the outcomes of interest was mixed. PMID- 23790362 TI - Fast coliform detection in portable microbe enrichment unit (PMEU) with Colilert((r)) medium and bubbling. AB - Laboratory strains of coliforms Escherichia coli and Klebsiella mobilis were used to artificially contaminate water samples in two different cultivation and detection systems, without and with bubble flow. Samples were collected with an automated system (ASCS). The positive coliform signal caused the color change into yellow (at 550-570nm). This signal could also be transmitted on-line to cell phones. E. coli containing samples emitted UV fluorescence at 480-560nm when activated by UV light. If cultivation was started with inocula varying from 10,000 to 1cfu/ml, the positive detection was obtained between 2 and 18h, respectively, in Colilert medium using Coline PMEU device without gas bubbling. Accordingly, a single K. mobilis cell produced detectable growth in 18h. Various clinical E. coli strains were compared to each other with equal inoculum sizes, and they showed slight variations in the initiation and speed of growth. The gas bubble flow in PMEU Spectrion promoted the mixing and interaction of bacteria and indicator media and speeded the onset of growth. Carbon dioxide also accelerated bacterial growth. In the presence of vancomycin, the onset of E. coli culture growth was speeded up by the volatile outlet flow from previous cultures. In the last cultivation syringe in a series of five, the lag phase disappeared and the growth of the inoculum continued without major interruption. IN CONCLUSION: the stimulation of the cultures by the gas flow turned out to be a useful means for improving the detection of indicator bacteria. It could also be used in combination with antibiotic selection in the broth medium. PMID- 23790361 TI - The Shu complex regulates Rad52 localization during rDNA repair. AB - The Shu complex, consisting of Rad51 paralogues, is an important regulator of homologous recombination, an error-free DNA repair pathway. Consequently, when members of this complex are disrupted, cells exhibit a mutator phenotype, sensitivity to DNA damage reagents and increased gross chromosomal rearrangements. Previously, we found that the Shu complex plays an important role in ribosomal DNA (rDNA) recombination when the Upstream Activating Factor (UAF) protein Uaf30 is disrupted. UAF30 encodes a protein needed for rDNA transcription and when deleted, rDNA recombination increases and the rDNA expands in a Shu1 dependent manner. Here we find using the uaf30-sensitized background that the central DNA repair protein Rad52, which is normally excluded from the nucleolus, frequently overlaps with the rDNA. This close association of Rad52 with the rDNA is dependent upon Shu1 in a uaf30 mutant. Previously, it was shown that in the absence of Rad52 sumoylation, Rad52 foci mislocalize to the nucleolus. Interestingly, here we find that using the uaf30 sensitized background the ability to regulate Rad52 sumoylation is important for Shu1 dependent rDNA recombination as well as Rad52 close association with rDNA. Our results suggest that in the absence of UAF30, the Shu complex plays a central role in Rad52 rDNA localization as long as Rad52 can be sumoylated. This discrimination is important for rDNA copy number homeostasis. PMID- 23790363 TI - Effect of oxygen on multidrug resistance in the first trimester human placenta. AB - INTRODUCTION: The multidrug resistance proteins, P-glycoprotein (P-gp, encoded by the ABCB1 gene) and breast cancer resistance protein (BCRP, encoded by ABCG2) are highly expressed in the first trimester placenta. These transporters protect the fetus from exposure to maternally derived toxins and xenobiotics. Since oxygen is a regulator of multidrug resistance in various tissues, we hypothesized that changes in oxygen tension alter placental ABCB1/P-gp and ABCG2/BCRP expression in the first trimester. METHODS: Placental specimens were collected from first (n = 7), second (n = 5) and term pregnancies (n = 5). First trimester placental villous explants were incubated (24 or 48 h) in different oxygen tension (3-20%). ABCB1, ABCG2 and VEGFA mRNA expression levels were assessed by RT-PCR and protein was localized by IHC. RESULTS: ABCB1 is expressed most highly in the first trimester placenta (p < 0.05), whereas ABCG2 expression does not change significantly over pregnancy. P-gp and BCRP staining is present in the syncytiotrophoblast and in cytotrophoblasts. ABCG2 mRNA is increased in hyperoxic (20%) conditions after 48 h (p < 0.05). In contrast, hypoxia (3%) did not change ABCB1 mRNA expression but significantly increased VEGFA mRNA (p < 0.05). Hypoxia resulted in increased BCRP staining in cytotrophoblasts and in the microvillous membrane of the syncytium. Whereas, hypoxia resulted in increased P-gp staining in proliferating cytotrophoblasts. CONCLUSION: We conclude that placental multidrug resistance expression, specifically ABCG2, is regulated by oxygen tension in the first trimester. It is possible that changes in placental oxygen supply are capable of altering fetal drug exposure especially during early pregnancy. PMID- 23790364 TI - Combining modeling and experiment to understand bacterial growth. PMID- 23790365 TI - Systems biophysics of gene expression. AB - Gene expression is a process central to any form of life. It involves multiple temporal and functional scales that extend from specific protein-DNA interactions to the coordinated regulation of multiple genes in response to intracellular and extracellular changes. This diversity in scales poses fundamental challenges to the use of traditional approaches to fully understand even the simplest gene expression systems. Recent advances in computational systems biophysics have provided promising avenues to reliably integrate the molecular detail of biophysical process into the system behavior. Here, we review recent advances in the description of gene regulation as a system of biophysical processes that extend from specific protein-DNA interactions to the combinatorial assembly of nucleoprotein complexes. There is now basic mechanistic understanding on how promoters controlled by multiple, local and distal, DNA binding sites for transcription factors can actively control transcriptional noise, cell-to-cell variability, and other properties of gene regulation, including precision and flexibility of the transcriptional responses. PMID- 23790366 TI - An x-ray scattering study into the structural basis of corneal refractive function in an avian model. AB - Avian vision diseases in which eye growth is compromised are helping to define what governs corneal shape and ultrastructural organization. The highly specific collagen architecture of the main corneal layer, the stroma, is believed to be important for the maintenance of corneal curvature and hence visual quality. Blindness enlarged globe (beg) is a recessively inherited condition of chickens characterized by retinal dystrophy and blindness at hatch, with secondary globe enlargement and loss of corneal curvature by 3-4 months. Here we define corneal ultrastructural changes as the beg eye develops posthatch, using wide-angle x-ray scattering to map collagen fibril orientation across affected corneas at three posthatch time points. The results disclosed alterations in the bulk alignment of corneal collagen in beg chicks compared with age-matched controls. These changes accompanied the eye globe enlargement and corneal flattening observed in affected birds, and were manifested as a progressive loss of circumferential collagen alignment in the peripheral cornea and limbus in birds older than 1 month. Progressive remodeling of peripheral stromal collagen in beg birds posthatch may relate to the morphometric changes exhibited by the disease, likely as an extension of myopia-like scleral remodeling triggered by deprivation of a retinal image. PMID- 23790367 TI - Dynamical scenarios for chromosome bi-orientation. AB - Chromosome bi-orientation at the metaphase spindle is essential for precise segregation of the genetic material. The process is error-prone, and error correction mechanisms exist to switch misaligned chromosomes to the correct, bi oriented configuration. Here, we analyze several possible dynamical scenarios to explore how cells might achieve correct bi-orientation in an efficient and robust manner. We first illustrate that tension-mediated feedback between the sister kinetochores can give rise to a bistable switch, which allows robust distinction between a loose attachment with low tension and a strong attachment with high tension. However, this mechanism has difficulties in explaining how bi orientation is initiated starting from unattached kinetochores. We propose four possible mechanisms to overcome this problem (exploiting molecular noise; allowing an efficient attachment of kinetochores already in the absence of tension; a trial-and-error oscillation; and a stochastic bistable switch), and assess their impact on the bi-orientation process. Based on our results and supported by experimental data, we put forward a trial-and-error oscillation and a stochastic bistable switch as two elegant mechanisms with the potential to promote bi-orientation both efficiently and robustly. PMID- 23790368 TI - Elasticity and biochemistry of growth relate replication rate to cell length and cross-link density in rod-shaped bacteria. AB - In rod-shaped bacteria, cell morphology is correlated with the replication rate. For a given species, cells that replicate faster are longer and have less cross linked cell walls. Here, we propose a simple mechanochemical model that explains the dependence of cell length and cross-linking on the replication rate. Our model shows good agreement with existing experimental data and provides further evidence that cell wall synthesis is mediated by multienzyme complexes; however, our results suggest that these synthesis complexes only mediate glycan insertion and cross-link severing, whereas recross-linking is performed independently. PMID- 23790369 TI - Dual gating mechanism and function of P2X7 receptor channels. AB - The ATP-gated P2X7 receptor channel (P2X7R) operates as a cytolytic and apoptotic receptor but also controls sustained cellular responses, including cell growth and proliferation. However, it has not been clarified how the same receptor mediates such opposing effects. To address this question, we have combined electrophysiological, imaging, and mathematical studies using wild-type and mutant rat P2X7Rs. Activation of naive (not previously stimulated) receptors by low agonist concentrations caused monophasic slow desensitizing currents and internalization of receptors without other changes in the cellular morphology, much like other P2XRs. In contrast, saturating agonist concentrations induced high-amplitude biphasic currents, reflecting pore dilation and causing rapid cell swelling and lysis. The existence of these two signaling patterns was accounted for using a revised Markov-state model that included, in addition to naive and sensitized states, desensitized states. Occupancy of one or two ATP-binding sites of naive receptors favored a slow transition to desensitized states, whereas occupancy of the third binding site favored a transition to sensitized/dilated states. Consistent with model predictions, nondilating P2X7R mutants always generated desensitizing currents. These results suggest that the level of saturation of the ligand binding sites determines the nature of the P2X7R gating and cellular actions. PMID- 23790370 TI - Thermal mechanisms of millimeter wave stimulation of excitable cells. AB - Interactions between millimeter waves (MMWs) and biological systems have received increasing attention due to the growing use of MMW radiation in technologies ranging from experimental medical devices to telecommunications and airport security. Studies have shown that MMW exposure alters cellular function, especially in neurons and muscles. However, the biophysical mechanisms underlying such effects are still poorly understood. Due to the high aqueous absorbance of MMW, thermal mechanisms are likely. However, nonthermal mechanisms based on resonance effects have also been postulated. We studied MMW stimulation in a simplified preparation comprising Xenopus laevis oocytes expressing proteins that underlie membrane excitability. Using electrophysiological recordings simultaneously with 60 GHz stimulation, we observed changes in the kinetics and activity levels of voltage-gated potassium and sodium channels and a sodium potassium pump that are consistent with a thermal mechanism. Furthermore, we showed that MMW stimulation significantly increased the action potential firing rate in oocytes coexpressing voltage-gated sodium and potassium channels, as predicted by thermal terms in the Hodgkin-Huxley model of neurons. Our results suggest that MMW stimulation produces significant thermally mediated effects on excitable cells via basic thermodynamic mechanisms that must be taken into account in the study and use of MMW radiation in biological systems. PMID- 23790371 TI - Minimal effect of lipid charge on membrane miscibility phase behavior in three ternary systems. AB - Giant unilamellar vesicles composed of a ternary mixture of phospholipids and cholesterol exhibit coexisting liquid phases over a range of temperatures and compositions. A significant fraction of lipids in biological membranes are charged. Here, we present phase diagrams of vesicles composed of phosphatidylcholine (PC) lipids, which are zwitterionic; phosphatidylglycerol (PG) lipids, which are anionic; and cholesterol (Chol). Specifically, we use DiPhyPG-DPPC-Chol and DiPhyPC-DPPG-Chol. We show that miscibility in membranes containing charged PG lipids occurs over similarly high temperatures and broad lipid compositions as in corresponding membranes containing only uncharged lipids, and that the presence of salt has a minimal effect. We verified our results in two ways. First, we used mass spectrometry to ensure that charged PC/PG/Chol vesicles formed by gentle hydration have the same composition as the lipid stocks from which they are made. Second, we repeated the experiments by substituting phosphatidylserine for PG as the charged lipid and observed similar phenomena. Our results consistently support the view that monovalent charged lipids have only a minimal effect on lipid miscibility phase behavior in our system. PMID- 23790372 TI - Skin membrane electrical impedance properties under the influence of a varying water gradient. AB - The stratum corneum (SC) is an effective permeability barrier. One strategy to increase drug delivery across skin is to increase the hydration. A detailed description of how hydration affects skin permeability requires characterization of both macroscopic and molecular properties and how they respond to hydration. We explore this issue by performing impedance experiments on excised skin membranes in the frequency range 1 Hz to 0.2 MHz under the influence of a varying gradient in water activity (aw). Hydration/dehydration induces reversible changes of membrane resistance and effective capacitance. On average, the membrane resistance is 14 times lower and the effective capacitance is 1.5 times higher when the outermost SC membrane is exposed to hydrating conditions (aw = 0.992), as compared to the case of more dehydrating conditions (aw = 0.826). Molecular insight into the hydration effects on the SC components is provided by natural abundance (13)C polarization transfer solid-state NMR and x-ray diffraction under similar hydration conditions. Hydration has a significant effect on the dynamics of the keratin filament terminals and increases the interchain spacing of the filaments. The SC lipids are organized into lamellar structures with ~ 12.6 nm spacing and hexagonal hydrocarbon chain packing with mainly all-trans configuration of the acyl chains, irrespective of hydration state. Subtle changes in the dynamics of the lipids due to mobilization and incorporation of cholesterol and long-chain lipid species into the fluid lipid fraction is suggested to occur upon hydration, which can explain the changes of the impedance response. The results presented here provide information that is useful in explaining the effect of hydration on skin permeability. PMID- 23790373 TI - Single-molecule motility: statistical analysis and the effects of track length on quantification of processive motion. AB - In vitro, single-molecule motility assays allow for the direct characterization of molecular motor properties including stepping velocity and characteristic run length. Although application of these techniques in vivo is feasible, the challenges involved in sample preparation, as well as the added complexity of the cell and its systems, result in a reduced ability to collect large datasets, as well as difficulty in simultaneous observation of the components of the motility system, namely motor and track. To address these challenges, we have developed simulations to characterize motility datasets as a function of sample size, processive run length of the motor, and distribution of track lengths. We introduce the use of a simple bootstrapping technique that allows for the quantification of measurement uncertainty and a Monte Carlo permutation resampling scheme for the measurement of statistical significance and the estimation of required sample size. In addition, we have found that, despite conventional wisdom, the measured characteristic run length is directly coupled to the characteristic track length that describes the microtubule length distribution. To be able to make comparisons between motility experiments performed on different track populations as well as make measurements of motility when motors and tracks cannot be simultaneously resolved, we have developed a theoretical framework for the determination of the effect that track length has on observed characteristic run lengths. This shows good agreement with in vitro motility experiments on two kinesin constructs walking on microtubule populations of different characteristic track lengths. PMID- 23790374 TI - An embryonic myosin isoform enables stretch activation and cyclical power in Drosophila jump muscle. AB - The mechanism behind stretch activation (SA), a mechanical property that increases muscle force and oscillatory power generation, is not known. We used Drosophila transgenic techniques and our new muscle preparation, the jump muscle, to determine if myosin heavy chain isoforms influence the magnitude and rate of SA force generation. We found that Drosophila jump muscles show very low SA force and cannot produce positive power under oscillatory conditions at pCa 5.0. However, we transformed the jump muscle to be moderately stretch-activatable by replacing its myosin isoform with an embryonic isoform (EMB). Expressing EMB, jump muscle SA force increased by 163% and it generated net positive power. The rate of SA force development decreased by 58% with EMB expression. Power generation is Pi dependent as >4 mM Pi was required for positive power from EMB. Pi increased EMB SA force, but not wild-type SA force. Our data suggest that when muscle expressing EMB is stretched, EMB is more easily driven backward to a weakly bound state than wild-type jump muscle. This increases the number of myosin heads available to rapidly bind to actin and contribute to SA force generation. We conclude that myosin heavy chain isoforms influence both SA kinetics and SA force, which can determine if a muscle is capable of generating oscillatory power at a fixed calcium concentration. PMID- 23790376 TI - Protein brownian rotation at the glass transition temperature of a freeze concentrated buffer probed by superparamagnetic nanoparticles. AB - For applications from food science to the freeze-thawing of proteins it is important to understand the often complex freezing behavior of solutions of biomolecules. Here we use a magnetic method to monitor the Brownian rotation of a quasi-spherical cage-shaped protein, apoferritin, approaching the glass transition Tg in a freeze-concentrated buffer (Tris-HCl). The protein incorporates a synthetic magnetic nanoparticle (Co-doped Fe3O4 (magnetite)). We use the magnetic signal from the nanoparticles to monitor the protein orientation. As T decreases toward Tg of the buffer solution the protein's rotational relaxation time increases exponentially, taking values in the range from a few seconds up to thousands of seconds, i.e., orders of magnitude greater than usually accessed, e.g., by NMR. The longest relaxation times measured correspond to estimated viscosities >2 MPa s. As well as being a means to study low-temperature, high-viscosity environments, our method provides evidence that, for the cooling protocol used, the following applies: 1), the concentration of the freeze-concentrated buffer at Tg is independent of its initial concentration; 2), little protein adsorption takes place at the interface between ice and buffer; and 3), the protein is free to rotate even at temperatures as low as 207 K. PMID- 23790375 TI - Submillisecond elastic recoil reveals molecular origins of fibrin fiber mechanics. AB - Fibrin fibers form the structural scaffold of blood clots. Thus, their mechanical properties are of central importance to understanding hemostasis and thrombotic disease. Recent studies have revealed that fibrin fibers are elastomeric despite their high degree of molecular ordering. These results have inspired a variety of molecular models for fibrin's elasticity, ranging from reversible protein unfolding to rubber-like elasticity. An important property that has not been explored is the timescale of elastic recoil, a parameter that is critical for fibrin's mechanical function and places a temporal constraint on molecular models of fiber elasticity. Using high-frame-rate imaging and atomic force microscopy based nanomanipulation, we measured the recoil dynamics of individual fibrin fibers and found that the recoil was orders of magnitude faster than anticipated from models involving protein refolding. We also performed steered discrete molecular-dynamics simulations to investigate the molecular origins of the observed recoil. Our results point to the unstructured alphaC regions of the otherwise structured fibrin molecule as being responsible for the elastic recoil of the fibers. PMID- 23790377 TI - Sugars communicate through water: oriented glycans induce water structuring. AB - Cells are coated with a glycocalyx-a layer of carbohydrate-containing biomolecules, such as glycoproteins. Although the structure and orientation of the cell-surface glycans are frequently regarded as being random, we have found, using alpha-1-acid glycoprotein and antitrypsin as model systems for surface glycans, that this is not the case. A glycoprotein monolayer was adsorbed onto hydrophilic and hydrophobic substrates. Surface-force measurements revealed that the orientation of the glycans with respect to the aqueous solution has a profound effect on the structure of vicinal water. The glycan antennae of the surface-adsorbed glycoproteins apparently impose an ordering on the water, resulting in a strong repulsive force over some tens of nanometers with superposed film-thickness transitions ranging from ~0.7 to 1.8 nm. When the glycan orientation is modified by chemical means, this long-range repulsion disappears. These results may provide an explanation as to why the multiantennary structure is ubiquitous in glycoproteins. Although direct, specific interactions between glycans and other biomolecules are essential for their functionality, these results indicate that glycans' long-range structuring of water may also influence their ability to interact with biomolecules in their vicinity. PMID- 23790378 TI - Protein-mediated antagonism between HIV reverse transcriptase ligands nevirapine and MgATP. AB - Nonnucleoside reverse transcriptase inhibitors (NNRTIs) play a central role in the treatment of AIDS, but their mechanisms of action are incompletely understood. The interaction of the NNRTI nevirapine (NVP) with HIV-1 reverse transcriptase (RT) is characterized by a preference for the open conformation of the fingers/thumb subdomains, and a reported variation of three orders of magnitude between the binding affinity of NVP for RT in the presence or absence of primer/template DNA. To investigate the relationship between conformation and ligand binding, we evaluated the use of methionine NMR probes positioned near the tip of the fingers or thumb subdomains. Such probes would be expected to be sensitive to changes in the local environment depending on the fractions of open and closed RT. Comparisons of the NMR spectra of three conservative mutations, I63M, L74M, and L289M, indicated that M63 showed the greatest shift sensitivity to the addition of NVP. The exchange kinetics of the M63 resonance are fast on the chemical shift timescale, but become slow in the presence of NVP due to the slow binding of RT with the inhibitor. The simplest model consistent with this behavior involves a rapid open/closed equilibrium coupled with a slow interaction of the inhibitor with the open conformation. Studies of RT in the presence of both NVP and MgATP indicate a strong negative cooperativity. Binding of MgATP reduces the fraction of RT bound to NVP, as indicated by the intensity of the NVP perturbed M230 resonance, and enhances the dissociation rate constant of the NVP, resulting in an increase of the open/closed interconversion rate, so that the M63 resonance moves into the fast/intermediate-exchange regime. Protein-mediated interactions appear to explain most of the affinity variation of NVP for RT. PMID- 23790379 TI - In vitro study of alpha-synuclein protofibrils by cryo-EM suggests a Cu(2+) dependent aggregation pathway. AB - The aggregation of alpha-synuclein is thought to play a role in the death of dopamine neurons in Parkinson's disease (PD). Alpha-synuclein transitions itself through an aggregation pathway consisting of pathogenic species referred to as protofibrils (or oligomer), which ultimately convert to mature fibrils. The structural heterogeneity and instability of protofibrils has significantly impeded advance related to the understanding of their structural characteristics and the amyloid aggregation mystery. Here, we report, to our knowledge for the first time, on alpha-synuclein protofibril structural characteristics with cryo electron microscopy. Statistical analysis of annular protofibrils revealed a constant wall thickness as a common feature. The visualization of the assembly steps enabled us to propose a novel, to our knowledge, mechanisms for alpha synuclein aggregation involving ring-opening and protofibril-protofibril interaction events. The ion channel-like protofibrils and their membrane permeability have also been found in other amyloid diseases, suggesting a common molecular mechanism of pathological aggregation. Our direct visualization of the aggregation pathway of alpha-synuclein opens up fresh opportunities to advance the understanding of protein aggregation mechanisms relevant to many amyloid diseases. In turn, this information would enable the development of additional therapeutic strategies aimed at suppressing toxic protofibrils of amyloid proteins involved in neurological disorders. PMID- 23790380 TI - Differences in beta-strand populations of monomeric Abeta40 and Abeta42. AB - Using homonuclear (1)H NOESY spectra, with chemical shifts, (3)JH(N)H(alpha) scalar couplings, residual dipolar couplings, and (1)H-(15)N NOEs, we have optimized and validated the conformational ensembles of the amyloid-beta 1-40 (Abeta40) and amyloid-beta 1-42 (Abeta42) peptides generated by molecular dynamics simulations. We find that both peptides have a diverse set of secondary structure elements including turns, helices, and antiparallel and parallel beta strands. The most significant difference in the structural ensembles of the two peptides is the type of beta-hairpins and beta-strands they populate. We find that Abeta42 forms a major antiparallel beta-hairpin involving the central hydrophobic cluster residues (16-21) with residues 29-36, compatible with known amyloid fibril forming regions, whereas Abeta40 forms an alternative but less populated antiparallel beta-hairpin between the central hydrophobic cluster and residues 9-13, that sometimes forms a beta-sheet by association with residues 35 37. Furthermore, we show that the two additional C-terminal residues of Abeta42, in particular Ile-41, directly control the differences in the beta-strand content found between the Abeta40 and Abeta42 structural ensembles. Integrating the experimental and theoretical evidence accumulated over the last decade, it is now possible to present monomeric structural ensembles of Abeta40 and Abeta42 consistent with available information that produce a plausible molecular basis for why Abeta42 exhibits greater fibrillization rates than Abeta40. PMID- 23790381 TI - Mechanical resistance in unstructured proteins. AB - Single-molecule pulling experiments on unstructured proteins linked to neurodegenerative diseases have measured rupture forces comparable to those for stable folded proteins. To investigate the structural mechanisms of this unexpected force resistance, we perform pulling simulations of the amyloid beta peptide (Abeta) and alpha-synuclein (alphaS), starting from simulated conformational ensembles for the free monomers. For both proteins, the simulations yield a set of rupture events that agree well with the experimental data. By analyzing the conformations occurring shortly before rupture in each event, we find that the mechanically resistant structures share a common architecture, with similarities to the folds adopted by Abeta and alphaS in amyloid fibrils. The disease-linked Arctic mutation of Abeta is found to increase the occurrence of highly force-resistant structures. Our study suggests that the high rupture forces observed in Abeta and alphaS pulling experiments are caused by structures that might have a key role in amyloid formation. PMID- 23790382 TI - Plasmolysis and cell shape depend on solute outer-membrane permeability during hyperosmotic shock in E. coli. AB - The concentration of chemicals inside the bacterial cytoplasm generates an osmotic pressure, termed turgor, which inflates the cell and is necessary for cell growth and survival. In Escherichia coli, a sudden increase in external concentration causes a pressure drop across the cell envelope that drives changes in cell shape, such as plasmolysis, where the inner and outer membranes separate. Here, we use fluorescence imaging of single cells during hyperosmotic shock with a time resolution on the order of seconds to examine the response of cells to a range of different conditions. We show that shock using an outer-membrane impermeable solute results in total cell volume reduction with no plasmolysis, whereas a shock caused by outer-membrane permeable ions causes plasmolysis immediately upon shock. Slowly permeable solutes, such as sucrose, which cross the membrane in minutes, cause plasmolysis to occur gradually as the chemical potential equilibrates. In addition, we quantify the detailed morphological changes to cell shape during osmotic shock. Nonplasmolyzed cells shrink in length with an additional lateral size reduction as the magnitude of the shock increases. Quickly plasmolyzing cells shrink largely at the poles, whereas gradually plasmolyzing cells invaginate along the cell cylinder. Our results give a comprehensive picture of the initial response of E. coli to hyperosmotic shock and offer explanations for seemingly opposing results that have been reported previously. PMID- 23790383 TI - Quantifying extrinsic noise in gene expression using the maximum entropy framework. AB - We present a maximum entropy framework to separate intrinsic and extrinsic contributions to noisy gene expression solely from the profile of expression. We express the experimentally accessible probability distribution of the copy number of the gene product (mRNA or protein) by accounting for possible variations in extrinsic factors. The distribution of extrinsic factors is estimated using the maximum entropy principle. Our results show that extrinsic factors qualitatively and quantitatively affect the probability distribution of the gene product. We work out, in detail, the transcription of mRNA from a constitutively expressed promoter in Escherichia coli. We suggest that the variation in extrinsic factors may account for the observed wider-than-Poisson distribution of mRNA copy numbers. We successfully test our framework on a numerical simulation of a simple gene expression scheme that accounts for the variation in extrinsic factors. We also make falsifiable predictions, some of which are tested on previous experiments in E. coli whereas others need verification. Application of the presented framework to more complex situations is also discussed. PMID- 23790384 TI - An excess-calcium-binding-site model predicts neurotransmitter release at the neuromuscular junction. AB - Despite decades of intense experimental studies, we still lack a detailed understanding of synaptic function. Fortunately, using computational approaches, we can obtain important new insights into the inner workings of these important neural systems. Here, we report the development of a spatially realistic computational model of an entire frog active zone in which we constrained model parameters with experimental data, and then used Monte Carlo simulation methods to predict the Ca(2+)-binding stoichiometry and dynamics that underlie neurotransmitter release. Our model reveals that 20-40 independent Ca(2+)-binding sites on synaptic vesicles, only a fraction of which need to bind Ca(2+) to trigger fusion, are sufficient to predict physiological release. Our excess Ca(2+)-binding-site model has many functional advantages, agrees with recent data on synaptotagmin copy number, and is the first (to our knowledge) to link detailed physiological observations with the molecular machinery of Ca(2+) triggered exocytosis. In addition, our model provides detailed microscopic insight into the underlying Ca(2+) dynamics during synapse activation. PMID- 23790385 TI - Mechanistic inquiry into the role of tissue remodeling in fibrotic lesions in human atrial fibrillation. AB - Atrial fibrillation (AF), the most common arrhythmia in humans, is initiated when triggered activity from the pulmonary veins propagates into atrial tissue and degrades into reentrant activity. Although experimental and clinical findings show a correlation between atrial fibrosis and AF, the causal relationship between the two remains elusive. This study used an array of 3D computational models with different representations of fibrosis based on a patient-specific atrial geometry with accurate fibrotic distribution to determine the mechanisms by which fibrosis underlies the degradation of a pulmonary vein ectopic beat into AF. Fibrotic lesions in models were represented with combinations of: gap junction remodeling; collagen deposition; and myofibroblast proliferation with electrotonic or paracrine effects on neighboring myocytes. The study found that the occurrence of gap junction remodeling and the subsequent conduction slowing in the fibrotic lesions was a necessary but not sufficient condition for AF development, whereas myofibroblast proliferation and the subsequent electrophysiological effect on neighboring myocytes within the fibrotic lesions was the sufficient condition necessary for reentry formation. Collagen did not alter the arrhythmogenic outcome resulting from the other fibrosis components. Reentrant circuits formed throughout the noncontiguous fibrotic lesions, without anchoring to a specific fibrotic lesion. PMID- 23790386 TI - A simplified implementation of the bubble analysis of biopolymer network pores. PMID- 23790387 TI - Response to "a simplified implementation of the bubble analysis of biopolymer networks pores". PMID- 23790388 TI - On phosphate release in actin filaments. PMID- 23790389 TI - Response to "on phosphate release in actin filaments". PMID- 23790390 TI - Comments on the article "rectification of SEMG as a tool to demonstrate synchronous motor unit activity during vibration". PMID- 23790391 TI - Comparison of exercises inducing maximum voluntary isometric contraction for the latissimus dorsi using surface electromyography. AB - The aim of this study was to compare muscular activation during five different normalization techniques that induced maximal isometric contraction of the latissimus dorsi. Sixteen healthy men participated in the study. Each participant performed three repetitions each of five types of isometric exertion: (1) conventional shoulder extension in the prone position, (2) caudal shoulder depression in the prone position, (3) body lifting with shoulder depression in the seated position, (4) trunk bending to the right in the lateral decubitus position, and (5) downward bar pulling in the seated position. In most participants, maximal activation of the latissimus dorsi was observed during conventional shoulder extension in the prone position; the percentage of maximal voluntary contraction was significantly greater for this exercise than for all other normalization techniques except downward bar pulling in the seated position. Although differences in electrode placement among various electromyographic studies represent a limitation, normalization techniques for the latissimus dorsi are recommended to minimize error in assessing maximal muscular activation of the latissimus dorsi through the combined use of shoulder extension in the prone position and downward pulling. PMID- 23790392 TI - Characteristics of human knee muscle coordination during isometric contractions in a standing posture: the effect of limb task. AB - Different functional roles for the hands have been demonstrated, however leg control is not as well understood. The purpose of the present study was to evaluate bilateral knee neuromuscular control to determine if the limb receiving greater attention would have more well-tuned control compared to an unattended limb. Surface electrodes were placed on seven muscles of each limb, before standing on two force platforms. Visual feedback was given of the forces and moments of the "focus limb," but not the "unattended limb." Static isometric forces were matched with their focus limb, requiring their unattended limb to push in the opposite direction, using a combination of forward-backward-medial lateral shear forces while muscle activity was collected bilaterally. There was a significant main effect for limb task (p = 0.02), with the medial hamstrings being more specific (p = 0.001) while performing the unattended limb and the lateral hamstring being more well-tuned (p = 0.007) while performing the focus limb task. The focus limb's medial and lateral gastrocnemius were principally active in the forwards direction, but only the unattended limb's lateral gastrocnemius was active in the backwards direction. Findings suggest unique neuromuscular control strategies are used for the legs depending on limb task. PMID- 23790393 TI - On evolutionary explanations of cognitive biases. AB - Apparently irrational biases such as overconfidence, optimism, and pessimism are increasingly studied by biologists, psychologists, and neuroscientists. Functional explanations of such phenomena are essential; we argue that recent proposals, focused on benefits from overestimating the probability of success in conflicts or practising self-deception to better deceive others, are still lacking in crucial regards. Attention must be paid to the difference between cognitive and outcome biases; outcome biases are suboptimal, yet cognitive biases can be optimal. However, given that cognitive biases are subjectively experienced by affected individuals, developing theory and collecting evidence on them poses challenges. An evolutionary theory of cognitive bias might require closer integration of function and mechanism, analysing the evolution of constraints imposed by the mechanisms that determine behaviour. PMID- 23790395 TI - Respiratory functions of burn patients undergoing decompressive laparotomy due to secondary abdominal compartment syndrome. AB - INTRODUCTION: The development of secondary abdominal compartment syndrome (ACS) is associated with multiple organ dysfunction. There is little information about the effects of decompressive laparotomy (DL) on respiratory function (RF) in burn patients developing ACS. PATIENTS AND METHODS: We retrospectively obtained data characterising RF from the database of an adult burn intensive care unit (BICU). Peak inspiratory pressure (Pip), PaO2/FiO2-ratio (P/F), static compliance (Cstat) and airway resistance (Raw) were analysed over the course of 60 h at 8 time points relative to DL. RESULTS: Thirty-five patients with ACS underwent DL with a mean percentage of total burned body surface area (TBSA) 39 +/- 23% and mean intra-abdominal pressure 33 +/- 7 mmHg. All patients presented with significantly deteriorating RF within 12h of DL (Pip 33 +/- 4 to 39 +/- 7 cm/H2O, p=0.003; P/F 232 +/- 59 to 160 +/- 55 mmHg, p<0.001, Cstat 34 +/- 5 to 26 +/- 6 mL/cmH2O, p<0.001; Raw 18 +/- 3 to 24 +/- 9 cm H2O/L/s, p=0.02). All these parameters improved significantly (p<0.001) after DL, regardless of the presence of inhalation injury or torso burns. Mortality was 71.4%. CONCLUSIONS: Variables characterising RF demonstrated a rapid deterioration before and a significant and sustained improvement after DL in burn patients developing ACS. Despite these respiratory improvements, DL was associated with low survival rates. Secondary ACS remains a challenge in burn patients and thus warrants particular attention during intensive care treatment. PMID- 23790396 TI - Dual-imaging system for burn depth diagnosis. AB - Currently, determination of burn depth and healing outcomes has been limited to subjective assessment or a single modality, e.g., laser Doppler imaging. Such measures have proven less than ideal. Recent developments in other non-contact technologies such as optical coherence tomography (OCT) and pulse speckle imaging (PSI) offer the promise that an intelligent fusion of information across these modalities can improve visualization of burn regions thereby increasing the sensitivity of the diagnosis. In this work, we combined OCT and PSI images to classify the degree of burn (superficial, partial-thickness and full-thickness burns). Algorithms were developed to integrate and visualize skin structure (with and without burns) from the two modalities. We have completed the proposed initiatives by employing a porcine burn model and compiled results that attest to the utility of our proposed dual-modal fusion approach. Computer-derived data indicating the varying burn depths were validated through immunohistochemical analysis performed on burned skin tissue. The combined performance of OCT and PSI modalities provided an overall ROC-AUC=0.87 (significant at p<0.001) in classifying different burn types measured after 1-h of creating the burn wounds. Porcine model studies to assess feasibility of this dual-imaging system for wound tracking are underway. PMID- 23790394 TI - Mechanobiology of bone marrow stem cells: from myosin-II forces to compliance of matrix and nucleus in cell forms and fates. AB - Adult stem cells and progenitors are of great interest for their clinical application as well as their potential to reveal deep sensitivities to microenvironmental factors. The bone marrow is a niche for at least two types of stem cells, and the prototype is the hematopoietic stem cell/progenitors (HSC/Ps), which have saved many thousands of patients for several decades now. In bone marrow, HSC/Ps interact functionally with marrow stromal cells that are often referred to as mesenchymal stem cells (MSCs) or derivatives thereof. Myosin and matrix elasticity greatly affect MSC function, and these mechanobiological factors are now being explored with HSC/Ps both in vitro and in vivo. Also emerging is a role for the nucleus as a mechanically sensitive organelle that is semi-permeable to transcription factors which are modified for nuclear entry by cytoplasmic mechanobiological pathways. Since therapies envisioned with induced pluripotent stem cells and embryonic stem cells generally involve in vitro commitment to an adult stem cell or progenitor, a very deep understanding of stem cell mechanobiology is essential to progress with these multi-potent cells. PMID- 23790397 TI - Gene correction of a duchenne muscular dystrophy mutation by meganuclease enhanced exon knock-in. AB - Duchenne muscular dystrophy (DMD) is a severe inherited, muscle-wasting disorder caused by mutations in the DMD gene. Gene therapy development for DMD has concentrated on vector-based DMD minigene transfer, cell-based gene therapy using genetically modified adult muscle stem cells or healthy wild-type donor cells, and antisense oligonucleotide-induced exon-skipping therapy to restore the reading frame of the mutated DMD gene. This study is an investigation into DMD gene targeting-mediated correction of deletions in human patient myoblasts using a target-specific meganuclease (MN) and a homologous recombination repair matrix. The MN was designed to cleave within DMD intron 44, upstream of a deletion hotspot, and integration-competent lentiviral vectors expressing the nuclease (LVcMN) were generated. MN western blotting and deep gene sequencing for LVcMN induced non-homologous end-joining InDels (microdeletions or microinsertions) confirmed efficient MN expression and activity in transduced DMD myoblasts. A homologous repair matrix carrying exons 45-52 (RM45-52) was designed and packaged into integration-deficient lentiviral vectors (IDLVs; LVdRM45-52). After cotransduction of DMD myoblasts harboring a deletion of exons 45 to 52 with LVcMN and LVdRM45-52 vectors, targeted knock-in of the RM45-52 region in the correct location in DMD intron 44, and expression of full-length, correctly spliced wild type dystrophin mRNA containing exons 45-52 were observed. This work demonstrates that genome surgery on human DMD gene mutations can be achieved by MN-induced locus-specific genome cleavage and homologous recombination knock-in of deleted exons. The feasibility of human DMD gene repair in patient myoblasts has exciting therapeutic potential. PMID- 23790398 TI - Autophagy as an immune effector against tuberculosis. AB - The now well-accepted innate immunity paradigm that autophagy acts as a cell autonomous defense against intracellular bacteria has its key origins in studies with Mycobacterium tuberculosis, an important human pathogen and a model microorganism infecting macrophages. A number of different factors have been identified that play into the anti-mycobacterial functions of autophagy, and recent in vivo studies in the mouse model of tuberculosis have uncovered additional anti-inflammatory and tissue-sparing functions of autophagy. Complementing these observations, genome wide association studies indicate a considerable overlap between autophagy, human susceptibility to mycobacterial infections and predisposition loci for inflammatory bowel disease. Finally, recent studies show that autophagy is an important regulator and effector of IL-1 responses, and that autophagy intersects with type I interferon pathology modulating responses. PMID- 23790399 TI - Ten-year experience on 644 patients undergoing single-port (uniportal) video assisted thoracoscopic surgery. AB - BACKGROUND: Uniportal video-assisted thoracic surgery (VATS) technique has been described both for diagnostic and therapeutic indications. Outcomes after uniportal VATS have never been reported in large series. METHODS: Between January 2000 and December 2010, 644 uniportal VATS procedures (334 male and 310 female patients; median age, 55.5 years; range, 16 to 85) were performed by a single surgeon. This figure represents 27.7% of all the thoracic surgical procedures in the study period (2,369). Of the 644 uniportal VATS, 329 (51.1%) were diagnostic procedures for pleural conditions. Of the remaining 315 uniportal VATS procedures, 14 (2.2%) were performed for pre-thoracotomy exploration for lung cancer, and 115 (17.8%) for miscellaneous conditions including diagnosis of mediastinal masses. In addition, 186 nonanatomic wedge resections (28.9% of the total uniportal VATS procedures) were performed for pulmonary conditions; of these, 146 were done for pulmonary nodules. RESULTS: Median operative time was 18 and 22 minutes for uniportal VATS for diagnostic non-pulmonary indications and for wedge resections, respectively. Out of 644 patients, conversion to either 2 or 3 port VATS or minithoracotomy was necessary in 3.7% of the patients, often due to incomplete lung collapse (92%). Inclusive of the day of insertion, the chest drain was removed after a median of 4.3 (range, 2 to 20) and 2.4 days (range, 0 to 6) after uniportal VATS for pleural effusions and uniportal VATS lung wedge resections, respectively. Mortality and major morbidity after uniportal VATS was 0.6% and 2.8%, respectively. All deaths reported after uniportal VATS were for pleural effusions. Inclusive of the operative day, median hospitalization after surgery for uniportal VATS for pleural effusions and for wedge resections were 5.3 and 3.4 days, respectively. CONCLUSIONS: In our experience, uniportal VATS was performed in one third of our surgical candidates with limited operative time, a very low conversion rate to conventional VATS or minithoracotomy, a very low morbidity and mortality, and, short hospitalization. Uniportal VATS is an underappreciated procedure that can be reliably used in the diagnostic pathways of several intrathoracic conditions and to resect small pulmonary nodules with either diagnostic or therapeutic purposes. As such, uniportal VATS represents a consolidated addition to the surgical armamentarium. PMID- 23790400 TI - Effects of intrahippocampal injection of ghrelin on spatial memory in PTZ-induced seizures in male rats. AB - Ghrelin (gh) is a peptide hormone that may affect learning and memory. There is some evidence that ghrelin can have antiepileptic effects. So we decided to investigate the possible effects of ghrelin on spatial memory following PTZ induced seizures in male rats. Ninety male rats were divided into 9 groups including control, saline, ghrelin (0.3, 1.5 or 3 nmol) and pentylenetetrazol (PTZ, 50 mg/kg, i.p.) plus saline or ghrelin (0.3, 1.5 or 3 nmol). All groups were trained in Morris water maze (MWM) for two consecutive days. Our results showed that ghrelin significantly improves spatial memory at the doses of 1.5 or 3 nmol (P<0.05) in normal rats. We also demonstrated the significant impairment of spatial memory in PTZ group (P<0.05). Intrahippocampal injection of ghrelin at the dose of 3 nmol significantly improved spatial memory in PTZ+gh group compared to PTZ group (P<0.05). These findings suggest that ghrelin as a neuropeptide can improve spatial memory in PTZ-treated rats. PMID- 23790401 TI - The good of non-sentient entities: Organisms, artifacts, and synthetic biology. AB - Synthetic organisms are at the same time organisms and artifacts. In this paper we aim to determine whether such entities have a good of their own, and so are candidates for being directly morally considerable. We argue that the good of non sentient organisms is grounded in an etiological account of teleology, on which non-sentient organisms can come to be teleologically organized on the basis of their natural selection etiology. After defending this account of teleology, we argue that there are no grounds for excluding synthetic organisms from having a good also grounded in their teleological organization. However, this comes at a cost; traditional artifacts will also be seen as having a good of their own. We defend this as the best solution to the puzzle about what to say about the good of synthetic organisms. PMID- 23790402 TI - Cardiothoracic-themed core surgical training programs in Scotland. AB - Cardiothoracic surgery generates an impression that only the most committed should pursue it. The book TSRA Review of Cardiothoracic Surgery (Thoracic Surgery Residents Association) is organized around topics core surgical trainees (ie, residents) are expected to understand and master, particularly as surgical selection and training has undergone recent change. PMID- 23790404 TI - Identification of metastatic nodal disease in a phase 1 dose-escalation trial of intraoperative sentinel lymph node mapping in non-small cell lung cancer using near-infrared imaging. AB - OBJECTIVES: Early-stage non-small cell lung cancer (NSCLC) has a high recurrence rate and poor 5-year survival, particularly if lymph nodes are involved. Our objective was to perform a dose-escalation study to assess safety and feasibility of intraoperative near-infrared (NIR) fluorescence imaging to identify the first tumor-draining lymph nodes (ie, sentinel lymph nodes [SLNs] in patients with NSCLC). METHODS: A-dose escalation phase 1 clinical trial assessing real-time NIR imaging after peritumoral injection of 3.8 to 2500 MUg indocyanine green (ICG) was initiated in patients with suspected stage I/II NSCLC. Visualization of lymphatic migration, SLN identification, and adverse events were recorded. RESULTS: Thirty-eight patients underwent ICG injection and NIR imaging via thoracotomy (n = 18) or thoracoscopic imaging (n = 20). SLN identification increased with ICG dose, with fewer than 25% SLNs detected in dose cohorts of 600 MUg or less versus 89% success at 1000 MUg or greater. Twenty-six NIR(+) SLNs were identified in 15 patients, with 7 NIR(+) SLNs (6 patients) harboring metastatic disease on histologic analysis. Metastatic nodal disease was never identified in patients with a histologically negative NIR(+) SLN. No adverse reactions were noted. CONCLUSIONS: NIR-guided SLN identification with ICG was safe and feasible in this initial dose-escalation trial. ICG doses greater than 1000 MUg yielded nearly 90% intrathoracic SLN visualization, with the presence or absence of metastatic disease in the SLN directly correlating with final nodal status of the lymphadenectomy specimen. Further studies are needed to optimize imaging parameters and confirm sensitivity and specificity of SLN mapping in NSCLC using this promising imaging technique. PMID- 23790405 TI - Exploring an optimal vector autoregressive model for multi-channel pulmonary sound data. AB - The purpose of this study is to find a useful mathematical model for multi channel pulmonary sound data. Vector auto-regressive (VAR) model schema is adopted and the best set of arguments, namely, the order and sample size of the model and the sampling rate of the data, is aimed to be determined. Both conventional prediction error criteria and a set of three new criteria which are derived specifically for pulmonary sound signals are used to evaluate the success of the model. In terms of these criteria, the second order 250-point model is selected to be the most descriptive VAR model for 14-channel pulmonary sound data. The preferred sampling rate is the original data acquisition rate, which is 9600 samples per second. The effect of normalization of the data with respect to the air flow is also examined. Six normalization schemes are implemented on the data prior to the model fit, and the resulting model parameters are examined in terms of the proposed criterion measures. It is concluded that normalization with respect to flow is not necessary prior to the VAR modeling of pulmonary sound data. PMID- 23790406 TI - Assessment of acrosome state in boar spermatozoa heads using n-contours descriptor and RLVQ. AB - This paper proposes a method for assessing the acrosome state of boar spermatozoa heads using digital image processing. We use gray level images in which spermatozoa have been labeled as acrosome-intact or acrosome damaged using the information of a coupled fluorescent image. The heads are segmented obtaining the outer head contour. A set of "n" inner contours separated by a logarithmic distance function is calculated later. For each point of the, in this case, seven contours a number of local texture features are computed. We have compared the classification performance of Relevance Learning Vector Quantization, class conditional means and KNN, employing cross-validation for the evaluation. Gradient magnitude data offer the best result with an overall test error of only 1%. This result outperforms previously applied methods and suggests this approach as an interesting automatized approach to this veterinarian problem. PMID- 23790407 TI - Ankle neurothekeoma: a case report. AB - Neurothekeoma is a rare, benign, cutaneous tumor of nerve sheath origin that is also termed benign nerve sheath myxoma. This tumor is usually asymptomatic and grows slowly. Neurothekeoma is typically found in young adults and seldom occurs in children. It is most commonly located in the head, neck, and upper extremity and extremely rarely found in the lower leg. We report a rare case of ankle neurothekeoma in a child, with a review of the related published data. PMID- 23790408 TI - A variety of variables. AB - In designing studies and developing plans for analyses, we must consider which tests are appropriate for the types of variables we are using. Here I describe the types of variables available to us, and I briefly consider the appropriate tools to use in their analysis. PMID- 23790409 TI - "C" is for "collaboration". PMID- 23790410 TI - Dairy products: how they fit in nutritionally adequate diets. AB - Individual diet modeling with linear programming recently provided evidence that plant-based products, fish, and fresh dairy products consumption should be increased in the French population to reach nutrient-based recommendations. The aim of our study was to estimate the number of portions of the different milk based food categories fitting into nutritionally adequate diets. Starting from the diet observed for each adult in the 1999 French Enquete Individuelle et Nationale sur les Consommations Alimentaires survey (n=1,171), an isocaloric nutritionally adequate diet was modeled that simultaneously met a whole set of nutrient constraints (based on nutrient recommendations) while deviating the least from the observed diet food content. Variations in weight, energy, and nutrients between observed and modeled diets were calculated for each food group (n=7), with a focus on milk-based products (n=4 categories). The diet optimization process increased the weights of three food groups: fruit and vegetables (+62%), starchy foods (+37%), and dairy products (+19%). Across milk based food categories, the optimization increased yogurts (+60%) and milk (+17%) and decreased cheeses (-48%) without change to milk desserts. Cheeses represented one out of two consumed portions of milk-based products in observed diets, whereas in modeled diets cheeses, milk, and yogurts each represented about one portion per day. Milk desserts were similar before and after optimization, at approximately one portion per week. These results confirm that a large increase in intake of plant-based products is needed. They show that rebalancing the intake of milk-based products in favor of the least energy-dense ones (ie, yogurts and milk) will help individuals in this population reach nutritional adequacy. PMID- 23790411 TI - Position of the Academy of Nutrition and Dietetics: the role of nutrition in health promotion and chronic disease prevention. AB - It is the position of the Academy of Nutrition and Dietetics that primary prevention is the most effective and affordable method to prevent chronic disease, and that dietary intervention positively impacts health outcomes across the life span. Registered dietitians and dietetic technicians, registered are critical members of health care teams and are essential to delivering nutrition focused preventive services in clinical and community settings, advocating for policy and programmatic initiatives, and leading research in disease prevention and health promotion. Health-promotion and disease-prevention strategies are effective at reducing morbidity and mortality and improving quality of life, and have a significant impact on the leading causes of disease. By applying these principles within a social ecological theoretical framework, positive influence can be applied across the spectrum of engagement: at intrapersonal, interpersonal, institutional, community, and public policy levels. Through the application of efficacious and cost-effective interventions, registered dietitians and dietetic technicians, registered, can positively impact public health as well as health outcomes for the individuals that they counsel. This position paper supports the "Practice Paper of the Academy of Nutrition and Dietetics: The Role of Nutrition in Health Promotion and Chronic Disease Prevention" published on the Academy's website at: www.eatright.org/positions. PMID- 23790412 TI - Practice paper of the Academy of Nutrition and Dietetics abstract: ethical and legal issues of feeding and hydration. AB - It is the position of the Academy of Nutrition and Dietetics that individuals have the right to request or refuse nutrition and hydration as medical treatment. Registered dietitians should work collaboratively as part of an interprofessional team to make recommendations on providing, withdrawing, or withholding nutrition and hydration in individual cases and serve as active members of institutional ethics committees. This practice paper provides a proactive, integrated, systematic process to implement the Academy's position. The position and practice papers should be used together to address the history and supporting information of ethical and legal issues of feeding and hydration identified by the Academy. Elements of collaborative ethical deliberation are provided for pediatrics and adults and in different conditions. The process of ethical deliberation is presented with the roles and responsibilities of the registered dietitian and the dietetic technician, registered. Understanding the importance and applying concepts dealing with cultural values and religious diversity is necessary to integrate clinical ethics into nutrition care. Incorporating screening for quality-of-life goals is essential before implementing the Nutrition Care Process and improving health literacy with individual interactions. Developing institution-specific policies and procedures is necessary to accelerate the practice change with artificial nutrition, clinical ethics, and quality improvement projects to determine best practice. This paper supports the "Position of the Academy of Nutrition and Dietetics: Ethical and Legal Issues of Feeding and Hydration" published in the June 2013 issue of the Journal of the Academy of Nutrition and Dietetics. PMID- 23790413 TI - Practice paper of the Academy of Nutrition and Dietetics abstract: the role of nutrition in health promotion and chronic disease prevention. AB - Food intake, lifestyle behaviors, and obesity are linked to the development of chronic diseases such as type 2 diabetes, certain cancers, and cardiovascular diseases. It is recognized that physical and social environment influences individuals' behaviors, and some population subgroups such as racial/ethnic minorities and individuals with low socioeconomic status or limited literacy or language abilities seem to be especially vulnerable to disparities in disease risk factors, disease prevalence, or health outcomes. Certain life cycle phases appear to be especially important for health promotion and disease prevention as the development of chronic diseases can take several decades. Such complex health issues often require system-wide, multifactorial, and multidisciplinary solutions. Social ecological models, with approaches spanning from individual level to macro policy level, can provide registered dietitians (RDs) and dietetic technicians, registered (DTRs) with a comprehensive framework to promote health and to prevent chronic diseases. Furthermore, the Nutrition Care Process can be utilized in carrying out the health promotion and disease prevention efforts. RDs and DTRs have the training and requisite skills to be leaders and active members of multidisciplinary teams to promote health and prevent chronic diseases across the life span. The position of the Academy of Nutrition and Dietetics states that primary prevention is the most effective, affordable method to prevent chronic disease, and that dietary intervention positively impacts health outcomes across the life span. RDs and DTRs are critical members of health care teams and are essential to delivering nutrition-focused preventive services in clinical and community settings, advocating for policy and programmatic initiatives, and leading research in disease prevention and health promotion. In concordance with the Academy's position, this practice paper provides an overview of practice examples, effective program components, and a comprehensive range of health promotion and chronic disease prevention strategies for RDs and DTRs. This paper supports the "Position of the Academy of Nutrition and Dietetics: The Role of Nutrition in Health Promotion and Chronic Disease Prevention" published in the July 2013 Journal of the Academy of Nutrition and Dietetics. PMID- 23790414 TI - Are there evidence-based dietary interventions for multiple sclerosis? PMID- 23790415 TI - Break-induced replication: functions and molecular mechanism. AB - Break-induced replication (BIR) is the pathway of homologous recombination (HR) conserved from phages to eukaryotes that serves to repair DNA breaks that have only one end. BIR contributes to the repair of broken replication forks and allows telomere lengthening in the absence of telomerase. Nonallelic BIR may lead to translocations and other chromosomal rearrangements. In addition, BIR initiated at sites of microhomology can generate copy number variations (CNVs) and complex chromosomal changes. The level of mutagenesis associated with DNA synthesis in BIR is significantly higher than during normal replication. These features make BIR a likely pathway to promote bursts of genetic changes that fuel cancer progression and evolution. PMID- 23790416 TI - [Surgical management of descending necrotizing mediastinitis]. AB - INTRODUCTION: Descending necrotizing mediastinitis (DNM) is a serious infection which occurs as a complication of oropharyngeal infection. Its surgical management and the routine transthoracic approach remain controversial. In this article we report our experience in the management of this disease, and review the different surgical approaches that have been reported in the medical literature. MATERIAL AND METHODS: A retrospective review was made of the clinical records of 29 patients treated between 1988 and 2009. Several demographic variables were analyzed, origin of the initial infection, stage of the disease according to Endo's classification, surgical technique and outcome. RESULTS: Surgical treatment consisted of both cervical and mediastinal drainage and radical debridement. The mediastinal drainage was made through a transcervical approach in 10 cases and transthoracic in 19, depending on the extent of the mediastinitis. The outcome was satisfactory in 24 patients and 5 died (mortality 17.2%). CONCLUSIONS: According to our results and the conclusions of the main authors, we recommend a prompt and aggressive surgery with a transthoracic approach in cases of widespread DNM. PMID- 23790417 TI - Cloning, expression, and purification of the hemolysin/cytolysin (HlyE antigen) from Salmonella enterica serovar Typhi: potential application for immunoassay development. AB - The hemolysin (HlyE) protein of Salmonella enterica serovar Typhi was reported to be antigenic. This work describes the cloning, expression, and purification of a hexahistidine-tagged HlyE protein under native conditions. Immunoblot analysis and a competitive enzyme-linked immunosorbent assay using sera from typhoid patients showed the presence of HlyE-specific antibodies in circulation. PMID- 23790418 TI - Study on Salmonella Typhi occurrence in gallbladder of patients suffering from chronic cholelithiasis-a predisposing factor for carcinoma of gallbladder. AB - Cholelithiasis is frequently associated with carcinoma of gallbladder, and the presence of Salmonella Typhi in gallbladder of patients suffering from cholelithiasis is implicated as a predisposing factor for carcinogenesis. This study was conducted on patients suffering from chronic cholelithiasis from a region in North India-endemic area for enteric fever with high incidence of gallstones and gallbladder cancer. Since culture studies rarely reveal the chronic Salmonella Typhi persistence, we use PCR assay to specifically amplify the H1-d flagellin gene sequence homologous with Salmonella Typhi. Seven cases (17.5%), none of which were positive for culture, showed positive PCR results for Salmonella Typhi, 4 (10%) of which were tissue, 2 bile (5%), and 1 gallstone (2.5%). The chronic existence of Salmonella Typhi in gallbladder disease was confirmed. Thus, the study would indicate the importance of vaccination so as to prevent chronic infection and need for early diagnostic tools to prevent any further complications. PMID- 23790419 TI - Prevalence, impact, and treatment of death rattle: a systematic review. AB - CONTEXT: Death rattle, or respiratory tract secretion in the dying patient, is a common and potentially distressing symptom in dying patients. Health care professionals often struggle with this symptom because of the uncertainty about management. OBJECTIVES: To give an overview of the current evidence on the prevalence of death rattle in dying patients, its impact on patients, relatives, and professional caregivers, and the effectiveness of interventions. METHODS: We systematically searched the databases PubMed, Embase, CINAHL, PsychINFO, and Web of Science. English-language articles containing original data on the prevalence or impact of death rattle or on the effects of interventions were included. RESULTS: We identified 39 articles, of which 29 reported on the prevalence of death rattle, eight on its impact, and 11 on the effectiveness of interventions. There is a wide variation in reported prevalence rates (12%-92%; weighted mean, 35%). Death rattle leads to distress in both relatives and professional caregivers, but its impact on patients is unclear. Different medication regimens have been studied, that is, scopolamine, glycopyrronium, hyoscine butylbromide, atropine, and/or octreotide. Only one study used a placebo group. There is no evidence that the use of any antimuscarinic drug is superior to no treatment. CONCLUSION: Death rattle is a rather common symptom in dying patients, but it is doubtful if patients suffer from this symptom. Current literature does not support the standard use of antimuscarinic drugs in the treatment of death rattle. PMID- 23790420 TI - The effect of night extension orthoses following surgical release of Dupuytren contracture: a single-center, randomized, controlled trial. AB - PURPOSE: To clarify the efficacy and detrimental effects of orthoses used to maintain finger extension following surgical release of Dupuytren contracture. METHODS: We conducted a single-center, randomized, controlled trial to investigate the effect of night extension orthoses on finger range of motion and hand function for 3 months following surgical release of Dupuytren contracture. We also wanted to determine how well finger extension was maintained in the total sample. We randomized 56 patients to receive a night extension orthosis plus hand therapy (n = 26) or hand therapy alone (n = 30). The primary outcome was total active extension of the operated fingers ( degrees ). Secondary outcomes were total active flexion of the operated fingers ( degrees ), active distal palmar crease (cm), grip strength (kg), and self-reported hand function using the Disabilities of the Arm, Shoulder, and Hand questionnaire (0-100 scale). RESULTS: There were no statistically significant differences between the no-orthosis and orthosis groups for total active extension or for any of the secondary outcomes. Between the first postoperative measure and 3 months after surgery, 62% of little fingers had maintained or improved total active extension. CONCLUSIONS: The use of a night extension orthosis in combination with standard hand therapy has no greater effect on maintaining finger extension than hand therapy alone in the 3 months following surgical release of Dupuytren contracture. Our results indicate that the practice of providing every patient with a night extension orthosis following surgical release of Dupuytren contracture may not be justified except for cases in which extension loss occurs after surgery. Our results also challenge clinicians to research ways of maintaining finger extension in a greater number of patients. PMID- 23790421 TI - The Thompson procedure for chronic mallet finger deformity. AB - PURPOSE: To evaluate the outcomes of the Thompson procedure for chronic mallet finger deformity and review the utility of this procedure. METHODS: Seven cases of chronic mallet finger with a swan neck deformity were treated by the Thompson procedure. Ranges of motion for the distal interphalangeal (DIP) and proximal interphalangeal (PIP) joints were measured, and complications were investigated at the final examination. Patients were evaluated using the criteria reported by Abouna and Brown. RESULTS: Four patients were men, and 3 were women. The average age at the time of surgery was 44 years (range, 25 to 71 y). The middle finger was affected in 4 cases, and the index, ring, and small finger were involved in 1 case each. The average extensor lag on the DIP joint was 42 degrees (range, 35 degrees to 50 degrees ). All cases were treated with the Thompson procedure. The swan neck deformity was corrected in all cases. The average motion at the final examination was -4 degrees (range, -30 degrees to 0 degrees ) in extension and 91 degrees (range, 85 degrees to 110 degrees ) in flexion for the PIP joint and -5 degrees (range, -10 degrees to 0 degrees ) in extension and 63 degrees (range, 45 degrees to 85 degrees ) in flexion for the DIP joint. A buttonhole deformity and a dimple at the proximal tied end of the graft were seen in 1 case. Assessment by the criteria of Abouna and Brown revealed that 6 of 7 patients were categorized as cured and one as improved. No patient was categorized as unchanged. CONCLUSIONS: The procedure provides a predictable method for correcting loss of DIP joint extension with or without PIP joint hyperextension. We believe that the Thompson procedure is an effective technique for the salvage, following failed treatment, of a closed mallet injury with an associated swan neck deformity. PMID- 23790422 TI - Annular ligament reconstruction using the distal tendon of the superficial head of the brachialis muscle: an anatomical feasibility study. AB - PURPOSE: To evaluate the potential use of the longer tendinous insertion of the superficial head of the brachialis as a local graft source for elbow annular ligament reconstruction. METHODS: The tendon of the superficial head of the brachialis muscle was harvested as a distally based graft in 24 unmatched, fresh frozen cadaveric specimens. The tendon insertion on the proximal ulna was preserved, and the graft was passed around the proximal radius to recreate the annular ligament. We measured the total length of the graft, the length of graft required to approximate the posterior insertion of the annular ligament reconstruction, and the length of excess graft. RESULTS: The average length of the superficial head of the brachialis muscle tendon available for use in reconstruction was 81 mm. The average length of tendon required to approximate the posterior anatomical insertion of the annular ligament was 69 mm. The average length of excess tendon was 12 mm. The tendon graft of the superficial head permitted potential annular ligament reconstruction in all specimens. CONCLUSIONS: A distally based tendon graft reconstruction of the annular ligament of the elbow using the tendon of the superficial head of the brachialis muscle would be feasible in most patients, based on this anatomic study. Future studies should consider the biomechanical stability of this ligament reconstruction, choices of optimal posterior graft fixation, and clinical outcomes. CLINICAL RELEVANCE: Incompetence of the annular ligament may cause persisting instability of the proximal radius requiring ligament reconstruction. The anatomic feasibility of using the distal tendon of the superficial head of the brachialis muscle as a distally based graft source is evaluated for annular ligament reconstruction. PMID- 23790423 TI - In vivo 3-dimensional analysis of dorsal intercalated segment instability deformity secondary to scapholunate dissociation: a preliminary report. AB - PURPOSE: To investigate in vivo 3-dimensional patterns of dorsal intercalated segment instability deformity resulting from scapholunate dissociation. METHODS: We studied 6 patients with stage IV scapholunate dissociation in which there were complete tears of the scapholunate interosseous ligament and dorsal intercalated segment instability deformity. Of these, 3 patients had a dorsally displaced distal radius malunion, a condition known to aggravate or produce a dorsal intercalated segment instability deformity. With the wrist in neutral, we created 3-dimensional bone models of the wrists from computed tomography. We calculated centroid locations of each carpal and the rotational angle of the scaphoid and lunate relative to the radius and compared them with those of 6 normal subjects. The joint contact area was visualized to evaluate congruity of the radiocarpal and midcarpal joints. RESULTS: In the scapholunate dissociated wrists, the scaphoid translated dorsally and radially with rotation in the direction of flexion and pronation. The lunate was extended and supinated. The capitate, trapezoid, and trapezium translated dorsally. Contact area of the radioscaphoid joint shifted dorsoradially owing to dorsoradial subluxation of the scaphoid proximal pole. Congruity was retained in the radiolunate, lunocapitate, and scaphotrapeziotrapezoid joints. In the malunion cases, the scaphoid and distal carpal rows translated more dorsally along dorsal angulation of the distal radius; therefore, incongruity of the radioscaphoid joint became more pronounced. CONCLUSIONS: Dorsoradial subluxation of the scaphoid proximal pole over the dorsal rim of the radius led to incongruity of the radioscaphoid joint. Dorsal translation of the distal carpal row occurred with maintaining congruency of the radiolunate, lunocapitate, and scaphotrapeziotrapezoid joints. These results suggest that for realignment of the carpal axis of an advanced scapholunate dissociated wrist, we should restore scapholunate rotational malalignment and reduce the dorsally translated distal carpal row back to the anatomical position. PMID- 23790424 TI - Physician value. PMID- 23790425 TI - Treatment of the "pink pulseless hand" in pediatric supracondylar humerus fractures. PMID- 23790426 TI - Toe-to-hand transfer: evolving indications and relevant outcomes. AB - Toe-to-hand transfer is indicated for many types of congenital and traumatic thumb absences. This review will highlight the applications of toe-to-hand transfer and their functional, aesthetic, and psychosocial outcomes. Despite its technical complexity, toe to hand reconstruction techniques can provide an elegant option to restore function for patients with difficult hand disabilities. PMID- 23790427 TI - Letter regarding "Effect of osteochondroma location on forearm deformity in patients with multiple hereditary osteochondromatosis". PMID- 23790428 TI - In reply. PMID- 23790429 TI - Letter regarding "Scaphocapitate arthrodesis for treatment of scapholunate instability in manual workers". PMID- 23790430 TI - In reply. PMID- 23790431 TI - Identifying and measuring heterogeneity across the studies in meta-analysis. PMID- 23790432 TI - In reply. PMID- 23790433 TI - Letter regarding "Functional outcome of open reduction of chronic perilunate injuries". PMID- 23790434 TI - In reply. PMID- 23790435 TI - Family planning intentions: a qualitative exploration of postpartum women of Mexican descent in North Carolina. AB - BACKGROUND: North Carolina has one of the fastest growing Mexican-American populations, yet health care providers have minimal information on how to address the family planning needs of this population. STUDY DESIGN: We conducted semistructured interviews with postpartum Mexican-American women, aged 18-35 years, within 1 month of delivery. Salient themes were identified, coded and analyzed. RESULTS: Twenty women were interviewed. The majority had firmly held family size intentions: most desired to have 2 to 4 children with 2 to 5 years between births. Partners' preferences and the family size in which the participant was raised were factors that most influenced their family size preference. First-generation Mexican-American participants were more likely to have a partner whose intentions are influenced by the gender(s) of their children compared with participants born in Mexico. Participants desired longer intrapartum intervals for optimal infant development, with financial considerations cited less frequently. CONCLUSION: Postpartum women of Mexican descent articulate consistent family planning intentions. Partners' desires may challenge the achievement of these intentions. Providers can encourage the most effective forms of contraception to promote ideal and intended family size. PMID- 23790436 TI - One-year continuation of the etonogestrel contraceptive implant in women with postabortion or interval placement. AB - BACKGROUND: Our study investigated whether women with etonogestrel implant placement in the immediate postabortion period have similar continuation rates to women with interval placement. STUDY DESIGN: This is a prospective cohort study of women at Boston Medical Center. We compared 1-year continuation rates in women who had immediate postabortion placement to interval placement using Cox proportional hazard models. RESULTS: One hundred five women were enrolled, 53 in the abortion and 52 in the interval group. There were two losses to follow-up leaving 103 women for analysis. The overall 1-year continuation rate was 74.8%, with 68.6% postabortion continuation and 80.8% interval continuation. The risk of discontinuation in women with postabortion placement was higher but not statistically different than women with interval placement (unadjusted hazard ratio: 1.79, 95% confidence interval: 0.81-3.96). CONCLUSION: Overall etonogestrel implant continuation was acceptable with similar rates for postabortion and interval placement. For women who want a contraceptive implant after an abortion, immediate placement should be available. PMID- 23790437 TI - Transfection and intracellular trafficking properties of carbon dot-gold nanoparticle molecular assembly conjugated with PEI-pDNA. AB - The work employs carbon dot (CD) which has been emerging as a fluorescent nanomaterial with excellent biocompatibility and perceived as a promising alternative to quantum dot (QD), to monitor the association/dissociation of polymeric carrier/plasmid DNA (pDNA) complex during transfection. To shed light on the underlying post-endosomal events and provide the insight to design rational and efficient gene delivery vector, the adopted strategy exploited the quenching of the fluorescence of CD by Au nanoparticles. The surface of CD and Au was modified with highly cationic polymer, polyethylenimine (PEI) and subsequent treatment with non-labeled pDNA gave rise to quenched delivery complex. High salt concentration triggered the dissociation of the complex with accompanied fluorescence recovery arising due to the increase in distance between CD and Au. The studies revealed the potential of the developed CD-PEI/Au-PEI/pDNA ternary nano-assembly as a highly efficient hybrid transfecting agent with high cell viability under the optimum condition. The changes occurred at the intracellular level during transfection especially post-endosomal step were monitored by fluorescence measurement using fluorescence microscope. This nano-assembly system was found to be very effective at monitoring the carrier/pDNA dissociation in a non-labeled manner, thus provides efficient strategy to study the mechanistic aspect of polymer-mediated pDNA delivery. PMID- 23790439 TI - Virtual reality systems in urologic surgery: an evaluation of the GreenLight simulator. PMID- 23790438 TI - The effect of polystyrene sodium sulfonate grafting on polyethylene terephthalate artificial ligaments on in vitro mineralisation and in vivo bone tissue integration. AB - This study investigates the impact of polystyrene sodium sulfonate (PolyNaSS) grafting onto the osseo-integration of a polyethylene terephthalate artificial ligament (Ligament Advanced Reinforcement System, LARSTM) used for Anterior Cruciate Ligament (ACL). The performance of grafted and non-grafted ligaments was assessed in vitro by culturing human osteoblasts under osteogenic induction and this demonstrated that the surface modification was capable of up-regulating the secretion of ALP and induced higher level of mineralisation as measured 6 weeks post-seeding by Micro-Computed Tomography. Grafted and non-grafted LARSTM were subsequently implanted in an ovine model for ACL reconstruction and the ligament to-bone interface was evaluated by histology and biomechanical testings 3 and 12 months post-implantation. The grafted ligaments exhibited more frequent direct ligament-to-bone contact and bone formation in the core of the ligament at the later time point than the non-grafted specimens, the grafting also significantly reduced the fibrous encapsulation of the ligament 12 months post-implantation. However, this improved osseo-integration was not translated into a significant increase in the biomechanical pull-out loads. These results provide evidences that PolyNaSS grafting improved the osseo-integration of the artificial ligament within the bone tunnels. This might positively influence the outcome of the surgical reconstructions, as higher ligament stability is believed to limit micro movement and therefore permits earlier and enhanced healing. PMID- 23790440 TI - Establishment of a multicolour fluorescence in situ hybridisation-based assay for subtyping of renal cell tumours. PMID- 23790441 TI - Statistics for surgeons writing and using the medical literature. PMID- 23790442 TI - Follicular lymphoma with leukemic phase at diagnosis: a series of seven cases and review of the literature. AB - Follicular lymphoma (FL) is a prevalent type of non-Hodgkin lymphoma in the United States and Europe. Although, FL typically presents with nodal involvement, extranodal sites are less common, and leukemic phase at diagnosis is rare. There is mounting evidence that leukemic presentation portends a worse prognosis in patients with FL. We describe 7 patients with a pathological diagnosis of FL who presented with a leukemic phase. We compared our cases with 24 additional cases reported in the literature. Based on our results, patients who present with leukemic FL tend to have higher risk disease. Leukemic FL also seems to be associated with a worse prognosis; however, larger studies are needed to confirm our findings. A discrepancy with previously reported cases of FL in leukemic phase raises the possibility of differences attributable to geographic regions. PMID- 23790443 TI - [Neglected orbital foreign body: a case report]. PMID- 23790444 TI - [Bilateral stellate neuroretinitis as presenting sign of pheochromocytoma]. AB - We report the case of a 21-year-old male patient admitted emergently with progressive bilateral severe visual loss for 1 month. Posterior segment examination revealed bilateral stellate neuroretinitis. Infectious serologies were negative, and brain CT was normal. Physical examination was remarkable for malignant hypertension of 220/150 mmHg. Diagnostic work-up revealed a pheochromocytoma documented by histopathological exam upon adrenalectomy. The disc edema and macular exudates resolved once the hypertension was controlled. PMID- 23790445 TI - Trace metals associated with deep-sea tailings placement at the Batu Hijau copper gold mine, Sumbawa, Indonesia. AB - The Batu Hijau copper-gold mine on the island of Sumbawa, Indonesia operates a deep-sea tailings placement (DSTP) facility to dispose of the tailings within the offshore Senunu Canyon. The concentrations of trace metals in tailings, waters, and sediments from locations in the vicinity of the DSTP were determined during surveys in 2004 and 2009. In coastal and deep seawater samples from Alas Strait and the South Coast of Sumbawa, the dissolved concentrations of Ag, As, Cd, Cr, Hg, Pb and Zn were in the sub MUg/L range. Dissolved copper concentrations ranged from 0.05 to 0.65 MUg/L for all depths at these sites. Dissolved copper concentrations were the highest in the bottom-water from within the tailings plume inside Senunu Canyon, with up to 6.5 MUg Cu/L measured in close proximity to the tailings discharge. In general, the concentrations of dissolved and particulate metals were similar in 2004 and 2009. PMID- 23790446 TI - Trace element contamination in the estuarine sediments along Tuticorin coast- Gulf of Mannar, southeast coast of India. AB - Sediment samples were collected from Kallar, Korampallam creek and Punnakayal estuaries of Tuticorin coast for assessing the level of contamination by trace elements in these estuarine sediments. The trace element concentration, calcium carbonate, organic carbon and mercury level were analyzed by Inductively Coupled Plasma Atomic Emission Spectrophotometer, Titrimetric method and SnCl2 reduction method. The results reveals that the enrichment factor, metal pollution index and geo-accumulation index of these estuarine sediments were predominantly polluted by Cd, As, Zn, Hg and Pb. The factor analysis revealed the source of trace element accumulation in the estuarine sediments particularly Mn and Fe are from riverine inputs and As and Hg from untreated industrial effluents. Among the selected estuaries, Korampallam creek was found to be highly contaminated by trace elements due to the discharge of effluents from thermal power plant, Tuticorin alkali chemicals, copper smelting, Petrochemical industries and shipping activities. PMID- 23790447 TI - Macrobenthos and multi-molecular markers as indicators of environmental contamination in a South American port (Mar del Plata, Southwest Atlantic). AB - We evaluated benthic habitat quality along a presumed contamination gradient in the Mar del Plata port (Southwestern Atlantic) by coupling biological and chemical proxies in a multidisciplinary approach. Organic matter and photosynthetic pigment contents were higher in silty-clay bottoms of the inner port sites. Levels of all fecal steroids decreased from the inner sites to the port inlet. High concentrations of coprostanol in the inner sites seemed to derive from a permanent population of sea lions rather than from sewage outfalls due to coprostanol/epicoprostanol ratio (IV) values <2.5. PAHs levels were also higher in the inner sector, related to both biomass combustion and petroleum combustion associated to local marine traffic. High disturbance and low ecological status were reflected in low benthic diversity and high AMBI values in the inner sites. PMID- 23790448 TI - Metal concentrations in sediments from tourist beaches of Miri City, Sarawak, Malaysia (Borneo Island). AB - Forty-three sediment samples were collected from the beaches of Miri City, Sarawak, Malaysia to identify the enrichment of partially leached trace metals (PLTMs) from six different tourist beaches. The samples were analyzed for PLTMs Fe, Mn, Cr, Co, Cu, Ni, Pb, Sr and Zn. The concentration pattern suggest that the southern side of the study area is enriched with Fe (1821-6097 MUg g(-1)), Mn (11.57-90.22 MUg g(-1)), Cr (51.50-311 MUg g(-1)), Ni (18-51 MUg g(-1)), Pb (8.81 84.05 MUg g(-1)), Sr (25.95-140.49 MUg g(-1)) and Zn (12.46-35.04 MUg g(-1)). Compared to the eco-toxicological values, Cr>Effects range low (ERL), Lowest effect level (LEL), Severe effect level (SEL); Cu>Unpolluted sediments, ERL, LEL; Pb>Unpolluted sediments and Ni>ERL and LEL. Comparative results with other regions indicate that Co, Cr, Cu, Ni and Zn are higher, indicating an external input rather than natural process. PMID- 23790449 TI - Fishery resource utilization of a restored estuarine borrow pit: a beneficial use of dredged material case study. AB - Numerous pits in coastal waters are subject to degraded water quality and benthic habitat conditions, resulting in degraded fish habitat. A pit in Barnegat Bay, New Jersey (USA) was partially filled with dredged sediment to increase flushing, alleviate hypoxia, and enhance benthic assemblages. Restoration objectives were assessed in terms of benthic community parameters and fishery resource occupation. Restoration resulted in increased benthic diversity (bottom samples) and the absence of water column stratification. Fisheries resources occupied the entire water column, unlike pre-restoration conditions where finfish tended to avoid the lower water column. The partial restoration option effectively reproduced an existing borrow pit configuration (Hole #5, control), by decreasing total depth from -11 m to -5.5 m, thereby creating a habitat less susceptible to hypoxic/anoxic conditions, while retaining sufficient vertical relief to maintain associations with juvenile weakfish and other forage fishes. Partially filling pits using dredged material represents a viable restoration alternative. PMID- 23790450 TI - Sample preparation methods for quantitative detection of DNA by molecular assays and marine biosensors. AB - The need for quantitative molecular methods is growing in environmental, food, and medical fields but is hindered by low and variable DNA extraction and by co extraction of PCR inhibitors. DNA extracts from Enterococcus faecium, seawater, and seawater spiked with E. faecium and Vibrio parahaemolyticus were tested by qPCR for target recovery and inhibition. Conventional and novel methods were tested, including Synchronous Coefficient of Drag Alteration (SCODA) and lysis and purification systems used on an automated genetic sensor (the Environmental Sample Processor, ESP). Variable qPCR target recovery and inhibition were measured, significantly affecting target quantification. An aggressive lysis method that utilized chemical, enzymatic, and mechanical disruption enhanced target recovery compared to commercial kit protocols. SCODA purification did not show marked improvement over commercial spin columns. Overall, data suggested a general need to improve sample preparation and to accurately assess and account for DNA recovery and inhibition in qPCR applications. PMID- 23790451 TI - The format type has impact on the quality of pathology reports of oncological lung resection specimens. AB - Most pathology reports are in a narrative form without a given structure and occasionally lack important information. Here we show that the format of pathology reports of oncological lung resection specimens correlates with the quality of the reports. All pathology reports of oncological lung resection specimens between 01/02 and 04/11 (N = 878) were classified into descriptive reports (DR, N = 249), structured reports (SR, N = 415) as well as template based synoptic reports (TBSR, N = 214) and compared regarding the content of organ specific essential data (ED). The amount of recorded ED was summarized in an essential data score (EDS). Median EDS of DR was 8, of SR 9, and of TBSR 10. Only 28.7% of all reports had an EDS of 10; divided into the report types 2.6% of DR, 16.4% of SR and 88.4% of TBSR obtained an EDS of 10 (paired comparison: P < 0.0001). Traditional descriptive reports showed the lowest quality sometimes lacking important information and clarity of data layout whereas the template based synoptic reports reached the highest quality level. The broader use of structured reports is recommended for oncological lung resection specimens as they lead to a reduction of failed data transfer and therefore to an increase of quality. PMID- 23790452 TI - The mismeasure of machine: Synthetic biology and the trouble with engineering metaphors. AB - The scientific study of living organisms is permeated by machine and design metaphors. Genes are thought of as the "blueprint" of an organism, organisms are "reverse engineered" to discover their functionality, and living cells are compared to biochemical factories, complete with assembly lines, transport systems, messenger circuits, etc. Although the notion of design is indispensable to think about adaptations, and engineering analogies have considerable heuristic value (e.g., optimality assumptions), we argue they are limited in several important respects. In particular, the analogy with human-made machines falters when we move down to the level of molecular biology and genetics. Living organisms are far more messy and less transparent than human-made machines. Notoriously, evolution is an opportunistic tinkerer, blindly stumbling on "designs" that no sensible engineer would come up with. Despite impressive technological innovation, the prospect of artificially designing new life forms from scratch has proven more difficult than the superficial analogy with "programming" the right "software" would suggest. The idea of applying straightforward engineering approaches to living systems and their genomes isolating functional components, designing new parts from scratch, recombining and assembling them into novel life forms-pushes the analogy with human artifacts beyond its limits. In the absence of a one-to-one correspondence between genotype and phenotype, there is no straightforward way to implement novel biological functions and design new life forms. Both the developmental complexity of gene expression and the multifarious interactions of genes and environments are serious obstacles for "engineering" a particular phenotype. The problem of reverse-engineering a desired phenotype to its genetic "instructions" is probably intractable for any but the most simple phenotypes. Recent developments in the field of bio-engineering and synthetic biology reflect these limitations. Instead of genetically engineering a desired trait from scratch, as the machine/engineering metaphor promises, researchers are making greater strides by co-opting natural selection to "search" for a suitable genotype, or by borrowing and recombining genetic material from extant life forms. PMID- 23790453 TI - Endovascular repair of aortoiliac aneurysmal disease with the helical iliac bifurcation device and the bifurcated-bifurcated iliac bifurcation device. AB - BACKGROUND: Iliac branch device (IBD) treatment of common and internal iliac artery (CIA and IIA) aneurysms has been controversial in the context of available embolization techniques or off-label adjunctive procedures. Two devices exist, a straight IBD (S-IBD) and a helical IBD (H-IBD). We report our midterm results with the latter and present outcomes with a third device intended to treat disease in the presence of short CIAs termed the bifurcated-bifurcated IBD (BB IBD). METHODS: Data were prospectively collected from IBD-treated patients with infrarenal aortoiliac or thoracoabdominal aortoiliac aneurysms. Preoperative aneurysmal characteristics were collected in accordance with the endovascular reporting standards document, including presence of IIA stenosis, CIA diameters, and the presence of an IIA aneurysm. Technical success was defined as IBD device placement, branch placement, and patency without type I or III endoleak at implantation in addition to 24 hours survival. Follow-up computed tomography scans at 1, 6 (optional), 12 months, and annually thereafter were performed and reinterventions, sac morphology changes, and endoleaks noted. Survival and patency were evaluated with life-table analyses, and differences among anatomic groups were compared with log-rank tests, whereas t-tests and Fisher exact tests were used to compare simple variables. RESULTS: Between 2003 and 2012, 138 IBD devices were placed into 130 patients (98 H-IBD and 40 BB-IBD). Median follow-up was 20.3 months (range, 1-72 months) with 30- day, 12-month, 3- and 5-year survival rates of 99%, 90%, 79%, and 62%, respectively. Technical success was 94%, and branch patency was 94.6% at 30 days and 81.8% at 5 years. Thirty-five percent (35%) of branches were placed into patients with IIA aneurysms (in addition to their proximal disease), 20% into stenotic IIAs, and 46% into iliac systems with narrow (<16 mm) CIAs. Technical success was significantly lower in patients with IIA stenosis (81.5 vs 96.4%; Fisher exact test, P = .015) but not affected by the presence of an IIA aneurysm or narrow CIA. Branch patency was similar in all groups throughout follow-up. No stent fractures or component separations were noted in the IBDs or mating devices throughout the study period. CONCLUSIONS: The H-IBD and BB-IBD configurations have high technical success and acceptable long-term patency for the treatment of CIA and IIA aneurysms, including those with challenging anatomy difficult to treat with the straight branch design. PMID- 23790454 TI - Inflammation-related induction of absent in melanoma 2 (AIM2) in vascular cells and atherosclerotic lesions suggests a role in vascular pathogenesis. AB - BACKGROUND: Absent in melanoma (AIM2) was recently identified to act as a cytosolic DNA sensor in innate immunity. Considering the role of chronic inflammation in atherosclerosis, we hypothesized that AIM2 may act as a damage signal that is activated in response to cellular stress likewise in vascular cells of larger arteries. We thus addressed AIM2 expression in healthy arterial wall and in different vascular lesions. In addition, AIM2 expression was characterized in cultured human aortic endothelial cells (HAoECs), smooth muscle cells (HAoSMCs), and T/G-HA-vascular smooth muscle cells (VSMCs) in response to different stimuli. METHODS: Carotid and aortic lesions from patients who underwent surgery and normal arterial specimens were analyzed by immunohistochemistry for AIM2 expression. Cultured HAoECs, HAoSMCs, and T/G-HA VSMCs were stimulated in vitro with proinflammatory cytokines (tumor necrosis factor-alpha, interferon-gamma) or poly(dA:dT) and analyzed for AIM2 transcript and protein expression. RESULTS: AIM2 was detected in ECs of the intima and vasa vasorum of normal carotid artery and aorta. Moreover, AIM2 was moderately expressed in VSMCs of normal media and intima layers, as well as in VSMCs of atherosclerotic lesions. Increased AIM2 expression was detected around the necrotic core of atherosclerotic carotid lesions and in the vasa vasorum neovasculature of aortic aneurysms. Subsequent in vitro analysis identified an endogenous AIM2 expression in cultured HAoECs, HAoSMCs, and T/G-HA-VSMCs that was markedly increased upon treatment of the cells with tumor necrosis factor-alpha, interferon-gamma, or cytosolic DNA. CONCLUSIONS: ECs and VSMC are able to respond to inflammatory signals by upregulation of AIM2 expression, indicating a role of AIM2 in vascular pathogenesis. PMID- 23790455 TI - Cytokine responses in patients with mild or severe influenza A(H1N1)pdm09. AB - BACKGROUND: Influenza virus affects millions of people worldwide each year. More severe infection occurs in the elderly, very young and immunocompromised. In 2009, a new variant of swine origin (influenza A(H1N1)pdm09 virus) emerged that produced severe disease in young healthy adults. OBJECTIVES: The aim of this study was to determine whether cytokine concentrations are associated with clinical outcome in patients infected influenza A(H1N1)pdm09 virus. STUDY DESIGN: Plasma concentration of 32 cytokines and growth factors were measured using a multiplex bead immunoassay and conventional ELISA in four patient groups. Patients with severe and mild influenza A(H1N1)pdm09 virus infection, rhinovirus infection and healthy volunteers were investigated. In addition, serial samples of respiratory secretions from five patients with severe influenza A(H1N1)pdm09 virus infection were examined. RESULTS: The majority of cytokines measured were elevated in patients with viral respiratory infections compared to the healthy controls. Concentrations of IL-6, IL-10, IL-15, IP-10, IL-2R, HGF, ST2 and MIG were significantly higher (p<0.05) and EGF significantly lower (p=0.0001) in patients with severe influenza A(H1N1)pdm09 virus infection compared to those with mild influenza A(H1N1)pdm09 virus and rhinovirus infection. CONCLUSIONS: A number of cytokines were found to be substantially elevated in patients with severe influenza A(H1N1)pdm09 virus infection. This supports and extends other published work suggesting a role for proinflammatory cytokines in influenza induced lung pathology. Interestingly, EGF was significantly lower in patients with severe infection suggesting it is actively suppressed. As EGF has a role in role in cell proliferation and tissue repair, it may protect the lung from host or virus mediated damage. PMID- 23790456 TI - An experimental assessment of toxic potential of nanoparticle preparation of heavy metals in streptozotocin induced diabetes. AB - Nanoparticle preparations of heavy metals have attracted enormous scientific and technological interest. Biologically produced nanoparticle preparations of heavy metals are elaborately described in traditional texts and being widely prescribed. The underlying interactions of nano preparations within the physiological fluids are key feature to understand their biological impact. In this perspective, we performed an experimental assessment of the toxicity potential of a marketed metallic preparation named Vasant Kusumakar Ras (VKR), wherein different heavy metals in composite form are reduced to nanoparticle size to produce the desired effect in diabetes and its complications. VKR (50mg/kg) was administered to Albino Wistar rats rendered diabetic using streptozotocin (90mg/kg) in 2 days old neonates. Anti-hyperglycemic effect was observed with VKR along with increased levels of plasma insulin. Renal variables including total proteins and albumin along with glomerular filtration rate were found to improve biochemically. The results were supplemented by effects on different inflammatory and growth factors like TNF-alpha, nitric oxide, TGF-beta and VEGF. However, the results observed in kidney histopathology were not in accordance with the biochemical parameters. Inflammation observed in kidney was confirmed by immunostaining metallothionein, which was due to the accumulation of heavy metals. Furthermore, mercury accumulation in kidney further confirmed by autometallography, which activated mononuclear phagocyte system, which generated an immune response. This was further supported by increase in the extent of apoptosis in kidney tissues. In conclusion, nanoparticle preparations of heavy metals can be toxic to kidney if it is not regulated with respect to its surface chemistry and dosage. PMID- 23790457 TI - Optimizing early detection of non-indigenous species: estimating the scale of dispersal of a nascent population of the invasive tunicate Ciona intestinalis (L.). AB - Knowledge of dispersal and establishment during the early stages of invasion is essential for allocating monitoring effort, detecting nascent populations and predicting spread. The scarcity of these data, however, provides little guidance for monitoring programs. Here we present data on the adult distribution and the subsequent pattern of larval recruitment from a nascent population of the invasive tunicate Ciona intestinalis in Prince Edward Island, Canada. Existing niche models indicate the entire study site is suitable for recruitment, suggesting an equal probability of detection throughout the site. In contrast, we found a heterogeneous pattern of larval recruitment, including areas of zero recruitment. By fitting a dispersal kernel, we show Ciona is not capable of naturally dispersing between bays, restricting further spread, and provide guidance for future monitoring. Our results also highlight how large-scale models, although important, lack the small-scale patterns essential for monitoring and early detection of invasive species. PMID- 23790458 TI - Environmental fate of fungicides and other current-use pesticides in a central California estuary. AB - The current study documents the fate of current-use pesticides in an agriculturally-dominated central California coastal estuary by focusing on the occurrence in water, sediment and tissue of resident aquatic organisms. Three fungicides (azoxystrobin, boscalid, and pyraclostrobin), one herbicide (propyzamide) and two organophosphate insecticides (chlorpyrifos and diazinon) were detected frequently. Dissolved pesticide concentrations in the estuary corresponded to the timing of application while bed sediment pesticide concentrations correlated with the distance from potential sources. Fungicides and insecticides were detected frequently in fish and invertebrates collected near the mouth of the estuary and the contaminant profiles differed from the sediment and water collected. This is the first study to document the occurrence of many current-use pesticides, including fungicides, in tissue. Limited information is available on the uptake, accumulation and effects of current-use pesticides on non-target organisms. Additional data are needed to understand the impacts of pesticides, especially in small agriculturally-dominated estuaries. PMID- 23790459 TI - Trace elements in the sediments of a large Mediterranean marina (Port Camargue, France): levels and contamination history. AB - The study of trace elements (Cu, Zn, Pb, As, Hg) and butyltin concentrations in the sediments of Port Camargue enabled assessment of the levels and history of the contamination of the largest European marina linked with the use of antifouling paints. Surface sediments near the boat maintenance area were heavily contaminated with up to 1497 MUg g(-1) of Cu, 475 MUg g(-1) of Zn, 0.82 MUg g(-1) of Hg, 94 MUg g(-1) of Pb and over 10,000 ngSn g(-1) of tributyltin (TBT). High concentrations of Hg and TBT indicate ongoing sources of these elements despite the ban on their use as biocides in paints. Sediment cores provided records of contamination since 1969. The peak concentrations of As, Hg, Pb and TBT in the sediment profile reflect their presence on boat hulls when the marina was built at the end of the 1960s. Degradation of TBT in the sediments near the boat maintenance area is slow compared to other less contaminated area of the marina. PMID- 23790460 TI - Assessment of marine debris on the Belgian Continental Shelf. AB - A comprehensive assessment of marine litter in three environmental compartments of Belgian coastal waters was performed. Abundance, weight and composition of marine debris, including microplastics, was assessed by performing beach, sea surface and seafloor monitoring campaigns during two consecutive years. Plastic items were the dominant type of macrodebris recorded: over 95% of debris present in the three sampled marine compartments were plastic. In general, concentrations of macrodebris were quite high. Especially the number of beached debris reached very high levels: on average 6429+/-6767 items per 100 m were recorded. Microplastic concentrations were determined to assess overall abundance in the different marine compartments of the Belgian Continental Shelf. In terms of weight, macrodebris still dominates the pollution of beaches, but in the water column and in the seafloor microplastics appear to be of higher importance: here, microplastic weight is approximately 100 times and 400 times higher, respectively, than macrodebris weight. PMID- 23790461 TI - Perfluorinated compounds in blood of Caretta caretta from the Mediterranean Sea. AB - Perfluorinated compounds (PFCs), widely used for their hydro-oil repellent properties, are almost non-degradable in the environment; there is scientific evidence that indicate bioaccumulation. They represent a threat to many organisms, because they are toxic and are endocrine disruptors. Scientific studies have demonstrated the presence of PFCs in blood and liver samples of fish, turtles, birds and mammals of marine ecosystems in different geographical areas. The aim of this study was to determine the distribution of PFOS and PFOA in blood samples of the marine turtle Caretta caretta, using a minimally invasive sampling procedure. 49 blood samples of marine turtle, taken from several Italian marine turtle rescue centers, were analyzed. While PFOA was never detected, measurable concentrations of PFOS were found in 15 blood samples; the values show a range from 1.14 ng/g to 28.51 ng/g (wet wt.). No differences between groups of samples taken from different areas were found. PMID- 23790462 TI - Automatic Synthetic Aperture Radar based oil spill detection and performance estimation via a semi-automatic operational service benchmark. AB - Today the health of ocean is in danger as it was never before mainly due to man made pollutions. Operational activities show regular occurrence of accidental and deliberate oil spill in European waters. Since the areas covered by oil spills are usually large, satellite remote sensing particularly Synthetic Aperture Radar represents an effective option for operational oil spill detection. This paper describes the development of a fully automated approach for oil spill detection from SAR. Total of 41 feature parameters extracted from each segmented dark spot for oil spill and 'look-alike' classification and ranked according to their importance. The classification algorithm is based on a two-stage processing that combines classification tree analysis and fuzzy logic. An initial evaluation of this methodology on a large dataset has been carried out and degree of agreement between results from proposed algorithm and human analyst was estimated between 85% and 93% respectively for ENVISAT and RADARSAT. PMID- 23790463 TI - Comparison of selected biomarkers in flounder (Platichthys flesus L.) from the Douro (Portugal) and Vistula (Poland) River estuaries. AB - Sixty female flounder (Platichthys flesus) were collected in Autumn 2011, 15 from each of the following sampling sites: at the mouths of the Douro and Vistula Rivers, and at nearby open sea locations. The aim of the study was to assess several biomarkers in the two geographically distant regions. Hepatic EROD, GST, SOD, GPx, POx, LP; muscular AChE, BChE, LP; and branchial Na(+)/K(+)-ATPase were analysed. Moreover, BTI, PY, and three gross morphometric indices were calculated. The results were analysed with t-test, ANOVA, and PCA. Many differences were found between the open sea sites and the river mouths, mainly in Portugal, and between the two rivers. Salinity and pollution seem to be the main factors that affected the biomarkers. Effects of chronic pollution were observed at the river mouths, and an indication of a possible temporary exposure to pollutants was found at the open ocean site in Portugal. PMID- 23790464 TI - Isolation and characterization of alkane degrading bacteria from petroleum reservoir waste water in Iran (Kerman and Tehran provenances). AB - Petroleum products spill and leakage have become two major environmental challenges in Iran. Sampling was performed in the petroleum reservoir waste water of Tehran and Kerman Provinces of Iran. Alkane degrading bacteria were isolated by enrichment in a Bushnel-Hass medium, with hexadecane as sole source of carbon and energy. The isolated strains were identified by amplification of 16S rDNA gene and sequencing. Specific primers were used for identification of alkane hydroxylase gene. Fifteen alkane degrading bacteria were isolated and 8 strains were selected as powerful degradative bacteria. These 8 strains relate to Rhodococcus jostii, Stenotrophomonas maltophilia, Achromobacter piechaudii, Tsukamurella tyrosinosolvens, Pseudomonas fluorescens, Rhodococcus erythropolis, Stenotrophomonas maltophilia, Pseudomonas aeruginosa genera. The optimum concentration of hexadecane that allowed high growth was 2.5%. Gas chromatography results show that all strains can degrade approximately half of hexadecane in one week of incubation. All of the strains have alkane hydroxylase gene which are important for biodegradation. As a result, this study indicates that there is a high diversity of degradative bacteria in petroleum reservoir waste water in Iran. PMID- 23790465 TI - The ruthenium compound KP1339 potentiates the anticancer activity of sorafenib in vitro and in vivo. AB - KP1339 is a promising ruthenium-based anticancer compound in early clinical development. This study aimed to test the effects of KP1339 on the in vitro and in vivo activity of the multi-kinase inhibitor sorafenib, the current standard first-line therapy for advanced hepatoma. Anticancer activity of the parental compounds as compared to the drug combination was tested against a panel of cancer cell lines with a focus on hepatoma. Combination of KP1339 with sorafenib induced in the majority of all cases distinctly synergistic effects, comprising both sorafenib-resistant as well as sorafenib-responsive cell models. Several mechanisms were found to underlie these multifaceted synergistic activities. Firstly, co-exposure induced significantly enhanced accumulation levels of both drugs resulting in enhanced apoptosis induction. Secondly, sorafenib blocked KP1339-mediated activation of P38 signalling representing a protective response against the ruthenium drug. In addition, sorafenib treatment also abrogated KP1339-induced G2/M arrest but resulted in check point-independent DNA-synthesis block and a complete loss of the mitotic cell populations. The activity of the KP1339/sorafenib combination was evaluated in the Hep3B hepatoma xenograft. KP1339 monotherapy led to a 2.4-fold increase in life span and, thus, was superior to sorafenib, which induced a 1.9-fold prolonged survival. The combined therapy further enhanced the mean survival by 3.9-fold. Synergistic activity was also observed in the VM-1 melanoma xenograft harbouring an activating braf mutation. Together, our data indicate that the combination of KP1339 with sorafenib displays promising activity in vitro and in vivo especially against human hepatoma models. PMID- 23790466 TI - Inhibition of polo-like kinase 1 in glioblastoma multiforme induces mitotic catastrophe and enhances radiosensitisation. AB - Glioblastoma multiforme (GBM) is the most common primary brain tumour in the United States of America (USA) with a median survival of approximately 14 months. Low survival rates are attributable to the aggressiveness of GBM and a lack of understanding of the molecular mechanisms underlying GBM. The disruption of signalling pathways regulated either directly or indirectly by protein kinases is frequently observed in cancer cells and thus the development of inhibitors of specific kinases has become a major focus of drug discovery in oncology. To identify protein kinases required for the survival of GBM we performed a siRNA based RNAi screen focused on the human kinome in GBM. Inhibition of the polo-like kinase 1 (PLK1) induced a reduction in the viability in two different GBM cell lines. To assess the potential of inhibiting PLK1 as a treatment strategy for GBM we examined the effects of a small molecule inhibitor of PLK1, GSK461364A, on the growth of GBM cells. PLK1 inhibition arrested cells in the mitotic phase of the cell cycle and induced cell kill by mitotic catastrophe. GBM engrafts treated with GSK461364A showed statistically significant inhibition of tumour growth. Further, exposure of different GBM cells to RNAi or GSK461364A prior to radiation resulted in an increase in their radiosensitivity with dose enhancement factor ranging from 1.40 to 1.53 with no effect on normal cells. As a measure of DNA double strand breaks, gammaH2AX levels were significantly higher in the combined modality as compared to the individual treatments. This study suggests that PLK1 is an important therapeutic target for GBM and can enhance radiosensitivity in GBM. PMID- 23790467 TI - Pharmacokinetic/pharmacodynamic modelling-based optimisation of administration schedule for the histone deacetylase inhibitor abexinostat (S78454/PCI-24781) in phase I. AB - Abexinostat, an oral pan-histone deacetylase inhibitor (HDACi), was evaluated in patients with advanced solid tumours in two single agent phase I studies (PCYC 402 and CL1-78454-002). In PCYC-402 study testing four different administration schedules, the maximum tolerated dose (MTD) was established at 75 mg/m(2) BID (twice daily) and the recommended dose at 60 mg/m(2) BID regardless of the schedule tested. The dose limiting toxicity (DLT), consistently observed across all these schedules, was reversible thrombocytopenia. The CL1-78454-002 study was initially investigating an additional schedule of 14 days on/7 days off. While testing two first cohorts, thrombocytopenia was observed without reaching DLT. To address this issue, a pharmacokinetic/pharmacodynamic (PK/PD) model was used to predict the optimal schedule allowing higher doses with minimal thrombocytopenia. Several administration schedules were simulated using this model. A 4 days on/3 days off schedule was associated with the smallest platelet decrease. Accordingly, the CL1-78454-002 study was amended. After reaching MTD1 (75 mg/m(2) BID) with the initial schedule, subsequent cohorts received abexinostat on a revised schedule of 4 days on/3 days off, starting at one dose level below MTD1 (60 mg/m(2) BID). As expected, the dose-escalation continued for two more dose levels beyond MTD1. The MTD2 reached for this optimised schedule was 105 mg/m(2) BID and the recommended dose 90 mg/m(2) BID. In conclusion, early understanding of toxicities and PK determination allowed us to build a PK/PD model of thrombocytopenia, which predicted the optimal administration schedule. This optimised schedule is currently used in the trials in solid tumours with abexinostat. PMID- 23790468 TI - Phase II study of pemetrexed and cisplatin plus cetuximab followed by pemetrexed and cetuximab maintenance therapy in patients with advanced nonsquamous non-small cell lung cancer. AB - OBJECTIVES: The aim was to determine if combined pemetrexed, cisplatin, and cetuximab was efficacious and safe as first-line treatment in advanced nonsquamous non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: In this single-arm, multicenter clinical trial, patients with Stage IIIB/IV nonsquamous NSCLC received first-line therapy consisting of pemetrexed (500 mg/m(2)) and cisplatin (75 mg/m(2)) on Day 1 (21-day cycles) plus weekly cetuximab (400 mg/m(2) loading dose, then 250 mg/m(2)) for 4-6 cycles. Non-progressing patients received maintenance therapy consisting of pemetrexed and cetuximab as above until disease progression. All patients received vitamin supplementation, dexamethasone, and antihistamine prophylaxis. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), 1 year survival rate, translational research (TR) and safety. RESULTS: Of the 113 patients receiving study drug, 109 were protocol-qualified. All patients completed >=1 cycle of induction, and 51 (45%) and 49 (43%) patients completed >=1 cycle of maintenance with pemetrexed and cetuximab, respectively. The ORR (n = 109) was 38.5% (80% confidence interval [CI], 32.3-45.1%), all partial responses. Median PFS was 5.8 (80% CI, 4.4-6.7) months. One-year survival rate was 45% (80% CI, 39-51%). In exploratory analyses, there was some preliminary evidence of potential prognostic relationships with efficacy outcomes for epidermal growth factor receptor and thyroid transcription factor-1 protein expression, but not for KRAS mutation or for thymidylate synthase or folate receptor-alpha protein expression. Seventy-three (64.6%) patients had study drug related Grade 3/4 adverse events (AEs). Drug-related serious AEs were reported in 31 (27.4%) patients. There were 3 (2.7%) potentially drug-related deaths on-study or within 30 days of follow up. CONCLUSION: Pemetrexed, cisplatin, and cetuximab appeared efficacious and tolerable in advanced nonsquamous NSCLC patients. The TR outcomes are hypothesis-generating given the study's size and nonrandomized nature. PMID- 23790469 TI - Single- and multi-level anterior decompression and fusion for cervical spondylotic myelopathy--a long term follow-up with a minimum of 5 years. AB - OBJECTIVE: Cervical spondylotic myelopathy (CSM) is a common disease leading to significant neurological disability. We compared patients suffering from a single and a multi-level pathology to analyze the influence of the natural course of the disease on the long-term outcome after surgery. METHODS: We analyzed the records of 52 patients with CSM after surgery. The neurological status of the patients was assessed by the modified Japanese Orthopaedic Association Scale (mJOAS). X-rays were conducted before and after surgery. RESULTS: 52 patients were treated by a single-level (n=27) or a multi-level approach (n=25) more than 5 years ago. A significant improvement of the neurological status could be seen even 5 years or more after surgery in both groups without differences. After one year no further improvement could be observed. In the single-level group a trend to a subsequent loss of lordotic correction could be seen. Anterior plates were only used in the multi-level group. CONCLUSION: The anterior approach is an effective procedure to improve the symptoms of a CSM for many years. The risk of a multi-level pathology does not appear to exceed the risks of a single-level pathology concerning clinical long-term outcome after surgery. The clinical success is not hindered by a loss of correction in this specific setting. PMID- 23790470 TI - Accuracy of tunnelated vs. bolt-connected external ventricular drains. AB - BACKGROUND: Ventriculostomy is one of the most common neurosurgical procedures and an important tool in the treatment and monitoring of elevated intracranial pressure. Low accuracy has frequently been reported in the literature with risk of drain misplacement over 20% and with a need for reinsertion in up to 40%. As an alternative to the tunnelated EVD technique we often use a bolt-connected EVD. The aim of the present study was to investigate whether the use of bolt-connected EVDs would lead to higher accuracy, fewer passes and reoperations due to poor placement compared to tunnelated EVDs. PATIENTS AND METHODS: We retrospectively identified all patients who received an EVD from January 1st 2008 to December 31st 2010. Postoperative images were evaluated for anatomical placement of the EVD-tip, distance from tip to optimal placement and were categorized as optimal, suboptimal and undesired. Patient files were evaluated for EVD technique, number of passes and postoperative complications and handling. RESULTS: 147 patients with 154 separate EVDs met the inclusion criteria. We found a statistical significant higher accuracy in the bolt-group compared to the tunnelated-group (p=0.023). Eleven patients were reoperated following ventriculostomy and we found a statistical significant 11.9% reduction in reoperations due to poor placement in the bolt-group (p=0.006). CONCLUSIONS: We have showed in this study that by using a bolt-connected EVD and maintaining the freehanded technique we can significantly increase precision and decrease the number of reoperations due to poor placement. PMID- 23790471 TI - Chronic fatigue syndrome from vagus nerve infection: a psychoneuroimmunological hypothesis. AB - Chronic fatigue syndrome (CFS) is an often-debilitating condition of unknown origin. There is a general consensus among CFS researchers that the symptoms seem to reflect an ongoing immune response, perhaps due to viral infection. Thus, most CFS research has focused upon trying to uncover that putative immune system dysfunction or specific pathogenic agent. However, no single causative agent has been found. In this speculative article, I describe a new hypothesis for the etiology of CFS: infection of the vagus nerve. When immune cells of otherwise healthy individuals detect any peripheral infection, they release proinflammatory cytokines. Chemoreceptors of the sensory vagus nerve detect these localized proinflammatory cytokines, and send a signal to the brain to initiate sickness behavior. Sickness behavior is an involuntary response that includes fatigue, fever, myalgia, depression, and other symptoms that overlap with CFS. The vagus nerve infection hypothesis of CFS contends that CFS symptoms are a pathologically exaggerated version of normal sickness behavior that can occur when sensory vagal ganglia or paraganglia are themselves infected with any virus or bacteria. Drawing upon relevant findings from the neuropathic pain literature, I explain how pathogen-activated glial cells can bombard the sensory vagus nerve with proinflammatory cytokines and other neuroexcitatory substances, initiating an exaggerated and intractable sickness behavior signal. According to this hypothesis, any pathogenic infection of the vagus nerve can cause CFS, which resolves the ongoing controversy about finding a single pathogen. The vagus nerve infection hypothesis offers testable hypotheses for researchers, animal models, and specific treatment strategies. PMID- 23790472 TI - Role of the glomerular-tubular imbalance with tubular predominance in the arterial hypertension pathophysiology. AB - In previous investigations we caused renal tubular reabsorption preponderance relating to the glomerular filtration (Glomerular-tubular imbalance) and we observed that this fact conducted to volume expansion and development of arterial hypertension, in rats that previously were normotens. We based on this evidence and other which are reflected in the literature arrived at the following hypothesis: a greater proportion of tubular reabsorption relating to the filtered volume is the base of the establishment of the glomerular-tubular imbalance with tubular predominance (GTI-T), which favors to the Na(+)-fluid retention and volume expansion. All of which conduced to arterial hypertension. These facts explain a primary hypertensive role of the kidney, consistent with the results of renal transplants performed in different lines of hypertensive rats and their respective controls and in humans: hypertension can be transferred with the kidney. GTI-T aims to be, a common phenomenon involved in the hypertension development in the multiple ways which is manifested the hypertensive syndrome. In secondary hypertension, GTI-T is caused by significant disruptions of hormone secretions that control renal function, or obvious vascular or parenchymal damage of these organs. In primary hypertension the GTI-T has less obvious causes inherently developed in the kidney, including humoral, cellular and subcellular mechanisms, which may insidiously manifest under environmental factors influence, resulting in insidious development of hypertension. This would explain the state of prehypertension that these individuals suffer. So it has great importance to study GTI-T before the hypertension is established, because when hypertensive state is established, other mechanisms are installed and they contribute to maintain the hypertension. Our hypothesis may explaining the inability of the kidneys to excrete salt and water in hypertension, as Guyton and colleagues have expressed and constitutes a step forward in line with the hypothesis of this author. PMID- 23790473 TI - Is there any relationship between recurrent oral aphthous stomatitis and prediabetes? AB - Periodontal disease has been associated with glycaemia. Recurrent aphthous stomatitis (RAS) is one of the most common oral lesions and is characterized by painful recurrent oral ulcers. However, the exact cause and treatment of RAS is not yet well-known. Furthermore, there is still unknown the relationship between RAS and glycaemia. Prediabetes has shown to have role on worse metabolic profile. However, there is still no data on the relationship between prediabetes and clinical RAS. Therefore, the purpose of this hypothesis is to assess whether the prediabetes aggravate RAS. PMID- 23790474 TI - Possible carcinogenesis of tumor suppressor let-7. AB - Cancer stem cells (CSCs), a group showing high capacities of sphere-forming and self renewal, are blamed for tumor initiation, recurrence and therapy resistance. Therefore, therapeutics specifically targeting and perishing CSCs may be promising. Let-7 miRNAs, one of the earliest discovered miRNAs, were considered as novel and vital agents to eliminate cancer and CSCs. However, in recent researches, many regulatory loops among let-7 and its targeted genes were noticed; the regulation of let-7 caused by its hunting mRNAs helped to form the hypotheses that hunters and preys may swap their roles when in confrontations. Besides, the evil side of let-7 was discovered occasionally, therefore, we hypothesize that dual characteristics of let-7 do exist, which will have significant impacts on anticancer research. Targeted therapies against cancer and CSCs by using let-7 or other miRNAs as weapons should be thought twice before clinical application. PMID- 23790475 TI - Irrigation with industrial wastewater activates antioxidant system and osmoprotectant accumulation in lettuce, turnip and tomato plants. AB - We focused on the impact of industrial wastes on the water quality of the El-Amia drain in Egypt and the effect of irrigation with industrial wastewater on the growth, cell membranes, photosynthetic pigment content, the antioxidant system and selected osmoprotectants (proline, total amino nitrogen and soluble sugars) in three crop plants: turnip, tomato and lettuce. Furthermore, the present work focused on the analysis of the heavy metal content and its accumulation in the studied plants. For this purpose, water samples were collected 1, 10 and 19 km from the beginning of the drain and used for irrigation, with fresh water as a control. We found that industrial wastewater contained significant amounts of heavy metals (Cd, Ni and Co) warranted a pollution problem as their amounts exceed the maximum recommended concentrations according to FAO guidelines for trace metals in irrigation water. The three crop plants accumulate significant amounts of heavy metals in their shoots and roots and showed a significant decrease in leaf area, fresh weight and dry weight of shoots and roots, accompanied by a marked reduction in photosynthetic pigment content and damage to cell membranes, as indicated by increased electrolyte leakage and a lower membrane stability index. Significant increases in the activities of antioxidant enzymes and in the glutathione, proline, soluble sugar and total amino nitrogen content in response to irrigation with wastewater may be defense mechanisms induced in response to heavy metal stress. PMID- 23790476 TI - Effects of peak exposure scenarios on Gammarus fossarum using field relevant pesticide mixtures. AB - The present study investigated sublethal effects of a field relevant pesticide mixture (one herbicide, three fungicides, five insecticides) on Gammarus fossarum by considering different peak exposure scenarios, which may be generated by the inherent properties of vegetated ditches. Additional experiments aimed at the identification of germane exposure pathways (food and water). Therefore, G. fossarum were exposed in independent experiments to three scenarios, which differed besides in the peak concentration of the pesticide mixture also in the mixture's composition and exposure duration (n=20 per treatment). The exposure duration of 12 or 120 min was followed by a seven-day post-exposure observation period. At a constant concentration-time product, a lower exposure duration in concert with a proportionally higher peak concentration caused a substantially elevated ecotoxicity compared to a treatment with a longer exposure duration at a lower peak concentration. Given the importance of the insecticide lambda cyhalothrin for the mixture's ecotoxicity it may be concluded that the fast mode of action of pyrethroids mainly explains this observation. Moreover, field relevant concentrations of the pesticide mixture applied at an exposure duration of 120 min resulted in reduced gammarids' feeding rate, which may be indicative for shifts in the ecosystem function of leaf litter breakdown and hence the provision of energy for local and downstream communities. Finally, the present study indicated that both pathways of exposure, namely via food or water, reduce gammarids' feeding rate synergistically. This suggests that both exposure pathways should be considered for compounds exhibiting a high Kow (e.g. pyrethroids) during the risk assessment of single substances and mixtures. PMID- 23790480 TI - Cyst carcinoembryonic antigen in differentiating pancreatic cysts: a meta analysis. AB - BACKGROUND: Using carcinoembryonic antigen in discriminating between benign and malignant disease remains controversial. AIMS: We aim to evaluate the diagnostic accuracy of cyst fluid carcinoembryonic antigen in predicting malignant pancreatic cystic lesions. METHODS: We performed a literature search of MEDLINE and EMBASE. We included studies that compared the diagnostic accuracy of carcinoembryonic antigen with histology. Pooled estimates of diagnostic precision were calculated using random-effects models. RESULTS: Eight studies (504 patients) were included. The carcinoembryonic antigen cutoff level for determining a malignant cyst ranged from 109.9 to 6000 ng/mL. Pooled estimates of carcinoembryonic antigen in malignant cysts prediction were poor: pooled sensitivity of 63%, pooled specificity of 63%. The positive likelihood ratio was 1.89 and the negative likelihood ratio was 0.62. The diagnostic odds ratio was 3.84. The area under the summary receiver-operating characteristic curve was 0.70. In subgroup analysis of patients with mucinous cysts (mucinous cystic neoplasm and intraductal papillary mucinous neoplasm; 5 studies, 227 patients), pooled sensitivity was 65%, pooled specificity 66% and diagnostic odds ratio 4.74 respectively. CONCLUSION: This meta-analysis suggests that the accuracy of carcinoembryonic antigen in differentiating "between benign and malignant" pancreatic cysts was poor. The decision to perform surgical resection for pancreatic cystic lesions should not be based solely on carcinoembryonic antigen level. PMID- 23790481 TI - Aortic intramural hematoma with pulmonary artery extension mimics pulmonary embolism. AB - A 59-year-old woman presented to emergency department with sudden onset of chest tightness and shortness of breath. Laboratory test revealed elevated D-dimer (1558 ng/mL). The electrocardiogram revealed right axis deviation, S1Q3T3 pattern, and T-wave inversion in leads V1 to V6. Computed tomographic angiography (CTA) was performed with 64-slice computed tomography for suspicious of pulmonary embolism. Contrast-enhanced CTA showed no filling defect in the pulmonary arteries; however, luminal narrowing of the right pulmonary artery was noted. Nonenhanced computed tomographic scan showed smooth eccentric high attenuation change along the wall of main pulmonary artery and right pulmonary artery and also along the ascending and descending aorta. The high attenuation lesions in both of the aorta and pulmonary artery showed no contrast enhancement indicating presence of intramural hematoma (IMH). Based on the image findings, a diagnosis of type A aortic IMH with pulmonary artery extension, instead of chronic pulmonary embolism, was made. Follow-up CTA 3 months later showed much improved of the right pulmonary artery narrowing and nearly complete resolution of the IMH. PMID- 23790482 TI - At the intersection of toxicology, psychiatry, and genetics: a diagnosis of ornithine transcarbamylase deficiency. AB - Ornithine transcarbamylase (OTC) deficiency is a genetic disorder involving a mutation of the ornithine transcarbamylase gene, located on the short arm of the X chromosome (Xp21.1). This makes the expression of the gene most common in homozygous males, but heterozygous females can also be affected and may be more likely to suffer from serious morbidity. Most males present early in the neonatal period with more devastating outcomes than their female counterparts. Up to 34% will present in the first 30 days of life (J Pediatr 2001;138:S30). Females often have partially functioning mitochondria due to uneven distribution of the mutant gene secondary to lyonization ("X-chromosome Inactivation". Genetics Home Reference, 2012). Occasionally, symptomatic females may not even present until they are placed under metabolic stress such as a severe illness, fasting, pregnancy, or new medication (Roth KS, Steiner RD. "Ornithine Transcarbamylase Deficiency". EMedicine, 2012). The urea cycle is the body's primary tool for the disposal of excess nitrogen, which is generated by the routine metabolism of proteins and amino acids. Mitochondrial dysfunction impairs urea production and result in hyperammonemia (Semin Neonatol 2002;7:27). The sine qua non among all degrees of OTC deficiency at presentation is hyperammonemia. As in adults, children will have similar symptoms of encephalopathy, but this may be expressed differently depending on the child's developmental level. We present an unusual case of OTC deficiency in an older child with undifferentiated symptoms of an anticholinergic toxidrome, liver failure, iron overdose, and mushroom poisoning. PMID- 23790483 TI - BGI Americas: commercializing next-generation sequencing. PMID- 23790484 TI - Ins and outs of kinase DFG motifs. AB - In this issue of Chemistry & Biology, Hari and colleagues show that two positions in kinase active sites, including the well-known "gatekeeper" residue, regulate "in" versus "out" conformations of the conserved "DFG" motif. These findings suggest yet another role for the gatekeeper residue. PMID- 23790485 TI - Visualization of redox-controlled protein fold in living cells. AB - Most mitochondrial proteins are encoded by nuclear DNA, synthesized in the cytoplasm, and imported into mitochondria. Several proteins of the intermembrane space (IMS) are imported and localized through an oxidative process, being folded through the formation of structural disulfide bonds catalyzed by Mia40, and trapped in the IMS. To be imported, these proteins need to be reduced and unfolded; however, no structural information in situ exists on these proteins in the cytoplasm. In humans, Mia40 undergoes the same mechanism, although its folding state in the cytoplasm is unknown. We provide atomic-level details on the Mia40 folding state in the human cell cytoplasm through in-cell nuclear magnetic resonance. Overexpressed cytoplasmic Mia40 is folded, and its folding state depends on the glutaredoxin 1 (Grx1) and thioredoxin 1 (Trx1) systems. Specifically, increased Grx1 levels keep most Mia40 unfolded, while Trx1 is less effective. PMID- 23790486 TI - Juxtaposition of chemical and mutation-induced developmental defects in zebrafish reveal a copper-chelating activity for kalihinol F. AB - A major hurdle in using complex systems for drug screening is the difficulty of defining the mechanistic targets of small molecules. The zebrafish provides an excellent model system for juxtaposing developmental phenotypes with mechanism discovery using organism genetics. We carried out a phenotype-based screen of uncharacterized small molecules in zebrafish that produced a variety of chemically induced phenotypes with potential genetic parallels. Specifically, kalihinol F caused an undulated notochord, defects in pigment formation, hematopoiesis, and neural development. These phenotypes were strikingly similar to the zebrafish mutant, calamity, an established model of copper deficiency. Further studies into the mechanism of action of kalihinol F revealed a copper chelating activity. Our data support this mechanism of action for kalihinol F and the utility of zebrafish as an effective system for identifying therapeutic and target pathways. PMID- 23790487 TI - An iterative type I polyketide synthase initiates the biosynthesis of the antimycoplasma agent micacocidin. AB - Micacocidin is a thiazoline-containing natural product from the bacterium Ralstonia solanacearum that shows significant activity against Mycoplasma pneumoniae. The presence of a pentylphenol moiety distinguishes micacocidin from the structurally related siderophore yersiniabactin, and this residue also contributes to the potent antimycoplasma effects. The biosynthesis of the pentylphenol moiety, as deduced from bioinformatic analysis and stable isotope feeding experiments, involves an iterative type I polyketide synthase (iPKS), which generates a linear tetraketide intermediate from acyl carrier protein tethered hexanoic acid by three consecutive, decarboxylative Claisen condensations with malonyl-coenzyme A. The final conversion into 6 pentylsalicylic acid depends on a ketoreductase domain within the iPKS, as demonstrated by heterologous expression in E. coli and subsequent site-directed mutagenesis experiments. Our results unveil the early steps in micacocidin biosynthesis and illuminate a bacterial enzyme that functionally resembles fungal polyketide synthases. PMID- 23790488 TI - Structural and stereochemical analysis of a modular polyketide synthase ketoreductase domain required for the generation of a cis-alkene. AB - The formation of an activated cis-3-cyclohexylpropenoic acid by Plm1, the first extension module of the phoslactomycin polyketide synthase, is proposed to occur through an L-3-hydroxyacyl-intermediate as a result of ketoreduction by an A-type ketoreductase (KR). Here, we demonstrate that the KR domain of Plm1 (PlmKR1) catalyzes the formation of an L-3-hydroxyacyl product. The crystal structure of PlmKR1 revealed a well-ordered active site with a nearby Trp residue characteristic of A-type KRs. Structural comparison of PlmKR1 with B-type KRs that produce D-3-hydroxyacyl intermediates revealed significant differences. The active site of cofactor-bound A-type KRs is in a catalysis-ready state, whereas cofactor-bound B-type KRs are in a precatalytic state. Furthermore, the closed lid loop in substrate-bound A-type KRs restricts active site access from all but one direction, which is proposed to control the stereochemistry of ketoreduction. PMID- 23790489 TI - Molecular and functional analysis of human beta-defensin 3 action at melanocortin receptors. AB - The beta-defensins are a class of small, cationic proteins first recognized as antimicrobial components of the innate and adaptive immune system. More recently, one of the major beta-defensins produced in skin, beta-defensin 3, has been discovered to function as a melanocortin receptor ligand in vivo and in vitro, but its biophysical and pharmacological basis of action has been enigmatic. Here, we report functional and biochemical studies focused on human beta-defensin 3 (HBD3) and melanocortin receptors 1 and 4. Genetic and pharmacologic studies indicate that HBD3 acts as a neutral melanocortin receptor antagonist capable of blocking the action of either stimulatory agonists such as alpha-melanocyte stimulating hormone or inhibitory inverse agonists such as Agouti signaling protein (ASIP) and Agouti-related protein (AGRP). A comprehensive structure function analysis demonstrates that two patches of positively charged residues, located on opposite poles of HBD3 and spatially organized by the compact beta defensin fold, are primarily responsible for high-affinity binding to melanocortin receptors. These findings identify a distinct mode of melanocortin receptor-ligand interactions based primarily on electrostatic complementarity, with implications for designing ligands that target melanocortin and potentially other seven transmembrane receptors. PMID- 23790490 TI - Unconventional origin and hybrid system for construction of pyrrolopyrrole moiety in kosinostatin biosynthesis. AB - Kosinostatin (KST), an antitumor antibiotic, features a pyrrolopyrrole moiety spirally jointed to a five-membered ring of an anthraquinone framework glycosylated with a gamma-branched octose. By a combination of in silico analysis, genetic characterization, biochemical assay, and precursor feeding experiments, a biosynthetic pathway for KST was proposed, which revealed (1) the pyrrolopyrrole moiety originates from nicotinic acid and ribose, (2) the bicyclic amidine is constructed by a process similar to the tryptophan biosynthetic pathway, and (3) a discrete adenylation enzyme and a peptidyl carrier protein (PCP) are responsible for producing a PCP-tethered building block parallel to type II polyketide synthase (PKS) rather than for the PKS priming step by providing the starter unit. These findings provide an opportunity to further explore the inexplicable enzymatic logic that governs the formation of pyrrolopyrrole moiety and the spirocyclic skeleton. PMID- 23790491 TI - Sequence determinants of a specific inactive protein kinase conformation. AB - Only a small percentage of protein kinases have been shown to adopt a distinct inactive ATP-binding site conformation, called the Asp-Phe-Gly-out (DFG-out) conformation. Given the high degree of homology within this enzyme family, we sought to understand the basis of this disparity on a sequence level. We identified two residue positions that sensitize mitogen-activated protein kinases (MAPKs) to inhibitors that stabilize the DFG-out inactive conformation. After characterizing the structure and dynamics of an inhibitor-sensitive MAPK mutant, we demonstrated the generality of this strategy by sensitizing a kinase (apoptosis signal-regulating kinase 1) not in the MAPK family to several DFG-out stabilizing ligands, using the same residue positions. The use of specific inactive conformations may aid the study of noncatalytic roles of protein kinases, such as binding partner interactions and scaffolding effects. PMID- 23790492 TI - Family-wide investigation of PDZ domain-mediated protein-protein interactions implicates beta-catenin in maintaining the integrity of tight junctions. AB - beta-catenin is a multifunctional protein that plays a critical role in cell-cell contacts and signal transduction. beta-catenin has previously been shown to interact with PDZ-domain-containing proteins through its C terminus. Using protein microarrays comprising 206 mouse PDZ domains, we identified 26 PDZ-domain mediated interactions with beta-catenin and confirmed them biochemically and in cellular lysates. Many of the previously unreported interactions involved proteins with annotated roles in tight junctions. We found that four tight junction-associated PDZ proteins-Scrib, Magi-1, Pard3, and ZO-3-colocalize with beta-catenin at the plasma membrane. Disrupting these interactions by RNA interference, overexpression of PDZ domains, or overexpression of the beta catenin C terminus altered localization of the full-length proteins, weakened tight junctions, and decreased cellular adhesion. These results suggest that beta catenin serves as a scaffold to establish the location and function of tight junction-associated proteins. PMID- 23790493 TI - Insights into the generation of structural diversity in a tRNA-dependent pathway for highly modified bioactive cyclic dipeptides. AB - The nocazines are a newly defined family of antibacterial and cytotoxic cyclic dipeptides produced by different actinobacterial species. Here, we identify a nocazine biosynthetic gene cluster in Nocardiopsis dassonvillei and describe the elucidation of the biosynthetic pathway leading to the nocazine family members nocazine E and XR334. Diketopiperazine (DKP) formation is carried out by a tRNA dependent cyclodipeptide synthase (CDPS) showing an unknown product profile, while tailoring of the DKP-scaffold is achieved through the combined and combinatorial action of a cyclodipeptide oxidase and two distinct SAM-dependent O /N-methyltransferases. Our results help to illuminate the biosynthetic logic resulting in the structural diversity of the nocazine family and set the stage for exploring the biological function of modified cyclic dipeptides as possible mediators of host-pathogen and host-parasite interactions. PMID- 23790494 TI - Manipulation of regulatory genes reveals complexity and fidelity in hormaomycin biosynthesis. AB - Hormaomycin (HRM) is a structurally remarkable peptide produced by Streptomyces griseoflavus W-384 that acts as a Streptomyces signaling metabolite and exhibits potent antibiotic activity against coryneform actinomycetes. HRM biosynthetic studies have been hampered by inconsistent and low production. To enhance fermentation titers, the role of its cluster-encoded regulatory genes was investigated. Extra copies of the putative regulators hrmA and hrmB were introduced into the wild-type strain, resulting in an increase of HRM production and its analogs up to 135-fold. For the HrmB overproducer, six bioactive analogs were isolated and characterized. This study demonstrates that HrmA and HrmB are positive regulators in HRM biosynthesis. A third gene, hrmH, was identified as encoding a protein capable of shifting the metabolic profile of HRM and its derivatives. Its manipulation resulted in the generation of an additional HRM analog. PMID- 23790496 TI - Confocal laser scanning microscopy and optical coherence tomography for the evaluation of the kinetics and quantification of wound healing after fractional laser therapy. AB - BACKGROUND: Information on the course of wound healing after fractional carbon dioxide laser therapy has so far been gathered by histopathology. Confocal laser scanning microscopy (CLSM) and optical coherence tomography (OCT) allow the visualization of the upper layers of the skin in vivo over time. OBJECTIVE: The aim of this study was to determine whether CLSM and OCT can be used to quantify the kinetics of the dynamic wound-healing process. METHODS: Twenty healthy probands were treated with fractional carbon-dioxide laser with 8- and 16-W laser power, respectively. Optical follow-ups using CLSM and OCT were performed right after laser application and during the next 3 weeks. RESULTS: Although wound healing seems to be completed after day 7 to 14 clinically, on day 21 in 89.5% of the 8 W-treated areas and in 100% of the 16 W-treated areas subepidermal skin damage was still visible using CLSM and OCT imaging. LIMITATIONS: The maximal penetration depth of CLSM is limited to the papillary dermis, whereas OCT can visualize deeper but with lower resolution. CONCLUSION: In vivo CLSM and OCT are able to visualize changes after fractional laser treatment noninvasively. They allow especially the detection and quantification of substance defects and thereby help to elucidate the therapeutic effects. PMID- 23790495 TI - Knowledge-based design of a biosensor to quantify localized ERK activation in living cells. AB - Investigation of protein activation in living cells is fundamental to understanding how proteins are influenced by the full complement of upstream regulators they experience. Here, we describe the generation of a biosensor based on the DARPin binding scaffold suited for intracellular applications. Combining library selection and knowledge-based design, we created an ERK activity biosensor by derivatizing a DARPin specific for phosphorylated ERK with a solvatochromatic merocyanine dye, whose fluorescence increases upon pERK binding. The biosensor specifically responded to pERK2, recognized by its conformation, but not to ERK2 or other closely related mitogen-activated kinases tested. Activated endogenous ERK was visualized in mouse embryo fibroblasts, revealing greater activation in the nucleus, perinuclear regions, and especially the nucleoli. The DARPin-based biosensor will serve as a useful tool for studying biological functions of ERK in vitro and in vivo. PMID- 23790498 TI - Tibial cementing in UKA: a three-dimensional analysis of the bone cement implant interface and the effect of bone lavage. AB - Loosening is a common cause for revision in cemented UKA. In a cadaver study, we analyzed the three-dimensional cement distribution under the tibial implant and the effect of bone lavage (pulsed lavage, syringe lavage) on maximum cement penetration and penetration volume. Analyses were determined by performing bone cuts in medio-lateral direction and converting this data into a 3D model. Pulsed lavage led to an increased mean maximum cement penetration 5.79 +/- 2.63 mm and penetration volume 6471.34 +/- 1156.43 mm(3) compared to syringe lavage 4.62 +/- 2.61 mm, 5069.81 +/- 1177.09 mm(3) (P<0.001; P<0.001). Our results show a complete cement mantle for both investigated lavage techniques. Cleansing the cancellous tibial bone bed using pulsed lavage is more effective than conventional syringe lavage and leads to a deeper cement penetration and lager cement penetration volume under the tibial component. PMID- 23790497 TI - Characterization of mutants of a highly cross-reactive calcium-binding protein from Brassica pollen for allergen-specific immunotherapy. AB - The major turnip (Brassica rapa) pollen allergen, belongs to a family of calcium binding proteins (i.e., two EF-hand proteins), which occur as highly cross reactive allergens in pollen of weeds, grasses and trees. In this study, the IgE binding capacity and allergenic activity of three recombinant allergen variants containing mutations in their calcium-binding sites were analyzed in sensitized patients with the aim to identify the most suitable hypoallergenic molecule for specific immunotherapy. Analysis of the wildtype allergen and the mutants regarding IgE reactivity and activation of basophils in allergic patients indicated that the allergen derivative mutated in both calcium-binding domains had the lowest allergenic activity. Gel filtration and circular dichroism experiments showed that both, the wildtype and the double mutant, occurred as dimers in solution and assumed alpha-helical fold, respectively. However, both fold and thermal stability were considerably reduced in the double mutant. The use of bioinformatic tools for evaluation of the solvent accessibility and charge distribution suggested that the reduced IgE reactivity and different structural properties of the double mutant may be due to a loss of negatively charged amino acids on the surface. Interestingly, immunization of rabbits showed that only the double mutant but not the wildtype allergen induced IgG antibodies which recognized the allergen and blocked binding of allergic patients IgE. Due to the extensive structural similarity and cross-reactivity between calcium-binding pollen allergens the hypoallergenic double mutant may be useful not only for immunotherapy of turnip pollen allergy, but also for the treatment of allergies to other two EF-hand pollen allergens. PMID- 23790499 TI - The effect of tranexamic acid on transfusion rate in primary total hip arthroplasty. AB - Total hip arthroplasty (THA) may produce blood loss requiring allogenic blood transfusion. Recently several authors have reported success decreasing their transfusion rate with tranexamic acid (TXA). We retrospectively reviewed our last 1595 primary THA in 1494 patients looking at whether the patients received TXA via IV infusion, topical application, or neither, and the need for a blood transfusion. Infusion of TXA acid produced a statistically significant difference in transfusion rate (p<0.001) while topical TXA failed to reach statistical significance (P=0.15). The transfusion rate without TXA was 19.86%, 4.39% with TXA infusion (odds ratio=5.36), and 12.86% (odds ratio=1.67) with topical TXA. PMID- 23790500 TI - beta-blocking agents for surgery: influence on mortality and major outcomes. A meta-analysis. AB - OBJECTIVE: To re-evaluate the effects of perioperative beta-blockade on mortality and major outcomes after surgery. DESIGN: A meta-analysis of parallel randomized, controlled trials published in English. SETTING: A university-based electronic search. PARTICIPANTS: Patients undergoing surgery. INTERVENTIONS: Two interventions were evaluated: (1) Stopping or continuing a beta-blocker in patients on long-term beta-blocker therapy; and (2) Adding a beta-blocker for the perioperative period. MEASUREMENTS AND MAIN RESULTS: Stopping a beta-blocker before the surgery did not change the risk of myocardial infarction (3 studies including 97 patients): risk ratio (RR), 1.08 (95% confidence interval 0.30, 3.95); I(2), 0%. Adding a beta-blocker reduced the risk of death at 1 year: RR, 0.56 (0.31, 0.99); I(2), 0%; p = 0.046; number needed to treat 28 (19, 369) (4 studies with 781 patients). Adding a beta-blocker reduced the 0-to-30 day risk of myocardial infarction: RR, 0.65 (0.47, 0.88); I(2), 12.9%; p = 0.006 (15 studies with 12,224 patients), but increased the risk of a stroke: RR, 2.18 (1.40, 3.38); I(2), 0%; p = 0.001 (8 studies with 11,737 patients); number needed to harm 177 (512, 88). CONCLUSIONS: beta-blockers reduced the 1-year risk of death, and this effect seemed greater than the risk of inducing a stroke. PMID- 23790501 TI - New aspects in the pathophysiology of rapid eye movement sleep behavior disorder: the potential role of glutamate, gamma-aminobutyric acid, and glycine. AB - Rapid eye movement sleep behavior disorder (RBD) is a parasomnia characterized by the occurrence of intense movements during rapid eye movement (REM) sleep, also named paradoxical sleep. The neuronal dysfunctions at the origin of the loss of atonia in RBD patients are not known. One possibility is that RBD is due to the degeneration of neurons inducing the muscle atonia of REM sleep. Therefore, in our paper we review data on the populations of neurons responsible for the atonia of REM sleep before discussing their potential role in RBD. We first review evidence that motoneurons are tonically hyperpolarized by gamma-aminobutyric acid (GABA) and glycine and phasically excited by glutamate during REM sleep. Then, we review data indicating that the atonia of REM sleep is induced by glycinergic/GABAergic REM-on premotoneurons contained within the raphe magnus and the ventral and alpha gigantocellular reticular nuclei localized in the ventral medullary reticular formation. These neurons are excited during REM sleep by a direct projection from glutamatergic REM-on neurons localized in the pontine sublaterodorsal tegmental nucleus (SLD). From these results, we discuss the possibility that RBD is due to a specific degeneration of descending REM-on glutamatergic neurons localized in the caudal SLD or that of the REM-on GABA/glycinergic premotoneurons localized in the ventral medullary reticular formation. We then propose that movements of RBD are induced by descending projections of cortical motor neurons before discussing possible modes of action of clonazepam and melatonin. PMID- 23790502 TI - Periodontal disease reduces water and sodium intake induced by injection of muscimol into the lateral parabrachial nucleus. AB - OBJECTIVE: Gamma-aminobutyric acid A (GABAA) receptor activation with muscimol in the lateral parabrachial nucleus (LPBN) induces water and 0.3M NaCl intake. The purpose of this study was to investigate whether a local inflammatory event, such as periodontal disease (PD), is able to alter the effects of muscimol on water and 0.3M NaCl intake in fluid-replete rats and in rats treated with furosemide (FURO) combined with captopril (CAP) injected subcutaneously. DESIGN: Male Wistar rats were divided into two groups: with PD and those without PD (control condition). Fifteen days after PD, both groups had cannulas implanted bilaterally into the LPBN. RESULTS: In fluid-replete rats without PD, injections of muscimol (0.5nmol/0.2MUl) into the LPBN induced 0.3M NaCl and water intake and a pressor response. In fluid-replete rats with PD, a decrease was observed in water intake and pressor response but not in 0.3M NaCl intake. In control rats with FURO+CAP treatment, injections of muscimol into the LPBN increased 0.3M NaCl and water intake. In PD rats with FURO+CAP treatment, a decrease was observed in 0.3M NaCl and water intake after muscimol in the LPBN. Alveolar bone loss and interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) plasmatic concentration were higher in PD rats in comparison with controls. CONCLUSION: These results suggest that PD is able to reduce the pressor response and the dipsogenic and natriorexigenic effects induced by the activation of GABAA receptors in the LPBN, probably due to the elevation of the plasmatic concentration of pro-inflammatory cytokines IL-6 and TNF-alpha. PMID- 23790504 TI - Future of contact lens usage. PMID- 23790503 TI - Genes expressed in dental enamel development are associated with molar-incisor hypomineralization. AB - Genetic disturbances during dental development influence variation of number and shape of the dentition. In this study, we tested if genetic variation in enamel formation genes is associated with molar-incisor hypomineralization (MIH), also taking into consideration caries experience. DNA samples from 163 cases with MIH and 82 unaffected controls from Turkey, and 71 cases with MIH and 89 unaffected controls from Brazil were studied. Eleven markers in five genes [ameloblastin (AMBN), amelogenin (AMELX), enamelin (ENAM), tuftelin (TUFT1), and tuftelin interacting protein 11 (TFIP11)] were genotyped by the TaqMan method. Chi-square was used to compare allele and genotype frequencies between cases with MIH and controls. In the Brazilian data, distinct caries experience within the MIH group was also tested for association with genetic variation in enamel formation genes. The ENAM rs3796704 marker was associated with MIH in both populations (Brazil: p=0.03; OR=0.28; 95% C.I.=0.06-1.0; Turkey: p=1.22e-012; OR=17.36; 95% C.I.=5.98 56.78). Associations between TFIP11 (p=0.02), ENAM (p=0.00001), and AMELX (p=0.01) could be seen with caries independent of having MIH or genomic DNA copies of Streptococcus mutans detected by real time PCR in the Brazilian sample. Several genes involved in enamel formation appear to contribute to MIH. PMID- 23790505 TI - Long-term visual and ocular health outcomes of 2 sets of bilaterally aphakic siblings utilizing contact lens correction. AB - We report the long-term clinical courses of 8 aphakic eyes of 2 sets of siblings who used contact lenses for both refractive correction and amblyopia treatment following neonatal cataract extraction. Early cataract removal, aggressive contact lens use, and robust professional supervision seem to have substantially contributed to visual success in our four patients. All eyes did well visually with contact lenses, all developing acuities close to 20/20 despite contact lens and non-contact lens related complications that were managed. Complications of most concern were corneal neovascularization and glaucoma. We believe this to be the first case series documenting consistent long-term visual and ocular health outcomes of sets of bilaterally aphakic siblings optically treated with contact lenses. PMID- 23790506 TI - Roles of sunlight and natural ventilation for controlling infection: historical and current perspectives. AB - BACKGROUND: Infections caught in buildings are a major global cause of sickness and mortality. Understanding how infections spread is pivotal to public health yet current knowledge of indoor transmission remains poor. AIM: To review the roles of natural ventilation and sunlight for controlling infection within healthcare environments. METHODS: Comprehensive literature search was performed, using electronic and library databases to retrieve English language papers combining infection; risk; pathogen; and mention of ventilation; fresh air; and sunlight. Foreign language articles with English translation were included, with no limit imposed on publication date. FINDINGS: In the past, hospitals were designed with south-facing glazing, cross-ventilation and high ceilings because fresh air and sunlight were thought to reduce infection risk. Historical and recent studies suggest that natural ventilation offers protection from transmission of airborne pathogens. Particle size, dispersal characteristics and transmission risk require more work to justify infection control practices concerning airborne pathogens. Sunlight boosts resistance to infection, with older studies suggesting potential roles for surface decontamination. CONCLUSIONS: Current knowledge of indoor transmission of pathogens is inadequate, partly due to lack of agreed definitions for particle types and mechanisms of spread. There is recent evidence to support historical data on the effects of natural ventilation but virtually none for sunlight. Modern practice of designing healthcare buildings for comfort favours pathogen persistence. As the number of effective antimicrobial agents declines, further work is required to clarify absolute risks from airborne pathogens along with any potential benefits from additional fresh air and sunlight. PMID- 23790507 TI - PTSD and marital satisfaction in military service members: examining the simultaneous roles of childhood sexual abuse and combat exposure. AB - Childhood sexual abuse (CSA) is relatively common and is associated with a multitude of negative outcomes in adulthood, including posttraumatic stress disorder (PTSD) and lower marital satisfaction. However, CSA has been understudied in military samples. The purpose of the present study was to examine the relative contributions of CSA and combat exposure to PTSD and marital satisfaction. Two hundred eighteen National Guard/Reserve veterans who deployed overseas between 2001 and 2008 completed self-report measures of CSA, marital satisfaction, combat exposure, and PTSD symptom severity. Data were analyzed using linear regression and path analysis to evaluate a comprehensive model including all variables. CSA accounted for unique variance in PTSD symptom severity independent of combat exposure. CSA also had a negative direct association with marital satisfaction, independent of combat exposure and PTSD symptom severity. In contrast, combat exposure had only a negative indirect association with marital satisfaction via PTSD when all variables were examined simultaneously. CSA accounted for unique variance in both PTSD symptom severity and marital satisfaction in this sample of combat veterans. Clinically, results suggest that assessment and treatment of CSA is indicated for military veterans suffering from PTSD. Further, treatment of CSA may improve marital satisfaction, which may positively affect psychological functioning in the veteran. PMID- 23790508 TI - Child physical abuse risk moderates spontaneously inferred traits from ambiguous child behaviors. AB - The present study examined whether parents at high-risk for child physical abuse (CPA) differed from low-risk parents in their tendency to infer positive traits and negative traits from children's behaviors. The final sample consisted of 58 (25 low CPA risk and 33 high CPA risk) parents. Parents completed a false recognition task, which involved viewing behavior descriptions paired with child photographs. Half of the behavior descriptions vaguely/strongly implied a trait and half of the implied traits were positive/negative. The contributions of automatic processes and controlled processes to task performance were examined using process dissociation procedures. Low CPA risk parents were significantly less likely to indicate negative traits were present in behavioral descriptions of children when negative traits were vaguely (compared to strongly) implied. In contrast, high CPA risk parents were equally likely to indicate negative traits were present regardless of whether the traits were vaguely or strongly implied. For low (but not high) CPA risk parents, automatic processes contributed significantly less to task performance when negative traits were vaguely implied compared to when the same traits were strongly implied. Given that parenting involves negotiating a seemingly endless series of ambiguous behaviors as children grow and develop, the capacity to refrain from automatically attributing negative traits to children when they exhibit vaguely negative behaviors may serve an important function in reducing risk of aggressive parenting behavior. PMID- 23790509 TI - Neighborhood informal social control and child maltreatment: A comparison of protective and punitive approaches. AB - This paper introduces a new measure of informal social control of child maltreatment (henceforth ISC_CM) by neighbors. Research literature typically uses collective efficacy (Sampson, Raudenbush, & Earls, 1997) to examine neighborhood informal social control. We argue that double standards about the application of informal social control to family versus street crime requires a measure of informal social control specific to child maltreatment. We also argue that how neighbors intervene may matter as much as whether they intervene. Neighbors may engage in ISC_CM aimed at protecting the child and calming the parent, or more punitive ISC_CM aimed at deterring future abuse. We tested the relationship of both with very severe physical abuse and with abuse related child behavior problems. We used a random, 2-stage cluster design of Hanoi to collect the sample. Thirty Hanoi wards were randomly selected using probability proportional to size sampling. A simple random sample of families in each ward was then drawn using local government lists of ward residents. Based on power analysis, the target sample size was 300. Of 315 residents contacted, 293 participated, yielding a response rate of 93%. Random effects regression models (which estimate a random effect for each ward) were run in Stata11. We found that protective ISC_CM is associated with lower odds of very severe physical abuse and lower reported externalizing problems when abuse is present. Perceived collective efficacy and punitive ISC_CM is not associated with lower odds of very severe physical abuse. Implications for research, policy and practice are discussed. We conclude that further investigation of neighbor ISC_CM is needed to replicate the findings in other cultural contexts, ultimately followed by experimental manipulation of ISC_CM in a neighborhood context to examine the effects on child maltreatment. If further research corroborates the current findings, the development of neighborhood intervention programs to enhance protective ISC_CM may assist materially in reducing very severe child abuse and negative consequences stemming from such abuse. PMID- 23790510 TI - Medical dimensions of child abuse and neglect. PMID- 23790511 TI - Modifications in dynamic contrast-enhanced magnetic resonance imaging parameters after alpha-particle-emitting 227Th-trastuzumab therapy of HER2-expressing ovarian cancer xenografts. AB - PURPOSE: The purpose of this study was to investigate the effect of alpha particle-emitting (227)Th-trastuzumab radioimmunotherapy on tumor vasculature to increase the knowledge about the mechanisms of action of (227)Th-trastuzumab. METHODS AND MATERIALS: Human HER2-expressing SKOV-3 ovarian cancer xenografts were grown bilaterally in athymic nude mice. Mice with tumor volumes 253 +/- 36 mm(3) (mean +/- SEM) were treated with a single injection of either (227)Th trastuzumab at a dose of 1000 kBq/kg body weight (treated group, n=14 tumors) or 0.9% NaCl (control group, n=10 tumors). Dynamic T1-weighted contrast-enhanced magnetic resonance imaging (DCEMRI) was used to study the effect of (227)Th trastuzumab on tumor vasculature. DCEMRI was performed before treatment and 1, 2, and 3 weeks after therapy. Tumor contrast-enhancement curves were extracted voxel by voxel and fitted to the Brix pharmacokinetic model. Pharmacokinetic parameters for the tumors that underwent radioimmunotherapy were compared with the corresponding parameters of control tumors. RESULTS: Significant increases of kep, the rate constant of diffusion from the extravascular extracellular space to the plasma (P<.05), and kel, the rate of clearance of contrast agent from the plasma (P<.01), were seen in the radioimmunotherapy group 2 and 3 weeks after injection, compared with the control group. The product of kep and the amplitude parameter A, associated with increased vessel permeability and perfusion, was also significantly increased in the radioimmunotherapy group 2 and 3 weeks after injection (P<.01). CONCLUSIONS: Pharmacokinetic modeling of MRI contrast enhancement curves evidenced significant alterations in parameters associated with increased tumor vessel permeability and tumor perfusion after (227)Th trastuzumab treatment of HER2-expressing ovarian cancer xenografts. PMID- 23790512 TI - Modern radiation therapy for Hodgkin lymphoma: field and dose guidelines from the international lymphoma radiation oncology group (ILROG). AB - Radiation therapy (RT) is the most effective single modality for local control of Hodgkin lymphoma (HL) and an important component of therapy for many patients. These guidelines have been developed to address the use of RT in HL in the modern era of combined modality treatment. The role of reduced volumes and doses is addressed, integrating modern imaging with 3-dimensional (3D) planning and advanced techniques of treatment delivery. The previously applied extended field (EF) and original involved field (IF) techniques, which treated larger volumes based on nodal stations, have now been replaced by the use of limited volumes, based solely on detectable nodal (and extranodal extension) involvement at presentation, using contrast-enhanced computed tomography, positron emission tomography/computed tomography, magnetic resonance imaging, or a combination of these techniques. The International Commission on Radiation Units and Measurements concepts of gross tumor volume, clinical target volume, internal target volume, and planning target volume are used for defining the targeted volumes. Newer treatment techniques, including intensity modulated radiation therapy, breath-hold, image guided radiation therapy, and 4-dimensional imaging, should be implemented when their use is expected to decrease significantly the risk for normal tissue damage while still achieving the primary goal of local tumor control. The highly conformal involved node radiation therapy (INRT), recently introduced for patients for whom optimal imaging is available, is explained. A new concept, involved site radiation therapy (ISRT), is introduced as the standard conformal therapy for the scenario, commonly encountered, wherein optimal imaging is not available. There is increasing evidence that RT doses used in the past are higher than necessary for disease control in this era of combined modality therapy. The use of INRT and of lower doses in early-stage HL is supported by available data. Although the use of ISRT has not yet been validated in a formal study, it is more conservative than INRT, accounting for suboptimal information and appropriately designed for safe local disease control. The goal of modern smaller field radiation therapy is to reduce both treatment volume and treatment dose while maintaining efficacy and minimizing acute and late sequelae. This review is a consensus of the International Lymphoma Radiation Oncology Group (ILROG) Steering Committee regarding the modern approach to RT in the treatment of HL, outlining a new concept of ISRT in which reduced treatment volumes are planned for the effective control of involved sites of HL. Nodal and extranodal non-Hodgkin lymphomas (NHL) are covered separately by ILROG guidelines. PMID- 23790513 TI - Phosphorus-modified poly(styrene-co-divinylbenzene)-PAMAM chelating resin for the adsorption of uranium(VI) in aqueous. AB - Polyamidoamine (PAMAM) modified poly(styrene-co-divinylbenzene) absorbents carrying phosphorus functional groups (PS-PAMAM-PPA) were prepared and used as adsorbents for the adsorption of uranium(VI) from aqueous solution. Different generations of PAMAM were used for obtaining different chelating resins, PS-PPA, PS-1.0G PAMAM-PPA, PS-2.0G PAMAM-PPA, PS-3.0G PAMAM-PPA and PS-4.0G PAMAM-PPA. The synthesized resins were characterized by FTIR and XPS. The effects of many physio-chemical properties on metal ion adsorption to adsorbent phase, such as solution pH, kinetic studies, initial uranium concentration, temperature, were investigated using batch method. The results showed that the maximum adsorption capacity (99.89 mg/g) was observed at the pH 5.0 and 25 degrees C with initial U(VI) concentration 100mg/L and adsorbent dose 1g/L. PS-1.0G PAMAM-PPA had the largest adsorption capacity for U(VI) compared with other prepared adsorbents. The adsorption kinetics of U(VI) onto PS-1.0G PAMAM-PPA followed the mechanism of the pseudo-second-order equation, indicating that the chemical adsorption was a rate-limiting step. The calculated thermodynamic parameters (DeltaG, DeltaH, DeltaS) stated that the adsorption of U(VI) onto PS-1.0G PAMAM-PPA were spontaneous, endothermic and feasible. The adsorption isotherms obeyed the Langmuir isotherm models. The desorption studies showed that PS-1.0G PAMAM-PPA could be used repeatedly and adsorption and desorption percentage did not have any noticeable loss after 27 cycles in a fixed bed. PMID- 23790514 TI - Proteins, patients and plasma. PMID- 23790515 TI - Efficacy of the active middle-ear implant in patients with sensorineural hearing loss. AB - INTRODUCTION: This systematic review aims to advise on the effectiveness of the active middle-ear implant in patients with sensorineural hearing loss, compared with external hearing aids. METHODS: A systematic search of several electronic databases, including PubMed and Embase, was used to identify relevant studies for inclusion. RESULTS: Fourteen comparative studies were included. Nine studies reported on the primary outcome of functional gain: one found that the middle-ear implant was significantly better than external hearing aids (p < 0.001), while another found that external hearing aids were generally significantly better than middle-ear implants (p < 0.05). Six of the seven remaining studies found that middle-ear implants were better than external hearing aids, although generally no clinically significant difference (i.e. >= 10 dB) was seen. CONCLUSION: Generally, the active middle-ear implant appears to be as effective as the external hearing aid in improving hearing outcomes in patients with sensorineural hearing loss. PMID- 23790516 TI - ADHD, autism spectrum disorder, temperament, and character: phenotypical associations and etiology in a Swedish childhood twin study. AB - OBJECTIVE: To explore the links between neurodevelopmental disorders - attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) - and personality in a population-based, genetically sensitive study of children. METHOD: A population-based sample of 1886 twins aged 9 and 12, enriched for childhood mental health problems, was recruited from the Child and Adolescent Twin Study in Sweden (CATSS). Parents were interviewed over the telephone using the Autism-Tics, AD/HD and other Comorbidities (A-TAC) inventory, and in a second step they rated their children according to the Junior Temperament and Character Inventory (JTCI). RESULTS: ADHD was strongly correlated with novelty seeking, while ASD was correlated positively with harm avoidance and negatively with reward dependence. The strongest associations between personality traits and neurodevelopmental disorders were negative correlations between the character dimensions of self-directedness and cooperativeness and ADHD and ASD alike. Cross twin cross-trait correlations between ADHD, ASD, and personality dimensions in monozygotic twins were more than double those in dizygotic twins, indicating a strong genetic effect behind the phenotypic covariation between neurodevelopmental disorders and personality. CONCLUSIONS: Neurodevelopmental disorders are linked specifically to particular temperament profiles and generally to hampered development of the self-governing strategies referred to as "character." Poor self-agency and cooperation may be core functional outcomes in the separation of children with handicapping conditions from those with traits only reminiscent of neurodevelopmental disorders. The associations between neurodevelopmental disorders and personality are at least partly due to genetic effects influencing both conditions. As a consequence, personality must be broadly considered in neuropsychiatry, just as neuropsychiatric disorders and their genetic, neurodevelopmental, and cognitive susceptibilities have to be in personality research and clinical treatment. PMID- 23790517 TI - Follow-up of patients with systemic lupus erythematosus: what is not found in the guidelines. AB - A series of measures in the management of patients with systemic lupus erythematosus (SLE) which usually are not found in the lupus guidelines are discussed. In the lupus patient who has been well-controlled in the long term, the dose of hydroxychloroquine should be progressively reduced, without decreasing more than approximately 600 mg per week. We recommend taking this drug in the morning in patients with insomnia, at night in those with dyspepsia and to separate the intake of the drug from the shower (and the water should be as cool as possible) in those patients with aquagenic pruritus. We do not use prednisone on alternate days and exceptionally divide the dose into 3/4 before breakfast and 1/4 before dinner. Twenty to 30 min should be used per patient in every scheduled visit to assure a good clinical and human practice. We analyzed the follow-up of 112 consecutive patients from our systemic disease unit and found that 71.4% of them had symptoms that were unexplained by lupus and we only referred 8.9% of them to other specialists, probably because of our general training as internal medicine doctors. We suggest that knowing the views of SLE specialists might be of interest since, well-designed studies that would allow to progress in the understanding of this disease could be performed based on their experience. PMID- 23790518 TI - Explaining medically unexplained symptoms: somatizing patients' responses in primary care. AB - OBJECTIVE: To examine (1) how physicians present an explanation of symptoms in terms of a hormonal imbalance as a means to initiate a psychosocial discussion with somatizing patients; and (2) how they respond to this explanation of symptoms. METHODS: Qualitative study of 11 sequences in which physicians explain patients' symptoms in terms of a hormonal imbalance are micro-analyzed using Conversation Analysis. RESULTS: Symptom explanations (SEs) were vague, tentative, and uncertain. Two patterns of SEs (general vs. specific) and five different patterns of patient response were found. Patient responses are classified according to whether they occur during or after the SE, and according to the degree of work patients carry out to verbalize a response. CONCLUSION: Symptom explanations elicited varying degrees of patient agreement, and allowed physicians to obtain patients' permission to conduct a psychosocial exploration. PRACTICE IMPLICATIONS: Physicians may start SEs by associating symptoms to a hormonal imbalance, and by relating them to universally recognizable emotions and familiar situations. Excessive emphasis on long and complex SEs and on seeking extended verbalizations of patient agreement may be counterproductive and antagonize the patient. PMID- 23790519 TI - 30th anniversary editorial. PMID- 23790520 TI - Pearl 30th anniversary: nanotechnology & regenerative medicine. PMID- 23790521 TI - Substituent contribution to the genotoxicity of benzophenone-type UV filters. AB - Benzophenones (BPs) are widely used in UV filters, fragrance enhancers, and plastic additives. In this study, the genotoxicity of 14 BPs was tested using the SOS/umu assay, and the related substituent contribution was disclosed. The results of this study revealed that the major contributor to the genotoxicity of the BPs was the ortho,para-di-substitution, and the increasing hydroxy substitution on the benzene ring. In addition, the higher the dispersion of the substituent species on the two benzene rings, the lower the genotoxicity exhibited by the compound. Furthermore, 2 dimensional and 3 dimenional quantitative structure-activity relationships (2D- and 3D-QSAR) studies indicated that hydrogen-bond interactions and electrostatic effects were determinants for the genotoxicity of the BPs. The current results provide useful information for the assessment of the potential ecological risk and health effects of BP-type UV filters. PMID- 23790522 TI - Attic dust assessment near a wood treatment plant: past air pollution and potential exposure. AB - The wood treatment process uses substances that generate hazardous compounds that may contaminate environmental compartments. In the present study, an area under influence of a deactivated wood treatment plant was investigated to evaluate past air pollution and to try to understand local air dispersion. Attic dust samples were collected from eight residences around the plant and from two residences outside this area, as reference samples. The presence of copper, chromium, arsenic, pentachlorophenol, sixteen priority polycyclic aromatic hydrocarbons and mutagenic activity using Salmonella/microsome assay was evaluated. The residences close to the entrance to the plant were the most affected, according to potentially toxic elements analysis. The PCP concentration was 0.49 mg/kg and the total PAHs content ranged from 0.40 to 13.31 MUg/g with greater dispersion than potentially toxic elements. The highest mutagenesis values were 15,905 and 10,399 revertants/g of dust in the absence and presence of S9 mix (mammalian metabolic activation), respectively. Samples in which the total PAHs concentration was less than 2 MUg/g no mutagenic effects were observed, including the residences in the reference area. The contribution of PAHs to mutagenesis was 10 percent, indicating that other compounds may contribute to the mutagenic effect. These results suggest that the population was or is potentially exposed to substances with strong effects on health. PMID- 23790523 TI - Toxicological assessment of heavy metals accumulated in vegetables and fruits grown in Ginfel river near Sheba Tannery, Tigray, Northern Ethiopia. AB - The accumulation of heavy metals in vegetables resulting from irrigation with contaminated water obtained from industrial effluents may create a potential public health risk. We quantified the concentration of heavy metals (Cu, Zn, Fe, Mn, Cr, Cd, Ni, Co and Pb) in soil, vegetables and the water used for irrigation at two sites (Laelay Wukro and Tahtay Wukro) around Wukro Town, Tigray, Northern Ethiopia. The concentrations of heavy metals in irrigation water measured during this study were lower than permissible limits of heavy metals allowed for irrigation water. The mean concentrations of heavy metals in irrigated soil samples obtained from Tahtay Wukro were higher for Mn, Zn, Cr, and Cu. The overall results of soil samples ranged 2.62-827, 1.4-51.6, 25.5-33.6, 23.5-28.2, 2.52-25.1, 15-17.8, 3-4, 2.5-40.49 and 0.7-0.8 mg/kg for Mn, Zn, Cr, Ni, Cu, Co, Pb, Fe and Cd, respectively. Higher concentrations of heavy metals were also observed in vegetable samples from Tahtay Wukro. Pb was found to accumulate the most in all vegetable samples. It was observed that green pepper and lettuce accumulate high amounts of Cu and Zn; Swiss chard accumulates excessive amounts of Fe, Mn, Cr, Cd, Ni and Co; lettuce and tomato higher amounts of Cd; and green pepper, tomato and onion a higher concentration of Pb. Significant differences in the elemental concentrations between the vegetables analyzed from Laelay and Tahtay Wukro were observed. This was attributed in part to the geological nature of the study area and the discharges from the town and from a tannery. The results also indicate that Fe, Pb and Cd have high transfer factor values (mean values: 42.89, 0.84 and 0.37, respectively). The transfer pattern for heavy metals in different vegetables showed a trend in the order: Fe>Pb>Cd>Mn>Cu>Zn>Ni>Zn>Cr=Co. The heavy metal contamination of vegetables grown in Tahtay Wukro, located downstream of the tannery, may pose increased health risks in the future to the local population through consumption of vegetables. PMID- 23790524 TI - Usefulness of a simple sleep-deprived EEG protocol for epilepsy diagnosis in de novo subjects. AB - OBJECTIVE: In case series concerning the role of EEG after sleep deprivation (SD EEG) in epilepsy, patients' features and protocols vary dramatically from one report to another. In this study, we assessed the usefulness of a simple SD-EEG method in well characterized patients. METHODS: Among the 963 adult subjects submitted to SD-EEG at our Center, in the period 2003-2010, we retrospectively selected for analysis only those: (1) evaluated for suspected epileptic seizures; (2) with a normal/non-specific baseline EEG; (3) still drug-free at the time of SD-EEG; (4) with an MRI analysis; (5) with at least 1 year follow-up. SD-EEG consisted in SD from 2:00 AM and laboratory EEG from 8:00 AM to 10:30 AM. We analyzed epileptic interictal abnormalities (IIAs) and their correlations with patients' features. RESULTS: Epilepsy was confirmed in 131 patients. SD-EEG showed IIAs in 41.2% of all patients with epilepsy, and a 91.1% specificity for epilepsy diagnosis; IIAs types observed during SD-EEG are different in generalized versus focal epilepsies; for focal epilepsies, the IIAs yield in SD EEG is higher than in second routine EEG. CONCLUSIONS: This simple SD-EEG protocol is very useful in de novo patients with suspected seizures. SIGNIFICANCE: This study sheds new light on the role of SD-EEG in specific epilepsy populations. PMID- 23790525 TI - Intracranial EEG evaluation of relationship within a resting state network. AB - OBJECTIVE: We tested if a relationship between distant parts of the default mode network (DMN), a resting state network defined by fMRI studies, can be observed with intracranial EEG recorded from patients with localization-related epilepsy. METHODS: Magnitude squared coherence, mutual information, cross-approximate entropy, and the coherence of the gamma power time-series were estimated, for one hour intracranial EEG recordings of background activity from 9 patients, to evaluate the relationship between two test areas which were within the DMN (anterior cingulate and orbital frontal, denoted as T1 and posterior cingulate and mesial parietal, denoted as T2), and one control area (denoted as C), which was outside the DMN. We tested if the relationship between T1 and T2 was stronger than the relationship between each of these areas and C. RESULTS: A low level of relationship was observed among the 3 areas tested. The relationships among T1, T2 and C did not demonstrate support for the DMN. CONCLUSIONS: This study suggests a lack of intracranial EEG support for the fMRI defined default mode network. SIGNIFICANCE: The results obtained underscore the considerable difference between electrophysiological and hemodynamic measurements of brain activity and possibly suggest a lack of neuronal involvement in the DMN. PMID- 23790526 TI - Using 222Rn to estimate submarine groundwater discharge (SGD) and the associated nutrient fluxes into Xiangshan Bay, East China Sea. AB - Continuous radon ((222)Rn) monitoring was conducted at two stations (site A and site B) with different perpendicular distance from the shoreline in Xiangshan Bay, East China Sea. Based on a (222)Rn balance model (various sources and sinks of (222)Rn in coastal water), the average rate of SGD was estimated to be 0.69 cm/day and 0.23 cm/day for site A and site B, respectively. The results from a nutrient analysis of the groundwater indicate that the associated nutrients fluxes loading through the SGD pathway were 4.27*10(6) mol/day for DIN, 2.24*10(4) mol/day for DIP and 1.82*10(6) mol/day for DSi, respectively, which were comparable to or even higher than the levels observed in the local streams. Therefore, adequate attention should be paid to the importance of SGD as one source of nutrients during the eutrophication control process in this area. PMID- 23790527 TI - Neonatal seizures: the journey so far. PMID- 23790528 TI - Dipeptidyl peptidase-4 inhibitor anagliptin ameliorates diabetes in mice with haploinsufficiency of glucokinase on a high-fat diet. AB - OBJECTIVE: Type 2 diabetes is a chronic metabolic disorder characterized by hyperglycemia with insulin resistance and impaired insulin secretion. DPP-4 inhibitors have attracted attention as a new class of anti-diabetic agents for the treatment of type 2 diabetes. We investigated the effects of anagliptin, a highly selective DPP-4 inhibitor, on insulin secretion and insulin resistance in high-fat diet-fed mice with haploinsufficiency of glucokinase (GckKO) as animal models of type 2 diabetes. MATERIALS/METHODS: Wild-type and GckKO mice were administered two doses of anagliptin by dietary admixture (0.05% and 0.3%) for 10weeks. RESULTS: Both doses of anagliptin significantly inhibited the plasma DPP 4 activity and increased the plasma active GLP-1 levels in both the wild-type and GckKO mice to a similar degree. After 10weeks of treatment with 0.3% anagliptin, body weight gain and food intake were significantly suppressed in both wild-type and GckKO mice. In addition, 0.3% anagliptin ameliorated insulin resistance and glucose intolerance in both genotypes of mice. On the other hand, treatment with 0.05% anagliptin was not associated with any significant change of the body weight, food intake or insulin sensitivity in either genotype of mice, but it did improve the glucose tolerance by enhancing insulin secretion and increasing the beta-cell mass in both genotypes of mice. CONCLUSIONS: High-dose anagliptin treatment improved glucose tolerance by suppression of body weight gain and amelioration of insulin resistance, whereas low-dose anagliptin treatment improved glucose tolerance by enhancing insulin secretion. PMID- 23790529 TI - Efficacy of single or paired intrastromal corneal ring segment implantation combined with collagen crosslinking in keratoconus. AB - PURPOSE: To evaluate the efficacy of single or paired intrastromal corneal ring segments (ICRS) combined with ultraviolet-A and riboflavin collagen crosslinking (CXL) in patients with keratoconus. SETTING: Cornea Unit, Toronto Western Hospital, Toronto, Ontario, Canada. DESIGN: Retrospective comparative case series. METHODS: Consecutive patients with keratoconus had femtosecond laser assisted ICRS implantation combined with same-day CXL between 2008 and 2011. The main outcome measures included improvement in visual acuity, subjective refractive error, keratometry values, and total higher-order aberration (HOA). RESULTS: Eighty-five eyes of 74 patients with keratoconus (paired ICRS: 47 eyes of 40 patients; single ICRS: 38 eyes of 34 patients) were included in the study. The uncorrected distance visual acuity was significantly improved after single ICRS (3.4 lines; P=.04) and paired ICRS (2.7 lines; P=.01) implantation combined with CXL, while corrected distance visual acuity (CDVA) remained stable. The single and paired ICRS groups had a significant reduction in mean cylinder at 1 year (single ICRS: -3.84 diopters [D] +/- 1.72 [SD] versus -2.19 +/- 1.54 D, P=.02; paired ICRS: -3.91 +/- 1.45 D versus -2.96 +/- 1.92 D) (P=.02). There was no significant difference in total HOAs. Single ICRS implantation and paired ICRS implantation with CXL were equivalent in all refractive parameters. No patient lost lines of CDVA. CONCLUSION: As determined by corneal topography, implantation of single or paired ICRS combined with same-day CXL was safe and effective in patients with keratoconus. PMID- 23790530 TI - Transepithelial corneal collagen crosslinking for progressive keratoconus: 24 month clinical results. AB - PURPOSE: To assess the clinical results of transepithelial collagen crosslinking (CXL) in patients 26 years and younger with progressive keratoconus suitable for epithelium-off (epi-off) CXL. SETTING: Department of Ophthalmology, Siena University Hospital, Siena, Italy. DESIGN: Prospective case series. METHODS: The study included 26 eyes (26 patients) treated by transepithelial (epithelium-on) CXL. The mean age was 22 years (range 11 to 26 years) (10 younger than 18 years; 16 between 19 years and 26 years). Preoperative and postoperative examinations included uncorrected (UDVA) and corrected (CDVA) distance visual acuities, simulated maximum keratometry (K), coma and spherical aberration, and corneal optical coherence tomography optical pachymetry. The solution for transepithelial CXL (Ricrolin TE) comprised riboflavin 0.1%, dextran 15.0%, trometamol (Tris), and ethylenediaminetetraacetic acid. Ultraviolet-A treatment was performed with the Caporossi Baiocchi Mazzotta X Linker Vega at 3 mW/cm(2). RESULTS: After relative improvement in the first 3 to 6 months, the UDVA and CDVA gradually returned to baseline preoperative values. After 12 months of stability, the simulated maximum K value worsened at 24 months. Coma aberration showed no statistically significant change. Spherical aberration increased at 24 months. Pachymetry showed a progressive, statistically significant decrease at 24 months. Fifty percent of pediatric patients were retreated with epi-off CXL due to significant deterioration of all parameters after 12 months of follow-up. CONCLUSIONS: Functional results after transepithelial CXL showed keratoconus instability, in particular in pediatric patients 18 years old and younger; there was also functional regression in patients between 19 years and 26 years old after 24 months of follow-up. mentioned. PMID- 23790531 TI - Transepithelial corneal collagen crosslinking for progressive keratoconus in a pediatric age group. AB - PURPOSE: To evaluate the effectiveness and safety of transepithelial corneal collagen crosslinking (CXL) in children with keratoconus and the refractive changes induced by this treatment. SETTING: Ophthalmology Department, Ain-Shams University Hospitals, Cairo, Egypt. DESIGN: Prospective comparative case series. METHODS: Patients younger than 18 years with bilateral keratoconus had transepithelial CXL with the use of transepithelial riboflavin. The other eye was used as a control and was treated conservatively. The uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), and corneal tomography at 12 months were the main outcome measures. RESULTS: The mean age of the 22 patients (22 eyes) was 15.7 years +/- 2.1 (SD). After transepithelial CXL, the improvement in the mean UDVA was statistically significant (from 0.95 +/- 0.34 logMAR to 0.68 +/- 0.45 logMAR) (P<.05). No eye lost lines of preoperative UDVA; 1 eye lost 1 line of preoperative CDVA. There was no improvement in the control group in UDVA or CDVA (P>.05). The mean simulated keratometry (K) decreased by a mean of 2.03 diopters (D), with mean flattening of the apical K by 2.20 D; both results were statistically significant (P<.05). In the control group, the simulated K increased by a mean of 0.59 D (P>.05), with mean steepening of the apical K by 2.9 D (P<.05). No significant changes occurred in the endothelial cell count in either group. CONCLUSION: Preliminary results of transepithelial CXL in children with keratoconus were encouraging, with no evidence of progression of keratoconus over 12 months. PMID- 23790532 TI - [Transfusional independence in a patient with refractory anemia with excess blasts-2 refractory to 5-azacitidine treated with deferasirox and colony stimulating factors]. PMID- 23790533 TI - Plant regeneration via somatic embryogenesis and shoot organogenesis from immature cotyledons of Camellia nitidissima Chi. AB - Camellia nitidissima Chi (Theaceae) is a world-famous economic and ornamental plant with golden-yellow flowers. It has been classified as one of the rarest and most endangered plants in China. Our objective was to induce somatic embryogenesis, shoot organogenesis and plant regeneration for C. nitidissima. Three types of callus (whitish, reddish and yellowish) were induced from immature cotyledons on improved woody plant medium (WPM) with different plant growth regulators (PGRs). Among the callus, whitish callus was induced by 4.5 MUM 2,4 dichlorophenoxyacetic acid (2,4-D) and reddish and yellowish callus were induced by strongly active cytokinins, thidiazuron (TDZ) or 6-benzylaminopurine (BAP), singly or combined with weakly active auxin, alpha-naphthaleneacetic acid (NAA). The embryogenic callus could differentiate into somatic embryos, nodular embryogenic structures (large embryo-like structures) or adventitious shoots depending on the PGR used in WPM. BAP was best for adventitious buds and zeatin was best for somatic embryogenesis while kinetin (Kt) was best for the formation of nodular embryogenic structures. The three regeneration pathways often occurred in the same embryogenic callus clumps. Most shoots (80.0%) developed roots in WPM supplemented with 24.6 MUM IBA and 0.3 MUM NAA while 47.5% of somatic embryos could germinate directly and develop into plantlets on induction medium supplemented with 0.9 MUM BAP and 0.1 MUM NAA. The nodular embryogenic structures could be sub-cultured and cyclically developed in one of two differentiation pathways: shoot organogenesis or somatic embryogenesis. Plantlets derived from shoot buds rooted and somatic embryos germinated when transplanted into soil in a greenhouse; 66.7% of plantlets from shoot culture and 78.6% of plantlets from somatic embryos survived after 8 weeks' acclimatization. PMID- 23790534 TI - Host pathogen interactions at the coalface of immunity. PMID- 23790535 TI - Kinematic changes during running-induced fatigue and relations with core endurance in novice runners. AB - OBJECTIVES: This study aimed to investigate kinematic changes experienced during running-induced fatigue. Further, the study examined relations between kinematic changes and core endurance. DESIGN: Repeated measures and correlation. METHODS: Seventeen novice runners participated in a running-induced fatigue protocol and underwent core endurance assessment. Participants ran at a steady state corresponding to an intensity of 13 on the Borg scale and continued until 2min after a Borg score of 17 or 90% of maximum heart rate was reached. Kinematic data were analyzed for the lower extremities and trunk throughout a running protocol and, on separate days, core endurance measures were recorded. Changes in pre- and post-fatigue running kinematics and their relations with core endurance measures were analyzed. RESULTS: Analysis of peak joint angles revealed significant increases in trunk flexion (4 degrees ), decreases in trunk extension (3 degrees ), and increases in non-dominant ankle eversion (1.6 degrees ) as a result of running-induced fatigue. Post-fatigue increased trunk flexion changes displayed a strong to moderate positive relation with trunk extensor core endurance measures, in contrast to expected negative relations. CONCLUSIONS: Novice runners displayed an overall increase in trunk inclination and increased ankle eversion peak angles when fatigued utilizing a running-induced fatigue protocol. As most pronounced changes were found for the trunk, trunk kinematics appear to be significantly affected during fatigued running and should not be overlooked. Core endurance measures displayed unexpected relations with running kinematics and require further investigation to determine the significance of these relations. PMID- 23790536 TI - Increased BCL2L12 expression predicts the short-term relapse of patients with TaT1 bladder cancer following transurethral resection of bladder tumors. AB - OBJECTIVES: More than half of the diagnosed patients with bladder cancer (BCa) recur at least once following their initial treatment. Thus, patients' monitoring and prognosis is of utmost importance. However, the need for intensive surveillance of BCa significantly burdens patients' health-related quality of life. The aim of the present study is the expression analysis of BCL2L12, a recently identified member of the BCL2 apoptosis-related gene family, in BCa and the evaluation of BCL2L12 prognostic significance for the survival outcome of the patients. METHODS AND MATERIALS: Our study included 115 patients with BCa, and tissue specimens were obtained from the tumor area as well as from adjacent normal bladder wall. BCL2L12 expression was determined using quantitative real time polymerase chain reaction assay, and was further correlated with patients' clinicopathological features and follow-up survival data. RESULTS: Up-regulated BCL2L12 expression levels were detected in malignant bladder specimens compared with normal ones. The higher BCL2L12 expression was further associated with shorter disease-free survival of the patients with BCa. Focusing on patients with TaT1 non-muscle invasive BCa, BCL2L12 expression levels were correlated with higher recurrence rate at the first follow-up cystoscopy and were unveiled to be an independent unfavorable predictor of patients' short-term recurrence following transurethral resection. Finally, BCL2L12 expression levels were also associated with poor disease-free survival of the high-grade TaT1 patients. CONCLUSIONS: Our data highlight the unfavorable prognostic value of BCL2L12 for patients with BCa and support its potential clinical use for the assessment of TaT1 patients' recurrence risk. PMID- 23790537 TI - Cryotherapy and its applications in the management of urologic malignancies: a review of its use in prostate and renal cancers. AB - Cryotherapy has been established as an ablative modality for the treatment of a wide range of malignancies. Being minimally invasive, it is associated with less morbidity than conventional extirpative surgical procedures. In recent years, it has been used with success for treating two of the common urologic malignancies, that is, prostate and renal cancer. In this review, we highlight the role of cryotherapy as a treatment modality, the proposed destructive mechanisms of action and the risks of its use in the management of prostate and renal malignancy. PMID- 23790538 TI - Elective extracorporeal membrane oxygenation bridge to recovery in otherwise "unusable" donor hearts for children: Preliminary outcomes. PMID- 23790539 TI - Design, synthesis and biological studies of novel tubulin inhibitors. AB - A series of compounds originally derived from the vascular endothelial growth factor receptor tyrosine kinase inhibitor, SU5416, were synthesized and evaluated. The most potent compound in this series, compound 3, which structurally resembles the potent anti-microtubule agent combretastatin A-4, inhibited tubulin polymerization and showed potent growth inhibitory activities on both prostate and breast cancer lines with IC50 values in the low nanomolar range. PMID- 23790540 TI - Structure-based design of flavone-based inhibitors of wild-type and T315I mutant of ABL. AB - The existence of drug resistance caused by mutations in the break-point cluster region-Abelson (BCR-ABL) tyrosine kinase domain remains a clinical challenge due to limited treatment options for effective CML therapies. Here, we report a series of flavone-based common inhibitors equipotent for the wild type and the most drug-resistant T315I mutant of BCR-ABL. The original hit 1 was extensively modified through a structure-based drug design strategy, especially by varying the C7 acetamide appendage of the scaffold to exploit extended interactions with P-loop residues. Structural features relevant to the stabilization of the newly identified inhibitors in the ATP-binding site of ABL are discussed in detail. PMID- 23790541 TI - Synthesis of artemisinin dimers using the Ugi reaction and their in vitro efficacy on breast cancer cells. AB - The Ugi four-component reaction was used to prepare a series of artemisinin monomers and dimers. We found that the endoperoxide group in artemisinin remains intact during the reaction. The new artemisinin dimers showed potent anti-cancer activity against two human breast cancer cell lines, MDA-MB-231 and BT-474. One of the Ugi artemisinin dimers showed an IC50 value of 12 nM when tested on BT474 cells, more than 600 times more potent than artesunate. Furthermore, the same Ugi artemisinin dimer showed a low toxicity when tested on MCF10A, a nontumorigenic cell line, resulting in a selectivity index of more than 8000. PMID- 23790542 TI - Plasma klotho levels decrease in both anorexia nervosa and obesity. AB - OBJECTIVE: The aim of this study was to examine the associations of klotho with body mass index (BMI) in patients with restricting-type anorexia nervosa (r-AN) and obesity. METHOD: We examined plasma klotho as well as adiponectin and its isoform levels in comparison in 11 obese patients, 12 r-AN patients, and 11 control participants. RESULTS: Plasma klotho levels were markedly lower in the obesity and r-AN groups than in the control group. Moreover, plasma klotho levels increased significantly after the recovery of BMI in r-AN patients. Total and high-molecular-weight adiponectin levels were significantly decreased only in obesity. There was no relationship between klotho and total adiponectin levels or klotho and respective adiponectin isoform levels in the entire study population. CONCLUSIONS: These results suggest that klotho may reflect normal nutritional state, and that the decrease of klotho in r-AN and obesity may underlie the deteriorating processes of these disorders. PMID- 23790543 TI - Reliable cutoff selection for total plasma homocysteine levels in prepubertal children: re. Homocysteine and cysteine levels in prepubertal children: association with waist circumference and lipid profile. PMID- 23790544 TI - Age and sex patterns of drug prescribing in a defined American population. AB - OBJECTIVE: To describe the age and sex patterns of drug prescribing in Olmsted County, Minnesota. PATIENTS AND METHODS: Population-based drug prescription records for the Olmsted County population in 2009 were obtained using the Rochester Epidemiology Project medical records linkage system (n=142,377). Drug prescriptions were classified using RxNorm codes and were grouped using the National Drug File-Reference Terminology. RESULTS: Overall, 68.1% of the population (n=96,953) received a prescription from at least 1 drug group, 51.6% (n=73,501) received prescriptions from 2 or more groups, and 21.2% (n=30,218) received prescriptions from 5 or more groups. The most commonly prescribed drug groups in the entire population were penicillins and beta-lactam antimicrobials (17%; n=23,734), antidepressants (13%; n=18,028), opioid analgesics (12%; n=16,954), antilipemic agents (11%; n=16,082), and vaccines/toxoids (11%; n=15,918). However, prescribing patterns differed by age and sex. Vaccines/toxoids, penicillins and beta-lactam antimicrobials, and antiasthmatic drugs were most commonly prescribed in persons younger than 19 years. Antidepressants and opioid analgesics were most commonly prescribed in young and middle-aged adults. Cardiovascular drugs were most commonly prescribed in older adults. Women received more prescriptions than men for several drug groups, in particular for antidepressants. For several drug groups, use increased with advancing age. CONCLUSION: This study provides valuable baseline information for future studies of drug utilization and drug-related outcomes in this population. PMID- 23790545 TI - Molecular and serological prevalence of Babesia bovis and Babesia bigemina in water buffaloes in the north region of Brazil. AB - Bovine babesiosis is a tick-borne disease caused mainly by Babesia bovis and Babesia bigemina, which are associated to considerable economic losses in cattle herds worldwide. Approximately 60% of buffalo herds in South America are located in Northern Brazil. Little is known about the impact of babesiosis on buffalo herds in Brazil. The present work aimed to verify the occurrence of B. bovis and B. bigemina in 542 water buffaloes in the state of Para, Northern Brazil, using molecular and serological techniques. The percentage of seropositive animals for B. bovis and B. bigemina was 41.2% and 19.0%, respectively, by ELISA. B. bovis and B. bigemina DNA were detected in 15 and 16% of sampled buffaloes, respectively. A high correlation (Kappa index of 0.9) between serological and molecular tests suggests that the combination of the utilized techniques in the present study is suitable for babesiosis diagnosis in an endemic unstable area. Significantly difference of positivity for serological and molecular assays was verified to localities and reproductive status of sampled animals, but not between buffalo breeds. The immune status of sampled buffaloes associated to the circulation of babesiosis agents in sampled population suggests that the studied area is at risk to clinical babesiosis outbreaks. Furthermore, this study demonstrated that this region can be classified as endemically unstable. PMID- 23790546 TI - First serosurvey of Besnoitia spp. infection in wild European ruminants in Spain. AB - Besnoitia besnoiti has been reported to affect cattle, wildebeest, kudu and impala, and B. tarandi other wild ruminants (caribou, reindeer, mule deer and musk ox), causing similar characteristic clinical signs and lesions. However, both Besnoitia species have been reported in different geographical areas and the link between the sylvatic and domestic life cycles of Besnoita spp. in wild ruminants and cattle remains unknown. The aim of this study was to evaluate the presence of specific antibodies against Besnoitia spp. in wild ruminants in Spain. A wide panel of sera from red deer (Cervus elaphus) (n=734), roe deer (Capreolus capreolus) (n=124), chamois (Rupicapra pyrenaica) (n=170) and mouflon (Ovis musimon) (n=20) collected from different locations of Spain was analyzed. Beef cattle were present in all sampled areas and, interestingly, bovine besnoitiosis has been widely reported in some of them (e.g., Pyrenees and Central Spain). Sera samples were first examined with an Enzyme-Linked Immunosorbent Assay (ELISA). For red deer and roe deer, the ELISA was standardized with positive and negative control sera from several Cervidae species (100% Se and 98% Sp). Chamois and mouflon sera samples were tested with a previously reported ELISA validated for bovine sera (97% Se and 95% Sp) using protein G as a conjugate. Positive results by ELISA were confirmed a posteriori with a tachyzoite-based Western blot. Sixty-one sera samples from red deer and 17 sera samples from roe-deer were seropositive or doubtful by ELISA. All samples from mouflon were seronegative and 15 sera samples from chamois were considered doubtful. B. besnoiti exposure was only confirmed clearly by Western blot in one red deer and one roe deer from the Spanish Pyrenees where the disease is traditionally endemic. This is the first serological report of Besnoitia spp. infection carried out in European wild ruminants and the results show that specific antibodies are present at least in red deer and roe-deer. Thus, wild ruminants from endemic regions of bovine besnoitiosis should be further studied because they may be putative reservoirs of the parasite. PMID- 23790547 TI - Characterization of a trifunctional fatty acid desaturase from oleaginous filamentous fungus Mortierella alpina 1S-4 using a yeast expression system. AB - A omega3-fatty acid desaturase gene (maw3) which is involved in biosynthesis of n 3 polyunsaturated fatty acids (PUFAs) was previously isolated from Mortierella alpina 1S-4. In this report, we investigated the products of MAW3 catalyzing reaction with endogenous and exogenous fatty acids in the yeast transformant. Two unusual fatty acids de novo synthesized in the yeast transformant expressing maw3 gene were identified as n-4 hexadecadienoic acid (16:2(9cis,12cis)) and n-1 hexadecatrienoic acid (16:3(9cis,12cis,15)) by GC-MS and (1)H NMR analyses. In addition to the desaturation activity at the omega3-position for 18- and 20 carbon PUFAs, MAW3 in the yeast transformant inserted a double bond at Delta12 position of endogenous palmitoleic acid (16:1(9cis)) and further at Delta15 position of the resulting 16:2(9cis,12cis) to result in the formation of 16:3(9cis,12cis,15) leading to a bifunctional Delta12/Delta15-desaturase for 16 carbon fatty acids. Moreover, we evaluated the activity of MAW3 in the yeast transformant under different temperatures. The MAW3 did not have desaturation activities in M. alpina 1S-4 at 28 degrees C but it had in the yeast transformant for various fatty acids. The MAW3 was demonstrated to be a trifunctional Delta12/Delta15/omega3-desaturase, exhibiting Delta12-desaturation for 16:1(9cis), Delta15-desaturation for 16- and 18-carbon fatty acids that had a preexisting cis-double bond at Delta12 position, and omega3-desaturation for 20 carbon fatty acids having that at Delta14-position. It is the first report that the fatty acid desaturase (MAW3) is shown to have Delta12- and Delta15 desaturation activities for a 16-carbon fatty acid, in addition to its major function, omega3-desaturation activity. PMID- 23790548 TI - Directed evolution study unveiling key sequence factors that affect translation efficiency in Escherichia coli. AB - Synonymous mutations in protein coding genes significantly impact translation efficiency. We synthesized a pair of genes encoding green fluorescent protein that were separated by 160 synonymous mutations to investigate key factors that affect translation efficiency. One sequence was optimized for Escherichia coli (GFP(Eco)) and the other for Bacillus subtilis (GFP(Bsu)). When the genes were expressed in E. coli, GFP(Eco) fluoresced 12-fold stronger than GFP(Bsu), confirming the suboptimal nature of the GFP(Bsu) gene. We then employed directed evolution to improve the expression of GFP(Bsu). Random mutagenesis and DNA shuffling was used to generate mutant libraries, which were screened for fluorescence. A variant showing 6-fold fluorescence enhancement was identified, which contained a single mutation (G10A) in a rare codon for Gly-4. However, the substitution generated another type of rare codon, AGA, for Arg, suggesting that the improvement was caused by a factor other than the rare codon. We next applied saturation mutagenesis to Gly-4. The darkest variant contained a GGG codon (GFP(Bsu)-G) for Gly-4. Taking the location of the mutation into account, we hypothesized that destabilization of the mRNA secondary structure around the initiation codon improved the expression. We then randomized the nucleotide triplet in 5'-untranslated region (5'UTR) of GFP(Bsu), which is complementary to the Gly-4 codon. A variant showing 6-fold fluorescence enhancement was identified, which exhibited a destabilized secondary structure. When this 5'UTR sequence was combined with GFP(Bsu)-G, 22-fold fluorescent improvement was achieved. Collectively, the stability of the mRNA secondary structure around the initiation codon predominantly affected the translation efficiency. PMID- 23790549 TI - The failing right ventricle in congenital heart disease. AB - In congenital heart disease (CHD) the right ventricle (RV) dons a variety of hats. It might be situated in the normal subpulmonary position and function as half of a 2-pump circulation, but nonetheless be subjected to abnormal loading conditions, surgical interventions, or electrical disturbance. Alternatively, it can be required to generate systemic cardiac output; either in the context of a univentricular circulation or else in concert with a subpulmonary left ventricle. Each role carries different hemodynamic stresses and physiologic demands and the long-term capacity of the RV to withstand the stresses and meet those demands has become recognized as a key contributor to late clinical outcomes. RV failure in CHD usually has an etiology and pathophysiology quite different from RV failure in other circumstances and there is little evidence to support direct transition of treatments well established in acquired heart failure in this patient group. In this review we discuss the requirements for normal RV function, situations in CHD in which the RV is prone to failure, the pathophysiology of RV dysfunction, and potential therapeutic options. PMID- 23790550 TI - Pharmacogenomics and heart failure in congenital heart disease. AB - Congenital heart disease (CHD) constitutes a lifelong challenge in heart failure management. Current therapy is based mainly on physiologic principles extrapolated from the management of left ventricular failure in adult populations with either ischemic or nonischemic cardiomyopathy. However, there is good evidence of genomic variability in the origin and progression of CHD that suggests the need for a individualized approach to treatment. The developing science of pharmacogenomics presents an opportunity for CHD management broadly, and especially in the context of heart failure. There is growing evidence that individualizing drug therapy for these patients might be beneficial, and that prediction of response to therapy might be possible by incorporating genomic data into the treatment algorithm for individual patients. PMID- 23790551 TI - Catheter intervention for congenital heart disease at risk of circulatory failure. AB - Percutaneous interventions complement other therapeutic modalities in the management of patients with heart failure secondary to congenital heart disease. The systemic left ventricle can fail when submitted to excessive afterload as seen with critical aortic stenosis or coarctation. Balloon dilation of the aortic valve is safe and effective in establishing adequate forward flow and improving myocardial function in neonates. A large left-to-right shunt caused by a ventricular septal defect or a patent ductus arteriosus can lead to left ventricular failure. In selected infants, device closure of these defects is a therapeutic option. The postoperative right ventricle burdened by chronic residual obstruction and volume overload is at risk of failure. Balloon dilation of the pulmonary valve, pulmonary artery angioplasty with or without stent implantation, and pulmonary conduit stenting are effective in minimizing afterload to the right ventricle. More recently, percutaneously implantable pulmonary valves have become an option, in selected patients, for full rehabilitation of dysfunctional pulmonary conduits. Patients with single ventricle physiology have a fragile physiology, justifying an aggressive catheter interventional approach to optimize hemodynamic characteristics. The hybrid approach to palliation of hypoplastic left heart syndrome has become a viable option in selected centres. PMID- 23790552 TI - Patent foramen ovale: when is intervention warranted? AB - In our desire to bring harmony to understanding of unexplained pathologies, we tend to relate commonly occurring entities and attempt to demonstrate meaningful association or causality. The foramen ovale is a universally present structure in utero, remaining patent in a substantial proportion of live births and through adulthood. In its commonness, it has been associated with many disease states and claims of causal inference. As we review the current state of best practice concerning patent foramen ovale (PFO) based on recent randomized controlled trials and practice guidelines, we are reminded that the human body, despite its medical frailties, remains an incredibly efficient machine; a decision to permanently alter its workings should demand knowledge gleaned from substantiated experience and validated data. Presently, no indications exist for PFO closure, whether via a transcatheter or surgical approach, within existing medical care guidelines. Recent randomized controlled trials examining reduction of risk for secondary prevention of stroke and/or transient ischemic attack and for elimination of migraine have underscored the message to restrain the temptation to intervene on a PFO; adversity appears to increase without accrued benefit from such an intervention. PMID- 23790553 TI - Insulin pen needles: effects of extra-thin wall needle technology on preference, confidence, and other patient ratings. AB - BACKGROUND: Pen needles (PNs) are essential for insulin injections using pen devices. PN characteristics affect patients' injection experience. OBJECTIVE: The goal of this study was to evaluate the impact of a new extra-thin wall (XTW) PN versus usual PNs on overall patient preference, ease of injection, perceived time to complete the full dose, thumb button force to deliver the injection, and dose delivery confidence in individuals with diabetes mellitus (DM). Subjects injected insulin with the KwikPen(TM) (Eli Lilly and Company, Indianapolis, Indiana), SoloSTAR((r)) (sanofi-aventis U.S. LLC, Bridgewater, New Jersey), and FlexPen((r)) (Novo Nordisk A/S, Bagsvaerd, Denmark) insulin pens, and included some with impaired hand dexterity. METHODS: We first performed quantitative testing of XTW and comparable PNs with the 3 insulin pens for thumb force, flow rate, and time to deliver medication. A prospective, randomized, 2-period, open label, crossover trial was then conducted in patients aged 35 to 80 years with type 1 or type 2 DM who injected insulin by pen for >=2 months, with at least 1 daily dose >=10 U. Patients who used 4- to 8-mm length PNs with 31- to 32-G diameter were randomly assigned to use their current PN or the same/similar size XTW PN at home for ~1 week and the other PN the second week. They completed several comparative 150-mm visual analog scales and direct questions at the end of period 2. RESULTS: XTW PNs had statistically significant better performance for each studied PN characteristic (thumb force, flow, and time to deliver medication) for all pens combined and each individual pen brand (all, P <= 0.05). Of 216 patients randomized to study groups (80, SoloSTAR; 77, FlexPen; 59, KwikPen), 209 completed both periods; 198 were evaluable. Baseline characteristics revealed a mean (SD) age of 60.8 (9.3) years, insulin pen use duration of 4.3 (4.1) years, and mean total daily dose of 75.1 (52.3) U (range, 10-420 U). Approximately 50% of patients were female; 81.5% were white and 14.8% were black; and 89.8% had type 2 DM. Nearly 99% used a single PN: 8 mm, 49.5%; 5 mm, 24.1%; 6 mm, 14.4%; and 4 mm, 12.0%. Patients rated the XTW PNs (mean [95% CI]) as preferable by a mean of 31.9 mm (27.2-36.6), P < 0.001; XTW PNs required less thumb force, less time to inject the dose, and were rated as providing greater confidence in full dose delivery by 28.4 mm (23.7-33.2), 21.7 mm (17.0 26.4), and 24.4 mm (19.7-29.1), respectively; all, P < 0.001. Results were similar for each of the 3 pens, those with impaired hand dexterity, and for all users of 4-mm PNs. Skin leakage and insulin dripping from the needle tip were rated as less frequent with the XTW PNs (P < 0.05). The most common adverse events were hypoglycemia in 8.3% and 6.0% of patients using XTW PNs and current PNs (P = NS), respectively; hyperglycemia occurred in 2.9% and 4.1% (P = NS). None of the adverse events was serious or considered device related. CONCLUSIONS: XTW PNs were preferred overall, rated as requiring less time and less thumb force to inject, and providing greater confidence in completing a full dose compared with usual PNs in this group of patients with type 1 or type 2 DM. ClinicalTrials.gov identifier: NCT01852136. PMID- 23790554 TI - Predicting relapse in major depressive disorder using patient-reported outcomes of depressive symptom severity, functioning, and quality of life in the Individual Burden of Illness Index for Depression (IBI-D). AB - BACKGROUND: Patients with Major Depressive Disorder (MDD) often experience unexpected relapses, despite achieving remission. This study examines the utility of a single multidimensional measure that captures variance in patient-reported Depressive Symptom Severity, Functioning, and Quality of Life (QOL), in predicting MDD relapse. METHODS: Complete data from remitted patients at the completion of 12 weeks of citalopram in the STAR*D study were used to calculate the Individual Burden of Illness index for Depression (IBI-D), and predict subsequent relapse at six (n=956), nine (n=778), and twelve months (n=479) using generalized linear models. RESULTS: Depressive Symptom Severity, Functioning, and QOL were all predictors of subsequent relapse. Using Akaike information criteria (AIC), the IBI-D provided a good model for relapse even when Depressive Symptom Severity, Functioning, and QOL were combined in a single model. Specifically, an increase of one in the IBI-D increased the odds ratio of relapse by 2.5 at 6 months (beta=0.921 +/- 0.194, z=4.76, p<2 * 10(-6)), by 2.84 at 9 months (beta=1.045 +/- 0.22, z=4.74, p<2.2 * 10(-6)), and by 4.1 at 12 months (beta=1.41 +/- 0.29, z=4.79, p<1.7 * 10(-6)). LIMITATIONS: Self-report poses a risk to measurement precision. Using highly valid and reliable measures could mitigate this risk. The IBI-D requires time and effort for filling out the scales and index calculation. Technological solutions could help ease these burdens. The sample suffered from attrition. Separate analysis of dropouts would be helpful. CONCLUSIONS: Incorporating patient-reported outcomes of Functioning and QOL in addition to Depressive Symptom Severity in the IBI-D is useful in assessing the full burden of illness and in adequately predicting relapse, in MDD. PMID- 23790555 TI - The Mood Disorder Questionnaire (MDQ) for detecting (hypo)manic episodes: its validity and impact of recall bias. AB - BACKGROUND: Bipolar disorders often remain unrecognized in clinical practice, which may be a consequence of imprecise recall of manic symptoms earlier in life. This study will therefore examine the validity of the widely-used Mood Disorder Questionnaire (MDQ) in detecting a (hypo)manic episode and explore the impact of recall bias. METHODS: As an indication of impairments in recalling manic symptoms, we examined the long-term reliability of the MDQ after two years of follow-up in a sample of 2087 persons. Then, the validity of the MDQ was tested against the gold standard of a CIDI-based DSM-IV (hypo)manic episode. Its performance was compared for detecting a lifetime episode (at T1) versus a recent episode in the past two years (at T2). RESULTS: The long-term reliability of the MDQ was limited as the correct recall of individual items ranged from 44.6% to 68.8% after two years. The overall validity of the MDQ in detecting a lifetime (hypo)manic episode was limited and no adequate cut-off point with acceptable sensitivity and specificity could be identified. However, the MDQ accurately detected a recent episode with a sensitivity of 0.83 and a specificity of 0.82 for the standard and optimal cut-off point of >= 7. Taking into account two additional MDQ questions on clustering in time and severity of problems decreased its validity. LIMITATIONS: Patients with a primary, clinical diagnosis of bipolar disorder were excluded. CONCLUSIONS: The MDQ accurately detected recent (hypo)manic episodes, but imprecise recall may result in a limited performance for episodes earlier in life. PMID- 23790556 TI - Affective temperaments and psychotropic adherence. AB - BACKGROUND: It is generally accepted that a range of factors affect adherence to psychotropic medications. In the present study, we focused on the influence of affective temperaments (i.e., depressive, hyperthymic, cyclothymic, irritable, and anxious temperaments) on treatment adherence. METHODS: Thirty-eight psychiatric consecutive inpatients were instructed to perform Temperament Evaluation of Memphis, Pisa, Paris, and San Diego-Autoquestionnaire version (TEMPS-A) for affective temperaments, Drug attitude inventory-10 (DAI-10) for concordance and persistence, and Visual Analogue Scale (VAS) for compliance. RESULTS: VAS scores for dose compliance were significantly and negatively associated with irritable temperament scores whereas DAI-10 scores were significantly and positively associated with male gender, depressive temperament scores and hyperthymic temperament scores. LIMITATIONS: The main limitations of the study were the relatively small number of subjects and the lack of objective method of adherence. CONCLUSIONS: These findings suggest that patients with irritable temperament may be poor in their compliance with treatment, and that more education may be required for patients with irritable temperament in order to maintain good compliance. In contrast, men and patients with depressive or hyperthymic temperament have a relatively positive attitude towards medication. PMID- 23790557 TI - Efficacy of ultrabrief pulse electroconvulsive therapy for depression: a systematic review. AB - BACKGROUND: Ultrabrief pulse electroconvulsive therapy (ECT) is increasingly used in daily practice when treating depression despite doubts about its efficacy compared to standard techniques. METHOD: Using electronic search techniques, we collected all studies on the comparison between ultrabrief pulse (UBP) versus brief pulse (BP) ECT in depressed patients which reported validated rating scales as outcome measures. The Jadad scale was used to evaluate the quality of the studies. RESULTS: Two randomized and one non-randomized prospective study using unilateral (UL) ECT, and two randomized and one retrospective study using bilateral (BL) ECT were identified comparing UBP with BP ECT. One UL randomized high quality study and one non-randomized study suggest an equal response and remission for both conditions. The number of treatment sessions to achieve remission using UBP is equal in one study and is higher in the second. Both BL studies, one of high quality, point to a lower efficacy for UBP ECT with a lower speed of remission. LIMITATIONS: We restricted our review to the efficacy of UBP vs. BP ECT in depressed patients and did not address other clinically important issues such as the cognitive adverse effects. A statistical meta-analysis was not possible, because of the heterogeneity of outcome measures and the small amount of studies. CONCLUSION: The literature shows no clear advantage for the efficacy of ultrabrief pulse over brief pulse ECT using unilateral as well as bilateral electrode placement. The increasing use of unilateral brief pulse ECT as first line method for depression is not supported by the current evidence. PMID- 23790558 TI - Orally administered dipeptidyl peptidase-4 inhibitor (alogliptin) prevents abdominal aortic aneurysm formation through an antioxidant effect in rats. AB - OBJECTIVE: Dipeptidyl peptidase-4 (DPP-4) inhibitor, a novel antidiabetic drug, has a cardioprotective effect on ischemia-reperfusion injury through an antioxidant effect. However, the effect of DPP-4 inhibitor on aneurysm formation has not been investigated. We aimed to test the hypothesis that the DPP-4 inhibitor, alogliptin, attenuates vascular oxidative stress and thus inhibits abdominal aortic aneurysm (AAA) formation. METHODS: AAAs were created with intraluminal elastase and extraluminal calcium chloride in 36 male rats. Rats were divided into three groups: a low dose of alogliptin group (group LD; 1 mg/kg/d), a high-dose group (group HD; 3 mg/kg/d), and a control group (group C, water). Alogliptin was administered by gastric gavage once daily beginning 3 days before surgery. On day 7 after aneurysm preparation, reactive oxygen species (ROS) expression was semiquantified by dihydroethidium staining, and the oxidation product of DNA produced by ROS, 8-hydroxydeoxyguanosine (8-OHdG), was measured by immunohistochemical staining. Blood glucose concentrations were measured. Hematoxylin and eosin and elastica Van Gieson stainings were performed on day 28, and the AAA dilatation ratio was calculated. RESULTS: On day 7 (six in each group), dihydroethidium staining of the aneurysm wall showed a reduced level of ROS expression (4.6 +/- 0.6 in group C, 2.7 +/- 0.3 in group LD, and 1.7 +/- 0.5 in group HD; P < .0001) and showed fewer 8-OHdG-positive cells in alogliptin treated samples (138.1 +/- 7.4 cells in group C, 102.5 +/- 4.5 cells in group LD, and 66.1 +/- 4.5 cells in group HD; P < .0001) The treatment significantly reduced messenger RNA expression of matrix metalloproteinases (MMPs) in aneurysm walls (relative expression: MMP-2: 2.1 +/- 0.4 in group C, 1.3 +/- 0.3 in group LD, and 0.9 +/- 0.2 in group HD; P < .001; MMP-9: 2.0 +/- 0.5 in group C, 0.3 +/- 0.3 in group LD, and 0.3 +/- 0.2 in group HD; P < .001). On day 28 (six in each group), the aortic wall in groups LD and HD was less dilated (dilatation ratio: 199.2% +/- 11.8% in group C, 159.6% +/- 2.8% in group LD, and 147.1% +/- 1.9% in group HD; P < .02 group C vs HD) and had higher elastin content than in group C. The difference in blood glucose levels among the three groups was not significant. CONCLUSIONS: The DPP-4 inhibitor, alogliptin, attenuates aneurysm formation and expansion dose-dependently in a rat AAA model via an antioxidative action. PMID- 23790559 TI - The Cocoon Strategy: does it work for Latin American countries? PMID- 23790561 TI - Neurectomy for breast reconstruction-related spasms of the pectoralis major muscle. AB - Tissue expander-based breast reconstruction is the most commonly utilized technique in the U.S. This modality, however, may be associated with significant pain related to pectoralis myospasms. Spasms of the pectoralis major likely result from trauma to the pectoral nerves during muscle elevation. In a subset of patients, Botox((r)) therapy may be inadequate for long-term relief. We describe a patient with intractable pectoralis myospasms after breast reconstruction. Upon failing Botox((r)) therapy, medial and lateral pectoral neurectomies were performed. Nine months after the procedure, the patient noted dramatic improvement in both symptoms and cosmesis with no musculoskeletal sequelae. We recommend medial and lateral pectoral neurectomy as an alternative in patients with intractable pectoral myospasms after tissue expander reconstruction. PMID- 23790562 TI - Human acellular dermal matrix (AlloDerm(r)) dimensional changes and stretching in tissue expander/implant breast reconstruction. AB - BACKGROUND: Human acellular dermal matrix (HADM) is widely used for post mastectomy tissue expander/implant breast reconstruction. Since HADM has been shown to stretch following placement in other surgical settings, we hypothesised that stretching would occur in breast reconstruction as well. The goal of the study was to quantify the in situ stretch properties of HADM over time in patients undergoing this procedure. METHODS: This was an open-label, prospective case series in adult women who underwent post-mastectomy tissue expander/implant breast reconstruction using HADM. HADM construct size was determined at postoperative day 1 and month 3 via ultrasound tracking of metallic 3-mm vessel clips embedded in the graft. Dimensional changes were further examined in four equally sized segments (medial, lateral and two central) of the matrix. Patient satisfaction was evaluated at month 3 (a modified version of the Breast QTM patient questionnaire) and compared with satisfaction reported by a non-HADM reconstruction cohort. RESULTS: A total of 31 patients underwent breast reconstruction with HADM. Mean (standard deviation) perimeter increased from 38 (6) cm on postoperative day 1-42 (7) cm at month 3 (+11%; P=0.002). Surface area increased from 73 (22) to 88 (28) cm2 (+21%; range, 4-35%; P=0.002). The greatest expansion occurred in the HADM medial and lateral segments (range, 18-30% across the four segments). Patient satisfaction was comparable with that of non-HADM patients. Complications in the HADM group included late seroma, red breast syndrome and urinary tract infection. Complications in the non-HADM cohort included cellulitis, expander explantation, delayed wound healing and skin necrosis. CONCLUSIONS: During short-term follow-up, HADM exhibited a modest degree of stretching during tissue expander/implant breast reconstruction and was associated with few complications and a high level of patient satisfaction. PMID- 23790565 TI - Diagnosis of pyriform sinus fistula in children via ultrasonography. AB - A pyriform sinus fistula is a rare congenital abnormality of the third or fourth branchial pouch that usually affects children. We report one case of the condition; ultrasound (US) imaged a heterogeneous mass with a hypoechoic area and air bubbles representing an abscess. Although these manifestations are rare, prominent and characteristic findings on US may facilitate the diagnosis of pyriform sinus fistula. PMID- 23790566 TI - Inattention, impulsive action, and subjective response to D-amphetamine. AB - BACKGROUND: Both impulsivity and sensitivity to the rewarding effects of drugs have long been considered risk factors for drug abuse. There is some preclinical evidence to suggest that the two are related; however, there is little information about how specific behavioral components of impulsivity are related to the acute euphorigenic effects of drugs in humans. The aim of the current study was to examine the degree to which both inattention and impulsive action predicted subjective response to amphetamine. METHODS: Healthy adults (n=165) performed the behavioral tasks and rated their subjective response to amphetamine (0, 5, 10, and 20 mg). Inattention was assessed as attention lapses on a simple reaction time task, and impulsive action was measured by stop RT on the stop task. Subjective response to amphetamine was assessed with the Drug Effects Questionnaire (DEQ) and the Profile of Mood States (POMS). RESULTS: Hierarchical linear regression analyses showed significant negative associations between attention lapses and subjective response to amphetamine on DEQ measures. By contrast, stop RT was positively associated with responses on both DEQ and POMS measures. Additionally, a dose-response relationship was observed, such that the strength of these associations increased with higher doses of amphetamine. CONCLUSIONS: These findings suggest that inattention is associated with less subjective response to amphetamine. By contrast, the heightened sensitivity to stimulant drug reward observed in individuals high in impulsive action suggests that this might be one mechanism contributing to increased risk for stimulant drug abuse in these individuals. PMID- 23790560 TI - Vitamin D for health: a global perspective. AB - It is now generally accepted that vitamin D deficiency is a worldwide health problem that affects not only musculoskeletal health but also a wide range of acute and chronic diseases. However, there remains cynicism about the lack of randomized controlled trials to support the association studies regarding the nonskeletal health benefits of vitamin D. This review was obtained by searching English-language studies published up to April 1, 2013, in PubMed, MEDLINE, and the Cochrane Central Register of Controlled Trials (search terms: vitamin D and supplementation) and focuses on recent challenges regarding the definition of vitamin D deficiency and how to achieve optimal serum 25-hydroxyvitamin D concentrations from dietary sources, supplements, and sun exposure. The effect of vitamin D on fetal programming epigenetics and gene regulation could potentially explain why vitamin D has been reported to have such wide-ranging health benefits throughout life. There is potentially a great upside to increasing the vitamin D status of children and adults worldwide for improving musculoskeletal health and reducing the risk of chronic illnesses, including some cancers, autoimmune diseases, infectious diseases, type 2 diabetes mellitus, neurocognitive disorders, and mortality. PMID- 23790567 TI - [Contact lens related corneal ulcers: clinical, microbiological and therapeutic features]. AB - INTRODUCTION: Corneal ulcers in contact lens wearers are becoming more common, and can sometimes lead to severe complications. The purpose of this study is to define the epidemiological, clinical, microbiological and therapeutic considerations of these ulcers within the above context. PATIENTS AND METHODS: We conducted an uncontrolled, descriptive, retrospective study of 51 patients presenting with contact lens related corneal ulcers to the ophthalmology department of the August 20, 1953 Hospital in Casablanca between January 2009 and January 2012. RESULTS: The average age of our patients was 22 years, with a gender ratio of 7.5 female to male. General risk factors (diabetes and tuberculosis) were found in 17.5% of cases. The average length of hospital stay was 15 days. Of our patients, 58.8% wore cosmetic contact lenses and 41.18% wore therapeutic contact lenses. Mean duration prior to consultation was 5 days. The predominant clinical signs were eye pain and redness, with a decrease in visual acuity worse than 1/10 in 82.3% of patients. In 70.6% of cases, the ulcer was central. The average size was 4.3mm. An anterior chamber reaction was found in 47.1%. Corneal bacterial cultures were positive in 47.8%. Pathogens found were Staphylococcus aureus, Pseudomonas aeruginosa and Acanthamoeba. Contact lens and solution cultures were positive in 73.6% of cases. Outcomes were favorable with local and systemic antibiotic treatment adapted to microbiological results in only 41.2% of cases. In the remaining patients, significant secondary opacities persisted. DISCUSSION: Cosmetic and therapeutic contact lens wear is a major cause of corneal ulcer. Delayed consultation results in severe sequelae with persistently decreased visual acuity. CONCLUSION: The ophthalmologist plays an important role in preventing complications of contact lens wear, through better hygiene instruction and follow-up of his or her patients. PMID- 23790568 TI - Left circumflex coronary-to-pulmonary artery fistula as the exclusive collateral to the occluded left anterior descending artery. AB - A 64 year-old male presented with a five month history of effort angina. Non invasive studies demonstrated preserved left ventricular function and a modest stress-induced myocardial perfusion defect at the anterior wall. Coronary angiography revealed occlusion of the proximal left anterior descending coronary artery with its distal segment well supplied by collaterals branching from a left circumflex-to-main pulmonary artery fistula. The occluded left anterior descending coronary artery was recanalised by percutaneous interventions, the collaterals vanished immediately, and the patient lived free of symptoms for the following five months. PMID- 23790569 TI - Cereal grain, rachis and pulse seed amino acid delta15N values as indicators of plant nitrogen metabolism. AB - Natural abundance delta(15)N values of plant tissue amino acids (AAs) reflect the cycling of N into and within plants, providing an opportunity to better understand environmental and anthropogenic effects on plant metabolism. In this study, the AA delta(15)N values of barley (Hordeum vulgare) and bread wheat (Triticum aestivum) grains and rachis and broad bean (Vicia faba) and pea (Pisum sativum) seeds, grown at the experimental farm stations of Rothamsted, UK and Bad Lauchstadt, Germany, were determined by GC-C-IRMS. It was found that the delta(15)N values of cereal grain and rachis AAs could be largely attributed to metabolic pathways involved in their biosynthesis and catabolism. The relative (15)N-enrichment of phenylalanine can be attributed to its involvement in the phenylpropanoid pathway and glutamate has a delta(15)N value which is an average of the other AAs due to its central role in AA-N cycling. The relative AA delta(15)N values of broad bean and pea seeds were very different from one another, providing evidence for differences in the metabolic routing of AAs to the developing seeds in these leguminous plants. This study has shown that AA delta(15)N values relate to known AA biosynthetic pathways in plants and thus have the potential to aid understanding of how various external factors, such as source of assimilated N, influence metabolic cycling of N within plants. PMID- 23790570 TI - Clinical indications for the albumin use: still a controversial issue. AB - Human serum albumin (HSA) is the most abundant circulating protein and accounts for about 70% of the plasma colloid osmotic pressure. Beside the well known capacity to act as plasma-expander, HSA is provided of many other properties which are unrelated to the regulation of fluid compartmentalization, including binding and transport of many endogenous and exogenous substances, antioxidant function, immuno-modulation, anti-inflammatory activity, and endothelial stabilization. Treatment (hepatorenal syndrome) or prevention (renal failure after spontaneous bacterial peritonitis and post-paracentesis circulatory dysfunction after large volume paracentesis) of severe clinical complications in patients with cirrhosis and fluid resuscitation in critically ill patients, when crystalloids and non-proteic colloids are not effective or contra-indicated, represents the major evidence-based clinical indications for HSA administration. However, a large proportion of HSA prescription is inappropriate. Despite the existence of solid data against a real benefit, HSA is still given for nutritional interventions or for correcting hypoalbuminemia per se (without hypovolemia). Other clinical uses for HSA administration not supported by definitive scientific evidence are long-term treatment of ascites, nephrotic syndrome, pancreatitis, abdominal surgery, acute distress respiratory syndrome, cerebral ischemia, and enteric diseases. HSA prescription should be not uncritically restricted. Enforcement of clinical practice recommendations has been shown to allow a more liberal use for indications supported by strong scientific data and to avoid the futile administration in settings where there is a lack of clinical evidence of efficacy. As a result, a more appropriate HSA use can be achieved maintaining the health care expenditure under control. PMID- 23790571 TI - Reliability and minimal detectable change of gait variables in community-dwelling and hospitalized older fallers. AB - PURPOSE: Gait variables may constitute surrogate outcomes for fall risk. Their reliability in a specific population of older fallers has not been fully established, which limits their research and clinical applications. This study aimed to determine test-retest reliability and minimal detectable change (MDC) values for selected fall-related gait variables in older adults with a recent fall history. METHODS: Community-dwelling (n=30) and hospitalized (n=30) fallers aged>=65 years were assessed twice using an instrumented pressure-sensitive walkway, under single- and dual-task gait conditions. Intraclass correlation coefficient (ICC(2,1)), standard error of measurement (SEM; SEM%) and MDC at 95% confidence level (MDC95; MDC95%), were used as reliability estimates. RESULTS: The ICC(2,1) for gait velocity was greater than 0.84 across all gait conditions and groups; SEM% and MDC95% did not exceed 6.5% and 18.1%, respectively. Gait variability measures returned lower ICC(2,1) (range 0.18-0.79), and markedly higher SEM% (16.3-31.9%) and MDC95% (45.3-88.3%). Overall, hospitalized fallers exhibited larger SEM and MDC95 values for variability measures compared to community-dwellers in all gait conditions, while larger values were found for all variables while dual-tasking compared to single-tasking in both groups. CONCLUSIONS: Gait velocity was found to be highly reliable and likely to be sensitive to change over repeated sessions in community-dwelling and hospitalized older fallers, both under single- and dual-task conditions. Gait variability measures showed lower reliability, irrespective of gait condition or group, displaying consistently larger measurement error, particularly under dual-task conditions. Clinicians should consider MDC95 values before using gait variability variables as evaluative outcome measures at patient level. PMID- 23790572 TI - An alternative technical marker set for the pelvis is more repeatable than the standard pelvic marker set. AB - Multiple marker sets and models are currently available for assessing pelvic kinematics in gait. Despite the presence of a variety models, there are still debates on their reliability and consistency, and consequently there is no clearly defined standard. Two marker sets were evaluated in this study: the 'Traditional' where markers are placed at the anterior and posterior superior iliac spines (ASISs, PSISs); and the 'Cluster', where a cluster of three orthogonal markers fixed on a rigid based is attached to the sacrum. The two sets were compared with respect to intra and inter session standard deviations of maximum pelvic tilt, obliquity and rotation angles. The repeatability between and within sessions was measured using coefficient of multiple correlation (CMC). Also the similarity between the two sets was assessed using inter-protocol CMC (ipCMC). Both data sets generated showed high within and between session repeatability in the sagittal plane (CMC>0.80), although the Cluster method showed higher repeatability than that of the Traditional method in non-sagittal plane motion for both within and between sessions. The authors are not aware of other studies reporting the differences in intra and inter session variability and repeatability values for different body mass index categories such as overweight and obese subjects with relatively large sample size. Hence the Cluster method overcomes a number of theoretical and experimental limitations such as minimising the marker occlusion and is a reliable alternative to the Traditional (the standard) marker set. PMID- 23790573 TI - [Chromosomal location of submicroscopic duplications in patients with neurodevelopmental disorders to identify cases with high risk of familial recurrence]. AB - BACKGROUND AND OBJECTIVE: An important proportion of neurodevelopmental disorders (NDDs) results from unbalanced genomic alterations (duplication or deletion). These chromosomal rearrangements may be considered as de novo, despite they arise as a result of a balanced rearrangement not detected in a phenotypically normal parent. Therefore, if the rearrangements are inherited, the recurrence risk and the genetic counseling of these cases change radically. Fluorescence in situ hybridization (FISH) is a technique that allows detecting both balanced and unbalanced rearrangements, identifying also the location of duplicated segments. We tried to locate in the genome the duplicated segments detected in patients with NDDs in order to identify those cases due to inherited rearrangements. PATIENTS AND METHOD: The study was conducted in 13 patients with NDDs and genomic duplications detected by compared genomic hybridization-array (CGH-array). Two approaches of FISH technique were taken: hybridization with painting chromosome probes and with specific probes for each duplication. RESULTS: In the studied series of 13 patients with duplication, 11 patients were found to carry tandem duplications, one with an intrachromosomal insertional translocation, and another with an interchromosomal insertional translocation. Therefore, 2 of the duplications considered de novo were actually an unbalanced rearrangement inherited from a parent who is a balanced carrier. CONCLUSION: The results illustrate the need to characterize by FISH technique the rearrangements that are detected by CGH-array to identify those cases with a high risk of recurrence. PMID- 23790574 TI - [About mind deviation of informed consent and other reflections of interest for clinical trials]. PMID- 23790575 TI - [Predictive variables for mortality in elderly patients hospitalized due to heart failure with preserved ejection fraction]. AB - BACKGROUND AND OBJECTIVES: The prevalence of heart failure (HF) increases with age. Even though the mortality of patients >= 80 years of age with HF and preserved left ventricle ejection fraction (LVEF) is very high, the predictor variables are not well-known. The main goal of this study was to evaluate the mortality predictor factors in this subgroup of the elderly population. PATIENTS AND METHODS: An observational and prospective study of patients hospitalized due to HF with preserved LVEF has been conducted. The demographic, clinical, functional and analytic factors were evaluated when the patients were admitted with special attention to the co-morbidities. The primary endpoint was the total mortality in the subgroup of patients >= 80 years of age after a year of follow up. The predictor variables were studied by means of a multivariate Cox regression model. RESULTS: From a total of 218 patients with an average age of 75.6 (+/-8.7) years of age, 75 patients (34.4%) were >= 80 years. The mortality rate of patients >= 80 years of age totaled 42.7%, in relation to 26.6% for the lower age group (log-rank<.001). After a multivariate analysis using the Cox regression model in patients >= 80, the serum urea levels above the average (hazard ratio [HR] 3.93; 95% confidence interval [95% CI] 1.58-9.75; P = .003), the age (HR 1.17; 95% CI 1.07-1.28; P<.001), the hyponatremia (HR 3.19; 95% CI 1.51-6.74; P = .002) and a lower score on the Barthel index (BI) (HR 1.016; 95% CI 1.002-1.031; P = .034) were independent mortality predictors after an one-year follow-up. CONCLUSIONS: Serum urea levels, age, hyponatremia and a low BI score could be proposed as independent mortality predictors in patients >= 80 of age hospitalized for HF with preserved LVEF. PMID- 23790576 TI - [Diagnosis of Lafora disease by armpit cutaneous biopsy]. PMID- 23790577 TI - [Delirium prevention and treatment in elderly hip fracture]. AB - The fracture of the proximal femur or hip fracture in the elderly usually happens after a fall and carries a high morbidity and mortality. One of the most common complications during hospitalization for hip fracture is the onset of delirium or acute confusional state that in elderly patients has a negative impact on the hospital stay, and prognosis, worsening functional ability, cognitive status and mortality. Also the development of delirium during hospitalization increases health care costs. Strategies to prevent and treat delirium during hospitalization for hip fracture have been less studied. In this context, this paper aims to conduct a review of the literature on strategies that exist in the prevention and treatment of delirium in elderly patients with hip fracture. PMID- 23790578 TI - [Relation between parathyroid hormone and cardiovascular risk in patients with vitamin D deficiency]. AB - BACKGROUND AND OBJECTIVES: Vitamin D deficiency and parathyroid hormone (PTH) are associated with an increased cardiovascular risk and arterial stiffness. The aim of our study is to compare the cardiovascular risk in subjects with low vitamin D, attending to the PTH concentration, as well as evaluating the response after administration of vitamin D. PATIENTS AND METHODS: Prospective study of patients with a concentration of 25(OH)-vitamin D below 30nmol/l. We evaluated vascular risk parameters as blood pressure, arterial stiffness, lipid profile and glucose metabolism. Patients received vitamin D supplements for 3 months, after which the previous parameters were reassessed. RESULTS: A total of 32 patients were included. Those with PTH over 65pg/ml were older, had worse renal function, higher systolic blood pressure, pulse pressure and arterial stiffness. Treatment with vitamin D showed a statistically significant trend to lower blood pressure and pulse wave velocity. CONCLUSIONS: The increase in PTH in patients with low vitamin D involves poor control of blood pressure and increased vascular stiffness. Vitamin D replacement shows a tendency to reduce these parameters. PMID- 23790579 TI - [Hormonal contraception and venous thromboembolism]. PMID- 23790580 TI - [Spontaneous intracerebral hemorrhage: current perspectives]. PMID- 23790581 TI - [Atherogenic dyslipidemia in patients with type 1 diabetes mellitus]. AB - BACKGROUND AND OBJECTIVE: To assess the prevalence of lipid abnormalities, with special emphasis on atherogenic dyslipidemia and its relationship with chronic complications in patients with type 1 diabetes mellitus (T1DM). PATIENTS AND METHOD: Cross-sectional study including all patients aged 18 and over, diagnosed of T1DM attending the outpatient clinic at Hospital del Mar and Hospital de Granollers, in Barcelona, during 2008. RESULTS: Of the 291 enrolled patients, 17.2 and 7.9% had high density lipoproteins (HDL) cholesterol<40 mg/dL (men) or<50mg/dL (women) and triglycerides>150 mg/dL, respectively. Hypoalphalipoproteinemic patients had a higher prevalence of peripheral neuropathy (28 vs. 7.1%, P<.001), macroalbuminuria (14 vs. 2.5%, P<.001) and higher concentrations of triglycerides (107.5 [55.8] vs. 82.7 [36] mg/dL, P<.0001) compared with those with normal/high HDL cholesterol levels. Hypertriglyceridemia was associated with increasing age (43.6 [11.2] vs. 37.6 [11.8] yr, P<.02), higher prevalence of hypertension (47.8 vs. 22.8%, P<.008), metabolic syndrome (82.6 vs. 22%, P<.001) and microangiopathic complications, lower insulin sensitivity (6.75 [2.1] vs. 8.54 [2.6] mg/Kg(-1)/min(-1), P<.004) compared with the normotriglyceridemic group. CONCLUSION: One in 5 patients with T1DM has hypoalphalipoproteinemia or hypertriglyceridemia and these conditions are associated with 3 fold-increase microangiopathy. Thus, in these patients glycemic and blood pressure but also lipid profile control must be optimum. PMID- 23790582 TI - [Predictive Khorana's model in patients with venous thromboembolic disease and cancer]. AB - BACKGROUND AND OBJECTIVE: The predictive Khorana's model was developed to score the thromboembolic disease risk in cancer patients on chemotherapy and to identify which patients would benefit from thromboprophylaxis. We analized the results and applied the predictive Khorana's model in patients with cancer and who were diagnosed with deep vein thrombosis. MATERIAL AND METHODS: Retrospective analysis of prognostic characteristics of Khorana's model in 122 patients based on a prospective analysis. RESULTS: Seventy-nine percent of the total were in the low and intermediate risk category and 21% had high risk according to the Khorana's predictive model. This model had a sensitivity and prognostic precision of 20.8% (95% confidence interval [95% CI]: 14.6-28.7) and a false negatives proportion of 79.2% (95% CI: 1.3-85.4). CONCLUSIONS: Application of this model in our patients would not be enough as the unique tool to identify cancer patients who should receive tromboprophylaxis. The use of both biomarkers and clinical models seems to be the best cost-effective strategy for this purpose. Future, randomized, prospective, placebo-controlled studies are needed for find better treatment strategies in cancer patients. PMID- 23790583 TI - [Thoughts about the usefulness of the preoperatory administration of intravenous iron in hip fracture surgery]. PMID- 23790584 TI - [Feasibility of hand-held-ultrasonography in the screening of abdominal aortic aneurysms and abdominal aortic atherosclerosis]. AB - BACKGROUND AND OBJECTIVE: To determine the prevalence of abdominal aortic aneurysm (AAA) and abdominal aortic atheromatosis (AA-At) using a hand-held ultrasound by a general practitioner in the public Primary Health Care system. PATIENTS AND METHOD: Pilot study that prospectively studied a cohort of men over 50 years with cardiovascular risk factors: active smokers, former smokers, or hypertensive patients, attended in primary health care center. The general practitioner completed an ultrasonography training in an Ultrasound Unit under supervision of experienced radiologists using an standard ultrasound equipment and hand-held ultrasound (VScan((r)), General Electric, USA). One hundred and six patients participated in the study and all imaging data recorded were blindly evaluated by a radiologist in order to establish the concordance in the interpretation of images between general practitioner and radiologist. The kappa index was calculated to study the agreement on the presence or absence of AAA and AA-At. RESULTS: We observed a prevalence of 5.88% of AAA. Kappa index for concordance in AAA diagnosis was absolute (kappa = 1.0), with a sensitivity and specificity of 100%. Otherwise, the general practitioner identified 59 patients (58.4%) with AA-At, while radiologist identified 39 (38.6%) in the image review, with moderate concordance (kappa = .435), sensitivity 89.74% and specificity 57.14%. Hypercholesterolemia (odds ratio [OR] 2.61; 95% confidence interval [95% CI] 0.92-7.39) and diabetes mellitus (OR 3.35; 95%CI 0.89-12.55) were independent risk factors for AA-At development in logistic regression. CONCLUSIONS: After an adequate training in ultrasonography, hand-held ultrasound is a useful tool for AAA screening in Primary Care. Its simplicity, security, validity, cost effectiveness and acceptance by the general population, makes it a feasible tool for cardiovascular risk assessment. PMID- 23790585 TI - [Guillain-Barre syndrome as extraintestinal manifestation during relapse of ulcerative colitis]. PMID- 23790586 TI - [Respiratory distress and purpura in an immunocompromised patient: hyperinfestation with dissemination of Strongyloides stercoralis]. PMID- 23790587 TI - Lack of precision of burn surface area calculation by UK Armed Forces medical personnel. AB - OBJECTIVE: Accurate determination of the severity of burn is essential for the care of thermally injured patients. We aimed to examine the accuracy and precision of TBSA calculation performed by specialist military burn care providers and non-specialist but experienced military clinicians. METHODS: Using a single case example with photographic montages and a modified Lund and Browder chart, the two cohorts of clinicians were each given 10min to map and calculate the case example TBSA involvement. The accuracy and precision of results from the two cohorts were compared to a set standard %TBSA. RESULTS: The set standard %TBSA involvement was 64.5%. Mean %TBSA mapped by non-specialists (52.53+/ 10.03%) differed significantly from the set standard (p<0.0001). No difference was observed when comparing results from the burn care providers (65.68+/-10.29%; p=0.622). However, when comparing precision of calculation of TBSA burned, there was no evidence of a difference in heterogeneity of results between the two cohorts (F test, p=0.639; Levene's test, p=0.448). CONCLUSIONS: These results indicate that experienced military burn care providers overall more accurately assess %TBSA burned than relatively inexperienced clinicians. However, results demonstrate a lack of precision in both groups. PMID- 23790588 TI - Antimicrobial efficacy of a novel silver hydrogel dressing compared to two common silver burn wound dressings: ActicoatTM and PolyMem Silver((r)). AB - A novel burn wound hydrogel dressing has been previously developed which is composed of 2-acrylamido-2-methylpropane sulfonic acid sodium salt with silver nanoparticles. This study compared the antimicrobial efficacy of this novel dressing to two commercially available silver dressings; ActicoatTM and PolyMem Silver((r)). Three different antimicrobial tests were used: disc diffusion, broth culture, and the Live/Dead((r)) BaclightTM bacterial viability assay. Burn wound pathogens (P. aeruginosa, MSSA, A. baumannii and C. albicans) and antibiotic resistant strains (MRSA and VRE) were tested. All three antimicrobial tests indicated that ActicoatTM was the most effective antimicrobial agent, with inhibition zone lengths of 13.9-18.4mm. It reduced the microbial inocula below the limit of detection (10(2)CFU/ml) and reduced viability by 99% within 4h. PolyMem Silver((r)) had no zone of inhibition for most tested micro-organisms, and it also showed poor antimicrobial activity in the broth culture and Live/Dead((r)) BaclightTM assays. Alarmingly, it appeared to promote the growth of VRE. The silver hydrogel reduced most of the tested microbial inocula below the detection limit and decreased bacterial viability by 94-99% after 24h exposure. These results support the possibility of using this novel silver hydrogel as a burn wound dressing in the future. PMID- 23790589 TI - Long-term results of bilateral mandibular distraction osteogenesis using an intraoral tooth-borne device in adult Class II patients. AB - The aim of this prospective clinical study was to evaluate the short-term and long-term skeletal and dental changes after mandibular osteodistraction with tooth-borne appliances in adult orthodontic patients. The sample consisted of 10 non-growing Caucasian patients with a Class II skeletal relationship due to mandibular deficiency, together with Class II dental malocclusion. All patients underwent mandibular distraction osteogenesis (MDO) using the ROD1 tooth-borne device. Lateral cephalograms were evaluated at four time intervals: pretreatment (T1), after mandibular distraction (T2), after orthodontic fixed appliance therapy (T3), and at long-term observation 8-year post-distraction (T4). Statistical analyses compared the skeletal and dental changes in intervals T1-T2, T2-T3, T3-T4, T1-T4, and T2-T4. MDO with the ROD1 tooth-borne device produced significant long-term (T1-T4) increases in the SNB angle (2.3 degrees ), total mandibular length (5.9mm), and corpus length (4.5mm). Potential adverse sequelae included significant increases in mandibular plane angle (4.3 degrees ), lower anterior dental height (2.8mm), and lower posterior dental height (2.5mm). Significant increases in lower incisor proclination occurred during distraction (7.5 degrees ). Distraction osteogenesis with tooth-borne appliances offers a minimally invasive surgical method with stable results for correcting mandibular deficiency in non-growing patients. PMID- 23790590 TI - Biomagnification of DDT and its metabolites in four fish species of a tropical lake. AB - The concentrations and biomagnifications of dichlorodiphenyltrichloroethane (DDT) and its metabolites were examined in four fish species (Clarias gariepinus, Oreochromis niloticus, Tilapia zillii, and Carassius auratus) from Lake Ziway, Rift Valley, Ethiopia. Paired stomach content analysis, and stable isotope ratio of nitrogen (delta(15)N, 0/00) and carbon (delta(13)C, 0/00) were used to study the trophic position of the fish species in the lake. 4,4'-DDE, 4,4'-DDT and 4,4' DDD were the main DDTs identified in the fish samples, with 4,4'-DDE as the most predominant metabolite, with mean concentration ranging from 1.4 to 17.8 ng g(-1) wet weight (ww). The concentrations of DDTs found in fish from Lake Ziway were, in general lower than those found in most studies carried out in other African Lakes. However, the presence of DDT in all tissue samples collected from all fish species in the lake indicates the magnitude of the incidence. Moreover, the observed mean 4,4'-DDE to 4,4'-DDT ratio below 1 in C. auratus from Lake Ziway may suggest a recent exposure of these species to DDT, indicating that a contamination source is still present. 4,4'-DDE was found to biomagnify in the fish species of the lake, and increases with trophic level, however, the biomagnification rate was generally lower than what has been reported from other areas. Significantly higher concentrations of 4,4'-DDE were found in the top consumer fish in Lake Ziway, C. gariepinus than in O. niloticus (t=2.6, P<0.01), T. zillii (t=2.5, P<0.02) and C. auratus (t=2.2, P<0.03). PMID- 23790591 TI - Influence of elevated alkalinity and natural organic matter (NOM) on tissue specific metal accumulation and reproductive performance in fathead minnows during chronic, multi-trophic exposures to a metal mine effluent. AB - Metal bioavailability in aquatic organisms is known to be influenced by various water chemistry parameters. The present study examined the influence of alkalinity and natural organic matter (NOM) on tissue-specific metal accumulation and reproductive performance of fathead minnows (Pimephales promelas) during environmentally relevant chronic exposures to a metal mine effluent (MME). Sodium bicarbonate (NaHCO3) or NOM (as commercial humic acid) were added to a Canadian MME [45 percent process water effluent (PWE)] in order to evaluate whether increases in alkalinity (3-4 fold) or NOM (~1.5-3mg/L dissolved organic carbon) would reduce metal accumulation and mitigate reproductive toxicity in fathead minnows during a 21-day multi-trophic exposure. Eleven metals (barium, boron, cobalt, copper, lithium, manganese, molybdenum, nickel, rubidium, selenium, and strontium) were elevated in the 45 percent PWE relative to the reference water. Exposure to the unmodified 45 percent PWE resulted in a decrease of fathead minnow egg production (~300 fewer eggs/pair) relative to the unmodified reference water, over the 21-day exposure period. Water chemistry modifications produced a modest decrease in free ion activity of some metals (as shown by MINTEQ, Version 3) in the 45 percent PWE exposure water, but did not alter the metal burden in the treatment-matched larval Chironomus dilutus (the food source of fish during exposure). The tissue-specific metal accumulation increased in fish exposed to the 45 percent PWE relative to the reference water, irrespective of water chemistry modifications, and the tissue metal concentrations were found to be similar between fish in the unmodified and modified 45 percent PWE (higher alkalinity or NOM) treatments. Interestingly however, increased alkalinity and NOM markedly improved fish egg production both in the reference water (~500 and ~590 additional eggs/pair, respectively) and 45 percent PWE treatments (~570 and ~260 additional eggs/pair, respectively), although fecundity over 21 day exposure consistently remained lower in the 45 percent PWE treatment groups relative to the treatment-matched reference groups. Collectively, these findings suggest that metal accumulation caused by chronic 45 percent PWE exposure cannot solely explain the reproductive toxicity in fish, and decrease in food availability (decrease in C. dilutus abundance in 45 percent PWE exposures) might have played a role. In addition, it appears that NaHCO3 or humic acid mitigated reproductive toxicity in fish exposed to 45 percent PWE by their direct beneficial effects on the physiological status of fish. PMID- 23790592 TI - Assessment of the biological effects of welding fumes emitted from metal inert gas welding processes of aluminium and zinc-plated materials in humans. AB - The aim of this study was to investigate biological effects and potential health risks due to two different metal-inert-gas (MIG) welding fumes (MIG welding of aluminium and MIG soldering of zinc coated steel) in healthy humans. In a threefold cross-over design study 12 male subjects were exposed to three different exposure scenarios. Exposures were performed under controlled conditions in the Aachener Workplace Simulation Laboratory (AWSL). On three different days the subjects were either exposed to filtered ambient air, to welding fumes from MIG welding of aluminium, or to fumes from MIG soldering of zinc coated materials. Exposure was performed for 6 h and the average fume concentration was 2.5 mg m(-3). Before, directly after, 1 day after, and 7 days after exposure spirometric and impulse oscillometric measurements were performed, exhaled breath condensate (EBC) was collected and blood samples were taken and analyzed for inflammatory markers. During MIG welding of aluminium high ozone concentrations (up to 250 MUg m(-3)) were observed, whereas ozone was negligible for MIG soldering. For MIG soldering, concentrations of high-sensitivity CRP (hsCRP) and factor VIII were significantly increased but remained mostly within the normal range. The concentration of neutrophils increased in tendency. For MIG welding of aluminium, the lung function showed significant decreases in Peak Expiratory Flow (PEF) and Mean Expiratory Flow at 75% vital capacity (MEF 75) 7 days after exposure. The concentration of ristocetin cofactor was increased. The observed increase of hsCRP during MIG-soldering can be understood as an indicator for asymptomatic systemic inflammation probably due to zinc (zinc concentration 1.5 mg m(-3)). The change in lung function observed after MIG welding of aluminium may be attributed to ozone inhalation, although the late response (7 days after exposure) is surprising. PMID- 23790593 TI - Anticoagulation for atrial fibrillation: state of the art and recommendations for a quickly moving target. PMID- 23790594 TI - Silent atrial fibrillation as a stroke risk factor and anticoagulation indication. AB - The term "silent" atrial fibrillation (AF) has recently re-emerged to describe atrial arrhythmias that are detected by implanted cardiac devices but would generally go undetected in the clinical setting. The precise role that silent AF plays in increasing the risk of ischemic stroke is not fully understood. The purpose of this article is to: (1) review the current evidence demonstrating that silent AF is associated with thromboembolic events; (2) describe the temporal proximity of silent AF episodes to thromboembolic events; (3) present data on the incidence of newly detected silent AF in patients without a previous history of AF; and (4) provide an overview of ongoing and new clinical studies on this important topic. The current evidence suggests that the prevalence of silent AF is considerable among patients with implanted devices, and that the presence of silent AF increases the risk of thromboembolism. The AF burden threshold which confers this increased thromboembolism risk is not precisely defined, but might be as brief as several minutes to several hours. The advent of novel oral anticoagulation medications, which offer the promise of improved efficacy along with superior safety profiles, might warrant more aggressive identification of patients who might benefit from these therapies. However, to find high risk patients who have brief episodes of silent AF will likely require new methods of monitoring to permit the detection of this elusive but potentially dangerous arrhythmia. PMID- 23790595 TI - Importance of pharmacokinetic profile and variability as determinants of dose and response to dabigatran, rivaroxaban, and apixaban. AB - Warfarin has been the mainstay oral anticoagulant (OAC) medication prescribed for stroke prevention in atrial fibrillation (AF) patients. However, warfarin therapy is challenging because of marked interindividual variability in dose and response, requiring frequent monitoring and dose titration. These limitations have prompted the clinical development of new OACs (NOACs) that directly target the coagulation cascade with rapid onset/offset of action, lower risk for drug drug interactions, and more predictable response. Recently, NOACs dabigatran (direct thrombin inhibitor), and rivaroxaban and apixaban (factor Xa [FXa] inhibitors) have gained regulatory approval as alternative therapies to warfarin. Though the anticoagulation efficacy of these NOACs has been characterized, differences in their pharmacokinetic and pharmacodynamic profiles have become a significant consideration in terms of drug selection and dosing. In this review, we outline key pharmacokinetic and pharmacodynamic features of each compound and provide guidance on selection and dosing of the 3 NOACs relative to warfarin when considering OAC therapy for AF patients. Importantly, we show that by better understanding the effect of clinical variables such as age, renal function, dosing interval, and drug metabolism (CYP3A4) and transport (P-glycoprotein), we might be able to better predict the risk for sub- and supratherapeutic anticoagulation response and individualize OAC selection and dosing. PMID- 23790596 TI - Assessment of anticoagulation intensity and management of bleeding with old and new oral anticoagulants. AB - Warfarin is effective for the prevention and treatment of thromboembolism but produces variable anticoagulant effects and requires routine monitoring of the international normalized ratio (INR) to optimize the balance between efficacy and safety. The new oral anticoagulants (NOACs) have a more predictable anticoagulant effect and were recently demonstrated to be at least as efficacious and safe as warfarin despite being administered in fixed doses without routine coagulation monitoring. Specific laboratory tests have been developed to measure the anticoagulant effect of the NOACs but are not yet widely available, and the relation between drug levels and both coagulation test results and outcomes is uncertain. It remains to be demonstrated whether adjustment of the dose of NOACs, according to the results of laboratory testing, may lead to even greater efficacy and safety. The principles of bleeding management in patients treated with NOACs compared with patients receiving warfarin are similar. Most patients can be safely managed by interrupting drug treatment, performing local measures to stem the bleeding, and providing transfusion support as required. In patients with major or life-threatening bleeding and those requiring surgery, the anticoagulant effects of warfarin can be reversed using oral or intravenous vitamin K, fresh frozen plasma (FFP), and prothrombin complex concentrates (PCCs). Specific antidotes are under development for the NOACs but are not yet approved for clinical use. PCCs and recombinant factor VIIa may improve hemostasis in patients in whom bleeding develops during treatment with a NOAC, but their efficacy is unproven. PMID- 23790597 TI - Recent developments in understanding epidemiology and risk determinants of atrial fibrillation as a cause of stroke. AB - The prevalence of atrial fibrillation (AF) is increasing because of the aging population and advances in the treatment of acute cardiac conditions. It is now approaching epidemic proportions and is associated with significant clinical and public health consequences. Risk factors for the development of AF are numerous and varied and highlight potential treatment measures that could help prevent the occurrence of AF. The emergence of novel risk factors might allow us to increase our understanding of the pathophysiology of the condition and develop novel therapeutic targets. Stroke is the most devastating consequence of AF, and can be prevented with effective oral anticoagulation in patients at increased stroke risk. Our understanding of stroke risk has advanced; we know that the risk is not homogenous and also that only the very lowest risk patients do not benefit from anticoagulation. Clinicians should target their efforts on identifying this "truly low-risk" patient cohort and consider offering formal anticoagulation to all other AF patients. The purpose of this review is to consider the traditional and emerging risk factors for the development of AF itself, and the risk factors for stroke in AF patients and how knowledge of these risk factors can affect clinical practice. PMID- 23790598 TI - Acute stroke management in patients with known or suspected atrial fibrillation. AB - Atrial fibrillation (AF) is an important cause of ischemic stroke, especially in older individuals. Strokes attributed to AF are often large and result in a high rate of fatality. The new oral anticoagulants offer advantages over warfarin in terms of dosing, pharmacokinetic characteristics, and lower rates of intracranial hemorrhage, but pose new management questions for physicians treating these patients. The management of acute stroke is not modified by the presence of AF, but is unique with respect to management of anticoagulation in the hyperacute and acute phases. We will review and discuss acute treatment options in anticoagulated patients with ischemic stroke, anticoagulation discontinuation, and timing of initiation with old and new oral anticoagulants, and managing intracranial hemorrhage in anticoagulated patients. We will end by briefly discussing investigations of stroke patients with suspected cardioembolic stroke. PMID- 23790599 TI - Periprocedural management of oral anticoagulation in patients with atrial fibrillation: approach in the era of new oral anticoagulants. AB - A growing number of patients with atrial fibrillation are treated with oral anticoagulation (OAC), and a large proportion of them will require surgical or other invasive procedures. These procedures typically involve interruption of OAC with or without the use of heparin bridging; however; there has been a dramatic change in this practice during the past 3 years. The introduction of short acting, new oral anticoagulants and the growing popularity of some low-risk procedures with continued OAC have transformed our practice. Physicians and surgeons who treat patients with atrial fibrillation must be aware of these changes and understand how to deal with the new challenges they may encounter. PMID- 23790600 TI - Oral antithrombotic therapy in atrial fibrillation associated with acute or chronic coronary artery disease. AB - Randomized controlled trials have demonstrated benefits from antithrombotic therapies for coronary artery disease (primary prevention, stable coronary artery disease, acute coronary syndromes, and percutaneous intervention) and for atrial fibrillation. The regimens with the optimal balance of efficacy and safety with coronary artery disease depend on the particular clinical manifestation, with atrial fibrillation on the risk of stroke, and with both conditions on the competing risk of major bleeding with the chosen antithrombotic therapy. The antithrombotic agents include aspirin, P2Y12 receptor inhibitors (clopidogrel, prasugrel, and ticagrelor) and oral anticoagulants (warfarin and the novel oral anticoagulants, dabigatran, rivaroxaban, and apixaban). Atrial fibrillation and coronary artery disease often occur in the same patient and require decisions as to what individual or combination of antithrombotic therapies are necessary to provide optimal protection against coronary events and stroke, and cause as little bleeding as possible. Practice guidelines now recommend oral anticoagulant therapy for most patients with atrial fibrillation and consideration of "triple therapy" (oral anticoagulant and aspirin and clopidogrel) when there is a concomitant acute coronary syndrome or stent placement, though acknowledging the risks of major bleeding. In the absence of definitive trials of combination therapies, such practice guidelines are based on extrapolations from randomized trials and observational data. PMID- 23790601 TI - Stroke prevention in atrial fibrillation patients with chronic kidney disease. AB - Chronic kidney disease (CKD) is prevalent in elderly patients with atrial fibrillation and is an independent risk factor for stroke. Warfarin anticoagulation is efficacious for stroke prevention in atrial fibrillation patients with moderate CKD (stage III, estimated glomerular filtration rate 30-59 mL/min), but recent observational studies have challenged its value for patients with end-stage renal disease requiring dialysis. The novel oral anticoagulants (i.e., dabigatran, apixaban, rivaroxaban) all undergo renal metabolism to varying degrees, and hence dosing, efficacy, and safety require special consideration in CKD patients. In randomized trials to date involving 11,169 patients with moderate CKD, the novel oral anticoagulants performed well, with similar efficacy and safety profiles as for non-CKD patients. For atrial fibrillation patients with stage III CKD, the available data are strongest for dabigatran 150 mg twice daily as superior to warfarin for stroke prevention and for apixaban as superior to warfarin regarding reduced major hemorrhage. Renal function should be monitored at least annually in patients receiving a novel oral anticoagulant, and more often in elderly patients and those with underlying CKD or comorbidities who are at special risk for dehydration and deterioration of renal function. Much remains to be learned about the optimal use of the novel oral anticoagulants in CKD patients; additional studies about optimal dosing of the novel oral anticoagulants and frequency of monitoring renal function in CKD patients with atrial fibrillation are needed. Anticoagulation options for hemodialysis patients require testing in randomized trials. PMID- 23790602 TI - Nonpharmacologic approaches to stroke prevention in atrial fibrillation. AB - The greatest priority in treating atrial fibrillation (AF) is stroke prevention. There are now 3 main approaches to prevention: (1) oral anticoagulation (OAC), (2) eradication of AF, and (3) exclusion of the left atrial appendage (LAA) from the systemic circulation. The goal of this article is to review these approaches, with particular emphasis on nonpharmacologic methods and their role in light of current evidence. OAC is effective but is limited by major bleeding, physician and patient reluctance to use anticoagulants, and patient noncompliance. Eradication of AF with antiarrhythmic drugs has not been effective, and suppression with ablation has not yet been properly tested for stroke prevention. Finally, occlusion of the LAA is promising, but definitive evidence of efficacy for stroke prevention is lacking. Trials such as WATCHMAN LAA System for Embolic Protection in Patients With Atrial Fibrillation (PROTECT AF) and Prospective Randomized Evaluation of the WATCHMAN LAA Closure Device in Patients With Atrial Fibrillation vs Long-Term Warfarin Therapy (PREVAIL) provide the best quality evidence for LAA device closure, with results suggesting noninferiority to OAC. Surgical trials have yet to show the efficacy of LAA occlusion for stroke prevention. This review highlights the evidence behind each of these approaches and concludes that to date OAC remains the standard for stroke prevention in AF. Future trials will need to address novel OAC therapy when comparing them with LAA exclusion, and large randomized trials will be required to ascertain indications for nonpharmacologic therapy in current practice. PMID- 23790603 TI - Effect of sampling rates on the quantification of forces, durations, and rates of loading of simulated side posture high-velocity, low-amplitude lumbar spine manipulation. AB - OBJECTIVE: Quantification of chiropractic high-velocity, low-amplitude spinal manipulation (HVLA-SM) may require biomechanical equipment capable of sampling data at high rates. However, there are few studies reported in the literature regarding the minimal sampling rate required to record the HVLA-SM force-time profile data accurately and precisely. The purpose of this study was to investigate the effect of different sampling rates on the quantification of forces, durations, and rates of loading of simulated side posture lumbar spine HVLA-SM delivered by doctors of chiropractic. METHODS: Five doctors of chiropractic (DCs) and 5 asymptomatic participants were recruited for this study. Force-time profiles were recorded during (i) 52 simulated HVLA-SM thrusts to a force transducer placed on a force plate by 2 DCs and (ii) 12 lumbar side posture HVLA-SM on 5 participants by 3 DCs. Data sampling rate of the force plate remained the same at 1000 Hz, whereas the sampling rate of the force transducer varied at 50, 100, 200, and 500 Hz. The data were reduced using custom-written MATLAB (Mathworks, Inc, Natick, MA) and MathCad (version 15; Parametric Technologies, Natick, MA) programs and analyzed descriptively. RESULTS: The average differences in the computed durations and rates of loading are smaller than 5% between 50 and 1000 Hz sampling rates. The differences in the computed preloads and peak loads are smaller than 3%. CONCLUSIONS: The small differences observed in the characteristics of force-time profiles of simulated manual HVLA SM thrusts measured using various sampling rates suggest that a sampling rate as low as 50 to 100 Hz may be sufficient. The results are applicable to the manipulation performed in this study: manual side posture lumbar spine HVLA-SM. PMID- 23790604 TI - Prevalence of self-reported childhood abuse in psychosis: a meta-analysis of retrospective studies. AB - There is extensive clinical literature reporting traumatic childhood experiences in patients with psychosis. A quantitative meta-analysis addressing the prevalence of self-reported childhood sexual (CSA), physical (CPA) and emotional abuse (CEA) in psychotic patients has yet to be done. We conducted, a systematic literature search to identify retrospective studies addressing self-reported childhood abuse in patients with DSM/ICD psychosis. Demographic, clinical, and methodological variables were extracted from each publication, or obtained directly from its authors. Quantitative meta-analysis of CSA, CPA, CEA in the sample of patients was performed. Statistical heterogeneity and publication bias were assessed and meta-regressions performed to control for different moderators. Twenty-three studies were retrieved and included a total of 2017 psychotic patients. The prevalence of self-reported CSA, CPA, CEA were respectively of 26%, 39% and 34%. Age, publication year, gender and substance abuse moderated CSA, while age, clinical setting and substance abuse moderated CPA. Results indicated that CEA was moderated by gender and publication year of the study. According to our meta-analysis, psychotic patients have a consistently high self-report of childhood traumatic events which are sexual, physical and emotional in nature. It is our opinion that clinicians should be trained and skilled to carefully investigate childhood abuse in psychosis. PMID- 23790605 TI - Clinical results of patellofemoral arthroplasty. AB - Isolated patellofemoral arthritis can be a disabling condition that can be challenging to treat. Patients with symptoms recalcitrant to conservative measures are considered for total or partial knee arthroplasty. This retrospective study reports the results of patellofemoral arthroplasty at a single center using a variety of implant designs. Thirty patients (37 knees) with isolated patellofemoral disease treated with patellofemoral arthroplasty with a minimum of one year follow-up were evaluated. The majority of patients were female (83%) and the underlying diagnosis was osteoarthritis in 98% of knees. Reported follow-up averaged 31 months. Average Knee Society Pain, Functional, and Clinical Scores improved from pre-op to most recent follow-up. Two complications (5.4%) required intervention. One patient was converted to a total knee arthroplasty secondary to patella instability. PMID- 23790606 TI - Dr. Mueller and colleagues. Foreword. PMID- 23790607 TI - Contemporary topics in pediatric pulmonology for the primary care clinician. AB - Disorders of the respiratory system are commonly encountered in the primary care setting. The presentations are myriad and this review will discuss some of the more intriguing or vexing disorders that the clinician must evaluate and treat. Among these are dyspnea, chronic cough, chest pain, wheezing, and asthma. Dyspnea and chest pain have a spectrum ranging from benign to serious, and the ability to effectively form a differential diagnosis is critical for reassurance and treatment, along with decisions on when to refer for specialist evaluation. Chronic cough is one of the more common reasons for primary care office visits, and once again, a proper differential diagnosis is necessary to assist the clinician in formulating an appropriate treatment plan. Infant wheezing creates much anxiety for parents and accounts for a large number of office visits and hospital admissions. Common diagnoses and evaluation strategies of early childhood wheezing are reviewed. Asthma is one of the most common chronic diseases of children and adults. The epidemiology, diagnosis, evaluation, treatment, and the patient/parent education process will be reviewed. A relatively new topic for primary care clinicians is cystic fibrosis newborn screening. The rationale, methods, outcomes, and implications will be reviewed. This screening program may present some challenges for clinicians caring for newborns, and an understanding of the screening process will help the clinician communicate effectively with parents of the patient. PMID- 23790608 TI - Commentary. PMID- 23790609 TI - Commentary. PMID- 23790610 TI - Elective bladder-sparing treatment for muscle invasive bladder cancer. AB - OBJETIVES: Radical cystectomy is the standard treatment for localised muscle invasive bladder cancer (MIBC). We offer a bladder-sparing treatment with TURB +/ Chemotherapy+Radiotherapy to selected patients as an alternative. MATERIAL AND METHODS: We analyze, retrospectively, 30 patients diagnosed with MIBC from March 1991 to October 2010. The mean age was 62.7 years (51-74). All patients were candidates for a curative treatment, and underwent strict selection criteria: T2 stage, primary tumor, solitary lesion smaller than 5cm with a macroscopic disease free status after TURB, negative random biopsy without hydronephrosis. Staging CT evaluation was normal. Restaging TURB or tumor bed biopsy showed a disease-free status or microscopic muscle invasion. 14 patients underwent TURB alone, 13 TURB+Chemotherapy and 3 TURB+Chemotherapy+Radiotherapy. RESULTS: The mean follow up was 88.7 months (19-220). 14 patients remained disease free (46.6%), 10 had recurrent non-muscle invasive bladder cancer (33%). 81.3% complete clinical response. 71% bladder preserved at 5-years. Overall, 5-years survival rate was 79% and 85% cancer-specific survival rate. CONCLUSIONS: Although radical cystectomy is the standard treatment for localised MIBC, in strictly selected cases, bladder-sparing treatment offers an alternative with good long term results. PMID- 23790611 TI - Crohn's disease and smoking: is it ever too late to quit? AB - BACKGROUND: Smoking increases CD risk. The aim was to determine if smoking cessation at, prior to, or following, CD diagnosis affects medication use, disease phenotypic progression and/or surgery. METHODS: Data on CD patients with disease for >=5 yrs were collected retrospectively including the Montreal classification, smoking history, CD-related abdominal surgeries, family history, medication use and disease behaviour at diagnosis and the time when the disease behaviour changed. RESULTS: 1115 patients were included across six sites (mean follow-up-16.6 yrs). More non-smokers were male (p=0.047) with A1 (p<0.0001), L4 (p=0.028) and perianal (p=0.03) disease. Non-smokers more frequently received anti-TNF agents (p=0.049). (p=0.017: OR 2.5 95%CI 1.18-5.16) and those who ceased smoking prior to diagnosis (p=0.045: OR 2.3 95%CI 1.02-5.21) progressed to complicated (B2/B3) disease as compared to those quitting at diagnosis. Patients with uncomplicated terminal ileal disease at diagnosis more frequently developed B2/B3 disease than isolated colonic CD (p<0.0001). B2/B3 disease was more frequent with perianal disease (p<0.0001) and if i.v. steroids (p=0.004) or immunosuppressants (p<0.0001) were used. 49.3% (558/1115) of patients required at least one intestinal surgery. More smokers had a 2nd surgical resection than patients who quit at, or before, the 1st resection and non-smokers (p=0.044: HR=1.39 95%CI 1.01-1.91). Patients smoking >3 cigarettes/day had an increased risk of developing B2/B3 disease (p=0.012: OR 3.8 95%CI 1.27-11.17). CONCLUSION: Progression to B2/B3 disease and surgery is reduced by smoking cessation. All CD patients regardless of when they were diagnosed, or how many surgeries, should be strongly encouraged to cease smoking. PMID- 23790612 TI - Acute metabolic amplification of insulin secretion in mouse islets is mediated by mitochondrial export of metabolites, but not by mitochondrial energy generation. AB - OBJECTIVE: The beta-cell metabolism of glucose and of some other fuels (e.g. alpha-ketoisocaproate) generates signals triggering and acutely amplifying insulin secretion. As the pathway coupling metabolism with amplification is largely unknown, we aimed to narrow down the putative amplifying signals. MATERIALS/METHODS: An experimental design was used which previously prevented glucose-induced, but not alpha-ketoisocaproate-induced insulin secretion. Isolated mouse islets were pretreated for one hour with medium devoid of fuels and containing the sulfonylurea glipizide in high concentration which closed all ATP-sensitive K(+) channels. This concentration was also applied during the subsequent examination of fuel-induced effects. In perifused or incubated islets, insulin secretion and metabolic parameters were measured. RESULTS: The pretreatment decreased the islet ATP/ADP ratio. Whereas glucose and alpha ketoisovalerate were ineffective or weakly effective, respectively, when tested separately, their combination strongly enhanced the insulin secretion. Compared with glucose, the strong amplifier alpha-ketoisocaproate caused less increase in NAD(P)H-fluorescence and less mitochondrial hyperpolarization. Compared with alpha-ketoisovalerate, alpha-ketoisocaproate caused greater increase in NAD(P)H fluorescence and greater mitochondrial hyperpolarization. Neither alpha-ketoacid anion enhanced the islet ATP/ADP ratio during onset of the insulin secretion. alpha-Ketoisocaproate induced a higher pyruvate content than glucose, slowly elevated the citrate content which was not changed by glucose and generated a much higher acetoacetate content than other fuels. alpha-Ketoisovalerate alone or in combination with glucose did not increase the citrate content. CONCLUSIONS: In beta-cells, mitochondrial energy generation does not mediate acute metabolic amplification, but mitochondrial production of acetyl-CoA and supplemental acetoacetate supplies cytosolic metabolites which induce the generation of specific amplifying signals. PMID- 23790613 TI - National variability in surveillance, testing, and infection prevention for Clostridium difficile infection in pediatric populations. AB - To assess national variability in methods of identifying and preventing Clostridium difficile infection (CDI) in pediatric populations, an anonymous survey was sent to hospital epidemiologists at US children's hospitals. Data from 30 hospitals indicate substantial variability in surveillance, testing, and infection control strategies, which may limit reliable interfacility comparison of CDI rates. In addition, only 60% of respondents perform surveillance for community-associated CDI. PMID- 23790614 TI - Identification of carotid plaque tissue properties using an experimental numerical approach. AB - A biomechanical stress analysis could help to identify carotid plaques that are vulnerable to rupture, and hence reduce the risk of thrombotic strokes. Mechanical stress predictions critically depend on the plaque's constitutive properties, and the present study introduces a concept to derive viscoelastic parameters through an experimental-numerical approach. Carotid plaques were harvested from two patients during carotid endarterectomy (CEA), and, in total, nine test specimens were investigated. A novel in-vitro mechanical testing protocol, which allows for dynamic testing, keeping the carotid plaque components together, was introduced. Macroscopic pictures overlaid by histological stains allowed for the segmentation of plaque tissues, in order to develop high-fidelity and low-fidelity Finite Element Method (FEM) models of the test specimens. The FEM models together with load-displacement data from the mechanical testing were used to extract constitutive parameters through inverse parameter estimation. The applied inverse parameter estimation runs in stages, first addressing the hyperelastic parameters then the viscoelastic ones. Load-displacement curves from the mechanical testing showed strain stiffening and viscoelasticity, as is expected for both normal and diseased carotid tissue. The estimated constitutive properties of plaque tissue were comparable to previously reported studies. Due to the highly non-linear elasticity of vascular tissue, the applied parameter estimation approach is, as with many similar approaches, sensitive to the initial guess of the parameters. PMID- 23790615 TI - Clinical significance of orthostatic dizziness in the diagnosis of benign paroxysmal positional vertigo and orthostatic intolerance. AB - PURPOSE: Orthostatic dizziness (OD) and positional dizziness (PD) are considerably common conditions in dizziness clinic, whereas those two conditions are not clearly separated. We aimed to evaluate the clinical significance of simple OD and OD combined with PD for the diagnosis of benign paroxysmal positional vertigo (BPPV) and orthostatic intolerance (OI). PATIENTS AND METHODS: Patients presenting with OD (n=102) were divided into two groups according to their symptoms: group PO, presenting with PD as well as OD; group O, presenting with OD. A thorough medical history, physical examination, and vestibular function tests were performed to identify the etiology of the dizziness. Orthostatic vital sign measurement (OVSM) was used to diagnose OI. RESULTS: The majority of patients were in group PO (87.3%). BPPV was the most common cause of OD for entire patients (36.3%) and group PO (37.1%), while OI was most common etiology for group O (38.5%). Total of 17 (16.7%) OI patients were identified by OVSM test. Orthostatic hypotension (n=10) was most frequently found, followed by orthostatic hypertension (n=5), and orthostatic tachycardia (n=2). Group O showed significantly higher percentage (38.5%) of OI than group PO (13.5%) (P=0.039). CONCLUSION: It is suggested that orthostatic testing such as OVSM or head-up tilt table test should be performed as an initial work up for the patients with simple OD. Positional tests for BPPV should be considered as an essential diagnostic test for patients with OD, even though their dizziness is not associated with PD. PMID- 23790616 TI - Legal aspects of patenting time. AB - Times of embryonic development are naturally occurring phenomena and, therefore, under the caveat that all things in nature without human intervention are not patentable, should not be patentable. PMID- 23790617 TI - An all-embracing problem description. The Swedish drug issue as a political catalyst 1982-2000. AB - BACKGROUND: This article examines the political formulation and ideological solution of the Swedish drug problem in 1982-2000. How was the drug problem described in the Swedish parliament at the time? How serious was the problem and what solutions were proposed? What were the ideological implications of the problem description, and how was the general political and ideological solution formulated? METHODS: The empirical basis for the textual analysis consists of parliamentary bills, government bills and parliamentary records discussing the drug issue during the years 1982-2000. RESULTS: In the prevailing spirit of consensus in the Swedish parliament at the time, both left-wing and right-wing parties portrayed drugs as a threat to the nation, people and the welfare state. Still, as the ideological dimension kept growing stronger, the drug question functioned even better as an arena for political discussions and ideological positions than in the 1970s. CONCLUSION: Compared to previous decades, the problem description broadened during the 1980s and 1990s, and the drug problem could be used to support arguments on almost any topic. The drug problem became a highly politicized issue about whom or what to change when the individual and the society clashed, but also about what the individual and/or society should be changed into. PMID- 23790618 TI - [Perfusion magnetic resonance imaging for high grade astrocytomas: Can cerebral blood volume, peak height, and percentage of signal intensity recovery distinguish between progression and pseudoprogression?]. AB - OBJECTIVES: To study the usefulness of common MRI perfusion parameters for identifying pseudoprogression in high grade astrocytomas. MATERIAL AND METHODS: This retrospective case-control study compared the relative cerebral blood volume (rCBV), the relative percentage of signal intensity recovery (rPSR), and the relative peak height (rPH) recorded in a sample of 17 cases of anaplastic astrocytomas and gliomas considered to be undergoing pseudoprogression by biopsy or follow-up with those recorded in a sample of histologically similar tumors that were treated and considered to be undergoing progression by histologic study or follow-up. We evaluated the accuracy of these parameters and the correlations among them. Statistical significance was set at P<.05. RESULTS: The rCBV, rPSR, and rPH were significantly different between the two groups (P=.001). The cutoff values rPH=1.37, rCBV=0.9, and rPSR=99% yielded sensitivity (S)=88% and specificity (Sp)=82.2% for rPH, S=100% and Sp=100% for rCBV, and S=100% and Sp=70.6% for rPSR, respectively. We found negative correlations between rPRS and rPH (-0.76) and between rPRS and rCBV (-0.81) and a high positive correlation between rPH and rCBV (0.87). CONCLUSION: The variables rPH and rCBV were useful for differentiating between pseudoprogression and true progression in our sample. The variable rPRS was also very sensitive, although the overlap in the values between samples make it less useful a priori. PMID- 23790619 TI - Dramatic improvement of truncal tardive dystonia following globus pallidus pars interna deep brain stimulation. AB - Truncal predominant tardive dystonia is an uncommon presentation of dystonia, and may be associated with significant disability. We report a patient with near complete resolution of severe, disabling truncal tardive dystonia following globus pallidus pars interna deep brain stimulation. Her unusual clinical presentation highlights the difficulties in diagnosing unusual forms of dystonia, and the therapeutic gains that can be achieved once the diagnosis is recognised. PMID- 23790620 TI - Clinical, immunohistochemical, Western blot, and genetic analysis in dystrophinopathy. AB - Dystrophin-deficient muscular dystrophies (dystrophinopathies) are the most common form of muscular dystrophy, with variable clinical phenotypes ranging from the severe Duchenne (DMD) to the milder Becker (BMD) forms. In this study, we investigated the relationship between clinical characteristics, findings at immunohistochemistry (IHC) and Western blot, and the pattern of exon deletions in 24 male patients with dystrophinopathies. We retrospectively reviewed findings from clinical and laboratory examinations, IHC for dystrophin of muscle biopsy tissue, Western blot analysis, and multiplex polymerase chain reaction (PCR) examination of genomic DNA. All tests were performed in every patient. PCR examination revealed exon deletions in 13 patients (54.2%). At Western blot analysis, 15 patients (62.5%) were negative at all three dystrophin domains. Most of these patients had a clinical presentation consistent with the DMD phenotype. Nine (37.5%) others were weakly positive at one or more domains. Most of these patients presented clinically as BMD phenotype. One patient whose clinical presentation was consistent with BMD phenotype had normal findings at IHC and was weakly positive at all three domains on Western blot analysis; however, with the exception of this patient, the findings at IHC and Western blot were consistent for individual patients. Based on these findings, we conclude that Western blot analysis appears useful for confirmation of dystrophinopathy in BMD patients with normal staining on IHC. Exon deletion analysis by multiplex PCR using peripheral blood is also a simple and useful test for the diagnosis of dystrophinopathy, although it has limited sensitivity. PMID- 23790621 TI - Acute lumbosacral transverse myelitis. AB - We report two patients with idiopathic acute lumbosacral myelitis, a rare form of acute transverse myelitis. Both patients developed urinary retention, moderate motor and sensory paresis of the lower extremities, severe sensory deficit in the anogenital region and reduced deep tendon reflexes. Steroid pulse therapy was initiated within 2 days after onset, and progress of the symptoms stopped immediately after administration in both of our patients. The sequelae of the sensory deficits in the sacral dermatome distribution and urinary retention impaired daily functioning. Immediate immunosuppressive therapy, including high dose steroid treatment, is important to improve the prognosis of acute lumbosacral transverse myelitis. PMID- 23790622 TI - Measuring competence development for performing high flow extracranial-to intracranial bypass. AB - We report our experience with competence development in the performance of high flow extracranial-to-intracranial (HF EC-IC) bypass surgery because of the infrequency of, and hence potential exposure to, this challenging surgery. We reviewed the National Hospital Morbidity Database for the incidence of EC-IC bypass surgery as well as a prospectively collected database (institutional experience). The following were recorded from the institutional experience: graft occlusion, stenosis, disruption, distal ischaemia, surgical complications of the bypass leading to a modified Rankin Scale (mRS) score >2, and intraoperative cross-clamping time. The cross-clamping time was considered the total time that circulation may have been impaired, which included both the distal and proximal cross-clamping periods. The Australian national EC-IC bypass rate (of all bypass types) averaged 1.9 cases per 1,000,000 head of population annually. The institutional experience (170 cases) of high flow EC-IC bypass in this series was associated with 14.7% (95% confidence interval [CI] 10.1-20.9) of graft complications. Graft-specific complications leading to a mRS score >2 were 5.9% (95% CI 3.1-10.6). For the 83 patients where the cross-clamping time was known, the time of cross-clamping was 44 +/- 14 min. We concluded that HF EC-IC bypasses are rarely performed procedures that challenge the development of surgical competence. Novel ways of developing and maintaining surgical skills are necessary, including simulation and laboratory experience. PMID- 23790623 TI - Late adult onset optic pathway astrocytoma. AB - A 70-year-old man presented with left-sided eye pain, impaired vision and restricted left ocular motility, later developing progressive visual decline with development of ataxia and incontinence. Fundoscopic examination revealed significant optic nerve head edema and hemorrhage on the left eye. Neuroimaging revealed an optic pathway mass, extending from the right optic nerve to the chiasm, which enlarged on serial imaging. After surgical excision of the mass, pathology showed a grade III astrocytoma. The patient died 16 months after presentation, which is longer than previously reported for late adult onset optic pathway astrocytoma. We believe that neuroimaging and pathological studies should be performed early in such patients to allow early diagnosis and intervention. PMID- 23790624 TI - Paraneoplastic cerebellar degeneration associated with squamous cell carcinoma of the lung. AB - We report a 78-year-old man who presented with rapidly progressive cerebellar ataxia, dysarthria and vertigo. MRI of the brain showed no evidence of infiltrative pathology in the posterior fossa. Cerebrospinal fluid analysis revealed an elevated protein and pleocytosis. He was subsequently diagnosed with squamous cell carcinoma of the lung on bronchoscopy. Paraneoplastic cerebellar degeneration (PCD) was diagnosed. To our knowledge, there are only two previously reported patients with PCD associated with squamous cell carcinoma of the lung. PMID- 23790625 TI - Ischaemic stroke provoked by sexual intercourse. AB - The association between long term risk factors and stroke has been well established, but very little is known about factors that may precipitate acute stroke. We describe two young women presenting with ischaemic stroke triggered by sexual intercourse. Patient 1 presented with a cardioembolic stroke probably secondary to the interaction between a patent foramen ovale and thrombophilic abnormalities; Patient 2, presenting with orgasmic headache, had a cryptogenic striatocapsular infarct. Sexual intercourse should be considered as an unusual, but possible, trigger of cerebral ischaemia, especially in young patients presenting with cryptogenic stroke. PMID- 23790626 TI - TALENs: customizable molecular DNA scissors for genome engineering of plants. AB - Precise genome modification with engineered nucleases is a powerful tool for studying basic biology and applied biotechnology. Transcription activator-like effector nucleases (TALENs), consisting of an engineered specific (TALE) DNA binding domain and a Fok I cleavage domain, are newly developed versatile reagents for genome engineering in different organisms. Because of the simplicity of the DNA recognition code and their modular assembly, TALENs can act as customizable molecular DNA scissors inducing double-strand breaks (DSBs) at given genomic location. Thus, they provide a valuable approach to targeted genome modifications such as mutations, insertions, replacements or chromosome rearrangements. In this article, we review the development of TALENs, and summarize the principles and tools for TALEN-mediated gene targeting in plant cells, as well as current and potential strategies for use in plant research and crop improvement. PMID- 23790627 TI - TALEN or Cas9 - rapid, efficient and specific choices for genome modifications. AB - Precise modifications of complex genomes at the single nucleotide level have been one of the big goals for scientists working in basic and applied genetics, including biotechnology, drug development, gene therapy and synthetic biology. However, the relevant techniques for making these manipulations in model organisms and human cells have been lagging behind the rapid high throughput studies in the post-genomic era with a bottleneck of low efficiency, time consuming and laborious manipulation, and off-targeting problems. Recent discoveries of TALEs (transcription activator-like effectors) coding system and CRISPR (clusters of regularly interspaced short palindromic repeats) immune system in bacteria have enabled the development of customized TALENs (transcription activator-like effector nucleases) and CRISPR/Cas9 to rapidly edit genomic DNA in a variety of cell types, including human cells, and different model organisms at a very high efficiency and specificity. In this review, we first briefly summarize the development and applications of TALENs and CRISPR/Cas9-mediated genome editing technologies; compare the advantages and constraints of each method; particularly, discuss the expected applications of both techniques in the field of site-specific genome modification and stem cell based gene therapy; finally, propose the future directions and perspectives for readers to make the choices. PMID- 23790628 TI - Short tandem target mimic: a long journey to the engineered molecular landmine for selective destruction/blockage of microRNAs in plants and animals. AB - MicroRNAs (miRNAs) are a population of highly conserved specific small ribo regulators that negatively regulate gene expressions in both plants and animals. They play a key role in post-transcriptional gene regulation by destabilizing the target gene transcripts or blocking protein translation from them. Interestingly, these negative regulators are largely compromised by an upstream layer of negative regulators "target mimics" found in plants or "endogenous competing RNAs" revealed recently in animals. These endogenous regulatory mechanisms of "double negatives making a positive" have now been developed into a key strategy in the study of small RNA functions. This review presents some reflections on the long journey to the short tandem target mimic (STTM) for selective destruction/blockage of specific miRNAs in plants and animals, and the potential applications of STTM are discussed. PMID- 23790629 TI - Characterization of the Drosophila atlastin interactome reveals VCP as a functionally related interactor. AB - At least 25 genes, many involved in trafficking, localisation or shaping of membrane organelles, have been identified as causative genes for the neurodegenerative disorder hereditary spastic paraplegia (HSP). One of the most commonly mutated HSP genes, atlastin-1, encodes a dynamin-like GTPase that mediates homotypic fusion of endoplasmic reticulum (ER) membranes. However, the molecular mechanisms of atlastin-1-related membrane fusion and axonopathy remain unclear. To better understand its mode of action, we used affinity purification coupled with mass spectrometry to identify protein interactors of atlastin in Drosophila. Analysis of 72 identified proteins revealed that the atlastin interactome contains many proteins involved in protein processing and transport, in addition to proteins with roles in mRNA binding, metabolism and mitochondrial proteins. The highest confidence interactor from mass spectrometry analysis, the ubiquitin-selective AAA-ATPase valosin-containing protein (VCP), was validated as an atlastin-interacting protein, and VCP and atlastin showed overlapping subcellular distributions. Furthermore, VCP acted as a genetic modifier of atlastin: loss of VCP partially suppressed an eye phenotype caused by atlastin overexpression, whereas overexpression of VCP enhanced this phenotype. These interactions between atlastin and VCP suggest a functional relationship between these two proteins, and point to potential shared mechanisms between HSP and other forms of neurodegeneration. PMID- 23790630 TI - Characterization and fine mapping of a necrotic leaf mutant in maize (Zea mays L.). AB - Maize (Zea mays L.) is a commercially important crop. Its yield can be reduced by mutations in biosynthetic and degradative pathways that cause death. In this paper, we describe the necrotic leaf (nec-t) mutant, which was obtained from an inbred line, 81647. The nec-t mutant plants had yellow leaves with necrotic spots, reduced chlorophyll content, and the etiolated seedlings died under normal growth conditions. Transmission electron microscopy revealed scattered thylakoids, and reduced numbers of grana lamellae and chloroplasts per cell. Histochemical staining suggested that spot formation of nec-t leaves might be due to cell death. Genetic analysis showed that necrosis was caused by the mutation of a recessive locus. Using simple sequence repeat markers, the Nec-t gene was mapped between mmc0111 and bnlg2277 on the short arm of chromosome 2. A total of 1287 individuals with the mutant phenotype from a F2 population were used for physical mapping. The Nec-t gene was located between markers T31 and H8 within a physical region of 131.7 kb. PMID- 23790631 TI - Lack of an additive effect between the deletions of Klf5 and Nkx3-1 in mouse prostatic tumorigenesis. PMID- 23790632 TI - Directed evolution of insoluble arabidopsis thaliana zeta class glutathione S transferase mutants for higher solubility in Escherichia coli. PMID- 23790633 TI - Resistance training may concomitantly benefit body composition, blood pressure and muscle MMP-2 activity on the left ventricle of high-fat fed diet rats. AB - OBJECTIVE: The purpose of this study was to evaluate the effect of resistance training (RT) on body composition, systolic and diastolic blood pressures (BP), and activity of muscle MMP-2 in the left ventricle of high-fat fed rats. MATERIALS/METHODS: We have evaluated 32 male Wistar rats divided into four experimental groups (n=8/each) according to diet and exercise status: sedentary (SED; standard diet), sedentary obese (SED-OB; diet: 30% of fat), RT (RT; standard diet) and RT obese (RT-OB; diet: 30% of fat). After weaning (day 21), animals were subjected to the experimental diet according to their groups during 24 weeks. A 12-week strength-training period was used, during which the rats climbed a 1.1-m vertical ladder with weights attached to their tails. Sessions were performed three times/week (Mondays, Wednesdays and Fridays), with 4-9 climbs/session and 8-12 dynamic movements/climb. RESULTS: RT induced higher muscle MMP-2 activity in the left ventricle in RT and RT-OB groups. Moreover, this study demonstrated that RT promoted lower body and fat masses, fat percentage, systolic and diastolic BPs and higher fat free mass in both trained groups. CONCLUSION: RT increased muscle MMP-2 activity in the left ventricle, induced positive changes on body composition and lowered BPs in high-fat diet fed rats, suggesting that it may be a useful tool to prevent alterations induced by high-fat diet consumption. PMID- 23790634 TI - Active immunotherapy using dendritic cells in the treatment of glioblastoma multiforme. AB - OBJECTIVE: Glioblastoma multiforme, the most common malignant brain tumor still has a dismal prognosis with conventional treatment. Therefore, it is necessary to explore new and/or adjuvant treatment options to improve patient outcomes. Active immunotherapy is a new area of research that may be a successful treatment option. The focus is on vaccines that consist of antigen presenting cells (APCs) loaded with tumor antigen. We have conducted a systematic review of prospective studies, case reports and clinical trials. The goal of this study was to examine the efficacy and safety in terms of complications, median overall survival (OS), progression free survival (PFS) and quality of life. METHODS: A PubMed search was performed to include all relevant studies that reported the characteristics, outcomes and complications of patients with GBM treated with active immunotherapy using dendritic cells. Reported parameters were immune response, radiological findings, median PFS and median OS. Complications were categorized based on association with the craniotomy or with the vaccine itself. RESULTS: A total of 21 studies with 403 patients were included in our review. Vaccination with dendritic cells (DCs) loaded with autologous tumor cells resulted in increased median OS in patients with recurrent GBM (71.6-138.0 wks) as well as those newly diagnosed (65.0-230.4 wks) compared to average survival of 58.4 wks. CONCLUSIONS: Active immunotherapy, specifically with autologous DCs loaded with autologous tumor cells, seems to have the potential of increasing median OS and prolonged tumor PFS with minimal complications. Larger clinical trials are needed to show the potential benefits of active immunotherapy. PMID- 23790636 TI - Predisposing factors and prevention of Clostridium perfringens-associated enteritis. AB - Clostridium perfringens is one of the major causes of intestinal disease in humans and animals. Its pathogenicity is contributed to by the production of a variety of toxins. In addition, predisposing environmental factors are important for the induction of C. perfringens-associated enteritis as shown by infection models. Environmental contamination, gastric and intestinal pH, intestinal microflora, nutrition, concurrent infections, and medical interventions may influence the intestinal colonization, growth, and toxin production by C. perfringens. Prevention of C. perfringens-associated enteritis may be mediated by the use of feed additives like probiotics, prebiotics, organic acids, essential oils, bacteriophages, lysozymes, bacteriocins, and antimicrobial peptides. Here we summarize and discuss published data on the influence of different environmental predisposing factors and preventive measures. Further research should focus on feed composition and feed additives in order to prevent C. perfringens-associated enteritis. PMID- 23790635 TI - Selective matrix (hyaluronan) interaction with CD44 and RhoGTPase signaling promotes keratinocyte functions and overcomes age-related epidermal dysfunction. AB - BACKGROUND: Mouse epidermal chronologic aging is closely associated with aberrant matrix (hyaluronan, HA)-size distribution/production and impaired keratinocyte proliferation/differentiation, leading to a marked thinning of the epidermis with functional consequence that causes a slower recovery of permeability barrier function. OBJECTIVE: The goal of this study is to demonstrate mechanism-based, corrective therapeutic strategies using topical applications of small HA (HAS) and/or large HA (HAL) [or a sequential small HA (HAS) and large HA(HAL) (HAs >HAL) treatment] as well as RhoGTPase signaling perturbation agents to regulate HA/CD44-mediated signaling, thereby restoring normal epidermal function, and permeability barrier homeostasis in aged mouse skin. METHODS: A number of biochemical, cell biological/molecular, pharmacological and physiological approaches were used to investigate matrix HA-CD44-mediated RhoGTPase signaling in regulating epidermal functions and skin aging. RESULTS: In this study we demonstrated that topical application of small HA (HAS) promotes keratinocyte proliferation and increases skin thickness, while it fails to upregulate keratinocyte differentiation or permeability barrier repair in aged mouse skin. In contrast, large HA (HAL) induces only minimal changes in keratinocyte proliferation and skin thickness, but restores keratinocyte differentiation and improves permeability barrier function in aged epidermis. Since neither HAS nor HAL corrects these epidermal defects in aged CD44 knock-out mice, CD44 likely mediates HA-associated epidermal functions in aged mouse skin. Finally, blockade of Rho-kinase activity with Y27632 or protein kinase-Ngamma activity with Ro31 8220 significantly decreased the HA (HAS or HAL)-mediated changes in epidermal function in aged mouse skin. CONCLUSION: The results of our study show first that HA application of different sizes regulates epidermal proliferation, differentiation and barrier function in aged mouse skin. Second, manipulation of matrix (HA) interaction with CD44 and RhoGTPase signaling could provide further novel therapeutic approaches that could be targeted for the treatment of various aging-related skin disorders. PMID- 23790637 TI - Autoantibodies against complement components and functional consequences. AB - The complement system represents a major component of our innate immune defense. Although the physiological contribution of the complement system is beneficial, it can cause tissue damage when inappropriately activated or when it is a target of an autoantibody response. Autoantibodies directed against a variety of individual complement components, convertases, regulators and receptors have been described. For several autoantibodies the functional consequences are well documented and clear associations exist with clinical presentation, whereas for other autoantibodies targeting complement components this relation is currently insufficiently clear. Several anti-complement autoantibodies can also be detected in healthy controls, indicating that a second hit is required for such autoantibodies to induce or participate in pathology or alternatively that these antibodies are part of the natural antibody repertoire. In the present review, we describe autoantibodies against complement components and their functional consequences and discuss about their clinical relevance. PMID- 23790638 TI - WITHDRAWN: Scald burns in children aged 14 and younger in Australia and New Zealand-An analysis based on the Bi-National Burns Registry (BiNBR). AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 23790639 TI - Pressure garment design tool to monitor exerted pressures. AB - Pressure garments are used in the treatment of hypertrophic scarring following serious burns. The use of pressure garments is believed to hasten the maturation process, reduce pruritus associated with immature hypertrophic scars and prevent the formation of contractures over flexor joints. Pressure garments are normally made to measure for individual patients from elastic fabrics and are worn continuously for up to 2 years or until scar maturation. There are 2 methods of constructing pressure garments. The most common method, called the Reduction Factor method, involves reducing the patient's circumferential measurements by a certain percentage. The second method uses the Laplace Law to calculate the dimensions of pressure garments based on the circumferential measurements of the patient and the tension profile of the fabric. The Laplace Law method is complicated to utilise manually and no design tool is currently available to aid this process. This paper presents the development and suggested use of 2 new pressure garment design tools that will aid pressure garment design using the Reduction Factor and Laplace Law methods. Both tools calculate the pressure garment dimensions and the mean pressure that will be exerted around the body at each measurement point. Monitoring the pressures exerted by pressure garments and noting the clinical outcome would enable clinicians to build an understanding of the implications of particular pressures on scar outcome, maturation times and patient compliance rates. Once the optimum pressure for particular treatments is known, the Laplace Law method described in this paper can be used to deliver those average pressures to all patients. This paper also presents the results of a small scale audit of measurements taken for the fabrication of pressure garments in two UK hospitals. This audit highlights the wide range of pressures that are exerted using the Reduction Factor method and that manual pattern 'smoothing' can dramatically change the actual Reduction Factors used. PMID- 23790640 TI - Increased risk of cancer among azoospermic men. AB - OBJECTIVE: To determine whether men with azoospermia are at an elevated risk of developing cancer in the years following an infertility evaluation. DESIGN: Cohort study. SETTING: United States andrology clinic. PATIENT(S): A total of 2,238 men with complete records were evaluated for infertility at a single andrology clinic in Texas from 1989 to 2009. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Cancer incidence was determined by linkage to the Texas Cancer Registry. RESULT(S): In all, 451 men had azoospermia, and 1,787 were not azoospermic, with a mean age at infertility evaluation of 35.7 years. Compared with the general population, infertile men had a higher risk of cancer, with 29 cases observed compared with 16.7 expected (standardized incidence rate [SIR] 1.7, 95% confidence interval [CI] 1.2-2.5). When stratifying by azoospermia status, azoospermic men had an elevated risk of cancer (SIR 2.9, 95% CI 1.4-5.4). Infertile men without azoospermia had a trend toward a higher rate of cancer (SIR 1.4, 95% CI 0.9-2.2). The Cox regression model revealed that azoospermic men had 2.2-fold higher cancer risk compared with nonazoospermic men (hazard ratio 2.2, 95% CI 1.0-4.8). CONCLUSION(S): Men with azoospermia have an increased risk of subsequently developing cancer, suggesting a possible common etiology between azoospermia and cancer development. Additional follow-up of azoospermic men after reproductive efforts end may be warranted. PMID- 23790641 TI - Promoter hypermethylation of tumor suppressor genes in serum as potential biomarker for the diagnosis of nasopharyngeal carcinoma. AB - PURPOSE: Promoter hypermethylation of tumor suppressor genes may serve as a promising biomarker for the diagnosis of cancer. Cell-free circulating DNA (cf DNA) shares hypermethylation status with primary tumors. This study investigated promoter hypermethylation of five tumor suppressor genes as markers in the detection of nasopharyngeal carcinoma (NPC) in serum samples. METHODS: cf-DNA was extracted from serum collected from 40 NPC patients and 41 age- and sex-matched healthy subjects. The promoter hypermethylation status of the five genes (RASSF1, CDKN2A, DLEC1, DAPK1 and UCHL1) was assessed by methylation-specific PCR after sodium bisulfite conversion. Differences in the methylation status of these five genes between NPC patients and healthy subjects were compared. RESULTS: The concentration of cf-DNA in the serum of NPC patients was significantly higher than that in normal controls. The five tumor suppressor genes - RASSF1, CDKN2A, DLEC1, DAPK1 and UCHL1 - were found to be methylated in 17.5%, 22.5%, 25.0%, 51.4% and 64.9% of patients, respectively. The combination of four-gene marker - CDKN2A, DLEC1, DAPK1 and UCHL1 - had the highest sensitivity and specificity in predicting NPC. CONCLUSION: Screening DNA hypermethylation of tumor suppressor genes in serum was a promising approach for the diagnosis of NPC. PMID- 23790642 TI - Metabolomic analysis of isonitrosoacetophenone-induced perturbations in phenolic metabolism of Nicotiana tabacum cells. AB - Plants have developed biochemical and molecular responses to adapt to different stress environments. One of the characteristics of the multi-component defence response is the production of defence-related metabolites. Plant defences can be triggered by various stimuli, including synthetic or naturally occurring molecules, especially those derived from pathogens. In the current study, Nicotiana tabacum cell suspensions were treated with isonitrosoacetophenone (INAP), a subcomponent of a plant-derived stress metabolite with anti-fungal and anti-oxidant properties, in order to investigate the effect thereof on cellular metabolism. Subsequent metabolomic-based analyses were employed to evaluate changes in the metabolome. UPLC-MS in conjunction with multivariate data analyses was found to be an appropriate approach to study the effect of chemical inducers like INAP on plant metabolism in this model system. Principal component analysis (PCA) indicated that INAP is capable of inducing time-dependent metabolic perturbations in the cultured cells. Orthogonal projection to latent structures discriminant analysis (OPLS-DA) revealed metabolites of which the levels are affected by INAP, and eight of these were tentatively annotated from the mass spectral data and online databases. These metabolites are known in the context of plant stress- and defence responses and include benzoic- or cinnamic acid derivatives that are either glycosylated or quinilated as well as flavonoid derivatives. The results indicate that INAP affects the shikimate-, phenylpropanoid- and flavonoid pathways, the products of which may subsequently lead to an anti-oxidant environment in vivo. PMID- 23790643 TI - Biotransformation of oleanolic and maslinic acids by Rhizomucor miehei. AB - Microbial transformation of oleanolic acid by Rhizomucor miehei produced three metabolites. A known compound, a 30-hydroxyl derivative (queretaroic acid), and two 7beta,30- and 1beta,30-dihydroxylated metabolites, respectively. The action of the same fungus (R. miehei) on maslinic acid produced an olean-11-en-28,13beta olide derivative, a metabolite hydroxylated at C-30, an 11-oxo derivative, and two metabolites with an 11alpha,12alpha-epoxy group, hydroxylated or not at C-30. Their structures were elucidated by extensive analyses of their spectroscopic data, and also by chemical correlations. PMID- 23790644 TI - Flower color polymorphism in Iris lutescens (Iridaceae): biochemical analyses in light of plant-insect interactions. AB - We describe a flower color polymorphism in Iris lutescens, a species widespread in the Northern part of the Mediterranean basin. We studied the biochemical basis of the difference between purple and yellow flowers, and explored the ecological and evolutionary consequences of such difference, in particular visual discrimination by insects, a potential link with scent emitted and the association between color and scent. Anthocyanins were found to be present in much greater concentrations in purple flowers than in yellow ones, but the anthocyanin composition did not differ between color morphs. Likewise, no quantitative difference in anthocyanin content was found between vegetative tissues of the two morphs. Floral anthocyanins were dominated by delphinidin 3-O (p-coumaroylrutinoside)-5-O-glucoside (also called delphanin) and its aliphatic derivatives. Small amounts of delphinidin 3-O-(p-caffeoylrutinoside)-5-O glucoside and its aliphatic derivatives were also characterized. Based on a description of bumblebees' (one of the main pollinators of I. lutescens) color perception, purple and yellow flowers of I. lutescens could be visually discriminated as blue and blue-green, respectively, and likely by a wide variety of other insects. The overall chemical composition of the scent produced was not significantly different between morphs, being dominated by terpenoids, mainly myrcene, (E)-beta-ocimene and limonene. A slight color-scent correlation was nevertheless detected, consistent with the shared biosynthetic origin of both pigments and volatile compounds. Therefore in this species, the difference in the amounts of pigments responsible for flower color difference seems to be the major difference between the two morphs. Pollinators are probably the main selective agent driving the evolution of flower color polymorphism in I. lutescens, which represents a suitable species for investigating how such polymorphism is maintained. PMID- 23790645 TI - [Health services utilization and the measures for the sostenibility of the Community of Madrid]. PMID- 23790646 TI - Modulation of Mcl-1 expression reduces age-related cochlear degeneration. AB - Mcl-1 is an anti-apoptotic member of the Bcl-2 family that modulates apoptosis related signaling pathways and promotes cell survival. We have previously demonstrated a reduction of Mcl-1 expression in aging cochleae. To investigate whether restoring Mcl-1 expression would reduce aging-related cochlear degeneration, we developed a rat model of Mcl-1 overexpression. A plasmid encoding human Mcl-1/enhanced green fluorescent protein was applied to the round window of the cochlea. This in vivo treatment transfected both the sensory and supporting cells of the cochlear sensory epithelium and enhanced Mcl-1 expression at both the mRNA and the protein level. The upregulation of Mcl-1 expression reduced the progression of age-related cochlear dysfunction and sensory cell death. Furthermore, the transfection of Mcl-1 exerted its protective effect by suppressing cochlear apoptosis at the mitochondrial level. This study demonstrates that the genetic modulation of Mcl-1 expression reduces the progression of age-related cochlear degeneration. PMID- 23790647 TI - Application of pH-sensitive fusogenic polymer-modified liposomes for development of mucosal vaccines. AB - To evaluate the usefulness of pH-sensitive fusogenic polymer (succinylated poly(glycidol) (SucPG) and 3-methylglutarylated poly(glycidol) (MGluPG))-modified liposomes as mucosal vaccine in the induction of a protective immune responses was evaluated. Mice were nasally immunized with OVA-containing SucPG-modified liposomes. After immunization, significant Ag-specific Abs were detected in the serum and intestine. When sera were analyzed for isotype distribution, antigen specific IgG1 Ab responses were noted in mice immunized with OVA-containing polymer-unmodified liposomes, whereas immunization with OVA-containing SucPG modified liposomes resulted in the induction of OVA-specific IgG1, IgG2a and IgG3 Ab responses. In spleen lymphocytes from mice immunized with OVA-containing SucPG modified liposomes, both IFN-gamma and IL-4 mRNA were detected. The same result was obtained also in the mouse immunized with OVA-containing MGluPG-modified liposomes. Furthermore, we examined the induction of immune responses in chickens following intraocular immunization with Salmonella Enteritidis Ag-containing MGluPG-modified liposomes, and the protective effect against the challenge with S. Enteritidis. Immunization with S. Enteritidis Ag-containing MGluPG-modified liposomes induced significant Ab responses against S. Enteritidis in the serum and intestine. Less fecal excretion of bacteria was observed in chickens immunized with S. Enteritidis Ag-containing MGluPG-modified liposomes after challenge. The numbers of bacteria in the caecum were also lower in immunized chickens than in unimmunized controls. PMID- 23790648 TI - Effect of dietary supplementation of vitamin E on production performance and some biochemical characteristics of cloacal foam in male Japanese quail. AB - This experiment was conducted to investigate the effects of increasing the level of dietary supplementation of vitamin E (VE) on production performance and biochemical characteristics of cloacal foam in male Japanese quail (Coturnix coturnix japonica). A total of 225 male Japanese quail chicks (day old) were randomly distributed to three dietary treatments for a period of 30 weeks. Each treatment comprised of three replicates, each containing 25 chicks. The basal diet (T1) contained 12.30IUVEkg(-1) and the two experimental diets were supplemented with 150 and 300IUVEkg(-1) (diets T2 and T3, respectively). dl-alpha Tocopherol acetate was used as the source of VE. All chicks were provided feed and water ad libitum. Mean body weights, feed intake, feed conversion ratio (FCR) and mortality of the birds in the different treatment groups showed no significant differences (P>0.05), whereas a significant (P<0.05) increase (29.81 and 50.83%) in average foam weight was evident in the VE-treated groups (T2) compared with control (T1) and T3 groups. The biochemical characteristics of foam, in terms of quantities of protein and nitric oxide (NO), did not differ significantly (P>0.05), whereas the quantities of glucose (60.01%) and acid phosphatase (ACP, 32.46%) were significantly (P<0.05) higher in the T3 group. By contrast, the quantities of alkaline phosphatase (ALP), glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) were significantly (P<0.05) lower (48.84%, 10.38% and 22.08%, respectively) in the T3 group and higher in the T1 (control) and T2 groups. From this study, it can be concluded that dietary supplementation of VE to the basal diet has no effect on the production performance but supplementation of a higher level of VE (300IUkg( 1)diet) improved the biochemical characteristics of the foam and moderate levels of VE (150IUkg(-1)diet) improved the foam production of male Japanese quail. PMID- 23790649 TI - Type 3 thyroplasty for patients with mutational dysphonia. AB - INTRODUCTION: The cases consisted of three men with mutational dysphonia, who were aged 37, 35, and 38 years. The speaking fundamental frequencies (SFFs) at the time of the initial diagnosis were 174.6, 170.2, and 180.0 Hz. METHODS: In all three patients, voice therapy proved ineffective; therefore, surgery was considered. In the anterior-posterior compression test performed preoperatively in the three patients, the voice became low-pitched. RESULTS: The SFFs decreased postoperatively to 106.9, 115.4, and 87.5 Hz, respectively, in the three patients. CONCLUSIONS: Type 3 thyroplasty (TP3) is effective for the treatment of patients with mutational dysphonia in whom voice therapy proved unsuccessful. OBJECTIVE: The SFF of men is high in childhood. At the time of the second pubescent sexual orientation, the frequency usually decreases. However, in some cases, the high-pitched voice of childhood may persist without successful switch to a low-pitched voice during puberty. Thus, there are rare cases of adults with a high-pitched boyish voice. Voice therapy is usually effective for the treatment; however, it may fail in some cases. We performed TP3 for subjects in whom voice therapy proved ineffective. With TP3, the tension of the vocal folds decreases, and the voice becomes low-pitched. PMID- 23790650 TI - Allogeneic stem cell transplantation for diffuse large B cell lymphoma: defining the role of allografts. AB - Allogeneic stem cell transplantation (allo-SCT) remains an option for patients who have disease progression post-autologous stem cell transplantation (ASCT) or who would not be eligible to ASCT for relapsed diffuse large B-cell lymphoma. Data with myeloablative or non-myeloablative allo-SCT demonstrate that allografts are safe and feasible with potential benefits including lack of tumour cell contamination and possible graft-versus-lymphoma (GVLY) effect although limited by high non-relapse mortality (NRM). However, the benefit of GVLY effect may be minimal or minimized by NRM. The current role of allo-SCT in DLBCL remains to be defined by prospective randomized controlled trials. PMID- 23790651 TI - Molecular advances come of age. PMID- 23790652 TI - [Bullous dermatosis: clinicopathological confrontation at the heart of expertise]. PMID- 23790653 TI - [International Society of Urological Pathology (ISUP) Consensus Conference on handling and staging of radical prostatectomy specimens]. AB - The 2009 International Society of Urological Pathology (ISUP) consensus conference on handling and staging of radical prostatectomy specimens issued recommendations for standardization of pathology reporting of radical prostatectomy specimens. The conference addressed specimen handling, T2 substaging, prostate cancer volume, extraprostatic extension, lymphovascular invasion, seminal vesicle invasion, lymph node metastases and surgical margins. This review summarizes the conclusions and recommendations resulting from the consensus process. PMID- 23790654 TI - [The inter-university learning website: a national university network for online teaching of pathology]. AB - Building online teaching materials is a highly time and energy consuming task for teachers of a single university. With the help of the College des pathologistes, we initiated a French national university network for building mutualized online teaching pathology cases, tests and other pedagogic resources. Nineteen French universities are associated to this project, initially funded by UNF3S (http://www.unf3s.org/). One national e-learning Moodle platform (http://virtual slides.univ-paris7.fr/moodle/) contains texts, medias and URL pointing toward decentralized virtual slides. The Moodle interface has been explained to the teachers since september 2011 using web-based conferences with screen-sharing. The following contents have been created: 20 clinical cases, several tests with multiple choices and short answer questions, and gross examination videos. A survey with 16 teachers and students showed a 94 % satisfaction rate, most of the 16 participants being favorable to the development of e-learning, in parallel with other courses in classroom. These tools will be further developed for the different study levels of pathology. In conclusion, these tools offer very interesting perspectives for pathology teaching. The organization of a national inter-university network is a useful way to create and share numerous and good quality pedagogic resources. PMID- 23790655 TI - [Pretest]. PMID- 23790656 TI - [Bullous dermatoses. Introduction]. PMID- 23790657 TI - [Case no. 1. Bullous dermatosis]. PMID- 23790658 TI - [Case no. 2. Bullous dermatosis]. PMID- 23790659 TI - [Case no. 3. Bullous dermatosis]. PMID- 23790660 TI - [Case no. 4. Bullous dermatosis]. PMID- 23790661 TI - [Case no. 5. Bullous dermatosis]. PMID- 23790662 TI - [Case no. 6. Bullous dermatosis]. PMID- 23790663 TI - [Case no. 7. Bullous dermatosis]. PMID- 23790664 TI - [Case no. 8. Bullous dermatosis]. PMID- 23790666 TI - [Breast angiosarcoma: a case report]. AB - The breast angiosarcoma is an endothelial malign tumor. Its prevalence is about 0.04% of all breast malignant tumors. The characteristics of angiosarcoma are its malignancy and its clinical and radiologic polymorphism. The breast angiocarcinoma has a bad prognostic because of the frequency of metastases and recurrence. The purpose of this paper is to report the clinical, imaging and pathological features of breast angiosarcoma, a rare but aggressive tumor, based on a review of one case. PMID- 23790667 TI - [Rare case of a cervix of uterus adenosarcome reported on a primipara 29 years old woman]. PMID- 23790668 TI - [Genomic signature in breast cancer: Oncotype DX((r))]. PMID- 23790669 TI - Isolation and characterization of a Myoviridae bacteriophage against Staphylococcus aureus isolated from dairy cows with mastitis. AB - A lytic bacteriophage (phage), designated SAH-1, was isolated from sewage effluent near a dairy cow farm in Gwacheon, South Korea to search for biocontrol agents against Staphylococcus aureus infections. The SAH-1 was morphologically classified as Myoviridae and possessed an approximate 144 kb double-stranded genomic DNA. The phage showed broad host ranges within S. aureus strains including methicillin-resistant strains, and its latent period and burst size were approximately 20 min and 100 PFU/cell, respectively. Moreover, morphologic and genomic analysis of SAH-1 revealed that the phage was closely related to other Myoviridae phages infecting Staphylococcus species. The bacteriolytic activity of phage SAH-1 at a multiplicity of infection (MOI) 1 and 100 indicated its efficiency for reducing bacterial growth. Based on these results, phage SAH-1 could be considered a potential therapeutic or prophylactic candidate against S. aureus infections. PMID- 23790670 TI - Influenza immunization coverage of residents and employees of long-term care facilities in New York State, 2000-2010. AB - We describe influenza immunization coverage trends from the New York State (NYS) Department of Health long-term care facility (LTCF) reports. Overall median immunization coverage levels for NYS LTCF residents and employees were 84.0% (range: 81.6%-86.0%) and 37.7% (range: 32.7%-50.0%), respectively. LTCF resident immunization coverage levels in NYS have neared the Healthy People 2020 target of 90% but have not achieved high LTCF employee coverage, suggesting a need for more regulatory interventions. PMID- 23790671 TI - Joint line position in revision total knee arthroplasty: the role of posterior femoral off-set stems. AB - BACKGROUND: Elevation of the joint line frequently occurs in revision total knee arthroplasty (RTKA) because of a wider flexion space than extension space. One solution to balance this flexion-extension space involves the introduction of couplers between the stem and femoral components, and the use of posteriorly offset femoral stems that we hypothesized would improve gap balancing and facilitate joint line restoration. METHODS: We retrospectively reviewed a selected series of 43 RTKA. Postoperative joint line height was subtracted from intended height using postoperative lateral radiographs. The value was negative if the joint line position was lowered, and positive if raised. RESULTS: Forty knees were followed for a mean of 3.5years. Mean postoperative joint line position change from intended position was 1.5mm (range -2.5-7.5mm). In 28 knees (70%), the joint line position was restored to within +/-2mm of the intended position; in eight knees (20%), from 2-4mm; and in four knees (10%), >4mm. Joint line position was raised in 32 knees (80%) and lowered in eight (20%). In the offset stem knees, the intended joint line position was 0.9mm (range -1.2-3.4mm) as compared with 3.2mm (range -2.5-7.5mm) for the straight stem knees. CONCLUSIONS: A coupler system between the femoral stem and femoral component restored the joint line in 70% of cases. The posterior offset stem provided increased posterior condylar offset, addressed the wider flexion space, provided better positioning of the stem, and restored the joint line. LEVEL OF EVIDENCE: Therapeutic Study Level IV. PMID- 23790672 TI - A preliminary investigation into the physical and chemical properties of biomass ashes used as aggregate fillers for bituminous mixtures. AB - Fly and bottom ashes are the main by-products arising from the combustion of solid biomass. Since the production of energy from this source is increasing, the processing and disposal of the resulting ashes has become an environmental and economic issue. Such ashes are of interest as a construction material because they are composed of very fine particles similar to fillers normally employed in bituminous and cementitious mixtures. This research investigates the potential use of ash from biomass as filler in bituminous mixtures. The morphological, physical and chemical characteristics of 21 different ashes and two traditional fillers (calcium carbonate and "recovered" plant filler) were evaluated and discussed. Leaching tests, performed in order to quantify the release of pollutants, revealed that five ashes do not comply with the Italian environmental re-use limits. Experimental results show a wide range of values for almost all the investigated properties and a low correlation with biomass type in terms of origin and chemical composition. Furthermore, sieving and milling processes were found to improve the properties of the raw material in terms of grading and sample porosity. The effectiveness of these treatments and the low content of organic matter and harmful fines suggest that most of the biomass ashes investigated may be regarded as potential replacements for natural filler in bituminous mixtures. PMID- 23790673 TI - Improved biogas production from rice straw by co-digestion with kitchen waste and pig manure. AB - In order to investigate the effect of feedstock ratios in biogas production, anaerobic co-digestions of rice straw with kitchen waste and pig manure were carried out. A series of single-stage batch mesophilic (37+/-1 degrees C) anaerobic digestions were performed at a substrate concentration of 54 g/L based on volatile solids (VS). The results showed that the optimal ratio of kitchen waste, pig manure, and rice straw was 0.4:1.6:1, for which the C/N ratio was 21.7. The methane content was 45.9-70.0% and rate of VS reduction was 55.8%. The biogas yield of 674.4 L/kg VS was higher than that of the digestion of rice straw or pig manure alone by 71.67% and 10.41%, respectively. Inhibition of biogas production by volatile fatty acids (VFA) occurred when the addition of kitchen waste was greater than 26%. The VFA analysis showed that, in the reactors that successfully produced biogas, the dominant intermediate metabolites were propionate and acetate, while they were lactic acid, acetate, and propionate in the others. PMID- 23790674 TI - Selecting the diameter of a radial head implant: an assessment of local landmarks. AB - INTRODUCTION: Little information exists on radial head implant diameter sizing methods. When the native head is absent due to extensive comminution or previous excision, the lesser sigmoid notch may be a useful landmark for sizing. We evaluated the reliability of native radial head measurements, and the lesser sigmoid notch, as landmarks for radial head implant diameter sizing. METHODS: We examined 27 fresh frozen ulnae and their corresponding radial heads. The maximum, minimum, and dish diameters of the radial heads were measured. A radial head implant diameter was selected based on the congruency of the trial implants with the radius of curvature of the lesser sigmoid notch. Intraobserver and interobserver reliability for all measurements and implant selection were assessed using intraclass correlation coefficients (ICC). Correlations between the native radial head measurements and the selected radial head implant diameter or the lesser sigmoid notch radius of curvature were assessed using the Pearson correlation coefficient (PCC). RESULTS: Radial head diameter measurements demonstrated strong to excellent intraobserver (ICC >= 0.75) and interobserver reliability (ICC >= 0.82). The lesser sigmoid notch sizing method showed poor interobserver reliability (ICC = 0.34). Only a moderate correlation was found between the native radial head and the lesser sigmoid notch (PCC <= 0.80) or the selected radial head implant size (PCC <= 0.59). CONCLUSION: Radial head diameter measurements showed excellent reliability, suggesting that the excised radial head, when available, should be used to select the implant diameter. The reliability of using the lesser sigmoid notch for sizing the diameter of radial head implants was only moderate, suggesting this is an unreliable landmark for implant diameter sizing. PMID- 23790675 TI - Reply: measurement of posterior capsule thickness. PMID- 23790677 TI - Elbow-specific clinical rating systems: extent of established validity, reliability, and responsiveness. AB - BACKGROUND: The modern standard of evaluating treatment results includes the use of rating systems. Elbow-specific rating systems are frequently used in studies aiming at elbow-specific pathology. However, proper validation studies seem to be relatively sparse. In addition, these scoring systems might not always be used for appropriate populations of interest. Both of these issues might give rise to invalid conclusions being reported in the literature. Our aim was to investigate the extent to which the available elbow-specific outcome measurement tools have been validated and the quality of the validation itself. We also aimed to provide characteristics of the populations used for validation of these scales to enable clinicians to use them appropriately. METHODS: A literature search identified 17 studies of 12 different elbow-specific scoring systems. These were assessed for validity, reliability, and responsiveness characteristics. The quality of these assessments was rated according to the Consensus Based Standards for the Selection of Health Measurement Instruments (COSMIN) checklist criteria, a standardized and validated tool developed specifically for this purpose. RESULTS: Currently, the only elbow-specific rating system that is validated using high quality methodology is the Oxford Elbow Score, a patient-administered outcome measure tool that has been validated on heterogeneous study populations. CONCLUSION: Other rating systems still have to be proven in the future to be as good as the Oxford Elbow Score for clinical or research purposes. Additional validation studies are needed. PMID- 23790676 TI - Aging-associated exacerbation in fatty degeneration and infiltration after rotator cuff tear. AB - BACKGROUND: Rotator cuff tears are one of the most common musculoskeletal complaints and a substantial source of morbidity in elderly patients. Chronic cuff tears are associated with muscle atrophy and an infiltration of fat to the area, a condition known as "fatty degeneration." To improve the treatment of cuff tears in elderly patients, a greater understanding of the changes in the contractile properties of muscle fibers and the molecular regulation of fatty degeneration is essential. METHODS: Using a full-thickness, massive supraspinatus and infraspinatus tear model in elderly rats, we measured fiber contractility and determined changes in fiber type distribution that develop 30 days after tear. We also measured the expression of messenger RNA and micro-RNA transcripts involved in muscle atrophy, lipid accumulation, and matrix synthesis. We hypothesized that a decrease in specific force of muscle fibers, an accumulation of type IIb fibers, and an upregulation in atrophic, fibrogenic, and inflammatory gene expression would occur in torn cuff muscles. RESULTS: Thirty days after the tear, we observed a reduction in muscle fiber force and an induction of RNA molecules that regulate atrophy, fibrosis, lipid accumulation, inflammation, and macrophage recruitment. A marked accumulation of advanced glycation end products and a significant accretion of macrophages in areas of fat accumulation were observed. CONCLUSIONS: The extent of degenerative changes in old rats was greater than that observed in adults. In addition, we identified that the ectopic fat accumulation that occurs in chronic cuff tears does not occur by activation of canonical intramyocellular lipid storage and synthesis pathways. PMID- 23790678 TI - The outcome of scapulothoracic arthrodesis using cerclage wires, plates, and allograft for facioscapulohumeral dystrophy. AB - BACKGROUND: Scapulothoracic arthrodesis is a recognized treatment for impaired shoulder function in patients with facioscapulohumeral dystrophy (FSHD) and is traditionally performed with autograft. The purpose of the study was to report our experience with scapulothoracic arthrodesis in patients with FSHD using allograft, rather than autograft, with particular respect to the effect of fusion on preoperative and postoperative Disabilities of the Arm, Shoulder and Hand (DASH) scores; forced vital capacity (FVC); and complications. MATERIALS AND METHODS: The early results of 14 consecutive scapulothoracic arthrodeses in FSHD patients with cerclage wires, plates, and allograft (fresh-frozen femoral heads) are reported. DASH scores were recorded preoperatively and 6 months postoperatively. Preoperative and 6-month FVCs were compared. The surgical technique is described. RESULTS: Eleven patients underwent 14 fusions. The mean follow-up period was 29 months (range, 6-50 months). Forward flexion improved from 70 degrees to 115 degrees (P = .001) and abduction from 68 degrees to 109 degrees (P = .007). The DASH score improved from 48 points to 34 points (P = .005). FVC decreased from 98% to 92% of predicted (P = .021), although this was not clinically significant. One patient required revision for nonunion, and metalwork was removed in 5 scapulae. A postoperative chest infection developed in 1 patient and a pleural effusion in another. One brachial plexus palsy occurred, which had almost completely resolved by 27 months postoperatively. CONCLUSION: Scapulothoracic arthrodesis can be performed successfully with allograft. The nonunion and complication rates are similar to those in the existing literature. A small decrease in FVC does occur but not to a clinically significant level. PMID- 23790679 TI - The interobserver reliability in diagnosing osseous lesions after first-time anterior shoulder dislocation comparing plain radiographs with computed tomography scans. AB - BACKGROUND: Recurrence after first-time traumatic anterior shoulder dislocation is frequent. The prevalence of glenoid bone loss ranges from 41% after a first time dislocation to 86% with recurrent dislocation. Postoperative recurrence can occur in up to 10% of cases. Thus, misdiagnosis of bony glenoid rim lesions has been assumed a major cause for failure. We evaluated the interobserver reliability of radiologic diagnoses after first-time traumatic shoulder dislocation based on radiographs and computed tomography (CT) images. METHODS: Digital radiographs before and after reduction and CT images after reduction of 20 patients with a first-time shoulder dislocation were assessed by 6 observers. It was recorded whether they diagnosed a lesion at the greater tuberosity, a lesion at the glenoid rim, a Hill-Sachs lesion, or any other skeletal pathology. The average agreement among the investigators was evaluated, and radiographic diagnoses were compared with those based on CT images. RESULTS: Of the 10 cases that presented with a glenoid rim fracture, each investigator had overlooked at least 1 fracture (range, 1-4) on the radiographs. No investigator had diagnosed all 8 Hill-Sachs lesions on the presented images. The average overall agreement among the investigators and corresponding sensitivity and specificity were calculated. Agreement of diagnoses based on radiographs with those based on CT images was lowest for glenoid rim fractures and Hill-Sachs lesions. CONCLUSION: Radiographs seem inferior to CT scans for assessing osseous lesions especially at the glenoid rim. We suggest performing a CT scan of the shoulder after primary dislocation to apply the correct treatment early and potentially avoid further dislocations. PMID- 23790680 TI - Response to: "Percutaneous balloon humeroplasty for Hill-Sachs lesions: a novel technique". PMID- 23790681 TI - Preexisting depressive symptoms are associated with long-term cognitive decline in patients after cardiac surgery. AB - OBJECTIVE: To examine whether preoperative psychological dysfunctions rather than intraoperative factors may differentially predict short- and long-term postoperative cognitive decline (POCD) in patients after cardiac surgery. METHOD: Forty-two patients completed a psychological evaluation, including the Trail Making Test Part A and B (TMT-A/B), the memory with 10/30-s interference, the phonemic verbal fluency and the Center for Epidemiological Studies of Depression (CES-D) scale for cognitive functions and depressive symptoms, respectively, before surgery, at discharge and at 18-month follow-up. RESULTS: Ten (24%) and 11 (26%) patients showed POCD at discharge and at 18-month follow-up, respectively. The duration of cardiopulmonary bypass significantly predicted short-term POCD [odds ratio (OR)=1.04, P<.05], whereas preoperative psychological factors were unrelated to cognitive decline at discharge. Conversely, long-term cognitive decline after cardiac surgery was significantly predicted by preoperative scores in the CES-D (OR=1.26, P<.03) but not by intraoperative variables (all Ps >.23). CONCLUSIONS: Our findings showed that preexisting depressive symptoms rather than perioperative risk factors are associated with cognitive decline 18 months after cardiac surgery. This study suggests that a preoperative psychological evaluation of depressive symptoms is essential to anticipate which patients are likely to show long-term cognitive decline after cardiac surgery. PMID- 23790682 TI - Differential central pathology and cognitive impairment in pre-diabetic and diabetic mice. AB - Although age remains the main risk factor to suffer Alzheimer's disease (AD) and vascular dementia (VD), type 2 diabetes (T2D) has turned up as a relevant risk factor for dementia. However, the ultimate underlying mechanisms for this association remain unclear. In the present study we analyzed central nervous system (CNS) morphological and functional consequences of long-term insulin resistance and T2D in db/db mice (leptin receptor KO mice). We also included C57Bl6 mice fed with high fat diet (HFD) and a third group of C57Bl6 streptozotocin (STZ) treated mice. Db/db mice exhibited pathological characteristics that mimic both AD and VD, including age dependent cognitive deterioration, brain atrophy, increased spontaneous hemorrhages and tau phosphorylation, affecting the cortex preferentially. A similar profile was observed in STZ-induced diabetic mice. Moreover metabolic parameters, such as body weight, glucose and insulin levels are good predictors of many of these alterations in db/db mice. In addition, in HFD-induced hyperinsulinemia in C57Bl6 mice, we only observed mild CNS alterations, suggesting that central nervous system dysfunction is associated with well established T2D. Altogether our results suggest that T2D may promote many of the pathological and behavioral alterations observed in dementia, supporting that interventions devoted to control glucose homeostasis could improve dementia progress and prognosis. PMID- 23790683 TI - Stress differentially affects fear conditioning in men and women. AB - Stress and fear conditioning processes are both important vulnerability factors in the development of psychiatric disorders. In behavioral studies considerable sex differences in fear learning have been observed after increases of the stress hormone cortisol. But neuroimaging experiments, which give insights into the neurobiological correlates of stress * sex interactions in fear conditioning, are lacking so far. In the current functional magnetic resonance imaging (fMRI) study, we tested whether a psychosocial stressor (Trier Social Stress Test) compared to a control condition influenced subsequent fear conditioning in 48 men and 48 women taking oral contraceptives (OCs). One of two pictures of a geometrical figure was always paired (conditioned stimulus, CS+) or never paired (CS-) with an electrical stimulation (unconditioned stimulus). BOLD responses as well as skin conductance responses were assessed. Sex-independently, stress enhanced the CS+/CS- differentiation in the hippocampus in early acquisition but attenuated conditioned responses in the medial frontal cortex in late acquisition. In early acquisition, stress reduced the CS+/CS- differentiation in the nucleus accumbens in men, but enhanced it in OC women. In late acquisition, the same pattern (reduction in men, enhancement in OC women) was found in the amygdala as well as in the anterior cingulate. Thus, psychosocial stress impaired the neuronal correlates of fear learning and expression in men, but facilitated them in OC women. A sex-specific modulation of fear conditioning after stress might contribute to the divergent prevalence of men and women in developing psychiatric disorders. PMID- 23790684 TI - Mechanotherapy: revisiting physical therapy and recruiting mechanobiology for a new era in medicine. AB - It has long been thought that the effectiveness and efficiency of physical therapy would improve if our understanding of the cell biology/biochemistry that participates in mechanics could be improved. Traditional physical therapy focuses primarily on rehabilitation, but recent developments in mechanobiology that illuminated the effects of physical forces on cells and tissues have led to the realization that the old therapy model should be updated. To achieve this here, the term mechanotherapy is proposed and recent studies showing how mechanotherapies target particular cells, molecules, and tissues are reviewed. These studies show how mechanical force modulates integrin-mediated processes and other mechanosensors such as gap junctions, hemichannels, primary cilia, transient receptor potential channels (cell targeting), and intracellular mechanosignaling pathways (molecule targeting). The role of mechanical force in various therapies, including microdeformation, shockwave, tissue expansion, distraction osteogenesis, and surgical tension reduction (tissue targeting) therapies, is reviewed. This review aims to jumpstart research into this field, which promises to generate a new era of viable and novel pharmacological and engineering interventions that can overcome human diseases. PMID- 23790685 TI - Octreotide may attenuate absorption and ameliorate toxicity following enteric drug overdose. AB - Drug overdose remains a common reason for Emergency Department presentation. Despite aggressive supportive care, and targeted antidotal therapy, deaths from intoxication still occur. For orally ingested toxins, absorption from the gastrointestinal tract is required before clinical evidence of toxin ingestion become manifest. Herein we postulate that octreotide, a synthetic analogue of naturally occurring somatostatin, may retard toxidrome development through an effect on reducing intestinal toxin absorption. Octreotide may therefore represent a useful adjunct to management of enteric self-poisoning. PMID- 23790686 TI - A right hemisphere safety backup at work: hypotheses for deep hypnosis, post traumatic stress disorder, and dissociation identity disorder. AB - Problem theory points to an a priori relation between six key problems of living, to which people have adapted through evolution. Children are guided through the problems one by one, learning to switch between them automatically and unawares. The first problem of raising hope of certainty (about the environment), is dealt with in the right hemisphere (RH). The second of raising hope of freedom (or power to control), is dealt with in the left hemisphere (LH). Here adventurousness and ignoring the goodness of outcomes potentially create recklessness. When uncertainty rises the RH activates a backup with an override that substitutes immobility, takes over sensory inputs, but allows obedience to parental commands, and a cut-out that stops new work on the freedom problem. Support for the use of the backup by infants is found in the immobility that precedes the crying in strange conditions, and in childhood EEGs. The hypothesis that the backup is active in deep hypnosis imposes accord on findings that appear contradictory. For example it accounts for why observations during deep hypnosis emphasize the activity of the RH, but observations of responsive people not under hypnosis emphasize the activity of the LH. The hypothesis that the backup is active in post-traumatic stress disorder (PTSD) is supported by (a) fMRI observations that could reflect the cut-out, in that part of the precuneus has low metabolism, (b) the recall of motionlessness at the time of the trauma, (c) an argument that playing dead as a defence against predators is illogical, (d) the ease of hypnosis. With dissociative identity disorder (DID), the theory is consistent with up to six alters that have executive control and one trauma identity state where childhood traumas are re-experienced. Support for the cut out affecting the trauma identity state comes from suppression of part of the precuneus and other parts of the parietal lobe when the trauma identity state is salient and a general script about a trauma is listened to. Support also comes from the ease of hypnosis. The cut-out acts independently of the override. It is linked to low metabolism at the same point in the left precuneus by evidence from all three conditions, hypnosis, PTSD and DID. The concept of dissociation is not required with any of the hypotheses. PMID- 23790687 TI - The SPAI-18, a brief version of the social phobia and anxiety inventory: reliability and validity in clinically referred and non-referred samples. AB - We developed a new version of the Social Phobia and Anxiety Inventory (SPAI) in order to have a brief instrument for measuring social anxiety and social anxiety disorder (SAD) with a strong conceptual foundation. In the construction phase, a set of items representing 5 core aspects of social anxiety was selected by a panel of social anxiety experts. The selected item pool was validated using factor analysis, reliability analysis, and diagnostic analysis in a sample of healthy participants (N = 188) and a sample of clinically referred participants diagnosed with SAD (N = 98). This procedure resulted in an abbreviated version of the Social Phobia Subscale of the SPAI consisting of 18 items (i.e. the SPAI-18), which correlated strongly with the Social Phobia Subscale of the original SPAI (both groups r = .98). Internal consistency and diagnostic characteristics using a clinical cut-off score > 48 were good to excellent (Cronbach's alpha healthy group = .93; patient group = .91; sensitivity: .94; specificity: .88). The SPAI 18 was further validated in a community sample of parents-to-be without SAD (N = 237) and with SAD (N = 65). Internal consistency was again excellent (both groups Cronbach's alpha = .93) and a screening cut-off of > 36 proved to result in good sensitivity and specificity. The SPAI-18 also correlated strongly with other social anxiety instruments, supporting convergent validity. In sum, the SPAI-18 is a psychometrically sound instrument with good screening capacity for social anxiety disorder in clinical as well as community samples. PMID- 23790688 TI - Imaging features of extrapulmonary small cell carcinoma. AB - Small cell carcinoma accounts for approximately 20% of lung cancers; however, it rarely occurs at other sites. Extrapulmonary small cell carcinoma (EPSCC) is notoriously aggressive with a strong propensity for both regional and distant spread. The majority of the literature on these uncommon tumours is from a clinicopathological viewpoint with a relative paucity of detail regarding the radiological findings. This review will focus on the imaging features of EPSCC in its predominant sites of origin: the gastrointestinal tract, genitourinary tract, head, neck, and breast. We will also discuss the role of positron-emission tomography (PET)/computed tomography (CT) in the staging of EPSCC. PMID- 23790689 TI - Contrast enhanced mammography: techniques, current results, and potential indications. PMID- 23790690 TI - Fenestration of the petrous internal carotid artery with short segment duplication mimicking an arterial dissection. PMID- 23790691 TI - [Greetings]. PMID- 23790692 TI - [Discussion forum on effectiveness assessment]. PMID- 23790693 TI - [The role of non-pharmaceutical and non-technical therapeutic interventions in patient care]. AB - A clear definition of the broad field of non-pharmaceutical and non-technical therapeutic interventions in patient care does not exist, making the discussion more difficult. Here, the relationship between patient and professional, contextual factors, and the influence of the patient play a more prominent role than with drug therapy and technical interventions. The vast majority of non pharmaceutical and non-technical procedures consist of complex and nearly always communication-based interventions. It is difficult to describe their role, since reliable data on criteria like frequency, time required, costs, quality, number of professionals involved and the importance for the patient are sparse. These therapeutic interventions may well form the core and biggest part of therapy in patient care. (As supplied by publisher). PMID- 23790694 TI - [Summary of the discussion part 1]. PMID- 23790695 TI - [What's the evidence base for non-medical and non-technical therapeutic interventions?]. AB - Health-related interventions that do not include drugs or technical procedures have not appeared very often in the German Federal Joint Committee's (GBA) evidence-based decision making process over the last years. In this regard the GBA has so far never given any instructions to the Institute for Quality and Efficiency in Health Care (IQWiG). The level of evidence for these methods is often limited by the lack of randomised controlled trials. The available studies often show a high risk of bias because of poor planning, processing and reporting as well as lack of blinding. External validity is often limited by use of a standardised monotherapy in the study, but a mix of different, individualised methods in the field. Another common problem is the lack of patient-related, long term outcome variables. Further research is needed to develop methods for high quality trials and evidence-based assessments in the area of non-medical, non technical therapeutic interventions. (As supplied by publisher). PMID- 23790696 TI - [Summary of the discussion part 2]. PMID- 23790697 TI - Methodological idiosyncracies, frameworks and challenges of non-pharmaceutical and non-technical treatment interventions. AB - In this brief article which summarises a presentation given at the "6. Diskussionsforum zur Nutzenbewertung im Gesundheitswesen" of the German Ministry of Education and Research "Gesundheitsforschungsrat (GFR)" and the Institute for Quality and Efficiency in Healthcare (IQWiG) I will analyse some methodological idiosyncrasies of studies evaluating non-pharmacological non-technical interventions (NPNTI). I will focus on how the methodological framework of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group may support design and appraisal of NPNTI. Specific design features that may be of particular value in NPNTI research, such as expertise-based randomised controlled trials, will be briefly described. Finally, based on an example, I will argue that - despite the methodological idiosyncrasies - there is neither a sufficient reason to accept different standards for the assessment of the confidence in the evidence from NPNTI nor for using study designs that are less rigorous compared to "simpler" interventions but that special measures have to be taken to reduce the risk of bias. The example that will be used in this article will primarily come from the field of respiratory rehabilitation, a typical multi component or complex intervention and by definition a complex NPNTI, which has been evaluated in many randomised controlled trials. (As supplied by publisher). PMID- 23790698 TI - [Summary of the discussion part 3]. PMID- 23790699 TI - [Practice example: neurodegenerative disorders: randomised controlled multicentre trial of home-based occupational therapy for patients with dementia]. AB - This paper summarises the methods and results of a seven-centre, single-blind, parallel group, actively controlled randomised trial evaluating the effectiveness of a Dutch 10-session community occupational therapy programme for patients with mild to moderate Alzheimer's disease in German routine healthcare. Methodological aspects for future research on complex psychosocial interventions are discussed. (As supplied by publisher). PMID- 23790700 TI - [Summary of the discussion part 4]. PMID- 23790701 TI - [Non-pharmacological, non-technical treatments for musculoskeletal disease: methodological challenges of clinical trials using the example of knee osteoarthritis and falls in the elderly]. AB - Physical therapy modalities are regarded as an integral part of the treatment of musculoskeletal diseases like osteoarthritis of the knee or falls in the elderly. Guidelines and treatment recommendations promote such interventions. However, the evidence supporting physical therapy modalities is often weaker than that found for drug treatments. One reason is that a simple blinding of treatment assignments by means of a placebo is usually not possible. Another issue is patient preferences that have an impact on the conduct of the study and the interpretation of the results. This article highlights methodological challenges of studies investigating physical therapy modalities, and points out some possible solutions. (As supplied by publisher). PMID- 23790702 TI - [Summary of the discussion part 5]. PMID- 23790703 TI - [Methodological aspects of controlled psychotherapy trials]. AB - The present paper deals with selected aspects of psychotherapy research. Psychotherapy is an effective treatment approach for mental disorders. Since research in psychotherapy is entirely dependent on public funding, several research questions remain open. Psychotherapy efficacy studies can be conducted in a randomised, but not in a placebo-controlled or double-blind manner. Apart from the effect of psychotherapy on the main outcome variables, one has to differentiate between specific and common factors of psychotherapy. Research in psychotherapy will gain societal relevance only after effective approaches have been successfully implemented in general practice. Transfer studies thus represent a new challenge in psychotherapy research. The funding activity of the German Federal Ministry of Education and Research (BMBF) "Networks in Research on Psychotherapy" made it possible that for the first time large multi-centre psychotherapy studies meeting GCP criteria can be conducted in Germany. These studies will generate highly innovative and in part unique findings. (As supplied by publisher). PMID- 23790704 TI - [Summary of the discussion part 6]. PMID- 23790705 TI - [Benefit assessment in nursing research: illustrative examples and questions left unanswered]. AB - Questions in nursing research are often studied in heterogeneous and instable fields such as nursing homes and use highly complex interventions. With the usual designs the mechanisms of their effects are difficult to evaluate. These interventions usually cannot be completely standardised. Comparison with 'care as usual' is hardly possible, since 'care as usual' can vary a lot. Moreover, the motivation to participate in a study with the chance of not getting an intervention is very low. Control groups with an active intervention, however, involve the risk that effects cannot be distinguished. This is why process evaluation and implementation research using multi-method approaches and triangulation are central to evaluating the effects of complex interventions. A solid theoretical foundation is the key to the proper interpretation of empirical results. (As supplied by publisher). PMID- 23790706 TI - [Summary of the discussion part 7]. PMID- 23790707 TI - [GRADE guidelines: 9. Rating up the quality of evidence]. AB - The most common reason for rating up the quality of evidence is a large effect. GRADE suggests considering rating up quality of evidence one level when methodologically rigorous observational studies show at least a two-fold reduction or increase in risk, and rating up two levels for at least a five-fold reduction or increase in risk. Systematic review authors and guideline developers may also consider rating up quality of evidence when a dose-response gradient is present, and when all plausible confounders or biases would decrease an apparent treatment effect, or would create a spurious effect when results suggest no effect. Other considerations include the rapidity of the response, the underlying trajectory of the condition and indirect evidence. PMID- 23790708 TI - [GRADE guidelines: 10. Considering resource use and rating the quality of economic evidence]. AB - In this article we describe how to include considerations about resource utilisation when making recommendations according to the GRADE approach. We focus on challenges with rating the confidence in effect estimates (quality of evidence) and incorporating resource use into evidence profiles and Summary of Findings (SoF) tables. GRADE recommends that important differences in resource use between alternative management strategies should be included along with other important outcomes in the evidence profile and SoF table. Key steps in considering resources in making recommendations with GRADE are the identification of items of resource use that may differ between alternative management strategies and that are potentially important to decision-makers, finding evidence for the differences in resource use, making judgements regarding confidence in effect estimates using the same criteria used for health outcomes, and valuing the resource use in terms of costs for the specific setting for which recommendations are being made. PMID- 23790709 TI - [A good decision: report of the 14th Annual Meeting of the German Network for Evidence Based Medicine Association]. PMID- 23790710 TI - [GQMG Annual Meeting in Dusseldorf great success - Brigitte Sens next chairman of the GQMG]. PMID- 23790711 TI - Comparison of indirect and direct blood pressure monitoring in normotensive swine. AB - The gold standard for blood pressure measurement in pigs is direct monitoring of arterial pressure, but this is an invasive technique adding complexity to surgical procedures. We sought to compare direct measurements obtained via catheterization to more easily-obtained indirect measurements using a sphygmomanometer with an automated cuff. Simultaneous measurements via an arterial pressure transducer and a child-size cuff were performed in pigs undergoing abdominal surgical procedures under normotensive conditions. Correlation between direct and indirect measurements was good (r=0.881). Systolic blood pressures for the cuff were higher than those for arterial measurements, while diastolic pressures were lower for the cuff than arterial. A Bland-Altman analysis confirmed this bias at the extremes of the normotensive range. For highly accurate readings, especially under stressed conditions, direct arterial catheterization remains the preferred method of measuring blood pressure. When monitoring surgical procedures, the more convenient blood pressure cuff can provide reliable measurements. PMID- 23790712 TI - Conservative management of paediatric renal abscess. AB - OBJECTIVE: Renal abscesses in the paediatric patient population are a rare entity. Patients are usually treated with percutaneous surgical drainage of the renal abscess as conservative treatment with broad-spectrum antibiotics is not considered as effective. We describe the conservative management of renal abscesses without percutaneous drainage in 6 children. MATERIALS AND METHODS: Six patients with a median age of 31 months, admitted over a 6 year period at two medical centers, were retrospectively studied. All patients were treated conservatively. RESULTS: In all patients, the abscesses were solitary, unilateral and located in the right kidney. The median abscess diameter was 38 mm. The diagnosis was made by ultrasonography. All 6 children were treated conservatively with a urinary catheter or suprapubic catheter and broad-spectrum antibiotics. None of the renal abscesses were surgically or percutaneously drained. CONCLUSIONS: A series of 6 paediatric renal abscesses, all successfully treated without surgical intervention, is presented. We believe that, in carefully selected cases, renal abscesses can be managed without percutaneous drainage. Furthermore, all children had complete resolution of the abscess. PMID- 23790713 TI - Our experience, technique and long-term outcomes in the management of posterior urethral strictures. AB - PURPOSE: To share our experience, technique and long-term outcomes in posterior urethral stricture management. MATERIALS AND METHODS: Thirty-seven boys with post traumatic posterior urethral stricture underwent resection and end-to-end anastomosis through pre-anal coronal approach or in combination with trans-pubic approach from January 2000 to December 2011. Follow up included symptomatic evaluation by micturating cystourethrogram and retrograde urethrogram in all patients, and urethroscopy in patients with voiding symptoms. RESULTS: Pre-anal coronal approach was used in 29 (78%) cases and in 8 (21%) cases it was combined with trans-pubic approach. In 33 (89.1%) patients it was first attempt, while in 4 (10.9%) it was redo surgery. Two patients required buccal mucosal graft to bridge the deficient urethra. Patient age was 5-17 years (mean 10.8 years). Mean follow up was 48.5 months (range 6-132 months). Thirty-two (86%) patients were symptom free. Failed repairs were successfully managed by urethral dilation in 3 and by redo urethroplasty in the remaining 2. All patients were continent. There was no chordee, penile shortening or urethral diverticula. CONCLUSIONS: Resection and end-to-end anastomosis of posterior urethral stricture is possible through pre-anal coronal incision; however, if slightest difficulty is envisaged in creating a satisfactory end-to-end anastomosis, extension to trans-pubic approach should be done. PMID- 23790714 TI - Erectile function after cystectomy with neurovascular preservation. AB - OBJECTIVES: To study the utility of neurovascular preservation for postoperative erection in radical cystectomy. MATERIALS AND METHODS: Retrospective analysis of 44 cystectomies performed at our center between January 2006-December 2009 in men <65 years. In 11 cases a neurovascular preservation was done. We analyzed age, BMI, indication for surgery, urinary diversion, use of i-PDE5 or alprostadil, and daytime and nighttime continence. Erection Hardness Score (EHS) was used to assess erectile function. RESULTS: Spontaneous postoperative erectile function in preservation group was 44,4% EHS 4, 33,3% EHS 3 and 22,3% EHS 1 (achieving EHS 3 or 4 with alprostadil). In the non preservation group, 4,5% achieved EHS 4 spontaneously. The other 95,5% had EHS 0 (4,5% achieved EHS 3 with tadalafil 20 mg and 9% with intracavernous injections). Variables age (P=.001) and nerve sparing surgery (P<.001) were related to postoperative erectile function recovery. In the multivariate analysis, nerve-sparing surgery remained statisticaly significant. CONCLUSIONS: The functional results in preserving cystectomy are promising. The preservation should be considered in young patients without erectile dysfunction. PMID- 23790715 TI - Relationship of back and neck pain with quality of life in the Croatian general population. AB - OBJECTIVE: The purpose of this study was to determine the prevalence of back pain and neck pain and their relationship with the quality of life in the Croatian general population. METHODS: This was a cross-sectional study using home-based face-to-face interviews of 1030 participants (51.6% females) 15 years or older. Back and neck pain frequencies were assessed using single items and quality of life using the Short Form Survey and Satisfaction with Life Scale. Analysis of covariance was conducted, where back pain or neck pain frequency was used as the categorical predictor; physical component summary or mental component summary, as the dependent variable; and age, body mass index, and physical activity level, as covariates. RESULTS: The prevalence of back pain was 66.3% (95% confidence interval [CI], 62.3%-70.3%) and 62.9% (95% CI, 58.7%-67.2%) in females and males, respectively. The prevalence of neck pain was 58.0% (95% CI, 53.8%-62.2%) for females and 53.6 (95% CI, 49.2%-58.0%) for males. Differences between men and women were not significant (P>.05). Adjusted mean values for physical component summary and mental component summary were substantially lower in participants who reported back or neck pain often/almost always compared with those without pain. Differences ranged from 8.11 to 11.86 points (95% CI, 5.54-13.99) and from 9.61 to 10.99 points (95% CI, 7.35-13.45) in females and males, respectively. CONCLUSIONS: The findings of this study showed that back and neck pain are highly prevalent and negatively related to quality of life in the Croatian general population. These data might raise the awareness of local government health authorities and lead to improvements in health care service for people with back and neck pain. PMID- 23790716 TI - Cervical muscle activity during loaded arm lifts in patients 10 years postsurgery for cervical disc disease. AB - OBJECTIVE: The purpose of this study was to compare the mechanical activity of the neck muscles during loaded arm lifting tasks in individuals with long standing disability after anterior cervical decompression and fusion (ACDF) with that of healthy controls. METHODS: Ten individuals (mean age, 60 years; SD, 7.1) who underwent ACDF (10-13 years previously) for cervical disc disease and 10 healthy age- and sex-matched controls participated in the study. Ultrasonography was used to investigate the degree of deformation and deformation rate of ventral and dorsal neck muscles at the C4 segmental level during a single (1* arm flexion to 120 degrees ) and repeated (10* arm flexion to 90 degrees ) loaded arm elevation condition. RESULTS: The ACDF group showed greater deformation and deformation rate of the longus capitis (P=.02) and deformation rate of the sternocleidomastoid (P=.04) during the 120 degrees arm lift. For repeated 90 degrees arm lift, there was a significant group effect with higher deformation rate values observed in the longus capitis (P=.005-.01) and multifidus (P=.03) muscles in the ACDF group. Muscle behavior did not change the repeated arm lifts (no group*time interactions) for either the ventral or the dorsal muscles. CONCLUSIONS: For study participants, greater muscle mechanical activity levels were observed in the ventral and multifidus muscles of patients with persistent symptoms after ACDF. These differences may indicate altered motor strategy in this patient group when performing the upper limb task and may need to be considered when prescribing exercise for postsurgical rehabilitation. PMID- 23790717 TI - Non-surgical access for enteral nutritional: gastrostomy and jejunostomy, technique and results. AB - Gastrostomy is the most efficient and best tolerated method of prolonged nutritional support. Jejunostomy is used more rarely. Indications for both techniques have increased because of progress in insertion techniques under endoscopic or radiologic guidance. The procedure is simple and rapid, performed under simple sedation with a success rate over 95% for gastrostomy, irrespective of the technique. Mortality directly related to the technique is less than 5%, but associated co-morbidity also explains a more variable but often higher 30-day mortality. Local care and maintenance of the catheter should help avoid most of the late complications such as peristomal leaks, local infection or sepsis of the tunneled catheter in the abdominal wall. The main indications are neurologic swallowing disorders, mechanical dysphagia from ENT or esophageal disease, when the expected duration of enteral nutrition is at least longer than 3 weeks. In patients with severe dementia, no benefit for either nutritional status or quality of life has been demonstrated. In all cases, adequate patient information and careful evaluation of the risk/benefit ratio are capital. PMID- 23790718 TI - Radiologic drainage of post-operative collections and abscesses. AB - Since the initial studies published in the eighties, percutaneous radiologic drainage, is considered the first-line treatment of infected post-operative collections and is successful in over 80% of patients. Mortality due to undrained abscesses is estimated between 45 and 100%. Radiology-guided percutaneous drainage can be performed either with curative intent or to improve patient status prior to re-operation under better conditions. Cross-sectional imaging, using either ultrasound or computed tomography (CT), has changed the management of post-operative complications. Percutaneous drainage is most often performed by interventional radiologists and imaging is essential for road-mapping and guiding the puncture and drainage of intra-abdominal collections. Indeed, such imaging allows both identification of adjacent anatomical structures and determination of the best tract and the safest route. Cooperation between the surgeon and the interventional radiologist is essential to optimize the management and to avoid, if possible, surgery, which is so often difficult in this setting. PMID- 23790719 TI - The effect of dioestrus on the racing performance of Greyhounds. AB - The degree of performance change during the dioestrus of racing Greyhounds has long been the subject of debate. Assessments have previously been on a qualitative basis. The analyses in this paper are unique and produce a quantitative assessment of the change in performance during dioestrus. By accessing a large dataset, race form and oestrous data were analysed using a longitudinal observational study design. The performance changes in dioestrus were modelled with a series of multilevel linear regressions revealing a pattern such that the performance loss varied from 0.031 to 0.733 s (90% confidence interval) between 41 and 56 days since oestrus over 450 m, returning to the baseline (anoestral) performance level after about 80-100 days. The changes in performance formed a temporal match with the changes in serum progesterone concentration noted by other workers. Whilst serum hormone concentrations were not measured, it is suggested that the performance changes are linked with the changes in serum progesterone concentrations rather than prolactin. It is therefore proposed that a minimum time off of 70 days could be set, which would capture the majority of females with a genuine change in performance, and with a caution regarding the use of entire female Greyhounds for performance studies. PMID- 23790720 TI - [Headaches, fever and dysuria in a 39-year-old man]. PMID- 23790721 TI - Synthesis and evaluation of N8-acetylspermidine analogues as inhibitors of bacterial acetylpolyamine amidohydrolase. AB - Polyamines are small essential polycations involved in many biological processes. Enzymes of polyamine metabolism have been extensively studied and are attractive drug targets. Nevertheless, the reversible acetylation of polyamines remains poorly understood. Although eukaryotic N(8)-acetylspermidine deacetylase activity has already been detected and studied, the specific enzyme responsible for this activity has not yet been identified. However, a zinc deacetylase from Mycoplana ramosa, acetylpolyamine amidohydrolase (APAH), has been reported to use various acetylpolyamines as substrates. The recently solved crystal structure of this polyamine deacetylase revealed the formation of an 'L'-shaped active site tunnel at the dimer interface, with ideal dimensions and electrostatic properties for accommodating narrow, flexible, cationic polyamine substrates. Here, we report the design, synthesis, and evaluation of N(8)-acetylspermidine analogues bearing different zinc binding groups as potential inhibitors of APAH. Most of the synthesized compounds exhibit modest potency, with IC50 values in the mid micromolar range, but compounds bearing hydroxamate or trifluoromethylketone zinc binding groups exhibit enhanced inhibitory potency in the mid-nanomolar range. These inhibitors will enable future explorations of acetylpolyamine function in both prokaryotes and eukaryotes. PMID- 23790722 TI - Anion inhibition studies of the alpha-carbonic anhydrase from the protozoan pathogen Trypanosoma cruzi, the causative agent of Chagas disease. AB - The protozoan pathogen Trypanosoma cruzi, the causative agent of Chagas disease, encodes an alpha-class carbonic anhydrase (CA, EC 4.2.1.1), TcCA, which was recently shown to be crucial for its life cycle. Thiols, a class of strong TcCA inhibitors, were also shown to block the growth of the pathogen in vitro. Here we report the inhibition of TcCA by inorganic and complex anions and other molecules interacting with zinc proteins, such as sulfamide, sulfamic acid, phenylboronic/arsonic acids. TcCA was inhibited in the low micromolar range by iodide, cyanate, thiocyanate, hydrogensulfide and trithiocarbonate (KIs in the range of 44-93 MUM), but the best inhibitor was diethyldithiocarbamate (KI=5 MUM). Sulfamide showed an inhibition constant of 120 MUM, but sulfamic acid was much less effective (KI of 10.6 mM). The discovery of diethyldithiocarbamate as a low micromolar TcCA inhibitor may be useful to detect leads for developing anti Trypanosoma agents with a diverse mechanism of action compared to clinically used drugs (benznidazole, nifurtimox) for which significant resistance emerged. PMID- 23790723 TI - The shortened EMpowerment of PArents in THe Intensive Care 30 questionnaire adequately measured parent satisfaction in pediatric intensive care units. AB - OBJECTIVE: To shorten and validate the EMpowerment of PArents in THe Intensive Care (EMPATHIC) questionnaire of optimal length to measure satisfaction of parents whose child has been admitted to pediatric intensive care units (PICUs). STUDY DESIGN AND SETTING: A total of 3,354 (55.4%) parents in eight PICUs completed the 65-item EMPATHIC questionnaire. Multiple regression analysis was applied to evaluate the statistical performances. The reduced domains were intercorrelated by the Pearson's product moment correlation coefficient. The robustness of the findings was evaluated by adjusted R(2) for internal cross validations. Reliability was assessed by internal consistency. RESULTS: Multiple regression analysis based on statistical redundancy established the optimal length at 30 items over five different domains: information (5 items), care and cure (8 items), organization (5 items), parental participation (6 items), and professional attitude (6 items). The explained variances of the domains ranged from 85% to 93%. The domains of the full and optimal version showed strong correlations (r = 0.92-0.97). Cross-validation among eight centers and across time provided adjusted R(2) values on domain level between 85% and 95%. The reliability estimates of the domains, assessed by Cronbach's alpha, varied between 0.73 and 0.93. CONCLUSION: By statistically eliminating the redundant items, the EMPATHIC questionnaire could be reduced from 65 to 30 items. PMID- 23790724 TI - No differential attrition was found in randomized controlled trials published in general medical journals: a meta-analysis. AB - OBJECTIVE: Differential attrition is regarded as a major threat to the internal validity of a randomized controlled trial (RCT). This study identifies the degree of differential attrition in RCTs covering a broad spectrum of clinical areas and factors that are related to this. STUDY DESIGN AND SETTING: A PubMed search was conducted to obtain a random sample of 100 RCTs published between 2008 and 2010 in journals from the ISI Web of Knowledge(SM) category of medicine, general and internal. Eligibility criteria for selecting studies were primary publications of two-arm parallel randomized clinical trials, containing human participants and one or multiple follow-up measurements whose availability depended on the patients' willingness to participate. RESULTS: A significant amount of differential attrition was observed in 8% of the trials. The average differential attrition rate was 0.99 (95% confidence interval: 0.97-1.01), indicating no general difference in attrition rates between intervention and control groups. Moreover, no indication of heterogeneity was found, suggesting that the occurrence of differential attrition in the published literature is mostly a chance finding, unrelated to any particular design factors. CONCLUSION: Differential attrition did not generally occur in RCTs covering a broad spectrum of clinical areas within general and internal medicine. PMID- 23790725 TI - Multiple imputation of missing values was not necessary before performing a longitudinal mixed-model analysis. AB - BACKGROUND AND OBJECTIVES: As a result of the development of sophisticated techniques, such as multiple imputation, the interest in handling missing data in longitudinal studies has increased enormously in past years. Within the field of longitudinal data analysis, there is a current debate on whether it is necessary to use multiple imputations before performing a mixed-model analysis to analyze the longitudinal data. In the current study this necessity is evaluated. STUDY DESIGN AND SETTING: The results of mixed-model analyses with and without multiple imputation were compared with each other. Four data sets with missing values were created-one data set with missing completely at random, two data sets with missing at random, and one data set with missing not at random). In all data sets, the relationship between a continuous outcome variable and two different covariates were analyzed: a time-independent dichotomous covariate and a time dependent continuous covariate. RESULTS: Although for all types of missing data, the results of the mixed-model analysis with or without multiple imputations were slightly different, they were not in favor of one of the two approaches. In addition, repeating the multiple imputations 100 times showed that the results of the mixed-model analysis with multiple imputation were quite unstable. CONCLUSION: It is not necessary to handle missing data using multiple imputations before performing a mixed-model analysis on longitudinal data. PMID- 23790726 TI - Absolute risks rather than incidence rates should be used to estimate the number needed to treat from time-to-event data. AB - BACKGROUND: When estimating the number needed to treat (NNT) from randomized controlled trials (RCTs) with time-to-event outcomes, varying follow-up times have to be considered. Two methods have been proposed, namely (1) inverting risk differences estimated by survival time methods (RD approach) and (2) inverting incidence differences (ID approach). STUDY DESIGN AND SETTING: A simulation study was conducted to compare the RD and the ID approaches regarding bias and coverage probability (CP) considering various distributions, baseline risks, effect sizes, and sample sizes. Additionally, the two approaches were compared by using two real data examples. RESULTS: The RD approach showed good estimation and coverage properties with only a few exceptions in the case of small sample sizes and small effect sizes. The ID approach showed considerable bias and low CPs in most of the considered data situations. CONCLUSIONS: Absolute risks estimated by means of survival time methods rather than incidence rates should be used to estimate NNTs in RCTs with time-to-event outcomes. PMID- 23790728 TI - Global surgery: parallels with surgical research and innovation. PMID- 23790727 TI - Neuronal circuits that regulate feeding behavior and metabolism. AB - Neurons within the central nervous system receive humoral and central (neurotransmitter or neuropeptide) signals that ultimately regulate ingestive behavior and metabolism. Recent advances in mouse genetics combined with neuroanatomical and electrophysiological techniques have contributed to a better understanding of these central mechanisms. This review integrates recently defined cellular mechanisms and neural circuits relevant to the regulation of feeding behavior, energy expenditure, and glucose homeostasis by metabolic signals. PMID- 23790729 TI - [Need for management and intensive supports to critical children in adult units]. PMID- 23790731 TI - Emergence of a new strain of the avian influenza A (H7N9) virus. PMID- 23790730 TI - Engineering peripheral nerve repair. AB - Current approaches for treating peripheral nerve injury have resulted in promising, yet insufficient functional recovery compared to the clinical standard of care, autologous nerve grafts. In order to design a construct that can match the regenerative potential of the autograft, all facets of nerve tissue must be incorporated in a combinatorial therapy. Engineered biomaterial scaffolds in the future will have to promote enhanced regeneration and appropriate reinnervation by targeting the highly sensitive response of regenerating nerves to their surrounding microenvironment. PMID- 23790732 TI - Deterioration in regional health status after the acute phase of a great disaster: respiratory physicians' experiences of the Great East Japan Earthquake. AB - BACKGROUND: The Great East Japan Earthquake occurred on March 11, 2011. The source of the ensuing devastation was not the tremors, but the subsequent tsunami. Responding emergency medical teams could not provide sufficient assistance, which led to many people dying before the rescue teams arrived. Thus, the main objective of healthcare professionals became to prevent deterioration in people's health statuses in the disaster area. METHODS: One month after the earthquake, the Health-Promoting Association of Respiratory Medicine of Tohoku conducted a survey regarding changing disease prevalence among inpatients in respiratory medicine departments of regional core hospitals in Miyagi Prefecture, the area that suffered the most damage. RESULTS: The number of patients from March 11 to April 10, 2011 was 2.7 times greater than that during the same period in 2010 (1223 vs. 443, respectively). The prevalence of asthma, exacerbations of chronic obstructive pulmonary disease, and community-acquired pneumonia were also 2-3 times greater in 2011 than in 2010 (98 vs. 32, 117 vs. 46, and 443 vs. 202, respectively) among all ages. Half of the community-acquired pneumonia cases originated in evacuation shelters. The number of inpatients with other diseases, including those who drowned, was relatively small, and mortality did not increase significantly at these hospitals. CONCLUSIONS: The findings may result from poor shelter or dwelling conditions, as well as overpopulation and lack of basic resources. Adequate shelters, supply systems, and protection from infection, including vaccinations, are needed to prevent deteriorations in health status after the acute phase of a natural disaster. PMID- 23790733 TI - Etiologic link between sarcoidosis and Propionibacterium acnes. AB - Propionibacterium acnes is the only microorganism isolated from sarcoid lesions by bacterial culture. Numerous P. acnes genomes are found in lymph node samples from Japanese and European patients with sarcoidosis, whereas a few genomes are found in some non-sarcoid samples. The high frequency and specificity of detecting P. acnes within sarcoid granulomas suggests that this indigenous bacterium causes granuloma formation in many patients with sarcoidosis. P. acnes is the most common commensal bacterium in the lungs and lymph nodes. Occasional detection of P. acnes in non-granulomatous areas of these organs from non-sarcoid patients suggests that host factors are more critical than agent factors in the etiology of sarcoidosis. A particular protein, i.e., trigger factor, from P. acnes causes a cellular immune response only in sarcoid patients. The P. acnes trigger-factor protein induces pulmonary granulomas in mice sensitized with the protein and adjuvant, but only in those with latent P. acnes infection in their lungs. Eradication of P. acnes by antibiotics prevents the development of granulomas in this experimental model. P. acnes can cause latent infection in the lung and lymph nodes and persists in a cell wall-deficient form. The dormant form is endogenously activated under certain conditions and proliferates at the site of latent infection. In patients with P. acnes hypersensitivity, granulomatous inflammation is triggered by intracellular proliferation of the bacterium. Proliferating bacteria may escape granulomatous isolation, spreading to other organs. Latent P. acnes infection in systemic organs can be reactivated by another triggering event, leading to systemic sarcoidosis. PMID- 23790734 TI - Effect of glucocorticoid monotherapy on pulmonary function and survival in Japanese patients with scleroderma-related interstitial lung disease. AB - BACKGROUND: Scleroderma-related interstitial lung disease (SSc-ILD) is a chronic, progressive condition that is characterized by a restrictive ventilator defect. Cyclophosphamide (CYC), with or without glucocorticoid, effectively alters the course of SSc-ILD. However, the effect of glucocorticoid monotherapy remains unclear. METHODS: Seventy-one patients with SSc-ILD were classified into 2 groups: 21 in the treatment group (glucocorticoid monotherapy [n=14] or immunosuppressive agents [n=7]) and 50 in the non-treatment group. Their backgrounds and prognoses were analyzed retrospectively. We also classified these patients into survival (n=55) and non-survival (n=16) groups to assess prognostic factors. RESULTS: The median follow-up period was 9.8 years. The treatment group had a greater proportion of patients with diffuse systemic sclerosis or respiratory symptoms than the non-treatment group. The treatment group's annual change in forced vital capacity (FVC) compared to baseline, which was 170.4mL (157.8mL for the glucocorticoid monotherapy subgroup and 191.3mL for the immunosuppressive agent subgroup), was better than that of the non-treatment group, -60.8mL (p<0.01). Still, in terms of 5- and 10-year survival, there was no statistically significant difference between these groups. No incidence of SSc renal crisis was reported in the treatment group. The non-survival group included more patients with pulmonary hypertension than the survival group, but multivariate analysis showed no other statistically significantly difference between these groups. CONCLUSIONS: Similar to CYC, glucocorticoid alone improved pulmonary function of Japanese SSc-ILD patients, suggesting that this monotherapy is a good alternative when CYC is contraindicated. PMID- 23790735 TI - Preventive effect of irbesartan on bleomycin-induced lung injury in mice. AB - BACKGROUND: Idiopathic pulmonary fibrosis is a specific form of chronic fibrosing interstitial pneumonia that is limited to the lung. Angiotensin receptor blockers (ARBs) and peroxisome proliferator-activated receptor (PPAR) gamma ligands have anti-inflammatory and anti-fibrotic effects. We investigated the effects of irbesartan-an ARB with PPAR gamma activity-on the development of bleomycin induced pulmonary fibrosis in mice. METHODS: Lung injury was induced in imprinting control region (ICR) mice by intratracheal instillation of 2mg/kg of bleomycin. The treatment group orally received 20mg/kg of irbesartan for 5 consecutive days before instillation. The mice were sacrificed and were evaluated 14 days after bleomycin instillation. RESULTS: Irbesartan reduced the fluid content and hydroxyproline level in the lung and improved the pathological findings as indicated by the Ashcroft score. Total cell counts, the numbers of macrophages, neutrophils, and lymphocytes, and the levels of transforming growth factor (TGF) beta1 and monocyte chemotactic protein (MCP) 1 in the bronchoalveolar lavage fluid (BALF) were decreased. Treatment with a PPARgamma antagonist GW9662 reversed some of the effects of irbesartan. CONCLUSIONS: The results of this study indicated that irbesartan attenuated the development of bleomycin-induced pulmonary fibrosis in mice by decreasing TGF-beta1 and MCP-1 via blocking of ATI, by binding to CCR2b, and by PPARgamma-mediated inhibition of inflammation. PMID- 23790736 TI - Persistent elevation of exhaled nitric oxide and modification of corticosteroid therapy in asthma. AB - BACKGROUND: Persistent airway inflammation, detected by fractional exhaled nitric oxide (FENO), is occasionally observed in asthmatic patients, even in those treated with inhaled corticosteroids (ICS). However, improvement in residual airway inflammation and pulmonary function through modification of corticosteroid therapy has not been proven. METHODS: Thirteen asthmatic patients whose FENO levels were over 40 parts per billion (ppb), despite dry-powder ICS therapy, were enrolled. A 3-step change in steroid treatment was undertaken until FENO was less than 40ppb. In the first step, the powder formula was changed to an ultra-fine particle compound as an equipotent ICS dose. In the second step, the ICS dose was doubled. In the third step, oral corticosteroids were added. We measured pulmonary function and FENO and alveolar NO concentrations (CAlvNO). RESULTS: Doubling the ICS dose and changing the ICS formula significantly improved FVC (p<0.001), FEV1 (p<0.05), the slope of the single nitrogen washout curve (dN2) (p<0.01), FENO (p<0.001), and CAlvNO (p<0.05), relative to baseline. The reductions in FENO were significantly associated with the improvement in airflow limitation assessed by dN2 (r=0.73, p=0.007). The remaining FENO elevation, even after doubling the ICS dose, did not decrease after oral corticosteroid administration. CONCLUSIONS: These results suggest that modification of ICS therapy can suppress residual FENO elevation, and that reduction in FENO levels is associated with improvement in airflow limitation. However, steroid-resistance mechanisms may exist in some asthmatic patients with sustained FENO elevations. PMID- 23790737 TI - Hyaluronic acid in the pleural fluid of patients with malignant pleural mesothelioma. AB - BACKGROUND: We retrospectively analyzed hyaluronic acid (HA) concentrations in pleural fluid and evaluated its utility for the differential diagnosis of malignant pleural mesothelioma (MPM). METHODS: Pleural fluid HA concentrations were measured in 334 patients, including 50, 48, 85, 18, 86, 6, and 41 patients with MPM, benign asbestos pleurisy (BAP), lung cancer (LC), other malignant conditions (OMCs), infectious pleuritis (IP), collagen disease (CD), and other conditions, respectively. RESULTS: The median (range) HA concentrations in pleural fluid were 78,700 (7920-2,630,000)ng/ml in the MPM group, 35,950 (900 152,000)ng/ml in the BAP group, 19,500 (2270-120,000)ng/ml in the LC group, 14,200 (900-101,000)ng/ml in the OMC group, 23,000 (900-230,000)ng/ml in the IP group, 24,600 (9550-80,800)ng/ml in the CD group, and 8140 (900-67,800)ng/ml in the other diseases group. HA levels were significantly higher in the MPM group than in the other groups. Receiver operating characteristic (ROC) analysis revealed an area under the ROC curve value of 0.832 (95% confidence interval, 0.765-0.898) for the differential diagnosis of MPM. With a cutoff value of 100,000ng/ml, the sensitivity and specificity were 44.0 and 96.5%, respectively. In the MPM group, HA values were significantly higher for the epithelioid subtype than for the sarcomatous subtype (p=0.007), and higher in earlier stages (I and II) than in advanced stages (III and IV) (p=0.007). CONCLUSIONS: A diagnosis of MPM should be strongly considered in patients with pleural fluid HA concentrations exceeding 100,000ng/ml. PMID- 23790738 TI - Fulminant hepatic failure and hepatomegaly caused by diffuse liver metastases from small cell lung carcinoma: 2 autopsy cases. AB - Fulminant hepatic failure (FHF) is defined as a liver disease that causes encephalopathy within 8 weeks of onset in the absence of pre-existing liver disease. Although liver metastases are commonly found in cancer patients, FHF secondary to diffuse liver infiltration is rare. Here, we report the rare autopsy cases of patients with small cell lung carcinoma (SCLC) and secondary FHF. These patients presented with remarkable hepatomegaly and a near complete replacement of the liver parenchyma with metastatic tumor. Neoplastic involvement of the liver should be considered in the differential diagnosis of FHF. PMID- 23790739 TI - Clinical practice guidelines for nursing- and healthcare-associated pneumonia (NHCAP) [complete translation]. PMID- 23790740 TI - Association between the so-called "activation syndrome" and bipolar II disorder, a related disorder, and bipolar suggestive features in outpatients with depression. AB - BACKGROUND: Activation syndrome (AS) is a cluster of symptoms listed by the US Food and Drug Administration as possible suicidality precursors during antidepressant treatment. We aimed to clarify whether AS is associated with bipolar II disorder (BP-II) and its related disorder, i.e., bipolar disorder not otherwise specified (BP-NOS), which are often mistreated as major depressive disorder (MDD), as well as bipolar suggestive features in outpatients with depression. METHODS: The frequency of AS, bipolar suggestive features, and background variables in consecutive outpatients with a major depressive episode (MDE) due to BP-II/BP-NOS or MDD, who were naturalistically treated with antidepressants, were investigated and analyzed retrospectively. RESULTS: Of 157 evaluable patients (46 BP-II/BP-NOS, 111 MDD), 39 (24.8%) experienced AS. Patients with BP-II/BP-NOS experienced AS significantly more frequently than patients with MDD (52.2% of BP-II/BP-NOS vs. 13.5% of MDD, p<0.01). Univariate analysis revealed that BP-II/BP-NOS diagnosis, cyclothymic temperament, early age at onset of first MDE, psychiatric comorbidities, and depressive mixed state (DMX) were significantly associated with AS development in the entire sample. Multivariate analysis revealed that BP-II/BP-NOS diagnosis and DMX were independent risk factors for AS. LIMITATIONS: This is a retrospective and naturalistic study; therefore, patient selection bias could have occurred. CONCLUSIONS: Cautious monitoring of AS is needed during antidepressant trials in patients with BP-II/BP-NOS. Clinicians should re-evaluate underlying bipolarity when they confront AS. Antidepressants should be avoided for treating a current DMX beyond the unipolar-bipolar dichotomy. Prospective studies are needed to confirm these results. PMID- 23790741 TI - The effects of mindfulness-based cognitive therapy in patients with bipolar disorder: a controlled functional MRI investigation. AB - BACKGROUND: Preliminary research findings have shown that mindfulness-based cognitive therapy improves anxiety and depressive symptoms in bipolar disorder. In this study, we further investigated the effects of MBCT in bipolar disorder, in a controlled fMRI study. METHOD: Twenty three patients with bipolar disorder underwent neuropsychological testing and functional MRI. Sixteen of these patients were tested before and after an eight-week MBCT intervention, and seven were wait listed for training and tested at the same intervals. The results were compared with 10 healthy controls. RESULTS: Prior to MBCT, bipolar patients reported significantly higher levels of anxiety and symptoms of stress, scored significantly lower on a test of working memory, and showed significant BOLD signal decrease in the medial PFC during a mindfulness task, compared to healthy controls. Following MBCT, there were significant improvements in the bipolar treatment group, in measures of mindfulness, anxiety and emotion regulation, and in tests of working memory, spatial memory and verbal fluency compared to the bipolar wait list group. BOLD signal increases were noted in the medial PFC and posterior parietal lobe, in a repeat mindfulness task. A region of interest analysis revealed strong correlation between signal changes in medial PFC and increases in mindfulness. LIMITATIONS: The small control group is a limitation in the study. CONCLUSION: These data suggest that MBCT improves mindfulness and emotion regulation and reduces anxiety in bipolar disorder, corresponding to increased activations in the medial PFC, a region associated with cognitive flexibility and previously proposed as a key area of pathophysiology in the disorder. PMID- 23790742 TI - Long-acting injectable depot naltrexone use in the Veterans' Health Administration: a national study. AB - INTRODUCTION: Alcohol use disorders affect millions, but few utilize medications. This paper examines factors contributing to the use of long-acting injectable depot naltrexone (LADN) in a large patient population. METHODS: Bivariate analysis, stepwise multivariate logistic regression, and multivariate logistic regression analysis were used. RESULTS: The sample had 101,026 patients of whom 3180 (3.1%) received any form of naltrexone and 240 (0.24%) received LADN. Of those who received naltrexone, only 7.5% (240/3180) received LADN. The LADN group was more likely to have outpatient mental health service use and a mental health inpatient admission. The LADN group was more likely to have a co-morbid Axis 1 psychiatric disorder and to fill a psychotropic prescription. CONCLUSION: In order to better serve and understand the implications of LADN treatment for the patient population that uses and may benefit from it, more research is needed on the effectiveness of this medication in the dually-diagnosed and high service use population. PMID- 23790743 TI - Biomarkers of meat tenderness: present knowledge and perspectives in regards to our current understanding of the mechanisms involved. AB - Biomarkers of the meat quality are of prime importance for meat industry, which has to satisfy consumers' expectations and, for them, meat tenderness is and will remain the primary and most important quality attribute. The tenderization of meat starts immediately after animal death with the onset of apoptosis followed by a cooperative action of endogenous proteolytic systems. Before consideration of the biomarkers identified so far, we present here some new features on the apoptotic process. Among them, the most important is the recent discovery of a complex family of serpins capable to inhibit, in a pseudo-irreversible manner, caspases, the major enzymes responsible of cell dismantling during apoptosis. The biomarkers so far identified have been then sorted and grouped according to their common biological functions. All of them refer to a series of biological pathways including glycolytic and oxidative energy production, cell detoxification, protease inhibition and production of Heat Shock Proteins. Some unusual biomarkers are also presented: annexins, galectins and peroxiredoxins. On this basis, a detailed analysis of these metabolic pathways allowed us to identify some domains of interest for future investigations. It was thus emphasized that mitochondria, an important organelle in the production of energy from carbohydrates, lipids and proteins are a central element in the initiation and development of apoptosis. It was therefore stressed forward that, in fact, very little is known about the postmortem fate of these organelles and their multiple associated activities. Other topics discussed here would provide avenues for the future in the context of identifying reliable predictors of the ultimate meat tenderness. PMID- 23790744 TI - New anomalies due to methotrexate and misoprostol exposure in early pregnancy. PMID- 23790745 TI - Non-invasive prenatal diagnosis from the perspective of a low-resource country. AB - Current clinical practice in obstetrics has shifted the paradigm from a conventional prenatal approach based on invasive procedures, risking both fetus and mother, to non-invasive prenatal testing for some fetal conditions via the analysis of cell-free fetal DNA in maternal blood. In the past 15 years, much research has been devoted to refining the methodology for measuring cell-free fetal DNA in maternal circulation and to exploring clinical applications of this technology as a potential tool for prenatal diagnosis. Since the rapid spread around the world of prenatal diagnosis based on cell-free fetal DNA, it is time to start thinking how this cutting-edge technology might influence current practice of obstetrics in low-resource countries. PMID- 23790746 TI - Examined mice having the angiotensin converting enzyme (ACE)-2 gene knock-out in comparison to wild-type mice. PMID- 23790747 TI - Surgery-induced remission of extraintestinal manifestations in inflammatory bowel diseases. PMID- 23790748 TI - Review of the integrity of a Self Administered Motivational Instrument. AB - BACKGROUND: Motivational interviewing (MI) was developed by Miller and Rollnick as an evidence-based counselling approach for use in supporting people with alcohol problems. Over the years the principles and spirit of MI have been reviewed and fine-tuned and the approach has been embraced by practitioners worldwide and across fields. Since 2001 a number of instruments have been designed to evaluate the fidelity of MI practice. For the purposes of this study, one such instrument is used to assess a self-administered motivational instrument, known as the SAMI, which takes the interviewer role. OBJECTIVES: The SAMI is evaluated against the MITI 3.1.1, which is designed to assess the extent to which MI interventions perform on five global dimensions. These are evocation, collaboration, autonomy/support, direction and empathy. DESIGN: The SAMI was assembled based on the principles and spirit of MI, problem solving and goal setting. The targeted behaviour changes were student learning styles and approaches to study. SETTING: The SAMI was distributed, completed and submitted electronically via the university virtual learning environment. PARTICIPANTS: Thirty three mature students of a university which delivered online nursing programme were invited to complete the SAMI. Of these, 25 submitted completed transcripts. METHODS: Transcripts of a sample of six completed SAMIs were assessed by a group of teachers and researchers with experience in the use and evaluation of MI, using five-point Likert scales to assess the SAMI on the five dimensions. RESULTS: Overall, an average score exceeding 4.5 was attained across the five dimensions. Conventionally, such a score is recognised as competency in MI. However, on one dimension (empathy), the rating was three. CONCLUSIONS: This current research confirms that global principles have been observed in the online delivery of MI using the SAMI to probe approaches to study. PMID- 23790749 TI - Chinese version of the nursing students' perception of instructor caring (C NSPIC): assessment of reliability and validity. AB - BACKGROUND: The nursing students' perceptions of instructor caring (NSPIC) is an instrument to assess the influence of caring interactions between students and faculty on students' ability to care. However, the validity and reliability of the Chinese version has not yet been studied. OBJECTIVES: The study aimed to assess the validity and reliability of the Chinese version of NSPIC (C-NSPIC). DESIGN: This is a cross-sectional study. SETTING: The study was performed in three Tertiary Grade A (top level in China) and teaching hospitals in Shanghai, China. PARTICIPANTS: The participants of the study are nursing students during clinical practice. METHODS: The English version of nursing students' perception of instructor caring scale was professionally translated into Chinese and a pilot test was undertaken to ensure the equivalence of meaning and cultural appropriateness. The content validity of the C-NSPIC was examined by a panel of eight experts, and test-retest was conducted to assess the item reliabilities of the scale. A convenience sampling method was used to recruit nursing students. A first sample (N=256) was recruited to explore the factorial structure of the C NSPIC using exploratory factor analysis (EFA), and a validation sample (N=358) was recruited to confirm the findings from the EFA using confirmatory factor analysis (CFA). SPSS version 16.0 was used for the EFA and Amos 17.0 was used for the CFA. RESULTS: The Cronbach's alpha coefficient of the C-NSPIC was 0.933. The test-retest reliability was satisfactory, with the ICC scores for each item ranging from 0.603 to 0.962. The overall content validity index was 0.96. Five factors (control versus flexibility, supportive learning climate, confidence through caring, appreciation of life meaning and respectful sharing) were identified in EFA, which was consistent with that of the original English version, and were confirmed by CFA. CONCLUSION: The C-NSPIC can serve as a reliable and valid instrument for assessing the nursing students' perception of instructor caring in China, which may help to improve the nursing students' caring ability in China. PMID- 23790750 TI - Defensive strategies in Geranium sylvaticum. Part 1: organ-specific distribution of water-soluble tannins, flavonoids and phenolic acids. AB - A combination of high-resolution mass spectrometry and modern HPLC column technology, assisted by diode array detection, was used for accurate characterization of water-soluble polyphenolic compounds in the pistils, stamens, petals, sepals, stems, leaves, roots and seeds of Geranium sylvaticum. The organs contained a large variety of polyphenols, five types of tannins (ellagitannins, proanthocyanidins, gallotannins, galloyl glucoses and galloyl quinic acids) as well as flavonoids and simple phenolic acids. In all, 59 compounds were identified. Geraniin and other ellagitannins dominated in all the green photosynthetic organs. The other organs seem to produce distinctive polyphenol groups: pistils accumulated gallotannins; petals acetylglucose derivatives of galloylglucoses; stamens kaempferol glycosides, and seeds and roots accumulated proanthocyanidins. The intra-plant distribution of the different polyphenol groups may reflect the different functions and importance of various types of tannins as the defensive chemicals against herbivory. PMID- 23790751 TI - Differentiation of ileostomy from colostomy procedures: assessing the accuracy of current procedural terminology codes and the utility of natural language processing. AB - BACKGROUND: Large databases provide a wealth of information for researchers, but identifying patient cohorts often relies on the use of current procedural terminology (CPT) codes. In particular, studies of stoma surgery have been limited by the accuracy of CPT codes in identifying and differentiating ileostomy procedures from colostomy procedures. It is important to make this distinction because the prevalence of complications associated with stoma formation and reversal differ dramatically between types of stoma. Natural language processing (NLP) is a process that allows text-based searching. The Automated Retrieval Console is an NLP-based software that allows investigators to design and perform NLP-assisted document classification. In this study, we evaluated the role of CPT codes and NLP in differentiating ileostomy from colostomy procedures. METHODS: Using CPT codes, we conducted a retrospective study that identified all patients undergoing a stoma-related procedure at a single institution between January 2005 and December 2011. All operative reports during this time were reviewed manually to abstract the following variables: formation or reversal and ileostomy or colostomy. Sensitivity and specificity for validation of the CPT codes against the mastery surgery schedule were calculated. Operative reports were evaluated by use of NLP to differentiate ileostomy- from colostomy-related procedures. Sensitivity and specificity for identifying patients with ileostomy or colostomy procedures were calculated for CPT codes and NLP for the entire cohort. RESULTS: CPT codes performed well in identifying stoma procedures (sensitivity 87.4%, specificity 97.5%). A total of 664 stoma procedures were identified by CPT codes between 2005 and 2011. The CPT codes were adequate in identifying stoma formation (sensitivity 97.7%, specificity 72.4%) and stoma reversal (sensitivity 74.1%, specificity 98.7%), but they were inadequate in identifying ileostomy (sensitivity 35.0%, specificity 88.1%) and colostomy (75.2% and 80.9%). NLP performed with greater sensitivity, specificity, and accuracy than CPT codes in identifying stoma procedures and stoma types. Major differences where NLP outperformed CPT included identifying ileostomy (specificity 95.8%, sensitivity 88.3%, and accuracy 91.5%) and colostomy (97.6%, 90.5%, and 92.8%, respectively). CONCLUSION: CPT codes can identify effectively patients who have had stoma procedures and are adequate in distinguishing between formation and reversal; however, CPT codes cannot differentiate ileostomy from colostomy. NLP can be used to differentiate between ileostomy- and colostomy-related procedures. The role of NLP in conjunction with electronic medical records in data retrieval warrants further investigation. PMID- 23790752 TI - Continuous monitoring of central venous oxygen saturation predicts postoperative liver dysfunction after liver resection. AB - BACKGROUND: We examined whether the data obtained by monitoring central venous oxygen saturation (ScvO2) and/or stroke volume variation (SVV) during hepatectomy, as measured with the FloTrac/Vigileo system, can predict postoperative liver dysfunction. METHODS: This study included 33 patients with normal liver function who underwent hepatectomy between December 2007 and August 2010. Baseline ScvO2 and baseline SVV, as control values, were defined as the mean of ScvO2 and SVV, respectively, measured with the FloTrac/Vigileo system before hepatectomy. ScvO2 decrease (DeltaScvO2) was defined as the difference between the baseline ScvO2 and the lowest intraoperative ScvO2 and SVV increase (DeltaSVV) was defined as the difference between the baseline SVV and the highest intraoperative SVV. Moreover, mean ScvO2 and mean SVV were defined as the means of all ScvO2 and SVV values measured during surgery, respectively. We examined correlations of the new parameters with the highest postoperative values of total bilirubin (T. Bil). RESULTS: The cutoff values for DeltaScvO2 and mean SVV for predicting the highest postoperative T. Bil level to be >= 3.0 mg/dL with the highest sensitivity and specificity were found to be 10.2% and 13.6%, respectively. The areas under curve in receiver-operating-characteristic analysis of DeltaScvO2 and mean SVV were 0.797 and 0.757, respectively, showing significant differences. CONCLUSION: Our results suggest that DeltaScvO2 and mean SVV can predict postoperative liver dysfunction. When DeltaScvO2 and mean SVV exceed 10.2% and 13.6%, respectively, we advocate that adequate attention be paid to postoperative liver dysfunction, and that early intraoperative general circulatory management measures be implemented as needed. PMID- 23790753 TI - SAD kinases sculpt axonal arbors of sensory neurons through long- and short-term responses to neurotrophin signals. AB - Extrinsic cues activate intrinsic signaling mechanisms to pattern neuronal shape and connectivity. We showed previously that three cytoplasmic Ser/Thr kinases, LKB1, SAD-A, and SAD-B, control early axon-dendrite polarization in forebrain neurons. Here, we assess their role in other neuronal types. We found that all three kinases are dispensable for axon formation outside of the cortex but that SAD kinases are required for formation of central axonal arbors by subsets of sensory neurons. The requirement for SAD kinases is most prominent in NT-3 dependent neurons. SAD kinases transduce NT-3 signals in two ways through distinct pathways. First, sustained NT-3/TrkC signaling increases SAD protein levels. Second, short-duration NT-3/TrkC signals transiently activate SADs by inducing dephosphorylation of C-terminal domains, thereby allowing activating phosphorylation of the kinase domain. We propose that SAD kinases integrate long- and short-duration signals from extrinsic cues to sculpt axon arbors within the CNS. PMID- 23790755 TI - Performance of the Glasgow-Blatchford score in predicting clinical outcomes and intervention in hospitalized patients with upper GI bleeding. AB - BACKGROUND: Data regarding the utility of the Glasgow-Blatchford bleeding score (GBS) in hospitalized patients with upper GI hemorrhage are limited. OBJECTIVE: To evaluate the performance of the GBS in predicting clinical outcomes and the need for interventions in patients with upper GI hemorrhage. DESIGN: Prospective observational study. SETTING: Single, tertiary-care endoscopic center. PATIENTS: Between July 2010 and July 2012, 888 consecutive hospitalized patients managed for upper GI hemorrhage were entered into the study. INTERVENTION: GBS and Rockall scores. MAIN OUTCOME MEASUREMENTS: GBS and Rockall scores were prospectively calculated. The performance of these scores to predict the need for interventions and outcomes was assessed by using a receiver operating characteristic curve. RESULTS: Endoscopy was performed in 708 patients (80%). A total of 286 patients (40.3%) required endoscopic therapy, and 29 patients (3.8%) underwent surgery. GBS and post-endoscopy Rockall scores (post-E RS) were superior to pre-endoscopy Rockall scores in predicting the need for endoscopic therapy (area under the curve [AUC] 0.76 vs 0.76 vs 0.66, respectively) and rebleeding (AUC 0.71 vs 0.64 vs 0.57). The GBS was superior to Rockall scores in predicting the need for blood transfusion (AUC 0.81 vs 0.70 vs 0.68) and surgery (AUC 0.71 vs 0.64 vs 0.51). Patients with GBS scores <= 3 did not require intervention. LIMITATIONS: Subjective decision making as to need for endoscopic therapy and blood transfusion. CONCLUSION: Compared with post-E RS, the GBS was superior in predicting the need for blood transfusion and surgery in hospitalized patients with upper GI hemorrhage and was equivalent in predicting the need for endoscopic therapy, rebleeding, and death. There are potential cutoff GBS scores that allow risk stratification for upper GI hemorrhage, which warrant further evaluation. PMID- 23790754 TI - Transient inhibition of TrkB kinase after status epilepticus prevents development of temporal lobe epilepsy. AB - Temporal lobe epilepsy is the most common and often devastating form of human epilepsy. The molecular mechanism underlying the development of temporal lobe epilepsy remains largely unknown. Emerging evidence suggests that activation of the BDNF receptor TrkB promotes epileptogenesis caused by status epilepticus. We investigated a mouse model in which a brief episode of status epilepticus results in chronic recurrent seizures, anxiety-like behavior, and destruction of hippocampal neurons. We used a chemical-genetic approach to selectively inhibit activation of TrkB. We demonstrate that inhibition of TrkB commencing after status epilepticus and continued for 2 weeks prevents recurrent seizures, ameliorates anxiety-like behavior, and limits loss of hippocampal neurons when tested weeks to months later. That transient inhibition commencing after status epilepticus can prevent these long-lasting devastating consequences establishes TrkB signaling as an attractive target for developing preventive treatments of epilepsy in humans. PMID- 23790756 TI - Safety of capsule endoscopy in the octogenarian as compared with younger patients. AB - BACKGROUND: There has been an increased use of capsule endoscopy for the evaluation of small-intestine pathology in very elderly patients, yet the safety profile of this procedure has not been well-established. OBJECTIVE: To estimate the adverse event rate of capsule endoscopy in patients aged >=80 years and to compare this rate with that of capsule endoscopy patients aged <80 years. DESIGN: Retrospective matched cohort study. SETTING: Single tertiary-care referral center. PATIENTS: All 195 patients aged >=80 years who underwent capsule endoscopy between 2005 and 2011 were included, along with 585 capsule endoscopy patients aged <80 years who were matched by sex in a 1:3 fashion. INTERVENTION: All patients underwent capsule endoscopy and, in selected cases, double-balloon enteroscopy. MAIN OUTCOME MEASUREMENTS: Adverse event rate of capsule endoscopy, which was defined as capsule retention or aspiration. RESULTS: Adverse events occurred at a similar frequency in patients aged >=80 years compared with those aged <80 years (1.03% vs 0.85%; P = 1.00), resulting in a difference of 0.2% (95% confidence interval, -1.8% to 2.1%). All adverse events were related to capsule retention, with no study patients experiencing aspiration. LIMITATIONS: This was a single-center, retrospective study. CONCLUSION: Adverse events resulting from capsule endoscopy occur at a similar rate in patients aged >=80 years compared with those aged <80 years. Capsule endoscopy can be performed safely in the very elderly patient population. PMID- 23790757 TI - Can pediatric bipolar-I disorder be diagnosed in the context of posttraumatic stress disorder? A familial risk analysis. AB - Despite ongoing concerns that traumatized children with severe symptoms of emotional dysregulation may be inappropriately receiving a diagnosis of pediatric bipolar-I (BP-I) disorder, this issue has not been adequately examined in the literature. Because both pediatric BP-I disorder and posttraumatic stress disorder (PTSD) are familial disorders, if children with both BP-I and PTSD were to be truly affected with BP-I disorder, their relatives would be at high risk for BP-I disorder. To this end, we compared patterns of familial aggregation of BP-I disorder in BP-I children with and without PTSD with age and sex matched controls. Participants were 236 youths with BP-I disorder and 136 controls of both sexes along with their siblings. Participants completed a large battery of measures designed to assess psychiatric disorders, psychosocial, educational, and cognitive parameters. Familial risk analysis revealed that relatives of BP-I probands with and without PTSD had similar elevated rates of BP-I disorder that significantly differed from those of relatives of controls. Pediatric BP-I disorder is similarly highly familial in probands with and without PTSD indicating that their co-occurrence is not due to diagnostic error. PMID- 23790758 TI - Farming up the city: the rise of urban vertical farms. PMID- 23790759 TI - Clinically important variants of diffuse large B-cell lymphoma. AB - It has become clear that diffuse large B-cell lymphoma is not a uniform antibody. Several recognizable variants have clinically distinct features and, frequently, require specific treatment approaches. Recognition of these variants and utilization of the appropriate treatments will improve the outcome for the patients. PMID- 23790760 TI - Endovascular management of severe bleeding after major abdominal surgery. AB - BACKGROUND: In this study we analyzed embolization and stent-graft results. METHODS: Demographics, indications, procedures, and outcomes of patients treated with embolization or stent grafting for late postoperative bleeding after major abdominal surgery were retrospectively recorded. Outcomes were analyzed on an intention-to-treat basis. RESULTS: Between 2004 and 2008, 14 consecutive patients (11 men and 3 women, mean age 64 years) were treated for hemorrhage responsible for shock in 6 patients (43%), occurring after pancreaticoduodenectomy (n=13) or subtotal gastrectomy (n=1). Mean onset occurred at 23 days postoperatively (range 7-75 days). Bleeding site included: the stump of the gastroduodenal artery (n=10), splenic artery (n=2), common hepatic artery (n=1), and right gastric artery (n=1). Initial success was obtained in 13 patients (93%); the only failure of stent-graft deployment required re-laparotomy. Treatment included embolization in 8 patients and stent grafting in 5 patients. In the embolization group, 5 complications (62%) occurred: 4 rebleeding and 1 gastric perforation, compared with no early complications in the stent-graft group. One patient died in each group. The mean follow-up was 25 months (range 6-57 months). CONCLUSIONS: Stent grafting seems to provide definitive hemostasis and fewer complications compared with embolization. PMID- 23790761 TI - Approaches to the management of spontaneous isolated visceral artery dissection. AB - BACKGROUND: Spontaneous isolated celiac and superior mesenteric artery dissection without aortic dissection is a rare disease. Recently, an increasing number of cases have been diagnosed and the prognosis has improved significantly because of technical progress in computed tomography (CT). However, management approaches vary from conservative treatment or endovascular repair to open surgery. This study analyzed the clinical findings of patients with spontaneous visceral artery dissection, and attempted to illuminate how to manage these cases. MATERIALS AND METHODS: From June 2005 to February 2012, a total of 17 patients were diagnosed with spontaneous isolated visceral artery dissection in the authors' hospital (4 celiac arteries, 12 superior mesenteric arteries, and 1 inferior mesenteric artery) based on CT findings. The clinical characteristics, Sakamoto's classification, imaging appearance, and early outcomes of these patients were retrospectively compared. RESULTS: The mean age of the patients was 51.47 +/- 8.65 years (range, 39-73 years) and the mean follow-up period was 35.18 +/- 25.55 months (range, 1-79 months). Fifteen (88.2%) patients had abdominal pain and no ischemic changes of the bowel. The dissections initiated at a mean distance of 13.04 +/- 10.41 mm (range, 4.00-43.39 mm) from the origin of the artery, with a mean length of 53.39 +/- 28.06 mm (range, 10.00-108.46 mm). There were 4 type I (23.8%), 1 type II (5.9%), 9 type III (52.9%), and 3 type IV (17.6%) dissections according to Sakamoto's classification. Treatments included observation without anticoagulation treatment in 3 patients (17.6%), anticoagulation treatment in 12 (70.6%), and endovascular stenting in 2 (11.8%). The disease stabilized in all patients during follow-up. CONCLUSIONS: If bowel perfusion is not compromised and patency is well compensated by collateral circulation, most patients can be managed conservatively with or without anticoagulation treatment. However, patients must be monitored closely and followed up regularly for early detection of progression. PMID- 23790762 TI - Endovascular treatment of thoracic aortic aneurysm: a single-center experience. AB - BACKGROUND: We assess the effectiveness of thoracic endovascular aortic repair (TEVAR) in patients with thoracic artery aneurysm with a retrospective analysis of our experience and a review of the literature. METHODS: Between January 2005 and December 2011, 53 patients with thoracic aortic aneurysm underwent TEVAR. We evaluated the technical success, periprocedural and long-term mortality and morbidity, and follow-up by enhanced computed tomographic scans at 1, 6, and 12 months and annually thereafter. RESULTS: TEVAR was performed in good general conditions in 62.3% of cases and in emergency conditions in 37.7% of cases. A total of 85 endoprostheses were correctly placed, with technical success of 100%. In 18.8% of cases, a carotid-subclavian bypass was performed; 35.8% of cases required drainage of cerebrospinal fluid. Postoperative mortality was 7.5%, and in all cases patients were treated in emergency regimen. The incidence of major postoperative complications was 9.4%, with 2 cases of paraplegia. At a mean follow-up of 25.6 months, 12 cases (22.6%) of endoleak were observed: 5 cases of type IB endoleak were treated with prosthetic extensions; 7 cases of type II endoleak were not treated. There were no thrombotic occlusions, stent migrations, or fractures. CONCLUSION: TEVAR represents an effective option in the treatment of thoracic aortic aneurysms, with good immediate and long-term results. PMID- 23790763 TI - Open conversion after endovascular aortic aneurysm repair: a single-center experience. AB - BACKGROUND: The endovascular treatment of an abdominal aortic aneurysm (AAA) is a treatment with low risk and good reported results. This retrospective study analyzed experience with patients requiring surgical conversion after endovascular abdominal aortic aneurysm repair (EVAR). METHODS: A total of 26 patients underwent open conversion (OC) after EVAR (18 endografts implanted at the authors' center and 8 in other centers). Patients were divided into 2 groups: early conversion if OC was performed within 30 days from the primary EVAR, and late conversion if OC was performed at least 30 days after EVAR. The authors analyzed all data on OC and the postoperative course. RESULTS: In this series, OC was performed for 22 endoleaks (13 type I, 5 type II, 2 type III, and 2 type V, which in 5 cases these were associated with AAA ruptures), 2 renal artery coverages, and 2 endograft infections. Six (23%) patients underwent early conversion with a mortality rate of 50%, and 20 (77%) had late conversion with a mortality rate of 20%. The overall mortality rate after OC, occurring before hospital discharge or within 30 days, was 26.9% (7 of 26). CONCLUSIONS: Endoleaks remain the weak point of endografts and can result in aneurysm rupture/death. Urgent OC and infections engender a high mortality. Elective OC can be performed with very low mortality and acceptable morbidity. Lifelong surveillance is necessary to detect and treat endoleaks. PMID- 23790764 TI - Review of the management of blunt thoracic aortic injuries according to current treatment recommendations. AB - BACKGROUND: Blunt thoracic aortic injury (BTAI) is associated with high mortality. Recent Society for Vascular Surgery (SVS) guidelines recommend repair of all but SVS grade I injuries. This study's objective was to retrospectively determine guideline adherence at the authors' trauma center, and its impact on mortality. METHODS: A retrospective review of the trauma database at the authors' university-affiliated trauma center identified and graded all BTAIs between 1999 and 2011. Patient demographics, treatment, and outcomes were recorded. RESULTS: Imaging was available for 52 of 59 (85.2%) patients with BTAI. For these 52 patients, injury distribution was: 14 (27.0%) grade 1; 1 (1.9%) grade 2; 35 (67.3%) grade 3; and 2 (3.8%) grade 4. Nonoperative management was used for 92.8% (13), 100% (1), 34.3% (12), and 0% of grade 1, 2, 3, and 4 injuries, respectively. The operatively managed grade I injury was initially misclassified as grade 3. He was lost to follow-up after discharge. Of the 12 patients with nonoperatively managed grade 3 injuries, 7 (58.3%) died before consideration of endovascular repair and another died early secondary to brain injury. The remaining 4 (11.4%) with nonoperatively managed grade 3 injuries survived to discharge but were lost to follow-up. For grade 3 injuries, endovascular repair was significantly associated with decreased mortality (odds ratio [OR], 0.10; 0.02-0.53; P=0.007). Exclusion of those with presentation-day mortality negated this significant association (OR, 0.84; 0.07-9.68; P=1.00). CONCLUSIONS: Minor deviation (9.6%) from guidelines did not result in additional morbidity/mortality. However, a high rate of loss to follow-up limits conclusions. The mortality reduction seen with endovascular repair for grade 3 injury is inflated by patients who die before repair is considered in the nonoperative group. Larger prospective studies with appropriate inclusion and exclusion criteria and improved follow-up are needed to determine the consequences of selective nonoperative management of these injuries. PMID- 23790765 TI - New cerebral ischemic lesions after carotid endarterectomy. AB - BACKGROUND: We sought to investigate the incidence and location of new cerebral ischemic lesions after carotid endarterectomy (CEA) using diffusion-weighted magnetic resonance imaging (DW-MRI). METHODS: Sixty-six consecutive patients (50 males with a mean [+/-SD] age of 69 +/- 9 years) who underwent CEA were included in this prospective study. Seventeen patients were symptomatic and 49 patients were asymptomatic. CEA was performed with patch closure without using a shunt. Carotid plaque echostructure was evaluated with the grayscale median (GSM) score. DW-MRI scanning of the brain was performed 24 hours before and 48 to 72 hours after the procedure. RESULTS: Thirty-day stroke and mortality rates were 0%. The mean GSM score for symptomatic patients was 27 +/- 15; for asymptomatic patients, the mean GSM score was 39 +/- 18 (P = 0.006). Patients were divided into 2 groups according to GSM score: GSM scores <=25 (22 patients) and GSM scores >26 (44 patients). New brain lesions were detected after 6 endarterectomies (8.9%), and all were clinically silent. These lesions were ischemic in 5 cases (7.5%) and micro-hemorrhagic in 1 case (1.4%). In 3 cases, new ischemic lesions were located within the treated carotid artery territory. In 2 cases, new lesions on DW-MRI were located outside of the treated carotid artery territory. There was no significant difference in the incidence of ischemic lesions between the 2 groups (GSM scores <=25, 2 lesions; GSM scores >26, 3 lesions; P = 0.544). CONCLUSIONS: New ischemic lesions on DW-MRI are detected in 7.5% of patients after CEA, and most of these lesions are clinically silent. Plaque echogenicity does not affect their incidence. New lesions seen on DW-MRI may be generated outside of the treated carotid artery territory. PMID- 23790766 TI - Patterns and management of blunt abdominal aortic injury. AB - BACKGROUND: Blunt abdominal aortic injury (BAAI) is historically associated with significant morbidity and mortality. Our institutional experience was analyzed to define current patterns of injury and to help guide management. METHODS: Adult patients with BAAI between January 2000 and July 2011 were identified from our trauma registry. Medical, radiographic, and autopsy records were reviewed for relevant clinical data. Management and outcomes were compared between patients with minimal aortic injury limited to the intima (MAI) compared to more significant aortic injury (SAI). RESULTS: Nine patients had MAI and 8 had SAI, including 2 dissections, 2 pseudoaneurysms, 2 branch avulsions, 1 thrombosis, and 1 transection. The MAI and SAI groups had similar demographics and patterns of injury, and all patients had significant polytrauma, with a mean injury severity score of 42. More MAI than SAI patients were managed nonoperatively (100% vs. 38%; P=0.01). All observed patients underwent repeat imaging during the index admission, 85% within 72 hours, and no observed lesions led to malperfusion, death, or progression during the index admission. One MAI progressed to a pseudoaneurysm within 8 months. Five SAI patients underwent aortic-related repairs, including 2 endovascular stent grafts, 2 open primary repairs, and 1 axillobifemoral bypass. Overall, 15 (88%) patients underwent procedures for any injury-9 required laparotomy (53%) and 2 underwent thoracotomy. There were 6 (35%) deaths, 2 attributable to aortic injury-1 from hemorrhage and 1 from hyperkalemic cardiac arrest after prolonged ischemia from infrarenal aortic occlusion. Among patients who survived the initial resuscitation, SAI was associated with a significantly higher mortality rate compared to MAI (50% vs. 0%; P=0.03). CONCLUSIONS: Patients with MAI are at low risk of complications and may be considered for observation. Patients with SAI requiring intervention manifest clinically and/or radiographically at presentation. Those not associated with bleeding, malperfusion, or thromboembolism may be observed with interval imaging. For all observed patients, long-term surveillance is required to document complete resolution or stability, because even MAI can progress to a more complex lesion. PMID- 23790767 TI - Safety and efficacy of carotid endarterectomy in octogenarians. AB - BACKGROUND: To evaluate the outcome of carotid endarterectomy (CEA) in octogenarians. METHOD: Between January 2005 and July 2010, all CEA patients were prospectively recorded. Patients were categorized into those <80 and >=80 years of age. Primary outcome measures were hospital duration of stay (HDOS), mortality, any stroke, and postprocedural complications. RESULTS: In total, 477 patients with carotid artery stenosis were treated with CEA. Seventy-one patients (13%) were >=80 years of age and 477 (87%) patients were <80 years of age. Median HDOS was 3.0 days (interquartile range [IQR], 2-5) for the entire cohort with a median of 3 days (IQR, 2-4) for patients <80 years of age and 4 days (IQR, 2-7) for patients >=80 years of age (P = 0.0001). Fifteen patients (3%) had an early adverse neurologic event, with 7 patients (1.3%) developing a transient ischemic attack, 2 patients (0.3%) a minor stroke with full neurologic recovery, and 6 patients (1.1%) had a major stroke. Forty patients (6.8%) had a postoperative nerve injury. No statistical differences were observed between the younger (<80 years of age) and older (>=80 years of age) group despite a significant difference in postoperative delirium (P < 0.0001). During follow-up, more fatal cardiac events occurred in the octogenarians group (4.2% vs. 0.4%; P = 0.02). Kaplan-Meier analysis revealed a significantly better survival for the younger patients (log rank test; P = 0.04). CONCLUSIONS: Octogenarians who suffer from carotid artery stenosis can be safely treated by CEA. The increased incidence of postoperative delirium is an important finding and requires extra attention in this vulnerable group. PMID- 23790768 TI - Clinical and subclinical varicocele incidence in patients with primary varicose veins requiring surgery. AB - BACKGROUND: The purpose of this study was to analyze the incidence of clinical and subclinical varicocele in patients with primary varicose veins requiring surgery. METHODS: A total of 100 patients with primary varicose veins requiring surgery were evaluated. Clinical varicocele was found in each patient through physical examination. Each patient was also evaluated with ultrasound because of evidence of subclinical varicocele. RESULTS: Among the patients with varicose veins, 28 had no clinical sign of varicocele, whereas the remaining 72 had varicocele with different clinical levels (72%). Doppler ultrasound revealed that 32 patients had no reflux flow, whereas the other 68 had different grades of reflux flow (68%). CONCLUSIONS: Clinical or subclinical varicocele may be highly present in patients with severe venous disease. However, these types of varicoceles do not cause infertility in most patients. Nevertheless, infertility may occur in subsequent years, especially in young patients who have venous disease and undergo surgery, and they should be aware of this condition. PMID- 23790769 TI - A practical index to predict 30-day mortality after major amputation. AB - BACKGROUND: Patients at risk of mortality after amputation have not been well identified. We sought to devise a clinical index predicting 30-day mortality after amputation that would allow stratification of intensity of postoperative care. METHODS: The National Surgical Quality Improvement Program (NSQIP) database (2005-2009) was analyzed for patients who had above- or below-knee amputations. An additive risk index was created based on logistic regression that examined patient demographics, comorbidities, and operative characteristics. A threshold score for clinical action was identified as the score at which the gain in certainty was maximized. The primary outcome measure was 30-day mortality. RESULTS: Among 9244 patients analyzed, there were 744 deaths (8.1%) at 30 days, with 280 occurring after hospital discharge (37.9%). The final index includes 11 components with a total score range of 0-13: age (60-79 or >=80 years), history of congestive heart failure, chronic obstructive pulmonary disease, or major cardiac surgery, using steroid medications, having dependent functional status, dyspnea, being on dialysis, having impaired sensorium, or preoperative sepsis. This index has a c-statistic of 0.7391, and the score at which clinical action should be taken is >=5. The observed probability of 30-day mortality increased from 1.06% at a score of 1 to 10% at 5 and 38.5% at a score of 10. CONCLUSIONS: More than one-third of deaths within 30 days of major amputation occur after discharge from acute care. A novel index to predict 30-day mortality after major amputation is described. Patients receiving a score >=5 face a substantial risk of mortality and should be held in the hospital longer or, if discharged, receive closer postoperative follow-up. PMID- 23790770 TI - Feasibility of an adaptive strategy in preoperative radiochemotherapy for rectal cancer with image-guided tomotherapy: boosting the dose to the shrinking tumor. AB - PURPOSE: To investigate the feasibility of preoperative adaptive radiochemotherapy by delivering a concomitant boost to the residual tumor during the last 6 fractions of treatment. METHODS AND MATERIALS: Twenty-five patients with T3/T4N0 or N+ rectal cancer were enrolled. Concomitant chemotherapy consisted of oxaliplatin 100 mg/m(2) on days -14, 0, and +14, and 5-fluorouracil 200 mg/m(2)/d from day -14 to the end of radiation therapy (day 0 is the start of radiation therapy). Radiation therapy consisted of 41.4 Gy in 18 fractions (2.3 Gy per fraction) with Tomotherapy to the tumor and regional lymph nodes (planning target volume, PTV) defined on simulation CT and MRI. After 9 fractions simulation CT and MRI were repeated for the planning of the adaptive phase: PTVadapt was generated by adding a 5-mm margin to the residual tumor. In the last 6 fractions a boost of 3.0 Gy per fraction (in total 45.6 Gy in 18 fractions) was delivered to PTVadapt while concomitantly delivering 2.3 Gy per fraction to PTV outside PTVadapt. RESULTS: Three patients experienced grade 3 gastrointestinal toxicity; 2 of 3 showed toxicity before the adaptive phase. Full dose of radiation therapy, oxaliplatin, and 5-fluorouracil was delivered in 96%, 96%, and 88% of patients, respectively. Two patients with clinical complete response (cCR) refused surgery and were still cCR at 17 and 29 months. For the remaining 23 resected patients, 15 of 23 (65%) showed tumor regression grade 3 response, and 7 of 23 (30%) had pathologic complete response; 8 (35%) and 12 (52%) tumor regression grade 3 patients had <=5% and 10% residual viable cells, respectively. CONCLUSIONS: An adaptive boost strategy is feasible, with an acceptable grade 3 gastrointestinal toxicity rate and a very encouraging tumor response rate. The results suggest that there should still be room for further dose escalation of the residual tumor with the aim of increasing pathologic complete response and/or cCR rates. PMID- 23790771 TI - Linear energy transfer-guided optimization in intensity modulated proton therapy: feasibility study and clinical potential. AB - PURPOSE: To investigate the feasibility and potential clinical benefit of linear energy transfer (LET) guided plan optimization in intensity modulated proton therapy (IMPT). METHODS AND MATERIALS: A multicriteria optimization (MCO) module was used to generate a series of Pareto-optimal IMPT base plans (BPs), corresponding to defined objectives, for 5 patients with head-and-neck cancer and 2 with pancreatic cancer. A Monte Carlo platform was used to calculate dose and LET distributions for each BP. A custom-designed MCO navigation module allowed the user to interpolate between BPs to produce deliverable Pareto-optimal solutions. Differences among the BPs were evaluated for each patient, based on dose-volume and LET-volume histograms and 3-dimensional distributions. An LET based relative biological effectiveness (RBE) model was used to evaluate the potential clinical benefit when navigating the space of Pareto-optimal BPs. RESULTS: The mean LET values for the target varied up to 30% among the BPs for the head-and-neck patients and up to 14% for the pancreatic cancer patients. Variations were more prominent in organs at risk (OARs), where mean LET values differed by a factor of up to 2 among the BPs for the same patient. An inverse relation between dose and LET distributions for the OARs was typically observed. Accounting for LET-dependent variable RBE values, a potential improvement on RBE weighted dose of up to 40%, averaged over several structures under study, was noticed during MCO navigation. CONCLUSIONS: We present a novel strategy for optimizing proton therapy to maximize dose-averaged LET in tumor targets while simultaneously minimizing dose-averaged LET in normal tissue structures. MCO BPs show substantial LET variations, leading to potentially significant differences in RBE-weighted doses. Pareto-surface navigation, using both dose and LET distributions for guidance, provides the means for evaluating a large variety of deliverable plans and aids in identifying the clinically optimal solution. PMID- 23790772 TI - Phase 1 trial of neoadjuvant radiation therapy before prostatectomy for high-risk prostate cancer. AB - PURPOSE: To evaluate, in a phase 1 study, the safety of neoadjuvant whole-pelvis radiation therapy (RT) administered immediately before radical prostatectomy in men with high-risk prostate cancer. METHODS AND MATERIALS: Twelve men enrolled and completed a phase 1 single-institution trial between 2006 and 2010. Eligibility required a previously untreated diagnosis of localized but high-risk prostate cancer. Median follow-up was 46 months (range, 14-74 months). Radiation therapy was dose-escalated in a 3 * 3 design with dose levels of 39.6, 45, 50.4, and 54 Gy. The pelvic lymph nodes were treated up to 45 Gy with any additional dose given to the prostate and seminal vesicles. Radical prostatectomy was performed 4-8 weeks after RT completion. Primary outcome measure was intraoperative and postoperative day-30 morbidity. Secondary measures included late morbidity and oncologic outcomes. RESULTS: No intraoperative morbidity was seen. Chronic urinary grade 2+ toxicity occurred in 42%; 2 patients (17%) developed a symptomatic urethral stricture requiring dilation. Two-year actuarial biochemical recurrence-free survival was 67% (95% confidence interval 34%-86%). Patients with pT3 or positive surgical margin treated with neoadjuvant RT had a trend for improved biochemical recurrence-free survival compared with a historical cohort with similar adverse factors. CONCLUSIONS: Neoadjuvant RT is feasible with moderate urinary morbidity. However, oncologic outcomes do not seem to be substantially different from those with selective postoperative RT. If this multimodal approach is further evaluated in a phase 2 setting, 54 Gy should be used in combination with neoadjuvant androgen deprivation therapy to improve biochemical outcomes. PMID- 23790773 TI - Adaptive stereotactic body radiation therapy planning for lung cancer. AB - PURPOSE: To investigate the dosimetric effects of adaptive planning on lung stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: Forty of 66 consecutive lung SBRT patients were selected for a retrospective adaptive planning study. CBCT images acquired at each fraction were used for treatment planning. Adaptive plans were created using the same planning parameters as the original CT-based plan, with the goal to achieve comparable comformality index (CI). For each patient, 2 cumulative plans, nonadaptive plan (PNON) and adaptive plan (PADP), were generated and compared for the following organs-at-risks (OARs): cord, esophagus, chest wall, and the lungs. Dosimetric comparison was performed between PNON and PADP for all 40 patients. Correlations were evaluated between changes in dosimetric metrics induced by adaptive planning and potential impacting factors, including tumor-to-OAR distances (dT-OAR), initial internal target volume (ITV1), ITV change (DeltaITV), and effective ITV diameter change (DeltadITV). RESULTS: 34 (85%) patients showed ITV decrease and 6 (15%) patients showed ITV increase throughout the course of lung SBRT. Percentage ITV change ranged from -59.6% to 13.0%, with a mean (+/-SD) of -21.0% (+/-21.4%). On average of all patients, PADP resulted in significantly (P=0 to .045) lower values for all dosimetric metrics. DeltadITV/dT-OAR was found to correlate with changes in dose to 5 cc (DeltaD5cc) of esophagus (r=0.61) and dose to 30 cc (DeltaD30cc) of chest wall (r=0.81). Stronger correlations between DeltadITV/dT-OAR and DeltaD30cc of chest wall were discovered for peripheral (r=0.81) and central (r=0.84) tumors, respectively. CONCLUSIONS: Dosimetric effects of adaptive lung SBRT planning depend upon target volume changes and tumor-to-OAR distances. Adaptive lung SBRT can potentially reduce dose to adjacent OARs if patients present large tumor volume shrinkage during the treatment. PMID- 23790774 TI - Interfractional position variation of pancreatic tumors quantified using intratumoral fiducial markers and daily cone beam computed tomography. AB - PURPOSE: The aim of this study was to quantify interfractional pancreatic position variation using fiducial markers visible on daily cone beam computed tomography (CBCT) scans. In addition, we analyzed possible migration of the markers to investigate their suitability for tumor localization. METHODS AND MATERIALS: For 13 pancreatic cancer patients with implanted Visicoil markers, CBCT scans were obtained before 17 to 25 fractions (300 CBCTs in total). Image registration with the reference CT was used to determine the displacement of the 2 to 3 markers relative to bony anatomy and to each other. We analyzed the distance between marker pairs as a function of time to identify marker registration error (SD of linear fit residuals) and possible marker migration. For each patient, we determined the mean displacement of markers relative to the reference CT (systematic position error) and the spread in displacements (random position error). From this, we calculated the group systematic error, Sigma, and group random error, sigma. RESULTS: Marker pair distances showed slight trends with time (range, -0.14 to 0.14 mm/day), possibly due to tissue deformation, but no shifts that would indicate marker migration. The mean SD of the fit residuals was 0.8 mm. We found large interfractional position variations, with for 116 of 300 (39%) fractions a 3-dimensional vector displacement of >10 mm. The spread in displacement varied significantly (P<.01) between patients, from a vector range of 9.1 mm to one of 24.6 mm. For the patient group, Sigma was 3.8, 6.6, and 3.5 mm; and sigma was 3.6, 4.7 and 2.5 mm, in left-right, superior-inferior, and anterior-posterior directions, respectively. CONCLUSIONS: We found large systematic displacements of the fiducial markers relative to bony anatomy, in addition to wide distributions of displacement. These results for interfractional position variation confirm the potential benefit of using fiducial markers rather than bony anatomy for daily online position verification for pancreatic cancer patients. PMID- 23790775 TI - Challenges with the diagnosis and treatment of cerebral radiation necrosis. AB - The incidence of radiation necrosis has increased secondary to greater use of combined modality therapy for brain tumors and stereotactic radiosurgery. Given that its characteristics on standard imaging are no different that tumor recurrence, it is difficult to diagnose without use of more sophisticated imaging and nuclear medicine scans, although the accuracy of such scans is controversial. Historically, treatment had been limited to steroids, hyperbaric oxygen, anticoagulants, and surgical resection. A recent prospective randomized study has confirmed the efficacy of bevacizumab in treating radiation necrosis. Novel therapies include using focused interstitial laser thermal therapy. This article will review the diagnosis and treatment of radiation necrosis. PMID- 23790776 TI - Single centre experience with surgical treatment of hilar cholangiocarcinoma. AB - BACKGROUND /AIMS: Surgical resection is a radical treatment option for hilar cholangiocarcinomas. However it is still difficult to cure and patient prognosis is poor. An evaluation of the surgical options and results may elucidate effective treatments. METHODOLOGY: We retrospectively examined the demographic characteristics, surgical records and outcome in 64 patients with hilar cholangiocarcinoma undergoing surgical resections or palliative surgical procedures for the period of 2004-2012. RESULTS: The patients included 43 males and 17 females with a mean age of 61.4 A+/- 10.4 years (A+/-SD, range 35-81 years). Forty four resections were done - R0-22 cases (34.4%), R1 - 10 (15.6 %) cases, R2 -12 cases (18.7%) and 20 palliative (31.3%) operations were performed. R0 - resection of common bile ducts with right hepatectomy with Sg 1 was done in 8 cases, resection of common hepatic duct with left hepatectomy with Sg 1 in 9 cases and resection of common hepatic duct in 5 cases. The total percentage of postoperative morbidity is 51.5 %. The types of complications are as follows: intra abdominal bleeding 31.25 %, temporary biliary leakage - 26.56 %, leakage of hepatico-jejunostomya7.81 %, biliary fistula 7.81%, liver insufficiency 17.18 %, pleural effusion 48.13 %, intraabdominal abscess 28.13 %, surgical site infection 48.3 %. The mean five-year overall survival for R0 - resection is 32%, for R1 - and R2 - resection is 12% and for the palliative operations - 0%. The mean overall survival for R0-resection is 37 months, for R1 - and R2 - resection is 19 months and for the palliative operations 7 months. CONCLUSIONS: Radically extended surgical resection for hilar cholangiocarcinoma is necessary to obtain improved patient survival. PMID- 23790777 TI - Laparoscopic incisional hernia repair by lightweight polypropylene mesh with resorbable coating. Technical notes, preliminary results. AB - Laparoscopic repair of ventral hernias has gained popularity, since many studies have reported encouraging results. The choice of the mesh and fixation methods are crucial issues in preventing complications and recurrence. 30 laparoscopic ventral hernia repair performed consecutively in 28 patients (11 males, 17 females) for different kinds of incisional hernias from February 2011 to June 2012 were prospectively evaluated. All patients received total laparoscopic incisional hernia repair by the use of the new lightweight polypropylene mesh with resorbable coating (PhysiomeshTM, Ethicon Endo-Surgery, Johnson Johnson, Inc.). No major postoperative complications were reported. Two recurrences were diagnosed after 5 months from the first repair. Both patients received laparoscopic repair by the same kind of mesh. Lightweight polypropylene mesh with resorbable coating, with its properties of easy positioning and bio compatibility, represents an innovation in laparoscopic incisional hernia repair, and should be considered for clinical intra-operative as well as long term evaluations. PMID- 23790778 TI - Mortality and need of surgical treatment in acute upper gastrointestinal bleeding: a one year study in a tertiary center with a 24 hours / day-7 days / week endoscopy call. Has anything changed? AB - BACKGROUND: Acute upper gastrointestinal bleeding, previously often a surgical problem, is now the most common gastroenterological emergency. AIM: To evaluate the current situation in terms of mortality and need of surgery. SUBJECTS AND METHODS: Retrospective non-randomised clinical study performed between 1st January-31st December 2011, at "Professor Dr. Octavian Fodor" Regional Institute of Gastroenterology and Hepatology in Cluj Napoca. 757 patients with upper gastrointestinal bleeding were endoscopically examined within 24 hours from presentation in the emergency unit. Data were collected from admission charts and Hospital Manager programme. Statistical analysis was performed with GraphPad 2004, using the following tests: chi square, Spearman, Kruskall-Wallis, Mann Whitney, area under receiver operating curve. RESULTS: Non-variceal etiology was predominant, the main cause was bleeding being peptic ulcer. In hospital global mortality was of 10.43%, global rebleeding rate was 12.02%, surgery was performed in 7.66% of patients. Urgent haemostatic surgery was needed in 3.68% of patients with nonvariceal bleeding. The need for surgery correlated with the postendoscopic Rockall score (p=0.0425). In peptic ulcer, the need for surgery was not influenced by time to endoscopy or type of treatment (p=0.1452). Weekend (p=0.996) or night (p=0.5414) admission were not correlated with a higher need for surgery. CONCLUSIONS: Over the last decade, the need for urgent surgery in upper gastrointestinal bleeding has decreased by half, but mortality has remained unchanged. PMID- 23790779 TI - Apoptosis, paraptosis, necrosis, and cell regeneration in posttraumatic cerebral arteries. AB - This study is to understand the nature and functional significance of the activated cell death programs and rehabilitation signs during late vascular changes after brain injury. We used light and transmission electron microscopy to describe changes of cells within the vascular endothelium and tunica media of the cortical arteries four weeks after craniocerebral traumatism. Within tunica media of the posttraumatic damaged artery, apoptotic and paraptotic phenotypes were identified as well as some early ultrastructural signs of smooth muscle cells regeneration, these cell highlighting a remarkable degree of plasticity. Surprisingly, some endothelial cells showed an extensive rough endoplasmic reticulum development, whereas other endothelial cells showed typical necrosis. In conclusion, two groups of suicidal cells apoptotic and paraptotic cells were encountered in the same lesional vascular wall after neurotrauma, showing also signs of cell regeneration. The pathophysiologic significance of the coexisting double cell death programs and cell regeneration seems to be in relation with late cell survival, after arterial damage when some cells disappear and other cells try to survive undergoing reversible injury. PMID- 23790780 TI - Intramedullary hemangioblastoma - local experience of a tertiary clinic. AB - BACKGROUND: Intramedullary hemangioblastomas are rare benign tumors, occurring sporadically or in von Hippel- Lindau disease. METHODS: We describe our local surgical experience with intramedullary hemangioblastomas. Clinical, imaging and surgical data from five consecutive hemangioblastoma cases identified from a series of 59 patients with intramedullary tumors treated between 2003-2009 are reviewed. RESULTS: The mean age of the patients was 39.6 years (range 21- 56). All of them were symptomatic and two patients had von Hippel-Lindau disease with associated posterior fossa hemangioblastomas. All tumors were preoperatively diagnosed as hemangioblastomas based on magnetic resonance findings. All patients underwent surgery with complete removal of the tumor in 4 cases and a partial removal in a case with extension towards the anterior part of the cord. Good neurological outcome was noted in four cases while in the fifth, complicated with a significant intraoperative hemorrhage, a fully reversible aggravation of neurological status occurred. CONCLUSIONS: Spinal cord hemangioblastomas are surgically curable tumors. Microsurgical complete resection is the standard of care and can be performed with good neurological outcome in most of the cases. Ventral tumor location and important intraoperative bleeding are associated with less optimal outcome. PMID- 23790781 TI - Peritoneal fibrinolytic activity and adhesiogenesis. AB - INTRODUCTION: Postoperative adhesions after abdominal or pelvic surgery remain an important clinical problem causing infertility, pain and bowel obstruction. Their prevention and treatment remains poorly understood and inadequate. The formation of adhesions is caused by the organization of a fibrin matrix, an organization that takes place during the coagulation process when there is suppression of fibrinolysis. METHODS: In this study peritoneal tissue and peritoneal fluid from two groups of patients were sampled and analysed. The first group comprised of 12 patients undergoing abdominal surgery for an acute abdomen during which known peritoneal factors of aggression (trauma, chemical, bacterial) were present which are known to increase the propensity for peritoneal adhesion formation. A second group consisting of 6 patients undergoing surgery in the absence of these peritoneal aggression factors acted as a reference control group. Each patient had peritoneal tissue sampled at the time of surgery and analysed for levels of gene expression of tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1). Patients also had peritoneal drain fluid collected postoperatively and analysed for quantities of fibrin degradation products (FDPs) and fibrinogen. RESULTS: The aim of this study was to evaluate the role of PAI-1 and tPA genes at peritoneal tissue level. Peritoneal tissue was obtained during surgery and the variation of expression of PAI-1 and tPA genes was quantified. The obtained results highlighted an increase of expression in PAI-1 gene and decrease of expression in tPA gene in patients with increased factors of peritoneal aggression compared to patients without, indicating a decreased fibrinolytic potential in patients with increased peritoneal adhesion propensity. Increased factors of peritoneal aggression also resulted in increased levels of FDPs and fibrinogen in peritoneal exudates. PMID- 23790782 TI - The use of gastrostomy procedures in HNC patients. AB - PURPOSE: To analyse the gastrostomy procedures performed in HNC patients admitted to Coltea Clinical Hospital in order to underline the similarities and differences to the data published worldwide. PATIENTS AND METHODS: Our retrospective study contains 64 HNC cases that met the inclusion criteria between 2008 and 2011. RESULTS AND DISCUSSIONS: The study group presents numerous specific characteristics (a larger number of cases aged over 55 than younger patients; elective use of classic gastrostomy instead of newer techniques; approximately two thirds of the gastrostomies were performed in patients with laryngeal carcinoma; only one third approximately of the cases benefited from prophylactic gastrostomy; etc.). CONCLUSIONS: 22% of the gastrostomies were made after the appearance of a pharyngocutaneous fistula. Therefore we will begin a future prospective study in order to ascertain the value of prophylactic PEG in preventing the appearance of pharyngocutaneous fistulas. PMID- 23790783 TI - Hysterectomy for benign uterine pathology: comparison between robotic assisted laparoscopy, classic laparoscopy and laparotomy. AB - OBJECTIVE: Hysterectomy is one of the most important surgeries in gynecology and requires a lot of care and skill. In this study we attempt to make a comparison between laparoscopic hysterectomy, robotic assisted hysterectomy and abdominal hysterectomy for treatment of uterine pathology. MATERIALS AND METHODS: We conducted a study comparing 29 patients who were treated by robotic assisted laparoscopic hysterectomy in Cisanello Hospital, Pisa, Italy, 30 patients who were treated by laparoscopy in General Surgery Clinic, Craiova and 30 patients who were treated by abdominal hysterectomy in General Surgery Clinic, Craiova. RESULTS: Comparing the surgeries, it was noticed that the operative time of a robotic assisted interventions is the largest, 183.9 minutes. Even if the duration was greater, the time needed to perform vaginal suture was lower, 17.75 minutes to 22.79 minutes by classic laparoscopic approach. In terms of blood loss we concluded that intraoperative blood loss was lowest during a robotic surgery, 199.3 ml versus 285 ml in the laparoscopic group and 417 ml in the laparotomic group. CONCLUSIONS: Robotic assisted laparoscopic hysterectomy is a feasible method that can be used very successfully to treat patients diagnosed with benign uterine pathology. PMID- 23790784 TI - The assessment of primitive or metastatic malignant pulmonary tumors in children. AB - BACKGROUND: The purpose of our study is to assess primitive and secondary malignant pulmonary tumors in children. The presence of lung tumors in newborns and infants is a point of interest to specialists in pediatric surgery, thoracic surgery and genetics due to the high death rate. The 5-years survival rate communicated by EUROCARE-study is less than 10% for primitive tumors and less than 15% in lung metastases. MATERIALS AND METHOD: We performed a retrospective study which analysed 11 children with pulmonary primary ormetastatic tumors admitted in the Pediatric Surgery Department "Prof. Dr. Al. Pesamosca" of the Emergency Clinical Hospital for Children "Maria Sklodowska Curie",Bucharest. The analysed and operated patients underwent surgery by Prof. Dr. Al. Pesamosca and the authors during the period of 1985-2011. In our series there where 4 primitive lung tumors and 7 secondary ones: 8 underwent surgery and 2 died before being operated on. The incidence of primitive pulmonary lung malignancies is higher for females, 3 to1, and secondary ones are more frequent in males, 6 to 1. RESULTS: Patients with primitive pulmonary malignancies were late diagnosed. Their age ranged between 1 to 6 years;3 were operated on, out of which 2 died, and 1 operated still survives. The 7 patients with secondary pulmonary malignancies were late diagnosed, too, probably as a consequence of a late diagnosis of the origin tumor. CONCLUSIONS: Even if all malignancies require an early diagnosis and treatment, this aim regarding malignant lung tumors is still a desideratum animating all practitioners. Primitive tumors are diagnosed presenting the main clinical manifestation abroncho pulmonary infection. Secondary lung malignancies are usually asymptomatic and are diagnosed when monitoring a patient for a malignancy with another origin. Chemotherapy,radiotherapy and surgery of malignant primitive tumors or metastatic ones in children remain unsatisfactory because of the late diagnosis and the limited methods of treatment. Nowadays genetics identified the responsible oncogenes for pulmonary blastic explosion and better results could be obtained by genetic surgery. PMID- 23790785 TI - Epidemiological features and management of complex neck trauma from an ENT surgeon's perspective. AB - OBJECTIVES: The aim of this study is to present a clear picture of the epidemiological aspects pertaining to the cases of neck trauma addressing to the ENT Emergency Room, as well as to display the complexity of the diagnostic and therapeutic management employed in two important Romanian ENTDepartments - "Sfantul Spiridon" Hospital Iasi and SfantaMaria Hospital Bucharest MATERIAL AND METHODS: We conducted a retrospective study on 538 patients with neck trauma that were referred to the abovementioned ENT Departments between March 2009 - March 2011, selecting 27 cases with forensic implications. RESULTS: In terms of aetiological mechanism, the most frequentneck injuries in our study were penetrating neck injuries due to assault or self-mutilation with white weapons (knives, razor blades, forks, glass) - 56%, followed by blunt trauma cases due to car accident, strangulation or accidental fall - 44%. The most important clinical findings recorded at admission were polytraumas (24.14%), hematomas, fractures, subcutaneous emphysema or skin perforation with visceral damages(representing each 13.8%) and tissue rip (10.34%), important bleedings (6.89%), as well as perforation of neck organs(3.45%). The most frequent postoperative complications were postoperative pharyngo-cutaneous fistula (7.4%) and laryngotrachealstenosis (7.4%). There were also 3 other patients with long-term complications, such as acute mediastinitis (3.4%)recurrential paralysis with Gerhardt's syndrome (3.4%) and dysphagia (3.4%). PMID- 23790786 TI - GST gene variants in synchronous colorectal cancers and synchronous association of colorectal cancers with other cancers. AB - BACKGROUND: the present study evaluates genetic polymorphisms of three glutathione S-transferases (GSTM1, GSTT1and GSTP1) in patients with synchronous malignant colorectal tumors and the association of synchronous colorectal cancers with other cancers. MATERIAL AND METHODS: from 420 patients with a colorectal cancer admitted to our hospital between 2005-2012, we selected for genetic analysis 20 patients with multiple synchronous malignant colorectal tumors and 9 patients with asynchronous association of colorectal cancer with another cancer. We searched for GST genotypes, comparing the results with controls. RESULTS: the genetic analysis was possible only in 19 patients with colorectal synchronous cancers and 9 patients with asynchronous association of colorectal cancer with another cancer; we found a statistically significant difference for null GSTM1 genotype frequency between these patients and the control group; we found no differences regarding the frequency of null GSTT1 genotype and Ile105Val polymorphism of GSTP1 in patients with synchronous cancers compared with the control group. CONCLUSION: in our study we found the null GSTM1 genotype as a risk factor for multiple colorectal synchronous cancers and for an association of synchronous colorectal with other cancers PMID- 23790787 TI - Technical aspects involved in the harvesting and preservation of the pancreas used for pancreatic islet allotransplantation. AB - The pancreas procurement from brain-dead donors used for pancreatic islet isolation and transplantation, was analyzed between 2007-2012. The pancreas was transported to the Fundeni Clinical Institute and the islet isolation process was performed in the Cell Therapy Laboratory. There were 20 en bloc pancreas-duodenum spleen procurement during multiorgan harvesting. Eighteen pancreata were used for islet isolation and two were used for whole pancreas transplantation.One pancreas was used for whole pancreas transplant alone and the other one was used for simultaneous pancreas and kidney transplantation. Donor age ranged between 12 and 61 years, with a median age of 35 years old. The donors were 9 females and 11 males. The causes of death were in 8 cases -brain injury, in 7 cases - aneurism rupture, and in 5 cases stroke. The donors' blood group was A(II) in 11 cases, O(I) in7 cases, and B(III) in 2 cases. The calculated BMI of the donors ranged between 15.6 and 27.8, with a median value of 24.1. The median calculated Vinkers score for our study group was 11. Cold ischemia time ranged between 1.5 and 8 hours,with a median value of 5 hours. PMID- 23790788 TI - Validation of the Romanian translation of the ABC-V (Assessment of Burden in Chronic Venous Disease) questionnaire. AB - The objective of this study was a psychometric evaluation of the Romanian translated version of ABC-V (Assessment of Burden in Chronic - Venous Disease) questionnaire in patients with uncomplicated varicose disease of lower limbs. All components of the questionnaire were translated from the English version into the Romanian language and after that backwards, discussed, adopted and pre-tested. Evaluation of the final version of the translated questionnaire demonstrated acceptable results: missed questions in 3% of forms, no ceiling effect and low floor effect, good split-half reliability (rs = 0.61,p < 0.01) and significant correlation between test and re-tests cores (rs = 0.86, p < 0.01). There was no significant influence of age and sex upon average ABC-V scores. Study results support the application of ABC-V questionnaire for assessing the severity of chronic venous disease as well as for quantitative evaluation of patient satisfaction and health status improvement after varicose vein treatment in the Romanian-speaking population. PMID- 23790789 TI - The importance of early diagnosis of sepsis in severe burned patients: outcomes of 100 patients. AB - BACKGROUND/AIM: The burn-injured patient has a major potential to develop an infection because the wound itself, surgical treatment, mechanical ventilation and blood transfusions may potentially lead to a secondary immunodeficiency syndrome. PATIENTS AND METHODS: A total number of 100 consecutive burn-injured patients with sepsis were treated in the Clinical Emergency Hospital of Plastic Surgery and Burns, Bucharest,between 2009 and 2011. Their clinical and bioumoral data were analyzed. RESULTS: Flame was the main cause of burn injuries in the present series (78%). The mean body surface area burn wound was 49.7%. Most of the patients (97%) experienced the first septic episode within two weeks after burn injury.Sepsis was mainly due to Gram-positive (58%) and Gramnegative(26%) bacteria. Staphylococcus aureus (32%) and Pseudomonas aeruginosa (21%) were the most frequently encountered germs. The susceptibility for Gram-positive bacteria was the best for imipenem/cilastatin, followed byamikacin, ceftriaxone and ciprofloxacin. For Gram-negative bacteria, the susceptibility decreased from ciprofloxacin to imipenem/ cilastatin, amikacin and gentamicin. Mortality rate was 9%. CONCLUSIONS: The extensive knowledge of physiopathology,clinics, epidemiology, bioumoral and microbiology features of the sepsis in burn-injured patients allows an early and precise diagnosis and an adequate and efficient treatment.All these elements have been associated with a significant improvement of the survival rates. Every patient with burn injured sepsis must be treated as a different entity in order to obtain the best results. PMID- 23790790 TI - Chewing stress developed in upper anterior teeth with root end resection. a finite element analysis study. AB - AIM: Because pulpless teeth have a higher risk of vertical root fracture, the present study investigated the additional effect of root end resection upon their mechanical resistence. METHODS: Finite element analysis (FEA) was used to evaluate the stress and deformations of upper anterior teeth after root end resection while loading them at 100N and 300N. RESULTS: Loading teeth with root end resection at 100N generates a mild increase of dentin stress. Even though von Misses stress is within the elastic range the whole toothbone structure is stressed while chewing. At higher load of300N the vertical and mesiodistal deformations cannot beany longer neglected. The highest stress occurs in vertical direction and involves the whole labial surface of the tooth crown. It is expressed as a compression stress (SY = 2.8 x 109N/m2) and comes close to the value of dentine Young's modulus. CONCLUSION: Loading the upper anterior teeth with root end resection at 100N lowers in a mild manner their mechanical resistance. A load of 300 N induces tooth deformations and a risky stress, mostly focused at tooth cervical area. The stress in the alveolar ridge bone is under the risk threshold of Young's modulus. PMID- 23790791 TI - Total necrotizing colitis proximal to obstructive left colon cancer: case report and literature review. AB - BACKGROUND: Necrotizing colitis (NC) is a rare complication of the obstructive cancer of the left colon and it is the result of intramural ischemia due to impairment of blood supply secondary to increased endoluminal pressure. CASE PRESENTATION: A 70 years old patient with significant comorbidities (ASA 4) was admitted for intestinal obstruction.The extensive necrosis of the entire proximal colon secondary to an obstructive sigmoid colon cancer has been diagnosed intraoperatively. Total colectomy and terminal ileostomy have been performed. The postoperative course was uneventful and the ileostomy closure with ileo-rectal anastomosis was performed 7 months later. A review of the literature discussing the epidemiology, pathogenesis, diagnosis and therapeutic approach of this type of colitis, was performed. CONCLUSIONS: NC implies diagnosis and therapeutic difficulties,especially from point of view of surgical strategy. We advocate of large colic resections, beyond the macroscopic limits of the necrosis in order to avoid the postoperative complications. We also consider seriate surgical procedures as a good choice for the high risk patients. PMID- 23790792 TI - Problems of diagnosis and treatment caused by ingested foreign bodies. AB - An ingested foreign body often passes the gastrointestinal tract without any complications. Foreign bodies, such as fish bones, chicken bones and toothpicks, have been known to cause perforation of the gastrointestinal tract. We present 4 cases: the first 2 of a 27-year-old male and a 48-years-old female respectively, with acute abdomen, diffuse purulent peritonitis, with ileum perforation, both caused by accidentally ingesting a wire, 1 case of a 64-year-old male with sigmoid perforation, caused by accidentally ingesting a toothpick and 1 case of a 52-year-old female presented with left buttock painful swelling for 1 week associated with fever,physical examination revealed an ischiorectal abscess.During incision and drainage a 3 cm chicken bone was found inside the abscess cavity. Evolution was favorable in all 4 cases. PMID- 23790793 TI - Associated type IIIB and type IV multiple intestinal atresia in a pediatric patient. AB - Multiple intestinal atresia (MIA) is a complex congenital defect which represents a challenge for the pediatric surgeon,especially in the rare event of encountering type IIIb or apple peel atresia, which has a high mortality rate. The surgeon's aim is to preserve as much bowel length as possible, to avoid postoperative sepsis and to prevent long-term complications such as short bowel syndrome. Access to a good neonatal intensive care unit and to parenteral nutritional support is crucial in the survival of these children. We report a rare case of multiple intestinal atresia associated with an apple peel atresia, which was managed by multiple intestinal resections and anastomosis without the placement of transanastomotic tubes or stomas. PMID- 23790794 TI - Perforation of Meckel's diverticulum by foreign body, a rare complication. AB - Meckel's diverticulum is a congenital disorder that results from an incomplete obliteration of the vitelline duct. Meckel's diverticulum may give rise to bleeding, intestinal obstruction and inflammation; however, its perforation by a foreign body is an extremely rare life-threatening complication. We report ona 37 year-old male presenting symptoms and signs of acute abdomen with an initial suspicion of acute appendicitis.However, the right diagnosis was made only during exploratory laparoscopy when the appendix was found to be normal,whereas Meckel's diverticulum was found to be inflamed and perforated by a chicken bone. The patient was treated successfully with laparoscopic resection of the diverticulum, and had an uncomplicated postoperative course. PMID- 23790795 TI - Abdominal compartment syndrome -- a major complication of large incisional hernia surgery. AB - The incidence of Intraabdominal Hypertension (IAH) and Abdominal Compartment Syndrome (ACS) is underestimated within the surgery of large size parietal abdominal defects, with the maximum transverse diameter above 10 cm, being considered the main risk factor for the development of intra abdominal hypertension, together with ventilatory restraint under 60% and obesity. Intraabdominal hypertension has a prevalence of at least 50% among critical patients and was identified as an independent life-threatening risk factor.However, doctors do not evaluate it properly and do not realize the potential lethal consequences of untreated intraabdominal hypertension. These consequences may be abdominal compartment syndrome, followed by multiple organ dysfunction and even patient death. The paper intends to highlight the importance of the early recognition of this pathology, as a key factor in the correct management of these complications. PMID- 23790796 TI - The MELD score exception for polycystic liver disease. AB - Polycystic Liver Disease (PLD) is a rare progressive disease characterized by increased liver volume due to many cysts, with symptoms related mainly to the size of the liver and the compression on adjacent organs. Most patients who have PLD require no medical or surgical intervention. On the other hand, massive hepatomegaly with severe symptoms which cannot be managed conservatively requires surgical procedures.Liver transplantation (LT) offers the only curative option for the relief of symptoms arising from cyst enlargement and compression of abdominal structures. We presented a rare case of a young man with highly symptomatic isolated PLD due to liver volume - 23,200 cm3, which provokes severe physical and social handicaps and we considered that only total hepatectomy and LT provides a chance of definitive treatment.To our knowledge this is the largest specimen from a PLD patient who was transplanted. PMID- 23790797 TI - Technical features of the robot-assisted trans-axillary thyroidectomy. AB - Numerous minimally invasive techniques for thyroid surgery have been described in recent years. Technical disadvantages have led to low practicability, although these techniques proved to be safe and to deliver good results. The robotic system was developed to overcome the limits of endoscopic surgery.Recently, based on the advantages of this new technology, robot assisted endoscopic surgery was introduced for minimally invasive thyroid surgery as well. Our experience with robot-assisted transaxillary thyroid surgery begins in November 2010 when we have practiced our first unilateral total lobectomy. From November 2010 to March 2012, 50 patients underwent robot assisted endoscopic thyroid surgery using the transaxillary approach. The aim of this study is to present the technical details and particularities of this procedure, based on our experience. PMID- 23790798 TI - Retrospective analysis of prognostic factors associated with response and overall survival by baseline marrow blast percentage in patients with myelodysplastic syndromes treated with decitabine. AB - BACKGROUND: After the World Health Organization (WHO) changed the definition of acute myeloid leukemia (AML) to >= 20% blasts, the International Working Group (IWG) response criteria for myelodysplasia were updated. This retrospective analysis evaluated response to decitabine using updated IWG criteria in patients pooled from 2 decitabine trials. PATIENTS AND METHODS: Outcomes for patients with myelodysplastic syndrome (MDS) with baseline marrow blasts >= 20% and < 30% (RAEB t group) and < 20% (MDS group) were compared. RESULTS: Patients with RAEB-t (n = 26) had a significantly shorter time from diagnosis to study treatment (7.3 vs. 18.3 months), a higher International Prognostic Scoring System (IPSS) risk (77% vs. 16% high-risk patients), and lower median baseline platelet count (62.3 vs. 112.7 * 10(3)/MUL) vs. patients with MDS (n = 157), yet no significant difference in overall response rate (ORR) (15.4% vs. 28.0%). Patients with MDS had better duration of response (9.9 vs. 5 months; P = .024) and overall survival (OS) (16.6 vs. 9.0 months; P = .021) compared with patients with RAEB-t. CONCLUSION: Decitabine is active in and may benefit patients with > 20% blasts (RAEB-t). PMID- 23790799 TI - Homoharringtonine/omacetaxine mepesuccinate: the long and winding road to food and drug administration approval. AB - Homoharringtonine/omacetaxine is a unique agent with a long history of research development. It has been recently approved by the Food and Drug Administration for the treatment of chronic myeloid leukemia after failure of 2 or more tyrosine kinase inhibitors. Research with this agent has spanned over 40 years, with many instructive lessons to cancer research, which are summarized in this review. PMID- 23790801 TI - New roles of cyclin D1. AB - Cyclins encode regulatory subunits of holoenzymes that phosphorylate a variety of cellular substrates. Although the classic role of cyclins in cell cycle progression and tumorigenesis has been well characterized, new functions have been identified, including the induction of cellular migration and invasion, enhancement of angiogenesis, inhibition of mitochondrial metabolism, regulation of transcription factor signaling via a DNA-bound form, the induction of chromosomal instability, enhancement of DNA damage sensing and DNA damage repair, and feedback governing expression of the noncoding genome. This review describes the mechanisms of these new functions of cyclin D1. PMID- 23790802 TI - Lin28 promotes growth of prostate cancer cells and activates the androgen receptor. AB - Prostate cancer (CaP) progresses to a castration-resistant state assisted by multifold molecular changes, most of which involve activation of the androgen receptor (AR). Having previously demonstrated the importance of the Lin28/let 7/Myc axis in CaP, we tested the hypothesis that Lin28 is overexpressed in CaP and that it activates AR and promotes growth of CaP cells. We analyzed human clinical CaP samples for the expression of Lin28 by quantitative real-time RT PCR, Western blot analysis, and IHC. Growth characteristics of CaP cell lines transiently and stably expressing Lin28 were examined. The clonogenic ability of CaP cells expressing Lin28 was determined by colony formation and soft agar assays. Increase in expression of AR and subsequent increase in transcription of AR-target genes were analyzed by quantitative real-time RT-PCR, luciferase assays, and ELISA. LNCaP cells stably expressing Lin28 were injected into nude mice, and tumorigenesis was monitored. We found that Lin28 is overexpressed in clinical CaP compared to benign prostates. Overexpression of Lin28 enhanced, while down-regulation reduced, growth of CaP cells. Lin28 enhanced the ability of CaP cells to form colonies in anchorage-dependent and anchorage-independent conditions. LNCaP cells stably expressing Lin28 exhibited significantly higher tumorigenic ability in vivo. Lin28 induced expression of the AR and its target genes such as PSA and NKX3.1. Collectively, our findings demonstrate a novel role for Lin28 in CaP development and activation of the AR axis. PMID- 23790803 TI - Relationship between blood manganese levels and children's attention, cognition, behavior, and academic performance--a nationwide cross-sectional study. AB - Manganese (Mn) is neurotoxic at high concentrations. However, Mn is an essential element that can protect against oxidative damage; thus, extremely low levels of Mn might be harmful. Our aim was to examine whether either high or low environmental Mn exposure is related to academic and attention function development among school-aged children. This cross-sectional study included 1089 children 8-11 years of age living in five representative areas in South Korea. Blood Mn, blood lead, and urine cotinine were measured. We assessed IQ with the Wechsler Abbreviated Scale of Intelligence; attention with a computerized continuous performance test called the Attention-deficit/hyperactivity disorder (ADHD) Diagnostic System (ADS), the Korean version of the Stroop Color-Word Test, the Children's Color Trails Test (CCTT), and the ADHD Rating Scale; academic functions with the Learning Disability Evaluation Scale (LDES); and emotional and behavioral problems with the Korean version of the Child Behavior Checklist (CBCL). We further assessed the presence of ADHD using a highly structured diagnostic interview, the Diagnostic Interview Schedule for Children Version IV (DISC-IV). The median blood concentration of Mn was 14.14 ug/L. We observed a nonlinear association between the CCTT2 completion time and the CPT commission error (F=3.14, p=0.03 and F=4.05, p=0.01, respectively). We divided the data into three groups: lower (<8.154 ug/L), and upper 5th percentile (>21.453 ug/L) and middle 90th percentile to determine whether a lack or overload of Mn could cause adverse effects. After adjusting for urine cotinine, blood lead, children's IQ, and other potential confounders, the high Mn group showed lower scores in thinking (B=-0.83, p=0.006), reading (B=-0.93, p=0.004), calculations (B=-0.72, p=0.005), and LQ (B=-4.06, p=0.006) in the LDES and a higher commission error in the CPT (B=8.02, p=0.048). The low Mn group showed lower color scores in the Stroop test (B=-3.24, p=0.040). We found that excess Mn in children is associated with lower scores of thinking, reading, calculation, and LQ in the LDES and higher scores of commission error in the ADS test. In contrast, lower Mn in children is associated with lower color scores in the Stroop test. The findings of this cross-sectional study suggest that excess exposure or deficiency of Mn can cause harmful effects in children. PMID- 23790804 TI - Effects of the hospital-based palliative care team on the care for cancer patients: an evaluation study. AB - BACKGROUND: The hospital-based palliative care team model has been implemented in most Western countries, but this model is new in Taiwan and there is little research to evaluate its outcomes. OBJECTIVES: The purpose of this study was to evaluate the effects of the hospital-based palliative care team on the care for cancer patients. DESIGN: The design was a quasi-experimental study with a pretest posttest design. SETTING: A medical center, National Taiwan University Hospital in Taipei, Taiwan. PARTICIPANTS: Cancer patients were excluded after the hospital based palliative care team visited if they were unable to give informed consent, were not well enough to finish the baseline assessment, were likely to die within 24h or would be discharged within 24h, or could not communicate in Mandarin or Taiwanese. A sample of 60 patients who consulted the hospital-based palliative care team was recruited. METHODS: Patients recruited to the study were divided to receive the usual care only (control group, n=30) or the usual care plus visits from the hospital-based palliative care team (intervention group, n=30). Data were collected using questionnaires including the Symptom Distress Scale, Hospital Anxiety and Depression Scale, Spiritual Well-Being Scale, and Social Support Scale at the initial assessment and one week later. RESULTS: Comparison between groups revealed that the degree change for edema, fatigue, dry mouth, abdominal distention, and spiritual well-being in the intervention group showed significant improvement compared to the control group (p<0.05). However, there was no difference between groups on measures of anxiety, depression and feeling of social support. Within group analysis showed patients' pain score, dyspnea, and dysphagia improved in both groups (p<0.05). In addition, the average degree of constipation and insomnia in the control group declined from baseline (p<0.05), while the degree of edema, fatigue, dry mouth, appetite loss, abdominal distention, and dizziness decreased significantly in the intervention group (p<0.05). CONCLUSION: The findings indicated the hospital-based palliative care team can improve the care for patients in relation to symptom management and spiritual well-being. The hospital-based palliative care team is a good care model for patients and worth implementing in clinical practice in Taiwan. The results also provide a general understanding about how the hospital-based palliative care team works in Taiwanese culture. PMID- 23790805 TI - Self-rated health and its determinants in Japan and South Korea. AB - OBJECTIVE: To compare self-rated health and its determinants between Japanese and South Koreans. STUDY DESIGN: A cross-sectional study was conducted on 2496 and 1576 adults (aged >=20 years) in Japan and Korea, respectively, who completed the 2010 East Asian Social Survey. METHODS: Ordinal logistic regression was conducted to identify significant factors for self-rated health in the two nations. RESULTS: Japan has a lower level, and a smaller variance, of self-rated health than Korea. This study confirmed traditional results by finding that socio economic status, daily activity and physical exercise had positive effects on self-rated health; and chronic disease, overweight/obesity and smoking had negative effects on self-rated health. In addition, this study found that: middle aged (40s/50s) Japanese have lower self-rated health than younger (20s/30s) Japanese; living with a spouse has a negative impact on self-related health in both Japanese and Koreans in their 20s/30s; and mental factors (i.e. happiness, hopelessness and mental health problems) have a greater impact on self-rated health in Japanese than in Koreans, whereas the reverse is true for physical health problems. DISCUSSION: This study found that many health dynamics depend on the unique context of each nation. Moreover, this study may help to inform the direction of future research on self-rated health and its determinants in other Asian nations. PMID- 23790806 TI - Handwashing behaviour among Chinese adults: a cross-sectional study in five provinces. AB - OBJECTIVES: To describe the patterns of handwashing behaviour among Chinese adults, and assess their associations with sociodemographic factors and knowledge of hand hygiene. STUDY DESIGN: A representative sample (n = 6159) of Chinese adults aged 18-60 years in five provinces was attained by multiple-stage, stratified sampling mainly based on geographical location and economic status. Data on handwashing behaviour, knowledge of hand hygiene and sociodemographic factors were collected through self-administrated questionnaires. METHODS: Associations between handwashing behaviour and sociodemographic factors were tested in logistic models. Path analysis was applied to examine the associations between sociodemographic factors, knowledge of hand hygiene and proper handwashing behaviour in order to evaluate the relative magnitude of these determinants and internal relationships. RESULTS: This study found that 52.7% (rural vs urban: 44.6% vs 56.8%) and 67.3% (rural vs urban: 59.7% vs 71.1%) of Chinese adults reported they always washed hands before eating and after defaecation, and 30.0% (rural vs urban: 25.1% vs 32.8%) of adults always used soap or other sanitizers during washing. Using the criteria of 'always or very often washing hands with soap before eating and after defaecation without sharing a towel with family members after washing', only 47.2% (rural vs urban: 23.8% vs 59.1%) of the adults were graded to practice proper handwashing behaviour. Urban area, high level of education level, high level of knowledge about diseases, female gender and older age were protective factors for good hand hygiene; of these, area was found to be associated most strongly with handwashing behaviour. CONCLUSIONS: Adherence to an appropriate handwashing method and duration of handwashing are critical problems among Chinese adults. Area difference, level of education and level of knowledge of hand hygiene were most strongly associated with handwashing behaviour, and should be targeted in future health education. PMID- 23790807 TI - Endoscope-assisted conservative condylectomy in the treatment of condylar osteochondroma through an intraoral approach. AB - Mandibular condylar osteochondroma (OC) can result in morphological and functional disturbances, including facial asymmetry and temporomandibular joint (TMJ) dysfunction. The aim of this study was to explore the feasibility of endoscope-assisted tumour resection and conservative condylectomy via an intraoral approach. Seven patients with condylar OC were enrolled in this study. Endoscope-assisted tumour resection and conservative condylectomy were achieved intraorally, and no conventional extraoral incision was needed. Direct vision of the magnified and illuminated operative field was realized with the assistance of an endoscope. No facial nerve injury or salivary fistula occurred in any patient. Stable occlusion was realized through postoperative orthodontic treatment. The patients showed no signs of tumour recurrence or TMJ ankylosis during follow-up (range 18-43 months). Endoscope-assisted condylar OC resection and conservative condylectomy via intraoral approach offers great advantages with no significant complications compared with conventional extraoral incisions. The endoscope provides us with a valuable treatment option for this potentially complicated procedure. PMID- 23790808 TI - Cervical necrotizing fasciitis and diabetic ketoacidosis: literature review and case report. AB - Necrotizing fasciitis (NF) is a rare polymicrobial infection that can be life threatening. It is a rapidly progressive inflammatory process affecting the deep fascia, with secondary necrosis of the subcutaneous tissue. It is characterized by its fulminant course and its high mortality rate. Most cases of NF affect the abdomen, groin, and extremities. NF in the neck is reported to be rare and most cases are odontogenic in origin. Misdiagnosis and delayed treatment can result in death from sepsis, mediastinitis, carotid artery erosion, jugular vein thrombophlebitis, or aspiration pneumonia. The diagnosis is based on a combination of clinical history and predisposing factors, Gram staining and culture, imaging, and surgical exploration. Early and aggressive surgical treatment and intensive medical care are essential. The aim of this article is to report a case of severe and extensive cervical NF worsened by a diabetic ketoacidosis as a first appearance of diabetes mellitus. PMID- 23790809 TI - [Iatrogenic dissection of the esophageal mucous membrane due to attempted dilatation of esophageal pemphigoid]. PMID- 23790810 TI - [Management of acute lower gastrointestinal hemorrhage: position statement of the Catalan Society of Gastroenterology]. PMID- 23790811 TI - Maintenance transcranial magnetic stimulation reduces depression relapse: a propensity-adjusted analysis. AB - BACKGROUND: The effectiveness of repetitive transcranial magnetic stimulation (TMS) is well established while studies of maintenance TMS are lacking. We aim here to determine whether maintenance is associated to a decrease in the relapse rate of depression, following successful acute treatment. METHODS: We enrolled 59 consecutive patients with pharmacoresistant depression who have responded (>50% decrease in symptom severity) up to 6 weeks of acute TMS treatment. These patients received either 20 weeks of maintenance TMS (n=37) or no additional TMS treatment (n=22). We performed propensity adjusted-analysis to examine the association between the relapse rate over this 20-week period and maintenance TMS. Propensity analysis eliminated differences in baseline characteristics between patient with and without maintenance TMS and approximated the conditions of random site-of-treatment assignment. RESULTS: At 20 weeks, relapse rate was significantly different between the two groups (p=0.004, propensity analysis): 14 patients in the maintenance TMS group (37.8%) vs. 18 in the non-maintenance TMS group (81.8%), with an adjusted Hazard Ratio (HR)=0.288 (0.124-0.669). CONCLUSIONS: Maintenance TMS was associated with a significantly lower relapse rate in patients with pharmacoresistant depression in routine practice among responders. PMID- 23790812 TI - Parenting behavior and the Interpersonal-Psychological Theory of Suicide: a mediated moderation analysis with adolescents. AB - BACKGROUND: Multiple features of parenting have been associated with development of suicide-related behaviors in adolescents. However, findings are inconsistent on which aspects of parenting are protective or harmful and why. This investigation sought to reconcile these discrepancies through the Interpersonal Psychological Theory of Suicide (IPTS), which argues that suicide ideation and the capability to attempt suicide are etiologically distinct. METHODS: Responses of 200 Midwestern public school students to the Profiles of Student Life: Attitudes and Behavior survey were analyzed using mediated moderation analysis. RESULTS: Participant sex significantly moderated the relationships between parenting variables and suicide attempts and these relationships were accounted for by IPTS variables. Specifically, the effect of parental support on suicide attempts was twice as strong for girls. Self-esteem mediated this interaction (b= .011, SE(boot)=.008, p<.05, kappa(2)=.07). Conversely, the effect of parental boundaries on suicide attempts was significant for boys, but not for girls, and was mediated by exposure to violence (b=.029, SE(boot)=.021, p<.05, kappa(2)=.07). LIMITATIONS: This study involved retrospective report with proxy measures of IPTS constructs. Future research should consider multiple informants and additional measures. CONCLUSION: Findings highlight potential mechanisms by which parenting behaviors could influence sex differences in adolescent suicide relate behaviors, and that some parenting behavior is associated with reduced adolescent suicide attempts. Findings also suggest the IPTS is able to account for previously identified inconsistencies in the effects of parenting behaviors on adolescent suicide-related behaviors. Implications for theory and intervention are discussed. PMID- 23790813 TI - Development and validation of prediction algorithms for major depressive episode in the general population. AB - BACKGROUND: To develop and validate sex specific prediction algorithms for 4-year risk of major depressive episode (MDE) using data from a population-based longitudinal cohort. METHODS: Household residents from 10 provinces were randomly recruited and interviewed by Statistics Canada. 10,601 participants who were aged 18 years and older and who did not meet the criteria for MDE in the 12 months prior to a baseline interview in 2000/01 were included in algorithm development; data from 7902 participants who were aged 18 and older and who were free of MDE in 2004/05 were used for validation. Validation was also conducted in sub populations that are of practice and policy importance. MDE was assessed using the World Health Organization's Composite International Diagnostic Interview(CIDI)-Short Form for Major Depression (CIDI-SFMD). RESULTS: In the training data, the C statistics for algorithms in men was 0.7953 and was 0.7667 for algorithm in women. The algorithms had good predictive power and calibrated well in the development and validation data. LIMITATIONS: The data relied on self report. MDE was assessed with CIDI-SFMD. It was not feasible to validate the algorithms in different populations from different countries. CONCLUSIONS: More studies are needed to further validate and refine these algorithms. However, the ability of a small number of easily assessed variables to predict MDE risk indicates that algorithms are a promising strategy for identifying individuals in need of enhanced monitoring and preventive interventions. Ultimately, application of algorithms may lead to increased personalization of treatment, and better clinical outcomes. PMID- 23790814 TI - Depression knowledge in high school students: effectiveness of the adolescent depression awareness program. AB - BACKGROUND: Major depression is a common disorder among teenagers and is associated with significant morbidity and mortality. Suicide is the third leading cause of death among 15-24 year olds. Early identification and treatment is essential to prevent suicide. Depression education is a potential intervention for improving knowledge about depression and help-seeking behavior. METHODS: The Adolescent Depression Awareness Program (ADAP) is a school-based depression education intervention with a core message that depression is a treatable medical illness. 710 high school students from six schools in Tulsa, OK participated in the study comparing changes in knowledge about depression and attitudes toward treatment-seeking between students receiving the intervention and those who did not. Changes in depression knowledge and attitude toward help-seeking were measured using the ADAP Depression Knowledge Questionnaire (ADKQ). RESULTS: There was a significant positive change in ADKQ score for students receiving the intervention but not in the control group. The intervention group also demonstrated a significant difference in willingness to "tell someone" if concerned about depression in a peer, which was not present in the control group. LIMITATIONS: The students were not randomized to the intervention and control groups. The ADKQ evaluates attitudes about help-seeking but not behavior. CONCLUSIONS: A school-based educational intervention improved knowledge about depression and attitudes toward help-seeking in adolescents. Future studies should investigate if such change in knowledge results in help-seeking behaviors. PMID- 23790815 TI - An everyday activity as a treatment for depression: the benefits of expressive writing for people diagnosed with major depressive disorder. AB - BACKGROUND: The benefits of expressive writing have been well documented among several populations, but particularly among those who report feelings of dysphoria. It is not known, however, if those diagnosed with Major Depressive Disorder (MDD) would also benefit from expressive writing. METHODS: Forty people diagnosed with current MDD by the Structured Clinical Interview for DSM-IV participated in the study. On day 1 of testing, participants completed a series of questionnaires and cognitive tasks. Participants were then randomly assigned to either an expressive writing condition in which they wrote for 20 min over three consecutive days about their deepest thoughts and feelings surrounding an emotional event (n=20), or to a control condition (n=20) in which they wrote about non-emotional daily events each day. On day 5 of testing, participants completed another series of questionnaires and cognitive measures. These measures were repeated again 4 weeks later. RESULTS: People diagnosed with MDD in the expressive writing condition showed significant decreases in depression scores (Beck Depression Inventory and Patient Health Questionnaire-9 scores) immediately after the experimental manipulation (Day 5). These benefits persisted at the 4 week follow-up. LIMITATIONS: Self-selected sample. CONCLUSIONS: This is the first study to demonstrate the efficacy of expressive writing among people formally diagnosed with current MDD. These data suggest that expressive writing may be a useful supplement to existing interventions for depression. PMID- 23790816 TI - Dr. Herman Kabat: neuroscience in translation ... from bench to bedside. PMID- 23790817 TI - Organization of physical and rehabilitation medicine in Italy: new ways toward developing our specialty. PMID- 23790818 TI - Commentary on organization of physical and rehabilitation medicine in Italy. PMID- 23790819 TI - Considerations for initiating and progressing running programs in obese individuals. AB - Running has rapidly increased in popularity and elicits numerous health benefits, including weight loss. At present, no practical guidelines are available for obese persons who wish to start a running program. This article is a narrative review of the emerging evidence of the musculoskeletal factors to consider in obese patients who wish to initiate a running program and increase its intensity. Main program goals should include gradual weight loss, avoidance of injury, and enjoyment of the exercise. Pre-emptive strengthening exercises can improve the strength of the foot and ankle, hip abductor, quadriceps, and trunk to help support the joints bearing the loads before starting a running program. Depending on the presence of comorbid joint pain, nonimpact exercise or walking (on a flat surface, on an incline, and at high intensity) can be used to initiate the program. For progression to running, intensity or mileage increases should be slow and consistent to prevent musculoskeletal injury. A stepwise transition to running at a rate not exceeding 5%-10% of weekly mileage or duration is reasonable for this population. Intermittent walk-jog programs are also attractive for persons who are not able to sustain running for a long period. Musculoskeletal pain should neither carry over to the next day nor be increased the day after exercising. Rest days in between running sessions may help prevent overuse injury. Patients who have undergone bariatric surgery and are now lean can also run, but special foci such as hydration and energy replacement must be considered. In summary, obese persons can run for exercise, provided they follow conservative transitions and progression, schedule rest days, and heed onset of pain symptoms. PMID- 23790820 TI - Interpreting "null" results. PMID- 23790821 TI - Corticosteroid choice for epidural injections. PMID- 23790822 TI - Bilateral ulnar neuropathy at the elbow secondary to neuropathic arthropathy associated with syringomyelia. AB - Neuropathic arthropathy (NA), also known as Charcot joint, refers to a chronic progressive degenerative arthritis that is associated with an underlying central or peripheral neurologic disorder. The elbow is rarely reported to be involved in NA, but when affected, it is commonly a result of a cervical syrinx or tabes dorsalis. Few reports in the literature describe ulnar neuropathy at the elbow (UNE) associated with NA of the elbow, and none describe bilateral UNE in association with a cervicothoracic syrinx. We present a unique case of bilateral UNE resulting from NA of the elbow associated with a cervicothoracic syrinx. PMID- 23790823 TI - Cauda equina syndrome resulting from lumbar arachnoiditis after intracranial subarachnoid hemorrhage: a case report. AB - Spinal arachnoiditis is a known but very rare late complication of subarachnoid hemorrhage (SAH). Since 1943, 17 cases of spinal arachnoiditis after intracranial hemorrhage have been reported internationally. The vast majority of these cases were related to aneurysmal SAH. All previously published cases have involved spinal arachnoiditis at the cervical and thoracic levels. In this report, we present an adult woman with lumbar spinal arachnoiditis causing cauda equina syndrome as a result of posterior circulation aneurysmal SAH. We believe this is the first reported case of this specific condition causing cauda equina syndrome. PMID- 23790824 TI - An atypical inverted reflex. PMID- 23790825 TI - Lower limb muscle volumes in bilateral spastic cerebral palsy. AB - AIM: Muscle weakness is a feature of individuals with spastic cerebral palsy (SCP) but there are few reports in the literature of muscle volume in this group. This study compares muscle volumes in adolescents and young adults with SCP with those of their typically developing (TD) peers. DESIGN: Measurements of the volumes of nine major lower limb muscles in 19 independently ambulant subjects with SCP (mean age 14.2 years (sd 2.7), 11 male, GMFCS I (n=5); GMFCS II (n=14)), 19 TD subjects (mean age 16.5 years (sd 3.0), 11 male) were made using magnetic resonance imaging. RESULTS: Lower limb muscles were smaller in the SCP group (p<=0.023 in all muscles) than the TD group with the exception of the vastii (lateralis+intermedius; p=0.868) and gluteus maximus (p=0.056). Average muscle volume deficit was 27.9%. Muscle volume deficits were significantly greater for distal muscles than proximal muscles (p<0.001). CONCLUSIONS: Reduced muscle size in adolescence and the natural history of sarcopenia in adulthood may contribute to the early loss of mobility of adults with SCP. PMID- 23790826 TI - Proton radiation therapy for pediatric medulloblastoma and supratentorial primitive neuroectodermal tumors: outcomes for very young children treated with upfront chemotherapy. AB - PURPOSE: To report the early outcomes for very young children with medulloblastoma or supratentorial primitive neuroectodermal tumor (SPNET) treated with upfront chemotherapy followed by 3-dimensional proton radiation therapy (3D CPT). METHODS AND MATERIALS: All patients aged <60 months with medulloblastoma or SPNET treated with chemotherapy before 3D-CPT from 2002 to 2010 at our institution were included. All patients underwent maximal surgical resection, chemotherapy, and adjuvant 3D-CPT with either craniospinal irradiation followed by involved-field radiation therapy or involved-field radiation therapy alone. RESULTS: Fifteen patients (median age at diagnosis, 35 months) were treated with high-dose chemotherapy and 3D-CPT. Twelve of 15 patients had medulloblastoma; 3 of 15 patients had SPNET. Median time from surgery to initiation of radiation was 219 days. Median craniospinal irradiation dose was 21.6 Gy (relative biologic effectiveness); median boost dose was 54.0 Gy (relative biologic effectiveness). At a median of 39 months from completion of radiation, 1 of 15 was deceased after a local failure, 1 of 15 had died from a non-disease-related cause, and the remaining 13 of 15 patients were alive without evidence of disease recurrence. Ototoxicity and endocrinopathies were the most common long-term toxicities, with 2 of 15 children requiring hearing aids and 3 of 15 requiring exogenous hormones. CONCLUSIONS: Proton radiation after chemotherapy resulted in good disease outcomes for a small cohort of very young patients with medulloblastoma and SPNET. Longer follow-up and larger numbers of patients are needed to assess long term outcomes and late toxicity. PMID- 23790827 TI - Evaluation of food chain transfer of the antibiotic oxytetracycline and human risk assessment. AB - There has been recent concern regarding the possibility of antibiotics entering the aquatic food chain and impacting human consumers. This work reports experimental results of the bioconcentration of the antibiotic oxytetracycline (OTC) by the Asian watermeal plant (Wolffia globosa Hartog & Plas) and bioaccumulation of OTC in watermeal and water by the seven-striped carp (Probarbus jullieni). They show, for the first time, the extent to which OTC is able to transfer from water to plant to fish and enter the food chain. The mean bioconcentration factor (dry weight basis) with watermeal was 1.28 * 10(3) L kg( 1). Separate experiments were undertaken to characterize accumulation of OTC by carp from water and watermeal. These showed the latter pathway to be dominant under the conditions employed. The bioconcentration and biomagnification factors for these processes were 1.75 L kg(-1) and 2 * 10(-4) kg g(-1) respectively. Using an aqueous concentration range of 0.34-3.0 MUg L(-1), hazard quotients for human consumption of contaminated fish of 1.3 * 10(-2) to 1.15 * 10(-1) were derived. PMID- 23790828 TI - Genotoxic effects of Bismuth (III) oxide nanoparticles by Allium and Comet assay. AB - Genotoxic effects of Bismuth (III) oxide nanoparticles (BONPs) were investigated on the root cells of Allium cepa by Allium and Comet assay. A. cepa roots were treated with the aqueous dispersions of BONPs at five different concentrations (12.5, 25, 50, 75, and 100ppm) for 4h. Exposure of BONPs significantly increased mitotic index (MI) except 12.5ppm, total chromosomal aberrations (CAs) in Allium test. While stickiness chromosome laggards, disturbed anaphase-telophase and anaphase bridges were observed in anaphase-telophase cells, pro-metaphase and c metaphase in other cells. A significant increase in DNA damage was also observed at all concentrations of BONPs except 12.5ppm by Comet assay. The results were also analyzed statistically by using SPSS for Windows; Duncan's multiple range test was performed. These results indicate that BONPs exhibit genotoxic activity in A. cepa root meristematic cells. PMID- 23790829 TI - Toxicological characterization of the landfill leachate prior/after chemical and electrochemical treatment: a study on human and plant cells. AB - In this research, toxicological safety of two newly developed methods for the treatment of landfill leachate from the Piskornica (Croatia) sanitary landfill was investigated. Chemical treatment procedure combined chemical precipitation with CaO followed by coagulation with ferric chloride and final adsorption by clinoptilolite. Electrochemical treatment approach included pretreatment with ozone followed by electrooxidation/electrocoagulation and final polishing by microwave irradiation. Cell viability of untreated/treated landfill leachate was examined using fluorescence microscopy. Cytotoxic effect of the original leachate was obtained for both exposure periods (4 and 24 h) while treated samples showed no cytotoxic effect even after prolonged exposure time. The potential DNA damage of the untreated/treated landfill leachate was evaluated by the comet assay and cytokinesis-block micronucleus (CBMN) assay using either human or plant cells. The original leachate exhibited significantly higher comet assay parameters compared to negative control after 24 h exposure. On the contrary, there was no significant difference between negative control and chemically/electrochemically treated leachate for any of the parameters tested. There was also no significant increase in either CBMN assay parameter compared to the negative control following the exposure of the lymphocytes to the chemically or electrochemically treated landfill leachate for both exposure periods while the original sample showed significantly higher number of micronuclei, nucleoplasmic bridges and nuclear buds for both exposure times. Results suggest that both methods are suitable for the treatment of such complex waste effluent due to high removal efficiency of all measured parameters and toxicological safety of the treated effluent. PMID- 23790830 TI - Photodynamic effects of 31 different phthalocyanines on a human keratinocyte cell line. AB - Phthalocyanines (Pcs, colored macromolecular compounds with the ability to generate singlet oxygen) represent a promising group of photosensitizers due to their intense absorption in the red and UV portion of the spectrum which leads to their excitation. In order to characterize possible toxic effects associated with eventual practical use and application of these chemicals, we employed an in vitro cell culture model to evaluate cytotoxic effects of 31 different phthalocyanines using neutral red uptake assay. An immortalized human keratinocyte cell line HaCaT was exposed to the tested chemicals for 2 or 24h, either with or without illumination in the last 60 min of the exposure period. After 2- or 24-h exposure without illumination, no cytotoxic effects or weak cytotoxic effects were induced by any Pc under the study and EC50 values could not be obtained within the tested concentration ranges (1.25-20 mg L(-1) or 0.625 10 mg L(-1)). On the other hand, exposure to phthalocyanines under illumination induced a significant cytotoxic effect. The most pronounced cytotoxicity was elicited by Pcs previously shown to have high positive charge densities at peripheral parts of substituent groups, which is most likely the factor responsible for the binding of Pc to negatively charged membranes on the cell surface and thus guaranteeing the tight connection necessary for the singlet oxygen attack on the cell surface. PMID- 23790831 TI - Synthesis and application of a new functionalized resin for use in an on-line, solid phase extraction system for the determination of trace elements in waters and reference cereal materials by flame atomic absorption spectrometry. AB - The synthesis and characterization of the resin Amberlite XAD-4 functionalized with 2,6-pyridinedicarboxaldehyde and its application in an on-line system for the preconcentration of cadmium, cobalt, copper, lead and manganese prior to determination using flame atomic absorption spectrometry (FAAS) is proposed. Metal ions retained on the modified resin were eluted using 1.0 mol L(-1) HNO3 solution and aspirated directly to the nebulizer-burner system of a FAAS instrument using a flow injection system. Detection limits (3sigma) were determined to be 0.13 MUg L(-1) for Cd, 0.29 MUg L(-1) for Cu, 0.23 MUg L(-1) for Mn, 0.58 MUg L(-1) for Co and 2.19 MUg L(-1) for Pb using a 10 mL of water sample loading volume. The limits of detection would be 100 times higher with units of MUg kg(-1) for the solid samples in which their dilution ratios as (volume/weight) were 100. Enrichment factors ranged from 23.6 to 28.9 (for Co and Mn, respectively). The proposed method was successfully applied to determination of the analytes in natural water samples and certified reference materials. PMID- 23790832 TI - Oxidation desensitizes actomyosin to magnesium pyrophosphate-induced dissociation. AB - This study aimed to establish the influence of protein oxidation on the ability of magnesium pyrophosphate (PP) to dissociate actomyosin. Actomyosin isolated from pork muscle then suspended in 0.1M NaCl at pH 6.2 was oxidatively stressed with 10 MUM FeCl3/0.1mM ascorbate/1mM H2O2 for 6 or 12h at 4 degrees C. Protein oxidation was evidenced by the loss of myosin and actin, the concomitant formation of disulphide-cross-linked polymers, and elevated myosin ATPase activity. The intrinsic viscosity of oxidized actomyosin had a weaker response to PP-Mg(2+) than that of non-oxidized actomyosin, indicating the suppression of actomyosin dissociation. Moreover, oxidized actomyosin solutions were devoid of small particles (<10nm) and the stressed actomyosin exhibited weaker binding of PP-Mg(2+) than non-oxidized, which further suggested a reduced myosin-PP interaction and subsequent dissociation of the actomyosin complexes. PMID- 23790833 TI - Synergistic cytotoxicity induced by alpha-solanine and alpha-chaconine. AB - alpha-Solanine and alpha-chaconine are well-known potato toxins, but the mechanism of the synergistic cytotoxic effect of these alkaloids has been little clarified. This study confirmed their synergistic cytotoxic effects on C6 rat glioma cells by three different cell viability tests, namely WST-1 (water-soluble tetrazolium) assay sensitive to intracellular NADH concentration, menadione catalysed chemiluminescent assay depending on both NAD(P)H concentration and NAD(P)H:quinone reductase activity, and LDH (lactate dehydrogenase) assay sensitive to the release of LDH from damaged cells. The maximum cytotoxic effect was observed at a ratio of 1:1 between alpha-solanine and alpha-chaconine at micromolar concentrations. The cytotoxic effects of these alkaloids were observed immediately after incubation and were constant after 30min, suggesting that rapid damage of plasma membrane causes the lethal disorder of metabolism. PMID- 23790834 TI - Changes in actomyosin dissociation and endogenous enzyme activities during heating and their relationship with duck meat tenderness. AB - The objectives of this study, were to examine the relationship between duck meat tenderness, actomyosin dissociation and endogenous enzyme activities when heating the duck breast muscle, to the internal temperature of 30, 40, 50, 60, 70, 80, 90 degrees C. The shear force increased in the temperature range of 30-50 degrees C and 70-90 degrees C and decreased from 50 to 70 degrees C, which was negatively related with liberated actin (P<0.05). The activity of cathepsin B and L was stable while heating the meat to a temperature below 50 degrees C, then it decreased rapidly with temperature increase. The calpain activity kept decreasing with the temperature increase. There was no significant change in the cathepsin D activity below 70 degrees C but it declined rapidly thereafter, and its activity was strongly correlated with actomyosin dissociation (P<0.05). The results suggest that actomyosin dissociation and cathepsin D, could contribute to the tenderness of duck meat during the cooking process. PMID- 23790835 TI - Metals and other elements in tissues of wild fish from fish farms and comparison with farmed species in sites with oxic and anoxic sediments. AB - Farmed fish and wild fish aggregating in the vicinity of four Mediterranean fish farms with different environmental conditions were sampled. Levels of metals (including As and Se) were measured in the muscle, liver, gills, bone and intestine. The wild fish from sites with anoxic substrata accumulate metals (including As and Se) from the ambient habitat in their gills whereas those from sites with oxic substrata concentrate these elements through their diet in their intestine. Tissues of wild fish aggregating around farm cages accumulate a greater number of these elements and with higher concentrations than farmed fish. Habitat, diet, ecological needs, fat content of fish, and protein expression may play an important role in these element differences between fish species. Fe in flathead grey mullet, As in surmullet, rainbow wrasse, grey gurnard and picarel and Hg in bogue may pose a risk for human health. Farmed and wild fish are good sources of P, K, Cr and Se while flathead grey mullet, picarel and comber are excellent sources of Ca and Se. PMID- 23790836 TI - Robust size control of bovine serum albumin (BSA) nanoparticles by intermittent addition of a desolvating agent and the particle formation mechanism. AB - In polymeric nanoparticle preparation, despite similar conditions, large fluctuations in particle size distributions are usually observed. Herein, we demonstrate that the intermittent addition of a desolvating agent can improve reproducibility in the preparation of polymeric bovine serum albumin (BSA) nanoparticles. Using this modification, BSA nanoparticles of controlled size can be manufactured with narrow particle size distributions. In our study, ethanol as a desolvating agent was added intermittently to 1% BSA solutions at different pHs with stirring at 700rpm. The effect of the preparation parameters on size and optical density of the fabricated nanoparticles were studied. The average particles sizes of BSA nanoparticles prepared at pH values of 6, 7 and 9 were approximately 100, 200 and 300nm, respectively. As ethanol addition increased, desolvation of BSA molecules resulted in formation of loose-structured particles with pH-dependent size. Beyond that, only particle density increased, but size remained unchanged with further addition of ethanol. Consistently uniform particle size distribution was achieved by adding ethanol intermittently. PMID- 23790837 TI - Comparative study of denaturation of whey protein isolate (WPI) in convective air drying and isothermal heat treatment processes. AB - The extent and nature of denaturation of whey protein isolate (WPI) in convective air drying environments was measured and analysed using single droplet drying. A custom-built, single droplet drying instrument was used for this purpose. Single droplets having 5+/-0.1MUl volume (initial droplet diameter 1.5+/-0.1mm) containing 10% (w/v) WPI were dried at air temperatures of 45, 65 and 80 degrees C for 600s at constant air velocity of 0.5m/s. The extent and nature of denaturation of WPI in isothermal heat treatment processes was measured at 65 and 80 degrees C for 600s and compared with those obtained from convective air drying. The extent of denaturation of WPI in a high hydrostatic pressure environment (600MPa for 600s) was also determined. The results showed that at the end of 600s of convective drying at 65 degrees C the denaturation of WPI was 68.3%, while it was only 10.8% during isothermal heat treatment at the same medium temperature. When the medium temperature was maintained at 80 degrees C, the denaturation loss of WPI was 90.0% and 68.7% during isothermal heat treatment and convective drying, respectively. The bovine serum albumin (BSA) fraction of WPI was found to be more stable in the convective drying conditions than beta lactoglobulin and alpha-lactalbumin, especially at longer drying times. The extent of denaturation of WPI in convective air drying (65 and 80 degrees C) and isotheral heat treatment (80 degrees C) for 600s was found to be higher than its denaturation in a high hydrostatic pressure environment at ambient temperature (600MPa for 600s). PMID- 23790838 TI - Modelling of solid-phase tea waste extraction for the removal of manganese from food samples by using artificial neural network approach. AB - In this study, a three-layer artificial neural network (ANN) model was employed to develop prediction model for removal of manganese from food samples using tea waste as a low cost adsorbent. After removal of manganese from food samples with acetic acid (5molL(-1)), manganese was adsorbed to a small amount of tea waste, desorbed with nitric acid as a eluent solvent, and determined by flame atomic absorption spectrometry. The input parameters chosen of the model was pH, amount of tea waste, extraction time and eluent concentration. After backpropagation (BP) training, the ANN model was able to predict extraction efficiency of manganese with a tangent sigmoid transfer function at hidden layer and a linear transfer function at output layer. Under the optimum conditions, the detection limit was 0.6ngg(-1). The method was applied to the separation, pre-concentration and determination of manganese in food samples and one reference material. PMID- 23790839 TI - The practical analysis of food: the development of Sakalar quantification table of DNA (SQT-DNA). AB - Practical and highly sensitive Sakalar quantification table of DNA (SQT-DNA) has been developed for the detection% of species-specific DNA amount in food products. Cycle threshold (Ct) data were obtained from multiple curves of real time qPCR. The statistical analysis was done to estimate the concentration of standard dilutions. Amplicon concentrations versus each Ct value were assessed by the predictions of targets at known concentrations. SQT-DNA was prepared by using the percentage versus each Ct values. The applicability of SQT-DNA to commercial foods was proved by using sausages containing varying ratios of beef, chicken, and soybean. The results showed that SQT-DNA can be used to directly quantify food DNA by a single PCR without the need to construct a standart curve in parallel with the samples every time the experiment is performed, and also quantification by SQT-DNA is as reliable as standard curve quantification for a wide range of DNA concentrations. PMID- 23790840 TI - Scoparone inhibits adipocyte differentiation through down-regulation of peroxisome proliferators-activated receptor gamma in 3T3-L1 preadipocytes. AB - This study was performed to investigate the effect of scoparone on the differentiation of 3T3-L1 preadipocytes. Scoparone inhibited triglyceride (TG) accumulation in the mature adipocytes, evidenced by Oil-red O staining and intracellular quantification. Real time-PCR analysis showed that scoparone significantly down-regulated the mRNA expression of key adipogenic transcription factors, PPARgamma, C/EBPalpha, compared with mature adipocytes. Scoparone appeared to reduce mRNA expression of SREBP1c and FAS being related to the late stage of adipogenesis. Furthermore, aP2 and CD36/FAT, as adipocyte-specific genes, were decreased in mature adipocytes by scoparone treatment. Moreover, scoparone inhibited the up-regulated expression of PPARgamma target genes by rosiglitazone to near that observed in cells treated with GW9662. The luciferase assay revealed that scoparone negatively regulates the transcriptional activity of PPARgamma. Chromatin immunoprecipitation assay also showed that participation of scoparone in the regulation of PPARgamma. Collectively, scoparone has a PPARgamma antagonic effect and suppresses differentiation through down-regulation of adipogenic genes by PPARgamma inhibition in 3T3-L1 preadipocytes. PMID- 23790841 TI - Hollow fibre-based liquid phase microextraction combined with high-performance liquid chromatography for the analysis of flavonoids in Echinophora platyloba DC. and Mentha piperita. AB - A simple, inexpensive and efficient three phase hollow fibre liquid phase microextraction (HF-LPME) technique combined with HPLC was used for the simultaneous determination of flavonoids in Echinophora platyloba DC. and Mentha piperita. Different factors affecting the HF-LPME procedure were investigated and optimised. The optimised extraction conditions were as follows: 1-octanol as an organic solvent, pHdonor=2, pHacceptor=9.75, stirring rate of 1000rpm, extraction time of 80min, without addition of salt. Under these conditions, the enrichment factors ranged between 146 and 311. The values of intra and inter-day relative standard deviations (RSD) were in the range of 3.18-6.00% and 7.25-11.00%, respectively. The limits of detection (LODs) ranged between 0.5 and 7.0ngmL(-1). Among the investigated flavonoids quercetin was found in E. platyloba DC. and luteolin was found in M. piperita. Concentration of quercetin and luteolin was 0.015 and 0.025mgg(-1) respectively. PMID- 23790842 TI - Solvent optimization extraction of antioxidants from foxtail millet species' insoluble fibers and their free radical scavenging properties. AB - In this study, water and 80% of four organic solvents were employed to optimize the extraction of antioxidants from two species of foxtail millet's insoluble fibers under the same temperature, time, and solid/solvent ratio. The results showed that the acetone was able to extract the maximum amount of antioxidants (2.32 mg/g fiber for white specie and 3.86 mg/g fiber for yellow specie) followed by methanol and propanol from both samples. The neutral and the ethanol on the other hand extracted small amount of the antioxidants from the two fiber materials. While considerable level of Total Polyphenols Content (TPC) was recorded in both the water and the organic solvents' extracts, only traces of Total Flavonoid content (TFC) were observed in water, methanol and ethanol extracts. Propanol and acetone extracts was negative to the TFC test. The potency of both white and yellow foxtail millets' insoluble fibers antioxidant extracts was investigated using five different in vitro tests. It was realized that there was a variation in their capacities to quench DPPH and ABTS(+) radicals for the time running of 0-60 min. The samples from the yellow cereal exhibited high inhibition capacity against ABTS(+). No correlation was observed between TPC and radical scavenging capacities for DPPH and ABTS(+). In general, the yellow species contained more antioxidants in comparison with the white one and this accounted for its high antioxidant activity. PMID- 23790843 TI - Determination of six steviol glycosides of Stevia rebaudiana (Bertoni) from different geographical origin by LC-ESI-MS/MS. AB - Liquid chromatography electro-spray tandem mass spectrometry (LC-ESI/MS/MS) was applied to the determination of sweet glycosides (steviol glycosides), and toxic aglycon steviol in 24 samples of Stevia rebaudiana (Bertoni) aerial parts, which had been experimentally cultivated in Italy, although derived from seeds of different geographical origin. On the basis of the specific fragmentation of these compounds, an LC-MS/MS method was developed with the aim of quantifying analytes in plant material. Although toxic steviol was not detectable in all the samples, the samples with the highest levels of steviol glycosides were identified. Analysis of the different samples revealed that they were good quality samples, quality being directly linked to the presence of sweet glycosides in the plants cultivated in Italy, although there were differences in the content of these compounds according to the origin of the seeds, and in particular, a major concentration of compounds with major sweetness activity and minor toxicity was found in the population coming from Brazil (for example: sample 10, stevioside content 15.74+/-2.0% p/p and rebaudioside A content 3.09+/ 0.39% p/p of dried plant). Finally, based on this metabolomic targeted approach, the results obtained for the samples were treated by Principal Component Analysis, identifying specific genotypic differences based on the geographic origin of the seeds. PMID- 23790844 TI - Protective effect of ligand-binding proteins against folic acid loss due to photodecomposition. AB - The B group vitamin known as folates is essential for a variety of physiological processes and plays an important role in the prevention of neural tube defects. However, it decomposes when exposed to UV light. In this study, the response of the synthetic form of folates known as folic acid to UV irradiation in the presence of beta-lactoglobulin (beta-LG), bovine serum albumin (BSA) and alpha lactalbumin (alpha-LA) was investigated using circular dichroism, absorbance and fluorescence spectroscopy. Photodecomposition of folic acid was delayed in the presence of the proteins, which ranked in the order beta-LG>BSA>alpha-LA in terms of effectiveness. Protein unfolding or decomposition occurred at the same time, due to interaction with folic acid photodecomposition products. The results suggest potential uses of ligand-binding proteins as carriers of water-soluble active compounds for nutraceutical applications. PMID- 23790845 TI - Reduction of major peanut allergens Ara h 1 and Ara h 2, in roasted peanuts by ultrasound assisted enzymatic treatment. AB - This study investigated the effects of ultrasound, enzyme concentration and enzyme treatment time on soluble protein and major allergenic proteins (Ara h 1 and Ara h 2) of roasted peanut kernels. A 3-factor, five-level orthogonal experimental design was implemented with various ultrasonication times, concentrations of trypsin or alpha-chymotrypsin and treatment times. The total soluble proteins were determined by the Bicinchoninic acid (BCA) method, Ara h 1 and Ara h 2 were evaluated by SDS-PAGE and sandwich ELISA. The IgE-binding of peanut extracts was analysed by a competitive inhibition ELISA. Results indicate that ultrasound treatment, followed by protease digestion of peanuts, significantly increased the solubility of peanut protein and decreased the concentrations of Ara h 1 and Ara h 2. The sequential treatment of peanuts by ultrasonication-trypsin-alpha chymotrypsin, resulted in maximum reductions of Ara h 1/Ara h 2, and lowest IgE-binding. This study provides an approach to significantly reduce allergenic proteins in peanut product. PMID- 23790846 TI - Green tea from purple leaf coloured tea clones in Kenya- their quality characteristics. AB - The Kenyan tea industry wishes to diversify its tea products, and in line with this, anthocyanin - rich teas were developed at the Tea Research Foundation of Kenya. These teas have purple-coloured leaves and the green colour is masked. In total, 12 accessions of the purple leaf coloured teas and 2 standard tea varieties were studied. Clones Hanlu and Yabukita are Chinese and Japanese tea varieties, respectively, known for good green tea, and they were used as reference standards. Little if any research had been done to characterize the quality of these purple leaf coloured teas and this study investigated their total polyphenols (TPP), catechins, caffeine, gallic acid and theanine. These are the major green tea quality parameters. Results showed that the new Kenyan tea clones had higher total polyphenols than had the reference standard tea varieties, which had 17.2% and 19.7% while the lowest among the Kenyan clones was 20.8%. On catechin quality index, K-purple and TRFK 91/1 showed high index values of 15.9 and 13.3, respectively, while clones TRFK 83/1 and 73/5 showed low index values of 0.74 and 1.0, respectively. Hanlu had the highest caffeine level with 2.42% while clones TRFK KS 3, TRFK KS 2 and TRFK 83/1 had relatively high caffeine levels among the purple leaf coloured teas, with 2.33%, 2.22% and 2.21%, respectively. Clone TRFK 73/5 had the lowest caffeine content, with 1.16%. Theanine analysis showed that most purple leaf coloured teas had more theanine than had the reference standard clones, except TRFK 83/1 and K-purple, which were lower than the reference standard clones. The implication of the green tea chemical quality parameters is also discussed. It is concluded that all the studied clones/varieties have above the minimum 14% of total polyphenols. Clones K-purple and TRFK 91/1 showed high green tea quality indices with the latter doubling with high levels of theanine; hence its highly recommended for green tea manufacture. PMID- 23790847 TI - Aroma characterisation and UV elicitation of purple basil from different plant tissue cultures. AB - Exposure to stressful environmental conditions can induce severe metabolic variations in basil (Ocimum basilicum) aroma. The aromatic profiles of Dark Opal and Red Rubim varieties (in vivo plants, in vitro shoots, callus, and suspension cultures) were investigated for the first time. The established calli represented the most interesting miniaturised aromatic plant systems, as they were able to emit many typical basil volatiles with very low amounts of phenylpropanoids (1 2%). The hydrocarbon monoterpenes and oxygenated volatiles emitted from calli of both varieties were greatly and conversely affected by UV-C and UV-B, in comparison with the non-irradiated samples. As calli of both varieties still maintained very low levels of phenylpropanoids even after UV elicitation, they might be regarded not only as efficient in vitro plant models to study volatile compounds under UV stress conditions, but also as safe aromatic biomass in comparison with in vivo basil plants. PMID- 23790848 TI - Rapid high-throughput assay to assess scavenging capacity index using DPPH. AB - A new microplate-adapted DPPH rapid assay was developed to assess the antioxidant capacity of pure compounds and foods. The assay was carried out in buffered medium (methanol: 10mmol/l Tris buffer pH 7.5, 1:1 v/v) and reaction was completed at 10min. The scavenging capacity index (SCI), a theoretical antioxidant parameter directly related to the antioxidant capacity of samples, was calculated. SCI for pure compounds: gallic acid (6.76+/-0.08), quercetin (7.89+/-0.24), catechin (6.05+/-0.23), trolox (2.32+/-0.03), ascorbic acid (2.52+/-0.15) and gluthatione (1.08+/-0.08) and foods (MUmol DPPH scavenged/100ml): tropical juice (655.62+/-12.18), mediterraneo juice (702.87+/ 11.13), apple juice (212.52+/-17.22), pomegranate juice (319.83+/-9.45), red grape nectar (1093.05+/-18.69), Don Simon orange juice (632.94+/-17.22) and date syrup (15992.34+/-250.7) were comparable to those in previous reports using the classic DPPH assay. The relative standard deviation (RSD) for the SCI on the same and different days was less than 8.12% in all cases. PMID- 23790849 TI - Odour-active compounds in banana fruit cv. Giant Cavendish. AB - Application of solid-phase microextraction, simultaneous distillation-extraction and liquid-liquid extraction, combined with GC-FID, GC-MS, aroma extract dilution analysis, and odour activity value were used to analyse volatile compounds from banana fruit cv. Giant Cavendish and to estimate the most odour-active compounds. The analyses led to the identification of 146 compounds, 124 of them were positively identified. Thirty-one odourants were considered as odour-active compounds and contribute to the typical banana aroma, eleven of them are reported for the first time as odour-active compounds. PMID- 23790850 TI - Postharvest stilbenes and flavonoids enrichment of table grape cv Redglobe (Vitis vinifera L.) as affected by interactive UV-C exposure and storage conditions. AB - Flavonoids and stilbenes are secondary metabolites produced in plants that can play an important health-promoting role. The biosynthesis of these compounds generally increases as a response to biotic or abiotic stress; therefore, in order to achieve as high phenolic accumulation as possible, the interactive effects of storage conditions (temperature and time) and UV-C radiation on polyphenols content in postharvest Redglobe table grape variety were investigated. During a storage time longer than 48h, both cold storage (4 degrees C) and UV-C exposure of almost 3min (2.4kJm(-2)) positively enhanced the content of cis- and trans-piceid (34 and 90MUgg(-1) of skin, respectively) together with quercetin-3-O-galactoside and quercetin-3-O-glucoside (15 and 140MUgg(-1) of skin, respectively) up to three fold respect to control grape samples. Conversely, catechin was not significantly affected by irradiation and storage treatments. With regard anthocyanins, the highest concentrations of cyanidin-3-O glucoside and peonidin-3-Oglucoside were observed in Redglobe, stored at both room temperature and 4 degrees C, after 5min (4.1kJm(-2)) of UV-C treatment and 24h of storage. Gathered findings showed that combined postharvest treatments can lead to possible "functional" grapes, within normal conditions of market commercialization, responding to the rising consumers demand to have foods that support and promote health. PMID- 23790851 TI - The in vitro and in vivo effects of yerba mate (Ilex paraguariensis) extract on adipogenesis. AB - The aim of this study was to evaluate the effects of yerba mate extract and its principal bioactive compounds on adipogenesis. The anti-adipogenic effects of yerba mate, chlorogenic acid, quercetin and rutin were evaluated in 3T3-L1 cells using a PCR array. The results obtained in vitro were validated in vivo in a high fat diet-induced model of obesity. The in vitro and in vivo results demonstrated that yerba mate extract down-regulated the expression of genes that regulate adipogenesis, such as Creb-1and C/EBPalpha, and the extract up-regulated the expression of genes related to the inhibition of adipogenesis, including Dlk1, Gata2, Gata3, Klf2, Lrp5, Ppargamma2, Sfrp1, Tcf7l2, Wnt10b, and Wnt3a. In summary, it was demonstrated that yerba mate and its bioactive compounds regulate the expression of genes related to in vitro adipogenesis. Furthermore, yerba mate might regulate adipogenesis through the Wnt pathway. PMID- 23790852 TI - Migration of antimony from PET containers into regulated EU food simulants. AB - Antimony migration from polyethylene terephthalate (PET) containers into aqueous (distilled water, 3% acetic acid, 10% and 20% ethanol) and fatty food simulants (vegetable oil), as well as into vinegar, was studied. Test conditions were according to the recent European Regulation 10/2011 (EU, 2011). Sb migration was assayed by ICP-MS and HG-AFS. The results showed that Sb migration values ranged from 0.5 to 1.2MUg Sb/l, which are far below the maximum permissible migration value for Sb, 40MUg Sb/kg, (EU, Regulation 10/2011). Parameters as temperature and bottle re-use influence were studied. To assess toxicity, antimony speciation was performed by HPLC-ICP-MS and HG-AFS. While Sb(V) was the only species detected in aqueous simulants, an additional species (Sb-acetate complex) was measured in wine vinegar. Unlike most of the studies reported in the literature, migration tests were based on the application of the EU directive, which enables comparison and harmonisation of results. PMID- 23790853 TI - Determination and quantification of the kokumi peptide, gamma-glutamyl-valyl glycine, in commercial soy sauces. AB - Recent studies have demonstrated that kokumi substances, such as glutathione, are perceived through the calcium-sensing receptor (CaSR), and screening by CaSR assay and sensory evaluation has shown that gamma-glutamyl-valyl-glycine (gamma Glu-Val-Gly) is a potent kokumi peptide. In this study, the contents of gamma-Glu Val-Gly in six commercial brands of dark-coloured soy sauces, two brands of light coloured soy sauce, and one brand of white soy sauce, were investigated by high performance liquid chromatography-tandem mass spectrometry (LC/MS/MS), followed by derivatization with 6-aminoquinoyl-N-hydroxysuccinimidyl-carbamate (AQC). The analyses indicated that gamma-Glu-Val-Gly was present in all investigated soy sauces at concentrations ranging from 0.15 to 0.61mg/dl, demonstrating that it is widely distributed in soy sauces. PMID- 23790854 TI - An HPLC-DAD method for the simultaneous determination of nine beta-lactam antibiotics in ewe milk. AB - The presence of beta-lactam residues in foodstuffs constitutes a potential risk to the human health and undesirable effects on consumers, and nowadays these antibiotic residues are also recognised as an emerging environmental problem. In addition, these are of great concern to prestigious Manchego cheese processors (Central Spain denomination of origin) because they reduce the curdling of milk and cause improper cheese ripening, which consequently lead to an important loss of monetary income. This work describes the development of a sensitive and reliable method using liquid chromatography with UV-diode array detection (LC DAD) for simultaneous determination of the beta-lactam antibiotics, ampicillin (AMP), benzylpenicillin (PEG), cephalexin (CFX), cefazolin (CFL), cefoperazone (CFP), cloxacillin (CLO), dicloxacillin (DCL), oxacillin (OXA) and phenoxymethylpenicillin (PEV), in Manchega ewe milk. The column, mobile phase, temperature and flow rate were optimised to provide the best resolution of these analytes. The extraction method of the antibiotic residues involves the deproteinisation of the milk sample using acetonitrile and centrifugation followed by a solid-phase extraction (SPE) clean-up. The recoveries for the studied beta-lactams ranged from 79% to 96% with relative standard deviations between 0.5% and 4.9%. The limits of quantification (LOQs) for all these compounds were in the range of 3.4-8.6MUgkg(-1), which are lower than the maximum residue limits (MRLs) established by the European Union for the studied beta lactams in milk, making the method suitable for performing routine analyses. The proposed multi-residue LC-UV-diode array detection (LC-DAD) method is a powerful and popular alternative for the determination and confirmation of antibiotic residues in small milk industries and is the first one capable of determining nine beta-lactam antibiotics in samples of Manchega ewe milk. PMID- 23790855 TI - A novel closed-tube method based on high resolution melting (HRM) analysis for authenticity testing and quantitative detection in Greek PDO Feta cheese. AB - Animal species identification of milk and dairy products has received increasing attention concerning food composition, traceability, allergic pathologies and accurate consumer information. Here we sought to develop an easy to use and robust method for species identification in cheese with emphasis on an authenticity control of PDO Feta cheese products. We used specific mitochondrial DNA regions coupled with high resolution melting (HRM) a closed-tube method allowing us to detect bovine, ovine and caprine species and authenticate Greek PDO Feta cheese. The primers successfully amplified DNA isolated from milk and cheese and showed a high degree of specificity. HRM was proven capable of accurately identifying the presence of bovine milk (not allowed in Feta) down to 0.1% and also of quantifying the ratio of sheep to goat milk mixture in different Feta cheese commercial products. In conclusion, HRM analysis can be a faster, with higher resolution and a more cost effective alternative method to authenticate milk and dairy products including PDO Feta cheese and to quantitatively detect its sheep milk adulterations. PMID- 23790856 TI - The effect of holding live sea urchins (Evechinus chloroticus) in air prior to gonad removal on gonad adenine nucleotide profiles during storage at 4 degrees C. AB - Sea urchin gonads are usually sold as a fresh chilled product. Thus, to evaluate the effect of live urchin's post-harvest conditions on gonad shelf-life, gonads were extracted either immediately after harvesting or after holding urchins in air at either 4 or 15 degrees C for 144 and 72h, respectively. Gonads were subsequently washed in brine and stored at 4 degrees C for 10days prior to adenine nucleotide (nmol/gw/w) profile determination. A decline in ATP (control: 376.16; urchins held in air: 231.58 and 245.16) and build-up of its degradation products, mainly inosine (control: 13.25; urchins held in air: 82.87 and 52.95), was observed in gonads recovered from urchins held in air. A faster increase in ATP degradation products was detected during storage of gonads recovered from urchins held in air, with final K-values (%) of 59.34 and 48.18 being significantly higher than K-values obtained from the controls (29.69, p<0.05), suggesting that post-harvest handling can negatively impact on gonad shelf-life. PMID- 23790857 TI - Protective effect of whey protein hydrolysates on H2O2-induced PC12 cells oxidative stress via a mitochondria-mediated pathway. AB - Whey protein hydrolysates (WPHs) were prepared with pepsin and trypsin. A PC12 cell model was built to observe the protective effect of WPHs against H2O2 induced oxidative stress. The results indicated that WPHs reduced apoptosis by 14% and increased antioxidant enzyme activities. Flow cytometry was used to assess the accumulation of reactive oxygen species (ROS), Ca(2+) levels and the mitochondrial membrane potential (MMP). The results showed that WPHs suppressed ROS elevation and Ca(2+) levels and stabilised MMP by 16%. The anti-apoptosis/pro apoptosis proteins Bcl-2/Bax and poly (ADP-ribose) polymerase (PARP) were investigated by Western-blot analysis, which indicated that WPHs increased the expression of Bcl-2 while inhibiting the expression of Bax and the degradation of PARP. WPHs also blocked Caspase-3 activation by 62%. The results demonstrate that WPHs can significantly protect PC12 cells against oxidative stress via a mitochondria-mediated pathway. These findings indicate the potential benefits of WPHs as valuable food antioxidative additives. PMID- 23790858 TI - The effect of heat moisture treatment on physicochemical properties of early indica rice. AB - Early indica rice was heat-moisture treated at different temperature (90 degrees C, 100 degrees C and 110 degrees C) for 3h, 5h and 7h at a moisture content of 28%, respectively. The effects of heat-moisture treatment (HMT) on the amylose content, pasting properties, texture properties, solubility and swelling power of early indica rice were studied. After HMT at 110 degrees C for 7h, the amylose content of early indica rice increased from 25.2% to 30.6%, and its pasting temperature increased from 80.1 degrees C to 92.2 degrees C; the peak viscosity, trough viscosity and final viscosity were all decreased significantly. Both the solubility and the swelling power of early indica rice starches decreased after 110 degrees C 7h heat-moisture treatment. The gel hardness of early indica rice increased significantly, but the adhesiveness decreased after HMT. PMID- 23790859 TI - Combined effects of potassium sorbate, hot water and thiabendazole against green mould of citrus fruit and residue levels. AB - Postharvest treatments of potassium sorbate only controlled recently established infections of Penicillium digitatum on Femminello siracusano lemons but did not confer any persistent protection. The loss of efficacy of potassium sorbate to control green mould decay was related to its irregular deposition on the fruit surface, as revealed by environmental scanning electron microscopy of oranges, and to the brief persistence of potassium sorbate residues. When treatment was done at 53 degrees C, the co-application of potassium sorbate with thiabendazole reduced thiabendazole residues in Moro and Sanguinello oranges, compared to thiabendazole treatment alone. However, treatment efficacy against two isolates of P. digitatum (thiabendazole-sensitive and thiabendazole-resistant) notably improved, indicating that potassium sorbate and hot water potentiated thiabendazole activity. Potassium sorbate residues remarkably decreased during fruit storage and were not affected by the co-application of thiabendazole. PMID- 23790860 TI - Quantification of 2,4-dichlorophenoxyacetic acid in oranges and mandarins by chemiluminescent ELISA. AB - Direct competitive enzyme-linked immunosorbent assay (ELISA) for 2,4 dichlorophenoxyacetic acid (2,4-D) was developed. Varying the concentrations of monoclonal anti-2,4-D-antibody and the conjugate of soybean peroxidase and 2,4-D the conditions of ELISA performance were optimised. The chemiluminescent method based on peroxidase-catalysed oxidation of luminol was applied to measure the enzyme activity of the conjugate. A mixture of 3-(10'-phenothiazinyl)propane-1 sulfonate and 4-morpholinopyridine was used as potent enhancer of chemiluminescence signal. It was shown that the values of the lower detection limit, IC50 and the working range were 1.5, 64.0, and 6.5-545ng/mL, respectively. The recovery values of CL-ELISA from 10 spiked samples of oranges (n=5) and mandarins (n=5) cultivated in green house without use of 2,4-D and containing different 2,4-D concentrations (10-300ng/mL) were ranged from 92% to 104% that indicated on the absence of matrix effect for the fruit extracts of interest. Determination of 2,4-D in peel of five oranges and five mandarins purchased from stores in Vietnam showed that 2,4-D content in oranges fruits (79-104MUg/kg) was significantly higher than that in mandarins (1.66-2.82MUg/kg). PMID- 23790861 TI - Influence of technological processes on phenolic compounds, organic acids, furanic derivatives, and antioxidant activity of whole-lemon powder. AB - The healthy properties of citrus fruits have been attributed to ascorbic acid and phenolic compounds, mainly to flavonoids. Flavonoids are important phytonutrients because they have a wide range of biological effects that provide health-related properties. In this context, this study seeks to characterise the phenolic compounds in lemon and their stability in different drying processes (freeze drying and vacuum-drying) and storage conditions (-18 and 50 degrees C for 1 and 3months). A powerful high-performance liquid chromatography coupled to DAD and electrospray-ionization time-of-flight mass spectrometry (HPLC-ESI-TOF-MS) method has been applied for the separation, identification, and quantification of 19 phenolic compounds and 4 organic acids. To our knowledge, two hydroxycinnamic acids have been identified for the first time in lemon. Folin-Ciocalteu was applied to determine total phenolic compounds and TEAC, FRAP, and ORAC were applied to determine the antioxidant capacity of lemon. Total phenolic content significantly differed in the samples analysed, vacuum-dried lemon showing the highest phenolic content, followed by freeze-dried lemon and, finally, vacuum dried lemon stored at 50 degrees C for 1 and 3months. The content in furanic compounds was determined to evaluate the heat damage in lemon and it was showed an increase with the thermal treatment because of the triggering of Maillard reaction. As exception of ORAC, antioxidant-capacity assays were not correlated to phenolic content by HPLC due to the formation of antioxidant compounds during Maillard reaction. PMID- 23790862 TI - Impact of primary amine group from aminophospholipids and amino acids on marine phospholipids stability: non-enzymatic browning and lipid oxidation. AB - The main objective of this study was to investigate the oxidative stability and non-enzymatic browning reactions of marine PL in the presence or in the absence of primary amine group from aminophospholipids and amino acids. Marine phospholipids liposomal dispersions were prepared from two authentic standards (phosphatidylcholine and phosphatidylethanolamine) and two purified PL from marine sources with and without addition of amino acids (leucine, methionine and lysine). Samples were incubated at 60 degrees C for 0, 2, 4 and 6days. Non enzymatic browning reactions were investigated through measurement of (i) Strecker derived volatiles, (ii) yellowness index (YI), (iii) hydrophobic and (iv) hydrophilic pyrroles content. The oxidative stability of the samples was assessed through measurement of secondary lipid derived volatile oxidation products. The result showed that the presence of PE and amino acids caused the formation of pyrroles, generated Strecker derived volatiles, decreased the YI development and lowered lipid oxidation. The lower degree of lipid oxidation in liposomal dispersions containing amino acids might be attributed to antioxidative properties of pyrroles or amino acids. PMID- 23790864 TI - Non-destructive flavour evaluation of red onion (Allium cepa L.) ecotypes: an electronic-nose-based approach. AB - This work reports preliminary results on the potential of a metal oxide sensor (MOS)-based electronic nose, as a non-destructive method to discriminate three "Tropea Red Onion" PGI ecotypes (TrT, TrMC and TrA) from each other and the common red onion (RO), which is usually used to counterfeit. The signals from the sensor array were processed using a canonical discriminant function analysis (DFA) pattern recognition technique. The DFA on onion samples showed a clear separation among the four onion groups with an overall correct classification rate (CR) of 97.5%. Onion flavour is closely linked to pungency and thus to the pyruvic acid content. The e-nose analysis results are in good agreement with pyruvic acid analysis. This work demonstrated that artificial olfactory systems have potential for use as an innovative, rapid and specific non-destructive technique, and may provide a method to protect food products against counterfeiting. PMID- 23790865 TI - Physicochemical characterisation of the supramolecular structure of luteolin/cyclodextrin inclusion complex. AB - The formation of supramolecular inclusion complexes between luteolin and five cyclodextrins namely beta-cyclodextrin (beta-CD), methyl-beta-cyclodextrin (M beta-CD), hydroxyethyl-beta-cyclodextrin (HE-beta-CD), hydroxypropyl-beta cyclodextrin (HP-beta-CD) and glucosyl-beta-cyclodextrin (G-beta-CD) was investigated. Results from phase-solubility studies showed that luteolin formed 1:1 stoichiometric inclusion complexes with these cyclodextrins with the G-beta CD complex displaying the greatest stability constant. The supramolecular structure of the luteolin/G-beta-CD complex was investigated by ultraviolet visible spectroscopy (UV), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and X ray diffractometry (XRD). Results showed clearly the formation of a supramolecular complex in which the guest molecule, luteolin, was entrapped inside the cavity of the host, G-beta-CD. The close association between luteolin and G-beta-CD resulted in changes in some of the characteristic spectral, phase transitional and morphological properties of luteolin. Furthermore, molecular docking study showed that the complex was formed with the B ring of luteolin inserted into the cavity of G-beta-CD. PMID- 23790863 TI - Phenolic-rich extract from the Costa Rican guava (Psidium friedrichsthalianum) pulp with antioxidant and anti-inflammatory activity. Potential for COPD therapy. AB - The potential therapeutic effects of Costa Rican guava (Psidium friedrichsthalianum) extracts for chronic obstructive pulmonary disease were examined. The ethyl acetate fraction displayed the highest antioxidant activity, as compared to the hexane, chloroform, and n-butanol fractions, as well as the crude extract. This fraction was evaluated for its anti-inflammatory activity response relationship against interleukin-8 (IL-8) and inhibition of matrix metalloproteinase-1 (MMP-1) expression before and after treatment with cigarette smoke. The ethyl acetate fraction exhibited inhibitory activity against IL-8 production and MMP-1 expression, showing the most potent inhibitory activities in both assays at 100MUg/mL, and nine compounds (1-9) were found. Phenolic compounds 1-O-trans-cinnamoyl-beta-d-glucopyranose (2), ellagic acid (3), myricetin (4), quercitrin (7), and quercetin (9) were identified using standard compounds or literature reports from related species. Compounds 1, 5, 6, and 8 were tentatively identified as 1,5-dimethyl citrate (1), sinapic aldehyde 4-O-beta-d glucopyranose (5), 3,3',4-tri-O-methylellagic acid-4'-O-d-glucopyranoside (6), and 1,3-O-diferuloylglycerol (8), All nine compounds are reported for the first time in Costa Rican guava. PMID- 23790866 TI - Physicochemical characterisation of beta-chitosan from Sepioteuthis lessoniana gladius. AB - beta-Chitin and its chitosan from the gladius of Sepioteuthis lessoniana have been isolated, purified, characterised and compared with the commercial chitosan. Ash, moisture, mineral, metal and elemental content were analyzed using standard techniques. The optical activity of chitin was found to be levorotatory. The degree of deacetylation was calculated by potentiometric titration and (1)H NMR. Viscosity average molecular weight of beta-chitosan was calculated by viscometry and size average molecular weight by GPC. The structure of beta-chitosan was elucidated with FT-IR and NMR. Thermal nature, crystalline structure and morphology of beta-chitosan were characterised through DSC, XRD and SEM, respectively. The water and fat binding capacity of beta-chitosan presently studied was significantly higher than that of the commercial chitosan. The result of the present study adds that S. lessoniana gladius is also an additional source of beta-chitin and chitosan of higher yield, lower molecular weight and higher degree of deacetylation. PMID- 23790867 TI - The effect of natural antioxidants on haemoglobin-mediated lipid oxidation during enzymatic hydrolysis of cod protein. AB - Heating and changes in pH often practised during fish protein hydrolysis can cause lipid oxidation. The effect of natural antioxidants towards haemoglobin mediated lipid oxidation during enzymatic hydrolysis of cod proteins was investigated. Different variants of a washed cod model system, containing different combinations of haemoglobin and natural antioxidants (l-ascorbic acid and Fuscus vesiculosus extract), were hydrolysed using Protease P "Amano" 6 at pH 8 and 36 degrees C to achieve 20% degree of hydrolysis. Lipid hydroperoxides and thiobarbituric acid reactive substances (TBARS) were analysed periodically during the hydrolysis process. The in vitro antioxidant activity of the final products was investigated. Results indicate that oxidation can develop rapidly during hydrolysis and antioxidant strategies are preferable to produce good quality products. Oxidation products did not have an impact on the in vitro antioxidant activity of the hydrolysates. The natural antioxidants inhibited oxidation during hydrolysis and contributed to the antioxidant activity of the final product. PMID- 23790868 TI - Protective effects of triterpenoids from Ganoderma resinaceum on H2O2-induced toxicity in HepG2 cells. AB - Ganoderma resinaceum Boud. (Polyporeseae) has long been used for antioxidant, immunoregulation and liver protection. From the fruiting bodies of G. resinaceum, eight new lanostanoids, lucidones D-G (1-4), 7-oxo-ganoderic acid Z2 (5), 7-oxo ganoderic acid Z3 (6), ganoderesin A (7), and ganoderesin B (8), together with six known lanostanoids (9-14) were isolated. The structures of new compounds were elucidated through extensive spectroscopic analysis. In an in vitro model, ganoderesin B (8), ganoderol B (10) and lucidone A (11) showed inhibitory effects against the increase of ALT and AST levels in HepG2 cells induced by H2O2 compared to a control group in the range of their maximum non-toxic concentration (MNTC). However, compounds 8, 10 and 11 displayed no anti-oxidant activities by DPPH assay. Meanwhile, activation for PXR (Pregnane X Receptor) of ganoderesin B (8), ganoderol B (10) and lucidone A (11) was evaluated; ganoderol (10) exhibited a vital activation for PXR-induced CYP3A4 expression. These results suggested that GTs (Ganoderma triterpenoids) exhibited hepatoprotective activities by lowering ALT and AST levels. PMID- 23790869 TI - Myricitrin protects against peroxynitrite-mediated DNA damage and cytotoxicity in astrocytes. AB - Peroxynitrite, a potent oxidising and nitrating species, has been implicated in the pathogenesis of neurodegenerative diseases. This study was undertaken to investigate the protective effect of myricitrin on peroxynitrite-mediated toxicity and the underlying mechanism. Our results showed that the presence of myricitrin was found to significantly inhibit peroxynitrite-mediated DNA damage. EPR spectroscopy demonstrated that myricitrin potently diminished the DMPO hydroxyl radical adduct signal from peroxynitrite. Further study showed that glutathione (GSH) depletion caused by peroxynitrite can be effectively prevented by pre-incubation of astrocytes with myricitrin. Moreover, co-incubation of astrocytes with myricitrin and buthionine sulfoximine (BSO) eliminated the myricitrin-induced GSH increase. In contrast, co-incubation of myricitrin with BSO slightly protected astrocytes against cytotoxicity and DNA damage mediated by peroxynitrite. These results revealed that myricitrin can protect against peroxynitrite-induced DNA damage and cytotoxicity, which might have implications for myricitrin-mediated neuroprotection. PMID- 23790870 TI - Cell viability and proteins release during ultrasound-assisted yeast lysis of light lees in model wine. AB - Light lees that spent more than one year in barrels were used for ultrasound assisted yeast lysis (22W/L, 18 degrees C) in a model wine. For comparison, a classical yeast autolysis at mild temperature (25 degrees C) was performed. The effect of ultrasound on lees was evaluated by analysing the release of proteins and polysaccharides to the model wine, and the viability of the yeasts contained in the lees. Under conditions tested, ultrasound-assisted yeast lysis increased the concentrations of proteins and polysaccharides in the model wine due to the release of these compounds from yeasts. Unlike the classical autolysis, ultrasound led to a high cell disruption, and after 20h of ultrasonic treatment, viable cells were hardly found. Furthermore, the final cell concentration for the ultrasound-assisted yeast lysis was much lower than that for the classical autolysis. The inactivation rate constant of ultrasound-assisted yeast lysis was 2.54*10(-5)s(-1). Finally, the morphological changes in cells were examined by scanning electron microscopy to verify the effect of ultrasound on yeast cells. PMID- 23790871 TI - Trypsin from viscera of vermiculated sailfin catfish, Pterygoplichthys disjunctivus, Weber, 1991: its purification and characterization. AB - Pterygoplichthys disjunctivus viscera trypsin was purified by fractionation with ammonium sulphate, gel filtration, affinity and ion exchange chromatography (DEAE Sepharose). Trypsin molecular weight was approximately 27.5kDa according to SDS PAGE, shown a single band in zymography. It exhibited maximal activity at pH 9.5 and 40 degrees C, using N-benzoyl-dl-arginine-p-nitroanilide (BAPNA) as substrate. Enzyme was effectively inhibited by phenyl methyl sulphonyl fluoride (PMSF) (100%), N-alpha-p-tosyl-l-lysine chloromethyl ketone (TLCK) (85.4%), benzamidine (80.2%), and soybean trypsin inhibitor (75.6%) and partially inhibited by N-tosyl-l-phenylalanine chloromethyl ketone (TPCK) (10.3%), ethylendiaminetetraacetic acid (EDTA) (8.7%) and pepstatin A (1.2%). Enzyme activity was slightly affected by metal ions (Fe(2+)>Hg(2+)>Mn(2+)>K(+)>Mg(2+)>Li(+)>Cu(2+)). Trypsin activity decreased continuously as NaCl concentration increased (0-30%). Km and kcat values were 0.13mM and 1.46s(-1), respectively. Results suggest the enzyme have a potential application where room processing temperatures (25-35 degrees C) or high salt (30%) concentration are needed, such as in fish sauce production. PMID- 23790872 TI - Structural characterization and immunostimulatory activity of a novel protein bound polysaccharide produced by Hirsutella sinensis Liu, Guo, Yu & Zeng. AB - HS002-II, a novel protein-bound polysaccharide with 44kDa molecular weight, was fractionated from submerged cultures of Hirsutella sinensis Liu, Guo, Yu & Zeng by DEAE-Sepharose and Sephacryl S200 chromatography. Based on the results of infrared spectroscopy, high performance liquid chromatography, methylation, amino acid analysis, NMR spectroscopy and atomic force microscopy, the polysaccharide moieties of HS002-II mainly contained a long backbone of (1->3)-linked alpha-d ribofuranosyl units (1->4)-linked alpha-d-xylopyranosyl units and (1->4)-linked beta-d-glucopyranosyl units, which was substituted at C-6. The two branches were beta-d-mannopyranosyl residues and beta-d-galactopyranosyl residues terminated with alpha-l-arabinopyranosyl residues, respectively. HS002-II consisted of 57.9% polysaccharide and 42.1% protein with the existence of N-type carbohydrate protein linkage. In terms of the pro-inflammatory cytokines assay (NO, TNF-alpha, IL-1beta and NF-kappaB) using murine macrophages cell line (RAW264.7), HS002-II exhibited significant immunomodulatory activity by stimulating the IkappaB-NF kappaB pathway. PMID- 23790873 TI - Effect of alginate/nano-Ag coating on microbial and physicochemical characteristics of shiitake mushroom (Lentinus edodes) during cold storage. AB - The effect of a novel alginate/nano-Ag coating material on the preservation quality of shiitake mushroom (Lentinus edodes) during 4+/-1 degrees C storage was investigated. The results showed that the alginate/nano-Ag coating had quite a beneficial effect on the physicochemical and sensory quality, compared to the control treatment. After a 16-day storage, mushroom weight loss, softening, and browning of the alginate/nano-Ag coating were significantly inhibited. The lower microbial counts, including mesophilic, psychrophilic, pseudomonad, and yeasts and moulds, in treated mushrooms during storage should be attributed to the alginate/nano-Ag coating. Meanwhile, the contents of the reducing sugar, total sugar, total soluble solids and electrolyte leakage rate were increased to 3.9mg/g, 11.2mg/g, 5.1% and 16.5% for the alginate/nano-Ag coating and 3.7mg/g, 8.3mg/g, 6.3% and 31.7% for the control treatment. Therefore, the alginate/nano Ag coating could be applied for preservation of the shiitake mushroom to expand its shelf life and improve its preservation quality. PMID- 23790874 TI - Anthocyanins profile, total phenolics and antioxidant activity of black currant ethanolic extracts as influenced by genotype and ethanol concentration. AB - Ethanolic extracts prepared from the fruits of three cultivars of black currant ('Record', 'Blackdown' and 'Ronix') macerated in three concentrations (40%, 60% and 96%) of aqueous ethanol were investigated for their anthocyanins profile, total phenolics and antioxidant activity. Nine individual anthocyanins were detected and quantified by using HPLC-MS in ethanolic extracts of black currants, i.e. delphinidin 3-glucoside, delphinidin 3-rutinoside, cyanidin 3-glucoside, cyanidin 3-rutinoside, petunidin 3-rutinoside, pelargonidin 3-rutinoside, peonidin 3-rutinoside, petunidin 3-(6-coumaroyl)-glucoside and cyanidin 3-(6 coumaroyl)-glucoside. The antioxidant activity of the alcoholic extracts was investigated by the 2,2'-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging method while the total phenolic content was determined by using the Folin Ciocalteu assay. The highest anthocyanins content was found in the extracts made in 60% ethanol while total phenolics content was highest at 96% ethanol concentration. The extraction yield of individual anthocyanins was differently influenced by the rise of the ethanolic concentration. Maximum extraction yield of most individual anthocyanins was reached at 60% ethanol concentration except the 3-(6-coumaroyl)-glucoside of cyanidin and petunidin whose maximum extraction occurred at 96% ethanol concentration. PMID- 23790875 TI - Classification of juices and fermented beverages made from unripe, ripe and senescent apples based on the aromatic profile using chemometrics. AB - The aim of this study was to assess differences between apple juices and fermented apple beverages elaborated with fruits from different varieties and at different ripening stages in the aroma profile by using chemometrics. Ripening influenced the aroma composition of the apple juice and fermented apple. For all varieties, senescent fruits provided more aromatic fermented apple beverages. However, no significant difference was noticed in samples made of senescent or ripe fruits of the Lisgala variety. Regarding the juices, ripe Gala apple had the highest total aroma concentration. Ethanal was the major compound identified in all the samples, with values between 11.83mg/L (unripe Lisgala juice) and 81.05mg/L (ripe Gala juice). 3-Methyl-1-butanol was the major compound identified in the fermented juices. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) were applied and classified the juices and fermented juices based on physicochemical and aroma profile, demonstrating their applicability as tools to monitor the quality of apple-based products. PMID- 23790876 TI - Food proteins: a review on their emulsifying properties using a structure function approach. AB - Proteins are of great interest due to their amphiphilic nature, which allows them to reduce the interfacial tension at the oil-water interface. The incorporation of proteins at the oil-water interface has allowed scientists to utilise them to form emulsions (O/W or W/O), which may be used in food formulations, drug and nutrient delivery. The systematic study of the proteins at the interface and the factors that affect their stability (i.e., conformation, pH, solvent conditions, and thermal treatment) has allowed for a broader use of these emulsions tailored for various applications. In this review, the factors affecting the stability of emulsions using food proteins will be discussed. The use of polysaccharides to complex with proteins will also be explored in relation to enhancing emulsion stability. PMID- 23790877 TI - Comparison of glycation in conventionally and microwave-heated ovalbumin by high resolution mass spectrometry. AB - The glycation extent of ovalbumin under two heating conditions, conventional and microwave heating was monitored by high resolution mass spectrometry, following pepsin digestion. The sequence coverage of the unglycated and glycated ovalbumin was 100% and 95%, respectively. About 35.2% of the lysines after microwave heating and 40.8% of the lysines after conventional heating were modified by d glucose. The glycation content increased quickly when ovalbumin-glucose mixture was incubated for 15min, under both processing conditions. These modifications were slowed down after 30min of heating and no obvious advanced stage products were observed. The glycated peptides exhibited varying degrees of glycation, under both conventional and microwave heating, suggesting that glycation is strongly relevant to the protein structure. The fact that some peptides showed a lower level of glycation when heated by microwave indicated that microwave radiation might be a non-thermal process. In addition, the lack of browning after microwave heating emphasised the difference between microwave and conventional heating. PMID- 23790878 TI - Production and purification of antioxidant peptides from a mungbean meal hydrolysate by Virgibacillus sp. SK37 proteinase. AB - Antioxidant peptides of mungbean meal hydrolysed by Virgibacillus sp. SK37 proteinases (VH), Alcalase (AH) and Neutrase (NH) were investigated. The antioxidant activities based on 2,2'-azinobis (3-ethyl-benzothiazoline-6 sulphonate) (ABTS) radical-scavenging, ferric-reducing antioxidant power (FRAP) and metal chelation of VH were comparable to those of NH. VH was purified using ultrafiltration, ion exchange and gel filtration chromatography. The purified peptides (F37) from VH, which had the highest specific antioxidant activity, consisted of four peptides containing an arginine residue at their C-termini. In addition, the ABTS radical-scavenging activity of the purified peptides (F42) at 0.148mg/ml was comparable to that of 1mM of butylated hydroxytoluene (BHT). These two fractions were stable over a wide pH (4-10) and temperature (25-121 degrees C) range. Virgibacillus sp. SK37 proteinase is a potential processing-aid for the production of a mungbean meal hydrolyzate with antioxidant properties. PMID- 23790879 TI - Cycloartenyl trans-ferulate, a component of the bran byproduct of sake-brewing rice, inhibits mammalian DNA polymerase and suppresses inflammation. AB - During the screening of selective DNA polymerase (pol) inhibitors, we isolated cycloartenyl trans-ferulate (CAF), which is a major component of gamma-oryzanol, which is a byproduct formed during the production of Japanese rice wine "sake". CAF selectively inhibited the activity of mammalian A, B, and X pol families, but Y family pols were not affected. CAF did not influence the activities of plant or prokaryotic pols, nor the activity of other DNA metabolic enzymes tested. Individual chemical components of CAF, including cycloartenol (CA) and ferulic acid (FA), did not inhibit pol enzyme activities. CAF suppressed TPA (12-O tetradecanoylphorbol-13-acetate)-induced inflammation in the mouse ear, but CA and FA did not. The ability to inhibit mammalian pol enzymes in vitro was positively correlated with their propensity to suppress inflammation in vivo. These results suggest that this byproduct formed during the sake-brewing process is useful as an anti-inflammatory agent. PMID- 23790880 TI - Differential effects of polyphenols-enriched extracts from hawthorn fruit peels and fleshes on cell cycle and apoptosis in human MCF-7 breast carcinoma cells. AB - This study was to investigate the anticancer effects of the peel polyphenolic extract (HPP) and flesh polyphenolic extract (HFP) from hawthorn fruit in human MCF-7 breast cancer cells. It was found that the polyphenol and flavonoid contents of HPP were significant higher than that of HFP. Both HPP and HFP inhibited cell growth in a dose-dependent manner with the IC50 of 88.6MUg/mL and 175.5MUg/mL, respectively, suggesting that HPP was more effective against MCF-7 cells than HFP. Flow cytometric analysis revealed that both HPP and HFP mediated the cell-cycle arrest at the S-phase, and also dose-dependently led to apoptosis of MCF-7 cells via the mitochondrial pathway, as evidenced by the activation of caspase-3 and caspase-9 and the elevation of intracellular ROS production. All these findings indicate that hawthorn fruit, especially its peel, is an excellent source of natural chemopreventive agents in the treatment of breast cancer. PMID- 23790881 TI - Effect of phytate reduction of sorghum, through genetic modification, on iron and zinc availability as assessed by an in vitro dialysability bioaccessibility assay, Caco-2 cell uptake assay, and suckling rat pup absorption model. AB - Improved iron and zinc availability from sorghum, a commonly consumed staple, will benefit many malnourished communities in rural Africa burdened with high prevalence of iron and zinc deficiency. This research compared the effect of genetic phytate reduction in sorghum on iron and zinc bioaccessibility and uptake measured by in vitro dialysability and Caco-2 cell uptake assays to that of iron and zinc absorption measured by a suckling rat pup model. The phytate reduction (80-86%) in these sorghums significantly increased zinc availability. The Caco-2 cell method, but not the dialysability assay, proved useful in estimating zinc absorption. The measured increase in iron availability differed between the methods, possibly due to the effect of varying mineral (Ca, Fe, Zn, P) contents of the sorghums. This effect was most prominent in the iron uptake results. More research is needed to determine the effect of naturally occurring variations in mineral contents of sorghum on the iron uptake by Caco-2 cells. PMID- 23790882 TI - Formation and destruction of biogenic amines in Chunjang (a black soybean paste) and Jajang (a black soybean sauce). AB - Chunjang and Jajang samples were analysed for biogenic amine contents by using HPLC equipped with a UV-Vis detector. Chunjang samples contained relatively large amounts of histamine (up to 273mg/kg) and tyramine (up to 131mg/kg), whereas Jajang samples had relatively small amounts of biogenic amines (mostly less than 40mg/kg). There appeared to be a strong relationship between biogenic amine contents in Chunjang and Jajang, and the biogenic amines in Chunjang were found to be pyrolysed during frying thereof to prepare Jajang. Meanwhile, the total plate counts of Chunjang samples ranged from 5 to 8logcfu/g, and most strains that were isolated from Chunjang samples were identified to be Bacillus subtilis (91.0%). The strains isolated from a sample in which relatively small amounts of biogenic amines were detected showed significantly weak abilities to produce biogenic amines. This indicates that biogenic amine contents in Chunjang are primarily attributed to bacterial abilities to produce biogenic amines. PMID- 23790883 TI - First mass spectrometry metabolic fingerprinting of bacterial metabolism in a model cheese. AB - Metabolic fingerprinting is an untargeted approach which has not yet been undertaken to investigate cheese. This study is a proof of concept, concerning the ability of mass spectrometry (MS) metabolic fingerprinting to investigate modifications induced by bacterial metabolism in cheese over time. An ultrafiltrated milk concentrate was used to manufacture model cheeses inoculated with Lactococcus lactis LD61. Metabolic fingerprints were acquired after 0, 8 and 48h from two different fractions of the metabolome: the water-soluble fraction using liquid chromatography-high resolution-MS and a volatile fraction using gas chromatography-MS. Metabolic fingerprints differed significantly over time. Forty five metabolites were identified, including well-known cheese metabolites, such as 12 amino acids and 25 volatile metabolites, and less studied ones, such as four vitamins, uric acid, creatine and l-carnitine. These results showed the relevance of cheese MS fingerprinting to generate new findings and to detect even slight differences between two conditions. PMID- 23790884 TI - Development and characterization of novel probiotic-residing pullulan/starch edible films. AB - An innovative approach was performed to prepare novel pullulan/starch blended edible films by direct incorporation of multiple probiotic bacterial strains. Various starches different in origin were blended into the pullulan solutions with different ratios. The physical and mechanical properties of the films were investigated in the presence and absence of probiotic cells. An increase in the starch content of pullulan films resulted in a substantial decrease in relative cell viabilities and mechanical properties. Moreover, slight changes in the physical and mechanical properties of the films were observed with the addition of probiotic strains. Pullulan and pullulan/potato starch films were found to be the most suitable carrier matrices, with a maximum relative cell viability of 70 80% after 2months of storage at 4 degrees C. The results suggest that pullulan and pullulan/starch films can be used as effective delivery and carrier systems for probiotics. PMID- 23790885 TI - Binding of resveratrol with sodium caseinate in aqueous solutions. AB - The interaction between resveratrol (Res) and sodium caseinate (Na-Cas) has been studied by measuring fluorescence quenching of the protein by resveratrol. Quenching constants were determined using Stern-Volmer equation, which suggests that both dynamic and static quenching occur between Na-Cas and Res. Binding constants for the complexation between Na-Cas and Res were determined at different temperatures. The large binding constants (3.7-5.1*10(5)M(-1)) suggest that Res has strong affinity for Na-Cas. This affinity decreases as the temperature is raised from 25 to 37 degrees C. The binding involves both hydrogen bonding and hydrophobic interaction, as suggested by negative enthalpy change and positive entropy change for the binding reaction. The present study indicates that Na-Cas, a common food protein, may be used as a carrier of Res, a bioactive polyphenol which is insoluble in both water and oils. PMID- 23790886 TI - Markers of typical red wine varieties from the Valley of Tulum (San Juan Argentina) based on VOCs profile and chemometrics. AB - We studied the VOCs profile of three red wine varieties, produced in the Valley of Tulum (San Juan-Argentina), over 4 consecutive years. Our main goal was to verify if different wine varieties could be differentiated from their VOCs profile, considering changes induced by their age, the yeast inoculated and the type of alcoholic fermentation, establishing those compounds that could be used as chemical markers of a particular variety. Stepwise LDA of selected VOCs allowed 100% differentiation between studied wines, showing that high levels of 1 hexanol were characteristic for Malbec, while low level of ethyl caproate was characteristic for Bonarda. Using controlled fermentations, 1-hexanol, a pre fermentative VOC, presented a similar trend in wines produced from different yeast; while other fermentative VOCs, like ethyl caproate and ethyl caprilate, presented lower levels for Bonarda but also for Syrah. To our knowledge, this is the first report on characterization of VOCs from Bonarda. Additionally, the quantitative analysis of VOCs profile, coupled to chemometrics, present a good alternative to differentiate wines from different varieties and also for studying wine fermentation. PMID- 23790887 TI - Antioxidant and anti-inflammatory activities of six flavonoids separated from licorice. AB - Licorice, the roots and rhizomes of several Glycyrrhiza species (Leguminosae), is an important natural sweetening agent and a widely used herbal medicine. In this work, six flavonoids, 5-(1,1-dimethylallyl)-3,4,4'-trihydroxy-2-methoxychalcone (1), licochalcone B (2), licochalcone A (3), echinatin (4), glycycoumarin (5) and glyurallin B (6), were isolated from the extracts of licorice (Glycyrrhiza inflata and Glycyrrhiza uralensis). Their structures were elucidated using various spectroscopic methods. To our knowledge, compound 1 was isolated from natural plants for the first time. All the isolates were tested by antioxidant and anti-inflammatory assays. Compounds 2, 4 and 5 showed strong scavenging activity toward the ABTS(+) radical, and compounds 1, 2, 3, 5 and 6 exhibited potent inhibition of lipid peroxidation in rat liver microsomes compared with the reference controls. Compounds 1-4 dose-dependently inhibited LPS induced reactive oxygen species (ROS) production in RAW 264.7 cells. Furthermore, compounds 1-5 were demonstrated to inhibit the production of nitric oxide (NO), interleukin-6 (IL-6) and prostaglandin E2 (PGE2) in LPS-induced macrophage cells. Moreover, the contents of the six compounds, in different Glycyrrhiza species, were quantified by HPLC-MS. PMID- 23790888 TI - Dipeptidyl peptidase-IV inhibitory peptides generated by tryptic hydrolysis of a whey protein concentrate rich in beta-lactoglobulin. AB - Dipeptidyl peptidase-IV (DPP-IV) is a serine protease involved in the degradation and inactivation of incretin hormones that act by stimulating glucose-dependent insulin secretion after meal ingestion. DPP-IV inhibitors have emerged as new and promising oral agents for the treatment of type 2 diabetes. The purpose of this study was to investigate the potential of beta-lactoglobulin as natural source of DPP-IV inhibitory peptides. A whey protein concentrate rich in beta-lactoglobulin was hydrolysed with trypsin and fractionated using a chromatographic separation at semipreparative scale. Two of the six collected fractions showed notable DPP IV inhibitory activity. These fractions were analysed by HPLC coupled to tandem mass spectrometry (HPLC-MS/MS) to identify peptides responsible for the observed activity. The most potent fragment (IPAVF) corresponded to beta-lactoglobulin f(78-82) which IC50 value was 44.7MUM. The results suggest that peptides derived from beta-lactoglobulin would be beneficial ingredients of foods against type 2 diabetes. PMID- 23790889 TI - Formation of cysteine-S-conjugates in the Maillard reaction of cysteine and xylose. AB - Cysteine-S-conjugates (CS-conjugates) occur in foods derived from plant sources like grape, passion fruit, onion, garlic, bell pepper and hops. During eating CS conjugates are degraded into aroma-active thiols by beta-lyases that originate from oral microflora. The present study provides evidence for the formation of the CS-conjugates S-furfuryl-l-cysteine (FFT-S-Cys) and S-(2-methyl-3-furyl)-l cysteine (MFT-S-Cys) in the Maillard reaction of xylose with cysteine at 100 degrees C for 2h. The CS-conjugates were isolated using cationic exchange and reversed-phase chromatography and identified by (1)H NMR, (13)C NMR and LC-MS(2). Spectra and LC retention times matched those of authentic standards. To the best of our knowledge, this is the first time that CS-conjugates are described as Maillard reaction products. Furfuryl alcohol (FFA) is proposed as an intermediate which undergoes a nucleophilic substitution with cysteine. Both FFT-S-Cys and MFT S-Cys are odourless but produce strong aroma when tasted in aqueous solutions, supposedly induced by beta -lyases from the oral microflora. The perceived aromas resemble those of the corresponding aroma-active thiols 2-furfurylthiol (FFT) and 2-methyl-3-furanthiol (MFT) which smell coffee-like and meaty, respectively. PMID- 23790890 TI - Antioxidant and anti-inflammatory properties of Taiwanese yam (Dioscorea japonica Thunb. var. pseudojaponica (Hayata) Yamam.) and its reference compounds. AB - Dioscorea japonica Thunb. var. pseudojaponica (DP) is consumed as food and widely used in traditional Chinese medicine in Taiwan. The aims of this study are to investigate the antioxidant and anti-inflammatory effects of ethanol extract of DP (EDP) and its reference compounds. Fingerprint chromatogram from HPLC indicated that EDP contains gallic acid and vanillic acid. EDP was evaluated for its antioxidant effects and LPS-induced nitrite oxide (NO) production in RAW264.7 cells. EDP decreased the LPS-induced NO production and expressions of iNOS and COX-2 in RAW264.7 cells. In-vivo anti-inflammatory activities of EDP were assessed in mouse paw oedema induced by lambda-carrageenan (Carr). We investigated the antioxidant mechanism of EDP via studies of the activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) and the levels of malondialdehyde (MDA) in the oedematous paw. The results showed that EDP might be a natural antioxidant and anti-inflammatory agent. PMID- 23790891 TI - Antibacterial and antimutagenic activities of novel zerumbone analogues. AB - Zerumbone, the key constituent of Zingiber zerumbet Smith, is a very important bioactive phytochemical. Two new compounds viz. azazerumbone 1 and azazerumbone 2 were synthesised by ZnCl2-catalysed Beckmann rearrangement of the zerumbone oxime. The structure elucidation of these analogues of zerumbone was carried out by 1D ((1)H NMR and (13)C NMR) and 2D-NMR (COSY, HSQC and NOESY) spectral analysis. Studies on the antibacterial activity established that azazerumbone 2 had better activity than zerumbone. Among the tested bacteria, Bacillus cereus was the most sensitive and Yersinia enterocolitica was found to be the most resistant. These compounds exhibited strong protection against sodium azide induced mutagenicity of Salmonella typhimurium strains TA 98 and TA 1531. Azazerumbone 2 showed better antibacterial and antimutagenic activity than azazerumbone 1. The antibacterial and antimutagenic activities exhibited by zerumbone and its analogues demonstrate their potential for use as nutraceuticals and in food preservation. PMID- 23790892 TI - Anti-inflammatory effects of 27 selected terpenoid compounds tested through modulating Th1/Th2 cytokine secretion profiles using murine primary splenocytes. AB - This study investigated 27 selected terpenoid compounds, including 8 monoterpenoids, 7 sesqui-terpenoids, 3 di-terpenoids, 8 tri-terpenoids, and 1 tetra-terpenoid, for their Th1/Th2 immunomodulatory potential using mouse primary splenocytes. Changes in Th1 cytokines, including interleukin (IL)-2 and interferon (IFN)-gamma, and Th2 cytokines, including IL-4, IL-5 and IL-10, secreted by terpenoid-treated splenocytes were measured using the ELISA method. The results showed that triptolide, a diterpenoid, was most cytotoxic, reflecting an IC50 value of 46nM. Eucalyptol, limonene, linalool, thymol, parthenolide, andrographolide, 18beta-glycyrrhetinic acid, lupeol, ursolic acid and beta sitosterol showed a strong Th2-inclination and anti-inflammation potential in vitro. In addition, (-)-trans-caryophyllene, oridonin, triptolide, diosgenin, betulinic acid, escin, and beta-sitosterol treatments significantly inhibited both IL-2 (Th1) and IL-10 (Th2) cytokine production at the same time, suggesting that these terpenoid compounds have an anti-inflammation potential through the inhibition of T-cell immune responses. Diosgenin treatments significantly increased IFN-gamma secretion levels using mouse splenocytes, suggesting that diosgenin may be useful in treating a viral infection through the stimulation of IFN-gamma production. Menthone, farnesol and oridonin treatments did not markedly increase IL-10/IL-2 (Th2/Th1) cytokine secretion ratios, suggesting that menthone, farnesol and oridonin may have a relative Th1-inclination property, compared to the other selected terpenoid compounds. The relative Th1-inclination property of menthone, farnesol and oridonin may be applied to improve Th2-skewed allergic diseases. PMID- 23790893 TI - Sequential extraction of polysaccharides from enzymatically hydrolyzed okara byproduct: physicochemical properties and in vitro fermentability. AB - Okara, a byproduct of soymilk production, has been upgraded through the use of an enzymatic treatment with Ultraflo L(r) to give a product (okara(ET)) which has a higher content of soluble dietary fibre and an enhanced ratio of soluble: insoluble fibre than is found in okara without treatment. Polysaccharides were isolated from okara(ET) by sequential extraction to yield soluble fractions in water (22%), CDTA (8.7%), alkali (37.7%) without and NaClO2 (9.1%) and the cellulosic residue represents a (22.5%). The physicochemical properties of okara(ET) were improved due to the enzymatic treatment: oil retention capacity (6.94g/g), water retention capacity (10.76g/g) and swelling capacity (13.85g/g) were higher than in okara that had not undergone enzymatic treatment. The gelation capacity (8%) and the cation exchange capacity (8.96mEq/kg) of okara(ET) were lower than that of other byproducts. Short chain fatty acid production during in vitro fermentation of okara(ET) by a pure culture of Bifidobacterium bifidus was mainly represented by acetic acid, followed by propionic and butyric acids. In addition, the decreases in pH and substrate consumption demonstrated the bifidogenic capacity of okara(ET). PMID- 23790894 TI - Multiclass determination of phytochemicals in vegetables and fruits by ultra high performance liquid chromatography coupled to tandem mass spectrometry. AB - In this study a simultaneous determination of several classes of phytochemicals (isoflavones, glucosinolates, flavones, flavonols and phenolic acids) in tomato, broccoli, carrot, eggplant and grape has been carried out by ultra high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC MS/MS). Solid-liquid extraction assisted by rotary agitator was utilised, using a mixture of methanol:water (80:20, v/v) as solvent. The analytical procedure was validated in all the matrices, obtaining recoveries ranging from 60% to 120% with repeatability values (expressed as relative standard deviations, RSDs) lower than 25%. Limits of quantification (LOQs) were always equal or lower than 50MUg/kg, except for some glucosinolates (125MUg/kg). Finally the method was applied to different matrices such as tomato, broccoli, carrot, grape and eggplant, observing that chlorogenic acid was detected in most of the samples at higher concentrations in relation to the other compounds. PMID- 23790895 TI - Use of front face fluorescence for monitoring lipid oxidation during ageing of cakes. AB - Front face fluorescence spectroscopy coupled with chemometric tools was used as a useful tool for the monitoring of sponge cakes freshness, produced at the pilot scale, during ageing (i.e. 1, 3, 6, 9, 16, and 20days). The fluorescence emission spectra were acquired in the 340-490nm and 390-680nm after excitation at 325 and 380nm, respectively, while excitation spectra (250-390nm) were scanned after emission at 410nm. The primary and secondary products of lipid oxidation were also determined on the same cakes. The principal component analysis (PCA) applied to the each spectral collection obtained after excitation at 325 and 380nm and emission at 410nm allowed a clear discrimination of cakes according to their ageing. A high correlation between the intensity of fluorescence at 521nm and the p-anisidine values was observed since squared correlation coefficient of 0.73 was obtained. The results showed that fluorescence spectroscopy could be used as a powerful tool for the evaluation of cake freshness throughout storage. PMID- 23790896 TI - Intermediate role of alpha-keto acids in the formation of Strecker aldehydes. AB - The ability of alpha-keto acids to covert amino acids into Strecker aldehydes was investigated in an attempt to both identify new pathways for Strecker degradation, and analyse the role of alpha-keto acids as intermediate compounds in the formation of Strecker aldehydes by oxidised lipids. The results obtained indicated that phenylalanine was converted into phenylacetaldehyde to a significant extent by all alpha-keto acids assayed; glyoxylic acid being the most reactive alpha-keto acid for this reaction. It has been proposed that the reaction occurs by formation of an imine between the keto group of the alpha-keto acid, and the amino group of the amino acid. This then undergoes an electronic rearrangement with the loss of carbon dioxide to produce a new imine. This final imine is the origin of both the Strecker aldehyde and the amino acid from which the alpha-keto acid is derived. When glycine was incubated in the presence of 4,5 epoxy-2-decenal, the amino acid was converted into glyoxylic acid, and this alpha keto acid was then able to convert phenylalanine into phenylacetaldehyde. All these results suggest that Strecker aldehydes can be produced by amino acid degradation initiated by different reactive carbonyl compounds, included those coming from amino acids and proteins. In addition, alpha-keto acids may act as intermediates for the Strecker degradation of amino acids by oxidised lipids. PMID- 23790897 TI - Tyrosol exerts a protective effect against dopaminergic neuronal cell death in in vitro model of Parkinson's disease. AB - Experimental evidence suggests that tyrosol [2-(4-hydroxyphenyl)ethanol] exhibits potent protective activities against several pathogeneses. In this study, we evaluated the protective effect of tyrosol against 1-methyl-4-phenylpyridinium (MPP(+))-induced CATH.a neuron cell death. Tyrosol dose-dependently protected CATH.a cells from MPP(+)-induced cell death and the protection was more apparent after prolong incubation (48h). The data showed that tyrosol treatment suppressed the reduction of phospho-tyrosine hydroxylase level in CATH.a cells. Further, the compound repressed MPP(+)-induced depletion of mitochondrial membrane potential (Deltapsim) and thereby maintained intracellular ATP production in the cell. The cellular signalling pathway studies revealed that tyrosol protected CATH.a cells from MPP(+)-induced apoptotic signalling, most likely via activation of PI3K/Akt signalling pathway along with up-regulation of anti-oxidative enzymes (SOD-1 and SOD-2) and DJ-1 protein in the cell. Collectively, present study demonstrates that tyrosol significantly protects dopaminergic neurons from MPP(+)-induced degradation, and reveals potential neuroprotective mechanism of tyrosol. PMID- 23790898 TI - Investigations into acrylamide precursors in sterilized table olives: evidence of a peptic fraction being responsible for acrylamide formation. AB - Formation of acrylamide from commercial model peptides containing protein-bound aspartic acid, alanine and methionine, respectively, at 200 degrees C and different times in the absence of any carbonyl sources, was demonstrated by HPLC MS/MS analyses. Further experiments using a more complex model system based on olive water, i.e., the aqueous fraction of olive pulp from untreated and lye treated green olives, were performed. After partial fractionation of olive water by solid-phase extraction, only peptides/proteins containing fractions, being devoid of free asparagine, generated significant amounts of acrylamide during less harsh heat treatment (121 degrees C for 30min). In contrast, acrylamide was not detected after heating the same fraction under identical thermal conditions when previously subjected to acid hydrolysis. Consistently, significant amounts of acrylamide were released after heating the albuminous precipitate resulting from acetone precipitation of olive water. These results strongly support the role of peptides/proteins as precursors of acrylamide formation in sterilized olives. PMID- 23790899 TI - Effects of baking on cyanidin-3-glucoside content and antioxidant properties of black and yellow soybean crackers. AB - Black soybean is a potential functional food ingredient with high anthocyanin content, but the ability to maintain anthocyanin content under dry heat processing has not been reported. This study investigated the effects of soybean seed coat colour and baking time-temperature combinations on the extractable antioxidant properties of a soy cracker food model. Crackers prepared with black soybeans had significantly higher TPC, total isoflavones, and peroxyl, hydroxyl, and ABTS(+) radical scavenging abilities than their yellow counterparts, at all time-temperature combinations. Cyanidin-3-glucoside (C3G) was detected only in black soybean crackers, and all baking treatments significantly decreased C3G. The greatest losses occurred at the low temperature*long time and high temperature*short time, the smallest loss with moderate temperature*short/medium time. The high temperature treatment altered phenolic acid and isoflavone profiles; however, total isoflavones were unaffected. Overall results suggest that moderate baking temperature at minimal time may best preserve anthocyanin and other phenolics in baked black soybean crackers. PMID- 23790900 TI - Validation of a fast and accurate chromatographic method for detailed quantification of vitamin E in green leafy vegetables. AB - Vitamin E analysis in green vegetables is performed by an array of different methods, making it difficult to compare published data or choosing the adequate one for a particular sample. Aiming to achieve a consistent method with wide applicability, the current study reports the development and validation of a fast micro-method for quantification of vitamin E in green leafy vegetables. The methodology uses solid-liquid extraction based on the Folch method, with tocol as internal standard, and normal-phase HPLC with fluorescence detection. A large linear working range was confirmed, being highly reproducible, with inter-day precisions below 5% (RSD). Method sensitivity was established (below 0.02 MUg/g fresh weight), and accuracy was assessed by recovery tests (>96%). The method was tested in different green leafy vegetables, evidencing diverse tocochromanol profiles, with variable ratios and amounts of alpha- and gamma-tocopherol, and other minor compounds. The methodology is adequate for routine analyses, with a reduced chromatographic run (<7 min) and organic solvent consumption, and requires only standard chromatographic equipment available in most laboratories. PMID- 23790901 TI - Purification, antitumor activity in vitro of steroidal glycoalkaloids from black nightshade (Solanum nigrum L.). AB - Six steroidal glycoalkaloids (1-6) were isolated and purified from Solanum nigrum L. (SNL) by acid extraction and alkaline precipitation, various chromatographic techniques, and their structures were elucidated by spectroscopic data. Antitumor activity, structure-activity and its molecular mechanism were investigated by methyl thiazolyl tetrazolium (MTT) method, flow cytometry, colorimetric assay and an immunocytochemical method. Experimental results showed that compounds 1 (solasonine), 2 (beta1-solasonine), 3 (solamargine) and 6 (solanigroside P) have cytotoxicity to MGC-803 cells. Compounds with three sugar units and a-l rhamnopyranose at C-2 or a hydroxyl group on the steroidal backbone may be potential candidates for the treatment of gastric cancer. The mechanism of action may be related to the decrease of mutation p53, the increase of the ratio of Bax to Bcl-2 and the activation of caspase-3 to induce apoptosis. PMID- 23790902 TI - Determination of amino acids in pomegranate juices and fingerprint for adulteration with apple juices. AB - A new chiral micellar electrokinetic chromatography-laser induced fluorescence (MEKC-LIF) method was developed using sodium dodecylbenzene sulphonate (SDBS) as surfactant for the determination of chiral amino acids in pomegranate juices. The use of SDBS as the micellar medium enhanced the fluorescence intensities of amino acids derivatised with fluorescein isothiocyanate (FITC). The amino acid profile of pomegranate juices was compared to apple amino acids and l-Asn was proposed as a marker for the adulteration of pomegranate juices with apple juices. PMID- 23790903 TI - Corn oil and milk enhance the absorption of orally administered allyl isothiocyanate in rats. AB - Allyl isothiocyanate, a chief component of mustard oil, exhibits anticancer effects in both cultured cancer cells and animal models. The accumulation of the N-acetylcysteine conjugate of allyl isothiocyanate, the final metabolite of allyl isothiocyanate, in urine was evaluated in rats that were orally coadministered allyl isothiocyanate with fluids (e.g., water, green tea, milk, and 10% ethanol) or corn oil. The N-acetylcysteine conjugate of allyl isothiocyanate content in urine when allyl isothiocyanate (2 or 4MUmol) was coadministered with corn oil or milk showed a greater increase (1.4+/-0.22 or 2.7+/-0.34MUmol or 1.2+/-0.32 or 2.5+/-0.36MUmol, 1.6- to 1.8-fold or 1.5-fold, respectively) than when allyl isothiocyanate (2 or 4MUmol) was coadministered with water (0.78+/-0.10 or 1.7+/ 0.17MUmol). This result demonstrates that corn oil and milk enhance the absorption of allyl isothiocyanate in rats. PMID- 23790904 TI - First evidence of the presence of S-cysteinylated and S-glutathionylated precursors in tannins. AB - Tannins are widely used in winemaking and food and beverage preparation for the many different contributions they can give to the overall characteristics of the product (e.g., colour stability, mouthfeel and aromatic composition). Varietal thiols and their precursors are one of the most interesting research areas in food science and a lot of effort has been put to further the current understanding on their formation and on the impact of different production strategies on their concentration in the final product. This paper reports the identification of two important thiol precursors (Cys-3MH and GSH-3MH) in commercial grape oenological tannins and, to the best of our knowledge, this information is reported here for the first time. This finding allows potential new perspectives in the winemaking and the food industry, offering the possibility of controlled additions of thiol precursors in pre-fermentative stages in order to tune the aroma profile of fermented products. PMID- 23790905 TI - Quantification of lactosylation of whey proteins in stored milk powder using multiple reaction monitoring. AB - Lactosylation in stored milk powder was quantified by multiple reaction monitoring (MRM), a mass spectrometry-based quantification method. The MRM method was developed from a knowledge of peptide fragmentation. The neutral losses of 162Da (cleavage of galactose) and 216Da (the formation of furylium ion) which were representative of lactosylated peptides were specifically selected as MRM transitions. Quantification of lactosylated protein was based on the peak areas of these fragmentation ions. The MRM results showed an increase in peak areas of the two transition fragments from tryptic digests of whey proteins in stored milk protein concentrate powder. A good correlation between the MRM and furosine results indicated that MRM based on tryptic digests of whole products was a feasible method for quantification of modified milk proteins. PMID- 23790906 TI - The fucoidans from brown algae of Far-Eastern seas: anti-tumor activity and structure-function relationship. AB - The sulfated polysaccharides from brown algae - the fucoidans - are known to be a topic of numerous studies, due to their beneficial biological activities including anti-tumour activity. In this study the effect of fucoidans isolated from brown algae Saccharina cichorioides, Fucus evanescens, and Undaria pinnatifida on the proliferation, neoplastic transformation, and colony formation of mouse epidermal cells JB6 Cl41, human colon cancer DLD-1, breast cancer T-47D, and melanoma RPMI-7951 cell lines was investigated. The algal fucoidans specifically and markedly suppressed the proliferation of human cancer cells with less cytotoxic effects against normal mouse epidermal cells. The highly sulfated (1->3)-alpha-l-fucan from S. cichorioides was found to be vitally important in the inhibition of EGF-induced neoplastic transformation of JB6 Cl41 cells. In colony formation assay the fucoidans from different species of brown algae showed selective anti-tumour activity against different types of cancer, which depended on unique structures of the investigated polysaccharides. These results provide evidence for further exploring the use of the fucoidans from S. cichorioides, F. evanescens, and U. pinnatifida as novel chemotherapeutics against different types of cancer. PMID- 23790907 TI - Simultaneous determination of prenylflavonoid and hop bitter acid in beer lee by HPLC-DAD-MS. AB - An HPLC-DAD-MS method with high accuracy and precision was developed for determination of prenylflavonoids and hop bitter acids in beer lee, a by-product from beer brewing process. Four prenylflavonoids and nine hop bitter acids can be simultaneously separated in 29 min using a Thermo HyPURITY C18 column in combination with diode array dectector and mass spectrometer with HPLC solvent gradient system of phosphoric acid aqueous solution at pH 1.6 and acetonitrile at a flow rate of 1.5 mL/min and detection wavelength at 314 nm. Beer lee is found to contain isoxanthohumol (36.2 MUg/g), xanthohumol (29.6 MUg/g), 8 prenylnaringenin (7.84 MUg/g), 6-prenylnaringenin (19.2 MUg/g), cohumulone (44.7 MUg/g), humulone (123 MUg/g), adhumulone (21.8 MUg/g), colupulone (44.2 MUg/g), lupulone (33.2 MUg/g), and adlupulone (5.76 MUg/g). PMID- 23790908 TI - Protection of flavonoids against hypochlorite-induced protein modifications. AB - Plant polyphenols, such as flavonoids, are ubiquitous components of human diet, and have been recognised as efficient radical scavengers and antioxidants. Their protective effects were especially seen in cell-free assays. Whilst in living cells, depending on experimental conditions, polyphenols may manifest both anti- and pro-oxidative activity. In the present study, the effectiveness of fifteen structurally different flavonoids against hypochlorite-mediated changes in in vitro systems, with and without cells, was tested and compared. Quercetin was found to be the best protector against hypochlorite-mediated fluorescein bleaching and BSA thiol groups oxidation, whilst in living cells its effects on hypochlorite-associated cytotoxicity were moderate. Contrary, epigallocatechin gallate, pelargonidin and catechin, with less impressive hypochlorite scavenging activity in cell-free assays, were the most effective against 3-chlorotyrosine formation after hypochlorite treatment. Taken together, special care should be taken when extrapolating the results on antioxidant propensity of food bioactive compounds in vitro to the cellular milieu. PMID- 23790909 TI - Selective solid-phase extraction using molecular imprinted polymer sorbent for the analysis of florfenicol in food samples. AB - A molecularly imprinted polymer (MIP) for the selective solid phase extraction (SPE) of florfenicol (FF) was prepared using FF as template and 4-vinyl pyridine (4-VP) as functional monomer. For comparison, non-imprinted polymer (NIP) was synthesized in the absence of FF. The synthesized polymers were characterised by infrared spectroscopy (IR), scanning electron microscopy (SEM), thermogravimetry analysis (TGA) and differential thermal analysis (DTA). A molecularly imprinted solid phase extraction (MISPE) procedure was performed in column method by spectrophotometry detection technique. The prepared FF-MIP showed higher adsorption capacity than the non-imprinted polymer (NIP) and the maximum static adsorption capacities of FF on the MIP and the NIP were 4.32 and 2.88mgg(-1), respectively. Kinetics of the adsorption was fast and the adsorption equilibrium was achieved in 30min. The accuracy of the developed method was satisfactory for determination of FF in fish, chicken meat and honey samples. PMID- 23790910 TI - A novel glycoprotein from mushroom Hypsizygus marmoreus (Peck) Bigelow with growth inhibitory effect against human leukemic U937 cells. AB - This study was to isolate the anti-leukaemic component from edible mushroom Hypsizygus marmoreus (Peck) Bigelow. Crude protein was extracted from the basidioma, and then purified with DEAE-Sepharose CL-6B ion exchange chromatography followed by Sephacryl S-300 gel filtration. A protein which exerted high growth inhibitory effect on human leukaemic U937 cells and sufficient toxicological safety on normal human white blood cells was isolated and named HM-3A. Electrophoresis showed HM-3A approximately 52kDa in size. N terminal analysis found the amino acid sequence ATTQWKTSAA and confirmed HM-3A a novel protein. High-performance anion-exchange column chromatography revealed HM 3A a glycoprotein with galactose as the major monosaccharide. Haemagglutination assay proved it non-lectin. We suggest that HM-3A is worth further investigation for antitumour use. PMID- 23790911 TI - Ortho-dihydroxychalcones as cupric ion-dependent prooxidants: activity and mechanisms. AB - The activity and chemical mechanisms of ortho-dihydroxychalcones as cupric ion dependent prooxidants were investigated under aerobic conditions. This work confirms that 3,4,3',4'-tetrahydroxychalcone and cupric ions could synergistically advance strand breakage of plasmid DNA, but also effectively induce DNA damage and apoptosis of human hepatoma HepG2 cells under low concentrations by promoting ROS production. Interestingly, ortho-dihydroxy groups on the aromatic B ring, connected by a double bond, possess higher DNA-cleaving activity than those on the aromatic A ring directly attached to a carbonyl group. Further mechanistic investigation on the cupric ion-mediated oxidation of 3,4,3',4'-tetrahydroxychalcone, by UV/vis spectral changes, reveals that at neutral pH, electron transfer is facilitated by means of sequential proton loss from the 4'-OH on the aromatic A ring and the subsequent formation of phenolate anion-Cu(II) complexes; the resulting phenoxyl radical could undergo the second deprotonation and electron transfer to give an ortho-quinone on the aromatic B ring. PMID- 23790912 TI - A single acute dose of pinitol from a naturally-occurring food ingredient decreases hyperglycaemia and circulating insulin levels in healthy subjects. AB - A limited amount of research suggests that oral ingestion of pinitol (3-O-methyl d-chiro-inositol) positively influences glucose tolerance in humans. This study assessed the effects of different doses of pinitol supplementation on glucose tolerance, insulin sensitivity and plasma pinitol concentrations. Thirty healthy subjects underwent two one-day trials in which they consumed a nutritive beverage (Fruit Up(r)) containing 2.5, 4.0 or 6.0g of pinitol and a corresponding placebo equivalent in both energy and carbohydrates. Blood samples were collected frequently over the 240-min test period. The pinitol-enriched beverage reduced serum glucose and insulin at 45 and 60min, but only at a dose of 6.0g. Plasma pinitol concentrations, maximum concentration and AUC increased according to the dose administered. The results show that a single dose of pinitol from a naturally-occurring food ingredient at the highest dose administered acutely influences indices of whole-body glucose tolerance and insulin sensitivity in healthy subjects. PMID- 23790913 TI - On the glucoside analysis: simultaneous determination of free and esterified steryl glucosides in olive oil. Detailed analysis of standards as compulsory first step. AB - This work covers two important gaps in the field of micronutrient databases: herein we describe a short and easy protocol that allows the analysis of both free and esterified steryl gulcosides in olive oil. By utilising accurate quantitative methods we achieve a better understanding of olive oil composition and health promoting properties. The procedure consists of isolating the fraction of interest through solid phase extraction, and using gas chromatography-flame ionisation detection for both identification and quantification of the derivatised species. Additionally, mass-spectrometry detection has been utilised for confirming the identity of the individual esterified steryl glucosides in some cases. The method's limit of detection has been set at 0.37mg/kg for each free steryl glucoside and 0.20mg/kg for each esterified steryl glucoside, whereas the recoveries are around 96% and 77%, respectively. Finally, we provide a complete analysis of the commercial standard for esterified steryl glucosides, since such information was not yet available. PMID- 23790914 TI - 1H NMR and multivariate data analysis of the relationship between the age and quality of duck meat. AB - To contribute to a better understanding of the factors affecting meat quality, we investigated the influence of age on the chemical composition of duck meat. Aging probably affects the quality of meat through changes in metabolism. Therefore, we studied the metabolic composition of duck meat using (1)H nuclear magnetic resonance (NMR) spectroscopy. Comprehensive multivariate data analysis showed significant differences between extracts from ducks that had been aged for four different time periods. Although lactate and anserine increased with age, fumarate, betaine, taurine, inosine and alkyl-substituted free amino acids decreased. These results contribute to a better understanding of changes in duck meat metabolism as meat ages, which could be used to help assess the quality of duck meat as a food. PMID- 23790915 TI - Proteolysis of noncollagenous proteins in sea cucumber, Stichopus japonicus, body wall: characterisation and the effects of cysteine protease inhibitors. AB - Proteolysis of noncollagenous proteins in sea cucumber, Stichopus Japonicus, body wall (sjBW) was investigated. The proteins removed from sjBW by SDS and urea extraction were mainly noncollagenous proteins with molecular weights about 200kDa (Band I) and 44kDa (Band II), respectively. Band I and Band II were identified as major yolk protein (MYP) and actin, respectively, from holothurian species by liquid chromatography-mass spectrometry (LC-MS/MS) with significant scores. Based on TCA-soluble oligopeptide assay, the optimum proteolysis condition of noncollagenous proteins was at 46.3 degrees C and pH 6.1, by response surface methodology. The proteolysis of MYP, and actin, was partially inhibited by cysteine protease inhibitors, including Trans-epoxysuccinyl-l-leucyl amido (4-guanidino) butane (E-64), iodoacetic acid, antipain and whey protein concentrate. These results suggest that cysteine proteases are partially involved in the proteolysis of noncollagenous proteins in body wall of sea cucumber, S. japonicus. PMID- 23790917 TI - Determination of ethyl carbamate in wine by high performance liquid chromatography. AB - Kinetics of pre-column derivatization with 9-xanthydrol for the determination of ethyl carbamate (EC) in wine by a previous high performance liquid chromatographic method with fluorescence detection was studied and further developed. The life-time of the derivatized product and its excitation/absorption spectra were systematically investigated. Using low acidity (pH=2.5 set by phosphate buffers) only 3% of 9-xanthyl ethyl carbamate (XEC) decomposes in ~48h, allowing a prolonged storage time of the derivatized EC conferring more accurate determination for large sample batches. Detection limit of this method is 3MUgL( 1), while its average recovery is 98.5+/-4.9%. Calibration is linear up to 400MUgL(-1). The EC content in 33 Hungarian wine samples ranges from 4.9 to 39.9MUgL(-1) (average: 17.7MUgL(-1), median: 16.7MUgL(-1)), while only three of them was slightly over 30MUgL(-1) EC, it being the maximum allowed concentration in countries already having legislation. PMID- 23790916 TI - Extraction, antioxidant capacity and identification of Semen Astragali Complanati (Astragalus complanatus R. Br.) phenolics. AB - A study about the ultrasonic extraction, antioxidant capacity and identification of phenolics from Semen Astragali Complanati was undertaken. The optimised extraction condition with an orthogonal experiment design of L9(3(4)) was 50 degrees C, 30min and 15:1 (methanol solution:sample, mL:g). An extraction yield of 40.12+/-1.10mg gallic acid/g dry seed and the antioxidant capacity of 0.85+/ 0.13mg dry extract/mg DPPH were obtained with the optimum condition, respectively. For each extraction set, the antioxidant capacity by 2,2-diphenyl-1 picrylhydrazyl radical assay highly correlated to its total phenolic content by Folin-Ciocalteu method. Twelve phenolic components obtained with the optimised extraction procedure were tentatively identified by Ultra Performance Liquid Chromatography coupled with Q-TOF Mass Spectrometer (UPLC-Q-TOF) according to their mass spectrometry, UV/vis spectrometry, and related literature reports. Furthermore, the ultrasonic effect on the particles' microstructure of Semen Astragali Complanati was also investigated by scanning electron microscopy (SEM) analysis. PMID- 23790918 TI - Antioxidant activity of white rice, brown rice and germinated brown rice (in vivo and in vitro) and the effects on lipid peroxidation and liver enzymes in hyperlipidaemic rabbits. AB - Antioxidant activity of different rice extract and the effect on the levels of antioxidant enzyme activity, superoxide dismutase (SOD) and glutathione peroxidase (GPx), vitamin E, lipid peroxidation and liver enzymes in hyperlipidaemia rabbits were investigated. Germinated brown rice (GBR) has the highest antioxidant activity compared to white rice (WR) and brown rice (BR). All rice grains increased the activity of SOD and GPx. However, vitamin E levels increased only in the groups that received the BR and GBR diets. The reduction of lipid peroxidation levels and activity of hepatic enzymes (alanine transferase, ALT and aspartate transaminase, AST) were only significantly observed in the GBR group. In conclusion, GBR supplementation has the greatest impact on increasing antioxidant enzyme activity and vitamin E level and on reducing lipid peroxidation in hypercholesterolaemia rabbit, thereby preventing the formation of atherosclerotic plaques. Furthermore, GBR diet can also reduce the level of hepatic enzymes. PMID- 23790919 TI - Cytotoxic impact of phenolics from Lamiaceae species on human breast cancer cells. AB - The aim of this study was to evaluate the cytotoxicity of dried aqueous extracts from Thymus serpyllum (ExTs), Thymus vulgaris (ExTv), Majorana hortensis (ExMh), and Mentha piperita (ExMp), and the phenolic compounds caffeic acid (CA), rosmarinic acid (RA), lithospermic acid (LA), luteolin-7-O-glucuronide (Lgr), luteolin-7-O-rutinoside (Lr), eriodictiol-7-O-rutinoside (Er), and arbutin (Ab), on two human breast cancer cell lines: Adriamycin-resistant MCF-7/Adr and wild type MCF-7/wt. In the MTT assay, ExMh showed the highest cytotoxicity, especially against MCF-7/Adr, whereas ExMp was the least toxic; particularly against MCF 7/wt cells. RA and LA exhibited the strongest cytotoxicity against both MCF-7 cell lines, over 2-fold greater than CA and Lgr, around 3-fold greater than Er, and around 4- to 7-fold in comparison with Lr and Ab. Except for Lr and Ab, all other phytochemicals were more toxic against MCF-7/wt, and all extracts exhibited higher toxicity against MCF-7/Adr. It might be concluded that the tested phenolics exhibited more beneficial properties when they were applied in the form of extracts comprising their mixtures. PMID- 23790920 TI - Absolute quantification of dehydroacetic acid in processed foods using quantitative 1H NMR. AB - An absolute quantification method for the determination of dehydroacetic acid in processed foods using quantitative (1)H NMR was developed and validated. The level of dehydroacetic acid was determined using the proton signals of dehydroacetic acid referenced to 1,4-bis (trimethylsilyl) benzene-d4 after simple solvent extraction from processed foods. All the recoveries from three processed foods spiked at two different concentrations were larger than 85%. The proposed method also proved to be precise, with inter-day precision and excellent linearity. The limit of quantification was confirmed as 0.13g/kg in processed foods, which is sufficiently low for the purposes of monitoring dehydroacetic acid. Furthermore, the method is rapid and easy to apply, and provides International System of Units traceability without the need for authentic analyte reference materials. Therefore, the proposed method is a useful and practical tool for determining the level of dehydroacetic acid in processed foods. PMID- 23790921 TI - Effect of high pressure processing on rheological and structural properties of milk-gelatin mixtures. AB - There is an increasing demand to tailor the functional properties of mixed biopolymer systems that find application in dairy food products. The effect of static high pressure processing (HPP), up to 600MPa for 15min at room temperature, on milk-gelatin mixtures with different solid concentrations (5%, 10%, 15% and 20% w/w milk solid and 0.6% w/w gelatin) was investigated. The viscosity remarkably increased in mixtures prepared with high milk solid concentration (15% and 20% w/w) following HPP at 300MPa, whereas HPP at 600MPa caused a decline in viscosity. This was due to ruptured aggregates and phase separation as confirmed by confocal laser scanning microscopy. Molecular bonding of the milk-gelatin mixtures due to HPP was shown by Fourier-transform infrared spectra, particularly within the regions of 1610-1690 and 1480-1575cm(-1), which reflect the vibrational bands of amide I and amide II, respectively. PMID- 23790922 TI - Monola oil versus canola oil as a fish oil replacer in rainbow trout feeds: effects on growth, fatty acid metabolism and final eating quality. AB - Monola oil, a high oleic acid canola cultivar, and canola oil were evaluated as replacers of fish oil at three levels of inclusion (60%, 75% and 90%) in rainbow trout diets. After a 27-week grow-out cycle, the diet-induced effects on growth, fatty acid metabolism and final eating quality were assessed. Overall, no effects were noted for growth, feed utilisation or fish biometry, and the fatty acid composition of fish fillets mirrored that of the diets. Dietary treatments affected fillet lipid oxidation (free malondialdehyde), pigmentation and flavour volatile compounds, but only minor effects on sensorial attributes were detected. Ultimately, both oils were demonstrated to possess, to differing extents, suitable qualities to adequately replace fish oil from the perspective of fish performance and final product quality. However, further research is required to alleviate on-going issues associated with the loss of health promoting attributes (n-3 long chain polyunsaturated fatty acids) of final farmed products. PMID- 23790923 TI - Identification of bitter compounds in whole wheat bread. AB - Bitterness in whole wheat bread can negatively influence product acceptability and consumption. The overall goal of this project was to identify the main bitter compounds in a commercial whole wheat bread product. Sensory-guided fractionation of the crust (most bitter portion of the bread sample) utilising liquid-liquid extraction, solid-phase extraction, ultra-filtration and 2-D offline RPLC revealed multiple bitter compounds existed. The compounds with the highest bitterness intensities were selected and structurally elucidated based on accurate mass-TOF, MS/MS, 1D and 2D NMR spectroscopy. Eight bitter compounds were identified: Acortatarins A, Acortatarins C, 5-(hydroxymethyl)furfural(HMF), 2,3 dihydro-3,5-dihydroxy-6-methyl-4(H)-pyran-4-one (DDMP), N-(1-deoxy-d-fructos-1 yl)-l-tryptophan (ARP), Tryptophol (TRO), 2-(2-formyl-5-(hydroxymethyl-1H-pyrrole 1-yl)butanoic acid (PBA) and Tryptophan (TRP). Based on the structures of these compounds, two main mechanisms of bitterness generation in wheat bread were supported, fermentation and Maillard pathways. PMID- 23790924 TI - Impact of flavour solvent (propylene glycol or triacetin) on vanillin, 5 (hydroxymethyl)furfural, 2,4-decadienal, 2,4-heptadienal, structural parameters and sensory perception of shortcake biscuits over accelerated shelf life testing. AB - The influence of choice of flavour solvent, propylene glycol (PG) or triacetin (TA), was investigated during accelerated shelf life (ASL) testing of shortcake biscuits. Specifically, the differential effect on the stability of added vanillin, the natural baked marker compound 5-(hydroxymethyl)furfural (HMF), specific markers of oxidative rancidity (2,4-decadienal, 2,4-heptadienal), and the structural parameters of hardness and fracturability. Significantly more HMF was formed during baking of biscuits prepared with TA; these biscuits were also more stable to oxidative degradation and loss of vanillin during ageing than biscuits prepared with PG. Fresh TA biscuits were significantly more brittle than fresh PG biscuits. There was no impact of solvent choice on hardness. Sensory evaluation of hardness, vanilla flavour and oily off-note was tested during ASL testing. There was no significant impact of storage on sensory ratings for either the PG or TA biscuits. PMID- 23790925 TI - Optimisation of ultrasonic-assisted extraction of antioxidant compounds from Artemisia absinthium using response surface methodology. AB - Response surface methodology was used to optimise experimental conditions for ultrasonic-assisted extraction of phenolic compounds from Artemisia absinthium. The central composite design was employed, the extracts were characterised by the determination of total phenolic content and antioxidant capacity. The total phenolic contents of extracts were determined by Folin method and also total antioxidant capacities of extracts were determined by ABTS and CUPRAC methods. The phenolic compounds of A. absinthium at optimum extraction conditions were determined by HPLC-DAD. The optimum conditions were determined as HCl concentration between 0.41 and 0.44mol/L, methanol volume between 55% and 59% (v/v), extraction temperature between 64 and 70 degrees C, extraction time between 101 and 107min. The experimental values agreed with those predicted within a 95% confidence level, thus indicating the suitability of response surface methodology in optimising the ultrasound-assisted extraction of phenolic compounds from A. absinthium. PMID- 23790926 TI - Mass production of the ginsenoside Rg3(S) through the combinative use of two glycoside hydrolases. AB - The ginsenoside Rg3(S), which is one of the exceptional components of Korean red ginseng extract, has been known to have anti-cancer, anti-metastatic, and anti obesity effects. An enzymatic bioconversion method was developed to obtain the ginsenoside Rg3(S) with a high specificity, yield, and purity. Two glycoside hydrolases (BglBX10 and Abf22-3) were employed to produce Rg3(S) as a 100g unit. The conversion reaction transformed ginsenoside Rc to Rd using Abf22-3, followed by Rb1 and Rd to Rg3(S), using BglBX10. It was performed in a 10L jar fermenter at pH 6.0 and 37 degrees C for 24h, with a high concentration of 50mg/ml of purified ginsenoside mixture obtained from ginseng roots. Finally, 144g of Rg3(S) was produced from 250g of root extract with 78+/-1.2% chromatographic purity. These results suggest that this enzymatic method would be useful in the preparation of ginsenoside Rg3(S) for the functional food and pharmaceutical industries. PMID- 23790927 TI - Changes of antioxidant activity and formation of 5-hydroxymethylfurfural in honey during thermal and microwave processing. AB - The paper presents the results of microwave irradiation and conventional heating of honey. These two kinds of thermal treatment result in the formation of 5 hydroxymethyl-2-furfural (HMF), and changes in the antioxidant potential of honeys, which were studied as well. Four types of honey (honeydew, lime, acacia, buckwheat) were analyzed. Honey samples were subjected to conventional heating in a water bath (WB) at 90 degrees C up to 60min or to the action of a microwave field (MW) with constant power of 1.26W/g of the sample up to 6min. Changes in the antioxidant capacity of honeys were measured as a percentage of free radical (ABTS(+)and DPPH) scavenging ability. Changes in the total polyphenols content (TPC) (equivalents of gallic acid mg/100g of honey) were also determined. Formation of HMF in honey treated with a microwave field was faster in comparison with the conventional process. Changes in the antioxidant properties of honey subjected to thermal or microwave processing might have been botanical origin dependent. PMID- 23790928 TI - Application of graphene-based solid-phase extraction for ultra-fast determination of malachite green and its metabolite in fish tissues. AB - An ultra-fast analytical protocol using graphene-based solid-phase extraction coupled with ultra-performance liquid chromatography-tandem mass spectrometry for the rapid determination of malachite green and its metabolite, leucomalachite green in fish tissues has been developed. In the present work, graphene was synthesized and evaluated as novel solid-phase extraction sorbents for the analytes enrichment and clean-up. The target analytes were separated on an ultra pressure BEH C8 column and quantified by a triple-quadrupole linear ion trap mass spectrometer in multiple-reaction monitoring mode. The proposed analytical procedures were carefully optimized and validated. The matrix-matched calibration curves were performed at six concentration levels and good linear relationship (R(2)>0.9990) was observed within the range of 0.25-50MUgkg(-1). The proposed method has been successfully applied to the analysis of MG and LMG in several fish samples, indicating that graphene was an efficient SPE sorbent for the enrichment of trace residues in food analysis. PMID- 23790929 TI - Effects of binary organic solvents and heating on lipid removal and the reduction of beany odour in Bambara groundnut (Vigna subterranean) flour. AB - Effects of various binary organic solvents at different temperatures on the removal of lipids and beany or grassy odour of Bambara groundnut flour were studied. The highest lipid removal was achieved at 60 degrees C (P<0.05), regardless of binary organic solvents used. Under the optimal temperature, chloroform/methanol showed the highest lipid removal (87%), followed by hexane/isopropanol (78%). All binary solvents containing methanol had higher efficiency in removal of phospholipids, and inactivation of lipoxygenase and trypsin inhibitors, as compared to isopropanol containing solvents (P<0.05). Based on FTIR spectra, lipids removed by methanol containing solvents had high content of phospholipids. The flours defatted by methanol containing solvents exhibited the lowest peroxide value, thiobarbituric acid-reactive substances and beany odour intensity than the non-defatted flour and those defatted by isopropanol containing solvents throughout the storage (P<0.05) of 30days at refrigerated and room temperatures. In general, chloroform/methanol was the most effective in inactivating lipoxygenase and trypsin inhibitors, retarding lipid oxidation as well as beany odour development in flour. Therefore, chloroform/methanol could be used to lower beany or grassy odour in Bambara groundnut flour. PMID- 23790930 TI - Effect of ionising radiation on polyphenolic content and antioxidant potential of parathion-treated sage (Salvia officinalis) leaves. AB - The gamma-irradiation effects on polyphenolic content and antioxidant capacity of parathion-pretreated leaves of Salvia officinalis plant were investigated. The analysis of phenolic extracts of sage without parathion showed that irradiation decreased polyphenolic content significantly (p<0.05) by 30% and 45% at 2 and 4kGy, respectively, compared to non-irradiated samples. The same trend was observed for the Trolox equivalent antioxidant capacity (TEAC), as assessed by the anionic DPPH and cationic ABTS radical-scavenging assays. The antioxidant potential decreased significantly (p<0.01) at 2 and 4kGy, by 11-20% and 40-44%, respectively. The results obtained with a pure chlorogenic acid solution confirmed the degradation of phenols; however, its TEAC was significantly (p<0.01) increased following irradiation. Degradation products of parathion formed by irradiation seem to protect against a decline of antioxidant capacity and reduce polyphenolic loss. Ionising radiation was found to be useful in breaking down pesticide residues without inducing significant losses in polyphenols. PMID- 23790931 TI - Effects of food formulation and thermal processing on flavones in celery and chamomile. AB - Flavones isolated from celery varied in their stability and susceptibility to deglycosylation during thermal processing at pH 3, 5, or 7. Apigenin 7-O apiosylglucoside was converted to apigenin 7-O-glucoside when heated at pH 3 and 100 degrees C. Apigenin 7-O-glucoside showed little conversion or degradation at any pH after 5h at 100 degrees C. Apigenin, luteolin, and chrysoeriol were most stable at pH 3 but progressively degraded at pH 5 or 7. Chamomile and celery were used to test the effects of glycosidase-rich foods and thermal processing on the stability of flavone glycosides. Apigenin 7-O-glucoside in chamomile extract was readily converted to apigenin aglycone after combination with almond, flax seed, or chickpea flour. Apigenin 7-O-apiosylglucoside in celery leaves was resistant to conversion by beta-glucosidase-rich ingredients, but was converted to apigenin 7-O-glucoside at pH 2.7 when processed at 100 degrees C for 90min and could then be further deglycosylated when mixed with almond or flax seed. Thus, combinations of acid hydrolysis and glycosidase enzymes in almond and flax seed were most effective for developing a flavone-rich, high aglycone food ingredient from celery. PMID- 23790932 TI - Potential antiradical and alpha-glucosidase inhibitors from Ecklonia maxima (Osbeck) Papenfuss. AB - Alpha-glucosidase inhibitors play a potential role in the treatment of type 2 diabetes by delaying glucose absorption in the small intestine. Ecklonia maxima, a brown alga which grows abundantly on the west coast of South Africa, is used to produce alginate, animal feed, nutritional supplements and fertilizer. The crude aqueous methanol extract, four solvent fractions and three phlorotannins: 1,3,5 trihydroxybenezene (phloroglucinol) (1), dibenzo [1,4] dioxine-2,4,7,9-tetraol (2) and hexahydroxyphenoxydibenzo [1,4] dioxine (eckol) (3) isolated from E. maxima were evaluated for antiradical and alpha-glucosidase inhibitory activities. All the phlorotannins tested had strong antioxidant activities on DPPH free radicals with EC50 values ranging from 0.008 to 0.128MUM. Compounds 2 and 3 demonstrated stronger antioxidant activity and an alpha-glucosidase inhibitory property than positive controls. These results suggest that E. maxima could be a natural source of potent antioxidants and alpha-glucosidase inhibitors. This study could facilitate effective utilization of E. maxima as an oral antidiabetic drug or functional food ingredient with a promising role in the formulation of medicines and nutrition supplements. PMID- 23790933 TI - Functional, thermal and molecular behaviours of ozone-oxidised cocoyam and yam starches. AB - Ozone-oxidised starches were prepared from the native starches isolated from white and red cocoyam, and white and yellow yam cultivars. The native and oxidised starches were evaluated for functional, thermal and molecular properties. The correlations between the amount of reacted ozone and carbonyl and carboxyl contents of the starches were positive, as ozone generation time (OGT) increased. Significant differences were obtained in terms of swelling power, solubility, pasting properties and textural properties of the native starches upon oxidation. The DSC data showed lower transition temperatures and enthalpies for retrograded gels compared to the gelatinized gels of the same starch types. The native starches showed CB-type XRD patterns while the oxidised starches resembled the CA-type pattern. As amylose content increased, amylopectin contents of the starches decreased upon oxidation. Similarly, an increase in Mw values were observed with a corresponding decrease in Mn values upon oxidation. PMID- 23790934 TI - Echium oil is better than rapeseed oil in improving the response of barramundi to a disease challenge. AB - Pathogen infection stimulates the fatty acid (FA) metabolism and the production of pro-inflammatory derivatives of FA. Barramundi, Lates calcarifer, was fed on a diet rich in preformed long-chain (?C20) polyunsaturated fatty acids (LC-PUFA) from fish oil (FO), to compare with diets containing high levels of C18 precursors for LC-PUFA - stearidonic (SDA) and gamma-linolenic acid (GLA) - from Echium plantagineum (EO), or rapeseed oil (RO) rich in alpha-linolenic acid (ALA), but a poor source of LC-PUFA and their precursors. After 6weeks, when growth rates were similar amongst the dietary treatments, a sub-lethal dose of Streptococcus iniae was administered to half of the fish, while the other half were maintained unchallenged and were pair-fed with the infected fish. Under a disease challenge situation, the tissue FA depots depleted at 3days post infection (DPI) and were then restored to their previous concentrations at 7DPI. During the infection period, EO fish had a higher content of n3 and n6 PUFA in their tissues, higher n3:n6 PUFA ratio and reduced levels of the eicosanoids, TXB2 and 6-keto-PGF1alpha, in their plasma compared with RO fish. Fish fed on FO and EO had a longer lasting and enduring response in their FA and eicosanoid concentrations, following a week of bacterial infection, compared with those fed on RO. EO, containing SDA and GLA and with a comparatively higher n3:n6 PUFA ratio, proved more effective than RO in compensating for immunity stress. PMID- 23790935 TI - A rapid HPLC column switching method for sample preparation and determination of beta-carotene in food supplements. AB - A simple and automated HPLC column-switching method with rapid sample pretreatment has been developed for quantitative determination of beta-carotene in food supplements. Commercially samples of food supplements were dissolved in chloroform with help of saponification with 1M solution of sodium hydroxide in ultrasound bath. A 20-min sample dissolution/extraction step was necessary before chromatography analysis to transfer beta-carotene from solid state of food supplements preparations (capsules,tablets) to chloroform solution. Sample volume - 3MUL of chloroform phase was directly injected into the HPLC system. Next on line sample clean-up was achieved on the pretreatment precolumn Chromolith Guard Cartridge RP-18e (Merck), 10*4.6mm, with a washing mobile phase (methanol:water, 92:8, (v/v)) at a flow rate of 1.5mL/min. Valve switch to analytical column was set at 2.5min in a back-flush mode. After column switching to the analytical column Ascentis Express C-18, 30*4.6mm, particle size 2.7MUm (Sigma Aldrich), the separation and determination of beta-carotene in food supplements was performed using a mobile phase consisting of 100% methanol, column temperature at 60 degrees C and flow rate 1.5mL/min. The detector was set at 450nm. Under the optimum chromatographic conditions standard calibration curve was measured with good linearity - correlation coefficient for beta-carotene (r(2)=0.999014; n=6) between the peak areas and concentration of beta-carotene 20-200MUg/mL. Accuracy of the method defined as a mean recovery was in the range 96.66-102.40%. The intraday method precision was satisfactory at three concentration levels 20, 125 and 200MUg/mL and relative standard deviations were in the range 0.90-1.02%. The chromatography method has shown high sample throughput during column-switching pretreatment process and analysis in one step in short time (6min) of the whole chromatographic analysis. PMID- 23790936 TI - Physicochemical, in vitro digestibility and functional properties of carboxymethyl rice starch cross-linked with epichlorohydrin. AB - Cross-linked carboxymethyl rice starches (CL-CMRSs) were prepared from reactions between native rice starch and varied concentrations (0.1-15%w/w, M-0.1 to M-15) of epichlorohydrin (ECH) in a simultaneous carboxymethylation-crosslinking reaction setup using methanol as the solvent. The degree of carboxymethyl substitution was between 0.24 and 0.28, while apparent amylose contents were lowered due to modification. SEM images showed minor change on the granule surface, while XRD profiles indicated slight loss of crystallinity. DSC thermograms revealed no transition peak in all treated samples. The water uptake (WU), swelling volume (SV) and free swelling capacity (FSC) of CL-CMRSs increased significantly as a result of the modification, while swelling of CMRSs cross linked with 2% (M-2) and 3% (M-3) ECH yielded FSC values and WU values that were much greater than those of native starches and were comparable to that of Explotab(r). All modified starch samples showed increased amount of rapidly digestible starch (RDS), while cross-linking with 5-7.5% ECH raised the resistant starch (RS) content, compared to native starch. M-2 also showed promising results in tablet disintegration test. ECH-CL-CMRSs could potentially be used as an excipient in pharmaceutical and food/food supplement products. PMID- 23790937 TI - Enzymatic browning and after-cooking darkening of Jerusalem artichoke tubers (Helianthus tuberosus L.). AB - Jerusalem artichoke tubers (Helianthus tuberosus L.) undergo enzymatic browning when peeled or cut, and turn grey after boiling, due to after-cooking darkening reactions between iron and phenolic acids. In an attempt to reveal the components responsible for these discolouration reactions, sensory evaluation and instrumental colour measurements were related to contents of total phenolics, phenolic acids, organic acids and iron in three varieties of raw and boiled Jerusalem artichoke tubers harvested in the autumn and the spring. No differences were found between varieties in sensory evaluated enzymatic browning, but Rema and Draga had higher scores than Mari in after-cooking darkening. Jerusalem artichoke tubers had higher contents of total phenolics, phenolic acids and citric acid in the autumn and low contents in the spring, while it was the opposite for malic acid. None of the chemical parameters investigated could explain the discolouration of the Jerusalem artichoke tubers. PMID- 23790938 TI - Ultra-high-performance liquid chromatography-ion trap mass spectrometry characterisation of milk polar lipids from dairy cows fed different diets. AB - Milk polar lipids are an important class of biologically active species for human health and for improving the physical functionality of food ingredients. Milk polar lipids from 144 multiparous Holstein-Friesian dairy cows fed different diets were analysed using ultra-high-performance liquid chromatography-ion trap mass spectrometry (UHPLC-MS(n)). A complex profile of polar lipids, consisting of 7 species of phosphatidylinositol (PI), 12 species of phosphatidylethanolamine (PE), 18 species of phosphatidylcholine (PC) and 13 species of sphingomyelin (SM) were identified from the molecular ions and sequential MS(n) fragmentation. Qualitative assessment of the data suggested that different cow diets influenced the relative amounts of a small number of species in the milk samples, e.g. PE 14:0/18:1, PE 18:0/18:1, PC 15:0/18:1, PC 18:0/18:1, SM d18:1/14:0, SM d18:1/15:0, SM d18:1/22:0 and SM d18:1/23:0. PMID- 23790939 TI - Authentication of a Turkish traditional aniseed flavoured distilled spirit, raki. AB - Consumption of traditional aniseed alcoholic beverage, raki, adulterated with methanol results in deaths, therefore, its detection is an important issue. In this study, mid-infrared spectra of pure and methanol adulterated (0.5-10% (vol/vol)) raki samples were collected with an attenuated total reflectance attachment of a Fourier-transform infrared spectrometer. Principal component analysis was used to discriminate pure and adulterated raki samples, then, a partial least square model was constructed to determine the adulterant methanol content in raki using mid-IR spectral data. A minimum threshold level of 0.5% methanol in raki samples was successfully detected. A good prediction model for determination of methanol adulteration ratio in raki samples was also constructed (R(2)=0.98 and RPD=8.35). PMID- 23790940 TI - Colloidal approach to prepare colour blends from colourants with different solubility profiles. AB - Food colouring plays a vital and a determining role in the processing and the manufacturing of food products because the appearance of products is critical for attracting consumers and influencing their food choices. However, factors such as legislative restrictions, limited number of approved colourants and the processing, formulation and stability issues of the natural colourants severely limits the application of food colouring in actual product formats. Hence, finding alternatives to the currently utilised formulation practises, represents an important area of research. Here, we report a simple colloidal approach to prepare colour blends by co-incorporating colourants with contrasting aqueous solubility profiles in composite colloidal particles. Curcumin and indigocarmine were selected as water insoluble and water soluble food-grade colourants respectively and incorporated in the colloidal particles prepared from food protein-zein. Composite particles obtained by loading of curcumin and indigocarmine (at different ratios) had mean particle size ranging from 76 to 300nm. The spherical shape of the colloidal particles was confirmed using transmission electron microscopy and the colloidal dispersions were further characterised using UV-Vis and fluorescence spectroscopy. The incorporation of colourants in colloidal particles led to the generation of different shade of colour in yellow-green-blue range. The encapsulation also led to the stabilization of individual pigments against photodegradation. Such composite colloidal particles could potentially serve as an approach for developing tuneable colouring system for food and nutraceutical applications. PMID- 23790941 TI - Influence of particle size on lipid digestion and beta-carotene bioaccessibility in emulsions and nanoemulsions. AB - The interest in incorporating carotenoids, such as beta-carotene, into foods and beverages is growing due to their potential health benefits. However, the poor water-solubility and low bioavailability of carotenoids is currently a challenge to their incorporation into many foods. The aim of this work was to study the influence of particle size on lipid digestion and beta-carotene bioaccessibility using corn oil-in-water emulsions with different initial droplet diameters: large (d43~23MUm); medium (d43~0.4MUm); and small (d43~0.2MUm). There was a progressive increase in the mean particle size of all the emulsions as they passed through a simulated gastrointestinal tract (GIT) consisting of mouth, stomach, and small intestine phases, which was attributed to droplet coalescence, flocculation, and digestion. The electrical charge on all the lipid particles became highly negative after passage through the GIT due to accumulation of anionic bile salts, phospholipids, and free fatty acids at their surfaces. The rate and extent of lipid digestion increased with decreasing mean droplet diameter (small~medium?large), which was attributed to the increase in lipid surface area exposed to pancreatic lipase with decreasing droplet size. There was also an appreciable increase in beta-carotene bioaccessibility with decreasing droplet diameter (small>medium>large). These results provide useful information for designing emulsion-based delivery systems for carotenoids for food and pharmaceutical uses. PMID- 23790942 TI - Polymethoxylated, C- and O-glycosyl flavonoids in tangelo (Citrus reticulata*Citrus paradisi) juice and their influence on antioxidant properties. AB - A separation/identification protocol based on RP-LC-DAD-ESI-MS-MS has been employed for the characterisation of the flavonoid fraction of the juice from tangelos (Citrus reticulata*Citrus paradisi) grown in Southern Italy. Eleven compounds were identified in a single chromatographic course. Of these, two C glycosyl flavones (lucenin-2 and vicenin-2) and an O-triglycosyl flavanone (narirutin 4'-O-glucoside) were identified for the first time. Fruit juice antioxidant activity was evaluated on the basis of its ability to scavenge DPPH, O2(-), OH and ABTS(+) radicals, and to reduce iron (FRAP). Moreover, the influence of the identified polymethoxylated, C- and O-glycosyl flavonoids on the total antioxidant activity has been elucidated. We also checked the antimicrobial activity of a broad fraction, containing all the detected flavonoids obtained by preparative HPLC, in terms of MICs for Staphylococcus aureus. PMID- 23790943 TI - Transfer of perfluorooctane sulfonic acid (PFOS) from contaminated feed to dairy milk. AB - Dietary intake is the predominant route for human exposure to perfluorooctane sulfonic acid (PFOS). Single pollution events may thus affect human exposure if polluted ground and water is used to produce animal feed or food. In this study, a physiologically based pharmacokinetic (PBPK-) model is derived that describes the uptake of PFOS from contaminated feed by cows and its subsequent elimination through the cows' milk. Parameter values of the model were estimated by fitting to experimental data of a cow feeding trial. Model calculations showed that almost all PFOS ingested is excreted through the cows' milk. The elimination rate, however, was low as the estimated half-life in the cow was 56days and it may, thus, take a long time after an initial pollution event to produce PFOS-free milk. The derived model can be used to estimate the transfer of PFOS through the dairy food chain and can be used for comparison of various contamination routes. PMID- 23790944 TI - Evaluation of the antioxidant and antiproliferative activities of extracted saponins and flavonols from germinated black beans (Phaseolus vulgaris L.). AB - Flavonoids and saponins from common beans have been widely studied due to their bioactivity. This research evaluated the effect of germination of black beans (Phaseolus vulgaris L.) on the antioxidant capacity and antiproliferative activity against cancer cell lines of saponins and flavonoids extracted from seed coats, cotyledons and sprouts. Principal component analysis was performed to achieve punctual associations between the black bean saponins and flavonoids concentrations to the antioxidant capacity and the antiproliferative activities. Total phenolic content and antioxidant capacity of extracts were higher when obtained from seed coats, mainly from the 3rd germination day. The extracts obtained from seed coats after 3 and 5 germination days inhibited all cancer cell lines proliferation with no cytotoxicity against control cells. Genistein was related with the activity against mammary cancer cells but flavonols and group B saponins were more related with hepatic and colon cancers. Non-glycosilated flavonols were related with antioxidant capacity. PMID- 23790945 TI - Binding of curcumin to beta-lactoglobulin and its effect on antioxidant characteristics of curcumin. AB - The binding of curcumin (CCM) to bovine beta-lactoglobulin (beta-Lg) was investigated by Fourier transform infrared and fluorescence. The effect of binding on antioxidant activity of CCM was determined by using ABTS and hydroxyl radical scavenging capacity and total reducing ability. Our results showed that when CCM binds to beta-Lg, it lead to a partial change in protein structure. In fact, CCM was bound respectively to two different sites of protein at pH 6.0 and 7.0 via hydrophobic interaction. CCM-beta-Lg complex was formed by one molecule of protein combining with one molecule of CCM. Moreover, the average distance from one binding site to Trp residues in protein is similar with another. This result suggested that fluorescence resonance energy transfer cannot be used as unique method to study the characteristics of binding of ligands to proteins. The antioxidant activity of CCM might be improved by binding with beta-Lg. PMID- 23790946 TI - Spirostane, furostane and cholestane saponins from Persian leek with antifungal activity. AB - A phytochemical investigation of the seeds of Persian leek afforded the isolation of two new spirostane glycosides, persicosides A (1) and B (2), four new furostane glycosides, isolated as a couple of inseparable mixture, persicosides C1/C2 (3a/3b) and D1/D2 (4a/4b), one cholestane glycoside, persicoside E (5), together with the furostane glycosides ceposides A1/A2 and C1/C2 (6a/6b and 7a/7b), tropeosides A1/A2 and B1/B2 (8a/8b and 9a/9b), and ascalonicoside A1/A2 (10a/10b), already described in white onion, red Tropea onion, and shallot, respectively. Structure elucidation of the compounds was carried out by comprehensive spectroscopic analyses, including 2D NMR spectroscopy and MS spectrometry, and by chemical evidences. The chemical structure of new compounds were identified as (25S)-spirostan-2alpha,3beta,6beta-triol 3-O-[beta-d glucopyranosyl-(1->3)] [beta-d-xylopyranosyl-(1->2)]-beta-d-glucopyranosyl-(1->4) beta-d-galactopyranoside (1), (25S)-spirostan-2alpha,3beta,6beta-triol 3-O-[beta d-xylopyranosyl-(1->3)] [alpha-l-rhamnopyranosyl-(1->2)]-beta-d-glucopyranosyl-(1 >4)-O-beta-d-galactopyranoside (2), furosta-1beta,3beta,22xi,26-tetraol 5-en 1-O beta-d-glucopyranosyl (1->3)-beta-d-glucopyranosyl (1->2)-beta-d-galactopyranosyl 26-O-alpha-l-rhamnopyranosyl (1->2)-beta-d-galactopyranoside (3a,3b), furosta 2alpha,3beta,22xi,26-tetraol 3-O-beta-d-glucopyranosyl (1->3)-beta-d glucopyranosyl (1->2)-beta-d-galactopyranosyl 26-O-beta-d-glucopyranoside (4a,4b), (22S)-cholesta-1beta,3beta,16beta,22beta-tetraol 5-en 1-O-alpha-l rhamnopyranosyl 16-O-alpha-l-rhamnopyranosyl (1->2)-beta-d-galactopyranoside (5). Antifungal activity of the isolated compounds was evaluated against the fungal pathogens, Penicillium italicum, Aspergillus niger, Trichoderma harzianum and Botrytis cinerea. Persicosides A and B showed the higher activity on the tested fungi highlighting the positive effect of the spirostane skeleton on the antifungal activity. PMID- 23790947 TI - Development of online sampling and matrix reduction technique coupled liquid chromatography/ion trap mass spectrometry for determination maduramicin in chicken meat. AB - An online sampling and matrix reduction technique coupled liquid chromatography electrospray-ion-trap mass spectrometry was developed for rapid analysis of maduramicin (MAD) residue in chicken meat. Multiple-reaction monitoring of mass spectrometry in positive ion mode was used to detect maduramicin. A post-column continuous infusion of internal standard (nigericin) with matrix-matched calibration method was utilised for quantification. The linear concentration range of the calibration curve was 0-10.0 ng mL(-1) (r(2)=0.999). The limit of detection (quantification) was 0.08 ng g(-1) (0.28 ng g(-1)). The analytical accuracy of chicken meat samples for four spiked MAD concentrations (0.5, 1.0, 5.0, and 10.0 ng g(-1)) was 84-97% and their corresponding intra-day and inter day precisions were 3.7-5.0% and 5.8-7.9%, respectively. The analysis time for one sample was 10 min. The application of the method for incurred chicken samples elucidates that MAD residue in chicken meat decreases during the withdrawal period. PMID- 23790948 TI - Thermogenesis is involved in the body-fat lowering effects of resveratrol in rats. AB - The effect of resveratrol on thermogenesis in skeletal muscle and interscapular brown adipose tissue (IBAT) was investigated. Rats were fed an obesogenic diet supplemented with resveratrol (30mg/kg/day) or not supplemented for 6weeks. Resveratrol intake led to increased gene expression of mitochondrial transcription-factor-A (TFAM), mitochondrial-protein-cytochrome-C-oxidase subunit 2 (COX2), sirtuin-1 (SIRT1), peroxisome-proliferator-activated-receptor beta/delta (PPARbeta/delta) and proliferator-activated-receptor-gamma coactivator1-alpha (PGC-1alpha) in IBAT and increased UCP1protein expression; however, peroxisome-proliferator-activated-receptor-alpha (PPARalpha) expression remained unchanged. In gastrocnemius muscle, resveratrol increased the gene expression of TFAM and COX2; however, no changes were observed in levels of SIRT1, PGC-1alpha and PPARbeta/delta. Acetylated-PGC-1alpha was decreased in the resveratrol-treated group, indicating a higher level of activation, and a significant increase of UCP3 protein expression was observed in this group. The increases in UCP protein expression in two important thermogenic tissues after resveratrol treatment may contribute to increased whole-body energy dissipation, which may help to better understand the body-fat lowering effect of this polyphenol. PMID- 23790949 TI - Preservation of saffron floral bio-residues by hot air convection. AB - Large amounts of floral bio-residues are wasted in saffron spice production, which need to be stabilized because of how quickly they deteriorate. These bio residues are rich in phenolic compounds, and the aim of this study was to evaluate the effect of drying temperatures and air flows on their color and phenolic composition. Anthocyanins and flavonols were degraded at 110 and 125 degrees C. The best drying temperatures were 70 and 90 degrees C for maintaining their physicochemical quality. The duration at 70 degrees C was double than that of 90 degrees C. Anthocyanins and flavonols were stable at 70 and 90 degrees C with 2, 4, 6 and 8ms(-1). Dehydrations at 90 degrees C with 2, 4 and 6ms(-1) were the most appropriate, due to a better color and greater similarity to control samples for their flavonols and anthocyanins. PMID- 23790950 TI - Rice varietal differences in bioactive bran components for inhibition of colorectal cancer cell growth. AB - Rice bran chemical profiles differ across rice varieties and have not yet been analysed for differential chemopreventive bioactivity. A diverse panel of seven rice bran varieties was analysed for growth inhibition of human colorectal cancer (CRC) cells. Inhibition varied from 0% to 99%, depending on the variety of bran used. Across varieties, total lipid content ranged 5-16%, individual fatty acids had 1.4- to 1.9-fold differences, vitamin E isoforms (alpha-, gamma-, delta tocotrienols, and tocopherols) showed 1.3- to 15.2-fold differences, and differences in gamma-oryzanol and total phenolics ranged between 100-275ng/mg and 57-146ngGAE/mg, respectively. Spearman correlation analysis was used to identify bioactive compounds implicated in CRC cell growth inhibitory activity. Total phenolics and gamma-tocotrienol were positively correlated with reduced CRC cell growth (p<0.05). Stoichiometric variation in rice bran components and differential effects on CRC viability merit further evaluation elucidate their role in dietary CRC chemoprevention. PMID- 23790952 TI - Bond dissociation free energy as a general parameter for flavonoid radical scavenging activity. AB - Notwithstanding multiple mechanisms of radical scavenging (RS), measured RS activities (RSA) of flavonoids are usually related to O-H bond dissociation enthalpy (BDE) for hydrogen atom transfer (HAT). For 12 flavonoids the reaction free energies were calculated for: (1) HAT, (2) single electron transfer-proton transfer (SET-PT) and (3) sequential proton loss electron transfer (SPLET) in gas and aqueous phases. Aqueous free energies, like bond dissociation (BDFEaq), ionisation (IFEaq) and deprotonation (DeltaGdeprot,aq) free energies were estimated using thermochemical cycles. While in gas HAT is a RS mechanism (BDFEg=40 years were analyzed in 2012 for visual impairment (presenting distance visual acuity worse than 20/40 in the better-seeing eye), and visual impairment not due to refractive error (distance visual acuity worse than 20/40 after refraction). Diabetic retinopathy (DR) and age-related macular degeneration (AMD) were assessed from retinal fundus images; glaucoma was assessed from two successive frequency-doubling tests and a cup-to-disc ratio measurement. RESULTS: Prevalence of visual impairment and of visual impairment not due to refractive error was 7.5% (95% CI=6.9%, 8.1%) and 2.0% (1.7%, 2.3%), respectively. The prevalence of visual impairment not due to refractive error was significantly higher among people with AMD (2.2%) compared to those without AMD (0.8%), or with DR (3.5%) compared to those without DR (1.2%). Independent predictive factors of visual impairment not due to refractive error were AMD (OR=4.52, 95% CI=2.50, 8.17); increasing age (OR=1.09 per year, 95% CI=1.06, 1.13); and less than a high school education (OR=2.99, 95% CI=1.18, 7.55). CONCLUSIONS: Visual impairment is a public health problem in the U.S. Visual impairment in two thirds of adults could be eliminated with refractive correction. Screening of the older population may identify adults at increased risk of visual impairment due to eye diseases. PMID- 23790988 TI - Promotion of healthy eating through public policy: a controlled experiment. AB - BACKGROUND: To induce consumers to purchase healthier foods and beverages, some policymakers have suggested special taxes or labels on unhealthy products. The potential of such policies is unknown. PURPOSE: In a controlled field experiment, researchers tested whether consumers were more likely to purchase healthy products under such policies. METHODS: From October to December 2011, researchers opened a store at a large hospital that sold a variety of healthier and less healthy foods and beverages. Purchases (N=3680) were analyzed under five conditions: a baseline with no special labeling or taxation, a 30% tax, highlighting the phrase "less healthy" on the price tag, and combinations of taxation and labeling. Purchases were analyzed in January-July 2012, at the single-item and transaction levels. RESULTS: There was no significant difference between the various taxation conditions. Consumers were 11 percentage points more likely to purchase a healthier item under a 30% tax (95% CI=7%, 16%, p<0.001) and 6 percentage points more likely under labeling (95% CI=0%, 12%, p=0.04). By product type, consumers switched away from the purchase of less-healthy food under taxation (9 percentage point decrease, p<0.001) and into healthier beverages (6 percentage point increase, p=0.001); there were no effects for labeling. Conditions were associated with the purchase of 11-14 fewer calories (9%-11% in relative terms) and 2 fewer grams of sugar. Results remained significant controlling for all items purchased in a single transaction. CONCLUSIONS: Taxation may induce consumers to purchase healthier foods and beverages. However, it is unclear whether the 15%-20% tax rates proposed in public policy discussions would be more effective than labeling products as less healthy. PMID- 23790989 TI - Physical activity loyalty cards for behavior change: a quasi-experimental study. AB - BACKGROUND: Financial incentives have been advocated by the UK and U.S. governments to encourage adoption of healthy lifestyles. However, evidence to support the use of incentives for changing physical activity (PA) behavior is sparse. PURPOSE: To investigate the effectiveness of financial incentives to increase PA in adults in the workplace. DESIGN: Two-arm quasi-experimental design. SETTING/PARTICIPANTS: Employees (n=406) in a workplace setting in Belfast, Northern Ireland, UK. INTERVENTION: Using a loyalty card to collect points and earn rewards, participants (n=199) in the Incentive Group monitored their PA levels and received financial incentives (retail vouchers) for minutes of PA completed over the course of a 12-week intervention period. Participants (n=207) in the comparison group used their loyalty card to self-monitor their PA levels but were not able to earn points or obtain incentives (No Incentive Group). MAIN OUTCOME MEASURES: The primary outcome was minutes of PA objectively measured using a novel PA tracking system at baseline (April 2011); Week 6 (June 2011); and Week 12 (July 2011). Other outcomes, including a self-report measure of PA, were collected at baseline, Week 12, and 6 months (October 2011). Data were analyzed in June 2012. RESULTS: No significant differences between groups were found for primary or secondary outcomes at the 12-week and 6-month assessments. Participants in the Incentive Group recorded 17.52 minutes of PA/week (95% CI=12.49, 22.56) compared to 16.63 minutes/week (95% CI=11.76, 21.51) in the No Incentive Group at Week 12 (p=0.59). At 6 months, participants in the Incentive Group recorded 26.18 minutes of PA/week (95% CI=20.06, 32.29) compared to 24.00 minutes/week (95% CI=17.45, 30.54) in the No Incentive Group (p=0.45). CONCLUSIONS: Financial incentives did not encourage participants to undertake more PA than self-monitoring PA. This study contributes to the evidence base and has important implications for increasing participation in physical activity and fostering links with the business sector. PMID- 23790990 TI - A participatory physical activity intervention in preschools: a cluster randomized controlled trial. AB - BACKGROUND: Previous studies on physical activity interventions in preschools have reported limited effectiveness. Participatory community-based approaches hold promise for increasing intervention effectiveness and involving parents as key stakeholders in a sustainable way. PURPOSE: To assess whether a participatory parent-focused approach using parents as agents of behavioral change enhances the efficacy of a preschool physical activity (PA) intervention. DESIGN: Two-armed, cluster-RCT with preschool as unit of randomization and children as unit of analysis. SETTING/PARTICIPANTS: 39 South German preschools applying for an existing state-sponsored PA program with 826 children (52% boys, aged 5.0+/-0.2 years), with 441 allocated to the intervention arm. INTERVENTION: Control preschools received a state-sponsored program consisting of twice-weekly gym classes over 6 months. In intervention preschools, this program was augmented by motivating parents to develop and implement their own project ideas for promoting children's PA. MAIN OUTCOME MEASURES: Primary outcomes included mean accelerometry counts and time spent in moderate- to vigorous-intensity PA or sedentary behavior. Secondary outcomes were BMI, percentage body fat, quality of life, sleep quality, and general health. Outcomes were measured at baseline and at 6 and 12 months in both study arms (time period: 2008-2010). Using an intention-to-treat-analysis, linear multilevel regression models assessed change over time and across study arms, adjusted for age, gender, season, and preschool location. Analysis was conducted in 2011. RESULTS: In 15 intervention preschools, parents implemented 25 PA projects. Compared with controls, intervention arm children were 11 minutes less sedentary per day (95% CI=5.39, 17.01, p=0.014); had significantly more mean accelerometry counts (1.4 counts/15 seconds [95% CI=0.22, 2.54], p=0.019); and showed benefits in perceived general health and quality of life. All other outcomes showed no difference between study arms. CONCLUSIONS: A participatory preschool intervention focusing on parents as agents of behavioral change may be able to promote PA and reduce sedentary behavior in preschoolers. These benefits may go beyond the effects of existing nonparticipatory interventions. TRIAL REGISTRATION: This study is registered at clinicaltrials.gov NCT00987532. PMID- 23790991 TI - Sociodemographic characteristics and beverage intake of children who drink tap water. AB - BACKGROUND: Tap water provides a calorie-free, no-cost, environmentally friendly beverage option, yet only some youth drink it. PURPOSE: To examine sociodemographic characteristics, weight status, and beverage intake of those aged 1-19 years who drink tap water. METHODS: National Health and Nutrition Examination Survey data (2005-2010) were used to examine factors associated with tap water consumption. A comparison was made of beverage intake among tap water consumers and nonconsumers, by age, race/ethnicity, and income. RESULTS: Tap water consumption was more prevalent among school-aged children (OR=1.85, 95% CI=1.47, 2.33, for those aged 6-11 years; OR=1.85, 95% CI=1.32, 2.59, for those aged 12-19 years) as compared to those aged 1-2 years. Tap water intake was less prevalent among girls/women (OR=0.76, 95% CI=0.64, 0.89); Mexican Americans (OR=0.32, 95% CI=0.23, 0.45); non-Hispanic blacks (OR=0.48, 95% CI=0.34, 0.67); and others (OR=0.50, 95% CI=0.36, 0.68) as compared to whites; Spanish speakers (OR=0.72, 95% CI=0.55, 0.95); and among referents with a lower than Grade-9 education (OR=0.52, 95% CI=0.31, 0.88); Grade 9-11 education (OR=0.50, 95% CI=0.32, 0.77); and high school/General Educational Development test completion (OR=0.50, 95% CI=0.33, 0.76), as compared to college graduates. Tap water consumers drank more fluid (52.5 vs 48.0 ounces, p<0.01); more plain water (20.1 vs 15.2 ounces, p<0.01); and less juice (3.6 vs 5.2 ounces, p<0.01) than nonconsumers. CONCLUSIONS: One in six children/adolescents does not drink tap water, and this finding is more pronounced among minorities. Sociodemographic disparities in tap water consumption may contribute to disparities in health outcomes. Improvements in drinking water infrastructure and culturally relevant promotion may help to address these issues. PMID- 23790992 TI - Disparities in obesity and related conditions among Americans with disabilities. AB - BACKGROUND: Despite representing nearly 20% of the U.S. population, individuals with disabilities are invisible in obesity surveillance and intervention efforts. PURPOSE: The current study (1) compares obesity and extreme obesity prevalence between Americans with and without disabilities and (2) examines the association between BMI category and weight-related chronic disease risk factors in both groups. METHODS: In 2012, six waves of data from the National Health and Nutrition Examination Survey (NHANES, 1999-2010) were pooled to compare the prevalence of obesity and extreme obesity between adults (aged >=20 years, N=31,990) with disabilities (n=11,556) versus without disabilities (n= 20,434). Chronic disease risk factors (blood pressure, lipids, C-reactive protein [CRP], glucose) were compared across weight categories, by disability severity, and disability status. RESULTS: Obesity (41.6%) and extreme obesity (9.3%) prevalence among those with disabilities were significantly higher than they were among those without disabilities (29.2% and 3.9%, respectively). Disability severity and disability status negatively affected nearly all chronic disease risk factors. Additionally, there was a disability-by-weight interaction: people with disabilities at all weight categories were significantly more likely to report being told they had hypertension, high cholesterol, or diabetes and to have been prescribed antihypertensive and lipid-lowering medications. CONCLUSIONS: The prevalence of obesity (41.6%) and extreme obesity (9.3%) found in individuals with disabilities is high. When compared to obese adults without disabilities, obese adults with disabilities are more likely to have diabetes, high cholesterol, hypertension, and higher CRP. Thus, the study provides convincing evidence of obesity-related health disparities between Americans with and without disabilities. PMID- 23790993 TI - Mortality rates and cause-of-death patterns in a vaccinated population. AB - BACKGROUND: Determining the baseline mortality rate in a vaccinated population is necessary to be able to identify any unusual increases in deaths following vaccine administration. Background rates are particularly useful during mass immunization campaigns and in the evaluation of new vaccines. PURPOSE: Provide background mortality rates and describe causes of death following vaccination in the Vaccine Safety Datalink (VSD). METHODS: Analyses were conducted in 2012. Mortality rates were calculated at 0-1 day, 0-7 days, 0-30 days, and 0-60 days following vaccination for deaths occurring between January 1, 2005, and December 31, 2008. Analyses were stratified by age and gender. Causes of death were examined, and findings were compared to National Center for Health Statistics (NCHS) data. RESULTS: Among 13,033,274 vaccinated people, 15,455 deaths occurred between 0 and 60 days following vaccination. The mortality rate within 60 days of a vaccination visit was 442.5 deaths per 100,000 person-years. Rates were highest in the group aged >=85 years, and increased from the 0-1-day to the 0-60-day interval following vaccination. Eleven of the 15 leading causes of death in the VSD and NCHS overlap in both systems, and the top four causes of death were the same in both systems. CONCLUSIONS: VSD mortality rates demonstrate a healthy vaccinee effect, with rates lowest in the days immediately following vaccination, most apparent in the older age groups. The VSD mortality rate is lower than that in the general U.S. population, and the causes of death are similar. PMID- 23790994 TI - Online narratives and peer support for colorectal cancer screening: a pilot randomized trial. AB - BACKGROUND: Delivering personal narratives and peer support for CRC screening in an online weight-loss community could be an efficient approach to engaging individuals at increased risk, because obesity is associated with excess colorectal cancer (CRC) mortality and lower screening rates. PURPOSE: Evaluate user engagement and impact of narratives and peer support for promoting CRC screening in an online weight-loss community. DESIGN: Pilot randomized trial. SETTING/PARTICIPANTS: Members of an online weight-loss community who were not up to-date with CRC screening were enrolled in the study in 2011. INTERVENTION: Basic and Enhanced groups (n=153 each) both received education. The Enhanced group also received narratives and peer support for CRC screening in online forums. MAIN OUTCOME MEASURES: The main measures were user engagement, psychosocial outcomes, and self-report CRC screening at 6 months. Analyses were conducted with (1) the full sample of participants and (2) a minimum dose sample of those who participated in their assigned intervention to a minimum degree. Analyses were completed in 2012. RESULTS: Participants were mostly female (92%) with a mean age of 56 years. More than 90% in both groups viewed the educational information. Only 57% in the Enhanced group joined the online team. The Enhanced group had greater improvement in motivation for screening than the Basic group at 1 month (p=0.03). In the full sample, there was no difference in CRC screening at 6 months (Enhanced 19% vs Basic 16%, adjusted OR=1.33, 95% CI=0.73, 2.42). In the minimum dose sample, fecal occult blood testing was higher in the Enhanced (14%) vs Basic (7%) group (adjusted OR=2.49, 95% CI=1.01, 6.17). CONCLUSIONS: Although no between-group differences in CRC screening were seen at 6 months, this study did demonstrate that it is feasible to deploy a narrative and peer support intervention for CRC screening in a randomized trial among members of an online community. However, modifications are needed to improve user engagement. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov NCT01411826. PMID- 23790995 TI - One-year follow-up of a coach-delivered dating violence prevention program: a cluster randomized controlled trial. AB - BACKGROUND: Perpetration of physical, sexual, and psychological abuse is prevalent in adolescent relationships. One strategy for reducing such violence is to increase the likelihood that youth will intervene when they see peers engaging in disrespectful and abusive behaviors. PURPOSE: This 12-month follow-up of a cluster RCT examined the longer-term effectiveness of Coaching Boys Into Men, a dating violence prevention program targeting high school male athletes. DESIGN: This cluster RCT was conducted from 2009 to 2011. The unit of randomization was the school, and the unit of analysis was the athlete. Data were analyzed in 2012. SETTING/PARTICIPANTS: Participants were male athletes in Grades 9-11 (N=1513) participating in athletics in 16 high schools. INTERVENTION: The intervention consisted of training athletic coaches to integrate violence prevention messages into coaching activities through brief, weekly, scripted discussions with athletes. MAIN OUTCOME MEASURES: Primary outcomes were intentions to intervene, recognition of abusive behaviors, and gender-equitable attitudes. Secondary outcomes included bystander behaviors and abuse perpetration. Intervention effects were expressed as adjusted mean between-arm differences in changes in outcomes over time, estimated via regression models for clustered, longitudinal data. RESULTS: Perpetration of dating violence in the past 3 months was less prevalent among intervention athletes relative to control athletes, resulting in an estimated intervention effect of -0.15 (95% CI=-0.27, -0.03). Intervention athletes also reported lower levels of negative bystander behaviors (i.e., laughing and going along with peers' abusive behaviors) compared to controls ( 0.41, 95% CI=-0.72, -0.10). No differences were observed in intentions to intervene (0.04, 95% CI=-0.07, 0.16); gender-equitable attitudes (-0.04, 95% CI= 0.11, 0.04); recognition of abusive behaviors (-0.03, 95% CI=-0.15, 0.09); or positive bystander behaviors (0.04, 95% CI=-0.11, 0.19). CONCLUSIONS: This school athletics-based dating violence prevention program is a promising approach to reduce perpetration and negative bystander behaviors that condone dating violence among male athletes. TRIAL REGISTRATION: This study is registered at www.clinicaltrials.gov NCTO1367704. PMID- 23790996 TI - Neonatal withdrawal syndrome, Michigan, 2000-2009. AB - BACKGROUND: Neonatal withdrawal syndrome, which is associated most frequently with opioid use in pregnancy, is an emerging public health concern, with recent studies documenting an increase in the rate of U.S. infants diagnosed. PURPOSE: This study examined neonatal withdrawal syndrome diagnosis among Michigan infants from 2000 to 2009 and hospital length of stay (LOS) between infants with and without the syndrome for a subset of years (2006-2009). METHODS: Michigan live birth records from 2000 to 2009 were linked with hospital discharge data to identify infants with neonatal withdrawal syndrome. Linked data were restricted to infants born between 2006 and 2009 to examine the difference in hospital LOS between infants with and without the syndrome. Multivariable regression models were constructed to examine the adjusted impact of syndrome diagnosis on infant LOS and fit using negative binomial distribution. Data were analyzed from July 2011 to February 2012. RESULTS: From 2000 to 2009, the overall birth rate of infants with neonatal withdrawal syndrome increased from 41.2 to 289.0 per 100,000 live births (p<0.0001). Among infants born from 2006 to 2009, the average hospital LOS for those with the syndrome was between 1.36 (95% CI=1.24, 1.49) and 5.75 (95% CI=5.41, 6.10) times longer than for infants without it. CONCLUSIONS: Diagnosis of neonatal withdrawal syndrome increased significantly in Michigan with infants who had the syndrome requiring a significantly longer LOS compared to those without it. PMID- 23790997 TI - Conscious consideration of herd immunity in influenza vaccination decisions. AB - BACKGROUND: Influenza vaccination decisions may be influenced by perceived risk reduction related to herd immunity. PURPOSE: This paper examines how free-riding (i.e., foregoing vaccination because of reduced risk perceptions related to herd immunity) or protective benefits to the community affect vaccination decisions. METHODS: A survey of a nationally representative panel of U.S. adults (N=442 respondents; data collected and analyzed during 2012) asked about how respondents made vaccination decisions, including whether and how vaccination among the members of respondents' social networks influenced their own vaccination decisions. RESULTS: Most individuals (61%) reported that vaccination in the social network would not influence their decision. Among those perceiving being influenced by vaccination in their social network, most stated that an increase in network vaccination coverage would make them more likely to get vaccinated, rather than less. Overall, only 6% (28 of 442) gave a response consistent with the reduced-risk logic of herd immunity, which was more common among those stating that they would be less likely to get vaccinated (emphasizing free riding) than among those more likely to get vaccinated (emphasizing social protection; 33% vs 11%, two-sided, p=0.0005). The reduced-risk logic of herd immunity, and more specifically free-riding, is consciously considered by relatively few individuals. Far more common are social influences bolstering personal vaccination, such as peer pressure and social learning (6% vs 11%, two sided, p=0.015). CONCLUSIONS: Interventionists may be more successful by capitalizing on existing social-influence considerations than by trying to combat the conscious lure of free-riding. PMID- 23790998 TI - A practical approach for content mining of Tweets. AB - Use of data generated through social media for health studies is gradually increasing. Twitter is a short-text message system developed 6 years ago, now with more than 100 million users generating over 300 million Tweets every day. Twitter may be used to gain real-world insights to promote healthy behaviors. The purposes of this paper are to describe a practical approach to analyzing Tweet contents and to illustrate an application of the approach to the topic of physical activity. The approach includes five steps: (1) selecting keywords to gather an initial set of Tweets to analyze; (2) importing data; (3) preparing data; (4) analyzing data (topic, sentiment, and ecologic context); and (5) interpreting data. The steps are implemented using tools that are publically available and free of charge and designed for use by researchers with limited programming skills. Content mining of Tweets can contribute to addressing challenges in health behavior research. PMID- 23790999 TI - Screening for sudden cardiac death before participation in high school and collegiate sports: American College of Preventive Medicine position statement on preventive practice. PMID- 23791000 TI - Our poet of public health has left the stage: in memoriam. PMID- 23791001 TI - Commuting by car, lifestyles, and weight gain. PMID- 23791002 TI - Author response. PMID- 23791003 TI - A two-case series of entrapment of a ruptured balloon in the coronary artery: Avoidable complications and nonsurgical management. AB - The entrapment of a ruptured catheter balloon during percutaneous coronary intervention (PCI) is rare, but it can lead to life-threatening complications, such as myocardial infarction (MI) and lethal arrhythmias. Ruptured balloon entrapment usually occurs in either tortuous, calcified, or angulated coronary lesions without adequate balloon deflation. The avoidance of drastic balloon pull out and the use of appropriate catheter-based retrieval techniques could prevent surgical intervention. Herein, we describe two cases of ruptured coronary balloon entrapment during emergency or elective PCI. We successfully removed the ruptured and entrapped balloons through nonsurgical techniques. Coronary interventionists should be aware of the possibility of balloon entrapment during complex coronary interventions; they should also become familiar with nonsurgical catheter-based methods for the retrieval of ruptured and entrapped balloons. PMID- 23791004 TI - Management of patients with rectus sheath hematoma: Personal experience. AB - BACKGROUND/PURPOSE: Rectus sheath hematoma (RSH) is a rare clinical entity. It can be mistaken for other intra-abdominal disorders, which can result in diagnostic and therapeutic difficulties. This study was undertaken to analyze the clinical presentation, diagnostic modalities, and management of patients affected with RSH. METHODS: Between January 2008 and June 2011, eight patients (5 men and 3 women with a mean age of 53 years) with RSH were evaluated according to demographic characteristics, clinical and radiological findings, and methods of treatment. RESULTS: Six patients developed RSH after anticoagulant therapy; one after local trauma, and one after laparoscopic intervention. Six patients were treated nonsurgically; one patient underwent embolization of the inferior epigastric artery and one underwent ligation of the bleeding vessel. The average hospital stay was 6 days. There were no mortality or thromboembolic complications. CONCLUSION: RSH is a rare nonneoplastic entity that is usually associated with abdominal trauma and/or anticoagulant therapy. The gold standard for diagnosis is computed tomography, and ultrasonography can be used in follow up. The treatment of choice is nonsurgical therapy because RSH is a self-limited condition. Surgical intervention should be reserved for cases with hemodynamic instability. PMID- 23791005 TI - Fascia tissue engineering with human adipose-derived stem cells in a murine model: Implications for pelvic floor reconstruction. AB - BACKGROUND/PURPOSE: Mesh-augmented vaginal surgery for treatment of pelvic organ prolapse (POP) does not meet patients' needs. This study aims to test the hypothesis that fascia tissue engineering using adipose-derived stem cells (ADSCs) might be a potential therapeutic strategy for reconstructing the pelvic floor. METHODS: Human ADSCs were isolated, differentiated, and characterized in vitro. Both ADSCs and fibroblastic-differentiated ADSCs were used to fabricate tissue-engineered fascia equivalents, which were then transplanted under the back skin of experimental nude mice. RESULTS: ADSCs prepared in our laboratory were characterized as a group of mesenchymal stem cells. In vitro fibroblastic differentiation of ADSCs showed significantly increased gene expression of cellular collagen type I and elastin (p < 0.05) concomitantly with morphological changes. By contrast, ADSCs cultured in control medium did not demonstrate these changes. Both of the engrafted fascia equivalents could be traced up to 12 weeks after transplantation in the subsequent animal study. Furthermore, the histological outcomes differed with a thin (111.0 +/- 19.8 MUm) lamellar connective tissue or a thick (414.3 +/- 114.9 MUm) adhesive fibrous tissue formation between the transplantation of ADSCs and fibroblastic-differentiated ADSCs, respectively. Nonetheless, the implantation of a scaffold without cell seeding (the control group) resulted in a thin (102.0 +/- 17.1 MUm) fibrotic band and tissue contracture. CONCLUSION: Our results suggest the ADSC-seeded implant is better than the implant alone in enhancing tissue regeneration after transplantation. ADSCs with or without fibroblastic differentiation might have a potential but different role in fascia tissue engineering to repair POP in the future. PMID- 23791006 TI - Epidermal growth factor receptor expression and KRAS and BRAF mutations: study of 39 sinonasal intestinal-type adenocarcinomas. AB - Sinonasal intestinal-type adenocarcinomas (ITACs) are uncommon tumors of poor prognosis defined by their similarities to colorectal adenocarcinomas. The involvement of the epidermal growth factor receptor (EGFR) pathway in colorectal adenocarcinoma oncogenesis is well established, and the same is expected to apply to ITACs. In a series of 39 ITACs, we investigated EGFR amplification and chromosome 7 polysomy by fluorescence in situ hybridization; EGFR, KRAS, and BRAF mutational status by polymerase chain reaction sequencing; EGFR variant messenger RNA expression by quantitative reverse transcriptase polymerase chain reaction; and EGFR protein expression by immunohistochemistry with antibodies targeting the extracellular domain, the intracellular domain, and the phosphorylated isoform. The findings were analyzed with respect to clinical data, histologic typing, and patient outcome. EGFR amplification was observed in 3 cases with a focal distribution. EGFR proteins were overexpressed in all these foci with both extracellular domain and intracellular domain antibodies, suggesting involvement of the whole receptor. Chromosome 7 polysomy was observed in 15 cases and was not associated with EGFR protein expression. EGFR, KRAS, or BRAF mutations were observed in 5 different cases. The EGFRvIII mutant was not detected. In all cases, EGFR variants were expressed. There was no association between these molecular features and patient survival. In conclusion, (1) our study revealed various EGFR expression patterns in ITACs, indicating tumor heterogeneity; (2) EGFR amplification should be distinguished from chromosome 7 polysomy; (3) fluorescence in situ hybridization analysis could be guided by immunohistochemistry; and (4) ITACs share common alterations of the EGFR pathway with colorectal adenocarcinomas, except for a lower frequency of KRAS and BRAF mutations. PMID- 23791007 TI - Expression of microsomal prostaglandin E2 synthase-1 and its role in human hepatocellular carcinoma. AB - Microsomal prostaglandin E2 synthase-1 (mPGES1), an inducible enzyme similar to cyclooxygenase-2, functions downstream of cyclooxygenase-2 in the synthesis of prostaglandin E2. It contributes to carcinogenesis in a variety of tumors. Here, mPGES1 expression was assessed using immunohistochemistry of tissue microarrays containing a total of 100 hepatocellular carcinoma (HCC) tissue samples, 100 peritumoral liver tissue samples, and 13 normal liver tissue samples. The expression of mPGES1 was significantly increased in the HCC tissue samples (P < .001), relative to normal liver tissue. Second, there was a significant positive correlation between mPGES1 expression and the Barcelona Clinic Liver Cancer stage (P < .001) in HCC tissue samples. This correlation was also observed with encapsulation (P = .004) and portal vein thrombosis (P < .001). In addition, the lentiviral vector (Lv-mPGES1-shRNA), which down-regulates mPGES1, inhibited tumor growth in an HCC animal model. Taken together, mPGES1 expression was associated with multiple malignant characteristics and enhanced tumorigenesis in HCC and may serve as an important clinical and pharmacologic biomarker. PMID- 23791008 TI - Plasmablastic transformation of low-grade CD5+ B-cell lymphoproliferative disorder with MYC gene rearrangements. AB - Plasmablastic transformation of low-grade B-cell lymphoproliferative disorders is rarely reported, particularly in cases with clonal evolution. Moreover, the relationship of these 2 morphologically and immunophenotypically distinctive neoplasms remains elusive. Here, we report 2 exceptional cases of plasmablastic transformation with apparently direct transformation from their preceding low grade B-cell lymphoproliferative disorder. In both cases, the plasmablastic transformation and low-grade lymphoproliferative disorder shared the same immunoglobulin heavy chain gene rearrangements and an identical chromosomal translocation. Notably, both plasmablastic transformation cases also carried MYC gene rearrangements on chromosome 8q24, which have been frequently identified in de novo plasmablastic lymphoma. Therefore, our data suggest that dysregulation of MYC gene may play a critical role in the pathogenesis of plasmablastic transformation. PMID- 23791009 TI - The nuclear protein expression levels of SNAI1 and ZEB1 are involved in the progression and lymph node metastasis of cervical cancer via the epithelial mesenchymal transition pathway. AB - Growing evidence illustrates that aberrant activation of the epithelial mesenchymal transition plays a key role in tumor cell invasion and metastasis. Transcription factors SNAI1 and ZEB1 regulate the epithelial-mesenchymal transition. To determine if SNAI1 and ZEB1 are involved in the metastasis of cervical cancer, we used immunohistochemistry to evaluate the expression of SNAI1, ZEB1, and vimentin in tumor and stromal compartments for a large set of cervical carcinoma samples. Results were evaluated using an H score (percentage * intensity). Of 70 samples, 64 cases (91.43%) were positive for SNAI1 expression. The median SNAI1 H score was 174.00 (range, 5-285). Sixty-seven cases (95.71%) were positive for ZEB1, with a median H score of 165.77 (range, 5-260). Nuclear expression of SNAI1 and ZEB1 in tumor cells was positively associated with International Federation of Gynecology and Obstetrics (FIGO) stages (P = .015 and P = .008, respectively) and lymph node metastasis (P = .007 and P = .007, respectively); meanwhile, expression of vimentin in tumor cells was positively associated with lymph node metastasis (P = .019). According to negative vimentin expression, nuclear expression of ZEB1 in tumor cells was positively associated with FIGO stages (P = .04). According to positive vimentin expression, nuclear expression of SNAI1 in tumor cells was positively associated with FIGO stages (P = .018) and pN (P = .029). In light of these findings, we propose that SNAI1 and ZEB1 have the potential to be used as a novel predictor of pelvic lymph node metastasis and represent promising therapeutic targets in patients with cervical cancer. PMID- 23791010 TI - ALG3-CDG (CDG-Id): clinical, biochemical and molecular findings in two siblings. AB - Congenital disorders of glycosylation (CDG) represent an expanding family of metabolic disorders with a wide range of biochemical, molecular and clinical phenotypes. ALG3-CDG (CDG-Id), due to a defect in endoplasmic reticulum (ER) mannosyltransferase VI, is one of the less common types of CDG-I. We describe two Vietnamese siblings with confirmed ALG3-CDG (CDG-Id) by molecular testing. As far as we are aware, they are the oldest reported patients in the literature at 15 and 21years. They share similar clinical features with previously reported patients including facial dysmorphism, severe psychomotor retardation, microcephaly, seizures, and gastrointestinal symptoms. Furthermore, our sibling pair highlights the intrafamilial variability, the natural clinical course of ALG3-CDG (CDG-Id) and the benefit of reassessing patients with undiagnosed and complex syndromes, particularly when they present with neurological deterioration. PMID- 23791011 TI - Re-admission to Level 2 unit after hip-fracture surgery - Risk factors, reasons and outcome. AB - INTRODUCTION: Hip fractures are common geriatric fractures with increasing incidence. Treatment of these fractures is still associated with high rates of complications and poor outcome. Data concerning unexpected re-admission to a Level 2 unit after an initial inconspicuous postoperative course are limited. We aimed to identify causes and associated risk factors for admission as well as impact of re-admission on acute care and short-term outcome. PATIENTS AND METHODS: Patients over 60 years of age with hip fractures were included in this prospective single-centre observational study. Patients with polytrauma or malignancy-associated fractures were excluded. Age, gender, fracture type, pre fracture residential, physical and cognitive status, recording to the American Society of Anesthesiologists (ASA) score, Barthel Index (BI) and Mini-Mental State Examination (MMSE) were recorded on admission. Date, type of surgery and operation time were evaluated. Postoperatively, the prevalence of and reasons for unexpected re-admission to the Level 2 unit and patients' outcome were measured. Parameters were hospital mortality, BI at discharge, length of stay in hospital and type of discharge. Univariate and multivariate analyses were performed to identify risk factors for admission to the Level 2 unit and influence on patients' outcome. RESULTS: Out of 402 included patients, 48 (12%) were re admitted to the Level 2 unit. The most frequent reasons were non-surgical (n=38), such as respiratory failure (n=12), cardiovascular diseases (n=8) and acute renal failure (n=5). Ten patients were re-admitted due to a revision surgery of the hip. We identified two independent risk factors for readmission: male gender (odds ratio (OR)=2.38, confidence interval (95% CI)=1.10-5.15, p=0.027) and type of fracture, especially femoral neck fracture (OR=7.40, 95% CI=2.39-23.26, p=0.001). Patients who were re-admitted to the Level 2 unit had a higher mortality (beta=2.09, OR=8.07, 95% CI=2.44-26.75, p=0.001), an increase in hospital stay (beta=7.0, 95% CI 5.2-8.7, p<0.001) and a lower functional outcome (BI, beta=-17, 95% CI=-23 to -10, p<0.001). CONCLUSION: Unexpected admission to the Level 2 unit in the post-surgical period is a frequent phenomenon in geriatric hip-fracture patients. Males and femoral neck fracture patients seem to be especially endangered. Although the majority of reasons for admissions were not immediately life-threatening illnesses, they had a substantial negative impact on patients' outcome. This emphasises the importance of careful handling of this frail patient population. PMID- 23791012 TI - Long-term follow up of percutaneous coronary intervention of coronary artery disease in women <=45 years of age. AB - The aim of the present study was to report the short- and long-term clinical outcomes of percutaneous coronary intervention in young women with premature coronary artery disease. From February 2003 to December 2011, 168 consecutive women aged <=45 years who underwent percutaneous coronary intervention with stent implantation were retrospectively analyzed. The primary end point was the incidence of major adverse cardiac events (MACEs) at short- and long-term follow up. The mean age was 40.3 +/- 2.0 years. Conventional coronary artery disease risk factors were common. Autoimmune or connective tissue diseases were present in 6.5% of the population, 4% had gynecologic diseases, 4 were postpartum, and 9 were taking contraceptives. The left anterior descending coronary artery was the most commonly affected vessel (83.3%) and the most common target vessel for stenting (76.8%). A total of 268 stents were implanted, 95.3% of which were drug eluting stents. During the hospital stay, 1 patient died, and the incidence of MACEs was 1.2%. No additional events had occurred at 30-day follow-up. After a median follow-up duration of 36 months (interquartile range 12 to 60), cumulate MACE-free survival was 80.5%, the rate of target vessel revascularization was 16.5%, and the rate of stent thrombosis was 3.6%. Cox regression showed that hypertension, smoking, a left ventricular ejection fraction <50%, anterior myocardial infarction, and autoimmune disease were independent predictors of MACEs. In conclusion, percutaneous coronary intervention in young women tends to result in an increased rate of target vessel revascularization during long-term follow-up, which may be influenced by conventional and nonconventional risk factors. PMID- 23791013 TI - Racial differences in rates of aortic valve replacement in patients with severe aortic stenosis. AB - Racial disparities exist in the treatment of many cardiovascular diseases. Aortic valve replacement (AVR) is the only treatment for aortic stenosis (AS) that improves patient symptoms and survival. To date, no studies have compared the rate of AVR among different races. The records of patients with an aortic valve area <1 cm(2) by echocardiography diagnosed between January 2004 and May 2010 at Barnes-Jewish Hospital were reviewed retrospectively. Patients were stratified by race. Of the 880 patients analyzed, 10% were African American (AA), and 90% were European American (EA). AA more frequently had hypertension (82% vs 67%, p <0.01), diabetes mellitus (45% vs 32%, p = 0.02), chronic kidney disease (28% vs 17%, p = 0.01), and end stage renal disease (18% vs 2%, p <0.001). AA underwent AVR less frequently than EA (39% vs 53%, p = 0.02) and refused intervention more often (33% vs 20%, p = 0.04). When treated, AA and EA had similar 3-year survival (49% [38 to 60] vs 50% [45 to 54], p = 0.31). Identification of the factors associated with treatment refusal would further our ability to counsel patients on the decision to pursue AVR. PMID- 23791014 TI - Safety effects of reducing the speed limit from 90km/h to 70km/h. AB - Speed is one of the main risk factors in traffic safety, as it increases both the chances and the severity of a crash. In order to achieve improved traffic safety by influencing the speed of travel, road authorities may decide to lower the legally imposed speed limits. In 2001 the Flemish government decided to lower speed limits from 90km/h to 70km/h on a considerable number of highways. The present study examines the effectiveness of this measure using a comparison group before- and after study to account for general trend effects in road safety. Sixty-one road sections with a total length of 116km were included. The speed limits for those locations were restricted in 2001 and 2002. The comparison group consisted of 19 road sections with a total length of 53km and an unchanged speed limit of 90km/h throughout the research period. Taking trend into account, the analyses showed a 5% decrease [0.88; 1.03] in the crash rates after the speed limit restriction. A greater effect was identified in the case of crashes involving serious injuries and fatalities, which showed a decrease of 33% [0.57; 0.79]. Separate analyses between crashes at intersections and at road sections showed a higher effectiveness at road sections. It can be concluded from this study that speed limit restrictions do have a favorable effect on traffic safety, especially on severe crashes. Future research should examine the cause for the difference in the effect between road sections and intersections that was identified, taking vehicle speeds into account. PMID- 23791015 TI - Neurogenesis recovery induced by granulocyte-colony stimulating factor in neonatal rat brain after perinatal hypoxia. AB - BACKGROUND: Perinatal hypoxia can lead to a wide range of neurological deficits depending on the differential vulnerability of the involved brain regions to oxygen deprivation. It remains unclear whether the differential vulnerability to oxygen deprivation leads to altered neurogenesis in the neonatal brain after perinatal hypoxia. The primary objective was to investigate whether perinatal hypoxia induces deleterious changes in neurogenesis within three representative brain regions (dentate gyrus of the hippocampus, midbrain, and temporal cortex), with regards to common pathological areas clinically. The secondary objective was to investigate whether granulocyte-colony stimulating factor (G-CSF) therapy exerts beneficial effects in neurogenesis in neonatal rat brains subjected to experimental perinatal hypoxia. MATERIALS AND METHODS: Rat pups were subjected to experimental perinatal hypoxia on the tenth day of life (P10). They were then given G-CSF (30 MUg/kg, single injection/day, intraperitoneal injection, P11-16). The neurogenesis efficacy was analyzed on P17 and the radial-arm maze task, a memory task for higher cognitive functions such as problem-solving abilities, was evaluated on P37-58. RESULTS: Perinatal hypoxia caused a significant decrease in neurogenesis within the three representative brain regions, and this deleterious outcome was alleviated by G-CSF (p < 0.05). In addition, the G-CSF therapy markedly improved the decreased performance of long-term cognitive functions induced by perinatal hypoxia (p < 0.05). CONCLUSION: This study suggests that G CSF may be a potentially beneficial therapy, at least in part, through universal recovery of neurogenesis effects in the neonatal brain after perinatal hypoxia insult. PMID- 23791016 TI - Oral desmopressin lyophilisate (MELT) for monosymptomatic enuresis: structured versus abrupt withdrawal. AB - OBJECTIVE: To investigate whether a structured withdrawal program from a sublingual formulation of fast-melting oral desmopressin lyophilisate (MELT) is superior to a sudden withdrawal from this formulation in the treatment of monosymptomatic nocturnal enuresis. MATERIALS AND METHODS: One hundred and three children presented to our pediatric nephrology outpatient clinic for bedwetting. Eighty-one children, aged between 51/2 and 14 years (mean age 8.64 years), were treated with MELT at a dosage of 120 mcg a day. Responders were randomized to been withdrawn from therapy, after 3 months, abruptly or in a structured withdrawal program (60 mcg/day for 15 days and then 60 mcg every second evening for another 15 days). Main outcome parameter was relapse rate 1 month after the end of treatment. Relapse was defined as bedwetting occurring more than 2 nights per month after the 1-month treatment-free period. RESULTS: Relapse rate at 1 month after the end of treatment was 47.83% in the group on a structured program versus 45.83% in the abrupt termination group (p = 0.89). CONCLUSION: Our study suggests that a structured withdrawal program from MELT therapy doesn't offer advantages compared to an abrupt termination in children with monosymptomatic nocturnal enuresis. PMID- 23791017 TI - Failure in activation of the canonical NF-kappaB pathway by human T-cell leukemia virus type 1 Tax in non-hematopoietic cell lines. AB - Human T-cell leukemia virus type 1 (HTLV-1) Tax (Tax1) plays crucial roles in leukemogenesis in part through activation of NF-kappaB. In this study, we demonstrated that Tax1 activated an NF-kappaB binding (gpkappaB) site of the gp34/OX40 ligand gene in a cell type-dependent manner. Our examination showed that the gpkappaBeta site and authentic NF-kappaB (IgkappaB) site were activated by Tax1 in hematopoietic cell lines. Non-hematopoietic cell lines including hepatoma and fibroblast cell lines were not permissive to Tax1-mediated activation of the gpkappaB site, while the IgkappaB site was activated in those cells in association with binding of RelB. However RelA binding was not observed in the gpkappaB and IgkappaB sites. Our results suggest that HTLV-1 Tax1 fails to activate the canonical pathway of NF-kappaB in non-hematopoietic cell lines. Cell type-dependent activation of NF-kappaB by Tax1 could be associated with pathogenesis by HTLV-1 infection. PMID- 23791018 TI - Isolation of a novel orthobunyavirus (Brazoran virus) with a 1.7 kb S segment that encodes a unique nucleocapsid protein possessing two putative functional domains. AB - In July, 2012 three isolations were made from mosquitoes collected in Brazoria, Orange and Montgomery counties, Texas, USA. Data from immunofluorescence testing suggested that these isolates are members of the genus Orthobunyavirus. Expanded analyses confirmed that these isolates comprise three independent isolations of the same virus; a novel orthobunyavirus. The genetic organization of the M and L segments of this virus is similar to that of other orthobunyaviruses. However, the S segment (~1.7 kb) is nearly twice the length of known orthobunyavirus S segments, encoding a significantly larger nucleocapsid, N (~50 kDa) and putative non-structural NSs (~20 kDa) proteins in a novel strategy by which the NSs ORF precedes the N ORF. The N protein appears to consist of two functional domains; an amino portion that possesses motifs similar to other orthobunyavirus N proteins and a carboxyl portion that possesses a glutamine-rich domain with no known homologue among Bunyaviridae. PMID- 23791019 TI - Epstein-Barr virus-encoded small non-coding RNAs induce cancer cell chemoresistance and migration. AB - Epstein-Barr virus (EBV) encoded small, non-coding, non-polyadenylated RNAs, known as EBERs are the most abundantly expressed viral transcripts in latently EBV infected cells. We found the specific role of EBERs in cell cycle progression, resistance against chemotherapeutic drug and cellular invasion in gastric cancer cells in vitro. Ectopic expression of EBERs upregulates the expression of IL-6 and activate its downstream STAT3, which is significantly involved in downregulating the expression of cell cycle inhibitor genes p21 and p27. Stable expression of EBERs regulates the activation of pFAK and pPAK1 and the expression of anti-metastatic genes RhoGDI and KAI-1 in gastric cancer cells. In addition, administration of neu-IL-6 antibody and dominant negative STAT3beta reduces chemoresistance and inhibits invasion of EBERs-expressing gastric cancer cells. Our results thus revealed a novel role of EBERs in the coordination of IL 6-STAT3 signaling pathway to chemoresistance and cellular migration. PMID- 23791020 TI - Biosynthesis of gold and silver nanoparticles using a novel marine strain of Stenotrophomonas. AB - The present study aims at exploiting marine microbial diversity for biosynthesis of metal nanoparticles and also investigates role of microbial proteins in the process of bio-mineralization of gold and silver. This is the first report for concurrent production of gold and silver nanoparticles (AuNPs and AgNPs) by extracellular secretion of a novel strain of Stenotrophomonas, isolated from Indian marine origin. This novel strain has faster rate kinetics for AgNPs synthesis than any other organism reported earlier. The nanoparticles were further characterized using UV-vis spectrophotometer, TEM, DLS and EDAX confirming their size ranging from 10-50 nm and 40-60 nm in dimensions for AuNPs and AgNPs, respectively. TEM analysis indicated formation of multi-shaped nanoparticles with heterogeneous size distribution in both the cases. Finally, the SDS-PAGE analysis of extracellular media supernatant suggested a potential involvement of certain low molecular weight secretory proteins in AuNPs and AgNPs biosynthesis. PMID- 23791021 TI - Breastfeeding and cognitive development: is there an association? PMID- 23791022 TI - Cardiorespiratory fitness and nutritional status of schoolchildren: 30-year evolution. AB - OBJECTIVE: To compare the changes in cardiorespiratory fitness in evaluations performed every ten years since 1978/1980, according to the nutritional status and gender of students in the city of Ilhabela, Brazil. METHODS: The study is part of the Mixed Longitudinal Project on Growth, Development and Physical Fitness of Ilhabela. The study included 1,291 students of both genders, aged 10 to 11 years old. The study periods were: 1978/1980, 1988/1990, 1998/2000, and 2008/2010. The variables analyzed were: body weight, height, and cardiorespiratory fitness (VO2max - L.min-1 and mL.kg-1.min-1) performed using a submaximal progressive protocol on a cycle ergometer. Individuals were classified as normal weight and overweight according to curves proposed by the World Health Organization of body mass index for age and gender. Analysis of variance (ANOVA) with three factors followed by the Bonferroni method were used to compare the periods. RESULTS: The number of normal weight individuals (61%) was higher than that of overweight. There was a significant decrease in cardiorespiratory fitness in both genders. Among the schoolchildren with normal weight, there was a decrease of 22% in males and 26% in females. In overweight schoolchildren, males showed a decrease of 12.7% and females, of 18%. CONCLUSION: During a 30-year analysis with reviews every ten years from 1978/1980, there was a significant decrease in cardiorespiratory fitness in schoolchildren of both genders, which cannot be explained by the nutritional status. The decline in cardiorespiratory fitness was greater in individuals with normal weight than in overweight individuals. PMID- 23791023 TI - Reference values for spirometry in preschool children. AB - OBJECTIVES: Reference values for lung function tests differ in samples from different countries, including values for preschoolers. The main objective of this study was to derive reference values in this population. METHODS: A prospective study was conducted through a questionnaire applied to 425 preschool children aged 3 to 6 years, from schools and day-care centers in a metropolitan city in Brazil. Children were selected by simple random sampling from the aforementioned schools. Peak expiratory flow (PEF), forced vital capacity (FVC), forced expiratory volumes (FEV1, FEV0.50), forced expiratory flow (FEF25-75) and FEV1/FVC, FEV0.5/FVC and FEF25-75/FVC ratios were evaluated. RESULTS: Of the 425 children enrolled, 321 (75.6%) underwent the tests. Of these, 135 (42.0%) showed acceptable results with full expiratory curves and thus were included in the regression analysis to define the reference values. Height and gender significantly influenced FVC values through linear and logarithmic regression analysis. In males, R(2) increased with the logarithmic model for FVC and FEV1, but the linear model was retained for its simplicity. The lower limits were calculated by measuring the fifth percentile residues. CONCLUSION: Full expiratory curves are more difficult to obtain in preschoolers. In addition to height, gender also influences the measures of FVC and FEV1. Reference values were defined for spirometry in preschool children in this population, which are applicable to similar populations. PMID- 23791024 TI - Blood transfusion reactions in children: associated factors. AB - OBJECTIVE: To analyze the profile of blood transfusion reactions in children and to identify the involved factors. METHODS: This was a cross-sectional study in a tertiary pediatric teaching hospital from the public healthcare system, involving all children admitted from January to July of 2011 (5,437), of which 1,226 received blood transfusions, constituting the sample. A documental study was performed by analyzing files from the hemovigilance service and notification forms of transfusion reactions. The variables investigated were: number and type of blood components transfused, transfusion site, reaction site, age, gender, type of blood components involved, type of incident, and previous history of multiple transfusions. A descriptive and inferential analysis was performed, using statistical tests to establish the association between the variables. RESULTS: There were 57 transfusion incidents involving 47 children and 72 different blood products, thus constituting a prevalence of reactions of 3.8%. At the inferential analysis, the chi-squared test showed that the following variables were significantly associated (p<0.05) with the type of reaction: age range and type of blood component. Similarly, the patient's underlying disease was associated with previous history of transfusion incident and type of blood component. CONCLUSIONS: The prevalence of transfusion reactions in children is high, and the intervening factors are: type of blood component, age, patient comorbidity, and multiple transfusions; type of blood component and age are also associated with type of reaction. PMID- 23791025 TI - Impact of breastfeeding on the intelligence quotient of eight-year-old children. AB - OBJECTIVE: This study aimed to determine the influence of breastfeeding on the intellectual capacity of children from a cohort in a developing country, with a control for the main confounding factors. METHODS: A prospective cohort study was performed including all infants born in the hospitals of a medium-size city, and a random sample of these newborns was monitored at 30, 90, and 180 days of life, and at age 8 years. Several aspects of breastfeeding were assessed in the follow up and, at 8 years, general intellectual capacity was assessed through the Raven's Colored Progressive Matrices test. The statistical analyses used Student's t-test, ANOVA, and linear regression and logistics, considering p values less than 0.05 as statistically significant associations. RESULTS: At age 8 years, 560 children were assessed with Raven's Colored Progressive Matrices test. The average score was 22.56 points, with a standard deviation of 5.93. The difference in the averages found between the breastfed and non-breastfed groups at six months of age was 1.33 (p=0.008). Mother's and child's skin color, social and economic class, maternal education and smoking, and breastfeeding at six months of age (p=0.007) were still associated with the outcome. CONCLUSIONS: Children that were breastfed for six months or more had better performance in the general intellectual assessment, even after adjusting for the main confounding factors. PMID- 23791026 TI - Sexual dysfunction in Chinese patients with first-episode psychosis: prevalence, clinical correlates and functioning. PMID- 23791027 TI - Binge drinking trajectory and neuropsychological functioning among university students: a longitudinal study. AB - BACKGROUND: Adolescence is a time of considerable neurodevelopment. Binge drinking (BD) during this period increases the vulnerability to its neurotoxic effects. This longitudinal study aimed to investigate the relationship between BD trajectory over university years and neuropsychological functioning. METHODS: Cohort-study. Two-year follow-up. A total of 89 university students were assessed: 40 Non-BD (at Initial and Follow-up), 16 Ex-BD (BD at Initial but not at Follow-up) and 33 BD (at both times). Neuropsychological assessment of working memory, episodic memory and executive abilities was carried out during their first (Initial) and third (Follow-up) academic year at the University of Santiago de Compostela. RESULTS: BD subjects performed less well on the Wechsler Memory Scale-III (WMS-III) Logical Memory Subtest (immediate theme recall, P=.034; delayed theme recall, P=.037; and percent retention, P=.035) and committed more perseverative errors on the Self-Ordered Pointing Task (SOPT) (P=.021) than Non BD. There were no differences between Ex-BD and Non-BD. CONCLUSIONS: Binge drinking trajectory during adolescence is associated with neuropsychological performance. Persistent BD, but not Ex-BD, is associated with verbal memory and monitoring difficulties. This is compatible with the hypothesis that heavy alcohol use during adolescence may affect cognitive functions that rely on the temporomesial and dorsolateral prefrontal cortex. PMID- 23791029 TI - Modelling the prevalence of HCV amongst people who inject drugs: an investigation into the risks associated with injecting paraphernalia sharing. AB - BACKGROUND: In order to prevent the spread of the hepatitis C virus (HCV) amongst people who inject drugs (PWID), it is imperative that any injecting risk behaviour which may contribute to the transmission of disease has its role quantified. To inform public health organisations, mathematical modelling techniques were used to explore the risk of HCV infection through the sharing of injecting paraphernalia (including filters, cookers and water). METHODS: A mathematical model was developed for the spread of HCV based on the injecting behaviour of PWID in Scotland, with transmission occurring through the sharing of needles/syringes and other injecting paraphernalia. Numerical simulations were used to estimate the transmission probability for HCV through the sharing of injecting paraphernalia such that the modelled endemic HCV prevalence fitted with that observed amongst PWID in Scotland. RESULTS: The transmission probability of HCV through injecting paraphernalia was modelled to be over 8 times lower than that through needles/syringes (approximately 0.19-0.30% and 2.5%, respectively), assuming transmission occurs through a combination of at least filters and cookers. In the context of reported needle/syringe and paraphernalia sharing rates in Scotland, it is estimated that 38% and 62% of HCV infections are contributed by these practices, respectively. If needle/syringe sharing rates were to be twice those reported, the contributions would be 70% and 30%, respectively. CONCLUSION: Given that the sharing of injecting paraphernalia among PWID is common, HCV transmission through this route could be contributing to the growing healthcare burden associated with this chronic disease. Every effort should therefore be made to establish (a) the contribution that paraphernalia sharing is making to the spread of HCV, and (b) the effectiveness of services providing sterile paraphernalia in preventing infection. PMID- 23791028 TI - Measuring historical trauma in an American Indian community sample: contributions of substance dependence, affective disorder, conduct disorder and PTSD. AB - BACKGROUND: The American Indian experience of historical trauma is thought of as both a source of intergenerational trauma responses as well as a potential causative factor for long-term distress and substance abuse among communities. The aims of the present study were to evaluate the extent to which the frequency of thoughts of historical loss and associated symptoms are influenced by: current traumatic events, post traumatic stress disorder (PTSD), cultural identification, percent Native American Heritage, substance dependence, affective/anxiety disorders, and conduct disorder/antisocial personality disorder (ASPD). METHODS: Participants were American Indians recruited from reservations that were assessed with the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA), The Historical Loss Scale and The Historical Loss Associated Symptoms Scale (to quantify frequency of thoughts and symptoms of historical loss) the Stressful Life-Events Scale (to assess experiences of trauma) and the Orthogonal Cultural Identification Scale (OCIS). RESULTS: Three hundred and six (306) American Indian adults participated in the study. Over half of them indicated that they thought about historical losses at least occasionally, and that it caused them distress. Logistic regression revealed that significant increases in how often a person thought about historical losses were associated with: not being married, high degrees of Native Heritage, and high cultural identification. Additionally, anxiety/affective disorders and substance dependence were correlated with historical loss associated symptoms. CONCLUSIONS: In this American Indian community, thoughts about historical losses and their associated symptomatology are common and the presence of these thoughts are associated with Native American Heritage, cultural identification, and substance dependence. PMID- 23791030 TI - Prevalence of suicidal ideation, attempts, and completed suicide rate in Chinese aging populations: a systematic review. AB - BACKGROUND: As one of the leading causes of death around the world, suicide is a global public health threat. Due to the paucity of systematic studies, there exist vast variations in suicide ideation, attempts and suicide rates between various regions of Chinese aging communities. OBJECTIVES: Our systematic study aims to (1) identify studies describing the epidemiology of suicidal ideation, suicide attempts and behaviors among global Chinese communities; (2) conduct systematic review of suicide prevalence; (3) provide cross-cultural insights on this public health issue in the diverse Chinese elderly in China, Hong Kong, Taiwan, Asian societies and Western countries. DATA SOURCES: Using the PRISMA statement, we performed systematic review including studies describing suicidal ideation, attempts, and behavior among Chinese older adults in different communities. Literature searches were conducted by using both medical and social science data bases in English and Chinese. RESULTS: Forty-nine studies met inclusion criteria. Whereas suicide in Chinese aging population is a multifaceted issue, culturally appropriate and inter-disciplinary approach to improve the quality of life for the Chinese older adults is critical. CONCLUSIONS: Future research is needed to explore the risk and protective factors associated with suicidal thoughts, attempts and behaviors in representative Chinese aging populations. PMID- 23791031 TI - [Imported hookworm infection in Almeria]. AB - OBJECTIVES: To study the clinical and epidemiological characteristics of immigrant patients diagnosed with a hookworm infection in the Tropical Medicine Unit of the Hospital de Poniente in El Ejido (Almeria, Spain). MATERIAL AND METHODS: A retrospective observational study of all immigrant patients diagnosed with hookworm, by direct visualization of eggs in stool samples, from October 2004 until December 2012. RESULTS: Of the 1872patients studied, 253 (13.5%) were diagnosed with a hookworm infection. In patients where hookworm was the only helminthiasis diagnosed, 8.3% had iron deficiency anaemia, 65.7% did not have eosinophilia, and of these, 25.9% had no abdominal pain. CONCLUSIONS: Hookworm is a frequent parasite infestation in the Sub-Saharan immigrant population. Many patients are asymptomatic; thus the implementation of a study protocol for immigrants from endemic areas could diagnose and treat more patients with this disease. PMID- 23791032 TI - How accurate is arthroscopy of the temporomandibular joint? A comparison of findings in patients who had open operations after arthroscopic management failed. AB - We examined the accuracy of arthroscopy to diagnose disease in the temporomandibular joint (TMJ) and to allocate an appropriate Wilkes' stage. We compared findings made during arthroscopy with those at subsequent open operation in the same patient. Overall, arthroscopy had 87% sensitivity and 99% specificity in diagnosing disease in the TMJ, and it also accurately allocated the Wilkes' stage (sensitivity 94%, specificity 98%). PMID- 23791033 TI - Evaluation of p53 protein as a prognostic factor for oral cancer surgery. AB - We have analysed concentrations of the p53 protein in advanced oral carcinomas immunohistochemically and genetically to detect the percentage of overexpression of this antioncogene that indicates a high probability of mutation. This would point to it being a useful prognostic factor, if we consider the importance of the relation between genetic alterations of p53 and poor overall survival. Seventy-five non-consecutive patients with oral squamous cell carcinoma and metastatic nodes were enrolled if there was homogeneity in histopathological grading (G2) of their tumours, and they were treated according to a multidisciplinary treatment plan. Monoclonal antibodies, extraction of DNA, and amplification of the polymerase chain reaction (PCR) were used for the immunohistochemical and genetic analyses. There was a significant inverse correlation between p53 overexpression and response to chemotherapy and a stronger association between high P53 overexpression (%) and a genetic mutation of p53 (p=0.0001). More than 50% overexpression indicated a strong probability of genetic mutation. There was no association between response to chemotherapy and age-groups or TNM classification (p=0.2), but there was a significant one between sex and site of tumour (p<0.001). Three prognostic factors were significantly related to prognosis: site of tumour (p=0.01), response to chemotherapy (p=0.002), and immuno p53 (p=0.0001). A tumour that is characterised by p53 overexpression of more than 50% indicates a poor prognosis. PMID- 23791034 TI - Bilateral benign paroxysmal positional vertigo: an unusual complication of orthognathic surgery. AB - Benign paroxysmal positional vertigo (BPPV) is a common cause of vertigo of labyrinthine origin and usually idiopathic. However, 15-20% of all cases occur after trauma to the head, and it has rarely been reported after maxillofacial surgery, so to the best of our knowledge this is the first report of its bilateral occurrence after orthognathic surgery. It resolves slowly, but symptoms are incapacitating. It can be diagnosed from the history and physical examination, including the Dix-Hallpike test. Maxillofacial surgeons should be aware of it in patients who complain of dizziness after orthognathic surgery, and should know how to manage it properly. PMID- 23791035 TI - Polyclonal immunoglobulin G for autoimmune demyelinating nervous system disorders. AB - Demyelinating diseases with presumed autoimmune pathogenesis are characterised by direct or indirect immune-mediated damage to myelin sheaths, which normally surround nerve fibres to ensure proper electrical nerve conduction. Parenteral administration of polyclonal IgG purified from multi-donor human plasma pools may beneficially modulate these misguided immune reactions via several mechanisms that are outlined in this review. Convincing therapeutic evidence from controlled trials now exists for certain disorders of the peripheral nervous system, including Guillain-Barre syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, and multifocal motor neuropathy. In addition, there is evidence for potential therapeutic benefits of IgG in patients with chronic inflammatory demyelinating diseases of the central nervous system, including multiple sclerosis and neuromyelitis optica. This review introduces these disorders, briefly summarises the established treatment options, and discusses therapeutic evidence for the use of polyclonal immunoglobulins with a particular emphasis on recent clinical trials and meta-analyses. PMID- 23791036 TI - Assessment of endothelial and neurovascular function in human skin microcirculation. AB - Peripheral microvascular dysfunction has been described in many physiological and pathological conditions. Owing to its accessibility, the cutaneous microcirculation provides a unique index of microvascular function. Skin microvascular function has therefore been proposed as a prognostic marker or for evaluating the effect of drugs on the microcirculation. Various reactivity tests, coupled with techniques measuring skin blood flux, are used to non-invasively explore both endothelial and neurovascular microvascular functioning in humans. We review the advantages and limitations of the main reactivity tests, including post-occlusive reactive hyperemia, local thermal hyperemia, pressure-induced vasodilation, and iontophoresis of vasodilators, combined with measurement techniques such as laser Doppler and laser speckle contrast imaging. Recent advances in our comprehension of the physiological pathways underlying these reactivity tests, as well as technological developments in microcirculation imaging, have provided reliable and reproducible tools for studying the microcirculation. PMID- 23791037 TI - [Socio-demographic factors and use of health services for psychological reasons in young adults]. AB - BACKGROUND: Although young adults exhibit a high rate of psychiatric disorders, their rate of access to mental health care is low compared with older age groups. Our study examined the relationship between socio-demographic factors and the use of health care services for psychological reasons. METHODS: We studied a community sample of 1103 French 22 to 35-year-old (TEMPO cohort study) who were surveyed by mailed questionnaire in 2009. Data were collected regarding participants' health (internalizing and externalizing psychological symptoms in 1991 and 2009), health care use (access to health professionals and psychotropic medications in case of psychological difficulties), and socio-demographic factors (sex, age, employment status, marital situation, social support). Parental history of depression was ascertained based on TEMPO participants' and their parents' reports (in the GAZEL cohort study). RESULTS: In the 12 months preceding the study, 16.7% of study participants saw a health professional and 12.8% took a psychotropic medication for psychological reasons. In multivariate regression, models adjusted for all socio-demographic and psychological characteristics, access to health professionals was associated with being unemployed/out of the labor force (OR=1.93; 95% CI=1.11-3.30), family situation (OR in participants living with a partner with no children: 2.16; 95% CI 1.26-3.72; OR in participants not living with a partner: 2.29; 95% CI=1.34-3.90), and having low social support (OR=1.75; 95% CI=1.21-2.54). The use of psychotropic medications was associated with female gender (OR=2.70; 95% CI=1.60-4.55), being unemployed/out of the labor force (OR=3.85; 95% CI=2.14-6.95), not living with a partner (OR=2.04; 95% CI=1.09-3.80) and having low social support (OR=1.65; 95% CI=1.05-2.59). Additionally, use of health services was associated with participants' and their parents' psychological difficulties. PMID- 23791038 TI - Effect of stentgraft model on aneurysm shrinkage in 1,450 endovascular aortic repairs. AB - BACKGROUND: Regression of the aneurysmal sac after endovascular repair of abdominal aortic aneurysm (AAA) is an accepted indicator of aneurysm exclusion. This study evaluated the spontaneous decrease in sac diameter over a 10-year period in patients undergoing endovascular aneurysm repair (EVAR) with different stentgrafts. METHODS: 1,450 patients (mean age 73.1 +/- 7.7 years; 1,325 male) undergoing EVAR and with a minimum of 1-year computed tomography (CT) imaging were included. Different implanted stentgrafts (n = 622 [42.9%] Zenith, n = 236 [16.3%] AneuRx, n = 179 [12.3%] Talent, n = 83 [5.7%] Endurant, n = 236 [16.3%] Excluder, n = 36 [2.5%] Fortron, 53 [3.7%] Anaconda, n = 5 [0.3%] others) were employed. "Persisting shrinkage" was measured as >= 5 mm AAA diameter regression spontaneously persisting or increasing until the end of follow-up without reintervention. Persisting shrinkage among devices was compared with survival and Cox regression analyses. RESULTS: During a median follow-up of 45 months (interquartile range, IQR, 21-79) persisting shrinkage was detected in 768 (53%) aneurysms. Kaplan-Meier estimates of persisting shrinkage were 25.8% at 1 year, 63% at 3 years and 72.6% at 10 years. Persisting shrinkage rates were significantly higher for Zenith (p < .0001), Endurant (p = .013) and new generation Excluder (p < .0001) devices. Cox analyses confirmed that persisting shrinkage rates were independently associated with Zenith (OR 1.33; 95% CI: 1.176 1.514) and Endurant (OR 1.52; 95% CI: 1.108-2.092) stentgrafts and negatively associated with the AneuRx (OR 0.57; 95% CI: 0.477-0.688) device. Survival rates were higher in the persisting shrinkage group: 84.1% vs. 77.8% at 3 years, and 53% vs. 38.1% at 10 years (p < .0001). Freedom from AAA-related-death rate was 100% at 3 years and 99.7% at 10 years in the persisting shrinkage group. CONCLUSIONS: Aneurysm diameter shrinkage can be achieved in most current EVARs with persisting effect at 10 years from repair and indicates the benefit and safety of treatment. Last generation devices seem to be important factors in inducing aneurysm sac shrinkage with similar clinically relevant effects among single models. PMID- 23791039 TI - Remission from substance dependence: differences between individuals in a general population longitudinal survey who do and do not seek help. AB - BACKGROUND: Only a minority of individuals who have substance use disorders receives treatment, and those who do typically have more severe disorders. The current study examines the relationship of help-seeking with remission from alcohol and/or drug dependence and other outcomes. METHODS: Data from the Wave 1 (2001-2002) and Wave 2 (2004-2005) National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) were used to examine remission at Wave 2 among respondents who had past-year substance dependence disorders at Wave 1 (N=1262). Multi-group structural equation modeling was used to compare individuals with (n=356) and without (n=906) prior help-seeking at Wave 1 on subsequent help seeking and other factors that influence outcomes. RESULTS: Baseline help-seekers sought help at higher levels over the follow-up period (31% vs. 8%) and had lower rates of remission (50% vs. 68%), as compared with those without prior help seeking, respectively. Among baseline help-seekers, there were stronger relationships between baseline stress and mental disorders and having sought help since baseline; age and past-year level of stress at follow-up; level of stress and health status at follow-up; and social support and mental disorders at follow up. Among baseline non-help-seekers, there were stronger relationships between being female and past-year stress at follow-up, and between having sought help since baseline and physical health status at follow-up. CONCLUSIONS: Findings extend our understanding of the factors associated with recovery from substance dependence, including "natural recovery", use of services outside of addiction treatment, and gender differences in help-seeking and remission. PMID- 23791040 TI - The influence of monetary punishment on cognitive control in abstinent cocaine users. AB - BACKGROUND: Dependent drug users show a diminished neural response to punishment, in both limbic and cortical regions, though it remains unclear how such changes influence cognitive processes critical to addiction. To assess this relationship, we examined the influence of monetary punishment on inhibitory control and adaptive post-error behavior in abstinent cocaine dependent (CD) participants. METHODS: 15 abstinent CD and 15 matched control participants performed a Go/No-go response inhibition task, which administered monetary fines for failed response inhibition, during collection of fMRI data. RESULTS: CD participants showed reduced inhibitory control and significantly less adaptive post-error slowing in response to punishment, when compared to controls. The diminished behavioral punishment sensitivity shown by CD participants was associated with significant hypoactive error-related BOLD responses in the dorsal anterior cingulate cortex (ACC), right insula and right prefrontal regions. Specifically, CD participants' error-related response in these regions was not modulated by the presence of punishment, whereas control participants' response showed a significant BOLD increase during punished errors. CONCLUSIONS: CD participants showed a blunted response to failed control (errors) that was not modulated by punishment. Consistent with previous findings of reduced sensitivity to monetary loss in cocaine users, we further demonstrate that such insensitivity is associated with an inability to increase cognitive control in the face of negative consequences, a core symptom of addiction. The pattern of deficits in the CD group may have implications for interventions that attempt to improve cognitive control in drug dependent groups via positive/negative incentives. PMID- 23791041 TI - Prognostic indicators of low back pain in primary care: five-year prospective study. AB - Back pain is common and many people experience long-term problems, yet little is known about what prognostic factors predict long-term outcomes. This study's objective was to determine which factors predict short- and long-term outcomes in primary care consulters with low back pain (LBP). Analysis was carried out on 488 patients who had consulted their physician about LBP. Patients were followed up at 6 months and 5 years. Clinically significant LBP at follow-up was defined as a score of 2, 3, or 4 on the Chronic Pain Grade, indicating substantial pain and disability. Cox regression was used to estimate relative risks (RRs) with 95% confidence intervals (CIs) on 32 potential predictive factors, organized into domains (demographic, physical, psychological, and occupational). Baseline pain intensity conferred a 12% increase in risk (RR = 1.12, 95% CI = 1.03-1.20), and patients' belief that their LBP would persist conferred a 4% increase in risk (RR = 1.04, 95% CI = 1.01-1.07) for poor outcome at 6 months. Outcome at 5 years was best predicted by a model with the same factors as in the 6-month model: pain intensity increased risk by 9% (RR = 1.09, 95% CI = .997-1.20), and a belief that their LBP would persist increased risk by 6% (RR = 1.06, 95% CI = 1.03-1.09). Both predictors have the potential to be targets for clinical intervention. PERSPECTIVE: Few studies have investigated factors that predict long-term back pain. This study has shown that pain intensity experienced during a period of primary care consultation, and patients' perception about whether their back pain will persist, were significant predictors of poor outcome at 6 months and at 5 years. PMID- 23791042 TI - Distance traveled and frequency of interstate opioid dispensing in opioid shoppers and nonshoppers. AB - Little is known about how far opioid shoppers travel or how often they cross state lines to fill their opioid prescriptions. This retrospective cohort study evaluated these measures for opioid shoppers and nonshoppers using a large U.S. prescription database. Patients with >=3 opioid dispensings were followed for 18 months. A subject was considered a shopper when he or she filled overlapping opioid prescriptions written by >1 prescriber at >=3 pharmacies. A heavy shopper had >=5 shopping episodes. Outcomes assessed were distance traveled among pharmacies and number of states visited to fill opioid prescriptions. A total of 10,910,451 subjects were included; .7% developed any shopping behavior and their prescriptions accounted for 8.6% of all opioid dispensings. Shoppers and heavy shoppers were younger than the nonshoppers. Shoppers traveled a median of 83.8 miles, heavy shoppers 199.5 miles, and nonshoppers 0 miles. Almost 20% of shoppers or heavy shoppers, but only 4% of nonshoppers, visited >1 state. Shoppers traveled greater distances and more often crossed state borders to fill opioid prescriptions than nonshoppers, and their dispensings accounted for a disproportionate number of opioid dispensings. Sharing of data among prescription monitoring programs will likely strengthen those programs and may decrease shopping behavior. PERSPECTIVE: This study shows that opioid shoppers travel greater distances and more often cross state borders to fill opioid prescriptions than nonshoppers, and their dispensings accounted for a disproportionate number of opioid dispensings. The findings support the need for data sharing among prescription-monitoring programs to deter opioid shopping behavior. PMID- 23791043 TI - Particulate pollutants are capable to 'degrade' epicuticular waxes and to decrease the drought tolerance of Scots pine (Pinus sylvestris L.). AB - Air pollution causes the amorphous appearance of epicuticular waxes in conifers, usually called wax 'degradation' or 'erosion', which is often correlated with tree damage symptoms, e.g., winter desiccation. Previous investigations concentrated on wax chemistry, with little success. Here, we address the hypothesis that both 'wax degradation' and decreasing drought tolerance of trees may result from physical factors following the deposition of salt particles onto the needles. Pine seedlings were sprayed with dry aerosols or 50 mM solutions of different salts. The needles underwent humidity changes within an environmental scanning electron microscope, causing salt expansion on the surface and into the epistomatal chambers. The development of amorphous wax appearance by deliquescent salts covering tubular wax fibrils was demonstrated. The minimum epidermal conductance of the sprayed pine seedlings increased. Aerosol deposition potentially 'degrades' waxes and decreases tree drought tolerance. These effects have not been adequately considered thus far in air pollution research. PMID- 23791044 TI - Least Disturbed Condition for European Mediterranean rivers. AB - The present report describes a three-step approach that was used to characterize and define thresholds for the Least Disturbed Condition in Mediterranean streams of four different types, regarding organic pollution and nutrients, hydrological and morphological alterations, and land use. For this purpose, a common database composed of national reference sites (929 records) from seven countries, sampled for invertebrates, diatoms and macrophytes was used. The analyses of reference sites showed that small (catchment <100 km(2)) siliceous and non-siliceous streams were mainly affected by channelization, bank alteration and hydropeaking. Medium-sized siliceous rivers were the most affected by stressors: 25-43% of the samples showed at least slight alterations regarding channelization, connectivity, upstream dam influence, hydropeaking and degradation of riparian vegetation. Temporary streams were the least affected by hydromorphological changes, but they were nevertheless affected by alterations in riparian vegetation. There were no major differences between all permanent stream types regarding water quality, but temporary streams showed lower values for oxygenation (DO) and wider ranges for other variables, such as nitrates. A lower threshold value for DO (60%) was determined for this stream type and can be attributed to the streams' natural characteristics. For all other river types, common limits were found for the remaining variables (ammonium, nitrate, phosphate, total P, % of artificial areas, % of intensive and extensive agriculture, % of semi-natural areas in the catchment). These values were then used to select the list of reference sites. The biological communities were characterized, revealing the existence of nine groups of Mediterranean invertebrate communities, six for diatoms and five for macrophytes: each group was characterized by specific indicator taxa that highlighted the differences between groups. PMID- 23791045 TI - Willingness to pay and benefit-cost analysis of modern contraceptives in Nigeria. AB - OBJECTIVE: To determine the willingness to pay (WTP) and the benefit-cost of modern contraceptives delivered through the public sector in Nigeria. METHODS: Data were collected from 4517 randomly selected households. The WTP for the 6 major contraceptive methods available in the public sector was elicited. Logistic regression was used to determine whether the decision to state a positive WTP amount was valid; Tobit regression was used to test the validity of the elicited WTP amounts. For each contraceptive, 3 BCR values were computed, based on the official unit price, the unit cost per couple-year of protection (CYP), and the average actual expenditure for contraceptives in the month preceding the interview. RESULTS: The mean WTP for the different contraceptives varied by socioeconomic status and geographic (urban versus rural) location (P<0.01). The BCR analysis showed that the benefits of providing contraceptives through the public sector far outweighed the costs, except for female condoms, where the CYP based BCR was 0.9. CONCLUSION: The benefits of providing contraceptives outweigh the costs, making public sector investment worthwhile. The median WTP amounts, which reflect the ideal upper thresholds for pricing, indicate that cost recovery is feasible for all contraceptives. PMID- 23791046 TI - Reply to: About the article "Single umbilical incision laparoscopic cholecystectomy: results of the prospective trial of the Coelio Club". PMID- 23791047 TI - About the article "Single umbilical incision laparoscopic cholecystectomy: results of the prospective trial of the Coelio Club". PMID- 23791048 TI - [A(H5N1) and A(H7N9) avian influenza: the H7N9 avian influenza outbreak of 2013]. AB - influenza virus can infect humans and cause disease. The clinical presentation of human infection is usually mild, but the infection caused by A(H5N1) avian influenza virus occurring initially in Hongkong in 1997 or the A(H7N9) virus isolated first at the beginning of this year in China is severe and characterized by high mortality. The mortality rate of adolescents and children caused by H5N1 avian influenza is lower than that of adults and the younger the child the lower the mortality rate. A few pediatric H7N9 avian influenza cases recovered soon after treatment. A child was determined to be a H7N9 avian influenza virus carrier. These findings suggested that the pediatric H7N9 avian influenza infection was mild. It is very important to start anti-virus treatment with oseltamivir as early as possible in cases of avian influenza infection is considered. Combined therapy, including respiratory and circulatory support and inhibiting immunological reaction, is emphasized in the treatment of severe cases. PMID- 23791049 TI - [Virological characteristics of avian influenza A H7N9 virus]. AB - From February 2013, a novel avian influenza A H7N9 virus causing human infection with fatal outcomes has been identified in eastern China. This avian influenza A H7N9 virus is a triple reassortant of viruses that are avian-origin only and it is low pathogenic in poultry. Several characteristic amino acid mutations in HA and PB2 polymerase subunit (including G186V, Q226L and E627K substitution) have been found through sequence analysis, and these mutations probably facilitate binding to human-type receptors and efficient replication in mammals. Other mutations in NA, M2 and NS genes were also found. Although sustained human-to human transmission has not been conclusively established, limited human-to-human transmission of the H7N9 virus remains possible. Intensified surveillance for the H7N9 virus in humans and animals is needed to answer questions about the viral origin, spread and potential threat. PMID- 23791050 TI - [A limited understanding of hazard of influenza A virus subtype H7N9 in children]. AB - Since the first human case of influenza A virus subtype H7N9 was reported in Shanghai, China in March 2013, there have been two H7N9-infected children and one healthy H7N9 carrier. With a brief introduction to the basic information of the three children, this paper discusses the variation of Avian influenza virus by referring to the literature, suggests that human-to-human transmission is not confirmed in the small outbreak, and reviews the measures for preventing and treating H7N9 infection in humans. In addition, this paper talks about the use of tamiflu in early stage of infection and the use of peramivir when the patient's condition is severe. PMID- 23791051 TI - [Treatment of pediatric critical trauma following earthquake disasters]. AB - Children are the most vulnerable in natural disasters for their poor self protection ability. Pediatric deaths in earthquakes are mainly due to cardiopulmonary arrest, severe craniocerebral injury, shock, crush syndrome, and multiple organ failure. Priority should be given to centralized, effective treatment for injured children, with multidisciplinary cooperation, and severe cases need to be transferred to the pediatric intensive care unit, thus improving survival and reducing disability. PMID- 23791052 TI - [Types of pediatric trauma in earthquake and key points of treatment]. AB - Limb trauma is the most common among pediatric victims in earthquake. Compared with traumatic brain injury, which is frequent in earthquake, intracranial injury is rare, but it is the leading cause of death from trauma in earthquake. Thoracoabdominal crush injury, which often causes such crises as visceral hemorrhage, is also one of the main causes of death among pediatric victims in earthquake. Crush syndrome and osteofascial compartment syndrome are often complicated by acute renal failure. Because trauma is emergent in earthquake, the principle of "life-saving first, critical injury priority" should be complied with during on-site rescue. The injured children must be transferred to the medical center as soon as possible. It is essential to treat the critically injured children by multidisciplinary cooperation, and much attention should be paid to prevention of complications, rehabilitation care, and psychological counseling. PMID- 23791053 TI - [Clinical characteristics of pediatric victims in the Lushan and Wenchuan earthquakes and experience of medical rescue]. AB - OBJECTIVE: To get a more comprehensive understanding of the clinical characteristics of pediatric victims in earthquake and to summarize the experience of medical rescue. METHODS: The clinical information was collected from the pediatric victims who were admitted to West China Hospital, Sichuan University following the Lushan earthquake in 2013 and Wenchuan earthquake in 2008. The clinical data were compared between the pediatric victims in the two earthquakes. RESULTS: Thirty-four children under 14 years of age, who were injured in the Lushan earthquake, were admitted to the West China Hospital before April 30, 2013. Compared with the data in the Wenchuan earthquake, the mean age of the pediatric victims in the Lushan earthquake was significantly lower (P<0.01), and the mean time from earthquake to hospitalization was significantly shorter (P<0.01). In the Lushan earthquake, 67.6% of the injured children had variable limb fractures; traumatic brain injury was found in 29.4% of hospitalized children, versus 9.5% in the Wenchuan earthquake (P<0.05). Among the 34 children, no amputation and death occurred, and all the 13 severe cases started to recover. CONCLUSIONS: There were higher proportions of severely injured children and children with traumatic brain injury in the Lushan earthquake than in the Wenchuan earthquake. But these cases recovered well, which was possibly due to timely on-site rescue and transfer and multi-sector, multi institution, and multidisciplinary cooperation. PMID- 23791054 TI - [Psychological trauma and crisis intervention in children after earthquake]. AB - As a momentous disaster, earthquake would bring severe psychological trauma to children, with an adverse effect not only on the physiological functions, but also on their behaviors, emotions, and cognition, and the short-term and long term consequences are much greater in children than in adults. The children of different ages have different psychological reactions, so psychological intervention varies with children's age. Psychological intervention is still important long afterwards to prevent permanent psychological trauma in children. PMID- 23791055 TI - [Prevalence and prevention of common nutritional risks in children after earthquake]. AB - Children have been identified as the most nutritionally vulnerable group when disaster happens. The most common nutritional risks include protein-energy malnutrition, iron-deficiency anemia, and trace element deficiency in children after earthquake. During the disaster relief, effective nutritional interventions should be performed according to the nutritional conditions of children in the affected area, so as to prevent the common nutritional risks. Timely diagnosis and treatment should be provided for children at a high risk of malnutrition. PMID- 23791056 TI - [Rehabilitation care for children after trauma in the earthquake disaster]. AB - For the children who suffer trauma in earthquake, rehabilitation care aims to promote functional recovery, shorten hospital stay, and reduce the incidence of complications or disability by evidence-based, multidisciplinary, and comprehensive early rehabilitation intervention on the basis of first aid and clinical treatment. Children are likely to suffer traumatic brain injury, spinal cord injury, peripheral nerve injury, limb fracture, and amputation in the earthquake disaster, so the clinical rehabilitation care designed considering the characteristics of children should be provided immediately after acute phase of trauma to promote functional recovery. PMID- 23791057 TI - [Common pediatric infectious diseases following natural disasters]. AB - Natural disasters may lead to the outbreaks of infectious diseases because they increase the risk factors for infectious diseases. This paper reviews the risk factors for infectious diseases after natural disasters, especially earthquake, and the infectious diseases following disasters reported in recent years. The infectious diseases after earthquake include diarrhea, cholera, viral hepatitis, upper respiratory tract infection, tuberculosis, measles, leptospirosis, dengue fever, tetanus, and gas gangrene, as well as some rare infections. Children are vulnerable to infectious diseases, so pediatricians should pay more attention to the research on relationship between infectious diseases and natural disasters. PMID- 23791058 TI - [Real-time quantitative detection of E2A-PBX1 fusion gene in children with acute lymphoblastic leukemia and its clinical application in minimal residual disease monitoring]. AB - OBJECTIVE: To establish a real-time reverse transcription-polymerase chain reaction (RT-PCR) for quantitative detection of E2A-PBX1 fusion gene mRNA in acute lymphoblastic leukemia (ALL) children and to explore its clinical significance in minimal residual disease monitoring and prognosis evaluation. METHODS: Real-time RT-PCR was used to quantitatively detect the mRNA expression of E2A-PBX1 gene in 11 newly diagnosed ALL patients at diagnosis (11 cases), complete remission (11 cases) and periods of relapse (3 cases). Ten children with normal bone marrow cell morphology and without hematopathy or tumor diseases were used as the control group. RESULTS: The median expression levels of E2A-PBX1 fusion gene in the ALL group at diagnosis and the relapse group were significantly higher than in the control and complete remission groups (P<0.01). Compared with E2A-PBX1 negative patients on day 33 during induction of remission, the recurrence rate increased and disease free survival rate at 3 year decreased significantly in E2A-PBX1 positive patients decreased (P<0.05). CONCLUSIONS: Measurement of E2A-PBX1 levels by real-time RT-PCR is useful for monitoing minimal residual disease, prediction of relapse and individual treatment. The expression level of E2A-PBX1 gene on day 33 during induction of remission can be used for prognosis evaluation. PMID- 23791059 TI - [Therapeutic effect of clofarabine in children with relapsed or refractory acute lymphoblastic leukemia]. AB - OBJECTIVE: To explore the efficacy and adverse effects of clofarabine for relapsed/refractory acute lymphoblastic leukemia in children. METHODS: Twenty-six pediatric patients with relapsed/refractory acute lymphoblastic leukemia were treated with clofarabine. There were 22 males and 4 females, with a mean age of 9.5 years (ranging from 4 to 17 years). They received clofarabine 52 mg/m2 intravenously over 2 hours daily for 5 days. Thirteen patients received two cycles and one patient received three cycles. RESULTS: In the first cycle of clofarabine, complete remission was obtained in 11 children (42%) and partial remission was obtained in 7 children (27%). Eight children (31%) were considered unresponsive. In the second cycle, 11 (85%) of the 13 children obtained complete remission, 1 (8%) partial remission and 1 (8%) was unresponsive. One child received three cycles and obtained complete remission in each cycle. The common adverse events were myelosuppression, infection, liver dysfunction and gastrointestinal adverse reactions. There were no chemotherapy-related deaths. CONCLUSIONS: Clofarabine is effective in the treatment of children with relapsed/refractory acute lymphoblastic leukemia and its adverse effects can be tolerated. Clofarabine could be a promising new treatment for relapsed/refractory acute lymphoblastic leukemia. PMID- 23791060 TI - [Clinical features of cytopenia with bone marrow hypoplasia in children: an analysis of 100 cases]. AB - OBJECTIVE: To summarize the clinical features of cytopenia with bone marrow hypoplasia in 100 children and to investigate an effective treatment regimen for myelodysplastic syndrome (MDS) in children. METHODS: A retrospective analysis was performed on the clinical data of 100 children non-randomly selected from Japan and China who were diagnosed with cytopenia with bone marrow hypoplasia between 2006 and 2011. The data of patients from China were subjected to prognostic analysis. RESULTS: There was no significant difference in the proportion of MDS cases and acquired aplastic anemia (AA) cases between the Japanese and Chinese children. Of the 100 patients, there were 29 cases of acquired AA, 58 cases of refractory cytopenia of childhood (RCC) and 13 cases of refractory cytopenia with multilineage dysplasia (RCMD). There were significant differences in reticulocyte absolute value in peripheral blood and degree of bone marrow proliferation among the three patient groups (P<0.05). The patients from China were followed up for 16-70 months (median, 41 months). After being treated with cyclosporine (CsA) combined with stanozolol, the patients with AA had response rates of 25% and 75%, the patients with RCC had response rates of 47.1% and 82.4%, and the patients with RCMD had response rates of 60% and 60% respectively at 3 and 6 months after treatment. CONCLUSIONS: There are significant differences in reticulocyte absolute value in peripheral blood and degree of bone marrow proliferation among patients with RCC, RCMD and acquired AA. CsA combined with stanozolol has a good therapeutic efficacy in the treatment of acquired AA and hypoplastic MDS in children, but studies of more cases and a longer follow-up duration are needed. PMID- 23791061 TI - [Protective effect of cold autologous blood cardioplegic solution on the heart of infants with cyanotic congenital heart disease]. AB - OBJECTIVE: To study the protective effect of cold autologous blood cardioplegic solution on the heart of infants with cyanotic congenital heart disease (CCHD). METHODS: Ninety-six infants with CCHD who underwent cardiopulmonary bypass (CPB) were randomly and equally divided into three groups: histidine-tryptophan ketoglutarate (HTK) solution, cold non-autologous blood cardioplegic solution, and cold autologous blood cardioplegic solution. The right auricular tissues were taken before aortic cross-clamping and at 30 minutes after aortic declamping, and ATP level and energy charge (EC) in the myocardium were measured. Venous blood was collected before and immediately after CPB, and the serum levels of creatine kinase (CK)-MB and cardiac troponin I (cTnI) were measured. The clinical parameters, such as the re-beat time and re-beat rate during CPB, cardiac index, dependence on positive inotropic agents, and left ventricular ejection fraction (LVEF) at 2 hours after CPB, the incidence rate of arrhythmia within 24 hours after CPB, and postoperative complications and mortality, were recorded. RESULTS: At 30 minutes after aortic declamping, the three groups showed significantly decreased ATP and EC levels (P<0.05), and the cold autologous blood group had significantly higher ATP and EC levels than the other two groups (P<0.05). Immediately after CPB, the three groups showed significantly increased serum levels of CK-MB and cTnI (P<0.05), and the cold autologous blood group had significantly lower serum levels of CK-MB and cTnI than the other two groups (P<0.05). The cold autologous blood group had significantly better outcomes than the other two groups in terms of the re-beat time during CPB and the dependence on positive inotropic agents and LVEF at 2 hours after CPB (P<0.05). CONCLUSIONS: Cold autologous blood cardioplegic solution is superior to HTK and cold non autologous blood cardioplegic solutions in preserving myocardial energy and reducing myocardial injury in infants with CCHD who undergo CPB, thus providing a better protective effect on the heart. PMID- 23791062 TI - [Investigation of 24-hour blood pressure monitoring for evaluating treatment outcome of nerve-mediated syncope in children]. AB - OBJECTIVE: To investigate the clinical significance of 24-hour blood pressure monitoring (ABPM) for evaluating the treatment outcome of nerve-mediated syncope (NMS) in children. METHODS: Twenty-eight children with NMS confirmed by a head-up tilt table test (HUTT) (12 males and 16 females, aged 6-13 years) and with a chief complaint of unexplained syncope or pre-syncope between February 2010 and August 2012, were included in the study. These children received health education combined with therapy using oral rehydration salts solution and were then reexamined for clinical symptoms as well as HUTT and ABPM results. RESULTS: Of 28 NMS cases, 22 were vasodepressive type, 5 were mixed type, and 1 was cardioinhibitory type. The follow-up showed that 27 (96%) of all cases had improved clinical symptoms, and 18 (64%) had improved HUTT results. The ABPM follow-up revealed no significant changes in 24-hour mean systolic pressure, 24 hour mean diastolic pressure, daytime mean systolic pressure, daytime mean diastolic pressure, nighttime mean systolic pressure, nighttime mean diastolic pressure, day-night difference of systolic pressure, and day-night difference of diastolic pressure after treatment (P>0.05). The percentage of children with a dipper blood pressure pattern increased from 29% (8/28) before treatment to 50% (14/28) after treatment; the percentage of children with a non-dipper blood pressure pattern decreased from 71% (20/28) before treatment to 50% (14/28) after treatment. CONCLUSIONS: As an effective, objective and non-invasive monitoring means, ABPM is of some clinical significance for evaluating the treatment outcome of NMS in children. PMID- 23791063 TI - [Efficacy and safety of tulobuterol patch versus oral salbutamol sulfate in children with mild or moderate acute attack of bronchial asthma: a comparative study]. AB - OBJECTIVE: To compare tulobuterol patch and oral salbutamol sulfate in terms of efficacy and safety in children with mild or moderate acute attack of bronchial asthma. METHODS: A total of 92 children with mild and moderate acute asthmatic attack were randomly divided into salbutamol group (n=46) and tulobuterol group (n=46). Both groups received routine treatment with antihistamine, selective leukotriene receptor antagonist and glucocorticoid. In addition, the salbutamol group was given slow-release capsules of salbutamol sulfate, and the tulobuterol group was treated with tulobuterol patch. The two groups were compared with respect to symptom scores of cough, wheeze, respiratory rate, wheezing sound, three depression sign and peak expiratory flow, as well as adverse events. RESULTS: As the treatment proceeded, symptom scores decreased in both groups; on the third day of treatment, all symptom scores except cough score showed a significant decrease in both groups (P<0.05), but the tulobuterol group had significantly lower symptom scores than the salbutamol group (P<0.05). On the fourteenth day of treatment, both groups had a significant decrease in cough score (P<0.05), but the tulobuterol group had a significantly lower cough score than the salbutamol group (P<0.05). One child developed hand trembling in the salbutamol group, while no adverse event occurred in the tulobuterol group. CONCLUSIONS: Compared with oral salbutamol sulfate, tulobuterol patch has a better therapeutic efficacy and a higher safety in children with mild or moderate acute asthmatic attack. PMID- 23791064 TI - [Surveillance of adverse events following immunization in Henan Province, China between 2010-2011]. AB - OBJECTIVE: To analyze the epidemiological features of adverse events following immunization (AEFI) in Henan Province, China and to evaluate the safety of vaccines currently used in Henan. METHODS: The AEFI cases reported in Henan from January 1, 2010 to December 31, 2011 were collected through the China Surveillance System of Information on National Immunization Program. The descriptive method was used for epidemiological analysis. RESULTS: A total of 2415 cases of AEFI were reported in Henan from January 1, 2010 to December 31, 2011, and 1238 (51.26%) of them were found in Zhengzhou, Luoyang, and Jiaozuo cities. The male-to-female ratio was 1.32:1. Seven hundred and ninety-nine (33.08%) of these cases were less than one year old. Measles vaccine and DPT vaccine (against diphtheria, pertussis, and tetanus) were the main causes of AEFI, contributing to 61.24% of cases; the incidence rates of AEFI among people receiving measles and DPT vaccines were 30.3/105 and 5.0/105, respectively. 1528 cases (63.27%) developed AEFI after the first dose of vaccination. Inflammation and allergic symptoms were the predominant adverse effects caused by the top 5 vaccines AEFI-causing vaccines, and the clinical manifestations were significantly different among AEFI cases caused by different vaccines (chi2=304.5, P<0.001). Among the 2415 AEFI cases, 1946 (80.58%) had common adverse reaction, 348 (14.41%) had rare adverse reaction, 98 (4.06%) had coupling disease, 13 (0.51%) had psychogenic reaction, and 10 (0.41%) had reaction for unknown reasons. The prognosis of most AEFI cases was good, with a cure rate as high as 90.64%. CONCLUSIONS: AEFI occurs mostly in young children and after the first dose of vaccination. This should be brought to the attention of vaccination service personnel and the children's parents. PMID- 23791065 TI - [Investigation of disease spectrum in the PICU of Shengjing Hospital of China Medical University between 2005 and 2012]. AB - OBJECTIVE: To summarize the spectrum of disease and common diseases that cause death in children admitted to the Pediatric Intensive Care Unit (PICU), Shengjing Hospital of China Medical University between 2005 and 2012. METHODS: A retrospective analysis was carried out on the clinical data of 4484 children admitted to the PICU of Shengjing Hospital between 2005 and 2012. RESULTS: Acute bronchopneumonia, which was found in 1099 (24.51%) of the 4484 cases, was the most common disease in the PICU between 2005 and 2012. The incidence of intracranial infection, sepsis, hand-foot-mouth disease and trauma showed an increasing trend from 2005 to 2012, but that of non-traumatic intracranial hemorrhage, epilepsy and congenital heart disease showed a decreasing trend. The mortality decreased from 11.5% in 2005 to 3.1% in 2012, and the overall mortality was significantly higher in 2005-2008 than in 2009-2012 (11.98% vs 4.41%; P<0.01). The main causes of death included severe acute bronchial pneumonia, severe sepsis, complex congenital heart disease, severe cerebral trauma, respiratory failure, severe hand-foot-mouth disease, acute poisoning and circulatory failure. CONCLUSIONS: Acute bronchopneumonia was the most common disease in the PICU of Shengjing Hospital between 2005 and 2012, but the spectrum of disease changed over time. The mortality showed a decreasing trend among the children in the PICU between 2005 and 2012, and the main causes of death included severe acute bronchial pneumonia and severe sepsis. PMID- 23791066 TI - [Association of new functional SNP rs72689236 of CASP3 with Kawasaki disease: a meta-analysis]. AB - OBJECTIVE: To investigate the association of rs72689236, a new functional single nucleotide polymorphism (SNP) of the gene encoding caspase-3 (CASP3), with the occurrence and development of Kawasaki disease by a meta analysis. METHODS: A literature search was performed using databases at home and abroad according to inclusion and exclusion criteria, to acquire studies on the relationship between rs72689236 and Kawasaki disease published up to November 2012, including case control studies and transmission disequilibrium tests. An integrated meta analysis was performed using RevMan 5.1 software after the studies were screened and evaluated. RESULTS: Six studies were extracted for systematic review of the association between rs72689236 and Kawasaki disease. The frequency of allele A of the SNP was significantly higher in patients with Kawasaki disease than in the controls (OR=1.34, 95%CI=1.24-1.46, P<0.001); the risk for Kawasaki disease in children with allele A (AA+AG) increased by approximately 44% compared with children with GG (OR=1.44, 95%CI=1.27-1.65, P<0.001). The frequency of allele A of the SNP was significantly higher in Kawasaki disease patients with coronary artery lesions than in those without coronary artery lesions (OR=1.51, 95%CI=1.10 2.07, P= 0.01); the risk for coronary artery lesions in Kawasaki disease patients with allele A (AA+AG) increased by approximately 59% compared with Kawasaki disease patients with GG (OR=1.59, 95%CI= 1.00-2.53, P=0.05]. No association between this SNP and the therapeutic effect of intravenous immunoglobulin (IVIG) was found in patients with Kawasaki disease. CONCLUSIONS: The allele A of functional SNP rs72689236 of CASP3 increases the risk for Kawasaki disease, and it may be used as the genetic marker for susceptibility to coronary artery lesions as a complication of Kawasaki disease. Currently, there is still no sufficient evidence that this SNP has an impact on the therapeutic effect of IVIG in patients with Kawasaki disease, and more studies are needed to investigate the feasibility of its application in individualized treatment. PMID- 23791067 TI - [Changes in MLS-BAEP in newborn piglets with hypoxic-ischemic brain damage during selective moderate head cooling therapy]. AB - OBJECTIVE: To study the effect of selective moderate head cooling therapy on maximum length sequences brainstem auditory evoked potential (MLS-BAEP) in newborn piglets with hypoxic-ischemic brain damage. METHODS: Sixteen newborn piglets aged 5-7 day old were randomly divided into three groups: normothermic control (n=4), HI (n=6) and mild hypothermia-treated (n=6). HI was induced through temporary occlusion of both carotid arteries, followed by mechanical ventilation with low concentration of oxygen (FiO2=0.06) for 30 minutes. Mild hypothermia was induced by equipment via circulating water. MLS-BAER was recorded before HI and at 12 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, 4 days, 7 days, 10 days, 13 days and 15 days after HI. RESULTS: Compared with the normothermic control group, all latencies and intervals tended to increase significantly at 72 hours in the HI group and reached peak values on day 7. From day 10, all latencies and intervals tended to decrease, but apart from wave I latency, still differed significantly from those of the normothermic control group. MLS-BAER variables did not reach normal values until day 15. III latency, I-III interval and I-V interval were significantly reduced in the hypothermia treated group between 60 and 7 days after HI compared with the HI group (P<0.05). V latency and III-V interval in the hypothermia-treated group were also reduced compared with the HI group between 72 hours and 7 days after HI (P<0.05). CONCLUSIONS: Both peripheral and central auditory systems are disturbed by HI, which shows as a significant increase in MLS-BAER variables (all latencies and intervals) in newborn piglets. Involvement in central brainstem auditory system reaches a peak on day 7 after injury. MLS-BAER variables still cannot reach to normal values until day 15. Selective moderate head cooling therapy can significantly reduce brainstem damage induced by HI. PMID- 23791068 TI - [Effect of insulin-like growth factor-1 on hyperoxia-induced apoptosis in A549 cells]. AB - OBJECTIVE: To investigate the effect of insulin-like growth factor-1 (IGF-1), which can promote cell differentiation and inhibit cell apoptosis, on hyperoxia induced apoptosis in A549 cells and its anti-apoptotic mechanism. METHODS: A549 cells were sub-cultured, exposed to hyperoxic conditions and were then treated with different concentrations of IGF-1 (1, 10, and 100 ng/mL) for 48 hours. Cell viability was measured by MTT assay. Cell apoptosis was evaluated by Annexin V FITC/PI double-staining flow cytometry. Expression levels of Bax and Bcl-2 were measured by flow cytometry. RESULTS: The middle-dose and high-dose IGF-1 intervention groups had higher cell viabilities than the hyperoxic exposure group [(64+/-3)% and (88+/-4)% vs (51+/-3)%; P<0.05]. Compared with the air control group, the hyperoxic exposure group had a significantly higher apoptotic rate [(38.3+/-5.4)% vs (2.4+/-0.9)%; P<0.05], a significantly lower expression level of Bcl-2 [(72+/-5)% vs (91+/-4)%; P<0.05], and a significantly higher expression level of Bax [(54+/-6)% vs (3+/-2)%; P<0.05]. Compared with the hyperoxic exposure group, the low-dose, middle-dose, and high-dose IGF-1 intervention groups had significantly lower apoptotic rates [(16.1+/-4.7)%, (9.2+/-2.8)%, and (6.9+/-2.5)% vs (38.3+/-5.4)%; P<0.05], significantly higher expression level of Bcl-2 [(79+/-4)%, (94+/-4)%, and (100+/-5)% vs (72+/-5)%; P<0.05], and significantly lower expression level of Bax [(26+/-4)%, (5+/-2)%, and (4+/-2)% vs (54+/-6)%; P<0.05]. CONCLUSIONS: Hyperoxia significantly inhibits proliferation and promotes apoptosis in A549 cells. IGF-1 may promote cell proliferation and inhibit hyperoxia-induced apoptosis in A549 cells by regulating the expression of Bcl-2 and Bax. PMID- 23791069 TI - [One case of pediatric multiple sclerosis with convulsions as initial symptoms]. PMID- 23791070 TI - [Mechanical ventilation in acute respiratory distress syndrome]. AB - The goal of mechanically ventilating patients with acute respiratory distress syndrome (ARDS) is to ensure adequate oxygenation and minimal ventilator associated lung injury. Non-invasive ventilation should be cautiously used in patients with ARDS. Protective ARDS mechanical ventilation strategies with low tidal volumes can reduce mortality. Driving pressure is the most reasonable parameter to optimize tidal volume. Available evidence does not support the routine use of higher positive end expiratory pressure (PEEP) in patients with ARDS. The optimal level of PEEP may be titrated by the inflection point obtained from static pressure-volume curve. Promising therapies include prone position ventilation, high frequency oscillatory ventilation and extracorporeal membrane oxygenation as salvage treatment. While mechanically ventilating, it is also important for ARDS patients to maintain spontaneous breathing via assisted ventilation mode such as bilevel positive airway pressure, pressure support ventilation and neurally adjusted ventilation assist. Exogenous surfactant, inhaled nitric oxide, bronchodilators, airway pressure release ventilation and partial liquid ventilation are not recommended therapies. PMID- 23791071 TI - Who should answer the question: "Can I drive with this plaster cast?". AB - INTRODUCTION: The application of a plaster cast is known to affect driving ability, but patients continue to drive. The individuals and authorities involved in assessing driving safely include doctors, the Driver and Vehicle Licensing Agency (DVLA), police, insurance companies, and patients, but it is unclear who should take responsibility for the advice given, especially in the event of an accident. METHODS: We contacted senior plaster technicians in 348 hospitals in the UK. We recorded their responses regarding advice given to patients on driving in specific casts. Sixteen motor insurance companies and 40 police forces were also contacted in order to canvass their opinions. RESULTS: 188 technician interviews (response rate 54%) were conducted. Only 10% of respondents offered advice unprompted; an average of 48% of patients asked for advice. 88% of respondents referred patients to their motor insurance companies, and also to the DVLA (11.7%), doctor (10.6%), or police (5.9%). Only 20.2% of plaster rooms provided written information. All insurance companies would insure patients provided the doctor had not explicitly objected to driving, but there was no consensus amongst the responses received from police. In the event of an accident after the treating doctor had advised against driving, insurance companies were likely to invalidate the policy, and the police would seek penalty punishment or prosecution. CONCLUSIONS: Although doctors are not specifically trained to assess the ability of patients to drive, insurance companies and police forces place the responsibility on doctors to advise patients. Since current evidence suggests plaster casts can impair driving ability, we suggest patients should be advised not to drive. Patients accept all responsibility if they continue to drive after receiving this specific advice and understanding its implications. PMID- 23791073 TI - Autoimmune-induced glutamatergic receptor dysfunctions: conceptual and psychiatric practice implications. AB - Glutamatergic neurotransmission is mediated via complex receptorial systems including N-methyl-d-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4 isoxazolpropionic acid (AMPA) and metabotropic receptor subtypes and plays a critical role in the modulation of synaptic plasticity, mood, cognitive processes and motor behavior. Glutamatergic function deficits are hypothesized to contribute to the pathogenesis of neuropsychiatric disorders, including schizophrenia, mood and movement disorders. Accumulating data are rapidly leading to the characterization of specific types of autoimmune encephalitis in which the receptors and proteins critically involved in glutamatergic neurotransmission, e.g., NMDA, AMPA receptors, are antigen targets. Characteristic of these syndromes, antibodies alter the structure and/or function of the corresponding neuronal antigen resulting in clinical pictures that resemble pharmacological disease models. Presently the best characterized autoimmune glutamatergic disorder is anti-NMDA receptor encephalitis. This disorder manifests with intertwined psychiatric and neurological features, defines a new syndrome, reclassifies poorly defined clinical states and extends previous hypotheses, such as hypo-NMDA receptor function in schizophrenia. The characterization of autoimmune-induced glutamatergic receptor dysfunctions (AGRD) is likely to have a substantial conceptual impact upon our understanding of neuropsychiatric disorders including schizophrenia, affective and movement dysfunctions. Further definition of AGRD will provide additional guidelines for psychiatric diagnoses, identification of homogeneous patient subtypes within broad phenomenological classifications and will contribute to the development of personalized treatments. The body of knowledge already accumulated on anti-NMDA receptor encephalitis highlights the need for wide dissemination of these concepts among psychiatrists, and in suspected cases, for early recognition, prompt clinical and laboratory investigation and efficient interface between mental health and medical teams. PMID- 23791074 TI - The influence of age at onset and duration of illness on long-term outcome in patients with obsessive-compulsive disorder: a report from the International College of Obsessive Compulsive Spectrum Disorders (ICOCS). AB - Several studies reported a negative effect of early onset and long duration of illness on long-term outcome in psychiatric disorders, including Obsessive Compulsive Disorder (OCD). OCD is a prevalent, comorbid and disabling condition, associated with reduced quality of life and overall well-being for affected patients and related caregivers. The present multicenter naturalistic study sought to assess the influence of early onset and duration of illness on long term outcome in a sample of 376 OCD out-patients worldwide, as part of the "International College of Obsessive-Compulsive Spectrum Disorders" (ICOCS) network. Binary logistic regressions were performed with age at the onset and duration of illness, as continuous independent variables, on a series of different outcome dependent variables, including lifetime number of hospitalizations and suicide attempts, poly-therapy and psychiatric comorbidity. Correlations in terms of disability (SDS) were analyzed as well. Results showed that a longer duration of illness (but not earlier age of onset) was associated with hospitalization (odds ratio=1.03, p=0.01), earlier age at onset with CBT (odds ratio=0.94, p<0.001) and both a later age at onset (odds ratio=1.05, p=0.02) and a shorter duration of illness (odds ratio=0.93, p=0.02) with panic disorder comorbidity. In addition, earlier age at onset inversely correlated with higher social disability (r=-0.12, p=0.048) and longer duration of illness directly correlated with higher disability in work, social and family life (r=0.14, p=0.017; r=0.13, p=0.035; r=0.14, p=0.02). The findings from the present large, multicenter study indicate early onset and long duration of illness as overall negative predictors of long-term outcome in OCD. PMID- 23791075 TI - Evaluation of tyrosine-kinase receptor c-kit mutations, mRNA and protein expression in canine lymphoma: might c-kit represent a therapeutic target? AB - c-kit plays an important role in proliferation, survival and differentiation of hematopoietic progenitor cells. In human hematopoietic malignancies, c-kit is mostly expressed by progenitor cell neoplasms and seldom by mature cell neoplasms. Aim of this study was to evaluate c-kit expression in canine lymphoma. Twenty-five B-cell lymphomas and 21 T-cell lymphomas were enrolled in the study. c-kit mRNA and protein expression was measured in lymph node fine needle aspirates by quantitative real-time RT-PCR, flow cytometry and immunocytochemistry, while the occurrence of KIT mutations on exons 8-11 and 17 was investigated by direct cDNA sequencing. KIT mRNA was amplifiable but below the limit of quantification in 76% of B-cell lymphomas and 33% of T-cell lymphomas. Remaining samples showed a very low expression of KIT, except for some high grade (HG) T-cell lymphomas where a comparatively higher mRNA amount was observed. Transcriptional data were confirmed at the protein level. No gain-of function mutations were observed. Among canine lymphomas, T-cell lymphoma typically shows an aggressive biological behavior, partly being attributable to the lack of efficacious treatment options, and the evidence of c-kit expression in HG T-cell lymphomas might represent the rationale for its routinely diagnostic evaluation and the use of tyrosine kinase inhibitors in future clinical trials. PMID- 23791072 TI - The potential role of dopamine D3 receptor neurotransmission in cognition. AB - Currently available treatments have limited pro-cognitive effects for neuropsychiatric disorders, such as schizophrenia, Parkinson's disease and Alzheimer's disease. The primary objective of this work is to review the literature on the role of dopamine D3 receptors in cognition, and propose dopamine D3 receptor antagonists as possible cognitive enhancers for neuropsychiatric disorders. A literature search was performed to identify animal and human studies on D3 receptors and cognition using PubMed, MEDLINE and EMBASE. The search terms included "dopamine D3 receptor" and "cognition". The literature search identified 164 articles. The results revealed: (1) D3 receptors are associated with cognitive functioning in both healthy individuals and those with neuropsychiatric disorders; (2) D3 receptor blockade appears to enhance while D3 receptor agonism seems to impair cognitive function, including memory, attention, learning, processing speed, social recognition and executive function independent of age; and (3) D3 receptor antagonists may exert their pro-cognitive effect by enhancing the release of acetylcholine in the prefrontal cortex, disinhibiting the activity of dopamine neurons projecting to the nucleus accumbens or prefrontal cortex, or activating CREB signaling in the hippocampus. These findings suggest that D3 receptor blockade may enhance cognitive performance in healthy individuals and treat cognitive dysfunction in individuals with a neuropsychiatric disorder. Clinical trials are needed to confirm these effects. PMID- 23791076 TI - Vialinin A is a ubiquitin-specific peptidase inhibitor. AB - Vialinin A, a small compound isolated from the Chinese mushroom Thelephora vialis, exhibits more effective anti-inflammatory activity than the widely used immunosuppressive drug tacrolimus (FK506). Here, we show that ubiquitin-specific peptidase 5/isopeptidase T (USP5/IsoT) is a target molecule of vialinin A, identified by using a beads-probe method. Vialinin A inhibited the peptidase activity of USP5/IsoT and also inhibited the enzymatic activities of USP4 among deubiquitinating enzymes tested. Although USPs are a member of thiol protease family, vialinin A exhibited no inhibitions for other thiol proteases, such as calpain and cathepsin. PMID- 23791077 TI - Selective inhibition of human acetylcholinesterase by xanthine derivatives: in vitro inhibition and molecular modeling investigations. AB - The commonly used beverage and psychostimulant caffeine is known to inhibit human acetylcholinesterase enzyme. This pharmacological activity of caffeine is partly responsible for its cognition enhancing properties. However, the exact mechanisms of its binding to human cholinesterases (acetyl and butyrylcholinesterase; hAChE and hBuChE) are not well known. In this study, we investigated the cholinesterase inhibition by the xanthine derivatives caffeine, pentoxifylline, and propentofylline. Among them, propentofylline was the most potent AChE inhibitor (hAChE IC50=6.40 MUM). The hAChE inhibitory potency was of the order: caffeine (hAChE IC50=7.25 MUM)50 MUM) relative to the reference agent donepezil (hBuChE IC50=13.60 MUM). Molecular modeling investigations indicate that caffeine binds primarily in the catalytic site (Ser203, Glu334 and His447) region of hAChE whereas pentoxifylline and propentofylline are able to bind to both the catalytic site and peripheral anionic site due to their increased bulk/size, thereby exhibiting superior AChE inhibition relative to caffeine. In contrast, their lack of hBuChE inhibition is due to a larger binding site and lack of key aromatic amino acids. In summary, our study has important implications in the development of novel caffeine derivatives as selective AChE inhibitors with potential application as cognitive enhancers and to treat various forms of dementia. PMID- 23791078 TI - Inhibitory effect of resveratrol dimerized derivatives on nitric oxide production in lipopolysaccharide-induced RAW 264.7 cells. AB - Four types of resveratrol dimerized analogues were synthesized and evaluated in vitro on LPS-induced NO production in RAW 264.7 cells. The results showed that several compounds, especially those containing 1,2-diphenyl-2,3-dihydro-1H-indene core (type I), exhibited good inhibitory activities. Among 25 analogues, 12b showed a significant inhibitory activity (49% NO production at 10 MUM, IC50=3.38 MUM). Further study revealed that compound 12b could suppress LPS-induced iNOS expression, NO production, and IL-1beta release in a concentration-dependently manner. The mechanism of action (MOA) involved for its anti-inflammatory responses was through signaling pathways of p38 MAPK and JNK1/2, but not ERK1/2. PMID- 23791079 TI - High potency improvements to weak aryl uracil HCV polymerase inhibitor leads. AB - Described herein is the development of a potent non-nucleoside, small molecule inhibitor of genotype 1 HCV NS5B Polymerase. A 23 MUM inhibitor that was active against HCV polymerase was further elaborated into a potent single-digit nanomolar inhibitor of HCV NS5B polymerase by additional manipulation of the R and R1 substituents. Subsequent modifications to improve physical properties were made in an attempt to achieve an acceptable pharmacokinetic profile. PMID- 23791080 TI - N-Benzyloxycarbonyl-S-(2,4-dinitrophenyl)glutathione dibutyl diester is inhibitory to melarsoprol resistant cell lines overexpressing the T. bruceiMRPA transporter. AB - A series of glutathione derivatives 1-4, modified at the N,S and/or COOH sites, with in vitro antitrypanosomal activity were tested against bloodstream form Trypanosoma brucei 247 wild type and a T. b. brucei 247 strain over-expressing the multiple drug resistance protein (MRPA) by 50-100x to assess the susceptibility of these compounds to resistance by the TbMRP protein. Of the compounds tested, only compound 1 inhibited both bloodstream form T. brucei and T. bruceiMRPA, with a resistance factor of 1.4, indicating it to be an inhibitor of this protein and proteins acting in synergy with the transporter, whilst 2 &3 and its derivatives showed reduced inhibitory activity against T. bruceiMRPA, indicating them to be substrates and susceptible to resistance. PMID- 23791082 TI - Acute skin lesions after surgical procedures: a clinical approach. AB - In the hospital setting, dermatologists are often required to evaluate inflammatory skin lesions arising during surgical procedures performed in other departments. These lesions can be of physical or chemical origin. Povidone iodine is the most common reported cause of such lesions. If this antiseptic solution remains in contact with the skin in liquid form for a long period of time, it can give rise to serious irritant contact dermatitis in dependent or occluded areas. Less common causes of skin lesions after surgery include allergic contact dermatitis and burns under the dispersive electrode of the electrosurgical device. Most skin lesions that arise during surgical procedures are due to an incorrect application of antiseptic solutions. Special care must therefore be taken during the use of these solutions and, in particular, they should be allowed to dry. PMID- 23791081 TI - Different motor tasks impact differently on cognitive performance of older persons during dual task tests. AB - BACKGROUND: Dual task paradigm states that the introduction of a second task during a cognitive or motor performance results in a decreased performance in either task. Treadmill walk, often used in clinical applications of dual task testing, has never been compared to overground walk, to ascertain its susceptibility to interference from a second task. We compared the effects of overground and treadmill gait on dual task performance. METHODS: Gait kinematic parameters and cognitive performance were obtained in 29 healthy older adults (mean age 75 years, 14 females) when they were walking freely on a sensorized carpet or during treadmill walking with an optoelectronic system, in single task or dual task conditions, using alternate repetition of letters as a cognitive verbal task. FINDINGS: During overground walking, speed, cadence, step length stride length, and double support time (all with P value<0.001) and cognitive performance (number of correct words, P<0.001) decreased substantially from single to dual task testing. When subjects walked at a fixed speed on the treadmill, cadence decreased significantly (P=0.005), whereas cognitive performance remained unaffected. INTERPRETATION: Both motor and cognitive performances decline during dual task testing with overground walking. Conversely, cognitive performance remains unaffected in dual task testing on the treadmill. In the light of current dual task paradigm, these findings may have relevant implication for our understanding of motor control, as they suggest that treadmill walk does not involve brain areas susceptible to interference from the introduction of a cognitive task. PMID- 23791083 TI - Computational tools for calculating alternative muscle force patterns during motion: a comparison of possible solutions. AB - Comparing the available electromyography (EMG) and the related uncertainties with the space of muscle forces potentially driving the same motion can provide insights into understanding human motion in healthy and pathological neuromotor conditions. However, it is not clear how effective the available computational tools are in completely sample the possible muscle forces. In this study, we compared the effectiveness of Metabolica and the Null-Space algorithm at generating a comprehensive spectrum of possible muscle forces for a representative motion frame. The hip force peak during a selected walking trial was identified using a lower-limb musculoskeletal model. The joint moments, the muscle lever arms, and the muscle force constraints extracted from the model constituted the indeterminate equilibrium equation at the joints. Two spectra, each containing 200,000 muscle force samples, were calculated using Metabolica and the Null-Space algorithm. The full hip force range was calculated using optimization and compared with the hip force ranges derived from the Metabolica and the Null-Space spectra. The Metabolica spectrum spanned a much larger force range than the NS spectrum, reaching 811N difference for the gluteus maximus intermediate bundle. The Metabolica hip force range exhibited a 0.3-0.4 BW error on the upper and lower boundaries of the full hip force range (3.4-11.3 BW), whereas the full range was imposed in the NS spectrum. The results suggest that Metabolica is well suited for exhaustively sample the spectrum of possible muscle recruitment strategy. Future studies will investigate the muscle force range in healthy and pathological neuromotor conditions. PMID- 23791085 TI - Repeatability of digital image correlation for measurement of surface strains in composite long bones. AB - Digital image correlation (DIC) can measure full-field surface strains during mechanical testing of hard and soft tissues. When compared to traditional methods, such as strain gauges, DIC offers larger validation data (~50,000 points) for, e.g., finite element models. Our main aim was to evaluate the repeatability of surface strain measurements with DIC during compressive testing of composite femurs mimicking human bones. We also studied the similarity of the composite femur samples using CT. Composite femurs were chosen as test material to minimize the uncertainties associated with the use of cadaveric tissues and to understand the variability of the DIC measurement itself. Six medium-sized fourth generation composite human proximal femora (Sawbones) were CT imaged and mechanically tested in stance configuration. The force-displacement curves were recorded and the 3D surface strains were measured with DIC on the anterior surface of the femurs. Five femurs fractured at the neck-trochanter junction and one at the site below the minor trochanter. CT image of this bone showed an air cavity at the initial fracture site. All femurs fractured through a sudden brittle crack. The fracture force for the composite bones was 5751+/-650N (mean+/ SD). The maximum von Mises strain during the fractures was 2.4+/-0.8%. Noise in one experiment was 5-30uepsilon. When applied loads were equalized the variation in strains between the bones was 20-25%, and when the maximum strains were equalized, variation in the other regions was 5-10%. DIC showed that the ability of nominally identical composite bones to bear high strains and loads before fracturing may vary between the samples. PMID- 23791084 TI - Tissue-engineered articular cartilage exhibits tension-compression nonlinearity reminiscent of the native cartilage. AB - The tensile modulus of articular cartilage is much larger than its compressive modulus. This tension-compression nonlinearity enhances interstitial fluid pressurization and decreases the frictional coefficient. The current set of studies examines the tensile and compressive properties of cylindrical chondrocyte-seeded agarose constructs over different developmental stages through a novel method that combines osmotic loading, video microscopy, and uniaxial unconfined compression testing. This method was previously used to examine tension-compression nonlinearity in native cartilage. Engineered cartilage, cultured under free-swelling (FS) or dynamically loaded (DL) conditions, was tested in unconfined compression in hypertonic and hypotonic salt solutions. The apparent equilibrium modulus decreased with increasing salt concentration, indicating that increasing the bath solution osmolarity shielded the fixed charges within the tissue, shifting the measured moduli along the tension compression curve and revealing the intrinsic properties of the tissue. With this method, we were able to measure the tensile (401+/-83kPa for FS and 678+/-473kPa for DL) and compressive (161+/-33kPa for FS and 348+/-203kPa for DL) moduli of the same engineered cartilage specimens. These moduli are comparable to values obtained from traditional methods, validating this technique for measuring the tensile and compressive properties of hydrogel-based constructs. This study shows that engineered cartilage exhibits tension-compression nonlinearity reminiscent of the native tissue, and that dynamic deformational loading can yield significantly higher tensile properties. PMID- 23791086 TI - Effect of bar cross-section geometry on stress distribution in overdenture retaining system simulating horizontal misfit and bone loss. AB - This study evaluated the influence of cross-section geometry of the bar framework on the distribution of static stresses in an overdenture-retaining bar system simulating horizontal misfit and bone loss. Three-dimensional FE models were created including two titanium implants and three cross-section geometries (circular, ovoid or Hader) of bar framework placed in the anterior part of a severely resorbed jaw. One model with 1.4-mm vertical loss of the peri-implant tissue was also created. The models set were exported to mechanical simulation software, where horizontal displacement (10, 50 or 100 MUm) was applied simulating the settling of the framework, which suffered shrinkage during the laboratory procedures. The bar material used for the bar framework was a cobalt- chromium alloy. For evaluation of bone loss effect, only the 50-MUm horizontal misfit was simulated. Data were qualitatively and quantitatively evaluated using von Mises stress for the mechanical part and maximum principal stress and MU strain for peri-implant bone tissue given by the software. Stresses were concentrated along the bar and in the join between the bar and cylinder. In the peri-implant bone tissue, the MU-strain was higher in the cervical third. Higher stress levels and MU-strain were found for the models using the Hader bar. The bone loss simulated presented considerable increase on maximum principal stresses and MU-strain in the peri-implant bone tissue. In addition, for the amplification of the horizontal misfit, the higher complexity of the bar cross-section geometry and bone loss increases the levels of static stresses in the peri-implant bone tissue. PMID- 23791088 TI - A quantifier-based fuzzy classification system for breast cancer patients. AB - OBJECTIVES: Recent studies of breast cancer data have identified seven distinct clinical phenotypes (groups) using immunohistochemical analysis and a range of different clustering techniques. Consensus between unsupervised classification algorithms has been successfully used to categorise patients into these specific groups, but often at the expenses of not classifying the whole set. It is known that fuzzy methodologies can provide linguistic based classification rules. The objective of this study was to investigate the use of fuzzy methodologies to create an easy to interpret set of classification rules, capable of placing the large majority of patients into one of the specified groups. MATERIALS AND METHODS: In this paper, we extend a data-driven fuzzy rule-based system for classification purposes (called 'fuzzy quantification subsethood-based algorithm') and combine it with a novel class assignment procedure. The whole approach is then applied to a well characterised breast cancer dataset consisting of ten protein markers for over 1000 patients to refine previously identified groups and to present clinicians with a linguistic ruleset. A range of statistical approaches was used to compare the obtained classes to previously obtained groupings and to assess the proportion of unclassified patients. RESULTS: A rule set was obtained from the algorithm which features one classification rule per class, using labels of High, Low or Omit for each biomarker, to determine the most appropriate class for each patient. When applied to the whole set of patients, the distribution of the obtained classes had an agreement of 0.9 when assessed using Kendall's Tau with the original reference class distribution. In doing so, only 38 patients out of 1073 remain unclassified, representing a more clinically usable class assignment algorithm. CONCLUSION: The fuzzy algorithm provides a simple to interpret, linguistic rule set which classifies over 95% of breast cancer patients into one of seven clinical groups. PMID- 23791087 TI - Automatic determination of an anatomical coordinate system for a three dimensional model of the human patella. AB - Measuring the in vivo 3-D kinematics of the patella requires a repeatable anatomical coordinate system (ACS). The purpose of this study was to develop an algorithm to determine an ACS using the patella's unique morphology. An ACS was automatically constructed that aligned the proximal/distal (PD) axis with the posterior vertical ridge. Inter-subject ACS repeatability was determined by registering all patellae and their associated ACSs to a reference patella. The mean angle between the reference patella ACS and each subject's axes was less than 2.5 degrees and the 95% CI was 1.0 degrees -4.0 degrees . Here, we presented an anatomical coordinate system that is independent of the observer's subjective judgement or orientation of the knee within the scanner. PMID- 23791089 TI - [Reactivation of parvovirus B19 infection in an HIV-infected woman]. AB - INTRODUCTION: Infection by human parvovirus B19 (erythrovirus B19) is common and usually asymptomatic during childhood conferring lasting protection against a new infection. Parvovirus B19 infection may cause erythema infectiosum (5th disease) and aplastic crisis. Secondary symptomatic parvovirus B19 infection in the same patient is rare and its physiopathology is not always clear. CASE REPORT: A 48 year-old HIV-infected female patient presented within 5 years two acute episodes of parvovirus B19 infection although her CD4 cells count was above 500/mm(3). Absence of specific antibodies production after the first episode and persisting parvovirus viremia suggested viral reactivation rather than re-infection. During the second episode, specific antibodies were produced. CONCLUSION: Similarly to most DNA viruses, parvovirus B19 reactivation is possible in HIV-infected patients while effectively treated by antiretroviral therapy. PMID- 23791090 TI - [An unusual cause of bone fracture]. PMID- 23791091 TI - Photooxidation of Amplex Red to resorufin: implications of exposing the Amplex Red assay to light. AB - The Amplex Red assay, a fluorescent assay for the detection of H2O2, relies on the reaction of H2O2, which, in the presence of horseradish peroxidase, oxidizes the colorless, nonfluorescent, Amplex Red with a 1:1 stoichiometry to form the colored, fluorescent resorufin. We have found that resorufin is artifactually formed when Amplex Red is exposed to light. This photochemistry is initiated by trace amounts of resorufin present in Amplex Red stock solutions. ESR spin trapping studies have demonstrated that superoxide radical is an intermediate in this process. Oxygen consumption measurements further confirmed that superoxide and H2O2 were artifactually produced by the photooxidation of Amplex Red. The artifactual formation of resorufin was also significantly increased by the presence of superoxide dismutase or HRP. This photooxidation process leads to a less sensitive assay for H2O2 under ambient light exposure and potentially invalid measurements under high energy exposure such as UVA irradiation. In general, precautions should be taken to minimize exposure to light, including that from instrumental light, during measurement of oxidative stress with Amplex Red. PMID- 23791092 TI - Boronate-based fluorescent probes: imaging hydrogen peroxide in living systems. AB - Hydrogen peroxide, a reactive oxygen species with unique chemical properties, is produced endogenously in living systems as a destructive oxidant to ward off pathogens or as a finely tuned second messenger in dynamic cellular signaling pathways. In order to understand the complex roles that hydrogen peroxide can play in biological systems, new tools to monitor hydrogen peroxide in its native settings, with high selectivity and sensitivity, are needed. Knowledge of organic synthetic reactivity provides the foundation for the molecular design of selective, functional hydrogen peroxide probes. A palette of fluorescent and luminescent probes that react chemoselectively with hydrogen peroxide has been developed, utilizing a boronate oxidation trigger. These indicators offer a variety of colors and in cellulo characteristics and have been used to examine hydrogen peroxide in a number of experimental setups, including in vitro fluorometry, confocal fluorescence microscopy, and flow cytometry. In this chapter, we provide an overview of the chemical features of these probes and information on their behavior to help researchers select the optimal probe and application. PMID- 23791093 TI - Visualization of intracellular hydrogen peroxide with HyPer, a genetically encoded fluorescent probe. AB - The fluorescent sensor HyPer allows monitoring of intracellular H2O2 levels with a high degree of sensitivity and specificity. Here, we provide a detailed protocol of ratiometric imaging of H2O2 produced by cells during phagocytosis, including instructions for experiments on different commercial confocal systems, namely, Leica SP2, Leica SP5, and Carl Zeiss LSM, as well as wide-field Leica 6000 microscope. The general experimental scheme is easily adaptable for imaging H2O2 production by various cell types under a variety of conditions. PMID- 23791094 TI - In vivo imaging of H2O2 production in Drosophila. AB - H2O2 plays many roles in cellular physiology. Therefore, we need tools for quantitative detection of H2O2 in tissues and whole model organisms. We recently introduced a genetically encoded H2O2 sensor, roGFP2-Orp1, which couples the redox-sensitive green fluorescent protein 2 (roGFP2) to the yeast H2O2 sensor protein Orp1. Expression of cytosolic or mitochondrial roGFP2-Orp1 in Drosophila allows the measurement of physiologically relevant changes in H2O2 levels, with compartment-specific resolution. Here, we provide a detailed protocol for the relative quantitation of H2O2 levels in living larvae by real-time imaging. We also describe a dissection and fixation method that conserves the redox state of the probe and thus allows reliable measurements on fixed adult tissues. Finally, we give recommendations for image processing, analysis, and interpretation, highlighting issues that require attention to detail, to ensure accuracy and validity of results. PMID- 23791095 TI - Single fluorescent probe distinguishes hydrogen peroxide and nitric oxide in cell imaging. AB - In combination with synthetic fluorescent probes, fluorescence microscopy has emerged as a powerful technique to investigate the production, localization, trafficking, and function of biomolecules in living systems in a noninvasive manner. Prompted by our interest in providing a molecular tool to disentangle the complicated interrelationship between H2O2 and NO in the signal transduction and oxidative pathways, our laboratory has developed a single fluorescent probe, FP H2O2-NO, that can report H2O2, NO, and H2O2/NO with three different sets of fluorescence signal patterns. In this chapter, we provide essential information about the probe FP-H2O2-NO in order to assist researchers interested to apply our probe to investigate H2O2 and NO biology. We describe the use of FP-H2O2-NO with the representative examples of imaging both exogenous and endogenous H2O2 and NO in live Hela and RAW 264.7 macrophage cells by fluorescence microscopy. PMID- 23791096 TI - Electrochemical biosensors for on-chip detection of oxidative stress from cells. AB - The production of reactive oxygen species (ROS) in the body has been shown to play a significant role in the development and progression of numerous diseases. This makes it important to develop a method of detection for hydrogen peroxide (H2O2), the most stable ROS. Several methods such as the use of fluorescent probes and electrochemistry have been utilized in the past to detect the imbalance in ROS levels generated from injured or stimulated cells. An imbalance in the levels of ROS leads to a state of oxidative stress within the body. Different enzymes such as horseradish peroxidase (HRP) and superoxide dismutase have been used in the detection of ROS. HRP is commonly used as the biorecognition element in many H2O2 sensors. Researchers have looked into immobilizing these enzymes onto carbon nanotubes and nanoparticles to increase sensor sensitivity. In this chapter, we present experimental procedures to perform electrochemical quantification of H2O2, one of the major ROS release from injured cells (macrophages and hepatocytes). PMID- 23791097 TI - Electrochemical detection of H2O2 formation in isolated mitochondria. AB - Mitochondrial respiration produces both complete and partially reduced oxygen species that are involved in physiological and pathological processes. Indeed, unspecific oxidative damage induced by excessive mitochondrial reactive oxygen species (ROS) plays a role in aging and several diseases, whereas low amounts of ROS act in physiological signaling processes. The exact molecular species, the rate, and the conditions of mitochondrial ROS release are not clearly evaluable by current methods based on oxidation sensitive markers. Recently, electrochemical analysis of biological samples has improved. Following latest methodology, we implemented a novel electrochemical assay for the investigation of aerobic metabolism in isolated mitochondria through simultaneous measurement of O2 consumption and H2O2 production. Our experiments confirm active H2O2 production by respiring mouse liver mitochondria and show that ATP synthase activation increases the rate of H2O2, suggesting that state 3 mitochondria might induce the cell through oxidative signals. PMID- 23791098 TI - Detection of H2O2 by fluorescence correlation spectroscopy. AB - Fluorescence correlation spectroscopy (FCS) is a technique in which measurement of fluorescence intensity fluctuations is used to clarify dynamic molecular interactions within a very small space in a solution containing a small number of fluorescent molecules. The FCS-based analysis gives the average number and average diffusion time of the fluorescent molecules during their passage through a very small space. One advantage of FCS is that physical separation between free and bound fluorescent probes is not required because the properties of fluorescence fluctuations are accounted for. Therefore, when fluorescent probes are bound with proteins by peroxidase and hydrogen peroxide (H2O2), FCS enables us to detect H2O2 with high sensitivity. In addition, because H2O2 is generated by oxidase-catalyzed reactions, a highly sensitive method for detecting H2O2 is applicable to the measurement of low levels of various oxidases and their substrates, such as glucose. We here describe the protocol of a de novo, highly sensitive method for the measurement of H2O2 and glucose using FCS. PMID- 23791099 TI - Real-time monitoring of reactive oxygen and nitrogen species in a multiwell plate using the diagnostic marker products of specific probes. AB - Developing rigorous assays for cellular detection of reactive oxygen and nitrogen species (O2(.-), H2O2, (.)NO, and ONOO(-)) is an active area of research in our laboratory. Published reports suggest that diagnostic marker products are formed as a result of interaction of these species with small molecular weight fluorescent and nonfluorescent probes. In this chapter, we describe an HPLC-based methodology to detect formation of these species in biological and cellular systems. By monitoring the diagnostic marker products formed from reaction between specific chemical probes and the oxidant species, it is possible to simultaneously assay these species using a multiwell plate (e.g., 384-well plate). PMID- 23791100 TI - H2O2 delivery to cells: steady-state versus bolus addition. AB - Hydrogen peroxide (H2O2) is a ubiquitous biological molecule whose wide range of biological functions depends on its concentration. In this chapter, we compare the delivery of H2O2 to cells as (1) a single initial dose (bolus addition); (2) a continuous source using, for example, glucose oxidase; and (3) a steady state, in which H2O2 concentration is kept constant during the assay. Both the bolus addition and the use of a continuous source of H2O2 have as outcome concentration profiles of H2O2 that are dependent on experimental conditions and that are difficult to reproduce from the information that is usually revealed in the experimental section of most research articles. On the other hand, the outcome of delivering H2O2 as a steady state is a concentration profile that is independent of experimental conditions. The implementation of the steady state starts with the determination of the kinetics of H2O2 consumption in the system under study. Then, the amount of glucose oxidase needed to produce H2O2 at a rate that matches the rate of its consumption by cells at the desired H2O2 steady-state concentration is calculated. The setup of the steady state is initiated by adding this amount of glucose oxidase simultaneously with the desired concentration of H2O2. Because H2O2 consumption and delivery rates are matched, the initial H2O2 concentration added is kept constant during the assay. Detailed explanations on how to implement the steady state, including H2O2 measurements and adjustments in the amount of H2O2 or glucose oxidase during the assay, are described. PMID- 23791101 TI - Imaging H2O2 microdomains in receptor tyrosine kinases signaling. AB - HyPer, a ratiometric genetically encoded fluorescent sensor, is a popular tool for intracellular hydrogen peroxide detection. When expressed in cultured cells, the freely diffusing version of the sensor (HyPer-cyto) detects temporal patterns of H2O2 generation. However, rapid diffusion of the probe within the nucleocytoplasmic compartment averages the H2O2 signal even in cases of local oxidant production. Consequently, we immobilized the sensor within specific subcellular compartments allowing it to monitor local increases in H2O2. Here, we provide a protocol of ratiometric imaging and ImageJ-based quantification of H2O2 microdomains produced by cells upon physiological stimulation. PMID- 23791103 TI - A microfluidic systems biology approach for live single-cell mitochondrial ROS imaging. AB - Most current studies of reactive oxygen species (ROS) production report globally averaged measurements within the cell; however, ROS can be produced in distinct subcellular locations and have local effects in their immediate vicinity. A microfluidic platform for high-throughput single-cell imaging allows mitochondrial ROS production to be monitored as varying in both space and time. Using this systems biology approach, single-cell variability can be viewed within a population. We discuss single-cell monitoring of contributors to mitochondrial redox state-mitochondrial hydrogen peroxide or superoxide-through the use of a small molecule probe or targeted fluorescent reporter protein. Jurkat T lymphoma cells were stimulated with antimycin A and imaged in an arrayed microfluidic device over time. Differences in single-cell responses were observed as a function of both inhibitor concentration and type of ROS measurement used. PMID- 23791102 TI - The determination and analysis of site-specific rates of mitochondrial reactive oxygen species production. AB - Mitochondrial reactive oxygen species (ROS) are widely implicated in physiological and pathological pathways. We propose that it is critical to understand the specific sites of mitochondrial ROS production and their mechanisms of action. Mitochondria possess at least eight distinct sites of ROS production in the electron transport chain and matrix compartment. In this chapter, we describe the nature of the mitochondrial ROS-producing machinery and the relative capacities of each site. We provide detailed methods for the measurement of H2O2 release and the conditions under which maximal rates from each site can be achieved in intact skeletal muscle mitochondria. PMID- 23791104 TI - Detection of oxidative damage in response to protein misfolding in the endoplasmic reticulum. AB - Disulfide bond formation in the endoplasmic reticulum (ER) requires the sequential transfer of electrons from thiol residues to protein disulfide isomerase and ER oxidase 1, with the final reduction of molecular oxygen to form hydrogen peroxide. Conditions that perturb correct protein folding lead to accumulation of misfolded proteins in the ER lumen, which induce ER stress and oxidative stress. Oxidative damage of cellular macromolecules is a common marker of aging and various pathological conditions including diabetes, cancer, and neurodegenerative disease. As accumulating evidence suggests a tight connection between the ER stress and oxidative stress, analysis of appropriate markers becomes particularly important. Here, we describe methods to analyze markers of oxidative damage associated with ER stress. PMID- 23791105 TI - Preface. Hydrogen peroxide and cell signaling, part A. PMID- 23791106 TI - Coding variants at hexa-allelic amino acid 13 of HLA-DRB1 explain independent SNP associations with follicular lymphoma risk. AB - Non-Hodgkin lymphoma represents a diverse group of blood malignancies, of which follicular lymphoma (FL) is a common subtype. Previous genome-wide association studies (GWASs) have identified in the human leukocyte antigen (HLA) class II region multiple independent SNPs that are significantly associated with FL risk. To dissect these signals and determine whether coding variants in HLA genes are responsible for the associations, we conducted imputation, HLA typing, and sequencing in three independent populations for a total of 689 cases and 2,446 controls. We identified a hexa-allelic amino acid polymorphism at position 13 of the HLA-DR beta chain that showed the strongest association with FL within the major histocompatibility complex (MHC) region (multiallelic p = 2.3 * 10-15). Out of six possible amino acids that occurred at that position within the population, we classified two as high risk (Tyr and Phe), two as low risk (Ser and Arg), and two as moderate risk (His and Gly). There was a 4.2-fold difference in risk (95% confidence interval = 2.9-6.1) between subjects carrying two alleles encoding high-risk amino acids and those carrying two alleles encoding low-risk amino acids (p = 1.01 * 10-14). This coding variant might explain the complex SNP associations identified by GWASs and suggests a common HLA-DR antigen-driven mechanism for the pathogenesis of FL and rheumatoid arthritis. PMID- 23791107 TI - Dissecting disease inheritance modes in a three-dimensional protein network challenges the "guilt-by-association" principle. AB - To better understand different molecular mechanisms by which mutations lead to various human diseases, we classified 82,833 disease-associated mutations according to their inheritance modes (recessive versus dominant) and molecular types (in-frame [missense point mutations and in-frame indels] versus truncating [nonsense mutations and frameshift indels]) and systematically examined the effects of different classes of disease mutations in a three-dimensional protein interactome network with the atomic-resolution interface resolved for each interaction. We found that although recessive mutations affecting the interaction interface of two interacting proteins tend to cause the same disease, this widely accepted "guilt-by-association" principle does not apply to dominant mutations. Furthermore, recessive truncating mutations in regions encoding the same interface are much more likely to cause the same disease, even for interfaces close to the N terminus of the protein. Conversely, dominant truncating mutations tend to be enriched in regions encoding areas between interfaces. These results suggest that a significant fraction of truncating mutations can generate functional protein products. For example, TRIM27, a known cancer-associated protein, interacts with three proteins (MID2, TRIM42, and SIRPA) through two different interfaces. A dominant truncating mutation (c.1024delT [p.Tyr342Thrfs*30]) associated with ovarian carcinoma is located between the regions encoding the two interfaces; the altered protein retains its interaction with MID2 and TRIM42 through the first interface but loses its interaction with SIRPA through the second interface. Our findings will help clarify the molecular mechanisms of thousands of disease-associated genes and their tens of thousands of mutations, especially for those carrying truncating mutations, often erroneously considered "knockout" alleles. PMID- 23791109 TI - Impact of nano-CuO stress on rice (Oryza sativa L.) seedlings. AB - Indiscriminate release of metal oxide nanoparticles (NPs) into the environment due to anthropogenic activities has become a serious threat to the ecological system including plants. The present study assesses the toxicity of nano-CuO on rice (Oryza sativa cv. Swarna) seedlings. Three different levels of stress (0.5 mM, 1.0 mM and 1.5 mM suspensions of copper II oxide, <50 nm particle size) were imposed and seedling growth performance was studied along control at 7 and 14 d of experiment. Modulation of ascorbate-glutathione cycle, membrane damage, in vivo ROS detection, foliar H2O2 and proline accumulation under nano-CuO stress were investigated in detail to get an overview of nano-stress response of rice. Seed germination percentage was significantly reduced under stress. Higher uptake of Evans blue by nano-CuO stressed roots over control indicates loss of root cells viability. Presence of dark blue and deep brown spots on leaves evident after histochemical staining with NBT and DAB respectively indicate severe oxidative burst under nano-copper stress. APX activity was found to be significantly increased in 1.0 and 1.5 mM CuO treatments. Nevertheless, elevated APX activity might be insufficient to scavenge all H2O2 produced in excess under nano-CuO stress. That may be the reason why stressed leaves accumulated significantly higher H2O2 instead of having enhanced APX activity. In addition, increased GR activity coupled with isolated increase in GSH/GSSG ratio does not seem to prevent cells from oxidative damages, as evident from higher MDA level in leaves of nano-CuO stressed seedlings over control. Enhanced proline accumulation also does not give much protection against nano-CuO stress. Decline in carotenoids level might be another determining factor of meager performance of rice seedlings in combating nano-CuO stress induced oxidative damages. PMID- 23791108 TI - Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome. AB - RAS GTPases mediate a wide variety of cellular functions, including cell proliferation, survival, and differentiation. Recent studies have revealed that germline mutations and mosaicism for classical RAS mutations, including those in HRAS, KRAS, and NRAS, cause a wide spectrum of genetic disorders. These include Noonan syndrome and related disorders (RAS/mitogen-activated protein kinase [RAS/MAPK] pathway syndromes, or RASopathies), nevus sebaceous, and Schimmelpenning syndrome. In the present study, we identified a total of nine missense, nonsynonymous mutations in RIT1, encoding a member of the RAS subfamily, in 17 of 180 individuals (9%) with Noonan syndrome or a related condition but with no detectable mutations in known Noonan-related genes. Clinical manifestations in the RIT1-mutation-positive individuals are consistent with those of Noonan syndrome, which is characterized by distinctive facial features, short stature, and congenital heart defects. Seventy percent of mutation-positive individuals presented with hypertrophic cardiomyopathy; this frequency is high relative to the overall 20% incidence in individuals with Noonan syndrome. Luciferase assays in NIH 3T3 cells showed that five RIT1 alterations identified in children with Noonan syndrome enhanced ELK1 transactivation. The introduction of mRNAs of mutant RIT1 into 1-cell-stage zebrafish embryos was found to result in a significant increase of embryos with craniofacial abnormalities, incomplete looping, a hypoplastic chamber in the heart, and an elongated yolk sac. These results demonstrate that gain-of-function mutations in RIT1 cause Noonan syndrome and show a similar biological effect to mutations in other RASopathy-related genes. PMID- 23791110 TI - Reductive debromination of tetrabromobisphenol A by Pd/Fe bimetallic catalysts. AB - The bimetallic catalysts of micron sizes were synthesized and the rates of tetrabromobisphenol A (TBBPA) transformation were measured under various conditions using a batch reactor system. The results showed that TBBPA was rapidly debrominated to tri-, di- and mono-bromobisphenol A and to bisphenol A (BPA). The pseudo-first-order rate constants normalized to the specific surface area of the catalysts were found to increase as functions of the Pd coverage on the Fe particles and the dosages of the catalysts and the mass of Pd within the reactors. The rate constants were also decreasing as the solution pH increased. At pH 4.2, Pd coverage of 0.022wt% and catalyst dosage of 4gL(-1), 99% of TBBPA was transformed within 2min, and tri-, di-, and mono-bromobisphenol A were detected as the major intermediate products. After reaction for 45min, BPA was the only compound found in this specific system. Meanwhile, the rate constants measured at constant solution pH correlated linearly with the Pd mass introduced to the reactors, regardless of Pd/Fe catalyst dosage or Pd surface coverage. The study suggested that Pd/Fe catalysts could be used for efficiently treating brominated flame retardants extracted from e-wastes. PMID- 23791111 TI - Elimination of high concentration hydrogen sulfide and biogas purification by chemical-biological process. AB - A chemical-biological process was performed to remove a high concentration of H2S in biogas. The high iron concentration tolerance (20gL(-1)) of Acidithiobacillus ferrooxidans CP9 provided sufficient ferric iron level for stable and efficient H2S elimination. A laboratory-scale apparatus was setup for a 45 d operation to analyze the optimal conditions. The results reveal that the H2S removal efficiency reached 98% for 1500ppm H2S. The optimal ferric iron concentration was kept between 9 and 11gL(-1) with a cell density of 10(8)CFUg(-1) granular activated carbon and a loading of 15gSm(-3)h(-1). In pilot-scale studies for biogas purification, the average inlet H2S concentration was 1645ppm with a removal efficiency of up to 97% for a 311d operation and an inlet loading 40.8gSm(-3)h(-1). When 0.1% glucose was added, the cell density increased twofold under the loading of 65.1gSm(-3)h(-1) with an H2S removal efficiency still above 96%. The analysis results of the distribution of microorganisms in the biological reactor by DGGE show that microorganism populations of 96.7% and 62.7% were identical to the original strain at day 200 and day 311, respectively. These results clearly demonstrate that ferric iron reduction by H2S and ferrous iron oxidation by A. ferrooxidans CP9 are feasible processes for the removal of H2S from biogas. PMID- 23791112 TI - Genotoxic potentials and related mechanisms of bisphenol A and other bisphenol compounds: a comparison study employing chicken DT40 cells. AB - Bisphenol A (BPA) has been found in plastic food containers, paper currencies and toys. BPA has been reported for various adverse health concerns including reproduction, development and carcinogenesis. These potential health implications have led to increasing use of alternative bisphenols such as bisphenol F and bisphenol S among many. However, little is known about the toxicity of alternative bisphenols and most of the toxicological information is limited to endocrine disrupting potentials. In this study, we evaluated cytotoxicity and the genotoxic potentials of several bisphenol compounds, and identified the mechanism of genotoxicity using a panel of mutant chicken DT40 cell lines deficient in DNA repair pathways. Several bisphenols including bisphenol AP, bisphenol M, or bisphenol P exerted genotoxic potentials that are greater than that of BPA. Generally RAD54(-/-) mutant cells were the most sensitive to all bisphenols except for bisphenol F, suggesting the induction of DNA double-strand breaks that could be rescued by homologous recombination. Genotoxic potential of bisphenols was confirmed by chromosomal aberration assay and gamma-H2AX foci forming assay between wild-type and RAD54(-/-) mutant. Among the tested bisphenols, BPP at 12.5MUM showed the greatest genotoxic potency, inducing chromosomal aberration and gamma-H2AX foci in RAD54(-/-) mutant by 2.6 and 4.8 folds greater than those in wild-type, respectively. Our results clearly show several alternative bisphenols can cause genotoxicity that could be rescued by homologous recombination pathway, and some bisphenols induced even greater genotoxic potentials than that of BPA. PMID- 23791113 TI - Left ventricular three-dimensional global systolic strain by real-time three dimensional speckle-tracking in children: feasibility, reproducibility, maturational changes, and normal ranges. AB - BACKGROUND: Three-dimensional (3D) strain analysis may help overcome the limitations of Doppler and two-dimensional strain analysis for the left ventricle and become the method of choice for left ventricular (LV) systolic function. The aims of this study were to evaluate the feasibility and reproducibility of LV global 3D systolic strain by real-time 3D speckle-tracking echocardiography (STE) in children and to establish their maturational growth patterns and normal values. METHODS: A prospective study was conducted in 256 consecutive healthy subjects using real-time 3D echocardiography. Full-volume 3D data were acquired using a 3D matrix-array transducer. Three-dimensional LV peak systolic global strain (GS), global longitudinal strain (GLS), global radial strain (GRS), and global circumferential strain (GCS) values were determined using real-time 3D STE. RESULTS: A total of 228 patients (89%) met the criteria for analysis; 28 (11%) were excluded. The correlations between age and strain variables by real time 3D STE were poor (R(2) = 0.01-0.05, P < .05). The differences in GLS and GCS among the five age groups were statistically significant but clinically irrelevant. There were no statistical differences in GRS and GS values among the age groups, nor were there statistical differences between the genders for all 3D strain parameters. Intraobserver and interobserver variability ranged from 5.0 +/ 4.3% to 10.1 +/- 8.5% versus 6.9 +/- 6.1% to 17.0 +/- 16.2% for coefficients of variation, respectively. Interclass correlation coefficients ranged from 0.78 to 0.87 and from 0.75 to 0.79 for intraobserver and interobserver measurements for GS, GLS, GCS, and GRS, respectively. CONCLUSIONS: LV global 3D systolic strain analysis using the new 3D STE is feasible and reproducible in the pediatric population. There are small maturational changes in GLS and GCS, but not in GRS and GS, that are statistically significant but probably clinically irrelevant. Further investigation is warranted for potential clinical application of this new technology in a pediatric population. PMID- 23791114 TI - Admission wall motion score and quantitative ST-segment depression in the assessment of 30-day mortality in patients with first non-ST-segment elevation acute coronary syndromes. AB - BACKGROUND: Whether admission myocardial wall motion score (WMS) in non-ST segment elevation acute coronary syndromes might be a better predictor of 30-day mortality than currently recognized prognostic markers is unknown. METHODS: Admission echocardiographic and electrocardiographic data as well as coronary angiographic data were prospectively evaluated in 488 patients. Variables analyzed were clinical data, quantitative ST-segment depression, peak troponin I, WMS, ejection fraction, extent of coronary artery disease, and Thrombolysis In Myocardial Infarction (TIMI) risk score. RESULTS: Severity of WMS in quartiles was associated with peak troponin I (quartile 1, 5.2 MUg/L; quartile 2, 9.4 MUg/L; quartile 3, 11.7 MUg/L; quartile 4, 23.7 MUg/L; P < .001) and with the sum of all leads with ST-segment depression (quartile 1, -2.5 mm; quartile 2, -3.2 mm; quartile 3, -3.8 mm; quartile 4, -5.1 mm; P < .001). Thirty-day mortality was associated with increased worsening of WMS (quartiles 1, 0.7%; quartile 2, 3.4%; quartile 3, 3.8%; quartile 4, 11.5%; P = .001) and quantitative ST-segment depression (0 mm, 2.7%; <1.0 mm, 1.8%; 1.0-1.9 mm, 3.5%; 2.0-2.9 mm, 7.3%; >=3.0 mm, 15.0%; P = .008). Mortality was also associated with age (P = .002), diabetes (P = .007), peripheral vascular disease (P < .001), Killip class >= II (P < .001), ejection fraction (P < .001), troponin I level (P < .001), three-vessel and/or left main coronary artery disease (P < .001), and admission TIMI risk score (P < .001). Nevertheless, WMS predicted 30-day mortality after adjusting for TIMI risk score (odds ratio per unit increase, 1.14; 95% confidence interval, 1.06-1.21; P < .001) or for TIMI score and Killip class > I (odds ratio per unit increase, 1.11; 95% confidence interval, 1.04-1.19; P = .004). CONCLUSIONS: In comparison with quantitative ST-segment depression, troponin I, and TIMI risk score, WMS on admission is a better early predictor of 30-day mortality in patients with first non-ST-segment elevation acute coronary syndromes. PMID- 23791115 TI - The role of echocardiography in thromboembolic risk assessment of patients with nonvalvular atrial fibrillation. AB - Echocardiography is a widely used and versatile technique that can provide comprehensive information concerning thromboembolic risk in patients with atrial fibrillation. The authors review the potential contributions of echocardiography to thromboembolic risk stratification and to decreasing the thromboembolic risk associated with procedures such as cardioversion and ablation. Unsolved questions and new possibilities that have arisen from the development of strain and strain rate imaging are also discussed. PMID- 23791116 TI - Mitral annular displacement by Doppler tissue imaging may identify coronary occlusion and predict mortality in patients with non-ST-elevation myocardial infarction. AB - BACKGROUND: Mitral annular displacement (MAD) is a simple marker of left ventricular (LV) systolic function. The aim of this study was to test the hypothesis that MAD can distinguish patients with non-ST-segment elevation myocardial infarctions (NSTEMIs) from those with significant coronary artery disease without infarctions, identify coronary occlusion, and predict mortality in patients with NSTEMIs. MAD was compared with established indices of LV function. METHODS: In this retrospective study, 167 patients with confirmed NSTEMIs were included at two Scandinavian centers. Forty patients with significant coronary artery disease but without myocardial infarctions were included as controls. Doppler tissue imaging was performed at the mitral level of the left ventricle in the three apical planes, and velocities were integrated over time to acquire MAD. LV ejection fraction, global longitudinal strain (GLS), and wall motion score index were assessed according to guidelines. RESULTS: MAD and GLS could accurately distinguish patients with NSTEMIs from controls. During 48.6 +/- 12.1 months of follow-up, 22 of 167 died (13%). MAD, LV ejection fraction, and GLS were reduced and wall motion score index was increased among those who died compared with those who survived (P < .001, P < .001, P < .001, and P = .02, respectively). Multivariate Cox proportional-hazards analyses revealed that MAD was an independent predictor of death (hazard ratio, 1.36; 95% confidence interval, 1.07-1.73; P = .01). MAD and GLS were reduced and wall motion score index was increased in patients with coronary artery occlusion compared with those without occlusion (P = .006, P = .001, and P = .02), while LV ejection fraction did not differ (P = .20). CONCLUSIONS: MAD accurately identified patients with NSTEMIs, predicted mortality, and identified coronary occlusion in patients with NSTEMIs. PMID- 23791117 TI - A tribute to Donna Diers. PMID- 23791118 TI - Child maltreatment: screening and anticipatory guidance. AB - Child maltreatment is a problem of epidemic proportions in the United States. Given the numbers of children affected by child maltreatment and the dire consequences that can develop, prompt identification of child maltreatment is crucial. Despite support of the implementation and development of protocols for child maltreatment screening by professional organizations such as the National Association of Pediatric Nurse Practitioners and American Academy of Pediatrics, little is available in the literature regarding the screening practices of pediatric nurse practitioners and other pediatric health care providers. This Continuing Education article will help pediatric nurse practitioners incorporate this vital screening intervention into their practice. Practical examples of when and how to incorporate screening questions and anticipatory guidance for discipline practices, crying, intimate partner violence (domestic violence), physical abuse, and sexual abuse will be discussed. PMID- 23791119 TI - Pain and decreased vision in a teenager. PMID- 23791120 TI - All about asthma: top resources for children, adolescents, and their families. PMID- 23791121 TI - Comparing control strategies against foot-and-mouth disease: will vaccination be cost-effective in Denmark? AB - Recent outbreaks of foot-and-mouth disease (FMD) in Europe have highlighted the need for assessment of control strategies to optimise control of the spread of FMD. Our objectives were to assess the epidemiological and financial impact of simulated FMD outbreaks in Denmark and the effect of using ring depopulation or emergency vaccination to control these outbreaks. Two stochastic simulation models (InterSpreadPlus (ISP) and the modified Davis Animal Disease Simulation model (DTU-DADS)) were used to simulate the spread of FMD in Denmark using different control strategies. Each epidemic was initiated in one herd (index herd), and a total of 5000 index herds were used. Four types of control measures were investigated: (1) a basic scenario including depopulation of detected herds, 3 km protection and 10 km surveillance zones, movement tracing and a three-day national standstill, (2) the basic scenario plus depopulation in ring zones around detected herds (Depop), (3) the basic scenario plus protective vaccination within ring zones around detected herds, and (4) the basic scenario plus protective vaccination within ring zones around detected herds. Disease spread was simulated through direct animal movements, medium-risk contacts (veterinarians, artificial inseminators or milk controllers), low-risk contacts (animal feed and rendering trucks, technicians or visitors), market contacts, abattoir trucks, milk tanks, or local spread. The two simulation models showed different results in terms of the estimated numbers. However, the tendencies in terms of recommendations of strategies were similar for both models. Comparison of the different control strategies showed that, from an epidemiological point of view, protective vaccination would be preferable if the epidemic started in a cattle herd in an area with a high density of cattle, whereas if the epidemic started in an area with a low density of cattle or in other species, protective vaccination or depopulation would have almost the same preventive effect. Implementing additional control measures either 14 days after detection of the first infected herd or when 10 herds have been diagnosed would be more efficient than implementing additional control measures when more herds have been diagnosed. Protective vaccination scenarios would never be cost-effective, whereas depopulation or suppressive vaccination scenarios would most often be recommended. Looking at the median estimates of the cost-benefit analysis, depopulation in zones would most often be recommended, although, in extreme epidemics, suppressive vaccination scenarios could be less expensive. The vast majority of the costs and losses associated with a Danish epidemic could be attributed to export losses. PMID- 23791122 TI - Schmallenberg virus in Italy: a retrospective survey in Culicoides stored during the bluetongue Italian surveillance program. AB - Following the first case of Schmallenberg (SBV) in northern Italy in February 2012, virus detection was conducted on midges collected during the national entomological surveillance program for bluetongue (BT). Six cattle farms, within a radius of 50 km from the SBV case, were selected for a 12 month study, aiming to determine when the virus entered the area, if it was capable of overwintering, and the possible role played by each species of the Obsoletus complex in disseminating the infection. A total of 33,724 Culicoides were collected at the six sites between June 2011 and June 2012. Species belonging to the Obsoletus Complex were the most abundant (94.44%) and, within the complex, Culicoides obsoletus was the most prevalent species in the studying area (65.4%). Nearly 7000 Culicoides midges were screened, either in pools or individually, for SBV by real-time RT-PCR. Viral genome was detected in six pools of the Obsoletus complex, collected at three sites between September and November 2011, and in a single parous female of C. obsoletus, collected in May 2012. As a result of the BT surveillance program in Italy it was possible to demonstrate, retrospectively, that SBV has circulated in at least three Italian provinces since early September 2011, nearly 5 months prior and as far as 40 km away from the first detected case. Similarly, the survey confirmed the presence of SBV in the vector population 3 months after the outbreak, following a cold winter during which the blacklight traps failed to catch active adult midges. PMID- 23791123 TI - Estimating the power of a Mycobacterium bovis vaccine trial in Irish badgers. AB - The aim of this study was to estimate the power, using simulation techniques, of a group randomized vaccine field trial designed to assess the effect of vaccination on Mycobacterium bovis transmission in badgers. The effects of sample size (recapture percentage), initial prevalence, sensitivity and specificity of the diagnostic test, transmission rate between unvaccinated badgers, Vaccine Efficacy for Susceptibility (VES) and Vaccine Efficacy for Infectiousness (VEI), on study power were determined. Sample size had a small effect on power. Study power increased with increasing transmission rate between non-vaccinated badgers. Changes in VES had a higher impact on power than changes in VEI. However, the largest effect on study power was associated with changes in the specificity of the diagnostic test, within the range of input values that were used for all other modelled parameters. Specificity values below 99.4% yielded a study power below 50% even when sensitivity was 100% and, VEI and VES were both equal to 80%. The effect of changes in sensitivity on study power was much lower. The results from our study are in line with previous studies, as study power was dependent not only on sample size but on many other variables. In this study, additional variables were studied, i.e. test sensitivity and specificity. In the current vaccine trial, power was highly dependent on the specificity of the diagnostic test. Therefore, it is critical that the diagnostic test used in the badger vaccine trial is optimized to maximize test specificity. PMID- 23791124 TI - Associations of herd- and cow-level factors, cow lying behavior, and risk of elevated somatic cell count in free-stall housed lactating dairy cows. AB - Recent evidence suggests that the risk of intramammary infection in dairy cows is related to lying patterns. The objectives of this study were to quantify the standing and lying behavior of dairy cows milked 3*/d, determine the cow- and herd-level factors associated with these behaviors, and relate these findings to the risk of an elevated somatic cell count (SCC). Five commercial free-stall dairy herds in Eastern Ontario, milking 3*/d, were enrolled in a longitudinal study. Forty Holstein-Friesian cows/herd were randomly selected as focal animals based on days in milk (<200 d) and SCC (<100,000 cells/mL). Farms were followed for 4, 5-week periods. Individual-cow SCC was recorded at the beginning of each period and end of the final period. Elevated SCC (eSCC) was used as an indicator of subclinical mastitis. A new incident eSCC was defined as an individual cow that started the period with a SCC <100,000 cells/mL but whose next SCC exceeded 200,000 cells/mL. Lying behavior was recorded 5d after each milk sampling using data loggers. For these 5d, individual milking times and feeding times were also recorded. On d1 of each recording period 2 trained observers scored focal cows for hygiene and lameness. Throughout the course of the study, cows averaged 11.2h/d of lying time, split into 8.6 lying bouts/d that were on average 84.6 min in length. Later lactation cows had longer daily lying times that were split into fewer lying bouts of longer duration than cows earlier in lactation. Lame cows had longer daily lying times and lying bout durations than non-lame cows. Cows with greater milk yield had lower lying times than lower producing cows. Average post-milking standing time across the study herds was 103 min. Manipulation of feed (feed delivery or push-up) by the stockperson, in the hour before milking or shortly thereafter, resulted in the longest post-milking standing times. Over the study period, 48 new eSCC were detected, resulting in a mean herd incidence rate of 0.91 eSCC/cow-year at risk for all study herds. A non-linear relationship between post-milking standing time and eSCC incidence was found; compared to those cows that lie down <90 min after milking, cows that lie down for the first time >90 min after milking had a lower risk of acquiring a new eSCC. The risk of experiencing an eSCC was also increased in multiparous cows, and in those cows with a higher SCC at the beginning of the study. These results indicate that management practices that promote post-milking standing time, such as the manipulation of feed delivery around milking times, should be encouraged to reduce the risk of cows experiencing new eSCC. PMID- 23791125 TI - Research at the interface between human and veterinary health. AB - Epidemiology is currently undergoing changes in its underlying philosophy and approach, as a result of the rapid global changes which are transforming the world in which epidemiologists live and work. This necessitates a multidisciplinary "population approach" involving "multilevel thinking" about the determinants of disease. These issues are of relevance to the interface between human and animal epidemiology, which has received considerable attention in recent years, particularly as a result of the arrival of H1N1 influenza, and the increasingly obvious need for coordinated systems of surveillance for human and animal infectious diseases. However, the need for coordination between human and veterinary epidemiology is broader than that, and there is no need to restrict the "one world one health" concept to communicable disease. In the current paper we will therefore consider the interface between human and animal health for the study of non-communicable disease, particularly those involving occupational and environmental risk factors. These issues are illustrated with two examples: one involving environmental health (asthma); and one involving occupational health (cancer). We will also discuss the potential to use animal health data as indicators for human environmental health risks. PMID- 23791126 TI - Herd-level prevalence of Map infection in dairy herds of southern Chile determined by culture of environmental fecal samples and bulk-tank milk qPCR. AB - Paratuberculosis, an infectious disease of domestic and wild ruminants caused by Mycobacterium avium subsp. paratuberculosis (Map), is an economically important disease in dairy herds worldwide. In Chile the disease has been reported in domestic and wildlife animals. However, accurate and updated estimations of the herd-prevalence in cattle at national or regional level are not available. The objectives of this study were to determine the herd-level prevalence of dairy herds with Map infected animals of Southern Chile, based on two diagnostic tests: culture of environmental fecal samples and bulk-tank milk qPCR. Two composite environmental fecal samples and one bulk-tank milk sample were collected during September 2010 and September 2011 from 150 dairy farms in Southern Chile. Isolation of Map from environmental fecal samples was done by culture of decontaminated samples on a commercial Herrold's Egg Yolk Medium (HEYM) with and without mycobactin J. Suspicious colonies were confirmed to be Map by conventional IS900 PCR. Map detection in bulk-tank milk samples was done by real time IS900 PCR assay. PCR-confirmed Map was isolated from 58 (19.3%) of 300 environmental fecal samples. Holding pens and manure storage lagoons were the two more frequent sites found positive for Map, representing 35% and 33% of total positive samples, respectively. However, parlor exits and cow alleyways were the two sites with the highest proportion of positive samples (40% and 32%, respectively). Herd prevalence based on environmental fecal culture was 27% (true prevalence 44%) compared to 49% (true prevalence 87%) based on bulk-tank milk real time IS900 PC. In both cases herd prevalence was higher in large herds (>200 cows). These results confirm that Map infection is wide spread in dairy herds in Southern Chile with a rough herd-level prevalence of 28-100% depending on the herd size, and that IS900 PCR on bulk-tank milk samples is more sensitive than environmental fecal culture to detect Map-infected dairy herds. PMID- 23791127 TI - [Perception of healthcare professionals on the Breast Cancer Screening Programme in Barcelona]. AB - OBJECTIVE: A good communication plan is vital for optimal results in any screening programme. The objective of this study was to assess the knowledge, involvement and opinion of health professionals regarding the Breast Cancer Screening Programme in Barcelona in 2008. MATERIAL AND METHODS: A cross-sectional study using an anonymous and self-administered questionnaire. The study population (N = 960) were health professionals from Primary Health-care (PH), Programs for Sexual and Reproductive Health (PSRH), and Community Pharmacies (CP). The dependent variables were: knowledge of the Programme, professional involvement and opinion of the Programme. The independent variables were: sex, age, qualifications, employment status, and health team. A descriptive and bivariate analysis was performed. Using multivariate logistic regression models adjusted for age, an Odds Ratios (OR) were obtained along with the 95% confidence intervals (CI 95%). RESULTS: PSRH professionals know the target population better; 80.2% versus 26.1% PH, and 14.0% CP, respectively. Professional involvement was related to the health care team (ORCP/PH: 0.32, CI 95%: 0.22 0.43) being observed more in PH. The opinion on the Programme in reducing breast cancer mortality was similar in the three teams (61.6% PH, 59.3% PSRH, and 56.5% CP). CONCLUSIONS: Healthcare professionals are unaware of some aspects of Programme, such as age range or periodicity. There is great professional involvement and belief that the Programme has helped disseminate information and knowledge on the early detection of breast cancer. PMID- 23791128 TI - Utility of intraoperative frozen section examination of sentinel lymph nodes in ductal carcinoma in situ of the breast. AB - BACKGROUND: Intraoperative frozen section (IFS) examination of sentinel lymph nodes (SLN) is useful in selecting patients with invasive breast cancer for immediate axillary lymph node dissection. However, whether IFS evaluation of the SLNs in ductal carcinoma in situ (DCIS) of the breast has any value has not been previously assessed. METHODS: Clinicopathologic data from patients with DCIS who underwent resection with SLN biopsy (2004-2010) were collected to assess the sensitivity, specificity, and accuracy of IFS, and its impact on axillary management. RESULTS: A total of 267 patients with DCIS underwent resection with SLN biopsy and IFS evaluation. Preoperative pathology was DCIS (n = 231), DCIS with microinvasion (n = 24), and DCIS with other lesions (n = 12). Fifty-two (19.5%) patients had invasive breast cancer on final pathology. SLN metastases were identified in 13 (4.8%) patients; however, only 4 (1.5%) were IFS positive. IFS examination was negative in 263 (98.5%) patients. Among patients with SLN metastases, the most common pattern of metastases was either micrometastasis (n = 6) or immunohistochemistry-positive individual tumor cells (n = 4), whereas 3 patients had a macrometastasis. IFS examination was falsely negative in 9 of these 13 patients for a false-negative rate of 69.3%, and a sensitivity and specificity of 31% and 100% respectively. Nine of the 13 patients underwent axillary lymph node dissection and only 1 patient had further axillary metastasis. CONCLUSIONS: SLN metastases in DCIS is rare and most commonly involves SLN micrometastasis or immunohistochemistry-positive individual tumor cells. SLN IFS evaluation in DCIS has a low yield and sensitivity, and can be safely omitted to reduce operative duration and cost. PMID- 23791130 TI - Observer agreement in the reporting of knee and lumbar spine magnetic resonance (MR) imaging examinations: selectively trained MR radiographers and consultant radiologists compared with an index radiologist. AB - PURPOSE: To assess agreement between trained radiographers and consultant radiologists compared with an index radiologist when reporting on magnetic resonance imaging (MRI) examinations of the knee and lumbar spine and to examine the subsequent effect of discordant reports on patient management and outcome. METHODS: At York Hospital two MR radiographers, two consultant radiologists and an index radiologist reported on a prospective, random sample of 326 MRI examinations. The radiographers reported in clinical practice conditions and the radiologists during clinical practice. An independent consultant radiologist compared these reports with the index radiologist report for agreement. Orthopaedic surgeons then assessed whether the discordance between reports was clinically important. RESULTS: Overall observer agreement with the index radiologist was comparable between observers and ranged from 54% to 58%; for the knee it was 46-57% and for the lumbar spine was 56-66%. There was a very small observed difference of 0.6% (95% CI -11.9 to 13.0) in mean agreement between the radiographers and radiologists (P=0.860). For the knee, lumbar spine and overall, radiographers' discordant reports, when compared with the index radiologist, were less likely to have a clinically important effect on patient outcome than the radiologists' discordant reports. Less than 10% of observer's reports were sufficiently discordant with the index radiologist's reports to be clinically important. CONCLUSION: Carefully selected MR radiographers with postgraduate education and training reported in clinical practice conditions on specific MRI examinations of the knee and lumbar spine to a level of agreement comparable with non-musculoskeletal consultant radiologists. PMID- 23791129 TI - Competitive advantage of PET/MRI. AB - Multimodality imaging has made great strides in the imaging evaluation of patients with a variety of diseases. Positron emission tomography/computed tomography (PET/CT) is now established as the imaging modality of choice in many clinical conditions, particularly in oncology. While the initial development of combined PET/magnetic resonance imaging (PET/MRI) was in the preclinical arena, hybrid PET/MR scanners are now available for clinical use. PET/MRI combines the unique features of MRI including excellent soft tissue contrast, diffusion weighted imaging, dynamic contrast-enhanced imaging, fMRI and other specialized sequences as well as MR spectroscopy with the quantitative physiologic information that is provided by PET. Most evidence for the potential clinical utility of PET/MRI is based on studies performed with side-by-side comparison or software-fused MRI and PET images. Data on distinctive utility of hybrid PET/MRI are rapidly emerging. There are potential competitive advantages of PET/MRI over PET/CT. In general, PET/MRI may be preferred over PET/CT where the unique features of MRI provide more robust imaging evaluation in certain clinical settings. The exact role and potential utility of simultaneous data acquisition in specific research and clinical settings will need to be defined. It may be that simultaneous PET/MRI will be best suited for clinical situations that are disease-specific, organ-specific, related to diseases of the children or in those patients undergoing repeated imaging for whom cumulative radiation dose must be kept as low as reasonably achievable. PET/MRI also offers interesting opportunities for use of dual modality probes. Upon clear definition of clinical utility, other important and practical issues related to business operational model, clinical workflow and reimbursement will also be resolved. PMID- 23791131 TI - Effects of pedunculopontine area and pallidal DBS on gait ignition in Parkinson's disease. AB - BACKGROUND: Freezing of gait is a disabling feature of Parkinson's disease, and so far no established treatment exists. Deep brain stimulation of the pedunculopontine area has been proposed to treat refractory gait disorders, yet data on measurable effects, especially in combination with stimulation of other targets, are scarce. METHODS: Acute effects of either low frequency pedunculopontine stimulation or high frequency stimulation of the posteroventral lateral globus pallidus internus and a combination of both in a 66-year-old man with advanced Parkinson's disease were assessed. Four weeks after the intervention, the gait was examined with patient blinded in each condition using computerized gait analysis. RESULTS: Isolated pedunculopontine or pallidal stimulation had a mild impact on gait ignition and freezing of gait, but combined stimulation had a marked effect. CONCLUSIONS: Combined multifocal stimulation may be a promising option for gait ignition and freezing of gait in advanced Parkinson's disease. PMID- 23791132 TI - Atorvastatin favorably modulates proinflammatory cytokine profile in patients following deep vein thrombosis. AB - BACKGROUND: Venous thromboembolism (VTE) has been shown to be associated with inflammation. Statins that might reduce VTE risk have been found to exert anti inflammatory properties in patients at cardiovascular risk. We sought to investigate whether anti-inflammatory effects of atorvastatin can be observed in VTE patients. MATERIALS AND METHODS: Atorvastatin 40 mg/d was given for 3 days to 26 consecutive VTE patients following discontinuation of anticoagulant therapy and 25 controls. We evaluated interleukin (IL)-1b, IL-6, IL-8, IL-10, soluble P selectin and von Willebrand factor (vWF) antigen in peripheral venous blood. RESULTS: The VTE patients displayed higher C-reactive protein (p=0.013), IL-1b (p=0.03), IL-8 (p=0.03) and vWF (p<0.0001) compared with the controls. In VTE patients atorvastatin decreased IL-6 (p=0.0003), IL-8 (p=0.003) and P-selectin (p<0.0001), but increased IL-10 (p=0.001), with no association with C-reactive protein or cholesterol-lowering effects. Atorvastatin reduced IL-1b (p=0.01), IL 6 (p=0.03) and P-selectin (p=0.002) in controls. Residual venous thrombosis was associated with elevated IL-6 and P-selectin, whereas patients with proximal deep vein thrombosis showed elevated P-selecitn prior to and following statin administration (all p<0.05). CONCLUSION: A 3-day administration of atorvastatin reduces inflammation without decrease in C-reactive protein in VTE patients. PMID- 23791133 TI - ASE 2013-14: Working to improve the quality and consistency of echo worldwide. PMID- 23791134 TI - Council on Cardiovascular Sonography: going strong at 20! PMID- 23791135 TI - Basic and comprehensive perioperative transesophageal echocardiography consensus statement documents. PMID- 23791136 TI - Altered resting-state functional connectivity in complex regional pain syndrome. AB - This study explored the functional connectivity between brain regions implicated in the default mode network, the sensorimotor cortex (S1/M1), and the intraparietal sulcus (IPS/MIP) at rest in patients with complex regional pain syndrome. It also investigated how possible alterations are associated with neuropathic pain. Our group used functional magnetic resonance imaging to investigate functional brain connectivity in 12 complex regional pain syndrome patients in comparison with that in 12 age- and sex-matched healthy controls. Data were analyzed using a seed voxel correlation analysis and an independent component analysis. An analysis of covariance was employed to relate alterations in functional connectivity with clinical symptoms. We found significantly greater reductions in functional default mode network connectivity in patients compared to controls. The functional connectivity maps of S1/M1 and IPS/MIP in patients revealed greater and more diffuse connectivity with other brain regions, mainly with the cingulate cortex, precuneus, thalamus, and prefrontal cortex. In contrast, controls showed greater intraregional connectivity within S1/M1 and IPS/MIP. Furthermore, there was a trend for correlation between alterations in functional connectivity and intensity of neuropathic pain. In our findings, patients with complex regional pain syndrome have substantial spatial alterations in the functional connectivity between brain regions implicated in the resting state default mode network, S1/M1, and IPS/MIP; these alterations show a trend of correlation with neuropathic pain intensity. PERSPECTIVE: This article presents spatial alterations in the functional resting-state connectivity of complex regional pain syndrome patients. Our results add further insight into the disease states of CRPS and into the functional architecture of the resting state brains of pain patients in general. PMID- 23791137 TI - Nutritional programming of insulin resistance: causes and consequences. AB - Strong evidence indicates that adverse prenatal and early postnatal environments have a significant long-term influence on risk factors that result in insulin resistance, type 2 diabetes (T2D), and cardiovascular disease later in life. Here we discuss current knowledge of how maternal and neonatal nutrition influence early growth and the long-term risk of developing insulin resistance in different organs and at the whole-body level. Accumulating evidence supports a role for epigenetic mechanisms underlying this nutritional programming, consisting of heritable changes that regulate gene expression which in turn shapes the phenotype across generations. Deciphering these molecular mechanisms in key tissues and discovering key biological markers may provide valuable insight towards the development of effective intervention strategies. PMID- 23791138 TI - Democratization and life expectancy in Europe, 1960-2008. AB - Over the past five decades, two successive waves of political reform have brought democracy to, first, Spain, Portugal and Greece, and, more recently, Central and Eastern European countries. We assessed whether democratization was associated with improvements in population health, as indicated by life expectancy and cause specific mortality rates. Data on life expectancy at birth, age-standardized total and cause-specific mortality rates, levels of democracy and potential time variant confounding variables were collected from harmonized international databanks. In two pooled cross-sectional time-series analyses with country-fixed effects, life expectancy and cause-specific mortality were regressed on measures of current and cumulative democracy, controlling for confounders. A first analysis covered the 1960-1990 period, a second covered the 1987-2008 period. In the 1960-1990 period, current democracy was more strongly associated with higher life expectancy than cumulative democracy. The positive effects of current democracy on total mortality were mediated mainly by lower mortality from heart disease, pneumonia, liver cirrhosis, and suicide. In the 1987-2008 period, however, current democracy was associated with lower, and cumulative democracy with higher life expectancy, particularly among men. The positive effects of cumulative democracy on total mortality were mediated mainly by lower mortality from circulatory diseases, cancer of the breast, and external causes. Current democracy was associated with higher mortality from motor vehicle accidents in both periods, and also with higher mortality from cancer and all external causes in the second. Our results suggest that in Europe during these two periods democratization has had mixed effects. That short-term changes in levels of democracy had positive effects in the first but not in the second period is probably due to the fact that democratization in Central and Eastern Europe was part of a complete system change which caused major societal disruptions. PMID- 23791139 TI - Are addictions diseases or choices? PMID- 23791140 TI - Escitalopram and QTc prolongation. PMID- 23791141 TI - Author response. PMID- 23791142 TI - Management of clozapine-induced fever: a case of continued therapy throughout fever. PMID- 23791143 TI - Successful treatment of chronic hepatitis B and D with pegylated-interferon plus entecavir. AB - Interferon-based regimen has been used to treat hepatitis D virus (HDV) super infection on top of hepatitis B virus (HBV) carriers; however, viral relapse is frequent after stopping therapy. Recently, quantitative hepatitis B surface antigen (qHBsAg) was introduced to help the management of chronic hepatitis B (CHB). Little is known about its role in the treatment of HBV and HDV dual infection. Herein, we reported a 45-year-old male HBV carrier with HDV co infection who received combination therapy of pegylated-interferon alpha-2a plus entecavir. The qHBsAg level was adopted as the treatment guidance and a consolidation therapy of 12 months was continued after HBsAg loss. The patient achieved HBsAg seroconversion with HDV RNA undetectable after 35 months of combination therapy and sustained therapeutic response 12 months post-therapy. Therefore, personalized response-guided therapy by using qHBsAg may be an option for the treatment for HBV and HDV dual infection. PMID- 23791144 TI - Evaluating the performance of different multicolumn setups for chromatographic separation of proteins on hydrophobic interaction chromatography media by a numerical study. AB - A theoretical study has been performed on the effectiveness of isolating a target component out of a multi-component protein mixture using different arrangements of chromatographic columns. Three continuous systems have been considered which were able to perform solvent gradient separations, such as: open loop simulated moving bed, countercurrent solvent gradient purification and carousel multicolumn setup. The performance of the continuous processes was examined with respect to productivity, yield and eluent consumption and compared to a single-column batch system. As a case study separation of a ternary mixture of proteins on HIC media has been selected. Two separation problems have been analyzed referring to the situation when the target component was the most strongly adsorbed as well as when it exhibited intermediate adsorption strength. A mathematical model has been used to simulate the process dynamics and to optimize operating conditions for the separation. The numerical study indicated that batch column arrangements can outperform SMB-based configurations regarding all performance indicators considered, which has been attributed to solvent mixing in the recycled streams and distortion of the gradient shape in SMB units. It has been concluded that the performance of complex multicolumn systems should be verified vs. batch column operations prior to the realization of the separation process. PMID- 23791145 TI - A validated analytical method to study the long-term stability of natural and synthetic glucocorticoids in livestock urine using ultra-high performance liquid chromatography coupled to Orbitrap-high resolution mass spectrometry. AB - Due to their growth-promoting effects, the use of synthetic glucocorticoids is strictly regulated in the European Union (Council Directive 2003/74/EC). In the frame of the national control plans, which should ensure the absence of residues in food products of animal origin, in recent years, a higher frequency of prednisolone positive bovine urines has been observed. This has raised questions with respect to the stability of natural corticoids in the respective urine samples and their potential to be transformed into synthetic analogs. In this study, a ultra high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) methodology was developed to examine the stability of glucocorticoids in bovine urine under various storage conditions (up to 20 weeks) and to define suitable conditions for sample handling and storage, using an Orbitrap ExactiveTM. To this end, an extraction procedure was optimized using a Plackett-Burman experimental design to determine the key conditions for optimal extraction of glucocorticoids from urine. Next, the analytical method was successfully validated according to the guidelines of CD 2002/657/EC. Decision limits and detection capabilities for prednisolone, prednisone and methylprednisolone ranged, respectively, from 0.1 to 0.5MUgL(-1) and from 0.3 to 0.8MUgL(-1). For the natural glucocorticoids limits of detection and limits of quantification for dihydrocortisone, cortisol and cortisone ranged, respectively, from 0.1 to 0.2MUgL(-1) and from 0.3 to 0.8MUgL(-1). The stability study demonstrated that filter-sterilization of urine, storage at -80 degrees C, and acidic conditions (pH 3) were optimal for preservation of glucocorticoids in urine and able to significantly limit degradation up to 20 weeks. PMID- 23791146 TI - Insight into virgin olive oil secoiridoids characterization by high-resolution mass spectrometry and accurate mass measurements. AB - With the aim to enhance characterization of virgin olive oil (VOO), high resolution mass spectrometry (HRMS) and high resolution tandem mass spectrometry (HRMS/MS), in positive and negative electrospray ionization (ESI) modes, coupled to fused-core reverse phase chromatography, were applied to distinct VOO phenolic extracts after the optimization of chromatographic conditions, ESI and fragmentation parameters. HRMS, but also HRMS/MS resulted fundamental to progress in secoiridoids structural elucidation. The former revealed that the secoiridoid composition of VOO was far more complicated than previously reported, while the latter helped clarify product ion elemental composition allowing new fragmentations, in addition to those reported in the literature, to be put forward. In particular, for the first time, different product ions with the same nominal mass were unequivocally identified in the spectra of secoiridoid compounds, confirming the greater capacity of HRMS/MS to clarify structure than low-resolution MS. Furthermore, and differing from previous studies, the multiple isomers of the main VOO secoiridoids could be differentiated on the basis of their HR product ion spectra in positive mode. PMID- 23791147 TI - Additional investigations into the retention mechanism of hydrophilic interaction liquid chromatography by linear solvation energy relationships. AB - In analogy to our previous publication, the hydrophilic interaction liquid chromatography mechanism was examined in terms of hydrogen bonding, coulombic interactions and phase ratio using linear solvation energy relationships. At first, 23 commercially available and in-house synthesized chromatographic supports are discussed in order to obtain system constants at pH 5.0 with ammonium acetate as buffer salt. Subsequently we compared these outcomes with our former results obtained at pH 3.0 with ammonium formate as buffer additive. Goodness of fit in terms of the adjusted multiple correlation coefficient was found to be reduced under the new conditions. No universal model which simultaneously comprised acidic, basic and neutral analytes could be performed. A significant enhancement of the HILIC systems hydrogen bond basicity was found when changing the pH and buffer counter ions. Even though packing materials showed similar selectivity profiles during the collection of the experimental retention data, different forces were found to account for the overall retention (e.g. Shiseido PC HILIC and Nucleodur HILIC). This indicates that HILIC type selectivity is rather based on a sum of additive or multiplicative phenomena. PMID- 23791148 TI - Average mass scan of the total ion chromatograms: a new gas chromatography-mass spectrometry derived variable for fast and reliable multivariate statistical treatment of essential oil compositional data. AB - Plant volatiles have been repeatedly shown to provide valuable insight into the evolutionary relationships among plant taxa on various taxonomical levels. The number of variables available from GC-MS analyses of these plant metabolites usually represents a large data set. The comparison of such data sets requires the use of multivariate statistical analyses (MSA) but with several serious shortcomings. In order to make multivariate statistical comparison of essential oils more applicable, reliable and faster, this work was set to explore the suitability of a complementary use of relative abundances of m/z values of the average mass scan of the total GC chromatograms instead of the traditionally used variables-percentages (peak areas) of individual oil constituents. To achieve this, essential oils extracted from 12 different Artemisia species were analyzed using GC-FID and GC-MS. Almost 500 different constituents were successfully identified. Average mass scans of the total GC chromatograms (AMS) and chemical compositions (relative percentages) of the analyzed oils were separately compared using two MSA methods: agglomerative hierarchical cluster analysis and principal component analysis. This approach was applied to an additional set of essential oil compositional data (representatives of a number of different genera/families; data from the literature) using both types of variables. The obtained results strongly suggest that MSA of complex volatile mixtures, using the corresponding directly obtainable AMS, could be considered as a promising time saving tool for easy and reliable comparison purposes. The AMS approach gives comparable or even better results than the traditional method - it reflected the natural relationships between observations within both studied groups of oils. PMID- 23791149 TI - Development of a liquid chromatography-electrospray chemical ionization tandem mass spectrometry analytical method for analysis of eleven hydroxylated polybrominated diphenyl ethers. AB - Recently, hydroxylated polybrominated diphenyl ethers (OH-PBDEs) have emerged as environmentally relevant pollutants due to recent reports of their natural production and metabolism. Recent mechanistic studies in human and rats have shown that some OH-PBDEs are more potent than parent compounds (PBDEs) and may contribute substantially to neurodevelopmental disorders by direct neurotoxicity, or indirectly through altered thyroid disruption. However, analytical methodologies for determination of OH-PBDEs are currently limited. In this study a robust liquid chromatography-electrospray tandem triple quadrupole-linear ion trap mass spectrometer (LC-ESI-QqLIT-MS-MS) in negative mode method was developed for the determination of eleven OH-tri- to OH-hexa-PBDEs. Two different columns were tested and compared for chromatographic separation: a C18 BetaBasic and a Purospher STAR RP 18, working at pH 8 and 10, respectively. Mobile phase (acetonitrile:water) was optimized by changing the pH of the aqueous phase and the concentration of the organic modifier (methanol). The MS-MS parameters (declustering potential (DP), collision energy (CE) and cell exit potential (CXP)) were optimized. Selected reaction monitoring (SRM) was used in order to increase sensitivity. Two SRM transitions ([M-H](-)>[Br](-)) were selected for each OH-PBDE, one for quantification and the second one for confirmation. Under the optimized conditions, the instrumental limits of detection were between 0.17 and 0.72injectedpg. The method provided good linearity (r>0.99 for a concentration range of 0.30-100ng/mL), accuracy and precision (%Dev and %RSD<=20% for intra- and inter-assays). PMID- 23791150 TI - Proteomic analysis of rat tibialis anterior muscles at different stages of experimental autoimmune myasthenia gravis. AB - Myasthenia gravis (MG) is an autoimmune disease in which autoantibodies, most commonly directed against the acetylcholine receptor (AChR), impair neuromuscular transmission and cause muscle weakness. In this study, we utilized two dimensional difference in-gel electrophoresis (2D-DIGE) to analyze the muscle's proteomic profile at different stages of experimental autoimmune myasthenia gravis (EAMG). We identified twenty-two differentially expressed proteins, mainly related to metabolic and stress-response pathways. Interestingly, these identified proteins have also been associated with other contraction-impairing muscle pathologies (e.g. inclusion body myositis), suggesting a similar response of the muscle to such conditions. PMID- 23791151 TI - Urban social stress--risk factor for mental disorders. The case of schizophrenia. AB - Living in an urban environment is associated with an increased prevalence of specific mental health disorders, particularly schizophrenia. While many factors have been discussed as possible mediators of this association, most researchers favour the hypothesis that urban living stands as a proxy for an increased exposure to social stress. This factor has been recognized as one of the most powerful causes for the development of mental disorders, and appears to correlate with the markedly increased incidence of schizophrenia in urban minority groups. However, the hypothesis that the general urban population is exposed to increased levels of social stress has to be validated. Pursuing the goal of understanding how social stress acts as a risk factor for mental disorder in urban populations must include factors like social conditions, environmental pollutants, infrastructure and economic issues. PMID- 23791152 TI - Bakri balloon tamponade for the management of postpartum hemorrhage. PMID- 23791153 TI - A randomized controlled trial on the value of misoprostol for the treatment of retained placenta in a low-resource setting. AB - OBJECTIVE: To evaluate the efficacy and safety of misoprostol among patients with retained placenta in a low-resource setting. METHODS: A prospective, multicenter, randomized, double-blind, placebo-controlled trial was carried out in Tanzania between April 2008 and November 2011. It included patients who delivered at a gestational age of 28 weeks or more and had blood loss of 750 mL or less at 30 minutes after delivery. Sublingual misoprostol (800 MUg) was compared with placebo as the primary treatment. Power analysis showed that 117 patients would be required to observe a reduction of 40% in the incidence of manual removal of the placenta (MRP; P=0.05, 80% power), the primary outcome. The secondary outcomes were blood loss and number of blood transfusions. RESULTS: Interim analysis after recruitment of 95 patients showed that incidence of MRP, total blood loss, and incidence of blood transfusions were similar in the misoprostol (MRP, 40%; blood loss, 803 mL; blood transfusion, 15%) and placebo (MRP, 33%, blood loss 787 mL, blood transfusion, 23%) groups. The trial was stopped because continuation would not alter the interim conclusion that misoprostol was ineffective. CONCLUSION: Treatment with misoprostol was found to have no clinically significant beneficial effect among women with retained placenta. CLINICAL TRIAL REGISTRATION: Current Controlled Trials ISRCTN16104753. PMID- 23791154 TI - Instrumented assessment of the effect of Botulinum Toxin-A in the medial hamstrings in children with cerebral palsy. AB - This study examined the sensitivity of an instrumented spasticity assessment of the medial hamstrings (MEH) in children with cerebral palsy (CP). Nineteen children received Botulinum Toxin type A (BTX-A) injections in the MEH. Biomechanical (position and torque) and electrophysiological (surface electromyography, EMG) signals were integrated during manually-performed passive stretches of the MEH at low, medium and high velocity. Signals were examined at each velocity and between stretch velocities, and compared pre and post BTX-A (43 +/- 16 days). Average change between pre and post BTX-A was interpreted in view of the minimal detectable change (MDC) calculated from previously published reliability results. Improvements greater than the MDC were found for nearly all EMG-parameters and for torque parameters at high velocity and at high versus low velocity (p<0.03), however large inter-subject variability was noted. Moderate correlations were found between the improvement in EMG and in torque (r=0.52, p<0.05). Biomechanical and electrophysiological parameters proved to be adequately sensitive to assess the response to treatment with BTX-A. Furthermore, studying both parameters at different velocities improves our understanding of spasticity and of the physiological effect of selective tone-reduction. This not only provides a clinical validation of the instrumented assessment, but also opens new avenues for further spasticity research. PMID- 23791157 TI - The Malthus Programme: developing radiotherapy demand models for breast and prostate cancer at the local, regional and national level. AB - AIMS: The Malthus Programme has delivered a tool for modelling radiotherapy demand in England. The model is capable of simulating demand at the local level. This article investigates the local and regional level variation in predicted demand with respect to Breast and Prostate cancer, the two tumour types responsible for the majority of radiotherapy treatment workload in England. MATERIALS AND METHODS: Simulations were performed using the Malthus model, using base population incidence data for the period from 2007-2009. Simulations were carried out at the level of Primary Care Trusts, Cancer Networks, and nationwide, with annual projections for 2012, 2016 and 2020. Benchmarking was undertaken against previously published models from the UK, Canada and Australia. RESULTS: For breast cancer, the fraction burden for 2012 varied from 5537 fractions per million in Tower Hamlets PCT to 18 896 fractions per million in Devon PCT (national mean - 13 592 fractions per million). For prostate cancer, the fraction burden for 2012 varied from 4874 fractions per million in Tower Hamlets PCT to 23 181 fractions per million in Lincolnshire PCT (national mean - 15 087 fractions per million). Predictions of population growth by age cohort for 2016 and 2020 result in the regional differences in radiotherapy demand becoming greater over time. Similar effects were also observed at the level of the cancer network. CONCLUSIONS: Our model shows the importance of local population demographics and cancer incidence rates when commissioning radiotherapy services. PMID- 23791158 TI - Effective writing and publishing scientific papers, part V: results. PMID- 23791159 TI - Bovine colostrum improves intestinal function following formula-induced gut inflammation in preterm pigs. AB - BACKGROUND & AIMS: Only few hours of formula feeding may induce proinflammatory responses and predispose to necrotizing enterocolitis (NEC) in preterm pigs. We hypothesized that bovine colostrum, rich in bioactive factors, would improve intestinal function in preterm pigs following an initial exposure to formula feeding after some days of total parenteral nutrition (TPN). METHODS: After receiving TPN for 2 days, preterm pigs were fed formula (FORM, n = 14), bovine colostrum (COLOS, n = 6), or formula (6 h) followed by bovine colostrum (FCOLOS, n = 14). Intestinal lesions, function, and structure, abundance and location of bacteria, and inflammation markers were investigated. RESULTS: NEC severity and interleukins (IL)-1beta and -8 protein concentrations were lower, while villus height, galactose absorption, and brush-border enzyme activities were increased in the distal small intestine in COLOS and FCOLOS pigs, relative to FORM pigs. Intestinal gene expression of serum amyloid A, IL-1beta, -6 and -8, and bacterial abundance, correlated positively with NEC severity of the distal small intestine. CONCLUSIONS: Bovine colostrum restores intestinal function after initial formula induced inflammation in preterm pigs. Further studies are required to test if bovine colostrum may also benefit preterm infants during the challenging transition from total parenteral nutrition to enteral nutrition, when human milk is unavailable. PMID- 23791160 TI - Reconstruction of the superior vena cava by biologic conduit: assessment of long term patency by magnetic resonance imaging. AB - BACKGROUND: To assess the long-term patency of the biologic prosthetic conduit used for reconstruction of the superior vena cava (SVC) by magnetic resonance imaging (MRI). METHODS: Patients undergoing oncologic resection and reconstruction of the SVC by a bovine pericardial prosthesis (January 2003 to April 2010) have been studied after 1 year (if surviving) by MRI for the assessment of the conduit long-term patency. Results were compared with those of a control group of patients with normal SVC. Blood flow and area of lumen section at 3 different levels (proximal, middle, distal) were analyzed. RESULTS: Sixteen consecutive patients surviving after 1 year from surgery out of 17 (9 lung cancer, 8 mediastinal malignancy) undergoing SVC reconstruction were included. One patient died postoperatively and was not included. Sixteen patients with similar demographic characteristics were studied in the control group. Mean blood flow was 18.4+/-3.5 mL/sec (range 14.3 to 25.7) in patients with reconstructed SVC and 20.8+/-4.1 mL/sec (range 15.3 to 27.7) in the control group. Mean area of the conduit lumen section was 2.2+/-0.6 cm2 (range 1.6 to 3.6) at proximal level, 2.9+/-1.3 cm2 at middle level (range 1.3 to 5.7), and 2.1+/-0.9 cm2 (range 0.5 to 4) at distal level in the reconstructed group, and 2.6+/-0.7 cm2 (range 1.8 to 4.2), 2.7+/-0.7 cm2 (range 1.9 to 4.3), and 2.4+/-0.3 cm2 (range 1.8 to 3.1), respectively, at proximal, middle, and distal levels in the control group. Differences between the 2 groups were not significant (p>0.05). CONCLUSIONS: The MRI assessment in terms of blood flow and area of lumen section at 3 different levels confirms that bovine pericardial conduit used for SVC replacement shows an optimal patency over the long term. PMID- 23791161 TI - Coronary revascularization in diabetic patients: off-pump versus on-pump surgery. AB - BACKGROUND: Coronary artery bypass grafting (CABG) is a well-established procedure for treating diabetic patients with multivessel disease, but extracorporeal circulation and cardioplegia-induced cardiac arrest introduce a severe burden to these patients. The present study investigated if off-pump CABG decreases 30-day mortality and mid-term mortality in diabetic patients in comparison with conventional CABG. METHODS: From February 2009 through October 2011, data from 355 consecutive adult diabetic patients undergoing off-pump CABG and 502 patients undergoing on-pump CABG were prospectively recorded. Data analysis was performed by propensity score (PS)-adjusted logistic regression analysis and PS-adjusted Cox regression analysis. The primary endpoint was 30-day mortality. Secondary endpoints were major complications and mortality on follow up. RESULTS: Off-pump CABG was associated with a significantly lower 30-day mortality rate (0.3% vs 4.2%; adjusted odds ratio [OR] = 0.09 [95% confidence interval (CI):0.01 to 0.70] p = 0.021) than on-pump CABG. Results coincided with a lower rate of postoperative neurologic complications in patients undergoing off pump CABG (1.7% vs 5.4%; adjusted OR = 0.31 [95% CI: 0.12 to 0.77] p = 0.012) and a less frequent need for hemofiltration in these patients (3.4% vs 10.4%; adjusted OR = 0.30 [95% CI: 0.14 to 0.64] p = 0.002). The off-pump technique decreased the 6-month mortality rate (2.3% vs 8.8%; adjusted hazard ratio = 0.27 [95% CI: 0.12 to 0.61] p = 0.002) and also the 1-year mortality rate (4.0% vs 10.6%; adjusted hazard ratio = 0.40 [95% CI: 0.22 to 0.75] p = 0.004) significantly. CONCLUSIONS: Our data indicate that in terms of postoperative complications and early and mid-term survival, off-pump CABG is superior to the on-pump technique in diabetic patients. PMID- 23791162 TI - Anomalous systemic arterial supply to the Basal segments of the lung: feasible thoracoscopic surgery. AB - BACKGROUND: Anomalous systemic arterial supply to the basal segments of the lung is a rare anomaly. This study aimed to evaluate the outcomes of thoracoscopic surgery for this anomaly. METHODS: We reviewed patients who underwent thoracoscopic surgery for anomalous systemic arterial supply to the basal segments of the lung between October 2007 and September 2012 at our institution. RESULTS: Four patients (mean age 37.5 years; range, 22 to 54) underwent thoracoscopic surgery for anomalous systemic arterial supply to the basal segments of the lung. The mean diameter of the anomalous arteries was 14 mm (range, 10 to 16 mm). Two patients underwent thoracoscopic segmentectomy, 1 of whom had a complicated anomaly that necessitated conversion to thoracotomy. The other 2 patients underwent thoracoscopic lower lobectomy of the left lung. One of them had an aneurysm in the anomalous artery; therefore, endovascular devices were kept on standby in case massive hemorrhage occurred. The anomalous arteries were divided uneventfully using a vascular stapler in all patients. No patient had severe postoperative complications. CONCLUSIONS: Thoracoscopic surgery for anomalous systemic arterial supply to the basal segments of the lung is feasible, safe, and minimally invasive, with confirmed effectiveness in typical cases. PMID- 23791163 TI - Surgical biopsy of suspected interstitial lung disease is superior to radiographic diagnosis. AB - BACKGROUND: Different modalities are used to diagnose interstitial lung disease. We compared the effectiveness of minimally invasive surgical biopsy versus high resolution computed tomography for the diagnosis of interstitial lung disease and report the mortality of the procedure. METHODS: We reviewed 194 patients undergoing video-assisted thoracoscopic lung biopsies for the suspicion of interstitial lung disease from January 2003 to February 2012 at Emory University. Demographics and patient characteristics were analyzed in addition to final diagnoses and clinical outcomes. RESULTS: Concordance of radiographic diagnosis with final diagnosis was poor, matching pathologic diagnosis in 15% of cases, and specific diagnoses were included in the radiographic differential in only 34% of cases. A specific diagnosis was made after surgical biopsy in 88% of cases. Overall mortality of surgical biopsy was 6.7% (13/194). Major risk factors for death were preoperative supplemental oxygen, ventilator dependence, and age (p < 0.0001, p < 0.0001, and p = 0.03, respectively). Among patients with ventilator dependence preoperatively, the mortality rate was 100% versus 4.8% in patients not ventilator dependent. All biopsy specimens were concordant 91% of the time, and the first two biopsy specimens were concordant 96% of the time. CONCLUSIONS: Surgical biopsy should remain the gold standard for diagnosis of interstitial lung disease. The mortality is low with proper patient selection. More than two surgical biopsy specimens may not be needed because the concordance rates among pathologic specimens are very high. PMID- 23791164 TI - Outcome of pericardiectomy for constrictive pericarditis in Japan: a nationwide outcome study. AB - BACKGROUND: We evaluated the current results and the predictors of in-hospital complications for a pericardiectomy procedure for constrictive pericarditis in Japan. METHODS: A total of 346 patients who underwent isolated pericardiectomy for constrictive pericarditis nationwide between 2008 and 2012 were identified from the Japan Adult Cardiovascular Surgery Database. RESULTS: The patients were a mean age of 65.7 +/- 11.7 years. The operative approach was through a median sternotomy in 90% of the patients. Cardiopulmonary bypass was used in 28.9%. The operative mortality rate was 10.0%, and the composite operative mortality or major morbidity (stroke, reoperation for bleeding, need for mechanical ventilation for more than 24 hours postoperatively due to respiratory failure, renal failure with newly required dialysis or mediastinitis) was 15.0%. Logistic regression analysis revealed that the predictive factors for composite operative mortality or major morbidity were preoperative chronic lung disease (odds ratio [OR], 4.75; p < 0.001), New York Heart Association functional class IV (OR, 3.85; p < 0.001), previous cardiac operation (OR, 2.68; p = .006), preoperative renal failure (OR, 2.62; p = .014), and cardiopulmonary bypass during the operation (OR, 2.46; p = .015). The frequency of using cardiopulmonary bypass was 2.9% in the patients treated through a left thoracotomy approach vs 31.8% in the patients treated through a median sternotomy approach (p < 0.0001). CONCLUSIONS: Pericardiectomy is associated with high morbidity and mortality rates. Careful consideration should be given to these risk factors in the process of patient selection and perioperative management. PMID- 23791165 TI - Predicting right ventricular failure in the modern, continuous flow left ventricular assist device era. AB - BACKGROUND: In the era of destination continuous flow left ventricular assist devices (LVAD), the decision of whether a patient will tolerate isolated LVAD support or will need biventricular support (BIVAD) can be challenging. Incorrect decision making with delayed right ventricular (RV) assist device implantation results in increased morbidity and mortality. Continuous flow LVADs have been shown to decrease pulmonary hypertension and improve RV function. We undertook this study to determine predictors in the continuous flow LVAD era that identify patients who are candidates for isolated LVAD therapy as opposed to biventricular support. METHODS: We reviewed demographic, hemodynamic, laboratory, and echocardiographic variables for 218 patients who underwent VAD implant from 2003 through 2011 (LVAD=167, BIVAD=51), during the era of continuous flow LVADs. RESULTS: Fifty preoperative risk factors were compared between patients who were successfully managed with an LVAD and those who required a BIVAD. Seventeen variables demonstrated statistical significance by univariate analysis. Multivariable logistic regression analysis identified central venous pressure>15 mmHg (OR 2.0, "C"), severe RV dysfunction (OR 3.7, "R"), preoperative intubation (OR 4.3, "I"), severe tricuspid regurgitation (OR 4.1, "T"), heart rate>100 (OR 2.0, Tachycardia-"T")-CRITT as the major criteria predictive of the need for biventricular support. Utilizing these data, a highly sensitive and easy to use risk score for determining RV failure was generated that outperformed other established risk stratification tools. CONCLUSIONS: We present a preoperative risk calculator to determine suitability of a patient for isolated LVAD support in the current continuous flow ventricular assist device era. PMID- 23791166 TI - Thoracoscopy without lung isolation utilizing single lumen endotracheal tube intubation and carbon dioxide insufflation. AB - BACKGROUND: This study evaluated the feasibility of performing thoracoscopy without lung isolation employing single lumen endotracheal tube (SLET) intubation and carbon dioxide insufflation. METHODS: Eighty-two patients underwent a variety of thoracoscopic procedures without lung isolation using SLET intubation and carbon dioxide (CO2) insufflation between January and December 2012. Sixty-five of these patients underwent wedge resections and were isolated for analysis. Operations were accomplished using percutaneously placed laparoscopic trocars and insufflation up to 15 mm Hg. Operative times, length of stay, and vital signs were compared with 52 patients who underwent thoracoscopic wedge resections with double lumen endotracheal tube (DLET) intubation. RESULTS: A retrospective analysis was performed on 65 patients (30 females, mean age 58) who underwent thoracoscopic wedge resections with SLET intubation compared with 52 patients undergoing the same procedure with DLET intubation. Operating room time (111 +/- 4.74 minutes), time to incision (49 +/- 1.91 minutes), and operative time (48 +/- 2.89 minutes) were significantly decreased in the SLET group (p < 0.05). Intraoperative hemodynamic parameters showed no significant aberrations. Two postoperative complications (3.1%) were identified in the SLET group. Length of stay was similar (3 +/- 0.49 days versus 3 +/- 0.23 days). CONCLUSIONS: Single lumen endotracheal tube intubation is a feasible and safe airway management alternative for thoracoscopic procedures. This method resulted in shorter operative times, no aberrant hemodynamic shifts, low complication rates, and similar hospital stays as compared with traditional DLET intubation. PMID- 23791167 TI - Integron attI1 sites, not riboswitches, associate with antibiotic resistance genes. PMID- 23791168 TI - Riboswitch regulation of aminoglycoside resistance acetyl and adenyl transferases. PMID- 23791169 TI - Aging well with a little wine and a good clock. AB - Age-related decline in mammalian circadian rhythm has been recognized for decades, but the underlying molecular mechanisms have remained elusive. In this issue of Cell, Chang and Guarente use brain-specific SIRT1 knockout mice and transgenic mice overexpressing SIRT1 to develop an enticing model for how SIRT1 helps maintain the robustness of the aging circadian clock. PMID- 23791170 TI - Inside-out connections: the ER meets the plasma membrane. AB - Junctions that connect the endoplasmic reticulum (ER) and the plasma membrane (PM) are unique yet ubiquitous subcellular compartments. Giordano et al. now report that extended synaptotagmins (E-Syts) promote their formation, providing fundamental insight into the molecular machinery controlling ER and plasma membrane crosstalk. PMID- 23791171 TI - Carving axon arbors to fit: master directs one kinase at a time. AB - Pyramidal neurons in the cortex require the master kinase LKB1 for early axon specification. Courchet et al. now uncover a later role for LKB1 and its tango with the downstream effector kinase NUAK1 in controlling terminal axonal branching through influencing mitochondrial motility in axons. PMID- 23791172 TI - Modeling the evolution of C4 photosynthesis. AB - The prediction and verification of adaptive trajectories on macroevolutionary timescales have rarely been achieved for complex biological systems. Employing a model linking biological information at multiple scales, Heckmann et al. simulate likely sequences of evolutionary changes from C3 to C4 photosynthesis biochemistry. PMID- 23791173 TI - Pyruvate as a pivot point for oncogene-induced senescence. AB - Regulation of pyruvate fate is an important determinant of anabolic versus catabolic metabolism. A new report in the journal Nature by Kaplon et al. suggests that driving pyruvate oxidation can thwart tumor growth in BRAF-driven melanoma by inducing oncogene-induced senescence, a finding that might be exploited therapeutically. PMID- 23791174 TI - Guarding against collateral damage during chromatin transactions. AB - Signal amplifications are vital for chromatin function, yet they also bear the risk of transforming into unrestrained, self-escalating, and potentially harmful responses. Examples of inbuilt limitations are emerging, revealing how chromatin transactions are confined within physiological boundaries. PMID- 23791175 TI - XBP-1 is a cell-nonautonomous regulator of stress resistance and longevity. AB - The ability to ensure proteostasis is critical for maintaining proper cell function and organismal viability but is mitigated by aging. We analyzed the role of the endoplasmic reticulum unfolded protein response (UPR(ER)) in aging of C. elegans and found that age-onset loss of ER proteostasis could be reversed by expression of a constitutively active form of XBP-1, XBP-1s. Neuronally derived XBP-1s was sufficient to rescue stress resistance, increase longevity, and activate the UPR(ER) in distal, non-neuronal cell types through a cell nonautonomous mechanism. Loss of UPR(ER) signaling components in distal cells blocked cell-nonautonomous signaling from the nervous system, thereby blocking increased longevity of the entire animal. Reduction of small clear vesicle (SCV) release blocked nonautonomous signaling downstream of xbp-1s, suggesting that the release of neurotransmitters is required for this intertissue signaling event. Our findings point toward a secreted ER stress signal (SERSS) that promotes ER stress resistance and longevity. PMID- 23791176 TI - SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging. AB - SIRT1 is a NAD(+)-dependent protein deacetylase that governs many physiological pathways, including circadian rhythm in peripheral tissues. Here, we show that SIRT1 in the brain governs central circadian control by activating the transcription of the two major circadian regulators, BMAL1 and CLOCK. This activation comprises an amplifying circadian loop involving SIRT1, PGC-1alpha, and Nampt. In aged wild-type mice, SIRT1 levels in the suprachiasmatic nucleus are decreased, as are those of BMAL1 and PER2, giving rise to a longer intrinsic period, a more disrupted activity pattern, and an inability to adapt to changes in the light entrainment schedule. Young mice lacking brain SIRT1 phenocopy these aging-dependent circadian changes, whereas mice that overexpress SIRT1 in the brain are protected from the effects of aging. Our findings indicate that SIRT1 activates the central pacemaker to maintain robust circadian control in young animals, and a decay in this activity may play an important role in aging. PMID- 23791177 TI - Eukaryotic stress granules are cleared by autophagy and Cdc48/VCP function. AB - Stress granules and P bodies are conserved cytoplasmic aggregates of nontranslating messenger ribonucleoprotein complexes (mRNPs) implicated in the regulation of mRNA translation and decay and are related to RNP granules in embryos, neurons, and pathological inclusions in some degenerative diseases. Using baker's yeast, 125 genes were identified in a genetic screen that affected the dynamics of P bodies and/or stress granules. Analyses of such mutants, including CDC48 alleles, provide evidence that stress granules can be targeted to the vacuole by autophagy, in a process termed granulophagy. Moreover, stress granule clearance in mammalian cells is reduced by inhibition of autophagy or by depletion or pathogenic mutations in valosin-containing protein (VCP), the human ortholog of CDC48. Because mutations in VCP predispose humans to amyotrophic lateral sclerosis, frontotemporal lobar degeneration, inclusion body myopathy, and multisystem proteinopathy, this work suggests that autophagic clearance of stress granule related and pathogenic RNP granules that arise in degenerative diseases may be important in reducing their pathology. PMID- 23791178 TI - PI(4,5)P(2)-dependent and Ca(2+)-regulated ER-PM interactions mediated by the extended synaptotagmins. AB - Most available information on endoplasmic reticulum (ER)-plasma membrane (PM) contacts in cells of higher eukaryotes concerns proteins implicated in the regulation of Ca(2+) entry. However, growing evidence suggests that such contacts play more general roles in cell physiology, pointing to the existence of additionally ubiquitously expressed ER-PM tethers. Here, we show that the three extended synaptotagmins (E-Syts) are ER proteins that participate in such tethering function via C2 domain-dependent interactions with the PM that require PI(4,5)P2 in the case of E-Syt2 and E-Syt3 and also elevation of cytosolic Ca(2+) in the case of E-Syt1. As they form heteromeric complexes, the E-Syts confer cytosolic Ca(2+) regulation to ER-PM contact formation. E-Syts-dependent contacts, however, are not required for store-operated Ca(2+) entry. Thus, the ER PM tethering function of the E-Syts (tricalbins in yeast) mediates the formation of ER-PM contacts sites, which are functionally distinct from those mediated by STIM1 and Orai1. PMID- 23791179 TI - Terminal axon branching is regulated by the LKB1-NUAK1 kinase pathway via presynaptic mitochondrial capture. AB - The molecular mechanisms underlying the axon arborization of mammalian neurons are poorly understood but are critical for the establishment of functional neural circuits. We identified a pathway defined by two kinases, LKB1 and NUAK1, required for cortical axon branching in vivo. Conditional deletion of LKB1 after axon specification or knockdown of NUAK1 drastically reduced axon branching in vivo, whereas their overexpression was sufficient to increase axon branching. The LKB1-NUAK1 pathway controls mitochondria immobilization in axons. Using manipulation of Syntaphilin, a protein necessary and sufficient to arrest mitochondrial transport specifically in the axon, we demonstrate that the LKB1 NUAK1 kinase pathway regulates axon branching by promoting mitochondria immobilization. Finally, we show that LKB1 and NUAK1 are necessary and sufficient to immobilize mitochondria specifically at nascent presynaptic sites. Our results unravel a link between presynaptic mitochondrial capture and axon branching. PMID- 23791180 TI - Dynein motion switches from diffusive to directed upon cortical anchoring. AB - Cytoplasmic dynein is a motor protein that exerts force on microtubules. To generate force for the movement of large organelles, dynein needs to be anchored, with the anchoring sites being typically located at the cell cortex. However, the mechanism by which dyneins target sites where they can generate large collective forces is unknown. Here, we directly observe single dyneins during meiotic nuclear oscillations in fission yeast and identify the steps of the dynein binding process: from the cytoplasm to the microtubule and from the microtubule to cortical anchors. We observed that dyneins on the microtubule move either in a diffusive or directed manner, with the switch from diffusion to directed movement occurring upon binding of dynein to cortical anchors. This dual behavior of dynein on the microtubule, together with the two steps of binding, enables dyneins to self-organize into a spatial pattern needed for them to generate large collective forces. PMID- 23791181 TI - Jpx RNA activates Xist by evicting CTCF. AB - In mammals, dosage compensation between XX and XY individuals occurs through X chromosome inactivation (XCI). The noncoding Xist RNA is expressed and initiates XCI only when more than one X chromosome is present. Current models invoke a dependency on the X-to-autosome ratio (X:A), but molecular factors remain poorly defined. Here, we demonstrate that molecular titration between an X-encoded RNA and an autosomally encoded protein dictates Xist induction. In pre-XCI cells, CTCF protein represses Xist transcription. At the onset of XCI, Jpx RNA is upregulated, binds CTCF, and extricates CTCF from one Xist allele. We demonstrate that CTCF is an RNA-binding protein and is titrated away from the Xist promoter by Jpx RNA. Thus, Jpx activates Xist by evicting CTCF. The functional antagonism via molecular titration reveals a role for long noncoding RNA in epigenetic regulation. PMID- 23791182 TI - The ubiquitin ligase FBXW7 modulates leukemia-initiating cell activity by regulating MYC stability. AB - Sequencing efforts led to the identification of somatic mutations that could affect the self-renewal and differentiation of cancer-initiating cells. One such recurrent mutation targets the binding pocket of the ubiquitin ligase Fbxw7. Missense FBXW7 mutations are prevalent in various tumors, including T cell acute lymphoblastic leukemia (T-ALL). To study the effects of such lesions, we generated animals carrying regulatable Fbxw7 mutant alleles. Here, we show that these mutations specifically bolster cancer-initiating cell activity in collaboration with Notch1 oncogenes but spare normal hematopoietic stem cell function. We were also able to show that FBXW7 mutations specifically affect the ubiquitylation and half-life of c-Myc protein, a key T-ALL oncogene. Using animals carrying c-Myc fusion alleles, we connected Fbxw7 function to c-Myc abundance and correlated c-Myc expression to leukemia-initiating activity. Finally, we demonstrated that small-molecule-mediated suppression of MYC activity leads to T-ALL remission, suggesting an effective therapeutic strategy. PMID- 23791183 TI - Horizontal gene transfer from diverse bacteria to an insect genome enables a tripartite nested mealybug symbiosis. AB - The smallest reported bacterial genome belongs to Tremblaya princeps, a symbiont of Planococcus citri mealybugs (PCIT). Tremblaya PCIT not only has a 139 kb genome, but possesses its own bacterial endosymbiont, Moranella endobia. Genome and transcriptome sequencing, including genome sequencing from a Tremblaya lineage lacking intracellular bacteria, reveals that the extreme genomic degeneracy of Tremblaya PCIT likely resulted from acquiring Moranella as an endosymbiont. In addition, at least 22 expressed horizontally transferred genes from multiple diverse bacteria to the mealybug genome likely complement missing symbiont genes. However, none of these horizontally transferred genes are from Tremblaya, showing that genome reduction in this symbiont has not been enabled by gene transfer to the host nucleus. Our results thus indicate that the functioning of this three-way symbiosis is dependent on genes from at least six lineages of organisms and reveal a path to intimate endosymbiosis distinct from that followed by organelles. PMID- 23791184 TI - Predicting C4 photosynthesis evolution: modular, individually adaptive steps on a Mount Fuji fitness landscape. AB - An ultimate goal of evolutionary biology is the prediction and experimental verification of adaptive trajectories on macroevolutionary timescales. This aim has rarely been achieved for complex biological systems, as models usually lack clear correlates of organismal fitness. Here, we simulate the fitness landscape connecting two carbon fixation systems: C3 photosynthesis, used by most plant species, and the C4 system, which is more efficient at ambient CO2 levels and elevated temperatures and which repeatedly evolved from C3. Despite extensive sign epistasis, C4 photosynthesis is evolutionarily accessible through individually adaptive steps from any intermediate state. Simulations show that biochemical subtraits evolve in modules; the order and constitution of modules confirm and extend previous hypotheses based on species comparisons. Plant species-designated C3-C4 intermediates lie on predicted evolutionary trajectories, indicating that they indeed represent transitory states. Contrary to expectations, we find no slowdown of adaptation and no diminishing fitness gains along evolutionary trajectories. PMID- 23791185 TI - Rate-limiting steps in yeast protein translation. AB - Deep sequencing now provides detailed snapshots of ribosome occupancy on mRNAs. We leverage these data to parameterize a computational model of translation, keeping track of every ribosome, tRNA, and mRNA molecule in a yeast cell. We determine the parameter regimes in which fast initiation or high codon bias in a transgene increases protein yield and infer the initiation rates of endogenous Saccharomyces cerevisiae genes, which vary by several orders of magnitude and correlate with 5' mRNA folding energies. Our model recapitulates the previously reported 5'-to-3' ramp of decreasing ribosome densities, although our analysis shows that this ramp is caused by rapid initiation of short genes rather than slow codons at the start of transcripts. We conclude that protein production in healthy yeast cells is typically limited by the availability of free ribosomes, whereas protein production under periods of stress can sometimes be rescued by reducing initiation or elongation rates. PMID- 23791186 TI - Method for non-optical quantification of in situ local soft tissue biomechanics. AB - Soft tissues exhibit significant biomechanical changes as they grow, adapt, and remodel under a variety of normal and pathogenic stimuli. Biomechanical measurement of intact soft tissues is challenging because of its large strain and nonlinear behavior. Tissue distention through applied vacuum pressure is an attractive method for acquiring local biomechanical information minimally invasive and non-destructive, but the current requirement for optical strain measurement limits its use. In this study, we implemented a novel flexible micro electrode array placed within a cylindrical probe tip. We hypothesized that upon tissue distention, contact with each electrode would result in a precipitous voltage drop (from the resistive connection formed between input and output electrodes) across the array. Hence, tissue distention (strain) can be derived directly from the electrode array geometry. In pilot studies, we compared the electrode array measurements directly against optical deformation measurements in situ of agar tissue phantoms and freshly isolated porcine tissue. Our results demonstrate that the probe derived stress-strain profiles and modulus measurements were statistically indistinguishable from optical measurement. We further show that electrode geometry can be scaled down to 50MUm in size (length and width) and spaced 50MUm apart without impairing measurement accuracy. These results establish a promising new method for minimally invasive local soft tissue biomechanical measurement, which may be useful for applications such as disease diagnosis and health monitoring. PMID- 23791187 TI - The effect of different inter-pad distances on the determination of active drag using the Measuring Active Drag system. AB - The Measuring Active Drag (MAD) system was developed to determine active drag in swimming by measuring the push-off force exerted at fixed pads placed below the waterline. The imposed inter-pad distance, which to date has been kept constant while using the MAD system, could affect the active drag because it requires the use of different stroke frequencies. The aim of the present study was therefore to determine the effect of inter-pad distance on active drag at a given speed. In particular, drag-velocity curves at three different inter-pad distances (1.25m, 1.35m and 1.45m) were determined using the MAD system for eleven competitive swimmers. Variation of 16% in inter-pad distance (14% change in stroke frequency) revealed no significant difference in calculated active drag between different inter-pad distances and a low (<5%) average coefficient of variation over different inter-pad distances was found. In addition, inter-test reliability, which was determined for the two 1.35m conditions only, was high (ICC>0.90) for measurements on two consecutive days. The results suggest that it may not be necessary to adapt the inter-pad distance of the MAD system based on anthropometric characteristics of the subject or the velocity-related stroke length in free swimming. PMID- 23791188 TI - Pancreatic serous cystadenoma with signs of compression. PMID- 23791189 TI - In search of the ever-elusive positive endozepine. AB - In this issue of Neuron, Christian et al. (2013) provide functional evidence for positive endozepines (positive allosteric modulators of GABAARs) within the thalamic reticular nucleus. These molecules are encoded by the Dbi gene and modulate thalamocortical oscillations. PMID- 23791190 TI - Time finds its place in the hippocampus. AB - In this issue of Neuron, Kraus et al. (2013) show that a population of "time cells" in the hippocampus responds to the passage of time rather than simply reflecting path integration. This study advances our understanding of how time is represented in the hippocampus. PMID- 23791191 TI - Topographic dynamics in the resting brain. AB - In this issue of Neuron, Wang et al. (2013) demonstrate that spontaneous neural activity measured using functional neuroimaging is strongly related to millisecond-scale neuronal interactions and topographically precise anatomical connections in the primate somatosensory cortex. PMID- 23791192 TI - Remodeling neurodegeneration: somatic cell reprogramming-based models of adult neurological disorders. AB - Epigenetic reprogramming of adult human somatic cells to alternative fates, such as the conversion of human skin fibroblasts to induced pluripotency stem cells (iPSC), has enabled the generation of novel cellular models of CNS disorders. Cell reprogramming models appear particularly promising in the context of human neurological disorders of aging such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), for which animal models may not recapitulate key aspects of disease pathology. In addition, recent developments in reprogramming technology have allowed for more selective cell fate interconversion events, as from skin fibroblasts directly to diverse induced neuron (iN) subtypes. Challenges to human reprogramming-based cell models of disease are the heterogeneity of the human population and the extended temporal course of these disorders. A major goal is the accurate modeling of common nonfamilial "sporadic" forms of brain disorders. PMID- 23791193 TI - Recombinant probes for visualizing endogenous synaptic proteins in living neurons. AB - The ability to visualize endogenous proteins in living neurons provides a powerful means to interrogate neuronal structure and function. Here we generate recombinant antibody-like proteins, termed Fibronectin intrabodies generated with mRNA display (FingRs), that bind endogenous neuronal proteins PSD-95 and Gephyrin with high affinity and that, when fused to GFP, allow excitatory and inhibitory synapses to be visualized in living neurons. Design of the FingR incorporates a transcriptional regulation system that ties FingR expression to the level of the target and reduces background fluorescence. In dissociated neurons and brain slices, FingRs generated against PSD-95 and Gephyrin did not affect the expression patterns of their endogenous target proteins or the number or strength of synapses. Together, our data indicate that PSD-95 and Gephyrin FingRs can report the localization and amount of endogenous synaptic proteins in living neurons and thus may be used to study changes in synaptic strength in vivo. PMID- 23791194 TI - The X-linked intellectual disability protein PHF6 associates with the PAF1 complex and regulates neuronal migration in the mammalian brain. AB - Intellectual disability is a prevalent disorder that remains incurable. Mutations of the X-linked protein PHF6 cause the intellectual disability disorder Borjeson Forssman-Lehmann syndrome (BFLS). However, the biological role of PHF6 relevant to BFLS pathogenesis has remained unknown. We report that knockdown of PHF6 profoundly impairs neuronal migration in the mouse cerebral cortex in vivo, leading to the formation of white matter heterotopias displaying neuronal hyperexcitability. We find that PHF6 physically associates with the PAF1 transcription elongation complex, and inhibition of PAF1 phenocopies the PHF6 knockdown-induced migration phenotype in vivo. We also identify Neuroglycan C/Chondroitin sulfate proteoglycan 5 (NGC/CSPG5), a potential schizophrenia susceptibility gene, as a critical downstream target of PHF6 in the control of neuronal migration. These findings define PHF6, PAF1, and NGC/CSPG5 as components of a cell-intrinsic transcriptional pathway that orchestrates neuronal migration in the brain, with important implications for the pathogenesis of developmental disorders of cognition. PMID- 23791195 TI - mSYD1A, a mammalian synapse-defective-1 protein, regulates synaptogenic signaling and vesicle docking. AB - Structure and function of presynaptic terminals are critical for the transmission and processing of neuronal signals. Trans-synaptic signaling systems instruct the differentiation and function of presynaptic release sites, but their downstream mediators are only beginning to be understood. Here, we identify the intracellular mSYD1A (mouse Synapse-Defective-1A) as a regulator of presynaptic function in mice. mSYD1A forms a complex with presynaptic receptor tyrosine phosphatases and controls tethering of synaptic vesicles at synapses. mSYD1A function relies on an intrinsically disordered domain that interacts with multiple structurally unrelated binding partners, including the active zone protein liprin-alpha2 and nsec1/munc18-1. In mSYD1A knockout mice, synapses assemble in normal numbers but there is a significant reduction in synaptic vesicle docking at the active zone and an impairment of synaptic transmission. Thus, mSYD1A is a regulator of presynaptic release sites at central synapses. PMID- 23791196 TI - Arc/Arg3.1 is a postsynaptic mediator of activity-dependent synapse elimination in the developing cerebellum. AB - Neural circuits are shaped by activity-dependent elimination of redundant synapses during postnatal development. In many systems, postsynaptic activity is known to be crucial, but the precise mechanisms remain elusive. Here, we report that the immediate early gene Arc/Arg3.1 mediates elimination of surplus climbing fiber (CF) to Purkinje cell (PC) synapses in the developing cerebellum. CF synapse elimination was accelerated when activity of channelrhodopsin-2 expressing PCs was elevated by 2-day photostimulation. This acceleration was suppressed by PC-specific knockdown of either the P/Q-type voltage-dependent Ca(2+) channels (VDCCs) or Arc. PC-specific Arc knockdown had no appreciable effect until around postnatal day 11 but significantly impaired CF synapse elimination thereafter, leaving redundant CF terminals on PC somata. The effect of Arc knockdown was occluded by simultaneous knockdown of P/Q-type VDCCs in PCs. We conclude that Arc mediates the final stage of CF synapse elimination downstream of P/Q-type VDCCs by removing CF synapses from PC somata. PMID- 23791197 TI - Dendritic peptide release mediates interpopulation crosstalk between neurosecretory and preautonomic networks. AB - Although communication between neurons is considered a function of the synapse, neurons also release neurotransmitter from their dendrites. We found that dendritic transmitter release coordinates activity across distinct neuronal populations to generate integrative homeostatic responses. We show that activity dependent vasopressin release from hypothalamic neuroendocrine neurons in the paraventricular nucleus stimulates neighboring (~100 MUm soma-to-soma) presympathetic neurons, resulting in a sympathoexcitatory population response. This interpopulation crosstalk was engaged by an NMDA-mediated increase in dendritic Ca(2+), influenced by vasopressin's ability to diffuse in the extracellular space, and involved activation of CAN channels at the target neurons. Furthermore, we demonstrate that this interpopulation crosstalk plays a pivotal role in the generation of a systemic, polymodal neurohumoral response to a hyperosmotic challenge. Because dendritic release is emerging as a widespread process, our results suggest that a similar mechanism could mediate interpopulation crosstalk in other brain systems, particularly those involved in generating complex behaviors. PMID- 23791198 TI - GABAergic lateral interactions tune the early stages of visual processing in Drosophila. AB - Early stages of visual processing must capture complex, dynamic inputs. While peripheral neurons often implement efficient encoding by exploiting natural stimulus statistics, downstream neurons are specialized to extract behaviorally relevant features. How do these specializations arise? We use two-photon imaging in Drosophila to characterize a first-order interneuron, L2, that provides input to a pathway specialized for detecting moving dark edges. GABAergic interactions, mediated in part presynaptically, create an antagonistic and anisotropic center surround receptive field. This receptive field is spatiotemporally coupled, applying differential temporal processing to large and small dark objects, achieving significant specialization. GABAergic circuits also mediate OFF responses and balance these with responses to ON stimuli. Remarkably, the functional properties of L2 are strikingly similar to those of bipolar cells, yet emerge through different molecular and circuit mechanisms. Thus, evolution appears to have converged on a common strategy for processing visual information at the first synapse. PMID- 23791199 TI - The fine structure of shape tuning in area V4. AB - Previous studies have shown that neurons in area V4 are involved in the processing of shapes of intermediate complexity and are sensitive to curvature. These studies also suggest that curvature-tuned neurons are position invariant. We sought to examine the mechanisms that endow V4 neurons with these properties. Consistent with previous studies, we found that response rank order to the most- and least-preferred stimuli was preserved throughout the receptive field. However, a fine-grained analysis of shape tuning revealed a surprising result: V4 neurons tuned to highly curved shapes exhibit very limited translation invariance. At a fine spatial scale, these neurons exhibit local variation in orientation. In contrast, neurons that prefer straight contours exhibit spatially invariant orientation-tuning and homogenous fine-scale orientation maps. Both of these patterns are consistent with a simple orientation-pooling model, with tuning for straight or curved shapes resulting, respectively, from pooling of homogenous or heterogeneous orientation signals inherited from early visual areas. PMID- 23791200 TI - The relationship of anatomical and functional connectivity to resting-state connectivity in primate somatosensory cortex. AB - Studies of resting-state activity in the brain have provoked critical questions about the brain's functional organization, but the biological basis of this activity is not clear. Specifically, the relationships between interregional correlations in resting-state measures of activity, neuronal functional connectivity and anatomical connectivity are much debated. To investigate these relationships, we have examined both anatomical and steady-state functional connectivity within the hand representation of primary somatosensory cortex (areas 3b and 1) in anesthetized squirrel monkeys. The comparison of three data sets (fMRI, electrophysiological, and anatomical) indicate two primary axes of information flow within the SI: prominent interdigit interactions within area 3b and predominantly homotopic interactions between area 3b and area 1. These data support a strikingly close relationship between baseline functional connectivity and anatomical connections. This study extends findings derived from large-scale cortical networks to the realm of local millimeter-scale networks. PMID- 23791201 TI - Detecting changes in scenes: the hippocampus is critical for strength-based perception. AB - Recent findings have ignited a controversy over whether the hippocampus is critical for visual perception as well as memory. Some studies have shown that hippocampal damage impairs perception of scenes, but others found no evidence for hippocampal involvement. These studies measured perception as a unitary phenomenon, but recent findings indicate that perceptual discriminations can be based on two kinds of information: states of perceiving local differences or global strength of relational match. In the current study, we separated state- and strength-based perception using a change detection paradigm with scenes. Patients with selective hippocampal damage exhibited significant reductions in strength-based perception but showed spared state-based responses. In a follow-up neuroimaging study, hippocampal activation linearly tracked confidence in strength-based perception, and was not differentially associated with state-based responses. The hippocampus therefore plays a selective role in perception, contributing high-resolution strength information possibly through its role in the representation of relational information. PMID- 23791202 TI - Abnormal bone quality versus low bone mineral density in adolescent idiopathic scoliosis: a case-control study with in vivo high-resolution peripheral quantitative computed tomography. AB - BACKGROUND CONTEXT: Adolescent idiopathic scoliosis (AIS) is associated with low bone mass that could persist into early adulthood and is an important prognostic factor for curve progression. Previous studies were confined to areal bone mineral density measurement that was a two-dimensional investigation for a three dimensional structure. Evaluation of volumetric BMD (vBMD) and other bone quality parameters are important for gaining in-depth understanding of the etiopathogenesis of AIS. PURPOSE: The objective of this study was to carry out direct in vivo measurement of bone quality in AIS using high-resolution peripheral quantitative computed tomography (HR-pQCT) and compare the correlation of bone quality with osteopenia between AIS and control subjects. STUDY DESIGN/SETTING: A case-control study. PATIENT SAMPLE: Newly diagnosed AIS girls (n=112) and non-AIS girls (n=115) between 11 and 13 years. OUTCOME MEASURES: Areal bone mineral density of bilateral femoral necks and HR-pQCT of the nondominant distal radius were performed. METHODS: Areal bone mineral density of femoral necks was measured by dual-energy X-ray absorptiometry. Subjects were classified into the osteopenic (Z score less than or equal to -1) and nonosteopenic (Z score more than -1) groups. Bone quality parameters, including bone morphometry, trabecular bone microarchitecture, and vBMD, were measured by HR-pQCT (XtremeCT; Scanco Medical, Zurich, Switzerland). RESULTS: In AIS, the osteopenic group had lower measurements in cortical area, cortical thickness, average vBMD, compact bone vBMD, trabecular vBMD, trabecular bone volume to tissue volume ratio, and trabecular thickness compared with nonosteopenic AIS subjects. In contrast, among the non-AIS controls, the osteopenic group had lower measurements only in bone morphometry, average vBMD, and compact bone vBMD but not in trabecular vBMD and all other trabecular bone microarchitecture parameters. CONCLUSIONS: This is the first study using HR-pQCT to compare the correlation of bone quality with osteopenia in AIS and non-AIS subjects. It provides new insights and highlights the unique bone quality profile with predominant changes in the trabecular compartment in association with osteopenia being notably only detected in the AIS subjects. Further studies in this area are warranted for defining the metabolic nature and biomechanical sequelae of derangement in bone mass and bone quality and their roles in the etiopathogenesis of AIS. PMID- 23791203 TI - Description of Bacillus toyonensis sp. nov., a novel species of the Bacillus cereus group, and pairwise genome comparisons of the species of the group by means of ANI calculations. AB - Strain BCT-7112(T) was isolated in 1966 in Japan from a survey designed to obtain naturally occurring microorganisms as pure cultures in the laboratory for use as probiotics in animal nutrition. This strain, which was primarily identified as Bacillus cereus var toyoi, has been in use for more than 30 years as the active ingredient of the preparation TOYOCERIN((r)), an additive for use in animal nutrition (e.g. swine, poultry, cattle, rabbits and aquaculture). Despite the fact that the strain was initially classified as B. cereus, it showed significant genomic differences from the type strains of the B. cereus group that were large enough (ANI values below 92%) to allow it to be considered as a different species within the group. The polyphasic taxonomic study presented here provides sufficient discriminative parameters to classify BCT-7112(T) as a new species for which the name Bacillus toyonensis sp. nov. is proposed, with BCT-7112(T) (=CECT 876(T); =NCIMB 14858(T)) being designated as the type strain. In addition, a pairwise comparison between the available genomes of the whole B. cereus group by means of average nucleotide identity (ANI) calculations indicated that besides the eight classified species (including B. toyonensis), additional genomospecies could be detected, and most of them also had ANI values below 94%. ANI values were on the borderline of a species definition only in the cases of representatives of B. cereus versus B. thuringiensis, and B. mycoides and B. weihenstephanensis. PMID- 23791204 TI - Survey on the community and dynamics of lactic acid bacteria in Grana Padano cheese. AB - Grana Padano (GP) is a Protected Designation of Origin cheese made with raw milk and natural whey culture (NWC) that is characterised by a long ripening period. In this study, six GP productions were considered in order to evaluate the trend of microbial dynamics and compare lactic acid bacteria (LAB) population levels in cheeses during the entire cheese-making process. To reach this goal, for each GP production, samples of vat raw milk, NWC and cheeses at 48h, 2, 6, 9 and 13 months were subjected to plate counts and direct counts by fluorescence microscopy, as well as amplicon length heterogeneity-PCR (LH-PCR). Statistical analysis was applied to the results and ecological indices were estimated. It was demonstrated that the LAB able to grow in the cheese-environment conditions could arise from both raw milk and NWC. Starter lactobacilli (SLAB) from NWC were the main species present during acidification, and non-starter LAB (NSLAB), mainly from milk but also from NWC, were able to grow after brining and they dominated during ripening. The peak areas of LH-PCR profiles were used to determine ecological indices during manufacture and ripening. Among cheese ecosystems with different ageing times, diversity, Evenness and Richness were different, with highest bacterial growth and diversity occurring in cheese ripening at 2 months. At this time point, which seemed to be a crucial moment for GP microbial evolution, cell lysis of both SLAB and NSLAB was also observed. Sampling modality and statistical analysis gave greater significance to the results used to describe the microbiological characteristics of a cheese recognised worldwide. PMID- 23791205 TI - Major crush: a solitary fibrous pleural tumor. PMID- 23791206 TI - A brief, low-cost intervention improves the quality of ambulatory gastroenterology consultation notes. AB - BACKGROUND: Effective communication between primary care providers and specialty providers is important to facilitate high-quality specialty care. Few studies have assessed the quality of communication from specialist to primary care providers or implemented interventions to improve quality. We developed a brief, low-cost intervention designed to improve the quality of ambulatory gastroenterology consultation notes written by fellows and nurse practitioners in our urban health care system. METHODS: Six physicians (3 specialists and 3 primary care providers) scored pre- and postintervention notes using an objective quality assessment instrument that had excellent inter-rater reliability. They were blinded to note date, author, and pre/postintervention status. The primary outcome was improvement in Composite Quality Score, an objective, comprehensive assessment of quality. Secondary outcomes included improvements in 3 specific domains, and Global Quality Score (a subjective measure of quality). RESULTS: Two hundred pre- and 200 postintervention notes written by 6 fellows and 2 nurse practitioners were included. Composite Quality Score improved from 3.74 (of 5) to 4.09 (P <.001 in adjusted analysis). All secondary outcomes improved in adjusted analyses as well. The largest increase was seen in Communication Domain (22% increase). Fellow-written notes had higher scores than nurse practitioner-written notes, but nurse practitioner-written notes improved to a greater degree. CONCLUSION: A brief, low-cost intervention significantly improved the quality of ambulatory gastroenterology consultation notes written by fellows and nurse practitioners. Communication between primary care providers and specialists is an important area for further study. PMID- 23791207 TI - Capturing the diagnosis: an internal medicine education program to improve documentation. AB - BACKGROUND: Specific and accurate documentation of patient diagnoses and comorbidities in the medical record is critical to drive quality improvement and to ensure accuracy of publicly reported data. Unfortunately, inpatient documentation is taught to internal medicine trainees and practitioners sporadically, if at all. At Harbor-UCLA Medical Center, a public, tertiary care, academic medical center, we implemented an educational program to enhance documentation of diagnoses and comorbidities by internal medicine resident and attending physicians. METHODS: The program consisted of a series of lectures and the creation of a pocket card. These were designed to guide providers in accurate documentation of common diagnoses that group to different levels of disease severity, achieved by capturing Centers for Medicare and Medicaid Services complication codes and major complication codes. We started the educational program in January 2010 and used a pre-post design to compare outcomes. The program's impact on complication codes and major complication codes capture rates, mortality index, and case mix index was evaluated using the University Health Consortium database. RESULTS: The median quarterly complication codes and major complication codes capture rate for inpatients on the internal medicine service was 42% before the intervention versus 48% after (P = .003). Observed mortality did not change but expected mortality increased, resulting in a 30% decline in median quarterly mortality index (P = .001). The median quarterly case mix index increased from 1.27 to 1.36 (P = .004). CONCLUSIONS: Thus, implementation of an internal medicine documentation curriculum improved accuracy in documenting diagnoses and comorbidities, resulting in improved capture of complication codes. PMID- 23791208 TI - CD123 is a useful immunohistochemical marker to facilitate diagnosis of acute graft-versus-host disease in colon. AB - The efficacy of hematopoietic stem cell transplantation (HSCT) is greatly hampered by graft-versus-host disease (GVHD) and opportunistic infection; the gastrointestinal tract is one of the main target organs involved by GVHD and opportunistic infectious agents. The presence of crypt apoptosis is the major criterion for the histologic diagnosis of GVHD; however, it can also be seen in infection, especially cytomegalovirus (CMV) colitis. Therefore, the definitive histopathologic diagnosis of GVHD in gastrointestinal tract can be challenging or impossible without reliable ancillary markers. We studied the expression of CD123 and C4d in 38 colonic biopsies from patients with HSCT with acute GVHD and 14 colon biopsies from patients with CMV colitis without history of HSCT. CD123 expression was significantly increased in the acute GVHD group compared with the CMV group (65.8% versus 14.3%; P < .05) with increasing sensitivity in higher grade GVHD (grades 1-2, 60%; grades 3-4, 72.2%). However, there was no significant difference in C4d deposition between the acute GVHD and CMV groups (68.4% versus 42.9%; P > .05). We further applied CD123 immunostaining to upper gastrointestinal (n = 23) and colonic biopsies (n = 24) in patients with HSCT without evidence of acute GVHD or infection and 11 biopsies from patients who had used mycophenolate. The negative staining of CD123 in all these cases further supports the specificity of CD123 in acute GVHD. In summary, CD123 might be a useful ancillary marker to aid in separating infection from GVHD in patients with HSCT. PMID- 23791209 TI - Anaplastic ependymoma with ependymoblastic multilayered rosettes. AB - Anaplastic ependymoma, World Health Organization grade III, is a malignant glioma with ependymal differentiation characterized by high mitotic activity often accompanied by microvascular proliferation and necrosis, where, generally, much fewer ependymal rosettes are found than in ependymoma, World Health Organization grade II. Ependymal rosettes, forming a single layer of tumor cells, differ from ependymoblastic multilayered rosettes, which are characteristic histologic features of ependymoblastoma, a variant of central nervous system primitive neuroectodermal tumor. Here, we report an autopsy case involving a 24-year-old woman with a frontal lobe tumor, which showed the aggregation of true rosettes with multilayering of tumor cells resembling the ependymoblastoma histology. Molecular and cytogenetic analyses revealed the absence of 19q13.42 amplification, a specific molecular hallmark of ependymoblastoma and embryonal tumor with abundant neuropil and true rosettes, supporting the diagnosis of anaplastic ependymoma. PMID- 23791210 TI - Astrocytoma grade IV (glioblastoma multiforme) displays 3 subtypes with unique expression profiles of intermediate filament proteins. AB - Astrocytoma grade IV (glioblastoma multiforme) is the most common and most malignant tumor of the central nervous system and is currently noncurable. Here, we have examined a population-based cohort of 47 patients with grade IV astrocytoma, who underwent tumor surgery at Sahlgrenska University Hospital in Sweden and who survived after surgery for less than 200 days (short survivors, 28 patients) and more than 500 days (long survivors, 19 patients). For each tumor, we ascertained information on patient age, sex, tumor location, oncological treatment, and survival after surgery. The analysis of the tumor volume and the extent of tumor resection (incomplete versus complete resection of the macroscopic tumor) was made retrospectively from the preoperative radiological investigations and, when available, also from postoperative radiology. We performed semiquantitative immunohistochemical evaluation of the presence of intermediate filament (nanofilament) proteins glial fibrillary acidic protein, vimentin, nestin, and synemin in tumor cells. The intermediate filament system helps cells and tissues to cope with various types of stress, and thus, it might affect the malignant potential of grade IV astrocytoma. We propose a subclassification of astrocytomas grade IV with respect to the expression of the intermediate filament proteins glial fibrillary acidic protein, vimentin, nestin, and synemin, namely, type A, B, and C. Our results suggest that the expression of the intermediate filament proteins glial fibrillary acidic protein, vimentin, nestin, and synemin is coregulated in grade IV astrocytomas. The expression patterns of the intermediate filament proteins in astrocytoma type A, B, and C might have biological and clinical significance. PMID- 23791211 TI - Recurrent nephrogenic adenoma: a case report of resolution after treatment with antibiotics and nonsteroidal anti-inflammatory medication. AB - Nephrogenic adenoma is an uncommon urothelial lesion that has been associated with chronic inflammation and surgical manipulation of the urinary tract. Several cases of vesical nephrogenic adenoma in patients with a history of renal transplantation have been reported. The present case report reviewed the management of recurrent nephrogenic adenoma in a 6-year-old boy with history of renal transplantation 3 years before the diagnosis of nephrogenic adenoma. After multiple surgical resections for recurrent nephrogenic adenoma, the lesion finally resolved with long-term treatment with ibuprofen (Motrin) and trimethoprim and sulfamethoxazole (Septra). PMID- 23791212 TI - Current computed tomography techniques can detect duct of Bellini plugging but not Randall's plaques. AB - OBJECTIVE: To assess the ability of noninvasive computed tomography (CT) scans to detect interstitial calcium phosphate deposits (Randall's plaques) and duct of Bellini plugs, which are possible stone precursor lesions. METHODS: At time of percutaneous nephrolithotomy (PCNL) for stone removal, all accessible individual papillae of 105 patients were endoscopically visualized and video recorded. Image processing software was used to estimate the percentage of papillary surface occupied by plaque or plug in each pole (upper, middle, lower). The location of stones was also recorded. A radiologist blinded to the mapping results scored presurgical (n = 98) and postsurgical (n = 105) abdominal CT scans for the presence or absence of calcification by pole. RESULTS: The cohort was a mean age of 56 years (range, 23-84 years). Maximum papillary surface area of each area of the kidney occupied by plug correlated with CT calcifications on pre- and postprocedure images by rank sum test. However, maximum plaque surface area did not correlate with radiographic findings (P = .10-.90 for each pole by rank sum test). Sensitivity was 81% and specificity was 69% of CT to detect plugs of at least 1% of the papillary surface area. CONCLUSION: Calcifications seen on current generation clinical CT scans correspond to ductal plugging involving at least 1% of the papillary surface area. Current clinical CT scan technology appears inadequate for detecting Randall's plaques. PMID- 23791213 TI - Parenchymal volume preservation and ischemia during partial nephrectomy: functional and volumetric analysis. AB - OBJECTIVE: To determine the relative effect of type and duration of ischemia and parenchymal volume preservation on renal function after partial nephrectomy (PN). MATERIALS AND METHODS: Ninety-two patients with localized renal tumors (2007 2012) managed with PN at our center with necessary studies for analysis were included. This comprised 37 patients with a solitary kidney and 55 with a contralateral kidney. Thirty-five patients were managed with hypothermia and 57 with limited warm ischemia. Volumetric computed tomography was used to measure the volume of functional parenchyma before and after PN in the operated and contralateral kidneys. Glomerular filtration rate (GFR) was determined by the modification of diet in renal disease 2 equation, along with renal scan data for patients with a contralateral kidney. Regression analysis assessed the relationships between %GFR preserved in the operated kidney and potential predictive factors. All postoperative analyses were performed 4-12 months after surgery. RESULTS: Median age was 61 years, median tumor size 3.5 cm, and median RENAL nephrometry score 8. Median cold ischemia time was 28 minutes and median warm ischemia time 21 minutes. Median %GFR preserved in the operated kidney was 79%. Median %parenchymal volume saved was 83%. Function in the contralateral kidney only increased marginally (median increase 6%). On regression analysis, %GFR preserved associated most strongly with %parenchymal volume saved (P <.0001), but also with lower RENAL scores (P = .0457) and the use of hypothermia (P = .0209). In contrast, ischemia time did not correlate with %GFR preserved (P = .5051). CONCLUSION: Ultimate function after PN primarily correlated with parenchymal volume preservation, whereas ischemia played a secondary role. Thus, maximal parenchymal preservation with a precise PN should be a priority during PN. PMID- 23791214 TI - Brown tumor and staghorn calculi in primary hyperparathyroidism. AB - A case of primary hyperparathyroidism with bilateral renal staghorn calculi and brown tumor right thumb is reported in these images, along with the appropriate sequential management. Percutaneous nephrolithotomy (PCNL)was done after management of hypercalcemia and after parathyroidectomy. This case highlights the need for urologists and general practitioners to have a holistic approach in patient management. PMID- 23791215 TI - Two laser ablation techniques for a prostate less than 60 mL: lessons learned 70 months after a randomized controlled trial. AB - OBJECTIVE: To report lessons learned and predictors of long-term outcome after a randomized trial comparing 2 widely available lasers (2123 nm and 532 nm) in prostate ablation as treatment of symptomatic benign prostatic hyperplasia. METHODS: Between March 2005 and April 2007, 109 patients with a prostate volume of less than 60 mL were recruited and randomized to treatment: 57 underwent holmium laser ablation of the prostate (HOLAP) and 52 underwent photoselective vaporization of the prostate (PVP) using an 80-W potassium titanyl phosphate laser. The changes in subjective (International Prostate Symptom Score quality of life and International Index of Erectile Function-15) and objective (postvoid residual urine maximal flow rate) outcome parameters were compared. The long-term outcome, timing, and predictors of negative outcome were assessed. Cost analysis was included. RESULTS: After a median of 71.3 months, significant comparable improvement was documented in all subjective and objective urinary parameters from baseline measures at different points of follow-up. Retreatment for infravesical obstruction was 19.2% in HOLAP and 25% in PVP (P >.05). Smaller prostate volume was significantly associated with bladder neck contracture (BNC) after laser ablation, regardless the type of laser used. BNC and de novo urethral stricture seem to be the main causes for an early (first-year) reintervention. Redo treatment for recurring prostate adenoma was associated with less postoperative prostate-specific antigen reduction (<20%). Procedure costs were CaD $200.45 higher in the PVP group (P >.05). CONCLUSION: PVP and HOLAP seem to be equally effective and safe, with similar long-term outcome data, including cost. Regardless the laser wavelength, at least 1 of 5 patients will need retreatment. BNC is a more prevalent cause of early retreatment in smaller glands with both lasers. Postoperative prostate-specific antigen reduction of less than 20% warrants careful follow-up for recurrent symptoms secondary to residual prostate tissue. PMID- 23791216 TI - Editorial comment. PMID- 23791217 TI - Differences in 24-hour urine composition between apatite and brushite stone formers. AB - OBJECTIVE: To determine the differences in 24-hour urine composition between apatite and brushite stone formers. METHODS: We conducted a retrospective review of 110 calcium phosphate (CaP) stone formers with both stone composition analysis and 24-hour urinalysis available. Analysis of 24-hour urine constituents between apatite and brushite stone formers was performed using univariable t test and multivariable linear regression models, adjusting for clinical and demographic factors. RESULTS: A total of 97 patients (88%) had predominantly apatite stones and 13 patients (12%) had predominantly brushite stones. In univariable analysis, brushite stone formers had significantly higher mean 24-hour urinary calcium excretion (apatite = 204.8 +/- 103.5 mg vs brushite = 329.7 +/- 136.6 mg, P = .007), higher mean super saturation (SS) CaP (apatite = 1.423 +/- 0.867 vs brushite = 2.576 +/- 0.171, P = .004) and lower mean SS uric acid (apatite = 0.688 +/- 0.796 vs brushite = 0.345 +/- 0.190, P <.001). Similarly in multivariable analysis, brushite stone formers had significantly higher mean 24 hour urinary calcium excretion (mean difference = 135.1 mg, P <.001) and higher mean SS CaP (mean difference = 1.14, P <.001) but similar mean SS uric acid (mean difference = -0.37, P = .103). All other factors analyzed including body-mass index, urinary pH, volume, oxalate, citrate, sodium, potassium, magnesium, phosphate, chloride, ammonium, sulfate, uric acid, and SS calcium oxalate were similar between both stone groups. CONCLUSION: In a cohort of CaP stone formers, brushite stones were associated with higher urinary calcium excretion and higher urinary SS CaP when compared to apatite stones. Aggressive measures to reduce urinary calcium may be particularly helpful to prevent brushite stone formation. PMID- 23791218 TI - Prospective analysis of the surgical outcomes and patients' satisfaction rate after the AMS Spectra penile prosthesis implantation. AB - OBJECTIVE: To evaluate the outcomes, the patients', and their partners' satisfaction concerning the AMS Spectra penile prosthesis implantation. METHODS: Twenty-two unresponsive or dissatisfied patients with phosphodiesterase 5 inhibitor oral therapy or prostaglandin intracavernous injection underwent a Spectra penile prosthesis implantation. No major intraoperative or postoperative complications were observed. The preoperative erectile dysfunction (ED) was rated by the International Index of Erectile Function (IIEF) questionnaire. The patients and their partners were submitted to the IIEF and Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) questionnaires through telephonic interviews at the third, sixth, and 12th months after the penile surgery. RESULTS: This study demonstrates that 86.4% of the patients and 52.6% of their partners are satisfied by the AMS Spectra penile prosthesis. The preoperative average IIEF score was equal to 28.5 (range 13-39). The postoperative IIEF rates were 47.7 (43-53), 51.8 (48-58), and 53.9 (50-58) at the third, sixth, and 12th months, respectively. The patient average EDITS score amounted to 39.5 (31-48), 43.4 (36-50), and 45.2 (38-50) at the third, sixth, and 12th months, respectively. The increase between the preoperative and postoperative IIEF parameters resulted to be statistically significant (P <.05) as well as the increase in EDITS at the third, sixth, and 12th months postoperatively. CONCLUSION: The AMS Spectra is a reliable device to treat ED as shown by the high grade of the patients' satisfaction. Moreover, the AMS Spectra is highly convenient in terms of cost savings in comparison to an inflatable device. In selected patients, this prosthesis should be considered as an effective solution to treat severe ED. PMID- 23791221 TI - Systemic absorption and pharmacokinetics of single-dose early intravesical mitomycin C after transurethral resection of non-muscle-invasive bladder cancer. AB - OBJECTIVE: To study the systemic absorption and pharmacokinetics of a single dose of intravesical mitomycin C (MMC) given immediately after transurethral resection of bladder tumor (TURBT). METHODS: Fourteen patients with primary or recurrent non-muscle-invasive bladder cancer were eligible for a single early intravesical instillation of MMC (40 mg in 50 mL distilled water) administered immediately after TURBT. Blood samples were obtained at baseline and at 20, 40, 60 (time of voiding), 90, 120, and 150 minutes after instillation. Concentrations of the drug were determined by validated high-performance liquid chromatography assay. During TURBT, we counted the number of excursions of the resecting loop required to completely eradicate the tumor, including a portion of the underlying muscular wall. TURBTs were categorized as small and large, defined as requiring <=6 or >6 full excursions of the resecting loop, respectively. RESULTS: Maximal MMC plasma concentrations were reached 40 minutes after instillation. At 150 minutes, only minimal drug plasma levels were detectable in 4 patients. The highest plasma peak was 49.25 ng/mL. In the first samples, at 20 minutes after instillation, the plasma concentration of MMC was significantly correlated with the extent of TURBT (P = .026). Four patients (28.6%) complained of G1 side effects, 3 after a large TURBT and 1 after a small TURBT, and 1 patient had G2 dysuria after a large TURBT. CONCLUSION: Low peak blood levels of MMC are observed after a single-dose intravesical instillation immediately after TURBT, with low systemic and local toxicity. The early absorption rate depends on TURBT extension. PMID- 23791222 TI - Editorial comment. PMID- 23791223 TI - Characterization of enterovirus 71 and coxsackievirus A16 isolated in hand, foot, and mouth disease patients in Guangdong, 2010. AB - BACKGROUND: Hand, foot, and mouth disease (HFMD) is an acute viral disease caused by human enteroviruses, especially human enterovirus 71 (HEV71) and coxsackievirus A16 (CVA16), and mainly affects infants and young children. After the outbreak in 2008 in Fuyang, China, HFMD was classified as a category C notifiable infectious disease by the Ministry of Health of China. METHODS: In this study, we report the epidemiologic and clinical manifestations of HFMD in Guangdong Province, China in 2010, and characterize HEV71 and CVA16 isolated from clinical specimens. RESULTS: Among the 542 HFMD patients, 495 (91.3%) were positive for enterovirus as detected by real-time reverse transcriptase PCR; 243 were positive for HEV71 (49.1%, 243/495) and 114 were positive for CVA16 (23.0%, 114/495). Most of the affected children were aged 5 years or under (93.7%, 508/542). Phylogenetic analyses of VP1 gene sequences showed that the HEV71 isolates belonged to C4a subgenotype, and CVA16 isolates belonged to B1 genotype. CONCLUSIONS: Our results demonstrate that HEV71 and CVA16 are the primary causative agents responsible for HFMD in Guangdong Province, and their co circulation poses a potential risk to public health. PMID- 23791224 TI - Cutaneous Cryptococcus laurentii infection in an immunocompetent child. AB - Cryptococcus laurentii is an extremely rare human pathogen. We report a case of primary cutaneous cryptococcosis caused by Cryptococcus laurentii in an immunocompetent patient, an 8-year-old child with a solitary lesion on the forearm. It was impossible to determine the source of infection and no predisposing factors were found. Oral treatment with fluconazole was totally successful. A review of the literature showed only three cases of cutaneous infection by Cryptococcus laurentii. All of the cases occurred in immunocompromised patients. To the best of our knowledge, this is the first case of Cryptococcus laurentii in an immunocompetent host. PMID- 23791225 TI - Infections associated with religious rituals. AB - This review evaluates the medical literature for religious rituals or ceremonies that have been reported to cause infection. These include an ultra-orthodox Jewish circumcision practice known as metzitzah b'peh, the Christian common communion chalice, Islamic ritual ablution, and the Hindu 'side-roll'. Infections associated with participation in the Islamic Hajj have been extensively reviewed and will not be discussed. PMID- 23791227 TI - Crimean-Congo hemorrhagic fever virus utilizes a clathrin- and early endosome dependent entry pathway. AB - The early events in Crimean-Congo hemorrhagic fever virus (CCHFV) have not been completely characterized. Earlier work indicated that CCHFV likely enters cells by clathrin-mediated endocytosis (CME). Here we provide confirmatory evidence for CME entry by showing that CCHFV infection is inhibited in cells treated with Pitstop 2, a drug that specifically and reversibly interferes with the dynamics of clathrin-coated pits. Additionally, we show that CCHFV infection is inhibited by siRNA depletion of the clathrin pit associated protein AP-2. Following CME entry, we show that CCHFV has a pH-dependent entry step, with virus inactivation occurring at pH 6.0 and below. To more precisely define the endosomal trafficking of CCHFV, we show for the first time that overexpression of the dominant negative forms of Rab5 protein but not Rab7 protein inhibits CCHFV infection. These results indicate that CCHFV likely enters cells through the early endosomal compartment. PMID- 23791226 TI - Elevated hypermutation levels in HIV-1 natural viral suppressors. AB - Mutations in the HIV-1 proviral genomes delay the progression of the disease. We compared the mutation status in full-length proviral genomes of 23 HIV-infected patients with undetectable viral loads in the absence of therapy named natural viral suppressors (NVS) or Elite Controllers with 23 HIV-infected controls (10 patients on HAART treatment and 13 untreated patients). Provirus DNA was extracted from PBMC for amplification and sequencing to determine the mutation status. Nine (39 %) of the 23 NVS patients had defective proviral genomes, compared to 4 of the treated controls (40%, p = 0.96) and only one of the untreated controls (8%, p = 0.059). Most of the defective genomes resulted from Gto-A hypermutation. Among patients with hypermutation, the rate ratio for mutation was significantly higher for the NVS compared to treated controls (p = 0.043). Our data suggests that inactivation of the virus through the APOBEC3G system may contribute to the NVS phenotype. PMID- 23791228 TI - Adsorption of phenolic compounds by organoclays: implications for the removal of organic pollutants from aqueous media. AB - Montmorillonite (MMT) was converted to organoclays by intercalation of cationic surfactants into its interlayer space. Two types of organoclays were prepared from different surfactants (DDTMA and DDDMA) at different surfactant loadings, and the structural changes in the clays investigated using various techniques. The arrangements of surfactant molecules in the interlayer space was visually aided by molecular mechanical calculation (MM calculation), and the adsorption capacities of MMT and the organoclays for the removal of p-chlorophenol (PCP) and p-nitrophenol (PNP) from aqueous solutions were tested under different conditions. Two adsorption isotherm models (Langmuir and Freundlich isotherms) were used to determine the best fit model and the Freundlich isotherm was found to provide better fit for both PCP and PNP. Due to its hydrophobic properties, the adsorption is more favourable for PNP than PCP. Overall, the adsorption capacity of the organoclays was significantly improved by intercalation with large surfactant molecules as well as highly loaded surfactants as the intercalation with large surfactant molecules created the partitioning phase, which strongly attracted large amounts of organic pollutants. Possible mechanisms and the implications of the results for the use of these organoclays as adsorbents for the removal of phenols from the environment are discussed. PMID- 23791229 TI - Surface complexation modeling and spectroscopic evidence of antimony adsorption on iron-oxide-rich red earth soils. AB - Few studies have investigated surface complexation of antimony (Sb) on natural sorbents. In addition, intrinsic acidic constants, speciation, and spectroscopic data are scarce for Sb sorption in soil. Only simple sorption models have been proposed to describe the sorption of Sb(V) on specific mineral surfaces. This study therefore assessed the mechanisms of Sb(III) and Sb(V) adsorption on natural red earth (NRE), a naturally occurring iron coated sand, at various pHs and Sb loadings. The Sb(V) adsorption followed typical anion adsorption curve with adsorption reaching maximum around pH 4-5, while no pH dependence was observed for Sb(III) sorption. The FT-IR spectra revealed that shifts in absorbance of the hydroxyl groups in iron-oxide were related to the Fe-O-Sb bonds and provided evidence for inner sphere bond formation. Direct evidence on the strong interaction of Sb(III) and Sb(V) with =Fe-O and =Al-O was observed from the decrease in Fe-2p, Al-2p, and Si-2p peaks of the X-ray photoelectron spectroscopy (XPS) data before and after Sb(V) and Sb(III) adsorption on NRE. Successful data modeling using the 2-pK diffuse double layer model (DDLM) with the FITEQL revealed that sorption occurs through the formation of bidentate mononuclear and binuclear complexes. Model simulations showed a high affinity to the =FeOH sites at high Sb loadings, whereas at low loadings, both= FeOH and =AlOH sites showed similar affinities to Sb. In the case of Sb(V), multilayer formation was also revealed in addition to surface complexation by the isotherm data fitted with the Freundlich model and two sites Langmuir equations, which indicated heterogeneous multilayer adsorption of Sb(V) on NRE. PMID- 23791230 TI - Influence of the organization of water-in-ionic liquid microemulsions on the size of silver particles during photoreduction. AB - Metal particles of silver (Ag) have been synthesized by the photoreduction of silver nitrate (AgNO3) in water-in-ionic liquid (IL) microemulsions consisting of nonionic surfactant Tween 20 or Triton X-100, water and ionic liquid, 1-octyl-3 methylimidazolium hexafluorophosphate ([OMIm][PF6]). The formation of microemulsions as well as Ag particles produced by the photoreduction has been investigated by UV-vis, cryo-TEM, small-angle X-ray scattering (SAXS), and extended X-ray absorption fine structure (EXAFS) measurements. At the early stage of Ag particle formation under ambient pressure, the size of Ag particles in water/[OMIm][PF6]/TX-100 microemulsions was slightly larger than that in water/[OMIm][PF6]/Tween20 microemulsions. With an increase in photoirradiation time beyond 30 min, precipitation of larger Ag aggregates occurred. In contrast to the preparation under ambient pressure, the growth of Ag particles and aggregates was suppressed in preparing under high pressure (25 MPa) of CO2, leading to no precipitation of Ag aggregates. The average diameters of the finally-obtained metallic Ag particles prepared under high pressure of CO2 in water/[OMIm][PF6]/Tween20 and water/[OMIm][PF6]/TX-100 microemulsions were estimated from cryo-TEM to be 3.7 nm and 2.8 nm, respectively. By using Guinier plots at q (<0.16 nm(-1)), it was demonstrated that the diameter of the water droplets during Ag particle formation under high pressure of CO2 remained unchanged in the range of 33-37 nm due to their higher stability compared to water droplets, whereas under ambient pressure the diameter drastically increases from 28 nm to 40 nm during the first 60 min of photoirradiation, resulting in the precipitation of larger Ag aggregates, especially in the case of water/[OMIm][PF6]/Tween20 microemulsions. PMID- 23791231 TI - Hybrid thiol-ene network nanocomposites based on multi(meth)acrylate POSS. AB - First, multi(meth)acrylate functionalized POSS monomers were synthesized in this paper. Secondly, FTIR was used to evaluate the homopolymerization behaviors of multi(meth)acrylate POSS and their copolymerization behaviors in the thiol-ene reactions with octa(3-mercaptopropyl) POSS in the presence of photoinitiator. Results showed that the photopolymerization rate of multimethacrylate POSS was faster than that of multiacrylate POSS. The FTIR results also showed that the copolymerizations were dominant in the thiol-ene reactions with octa(3 mercaptopropyl) POSS, different from traditional (meth)acrylate-thiol system, in which homopolymerizations were predominant. Finally, the resulted hybrid networks based on POSS were characterized by XRD, FE-SEM, DSC, and TGA. The characterization results showed that hybrid networks based on POSS were homogeneous and exhibited high thermal stability. PMID- 23791232 TI - Very early feeding in stable small for gestational age preterm infants: a randomized clinical trial. AB - OBJECTIVE: To examine the effect of initiating very early feeding on time-to reach full feeding in stable, small for gestational age (SGA) preterm infants. METHOD: Preterm infants with gestational age below 37 weeks and birth weight below the 10(th) percentile were randomly allocated to a very early (within 24 hours of birth) feeding regimen or delayed (after 24 hours of birth) feeding. All infants had in utero evidence of absent or reverse diastolic flow. Infants unable to start early feeding were excluded. Time-to-reach full feeding, feeding progression, and related morbidity were compared. Electrogastrography (EGG) was used to measure pre- and postprandial gastric motility on the second and seventh day after feeding initiation. RESULTS: Sixty infants were included in the study, 30 in each group. Infants included in the very early feeding regimen achieved full enteral feeding sooner than controls (98+/-80-157 vs. 172+/-123-261 hours of age, respectively; p= 0.004) and were discharged home earlier (p=0.04). No necrotizing enterocolitis (NEC) was documented in both study groups. Gastric motility was improved at day seven after feeding initiation in both study groups, with no difference between groups. CONCLUSIONS: Stable SGA preterm infants on a very early feeding regimen achieved full enteral feeding and were discharged home significantly earlier than those on a delayed regimen, with no excess morbidity. PMID- 23791233 TI - Association of uric acid levels with components of metabolic syndrome and non alcoholic fatty liver disease in overweight or obese children and adolescents. AB - OBJECTIVE: To investigate the association between serum uric acid concentration according to the presence or absence of non-alcoholic fatty liver disease (NAFLD) and/or metabolic syndrome (MS) in overweight or obese children and adolescents. METHODS: This was a cross-sectional study conducted from April of 2009 to March of 2010, including 129 children and adolescents treated at the Center for Childhood Obesity. Anthropometric data, blood pressure measurements, and laboratory test results were obtained, and NAFLD diagnosis was made by ultrasound. The diagnosis of MS was made using the criteria of the National Cholesterol Education Program/Adult Treatment Panel III, adapted to age range. The chi-squared test or or Fisher's test were used to evaluate the association of uric acid with the groups, with a 95% confidence interval. One-way analysis of variance (ANOVA) was used for comparison of means. Multiple logistic regression was used for adjustment of variables. The data were analyzed with the Statistical Package for Social Sciences (SPSS), release 17. RESULTS: High levels of uric acid were significantly associated with adolescence, MS, and systolic blood pressure. The highest quartile of uric acid showed significantly higher values of body mass index, waist circumference, systolic blood pressure, diastolic blood pressure, triglycerides, total cholesterol, and homeostatic model assessment index (HOMA IR), and lower mean values of HDL cholesterol. In the final model, only age range and the presence of MS remained associated with uric acid levels. CONCLUSIONS: High levels of uric acid were associated with MS and adolescence, which was not observed with NAFLD. PMID- 23791234 TI - Increasing the knowledge base of ocular allergy epidemiology. PMID- 23791235 TI - Effects of human milk fortifier with iron on the bacteriostatic properties of breast milk. AB - OBJECTIVE: To compare bacterial growth in pure colostrum versus colostrum with human milk fortifier (HMF) containing iron. METHODS: The growth of Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa in 78 samples of pure colostrum or colostrum with added iron-containing HMF was compared. For qualitative analysis, filter paper discs were immersed in samples from each group and incubated for 48 hours with 10(1) colony forming units (CFUs)/mL of each strain. For quantitative assessment, 1 mL of each strain containing 10(7) CFUs/mL was homogenized with 1 mL of either colostrum or colostrum with human milk fortifier, seeded into a Petri dish, and incubated at 37 degrees C. Twenty-four hours later, the number of CFUs was counted. RESULTS: The qualitative analysis showed no difference in bacterial growth. In the quantitative evaluation, E. coli growth in the control group was 29.4+/-9.7*10(6)CFU/mL, while in the HMF group it was 31.2+/-10.8*10(6)CFU/mL. The difference between the average growth was 1.9+/ 4.9*10(6)CFU/mL (p=0.001). There were no differences in S. aureus and P. aeruginosa growth. CONCLUSION: Addition of iron at this concentration reduces breast milk bacteriostatic action against E. coli. PMID- 23791236 TI - Breastfeeding and postpartum depression: state of the art review. AB - OBJECTIVE: To review the literature on the association between breastfeeding and postpartum depression. SOURCES: A review of literature found on MEDLINE/PubMed database. SUMMARY OF FINDINGS: The literature consistently shows that breastfeeding provides a wide range of benefits for both the child and the mother. The psychological benefits for the mother are still in need of further research. Some studies point out that pregnancy depression is one of the factors that may contribute to breastfeeding failure. Others studies also suggest an association between breastfeeding and postpartum depression; the direction of this association is still unclear. Breastfeeding can promote hormonal processes that protect mothers against postpartum depression by attenuating cortisol response to stress. It can also reduce the risk of postpartum depression, by helping the regulation of sleep and wake patterns for mother and child, improving mother's self-efficacy and her emotional involvement with the child, reducing the child's temperamental difficulties, and promoting a better interaction between mother and child. CONCLUSIONS: Studies demonstrate that breastfeeding can protect mothers from postpartum depression, and are starting to clarify which biological and psychological processes may explain this protection. However, there are still equivocal results in the literature that may be explained by the methodological limitations presented by some studies. PMID- 23791237 TI - Epidemiology of ocular allergy and co-morbidities in adolescents. AB - OBJECTIVE: The prevalence of allergic conjunctivitis (AC) has not been established. Estimates suggest that ocular allergies affect 15% to 20% of the worldwide population, yet most epidemiological studies encompass nasal and ocular allergy symptoms and have not been specific to AC. The aim of this study was to verify the prevalence of ocular allergy symptoms, co-morbidities, and their impact on adolescents. METHODS: Adolescents were selected from a sample of schools, and completed in classrooms a previously validated questionnaire on symptoms of AC. AC diagnosis was considered when more than three episodes of ocular itching were reported in the past 12 months. Related symptoms such as tearing, photophobia, foreign body sensation, impact on daily activities, and diagnosis of AC were analyzed. RESULTS: Questionnaires were obtained from 3,120 adolescents (mean age 13.3+/-1.1 years). Ocular itching in the past 12 months occurred in 1,592 (51%). The most frequently associated symptom was tearing (74%), followed by photophobia (50.1%) and foreign body sensation (37.1%). The prevalence of AC was 20.7%, affecting more females than males (56.1% versus 45.9%; p= 0.01). The risks of an adolescent with ocular allergy to present asthma, rhinitis, and atopic eczema were (OR= 5.7; 95% CI: 4.5 to 7.1), (OR=3.6; 95% CI: 3.0 to 4.3), and (OR=2.6; 95% CI: 2.0 to 3.5), respectively. Severe interference in daily activities was reported by 30.5%. CONCLUSIONS: Symptoms of ocular allergy are common, frequently associated to other allergic diseases, and impact the daily activities of adolescents. PMID- 23791238 TI - Artificial spores: cytoprotective nanoencapsulation of living cells. AB - In this Opinion we discuss the development of artificial spores and their maturation as an independent field of research. The robust cell-in-shell structures have displayed unprecedented characteristics, which include the retardation of cell division and extensive cytoprotective capabilities that encompass exposure to osmotic pressure, shear force, heat, UV radiation, and lytic enzymes. Additionally, the nanothin shells act as highly versatile scaffolds for chemical functionalization to equip cells for implementation in tissue engineering, biosensors, cell therapy, or other biotechnological applications. We also explore the future direction of this emerging field and dictate that the next phase of research should focus on attaining more intricate engineering to achieve stimulus-responsive shell-degradation, multilayer casings with orthogonal functions, and the encapsulation of multiple cells for multicellular artificial spores. PMID- 23791239 TI - Rapid FTIR chemical imaging: highlighting FPA detectors. AB - Fourier transform infrared (FTIR) spectroscopy is an established analytical technique that measures molecular bond vibrations via infrared absorption. The technique traditionally obtains single spectra from a sample, averaging the absorption information over a pre-determined aperture size. However, this averaging of information can be detrimental to pure biochemical analysis. The coupling of focal plane array (FPA) detectors to conventional FTIR systems and recent technical advances in FPA technology have allowed the concurrent rapid collection of thousands of infrared spectra over large areas of a sample, which has been particularly useful in tissue analysis. This novel technique presents a strong case for its use as a potential tool to aid in the clinic for disease diagnosis and assessment. PMID- 23791240 TI - Pinealectomy in a broiler chicken model impairs endochondral ossification and induces rapid cancellous bone loss. AB - BACKGROUND CONTEXT: Adolescent idiopathic scoliosis (AIS) in humans is a lateral curvature of the spine often associated with osteopenia. It has recently been accepted that the development of AIS is closely associated with spinal overgrowth. Pinealectomy (PNX) in a chicken model consistently induces scoliosis with anatomic features similar to human AIS; however, the mechanism of PNX inducing scoliosis is poorly understood. PURPOSE: This experimental study attempts to improve the understanding of the mechanisms underlying the onset of scoliosis in a PNX broiler chicken model. METHODS: A histomorphometric study was performed to analyze longitudinal bone growth and cancellous bone remodeling before the development of scoliosis. Static and dynamic parameters in cancellous bone and chondro-osseous junction of the 7th thoracic vertebral body at 9 days after hatching were compared between PNX chickens (n=9) and control chickens with no surgery (n=5). RESULTS: PNX resulted in a rapid and marked loss of cancellous bone volume (7.9+/-0.9% vs. 14.2+/-1.8%, mean+/-SD, p<.0005) and profoundly disrupted trabecular structure with increases in dynamic formative parameters, such as mineralizing surface, mineralization apposition rate, and adjusted appositional rate. In the chondro-osseous junction, activated osteoclasts phagocytized degenerating chondrocytes, leaving a minimal amount of cartilage matrix and activated osteoblasts, losing their scaffolding for bone formation, and directly covering the hypertrophic zone cells. The osteoid surface and thickness in the chondro-osseous junction were significantly increased in PNX chickens (43.1+/-14.2% vs. 11.6+/-5.7% and 4.1+/-0.2 MUm vs. 2.9+/-0.4 MUm). In the subjacent cartilage regions being protected from further resorption, abundant labeled cartilage remained with higher cellularity. CONCLUSIONS: It is known that fast-growing birds have a unique paradigm of rapid bone elongation with minimal metaphyseal bone production. A bone-forming surface exists at the front of cartilage ossification in the growth plate; therefore, papillae of hypertrophic chondrocytes become included between the trabeculae of metaphyseal bone and the overall thickness of the growth plate increases considerably in addition to distal expansion. Our results indicate that the unique mechanism for rapid bone elongation in chicken is more pronounced after PNX. PNX also induces high turnover osteoporosis, which may also contribute to the development of scoliosis in the chicken. PMID- 23791241 TI - New strategy toward dioxin risk reduction for local residents surrounding severe dioxin hotspots in Vietnam. AB - BACKGROUND: A public health intervention program with active involvement of local related stakeholders was piloted in the Bien Hoa dioxin hotspot (2007-2009), and then expanded to the Da Nang dioxin hotspot in Vietnam (2009-2011). It aimed to reduce the risk of dioxin exposure of local residents through foods. This article presents the results of the intervention in Da Nang. METHODOLOGY: To assess the results of this intervention program, pre- and post-intervention knowledge, attitude, and practice (KAP) surveys were implemented in 400 households, randomly selected from four wards surrounding the Da Nang Airbase in 2009 and 2011, respectively. RESULTS: After the intervention, the knowledge on the existence of dioxin in food, dioxin exposure pathways, potential high-risk foods, and preventive measures significantly increased (P<0.05). Ninety-eight percent were willing to follow advice on preventing dioxin exposure. Practices to reduce the risk of dioxin exposure also significantly improved (P<0.05). After intervention, 60.4% of households undertook exposure preventive measures, significantly higher than that of the pre-intervention survey (39.6%; chi(2)=40.15, P<0.001). High risk foods had quite low rates of daily consumption (from 0 to 2.5%) and were significantly reduced (P<0.05). CONCLUSIONS: This is seen as an effective intervention strategy toward reducing the risk of human exposure to dioxin at dioxin hotspots. While greater efforts are needed for remediating dioxin-polluted areas inside airbases, there is also evidence to suggest that, during the past four decades, pollution has expanded to the surrounding areas. For this reason, this model should be quickly expanded to the remaining dioxin hotspots in Vietnam to further reduce the exposure risks in other areas. PMID- 23791242 TI - Idiopathic pulmonary fibrosis: importance of accurate diagnosis and treatment. PMID- 23791243 TI - Chondroid chordoma in an atypical location. AB - Chondroid chordoma is an extremely rare tumour with an annual incidence of around 0.1 cases per 100,000population. Involvement of the thoracic vertebrae may be present in 2-5% of cases. Definitive diagnosis usually requires a suitable distinction between this and other mesenchymal tumours such as chondrosarcomas, so immunohistochemical analysis is virtually mandatory. In spite of its slow growing nature, chondroid chordoma tends to relapse, and it may eventually become malignant, often jeopardising the patient's prognosis. Although surgery remains the main therapeutic approach, research into the molecular and genetic aspects of this tumour is ongoing. These new advances are likely to improve future oncology therapies by complementing surgery and radiotherapy, changing the currently poor prognosis. We report the case of a patient with a chondroid chordoma involving the thoracic vertebrae and pleural cavity, and the treatment performed. PMID- 23791244 TI - Volatile organic compounds in exhaled breath in a healthy population: effect of tobacco smoking. AB - INTRODUCTION: Tobacco smoke is a source of free radicals and reactive oxygen and nitrogen species, which are the main causes of oxidative stress. The analysis of volatile organic compounds (VOC) in exhaled breath is an indirect method of measuring the level of oxidative stress that occurs in the airways caused by tobacco consumption. The aim of this study was to determine whether smoking influences the production of VOC, in a clinically healthy population. METHODS: Exhaled breath from 89 healthy volunteers, divided into three groups (non smokers, ex-smokers and smokers) was analysed. Samples were collected using Bio VOC(r) devices and transferred to universal desorption tubes. Chemical compounds were analysed by thermal desorption, gas chromatography and mass spectrometry. We analysed hexanal, heptanal, octanal, nonanal, nonanoic acid and propanoic acid, all identified by retention time and mass spectra referenced in the NIST 08 mass spectral library; confirmation was carried out using reference standards of the pure chemical compound. RESULTS: These VOC were found in very low concentrations. Only nonanal showed significant quantitative and qualitative statistical differences among the study groups. Nonanal concentration is dependent on smoking, but is independent of the amount of tobacco consumed, age and gender. CONCLUSIONS: Nonanal in exhaled breath is associated with tobacco consumption, current or previous. Nonanal is a sub-product of the destruction of the cell membrane, and its finding may be indicative of cell damage in smokers. This result appears in many farmers who smoke. PMID- 23791245 TI - Diagnosis of non-nodal paratracheobronchial lesions by linear endobronchial ultrasound. AB - Linear endobronchial ultrasound (EBUS) allows samples of lesions close to the airways to be obtained, as it enables aspiration to be performed under visual control in real time, opening new possibilities for minimally invasive examination of the mediastinum. While there are many publications on its usefulness in the study of mediastinal or hilar lymphadenopathies, there are few that analyse the role of EBUS-guided transbronchial needle aspiration for the diagnosis of other lesions adjacent to the airways or digestive tract. We describe the characteristics and results obtained in a series of 26 cases of non nodal lesions of different aetiologies studied by EBUS- guided transbronchial needle aspiration through the airways or oesophagus, demonstrating the usefulness and safety of this technique in the diagnosis of these types of lesions. PMID- 23791246 TI - Acute kidney injury and death associated with renin angiotensin system blockade in cardiothoracic surgery: a meta-analysis of observational studies. AB - BACKGROUND: Acute kidney injury (AKI) is a common complication after cardiovascular surgery. The use of renin angiotensin system (RAS) blockers preoperatively is controversial due to conflicting results of their effect on the incidence of postoperative AKI and mortality. STUDY DESIGN: Meta-analysis of prospective or retrospective observational studies (1950 to January 2013) using MEDLINE, EMBASE, the Cochrane Library, conferences, and ClinicalTrials.gov, without language restriction. SETTING & POPULATION: Patients undergoing cardiovascular surgery. SELECTION CRITERIA FOR STUDIES: Retrospective or prospective studies evaluating the effect of preoperative use of RAS blockers in the development of postoperative AKI and/or mortality in adult patients. INTERVENTION: Preoperative use of RAS blockers. RAS-blocker use was defined as long-term use of either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers until the day of surgery. OUTCOMES: The primary outcome was the development of postoperative AKI; the secondary outcome was mortality. AKI was defined by different authors using different criteria. Death was ascertained in the hospital, at 30 days, or at 90 days in different studies. RESULTS: 29 studies were included (4 prospective and 25 retrospective); 23 of these involving 69,027 patients examined AKI, and 18 involving 54,418 patients studied mortality. Heterogeneity was found across studies regarding AKI (I2 = 82.5%), whereas studies were homogeneous regarding mortality (I2 = 20.5%). Preoperative RAS blocker use was associated with increased odds for both postoperative AKI (OR, 1.17; 95% CI, 1.01-1.36; P = 0.04) and mortality (OR, 1.20; 95% CI, 1.06-1.35; P = 0.005). LIMITATIONS: Lack of randomized controlled trials, different definitions of AKI, different durations of follow-up used to analyze death outcome, and inability to exclude outcome reporting bias. CONCLUSIONS: In retrospective studies, preoperative use of RAS blockers was associated with increased odds of postoperative AKI and mortality in patients undergoing cardiovascular surgery. A large, multicenter, randomized, controlled trial should be performed to confirm these findings. PMID- 23791247 TI - Nutraceuticals for older people: facts, fictions and gaps in knowledge. AB - In the last decades nutraceuticals have entered the health market as an easy and attractive means of preventing diseases. These products are of interest for an increasingly health-concerned society and may be especially relevant for preventing or delaying a number of age-related diseases, i.e. arthritis, cancer, metabolic and cardiovascular diseases, osteoporosis, cataracts, brain disorders, etc. Nutraceuticals are marketed in a variety of forms, composition and potential applications which have made their definition ambiguous and their use uncontrolled and poorly funded. Although epidemiological, animal and in vitro studies have given evidence of the potential benefits of some of these nutraceuticals or of their components, definitive proof of their effects in appropriate human clinical trials is still lacking in most cases, more critically among people above 65 years of age. We cover the well-established nutraceuticals (polyvitamins, omega-3 fatty acids, etc.) and will focus on many other 'novel' commercial nutraceuticals where the scientific evidence is more limited (food extracts, polyphenols, carotenoids, etc.). Solid scientific evidence has been reported only for a few nutraceuticals, which have some health claims approved by the European Food Safety Authority (EFSA). Further well-designed trials are needed to improve the current knowledge on the health benefits of nutraceuticals in the elderly. Overall, there are some facts, a lot of fiction and many gaps in the knowledge of nutraceutical benefits. PMID- 23791248 TI - Post-traumatic amnesia. AB - Of patients hospitalised for traumatic brain injury (TBI), most pass through a state of altered consciousness known as "post-traumatic amnesia" (PTA). Despite the lack of a consistent definition, PTA is widely used as a construct in neurosurgical practice to guide decision-making and prognosis. Accurate PTA assessment is important, because over-evaluation leads to excess social, financial and opportunity costs, whilst under-evaluation risks patient welfare. Whilst anterograde memory is certainly disrupted in PTA, PTA in fact involves a far more extensive memory disturbance. More instructively, the complete "post-TBI syndrome" also comprises an extensive cognitive deficit which includes a confusional state, as well as a behavioural disturbance characterised by acute agitation. Recently, impairments in attention and executive functioning have also been emphasised; indeed, some consider these the primary disturbance with PTA. Although all of these features were fully described (or implied) by the earliest pioneers, most current PTA scores do not assess the complete "post-TBI syndrome". Currently, the Westmead PTA scale (WPTAS) directs most in-hospital TBI management throughout Australasia: however, in addition to general defects, specific limitations have been identified in the levels of evidence for WPTAS validity. We review the literature regarding PTA and, in particular, the continued role of the WPTAS in directing neurosurgical practice. PMID- 23791249 TI - Augmented mandibular bone structurally adapts to functional loading. AB - Long-term changes in trabecular bone structure during the 10 years following onlay grafting with simultaneous mandibular implant placement were studied. Extraoral radiographs of both mandibular sides in eight patients were taken regularly. Bone structure was analysed using a custom-written image analysis program. Parameters studied were trabecular area and perimeter and marrow cavity area and perimeter. After skeletonisation of the trabecular network, the number of end points and branching points, skeleton length, and branch angle were determined. The observed structural changes agree with the development of a more complex and more delicate or fine osseous structure. The bone shows more trabecular branching. All changes are most pronounced in the graft spongiosa, but are also found in the graft cortex and in the original mandible. The mean trabecular branch angle becomes more horizontal. The applied technique can be used to analyse long-term changes in the architecture of bone grafts. Changes found in the graft architecture correspond to changes expected after functional adaptation to loading. PMID- 23791250 TI - Evaluation of root canal configuration of mandibular molars in a Brazilian population by using cone-beam computed tomography: an in vivo study. AB - INTRODUCTION: The aim of this study was to analyze and characterize root canal morphology of mandibular molars of the Brazilian population by using cone-beam computed tomography (CBCT). METHODS: Patients who required CBCT radiographic examinations as part of their routine examination, diagnosis, and treatment planning were enrolled in the study. A total of 460 healthy, untreated, fully developed mandibular first and second molars were included (234 first molars and 226 second molars). The following observations were recorded: (1) number of roots and their morphology, (2) number of canals per root, (3) C-shaped canals, and (4) primary variations in the morphology of the root canal systems. RESULTS: First molars showed a higher prevalence of 2 canals in the mesial root and 1 in the distal root with 2 separate roots (74%). In the mandibular second molars, the presence of 2 separate roots with 2 canals in the mesial root and 1 canal in the distal root represented 54% of the total. In 32% of the cases, 2 separate roots with 1 canal each in the mesial and distal roots were presented. The incidence of C-shaped canals was 1.7% of first molars and 3.5% of second molars. CONCLUSIONS: A higher prevalence of 2 separate roots with 2 canals in the mesial root and 1 canal in the distal root was observed in mandibular first and second molars (74% and 54%, respectively). Also, a lower incidence of C-shaped canals and 3-rooted teeth was observed in a Brazilian population. CBCT is a clinically useful tool for endodontic diagnosis and treatment. PMID- 23791251 TI - Association between periapical lesions and maxillary sinus mucosal thickening: a retrospective cone-beam computed tomographic study. AB - INTRODUCTION: Odontogenic infections are a common cause of maxillary sinusitis. This study aimed to evaluate the relationship between teeth with periapical lesions or periodontal disease and sinus mucosal thickening using cone-beam computed tomography (CBCT) imaging. METHODS: CBCT scans of 243 patients (485 sinuses) were evaluated retrospectively for the presence of periapical lesions and/or periodontal disease in posterior maxillary teeth and associated sinus mucosal thickening. Thickening >2 mm was considered pathological and was categorized by degree (2-5 mm, 5-10 mm, and >10 mm) and type (flat or polypoid). Descriptive, bivariate, and multivariate statistical analyses were performed. RESULTS: Mucosal thickening >2 mm was observed in 147 (60.5%) patients and 211 (44.6%) sinuses and was mostly of a "flat" type. Bivariate analysis revealed significant associations between mucosal thickening >2 mm and sex (males), age (>60 years), and teeth with periapical lesions and periodontal disease (P <= .027). Multivariate regression analysis identified only sex (males, odds ratio = 1.98, P = .004) and teeth with periapical lesions (odds ratio = 9.75, P < .001) to be associated with mucosal thickening >2 mm. CONCLUSIONS: Sinus mucosal thickening is a common radiographic finding, which is more likely to be observed in males (2*) and in relation to teeth with periapical lesions (9.75*). PMID- 23791252 TI - Analysis of genetic lineages and their correlation with virulence genes in Enterococcus faecalis clinical isolates from root canal and systemic infections. AB - INTRODUCTION: Enterococcus faecalis is a member of the mammalian gastrointestinal microbiota but has been considered a leading cause of hospital-acquired infections. In the oral cavity, it is commonly detected from root canals of teeth with failed endodontic treatment. However, little is known about the virulence and genetic relatedness among E. faecalis isolates from different clinical sources. This study compared the presence of enterococcal virulence factors among root canal strains and clinical isolates from hospitalized patients to identify virulent clusters of E. faecalis. METHODS: Multilocus sequence typing analysis was used to determine genetic lineages of 40 E. faecalis clinical isolates from different sources. Virulence clusters were determined by evaluating capsule (cps) locus polymorphisms, pathogenicity island gene content, and antibiotic resistance genes by polymerase chain reaction. RESULTS: The clinical isolates from hospitalized patients formed a phylogenetically separate group and were mostly grouped in the clonal complex 2, which is a known virulent cluster of E. faecalis that has caused infection outbreaks globally. The clonal complex 2 group comprised capsule-producing strains harboring multiple antibiotic resistance and pathogenicity island genes. On the other hand, the endodontic isolates were more diverse and harbored few virulence and antibiotic resistance genes. In particular, although more closely related to isolates from hospitalized patients, capsule-producing E. faecalis strains from root canals did not carry more virulence/antibiotic genes than other endodontic isolates. CONCLUSIONS: E. faecalis isolates from endodontic infections have a genetic and virulence profile different from pathogenic clusters of hospitalized patients' isolates, which is most likely due to niche specialization conferred mainly by variable regions in the genome. PMID- 23791253 TI - Osteocalcin expression in pulp inflammation. AB - INTRODUCTION: Dental pulp inflammation and repair are closely related. Osteocalcin (OCN), a glycoprotein present in dentin matrix, is expressed by odontoblasts. Although OCN is considered a reparative molecule inside the dental pulp, it is not clear if it is involved in pulpal inflammation. The objective of this study was to localize OCN in reversible and irreversible pulpitis and to describe its possible function in inflammation. METHODS: Pulp tissues in the form of reversible and irreversible pulpitis were collected from the endodontic clinic. Those from impacted teeth were used as controls. Immunohistochemistry was used to localize OCN. Samples were analyzed for OCN and inflammatory mediator expression using multiplex assay. RESULTS: OCN in inflamed tissues was localized in cells and matrix around calcification areas and in cells around blood vessels but not in normal tissues. The plex assay (Bio-Plex 200, Bio-Rad Laboratories Ltd, Mississauga, ON, Canada) showed OCN expression in reversible pulpitis significantly higher than in irreversible pulpitis, and both were significantly higher than in the controls. A panel of inflammatory mediators showed an increase in reversible and irreversible pulpitis. Another panel was decreased in both stages compared with the controls. OCN expression in reversible pulpitis was positively correlated to the expression of vascular endothelial growth factor, fibroblast growth factor, macrophage inflammatory protein-1beta, monocyte-derived chemokine, monocyte chemoattractant protein-1, interleukin (IL)-17, and soluble IL-2 receptor alpha and negatively correlated to that of IL-1alpha, IL-1beta, IL 8, granulocyte macrophage colony-stimulating factor, and macrophage inflammatory protein-1alpha. CONCLUSIONS: Profound understanding of the pulp inflammatory process would lead to new molecular treatment strategies. Our data indicate that OCN expression in reversible pulpitis is associated with angiogenic markers, suggesting its potential use in regenerative treatment. PMID- 23791254 TI - Advanced glycation end-products enhance calcification in cultured rat dental pulp cells. AB - INTRODUCTION: Amorphous calcification frequently appears in dental pulp tissues of diabetic patients; however, its pathologic process has not been fully elucidated. We previously found that pulp stones and thickened predentin occurred more frequently in diabetic rats. Recent findings demonstrated that accumulation of advanced glycation end-products (AGE) might be involved in vascular calcification complicated with diabetes. The aim of this study was to determine the effect of AGE on calcified nodule formation by rat dental pulp cells in culture. METHODS: Rat dental pulp cells and gingival fibroblasts were independently cultured with 50 and 100 MUg/mL AGE. Alkaline phosphatase activity and calcified nodule formation were measured. Expressions of receptor for AGE, osteopontin (OPN), and osteocalcin (OCN) mRNA were determined by quantitative real-time polymerase chain reaction. Protein levels of OPN and OCN secreted in culture medium were quantified by enzyme-linked immunosorbent assay. RESULTS: AGE (50 and 100 MUg/mL) markedly increased both alkaline phosphatase activity and calcified nodule formation in dental pulp cells (P < .01), whereas it did not affect those in gingival fibroblasts. Real-time polymerase chain reaction analysis revealed that AGE increased mRNA expressions of receptor for AGE, OPN, and OCN in dental pulp cells (P < .05). Enzyme-linked immunosorbent assay analysis revealed that the protein levels of OPN and OCN produced by dental pulp cells were higher in AGE-treated than in untreated cells (P < .05). CONCLUSIONS: AGE enhanced the calcification potentials of rat dental pulp cells, suggesting that it may stimulate pathologic calcification of diabetic dental pulp tissues. PMID- 23791255 TI - Evaluation of gelatinases, tissue inhibitor of matrix metalloproteinase-2, and myeloperoxidase protein in healthy and inflamed human dental pulp tissue. AB - INTRODUCTION: The aim of this study was to compare the gelatinolytic activity of matrix metalloproteinase (MMP)-2 and MMP-9 and the expression of tissue inhibitor of matrix metalloproteinase (TIMP)-2 and myeloperoxidase protein (MPO) in clinically healthy human pulp and inflamed pulp tissue specimens. METHODS: Twenty dental pulps clinically diagnosed as inflammatory tissues and 20 healthy pulp tissues from enclosed third molars were harvested and evaluated. The gelatinolytic activity for MMP-2 and MMP-9 was assessed by using the zymography technique, TIMP-2 gene expression was evaluated using the enzyme-linked immunosorbent assay, and MPO was determined using the MPO assay. RESULTS: Data showed increased levels of MMP-9, active MMP-2, TIMP-2, and MPO in inflammatory pulp tissues compared with healthy tissues (P < .05). No statistical difference could be observed for pro-MMP-2 (P > .05). CONCLUSIONS: Although all samples were associated with MMP-2 expression, the active form of this MMP was observed only in inflamed pulps. Inflamed pulps showed an up-regulation of MMP-9, TIMP-2, and MPO. PMID- 23791256 TI - In Vitro biocompatibility evaluation of a root canal filling material that expands on water sorption. AB - INTRODUCTION: CPoint is a polymeric endodontic point that takes advantage of water-induced, non-isotropic radial expansion to adapt to canal irregularities. This study evaluated the effects of CPoint on the viability and mineralization potential of odontoblast-like cells. METHODS: The biocompatibility of CPoint and commercially available gutta-percha points was evaluated by using a rat odontoblast-like cell line (MDPC-23). Cell viability was evaluated with 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometry, and confocal laser scanning microscopy. The mineralization potential of MDPC-23 cells, in the presence of the root-filling materials, was evaluated by examining the changes in osteogenic gene marker expression (quantitative real-time polymerase chain reaction), alkaline phosphatase activity, alizarin red S assay, and transmission electron microscopy. RESULTS: CPoint showed higher initial cytotoxicity compared with gutta-percha and Teflon (P < .05), which became nonsignificant after 4 immersion cycles. Significant differences were also found between eluents from CPoint and gutta-percha at 1:1 concentration (P < .05) but not at 1:10 or 1:100 concentration. Both materials induced minimal apoptosis induced alteration in plasma membrane permeability, as evidenced by flow cytometry and confocal laser scanning microscopy. Compared with the Teflon negative control, CPoint and gutta-percha groups showed up-regulation of most osteogenic gene markers except for dentin sialophosphoprotein, which was down regulated. Alkaline phosphatase activity and alizarin red assay for CPoint and gutta-percha were both significantly higher than for Teflon but not significantly different from each other (P > .05). Transmission electron microscopy showed discrete nodular electron-dense mineralization foci in all 3 groups. CONCLUSIONS: The in vitro biocompatibility of CPoint is comparable to gutta-percha with minimal adverse effects on osteogenesis after elution of potentially toxic components. PMID- 23791257 TI - The impact of chlorhexidine-based endodontic treatment on periapical cytokine expression in teeth. AB - INTRODUCTION: Root canal treatment typically involves cleaning and shaping procedures followed by treatment with antibacterial endodontic dressing between appointments and, ultimately, 3-dimensional,hermetic filling. Chlorhexidine (CHX) is effective as an irrigation solution and is used as an endodontic dressing. The aim of this study was to examine the influence of CHX on periapical cytokine expression. METHODS: Expression levels of the cytokines interferon gamma, tumor necrosis factor alpha, interleukin (IL)-1beta, IL-17A, IL-10, and the chemokine monocyte chemoattractant protein-1 (CCL2/MCP-1) were assayed by real-time polymerase chain reaction immediately after root canal cleaning and 15 days later. RESULTS: Messenger RNA expression of IL-1beta, interferon gamma, IL-10, and CCL2/MCP-1 was increased on day 15 in teeth without endodontic dressing. No statistical change was observed in the messenger RNA expression of cytokines when comparing sampling times for teeth that received endodontic dressing. CONCLUSIONS: The results show that CHX application between appointments prevented the increase of both proinflammatory and immunoregulatory cytokines 15 days after the dental procedure. PMID- 23791258 TI - Retreatability of 2 mineral trioxide aggregate-based root canal sealers: a cone beam computed tomography analysis. AB - INTRODUCTION: The retreatability of recent calcium silicate or mineral trioxide aggregate (MTA) sealers has not yet been assessed. The aim of this study was to evaluate the removal of 2 MTA-based sealers (MTA Fillapex [Angelus Solucoes Odontologicas, Londrina, PR, Brazil] and MTA Plus [Prevest-Denpro, Jammu City, India]) using a rotary retreatment system, considering an epoxy resin sealer (AH Plus [Dentsply Maillefer, Ballaigues, Switzerland]) as the standard for comparison. METHODS: Root canals in 45 single-rooted teeth were instrumented using a rotary nickel-titanium system (MTwo; VDW GmbH, Munich, Germany) and obturated with gutta-percha using one of the following sealers (n = 15): group 1, MTA Fillapex; group 2, MTA Plus; and group 3, AH Plus. The teeth were scanned using a cone-beam computed tomography scanner. After 2 months, the root canals were retreated with a rotary retreatment system (ProTaper Universal Retreatment; Dentsply Maillefer, Ballaigues, Switzerland) and a second cone-beam computed tomography scan was performed to assess the amount of remaining root filling material (in percentage) and dentin removal (in cubic millimeters). The time taken to reach the working length was calculated in minutes. Group comparisons were performed using 1-way analysis of variance and the Student-Newman-Keuls post hoc test (P = .05). RESULTS: There was a significant difference in the amount of remaining root filling material between the 3 groups (P < .05), with group 1 showing the least amount of root filling material (1.8% +/- 0.22%) and group 3 showing the highest (10.4% +/- 0.71%). The amount of dentin removal and the time taken to reach the working length was significantly higher in group 3 than in groups 1 and 2 (P < .05). There was no significant difference between groups 1 and 2 in these outcome variables (P > .05). CONCLUSIONS: The rotary retreatment system evaluated was not able to completely remove any of the sealers. MTA Fillapex showed less remaining root filling material than MTA Plus. PMID- 23791259 TI - A comparison of the dentin cutting efficiency of 4 pointed ultrasonic tips. AB - INTRODUCTION: Pointed ultrasonic tips can be used for several applications including troughing around intracanal obstructions. With the variety of pointed ultrasonic tips available, the purpose of this in vitro investigation was to compare the dentin cutting efficiency of 4 commonly used pointed ultrasonic tips. METHODS: The ultrasonic tips (n = 5 tips/group) included in the study were the following: CPR-3D (Obtura Spartan, Algonquin, IL), BL 6A (B&L Biotech, Bala Cynwyd, PA), PUENDO2 (Dentsply Tulsa Dental Specialties, Tulsa, OK), and WH1 (eie2, San Diego, CA). The tips were attached to a testing apparatus that produced linear movement and a 15-g axial force during instrumentation of a human dentin specimen. For all tips, instrumentation was completed at the same power setting, which fell within the power setting range recommended by each manufacturer. Dentin specimens were weighed at baseline and after 6 minutes of instrumentation to measure dentin loss to the nearest 0.01 mg. A qualitative analysis of the shape and surface topography of new and used ultrasonic tips was performed via scanning electron microscopy. RESULTS: A 1-factor analysis of variance and Tukey post hoc analysis of dentin removal revealed a statistically significant difference between the 4 ultrasonic tips (P < .05). The CPR-3D removed more dentin than the other 3 tips, whereas the BL 6A removed more dentin than the WH1. Scanning electron microscopic analysis revealed the CPR-3D as having the least change to tip shape and topography as compared with the other tips. CONCLUSIONS: Within the limits of this study, CPR-3D showed the greatest dentin removal, which may be linked to the stability of the CPR-3D tip shape and topography. PMID- 23791260 TI - An ex vivo comparison of digital radiography and cone-beam and micro computed tomography in the detection of the number of canals in the mesiobuccal roots of maxillary molars. AB - INTRODUCTION: The purpose of this study was to compare digital periapical and cone-beam computed tomography (CBCT) images to determine the number of canals in the mesiobuccal root of maxillary molars and to compare these counts with micro computed tomography (MUCT), which was also used to determine canal configuration. METHODS: Digital periapical (RVG 6100), CBCT (9000 3D), and MUCT images (the reference standard) were obtained of 18 hemi-maxillas. With periapical and CBCT images, 2 endodontists independently counted the number of canals in each molar and repeated the counts 2 weeks later. Teeth were extracted and scanned with MUCT, and 2 additional endodontists, by consensus, determined the number and configuration of canals. The Friedman test was used to test for differences. RESULTS: In mesiobuccal roots, 2 canals were present in 100% of maxillary first molars (13 of 13) and 57% of second molars (8 of 14), and 69% (9 of 13) and 100% (8 of 8) of these exited as 2 or more foramina. There was no difference in canal counts for original and repeat reads by the 2 observers with periapical (P = .06) and with CBCT (P = .88) and no difference when CBCT counts were compared with MUCT counts (P = .52); however, when periapical counts were compared with MUCT counts, there was a significant difference (P = .04). CONCLUSIONS: For cadaver maxillary molars, MUCT canal counts were significantly different from digital periapical radiograph counts but not different from Carestream9000 3D CBCT counts. PMID- 23791261 TI - Computed tomographic evaluation of canal shape instrumented by different kinematics rotary nickel-titanium systems. AB - INTRODUCTION: This study evaluated the effects of 2 different kinematics rotary nickel-titanium (NiTi) systems, Twisted File (TF), a continuous rotation full sequence system, and WaveOne (WO), a reciprocating single-file system, on transportation, curvature, and volumetric changes of curved root canals by using cone-beam computed tomography. METHODS: Forty mesiobuccal canals of mandibular molars with angle of curvature ranging from 25 degrees -35 degrees were divided according to the NiTi rotary system used in canal preparation into 2 groups of 20 samples each, TF group and WO group. Canals were scanned by using an i-CAT cone beam computed tomography scanner before and after instrumentation to evaluate canal transportation at coronal, middle, and apical thirds, canal curvature, and volumetric changes. The significance level was set at P <= .05. RESULTS: TF system recorded significantly lower mean of canal transportation than WO group at all canal thirds (apical P = .034, middle P = .003, and coronal P = .012). In both groups the apical third recorded the significantly least amount of transportation (P < .05). There was no significant difference between the 2 groups in canal curvature and volumetric changes after instrumentation (P > .05). CONCLUSIONS: Both TF and WO NiTi systems can be safely used to the full working length, resulting in satisfactory preservation of the original canal shape. PMID- 23791262 TI - Efficacy of flowable gel-type EDTA at removing the smear layer and inorganic debris under manual dynamic activation. AB - INTRODUCTION: A flowable gel-type EDTA solution containing urea peroxide and polyacrylic acid was recently introduced into the endodontic market. However, its efficacy for removing the smear layer and inorganic debris remains unknown. This study was performed to investigate the relative efficacies of the flowable gel type and liquid-type EDTA solutions for removal of the smear layer and inorganic debris. We also evaluated the effects of manual dynamic activation (MDA). METHODS: Wettability was evaluated by measuring the contact angle. The incidence of accidental extrusion of irrigant was determined. The effervescent effect was evaluated by mixing the solutions with sodium hypochlorite. The efficacies of the EDTA solutions at removing the smear layer and inorganic debris were evaluated by scanning electron microscopic examination. RESULTS: The contact angles of the 2 EDTA solutions did not differ significantly throughout the experiment (P > .05). Accidental extrusion occurred 4 times for the liquid-type EDTA but never for the gel-type EDTA. The gel-type but not the liquid-type EDTA showed an effervescent effect. The EDTA/MDA treatment combinations did not produce significantly different smear layer scores (P > .05). However, the debris scores for the coronal and middle parts were significantly lower for the gel-type EDTA with MDA than for the liquid-type EDTA without MDA (P < .05). CONCLUSIONS: Our results suggest that the newly introduced gel-type EDTA might be an acceptable irrigant for removing the smear layer and inorganic debris present on the root canal wall. PMID- 23791263 TI - Physical properties of MTA Fillapex sealer. AB - INTRODUCTION: The aim of this study was to evaluate and compare several physicochemical properties including working and setting times, flow, solubility, and water absorption of a recent calcium silicate-based sealer (MTA Fillapex; Angelus, Londrina, Brazil) and an epoxy resin-based sealer (AH Plus; Dentsply, Konstanz, Germany). METHODS: The materials were handled following the manufacturer's instructions. The working time and flow were tested according to ISO 6876:2001 and the setting time according to American Society for Testing and Materials C266. For solubility and water absorption tests, the materials were placed into polyvinyl chloride molds (8 * 1.6 mm). The samples (n = 10 for each material and test) were placed in a cylindrical polystyrene-sealed container with 20 mL deionized water at 37 degrees C. At 1, 7, 14, and 28 days, the samples were removed from the solutions and blotted dry for solubility and water absorption tests. The data were analyzed using 1-way analysis of variance with the Tukey test (P < .05). RESULTS: MTA Fillapex showed the lowest values of flow, working and setting times, solubility, and water absorption (P < .05). The solubility and water absorption increased significantly over time for both materials in a 1- to 28-day period (P < .05). CONCLUSIONS: MTA Fillapex showed suitable physical properties to be used as an endodontic sealer. PMID- 23791264 TI - Phase transformation behavior and mechanical properties of thermomechanically treated K3XF nickel-titanium instruments. AB - INTRODUCTION: The bending and torsional properties of thermomechanically treated K3XF (SybronEndo, Orange, CA) nickel-titanium instruments in relation to their phase transformation behavior were evaluated. METHODS: NiTi instruments K3 (SybronEndo) and K3XF, both in sizes 25/.04 and 40/.04, were examined by differential scanning calorimetry and X-ray diffraction. The metal composition was determined by scanning electron microscopy with X-ray energy-dispersive spectrometric analyses. The bending property of K3 and K3XF instruments was measured in a cantilever-bending test with a maximum deflection of 4.00 mm. A torsional test of the instruments was evaluated according to the American National Standards Institute/American Dental Association Specification No. 28. RESULTS: K3 and K3XF instruments had approximately the same chemical composition with a nickel content of 48-49 atomic %. The differential scanning calorimetry analyses showed that each segment of the K3XF instruments (24.89 degrees C +/- 1.98 degrees C) had a higher austenite finish temperature than the K3 instruments (17.63 degrees C +/- 1.76 degrees C) (P < .05). The bending load values were significantly lower for K3XF than for K3 in the superelastic ranges (P < .05). There was no statistically significant difference between K3 and K3XF in the maximum torque or maximum angular deflection before failure. The torque at fracture values of K3 and K3XF increased significantly with the diameter (P < .05). CONCLUSIONS: K3XF exhibited different phase transformation behavior and flexibility when compared with K3, which may be attributed to the special heat treatment history of K3XF instruments. PMID- 23791265 TI - Percentage of gutta-percha-filled areas in canals instrumented with nickel titanium systems and obturated with matching single cones. AB - INTRODUCTION: The purpose of this study was to compare different single-cone obturation techniques in terms of the percentage of gutta-percha-filled areas (PGFA), sealer-filled areas (PSFA), and voids. METHODS: Sixty extracted mandibular incisors with straight canals were allocated into 6 groups: (A) FlexMaster, (B) Mtwo, (C) ProTaper, (D) Reciproc, (E) WaveOne, and (F) control. In groups A-E, obturation was performed by using matching single-cone gutta percha. In group F (control), manual instrumentation and obturation were performed by using cold lateral compaction with standardized gutta-percha cones. The teeth were sectioned at 2, 4, 6, and 8 mm from the apex. The total area of each canal segment was measured, and the areas were converted to PGFA, PSFA, and percentage of voids. Data were subjected to the Kruskal-Wallis and post hoc Dunn test. RESULTS: At the 2-mm level, group B produced significantly higher PGFA than all other groups, whereas group B produced significantly higher PGFA than groups C, D, and E (P < .05). At the 4-mm level, groups A and B produced significantly higher PGFA than all other groups, whereas group F produced significantly higher PGFA and lower PSFA than groups C, D, and E (P < .05). At the 6-mm level, group F produced significantly higher PGFA and lower PSFA (P < .05) than all other groups, whereas groups A and B produced significantly higher PGFA and lower PSFA than groups C, D, and E (P < .05). At the 8-mm level, group F produced significantly higher PGFA and lower PSFA (P < .05) than all other groups. CONCLUSIONS: Under the conditions of this study, lateral compaction and single cone techniques that used constant tapered gutta-percha (FlexMaster, Mtwo) produced higher PGFA at the apical levels than variable tapered single-cone gutta percha (ProTaper, Reciproc, WaveOne). PMID- 23791266 TI - Regenerative endodontic treatment of permanent teeth after completion of root development: a report of 2 cases. AB - INTRODUCTION: Clinical regenerative endodontic treatment has been focused on immature necrotic teeth, but it should be extended to mature teeth as an alternative to conventional endodontic treatment. There have been no clinical reports to attempt to revascularize pulp in the entire root canals of mature necrotic teeth. The present report describes the treatment of mature, necrotic, permanent incisors with apical periodontitis by using regenerative endodontic therapy. METHODS: In this case report, modified regenerative endodontic procedures were used to enhance the probability of pulp revasuclarization in mature necrotic teeth. At the first appointment, the root canals were mechanically instrumented to the apices with a large apical size by using the step-back technique and irrigated copiously with antimicrobial solution. Intracanal medicaments (calcium hydroxide or ciprofloxacin) were placed in the root canals. At the following appointment, the root canals were irrigated with antimicrobial solution, and bleeding was induced into the root canals by passing hand files beyond apices. Collagen membranes were placed in the canals as a matrix against which mineral trioxide aggregate was placed. Glass ionomer was used to restore the teeth. The resolution of apical radiolucency and regression of clinical signs and symptoms were observed at recall appointments. CONCLUSIONS: The present report presents modified regenerative endodontic procedures for mature necrotic permanent teeth. Further clinical studies with a large number of cases are needed to investigate the outcome of regenerative endodontic therapy for mature necrotic teeth. PMID- 23791267 TI - Malignant lymphoma in maxilla with cystic involvement: a case report. AB - INTRODUCTION: Most radiolucent jaw lesions are benign and resolve with proper diagnosis and treatment. However, a small percentage of radiolucent jaw lesions are malignant and more difficult to manage. METHODS: A biopsy of the radiolucent jaw lesion associated with swelling after nonsurgical root canal therapy was submitted. RESULTS: The lesion had the combined diagnosis of diffuse large B-cell lymphoma with cystic involvement. The patient has since undergone radiation and chemotherapy treatments. Recall appointments indicate healing of the lesion, and no other areas of lymphoma have been found. CONCLUSIONS: The existence of a nonhealing radiolucent jaw lesion emphasizes the importance of an early, definitive diagnosis with biopsy. PMID- 23791271 TI - Incidence of sentinel lymph node involvement in a modern, large series of desmoplastic melanoma. AB - BACKGROUND: Recent studies have suggested that sentinel lymph node (SLN) biopsy is of limited value in desmoplastic melanoma. This study was performed to compare the rate of positive SLN biopsy in the Surveillance, Epidemiology, and End Results (SEER) database with that of a multi-institutional clinical trial and to investigate relevant prognostic factors in desmoplastic melanoma. STUDY DESIGN: Patients with desmoplastic melanoma >=1.0 mm Breslow thickness, who underwent SLN biopsy in a multi-institutional prospective clinical trial, were combined with a single institution melanoma database (combined database) and compared with patients from the SEER database (1998 to 2009). Disease-free survival (DFS) and overall survival (OS) were summarized using Kaplan-Meier curves and compared using Cox proportional hazard models. RESULTS: The rate of positive SLN in the combined database was 17.0% (8 of 47). By comparison, the rate of positive SLN in SEER was lower: 2.5% (15 of 594). On multivariable analysis, Breslow thickness >=2.6 mm (hazard ratio 8.17, 95% CI 1.26 to 160.1; p = 0.0259) and an interaction between SLN status and ulceration (p = 0.0013) were independent risk factors for worse OS in the combined database; patients with ulceration and a positive SLN had significantly worse OS. In the combined database on multivariable analysis, SLN positivity (p = 0.0161) and ulceration (p = 0.0004) were independent risk factors for worse DFS. CONCLUSIONS: The rate of positive SLN in desmoplastic melanoma may be higher than that reported in the SEER database. Sentinel lymph node biopsy may be considered as part of the comprehensive staging of desmoplastic melanoma >=1.0 mm Breslow thickness. PMID- 23791283 TI - Living donor kidney transplantation using laparoscopically procured multiple renal artery kidneys and right kidneys. AB - BACKGROUND: The use of kidneys with multiple renal arteries (MRA) and right kidneys procured laparoscopically for living donor kidney transplantation (LDKT) remains controversial. We aimed to evaluate the short- and long-term outcomes of recipients of LDKT using laparoscopically procured MRA and right kidneys. STUDY DESIGN: We reviewed the medical records of all LDKT recipients with laparoscopically procured kidneys from 2000 to 2009. Pediatric recipients and recipients of positive crossmatch and/or ABO-incompatible transplants were excluded. We compared the outcomes of recipients of MRA kidneys with those receiving single renal artery (SRA) kidneys and the outcomes of recipients of right kidneys with those of left kidneys. Renal function was measured by iothalamate clearance and estimated by the abbreviated Modification of Diet in Renal Disease equation. RESULTS: Multiple renal artery kidneys (192 2-artery and 18 3-artery kidneys) were used in 210 (18.5%) of 1,134 transplantations. The most common reconstructive technique used for MRA kidneys was a side-to-side anastomosis (64.3%). There were no significant differences in vascular complications (1.1% vs 2.4%, p = 0.17), urologic complications (3.1% vs 2.9%, p = 0.47), graft survival at 1 year (94.6% vs 96.1%, p = 0.37), and 1-year iothalamate clearance (64 mL/min/1.73 m(2) vs 66 mL/min/1.73 m(2), p = 0.52) between recipients of SRA and MRA kidneys. Five-year graft survival was similar for recipients of SRA and MRA kidneys (83.6% vs 82.6%, p = 0.82) and for recipients of left vs right kidneys (83.7% vs 82.6%, p = 0.70). CONCLUSIONS: Excellent long-term outcomes can be obtained after LDKT using laparoscopically procured MRA and right-sided donor kidneys. Unavailability of an SRA left kidney should not preclude LDKT. PMID- 23791286 TI - A simplified approach to incisional hernias. PMID- 23791287 TI - Avoidance of grafts for mesenterico-portal vein resections during pancreatoduodenectomy: what is the cost? PMID- 23791288 TI - Prevention of lymphedema. PMID- 23791289 TI - Reply: To PMID 23266421. PMID- 23791290 TI - Inevitability of venous thromboembolism. PMID- 23791291 TI - Negative randomized trials. PMID- 23791292 TI - Reply: To PMID 23177270. PMID- 23791293 TI - Outcomes in autologous breast reconstruction. PMID- 23791294 TI - Reply: To PMID 23211118. PMID- 23791296 TI - [Anatomical radiology of the descending colon in the left pararenal space: about 1084 cases]. AB - AIMS: Due to the severity of colonic injuries and their frequency on the left side, we study relationships between the left kidney and the descending colon to identify subjects at risk of colonic perforation during percutaneous surgery of the left kidney. MATERIAL AND METHODS: Over a period of 3 years we exploited abdominal CT scans for 1084 patients in both sexes without any visceral or parietal lesions. We studied the situation and relationships of the lumbar part of the descending colon in the left pararenal space using a conventional grid technique. RESULTS: The preferential site of the colon in both sexes was laterorenal in 55.8% of cases. We also found the descending colon in a posterolateral situation in 21.1% of cases, and in an anterolateral situation in 14.8% of cases. In women, the posterolateral situation was twice more common than in men, but we did not observe any post-renal situation. Laterorenal and posterolateral situations were the most frequent in patients less than 50 years; while beyond this age 70.1% of subjects had a laterorenal type. CONCLUSION: Sex and age affect topographic variations of the lumbar part of the descending colon in the left pararenal space. Although they are rare or aberrant, some locations exist and should not be ignored by the operator. These locations are risk factors of colonic lesion during percutaneous approach of the left kidney. PMID- 23791297 TI - Uric acid in-hospital changes predict mortality in patients with acute myocardial infarction. AB - BACKGROUND AND AIMS: The prognostic impact of admission uric acid (UA) levels in patients with acute myocardial infarction (AMI) is controversial. We assessed the prognostic role of in-hospital UA changes in patients with AMI. METHODS AND RESULTS: We studied 375 consecutive patients (320 males, mean age 62.6 years) with AMI (232 with ST elevation MI) within 12 h of symptoms' onset. UA levels were daily measured throughout hospitalization and their admission and peak values were recorded. End-points were 30-day and 1-year mortality. Mortality rate at 30 days was 7.2% and at 1 year 10.9%. Patients who died within 30 days exhibited higher peak UA (10.24 mg/dl vs. 7.06 mg/dl, p < 0.001) and absolute UA elevation (1.7 mg/dl vs. 0.7 mg/dl, p < 0.001). Optimal values for predicting 30 day mortality were 9.65 mg/dl for peak UA and 2.35 mg/dl for UA elevation. Concerning 1-year mortality, deceased patients had higher peak UA levels (9.71 mg/dl vs. 7 mg/dl, p < 0.001) and absolute UA elevation (1.5 mg/dl vs. 0.6 mg/dl, p < 0.001). Optimal values for predicting 1-year mortality were 9.55 mg/dl for peak UA and 1.1 mg/dl for UA elevation. With Cox regression analysis peak UA (adjHR 1.157, p = 0.030) and UA elevation (adjHR 1.288, p = 0.009) were independent predictors of 30-day mortality. Similarly, peak UA levels (adjHR 1.204, p = 0.001) and UA elevation (adjHR 1.213, p = 0.001) predicted 1-year mortality. CONCLUSIONS: In patients with AMI peak rather than admission UA levels, and absolute in-hospital UA elevation predict both 30-day and 1-year mortality. Serial in-hospital UA measurements add prognostic information in AMI patients. PMID- 23791298 TI - Plasma adiponectin in heart failure with and without cachexia: catabolic signal linking catabolism, symptomatic status, and prognosis. AB - BACKGROUND AND AIMS: Adiponectin (ADPN) as an adipose tissue hormone contributes to regulation of energy metabolism and body composition and is associated with cardiovascular risk profile parameters. Cardiac cachexia may develop as a result of severe catabolic derangement in chronic heart failure (CHF). We aimed to determinate an abnormal ADPN regulation as a link between catabolic signalling, symptomatic deterioration and poor prognosis. METHODS AND RESULTS: We measured plasma ADPN in 111 CHF patients (age 65 +/- 11, 90% male, left ventricular ejection fraction (LVEF) 36 +/- 11%, peak oxygen consumption (peakVO2) 18.1 +/- 5.7 l/kg*min, body mass index (BMI) 27 +/- 4 kg/m(2), all mean +/- standard deviation) and 36 healthy controls of similar age and BMI. Body composition was assessed by dual energy X-ray absorptiometry, insulin sensitivity was evaluated by homoeostasis model assessment, exercise capacity by spiroergometry. Plasma ADPN did not differ between CHF vs. controls (13.5 +/- 11.0 vs. 10.5 +/- 5.3 mg/l, p > 0.4), but increased stepwise with NYHA functional class (I/II/III: 5.7 +/- 1.4/10.7 +/- 8.3/19.2 +/- 14.0 mg/l, ANOVA p < 0.01). Furthermore, ADPN correlated with VO2 at anaerobic threshold (r = -0.34, p < 0.05). ADPN was highest in cachectic patients (cCHF, 16%) vs. non-cachectic (ncCHF) (18.7 +/- 15.0 vs. 12.5 +/- 9.9 mg/l; p < 0.05). ADPN indicated mortality risk independently of established prognosticators (HR: 1.04 95% CI: 1.02-1.07; p < 0.0001). ADPN above the mean (13.5 mg/l) was associated with a 3.4 times higher mortality risk in CHF vs. patients with ADPN levels below the mean. CONCLUSION: Circulating ADPN is abnormally regulated in CHF. ADPN may be involved in impaired metabolic signalling linking disease progression, tissue wasting, and poor outcome in CHF. PMID- 23791299 TI - Gastric obstruction due to adhesions 3 months after removal of an adjustable gastric band. PMID- 23791300 TI - Gastrobronchial fistula as a late complication of sleeve gastrectomy. PMID- 23791301 TI - Transverse ionic mobility measured in a dynamic light scattering device. AB - We describe here some novel experiments with a commercial dynamic light scattering device. By inserting a quarter-wave plate in the light beam of the HeNe laser used in the Malvern DLS 'Zetasizer', one can obtain right handed (RH) or left-handed (LH) circularly polarized light from the incoming horizontally polarized laser light. This RH vs LH light is used in the ionic mobility (zeta potential) measuring mode to detect what we believe are phenomena related to transverse ionic mobility, i.e. speed of a particle (or portions of the particle) as a function of applied static electric field, in directions transverse to those fields, and which, we suggest, arise from surface impedence phenomena related to the (1) parity-biased mechanical flexing of charged molecular moieties at the surface of a chiral particle or of an achiral particle+chiral co-solvents, possibly driven by the electrophoresis field and (2) electro-optic effects (induced currents) arising from the interaction of chiral co-solvents upon the surface of charged colloid particles in the presence of a (high frequency) electric field. Fluctuations of structure induce currents which are chirally biased either in themselves (in a chiral particle) or which 'borrow' chirality from chiral co-solvents conditioning the local high frequency E-field, and advance or retard the scattered phase of RH or LH polarized light. In either case the 'differential mobility' observed is related to the relative extent of motion in internal portions of the colloid particle - i.e. 'floppiness' in the particle. PMID- 23791302 TI - Target volume for postoperative radiotherapy in non-small cell lung cancer: results from a prospective trial. AB - BACKGROUND AND PURPOSE: A previous prospective trial reported that three dimensional conformal postoperative radiotherapy (PORT) for pN2 NSCLC patients using a limited clinical target volume (CTV) had a late morbidity rate and pulmonary function that did not differ from those observed in pN1 patients treated with surgery without PORT. The aim of this study was to assess locoregional control and localization of failure in patients treated with PORT. MATERIALS AND METHODS: The pattern of locoregional failure was evaluated retrospectively in 151 of 171 patients included in the PORT arm. The CTV included the involved lymph node stations and those with a risk of invasion >10%. Competing risk analysis was used to assess the incidence of locoregional failure and its location outside the CTV. RESULTS: Overall survival at 5years was 27.1% with a median follow-up of 67months for 40 living patients. The 5-year cumulative incidence of locoregional failure was 19.4% (95% CI: 18.2-20.5%) including a failure rate of 2% (95% CI: 0-17%) in locations outside or at the border of the CTV. CONCLUSIONS: The use of limited CTV was associated with acceptable risk of geographic miss. Overall locoregional control was similar to that reported by other studies using PORT for pN2 patients. PMID- 23791303 TI - Analytical techniques for the determination of biologically active quinones in biological and environmental samples. AB - Quinones are compounds that have various characteristics such as biological electron transporter, therapeutic agent and harmful environmental pollutant. Therefore, an effective analytical method for quinones is useful in many fields including biomedical, clinical and toxicological studies. This review describes the principle and feature of analytical techniques for quinones including high performance liquid chromatography with ultraviolet, fluorescence, chemiluminescence, electrochemical detection and mass spectrometry, gas chromatography with mass spectrometry and capillary electrophoresis. Furthermore, the sensitivity and the sample preparation method for the determination of several quinones such as vitamin K, ubiquinone, doxorubicin and polycyclic aromatic hydrocarbon quinone in biological and environmental samples are summarized. PMID- 23791304 TI - Genetic engineering of multispecies microbial cell factories as an alternative for bioenergy production. AB - There is currently much interest in developing technology to use microlgae or cyanobacteria for the production of bioenergy and biomaterials. Here, we summarize some remarkable achievements in strains improvement by traditional genetic engineering and discuss common drawbacks for further progress. We present general knowledge on natural microalgal-bacterial mutualistic interactions and discuss the potential of recent developments in genetic engineering of multispecies microbial cell factories. This synthetic biology approach would rely on the assembly of complex metabolic networks from optimized metabolic modules such as photosynthetic or nitrogen-fixing parts. PMID- 23791305 TI - Evaluation of localization errors for craniospinal axis irradiation delivery using volume modulated arc therapy and proposal of a technique to minimize such errors. AB - PURPOSE: To dosimetrically evaluate the effects of improper patient positioning in the junction area of a VMAT cranio-spinal axis irradiation technique consisting of one superior and one inferior arc and propose a solution to minimize these patient setup errors. METHODS: Five (n=5) cranio-spinal axis irradiation patients were planned with 2 arcs: one superior and one inferior. In order to mimic patient setup errors, the plans were recalculated with the inferior isocenter shifted by: 1, 2, 5, and 10mm superiorly, and 1, 2, 5, and 10mm inferiorly. The plans were then compared with the corresponding original, non-shifted arc plans on the grounds of target metrics such as conformity number and homogeneity index, as well as several normal tissue dose descriptors. "Gradient-optimized" plans were then created for each patient in an effort to reduce dose discrepancies due to setup errors. RESULTS: Percent differences were calculated in order to compare each of the eight shifted plans with the original non-shifted arc plan, which corresponds to the ideal patient setup. The conformity number was on average lower by 0.9%, 2.7%, 5.8%, and 9.1% for the 1, 2, 5, and 10mm inferiorly-shifted plans and 0.4%, 0.8%, 2.8%, and 6.0% for the respective superiorly-shifted plans. The homogeneity indices were, averaged among the five patients and they indicated less homogeneous dose distributions by 0.03%, 0.3%, 1.0%, and 2.8% for the inferior shifts and 0.2%, 1.2%, 6.3%, and 15.3% for the superior shifts. Overall, the mean doses to the organs at risk deviate by less than 2% for the 1, 2, and 5mm shifted plans. The 10mm shifted plans, however, showed average percent differences, over all studied organs, from the original plan of up to 5.6%. Using "gradient-optimized" plans, the average dose differences were reduced by 0.2%, 0.5%, 1.2%, and 2.1% for 1, 2, 5, and 10mm shifts, respectively compared to the originally optimized plans, and the maximum dose differences were reduced by 11.7%, 8.5%, 12.4%, and 13.9% on average for the 1, 2, 5, and 10mm shifted plans. CONCLUSIONS: Setup errors related to isocenter shifting should be minimized in order to provide the patient with the most dosimetrically accurate treatment possible. Errors of 1-2mm can negatively affect the quality of the delivered treatment, most notably in the arc junction area, but the deterioration of the treatment plan accuracy is not as problematic as in the cases of larger errors such as 5-10mm. By employing a new planning technique, the dose differences due to setup errors can be greatly reduced. PMID- 23791306 TI - Boosting imaging defined dominant prostatic tumors: a systematic review. AB - INTRODUCTION: Dominant cancer foci within the prostate are associated with sites of local recurrence post radiotherapy. In this systematic review we sought to address the question: "what is the clinical evidence to support differential boosting to an imaging defined GTV volume within the prostate when delivered by external beam or brachytherapy". MATERIALS AND METHODS: A systematic review was conducted to identify clinical series reporting the use of radiation boosts to imaging defined GTVs. RESULTS: Thirteen papers describing 11 unique patient series and 833 patients in total were identified. Methods and details of GTV definition and treatment varied substantially between series. GTV boosts were on average 8 Gy (range 3-35 Gy) for external beam, or 150% for brachytherapy (range 130-155%) and GTV volumes were small (<10 ml). Reported toxicity rates were low and may reflect the modest boost doses, small volumes and conservative DVH constraints employed in most studies. Variability in patient populations, study methodologies and outcomes reporting precluded conclusions regarding efficacy. CONCLUSIONS: Despite a large cohort of patients treated differential boosts to imaging defined intra-prostatic targets, conclusions regarding optimal techniques and/or efficacy of this approach are elusive, and this approach cannot be considered standard of care. There is a need to build consensus and evidence. Ongoing prospective randomized trials are underway and will help to better define the role of differential prostate boosts based on imaging defined GTVs. PMID- 23791307 TI - Feasibility of adjunct therapeutic hypothermia treatment for hyperammonemia and encephalopathy due to urea cycle disorders and organic acidemias. AB - BACKGROUND: Children with urea cycle disorders (UCDs) or organic acidemias (OAs) and acute hyperammonemia and encephalopathy are at great risk for neurological injury, developmental delay, intellectual disability, and death. Nutritional support, intravenous alternative pathway therapy, and dialysis are used to treat severe hyperammonemia associated with UCDs and nutritional support and dialysis are used to treat severe hyperammonemia in OAs. Brain protective treatment while therapy is initiated may improve neurological and cognitive function for the lifetime of the child. Animal experiments and small clinical trials in hepatic encephalopathy caused by acute liver failure suggest that therapeutic hypothermia provides neuroprotection in hyperammonemia associated encephalopathy. We report results of an ongoing pilot study that assesses if whole body cooling during rescue treatment of neonates with acute hyperammonemia and encephalopathy is feasible and can be conducted safely. METHODS: Adjunct whole body therapeutic hypothermia was conducted in addition to standard treatment in acutely encephalopathic, hyperammonemic neonates with UCDs and OAs requiring dialysis. Therapeutic hypothermia was initiated using cooling blankets as preparations for dialysis were underway. Similar to standard therapeutic hypothermia treatment for neonatal hypoxic ischemic encephalopathy, patients were maintained at 33.5 degrees C+/-1 degrees C for 72h, they were then slowly rewarmed by 0.5 degrees C every 3h over 18h. In addition data of age-matched historic controls were collected for comparison. RESULTS: Seven patients were cooled using the pilot study protocol and data of seven historic controls were reviewed. All seven patients survived the initial rescue and cooling treatment, 6 patients were discharged home 2-4weeks after hospitalization, five of them feeding orally. The main complication observed in a majority of patients was hypotension. CONCLUSION: Adjunct therapeutic hypothermia for neonates with UCDs and OAs receiving standard treatment was feasible and could be conducted safely in pediatric and neonatal intensive care units experienced in the application of therapeutic hypothermia in critically ill neonates. However, including adjunct therapeutic hypothermia in the already involved treatment regimen of critically ill patients with hyperammonemia and encephalopathy adds to the complexity of care and should not be done unless it is proven efficacious in a randomized clinical trial. PMID- 23791308 TI - Use of carglumic acid in the treatment of hyperammonaemia during metabolic decompensation of patients with propionic acidaemia. AB - Propionic acidaemia (PA) results from propionyl-CoA carboxylase deficiency. During metabolic decompensation, the accumulation of propionyl-CoA causes secondary hyperammonaemia through N-acetylglutamate synthetase inactivation. Carglumic acid, a structural analogue of N-acetylglutamate, was given to patients with PA (n=3) during episodes of metabolic decompensation (n=8; age range: birth to 4years), in addition to high energy/low protein intake and carnitine. Plasma ammonia concentrations normalised within 6-19h. Carglumic acid was well tolerated with no side effects noted. PMID- 23791309 TI - Identification of mutation in NPC2 by exome sequencing results in diagnosis of Niemann-Pick disease type C. AB - We report identification of a homozygous mutation in NPC2 in two Iranian siblings with a neurologic dysfunction whose disease had not been diagnosed prior to our genetic analysis. The mutation was identified by exome sequencing. The finding resulted in diagnosis of Niemann-Pick disease type C (NPC) in the siblings, and initiation of treatment with Miglustat. The clinical features of the patients are presented. It has been suggested that NPC is under diagnosed, particularly when presentations are not very severe, as was the situation in the cases studied here. NPC is a fatal autosomal recessive disorder clinically characterized by hepatosplenomegaly and progressive neurological deterioration. At the cellular level, it causes aberrant cholesterol trafficking and accumulation of unesterified cholesterol in lysosomes. Mutations in NPC1 and NPC2 are cause of disease in respectively, 95% and 5% of NPC patients. The p.Pro120Ser causing mutation in NPC2 observed in the Iranian patients was earlier observed in the only other NPC2 patient reported from the Middle East. The study demonstrates that in addition to greatly facilitating gene discovery, exome sequencing has notable potentials for diagnosis, particularly for diagnosis of atypical cases. PMID- 23791311 TI - Systematic reviews of the effectiveness of interventions used in occupational therapy early childhood services. PMID- 23791310 TI - Defining incident cases of epilepsy in administrative data. AB - PURPOSE: To determine the minimum enrollment duration for identifying incident cases of epilepsy in administrative data. METHODS: We performed a retrospective dynamic cohort study using Ohio Medicaid data from 1992 to 2006 to identify a total of 5037 incident epilepsy cases who had at least 1 year of follow-up prior to epilepsy diagnosis (epilepsy-free interval). The incidence for epilepsy-free intervals from 1 to 8 years, overall and stratified by pre-existing disability status, was examined. The graphical approach between the slopes of incidence estimates and the epilepsy-free intervals was used to identify the minimum epilepsy-free interval that minimized misclassification of prevalent as incident epilepsy cases. RESULTS: As the length of epilepsy-free interval increased, the incidence rates decreased. A graphical plot showed that the decline in incidence of epilepsy became nearly flat beyond the third epilepsy-free interval. CONCLUSION: The minimum of 3-year epilepsy-free interval is needed to differentiate incident from prevalent cases in administrative data. Shorter or longer epilepsy-free intervals could result in over- or under-estimation of epilepsy incidence. PMID- 23791312 TI - P4 medicine and pediatric occupational therapy. AB - Pediatric occupational therapy practitioners face a complex and ever-changing health care environment, creating many challenges and opportunities. P4 medicine is a systems approach to health care that emphasizes proactive wellness over reactive acute care disease management. The four Ps of P4 medicine stand for predictive, personalized, preventive, and participatory, concepts that align well with the practice of pediatric occupational therapy. P4 medicine offers a model for pediatric occupational therapy practitioners to demonstrate the value of occupational therapy services. PMID- 23791313 TI - Method for the systematic reviews on occupational therapy and early intervention and early childhood services. AB - Systematic reviews of literature relevant to early intervention and early childhood services are important to the practice of occupational therapy. We describe the five questions that served as the focus for the systematic reviews of the effectiveness of occupational therapy interventions in early intervention and early childhood services. We include the background for the reviews; the process followed for each question, including search terms and search strategy; the databases searched; and the methods used to summarize and critically appraise the literature. The final number of articles included in each systematic review; a summary of the themes of the results; the strengths and limitations of the findings; and implications for practice, education, and research are presented. PMID- 23791314 TI - Systematic review of interventions to promote social-emotional development in young children with or at risk for disability. AB - This systematic review synthesized the research on interventions used by occupational therapy practitioners to promote social-emotional development in young children (birth-5 yr) with or at risk for disabilities. After a comprehensive search of the research literature, 23 studies were reviewed and then synthesized into five themes: (1) touch-based interventions to enhance calming and parent-infant bonding, (2) relationship-based interventions to promote positive caregiver-child interactions, (3) joint attention interventions, (4) naturalistic preschool interventions to promote peer-to-peer engagement, and (5) instruction-based interventions to teach children appropriate social behaviors. The interventions for infants primarily involved coaching parents in specific strategies to promote positive interactions; interventions for preschool age children typically involved encouraging peer support, instructing children, and applying naturalistic behavioral techniques to develop higher-level social competence. The studies demonstrated low to moderate positive effects for interventions used by occupational therapy practitioners to improve social emotional development across ages, diagnoses, and settings. PMID- 23791315 TI - Systematic review of interventions used in or relevant to occupational therapy for children with feeding difficulties ages birth-5 years. AB - Research articles on the effectiveness of feeding interventions for infants and young children were identified, appraised, and synthesized. Thirty-four studies met the inclusion criteria and were reviewed. Three broad intervention themes regarding feeding approaches were identified on the basis of their theoretical orientations. These three feeding approaches were (1) behavioral interventions, (2) parent-directed and educational interventions, and (3) physiological interventions. Synthesis of the evidence suggested that various feeding approaches may result in positive outcomes in the areas of feeding performance, feeding interaction, and feeding competence of parents and children. This synthesis of empirical evidence supporting interventions for feeding problems provides a foundation for future research to define the types of outcomes that can be expected for children with different diagnoses or functional impairments and to develop best practice guidelines. PMID- 23791316 TI - Systematic review of interventions used in occupational therapy to promote motor performance for children ages birth-5 years. AB - We examined the research evidence for interventions used in occupational therapy to promote the motor performance of young children ages 0-5 yr. We identified 24 trials, Levels I-III, that met our review criteria. The studies fell into three categories: (1) developmental interventions for infants (ages 0-3 yr), (2) interventions for young children with or at risk for cerebral palsy (CP), and (3) visual-motor interventions for preschool children (ages 3-5 yr). Developmental interventions showed low positive short-term effects with limited evidence for long-term effects, and findings on the benefits of neurodevelopmental treatment were inconclusive. Interventions using specific protocols for children with CP resulted in positive effects. Visual-motor interventions for children with developmental delays (ages 3-5 yr) resulted in short-term effects on children's visual-motor performance. Of the intervention approaches used in occupational therapy, those that embed behavioral and learning principles appear to show positive effects. PMID- 23791317 TI - Systematic review of occupational therapy interventions to improve cognitive development in children ages birth-5 years. AB - This systematic review examined the research evidence for interventions used by occupational therapists to improve cognitive development in children from birth to age 5. Thirteen studies met the inclusion criteria and were reviewed by three teams of two people. From the selected articles, which described Level I and IV studies, two general categories emerged: (1) developmental interventions and (2) joint attention interventions. Developmental interventions occurred in neonatal intensive care units, home, child care centers, and preschools. Synthesis of the articles indicates that developmental interventions result in gains in early cognitive development (e.g., infant and preschool age) with inconclusive evidence for gains through school age. Educating parents of preterm infants to be more sensitive to their child's needs and more responsive in interactions increased cognitive outcomes and joint attention. Interventions using joint attention enhanced generalization to novel situations and increased play, language, and social interactions in preschoolers with autism. Further studies that describe intervention strategies used to enhance cognitive functioning to promote preliteracy skills such as joint attention, imitation, memory, problem solving, and decision making and are conducted by occupational therapists are needed. PMID- 23791318 TI - Evidence for the effectiveness of different service delivery models in early intervention services. AB - Consideration of the evidence for all aspects of service delivery is a growing relevant concern of occupational therapists, including those providing early intervention to children and families. We conducted a review of the literature to uncover what evidence existed for determining the effectiveness of different service delivery models and methods used to improve occupational performance for children and families who receive early intervention services. Through a comprehensive search, we reviewed and synthesized studies, finding common themes of family-centered and routine-based approaches, service setting, and the inclusion of parent participation and training. Families consistently reported positive perceptions of family-centered and routine-based approaches. Parent participation and training resulted in positive outcomes. No specific setting or method of service delivery was identified as clearly most effective, with most studies reporting combined approaches and environments for interventions. PMID- 23791319 TI - Effects of visual rehabilitation on a child with severe visual impairment. AB - We examined the effects of visual rehabilitation, including a chromatic luminance discrimination program and a fixation training program, on a 6-yr-old boy with severe visual impairment. Single-subject ABA and AB designs were used. The programs were conducted 2*/wk and included 6 to 7 sessions for the baseline phase and 10 to 11 sessions for the intervention phase. Play was integrated into the visual training programs. Goggle visual evoked potential (VEP) testing was used to evaluate neural activity in the primary visual cortex. Correct responses increased and response times were shortened after training in luminance discrimination. The total and maximum fixation time also improved, as did P100 latency and amplitude of VEPs. While walking, the boy was able to detect obstacles he had not noticed before training. The results indicate the value of visual training and the possibility of brain plasticity in a child with severe visual impairment. PMID- 23791320 TI - Investigating the effectiveness of full-time wrist splinting and education in the treatment of carpal tunnel syndrome: a randomized controlled trial. AB - This study investigated the effects of wearing a wrist support splint for 8 wk and receiving a formal education program on patients with carpal tunnel syndrome (CTS), as well as factors associated with patients' desire to seek surgical intervention. Participants were recruited from a hospital surgical wait list and randomly assigned to an intervention group (n = 30) or a control group (n = 24). Significant improvements in measures of symptom severity and functional status over the duration of the study appeared in the intervention group but not in the control group. Logistic regression for the intervention group showed that symptom severity (odds ratio [OR] = 1.53, 95% confidence interval [CI] [1.20-1.93]), functional deficits (OR = 1.31, 95% CI [1.08-1.57]), pain score (OR = 1.25, 95% CI [1.11-1.61]), and symptom duration (OR = 1.11, 95% CI [1.01-1.24]) were positively associated with the desire to seek surgical intervention. This conservative CTS treatment program conducted by occupational therapists can improve symptoms and hand function in CTS patients. PMID- 23791322 TI - Rasch analysis of the Mental Health Recovery Measure. AB - Consumer-oriented recovery among people with mental illness has been discussed for more than two decades, but few reliable and valid recovery measurements are currently available. This study used Rasch methods to assess the Mental Health Recovery Measure (MHRM). Participants were 156 adults with mental illness who lived in the community. After the Rasch analyses, the MHRM was modified to a 26 item measure with a 4-point Likert scale. Unidimensionality was confirmed for the revised MHRM, and it also showed proper rating scale functioning and high reliability. The revised MHRM is sufficient to assess only those in the initial and middle stages of recovery. More high-recovery-level items are needed to assess people in a high-recovery stage. Occupational therapists can use the revised MHRM in future quantitative studies and program evaluation. PMID- 23791321 TI - Multiple Errands Test-Revised (MET-R): a performance-based measure of executive function in people with mild cerebrovascular accident. AB - OBJECTIVE. This article describes a performance-based measure of executive function, the Multiple Errands Test-Revised (MET-R), and examines its ability to discriminate between people with mild cerebrovascular accident (mCVA) and control participants. METHOD. We compared the MET-R scores and measures of CVA outcome of 25 participants 6 mo post-mCVA and 21 matched control participants. RESULTS. Participants with mCVA showed no to minimal impairment on measures of executive function at hospital discharge but reported difficulty with community integration at 6 mo. The MET-R discriminated between participants with and without mCVA (p <= .002). CONCLUSION. The MET-R is a valid and reliable measure of executive functions appropriate for the evaluation of clients with mild executive function deficits who need occupational therapy to fully participate in community living. PMID- 23791323 TI - Interinstrument reliability of the Jamar electronic dynamometer and pinch gauge compared with the Jamar hydraulic dynamometer and B&L Engineering mechanical pinch gauge. AB - OBJECTIVE. This study sought to determine interinstrument reliability of the Jamar electronic dynamometer and pinch gauge compared with the commonly used Jamar hydraulic dynamometer and B&L Engineering mechanical pinch gauge. METHOD. Twenty men and 20 women were tested for grip strength with the two different dynamometers, and 17 men and 25 women were tested for lateral pinch strength with the two different pinch gauges. RESULTS. Grip strength measurements were approximately 10% higher with the hydraulic dynamometer, and lateral pinch strength measurements were approximately 18% higher with the mechanical pinch gauge. Paired t tests and intraclass correlation coefficients (ICCs) were used for statistical analyses. The two-tailed p value was <.0001, and the ICC indicated poor to moderate reliability. CONCLUSION. When retesting patients, it is recommended that occupational therapists use the same instrument to measure hand strength because interinstrument reliability may be lacking. PMID- 23791324 TI - Self-reported versus objectively assessed exercise adherence. AB - OBJECTIVE. We examined agreement of data between self-reported and objectively assessed exercise adherence among women with systemic lupus erythematosus. METHOD. Eleven participants completed weekly exercise logs on date and duration of exercise during a 10-wk Wii FitTM home-based program. Afterward, exercise data from the log were compared with those recorded in the Wii console. RESULTS. Of the paired data, the mean duration of exercise recorded in the Wii was 29.5 min and that recorded in the log was 33.3 min. The composite intraclass correlation for exercise duration between exercise log and the Wii Fit was 0.4. The 95% limits of agreement indicated large between-subjects variability. CONCLUSION. Exercise logs exhibit a marginally acceptable agreement with Wii estimation of exercise duration at a group level. However, caution should be applied when using the exercise log as a measure of a person's exercise behavior because of the tendency to overreport. PMID- 23791325 TI - Research utilization and evidence-based practice in occupational therapy: a scoping study. AB - Many articles have been written on the barriers to and facilitators of the use of evidence in practice in nursing and medicine, but to date no extensive review has been published of the literature on evidence-based practice (EBP) supports in occupational therapy. This article presents the results of a scoping review that examined factors that support the integration of research into practice. A review of 69 articles revealed four themes: (1) attitudes toward, perceptions of, confidence in, and use of research and EBP; (2) factors that support the use of research in practice; (3) effects of interventions targeting changes in knowledge, attitudes, skills, behaviors, and evidence-based practices; and (4) identification of the processes involved in the acquisition of EBP skills and their application in clinical practice. A process that integrates client-centered practice, structured reflection, case application, and peer consultations within a scholarship of practice model facilitates occupational therapists' evaluation and integration of research evidence. PMID- 23791326 TI - Emergence of scholarship in the American Journal of Occupational Therapy. AB - We undertook a content analysis of 192 American Journal of Occupational Therapy articles published from 1947 to 2010 to understand and explicate the emergence of scholarship within the profession. Scholarship includes scientific inquiry, empirical research, and other forms of inquiry. We identified and coded three aspects of the development of scholarship: argument, methodological rigor, and occupational focus. All three aspects increased over the evaluated period, during which substantial changes occurred in the profession's practice and access to higher education. We see the development of scholarship as aligned with the claiming of the profession's independence and voice. PMID- 23791327 TI - Update on productive aging research in the American Journal of Occupational Therapy, 2012. AB - This article describes a review of articles on productive aging published in the American Journal of Occupational Therapy (AJOT) during 2012 in light of the Centennial Vision charge of supporting practice through evidence. Seventeen AJOT articles published in 2012 specifically addressed productive aging. Of 6 Level I studies, 4 were systematic reviews that identified effective occupational therapy interventions for community-dwelling older adults; 1 randomized controlled trial examined the effectiveness of writing life reviews for residents of senior residences, and 1 meta-analysis investigated the effectiveness of fall-related efficacy and engagement in activity or occupation. Two Level II studies and 2 Level III studies produced support for the effectiveness of individual and group based occupational therapy interventions. Of 7 descriptive studies addressing a variety of areas, 4 addressed the reliability and validity of assessments. In 2012, AJOT published more and higher quality studies addressing a variety of issues related to productive aging. PMID- 23791328 TI - [Chronic radiodermatitis following coronaroplasty]. AB - We report the case of a 72-year-old patient sent by his dermatologist in January 2009 for a back burn. His medical history reported one coronarography and two coronaroplasties between September and October 2005. This enabled us to form the diagnosis of chronic radiodermatitis after coronaroplasty from literature data. The occurrence of chronic radiodermatitis of the back and axilla area after cardiac catheterization has been observed in many countries. It almost always occurred in patients who underwent difficult and long-acting procedures leading to high doses radiation. There is not always acute radiodermatitis. Lesions appear between three and 30 months after exposure or even later. They are well defined four-sided centimetrics lesions going from simple radiodystrophy to ulceration such as late radionecrosis requiring surgical coverage procedure. PMID- 23791329 TI - [Morphological evaluation of genioplasty associated with orthognathic surgery]. AB - INTRODUCTION: The maxillo-mandibulary dysphormias are frequently associated with morphological abnormalities of the chin. Their correction in the sagittal and transverse planes can benefit both morphologically and functionally. The purpose of this study was to evaluate the morphological benefit of the osseous genioplasty associated with orthognathic surgery depending on the type of technique used, as well as complications occurred. PATIENTS AND METHODS: We identified patients who underwent osseous genioplasty associated with orthognathic surgery in our department between 2004 and 2010. For each patient Angle class, type of osteotomy, genioplasty and postoperative complications were recorded. The morphological results were evaluated by a group of surgeons and a group of observers using standardized photographs. RESULTS: Of the 203 facial osteotomies performed during this period, 101 osseous genioplasties were made. In most cases, there was a height reduction associated with advancement of the chin. The morphological results were considered as satisfactory all evaluators alike (3.92). The best results were obtained in height reductions with advancement techniques as sliding genioplasty (4.03) and jumping divided genioplasty (4.19). Five patients (5.9%) had a postoperative complication. This was especially one mental nerve injury and two dental mortifications. No default of consolidation or necrosis or hematoma of mouth floor have been reported. CONCLUSION: Osseous genioplasty is a safe, reliable procedure with morphological satisfactory outcome, in combination with orthognathic surgery. The best results were obtained with cases of height reduction with advancement of the chin, especially the original technique of the jumping divided genioplasty. PMID- 23791330 TI - Violence against women: ending the global scourge. PMID- 23791331 TI - Adolescent health, youth participation, and Taksim square. PMID- 23791332 TI - Dengue--an infectious disease of staggering proportions. PMID- 23791333 TI - AIDS governance: best practices for a post-2015 world. PMID- 23791335 TI - Anita Zaidi: promoting newborn and child health in Pakistan. PMID- 23791336 TI - Immunosuppression for membranous nephropathy. PMID- 23791337 TI - Immunosuppression for membranous nephropathy. PMID- 23791338 TI - Immunosuppression for membranous nephropathy. PMID- 23791339 TI - Immunosuppression for membranous nephropathy. PMID- 23791340 TI - Immunosuppression for membranous nephropathy. PMID- 23791341 TI - Health and medicine in Russia. PMID- 23791342 TI - Immunosuppression for membranous nephropathy - Authors' reply. PMID- 23791343 TI - Screening immigrants for tuberculosis--why not for HBV infection? PMID- 23791344 TI - UK medical students, academia, and the financial crisis. PMID- 23791345 TI - Deep coma and diffuse white matter abnormalities caused by sepsis-associated encephalopathy. PMID- 23791346 TI - Photoelectrocatalytic degradation of triclosan on TiO2 nanotube arrays and toxicity change. AB - Triclosan, one of the most widely used disinfectants, has been found to be toxic to animals and human beings. In this paper, triclosan was degraded on TiO2 nanotube arrays, using a photoelectrocatalytic (PEC) process under UV illumination, with Na2SO4 as the supporting electrolyte. The effect of bias potential was investigated and the results showed that 0V was the most appropriate potential for the degradation of triclosan. In 30min, 78.7% of triclosan had degraded during the PEC process. Intermediate analysis showed that 2,7-dichlorodibenzodioxin (DCDD) had formed during the degradation. The toxicity change during the PEC process was investigated using a luminescent bacteria test, with the results demonstrating that the toxicity of the reaction liquid decreased at the beginning and subsequently increased to a stable level. The indications were that some intermediates such as 2,7-dichlorodibenzodioxin was more toxic and stable than triclosan in the solution. PMID- 23791347 TI - Atmospheric partitioning and the air-water exchange of polycyclic aromatic hydrocarbons in a large shallow Chinese lake (Lake Chaohu). AB - The residual levels of polycyclic aromatic hydrocarbons (PAHs) in the atmosphere and in dissolved phase from Lake Chaohu were measured by (GC-MS). The composition and seasonal variation were investigated. The diffusive air-water exchange flux was estimated by a two-film model, and the uncertainty in the flux calculations and the sensitivity of the parameters were evaluated. The following results were obtained: (1) the average residual levels of all PAHs (PAH16) in the atmosphere from Lake Chaohu were 60.85+/-46.17 ng m(-3) in the gaseous phase and 14.32+/ 23.82 ng m(-3) in the particulate phase. The dissolved PAH16 level was 173.46+/ 132.89 ng L(-1). (2) The seasonal variation of average PAH16 contents ranged from 43.09+/-33.20 ng m(-3) (summer) to 137.47+/-41.69 ng m(-3) (winter) in gaseous phase, from 6.62+/-2.72 ng m(-3) (summer) to 56.13+/-22.99 ng m(-3) (winter) in particulate phase, and 142.68+/-74.68 ng L(-1) (winter) to 360.00+/-176.60 ng L( 1) (summer) in water samples. Obvious seasonal trends of PAH16 concentrations were found in the atmosphere and water. The values of PAH16 for both the atmosphere and the water were significantly correlated with temperature. (3) The monthly diffusive air-water exchange flux of total PAH16 ranged from -1.77*10(4) ng m(-2) d(-1) to 1.11*10(5) ng m(-2) d(-1), with an average value of 3.45*10(4) ng m(-2) d(-1). (4) The results of a Monte Carlo simulation showed that the monthly average PAH fluxes ranged from -3.4*10(3) ng m(-2) d(-1) to 1.6*10(4) ng m(-2) d(-1) throughout the year, and the uncertainties for individual PAHs were compared. (5) According to the sensitivity analysis, the concentrations of dissolved and gaseous phase PAHs were the two most important factors affecting the results of the flux calculations. PMID- 23791348 TI - Comment on "In situ air-water and particle-water partitioning of perfluorocarboxylic acids, perfluorosulfonic acids and perfluorooctyl sulfonamide at a wastewater treatment plant [Vierke et al. Chemosphere 2013 doi:10.1016/j.chemosphere.2013.02.067]". PMID- 23791349 TI - Automatic non-rigid temporal alignment of intravascular ultrasound sequences: method and quantitative validation. AB - Clinical studies on atherosclerosis regression/progression performed by intravascular ultrasound analysis would benefit from accurate alignment of sequences of the same patient before and after clinical interventions and at follow-up. In this article, a methodology for automatic alignment of intravascular ultrasound sequences based on the dynamic time warping technique is proposed. The non-rigid alignment is adapted to the specific task by applying it to multidimensional signals describing the morphologic content of the vessel. Moreover, dynamic time warping is embedded into a framework comprising a strategy to address partial overlapping between acquisitions and a term that regularizes non-physiologic temporal compression/expansion of the sequences. Extensive validation is performed on both synthetic and in vivo data. The proposed method reaches alignment errors of approximately 0.43 mm for pairs of sequences acquired during the same intervention phase and 0.77 mm for pairs of sequences acquired at successive intervention stages. PMID- 23791350 TI - Contrast-ultrasound dispersion imaging for prostate cancer localization by improved spatiotemporal similarity analysis. AB - Angiogenesis plays a major role in prostate cancer growth. Despite extensive research on blood perfusion imaging aimed at angiogenesis detection, the diagnosis of prostate cancer still requires systematic biopsies. This may be due to the complex relationship between angiogenesis and microvascular perfusion. Analysis of ultrasound-contrast-agent dispersion kinetics, determined by multipath trajectories in the microcirculation, may provide better characterization of the microvascular architecture. We propose the physical rationale for dispersion estimation by an existing spatiotemporal similarity analysis. After an intravenous ultrasound-contrast-agent bolus injection, dispersion is estimated by coherence analysis among time-intensity curves measured at neighbor pixels. The accuracy of the method is increased by time domain windowing and anisotropic spatial filtering for speckle regularization. The results in 12 patient data sets indicated superior agreement with histology (receiver operating characteristic curve area = 0.88) compared with those obtained by reported perfusion and dispersion analyses, providing a valuable contribution to prostate cancer localization. PMID- 23791352 TI - Tissue Doppler imaging and tissue strain imaging for the evaluation of hepatic fibrosis in patients with chronic hepatitis B. AB - We studied the feasibility of evaluating the stages of liver fibrosis with tissue Doppler imaging (TDI) and tissue strain imaging (TSI) for patients with chronic hepatitis B virus infection. One hundred ten patients were divided into two groups: normal adult group (n = 38) and chronic liver disease group (n = 72, patients infected with HBVs). The chronic liver disease group was divided into three subgroups on the basis of the Scheuer scoring system and clinical evidence: mild fibrosis (S0 and S1, n = 11), moderate fibrosis (S2 and S3, n = 27) and cirrhosis (S4 and clinically typical cirrhosis, n = 34) groups. TDI was performed for a chosen oblique section. Four regions of interest (ROIs), A-D, were chosen in the hepatic parenchyma based on the direction of propagation from the heart to the liver. Strain rate curves were obtained on the basis of TDI and TSI findings. Strain peak rates (SPRs) of all ROIs and the differences in times to SPRs for the four ROIs (TA-B, TB-C and TC-D) in the hepatic parenchyma were measured with TDI and TSI. Strain rate curves were analyzed for each ROI. The strain rate curves for the normal adult group were synchronous, whereas those for the chronic liver disease group were asynchronous. SPRs of the ROIs gradually decreased with the progression of liver fibrosis. The SPRs of ROI B significantly correlated with chronic liver disease severity (r = 0.991, p < 0.05). Areas under the curve (AUCs) of the ROI A and ROI B SPRs at the moderate fibrosis and cirrhosis stages were 0.86 +/- 0.06, 0.81 +/- 0.56 and 0.90 +/- 0.65, 0.92 +/- 0.04, respectively. The AUC of the SPRs of ROIs A and B correlated better than the platelet/age/phosphatase/alpha-fetoprotein/aspartate aminotransferase (PAPAS) index for advanced fibrosis. The differences in time to SPRs among the peaks of the four ROIs (TA-B, TB-C and TC-D) gradually increased with the progression of liver fibrosis. TDI and TSI with quantitative measurements using tissue Doppler analysis software (TDIQ, GE Medical Systems, Horten, Norway) provided reliable information for evaluating non-invasive liver fibrosis in patients with chronic hepatitis B. PMID- 23791351 TI - Age- and gender-related changes in ventricular performance in wild-type FVB/N mice as evaluated by conventional and vector velocity echocardiography imaging: a retrospective study. AB - Detailed studies in animal models to assess the importance of aging animals in cardiovascular research are rather scarce. The increase in mouse models used to study cardiovascular disease makes the establishment of physiologic aging parameters in myocardial function in both male and female mice critical. Forty four FVB/N mice were studied at multiple time points between the ages of 3 and 16 mo using high-frequency echocardiography. Our study found that there is an age dependent decrease in several systolic and diastolic function parameters in male mice, but not in female mice. This study establishes the physiologic age- and gender-related changes in myocardial function that occur in mice and can be measured with echocardiography. We report baseline values for traditional echocardiography and advanced echocardiographic techniques to measure discrete changes in cardiac function in the commonly employed FVB/N strain. PMID- 23791353 TI - Ultrasound imaging velocimetry: effect of beam sweeping on velocity estimation. AB - As an emerging flow-mapping tool that can penetrate deep into optically opaque media such as human tissue, ultrasound imaging velocimetry has promise in various clinical applications. Previous studies have shown that errors occur in velocity estimation, but the causes have not been well characterised. In this study, the error in velocity estimation resulting from ultrasound beam sweeping in image acquisition is quantitatively investigated. The effects on velocity estimation of the speed and direction of beam sweeping relative to those of the flow are studied through simulation and experiment. The results indicate that a relative error in velocity estimation of up to 20% can be expected. Correction methods to reduce the errors under steady flow conditions are proposed and evaluated. Errors in flow estimation under unsteady flow are discussed. PMID- 23791354 TI - Design of anthropomorphic flow phantoms based on rapid prototyping of compliant vessel geometries. AB - Anatomically realistic flow phantoms are essential experimental tools for vascular ultrasound. Here we describe how these flow phantoms can be efficiently developed via a rapid prototyping (RP) framework that involves direct fabrication of compliant vessel geometries. In this framework, anthropomorphic vessel models were drafted in computer-aided design software, and they were fabricated using stereolithography (one type of RP). To produce elastic vessels, a compliant photopolymer was used for stereolithography. We fabricated a series of compliant, diseased carotid bifurcation models with eccentric stenosis (50%) and plaque ulceration (types I and III), and they were used to form thin-walled flow phantoms by coupling the vessels to an agar-based tissue-mimicking material. These phantoms were found to yield Doppler spectrograms with significant spectral broadening and color flow images with mosaic patterns, as typical of disturbed flow under stenosed and ulcerated disease conditions. Also, their wall distension behavior was found to be similar to that observed in vivo, and this corresponded with the vessel wall's average elastic modulus (391 kPa), which was within the nominal range for human arteries. The vessel material's acoustic properties were found to be sub-optimal: the estimated average acoustic speed was 1801 m/s, and the attenuation coefficient was 1.58 dB/(mm.MHz(n)) with a power-law coefficient of 0.97. Such an acoustic mismatch nevertheless did not notably affect our Doppler spectrograms and color flow image results. These findings suggest that phantoms produced from our design framework have the potential to serve as ultrasound-compatible test beds that can simulate complex flow dynamics similar to those observed in real vasculature. PMID- 23791355 TI - Measuring fetal volume during late first trimester by three-dimensional ultrasonography using virtual organ computer-aided analysis. AB - Our aim was to determine whether rotating the fetus over its largest axis and reducing the rotational step angle can improve reliability/agreement of fetal volume measurements obtained with three-dimensional ultrasonography (3-DUS). Two observers acquired three 3-DUS data sets for a fetus with a crown-rump length between 45 and 84 mm. These observers determined the fetal volume using virtual organ computer-aided analysis (VOCAL), by three different methods, with a rotational step angle of 30 degrees : (1) minimal manipulation of the 3-DUS data set, fetus rotated over any axis; (2) manipulation of the 3-DUS data set until the fetus could be seen in a standardized manner, fetus rotated over its anteroposterior axis; (3) same 3-DUS data set manipulation, fetus rotated over its longitudinal axis. Intra- and inter-observer reliability/agreement was determined with intra-class correlation coefficients and limits of agreement. In addition, we tested the method that provided the best reliability/agreement results using 15 degrees and 9 degrees of rotational step angles. The time taken to manipulate 3-DUS and determine fetal volume was recorded. The best intra and inter-observer reliability/agreement results were observed when the fetus was rotated over its longitudinal axis. Reducing rotational step angle to 15 degrees or 9 degrees did not further improve reliability/agreement. The observer took approximately 1 min to determine fetal volume using this method. Our findings indicate that fetal volume should be determined by rotating the fetus over its longitudinal axis, at a rotational step angle of 30 degrees , which is relatively fast and allows analysis of fetal volume with good reliability and agreement. PMID- 23791356 TI - Quantitative analysis of dynamic power Doppler sonograms for patients with thyroid nodules. AB - To clarify and determine whether power Doppler sonograms are useful for the detection of malignant thyroid nodules, a computerized quantification method was used to evaluate the vascular density of a thyroid nodule in a prospective setting. Sonographic power Doppler images were collected in consecutive frames (45 frames of images), and a proprietary program (AmCAD-UV) was implemented using methods proposed in this article automatically calculated a quantified power Doppler vascular index (PDVI). The minimum PDVI value (PDVImin) was suggested as a measure of the vascular density of the nodule. The vascular densities of the peripheral and central areas of the nodule, referred to as central PDVImin and Ring PDVImin, respectively, were also evaluated. For 238 tumors (79 malignant and 159 benign) from 208 patients, all of the proposed indices of benign lesions were significantly higher than those of the malignant lesions. The area under the receiver operating characteristic curve (AUC) reaches 71% with the PDVImin. When the vascular patterns were further classified into intra-nodular and peripheral vascularity types, no vascularity type was observed significantly more frequently in malignant nodules than in benign nodules. These proposed computerized vascular indices provide a quantification method to objectively evaluate thyroid nodules and have potential as predictors of thyroid malignancy. The conventional vascular characterizations of malign nodules, that is, more vessels are observed in malignant nodules than in benign nodules, are shown to be unreliable in our study. Instead, a higher value of the quantified power Doppler vascular density was observed in benign nodules. PMID- 23791357 TI - Hematopoietic cell transplantation in high-risk childhood acute myelogenous leukemia. PMID- 23791358 TI - A clever person solves a problem; a wise person avoids it. PMID- 23791361 TI - Urinary cystatin C as a renal biomarker and its immunohistochemical localization in anti-GBM glomerulonephritis rats. AB - The usefulness of urinary cystatin C for the early detection of renal damage in anti-glomerular basement membrane (GBM) glomerulonephritis rats was investigated and compared to other biomarkers (beta2-microglobulin, calbindin, clusterin, epidermal growth factor (EGF), alpha-glutathione S-transferase (GST-alpha), mu glutathione S-transferase (GST-MU), kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), osteopontin, tissue inhibitor of metalloprotease-1 (TIMP-1), and vascular endothelial growth factor (VEGF)). Urinary levels of cystatin C increased in anti-GBM glomerulonephritis rats, whereas the conventional markers, plasma creatinine and UN did not, demonstrating its usefulness for the early detection of renal damage associated with anti-GBM glomerulonephritis. As well as cystatin C, urinary beta2-microglobulin, clusterin, GST-alpha, GST-MU, KIM-1, and NGAL also had the potential to detect renal damage associated with anti-GBM glomerulonephritis. Furthermore, the immunohistochemical localization of cystatin C in the kidney was examined. Cystatin C expression was mainly observed in the proximal renal tubules in anti GBM glomerulonephritis rats, and its expression barely changed with the progression of glomerulonephritis. Cystatin C expression was also observed in the tubular lumen of the cortex and medulla when glomerulonephritis was marked, which was considered to be characteristic of renal damage. In conclusion, urinary cystatin C, beta2-microglobulin, clusterin, GST-alpha, GST-MU, KIM-1, and NGAL could be useful biomarkers of renal damage in anti-GBM glomerulonephritis rats. Immunohistochemical cystatin C expression in the proximal renal tubules was barely changed by the progression of glomerulonephritis, but it was newly observed in the tubular lumen when renal damage was apparent. PMID- 23791360 TI - The association of subjective workload dimensions on quality of care and pharmacist quality of work life. AB - BACKGROUND: Workload has been described both objectively (e.g., number of prescriptions dispensed per pharmacist) as well as subjectively (e.g., pharmacist's perception of busyness). These approaches might be missing important characteristics of pharmacist workload that have not been previously identified and measured. OBJECTIVES: To measure the association of community pharmacists' workload perceptions at three levels (organization, job, and task) with job satisfaction, burnout, and perceived performance of two tasks in the medication dispensing process. METHODS: A secondary data analysis was performed using cross sectional survey data collected from Wisconsin (US) community pharmacists. Organization-related workload was measured as staffing adequacy; job-related workload was measured as general and specific job demands; task-related workload was measured as internal and external mental demands. Pharmacists' perceived task performance was assessed for patient profile review and patient consultation. The survey was administered to a random sample of 500 pharmacists who were asked to opt in if they were a community pharmacist. Descriptive statistics and correlations of study variables were determined. Two structural equation models were estimated to examine relationships between the study variables and perceived task performance. RESULTS: From the 224 eligible community pharmacists that agreed to participate, 165 (73.7%) usable surveys were completed and returned. Job satisfaction and job-related monitoring demands had direct positive associations with both dispensing tasks. External task demands were negatively related to perceived patient consultation performance. Indirect effects on both tasks were primarily mediated through job satisfaction, which was positively related to staffing adequacy and cognitive job demands and negatively related to volume job demands. External task demands had an additional indirect effect on perceived patient consultation performance, as it was associated with lower levels of job satisfaction and higher levels of burnout. IMPLICATIONS/CONCLUSIONS: Allowing community pharmacists to concentrate on tasks and limiting interruptions while performing these tasks are important factors in improving quality of patient care and pharmacist work life. The results have implications for strategies to improve patient safety and pharmacist performance. PMID- 23791362 TI - Culture independent methods to assess the diversity and dynamics of microbiota during food fermentation. AB - Culture independent methods first appeared in the food microbiology field at the end of the 90s and since then they have been applied extensively. These methods do not rely on cultivation and target nucleic acids (DNA and RNA) to identify and follow the changes that occur in the main populations present in a specific ecosystem. The method that has most often been used as a culture independent method in food microbiology is denaturing gradient gel electrophoresis (DGGE). The number of papers dealing with DGGE grew exponentially in the late nineties and, by analysing the studies available in the literature, it is possible to describe a trend in the subjects that have been investigated. DGGE was first used as a tool to monitor the ecology of fermented food, such as fermented sausage, cheese and sourdough, and later it also showed its potential in microbial spoilage process. In the last few years, the main application of DGGE has been to study fermented food from Asia, Africa and South America. The information collected using DGGE has made it possible to confirm the existing knowledge on food fermentation and spoilage. However, in some cases, new evidence that helps scientists to fully comprehend a specific microbial ecosystem has emerged. In this review, the roadmap of culture independent methods in food microbiology will be summarized, focusing on the DGGE technique. Examples of how this approach is useful to obtain a better understanding of microbial diversity are reported for several kinds of fermented food, such as fermented sausage, cheese and wine. The future of culture independent methods in food microbiology, with the increasing availability of next generation sequencing techniques, is also discussed. PMID- 23791363 TI - Long-term clinical course of acute pulmonary embolism. AB - The long-term clinical course of acute pulmonary embolism (PE) is complicated by high rates of serious adverse events, both before and after cessation of anticoagulant therapy. These adverse events include recurrent venous thromboembolism, chronic thromboembolic pulmonary hypertension, arterial thrombotic events and increased risk of death, all compared to patients without thromboembolic disease. Several pharmacological options are available that may beneficially influence patients' prognosis. Nonetheless, because of insufficient knowledge of the benefit-to-harm ratio of these pharmacological agents, unambiguous recommendations are scarcely available. This review will cover the epidemiological aspects of the various possible complications in the long-term clinical course of acute PE as well as the latest evidence on preventive strategies. In addition, the unresolved issues regarding frequency, duration and focus of medical follow-up after acute PE are discussed. PMID- 23791364 TI - Early biomarkers related to secondary primary cancer risk in radiotherapy treated prostate cancer patients: IMRT versus IMAT. AB - PURPOSE: To investigate whether rotational techniques (Volumetric Modulated Arc Therapy - VMAT) are associated with a higher risk for secondary primary malignancies compared to step-and-shoot Intensity Modulated Radiation Therapy (ss IMRT). To this end, radiation therapy (RT) induced DNA double-strand-breaks and the resulting chromosomal damage were assessed in peripheral blood T-lymphocytes of prostate cancer (PCa) patients applying gammaH2AX foci and G0 micronucleus (MN) assays. METHODS AND MATERIALS: The study comprised 33PCa patients. A blood sample was taken before start of therapy and after the 1st and 3rd RT fraction to determine respectively the RT-induced gammaH2AX foci and MN. The equivalent total body dose (D(ETB)) was calculated based on treatment planning data. RESULTS: A linear dose response was obtained for gammaH2AX foci yields versus D(ETB) while MN showed a linear-quadratic dose response. Patients treated with large volume (LV) VMAT show a significantly higher level of induced gammaH2AX foci and MN compared to IMRT and small volume (SV) VMAT (p<0.01). Assuming a linear-quadratic relationship, a satisfactory correlation was found between both endpoints (R(2) 0.86). CONCLUSIONS: Biomarker responses were governed by dose and irradiated volume of normal tissues. No significant differences between IMRT and rotational therapy inherent to the technique itself were observed. PMID- 23791365 TI - Late dysphagia after IMRT for head and neck cancer and correlation with dose volume parameters. AB - BACKGROUND AND PURPOSE: Many head and neck cancer (HNC) survivors experience diminished quality of life due to radiation-induced dysphagia. The aim of this study was to investigate frequency, intensity and dose-volume dependency for late dysphagia in HNC patients treated with curative IMRT. MATERIALS AND METHODS: Candidates for the study were 294 patients treated with primary IMRT from 2006 to 2010; a total of 259 patients accepted to participate by answering the EORTC QLQ C30 and H&N35 questionnaires. A total of 65 patients were further examined with modified barium swallow (MBS) and saliva collection. Data on patient, tumor and treatment characteristics were prospectively recorded in the DAHANCA database. Dose-volume histograms (DVH) of swallowing-related structures were retrospectively analyzed. RESULTS: QoL data showed low degree of dysphagia (QoL subscales scores of 17 and below) compared to objective measures. The most frequent swallowing dysfunction was retention; penetration and aspiration was less common. In general, objective measurements and observer-assessed late dysphagia correlated with dose to pharyngeal constrictor muscles (PCM), whereas QoL endpoints correlated with DVH parameters in the glottis/supraglottic larynx. Both xerostomia and dysphagia has been reduced after introduction of IMRT. CONCLUSIONS: Radiation-induced dysphagia is still important, with a high degree of retention and penetration. Introduction of parotid-sparing IMRT has reduced the severity of dysphagia, primarily through a major reduction in xerostomia. Dose-response relationships were found for specific dysphagia endpoints. PMID- 23791366 TI - Pulsed low-dose irradiation of orthotopic glioblastoma multiforme (GBM) in a pre clinical model: effects on vascularization and tumor control. AB - BACKGROUND AND PURPOSE: To compare dose-escalated pulsed low-dose radiation therapy (PLRT) and standard radiation therapy (SRT). METHODS AND MATERIALS: Intracranial U87MG GBM tumors were established in nude mice. Animals received whole brain irradiation with daily 2-Gy fractions given continuously (SRT) or in ten 0.2-Gy pulses separated by 3-min intervals (PLRT). Tumor response was evaluated using weekly CT and [(18)F]-FDG-PET scans. Brain tissue was subjected to immunohistochemistry and cytokine bead array to assess tumor and normal tissue effects. RESULTS: Median survival for untreated animals was 18 (SE+/-0.5) days. A significant difference in median survival was seen between SRT (29+/-1.8days) and PLRT (34.2+/-1.9days). Compared to SRT, PLRT resulted in a 31% (p<0.01), 38% (p<0.01), and 53% (p=0.01) reduction in normalized tumor volume and a 48% (p<0.01), 51% (p<0.01), and 70% (p<0.01) reduction in tumor growth rate following the administration of 10Gy, 20Gy, and 30Gy, respectively. Compared to untreated tumors, PLRT resulted in similar tumor vascular density, while SRT produced a 40% reduction in tumor vascular density (p=0.05). Compared to SRT, PLRT was associated with a 28% reduction in degenerating neurons in the surrounding brain parenchyma (p=0.05). CONCLUSIONS: Compared to SRT, PLRT resulted in greater inhibition of tumor growth and improved survival, which may be attributable to preservation of vascular density. PMID- 23791368 TI - Imaging for inflammatory bowel disease: the new "sounding board". PMID- 23791367 TI - Anticancer activity and SAR studies of substituted 1,4-naphthoquinones. AB - In this paper, we report the structure-activity relationship studies of substituted 1,4-naphthoquinones for its anticancer properties. 1,4 Naphthoquinone, Juglone, Menadione, Plumbagin and LLL12.1 were used as lead molecules to design PD compounds. Most of the PD compounds showed improved antiproliferative activity in comparison to the lead molecule in prostate (DU 145), breast (MDA-MB-231) and colon (HT-29) cancer cell lines. PD9, PD10, PD11, PD13, PD14 and PD15 were found to be the most potent compound with an IC0 value of 1-3 MUM in all cancer cell lines. Fluorescent polarization assay was employed to study the inhibition of STAT3 dimerization by PD compounds. PD9 and PD18 were found to be potent STAT3 dimerization inhibitors. PMID- 23791369 TI - Switching anti-vascular endothelial growth factor therapy for neovascular age related macular degeneration. PMID- 23791370 TI - Surgical removal of intraocular tumors: dismissing old wives' tales. PMID- 23791371 TI - Vitrectomy with or without preoperative intravitreal bevacizumab for proliferative diabetic retinopathy: a meta-analysis of randomized controlled trials. AB - PURPOSE: To compare safety and functional outcomes of vitrectomy with or without preoperative intravitreal bevacizumab (IVB) for proliferative diabetic retinopathy (PDR). DESIGN: A meta-analysis of randomized controlled trials. METHODS: PubMed, Medline, EMBASE, and Cochrane Controlled Trials Register were searched to identify potentially relevant randomized controlled trials. A total of 394 participants with 414 eyes in 8 trials were analyzed using RevMan 5.1 software. The primary measures included intraoperative bleeding, total surgical time, and early and late recurrent hemorrhage. RESULTS: Vitrectomy with IVB pretreatment achieved shorter overall surgical time (mean difference = -26.89 minutes, 95% confidence interval [CI] -31.38 to -22.39, P < .00001) and smaller number of endodiathermy applications (mean difference = -3.46, 95% CI -6.43 to 0.49, P = .02) compared to vitrectomy alone. The IVB group was also associated with less intraoperative bleeding (odds ratio [OR] = 0.10; 95% CI 0.02 to 0.46; P = .003) and recurrent vitreous hemorrhage within first month (OR = 0.35; 95% CI 0.21 to 0.58; P < .0001), but the proportion of recurrent vitreous hemorrhage after the first month was comparable between both groups. There were no significant differences in other complication rates between the 2 groups, with the exception of iatrogenic retinal break, which was more likely with the vitrectomy-alone group (OR = 0.27, 95% CI 0.12 to 0.63, P = .003). Results were robust to sensitivity analyses. CONCLUSIONS: Adjuvant intravitreal injection of bevacizumab prior to vitrectomy in PDR patients significantly eased the procedure, diminished intraoperative complications, and reduced early postoperative hemorrhage without increasing the risk of vision-threatening complications. Further trials should determine the optimal interval and dosage for IVB injection. PMID- 23791372 TI - Reactive retinal astrocytic tumors (so-called vasoproliferative tumors): histopathologic, immunohistochemical, and genetic studies of four cases. PMID- 23791373 TI - Reply: To PMID 23219067. PMID- 23791374 TI - Short-term topical bevacizumab in the treatment of stable corneal neovascularization. PMID- 23791375 TI - Reply: To PMID 22967868. PMID- 23791376 TI - In vivo confocal microscopy and diagnosis of limbal stem cell deficiency. Photographing the palisades of vogt and limbal stem cells. PMID- 23791377 TI - Reply: To PMID 23127748. PMID- 23791378 TI - Regional practice patterns for retinal detachment repair in the United States. PMID- 23791379 TI - Reply: To PMID 22321800. PMID- 23791380 TI - Facial soft tissue thickness in the Brazilian population: new reference data and anatomical landmarks. AB - Facial soft tissue thickness measurement can be useful among several medico-legal techniques that aim to establish the identity of skeletal remains. This study examined the soft tissue thickness that covered the faces of autopsied cadavers sent to the Medico-Legal Institute of Guarulhos from September 2010 to September 2011. Forty-nine anatomical facial landmarks were measured in cadavers less than 24h after death; these data were analysed using two-tailed t-tests. This project was approved by an ethics committee. One hundred cadavers were studied (74 males and 26 females). A majority of these individuals had died between 41 and 60 years old. Of the 49 anatomical landmarks, only five differed between the sexes (i.e., p-value less than 0.05): upper lip margin (p=0.006), superior labial sulcus (p=0.006), stomion (p=0.001), right lateral orbit (p=0.008), and left cheilion (p=0.009). The inclusion of additional anatomical landmarks allowed us to establish more precise facial thickness parameters that have the potential to be applied to cadaver facial approximations in Brazil; furthermore, some anatomic landmarks presented a higher discriminant power with regard to sex. PMID- 23791381 TI - Suicide by carbon dioxide. AB - Suicides by self-poisoning are common in all parts of the world. Among these intoxications, gases are rarely used, especially carbon dioxide (CO2). Very few cases of self-inflicted and deliberate carbon dioxide poisonings have been reported. This paper presents two uncommon suicides by carbon dioxide intoxication. In one case, a 53-year-old man tightly sealed a small bathroom and locked himself in it likely with dry ice. Warning notices were tagged to the door. In another case, a 48-year-old man working in a restaurant committed suicide by closing himself in a walk-in refrigerator and opening the stored carbon dioxide containers intended for the beverage dispensing equipment. The limited possibilities of proving lethal CO2 intoxications post-mortem necessitate a close cooperation of the involved parties during investigation. Only the synopsis of all findings permits a sound assessment regarding the manner and cause of death. PMID- 23791382 TI - Experience of a monographic tuberculosis unit: the first 500 cases. AB - INTRODUCTION: Tuberculosis (TB) remains a highly prevalent and potentially severe disease. However, since 2002 the annual incidence has been decreasing both worldwide and in Spain, where the incidence varies widely between regions. The main objective of this study is to describe the experience of a monographic TB unit in a second level hospital. PATIENTS AND METHODS: A descriptive study was carried out which included all cases of TB diagnosed in a monographic unit of a secondary hospital between 2003 and 2011. Demographic, clinical, epidemiological and microbiological data were recorded. RESULTS: We analyzed 500 TB cases and found an increasing annual incidence in all subgroups, including native and immigrant populations. Most cases (63.8%) were male, with a median age of 36 years (range 8 months-90 years). In total, 39.8% of patients were foreign born. Coinfection with human immunodeficiency virus was found in 11% of cases. The pulmonary form was most frequently diagnosed (63.8%). Overall mortality was 5.8% with no significant differences between groups (including foreign born and human immunodeficiency virus positive patients). CONCLUSIONS: Although TB incidence is globally decreasing, in our study we found an increasing number of cases in recent years in all subgroups, which can be explained by this being a monographic unit with an intensive contact tracing program. PMID- 23791383 TI - Prevalence of anaemia associated with chronic obstructive pulmonary disease. Study of associated variables. AB - BACKGROUND: Anaemia is one of the extrapulmonary manifestations of chronic obstructive pulmonary disease (COPD). Its real prevalence, physiopathology and clinical repercussion are unknown. The objectives of our study were: to determine the prevalence of anaemia in patients with stable COPD not attributable to other causes and to establish the relationship of anaemia with clinical, prognostic and inflammatory markers with an important role in COPD. METHODS: The study included stable COPD patients with no other known causes of anaemia. The following tests were carried out: respiratory function tests; serum determination of erythropoietin and inflammatory markers: high sensitivity C-reactive protein (hs CRP), fibrinogen, interleukin 6 (IL-6), interleukin 8 (IL-8) and tumour necrosis factor alpha (TNF-alpha). Body mass index (BMI), Charlson and BODE indices, the number of exacerbations in the previous year, dyspnoea and quality of life were also calculated. RESULTS: One hundred and thirty patients were included. Anaemia prevalence was 6.2%. Mean haemoglobin value in anaemic patients was 11.9+/ 0.95g/dL. Patients with anaemia had a lower BMI (P=.03), higher Charlson index (P=.002), more elevated erythropoietin levels (P=.016), a tendency to present a lower FEV1% value (P=.08) and significantly lower IL-6 values when compared to non-anaemic patients (P=.003). CONCLUSIONS: In our series, the anaemia associated with COPD was less prevalent than that published in the literature to date, and was related to certain clinical and inflammatory markers. PMID- 23791384 TI - PolyQ proteins interfere with nuclear degradation of cytosolic proteins by sequestering the Sis1p chaperone. AB - Dysfunction of protein quality control contributes to the cellular pathology of polyglutamine (polyQ) expansion diseases and other neurodegenerative disorders associated with aggregate deposition. Here we analyzed how polyQ aggregation interferes with the clearance of misfolded proteins by the ubiquitin-proteasome system (UPS). We show in a yeast model that polyQ-expanded proteins inhibit the UPS-mediated degradation of misfolded cytosolic carboxypeptidase Y(*) fused to green fluorescent protein (GFP) (CG(*)) without blocking ubiquitylation or proteasome function. Quantitative proteomic analysis reveals that the polyQ aggregates sequester the low-abundant and essential Hsp40 chaperone Sis1p. Overexpression of Sis1p restores CG(*) degradation. Surprisingly, we find that Sis1p, and its homolog DnaJB1 in mammalian cells, mediates the delivery of misfolded proteins into the nucleus for proteasomal degradation. Sis1p shuttles between cytosol and nucleus, and its cellular level limits the capacity of this quality control pathway. Upon depletion of Sis1p by polyQ aggregation, misfolded proteins are barred from entering the nucleus and form cytoplasmic inclusions. PMID- 23791385 TI - Performances of malaria P.f/Pan rapid test device Acon(r) (Pf HRP2/pan aldolase) and malaria Pf rapid test device Acon(r) (Pf HRP2) for the diagnosis of malaria in adults and children living in Gabon, Central Africa. AB - The Malaria Pf Rapid Test Device Acon(r) (Acon Labs) and the pan HRP2/aldolase RDT, Malaria P.f/Pan Rapid Test Device Acon(r) (Acon Labs), performances were evaluated for malaria species diagnosis in 592 febrile patients living in Gabon using microscopy as gold standard. Sensitivities were equal or above 96.0% for Plasmodium falciparum detection, of 62.5% for non-P. falciparum malaria species detection and higher in younger children (100%). Negative predictive values were greater than 97.0%. Acon(r)HRP2 had a higher specificity (96.6%) and lower false positive (FP) rate (9.3%) compared to Acon(r)Pf/Pan, which had a specificity of 87.3% and a FP rate of 27.1% (P < 0.01). Overall, 32.5% of all Acon(r) Pf/Pan tests resulted in a "faint band" with only 2 resulted from samples with a parasitemia below 100 p/MUL. The accuracy of Acon(r)HRP2 RDT for the diagnosis of P. falciparum infection is confirmed. However, the high FP rate observed with Acon(r)Pf/Pan is a limitation for its use. PMID- 23791386 TI - Comparison of the analytical and clinical performances of Abbott RealTime High Risk HPV, Hybrid Capture 2, and DNA Chip assays in gynecology patients. AB - The detection of high-risk (HR) HPV in cervical cancer screening is important for early diagnosis of cervical cancer or pre-cancerous lesions. We evaluated the analytical and clinical performances of 3 HR HPV assays in Gynecology patients. A total of 991 specimens were included in this study: 787 specimens for use with a Hybrid Capture 2 (HC2) and 204 specimens for a HPV DNA microarray (DNA Chip). All specimens were tested using an Abbott RealTime High Risk HPV assay (Real-time HR), PGMY PCR, and sequence analysis. Clinical sensitivities for severe abnormal cytology (severe than high-grade squamous intraepithelial lesion) were 81.8% for Real-time HR, 77.3% for HC2, and 66.7% for DNA Chip, and clinical sensitivities for severe abnormal histology (cervical intraepithelial neoplasia grade 2+) were 91.7% for HC2, 87.5% for Real-time HR, and 73.3% for DNA Chip. As compared to results of the sequence analysis, HC2, Real-time HR, and DNA Chip showed concordance rates of 94.3% (115/122), 90.0% (117/130), and 61.5% (16/26), respectively. The HC2 assay and Real-time HR assay showed comparable results to each other in both clinical and analytical performances, while the DNA Chip assay showed poor clinical and analytical performances. The Real-time HR assay can be a good alternative option for HR HPV testing with advantages of allowing full automation and simultaneous genotyping of HR types 16 and 18. PMID- 23791387 TI - Probe ligation and real-time detection of KPC, OXA-48, VIM, IMP, and NDM carbapenemase genes. AB - The Check-MDR Carba test (Check-Points, Wageningen, Netherlands), which is based on specific molecular recognition of blaNDM, blaKPC, blaOXA-48, blaVIM, and blaIMP genes by DNA probe ligation and real-time PCR detection, was evaluated on 183 well-characterized Gram-negative rods. Representatives of the 5 gene families were accurately identified (specificities and sensitivities of 100%) within 4.5 hours. This test may be helpful to differentiate carbapenem resistance mediated by carbapenemases from those involving other mechanisms. PMID- 23791388 TI - Cutaneous manifestations of Nocardia brasiliensis infection in Taiwan during 2002 2012-clinical studies and molecular typing of pathogen by gyrB and 16S gene sequencing. AB - To observe the clinicopathologic and resistance profiles of the Nocardia brasiliensis causing cutaneous nocardiosis in Taiwan, 12 N. brasiliensis isolates were prospectively collected from patients with cutaneous nocardiosis in a hospital during 2002-2012. Clinicopathologic data were obtained, and isolates were identified by biochemical methods and 16S rRNA sequencing. Susceptibilities to 14 antimicrobial compounds were tested. Isolates were further genotyped by sequencing of 16S rRNA, secA1, hsp65, and gyrB genes. The nodulopustular pyoderma associated with sporotrichoid spreading was the most common skin presentations caused by N. brasiliensis. All of the isolates were susceptible to amikacin, gentamicin, tobramycin, piperacillin/tazobactam, and trimethoprim/sulfamethoxazole and resistant to kanamycin, erythromycin, and oxacillin, while susceptibilities to imipenem, vancomycin, penicillin-G, tetracycline, clindamycin, and ciprofloxacin varied among the 12 isolates. GyrB genotyping delineated the 12 isolates into 2 major groups, which was coincident with different single nucleotide substitutions at position 160 (G versus T) of 16S rRNA, different levels of imipenem minimum inhibition concentration (4-32 versus 0.25-0.75 mg/L), and prevalence of lymphadenitis (66.7 versus 16.7%). We have noted that tiny pustular lesions can be the first sign of cutaneous nocardiosis, which we believe has not been previously emphasized. No resistance to trimethoprim and sulfamethoxazole was found; therefore, sulphonamide drugs remain effective for treatment of cutaneous nocardiosis in Taiwan. PMID- 23791389 TI - Brain metabolite alterations in young adults at familial high risk for schizophrenia using proton magnetic resonance spectroscopy. AB - BACKGROUND: Proton magnetic resonance spectroscopy ((1)H MRS) enables in-vivo measurement of several relevant brain metabolites and has provided evidence of a range of neurochemical abnormalities in schizophrenia, especially in glutamate and N-acetyl-aspartate (NAA). While individuals at high familial risk for schizophrenia (HR) exhibit some neurobiological findings observed in the disorder, (1)H MRS findings and their clinical correlates are not well characterized in this population. METHODS: We compared 23 adolescent and young adult offspring of schizophrenia patients with 24 age- and sex-matched healthy controls using (1)H MRS. We acquired multi-voxel, short TE (1)H MRS measurements at 1.5T and obtained metabolite concentrations of N-acetyl-aspartate (NAA), combined glutamate and glutamine (Glu+Gln) and choline-containing compounds (GPC+PC) for the left and right thalamus, anterior cingulate gyrus, and caudate. We also assessed the relationship between regional metabolite levels, clinical measures and brain volume in a subset of 16 high-risk and 15 control subjects. RESULTS: Compared to healthy controls, high-risk subjects showed reductions in NAA levels in all three regions (thalamus, caudate, and anterior cingulate cortex), increases in Glu+Gln in the thalamus and caudate, and increases in GPC+PC in the anterior cingulate. In HR, thalamic Glu+Gln concentration was positively correlated and thalamic NAA inversely correlated with measures of schizotypy. Anterior cingulate GPC+PC and caudate Glu+Gln were significantly correlated with attenuated psychotic symptom severity. Anterior cingulate NAA was correlated with executive function. CONCLUSIONS: Our data suggest the occurrence of metabolic alterations in young relatives of schizophrenia patients similar to those seen in patients with established illness. The observed correlations with cognitive deficits and psychosis-related psychopathology suggest that these metabolic measures may have value as biomarkers of risk for schizophrenia. PMID- 23791390 TI - Comparison of the effectiveness of Conners' CPT and the CPT-identical pairs at distinguishing between smokers and nonsmokers with schizophrenia. AB - Sustained attention deficits and high rates of smoking are often observed in patients with schizophrenia. This has led to the hypothesis that patients may smoke as an attempt to ameliorate cognitive deficits related to abnormal nicotinic structure and function. Continuous performance tasks (CPT) are often used to index sustained attention deficits in patients with schizophrenia, however, there are important differences between tasks that may impact performance in smokers and nonsmokers with schizophrenia differently. The Conners' CPT (C-CPT) has a high signal-to-noise ratio and is commonly used to assess impulsivity. The CPT-Identical Pairs (CPT-IP) has a low signal-to-noise ratio and is commonly used to assess negative symptoms in patients with schizophrenia. We sought to determine whether there were differences of sustained attention between patient smokers vs. nonsmokers, and if one CPT would provide a better separation of sustained attention between groups. Results revealed that both instruments detect more impaired sustained attention deficits in patient smokers compared to nonsmokers. Patient smokers performed significantly worse on the majority of the CPT-IP composite scores compared to the C-CPT composite scores. These results do not support the self-medication theory, as patient smokers performed worse than patient nonsmokers. Researchers studying sustained attention in schizophrenia may wish to consider the CPT-IP over the C-CPT, as well as control for smoking status. PMID- 23791391 TI - Neuropsychological functioning predicts community outcomes in affective and non affective psychoses: a 6-month follow-up. AB - INTRODUCTION: Neurocognitive dysfunction is a major symptom feature of schizophrenia and bipolar disorder. A prognostic relationship between cognition and community outcomes is well-documented in schizophrenia and increasingly recognized in bipolar disorder. However, specific associations among neurocognition, diagnosis, state symptomatology, and community functioning are unclear, and few studies have compared these relationships among patients with affective and non-affective psychoses in the same study. We examined neurocognitive, clinical, and community functioning in a cross-diagnostic sample of patients with psychotic disorders over a 6-month follow-up interval. METHOD: Neurocognitive, clinical and community functioning were assessed in participants with schizophrenia (n=13), schizoaffective disorder (n=17), or bipolar disorder with psychosis (n=18), and healthy controls (n=18) at baseline and 6months later. RESULTS: Neurocognitive functioning was impaired in all diagnostic groups and, despite reductions in primary symptoms, did not recover on most measures over the follow-up period. Neurocognitive impairment was not associated with diagnosis or clinical improvement. Several neurocognitive scores at baseline (but not diagnosis or clinical baseline or follow-up scores) predicted community functioning at follow-up. DISCUSSION: In one of the few studies to longitudinally examine neurocognition in association with clinical and outcomes variables in a cross diagnostic sample of psychotic disorders patients, neurocognitive deficits were pronounced across diagnoses and did not recover on most measures despite significant reductions in clinical symptoms. Baseline neurocognitive functioning was the only significant predictor of patients' community functioning six months later. Efforts to recognize and address cognitive deficits, an approach that has shown promise in schizophrenia, should be extended to all patients with psychosis. PMID- 23791394 TI - Care mechanisms to avoid readmission of patients with chronic obstructive pulmonar disease. PMID- 23791392 TI - A multicenter phase 1 study of EMD 525797 (DI17E6), a novel humanized monoclonal antibody targeting alphav integrins, in progressive castration-resistant prostate cancer with bone metastases after chemotherapy. AB - BACKGROUND: EMD 525797 (DI17E6) is a deimmunized, humanized monoclonal immunoglobulin G2 antibody against the alphav subunit of human integrins. Blocking alphav integrins may be an effective strategy for inhibiting prostate cancer (PCa) metastasis. OBJECTIVE: Evaluate EMD 525797 safety/tolerability and pharmacokinetics (PK) in castration-resistant PCa patients. Secondary objectives included antitumor activity assessments. DESIGN, SETTING, AND PARTICIPANTS: A phase 1 open-label study in 26 patients (four European centers). Eligible patients (>= 18 yr) had histologically proven PCa with bone metastases after prior chemotherapy and evidence of progressive disease (PD) based on prostate specific antigen (PSA) values. INTERVENTION: Patients received three intravenous EMD 525797 infusions (250, 500, 1000, or 1500 mg every 2 wk). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Treatment-emergent adverse events (TEAEs) and dose-limiting toxicities (DLTs) were assessed. PK parameters were calculated according to noncompartmental standard methods. Antitumor activity measures were response after 6 wk, changes in PSA levels, and pain interference total score. Descriptive statistics were used. RESULTS AND LIMITATIONS: Patients were treated for a mean of 16.8 +/- 16.7 wk. No DLTs were reported in any of the cohorts. All patients experienced TEAEs, which were considered drug-related in 11 patients. Four deaths occurred during the trial and were considered not related to EMD 525797. EMD 525797 showed dose-dependent, nonlinear PK. Eighteen of 26 patients did not show PD for >= 18 wk. Two patients (500-mg cohort), treated for 42.4 and 76.3 wk, had clinically significant PSA reductions and pain relief, including one patient with confirmed partial response. This trial was not specifically designed to assess clinical activity, and further investigations are needed in randomized controlled trials. CONCLUSIONS: No DLTs were reported in any of the evaluated cohorts. There was evidence of clinical activity. For the currently ongoing phase 2 trial, EMD 525797 doses of 750 and 1500 mg every 3 wk were chosen. TRIAL REGISTRATION: NCT00958477 (EMR 62242-002). PMID- 23791395 TI - Platelet inhibition by abciximab bolus-only administration and oral ADP receptor antagonist loading in acute coronary syndrome patients: the blocking and bridging strategy. AB - INTRODUCTION: Current guidelines still recommend the bolus and infusion administration of glycoprotein IIbIIIa inhibitors in patients with high-risk acute coronary syndrome undergoing percutaneous coronary intervention. We sought to evaluate the extent of platelet inhibition by a blocking and bridging strategy with intracoronary abciximab bolus-only administration and oral loading of adenosine diphosphate receptor antagonists. PATIENTS AND METHODS: Fifty-six consecutive high-risk acute coronary syndrome patients with bolus-only abciximab administration (0.25 mg/kg i.c.) and loading with 600 mg clopidogrel (55%) or 60 mg prasugrel (45%) were included in this study. Platelet aggregation induced by thrombin receptor-activating peptide and adenosine diphosphate was measured by multiple electrode aggregometry up to 7 days. RESULTS: Thrombin receptor activating peptide induced platelet aggregation was significantly suppressed for a minimum of 48 h (45+/-17U) and returned to a normal range (>84 U) after 6 days (90+/-26U; p<0.001). Co-medication with prasugrel significantly reduced adenosine diphosphate-induced (p=0.002) and thrombin receptor-activating peptide-induced (p=0.02) platelet aggregation compared with clopidogrel throughout the observation period. No stent thrombosis or repeat myocardial infarction occurred at 30-day follow-up. CONCLUSIONS: Immediate blocking of platelet aggregation in high-risk acute coronary syndrome patients by intracoronary abciximab bolus-only administration and bridging to prolonged inhibition via oral blockade of ADP receptors effectively inhibited overall platelet reactivity for at least 48 h, questioning the value of continuous abciximab infusion. Co-medication with prasugrel vs. clopidogrel synergistically augmented platelet inhibition. PMID- 23791396 TI - Trait anhedonia is associated with reduced reactivity and connectivity of mesolimbic and paralimbic reward pathways. AB - Anhedonia is the inability to experience pleasure from normally pleasant stimuli. Although anhedonia is a prominent feature of many psychiatric disorders, trait anhedonia is also observed dimensionally in healthy individuals. Currently, the neurobiological basis of anhedonia is poorly understood because it has been mainly investigated in patients with psychiatric disorders. Thus, previous studies have not been able to adequately disentangle the neural correlates of anhedonia from other clinical symptoms. In this study, trait anhedonia was assessed in well-characterized healthy participants with no history of Axis I psychiatric illness. Functional magnetic resonance imaging with musical stimuli was used to examine brain responses and effective connectivity in relation to individual differences in anhedonia. We found that trait anhedonia was negatively correlated with pleasantness ratings of music stimuli and with activation of key brain structures involved in reward processing, including nucleus accumbens (NAc), basal forebrain and hypothalamus which are linked by the medial forebrain bundle to the ventral tegmental area (VTA). Brain regions important for processing salient emotional stimuli, including anterior insula and orbitofrontal cortex were also negatively correlated with trait anhedonia. Furthermore, effective connectivity between NAc, VTA and paralimbic areas, that regulate emotional reactivity to hedonic stimuli, was negatively correlated with trait anhedonia. Our results indicate that trait anhedonia is associated with reduced reactivity and connectivity of mesolimbic and related limbic and paralimbic systems involved in reward processing. Critically, this association can be detected even in individuals without psychiatric illness. Our findings have important implications both for understanding the neurobiological basis of anhedonia and for the treatment of anhedonia in psychiatric disorders. PMID- 23791397 TI - Cerebrospinal fluid glutamate concentration correlates with impulsive aggression in human subjects. AB - Neurochemical studies have pointed to a modulatory role in human aggression for various central neurotransmitters. Some (e.g., serotonin) appear to play an inhibitory role, while others appear to play a facilitator role. While recent animal studies of glutaminergic activity suggest a facilitator role for central glutamate in the modulation of aggression, no human studies of central glutaminergic indices have yet been reported regarding aggression. Basal lumbar cerebrospinal fluid (CSF) was obtained from 38 physically healthy subjects with DSM-IV Personality Disorder (PD: n = 28) and from Healthy Volunteers (HV: n = 10) and assayed for glutamate, and other neurotransmitters, in CSF and correlated with measures of aggression and impulsivity. CSF Glutamate levels did not differ between the PD and HC subjects but did directly correlate with composite measures of both aggression and impulsivity and a composite measure of impulsive aggression in both groups. These data suggest a positive relationship between CSF Glutamate levels and measures of impulsive aggression in human subjects. Thus, glutamate function may contribute to the complex central neuromodulation of impulsive aggression in human subjects. PMID- 23791398 TI - Melanogenesis affects overall and disease-free survival in patients with stage III and IV melanoma. AB - Because melanogenesis can affect immune responses to and chemotherapy and radiotherapy for melanoma, we analyzed overall survival and disease-free survival times in melanoma patients in relation to the degree of tumor pigmentation. Clinicopathologic data were obtained from the Oncology Centre, Prof Franciszek Lukaszczyk Memorial Hospital, Bydgoszcz, Poland. The overall survival and disease free survival analyses were performed using the log-rank test, whereas differences between mean/median overall survival and disease-free survival (days) were analyzed using the Student t test. In patients with metastatic disease, those with melanotic melanomas exhibited significantly shorter disease-free survival and overall survival than those with amelanotic lesions. Similarly, melanin-producing lymph node metastases were linked to shorter overall survival and disease-free survival, which was confirmed by a significantly longer mean/median disease-free survival for amelanotic versus melanotic metastases. Melanogenesis shortens overall survival and disease-free survival in patients with metastatic melanoma. Inhibition of melanogenesis appears a rational adjuvant approach to the therapy of metastatic melanoma. PMID- 23791399 TI - Laparoscopic supracervical hysterectomy using EnSeal vs standard bipolar coagulation technique: randomized controlled trial. AB - OBJECTIVE: To compare the EnSeal device with standard bipolar coagulation forceps in laparoscopic supracervical hysterectomy (LASH). DESIGN: Prospective, randomized, controlled trial (Canadian Task Force classification I). SETTING: University hospital. PATIENTS: One hundred sixty patients who underwent LASH. INTERVENTION: Eighty patients underwent LASH using the EnSeal device (experimental group), and 80 patients underwent LASH using standard bipolar coagulation forceps (control group) (www.clinicaltrials.gov; study identifier NCT01806012). MEASUREMENTS AND MAIN RESULTS: Mean (SD) total operative time was 78.18 (33.96) minutes in the experimental group and 86.30 (35.34) minutes in the control group (p = .03). Documented blood loss was <50 mL in 72 patients in the experimental group and 62 patients in the control group (p = .03), and was 50 to 100 mL in 8 patients in the experimental group and 18 patients in the control group (p < .001). Postoperative hospital stay was significantly shorter for patients in the experimental group compared with the control group: 2.01 (0.44) days vs 2.17 (0.47) days, respectively (p = .03). There was no difference in postoperative pain scores and complications between the two treatment groups. CONCLUSION: Total resection time was shorter in the experimental group, and the other investigated clinical parameters were not inferior in the experimental group compared with the control group. The results of the present study indicate that use of the EnSeal device is at least as reliable as the conventional electrocoagulation technique in LASH. PMID- 23791400 TI - Predicting pelvic pain after endometrial ablation: which preoperative patient characteristics are associated? AB - STUDY OBJECTIVE: To determine which patient characteristics are associated with an increased risk of postablation pelvic pain. DESIGN: Canadian Task Force classification II-2. METHODS: Data were collected from a retrospective cohort of patients who underwent endometrial ablation between January 2006 and September 2010 at a large academic medical center. Patients were identified via Current Procedural Terminology codes (58563, 58353, and 58356) for any type of endometrial ablation (rollerball or global); the sample size was 437 women. Multiple conditions and comorbidities were recorded for each patient. Bivariate analysis of patient demographics and the incidence of pain after endometrial ablation were evaluated using the chi square, Fisher exact, and independent t tests where appropriate. A final multivariate analysis with logistic regression was conducted to determine the exact patient characteristics that are associated with pelvic pain after endometrial ablation. RESULTS: Of 437 women who underwent endometrial ablation, 20.8% reported pain after their ablation. Patients were followed for up to 6.5 years postablation with a median follow-up of 794 days. The median number of days for the development of pain after ablation was 301 days, with 75% of patients who developed pain reporting it within approximately 2 years of their procedure. The median time to hysterectomy for those with pain was 570 days. Other postablation treatments included hormonal therapies in 9.4% of the total population. A total of 20.8% of patients reported postablation pelvic pain, but only 6.3% underwent subsequent hysterectomy for that indication. Preablation patient characteristics significantly associated with the development of postablation pain include dysmenorrhea (aOR = 1.73), smoking status (aOR = 2.31), prior tubal ligation (aOR = 1.68), and age less than 40 (aOR 1.90). Although not statistically significant, a diagnosis of endometriosis appears to be related to postablation pain (aOR = 2.24). Adenomyosis (suggested on ultrasound) and body mass index associations were not statistically significant. A patient with all 4 risk factors for postablation pain (i.e., dysmenorrhea, smoking, prior tubal ligation, and <40 years old) has a 53% (95% confidence interval, 0.40-0.66) chance of experiencing postablation pain. CONCLUSION: The observed incidence of pelvic pain is 20.8% after endometrial ablation and is more frequently observed in women with preablation dysmenorrhea, tobacco use, prior tubal ligation, age less than 40, and possibly endometriosis. One should consider these preexisting conditions when counseling patients regarding outcome expectations after an endometrial ablation procedure. PMID- 23791401 TI - Radiosynthesis and biological evaluation of 5-(3-[18F]fluoropropyloxy)-L tryptophan for tumor PET imaging. AB - INTRODUCTION: [(18)F]FDG PET has difficulty distinguishing tumor from inflammation in the clinic because of the same high uptake in nonmalignant and inflammatory tissue. In contrast, amino acid tracers do not accumulate in inflamed tissues and thus provide an excellent opportunity for their use in clinical cancer imaging. In this study, we developed a new amino acid tracer 5-(3 [(18)F]Fluoropropyloxy)-L-tryptophan ([(18)F]-L-FPTP) by two-step reactions and performed its biologic evaluation. METHODS: [(18)F]-L-FPTP was prepared by [(18)F]fluoropropylation of 5-hydroxy-L-tryptophan disodium salt and purification on C18 cartridges. The biodistribution of [(18)F]-L-FPTP was determined in normal mice and the incorporation of [(18)F]-L-FPTP into tissue proteins was investigated. In vitro competitive inhibition experiments were performed with Hepa1-6 hepatoma cell lines. [(18)F]-L-FPTP PET imaging was performed on tumor bearing and inflammation mice and compared with [(18)F]-L-FEHTP PET. RESULTS: The overall uncorrected radiochemical yield of [(18)F]-L-FPTP was 21.1 +/- 4.4% with a synthesis time of 60 min, the radiochemical purity was more than 99%. Biodistribution studies demonstrate high uptake of [(18)F]-L-FPTP in liver, kidney, pancreas, and blood at the early phase, and fast clearance in most tissues over the whole observed time. The uptake studies in Hepa1-6 cells suggest that [(18)F]-L-FPTP is transported by the amino acid transport system B(0,+), LAT2 and ASC. [(18)F]-L-FPTP displays good stability and is not incorporated into proteins in vitro. PET imaging shows that [(18)F]-L-FPTP can be a better potential PET tracer for differentiating tumor from inflammation than [(18)F]FDG and 5-(3-[(18)F]fluoroethyloxy)-L-tryptophan ([(18)F]-L-FEHTP), with high [(18)F] L-FPTP uptake ratio (2.53) of tumor to inflammation at 60 min postinjection. CONCLUSIONS: Using [(18)F]fluoropropyl derivatives as intermediates, the new tracer [(18)F]-L-FPTP was achieved with good yield and radiochemical purity, and the biological evaluation results of [(18)F]-L-FPTP showed that it was a hopeful tracer for PET tumor imaging. PMID- 23791402 TI - Serum selenium levels of the very low birth weight premature newborn infants with bronchopulmonary dysplasia. AB - BACKGROUND: The selenium (Se) is an essential trace element that has a critical role in synthesis and activity of a number of selenoproteins with protective properties against free radical damage. This study was conducted to detect the serum Se concentration in very low birth weight (VLBW) preterm infants and its association with bronchopulmonary dysplasia (BPD). MATERIALS AND METHODS: Cord blood Se concentration was determined in 54 neonates with gestation age 30 week or less. Another sample was obtained from these infants at day 28 of birth and serum Se levels were measured by atomic absorption spectrophotometer. All neonates were followed for oxygen dependency at 28 day after birth and 36 week postmenstrual age. RESULTS: The mean cord blood Se concentration in studied neonates was 64.78 +/- 20.73 MUgL(-1). Serum Se concentration was 60.33 +/- 26.62 MUgL(-1) at age 28-day. No significant correlation was observed for serum Se concentration at birth and at one month after birth (r = -0.04, p = 0.72). BPD was diagnosed in 25 neonates (46%). The mean serum Se concentration at one month was 57.16 +/- 29.68 MUgL(-1) in patients with BPD (25 cases) and 63.27 +/- 23.6 MUgL(-1) in 29 patients without BPD (p = 0.40). CONCLUSION: In our study, serum Se concentration at 28 day of birth was lower than cord blood levels in preterm neonates, but we have not found significant difference among patients who had BPD or not with respect to serum Se concentrations at this age. PMID- 23791403 TI - Predictors of microinvasion and its prognostic role in ductal carcinoma in situ. AB - BACKGROUND: We sought to determine factors predicting microinvasion and the prognostic role it plays in patients with ductal carcinoma in situ (DCIS). METHODS: A retrospective cohort study of 205 consecutive patients presenting to the Yale Breast Center, New Haven, CT, was performed. RESULTS: Fifty-one (24.9%) patients had microinvasion on pathology. Patients with microinvasion had larger areas of DCIS and were more likely to have high-grade DCIS of the comedo and solid type associated with necrosis and microcalcifications. On multivariate analysis, none of these factors were independent predictors of microinvasion. With a median follow-up of 8.5 years, there was no difference in the recurrence rate or 5-year actuarial survival between those with microinvasion vs those with pure DCIS. CONCLUSIONS: Microinvasion was associated with more extensive DCIS, higher grade, comedo or solid histology, necrosis, and microcalcifications although none of these were found to be an independent predictor of microinvasion. Furthermore, the presence of microinvasion does not seem to significantly increase the risk of recurrence or decrease survival. PMID- 23791405 TI - Cyclic (alternate day) vertical deviation--possible forme fruste of ocular neuromyotonia. AB - PURPOSE: Cyclic ocular deviations are relatively uncommon and are seldom seen in adults. We report 3 adult patients with cyclic hypotropia that has clinical characteristics similar to neuromyotonia, suggesting a possible common etiology. METHODS: Three consecutive patients with 48-hour cyclic hypotropia underwent full neuro-ophthalmologic, oculoplastics, and orthoptic evaluations as well as appropriate medical and neurologic studies. Examinations were arranged on consecutive days on multiple visits to document the cyclic pattern. RESULTS: All 3 patients had sustained contraction of a vertically acting extraocular muscle lasting 24 hours and demonstrated characteristics of ocular neuromyotonia. The contraction was absent for the next 24 hours. Two of the patients had thyroid eye disease; the third patient had unilateral ophthalmoparesis and had subsequent frameless robotic radiosurgery for a cavernous sinus schwannoma. Regular cycles lasting 6, 9, or 14 months were documented by all 3 patients. In 2 patients, treatment with carbamazepine and gabapentin effectively reduced or eliminated the cycle. The cyclic deviation in the third patient resolved spontaneously. CONCLUSIONS: On the basis of the response of these patients to membrane stabilizing medications and the behavior noted as the cycle broke each day, we propose that cyclic vertical strabismus and ocular neuromyotonia may be related conditions with similar underlying physiology. PMID- 23791404 TI - Effects of oxygen on the development and severity of retinopathy of prematurity. AB - In 1942, when retinopathy of prematurity (ROP) first manifested as retrolental fibroplasia, the technology to monitor or regulate oxygen did not exist, and a fundus examination of preterm infants was not routinely performed. Supplemental, uncontrolled oxygen at birth has since been found to cause retrolental fibroplasia. At the same time, technological advances have made it possible to regulate oxygen and detect early forms of ROP. Nevertheless, despite our better understanding of ROP and ongoing investigations of supplemental therapeutic oxygen, including recent clinical trials (Surfactant, Positive Airway Pressure, Pulse Oximetry Randomized Trial [SUPPORT] and Benefits of Oxygen Saturation Targeting [BOOST]), the best oxygen profiles to reduce ROP risk while optimizing preterm infant health and development remain unknown. This article reviews major studies on oxygen use in preterm infants and the effects on the development of ROP. PMID- 23791406 TI - Improving ophthalmic outcomes in children with unilateral coronal synostosis by treatment with endoscopic strip craniectomy and helmet therapy rather than fronto orbital advancement. AB - PURPOSE: To compare long-term ophthalmic outcomes in infants treated for unilateral coronal synostosis (UCS) by endoscopic strip craniectomy (ESC) and helmet therapy with those treated by fronto-orbital advancement (FOA). METHODS: Consecutive patients with UCS, uncomplicated by other suture synostosis, were identified by a retrospective review of medical records. Assessment of presence of amblyopia, cycloplegic refraction, strabismus, and strabismus surgical intervention at all visits was recorded. RESULTS: Between 2004 and 2010, 22 patients were treated by FOA (mean follow-up, 21.5 months) and 21 patients with ESC and helmet therapy (mean follow-up, 23.5 months). The mean aniso-astigmatism was equal; however, the SD was greater for those treated by FOA (P < 0.05). A more severe pattern of strabismus developed in those treated by FOA (P < 0.0001). Those treated by FOA were more likely to have amblyopia (P = 0.0015) and to undergo surgical correction of their strabismus (odds ratio, 6.3:1). CONCLUSIONS: Children with UCS treated with ESC and helmeting had less severe overelevation in adduction, amblyopia, extremes of astigmatism, and less need for strabismus surgery than those treated by FOA. Although the reason for these more favorable outcomes remains uncertain, we speculate that the earlier timing of ESC or differences in the anatomical changes resulting from the two procedures may play a role. PMID- 23791407 TI - Bilateral lateral rectus muscle recession with medial rectus pulley fixation for divergence excess intermittent exotropia with high AC/A ratio. AB - PURPOSE: To evaluate the efficacy of bilateral rectus muscle recession with medial rectus pulley posterior fixation for patients with intermittent exotropia with high AC/A ratio. METHODS: This study included consecutive patients with exodeviation >=10(Delta) greater at distance than at near fixation and with a high AC/A ratio who underwent bilateral lateral rectus muscle recession to eliminate the exotropia at distance and pulley posterior suturing on both medial rectus muscles to prevent consecutive esotropia at near fixation. A successful outcome was defined as near or distance angle of exodeviation <=8(Delta) and a <=10(Delta) difference between the two. RESULTS: A total of 7 patients were enrolled. Of these, 5 (71%) achieved successful results. One patient required bifocal correction for postoperative esodeviation at near fixation. CONCLUSIONS: In this case series, most patients with intermittent exotropia and a high AC/A ratio were successfully treated with bilateral lateral rectus muscle recession combined with medial rectus pulley posterior fixation. PMID- 23791408 TI - The effect of simulated normal and amblyopic higher-order aberrations on visual performance. AB - PURPOSE: To study the effect of simulated amblyopic and normal higher-order aberrations on visual performance of normal eyes. METHODS: To assess visual function, an adaptive optics visual simulator was used to compensate volunteers' ocular aberrations and simulate the wavefront aberration patterns found in healthy and amblyopic eyes in 7 healthy individuals. Visual acuity for high (100%), medium (50%), and low (10%) contrast and contrast sensitivity at 10, 20, and 25 cycles per degree (cpd) were measured after simulation of both pattern aberrations. The modulation transfer function and the point spread function were computed based on the aberration data. All measures were taken for 3 and 5.5 mm pupil sizes. RESULTS: No statistically significant differences in visual acuity and contrast sensitivity were found between both groups for any analyzed contrast level, spatial frequency, and pupil size values. Mean logMAR visual acuity for a 3 mm pupil was -0.11 +/- 0.04 for 100% contrast levels, -0.06 +/- 0.06 for 50%, and 0.17 +/- 0.07 for 10%. For a 5.5 mm pupil, the values were -0.06 +/- 0.04 (100%), 0.00 +/- 0.05 (50%), and 0.21 +/- 0.06 (10%). Mean contrast sensitivity for a 3 mm pupil was 1.9 +/- 0.2 for 10 cpd, 1.2 +/- 0.15 for 20 cpd, and 0.9 +/- 0.1 for 25 cpd. For a 5.5 mm pupil, contrast sensitivity was 1.4 +/- 0.2 (10 cpd), 0.9 +/- 0.2 (20 cpd), and 0.6 +/- 0.2 (25 cpd). MTFs and PSFs were comparable in the two groups for both pupils. CONCLUSIONS: The higher-order aberrations seen in idiopathic amblyopic eyes alone do not appear to contribute to the decreased visual function. PMID- 23791409 TI - Fetal ocular measurements by three-dimensional ultrasound. AB - PURPOSE: To establish a reference range for normal fetal eye volume (FEV) by three-dimensional ultrasound using Virtual Organ Computer-aided AnaLysis (VOCAL) method and compare the reproducibility between the two trace modes (manual and sphere). METHODS: This prospective, longitudinal observational study was performed at a single center and involved 71 eyes of 37 fetuses between 17 and 40 weeks of gestational age. Only pregnancies without fetal growth restriction, diabetes mellitus, hypertension, or major fetal malformation were included. Fetuses' eye measurements were obtained by a single observer during routine ultrasonographic examination. RESULTS: Mean FEV manual mode ranged from 309.5 +/- 80.1 mm(3) at 17-18 weeks to 2552.1 +/- 384.9 mm(3) at 39-40 weeks. Mean FEV sphere mode ranged from 394.8 +/- 71.8 mm(3) at 17-18 weeks to 2682.1 +/- 343.4 mm(3) at 39-40 weeks. Correlations ranged from R2 = 0.85 (transversal diameter and gestational age) to R2 = 0.91 (FEV sphere mode and gestational age). All correlations were statistically significant (P < 0.001). Although highly correlated (R2 = 0.97, P < 0.001), there was a fixed bias between manual and sphere measurements. The agreement between these measurements showed no proportional bias (P = 0.89). CONCLUSIONS: The present study establishes reference values for FEV using the VOCAL method manual mode. These normal growth parameters can be used in routine ultrasound assessment of the fetal eye, especially in families at risk of genetic diseases that affect ocular growth, such as congenital glaucoma. PMID- 23791410 TI - Retinoblastoma presenting with orbital cellulitis. AB - PURPOSE: To study the effectiveness of pre-enucleation steroids in reducing inflammation in patients with retinoblastoma presenting as orbital cellulitis. METHODS: Medical records of consecutive retinoblastoma patients presenting at a single tertiary eye care center during a period of 3 years were retrospectively reviewed. For those who presented with orbital cellulitis, clinical, radiological, and histopathological variables were assessed. The effect of pre enucleation steroids was noted in this group of patients. RESULTS: Of 260 retinoblastoma cases reviewed, 14 had retinoblastoma-associated cellulitis (5.39%). Of these 14 patients, 4 received neoadjuvant chemotherapy and were excluded from the series. Of the remaining 10 cases (mean age at presentation, 14.2 months; mean follow-up, 16.4 months), 9 presented with orbital cellulitis and were included in the study. Radiological imaging depicted intraocular tumors occupying 80% to 100% of the globe in each case. All patients underwent enucleation. Five children received pre-enucleation systemic steroids (mean, 5.4 days), which resulted in a prompt decrease in inflammation. Postenucleation chemotherapy was administered in 4 (6 cycles) and external beam radiation therapy in 1 patient with high-risk histopathological characteristics. CONCLUSIONS: Advanced necrotic retinoblastoma with anterior segment involvement may present as orbital cellulitis. Pre-enucleation systemic steroids can aid in the surgical management of these tumors. PMID- 23791411 TI - Fixation instability in anisometropic children with reduced stereopsis. AB - BACKGROUND: Hyperopic anisometropia in children can be associated with abnormal stereoacuity and "microstrabismus," a small temporalward "flick" as each eye assumes fixation on cover testing. The prevailing hypothesis is that abnormal sensory experience leads to foveal suppression and, subsequently, secondary microstrabismus. This study investigated the hypothesis that disruption of bifoveal fusion by anisometropia directly affects ocular motor function. METHODS: A total of 94 children with hyperopic anisometropia (ages 5-13 years) were evaluated prospectively between June 2010 and December 2012 with the use of the Nidek MP-1 microperimeter. Fixation instability was quantified by the area of the bivariate contour ellipse that included 95% of fixation points during a 30-second test interval. Each eye movement waveform during the 30-second test interval also was examined with the use of custom software and classified as normal, fusion maldevelopment nystagmus (FMNS), or infantile nystagmus. Finally, the Randot Preschool Stereoacuity Test (Stereo Optical Company Inc, Chicago, IL) was administered. RESULTS: Stereoacuity was correlated with fixation instability (Spearman r = 0.50; 95% CI, 0.33-0.64); visual acuity was more weakly correlated (r = 0.28). All children with normal stereoacuity had stable fixation, children with subnormal stereoacuity had fixation instability, and those with nil stereoacuity had the most instability. Eye movement records during attempted fixation were of sufficient quality for classification in 81 children; 61% of those with reduced stereoacuity and 88% of those with nil stereoacuity had FMNS eye movement waveforms. CONCLUSIONS: Our data support the hypothesis that the binocular decorrelation caused by anisometropia can disrupt ocular motor development, resulting in FMNS and its temporalward refoveating "flicks" that may mimic microstrabismus. PMID- 23791412 TI - Changes in refractive error and anterior segment parameters after isolated lateral rectus muscle recession. AB - PURPOSE: To evaluate the short-term effect of isolated lateral rectus muscle recession surgery on refractive error, corneal measurements, and anterior chamber depth and volume. METHODS: Consecutive patients who underwent isolated lateral rectus muscle recession from July 2008 to March 2009 were prospectively studied. Refractive error; corneal power, thickness, and volume; and anterior chamber depth and volume were measured (Pentacam) before and at 1 week and 1 month after surgery. Patients who could not maintain reliable fixation and those with sensory strabismus or a history of eye surgery were excluded. Pre- and postoperative measurements were compared by analysis of variance. RESULTS: A total of 24 eyes of 24 patients (average age, 8 years) were included. Bilateral lateral rectus muscle recession was performed in 19 patients; unilateral in 5. Overall, patients manifested statistically significant changes in spherical equivalent, horizontal and mean keratometry, corneal astigmatism, anterior chamber volume, and center and peripheral anterior chamber depth at 1 week after surgery (P < 0.05). Changes became progressively smaller during the first month after surgery, although significant changes in spherical equivalent persisted at 1 month. CONCLUSIONS: Lateral rectus muscle recession resulted in short-term changes in refractive error in this cohort. The etiology of the refractive change is unknown but could be due to alterations in muscle tension that affect corneal remodeling, segmental interruption of the ciliary body circulation affecting the lens curvature, postoperative tissue edema, and/or other postsurgical factors. The decrease in change after 1 month may be due to the effects of compensation by other quadrants of the eye or resolution of the surgical induced tissue damage. Longer follow-up is necessary to ascertain clinical significance. PMID- 23791413 TI - The effectiveness of policy changes designed to increase the attendance rate for outpatient retinopathy of prematurity (ROP) screening examinations. AB - PURPOSE: To determine the effectiveness of a series of policy changes designed to increase the attendance rate for outpatient retinopathy of prematurity (ROP) screening examinations. METHODS: We retrospectively reviewed the records of consecutive neonatal intensive care unit patients before and after the implementation of policy changes. Policy changes included parent education forms, streamlined scheduling, and creation of a log for all patients seen. The primary outcome measure was attendance rates for the first outpatient appointment after discharge. The Fisher exact test was used to compare rates between the two groups. RESULTS: Before the policy was implemented, 22 of 52 (42%) neonates and their caregivers attended their first outpatient ROP screening examination on the recommended date. This rate improved significantly after policy implementation, when 46 of 57 (81%) neonates and their caregivers were seen on the recommended date (P < 0.01). The number of patients who ultimately met the criteria for conclusion of acute retinal screening examinations also significantly improved, from 47 of 52 (90%) of neonates in the pre-implementation group to 57 of 57 (100%) in the post-implementation group (P = 0.02). CONCLUSIONS: The attendance rates for initial outpatient ROP examinations and the number of patients who ultimately met criteria for conclusion of acute retinal screening examinations significantly improved after the implementation of new policies. PMID- 23791414 TI - The accuracy of the plusoptiX A08 photoscreener in detecting risk factors for amblyopia in central Iowa. AB - PURPOSE: To evaluate the accuracy of the plusoptiX A08 photoscreener in detecting risk factors for amblyopia in children aged 0-5 years in central Iowa. METHODS: The medical records of consecutive patients seen at 1 practice during a 2-month period were retrospectively reviewed. All patients were screened with the plusoptiX A08 photoscreener and received a comprehensive pediatric ophthalmology examination. Photoscreening results, according to our age-based criteria, were compared with the comprehensive examination findings. Patients were considered to have amblyopia or amblyogenic risk factors in the comprehensive examination based on the American Association for Pediatric Ophthalmology and Strabismus referral criteria guidelines. RESULTS: A total of 290 children were examined during the study period. Of these, 190 (66%) patients were found to have amblyopia or amblyogenic risk factors during the pediatric ophthalmology examination on the basis of American Association for Pediatric Ophthalmology and Strabismus guidelines. The plusoptiX A08 offered an overall testability rate of 98%, sensitivity of 87%, specificity of 88%, positive predictive value of 93%, and negative predictive value of 78%. The sensitivity for detection of strabismus <=20(Delta) was 52%. CONCLUSIONS: The plusoptiX showed a high sensitivity for the detection of refractive amblyogenic risk factors and had a high successful testability rate in infants; however, it had low sensitivity for detecting strabismus <=20(Delta). We postulate that sensitivity for detecting amblyogenic risk factors can be improved by combining the use of this instrument with a cover or stereo test. PMID- 23791415 TI - Malignant teratoid medulloepithelioma with retinoblastic and rhabdomyoblastic differentiation. AB - We describe an unusual case of malignant teratoid medulloepithelioma in which distinct populations of tumor cells with different immunohistochemical staining patterns existed within the same eye. A neuroblastic population exhibited atypical features of retinoblastoma, including organization into pseudo-Flexner Wintersteiner and Homer-Wright rosettes. Other populations evolved in strikingly different patterns, with large fields of cells resembling astrocytes and intervening streams of spindle cells that suggested smooth muscle. The spindle cell population was negative for smooth muscle antigen but stained positively for desmin, myoglobin, and myogenin. Under high magnification, the desmin, myoglobin, and myogenin-staining cells exhibited striations consistent with skeletal muscle differentiation. PMID- 23791416 TI - Reply: To PMID 22929447. PMID- 23791417 TI - First bilateral pediatric Descemet stripping automated endothelial keratoplasty after failed penetrating keratoplasty. PMID- 23791418 TI - Superior limbic keratoconjunctivitis causing chronic ocular irritation in a child. PMID- 23791419 TI - Reply: To PMID 23158547. PMID- 23791420 TI - A review of the structure, and fundamental mechanisms and kinetics of the leaching of chalcopyrite. AB - Most investigators regard CuFeS2 as having the formal oxidation states of Cu(+)Fe(3+)(S(2-))2. However, the spectroscopic characterisation of chalcopyrite is clearly influenced by the considerable degree of covalency between S and both Fe and Cu. The poor cleavage of CuFeS2 results in conchoidal surfaces. Reconstruction of the fractured surfaces to form, from what was previously bulk S(2-), a mixture of surface S(2-), S2(2) and S(n)(2-) (or metal deficient sulfide) takes place. Oxidation of chalcopyrite in air (i.e. 0.2 atm of O2 equilibrated with atmospheric water vapour) results in a Fe(III)-O-OH surface layer on top of a Cu rich sulfide layer overlying the bulk chalcopyrite with the formation of Cu(II) and Fe(III) sulfate, and Cu(I)-O on prolonged oxidation. Cu2O and Cu2S-like species have also been proposed to form on exposure of chalcopyrite to air. S2(2-), S(n)(2-) and S(0) form on the chalcopyrite surface upon aqueous leaching. The latter two of these species along with a jarosite-like species are frequently proposed to result in surface leaching passivation. However, some investigators have reported the formation of S(0) sufficiently porous to allow ion transportation to and from the chalcopyrite surface. Moreover, under some conditions both S(n)(2-) and S(0) were observed to increase in surface concentration for the duration of the leach with no resulting passivation. The effect of a number of oxidants, e.g. O2, H2O2, Cu(2+), Cr(6+) and Fe(3+), has been examined. However, this is often accompanied by poor control of leach parameters, principally pH and E(h). Nevertheless, there is general agreement in the literature that chalcopyrite leaching is significantly affected by solution redox potential with an optimum E(h) range suggesting the participation of leach steps that involve both oxidation and reduction. Three kinetic models have generally been suggested by researchers to be applicable: diffusion, chemical reaction and a mixed model containing diffusion and chemical components which occur at different stages of leaching. Passivation effects, due to surface diffusion rate control, may be affected by leach conditions such as pH or E(h). However, only initial conditions are generally described and these parameters are not controlled in most studies. However, at fixed pH, E(h) and temperature, it appears most likely that leaching in sulfuric acid media in the presence of added Fe(3+) is surface reaction rate controlled with some initial period, depending on leach conditions, where the leach rate is surface layer diffusion controlled. Although bioleaching of some copper ores has been adopted by industry, bioleaching has yet to be applied to predominantly chalcopyrite ores due to the slow resulting leach rates. Mixed microbial strains usually yield higher leach rates, as compared to single strains, as different bacterial strains are able to adapt to the changing leach conditions throughout the leach process. As for chemical leaching, passivation is also observed on bioleaching with jarosite being likely to be the main contributor. In summary, whilst much has been observed at the macro-scale regarding the chalcopyrite leach process it is clear that interpretation of these phenomena is hampered by lack of understanding at the molecular or atomic scale. Three primary questions that require elucidation, before the overall mechanism can be understood are: 1. How does the surface of chalcopyrite interact with solution or air borne oxidants? 2. How does the nature of these oxidants affect the surface products formed? 3. What determines whether the surface formed will be passivating or not? These can only realistically be tackled by the application of near atomic-scale analytical approaches, which may include quantum chemical modelling, PEEM/SPEM, TEM, AFM etc. PMID- 23791421 TI - The impact of body weight management in chronic kidney disease patients with obesity. AB - OBJECTIVE: Chronic kidney disease (CKD) and obesity are important public health concerns. Because obesity may initiate and/or accelerate kidney damage, weight control may benefit CKD patients. DESIGN AND METHODS: We examined the influence of dietary management and physical exercise in 38 obese CKD patients with or without target reduction of body weight 3% or more from baseline. RESULTS: After a 2-month lifestyle intervention program, those with target body weight control had significant improvement of blood pressure control, as well as reduced lipid profiles, serum creatinine level (1.1 +/- 0.3 vs. 0.8 +/- 0.3; P < .001), estimated glomerular filtration rate (75.9 +/- 21.2 vs. 104.9 +/- 38.1; P < .001), and proteinuria (76.3% vs. 50.0%; P = .02). They had greater improvement in cardiorespiratory endurance in an 800-m running test (375.1 +/- 64.7 vs. 327.1 +/- 84.0 seconds; P = .001), better abdominal muscle strength and endurance in a timed sit-up test (13.6 +/- 9.1 vs. 19.9 +/- 9.2 number/minute; P = .005), and greater flexibility in a sit-and-reach test (18.8 +/- 10.9 vs. 27.8 +/- 10.9 cm; P < .001) comparing baseline and postintervention values. CONCLUSIONS: A combination of dietary management and exercise were associated with improvements in health-related physical fitness, cardiovascular risk factors (blood pressure and lipid control), and renal profiles in obese CKD patients. Supportive individualized programs for lifestyle change could exert beneficial effects, but long-term research with a larger patient population is needed to elucidate the optimal effective combination of dietary management and exercise. PMID- 23791422 TI - Membrane bioreactor technology: a novel approach to the treatment of compost leachate. AB - Compost leachate forms during the composting process of organic material. It is rich in oxidizable organics, ammonia and metals, which pose a risk to the environment if released without proper treatment. An innovative method based on the membrane bioreactor (MBR) technology was developed to treat compost leachate over 39days. Water quality parameters, such as pH, dissolved oxygen, ammonia, nitrate, nitrite and chemical oxygen demand (COD) were measured daily. Concentrations of caffeine and metals were measured over the course of the experiment using gas chromatography - mass spectrometry (GC/MS) and inductively coupled plasma - mass spectrometry (ICP-MS) respectively. A decrease of more than 99% was achieved for a COD of 116g/L in the initial leachate. Ammonia was decreased from 2720mg/L to 0.046mg/L, while the nitrate concentration in the effluent rose to 710mg/L. The bacteria in the MBR system adjusted to the presence of the leachate, and increased 4 orders of magnitude. Heavy metals were removed by at least 82.7% except copper. These successful results demonstrated the membrane bioreactor technology is feasible, efficient method for the treatment of compost leachate. PMID- 23791423 TI - GHG emission factors developed for the recycling and composting of municipal waste in South African municipalities. AB - GHG (greenhouse gas) emission factors for waste management are increasingly used, but such factors are very scarce for developing countries. This paper shows how such factors have been developed for the recycling of glass, metals (Al and Fe), plastics and paper from municipal solid waste, as well as for the composting of garden refuse in South Africa. The emission factors developed for the different recyclables in the country show savings varying from -290kg CO2 e (glass) to 19111kg CO2 e (metals - Al) per tonne of recyclable. They also show that there is variability, with energy intensive materials like metals having higher GHG savings in South Africa as compared to other countries. This underlines the interrelation of the waste management system of a country/region with other systems, in particular with energy generation, which in South Africa, is heavily reliant on coal. This study also shows that composting of garden waste is a net GHG emitter, releasing 172 and 186kg CO2 e per tonne of wet garden waste for aerated dome composting and turned windrow composting, respectively. The paper concludes that these emission factors are facilitating GHG emissions modelling for waste management in South Africa and enabling local municipalities to identify best practice in this regard. PMID- 23791424 TI - Risk factors for recurrent epistaxis: importance of initial treatment. AB - OBJECTIVE: A retrospective study of risk factors for recurrent epistaxis and initial treatment for refractory posterior bleeding was performed. Based on the results, proposals for appropriate initial treatment for epistaxis by otolaryngologists are presented. METHODS: The data of 299 patients with idiopathic epistaxis treated during 2008-2009 were analyzed by multivariate logistic regression analysis. Treatment data for 101 cases of posterior bleeding were analyzed using the chi-square test. RESULTS: Recurrent epistaxis occurred in 32 cases (10.7%). Unidentified bleeding point (adjusted odds ratio (OR) 5.67, 95% confidence interval (CI) 1.83-17.55, p=0.003) was predictive of an increased risk of recurrent epistaxis, and electrocautery (adjusted odds ratio (OR) 0.07, 95% confidence interval (CI) 0.03-0.17, p=0.000) was predictive of a decreased risk of recurrent epistaxis. In terms of initial treatment for posterior bleeding, the rate of recurrent epistaxis was significantly lower for patients who underwent electrocautery as initial treatment compared with those who did not (6.4% vs. 40.7%, p<0.01), and it was significantly higher for those who underwent endoscopic gauze packing compared with those who did not (39.5% vs. 15.9%, p<0.01). CONCLUSION: In the present study, the risk factors for recurrent epistaxis were unidentified bleeding point. Thus, it is important to identify and cauterize a bleeding point to prevent recurrent epistaxis. The present results also suggest the effectiveness of electrocautery and the higher rate of recurrent epistaxis for patients who underwent gauze packing as initial treatment for posterior bleeding. Electrocautery should be the first-choice treatment of otolaryngologists for all bleeding points of epistaxis, and painful gauze packing may be inadvisable for posterior bleeding. More cases of posterior bleeding are needed for future studies involving multivariate analyses and appropriate analyses of factors related to hospitalization, surgery, and embolization. PMID- 23791425 TI - Boar sperm changes after sorting and encapsulation in barium alginate membranes. AB - A routine use of boar-sexed semen is limited by the long sorting time necessary to obtain an adequate number of sexed spermatozoa for artificial insemination and by the high susceptibility of spermatozoa of this species to damages induced by sorting procedure and subsequent cryopreservation. The aim of this work was to study the impact of encapsulation in barium alginate membrane on sorted boar spermatozoa by evaluating membrane integrity, chlortetracycline staining patterns, protein tyrosine phosphorylation, and Hsp70 immunolocalization during storage over 72 hours in liquid or encapsulated form. The encapsulation procedure significantly (P < 0.05) decreased the overall membrane integrity of control unsorted semen (81.8 vs. 57.4, CTR vs. CPS), but did not negatively affect the overall viability and the chlortetracycline staining patterns of sorted encapsulated cells. Moreover, encapsulation significantly decreased (P < 0.05) the overall phosphotyrosin A pattern cell percentage in unsorted (98.4 vs. 92.6, CTR vs. CPS) but not in sorted semen (64.0 vs. 74.2; SORT CTR vs. SORT CPS). As for Hsp70, the overall percentage of cells displaying the different patterns was significantly influenced (P < 0.05) by treatment but not by storage time. The sorting procedure seems to induce the major changes, whereas encapsulation tends to exert a protective effect on sorted semen by increasing the percentage of spermatozoa displaying the T pattern (2.8 vs. 24.3; SORT CTR vs. SORT CPS). In conclusion, our data confirm that the damaging impact of the encapsulation in barium alginate capsules seems to be limited when compared with that of the sorting procedure and, moreover, the association of the two procedures does not result in an algebraic sum of the negative effects. These results suggest the possibility of a future utilization of the encapsulation technology in order to store sorted spermatozoa and permit their controlled release in the female genital tract. PMID- 23791427 TI - Quantification of major urinary metabolites of PGE2 and PGD2 in cystic fibrosis: correlation with disease severity. AB - Cystic fibrosis transmembrane conductance (CFTR) alterations are involved in the overproduction of prostaglandins (PG) in CF in vitro. We assessed the relationship between PGE-M and PGD-M urinary metabolites of PGE2 and PGD2 and CF severity. Twenty-four controls and 35 CF patients were recruited. PGE-M and PGD-M levels were measured by liquid chromatography/mass spectrometry and results were expressed as median and 25th-75th interquartile of ng/mg creatinine (Cr). PGE-M (15.63; 9.07-43.35ng/mg Cr) and PGD-M (2.16; 1.43-3.53ng/mg Cr) concentrations were higher in CF than in controls: PGE-M, (6.63; 4.35-8.60ng/mg Cr); PGD-M (1.23; 0.96-1.54ng/mg Cr). There was no correlation between metabolite levels and spirometric values. Patients with pancreatic insufficiency (n=29) had higher PGE M levels (19.09; 9.36-52.69ng/mg Cr) than those with conserved function (n=6) (9.61; 5.78-14.34ng/mg Cr). PGE-M levels were associated with genotype severity: mild (7.14; 5.76-8.76, n=8), moderate (16.67; 13.67-28.62ng/mg Cr, n=5) and severe (22.82; 10.67-84.13ng/mg Cr). Our study confirms the key role of CFTR in the regulation of the cyclooxygenase pathway of arachidonic acid metabolism found in in vitro studies. PMID- 23791426 TI - Maternal risk factors for HIV infection in infants in northeastern Brazil. AB - INTRODUCTION: While the rate of vertically transmitted HIV infection has fallen in most regions of Brazil, there have been no similar decreases in northern and northeastern Brazil. OBJECTIVE: The objective of this study was to evaluate the risk factors associated with vertical transmission in the state of Sergipe in northeastern Brazil. METHODS: This was a retrospective cohort study. We recorded clinic and registry data for all HIV-infected pregnant women and exposed children diagnosed in Sergipe from 1990 to 2011. RESULTS: We identified 538 deliveries and 561 HIV-exposed infants (23 sets of twins). One hundred one (18.9%) infants were HIV-infected. In the multivariate analysis, infant antiretroviral prophylaxis was a significant protective factor (adjusted odds ratio (aOR) 0.07, 95% confidence interval (CI) 0.01-0.41, p=0.003). Breastfeeding was marginally associated with an increased odds of perinatal transmission (aOR 4.52, 95% CI 0.78-26.17, p = 0.092). The attributable risk percentage for breastfeeding over the study period was 91.0%. Transmission decreased from 91 per 100 live births before 1997 to 2 per 100 in 2011 following the adoption of the prevention protocol. CONCLUSION: Transmission declined over the study period. The screening of pregnant women and timely initiation of prophylaxis and therapy are issues that require further attention. PMID- 23791428 TI - Ultrasound-induced emulsification of subcritical carbon dioxide/water with and without surfactant as a strategy for enhanced mass transport. AB - Pulsed ultrasound was used to disperse a biphasic mixture of CO2/H2O in a 1 dm(3) high-pressure reactor at 30 degrees C/80 bar. A view cell positioned in-line with the sonic vessel allowed observation of a turbid emulsion which lasted approximately 30 min after ceasing sonication. Within the ultrasound reactor, simultaneous CO2-continuous and H2O-continuous environments were identified. The hydrolysis of benzoyl chloride was employed to show that at similar power intensities, comparable initial rates (1.6+/-0.3*10(-3) s(-1) at 95 W cm(-2)) were obtained with those reported for a 87 cm(3) reactor (1.8+/-0.2*10(-3) s(-1) at 105 W cm(-2)), demonstrating the conservation of the physical effects of ultrasound in high-pressure systems (emulsification induced by the action of acoustic forces near an interface). A comparison of benzoyl chloride hydrolysis rates and benzaldehyde mass transport relative to the non-sonicated, 'silent' cases confirmed that the application of ultrasound achieved reaction rates which were over 200 times faster, by reducing the mass transport resistance between CO2 and H2O. The versatility of the system was further demonstrated by ultrasound induced hydrolysis in the presence of the polysorbate surfactant, Tween, which formed a more uniform CO2/H2O emulsion that significantly increased benzoyl chloride hydrolysis rates. Finally, pulse rate was employed as a means of slowing down the rate of hydrolysis, further illustrating how ultrasound can be used as a valuable tool for controlling reactions in CO2/H2O solvent mixtures. PMID- 23791430 TI - Outcomes in octogenarians with subdural hematomas. PMID- 23791429 TI - The Eluana Englaro Case: cause of death after the withdrawal of artificial nutrition and hydration in a subject in a permanent vegetative state and with quadriplegia. AB - A 38-year-old woman, who had been in a permanent vegetative state with quadriplegia for 17 years following a motor vehicle accident, died 87 h after the judicially authorised suspension of artificial nutrition and hydration. Medico legal investigations, requested by the Judicial Authorities and focusing on the evaluation of clinical and necroscopic data, aimed to explain the cause of death, to exclude any lethal cause other than one deriving from the withdrawal of artificial nutrition and hydration and to verify the level of perceived discomfort and the correctness in the application of the supportive protocol during the end of life phase. The inability of quadriplegic patients to compensate critical hyperthermic and haemodynamic disturbances induced by dehydration was considered to be the cause of a rapid demise after the withdrawal of artificial sustenance. PMID- 23791431 TI - The role of nocturnal polysomnography in assessing children with Chiari type I malformation. AB - OBJECTIVE: To evaluate nocturnal polysomnogram findings in children with suspected symptomatic Chiari type I malformation, correlate them with clinical and magnetic resonance imaging data and to determine if this information has value in clinical decision making process. METHODS: A retrospective review identified 24 children with type I Chiari malformation, presumed symptomatic who had undergone neurological assessment, cranial magnetic resonance imaging and nocturnal polysomnography. Perimedullary subarachnoid space effacement on the magnetic resonance studies and the magnitude of cerebellar tonsillar descent in relation to the McRae line were correlated with frequency of obstructive or central sleep apnea, number of cortical arousals and evidence of impaired vocal mobility on laryngoscopy. The Wilcoxon rank sum test was applied for continuous variables and the Fisher exact test for categorical variables. RESULTS: The median age of the subjects was 6 years. The findings from 16/24 subjects with perimedullary subarachnoid space effacement (effaced group) were compared with those of 8/24 in the non-effaced group. The central apnea index [1.5 (IQR 1-3.5) versus 0.5 (IQR 0-1.5)] and cortical arousal index [12 (IQR 10-19) versus 8 (IQR 6.5-9)] were significantly higher in the effaced group than in the non-effaced group (p=0.0376 and 0.0036 respectively). Greater descent of tonsils as measured by distance from the McRae line to the tonsil tip was associated with significantly higher central apnea index, total arousal index and respiratory event related arousals. Measurements of clivus-canal angle, Klauss index and pB C2 line did not correlate with abnormalities on polysomnography. CONCLUSION: The central apnea and arousal indices derived from the nocturnal polysomnogram correlate well with magnetic resonance imaging findings of subarachnoid space effacement and degree of tonsillar herniation. In children with Chiari type I malformation, the nocturnal polysomnogram findings provides important information that aids in the decision making process about proceeding with surgical decompression. PMID- 23791432 TI - A giant mastoid cholesteatoma with posterior cranial extension causing mass effect and obstructive hydrocephalus. PMID- 23791433 TI - Intoxications with the monoamine oxidase inhibitor tranylcypromine: an analysis of fatal and non-fatal events. AB - Tranylcypromine (TCP) is a non-selective and irreversible monoamine oxidase inhibitor and an effective agent in the treatment of major depression. It features a complex pharmacologic profile and overdoses might induce severe intoxications. To identify typical clinical presentations of TCP-intoxications, range of associated TCP-dosages and possible differences between fatal and non fatal intoxications a systematic review of all previously published cases of TCP intoxications was conducted. We detected n=20 reports of TCP-intoxications in the literature (fatalities n=10). Mean age was 36.7 years (median 37); the majority of patients were female (60%). Frequent findings in patients with TCP intoxications were disturbance of consciousness/cognitive dysfunction (90%), cardio-vascular symptoms (55%), hyperthermia (50%), respiratory distress (45%), delirium (45%), muscular rigidity (30%) and renal failure (20%). Suicidal intent was present in n=18 (90%) patients. First clinical symptoms related to TCP intoxication developed on average in less than 1 day. The average dosage related to TCP-intoxication was 677 mg. The highest survived TCP-dosage was 4000 mg and the lowest fatal dosage was 170 mg. Patients with fatal intoxications were on average older (40.5 vs. 32.8 years) and developed a more rapid onset of symptoms (0.2 vs. 0.8 days). Death occurred after a mean time of 0.6 days; symptom relief in patients with non-fatal intoxications developed on average after 3.2 days. Considering the large dose spectrum between survived and lethal TCP-dosages individual susceptibility factors might play a role regarding the severity of clinical symptoms independently of the ingested dosage. PMID- 23791434 TI - Snowmelt contributions to discharge of the Ganges. AB - Himalayan headwaters supply large quantities of runoff derived from snowmelt and monsoon rainfall to the Ganges River. Actual snowmelt contribution to discharge in the Ganges remains conjectural under both present and future climatic conditions. As snowmelt is likely to be perturbed through climatic warming, four hydrological models, VIC, JULES, LPJmL and SWAT, appropriate for coupling with regional climate models, were used to provide a baseline estimate of snowmelt contribution to flow at seasonal and annual timescales. The models constrain estimates of snowmelt contributions to between 1% and 5% of overall basin runoff. Snowmelt is, however, significant in spring months, a period in which other sources of runoff are scarce. PMID- 23791435 TI - Prognostic role of pancreatic metastases from renal cell carcinoma: results from an Italian center. AB - BACKGROUND: Pancreatic metastasis accounts for 2% to 11% of all mRCC cases. The prognostic value of pancreatic metastases in the era of TTs is unclear. We evaluated outcomes in a cohort of mRCC patients with pancreatic metastases (PmRCC) who were treated with TTs. PATIENTS AND METHODS: We retrospectively reviewed the records of 354 mRCC patients treated at our institute between January 2005 and June 2012. Differences in terms of OS between this unselected cohort of mRCC patients and a subgroup of patients with PmRCC were investigated. Kaplan-Meier and log-rank test methods were used to evaluate OS. RESULTS: In total, 24 PmRCC (7%) patients were identified, and were compared with a cohort of 330 mRCC patients with metastasis at other sites. Pancreatic metastases were synchronous in 3 patients, and they were metachronous in 11 patients. Surgical resection of pancreatic metastases was performed in 2 (8%) patients. At a maximum follow-up of 89 months (median, 51 months), median OS was 39 months in PmRCC patients, vs. 23 months in the mRCC patient group (P = .0004). CONCLUSION: Among mRCC patients treated with TTs, the presence of pancreatic metastasis seems to be associated with a longer survival than the presence of metastasis at other sites. PMID- 23791436 TI - Insulin use and smoking jointly increase the risk of bladder cancer mortality in patients with type 2 diabetes. AB - BACKGROUND: Whether insulin use predicts bladder cancer mortality has not been investigated. Furthermore, it is not known whether insulin use and smoking jointly influence the risk. MATERIALS AND METHODS: A total of 86,939 patients (40,014 men, 46,925 women) with type 2 diabetes mellitus (T2DM) and aged >= 25 years in a nationally representative cohort were followed prospectively from 1995 to 2006 for bladder cancer mortality. Cox regression was used considering the following independent variables: age, sex, diabetes duration, body mass index, smoking, insulin use, and area of residence. The models were created for patients aged >= 25 and >= 65 years, separately; and sensitivity analyses were conducted after excluding (1) patients with duration between onset of diabetes and bladder cancer mortality < 5 years, and (2) patients with diabetes duration at recruitment < 3 years. The joint effect of insulin use and smoking was evaluated. RESULTS: Patients who died of bladder cancer were characterized by older age, male predominance, longer diabetes duration, smoking, and insulin use. In multivariable Cox models, age, male sex, and insulin use were consistently predictive for bladder cancer mortality in all analyses, whereas the other variables were not. The adjusted hazard ratios for bladder cancer mortality for insulin users vs. nonusers ranged from 1.877 to 2.502 in different models (all P values < .05). Insulin use and smoking jointly increased the adjusted hazard ratio to 3.120 (95% confidence interval, 1.329-7.322). CONCLUSIONS: Insulin use is significantly predictive for bladder cancer mortality in patients with T2DM. Insulin use and smoking jointly increase the risk. PMID- 23791437 TI - Dramatic and prolonged PSA response after retreatment with a PSA vaccine. PMID- 23791438 TI - Flutamide fails to reduce resuscitation requirements in a porcine ischemia reperfusion model. AB - BACKGROUND: Hemorrhagic shock and subsequent resuscitation can lead to ischemia reperfusion injury, followed by multiorgan failure and death. Flutamide, a vasoactive nonsteroidal antiandrogen compound, is thought to improve tissue and organ perfusion. We tested whether administration of flutamide-cyclodextrin (FLU CYD) alters physiologic parameters or resuscitation requirements in a porcine model of severe acidosis and shock secondary to combined hemorrhage + ischemia reperfusion injury. METHODS AND MATERIALS: Fifteen male pigs underwent a 35% blood-volume hemorrhage. Ischemia was induced by cross-clamping the supraceliac aorta for 50 min followed by reperfusion and resuscitation. FLU-CYD complex was administered during aortic clamping. Fluid resuscitation and epinephrine were titrated by protocol to maintain mean arterial pressure >=40 mm Hg for 6 h. Sequential laboratory results were obtained and serum levels of FLU and 2-hydroxy flutamide (FLUOH) were measured by mass spectrometry. RESULTS: Mean requirements for injured control swine were 14.6 (+/- 1.21 standard error of the mean [SEM]) L crystalloid saline and 0.59 (+/- 0.29 SEM) g epinephrine, compared with 16.30 (+/ 1.33 SEM) L and 0.54 (+/- 0.16 SEM) g, respectively, in the FLU-CYD group (both P > 0.05). There were no significant differences in central hemodynamics between control and experimental groups. No significant differences for pH, bicarbonate, fibrinogen, or international normalized ratio were evident. FLU-CYD resuscitation was associated with a significant increase in lactate levels compared with controls (10.1 versus 5.7 mmol/L, P < 0.05). Histologic injury was significantly increased in the livers of FLU-CYD compared with sham (P = 0.022). High serum levels of FLU and the active metabolite FLUOH were measurable throughout the resuscitation period. CONCLUSIONS: Flutamide failed to show any benefit to resuscitation in a model of severe injury and was associated with increased acidosis, hemodilution, and liver injury compared with standard crystalloid resuscitation. PMID- 23791439 TI - Epidemiological analysis of maxillofacial fractures treated at a university hospital, Xinjiang, China: A 5-year retrospective study. AB - PURPOSE: To investigate the epidemiological characteristics of maxillofacial fractures treated at a university hospital, Xinjiang, China over a 5-year period. PATIENTS AND METHODS: Between 2006 and 2010, a total of 1350 patients with maxillofacial fractures were reviewed retrospectively. The data collected included demographics, aetiology, site of fracture, time regarding injuries, presence of associated injuries, treatment modalities, and complications. RESULTS: A total of 1860 maxillofacial fractures were seen in 1350 patients with a male to female ratio of 4.9:1. The most common aetiology of the fractures was motor vehicle accident, followed by interpersonal violence. The age group 21-30 years accounted for the largest subgroup in both sexes. The mandible was the most common site of fracture followed by the zygoma. Associated injuries were found in 48.3% of patients, with a prevalence of intracranial injuries (37.0%). Majority of fractures were treated with open reduction (62.4%), and 7.2% of patients presented post-operative complications. CONCLUSION: Road traffic accident is the most common cause of maxillofacial fractures in China, which is characterized by an increasing prevalence and resulting in more associated injuries. Thus, more attention should be paid on the prevention and treatment of these injuries caused by road traffic accidents in our country. PMID- 23791440 TI - Cohesive, trusting communities buoy at-risk youth throughout adolescence. PMID- 23791441 TI - Rounding the next curve on the road toward reducing teen drivers' crash risk. PMID- 23791442 TI - The world of community-based research is a complicated place. PMID- 23791443 TI - The authors reply. PMID- 23791444 TI - Significant and non-significant associations between technology use and sexual risk: a need for more empirical attention. PMID- 23791445 TI - The author replies. PMID- 23791446 TI - New guideline sets the ground rules for routine molecular testing in non-small cell lung cancer. PMID- 23791447 TI - The challenges of comparing a clinically validated test to other methods. PMID- 23791448 TI - Improved sedimentation field-flow fractionation separation channel for concentrated cellular elution. AB - SdFFF is now commonly used for cell sorting. Nevertheless, as with many other separation methods, SdFFF Hyperlayer elution leads (1) to sample dilution resulting in cell loss which could restrict further use; and (2) to a high output flow rate impacting detector sensitivity and selectivity. In order to limit these problems, we proposed modifications of the SdFFF separation channel consisting both in downscaling and the insertion of an outlet stream splitter. This last system corresponded to a strip which divides the flow rate output into two parts, one containing concentrated cells in a reduced volume and flow rate, the other containing the excess mobile phase useless for further cell manipulation, detection and characterization. For the first time we have shown that splitter implementation and downscaling respected channel flowing and resulted in Hyperlayer elution of around 95% of cells in less than 50% of input flow rate. Improved cell sorting was demonstrated by enrichment (~10 times) of cancer stem cells from WiDr cells with two times less quantity of injected cells. PMID- 23791449 TI - Thorough investigation of the retention mechanisms and retention behavior of amides and sulfonamides on amino column in hydrophilic interaction liquid chromatography. AB - In this paper detailed analysis of a mixture of four amides (tropicamide, nicotinamide, tiracetam, and piracetam) and six sulfonamides (sulfanilamide, sulfacetamide, sulfamethoxazole, sulfafurazole, furosemide, and bumetanide) on aminopropyl column in hydrophilic interaction chromatography (HILIC) was carried out. Since, there are no papers on the topic of the assessment of the contribution of ion-exchange retention mechanism involved in the separation of the acidic compounds on aminopropyl column in HILIC mode, the authors utilized the retention data of the acidic sulfonamides for this purpose. Next, broad range of the aqueous buffer concentrations in the mobile phase was examined providing the separation under either HILIC or RP conditions. Turning points between these two mechanisms were determined and then the fitting of the experimental data in the localized and non-localized adsorption models in both RP and HILIC regions was assessed. Since not many papers in the literature were dealing with the estimation of factor influence on the retention behavior of neutral and acidic compounds on aminopropyl column in HILIC, Box-Behnken design and Response Surface Methodology were applied. On the basis of the obtained data, ten quadratic models were proposed and their adequacy was confirmed using ANOVA test. Furthermore, retention data was graphically evaluated by the construction of 3D response surface plots. Finally, good predictive ability of the suggested models was proved with five additional verification experiments. PMID- 23791450 TI - Identification of cholesteryl ester of ferulic acid in human plasma by mass spectrometry. AB - Epidemiological data suggests that regular consumption polyphenol rich foods and beverages is associated with a reduced risk of certain pathological conditions. While the in vivo "per se" antioxidant benefit of polyphenols still has not been clearly demonstrated, it has been suggested that phenolic acids can be incorporated into low-density lipoproteins (LDL). In the present study, we hypothesized that esterification of phenolic acids - such as ferulic acid - with lipophilic substances such as cholesterol can occur in vivo. To prove this hypothesis, we have synthesized pure cholesteryl-ferulate standard and used gas- and liquid chromatography coupled with mass spectrometry to confirm the presence of endogenous form in human plasma. The detection and identification of cholesteryl ferulate was based on: (1) matching gas- and liquid chromatographic retention time with the reference standard; (2) accurate mass of the molecular ion; (3) matching electron ionization mass spectrum and (4) matching electrospray product ion spectrum. The identified cholesteryl ferulate demonstrated an in vitro antioxidant capacity in various assays. The present study confirmed that phenolic acid can be found in human plasma as lipophilic conjugates which exert antioxidant capacity. These molecules can potentially be involved in the protection of lipoproteins against oxidative damages. PMID- 23791451 TI - Long-term cardiovascular risk and coronary events in morbidly obese patients treated with laparoscopic gastric banding. AB - BACKGROUND: Long-term studies reporting the effects of bariatric surgery on cardiovascular risk factors and events are scarce. The aim of this study was to analyze reduction of multiple cardiovascular risk factors and rates of coronary events in morbidly obese patients treated with bariatric surgery and with>10 years of follow-up. METHODS: This was a prospective uncontrolled study with laparoscopic adjustable gastric banding. Cardiovascular risk factors (fasting glucose, total cholesterol, HDL-C, triglycerides, blood pressure) have been previously determined both at surgery and 12-18 months after in 650 patients treated with laparoscopic adjustable gastric banding from 1993 to 1999. Cardiovascular risk status was again determined in 2010, and the rate of coronary events during long-term (>10 years) follow-up was collected. RESULTS: A total of 318 patients (58 men and 260 women) were retrieved. Age at surgery was 38.6 +/- 10.4 years. Body mass index was 46.7 +/- 7.2 kg/m(2). Follow-up was 12.7 +/- 1.5 years. Weight loss was 17.6% +/- 15.7% of baseline weight at 12-18 months and 17.1% +/- 14.8% at 12.7 years. A significant reduction in blood glucose, total cholesterol, triglycerides, and systolic and diastolic blood pressure was observed at the short-term evaluation and confirmed in the long term. HDL-C was unchanged at 12-18 months and significantly increased at 12.7 years. Five coronary events (1.6%) were recorded during long-term follow-up. The rate of observed events was compared with the rate of events expected according to baseline 10-year probability of myocardial infarction calculated with the Prospective Cardiovascular Munster study (PROCAM) score. Observed rate (1.6%) was slightly lower than the expected rate (2.0%+/- 4.9%). CONCLUSIONS: Stable weight loss and significant improvement of cardiovascular risk profile were observed in morbidly obese patients 10 years after laparoscopic adjustable gastric banding. PMID- 23791452 TI - Impaired skeletal muscle mitochondrial function in morbidly obese patients is normalized one year after bariatric surgery. AB - BACKGROUND: Obesity and type 2 diabetes are associated with impaired skeletal muscle mitochondrial metabolism. As an intrinsic characteristic of an individual, skeletal muscle mitochondrial dysfunction could be a risk factor for weight gain and obesity-associated co-morbidities, such as type 2 diabetes. On the other hand, impaired skeletal muscle metabolism could be a consequence of obesity. We hypothesize that marked weight loss after bariatric surgery recovers skeletal muscle mitochondrial function. METHODS: Skeletal muscle mitochondrial function as assessed by high-resolution respirometry was measured in 8 morbidly obese patients (body mass index [BMI], 41.3+/-4.7 kg/m(2); body fat, 48.3%+/-5.2%) before and 1 year after bariatric surgery (mean weight loss: 35.0+/-8.6 kg). The results were compared with a lean (BMI 22.8+/-1.1 kg/m(2); body fat, 15.6%+/ 4.7%) and obese (BMI 33.5+/-4.2 kg/m(2); body fat, 34.1%+/-6.3%) control group. RESULTS: Before surgery, adenosine diphosphate (ADP)-stimulated (state 3) respiration on glutamate/succinate was decreased compared with lean patients (9.5+/-2.4 versus 15.6+/-4.4 O2 flux/mtDNA; P<.05). One year after surgery, mitochondrial function was comparable to that of lean controls (after weight loss, 12.3+/-5.5; lean, 15.6+/-4.4 O2 flux/mtDNA). In addition, we observed an increased state 3 respiration on a lipid substrate after weight loss (10.0+/-3.2 versus 14.0+/-6.6 O2 flux/mtDNA; P< .05). CONCLUSION: We conclude that impaired skeletal muscle mitochondrial function is a consequence of obesity that recovers after marked weight loss. PMID- 23791453 TI - Treatment: symptomatic treatment of hypoglycaemia. PMID- 23791454 TI - Hypoglycaemia in adults: when should it be raised? How can hypoglycaemia be confirmed in non-diabetic adults? PMID- 23791455 TI - Persistent overexpression of DNA methyltransferase 1 attenuating GABAergic inhibition in basolateral amygdala accounts for anxiety in rat offspring exposed perinatally to low-dose bisphenol A. AB - Substantial evidence indicates that predisposition to diseases can be acquired during early stages of development and interactions between environmental and genetic factors may be implicated in the onset of many pathological conditions. We have shown that perinatal exposure to bisphenol A (BPA) at environmental dose level causes long-term anxiety-like behaviors in rats. The aim of this study was to examine epigenetic reprogramming effect of BPA on anxiety-related neurobehavior in the rat offspring. The results of real-time RT-PCR displayed that the overexpression of DNA methyltransferase 1 (DNMT1) mRNA was accompanied by the reduction of glutamic acid decarboxylase 67 (GAD67) mRNA level in the basolateral amygdala (BLA) of postnatal day 45 BPA-exposed female rats. Chronic intro-BLA injection with 5-ada-CdR could rectify the GAD67 mRNA expression. Behavioral data showed that the anxiety-like behaviors in BPA-exposed rats were reversed by intro-BLA treatment with 5-ada-CdR which could be further blocked by PTX. Electrophysiological study revealed behavioral alterations were associated with the increase of postsynaptic neuronal excitability in the cortical-BLA pathway which appeared as multispike responses, paired-pulse facilitation instead of paired-pulse inhibition and long-term potentiation and 5-aza-CdR treatment restored the increased synaptic transmission in the BLA via improving GABAergic system. The above results suggest that the overexpression of DNMT1 in the BLA is responsible for the etiology of anxiety associated with BPA exposure via GABAergic disinhibition. In addition, we also find these long-term neurobehavioral effects of developmental BPA exposure are reversible in adolescent period. PMID- 23791456 TI - Extreme attributions predict transition from depression to mania or hypomania in bipolar disorder. AB - BACKGROUND: Relatively little is known about psychological predictors of the onset of mania among individuals with bipolar disorder, particularly during episodes of depression. In the present study we investigated attributional style as a predictor of onset of hypomanic, manic or mixed episodes among bipolar adults receiving psychosocial treatment for depression. We hypothesized that "extreme" (i.e., excessively pessimistic or optimistic) attributions would predict a greater likelihood of developing an episode of mood elevation. METHOD: Outpatients with DSM-IV bipolar I or II disorder (N = 105) enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) were randomly allocated to one of three types of intensive psychotherapy for depression or a brief psychoeducational intervention. Patients completed a measure of attributional style at baseline and were followed prospectively for up to one year. All analyses were by intent to treat. RESULTS: Logistic regressions and Cox proportional hazards models indicated that extreme (both positively- and negatively-valenced) attributions predicted a higher likelihood of (and shorter time until) transition from depression to a (hypo)manic or mixed episode (ps < .04), independent of the effects of manic or depressive symptom severity at baseline. Extreme attributions were also retrospectively associated with more lifetime episodes of (hypo)mania and depression (ps < .05). CONCLUSIONS: Evaluating extreme attributions may help clinicians to identify patients who are at risk for experiencing a more severe course of bipolar illness, and who may benefit from treatments that introduce greater cognitive flexibility. PMID- 23791457 TI - Prevalence, demographic and clinical correlates of suicide attempts in Chinese medicated chronic inpatients with schizophrenia. AB - The high prevalence of suicide in schizophrenia may be related to its demographic and clinical characteristics. Because suicide prevalence and its associations with clinical variables are less well characterized in Chinese than European patients with schizophrenia, we assessed the suicide attempts in 520 Chinese inpatients with schizophrenia. The suicide attempt data were collected from medical case notes and interviews with the patients and their family members. Patients were rated on the Positive and Negative Syndrome Scale (PANSS), the Simpson and Angus Extrapyramidal Symptom Rating Scale (SAES), and the Abnormal Involuntary Movement Scale (AIMS). Smoking severity was evaluated using clinician administered questionnaires and the Fagerstrom Test for Nicotine Dependence (FTND). We found a suicide attempt rate of 9.2% in these schizophrenic inpatients. The attempters were single, had a significantly younger age but more hospitalizations, had higher depressive symptoms, and began smoking at an earlier age, smoked more cigarettes each day and had higher FTND total scores than patients without suicide attempts. The logistic regression analysis also indicated that suicide attempts were associated with the number of hospitalizations, depressive symptoms and FTND total scores. These results suggest that Chinese inpatients with schizophrenia attempt suicide more often than the general population. Further, some demographic and clinical variables are risk factors for suicide attempts in schizophrenia. PMID- 23791458 TI - Antabuse reaction due to occupational exposure--an another road on the map? PMID- 23791459 TI - The relationship between acute coronary syndrome and sildenafil. AB - Sildenafil is a drug used for male erectile dysfunction. Sildenafil's fatal cardiac effects except due to hypotension with simultaneous nitrate use have not been reported.We reported in this case a 70-year-old man admitted to the emergency service with chest pain, which occurs in an hour after sildenafil use. Electrocardiogram showed inferoposterior ST-segment elevation. In angiography, total circumflex artery occlusion has been seen. PMID- 23791460 TI - New predictors of mortality in the acute coronary syndromes. PMID- 23791461 TI - Intrahepatic hematoma requiring hepatic artery embolization: a rare complication of extracorporeal shock wave lithotripsy. AB - Extracorporeal shock wave lithotripsy is a well-established treatment modality for renal calculi since the 1980s (Urology 1984;23(5):59-66). In general, it is a safe and effective noninvasive therapeutic modality for treatment of urolithiasis. Bleeding complications of this procedure are rare and usually involve the kidneys. In this case report, a 56-year-old woman developed severe abdominal pain with signs of hemorrhagic shock 2 days post-extracorporeal shock wave lithotripsy procedure. Computed tomography of the abdomen and pelvis showed a large intrahepatic hemorrhage that required hepatic artery embolization. PMID- 23791462 TI - Fibrosing interstitial pneumonia predicts survival in patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). AB - BACKGROUND: Rheumatoid arthritis (RA) is a systemic autoimmune disorder with a variety of extra-articular manifestations. The lung is a common target and diffuse parenchymal lung disease can appear as any of the patterns found with idiopathic interstitial pneumonia. Controversy exists as to the prognostic significance of these patterns among patients with RA-ILD. METHODS: We retrospectively identified 48 patients with a diagnosis of RA-ILD confirmed by surgical lung biopsy. The pathology was reviewed by four expert pulmonary pathologists. We examined survival after stratifying on the presence or absence of fibrotic ILD, and contrasted it with a matched idiopathic pulmonary fibrosis (IPF) population. The Cox proportional hazards model was used to identify independent predictors of survival. RESULTS: The majority of subjects were male smokers with physiologic restriction. A usual interstitial pneumonia (UIP) pattern was identified in 31% of subjects. Median survival time for the entire cohort was 1360 days. Subjects with fibrotic ILD had worse survival than subjects with non-fibrotic ILD (log rank p = 0.02). There was no difference in survival between UIP-pattern RA-ILD subjects and IPF controls (log rank p = 0.94). Multivariable analysis revealed that age (hazard ratio [HR] = 1.04, p = 0.01) and fibrosis (HR = 2.1, p = 0.02) were independent predictors of mortality. CONCLUSIONS: Both cellular and fibrosing ILD patterns are common among RA-ILD patients who undergo surgical lung biopsy. These patients have a shortened survival when compared to the general population and all-comers with RA. Age and the presence of a fibrosing interstitial pneumonia predict shortened survival in these patients. Survival in UIP is similar to matched IPF patients. PMID- 23791463 TI - Comorbidity, systemic inflammation and outcomes in the ECLIPSE cohort. AB - Comorbidities, are common in COPD, have been associated with poor outcomes and are thought to relate to systemic inflammation. To investigate comorbidities in relation to systemic inflammation and outcomes we recorded comorbidities in a well characterized cohort (ECLIPSE study) for 2164 clinically stable COPD subjects, 337 smokers and 245 non-smokers with normal lung function. COPD patients had a higher prevalence of osteoporosis, anxiety/panic attacks, heart trouble, heart attack, and heart failure, than smokers or nonsmokers. Heart failure (Hazard Ratio [HR] 1.9, 95% Confidence Interval [CI] 1.3-2.9), ischemic heart disease (HR 1.5, 95% CI 1.1-2.0), heart disease (HR 1.5, 95% CI 1.2-2.0), and diabetes (HR 1.7, 95% CI 1.2-2.4) had increased odds of mortality when coexistent with COPD. Multiple comorbidities had accumulative effect on mortality. COPD and cardiovascular disease was associated with poorer quality of life, higher MRC dyspnea scores, reduced 6MWD, higher BODE index scores. Osteoporosis, hypertension and diabetes were associated with higher MRC dyspnea scores and reduced 6MWD. Higher blood concentrations of fibrinogen, IL-6 and IL-8 levels occurred in those with heart disease. Comorbidity is associated with poor clinical outcomes in COPD. The comorbidities of heart disease, hypertension and diabetes are associated with increased systemic inflammation. PMID- 23791464 TI - Diagnostic and prognostic significance of survivin levels in malignant pleural effusion. AB - We aimed to evaluate the diagnostic and prognostic value of measuring survivin levels, which is an inhibitor of apoptosis in pleural effusions. METHODS: Group I, malignant (MPE) (n = 51); Group II, tuberculosis (TPE) (n = 18); Group III transudative (TE) (n = 9) effusions were enrolled prospectively. We used ELISA to analyze 78 effusions. The value for the differential diagnosis and the correlation between survivin and survival in MPE were analyzed. RESULTS: Survivin level was 41.75 +/- 76.20 in MPE, 15.83 +/- 10.92 in TPE and 8.33 +/- 8.67 in TE. When the patients divided two groups as malignant and non-malignant pleural effusion (non-MPE), survivin level was significantly higher in MPE (41.75 +/- 76.20) than in non-MPE (13.33+/-2.05) (p = 0.012). The cutoff value for survivin levels detected by ROC curve analysis was 7.5 pg/ml, with sensitivity and specificity values of 72%, 44%, respectively. Survivin had no discriminative power in differentiating exudative effusions of MPE from TPE (p = 0.405). There was no correlation between survivin level and age, sex, location, fluid pH, glucose, protein, albumine and ADA level while there was significant moderate correlation with fluid LDH (r = 0.49; p < 0.001). Survivin levels can distinguish patients who had poor prognosis (median survival 75 days, n = 24) and those who had good prognosis (median survival 219 days, n = 27, p = 0.03) in MPE. In conclusion, survivin expression levels detected with ELISA had no discriminative power in differentiating exudative effusions included MPE and TPE. Elevated survivin levels are associated with poor survival in MPE. Our results suggest that survivin may be a potential prognostic marker in MPE. PMID- 23791467 TI - Ancient cis-regulatory constraints and the evolution of genome architecture. AB - The order of genes along metazoan chromosomes has generally been thought to be largely random, with few implications for organismal function. However, two recent studies, reporting hundreds of pairs of genes that have remained linked in diverse metazoan species over hundreds of millions of years of evolution, suggest widespread functional implications for gene order. These associations appear to largely reflect cis-regulatory constraints, with either (i) multiple genes sharing transcriptional regulatory elements, or (ii) regulatory elements for a developmental gene being found within a neighboring 'bystander' gene (known as a genomic regulatory block). We discuss implications, questions raised, and new research directions arising from these studies, as well as evidence for similar phenomena in other eukaryotic groups. PMID- 23791465 TI - Engineered liver for transplantation. AB - Orthotopic liver transplantation is the only definitive treatment for end stage liver failure and the shortage of donor organs severely limits the number of patients receiving transplants. Liver tissue engineering aims to address the donor liver shortage by creating functional tissue constructs to replace a damaged or failing liver. Despite decades of work, various bottoms-up, synthetic biomaterials approaches have failed to produce a functional construct suitable for transplantation. Recently, a new strategy has emerged using whole organ scaffolds as a vehicle for tissue engineering. This technique involves preparation of these organ scaffolds via perfusion decellularization with the resulting scaffold retaining the circulatory network of the native organ. This important phenomenon allows for the construct to be repopulated with cells and to be connected to the blood torrent upon transplantation. This opinion paper presents the current advances and discusses the challenges of creating fully functional transplantable liver grafts with this whole liver engineering approach. PMID- 23791468 TI - Combined treatment of methylprednisolone pulse and memantine hydrochloride prompts recovery from neurological dysfunction and cerebral hypoperfusion in carbon monoxide poisoning: a case report. AB - A 49-year-old healthy man developed sudden unconsciousness under inadequate ventilation. Blood gas analysis showed carboxyhemoglobin of 7.3%. After normobaric oxygen therapy, he recovered completely 7 days later. At 3 weeks after carbon monoxide (CO) exposures, memory and gait disturbances appeared. Neurological examination revealed Mini-Mental State Examination (MMSE) score of 5 of 30 points, leg hyper-reflexia with Babinski signs, and Parkinsonism. Brain fluid-attenuated inversion recovery imaging disclosed symmetric hypointense lesions in the thalamus and the globus pallidus, and hyperintense lesions in the cerebral white matter. Brain single-photon emission tomography (SPECT) scanning with (99m)Technesium-ethyl cysteinate dimer displayed marked hypoperfusion in the cerebellum, the thalamus, the basal ganglia, and the entire cerebral cortex. He was diagnosed as CO poisoning and treated with hyperbaric oxygen therapy. The neurological deficits were not ameliorated. At 9 weeks after neurological onset, methylprednisolone (1000 mg/day, intravenous, 3 days) and memantine hydrochloride (20 mg/day, per os) were administered. Three days later, MMSE score was increased from 3 to 20 points. Neurological examination was normal 3 weeks later. Brain SPECT exhibited 20% increase of regional cerebral blood flows in the cerebellum, the thalamus, the basal ganglia, and the entire cerebral cortex. These clinicoradiological changes supported that the treatment with steroid pulse and memantine hydrochloride could prompt recovery from neurological dysfunction and cerebral hypoperfusion. Further clinical trials are warranted whether such combined therapy can attenuate neurological deficits and cerebral hypoperfusion in patients with CO poisoning. PMID- 23791469 TI - Paroxysmal atrial fibrillation in cryptogenic stroke: a case-control study. AB - BACKGROUND: It is unclear if brief episodes of paroxysmal atrial fibrillation (PAF) detected by prolonged cardiac monitoring are an occult of cause of cryptogenic strokes (CS). We compared the incidence of PAF in patients with CS and patients with stroke of known cause (SKC) using prolonged ambulatory cardiac monitoring. METHODS: We prospectively enrolled patients within 3 months of ischemic stroke to undergo noninvasive cardiac monitoring for 3 weeks. Primary end point was PAF detection independently confirmed by 2 blinded cardiologists. RESULTS: The study consisted of 132 patients, 66 had CS and 66 had SKC. Episodes of PAF were detected in 16 of 64 (25%) patients with CS and 9 of 64 (14%) patients with SKC (P=.12). Duration and number of PAF episodes, PAF burden, and time of first PAF detection did not differ significantly between the 2 groups (P>.05 for all). In patients younger than 65 years, PAF was more common in the CS group (22% versus 3%; P=.07), whereas in patients 65 years or older, the rates of detection were similar (27% in CS versus 25% in SKC; P=.9). Among patients younger than 65 years with embolic imaging pattern, PAF was only observed in the CS group (21% versus 0%; P=.03). CONCLUSIONS: Very short episodes of PAF are common in patients with CS and with SKC, but their pathogenic significance is unclear. Predominance of PAF in younger patients with CS and embolic infarct pattern suggests a causative role in these cases. More research is needed before prolonged cardiac rhythm monitoring can be recommended to guide anticoagulation in CS patients. PMID- 23791470 TI - Thrombosis of a developmental venous anomaly causing venous infarction and pontine hemorrhage. AB - Developmental venous anomalies are often incidental findings on brain imaging. We report a case of a thrombosed developmental venous anomaly with venous congestion and pontine hemorrhage that improved after anticoagulation therapy. PMID- 23791471 TI - Regulatory science in Europe: the case of schizophrenia trials. PMID- 23791472 TI - First case of infection with vancomycin-resistant Staphylococcus aureus in Europe. PMID- 23791473 TI - Twiddler's syndrome. PMID- 23791474 TI - The global prevalence of intimate partner homicide: a systematic review. AB - BACKGROUND: Homicide is an important cause of premature mortality globally, but evidence for the magnitude of homicides by intimate partners is scarce and hampered by the large amount of missing information about the victim-offender relationship. The objective of the study was to estimate global and regional prevalence of intimate partner homicide. METHODS: A systematic search of five databases (Medline, Global Health, Embase, Social Policy, and Web of Science) yielded 2167 abstracts, and resulted in the inclusion of 118 full-text articles with 1122 estimates of the prevalence of intimate partner homicide after double blind screening. All studies were included that reported the number or proportion of women or men who were murdered by an intimate partner in a country, province, or town, using an inclusive definition of an intimate partner. Additionally, a survey of official sources of 169 countries provided a further 53 estimates. We selected one estimate per country-year using a quality assessment decision algorithm. The median prevalence of intimate partner homicide was calculated by country and region overall, and for women and men separately. FINDINGS: Data were obtained for 66 countries. Overall 13.5% (IQR 9.2-18.2) of homicides were committed by an intimate partner, and this proportion was six times higher for female homicides than for male homicides (38.6%, 30.8-45.3, vs 6.3%, 3.1-6.3). Median percentages for all (male and female) and female intimate partner homicide were highest in high-income countries (all, 14.9%, 9.2-18.2; female homicide, 41.2%, 30.8-44.5) and in southeast Asia (18.8%, 11.3-18.8; 58.8%, 58.8-58.8). Adjustments to account for unknown victim-offender relationships generally increased the prevalence, suggesting that results presented are conservative. INTERPRETATION: At least one in seven homicides globally and more than a third of female homicides are perpetrated by an intimate partner. Such violence commonly represents the culmination of a long history of abuse. Strategies to reduce homicide risk include increased investment in intimate partner violence prevention, risk assessments at different points of care, support for women experiencing intimate partner violence, and control of gun ownership for people with a history of violence. Improvements in country-level data collection and monitoring systems are also essential, because data availability and quality varied strongly across regions. FUNDING: WHO, Sigrid Rausing Trust, and the UK Economic and Social Research Council. PMID- 23791475 TI - Immunolocalization of Wilms' Tumor protein (WT1) in developing human peripheral sympathetic and gastroenteric nervous system. AB - Developmental expression of Wilms' tumor gene (WT1) and protein is crucial for cell proliferation, apoptosis, differentiation and cytoskeletal architecture regulation. Recently, a potential role of WT1 has been suggested in the development of neural tissue and in neurodegenerative disorders. We have investigated immunohistochemically the developmentally regulated expression and distribution of WT1 in the human fetal peripheral sympathetic nervous system (PSNS) and the gastro-enteric nervous system (GENS) from weeks 8 to 28 gestational age. WT1 expression was restricted to the cytoplasm of sympathetic neuroblasts, while it progressively disappeared with advancing morphologic differentiation of these cells along both ganglionic and chromaffin cell lineages. In adult tissues, both ganglion and chromaffin cells lacked any WT1 expression. These findings show that WT1 is a reliable marker of human sympathetic neuroblasts, which can be used routinely in formalin-fixed, paraffin embedded tissues. The progressive loss of WT1 in both ganglion and chromaffin cells, suggests its potential repressor role of differentiation in a precise temporal window during the development of the human PSNS and GENS. PMID- 23791476 TI - Optimization of breast lesion segmentation in texture feature space approach. AB - This paper develops a method for semi-automatic detection of breast lesion boundaries by combining the snake evolution techniques with statistical texture information of images. We propose an efficient image energy function in segmentation based on image features, first-order textural features and four n*n masks. The segmentation results were evaluated by using area error rate. The image features were evaluated qualitatively by using the contrast-to-noise ratio and fractal dimension analysis. In our study, standard deviation, skewness and entropy are indicated as being the most relevant image features. PMID- 23791477 TI - Cystatin C and its emerging role in oncology: clinical benefit beyond its prognostic role in heart failure. PMID- 23791478 TI - Epidemic myalgia associated with human parechovirus type 3 infection among adults occurs during an outbreak among children: findings from Yamagata, Japan, in 2011. AB - BACKGROUND: Based on our findings in Yamagata, Japan, in 2008, we reported that human parechovirus type 3 (HPeV3) could be associated with epidemic myalgia among adults, although HPeV3 is generally associated with infectious diseases in children. OBJECTIVES: To clarify the relationship between community outbreaks among children and myalgia through the continued surveillance of HPeV3 infections. STUDY DESIGN: In the summer season (June-August) of 2011, we collected 586 specimens from children with infectious diseases, and throat swabs, and stool and serum specimens from 5 patients with myalgia. We detected HPeV3 using virus isolation and reverse-transcription PCR, and carried out phylogenetic analysis. We also performed screening for HPeV3 using 309 stocked frozen specimens collected in 2008 for a comparison between 2008 and 2011 strains. RESULTS: We detected HPeV3 in 59 children and isolated HPeV3 from all myalgia patients. Phylogenetic analysis indicated that the HPeV3 strains circulating in 2008 and 2011 could be clearly distinguished, apart from two strains. Further, we detected HPeV3 strains with identical nucleotide sequences from children and adults in 2008 and 2011, respectively. Two children belonging to one myalgia patient had upper respiratory infections prior to the onset of their father's illness, and the HPeV3 isolates from these three patients had identical nucleotide sequences. CONCLUSIONS: These findings suggest that HPeV3, circulating among children in the community, infects their household, including parents, a portion of whom may subsequently show symptoms of myalgia. Our observations in 2008 and 2011 strongly suggest that clinical consideration should be given to HPeV3 in children as well as in adults during summer seasons in which an HPeV3 outbreak occurs among the children in the community. PMID- 23791479 TI - Differential regulation of macropinocytosis in macrophages by cytokines: implications for foam cell formation and atherosclerosis. AB - A key event during the formation of lipid-rich foam cells during the progression of atherosclerosis is the uptake of modified low-density lipoproteins (LDL) by macrophages in response to atherogenic mediators in the arterial intima. In addition to scavenger receptor-dependent uptake of LDL, macropinocytosis is known to facilitate the uptake of LDL through the constitutive and passive internalization of large quantities of extracellular solute. In this study we confirm the ability of macropinocytosis to facilitate the uptake of modified LDL by human macrophages and show its modulation by TGF-beta, IFN-gamma, IL-17A and IL-33. Furthermore we show that the TGF-beta-mediated inhibition of macropinocytosis is a Smad-2/-3-independent process. PMID- 23791480 TI - Towards early diagnosis and treatment to save children from catastrophic epilepsy -- focus on epilepsy surgery. AB - OBJECTIVE: To analyze and to discuss whether by paying attention to the many recent advancements in the field of pediatric epilepsy surgery catastrophic childhood epilepsies caused by definitive or suspected structural lesions can be prevented more often these days in comparison to the past. METHODS: Based on data from the literature and supplemented by the authors own experience, risks for children suffering from structural focal epilepsies that the epilepsy becomes catastrophic and ways how such evolutions can possibly be prevented are discussed for the different lesion-types separately - in the order of their frequency as they are seen at pediatric epilepsy surgery centers. Special emphasis is put on data regarding attempts to prevent permanent severe mental retardations. RESULTS: There are common factors predisposing to catastrophic courses in all structural focal epilepsies, such as early onset and a longer duration of epilepsy (with respect to cognitive outcome not with respect to seizure outcome), but there are also differences. Moreover the better perspectives now in comparison to the past for children with conditions like MRI-negative focal epilepsies, subtle focal cortical dysplasias, epilepsies post hypoxic-ischemic events, tuberous sclerosis etc. are not well recognized yet. While there is agreement that "early" (and successful) surgery is essential in many instances to prevent permanent mental retardations there is insufficient data regarding the issue that "early surgery "might not be early enough under certain circumstances and there is also only little data regarding variables which would allow to keep calm when a child is presenting with early onset difficult to control seizures. One of the biggest changes seen over the last decade is the fact that children with very severe epilepsies, who have unilateral lesions, but "generalized" seizures and/or "generalized" EEGs, are not excluded anymore from considerations for epilepsy surgery. Even children with bilateral lesions can be surgical candidates. CONCLUSION: The gradually widening spectrum of indications for epilepsy surgery in children is resulting in an increasing number of preventions of catastrophic epilepsies. Insufficient data regarding timing of surgery in order to prevent permanent mental retardations are calling for prospective multi-center studies. PMID- 23791482 TI - Psychometric properties of the Fatigue Severity Scale and the Modified Fatigue Impact Scale. AB - OBJECTIVE: Fatigue is one of the most common, debilitating and life altering symptoms experienced by those with multiple sclerosis (MS) and has become the focus of therapeutic interventions and clinical rehabilitation. There is limited evidence regarding the psychometric properties and clinical relevance of fatigue outcomes for interpreting the effectiveness of intervention and rehabilitation strategies. This study determined the reliability, precision and clinically important change of the uni-dimensional Fatigue Severity Scale (FSS) and the multi-dimensional Modified Fatigue Impact Scale (MFIS). METHODS: The FSS and MFIS along with physical, psychological and cognitive clinical outcomes were administered to a sample of 82 persons with MS in a clinical research setting on two time points, separated by six months. Intraclass correlation coefficient (ICC) analyses established reliability; standard error of measurement (SEM) and coefficient of variation (CV) determined precision; minimal detectable change (MDC) defined clinically important change. RESULTS: Participants varied in type of MS and disability status, with 77% of participants classified as having substantial fatigue, based on the criteria of a mean FSS score >=4. The MFIS (ICC=0.863) and the FSS (ICC=0.751) had acceptable reliability over six months. Precision was reasonable for both scales (based on SEM and CV estimates) but better for the FSS. MDC estimates were established and were lower for the FSS. CONCLUSION: Reliability of the FSS and MFIS falls within acceptable ranges, and precision and clinically important change estimates provide guidelines for interpreting change in scores from these outcomes in clinical research of intervention and rehabilitation approaches for managing fatigue. PMID- 23791481 TI - In vivo mapping of notch pathway activity in normal and stress hematopoiesis. AB - Accumulating evidence suggests that Notch signaling is active at multiple points during hematopoiesis. Until recently, the majority of such studies focused on Notch signaling in lymphocyte differentiation and knowledge of individual Notch receptor roles has been limited due to a paucity of genetic tools available. In this manuscript we generate and describe animal models to identify and fate-map stem and progenitor cells expressing each Notch receptor, delineate Notch pathway activation, and perform in vivo gain- and loss-of-function studies dissecting Notch signaling in early hematopoiesis. These models provide comprehensive genetic maps of lineage-specific Notch receptor expression and activation in hematopoietic stem and progenitor cells. Moreover, they establish a previously unknown role for Notch signaling in the commitment of blood progenitors toward the erythrocytic lineage and link Notch signaling to optimal organismal response to stress erythropoiesis. PMID- 23791483 TI - Metabolic signaling in fuel-induced insulin secretion. AB - The pancreatic islet beta cell senses circulating levels of calorigenic nutrients to secrete insulin according to the needs of the organism. Altered insulin secretion is linked to various disorders such as diabetes, hypoglycemic states, and cardiometabolic diseases. Fuel stimuli, including glucose, free fatty acids, and amino acids, promote insulin granule exocytosis primarily via their metabolism in beta cells and the production of key signaling metabolites. This paper reviews our current knowledge of the pathways involved in both positive and negative metabolic signaling for insulin secretion and assesses the role of established and candidate metabolic coupling factors, keeping recent developments in focus. PMID- 23791485 TI - pH treatment as an effective tool to select the functional and structural properties of yak milk caseins. AB - Qula is made from yak milk after defatting, acidifying, and drying. Yak milk caseins are purified from Qula by dissolving in alkali solution. The effects of different pH treatments on the functional and structural properties of yak milk caseins were investigated. Over a broad range of pH (from 6.0 to 12.0), functional properties of yak milk caseins, including solubility, emulsifying activities, and thermal characteristics, and the structural properties, including 1-anilino-8-naphthalene-sulfonate fluorescence, turbidity and particle diameter, were evaluated. The results showed that the yak milk casein yield increased as the pH increased from 6.0 to 12.0. The solubility dramatically increased as the pH increased from 6.0 to 8.0, and decreased as the pH increased from 9.0 to 12.0. The changes in emulsifying activity were not significant. Caseins were remarkably heat stable at pH 9.0. The turbidity of the casein solution decreased rapidly as the pH increased from 6.0 to 12.0, and the results suggested that reassembled casein micelles were more compact at low pH than high pH. At pH values higher than 8.0, the yield of yak milk caseins reached more than 80%. The highest solubility was at pH 8.0, the best emulsification was at pH 10.0 and the greatest thermal stability was at pH 9.0. According to the functional characteristics of yak milk caseins, alkali conditions (pH 8.0-10.0) should be selected for optimum production. These results suggested that pH-dependent treatment could be used to modify the properties of yak milk caseins by appropriate selection of the pH level. PMID- 23791484 TI - Cellular fatty acid metabolism and cancer. AB - Cancer cells often have characteristic changes in metabolism. Cellular proliferation, a common feature of all cancers, requires fatty acids for synthesis of membranes and signaling molecules. Here, we provide a view of cancer cell metabolism from a lipid perspective, and we summarize evidence that limiting fatty acid availability can control cancer cell proliferation. PMID- 23791486 TI - Glomerular filtration rate in Holstein dairy cows estimated from a single blood sample using iodixanol. AB - The isotonic, nonionic, contrast medium iodixanol, as a test substance, was compared with the conventional glomerular filtration rate (GFR) tracer inulin to establish a simplified procedure for estimating the GFR in Holstein dairy cows. First, inulin and iodixanol were coadministered as a bolus intravenous injection to clinically healthy cows at 30 mg/kg and 10mg of I/kg of body weight, respectively, followed by blood collection for multisample strategies. Serum iodixanol and inulin concentrations were separately determined by using HPLC and colorimetry, respectively, and blood urea nitrogen and creatinine concentrations in sera were measured. In the multisample method, the GFR values estimated by iodixanol were consistent with those estimated by inulin. No effects of body weight, age, or parity on GFR estimates were noted with either protocol used. No difference was observed between the GFR values obtained from nonlactating and lactating cows, suggesting that no transfer of iodixanol to milk occurred. An equation for calculating the GFR in the single-sample method was derived from the injected dose, sampling time, serum concentration, and estimated volume of distribution based on data from the multisample method in clinically healthy cows and cows with reduced renal function. The GFR values estimated by the single sample method were in good agreement with those calculated by using the multisample method. These results demonstrate that the single-sample method using iodixanol can be applied as an alternative procedure for screening GFR in dairy cows. PMID- 23791487 TI - Views on contentious practices in dairy farming: the case of early cow-calf separation. AB - The public has become increasingly interested in the welfare of food animals, but the food animal industries possess few mechanisms for public engagement. Here we present results from a web-based forum designed to allow stakeholders to share views on controversial issues in dairying. In response to the question "Should dairy calves be separated from the cow within the first few hours after birth?" participants were able to indicate "yes," "no," or "neutral" and either write a reason in support of their view or select reasons provided by other participants. Four independent groups of participants were recruited (a total of 163 people); 31% said they had no involvement in the dairy industry; the remaining 69% (with some involvement in the industry) were students or teachers (33%), animal advocates (13%), producers (11%), veterinarians (9%) and other dairy industry professionals (3%). Overall, little consensus existed among participants across groups; 44% chose "yes," 48% "no," and 9% "neutral." Responses varied with demographics, with opposition to early separation higher among females, animal advocates, and those with no involvement with the dairy industry. A fifth group was recruited at a dairy industry conference (an additional 28 participants); 46% chose "yes," 32% "no," and 21% "neutral." Across all 5 groups, opponents and supporters often referenced similar issues in the reasons they provided. Opponents of early separation contended that it is emotionally stressful for the calf and cow, it compromises calf and cow health, it is unnatural, and the industry can and should accommodate cow-calf pairs. In contrast, supporters of early separation reasoned that emotional distress is minimized by separating before bonds develop, that it promotes calf and cow health, and that the industry is limited in its ability to accommodate cow-calf pairs. These results illustrate the potential of web-based forums to identify areas of agreement and conflict among stakeholders, providing a basis for the development of practices that address shared concerns. PMID- 23791488 TI - Rumination time during the summer season and its relationships with metabolic conditions and milk production. AB - The main objective of this experiment was to monitor the rumination pattern during the summer season in lactating dairy cows and to investigate its relationships with metabolic conditions and physiological markers of heat stress. The study was carried out in an experimental freestall barn located near Piacenza, Italy (45 degrees 01'N, 9 degrees 40'E; 68 m above sea level), and involved 21 Italian Friesian cows (11 primiparous and 10 multiparous) during the summer season. Rumination time (RT) was recorded by using an automatic system and data were calculated and summarized in 2-h intervals. Microclimatic conditions (temperature and relative humidity) inside the barn were recorded during the trial, and the temperature-humidity index (THI) was calculated. Breathing rates and rectal temperatures were recorded following stable meteorological periods characterized by lower and higher temperatures. At the same times, blood samples were collected to assess biochemical variables related to energy, protein, and mineral metabolism, as well as markers of inflammatory conditions and enzyme activity. Daily milk yield, body weight, nutritional condition, and health status were also recorded. The average RT was 501 min/d, with no significant differences between primiparous and multiparous cows. According to the microclimatic conditions and physiological markers of heat stress, the cows suffered mild to moderate heat stress during the summer. A negative relationship between daily maximum THI and RT was observed (r=-0.32), with a reduction of 2.2 min of RT for every daily maximum THI unit over the threshold of daily maximum THI of 76. Most of the rumination occurred during the night (on average the nighttime RT was 63.2% of daytime and nighttime RT); moreover, the proportion of nighttime RT slightly but significantly increased as THI increased. Rumination time throughout the trial was negatively related to breathing rate and positively related to milk yield. Daily maximum THI was negatively correlated with plasma glucose (r=-0.52) and positively correlated with plasma beta-hydroxybutyric acid (r=0.26). Values of plasma beta-hydroxybutyric acid were positively related to RT through the trial. Our results indicate that hot conditions negatively affect RT and modify its daily pattern. The relationship between RT and the physiological markers used in our trial support the use of RT as a marker of heat stress. PMID- 23791489 TI - Short communication: Change in dose delivery of prostaglandin F2alpha in a 5-day timed artificial insemination program in lactating dairy cows. AB - We hypothesized that 50mg of prostaglandin F2alpha (PG) on d 6 would induce luteolysis in a traditional 5-d Ovsynch-72 program [GnRH 5 d before (d 0) and 72 h after (d 8) 25-mg PG doses (d 5 and 6 after GnRH); timed artificial insemination (AI) on d 8]. Experiment 1 monitored luteal regression of original and GnRH-induced luteal tissue (corpus luteum, CL) by transrectal ultrasonography and blood serum concentrations of progesterone after both 25-mg doses of PG (d 5 and 6; control; n=31) or a single 50-mg dose of PG on d 6 (n=30). Estrous cycles were presynchronized (GnRH 7d before 25 mg of PG); 11 d later, cows were enrolled in a 5-d Ovsynch-72 program (62 to 71 d in milk) and treatments were administered. Blood was sampled for progesterone analysis and luteal structures were measured on d 0 (original CL) and d 5 through 9 to monitor original and new GnRH-induced CL. Control PG reduced luteal tissue area of original CL on d 6 and 7 compared with PG administered only on d 6, but no difference between treatments was detected by d 9. In contrast, no differences were detected in luteal tissue area of the induced CL on d 5 through 9. Serum progesterone on d 5 through 9 differed only on d 6 for control and the 50-mg dose. Luteolysis occurred in all 31 controls, but luteolytic failure occurred in 2 of 30 cows receiving 50mg, in which no CL were present on d 0 but 1 or 3 new CL were present on d 5 in these 2 cows. Pregnancy outcome 32 d after AI was 14 of 30 (40%) compared with 15 of 30 (50%) for control versus 50-mg dose, respectively. Experiment 2 monitored luteolysis in nonpregnant repeat-service cows subsequently treated with the same 2 treatments as in experiment 1. Serum progesterone in 63 cows (serum progesterone >=1 ng/mL on d 5) on d 5, 6, and 8 differed only on d 6 for control and the 50-mg dose. Luteolysis occurred in 32 of 34 controls and in 29 of 29 cows treated with 50mg. Pregnancy outcome 32 d after AI was 17 of 33 (52%) compared with 13 of 29 (45%) for control versus 50-mg dose, respectively. We concluded that the single 50-mg dose was equivalent to the control based on actual luteal tissue regression and decreased progesterone. PMID- 23791490 TI - Collective migration and cell jamming. AB - Our traditional physical picture holds with the intuitive notion that each individual cell comprising the cellular collective senses signals or gradients and then mobilizes physical forces in response. Those forces, in turn, drive local cellular motions from which collective cellular migrations emerge. Although it does not account for spontaneous noisy fluctuations that can be quite large, the tacit assumption has been one of linear causality in which systematic local motions, on average, are the shadow of local forces, and these local forces are the shadow of the local signals. New lines of evidence now suggest a rather different physical picture in which dominant mechanical events may not be local, the cascade of mechanical causality may be not so linear, and, surprisingly, the fluctuations may not be noise as much as they are an essential feature of mechanism. Here we argue for a novel synthesis in which fluctuations and non local cooperative events that typify the cellular collective might be illuminated by the unifying concept of cell jamming. Jamming has the potential to pull together diverse factors that are already known to contribute but previously had been considered for the most part as acting separately and independently. These include cellular crowding, intercellular force transmission, cadherin-dependent cell-cell adhesion, integrin-dependent cell-substrate adhesion, myosin-dependent motile force and contractility, actin-dependent deformability, proliferation, compression and stretch. PMID- 23791491 TI - An unusual cause of epistaxis: rupture of a rapidly growing internal carotid artery pseudoaneurysm. PMID- 23791492 TI - Three-dimensional computed tomography scan evaluation of the pattern of erosion in type B glenoids. AB - BACKGROUND: Type B glenoids according to Walch are subclassified into a group with no posterior erosion (B1) and a group with important posterior erosion (B2) based on 2-dimensional axial computed tomography (CT) scan images. Three dimensional (3D) CT scan reconstruction seems to improve the accuracy of the measurement of erosion because of its independence from positional errors. The aim is to quantify the direction and amount of posterior erosion of type B glenoids using a reproducible 3D measuring technique. METHODS: We performed 3D reconstruction of 72 type B glenoids (24 type B1 glenoids and 48 type B2 glenoids) using Mimics (Materialise, Haasrode, Belgium). The native glenoid plane and intermediate glenoid plane were determined by use of 3-Matic (Materialise). The normal glenoid version, eroded retroversion, and difference in retroversion were measured. Next, the maximum erosion and its orientation were quantified. RESULTS: There was always minimum erosion of 1.7 mm, and the mean erosion was 4.2 mm. There was a significant difference between the mean erosion in type B1 glenoids (3.5 mm) and type B2 glenoids (4.5 mm) (P = .019). The mean orientation of the erosion was mostly to the posteroinferior side (119 degrees ; SD, 26.8). There was a significant difference between the mean orientation in type B1 glenoids (132 degrees ; SD, 25.2) and type B2 glenoids (113 degrees ; SD, 25.5) (P = .004). CONCLUSIONS: With the use of this newly developed reproducible measuring technique, the maximum erosion in type B glenoids can be adequately quantified. All glenoids showed signs of important erosion. Because the orientation of the maximum erosion in type B1 glenoids is situated more inferiorly, the 2-dimensional CT scan technique can be insufficient to evaluate this erosion. PMID- 23791493 TI - Age-related changes affect rat rotator cuff muscle function. AB - BACKGROUND: The influence of age on rotator cuff function and muscle structure remains poorly understood. We hypothesize that normal aging influences rotator cuff function, muscle structure, and regulatory protein expression in an established rat model of aging. METHODS: Seventeen rats were obtained from the National Institute on Aging. The supraspinatus muscles in 11 middle-aged (12 months old) and 6 old (28 months old) rats were studied for age-related changes in rotator cuff neuromuscular function by in vivo muscle force testing and electromyography (EMG). Changes in muscle structure and molecular changes were assessed with quantitative immunohistochemistry for myogenic determination factor 1 (MyoD) and myogenic factor 5 (Myf5) expression. RESULTS: Old animals revealed significantly decreased peak tetanic muscle force at 0.5 N and 0.7 N preload tension (P < .05). The age of the animal accounted for 20.9% of variance and significantly influenced muscle force (P = .026). Preload tension significantly influenced muscle force production (P < .001) and accounted for 12.7% of total variance. There was regional heterogeneity in maximal compound motor action potential (CMAP) amplitude in the supraspinatus muscle; the proximal portion had a significantly higher CMAP than the middle and distal portions (P < .05). The expression of muscle regulatory factors MyoD and Myf5 was significantly decreased in old animals compared with middle-aged animals (P < .05). CONCLUSIONS: The normal aging process in this rat model significantly influenced contractile strength of the supraspinatus muscle and led to decreased expression of muscle regulatory factors. High preload tensions led to a significant decrease in force production in both middle-aged and old animals. PMID- 23791494 TI - Association of plasma dilution with cardiopulmonary bypass-associated bleeding and morbidity. AB - OBJECTIVE: To investigate the relationship of cardiopulmonary bypass-associated plasma dilution with blood product transfusion and postoperative morbidity. DESIGN: Retrospective chart review. SETTING: Single academic medical center. PARTICIPANTS: Five hundred forty adults undergoing cardiac surgery between January 4, 2005 and September 19, 2007. INTERVENTIONS: Records were analyzed for demographics, blood volumes (BVs), and fluid balance. Plasma protein concentrations (% of baseline) at the end of bypass were calculated. The lowest and highest quartiles of plasma protein concentration were correlated with blood product administration and postoperative complications. MEASUREMENTS AND MAIN RESULTS: At the end of bypass, calculated plasma protein concentrations ranged from a low of 10% to a high of 111% of baseline. Concentrations below 45% of baseline were associated with increased blood product administration, longer ventilator support, and longer intensive care unit stay. CONCLUSIONS: Patient morbidity and likelihood of transfusion were associated with calculated plasma protein concentrations below 45% of baseline. Bleeding and administered fluids decrease both hematocrit and plasma proteins. Infusion of washed, salvaged blood or red blood cells raises hematocrit, but further dilutes clotting factors. If this dilution is excessive, coagulopathy may ensue. Patients with the smallest BVs are at greatest risk, but dilution can negatively impact patients with large BVs as well if the fluid used for cardiopulmonary bypass prime and anesthesia management represents a significant fraction of total BV. PMID- 23791495 TI - Morphine is a reasonable alternative to haloperidol in the treatment of postoperative hyperactive-type delirium after cardiac surgery. AB - OBJECTIVES: Patients who undergo cardiac surgery have an increased risk of delirium. Currently, there are few choices of treatment for postoperative hyperactive delirium in cardiac surgical patients. The aim of this study was to assess the effect of morphine compared with a haloperidol-based regimen in hyperactive-type delirium in patients after cardiac surgery. DESIGN: A prospective, randomized clinical study. SETTING: A single community hospital. PARTICIPANTS: Fifty-three consecutive, adult, delirious patients. INTERVENTIONS: Patients were randomized into 2 groups; in group 1, patients received 5mg of haloperidol intramuscularly and in group 2, patients received 5mg of morphine sulfate intramuscularly to control delirium symptoms. MEASUREMENTS AND MAIN RESULTS: During the second and third hour of the morphine treatment, statistically low Richmond Agitation and Sedation Scale scores were found and the target Richmond Agitation and Sedation Scale scores percentages were statistically higher than those of the haloperidol group (p = 0.042 and p = 0.028, respectively). The number of patients requiring additive sedatives was significantly more in the haloperidol group when compared with the morphine group (p = 0.011). CONCLUSION: During the treatment of patients, it was determined that the patients who were receiving morphine treatment responded more quickly compared with the patients receiving haloperidol treatment. Morphine was found to be a reasonable alternative to haloperidol in the treatment of postoperative hyperactive delirious patients after cardiac surgery. PMID- 23791496 TI - Ultrasound destruction of air microemboli as a novel approach to brain protection in cardiac surgery. AB - OBJECTIVE: Evaluation of a novel approach to eliminate air microemboli from extracorporeal circulation via ultrasonic destruction. DESIGN: In vitro proof-of concept study. SETTING: Research laboratory. PARTICIPANTS: None. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: An extracorporeal circulation device was filled with human blood circulating at 3 L/min. Air bubbles were injected into the system. For bubble destruction, the blood in the tubing system was repeatedly insonated for 3 minutes using a therapeutic 60-kHz device, with variation of intensity and duty cycle settings, ranging from 0.2 W/cm2 to 1.0 W/cm2 and from duty cycle 60% to continuous wave (CW). Number and diameter of air microemboli were counted upstream and downstream of the ultrasound device by a 2-channel microemboli Doppler detector. For safety assessment, circulating blood was insonated continuously for 2 hours at 0.8 W/cm2 CW and compared with circulation without insonation; and standard blood parameters were analyzed. Without treatment, 1,313 to 1,580 emboli were detected upstream, diameter ranging between 10 and 130 MUm. Ultrasound treatment eliminated up to 87% of all detected bubbles in cw application (p<0.01) and showed comparable effects at intensities from 0.4 W/cm2 to 1.0 W/cm2 cw. Bubbles sized>15 MUm almost were eliminated completely (p<0.001). Pulsed wave application rendered inferior results (p>0.05). No relevant changes of blood parameters were observed compared with control circulation. CONCLUSIONS: Ultrasound destruction of air emboli is a very efficient method to reduce number and size of emboli. Within the limits of safety assessment, the authors could not detect relevant side effects on standard blood parameters. PMID- 23791497 TI - A combined ultrafiltration strategy during pediatric cardiac surgery: a prospective, randomized, controlled study with clinical outcomes. AB - OBJECTIVE: To investigate the clinical effects of a combined ultrafiltration strategy on the surgical treatment of pediatric patients with congenital heart diseases. DESIGN: A prospective, randomized, controlled study. SETTING: A single institution study in an affiliated hospital of a university. PARTICIPANTS: Sixty five pediatric patients who underwent open heart surgery with cardiopulmonary bypass (CPB) to treat congenital heart disease were enrolled. The participants were randomized into 2 groups: conventional + modified ultrafiltration (MUF) (CM) group and prime + zero-balanced + MUF (PZM) group. INTERVENTIONS: In the CM group (n = 33), conventional ultrafiltration was performed after removal of the aortic clamp, and MUF was performed after the completion of CPB. In the PZM group (n = 32), ultrafiltration was performed for the circuit prime solution, zero-balance ultrafiltration was performed after removal of the aortic clamp, and MUF was performed after the completion of CPB. MEASUREMENTS AND MAIN RESULTS: The blood gas parameters and tumor necrosis factor alpha content in the priming solution and perioperative blood samples were analyzed. Postoperative parameters, including mechanical ventilation time, respiratory indices, intensive care unit time, and hospital time, also were recorded. One hospital death occurred in each group. No severe complications occurred in either group. The lactic acid, glucose, and tumor necrosis factor alpha contents in the priming solution and perioperative blood samples were significantly lower in the PZM group compared with the CM group. The respiratory indices were statistically significantly better in the PZM group compared with the CM group in the early postoperative period. No significant differences were found between the 2 groups regarding the postoperative ventilation time, inotropic support, homologous blood transfusion, drainage, intensive care unit time, or postoperative hospital time. CONCLUSION: The combined use of ultrafiltration of prime solution, zero-balance ultrafiltration, and MUF strategy is associated with a modest improvement in pulmonary function compared with the combination of conventional and MUF strategies in the early postoperative period, but the principal clinical outcomes are similar. PMID- 23791498 TI - Reversal of decreases in cerebral saturation in high-risk cardiac surgery. AB - OBJECTIVES: To measure the incidence of cerebral desaturation during high-risk cardiac surgery and to evaluate strategies to reverse cerebral desaturation. DESIGN: Prospective observational study followed by a randomized controlled study with 1 intervention group and 1 control group. SETTING: Tertiary care center specialized in cardiac surgery. PARTICIPANTS: All patients were scheduled for high-risk cardiac surgery, 279 consecutive patients in the prospective study and 48 patients in the randomized study. INTERVENTIONS: An algorithmic approach of strategies to reverse cerebral desaturation. In the control group, no attempts were made to reverse cerebral desaturation. MEASUREMENTS AND MAIN RESULTS: Cerebral saturation was measured using near-infrared reflectance spectroscopy. A decrease of 20% from baseline for 15 seconds defined cerebral desaturation. The success or failure of the interventions was noted. Demographic data were collected. Models for predicting the probability and the reversal of cerebral desaturation were based on multiple logistic regressions. In the randomized study, 12 hours of measurements were continued in the intensive care unit without interventions. Differences in desaturation load (% desaturation * time) were compared between groups. Half of the high-risk patients had cerebral desaturation that could be reversed 88% of the time. Interventions resulted in smaller desaturation loads in the operating room and in the intensive care unit. CONCLUSIONS: Cerebral desaturation in high-risk cardiac surgery is frequent but can be reversed most of the time resulting in a smaller desaturation load. A large randomized study will be needed to measure the impact of reversing cerebral desaturation on patient's outcome. PMID- 23791499 TI - Enhanced recovery after elective coronary revascularization surgery with minimal versus conventional extracorporeal circulation: a prospective randomized study. AB - OBJECTIVE: A minimal extracorporeal circulation (MECC) circuit integrates the advances in cardiopulmonary bypass (CPB) technology into a single circuit and is associated with improved short-term outcome. The aim of this study was to prospectively evaluate MECC compared with conventional CPB in facilitating fast track recovery after elective coronary revascularization procedures. DESIGN: Prospective randomized study. SETTING: All patients scheduled for elective coronary artery surgery were evaluated, excluding those considered particularly high risk for fast-track failure. The fast-track protocol included careful preoperative patient selection, a fast-track anesthetic technique based on minimal administration of fentanyl, surgery at normothermia, early postoperative extubation in the cardiac recovery unit, and admission to the cardiothoracic ward within the first 24 hours postoperatively. PARTICIPANTS: One hundred twenty patients were assigned randomly into 2 groups (60 in each group). INTERVENTIONS: Group A included patients who were operated on using the MECC circuit, whereas patients in Group B underwent surgery on conventional CPB. MEASUREMENTS AND MAIN RESULTS: Incidence of fast-track recovery was significantly higher in patients undergoing MECC (25% v 6.7%, p = 0.006). MECC also was recognized as a strong independent predictor of early recovery, with an odds ratio of 3.8 (p = 0.011). Duration of mechanical ventilation and cardiac recovery unit stay were significantly lower in patients undergoing MECC together with the need for blood transfusion, duration of inotropic support, need for an intra-aortic balloon pump, and development of postoperative atrial fibrillation and renal failure. CONCLUSIONS: MECC promotes successful early recovery after elective coronary revascularization procedures, even in a nondedicated cardiac intensive care unit setting. PMID- 23791500 TI - pH-sensitive pullulan-based nanoparticle carrier of methotrexate and combretastatin A4 for the combination therapy against hepatocellular carcinoma. AB - This study designs a pH-sensitive nanoparticle carrier of methotrexate (MTX) and combretastatin A4 (CA4) based on pullulan for the combination therapy against hepatocellular carcinoma (HCC). Briefly, N-urocanyl pullulan (URPA) with the degree of substitution (DS) of 5.2% was synthesized and then conjugated with MTX to form MTX-URPA, in which MTX content was 17.8%. MTX-URPA nanoparticles prepared by the dialysis method had spherical shape and the mean size of 187.1 nm, and showed high affinity for HepG2 cells. CA4 was successfully loaded into MTX-URPA nanoparticles and exhibited pH-sensitive in vitro release property. After intravenous injection to PLC/PRF/5-bearing nude mice, CA4 loaded MTX-URPA (CA4/MTX-URPA) nanoparticles achieved the enhanced antitumor and anti-angiogenic effects, the prolonged circulation time in blood, and the increased distributions both in the liver and the tumor. In conclusion, this drug carrier system has significant liver-targeting property and exhibits advantages for the combination therapy against hepatocellular carcinoma. PMID- 23791501 TI - Multifunctional calcium phosphate nano-contrast agent for combined nuclear, magnetic and near-infrared in vivo imaging. AB - Combination of three imaging techniques such as nuclear, magnetic and near infrared fluorescence can aid in improved diagnosis of disease by synergizing specific advantages of each of these techniques such as deep tissue penetration of radiation signals, anatomical and functional details provided by magnetic contrast and better spatial resolution of optical signals. In the present work, we report the development of a multimodal contrast agent based on calcium phosphate nanoparticles (nCP), doped with both indocyanine green (ICG) and Gadolinium (Gd(3+)), and labeled with 99m-Technetium-methylene diphosphonate ((99m)Tc-MDP) for combined optical, magnetic and nuclear imaging. In order to obtain the desired tri-modal contrast properties, the concentrations of ICG, Gd(3+) and (99m)Tc were optimized at ~0.15wt%, 3.38at% and ~0.002ng/mg of nCP, respectively. The leaching-out of ICG was protected by an additional coating of polyethyleneimine (PEI). Toxicological evaluation of the final construct carried out on healthy human mononuclear cells, red-blood cells and platelets, showed excellent hemocompatibility. In vivo multimodal imaging using mice models revealed the ability to provide near-infrared, magnetic and nuclear contrast simultaneously. The nanoparticles also showed the potential for improved MR based angio-imaging of liver. Retention of intravenously administrated nanoparticles in the liver was reduced with PEGylation and the clearance was observed within 48h without causing any major histological changes in vital organs. Thus, we developed a non-toxic tri-modal nano-contrast agent using calcium phosphate nanoparticles and demonstrated its potential for combined nuclear, magnetic and near-infrared imaging in vivo. PMID- 23791502 TI - The effects of gradients of nerve growth factor immobilized PCLA scaffolds on neurite outgrowth in vitro and peripheral nerve regeneration in rats. AB - Introducing concentration gradients of nerve growth factor (NGF) into conduits for repairing of peripheral nerve injury is crucial for nerve regeneration and guidance. Herein, combining differential adsorption of NGF/silk fibroin (SF) coating, the gradient of NGF-immobilized membranes (G-Ms) and nanofibrous nerve conduits (G-nNCs) were successfully fabricated. The efficacy of NGF gradients was confirmed by a quantitative comparison of dorsal root ganglia (DRG) neurite outgrowth on the G-Ms or uniform NGF-immobilized membranes (U-Ms). Significantly, the neurite turning ratio was 0.48 +/- 0.11 for G-M group, but it was close to zero for U-M group. The neurite length of DRGs in the middle of the G-Ms was significantly longer than that of U-M group, even though the average NGF concentration was approximated. Furthermore, 12 weeks after implantation in rats with a 14 mm gap of sciatic nerve injury, G-nNCs achieved satisfying outcomes of nerve regeneration associated with morphological and functional improvements, which was superior to that of the uniform NGF-immobilized nNCs (U-nNCs). Sciatic function index (SFI), compound muscle action potentials (CMAPs), total number of myelinated nerve fibers, thickness of myelin sheath were similar for the G-nNCs and autografts, with the G-nNCs having a higher density of axons than the autografts. Our results demonstrated the significant role of introducing NGF gradients into scaffolds in promoting nerve regeneration. PMID- 23791503 TI - The effect of resveratrol on neurodegeneration and blood brain barrier stability surrounding intracortical microelectrodes. AB - The current study seeks to elucidate a biological mechanism which may mediate neuroinflammation, and decreases in both blood-brain barrier stability and neuron viability at the intracortical microelectrode-tissue interface. Here, we have focused on the role of pro-inflammatory reactive oxygen species. Specifically, adult rats implanted within intracortical microelectrodes were systemically administered the anti-oxidant, resveratrol, both the day before and the day of surgery. Animals were sacrificed at two or four weeks post-implantation for histological analysis of the neuroinflammatory and neurodegenerative responses to the microelectrode. At two weeks post-implantation, we found animals treated with resveratrol demonstrated suppression of reactive oxygen species accumulation and blood-brain barrier instability, accompanied with increased density of neurons at the intracortical microelectrode-tissue interface. Four weeks post-implantation, animals treated with resveratrol exhibited indistinguishable levels of markers for reactive oxygen species and neuronal nuclei density in comparison to untreated control animals. However, of the neurons that remained, resveratrol treated animals were seen to display reductions in the density of degenerative neurons compared to control animals at both two and four weeks post-implantation. Initial mechanistic evaluation suggested the roles of both anti-oxidative enzymes and toll-like receptor 4 expression in facilitating microglia activation and the propagation of neurodegenerative inflammatory pathways. Collectively, our data suggests that short-term attenuation of reactive oxygen species accumulation and blood-brain barrier instability can result in prolonged improvements in neuronal viability around implanted intracortical microelectrodes, while also identifying potential therapeutic targets to reduce chronic intracortical microelectrode mediated neurodegeneration. PMID- 23791504 TI - Single-arc volumetric-modulated arc therapy (sVMAT) as adjuvant treatment for gastric cancer: dosimetric comparisons with three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT). AB - To compare the dosimetric differences between the single-arc volumetric-modulated arc therapy (sVMAT), 3-dimensional conformal radiotherapy (3D-CRT), and intensity modulated radiotherapy (IMRT) techniques in treatment planning for gastric cancer as adjuvant radiotherapy. Twelve patients were retrospectively analyzed. In each patient's case, the parameters were compared based on the dose-volume histogram (DVH) of the sVMAT, 3D-CRT, and IMRT plans, respectively. Three techniques showed similar target dose coverage. The maximum and mean doses of the target were significantly higher in the sVMAT plans than that in 3D-CRT plans and in the 3D CRT/IMRT plans, respectively, but these differences were clinically acceptable. The IMRT and sVMAT plans successfully achieved better target dose conformity, reduced the V20/30, and mean dose of the left kidney, as well as the V20/30 of the liver, compared with the 3D-CRT plans. And the sVMAT technique reduced the V20 of the liver much significantly. Although the maximum dose of the spinal cord were much higher in the IMRT and sVMAT plans, respectively (mean 36.4 vs 39.5 and 40.6Gy), these data were still under the constraints. Not much difference was found in the analysis of the parameters of the right kidney, intestine, and heart. The IMRT and sVMAT plans achieved similar dose distribution to the target, but superior to the 3D-CRT plans, in adjuvant radiotherapy for gastric cancer. The sVMAT technique improved the dose sparings of the left kidney and liver, compared with the 3D-CRT technique, but showed few dosimetric advantages over the IMRT technique. Studies are warranted to evaluate the clinical benefits of the VMAT treatment for patients with gastric cancer after surgery in the future. PMID- 23791505 TI - A new nucleic acid-based agent inhibits cytotoxic T lymphocyte-mediated immune disorders. AB - BACKGROUND: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and graft-versus-host disease (GVHD) are distinct immune reactions elicited by drugs or allogeneic antigens; however, they share a pathomechanism with the activation of cytotoxic T lymphocytes (CTLs). CTLs produce cytotoxic proteins, cytokines, chemokines, or immune alarmins, such as granulysin (GNLY), leading to the extensive tissue damage and systemic inflammation seen in patients with SJS/TEN or GVHD. Currently, there is no effective therapeutic agent specific for CTL mediated immune disorders. OBJECTIVES: By targeting GNLY(+) CTLs, we aimed to develop a nucleic acid-based agent consisting of an anti-CD8 aptamer with GNLY small interfering RNA (siRNA). METHODS: We performed systematic evolution of ligands using exponential enrichment to select and identify effective anti-CD8 aptamers. We developed an aptamer-siRNA chimera using a "sticky bridge" method by conjugating the aptamer with siRNA. We analyzed the inhibitory effects of the aptamer-siRNA chimera on CTL responses in patients with SJS/TEN or GVHD. RESULTS: We identified a novel DNA aptamer (CD8AP17s) targeting CTLs. This aptamer could be specifically internalized into human CTLs. We generated the CD8AP17s aptamer GNLY siRNA chimera, which showed a greater than 79% inhibitory effect on the production of GNLY by drug/alloantigen-activated T cells. The CD8AP17s aptamer GNLY siRNA chimera decreased cytotoxicity in in vitro models of both SJS/TEN (elicited by drug-specific antigen) and GVHD (elicited by allogeneic antigens). CONCLUSIONS: Our results identified a new nucleic acid-based agent (CD8 aptamer GNLY siRNA chimera) that can significantly inhibit CTL-mediated drug hypersensitivity, such as that seen in patients with SJS/TEN, as well as the alloreactivity seen in patients with GVHD. This study provides a novel therapeutic strategy for CTL-mediated immune disorders. PMID- 23791507 TI - A protracted case of diarrhoea caused by Cryptosporidium in a non immunocompromised patient. PMID- 23791506 TI - Increased periostin associates with greater airflow limitation in patients receiving inhaled corticosteroids. AB - BACKGROUND: Periostin, an extracellular matrix protein, contributes to subepithelial thickening in asthmatic airways, and its serum levels reflect airway eosinophilic inflammation. However, the relationship between periostin and the development of airflow limitation, a functional consequence of airway remodeling, remains unknown. OBJECTIVE: We aimed to determine the relationship between serum periostin levels and pulmonary function decline in asthmatic patients on inhaled corticosteroid (ICS) treatment. METHODS: Two hundred twenty four asthmatic patients (average age, 62.3 years) treated with ICS for at least 4 years were enrolled. Annual changes in FEV1, from at least 1 year after the initiation of ICS treatment to the time of enrollment or later (average, 16.2 measurements over 8 years per individual), were assessed. At enrollment, clinical indices, biomarkers that included serum periostin, and periostin gene polymorphisms were examined. Associations between clinical indices or biomarkers and a decline in FEV1 of 30 mL or greater per year were analyzed. RESULTS: High serum periostin levels (>= 95 ng/mL) at enrollment, the highest treatment step, higher ICS daily doses, a history of admission due to asthma exacerbation, comorbid or a history of sinusitis, and ex-smoking were associated with a decline in FEV1 of 30 mL or greater per year. Multivariate analysis showed that high serum periostin, the highest treatment step, and ex-smoking were independent risk factors for the decline. Polymorphisms of periostin gene were related to higher serum periostin levels (rs3829365) and a decline in FEV1 of 30 mL or greater per year (rs9603226). CONCLUSIONS: Serum periostin appears to be a useful biomarker for the development of airflow limitation in asthmatic patients on ICS. PMID- 23791508 TI - Practical interest of both skin prick test and specific IgE in the evaluation of tolerance acquisition in IgE mediated cow's milk allergy (CMA). A clinical retrospective study in a cohort of 184 children. AB - BACKGROUND: Cow's milk protein allergy (CMPA) represents one of the leading causes of food allergy in infants and young children. The immune reaction may be IgE mediated, non-IgE mediated, or mixed. IgE-mediated cow's milk protein allergy is revealed by immediate and acute symptoms which can be severe. The aim of this study is to report a one centre experience in the real life of testing children with IgE-mediated CMPA and try to identify predictive factor for follow-up challenges. METHOD: Retrospective and monocentric study between September 1997 and February 2008. 178 infants diagnosed with IgE-mediated CMPA during breastfeeding weaning were included. Initial factors such as age, sex, skin prick tests (SPTs), specific IgE (sIgE), atopic dermatitis and types of reaction were noted. Between 12 and 24 months all infants have undergone at least one evaluation including SPT. RESULTS: At the food challenge, 138 (75.8%) infants were found tolerant. Results of the skin prick test (SPT) were statistically different according to the food challenge result (2.2mm vs. 5.1mm, p<0.0001). It was the same result for sIgE for CM 2.0ku/l vs. 11.5ku/l - p<0.0001 and for casein 1.0ku/l vs. 16.0ku/l - p=0.0014. CONCLUSION: This study confirms the practical interest of both SPT and sIgE in the evaluation of tolerance induction in IgE-mediated CMPA, but with no corresponding results. Sensitivity, specificity and probability curves of success for cow's milk challenge can be determined and have clinical utility. PMID- 23791509 TI - Continuous G-CSF therapy for isolated chronic mucocutaneous candidiasis: complete clinical remission with restoration of IL-17 secretion. PMID- 23791511 TI - Reply: To PMID 23021885. PMID- 23791510 TI - Omalizumab increases the intrinsic sensitivity of human basophils to IgE-mediated stimulation. AB - BACKGROUND: Treatment of allergic patients with omalizumab results in a paradoxical increase in their basophil histamine release (HR) response ex vivo to cross-linking anti-IgE antibody. It is not known whether this change in response is associated with an increase in intrinsic cellular sensitivity, which would be a paradoxical response. OBJECTIVE: We sought to determine whether the increase in response to anti-IgE antibody is a reflection of an increased cellular sensitivity expressed as molecules of antigen-specific IgE per basophil required to produce 50% of the maximal response. METHODS: Patients were treated with omalizumab or placebo for 12 weeks (NCT01003301 at ClinicalTrials.gov), and the metric of basophil sensitivity was assessed at 4 time points: baseline, 6 to 8 weeks, 12 weeks (after which treatment stopped), and 24 weeks (12 weeks after the end of treatment). RESULTS: As observed previously, treatment with omalizumab resulted in a marked increase in the maximal HR induced by cross-linking anti-IgE antibody. This change was accompanied by a marked shift in intrinsic basophil sensitivity, ranging from 2.5- to 125-fold, with an average of 6-fold at the midpoint of the treatment to 12-fold after 12 weeks. The magnitude of the increase in cellular sensitivity was inversely related to the starting sensitivity or the starting maximum HR. The increased cellular sensitivity also occurred when using leukotriene C4 secretion as a metric of the basophil response. Twelve weeks after the end of treatment, cellular sensitivity was found to shift toward the baseline value, although the return to baseline was not yet complete at this time point. CONCLUSIONS: Treatment with omalizumab results in a markedly increased sensitivity of basophils to IgE-mediated stimulation in terms of the number of IgE molecules required to produce a given response. These results provide a better quantitative sense of the phenotypic change that occurs in basophils during omalizumab treatment, which has both mechanistic and clinical implications. PMID- 23791512 TI - Component-resolved diagnosis of peach allergy and its relationship with prevalent allergenic pollens in China. PMID- 23791513 TI - A proof-of-concept study of the effect of a novel H3-receptor antagonist in allergen-induced nasal congestion. AB - BACKGROUND: H1-receptor inverse agonists are used effectively for treating several symptoms of allergic rhinitis, including nasal itching, rhinorrhea, and sneezing, although most agents are not very effective in treating nasal congestion. OBJECTIVE: This study evaluated the relative efficacy of a novel selective H3-receptor antagonist, JNJ-39220675, in preventing nasal congestion induced by exposing participants with ragweed allergy to ragweed allergen in an environmental exposure chamber model. METHODS: In this single-dose, patient blind, double-dummy, placebo- and active-controlled, phase IIa cross-over study, 53 participants were randomized to JNJ-39220675 plus placebo, placebo plus pseudoephedrine, or only placebo. The primary efficacy assessment was change in nasal patency assessed by measuring the minimal cross-sectional area of the nasal cavity by using acoustic rhinometry. Secondary assessment included total nasal symptom scores (TNSSs) over the 8-hour environmental exposure chamber exposure period. RESULTS: Smaller decreases in minimal cross-sectional area were observed after JNJ-39220675 (least square mean difference, -0.126; P = .06) and pseudoephedrine (least square mean difference, -0.195; P = .004) treatment compared with placebo. The means for the baseline-adjusted area under the curve of TNSSs were significantly smaller for JNJ-39220675 (P = .0003) and pseudoephedrine (P = .04) versus placebo. JNJ-39220675 was significantly effective in treating all 4 individual symptoms (P <= .05 for all scores) compared with placebo, whereas pseudoephedrine only showed a trend for improvement in individual symptom scores of the TNSS. Insomnia was the most frequent adverse event (17.3%) associated with JNJ-39220675 treatment. CONCLUSION: Prophylactic treatment with the H3-antagonist JNJ-39220675 relieved allergen-induced nasal congestion by using standard nasal symptom scoring; however, in contrast to pseudoephedrine, it only showed a trend for increasing nasal patency by using objective measures. PMID- 23791514 TI - Efficacy and safety of thalidomide in patients with inflammatory manifestations of chronic granulomatous disease: a retrospective case series. PMID- 23791515 TI - Are meta-analysis-based comparisons solid evidence? PMID- 23791516 TI - Fish oil disrupts MHC class II lateral organization on the B-cell side of the immunological synapse independent of B-T cell adhesion. AB - Fish oil-enriched long chain n-3 polyunsaturated fatty acids disrupt the molecular organization of T-cell proteins in the immunological synapse. The impact of fish oil derived n-3 fatty acids on antigen-presenting cells, particularly at the animal level, is unknown. We previously demonstrated B-cells isolated from mice fed with fish oil-suppressed naive CD4(+) T-cell activation. Therefore, here we determined the mechanistic effects of fish oil on murine B cell major histocompatibility complex (MHC) class II molecular distribution using a combination of total internal reflection fluorescence, Forster resonance energy transfer and confocal imaging. Fish oil had no impact on presynaptic B-cell MHC II clustering. Upon conjugation with transgenic T-cells, fish-oil suppressed MHC II accumulation at the immunological synapse. As a consequence, T-cell protein kinase C theta (PKCtheta) recruitment to the synapse was also diminished. The effects were independent of changes in B-T cell adhesion, as measured with microscopy, flow cytometry and static cell adhesion assays with select immune ligands. Given that fish oil can reorganize the membrane by lowering membrane cholesterol levels, we then compared the results with fish oil to cholesterol depletion using methyl-B-cyclodextrin (MbetaCD). MbetaCD treatment of B-cells suppressed MHC II and T-cell PKCtheta recruitment to the immunological synapse, similar to fish oil. Overall, the results reveal commonality in the mechanism by which fish oil manipulates protein lateral organization of B-cells compared to T cells. Furthermore, the data establish MHC class II lateral organization on the B cell side of the immunological synapse as a novel molecular target of fish oil. PMID- 23791517 TI - Four monoclonal antibodies against capsular polysaccharides of Neisseria meningitidis serogroups A, C, Y and W135: its application in identity tests. AB - Murine hybridoma monoclonal antibodies (MAbs) were produced against the capsular polysaccharide (CPs) of serogroups A, C, W135 and Y meningococci (MenA, MenC, MenW, MenY) in order to develop immunological reagents for the identification of meningococcal polysaccharides. Each serogroup-specific MAb reacted with the CPs from its homologous serogroup only and did not react with CPs from the other three serogroups. The affinity constant (Ka) of the four MAbs measured by non competitive ELISA was 6.62 * 10(9), 2.76 * 10(9), 1.48 * 10(9) and 3.8 * 10(9) M( 1) for MenA, MenC, MenW and MenY MAbs respectively. The application of these MAbs for identity tests was demonstrated by their abilities to correctly identify the CPs from serogroups A, C, W135 and Y in meningococcal CPs-based vaccines through ELISA. The MAbs obtained in this work are a very valuable set of tools for study meningococcal polysaccharides vaccines. PMID- 23791518 TI - Adult form of Niemann-Pick type C with the variant biochemical phenotype on treatment with Miglustat. PMID- 23791519 TI - The MDS-UPDRS Part II (motor experiences of daily living) resulted useful for assessment of disability in Parkinson's disease. AB - OBJECTIVE: To evaluate the motor experiences of daily living section of the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS M EDL) for assessing disability in PD patients; to determine the association between disability and quality of life; and to identify cut-off score ranges for no, mild, moderate and severe disability with this measure. METHODS: International, observational, cross-sectional study of 435 PD patients, assessed with: MDS-UPDRS, Hoehn and Yahr staging, Rapid Assessment of Disability Scale, Clinical Impression of Severity Index for PD, Parkinson's Disease Questionnaire-8 and EQ-5D. Descriptive statistics, Spearman's rank correlation coefficients, Kruskal-Wallis test for group comparisons, ordinal logistic regression analysis for setting cut-off values and a step-wise multiple linear regression model were calculated. RESULTS: MDS-UPDRS M-EDL correlated 0.70-0.80 with other disability measures, and -0.46 to 0.74 with quality of life scales. Scores significantly increased with higher disease duration and severity (p < 0.001). Cut-off values for the M-EDL were: 0-2 points, no disability; 3-16, mild; 17-31, moderate; and 32 points or more, severe. Linear regression analysis identified the MDS-UPDRS nM EDL section as the main determinant of M-EDL, followed by the rest of MDS-UPDRS sections (explained variance: 59%). CONCLUSIONS: MDS-UPDRS M-EDL proved to be useful for assessing disability in PD. PMID- 23791520 TI - Complications of pneumoconiosis: radiologic overview. AB - A wide spectrum of pulmonary complications occurs in patients with pneumoconiosis. Those complications include chronic obstructive pulmonary disease, hemoptysis, pneumothorax, pleural disease, tuberculosis, autoimmune disease, anthracofibrosis, chronic interstitial pneumonia, and malignancy. Generally, imaging workup starts with plain chest radiography. However, sometimes, plain radiography has limited role in the diagnosis of pulmonary complications of pneumoconiosis because of overlapping pneumoconiotic infiltration. Computed tomography (CT), ultrasonography (US), and magnetic resonance imaging (MRI) are potentially helpful for the detection of pulmonary complications in patients with pneumoconiosis. CT, with its excellent contrast resolution, is more sensitive and specific method than plain radiograph in the evaluation of pulmonary abnormalities. CT is useful in detecting lung parenchymal abnormalities caused by infection, anthracofibrosis, and chronic interstitial pneumonia. Also, CT is valuable in distinguishing localized pneumothorax from bullae and aiding the identification of multiloculated effusions. US can be used in detection of complicated pleural effusions and guidance of the thoracentesis procedure. MRI is useful for differentiating between progressive massive fibrosis and lung cancer. Radiologists need to be familiar with the radiologic and clinical manifestations of, as well as diagnostic approaches to, complications associated with pneumoconiosis. Knowledge of the various imaging features of pulmonary complications of pneumoconiosis can enhance early diagnosis and improve the chance to cure. PMID- 23791521 TI - Computed-tomography-guided high-dose-rate brachytherapy (CT-HDRBT) ablation of metastases adjacent to the liver hilum. AB - PURPOSE: To evaluate technical feasibility and clinical outcome of computed tomography-guided high-dose-rate-brachytherapy (CT-HDRBT) ablation of metastases adjacent to the liver hilum. MATERIALS AND METHODS: Between November 2007 and May 2012, 32 consecutive patients with 34 metastases adjacent to the liver hilum (common bile duct or hepatic bifurcation <=5 mm distance) were treated with CT HDRBT. Treatment was performed by CT-guided applicator placement and high-dose rate brachytherapy with an iridium-192 source. MRI follow-up was performed 6 weeks and every 3 months post intervention. The primary endpoint was local tumor control (LTC); secondary endpoints included time to progression (TTP) and overall survival (OS). RESULTS: Patients were available for MRI evaluation for a mean follow-up time of 18.75 months (range: 3-56 months). Mean tumor diameter was 4.3 cm (range: 1.3-10.7 cm). One major complication was observed. Four (11.8%) local recurrences were observed after a local tumor control of 5, 8, 9 and 10 months, respectively. Twenty-two patients (68.75%) experienced a systemic tumor progression during the follow up period. Mean TTP was 12.9 months (range: 2-56 months). Nine patients died during the follow-up period. Median OS was 20.24 months. CONCLUSION: Minimally invasive CT-HDRBT is a safe and effective option also for unresectable liver metastases adjacent to the liver hilum that would have been untreatable by thermal ablation. PMID- 23791523 TI - Adult neurogenesis in Drosophila. AB - Adult neurogenesis has been linked to several cognitive functions and neurological disorders. Description of adult neurogenesis in a model organism like Drosophila could facilitate the genetic study of normal and abnormal neurogenesis in the adult brain. So far, formation of new neurons has not been detected in adult fly brains and hence has been thought to be absent in Drosophila. Here, we used an improved lineage-labeling method to show that, surprisingly, adult neurogenesis occurs in the medulla cortex of the Drosophila optic lobes. We also find that acute brain damage to this region stimulates adult neurogenesis. Finally, we identify a factor induced by acute damage, which is sufficient to specifically activate the proliferation of a cell type with adult neuroblast characteristics. Our results reveal unexpected plasticity in the adult Drosophila brain and describe a unique model for the genetic analysis of adult neurogenesis, plasticity, and brain regeneration. PMID- 23791522 TI - Nontelomeric role for Rap1 in regulating metabolism and protecting against obesity. AB - The mammalian telomere-binding protein Rap1 was recently found to have additional nontelomeric functions, acting as a transcriptional cofactor and a regulator of the NF-kappaB pathway. Here, we assess the effect of disrupting mouse Rap1 in vivo and report on its unanticipated role in metabolic regulation and body-weight homeostasis. Rap1 inhibition causes dysregulation in hepatic as well as adipose function, leading to glucose intolerance, insulin resistance, liver steatosis, and excess fat accumulation. Furthermore, Rap1 appears to play a pivotal role in the transcriptional cascade that controls adipocyte differentiation in vitro. Using a separation-of-function allele, we show that the metabolic function of Rap1 is independent of its recruitment to TTAGGG binding elements found at telomeres and at other interstitial loci. In conclusion, our study underscores an additional function for the most conserved telomere-binding protein, forging a link between telomere biology and metabolic signaling. PMID- 23791524 TI - Inorganic phosphate export by the retrovirus receptor XPR1 in metazoans. AB - Inorganic phosphate uptake is a universal function accomplished by transporters that are present across the living world. In contrast, no phosphate exporter has ever been identified in metazoans. Here, we show that depletion of XPR1, a multipass membrane molecule initially identified as the cell-surface receptor for xenotropic and polytropic murine leukemia retroviruses (X- and P-MLV), induced a decrease in phosphate export and that reintroduction of various XPR1 proteins, from fruit fly to human, rescued this defect. Inhibition of phosphate export was also obtained with a soluble ligand generated from the envelope-receptor-binding domain of X-MLV in all human cell lines tested, as well as in diverse stem cells and epithelial cells derived from renal proximal tubules, the main site of phosphate homeostasis regulation. These results provide new insights on phosphate export in metazoans and the role of Xpr1 in this function. PMID- 23791525 TI - Cryptopatches are essential for the development of human GALT. AB - Abnormal gut-associated lymphoid tissue (GALT) in humans is associated with infectious and autoimmune diseases, which cause dysfunction of the gastrointestinal (GI) tract immune system. To aid in investigating GALT pathologies in vivo, we bioengineered a human-mouse chimeric model characterized by the development of human GALT structures originating in mouse cryptopatches. This observation expands our mechanistic understanding of the role of cryptopatches in human GALT genesis and emphasizes the evolutionary conservation of this developmental process. Immunoglobulin class switching to IgA occurs in these GALT structures, leading to numerous human IgA-producing plasma cells throughout the intestinal lamina propria. CD4+ T cell depletion within GALT structures results from HIV infection, as it does in humans. This human-mouse chimeric model represents the most comprehensive experimental platform currently available for the study and for the preclinical testing of therapeutics designed to repair disease-damaged GALT. PMID- 23791526 TI - RAP1 protects from obesity through its extratelomeric role regulating gene expression. AB - RAP1 is part of shelterin, the protective complex at telomeres. RAP1 also binds along chromosome arms, where it is proposed to regulate gene expression. To investigate the nontelomeric roles of RAP1 in vivo, we generated a RAP1 whole body knockout mouse. These mice show early onset of obesity, which is more severe in females than in males. Rap1-deficient mice show accumulation of abdominal fat, hepatic steatosis, and high-fasting plasma levels of insulin, glucose, cholesterol, and alanine aminotransferase. Gene expression analyses of liver and visceral white fat from Rap1-deficient mice before the onset of obesity show deregulation of metabolic programs, including fatty acid, glucose metabolism, and PPARalpha signaling. We identify Pparalpha and Pgc1alpha as key factors affected by Rap1 deletion in the liver. We show that RAP1 binds to Pparalpha and Pgc1alpha loci and modulates their transcription. These findings reveal a role for a telomere-binding protein in the regulation of metabolism. PMID- 23791527 TI - SOX2 regulates YAP1 to maintain stemness and determine cell fate in the osteo adipo lineage. AB - The osteoblastic and adipocytic lineages arise from mesenchymal stem cells (MSCs), but few regulators of self-renewal and early cell-fate decisions are known. Here, we show that the Hippo pathway effector YAP1 is a direct target of SOX2 and can compensate for the self-renewal defect caused by SOX2 inactivation in osteoprogenitors and MSCs. Osteogenesis is blocked by high SOX2 or YAP1, accelerated by depletion of either one, and the inhibition of osteogenesis by SOX2 requires YAP1. SOX2 favors adipogenesis and induces PPARgamma, but adipogenesis can only occur with moderate levels of YAP1. YAP1 induction by SOX2 is restrained in adipogenesis, and both YAP1 overexpression and depletion inhibit the process. YAP1 binds beta-catenin and directly induces the Wnt antagonist Dkk1 to dampen pro-osteogenic Wnt signals. We demonstrate a Hippo-independent regulation of YAP1 by SOX2 that cooperatively antagonizes Wnt/beta-catenin signals and regulates PPARgamma to determine osteogenic or adipocytic fates. PMID- 23791528 TI - An iPSC line from human pancreatic ductal adenocarcinoma undergoes early to invasive stages of pancreatic cancer progression. AB - Pancreatic ductal adenocarcinoma (PDAC) carries a dismal prognosis and lacks a human cell model of early disease progression. When human PDAC cells are injected into immunodeficient mice, they generate advanced-stage cancer. We hypothesized that if human PDAC cells were converted to pluripotency and then allowed to differentiate back into pancreatic tissue, they might undergo early stages of cancer. Although most induced pluripotent stem cell (iPSC) lines were not of the expected cancer genotype, one PDAC line, 10-22 cells, when injected into immunodeficient mice, generated pancreatic intraepithelial neoplasia (PanIN) precursors to PDAC that progressed to the invasive stage. The PanIN-like cells secrete or release proteins from many genes that are known to be expressed in human pancreatic cancer progression and that predicted an HNF4alpha network in intermediate-stage lesions. Thus, rare events allow iPSC technology to provide a live human cell model of early pancreatic cancer and insights into disease progression. PMID- 23791529 TI - DNA-damage-induced nuclear export of precursor microRNAs is regulated by the ATM AKT pathway. AB - Expression of microRNAs (miRNAs) involves transcription of miRNA genes and maturation of the primary transcripts. Recent studies have shown that posttranscriptional processing of primary and precursor miRNAs is induced after DNA damage through regulatory RNA-binding proteins in the Drosha and Dicer complexes, such as DDX5 and KSRP. However, little is known about the regulation of nuclear export of pre-miRNAs in the DNA-damage response, a critical step in miRNA maturation. Here, we show that nuclear export of pre-miRNAs is accelerated after DNA damage in an ATM-dependent manner. The ATM-activated AKT kinase phosphorylates Nup153, a key component of the nucleopore, leading to enhanced interaction between Nup153 and Exportin-5 (XPO5) and increased nuclear export of pre-miRNAs. These findings define an important role of DNA-damage signaling in miRNA transport and maturation. PMID- 23791530 TI - Stage-specific regulation of reprogramming to induced pluripotent stem cells by Wnt signaling and T cell factor proteins. AB - Wnt signaling is intrinsic to mouse embryonic stem cell self-renewal. Therefore, it is surprising that reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) is not strongly enhanced by Wnt signaling. Here, we demonstrate that active Wnt signaling inhibits the early stage of reprogramming to iPSCs, whereas it is required and even stimulating during the late stage. Mechanistically, this biphasic effect of Wnt signaling is accompanied by a change in the requirement of all four of its transcriptional effectors: T cell factor 1 (Tcf1), Lef1, Tcf3, and Tcf4. For example, Tcf3 and Tcf4 are stimulatory early but inhibitory late in the reprogramming process. Accordingly, ectopic expression of Tcf3 early in reprogramming combined with its loss of function late enables efficient reprogramming in the absence of ectopic Sox2. Together, our data indicate that the stepwise process of reprogramming to iPSCs is critically dependent on the stage-specific control and action of all four Tcfs and Wnt signaling. PMID- 23791531 TI - Cellular source and mechanisms of high transcriptome complexity in the mammalian testis. AB - Understanding the extent of genomic transcription and its functional relevance is a central goal in genomics research. However, detailed genome-wide investigations of transcriptome complexity in major mammalian organs have been scarce. Here, using extensive RNA-seq data, we show that transcription of the genome is substantially more widespread in the testis than in other organs across representative mammals. Furthermore, we reveal that meiotic spermatocytes and especially postmeiotic round spermatids have remarkably diverse transcriptomes, which explains the high transcriptome complexity of the testis as a whole. The widespread transcriptional activity in spermatocytes and spermatids encompasses protein-coding and long noncoding RNA genes but also poorly conserves intergenic sequences, suggesting that it may not be of immediate functional relevance. Rather, our analyses of genome-wide epigenetic data suggest that this prevalent transcription, which most likely promoted the birth of new genes during evolution, is facilitated by an overall permissive chromatin in these germ cells that results from extensive chromatin remodeling. PMID- 23791532 TI - Inter-ictal spike detection using a database of smart templates. AB - OBJECTIVE: Visual analysis of EEG is time consuming and suffers from inter observer variability. Assisted automated analysis helps by summarizing key aspects for the reviewer and providing consistent feedback. Our objective is to design an accurate and robust system for the detection of inter-ictal epileptiform discharges (IEDs) in scalp EEG. METHODS: IED Templates are extracted from the raw data of an EEG training set. By construction, the templates are given the ability to learn by searching for other IEDs within the training set using a time-shifted correlation. True and false detections are remembered and classifiers are trained for improving future predictions. During detection, trained templates search for IEDs in the new EEG. Overlapping detections from all templates are grouped and form one IED. Certainty values are added based on the reliability of the templates involved. RESULTS: For evaluation, 2160 templates were used on an evaluation dataset of 15 continuous recordings containing 241 IEDs (0.79/min). Sensitivities up to 0.99 (7.24fp/min) were reached. To reduce false detections, higher certainty thresholds led to a mean sensitivity of 0.90 with 2.36fp/min. CONCLUSION: By using many templates, this technique is less vulnerable to variations in spike morphology. A certainty value for each detection allows the system to present findings in a more efficient manner and simplifies the review process. SIGNIFICANCE: Automated spike detection can assist in visual interpretation of the EEG which may lead to faster review times. PMID- 23791533 TI - Toxicity of synthetic chelators and metal availability in poultry manure amended Cd, Pb and As contaminated agricultural soil. AB - Chelating agents added to contaminated soils may increase solubility and phytoextraction efficiency of soil metals. However, they can create negative effects on soil biological quality. A 90-day incubation experiment was conducted to evaluate mixed effects of chelating agents and poultry manure on changes in available Cd, Pb and As, CO2-C efflux, microbial biomass C, dissolved organic C (DOC), and N mineralization in metal-polluted agricultural soil. Application of poultry manure resulted in a considerable increase in soil pH, DOC, CO2-C efflux, net N mineralization, net N nitrification, and microbial biomass C compared to those in unmanured soil. Availability of arsenic increased twice in manure amended soil due to changes in pH and DOC. However, adding poultry manure did not affect the concentrations of available Pb and Cd compared to those in control soil. Chelating agents increased CO2-C efflux, DOC, and metal availability but decreased microbial biomass C and net N mineralization. Maximum decrease in microbial biomass C, net N mineralization, and net N nitrification, was observed in EDTA applied soil possibly due to high metal availability to soil microorganisms. Overall results revealed that the application of synthetic chelators in combination with poultry manure enhances available As and demonstrates better environment for soil biota. PMID- 23791534 TI - Cognitive function is linked to adherence to bariatric postoperative guidelines. AB - BACKGROUND: Impairment in cognitive function is found in a significant subset of individuals undergoing bariatric surgery, and recent work shows this impairment is associated with smaller postoperative weight loss. Reduced cognitive function could contribute to poorer adherence to postoperative guidelines, although this has not been previously examined. The present study examined the relationship between cognitive function and adherence to bariatric postoperative guidelines. We expected that higher cognitive function would be associated with better adherence to postoperative guidelines. METHODS: Thirty-seven bariatric surgery patients completed cognitive testing and a self-report measure of adherence to postoperative bariatric guidelines during their 4- to 6-week postoperative appointment. RESULTS: Strong correlations were observed between adherence to postoperative guidelines and cognitive indices of attention, executive function, and memory. CONCLUSIONS: Results show that cognitive performance is strongly associated with adherence to postoperative guidelines shortly after bariatric surgery. Further work is needed to clarify whether this relationship is present at later postoperative stages and the degree to which this relationship mediates postoperative weight loss outcomes. PMID- 23791535 TI - Minimally invasive esophagectomy is safe in patients with previous gastric bypass. AB - BACKGROUND: The prevalence of morbid obesity in the United States has been steadily increasing, and there is an established relationship between obesity and the risk of developing certain cancers. Patients who have undergone prior gastric bypass (GB) and present with newly diagnosed esophageal cancer represent a new and challenging cohort for surgical resection of their disease. We present our case series of consecutive patients with previous GB who underwent minimally invasive esophagectomy (MIE). METHODS: Retrospective review of consecutive patients with a history of GB who underwent a MIE for esophageal cancer between July 2010 and August 2012. RESULTS: Five patients were identified with a mean age of 57 years. Mean follow-up was 9.1 months. Four patients had undergone laparoscopic GB, and 1 patient had an open GB. Two patients received neoadjuvant chemoradiation therapy for locally advanced disease. Minimally invasive procedures were thoracoscopic/laparoscopic esophagectomy with cervical anastomosis in 4 patients and colonic interposition in 1 patient. Mean operative time was 6 hours and 52 minutes. Median length of stay was 7 days. There was no mortality. Postoperative complications occurred in 3 patients and included pneumonia/respiratory failure, recurrent laryngeal nerve injury, and pyloric stenosis. All patients are alive and disease free at last follow-up. CONCLUSIONS: Minimally invasive esophagectomy after prior GB is well tolerated, is technically feasible, and has acceptable oncologic and perioperative outcomes. We conclude that precise endoscopic evaluation before bariatric surgery in patients with gastroesophageal reflux disease is essential, as is the necessity for continuing postsurgical surveillance in patients with known Barrett's esophagitis and for early evaluation in patients who develop new symptoms of gastroesophageal reflux disease after bariatric surgery. PMID- 23791536 TI - Comment on: Prevalence of hiatal hernia in the morbidly obese. PMID- 23791537 TI - Does duration of spousal caregiving affect risk of depression onset? Evidence from the Health and Retirement Study. AB - OBJECTIVES: To assess the association of current and long-term spousal caregiving with risk of depression in a nationally (U.S.) representative sample of older adults. METHODS: We studied married and depression-free Health and Retirement Study respondents aged 50 years and older (n = 9,420) at baseline from 2000 to 2010. Current (>=14 hours per week of help with instrumental/activities of daily living for a spouse in the most recent biennial survey) and long-term caregiving (care at two consecutive surveys) were used to predict onset of elevated depressive symptoms (>=3 on a modified Centers for Epidemiologic Studies Depression scale) with discrete-time hazards models and time-updated exposure and covariate information. RESULTS: Current caregiving was associated with significant elevations in risk of depression onset (hazard ratio: 1.64; Wald chi(2), 1 df: 28.34; p <0.0001). Effect estimates for long-term caregiving were similar (hazard ratio: 1.52, Wald chi(2), 1 df: 3.63; p = 0.06). CONCLUSIONS: Current spousal caregiving significantly predicted onset of depression; the association was not exacerbated by longer duration of caregiving. PMID- 23791539 TI - EASL recognition awardee 2013: Dr. Andrew Kenneth Burroughs. PMID- 23791538 TI - Depression and incident Alzheimer disease: the impact of disease severity. AB - OBJECTIVES: To test the hypothesis that clinically significant depression (particularly severe depression) increases the risk of Alzheimer's disease (AD). METHODS: A longitudinal, three-wave epidemiologic study was implemented in a sample of individuals aged 55 years and older (n = 4,803) followed up at 2.5 years and 4.5 years. This was a population-based cohort drawn from the Zaragoza Dementia and Depression (ZARADEMP) Project, in Zaragoza, Spain. Participants included individuals cognitively intact at baseline (n = 3,864). The main outcome measures were depression as assessed by using the diagnostic interview Geriatric Mental State- Automated Geriatric Examination for Computer Assisted Taxonomy package; and AD diagnosed by a panel of research psychiatrists according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria. The Fine and Gray multivariate regression model was used in the analysis, accounting for mortality. RESULTS: At baseline, clinically significant depression was diagnosed in 452 participants (11.7%); of these, 16.4% had severe depression. Seventy incident cases of AD were found at follow-up. Compared with nondepressed individuals, the incidence rate of AD was significantly higher in the severely depressed subjects (incidence rate ratio: 3.59 [95% confidence interval: 1.30 9.94]). A consistent, significant association was observed between severe depression at baseline and incident AD in the multivariate model (hazard ratio: 4.30 [95% CI: 1.39-13.33]). Untreated depression was associated with incident AD in the unadjusted model; however, in the final model, this association was attenuated and nonsignificant. CONCLUSIONS: Severe depression increases the risk of AD, even after controlling for the competing risk of death. PMID- 23791540 TI - Postprogression survival for first-line chemotherapy in patients with advanced gastric cancer. AB - BACKGROUND: With the increasing availability of active agents, the importance of postprogression survival (PPS) has been recognised for several malignancies. However, little is known of PPS in advanced gastric cancer. PATIENTS AND METHODS: A literature search identified 43 randomised trials in chemotherapy-naive patients with advanced gastric cancer. We partitioned overall survival (OS) into progression-free survival (PFS) and PPS, and then examined the correlation between median OS and either median PFS or median PPS. The correlation between differences in OS (DeltaOS) and those in PFS (DeltaPFS) between trial arms was also investigated. RESULTS: The average median OS was significantly longer in recent (2006 and later) trials than in older (2005 and earlier) trials (10.60 versus 8.64 months, P < 0.001), as was the average median PPS (5.34 versus 3.74 months, P = 0.001). Median PPS was correlated with median OS for all trials (r = 0.732), and this correlation was more pronounced in recent trials (r = 0.850). By contrast, the correlation between median PFS and median OS was less pronounced in recent trials (r = 0.282), as was that between DeltaPFS and DeltaOS (r = 0.365). CONCLUSION: An increase in median PPS was found in accordance with an increase in median OS in recent trials compared with older trials for patients with advanced gastric cancer. PMID- 23791541 TI - Phase II study of first-line bortezomib and cisplatin in malignant pleural mesothelioma and prospective validation of progression free survival rate as a primary end-point for mesothelioma clinical trials (European Organisation for Research and Treatment of Cancer 08052). AB - BACKGROUND: This was a prospective phase II study of cisplatin and bortezomib (CB) in the first line treatment of malignant pleural mesothelioma (MPM) with validation of progression free survival rate at 18 weeks (PFSR-18)(1) as primary end-point. METHODS: Chemotherapy-naive patients with histologically proven MPM and performance status (PS) 0/1, were treated with cisplatin 75 mg/m(2) on day 1 and bortezomib 1.3mg/m(2) on days 1, 4, 8, 11 every 3 weeks. The primary end point validation utilised the landmark method. RESULTS: Between 2007 and 2010 82 patients were entered. PFSR-18 was 53% (80% confidence intervals, CIs, 42-64%). The overall survival (OS) was 13.5 months (95% CI 10.5-15) with 56% (95% CI 44 66%) alive at 1 year. The median PFS was 5.1months (95% CI 3.3-6.5) and the response rate was 28.4% (95% CI 18.9-39.5%). The most frequent grade 3-4 toxicities were hyponatremia (46%), hypokalaemia (17%), fatigue (12.2%), thrombocytopenia (11%), neutropenia (9.7%) and neurotoxicity (motor, sensory, other: 1.2%, 8.5%, 2.4%). There were two toxic deaths (32 and 74days) due to acute pneumonitis and cardiac arrest. End-point validation showed that patients with no progression/progression at 18 weeks had median OS of 16.9/11.9 months, respectively. Hazard ratio was 0.46 (CI 0.32-0.67), logrank test and C-index were 0.007 and 0.60. CONCLUSION: The 50% PFSR-18 for CB was contained within the 80% CI for (42-64%). Therefore the null hypothesis could not be rejected. Accordingly this combination does not warrant further investigation. PFSR-18 was confirmed as a strong predictor of survival. PMID- 23791542 TI - The prognostic impact of tumour-associated macrophages and Reed-Sternberg cells in paediatric Hodgkin lymphoma. AB - BACKGROUND: Tumour-associated macrophages (TAM) are associated with treatment failure in adults with Hodgkin lymphoma (HL). Equivalent data in paediatric HL are sparse. We aimed to determine the prognostic significance of TAM and Reed Sternberg (RS) cells in paediatric HL. METHODS: All children aged 0-18 with HL between 1980 and 2009 with available diagnostic biopsy material were identified. A treatment failure-enriched cohort was assembled. Demographic, disease and outcome data were abstracted. Tissue microarrays with duplicate cores were constructed from diagnostic biopsy material and stained with immunohistochemical markers for TAM (CD68, CD163) and RS (CD30). A high score was defined as >5% positive cells relative to overall cellularity in any core. The association of candidate variables with event-free survival (EFS) was determined using Cox proportional hazards. RESULTS: The final study cohort comprised 96 patients with a median age of 14 years (interquartile range 11-15). Agreement on scores between cores from the same biopsy revealed weighted kappas of 0.60, 0.68 and 0.73 for CD30, CD68 and CD163 respectively, indicating moderate tumour heterogeneity. In univariate analysis, a high CD30 score was significantly associated with treatment failure (hazard ratio (HR) 2.27; 95th confidence interval 1.01-5.11; p<0.05). High CD68 and CD163 scores were not associated with EFS. CONCLUSIONS: Unlike adult HL, a higher percentage of RS cells was associated with poor outcome, while a higher percentage of TAM was not. Adult HL findings may not extend to paediatric HL. Cooperative group trials of paediatric HL should prospectively determine the association of different components of the tumour microenvironment with outcome. PMID- 23791543 TI - Elastic image registration to quantify 3-D regional myocardial deformation from volumetric ultrasound: experimental validation in an animal model. AB - Although real-time 3-D echocardiography has the potential to allow more accurate assessment of global and regional ventricular dynamics compared with more traditional 2-D ultrasound examinations, it still requires rigorous testing and validation should it break through as a standard examination in routine clinical practice. However, only a limited number of studies have validated 3-D strain algorithms in an in vivo experimental setting. The aim of the present study, therefore, was to validate a registration-based strain estimation methodology in an animal model. Volumetric images were acquired in 14 open-chest sheep instrumented with ultrasonic microcrystals. Radial strain (ERR), longitudinal strain (ELL) and circumferential strain (ECC) were estimated during different stages: at rest, during reduced and increased cardiac inotropy induced by esmolol and dobutamine infusion, respectively, and during acute ischemia. Agreement between image-based and microcrystal-based strain estimates was evaluated by their linear correlation, indicating that all strain components could be estimated with acceptable accuracy (r = 0.69 for ERR, r = 0.64 for ELL and r = 0.62 for ECC). These findings are comparable to the performance of the current state-of-the-art commercial 3-D speckle tracking methods. Furthermore, shape of the strain curves, timing of peak values and location of dysfunctional regions were identified well. Whether 3-D elastic registration performs better than 3-D block matching-based methodologies still remains to be proven. PMID- 23791544 TI - Plasmablastic lymphoma of the oral cavity in a human immunodeficiency virus negative patient: a case report with literature review. AB - Plasmablastic lymphoma (PBL) is an aggressive diffuse large B-cell lymphoma variant that is most frequently observed in the oral cavity of human immunodeficiency virus (HIV)-infected individuals. However, in recent years, some cases have emerged in patients without HIV infection and involve other sites like stomach, lung, nasal cavity, and jejunum. We report a rare case of PBL in the maxillary anterior area of a 62-year-old man without HIV infection. The tumor cells were characterized by non-cohesive round or oval shape cells with eccentrically-placed nuclei with a prominent perinuclear halo. Immunohistochemical studies showed that the tumor cells were strongly positive for MUM1, VS38c, VMT, and kappa light chain, focally positive for LCA and CD79a, and negative for CD3, CD20, CD56, lambda light chain, CK-pan, EMA, and HMB45. The patient was treated with chemotherapy using cyclophosphamide, doxorubicin, vincristine, and prednisone. The lesion showed partial remission. PMID- 23791545 TI - Intra-prosthetic breast MR virtual navigation: a preliminary study for a new evaluation of silicone breast implants. AB - OBJECTIVES: To assess the contribute of intra-prosthetic MRI virtual navigation for evaluating breast implants and detecting implant ruptures. METHODS: Forty five breast implants were evaluated by MR examination. Only patients with a clinical indication were assessed. A 1.5-T device equipped with a 4-channel breast coil was used by performing axial TSE-T2, axial silicone-only, axial silicone suppression and sagittal STIR images. The obtained dicom files were also analyzed by using virtual navigation software. Two blinded radiologists evaluated all MR and virtual images. Eight patients for a total of 13 implants underwent surgical replacement. Sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were calculated for both imaging strategies. RESULTS: Intra-capsular rupture was diagnosed in 13 out of 45 (29%) implants by using MRI. Basing on virtual navigation, 9 (20%) cases of intra capsular rupture were diagnosed. Sensitivity, specificity, accuracy, PPV and NPV values of 100%, 86%, 89%, 62% and 100%, respectively, were found for MRI. Virtual navigation increased the previous values up to 100%, 97%, 98%, 89% and 100%. CONCLUSION: Intra-prosthetic breast MR virtual navigation can represent an additional promising tool for the evaluation of breast implants being able to reduce false positives and to provide a more accurate detection of intra-capsular implant rupture signs. PMID- 23791546 TI - Differentiation of central gland prostate cancer from benign prostatic hyperplasia using monoexponential and biexponential diffusion-weighted imaging. AB - PURPOSE: To investigate biexponential apparent diffusion parameters of prostate central gland (CG) cancer, stromal hyperplasia (SH), and glandular hyperplasia (GH) and compare with monoexponential apparent diffusion coefficient (ADC) value for discriminating prostate cancer from benign hyperplasia. MATERIALS AND METHODS: Twenty-one CG cancer foci, 23 SH and 26 GH nodules in the CG were analyzed in 39 patients (19 with CG cancer, 20 with peripheral zone cancer but no CG cancer) who underwent preoperative conventional DWI (b-value 0, 1000s/mm(2)) and a 10 b-value (range 0 to 3000s/mm(2)) DWI. All of the cancer and hyperplastic foci on MR images were localized on the basis of histopathologic correlation. The ADC value of the monoexponential DWI, and the fast apparent diffusion coefficient (ADCf), slow apparent diffusion coefficient (ADCs) value and the fraction of ADCf (f) of the biexponential DWI were calculated for all of the lesions. Receiver operating characteristic (ROC) analysis was performed for the differentiation of CG cancer from SH and GH. RESULTS: The ADC values (*10(-3)mm(2)/s) were 0.87+/ 0.11, 1.06+/-0.15, and 1.61+/-0.27 in CG cancer, SH and GH foci, respectively, and differed significantly, yielding areas under the ROC curve (AUCs) of 1.00 and 0.80 for the differentiation of carcinoma from GH and SH, respectively. The ADCf (*10(-3)mm(2)/s), ADCs (*10(-3)mm(2)/s) and f for cancer were 1.92+/-0.38, 0.53+/ 0.17, and 47.7+/-6.1%, respectively, which were lower than the same values for GH (3.43 +/-0.65, 1.12+/-0.21, 61.1+/-8.7%) (all p<0.01). The ADCf and ADCs for cancer were also lower than those for SH (3.11+/-0.30, 0.79+/-0.21) (all p<0.01). The ADCf yielded AUCs (1.00, p>0.01) that were comparable to those from ADC for the differentiation of cancer from GH, while ADCf yielded higher AUCs (0.92) compared with ADC (p<0.01) for the differentiation of cancer from SH. ADCs and f revealed AUCs of 0.97 and 0.90, respectively, for the differentiation of cancer from GH, and the ADCs offered relatively lower AUCs (0.68) for differentiating cancer from SH. CONCLUSION: Biexponential DWI could potentially improve the differentiation of prostate cancer in CG, and the ADCf of the biexponential model offers better accuracy than ADC. PMID- 23791547 TI - Experimental challenge of chicken vaccinated with commercially available H5 vaccines reveals loss of protection to some highly pathogenic avian influenza H5N1 strains circulating in Hong Kong/China. AB - Highly pathogenic avian influenza (HPAI) H5N1 virus continues to circulate in poultry in Asia and Africa posing a threat to both public and animal health. Vaccination, used as an adjunct to improved bio-security and stamping-out policies, contributed to protecting poultry in Hong Kong from HPAI H5N1 infection in 2004-2008 although the virus was repeatedly detected in dead wild birds. The detection of clade 2.3.4 H5N1 viruses in poultry markets and a farm in Hong Kong in 2008 raised the question whether this virus has changed to evade protection from the H5 vaccines in use. We tested the efficacy of three commercial vaccines (Nobilis, Poulvac and Harbin Re-5 vaccine) in specific pathogen free white leghorn chickens against a challenge with A/chicken/Hong Kong/8825-2/2008 (clade 2.3.4) isolated from vaccinated poultry in Hong Kong and A/chicken/Hong Kong/782/2009 (clade 2.3.2). Harbin Re5 vaccine provided the best, albeit not complete protection against challenge with the clade 2.3.4 virus. All three vaccines provided good protection from death and significantly reduced virus shedding following challenge with the clade 2.3.2 virus. Only Harbin Re-5 was able to completely protect chickens from virus shedding as well as mortality. Sera from vaccinated chickens had lower geometric hemagglutination inhibition titers against A/chicken/Hong Kong/8825-2/08, as compared to two other clade 2.3.4 and one clade 0 virus. Alignment of amino-acid sequences of the haemagglutinin of A/chicken/Hong Kong/8825-2/08 and the other H5 viruses revealed several mutations in positions including 69, 71, 83, 95, 133,140, 162, 183, 189, 194 and 270 (H5 numbering) which may correlate with loss of vaccine protection. Our results indicated that the tested HPAI H5N1 (2.3.4) virus has undergone antigenic changes that allow it to evade immunity from poultry vaccines. This highlights the need for continued surveillance and monitoring of vaccine induced immunity, with experimental vaccine challenge studies being done where indicated. PMID- 23791548 TI - Evaluation of the humoral immune responses in adult cattle and sheep, 4 and 2.5 years post-vaccination with a bluetongue serotype 8 inactivated vaccine. AB - One of the big surprises about the devastating outbreak of bluetongue serotype-8 that spread across Northern and Western Europe between 2006 and 2008 was how relatively quickly the virus was controlled and eradicated from affected countries. This was at least in part attributed to the high levels of vaccine coverage achieved in affected countries. A previous study revealed that neutralising antibodies persisted in the majority of vaccinated cattle for at least 3 years post-vaccination, indicating that cattle are likely to be protected for this time period. The current study revealed that neutralising antibodies persisted in the same group of cattle for up to 4 years post-vaccination, and that neutralising antibodies persisted for up to 2.5 years in sheep that had been vaccinated on two occasions one year apart. These results have implications for future bluetongue surveillance programmes and vaccine control strategies. PMID- 23791549 TI - Malignant epithelioid angiomyolipoma: tumor and metabolic response to everolimus as evaluated with positron emission tomography. PMID- 23791550 TI - Novel bioactivity of phosvitin in connective tissue and bone organogenesis revealed by live calvarial bone organ culture models. AB - Egg yolk phosvitin is one of the most highly phosphorylated extracellular matrix proteins known in nature with unique physico-chemical properties deemed to be critical during ex-vivo egg embryo development. We have utilized our unique live mouse calvarial bone organ culture models under conditions which dissociates the two bone remodeling stages, viz., resorption by osteoclasts and formation by osteoblasts, to highlight important and to date unknown critical biological functions of egg phosvitin. In our resorption model live bone cultures were grown in the absence of ascorbate and were stimulated by parathyroid hormone (PTH) to undergo rapid osteoclast formation/differentiation with bone resorption. In this resorption model native phosvitin potently inhibited PTH-induced osteoclastic bone resorption with simultaneous new osteoid/bone formation in the absence of ascorbate (vitamin C). These surprising and critical observations were extended using the bone formation model in the absence of ascorbate and in the presence of phosvitin which supported the above results. The results were corroborated by analyses for calcium release or uptake, tartrate-resistant acid phosphatase activity (marker for osteoclasts), alkaline phosphatase activity (marker for osteoblasts), collagen and hydroxyproline composition, and histological and quantitative histomorphometric evaluations. The data revealed that the discovered bioactivity of phosvitin mirrors that of ascorbate during collagen synthesis and the formation of new osteoid/bone. Complementing those studies use of the synthetic collagen peptide analog and cultured calvarial osteoblasts in conjunction with mass spectrometric analysis provided results that augmented the bone organ culture work and confirmed the capacity of phosvitin to stimulate differentiation of osteoblasts, collagen synthesis, hydroxyproline formation, and biomineralization. There are striking implications and interrelationships of this affect that relates to the evolutionary inactivation of the gene of an enzyme L gulono-gamma-lactone oxidase, which is involved in the final step of ascorbate biosynthesis, in many vertebrate species including passeriform birds, reptiles and teleost fish whose egg yolk contain phosvitin. These represent examples of how developing ex-vivo embryos of such species can achieve connective tissue and skeletal system formation in the absence of ascorbate. PMID- 23791551 TI - Regulation of sperm motility by PIP2(4,5) and actin polymerization. AB - Actin polymerization and development of hyperactivated (HA) motility are two processes that take place during sperm capacitation. In previous studies, we demonstrated that the increase in F-actin during capacitation depends upon inactivation of the actin severing protein, gelsolin, by its binding to phosphatydilinositol-4, 5-bisphosphate (PIP2). Here, we showed for the first time the involvement of PIP2/gelsolin in human sperm motility before and during capacitation. Activation of gelsolin by causing its release from PIP2 inhibited sperm motility, which could be restored by adding PIP2 to the cells. Reduction of PIP2 synthesis inhibited actin polymerization and motility, and increasing PIP2 synthesis enhanced these activities. Furthermore, sperm demonstrating low motility contained low levels of PIP2 and F-actin. During capacitation there was an increase in PIP2 and F-actin levels in the sperm head and a decrease in the tail. In sperm with high motility, gelsolin was mainly localized to the sperm head before capacitation, whereas in low motility sperm, most of the gelsolin was localized to the tail before capacitation and translocated to the head during capacitation. We also showed that phosphorylation of gelsolin on tyrosine-438 depends on its binding to PIP2. Activation of phospholipase C by Ca(2+)-ionophore or by activating the epidermal-growth-factor-receptor inhibits tyrosine phosphorylation of gelsolin. In conclusion, the data indicate that the increase of PIP2 and/or F-actin in the head during capacitation enhances gelsolin translocation to the head. As a result the decrease of gelsolin in the tail allows keeping high level of F-actin in the tail, which is essential for the development of HA motility. PMID- 23791552 TI - Adjuvant breast cancer vaccine improves disease specific survival of breast cancer patients with depressed lymphocyte immunity. AB - PURPOSE: Beginning in 1995 breast cancer patients were vaccinated in the adjuvant setting with an autologous, allogeneic whole cell vaccine to evaluate the effect on host lymphocyte immunity and disease specific survival. METHODS: The breast cancer patients had host lymphocyte immunity against tumor associated antigens evaluated by a Lymphocyte Blastogenesis Assay (LBA) before vaccination. Thirty seven patients with depressed immunity were vaccinated in the adjuvant setting. Patients were given six intradermal injections (three weekly followed by three monthly). Ten weeks after the last injection the LBA was repeated. RESULTS: Some patients experienced slight pain and swelling at the injection site with slight chills and fever, but there were no severe toxicities. The vaccinated patients had a mean follow-up of 12.7 years with mean follow-up of 8.9 and 9.2 years for the patients with normal and depressed immunity, respectively, in the historic control. The 10 year survival was 95% (20 of 21 patients) in the normal immunity historic control, 59% (33 of 56 patients) in the depressed immunity historic control and 89% (33 of 37 patients) in the patients with depressed immunity that were vaccinated in the present clinical trial. The disease specific survival of the vaccinated patients with depressed immunity in this trial is significantly greater than that of the historic controls of unvaccinated patients with depressed immunity to their tumor associated antigens. CONCLUSION: This study confirms the importance of maintaining good host lymphocyte immunity after completion of standard therapy and validates the value of cancer immunotherapy in the adjuvant setting. PMID- 23791553 TI - Molecular insights into 4-nitrophenol-induced hepatotoxicity in zebrafish: transcriptomic, histological and targeted gene expression analyses. AB - BACKGROUND: 4-Nitrophenol (4-NP) is a prioritized environmental pollutant and its toxicity has been investigated using zebrafish, advocated as an alternative toxicological model. However, molecular information of 4-NP induced hepatotoxicity is still limited. This study aimed to obtain molecular insights into 4-NP-induced hepatotoxicity using zebrafish as a model. METHODS: Adult male zebrafish were exposed to 4-NP for 8, 24, 48 and 96h. Livers were sampled for microarray experiment, qRT-PCR and various histological analyses. RESULTS: Transcriptomic analysis revealed that genes associated with oxidative phosphorylation and electron transport chain were significantly up-regulated throughout early and late stages of 4-NP exposure due to oxidative phosphorylation uncoupling by 4-NP. This in turn induced oxidative stress damage and up-regulated pathways associated with tumor suppressors Rb and p53, cell cycle, DNA damage, proteasome degradation and apoptosis. Pathways associated with cell adhesion and morphology were deregulated. Carbohydrate and lipid metabolisms were down-regulated while methionine and aromatic amino acid metabolisms as well as NFKB pathway associated with chronic liver conditions were up-regulated. Up regulation of NFKB, NFAT and interleukin pathways suggested hepatitis. Histological analyses with specific staining methods and qRT-PCR analysis of selected genes corroborated with the transcriptomic analysis suggesting 4-NP induced liver injury. CONCLUSION: Our findings allowed us to propose a plausible model and provide a broader understanding of the molecular events leading to 4-NP induced acute hepatotoxicity for future studies involving other nitrophenol derivatives. GENERAL SIGNIFICANCE: This is the first transcriptomic report on 4 NP induced hepatotoxicity. PMID- 23791554 TI - Mitochondrial dysfunction represses HIF-1alpha protein synthesis through AMPK activation in human hepatoma HepG2 cells. AB - BACKGROUND: Hypoxia-inducible factor-1alpha (HIF-1alpha) is an important transcription factor that modulates cellular responses to hypoxia and also plays critical roles in cancer progression. Recently, somatic mutations and decreased copy number of mitochondrial DNA (mtDNA) were detected in hepatocellular carcinoma (HCC). These mutations were shown to have the potential to cause mitochondrial dysfunction. However, the effects and mechanisms of mitochondrial dysfunction on HIF-1alpha function are not fully understood. This study aims to explore the underlying mechanism by which mitochondrial dysfunction regulates HIF 1alpha expression. METHODS: Human hepatoma HepG2 cells were treated with various mitochondrial respiration inhibitors and an uncoupler, respectively, and the mRNA and protein expressions as well as transactivation activity of HIF-1alpha were determined. The role of AMP-activated protein kinase (AMPK) was further analyzed by compound C and AMPK knock-down. RESULTS: Treatments of mitochondrial inhibitors and an uncoupler respectively reduced both the protein level and transactivation activity of HIF-1alpha in HepG2 cells under normoxia or hypoxia. The mitochondrial dysfunction-repressed HIF-1alpha protein synthesis was associated with decreased phosphorylations of p70(S6K) and 4E-BP-1. Moreover, mitochondrial dysfunction decreased intracellular ATP content and elevated the phosphorylation of AMPK. Treatments with compound C, an AMPK inhibitor, and knock down of AMPK partially rescued the mitochondrial dysfunction-repressed HIF-1alpha expression. CONCLUSIONS: Mitochondrial dysfunctions resulted in reduced HIF 1alpha protein synthesis through AMPK-dependent manner in HepG2 cells. GENERAL SIGNIFICANCE: Our results provided a mechanism for communication from mitochondria to the nucleus through AMPK-HIF-1alpha. Mitochondrial function is important for HIF-1alpha expression in cancer progression. PMID- 23791556 TI - Visual cortical contributions to associative cerebellar learning. AB - Eye-blink conditioning (EBC) is a form of associative learning that depends on the cerebellum. Previous reports suggested that sensory cortex is necessary for trace EBC but not for delay EBC. The trace and delay EBC procedures used in these studies differed by the presence or absence of a temporal gap between the end of the conditioned stimulus and the onset of the unconditioned stimulus (trace interval) and in the interval between the onset of the CS and the US (inter stimulus interval, ISI). The current study examined the role of the visual cortex in delay, long-delay, and trace EBC, matching CS duration and inter-stimulus interval between groups. In Experiment 1, extensive removal of the visual cortex impaired acquisition of long-delay and trace EBC but had no effect on delay EBC. In Experiment 2, bilateral inactivation of the visual cortex impaired acquisition and retention of long-delay and trace EBC, but had no effect on delay EBC. In Experiment 3, unilateral inactivation of the visual cortex impaired long-delay EBC but had no effect on trace EBC. The results indicate that the visual cortex facilitates EBC with relatively long ISIs, regardless of whether there is a trace interval or not. Moreover, the ipsilateral projections from the visual cortex to the pontine nuclei are sufficient for modulating long-delay EBC, whereas trace EBC involves bilateral visual cortical interactions with forebrain systems including the hippocampus and prefrontal cortex. PMID- 23791555 TI - Fear of the unexpected: hippocampus mediates novelty-induced return of extinguished fear in rats. AB - Several lines of evidence indicate an important role for the hippocampus in the recovery of fear memory after extinction. For example, hippocampal inactivation prevents the renewal of fear to an extinguished conditioned stimulus (CS) when it is presented outside the extinction context. Renewal of extinguished responding is accompanied by associative novelty (an unexpected occurrence of a familiar CS in a familiar place), the detection of which may require the hippocampus. We therefore examined whether the hippocampus also mediates the recovery of extinguished fear caused by other unexpected events, including presenting a familiar CS in a novel context or presenting a novel cue with the CS in a familiar context (e.g., external disinhibition). Rats underwent Pavlovian fear conditioning and extinction using an auditory CS and freezing behavior served as the index of conditioned fear. In Experiment 1, conditioned freezing to the extinguished CS was renewed in a novel context and this was eliminated by intra hippocampal infusions of the GABAA agonist, muscimol, prior to the test. In Experiment 2, muscimol inactivation of the hippocampus reduced the external disinhibition of conditioned freezing that occurred when a novel white noise accompanied the extinguished tone CS. Collectively, these results suggest that the hippocampus mediates the return of fear when extinguished CSs are unexpected, or when unexpected stimuli accompany CS presentation. Ultimately, a violation of expectations about when, where, and with what other stimuli an extinguished CS will occur may form the basis of spontaneous recovery, renewal, and external disinhibition. PMID- 23791557 TI - Inactivation of muscarinic receptors impairs place and response learning: implications for multiple memory systems. AB - Extensive research has shown that the hippocampus and striatum have dissociable roles in memory and are necessary for place and response learning, respectively. Additional evidence indicates that muscarinic cholinergic receptors in the hippocampus and striatum exert an important role in the modulation of these memory systems. In our experiments, we assessed whether intact hippocampal and striatal muscarinic cholinergic transmission may be essential and/or necessary for place and response learning. We addressed these questions using administration of the muscarinic receptor antagonist, scopolamine, on both place and response learning in a food-rewarded T-maze task. The administration of scopolamine (15 MUg or 30 MUg) directly into the dorsal hippocampus impaired the performance of rats subjected to both place and cue-rich response version of the task, but did not affect the response version, when the task was performed under cue-poor conditions. However, the administration of scopolamine in the dorsolateral striatum impaired the cue-poor response version of the T-maze task without interfering with the place version or cue-rich response version. Taken together, these results indicate that activation of muscarinic cholinergic receptors in the hippocampus and striatum facilitate the use of different strategies of learning, thus strengthening the hypothesis of multiple memory systems. Additionally, these results emphasize the importance of the environmental conditions under which tasks are performed. PMID- 23791558 TI - A novel, potent, oral active and safe antinociceptive pyrazole targeting kappa opioid receptors. AB - Pyrazole compounds are an intriguing class of compounds with potential analgesic activity; however, their mechanism of action remains unknown. Thus, the goal of this study was to explore the antinociceptive potential, safety and mechanism of action of novel 1-pyrazole methyl ester derivatives, which were designed by molecular simplification, using in vivo and in vitro methods in mice. First, tree 1-pyrazole methyl ester derivatives (DMPE, MPFE, and MPCIE) were tested in the capsaicin test and all presented antinociceptive effect; however the MPClE (methyl 5-trichloromethyl-3-methyl-1H-pyrazole-1-carboxylate) was the most effective. Thus, we selected this compound to assess the effects and mechanisms in subsequent pain models. MPCIE produced antinociception when administered by oral, intraperitoneal, intrathecal and intraplantar routes and was effective in the capsaicin and the acetic acid-induced nociception tests. Moreover, this compound reduced the hyperalgesia in diverse clinically-relevant pain models, including postoperative, inflammatory, and neuropathic nociception in mice. The antinociception produced by orally administered MPClE was mediated by kappa opioid receptors, since these effects were prevented by systemically pre treatment with naloxone and the kappa-opioid receptor antagonist nor binaltorphimine. Moreover, MPCIE prevented binding of the kappa-opioid ligand [(3)H]-CI-977 in vitro (IC50 of 0.68 (0.32-1.4) MUM), but not the TRPV1 ([(3)H] resiniferatoxin) or the alpha2-adrenoreceptor ([(3)H]-idazoxan) binding. Regarding the drug-induced side effects, oral administration of MPClE did not produce sedation, constipation or motor impairment at its active dose. In addition, MPCIE was readily absorbed after oral administration. Taken together, these results demonstrate that MPClE is a novel, potent, orally active and safe analgesic drug that targets kappa-opioid receptors. PMID- 23791559 TI - Histamine up-regulates astrocytic glutamate transporter 1 and protects neurons against ischemic injury. AB - Astrocytic glutamate transporter 1 (GLT-1) is responsible for the majority of extracellular glutamate clearance and is essential for preventing excitotoxicity in the brain. Up-regulation of GLT-1 shows benefit effect on ischemia-induced neuronal damage. In present study, we examined the effect of histamine, a neurotransmitter or neuromodulator, on GLT-1 expression and function. In acute hippocampal slices, histamine selectively increased GLT-1 expression independent of neuronal activities. Similar up-regulation of GLT-1 was also observed after histamine treatment in pure cultured astrocytes, which was abolished by H1 receptor antagonist or PKC inhibitor. Cell surface biotinylation and whole-cell patch recordings of glutamate transporter current confirmed the up-regulation of functional GLT-1 following histamine exposure. Histamine treatment decreased the extracellular glutamate content and alleviated neuronal cell death induced by exogenous glutamate challenge. Moreover, we found a significant neuroprotective effect of histamine in brain slices after oxygen-glucose deprivation (OGD). In addition, histidine, the precursor of histamine, also showed neuroprotection against ischemic injury, which was accompanied by reversion of declined expression of GLT-1 in adult rats subjected to middle cerebral artery occlusion (MCAO). These neuroprotective effects of histamine/histidine were blocked by GLT 1 specific inhibitor dihydrokainate or H1 receptor antagonist. In summary, our results suggest that histamine up-regulates GLT-1 expression and function via astrocytic H1 receptors, thus resulting in neuroprotection against excitotoxicity and ischemic injury. PMID- 23791560 TI - Resting scapular posture in healthy overhead throwing athletes. AB - INTRODUCTION: On shoulder examination, asymmetric scapular posture is often associated to abnormalities of the shoulder complex joint. However, shoulder asymmetries may also be related to adaptations to sports practice. The overhead throwing motion is a highly repetitive skilled motion performed at high velocities. Due to overuse of the dominant overhead-throwing shoulder, athletes may develop some kind of overhead throwing shoulder adaptation pattern that possibly includes scapular asymmetry at the resting position. PURPOSE: To quantify the asymmetry between dominant and non-dominant resting scapular posture in 3 groups of healthy subjects (volleyball players, team-handball players and a control group). METHODS: Bilateral 3D scapular kinematics with the arm at rest was measured using a 6 degrees-of-freedom electromagnetic tracking device. RESULTS: In handball athletes, the dominant scapula was more in internal rotation and anteriorly tilted than in volleyball players. Between athletes and non athletes groups, the dominant scapula was more anteriorly tilted in the athletes. CONCLUSIONS: Clinicians should be aware that some degree of scapular asymmetry may be normal in some athletes. It should not be considered automatically as a pathological sign but rather an adaptation to sports practice and extensive use of upper limb. PMID- 23791561 TI - The addition of cervical unilateral posterior-anterior mobilisation in the treatment of patients with shoulder impingement syndrome: a randomised clinical trial. AB - Shoulder impingement syndrome (SIS) is a complex, multi-factorial problem that is treated with a variety of different conservative options. One conservative option that has shown effectiveness is manual therapy to the thoracic spine. Another option, manual therapy to the cervical spine, has been studied only once with good results, evaluating short-term outcomes, in a small sample size. The purpose of this study was to investigate the benefit of neck manual therapy for patients with SIS. The study was a randomised, single blinded, clinical trial where both groups received pragmatic, evidence-based treatment to the shoulder and one group received neck manual therapy. Subjects with neck pain were excluded from the study. Comparative pain, disability, rate of recovery and patient acceptable symptom state (PASS) measures were analyzed on the 68 subjects seen over an average of 56.1 days (standard deviation (SD)=55.4). Eighty-six percent of the sample reported an acceptable change on the PASS at discharge. There were no between-groups differences in those who did or did not receive neck manual therapy; however, both groups demonstrated significant within-groups improvements. On average both groups improved 59.7% (SD=25.1) for pain and 53.5% (SD=40.2) for the Quick Disabilities of the Shoulder and Hand Questionnaire (QuickDASH) from baseline. This study found no value when neck manual therapy was added to the treatment of SIS. Reasons may include the lack of therapeutic dosage provided for the manual therapy approach or the lack of benefit to treating the neck in subjects with SIS who do not have concomitant neck problems. PMID- 23791562 TI - Retrocaval renal artery bifurcation is not a contraindication to laparoscopic right donor nephrectomy. AB - BACKGROUND: Laparoscopic donor nephrectomy is preferentially performed on the left side vs the right, even in instances where more complex arterial vasculature is present on the left. This finding is significant given the observation that living donor kidneys with multiple arteries are associated with increased incidence of ureteral complications in the recipient. One common anatomic variant, retrocaval bifurcation of the right renal artery, has potential risks that prompt the decision to procure left-sided kidneys with more complex arterial anatomy. However, these risks may be mitigated by the surgical approaches that can successfully procure right kidneys with this type of arterial variant. STUDY DESIGN: Of 321 total nephrectomies performed, there were 44 right-sided laparoscopic donor nephrectomies. Nineteen of these 44 patients had retrocaval bifurcation and were compared with a cohort of 25 patients without this variant. Standardized parameters were collected including demographics, donor and recipient outcomes, graft function, and renal artery anastomotic velocity. The Mann-Whitney U test and Fisher's exact test were used to show statistical significance. RESULTS: Donor and recipient outcomes and complication rates were not significantly different between the retrocaval bifurcation group and the nonbifurcation group. Notably, graft anastomotic velocity and rates of delayed graft function (DGF) were the same between recipients in the 2 study groups. Comparisons between left-sided nephrectomies and kidneys from the retrocaval bifurcation group showed a slower reduction in immediate creatinine clearance in the retrocaval group; however, both groups had similar outcomes 30 days post transplantation. CONCLUSIONS: This study provides a detailed, technical laparoscopic methodology for procurement of right-sided kidneys with retrocaval arterial bifurcation, which was associated with outcomes similar to right and left kidneys with single arteries. PMID- 23791563 TI - Cesarean section for HIV-infected women in the combination antiretroviral therapies era, 2000-2010. AB - OBJECTIVE: Elective cesarean section (CS) is a proven method to prevent mother-to child transmission (MTCT), but is no longer recommended for women with antiretroviral therapy resulting in a low viral load (VL): <400 copies/mL in French and <1000 copies/mL in US guidelines. We sought to describe mode of delivery practices in human immunodeficiency virus (HIV)-infected women and their association with MTCT and postpartum complications. STUDY DESIGN: All deliveries from HIV-1-infected women in the French Perinatal Cohort (Agence Nationale de Recherches sur le Sida/Enquete Perinatale Francaise) 2000 through 2010 (N = 8977) were analyzed, with additional details for 2005 through 2010 (n = 4717). RESULTS: Vaginal deliveries increased from 25% in 2000 to 53% in 2010. Over 2005 through 2010, 4300 women had VL before delivery <400 copies/mL; among them only 49.3% delivered vaginally, 22.0% had nonelective CS, and 28.7% had elective CS. Elective CS were performed for scarred uterus in 45.4%, other obstetrical indications in 37.1%, and solely because of HIV in 15.7%. Of the 417 women with VL >=400 copies/mL, 48.9% had elective CS as recommended, 25.9% had nonelective CS, and 25.2% had vaginal delivery. The MTCT rate did not differ according to the mode of delivery in term deliveries (>=37 gestational weeks) in 2000 through 2010: 0.3% after both vaginal delivery and elective CS with VL <50 copies/mL, 4.0% vs 5.3%, respectively, with VL >=10,000 copies/mL. In case of preterm delivery, MTCT rates tended to be higher with vaginal delivery. Postpartum complications were more frequent following CS than vaginal deliveries (6.5% vs 2.9, P < .01). CONCLUSION: Our findings suggest that HIV-infected women on antiretroviral therapy with low VL can safely opt for vaginal delivery in the absence of obstetrical risk factors. PMID- 23791564 TI - Selected perinatal outcomes associated with planned home births in the United States. AB - OBJECTIVE: More women are planning home birth in the United States, although safety remains unclear. We examined outcomes that were associated with planned home compared with hospital births. STUDY DESIGN: We conducted a retrospective cohort study of term singleton live births in 2008 in the United States. Deliveries were categorized by location: hospitals or intended home births. Neonatal outcomes were compared with the use of the chi(2) test and multivariable logistic regression. RESULTS: There were 2,081,753 births that met the study criteria. Of these, 12,039 births (0.58%) were planned home births. More planned home births had 5-minute Apgar score <4 (0.37%) compared with hospital births (0.24%; adjusted odds ratio, 1.87; 95% confidence interval, 1.36-2.58) and neonatal seizure (0.06% vs 0.02%, respectively; adjusted odds ratio, 3.08; 95% confidence interval, 1.44-6.58). Women with planned home birth had fewer interventions, including operative vaginal delivery and labor induction/augmentation. CONCLUSION: Planned home births were associated with increased neonatal complications but fewer obstetric interventions. The trade-off between maternal preferences and neonatal outcomes should be weighed thoughtfully. PMID- 23791565 TI - Professionally responsible intrapartum management of patients with major mental disorders. AB - Pregnant women with major mental disorders present obstetricians with a range of clinical challenges, which are magnified when a psychotic or agitated patient presents in labor and there is limited time for decision making. This article provides the obstetrician with an algorithm to guide professionally responsible decision making with these patients. We searched for articles related to the intrapartum management of pregnant patients with major mental disorders, using 3 main search components: pregnancy, chronic mental illness, and ethics. No articles were found that addressed the clinical ethical challenges of decision making during the intrapartum period with these patients. We therefore developed an ethical framework with 4 components: the concept of the fetus as a patient; the presumption of decision-making capacity; the concept of assent; and beneficence-based clinical judgment. On the basis of this framework we propose an algorithm to guide professionally responsible decision making that asks 5 questions: (1) Does the patient have the capacity to consent to treatment?; (2) Is there time to attempt restoration of capacity?; (3) Is there an opportunity for substituted judgment?; (4) Is the patient accepting treatment?; (5) Is there an opportunity for active assent?; and (6) coerced clinical management as the least worst alternative. The algorithm is designed to support a deliberative, clinically comprehensive, preventive-ethics approach to guide obstetricians in decision making with this challenging population of patients. PMID- 23791566 TI - Congenital cerebral palsy and prenatal exposure to self-reported maternal infections, fever, or smoking. AB - OBJECTIVE: The objective of the study was to investigate the association between maternal self-reported infections, fever, and smoking in the prenatal period and the subsequent risk for congenital cerebral palsy (CP). STUDY DESIGN: We included the 81,066 mothers of singletons born between 1996 and 2003 who participated in the Danish National Birth Cohort. Children were followed up through December 2008. Information on maternal infections, fever, smoking, and other demographic and lifestyle factors during pregnancy were reported by mothers in computer assisted telephone interviews in early and midgestation. We identified 139 CP cases including 121 cases of spastic CP (sCP) as confirmed by the Danish National Cerebral Palsy Register. Cox proportional hazards regression models were used to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). RESULTS: Self-reported vaginal infections were associated with an increased risk of CP and sCP (aHR, 1.52; 95% CI, 1.04-2.24; and aHR, 1.73; 95% CI, 1.16-2.60, respectively) and particularly untreated vaginal infections were associated with an increased risk of sCP (aHR, 1.95; 95% CI, 1.16-3.26). Fever was associated with the risk of CP (aHR, 1.53; 95% CI, 1.06-2.21). Smoking 10 or more cigarettes per day during pregnancy was also associated with sCP (aHR, 1.80; 95% CI, 1.10 2.94). There was a modest excess in risk for children exposed to both heavy smoking and vaginal infections. No other self-reported infections were significantly associated with CP. CONCLUSION: Self-reported vaginal infections, fever, and smoking 10 or more cigarettes per day during pregnancy were associated with a higher risk of overall CP and/or sCP. PMID- 23791567 TI - Activation of MAPK by inverse agonists in six naturally occurring constitutively active mutant human melanocortin-4 receptors. AB - The melanocortin-4 receptor (MC4R) is a G protein-coupled receptor that plays an essential role in regulating energy homeostasis. Defects in MC4R are the most common monogenic form of obesity, with about 170 distinct mutations identified in human. In addition to the conventional Gs-stimulated adenylyl cyclase pathway, it has been recently demonstrated that MC4R also activates mitogen-activated protein kinases, extracellular signal-regulated kinases 1 and 2 (ERK1/2). Herein, we investigated the potential of four MC4R ligands that are inverse agonists at the Gs-cAMP signaling pathway, including agouti-related peptide (AgRP), MCL0020, Ipsen 5i and ML00253764, to regulate ERK1/2 activation (pERK1/2) in wild type and six naturally occurring constitutively active mutant (CAM) MC4Rs. We showed that these four inverse agonists acted as agonists for the ERK1/2 signaling cascade in wild type and CAM MC4Rs. Three mutants (P230L, L250Q and F280L) had significantly increased pERK1/2 level upon stimulation with all four inverse agonists, with maximal induction ranging from 1.6 to 4.2-fold. D146N had significantly increased pERK1/2 level upon stimulation with AgRP, MCL0020 or ML00253764, but not Ipsen 5i. The pERK1/2 levels of H76R and S127L were significantly increased only upon stimulation with AgRP or MCL0020. In summary, our studies demonstrated for the first time that MC4R inverse agonists at the Gs-cAMP pathway could serve as agonists in the MAPK pathway. These results suggested that there were multiple activation states of MC4R with ligand-specific and/or mutant-specific conformations capable of differentially coupling the MC4R to distinct signaling pathways. PMID- 23791568 TI - Complex rearrangement of the exon 6 genomic region among Opitz G/BBB Syndrome MID1 alterations. AB - Opitz G/BBB Syndrome (OS) is a multiple congenital anomaly disorder characterized by developmental defects of midline structures. The most relevant clinical signs are ocular hypertelorism, hypospadias, cleft lip and palate, laryngo-tracheo esophageal abnormalities, imperforate anus, and cardiac defects. Developmental delay, intellectual disability and brain abnormalities are also present. The X linked form of this disorder is caused by mutations in the MID1 gene coding for a member of the tripartite motif family of E3 ubiquitin ligases. Here, we describe 12 novel patients that carry MID1 mutations emphasizing that laryngo-tracheo esophageal defects are very common in OS patients and, together with hypertelorism and hypospadias, are the most frequent findings among the full spectrum of OS clinical manifestations. Besides missense and nonsense mutations, small insertions and deletions scattered along the entire length of the gene, we found that a consistent number of MID1 alterations are represented by the deletion of single coding exons. Deep characterization of one of these deletions reveals, for the first time within the MID1 gene, a complex rearrangement composed of two deletions, an inversion and a small insertion that may suggest the involvement of concurrent non-homologous mechanisms in the generation of the observed structural variant. PMID- 23791569 TI - Effects of (-)-epicatechin and derivatives on nitric oxide mediated induction of mitochondrial proteins. AB - Impaired mitochondrial function represents an early manifestation of endothelial dysfunction and likely contributes to the development of cardiovascular diseases (CVD). The stimulation of mitochondrial function and/or biogenesis is seen as a means to improve the bioenergetic and metabolic status of cells and thus, reduce CVD. In this study we examined the capacity of the flavanol (-)-epicatechin and two novel derivatives to enhance mitochondrial function and protein levels in cultured bovine coronary artery endothelial cells. As nitric oxide production by endothelial cells is suspected in mediating mitochondria effects (including biogenesis), we also examined the dependence of responses on this molecule using an inhibitor of nitric oxide synthase. Results indicate that the flavanol (-) epicatechin and derivatives are capable of stimulating mitochondrial function as assessed by citrate synthase activity as well as induction of structural (porin, mitofilin) and oxidative phosporylation protein levels (complex I and II). Effects were blocked by the use of the chemical inhibitor of the synthase thus, evidencing a role for nitric oxide in mediating these effects. The results observed indicate that the three agents are effective in enhancing mitochondria function and protein content. The effects noted for (-)-epicatechin may serve to explain the healthy effects on cardiometabolic risk ascribed to the consumption of cocoa products. PMID- 23791570 TI - Synthesis of (Z)-2-((1H-indazol-3-yl)methylene)-6-[11C]methoxy-7-(piperazin-1 ylmethyl)benzofuran-3(2H)-one as a new potential PET probe for imaging of the enzyme PIM1. AB - (Z)-2-((1H-Indazol-3-yl)methylene)-6-methoxy-7-(piperazin-1-ylmethyl)benzofuran 3(2H)-one is a potent and selective proviral integration site in moloney murine leukemia virus kinase 1 (PIM1) inhibitor with an IC50 value of 3 nM. (Z)-2-((1H Indazol-3-yl)methylene)-6-[(11)C]methoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H) one, a new potential PET probe for imaging of the enzyme PIM1, was first designed and synthesized in 20-30% decay corrected radiochemical yield and 370-740 GBq/MUmol specific activity at end of bombardment (EOB). The synthetic strategy was to prepare a carbon-11-labeled Boc-protected intermediate followed by a quick acidic de-protection. PMID- 23791571 TI - Synthesis and antimicrobial activity of imidazole and pyridine appended cholestane-based conjugates. AB - A series of 3alpha-amino-5alpha-cholestane and 3alpha,7alpha-diamino-5alpha cholestane derivatives containing imidazole and pyridine rings were synthesized by simple and effective reductive amination, and their in vitro activities against a range of Gram-positive and Gram-negative strains were evaluated. Most of the compound exhibited enhanced activity against MRSA pathogen. 3alpha,7alpha Di(pyridylmethyl)amino-5alpha-cholestane 10 showed the highest potency in these series toward the Gram-positive bacteria, Staphylococcus epidermidis 887E, with the lowest MIC value of 1 MUg/mL. PMID- 23791573 TI - The challenge of Bacillus Calmette-Guerin failure in nonmuscle invasive bladder cancer--what is the next step in management? PMID- 23791575 TI - Editorial comment. PMID- 23791576 TI - "pH phoresis": a new concept that can be used for improving drug delivery to tumor cells. AB - We propose a new concept describing how nanoparticles composed of weak polybases (such as polyamines) would behave when they are exposed to a pH gradient; weak polybase-containing particles will tend to accumulate preferentially in low pH regions under a pH gradient environment. This phenomenon, which we term "pH phoresis", may provide a useful mechanism for improving the delivery of drugs to cancer cells in solid tumor tissues. PMID- 23791577 TI - Bodyguard manipulation in a multipredator context: different processes, same effect. AB - Parasites have evolved various strategies to exploit hosts to their own advantage. Bodyguard manipulations consist of usurping the behaviour of the host to confer some protection to the parasite and/or its offspring. Dinocampus coccinellae Schrank is a solitary endoparasitoid of the spotted lady beetle Coleomegilla maculata lengi Timberlake. The parasitoid larva grows inside the host until mature, then egresses and spins a cocoon between the ladybird's legs. Unlike most parasitoids, D. coccinellae does not kill its host during development, but keeps the coccinellid partially paralysed on top of the cocoon, where it acts as a bodyguard against natural enemies. As recently shown, the presence of a living ladybird on the parasitoid cocoon provides efficient protection against a predator, lacewing larvae. In the present study, we used predators with different foraging behaviours--jumping spiders and crickets--to explore the relevance of the bodyguard strategy for D. coccinellae in a multipredator context. Although the manner of the protection differs among the different tested predators, the presence of the ladybird always enhances parasitoid survival, even when it first increases detection of the cocoon ladybird complex, as is the case with jumping spiders. Furthermore, although a dead bodyguard is sufficient to passively defend parasitoid cocoons against crickets, it provides only partial protection against jumping spiders. Altogether, these results support the bodyguard hypothesis in a multipredator context, since the presence of a living coccinellid significantly reduces cocoon predation by predators having different prey specificities, morphologies, and hunting behaviours. PMID- 23791578 TI - Internal thoracic artery pseudoaneurysm after coronary artery bypass. PMID- 23791579 TI - Multiple valvular regurgitation associated with bromocriptine therapy. PMID- 23791580 TI - Aortic root abscess configuration identified by 3-dimensional echocardiography. PMID- 23791581 TI - Control of iatrogenic coronary dissection with optical coherence tomography. PMID- 23791582 TI - "Squatting". PMID- 23791583 TI - Cryptogenic stroke with right-to-left shunt and no patent foramen ovale. PMID- 23791584 TI - Multimodality imaging in the diagnosis of caseous calcification of mitral annulus. PMID- 23791585 TI - First-degree atrioventricular block and pseudopacemaker syndrome. PMID- 23791586 TI - Giant thrombosed aneurysm of the right coronary artery. PMID- 23791587 TI - Dynamic left main coronary artery compression by a ventricular pseudoaneurysm in a child. PMID- 23791588 TI - Diagnosis of cor triatriatum dextrum using transoesophageal echocardiography with a bubble study. PMID- 23791589 TI - Thrombosis of external iliac artery due to endofibrosis. PMID- 23791590 TI - Venous stenting as a treatment for pacemaker-induced superior vena cava syndrome. PMID- 23791591 TI - An uncommon cause of malignant hypertension. PMID- 23791592 TI - Pacemaker lead malposition: When right is not right! PMID- 23791593 TI - Inferior vena cava into the left atrium. PMID- 23791594 TI - Early mitral valve surgery two days after an ischaemic embolic stroke. PMID- 23791595 TI - Abnormal atrial rhythm in a heterotaxy syndrome. PMID- 23791596 TI - Mitral paravalvular leak detected by three-dimensional transoesophageal echocardiography. PMID- 23791598 TI - Endovascular treatment of peripheral aneurysms in Kawasaki disease. PMID- 23791597 TI - Usefulness of cardiac magnetic resonance imaging in the diagnosis of cardiac myocarditis revealed by complete atrioventricular block. PMID- 23791599 TI - Voluminous pseudotumoral lipomatous hypertrophy of the interatrial septum. PMID- 23791600 TI - Spontaneous dissecting coronary haematoma with and without intimal tear. PMID- 23791601 TI - Visualization of a giant left atrial myxoma by right ventriculography: ball in the heart. PMID- 23791602 TI - Myocardial abscess, a rare form of cardiac aspergillosis. PMID- 23791603 TI - Conversion of Brugada type I to type III and successful control of recurrent ventricular arrhythmia with cilostazol. PMID- 23791604 TI - Very late active stent thrombosis: contribution of optical coherence tomography. PMID- 23791605 TI - Unusual presentation of posterior papillary muscle rupture. PMID- 23791606 TI - Heightened motor and sensory (mirror-touch) referral induced by nerve block or topical anesthetic. AB - Mirror neurons allow us to covertly simulate the sensation and movement of others. If mirror neurons are sensory and motor neurons, why do we not actually feel this simulation- like "mirror-touch synesthetes"? Might afferent sensation normally inhibit mirror representations from reaching consciousness? We and others have reported heightened sensory referral to phantom limbs and temporarily anesthetized arms. These patients, however, had experienced illness or injury of the deafferented limb. In the current study we observe heightened sensory and motor referral to the face after unilateral nerve block for routine dental procedures. We also obtain double-blind, quantitative evidence of heightened sensory referral in healthy participants completing a mirror-touch confusion task after topical anesthetic cream is applied. We suggest that sensory and motor feedback exist in dynamic equilibrium with mirror representations; as feedback is reduced, the brain draws more upon visual information to determine- perhaps in a Bayesian manner- what to feel. PMID- 23791607 TI - Phytoplankton-zooplankton dynamics in periodic environments taking into account eutrophication. AB - In this paper, we derive and analyze a mathematical model for the interactions between phytoplankton and zooplankton in a periodic environment, in which the growth rate and the intrinsic carrying-capacity of phytoplankton are changing with respect to time and nutrient concentration. A threshold value: "Predator's average growth rate" is introduced and it is proved that the phytoplankton zooplankton ecosystem is permanent (both populations survive cronically) and possesses a periodic solution if and only if the value is positive. We use TP (Total Phosphorus) concentration to mark the degree of eutrophication. Based on experimental data, we fit the growth rate function and the environmental carrying capacity function with temperature and nutrient concentration as independent variables. Using measured data of temperature on water bodies we fit a periodic temperature function of time, and this leads the growth rate and intrinsic carrying-capacity of phytoplankton to be periodic functions of time. Thus we establish a periodic system with TP concentration as parameter. The simulation results reveal a high diversity of population levels of the ecosystem that are mainly sensitive to TP concentration and the death-rate of zooplankton. It illustrates that the eruption of algal bloom is mainly resulted from the increasing of nutrient concentration while zooplankton only plays a role to alleviate the scale of algal bloom, which might be used to explain the mechanism of algal bloom occurrence in many natural waters. What is more, our results provide a better understanding of the traditional manipulation method. PMID- 23791608 TI - Selenium supplementation for sepsis: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Recently, several studies were conducted to investigate the effect of selenium supplementation in septic patients. However, no consistent conclusion was made. Thus, we aimed to systematically summarize the available randomized controlled trials (RCTs) to evaluate the effect of selenium supplementation on important clinical outcomes in septic patients. METHODS: A systematic literature search of Pubmed, Embase, and the Cochrane Central Register of Controlled Trials was conducted (up to August 25, 2012). RCTs were included if they reported the effect of selenium supplementation on the treatment of septic patients. A fixed effect model was used, and in the case of significant heterogeneity, a random effects model was employed. RESULTS: Five studies with a total of 530 patients were included. Pooled analysis showed that selenium supplementation did not reduce all-cause mortality (relative risk [RR] = 0.89, 95% confidence interval [CI]: 0.73-1.07, P = .21), hospital-acquired pneumonia (RR = 1.15, 95% CI: 0.73 1.82, P = .55), or length of intensive care unit stay (weighted mean differences = 2.32 days, 95% CI: -0.05 to 4.69; P = .05). In addition, no significant difference was observed regarding adverse events between groups (RR = 0.97, 95% CI: 0.72-1.33, P = .87). CONCLUSIONS: The present meta-analysis showed no benefit of selenium supplementation in patients with sepsis. Due to the limited number of RCTs included, more prospective multicenter clinical trials on selenium therapy in septic patients are warranted in the future. PMID- 23791609 TI - Hispidulin attenuates bone resorption and osteoclastogenesis via the RANKL induced NF-kappaB and NFATc1 pathways. AB - Hispidulin, a flavonoid that is known to have anti-inflammatory and anti-oxidant effects, attenuates osteoclastogenesis and bone resorption. To investigate the molecular mechanism of its inhibitory effect on osteoclastogenesis, we employed the receptor activator of the nuclear factor kappaB (NF-kappaB) ligand (RANKL) induced murine monocyte/macrophage RAW 264.7 cells and bone marrow-derived macrophages (BMMs) for osteoclastic differentiation in vitro. The inhibitory effect on in vitro osteoclastogenesis was evaluated by counting the number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells and by measuring the expression levels of osteoclast-specific genes such as matrix metalloproteinase 9 (MMP9), TRAP and cathepsin K. Similarly, hispidulin significantly inhibited osteoclast activity in RAW 264.7 cell as well as stimulated the ALP activity of MC3T3E1 cells. Furthermore, the in vivo suppressive effect on bone loss was assessed quantitatively in a lipopolysaccharide (LPS)-induced mouse model using microcomputational tomography (MUCT) and histochemical analyses. Hispidulin was found to inhibit RANKL-induced activation of Jun N-terminal kinase (JNK) and p38, in addition to NF-kappaB in vitro experiment. Additionally, hispidulin decreased NFATc1 transcriptional activity in RANKL-induced osteoclastogenesis. This study identifies hispidulin as a potent inhibitor of osteoclastogenesis and bone resorption and provides evidence for its therapeutic potential to treat diseases involving abnormal bone lysis. PMID- 23791610 TI - Oxymatrine attenuates hepatic steatosis in non-alcoholic fatty liver disease rats fed with high fructose diet through inhibition of sterol regulatory element binding transcription factor 1 (Srebf1) and activation of peroxisome proliferator activated receptor alpha (Pparalpha). AB - The aim of this study was to examine the therapeutic effect of oxymatrine, a monomer isolated from the medicinal plant Sophora flavescens Ait, on the hepatic lipid metabolism in non-alcoholic fatty liver (NAFLD) rats and to explore the potential mechanism. Rats were fed with high fructose diet for 8 weeks to establish the NAFLD model, then were given oxymatrine treatment (40, 80, and 160 mg/kg, respectively) for another 8 weeks. Body weight gain, liver index, serum and liver lipids, and histopathological evaluation were measured. Enzymatic activity and gene expression of the key enzymes involved in the lipogenesis and fatty acid oxidation were assayed. The results showed that oxymatrine treatment reduced body weight gain, liver weight, liver index, dyslipidemia, and liver triglyceride level in a dose dependant manner. Importantly, the histopathological examination of liver confirmed that oxymatrine could decrease the liver lipid accumulation. The treatment also decreased the fatty acid synthase (FAS) enzymatic activity and increased the carnitine palmitoyltransferase 1A (CPT1A) enzymatic activity. Besides, oxymatrine treatment decreased the mRNA expression of sterol regulatory element binding transcription factor 1(Srebf1), fatty acid synthase (Fasn), and acetyl CoA carboxylase (Acc), and increased the mRNA expression of peroxisome proliferator activated receptor alpha (Pparalpha), carnitine palmitoyltransferase 1A (Cpt1a), and acyl CoA oxidase (Acox1) in high fructose diet induced NAFLD rats. These results suggested that the therapeutic effect of oxymatrine on the hepatic steatosis in high fructose diet induced fatty liver rats is partly due to down-regulating Srebf1 and up-regulating Pparalpha mediated metabolic pathways simultaneously. PMID- 23791611 TI - The changes induced by cyclophosphamide in intestinal barrier and microflora in mice. AB - Infection is one of the most commonly encountered complication during chemotherapy treatment, and recent studies showed that such infections are aroused primarily from the intestinal microflora through bacterial translocation. We aimed to investigate the alterations of mucosal barrier and colonization resistance in mouse treated with cyclophosphamide (CTX) to further understand the translocation mechanism. Male Balb/c mice were administered intraperitoneally with CTX at 25 mg/kg, 50 mg/kg and 100 mg/kg for 5 days. We found that pretreatment with CTX, especially at high dose, increased the potentially pathogenic bacteria counts (Escherichia coli, enterobacteraceae, Pseudomonas and enterococci) and the intestinal permeability, which was associated with the reduction of tight junctions and adherens junctions. Our results suggested that disruption of mucosal barrier and colonization resistance may be partly responsible for the bacterial translocation during chemotherapy. Thus, modulation of mechanical mucosal barrier and colonization resistance might represent a new opportunity for applications in cancer patients to reduce infectious complications. PMID- 23791612 TI - Wedelolactone exhibits anti-fibrotic effects on human hepatic stellate cell line LX-2. AB - Wedelolactone is a major coumarin of Eclipta prostrata, which is used for preventing liver damage. However the effects of wedelolactone on hepatic fibrosis remained unexplored. The purpose of this study was to demonstrate the anti fibrotic effects of wedelolactone on activated human hepatic stellate cell (HSC) line LX-2 and the possible underlying mechanisms by means of MTT assay, Hoechst staining, as well as real-time quantitative PCR and western blot. The results showed that wedelolactone reduced the cellular viability of LX-2 in a time and dose-dependent manner. After treatment of wedelolactone, the expressions of collagen I and alpha-smooth muscle actin, two biomarkers of LX-2 activation, were remarkably decreased. The apoptosis of LX-2 cells was induced by wedelolactone accompanied with the decreasing expression of anti-apoptotic Bcl-2 and increasing expression of pro-apoptotic Bax. In addition, phosphorylated status of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) was up-regulated, but not in p38. Moreover, wedelolactone significantly repressed the level of phosphorylated inhibitor of nuclear factor kappaB (IkappaB) and p65 in nucleus in spite of tumor necrosis factor-alpha stimulation. In conclusion, wedelolactone could significantly inhibit the activation of LX-2 cells, the underlying mechanisms of which included inducing Bcl-2 family involved apoptosis, up-regulating phosphorylated status of ERK and JNK expressions, and inhibiting nuclear factor-kappaB (NF-kappaB) mediated activity. Wedelolactone might present as a useful tool for the prevention and treatment of hepatic fibrosis. PMID- 23791613 TI - PPAR-gamma activation by rosiglitazone suppresses angiotensin II-mediated proliferation and phenotypictransition in cardiac fibroblasts via inhibition of activation of activator protein 1. AB - Cardiac fibroblasts play an important role in myocardial remodeling by proliferating, differentiating, and secreting extracellular matrix proteins. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands have been reported to have a number of cardioprotective properties. However, the mechanism underlying this protective effect has not yet been elucidated. The purpose of the present study was to investigate the effect of rosiglitazone on angiotensin II induced cardiac fibroblast proliferation and differentiation. Cardiac fibroblasts were stimulated with angiotensin II (10(-7)M) in the presence or absence of rosiglitazone (10(-5)nM). Pretreatment of cardiac fibroblasts with rosiglitazone significantly inhibited angiotensin II-induced cardiac fibroblast proliferation and profibrotic phenotypes differentiation and, thus, reduced the overall production of collagen components. PPAR-gamma antagonist GW9662 significantly inhibited these effects of rosiglitazone, suggesting that these effects of rosiglitazone were PPAR-gamma-dependent. To investigate the mechanisms involved, we found that PPAR-gamma activation by rosiglitazone inhibited the formation of c fos/c-jun heterodimers and expression of activator protein 1 induced by ANG II and thus inhibited transcription of the downstream genes involved in CFs proliferation and differentiation. Our data suggests PPAR-gamma activation could have an anti-fibrotic effect through limiting cardiac fibroblast proliferation and differentiation, which are the critical steps in the pathogenesis of cardiac fibrosis. PMID- 23791614 TI - Neuroprotective effect of hydroxysafflor yellow A on 6-hydroxydopamine-induced Parkinson's disease in rats. AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting predominantly the dopaminergic mesotelencephalic system. Enormous progress has been made in the treatment of PD. Our previous study has shown that hydroxysafflor yellow A (HSYA) could attenuate the neurotoxicity induced by 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice. In the present work, we examined whether HSYA had the neuroprotective effect on dopaminergic neurons of substantia nigra in a rat model of PD. Adult Sprague-Dawley rats were unilaterally injected with 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. The PD rats were treated with HSYA (2 or 8 mg/kg) via caudal vein injection daily for 4 weeks. Rotational tests showed that HSYA significantly attenuated apomorphine-induced turns in 6-OHDA-induced PD rats. HSYA treatment resulted in a significant protection against the loss of tyrosine hydroxylase positive cells. Our data showed that HSYA also increased the levels of dopamine and its metabolites, glial cell line-derived neurotrophic factor and brain derived neurotrophic factor in striatum of PD rats. In conclusion, these results supported a role for HSYA in preserving dopamine neuron integrity and motor function in a rodent model of PD, and implied a potential neuroprotective role for HSYA in this disease. PMID- 23791615 TI - Abnormal gray and white matter volume in delusional infestation. AB - Little is known about the neural basis of delusional infestation (DI), the delusional belief to be infested with pathogens. Case series and the response to anti-dopaminergic medication indicate disruptions in dopaminergic neurotransmission in the striatum (caudate, putamen), but did not allow for population-based inference. Here, we report the first whole-brain structural neuroimaging study to investigate gray and white matter abnormalities in DI compared to controls. In this study, we used structural magnetic resonance imaging and voxel-based morphometry to investigate gray and white matter volume in 16 DI patients and 16 matched healthy controls. Lower gray matter volume in DI patients compared to controls was found in left medial, lateral and right superior frontal cortices, left anterior cingulate cortex, bilateral insula, left thalamus, right striatal areas and in lateral and medial temporal cortical regions (p<0.05, cluster-corrected). Higher white matter volume in DI patients compared to controls was found in right middle cingulate, left frontal opercular and bilateral striatal regions (p<0.05, cluster-corrected). This study shows that structural changes in prefrontal, temporal, insular, cingulate and striatal brain regions are associated with DI, supporting a neurobiological model of disrupted prefrontal control over somato-sensory representations. PMID- 23791616 TI - Cannabidiol attenuates catalepsy induced by distinct pharmacological mechanisms via 5-HT1A receptor activation in mice. AB - Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa plant that produces antipsychotic effects in rodents and humans. It also reverses L dopa-induced psychotic symptoms and improves motor function in Parkinson's patients. This latter effect raised the possibility that CBD could have beneficial effects on motor related striatal disorders. To investigate this possibility we evaluated if CBD would prevent catalepsy induced by drugs with distinct pharmacological mechanisms. The catalepsy test is largely used to investigate impairments of motor function caused by interference on striatal function. Male Swiss mice received acute pretreatment with CBD (5, 15, 30 or 60mg/kg, ip) 30min prior to the D2 receptor antagonist haloperidol (0.6mg/kg), the non-selective nitric oxide synthase (NOS) inhibitor L-nitro-N-arginine (L NOARG, 80mg/kg) or the CB1 receptor agonist WIN55,212-2 (5mg/kg). The mice were tested 1, 2 or 4h after haloperidol, L-NOARG or WIN55,212-2 injection. These drugs significantly increased catalepsy time and this effect was attenuated dose dependently by CBD. CBD, by itself, did not induce catalepsy. In a second set of experiments the mechanism of CBD effects was investigated. Thirty minutes before CBD (30mg/kg) the animals received the 5-HT1A receptor antagonist WAY100635 (0.1mg/kg). The anticataleptic effect of CBD was prevented by WAY100635. These findings indicate that CBD can attenuate catalepsy caused by different mechanisms (D2 blockade, NOS inhibition and CB1 agonism) via 5-HT1A receptor activation, suggesting that it could be useful in the treatment of striatal disorders. PMID- 23791617 TI - Influence of lifelong dietary fats on the brain fatty acids and amphetamine induced behavioral responses in adult rat. AB - The influence of dietary fatty acids (FA) on mania-like behavior and brain oxidative damage were evaluated in rats. First generation of rats born and maintained under supplementation with soybean-oil (SO), fish-oil (FO) or hydrogenated-vegetable-fat (HVF), which are rich in n-6, n-3 and trans (TFA) FA, respectively, until adulthood, were exposed to an amphetamine (AMPH)-induced mania animal model to behavioral and biochemical evaluations. While AMPH caused hyperlocomotion in HVF and, to a less extent, in SO- and FO-groups, a better memory performance was observed in FO group. Among vehicle-groups, HVF increased reactive species (RS) generation and protein-carbonyl (PC) levels in cortex; FO reduced RS generation in hippocampus and decreased PC levels in hippocampus and striatum. Among AMPH-treated animals, HVF exacerbated RS generation in all evaluated brain areas and increased PC levels in cortex and striatum; FO reduced RS generation in hippocampus and decreased PC levels in hippocampus and striatum. FO was related to higher percentage of polyunsaturated fatty acids (PUFA) and docosahexaenoic acid (DHA) in cortex and striatum, while HVF was associated to higher incorporation of TFA in cortex, hippocampus and striatum, besides increased n-6/n-3 FA ratio in striatum. While a continuous exposure to TFA may intensify oxidative events in brain, a prolonged FO consumption may prevent mania like-behavior; enhance memory besides decreasing brain oxidative markers. A substantial inclusion of processed foods, instead of foods rich in omega-3, in the long term is able to influence the functionality of brain structures related to behavioral disturbances and weaker neuroprotection, whose impact should be considered by food safety authorities and psychiatry experts. PMID- 23791618 TI - The radiosensitizing effect of CpG ODN107 on human glioma cells is tightly related to its antiangiogenic activity via suppression of HIF-1alpha/VEGF pathway. AB - Malignant glioma displays invasive growth and is difficult to be completely excised; surgery combined with subsequent radiotherapy is a standard treatment for patients. CpG oligodeoxynucleotides (CpG ODN) can enhance radiotherapeutic effect in some tumors. Angiogenesis is crucial for tumor progression and metastasis. Anti-angiogenic strategy thus may be effective for tumor treatment. Herein, the antiangiogenic activity and radiosensitizing effect of CpG ODN107 on glioma were investigated. Our results showed that the growth of glioma cell line U87 was significantly inhibited by CpG ODN107 (10MUg/ml) in combination with irradiation (5Gy) in vitro. In orthotopic implantation model of nude mice, the survival rate of mice significantly increased after treatment with CpG ODN107 (0.083mg/kg) in combination with radiotherapy (10Gy) as compared with treatment with local radiotherapy alone. CpG ODN107 in combination with radiotherapy significantly decreased microvessel density (MVD), VEGF level and HIF-1alpha expression in orthotopic implantation glioma. In conclusion, CpG ODN107 significantly increased the radiosensitivity of U87 human glioma cells in vitro and in vivo. The radiosensitizing effect of CpG ODN 107 is tightly related to its anti-angiogenic activity via suppression of HIF-1alpha/VEGF pathway. PMID- 23791619 TI - Humoral immunity and delayed-type hypersensitivity in healthy subjects treated for 30 days with MK-7123, a selective CXCR2 antagonist. AB - Antagonism of the chemokine receptor CXCR2 inhibits neutrophil trafficking and may thus be therapeutic in patients with chronic obstructive pulmonary disease and other lung disorders in which there is substantial infiltration by neutrophils. Here, we report the findings from a randomized, placebo-controlled, double-blind clinical trial of the small-molecule CXCR2 antagonist MK-7123 (formerly SCH 527123) that evaluated potential downstream effects of CXCR2 antagonism on immunogenic competency (B cell antibody response) in the adaptive immune system and delayed-type hypersensitivity (DTH) in healthy subjects (ages 34-65 years) dosed once daily for 30 days either with 30 mg MK-7123 (n=24) or placebo (n=7). Eligible subjects were seronegative for anti-hepatitis A virus (HAV) immunoglobulin G (IgG) and positive for DTH response to intradermal injection of Candida albicans antigen at screening. Subjects were vaccinated for HAV on treatment Day 2. The primary endpoints were anti-HAV IgG titer on Day 30 and DTH response magnitude on Day 27. Pharmacokinetic and safety endpoints were also assessed. We observed that anti-HAV IgG titers and DTH responses did not differ significantly between MK-7123-treated and placebo-treated subjects. Twenty eight days postvaccination, seroconversion (anti-HAV IgG titer>=10mIU/mL) was observed in 87.5% and 85.7% of MK-7123-treated and placebo-treated subjects, respectively; mean (+/-SE) titers were 27.3+/-5.5 and 21.4+/-4.3mIU/mL, respectively. Treatment with MK-7123 was generally well tolerated. Doses were followed by temporary reductions in absolute peripheral blood neutrophil count. In conclusion, this study found that B cell response and cell-mediated immunity were not altered by CXCR2 antagonism with MK-7123. PMID- 23791620 TI - Identification of a methicillin-resistant Staphylococcus aureus inhibitory compound isolated from Serratia marcescens. AB - In this study, we identified an antimicrobial compound produced by the Gram negative bacterium Serratia marcescens. Colonies of S. marcescens inhibited the growth of nine different methicillin-resistant Staphylococcus aureus (MRSA) isolates and several other tested Gram-positive bacterial species, but not Gram negative bacteria. Genetic analysis revealed the requirement for the swrW gene which codes for a non-ribosomal peptide synthetase that generates the cyclodepsipeptide antibiotic serratamolide, also known as serrawettin W1. This is the first report describing the anti-MRSA properties of serratamolide. PMID- 23791621 TI - Bacterial determinants of the social behavior of Bacillus subtilis. AB - Bacteria utilize sophisticated cellular machinery to sense environmental changes and coordinate the most appropriate response. Fine sensors located on cell surfaces recognize a myriad of triggers and initiate genetic cascades leading to activation or repression of certain groups of genes. Structural elements such as pilli, exopolysaccharides and flagella are also exposed at the cell surface and contribute to modulating the intimate interaction with surfaces and host cells. This review will cover the latest advances in our understanding of the biology and functionality of these bacterial determinants within the context of biofilm formation of Bacillus subtilis. PMID- 23791622 TI - Similar overall survival using sibling, unrelated donor, and cord blood grafts after reduced-intensity conditioning for older patients with acute myelogenous leukemia. AB - For older patients with acute myeloid leukemia (AML), allogeneic hematopoietic cell transplantation (HCT) provides the best chance of long-term survival. A formal comparison between matched sibling (SIB), unrelated donor (URD), or umbilical cord blood (UCB) transplantation has not yet been reported in this setting. We compared reduced-intensity conditioning HCT in 197 consecutive patients 50 years and older with AML in complete remission from SIB (n = 82), URD (n = 35), or UCB (n = 80) transplantation. The 3-year cumulative incidences of transplantation-related mortality were 18%, 14%, and 24% with SIB, URD, and UCB transplantation, respectively (P = .22). The 3-year leukemia-free survival rates were 48%, 57%, and 33% with SIB, URD, and UCB transplantation, respectively (P = .009). In multivariate analysis, poor-risk cytogenetics was associated with relapse (hazard ratio, 1.7 [95% confidence interval, 1.0 to 3.0]; P = .04) and worse leukemia-free survival (hazard ratio, 1.6 [95% confidence interval, 1.0 to 2.5]; P = .03), whereas donor choice had no significant impact on overall survival (P = .73). Adjusted 3-year overall survival rates were 55% with SIB, 45% with URD, and 43% with UCB transplantation (P = .26). Until prospective studies are completed, this study supports the recommendation to consider SIB donor, URD, or UCB for HCT for older patients with AML in complete remission. PMID- 23791623 TI - Can we predict hemorrhagic cystitis based on BK viremia? PMID- 23791624 TI - A novel soluble form of Tim-3 associated with severe graft-versus-host disease. AB - The T cell Ig and mucin domain 3 (Tim-3) receptor has been implicated as a negative regulator of adaptive immune responses. We have utilized a proteomic strategy to identify novel proteins associated with graft versus host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). Mass spectrometry analysis of plasma from subjects with mid-gut and upper-gut GVHD compared with those without GVHD identified increased levels of a protein identified with high confidence as Tim-3. A follow-up validation study using an immunoassay to measure Tim-3 levels in individual plasma samples from 127 patients demonstrated significantly higher plasma Tim-3 concentrations in patients with the more severe mid-gut GVHD, compared with those with upper-gut GVHD (P = .005), patients without GVHD (P = .002), and normal controls (P < .0001). Surface expression of Tim-3 was increased on CD8(+) T cells from patients with grade 2 to 4 acute GVHD (P = .01). Mass spectrometry-based profiling of plasma from multiple subjects diagnosed with common diseases provided evidence for restricted release of soluble Tim-3 in the context of GVHD. These findings have mechanistic implications for the development of novel strategies for targeting the Tim-3 immune regulatory pathway as an approach to improving control of GVHD. PMID- 23791625 TI - Human metapneumovirus infection: worthy of recognition. PMID- 23791626 TI - Outcomes in patients age 70 or older undergoing allogeneic hematopoietic stem cell transplantation for hematologic malignancies. AB - Allogeneic hematopoietic stem cell transplantation (HSCT) can achieve durable remissions in a number of patients with advanced hematologic malignancies. Little is known about the safety of HSCT in patients age 70 or older. Consecutive patients (n = 54) age 70 or older underwent HSCT between 2007 and 2012. Diseases included acute myelogenous leukemia (n = 25), myelodysplastic syndrome (n = 12), chronic lymphocytic leukemia (n = 5), non-Hodgkin lymphoma (n = 4), acute lymphoblastic leukemia (n = 3), myeloproliferative neoplasm (n = 4), and chronic myelogenous leukemia (n = 1). Median follow-up for survivors was 21 months. All patients received reduced-intensity conditioning regimens, primarily busulfan/fludarabine. All patients received unmanipulated peripheral blood stem cell grafts: 44 from 8/8 matched unrelated donors, 8 from matched related donors, and 2 from 7/8 matched unrelated donors. Graft-versus-host disease (GVHD) prophylaxis was calcineurin inhibitor-based in all patients. The median age at transplantation was 71 years (range, 70 to 76); the median HCT comorbidity index score was 1 (range, 0 to 5). Two patients died before hematopoietic recovery (1 with graft failure and 1 with disease progression), and 1 patient relapsed before hematopoietic recovery; otherwise, all engrafted with median donor chimerism of 94% at 1 month. Cumulative incidence of grades II to IV acute GVHD was 13% and of grades III to IV acute GVHD, 9.3%. At 2 years, the cumulative incidence of chronic GVHD was 36%, progression-free survival was 39%, overall survival was 39%, and relapse was 56%. Nonrelapse mortality was 3.7% at day +100 and 5.6% at 2 years. We conclude that allogeneic HSCT is a safe and effective option for carefully selected patients age 70 or older. PMID- 23791627 TI - 195th ENMC International Workshop: Newborn screening for Duchenne muscular dystrophy 14-16th December, 2012, Naarden, The Netherlands. PMID- 23791628 TI - The contribution of two disulfide bonds in the trypsin binding domain of horsegram (Dolichos biflorus) Bowman-Birk inhibitor to thermal stability and functionality. AB - The major Bowman-Birk inhibitor (BBIs) of horsegram (Dolichos biflorus) HGI-III, contains seven interweaving disulfides and is extremely stable to high temperatures. The contributions of two disulfide bonds in the trypsin domain to thermal stability and functionality were evaluated using disulfide deletion variants of wild type protein. Thermal denaturation kinetics, differential scanning calorimetry and urea denaturation studies indicate that the absence of either of the two disulfides destabilizes the protein significantly. C20-C66 contributes substantially to both thermal stability and controls trypsin and chymotrypsin inhibitor activity. These two disulfides act in synergy as deletion of both disulfides leads to a complete loss of thermal stability. The data indicate that the two subdomains are not entirely independent of each other. Long range interactions, between the domains are facilitated by C20-C66. The deletion of the disulfide bonds also increased proteolytic susceptibility in a manner similar to the decreased thermal stability. From this study of rHGI a prototype of legume BBIs in can be concluded that among the array of seven evolutionarily conserved disulfide bonds, the disulfide C20-C66 that connects a residue in the trypsin domain with a residue at the border of the same domain plays a dominant role in maintaining functional and structural stability. PMID- 23791630 TI - Sexual experience blocks the ability of clitoral stimulation to induce a conditioned place preference in the rat. AB - We have previously established the rewarding value of clitoral stimulation (CLS) through the demonstration that manual, distributed, CLS induces a significant conditioned place preference (CPP) and conditioned partner preference in naive, hormonally primed and non-hormonally primed rats. The present experiment asks whether previous sexual experience might inhibit the ability of clitoral stimulation to induce a conditioned place preference. Female Long-Evans rats were ovariectomized and treated with 10 MUg of estradiol benzoate (EB) 48 h and 500 MUg of progesterone (P) 4h prior to receiving either 0, 1, or 5 consecutive copulatory sessions with a sexually vigorous male. Each copulatory session ended when females received at least 1 ejaculation. Females then experienced 10 alternating trials of distributed CLS or no CLS paired with one side of a non biased CPP box under the same hormone-priming regimen. Females that experienced 5 consecutive copulatory sessions did not develop a significant place preference indicated by both a preference score (the proportion of time spent in the reinforced chamber) and a difference score (time in the non-reinforced chamber minus the time in the reinforced chamber) compared prior to and following the 10 conditioning trials. This suggests that repeated copulatory experience might induce a desensitization of the genitosensory circuit since copulation includes both clitoral, and vaginocervical stimulation from mounts plus intromissions. Alternatively, repeated sexual experience prior to conditioning may generate a UCS pre-exposure effect that cannot be altered when manual clitoral stimulation is paired with a new environment. PMID- 23791629 TI - Comparable mechanisms of working memory interference by auditory and visual motion in youth and aging. AB - Intrasensory interference during visual working memory (WM) maintenance by object stimuli (such as faces and scenes), has been shown to negatively impact WM performance, with greater detrimental impacts of interference observed in aging. Here we assessed age-related impacts by intrasensory WM interference from lower level stimulus features such as visual and auditory motion stimuli. We consistently found that interference in the form of ignored distractions and secondary task interruptions presented during a WM maintenance period, degraded memory accuracy in both the visual and auditory domain. However, in contrast to prior studies assessing WM for visual object stimuli, feature-based interference effects were not observed to be significantly greater in older adults. Analyses of neural oscillations in the alpha frequency band further revealed preserved mechanisms of interference processing in terms of post-stimulus alpha suppression, which was observed maximally for secondary task interruptions in visual and auditory modalities in both younger and older adults. These results suggest that age-related sensitivity of WM to interference may be limited to complex object stimuli, at least at low WM loads. PMID- 23791631 TI - Prospective study to evaluate the clinical and radiological outcome of patients with scleroderma of the face. AB - INTRODUCTION: Scleroderma featuring rare connective tissue disease that manifests as skin sclerosis and variable systemic involvement. Two categories of scleroderma are known: systemic sclerosis, characterized by cutaneous sclerosis and visceral involvement and localized scleroderma or morphea which classically presents benign evolution and self-limited, confined to the skin and/or underlying tissue. Recent studies show that the localized form may possibly course with involvement of internal organs and variable morbidity. This study aimed to determine the demographic characteristics, the prevalence of systemic manifestations and laboratory findings, as well as the association with autoimmune diseases, and the evolution of neurological findings, both clinical as brain MRI in patients with scleroderma of the face and its relation with the activity skin. METHODS: Patients with localized scleroderma with facial involvement were evaluated and underwent neurological examination, magnetic resonance imaging and ophthalmology evaluation. After 3years, the patients were subjected again to MRI. RESULTS: We studied 12 patients with localized scleroderma of the face. Of this total, headache being the most frequent complaint found in 66.7% of patients, 33.3% had neurological changes possibly associated with scleroderma. As for ophthalmologic evaluation, 25% of patients showed abnormalities. The most frequent parenchymal finding was the presence of lesions with hyperintense or hypointense signal in 75% of patients, followed by ventricular asymmetry at 16.7%. Of the patients who had neurological deficits, 75% also had a change to MRI. In all patients, imaging findings after 3years were unchanged. During this interval of 3years, 25% of patients showed signs of activity of scleroderma. CONCLUSION: Patients with localized scleroderma of the face have a high prevalence of neurological and ophthalmological changes. Based on these findings, we suggest that all cases of localized scleroderma of the face should be thoroughly examined for the presence of systemic changes. PMID- 23791632 TI - Systemic sclerosis at the crossroad of polyautoimmunity. AB - OBJECTIVES: Several epidemiological studies have revealed the co-occurrence of other autoimmune diseases (AIDs) within patients with systemic sclerosis (SSc). However, some of these studies were based on small cohorts and wide ranges of prevalence have been reported. Therefore to overcome these limitations of individual studies, we sought to perform a meta-analysis to determine the accurate prevalence of polyautoimmunity in SSc. METHODS: We performed a systematic review and a meta-analysis of literature in MEDLINE and Embase databases from January 1960 to March 2013. All cohort studies reporting on prevalence of other AIDs known to be associated with SSc were analyzed. Prevalence of polyautoimmunity and of each AID were then calculated. RESULTS: Ten studies reporting polyautoimmunity were identified corresponding to a total of 6102 SSc patients. Overall 1432 patients with at least one AID were identified corresponding to a weighted prevalence of polyautoimmunity equal to 25.7% CI 95% [20.1%-31.6%]. Overall 208/5139 SSc-patients had at least two additional AIDs resulting in a weighted prevalence of 3.9% [3.3%-4.4%]. The most prevalent associated AIDs were autoimmune thyroid disease (10.4%) followed by Sjogren's syndrome (7.7%) and dermatopolymyositis/polymyositis (5.6%). CONCLUSION: Our results confirm that SSc polyautoimmunity is a frequent condition in SSc affecting a quarter of SSc-patients. The impact on the phenotype and also on the management and therapy will need to be addressed now in further works. PMID- 23791633 TI - Eating by example. Effects of environmental cues on dietary decisions. AB - OBJECTIVE: The present studies examined the role of environmental cues in steering people's dietary decisions in response to food temptations. Based on the notion that people show a tendency to conform to eating standards derived from the eating behavior of others, it was hypothesized that communication of other people's dietary decisions through environmental cues affect whether and what people eat. METHODS: Conformity to environmental cues about food intake was assessed in a local bakery (Study 1, N=144) and a lab setting (Study 2, N=65). Participants were unobtrusively presented with a bowl of individually wrapped chocolates. The presence of empty wrappers was manipulated, to indicate whether others who had been in the same situation had or had not eaten. Conformity to environmental cues about food choice was assessed in Study 3 (N=90). Participants were required to choose between a healthy and an unhealthy snack. Food wrappers indicated whether previous participants had chosen the healthy or the unhealthy snack. RESULTS: As expected, participants were more likely to take chocolates in the presence of an environmental cue that others did too. Also, participants were more likely to choose a snack that was consistent with the choice of others. CONCLUSIONS: Together, these findings support our main hypothesis that environmental cues steer people's decisions concerning food intake and food choice. Moreover, the results suggest that only small changes in the environment may support healthy eating behavior. PMID- 23791634 TI - Significance of microbial symbiotic coexistence in traditional fermentation. AB - Symbiosis has long been a central theme in microbiology. There have been many studies on the symbioses between microorganisms and higher organisms such as plants and animals. There also have been some studies on the symbiosis or coexistence of microorganisms, such as yeasts, lactic acid bacteria (LAB), acetic acid bacteria (AAB) and koji molds, in traditional fermentation (brewing). These microorganisms are considered to interact and cooperate with each other in various natural environments, such as dropped cereal crops or ripe fruits. Human beings have taken advantage of these microbial interactions for producing various fermented foods. PMID- 23791635 TI - Diadenosine polyphosphates release by human corneal epithelium. AB - Diadenosine polyphosphates are a type of dinucleotides that have been detected in rabbit and human tears. However, their origin and their mechanism of release have not been fully elucidated. In this work we investigated whether the dinucleotides Ap4A and Ap5A can be released from human corneal epithelia as a consequence of shear stress stimuli. In in vitro experiments, concentrations of Ap4A and Ap5A before mechanical stimulus of stratified human corneal epithelial cells were 3.18 +/- 0.43 nM and 0.81 +/- 0.13 nM, respectively. After shear stimulation, concentrations significantly increased to 12.01 +/- 2.19 nM for Ap4A and 2.83 +/- 0.41 nM for Ap5A. No significant differences in lactate dehydrogenase activity were detected between non-stimulated stratified human corneal epithelial cells and cells exposed to mechanical shear-stress, indicating that the rise of dinucleotide levels was not due to cell lysis. In in vivo experiments, individuals subjected to a rise in blinking frequency showed a significant increase of Ap4A (~25-fold when experiment was performed without anaesthetic and 75-fold with anaesthetic) and Ap5A concentration in tears (~50-fold when experiment was performed without anaesthetic and 125-fold with anaesthetic). Shear-stress stimuli induces Ap4A and Ap5A release from human corneal epithelium, thus explaining the origin of these relevant compounds for the ocular surface biochemistry and physiology. PMID- 23791637 TI - Regional variation in human retinal vessel oxygen saturation. AB - The purpose of this study was to investigate regional differences in oxygen saturation of blood in first degree retinal vessels using a novel non-flash hyperspectral retinal camera (Photon etc Inc). Nine healthy individuals (mean age 24.4 +/- 3.6 yrs, 5 males) were imaged at 548, 569, 586, 600, 605 and 610 nm wavelengths. Optical density values were extracted with the aid of Image-J software for blood oxygen saturation (SO2) determination. Arteriolar and venular SO2 were measured at three locations (ranging 1-3 optic nerve head radii) from the disc margin along the vessels in the superior and inferior temporal quadrants. Retinal SO2 was significantly higher in the superior temporal arteriole and venule as compared to the inferior temporal vessels (p = 0.033 and p = 0.032 for arterioles and venules, respectively). SO2 was not significantly different between the three measurement sites for any of the given vessels imaged (p > 0.05). In conclusion, greater SO2 values were found in the superior temporal first degree retinal arterioles and venules in young healthy individuals than in the equivalent inferior vessels. However, there were no detectable differences in retinal SO2 along each of the major vessels, a finding that is consistent with the concept of these vessels not contributing primarily to gas exchange. Moreover, the SO2 was consistently higher in the arterioles than in the equivalent venules (p < 0.0001). PMID- 23791636 TI - Specific roles for Group V secretory PLA2 in retinal iron-induced oxidative stress. Implications for age-related macular degeneration. AB - Iron accumulation and oxidative stress are hallmarks of retinas from patients with age-related macular degeneration (AMD). We have previously demonstrated that iron-overloaded retinas are a good in vitro model for the study of retinal degeneration during iron-induced oxidative stress. In this model we have previously characterized the role of cytosolic phospholipase A2 (cPLA2) and calcium-independent isoform (iPLA2). The aim of the present study was to analyze the implications of Group V secretory PLA2 (sPLA2), another member of PLA2 family, in cyclooxygenase (COX)-2 and nuclear factor kappa B (NF-kappaB) regulation. We found that sPLA2 is localized in cytosolic fraction in an iron concentration-dependent manner. By immunoprecipitation (IP) assays we also demonstrated an increased association between Group V sPLA2 and COX-2 in retinas exposed to iron overload. However, COX-2 activity in IP assays was observed to decrease in spite of the increased protein levels observed. p65 (RelA) NF-kappaB levels were increased in nuclear fractions from retinas exposed to iron. In the presence of ATK (cPLA2 inhibitor) and YM 26734 (sPLA2 inhibitor), the nuclear localization of both p65 and p50 NF-kappaB subunits was restored to control levels in retinas exposed to iron-induced oxidative stress. Membrane repair mechanisms were also analyzed by studying the participation of acyltransferases in phospholipid remodeling during retinal oxidation stress. Acidic phospholipids, such as phosphatidylinositol (PI) and phosphatidylserine (PS), were observed to show an inhibited acylation profile in retinas exposed to iron while phosphatidylethanolamine (PE) showed the opposite. The use of PLA2 inhibitors demonstrated that PS is actively deacylated during iron-induced oxidative stress. Results from the present study suggest that Group V sPLA2 has multiple intracellular targets during iron-induced retinal degeneration and that the specific role of sPLA2 could be related to inflammatory responses by its participation in NF-kappaB and COX-2 regulation. PMID- 23791638 TI - Highly ordered mesoporous carbon nanomatrix as a new approach to improve the oral absorption of the water-insoluble drug, simvastatin. AB - Three different kinds of highly ordered mesoporous carbon (HMC) matrices with different morphologies (hexagonal, spherical and fibrous), particle sizes (700 nm, 400-900 nm and 1-4 MUm) and pore diameters were compared as drug carriers for a model drug, simvastatin (SIM). The physicochemical properties of the SIM-loaded composites were studied using field emission scanning electron microscopy (FESEM), specific surface area analysis, differential scanning calorimetry (DSC), wide-angle X-ray scattering (WAXS), HPLC, solubility measurement and dissolution testing. Furthermore, the oral bioavailability of SIM-loaded SHMC (spherical HMC nanomatrix) in beagle dogs was compared with that of the reference formulation (Zocor(r)). The results obtained showed that SIM molecules are encapsulated in a noncrystalline state due to geometric confinement in the nanopores of HMC. In vitro dissolution testing showed that the dissolution rate of SIM released from monodispersed SHMC was significantly faster compared with that of crystalline SIM and other SIM-loaded composites. In addition, in vivo bioavailability study demonstrated that the relative bioavailability of SIM and SIM beta-hydroxy acid (an active metabolite of SIM) for SIM-loaded SHMC formulation was 138.42% and 163.55%, respectively. In conclusion, monodispersed SHMC appear to be a more promising candidate as a new oral drug delivery vehicle providing a rapid drug release and enhanced oral bioavailability. PMID- 23791639 TI - Kinetic and thermodynamic studies of 9-aminocamptothecin hydrolysis at physiological pH in the presence of human serum albumin. AB - As a first step towards improving the aqueous stability of 9-aminocamptothecin (9AC), a detailed kinetic and thermodynamic investigation of the hydrolysis reaction of 9AC was carried out, using a first derivative absorption spectrophotometry technique. It was found that 9AC-lactone decayed with a half life of 25 min in PBS at pH 7.4 and 310.15K. The activation energy (Ea) associated with the hydrolysis of 9AC-lactone was 87.3 +/- 3.8 kJmol(-1), whereas the positive enthalpy and entropy values of the 9AC-lactone hydrolysis reaction indicated that the reaction is endothermic and entropically driven. Similarly to other camptothecin analogs, except for SN38, the activation energy for 9AC lactone hydrolysis in the presence of Human Serum Albumin (HSA) was about 10 kJmol(-1) lower than that determined in plain PBS, whereas the equilibrium 9AC lactone concentration was decreased in the presence of HSA as compared to that in plain PBS. The lower Ea for 9AC hydrolysis in presence of HSA fully explained the shift of lactone-carboxylate equilibrium towards the carboxylate form with only 4% of active 9AC-lactone remaining in the presence of HSA under physiological conditions. Finally, affinity studies of several camptothecin analogs with HSA, showed that the association constants of the lactone species with HSA are similar and pointed out that the superior stability of the SN38 over the other two analogs (9AC and 9-nitrocamptothecin) is not due to the higher affinity of lactone toward HSA, but it is rather due to the lower affinity of the SN38 carboxylate toward HSA. PMID- 23791640 TI - Functional characterization of hepatic transporters using intravital microscopy. AB - A better understanding of the role of hepatic transporters in drug elimination is of crucial importance for drug development and therapy. This study examined the usefulness of intravital microscopy to quantitatively evaluate the function of hepatic transporters in the exposed liver of anesthetized rats. In one experiment the function of the organic anion transporting polypeptide (Oatp) in sinusoidal uptake was investigated by administering an Oatp inhibitor, rifampicin, prior to the probe substrate Na-fluorescein. In another experiment, rhodamine 123 was used to quantify the biliary canalicular transporter P-glycoprotein (P-gp, Abcb1a/b) with cyclosporin A as an inhibitor of P-gp activity. Calibrated fluorescence intensity time curves measured in sinusoids and hepatocytes together with cumulative biliary excretion data from control and inhibitor treated animals were analyzed with a three-compartment model. A robust parameter estimation was achieved using nonlinear mixed effects modeling. Rifampicin reduced the hepatic uptake clearance of Na-fluorescein to 25% of the control (p<0.05) without affecting other parameters. In the presence of cyclosporin A, biliary excretion of rhodamine 123 decreased to 7% of the control (p<0.01). The novelty of this approach is that it allows a quantitative evaluation of transporter function in the in vivo rat liver. PMID- 23791641 TI - Amphotericin B-copper(II) complex as a potential agent with higher antifungal activity against Candida albicans. AB - Amphotericin B (AmB) is a polyene antibiotic produced by Streptomyces nodosus used for more than 50 years in the treatment of acute systemic fungal infections. It exhibits a broad spectrum of activity against fungal and protozoan pathogens with relatively rare resistance. The aim of this study was to prepare and evaluate the utility of the AmB-Cu(2+) complex as a potential compound with a high fungicidal activity at lower concentrations, compared with conventional AmB. It was hypothesized that insertion of copper ions into fungal cell membranes, together with the AmB-Cu(2+) complex bypassing the natural homeostatic mechanisms of this element, may contribute to the increased fungicidal activity of AmB. The analysis of results indicates the increased antifungal activity of the AmB-Cu(2+) complex against Candida albicans in comparison with the pure AmB and Fungizone. Additionally, it was stated that the increased antifungal activity of the AmB Cu(2+) complex is not the sum of the toxic effects of AmB and Cu(2+) ions, but is a result of the unique structure of this compound. PMID- 23791642 TI - RORgammat+ innate lymphoid cells acquire a proinflammatory program upon engagement of the activating receptor NKp44. AB - RORgammat+ innate lymphoid cells (ILCs) are crucial players of innate immune responses and represent a major source of interleukin-22 (IL-22), which has an important role in mucosal homeostasis. The signals required by RORgammat+ ILCs to express IL-22 and other cytokines have been elucidated only partially. Here we showed that RORgammat+ ILCs can directly sense the environment by the engagement of the activating receptor NKp44. NKp44 triggering in RORgammat+ ILCs selectively activated a coordinated proinflammatory program, including tumor necrosis factor (TNF), whereas cytokine stimulation preferentially induced IL-22 expression. However, combined engagement of NKp44 and cytokine receptors resulted in a strong synergistic effect. These data support the concept that NKp44+ RORgammat+ ILCs can be activated without cytokines and are able to switch between IL-22 or TNF production, depending on the triggering stimulus. PMID- 23791643 TI - Dendritic cell expression of the signaling molecule TRAF6 is critical for gut microbiota-dependent immune tolerance. AB - The intracellular signaling molecule TRAF6 is critical for Toll-like receptor (TLR)-mediated activation of dendritic cells (DCs). We now report that DC specific deletion of TRAF6 (TRAF6DeltaDC) resulted, unexpectedly, in loss of mucosal tolerance, characterized by spontaneous development of T helper 2 (Th2) cells in the lamina propria and eosinophilic enteritis and fibrosis in the small intestine. Loss of tolerance required the presence of gut commensal microbiota but was independent of DC-expressed MyD88. Further, TRAF6DeltaDC mice exhibited decreased regulatory T (Treg) cell numbers in the small intestine and diminished induction of iTreg cells in response to model antigen. Evidence suggested that this defect was associated with diminished DC expression of interleukin-2 (IL-2). Finally, we demonstrate that aberrant Th2 cell-associated responses in TRAF6DeltaDC mice could be mitigated via restoration of Treg cell activity. Collectively, our findings reveal a role for TRAF6 in directing DC maintenance of intestinal immune tolerance through balanced induction of Treg versus Th2 cell immunity. PMID- 23791644 TI - Global chromatin state analysis reveals lineage-specific enhancers during the initiation of human T helper 1 and T helper 2 cell polarization. AB - Naive CD4+ T cells can differentiate into specific helper and regulatory T cell lineages in order to combat infection and disease. The correct response to cytokines and a controlled balance of these populations is critical for the immune system and the avoidance of autoimmune disorders. To investigate how early cell-fate commitment is regulated, we generated the first human genome-wide maps of histone modifications that reveal enhancer elements after 72 hr of in vitro polarization toward T helper 1 (Th1) and T helper 2 (Th2) cell lineages. Our analysis indicated that even at this very early time point, cell-specific gene regulation and enhancers were at work directing lineage commitment. Further examination of lineage-specific enhancers identified transcription factors (TFs) with known and unknown T cell roles as putative drivers of lineage-specific gene expression. Lastly, an integrative analysis of immunopathogenic-associated SNPs suggests a role for distal regulatory elements in disease etiology. PMID- 23791645 TI - The Satb1 protein directs hematopoietic stem cell differentiation toward lymphoid lineages. AB - How hematopoietic stem cells (HSCs) produce particular lineages is insufficiently understood. We searched for key factors that direct HSC to lymphopoiesis. Comparing gene expression profiles for HSCs and early lymphoid progenitors revealed that Satb1, a global chromatin regulator, was markedly induced with lymphoid lineage specification. HSCs from Satb1-deficient mice were defective in lymphopoietic activity in culture and failed to reconstitute T lymphopoiesis in wild-type recipients. Furthermore, Satb1 transduction of HSCs and embryonic stem cells robustly promoted their differentiation toward lymphocytes. Whereas genes that encode Ikaros, E2A, and Notch1 were unaffected, many genes involved in lineage decisions were regulated by Satb1. Satb1 expression was reduced in aged HSCs with compromised lymphopoietic potential, but forced Satb1 expression partly restored that potential. Thus, Satb1 governs the initiating process central to the replenishing of lymphoid lineages. Such activity in lymphoid cell generation may be of clinical importance and useful to overcome immunosenescence. PMID- 23791646 TI - Double-stranded RNA of intestinal commensal but not pathogenic bacteria triggers production of protective interferon-beta. AB - The small intestine harbors a substantial number of commensal bacteria and is sporadically invaded by pathogens, but the response to these microorganisms is fundamentally different. We identified a discriminatory sensor by using Toll-like receptor 3 (TLR3). Double-stranded RNA (dsRNA) of one major commensal species, lactic acid bacteria (LAB), triggered interferon-beta (IFN-beta) production, which protected mice from experimental colitis. The LAB-induced IFN-beta response was diminished by dsRNA digestion and treatment with endosomal inhibitors. Pathogenic bacteria contained less dsRNA and induced much less IFN-beta than LAB, and dsRNA was not involved in pathogen-induced IFN-beta induction. These results identify TLR3 as a sensor to small intestinal commensal bacteria and suggest that dsRNA in commensal bacteria contributes to anti-inflammatory and protective immune responses. PMID- 23791649 TI - Discrimination against major groove adducts by Y-family polymerases of the DinB subfamily. AB - Y-family DNA polymerases bypass DNA adducts in a process known as translesion synthesis (TLS). Y-family polymerases make contacts with the minor groove side of the DNA substrate at the nascent base pair. The Y-family polymerases also contact the DNA major groove via the unique little finger domain, but they generally lack contacts with the major groove at the nascent base pair. Escherichia coli DinB efficiently and accurately copies certain minor groove guanosine adducts. In contrast, we previously showed that the presence in the DNA template of the major groove-modified base 1,3-diaza-2-oxophenothiazine (tC) inhibits the activity of E. coli DinB. Even when the DNA primer is extended up to three nucleotides beyond the site of the tC analog, DinB activity is strongly inhibited. These findings prompted us to investigate discrimination against other major groove modifications by DinB and its orthologs. We chose a set of pyrimidines and purines with modifications in the major groove and determined the activity of DinB and several orthologs with these substrates. DinB, human pol kappa, and Sulfolobus solfataricus Dpo4 show differing specificities for the major groove adducts pyrrolo-dC, dP, N(6)-furfuryl-dA, and etheno-dA. In general, DinB was least efficient for bypass of all of these major groove adducts, whereas Dpo4 was most efficient. DinB activity was essentially completely inhibited by the presence of etheno-dA, while pol kappa activity was strongly inhibited. All three of these DNA polymerases were able to bypass N(6)-furfuryl-dA with modest efficiency, with DinB being the least efficient. We also determined that the R35A variant of DinB enhances bypass of N(6)-furfuryl-dA but not etheno-dA. In sum, we find that whereas DinB is specific for bypass of minor groove adducts, it is specifically inhibited by major groove DNA modifications. PMID- 23791647 TI - Pathogen-specific Treg cells expand early during mycobacterium tuberculosis infection but are later eliminated in response to Interleukin-12. AB - Thymically derived Foxp3+ regulatory T (Treg) cells have a propensity to recognize self-peptide:MHC complexes, but their ability to respond to epitope defined foreign antigens during infectious challenge has not been demonstrated. Here we show that pulmonary infection with Mycobacterium tuberculosis (Mtb), but not Listeria monocytogenes (Lm), induced robust lymph node expansion of a highly activated population of pathogen-specific Treg cells from the pre-existing pool of thymically derived Treg cells. These antigen-specific Treg cells peaked in numbers 3 weeks after infection but subsequently underwent selective elimination driven, in part, by interleukin-12-induced intrinsic expression of the Th1-cell promoting transcription factor T-bet. Thus, the initial Mtb-induced inflammatory response promotes pathogen-specific Treg cell proliferation, but these cells are actively culled later, probably to prevent suppression during later stages of infection. These findings have important implications for the prevention and treatment of tuberculosis and other chronic diseases in which antigen-specific Treg cells restrict immunity. PMID- 23791650 TI - Chromosome 22q11.2 deletion syndrome: prenatal diagnosis, array comparative genomic hybridization characterization using uncultured amniocytes and literature review. AB - We present prenatal diagnosis of de novo 22q11.2 microdeletion syndrome using uncultured amniocytes in a pregnancy with conotruncal heart malformations in the fetus. We discuss the genotype-phenotype correlation and the consequence of haploinsufficiency of TBX1, COMT, UFD1L, GNB1L and MED15 in the deleted region. We review the literature of chromosomal loci and genes responsible for conotruncal heart malformations and tetralogy of Fallot. PMID- 23791648 TI - Novel ALPL genetic alteration associated with an odontohypophosphatasia phenotype. AB - Hypophosphatasia (HPP) is an inherited disorder of mineral metabolism caused by mutations in ALPL, encoding tissue non-specific alkaline phosphatase (TNAP). Here, we report the molecular findings from monozygotic twins, clinically diagnosed with tooth-specific odontohypophosphatasia (odonto-HPP). Sequencing of ALPL identified two genetic alterations in the probands, including a heterozygous missense mutation c.454C>T, leading to change of arginine 152 to cysteine (p.R152C), and a novel heterozygous gene deletion c.1318_1320delAAC, leading to the loss of an asparagine residue at codon 440 (p.N440del). Clinical identification of low serum TNAP activity, dental abnormalities, and pedigree data strongly suggests a genotype-phenotype correlation between p.N440del and odonto-HPP in this family. Computational analysis of the p.N440del protein structure revealed an alteration in the tertiary structure affecting the collagen binding site (loop 422-452), which could potentially impair the mineralization process. Nevertheless, the probands (compound heterozygous: p.[N440del];[R152C]) feature early-onset and severe odonto-HPP phenotype, whereas the father (p.[N440del];[=]) has only moderate symptoms, suggesting p.R152C may contribute or predispose to a more severe dental phenotype in combination with the deletion. These results assist in defining the genotype-phenotype associations for odonto HPP, and further identify the collagen-binding site as a region of potential structural importance for TNAP function in the biomineralization. PMID- 23791651 TI - SIR-nucleosome interactions: structure-function relationships in yeast silent chromatin. AB - Discrete regions of the eukaryotic genome assume a heritable chromatin structure that is refractory to gene expression, referred to as heterochromatin or "silent" chromatin. Constitutively silent chromatin is found in subtelomeric domains in a number of species, ranging from yeast to man. In addition, chromatin-dependent repression of mating type loci occurs in both budding and fission yeasts, to enable sexual reproduction. The silencing of chromatin in budding yeast is characterized by an assembly of Silent Information Regulatory (SIR) proteins Sir2, Sir3 and Sir4-with unmodified nucleosomes. Silencing requires the lysine deacetylase activity of Sir2, extensive contacts between Sir3 and the nucleosome, as well as interactions among the SIR proteins, to generate the Sir2-3-4 or SIR complex. Results from recent structural and reconstitution studies suggest an updated model for the ordered assembly and organization of SIR-dependent silent chromatin in yeast. Moreover, studies of subtelomeric gene expression reveal the importance of subtelomeric silent chromatin in the regulation of genes other than the silent mating type loci. This review covers recent advances in this field. PMID- 23791652 TI - Xp22.3 interstitial deletion: a recognizable chromosomal abnormality encompassing VCX3A and STS genes in a patient with X-linked ichthyosis and mental retardation. AB - X-linked ichthyosis is a genetic disorder affecting the skin and caused by a deficit in the steroid sulfatase enzyme (STS), often associated with a recurrent microdeletion at Xp22.31. Most of the STS deleted patients have X-linked ichthyosis as the only clinical feature and it is believed that patients with more complex disorders including mental retardation could be present as a result of contiguous gene deletion. In fact, VCX3A gene, a member of the VCX (variable charge, X chromosome) gene family, was previously proposed as the candidate gene for X-linked non-specific mental retardation in patients with X-linked ichthyosis. We report on a boy with familial ichthyosis, dysmorphic features and moderate mental retardation with approximately 2 Mb interstitial deletion on Xp22.3 involving VCX3A and STS genes. PMID- 23791653 TI - Evolution of the salivary apyrases of blood-feeding arthropods. AB - Phylogenetic analyses of three families of arthropod apyrases were used to reconstruct the evolutionary relationships of salivary-expressed apyrases, which have an anti-coagulant function in blood-feeding arthropods. Members of the 5'nucleotidase family were recruited for salivary expression in blood-feeding species at least five separate times in the history of arthropods, while members of the Cimex-type apyrase family have been recruited at least twice. In spite of these independent events of recruitment for salivary function, neither of these families showed evidence of convergent amino acid sequence evolution in salivary expressed members. On the contrary, in the 5'-nucleotide family, salivary expressed proteins conserved ancestral amino acid residues to a significantly greater extent than related proteins without salivary function, implying parallel evolution by conservation of ancestral characters. This unusual pattern of sequence evolution suggests the hypothesis that purifying selection favoring conservation of ancestral residues is particularly strong in salivary-expressed members of the 5'-nucleotidase family of arthropods because of constraints arising from expression within the vertebrate host. PMID- 23791654 TI - The identification of microRNAs in the whitespotted bamboo shark (Chiloscyllium plagiosum) liver by Illumina sequencing. AB - MicroRNAs are indispensable players in the regulation of a broad range of biological processes. Here, we report the first deep sequencing of the whitespotted bamboo shark (Chiloscyllium plagiosum) liver. We mapped 91 miRNAs in the Callorhinchus milii genome that have previously been described in the Danio rerio, Fugu rubripes, Oryzias latipes, Xenopus laevis, Xenopus tropicalis, Homo sapiens, and Mus musculus. In addition, 156 new putative candidate (PC) C. plagiosum miRNAs were identified. From these 247 miRNAs, 39 miRNA clusters were identified, and the expression of these clustered miRNAs was observed to vary significantly. A total of 7 candidate miRNAs were selected for expression confirmation by stem-loop RT-PCR. This study resulted in the addition of a significant number of novel miRNA sequences to GenBank and laid the foundation for further understanding of the function of miRNAs in the regulation of C. plagiosum liver development. PMID- 23791655 TI - Trimethylaminuria (fish odor syndrome): genotype characterization among Portuguese patients. AB - Trimethylaminuria (TMAu) or "fish odor syndrome" is a metabolic disorder characterized by the inability to convert malodorous dietarily-derived trimethylamine (TMA) to odorless TMA N-oxide by the flavin-containing monooxygenase 3 (FMO3). Affected individuals unable to complete this reaction exude a "fishy" body odor due to the secretion of TMA in their corporal fluids leading to a variety of psychosocial problems. Interindividual variability in the expression of FMO3 gene may affect drug and foreign chemical metabolism in the liver and other tissues. Therefore, it is important to screen for common TMAu mutations but also extend the search to other genetic variants in order to correlate genotype and disease-associated phenotypes. In this study, 25 Portuguese patients with phenotype suggestive of TMAu were evaluated for molecular screening of the FMO3 gene. Herein, we found 16 variants in the FMO3 coding region, some of which had not been previously documented (Gly38Trp, Asp232Val, Thr307Pro, Ser310Leu). Whenever common variants (Glu158Lys, Glu308Gly) were considered in combination a distinct pattern between the control population and patients was observed, mainly in what concerns the presence of Lys158 and Gly308 in homozygous state. Further studies are necessary to clarify the pathogenicity of novel variants identified in this study, as well as the effect of the common single nucleotide polymorphisms, which may play an important role in disease presentation and/or protective mechanism to xenobiotics drugs or environment. PMID- 23791656 TI - Three common functional polymorphisms in microRNA encoding genes in the susceptibility to hepatocellular carcinoma: a systematic review and meta analysis. AB - Emerging evidences have shown that common genetic polymorphisms in microRNAs may be associated with the development of hepatocellular carcinoma (HCC); but individually published studies and previous meta-analyses revealed inconclusive results. The aims of this review and meta-analysis are to assess whether common single-nucleotide polymorphisms (SNPs) in the genes encoding the microRNAs are associated with susceptibility to HCC development and clinicopathologic characteristics of hepatitis B virus (HBV) related HCC. A computerized search was performed in PubMed, Embase, Web of Science and China BioMedicine (CBM) databases to identify relevant articles published before January 1st 2013. Ten case-control studies were assessed with a total of 3437 cases and 3437 healthy controls. Three common functional SNPs in miRNA-encoding genes were found, including miR-146a G>C (rs2910164), miR-196a-2 C>T (rs11614913) and miR-499 T>C (rs3746444). This meta analysis revealed that the miR-146a C variant was associated with a decrease in HCC risk, especially among Asian and male populations; while the miR-196a-2 T variant was associated with susceptibility to HCC among Caucasian populations. However, we failed to find any significant correlations between the miR-499 C polymorphism and HCC risks. When further stratification on HBV status was conducted, a similar trend of association between the three SNPs and the HBV related HCC risks was observed, but these results were not statistically significant due to small sample sizes. The current meta-analysis demonstrates that SNPs contained in the genes encoding miR-146a and miR-196a-2 may play a major role in genetic susceptibility to HCC. PMID- 23791657 TI - Meta-analysis of microRNA-183 family expression in human cancer studies comparing cancer tissues with noncancerous tissues. AB - MicroRNA-183 (miR-183) family is proposed as promising biomarkers for early cancer detection and accurate prognosis as well as targets for more efficient treatment. The results of their expression feature in cancer tissues are inconsistent and controversy still exists in identifying them as new biomarkers of cancers. Therefore, to systemically evaluate the most frequently reported cancers in which miR-183 family members were up- or down-regulated is critical for further investigation on physiological impact of its aberrant regulation in specific cancers. The published studies that compared the level of miR-183 family expression in cancer tissues with those in noncancerous tissues were reviewed by the meta-analysis with a vote-counting strategy. Among the 49 included studies, a total of 18 cancers were reported, with 11 cancers reported in at least two studies. In the panel of miR-183 family members' expression analysis, colorectal cancer and prostate cancer ranked at the top among consistently reported cancer types with up-regulated feature. Bladder cancer, lung cancer and hepatocellular carcinoma were the third most frequently reported cancer types with significant over-expression of miR-96, miR-182 and miR-183 respectively. Breast cancer and gastric cancer were presented with inconsistent regulations and the members of this family had their own distinct regulated features in other different cancers. MiR-183 family, either individually or as a cluster, may be useful prognostic markers and/or therapeutic targets in several cancers. Further studies and repeat efforts are still required to determine the role of miR-183 family in various cancer progressions. PMID- 23791658 TI - Nucleosomal TATA-switch: competing orientations of TATA on the nucleosome. AB - Transcription is known to be affected by the rotational setting of the transcription response elements within nucleosomes. We studied the rotational positioning of the TATA box, the most universal promoter motif. We applied a bioinformatic high-resolution nucleosome mapping technique to eukaryotic promoters. Our results show that the nucleosome DNA sequence harboring the TATA box encodes alternative rotational positions for the same piece of DNA. This may serve for switching the gene activity on and off. PMID- 23791659 TI - Ciclohexadespipeptide beauvericin degradation by different strains of Saccharomyces cerevisiae. AB - The interaction between the mycotoxin beauvericin (BEA) and 9 yeast strains of Saccharomyces cerevisiae named LO9, YE-2, YE5, YE-6, YE-4, A34, A17, A42 and A08 was studied. The biological degradations were carried out under aerobic conditions in the liquid medium of Potato Dextrose Broth (PDB) at 25 degrees C for 48 h and in a food/feed system composed of corn flour at 37 degrees C for 3 days, respectively. BEA present in fermented medium and corn flour was determined using liquid chromatography coupled to the mass spectrometry detector in tandem (LC-MS/MS) and the BEA degradation products produced during the fermentations were determined using the technique of the liquid chromatography coupled to a linear ion trap (LIT). Results showed that the S. cerevisiae strains reduced meanly the concentration of the BEA present in PDB by 86.2% and in a food system by 71.1%. All the S. cerevisiae strains used in this study showed a significant BEA reduction during the fermentation process employed. PMID- 23791660 TI - Time and temporality: role of rhythmicity in psychic organization. PMID- 23791661 TI - Effects of osmolytes on Pelodiscus sinensis creatine kinase: a study on thermal denaturation and aggregation. AB - The protective effect of osmolytes on the thermal denaturation and aggregation of Pelodiscus sinensis muscle creatine kinase (PSCK) was investigated by a combination of spectroscopic methods and thermodynamic analysis. Our results demonstrated that the addition of osmolytes, such as glycine and proline, could prevent thermal denaturation and aggregation of PSCK in a concentration-dependent manner. When the concentration of glycine and proline increased in the denatured system, the relative activation was significantly enhanced; meanwhile, the aggregation of PSCK during thermal denaturation was decreased. Spectrofluorometer results showed that glycine and proline significantly decreased the tertiary structural changes of PSCK and that thermal denaturation directly induced PSCK aggregation. In addition, we also built the 3D structure of PSCK and osmolytes by homology models. The results of computational docking simulations showed that the docking energy was relatively low and that the clustering groups were spread to the surface of PSCK, indicating that osmolytes directly protect the surface of the protein. P. sinensis are poikilothermic and quite sensitive to the change of ambient temperature; however, there were few studies on the thermal denaturation of reptile CK. Our study provides important insight into the protective effects of osmolytes on thermal denaturation and aggregation of PSCK. PMID- 23791662 TI - Comparison of EDC and DMTMM efficiency in glycoconjugate preparation. AB - A series of mono- or disaccharide-protein conjugates were prepared by amide bond formation. Incorporation efficiency of the aminosaccharides on bovine serum albumin was determined by colorimetry and matrix assisted laser desorption/ionization mass spectrometry. Study compares two amide bond coupling agents, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 4-(4,6 dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride. Paper demonstrates a practical usefulness of natural bovine serum albumin succinylation. Large number of its carboxyl groups results in its superior reactivity towards simple aminosaccharides. PMID- 23791663 TI - Control of human vascular tone by prostanoids derived from perivascular adipose tissue. AB - Perivascular adipose tissue (PVAT) surrounds most vessels and has now been recognized as a regulator of vascular functions. This effect of PVAT has been mostly demonstrated in vessels obtained from rats and mice. Thus, the aim of this study was to investigate anti-contractile effect of PVAT surrounding human coronary bypass grafts such as saphenous vein (SV) and internal mammary artery (IMA). Moreover, we aimed to determine the involvement of prostanoids in the anticontractile effect of PVAT. Human SV and IMA preparations were set up in an organ bath. The presence of PVAT in SV and IMA preparations significantly attenuated the contractile response to noradrenaline (NA). Preincubation with indomethacin, a cyclooxygenase inhibitor, increased NA contraction in SV preparations with PVAT. This effect was not observed in IMA preparation with PVAT incubated with indomethacin. The lower measurements of prostaglandin E2 (PGE2) released from PVAT surrounding IMA versus SV supported these effects. In conclusion, our results show that PVAT of SV could attenuate NA-induced contraction by releasing both PGE2 and prostacyclin (PGI2). In contrast to SV, PVAT of IMA exerts its anti-contractile effect independently from prostanoids. These observations suggest that retaining PVAT in human SV and IMA preparations may have potential clinical implications to improve coronary bypass graft patency. PMID- 23791664 TI - Pregnancy-associated breast cancer and pregnancy following treatment for breast cancer, in a cohort of women from Victoria, Australia, with a first diagnosis of invasive breast cancer. AB - BACKGROUND: This study examined pregnancy-associated breast cancer (PABC) and pregnancy following treatment for breast cancer. METHODS: We analysed data from a questionnaire-based, prospective study of women diagnosed with breast cancer. Timing of diagnosis in relation to pregnancy was self-reported in the enrolment questionnaire. Women reported subsequent pregnancies in annual follow-up questionnaires, up to at least 5 years from diagnosis. RESULTS: Women with PABC made up 3.3% of women <48 years at diagnosis and 14.3% of women aged <35 years at diagnosis. Nine of 46 (19.6%) women who were aged <40 years at diagnosis, and had either no children, or only one child, became pregnant subsequent to their diagnosis, and 8 experienced a live birth. DISCUSSION: As the number of women with PABC was small, conclusions from this study are limited. However, young women should be alert to PABC, especially in the post-partum period. Some women, with incomplete families at diagnosis, are choosing to have one or more pregnancies following treatment. PMID- 23791665 TI - The origins of enzyme kinetics. AB - The equation commonly called the Michaelis-Menten equation is sometimes attributed to other authors. However, although Victor Henri had derived the equation from the correct mechanism, and Adrian Brown before him had proposed the idea of enzyme saturation, it was Leonor Michaelis and Maud Menten who showed that this mechanism could also be deduced on the basis of an experimental approach that paid proper attention to pH and spontaneous changes in the product after formation in the enzyme-catalysed reaction. By using initial rates of reaction they avoided the complications due to substrate depletion, product accumulation and progressive inactivation of the enzyme that had made attempts to analyse complete time courses very difficult. Their methodology has remained the standard approach to steady-state enzyme kinetics ever since. PMID- 23791666 TI - Acetate in mixotrophic growth medium affects photosystem II in Chlamydomonas reinhardtii and protects against photoinhibition. AB - Chlamydomonas reinhardtii is a photoautotrophic green alga, which can be grown mixotrophically in acetate-supplemented media (Tris-acetate-phosphate). We show that acetate has a direct effect on photosystem II (PSII). As a consequence, Tris acetate-phosphate-grown mixotrophic C. reinhardtii cultures are less susceptible to photoinhibition than photoautotrophic cultures when subjected to high light. Spin-trapping electron paramagnetic resonance spectroscopy showed that thylakoids from mixotrophic C. reinhardtii produced less (1)O2 than those from photoautotrophic cultures. The same was observed in vivo by measuring DanePy oxalate fluorescence quenching. Photoinhibition can be induced by the production of (1)O2 originating from charge recombination events in photosystem II, which are governed by the midpoint potentials (Em) of the quinone electron acceptors. Thermoluminescence indicated that the Em of the primary quinone acceptor (QA/QA( )) of mixotrophic cells was stabilised while the Em of the secondary quinone acceptor (QB/QB(-)) was destabilised, therefore favouring direct non-radiative charge recombination events that do not lead to (1)O2 production. Acetate treatment of photosystem II-enriched membrane fragments from spinach led to the same thermoluminescence shifts as observed in C. reinhardtii, showing that acetate exhibits a direct effect on photosystem II independent from the metabolic state of a cell. A change in the environment of the non-heme iron of acetate treated photosystem II particles was detected by low temperature electron paramagnetic resonance spectroscopy. We hypothesise that acetate replaces the bicarbonate associated to the non-heme iron and changes the environment of QA and QB affecting photosystem II charge recombination events and photoinhibition. PMID- 23791667 TI - Unfolding stabilities of two paralogous proteins from Naja naja naja (Indian cobra) as probed by molecular dynamics simulations. AB - Structurally similar but functionally different two paralogous proteins, CTX1 (a cardiotoxin) and LNTX2 (an alpha-neurotoxin), from venom of Naja naja naja have been homology modeled and subjected to molecular dynamics (MD) simulations at four different temperatures (298 K, 310 K, 373 K & 473 K) under close quarters of physiological conditions. Each MD simulation was performed for 25 ns and trajectory structures stored at every 25 ps were used to probe various structural events occurring in the temperature-induced unfolding of the proteins. Notwithstanding their similar scaffolds, the two proteins are drastically differing in their unfolding stabilities from each other. The structural orders of flexibilities for the CTX1 and LNTX2 were found to be loop II > loop III > loop I > C-terminal and C-terminal > loop I > loop III > loop II, respectively. Based on the comprehensive analyses of the simulation data and studies on the various structural interactions of all cardiotoxins (CTXs) and alpha-neurotoxins (NTXs) for which three-dimensional structures determined by experimental techniques are available to date, we have herein proposed a hypothesis ('CN network') rationalizing the differential stabilities of the CTXs and NTXs belonging to a three-finger toxin superfamily of snake venoms. PMID- 23791668 TI - Isolation of acetylated bile acids from the sponge Siphonochalina fortis and DNA damage evaluation by the comet assay. AB - From the organic extracts of the sponge Siphonochalina fortis, collected at Bahia Bustamante, Chubut, Argentina, three major compounds were isolated and identified as deoxycholic acid 3, 12-diacetate (1), cholic acid 3, 7, 12-triacetate (2) and cholic acid, 3, 7, 12-triacetate. (3). This is the first report of acetylated bile acids in sponges and the first isolation of compound 3 as a natural product. The potential induction of DNA lesions by the isolated compounds was investigated using the comet assay in lymphocytes of human peripheral blood as in vitro model. The results showed that the administration of the bile acid derivatives would not induce DNA damages, indicating that acetylated bile acids are nontoxic metabolites at the tested concentrations. Since the free bile acids were not detected, it is unlikely that the acetylated compounds may be part of the sponge cells detoxification mechanisms. These results may suggest a possible role of acetylated bile acids as a chemical defense mechanism, product of a symbiotic relationship with microorganisms, which would explain their seasonal and geographical variation, and their influence on the previously observed genotoxicity of the organic extract of S. fortis. PMID- 23791669 TI - Angiotensin AT2 receptor agonist stimulates high stretch induced- ANP secretion via PI3K/NO/sGC/PKG/pathway. AB - Angiotensin II (Ang II) type 1 receptor (AT1R) mediates the major cardiovascular effects of Ang II. However, the effects mediated via AT2R are still controversial. The aim of the present study is to define the effect of AT2R agonist CGP42112A (CGP) on high stretch-induced ANP secretion and its mechanism using in vitro and in vivo experiments. CGP (0.01, 0.1 and 1MUM) stimulated high stretch-induced ANP secretion and concentration from isolated perfused rat atria. However, atrial contractility and the translocation of extracellular fluid did not change. The augmented effect of CGP (0.1MUM) on high stretch-induced ANP secretion was attenuated by the pretreatment with AT2R antagonist or inhibitor for phosphoinositol 3-kinase (PI3K), nitric oxide (NO), soluble guanylyl cyclase (sGC), or protein kinase G (PKG). However, antagonist for AT1R or Mas receptor did not influence CGP-induced ANP secretion. In vivo study, acute infusion of CGP for 10min increased plasma ANP level without blood pressure change. In renal hypertensive rat atria, AT2R mRNA and protein levels were up-regulated and the response of plasma ANP level to CGP infusion in renal hypertensive rats augmented. The pretreatment with AT2R antagonist for 10min followed by CGP infusion attenuated an increased plasma ANP level induced by CGP. However, pretreatment with AT1R or Mas receptor antagonist unaffected CGP-induced increase in plasma ANP level. Therefore, we suggest that AT2R agonist CGP stimulates high stretch-induced ANP secretion through PI3K/NO/sGC/PKG pathway and these effects are augmented in renal hypertensive rats. PMID- 23791670 TI - Bio-inspired stable antimicrobial peptide coatings for dental applications. AB - We developed a novel titanium coating that has applications for preventing infection-related implant failures in dentistry and orthopedics. The coating incorporates an antimicrobial peptide, GL13K, derived from parotid secretory protein, which has been previously shown to be bactericidal and bacteriostatic in solution. We characterized the resulting physicochemical properties, resistance to degradation, activity against Porphyromonas gingivalis and in vitro cytocompatibility. Porphyromonas gingivalis is a pathogen associated with dental peri-implantitis, an inflammatory response to bacteria resulting in bone loss and implant failure. Our surface modifications obtained a homogeneous, highly hydrophobic and strongly anchored GL13K coating that was resistant to mechanical, thermochemical and enzymatic degradation. The GL13K coatings had a bactericidal effect and thus significantly reduced the number of viable bacteria compared to control surfaces. Finally, adequate proliferation of osteoblasts and human gingival fibroblasts demonstrated the GL13K coating's cytocompatibility. The robustness, antimicrobial activity and cytocompatibility of GL13K biofunctionalized titanium make it a promising candidate for sustained inhibition of bacterial biofilm growth. This surface chemistry provides a basis for development of multifunctional bioactive surfaces to reduce patient morbidities and improve long-term clinical efficacy of metallic dental and orthopedic implants. PMID- 23791671 TI - Calcium phosphate ceramics in bone tissue engineering: a review of properties and their influence on cell behavior. AB - Calcium phosphate ceramics (CPCs) have been widely used as biomaterials for the regeneration of bone tissue because of their ability to induce osteoblastic differentiation in progenitor cells. Despite the progress made towards fabricating CPCs possessing a range of surface features and chemistries, the influence of material properties in orchestrating cellular events such as adhesion and differentiation is still poorly understood. Specifically, questions such as why certain CPCs may be more osteoinductive than others, and how material properties contribute to osteoinductivity/osteoconductivity remain unanswered. Therefore, this review article systematically discusses the effects of the physical (e.g. surface roughness) and chemical properties (e.g. solubility) of CPCs on protein adsorption, cell adhesion and osteoblastic differentiation in vitro. The review also provides a summary of possible signaling pathways involved in osteoblastic differentiation in the presence of CPCs. In summary, these insights on the contribution of material properties towards osteoinductivity and the role of signaling molecules involved in osteoblastic differentiation can potentially aid the design of CPC-based biomaterials that support bone regeneration without the need for additional biochemical supplements. PMID- 23791672 TI - An in situ forming biodegradable hydrogel-based embolic agent for interventional therapies. AB - We present here the characteristics of an in situ forming hydrogel prepared from carboxymethyl chitosan and oxidized carboxymethyl cellulose for interventional therapies. Gelation, owing to the formation of Schiff bases, occurred both with and without the presence of a radiographic contrast agent. The hydrogel exhibited a highly porous internal structure (pore diameter 17+/-4 MUm), no cytotoxicity to human umbilical vein endothelial cells, hemocompatibility with human blood, and degradability in lysozyme solutions. Drug release from hydrogels loaded with a sclerosant, tetracycline, was measured at pH 7.4, 6 and 2 at 37 degrees C. The results showed that tetracycline was more stable under acidic conditions, with a lower release rate observed at pH 6. An anticancer drug, doxorubicin, was loaded into the hydrogel and a cumulative release of 30% was observed over 78 h in phosphate-buffered saline at 37 degrees C. Injection of the hydrogel precursor through a 5-F catheter into a fusiform aneurysm model was feasible, leading to complete filling of the aneurysmal sac, which was visualized by fluoroscopy. The levels of occlusion by hydrogel precursors (1.8% and 2.1%) and calibrated microspheres (100-300 MUm) in a rabbit renal model were compared. Embolization with hydrogel precursors was performed without clogging and the hydrogel achieved effective occlusion in more distal arteries than calibrated microspheres. In conclusion, this hydrogel possesses promising characteristics potentially beneficial for a wide range of vascular intervention procedures that involve embolization and drug delivery. PMID- 23791673 TI - Polyelectrolyte/silver nanocomposite multilayer films as multifunctional thin film platforms for remote activated protein and drug delivery. AB - We demonstrate a nanoparticle loading protocol to develop a transparent, multifunctional polyelectrolyte multilayer film for externally activated drug and protein delivery. The composite film was designed by alternate adsorption of poly(allylamine hydrochloride) (PAH) and dextran sulfate (DS) on a glass substrate followed by nanoparticle synthesis through a polyol reduction method. The films showed a uniform distribution of spherical silver nanoparticles with an average diameter of 50+/-20 nm, which increased to 80+/-20 nm when the AgNO3 concentration was increased from 25 to 50 mM. The porous and supramolecular structure of the polyelectrolyte multilayer film was used to immobilize ciprofloxacin hydrochloride (CH) and bovine serum albumin (BSA) within the polymeric network of the film. When exposed to external triggers such as ultrasonication and laser light the loaded films were ruptured and released the loaded BSA and CH. The release of CH is faster than that of BSA due to a higher diffusion rate. Circular dichroism measurements confirmed that there was no significant change in the conformation of released BSA in comparison with native BSA. The fabricated films showed significant antibacterial activity against the bacterial pathogen Staphylococcus aureus. Applications envisioned for such drug loaded films include drug and vaccine delivery through the transdermal route, antimicrobial or anti-inflammatory coatings on implants and drug-releasing coatings for stents. PMID- 23791674 TI - Non-invasive imaging of the crystalline structure within a human tooth. AB - The internal crystalline structure of a human molar tooth has been non destructively imaged in cross-section using X-ray diffraction computed tomography. Diffraction signals from high-energy X-rays which have large attenuation lengths for hard biomaterials have been collected in a transmission geometry. Coupling this with a computed tomography data acquisition and mathematically reconstructing their spatial origins, diffraction patterns from every voxel within the tooth can be obtained. Using this method we have observed the spatial variations of some key material parameters including nanocrystallite size, organic content, lattice parameters, crystallographic preferred orientation and degree of orientation. We have also made a link between the spatial variations of the unit cell lattice parameters and the chemical make-up of the tooth. In addition, we have determined how the onset of tooth decay occurs through clear amorphization of the hydroxyapatite crystal, and we have been able to map the extent of decay within the tooth. The described method has strong prospects for non-destructive probing of mineralized biomaterials. PMID- 23791675 TI - An amphiphilic degradable polymer/hydroxyapatite composite with enhanced handling characteristics promotes osteogenic gene expression in bone marrow stromal cells. AB - Electrospun polymer/hydroxyapatite (HA) composites combining biodegradability with osteoconductivity are attractive for skeletal tissue engineering applications. However, most biodegradable polymers such as poly(lactic acid) (PLA) are hydrophobic and do not blend with adequate interfacial adhesion with HA, compromising the structural homogeneity, mechanical integrity and biological performance of the composite. To overcome this challenge, we combined a hydrophilic polyethylene glycol (PEG) block with poly(d,l-lactic acid) to improve the adhesion of the degradable polymer with HA. The amphiphilic triblock copolymer PLA-PEG-PLA (PELA) improved the stability of HA-PELA suspension at 25wt.% HA content, which was readily electrospun into HA-PELA composite scaffolds with uniform fiber dimensions. HA-PELA was highly extensible (failure strain>200% vs. <40% for HA-PLA), superhydrophilic (~0 degrees water contact angle vs. >100 degrees for HA-PLA), and exhibited an 8-fold storage modulus increase (unlike deterioration for HA-PLA) upon hydration, owing to the favorable interaction between HA and PEG. HA-PELA also better promoted osteochondral lineage commitment of bone marrow stromal cells in unstimulated culture and supported far more potent osteogenic gene expression upon induction than HA-PLA. We demonstrate that the chemical incorporation of PEG is an effective strategy to improve the performance of degradable polymer/HA composites for bone tissue engineering applications. PMID- 23791676 TI - Aptamers that bind to the hemagglutinin of the recent pandemic influenza virus H1N1 and efficiently inhibit agglutination. AB - Influenza virus hemagglutinin (HA) mediates both receptor (glycan) binding and membrane fusion for cell entry and has been the basis for typing influenza A viruses. In this study we have selected RNA aptamers (D-12 and D-26) that specifically target the HA protein of the recent pandemic influenza virus pdmH1N1 (A/California/07/2009). Among the selected aptamers the D-26 aptamer showed higher affinity for the HA of pdmH1N1 and was able to distinguish HA derived from other sub-types of influenza A viruses. The affinity of the D-26 aptamer was further improved upon incorporation of 2'-fluoropyrimidines to a level of 67 fM. Furthermore, the high affinity D-12 and D-26 aptamers were tested for their ability to interfere with HA-glycan interactions using a chicken red blood cell (RBC) agglutination assay. At a concentration of 200 nM the D-26 aptamer completely abolished the agglutination of RBCs, whereas D-12 only did so at 400 nM. These studies suggest that the selected aptamer D-26 not only has a higher affinity and specificity for the HA of pdmH1N1 but also has a better ability to efficiently interfere with HA-glycan interactions compared with the D-12 aptamer. The D-26 aptamer warrants further study regarding its application in developing topical virucidal products against the pdmH1N1 virus and also in surveillance of the pdmH1N1 influenza virus. PMID- 23791677 TI - Dynamic cell-adhesive microenvironments and their effect on myogenic differentiation. AB - Integrin-mediated cell adhesion plays a central role in cell behavior on biomaterial surfaces and influences various cell functions. Photoactivatable RGD adhesive peptides were used to investigate the effect of the density and time point of bioadhesive ligand presentation on cell adhesion, proliferation and differentiation. PEGylated self-assembled monolayers were functionalized with RGD and caged RGD ligands and seeded with C2C12 myoblasts. The cultures were irradiated at various time points between 1 and 48 h after cell seeding in order to increase RGD surface concentration at defined time points. Attachment, spreading and myogenic differentiation of C2C12 myoblasts strongly varied with the density of RGD at the surface. Proliferation and myogenesis were further regulated by the time point at which RGD was presented to the cell, reaching highest levels when RGD exposure occurred<=6 h after cell seeding. These results provide fundamental insights in cell-biomaterial interactions of C2C12 myoblasts in terms of temporal integrin-mediated cell responses. PMID- 23791678 TI - Marine hydroid perisarc: a chitin- and melanin-reinforced composite with DOPA iron(III) complexes. AB - Many marine invertebrates utilize biomacromolecules as building blocks to form their load-bearing tissues. These polymeric tissues are appealing for their unusual physical and mechanical properties, including high hardness and stiffness, toughness and low density. Here, a marine hydroid perisarc of Aglaophenia latirostris was investigated to understand how nature designs a stiff, tough and lightweight sheathing structure. Chitin, protein and a melanin like pigment, were found to represent 10, 17 and 60 wt.% of the perisarc, respectively. Interestingly, similar to the adhesive and coating of marine mussel byssus, a DOPA (3,4-dihydroxyphenylalanine) containing protein and iron were detected in the perisarc. Resonance Raman microprobe analysis of perisarc indicates the presence of catechol-iron(III) complexes in situ, but it remains to be determined whether the DOPA-iron(III) interaction plays a cohesive role in holding the protein, chitin and melanin networks together. PMID- 23791679 TI - Aortic aneurysm patients are not fit! PMID- 23791681 TI - Investigating factors leading to fogging of glass vials in lyophilized drug products. AB - Vial "Fogging" is a phenomenon observed after lyophilization due to drug product creeping upwards along the inner vial surface. After the freeze-drying process, a haze of dried powder is visible inside the drug product vial, making it barely acceptable for commercial distribution from a cosmetic point of view. Development studies were performed to identify the root cause for fogging during manufacturing of a lyophilized monoclonal antibody drug product. The results of the studies indicate that drug product creeping occurs during the filling process, leading to vial fogging after lyophilization. Glass quality/inner surface, glass conversion/vial processing (vial "history") and formulation excipients, e.g., surfactants (three different surfactants were tested), all affect glass fogging to a certain degree. Results showed that the main factor to control fogging is primarily the inner vial surface hydrophilicity/hydrophobicity. While Duran vials were not capable of reliably improving the level of fogging, hydrophobic containers provided reliable means to improve the cosmetic appearance due to reduction in fogging. Varying vial depyrogenation treatment conditions did not lead to satisfying results in removal of the fogging effect. Processing conditions of the vial after filling with drug product had a strong impact on reducing but not eliminating fogging. PMID- 23791680 TI - fH-dependent complement evasion by disease-causing meningococcal strains with absent fHbp genes or frameshift mutations. AB - Meningococci bind human fH to down-regulate complement, which enhances survival of the bacteria in serum. A major fH ligand is the vaccine candidate, factor H binding protein (fHbp). Although fHbp has been considered an essential meningococcal virulence factor, rarely, invasive isolates with absent fHbp genes or frameshift mutations have been identified. In previous studies fH binding to these isolates was not detected. The aim of the present study was to investigate fH binding and complement evasion by invasive meningococcal serogroup B clinical isolates with absent fHbp genes or frameshift mutations. Four of the seven isolates tested bound human fH by flow cytometry and survived in IgG-depleted human serum. In all four, fH binding was decreased after inactivating the gene encoding NspA. Binding of fH to fHbp and NspA is specific for human fH. To investigate fH-dependent evasion of host defenses, human fH transgenic infant rats, or control littermates negative for human fH, were challenged IP with 10(3) 10(4)CFU of two of the isolates with no detectable fH binding by flow cytometry. At 6h, bacteremia caused by both strains was higher in human fH transgenic rats than in control rats (P<0.002). In conclusion, six of the seven isolates had evidence of fH binding and/or human fH-dependent complement evasion in transgenic rats. In four, NspA was as an alternative fH ligand. fHbp vaccination may select for mutants that do not require fHbp for complement evasion. Inclusion of additional target antigens in vaccines containing fHbp may delay emergence of these mutants. PMID- 23791682 TI - Controlled release of multiple epidermal induction factors through core-shell nanofibers for skin regeneration. AB - With advances in the field of tissue engineering, it is increasingly recognized that biodegradable and biocompatible scaffolds incorporated with multiple wound healing mediators might serve as the most promising medical devices for skin tissue regeneration. Through controlled drug delivery, these medical devices can reduce the toxicity effects and optimize clinical efficiency. In this study, we first encapsulated multiple epidermal induction factors (EIF) such as the epidermal growth factor (EGF), insulin, hydrocortisone, and retinoic acid (RA) with gelatin and poly(L-lactic acid)-co-poly-(epsilon-caprolactone) (PLLCL) solutions and performed electrospinning by two different approaches: blend spinning and core-shell spinning. No burst release was detected from EIF encapsulated core-shell nanofibers; however, an initial 44.9% burst release from EIF blended nanofibers was observed over a period of 15 days. The epidermal differentiation potential of adipose-derived stem cells (ADSCs) was evaluated for EIF-containing scaffolds prepared either by core-shell spinning or by blend spinning. After 15 days of cell culture, the proliferation of ADSCs on EIF encapsulated core-shell nanofibers was the highest. Moreover, a higher percentage of ADSCs got differentiated to epidermal lineages on EIF encapsulated core-shell nanofibers compared to the cell differentiation on EIF blended nanofibers, which can be attributed to the sustained release of EIF from the core-shell nanofibers. Our study demonstrated that the EIF encapsulated core-shell nanofibers might serve as a promising tissue engineered graft for skin regeneration. PMID- 23791683 TI - Delivery of analgesic peptides to the brain by nano-sized bolaamphiphilic vesicles made of monolayer membranes. AB - Inefficient drug delivery to the brain is a major obstacle for pharmacological management of brain diseases. We investigated the ability of bolavesicles - monolayer membrane vesicles self-assembled from synthetic bolaamphiphiles that contain two hydrophilic head groups at each end of a hydrophobic alkyl chain - to permeate the blood-brain barrier and to deliver the encapsulated materials into the brain. Cationic vesicles with encapsulated kyotorphin and leu-enkephalin (analgesic peptides) were prepared from the bolalipids GLH-19 and GLH-20 and studied for their analgesic effects in vivo in experimental mice. The objectives were to determine: (a) whether bolavesicles can efficiently encapsulate analgesic peptides, (b) whether bolavesicles can deliver these peptides to the brain in quantities sufficient for substantial analgesic effect, and to identify the bolavesicle formulation/s that provides the highest analgetic efficiency. The results indicate that the investigated bolavesicles can deliver analgesic peptides across the blood-brain barrier and release them in the brain in quantities sufficient to elicit efficient and prolonged analgesic activity. The analgesic effect is enhanced by using bolavesicles made from a mixture the bolas GLH-19 (that contains non-hydrolyzable acetylcholine head group) and GLH-20 (that contains hydrolysable acetylcholine head group) and by incorporating chitosan pendants into the formulation. The release of the encapsulated materials (the analgesic peptides kyotorphin and leu-enkephalin) appears to be dependent on the choline esterase (ChE) activity in the brain vs. other organs and tissues. Pretreatment of experimental animals with pyridostigmine (the BBB-impermeable ChE inhibitor) enhances the analgesic effects of the studied formulations. The developed formulations and the approach for their controlled decapsulation can serve as a useful modality for brain delivery of therapeutically-active compounds. PMID- 23791684 TI - Hyaluronic acid-coated liposomes for active targeting of gemcitabine. AB - The aim of this work was the preparation, characterization, and preliminary evaluation of the targeting ability toward pancreatic adenocarcinoma cells of liposomes containing the gemcitabine lipophilic prodrug [4-(N)-lauroyl gemcitabine, C12GEM]. Hyaluronic acid (HA) was selected as targeting agent since it is biodegradable, biocompatible, and can be chemically modified and its cell surface receptor CD44 is overexpressed on various tumors. For this purpose, conjugates between a phospholipid, the 1,2-dipalmitoyl-sn-glycero-3 phosphoethanolamine (DPPE), and HA of two different low molecular weights 4800 Da (12 disaccharidic units) and 12,000 Da (32 disaccharidic units), were prepared, characterized, and introduced in the liposomes during the preparation. Different liposomal formulations were prepared and their characteristics were analyzed: size, Z potential, and TEM analyses underline a difference in the HA-liposomes from the non-HA ones. In order to better understand the HA-liposome cellular localization and to evaluate their interaction with CD44 receptor, confocal microscopy studies were performed. The results demonstrate that HA facilitates the recognition of liposomes by MiaPaCa2 cells (CD44(+)) and that the uptake increases with increase in the polymer molecular weight. Finally, the cytotoxicity of the different preparations was evaluated and data show that incorporation of C12GEM increases their cytotoxic activity and that HA-liposomes inhibit cell growth more than plain liposomes. Altogether, the results demonstrate the specificity of C12GEM targeting toward CD44-overexpressing pancreatic adenocarcinoma cell line using HA as a ligand. PMID- 23791685 TI - Investigating the feasibility of temperature-controlled accelerated drug release testing for an intravaginal ring. AB - The objective of the present study was to investigate if temperature can be utilized to accelerate drug release from Nuvaring(r), a reservoir type intravaginal ring based on polyethylene vinyl acetate copolymer that releases a constant dose of contraceptive steroids over a duration of 3 weeks. The reciprocating holder apparatus (USP 7) was utilized to determine real-time and accelerated etonogestrel release from ring segments. It was demonstrated that drug release increased with increasing temperature which can be attributed to enhanced drug diffusion. An Arrhenius relationship of the zero-order release constants was established, indicating that temperature is a valid parameter to accelerate drug release from this dosage form and that the release mechanism is maintained under these accelerated test conditions. Accelerated release tests are particularly useful for routine quality control to assist during batch release of extended release formulations that typically release the active over several weeks, months or even years, since they can increase the product shelf life. The accelerated method should therefore be able to discriminate between formulations with different release characteristics that can result from normal manufacturing variance. In the case of Nuvaring(r), it is well known that the process parameters during the extrusion process strongly influence the polymeric structure. These changes in the polymeric structure can affect the permeability which, in turn, is reflected in the release properties. Results from this study indicate that changes in the polymeric structure can lead to a different temperature dependence of the release rate, and as a consequence, the accelerated method can become less sensitive to detect changes in the release properties. When the accelerated method is utilized during batch release, it is therefore important to take this possible restriction into account and to evaluate the accelerated method with samples from non-conforming batches that are explicitly "out of specification" under real-time test conditions. PMID- 23791686 TI - The efficacy of intravenous immunoglobulin on lipopolysaccharide-induced fetal brain inflammation in preterm rats. AB - OBJECTIVE: Interleukin-1 is accepted as one of the major cytokines; it is involved in inflammatory processes and systemic fetal inflammatory response that is triggered by maternal lipopolysaccharide (LPS) injection. Because it is an antiinflammatory agent, we investigated (in the brain damage of rat pups) the role of intravenous immunoglobulin (IVIG) in decreasing interleukin-1 beta (IL 1beta) expression and caspase 3 activity that was induced by maternal LPS administration. STUDY DESIGN: Dams were divided into 3 groups. Pyrogen-free saline solution (NS) was administered intraperitoneally to group 1; LPS (0.3 mg/kg) suspension in NS was administered to groups 2 and 3 at 19 days of gestation. Two hours after the first injection, a second injection of NS was administered intravenously to group 1 (NS + NS), of IVIG was administered intravenously to group 2 (LPS + IVIG), and of NS was administered intravenously to group 3 (LPS + NS). Hysterectomy was performed in one-half of the dams 2 hours after the second injection and in the other one-half of the dams 22 hours after the second injection. Pups were delivered, and the brains were extracted just after delivery. IL-1beta expression and caspase 3 activity were determined in brain tissues. RESULTS: For the pups at 4 hours, the IL-1beta expression of group 2 was significantly lower than groups 1 and 3. For the pups at 24 hours, the IL 1beta expression of group 2 was significantly lower than group 3 but was similar to group 1. For the pups at 24 hours, caspase 3 activity of groups 1 and 2 were significantly lower than group 3. CONCLUSION: Maternal IVIG administration decreased IL-1beta expression and caspase 3 activity in the brain tissue of rat pups, which had been induced by maternal LPS-administration. PMID- 23791687 TI - Combined medroxyprogesterone acetate/levonorgestrel-intrauterine system treatment in young women with early-stage endometrial cancer. AB - OBJECTIVE: The purpose of this study was to evaluate the efficacy of the combined oral medroxyprogesterone acetate (MPA)/levonorgestrel-intrauterine system (LNG IUS) treatment in young women with early-stage endometrial cancer who wish to preserve their fertility. STUDY DESIGN: A prospective observational study was conducted. The study population comprised women aged <=40 years who were diagnosed with endometrioid endometrial cancer, grade 1, tumor size <2 cm presumably confined to the endometrium. A LNG-IUS was inserted in the uterine cavity of each woman, and all of the women received oral MPA (500 mg/d). Dilation was conducted every 3 months. RESULTS: From September 2008 to December 2012, 16 patients were enrolled. The overall complete remission rate was 87.5% (14/16 patients); the average time to complete remission was 9.8 +/- 8.9 months (range, 3-35 months). In the initial 3 months of treatment, complete remission was observed in 25% of cases (4/16 patients), partial response in 25% (4/16), and no change in 50% (8/16); there were no cases of progressive disease. Three patients achieved pregnancies. The average follow-up period was 31.1 +/- 11.8 months (range, 16-50 months), and there were no treatment-related complications. CONCLUSION: Combined oral MPA/LNG-IUS treatment is considered to be effective and favorable for young patients with early-stage endometrial cancer who want to preserve their fertility. PMID- 23791688 TI - Cost-effectiveness analysis of cervical length measurement and fibronectin testing in women with threatened preterm labor. AB - OBJECTIVE: The objective of the study was to evaluate the cost-effectiveness of risk stratification with cervical length (CL) measurement and/or fetal fibronectin (fFN) tests in women with threatened preterm labor between 24 and 34 weeks' gestation. STUDY DESIGN: We performed a model-based cost-effectiveness analysis to evaluate 7 test-treatment strategies in women with threatened preterm labor from a health care system perspective. Estimates on disease prevalence, costs, and test accuracy were based on medical literature. RESULTS: We found that additional fFN testing in the case of a CL between 10 and 30 mm is cost saving without compromising neonatal health outcomes, compared with a treat-all strategy or single CL testing. Implementing this strategy could lead to an annual cost saving between ?2.8 million and ?14.4 million in The Netherlands, a country with about 180,000 deliveries annually. CONCLUSION: In women with threatened preterm labor between 24 and 34 weeks of gestation, the most cost-effective test strategy uses a combination of CL and fFN testing. PMID- 23791690 TI - Prediction of cesarean delivery using the fetal-pelvic index. AB - OBJECTIVE: The purpose of this study was to estimate the usefulness of the fetal pelvic index (FPI) in the prediction of cesarean delivery among nulliparous and women who undergo a trial of labor after cesarean delivery (TOLAC). STUDY DESIGN: This prospective cohort study included subjects at 2 hospitals from the University of Pennsylvania Health system. The study sample included nulliparous women and women who attempted TOLAC, with nonanomalous pregnancies at >=37 weeks of gestation in vertex presentation (n = 221 and 207, respectively). FPI score was calculated with the ultrasound-based fetal biometric measures that were performed within 2 weeks of delivery and x-ray pelvimetry that was performed within 48 hours of delivery. Multivariable logistic regression was used to develop a clinical predictive index for cesarean delivery, which included FPI and clinical factors, in nulliparous women or women who attempted TOLAC. The prediction models were tested for accuracy with the area under the receiver operating characteristics curve. RESULTS: Higher FPI scores were associated with greater odds of cesarean delivery. A unit increase in FPI score increased the odds of cesarean delivery by 15% (adjusted odds ratio, 1.15; 95% confidence interval, 1.09-1.21) for nulliparous women and 15% for women who attempted TOLAC (adjusted odds ratio, 1.15; 95% confidence interval, 1.10-1.20) after adjustment for maternal age, race, medical risk factors, and labor method. Among nulliparous women, the receiver operating characteristics analysis estimated an area under the curve of 0.88, with positive and negative predictive values of 76% and 87%, respectively. Similar findings were observed in the subgroup of women who attempted TOLAC. CONCLUSION: The FPI when combined with clinical risk factors can identify accurately women who are at a high risk for cesarean delivery. PMID- 23791689 TI - Hypertension in pregnancy is associated with elevated homocysteine levels later in life. AB - OBJECTIVE: Hyperhomocysteinemia is associated with an elevated cardiovascular disease risk. We examined whether women with a history of hypertension in pregnancy are more likely to have a high level of serum homocysteine decades after pregnancy. STUDY DESIGN: Serum homocysteine was measured at a mean age of 60 years in nulliparous women (n = 216), and women with a history of normotensive (n = 1825) or hypertensive (n = 401) pregnancies who participated in the Genetic Epidemiology Network of Arteriopathy (GENOA) study. Relationships between homocysteine and pregnancy history were examined by linear and logistic regression, controlling for multiple covariates including personal and family history of hypertension, diabetes, obesity, tobacco use, and demographics. RESULTS: A history of hypertension in pregnancy, when compared with normotensive pregnancy, was associated with a 4.5% higher serum homocysteine level (P = .015) and 1.60-fold increased odds of having an elevated homocysteine (95% confidence interval, 1.15-2.21; P = .005) after adjusting for potentially confounding covariates. In contrast, a history of normotensive pregnancy, as compared with nulliparity, was associated with a 6.1% lower serum homocysteine level (P = .005) and a 0.49-fold reduced odds of elevated homocysteine levels (95% confidence interval, 0.32-0.74; P < .001). CONCLUSION: Homocysteine levels decades after pregnancy are higher in women with a history of pregnancy hypertension, even after controlling for potential confounders. Thus, pregnancy history may prompt homocysteine assessment and risk modification in an attempt at primary prevention of cardiovascular disease. PMID- 23791691 TI - Maternal preeclampsia and bone mineral density of the adult offspring. AB - OBJECTIVE: Preterm birth at very low birthweight (<1500 g) is associated with cardiometabolic risk factors and reduced bone mineral density in the adult offspring. Preeclampsia is a frequent cause of preterm birth and is also associated with cardiometabolic risk factors in the offspring. Whether it is associated with bone mineral density is not known. STUDY DESIGN: We evaluated skeletal health in participants of the Helsinki Study of Very Low Birthweight Adults: 144 born at very low birthweight and 139 born at term. From the very low birthweight and term offspring a respective 32 and 11 were born from pregnancy complicated by preeclampsia. We measured bone mineral density at age 18.5 to 27.1 years by dual X-ray absorptiometry. RESULTS: Very low birthweight adults exposed to maternal preeclampsia had higher lumbar spine Z score (mean -0.44, compared with -1.07 in very low birthweight unexposed adults, P = .002), femoral neck Z score (-0.05 vs -0.53, P = .003) and whole body bone mineral density Z score ( 0.14 vs -0.72, P = .001). Corresponding Z scores for those born at term were 0.02 (preeclampsia) and -0.45 (no preeclampsia) for lumbar spine (P = .2), 0.78 and 0.08 for femoral neck (P = .02) and 0.02 and -0.31 for whole body bone mineral density Z score (P = .08). The results survived adjustment for offspring current height, body mass index, leisure time physical activity, socioeconomic position, smoking, and maternal smoking during pregnancy, and maternal prepregnancy body mass index. CONCLUSION: Young adults exposed to maternal preeclampsia have higher bone mineral density than those not exposed. This difference is seen among those born at very low birthweight and seems also to be present among those born at term. PMID- 23791692 TI - Apgar score of 0 at 5 minutes and neonatal seizures or serious neurologic dysfunction in relation to birth setting. AB - OBJECTIVE: To examine the occurrence of 5-minute Apgar scores of 0 and seizures or serious neurologic dysfunction for 4 groups by birth setting and birth attendant (hospital physician, hospital midwife, free-standing birth center midwife, and home midwife) in the United States from 2007-2010. METHODS: Data from the United States Centers for Disease Control's National Center for Health Statistics birth certificate data files were used to assess deliveries by physicians and midwives in and out of the hospital for the 4-year period from 2007-2010 for singleton term births (>=37 weeks' gestation) and >=2500 g. Five minute Apgar scores of 0 and neonatal seizures or serious neurologic dysfunction were analyzed for 4 groups by birth setting and birth attendant (hospital physician, hospital midwife, freestanding birth center midwife, and home midwife). RESULTS: Home births (relative risk [RR], 10.55) and births in free standing birth centers (RR, 3.56) attended by midwives had a significantly higher risk of a 5-minute Apgar score of 0 (P < .0001) than hospital births attended by physicians or midwives. Home births (RR, 3.80) and births in freestanding birth centers attended by midwives (RR, 1.88) had a significantly higher risk of neonatal seizures or serious neurologic dysfunction (P < .0001) than hospital births attended by physicians or midwives. CONCLUSION: The increased risk of 5 minute Apgar score of 0 and seizures or serious neurologic dysfunction of out-of hospital births should be disclosed by obstetric practitioners to women who express an interest in out-of-hospital birth. Physicians should address patients' motivations for out-of-hospital delivery by continuously improving safe and compassionate care of pregnant, fetal, and neonatal patients in the hospital setting. PMID- 23791693 TI - Insomnia and healthcare-seeking behaviors: impact of case definitions, comorbidity, sociodemographic, and cultural factors. PMID- 23791694 TI - Differential immune modulation by deoxynivalenol (vomitoxin) in mice. AB - Mycotoxin deoxynivalenol (DON), a secondary metabolite produced by Fusarium fungi, is a contaminant in wheat, barley, and corn worldwide. It has been suggested that DON exhibits toxicity in various organs. Due to the lack of immunotoxicity data for DON, we investigated the differential immunomodulatory effects of DON in mice. DON was orally administered to female BALB/c mice at a dose of 0, 0.5, or 2mg/kg body weight for 14 days and various immunotoxicity tests were performed with standard protocols. The population of CD19(+) and CD11c(+) cells in the spleen and mesenteric lymph node (MLN) and of F4/80(+) cells in the spleen was significantly decreased in DON-treated mice, whereas the level of CD8(+) and CD4(+)CD25(+)Foxp3(+) cells in the spleen and CD4(+) T cells in MLN was significantly increased. In intra-epithelial lymphocytes (IELs) of the small intestine, the population of CD4 (+) and CD19(+) cells was increased but that of CD8(+) cells was decreased. Levels of CD4 (+) and CD8(+) cells were decreased in lamina propria lymphocytes (LPLs) of small intestine; however, the level of CD4(+) and CD8(+) lymphocytes was increased but that of CD19(+) cells was decreased in Peyer's patches lymphocytes (PPLs). Normalized expression of TLR4 in spleen, TLR9 in PPs, and TLR2, TLR3 and TLR4 in MLNs was significantly decreased, whereas expression of TLR5 and TLR9 was increased in spleen. The concentration of IgA and IgE was decreased and increased, respectively, in serum; however, the mucosal IgA level was significantly increased in the duodenum. Levels of IFN-gamma, IL-2, IL-4, and IL-6 were significantly increased in serum. Furthermore, DON induced apoptosis in spleen, MLNs, and PPs, and DON-induced apoptosis was promoted by increased expression of Bax and decreased expression of Bcl-2. The autophagy genes Atg5 and Beclin-1 were up-regulated in spleen but down regulated in MLN. After priming of the RAW 264.7 macrophage cell line with different TLR ligands, DON exposure differentially modulated IL-1beta, IL-10, and TNF-alpha production. These results indicate that DON can cause various immunomodulatory effects in mice, creating a milieu that might allow invasion by other microorganisms. PMID- 23791695 TI - Health care professional communication about STI vaccines with adolescents and parents. AB - Vaccination of adolescents against sexually transmitted infections (STIs) is an important prevention strategy that may reduce the global burden of disease. The World Health Organization, Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices, and other national health agencies recommend the use of existing STI vaccines, and many countries have incorporated them into their routine vaccination schedule. Despite this, however, data indicate that STI vaccine uptake is suboptimal for a variety of reasons. Health care professionals (HCP) have been shown to have a strong beneficial effect on STI vaccine uptake, yet studies demonstrate that many HCPs fail to discuss or recommend them to adolescent patients. This review article focuses on HCP communication about STI vaccines with adolescents and their parents. It describes STI vaccine message content and delivery as well as the context in which HCPs formulate their messaging approach. It also examines other contextual factors that may shape communication about STI vaccines. Studies from many countries indicate that HCPs often possess misinformation about adolescents, including their sexual risk behaviors, as well as STIs, vaccine safety and efficacy, and STI vaccination recommendations. They also have misconceptions of parental barriers to STI vaccination. These may impact STI vaccine communication and have a negative influence on STI vaccine uptake. These findings highlight the critical need for improved HCP education related to adolescent health, sexuality, and STI vaccination. This may be particularly important in settings without an existing infrastructure or expertise in caring for this unique patient population. PMID- 23791696 TI - Dengue dynamics and vaccine cost-effectiveness in Brazil. AB - Recent Phase 2b dengue vaccine trials have demonstrated the safety of the vaccine and estimated the vaccine efficacy with further trials underway. In anticipation of vaccine roll-out, cost-effectiveness analysis of potential vaccination policies that quantify the dynamics of disease transmission are fundamental to the optimal allocation of available doses. We developed a dengue transmission and vaccination model and calculated, for a range of vaccination costs and willingness-to-pay thresholds, the level of vaccination coverage necessary to sustain herd-immunity, the price at which vaccination is cost-effective and is cost-saving, and the sensitivity of our results to parameter uncertainty. We compared two vaccine efficacy scenarios, one a more optimistic scenario and another based on the recent lower-than-expected efficacy from the latest clinical trials. We found that herd-immunity may be achieved by vaccinating 82% (95% CI 58 100%) of the population at a vaccine efficacy of 70%. At this efficacy, vaccination may be cost-effective for vaccination costs up to US$ 534 (95% CI $369-1008) per vaccinated individual and cost-saving up to $204 (95% CI $39-678). At the latest clinical trial estimates of an average of 30% vaccine efficacy, vaccination may be cost-effective and cost-saving at costs of up to $237 (95% CI $159-512) and $93 (95% CI $15-368), respectively. Our model provides an assessment of the cost-effectiveness of dengue vaccination in Brazil and incorporates the effect of herd immunity into dengue vaccination cost effectiveness. Our results demonstrate that at the relatively low vaccine efficacy from the recent Phase 2b dengue vaccine trials, age-targeted vaccination may still be cost-effective provided the total vaccination cost is sufficiently low. PMID- 23791697 TI - In situ effect of chewing gum containing CPP-ACP on the mineral precipitation of eroded bovine enamel-a surface hardness analysis. AB - OBJECTIVES: Stimulation of salivary flow is considered a preventive strategy for dental erosion. Alternatively, products containing calcium phosphate, such as a complex of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP), have also been tested against dental erosion. Therefore, this in situ study analyzed the effect of chewing gum containing CPP-ACP on the mineral precipitation of initial bovine enamel erosion lesions. METHODS: Twelve healthy adult subjects wore palatal appliances with two eroded bovine enamel samples. The erosion lesions were produced by immersion in 0.1% citric acid (pH 2.5) for 7 min. During three experimental crossover in situ phases (1 day each), the subjects chewed a type of gum, 3 times for 30 min, in each phase: with CPP-ACP (trident total), without CPP ACP (trident), and no chewing gum (control). The Knoop surface microhardness was measured at baseline, after erosion in vitro and the mineral precipitation in situ. The differences in the degree of mineral precipitation were analyzed using repeated measures (RM-) ANOVA and post hoc Tukey's test (p<0.05). RESULTS: Significant differences were found among the remineralizing treatments (p<0.0001). Chewing gum (19% of microhardness recovery) improved the mineral precipitation compared to control (10%) and the addition of CPP-ACP into the gum promoted the best mineral precipitation effect (30%). CONCLUSIONS: Under this protocol, CPP-ACP chewing gum improved the mineral precipitation of eroded enamel. CLINICAL SIGNIFICANCE: Since the prevalence of dental erosion is steadily increasing, CPP-ACP chewing gum might be an important strategy to reduce the progression of initial erosion lesions. PMID- 23791698 TI - Validity of caries risk assessment programmes in preschool children. AB - OBJECTIVES: Various programmes have been developed for caries risk assessment (CRA). Nevertheless, scientific evidence on their validity is lacking. This study aimed to compare the validity of 4 CRA programmes (CAT, CAMBRA, Cariogram, and NUS-CRA) in predicting early childhood caries. METHODS: A total of 544 children aged 3 years underwent oral examination and biological tests (saliva flow rate, salivary buffering capacity and abundance of cariogenic bacteria mutans Streptococci and Lactobacilli). Their parents completed a questionnaire. Children's caries risk was predicted using the 4 study programmes without biological tests (screening mode) and with biological tests (comprehensive mode). After 12 months, caries increment in 485 (89%) children was recorded and compared with the baseline risk predictions. RESULTS: Reasoning-based programmes (CAT and CAMBRA screening) had high sensitivity (>= 93.8%) but low specificity (<= 43.6%) in predicting caries in children. CAMBRA comprehensive assessment reached a better balance (sensitivity/specificity of 83.7%/62.9%). Algorithm-based programmes (Cariogram and NUS-CRA) generated better predictions. The sensitivity/specificity of NUS-CRA screening and comprehensive models were 73.6%/84.7% and 78.1%/85.3%, respectively, higher than those of the Cariogram screening (62.9%/77.9%) and comprehensive assessment (64.6%/78.5%). NUS-CRA comprehensive model met the criteria for a useful CRA tool (sensitivity+specificity >= 160%), while its screening model approached that target. CONCLUSIONS: Our results supported algorithm-based approach of caries risk modelling and the usefulness of NUS-CRA in identifying children susceptible to caries. CLINICAL SIGNIFICANCE: This prospective study provided evidence for practitioners to select tools for assessing children's caries risk, so that prevention measures can be tailored and treatment plan can be optimised. PMID- 23791699 TI - Plant-animal mutualism in biological markets: evolutionary and ecological dynamics driven by non-heritable phenotypic variance. AB - Mutualism between plants and animals, such as in pollination and seed dispersal, is a fundamental mechanism facilitating the productivity and biodiversity of ecosystems, and it is often considered as an analog of a free-market economy. The coevolution of plant reward and animal choosiness, however, involves an apparent paradox due to incomplete information and limited mutation rates: plant rewards evolve only when animals are choosy, but choosy animals purge the heritable variations of plants, which then favors less choosy animals. Here we use a two species mathematical model to illustrate how non-heritable phenotypic variances of plants may facilitate the coevolution of rewards and choosiness and solve the paradox with low mutation rates. We simultaneously track the ecological and evolutionary dynamics and show that the population ratio links the two processes and tunes the stable eco-evolutionary equilibrium. Numerical simulations confirm the analytic prediction with varying mutation rates (heritable variance). The efficiency of a biological market is generally suboptimal due to the information constraint and individual competition. PMID- 23791700 TI - A serine palmitoyltransferase inhibitor blocks hepatitis C virus replication in human hepatocytes. AB - BACKGROUND & AIMS: Host cell lipid rafts form a scaffold required for replication of hepatitis C virus (HCV). Serine palmitoyltransferases (SPTs) produce sphingolipids, which are essential components of the lipid rafts that associate with HCV nonstructural proteins. Prevention of the de novo synthesis of sphingolipids by an SPT inhibitor disrupts the HCV replication complex and thereby inhibits HCV replication. We investigated the ability of the SPT inhibitor NA808 to prevent HCV replication in cells and mice. METHODS: We tested the ability of NA808 to inhibit SPT's enzymatic activity in FLR3-1 replicon cells. We used a replicon system to select for HCV variants that became resistant to NA808 at concentrations 4- to 6-fold the 50% inhibitory concentration, after 14 rounds of cell passage. We assessed the ability of NA808 or telaprevir to inhibit replication of HCV genotypes 1a, 1b, 2a, 3a, and 4a in mice with humanized livers (transplanted with human hepatocytes). NA808 was injected intravenously, with or without pegylated interferon alfa-2a and HCV polymerase and/or protease inhibitors. RESULTS: NA808 prevented HCV replication via noncompetitive inhibition of SPT; no resistance mutations developed. NA808 prevented replication of all HCV genotypes tested in mice with humanized livers. Intravenous NA808 significantly reduced viral load in the mice and had synergistic effects with pegylated interferon alfa-2a and HCV polymerase and protease inhibitors. CONCLUSIONS: The SPT inhibitor NA808 prevents replication of HCV genotypes 1a, 1b, 2a, 3a, and 4a in cultured hepatocytes and in mice with humanized livers. It might be developed for treatment of HCV infection or used in combination with pegylated interferon alfa-2a or HCV polymerase or protease inhibitors. PMID- 23791702 TI - Upper abdominal procedures in advanced stage ovarian or primary peritoneal carcinoma patients with minimal or no gross residual disease: an analysis of Gynecologic Oncology Group (GOG) 182. AB - PURPOSE: To examine the utility of upper abdominal procedures (UAPs) performed in a cohort of optimally cytoreduced patients with advanced stage epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC) and identify potential areas where aggressive surgery may impact survival. PATIENTS AND METHODS: We reviewed 2655 patients enrolled in Gynecologic Oncology Group (GOG) 182 who had complete resection (CR) or minimal residual (MR) disease <1cm. Demographic, pathologic, surgical, and outcome data were collected. UAPs included diaphragm stripping or resection, liver resection, splenectomy, pancreatectomy, and porta hepatis surgery. Effect of UAP and CR on PFS/OS was assessed by Kaplan-Meier and proportional hazards methods. RESULTS: Four-hundred eighty-two patients (18.1%) underwent a total of 590 UAPs. There were 351 (13.1%) diaphragm surgeries, 112 (4.2%) liver surgeries, 108 (4%) splenectomies, 12 (0.5%) pancreatectomies, and 7 (0.2%) porta hepatis surgeries. Comparing patients who did not have UAPs to patients who had UAPs, the PFS was 18.2 months (mos) and 14.8 mos (p < 0.01) and OS was 49.8 mos v. 43.7 mos (p = 0.01), respectively. However, in the multivariable analysis this survival benefit did not remain (PFS HR = 1.03, 95% CI 0.91-1.15; OS HR=0.92, 95%CI 0.81-1.04). The OS of the 141 patients who had an UAP and achieved CR compared to the 341 patients who had an UAP with MR was 54.6 compared to 40.4 mos (p=0.0005). CONCLUSIONS: UAP procedures should only be performed when CR is attainable. A significant proportion of patients with MR were left with diaphragmatic disease that could potentially be completely resected. PMID- 23791701 TI - Detection of pancreatic ductal adenocarcinoma in mice by ultrasound imaging of thymocyte differentiation antigen 1. AB - BACKGROUND & AIMS: Early detection of pancreatic ductal adenocarcinoma (PDAC) allows for surgical resection and increases patient survival times. Imaging agents that bind and amplify the signal of neovascular proteins in neoplasms can be detected by ultrasound, enabling accurate detection of small lesions. We searched for new markers of neovasculature in PDAC and assessed their potential for tumor detection by ultrasound molecular imaging. METHODS: Thymocyte differentiation antigen 1 (Thy1) was identified as a specific biomarker of PDAC neovasculature by proteomic analysis. Up-regulation in PDAC was validated by immunohistochemical analysis of pancreatic tissue samples from 28 healthy individuals, 15 with primary chronic pancreatitis tissues, and 196 with PDAC. Binding of Thy1-targeted contrast microbubbles was assessed in cultured cells, in mice with orthotopic PDAC xenograft tumors expressing human Thy1 on the neovasculature, and on the neovasculature of a genetic mouse model of PDAC. RESULTS: Based on immunohistochemical analyses, levels of Thy1 were significantly higher in the vascular of human PDAC than chronic pancreatitis (P = .007) or normal tissue samples (P < .0001). In mice, ultrasound imaging accurately detected human Thy1-positive PDAC xenografts, as well as PDACs that express endogenous Thy1 in genetic mouse models of PDAC. CONCLUSIONS: We have identified and validated Thy1 as a marker of PDAC that can be detected by ultrasound molecular imaging in mice. The development of a specific imaging agent and identification of Thy1 as a new biomarker could aid in the diagnosis of this cancer and management of patients. PMID- 23791703 TI - Characterization of the mouse ClC-K1/Barttin chloride channel. AB - Several Cl(-) channels have been described in the native renal tubule, but their correspondence with ClC-K1 and ClC-K2 channels (orthologs of human ClC-Ka and ClC Kb), which play a major role in transcellular Cl(-) absorption in the kidney, has yet to be established. This is partly because investigation of heterologous expression has involved rat or human ClC-K models, whereas characterization of the native renal tubule has been done in mice. Here, we investigate the electrophysiological properties of mouse ClC-K1 channels heterologously expressed in Xenopus laevis oocytes and in HEK293 cells with or without their accessory Barttin subunit. Current amplitudes and plasma membrane insertion of mouse ClC-K1 were enhanced by Barttin. External basic pH or elevated calcium stimulated currents followed the anion permeability sequence Cl(-)>Br(-)>NO3(-)>I(-). Single channel recordings revealed a unit conductance of ~40pS. Channel activity in cell attached patches increased with membrane depolarization (voltage for half-maximal activation: ~-65mV). Insertion of the V166E mutation, which introduces a glutamate in mouse ClC-K1, which is crucial for channel gating, reduced the unit conductance to ~20pS. This mutation shifted the depolarizing voltage for half maximal channel activation to ~+25mV. The unit conductance and voltage dependence of wild-type and V166E ClC-K1 were not affected by Barttin. Owing to their strikingly similar properties, we propose that the ClC-K1/Barttin complex is the molecular substrate of a chloride channel previously detected in the mouse thick ascending limb (Paulais et al., J Membr. Biol, 1990, 113:253-260). PMID- 23791704 TI - How does acyl chain length affect thermotropic phase behavior of saturated diacylphosphatidylcholine-cholesterol binary bilayers? AB - Thermotropic phase behavior of diacylphosphatidylcholine (CnPC)-cholesterol binary bilayers (n=14-16) was examined by fluorescence spectroscopy using 6 propionyl-2-(dimethylamino)naphthalene (Prodan) and differential scanning calorimetry. The former technique can detect structural changes of the bilayer in response to the changes in polarity around Prodan molecules partitioned in a relatively hydrophilic region of the bilayer, while the latter is sensitive to the conformational changes of the acyl chains. On the basis of the data from both techniques, we propose possible temperature T-cholesterol composition Xch phase diagrams for these binary bilayers. A notable feature of our phase diagrams, including our previous results for diheptadecanoylphosphatidylcholine (C17PC) and distearoylphosphatidylcholine (C18PC), is that there is a peritectic-like point around Xch=0.15, which can be interpreted as indicating the formation of a 1:6 complex of cholesterol and CnPCs within the binary bilayer irrespective of the acyl chain length. We could give a reasonable explanation for such complex formation using the modified superlattice view. Our results also showed that the Xch value of the abolition of the main transition is almost constant for n=14-17 (ca. 0.33), while it increases to ca. 0.50 for n=18. By contrast, a biphasic n dependence of Xch was observed for the abolition of the pretransition, suggesting that there are at least two antagonistic n-dependent factors. We speculate that this could be explained by the enhancement of the van der Waals interaction with increases in n and the weakening of the repulsion between the neighboring headgroups with decreases in n. PMID- 23791705 TI - Effects of water gradients and use of urea on skin ultrastructure evaluated by confocal Raman microspectroscopy. AB - The rather thin outermost layer of the mammalian skin, stratum corneum (SC), is a complex biomembrane which separates the water rich inside of the body from the dry outside. The skin surface can be exposed to rather extreme variations in ambient conditions (e.g. water activity, temperature and pH), with potential effects on the barrier function. Increased understanding of how the barrier is affected by such changes is highly relevant for regulation of transdermal uptake of exogenous chemicals. In the present study we investigate the effect of hydration and the use of a well-known humectant, urea, on skin barrier ultrastructure by means of confocal Raman microspectroscopy. We also perform dynamic vapor sorption (DVS) microbalance measurements to examine the water uptake capacity of SC pretreated with urea. Based on novel Raman images, constructed from 2D spectral maps, we can distinguish large water inclusions within the skin membrane exceeding the size of fully hydrated corneocytes. We show that these inclusions contain water with spectral properties similar to that of bulk water. The results furthermore show that the ambient water activity has an important impact on the formation of these water inclusions as well as on the hydration profile across the membrane. Urea significantly increases the water uptake when present in skin, as compared to skin without urea, and it promotes formation of larger water inclusions in the tissue. The results confirm that urea can be used as a humectant to increase skin hydration. PMID- 23791706 TI - Viral potassium channels as a robust model system for studies of membrane-protein interaction. AB - The viral channel KcvNTS belongs to the smallest K(+) channels known so far. A monomer of a functional homotetramer contains only 82 amino acids. As a consequence of the small size the protein is almost fully submerged into the membrane. This suggests that the channel is presumably sensitive to its lipid environment. Here we perform a comparative analysis for the function of the channel protein embedded in three different membrane environments. 1. Single channel currents of KcvNTS were recorded with the patch clamp method on the plasma membrane of HEK293 cells. 2. They were also measured after reconstitution of recombinant channel protein into classical planar lipid bilayers and 3. into horizontal bilayers derived from giant unilamellar vesicles (GUVs). The recombinant channel protein was either expressed and purified from Pichia pastoris or from a cell-free expression system; for the latter a new approach with nanolipoprotein particles was used. The data show that single-channel activity can be recorded under all experimental conditions. The main functional features of the channel like a large single-channel conductance (80pS), high open probability (>50%) and the approximate duration of open and closed dwell times are maintained in all experimental systems. An apparent difference between the approaches was only observed with respect to the unitary conductance, which was ca. 35% lower in HEK293 cells than in the other systems. The reason for this might be explained by the fact that the channel is tagged by GFP when expressed in HEK293 cells. Collectively the data demonstrate that the small viral channel exhibits a robust function in different experimental systems. This justifies an extrapolation of functional data from these systems to the potential performance of the channel in the virus/host interaction. This article is part of a Special Issue entitled: Viral Membrane Proteins-Channels for Cellular Networking. PMID- 23791708 TI - An introduction to statistical process control in research proteomics. AB - BACKGROUND: Statistical process control is a well-established and respected method which provides a general purpose, and consistent framework for monitoring and improving the quality of a process. It is routinely used in many industries where the quality of final products is critical and is often required in clinical diagnostic laboratories [1,2]. To date, the methodology has been little utilised in research proteomics. It has been shown to be capable of delivering quantitative QC procedures for qualitative clinical assays [3] making it an ideal methodology to apply to this area of biological research. OBJECTIVE: To introduce statistical process control as an objective strategy for quality control and show how it could be used to benefit proteomics researchers and enhance the quality of the results they generate. RESULTS: We demonstrate that rules which provide basic quality control are easy to derive and implement and could have a major impact on data quality for many studies. CONCLUSIONS: Statistical process control is a powerful tool for investigating and improving proteomics research work-flows. The process of characterising measurement systems and defining control rules forces the exploration of key questions that can lead to significant improvements in performance. BIOLOGICAL SIGNIFICANCE: This work asserts that QC is essential to proteomics discovery experiments. Every experimenter must know the current capabilities of their measurement system and have an objective means for tracking and ensuring that performance. Proteomic analysis work-flows are complicated and multi-variate. QC is critical for clinical chemistry measurements and huge strides have been made in ensuring the quality and validity of results in clinical biochemistry labs. This work introduces some of these QC concepts and works to bridge their use from single analyte QC to applications in multi-analyte systems. This article is part of a Special Issue entitled: Standardization and Quality Control in Proteomics. PMID- 23791707 TI - gamma-Secretase inhibitors and modulators. AB - gamma-Secretase is a fascinating, multi-subunit, intramembrane cleaving protease that is now being considered as a therapeutic target for a number of diseases. Potent, orally bioavailable gamma-secretase inhibitors (GSIs) have been developed and tested in humans with Alzheimer's disease (AD) and cancer. Preclinical studies also suggest the therapeutic potential for GSIs in other disease conditions. However, due to inherent mechanism based-toxicity of non-selective inhibition of gamma-secretase, clinical development of GSIs will require empirical testing with careful evaluation of benefit versus risk. In addition to GSIs, compounds referred to as gamma-secretase modulators (GSMs) remain in development as AD therapeutics. GSMs do not inhibit gamma-secretase, but modulate gamma-secretase processivity and thereby shift the profile of the secreted amyloid beta peptides (Abeta) peptides produced. Although GSMs are thought to have an inherently safe mechanism of action, their effects on substrates other than the amyloid beta protein precursor (APP) have not been extensively investigated. Herein, we will review the current state of development of GSIs and GSMs and explore pertinent biological and pharmacological questions pertaining to the use of these agents for select indications. This article is part of a Special Issue entitled: Intramembrane Proteases. PMID- 23791710 TI - Biomarkers in Parkinson's disease (recent update). AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder mostly affecting the aging population over sixty. Cardinal symptoms including, tremors, muscle rigidity, drooping posture, drooling, walking difficulty, and autonomic symptoms appear when a significant number of nigrostriatal dopaminergic neurons are already destroyed. Hence we need early, sensitive, specific, and economical peripheral and/or central biomarker(s) for the differential diagnosis, prognosis, and treatment of PD. These can be classified as clinical, biochemical, genetic, proteomic, and neuroimaging biomarkers. Novel discoveries of genetic as well as nongenetic biomarkers may be utilized for the personalized treatment of PD during preclinical (premotor) and clinical (motor) stages. Premotor biomarkers including hyper-echogenicity of substantia nigra, olfactory and autonomic dysfunction, depression, hyposmia, deafness, REM sleep disorder, and impulsive behavior may be noticed during preclinical stage. Neuroimaging biomarkers (PET, SPECT, MRI), and neuropsychological deficits can facilitate differential diagnosis. Single-cell profiling of dopaminergic neurons has identified pyridoxal kinase and lysosomal ATPase as biomarker genes for PD prognosis. Promising biomarkers include: fluid biomarkers, neuromelanin antibodies, pathological forms of alpha-Syn, DJ-1, amyloid beta and tau in the CSF, patterns of gene expression, metabolomics, urate, as well as protein profiling in the blood and CSF samples. Reduced brain regional N-acetyl-aspartate is a biomarker for the in vivo assessment of neuronal loss using magnetic resonance spectroscopy and T2 relaxation time with MRI. To confirm PD diagnosis, the PET biomarkers include [(18)F]-DOPA for estimating dopaminergic neurotransmission, [(18)F]dG for mitochondrial bioenergetics, [(18)F]BMS for mitochondrial complex-1, [(11)C](R) PK11195 for microglial activation, SPECT imaging with (123)Iflupane and betaCIT for dopamine transporter, and urinary salsolinol and 8-hydroxy, 2-deoxyguanosine for neuronal loss. This brief review describes the merits and limitations of recently discovered biomarkers and proposes coenzyme Q10, mitochondrial ubiquinone-NADH oxidoreductase, melatonin, alpha-synculein index, Charnoly body, and metallothioneins as novel biomarkers to confirm PD diagnosis for early and effective treatment of PD. PMID- 23791711 TI - The role of alpha-synuclein in the pathophysiology of alcoholism. AB - Alcoholism has complex etiology and there is evidence for both genetic and environmental factors in its pathophysiology. Chronic, long-term alcohol abuse and alcohol dependence are associated with neuronal loss with the prefrontal cortex being particularly susceptible to neurotoxic damage. This brain region is involved in the development and persistence of alcohol addiction and neurotoxic damage is likely to exacerbate the reinforcing effects of alcohol and may hinder treatment. Understanding the mechanism of alcohol's neurotoxic effects on the brain and the genetic risk factors associated with alcohol abuse are the focus of current research. Because of its well-established role in neurodegenerative and neuropsychological disorders, and its emerging role in the pathophysiology of addiction, here we review the genetic and epigenetic factors involved in regulating alpha-synuclein expression and its potential role in the pathophysiology of chronic alcohol abuse. Elucidation of the mechanisms of alpha synuclein regulation may prove beneficial in understanding the role of this key synaptic protein in disease and its potential for therapeutic modulation in the treatment of substance use disorders as well as other neurodegenerative diseases. PMID- 23791713 TI - Ventricular arrhythmias due to left ventricular noncompaction cardiomyopathy: a diagnosis in hindsight. AB - Left ventricular noncompaction cardiomyopathy is a rare congenital cardiomyopathy which predisposes to sudden cardiac death. We describe the case of a 24 year-old man who had previously received an implantable cardioverter-defibrillator for sustained ventricular tachycardia and was later diagnosed with left ventricular noncompaction cardiomyopathy during a hospitalisation for device infection. PMID- 23791709 TI - Regulation of astrocyte glutamine synthetase in epilepsy. AB - Astrocytes play a crucial role in regulating and maintaining the extracellular chemical milieu of the central nervous system under physiological conditions. Moreover, proliferation of phenotypically altered astrocytes (a.k.a. reactive astrogliosis) has been associated with many neurologic and psychiatric disorders, including mesial temporal lobe epilepsy (MTLE). Glutamine synthetase (GS), which is found in astrocytes, is the only enzyme known to date that is capable of converting glutamate and ammonia to glutamine in the mammalian brain. This reaction is important, because a continuous supply of glutamine is necessary for the synthesis of glutamate and GABA in neurons. The known stoichiometry of glutamate transport across the astrocyte plasma membrane also suggests that rapid metabolism of intracellular glutamate via GS is a prerequisite for efficient glutamate clearance from the extracellular space. Several studies have indicated that the activity of GS in astrocytes is diminished in several brain disorders, including MTLE. It has been hypothesized that the loss of GS activity in MTLE leads to increased extracellular glutamate concentrations and epileptic seizures. Understanding the mechanisms by which GS is regulated may lead to novel therapeutic approaches to MTLE, which is frequently refractory to antiepileptic drugs. This review discusses several known mechanisms by which GS expression and function are influenced, from transcriptional control to enzyme modification. PMID- 23791712 TI - The demographic profile of young patients (<45 years-old) with acute coronary syndromes in Queensland. AB - BACKGROUND: There is little data regarding the demographic profile of young (<45 years) Australian acute coronary syndrome patients. The aim of this study was to compare baseline characteristics, risk factor profile and outcomes of young patients compared with their older counterparts referred to two metropolitan Queensland hospitals. METHODS: Over a four-year period, data on acute coronary syndrome patients referred to The Prince Charles and Royal Brisbane Hospitals were retrospectively analysed. Three major groups were identified: <45 years, 45 60 years and those >60 years. Age, sex, body mass index, risk factor profile, degree of coronary disease, left ventricular dysfunction, mode of presentation, initial pharmacological therapy and mortality data were compared between the three groups. RESULTS: 4549 patients were analysed of whom, 277 were less than 45 years old. Younger patients tended to be male, more overweight and present more commonly with ST segment elevation myocardial infarction compared to their older counterparts. Smoking, family history and dyslipidaemia tended to occur more frequently in younger patients as compared to those >45 years. Those patients >45 years tended to present with non-ST segment elevation myocardial infarction and have a higher degree of ischaemic burden and left ventricular dysfunction. No patients <45 years died in their index admission at 30 days or at one year. CONCLUSIONS: Although young patients <45 years make up the minority (6.1%) of patients presenting with acute coronary syndrome and generally have a favourable prognosis, this paper highlights the need for aggressive risk factor modification, with particular attention to smoking and dyslipidaemia, before the onset of overt clinical disease. PMID- 23791714 TI - Right ventricular loop indicating malposition of J-wire introducer for double lumen bicaval venovenous extracorporeal membrane oxygenation (VV ECMO) cannula. AB - The key to safe placement of a bicaval double lumen cannula for Venovenous Extracorporeal Membrane Oxygenation (VV ECMO) is to visualise correct guide wire placement in the inferior vena cava (IVC), thus aiding subsequent correct advancement of the cannula. Transoesophageal (TOE) and transthoracic (TTE) echocardiography, as well as fluoroscopy, have been described as aiding imaging techniques. We report a case of guide wire malposition into the right ventricle, despite echocardiographic confirmation of guide wire position deep into the IVC. This malposition, if undetected, may have resulted in potential life threatening complications. PMID- 23791715 TI - Valvular and aortic diseases in osteogenesis imperfecta. AB - Osteogenesis imperfecta (OI) is an inheritable connective tissue disorder caused by defective collagen synthesis with the principal manifestations of bone fragility. OI has been associated with left sided valvular regurgitation and aortic dilation. Valve and aortic surgery are technically feasible in patients with OI but are inherently high risk due to the underlying connective tissue defect. This report reviews the valvular and aortic pathology associated with OI and their management. We describe two cases of patients with OI who have significant aortic and mitral valve regurgitation, one of whom has been managed conservatively and the other who has undergone successful mitral valve repair and aortic valve replacement. The latter case represents the fifth case of mitral valve repair in a patient with OI reported in the medical literature. PMID- 23791716 TI - Polymethyl methacrylate induced pulmonary embolism. PMID- 23791717 TI - In situ forming parenteral depot systems based on poly(ethylene carbonate): effect of polymer molecular weight on model protein release. AB - The objective of this study was to investigate the effect of molecular weight (MW) on the drug release from poly(ethylene carbonate) (PEC) based surface eroding in situ forming depots (ISFD). In phosphate buffered saline (PBS) pH 7.4, 63.7% of bovine serum albumin BSA was released from high MW PEC of 200 kDa (PEC200) in DMSO (15%, w/w) in 2 days, while during the same time period, the release of BSA from PEC41 samples was only 22.5%. At higher concentrations of PEC41 (25%, w/w), the initial burst was further reduced, and even after 6 days, only 16.3% was released. Compared to depots based on PEC200, there was lower rate of solvent release, slower phase inversion, and a denser surface in PEC41 samples. An expansion in size of PEC41 depots suggested that the polymer barrier of PEC41 impeded the diffusion of solvent out of the samples effectively. In conclusion, the initial burst of protein from ISFD of PEC41 was significantly reduced, which would be a promising candidate as polymeric carrier. PMID- 23791718 TI - Iontophoretic transport kinetics of ketorolac in vitro and in vivo: demonstrating local enhanced topical drug delivery to muscle. AB - The objective of the study was to investigate the iontophoretic delivery kinetics of ketorolac (KT), a highly potent NSAID and peripherally-acting analgesic that is currently indicated to treat moderate to severe acute pain. It was envisaged that, depending on the amounts delivered, transdermal iontophoretic administration might have two distinct therapeutic applications: (i) more effective and faster local therapy with shorter onset times (e.g. to treat trauma related pain/inflammation in muscle) or (ii) a non-parenteral, gastrointestinal tract sparing approach for systemic pain relief. The first part of the study investigated the effect of experimental conditions on KT iontophoresis using porcine and human skin in vitro. These results demonstrated that KT electrotransport was linearly dependent on current density - from 0.1875 to 0.5mA/cm(2) - (r(2)>0.99) and drug concentration - from 5 to 20mg/ml (r(2)>0.99). Iontophoretic permeation of KT from a 2% hydroxymethyl cellulose gel was comparable to that from an aqueous solution with equivalent drug loading (584.59+/-114.67 and 462.05+/-66.56MUg/cm(2), respectively). Cumulative permeation (462.05+/-66.56 and 416.28+/-95.71MUg/cm(2)) and steady state flux (106.72+/-11.70 and 94.28+/-15.47MUg/cm(2)h), across porcine and human skin, were statistically equivalent confirming the validity of the model. Based on the results in vitro, it was decided to focus on topical rather than systemic applications of KT iontophoresis in vivo. Subsequent experiments, in male Wistar rats, investigated the local enhancement of KT delivery to muscle by iontophoresis. Drug biodistribution was assessed in skin, in the biceps femoris muscle beneath the site of iontophoresis ('treated muscle'; TM), in the contralateral muscle ('non-treated muscle'; NTM) and in plasma (P). Passive topical delivery and oral administration served as negative and positive controls, respectively. Iontophoretic administration for 30min was superior to passive topical delivery for 1h and resulted in statistically significant increases in KT levels in the skin (91.04+/-15.48 vs. 20.16+/-8.58MUg/cm(2)), in the biceps femoris at the treatment site (TM; 6.74+/-3.80 vs. = 5 mm was 8.25 (95%CI: 3.15-21.56; P=.0001). CONCLUSION: An EAT value >= 5 mm has good sensitivity and specificity for predicting MS in the Venezuelan population. PMID- 23791774 TI - Functional characterization of Penicillium occitanis Pol6 and Penicillium funiculosum GH11 xylanases. AB - Xylanases are hemicellulolytic enzymes, which are responsible for the degradation of heteroxylans constituting the lignocellulosic plant cell wall. Xylanases from the GH11 family are considered as true xylanases because of their high substrate specificity. In order to study in depth a crucial difference in the thumb region between two closely related xylanases from Penicillium in terms of kinetic parameters and inhibition sensitivity, the GH11 xylanases from Penicillium occitanis Pol6 (PoXyn3) and from Penicillium funiculosum (PfXynC) were heterologously expressed in Pichia pastoris. The PoXyn3 and PfXynC cDNAs encoding mature xylanases were cloned into pGAPZalphaA vectors and integrated into the genome of P. pastoris X-33 under the control of the glyceraldehyde 3-phosphate dehydrogenase constitutive promoter. PfXynC was expressed as a His-tagged recombinant protein and purified from the supernatant homogeneity by a one-step purification protocol using immobilized metal affinity chromatography. The recombinant PoXyn3 was purified using a single anion-exchange chromatography. The purified recombinant enzymes were optimally active at 45 degrees C and pH 4.0 for PoXyn3 and 40 degrees C and pH 3.0 for PfXynC. The measured kinetic parameters (k(cat) and Vmax) showed that PfXynC was five times more active than PoXyn3 irrespective of the substrate whereas the apparent affinity (K(m)) was similar. The recombinant enzymes showed distinct sensitivity to the Triticum aestivum xylanase inhibitor TAXI-I. PMID- 23791775 TI - Perceived clinical constraints in the nurse student-instructor interactions: a qualitative study. AB - Effective student-instructor interactions impact the quality of nursing clinical education. There are a myriad of different factors related to clinical settings that affect these interactions and they have received less attention in nursing studies. Identifying clinical constraints that impact the nursing student instructor relationships will help nursing instructors to manage clinical learning situations in a more effective manner. OBJECTIVE: The goal of this study was to identify the primary factors that influence the student-instructor interactions within clinical settings. METHODS: A purposeful sampling strategy was applied to recruit 18 nursing students and instructors to participate in qualitative, semi-structured interviews. In order to identify relevant themes of transcribed interviews, qualitative content analysis was utilized. RESULTS: Data analysis resulted in the development of five main themes that represent essential interaction constraints in clinical contexts. These themes include: outsiders' eyes, dominance of act, close contact, clinical workplaces' disputes, and instability and uncertainty. CONCLUSIONS: The results of this study can serve to improve the understanding and practice of international clinical nursing instructors within the clinical education context. The behaviors that emerged were based on clinical constrains and an awareness each can serve to enhance the instructor-student relationship. PMID- 23791776 TI - Influence of inter-field communication on neuronal response synchrony across auditory cortex. AB - Sensory information is encoded by cortical neurons in the form of synaptic discharge time and rate level. These neuronal codes generate response patterns across cell assemblies that are crucial to various cognitive functions. Despite pivotal information about structural and cognitive factors involved in the generation of synchronous neuronal responses such as stimulus context, attention, age, cortical depth, sensory experience, and receptive field properties, the influence of cortico-cortical connectivity on the emergence of neuronal response patterns is poorly understood. The present investigation assesses the role of cortico-cortical connectivity in the modulation of neuronal discharge synchrony across auditory cortex cell-assemblies. Acute single-unit recording techniques in combination with reversible cooling deactivation procedures were used in the domestic cat (Felis catus). Recording electrodes were positioned across primary and non-primary auditory fields and neuronal activity was measured before, during, and after synaptic deactivation of adjacent cortical regions in the presence of acoustic stimulation. Cross-correlation functions of simultaneously recorded units were generated and changes in response synchrony levels across cooling conditions were measured. Data analyses revealed significant decreases in response time coincidences between cortical neurons during periods of cortical deactivation. Collectively, the results of the present investigation demonstrate that cortical neurons participate in the modulation of response synchrony levels across neuronal assemblies of primary and non-primary auditory fields. PMID- 23791777 TI - High-resolution peripheral quantitative computed tomography and finite element analysis of bone strength at the distal radius in ovariectomized adult rhesus monkey demonstrate efficacy of odanacatib and differentiation from alendronate. AB - Translational evaluation of disease progression and treatment response is critical to the development of therapies for osteoporosis. In this study, longitudinal in-vivo monitoring of odanacatib (ODN) treatment efficacy was compared to alendronate (ALN) in ovariectomized (OVX) non-human primates (NHPs) using high-resolution peripheral computed tomography (HR-pQCT). Treatment effects were evaluated using several determinants of bone strength, density and quality, including volumetric bone mineral density (vBMD), three-dimensional structure, finite element analysis (FEA) estimated peak force and biomechanical properties at the ultradistal (UD) radius at baseline, 3, 6, 9, 12, and 18 months of dosing in three treatment groups: vehicle (VEH), low ODN (2 mg/kg/day, L-ODN), and ALN (30 MUg/kg/week). Biomechanical axial compression tests were performed at the end of the study. Bone strength estimates using FEA were validated by ex-vivo mechanical compression testing experiments. After 18months of dosing, L-ODN demonstrated significant increases from baseline in integral vBMD (13.5%), cortical thickness (24.4%), total bone volume fraction BV/TV (13.5%), FEA estimated peak force (26.6%) and peak stress (17.1%), respectively. Increases from baseline for L-ODN at 18 months were significantly higher than that for ALN in DXA-based aBMD (7.6%), cortical thickness (22.9%), integral vBMD (12.2%), total BV/TV (10.1%), FEA peak force (17.7%) and FEA peak stress (11.5%), respectively. These results demonstrate a superior efficacy of ODN treatment compared to ALN at the UD radii in ovariectomized NHPs. PMID- 23791778 TI - Fifteen days of microgravity causes growth in calvaria of mice. AB - Bone growth may occur in spaceflight as a response to skeletal unloading and head ward fluid shifts. While unloading causes significant loss of bone mass and density in legs of animals exposed to microgravity, increased blood and interstitial fluid flows accompanying microgravity-induced fluid redistribution may elicit an opposite effect in the head. Seven 23-week-old, adult female wild type C57BL/6 mice were randomly chosen for exposure to 15 days of microgravity on the STS-131 mission, while eight female littermates served as ground controls. Upon mission completion, all 15 murine calvariae were imaged on a micro-computed tomography scanner. A standardized rectangular volume was placed on the parietal bones of each calvaria for analyses, and three parameters were determined to measure increased parietal bone volume: bone volume (BV), average cortical thickness (Ct.Th), and tissue mineral density (TMD). Microgravity exposure caused a statistically significant increase in BV of the spaceflight (SF) group compared to that of the ground control (GC) group, the mean BV+/-SD for the SF group was 1.904+/-0.842 mm3, compared to 1.758+/-0.122 mm3 for the GC group (p<0.05). Ct.Th demonstrated a trend of increase from 0.099+/-0.006 mm in the GC group to 0.104+/ 0.005 mm in the SF group (p=0.12). TMD was similar between the two groups with 0.878+/-0.029 g/cm3 for the GC group and 0.893+/-0.028 g/cm3 for the SF group (p=0.31). Our results indicate that microgravity causes responsive changes in calvarial bones that do not normally bear weight. These findings suggest that fluid shifts alone accompanying microgravity may initiate bone adaptation independent of skeletal loading by tissue. PMID- 23791779 TI - Questions regarding the predictive value of one evolved complex adaptive system for a second: exemplified by the SOD1 mouse. AB - We surveyed the scientific literature regarding amyotrophic lateral sclerosis, the SOD1 mouse model, complex adaptive systems, evolution, drug development, animal models, and philosophy of science in an attempt to analyze the SOD1 mouse model of amyotrophic lateral sclerosis in the context of evolved complex adaptive systems. Humans and animals are examples of evolved complex adaptive systems. It is difficult to predict the outcome from perturbations to such systems because of the characteristics of complex systems. Modeling even one complex adaptive system in order to predict outcomes from perturbations is difficult. Predicting outcomes to one evolved complex adaptive system based on outcomes from a second, especially when the perturbation occurs at higher levels of organization, is even more problematic. Using animal models to predict human outcomes to perturbations such as disease and drugs should have a very low predictive value. We present empirical evidence confirming this and suggest a theory to explain this phenomenon. We analyze the SOD1 mouse model of amyotrophic lateral sclerosis in order to illustrate this position. PMID- 23791780 TI - No evidence hip joint angle modulates intrinsically produced stretch reflex in human hopping. AB - Motor output in activities such as walking and hopping is suggested to be mediated neurally by purported stretch reflex augmentation of muscle output. Reflex EMG activity during these tasks has been frequently investigated in the soleus muscle; with alterations in reflex amplitude being associated with changes in hip joint angle/phase of the gait cycle. Previous work has focussed on reflex activity induced by an artificial perturbation or by induction of H-reflexes. As such, it is currently unknown if stretch reflex activity induced intrinsically (as part of the task) is modulated by changes in hip joint angle. This study investigated whether hip joint angle modulated reflex EMG 'burst' activity during a hopping task performed on a custom-built partially reclined sleigh. Ten subjects participated; EMG and kinematic data (VICON motor capture system) was collected for each hop cycle. Participants completed 5 sets of 30s of self-paced hopping in (1) hip neutral and (2) hip 60 degrees flexion conditions. There was no difference in EMG 'burst' activity or in sagittal plane kinematics (knee/ankle) in the hopping task between the two conditions. The results indicate that during a functional task such as hopping, changes in hip angle do not alter the stretch reflex-like activity associated with landing. PMID- 23791781 TI - Falls classification using tri-axial accelerometers during the five-times-sit-to stand test. AB - The five-times-sit-to-stand test (FTSS) is an established assessment of lower limb strength, balance dysfunction and falls risk. Clinically, the time taken to complete the task is recorded with longer times indicating increased falls risk. Quantifying the movement using tri-axial accelerometers may provide a more objective and potentially more accurate falls risk estimate. 39 older adults, 19 with a history of falls, performed four repetitions of the FTSS in their homes. A tri-axial accelerometer was attached to the lateral thigh and used to identify each sit-stand-sit phase and sit-stand and stand-sit transitions. A second tri axial accelerometer, attached to the sternum, captured torso acceleration. The mean and variation of the root-mean-squared amplitude, jerk and spectral edge frequency of the acceleration during each section of the assessment were examined. The test-retest reliability of each feature was examined using intra class correlation analysis, ICC(2,k). A model was developed to classify participants according to falls status. Only features with ICC>0.7 were considered during feature selection. Sequential forward feature selection within leave-one-out cross-validation resulted in a model including four reliable accelerometer-derived features, providing 74.4% classification accuracy, 80.0% specificity and 68.7% sensitivity. An alternative model using FTSS time alone resulted in significantly reduced classification performance. Results suggest that the described methodology could provide a robust and accurate falls risk assessment. PMID- 23791782 TI - Reliability of ultrasound for measurement of selected foot structures. AB - BACKGROUND: Understanding the relationship between the lower leg muscles, foot structures and function is essential to explain how disease or injury may relate to changes in foot function and clinical pathology. The aim of this study was to investigate the inter-operator reliability of an ultrasound protocol to quantify features of: rear, mid and forefoot sections of the plantar fascia (PF); flexor hallucis brevis (FHB); flexor digitorum brevis (FDB); abductor hallucis (AbH); flexor digitorum longus (FDL); flexor hallucis longus (FHL); tibialis anterior (TA); and peroneus longus and brevis (PER). METHODS: A sample of 6 females and 4 males (mean age 29.1 +/- 7.2 years, mean BMI 25.5 +/- 4.8) was recruited from a university student and staff population. Scans were obtained using a portable Venue 40 musculoskeletal ultrasound system (GE Healthcare UK) with a 5-13 MHz wideband linear array probe with a 12.7 mm * 47.1mm footprint by two operators in the same scanning session. RESULTS: Intraclass Correlation Coefficients (ICC) values for muscle thickness (ICC range 0.90-0.97), plantar fascia thickness (ICC range 0.94-0.98) and cross sectional muscle measurements (ICC range 0.91-0.98) revealed excellent inter-operator reliability. The limits of agreement, relative to structure size, ranged from 9.0% to 17.5% for muscle thickness, 11.0-18.0% for plantar fascia, and 11.0-26.0% for cross sectional area measurements. CONCLUSIONS: The ultrasound protocol implemented in this work has been shown to be reliable. It therefore offers the opportunity to quantify the structures concerned and better understand their contributions to foot function. PMID- 23791783 TI - Catalytic assembly of the mitotic checkpoint inhibitor BubR1-Cdc20 by a Mad2 induced functional switch in Cdc20. AB - The mitotic checkpoint acts to maintain chromosome content by generation of a diffusible anaphase inhibitor. Unattached kinetochores catalyze a conformational shift in Mad2, converting an inactive open form into a closed form that can capture Cdc20, the mitotic activator of the APC/C ubiquitin ligase. Mad2 binding is now shown to promote a functional switch in Cdc20, exposing a previously inaccessible site for binding to BubR1's conserved Mad3 homology domain. BubR1, but not Mad2, binding to APC/C(Cdc20) is demonstrated to inhibit ubiquitination of cyclin B. Closed Mad2 is further shown to catalytically amplify production of BubR1-Cdc20 without necessarily being part of the complex. Thus, the mitotic checkpoint is produced by a cascade of two catalytic steps: an initial step acting at unattached kinetochores to produce a diffusible Mad2-Cdc20 intermediate and a diffusible step in which that intermediate amplifies production of BubR1 Cdc20, the inhibitor of cyclin B ubiquitination, by APC/C(Cdc20). PMID- 23791784 TI - Extensive rewiring and complex evolutionary dynamics in a C. elegans multiparameter transcription factor network. AB - Gene duplication results in two identical paralogs that diverge through mutation, leading to loss or gain of interactions with other biomolecules. Here, we comprehensively characterize such network rewiring for C. elegans transcription factors (TFs) within and across four newly delineated molecular networks. Remarkably, we find that even highly similar TFs often have different interaction degrees and partners. In addition, we find that most TF families have a member that is highly connected in multiple networks. Further, different TF families have opposing correlations between network connectivity and phylogenetic age, suggesting that they are subject to different evolutionary pressures. Finally, TFs that have similar partners in one network generally do not in another, indicating a lack of pressure to retain cross-network similarity. Our multiparameter analyses provide unique insights into the evolutionary dynamics that shaped TF networks. PMID- 23791785 TI - Class I HDACs share a common mechanism of regulation by inositol phosphates. AB - Class I histone deacetylases (HDAC1, HDAC2, and HDAC3) are recruited by cognate corepressor proteins into specific transcriptional repression complexes that target HDAC activity to chromatin resulting in chromatin condensation and transcriptional silencing. We previously reported the structure of HDAC3 in complex with the SMRT corepressor. This structure revealed the presence of inositol-tetraphosphate [Ins(1,4,5,6)P4] at the interface of the two proteins. It was previously unclear whether the role of Ins(1,4,5,6)P4 is to act as a structural cofactor or a regulator of HDAC3 activity. Here we report the structure of HDAC1 in complex with MTA1 from the NuRD complex. The ELM2-SANT domains from MTA1 wrap completely around HDAC1 occupying both sides of the active site such that the adjacent BAH domain is ideally positioned to recruit nucleosomes to the active site of the enzyme. Functional assays of both the HDAC1 and HDAC3 complexes reveal that Ins(1,4,5,6)P4 is a bona fide conserved regulator of class I HDAC complexes. PMID- 23791786 TI - Strong modulation of ectopic focus as a mechanism of repetitive interpolated ventricular bigeminy with heart rate doubling. AB - BACKGROUND: Repetitive interpolated ventricular bigeminy (RIVB) can introduce a doubling of the ventricular rate. OBJECTIVE: To clarify the mechanism of RIVB, we hypothesized that it was introduced by a strong modulation of the ventricular automatic focus. METHODS: RIVB, defined as more than 7 bigeminy events, was detected by instantaneous heart rate and bigeminy interval (BI) tachograms in 1450 successive patients with frequent ventricular premature contractions (>=3000 per day). Postextrasystolic interval bigeminy interval curves were plotted to determine the degree of modulation. Mean sinus cycle length bigeminy interval curves were plotted for selection. RIVB was simulated by using a computer-based parasystole model. RESULTS: RIVB was observed in 7 patients (age 60 +/- 16 years; 2 men and 5 women) with a heart rate of 58.2 +/- 6.5 beats/min during a rest period both during the day and at night. The tachograms disclosed the onset of the RIVB with a doubled ventricular rate to 112.3 +/- 8.5 beats/min. On the postextrasystolic interval bigeminy interval curves, compensatory bigeminy and interpolated bigeminy constituted overlapping regression lines with slopes close to 1.00 and RIVB was located in the lower left portion. RIVB lasting for up to 3 hours was quickly detected by mean sinus cycle length bigeminy interval curve. The PQ interval immediately after RIVB was prolonged in comparison with baseline (0.18 +/- 0.02 to 0.21 +/- 0.02 seconds; P < .001). The simulation was able to reproduce RIVB faithfully at a slow heart rate. CONCLUSIONS: Our findings support the hypothesis that RIVB was introduced by strongly modulated ventricular pacemaker accelerated by an intervening normal QRS. PMID- 23791787 TI - The role of behavior in translational models for psychopathology: functionality and dysfunctional behaviors. AB - The history of science has frequently included a problem-based impetus toward research that can be translated expeditiously into solutions. A current problem is that psychopathologies, typically chronic, contribute hugely to the economic and social burden of medical care, especially in the United States. For behavioral neuroscientists a psychopathology-aimed translational research emphasis particularly involves animal models to facilitate the experimental and invasive work necessary to an understanding of the biology of normal and aberrant behavior. When the etiology of a particular psychopathology is unknown, and there are no specific biomarkers, behavioral parallels between the focal disorder and its putative models become crucial elements in assessing model validity. Evaluation of these parallels is frequently neglected, reflecting in part the lack of a systematic conceptualization of the organization of behavior and how this may be conserved across species. Recent work specifically attempting to bridge this gap suggests that analysis of behaviors that are functional - adaptive in crucial situations such as danger or social contexts - can facilitate an understanding of the parallels between behaviors of human and nonhuman species, including the dysfunctional behaviors of psycho pathologies. As research with animal models comes to provide a more systematic analysis of particular behaviors and their adaptive functions, cross-talk between model and focal psychopathology may be advantageous to understanding both. PMID- 23791788 TI - Force control in object manipulation--a model for the study of sensorimotor control strategies. AB - The control of prehensile finger forces when grasping and lifting an object is a well-established model to study sensorimotor and cognitive control processes of the human sensorimotor system. The simple task of grasping and lifting objects in the environment is orchestrated by a complex interplay between multiple sensorimotor systems to signal, analyze and process the mechanical interactions and constraints between body and object. These processes involve internal action plans, integration of visual, haptic and other sensory information about both body and object, sensorimotor predictions, as well as fast reactive adaptations based on experienced sensory events at various levels of complexity. This review briefly summarizes predictive and reactive control strategies of grip and lift force control, current concepts of internal models for predictive force control and recent controversies of the internal model theory in object manipulation. PMID- 23791789 TI - Allopurinol and xanthine use different translocation mechanisms and trajectories in the fungal UapA transporter. AB - In Aspergillus nidulans UapA is a H(+)-driven transporter specific for xanthine, uric acid and several analogues. Here, genetic and physiological evidence is provided showing that allopurinol is a high-affinity, low-capacity, substrate for UapA. Surprisingly however, transport kinetic measurements showed that, uniquely among all recognized UapA substrates, allopurinol is transported by apparent facilitated diffusion and exhibits a paradoxical effect on the transport of physiological substrates. Specifically, excess xanthine or other UapA substrates inhibit allopurinol uptake, as expected, but the presence of excess allopurinol results in a concentration-dependent enhancement of xanthine binding and transport. Flexible docking approaches failed to detect allopurinol binding in the major UapA substrate binding site, which was recently identified by mutational analysis and substrate docking using all other UapA substrates. These results and genetic evidence suggest that the allopurinol translocation pathway is distinct from, but probably overlapping with, that of physiological UapA substrates. Furthermore, although the stimulating effect of allopurinol on xanthine transport could, in principle, be rationalized by a cryptic allopurinol specific allosteric site, evidence was obtained supporting that accelerated influx of xanthine is triggered through exchange with cytoplasmically accumulated allopurinol. Our results are in line with recently accumulating evidence revealing atypical and complex mechanisms underlying transport systems. PMID- 23791790 TI - Molecular dynamics simulation of a myosin subfragment-1 docking with an actin filament. AB - Myosins are typical molecular motor proteins, which convert the chemical energy of ATP into mechanical work. The fundamental mechanism of this energy conversion is still unknown. To explain the experimental results observed in molecular motors, Masuda has proposed a theory called the "Driven by Detachment (DbD)" mechanism for the working principle of myosins. Based on this theory, the energy used during the power stroke of the myosins originates from the attractive force between a detached myosin head and an actin filament, and does not directly arise from the energy of ATP. According to this theory, every step in the myosin working process may be reproduced by molecular dynamics (MD) simulations, except for the ATP hydrolysis step. Therefore, MD simulations were conducted to reproduce the docking process of a myosin subfragment-1 (S1) against an actin filament. A myosin S1 directed toward the barbed end of an actin filament was placed at three different positions by shifting it away from the filament axis. After 30 ns of MD simulations, in three cases out of ten trials on average, the myosin made a close contact with two actin monomers by changing the positions and the orientation of both the myosin and the actin as predicted in previous studies. Once the docking was achieved, the distance between the myosin and the actin showed smaller fluctuations, indicating that the docking is stable over time. If the docking was not achieved, the myosin moved randomly around the initial position or moved away from the actin filament. MD simulations thus successfully reproduced the docking of a myosin S1 with an actin filament. By extending the similar MD simulations to the other steps of the myosin working process, the validity of the DbD theory may be computationally demonstrated. PMID- 23791791 TI - An interesting cause of rectal bleeding in an African immigrant. PMID- 23791792 TI - Fecal DNA testing for colorectal neoplasia in IBD: could it be as simple as a stool study? PMID- 23791793 TI - Regression of cirrhosis with long-term tenofovir treatment. PMID- 23791794 TI - Linaclotide for the treatment of irritable bowel syndrome with constipation: is it time to reshuffle the deck? PMID- 23791795 TI - Obesity and IBD: are we tipping the scales toward an epidemic? PMID- 23791798 TI - Blood doping: the flip side of transfusion and transfusion alternatives. AB - Blood doping in sports has been a hot topic of present. Longitudinal follow up of hematological parameters in different endurance sports, during the 1990s and early 2000s, has provided considerable suspicions about extensive blood manipulation, with performance enhancing effects. Recent doping revelations in the media also prove that blood doping is not an anticipated myth but it is, in fact, real. Erythropoiesis stimulating agents and autologous blood transfusions are used in synergy with substantial effect on the maximum oxygen uptake and delivery to muscles. Whilst both methods of blood manipulation represent a potential health hazard, in the context of an elevated hematocrit, nevertheless despite a number of suspicious deaths amongst athletes, this has not yet been fully documented. A reliable test for detection of recombinant human erythropoietin was implemented in 2000, but this is probably circumvented by microdose regimens. The Athlete's Biological Passport represents the progeny of the idea of an indirect approach based on long term monitoring of hematological parameters, thus making it possible to detect autologous blood doping and erythropoietin use after the substance is excreted. Nevertheless with advances in anti-doping measures it is possible that the levels of excretion of substances used can be masked. Clearly more sensitive and specific diagnostic tools and research/development in these areas of major concern are warranted, which, combined with changes in the athlete's attitude, will help in reaching the vision of fair play. PMID- 23791799 TI - Early-onset plasmapheresis and LDL-apheresis provide better disease control for pediatric homozygous familial hypercholesterolemia than HMG-CoA reductase inhibitors and ameliorate atherosclerosis. AB - Plasmapheresis (PA) and low-density lipoprotein apheresis (LDL-A) were assessed in five children with homozygous familial hypercholesterolemia (HFH) previously receiving statins. LDL-A required smaller extracorporeal blood volumes. Mean HDL cholesterol reduction post-procedure was 32% and 60% with LDL-A and PA, respectively. Non-HDL-C reduction was 64% and 69%, respectively. Pre-procedural LDL-C decreased significantly with weekly versus biweekly LDL-A. Carotid intimal media thickness (IMT) studies demonstrated disappearance of atheromatous lesions and normal ITM in 4/5 patients. Echocardiography revealed normal aortic valves, coronary orifices and supra-valvular area in all patients. Apheresis is effective in pediatric HFH. It may be started in patients weighing 14 kg. PMID- 23791800 TI - Bacillus subtilis alkaline phosphatase IV acquires activity only late at the stationary phase when produced in Escherichia coli. Overexpression and characterization of the recombinant enzyme. AB - The availability of recombinant monomeric alkaline phosphatase (AP) is highly desirable in analytical applications involving AP fusion proteins. The cobalt dependant alkaline phosphatase IV from Bacillus subtilis (BSAP), which was reported to be strongly monomeric, was overexpressed in Escherichia coli using pET autoinduction system as a cytoplasmic protein without export signal sequence. After 1 day of growth, when the E. coli culture was near the stationary phase (standard time to harvest protein in this expression method), high amounts of BSAP were produced but the soluble fraction of BSAP was nearly inactive: the AP activity in the cell-free extract was near the background level. However, further incubation of bacterial culture lead to a tremendous increase in AP activity which was maximal at the 3rd day of incubation and was 48-100 times higher than at the 1st day of growth. The recombinant BSAP was purified by metal-chelate chromatography and characterized. Typically, 90-140 mg of active protein was produced in 1L of culture (20 g wet cells). BSAP shows 515 U/mg activity at optimum conditions (pH 11 and 0.8-2M NaCl). Contrary to the previous report on the native enzyme, BSAP was found to be dimeric and showed only negligible diesterase activity. The observed unusual late activation of BSAP indicates that prolonged incubation at the stationary phase may be useful for functional expression of some problematic proteins in E. coli. PMID- 23791796 TI - Coevolution of Cryptosporidium tyzzeri and the house mouse (Mus musculus). AB - Two house mouse subspecies occur in Europe, eastern and northern Mus musculus musculus (Mmm) and western and southern Mus musculus domesticus (Mmd). A secondary hybrid zone occurs where their ranges meet, running from Scandinavia to the Black Sea. In this paper, we tested a hypothesis that the apicomplexan protozoan species Cryptosporidium tyzzeri has coevolved with the house mouse. More specifically, we assessed to what extent the evolution of this parasite mirrors divergence of the two subspecies. In order to test this hypothesis, we analysed sequence variation at five genes (ssrRNA, Cryptosporidium oocyst wall protein (COWP), thrombospondin-related adhesive protein of Cryptosporidium 1 (TRAP-C1), actin and gp60) in C. tyzzeri isolates from Mmd and Mmm sampled along a transect across the hybrid zone from the Czech Republic to Germany. Mmd samples were supplemented with mice from New Zealand. We found two distinct isolates of C. tyzzeri, each occurring exclusively in one of the mouse subspecies (C. tyzzeri Mmm and C. tyzzeri-Mmd). In addition to genetic differentiation, oocysts of the C. tyzzeri-Mmd subtype (mean: 4.24*3.69MUm) were significantly smaller than oocysts of C. tyzzeri-Mmm (mean: 4.49*3.90 MUm). Mmm and Mmd were susceptible to experimental infection with both C. tyzzeri subtypes; however, the subtypes were not infective for the rodent species Meriones unguiculatus, Mastomys coucha, Apodemus flavicollis or Cavia porcellus. Overall, our results support the hypothesis that C. tyzzeri is coevolving with Mmm and Mmd. PMID- 23791801 TI - Intrahepatic cholangiocarcinoma in liver hemangioma with hepatitis B infection. PMID- 23791802 TI - Assessing physician utilization of laboratory practice guidelines: barriers and opportunities for improvement. AB - OBJECTIVES: To assess physician utilization of laboratory practice guidelines (LPGs)3 to improve LPG uptake and use. DESIGN AND METHODS: A statewide survey of 4987 primary care physicians (PCPs) and 75 infectious disease (ID) specialists was conducted in 2005-2006 to correlate guideline source with users' awareness, utilization, and perceived usefulness of LPGs. We compared LPGs developed by the Centers for Disease Control and Prevention (CDC) to LPGs developed by the Washington State Department of Health through its Clinical Laboratory Advisory Council (CLAC). RESULTS: Physician awareness of LPGs was a major impediment to utilization of CLAC LPGs, and they were perceived as inaccessible, too numerous and unhelpful. However, once aware, respondents tended to use LPGs and there were no important differences in impediments or the ways CDC and CLAC LPGs were used. Of the PCPs who had a computerized physician order entry system (CPOE), a majority (92%) found, or expected that they would find, the integration of guidelines into their system helpful. CONCLUSIONS: For both CDC and CLAC LPGs, the greatest impediments to uptake were awareness and familiarity, which depended upon LPG source, physician specialty, and practice setting. There was no apparent impediment to uptake of CLAC or CDC LPGs based upon their credibility. Because better promotion could increase uptake, CLAC LPGs are now promoted by the Washington State Medical Association. Integration of LPGs into CPOE and smart phone applications could address major impediments to clinician use. The Cabana paradigm would be useful for any organization seeking to improve LPG impact. PMID- 23791803 TI - Efficacy of praziquantel and reinfection patterns in single and mixed infection foci for intestinal and urogenital schistosomiasis in Cameroon. AB - The regular administration of the anthelminthic drug praziquantel (PZQ) to school aged children (and other high-risk groups) is the cornerstone of schistosomiasis control. Whilst the performance of PZQ against single schistosome species infections is well-known, performance against mixed species infections is less so, as are patterns of re-infection following treatment. To address this, a study using a double treatment with PZQ, administered at 40 mg/kg spaced by 3 weeks, took place in two mixed intestinal-urogenital schistosomiasis foci in northern Cameroon (Bessoum and Ouro-Doukoudje) and in one single intestinal schistosomiasis infection focus (Makenene). A total of just under 1000 children were examined and the Schistosoma-infected children were re-examined at several parasitological follow-ups over a 1-year period posttreatment. Overall cure rates against Schistosoma spp. in the three settings were good, 83.3% (95% confidence interval (CI)=77.9-87.7%) in Bessoum, 89.0% (95% CI=79.1-94.6%) in Ouro Doukoudje, and 95.3% (95% CI=89.5-98.0%) in Makenene. Interestingly, no case of mixed schistosome infection was found after treatment. Cure rates for S. mansoni varied from 99.5% to 100%, while that for S. haematobium were considerably lower, varying from 82.7% to 88.0%. Across transmission settings, patterns of re infection for each schistosome species were different such that generalizations across foci were difficult. For example, at the 6-month follow-up, re-infection rates were higher for S. haematobium than for S. mansoni with re-infection rates for S. haematobium varying from 9.5% to 66.7%, while for S. mansoni, lower rates were observed, ranging between nil and 24.5%. At the 12-month follow-up, re infection rates varied from 9.1% to 66.7% for S. haematobium and from nil to 27.6% for S. mansoni. Alongside these parasitological studies, concurrent malacological surveys took place to monitor the presence of intermediate host snails of schistosomiasis. In the two northern settings, three species of Bulinus (intermediate host snail of S. haematobium) were collected; i.e. Bulinus truncatus, B. globosus and B. senegalensis, however, Biomphalaria pfeifferi (intermediate host snail of S. mansoni) was much rarer despite repeated and intensive searching and was suggestive of limited local transmission potential of S. mansoni during this time. While this study highlights that performance of PZQ was satisfactory in this region, with somewhat greater impact upon intestinal than urogenital schistosomiasis, the dynamics of local transmission are shown, however, to be complex. PMID- 23791804 TI - Bidirectional binding property of high glycine-tyrosine keratin-associated protein contributes to the mechanical strength and shape of hair. AB - Since their first finding in wool 50years ago, keratin-associated proteins (KAPs), which are classified into three groups; high sulfur (HS) KAPs, ultra high sulfur (UHS) KAPs, and high glycine-tyrosine (HGT) KAPs, have been the target of curiosity for scientists due to their characteristic amino acid sequences. While HS and UHS KAPs are known to function in disulfide bond crosslinking, the function of HGT KAPs remains unknown. To clarify the function as well as the binding partners of HGT KAPs, we prepared KAP8.1 and other KAP family proteins, the trichocyte intermediate filament proteins (IFP) K85 and K35, the head domain of K85, and the C subdomain of desmoplakin C-terminus (DPCT-C) and investigated the interactions between them in vitro. Western blot analysis and isothermal titration calorimetry (ITC) indicate that KAP8.1 binds to the head domain of K85, which is helically aligned around the axis of the intermediate filament (IF). From these results and transmission electron microscopy (TEM) observations of bundled filament complex in vitro, we propose that the helical arrangement of IFs found in the orthocortex, which is uniquely distributed on the convex fiber side of the hair, is regulated by KAP8.1. Structure-dependent binding of DPCT-C to trichocyte IFP was confirmed by Western blotting, ITC, and circular dichroism. Moreover, DPCT-C also binds to some HGT KAPs. It is probable that such bidirectional binding property of HGT KAPs contribute to the mechanical robustness of hair. PMID- 23791805 TI - [Assessment of quality indicators in pediatric poisoning in an emergency service]. AB - INTRODUCTION: Assessment of quality indicators allows clinicians to evaluate clinical assistance with a standard, to detect deficiencies and to improve medical assistance. MATERIAL AND METHOD: Patients who came to emergency services of a tertiary level hospital for suspicion of poisoning from January 2011 to June 2012 were assessed using 20 quality indicators of pediatric poisoning. Data collection was performed by retrospective review of clinical reports. RESULTS: A total of 393 patients were admitted for suspicion of poisoning (0.3% of all admissions).The standard was reached in 11 indicators and not reached in 6: administration of activated charcoal within 2hours of poison ingestion (standard=90%, result=83.5%); attention within the first 15minutes of arriving in the emergency service (standard=90%, result=60.4%); start of gastrointestinal decontamination within 20minutes of arrival in emergency services (standard=90%, result=29.7%); performing of electrocardiogram on the patients poisoned with cardiotoxic substances (standard=95%, result=87%); judicial communication of cases of poisoning that could conceal a crime (standard=95%, result=31.3%), and collection of the minimal set of information of poisoned patients (standard=90%, result=1.9%). Three indicators could not be evaluated as a consequence of the limited number of cases where they could be applied (<5). CONCLUSIONS: The main deficiencies are related to delay in assistance, collection of information and completion of judicial reports. Giving these patients priority, designing a checklist to collect the main points of their management, and creating obligatory fields for data in computerized medical records, are the main actions available to achieve pediatric poisoning quality indicators in this emergency service. PMID- 23791806 TI - [Chemical pollution and breast milk: Taking positions]. AB - Chemical pollution affects all ecosystems of our planet. Human milk has been used as a biomarker of environmental pollution as, due to bioaccumulation processes in fat tissue, many chemical compounds reach measurable concentrations that can be readily tested in breast milk. Quite frequently information about the presence of contaminants in breast milk appears in the media, leading to misunderstanding among parents and health professionals, and in some cases breastfeeding the child is stopped. In this article, the Breastfeeding Committee of the Spanish Association of Paediatrics stresses the importance of promoting breastfeeding as the healthiest option, because its benefits clearly outweigh any health risks associated with chemical contaminants in breast milk. Breast milk contains protective factors that counteract the potential effects related to prenatal exposure to environmental pollutants. This article summarises the key recommendations to reduce the level of chemical contaminants in breast milk. It also highlights the importance of government involvement in the development of programs to eliminate or reduce chemical contamination of food and the environment. In this way, the negative effects on child health resulting from exposure to these toxic compounds through the placenta and breast milk may be prevented. PMID- 23791807 TI - Involvement of bradykinin and prostaglandins in the diuretic effects of Achillea millefolium L. (Asteraceae). AB - ETHNOPHARMACOLOGICAL RELEVANCE: Achillea millefolium L. (Asteraceae), popularly known as "mil-folhas", is well recognized and widely used in Brazilian folk medicine to treat heart and kidney disorders. Among its popularly described effects are diuretic and hypotensive actions. AIM OF THE STUDY: The diuretic activity of Achillea millefolium L. extracts and its semi-purified fractions, as well as the mechanisms involved, were evaluated in male Wistar rats. MATERIAL AND METHODS: An aqueous extract (AEAM, 125-500 mg/kg), hydroethanolic extract (HEAM, 30-300 mg/kg), dichloromethane subfractions (DCM-2, 10 and 30 mg/kg), or hydrochlorothiazide (10mg/kg), were orally administered and the animals were kept in metabolic cages for 8h for urine collection. To evaluate the involvement of bradykinin and prostaglandins in the diuretic action of Achillea millefolium, selected groups of rats received HOE-140 (1.5mg/kg, i.p.) or indomethacin (5mg/kg, p.o.), before treatment with a DCM-2 subfraction (30 mg/kg). The urinary volume, conductivity, pH, density and electrolyte excretion were measured. RESULTS: Similar to hydrochlorothiazide, both HEAM and DCM-2, but not AEAM, increased urinary volume and the excretion of Na(+) and K(+) when compared with the control group (vehicle). The diuretic effect of DCM-2 was abolished by HOE 140 (a bradykinin B2 receptor antagonist), as well as by indomethacin (a cyclooxygenase inhibitor). CONCLUSION: The present study reveals that extracts obtained from Achillea millefolium are able to effectively increase diuresis when orally administered in rats. This effect depends on both the activation of bradykinin B2 receptors and the activity of cyclooxygenases. PMID- 23791808 TI - Comparative pharmacokinetics of swertiamarin in rats after oral administration of swertiamarin alone, Qing Ye Dan tablets and co-administration of swertiamarin and oleanolic acid. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Qing Ye Dan is a well-known herbal drug that is widely used to treat viral hepatitis in the Yi and Hani minority regions in the Yunnan province of China. MATERIALS AND METHODS: An LC-MS/MS method was developed to determine the levels of swertiamarin in rat plasma. Swertiamarin and naringin (internal standard, IS) were extracted from rat plasma using solid-phase extraction (SPE) to purify the samples. The pharmacokinetics of the following different administration methods of swertiamarin in rats were studied: oral administration of swertiamarin alone, a Qing Ye Dan tablet (QYDT) and co administration of swertiamarin and oleanolic acid, with each method delivering approximately 20mg/kg of swertiamarin. Non-compartmental pharmacokinetic profiles were constructed by using the software DAS (version 2.1.1), and the pharmacokinetic parameters were compared using an unpaired Student's t-test. RESULTS: The results showed that the pharmacokinetic parameters Cmax, AUC0 infinity, Vz/F and CLz/F were significantly different (P<0.05) among the three types of swertiamarin administration. CONCLUSIONS: The data indicate that oleanolic acid and the other ingredients present in QYDT could affect the pharmacokinetic behaviour of swertiamarin in rats. PMID- 23791809 TI - Brine shrimp toxicity and antimalarial activity of some plants traditionally used in treatment of malaria in Msambweni district of Kenya. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In Kenya, most people especially in rural areas use traditional medicine and medicinal plants to treat many diseases including malaria. Malaria is of national concern in Kenya, in view of development of resistant strains of Plasmodium falciparum to drugs especially chloroquine, which had been effective and affordable. There is need for alternative and affordable therapy. Many antimalarial drugs have been derived from medicinal plants and this is evident from the reported antiplasmodial activity. AIM OF THE STUDY: The present study reports on the in vivo antimalarial activity and brine shrimp lethality of five medicinal plants traditionally used to treat malaria in Msambweni district, Kenya. MATERIALS AND METHODS: A total of five aqueous crude extracts from different plant parts used in traditional medicine for the treatment of malaria were evaluated for their in vivo antimalarial activity using Plasmodium berghei infected Swiss mice and for their acute toxicity using Brine shrimp lethality test. RESULTS: The screened crude plant extracts suppressed parasitaemia as follows: Azadirachta indica (L) Burm. (Meliaceae), 3.1%; Dichrostachys cinerea (L) Wight et Arn (Mimosaceae), 6.3%; Tamarindus indica L. (Caesalpiniaceae), 25.1%; Acacia seyal Del. (Mimosaceae) 27.8% and Grewia trichocarpa Hochst ex A.Rich (Tiliaceae) 35.8%. In terms of toxicity, A.indica root bark extract had an LC50 of 285.8 ug/ml and was considered moderately toxic. T.indica stem bark extract and G.trichocarpa root extract had an LC50 of 516.4 and 545.8 ug/ml respectively and were considered to be weakly toxic while A.seyal and D.cinerea root extracts had a LC50>1000 ug/ml and were therefore considered to be non toxic. CONCLUSIONS: The results indicate that the aqueous extracts of the tested plants when used alone as monotherapy had antimalarial activity which was significantly different from that of chloroquine (P<=0.05). The results also suggest that the anecdotal efficacy of the above plants reported by the study community is related to synergism of phytoconstituents since the assayed plant parts are used in combination with others to treat malaria. It is also evident that none of the screened plant extracts is toxic to the arthropod invertebrate, Artemia salina L. (Artemiidae) larvae, justifying the continued use of the plant parts to treat malaria. A.seyal, G.trichocarpa and T.indica have not been reported before for in vivo antimalarial activity and brine shrimp lethality. PMID- 23791810 TI - We still need a real-time hemodynamic monitor for CPR. PMID- 23791811 TI - Education as standardised teaching or individual training or both. PMID- 23791812 TI - Outcome after cardiac arrest: are the feet of our predictors made of clay? PMID- 23791813 TI - Mitochondrial endocrinology--mitochondria as key to hormones and metabolism. PMID- 23791815 TI - Identification of daidzein as a ligand of retinoic acid receptor that suppresses expression of matrix metalloproteinase-9 in HaCaT cells. AB - Retinoids have been used as therapeutics for diverse skin diseases, but their side effects limit clinical usage. Here, we report that extracts of two soybeans, Glycine max and Rhynchosia nulubilis, and their ethyl acetate fractions increased the transcriptional activity of retinoic acid receptors (RARs), and that daidzin and genistin were the major constituents of the active fractions. Daidzin and its aglycone, daidzein, induced transcriptional activity of RAR and RARgamma. FRET analysis demonstrated that daidzein, but not daidzin, bound both RAR and RARgamma with EC50 values of 28MUM and 40MUM, respectively. Daidzein increased expression of mRNA of RARgamma through direct binding of RAR and recruitment of p300 to the RARgamma2 promoter. Further, mRNA and gelatinolytic activity of matrix metalloproteinase-9 were decreased by daidzein in HaCaT cells. Together, these results indicate that daidzein functions as a ligand of RAR that could be a candidate therapeutic for skin diseases. PMID- 23791814 TI - The immune system and inflammation in breast cancer. AB - During different stages of tumor development the immune system can either identify and destroy tumors, or promote their growth. Therapies targeting the immune system have emerged as a promising treatment modality for breast cancer, and immunotherapeutic strategies are being examined in preclinical and clinical models. However, our understanding of the complex interplay between cells of the immune system and breast cancer cells is incomplete. In this article, we review recent findings showing how the immune system plays dual host-protective and tumor-promoting roles in breast cancer initiation and progression. We then discuss estrogen receptor alpha (ERalpha)-dependent and ERalpha-independent mechanisms that shield breast cancers from immunosurveillance and enable breast cancer cells to evade immune cell induced apoptosis and produce an immunosuppressive tumor microenvironment. Finally, we discuss protumorigenic inflammation that is induced during tumor progression and therapy, and how inflammation promotes more aggressive phenotypes in ERalpha positive breast cancers. PMID- 23791817 TI - A transgenic zebrafish model of a human cardiac sodium channel mutation exhibits bradycardia, conduction-system abnormalities and early death. AB - The recent exponential increase in human genetic studies due to the advances of next generation sequencing has generated unprecedented numbers of new gene variants. Determining which of these are causative of human disease is a major challenge. In-vitro studies and murine models have been used to study inherited cardiac arrhythmias but have several limitations. Zebrafish models provide an attractive alternative for modeling human heart disease due to similarities in cardiac electrophysiology and contraction, together with ease of genetic manipulation, external development and optical transparency. Although zebrafish cardiac mutants and morphants have been widely used to study loss and knockdown of zebrafish gene function, the phenotypic effects of human dominant-negative gene mutations expressed in transgenic zebrafish have not been evaluated. The aim of this study was to generate and characterize a transgenic zebrafish arrhythmia model harboring the pathogenic human cardiac sodium channel mutation SCN5A D1275N, that has been robustly associated with a range of cardiac phenotypes, including conduction disease, sinus node dysfunction, atrial and ventricular arrhythmias, and dilated cardiomyopathy in humans and in mice. Stable transgenic fish with cardiac expression of human SCN5A were generated using Tol2-mediated transgenesis and cardiac phenotypes were analyzed using video microscopy and ECG. Here we show that transgenic zebrafish expressing the SCN5A-D1275N mutation, but not wild-type SCN5A, exhibit bradycardia, conduction-system abnormalities and premature death. We furthermore show that SCN5A-WT, and to a lesser degree SCN5A D1275N, are able to compensate the loss of endogenous zebrafish cardiac sodium channels, indicating that the basic pathways, through which SCN5A acts, are conserved in teleosts. This proof-of-principle study suggests that zebrafish may be highly useful in vivo models to differentiate functional from benign human genetic variants in cardiac ion channel genes in a time- and cost-efficient manner. This article is part of a Special Issue entitled "Na(+) Regulation in Cardiac Myocytes". PMID- 23791816 TI - Exposure to chemical cocktails before or after conception--- the effect of timing on ovarian development. AB - Exposure of female fetuses to environmental chemicals (ECs) during pregnancy results in a disturbed ovarian adult phenotype. We investigated the influence of pre- and/or post-conception exposure to low-level mixtures of ECs on the structure and function of the fetal ovine ovary. We examined ovarian morphology, expression of oocyte and granulosa cell-specific genes and proteome. Female fetuses were collected at day 110 of gestation, from dams exposed continuously until, and after mating, by grazing in pastures treated with sewage sludge as a fertiliser (TT) or in control fields treated with inorganic fertiliser (CC). In addition, in a cross-over design, fetal ovaries were collected from dams maintained on sludge pastures up to the time of mating but then transferred to control pastures (TC) and, reciprocally, those transferred from control to treated pastures at mating (CT). On examination, the proportion of type 1a follicles (activating primordial follicles) was significantly lower in animals from the CT groups compared with CC and TT groups (P<0.05). Of the 23 ovarian gene transcripts studied, 14 were altered in the ovaries of exposed fetuses (CT, TC, and TT) relative to controls, with the largest number of changes observed in cross-exposure pattern groups (CT or TC). Continuous EC exposure (TT) produced fewer transcript alterations and only two genes (INHBA and GSN) presented differential profiles between CC and TT. Fetal ovarian proteome analysis (2-DE gels) showed, across all exposure groups, 86 differentially expressed protein spots compared to controls. Animals in the CT group exhibited the highest number (53) while TC and TT presented the same number of affected protein spots (42). Fetal ovarian proteins with altered expression included MVP (major vault protein) and several members of the heat-shock family (HSPA4L, HSP90AA1 and HSF1). The present findings indicate that continuous maternal EC exposure before and during gestation, are less deleterious for fetal ovarian development than a change in maternal EC exposure between pre and post-conception. The pathways by which the ovary responds to this chemical stress were common in TT, CT, TC exposed foetuses. In addition to the period of pregnancy, the pre-conception period appears also as crucial for conditioning long-term effects of EC exposure on ovarian development and primordial follicle reserve and hence future fertility. PMID- 23791818 TI - Fibronectin and integrin alpha 5 play requisite roles in cardiac morphogenesis. AB - Fibronectin and its major receptor, integrin alpha5beta1 are required for embryogenesis. These mutants have similar phenotypes, although, defects in integrin alpha5-deficient mice are milder. In this paper, we examined heart development in those mutants, in which the heart is formed, and discovered that both fibronectin and integrin alpha5 were required for cardiac morphogenesis, and in particular, for the formation of the cardiac outflow tract. We found that Isl1+ precursors are specified and migrate into the heart in fibronectin- or integrin alpha5-mutant embryos, however, the hearts in these mutants are of aberrant shape, and the cardiac outflow tracts are short and malformed. We show that these defects are likely due to the requirement for cell adhesion to fibronectin for proliferation of myocardial progenitors and for Fgf8 signaling in the pharyngeal region. PMID- 23791819 TI - Dvr1 transfers left-right asymmetric signals from Kupffer's vesicle to lateral plate mesoderm in zebrafish. AB - An early step in establishing left-right (LR) symmetry in zebrafish is the generation of asymmetric fluid flow by Kupffer's vesicle (KV). As a result of fluid flow, a signal is generated and propagated from the KV to the left lateral plate mesoderm, activating a transcriptional response of Nodal expression in the left lateral plate mesoderm (LPM). The mechanisms and molecules that aid in this transfer of information from the KV to the left LPM are still not clear. Here we provide several lines of evidence demonstrating a role for a member of the TGFbeta family member, Dvr1, a zebrafish Vg1 ortholog. Dvr1 is expressed bilaterally between the KV and the LPM. Knockdown of Dvr1 by morpholino causes dramatically reduced or absent expression of southpaw (spaw, a Nodal homolog), in LPM, and corresponding loss of downstream Lefty (lft1 and lft) expression, and aberrant brain and heart LR patterning. Dvr1 morphant embryos have normal KV morphology and function, normal expression of southpaw (spaw) and charon (cha) in the peri-KV region and normal expression of a variety of LPM markers in LPM. Additionally, Dvr1 knockdown does not alter the capability of LPM to respond to signals that initiate and propagate spaw expression. Co-injection experiments in Xenopus and zebrafish indicate that Dvr1 and Spaw can enhance each other's ability to activate the Nodal response pathway and co-immunoprecipitation experiments reveal differential relationships among activators and inhibitors in this pathway. These results indicate that Dvr1 is responsible for enabling the transfer of a left-right signal from KV to the LPM. PMID- 23791820 TI - Eif3ba regulates cranial neural crest development by modulating p53 in zebrafish. AB - Congenital diseases caused by abnormal development of the cranial neural crest usually present craniofacial malformations and heart defects while the precise mechanism is not fully understood. Here, we show that the zebrafish eif3ba mutant caused by pseudo-typed retrovirus insertion exhibited a similar phenotype due to the hypogenesis of cranial neural crest cells (NCCs). The derivatives of cranial NCCs, including the NCC-derived cell population of pharyngeal arches, craniofacial cartilage, pigment cells and the myocardium derived from cardiac NCCs, were affected in this mutant. The expression of several neural crest marker genes, including crestin, dlx2a and nrp2b, was specifically reduced in the cranial regions of the eif3ba mutant. Through fluorescence-tracing of the cranial NCC migration marker nrp2b, we observed reduced intensity of NCC-derived cells in the heart. In addition, p53 was markedly up-regulated in the eif3ba mutant embryos, which correlated with pronounced apoptosis in the cranial area as shown by TUNEL staining. These findings suggest a novel function of eif3ba during embryonic development and a novel level of regulation in the process of cranial NCC development, in addition to providing a potential animal model to mimic congenital diseases due to cranial NCC defects. Furthermore, we report the identification of a novel transgenic fish line Et(gata2a:EGFP)pku418 to trace the migration of cranial NCCs (including cardiac NCCs); this may serve as an invaluable tool for investigating the development and dynamics of cranial NCCs during zebrafish embryogenesis. PMID- 23791821 TI - Thrombolysis with alteplase after stroke: extending outcomes. PMID- 23791822 TI - Effect of thrombolysis with alteplase within 6 h of acute ischaemic stroke on long-term outcomes (the third International Stroke Trial [IST-3]): 18-month follow-up of a randomised controlled trial. AB - BACKGROUND: Few data are available from randomised trials about the effect of thrombolysis with alteplase on long-term functional outcome in patients who have had acute ischaemic stroke and no trial has reported effects on health-related quality of life. A secondary objective of the third International Stroke Trial (IST-3) was to assess the effect of thrombolysis on such outcomes at 18 months. METHODS: In this open-label, international, multicentre, randomised, controlled trial, 3035 patients with ischaemic stroke from 12 countries were randomly allocated within 6 h of onset via a secure central system to either intravenous alteplase (0.9 mg/kg; n=1515) plus standard care or standard care alone (control; n=1520). 2348 patients were scheduled for 18-month follow-up. For our main analysis, survivors were assessed at 18 months with the Oxford handicap scale (OHS; the primary outcome was the adjusted odds of OHS score 0-2). We also used the EuroQoL (EQ) instrument and asked questions about overall functioning and living circumstances. We analysed the OHS and the five EQ domains by ordinal logistic regression and calculated the mean difference between treatment groups in EQ utility index and visual analogue scale score. Analyses were adjusted for key baseline prognostic factors. This study is registered with controlled trials.com, number ISRCTN25765518. FINDINGS: At 18 months, 408 (34.9%) of 1169 patients in the alteplase group versus 414 (35.1%) of 1179 in the control group had died (p=0.85). 391 (35.0%) of 1117 patients versus 352 (31.4%) of 1122 had an OHS score of 0-2 (adjusted odds ratio [OR] 1.28, 95% CI 1.03-1.57; p=0.024). Treatment was associated with a favourable shift in the distribution of OHS grades (adjusted common OR 1.30, 95% CI 1.10-1.55; p=0.002). Alteplase treatment was associated with significantly higher overall self-reported health (adjusted mean difference in EQ utility index 0.060; p=0.019). The differences between the groups in visual analogue scale score and the proportion living at home were not significant. INTERPRETATION: IST-3 provides evidence that thrombolysis with intravenous alteplase for acute ischaemic stroke does not affect survival, but does lead to statistically significant, clinically relevant improvements in functional outcome and health-related quality of life that are sustained for at least 18 months. FUNDING: UK Medical Research Council, Health Foundation UK, Stroke Association UK, Research Council of Norway, AFA Insurances Sweden, Swedish Heart Lung Fund, The Foundation of Marianne and Marcus Wallenberg, Polish Ministry of Science and Education, the Australian Heart Foundation, Australian National Health and Medical Research Council, Swiss National Research Foundation, Swiss Heart Foundation, Assessorato alla Sanita (Regione dell'Umbria, Italy), and Danube University. PMID- 23791823 TI - Transmission of the respiratory rhythm to trigeminal and hypoglossal motor neurons in the American Bullfrog (Lithobates catesbeiana). AB - Spatially distinct, interacting oscillators in the bullfrog medulla generate and coordinated buccal and lung ventilatory rhythms, but how these rhythms are transmitted onto trigeminal and hypoglossal motor neurons is unknown. Using a vertically-mounted isolated brainstem preparation, the Sheep Dip, we identified the regions of the brainstem containing motor nuclei using a solution capable of blocking synaptic release and, following washout, locally exposed these regions to 5 MUM NBQX and/or 50 MUM AP5. Local application of NBQX significantly reduced the amplitude of buccal and lung bursts on the trigeminal nerve, and lung bursts on the hypoglossal nerve. Local AP5 caused a significant reduction in lung burst amplitude on both nerves, but for buccal bursts, hypoglossal amplitude increased and trigeminal amplitude was unchanged. Local co-application of NBQX and AP5 eliminated fictive respiratory motor output completely in both nerves. These results are consistent with mammalian data, suggesting a critical role for glutamate in transmission of respiratory activity from oscillators to motor neurons. PMID- 23791825 TI - Respiratory stimulant drugs in the post-operative setting. AB - Drug-induced respiratory depression (DIRD) is a common problem encountered post operatively and can persist for days after surgery. It is not always possible to predict the timing or severity of DIRD due to the number of contributing factors. A safe and effective respiratory stimulant could improve patient care by avoiding the use of reversal agents (e.g., naloxone, which reverses analgesia as well as respiratory depression) thereby permitting better pain management by enabling the use of higher doses of analgesics, facilitate weaning from prolonged ventilation, and ameliorate sleep-disordered breathing peri-operatively. The purpose of this review is to discuss the current pharmaceutical armamentarium of drugs (doxapram and almitrine) that are licensed for use in humans as respiratory stimulants and that could be used to reverse drug-induced respiratory depression in the post operative period. We also discuss new chemical entities (AMPAkines and GAL-021) that have been recently evaluated in Phase 1 clinical trials and where the initial regulatory registration would be as a respiratory stimulant. PMID- 23791826 TI - Prognostic value of preoperative metabolic tumor volume measured by 18F-FDG PET/CT and MRI in patients with endometrial cancer. AB - OBJECTIVE: Tumor metabolic activity is a significant prognostic factor for endometrial cancer; however, there are few reports on the clinical importance of metabolic tumor volume (MTV) in patients with endometrial cancer. Therefore, we evaluated the prognostic value of preoperative MTV measured by (18)F-FDG PET/CT and MRI in a group of these patients. METHODS: We retrospectively reviewed patients with pathologically proven endometrial cancer who had undergone preoperative (18)F-FDG PET/CT and MRI scans. The prognostic significance of PET/CT parameters and other clinicopathological variables was evaluated. RESULTS: A total of 76 consecutive patients were included in the study. The median follow up duration was 27 mo (range 3 to 96 mo) after surgery. MTV was correlated with FIGO stage and SUVmax. Age and FIGO stage were independent prognostic factors for recurrence in the multivariate analysis. In the subgroup analysis for 62 patients with endometrioid endometrial cancer, age (hazard ratio 1.098, P = 0.007, 95% confidence interval (CI) 1.026-1.175) and an MTV index of >= 876.4 (hazard ratio 5.795, P = 0.032, 95% CI 1.160-28.958) were determined to be independent prognostic factors of recurrence, and there was a statistically significant difference in progression-free survival (PFS) between patients in the high MTV and low MTV groups (log-rank test, P = 0.002). CONCLUSION: Preoperative MTV of the primary tumor was an independent prognostic factor for PFS and was significantly associated with recurrence in patients with endometrioid endometrial cancer. MTV is a promising tool for the prediction of outcome in patients with endometrioid endometrial cancer. PMID- 23791824 TI - The impact of spinal cord injury on breathing during sleep. AB - The prevalence of sleep disordered breathing (SDB) following spinal cord injury (SCI) is considerably greater than in the general population. While the literature on this topic is still relatively small, and in some cases contradictory, a few general conclusions can be drawn. First, while both central and obstructive sleep apnea (OSA) has been reported after SCI, OSA appears to be more common. Second, SDB after SCI likely reflects a complex interplay between multiple factors including body mass, lung volume, autonomic function, sleep position, and respiratory neuroplasticity. It is not yet possible to pinpoint a "primary factor" which will predispose an individual with SCI to SDB, and the underlying mechanisms may change during progression from acute to chronic injury. Given the prevalence and potential health implications of SDB in the SCI population, we suggest that additional studies aimed at defining the underlying mechanisms are warranted. PMID- 23791827 TI - Inpatient versus outpatient management of neutropenic fever in gynecologic oncology patients: is risk stratification useful? AB - OBJECTIVE: This study aimed to evaluate the utility of risk stratification of gynecologic oncology patients with neutropenic fever (NF). METHODS: A retrospective chart review of gynecologic cancer patients admitted with NF from 2007 to 2011 was performed, wherein demographic, oncologic, and NF characteristics (hospitalization length, complications, and death) were collected. The Multinational Association for Supportive Care in Cancer (MASCC) risk index score was calculated; low risk was considered >= 21. SAS 9.2 was used for statistical analyses. RESULTS: Eighty-three patients met the study criteria. Most (92%) were Caucasian and had advanced stage disease (71%). Primary tumors were 58% ovary, 35% endometrium, and 6% cervix. All patients were receiving chemotherapy on admission (72% for primary, 28% for recurrent disease). Forty eight percent had a positive culture, and most (58%) positive cultures were urine. Seventy-six percent of patients were considered low risk. High-risk patients were more likely to have a severe complication (10% versus 50%, p=0.0003), multiple severe complications (3% versus 20%, p=0.0278), ICU admission (2% versus 40%, p<0.0001), overall mortality (2% versus 15%, p=0.0417), and death due to neutropenic fever (0% versus 15%, p=0.0124). MASCC had a positive predictive value of 50% and negative predictive value of 90%. The median MASCC score for all patients was 22 (range, 11-26), but the median MASCC score for those with death or a severe complication was 17 (range, 11-24). CONCLUSION: Based on this pilot data, MASCC score appears promising in determining suitability for outpatient management of NF in gynecologic oncology patients. Prospective study is ongoing to confirm safety and determine impact on cost. PMID- 23791828 TI - Comprehensive genomic profiling of epithelial ovarian cancer by next generation sequencing-based diagnostic assay reveals new routes to targeted therapies. AB - OBJECTIVE: Targeted next generation sequencing (NGS) was evaluated for its ability to identify unanticipated targetable genomic alterations (GA) for patients with relapsed ovarian epithelial carcinoma (OC). METHODS: DNA sequencing was performed for 3320 exons of 182 cancer-related genes and 37 introns of 14 genes frequently rearranged in cancer on indexed, adaptor ligated, hybridization captured libraries using DNA isolated from FFPE sections from 48 histologically verified relapsed OC specimens. The original primary tumor was sequenced in 26 (54%) of the cases and recurrent/metastatic tumor site biopsies were sequenced in 22 (46%) of the cases. Actionability was defined as: GA that predict sensitivity or resistance to approved or standard therapies or are inclusion or exclusion criteria for specific experimental therapies in NCI registered clinical trials. RESULTS: There were 38 (80%) serous, 5 (10%) endometrioid, 3 (6%) clear cell, 1 mucinous (2%) and 1 (2%) undifferentiated carcinomas. 141 GA were identified with an average of 2.9 GA (range 0-8) per tumor, of which 67 were actionable for an average of 1.4 actionable GA per patient (range 0-5). 33/48 (69%) of OC patient samples harbored at least one actionable GA. Most common GA were TP53 (79%); MYC (25%); BRCA1/2 (23%); KRAS (16.6%) and NF1 (14.5%). One tumor featured an ERBB2 point mutation. One of 3 (33%) of clear cell tumors featured cMET amplification validated by both FISH and IHC. CONCLUSIONS: NGS assessment of therapy resistant OC identifies an unexpectedly high frequency of GA that could influence targeted therapy selection for the disease. PMID- 23791829 TI - Ovarian cancer patients with localized relapse: clinical outcome and prognostic factors. AB - OBJECTIVE: We evaluated the clinical outcome and prognostic factors for post relapse survival (PRS) in a large retrospective series of ovarian cancer patients with localized relapse. PATIENTS AND METHODS: The following radiological inclusion criteria were adopted: relapse in single anatomic site and <= 3 nodules. All cases were followed for at least 24 months after recurrent disease. RESULTS: Two hundred twenty ovarian cancer patients met the inclusion criteria. Serous histotype and G3 tumors were observed in 173 (78.6%) and 151 (77.4%) cases, respectively. All women received platinum-based first-line chemotherapy. Overall, the median follow-up was 46 (8-249) months, and platinum-resistant relapse was documented in 51 women (23.2%). Eighty-one patients (36.8%) recurred in the peritoneum (LPeR), 76 patients (34.5%) in the abdominal lymph nodes (LLNR), and 63 patients (28.7%) in parenchymal organs (LPaR); 142 patients (64.5%) recurred with a single nodule; and 78 patients (35.5%) recurred with 2-3 nodules. Secondary cytoreductive surgery (SCS) was attempted in 73 cases (33.2%), and complete debulking was achieved in all patients. On multivariate analysis, platinum-free interval (PFI, chi(2)=13.457, p value=0.001), complete SCS (median PRS, 69 months vs 25 months, p=0.001), anatomic site of relapse (median PRS, 41months in LPeRs, 63 months in LLNRs and 24 months in LPaRs, p=0.001), and number of nodules (median PRS, 58months in patients with one nodule, 24months in patients with 2-3 nodules, p=0.001) were identified as predictors of PRS. CONCLUSIONS: Beside the duration of PFI, the complete SCS, the anatomic site of relapse, and the number of nodules were independent prognostic factor for duration of PRS. PMID- 23791830 TI - [The risk and its communication to patients for decision-making in healthcare]. AB - Informing the patients before starting diagnostic and therapeutic procedures is advisable in order to establish a trusting and caring relationship. In this article, we analyze factors that determine the risk perception by the patients, as well as elements which facilitate a good information process by health professionals. PMID- 23791832 TI - Ube3a/E6AP is involved in a subset of MeCP2 functions. AB - Rett syndrome (RTT) and Angelman syndrome (AS) are devastating neurological disorders that share many clinical features. The disease-causing mutations have been identified for both syndromes. Mutations in Methyl-CpG Binding Protein 2 (MECP2) are found in a majority of patients with classical RTT while absence of maternal allele or intragenic mutation in the maternal copy of UBE3A gene encoding the human papilloma virus E6-associated protein (E6AP) cause most cases of AS. Extensive studies have been performed to determine the cause of the neurological problems in each disease. However, the genetic and molecular basis of the overlap in phenotypes between RTT and AS remains largely unknown. Here we present evidence that the phenotypic similarities between the two syndromes might be due to the shared molecular functions between MeCP2 and E6AP in gene expression. Our genetic and biochemical studies suggest that E6AP acts as an essential cofactor for a subset of MeCP2 functions. Specifically, decreased expression of Ube3a was able to rescue the cellular phenotypes induced by MECP2 overexpression in Drosophila. And biochemical assays using mice and cell culture systems show that MeCP2 and E6AP physically interact and regulate the expression of shared target genes. Together these data suggest that MeCP2 and E6AP play a role in the transcriptional control of common target gene expression and provide some insight into why RTT and AS share several neurological phenotypes. PMID- 23791833 TI - Interleukin-6 upregulates paraoxonase 1 gene expression via an AKT/NF-kappaB dependent pathway. AB - The aim of this study is to investigate the relationship between paraoxonase 1 (PON1) and atherosclerosis-related inflammation. In this study, human hepatoma HepG2 cell line was used as a hepatocyte model to examine the effects of the pro inflammatory cytokines on PON1 expression. The results showed that IL-6, but not TNF-alpha and IL-1beta, significantly increased both the function and protein level of PON1; data from real-time RT-PCR analysis revealed that the IL-6-induced PON1 expression occurred at the transcriptional level. Increase of IkappaB kinase activity and IkappaB phosphorylation, and reduction of IkappaB protein level were also observed in IL-6-treated HepG2 cells compared with untreated culture. This event was accompanied by increase of NF-kappaB-p50 and -p65 nuclear translocation. Moreover, treatment with IL-6 augmented the DNA binding activity of NF-kappaB. Furthermore, pharmacological inhibition of NF-kappaB activation by PDTC and BAY 11-7082, markedly suppressed the IL-6-mediated PON1 expression. In addition, IL-6 increased the levels of phosphorylated protein kinase B (PKB, AKT). An AKT inhibitor LY294002 effectively suppressed IKK/IkappaB/NF-kappaB signaling and PON1 gene expression induced by IL-6. Our findings demonstrate that IL-6 upregulates PON1 gene expression through an AKT/NF-kappaB signaling axis in human hepatocyte-derived HepG2 cell line. PMID- 23791831 TI - Water in the formation of biogenic minerals: peeling away the hydration layers. AB - Minerals of biogenic origin form and crystallize from aqueous environments at ambient temperatures and pressures. The in vivo environment either intracellular or intercellular, contains many components that modulate both the activity of the ions which associate to form the mineral, as well as the activity and structure of the crowded water. Most of the studies about the mechanism of mineralization, that is, the detailed pathways by which the mineral ions proceed from solution to crystal state, have been carried out in relatively dilute solutions and clean solutions. These studies have considered both thermodynamic and kinetic controls. Most have not considered the water itself. Is the water a passive bystander, or is it intimately a participant in the mineral ion densification reaction? A wide range of experiments show that the mineralization pathways proceed through a series of densification stages with intermediates, such as a "dense liquid" phase and the prenucleation clusters that form within it. This is in contrast to the idea of a single step phase transition, but consistent with the Gibbs concept of discontinuous phase transitions from supersaturated mother liquor to crystal. Further changes in the water structure at every surface and interface during densification guides the free energy trajectory leading to the crystalline state. In vertebrates, mineralization takes place in a hydrated collagen matrix, thus water must be considered as a direct participant. Although different in detail, the crystallization of calcium phosphates, as apatite, and calcium carbonates, as calcite, are mechanistically identical from the viewpoint of water. PMID- 23791834 TI - Cortical blindness following posterior lumbar decompression and fusion. AB - Perioperative vision loss following non-ocular surgery is a well-documented phenomenon. In particular, perioperative vision loss has been frequently cited following spinal surgery. Although the rate of vision compromise in spinal surgery is relatively low, the consequences can be quite severe and devastating for the patient. We report a 60-year-old woman who initially presented with back and left leg pain as well as paraparesis. Imaging studies of the lumbar spine showed bony erosion consistent with tumor infiltration of the L3 and L4 spinal segments. Laminectomy at the L2-L4 levels for decompression of the intraspinal tumor was performed. Pathology of the resected bone was consistent with metastatic adenocarincoma. Postoperatively, the patient suffered severe anemia and bilateral infarctions of the posterior cerebral arteries and occipital lobes resulting in vision compromise. Although a definitive pathogenesis remains unknown, preoperative cardiovascular issues and intraoperative hemodynamic instabilities have typically been implicated as high risk factors. High risk factors for this novel clinical presentation of visual compromise following posterior lumbar laminectomy with decompression for an intraspinal tumor are reported. PMID- 23791835 TI - Amphetamine makes caudate tissue more susceptible to oxygen and glucose deprivation. AB - Amphetamine is being investigated to reduce morbidity following stroke. However, the medicinal use of amphetamine is complicated because this drug is addictive, cardiotoxic, and can be neurotoxic. Thus, further research into the safety of giving amphetamine to stroke patients is required. Here, we examine whether prior treatment with amphetamine has any effect on oxygen-glucose deprivation (OGD) evoked transmitter efflux and mitochondrial function. To circumvent the well documented cardiovascular effects of amphetamine we have used rat brain slices. Brain slices were exposed to 30MUM of amphetamine for 10min 1h before being exposed to OGD. Using fast cyclic voltammetry in rat caudate, dopamine efflux induced by OGD was measured. The effect of amphetamine on mitochondrial function was examined using triphenyltetrazolium chloride (TTC) staining. Prior amphetamine exposure decreased the time to onset of OGD-evoked dopamine efflux (from 460 to 220s), suggesting that the caudate was more sensitive to OGD. This increased sensitivity to OGD was attenuated by pre-treatment with the dopamine transporter blocker GBR12909 (1MUM). Pre-treatment with the dopamine D2 receptor antagonist metoclopramide (1MUM) had no effect on the amphetamine-evoked sensitisation to OGD. Amphetamine decreased TTC staining in the caudate suggesting that amphetamine compromised the dopamine system by disrupting mitochondrial function. Amphetamine treatment may be harmful in stroke recovery by making the brain more vulnerable to ischaemia. These data also suggest that amphetamine abusers might be more susceptible to cerebral ischaemia. PMID- 23791836 TI - Primary CNS lymphoplasmacytic lymphoma: a case report and review of literature. AB - Lymphoplasmacytic lymphoma is a chronic lymphoproliferative disorder characterized by a proliferation of plasma cells, small lymphocytes, plasmacytoid lymphocytes and the production of monoclonal IgM. Primary central nervous system lymphomas (PCNSL) are rare non-Hodgkin lymphomas (NHL) that can be found in the brain, leptomeninges, eyes or spinal cord, and are mostly intracerebral. PCNSLs constitute 3-4% of primary brain tumors, and in most cases are diffuse large B cell lymphomas (DLBCL).(1) Low grade lymphomas as primary central nervous system (CNS) lymphoma are very rare. We present here a case report of a woman who presented with headache and was found to have primary intracranial lymphoplasmacytic lymphoma (LPL). PMID- 23791837 TI - General fluid-type intelligence is related to indices of white matter structure in middle-aged and old adults. AB - General fluid-type intelligence (gF) reflects abstract reasoning and problem solving abilities, and is an important predictor for lifetime trajectories of cognition, and physical and mental health. Structural and functional neuroimaging studies have demonstrated the role of parieto-frontal gray matter, but the white matter (WM) underpinnings of gF and the contribution of individual gF components to gF-WM relationship still need to be explored. The aim of this study was to characterize, in a sample of 100 healthy middle-aged and old subjects (mean=63.8 years), the relationship between gF and indices of WM structure obtained from diffusion tensor magnetic resonance imaging (DT-MRI) (fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD)). gF was estimated by principal component analysis including measures of episodic memory, reasoning, and processing speed. Tract-based spatial statistics and permutation-based inference statistics were used to test the association between gF and WM indices, while controlling for the effect of age and sex. We hypothesized a positive relationship between gF and WM structure. Based on previous studies, we further hypothesized that this relationship was heavily influenced by the processing speed component of gF. We found a robust relationship between gF and DT-MRI measures of FA, RD and MD in all major WM tracts. Higher gF score was related to higher degree of WM integrity, in middle aged as well as old individuals. Thus, the distributed relationship between gF and indices of WM microstructure is consistent with the notion that gF reflects efficient signaling between cortical areas. Furthermore, analysis of relationships between WM measures and gF components revealed an association with information processing speed and reasoning ability, but not with episodic memory. Thus, although all subcomponents loaded high on gF factor, the speed-related components were most strongly associated with DT-MRI-derived measures. These results suggest that DT-MRI can be used to parse gF. PMID- 23791838 TI - Neurofeedback-mediated self-regulation of the dopaminergic midbrain. AB - The dopaminergic system is involved in reward encoding and reinforcement learning. Dopaminergic neurons from this system in the substantia nigra/ventral tegmental area complex (SN/VTA) fire in response to unexpected reinforcing cues. The goal of this study was to investigate whether individuals can gain voluntary control of SN/VTA activity, thereby potentially enhancing dopamine release to target brain regions. Neurofeedback and mental imagery were used to self-regulate the SN/VTA. Real-time functional magnetic resonance imaging (rtfMRI) provided abstract visual feedback of the SN/VTA activity while the subject imagined rewarding scenes. Skin conductance response (SCR) was recorded as a measure of emotional arousal. To examine the effect of neurofeedback, subjects were assigned to either receiving feedback directly proportional (n=15, veridical feedback) or inversely proportional (n=17, inverted feedback) to SN/VTA activity. Both groups of subjects were able to up-regulate SN/VTA activity initially without feedback. Veridical feedback improved the ability to up-regulate SN/VTA compared to baseline while inverted feedback did not. Additional dopaminergic regions were activated in both groups. The ability to self-regulate SN/VTA was differentially correlated with SCR depending on the group, suggesting an association between emotional arousal and neurofeedback performance. These findings indicate that SN/VTA can be voluntarily activated by imagery and voluntary activation is further enhanced by neurofeedback. The findings may lead the way towards a non invasive strategy for endogenous control of dopamine. PMID- 23791839 TI - Acoustic landmarks drive delta-theta oscillations to enable speech comprehension by facilitating perceptual parsing. AB - A growing body of research suggests that intrinsic neuronal slow (<10 Hz) oscillations in auditory cortex appear to track incoming speech and other spectro temporally complex auditory signals. Within this framework, several recent studies have identified critical-band temporal envelopes as the specific acoustic feature being reflected by the phase of these oscillations. However, how this alignment between speech acoustics and neural oscillations might underpin intelligibility is unclear. Here we test the hypothesis that the 'sharpness' of temporal fluctuations in the critical band envelope acts as a temporal cue to speech syllabic rate, driving delta-theta rhythms to track the stimulus and facilitate intelligibility. We interpret our findings as evidence that sharp events in the stimulus cause cortical rhythms to re-align and parse the stimulus into syllable-sized chunks for further decoding. Using magnetoencephalographic recordings, we show that by removing temporal fluctuations that occur at the syllabic rate, envelope-tracking activity is reduced. By artificially reinstating these temporal fluctuations, envelope-tracking activity is regained. These changes in tracking correlate with intelligibility of the stimulus. Together, the results suggest that the sharpness of fluctuations in the stimulus, as reflected in the cochlear output, drive oscillatory activity to track and entrain to the stimulus, at its syllabic rate. This process likely facilitates parsing of the stimulus into meaningful chunks appropriate for subsequent decoding, enhancing perception and intelligibility. PMID- 23791840 TI - Superoxide dismutase 1 overexpression in mice abolishes maternal diabetes-induced endoplasmic reticulum stress in diabetic embryopathy. AB - OBJECTIVE: Both oxidative stress and endoplasmic reticulum stress (ER stress) are causal events in diabetic embryopathy. We tested whether oxidative stress causes ER stress. STUDY DESIGN: Wild-type (WT) and superoxide dismutase 1 (SOD1) overexpressing day 8.75 embryos from nondiabetic WT control with SOD1 transgenic male and diabetic WT female with SOD1 transgenic male were analyzed for ER stress markers: C/EBP-homologous protein (CHOP), calnexin, eukaryotic initiation factor 2alpha (eIF2alpha), protein kinase ribonucleic acid (RNA)-like ER kinase (PERK), binding immunoglobulin protein, protein disulfide isomerase family A member 3, kinases inositol-requiring protein-1alpha (IRE1alpha), and the X-box binding protein (XBP1) messenger RNA (mRNA) splicing. RESULTS: Maternal diabetes significantly increased the levels of CHOP, calnexin, phosphorylated (p) eIF2alpha, p-PERK, and p-IRE1alpha; triggered XBP1 mRNA splicing; and enhanced ER chaperone gene expression in WT embryos. SOD1 overexpression blocked these diabetes-induced ER stress markers. CONCLUSION: Mitigating oxidative stress via SOD1 overexpression blocks maternal diabetes-induced ER stress in vivo. PMID- 23791841 TI - An ENU mutagenesis-derived mouse model with a dominant Jak1 mutation resembling phenotypes of systemic autoimmune disease. AB - Within the Munich, Germany, N-ethyl-N-nitrosourea mouse mutagenesis program, we isolated a dominant Jak1 mouse model resembling phenotypic characteristics related to autoimmune disease. Chromosomal sequencing revealed a new Jak1 (p.Ser645Pro) point mutation at the conserved serine of the pseudokinase domain, corresponding to a somatic human mutation (p.Ser646Phe) inducing a constitutive activation of the Janus kinase (JAK)/STAT pathway. Morphologically, all Jak1(S645P+/-) mice showed a progressive structural deterioration of ears starting at the age of 4 months, with mononuclear cell infiltration into the dermis. Female mutant mice, in particular, developed severe skin lesions in the neck from 7 months of age. The IHC analysis of these lesions showed an activation of Stat3 downstream to Jak1(S645P) and elevated tissue levels of IL-6. Histopathological analysis of liver revealed a nodular regenerative hyperplasia. In the spleen, the number of Russell bodies was doubled, correlating with significant increased levels of all immunoglobulin isotypes and anti-DNA antibodies in serum. Older mutant mice developed thrombocytopenia and altered microcytic red blood cell counts. Jak1(S645P+/-) mice showed phenotypes related to impaired bone metabolism as increased carboxy-terminal collagen cross-link-1 levels and alkaline phosphatase activities in plasma, hypophosphatemia, and strongly decreased bone morphometric values. Taken together, Jak1(S645P+/-) mice showed an increased activation of the IL-6-JAK-STAT pathway leading to a systemic lupus erythematosus-like phenotype and offering a new valuable tool to study the role of the JAK/STAT pathway in disease development. PMID- 23791842 TI - Drive for leanness and health-related behavior within a social/cultural perspective. AB - We examined relationships between drive for leanness and perceived media pressure to change appearance, internalization of an ideal physique, exercise frequency, and dieting. Men and women (N=353) completed the Drive for Leanness Scale, the Sociocultural Attitudes Toward Appearance Questionnaire-3, the Eating Attitudes Test-26, and a demographic inventory. Drive for leanness was significantly correlated with athletic internalization (.52), pressure to attain an ideal physique (.25), exercise frequency (.36), and dieting (.25). Structural equation modeling revealed a good fitting model (chi(2)=2.85, p<.241; CFI=.99; NNFI=.98; RMSEA=.04; SRMR=.02) with internalization predicting drive for leanness, which in turn predicted dieting and exercise. Results reveal social/cultural theory helps enhance the understanding of the drive for leanness and its relationship with health-related behavior. PMID- 23791843 TI - "SEGRAs" and beyond. PMID- 23791844 TI - Oleanolic acid improves hepatic insulin resistance via antioxidant, hypolipidemic and anti-inflammatory effects. AB - Insulin resistance is the hallmark of type 2 diabetes mellitus (T2DM), which is closely related to disorder of lipid metabolism. The study was designed to evaluate the effects of oleanolic acid (OA) on hepatic insulin resistance and underlying mechanisms in Lep(db)(/)(db) obese diabetic mice. db/db Mice were administered with OA (20mg/kg/day, i.p.) for two weeks. OA reduced body weight, liver weight, and fat weight, and protected liver morphology and function. OA decreased fasting blood glucose, improved glucose and insulin tolerance, enhanced insulin signaling and inhibited gluconeogenesis. In livers, mitochondrial biogenesis, ultrastructure and function were influenced, accompanied by increased cellular and mitochondrial ROS production. OA inhibited all these changes, in which process Nrf2-GCLc mediated stabilization of mitochondrial glutathione pool may be involved. Moreover, OA decreased serum triglyceride, total cholesterol, LDL, HDL, and free fatty acids, increased serum HDL, and reduced hepatic lipid accumulation. Furthermore, inflammatory condition in db/db mice was improved by OA, as evidenced by decreased level of IL-1 beta, IL-6, and TNFalpha in circulation and in liver. The evidence suggests that OA improves hepatic insulin resistance through inhibition of mitochondrial ROS, hypolipidemic and anti inflammatory effects. The effectiveness of OA leads to interesting therapeutic perspectives. PMID- 23791845 TI - Proteomic analysis of visceral adipose tissue in pre-obese patients with type 2 diabetes. AB - The mechanisms involved in the progression to overt diabetes in pre-obese subjects remain unclear. Therefore, a nontargeted evaluation of differences in the protein abundance of visceral adipose tissue (VAT) obtained from pre-obese diabetic subjects and pre-obese subjects showing normal glucose tolerance may provide novel insights on the molecular processes involved in the progression to overt diabetes in pre-obesity. Diabetic patients showed increased VAT abundance of glutathione S-transferase Mu 2, peroxiredoxin-2, antithrombin-III, apolipoprotein A-IV, Ig kappa chain C region, mitochondrial aldehyde dehydrogenase and actin, and decreased abundance of annexin-A1, retinaldehyde dehydrogenase-1, and vinculin, compared with their non-diabetic counterparts. These proteins are involved in cytoskeleton function and structure, oxidative stress, inflammation and retinoid metabolism. The presence of diabetes influences the VAT abundance of several proteins. Hence, the proteins identified here could be considered candidate molecules in future studies addressing the role that VAT dysfunction plays in the development of type 2 diabetes. PMID- 23791846 TI - Vesicle size determines unitary exocytic properties and their sensitivity to sphingosine. AB - Neuroendocrine cells contain small and large vesicles, but the functional significance of vesicle diameter is unclear. We studied unitary exocytic events of prolactin-containing vesicles in lactotrophs by monitoring discrete steps in membrane capacitance. In the presence of sphingosine, which recruits VAMP2 for SNARE complex formation, the frequency of transient and full fusion events increased. Vesicles with larger diameters proceeded to full fusion, but smaller vesicles remained entrapped in transient exocytosis. The diameter of vesicle dense cores released by full fusion exocytosis into the extracellular space was larger than the diameter of the remaining intracellular vesicles beneath the plasma membrane. Labeling with prolactin- and VAMP2-antibodies revealed a correlation between the diameters of colocalized prolactin- and VAMP2-positive structures. It is proposed that sphingosine-mediated facilitation of regulated exocytosis is not only related to the number of SNARE complexes per vesicle but also depends on the vesicle size, which may determine the transition between transient and full fusion exocytosis. PMID- 23791847 TI - Calcium induces pro-anabolic effects on human primary osteoblasts associated with acquisition of mature osteocyte markers. AB - Calcium, in combination with vitamin D, is an effective treatment for osteoporosis. Since bone mineralisation occurs concurrently with osteoblast to osteocyte transition, we hypothesised that calcium would stimulate this process. The effect of calcium (1.8-11.8mM) was tested on human primary osteoblast (NHBC) differentiation in vitro. Cultures were assayed for cell-associated mineral and gene expression associated with osteoblast differentiation and mineralisation. Treatment with calcium resulted in a striking dose- and time-dependent increase in cell-associated mineralisation. Calcium appeared to promote osteoblast to osteocyte differentiation, as indicated by increased expression of osteocalcin (OCN), E11, dentin matrix protein 1 (DMP1) and SOST mRNA. The expression of the osteoclast inhibitor, osteoprotegerin, was dramatically enhanced by calcium. Calcium also increased the ratio of PHEX mRNA expression relative to that of MEPE, suggesting a mechanism for the pro-anabolic effect. Consistent with this, calcium-dependent mineralisation was reversed in the presence of MEPE-ASARM peptides. This study suggests that calcium promotes osteoblast to osteocyte transition and concurrent matrix mineralisation, at least in part through the PHEX-MEPE axis. PMID- 23791848 TI - Involvement of lipid rafts in the budding-like exit of Orientia tsutsugamushi. AB - Orientia tsutsugamushi is an intracellular parasite that causes scrub typhus. After entering the cytoplasm by induced phagocytosis, O. tsutsugamushi escapes from the primary phagosome into the host cytosol, where it replicates slowly. Subsequently, it is released from the host cells by a process resembling viral budding with a remaining bacterial aggregate near the nucleus. Lipid rafts have been implicated in the life cycle of a wide variety of pathogenic microorganisms. We have observed that proteins of O. tsutsugamushi were co-fractionated with the lipid rafts over a sucrose density gradient, suggesting the possible involvement of lipid rafts during the intracellular life cycle of O. tsutsugamushi. The entry of O. tsutsugamushi into the host cells was shown to be independent on lipid rafts as judged by the inability of lipid raft-disrupting agents to inhibit bacterial entry and no co-localization of bacterial proteins with caveolin. To our interest, a 47-kDa protein (HtrA) was observed to be co-localized with caveolin at the cell membrane at 72 h after infection, when bacterial particles move to the cell membrane and initiate the exit into the extracellular environment. Our results suggest that O. tsutsugamushi involves lipid rafts of the host cells in the budding-like process to exit from host cells. PMID- 23791849 TI - Effects of "in vivo" administration of baclofen on rat renal tubular function. AB - The effects of the in vivo administration of baclofen on renal tubular transport and aquaporin-2 (AQP2) expression were evaluated. In conscious animals kept in metabolic cages, baclofen (0.01-1mg/kg, s.c.) induced a dose-dependent increment in the urine flow rate (UFR) and in sodium and potassium excretion, associated with an increased osmolal clearance (Closm), a diminished urine to plasma osmolality ratio (Uosm/Posm) and a decrease in AQP2 expression. The above mentioned baclofen effects on functional parameters were corroborated by using conventional renal clearance techniques. Additionally, this model allowed the detection of a diminution in glucose reabsorption. Some experiments were performed with water-deprived or desmopressin-treated rats kept in metabolic cages. Either water deprivation or desmopressin treatment decreased the UFR and increased the Uosm/Posm. Baclofen did not change the Uosm/Posm or AQP2 expression in desmopressin-treated rats; but it increased the UFR and diminished the Uosm/Posm and AQP2 expression in water-deprived animals. These results indicate that in vivo administration of baclofen promotes alterations in proximal tubular transport, since glucose reabsorption was decreased. The distal tubular function was also affected. The increased Closm indicates an alteration in solute reabsorption at the ascending limb of the Henle's loop. The decreased Uosm/Posm and AQP2 expression in controls and in water-deprived, but not in desmopressin treated rats, lead us to speculate that some effect of baclofen on endogenous vasopressin availability could be responsible for the impaired urine concentrating ability, more than any disturbance in the responsiveness of the renal cells to the hormone. PMID- 23791850 TI - The role of temperature variability in stabilizing the mountain pine beetle fungus mutualism. AB - As global climate patterns continue to change and extreme weather events become increasingly common, it is likely that many ecological interactions will be affected. One such interaction is the multipartite symbiosis that exists between the mountain pine beetle and two species of fungi, Grosmannia clavigera and Ophiostoma montium. In this mutualism, the fungi provide nutrition to the beetle, while the fungi benefit by being dispersed to new host trees. Multi-partite mutualisms are predicted to be unstable due to strong direct competition among symbionts or natural selection for superior over inferior mutualists. However, this mutualism has remained stable over long periods of evolutionary time. In this paper, we developed a temperature-based model for the spread of fungi within a tree and connected it to an existing model for mountain pine beetle development. Using this integrated model for fungal growth, we explored the possibility that temperature variability is a stabilizing mechanism for the mountain pine beetle-fungi mutualism. Of the three types of temperature variability we tested: intra-year, inter-year and variability due to transitioning between different thermal habitats (thermal migration), we found that thermal migration was the most robust stabilizing mechanism. Additionally, we found that the MPB attack density or spacing between fungal lesions also had a significant effect on the stability of the system. High attack densities or close lesion spacings also tended to stabilize the system, regardless of temperature. PMID- 23791851 TI - Model of annual plants dynamics with facilitation and competition. AB - An individual-based model describing the dynamics of one type of annual plants is presented. We use Monte Carlo simulations where each plant has its own history and the interactions among plants are between nearest neighbours. The character of the interaction (positive or negative) depends on local conditions. The plants compete for two external resources-water and light. The amount of water and/or light a plant receives depends on the external factor but also on local arrangement. Survival, growth and seed production of plants are determined by how well their demands for the resources are met. The survival and seeds production tests have a probabilistic character, which makes the dynamics more realistic than by using a deterministic approach. There is a non-linear coupling between the external supplies. Water evaporates from the soil at a rate depending on constant evaporation rate, local conditions and the amount of light. We examine the dynamics of the plant population along two environmental gradients, allowing also for surplus of water and/or light. We show that the largest number of plants is when the demands for both resources are equal to the supplies. We estimate also the role of evaporation and we find that it depends on the situation. It could be negative, but sometimes it has a positive character. We show that the link between the type of interaction (positive or negative) and external conditions has a complex character. In general in favourable environment plants have a stronger tendency for competitive interactions, leading to mostly isolated plants. When the conditions are getting more difficult, cooperation becomes the dominant type of interactions and the plants grow in clusters. The type of plants sun-loving or shade tolerating, plays also an important role. PMID- 23791852 TI - Conditions for neutral speciation via isolation by distance. AB - The branching of new species from an ancestral population requires the evolution of reproductive isolation between groups of individuals. Geographic separation of sub-populations by natural barriers, if sustained for sufficiently long times, may lead to the accumulation of independent genetic changes in each group and to mating incompatibilities (Mayr, 2001; Fitzpatrick et al., 2009). A similar phenomenon may occur in the absence of barriers via isolation by distance if the population is distributed over large areas (de Aguiar et al., 2009; Etienne and Haegeman, 2011; Gavrilets et al., 2000). The first demonstration of this process was based on computer simulations employing agent-based models. Recently, analytical results were derived combining network theory, to model the spatial structure of the population, and an ansatz that accounts for the effect of forbidding mating between individuals that are too different genetically (de Aguiar and Bar-Yam, 2011). The main result obtained with this approach is an expression that indicates when speciation is possible as a function of the parameters describing the population. The aim of this work is to test this analytical result by comparing it with numerical simulations for a hermaphroditic population (de Aguiar et al., 2009) and for a population whose individuals are explicitly separated into males and females (Baptestini et al., 2013). We show that the analytical formula is indeed a very good overall description of the simulations and that the exponents describing dependence of the critical threshold of speciation with the parameters are in good agreement with the simulations. PMID- 23791853 TI - Neuroprotective effect of paeonol on cognition deficits of diabetic encephalopathy in streptozotocin-induced diabetic rat. AB - Diabetic encephalopathy (DE) has been characterized by the impaired cognition and the abnormalities of neurochemistry and neurostructure. The study was conducted to evaluate the neuroprotective effect of paeonol on STZ-induced DE rats. Paeonol of 25, 50, 100mg/kg (p.o.) could decrease the latency time and path length, and enhance significantly the spent time in the target quadrant and platform crossings in Morris water maze test. The treatment with paeonol could also increase significantly Na(+)-K(+)-ATP enzyme and ChAT activities, as well as decreasing significantly AchE activity in hippocampal tissue. Immunohistochemistry and TUNEL staining showed that paeonol could attenuate apoptosis of neurons and caspase 3 expression, improve two neurotrophic factors BDNF and IGF expressions, and also ameliorate Abeta deposition in the hippocampus and cerebral cortex. In conclusion, the present study demonstrated diabetic rats treated with paeonol could ameliorate the cognition deficits. These findings indicated paeonol might act as a beneficial agent for the prevention and treatment of DE. PMID- 23791854 TI - Transplantation of NSCs with OECs alleviates neuropathic pain associated with NGF downregulation in rats following spinal cord injury. AB - Spinal cord injury (SCI) is a common and serious disease which often induces catastrophic consequence in patients. Part of them exhibit neuropathic pain which presents unique challenges to clinicians, and there is no effective approach for the treatment up to now. Neural stem cells (NSCs) transplantation, as a promising and an effective method, could be considered for the treatment of SCI, whereas a main problem is the low survival of NSCs in traumatic milieu in host spinal cords, and the effect of NSCs on sensory function remains elusive. In this study, we investigated the effect and underlying molecular mechanism of co transplantation of NSCs with olfactory ensheathing cells (OECs) on sensory functional improvement. In the measurement of thermal and mechanical stimuli, NSCs grafts recovered sensory function in SCI rats, while OECs led to hyperalgesia, indicated by the tail flick latency (TFL) and paw withdraw latency (PWL) (p<0.05). Co-transplantation could promote NSCs survival, and reverses the hyperalgesia triggered by OECs. This was corresponding to a significant improvement in sensory function. Moreover, NGF expression was substantial downregulated in the spinal cord of co-transplantation rats. The present findings suggested that co-transplantation of NSCs with OECs could improve sensory function and the possible mechanism is involved in NGF downregulation in rats with SCI. This may give some new indications for the treatment of SCI in future clinic cell therapy trial. PMID- 23791855 TI - Glycosaminoglycan entrapment by fibrin in engineered heart valve tissues. AB - Tissue engineered heart valves (TEHVs) may provide a permanent solution to congenital heart valve disease by permitting somatic valve growth in the pediatric patient. However, to date, TEHV studies have focused primarily on collagen, the dominant component of valve extracellular matrix (ECM). Temporal decreases in other ECM components, such as the glycosaminoglycans (GAGs), generally decrease as cells produce more collagen under mechanically loaded states; nevertheless, GAGs represent a key component of the valve ECM, providing structural stability and hydration to the leaflets. In an effort to retain GAGs within the engineered constructs, here we investigated the utility of the protein fibrin in combination with a valve-like, cyclic flexure and steady flow (flex flow) mechanical conditioning culture process using adult human periodontal ligament cells (PLCs). We found both fibrin and flex-flow mechanical components to be independently significant (p<0.05), and hence important in influencing the DNA, GAG and collagen contents of the engineered tissues. In addition, the interaction of fibrin with flex-flow was found to be significant in the case of collagen; specifically, the combination of these environments promoted PLC collagen production resulting in a significant difference compared to dynamic and statically cultured specimens without fibrin. Histological examination revealed that the GAGs were retained by fibrin entrapment and adhesion, which were subsequently confirmed by additional experiments on native valve tissues. We conclude that fibrin in the flex-flow culture of engineered heart valve tissues: (i) augments PLC-derived collagen production; and (ii) enhances retention of GAGs within the developing ECM. PMID- 23791856 TI - Commentary to 'Urethral strictures following urethral plate and proximal urethral elevation during proximal TIP hypospadias repair'. PMID- 23791857 TI - Single-dose administration of inactivated hepatitis A vaccination in the context of hepatitis A vaccine recommendations. AB - OBJECTIVES: Our objective was to identify evidence on the protection achieved by single-dose use of inactivated hepatitis A vaccines in order to evaluate the potential of a flexible booster administration in the form of a second dose. METHODS: A search was conducted for evidence on single-dose administration of inactivated hepatitis A vaccine and its potential impacts on long-term seropositivity rates. The main pharmaceutical vaccine manufacturer federations and the corresponding authors of manuscripts were approached for additional epidemiologic data. Correspondence was also sent to the Argentinean Ministry of Health. RESULTS: We identified 15 data sources reporting on protection achieved by a single dose of inactivated hepatitis A vaccine. The consistent finding was that the immune and memory response to the booster dose, or post-booster geometric mean titer, was independent of the time since initial vaccination. The impact of the booster on seroprotection was the same across sexes and age-groups. The longest time interval between initial and booster dose was 10.67 years, indicating that booster doses can be highly immunogenic for up to 10.67 years after primary vaccination. CONCLUSIONS: Protective anti-hepatitis A virus antibody levels after a single dose of inactivated hepatitis A vaccine can persist for almost 11 years and increase or reappear after booster vaccination. Further research on the vaccine doses needed to achieve long-term protection against hepatitis A infection is required. PMID- 23791858 TI - Successful treatment of skin and soft tissue infection due to carbapenem resistant Acinetobacter baumannii by ampicillin-sulbactam and meropenem combination therapy. AB - In recent years, carbapenem-resistant Acinetobacter baumannii infections have been responsible for outbreaks in medical facilities. A 35-year-old Japanese woman developed a skin and soft tissue infection due to carbapenem-resistant A. baumannii. The isolate was resistant to antibiotics other than ampicillin sulbactam and colistin, suggesting drug resistance due to carbapenemase production by OXA-23. We selected a combination therapy consisting of intravenous ampicillin-sulbactam and meropenem. No changes were observed in aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, or serum creatinine during therapy, and carbapenem-resistant A. baumannii was not detected in wound exudates 3 days after therapy initiation. In our patient's case, combination therapy with ampicillin-sulbactam and meropenem was successful. Thus, combination therapy with ampicillin-sulbactam and meropenem is effective against skin and soft tissue infection due to carbapenem-resistant A. baumannii. Combination therapy with intravenous ampicillin-sulbactam and meropenem may be an option for skin and soft tissue infections due to carbapenem-resistant A. baumannii. PMID- 23791859 TI - Characterization of MMP-9 gene from grass carp (Ctenopharyngodon idella): an Aeromonas hydrophila-inducible factor in grass carp immune system. AB - Matrix metalloproteinase-9 (MMP-9) belongs to a family of zinc-dependent endopeptidases and is associated with vital inflammatory processes. Here, we isolated and characterized MMP-9 cDNA from grass carp (Ctenopharyngodon idella) (designated as CiMMP-9). The cDNA was 2880 bp long and encoded a putative protein of 675 amino acids, with a predicted molecular mass of 75.816 kDa and an isoelectric point (pI) of 5.25. CiMMP-9 contained all three classical MMP-9 family signatures. The mRNA of CiMMP-9 was constitutively expressed in all tested tissues of untreated grass carp, with the highest expression levels in the blood, trunk kidney, head kidney and spleen. CiMMP9 transcript was present in unfertilized eggs, which suggests that CiMMP9 transcription is maternally inherited. Fluorescent real-time quantitative RT-PCR was used to examine the expression of the CiMMP-9 gene in C. idella after being challenged with Aeromonas hydrophila. A clear time-dependent expression pattern of CiMMP-9 was found after the bacterial challenge, and mRNA expression reached a maximum level at 7 days post challenge. This indicates that MMP-9 is inducible and is involved in immune responses, thus suggesting that CiMMP-9 plays an important role in A. hydrophila related diseases and in early embryonic development stages in C. idella. PMID- 23791860 TI - Two Rab GTPases, EsRab-1 and EsRab-3, involved in anti-bacterial response of Chinese mitten crab Eriocheir sinensis. AB - Rab GTPase is essential for the control of intracellular membrane trafficking in all eukaryotic cells and further affects the ability of phagocytic cells to scavenge pathogen. In the present study, the cDNAs for two crab Rab proteins (EsRab-1 and EsRab-3) were identified from the Chinese mitten crab Eriocheir sinensis by rapid amplification of cDNA ends (RACE) approaches and expressed sequence tag (EST) analysis. The full-length cDNAs of EsRab-1 and EsRab-3 were of 892 bp and 965 bp with ORFs of 615 bp and 630 bp, respectively. The cDNAs encoded two peptides of 204 and 209 amino acid residues with the conserved GTP/Mg(2+) binding sites, Switch I region and Switch II region in RAB domains. The mRNA transcripts of EsRab-1 and EsRab-3 were both highest expressed in hepatopancreas, and marginally expressed in other tissues including hemocytes, muscle, gonad, gill and heart. After the crabs were challenged by bacteria Vibrio anguillarum, the expression levels of both EsRab-1 and EsRab-3 in hemocytes were significantly up-regulated, and reached the highest level at 1.5 h post-stimulation, which was 7-fold (P < 0.05) and 6-fold (P < 0.01) of blank group for EsRab-1 and EsRab-3, respectively. No significant change of mRNA expression was detected for either EsRab-1 or EsRab-3 in crabs stimulated by Pichia pastoris. These results clearly suggested the involvement of Rab proteins in crab anti-bacterial immunity. PMID- 23791861 TI - Development of a sandwich ELISA for quantifying hepcidin in Rainbow trout. AB - One of the most widespread antimicrobial peptides (AMPs) in fish is the hepcidins, which have potent, broad-spectrum activity against viruses, bacteria, fungi, and parasites. Moreover, they play the role of central regulation of iron metabolism and their expression is over-regulated by bacterial and viral infections, inflammation and vaccination. Quantification of their expression is an important factor in understanding their function. We therefore generated two polyclonal antibodies using synthetic peptides in order to measure hepcidin expression via sandwich ELISA. The specificity of both antibodies was confirmed by identifying an absence of cross-reactivity with other peptides that have similar pI and with the detection by Western blot of only one 9.6 kDa immunoreactive band corresponding to the hepcidin prepropeptide. The sensitivity of the sandwich ELISA was in the order of 0.005 ng/MUL of hepcidin, which allowed analysis of the presence of the peptide and its variation in different tissues of Oncorhynchus mykiss. With the sandwich ELISA it could be seen that hepcidin expression in rainbow trout challenged with Aeromonas salmonicida was increased twofold over the untreated fish in head kidney samples, in correlation with the increase in the observed transcriptional level in the head kidney cells. These results provide the first evidence for quantifying the presence of active hepcidin and may be a useful indicator of disease susceptibility, providing a new, sensitive tool for rapid screening of population health. PMID- 23791863 TI - Calreticulin is a microbial-binding molecule with phagocytosis-enhancing capacity. AB - Calreticulin (CRT) is a highly conserved calcium-binding protein mainly involved in directing proper conformation of proteins and controlling calcium level. Accumulating data also show that CRT is emerging as an immune-relevant molecule. In this study, we demonstrated that the CRT gene from the amphioxus Branchiostoma japonicum, named Bjcrt, consisted of a signal peptide, three domains (N-, P-, C domains) and an ER retrieval signal sequence (KDEL), which appears to be the ancient form of vertebrate CRTs, and Bjcrt was expressed in a tissue-specific manner, with the most abundant expression in the notochord. We also demonstrated for the first time that the recombinant BjCRT (rBjCRT) was able to bind the Gram negative bacterium Escherichia coli and the Gram-positive bacterium Staphylococcus aureus. Moreover, both BjCRT as well as human recombinant calreticulin were able to promote the phagocytosis of E. coli and S. aureus by sea bass macrophages. These results indicate that CRT is a microbial-binding molecule and possesses an ability to enhance phagocytosis, a novel function assigned to CRT, reenforcing the notion that CRT is an immune-relevant molecule associated with host immune responses. PMID- 23791862 TI - Accumulation, histopathology and immunotoxicological effects of waterborne cadmium on gilthead seabream (Sparus aurata). AB - Studies in fish have demonstrated that Cd-exposure produce skeletal deformities and alterations in tissue morphology, enzyme activities, stress response, ion regulation and immune response. In the present work, gilthead seabream (Sparus aurata) specimens were exposed to waterborne Cd (5 MUM CdCl2 or 1 mg L(-1)) for 2, 10 or 30 days. Organo-somatic changes, Cd accumulation, liver histology and humoral and cellular immune responses were determined. Results showed that exposure of seabream specimens to Cd induced no alterations on spleen and liver organo-somatic indexes whilst produced progressive deleterious morphological alterations in liver and exocrine pancreas that correlated with the hepatic Cd accumulation. Regarding the immunotoxicological potential, strikingly, Cd exposure produced a reduction in the serum complement activity and leucocyte respiratory burst to a significant extent after 10 and 30 days whilst the serum peroxidase activity and leucocyte phagocytosis were increased at different sampling times. On the other hand, serum IgM levels and leucocyte peroxidase activity resulted unaltered. The present results seem to indicate that seabream exposed to Cd in the present conditions suffer toxicity. PMID- 23791864 TI - A galectin from roughskin sculpin, Trachidermus fasciatus: molecular cloning and characterization. AB - Galectins are a family of beta-galactoside-binding lectins, which have been proved to be involved in host-pathogen interactions by recognizing pathogen associated molecular patterns (PAMPs) on the surface of virus, bacteria, fungi and protozoa. In this study, a galactoside-binding lectin homolog was identified from roughskin sculpin Trachidermus fasciatus, named TfGal. The full-length of TfGal cDNA was 1016 bp with a 5' untranslated region (UTR) of 134 bp and a 3' UTR of 474 bp, and the open reading frame (ORF) is 408 bp. The deduced protein was composed of 135 amino acids, including a carbohydrate-recognition domain and a galactoside-type carbohydrate-binding motif H-NPR/W--E-R. The deduced amino acid sequence shared 58.52%-87.4% similarities with the galectins of the other fishes. Quantitative real-time PCR (qRT-PCR) analysis demonstrated that TfGal mRNA was abundantly expressed in the ovary, heart, stomach, skin, moderately expressed in the liver, brain, gills, spleen, and rarely expressed in the hemocytes, meat and intestine. The expression of TfGal mRNA in the hemocytes and the skin was dramatically up-regulated after challenged with LPS, reaching the highest level at 2 h post-challenge, and then dropped abruptly, while the expression of TfGal mRNA in the liver was up-regulated at 2-6 h post-challenge, and then returned to the normal level, with an increase at 96 h post-challenge again. However, no obvious change of the expression of TfGal mRNA was detected in the stomach. Recombinant TfGal purified from Escherichia coli (BL21) could agglutinate and/or bind microorganisms in Ca(2+)-independent manner. These results suggested that TfGal might be involved in the innate immune response of roughskin sculpin. PMID- 23791865 TI - Environmental and demographic correlates of bicycling. AB - OBJECTIVE: The present study examined correlates of bicycle ownership and bicycling frequency, and projected increases in cycling if perceived safety from cars was improved. METHODS: Participants were 1780 adults aged 20-65 recruited from the Seattle, Washington and Baltimore, Maryland regions (48% female; 25% ethnic/racial minority) and studied in 2002-2005. Bicycling outcomes were assessed by survey. Multivariable models were conducted to examine demographic and built environment correlates of bicycling outcomes. RESULTS: About 71% of the sample owned bicycles, but 60% of those did not report cycling. Among bicycle owners, frequency of riding was greater among young, male, White, educated, and lean subgroups. Neighborhood walkability measures within 1 km were not consistently related to bicycling. For the whole sample, bicycling at least once per week was projected to increase from 9% to 39% if bicycling was safe from cars. Ethnic-racial minority groups and those in the least safe neighborhoods for bicycling had greater projected increases in cycling if safety from traffic was improved. CONCLUSION: Implementing measures to improve bicyclists' safety from cars would primarily benefit racial-ethnic groups who cycle less but have higher rates of chronic diseases, as well as those who currently feel least safe bicycling. PMID- 23791867 TI - Substituents effects on activity of kynureninase from Homo sapiens and Pseudomonas fluorescens. AB - A series of substituted kynurenines (3-bromo-DL, 3-chloro-DL, 3-fluoro-DL, 3 methyl-DL, 5-bromo-L, 5-chloro-L, 3,5-dibromo-L and 5-bromo-3-chloro-DL) have been synthesized and tested for their substrate activity with human and Pseudomonas fluorescens kynureninase. All of the substituted kynurenines examined have substrate activity with both human as well as P. fluorescens kynureninase. For the human enzyme, 3- and 5-substituted kynurenines have kcat and kcat/Km values higher than L-kynurenine, but less than that of the physiological substrate, 3-hydroxykynurenine. However, 3,5-dibromo- and 5-bromo-3 chlorokynurenine have kcat and kcat/Km values close to that of 3 hydroxykynurenine with human kynureninase. The effects of the 3-halo substituents on the reactivity with human kynureninase may be due to electronic effects and/or halogen bonding. In contrast, for the bacterial enzyme, 3-methyl, 3-halo and 3,5 dihalokynurenines are much poorer substrates, while 3-fluoro, 5-bromo, and 5 chlorokynurenine have kcat and kcat/Km values comparable to that of its physiological substrate, L-kynurenine. Thus, 5-bromo and 5-chloro-L-kynurenine are good substrates for both human as well as bacterial enzyme, indicating that both enzymes have space for substituents in the active site near C-5. The increased activity of the 5-halokynurenines may be due to van der Waals contacts or hydrophobic effects. These results may be useful in the design of potent and/or selective inhibitors of human and bacterial kynureninase. PMID- 23791866 TI - Probing the microRNA pathway with small molecules. AB - MicroRNA (miRNA)/RNA interference (RNAi) is recognized as one of the most important mechanisms regulating gene expression at the posttranscriptional level in eukaryotic cells. The main components within the miRNA/RNAi pathway are now known and well characterized, but studies on the molecular mechanisms that regulate the activity of the miRNA/RNAi pathway are just beginning to emerge. High-throughput reporter assays have been developed to monitor the activity of the miRNA/RNAi pathway and applied in a proof-of-concept pilot screening, which has led to the identification of some inhibitors and activators that either generally or specifically regulate the activity of the miRNA/RNAi pathway. In addition, combined with multidisciplinary approaches like proteomics, biochemistry, and genetics, some protein co-factors were found to play important roles in the regulation of the miRNA/RNAi pathway. Herein we highlight the high throughput reporter assays developed in recent years and the resulting discovery of miRNA/RNAi enhancers and inhibitors. PMID- 23791868 TI - Control of the intracellular levels of prostaglandin E2 through inhibition of the 15-hydroxyprostaglandin dehydrogenase for wound healing. AB - Excessive scar formation is an aberrant form of wound healing and is an indication of an exaggerated function of fibroblasts and excess accumulation of extracellular matrix during wound healing. Much experimental data suggests that prostaglandin E2 (PGE2) plays a role in the prevention of excessive scarring. However, it has a very short half-live in blood, its oxidization to 15 ketoprostaglandins is catalyzed by 15-hydroxyprostaglandin dehydrogenase (15 PGDH). Previously, we reported that 15-PGDH inhibitors significantly increased PGE2 levels in A549 cells. In our continuing attempts to develop highly potent 15 PGDH inhibitors, we newly synthesized various thiazolidine-2,4-dione derivatives. Compound 27, 28, 29, and 30 demonstrated IC50 values of 0.048, 0.020, 0.038 and 0.048 MUM, respectively. They also increased levels of PGE2 in A549 cells. Especially, compound 28 significantly increased level of PGE2 at 260 pg/mL, which was approximately fivefold higher than that of control. Scratch wounds were analyzed in confluent monolayers of HaCaT cells. Cells exposed to compound 28 showed significantly improved wound healing with respect to control. PMID- 23791869 TI - Chemically modified siRNAs and miRNAs bearing urea/thiourea-bridged aromatic compounds at their 3'-end for RNAi therapy. AB - We have developed chemically modified siRNAs and miRNAs bearing urea/thiourea bridged aromatic compounds at their 3'-end for RNAi therapy. Chemically modified RNAs possessing urea/thiourea-bridged aromatic compounds instead of naturally occurring dinucleotides at the 3'-overhang region were easily prepared in good yields and were more resistant to nucleolytic hydrolysis than unmodified RNA. siRNAs containing urea or thiourea derivatives showed the desired knockdown effect. Furthermore, modified miR-143 duplexes carrying the urea/thiourea compounds in the 3'-end of each strand were able to inhibit the growth of human bladder cancer T24 cells. PMID- 23791870 TI - Neuraminidase inhibitor susceptibility profile of pandemic and seasonal influenza viruses during the 2009-2010 and 2010-2011 influenza seasons in Japan. AB - Two new influenza virus neuraminidase inhibitors (NAIs), peramivir and laninamivir, were approved in 2010 which resulted to four NAIs that were used during the 2010-2011 influenza season in Japan. This study aims to monitor the susceptibility of influenza virus isolates in 2009-2010 and 2010-2011 influenza seasons in Japan to the four NAIs using the fluorescence-based 50% inhibitory concentration (IC50) method. Outliers were identified using box-and-whisker plot analysis and full NA gene sequencing was performed to determine the mutations that are associated with reduction of susceptibility to NAIs. A total of 117 influenza A(H1N1)pdm09, 59 A(H3N2), and 18 type B viruses were tested before NAI treatment and eight A(H1N1)pdm09 and 1 type B viruses were examined from patients after NAI treatment in the two seasons. NA inhibition assay showed type A influenza viruses were more susceptible to NAIs than type B viruses. The peramivir and laninamivir IC50 values of both type A and B viruses were significantly lower than the oseltamivir and zanamivir IC50 values. Among influenza A(H1N1)pdm09 viruses, the prevalence of H274Y viruses increased from 0% in the 2009-2010 season to 3% in the 2010-2011 season. These H274Y viruses were resistant to oseltamivir and peramivir with 200-300 fold increase in IC50 values but remained sensitive to zanamivir and laninamivir. Other mutations in NA, such as I222T and M241I were identified among the outliers. Among influenza A(H3N2) viruses, two outliers were identified with D151G and T148I mutations, which exhibited a reduction in susceptibility to oseltamivir and zanamivir, respectively. Among type B viruses, no outliers were identified to the four NAIs. For paired samples that were collected before and after drug treatment, three (3/11; 27.3%) H274Y viruses were identified among A(H1N1)pdm09 viruses after oseltamivir treatment but no outliers were found in the laninamivir-treatment group (n=3). Despite widespread use of NAIs in Japan, the prevalence of NAI resistant influenza viruses is still low. PMID- 23791871 TI - Utilization of 6-(methylsulfinyl)hexyl isothiocyanate for sensitization of tumor cells to antitumor agents in combination therapies. AB - In the present study, we performed in silico and in vitro analyses to evaluate the chemosensitizing effects of 6-(methylsulfinyl)hexyl isothiocyanate (6-MITC) on tumor cells. Our in silico analyses of the ligand-receptor interactions between 6-MITC and the glutamate cysteine ligase (GCL) catalytic subunit (GCLC) revealed that 6-MITC possibly inhibited GCL enzyme activity, and that Cys-249 and Gln-251 were important residues for stable binding of ligands to GCLC. It was further found that 6-MITC interfered with the hydrogen bonds of the cysteinyl and glutamyl moieties of GSH with Cys-249 and Gln-251, respectively, and possibly overrode the feedback inhibition of GCL enzyme activity by GSH. To the best of our knowledge, this is the first in silico analysis to suggest an overriding effect of 6-MITC on GSH-induced feedback inhibition of GCL. In our in vitro analyses, combined treatment with 6-MITC and L-buthionine-S,R-sulfoximine (BSO) depleted GSH within 4 h in tumorigenic human c-Ha-ras and mouse c-myc cotransfected highly metastatic serum-free mouse embryo-1 (r/m HM-SFME-1) cells, but did not deplete GSH in normal SFME cells. Furthermore, exposure to 6-MITC plus BSO for 4h, followed by glycyrrhetinic acid (GA) treatment for 3h, eradicated the tumor cells with minimal damage to the normal cells. The present findings suggest that 6-MITC in combination therapies could be used to sensitize tumor cells to antitumor agents, thereby leading to their eradication. PMID- 23791872 TI - The association between hip bone marrow lesions and bone mineral density: a cross sectional and longitudinal population-based study. AB - OBJECTIVE: To describe the cross-sectional and longitudinal association between hip Bone marrow lesions (BMLs) and bone density. DESIGN: 198 subjects with a right hip MRI and dual-energy X-ray absorptiometry (DXA) scans conducted at two time points, approximately 2.6 years apart were included. MR images were used to assess hip BML presence and size (cm(2)) while DXA scans were used to determine bone mineral density (BMD) of the total hip, spine and femoral neck. RESULTS: Fifty-five subjects (28%) had either a femoral and/or acetabular BML. Cross sectionally, acetabular BMLs were associated with 5-6% lower total hip [P = 0.01] and femoral neck BMD [P < 0.001]. Resolving acetabular BMLs were associated with a 1-2% increase in BMD at hip [P = 0.05] and femoral neck [P = 0.01]. In contrast, resolving femoral BMLs were associated with a 4% lower and incident femoral BMLs with 3% higher femoral neck BMD [P = 0.04, P < 0.001 resp.]. Finally, each 1 cm(2) change femoral BMLs was associated with increase in femoral neck BMD: +0.03 g/cm(2), 95% confidence intervals (CI): +0.00, +0.05, and enlarging acetabular BMLs was associated with decrease in hip: -0.01 g/cm(2), 95% CI: -0.03, -0.00 and femoral neck BMD: -0.01 g/cm(2), 95% CI: -0.03, -0.001. CONCLUSION: Hip BMLs were associated with local BMD (hip and femoral neck) but not with spine BMD and these associations vary according to site. BML prevalence and change was low in this study, hence these findings need confirmation. However, we hypothesize that these associations represent a combination of changes related directly to the BML pathology or changes adjacent to the disease process. PMID- 23791873 TI - Insect peptide CopA3-induced protein degradation of p27Kip1 stimulates proliferation and protects neuronal cells from apoptosis. AB - We recently demonstrated that the antibacterial peptide, CopA3 (a D-type disulfide dimer peptide, LLCIALRKK), inhibits LPS-induced macrophage activation and also has anticancer activity in leukemia cells. Here, we examined whether CopA3 could affect neuronal cell proliferation. We found that CopA3 time dependently increased cell proliferation by up to 31 +/- 2% in human neuroblastoma SH-SY5Y cells, and up to 29 +/- 2% in neural stem cells isolated from neonatal mouse brains. In both cell types, CopA3 also significantly inhibited the apoptosis and viability losses caused by 6-hydroxy dopamine (a Parkinson disease-mimicking agent) and okadaic acid (an Alzheimer's disease mimicking agent). Immunoblotting revealed that the p27Kip1 protein (a negative regulator of cell cycle progression) was markedly degraded in CopA3-treated SH SY5Y cells. Conversely, an adenovirus expressing p27Kip1 significantly inhibited the antiapoptotic effects of CopA3 against 6-hydroxy dopamine- and okadaic acid induced apoptosis, and decreased the neurotropic effects of CopA3. These results collectively suggest that CopA3-mediated protein degradation of p27Kip1 may be the main mechanism through which CopA3 exerts neuroprotective and neurotropic effects. PMID- 23791874 TI - Targeted introduction of tissue plasminogen activator (TPA) at the AAVS1 locus in mesenchymal stem cells (MSCs) and its stable and effective expression. AB - Thrombolytic therapy using tissue plasminogen activator (TPA) is an effective method for treating acute myocardial infarction. However, the systemic administration of TPA is associated with the risk of hemorrhage. Mesenchymal stem cells (MSCs) from bone marrow are characterized by low immunogenicity and homing toward damaged tissues and are therefore ideal cell carriers to achieve lesion targeting medication. In this article, TPA gene was integrated into the AAVS1 of mesenchymal stem cells, which has been confirmed to be a safe chromosomal locus. The targeting efficiency was 83%. The clones with the site-specific integration retained the stem cell traits of MSCs, displayed a normal karyotype and could persistently and effectively express TPA, as demonstrated by an average expression activity of 1.5 units/mL (3.4-fold that of the control group). After subculture and subsequent growth for two weeks, the clones showed an average TPA activity of 1.43 units/mL and exhibited no significant differences among the individual clones. In summary, the foreign TPA gene can be specifically introduced to the AAVS1 locus, whereby it can be stably and effectively expressed. MSCs can serve as cell carriers for the targeted treatment of a thrombus using TPA. PMID- 23791875 TI - Specificity of SecYEG for PhoA precursors and SecA homologs on SecA protein conducting channels. AB - Previous studies showed that Escherichia coli membranes depleted of SecYEG are capable of translocating certain precursor proteins, but not other precursors such as pPhoA, indicating a differential requirement for SecYEG. In this study, we examined the role of SecYEG in pPhoA translocation using a purified reconstituted SecA-liposomes system. We found that translocation of pPhoA, in contrast to that of pOmpA, requires the presence of purified SecYEG. A differential specificity of the SecYEG was also revealed in its interaction with SecA: EcSecYEG did not enhance SecA-mediated pOmpA translocation by purified SecA either from Pseudomonas aeruginosa or Bacillus subtilis. Neither was SecYEG required for eliciting ion channel activity, which could be opened by unfolded pPhoA or unfolded PhoA. Addition of the SecYEG complex did restore the specificity of signal peptide recognition in the ion-channel activity. We concluded that SecYEG confers specificity in interacting with protein precursors and SecAs. PMID- 23791876 TI - Thio-Cl-IB-MECA, a novel A3 adenosine receptor agonist, suppresses angiogenesis by regulating PI3K/AKT/mTOR and ERK signaling in endothelial cells. AB - Although A3AR agonists exhibit a variety of biological activities including anticancer effects, their possible anti-angiogenic effects have not yet been investigated. In the present study, we assayed the anti-angiogenic activity of thio-Cl-IB-MECA, a novel A3AR agonist, in cultured HUVECs and mES/EB-derived endothelial cells. Thio-Cl-IB-MECA inhibited migration and tube formation by endothelial cells and dramatically decreased ex vivo microvessel sprouting in cultured mouse aortic rings. The anti-angiogenic activity of thio-Cl-IB-MECA was associated with suppression of the expression of the endothelial biomarker PECAM via regulation of PI3K/AKT/mTOR and ERK signaling in mES/EB-derived endothelial cells. PMID- 23791877 TI - Ascorbic acid derivatives as a new class of antiproliferative molecules. AB - Ascorbic acid (AA) has long been described as an antiproliferative agent. However, the molecule has to be used at a very high concentrations, which necessitates i.v. injection, and the tight regulation of in-blood and in-cell AA concentrations making it impossible to hold very high concentrations for any substantial length of time. Here we report evidence that AA derivates are antiproliferative and cytotoxic molecules at an IC50 lower than AA itself. Among these new molecules, we selected K873 that has cytotoxic and antiproliferative effects on different human tumor cells at tenth micromolar concentration. In a further step, we demonstrated that K873 selectively to kills only cancer cells without being toxic for normal non-dividing (or poorly dividing) cells. Finally, we tested the effect of treatment with K873 (5-10 mg/kg/d by i.p. route) on tumor progression in xenografted immunodeficient mice (BALB/c Nude). Our data suggest that K873 administration strongly inhibits tumor progression. In a previous study using microarrays, we demonstrated that AA decreases the expression of two genes families involved in cell cycle progression, i.e. initiation factor of translation and tRNA synthetases. Here we show that K873 treatment also decreases the expression of four of these genes in xenografted tumors, in proportions similar to that previously observed with AA. Taken together, our data suggest that AA and K873 share similar action. Our findings suggest that AA derivatives could be a promising new class of anti-cancer drugs, either alone or in combination with other molecules. PMID- 23791878 TI - Human effector T cells derived from central memory cells rather than CD8(+)T cells modified by tumor-specific TCR gene transfer possess superior traits for adoptive immunotherapy. AB - Adoptive cell therapy provides an attractive treatment of cancer, and our expanding capacity to target tumor antigens is driven by genetically engineered human T lymphocytes that express genes encoding tumor-specific T cell receptors (TCRs). The intrinsic properties of cultured T cells used for therapy were reported to have tremendous influences on their persistence and antitumor efficacy in vivo. In this study, we isolated CD8(+) central memory T cells from peripheral blood lymphocytes of healthy donors, and then transferred with the gene encoding TCR specific for tumor antigen using recombinant adenovirus vector Ad5F35-TRAV-TRBV. We found effector T cells derived from central memory T cells improved cell viability, maintained certain level of CD62L expression, and reacquired the CD62L(+)CD44(high) phenotype of central memory T cells after effector T cells differentiation. We then compared the antitumor reactivity of central memory T cells and CD8(+)T cells after TCR gene transferred. The results indicated that tumor-specific TCR gene being transferred to central memory T cells effectively increased the specific killing of antigen positive tumor cells and the expression of cytolytic granule protein. Furthermore, TCR gene transferred central memory T cells were more effective than TCR gene transferred CD8(+)T cells in CTL activity and effector cytokine secretion. These results implicated that isolating central memory T cells rather than CD8(+)T cells for insertion of gene encoding tumor-specific TCR may provide a superior tumor reactive T cell population for adoptive transfer. PMID- 23791879 TI - Adenovirus vector-mediated Gli1 siRNA induces growth inhibition and apoptosis in human pancreatic cancer with Smo-dependent or Smo-independent Hh pathway activation in vitro and in vivo. AB - Activation of Hedgehog (Hh) signaling pathway is a core molecular mechanism in pancreatic carcinogenesis. However, the inhibition of upstream Hh signals does not inhibit the growth of a subset of pancreatic cancer (PC). This study was to examine the effect of siRNA targeting Gli1, the downstream component of Hh pathway, on PC cells and to provide some insight into the underlying mechanisms. A Gli1siRNA-expressing adenovirus (Ad-U6-Gli1siRNA) was constructed, and its effect on PC cells was investigated in vitro and in vivo. Gli1 was expressed in 83.3% (20/24) PC tissues, whereas no expression was found in normal pancreatic ductal epithelium. Gli1 was expressed in SW1990 and CFPAC cells in which Smo was completely absent, as well as in PaTu8988, Panc-1 and BxPC-3 cells in which Smo was concomitantly present. Ad-U6-Gli1siRNA induced cell growth inhibition, strong G0/G1 cell cycle arrest and apoptosis in all five human PC cell lines. Meanwhile, Ad-U6-Gli1siRNA significantly suppressed the expression of Gli1, Ptch1 and two target genes, Cyclin D2 and Bcl-2, in all five lines. Furthermore, two tumor xenograft nude mice models were established by subcutaneously injecting Smo positive Panc-1 cells or Smo-negative SW1990 cells. The in vivo experimental results demonstrated that Ad-U6-Gli1siRNA inhibited the growth of both Panc1 derived and SW1990-derived tumors and induced cell apoptosis. Our study indicates that Gli1-targeting siRNA could induce growth inhibition and apoptosis in PC through knockdown of Gli1 and its target genes; and this method may represent a more effective therapeutic strategy for PC with Smo-dependent or Smo-independent Hh pathway activation. PMID- 23791880 TI - Contrast-enhanced high-frequency ultrasound imaging of early stage liver metastasis in a preclinical mouse model. AB - Monitoring angiogenesis is potentially an effective strategy for the early detection of cancer. In this study, early detection was achieved by evaluating blood vessel density in the liver using a three-dimensional contrast-enhanced high-frequency ultrasound (CE-HFUS) system and Sonazoid microbubbles. Three dimensional CE-HFUS detected an increase in blood vessel density in the liver after intrasplenic injection of breast tumor cells into mice. The results were in agreement with immunohistochemical analysis of blood vessel density. Three dimensional CE-HFUS using microbubbles is an attractive, novel approach for the early detection of liver metastases through quantification of new, pathological vascular growth (i.e. tumor angiogenesis). PMID- 23791881 TI - A systems biology analysis of autophagy in cancer therapy. AB - Autophagy, which degrades redundant or damaged cellular constituents, is intricately relevant to a variety of human diseases, most notably cancer. Autophagy exerts distinct effects on cancer initiation and progression, due to the intrinsic overlapping of autophagic and cancer signalling pathways. However, due to the complexity of cancer as a systemic disease, the fate of cancer cells is not decided by any one signalling pathway. Numerous autophagic inter connectivity and cross-talk pathways need to be further clarified at a systems level. In this review, we propose a systems biology perspective for the comprehensive analysis of the autophagy-cancer network, focusing on systems biology analysis in autophagy and cancer therapy. Together, these analyses may not only improve our understanding on autophagy-cancer relationships, but also facilitate cancer drug discovery. PMID- 23791882 TI - DYRK2 controls the epithelial-mesenchymal transition in breast cancer by degrading Snail. AB - The epithelial-mesenchymal transition (EMT) plays a fundamental role in the early stages of breast cancer invasion. Snail, a zinc finger transcriptional repressor, is an important regulator of EMT. Snail is phosphorylated by GSK3beta and is subsequently degraded by betaTrCP-mediated ubiquitination. We identified an additional kinase, DYRK2, that regulates Snail stability. Knockdown of DYRK2 promoted EMT and cancer invasion in vitro and in vivo. Consistent with these results, DYRK2 was found to be down-regulated in human breast cancer tissue. Patients with low DYRK2-expressing tumors had a worse outcome than those with high DYRK2-expressing tumors. These findings revealed that DYRK2 regulates cancer invasion and metastasis by degrading Snail. PMID- 23791883 TI - Multiple drug resistant, tumorigenic stem-like cells in oral cancer. AB - An in vitro cell line model was established to exemplify tumor stem cell concept in oral cancer. We were able to identify CD147 expressing fractions in SCC172 OSCC cell line with differing Hoechst dye efflux activity and DNA content. In vivo tumorigenic assay revealed three fractions enriched with stem-like cells capable of undergoing mesenchymal transition and a non-tumorigenic fraction. The regeneration potential and transition of one fraction to other imitated the phenotypic switch and functional disparities evidenced during oral tumor progression. Knowledge of these additional stem-like subsets will improve understanding of stem cell based oral epithelial tumor progression from normal to malignant lesions. PMID- 23791884 TI - Long non-coding RNAs: a new frontier in the study of human diseases. AB - With the development of whole genome and transcriptome sequencing technologies, long noncoding RNAs (lncRNAs) have received increased attention. Multiple studies indicate that lncRNAs act not only as the intermediary between DNA and protein but also as important protagonists of cellular functions. LncRNAs can regulate gene expression in many ways, including chromosome remodeling, transcription and post-transcriptional processing. Moreover, the dysregulation of lncRNAs has increasingly been linked to many human diseases, especially in cancers. Here, we reviewed the rapidly advancing field of lncRNAs and described the relationship between the dysregulation of lncRNAs and human diseases, highlighting the specific roles of lncRNAs in human diseases. PMID- 23791885 TI - MicroRNA 'signature' during estrogen-mediated mammary carcinogenesis and its reversal by ellagic acid intervention. AB - Dysregulated miRNA expression has been associated with the development and progression of cancers, including breast cancer. The role of estrogen (E2) in regulation of cell proliferation and breast carcinogenesis is well-known. Recent reports have associated several miRNAs with estrogen receptors in breast cancers. Investigation of the regulatory role of miRNAs is critical for understanding the effect of E2 in human breast cancer, as well as developing strategies for cancer chemoprevention. In the present study we used the well-established ACI rat model that develops mammary tumors upon E2 exposure and identified a 'signature' of 33 significantly modulated miRNAs during the process of mammary tumorigenesis. Several of these miRNAs were altered as early as 3 weeks after initial E2 treatment and their modulation persisted throughout the mammary carcinogenesis process, suggesting that these molecular changes are early events. Furthermore, ellagic acid, which inhibited E2-induced mammary tumorigenesis in our previous study, reversed the dysregulation of miR-375, miR-206, miR-182, miR-122, miR-127 and miR-183 detected with E2 treatment and modulated their target proteins (ERalpha, cyclin D1, RASD1, FoxO3a, FoxO1, cyclin G1, Bcl-w and Bcl-2). This is the first systematic study examining the changes in miRNA expression associated with E2 treatment in ACI rats as early as 3 week until tumor time point. The effect of a chemopreventive agent, ellagic acid in reversing miRNAs modulated during E2-mediated mammary tumorigenesis is also established. These observations provide mechanistic insights into the new molecular events behind the chemopreventive action of ellagic acid and treatment of breast cancer. PMID- 23791886 TI - Ovarian tumor initiating cell populations persist following paclitaxel and carboplatin chemotherapy treatment in vivo. AB - Development of recurrent platinum resistant disease following chemotherapy presents a challenge in managing ovarian cancer. Using tumors derived from genetically defined mouse ovarian cancer cells, we investigated the stem cell properties of residual cells post-chemotherapy. Utilizing CD133 and Sca-1 as markers of candidate tumor initiating cells (TIC), we determined that the relative levels of CD133+ and Sca-1+ cells were unaltered following chemotherapy. CD133+ and Sca-1+ cells exhibited increased stem cell-related gene expression, were enriched in G0/G1-early S phase and exhibited increased tumor initiating capacity, giving rise to heterogeneous tumors. Our findings suggest that residual TICs may contribute to recurrent disease. PMID- 23791887 TI - Regulation and function of pyruvate kinase M2 in cancer. AB - Altered metabolism is fundamental to the growth and survival of cancer cells. Pyruvate kinase M2 (PKM2), a key enzyme in cancer metabolism, has been demonstrated to play a central role not only in metabolic reprogramming but also in direct regulation of gene expression and subsequent cell cycle progression. This review outlines the current understanding of PKM2 protein kinase activity and regulatory mechanisms underlying PKM2 expression, enzymatic activity, and nuclear localization, thus highlighting PKM2 as a potential therapeutic target. PMID- 23791889 TI - Neuronal alpha1/2-adrenergic stimulation of IFN-gamma, IL-6, and CXCL-1 in murine spleen in late experimental arthritis. AB - OBJECTIVE: Functional cross-talk exists between sympathetic nerve fibers and cytokine-producing splenic cells in early collagen type II-induced arthritis (CIA) (day 32). These earlier experiments demonstrated exclusively neuronal sympathetic regulation of IFN-gamma, CXCL1, IL-6, and TGF-beta. However, in late arthritis, the sympathetic influence might change due to loss of sympathetic nerve fibers and appearance of neurotransmitter-producing cells. We aimed to investigate neurotransmitter-dependent regulation of IFN-gamma, CXCL1, IL-6, and TGF-beta in murine spleen in late CIA. METHODS: Spleens were removed when animals reached day 58 (46-68) after immunization to generate 0.35 mm-thick spleen slices, which were transferred to superfusion microchambers to electrically induce release of neurotransmitters. Using respective neurotransmitter antagonists, effects of released neurotransmitters on cytokine secretion were investigated. RESULTS: There was electrically induced inhibition of IFN-gamma, CXCL1, and IL-6, and stimulation of TGF-beta, which was much less pronounced than in early CIA. There existed beta adrenergic inhibition of IFN-gamma, IL-6, and TGF-beta (and stimulation of CXCL1) independent of electrical stimulation (interpreted as non-neuronal). However, there was a neuronal alpha1/2 adrenergic stimulation of IFN-gamma, CXCL1, and IL-6 and, we observed neuronal A1 adenosinergic stimulation of TGF-beta. CONCLUSIONS: In the late phase of CIA, non neuronal modulation of cytokine secretion increases while neuronal regulation strikingly decreases. Particularly, beta-adrenergic effects are non-neuronal while alpha1/2-adrenergic effects are clearly neuronal. We suggest that alterations in sympathetic innervation of the spleen fundamentally change the functional neuroimmune interplay in the spleen of arthritic mice. PMID- 23791888 TI - Clinico-pathologic relevance of Survivin splice variant expression in cancer. AB - Survivin is a member of the inhibitor of apoptosis (IAP) family and has multifunctional properties that include aspects of proliferation, invasion and cell survival control. Survivin is a promising candidate for targeted cancer therapy as its expression is associated with poor clinical outcome, more aggressive clinico-pathologic features, and resistance to radiation and chemotherapy. In the present review the different properties of the Survivin splice variants are discussed and their activities correlated with different aspects of cancer cell biology, to include subcellular location. Special emphasis is placed on our current understanding of these Survivin splice variants influence on each other and on the phenotypic responses to therapy that they may control. PMID- 23791890 TI - Incremental value of magnetic resonance imaging for clinically high risk prostate cancer in 922 radical prostatectomies. AB - PURPOSE: We investigated the incremental value of magnetic resonance imaging in addition to clinical variables for predicting pathological outcomes and disease recurrence in patients with clinically high risk prostate cancer. MATERIALS AND METHODS: A total of 922 consecutive patients with clinically high risk prostate cancer underwent magnetic resonance imaging before radical prostatectomy. We created multivariate logistic regression and Cox proportional hazards models with clinical variables only or combined with magnetic resonance imaging data to predict pathological outcomes and biochemical recurrence. The models were compared using ROC curves and the Harrell concordance index. RESULTS: The proportion of patients with pathological extracapsular extension, seminal vesicle invasion and lymph node metastasis was 57.5%, 12.7% and 6.3%, respectively. The sensitivity and specificity of extracapsular extension, seminal vesicle invasion and lymph node metastasis detection were 43% and 84.2%, 34.9% and 93.8%, and 14.0% and 96.9%, respectively. The area under the ROC curve of the model with clinical variable and magnetic resonance imaging data was greater than that of the model with clinical variables alone to predict extracapsular extension and seminal vesicle invasion (0.734 vs 0.697, p=0.001 and 0.750 vs 0.698, p<0.001, respectively). The 5-year biochemical recurrence-free survival rate was 56.1%. To predict biochemical recurrence the concordance index of the multivariate model with clinical variables only and with clinical variables plus magnetic resonance imaging data was 0.563 and 0.599, respectively (p=0.003). CONCLUSIONS: Magnetic resonance imaging findings have incremental value in addition to clinical variables for predicting pathological outcomes and disease recurrence. PMID- 23791891 TI - Antifibrotic effect of synthetic Smad/Sp1 chimeric decoy oligodeoxynucleotide through the regulation of epithelial mesenchymal transition in unilateral ureteral obstruction model of mice. AB - Renal tubulointerstitial fibrosis is considered to be a common final pathway related to the progressive loss of renal function in chronic kidney disease. It is characterized by the excessive accumulation of extracellular matrix through the pivotal role of epithelial-mesenchymal transition. Transforming growth factor beta1 is postulated to play a central role in renal fibrosis via a downstream pathway such as Smad. Specificity protein 1 (Sp1), which is another transcription factor, is also involved in the basal expression of extracellular matrix. In this study, we investigate the effect of Smad decoy oligodeoxynucleotides (ODN) and Sp1 decoy ODN in unilateral ureteral obstruction induced renal fibrosis in mice. Furthermore, the effectiveness of the newly designed chimeric decoy ODN, which contains both Smad and Sp1 binding sequences in one decoy molecule (Smad/Sp1 chi decoy ODN), was demonstrated. The expression of fibrosis and inflammatory related cytokines and products of fibrosis were ameliorated in the Smad, Sp1 and chimeric decoy ODN treated groups compared with the scrambled decoy ODN treated group. Epithelial-mesenchymal transition was suppressed by the Smad, Sp1 and Smad/Sp1 chi decoy ODN. Immunohistochemistry and Western-blot analysis revealed that Smad/Sp1 chi decoy ODN showed a more significant inhibitory effect on fibrosis and EMT compared with Smad and Sp1 decoy ODNs. These results support the efficacy of Smad/Sp1 chi decoy compared with a single Smad or Sp1 decoy ODNs in preventing renal fibrosis induced by unilateral ureteral obstruction. PMID- 23791892 TI - Balance of apoptotic and anti-apoptotic marker and perforin granule release in squamous intraepithelial lesions. HIV infection leads to a decrease in perforin degranulation. AB - Cell-mediated cytotoxicity plays an important role in the regulation to HPV associated cervical intraepithelial neoplasia. HIV co-infection is related to poorer prognosis and more rapid clinical progression to cancer. We evaluated the presence of cervical inflammatory cells, apoptotic (Bax, Bcl-2, FasL, NOS2, perforin) markers and the degranulating expressing cell marker (CD107a) in low and high squamous intraepithelial lesions (LSIL and HSIL, respectively) from HIV negative and -positive women. Higher percentage of cervical CD4(+), CD8(+) T cells and macrophage were observed in LSIL and HSIL groups when compared with control, especially in epithelium and basal layer of epithelium. However, progression from LSIL to HSIL did not change the frequency of inflammatory cells. HIV-infection lead to a reduction on cervical CD4(+) T cell infiltration and an increased CD8(+) T cell distribution in LSIL groups. A balance between pro- and anti-apoptotic protein expressions was verified. Bax-expressing cells were present in all groups and were rarely expressed in keratinocytes in the epithelium in LSIL and control groups, but notably decreased in HSIL group. However, its frequency was enhanced in the basal layer of the epithelium meanly in LSIL group. Bcl2-expressing cells in the epithelium and the stroma were enhanced in HSIL group when compared with LSIL group. HIV-infection did not interfere in both expressions NOS2 expression was located on keratinocytes in both LSIL and HSIL groups when compared with control group. There were few FasL cervical expressing cells in all groups. Indeed, perforin was identified in few cervical cells. However, CD107a, a surface marker for cellular degranulation was significantly higher in epithelium, basal layer of epithelium and stroma in LSIL and HSIL, respectively, when compared with control group. These results support that HIV infection may induce reduction on inflammatory cervical cell degranulation corroborating to carcinogenesis process. This is the first description on the role of HIV in downregulation of perforin degranulation in the cervical lesions and it might be related to carcinogenesis. PMID- 23791893 TI - The effects of Pycnogenol((r)) on colon anastomotic healing in rats given preoperative irradiation. AB - Pycnogenol((r)) has excellent radical scavenging properties and enhances the production of antioxidative enzymes which contributes to the anti-inflammatory effect of the extract. Irradiation delivered to the abdominal region, typically results in severe damage to the intestinal mucosa. The effects of ionizing radiation are mediated by the formation of free radicals through radiolysis. Irradiation has local effects on tissues. These local effects of irradiation on the bowel are believed to involve a two-stage process which includes both short and long term components. In our study we aimed to investigate the short term effects of Pycnogenol((r)) on the healing of colon anastomoses in irradiated bowel. Sixty male Wistar-Albino rats were used in this study. There were three groups: Group I, control group (n = 20); group II which received preoperative irradiation (n = 20); group III which received per oral Pycnogenol((r)) before irradiation (n = 20). Only segmeter colonic resection and anastomosis was performed to the control group (Group I). The other groups (Group II, III) underwent surgery on the 5th day after pelvic irradiation. On postoperative days 3 and 7, half of the rats in each group were sacrificed and then relaparotomy was performed. There was no statistical difference between groups with respect to biochemical parameters. Bursting pressure was significantly higher in the Control and Group III compared with the Group II. In conclusion, the present study showed that preoperative irradiation effect negatively on colonic anastomoses in rats by means of mechanical parameters and administration of Pycnogenol((r)) preoperatively ameliorates this unfavorable effect. PMID- 23791894 TI - Eugenol and carvacrol induce temporally desensitizing patterns of oral irritation and enhance innocuous warmth and noxious heat sensation on the tongue. AB - Eugenol and carvacrol, from the spices clove and oregano, respectively, are agonists of TRPV3, which is implicated in transduction of warmth and possibly heat pain. We investigated the temporal dynamics of lingual irritation elicited by these agents, and their effects on innocuous warmth and heat pain, using a half-tongue method in human subjects. The irritant sensation elicited by both eugenol and carvacrol decreased across repeated applications at a 1-minute interstimulus interval (self-desensitization) which persisted for at least 10 minutes. Both agents also cross-desensitized capsaicin-evoked irritation. Eugenol and carvacrol significantly increased the magnitude of perceived innocuous warmth (44 degrees C) for >10 minutes, and briefly (<5 minutes) enhanced heat pain elicited by a 49 degrees C stimulus. Similar albeit weaker effects were observed when thermal stimuli were applied after the tongue had been desensitized by repeated application of eugenol or carvacrol, indicating that the effect is not due solely to summation of chemoirritant and thermal sensations. Neither chemical affected sensations of innocuous cool or cold pain. A separate group of subjects was asked to subdivide eugenol and carvacrol irritancy into subqualities, the most frequently reported being numbing and warmth, with brief burning, stinging/pricking, and tingle, confirming an earlier study. Eugenol, but not carvacrol, reduced detection of low-threshold mechanical stimuli. Eugenol and carvacrol enhancement of innocuous warmth may involve sensitization of thermal gating of TRPV3 expressed in peripheral warm fibers. The brief heat hyperalgesia following eugenol may involve a TRPV3-mediated enhancement of thermal gating of TRPV1 expressed in lingual polymodal nociceptors. PMID- 23791895 TI - Daily verbal and nonverbal expression of osteoarthritis pain and spouse responses. AB - The current study applied a model of pain communication to examine the distinction between verbal and nonverbal pain expression in their prediction of punishing, empathic, and solicitous spouse responses to patient pain. It was hypothesized that on days when patients engaged in more nonverbal expression, spouses would respond more positively (ie, with less punishing and more solicitous and empathic behavior). The same pattern was predicted for verbal expression. In addition, it was expected that associations between patient nonverbal pain expression and positive spouse responses would be strengthened, and that the association with punishing responses would be weakened, on days when levels of verbal pain expression were higher than usual, regardless of daily pain severity. In a 22-day diary study, 144 individuals with knee osteoarthritis and their spouses completed daily measures of pain expression, spouse responses, health, and affect. The predicted positive main effect of nonverbal expression on empathic and solicitous responses was supported by the data, as was the positive main effect for verbal pain expression. Results from moderation analyses partially supported our hypothesis in that patients' nonverbal pain expression was even more strongly related to empathic and solicitous spouse responses on days of high verbal pain expression, and patients were buffered from spouse punishing responses on days when both nonverbal and verbal expression were high. These findings suggest that pain expression in both verbal and nonverbal modes of communication is important for positive and negative spousal responses. PMID- 23791897 TI - Factors and barriers associated with early adoption of nutrition guidelines in Alberta, Canada. AB - OBJECTIVE: To identify factors that influenced early adoption and implementation of the Alberta Nutrition Guidelines for Children and Youth (ANGCY) in schools in Alberta, Canada; and to identify healthy eating strategies that were implemented as a result of the guidelines. Barriers and facilitators were also investigated. DESIGN: Multiple case study design (n = 3). Semi-structured interviews and direct observations were used to collect data. SETTING AND PARTICIPANTS: Three schools in Alberta were selected for individual case studies. Eighteen key informants were interviewed from the 3 cases. PHENOMENON OF INTEREST: To investigate how the motivation shown by school administration and stakeholders for the ANGCY influenced the early adoption and implementation of the guidelines. ANALYSIS: Content analysis was used to analyze data. RESULTS: Various healthy eating strategies were implemented within the 3 cases after uptake of the guidelines. Support from the school superintendent and the work of a health champion facilitated the adoption and implementation of the guidelines, whereas parents posed some barriers to the adoption and implementation of the ANGCY. CONCLUSIONS AND IMPLICATIONS: This study reinforces the importance of identifying a health champion to oversee healthy eating strategies in schools, and of involving parents in the promotion of children's healthy lifestyles. PMID- 23791896 TI - Sex differences in emotion-related cognitive processes in irritable bowel syndrome and healthy control subjects. AB - Greater responsiveness of emotional arousal circuits in relation to delivered visceral pain has been implicated as underlying central pain amplification in irritable bowel syndrome (IBS), with female subjects showing greater responses than male subjects. Functional magnetic resonance imaging was used to measure neural responses to an emotion recognition paradigm, using faces expressing negative emotions (fear and anger). Sex and disease differences in the connectivity of affective and modulatory cortical circuits were studied in 47 IBS (27 premenopausal female subjects) and 67 healthy control subjects (HCs; 38 premenopausal female subjects). Male subjects (IBS+HC) showed greater overall brain responses to stimuli than female subjects in prefrontal cortex, insula, and amygdala. Effective connectivity analyses identified major sex- and disease related differences in the functioning of brain networks related to prefrontal regions, cingulate, insula, and amygdala. Male subjects had stronger connectivity between anterior cingulate subregions, amygdala, and insula, whereas female subjects had stronger connectivity to and from the prefrontal modulatory regions (medial/dorsolateral cortex). Male IBS subjects demonstrate greater engagement of cortical and affect-related brain circuitry compared to male control subjects and female subjects, when viewing faces depicting emotions previously shown to elicit greater behavioral and brain responses in male subjects. PMID- 23791898 TI - Who's using MyPlate? AB - OBJECTIVE: To understand key characteristics of mothers who were early adopters of MyPlate (the iconic representation of the 2010 Dietary Guidelines for Americans) in order to speed adoption among others. METHODS: Through a national online survey, 497 mothers answered questions about MyPlate, demographics, attitudes, and behaviors. Spearman's rho correlation analysis was conducted between MyPlate familiarity and usage and these attitudinal and behavioral predictor variables. RESULTS: MyPlate familiarity was highest among those who found it easy to understand (P = .001) and who were also familiar with MyPyramid (P < .001). Vegetable lovers most strongly believed that MyPlate would help them eat better (P = .009). This was not true with fruit lovers (P = .36). CONCLUSIONS AND IMPLICATIONS: Early MyPlate adopters found it clear and easy to use, perhaps owing to nutrition knowledge and cooking experience. Efforts to expand MyPlate to new user groups should explain its purpose and applications, build on familiarity with MyPyramid, and offer practical guidance for preparing vegetables. PMID- 23791899 TI - Electronic media and beverage intake among United States high school students- 2010. AB - OBJECTIVE: To describe electronic media exposure and its associations with beverage intake among United States high school students. METHODS: School-based survey data from a nationally representative sample of 9th- through 12th-grade students from the National Youth Physical Activity and Nutrition Study were analyzed using chi-square and multivariate logistic analyses. RESULTS: On an average school day, 23.5% of students used a computer or played video/computer games >= 3 h/d, 28.3% watched television (TV) >= 3 h/d, 79.9% had >= 3 TVs in the home, 70.2% had a TV in their bedroom, and 41.0% most of the time or always had a TV on while eating dinner at home. Students with high media exposure were more likely to drink sugar-sweetened beverages >= 3 times per day and less likely to drink water >= 3 times per day and drink >= 2 glasses of milk per day. CONCLUSIONS AND IMPLICATIONS: Efforts to reduce sugar-sweetened beverage intake among adolescents may include limiting exposure to electronic media. PMID- 23791900 TI - Editorial comment. PMID- 23791901 TI - Editorial comment. PMID- 23791902 TI - Reply by authors. PMID- 23791903 TI - Contemporary epidemiological trends in complex congenital genitourinary anomalies. AB - PURPOSE: Anecdotal evidence suggests that complex congenital genitourinary anomalies are occurring less frequently. However, few epidemiological studies are available to confirm or refute this suggestion. MATERIALS AND METHODS: The Kids' Inpatient Database (KID) is a national, all payer database of several million inpatient pediatric hospitalizations per year, including complicated and uncomplicated in-hospital births. We reviewed the 1997 to 2009 KID to determine the birth prevalence of spina bifida, posterior urethral valves, bladder exstrophy, epispadias, prune belly syndrome, ambiguous genitalia and imperforate anus. For posterior urethral valves and prune belly syndrome we limited our search to newborn males only. RESULTS: During the study period, there was a diagnosis of spina bifida in 3,413 neonates, bladder exstrophy in 214, epispadias in 1,127, ambiguous genitalia in 726, prune belly syndrome in 180, posterior urethral valves in 578 and imperforate anus in 4,040. We identified no significant change in the birth prevalence of spina bifida (from 33.9 new spina bifida births of 100,000 uncomplicated births to 29.0/100,000, p = 0.08), posterior urethral valves (from 10.4/100,000 to 11.0/100,000, p = 0.51), prune belly syndrome (from 4.8/100,000 to 3.3/100,000, p = 0.44) or ambiguous genitalia (from 5.82/100,000 to 5.87/100,000, p = 0.38). There was a significant decrease in the birth prevalence of bladder exstrophy (from 2.4/100,000 to 1.6/100,000 uncomplicated births, p = 0.01) and a significant increase in epispadias (from 8.0/100,000 to 11.6/100,000) and imperforate anus (from 33.6/100,000 to 35.0/100,000, each p = 0.04) during the study period. CONCLUSIONS: The birth prevalence of spina bifida, posterior urethral valves and prune belly syndrome appears to have been stable in the last 12 years. Epispadias, ambiguous genitalia and imperforate anus diagnoses in newborns became more common in the same period, while bladder exstrophy diagnoses became less common. PMID- 23791904 TI - Editorial comment. PMID- 23791905 TI - Pediatric resident exposure to urology: identifying a need. AB - PURPOSE: We evaluated current trends of pediatric urology exposure during the 3 year pediatric residency period nationwide. We also evaluated the opinions of urology and pediatric residency program directors regarding the need for additional exposure to pediatric urology. MATERIALS AND METHODS: From February to October 2011 we administered 2 concurrent electronic surveys. One set was sent to urology residency program directors and the other was sent to pediatric residency program directors. The surveys consisted of 6 and 12 questions, respectively. The questions were created to best evaluate exposure to pediatric urology from the perspective of each cohort. Response data were analyzed using the chi-square test and case-control methods. RESULTS: Of the 117 accredited urology residency program directors and 190 pediatric residency program directors 51 (43.5%) and 78 (41.1%), respectively, completed the survey. Urology program directors answered favorably by a margin of 66% toward increased involvement with pediatric residents, while 84.6% of pediatric residency directors would like increased exposure to pediatric urology. Furthermore, 87% of pediatric residency directors reported that they do not require residents to have a formal pediatric urology rotation. However, in 65% of pediatric programs residents received some form of didactic education. CONCLUSIONS: These results show the desire on the part of urology and pediatric residency program directors for pediatric residents to have greater exposure to pediatric urology, particularly didactic and bedside teaching in the management of pediatric urological disorders. Increasing pediatric resident exposure to pediatric urological pathology and treatment during training would have a positive impact on the subsequent diagnosis and care of pediatric urological conditions. PMID- 23791907 TI - Editorial comment. PMID- 23791906 TI - Urinary NGAL levels correlate with differential renal function in patients with ureteropelvic junction obstruction undergoing pyeloplasty. AB - PURPOSE: Recent investigations described the use of NGAL, a sensitive biomarker for kidney injury, in the setting of ureteropelvic junction obstruction. We prospectively evaluated urinary NGAL levels in the affected renal pelvis and bladder of children with ureteropelvic junction obstruction undergoing unilateral dismembered pyeloplasty. Our hypothesis was that higher NGAL in the kidney and bladder would correlate with decreased ipsilateral differential function. MATERIALS AND METHODS: We performed a prospective cohort study in patients treated with unilateral dismembered pyeloplasty from 2010 to 2012. Urine was obtained intraoperatively from the bladder and obstructed renal pelvis. A control population of unaffected children was recruited to provide a voided bladder specimen. Bladder NGAL levels were compared between the study and control populations. We tested our study hypothesis by correlating bladder and renal pelvic NGAL levels with the differential renal function of the affected kidney. RESULTS: A total of 61 patients with a median age at surgery of 1.62 years (range 0.12 to 18.7) were enrolled in the study. Median bladder NGAL was 18.6 ng/mg (range 1.4-1,650.8) and median renal pelvic NGAL was 26.2 ng/mg (range 1.2 18,034.5, p = 0.004). Median bladder NGAL was significantly higher than in controls (p = 0.004). The correlation of bladder and renal pelvic NGAL with differential renal function was r = -0.359 (p = 0.004) and r = -0.383 (p = 0.002), respectively. CONCLUSIONS: Bladder NGAL is increased in children with ureteropelvic junction obstruction. Renal pelvic and bladder normalized urinary NGAL levels correlate inversely with the relative function of the affected kidney in cases of unilateral ureteropelvic junction obstruction. PMID- 23791908 TI - Editorial comment. PMID- 23791909 TI - Society for fetal urology recommendations for postnatal evaluation of prenatal hydronephrosis--will fewer voiding cystourethrograms lead to more urinary tract infections? AB - PURPOSE: There is no consensus on the extent and mode of postnatal imaging after a diagnosis of prenatal hydronephrosis. We validated the protocol of our practice, which parallels current Society for Fetal Urology (SFU) recommendations, in limiting voiding cystourethrogram, while examining its impact on the incidence of febrile urinary tract infections. A secondary goal was to examine predictors of postnatal intervention. MATERIALS AND METHODS: We evaluated a cohort of 117 infants with prenatal hydronephrosis and retrospectively reviewed outcomes. Excluded from study were 30 infants with anatomical abnormalities. Third trimester prenatal ultrasound was done to evaluate SFU grade, laterality and anteroposterior diameter. Cox proportional hazard model and chi-square analysis were used to assess predictors of resolution and surgical intervention. RESULTS: A total of 87 infants with a median followup of 33.5 months were included in analysis. Postnatal voiding cystourethrogram was done in 52 patients, of whom 7 had vesicoureteral reflux. In 6 infants (6.9%) a febrile urinary tract infection developed, which was diagnosed with a catheter specimen during followup. In 3 infants a urinary tract infection developed immediately after catheterization. Anteroposterior diameter 9 mm or greater and SFU grade 3 or greater independently predicted the need for postnatal intervention (p = 0.0014 and 0.001, respectively). CONCLUSIONS: With adherence to our protocol, voiding cystourethrogram was avoided in almost half of evaluated infants. No infant diagnosed with vesicoureteral reflux had a urinary tract infection. Catheterization was associated with a urinary tract infection in 50% of cases. An anteroposterior diameter of 9 mm or greater and a SFU grade of 3 or greater were associated with postnatal progression to surgery. Patients with a SFU grade of 4 progressed to surgical intervention at a faster rate than those with a grade of greater than 3. PMID- 23791910 TI - Hypertrigyceridemia during infliximab therapy. PMID- 23791911 TI - SAPHO syndrome. PMID- 23791912 TI - Density measurement of thin layers by electron energy loss spectroscopy (EELS). AB - A method to measure the density of thin layers is presented which utilizes electron energy loss spectroscopy (EELS) techniques within a transmission electron microscope. The method is based on the acquisition of energy filtered images in the low loss region as well as of an element distribution map using core loss edges. After correction of multiple inelastic scattering effects, the intensity of the element distribution map is proportional to density and thickness. The dependence of the intensities of images with low energy loss electrons on the density is different from that. This difference allows the calculation of the relative density pixel by pixel and to determine lateral density gradients or fluctuations in thin films without relying on a constant specimen thickness. The method is demonstrated at thin carbon layers produced with density gradients. PMID- 23791913 TI - Ultrastructural observations on Raillietina echinobothrida exposed to crude extract and active compound of Securinega virosa. AB - Securinega virosa has been used traditionally by the natives of Mizoram, India, to control intestinal worm infections. In the present study, the crude ethanol extract of the plant and its active component virosecurinine were tested in vitro on Raillietina echinobothrida to evaluate its potential anthelmintic efficacy and ultrastructural changes. The test parasites were exposed to different concentrations of the plant extract, active compound virosecurinine and reference drug praziquantel. Scanning and transmission electron microscopic observations on the paralyzed worms revealed wide scale destruction of the tegument with intense vacuolization of the syncytium and swellings of the basal lamina accompanied by deformities in the cell organelles. Extensive structural alteration of tegument indicates that the plant extract and its active component alter membrane permeability of the parasite leading to paralysis and subsequent death, as confirmed by in vitro tests. PMID- 23791914 TI - Collaborative patch-based super-resolution for diffusion-weighted images. AB - In this paper, a new single image acquisition super-resolution method is proposed to increase image resolution of diffusion weighted (DW) images. Based on a nonlocal patch-based strategy, the proposed method uses a non-diffusion image (b0) to constrain the reconstruction of DW images. An extensive validation is presented with a gold standard built on averaging 10 high-resolution DW acquisitions. A comparison with classical interpolation methods such as trilinear and B-spline demonstrates the competitive results of our proposed approach in terms of improvements on image reconstruction, fractional anisotropy (FA) estimation, generalized FA and angular reconstruction for tensor and high angular resolution diffusion imaging (HARDI) models. Besides, first results of reconstructed ultra high resolution DW images are presented at 0.6*0.6*0.6 mm3 and 0.4*0.4*0.4 mm3 using our gold standard based on the average of 10 acquisitions, and on a single acquisition. Finally, fiber tracking results show the potential of the proposed super-resolution approach to accurately analyze white matter brain architecture. PMID- 23791916 TI - Multiscale topological properties of functional brain networks during motor imagery after stroke. AB - In recent years, network analyses have been used to evaluate brain reorganization following stroke. However, many studies have often focused on single topological scales, leading to an incomplete model of how focal brain lesions affect multiple network properties simultaneously and how changes on smaller scales influence those on larger scales. In an EEG-based experiment on the performance of hand motor imagery (MI) in 20 patients with unilateral stroke, we observed that the anatomic lesion affects the functional brain network on multiple levels. In the beta (13-30 Hz) frequency band, the MI of the affected hand (Ahand) elicited a significantly lower smallworldness and local efficiency (Eloc) versus the unaffected hand (Uhand). Notably, the abnormal reduction in Eloc significantly depended on the increase in interhemispheric connectivity, which was in turn determined primarily by the rise of regional connectivity in the parieto occipital sites of the affected hemisphere. Further, in contrast to the Uhand MI, in which significantly high connectivity was observed for the contralateral sensorimotor regions of the unaffected hemisphere, the regions with increased connectivity during the Ahand MI lay in the frontal and parietal regions of the contralaterally affected hemisphere. Finally, the overall sensorimotor function of our patients, as measured by Fugl-Meyer Assessment (FMA) index, was significantly predicted by the connectivity of their affected hemisphere. These results improve on our understanding of stroke-induced alterations in functional brain networks. PMID- 23791917 TI - Use of Strep-tag II for rapid detection and purification of Mycobacterium tuberculosis recombinant antigens secreted by Streptomyces lividans. AB - Recent results with respect to the secretory production of bio-active Mycobacterium tuberculosis proteins in Streptomyces have stimulated the further exploitation of this host as a bacterial cell factory. However, the rapid isolation of a recombinant protein by conventional procedures can be a restrictive step. A previous attempt to isolate recombinant antigens fused to the widely used 6His-tag was found to be relatively incompatible with secretory production in the Streptomyces host. As an alternative, the eight-residue Strep tag(r) II (WSHPQFEK), displaying intrinsic binding affinity towards streptavidin, was evaluated for the secretory production of two M. tuberculosis immunodominant antigens in Streptomyces lividans and their subsequent downstream processing. Therefore, the genes ag85A (Rv3804c, encoding the mycolyl-transferase Ag85A) and Rv2626c (encoding hypoxic response protein 1), were equipped with a 3'-Strep tag(r) II-encoding sequence and placed under control of the Streptomyces venezuelae CBS762.70 subtilisin inhibitor (vsi) transcriptional, translational and signal sequences. Strep-tagged Ag85A and Rv2626c proteins were detected in the spent medium of recombinant S. lividans cultures at 48h of growth, and purified using a Strep-Tactin Superflow(r) matrix. Recombinant Ag85A appeared as a 30-kDa protein of which the N-terminal amino acid sequence was identical to the expected one. Rv2626c was produced in two forms of 17 and 37kDa respectively, both with the same predicted N-terminal sequence, suggesting that the 37-kDa product is an Rv2626c dimer. The obtained results indicate that the Strep-tagII is proteolytically stable in Streptomyces and does not interfere with the membrane translocation of Ag85A and Rv2626c. A comparison of reactivity of serum from tuberculosis patients versus healthy persons by ELISA showed that both S. lividans-derived antigens were recognized by sera of individuals infected with M. tuberculosis, indicating that they remained antigenetically active. To our knowledge, this is the first report showing the usefulness of an affinity peptide for detection and efficient downstream processing of recombinant proteins produced in Streptomyces. The present results add up strength to the significance of S. lividans as a valuable host to produce M. tuberculosis proteins with vaccine and diagnostic potential. PMID- 23791915 TI - Tackling the multifunctional nature of Broca's region meta-analytically: co activation-based parcellation of area 44. AB - Cytoarchitectonic area 44 of Broca's region in the left inferior frontal gyrus is known to be involved in several functional domains including language, action and music processing. We investigated whether this functional heterogeneity is reflected in distinct modules within cytoarchitectonically defined left area 44 using meta-analytic connectivity-based parcellation (CBP). This method relies on identifying the whole-brain co-activation pattern for each area 44 voxel across a wide range of functional neuroimaging experiments and subsequently grouping the voxels into distinct clusters based on the similarity of their co-activation patterns. This CBP analysis revealed that five separate clusters exist within left area 44. A post-hoc functional characterization and functional connectivity analysis of these five clusters was then performed. The two posterior clusters were primarily associated with action processes, in particular with phonology and overt speech (posterior-dorsal cluster) and with rhythmic sequencing (posterior ventral cluster). The three anterior clusters were primarily associated with language and cognition, in particular with working memory (anterior-dorsal cluster), with detection of meaning (anterior-ventral cluster) and with task switching/cognitive control (inferior frontal junction cluster). These five clusters furthermore showed specific and distinct connectivity patterns. The results demonstrate that left area 44 is heterogeneous, thus supporting anatomical data on the molecular architecture of this region, and provide a basis for more specific interpretations of activations localized in area 44. PMID- 23791918 TI - High-throughput 16S rRNA gene sequencing reveals alterations of intestinal microbiota in myalgic encephalomyelitis/chronic fatigue syndrome patients. AB - Human intestinal microbiota plays an important role in the maintenance of host health by providing energy, nutrients, and immunological protection. Intestinal dysfunction is a frequent complaint in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients, and previous reports suggest that dysbiosis, i.e. the overgrowth of abnormal populations of bacteria in the gut, is linked to the pathogenesis of the disease. We used high-throughput 16S rRNA gene sequencing to investigate the presence of specific alterations in the gut microbiota of ME/CFS patients from Belgium and Norway. 43 ME/CFS patients and 36 healthy controls were included in the study. Bacterial DNA was extracted from stool samples, PCR amplification was performed on 16S rRNA gene regions, and PCR amplicons were sequenced using Roche FLX 454 sequencer. The composition of the gut microbiota was found to differ between Belgian controls and Norwegian controls: Norwegians showed higher percentages of specific Firmicutes populations (Roseburia, Holdemania) and lower proportions of most Bacteroidetes genera. A highly significant separation could be achieved between Norwegian controls and Norwegian patients: patients presented increased proportions of Lactonifactor and Alistipes, as well as a decrease in several Firmicutes populations. In Belgian subjects the patient/control separation was less pronounced, however some abnormalities observed in Norwegian patients were also found in Belgian patients. These results show that intestinal microbiota is altered in ME/CFS. High throughput sequencing is a useful tool to diagnose dysbiosis in patients and could help designing treatments based on gut microbiota modulation (antibiotics, pre and probiotics supplementation). PMID- 23791919 TI - Lack of interaction of endocannabinoids and 5-HT(3) neurotransmission in associative fear circuits of the amygdala: evidence from electrophysiological and behavioural experiments. AB - Both the serotonergic and the endocannabinoid system play a major role in mediating fear and anxiety. In the basolateral amygdala (BLA) it has been shown that the cannabinoid receptor 1 (CB1) is highly co-expressed with 5-HT3 receptors on GABAergic interneurons suggesting that 5-HT3 receptor activity modulates CB1 mediated effects on inhibitory synaptic transmission. In the present study, we investigated the possible interactions of CB1 and 5-HT3-mediated neuronal processes in the BLA using electrophysiological and behavioural approaches. Whole cell patch-clamp recordings were performed in coronal brain slices of mice. Electric stimuli were delivered to the lateral amygdala to evoke GABAA receptor mediated inhibitory postsynaptic currents (GABAA-eIPSCs) in the BLA. The induction of LTDi, a CB1-mediated depression of inhibitory synaptic transmission, was neither affected by the 5-HT3 antagonists ondansetron (OND; 20 uM) and tropisetron (Trop; 50 nM) nor by the 5-HT3 agonists SR57227A (10 uM). In auditory fear conditioning tests, mice treated with SR57227A (3.0mg/kg i.p.) showed sustained freezing, whereas treatment with Trop (1.0 mg/kg i.p.) decreased the expression of conditioned fear. These effects were overruled by the CB1 antagonist rimonabant (RIM; 3.0 mg/kg), which caused increased freezing with or without co-treatment with Trop. In summary, these experiments do not support a functional interaction between CB1 and 5-HT3 receptors at the level of GABA neurotransmission in the BLA nor in terms of fear regulation. PMID- 23791920 TI - Investigation into the effect of the general anaesthetic etomidate on local neuronal synchrony in the mouse neocortical slice. AB - How general anaesthetic drugs cause unconsciousness is a topic of ongoing clinical and scientific interest. It is becoming increasingly apparent that they disrupt cortical information processing, but the effects appear to depend on the spatial scale under investigation. In this study we investigated whether the intravenous anaesthetic etomidate synchronises neuronal activity on a sub millimetre scale in mouse neocortical slices. In slices generating no-magnesium seizure-like event (SLE) field activity, we analysed the morphology of field potential activity recorded with 50um extracellular electrodes. The analysis was based on the understanding that the amplitude and sheerness of field potential oscillations correlates with the synchrony of the underlying neural activity. When recorded from the region of the slice initiating SLE activity, etomidate consistently increased both population event amplitude (median(range) 85(24-350) to 101(30-427) uV) and slope 16.6(1.5-106.2) to 20.2(1.7-111.1) uV/ms (p=0.016 and p=0.0013, respectively). The results are consistent with an increase in neuronal synchrony within the receptive field of the recording electrode, estimated to be a circle diameter of 300um. In conclusion, the neocortical slice preparation supports in vivo data showing that general anaesthetics increase neuronal synchrony on a local scale and provides an ideal model for investigating underlying mechanisms. PMID- 23791921 TI - Behavioral and neural correlates of emotional intelligence: an event-related potentials (ERP) study. AB - The present study was aimed at identifying potential behavioral and neural correlates of emotional intelligence (EI) by using scalp-recorded Event-Related Potentials (ERPs). EI levels were defined according to both self-report questionnaire and a performance-based test. We identified ERP correlates of emotional processing by comparing ERPs elicited in trials using pleasant, neutral and unpleasant pictures. The effects of these emotion-inducing pictures were then compared across groups with low and high EI levels. Behavioral results revealed a significant valence*EI group interaction effect since valence ratings were lower for unpleasant pictures and higher for pleasant pictures in the high EI group compared with the low EI group. The groups did not differ with respect to neutral picture ratings. The ERP results indicate that participants with high EI exhibited significantly greater mean amplitudes of the P2 (200-300ms post stimulus) and P3 (310-450ms post-stimulus) ERP components in response to emotional and neutral pictures, at posterior-parietal as well as at frontal scalp locations. This may suggest greater recruitment of resources to process all emotional and non-emotional stimuli at early and late processing stages among individuals with higher EI. The present study also underscores the usefulness of ERP methodology as a sensitive measure for the study of emotional stimuli processing in the research field of EI. PMID- 23791922 TI - Hydroquinone-induced miR-122 down-regulation elicits ADAM17 up-regulation, leading to increased soluble TNF-alpha production in human leukemia cells with expressed Bcr/Abl. AB - Studies on HQ-treated human leukemia K562 (Bcr/Abl-positive) cells were conducted to address the hydroquinone (HQ) mechanism that promotes soluble TNF-alpha (sTNF alpha) production. HQ post-translationally down-regulated cell surface TNF-alpha expression increases the release of sTNF-alpha into K562 cell culture medium. Meanwhile, HQ increased ADAM17 mRNA stability, leading to ADAM17 up-regulation in HQ-treated cells. Knock-down of ADAM17 abrogated HQ-induced sTNF-alpha secretion. HQ-evoked miR-122 down-regulation was proven to promote ADAM17 mRNA stability and up-regulate ADAM17 expression. HQ-induced p38 MAPK and JNK activation were responsible for suppression of miR-122 promoter luciferase activity and miR-122 expression. Activation of p38 MAPK and JNK elicited phosphorylation of c-Jun, ATF 2 and c-Fos, and knock-down of c-Jun, ATF-2 and c-Fos restored miR-122 expression in HQ-treated cells. Chromatin immunoprecipitating and DNA affinity purification assay revealed c-Jun, ATF-2 and c-Fos binding to the miR-122 gene promoter region. Moreover, HQ-induced sTNF-alpha production in Bcr/Abl-positive leukemia cell lines KU812 and MEG-01 was also connected with miR-122 down-regulation and ADAM17 up-regulation, while HQ was unable to affect miR-122 and ADAM-17 expression on Bcr/Abl-negative leukemia U937 cells. Taken together, our data indicate that HQ induces down-regulation of miR-122 expression, leading to ADAM17 up-regulation and ADAM17-mediated TNF-alpha shedding. Consequently, HQ treatment increases the production of sTNF-alpha in leukemia cells with expressed Bcr/Abl. PMID- 23791923 TI - Opposing effects of dexamethasone, agrin and sugammadex on functional innervation and constitutive secretion of IL-6 in in vitro innervated primary human muscle cells. AB - Neuromuscular junction development is the key process required for successful neuromuscular transmission and functional innervation of skeletal muscle fibres. Various substances can influence these processes, some of which are in common use in clinical practice. In the present study, the effects of the potentially new therapeutic agent agrin were followed, along with the widely used glucocorticoid dexamethasone. The in vitro experimental model used was functional innervation and constitutive interleukin 6 (IL-6) secretion of human muscle cells. Additionally, the selective relaxant binding agent sugammadex and its possible interaction with dexamethasone were followed. Dexamethasone impaired functional innervation while agrin had opposing effects. Furthermore, based on interference with IL-6 secretion, we show potential (chemical) interactions between dexamethasone and sugammadex. The physiological effects of this interaction should be taken into consideration under clinical conditions where these two drugs might be applied simultaneously. PMID- 23791924 TI - Modulation of astrocytic glutamine synthetase expression and cell viability by histamine in cultured cortical astrocytes exposed to OGD insults. AB - Histamine, a neurotransmitter or neuromodulator has been demonstrated to be neuroprotective in cerebral ischemia. However, few reports concern its function on astrocytes during cerebral ischemia. The purpose of this study was to investigate the effects of histamine on astrocytic cell damage and glutamate signaling, especially on glutamine synthetase (GS) expression in primary cultured cortical astrocytes exposed to oxygen-glucose deprivation (OGD) insult. OGD for 6h caused a severe damage of astrocytic mitochondrial function, and decreased GS expression and then increased the extracellular glutamate level. Pretreatment with histamine significantly prevented the cell damage and rescued the expression of GS in a concentration-dependent manner. The protective effect of histamine on astrocytic cell damage could be partly reversed either by H1 receptor antagonist pyrilamine or H2 receptor antagonist cimetidine. However, the regulatory effect of histamine on GS expression was antagonized only by pyrilamine. In addition, bisindolylmaleimide II, a broad-spectrum inhibitor of PKC, reversed the regulatory action of histamine on GS expression. These results indicate that histamine can effectively protect against OGD-induced cell damage in astrocytes through H1 and H2 receptors, and its regulatory effect on astrocytic GS expression may be due to the activation of H1 receptor and PKC pathway. Histamine may be an endogenous protective factor and calls for its further study as a regulator of astrocyte function during ischemic stroke. PMID- 23791925 TI - The resistive index as a function of vessel diameter in the human carotid arterial tree. AB - The average resistive index (RI) as a function of the average vessel diameter (D) was studied in the human carotid arterial tree. Data were used from previously published research measurements taken from 505 different vessels of 371 healthy humans. When the RI from the carotid arteries was included in the data set the standard trend lines did not give efficient fits. However, when only data from the eye were used, the Neperian logarithmic function gave a best fit with a correlation coefficient r=0.99 and an absolute relative error less than 2.6%. This logarithmic model could be proved a valuable tool for both basic research and clinical practice in the human eye. PMID- 23791926 TI - Reproductive toxicology. PMID- 23791927 TI - Associations of urinary metal concentrations and circulating testosterone in Chinese men. AB - Toxicological studies have shown that metals directly or indirectly influence testosterone (T) production, but the data from humans is limited and inconsistent. The aim of this study was to examine the associations between urinary metal concentrations and circulating T in Chinese men. Urinary concentrations of 13 metals (arsenic, cadmium, cobalt, chromium, copper, iron, lead, manganese, molybdenum, mercury, nickel, selenium and zinc) and serum levels of T were analyzed in 118 men from an infertility clinic. Multivariable linear regression was used to assess the effect of metals exposure on T. Among the measured metals, the median urinary Zn (359.36MUg/g creatinine) and Co (0.16MUg/g creatinine) concentrations were the highest and the lowest, respectively. Significant dose-response relationships were found between decreased T and urinary Mn and Zn, even when considering multiple metals (both P for trend <0.05). Our results indicate that elevated Mn and Zn are inversely associated with T production. PMID- 23791929 TI - Alobar holoprosencephaly with cyclopia - autopsy-based observations from one medical center. AB - Holoprosencephaly, a major congenital malformation of the brain, consists in a complete or partial failure of the prosencephalon to divide into separate hemispheres. Alobar holoprosencephaly with cyclopia was analyzed on the basis of autopsy reports performed for hospitals admitting patients from the Lublin Region in Eastern Poland in the period of 20 years (1981-2000). The malformation was found in seven newborns - five girls, one boy and one child with sex not established due to agenesia of the genital organs, all autopsied in the years 1990-1999. According to clinical data, none of the mothers (age 24-39 years) was exposed to any prescribed or over-the-counter (OTC) drugs during pregnancy, but one was exposed to paints in early pregnancy. The proboscis was present in four of seven cases. Six of seven children displayed additional congenital malformations. In two cases intrapancreatic accessory spleen suggesting trisomy 13 was found. Alobar holoprosencephaly with cyclopia is a rare lethal congenital anomaly frequently accompanied by other malformations and characterized by large variations in incidence. PMID- 23791930 TI - Developmental outcomes at preschool age after fetal exposure to valproic acid and lamotrigine: cognitive, motor, sensory and behavioral function. AB - This prospective, observational study assessed the development of preschool children aged 3-6 years, 11 months (n=124) after in-utero anti-epileptic drug (AED) monotherapy exposure to valproic acid (VPA) (n=30, mean age 52.00[+/-15.22] months) and lamotrigine (LT) (n=42, mean age 50.12[+/-12.77] months), compared to non-exposed control children (n=52, mean age 59.96[+/-14.51] months). As a combined group, AED-exposed children showed reduced non-verbal IQ scores, and lower scores on motor measures, sensory measures, and parent-report executive function, behavioral and attentional measures. When the VPA- and LT-exposed groups were analyzed separately, no cognitive differences were found, but control VPA and control-LT differences emerged for most motor and sensory measures as well as control-VPA parent-report behavioral and attentional differences. No differences were noted between the VPA and LT groups. These findings suggest that VPA- and LT-exposed children should be monitored on a wider range of developmental measures than currently used, and at differing developmental stages. PMID- 23791931 TI - Puberty dysregulation and increased risk of disease in adult life: possible modes of action. AB - Puberty is the developmental window when the final maturation of body systems is orchestrated by hormones; lifelong sex-related differences and capacity to interact with the environment are defined during this life stage. Increased incidence in a number of chronic, multifactorial diseases could be related to environmental exposures during puberty: however, insight on the susceptibility of the peripubertal period is still limited. The estrogen/androgen balance is a crucial axis in harmonizing the whole pubertal development, pointing out the significance of exposures to endocrine disruptors. Besides the reproductive system, endocrine-related perturbations may affect the maturation of skeleton, adipose tissues, brain, immune system, as well as cancer predisposition. Thus, risk assessment of environmental stressors should duly consider specific aspects of the pubertal window. Besides endocrine-related mechanisms, suggested research priorities include signaling molecules (e.g., kisspeptins, dopamine) as xenobiotic targets and disturbances of specific pubertal methylation processes potentially involved in neurobehavioral disorders and cancer risk in adulthood. PMID- 23791932 TI - Environmental enrichment ameliorates depressive-like symptoms in young rats bred for learned helplessness. AB - The incidence of major depression is known to be influenced by both genetic and environmental factors. In the current study, we therefore set out to investigate depressive-like behavior and its modification by environmental enrichment using rats bred for 'learned helplessness'. 45 males of congenitally helpless (cLH, n=22) and non-helpless (cNLH, n=23) rats of two different generations were used to systematically investigate differential effects of environmental enrichment on learned helpless behavior, anhedonic-like behavior (sweetened condensed milk consumption) and spontaneous behavior in the home cage. While enrichment was found to reduce learned helpless behavior in 14 weeks old, but not 28 weeks old cLH rats, it did not affect the consumption of sweetened condensed milk. Regarding the home cage behavior, no consistent changes between rats of different strains, housing conditions, and ages were observed. We could thus demonstrate that a genetic predisposition for learned helplessness may interact with environmental conditions in mediating some, but not all depressive-like symptoms in congenitally learned helpless rats. However, future efforts are needed to isolate the differential benefits of environmental factors in mediating the different depression-related symptoms. PMID- 23791933 TI - Correlated activation of the thalamocortical network in a simple learning paradigm. AB - The thalamocortical loop is a key player in sensory processing. We examined the functional interactions among its elements, expressed as cross-correlations between metabolic activity of the barrel cortex, somatosensory thalamic nuclei and posterior parietal cortex, in classical conditioning. In the training stimulation of vibrissae in mice was paired with a tail shock. [14C]-2 Deoxyglucose brain mapping was performed during the first and the final sessions of conditioning (conditioned stimulus+unconditioned stimulus; CS+UCS), in groups that received only the stimulation of vibrissae (conditioned stimulus; CS-only) and in nonstimulated controls (NS). In the CS-only group, the CS evoked the correlated activity of the examined structures during the first session, but in the third session these structures did not act in a correlated manner. Conversely, in the CS+UCS condition correlations among the thalamocortical loop structures activities became stronger during the course of the training. Particularly, the posterior parietal cortex, which controls voluntary deployment of attention, together with the barrel cortex becomes involved in the network of structures with the correlated activity. The results suggest a predominant role for bottom-up processing in the somatosensory pathway at the beginning of conditioning followed by top-down processing. This is consistent with the idea that the thalamocortical loop plays a crucial role in attentional processes. PMID- 23791934 TI - Infusion of galanin into the mid-caudal portion of the dorsal raphe nucleus has an anxiolytic effect on rats in the elevated T-maze. AB - Galanin and 5-HT coexist in dorsal raphe nucleus (DRN) neurons. Microinjection of galanin into the DRN reduces the firing rate of serotonin neurons. Serotonergic neurons projecting from the DRN to the amygdala facilitate learned anxiety producing an anxiogenic effect, while those projecting from the periaqueductal grey affect innate anxiety producing a panicolytic effect. We tested the hypothesis that injection of galanin into rat DRN would induce anxiolytic/panicogenic effects in the elevated T-maze (ETM), a model that allows for the evaluation of both of these effects. Galanin infusion into the mid-caudal DRN, but not into the rostral DRN, impaired inhibitory avoidance, suggesting an anxiolytic effect. The effective dose of galanin (0.3 nmol) did not modify locomotor activity in the open field. Contrary to expectations, microinjection of galanin into the DRN did not facilitate the latency of one-way escape in the ETM. Pretreatment with a galanin antagonist, M40, attenuated galanin-induced impairment of inhibitory avoidance. The results show that microinjection of a low dose of galanin only into the mid-caudal DRN has an anxiolytic effect. This effect seems to be mediated, at least in part, by galanin receptors. Further investigation is necessary to identify the receptor subtypes and the DRN subregion involved in the anxiolytic effect of galanin. PMID- 23791935 TI - Proteome analysis of post-transplantation recovery mechanisms of an EAE model of multiple sclerosis treated with embryonic stem cell-derived neural precursors. AB - Multiple sclerosis (MS) is a chronic inflammatory and progressive disorder of the central nervous system (CNS), which ultimately causes demyelination and subsequent axonal injury. Experimental autoimmune encephalomyelitis (EAE) is a well-characterized animal model to study the etiology and pathogenesis of MS. This model can also be used to investigate various therapeutic approaches for MS. Herein; we have treated a score 3 EAE mouse model with an embryonic stem cell derived neural precursor. Clinical analysis showed recovery of the EAE model of MS following transplantation. We analyzed the proteome of spinal cords of healthy and EAE samples before and after transplantation. Proteome analysis revealed that expressions of 86 spinal cord protein spots changed in the EAE or transplanted mouse compared to controls. Mass spectrometry resulted in identification of 72 proteins. Of these, the amounts of 27 differentially expressed proteins in EAE samples returned to sham levels after transplantation, suggesting a possible correlation between changes at the proteome level and clinical signs of EAE in transplanted mice. The recovered proteins belonged to various functional groups that included disturbances in ionic and neurotransmitter release, apoptosis, iron hemostasis, and signal transduction. Our results provided a proteomic view of the molecular mechanisms of EAE recovery after stem cell transplantation. BIOLOGICAL SIGNIFICANCE: In this study, we applied proteomics to analyze the changes in proteome pattern of EAE mouse model after embryonic stem cell-derived neural precursor transplantation. Our proteome results clearly showed that the expression levels of several differentially expressed proteins in EAE samples returned to sham levels after transplantation, which suggested a possible correlation between changes at the proteome level and decreased clinical signs of EAE in transplanted mice. These results will serve as a basis to address new questions and design new experiments to elucidate the biology of EAE and recovery after transplantation. A thorough understanding of stem cell-mediated therapeutic mechanisms might result in the development of more efficacious therapies for MS than are currently available. PMID- 23791936 TI - Detection and interpretation of 8-oxodG and 8-oxoGua in urine, plasma and cerebrospinal fluid. AB - BACKGROUND: DNA and RNA oxidations have been linked to diseases such as cancer, arteriosclerosis, neurodegeneration and diabetes. The prototype base modification studied is the 8-hydroxylation of guanine. DNA integrity is maintained by elaborate repair systems and RNA integrity is less studied but relies mainly on degradation. SCOPE OF REVIEW: DNA and RNA oxidations are measured by very similar techniques. The scope of this review is to highlight the preferred methods of measurement of oxidized nucleic acid metabolites, to highlight novel findings particularly in RNA oxidation, and to present the interpretation of the measurements. MAJOR CONCLUSIONS: Tissue levels are snap-shots of the level in a specific organ or cell system and reflect the balance between formation rate and elimination rate (repair), and must be interpreted as such. Urinary excretion is a global measure of oxidative stress in an organism and is therefore best suited for situations or diseases where large parts or the entire organism is stressed by oxidation. It represents the body average rate by which either RNA or DNA is oxidized and is interpreted as oxidative stress. Oxidations of RNA and DNA precursors have been demonstrated and the quantitative importance is debated. GENERAL SIGNIFICANCE: Careful experimental designs and appropriate choice of methodology are paramount for correct testing of hypotheses related to oxidative stress, and pitfalls are plentiful. There is accumulating evidence that DNA oxidation is associated with disease, particularly cancer, and recent evidence points at an association between RNA oxidation and neurodegenerative diseases and diabetes. This article is part of a Special Issue entitled Current methods to study reactive oxygen species - pros and cons and biophysics of membrane proteins. Guest Editor: Christine Winterbourn. PMID- 23791937 TI - Enzyme dimension of the ribosomal protein S4 across plant and animal kingdoms. AB - BACKGROUND: The protein S4 of the smaller ribosomal subunit is centrally important for its anchorage role in ribosome assembly and rRNA binding. Eubacterial S4 also facilitates synthesis of rRNA, and restrains translation of ribosomal proteins of the same polycistronic mRNA. Eukaryotic S4 has no homolog in eubacterial kingdom, nor are such extraribosomal functions of S4 known in plants and animals even as genetic evidence suggests that deficiency of S4X isoform in 46,XX human females may produce Turner syndrome (45,XO). METHODS: Recombinant human S4X and rice S4 were used to determine their enzymatic action in the cleavage of synthetic peptide substrates and natural proteins. We also studied autoproteolysis of the recombinant S4 proteins, and examined the growth and proliferation of S4-transfected human embryonic kidney cells. RESULTS: Extraribosomal enzyme nature of eukaryotic S4 is described. Both human S4X and rice S4 are cysteine proteases capable of hydrolyzing a wide spectrum of peptides and natural proteins of diverse origin. Whereas rice S4 also cleaves the -XXXD?- consensus sequence assumed to be specific for caspase-9 and granzyme B, human S4 does not. Curiously, both human and rice S4 show multiple-site autoproteolysis leading to self-annihilation. Overexpression of human S4 blocks the growth and proliferation of transfected embryonic kidney cells, presumably due to the extraribosomal enzyme trait reported. CONCLUSIONS: The S4 proteins of humans and rice, prototypes of eukaryota, are non-specific cysteine proteases in the extraribosomal milieu. GENERAL SIGNIFICANCE: The enzyme nature of S4 is relevant toward understanding not only the origin of ribosomal proteins, but also processes in cell biology and diseases. PMID- 23791938 TI - Cysteine endoprotease activity of human ribosomal protein S4 is entirely due to the C-terminal domain, and is consistent with Michaelis-Menten mechanism. AB - BACKGROUND: It is known that tandem domains of enzymes can carry out catalysis independently or by collaboration. In the case of cysteine proteases, domain sequestration abolishes catalysis because the active site residues are distributed in both domains. The validity of this argument is tested here by using isolated human ribosomal protein S4, which has been recently identified as an unorthodox cysteine protease. METHODS: Cleavage of the peptide substrate Z-FR? AMC catalyzed by recombinant C-terminal domain of human S4 (CHS4) is studied by fluorescence-monitored steady-state and stopped-flow kinetic methods. Proteolysis and autoproteolysis were analyzed by electrophoresis. RESULTS: The CHS4 domain comprised of sequence residues 116-263 has been cloned and ovreexpressed in Escherichia coli. The purified domain is enzymatically active. Barring minor differences, steady-state kinetic parameters for catalysis by CHS4 are very similar to those for full-length human S4. Further, stopped-flow transient kinetics of pre-steady-state substrate binding shows that the catalytic mechanism for both full-length S4 and CHS4 obeys the Michaelis-Menten model adequately. Consideration of the evolutionary domain organization of the S4e family of ribosomal proteins indicates that the central domain (residues 94-170) within CHS4 is indispensable. CONCLUSION: The C-terminal domain can carry out catalysis independently and as efficiently as the full-length human S4 does. SIGNIFICANCE: Localization of the enzyme function in the C-terminal domain of human S4 provides the only example of a cysteine endoprotease where substrate-mediated intramolecular domain interaction is irrelevant for catalytic activity. PMID- 23791939 TI - Comparison of glioma stem cells to neural stem cells from the adult human brain identifies dysregulated Wnt- signaling and a fingerprint associated with clinical outcome. AB - Glioblastoma is the most common brain tumor. Median survival in unselected patients is <10 months. The tumor harbors stem-like cells that self-renew and propagate upon serial transplantation in mice, although the clinical relevance of these cells has not been well documented. We have performed the first genome-wide analysis that directly relates the gene expression profile of nine enriched populations of glioblastoma stem cells (GSCs) to five identically isolated and cultivated populations of stem cells from the normal adult human brain. Although the two cell types share common stem- and lineage-related markers, GSCs show a more heterogeneous gene expression. We identified a number of pathways that are dysregulated in GSCs. A subset of these pathways has previously been identified in leukemic stem cells, suggesting that cancer stem cells of different origin may have common features. Genes upregulated in GSCs were also highly expressed in embryonic and induced pluripotent stem cells. We found that canonical Wnt signaling plays an important role in GSCs, but not in adult human neural stem cells. As well we identified a 30-gene signature highly overexpressed in GSCs. The expression of these signature genes correlates with clinical outcome and demonstrates the clinical relevance of GSCs. PMID- 23791940 TI - Migration-stimulating factor (MSF) is over-expressed in non-small cell lung cancer and promotes cell migration and invasion in A549 cells over-expressing MSF. AB - Migration-stimulating factor (MSF), an oncofetal truncated isoform of fibronectin, is a potent stimulator of cell invasion. However, its distribution and motogenic role in non-small cell lung cancer (NSCLC) have never been identified. In this study, real-time PCR and immunohistochemical staining (IHC) were performed to detect MSF mRNA and protein levels in tumor tissues and matched adjacent tumor-free tissues. Furthermore, to examine the effect of MSF on invasiveness, MSF was upregulated in A549 cells. The invasiveness and viability of A549 cells were then determined using a transwell migration assay and the 3 (4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) viability assays, respectively. The expression level of MSF in NSCLC tissue was markedly higher than in matched adjacent tumor-free tissue. Additionally, the level of MSF protein expression in stage III and IV NSCLC samples was higher than in stage I and II NSCLC samples. More importantly, we also demonstrated that migration and invasion of A549 cells increased substantially after upregulating MSF, although proliferation remained unchanged. Meanwhile, we found no correlation between increasing motility and invasiveness of MSF-overexpressing cells and expression levels and activities of matrix metalloprotease MMP-2 and MMP-9. Our current study shows that MSF plays a role in migration and invasion of A549 cells and suggests that MSF may be a potential biomarker of NSCLC progression. PMID- 23791941 TI - Molecular biomarkers in esophageal, gastric, and colorectal adenocarcinoma. AB - Cancers of the esophagus, stomach and colon contribute to a major health burden worldwide and over 20% of all cancer deaths. Biomarkers that should indicate pathogenic process and are measureable in an objective manner for these tumors are rare and not established in the clinical setting. In general biomarkers can be very useful for cancer management as they can improve clinical decision-making regarding diagnosis, surveillance, and therapy. Biomarkers can be different types of molecular entities (such as DNA, RNA or proteins), which can be detected, in different tissues or body fluids. However, more important is the type of biomarker itself, which allows diagnostic, prognostic or predictive analyses for different clinical problems. This review aims to systematically summarize the recent findings of genetic and epigenetic markers for gastrointestinal tumors within the last decade. While many biomarkers seem to be very promising, especially if used as panels, further development is urgently needed to address practical considerations of biomarkers in cancer treatment. PMID- 23791942 TI - Methodology to determine skull bone and brain responses from ballistic helmet-to head contact loading using experiments and finite element analysis. AB - The objective of the study was to obtain helmet-to-head contact forces from experiments, use a human head finite element model to determine regional responses, and compare outputs to skull fracture and brain injury thresholds. Tests were conducted using two types of helmets (A and B) fitted to a head-form. Seven load cells were used on the head-form back face to measure helmet-to-head contact forces. Projectiles were fired in frontal, left, right, and rear directions. Three tests were conducted with each helmet in each direction. Individual and summated force- and impulse-histories were obtained. Force histories were inputted to the human head-helmet finite element model. Pulse durations were approximately 4 ms. One-third force and impulse were from the central load cell. 0.2% strain and 40 MPa stress limits were not exceeded for helmet-A. For helmet-B, strains exceeded in left, right, and rear; pressures exceeded in bilateral directions; volume of elements exceeding 0.2% strains correlated with the central load cell forces. For helmet-A, volumes exceeding brain pressure threshold were: 5-93%. All elements crossed the pressure limit for helmet-B. For both helmets, no brain elements exceeded peak principal strain limit. These findings advance our understanding of skull and brain biomechanics from helmet-head contact forces. PMID- 23791943 TI - Crystal structures of malonyl-coenzyme A decarboxylase provide insights into its catalytic mechanism and disease-causing mutations. AB - Malonyl-coenzyme A decarboxylase (MCD) is found from bacteria to humans, has important roles in regulating fatty acid metabolism and food intake, and is an attractive target for drug discovery. We report here four crystal structures of MCD from human, Rhodopseudomonas palustris, Agrobacterium vitis, and Cupriavidus metallidurans at up to 2.3 A resolution. The MCD monomer contains an N-terminal helical domain involved in oligomerization and a C-terminal catalytic domain. The four structures exhibit substantial differences in the organization of the helical domains and, consequently, the oligomeric states and intersubunit interfaces. Unexpectedly, the MCD catalytic domain is structurally homologous to those of the GCN5-related N-acetyltransferase superfamily, especially the curacin A polyketide synthase catalytic module, with a conserved His-Ser/Thr dyad important for catalysis. Our structures, along with mutagenesis and kinetic studies, provide a molecular basis for understanding pathogenic mutations and catalysis, as well as a template for structure-based drug design. PMID- 23791945 TI - Structure of Osh3 reveals a conserved mode of phosphoinositide binding in oxysterol-binding proteins. AB - The oxysterol-binding protein (OSBP)-related proteins (ORPs) are conserved from yeast to humans, and implicated in the regulation of lipid homeostasis and in signaling pathways. Saccharomyces cerevisiae has seven ORPs (Osh1-Osh7) that share one unknown essential function. Here, we report the 1.5-2.3 A structures of the PH domain and ORD (OSBP-related domain) of yeast Osh3 in apo-form or in complex with phosphatidylinositol 4-phosphate (PI[4]P). Osh3 recognizes PI(4)P by the highly conserved residues in the tunnel of ORD whereas it lacks sterol binding due to the narrow hydrophobic tunnel. Yeast complementation tests suggest that PI(4)P binding to PH and ORD is essential for function. This study suggests that the unifying feature in all ORP homologs is the binding of PI(4)P to ORD and sterol binding is additional to certain homologs. Structural modeling of full length Osh3 is consistent with the concept that Osh3 is a lipid transfer protein or regulator in membrane contact sites. PMID- 23791944 TI - Structural evaluation of EGFR inhibition mechanisms for nanobodies/VHH domains. AB - The epidermal growth factor receptor (EGFR) is implicated in human cancers and is the target of several classes of therapeutic agents, including antibody-based drugs. Here, we describe X-ray crystal structures of the extracellular region of EGFR in complex with three inhibitory nanobodies, the variable domains of heavy chain only antibodies (VHH). VHH domains, the smallest natural antigen-binding modules, are readily engineered for diagnostic and therapeutic applications. All three VHH domains prevent ligand-induced EGFR activation, but use two distinct mechanisms. 7D12 sterically blocks ligand binding to EGFR in a manner similar to that of cetuximab. EgA1 and 9G8 bind an epitope near the EGFR domain II/III junction, preventing receptor conformational changes required for high-affinity ligand binding and dimerization. This epitope is accessible to the convex VHH paratope but inaccessible to the flatter paratope of monoclonal antibodies. Appreciating the modes of binding and inhibition of these VHH domains will aid in developing them for tumor imaging and/or cancer therapy. PMID- 23791946 TI - structural Studies of Wnts and identification of an LRP6 binding site. AB - Wnts are secreted growth factors that have critical roles in cell fate determination and stem cell renewal. The Wnt/beta-catenin pathway is initiated by binding of a Wnt protein to a Frizzled (Fzd) receptor and a coreceptor, LDL receptor-related protein 5 or 6 (LRP5/6). We report the 2.1 A resolution crystal structure of a Drosophila WntD fragment encompassing the N-terminal domain and the linker that connects it to the C-terminal domain. Differences in the structures of WntD and Xenopus Wnt8, including the positions of a receptor binding beta hairpin and a large solvent-filled cavity in the helical core, indicate conformational plasticity in the N-terminal domain that may be important for Wnt-Frizzled specificity. Structure-based mutational analysis of mouse Wnt3a shows that the linker between the N- and C-terminal domains is required for LRP6 binding. These findings provide important insights into Wnt function and evolution. PMID- 23791947 TI - Viral protein-coating of magnetic nanoparticles using simian virus 40 VP1. AB - Artificial beads including magnetite and fluorescence particles are useful to visualize pathologic tissue, such as cancers, from harmless types by magnetic resonance imaging (MRI) or fluorescence imaging. Desirable properties of diagnostic materials include high dispersion in body fluids, and the ability to target specific tissues. Here we report on the development of novel magnetic nanoparticles (MNPs) intended for use as diagnosis and therapy that are coated with viral capsid protein VP1-pentamers of simian virus 40, which are monodispersive in body fluid by conjugating epidermal growth factor (EGF) to VP1. Critically, the coating of MNPs with VP1 facilitated stable dispersion of the MNPs in body fluids. In addition, EGF was conjugated to VP1 coating on MNPs (VP1 MNPs). EGF-conjugated VP1-MNPs were successfully used to target EGF receptor expressing tumor cells in vitro. Thus, using viral capsid protein VP1 as a coating material would be useful for medical diagnosis and therapy. PMID- 23791948 TI - Identifying localized biases in large datasets: a case study using the avian tree of life. AB - Large-scale multi-locus studies have become common in molecular phylogenetics, with new studies continually adding to previous datasets in an effort to fully resolve the tree of life. Total evidence analyses that combine existing data with newly collected data are expected to increase the power of phylogenetic analyses to resolve difficult relationships. However, they might be subject to localized biases, with one or a few loci having a strong and potentially misleading influence upon the results. To examine this possibility we combined a newly collected 31-locus dataset that includes representatives of all major avian lineages with a published dataset of 19 loci that has a comparable number of sites (Hackett et al., 2008. Science 320, 1763-1768). This allowed us to explore the advantages of conducting total evidence analyses, and to determine whether it was also important to analyze new datasets independent of published ones. The total evidence analysis yielded results very similar to the published results, with only slightly increased support at a few nodes. However, analyzing the 31- and 19-locus datasets separately highlighted several differences. Two clades received strong support in the published dataset and total evidence analysis, but the support appeared to reflect bias at a single locus (beta-fibrinogen [FGB]). The signal in FGB that supported these relationships was sufficient to result in their recovery with bootstrap support, even when combined with 49 loci lacking that signal. FGB did not appear to have a substantial impact upon the results of species tree methods, but another locus (brain-derived neurotrophic factor [BDNF]) did have an impact upon those analyses. These results demonstrated that localized biases can influence large-scale phylogenetic analyses but they also indicated that considering independent evidence and exploring multiple analytical approaches could reveal them. PMID- 23791949 TI - Protein mechanics: how force regulates molecular function. AB - BACKGROUND: Regulation of proteins is ubiquitous and vital for any organism. Protein activity can be altered chemically, by covalent modifications or non covalent binding of co-factors. Mechanical forces are emerging as an additional way of regulating proteins, by inducing a conformational change or by partial unfolding. SCOPE: We review some advances in experimental and theoretical techniques to study protein allostery driven by mechanical forces, as opposed to the more conventional ligand driven allostery. In this respect, we discuss recent single molecule pulling experiments as they have substantially augmented our view on the protein allostery by mechanical signals in recent years. Finally, we present a computational analysis technique, Force Distribution Analysis, that we developed to reveal allosteric pathways in proteins. MAJOR CONCLUSIONS: Any kind of external perturbation, being it ligand binding or mechanical stretching, can be viewed as an external force acting on the macromolecule, rendering force-based experimental or computational techniques, a very general approach to the mechanics involved in protein allostery. GENERAL SIGNIFICANCE: This unifying view might aid to decipher how complex allosteric protein machineries are regulated on the single molecular level. PMID- 23791950 TI - Cerebroprotective effects of TAK-937, a novel cannabinoid receptor agonist, in permanent and thrombotic focal cerebral ischemia in rats: therapeutic time window, combination with t-PA and efficacy in aged rats. AB - Some occluded arteries of acute ischemic stroke (AIS) patients are not recanalized, even if thrombolytic therapy is performed. Considering such clinical settings, we examined the potential cerebroprotective efficacy of TAK-937, a novel cannabinoid receptor agonist, in young adult and aged rats with a permanent middle cerebral artery occlusion (MCAO) model and conducted a combination study with TAK-937 and tissue type plasminogen activator (t-PA) in a rat thrombotic MCAO model. TAK-937 significantly reduced infarct volume when it was administered 3 and 5h after permanent MCAO in young adult rats. A thrombotic MCAO was induced by photo-irradiation of the middle cerebral artery with Rose Bengal administration and a permanent MCAO was produced by thermoelectric coagulation of occluded arteries. TAK-937 (10, 30 and 100MUg/kg/h) was intravenously infused 1, 3, 5, or 8-24h after MCAO. t-PA (3 or 10mg/kg) was intravenously administered 1, 1.5 or 2h after MCAO. Infarct volume was determined using a 2,3,5 triphenyltetrazolium chloride staining method 24 or 48h after MCAO. The combined treatment of TAK-937 with t-PA significantly reduced the cerebral infarction compared with t-PA treatment alone in a rat thrombotic MCAO model. TAK-937 reduced infarct volume of aged rats as well, when it was administered 1h after permanent MCAO. These results suggest that TAK-937 exerts protective effects regardless of age and has a wide therapeutic time window in permanent occlusion. Furthermore, combined treatment of TAK-937 with t-PA would provide more therapeutic efficacy compared to t-PA treatment alone. PMID- 23791951 TI - Fear conditioning alters neuron-specific hippocampal place field stability via the basolateral amygdala. AB - It is well established that physical changes to an environment result in plasticity of hippocampal place cell activity, while in the absence of changes, place fields are remarkably stable. Manipulations of a rat's perception of the environment without physically changing the environment also result in plasticity of place cell firing. Here, we tested the hypothesis that a rat's perception of an environment could be changed by introducing an auditory fear-conditioned stimulus (CS) to a previously neutral environment, inducing plasticity of hippocampal place fields. First, stable place fields were isolated for rats exploring a radial-arm maze in one environment, and then the rats were fear conditioned to an auditory CS in a completely separate environment. Later, the CS was specifically paired once with a location in the previously neutral radial-arm maze, either within the given neuron's place field (in-field) or an area outside of the place field (out-of-field). A single, paired presentation of the CS with a location in-field for a specific place cell disrupted the stability of that neuron's place field, whereas pairing the CS with a location out-of-field did not affect place field stability. We further showed that this place field disruption for a CS presented in-field was mediated by inputs from the basolateral amygdala (BLA). Temporarily inactivating the BLA immediately post-CS re-exposure attenuated the CS-induced place field destabilization. Our results show neuron specific conditional plasticity for actively firing hippocampal place cells, and that the BLA mediates this plasticity when an emotionally arousing or fear related CS is used. PMID- 23791952 TI - The physiological response of skin tissues to alternating support pressures in able-bodied subjects. AB - Prolonged mechanical loading can lead to breakdown of skin and underlying tissues which can, in turn, develop into a pressure ulcer. The benefits of pressure relief and/or redistribution to minimise risk have been well documented and these strategies can be provided by employing support mattresses in which internal air pressures can be alternated to minimise the risk of pressure ulcers in patients during prolonged periods of bed-rest. The paper describes the performance of a prototype alternating pressure air mattress (APAM), in terms of its ability to maintain skin viability in a group of healthy volunteers lying in a supine position. In particular, the mattress includes a sacral section supported with alternating low pressure (ALP), with values adjusted to subject morphology, using an in-built pressure sensor. The mattress was supported at four different head of bed (HOB) angles ranging from 0 to 60 degrees . Internal mattress pressures and transcutaneous gas (TcPO2/TcPCO2) tensions at the sacrum and a control site, the scapula, were monitored. Interface pressures were also measured. The sensor was found to be sensitive to the BMI values of the 12 healthy volunteers. In the majority of test conditions the internal support produced sacral TcPO2 values, which either remained similar to those at the scapula or fluctuated at levels providing adequate viability. However in a few cases, associated with a raised HOB angle (>=45 degrees ), there was compromise to the skin viability at the sacrum, as reflected in depressed TcPO2 levels associated with an elevation of TcPCO2 levels above the normal range. In all cases, interface pressures at the sacrum rarely exceeded 60mmHg. Although such studies need to be extended to involve bed-bound individuals, the results offer the potential for the development of intelligent APAM systems, whose characteristics can be adjusted to an individual morphology. Such preventive strategies to maintain skin viability at loaded sites will be designed for subjects deemed to be at high risk of developing pressure ulcers. PMID- 23791954 TI - IL-21-producer CD4+ T cell kinetics during primary simian immunodeficiency virus infection. AB - IL-21 signaling is important for T cell and B cell-mediated clearance of chronic viral infections. While non-cognate follicular helper CD4+ T cells (TFH) are indicated to be pivotal in providing IL-21-mediated help to activated B cells within germinal centers, how this signaling may be disrupted in early AIDS virus infection is not clear. In this study, we assessed the lineage and kinetics of peripheral blood IL-21-producing CD4+ T cells in primary simian immunodeficiency virus (SIV) infection of rhesus macaques. After SIV challenge, antigen nonspecific IL-21 production was observed in Th1, Th2 and Th17 cells with Th1 dominance. While IL-21+ Th2 and IL-21+ Th17 showed variable kinetics, an increase in total IL-21+ CD4+ T cells and IL-21+ Th1 from week 3 to week 8 was observed, preceding plasma SIV-specific IgG development from week 5 to week 12. SIV Gag specific IL-21+ CD4+ T cells detectable at week 2 were decreased in frequencies at week 5. Results imply that kinetics of IL-21+ CD4+ T cells comprised of multiple lineages, potentially targeted by SIV with a bias of existing frequencies during their precursor stage, associate with availability of cooperative B-cell help provided through a proportionate precursor pool developing into TFH and subsequent anti-SIV antibody responses. PMID- 23791955 TI - Model casting. PMID- 23791956 TI - Middle East respiratory syndrome coronavirus (MERS-CoV): challenges in identifying its source and controlling its spread. AB - Middle East respiratory syndrome coronavirus (MERS-CoV), a novel human coronavirus that caused outbreaks of a SARS-like illness in the Middle East, is now considered a threat to global public health. This review discusses the challenges in identifying the source of this fatal virus and developing effective and safe anti-MERS-CoV vaccines and therapeutics in order to control its spread and to combat any future pandemic. PMID- 23791957 TI - Cerebral veins: to sacrifice or not to sacrifice, that is the question. PMID- 23791958 TI - The management of cerebral arteriovenous malformations associated with aneurysms. PMID- 23791959 TI - Pre- and postsynaptic twists in BDNF secretion and action in synaptic plasticity. AB - Overwhelming evidence collected since the early 1990's strongly supports the notion that BDNF is among the key regulators of synaptic plasticity in many areas of the mammalian central nervous system. Still, due to the extremely low expression levels of endogenous BDNF in most brain areas, surprisingly little data i) pinpointing pre- and postsynaptic release sites, ii) unraveling the time course of release, and iii) elucidating the physiological levels of synaptic activity driving this secretion are available. Likewise, our knowledge regarding pre- and postsynaptic effects of endogenous BDNF at the single cell level in mediating long-term potentiation still is sparse. Thus, our review will discuss the data currently available regarding synaptic BDNF secretion in response to physiologically relevant levels of activity, and will discuss how endogenously secreted BDNF affects synaptic plasticity, giving a special focus on spike timing dependent types of LTP and on mossy fiber LTP. We will attempt to open up perspectives how the remaining challenging questions regarding synaptic BDNF release and action might be addressed by future experiments. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'. PMID- 23791961 TI - Response inhibition and elevated parietal-cerebellar correlations in chronic adolescent cannabis users. AB - The ability to successfully inhibit an inappropriate behaviour is a crucial component of executive functioning and its impairment has been linked to substance dependence. Cannabis is the most widely used illicit drug in adolescence and, given the accelerated neuromaturation during adolescence, it is important to determine the effects of cannabis use on neurocognitive functioning during this developmental period. In this study, a cohort of adolescent heavy cannabis users and age-matched non-cannabis-using controls completed a Go/No-Go paradigm. Users were impaired in performance on the task but voxelwise and region of-interest comparisons revealed no activation differences between groups. Instead, an analysis of correlation patterns between task-activated areas revealed heightened correlation scores in the users between bilateral inferior parietal lobules and the left cerebellum. The increased correlation activity between these regions was replicated with resting state fMRI data and was positively correlated with self-reported, recent cannabis usage. The results suggests that the poorer inhibitory control of adolescent cannabis users might be related to aberrant connectivity between nodes of the response inhibition circuit and that this effect is observable in both task-induced and intrinsic correlation patterns. This article is part of the Special Issue Section entitled 'Neuroimaging in Neuropharmacology'. PMID- 23791962 TI - Nucleotide polymorphisms in the 5'-UTR region of HCV can affect the ability of two widely used assays to assign an HCV genotype. AB - Determination of hepatitis C virus genotype is crucial for establishing the duration of antiviral therapy and predicts response to treatment. In this study, consecutive serum samples collected from two patients with chronic hepatitis C infection were tested by two assays used widely, the Abbott RealTime HCV Genotype II and the Versant HCV Genotype 2.0 assays, in order to assign a genotype to the virus. The obtained results were verified by phylogenetic analysis of the NS5B region and sequencing of the 5'-UTR of the viral genome. Testing of the serum samples from both patients gave an indeterminate result with the Abbott assay. By contrast, the Versant assay gave an indeterminate result for one patient and identified an HCV-2b subtype in the other patient. Phylogenetic analysis of the NS5B region confirmed the presence of HCV-2b in this latter patient and disclosed the presence of HCV-3h in the other patient. Sequencing of the 5'-UTR revealed the presence of nucleotide changes at positions -166 and -119 of HCV-2b, and at positions -138, -108 and -99 of HCV-3h. Nucleotide mutations located in the 5' untraslated region of hepatitis C virus may impair the ability of commercial assays to assign an HCV genotype. PMID- 23791960 TI - Rats are the smart choice: Rationale for a renewed focus on rats in behavioral genetics. AB - Due in part to their rich behavioral repertoire rats have been widely used in behavioral studies of drug abuse-related traits for decades. However, the mouse became the model of choice for researchers exploring the genetic underpinnings of addiction after the first mouse study was published demonstrating the capability of engineering the mouse genome through embryonic stem cell technology. The sequencing of the mouse genome and more recent re-sequencing of numerous inbred mouse strains have further cemented the status of mice as the premier mammalian organism for genetic studies. As a result, many of the behavioral paradigms initially developed and optimized for rats have been adapted to mice. However, numerous complex and interesting drug abuse-related behaviors that can be studied in rats are very difficult or impossible to adapt for use in mice, impeding the genetic dissection of those traits. Now, technological advances have removed many of the historical limitations of genetic studies in rats. For instance, the rat genome has been sequenced and many inbred rat strains are now being re-sequenced and outbred rat stocks are being used to fine-map QTLs. In addition, it is now possible to create "knockout" rats using zinc finger nucleases (ZFN), transcription activator-like effector nucleases (TALENs) and related techniques. Thus, rats can now be used to perform quantitative genetic studies of sophisticated behaviors that have been difficult or impossible to study in mice. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. PMID- 23791963 TI - AAV2 production with optimized N/P ratio and PEI-mediated transfection results in low toxicity and high titer for in vitro and in vivo applications. AB - The adeno-associated virus (AAV) is one of the most useful viral vectors for gene delivery for both in vivo and in vitro applications. A variety of methods have been established to produce and characterize recombinant AAV (rAAV) vectors; however most methods are quite cumbersome and obtaining consistently high titer can be problematic. This protocol describes a triple-plasmid co-transfection approach with 25 kDa linear polyethylenimine (PEI) in 293 T cells for the production of AAV serotype 2. Seventy-two hours post-transfection, supernatant and cells were harvested and purified by a discontinuous iodixanol density gradient ultracentrifugation, then dialyzed and concentrated with an Amicon 15 100,000 MWCO concentration unit. To optimize the protocol for AAV2 production using PEI, various N/P ratios and DNA amounts were compared. We found that an N/P ratio of 40 coupled with 1.05 MUg DNA per ml of media (21 MUg DNA/15 cm dish) was found to produce the highest yields for viral replication and assembly measured multiple ways. The infectious units, as determined by serial dilution, were between 1*10(8) and 2*10(9) IU/ml. The genomic titer of the viral stock was determined by qPCR and ranged from 2*10(12) to 6*10(13) VG/ml. These viral vectors showed high expression both in vivo within the brain and in vitro in cell culture. The use of linear 25 kDa polyethylenamine PEI as a transfection reagent is a simple, more cost-effective, and stable means of high-throughput production of high-titer AAV serotype 2. The use of PEI also eliminates the need to change cell medium post-transfection, lowering cost and workload, while producing high titer, efficacious AAV2 vectors for routine gene transfer. PMID- 23791964 TI - Rapid detection of Piper yellow mottle virus and Cucumber mosaic virus infecting black pepper (Piper nigrum) by loop-mediated isothermal amplification (LAMP). AB - The loop-mediated isothermal amplification (LAMP) assay for Piper yellow mottle virus and the reverse transcription (RT) LAMP assay for Cucumber mosaic virus each consisted of a set of five primers designed against the conserved sequences in the viral genome. Both RNA and DNA isolated from black pepper were used as a template for the assay. The results were assessed visually by checking turbidity, green fluorescence and pellet formation in the reaction tube and also by gel electrophoresis. The assay successfully detected both viruses in infected plants whereas no cross-reactions were recorded with healthy plants. Optimum conditions for successful amplification were determined in terms of the concentrations of magnesium sulphate and betaine, temperature, and duration. The detection limit for both LAMP and RT-LAMP was up to 100 times that for conventional PCR and up to one-hundredth of that for real-time PCR. The optimal conditions arrived at were validated by testing field samples of infected vines of three species from different regions. PMID- 23791965 TI - Mouse strain variation in SMA(+) myofibroblast development after corneal injury. AB - The purpose of present study was to investigate differences in myofibroblast development after haze-generating injury in different commonly used strains of mice. The inbred mouse strains used in this study were Balb/c, C57BL/6, C3H/HeJ and DBA/1J. All mice had uniform irregular phototherapeutic keratectomy with an excimer laser according to a previously published method to generate stromal haze. DBA/1J mice generated significantly greater density of alpha smooth muscle actin (SMA)-positive myofibroblasts in the anterior stroma compared to Balb/c (p < 0.05), C57BL/6 (p < 0.05) and C3H/HeJ (p < 0.01) mice. The C3H/HeJ strain had significantly lower density of SMA-positive myofibroblasts compared to other three mouse strains. These results indicate that mouse strain must be considered in designing experiments and interpreting the results of experiments in which corneal haze and myofibroblast generation is studied in mice. Further investigation of genetics underlying mouse strain variation could provide insight into the corneal wound healing and haze generation processes. PMID- 23791966 TI - Association of MMP2-1306C/T and TIMP2G-418C polymorphisms in retinal vein occlusion. AB - Matrix metalloproteinases (MMPs) are large groups of zinc-dependent proteases that play an important role in many diseases and pathological processes such as cancer, angiogenesis, atherosclerosis, and vascular disease. Also, it was found that the expression of MMPs was high during the initial period of thrombosis in a rat model of traumatic deep vein thrombosis. Moreover, the presence of metalloproteinase activity and endogenous inhibitor activity in vitrectomy samples are associated with neovascularization of several retinal diseases such as exudative age related maculopathy, proliferative diabetic retinopathy, and central retinal vein occlusion. In this study, we aimed to investigate the possible association of the matrix metalloproteinase 2-1306C/T (rs 243865) and tissue inhibitors of matrix metalloproteinase 2 G-418C (rs 8179090) polymorphisms with the risk of retinal vein occlusion (RVO). Genomic DNA was extracted from peripheral leukocytes from ethylenediaminetetraacetic acid anticoagulated blood. Genotyping of the MMP2-1306C/T and TIMP2G-418C polymorphisms were performed using real-time polymerase chain reaction. The MMP2-1306 T allele carriers (CT + TT) had a significantly increased risk of RVO compared with the CC homozygotes (p < 0.001, odds ratio = 4.78; 95% CI = 2.85-8.09). After adjusting for hypertension, diabetes, hypertriglyceridemia, and hypercholesterolemia, MMP2-1306 T allele carriers (CT + TT) also had a significantly increased risk of RVO (B = 1.453; p < 0.001; odds ratio = 4.275; 95% CI:2.529-7.224). MMP2-1306C/T, but not TIMP2G 418C, gene variants are a risk factor for the development of retinal vein occlusion. PMID- 23791967 TI - Magnetic resonance imaging (MRI) study of the water content and transport in rat lenses. AB - NMR micro-imaging technique has been used for the measurement of the water content distribution in lenses of senescence-accelerated OXYS rats and age matched Wistar rats, as well as for the study of water and phosphate transport in rat lenses. The water content in the lens cortex is significantly higher than in the nucleus; the spatial gradient of the water content becomes steeper with age. No difference in the water content distribution has been found between Wistar and OXYS rat lenses of matching ages, although cataract onset in the OXYS rat lens occurs much earlier due to the enhanced generation of reactive oxygen species associated with oxidative stress. This finding implies that cataract development does not lead to significant changes in water content distribution inside the lens. The water transport in rat lenses slows down with age, and in OXYS lenses it is somewhat faster than in lenses of Wistar rats, probably due to the compensatory response to oxidative stress. The application of (31)P MRI for the monitoring of phosphate penetration into a lens has been performed for the first time. It is found that phosphate transport in a lens is significantly slower than that of water. PMID- 23791968 TI - Changing coupling pattern of The ON-OFF direction-selective ganglion cells in early postnatal mouse retina. AB - In the adult rabbit and mouse retina, about 30% of the ON-OFF direction selective ganglion cells (DSGCs) are coupled via gap junctions. In early postnatal rabbit retinas, a greater proportion of morphological ON-OFF DSGCs shows coupling with a larger number of nearby somas. It is not clear whether the coupled ON-OFF DSGCs belong to the same subtype, or how coupling patterns change during development. In this study, we showed that in adult mouse retinas, all coupled ON-OFF DSGCs exhibited preferred directions (PDs) to superior, and this pattern emerged at postnatal day 15 (P15). At P13, the ON-OFF DSGCs with PDs to posterior were also coupled. Every ON-OFF DSGC in every subtype injected at P12 exhibited coupling. Therefore, a rapid decoupling process takes place in DSGCs around eye opening. Light deprivation delayed but did not halt the decoupling process. By using a transgenic mouse line in which green fluorescent protein (GFP) is selectively expressed in DSGCs with PDs to posterior and by performing in situ hybridization of cadherin-6, a marker for the DSGCs with PDs to superior and inferior, we showed that heterologous coupling existed between DSGCs with PDs to anterior and posterior till P12, but this heterologous coupling never spread to DSGCs positive for cadherin-6. PMID- 23791969 TI - Validating reference genes within a mouse model system of 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) toxicity. AB - BACKGROUND: Quantitative real-time PCR (qPCR) is the "gold-standard" technique for measuring mRNA abundances. To correctly compare samples and generate biologically valid results, qPCR data usually require comprehensive normalization to account for sample content variation between reactions. The most common normalization approaches use one or more endogenous controls (reference or house keeping genes) to adjust the measured levels of experimental genes appropriately. Ideal reference genes are those that display minimal variation across experimental conditions, and thus can vary widely across different biological systems. In particular, toxicogenomic studies of transcriptionally-disruptive toxins, like 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), require careful consideration of reference genes. RESULTS: We examined seven candidate reference genes in 199 mice varying in genotype and time/dose of TCDD exposure. We assessed gene-stability in four ways: (1) the variance of the raw Cq values across biological replicates, (2) the fold-change from basal mRNA levels following treatment, (3) the inter- and intra-group stability evaluated using the NormFinder algorithm, (4) the comparative DeltaCq method for each candidate gene. Univariate analyses showed Hprt and Eef1a1 are the two most stable individual reference genes. It has been suggested that using multiple genes would produce a more consistent normalization factor; multivariate analysis was performed using NormFinder. In general, stability increased with the number of genes used, but specific gene-combinations synergized. CONCLUSIONS: We have validated seven reference genes for use in analyzing mRNA abundances in mouse models of TCDD toxicity. The use of multiple reference genes increases stability, providing more consistent normalization and more reliable results. The number of reference genes used should be maximized, based on experimental capabilities (platform, sample availability, etc.). Our results show the benefit of validating reference genes using multiple methods prior to generating large biological datasets. PMID- 23791971 TI - Anti-inflammatory and immunosuppressive activities of 1,3-dicyclopentyl-1,2,3,6 tetrahydropyrimidine-4,5-dicarboxylic acid diethyl ester (ZL-5015). AB - The aim of this study is to investigate the anti-inflammatory and immunosuppressive effects of ZL-5015 (1,3-dicyclopentyl-1,2,3,6 tetrahydropyrimidine-4,5-dicarboxylic acid diethyl ester) in order to determine its potential as a lead compound to develop novel drugs with both anti inflammatory and immunosuppressive activities. Inflammatory in vivo models (specifically, acetic acid-induced mouse writhing, xylene-induced mouse ear swelling and carrageenan-induced rat paw edema) and in vitro models (specifically, lipopolysaccharide (LPS)-induced production of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor alpha (TNF-alpha) and interleukin 10 (IL-10) by mouse peritoneal macrophages and RAW264.7 cells) were used to evaluate the anti-inflammatory activities. Immunological in vivo models (specifically, rabbit red blood cells (RRBC)-induced mouse hemolysin production, 2,4-dinitrofluorobenzene (DNFB)-induced delayed type hypersensitivity (DTH) and adjuvant-induced rat arthritis) and in vitro models (specifically, concanavalin A (Con A) and LPS-stimulated mouse splenocyte proliferation) were applied to estimate the immunosuppressive effects. It was found that ZL-5015 significantly decreased acetic acid-induced mouse writhing, xylene-induced mouse ear swelling, and carrageenan-induced rat paw edema at the doses from 25 to 100mg/kg, and inhibited mouse hemolysin production, DTH response, and adjuvant-induced rat arthritis at the doses from 50 to 200mg/kg. The compound appeared to be more potent in inhibition of inflammation than in suppression of immune function, as judged by the minimal statistically effective dose. The in vitro studies revealed that ZL-5015 greatly inhibited the production of NO, PGE2 and TNF-alpha, slightly promoted IL-10 production and suppressed the splenocyte proliferation stimulated by Con A or LPS at the concentrations from 10 to 40MUM. In conclusion, our study demonstrates that the tetrahydropyrimidine derivative, ZL-5015, has both anti inflammatory and immunosuppressive activities, although its potency is not satisfactory. Therefore ZL-5015 should be considered as a lead compound for further structural modification in the continuing search for novel and effective drugs in this area. PMID- 23791970 TI - Connecting glutathione with immune responses to occupational methylene diphenyl diisocyanate exposure. AB - Methylene diphenyl diisocyanate (MDI) is among the leading chemical causes of occupational asthma world-wide, however, the mechanisms of disease pathogenesis remain unclear. This study tests the hypothesis that glutathione (GSH) reacts with MDI to form quasi-stable conjugates, capable of mediating the formation of MDI-conjugated "self" protein antigens, which may participate in pathogenic inflammatory responses. To test this hypothesis, an occupationally relevant dose of MDI (0.1%w/v) was reacted with varying concentrations of GSH (10MUM-10mM), and the reaction products were characterized with regard to mass/structure, and ability to carbamoylate human albumin, a major carrier protein for MDI in vivo. LC-MS/MS analysis of GSH-MDI reaction products identified products possessing the exact mass of previously described S-linked bis(GSH)-MDI and its partial hydrolysis product, as well as novel cyclized GSH-MDI structures. Upon co incubation of GSH-MDI reaction products with human albumin, MDI was rapidly transferred to specific lysines of albumin, and the protein's native conformation/charge was altered, based on electrophoretic mobility. Three types of modification were observed, intra-molecular MDI cross-linking, addition of partially hydrolyzed MDI, and addition of "MDI-GSH", where MDI's 2nd NCO had reacted with GSH's "N-terminus". Importantly, human albumin carbamoylated by GSH MDI was specifically recognized by serum IgG from MDI exposed workers, with binding dependent upon the starting GSH concentration, pH, and NaCl levels. Together, the data define a non-enzymatic, thiol-mediated transcarbamoylating mechanism by which GSH may promote immune responses to MDI exposure, and identify specific factors that might further modulate this process. PMID- 23791972 TI - Mesenchymal stem cells transplantation ameliorates glomerular injury in streptozotocin-induced diabetic nephropathy in rats via inhibiting macrophage infiltration. AB - Mesenchymal stem cells (MSCs) treatment has been shown to be effective in diabetic nephropathy (DN). However, the mechanisms involved in the renoprotective effects of MSCs have not been clearly demonstrated. Especially, there was no study on the relationship of MSCs and macrophages in diabetic kidney. To explore the effect of MSCs on macrophages in DN, streptozotocin-induced diabetes animals received no treatment or treatment with MSCs (2*10(6), via tail vein) for two continuous weeks. Eight weeks after treatment, physical, biochemical and morphological parameters were measured. Immunohistochemistry for fibronectin (FN), CollagenI, ED-1, monocyte chemoattractant protein-1 (MCP-1) was performed. Expressions of pro-inflammatory cytokines and hepatocyte growth factor (HGF) at gene level and protein level were determined by real-time reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Blood glucose, urinary albumin excretion, creatinine clearance were significantly reduced after MSCs treatment. The glomerulosclerosis as revealed by periodic acid Schiff stain and expression of FN and CollagenI was also dramatically attenuated. Most importantly, the expression of MCP-1 and the number of infiltrated macrophages in kidney were effectively suppressed by MSCs treatment. The expression of HGF in MSCs group was up-regulated. Meanwhile, the expressions of IL-1beta, IL-6 and TNFalpha were significantly down-regulated by MSCs treatment. Our study suggest that MSCs treatment ameliorates DN via inhibition of MCP-1 expression by secreting HGF, thus reducing macrophages infiltration, down regulating IL-1beta, IL-6, TNFalpha expression in renal tissue in diabetic rats. PMID- 23791974 TI - gamma-Hydroxybutyric acid induces actions via the GABAB receptor in arousal and motor control-related nuclei: implications for therapeutic actions in behavioral state disorders. AB - gamma-Hydroxybutyric acid (GHB) is used as an effective therapeutic for reducing the hypersomnolence and cataplexy (loss of motor control) of the sleeping disorder, narcolepsy, with an immediate pharmacologic behavioral action of inducing a natural sleep-like state. Despite its clinical use, few studies have examined the cellular actions of this drug on behavioral state-related neurons. Therefore, we monitored GHB-induced responses using calcium imaging within the laterodorsal tegmentum (LDT) and the dorsal raphe (DR), two pontine nuclei important in state and motor control. In addition, we recorded GHB-induced membrane responses using whole cell, patch clamp electrophysiology of immunohistochemically-identified principal neurons within these nuclei. GHB induced GABAB receptor-mediated rises in calcium in neurons of the LDT and the DR. However, the pattern and amplitude of calcium rises differed greatly between these two nuclei. GHB induced GABAB receptor antagonist-sensitive outward currents/hyperpolarizations in immunohistochemically-identified cholinergic LDT and serotonergic DR neurons. However, GHB had this action in a greater proportion of DR cells than LDT neurons. Further, larger inhibitory currents were induced in DR cells when compared to the amplitude of GHB-induced current in LDT-responding cells. Finally, NCS-382 and HOCPCA, a reported antagonist and agonist specific to activity at the putative GHB receptor, respectively, with no demonstrated binding at the GABAB receptor, failed to block GHB-induced effects or elicit any discernible electrophysiological action when applied alone, indicating a lack of involvement of a GHB receptor in mediating GHB actions. Taken together, our data support the conclusion that GHB may be exerting its actions on state and motor control, in part, via an acutely mediated strong inhibition of serotonergic DR neurons and a more modest inhibitory action on a smaller proportion of LDT cholinergic neurons. Given the roles played by these nuclei, these actions are consistent with acute pharmacologic effects of GHB: hypotonia and promotion of sleep, including presence of REM, a sub-state of sleep. Differences in GHB mediated calcium suggest differential regulation of calcium-dependent processes, which may also contribute to functioning of the LDT and DR in state and motor control and the therapeutic pharmacologic actions of GHB, which develop following chronic administration. These findings add to knowledge of cellular actions of GHB and it is hoped that, combined with findings from other studies examining GHB neurotransmission, these data can contribute to development of highly targeted therapeutics at the GABAB receptor for management of human disorders presenting with alterations in motor and arousal control. PMID- 23791973 TI - Metabolic mystery: aging, obesity, diabetes, and the ventromedial hypothalamus. AB - We propose that energy balance, glucose homeostasis, and aging are all regulated largely by the same nutrient-sensing neurons in the ventromedial hypothalamus (VMH). Although the central role of these neurons in regulating energy balance is clear, their role in regulating glucose homeostasis has only recently become more clear. This latter function may be most relevant to aging and lifespan by controlling the rate of glucose metabolism. Specifically, glucose-sensing neurons in VMH promote peripheral glucose metabolism, and dietary restriction, by reducing glucose metabolism in these neurons, reduces glucose metabolism of the rest of the body, thereby increasing lifespan. Here we discuss recent studies demonstrating the key role of hypothalamic neurons in driving aging and age related diseases. PMID- 23791975 TI - Development of a novel therapeutic approach using a retinoic acid-loaded microneedle patch for seborrheic keratosis treatment and safety study in humans. AB - Seborrheic keratosis is one of the most common skin benign tumors in humans with a high occurrence rate of 80%-100% in people > 50 years of age; however, its pathogenesis is still unclear. The standard treatment includes cryotherapy and laser surgery for physically removing lesions. Drug therapy for this condition has not been well established. We aimed to evaluate the use of all-trans retinoic acid (ATRA)-loaded microneedle (MN) patches as a simple, alternative therapeutic option to traditional surgical treatments. This therapeutic strategy was designed to induce the proliferation of basal keratinocytes and accelerate stratum corneum turnover, leading to the lesion falling off the surface of the skin. The MN patch induced epidermal hyperplasia and marked expression of heparin-binding epidermal growth factor-like growth factor mRNA and protein corresponding to ATRA activity in the skin of HR-1 hairless mice. The acceleration of stratum corneum turnover was also observed by the dansyl chloride method. The skin irritation study in mice and safety study in humans support the safety findings of our study. Overall, MN patches can offer an effective and safe means of ATRA delivery into the skin, and the ATRA-loaded MN patch appears to be an effective pharmaceutical product providing a novel therapeutic option for seborrheic keratosis. PMID- 23791976 TI - On employing a translationally controlled tumor protein-derived protein transduction domain analog for transmucosal delivery of drugs. AB - Protein transduction domains (PTDs) are recognized as promising vehicles for the delivery of macromolecular drugs. We have previously shown that a region in the N terminus (residues 1-10) of translationally controlled tumor protein (TCTP) contains a PTD (TCTP-PTD), MIIYRDLISH, which can serve as a vehicle for the delivery of macromolecules into the cells and tissues. In the current study, we evaluated the potential and safety of TCTP-PTD and its three mutant analogs as nasal absorption enhancers for delivery of drugs. We conducted this evaluation employing insulin as test drug. We examined the degree to which insulin was absorbed in nasal mucosa and also if any mucosal damage occurs following such nasal delivery of insulin using TCTP-PTDs as a vehicle. The systemic delivery of insulin was assessed by measuring the changes in blood glucose levels after nasal coadministration insulin and four PTDs. Of the three TCTP-PTD analogs examined, one, TCTP-PTD analog (MIIFRALISHKK) significantly enhanced the nasal absorption of insulin in both normal and streptozotocin-induced diabetic mice. The relative pharmacological bioavailability of insulin nasally coadministered with the TCTP PTD analog was 21.3% relative to the subcutaneous route. Molecular association between insulin and the TCTP-PTD analog was observed by fluorescence resonance energy transfer measurements. The binding between the TCTP-PTD analog and insulin may enable the penetration of insulin through the nasal mucosa. Histological examination of mice nasal mucosa 7 days after repeated nasal administration showed no evidence of toxicity at the site of nasal administration. In this study using insulin as a test system we demonstrate that the TCTP-PTD analog offers a promising approach for nasal peptides and protein-drugs delivery. PMID- 23791977 TI - Turning an antiviral into an anticancer drug: nanoparticle delivery of acyclovir monophosphate. AB - Anti-herpes simplex virus (HSV) drug acyclovir (ACV) is phosphorylated by the viral thymidine kinase (TK), but not the cellular TK. Phosphorylated ACV inhibits cellular DNA synthesis and kills the infected cells. We hypothesize that ACV monophosphate (ACVP), which is an activated metabolite of ACV, should be efficient in killing cells independent of HSV-TK. If so, ACVP should be a cytotoxic agent if properly delivered to the cancer cells. The Lipid/Calcium/Phosphate (LCP) nanoparticles (NPs) with a membrane/core structure were used to encapsulate ACVP to facilitate the targeted delivery of ACVP to the tumor. The LCP NPs showed entrapment efficiency of ~70%, the nano-scaled particle size and positive zeta potential. Moreover, ACVP-loaded LCP NPs (A-LCP NPs) exhibited concentration-dependent cytotoxicity against H460 cells and increased S phase arrest. More importantly, a significant reduction of the tumor volume over 4 days following administration (p<0.05-0.005) of A-LCP NPs, suggests excellent in vivo efficacy. Whereas, two free drugs (ACV and ACVP) and blank LCP NPs showed little or no therapeutic effect. It was also found that the high efficacy of A LCP NPs was associated with the ability to induce dramatic apoptosis of the tumor cells, as well as significantly inhibit tumor cell proliferation and cell cycle progression. In conclusion, with the help of LCP NPs, monophosphorylation modification of ACV can successfully modify an HSV-TK-dependent antiviral drug into an anti-tumor drug. PMID- 23791979 TI - Stabilization of cancer-specific gene carrier via hydrophobic interaction for a clear-cut response to cancer signaling. AB - Here, we developed a new gene carrier, comprising a linear polyethylenimine (LPEI) grafted with a hydrophobically modified cationic peptide containing a long alkyl chain, for use in cancer-specific gene delivery. The cationic peptide is a substrate of protein kinase Calpha (PKCalpha), which is known to be activated specifically in cancer cells. The hydrophobically modified LPEI-peptide conjugate (LPEI-C10-peptide) could form a polyplex with DNA through electrostatic and hydrophobic interactions between the anionic DNA strands and the cationic peptide substrate. The hydrophobic modification of the peptide did not affect the reactivity of the peptide toward PKCalpha, while the polyplex showed improved intracellular uptake. Because of the efficient endosomal escape and enhanced stability, the polyplex significantly improved the transgene regulation responding to intracellular PKCalpha activity. PMID- 23791978 TI - Rosiglitazone-loaded nanospheres for modulating macrophage-specific inflammation in obesity. AB - PPARgamma nuclear receptor agonists have been shown to attenuate macrophage inflammatory responses implicated in the metabolic complications of obesity and in atherosclerosis. However, PPARgamma agonists currently in clinical use, including rosiglitazone (RSG), are often associated with severe side effects that limit their therapeutic use. Here, 200nm PLGA/PVA nanospheres were formulated for the systemic delivery of RSG specifically to macrophages. RSG was encapsulated with over 50% efficiency in the hydrophobic PLGA core and released specifically within the acidifying macrophage phagosomes. In bone marrow derived macrophages, RSG-loaded nanoparticles (RSG-NPs) induce a dose dependent upregulation (1.5 to 2.5-fold) of known PPARgamma target genes, with maximal induction at 5MUM; and downregulate the expression of genes related to the inflammatory process, with a maximum effect at 10MUM. In Ldlr(-/-) mice fed high fat diet, treatment with RSG NPs alleviated inflammation in white adipose tissue and liver but, unlike treatment with free RSG, did not alter genes associated with lipid metabolism or cardiac function, indicating a reduction in the RSG side effect profile. These biocompatible, biodegradable RSG-NPs represent a preliminary step towards the specific delivery of nuclear receptor agonists for the treatment of macrophage mediated inflammatory conditions associated with obesity, atherosclerosis and other chronic disease states. PMID- 23791980 TI - Synergistic effects of ultrasound-targeted microbubble destruction and TAT peptide on gene transfection: an experimental study in vitro and in vivo. AB - Cell-permeable peptides (CPPs) and ultrasound-targeted microbubble destruction (UTMD) have tremendous potential for gene delivery. However, their applications are limited due to nonspecificity of CPPs and low transfection efficiency of UTMD. Here, we developed a 'smart' gene delivery system by encapsulating TAT peptide (TATp) and hepatocyte growth factor (HGF) gene within lipid microbubbles, in which TATp was protected from being enzymatically cleaved and HGF gene was protected from degradation. This new strategy had synergistic effects of UTMD and TATp on gene transfection. We investigated the efficacy and safety of HGF gene transfection mediated by the combination of UTMD and TATp in vitro and in vivo. The results from MTT assay and flow cytometry analyses indicated that the combination of UTMD and TATp could enhance HGF gene expression in HUVECs without any significant side effect on cell viability. In rat myocardial infarction models, we demonstrated that the protein and mRNA expressions of HGF in myocardium caused by the combination of UTMD and TATp were the highest. Histopathological findings demonstrated that the combination of UTMD and TATp enhanced myocardial microvasculature and ameliorated myocardial fibrosis. In conclusion, the combination of UTMD and TATp might be a safe and efficient technique for gene delivery. PMID- 23791982 TI - Poly(I:C) inhibits porcine reproductive and respiratory syndrome virus replication in MARC-145 cells via activation of IFIT3. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is a major cause of heavy economic losses in many swine-producing regions. Current vaccination strategies and antiviral drugs provide only limited protection. Interferon (IFN) induced protein with tetratricopeptide repeats 3 (IFIT3) has been characterized as the product of a novel antiviral gene and as an important modulator in innate immunity. However, the role of IFIT3 in PRRSV infection is scarcely understood. In this study, polyinosinic-polycytidylic acid (poly(I:C)) inhibited PRRSV replication in MARC-145 cells, following the appearance of increased IFIT3. Overexpression of porcine IFIT3 resulted in a decrease of PRRSV. Knockdown of IFIT3 in MARC-145 cells increased PRRSV replication and impaired the antiviral activity mediated by poly(I:C). Moreover, in the presence or absence of IFIT3, poly(I:C)-induced IFN-beta promoter activity was significantly boosted or crippled, respectively. IFIT3, TBK1 and phosphorylation of IRF3 were activated in poly(I:C)-transfected MARC-145 cells. It demonstrated that IFIT3 plays an important role in IFN-beta induction in MARC-145 cells, and, when activated, it can inhibit PRRSV replication. PMID- 23791981 TI - Polysaccharide-modified scaffolds for controlled lentivirus delivery in vitro and after spinal cord injury. AB - Gene delivering biomaterials have increasingly been employed to modulate the cellular microenvironment to promote tissue regeneration, yet low transduction efficiency has been a persistent challenge for in vivo applications. In this report, we investigated the surface modification of poly(lactide-co-glycolide) (PLG) scaffolds with polysaccharides, which have been implicated in binding lentivirus but have not been used for delivery. Chitosan was directly conjugated onto PLG scaffolds, whereas heparin and hyaluronan were indirectly conjugated onto PLG scaffolds with multi-amine crosslinkers. The addition of chitosan and heparin onto PLG promoted the association of lentivirus to these scaffolds and enhanced their transduction efficiency in vitro relative to hyaluronan-conjugated and control scaffolds that had limited lentivirus association and transduction. Transduction efficiency in vitro was increased partly due to an enhanced retention of virus on the scaffold as well as an extended half-life of viral activity. Transduction efficiency was also evaluated in vivo using porous, multiple channel PLG bridges that delivered lentivirus to the injured mouse spinal cord. Transgene expression persisted for weeks after implantation, and was able to enhance axon growth and myelination. These studies support gene delivering PLG scaffolds for in vivo regenerative medicine applications. PMID- 23791983 TI - Orexin modulation of adipose tissue. AB - The orexins are neuropeptides with critical functions in the central nervous system. These neuropeptides have important roles in energy balance and obesity, and therefore on the accumulation of adipose tissue. Rodents lacking orexins, typically through genetic knockouts, experience increased weight gain and accumulation of adipose tissue. Evidence indicates that the lack of the orexins increase adiposity as a result of decreased energy expenditure, principally through a reduction of physical activity. Different lines of evidence suggest that other mechanisms are likely also in play, and neural influences on both white and brown adipose tissues remain to be fully and functionally defined. In addition, the orexin peptides and their receptors are expressed in adipose tissue, with little available information as to their significance. This review summarizes our current understanding of how the orexin peptides affect adipose tissue. We provide a brief introduction to the physiology of orexins and their effects on white and brown adipose tissues in the context of energy balance. We conclude this review by integrating this information in the context of the known physiology of the orexins. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease. PMID- 23791984 TI - Management of bile duct leaks. AB - The cause of bile duct leaks can be either iatrogenic or more rarely, traumatic. The most common cause is related to laparoscopic cholecystectomy. While surgical repair has been the standard for many years, management in these often morbid and complex situations must currently be multidisciplinary incorporating the talents of interventional radiologists and endoscopists. Based on the literature and in particular the recent recommendations of the European Society of Gastrointestinal Endoscopy (ESGE), this review aims to update the management strategy. The incidence of these complications decreases with surgeon experience attesting to the value of training to prevent these injuries. Bile duct injuries must be categorized and their mapping detailed by magnetic resonance cholangiography MRCP or endoscopic cholangiography (ERCP) when endoscopic therapy is considered. Endoscopic management should be preferred in the absence of complete circumferential interruption of the common bile duct. The ESGE recommends insertion of a plastic stent for 4 to 8 weeks without routine sphincterotomy. For complete circumferential injuries, hepaticojejunostomy is usually necessary. In conclusion, adequate training of surgeons is essential for prevention since the incidence of bile duct injury decreases with experience. Faced with a bile duct injury, a multidisciplinary team approach, involving radiologists, endoscopists and surgeons improves patient outcome. PMID- 23791985 TI - Th1/Th2/Th17/Treg cytokines in Guillain-Barre syndrome and experimental autoimmune neuritis. AB - Guillain-Barre syndrome (GBS) is an immune-mediated acute inflammatory disorder in the peripheral nervous system (PNS) of humans characterized by inflammatory infiltration and damage to myelin and axon. Experimental autoimmune neuritis (EAN) is a useful animal model for GBS. Although GBS and EAN have been widely studied, the pathophysiological basis of GBS/EAN remains largely unknown. Immunocompetent cells together with cytokines produced by various cells contribute to the inflammatory process of EAN by acting as mediators or effectors. Both GBS and EAN have hitherto been attributed to T helper (Th)1 cells mediated disorders, however, some changes in GBS and EAN could not be explained by the pathogenic role of Th1 cells and a disturbance of the Th1/Th2 balance, which has previously been considered to be important for the homeostatic maintenance of the immune responses and to explain the adaptive immunity and autoimmune diseases. The Th1/Th2 paradigm in autoimmune diseases has been greatly challenged in recent years, with the identification of a particular T cell subset Th17 cells. Studies on the associations between Th17 cells/cytokines and GBS/EAN are reviewed. But some of them occasionally yield conflicting results, indicating an intricate network of cytokines in immune response. PMID- 23791986 TI - The role of IL-15 in gastrointestinal diseases: a bridge between innate and adaptive immune response. AB - IL-15 is a member of the IL-2 family of cytokines whose signaling pathways are a bridge between innate and adaptive immune response. IL-15 is part of the intestinal mucosal barrier, and functions to modulate gut homeostasis. IL-15 has pivotal roles in the control of development, proliferation and survival of both innate and adaptive immune cells. IL-15 becomes up-regulated in the inflamed tissue of intestinal inflammatory disease, such as IBD, Celiac Disease and related complications. Indeed, several studies have reported that IL-15 may participate to the pathogenesis of these diseases. Furthermore, although IL-15 seems to be responsible for inflammation and autoimmunity, it also may increase the immune response against cancer. For these reasons, we decided to study the intestinal mucosa as an 'immunological niche', in which immune response, inflammation and local homeostasis are modulated. Understanding the role of the IL-15/IL-15R system will provide a scientific basis for the development of new approaches that use IL-15 for immunotherapy of autoimmune diseases and malignancies. Indeed, a better understanding of the complexity of the mucosal immune system will contribute to the general understanding of immuno-pathology, which could lead to new therapeutical tools for widespread immuno-mediated diseases. PMID- 23791987 TI - Reply by authors. PMID- 23791988 TI - Editorial comment. PMID- 23791989 TI - Editorial comment. PMID- 23791990 TI - Improvements in minimally invasive stone treatment: experimental studies. PMID- 23791991 TI - Editorial comment. PMID- 23791992 TI - Reply by author. PMID- 23791993 TI - Editorial comment. PMID- 23791994 TI - Reply by author. PMID- 23791995 TI - Editorial comment. PMID- 23791996 TI - Reply by authors. PMID- 23791997 TI - Reply by author. PMID- 23791998 TI - Editorial comment. PMID- 23791999 TI - Reply by authors. PMID- 23792000 TI - Editorial comment. PMID- 23792001 TI - Editorial comment. PMID- 23792002 TI - Evolution of phototransduction, vertebrate photoreceptors and retina. AB - Evidence is reviewed from a wide range of studies relevant to the evolution of vertebrate photoreceptors and phototransduction, in order to permit the synthesis of a scenario for the major steps that occurred during the evolution of cones, rods and the vertebrate retina. The ancestral opsin originated more than 700 Mya (million years ago) and duplicated to form three branches before cnidarians diverged from our own lineage. During chordate evolution, ciliary opsins (C opsins) underwent multiple stages of improvement, giving rise to the 'bleaching' opsins that characterise cones and rods. Prior to the '2R' rounds of whole genome duplication near the base of the vertebrate lineage, 'cone' photoreceptors already existed; they possessed a transduction cascade essentially the same as in modern cones, along with two classes of opsin: SWS and LWS (short- and long-wave sensitive). These cones appear to have made synaptic contact directly onto ganglion cells, in a two-layered retina that resembled the pineal organ of extant non-mammalian vertebrates. Interestingly, those ganglion cells appear to be descendants of microvillar photoreceptor cells. No lens was associated with this two-layered retina, and it is likely to have mediated circadian timing rather than spatial vision. Subsequently, retinal bipolar cells evolved, as variants of ciliary photoreceptors, and greatly increased the computational power of the retina. With the advent of a lens and extraocular muscles, spatial imaging information became available for central processing, and gave rise to vision in vertebrates more than 500 Mya. The '2R' genome duplications permitted the refinement of cascade components suitable for both rods and cones, and also led to the emergence of five visual opsins. The exact timing of the emergence of 'true rods' is not yet clear, but it may not have occurred until after the divergence of jawed and jawless vertebrates. PMID- 23792003 TI - Investigation of antileishmanial activities of Tio2@Ag nanoparticles on biological properties of L. tropica and L. infantum parasites, in vitro. AB - Leishmaniasis is a public health problem which is caused by protozoon parasites belonging to Leishmania species. The disease threatens approximately 350 million people in 98 countries all over the world. Cutaneous Leishmaniasis (CL) and Visceral Leishmaniasis (VL) are the mostly commonly seen forms of the disease. Treatment of the disease has remained insufficient since current antileishmanial drugs have several disadvantages such as toxicity, costliness and drug resistance. Therefore, there is an immediate need to search for new antileishmanial compounds. TiO2@Ag nanoparticles (TiAg-Nps) have been demonstrated as promising antimicrobial agents since they provide inhibition of several types of bacteria. The basic antimicrobial mechanism of TiAg-Nps is the generation of reactive oxygen species (ROS). Even though Leishmania parasites are sensitive to ROS, there is no study in literature indicating antileishmanial activities of TiAg-Nps. Herein, in this study, TiAg-Nps are shown to possess antileishmanial effects on Leishmania tropica and Leishmania infantum parasites by inhibiting their biological properties such as viability, metabolic activity, and survival within host cells both in the dark and under visible light. The results indicate that TiAg-Nps decreased viability values of L. tropica, and L. infantum promastigotes 3- and 10-fold, respectively, in the dark, while these rates diminished approximately 20-fold for each species in the presence of visible light, in contrast to control. On the other hand, non-visible light exposed TiAg-Nps inhibited survival of amastigotes nearly 2- and 2.5-fold; while visible light-exposed TiAg-Nps inhibited 4- and 4.5-fold for L. tropica and L. infantum parasites, respectively. Consequently, it was determined that non visible light-exposed TiAg-Nps were more effective against L. infantum parasites while visible light-exposed TiAg-Nps exhibited nearly the same antileishmanial effect against both species. Therefore, we think that a combination of TiAg-Nps and visible light can be further used for treatment of CL, while application of TiAg-Nps alone can be a promising alternative in VL treatment. PMID- 23792004 TI - Effects of macrocyclic lactones on the reproductive parameters of engorged Rhipicephalus (Boophilus) microplus females detached from experimentally infested cattle. AB - The present study therefore assessed the deleterious effects of MLs (ivermectin, abamectin, doramectin and moxidectin) on the reproductive parameters of engorged Rhipicephalus (Boophilus) microplus females that naturally detached from experimentally infested cattle in two experiments. The following reproductive parameters of engorged female ticks were analyzed: female weight, egg mass weight, percentage of hatchability, percentage of reduction in oviposition, percentage of reduction in hatchability, reproductive efficiency and percent control/efficacy of formulations with respect to reproductive parameters. In the experiment I, statistical analysis of the data grouped into 5-days intervals revealed that pour-on application of abamectin (500 mcg/kg) had significantly (p <= 0.05) reduced engorged female weight, egg mass weight and percent hatchability on days 6-15, 6-20 and 11-20 post-treatment (p. t.) compared to the respective data for detached and pre-selected engorged females in the control group. The abamectin, demonstrated 33.41% of reduction in oviposition, 6.77% in hatchability and abamectin efficacy was of 13.99%. In the experiment II, statistically significant reductions (p >= 0.05) were observed in animals treated subcutaneous with ivermectin (630 mcg/kg), doramectin (700 mcg/kg) and moxidectin (1000 mcg/kg) relative to the control for days 6-40, 6-48 and 6-40 p. t., respectively. Ivermectin reduced hatchability only on days 16-20 p. t., whereas doramectin significantly reduced (p <= 0.05) hatchability on days 6-10 and 16-35 p. t. For moxidectin, deleterious effects on hatchability were observed on days 16-35 p. t. The percent reductions in oviposition of engorged female ticks were 46.31%, 62.17% and 61.02% with ivermectin, doramectin and moxidectin treatments, respectively. The percent efficacy of the formulations on the reproductive parameters of engorged female ticks was 21.22% for ivermectin, 36.03% for doramectin and 35.45% for moxidectin. Among the MLs assessed, doramectin and moxidectin had the highest acaricidal efficacies and the most deleterious effects on the reproductive parameters of engorged R. (B.) microplus females. However, future studies will be necessary to assess the extent to which these effects, along with acaricidal activity, can be used to control the ectoparasite in cattle. PMID- 23792005 TI - Actin polymerization mediated by Babesia gibsoni aldolase is required for parasite invasion. AB - Host cell invasion by apicomplexan parasites driven by gliding motility and empowered by actin-based movement is essential for parasite survival and pathogenicity. The parasites share a conserved invasion process: actin-based motility led by the coordination of adhesin-cytoskeleton via aldolase. A number of studies of host cell invasion in the Plasmodium species and Toxoplasma gondii have been performed. However, the mechanisms of host cell invasion by Babesia species have not yet been studied. Here, we show that Babesia gibsoni aldolase (BgALD) forms a complex with B. gibsoni thrombospondin-related anonymous protein (BgTRAP) and B. gibsoni actin (BgACT), depending on tryptophan-734 (W-734) in BgTRAP. In addition, actin polymerization is mediated by BgALD. Moreover, cytochalasin D, which disrupts actin polymerization, suppressed B. gibsoni parasite growth and inhibited the host cell invasion by parasites, indicating that actin dynamics are essential for erythrocyte invasion by B. gibsoni. This study is the first molecular approach to determine the invasion mechanisms of Babesia species. PMID- 23792006 TI - Increased incidence of dog-bite injuries after the Fukushima nuclear accident. AB - OBJECTIVE: The objective of this study is to assess the localized incidence of dog bites following the nuclear accident related to the Great East Japan Earthquake in March 2011. METHODS: We identified the patients with dog bites in our hospital in Minamisoma City, Fukushima, during the period from 1year prior to the earthquake to 3.5months following it, and calculated the monthly and weekly incidence proportions by dividing the patient number by the total emergency room visits. We also analyzed the data by the characteristics of the patients. RESULTS: We identified 27 dog-bite cases during the post-disaster period. The median monthly incidence proportion during the pre-disaster period and the highest monthly incidence proportion during the post-disaster period were 0.21 and 6.50 per 100 visits, respectively. The weekly incidence proportion peaked at 3weeks after the earthquake and thereafter decreased to the baseline level. CONCLUSION: The Fukushima nuclear accident may be associated with an increased incidence of dog bites, and the prolonged evacuation in response to the radiation contamination may have prolonged the increased incidence after the disaster. Physicians and local residents should recognize this potential hazard. Countermeasures to contend with this risk should be a mandatory aspect of disaster preparedness, including for nuclear accidents. PMID- 23792007 TI - Age-related neuropsychiatric symptoms in presenilins conditional double knockout mice. AB - Alzheimer's disease (AD) is the most common form of dementia and causes impairments of memory, cognition and behavior. Remarkably, most AD patients exhibit personality changes that often precede other early clinical manifestations. Conditional presenilin1 (PS1) and presenilin2 (PS2) double knockout (DKO) mice have age-related forebrain atrophy, tau hyperphosphorylation, synaptic dysfunction, cognitive deficits and increased inflammatory responses in both the periphery and the brain. Whether these mice have age-related emotional changes have not yet been investigated. In the present study, we used 2-, 6- and 11-month-old DKO and littermate control (CON) mice to examine their age-related emotional conditions. Our results indicate that DKO mice have observable age related neuropsychiatric symptoms, such as anxiety, irritability, depression, apathy, aggressivity, anhedonia and aberrant motor behavior when compared with other AD-like mouse models. In summary, our results not only indicate that DKO mice may be a valuable model for probing age-related AD diagnoses but also suggest a new pathogenesis of neurodegenerative diseases that is worth further investigation. PMID- 23792008 TI - The differences of biological behavior based on the clinicopathological data between resectable large-cell neuroendocrine carcinoma and small-cell lung carcinoma. AB - INTRODUCTION: Large cell neuroendocrine carcinoma of the lung and SCLC are collectively classified as high-grade NECs. However, there have been few reports focusing on the differences of clinicopathological prognostic factors between resectable LCNEC and SCLC. PATIENTS AND METHODS: We reviewed the clinical data of 140 patients who underwent complete resection of high grade NEC in our institute and analyzed the clinicopathological features in relation to their survival. RESULTS: There were no statistically significant differences in overall and recurrence-free survival between pure and combined subtypes in either LCNEC or SCLC. In LCNEC, larger tumor diameter (P = .01), nodal metastasis (P < .01), lymphatic permeation (P < .01), and vascular invasion (P = .01) were unfavorable prognostic factors. However, in SCLC, tumor diameter and vascular invasion were not prognostic factors, but nodal metastasis (P < .01) and lymphatic permeation (P = .03) were strongly correlated with poor prognosis. CONCLUSION: There were no apparent differences in biological behavior between pure and combined subtypes in either LCNEC or SCLC. Lymphatic involvement was an important unfavorable prognostic factor in SCLC, whereas tumor diameter, vascular invasion, and lymphatic involvement had a poor prognostic effect in LCNEC. PMID- 23792009 TI - Patients treated with platinum-doublet chemotherapy for advanced non--small-cell lung cancer have inferior outcomes if previously treated with platinum-based chemoradiation. AB - INTRODUCTION: The standard of care for locoregionally advanced non-small-cell lung cancer is concurrent platinum-based chemoradiation. Many patients relapse, and subsequent systemic treatment may involve platinum-doublet chemotherapy. It is not known if prior platinum-based chemoradiation influences the response to platinum-based chemotherapy given subsequently for relapse. Therefore, we compared outcomes in these patients with those in patients without prior treatment. METHODS: A retrospective study of patients who had been treated with carboplatin and gemcitabine chemotherapy for de novo metastatic disease or recurrent non--small-cell lung cancer after receiving platinum-based chemoradiation. The primary outcome was progression-free survival (PFS). RESULTS: A total of 104 patients were analyzed. The median age was 63 years (range, 35-81 years), with 63 (61%) patients with newly diagnosed disease and with 41 (39%) who were previously treated. The response rate was significantly lower for those previously exposed to chemoradiation (10% vs. 29%: P = .001), as was the median PFS (3.6 months vs. 5.7 months; P = .002), and median overall survival (OS) (8.6 months vs. 12.1 months; P = .007). Only the treatment group was a significant predictor (P = .032) of PFS by univariate analysis. In univariate analysis; sex (men; P = .04), histology (squamous cell; P = .04), Eastern Cooperative Oncology Group Performance Status Scale (P = .002), and treatment group (P = .023) predicted significantly inferior OS. Multivariate analysis showed that performance status was the only significant predictor of inferior OS. CONCLUSION: Outcomes were inferior in patients previously exposed to platinum-based chemoradiation. An approach of stratifying such patients in future trials of chemotherapy should be adopted. Alternative options such as non--platinum-based agents or targeted therapies should be considered in this group. PMID- 23792010 TI - The TNF cytokine family: one track in a road paved by many. AB - During the quarter of a century since TNF was isolated, much knowledge has been gained of the identity of other ligands besides TNF in the TNF cytokine family, and of the proximal signaling molecules that these ligands activate. The numerous laboratories contributing to this advance have approached TNF research from various points of view. The research pathway taken in my own laboratory, which is outlined in this article, has been driven by the desire to elucidate mechanisms that regulate cell death. PMID- 23792011 TI - A first report of Anopheles funestus sibling species in western Kenya highlands. AB - Understanding disease vector composition is of priority in designing effective disease control programs. In integrated vector control management, understanding of disease vector species among species complexes simplifies priorities for effective control tools selection. This study identified members of the Anopheles funestus complex sampled in western Kenya from 2002 to 2011 from different breeding sites. Larval sampling was carried out using the standard dipper (350ml) in larval habitats in western Kenya highlands from January 2002 to December 2012. The morphologically identified An. funestus larvae were preserved in absolute ethanol for molecular identification using polymerase chain reaction (PCR). Among the 184 identified specimens of An. funestus sampled, only 76 specimens were clearly identified after DNA amplification and PCR. Among these, 25 (32.9%) were An. funestus s.s, 22 (28.9%) An. leesoni, 9 (11.8%) An. rivulorum and 20 (26.3%) were An. vaneedeni. None was identified as An. parensis. This study has demonstrated the existence of the siblings species of An. funestus complex in western Kenya highlands. However, there is need for further studies to evaluate the dynamics of the adults and sporozoite infectivity rates throughout the region based on these findings. PMID- 23792012 TI - Towards effective prevention and control of helminth neglected tropical diseases in the Western Pacific Region through multi-disease and multi-sectoral interventions. AB - Neglected tropical diseases (NTDs) cause serious health, social and economic burdens in the countries of the World Health Organization Western Pacific Region. Among the NTDs, helminth infections are particularly prominent with regard to the number of infected individuals and health impact. Co-endemicity is common among impoverished and marginalized populations. To achieve effective and sustainable control of helminth NTDs, a deeper understanding of the social-ecological systems governing their endemicity and strategies beyond preventive chemotherapy are required to tackle the multiple causes of infection and re-infection. We discuss the feasibility of implementing multi-disease, multi-sectoral intervention packages for helminth NTDs in the Western Pacific Region. After reviewing the main determinants for helminth NTD endemicity and current control strategies, key control activities that involve or concern other programmes within and beyond the health sector are discussed. A considerable number of activities that have an impact on more than one helminth NTD are identified in a variety of sectors, suggesting an untapped potential for synergies. We also highlight the challenges of multi-sectoral collaboration, particularly of involving non-health sectors. We conclude that multi-sectoral collaboration for helminth NTD control is feasible if the target diseases and sectors are carefully selected. To do so, an incentive analysis covering key stakeholders in the sectors is crucial, and the disease control strategies need to be well understood. The benefits of multi-disease, multi-sectoral approaches could go beyond immediate health impacts by contributing to sustainable development, raising educational attainment, increasing productivity and reducing health inequities. PMID- 23792013 TI - Liposome clusters with shear stress-induced membrane permeability. AB - Clusters of negatively charged liposomes were prepared by the addition of Ca(2+) and characterized in their structure and membrane permeability under shear stress. The liposomes mainly used were composed of zwitterionic 1-palmitoyl-2 oleoyl-sn-glycero-3-phosphocholine (POPC), 20 mol% negatively charged 1-palmitoyl 2-oleoyl-sn-glycero-3-phosphoglycerol (POPG) and 30 mol% cholesterol. The liposomes with mean diameter of 193 nm were aggregated into the clusters with a distribution peak at about 1.5 MUm in the 50mM Tris buffer solution of pH 8.5 at the lipid and Ca(2+) concentrations of 1.0mM and 40 mM, respectively. More than 90% of liposomes were redispersed at the Ca(2+) concentration of 80 mM. POPG-rich liposomes (POPC/POPG/cholesterol=5:65:30 [lipid]=1.0mM) were irreversibly aggregated at [Ca(2+)]>= 10 mM, indicating the significant contribution of POPC to the reversible clustering of liposomes. The membranes of liposome clusters were impermeable to 5(6)-carboxyfluorescein (CF) in the static liquid system at 25 degrees C due to the decrease in specific surface area of the liposomal system. In the shear flow, in clear contrast, continuous membrane permeation of CF was observed at the shear rate of 1.5 * 10(3)s(-1), exhibiting comparable membrane permeability to the non-clustered liposomes. The theoretical analysis of modified DLVO potential indicated that liposome membranes were not in contact with each other within the clusters. Therefore, the liposome clusters are structurally flexible under the applied shear stress, providing sufficient lipid membrane-water interfacial area for the permeation of CF. The results obtained would be important to control the formation of liposome clusters and their permeabilization for biochemical and biomedical applications. PMID- 23792014 TI - Evolutionary anthropology and genes: investigating the genetics of human evolution from excavated skeletal remains. AB - The development of molecular tools for the extraction, analysis and interpretation of DNA from the remains of ancient organisms (paleogenetics) has revolutionised a range of disciplines as diverse as the fields of human evolution, bioarchaeology, epidemiology, microbiology, taxonomy and population genetics. The paper draws attention to some of the challenges associated with the extraction and interpretation of ancient DNA from archaeological material, and then reviews the influence of paleogenetics on the field of human evolution. It discusses the main contributions of molecular studies to reconstructing the evolutionary and phylogenetic relationships between extinct hominins (human ancestors) and anatomically modern humans. It also explores the evidence for evolutionary changes in the genetic structure of anatomically modern humans in recent millennia. This breadth of research has led to discoveries that would never have been possible using traditional approaches to human evolution. PMID- 23792015 TI - TRAIL mRNA expression in peripheral blood mononuclear cells of Egyptian SLE patients. AB - Although the definite etiopathogenesis of systemic lupus erythematosus (SLE) remains unclear, many different mechanisms may contribute to its pathogenesis. Tumor-necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor (TNF) family with pro-apoptotic activity. The accumulation of apoptotic cell debris has been hypothesized to induce the autoimmune inflammation in SLE, and TRAIL may trigger this programmed cell death. We investigated TRAIL mRNA expression levels in peripheral blood mononuclear cells (PBMCs) from 60 SLE patients and 40 controls using quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR), and we studied the association between the results and clinical and laboratory parameters of the patients. Expression levels of TRAIL mRNAs in SLE patients were significantly higher than in controls (p<0.001). A statistically significant association was detected between TRAIL mRNA expression and SLE activity (p=0.001). PMID- 23792017 TI - Cyclooxygenase-2 169C>G and 8473T>C gene polymorphisms and prostaglandin E2 level in breast cancer: a case-control study. AB - AIMS: Cyclooxygenase 2 (COX-2) with the resulting prostaglandin E2 (PGE2) is linked to increased risk of human breast cancer (BC). The aim of this study was to determine COX-2 169C>G and 8473T>C gene polymorphisms and PGE2 level at various stages of BC clarifying the role of COX-2 gene polymorphism and PGE2 in relation to BC. METHODS: The study population comprised 160 women at different stages of BC and 150 gender- and age-matched healthy control subjects. Plasma PGE2 was measured by ELISA, the COX-2 gene polymorphisms were determined using PCR-RFLP. RESULTS: The variant alleles COX-2 169G and 8473C were significantly associated with BC susceptibility [OR=3.1, 95% CI (2.2-4.4), P<0.001 for 169C>G and OR=1.74, 95%CI (1.3-2.4), P=0.005 for 8473C]. However, both COX-2 gene polymorphisms were not associated with breast cancer stage. Plasma PGE2 levels were significantly increased in patients compared to the controls. In early and late stages of BC, there was a significant increase in the plasma PGE2 levels towards the presence of homozygous GG compared with homozygous CC (P<0.001) for 169 C>G, also towards the presence of CC than TT (P<0.001) for 8473T>C SNP. CONCLUSION: The 169C>G and 8473T>C polymorphisms of the COX-2 gene were associated with the BC in Egyptian women. Furthermore, individuals with COX-2 169GG and 8473CC genotypes showed significant increase in plasma PGE2 levels. PGE2 levels may serve as a predictor of poor prognosis in patients with BC. PMID- 23792016 TI - Novel polymorphisms in UTR and coding region of inducible heat shock protein 70.1 gene in tropically adapted Indian zebu cattle (Bos indicus) and riverine buffalo (Bubalus bubalis). AB - Due to evolutionary divergence, cattle (taurine, and indicine) and buffalo are speculated to have different responses to heat stress condition. Variation in candidate genes associated with a heat-shock response may provide an insight into the dissimilarity and suggest targets for intervention. The present work was undertaken to characterize one of the inducible heat shock protein genes promoter and coding regions in diverse breeds of Indian zebu cattle and buffaloes. The genomic DNA from a panel of 117 unrelated animals representing 14 diversified native cattle breeds and 6 buffalo breeds were utilized to determine the complete sequence and gene diversity of HSP70.1 gene. The coding region of HSP70.1 gene in Indian zebu cattle, Bos taurus and buffalo was similar in length (1,926 bp) encoding a HSP70 protein of 641 amino acids with a calculated molecular weight (Mw) of 70.26 kDa. However buffalo had a longer 5' and 3' untranslated region (UTR) of 204 and 293 nucleotides respectively, in comparison to Indian zebu cattle and Bos taurus wherein length of 5' and 3'-UTR was 172 and 286 nucleotides, respectively. The increased length of buffalo HSP70.1 gene compared to indicine and taurine gene was due to two insertions each in 5' and 3'-UTR. Comparative sequence analysis of cattle (taurine and indicine) and buffalo HSP70.1 gene revealed a total of 54 gene variations (50 SNPs and 4 INDELs) among the three species in the HSP70.1 gene. The minor allele frequencies of these nucleotide variations varied from 0.03 to 0.5 with an average of 0.26. Among the 14 B. indicus cattle breeds studied, a total of 19 polymorphic sites were identified: 4 in the 5'-UTR and 15 in the coding region (of these 2 were non synonymous). Analysis among buffalo breeds revealed 15 SNPs throughout the gene: 6 at the 5' flanking region and 9 in the coding region. In bubaline 5'-UTR, 2 additional putative transcription factor binding sites (Elk-1 and C-Re1) were identified, other than three common sites (CP2, HSE and Pax-4) observed across all the analyzed animals. No polymorphism was found within the 3'-UTR of Indian cattle or buffalo as it was found to be monomorphic. The promoter sequences generated in 117 individuals showed a rich array of sequence elements known to be involved in transcription regulation. A total of 11 nucleotide changes were observed in the promoter sequence across the analyzed species, 3 of these changes were located within the potential transcription factor binding domains. We also identified 4 microsatellite markers within the buffalo HSP70.1 gene and 3 microsatellites within bovine HSP70.1. The present study identified several distinct changes across indicine, taurine and bubaline HSP70.1 genes that could further be evaluated as molecular markers for thermotolerance. PMID- 23792018 TI - Molecular characterisation and expression analysis of interferon gamma in response to natural Chlamydia infection in the koala, Phascolarctos cinereus. AB - Interferon gamma (IFNgamma) is a key Th1 cytokine, with a principal role in the immune response against intracellular organisms such as Chlamydia. Along with being responsible for significant morbidity in human populations, Chlamydia is also responsible for wide spread infection and disease in many animal hosts, with reports that many Australian koala subpopulations are endemically infected. An understanding of the role played by IFNgamma in koala chlamydial diseases is important for the establishment of better prophylactic and therapeutic approaches against chlamydial infection in this host. A limited number of IFNgamma sequences have been published from marsupials and no immune reagents to measure expression have been developed. Through preliminary analysis of the koala transcriptome, we have identified the full coding sequence of the koala IFNgamma gene. Transcripts were identified in spleen and lymph node tissue samples. Phylogenetic analysis demonstrated that koala IFNgamma is closely related to other marsupial IFNgamma sequences and more distantly related to eutherian mammals. To begin to characterise the role of this important cytokine in the koala's response to chlamydial infection, we developed a quantitative real time PCR assay and applied it to a small cohort of koalas with and without active chlamydial disease, revealing significant differences in expression patterns between the groups. Description of the IFNgamma sequence from the koala will not only assist in understanding this species' response to its most important pathogen but will also provide further insight into the evolution of the marsupial immune system. PMID- 23792019 TI - Association study of CD36 single nucleotide polymorphisms with essential hypertension in the Northeastern Han Chinese. AB - We found that cluster determinant 36 (CD36) gene is up-regulated in essential hypertension (EH) patients in our former research, but the association between CD36 gene variations and EH has not yet been clearly demonstrated. The relationship between CD36 gene single nucleotide polymorphisms (SNPs) and EH in the northeastern Han Chinese was examined in the present study through direct sequencing and genotype-detection. A total of 589 unrelated northeastern Han Chinese including 276 with EH and 313 controls were studied. SNPs in exon 7, exon 13 and intron 4 were detected using PCR-sequencing. The genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). +216T/C, +273A/G, +132C/T, +217T/C, +212T/G and +233T/C polymorphisms were identified. Distributions of genotypes AA, GA and GG of +273A/G polymorphism were significantly different between EH group and the control group (chi2: 9.056, p=0.011) and G allelic frequency was higher in EH (p=0.006, OR=1.629, 95% CI [1.224-2.168]). Logistic regression analysis showed that +273A/G polymorphism was closely associated with blood pressure (BP) after adjusting for ages. When subclassified by sex, the genotype distribution of +273A/G (p=0.011) and allelic frequency of G allele (p=0.006) were significantly different between EH participants and controls in males, but not in females. Subgroup analysis performed by body mass index (BMI) suggested that the genotype distribution of +273A/G and allelic frequency were significantly different in non-obese group and non-obese men, but the associations were not significant (non-obese group: p=0.016, OR=1.664, 95% CI [1.459-2.409]; non-obese men: p=0.073, OR=1.898, 95% CI [1.033-3.487]). +273A/G polymorphism in CD36 gene was associated with EH, and +273G could be an independent predictor. PMID- 23792022 TI - The role of the hippocampo-prefrontal cortex system in phencyclidine-induced psychosis: a model for schizophrenia. AB - Phencyclidine (PCP) is a psychotomimetic drug that induces schizophrenia-like symptoms in healthy individuals and exacerbates pre-existing symptoms in patients with schizophrenia. PCP also induces behavioral and cognitive abnormalities in non-human animals, and PCP-treated animals are considered a reliable pharmacological model of schizophrenia. However, the exact neural mechanisms by which PCP modulates behavior are not known. During the last decade several studies have indicated that disturbed activity of the prefrontal cortex (PFC) may be closely related to PCP-induced psychosis. Systemic administration of PCP produces long-lasting activation of medial PFC (mPFC) neurons in rats, almost in parallel with augmentation of locomotor activity and behavioral stereotypies. Later studies have showed that such PCP-induced behavioral abnormalities are ameliorated by prior administration of drugs that normalize or inhibit excess excitability of PFC neurons. Similar activation of mPFC neurons is not induced by systemic injection of a typical psychostimulant such as methamphetamine, even though behavioral hyperactivity is induced to almost the same level. This suggests that the neural circuits mediating PCP-induced psychosis are different to those mediating methamphetamine-induced psychosis. Locally applied PCP does not induce excitation of mPFC neurons, indicating that PCP-induced tonic excitation of mPFC neurons is mediated by inputs from regions outside the mPFC. This hypothesis is strongly supported by experimental results showing that local perfusion of PCP in the ventral hippocampus, which has dense fiber projections to the mPFC, induces tonic activation of mPFC neurons with accompanying augmentation of behavioral abnormalities. In this review we summarize current knowledge on the neural mechanisms underlying PCP-induced psychosis and highlight a possible involvement of the PFC and the hippocampus in PCP-induced psychosis. PMID- 23792021 TI - Distributed neural networks of tactile working memory. AB - Microelectrode recordings of cortical activity in primates performing working memory tasks reveal some cortical neurons exhibiting sustained or graded persistent elevations in firing rate during the period in which sensory information is actively maintained in short-term memory. These neurons are called "memory cells". Imaging and transcranial magnetic stimulation studies indicate that memory cells may arise from distributed cortical networks. Depending on the sensory modality of the memorandum in working memory tasks, neurons exhibiting memory-correlated patterns of firing have been detected in different association cortices including prefrontal cortex, and primary sensory cortices as well. Here we elaborate on neurophysiological experiments that lead to our understanding of the neuromechanisms of working memory, and mainly discuss findings on widely distributed cortical networks involved in tactile working memory. PMID- 23792020 TI - Set and setting: how behavioral state regulates sensory function and plasticity. AB - Recently developed neuroimaging and electrophysiological techniques are allowing us to answer fundamental questions about how behavioral states regulate our perception of the external environment. Studies using these techniques have yielded surprising insights into how sensory processing is affected at the earliest stages by attention and motivation, and how new sensory information received during wakefulness (e.g., during learning) continues to affect sensory brain circuits (leading to plastic changes) during subsequent sleep. This review aims to describe how brain states affect sensory response properties among neurons in primary and secondary sensory cortices, and how this relates to psychophysical detection thresholds and performance on sensory discrimination tasks. This is not intended to serve as a comprehensive overview of all brain states, or all sensory systems, but instead as an illustrative description of how three specific state variables (attention, motivation, and vigilance [i.e., sleep vs. wakefulness]) affect sensory systems in which they have been best studied. PMID- 23792023 TI - Genomic code for Sox2 binding uncovers its regulatory role in Six3 activation in the forebrain. AB - The SRY-related HMG box transcription factor Sox2 plays critical roles throughout embryogenesis. Haploinsufficiency for SOX2 results in human developmental defects including anophthalmia, microphthalmia and septo-optic dysplasia, a congenital forebrain defect. To understand how Sox2 plays a role in neurogenesis, we combined genomic and in vivo transgenic approaches to characterize genomic regions occupied by Sox2 in the developing forebrain. Six3, a homeobox gene associated with holoprosencephaly, a forebrain midline defect, was identified as a Sox2 transcriptional target. This study shows that Sox2 directly regulates a previously unidentified long-range forebrain enhancer to activate Six3 expression in the rostral diencephalon. Further biochemical and genetic evidences indicated a direct regulatory link between Sox2 and Six3 during forebrain development, providing a better understanding of a common molecular mechanism underlying these forebrain defects. PMID- 23792024 TI - Ceramide metabolism in mouse tissue. AB - Ceramides with different N-acyl chains can act as second messengers in various signaling pathways. They are involved in cell processes such as apoptosis, differentiation and inflammation. Ceramide synthases (CerS) are key enzymes in the biosynthesis of ceramides and dihydroceramides. Six isoenzymes (CerS1-6) catalyze the N-acylation of the sphingoid bases, albeit with strictly acyl Coenzyme A (CoA) chain length specificity. We analyzed the mRNA expression, the protein expression, the specific activity of the CerS, and acyl-CoA, dihydroceramide and ceramide levels in different tissues by LC-MS/MS. Our data indicate that each tissue express a distinct composition of CerS, whereby the CerS mRNA expression levels do not correlate with the respective protein expression levels in the tissues. Furthermore, we found a highly significant negative correlation between the protein expression level of CerS6 and the C16:0 acyl-CoA amounts as well as between the protein expression of CerS2 and C24:0 acyl-CoA amounts. These data indicate that in mouse tissues low substrate availability is compensated by higher CerS protein expression level and vice versa. Apart from the expression level and the specific activity of the CerS, other enzymes of the sphingolipid pathway also influence the composition of ceramides with distinct chain lengths in each cell. Acyl-CoA availability seems to be less important for ceramide composition and might be compensated for by CerS expression/activity. PMID- 23792025 TI - Monogenic heritable autism gene neuroligin impacts Drosophila social behaviour. AB - Autism spectrum disorders (ASDs) are characterized by deficits in social interactions, language development and repetitive behaviours. Multiple genes involved in the formation, specification and maintenance of synapses have been identified as risk factors for ASDs development. Among these are the neuroligin genes which code for postsynaptic cell adhesion molecules that induce the formation of presynapses, promote their maturation and modulate synaptic functions in both vertebrates and invertebrates. Neuroligin-deficient mice display abnormal social and vocal behaviours that resemble ASDs symptoms. Here we show for the fly Drosophila melanogaster that deletion of the dnl2 gene, coding for one of four Neuroligin isoforms, impairs social interactions, alters acoustic communication signals, and affects the transition between different behaviours. dnl2-Deficient flies maintain larger distances to conspecifics and males perform less female-directed courtship and male-directed aggressive behaviours while the patterns of these behaviours and general locomotor activity were not different from wild type controls. Since tests for olfactory, visual and auditory perception revealed no sensory impairments of dnl2-deficient mutants, reduced social interactions seem to result from altered excitability in central nervous neuropils that initiate social behaviours. Our results demonstrate that Neuroligins are phylogenetically conserved not only regarding their structure and direct function at the synapse but also concerning a shared implication in the regulation of social behaviours that dates back to common ancestors of humans and flies. In addition to previously described mouse models, Drosophila can thus be used to study the contribution of Neuroligins to synaptic function, social interactions and their implication in ASDs. PMID- 23792026 TI - ER stress in human hepatic cells treated with Efavirenz: mitochondria again. AB - BACKGROUND & AIMS: ER stress is associated with a growing number of liver diseases, including drug-induced hepatotoxicity. The non-nucleoside analogue reverse transcriptase inhibitor Efavirenz, a cornerstone of the multidrug strategy employed to treat HIV1 infection, has been related to the development of various adverse events, including metabolic disturbances and hepatic toxicity, the mechanisms of which remain elusive. Recent evidence has pinpointed a specific mitochondrial effect of Efavirenz in human hepatic cells. This study assesses the induction of ER stress by Efavirenz in the same model and the implication of mitochondria in this process. METHODS: Primary human hepatocytes and Hep3B were treated with clinically relevant concentrations of Efavirenz and parameters of ER stress were studied using standard cell biology techniques. RESULTS: ER stress markers, including CHOP and GRP78 expression (both protein and mRNA), phosphorylation of eIF2alpha, and presence of the spliced form of XBP1 were upregulated. Efavirenz also enhanced cytosolic Ca(2+) content and induced morphological changes in the ER suggestive of ER stress. This response was greatly attenuated in cells with altered mitochondrial function (Rho degrees ). The effects of Efavirenz on the ER, and particularly in regard to the mitochondrial involvement, differed from those elicited by a standard pharmacological ER stressor. CONCLUSIONS: This newly discovered mechanism of cellular insult involving ER stress and UPR response may help comprehend the hepatic toxicity that has been associated with the widespread and life-long use of Efavirenz. In addition, the specificity of the actions of Efavirenz observed expands our knowledge of the mechanisms that trigger ER stress and shed some light on the mitochondria/ER interplay in drug-induced hepatic challenge. PMID- 23792027 TI - Is biliary atresia an immune mediated disease? PMID- 23792028 TI - Diagnostic and prognostic significance of cell death and macrophage activation markers in patients with hepatocellular carcinoma. AB - BACKGROUND & AIMS: The serum cell death parameters M30 and M65 and the macrophage activation marker sCD163 (soluble CD163) are elevated in patients with acute and chronic liver diseases. However, their diagnostic and prognostic potential in patients with hepatocellular carcinoma (HCC) has not yet been investigated. METHODS: Serum levels of M30, M65, and sCD163 were measured in two cohorts of HCC patients and a cohort of cirrhotic patients. The parameters were compared between patients with and without HCC and the overall survival (OS) times according to M30, M65, and sCD163 were assessed. RESULTS: M30 and M65 levels were higher in HCC patients than in cirrhotic patients (both p < 0.001). M65 was an independent parameter for non-invasive identification of HCC patients by logistic regression analysis and could supplement AFP (alpha-fetoprotein) and abdominal ultrasound in non-invasive detection of HCC patients. High M65 serum levels as well as high sCD163 concentrations were associated with an impaired prognosis in univariate Cox regression analysis. The sCD163 level was associated with OS independently of the CLIP (Cancer of the Liver Italian Program) score, the BCLC (Barcelona Clinic Liver Cancer) stage, and the CRP (C-reactive protein) level in a multivariate Cox regression model. CONCLUSIONS: Serum M65 has the potential as a new diagnostic parameter for HCC and serum sCD163 is a new prognostic parameter in HCC patients. PMID- 23792029 TI - Patterns of hepatitis B surface antigen decline and HBV DNA suppression in Asian treatment-experienced chronic hepatitis B patients after three years of tenofovir treatment. AB - BACKGROUND & AIMS: Patterns of serum hepatitis B surface antigen (HBsAg) decline during nucleos(t)ide analogue (NA) therapy have not been well investigated. METHODS: We determined the cumulative serologic, virologic, and biochemical outcomes of 142 Asian CHB patients, with at least 6 months exposure to other NAs, receiving tenofovir with or without lamivudine for up to 3 years. Liver biochemistry, serum HBV DNA, and HBsAg levels were determined at baseline, 6 months and yearly from years 1 to 3. RESULTS: 142, 123 (86.6%), and 70 (49.3%) CHB patients were followed up for 1, 2, and 3 years, respectively. Two phases of HBsAg decline were observed. Patients with baseline HBsAg >=3 log IU/ml, when compared to patients with baseline HBsAg < 3 log IU/ml, had a greater median rate of HBsAg reduction through 3 years of treatment (0.155 and 0.039 log IU/ml/year respectively, p < 0.001). Among patients with 3 years of follow-up, there was a significantly greater median rate of HBsAg reduction during the first year when compared to the second and third years (0.220, 0.136, and 0.081 log IU/ml/year respectively, p < 0.001). HBeAg status, HBV genotype, and concomitant lamivudine therapy were not important determinants of HBsAg kinetics (all p > 0.05). The 3 year cumulative virologic suppression rate was 93.3%, with no cases of resistance detected. CONCLUSIONS: Serum HBsAg levels in NA-experienced patients receiving tenofovir demonstrated a variable pattern of decline, with slower rates of reduction noted in patients with lower baseline HBsAg levels, and could explain the rarity of HBsAg seroclearance during NA therapy. PMID- 23792030 TI - Infliximab as rescue therapy in paediatric autoimmune hepatitis. PMID- 23792031 TI - The role of hepassocin in the development of non-alcoholic fatty liver disease. AB - BACKGROUND & AIMS: While non-alcoholic fatty liver disease (NAFLD) is the most common risk factor of chronic liver disease, the mechanisms that initiate its development are obscure. Hepassocin (HPS) is a hepatokine that has been reported to be involved in liver regeneration. In addition to the mitogenic activity of HPS, HPS expression is decreased in patients with hepatoma. However, the role of HPS in NAFLD is still unknown. METHODS: A total of 393 subjects with (n=194) or without (n=199) NAFLD were enrolled to evaluate the serum HPS concentration. In order to clarify the causal inference between HPS and NAFLD, we used experimental animal and cell models. Hepatic overexpression or silencing of HPS was achieved by lentiviral vector delivery in mice and lipofectamine transfection in HepG2 cells. Lipogenesis related proteins were detected by Western blots. The expression of inflammatory factors was determined by real-time polymerase chain reaction. RESULTS: Subjects with NAFLD had a higher serum HPS concentration than those without it. Overexpression of HPS increased hepatic lipid accumulation and NAFLD activity scores (NAS), whereas deletion of HPS improved high fat diet induced hepatic steatosis and decreased NAS in mice. Additionally, oleic acid, a steatogenic reagent, increased HPS expression in hepatocytes. Furthermore, overexpression of HPS in HepG2 cells induced lipid accumulation through an extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent pathway, whereas deletion of HPS decreased oleic acid-induced lipid accumulation. CONCLUSIONS: The present study provides evidence that HPS plays an important role in NAFLD and induces hepatic lipid accumulation through an ERK1/2-dependent pathway. PMID- 23792032 TI - Structural characterization of an immunoenhancing glucan isolated from a mushroom Macrolepiota dolichaula. AB - A water soluble branched glucan (PS-I) was isolated from aqueous extract of the fruit bodies of an edible mushroom Macrolepiota dolichaula, having average molecular weight ~2.02*10(5) Da. The structure of this PS-I was determined using total hydrolysis, methylation analysis, Smith degradation, partial hydrolysis, and 1D/2D NMR experiments. Total hydrolysis and methylation analysis results showed the presence of (1->3, 6)-, (1->6)-, (1->4)-, (1->3)-linked and terminal beta-D-glucopyranosyl residues in a relative proportion of nearly 1:2:1:1:1. All the chemical and NMR results indicated that the PS-I was a branched glucan, and the repeating unit of this glucan consisted of a backbone chain of three (1->6) linked-beta-D-glucopyranosyl residues where one of the backbone residues is branched at O-3 with (1->3)- moiety which is further attached to another (1->4)- residue and terminated with a non-reducing beta-D-glucopyranosyl residue. The PS I exhibited in vitro macrophage activation in RAW 264.7 cell line as well as splenocyte and thymocyte activation in mouse cell culture medium. PMID- 23792033 TI - Effects of graded levels of arachidonic acid on the reproductive physiology of Senegalese sole (Solea senegalensis): Fatty acid composition, prostaglandins and steroid levels in the blood of broodstock bred in captivity. AB - Previous studies on Senegalese sole (Solea senegalensis) indicated that cultured broodstock (first generation, G1) have lower tissue levels of arachidonic acid (20:4n-6, ARA) than wild counterparts. ARA is metabolized to form prostaglandins (PGs) that are involved in steroid production and follicle maturation in fish. In the present study the effects of different dietary levels of ARA on blood lipid and fatty acid composition, prostaglandin (PGF2alpha, PGF3alpha, PGE2 and PGE3) levels and plasmatic steroid levels (11-ketotestosterone, 11-KT, testosterone, T and estradiol, E2) in G1 Senegalese sole were studied. For this purpose, 12 groups of ten fish (1:1 male and female), were fed six diets (each diets was fed to two groups) with different dietary ARA levels over nine months (diets A=0.7, B=1.6, C=2.3, D=3.2, E=5.0, F=6.0% ARA). ARA and CHOL levels in blood showed a significant increase in an ARA dose related manner (P<0.05) whereas EPA and EPA/ARA ratio were reduced. In males, steroid (11-KT and T) levels increased significantly with increasing dietary ARA in a dose dependent manner, whereas in females E2 did not show any change related to dietary ARA content. Plasma concentration of 3-series PGs (i.e., PGE3 and PGF3alpha) were reduced in parallel to increased ARA levels in blood (P<0.05) and levels of PGs 3-series were always higher than 2-series PGs (PGE2 and PGF2alpha). In conclusion there is an effect of dietary ARA on steroid production of Senegalese sole males, which might have important consequences in the reproduction of cultured fish. PMID- 23792035 TI - Fluorimetric urease inhibition assay on a multilayer microfluidic chip with immunoaffinity immobilized enzyme reactors. AB - We fabricated a three-layer polydimethylsiloxane (PDMS)-based microfluidic chip for realizing urease inhibition assay with sensitive fluorescence detection. Procedures such as sample prehandling, enzyme reaction, reagent mixing, fluorescence derivatization, and detection can be readily carried out. Urease reactors were prepared by adsorption of rabbit immunoglobulin G (IgG) and immunoreaction with urease-conjugated goat anti-rabbit IgG. Acetohydroxamic acid (AHA) as a competitive inhibitor of urease was tested on the chip. Microfluidically generated gradient concentrations of AHA with substrate (urea) were loaded into urease reactors. After incubation, the produced ammonia was transported out of reactors and then reacted with o-phthalaldehyde (OPA) to generate fluorescent products. Urease inhibition was indicated by a decrease in fluorescence signal detected by microplate reader. The IC50 value of AHA was determined and showed good agreement with that obtained in microplate. The presented device combines several steps of the analytical process with advantages of low reagent consumption, reduced analysis time, and ease of manipulation. This microfluidic approach can be extended to the screening of inhibitory compounds in drug discovery. PMID- 23792034 TI - Sex-specific effect of the anabolic steroid, 17alpha-methyltestosterone, on inhibitory avoidance learning in periadolescent rats. AB - The illicit use of anabolic androgenic steroids (AAS) has gained popularity among adolescents in the last decade. However, although it is known that exposure to AAS impairs cognition in adult animal models, the cognitive effects during adolescence remain undetermined. An inhibitory avoidance task (IAT) was used to assess the effect of AAS (17alpha-methyltestosterone; 17alpha-meT--7.5 mg/kg) in male and female periadolescent rats. A single injection of 17alpha-meT immediately before the footshock produced significant impairment of inhibitory avoidance learning in males but not females. Generalized anxiety, locomotion, and risk assessment behaviors (RAB) were not affected. Our results show that exposure to a single pharmacological dose of 17alpha-meT during periadolescence exerts sex specific cognitive effects without affecting anxiety. Thus, disruption of the hormonal milieu during this early developmental period might have negative impact on learning and memory. PMID- 23792036 TI - Proinflammatory cytokines, aging, and age-related diseases. AB - Inflammation is a physiological process that repairs tissues in response to endogenous or exogenous aggressions. Nevertheless, a chronic state of inflammation may have detrimental consequences. Aging is associated with increased levels of circulating cytokines and proinflammatory markers. Aged related changes in the immune system, known as immunosenescence, and increased secretion of cytokines by adipose tissue, represent the major causes of chronic inflammation. This phenomenon is known as "inflamm-aging." High levels of interleukin (IL)-6, IL-1, tumor necrosis factor-alpha, and C-reactive protein are associated in the older subject with increased risk of morbidity and mortality. In particular, cohort studies have indicated TNF-alpha and IL-6 levels as markers of frailty. The low-grade inflammation characterizing the aging process notably concurs at the pathophysiological mechanisms underlying sarcopenia. In addition, proinflammatory cytokines (through a variety of mechanisms, such as platelet activation and endothelial activation) may play a major role in the risk of cardiovascular events. Dysregulation of the inflammatory pathway may also affect the central nervous system and be involved in the pathophysiological mechanisms of neurodegenerative disorders (eg, Alzheimer disease).The aim of the present review was to summarize different targets of the activity of proinflammatory cytokines implicated in the risk of pathological aging. PMID- 23792037 TI - Conceptualization of a toolkit to evaluate everyday competence in planning transitions from nursing homes to the community. AB - Living independently in the community is a primary goal for older adults, particularly for the estimated 10% to 20% of long-stay nursing home residents who have low care requirements. According to the model of person-environment fit, individuals with high levels of everyday competence have the ability to solve problems associated with everyday life. Nursing home residents with high levels of everyday competence and low care needs have poor person-environment fit, placing them at risk for declines in function, maladaptive behavior, and affective disorders. The goal of this article is to present a framework for the integration of everyday competence with standardized goal-setting and care planning processes to enable the transition of appropriate nursing home residents back to the community. Barriers to community transitions exist across several Key Domains: rehabilitation, personal assistance and services, caregiver support, finances, housing, and transportation. We propose a research agenda to develop and implement a toolkit based on this framework that nursing home staff can use to overcome barriers to transition by (1) assessing residents' everyday competence, (2) developing personally meaningful goals that facilitate transition, and (3) conducting structured care planning to support resident goals around returning to the community. If successful, this toolkit has the potential to reduce costs associated with nursing home care and to improve functional health, psychological well-being, and quality of life for older adults. The proposed framework and toolkit complement national efforts focused on transitioning nursing home residents back into the community. PMID- 23792038 TI - Nocistatin inhibits pregnant rat uterine contractions in vitro: roles of calcitonin gene-related peptide and calcium-dependent potassium channel. AB - The endogenous neuropeptide nociceptin/orphanin FQ, translated from the prepronociceptin gene, exerts a contraction-inhibitory effect on the rat uterus. As nocistatin has been reported to cause functional antagonism of the pro nociceptive effects of nociceptin, we set out to investigate its effects on the pregnant rat uterus and to elucidate its signalling pathway. The expression of prepronociceptin mRNA in the uterus and nocistatin levels in the uterus and the plasma were confirmed by RT-PCR and radioimmunoassay. The uterine levels of prepronociceptin mRNA and nocistatin were significantly increased by the last day of pregnancy, while the plasma nocistatin levels remained unchanged. In the isolated organ bath studies nocistatin inhibited the prostaglandin- and the KCl evoked contractions in the uterus dose-dependently. This latter effect was decreased by preincubation with capsaicin. Incubation with calcitonin gene related peptide after capsaicin treatment caused an elevation in the contraction inhibitory effect of nocistatin. The effect of nocistatin was also decreased by the Ca(2+)-dependent K(+) channel inhibitor paxilline, against spontaneous uterine contractions. Nociceptin potentiated the action of nocistatin. Naloxone decreased the effect of nocistatin administered either alone or in combination with nociceptin. In Ca(2+)-poor environment, this effect of naloxone was suspended. Enzyme immunoassay for the uterine intracellular cAMP levels partially confirmed the results of in vitro contractility studies. We conclude that nocistatin, generated locally in the uterus, exerts an inhibitory effect, the mechanism being mediated in part by Ca(2+)-dependent K(+) channels, the elevation of cAMP levels and sensory neuropeptides. PMID- 23792040 TI - Stimulation of alpha1-adrenoceptor or angiotensin type 1 receptor enhances DNA synthesis in human-induced pluripotent stem cells via Gq-coupled receptor dependent signaling pathways. AB - Stimulation of either alpha1-adrenoceptor or angiotensin type 1 receptor (AT1 receptor) induces proliferation of mouse induced pluripotent stem (iPS) cells. Both alpha1-adrenoceptor and AT1 receptor are guanine nucleotide-binding protein q polypeptide (Gq)-coupled receptors. However, it is not fully understood whether stimulation of these Gq-coupled receptors exert a similar effect in human iPS cells, i.e. proliferation of human iPS cells. In this study, we evaluated the involvement of alpha1-adrenoceptor and AT1 receptor in the DNA synthesis of human iPS cells. Treatment with either l-phenylephrine (a selective alpha1-adrenoceptor agonist) or angiotensin II (Ang II) significantly increased DNA synthesis in human iPS cells. Enhanced DNA synthesis was significantly inhibited by pretreatment with protein kinase C (PKC) inhibitors, mitogen-activated protein kinase kinase (MEK) inhibitor, or phosphatidylinositol-3 phosphate kinase (PI3K) inhibitor. Treatment with either l-phenylephrine or Ang II significantly increased Akt and p44/42 MAPK phosphorylation. Short interfering RNA (siRNA) directed against Gq significantly inhibited DNA synthesis and phosphorylation of Akt and p44/42 MAPK enhanced by l-phenylephrine or Ang II. These results suggest that stimulation of alpha1-adrenoceptor or AT1 receptor may enhance DNA synthesis in human iPS cells via Gq-coupled receptor-dependent signaling pathways. PMID- 23792039 TI - Effect of 18beta-glycyrrhetinic acid and hydroxypropyl gammacyclodextrin complex on indomethacin-induced small intestinal injury in mice. AB - Non-steroidal anti-inflammatory drugs (NSAIDs)-induced small intestinal injury is a serious clinical event with recent advances of diagnostic technologies, but a successful therapeutic method to treat such injuries is still lacking. Licorice, a traditional herbal medicine, and its derivatives have been widely used for the treatment of a variety of diseases due to their extensive biological actions. However, it is unknown whether these derivatives have an effect on NSAIDs-induced small intestinal damage. Previously, the anti-inflammatory effects of three compounds extracted from the licorice root, glycyrrhizin, 18beta-glycyrrhetinic acid, and dipotassium glycyrrhizinate, were compared in vitro cell culture. The most prominent inhibitory effect on the tumor necrosis factor-alpha (TNF-alpha) production was observed with the administration of 18beta-glycyrrhetinic acid as an active metabolite of glycyrrhizin. In this study, a complex compound of 18beta glycyrrhetinic acid and hydroxypropyl gammacyclodextrin was examined to improve the oral bioavailability. After administration of this complex to indomethacin treated mice, a significantly high plasma concentration of 18beta-glycyrrhetinic acid was detected using the tandem mass spectrometry coupled with the HPLC. Furthermore, the complex form of 18beta-glycyrrhetinic acid and hydroxypropyl gammacyclodextrin reduced mRNA expressions of TNF-alpha, interleukin (IL)-1beta, and IL-6, which was histologically confirmed in the improvement of indomethacin induced small intestinal damage. These results suggest that the complex of 18beta glycyrrhetinic acid and hydroxypropyl gammacyclodextrin has the potential therapeutic value for preventing the adverse effects of indomethacin-induced small intestinal injury. PMID- 23792041 TI - An endothelin-3-related synthetic biotinylated pentapeptide as a novel inhibitor of platelet-activating factor. AB - Platelet-activating factor (PAF), a potent proinflammatory mediator, is involved in many inflammatory diseases. We recently reported that synthetic biotinylated peptides having a Tyr-Lys-Asp-Gly sequence inhibit PAF-induced inflammation by directly binding to PAF. In this study, we investigated the effect of two synthetic biotinylated peptides, both of which have a sequence similar to Tyr-Lys Asp-Gly-an endothelin-3 (ET-3)-related biotinylated pentapeptide (Tyr-Lys-Asp-Lys Glu, BPET3) and a scavenger receptor CD36-related biotinylated tetrapeptide (Tyr Lys-Gly-Lys, BPCD36)-on PAF-induced inflammation by using a rat model of hind paw oedema. BPET3 markedly inhibited PAF-induced oedema in a dose-dependent manner, and the dose that caused 50% inhibition was estimated to be approximately 2.64 nmol/paw. The inhibitory effect of BPCD36 on PAF-induced paw oedema was less than that of BPET3, while a synthetic biotinylated pentapeptide (Lys-Lys-Tyr-Asp-Glu) shuffling amino acid sequence of BPET3, an ET-1-related synthetic biotinylated pentapeptide (Leu-Met-Asp-Lys-Glu), or an ET-2-related synthetic biotinylated pentapeptide (Trp-Leu-Asp-Lys-Glu) did not inhibit PAF-induced paw oedema. Furthermore, intrinsic tryptophan fluorescence studies demonstrated that ET-3 specifically interacted with both PAF and its metabolite/precursor lyso-PAF. These results provide evidence that the Tyr-Lys-Asp region in both ET-3 and BPET3 is essential for marked inhibition of the peptide on PAF-induced inflammation, and strongly suggest that BPET3 may be useful as a novel anti-inflammatory drug targeting PAF. PMID- 23792042 TI - Microemulsion and poloxamer microemulsion-based gel for sustained transdermal delivery of diclofenac epolamine using in-skin drug depot: in vitro/in vivo evaluation. AB - Microemulsion (ME) and poloxamer microemulsion-based gel (PMBG) were developed and optimized to enhance transport of diclofenac epolamine (DE) into the skin forming in-skin drug depot for sustained transdermal delivery of drug. D-optimal mixture experimental design was applied to optimize ME that contains maximum amount of oil, minimum globule size and optimum drug solubility. Three formulation variables; the oil phase X1 (Capryol((r))), Smix X2 (a mixture of Labrasol((r))/Transcutol((r)), 1:2 w/w) and water X3 were included in the design. The systems were assessed for drug solubility, globule size and light absorbance. Following optimization, the values of formulation components (X1, X2, and X3) were 30%, 50% and 20%, respectively. The optimized ME and PMBG were assessed for pH, drug content, skin irritation, stability studies and ex vivo transport in rat skin. Contrary to PMBG and Flector((r)) gel, the optimized ME showed the highest cumulative amount of DE permeated after 8h and the in vivo anti-inflammatory efficacy in rat paw edema was sustained to 12h after removal of ME applied to the skin confirming the formation of in-skin drug depot. Our results proposed that topical ME formulation, containing higher fraction of oil solubilized drug, could be promising for sustained transdermal delivery of drug. PMID- 23792043 TI - Comparative static curing versus dynamic curing on tablet coating structures. AB - Curing is generally required to stabilize film coating from aqueous polymer dispersion. This post-coating drying step is traditionally carried out in static conditions, requiring the transfer of solid dosage forms to an oven. But, curing operation performed directly inside the coating equipment stands for an attractive industrial application. Recently, the use of various advanced physico chemical characterization techniques i.e., X-ray micro-computed tomography, vibrational spectroscopies (near infrared and Raman) and X-ray microdiffraction, allowed new insights into the film-coating structures of dynamically cured tablets. Dynamic curing end-point was efficiently determined after 4h. The aim of the present work was to elucidate the influence of curing conditions on film coating structures. Results demonstrated that 24h of static curing and 4h of dynamic curing, both performed at 60 degrees C and ambient relative humidity, led to similar coating layers in terms of drug release properties, porosity, water content, structural rearrangement of polymer chains and crystalline distribution. Furthermore, X-ray microdiffraction measurements pointed out different crystalline coating compositions depending on sample storage time. An aging mechanism might have occur during storage, resulting in the crystallization and the upward migration of cetyl alcohol, coupled to the downward migration of crystalline sodium lauryl sulfate within the coating layer. Interestingly, this new study clearly provided further knowledge into film-coating structures after a curing step and confirmed that curing operation could be performed in dynamic conditions. PMID- 23792044 TI - Novel single nucleotide polymorphisms in the superoxide dismutase 1 and 2 genes among children with myelomeningocele. AB - OBJECTIVE: Excessive oxidative stress has been demonstrated as a mechanism for neural tube defects (NTDs). The current exploratory study sought to examine sequence variations in the superoxide dismutase 1 (SOD1) and 2 (SOD2) genes in patients with myelomeningocele and to identify variants altering risk for myelomeningocele. STUDY DESIGN: We sequenced deoxyribonucleic acid from 96 patients with myelomeningocele. The 11 exons were amplified by polymerase chain reaction, and the products were sequenced with the Sanger method. Results were compared with reference sequences (NM_000454, NM_000636, and NM_001024466) obtained from University of California Santa Cruz Genome Browser. Observed alleles that differed from the reference sequences were considered novel variants. RESULTS: We found 1 novel variant and 1 variant only recently described in phase 1 of the 1000 Genomes Project but not yet validated. The novel variant is located in the 3'-untranslated region (UTR) of SOD2 and is present in 2 of 96 patients (1.0% allele frequency). The other variant is located in the 3'-UTR of SOD1 and is present in 2 of 96 patients (1.0% allele frequency). Minor allele frequencies of known single nucleotide polymorphisms were compared with unaffected population controls. CONCLUSION: We identified 1 novel variant and made the second report of an additional variant in the SOD genes studied. The variant located in the 3'-UTR of SOD1 is predicted to alter microribonucleic acid (miRNA) binding. The variant located in the 3'-UTR of SOD2 is predicted to alter 2 miRNA binding sites and potentially affects messenger ribonucleic acid production. We also identified 2 known single-nucleotide polymorphisms that occur in significantly different frequency compared with the unaffected population controls. PMID- 23792046 TI - Ultrastructure and morphogenesis of the wing scales in Heliconius erato phyllis (Lepidoptera: Nymphalidae): what silvery/brownish surfaces can tell us about the development of color patterning? AB - Usually the literature on Heliconius show three types of scales, classified based on the correlation between color and ultrastructure: type I - white and yellow, type II - black, and type III - orange and red. The ultrastructure of the scales located at the silvery/brownish surfaces of males/females is for the first time described in this paper. Besides, we describe the ontogeny of pigmentation, the scale morphogenesis and the maturation timing of scales fated to different colors in Heliconius erato phyllis. The silvery/brownish surfaces showed ultrastructurally similar scales to the type I, II and III. The ontogeny of pigmentation follows the sequence red, black, silvery/brownish and yellow. The maturation of yellow-fated scales, however, occurred simultaneously with the red fated scales, before the pigmentation becomes visible. In spite of the scales at the silvery/brownish surfaces being ultrastructurally similar to the yellow, red and black scales, they mature after them; this suggests that the maturation timing does not show a relationship with the scale ultrastructure, with the deposition timing of the yellow pigment. The analysis of H. erato phyllis scale morphogenesis, as well as the scales ultrastructure and maturation timing, provided new findings into the developmental architecture of color pattern in Heliconius. PMID- 23792045 TI - Why cellular stress suppresses adipogenesis in skeletal tissue, but is ineffective in adipose tissue: control of mesenchymal cell differentiation via integrin binding sites in extracellular matrices. AB - This Perspective addresses one of the major puzzles of adipogenesis in adipose tissue, namely its resistance to cellular stress. It introduces a concept of "density" of integrin binding sites in extracellular matrix, proposes a cellular signaling explanation for the observed effects of matrix elasticity and of cell shape on mesenchymal stem cell differentiation, and discusses how specialized integrin binding sites in collagen IV-containing matrices guard two pivotal physiological and evolutionary processes: stress-resistant adipogenesis in adipose tissues and preservation of pluripotency of mesenchymal stem-like cells in their storage niches. Finally, it proposes strategies to suppress adipogenesis in adipose tissues. PMID- 23792047 TI - NMDA-receptor coagonists in serum, plasma, and cerebrospinal fluid of schizophrenia patients: a meta-analysis of case-control studies. AB - Serine and other amino acids that function as coagonists at the N-methyl-d aspartate receptor (NMDAR) have been extensively investigated in schizophrenia (SCZ). However, studies comparing amino acid levels in body fluids of SCZ patients with healthy controls have yielded inconsistent results. We therefore conducted a meta-analysis (search: May 9, 2013) of serine, l-serine, d-serine, glycine, alanine, proline, and aspartate levels in blood and cerebrospinal fluid (CSF) obtained from adult SCZ patients and healthy controls. Standardized differences of means (SDMs) were computed, and heterogeneity, subgroup, sensitivity, and publication bias analyses were conducted. Blood serine levels were found to be significantly higher in SCZ patients compared to healthy controls (SDM=0.280 (0.021-0.540), p=0.034; N=1671 subjects), whereas CSF serine, l-serine, d-serine, glycine, alanine, proline, and aspartate levels did not differ. Stratification by sex suggested that the case-control difference in blood serine levels particularly applies to male subjects. These results provide support for blood serine level aberrations in SCZ patients and warrant further research to disentangle the involvement of serine with SCZ in both sexes. PMID- 23792048 TI - Primitive mechanisms of trauma response: an evolutionary perspective on trauma related disorders. AB - The symptoms we identify and the behaviors we recognize as defenses define which symptoms we see as trauma-related. Early conceptions of trauma-related disorders focused on physical signs of distress while current ones emphasize mental symptoms, but traumatizing experiences evoke psychobiological reactions. An evolutionary perspective presumes that psychophysical reactions to traumatizing events evolved to ensure survival. This theoretical review examines several primitive mechanisms (e.g., sensitization and dissolution) associated with responses to diverse stressors, from danger to life-threat. Some rapidly acquired symptoms form without conscious awareness because severe stresses can dysregulate mental and physical components within systems ensuring survival. Varied defensive options engage specialized and enduring psychophysical reactions; this allows for more adaptive responses to diverse threats. Thus, parasympathetically mediated defense states such as freeze or collapse increase trauma-related symptom variability. Comorbidity and symptom variability confuse those expecting mental rather than psychophysical responses to trauma, and active (sympathetically mediated flight and fight) rather than immobility defenses. Healthcare implications for stress research, clinical practice and diagnostic nosology stem from the broader evolutionary view. PMID- 23792049 TI - Testing long-term memory in animal models of schizophrenia: suggestions from CNTRICS. AB - This paper reports the results of discussions at the fourth meeting of Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) meeting, held over two days in Washington, DC in April 2011. The meeting focused on animal paradigms for assessing the cognitive constructs relevant to schizophrenia identified in previous CNTRICS meetings. This report focuses on the outcome of discussions in the general area of long-term memory. A number of candidate animal paradigms were discussed. Two of these - one for rodents and one for non-human primates - were recommended as particularly promising for further development. PMID- 23792050 TI - The role of COMT gene variants in depression: Bridging neuropsychological, behavioral and clinical phenotypes. AB - Depression is a common and disabling psychiatric disorder with a complex etiology, which includes predisposing risk genes and environmental stressors. Variation in the Catechol-O-Methyltransferase (COMT) gene, the Val158Met polymorphism in particular, has been extensively investigated in relation to clinical phenotypes of depression and, in parallel, neurocognitive processes. In this review, we bridge evidence from neuroimaging, behavioral and clinical studies that have examined the role of COMT variants on depression-relevant phenotypes. We observed that clinical phenotypes such as depression severity and diagnosis, or behavioral endophenotypes, are less reliably associated with COMT genetic variation. On the other hand, genetic effects are more discernible on brain systems of emotional processing. Specifically, the Met allele is associated with increased activity in limbic areas and prefrontal cortex, but is also more likely to have a better response to antidepressant treatment, compared to the Val allele. Gender and stress are important modulators of COMT genetic effects. On the basis of current evidence, we propose a tentative pathway through which the COMT gene may influence cognitive vulnerability to depression. PMID- 23792051 TI - Cell death by cornification. AB - Epidermal keratinocytes undergo a unique form of terminal differentiation and programmed cell death known as cornification. Cornification leads to the formation of the outermost skin barrier, i.e. the cornified layer, as well as to the formation of hair and nails. Different genes are expressed in coordinated waves to provide the structural and regulatory components of cornification. Differentiation-associated keratin intermediate filaments form a complex scaffold accumulating in the cytoplasm and, upon removal of cell organelles, fill the entire cell interior mainly to provide mechanical strength. In addition, a defined set of proteins is cross-linked by transglutamination in the cell periphery to form the so-called cornified envelope. Extracellular modifications include degradation of the tight linkages between corneocytes by excreted proteases, which allows corneocyte shedding by desquamation, and stacking and modification of the excreted lipids that fill the intercellular spaces between corneocytes to provide a water-repellant barrier. In hard skin appendages such as hair and nails these tight intercorneocyte connections remain permanent. Various lines of evidence exist for a role of organelle disintegration, proteases, nucleases, and transglutaminases contributing to the actual cell death event. However, many mechanistic aspects of kearatinocyte death during cornification remain elusive. Importantly, it has recently become clear that keratinocytes activate anti-apoptotic and anti-necroptotic pathways to prevent premature cell death during terminal differentiation. This review gives an overview of the current concept of cornification as a mode of programmed cell death and the anti cell death mechanisms in the epidermis that secure epidermal homeostasis. This article is part of a Special Section entitled: Cell Death Pathways. PMID- 23792052 TI - Clinical evaluation of the endothelial tie-2 crossmatch in ABO compatible and ABO incompatible renal transplants. AB - The necessity of detection of other than the classical major histocompatibility complex (MHC) and MHC class I-related chain A (MICA) directed antibodies prior to organ transplantation has already been repeatedly reported. A commercial flow cytometric endothelial crossmatch (CM) using isolated peripheral blood tie-2 positive cells provides a tool to detect non-MHC antibodies in addition to antibodies directed to MHC class I and II. The vast majority of circulating tie-2 positive cells expresses HLA-DR but not the A, B blood group antigens. Tie-2 cells are circulating surrogate endothelial cells. In this retrospective study we evaluated the endothelial CM in 51 renal transplantations, 30 with ABO compatible grafts and 21 with ABO incompatible grafts. Fifteen of the ABO compatible recipients (group A) developed unexplained rejection episodes (RE) while the remaining 15 had no RE (group B). Five cases of group A and none of group B had a positive tie-2 CM before transplantation (p=0.042). A positive tie-2 CM was also correlated with graft failure in ABO compatible transplants (p=0.02). No significant correlation was found between a positive pre-transplant tie-2 CM and RE in the ABO incompatible group. This study strongly suggest that a positive tie 2 CM may predict post-transplantation complications in ABO compatible grafts while negative reactions are not predictive. The test is not significantly correlated with RE in ABO incompatible grafts possibly due to applied desensitization. PMID- 23792053 TI - MiR-196a2 rs11614913 T > C polymorphism and risk of esophageal cancer in a Chinese population. AB - BACKGROUND: Esophageal cancer is the eighth most common cancer and sixth leading cause of cancer associated death worldwide. Besides environmental risk factors, genetic factors might play an important role in the esophageal cancer carcinogenesis. METHODS: We conducted a hospital based case-control study to evaluate the genetic susceptibility of functional single nucleotide polymorphisms (SNPs) in the microRNAs on the development of esophageal cancer. A total of 380 esophageal squamous cell carcinoma (ESCC) cases and 380 controls were recruited for this study. The miR-196a2 rs11614913 T > C, miR-146a rs2910164 C > G, miR-499 rs3746444 T > C, miR-26a-1 rs7372209 C > T and miR-27a rs895819 T > C genotypes were determined using a custom-by-design 48-Plex SNPscanTM Kit and matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). RESULTS: MiR-196a2 rs11614913 T > C polymorphism was associated with borderline statistically decreased risk of ESCC. In the recessive model, when the miR-196a2 rs11614913 TT/TC genotypes were used as the reference group, the CC homozygote genotype was associated with a borderline statistically decreased risk for ESCC (adjusted OR 0.72, 95% CI 0.50-1.03, p = 0.070). In stratification analyses, a significantly decreased risk of ESCC associated with the miR-196a2 rs11614913 T > C polymorphism was evident among women patients and patients who never smoking or drinking. CONCLUSIONS: These findings indicated that functional polymorphism miR-196a2 rs11614913 T > C might contribute to decreased ESCC risk among women patients and patients who never smoking or drinking. However, our results were obtained with a limited sample size. Future larger studies with other ethnic populations and tissue-specific biological characterization are required to confirm current findings. PMID- 23792054 TI - Frequent development of subclinical chronic antibody-mediated rejection within 1 year after renal transplantation with pre-transplant positive donor-specific antibodies and negative CDC crossmatches. AB - Although short-term graft survival has been improved by recent desensitization protocols including B cell depletion therapy, little is known about risk factors of chronic antibody-mediated rejection (CAMR) in HLA-incompatible (HLA-I) renal transplantation (RTx). Twenty-six HLA-I RTx with positive donor-specific antibodies (DSA) and negative T cell cytotoxic crossmatches were compared with 88 ABO-incompatible (ABO-I) and 207 ABO-identical/compatible (ABO-Id/C) RTx. The desensitization therapy consisted of mycophenolate mofetil, rituximab and double filtration plasmapheresis. Protocol biopsies within 1 year revealed subclinical CAMR in 36% of HLA-I, 5% of ABO-I and 3% of ABO-Id/C, although clinical acute AMR was observed in 8%, 3% and 1%, respectively. The incidence of CAMR was not different between class I and class II DSA. Most of class I DSA (94%) changed to negative 1 year after RTx, whereas 77% of class II DSA remained positive. In addition, the remaining DRB +/- DQB DSA caused CAMR in 80% of patients, while DQB DSA alone did not. The progress of subclinical CAMR within 1 year could not be circumvented by rituximab. Sustained class II (DRB +/- DQB) DSA detection after RTx may pose a potential risk for developing CAMR, but negative change in class I DSA could also elicit CAMR. PMID- 23792055 TI - Analysis of KIR gene frequencies and HLA class I genotypes in breast cancer and control group. AB - Breast cancer is the main cause of cancer-related death among women, with a 0.5% increase in incidence per year. Natural killer cells (NK) are part of the innate immune system recognizing class I HLA molecules on target cells through their membrane receptors, called killer cell immunoglobulin-like receptors (KIR). The aim of our study was to evaluate the association between the KIR genes and HLA alleles in patients with breast cancer and healthy controls. Two hundred thirty patients with breast cancer and 272 healthy controls were typed for HLA class I and KIR genes by PCR-SSO. When both groups were compared, the presence of inhibitory KIR2DL2 receptors was significantly higher in breast cancer patients than in healthy controls. No significant differences were found for HLA-C2 and HLA-Bw4. However, a higher frequency of HLA-C1 in breast cancer patients was observed. These findings suggest a potential role for the KIR gene system in breast cancer. Further studies to confirm this observation are warranted. PMID- 23792056 TI - Clinical relevance of GSTT1 mismatch in solid organ and hematopoietic stem cell transplantation. AB - Since 2001, year in which Glutathione S-transferase theta class 1 (GSTT1) gene appeared to be related to the occurrence of de novo immune hepatitis after liver transplantation, this gene with two allelic variants, GSTT1(*)A (wild type copy) and GSTT1(*)0 (deletion copy), has emerged as a potent histocompatibility antigen. Namely, a donor-recipient liver graft combination of a GSTT1-negative recipient (homozygous for GSTT1(*)0) and a GSTT1-positive donor results, very frequently, in the appearance of a severe immune-related graft hepatitis with production of IgG anti-GSTT1 antibodies. In kidney transplantation, GSTT1 donor recipient mismatch is also associated with production of anti-GSTT1 antibodies and antibody-related rejection episodes with C4d deposition in graft biopsy. The more recent discovery of anti-GSTT1 antibodies in hematopoietic stem cell transplantation, clearly confirms a role of GSTT1 as histocompatibility antigen in this setting. Interestingly, the consequences of GSTT1 mismatch might be either rejection or graft-versus-host disease, depending on the GSTT1 mismatch's sense of direction. The involvement of GSTT1 in immunological allo-recognition is unquestionable although there are still many aspects that remain to be explored. PMID- 23792057 TI - The impact of maternal anti-retroviral therapy on cytokine profile in the uninfected neonates. AB - The number of HIV-infected young women has been increasing since the beginning of the AIDS epidemic. The objective of the present study was to investigate the impact of anti-retroviral treatment (ART) of HIV-1-infected pregnant women (PW) on cytokine profile of uninfected neonates. Our results demonstrated that higher levels of IL-1beta and TNF-alpha associated with lower IL-10 production were detected in the plasma obtained from neonates born from ART-treated PW. Furthermore, the production of TNF- alpha and IFN-gamma was also significantly higher in polyclonally-activated T cells from those neonates. This elevated pro inflammatory pattern detected by these activated-T cells was not associated to HIV-1 antigens sensitization. Finally, ART-exposed neonates showed to be born with lower weight, and it was inversely correlated with maternal peripheral TNF-a level. In summary, the data presented here suggest a significant disturbance in cytokine network of HIV-1-uninfected neonates exposed to potent anti-retroviral schemes during pregnancy. PMID- 23792058 TI - HLA and MICA polymorphism in Polynesians and New Zealand Maori: implications for ancestry and health. AB - Data from HLA typing studies have made significant contributions to genetic theories about the Austronesian diaspora and the health of descendant populations. To help further unravel pattern and process elements, we have typed HLA and MICA loci at high resolution in DNA samples from well defined groups of Maori and Polynesian individuals. Our results show a restricted set of HLA class I alleles compared with other well characterised populations. In contrast, the class II HLA-DRB1 locus seems to be diverse in Maori and Polynesians and both groups show high frequencies of HLA-DRB1(*)04:03, -DRB1(*)08:03, -DRB1(*)09:01 and -DRB1(*)12:01. Our survey also provides the first ever MICA datasets for Polynesians and reveal unusual distributions and associations with the HLA-B locus. Overall, our data provide further support for a hybrid origin for Maori and Polynesians. One novel feature of our study is the finding that the gene sequence of the HLA-B(*)40:10 allele in Polynesians is a recombinant of HLA B(*)55:02 and -B(*)40:01. HLA-B(*)40:10 is in close association with HLA C(*)04:03, an allele identified as a hybrid of HLA-C(*)04 and -C(*)02. In this respect, our data resemble those reports on Amerindian tribes where inter-allele recombination has been a common means of generating diversity. However, we emphasize that Amerindian gene content per se is only a very minor element of the overall Polynesian genepool. The wider significance of HLA and MICA allele frequencies across the Pacific for modern day health is also discussed in terms of the frequency relative to reference populations of disease known to be associated with specific HLA and MICA markers. Thus, Polynesians and Maori are largely unaffected by "European autoimmune diseases" such as ankylosing spondylitis, uveitis and coeliacs disease, yet there are several Maori- and Polynesian-specific autoimmune diseases where the HLA and MICA associations are still to be determined. PMID- 23792059 TI - Autoimmune associations and autoantibody screening show focused recognition in patient subgroups with generalized myasthenia gravis. AB - Autoimmune associations in myasthenia gravis (MG)-patients and their relatives have not been re-assessed since their separation into early- or late-onset MG (EOMG, LOMG), or thymoma-associated MG. Here, we analysed 226 EOMG-, 97 LOMG-, and 150 thymoma-patients for autoimmune disorders in themselves and their relatives. From 283 of them sera were tested for different organ- and non-organ specific autoantibodies (autoAbs) by immunofluorescence test (IFT) and ELISA; genotyping was performed in 213 patients. Relatives with autoimmune disorders were reported by more patients with EOMG (40% of 210) than LOMG (20% of 89; p < 0.01) than thymomas (8% of 150; p < 0.001). In 150 genotyped EOMG-females, the known risk allele of the immuno-regulatory PTPN2 2 (R620W) appeared commoner in those with second autoimmune diseases (p ~ 0.06), or with autoimmune relatives (p ~ 0.03), than in those without. Organ-specific autoAbs were found in ~ 30% of all MG-patients, autoAbs to striated muscle only in patients with thymoma-MG (62%) or LOMG (61%). Titers against adrenal cortex were lower in LOMG-patients. Disease associated autoAbs against systemic targets or 'natural autoAbs' - except of autoAbs to nuclei - were uncommon in all groups (< 13%). Thus-with rare exceptions in EOMG and LOMG-we found minimal support for the notion that autoimmune patients have wide-ranging autoreactivity that causes disease only if it targets such Achilles' heels as the muscle acetylcholine receptor; even in thymoma-patients the autoAbs are sharply focused on a restricted range of muscle, cytokine and endocrine targets. PMID- 23792060 TI - Molecular characterization and functional analysis of Toll-like receptor 3 gene in orange-spotted grouper (Epinephelus coioides). AB - Toll-like receptor 3 (TLR3) plays an important role in activating innate immune responses during viral infection. In this report, TLR3 (EcTLR3) was characterized and analyzed for the first time in Epinephelus coioides. The full-length EcTLR3 cDNA is predicted to encode a 909 amino acid polypeptide that contains a signal peptide sequence, 18 leucine-rich repeat (LRR) motifs, a transmembrane region and a Toll/interleukin-1 receptor (TIR) domain. Quantitative real-time PCR revealed that the EcTLR3 mRNA was much more abundant in the liver than in other immune organs, and that the expression levels were very low in hemocyte and muscle. During development of the grouper, the levels of EcTLR3 transcripts increased with age, with very low expression levels at the early stages of development. EcTLR3 mRNA levels were examined in the liver at different times after treatment with polyriboinosinic polyribocytidylic acid (Poly I:C), and in nervous necrosis virus (NNV)-infected larval groupers. The results suggested that EcTLR3 plays an important role in a fish's defense against viral infection. PMID- 23792061 TI - Meta-analyses of HFE variants in coronary heart disease. AB - AIM: HFE gene variants can cause hereditary hemochromatosis (HH) that often comes along with an increased risk of coronary heart disease (CHD). The goal of our study is to assess the contribution of four HFE gene variants to the risk of CHD. METHODS AND RESULTS: We conducted four meta-analyses of the studies examining the association between four HFE gene variants and the risk of CHD. A systematic search was conducted using MEDLINE, EMBASE, Web of Science and China National Knowledge Infrastructure (CNKI), Wanfang Chinese Periodical. RESULTS: Meta analyses showed that HFE rs1799945-G allele was associated with a 6% increased risk of CHD (P=0.02, odds ratio (OR)=1.06, 95% confidence interval (CI)=1.01 1.11). However, no association between the other three HFE gene variants (rs1800562, rs1800730, and rs9366637) and CHD risk was observed by the meta analyses (all P values>0.05). In addition, the results of our case-control study indicated that rs1800562 and rs1800730 were monomorphic, and that rs1799945 and rs9366637 were not associated with CHD in Han Chinese. CONCLUSIONS: Our meta analysis suggested that a significant association existed between rs1799945 mutation and CHD, although this mutation was rare in Han Chinese. PMID- 23792062 TI - Palaeopathology and genes: investigating the genetics of infectious diseases in excavated human skeletal remains and mummies from past populations. AB - The aim of this paper is to review the use of genetics in palaeomicrobiology, and to highlight the importance of understanding past diseases. Palaeomicrobiology is the study of disease pathogens in skeletal and mummified remains from archaeological contexts. It has revolutionarised our understanding of health in the past by enabling a deeper knowledge of the origins and evolution of many diseases that have shaped us as a species. Bacterial diseases explored include tuberculosis, leprosy, bubonic plague, typhoid, syphilis, endemic and epidemic typhus, trench fever, and Helicobacter pylori. Viral diseases discussed include influenza, hepatitis B, human papilloma virus (HPV), human T-cell lymphotrophic virus (HTLV-1) and human immunodeficiency virus (HIV). Parasitic diseases investigated include malaria, leishmaniasis, Chagas' disease, roundworm, whipworm, pinworm, Chinese liver fluke, fleas and lice. Through a better understanding of disease origins and their evolution, we can place into context how many infectious diseases are changing over time, and so help us estimate how they may change in the future. PMID- 23792063 TI - Mosaicism for FMR1 gene full mutation and intermediate allele in a female foetus: a postzygotic retraction event. AB - Fragile X syndrome is caused by the expansion of an unstable CGG repeat in the 5'UTR of FMR1 gene. The occurrence of mosaicism is not uncommon, especially in male patients, whereas in females it is not so often reported. Here we report a female foetus that was subject to prenatal diagnosis, because of her mother being a premutation carrier. The foetus was identified as being a mosaic for an intermediate allele and a full mutation of FMR1 gene, in the presence of a normal allele. The mosaic status was confirmed in three different tissues of the foetus- amniotic fluid, skin biopsy and blood--the last two obtained after pregnancy termination. Karyotype analysis and X-chromosome STR markers analysis do not support the mosaicism as inheritance of both maternal alleles. Oligonucleotide array-CGH excluded an imbalance that could contain the primer binding site with a different repeat size. The obtained results give compelling evidence for a postzygotic expansion mechanism where the foetus mosaic pattern originated from expansion of the mother's premutation into a full mutation and consequent regression to an intermediate allele in a proportion of cells. These events occurred in early embryogenesis before the commitment of cells into the different tissues, as the three tested tissues of the foetus have the same mosaic pattern. The couple has a son with Fragile X mental retardation syndrome and choose to terminate this pregnancy after genetic counselling. PMID- 23792064 TI - Is LB1 diseased or modern? A review of the proposed pathologies. AB - The fossil remains of Homo floresiensis have been debated extensively over the past few years. This paper gives a review of the various pathologies ascribed to LB1, the type specimen of H. floresiensis, and associated individuals. This paper will assess the arguments for growth anomalies, microcephaly, Laron syndrome and cretinism. Additionally, some of the analyses done by proponents of the pathology theory will be methodologically evaluated. Subsequently, a brief overview of the alternative hypotheses regarding the origin of H. floresiensis will be given. PMID- 23792065 TI - Geographic variation in diapause induction and termination of the cotton bollworm, Helicoverpa armigera Hubner (Lepidoptera: Noctuidae). AB - Overwintering diapause in Helicoverpa armigera, a multivoltine species, is controlled by response to photoperiod and temperature. Photoperiodic responses from 5 different geographical populations showed that the variation in critical photoperiod for diapause induction was positively related to the latitudinal origin of the populations at 20, 22 and 25 degrees C. Diapause response to photoperiod and temperature was quite different between northern and southern populations, being highly sensitive to photoperiod in northern populations and temperature dependence in southern populations. Diapause pupae from southern population showed a significantly shorter diapause duration than from northern most populations when they were cultured at 20, 22, 25, 28 and 31 degrees C; by contrast, overwintering pupae from southern populations emerged significantly later than from northern populations when they were maintained in natural conditions, showing a clinal latitudinal variation in diapause termination. Diapause-inducing temperature had a significant effect on diapause duration, but with a significant difference between southern and northern populations. The higher rearing temperature of 22 degrees C evoked a more intense diapause than did 20 degrees C in northern populations; but a less intense diapause in southern population. Cold exposure (chilling) is not necessary to break the pupal diapause. The higher the temperature, the quicker the diapause terminated. Response of diapause termination to chilling showed that northern populations were more sensitive to chilling than southern population. All results demonstrate that H. armigera is not genetically homogeneous throughout its range, but rather is composed of distinct populations genetically adapted to local environmental conditions despite the potential for gene flow via seasonal migration of adults. PMID- 23792066 TI - Partitioning of liquid-ordered/liquid-disordered membrane microdomains induced by the fluidifying effect of 2-hydroxylated fatty acid derivatives. AB - Cellular functions are usually associated with the activity of proteins and nucleic acids. Recent studies have shown that lipids modulate the localization and activity of key membrane-associated signal transduction proteins, thus regulating the cell's physiology. Membrane Lipid Therapy aims to reverse cell dysfunctions (i.e., diseases) by modulating the activity of membrane signaling proteins through regulation of the lipid bilayer structure. The present work shows the ability of a series of 2-hydroxyfatty acid (2OHFA) derivatives, varying in the acyl chain length and degree of unsaturation, to regulate the membrane lipid structure. These molecules have shown greater therapeutic potential than their natural non-hydroxylated counterparts. We demonstrated that both 2OHFA and natural FAs induced reorganization of lipid domains in model membranes of POPC:SM:PE:Cho, modulating the liquid-ordered/liquid-disordered structures ratio and the microdomain lipid composition. Fluorescence spectroscopy, confocal microscopy, Fourier transform infrared spectroscopy and differential detergent solubilization experiments showed a destabilization of the membranes upon addition of the 2OHFAs and FAs which correlated with the observed disordering effect. The changes produced by these synthetic fatty acids on the lipid structure may constitute part of their mechanism of action, leading to changes in the localization/activity of membrane proteins involved in signaling cascades, and therefore modulating cell responses. PMID- 23792067 TI - Which agonist properties are important for the activation of 5-HT3A receptors? AB - PURPOSE: Why do anesthetics not activate excitatory ligand-gated ion channels such as 5-HT3 receptors in contrast to inhibitory ligand-gated ion channels? This study examines the actions of structural closely-related 5-HT derivatives and 5 HT constituent parts on 5-HT3A receptors with the aim of finding simpler if not minimal agonists and thus determining requirements for successful agonist action. EXPERIMENTAL APPROACH: Responses to 5-HT derivatives of human 5-HT3A receptors stably expressed in HEK 293 cells have been examined with the patch-clamp technique in the outside-out configuration combined with a fast solution exchange system. RESULTS: Phenol, pyrrole and alkyl amines, constituents of 5-HT, even at high concentrations, cannot activate 5-HT3A receptors but they can inhibit them. To date, tyramines are the smallest known agonists. However, an aromatic ring is not required for activation as acetylcholine is also an agonist of similar strength. CONCLUSION: Simultaneous interactions of adequate strength at two separate subsites within the 5-HT binding domain appear to be essential for successful agonist function. Anesthetics either fail to achieve this or the activation they produce is so weak that it is masked by a comparatively very strong inhibition. PMID- 23792068 TI - rBPI21 interacts with negative membranes endothermically promoting the formation of rigid multilamellar structures. AB - rBPI21 belongs to the antimicrobial peptide and protein (AMP) family. It has high affinity for lipopolysaccharide (LPS), acting mainly against Gram-negative bacteria. This work intends to elucidate the mechanism of action of rBPI21 at the membrane level. Using isothermal titration calorimetry, we observed that rBPI21 interaction occurs only with negatively charged membranes (mimicking bacterial membranes) and is entropically driven. Differential scanning calorimetry shows that membrane interaction with rBPI21 is followed by an increase of rigidity on negatively charged membrane, which is corroborated by small angle X-ray scattering (SAXS). Additionally, SAXS data reveal that rBPI21 promotes the multilamellarization of negatively charged membranes. The results support the proposed model for rBPI21 action: first it may interact with LPS at the bacterial surface. This entropic interaction could cause the release of ions that maintain the packed structure of LPS, ensuring peptide penetration. Then, rBPI21 may interact with the negatively charged leaflets of the outer and inner membranes, promoting the interaction between the two bacterial membranes, ultimately leading to cell death. PMID- 23792069 TI - Multicenter evaluation of hemoglobin A1c assay on capillary electrophoresis. AB - BACKGROUND: Hemoglobin A1c (HbA1c) measurement is currently used for the routine monitoring of long-term glycemic status, thus playing a fundamental role in the management of this disease. Since this marker has recently been recommended as an additional tool for diagnosing diabetes, it's of the utmost importance to ensure that the precision and accuracy of HbA1c methods are satisfactory. METHODS: We assessed the analytical performances of the Capillarys 2 Flex Piercing(r) analyzer and compared the results obtained with those from two other widely used HPLC instruments. Furthermore, we evaluated the convenience and ergonomics of the system in authentic routine work conditions in three centers. RESULTS: Within laboratory (n=40) and between-laboratory (n=120) imprecision CV% using four blood samples with different concentrations of HbA1c were <3.4% and <3.1% using IFCC units and <2.1% and <2.0% using NGSP units, respectively. The obtained trueness (<3 mmol/mol, <0.3%) was highly satisfactory, nor was HbA1c measurement compromised by the presence of the commonly present hemoglobinopathies. The comparison made with established methods revealed excellent agreement (r>0.985). CONCLUSIONS: The evaluated method is precise, accurate and robust, with a high throughput. It also allows the identification of the most frequent Hb variants and therefore may be a valid alternative to other methods currently proposed for routine use in clinical laboratories. PMID- 23792070 TI - Plasma allantoin measurement by isocratic liquid chromatography with tandem mass spectrometry: method evaluation and application in oxidative stress biomonitoring. AB - BACKGROUND: Allantoin in human plasma is a specific biomarker of oxidative stress. We describe a sensitive method to measure plasma allantoin using isocratic liquid chromatography and mass spectrometry (LC-MS/MS). METHODS: Direct injection of deproteinized plasma into the LC-MS/MS system was performed. The method was technically evaluated. Results on 200 healthy and 35 Type 2 diabetic Chinese subjects were compared. RESULTS: Dose-response of allantoin was linear to at least 21 pmol (20 MUmol/l in plasma); LOD was 0.16 pmol; recovery 99.2-100.2% at 1-5 MUmol/l; accuracy, 98.5-100.8%; within-day and between-day CVs (n=6), <4.0% (at 5.00-40 MUmol/l) and <2.0% (at 1-5 MUmol/l), respectively. Plasma allantoin in diabetic patients was ~8-fold higher than in healthy subjects; mean (SD): 8.82 (7.26) and 1.08 (0.86) MUmol/l, respectively (p<0.0001). Allantoin was slightly higher in healthy men than in age- and BMI-matched women: 1.21 (0.99) MUmol/l, n=88 compared to 0.97 (0.74) MUmol/l, n=112; p<0.001. No association with age was seen. Gender difference was also seen in the diabetes patients: men, n=14, 11.57 (8.57) MUmol/l; women, n=21, 6.99 (5.75) MUmol/l, p<0.05. CONCLUSIONS: Based on 95th percentiles of the healthy subjects, plasma allantoin of >2.2 MUmol/l in women and >3.1 MUmol/l in men indicates increased oxidative stress. Allantoin in diabetes subjects is clearly and markedly increased. The method will facilitate future studies of oxidative stress in human biomonitoring studies. PMID- 23792071 TI - The circulating level of MMP-9 and its ratio to TIMP-1 as a predictor of severity in patients with community-acquired pneumonia. AB - BACKGROUND: Here, we have examined the plasma levels of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1), the MMP-9/TIMP-1 molar ratio, the TIMP-1 single nucleotide polymorphisms (SNPs) 372C/T and the susceptibility to community-acquired pneumonia (CAP). METHODS: An enzyme-linked immunosorbent assay (ELISA) was used to measure plasma MMP-9 and TIMP-1 concentrations in 60 patients with CAP and 60 healthy individuals. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was used to detect the TIMP-1 SNPs 372C/T. RESULTS: The plasma MMP-9, TIMP-1 levels and the MMP-9/TIMP-1 molar ratio were significantly increased in patients with CAP compared to normal controls. The MMP-9/TIMP-1 molar ratio decreased significantly in patients with CAP after treatment. Furthermore, the plasma TIMP-1 concentration was positively correlated with the pneumonia severity index (PSI), the CURB score, the results of the acute physiology and chronic health evaluation II (APACHE II) and the length of the hospital stay. No significant difference was found in the genotype distribution of TIMP-1 372C/T between patients with CAP and normal controls. CONCLUSIONS: We hypothesize that MMP-9 levels and the MMP-9/TIMP 1 molar ratio play a role in the development of CAP and are related to the severity of CAP. Based on our data, we suggest that incorporating plasma MMP-9 levels and the MMP-9/TIMP-1 molar ratio into a clinical evaluation will aid in CAP diagnosis. PMID- 23792073 TI - Right orbital tumor: which diagnostic orientation? What therapeutic approach to adopt? What definitive diagnosis? Orbital schwannoma. PMID- 23792072 TI - Altered cortical activation in adolescents with acute migraine: a magnetoencephalography study. AB - To quantitatively assess cortical dysfunction in pediatric migraine, 31 adolescents with acute migraine and age- and gender-matched controls were studied using a magnetoencephalography (MEG) system at a sampling rate of 6,000 Hz. Neuromagnetic brain activation was elicited by a finger-tapping task. The spectral and spatial signatures of magnetoencephalography data in 5 to 2,884 Hz were analyzed using Morlet wavelet and beamformers. Compared with controls, 31 migraine subjects during their headache attack phases (ictal) showed significantly prolonged latencies of neuromagnetic activation in 5 to 30 Hz, increased spectral power in 100 to 200 Hz, and a higher likelihood of neuromagnetic activation in the supplementary motor area, the occipital and ipsilateral sensorimotor cortices, in 2,200 to 2,800 Hz. Of the 31 migraine subjects, 16 migraine subjects during their headache-free phases (interictal) showed that there were no significant differences between interictal and control MEG data except that interictal spectral power in 100 to 200 Hz was significantly decreased. The results demonstrated that migraine subjects had significantly aberrant ictal brain activation, which can normalize interictally. The spread of abnormal ictal brain activation in both low- and high-frequency ranges triggered by movements may play a key role in the cascade of migraine attacks. PERSPECTIVE: This is the first study focusing on the spectral and spatial signatures of cortical dysfunction in adolescents with migraine using MEG signals in a frequency range of 5 to 2,884 Hz. This methodology analyzing aberrant brain activation may be important for developing new therapeutic interventions for migraine in the future. PMID- 23792074 TI - Prophylactic and therapeutic functions of drug combinations against noise-induced hearing loss. AB - Noise is the most common occupational and environmental hazard. Noise-induced hearing loss (NIHL) is the second most common form of sensorineural hearing deficit, after age-related hearing loss (presbycusis). Although promising approaches have been identified for reducing NIHL, currently there are no effective medications to prevent NIHL. Development of an efficacious treatment has been hampered by the complex array of cellular and molecular pathways involved in NIHL. We turned this difficulty into an advantage by asking whether NIHL could be effectively prevented by targeting multiple signaling pathways with a combination of drugs already approved by U.S. Food and Drug Administration (FDA). We previously found that antiepileptic drugs blocking T-type calcium channels had both prophylactic and therapeutic effects for NIHL. NIHL can also be reduced by an up-regulation of glucocorticoid (GC) signaling pathways. Based on these findings, we tested a combination therapy for NIHL that included ethosuximide and zonisamide (anticonvulsants) and dexamethasone and methylprednisolone (synthetic GCs) in mice under exposure conditions typically associated with dramatic permanent threshold shifts (PTS). We first examined possible prophylactic effects for each drug when administered alone 2 h before noise, and calculated the median effective dose (ED50). We then tested for synergistic effects of two-drug combinations (anticonvulsant + GC), and identified combinations with the strongest synergy against NIHL, based on a previously established combination index (CI) metric. We repeated similar tests to determine their therapeutic effects when administered the same drugs 24 h after the noise exposure. Our study shows the feasibility of developing pharmacological intervention in multiple pathways, and discovering drug combinations with optimal synergistic effects in preventing permanent NIHL. PMID- 23792075 TI - Changes in utricular function during artificial endolymph injections in guinea pigs. AB - Various theories suggest endolymphatic hydrops may cause a rupture of the membranous labyrinth or may force open the utriculo-saccular duct, resulting in a sudden change in inner ear function. Here, we have used slow injections of artificial endolymph into either scala media or the utricle of anaesthetised guinea pigs to investigate the effects of hydrops. Vestibular function was continuously monitored in addition to the measurements of cochlear function developed in our laboratory (Brown et al. Hear Res, 2013). Scala media injection induced consistent functional changes, which occurred in two stages. Initial changes involved were associated with an increased hydrostatic pressure in scala media that only affected cochlear function. After 3-4 MUl of endolymph had been injected, cochlear function spontaneously recovered, and was often shortly followed by a transient increase or decrease in utricular sensitivity, with the effects varying between animals. Endolymph injection directly into the utricle produced variable effects across animals, although in 2 experiments it produced similar changes as those observed for scala media injections, suggesting that the fluid pathway between scala media and the utricle was continuous in these animals. The mechanism underlying the sudden, spontaneous functional changes is not yet clear, but we tentatively suggest that in some cases it may be caused by the utriculo-saccular duct suddenly opening to alleviate an elevated hydrostatic pressure in the pars inferior, resulting in a change in utricular function due to an increase in its volume. These changes are comparable to the sudden or fluctuating functional changes in Meniere's sufferers, and support the hypothesis that endolymphatic hydrops can directly cause some symptoms of this syndrome. PMID- 23792077 TI - Acoustic basis of context dependent brainstem encoding of speech. AB - The newfound context dependent brainstem encoding of speech is evidence of online regularity detection and modulation of the sub-cortical responses. We studied the influence of spectral structure of the contextual stimulus on context dependent encoding of speech at the brainstem, in an attempt to understand the acoustic basis for this effect. Fourteen normal hearing adults participated in a randomized true experimental design in whom brainstem responses were recorded. Brainstem responses for a high pass filtered /da/ in the context of syllables, that either had same or different spectral structure were compared with each other. The findings suggest that spectral structure is one of the parameters which cue the context dependent sub-cortical encoding of speech. Interestingly, the results also revealed that, brainstem can encode pitch even with negligible acoustic information below the second formant frequency. PMID- 23792076 TI - Representation of speech in human auditory cortex: is it special? AB - Successful categorization of phonemes in speech requires that the brain analyze the acoustic signal along both spectral and temporal dimensions. Neural encoding of the stimulus amplitude envelope is critical for parsing the speech stream into syllabic units. Encoding of voice onset time (VOT) and place of articulation (POA), cues necessary for determining phonemic identity, occurs within shorter time frames. An unresolved question is whether the neural representation of speech is based on processing mechanisms that are unique to humans and shaped by learning and experience, or is based on rules governing general auditory processing that are also present in non-human animals. This question was examined by comparing the neural activity elicited by speech and other complex vocalizations in primary auditory cortex of macaques, who are limited vocal learners, with that in Heschl's gyrus, the putative location of primary auditory cortex in humans. Entrainment to the amplitude envelope is neither specific to humans nor to human speech. VOT is represented by responses time-locked to consonant release and voicing onset in both humans and monkeys. Temporal representation of VOT is observed both for isolated syllables and for syllables embedded in the more naturalistic context of running speech. The fundamental frequency of male speakers is represented by more rapid neural activity phase locked to the glottal pulsation rate in both humans and monkeys. In both species, the differential representation of stop consonants varying in their POA can be predicted by the relationship between the frequency selectivity of neurons and the onset spectra of the speech sounds. These findings indicate that the neurophysiology of primary auditory cortex is similar in monkeys and humans despite their vastly different experience with human speech, and that Heschl's gyrus is engaged in general auditory, and not language-specific, processing. This article is part of a Special Issue entitled "Communication Sounds and the Brain: New Directions and Perspectives". PMID- 23792080 TI - Spliceosome twin introns in fungal nuclear transcripts. AB - The spliceosome is an RNA/protein complex, responsible for intron excision from eukaryotic nuclear transcripts. In bacteria, mitochondria and plastids, intron excision does not involve the spliceosome, but occurs through mechanisms dependent on intron RNA secondary and tertiary structure. For group II/III chloroplast introns, "twintrons" (introns within introns) have been described. The excision of the external intron, and thus proper RNA maturation, necessitates prior removal of the internal intron, which interrupts crucial sequences of the former. We have here predicted analogous instances of spliceosomal twintrons ("stwintrons") in filamentous fungi. In two specific cases, where the internal intron interrupts the donor of the external intron after the first or after the second nucleotide, respectively, we show that intermediates with the sequence predicted by the "stwintron" hypothesis, are produced in the splicing process. This implies that two successive rounds of RNA scanning by the spliceosome are necessary to produce the mature mRNA. The phylogenetic distributions of the stwintrons we have identified suggest that they derive from "late" events, subsequent to the appearance of the host intron. They may well not be limited to fungal nuclear transcripts, and their generation and eventual disappearance in the evolutionary process are relevant to hypotheses of intron origin and alternative splicing. PMID- 23792079 TI - A new Atp2b2 deafwaddler allele, dfw(i5), interacts strongly with Cdh23 and other auditory modifiers. AB - Tight regulation of calcium (Ca2+) concentrations in the stereocilia bundles of auditory hair cells of the inner ear is critical to normal auditory transduction. The plasma membrane Ca2+ ATPase 2 (PMCA2), encoded by the Atp2b2 gene, is the primary mechanism for clearance of Ca2+ from auditory stereocilia, keeping intracellular levels low, and also contributes to maintaining adequate levels of extracellular Ca2+ in the endolymph. This study characterizes a novel null Atp2b2 allele, dfw(i5), by examining cochlear anatomy, vestibular function and auditory physiology in mutant mice. Loss of auditory function in PMCA2 mutants can be attributed to dysregulation of intracellular Ca2+ inside the stereocilia bundles. However, extracellular Ca2+ ions surrounding the stereocilia are also required for rigidity of cadherin 23, a component of the stereocilia tip-link encoded by the Cdh23 gene. This study further resolves the interaction between Atp2b2 and Cdh23 in a gene dosage and frequency-dependent manner, and finds that low frequencies are significantly affected by the interaction. In +/dfw(i5) mice, one mutant copy of Cdh23 is sufficient to cause broad frequency hearing impairment. Additionally, we report another modifying interaction with Atp2b2 on auditory sensitivity, possibly caused by an unidentified hearing loss gene in mice. PMID- 23792081 TI - Endothelial cell preservation at hypothermic to normothermic conditions using clinical and experimental organ preservation solutions. AB - INTRODUCTION: Endothelial barrier function is pivotal for the outcome of organ transplantation. Since hypothermic preservation (gold standard) is associated with cold-induced endothelial damage, endothelial barrier function may benefit from organ preservation at warmer temperatures. We therefore assessed endothelial barrier integrity and viability as function of preservation temperature and perfusion solution, and hypothesized that endothelial cell preservation at subnormothermic conditions using metabolism-supporting solutions constitute optimal preservation conditions. METHODS: Human umbilical vein endothelial cells (HUVEC) were preserved at 4-37 degrees C for up to 20 h using Ringer's lactate, histidine-tryptophan-ketoglutarate solution, University of Wisconsin (UW) solution, Polysol, or endothelial cell growth medium (ECGM). Following preservation, the monolayer integrity, metabolic capacity, and ATP content were determined as positive parameters of endothelial cell viability. As negative parameters, apoptosis, necrosis, and cell activation were assayed. A viability index was devised on the basis of these parameters. RESULTS: HUVEC viability and barrier integrity was compromised at 4 degrees C regardless of the preservation solution. At temperatures above 20 degrees C, the cells' metabolic demands outweighed the preservation solutions' supporting capacity. Only UW maintained HUVEC viability up to 20 degrees C. Despite high intracellular ATP content, none of the solutions were capable of sufficiently preserving HUVEC above 20 degrees C except for ECGM. CONCLUSION: Optimal HUVEC preservation is achieved with UW up to 20 degrees C. Only ECGM maintains HUVEC viability at temperatures above 20 degrees C. PMID- 23792082 TI - The senescence-accelerated mouse-prone 8 is not a suitable model for the investigation of cardiac inflammation and oxidative stress and their modulation by dietary phytochemicals. AB - Aging is associated with chronic inflammation and oxidative stress, which both may promote age-associated disorders including cardiovascular diseases. The cardiovascular system suffers from the life-long impact of stressors, such as reactive oxygen and nitrogen species. A diet rich in vegetables and fruits, and thus phytochemicals, may extend healthy lifespan in humans, in part by improving heart health by lowering of oxidative stress and modulating signal transduction pathways. To investigate the potential impact of dietary anthocyanin-rich bilberry extract and curcumin on oxidative stress and inflammatory markers in the heart, two groups of senescence-accelerated mouse-resistant 1 (SAMR1) and senescence-accelerated mouse-prone 8 (SAMP8) mice, respectively, were fed a Western-type diet (normal control and aged control, respectively) and two groups of SAMP8 mice were fed either bilberry extract (20g/kg diet) or curcumin (500mg/kg diet) over a period of 5 months. An activation of the transcription factor nuclear factor kappa B (NFkappaB), but no differences in the gene and protein expression of NFkappaB-regulated pro-inflammatory mediators, was observed in the hearts of SAMP8 compared to SAMR1 control mice. Cardiac concentrations of protein and lipid oxidation parameters were similar in SAMR1 and SAMP8 control mice and the phytochemical-fed SAMP8 mice. Our data question the suitability of the SAMP8 and SAMR1 strains as a model for age-dependent changes of pro inflammatory cytokines and oxidative stress in the heart. PMID- 23792078 TI - Processing of communication sounds: contributions of learning, memory, and experience. AB - Abundant evidence from both field and lab studies has established that conspecific vocalizations (CVs) are of critical ecological significance for a wide variety of species, including humans, non-human primates, rodents, and other mammals and birds. Correspondingly, a number of experiments have demonstrated behavioral processing advantages for CVs, such as in discrimination and memory tasks. Further, a wide range of experiments have described brain regions in many species that appear to be specialized for processing CVs. For example, several neural regions have been described in both mammals and birds wherein greater neural responses are elicited by CVs than by comparison stimuli such as heterospecific vocalizations, nonvocal complex sounds, and artificial stimuli. These observations raise the question of whether these regions reflect domain specific neural mechanisms dedicated to processing CVs, or alternatively, if these regions reflect domain-general neural mechanisms for representing complex sounds of learned significance. Inasmuch as CVs can be viewed as complex combinations of basic spectrotemporal features, the plausibility of the latter position is supported by a large body of literature describing modulated cortical and subcortical representation of a variety of acoustic features that have been experimentally associated with stimuli of natural behavioral significance (such as food rewards). Herein, we review a relatively small body of existing literature describing the roles of experience, learning, and memory in the emergence of species-typical neural representations of CVs and auditory system plasticity. In both songbirds and mammals, manipulations of auditory experience as well as specific learning paradigms are shown to modulate neural responses evoked by CVs, either in terms of overall firing rate or temporal firing patterns. In some cases, CV-sensitive neural regions gradually acquire representation of non-CV stimuli with which subjects have training and experience. These results parallel literature in humans describing modulation of responses in face-sensitive neural regions through learning and experience. Thus, although many questions remain, the available evidence is consistent with the notion that CVs may acquire distinct neural representation through domain-general mechanisms for representing complex auditory objects that are of learned importance to the animal. This article is part of a Special Issue entitled "Communication Sounds and the Brain: New Directions and Perspectives". PMID- 23792083 TI - Opportunity to monitor immunosuppressive drugs in peripheral blood mononuclear cells: where are we and where are we going? AB - Immunosuppressive (IS) drugs are now widely used as preventive treatments of allograft rejection in transplantation. Therapeutic drug monitoring (TDM) using trough whole blood concentrations is usually warranted and therapeutic range is recommended to ensure efficacy and prevent toxicity from these drugs. This intensive TDM reduces acute graft rejection but despite this management, the acute rejection rate still remains high in the first two years post transplantation and few improvements have been made recently to reduce this rate. Moreover, in some patients, acute rejections occur despite adequate trough whole blood IS concentrations. Thus, other ways to monitor immunosuppressive drug effects have to be investigated. As lymphocyte cells are the site of action of IS drugs and so the effect compartment of the drug, monitoring IS drugs in lymphocytes, or for practical reasons in peripheral blood mononuclear cells (PBMC), could be more relevant than standard TDM. The aim of this paper is to review the recent work conducted on the advantages of monitoring IS drugs in PBMC, particularly for calcineurin inhibitors and mammalian target of rapamycin (m-TOR) inhibitors, from an analytical point of view as well as a clinical point of view. PMID- 23792084 TI - A sweet piece of dark chocolate in a hot cup of dark coffee: a novel elixir for a long and happy life? PMID- 23792085 TI - Infant dietary exposure to dioxins and dioxin-like compounds in Greece. AB - The dietary exposure of infants to polychlorinated dibenzo dioxins and furans (PCDD/Fs) and dioxin like polychlorinated biphenyls (dl-PCBs) is an issue of great social impact. We investigated for the first time the dietary intake of these compounds in infants living in Greece. We included in our study two age groups: 0-6 months, when infants are fed exclusively by human milk and/or formula milk, and 6 to 12 months, when solid food is introduced to nutrition. We took into consideration analytical results for PCDD/Fs and dl-PCBs concentrations in the most popular infant formulae in the Greek market, previous data for mother milk concentrations of PCDD/Fs and dl-PCBs from Greece, and finally analytical data for fat-containing food products from the Greek market. In the first study group, it was found than in infants exclusively fed by breast milk, the calculated sum of PCDD/Fs and dioxin-like PCBs (60.3-80.4 TEQ pg/kg body weight) was significantly higher than that of infants that consume a combination of human milk and formula (31.2-41.6 TEQ pg/kg body weight). In the second study group, separate daily intake estimations were performed for babies receiving human milk (estimated total daily intake 19.76-24.95 TEQ pg/kg body weight) and formula milk (estimated total daily intake 1.60-2.24 TEQ pg/kg body weight). The risks of this exposure should not be overestimated because nursing is restricted to a limited period of human life and besides, the potential consumption of higher levels of dioxin-like compounds is fully compensated by the significant benefits of breast feeding. PMID- 23792086 TI - ROS-major mediators of extracellular matrix remodeling during tumor progression. AB - Extracellular matrices (ECMs) represent a complex network of proteins, proteoglycans and glycosaminoglycans (GAGs), composed of independent structural domains, ultimately constituting the cell microenvironment. As a highly organized, insoluble suprastructure, the ECM can, in a spatially patterned and regulated manner, integrate and deliver multiple complex signals to cells that affect their behavior. During the progression of carcinogenesis, tumor cells, through a continually changing interface, remodel and simultaneously interact with the components of ECM, as well as with surrounding stromal cells. Within this complex network of ECM components affecting tumor progression, reactive oxygen species/reactive nitrogen species (ROS/RNS) play a wide emerging role. In this minireview we will focus on the ROS-dependent modulations of tumor ECM and how this in turn affects the insidious pathways of tumor progression and dissemination. PMID- 23792088 TI - Pathophysiology-based novel pharmacotherapy for heart failure with preserved ejection fraction. AB - Heart failure has become increasingly prevalent and poses a significant socioeconomic burden in the developed world. Approximately half of heart failure patients have preserved ejection fraction (HFpEF) and experience an increased morbidity and mortality attributed to the lack of effective therapies and to the presence of comorbidities. Suppression of neurohormonal activation by beta blockers and renin-angiotensin-aldosterone system inhibitors is the cornerstone in the pharmacotherapy of heart failure with reduced ejection fraction (HFrEF). However, these medications are not associated with significant clinical benefit in HFpEF. In this review, we provide an in-depth pathophysiology-based update on novel pharmacotherapies of HFpEF. A deeper insight into the pathophysiologic mechanisms of HFpEF may create opportunities for novel pharmacological interventions. PMID- 23792089 TI - Vitamin D deficiency and severe asthma. AB - Vitamin D has received tremendous amount of attention recently due to the ever increasing reports of association between vitamin D deficiency and a wide range of conditions, from cancer to fertility to longevity. The fascination of disease association with vitamin D deficiency comes from the relatively easy solution to overcome such a risk factor, that is, either by increase in sun exposure and/or diet supplementation. Many reviews have been written on a protective role of vitamin D in asthma and related morbidities; here, we will summarize the epidemiological evidence supporting a role of vitamin D against hallmark features of severe asthma, such as airway remodeling and asthma exacerbations. Furthermore, we discuss data from in vitro and in vivo studies which provide insights on the potential mechanisms of how vitamin D may protect against severe asthma pathogenesis and how vitamin D deficiency may lead to the development of severe asthma. Approximately 5-15% of asthmatic individuals suffer from the more severe forms of disease in spite of aggressive therapies and they are more likely to have irreversible airflow obstruction associated with airway remodeling. At present drugs commonly used to control asthma symptoms, such as corticosteroids, do not significantly reverse or reduce remodeling in the airways. Hence, if vitamin D plays a protective role against the development of severe asthma, then the most effective therapy may simply be a healthy dose of sunshine. PMID- 23792090 TI - Organism and artifact: Proper functions in Paley organisms. AB - In this paper I assess the explanatory powers of theories of function in the context of products that may result from synthetic biology. The aim is not to develop a new theory of functions, but to assess existing theories of function in relation to a new kind of biological and artifactual entity that might be produced in the not-too-distant future by means of synthetic biology. The paper thus investigates how to conceive of the functional nature of living systems that are not the result of evolution by natural selection, or instantly generated by cosmic coincidence, but which are products of intelligent design. The paper argues that the aetiological theory of proper functions in organisms and artifacts is inadequate as an account of proper functions in such 'Paley organisms' and defends an alternative organisational approach. The paper ends by considering the implications of the discussion of biological function for questions about the interests and moral status of non-sentient organisms. PMID- 23792087 TI - Multiplicity of effectors of the cardioprotective agent, diazoxide. AB - Diazoxide has been identified over the past 50years to have a number of physiological effects, including lowering the blood pressure and rectifying hypoglycemia. Today it is used clinically to treat these conditions. More recently, another important mode of action emerged: diazoxide has powerful protective properties against cardiac ischemia. The heart has intrinsic protective mechanisms against ischemia injury; one of which is ischemic preconditioning. Diazoxide mimics ischemic preconditioning. The purpose of this treatise is to review the literature in an attempt to identify the many effectors of diazoxide and discuss how they may contribute to diazoxide's cardioprotective properties. Particular emphasis is placed on the concentration ranges in which diazoxide affects its different targets and how this compares with the concentrations commonly used to study cardioprotection. It is concluded that diazoxide may have several potential effectors that may potentially contribute to cardioprotection, including KATP channels in the pancreas, smooth muscle, endothelium, neurons and the mitochondrial inner membrane. Diazoxide may also affect other ion channels and ATPases and may directly regulate mitochondrial energetics. It is possible that the success of diazoxide lies in this promiscuity and that the compound acts to rebalance multiple physiological processes during cardiac ischemia. PMID- 23792091 TI - Machine wanting. AB - Wants, preferences, and cares are physical things or events, not ideas or propositions, and therefore no chain of pure logic can conclude with a want, preference, or care. It follows that no pure-logic machine will ever want, prefer, or care. And its behavior will never be driven in the way that deliberate human behavior is driven, in other words, it will not be motivated or goal directed. Therefore, if we want to simulate human-style interactions with the world, we will need to first understand the physical structure of goal-directed systems. I argue that all such systems share a common nested structure, consisting of a smaller entity that moves within and is driven by a larger field that contains it. In such systems, the smaller contained entity is directed by the field, but also moves to some degree independently of it, allowing the entity to deviate and return, to show the plasticity and persistence that is characteristic of goal direction. If all this is right, then human want-driven behavior probably involves a behavior-generating mechanism that is contained within a neural field of some kind. In principle, for goal directedness generally, the containment can be virtual, raising the possibility that want driven behavior could be simulated in standard computational systems. But there are also reasons to believe that goal-direction works better when containment is also physical, suggesting that a new kind of hardware may be necessary. PMID- 23792092 TI - Natural occurrence of White spot syndrome virus and Infectious hypodermal and hematopoietic necrosis virus in Neohelice granulata crab. AB - White spot syndrome virus (WSSV) and Infectious hypodermal and hematopoietic necrosis virus (IHHNV) are two infectious agents associated to economic losses in shrimp aquaculture. As virus spread occurs through vectors and hosts, this study sought to verify the presence of WSSV and IHHNV in Neohelice granulata crab from Lagoa dos Patos estuary in Brazil and nearby shrimp farms. DNA extractions were performed with phenol/chloroform protocol. Molecular diagnosis was carried out by nested PCR for WSSV and one-step PCR for IHHNV. Results showed the presence of WSSV on crabs of both Lagoa dos Patos and farms, while IHHNV was found only on crabs collected in estuary. This is the first study to report IHHNV presence in N. granulata. Moreover, as analyzed crabs had no clinical symptoms or showed in situ mortality, we suggest its use as a bioindicator for virus occurrence in aquatic environments. PMID- 23792093 TI - IGF-1R and ErbB3/HER3 contribute to enhanced proliferation and carcinogenesis in trastuzumab-resistant ovarian cancer model. AB - Trastuzumab (Herceptin(r)) has demonstrated clinical potential in several types of HER2-overexpressing human cancers. However, primary and acquired resistance occurs in many HER2-positive patients with regimens. To investigate the possible mechanism of acquired therapeutic resistance to trastuzumab, we have developed a preclinical model of human ovarian cancer cells, SKOV3/T, with the distinctive feature of stronger carcinogenesis. The differences in gene expression between parental and the resistant cells were explored by microarray analysis, of which IGF-1R and HER3 were detected to be key molecules in action. Their correctness was validated by follow-up experiments of RT-PCR, shRNA-mediated knockdown, downstream signal activation, cell cycle distribution and survival. These results suggest that IGF-1R and HER3 differentially regulate trastuzumab resistance and could be promising targets for trastuzumab therapy in ovarian cancer. PMID- 23792094 TI - Increasing the electron-transfer ability of Cyanidioschyzon merolae ferredoxin by a one-point mutation--a high resolution and Fe-SAD phasing crystal structure analysis of the Asp58Asn mutant. AB - Cyanidioschyzon merolae (Cm) is a single cell red algae that grows in rather thermophilic (40-50 degrees C) and acidic (pH 1-3) conditions. Ferredoxin (Fd) was purified from this algae and characterized as a plant-type [2Fe-2S] Fd by physicochemical techniques. A high resolution (0.97A) three-dimensional structure of the CmFd D58N mutant molecule has been determined using the Fe-SAD phasing method to clarify the precise position of the Asn58 amide, as this substitution increases the electron-transfer ability relative to wild-type CmFd by a factor of 1.5. The crystal structure reveals an electro-positive surface surrounding Asn58 that may interact with ferredoxin NADP(+) reductase or cytochrome c. PMID- 23792095 TI - C6-Deoxy coelenterazine analogues as an efficient substrate for glow luminescence reaction of nanoKAZ: the mutated catalytic 19 kDa component of Oplophorus luciferase. AB - The codon-optimized gene for the mutated 19 kDa protein (nanoKAZ), which is the catalytic component of Oplophorus luciferase, was expressed in Escherichia coli cells and the recombinant protein was highly purified. The secretory expression of nanoKAZ from CHO-K1 cells was performed by fusing the secretory signal peptide sequence of Gaussia luciferase to the amino-terminus of nanoKAZ. The substrate specificity for the purified nanoKAZ and the nanoKAZ secreted into the cultured medium was determined, indicating that bis-coelenterazine (bis-CTZ) and newly synthesized 6h-f-coelenterazine (6h-f-CTZ) are an efficient substrate for the glow luminescence reaction of nanoKAZ. PMID- 23792096 TI - Crystallographic study of multi-drug resistant HIV-1 protease lopinavir complex: mechanism of drug recognition and resistance. AB - Lopinavir (LPV) is a second generation HIV-1 protease inhibitor. Drug resistance has rapidly emerged against LPV since its US FDA approval on September 15, 2000. Mutations at residues 32I, L33F, 46I, 47A, I54V, V82A, I84V, and L90M render the protease drug resistant against LPV. We report the crystal structure of a clinical isolate multi-drug resistant (MDR) 769 HIV-1 protease (resistant mutations at residues 10, 36, 46, 54, 62, 63, 71, 82, 84, and 90) complexed with LPV and the in vitro enzymatic IC50 of LPV against MDR 769. The structural and functional studies demonstrate significant drug resistance of MDR 769 against LPV, arising from reduced interactions between LPV and the protease target. PMID- 23792097 TI - Combined treatment with SAHA, bortezomib, and clarithromycin for concomitant targeting of aggresome formation and intracellular proteolytic pathways enhances ER stress-mediated cell death in breast cancer cells. AB - The ubiquitin-proteasome pathway and the autophagy-lysosome pathway are two major intracellular protein degradation systems. We previously reported that clarithromycin (CAM) blocks autophagy flux, and that combined treatment with CAM and proteasome inhibitor bortezomib (BZ) enhances ER-stress-mediated apoptosis in breast cancer cells, whereas treatment with CAM alone results in almost no cytotoxicity. Since HDAC6 is involved in aggresome formation, which is recognized as a cytoprotective response serving to sequester misfolded proteins and facilitate their clearance by autophagy, we further investigated the combined effect of vorinostat (suberoylanilide hydroxamic acid (SAHA)), which has a potent inhibitory effect for HDAC6, with CAM and BZ in breast cancer cell lines. SAHA exhibited some cytotoxicity along with an increased acetylation level of alpha tubulin, a substrate of HDAC6. Combined treatment of SAHA, CAM, and BZ potently enhanced the apoptosis-inducing effect compared with treatment using each reagent alone or a combination of two of the three. Expression levels of ER-stress related genes, including the pro-apoptotic transcription factor CHOP (GADD153), were maximally induced by the simultaneous combination of three reagents. Like breast cancer cell lines, a wild-type murine embryonic fibroblast (MEF) cell line exhibited enhanced cytotoxicity and maximally up-regulated Chop after combined treatment with SAHA, CAM, and BZ; however, a Chop knockout MEF cell line almost completely canceled this enhanced effect. The specific HDAC6 inhibitor tubacin also exhibited a pronounced cytocidal effect with a combination of CAM plus BZ. These data suggest that simultaneous targeting of intracellular proteolytic pathways and HDAC6 enhances ER-stress-mediated apoptosis in breast cancer cells. PMID- 23792098 TI - Mitochondrial function is impaired in yeast and human cellular models of Shwachman Diamond syndrome. AB - Shwachman Diamond syndrome (SDS) is an inherited bone marrow failure syndrome typically characterized by neutropenia, exocrine pancreas dysfunction, metaphyseal chondrodysplasia, and predisposition to myelodysplastic syndrome and leukemia. SBDS, the gene affected in most cases of SDS, encodes a protein known to influence many cellular processes including ribosome biogenesis, mitotic spindle assembly, chemotaxis, and the regulation of reactive oxygen species production. The best characterized role for the SBDS protein is in the production of functional 60S ribosomal subunits. Given that a reduction in functional 60S subunits could impact on the translational output of cells depleted of SBDS we analyzed protein synthesis in yeast cells lacking SDO1, the ortholog of SBDS. Cells lacking SDO1 selectively increased the synthesis of POR1, the ortholog of mammalian VDAC1 a major anion channel of the mitochondrial outer membrane. Further studies revealed the cells lacking SDO1 were compromised in growth on non fermentable carbon sources suggesting mitochondrial function was impaired. These observations prompted us to examine mitochondrial function in human cells where SBDS expression was reduced. Our studies indicate that reduced expression of SBDS decreases mitochondrial membrane potential and oxygen consumption and increases the production of reactive oxygen species. These studies indicate that mitochondrial function is also perturbed in cells expressing reduced amounts of SBDS and indicate that disruption of mitochondrial function may also contribute to SDS pathophysiology. PMID- 23792099 TI - Systems-level understanding of how Propionibacterium acidipropionici respond to propionic acid stress at the microenvironment levels: mechanism and application. AB - In previous work, three evolved Propionibacterium acidipropionici mutants with higher tolerant capacity of propionic acid (PA) were obtained by genome shuffling. Here, we attempted to unravel the acid-tolerant mechanism of P. acidipropionici by comparing the physiological changes between P. acidipropionici and three mutants. The parameters used for comparison included intracellular pH (pHi), NAD+/NADH ratio, H+-ATPase activity, and the intracellular amino acids concentrations. It was indicated that the acid tolerance of P. acidipropionici was systematically regulated. Specifically, low pHi promoted the P. acidipropionici to biosynthesize more H+-ATPase to pump the protons out of the cells, and as a result, the NAD+/NADH ratio increased due to the decreased protons concentration. The increased arginine, aspartic acid, and glutamic acid concentrations helped to resist the acidic environment by consuming more H+ and generating more ATP and NH3. Based on what was analyzed above, 20 mM arginine and aspartic acid were added during the shaker culture of P. acidipropionici, and the maximal PA titer reached 14.38 g/L, which was increased by 39.9% compared with the control. PMID- 23792100 TI - Long term stability of lyophilized plasmid DNA pDERMATT. AB - In this short note we report on the shelf-life stability of pDERMATT (plasmid DNA encoding recombinant MART-1 and tetanus toxin fragment-c) 2mg lyophilized powder for reconstitution for intradermal administration, used in an in-house, investigator-initiated clinical phase I study. pDERMATT was stored at 25 degrees C/60% relative humidity (6 months), 2-8 degrees C (24 months), and -20 degrees C (66 months) in the dark and analyzed at several timepoints during the conduct of the clinical study for appearance, identity, purity (plasmid topology), content and residual water content. pDERMATT appeared stable at all storage conditions for the periods tested which, although patient inclusion in the study was significantly delayed, ensured the clinical supply needs. This study shows that lyophilization is an useful tool to preserve the quality of the pDNA and can prevent the need for costly and time-consuming additional manufacture of drug product in case of study delays, not uncommon at the early stage of drug development. To our knowledge, this is the first study reporting shelf life stability of a pDNA formulation for more than 5 years. PMID- 23792101 TI - Symptomatic calcified perineural cyst after use of bone morphogenetic protein in transforaminal lumbar interbody fusion: a case report. AB - BACKGROUND CONTEXT: Human recombinant bone morphogenetic protein-2 (BMP-2) is commonly used in spinal surgery to augment arthrodesis, and a number of potential complications have been documented. PURPOSE: To present the case of a delayed radiculopathy that occurred because of a calcified perineural cyst that formed after an L4-L5 transforaminal lumbar interbody fusion (TLIF) in which BMP-2 was used. STUDY DESIGN/SETTING: Case report of a 70-year-old man presented with back and right lower extremity pain. METHODS: A 70-year-old man who had previously undergone a right L4-L5 TLIF presented 20 months after surgery with progressively radiating right leg pain. Imaging revealed a right-sided L4-L5 cystic lesion posterior to the interbody cage. The patient underwent reexploration, and a calcified mass was discovered. RESULTS: Histopathology revealed fragments of organized collagenous connective tissue, new collagen, and partially calcified fragments of fibrocartilage, bone, and ligament. CONCLUSIONS: This is the first reported case of a symptomatic calcified perineural cyst developing after a fusion procedure in which BMP-2 was used. The presence of connective tissue with metaplastic bone formation and maturation within the lesion suggests that formation of the cyst was secondary to application of BMP-2, as it possesses both osteogenic and chondrogenic capabilities. PMID- 23792102 TI - Phenotype variations affect genetic association studies of degenerative disc disease: conclusions of analysis of genetic association of 58 single nucleotide polymorphisms with highly specific phenotypes for disc degeneration in 332 subjects. AB - BACKGROUND CONTEXT: Although the influence of genetics on the process of disc degeneration is well recognized, in recently published studies, there is a wide variation in the race and selection criteria for such study populations. More importantly, the radiographic features of disc degeneration that are selected to represent the disc degeneration phenotype are variable in these studies. The study presented here evaluates the association between single nucleotide polymorphisms (SNPs) of candidate genes and three distinct radiographic features that can be defined as the degenerative disc disease (DDD) phenotype. PURPOSE: The study objectives were to examine the allelic diversity of 58 SNPs related to 35 candidate genes related to lumbar DDD, to evaluate the association in a hitherto unevaluated ethnic Indian population that represents more than one-sixth of the world population, and to analyze how genetic associations can vary in the same study subjects with the choice of phenotype. STUDY DESIGN: A cross sectional, case-control study of an ethnic Indian population was carried out. METHODS: Fifty-eight SNPs in 35 potential candidate genes were evaluated in 342 subjects and the associations were analyzed against three highly specific markers for DDD, namely disc degeneration by Pfirrmann grading, end-plate damage evaluated by total end-plate damage score, and annular tears evaluated by disc herniations and hyperintense zones. Genotyping of cases and controls was performed on a genome-wide SNP array to identify potential associated disease loci. The results from the genome-wide SNP array were then used to facilitate SNP selection and genotype validation was conducted using Sequenom-based genotyping. RESULTS: Eleven of the 58 SNPs provided evidence of association with one of the phenotypes. For annular tears, rs1042631 SNP of AGC1 and rs467691 SNP of ADAMTS5 were highly significantly associated (p<.01) and SNPs in NGFB, IL1B, IL18RAP, and MMP10 were also significantly associated (p<.05). The rs4076018 SNP of NGFB was highly significant (p<.01) and rs2292657 SNP of GLI1 was significantly (p<.05) correlated to disc degeneration. For end-plate damage, the rs2252070 SNP of MMP 13 showed a significant association (p<.05). Previously associated genes such as COL 9, SKT, CHST 3, CILP, IGFR, SOXp, BMP, MMP 2-12, ADH2, IL1RN, and COX2 were not significantly associated and new associations (NGFB and GLI1) were identified. The validity of all the associations was found to be phenotype dependent. CONCLUSIONS: For the first time, genetic associations with DDD have been performed in an Indian population. Apart from identifying new associations, the highlight of the study was that in the same study population with DDD, SNP associations completely changed when different radiographic features were used to define the DDD phenotype. Our study results therefore indicate that standardization of the phenotypes chosen to study the genetics of disc degeneration is essential and should be strongly considered before planning genetic association studies. PMID- 23792103 TI - The 7th International Nitric Oxide Meeting. PMID- 23792104 TI - Adverse drug reactions induced by valproic acid. AB - Valproic acid is a widely-used first-generation antiepileptic drug, prescribed predominantly in epilepsy and psychiatric disorders. VPA has good efficacy and pharmacoeconomic profiles, as well as a relatively favorable safety profile. However, adverse drug reactions have been reported in relation with valproic acid use, either as monotherapy or polytherapy with other antiepileptic drugs or antipsychotic drugs. This systematic review discusses valproic acid adverse drug reactions, in terms of hepatotoxicity, mitochondrial toxicity, hyperammonemic encephalopathy, hypersensitivity syndrome reactions, neurological toxicity, metabolic and endocrine adverse events, and teratogenicity. PMID- 23792105 TI - Rapid detection of K-, N-, H-RAS, and BRAF hotspot mutations in thyroid cancer using the multiplex primer extension. AB - OBJECTIVES: The objective of this study is to develop a multiplex PCR and primer extension to detect K-, N-, H-RAS, and BRAF mutations. DESIGN AND METHODS: DNA samples were isolated from 76 thyroid cancer patients. Multiplex amplification of exons 2 and 3 of three RAS genes and exon 15 of the BRAF gene using three pairs of primers was performed in a single tube. The products were split into three tubes. First, we used nine different-sized N-RAS and BRAF primers to detect base changes in N-RAS and BRAF. The other two tubes used seven separate different sized K-RAS and H-RAS primers to detect base changes. RESULTS: We compared these results with direct sequencing. The two methods generated identical results, but our method was superior to direct sequencing in terms of the amount of work and time involved. CONCLUSIONS: We present a rapid method to detect mutations of K-, N-, H-RAS, and BRAF in human cancers. PMID- 23792106 TI - Atorvastatin in stable angina patients lowers CCL2 and ICAM1 expression: pleiotropic evidence from plasma mRNA analyses. AB - OBJECTIVE: Statin pleiotropy is still an evolving concept, and the lack of clarity on this subject is due at least in part to the lack of a definitive biomarker for statin pleiotropy. Using plasma mRNA analysis as a novel research tool for the non-invasive in vivo assessment of gene expression in vascular beds, we hypothesised that atorvastatin lowers the plasma mRNA level from statin pleiotropy-target genes, and the reduction is independent of the reduction of low density lipoprotein cholesterol (LDL-C). DESIGN AND METHODS: Forty-four patients with stable angina received atorvastatin therapy (20 mg/day, 10 weeks). Plasma chemokine (C-C motif) ligand 2 (CCL2) and intercellular adhesion molecule-1 (ICAM1) mRNA levels and their protein concentrations (MCP-1, sICAM-1) were analysed before and after the treatment. Plasma vascular adhesion molecule-1 (sVCAM-1) concentrations were also analysed. RESULTS: Atorvastatin lowered plasma mRNA levels (CCL2: -31.76%, p=0.037; ICAM1: -34.09%, p<0.001) and MCP-1 protein concentration (-18.88%, p=0.008) but did not lower sICAM-1 and sVCAM-1 protein concentrations, and the decreases appeared to be independent from the lowering of LDL-C. The plasma mRNA levels correlated with their protein concentrations following statin treatment only. CONCLUSION: Our results significantly strengthen the clinical evidence in support of statin pleiotropy. Furthermore, this unique simultaneous measurement of plasma mRNAs and their protein concentrations offers an advanced non-invasive in vivo assessment of the circulation pathology. PMID- 23792107 TI - Cancer systems biology in the genome sequencing era: part 2, evolutionary dynamics of tumor clonal networks and drug resistance. AB - A tumor often consists of multiple cell subpopulations (clones). Current chemo treatments often target one clone of a tumor. Although the drug kills that clone, other clones overtake it and the tumor recurs. Genome sequencing and computational analysis allows to computational dissection of clones from tumors, while singe-cell genome sequencing including RNA-Seq allows profiling of these clones. This opens a new window for treating a tumor as a system in which clones are evolving. Future cancer systems biology studies should consider a tumor as an evolving system with multiple clones. Therefore, topics discussed in Part 2 of this review include evolutionary dynamics of clonal networks, early-warning signals (e.g., genome duplication events) for formation of fast-growing clones, dissecting tumor heterogeneity, and modeling of clone-clone-stroma interactions for drug resistance. The ultimate goal of the future systems biology analysis is to obtain a 'whole-system' understanding of a tumor and therefore provides a more efficient and personalized management strategies for cancer patients. PMID- 23792109 TI - Optimal codon randomization via mathematical programming. AB - Codon randomization via degenerate oligonucleotides is a widely used approach for generating protein libraries. We use integer programming methodology to model and solve the problem of computing the minimal mixture of oligonucleotides required to induce an arbitrary target probability over the 20 standard amino acids. We consider both randomization via conventional degenerate oligonucleotides, which incorporate at each position of the randomized codon certain nucleotides in equal probabilities, and randomization via spiked oligonucleotides, which admit arbitrary nucleotide distribution at each of the codon's positions. Existing methods for computing such mixtures rely on various heuristics. PMID- 23792108 TI - Role of phospholipase A2 (PLA2) inhibitors in attenuating apoptosis of the corneal epithelial cells and mitigation of Acanthamoeba keratitis. AB - The aim of this study is to determine if the mannose-induced protein (MIP-133) from Acanthamoeba castellanii trophozoites induces apoptosis of corneal epithelial cells through a cytosolic phospholipase A2alpha (cPLA2alpha)-mediated pathway. The efficacy of cPLA2alpha inhibitors to provide protection against Acanthamoeba keratitis was examined in vivo. Chinese hamster corneal epithelial (HCORN) cells were incubated with or without MIP-133. MIP-133 induces significant increase in cPLA2alpha and macrophage inflammatory protein-2 (MIP-2/CXCL2) levels from corneal cells. Moreover, cPLA2alpha inhibitors, MAFP (Methyl-arachidonyl fluorophosphonate) and AACOCF3 (Arachidonyl trifluoromethyl ketone), significantly reduce cPLA2alpha and CXCL2 from these cells (P < 0.05). Additionally, cPLA2alpha inhibitors significantly inhibit MIP-133-induced apoptosis in HCORN cells (P < 0.05). Subconjunctival injection of purified MIP 133 in Chinese hamster eyes induced cytopathic effects resulting in corneal ulceration. Animals infected with A. castellanii-laden contact lenses and treated with AACOCF3 and CAY10650, showed significantly less severe keratitis as compared with control animals. Collectively, the results indicate that cPLA2alpha is involved in MIP-133 induced apoptosis of corneal epithelial cells, polymorphonuclear neutrophil infiltration, and production of CXCL2. Moreover, cPLA2alpha inhibitors can be used as a therapeutic target in Acanthamoeba keratitis. PMID- 23792110 TI - Balloon warming time is the strongest predictor of late pulmonary vein electrical reconnection following cryoballoon ablation for atrial fibrillation. AB - BACKGROUND: Pulmonary vein isolation by cryoballoon ablation is an accepted method of treating atrial fibrillation. Little data exist regarding factors affecting late electrical reconnection of pulmonary veins following cryoballoon ablation. OBJECTIVE: To investigate factors determining pulmonary vein reconnection in patients undergoing repeat catheter ablation for recurrent atrial fibrillation following cryoballoon ablation. METHODS: Fifty-one consecutive patients undergoing repeat catheter ablation for recurrent atrial fibrillation following initial cryoballoon ablation underwent retrospective assessment of initial cryoablation characteristics, including balloon and vein sizes, venogram occlusion score, balloon freezing time from 0 to -30 degrees C, nadir temperature, and balloon warming time from -30 to +15 degrees C, recorded during the initial cryoballoon procedure. RESULTS: Of 199 veins assessed, 91 had reconnected (1.8 per patient). Balloon warming time (odds ratio [OR] 3.21; 95% confidence interval [CI] 2.00-5.13; P < .0001), nadir temperature (OR 1.94; 95% CI 1.42-2.66; P < .0001), vein occlusion score (OR 1.74; 95% CI 1.29-2.34; P = .0003), and balloon freezing time (OR 1.58; 95% CI 1.03-2.42; P = .037) predicted pulmonary vein reconnection. On multivariate analysis, balloon warming time (OR 3.71; 95% CI 2.2-6.24; P <= .0001), pulmonary vein size (OR 1.63; 95% CI 1.08 2.43; P = .020), and vein occlusion score (OR 1.48; 95% CI 1.06-2.08; P = .021) remained statistically significant independent predictors of pulmonary vein reconnection. The receiver operating characteristic for the multivariate model yielded an area under the curve of 0.82. CONCLUSIONS: Balloon warming time, vein occlusion score, and pulmonary vein size predict pulmonary vein reconnection. Balloon warming time was the most important predictive factor, and the manipulation of balloon warming may be a novel therapeutic strategy for improving outcomes of cryoballoon ablation for atrial fibrillation. PMID- 23792111 TI - Dispatcher-assisted bystander cardiopulmonary resuscitation in a metropolitan city: a before-after population-based study. AB - BACKGROUND: The goal of this study was to determine the effects of dispatcher assisted bystander cardiopulmonary resuscitation (DA-CPR) on outcomes of out-of hospital cardiac arrest (OHCA). METHODS: All EMS in a metropolitan city with a population of 10 million are dispatched by a single, centralized, and physician supervised center. Data on patients with adult OHCA with cardiac etiology were collected from the dispatch center registry and from EMS run sheets and hospital medical record review from 2009 to 2011. A standardized DA-CPR protocol (aligned with the 2010 AHA guidelines) we implemented as an intervention in January 2011. The end points were survival to discharge, good neurological outcome, and bystander CPR rate. Multivariate logistic analysis was used to compare between intervention group (2011) and historical control group (2009-2010). RESULTS: Of 8.144 eligible patients, bystander CPR was performed for the patients in 5.7% (148/2600) of cases in 2009, 6.7% (190/2857) in 2010, and 12.4% (334/2686) in 2011 (p<0.001). The survival to discharge rates was 7.1% (2009), 7.1% (2010), and 9.4% (2011) (p=0.001). Good neurological outcomes occurred in 2.1% (2009), 2.0% (2010), and 3.6% (2011) of cases (p<0.001). The adjusted ORs (95% CIs) for survival to discharge compared with 2009 were 1.33 (1.07-1.66) in 2011 and 1.12 (0.89-1.41) in 2010. The adjusted ORs (95% CIs) for good neurological outcomes were 1.67 (1.13-2.45) in 2011 and 1.13 (0.74-1.72) in 2010. CONCLUSIONS: An EMS intervention using the DA-CPR protocol was associated with a significant increase in bystander CPR and an improved survival and neurologic outcome after OHCA. PMID- 23792112 TI - Combining brain computed tomography and serum neuron specific enolase improves the prognostic performance compared to either alone in comatose cardiac arrest survivors treated with therapeutic hypothermia. AB - AIM OF THE STUDY: We determined whether combining the grey-to-white matter ratio (GWR) on brain computed tomography (CT) and serum neuron specific enolase (NSE) improves the prognostic performance when compared to either alone in cardiac arrest patients treated with therapeutic hypothermia (TH). METHODS: We performed a retrospective study of a cohort of cardiac arrest patients treated with TH. The Hounsfield unit was measured in the caudate nucleus (CN), putamen (P), posterior limb of internal capsule (PIC) and corpus callosum (CC); GWR was calculated as CN/PIC and P/CC. The NSE value was obtained at 0, 24, and 48h after restoration of spontaneous circulation (ROSC). We analysed the prognostic performance of GWR and NSE, singly and in combination, in predicting poor neurologic outcome (cerebral performance category 3-5). RESULTS: Of the 224 included patients, 82 showed good neurologic outcome at hospital discharge, while 142 showed poor neurologic outcome. The P/CC (area under receiver operating characteristics (AUROC) 0.864, sensitivity/specificity 52.9%/100%) showed better prognostic performance than did the CN/PIC (AUROC 0.721, sensitivity/specificity 19.8%/100%). The NSE value at 48h after ROSC (AUROC 0.895, sensitivity/specificity 60.2%/100%) showed the highest prognostic value among the three NSE time points. Analysis of 119 patients undergoing both brain CT and NSE at 48h indicated that combining P/CC and NSE improved the sensitivity (78.6%) compared to either alone (48.6%, 62.9%). CONCLUSION: Combining brain CT and serum NSE improves the prognostic performance when compared to either alone in predicting poor neurologic outcome in cardiac arrest patients treated with TH. PMID- 23792113 TI - Establishment of real-time TaqMan-fluorescence quantitative RT-PCR assay for detection and quantitation of ten kinds of porcine inflammation markers mRNA. AB - Real-time PCR assays based on TaqMan probes for detection of porcine inflammation markers including interferon-alpha (IFN-alpha), interferon-beta (IFN-beta), retinoic acid-inducible gene 1 (RIG-1), toll-like receptor 9 (TLR-9), interferon regulatory factors (IRF-3, IRF-7), Janus kinase (JAK-1, JAK-2), signal transducers and activators of transcription (STAT-1, STAT-2) were established in this study. The results indicated that the established assays were highly specific and sensitive with a detection limit of 1.0 * 10(1)copies/MUl, and coefficient of variations was less than three percent for both inter- and intra assay. The established assays were used to detect mRNA levels of these inflammation markers and beta-actin in swine testicle (ST) cells transfected with polyinosinic: polycytidylic acid (poly (I:C)). The results showed that the transcription levels (mRNA) of IFN-alpha, IFN-beta, RIG-1 and IRF-7 were up regulated in ST cells transfected with poly (I:C), and the transcription levels (mRNA) of TLR-9, IRF-3, JAK-1, JAK-2, STAT-1 and STAT-2 showed minimal change. The real-time PCR assays established in this study with high specificity, sensitivity and reproducibility could be used to quantify mRNA levels of porcine inflammation markers. PMID- 23792114 TI - Sensitivity of male reproductive endpoints in nonhuman primate toxicity studies: a statistical power analysis. AB - To determine the sensitivity of male reproductive toxicity endpoints in NHPs we performed a power analysis of routine and triggered endpoints using control data from sexually mature Asian and Mauritian NHPs. The power to detect a 50% change from control was 13-30% for male reproductive organ weights, ~30% for testicular volume, 6-66% for seminal analyses and 10-78% for male hormones. Overall, male reproductive endpoints have poor power (less than 80%) to detect a 50% change from control with a group size of 3 monkeys. Confidently identifying adverse male reproductive effects with these endpoints would likely require specialized study designs with larger group sizes. Triggering of non-routine endpoints in cases where there is special concern for male reproductive toxicity is unlikely to increase sensitivity to detect adverse effects. PMID- 23792115 TI - optix functions as a link between the retinal determination network and the dpp pathway to control morphogenetic furrow progression in Drosophila. AB - optix, the Drosophila ortholog of the SIX3/6 gene family in vertebrate, encodes a homeodomain protein with a SIX protein-protein interaction domain. In vertebrates, Six3/6 genes are required for normal eye as well as brain development. However, the normal function of optix in Drosophila remains unknown due to lack of loss-of-function mutation. Previous studies suggest that optix is likely to play an important role as part of the retinal determination (RD) network. To elucidate normal optix function during retinal development, multiple null alleles for optix have been generated. Loss-of-function mutations in optix result in lethality at the pupae stage. Surprisingly, close examination of its function during eye development reveals that, unlike other members of the RD network, optix is required only for morphogenetic furrow (MF) progression, but not initiation. The mechanisms by which optix regulates MF progression is likely through regulation of signaling molecules in the furrow. Specifically, although unaffected during MF initiation, expression of dpp in the MF is dramatically reduced in optix mutant clones. In parallel, we find that optix is regulated by sine oculis and eyes absent, key members of the RD network. Furthermore, positive feedback between optix and sine oculis and eyes absent is observed, which is likely mediated through dpp signaling pathway. Together with the observation that optix expression does not depend on hh or dpp, we propose that optix functions together with hh to regulate dpp in the MF, serving as a link between the RD network and the patterning pathways controlling normal retinal development. PMID- 23792116 TI - An ancient role for Gata-1/2/3 and Scl transcription factor homologs in the development of immunocytes. AB - Although vertebrate hematopoiesis is the focus of intense study, immunocyte development is well-characterized in only a few invertebrate groups. The sea urchin embryo provides a morphologically simple model for immune cell development in an organism that is phylogenetically allied to vertebrates. Larval immunocytes, including pigment cells and several blastocoelar cell subtypes, emerge from a population of non-skeletal mesodermal (NSM) precursors that is specified at the blastula stage. This ring of cells is first partitioned into oral and aboral fields with distinct blastocoelar and pigment cell gene regulatory programs. The oral field is subsequently specified into several distinct immune and non-immune cell types during gastrulation. Here we characterize the oral NSM expression and downstream function of two homologs of key vertebrate hematopoietic transcription factors: SpGatac, an ortholog of vertebrate Gata-1/2/3 and SpScl, an ortholog of Scl/Tal-2/Lyl-1. Perturbation of SpGatac affects blastocoelar cell migration at gastrulation and later expression of immune effector genes, whereas interference with SpScl function disrupts segregation of pigment and blastocoelar cell precursors. Homologs of several transcription regulators that interact with Gata-1/2/3 and Scl factors in vertebrate hematopoiesis are also co-expressed in the oral NSM, including SpE protein, the sea urchin homolog of vertebrate E2A/HEB/E2-2 and SpLmo2, an ortholog of a dedicated cofactor of the Scl-GATA transcription complex. Regulatory analysis of SpGatac indicates that oral NSM identity is directly suppressed in presumptive pigment cells by the transcription factor SpGcm. These findings provide part of a comparative basis to understand the evolutionary origins and regulatory biology of deuterostome immune cell differentiation in the context of a tractable gene regulatory network model. PMID- 23792117 TI - A new tool to ensure the fluorescent dye labeling stability of nanocarriers: a real challenge for fluorescence imaging. AB - Numerous studies on nanocarriers use fluorescent dye labeling to investigate their biodistribution or cellular trafficking. However, when the fluorescence dye is not grafted to the nanocarrier, the question of the stability of the labeling arises. How can it be validated that the fluorescence observed during an experiment corresponds to the nanocarriers, and not to the free dye released from the nanocarriers? Studying the integrity of the labeling is challenging. Therefore, an innovative approach to confirm the labeling stability was developed, based on the transfer of a fluorescent dye from its hosting nanocarrier to a lipophilic compartment. Lipid nanocapsules (LNC) and triglyceride oil were used as models. The protocol involved mixing of LNC suspension and oil, and then separation by centrifugation. The quality of the separation was controlled by light scattering, using the derived count rate tool. Dye transfer from loaded LNCs to the lipophilic compartment or from a lipophilic compartment containing dye to non-loaded LNC was investigated by varying the nature of the dye and the oil, the oil volume and the LNC dilution. Tensiometry was used to define the dye location in the nanocarrier. Results showed that when dyes such as Nile Red and Coumarin-6 are located in oily core, the transfer occurred in a partition-dependent manner. In contrast, when the dye was entrapped in the surfactant shell of LNCs such as lipophilic indocarbocyanines (i.e. DiO, DiI and DiD), no transfer was observed. Dye diffusion was also observed in cell culture, with Nile Red inside lipid bodies of HEI-OC1 cells, without uptake of LNCs. In contrast, DiO-loaded LNCs had to be internalized to observe fluorescence inside the cells, providing a further confirmation of the absence of transfer in this case, and the stability of fluorescence labeling of the LNCs. PMID- 23792118 TI - Enhanced anti-tumor and anti-angiogenic efficacy of a novel liposomal fenretinide on human neuroblastoma. AB - Neuroblastoma is an embryonal tumor originating from the simpatico-adrenal lineage of the neural crest. It approximately accounts for about 15% of all pediatric oncology deaths. Despite advances in multimodal therapy, metastatic neuroblastoma tumors at diagnosis remain a clinical challenge. Retinoids are a class of compounds known to induce both terminal differentiation and apoptosis/necrosis of neuroblastoma cells. Among them, fenretinide (HPR) has been considered one of the most promising anti-tumor agent but it is partially efficacious due to both poor aqueous solubility and rapid metabolism. Here, we have developed a novel HPR formulation, by which the drug was encapsulated into sterically stabilized nanoliposomes (NL[HPR]) according to the Reverse Phase Evaporation method. This procedure led to a higher structural integrity of liposomes in organic fluids for a longer period of time, in comparison with our previous liposomal formulation developed by the film method. Moreover, NL[HPR] were further coupled with NGR peptides for targeting the tumor endothelial cell marker, aminopeptidase N (NGR-NL[HPR]). Orthotopically xenografted neuroblastoma bearing mice treated with NGR-NL[HPR] lived statistically longer than mice untreated or treated with free HPR (NGR-NL[HPR] vs both control and HPR: P<0.0001). Also, NL[HPR] resulted in a statistically improved survival (NL[HPR] vs both control and HPR: P<0.001) but to a less extent if compared with that obtained with NGR-NL[HPR] (NGR-NL[HPR] vs NL[HPR]: P<0.01). Staining of tumor sections with antibodies specific for neuroblastoma and for either pericytes or endothelial cells evidenced that HPR reduced neuroblastoma growth through both anti-tumor and anti-angiogenic effects, mainly when delivered by NGR-NL[HPR]. Indeed, in this group of mice a marked reduction of tumor progression, of intra tumoral vessel counts and VEGF expression, together with a marked down-modulation of matrix metalloproteinases MMP2 and MMP9, was observed. In conclusion, the use of this novel targeted delivery system for the apoptotic and antiangiogenic drug, fenretinide, could be considered as an adjuvant tool in the future treatment of neuroblastoma patients. PMID- 23792119 TI - Discovery of a subtype selective inhibitor of the human betaine/GABA transporter 1 (BGT-1) with a non-competitive pharmacological profile. AB - The gamma-aminobutyric acid (GABA) transporters (GATs) are essential regulators of the activity in the GABAergic system through their continuous uptake of the neurotransmitter from the synaptic cleft and extrasynaptic space. Four GAT subtypes have been identified to date, each displaying different pharmacological properties and expression patterns. The present study focus on the human betaine/GABA transporter 1 (BGT-1), which has recently emerged as a new target for treatment of epilepsy. However, the lack of selective inhibitors of this transporter has impaired the exploration of this potential considerably. With the objective of identifying novel compounds displaying selectivity for BGT-1, we performed a screening of a small compound library at cells expressing BGT-1 using a [(3)H]GABA uptake assay. The screening resulted in the identification of the compound N-(1-benzyl-4-piperidinyl)-2,4-dichlorobenzamide (BPDBA), a selective inhibitor of the human BGT-1 transporter with a non-competitive profile exhibiting no significant inhibitory activity at the other three human GAT subtypes. The selectivity profile of the compound was subsequently confirmed at cells expressing the four mouse GAT subtypes. Thus, BPDBA constitutes a potential useful pharmacological tool compound for future explorations of the function of the BGT-1 subtype. PMID- 23792120 TI - 7-Ketocholesterol induces P-glycoprotein through PI3K/mTOR signaling in hepatoma cells. AB - 7-Ketocholesterol (7-KC) is found at an elevated level in patients with cancer and chronic liver disease. The up-regulation of an efflux pump, P-glycoprotein (P gp) leads to drug resistance. To elucidate the effect of 7-KC on P-gp, P-gp function and expression were investigated in hepatoma cell lines Huh-7 and HepG2 and in primary hepatocyte-derived HuS-E/2 cells. At a subtoxic concentration, 48 h exposure to 7-KC reduced the intracellular accumulation and cytotoxicity of P gp substrate doxorubicin in hepatoma cells, but not in HuS-E/2 cells. In Huh-7 cells, 7-KC elevated efflux function through the activation of phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway. 7-KC activated the downstream protein synthesis initiation factor 4E-BP1 and induced P-gp expression post-transcriptionally. The stimulation of efflux was reversible and could not be prevented by N-acetyl cysteine. Total cellular ATP content remained the same, whereas the lactate production was increased and fluorescence lifetime of protein-bound NADH was shortened. These changes suggested a metabolic shift to glycolysis, but glycolytic inhibitors did not eliminate 7-KC-mediated P-gp induction. These results demonstrate that 7-KC induces P-gp through PI3K/mTOR signaling and decreased the cell-killing efficacy of doxorubicin in hepatoma cells. PMID- 23792121 TI - A multicenter study of neurocognition in children with hypertension: methods, challenges, and solutions. AB - Hypertensive adults demonstrate decreased performance on neurocognitive testing compared with that of normotensive controls. There is now emerging, preliminary evidence that children with hypertension also manifest neurocognitive differences when compared with normotensive controls, findings postulated to potentially represent early signs of hypertensive target organ damage to the brain. However, reports in children to date have been limited to database and single-center studies. We have established an ongoing, prospective, multicenter study of neurocognition in children with primary hypertension. This article outlines the study methods, with particular attention to the unique challenges in this area of clinical research. We highlight aspects of the study design that are specifically designed as solutions to these challenges. PMID- 23792122 TI - [Use of molecular typing tools for the study of hospital outbreaks of candidemia]. AB - Candidemia is an infectious complication mainly affecting hospitalized patients, particularly those admitted to intensive care units. Patient mortality can reach up to 40%. Candidemia is typically nosocomially-acquired, and horizontal transmission of Candida spp. can lead to the presence of outbreaks of candidemia. Genotyping of isolates of Candida causing candidemia can help us to understand the source of the infection, detect the hospital wards with active Candida spp. transmission and, consequently, improve the prevention of the infection. Several genotyping tools have been used for the molecular characterization of Candida isolates involved in outbreaks of candidemia. Genotyping procedures based on microsatellites are reproducible and show a high discriminatory power. Microsatellites are recommended for the study of outbreaks of candidemia. In most hospital outbreaks of candidemia, patients admitted to intensive care units are involved, mostly neonatal patients. The role of genotyping Candida isolates causing candidemia for the study of nosocomial outbreaks of candidemia is reviewed, as well as the patients more commonly affected by epidemic strains. PMID- 23792123 TI - [Paracoccidioidomycosis in pediatric patients: a description of 4 cases]. AB - BACKGROUND: Paracoccidioidomycosis is the most frequent systemic mycosis in Latin America, caused by the dimorphic fungus Paracoccidioides. Paracoccidioidomycosis in children is uncommon. Our aim is to describe clinical features of patients who had a confirmed diagnosis of paracoccidioidomycosis in our hospital in the last 10 years. CASE REPORTS: We describe 4 cases of paracoccidioidomycosis in previously healthy children from the north of our country. Diagnoses were made by biopsy or culture. CONCLUSIONS: The diagnosis of paracoccidioidomycosis should be considered in a patient coming from regions where Paracoccidioides is endemic, and presenting with a lymphoproliferative syndrome, anemia, eosinophilia and hypergammaglobulinemia. PMID- 23792124 TI - Abarema cochliacarpos reduces LPS-induced inflammatory response in murine peritoneal macrophages regulating ROS-MAPK signal pathway. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Abarema cochliacarpos (Gomes) Barneby and Grimes (Fabaceae), known by the vulgar name of Babatena, has been traditionally used in Northeast Brazil, as an anti-inflammatory remedy. Previous studies have demonstrated its anti-inflammatory and antiulcer effects in skin lesion, alcohol gastric ulcer and acute and chronic colitis. AIMS: The present study was designed to evaluate the antioxidant and anti-inflammatory effects of the butanolic fraction from A. cochliacarpos (BFAC) and its major flavonoid, (+)-catechin, in LPS-stimulated murine peritoneal macrophages. Moreover, we studied the role of mitogen-activated protein kinase (MAPK)s and NF-kB signaling pathways possibly involved in the beneficial effects. MATERIALS AND METHODS: The quantification of the extract was carried out by ultra-performance liquid chromatography analysis. Cell viability was determined using SRB assay. Nitric oxide (NO) production was analyzed by Griess method and intracellular reactive oxygen species (ROS) by fluorescence analysis. In addition, cyclooxygenase (COX-2) and inducible nitric oxide synthase (iNOS) expression, MAPK activation and IkappaBalpha (IKBalpha) degradation, were determined by Western blot. RESULTS: After BFAC characterization, (+)-catechin was revealed as its major constituent. Both BFAC and (+)-catechin, exerted significant anti-oxidant and anti-inflammatory effects inhibiting LPS-induced intracellular ROS and NO production in peritoneal macrophages. Additionally, the extract but also its major component reduced pro inflammatory proteins expression probably through c-Jun N-terminal kinase and p38 MAPK signaling pathways. CONCLUSION: These data suggest that the beneficial effects of BFAC might be mediated, at least in part, by the presence of (+) catechin. Conclusively our findings confirm the potential of A. cochliacarpos as a new therapeutic strategy for the management of inflammatory and oxidative stress-related diseases. PMID- 23792125 TI - In vivo antimalarial activity of Keetia leucantha twigs extracts and in vitro antiplasmodial effect of their constituents. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The West African tree Keetia leucantha (Rubiaceae) is used in traditional medicine in Benin to treat malaria. The twigs dichloromethane extract was previously shown to inhibit in vitro Plasmodium falciparum growth with no cytotoxicity (>100ug/ml on human normal fibroblasts). MATERIALS AND METHODS: The dichloromethane and aqueous extracts of twigs of K. leucantha were evaluated in vivo against Plasmodium berghei NK 173 by the 4-day suppressive test and in vitro against a chloroquine-sensitive strain of Plasmodium falciparum (3D7) using the measurement of the plasmodial lactate dehydrogenase activity. Bioguided fractionations were realized and compounds were structurally elucidated using extensive spectroscopic analysis. RESULTS: The in vivo antimalarial activity of K. leucantha dichloromethane and aqueous twigs extracts were assessed in mice at the dose of 200mg/kg/day. Both extracts exhibited significant effect in inhibiting parasite growth by 56.8% and 53.0% (p<0.0001) on day 7-postinfection. An LC-MS analysis and bioguided fractionations on the twigs dichloromethane extract led to the isolation and structural determination of scopoletin (1), stigmasterol (2), three phenolic compounds: vanillin (3), hydroxybenzaldehyde (4) and ferulaldehyde (5), eight triterpenic esters (6-13), oleanolic acid and ursolic acid. The antiplasmodial activity of the mixture of the eight triterpenic esters showed an antiplasmodial activity of 1.66 +/- 0.54 ug/ml on the 3D7 strain, and the same range of activity was observed for isolated isomers mixtures. CONCLUSIONS: This is the first report on the in vivo activity of K. leucantha extracts, the isolation of thirteen compounds and analysis of their antiplasmodial activity. The results obtained may partially justify the traditional use of K. leucantha to treat malaria in Benin. PMID- 23792126 TI - Comparison of positron emission tomography and bremsstrahlung imaging to detect particle distribution in patients undergoing yttrium-90 radioembolization for large hepatocellular carcinomas or associated portal vein thrombosis. AB - PURPOSE: To compare positron emission tomography/computed tomography (PET/CT) imaging with bremsstrahlung single photon emission computed tomography (SPECT) in patients after yttrium-90 ((90)Y) microsphere radioembolization to assess particle uptake. MATERIALS AND METHODS: This prospective study comprised patients with large (> 5 cm) hepatocellular carcinoma (HCC) or tumor-associated portal vein thrombus (PVT), or both. After radioembolization for HCC, patients underwent bremsstrahlung SPECT/CT and time-of-flight PET/CT imaging of (90)Y without additional tracer administration. Follow-up imaging and toxicity was analyzed. Imaging analyses of PET/CT and bremsstrahlung SPECT/CT were independently performed. RESULTS: There were 13 patients enrolled in the study, including 7 with PVT. Median tumor diameter was 7 cm. PET/CT demonstrated precise localization of (90)Y particles in the liver, with specific patterns of uptake in large tumors. In cases of PVT, PET/CT showed activity within the PVT. When correlated to short-term follow-up imaging, areas of necrosis correlated with regions of uptake seen on PET/CT. Compared with bremsstrahlung imaging, PET/CT demonstrated at least comparable spatial resolution with less scatter. Quantitative uptake in nontreated regions of interest showed significantly reduced scatter with PET/CT versus SPECT/CT (1% vs 14%, P < .001). CONCLUSIONS: Evaluation of (90)Y particle uptake with PET/CT potentially demonstrates high spatial resolution and low scatter compared with bremsstrahlung SPECT/CT. Confirmation of particles within PVT on PET/CT correlates with response on follow up imaging and may account for the efficacy of radioembolization in patients with PVT. PMID- 23792127 TI - Prospective evaluation of absorbable gastropexy anchor indwelling time in 33 patients. AB - PURPOSE: To evaluate the time to absorbable suture gastropexy anchor release and gastropexy-related complications in patients receiving percutaneous image-guided transabdominal gastrostomy or gastrojejunostomy tube placement. MATERIALS AND METHODS: Thirty-three consecutive patients (16 women; mean age, 63.5 y; range, 25 92 y) undergoing fluoroscopically guided (n = 32) or computed tomography-guided (n = 1) percutaneous transabdominal gastrostomy (n = 26) or gastrojejunostomy (n = 7) were prospectively enrolled in a single-center study. Each patient had three synthetic absorbable suture T-fasteners inserted and were followed until all gastropexy button-locks released naturally, were cut by a health care provider, or were lost to follow-up. Patients or caregivers were contacted weekly to determine timing of gastropexy button-lock release and assess for postprocedural complications. RESULTS: All three T-fastener button-type suture locks released naturally in 14 of 33 patients (42.4%) at a median of 29.5 days (mean, 26.7 d; range, 8-40 d). One or more T-fastener sutures were cut in 10 of 33 patients (30.3%), and nine patients (27.3%) were lost to follow-up. Accounting for patient censorship, T-fasteners in all 33 patients remained intact for a median of 35 days. Local infections developed in three patients (9%) on days 22, 25, and 34. CONCLUSIONS: Relative to nonabsorbable gastropexy sutures, absorbable suture gastropexy anchors offer the potential to reduce complications associated with long gastropexy indwelling times. However, absorbable gastropexy anchor buttons usually remain intact for longer than 3 weeks after insertion. A postprocedural plan for gastropexy inspection and removal within 3 weeks should continue to be emphasized to avoid local complications, even for absorbable suture kits. PMID- 23792128 TI - Quantification of tissue shrinkage and dehydration caused by microwave ablation: experimental study in kidneys for the estimation of effective coagulation volume. AB - PURPOSE: To quantify the extent of tissue shrinkage and dehydration caused by microwave (MW) ablation in kidneys for estimation of effective coagulation volume. MATERIALS AND METHODS: MW ablations were carried out in ex vivo porcine kidneys. Six study groups were defined: groups 1A, 2A, and 3A for MW ablation (90 W for 5 min, 7.5 min, or 10 min), and groups 1B, 2B, and 3B for control (without MW ablation). Pre- and postinterventional volume analyses were performed. Effective coagulation volumes (original tissue included in coagulation) were determined. Postinterventional dehydration analyses were performed with calculation of mean mass fractions of water. RESULTS: Mean deployed energies were 21.6 kJ +/- 1.1 for group 1A, 29.9 kJ +/- 1.0 for group 2A, and 42.1 kJ +/- 0.5 kJ for group 3A, and were significantly different (P < .0001). Differences between pre- and postinterventional volumes were -3.8% +/- 0.6 for group 1A, 5.6% +/- 0.9 for group 2A, and -7.2% +/- 0.4 for group 3A, and -1.1% +/- 0.3 for group 1B, -1.8% +/- 0.4 for group 2B, and -1.1% +/- 0.4 for group 3B. Postinterventional volumes were significantly smaller than preinterventional volumes for all groups (P < .01). Underestimations of effective coagulation volume from visualized coagulation volume were 26.1% +/- 3.5 for group 1A, 35.2% +/- 11.2 for group 2A, and 42.1% +/- 4.9 for group 3A, which were significantly different (P < .01). Mean mass fractions of water were 64.2% +/- 1.4 for group 1A, 63.2% +/- 1.7 for group 2A, and 62.6% +/- 1.8% for group 3A, with significant differences versus corresponding control groups (P < .01). CONCLUSIONS: For MW ablation in kidneys, underestimation of effective coagulation volume based on visualized coagulation volume is significantly greater with greater deployed energy. Therefore, local dehydration with tissue shrinkage is a potential contributor. PMID- 23792129 TI - Practice based collaboration to improve the use of immediate intravesical therapy after resection of nonmuscle invasive bladder cancer. AB - PURPOSE: Perioperative instillation of intravesical chemotherapy after bladder tumor resection is supported by level I evidence showing a 30% decrease in tumor recurrence. However, studies of administrative data sets show poor use in practice. MATERIALS AND METHODS: We prospectively evaluated the use of perioperative intravesical chemotherapy in a multipractice quality improvement collaborative. Cases were categorized as ideal for intravesical chemotherapy (1 or 2 papillary tumors, cTa/cT1 and completely resected) and nonideal. The reasons for not administering intravesical chemotherapy in ideal cases were classified as appropriate or modifiable. Before and after comparative feedback and educational interventions we calculated judicious use of intravesical chemotherapy (nonuse in nonideal cases plus use in ideal cases plus appropriate nonuse in ideal cases) and quality improvement potential (use in nonideal cases plus nonuse in ideal cases attributable to modifiable factors). RESULTS: We accrued a total of 2,794 cases at the 5 sites in 22 months. The rate of use in ideal cases was 38% before and 34.8% after intervention (p=0.36), while use in nonideal cases decreased from 15% to 12% (p=0.08). Overall, intravesical chemotherapy was used judiciously in 83.0% to 85.7% of cases, while the remaining 14.3% to 17.0% represented quality improvement potential. CONCLUSIONS: Judicious use of perioperative intravesical chemotherapy is relatively high in routine practice. Most instances of nonuse represent appropriate clinical judgment. Utilization did not change after quality improvement interventions, suggesting that there may a ceiling effect that makes it difficult to improve care that is high quality at baseline. Moreover, decreasing unnecessary use of an intervention may be easier than encouraging appropriate use of potentially toxic therapy. PMID- 23792130 TI - Can magnetic resonance-ultrasound fusion biopsy improve cancer detection in enlarged prostates? AB - PURPOSE: Patients with an enlarged prostate and suspicion of prostate cancer pose a diagnostic dilemma. The prostate cancer detection rate of systematic 12-core transrectal ultrasound guided biopsy is between 30% and 40%. For prostates greater than 40 cc this decreases to 30% or less. Magnetic resonance-ultrasound fusion biopsy has shown superior prostate cancer detection rates. We defined the detection rate of magnetic resonance-ultrasound fusion biopsy in men with an enlarged prostate gland. MATERIALS AND METHODS: We retrospectively analyzed the records of patients who underwent multiparametric prostate magnetic resonance imaging followed by magnetic resonance-ultrasound fusion biopsy at our institution. Whole prostate volumes were calculated using magnetic resonance imaging reconstructions. Detection rates were analyzed with respect to age, prostate specific antigen and whole prostate volumes. Multivariable logistic regression was used to assess these parameters as independent predictors of prostate cancer detection. RESULTS: We analyzed 649 patients with a mean+/-SD age of 61.8+/-7.9 years and a median prostate specific antigen of 6.65 ng/ml (IQR 4.35-11.0). Mean whole prostate volume was 58.7+/-34.3 cc. The overall detection rate of the magnetic resonance-ultrasound fusion platform was 55%. For prostates less than 40 cc the detection rate was 71.1% compared to 57.5%, 46.9%, 46.9% 33.3%, 36.4% and 30.4% for glands 40 to 54.9, 55 to 69.9, 70 to 84.9, 85 to 99.9, 100 to 114.9 and 115 cc or greater, respectively (p<0.0001). Multivariable logistic regression showed a significant inverse association of magnetic resonance imaging volume with prostate cancer detection, controlling for age and prostate specific antigen. CONCLUSIONS: Transrectal ultrasound guided and fusion biopsy cancer detection rates decreased with increasing prostate volume. However, magnetic resonance-ultrasound fusion biopsy had a higher prostate cancer detection rate compared to that of transrectal ultrasound guided biopsy in the literature. Magnetic resonance-ultrasound fusion biopsy represents a promising solution for patients with suspicion of prostate cancer and an enlarged prostate. PMID- 23792131 TI - Vaccination with intestinal tract antigens does not induce protective immunity in a permissive model of filariasis. AB - Antigens obtained from the intestinal tract of filarial nematodes have been proposed as potential safe and effective vaccine candidates. Because they may be 'hidden' from the immune response during natural infection, yet accessible by antibodies induced by vaccination, intestinal antigens may have a low potential for eliciting allergic responses when vaccinating previously infected individuals. Despite prior promising data, vaccination with intestinal antigens has yet to be tested in a permissive model of filariasis. In this study we investigated the efficacy of vaccination with filarial intestinal antigens in the permissive Litomosoides sigmodontis BALB/c model of filariasis, and we evaluated the extent to which these antigens are recognized by the immune system during and after infection. Infected BALB/c mice developed lower IgG antibody responses to soluble intestinal antigens (GutAg) than to soluble antigens of whole worms (LsAg). Similarly, GutAg induced less proliferation and less production of IL-4 and IFNgamma from splenocytes of infected mice than LsAg. In contrast to these differences, active infection resulted in equivalent levels of circulating GutAg specific IgE and LsAg-specific IgE levels. Consistent with this, basophil activation, as assessed by flow cytometric staining of intracellular basophil IL 4 expression, was equivalent in response to GutAg and LsAg. Vaccination with GutAg adsorbed to CpG/alum induced GutAg specific IgG1 and IgG2A production, with GutAg specific IgG titers greater than 5-fold higher than those measured in previously infected animals. Despite this response to GutAg vaccination, vaccinated mice harbored similar parasite burdens 8 weeks post infection when compared to non-vaccinated controls. These studies demonstrate that soluble antigens obtained from the intestinal tracts of L. sigmodontis have some qualities of 'hidden' antigens, but they still sensitize mice to allergic reactions and fail to protect against future infection when given as a vaccine adsorbed to alum/CPG. PMID- 23792132 TI - Expression, purification and biochemical characterization of recombinant Ca dependent protein kinase 2 of the malaria parasite Plasmodium falciparum. AB - Calcium-dependent protein kinases (CDPKs) are serine/threonine kinases that react in response to calcium which functions as a trigger for several mechanisms in plants and invertebrates, but not in mammals. Recent structural studies have defined the role of calcium in the activation of CDPKs and have elucidated the important structural changes caused by calcium in order to allow the kinase domain of CDPK to bind and phosphorylate the substrate. However, the role of autophosphorylation in CDPKs is still not fully understood. In Plasmodium falciparum, seven CDPKs have been identified by sequence comparison, and four of them have been characterized and assigned to play a role in parasite motility, gametogenesis and egress from red blood cells. Although PfCDPK2 was already discovered in 1997, little is known about this enzyme and its metabolic role. In this work, we have expressed and purified PfCDPK2 at high purity in its unphosphorylated form and characterized its biochemical properties. Moreover, propositions about putative substrates in P. falciparum are made based on the analysis of the phosphorylation sites on the artificial substrate myelin basic protein (MBP). PMID- 23792133 TI - EMPOWER: a randomized trial using community health workers to deliver a lifestyle intervention program in African American women with Type 2 diabetes: design, rationale, and baseline characteristics. AB - BACKGROUND: African American (AA) women with Type 2 diabetes mellitus (T2DM) in the rural south experience less weight loss and poorer glycemic control in traditional diabetes management programs compared to Caucasians. This paper describes the design, rationale, and baseline characteristics from an innovative community health worker (CHW) delivered intervention program in this population. METHODS/DESIGN: This prospective trial randomized rural AA women with uncontrolled T2DM (HbA1c >= 7.0) to receive a behaviorally-centered, culturally tailored lifestyle intervention during 16 contacts from a trained AA CHW or 16 approved diabetes educational mailings. Changes from baseline in glycosylated hemoglobin levels (HbA1c), blood pressure (BP), weight, body mass index (BMI), self-reported dietary and physical activity patterns, and psychosocial measures including diabetes distress, empowerment, depression, self-care, medication adherence, and life satisfaction will be assessed at 6- and 12-months. BASELINE RESULTS: Two hundred AA women (mean age = 53.09 +/- 10.89 years) with T2DM from impoverished rural communities were enrolled. Baseline data demonstrated profoundly uncontrolled diabetes of long term duration (mean HbA1c = 9.11 +/- 1.82; mean BMI = 37.68 +/- 8.20; mean BP = 134.51 +/- 20.39/84.19 +/- 11.68; 10.5 +/- 0.7 years). Self-care behavior assessment revealed poor dietary and medication adherence and sedentary lifestyle. Most psychosocial measures ranged within normal limits. CONCLUSION: The present sample of AA women from impoverished rural communities exhibited significantly uncontrolled T2DM of long duration with associated obesity and poor lifestyle behaviors. An innovative CHW led lifestyle intervention may lead to more effective strategies for T2DM management in this population. PMID- 23792134 TI - Different adaptation of the motor activity rhythm to chronic phase shifts between adolescent and adult rats. AB - Chronic phase shifts is a common feature in modern societies, which may induce sleep alterations and other health problems. The effects of phase shift on the circadian rhythms have been described to be more pronounced in old than in young animals. However, few works address the effects of chronic phase shifts during adolescence. Here we tested the development of the motor activity circadian rhythm of young rats under chronic phase shifts, which consisted on 6-h advances (A), 6h delays (D) or 6h advances and delays alternated every 5 days (AD) during the first 60 days after weaning. Moreover, the rhythmic pattern was compared to that of adult rats under the same lighting conditions. Results indicate that adolescent rats, independently on the lighting environment, developed a clear circadian rhythm, whose amplitude increased the first 50 days after weaning and showed a more stable circadian rhythm than adults under the same lighting conditions. In the case of A and AD groups, circadian disruption was observed only in adult rats. In all groups, the offset of activity correlated with light pattern better than the onset, and this correlation was always higher in the case of the rhythm of the pubertal rats. When AD groups were transferred to constant darkness, the group submitted to this condition during adolescence showed shorter period than that submitted in their adulthood. In conclusion, differently from adult rats, adolescent rats submitted to chronic phase shifts did not show circadian disruption and developed a single circadian rhythm, suggesting permanent changes in the circadian system. PMID- 23792135 TI - Distinct functional brain regional integration of Casp3, Ascl1 and S100a6 gene expression in spatial memory. AB - Evaluating the brain structural expression of defined genes involved in basic biological processes of neurogenesis, apoptosis or neural plasticity may facilitate the understanding of genetic mechanisms underlying spatial memory. The aim of the present study was to compare Ascl1, Casp3 and S100a6 gene expression in the hippocampus, prefrontal cortex and cerebellum of adult rats in water maze spatial memory performance. After four days training, the mean platform time (<10s) was evidence of stable long-term spatial memory formation. Real time PCR analysis revealed a positive inter-structural correlation for S100a6/Casp gene expression between the prefrontal cortex and the cerebellum but a negative correlation for S100a6/Ascl1 transcribed genes between the prefrontal cortex and hippocampus during swimming in the active controls. However, during spatial memory performance there was only one inter-structural correlation between the prefrontal cortex and cerebellum with respect to Casp3 expression, though there were intra-structural correlations between Casp3/Ascl1 transcriptions within the prefrontal cortex and hippocampus as well as between Ascl1/S100a6 in the cerebellum. In active learners versus naive controls, the transcrption of all genes was augmented in the prefrontal cortex but Casp3 and Ascl1 were also elevated in hippocampus whilst only S100a6 increased in the cerebellum. The findings endorsed the role of the hippocampus in memory acquisition in addition to an integrative relationship with the prefrontal cortex and cerebellum. This structural and molecular configuration is important for creation of novel neural circuitry for consolidation and reconsolidation of memory trace with an involvement of coupled processes of neurogenesis, apoptosis or neural plasticity. PMID- 23792136 TI - Atypical autonomic regulation, auditory processing, and affect recognition in women with HIV. AB - This study examined the effect of HIV on visceromotor (i.e., heart rate and heart rate variability) and somatomotor (i.e., auditory processing and affect recognition) components of a Social Engagement System defined by the Polyvagal Theory (Porges, 1995) that links vagal regulation of the heart with brainstem regulation of the striated muscles of the face and head. Relative to at risk HIV seronegative women, HIV-seropositive women had less heart rate variability (i.e., respiratory sinus arrhythmia) and had poorer performance on auditory processing and affect recognition tasks. CD4 was negatively correlated with the accuracy to detect specific emotions. The observed indices of atypical autonomic and behavioral regulation may contribute to greater difficulties in social behavior and social communication between HIV-infected women and other individuals in their social network. PMID- 23792137 TI - A systematic review of IT for diabetes self-management: are we there yet? AB - BACKGROUND: Recent advances in information technology (IT) coupled with the increased ubiquitous nature of information technology (IT) present unique opportunities for improving diabetes self-management. The objective of this paper is to determine, in a systematic review, how IT has been used to improve self management for adults with Type 1 and Type 2 diabetes. METHODS: The review covers articles extracted from relevant databases using search terms related information technology and diabetes self-management published after 1970 until August 2012. Additional articles were extracted using the citation map in Web of Science. Articles representing original research describing the use of IT as an enabler for self-management tasks performed by the patient are included in the final analysis. RESULTS: Overall, 74% of studies showed some form of added benefit, 13% articles showed no-significant value provided by IT, and 13% of articles did not clearly define the added benefit due to IT. Information technologies used included the Internet (47%), cellular phones (32%), telemedicine (12%), and decision support techniques (9%). Limitations and research gaps identified include usability, real-time feedback, integration with provider electronic medical record (EMR), as well as analytics and decision support capabilities. CONCLUSION: There is a distinct need for more comprehensive interventions, in which several technologies are integrated in order to be able to manage chronic conditions such as diabetes. Such IT interventions should be theoretically founded and should rely on principles of user-centered and socio-technical design in its planning, design and implementation. Moreover, the effectiveness of self management systems should be assessed along multiple dimensions: motivation for self-management, long-term adherence, cost, adoption, satisfaction and outcomes as a final result. PMID- 23792138 TI - MitomiRs delineating the intracellular localization of microRNAs at mitochondria. AB - Mitochondria play a crucial role in energetic metabolism, signaling pathways, and overall cell viability. Mitochondrial dysfunctions are known to cause a wide range of human diseases that affect tissues especially those with high energetic requirements, such as skeletal muscle, heart, kidney, and central nervous system, while being involved in cancer, aging, and metabolic processes. At the same time, the microRNA (miRNA) gene family has been demonstrated to be involved in most cellular processes through modulation of proteins critical for cellular homeostasis. Given the broad scope of reactivity profiles and the ability of miRNAs to modify numerous proteomic and genomic processes, new emphasis is being placed on the influence of miRNAs at the mitochondrial level. Recently, the localization of miRNAs in mitochondria was characterized in different species. This raises the idea that those miRNAs, noted "mitomiRs," could act as "vectors" that sense and respond dynamically to the changing microenvironment of mitochondria at the cellular level. Reciprocally, we present the involvement of mitochondria in small RNA biogenesis. With the aim of deciphering the significance of this localization, we discuss the putative mechanism of import of miRNAs at mitochondria, their origin, and their hypothetical roles within the organelle. PMID- 23792139 TI - The SaeR/S two-component system induces interferon-gamma production in neutrophils during invasive Staphylococcus aureus infection. AB - Invasive Staphylococcus aureus (S. aureus) disease is associated with neutrophil activity and pro-inflammatory cytokine expression, including interferon-gamma (IFNgamma). Using a mouse model of S. aureus peritonitis, we identify neutrophils as the predominant source of IFNgamma and link this induction with the SaeR/S two component gene regulatory system. Relative to wild-type (BALB/c) mice, IFNgamma deficient mice demonstrated increased bacterial clearance and reduced cellular cytotoxicity following intraperitoneal challenge with S. aureus. Interestingly, bacterial burden and cytotoxicity were similar in BALB/c and IFNgamma-deficient mice when infected with an isogenic saeR/S mutant strain. These findings suggest saeR/S-mediated neutrophil-derived IFNgamma diminishes innate antibacterial mechanisms against S. aureus. PMID- 23792140 TI - Effects of allicin on hyperhomocysteinemia-induced experimental vascular endothelial dysfunction. AB - This study was designed to investigate the effect and mechanism of allicin on hyperhomocysteinemia-induced experimental vascular endothelial dysfunction in rats. Fifty male Wistar rats were randomly divided into five groups: the normal control rats (NC), the high-methionine-diet rats (Met), the high-methionine-diet rats treated with folic acid, vitaminB6 and vitaminB12 (Met+F), or with low-dose allicin (Met+L), or with high-dose allicin (Met+H). After 6 weeks, we collected blood samples of all groups to determine plasma endothelin (ET), serum homocysteine (Hcy), nitric oxide (NO), superoxide dismutase (SOD), malondialdehyde (MDA), and detected the expression of basic fibroblast growth factors (bFGF), transforming growth factor beta (TGF-beta), tumor necrosis factor alpha (TNF-alpha), and intercellular adhesion molecule-1 (ICAM-1) in the aorta. The Hcy and the expression of TGF-beta in both the Met+L and Met+H groups were significantly lower than the Met and Met+F groups. The ET, ET/NO ratio and the MDA levels of the Met+L and Met+H groups were significantly lower than the Met group. The SOD and NO levels and the expression of bFGF, TNF-alpha and ICAM-1 of the Met+L and Met+H groups were significantly higher than the Met group. Our data indicate that allicin inhibits lipid peroxidation induced by hyperhomocysteinemia and regulates the excretion and equilibrium of ET and NO, and suggest that allicin might be useful in the prevention of endothelial dysfunction caused by hyperhomocysteinemia. PMID- 23792141 TI - Phytoestrogenic molecule desmethylicaritin suppressed adipogenesis via Wnt/beta catenin signaling pathway. AB - Epimedium flavonoids inhibit extravascular lipid deposition during prevention of steroid-associated osteonecrosis. Desmethylicaritin is a bioactive metabolite of Epimedium flavonoids in serum. As it is well known that estrogen inhibits aidpogenesis, so we hypothesized that desmethylicaritin as a phytoestrogen might have the potential to inhibit lipid deposition. This study was designed to investigate the effect of desmethylicaritin on adipogenesis and its underlying mechanism in vitro. Adipogenesis was assessed by Oil Red O staining in 3T3-L1 preadipocytes. Bromodeoxyuridine was used to test the clonal expansion. Further, the mRNA level and protein expression of adipgenic and related factors were detected by qRT-PCR and western blot, respectively. The nuclear location of beta catenin was identified using immunofluoresence assay. Our results showed that desmethylicaritin suppressed the adipogenesis in 3T3-L1 cells in a dose-dependent manner. In addition, desmethylicaritin inhibited clonal expansion during adipogenesis. Desmethylicaritin did not affect CCAAT/enhancer binding protein delta and beta mRNA expression, but decreased the mRNA expression of CCAAT/enhancer binding protein alpha, peroxisome proliferator-activated receptor gamma, adipocyte lipid-binding protein and lipoprotein lipase. Desmethylicaritin up-regulated the mRNA expression of Wnt10b that was however down-regulated after adipogenic induction. Desmethylicaritin increased the protein expression of beta catenin both in the cytoplasm and nuclei and immunofluorescence results confirmed that desmethylicaritin increased nuclear translocation of beta-catenin. Above findings implied that desmethylicaritin was able to inhibit adipogenesis and Wnt/beta-catenin signaling pathway was regulated by desmethylicaritin in the process of suppression of adipogenesis. Above findings supported desmethylicaritin as a novel phytochemical agent for potential prevention of disorders involving lipid metabolism. PMID- 23792142 TI - Phenotypic interaction of simultaneously administered isoniazid and phenytoin in patients with tuberculous meningitis or tuberculoma having seizures. AB - Treatment of tuberculous meningitis or tuberculoma has become complicated because of adverse drug interactions found amongst antitubercular and anticonvulsant drugs. The aim of the study is to evaluate the effect of simultaneously administered isoniazid (300 mg/day) and phenytoin (300 mg/day) on 60 patients with tuberculous meningitis or tuberculoma having seizures. Plasma samples were analyzed for isoniazid, acetylated-isoniazid (AcINH) and phenytoin levels by high performance liquid chromatography at 3h of drugs administration and patients were classified as rapid or slow acetylator on the basis of metabolic ratio of isoniazid (Rm) and percentage of acetylated-isoniazid (%AcINH). Out of 60 patients studied, 23 were slow acetylators and 37 were rapid acetylators. Slow acetylators revealed higher plasma isoniazid levels and lower plasma AcINH levels, metabolic ratio and %AcINH as compared to rapid acetylators. Plasma phenytoin levels were found to be significantly higher (above therapeutic range) in slow acetylators as compared to rapid acetylators. Plasma phenytoin concentration was moderately strong, negatively correlated with metabolic ratio (r=-0.439, P<0.001) and %AcINH (r=-0.729, P<0.001). Eight comatose patients (34.8%) also showed significantly higher plasma phenytoin levels. Our results suggest that assessment of acetylator status and plasma phenytoin level is critical for dose optimization of isoniazid and phenytoin and to predict the patients at risk of intoxication. PMID- 23792143 TI - Involvement of 5-hydroxytryptamine 5-HT3 serotonergic receptors in the acquisition and reinstatement of the conditioned place preference induced by MDMA. AB - Some MDMA (3,4-methylenedioxymethamphetamine) users develop dependence as a result of chronic consumption. The present study evaluated the role of 5 hydroxytryptamine 5-HT3 receptors in the acquisition, expression and reinstatement of the conditioned place preference (CPP) induced by MDMA. Adolescent male mice were conditioned with 10 mg/kg of MDMA and then treated with 1 or 3mg/kg of the 5-hydroxytryptamine 5-HT3 antagonist MDL72222 during acquisition of conditioning (experiment 1), before expression of CPP in a post conditioning test (experiment 2) or before a reinstatement test (experiment 3). MDL72222 was devoid of motivational effects but blocked acquisition of the MDMA induced CPP. Moreover, following extinction, the low dose of MDL72222 blocked reinstatement of the CPP induced by priming with MDMA. Acute MDMA reduced levels of dihydroxypheylacetic acid (DOPAC) in the striatum and levels of acid 5 hydroxyindoleacetic (5-HIAA) in the cortex. Acute MDMA+MDL72222 also reduced striatal DOPAC. The repeated co-administration of MDMA plus MDL72222 (on PND 32 34-36-38) increased dopamine and decreased DOPAC in the striatum, and increased cortical serotonin and enhanced transporters of dopamine and serotonin. The acute administration (on PND +/-55) of MDMA or MDL72222 increased levels of dopamine and reduced those of DOPAC in the striatum and co-administration of MDMA plus MDL72222 increased striatal serotonin. Our results confirm that 5 hydroxytryptamine 5-HT3 receptors are involved in the acquisition of conditioned rewarding effects of MDMA and demonstrate that these receptors are also involved in reinstatement after extinction. PMID- 23792144 TI - Protective effects of neferine on amiodarone-induced pulmonary fibrosis in mice. AB - The effects of neferine, a bisbenzylisoquinline alkaloid extracted from the Chinese traditional medicine seed embryo of Nelumbo nucifera Gaertn, on amiodarone-induced pulmonary fibrosis in mice were evaluated. Adult Kunming mice were induced to develop pulmonary fibrosis through intratracheal instillation of amiodarone (6.25 mg/kg) on the 1st, 3rd and 5th day. Mice were treated orally with saline, neferine (20 mg/kg), prednisolone (15 mg/kg), pirfenidone (100 mg/kg) twice a day after the third amiodarone instillation. On Day 21, all the lung tissues were collected for hydroxyproline measurement and the histological examination by hematoxylin-eosin and Masson staining. All the blood sample were collected for surfactant protein-D (SP-D) levels assay, Th1/Th2 balance valuation, CD4+CD25+ regulatory T cells (Tregs) analysis by Enzyme-linked immunosorbent assay and flow cytometry. Our data showed that neferine significantly restored the significant reductions in body weights, the increased levels of lung index and hydroxyproline, the abnormal histological findings, the serum SP-D increase, the Th1/Th2 imbalance by decreasing IL-4 and increasing IFN gamma levels and the increases in the population of CD4+CD25+ Tregs associated with amiodarone instillation in mice. Similar changes were also observed in the prednisolone or pirfenidone treated mice. In conclusion, these results indicated that neferine possessed a significant inhibitory effect on amiodarone-induced pulmonary fibrosis, probably due to its properties of anti-inflammation, SP-D inhibition and restoring increased CD4+CD25+ Tregs which may modulate Th1/Th2 imbalance by suppressing Th2 response (from Th2 polarity toward a Th1 dominant response). PMID- 23792145 TI - Diaphragm muscle sarcopenia in aging mice. AB - Sarcopenia, defined as muscle weakness and fiber atrophy, of respiratory muscles such as the diaphragm (DIAm) has not been well characterized. The DIAm is the main inspiratory muscle and knowledge of DIAm sarcopenia is important for establishing the effects of aging on respiratory function. We hypothesized that aging is associated with a loss of DIAm force and reduced fiber cross-sectional area (CSA), and that these changes vary across fiber types. DIAm sarcopenia was assessed in young (5 month; n = 11) and old (23 month; n = 12) wild-type mice reflecting ~100 and 75% survival, respectively. In addition, DIAm sarcopenia was evaluated in BubR1(H/H) mice (n = 4) that display accelerated aging (~60% survival at 5 months) as a result of expression of a hypomorphic allele (H) of the mitotic checkpoint protein BubR1. Maximum specific force (normalized for CSA) of the DIAm was 34% less in old mice and 57% lower in BubR1(H/H) mice compared to young mice. Mean CSA of type IIx and/or IIb DIAm fibers was 27% smaller in old wild-type mice and 47% smaller in BubR1(H/H) mice compared to young mice. Mean CSA of type I or IIa fibers was not different between groups. Collectively these results demonstrate sarcopenia of the DIAm in aging wild-type mice and in BubR1(H/H) mice displaying accelerated aging. Sarcopenia may limit the ability of the DIAm to accomplish expulsive, non-ventilatory behaviors essential for airway clearance. As a result, these changes in the DIAm may contribute to respiratory complications with aging. PMID- 23792148 TI - Prognostic role of cell cycle and proliferative biomarkers in patients with clear cell renal cell carcinoma. AB - PURPOSE: Cell cycle regulatory molecules are implicated in various stages of carcinogenesis. In this proof of principle study we systematically evaluate the association of aberrant expression of cell cycle regulators and proliferative markers and their effect on oncologic outcomes of patients with clear cell renal carcinoma. MATERIALS AND METHODS: Immunohistochemistry for Cyclin D, Cyclin E, p16, p21, p27, p53, p57 and Ki67 was performed on tissue microarray constructs of 452 patients treated with extirpative therapy for clear cell renal cell carcinoma between 1997 and 2010. Clinical and pathological data elements were collected. A prognostic marker score was defined as unfavorable if more than 4 biomarkers were altered. The relationship between marker score and pathological features and oncologic outcomes was evaluated. RESULTS: Median age was 57 years (range 17 to 85) and median followup was 24 months (range 6 to 150). An unfavorable marker score was found in 55 (12.2%) patients and was associated with adverse pathological features. A significant correlation between unfavorable marker score and disease-free survival (HR 26.62, 95% CI 43.38-100.04, p=0.000) and with cancer specific survival (HR 8.15, 95% CI 74.42-101.56, p=0.004) was demonstrated on Kaplan-Meier survival analysis. On multivariate analysis an unfavorable marker score was an independent predictor of disease-free survival (HR 2.63, 95% CI 1.08 6.38, p=0.033). CONCLUSIONS: The cumulative number of aberrantly expressed cell cycle and proliferative biomarkers correlates with aggressive pathological features and inferior oncologic outcomes in patients with clear cell renal cell carcinoma. Our findings indicate that interrogation of cell cycle and proliferative markers is feasible, and further prospective pathway based exploration of biomarkers is needed. PMID- 23792147 TI - Cell-type-specific profiling of gene expression and chromatin binding without cell isolation: assaying RNA Pol II occupancy in neural stem cells. AB - Cell-type-specific transcriptional profiling often requires the isolation of specific cell types from complex tissues. We have developed "TaDa," a technique that enables cell-specific profiling without cell isolation. TaDa permits genome wide profiling of DNA- or chromatin-binding proteins without cell sorting, fixation, or affinity purification. The method is simple, sensitive, highly reproducible, and transferable to any model system. We show that TaDa can be used to identify transcribed genes in a cell-type-specific manner with considerable temporal precision, enabling the identification of differential gene expression between neuroblasts and the neuroepithelial cells from which they derive. We profile the genome-wide binding of RNA polymerase II in these adjacent, clonally related stem cells within intact Drosophila brains. Our data reveal expression of specific metabolic genes in neuroepithelial cells, but not in neuroblasts, and highlight gene regulatory networks that may pattern neural stem cell fates. PMID- 23792146 TI - Planar cell polarity protein Celsr1 regulates endothelial adherens junctions and directed cell rearrangements during valve morphogenesis. AB - Planar cell polarity (PCP) signaling controls tissue morphogenesis by coordinating collective cell behaviors. We show a critical role for the core PCP proteins Celsr1 and Vangl2 in the complex morphogenetic process of intraluminal valve formation in lymphatic vessels. We found that valve-forming endothelial cells undergo elongation, reorientation, and collective migration into the vessel lumen as they initiate valve leaflet formation. During this process, Celsr1 and Vangl2 are recruited from endothelial filopodia to discrete membrane domains at cell-cell contacts. Celsr1- or Vangl2-deficient mice show valve aplasia due to failure of endothelial cells to undergo rearrangements and adopt perpendicular orientation at valve initiation sites. Mechanistically, we show that Celsr1 regulates dynamic cell movements by inhibiting stabilization of VE-cadherin and maturation of adherens junctions. These findings reveal a role for PCP signaling in regulating adherens junctions and directed cell rearrangements during vascular development. PMID- 23792149 TI - A randomized, double-blind, placebo controlled trial of adalimumab for interstitial cystitis/bladder pain syndrome. AB - PURPOSE: The efficacy of adalimumab for the treatment of interstitial cystitis/bladder pain syndrome was investigated in a phase III, randomized, double-blind, placebo controlled, proof of concept study. MATERIALS AND METHODS: Patients with interstitial cystitis/bladder pain syndrome were randomized to receive a loading dose of 80 mg subcutaneous adalimumab followed by 40 mg every 2 weeks or subcutaneous placebo for 12 weeks, and outcome measures were assessed. The incidence of adverse events was also assessed. RESULTS: Of a total of 43 patients 21 received adalimumab and 22 received placebo. Of the patients who received adalimumab, there was a statistically significant improvement demonstrated in the O'Leary-Sant Interstitial Cystitis Symptom and Problem Indexes (p = 0.0002), Interstitial Cystitis Symptom Index (p = 0.0011), Interstitial Cystitis Problem Index (p = 0.0002), and Pelvic Pain, Urgency, Frequency Symptom Scale (p = 0.0017) at 12 weeks compared to baseline. At 12 weeks 11 of 21 (53%) patients in the adalimumab group had a 50% or greater improvement in global response assessment (p <= 0.0001). There was not a statistically significant improvement in any outcome measure in patients receiving adalimumab compared to placebo. There were no significant adverse events. CONCLUSIONS: Adalimumab treatment resulted in a statistically significant improvement in outcome measures compared to baseline in patients with moderate to severe interstitial cystitis/bladder pain syndrome. Adalimumab failed to demonstrate positive proof of concept compared to placebo due to a significant placebo effect. PMID- 23792150 TI - Behavioral effects of long-term antimuscarinic use in patients with spinal dysraphism: a case control study. AB - PURPOSE: We explored possible associations between long-term antimuscarinic use and behavioral problems in children with spinal dysraphism and neurogenic bladder. MATERIALS AND METHODS: Children with open and closed spinal dysraphism were recruited from 2 pediatric hospitals, 1 in Amsterdam and 1 in Utrecht, The Netherlands. At the Amsterdam facility antimuscarinics were prescribed in selected patients with detrusor overactivity. At the Utrecht facility antimuscarinics were prescribed from birth onward in patients with spinal dysraphism beginning in the early 1990s. Parents of study participants were asked to fill out a Child Behavior Checklist. Demographics, data on level and type(s) of lesion, and presence of hydrocephalus with a drain (and, if applicable, number of drain revisions) were retrieved for each patient. Cases and controls (8 boys and 8 girls per group) were matched on a 1-to-1 basis. RESULTS: Data on 32 children were analyzed. Median age was 10.6 years in cases and 10.5 years in controls (p=0.877). In each group 9 of 16 patients had hydrocephalus with a drain. No significant difference in Child Behavior Checklist scores for total problems was found between cases and controls (median 52.0 vs 59.5, p=0.39). No differences were found between the groups on any subdomain of the Child Behavior Checklist. CONCLUSIONS: No significant differences in behavior were found between children with spinal dysraphism with and without long-term use of antimuscarinics. PMID- 23792151 TI - Zonation of glucose and fatty acid metabolism in the liver: mechanism and metabolic consequences. AB - The liver is generally considered as a relatively homogeneous organ containing four different cell types. It is however well-known that the liver is not homogeneous and consists of clearly demarcated metabolic zones. Hepatocytes from different zones show phenotypical heterogeneity in metabolic features, leading to zonation of metabolic processes across the liver acinus. Zonation of processes involved in glucose and fatty acid metabolism is rather flexible and therefore prone to change under (patho)physiological conditions. Hepatic zonation appears to play an important role in the segregation of the different metabolic pathways in the liver. As a consequence, perturbations in metabolic zonation may be a part of metabolic liver diseases. The metabolic syndrome is characterized by the inability of insulin to adequately suppress hepatic gluconeogenesis, leading to hyperglycemia, hyperinsulinemia and eventually to type II diabetes. As insulin promotes lipogenesis through the transcription factor sterol regulatory element binding protein (SREBP)-1c, one would expect that lipogenesis should also be impaired in insulin-resistant states. However, in the metabolic syndrome hepatic de novo lipogenesis is increased, leading to hyperlipidemia and hepatosteatosis, primarily in the pericentral zone. These observations suggest the co-existence of insulin resistant glucose metabolism and insulin sensitive lipid metabolism in the metabolic syndrome. Here we provide a theoretical framework to explain this so-called 'insulin signaling paradox' in the context of metabolic zonation of the liver. PMID- 23792153 TI - Multilocus phylogeny of the avian family Alaudidae (larks) reveals complex morphological evolution, non-monophyletic genera and hidden species diversity. AB - The Alaudidae (larks) is a large family of songbirds in the superfamily Sylvioidea. Larks are cosmopolitan, although species-level diversity is by far largest in Africa, followed by Eurasia, whereas Australasia and the New World have only one species each. The present study is the first comprehensive phylogeny of the Alaudidae. It includes 83.5% of all species and representatives from all recognised genera, and was based on two mitochondrial and three nuclear loci (in total 6.4 kbp, although not all loci were available for all species). In addition, a larger sample, comprising several subspecies of some polytypic species was analysed for one of the mitochondrial loci. There was generally good agreement in trees inferred from different loci, although some strongly supported incongruences were noted. The tree based on the concatenated multilocus data was overall well resolved and well supported by the data. We stress the importance of performing single gene as well as combined data analyses, as the latter may obscure significant incongruence behind strong nodal support values. The multilocus tree revealed many unpredicted relationships, including some non monophyletic genera (Calandrella, Mirafra, Melanocorypha, Spizocorys). The tree based on the extended mitochondrial data set revealed several unexpected deep divergences between taxa presently treated as conspecific (e.g. within Ammomanes cinctura, Ammomanes deserti, Calandrella brachydactyla, Eremophila alpestris), as well as some shallow splits between currently recognised species (e.g. Certhilauda brevirostris-C. semitorquata-C. curvirostris; Calendulauda barlowi-C. erythrochlamys; Mirafra cantillans-M. javanica). Based on our results, we propose a revised generic classification, and comment on some species limits. We also comment on the extraordinary morphological adaptability in larks, which has resulted in numerous examples of parallel evolution (e.g. in Melanocorypha mongolica and Alauda leucoptera [both usually placed in Melanocorypha]; Ammomanopsis grayi and Ammomanes cinctura/deserti [former traditionally placed in Ammomanes]; Chersophilus duponti and Certhilauda spp.; Eremopterix hova [usually placed in Mirafra] and several Mirafra spp.), as well as both highly conserved plumages (e.g. within Mirafra) and strongly divergent lineages (e.g. Eremopterix hova vs. other Eremopterix spp.; Calandrella cinerea complex vs. Eremophila spp.; Eremalauda dunni vs. Chersophilus duponti; Melanocorypha mongolica and male M. yeltoniensis vs. other Melanocorypha spp. and female M. yeltoniensis). Sexual plumage dimorphism has evolved multiple times. Few groups of birds show the same level of disagreement between taxonomy based on morphology and phylogenetic relationships as inferred from DNA sequences. PMID- 23792152 TI - Correlated sodium and potassium imbalances within the ischemic core in experimental stroke: a 23Na MRI and histochemical imaging study. AB - This study addresses the spatial relation between local Na(+) and K(+) imbalances in the ischemic core in a rat model of focal ischemic stroke. Quantitative [Na(+)] and [K(+)] brain maps were obtained by (23)Na MRI and histochemical K(+) staining, respectively, and calibrated by emission flame photometry of the micropunch brain samples. Stroke location was verified by diffusion MRI, by changes in tissue surface reflectivity and by immunohistochemistry with microtubule-associated protein 2 antibody. Na(+) and K(+) distribution within the ischemic core was inhomogeneous, with the maximum [Na(+)] increase and [K(+)] decrease typically observed in peripheral regions of the ischemic core. The pattern of the [K(+)] decrease matched the maximum rate of [Na(+)] increase ('slope'). Some residual mismatch between the sites of maximum Na(+) and K(+) imbalances was attributed to the different channels and pathways involved in transport of the two ions. A linear regression of the [Na(+)]br vs. [K(+)]br in the samples of ischemic brain indicates that for each K(+) equivalent leaving ischemic tissue, 0.8+/-0.1 Eq, on average, of Na(+) enter the tissue. Better understanding of the mechanistic link between the Na(+) influx and K(+) egress would validate the (23)Na MRI slope as a candidate biomarker and a complementary tool for assessing ischemic damage and treatment planning. PMID- 23792154 TI - New insights in the long-debated evolutionary history of Triuridaceae (Pandanales). AB - The mycoheterotrophic plant family Triuridaceae (Pandanales) is hypothesized to be an old family, mainly based on its pantropical distribution. The existence of fossils from the Upper Cretaceous, assigned to Triuridaceae may form additional support for a great age of the family, although the affinity of these fossils to Triuridaceae is questioned. Although the circumscription of Triuridaceae has never been problematic, probably due to its distinct morphological characters, its systematic relationship has been under debate since the family was described around 1840. The lack of synapomorphies suitable for resolving higher taxonomic relationships is a function of the family's reduced vegetative growth and the highly modified floral structures. Molecular studies have assigned Triuridaceae to Pandanales, but its exact phylogenetic position remains unknown. In the present study the phylogeny of the Pandanales was reconstructed using four molecular markers and the divergence age estimates were obtained with a relaxed molecular clock method. We found that Triuridaceae are monophyletic and most likely descent form the second major split in Pandanales. The relationships between the other Pandanales families (Cyclanthaceae, Pandanaceae, Stemonaceae and Velloziaceae) are otherwise in accordance with earlier studies. Velloziaceae are sister to the rest of the Pandanales, Stemonaceae are most likely sister to a clade consisting of Pandanaceae and Cyclanthaceae, and the latter two families are sister to each other. All currently recognized tribes within Triuridaceae are also monophyletic at current taxon sampling. We estimate that the family has a Cretaceous (or Lower Paleocene) stem age, which is in accordance with earlier predictions. This old age, along with elevated mutation rates indicated by long branch lengths and the family's mycoheterotrophic lifestyle, might account for the substantial morphological differences between Triuridaceae and its closest relatives. PMID- 23792155 TI - Phylogeography of the sand dollar genus Mellita: cryptic speciation along the coasts of the Americas. AB - Sand dollars of the genus Mellita are members of the sandy shallow-water fauna. The genus ranges in tropical and subtropical regions on the two coasts of the Americas. To reconstruct the phylogeography of the genus we sequenced parts of the mitochondrial cytochrome oxidase I and of 16S rRNA as well as part of the nuclear 28S rRNA gene from a total of 185 specimens of all ten described morphospecies from 31 localities. Our analyses revealed the presence of eleven species, including six cryptic species. Sequences of five morphospecies do not constitute monophyletic molecular units and thus probably represent ecophenotypic variants. The fossil-calibrated phylogeny showed that the ancestor of Mellita diverged into a Pacific lineage and an Atlantic+Pacific lineage close to the Miocene/Pliocene boundary. Atlantic M. tenuis, M. quinquiesperforata and two undescribed species of Mellita have non-overlapping distributions. Pacific Mellita consist of two highly divergent lineages that became established at different times, resulting in sympatric M. longifissa and M. notabilis. Judged by modern day ranges, not all divergence in this genus conforms to an allopatric speciation model. Only the separation of M. quinquiesperforata from M. notabilis is clearly due to vicariance as the result of the completion of the Isthmus of Panama. The molecular phylogeny calibrated on fossil evidence estimated this event as having occurred ~3 Ma, thus providing evidence that, contrary to a recent proposal, the central American Isthmus was not completed until this date. PMID- 23792156 TI - Athlete use and opinion of point of choice nutrition labels at a major international competition. AB - Point of choice (POC) labels may assist individuals to choose food appropriate for their needs when dining away from home. However, limited research exists on the use and opinion of labels by athletes in a large dining hall environment. The aim of this study was to evaluate athletes' utilisation and opinion of POC nutrition labels provided in the athletes village main dining hall at a major competition event (the 2010 Commonwealth Games, New Delhi, India). A questionnaire was distributed to athletes from a range of cultural and sporting backgrounds (n=351) while present within the dining hall during main meal periods throughout the competition event (23rd September-14th October, 2010). While the majority of respondents (79%) reported that it was important/very important to provide POC information for menu items and 59% rated the POC labels as useful/very useful, only 14% of athletes reported using labels all of the time. Athletes from specific regions (India/Sri Lanka, Africa), sports (team and weight category), and those with less education reported using the labels more frequently. Although females rated the importance of providing nutrition information higher than males (p=0.008), there was no gender difference in reported use of POC labels. Athletes believed that POC labels could be improved with the addition of more information, better aesthetic properties, and better positioning in more convenient locations. Further research to identify the most effective POC label for use in this environment, and ultimately the development of a standardised label may assist a broader range of athletes at future competitions. PMID- 23792157 TI - Reactive astrocytes associated with plaques in TgCRND8 mouse brain and in human Alzheimer brain express phosphoprotein enriched in astrocytes (PEA-15). AB - To identify potential biomarkers associated with Alzheimer's disease (AD)-like neuropathologies in the murine brain, we conducted proteomic analyses of neocortices from TgCRND8 mice. Here we found that phosphoprotein enriched in astrocytes 15 kDa (PEA-15) is expressed at higher levels in the neocortical proteomes from 6-month old TgCRND8 mice, as compared to non-transgenic mice. Immunostaining for PEA-15 revealed reactive astrocytes associated with the neocortical amyloid plaques in TgCRND8 mice and in post-mortem human AD brains. This is the first report of increased phosphoprotein enriched in astrocytes (PEA 15) expression in reactive astrocytes of an AD mouse model and human AD brains. PMID- 23792158 TI - Circadian gene Clock contributes to cell proliferation and migration of glioma and is directly regulated by tumor-suppressive miR-124. AB - Although the roles of circadian Clock genes and microRNAs in tumorigenesis have been profoundly studied, mechanisms of cross-talk between them in regulation of gliomagenesis are poorly understood. Here we show that the expression level of CLOCK is significantly increased in high-grade human glioma tissues and glioblastoma cell lines. In contrast miR-124 is attenuated in similar samples. Further studies show that Clock is a direct target of miR-124, and either restoration of miR-124 or silencing of CLOCK can reduce the activation of NF kappaB. In conclusion, we suggest that as a target of glioma suppressor miR-124, CLOCK positively regulates glioma proliferation and migration by reinforcing NF kappaB activity. PMID- 23792159 TI - Structural evidence for native state stabilization of a conformationally labile amyloidogenic transthyretin variant by fibrillogenesis inhibitors. AB - Several classes of chemicals are able to bind to the thyroxine binding sites of transthyretin (TTR), stabilizing its native state and inhibiting in vitro the amyloidogenic process. The amyloidogenic I84S TTR variant undergoes a large conformational change at moderately acidic pH. Structural evidence has been obtained by X-ray analysis for the native state stabilization of I84S TTR by two chemically distinct fibrillogenesis inhibitors. In fact, they fully prevent the acidic pH-induced protein conformational change as a result of a long-range stabilizing effect. This study provides further support to the therapeutic strategy based on the use of TTR stabilizers as anti-amyloidogenic drugs. PMID- 23792160 TI - Elevated citrate levels in non-alcoholic fatty liver disease: the potential of citrate to promote radical production. AB - Plasma citrate levels were found to be elevated in non-alcoholic fatty liver disease (NAFLD) patients. Cellular experiments indicated that increased citrate levels might originate from an excess of fatty acids. The impact of elevated citrate levels on oxidative stress was examined. It was found that citrate stimulated hydrogen peroxide induced intracellular oxidative stress in HepG2 cells. This was related to the promotion of iron mediated hydroxyl radical formation from hydrogen peroxide by citrate. The stimulating effect of citrate on the reactivity of iron promotes oxidative stress, a crucial process in the progression of NAFLD. PMID- 23792161 TI - A Phe-rich region in short-wavelength sensitive opsins is responsible for their aggregation in the absence of 11-cis-retinal. AB - Human blue and mouse S-opsin are prone to aggregation in the absence of 11-cis retinal, which underlie the rapid cone degeneration in human patients and animal models of Leber congenital amaurosis (LCA). By in silico analysis and domain swapping experiments, we show that a Phe-rich region in short-wavelength sensitive (SWS) opsins, but not in medium/long-wavelength sensitive opsins, is responsible for SWS opsin aggregation. Mutagenesis studies suggest that Phe residues in this region are critical in mediating protein aggregation. Fusing the Phe-rich region of SWS opsins to GFP causes the latter to aggregate. Our findings suggest that new therapeutics can be designed to disrupt the Phe-rich region in preventing cone degeneration due to S-opsin aggregation in LCA. PMID- 23792162 TI - Next-generation sequencing of Okazaki fragments extracted from Saccharomyces cerevisiae. AB - Genome-wide Okazaki fragment distribution can differentiate the discontinuous from the semi-discontinuous DNA replication model. Here, we investigated the genome-wide Okazaki fragment distribution in Saccharomyces cerevisiae S288C. We improved the method based upon lambda exonuclease digestion to purify Okazaki fragments from S288C yeast cells, followed by Illumina sequencing. The distribution of Okazaki fragments around confirmed replication origins, including two highly efficient replication origins, supported the discontinuous DNA replication model. In S. cerevisiae mitochondria, Okazaki fragments were overrepresented in the transcribed regions, indicating the interplay between transcription and DNA replication. PMID- 23792163 TI - HIF1 regulates WSB-1 expression to promote hypoxia-induced chemoresistance in hepatocellular carcinoma cells. AB - WSB-1 is involved in DNA damage response by targeting homeodomain-interacting protein kinase 2 (HIPK2) for ubiquitination and degradation. Here, we report that hypoxia significantly up-regulates the expression of WSB-1 in human hepatocellular carcinoma (HCC) cells. We also provide evidence that WSB-1 is a target of hypoxia-inducible factor 1 (HIF-1). Silencing the expression of HIF 1alpha in HCC cells by RNA interference abolishes hypoxia-induced WSB-1 expression. Using chromatin immunoprecipitation and luciferase reporter assays, we identified a HRE of the WSB-1 gene. Moreover, silencing the expression of WSB 1 by RNA interference rescues HIPK2 expression in hypoxic HCC cells and promotes etoposide-induced cell death in hypoxic HCC cells. Taken together, these data shed light on the mechanisms underlying hypoxia-induced chemoresistance in HCC cells. PMID- 23792164 TI - ATF4 activation by the p38MAPK-eIF4E axis mediates apoptosis and autophagy induced by selenite in Jurkat cells. AB - Previous studies have shown that selenite exerts pro-apoptosis and pro-autophagy effects and is associated with the activation of ER stress in T-cell acute lymphoblastic leukemia (T-ALL). Herein we demonstrate the underlying mechanisms by which the activation of p38MAPK plays essential roles in apoptosis and autophagy and the coordination of cellular metabolic processes during leukemia therapy. MKK3/6-dependent activation of p38MAPK is required for the phosphorylation of eIF4E, thus initiating the translation of ER stress-related transcription factor ATF4. Upregulated ATF4 results in the transcriptional initiation of the apoptosis-related chop gene and autophagy-related map1lc3b gene, through which selenite links ER stress to apoptosis and autophagy during leukemia treatment. Moreover, autophagy induction enhances cell apoptosis under this condition. PMID- 23792165 TI - Inner membrane dynamics in mitochondria. AB - Combining the use of cells with sparse cristae marked with IMP-EGFP and short pulsed sub-saturating fluorescence excitation (non-saturation fluorescence microscopy/NSFM) revealed inhomogeneous fluorescence distribution along mitochondria in living cells. Also the matrix located TMRE was distributed non uniformly and at least in part filling the gaps between the IMP-EGFP fluorescence: fluorescence intensities are modulated in space and time in part in an antidromic manner. The spatial modulations can be interpreted to represent cristae/matrix distributions. The temporal fluctuations of fluorescence vary within 0.3-3s. Because most peak positions of IMP fluorescence remain stationary up to at least several minutes, temporal intensity modulations may result from varying emissions related to the degree of excitation and/or represent wobbling of cristae, i.e. lateral movements, bending or size changes. Modulations by noise and non-saturated excitation have been reduced by 3 steps of deconvolution followed by averaging 4 images. This allowed a final temporal resolution of 150ms. Disappearance of cristae or formation of new ones takes place within a few seconds, but these are rare events. Thus position of cristae seems to be rather stable, but they regularly disassemble close to fission sites. Treatment with oligomycin strongly reduces "wobbling" activity. PMID- 23792166 TI - Change in protein-ligand specificity through binding pocket grafting. AB - Recognition and discrimination of small molecules are crucial for biological processes in living systems. Understanding the mechanisms that underlie binding specificity is of particular interest to synthetic biology, e.g. the engineering of biosensors with de novo ligand affinities. Promising scaffolds for such biosensors are the periplasmic binding proteins (PBPs) due to their ligand mediated structural change that can be translated into a physically measurable signal. In this study we focused on the two homologous polyamine binding proteins PotF and PotD. Despite their structural similarity, PotF and PotD have different binding specificities for the polyamines putrescine and spermidine. To elucidate how specificity is determined, we grafted the binding site of PotD onto PotF. The introduction of 7 mutations in the first shell of the binding pocket leads to a swap in the binding profile as confirmed by isothermal titration calorimetry. Furthermore, the 1.7A crystal structure of the new variant complexed with spermidine reveals the interactions of the specificity determining residues including a defined water network. Altogether our study shows that specificity is encoded in the first shell residues of the PotF binding pocket and that transplantation of these residues allows the swap of the binding specificity. PMID- 23792167 TI - Nailfold capillaroscopy in systemic sclerosis: data from the EULAR scleroderma trials and research (EUSTAR) database. AB - OBJECTIVE: The aims of this study were to obtain cross-sectional data on capillaroscopy in an international multi-center cohort of Systemic Sclerosis (SSc) and to investigate the frequency of the capillaroscopic patterns and their disease-phenotype associations. METHODS: Data collected between June 2004 and October 2011 in the EULAR Scleroderma Trials and Research (EUSTAR) registry were examined. Patients' profiles based on clinical and laboratory data were obtained by cluster analysis and the association between profiles and capillaroscopy was investigated by multinomial logistic regression. RESULTS: 62 of the 110 EUSTAR centers entered data on capillaroscopy in the EUSTAR database. 376 of the 2754 patients (13.65%) were classified as scleroderma pattern absent, but non-specific capillary abnormalities were noted in 55.48% of the cases. Four major patients' profiles were identified characterized by a progressive severity for skin involvement, as well as an increased number of systemic manifestations. The "early" and "active" scleroderma patterns were generally observed in patients with mild/moderate skin involvement and a low number of disease manifestations, while the "late" scleroderma pattern was found more frequently in the more severe forms of the disease. CONCLUSION: These data indicate the importance of capillaroscopy in SSc management and that capillaroscopic patterns are directly related to the extent of organ involvement. PMID- 23792168 TI - Lagooning of wastewaters favors dissemination of clinically relevant Pseudomonas aeruginosa. AB - The significance of wastewater treatment lagoons (WWTLs) as point sources of clinically relevant Pseudomonas aeruginosa that can disseminate through rural and peri-urban catchments was investigated. A panel of P. aeruginosa strains collected over three years from WWTLs and community-acquired infections was compared by pulsed field gel electrophoresis (PFGE) DNA fingerprinting and multilocus sequence typing (MLST). Forty-four distantly related PFGE profiles and four clonal complexes were found among the WWTL strains analyzed. Some genotypes were repeatedly detected from different parts of WWTLs, including the influent, suggesting an ability to migrate and persist over time. MLST showed all investigated lineages to match sequence types described in other countries and strains from major clinical clones such as PA14 of ST253 and "C" of ST17 were observed. Some of these genotypes matched isolates from community-acquired infections recorded in the WWTL geographic area. Most WWTL strains harbored the main P. aeruginosa virulence genes; 13% harbored exoU-encoded cytoxins, but on at least six different genomic islands, with some of these showing signs of genomic instability. P. aeruginosa appeared to be highly successful opportunistic colonizers of WWTLs. Lagooning of wastewaters was found to favor dissemination of clinically relevant P. aeruginosa among peri-urban watersheds. PMID- 23792169 TI - CD4 positive T helper cells contribute to retinal ganglion cell death in mouse model of ischemia reperfusion injury. AB - Neuron degeneration is a common pathological process associated with many disease conditions in the central nervous system including retina. Although immune responses have been proposed as one potential element in triggering neural damage, the mechanism of action of specific immune components underlying the pathogenesis is unclear. In this study we focus on adaptive immune activities to evaluate CD4 positive helper cells in the retinal ganglion cell (RGC) degeneration in response to transient retinal ischemic/reperfusion (I/R) injury. Transient retinal ischemia was induced in four mouse strains with different immune backgrounds, including wild type mice from C57BL/6 and BABL/c strains, severe combined immunodeficient (SCID) mice lacking T and B lymphocytes, SCID mice with transferred wild type CD4+ T cells, and the STAT6 deficient mice without T helper 2 (TH2) cells. In SCID mice RGCs showed a strong resistance to cell death in response to I/R injury (89% +/- 3% of the survival cells in contralateral eye) compared with C57BL/6 (p = 0.018) and BALB/C (p = 0.038) wild types. By transferring the mature CD4+ T cells from matched wild type into SCID mice, the resistance of RGCs to injury was significantly compromised (p < 0.05). Furthermore a significant resistance of RGCs to cell death (p < 0.05) accompanied with an overexpression of STAT1 and STAT3 was confirmed in STAT6 deficient mice in response to I/R injury compared with the wild type controls, indicating that TH2 cells maturation might be involved in RGC damage. Adaptive immunity carried by CD4 T cells plays an essential role in RGC degeneration. PMID- 23792170 TI - An investigation of the likely role of (O-acyl) omega-hydroxy fatty acids in meibomian lipid films using (O-oleyl) omega-hydroxy palmitic acid as a model. AB - (O-acyl) omega-hydroxy fatty acids (OAHFAs) are a recently found group of polar lipids in meibum. Since these lipids can potentially serve as a surfactant in the tear film lipid layer, the surface properties of a molecule of this lipid class was investigated and compared with a structurally related wax ester and a fatty acid. (O-oleyl) omega-hydroxy palmitic acid was synthesized and used as the model OAHFA. It was spread either alone or mixed with human meibum on an artificial tear buffer in a Langmuir trough, and pressure-area isocycle profiles were recorded at different temperatures and compared with those of palmityl oleate and oleic acid. These measurements were accompanied by fluorescence microscopy of meibum mixed films during pressure-area isocycles. The pressure area curves indicated that pure films of the model OAHFA are as surface active as oleic acid films, cover a much larger surface area than either palmityl oleate or oleic acid and show a distinct biphasic pressure-area isocycle profile. The OAHFAs appeared to remain on the aqueous surface and show only a minor re-arrangement into multi layered structures during repetitive pressure area isocycles. All these properties can be explained by OAHFAs binding weakly to the aqueous surface via an ester group and strongly via a carboxyl group. By contrast, the pressure area profiles of palmityl oleate films indicate that they form multi-layers and oleic acid presumably forms micelles and desorbs into the subphase. When mixed with meibum, similar features as for pure films were observed. In addition, meibum OAHFA films appeared very homogeneous; a feature not seen with other mixtures. In conclusion these data support the notion that the tested OAHFA is a very potent surfactant which is important in spreading and stabilising meibomian lipid films. PMID- 23792171 TI - Amniotic membrane extract ameliorates benzalkonium chloride-induced dry eye in a murine model. AB - Human amniotic membrane (AM) is avascular but contains various beneficial bioactive factors, its extract (AE) is also effective in treating many ocular surface disorders. In this study, we for the first time evaluated the therapeutic effects of AE on dry eye induced by benzalkonium chloride in a BALB/c mouse model. Topical application of AE (1.5 and 3 MUg/eye/day) resulted in significantly longer tear break-up time on Day 3 and 6, lower fluorescein staining scores on Day 3, and lower inflammatory index on Day 6. AE reduced corneal epithelial K10 expression, inflammatory infiltration, and levels of TNF alpha, IL-1beta and IL-6 in BAC treated mice than that in the control mice. Moreover, decreased TUNEL positive cells in cornea and increased goblet cells in conjunctiva were also observed in AE treated corneas. Finally, AE induced more Ki 67 positive cells in corneal epithelium of dry eye mouse. Taken together, our data provide further support for BAC induced dry eye model as a valuable for dry eye study and suggest a great potential for AE as a therapeutic agent in the clinical treatment of dry eye. PMID- 23792173 TI - Variable steroid receptor responses: Intrinsically disordered AF1 is the key. AB - Steroid hormones, acting through their cognate receptor proteins, see widespread clinical applications due to their ability to alter the induction or repression of numerous genes. However, steroid usage is limited by the current inability to control off-target, or non-specific, side-effects. Recent results from three separate areas of research with glucocorticoid and other steroid receptors (cofactor-induced changes in receptor structure, the ability of ligands to alter remote regions of receptor structure, and how cofactor concentration affects both ligand potency and efficacy) indicate that a key element of receptor activity is the intrinsically disordered amino-terminal domain. These results are combined to construct a novel framework within which to logically pursue various approaches that could afford increased selectivity in steroid-based therapies. PMID- 23792174 TI - Multiple FAS1 domains and the RGD motif of TGFBI act cooperatively to bind alphavbeta3 integrin, leading to anti-angiogenic and anti-tumor effects. AB - TGFBI, a transforming growth factor beta-induced extracellular matrix protein, circulates at a level of ~300ng/ml in humans and modulates several integrin mediated cellular functions. The protein contains an N-terminal EMI domain, four consecutive FAS1 domains, and the RGD motif. Each FAS1 domain and the RGD motif have been known to interact with avb3 integrin. Here, we found that the binding affinity (Kd) of TGFBI for alphavbeta3 integrin was approximately 3.8*10(-8)M, a value ~2300-fold higher than that of a single FAS1 domain, and demonstrated that this greater affinity was due to the cooperative action of the four FAS1 domains and the RGD motif. Moreover, TGFBI exhibited more potent anti-angiogenic and anti tumorigenic activities, even at a 100-fold lower molar dose than the reported effective dose of the FAS1 domain. Finally, our data showed that TGFBI specifically targeted the tumor vasculature and accumulated at the tumor site. Collectively, our results support the theory that TGFBI acts as a potent endogenous anti-tumor and anti-angiogenic molecule by targeting alphavbeta3 integrin, and highlights the importance of physiological circulating TGFBI levels in inhibiting tumor growth. PMID- 23792175 TI - A novel retro-inverso peptide is a preferential JNK substrate-competitive inhibitor. AB - A novel 18 amino acid peptide PYC98 was demonstrated to inhibit JNK1 activity toward c-Jun. We observed a 5-fold increase in the potency of the retro-inverso form, D-PYC98 (a D-amino acid peptide in the reversed sequence) when compared with the inhibition achieved by L-PYC98, prompting our further evaluation of the D-PYC98 inhibitory mechanism. In vitro assays revealed that, in addition to the inhibition of c-Jun phosphorylation, D-PYC98 inhibited the JNK1-mediated phosphorylation of an EGFR-derived peptide, the ATF2 transcription factor, and the microtubule-regulatory protein DCX. JNK2 and JNK3 activities toward c-Jun were also inhibited, and surface plasmon resonance analysis confirmed the direct interaction of D-PYC98 and JNK1. Further kinetics analyses revealed the non-ATP competitive mechanism of action of D-PYC98 as a JNK1 inhibitor. The targeting of the JNK1 common docking site by D-PYC98 was confirmed by the competition of binding by TIJIP. However, as mutations of JNK1 R127 and E329 within the common docking domain did not impact on the affinity of the interaction with D-PYC98 measured by surface plasmon resonance analysis, other residues in the common docking site appear to contribute to the JNK1 interaction with D-PYC98. Furthermore, we found that D-PYC98 inhibited the related kinase p38 MAPK, suggesting a broader interest in developing D-PYC98 for possible therapeutic applications. Lastly, in evaluating the efficacy of this peptide to act as a substrate competitive inhibitor in cells, we confirmed that the cell-permeable D PYC98-TAT inhibited c-Jun Ser63 phosphorylation during hyperosmotic stress. Thus, D-PYC98-TAT is a novel cell-permeable JNK inhibitor. PMID- 23792172 TI - What do mechanotransduction, Hippo, Wnt, and TGFbeta have in common? YAP and TAZ as key orchestrating molecules in ocular health and disease. AB - Cells in vivo are exposed to a complex signaling environment. Biochemical signaling modalities, such as secreted proteins, specific extracellular matrix domains and ion fluxes certainly compose an important set of regulatory signals to cells. However, these signals are not exerted in isolation, but rather in concert with biophysical cues of the surrounding tissue, such as stiffness and topography. In this review, we attempt to highlight the biophysical attributes of ocular tissues and their influence on cellular behavior. Additionally, we introduce the proteins YAP and TAZ as targets of biophysical and biochemical signaling and important agonists and antagonists of numerous signaling pathways, including TGFbeta and Wnt. We frame the discussion around this extensive signaling crosstalk, which allows YAP and TAZ to act as orchestrating molecules, capable of integrating biophysical and biochemical cues into a broad cellular response. Finally, while we draw on research from various fields to provide a full picture of YAP and TAZ, we attempt to highlight the intersections with vision science and the exciting work that has already been performed. PMID- 23792177 TI - Ringing effects eliminated spin echo in solids. AB - Two types of ringing effects eliminated spin echo sequences have been introduced. To achieve the task, two additional 90 degrees pulses with proper phase cycles are placed at the beginning of the pulse sequences. The spin echo time is calculated with the perturbation method to the first order, i.e. taking into account only the dipolar secular term. The non-secular term causes an imaginary part of the FID, leading to an unsymmetrical NMR spectrum. This effect, according to a symmetry of NMR sequences under phase inversion, can be compensated by inverting all the x and -x or y and -y phases. The properties of the symmetry are derived based on the theory of density matrix. In addition, the non-secular term also results in a small drop (several per cent) of the echo amplitude, but it nearly does not affect the echo time. With these pulse sequences we are able to get a spectrum with an echo delay only 1.1MUs without distortion using a Bruker AVANCE III NMR instrument. PMID- 23792176 TI - Dysferlin interacts with calsequestrin-1, myomesin-2 and dynein in human skeletal muscle. AB - Dysferlinopathies are a group of progressive muscular dystrophies characterized by mutations in the gene DYSF. These mutations cause scarcity or complete absence of dysferlin, a protein that is expressed in skeletal muscle and plays a role in membrane repair. Our objective was to unravel the proteins that constitute the dysferlin complex and their interaction within the complex using immunoprecipitation assays (IP), blue native gel electrophoresis (BN) in healthy adult skeletal muscle and healthy cultured myotubes, and fluorescence lifetime imaging-fluorescence resonance energy transfer (FLIM-FRET) analysis in healthy myotubes. The combination of immunoprecipitations and blue native electrophoresis allowed us to identify previously reported partners of dysferlin - such as caveolin-3, AHNAK, annexins, or Trim72/MG53 - and new interacting partners. Fluorescence lifetime imaging showed a direct interaction of dysferlin with Trim72/MG53, AHNAK, cytoplasmic dynein, myomesin-2 and calsequestrin-1, but not with caveolin-3 or dystrophin. In conclusion, although IP and BN are useful tools to identify the proteins in a complex, techniques such as fluorescence lifetime imaging analysis are needed to determine the direct and indirect interactions of these proteins within the complex. This knowledge may help us to better understand the roles of dysferlin in muscle tissue and identify new genes involved in muscular dystrophies in which the responsible gene is unknown. PMID- 23792178 TI - Convergence and divergence in the delivery of cognitive therapy in two randomized clinical trials. AB - OBJECTIVE: Research indicates that cognitive therapy (CT) can be differentiated from other treatment modalities based on in-session therapist behavior. However, to our knowledge, consistency in the implementation of individual CT across clinical trials has not been tested. We compared therapist adherence to CT, as well as the therapeutic alliance, in two randomized clinical trials (RCTs) of depression treatment. METHOD: Data were drawn from two highly cited RCTs of CT for major depression, representing a total of three sites. Trained raters coded sessions for therapist adherence to CT and the therapeutic alliance. RESULTS: Significant differences were obtained between sites in overall level of adherence to CT, therapist emphasis on cognitive vs behavioral strategies, and therapist focus on homework. In contrast, no significant differences emerged in the collaborative structure of CT and in the therapeutic alliance. CONCLUSIONS: Despite efforts to maximize the consistency of CT implementation (e.g., via the use of the same treatment manuals, delivered by carefully-selected and experienced therapists), differences in the implementation of CT can result. Although preliminary, these findings raise questions regarding the uniformity of CT delivery across published clinical trials, and underline the importance of assessing treatment integrity, both across clinical trials and in dissemination research. PMID- 23792179 TI - The influence of comorbid personality disorder on the effects of behavioural activation vs. antidepressant medication for major depressive disorder: results from a randomized trial in Iran. AB - There is a disagreement about the impact of personality disorder (PD) on treatment outcome for patients with major depressive disorder (MDD). 100 out patients with MDD were randomized to 16 sessions of behavioural activation (BA) (n = 50) or antidepressant medication (ADM) (n = 50) in Iran. Main outcome was depression severity, measured with the Beck Depression Inventory (BDI-II) and the Hamilton Rating Scale for Depression (HRSD), and assessed at 0, 4, 13 and 49 weeks. Participants with comorbid PDs had higher scores on BDI and HRSD at baseline and throughout the study than participants without comorbid PD. Patients with and without comorbid personality pathology responded equally to treatment on the short-and the long-term. Overall, BA was better in reducing symptoms in patients but this effect was not influenced by comorbid PD. Similar effects were found for a dimensional PD-measure. Only cluster-C PD-traits turned out to be associated with overall depression severity. Cluster-A PD-traits predicted poorer long-term treatment response to ADM and BA, but only on the BDI, not on the HRSD. No effects of cluster-B PD-traits were found. However, PD was associated with higher dropout. The general conclusion is that comorbid PD pathology, especially from cluster-C, is associated with higher depression severity, but not with less response to treatment. Comorbid PD did predict increased chance of dropout. PMID- 23792180 TI - A naturalistic examination of body checking and dietary restriction in women with anorexia nervosa. AB - Body checking has been conceptualized as a behavioral manifestation of the core overvaluation of eating, shape, and weight concerns underlying eating disorder psychopathology. Cognitive-behavioral theories suggest that body checking behaviors may function to maintain dietary restriction. The current study examined the association between body checking frequency and dietary restriction among women with anorexia nervosa (AN) in the natural environment. Women (N = 118) with full or partial AN completed baseline clinical interviews and a two week ecological momentary assessment protocol, during which they reported on body checking behaviors (i.e., checking whether one's thighs touch; checking joints/bones for fat) and dietary restriction (i.e., 8 waking hours without eating; consuming less than 1200 calories per day). Average daily body checking frequency was positively associated with baseline eating disorder symptoms and body mass index. Daily body checking frequency was associated with both forms of dietary restriction on the same day, as well as the following day. Results support the theorized association between body checking and overvaluation of shape and weight, and suggest that targeting such behaviors in treatment may have utility in reducing dietary restriction. PMID- 23792181 TI - Personality-based subtypes of anorexia nervosa: examining validity and utility using baseline clinical variables and ecological momentary assessment. AB - OBJECTIVE: This study sought to empirically derive and validate clinically relevant personality-based subtypes of anorexia nervosa (AN). METHODS: Women (N = 116) with full or subthreshold AN completed baseline measures of personality, clinical variables, and eating disorder (ED) symptoms, followed by two weeks of ecological momentary assessment (EMA). A latent profile analysis was conducted to identify personality subtypes, which were compared on baseline clinical variables and EMA variables. RESULTS: The best-fitting model supported three subtypes: underregulated, overregulated, and low psychopathology. The underregulated subtype (characterized by high Stimulus Seeking, Self-Harm, and Oppositionality) displayed greater baseline ED symptoms, as well as lower positive affect and greater negative affect, self-discrepancy, and binge eating in the natural environment. The overregulated subtype (characterized by high Compulsivity and low Stimulus Seeking) was more likely to have a lifetime obsessive-compulsive disorder diagnosis and exhibited greater perfectionism; levels of negative affect, positive affect, and self-discrepancy in this group were intermediate between the other subtypes. The low psychopathology subtype (characterized by normative personality) displayed the lowest levels of baseline ED symptoms, co occurring disorders, and ED behaviors measured via EMA. CONCLUSIONS: Findings support the validity of these personality-based subtypes, suggesting the potential utility of addressing within-diagnosis heterogeneity in the treatment of AN. PMID- 23792182 TI - Minimization of excess sludge production by in-situ activated sludge treatment processes--a comprehensive review. AB - The widespread application of conventional activated sludge treatment process has been employed to deal with a variety of municipal and industrial sewage. While the generation of waste activated sludge (WAS) was considerably huge, the management and disposal expenses were substantially costly. A promising process aimed for WAS reduction during the operation process is urgently needed. Thus, increasing attentions emphasizing on the improved or novel sludge reduction processes should be intensively recommended in the future. This review presents the current and emerging technologies for excess sludge minimization within the process of sewage treatment. The ultimate purpose of this paper is to guide or inspire researchers who are seeking feasible and promising technologies (or processes) to tackle the severe WAS problem. PMID- 23792183 TI - Zoonotic transmission of reassortant porcine G4P[6] rotaviruses in Hungarian pediatric patients identified sporadically over a 15 year period. AB - Genotype G4P[6] Rotavirus A (RVA) strains collected from children admitted to hospital with gastroenteritis over a 15 year period in the pre rotavirus vaccine era in Hungary were characterized in this study. Whole genome sequencing and phylogenetic analysis was performed on eight G4P[6] RVA strains. All these RVA strains shared a fairly conservative genomic configuration (G4-P[6]-I1/I5-R1-C1 M1-A1/A8-N1-T1/T7-E1-H1) and showed striking similarities to porcine and porcine derived human RVA strains collected worldwide, although genetic relatedness to some common human RVA strains was also seen. The resolution of phylogenetic relationship between porcine and human RVA genes was occasionally low, making the evaluation of host species origin of individual genes sometimes difficult. Yet the whole genome constellations and overall phylogenetic analyses indicated that these eight Hungarian G4P[6] RVA strains may have originated by independent zoonotic transmission, probably from pigs. Future surveillance studies of human and animal RVA should go parallel to enable the distinction between direct interspecies transmission events and those that are coupled with reassortment of cognate genes. PMID- 23792184 TI - Staphylococcus aureus innate immune evasion is lineage-specific: a bioinfomatics study. AB - Staphylococcus aureus is a major human pathogen, and is targeted by the host innate immune system. In response, S. aureus genomes encode dozens of secreted proteins that inhibit complement, chemotaxis and neutrophil activation resulting in successful evasion of innate immune responses. These proteins include immune evasion cluster proteins (IEC; Chp, Sak, Scn), staphylococcal superantigen-like proteins (SSLs), phenol soluble modulins (PSMs) and several leukocidins. Biochemical studies have indicated that genetic variants of these proteins can have unique functions. To ascertain the scale of genetic variation in secreted immune evasion proteins, whole genome sequences of 88 S. aureus isolates, representing 25 clonal complex (CC) lineages, in the public domain were analysed across 43 genes encoding 38 secreted innate immune evasion protein complexes. Twenty-three genes were variable, with between 2 and 15 variants, and the variants had lineage-specific distributions. They include genes encoding Eap, Ecb, Efb, Flipr/Flipr-like, Hla, Hld, Hlg, Sbi, Scin-B/C and 13 SSLs. Most of these protein complexes inhibit complement, chemotaxis and neutrophil activation suggesting that isolates from each S. aureus lineage respond to the innate immune system differently. In contrast, protein complexes that lyse neutrophils (LukSF PVL, LukMF, LukED and PSMs) were highly conserved, but can be carried on mobile genetic elements (MGEs). MGEs also encode proteins with narrow host-specificities arguing that their acquisition has important roles in host/environmental adaptation. In conclusion, this data suggests that each lineage of S. aureus evades host immune responses differently, and that isolates can adapt to new host environments by acquiring MGEs and the immune evasion protein complexes that they encode. Cocktail therapeutics that targets multiple variant proteins may be the most appropriate strategy for controlling S. aureus infections. PMID- 23792185 TI - Swimming training prevents fat deposition and decreases angiotensin II-induced coronary vasoconstriction in ovariectomized rats. AB - We investigated the effects of chronic swimming training (ST) on the deposition of abdominal fat and vasoconstriction in response to angiotensin II (ANG II) in the coronary arterial bed of estrogen deficient rats. Twenty-eight 3-month old Wistar female rats were divided into 4 groups: sedentary sham (SS), sedentary ovariectomized (SO), swimming-trained sham (STS) and swimming-trained ovariectomized (STO). ST protocol consisted of a continuous 60-min session, with a 5% BW load attached to the tail, completed 5 days/week for 8-weeks. The retroperitoneal, parametrial, perirenal and inguinal fat pads were measured. The intrinsic heart rate (IHR), coronary perfusion pressure (CPP) and a concentration response curve to ANG II in the coronary bed was constructed using the Langendorff preparation. Ovariectomy (OVX) significantly reduced 17-beta estradiol plasma levels in SO and STO groups (p<0.05). The STO group had a significantly reduced retroperitoneal and parametrial fat pad compared with the SO group (p<0.05). IHR values were similar in all groups; however, baseline CPP was significantly reduced in the SO, STS and STO groups compared with the SS group (p<0.05). ANG II caused vasoconstriction in the coronary bed in a concentration-dependent manner. The SO group had an increased response to ANG II when compared with all other experimental groups (p<0.05), which was prevented by 8-weeks of ST in the STO group (p<0.05). OVX increased ANG II-induced vasoconstriction in the coronary vascular bed and abdominal fat pad deposition. Eight weeks of swimming training improved these vasoconstrictor effects and decreased abdominal fat deposition in ovariectomized rats. PMID- 23792186 TI - The role of weight loss and exercise in correcting skeletal muscle mitochondrial abnormalities in obesity, diabetes and aging. AB - Mitochondria within skeletal muscle have been implicated in insulin resistance of obesity and type 2 diabetes mellitus as well as impaired muscle function with normal aging. Evaluating the potential of interventions to improve mitochondria is clearly relevant to the prevention or treatment of metabolic diseases and age related dysfunction. This review provides an overview and critical evaluation of the effects of weight loss and exercise interventions on skeletal muscle mitochondria, along with implications for insulin resistance, obesity, type 2 diabetes and aging. The available literature strongly suggests that the lower mitochondrial capacity associated with obesity, type 2 diabetes and aging is not an irreversible lesion. However, weight loss does not appear to affect this response, even when the weight loss is extreme. In contrast, increasing physical activity improves mitochondrial content and perhaps the function of individual mitochondrion. Despite the consistent effect of exercise to improve mitochondrial capacity, studies mechanistically linking mitochondria to insulin resistance, reductions in intramyocellular lipid or improvement in muscle function remain inconclusive. In summary, studies of diet and exercise training have advanced our understanding of the link between mitochondrial oxidative capacity and insulin resistance in obesity, type 2 diabetes and aging. Nevertheless, additional inquiry is necessary to establish the significance and clinical relevance of those perturbations, which could lead to targeted therapies for a myriad of conditions and diseases involving mitochondria. PMID- 23792187 TI - Mitochondrial function and insulin secretion. AB - In the endocrine fraction of the pancreas, the beta-cell rapidly reacts to fluctuations in blood glucose concentrations by adjusting the rate of insulin secretion. Glucose-sensing coupled to insulin exocytosis depends on transduction of metabolic signals into intracellular messengers recognized by the secretory machinery. Mitochondria play a central role in this process by connecting glucose metabolism to insulin release. Mitochondrial activity is primarily regulated by metabolic fluxes, but also by dynamic morphology changes and free Ca(2+) concentrations. Recent advances of mitochondrial Ca(2+) homeostasis are discussed; in particular the roles of the newly-identified mitochondrial Ca(2+) uniporter MCU and its regulatory partner MICU1, as well as the mitochondrial Na(+)-Ca(2+) exchanger. This review describes how mitochondria function both as sensors and generators of metabolic signals; such as NADPH, long chain acyl-CoA, glutamate. The coupling factors are additive to the Ca(2+) signal and participate to the amplifying pathway of glucose-stimulated insulin secretion. PMID- 23792188 TI - Finite element predictions of cartilage contact mechanics in hips with retroverted acetabula. AB - BACKGROUND: A contributory factor to hip osteoarthritis (OA) is abnormal cartilage mechanics. Acetabular retroversion, a version deformity of the acetabulum, has been postulated to cause OA via decreased posterior contact area and increased posterior contact stress. Although cartilage mechanics cannot be measured directly in vivo to evaluate the causes of OA, they can be predicted using finite element (FE) modeling. OBJECTIVE: The objective of this study was to compare cartilage contact mechanics between hips with normal and retroverted acetabula using subject-specific FE modeling. METHODS: Twenty subjects were recruited and imaged: 10 with normal acetabula and 10 with retroverted acetabula. FE models were constructed using a validated protocol. Walking, stair ascent, stair descent and rising from a chair were simulated. Acetabular cartilage contact stress and contact area were compared between groups. RESULTS: Retroverted acetabula had superomedial cartilage contact patterns, while normal acetabula had widely distributed cartilage contact patterns. In the posterolateral acetabulum, average contact stress and contact area during walking and stair descent were 2.6-7.6 times larger in normal than retroverted acetabula (P <= 0.017). Conversely, in the superomedial acetabulum, peak contact stress during walking was 1.2-1.6 times larger in retroverted than normal acetabula (P <= 0.044). Further differences varied by region and activity. CONCLUSIONS: This study demonstrated superomedial contact patterns in retroverted acetabula vs widely distributed contact patterns in normal acetabula. Smaller posterolateral contact stress in retroverted acetabula than in normal acetabula suggests that increased posterior contact stress alone may not be the link between retroversion and OA. PMID- 23792189 TI - Patient education with or without manual therapy compared to a control group in patients with osteoarthritis of the hip. A proof-of-principle three-arm parallel group randomized clinical trial. AB - OBJECTIVE: To investigate the effectiveness of a patient education (PE) program with or without the added effect of manual therapy (MT) compared to a minimal control intervention (MCI). METHODS: In a single-center university hospital setting, a total of 118 patients with clinical and radiographic unilateral hip osteoarthritis (OA) from primary care were randomized into one of three groups: PE, PE plus MT or MCI. The PE was taught by a physiotherapist involving five sessions. The MT was delivered by a chiropractor involving 12 sessions and the MCI included a home stretching program. Primary outcome was self-reported pain severity on an 11-box numeric rating scale (NRS) immediately following a 6-week intervention period. Patients were followed for 1 year. RESULTS: Primary analysis included 111 patients (94%). In the combined group (PE + MT), a clinically relevant reduction in pain severity compared to the MCI of 1.90 points (95% confidence interval (CI) 0.9-2.9) was achieved. Effect size (Cohen's d) for the PE + MT minus the MCI was 0.92 (95% CI 0.41-1.42). Number needed to treat for PE + MT was 3 (95% CI 2-7). No difference was found between the PE and MCI groups, with mean difference 0.0 (95% CI -1.0 to 1.0). At 12 months, not including patients receiving hip surgery the statistically significant difference favoring PE + MT was maintained. CONCLUSIONS: For primary care patients with OA of the hip, a combined intervention of MT and PE was more effective than a MCI. PE alone was not superior to the MCI. TRIAL REGISTRATION: clinicaltrials.govNCT01039337. PMID- 23792190 TI - Directed phenotype switching as an effective antimelanoma strategy. AB - Therapeutic resistance in melanoma and other cancers arises via irreversible genetic, and dynamic phenotypic, heterogeneity. Here, we use directed phenotype switching in melanoma to sensitize melanoma cells to lineage-specific therapy. We show that methotrexate (MTX) induces microphthalmia-associated transcription factor (MITF) expression to inhibit invasiveness and promote differentiation associated expression of the melanocyte-specific Tyrosinase gene. Consequently, MTX sensitizes melanomas to a tyrosinase-processed antifolate prodrug 3-O-(3,4,5 trimethoxybenzoyl)-(-)-epicatechin (TMECG), that inhibits the essential enzyme DHFR with high affinity. The combination of MTX and TMECG leads to depletion of thymidine pools, double-strand DNA breaks, and highly efficient E2F1-mediated apoptosis in culture and in vivo. Importantly, this drug combination delivers an effective and tissue-restricted antimelanoma therapy in vitro and in vivo irrespective of BRAF, MEK, or p53 status. PMID- 23792191 TI - Small molecule inhibitors of aurora-a induce proteasomal degradation of N-myc in childhood neuroblastoma. AB - Amplification of MYCN is a driver mutation in a subset of human neuroendocrine tumors, including neuroblastoma. No small molecules that target N-Myc, the protein encoded by MYCN, are clinically available. N-Myc forms a complex with the Aurora-A kinase, which protects N-Myc from proteasomal degradation. Although stabilization of N-Myc does not require the catalytic activity of Aurora-A, we show here that two Aurora-A inhibitors, MLN8054 and MLN8237, disrupt the Aurora A/N-Myc complex and promote degradation of N-Myc mediated by the Fbxw7 ubiquitin ligase. Disruption of the Aurora-A/N-Myc complex inhibits N-Myc-dependent transcription, correlating with tumor regression and prolonged survival in a mouse model of MYCN-driven neuroblastoma. We conclude that Aurora-A is an accessible target that makes destabilization of N-Myc a viable therapeutic strategy. PMID- 23792192 TI - Induction of a whole chromosome loss by colcemid in human cells elucidated by discrimination between FISH signal overlap and chromosome loss. AB - Aneuploidy is a change in the number of chromosomes and an essential component in tumorigenesis. Therefore, accurate and sensitive detection of aneuploidy is important in screening for carcinogens. In vitro micronucleus (MN) assay has been adopted in the recently revised International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) S2 guideline and can be employed to predict both clastogenic and aneugenic chromosomal aberrations in interphase cells. However, distinguishing clastogens and aneugens is not possible using this assay. The Organization for Economic Co operation and Development (OECD) guideline TG487 therefore recommends the use of centromere/kinetochore staining in micronuclei to differentiate clastogens from aneugens. Here, we analyzed numerical changes of a specific chromosome in cytokinesis-blocked binucleated cells by fluorescence in situ hybridization (FISH) using the specific centromere probe in human lymphoblastoid TK6 cells treated with aneugens (colcemid and vincristine) or clastogens (methyl methanesulfonate [MMS] and 4-nitroquinoline-1-oxide [4-NQO]). Colcemid and vincristine significantly increased the frequencies of nondisjunction and loss of FISH signals, while MMS and 4-NQO slightly increased only the frequency of loss of FISH signals. The loss of FISH signals of a specific chromosome from two to one per nucleus implies either a loss of a whole chromosome or an overlap of two signals. To distinguish a chromosome loss from signal overlap, we investigated the number of FISH signals and the fluorescent intensity of each signal per nucleus using a probe specific for whole chromosome 2 in binucleated TK6 cells and primary human lymphocytes treated with colcemid and MMS. By discriminating between chromosome loss and FISH signal overlap, we revealed that colcemid, but not MMS, induced a loss of a whole chromosome in primary lymphocytes and TK6 cells. PMID- 23792193 TI - Computed tomography angiography and myocardial computed tomography perfusion in patients with coronary stents: prospective intraindividual comparison with conventional coronary angiography. AB - OBJECTIVES: This study sought to determine whether adding myocardial computed tomography perfusion (CTP) to computed tomography angiography (CTA) improves diagnostic performance for coronary stents. BACKGROUND: CTA of coronary stents has been limited by nondiagnostic studies caused by metallic stent material and coronary motion. METHODS: CTA and CTP were performed in 91 consecutive patients with stents before quantitative coronary angiography, the reference standard for obstructive stenosis (>=50%). If a coronary stent or vessel was nondiagnostic on CTA, adenosine stress CTP in the corresponding myocardial territory was read for combined CTA/CTP. RESULTS: Patients had an average of 2.5 +/- 1.8 coronary stents (1 to 10), with a diameter of 3.0 +/- 0.5 mm. Significantly more patients were nondiagnostic for stent assessment by CTA (22%; mainly due to metal artifacts [75%] or motion [25%]) versus CTP (1%; p < 0.001; severe angina precluded CTP in 1 case). The per-patient diagnostic accuracy of CTA/CTP for stents (87%, 95% confidence interval [CI]: 78% to 93%) was significantly higher than that of CTA alone (71%, 95% CI: 61% to 80%; p < 0.001), mainly because nondiagnostic examinations were significantly reduced (p < 0.001). In the analysis of any coronary artery disease, diagnostic accuracy and nondiagnostic rate were also significantly improved by the addition of CTP (p < 0.001). CTA/CTP (7.9 +/- 2.8 mSv) had a significantly lower effective radiation dose than angiography (9.5 +/- 5.1 mSv; p = 0.005). The area under the receiver-operating characteristic curve for CTA/CTP (0.82, 95% CI: 0.69 to 0.95) was superior to that for CTA (0.69, 95% CI: 0.57 to 0.82; p < 0.001) in identifying patients requiring stent revascularization. CONCLUSIONS: Combined coronary CTA and myocardial CTP improves diagnosis of CAD and in-stent restenosis in patients with stents compared with CTA alone. (Coronary Artery Stent Evaluation With 320-Slice Computed Tomography The CArS 320 Study [CARS-320]; NCT00967876). PMID- 23792194 TI - Spectroscopic and electrochemical characterization of some Schiff base metal complexes containing benzoin moiety. AB - The ligation behavior of bis-benzoin ethylenediamine (B2ED) and benzoin thiosemicarbazone (BTS) Schiff bases towards Ru(3+), Rh(3+), Pd(2+), Ni(2+) and Cu(2+) were determined. The bond length of M-N and spectrochemical parameters (10Dq, beta, B and LFSE) of the complexes were evaluated. The redox characteristics of selected complexes were explored by cyclic voltammetry (CV) at Pt working electrode in non aqueous solvents. Au mesh (100 w/in.) optically transparent thin layer electrode (OTTLE) was also used for recording thin layer CV for selected Ru complex. Oxidation of some complexes occurs in a consecutive chemical reaction of an EC type mechanism. The characteristics of electron transfer process of the couples M(2+)/M(3+) and M(3+)/M(4+) (M=Ru(3+), Rh(3+)) and the stability of the complexes towards oxidation and/or reduction were assigned. The nature of the electroactive species and reduction mechanism of selected electrode couples were assigned. PMID- 23792195 TI - CYP46A1 intron-2T/C polymorphism and Alzheimer's disease: an updated meta analysis of 16 studies including 3,960 cases and 3,828 controls. AB - Whether the variations in the cholesterol 24S-hydroxylase (CYP46A1) gene would raise Alzheimer's risk is still undetermined. A previous meta-analysis about the association between AD susceptibility and CYP46A1 intron-2T/C (rs754203) has led to inconsistent conclusions. To assess the relationship between the CYP46A1 rs754203 polymorphism and AD risk more exactly, relevant literature was recruited by searching the Cochrane Library, PubMed, Medline (Ovid), Embase (Ovid), ISI Web of Science, the Chinese Biomedicine Database (CBM), CNKI, Wan fang, and reference lists of articles. Odds ratio (ORs) and 95% confidence intervals (CIs) were calculated using fixed and random effects models, publication bias was tested by funnel plot and Egger's test, heterogeneity was assessed with I(2) statistics. Sixteen case-control studies were included with a total of 7788 individuals, involving 3960 AD patients and 3828 controls. The combined results showed no significant differences in allele comparison C vs. T (OR=1.04, 95% CI=0.86-1.26), recessive model CC vs. TC+TT (OR=1.24, 95% CI=0.90-1.69) and dominant model CC+TC vs. TT (OR=1.03, 95% CI=0.84-1.27). When stratifying for ethnicity, no significant associations were detected in Caucasians or in Asians. Our results suggested that CYP46A1 rs754203 is a minor risk factor for AD. However, more wide samples of highly selected AD patients, based on different onset age and other confirmed genetic factors interactions, are needed to clarify these association and further researches should be carried out to explore the effect of genetic networks, environmental factors, individual biological characteristics and their mutual interactions. PMID- 23792196 TI - Positive effects of aerobic exercise on learning and memory functioning, which correlate with hippocampal IGF-1 increase in adolescent rats. AB - It is already known that regular aerobic exercise during adolescent period improves learning and memory in rats. In this study, we investigated the effects of regular aerobic exercise on learning, memory functioning and IGF-1 levels. IGF 1 is known to have positive effects on cognitive functions in adolescent rats. Exercise group was separated into two different groups. First half was run on a treadmill for 30 min per session at a speed of 8m/min and 0 degrees slope, five times a week for 6 weeks. The second half was given free access to a running wheel (diameter 11.5 cm) which was connected to a digital counter and run on a treadmill for 6 weeks. Learning and memory functioning were found to be positively correlated with the exercise activity. Findings suggest increased neuron density in CA1 hippocampal region and dentate gyrus. Increased IGF-1 level was detected in hippocampus and blood serum, while IGF-1 level in liver tissue did not change with exercise activity. In conclusion, our findings indicate that learning and memory functioning were positively affected by voluntary and involuntary physical exercise which correlated increased hippocampal activity and elevated IGF-1 levels in adolescent rats. PMID- 23792197 TI - The effect of motion aftereffect on optomotor response in larva and adult zebrafish. AB - Motion aftereffect (MAE) occurs after presenting a moving stimulus to fixed subjects, as an apparent MAE the subject moves in the opposite direction. This natural process provides an excellent tool to investigate visual motion perception. Zebrafish is an important animal model with an extensive molecular toolkit, but there is a lack of the comparative understanding of its perceptual processes. This study was designed to study the optomotor response (OMR), in which the fish swims in the same direction of a moving stimulus in both adult and larvae zebrafish. Simple square wave gratings moving in a specific horizontal direction (with a precise visual angle) were shown to a test group. After an adaptation phase, a static grating was shown for a short period during which the movement of the fish was recorded. In the control group, the same procedure was applied but the grating pattern was shown moving randomly back and forth followed by a static grating. Time spent swimming in either the same or the opposite direction of the adaptation grating was recorded as line index (LI) and non-line index (NI). The results indicate that NI was more than LI for the test group, while there was no significant difference between NI and LI in the control group. These results suggest that MAE occurs in zebrafish causing OMR. PMID- 23792198 TI - Exosomes of BV-2 cells induced by alpha-synuclein: important mediator of neurodegeneration in PD. AB - Parkinson's disease (PD) is a progressive neurodegenerative disease. Alpha synuclein aggregation, which can activate microglia to enhance its dopaminergic neurotoxicity, plays a central role in the progression of PD. However the mechanism is still unclear. To investigate how alpha-synuclein affects the neuron, exosomes were derived from alpha-synuclein treated mouse microglia cell line BV-2 cells by differential centrifugation and ultracentrifugation. We found that alpha-synuclein can induce an increase of exosomal secretion by microglia. These activated exosomes expressed a high level of MHC class II molecules and membrane TNF-alpha. In addition, the activated exosomes cause increased apoptosis. Exosomes secreted from activated microglias might be important mediator of alpha-synuclein-induced neurodegeneration in PD. PMID- 23792199 TI - Glycated albumin is set lower in relation to plasma glucose levels in patients with Cushing's syndrome. AB - BACKGROUND: Glycated albumin (GA) is an indicator of glycemic control, which has some specific characters in comparison with HbA1c. Since glucocorticoids (GC) promote protein catabolism including serum albumin, GC excess state would influence GA levels. We therefore investigated GA levels in patients with Cushing's syndrome. METHODS: We studied 16 patients with Cushing's syndrome (8 patients had diabetes mellitus and the remaining 8 patients were non-diabetic). Thirty-two patients with type 2 diabetes mellitus and 32 non-diabetic subjects matched for age, sex and BMI were used as controls. RESULTS: In the patients with Cushing's syndrome, GA was significantly correlated with HbA1c, but the regression line shifted downwards as compared with the controls. The GA/HbA1c ratio in the patients with Cushing's syndrome was also significantly lower than the controls. HbA1c in the non-diabetic patients with Cushing's syndrome was not different from the non-diabetic controls, whereas GA was significantly lower. In 7 patients with Cushing's syndrome who performed self-monitoring of blood glucose, the measured HbA1c was matched with HbA1c estimated from mean blood glucose, whereas the measured GA was significantly lower than the estimated GA. CONCLUSIONS: We clarified that GA is set lower in relation to plasma glucose levels in patients with Cushing's syndrome. PMID- 23792200 TI - Opportunities and challenges for women PhD investigators in gastrointestinal research. PMID- 23792202 TI - Experience with endoscopic management of high-risk gastroesophageal varices, with and without bleeding, in children with biliary atresia. AB - BACKGROUND & AIMS: Biliary atresia, the most common cause of childhood cirrhosis, increases the risks for portal hypertension and gastrointestinal bleeding. We report the results from a single-center study of primary and secondary prophylaxis of bleeding in children with portal hypertension and high-risk varices. METHODS: We collected data from 66 children with major endoscopic signs of portal hypertension, including grade 3 esophageal varices or grade 2 varices with red wale markings and/or gastric varices, treated consecutively from February 2001 through May 2011. Thirty-six children (mean age, 22 mo) underwent primary prophylaxis (sclerotherapy and/or banding, depending on age and weight). Thirty children (mean age, 24 mo) who presented with gastrointestinal bleeding received endoscopic treatment to prevent a relapse of bleeding (secondary prophylaxis). RESULTS: In the primary prophylaxis group, a mean number of 4.2 sessions were needed to eradicate varices; no bleeding from gastroesophageal varices was observed after eradication. Varices reappeared in 37% of children, and 97% survived for 3 years. In the secondary prophylaxis group, a mean number of 4.6 sessions was needed to eradicate varices. Varices reappeared in 45%, and 10% had breakthrough bleeding; 84% survived for 3 years. There were no or only minor complications of either form of prophylaxis. CONCLUSIONS: Endoscopic therapy as primary or secondary prophylaxis of bleeding appears to be well tolerated and greatly reduces the risk of variceal bleeding in children with biliary atresia and high-risk gastroesophageal varices. However, there is a risk that varices will recur, therefore continued endoscopic surveillance is needed. PMID- 23792203 TI - Geranylgeranylacetone inhibits melanin synthesis via ERK activation in Mel-Ab cells. AB - AIMS: Geranylgeranylacetone (GGA) has shown cytoprotective activity through induction of a 70-kDa heat shock protein (HSP70). Although HSP70 is reported to regulate melanogenesis, the effects of GGA on melanin synthesis in melanocytes have not been previously studied. Therefore, this study investigated the effects of GGA on melanogenesis and the related signaling pathways. MAIN METHODS: Melanin content and tyrosinase activities were measured in Mel-Ab cells. GGA-induced signal transduction pathways were investigated by western blot analysis. KEY FINDINGS: Our results showed that GGA significantly decreased melanin content in a concentration-dependent manner. Similarly, GGA reduced tyrosinase activity dose dependently, but it did not directly inhibit tyrosinase. Western blot analysis indicated that GGA downregulated microphthalmia-associated transcription factor (MITF) and tyrosinase protein expression, whereas it increased the phosphorylation of extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR). Furthermore, a specific ERK pathway inhibitor, PD98059, blocked GGA-induced melanin reduction and then prevented downregulation of MITF and tyrosinase by GGA. However, a specific mTOR inhibitor, rapamycin, only slightly restored inhibition of melanin production by GGA, indicating that mTOR signaling is not a key mechanism regulating the inhibition of melanin production. SIGNIFICANCE: These findings suggest that activation of ERK by GGA reduces melanin synthesis in Mel-Ab cells through downregulation of MITF and tyrosinase expression. PMID- 23792204 TI - Neurokinin-1 receptor, a new modulator of lymphangiogenesis in obese-asthma phenotype. AB - AIMS: Obesity and asthma are widely prevalent and associated disorders. Recent studies of our group revealed that Substance P (SP) is involved in pathophysiology of obese-asthma phenotype in mice through its selective NK1 receptor (NK1-R). Lymphangiogenesis is impaired in asthma and obesity, and SP activates contractile and inflammatory pathways in lymphatics. Our aim was to study whether NK1-R expression was involved in lymphangiogenesis on visceral (VAT) and subcutaneous (SAT) adipose tissues and in the lungs, in obese-allergen sensitized mice. MAIN METHODS: Diet-induced obese and ovalbumin (OVA)-sensitized Balb/c mice were treated with a selective NK1-R antagonist (CJ 12,255, Pfizer Inc., USA) or placebo. Lymphatic structures (LYVE-1+) and NK1-R expression were analyzed by immunohistochemistry. A semi-quantitative score methodology was used for NK1-R expression. KEY FINDINGS: Obesity and allergen-sensitization together increased the number of LYVE-1+ lymphatics in VAT and decreased it in SAT and lungs. NK1-R was mainly expressed on adipocyte membranes of VAT, blood vessel areas of SAT, and in lung epithelium. Obesity and allergen-sensitization combined increased the expression of NK1-R in VAT, SAT and lungs. NK1-R antagonist treatment reversed the effects observed in lymphangiogenesis in those tissues. SIGNIFICANCE: The obese-asthma phenotype in mice is accompanied by increased expression of NK1-R on adipose tissues and lung epithelium, reflecting that SP released during inflammation may act directly on these tissues. Blocking NK1-R affects lymphangiogenesis, implying a role of SP, with opposite physiological consequences in VAT, and in SAT and lungs. Our results provide a clue for a novel SP role in the obese-asthma phenotype. PMID- 23792201 TI - Cdc42 coordinates proliferation, polarity, migration, and differentiation of small intestinal epithelial cells in mice. AB - BACKGROUND & AIMS: Cdc42 is a Rho GTPase that regulates diverse cellular functions, including proliferation, differentiation, migration, and polarity. In the intestinal epithelium, a balance among these events maintains homeostasis. We used genetic techniques to investigate the role of Cdc42 in intestinal homeostasis and its mechanisms. METHODS: We disrupted Cdc42 specifically in intestinal epithelial cells by creating Cdc42flox/flox-villin-Cre+ and Cdc42flox/flox-Rosa26-CreER+ mice. We collected intestinal and other tissues, and analyzed their cellular, molecular, morphologic, and physiologic features, compared with the respective heterozygous mice. RESULTS: In all mutant mice studied, the intestinal epithelium had gross hyperplasia, crypt enlargement, microvilli inclusion, and abnormal epithelial permeability. Cdc42 deficiency resulted in defective Paneth cell differentiation and localization without affecting the differentiation of other cell lineages. In mutant intestinal crypts, proliferating stem and progenitor cells increased, compared with control mice, resulting in increased crypt depth. Cdc42 deficiency increased migration of stem and progenitor cells along the villi, caused a mild defect in the apical junction orientation, and impaired intestinal epithelium polarity, which can contribute to the observed defective intestinal permeability. The intestinal epithelium of the Cdc42flox/flox-villin-Cre+ and Cdc42flox/flox-Rosa26-CreER+ mice appeared similar to that of patients with microvillus inclusion disease. In the digestive track, loss of Cdc42 also resulted in crypt hyperplasia in the colon, but not the stomach. CONCLUSIONS: Cdc42 regulates proliferation, polarity, migration, and differentiation of intestinal epithelial cells in mice and maintains intestine epithelial barrier and homeostasis. Defects in Cdc42 signaling could be associated with microvillus inclusion disease. PMID- 23792205 TI - Increased matrix metalloproteinases-9 after sleep in plasma and in monocytes of obstructive sleep apnea patients. AB - AIMS: Obstructive sleep apnea is known to be a risk factor of coronary artery disease. Matrix metalloproteinases (MMPs) contribute to the instability and rupture of atherosclerotic plaque and acute coronary syndrome. The present study aimed to determine the correlation of MMPs including MMP-1, -2, -3 and -9 with the severity of obstructive sleep apnea (OSA). MAIN METHODS: Peripheral blood was sampled before and after overnight polysomnography study from OSA patients. Plasma was processed for ELISA and zymography. Monocytes were isolated from peripheral blood and RNA was prepared for RT/real-time PCR. KEY FINDINGS: The plasma level of MMP-9, but not MMP-1, -2, and -3 and TIMP-1 was remarkably increased in OSA patients. The plasma MMP-9 level was considerably higher after sleep and the net difference was most significant in patients with severe OSA. The plasma MMP-9 activity was also demonstrated to be significantly higher after sleep. The mRNA expression of MMP-9 in monocytes not only correlated well to the plasma MMP-9 level in the patients, but also was found to be significantly higher in patients with severe OSA. SIGNIFICANCE: This study for the first time proves that the increase of plasma MMP-9 level in OSA patients is likely due to the up regulated MMP-9 mRNA expression of monocytes in the peripheral blood. PMID- 23792206 TI - A multifunctional neurotrophin with reduced affinity to p75NTR enhances transplanted Schwann cell survival and axon growth after spinal cord injury. AB - The lack of regeneration of axonal pathways after SCI is associated with the presence of inhibitory molecules within the glial scar, the loss of the neuron's intrinsic capacity to grow and the absence of growth factors. The NGF family of neurotrophins is a potent growth factor for several types of supraspinal and sensory axons. It is unclear, however, whether the neurotrophin's axon growth promoting activities after central nervous system (CNS) injuries are mediated through the Trk receptors or p75 neurotrophin receptor (p75(NTR)) or both. To investigate the role of these receptors in the re-growth of specific fiber tracts after SCI, we created a series of neurotrophins that preferentially bind to either TrkB/C or p75(NTR) receptors. All the mutations were made on the NT-3/D15A backbone, a multifunctional neurotrophin that can bind TrkB, TrkC and p75(NTR). To test the mutants' axon growth-promoting activity after rat contusion SCI, we examined several spinal cord fiber projections after transplanting Schwann cells (SCs) expressing the different multi-neurotrophins. Grafts expressing the NT 3/D15A with reduced binding affinity to p75(NTR) contained more surviving SCs, and sensory as well as supra-spinal fibers, within the transplant than the NT 3/D15A neurotrophin-SC grafts. These data support the idea that neurotrophins lacking p75 activity can be more effective in promoting axon growth after CNS injury. PMID- 23792208 TI - Prediction of boiling points of organic compounds by QSPR tools. AB - The novel electro-negativity topological descriptors of YC, WC were derived from molecular structure by equilibrium electro-negativity of atom and relative bond length of molecule. The quantitative structure-property relationships (QSPR) between descriptors of YC, WC as well as path number parameter P3 and the normal boiling points of 80 alkanes, 65 unsaturated hydrocarbons and 70 alcohols were obtained separately. The high-quality prediction models were evidenced by coefficient of determination (R(2)), the standard error (S), average absolute errors (AAE) and predictive parameters (Qext(2),RCV(2),Rm(2)). According to the regression equations, the influences of the length of carbon backbone, the size, the degree of branching of a molecule and the role of functional groups on the normal boiling point were analyzed. Comparison results with reference models demonstrated that novel topological descriptors based on the equilibrium electro negativity of atom and the relative bond length were useful molecular descriptors for predicting the normal boiling points of organic compounds. PMID- 23792207 TI - AutoGrow 3.0: an improved algorithm for chemically tractable, semi-automated protein inhibitor design. AB - We here present an improved version of AutoGrow (version 3.0), an evolutionary algorithm that works in conjunction with existing open-source software to automatically optimize candidate ligands for predicted binding affinity and other druglike properties. Though no substitute for the medicinal chemist, AutoGrow 3.0, unlike its predecessors, attempts to introduce some chemical intuition into the automated optimization process. AutoGrow 3.0 uses the rules of click chemistry to guide optimization, greatly enhancing synthesizability. Additionally, the program discards any growing ligand whose physical and chemical properties are not druglike. By carefully crafting chemically feasible druglike molecules, we hope that AutoGrow 3.0 will help supplement the chemist's efforts. To demonstrate the utility of the program, we use AutoGrow 3.0 to generate predicted inhibitors of three important drug targets: Trypanosoma brucei RNA editing ligase 1, peroxisome proliferator-activated receptor gamma, and dihydrofolate reductase. In all cases, AutoGrow generates druglike molecules with high predicted binding affinities. AutoGrow 3.0 is available free of charge (http://autogrow.ucsd.edu) under the terms of the GNU General Public License and has been tested on Linux and Mac OS X. PMID- 23792209 TI - Investigation of simple and water assisted tautomerism in a derivative of 1,3,4 oxadiazole: a DFT study. AB - Investigation of tautomerism and transition states in a derivative of 1,3,4 oxadiazole (A, B, C and D) in the gas phase and in solution and in a micro hydrated environment with 1-3 water molecules was performed by calculations at the DFT-B3LYP/6-311++G(d,p) level of theory. The solvent effect is taken into account via the self-consistent reaction field (SCRF) method. The geometries of four possible tautomers of 5-amino-1,3,4-oxadiazole-2(3H)-one were optimized in the gas phase and solution with polarized continuum model (PCM). It was found that in the gas phase and different solvents, A and C tautomers are the most stable and unstable forms, respectively. The results show that the tautomeric interconversion C to D has the lowest Gibbs free energy changes and so the highest equilibrium constant in the gas phase and solution. The equilibrium and rate constants of intermolecular tautomerism in the absence and presence of 1-3 molecules of water were also calculated. The calculated results show that the presence of water molecules considerably reduces the barrier energy of the various reactions. Therefore, this water-assisted tautomerism can be performed fast, especially, with the assistance of two molecules of water. PMID- 23792210 TI - Biochemical DSB-repair model for mammalian cells in G1 and early S phases of the cell cycle. AB - The paper presents a model of double strand breaks (DSB) repair in G1 and early S phases of the cell cycle. The model is based on a plethora of published information on biochemical modification of DSB induced by ionizing radiation. So far, three main DSB repair pathways have been identified, including nonhomologous end-joining (NHEJ), homologous recombination (HR), and microhomology-mediated end joining (MMEJ). During G1 and early S phases of the cell cycle, NHEJ and MMEJ repair pathways are activated dependent on the type of double strand breaks. Simple DSB are a substrate for NHEJ, while complex DSB and DSB in heterochromatin require further end processing. Repair of all DSB start with NHEJ presynaptic processes, and depending on the type of DSB pursue simple ligation, further end processing prior to ligation, or resection. Using law of mass action the model is translated into a mathematical formalism. The solution of the formalism provides the step by step and overall repair kinetics. The overall repair kinetics are compared with the published experimental measurements. Our calculations are in agreement with the experimental results and show that the complex types of DSBs are repaired with slow repair kinetics. The G1 and early S phase model could be employed to predict the kinetics of DSB repair for damage induced by high LET radiation. PMID- 23792211 TI - Persisting ring chromosomes detected by mFISH in lymphocytes of a cancer patient a case report. AB - We report the case of an 84 years old prostate cancer patient with severe side effects after radiotherapy in 2006. He was cytogenetically analysed in 2009 and in 2012 in a comparative study for individual radiosensitivity of prostate cancer patients. No other patient had clonal aberrations, but this patient showed ring chromosomes in the range of 21-25% of lymphocytes. He received 5 cycles of 5 fluorouracil/folic acid for chemotherapy of sigmoid colon carcinoma in 2003, three years before radiotherapy of prostate cancer. Blood samples were irradiated ex vivo with Cs-137 gamma-rays (0.7Gy/min) in the G0-phase of the cell cycle. 100 FISH painted metaphases were analysed for the control and the irradiated samples each. Multicolour in situ hybridisation techniques like mFISH and mBand as well as MYC locus, telomere and centromere painting probes were used to characterise ring metaphases. Metaphase search and autocapture was performed with a Zeiss Axioplan 2 imaging microscope followed by scoring and image analysis using Metafer 4/ISIS software (MetaSystems). In 2009 chromosome 8 rings were found in about 25% of lymphocytes. Rings were stable over time and increased to about 30% until 2012. The ring chromosome 8 always lacked telomere signals and a small amount of rings displayed up to four centromere signals. In aberrant metaphases 8pter and 8qter were either translocated or deleted. Further analyses revealed that the breakpoint at the p arm is localised at 8p21.2-22. The breakpoint at the q arm turned out to be distal from the MYC locus at 8q23-24. We hypothesise that the ring chromosome 8 has been developed during the 5 FU/folic acid treatments in 2003. The long term persistence might be due to clonal expansion of a damaged but viable hematopoietic stem cell giving rise to cycling progenitor cells that permit cell survival and proliferation. PMID- 23792213 TI - CytoBayesJ: software tools for Bayesian analysis of cytogenetic radiation dosimetry data. AB - A number of authors have suggested that a Bayesian approach may be most appropriate for analysis of cytogenetic radiation dosimetry data. In the Bayesian framework, probability of an event is described in terms of previous expectations and uncertainty. Previously existing, or prior, information is used in combination with experimental results to infer probabilities or the likelihood that a hypothesis is true. It has been shown that the Bayesian approach increases both the accuracy and quality assurance of radiation dose estimates. New software entitled CytoBayesJ has been developed with the aim of bringing Bayesian analysis to cytogenetic biodosimetry laboratory practice. CytoBayesJ takes a number of Bayesian or 'Bayesian like' methods that have been proposed in the literature and presents them to the user in the form of simple user-friendly tools, including testing for the most appropriate model for distribution of chromosome aberrations and calculations of posterior probability distributions. The individual tools are described in detail and relevant examples of the use of the methods and the corresponding CytoBayesJ software tools are given. In this way, the suitability of the Bayesian approach to biological radiation dosimetry is highlighted and its wider application encouraged by providing a user-friendly software interface and manual in English and Russian. PMID- 23792212 TI - Mouse embryonic stem cells irradiated with gamma-rays differentiate into cardiomyocytes but with altered contractile properties. AB - Embryonic stem cells (ESCs) for their derivation from the inner cell mass of a blastocyst represent a valuable in vitro model to investigate the effects of ionizing radiation on early embryonic cellular response. Following irradiation, both human and mouse ESCs (mESCs) maintain their pluripotent status and the capacity to differentiate into embryoid bodies and to form teratomas. Although informative of the maintenance of a pluripotent status, these studies never investigated the capability of irradiated ESCs to form specific differentiated phenotypes. Here, for the first time, 5Gy-irradiated mESCs were differentiated into cardiomyocytes, thus allowing the analysis of the long-term effects of ionizing radiations on the differentiation potential of a pluripotent stem cell population. On treated mESCs, 96h after irradiation, a genome-wide expression analysis was first performed in order to determine whether the treatment influenced gene expression of the surviving mESCs. Microarrays analysis showed that only 186 genes were differentially expressed in treated mESCs compared to control cells; a quarter of these genes were involved in cellular differentiation, with three main gene networks emerging, including cardiogenesis. Based on these results, we differentiated irradiated mESCs into cardiomyocytes. On day 5, 8 and 12 of differentiation, treated cells showed a significant alteration (qRT-PCR) of the expression of marker genes (Gata-4, Nkx-2.5, Tnnc1 and Alpk3) when compared to control cells. At day 15 of differentiation, although the organization of sarcomeric alpha-actinin and troponin T proteins appeared similar in cardiomyocytes differentiated from either mock or treated cells, the video evaluation of the kinematics and dynamics of the beating cardiac syncytium evidenced altered contractile properties of cardiomyocytes derived from irradiated mESCs. This alteration correlated with significant reduction of Connexin 43 foci. Our results indicate that mESCs populations that survive an ionizing irradiation treatment are capable to differentiate into cardiomyocytes, but they have altered contractile properties. PMID- 23792214 TI - Optimizing anti-TNF treatments in inflammatory bowel disease. AB - BACKGROUND: Failure of anti-TNF treatment in inflammatory bowel disease (IBD) patients can take on several forms, each posing distinct etio-pathogenic considerations and management dilemmas. AIM: The aim of this study is to review the mechanisms responsible for the various forms of anti-TNF failures in IBD and to elucidate strategies for optimizing clinical efficacy. RESULTS: Primary failures of anti-TNF induction therapy occur in up to 40% of patients in clinical trials and in 10-20% in clinical series. Longer disease duration, smoking and several genetic mutations are predisposing factors for primary failures. Curiously, primary non-response is probably not a class-effect phenomenon since switching to another anti-TNF is effective in over 50% of such patients. Secondary loss of response is also a common clinical problem with incidence ranging between 23 and 46% at 12months after anti-TNF initiation. Underlying mechanisms are often related to increased anti-TNF clearance by anti-drug antibodies, but may also include other causes for recalcitrant IBD activity as well as disorders that are unrelated to IBD itself. Astute management begins with verifying the presence of uncontrolled inflammatory IBD activity as a cause for patient's symptoms. Next, it is prudent to consider a trial of wait-and-see approach, since in some patients with mild-moderate symptoms, loss of response may resolve without alteration of therapy. If it does not, measuring anti-TNF trough levels and anti-drug antibodies may clarify the underlying mechanism in individual patients although there are still limited and conflicting data regarding the role of these measurements in guiding the choice between dose intensification, switch to another anti-TNF or to another immuno-modulator, and the addition of an immuno-modulator as a combination therapy with the failing anti-TNF. Anti-TNF re-induction after prior drug-holiday is a distinct clinical scenario and scarce evidence suggests re-induction outcome to be dependent on the circumstances when drug-holiday was commenced. Finally, discontinuation of anti TNF in patients with stable deep clinico-biologic and mucosal remission may be a viable option, as in these carefully selected patients the majority may enjoy long-term remission without the need for continued anti-TNF treatment. PMID- 23792215 TI - Impaired emotional contagion following severe traumatic brain injury. AB - Empathy deficits are widely-documented in individuals after severe traumatic brain injury (TBI). This study examined the relationship between empathy deficits and psychophysiological responsivity in adults with TBI to determine if impaired responsivity is ameliorated through repeated emotional stimulus presentations. Nineteen TBI participants (13 males; 41 years) and 25 control participants (14 males; 31 years) viewed five repetitions of six 2-min film clip segments containing pleasant, unpleasant, and neutral content. Facial muscle responses (zygomaticus and corrugator), tonic heart rate (HR) and skin conductance level (SCL) were recorded. Mean responses for each viewing period were compared to a pre-experiment 2-min resting baseline period. Self-reported emotional empathy was also assessed. TBI participants demonstrated identical EMG response patterns to controls, i.e. an initial large facial response to both pleasant and unpleasant films, followed by habituation over repetitions for pleasant films, and sustained response to unpleasant films. Additionally, an increase in both arousal and HR deceleration to stimulus repetitions was found, which was larger for TBI participants. Compared to controls, TBI participants self-reported lower emotional empathy, and had lower resting arousal, and these measures were positively correlated. Results are consistent with TBI producing impairments in emotional empathy and responsivity. While some normalisation of physiological arousal appeared with repeated stimulus presentations, this came at the cost of greater attentional effort. PMID- 23792216 TI - Can event-related potentials serve as neural markers for wins, losses, and near wins in a gambling task? A principal components analysis. AB - Originally, the feedback related negativity (FRN) event-related potential (ERP) component was considered to be a robust neural correlate of non-reward/punishment processing, with greater negative deflections observed following unfavourable outcomes. More recently, it has been suggested that this component is better conceptualised as a positive deflection following rewarding outcomes. The current study sought to elucidate the nature of the FRN, as well as another component associated with incentive-value processing, the P3b, through application of a spatiotemporal principal components analysis (PCA). Seventeen healthy controls played a computer electronic gaming machine (EGM) task and received feedback on credits won or lost on each trial, and ERPs were recorded. The distribution of reward/non-reward outcomes closely matched that of a real EGM, with frequent losses, and infrequent wins and near-wins. The PCA revealed that feedback elicited both a frontally maximal negative deflection to losses, and a positive deflection to wins (which was also sensitive to reward magnitude), implying that the neural generator/s of the FRN are differentially activated following these outcomes. As expected, greater P3b amplitudes were found for wins compared to losses. Interestingly, near-wins elicited significantly smaller FRN amplitudes than losses (with no differences in P3b amplitude), and may contribute to the maintenance of gambling behaviours on EGMs. The results of the current study are integrated into a response profile of healthy controls to outcomes of varying incentive value. This may provide a foundation for the future examination of individuals who exhibit abnormalities in reward/punishment processing, such as problem gamblers. PMID- 23792217 TI - Sequential processing in the equiprobable auditory Go/NoGo task: a temporal PCA study. AB - The unwarned auditory equiprobable Go/NoGo task provides a convenient means to assess differential processing, although our interpretations remain limited by the lack of research regarding the range of elicited components and their functional significance. We examined sequential processing in this paradigm, presenting 24 participants with a total of 300 trials in two blocks. EEG was recorded from 19 channels, and the Go and NoGo event-related potentials were decomposed using temporal Principal Components Analysis. Of the 218 unrestricted Varimax-rotated factors, seven were identifiable as components based on their latency, polarity, and topography: early N1, Processing Negativity (PN), and P2 components were followed by N2, P3, the classic Slow Wave (SW), and a diffuse Late Positivity (LP). N1 was enhanced to Go, as was the defining temporal topography of PN. NoGo produced increased centroparietal P2, frontocentral N2, and P3a, in comparison to Go, which produced a more parietal N2 and P3b, and an enhanced SW. The LP was larger in NoGo. These results suggest that N1 marks the beginning of Go and NoGo differentiation. Complete Go/NoGo categorisation is marked by N2; this is followed by different processing chains leading to the NoGo non-response (marked by P3a) and Go response (marked by P3b and SW). The larger LP in NoGo marks the cortical inactivation following the earlier cessation of processing in this condition. PMID- 23792218 TI - Are high frequency oscillations associated with altered network topology in partial epilepsy? AB - Neurophysiological studies have reported functional network alterations in epilepsy, most consistently in the theta frequency band. Highly interconnected brain regions (so-called 'hubs') seem to be important in these epileptic networks. High frequency oscillations (HFOs) in intracranial EEG recordings are recently discovered biomarkers that can identify the epileptogenic area and are thought to result from altered neuronal interactions. We studied whether the epileptogenic zone (identified by HFOs and seizure onset zone) is associated with pathological hubs. Bilateral depth electrode recordings from the hippocampus and amygdala were available from twelve patients suspected of temporal lobe epilepsy. HFOs, classified as ripples (80-250 Hz) and fast ripples (250-500 Hz), and epileptiform spikes were marked for all patients in a five-minute epoch of slow wave sleep. For each channel, we computed hub-measures from a period without epileptiform spikes and found that the epileptogenic zone was associated with a decreased hub-value in the theta frequency band. The amount of HFOs, especially fast ripples, was negatively correlated with the hub-value per channel. Results from post-hoc analyses of other frequency bands, particularly the broad- and gamma frequency band, pointed in the same direction as the results for the theta frequency band. These findings suggest a pathological functional 'isolation' of the epileptogenic zone in the interictal state. PMID- 23792219 TI - Combining ESI, ASL and PET for quantitative assessment of drug-resistant focal epilepsy. AB - When localization of the epileptic focus is uncertain, the epileptic activity generator may be more accurately identified with non-invasive imaging techniques which could also serve to guide stereo-electroencephalography (sEEG) electrode implantation. The aim of this study was to assess the diagnostic value of perfusion magnetic resonance imaging with arterial spin labeling (ASL) in the identification of the epileptogenic zone, as compared to the more invasive positron-emission tomography (PET) and other established investigation methods for source imaging of electroencephalography (EEG) data. In 6 patients with drug resistant focal epilepsy, standard video-EEG was performed to identify clinical seizure semeiology, and high-density EEG, ASL and FDG-PET to non-invasively localize the epileptic focus. A standardized source imaging procedure, low resolution brain electromagnetic tomography constrained to the individual matter, was applied to the averaged spikes of high-density EEG. Quantification of current density, cerebral blood flow, and standardized uptake value were compared over the same anatomical areas. In most of the patients, source in the interictal phase was associated with an area of hypoperfusion and hypometabolism. Conversely, in the patients presenting with early post-ictal discharges, the brain area identified by electrical source imaging (ESI) as the generating zone appeared to be hyperperfused. In 2 patients in whom the focus remained uncertain, the postoperative follow-up showed the disappearance of epileptic activity. As an innovative and more comprehensive approach to the study of epilepsy, the combined use of ESI, perfusion MRI, and PET may play an increasingly important role in the non-invasive evaluation of patients with refractory focal epilepsy. PMID- 23792220 TI - Bayesian scalar-on-image regression with application to association between intracranial DTI and cognitive outcomes. AB - Diffusion tensor imaging (DTI) measures water diffusion within white matter, allowing for in vivo quantification of brain pathways. These pathways often subserve specific functions, and impairment of those functions is often associated with imaging abnormalities. As a method for predicting clinical disability from DTI images, we propose a hierarchical Bayesian "scalar-on-image" regression procedure. Our procedure introduces a latent binary map that estimates the locations of predictive voxels and penalizes the magnitude of effect sizes in these voxels, thereby resolving the ill-posed nature of the problem. By inducing a spatial prior structure, the procedure yields a sparse association map that also maintains spatial continuity of predictive regions. The method is demonstrated on a simulation study and on a study of association between fractional anisotropy and cognitive disability in a cross-sectional sample of 135 multiple sclerosis patients. PMID- 23792221 TI - Enzymatic polymerization to an alternating N-L-cysteinyl chitin derivative: a novel class of multivalent glycopeptidomimetics. AB - A novel chitin derivative with an alternating N-L-cysteinyl group was successfully prepared. The precursor chitin derivative with an alternating N-L thioprolinyl group could be obtained via chitinase-catalyzed polymerization of the N'-L-thioprolinyl chitobiose oxazoline derivative as a transition state analog substrate monomer under weak alkaline conditions. Conversion of the L thioprolinyl group to an L-cysteinyl group in the product chitin derivative proceeded in a dose-dependent manner by methoxyamine hydrochloride, and the reaction could be completed almost quantitatively. The obtained chitin derivative is a uniformly amino acid-branching polysaccharide, which is categorized into a novel class of multivalent glycopeptidomimetics. PMID- 23792222 TI - Synthesis and evaluation of 3-deoxy and 3-deoxy-3-fluoro derivatives of gluco- and manno-configured tetrahydropyridoimidazole glycosidase inhibitors. AB - Three tetrahydropyridoimidazole-type glycosidase inhibitors have been synthesized with the 3-deoxy ribo- and arabino-, and 3-deoxy-3-fluoro gluco-configurations and two of them screened for activity against alpha- and beta-gluco- and mannosidase enzymes. Only one substance, the 3-deoxy-3-fluoro-derivative of the gluco-configured tetrahydropyridoimidazole was found to have any activity against a single enzyme, sweet almond beta-glucosidase, and even then at a level 100-fold lower than that of the corresponding simple gluco-configured tetrahydropyridoimidazole thereby underlining the importance of the 3-hydroxy group in the key substrate-enzyme interactions. PMID- 23792223 TI - Leukotriene receptor antagonists, LY293111 and ONO-1078, protect neurons from the sPLA2-IB-induced neuronal cell death independently of blocking their receptors. AB - In the ischemic brain, leukotrienes (LTs) are increased and their receptor antagonists protect neurons. However, it has not yet been sufficiently clarified how antagonists for LT receptors exhibit neuroprotective effects. In the present study, we evaluated protective effects of receptor antagonists for LTB4 (LY293111) and cysteinyl LTs (ONO-1078) in the primary culture of rat cortical neurons. The group IB secretory phospholipase A2 (sPLA2-IB)-induced neuronal cell death had been established as the in vitro model for cerebral ischemia. sPLA2-IB triggered the influx of Ca(2+) into neurons via L-type voltage-dependent calcium channel (L-VDCC). Subsequently, the enzyme produced eicosanoids including LTB4 before neuronal cell death. Neither administration of LTB4 nor cysteinyl LTs such as LTC4, LTD4 and LTE4 killed neurons. However, both LY293111 and ONO-1078 significantly prevented neurons from the neurotoxicity of sPLA2-IB, suggesting that the two LT receptor blockers protected neurons through alternative pathways beside LT receptors. An L-VDCC blocker does not only inhibit the influx of Ca(2+) into neurons but also rescues neurons from the sPLA2-IB-induced neuronal cell death. The two LT receptor antagonists also blocked the sPLA2-IB-induced Ca(2+) influx significantly. Thus, LTs exhibited no neurotoxicity, but their receptor antagonists protected neurons directly in the in vitro ischemic model. Furthermore, the suppression of L-VDCC appeared to be involved in the neuroprotective effects of LY293111 and ONO-1078 independent of blocking their receptors. PMID- 23792224 TI - A peptide derived from phage display library exhibits anti-tumor activity by targeting GRP78 in gastric cancer multidrug resistance cells. AB - Multidrug resistance (MDR) remains a significant challenge to the clinical treatment of gastric cancer (GC). In the present study, using a phage display approach combined with MTT assays, we screened a specific peptide GMBP1 (Gastric cancer MDR cell-specific binding peptide), ETAPLSTMLSPY, which could bind to the surface of GC MDR cells specifically and reverse their MDR phenotypes. Immunocytochemical staining showed that the potential receptor of GMBP1 was located at the membrane and cytoplasm of MDR cells. In vitro and in vivo drug sensitivity assays, FACS analysis and Western blotting confirmed that GMBP1 was able to re-sensitize MDR cells to chemical drugs. Western blotting and proteomic approaches were used to screen the receptor of GMBP1, and GRP78, a MDR-related protein, was identified as a receptor of GMBP1. This result was further supported by immunofluoresence microscopy and Western blot. Additionally, Western blotting demonstrated that pre-incubation of GMBP1 in MDR cells greatly diminished MDR1, Bcl-2 and GRP78 expression but increased the expression of Bax, whereas downregulation of GRP78, function as a receptor and directly target for GMBP1, only inhibited MDR1 expression. Our findings suggest that GMBP1 could re sensitize GC MDR cells to a variety of chemotherapeutic agents and this role might be mediated partly through down-regulating GRP78 expression and then inhibiting MDR1 expression. These findings indicate that peptide GMBP1 likely recognizes a novel GRP78 receptor and mediates cellular activities associated with the MDR phenotype, which provides new insight into research on the management of MDR in gastric cancer cells. PMID- 23792225 TI - mTOR kinase inhibitors as potential cancer therapeutic drugs. AB - The mammalian target of rapamycin (mTOR) plays a critical role in the positive regulation of cell growth and survival primarily through direct interaction with raptor (forming mTORC complex 1; mTORC1) or rictor (forming mTOR complex 2; mTORC2). The mTOR axis is often activated in many types of cancer and thus has become an attractive cancer therapeutic target. The modest clinical anticancer activity of conventional mTOR allosteric inhibitors, rapamycin and its analogs (rapalogs), which preferentially inhibit mTORC1, in most types of cancer, has encouraged great efforts to develop mTOR kinase inhibitors (TORKinibs) that inhibit both mTORC1 and mTORC2, in the hope of developing a novel generation of mTOR inhibitors with better therapeutic efficacy than rapalogs. Several TORKinibs have been developed and actively studied pre-clinically and clinically. This review will highlight recent advances in the development and research of TORKinibs and discuss some potential issues or challenges in this area. PMID- 23792226 TI - Inhibition of VTA neurons activates the centrally projecting Edinger-Westphal nucleus: evidence of a stress-reward link? AB - The primary site of urocortin 1 (Ucn1) expression in the brain is the centrally projecting Edinger-Westphal nucleus. The EWcp is innervated by dopaminergic neurons of the ventral tegmental area (VTA). To investigate whether activity of EWcp is regulated by the VTA, we investigated the effects of local pharmacological inhibition of VTA activity on the induction of Fos immunoreactivity in the EWcp of male C57BL/6J mice. A unilateral intracranial administration of the GABA agonist muscimol aimed at the VTA resulted in increased number of Fos-positive cells in the EWcp. This induction was lower than that produced by an intraperitoneal injection of 2.5 g/kg of ethanol. To investigate whether inhibition of dopaminergic neurons was responsible for induction of Fos, a second experiment was performed where the dopamine agonist quinpirole was unilaterally injected targeting the VTA. Injections of quinpirole also significantly induced Fos in the EWcp neurons. The induction occurred only on the side of the EWcp ipsilateral to the VTA injection. These results indicate that activity of EWcp is inhibited by tonic activity of dopaminergic VTA neurons, and that unilateral projections of VTA onto Ucn1-containing EWcp neurons provide a link between systems regulating approach and avoidance behaviors. PMID- 23792227 TI - Insecticide resistance in Bemisia tabaci Gennadius (Homoptera: Aleyrodidae) and Anopheles gambiae Giles (Diptera: Culicidae) could compromise the sustainability of malaria vector control strategies in West Africa. AB - Insecticides from the organophosphate (OP) and pyrethroid (PY) chemical families, have respectively, been in use for 50 and 30 years in West Africa, mainly against agricultural pests, but also against vectors of human disease. The selection pressure, with practically the same molecules year after year (mainly on cotton), has caused insecticide resistance in pest populations such as Bemisia tabaci, vector of harmful phytoviruses on vegetables. The evolution toward insecticide resistance in malaria vectors such as Anopheles gambiae sensus lato (s.l.) is probably related to the current use of these insecticides in agriculture. Thus, successful pest and vector control in West Africa requires an investigation of insect susceptibility, in relation to the identification of species and sub species, such as molecular forms or biotypes. Identification of knock down resistance (kdr) and acetylcholinesterase gene (Ace1) mutations modifying insecticide targets in individual insects and measure of enzymes activity typically involved in insecticide metabolism (oxidase, esterase and glutathion-S transferase) are indispensable in understanding the mechanisms of resistance. Insecticide resistance is a good example in which genotype-phenotype links have been made successfully. Insecticides used in agriculture continue to select new resistant populations of B. tabaci that could be from different biotype vectors of plant viruses. As well, the evolution of insecticide resistance in An. gambiae threatens the management of malaria vectors in West Africa. It raises the question of priority in the use of insecticides in health and/or agriculture, and more generally, the question of sustainability of crop protection and vector control strategies in the region. Here, we review the susceptibility tests, biochemical and molecular assays data for B. tabaci, a major pest in cotton and vegetable crops, and An. gambiae, main vector of malaria. The data reviewed was collected in Benin and Burkina Faso between 2008 and 2010 under the Corus 6015 research program. This review aims to show: (i) the insecticide resistance in B. tabaci as well as in An. gambiae; and (ii) due to this, the impact of selection of resistant populations on malaria vector control strategies. Some measures that could be beneficial for crop protection and vector control strategies in West Africa are proposed. PMID- 23792228 TI - Influence of the nutritional status in the clinical and therapeutical evolution in adults and elderly with American Tegumentary Leishmaniasis. AB - The objective of this study is to describe the nutritional status of adult and elderly patients with American Tegumentary Leishmaniasis (ATL). It was conducted a longitudinal study in 68 adult and elderly patients with ATL treating at the Surveillance Leishmaniasis Laboratory at the Evandro Chagas Clinical Research Institute, Oswaldo Cruz Foundation (Fiocruz), from 2009 to 2012. The nutritional assessment included the body mass index (BMI) and serum albumin levels. The clinical evolution (epithelialization and wound healing) was measured up to two years after ATL treatment. Most of the sample was composed of men (71%), adults (73%), with household income of 1-5 minimum wages (79%), and incomplete elementary school (48.5%). The predominant ATL form was cutaneous (72%), and 39% presented comorbidities, the most frequent was hypertension (30.8%). The most prevalent clinical and nutritional events were: recent decrease in food intake (23.9%); nasal obstruction (22.1%); oral ulcer (14.7%), anorexia and dysphagia (13.2% each) and odynophagia (10.3%). The total healing time was 115.00 (IR=80 230) days for skin lesions, and 120.00 (IR=104.50-223.50) days for mucous membrane lesions. Low body weight in 10%, and hypoalbuminemia in 12% of the patients have been observed. Low body weight was associated with age, mucosal leishmaniasis (ML), nasal obstruction, recent decrease in food intake and hypoalbuminemia. As for serum albumin depletion, association with the ML, dyspnea, dysphagia, odynophagia, recent decrease in food intake, absence of complete healing of the skin lesions, and increased healing time for mucous membrane lesions, was observed. The ML and their events that affect the alimentary intake have been related to the impairment of the nutritional status. Additionally, serum albumin depletion negatively affected the healing of the lesions, suggesting that a nutritional intervention can increase the effectiveness of the ATL treatment. PMID- 23792229 TI - Identification and evaluation of the probiotic potential of Lactobacillus paraplantarum FT259, a bacteriocinogenic strain isolated from Brazilian semi-hard artisanal cheese. AB - This study aimed to identify a bacteriocinogenic Lactobacillus isolate (FT259) obtained from Brazilian semi-hard Minas type cheese and to evaluate its probiotic and antimicrobial potentials. The strain was identified by biochemical tests (at genus level), and by 16S rDNA sequencing combined with recA gene amplification (for species). To determine the inhibitory spectrum towards food borne pathogens and lactic acid bacteria, the spot-on-the-lawn assay was carried out. Moreover, the proteinaceous nature of the antimicrobial compound produced was evaluated by susceptibility to degradation by proteolytic enzymes. The isolated strain was tested for survival in acidified culture media (pH 2.0, 2.5 and 3.5), in vitro tolerance to bile salts and viability under gastric conditions. Adhesion of Lactobacillus paraplantarum FT259 to Caco-2 cells was evaluated by surface plate count on De Man, Rogosa, and Sharpe (MRS) agar and also by FISH method (fluorescent in situ hybridization) with the aid of Eub338 probe for fluorescence microscopy analysis. The isolate was identified as L. paraplantarum FT259 and it produced bacteriocins that inhibited the growth of Listeria monocytogenes, Listeria innocua and several lactic acid bacteria. It was also observed that L. paraplantarum FT259 tolerated exposure to pH 3.5, and bile salts 0.3% for up to 180 min. In experiments with simulated gastric juice, viable cells of L. paraplantarum FT259 decreased from 8.6 log CFU/mL to 3.5 log CFU/mL after 180 min. For the same strain, in studies with Caco-2 cells, 74% of adhesion was observed through plate count and FISH assays. It was also demonstrated isolated FT259 was susceptible to the majority the antibiotics tested. Overall, the results indicated L. paraplantarum FT259 is a potential probiotic and the production of bacteriocin may be an interesting feature for food applications. PMID- 23792230 TI - Adhesive ability means inhibition activities for lactobacillus against pathogens and S-layer protein plays an important role in adhesion. AB - Eighty-five strains of lactobacillus were isolated from the pig intestine and identified by sequencing analysis based on 16S rRNA gene, from which five lactobacillus strains with high adhesive ability were selected. The inhibition ability of the five lactobacillus strains with or without S-layer proteins against adherence of Escherichia coli K88 and Salmonella enteritidis 50335 to Caco-2 was evaluated in vitro with Lactobacillus rhamnosus GG strain (LGG) as a positive control. In addition, tolerance of lactobacilli to heat, acid, bile, Zn(2+) and Cu(2+) were assessed. All five selected strains, Lactobacillus salivarius ZJ614 (JN981856), Lactobacillus reuteri ZJ616 (JN981858), L. reuteri ZJ617 (JN981859), L. reuteri ZJ621 (JN981863) and L. reuteri ZJ623 (JN981865), showed inhibition against the two pathogens, E. coli K88 and S. enteritidis 50335. L. reuteri ZJ621 showed higher inhibition ability than the others to S. enteritidis 50335 (P < 0.05). Sodium dodecyl sulfate-Polyacrylamide gel electrophoresis (SDS-PAGE) analysis indicated that all five strains had abundant bands with molecular weight ranging from 34 to 130 KDa as well as had a common band of approximately 42 KDa. After treatment with 5 M LiCl to remove S-layer protein, the inhibition activities of the lactobacilli against pathogens decreased significantly (P < 0.05). The results showed that higher adhesive ability means higher inhibition activity for lactobacillus against pathogen, in which S-layer proteins plays an important role. PMID- 23792231 TI - The impact of Lactobacillus plantarum TUA1490L supernatant on in vitro rumen methanogenesis and fermentation. AB - This study investigated the suppression of in vitro rumen methane (CH4) output by the supernatant of Lactobacillus plantarum TUA1490L. Hydrogen peroxide (H2O2) was detected in the supernatant. Although CH4 output was reduced by 72%, the supernatant had an adverse effect on total volatile fatty acid (VFA) concentration. PMID- 23792232 TI - Prevalence of Campylobacter spp. relative to other enteric pathogens in grow finish pigs with diarrhea. AB - Salmonella spp., Lawsonia intracellularis, and Brachyspira spp. are pathogens commonly associated with diarrhea in growing and finishing pigs. Brachyspira spp. infection has recently reemerged as a significant concern due to an increase in the incidence of swine dysentery; however, the mechanisms underlying this increase in dysentery remain largely unknown. Pigs are also well-recognized as potential carriers of Campylobacter spp., particularly Campylobacter coli, yet enteric disease in swine associated with infection by these bacteria is considered uncommon and diagnosis has historically been based upon exclusion of other causes. Accordingly, Campylobacter culture is often excluded in routine diagnostic testing of cases of porcine enterocolitis and the incidence of infection is therefore largely unknown. In this study, feces from 155 cases of clinical diarrhea in grow-finish pigs submitted to the Iowa State University Veterinary Diagnostic Laboratory were cultured for Campylobacter spp. in addition to other testing as indicated for routine diagnostic investigation. Campylobacter culture was positive from 82.6% (128/155) of samples with C. coli accounting for 75% of isolates and Campylobacter jejuni for the remaining 25%. In 14.8% (23/155) of cases a Campylobacter spp. was the sole infectious agent detected; however, there was no association with any particular Campylobacter spp. Interestingly, for those cases with a laboratory diagnosis of Brachyspira-associated disease, 100% (15/15) were also culture positive for Campylobacter spp. suggesting a possible interrelationship between these bacteria in the pig gut. No association was noted between Campylobacter culture results and infection with either Salmonella spp. or L. intracellularis. PMID- 23792233 TI - Involvement of retinoic acid-induced peroxiredoxin 6 expression in recovery of noise-induced temporary hearing threshold shifts. AB - All-trans retinoic acid (ATRA) is reported to reduce hair cell loss and hearing deterioration caused by noise-induced hearing loss (NIHL). The present study investigates the involvement of peroxiredoxin 6 (Prdx 6) in ATRA-mediated protection of temporary threshold shift of hearing. Mice fed with ATRA before or after exposure to white noise showed a faster recovery than untreated controls within 1 week, with a concomitant increase of cochlear Prdx 6 expression. Treatment of mouse auditory cells with ATRA induced Prdx 6 expression. A putative retinoic acid (RA)-response element (RARE) was identified in a murine Prdx 6 promoter region. Prdx 6 promoter activities were elevated in wild-type reporter plasmid-transfected cells, whereas no significant change in activity was in those with RARE-disrupted mutant reporter. RA receptor alpha (RARalpha) functions as a transactivator of Prdx 6 gene expression. These findings suggest that ATRA induced Prdx 6 expression may be associated with rapid recovery from temporary NIHL. PMID- 23792234 TI - Modulating efficacy of Rebaudioside A, a diterpenoid on antioxidant and circulatory lipids in experimental diabetic rats. AB - The present study was to evaluate the protective effects of Rebaudioside A (Reb A) on antioxidant status and lipid profile in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced in Wistar rats by a single intraperitoneal administration of STZ (40mg/kg b.w). Diabetic rats showed significantly increased levels of plasma glucose, thiobarbituric acid reactive substances, hydroperoxides and decreased levels of insulin. The activity of enzymatic antioxidants (superoxide dismutase, catalase and glutathione peroxidase) and the levels of non enzymatic antioxidants (vitamin C, vitamin E and reduced glutathione) were decreased in diabetic rats. The levels of total cholesterol (TC), triglycerides (TGs), free fatty acids (FFAs), phospholipids (PLs), low density lipoproteins (LDL-cholesterol) and very low-density lipoproteins (VLDL-cholesterol) in the plasma significantly increased, while plasma high-density lipoproteins (HDL cholesterol) were significantly decreased in diabetic rats. Oral administration of Reb A (200mg/kg b.w) brought back plasma glucose, insulin, lipid peroxidation products, enzymatic, non-enzymatic antioxidants and lipid profile levels to near normal. The results of the present investigation suggests that Reb A, a natural sweetener exhibits antilipid peroxidative, antihyperlipidemic and antioxidant properties. PMID- 23792235 TI - Spectroscopic, nonlinear optical and quantum chemical studies on Pyrrolidinium p Hydroxybenzoate--a phase matchable organic NLO crystal. AB - Good quality and bulk single crystals of Pyrrolidinium p-Hydroxybenzoate (PYPHB), a newly identified nonlinear optical material, were grown for the first time. It crystallizes in monoclinic system with an acentric space group Cc. The molecular structure including carbon, proton positions and functional groups has been confirmed through nuclear magnetic resonance and Fourier transform infrared spectra. Its transmission window has been observed for UV-VIS-NIR region along with its theoretical limit. The photoluminescence behavior has been observed by exciting the crystal at 310 nm. The principal refractive indices and second order NLO coefficient of PYPHB are determined by Mach-Zehnder interferometer and Maker Fringe experiments respectively. The coherence length and phase-matchablility of PYPHB crystals are measured to explore its efficacy towards device fabrications. The dipole moment, polarizability and molecular orbital energy of an isolated PYPHB molecule have also been calculated theoretically and the results are found to corroborate the experimental values. PMID- 23792236 TI - Molecular structure, intramolecular hydrogen bonding and vibrational spectral investigation of 2-fluoro benzamide--a DFT approach. AB - The FTIR and FT-Raman spectra of 2-fluoro benzamide (2FBA) have been recorded in the region 4000-400 and 4000-100 cm(-1), respectively. The structuralanalysis, hydrogen bonding, optimized geometry, frequency and intensity of the vibrational bands of 2FBA were obtained by the density functional theory (DFT) with complete relaxation in the potential energy surface using 6-31G** basis set. The harmonic vibrational frequencies were calculated and the scaled values have been compared with experimental FTIR and FT-Raman spectra. The observed and the calculated frequencies are found to be in good agreement. The (13)C NMR spectra have been recorded and (13)C nuclear magnetic resonance chemical shifts of the molecule were also calculated using the gauge independent atomic orbital (GIAO) method and their respective linear correlations were obtained. The electronic properties, such as HOMO and LUMO energies, were performed by time-dependent DFT (TD-DFT) approach. The Mulliken charges, the values of electric dipole moment (MU) of the molecule were computed using DFT calculations. The change in electron density (ED) in the sigma* antibonding orbitals and stabilization energies E(2) have been calculated by natural bond (NBO) analysis to give clear evidence of stabilization originating in the hyper conjugation of hydrogen-bonded interactions. PMID- 23792237 TI - Rapid discrimination of Herba Cistanches by multi-step infrared macro fingerprinting combined with soft independent modeling of class analogy (SIMCA). AB - Herba Cistanche, an important Chinese herbal medicine, has common four species, Cistanche deserticola (CD), Cistanche tubulosa (CT), Cistanche salsa (CS) and Cistanche sinensis (CSN) which have been frequent mixed used. To clarify the sources of Herba Cistanches and ensure the clinical efficacy and safety, a method combing IR macro-fingerprinting with statistical pattern recognition was developed to analyze and discriminate the four species of Herba Cistanche. By comparing FT-IR, second derivative spectral fingerprints via group-peak matching, the similarity to CD and total saccharides (TS) followed an increasing sequence, CTCSN>CS>CD. Characteristic fingerprints of their 2D-IR correlation spectra in 1750-1000 cm(-1) have confirmed the above findings in a more intuitive way. In terms of sources for phenylethanoid glycosides (PhGs), CT can be an ideal alternative species. However, in terms of using them as a whole, more pharmacological study should be conducted due to the different ratios of their chemical constituents, which is also applicable to CSN and CS. Moreover, the four species (179 samples) has been objectively classified by SIMCA based on IR macro fingerprints. PMID- 23792238 TI - Density functional theory study, FT-IR and FT-Raman spectra and SQM force field calculation for vibrational analysis of 1, 3-Bis (hydroxymethyl) benzimidazolin-2 one. AB - FT-IR and FT-Raman spectra of 1, 3-Bis (hydroxymethyl) benzimidazolin-2-one were recorded and analyzed in the solid phase. The optimized molecular geometry and vibrational wavenumbers have also been calculated in optimized structure by using DFT method. Scaled quantum mechanical force fields have also been used to calculate potential energy distributions in order to make conspicuous vibrational assignments. The red shifting of the O-H stretching wavenumber is due to the formation of O-H...O intermolecular hydrogen bonding. The lowering and splitting of the carbonyl stretching vibrational modes is assigned to the intermolecular association based on C=O...H type hydrogen bonding in the molecule. Chemical interpretation of hyperconjugative interactions was done by natural bond orbital analysis. PMID- 23792239 TI - Development of a multivariate calibration model for the determination of dry extract content in Brazilian commercial bee propolis extracts through UV-Vis spectroscopy. AB - This study had the objective of determining the content of dry extract of commercial alcoholic extracts of bee propolis through Partial Least Squares (PLS) multivariate calibration and electronic spectroscopy. The PLS model provided a good prediction of dry extract content in commercial alcoholic extracts of bee propolis in the range of 2.7 a 16.8% (m/v), presenting the advantage of being less laborious and faster than the traditional gravimetric methodology. The PLS model was optimized with outlier detection tests according to the ASTM E 1655-05. In this study it was possible to verify that a centrifugation stage is extremely important in order to avoid the presence of waxes, resulting in a more accurate model. Around 50% of the analyzed samples presented content of dry extract lower than the value established by Brazilian legislation, in most cases, the values found were different from the values claimed in the product's label. PMID- 23792240 TI - Spectroscopic (FT-IR, FT-Raman, UV and NMR) investigation, conformational stability, NLO properties, HOMO-LUMO and NBO analysis of hydroxyquinoline derivatives by density functional theory calculations. AB - The FTIR and FT-Raman spectra of 2-hydroxyquinoline and its derivatives have been recorded in the region 4000-400 cm(-1) and 3500-100 cm(-1), respectively. The optimized geometry, frequency and intensity of the vibrational bands of these compounds were obtained by the density functional theory using 6-311++G(d,p) basis sets. The harmonic vibrational frequencies were calculated and the scaled values have been compared with experimental FTIR and FT-Raman spectra. A detailed interpretation of the infrared and Raman spectra were also reported based on total energy distribution (TED). The observed and the calculated frequencies are found to be in good agreement. The experimental spectra also coincide satisfactorily with those of theoretically simulated spectra. (1)H and (13)C NMR spectra were recorded and its corresponding nuclear magnetic resonance chemical shifts of the molecule were also calculated using the gauge independent atomic orbital (GIAO) method. UV-visible spectrum of the compound was recorded and the electronic properties HOMO and LUMO energies were measured by time-dependent (TD DFT) approach. Molecular stability and bond strength were investigated by applying the natural bond orbital analysis (NBO). The calculated HOMO and LUMO energies show that charge transfer occurs in the molecules. In addition, the non linear optical properties were discussed from the dipole moment values and excitation wavelength in the UV-visible region. PMID- 23792241 TI - Relation of N-terminal pro-B-type natriuretic peptide with diastolic function in hypertensive heart disease. AB - BACKGROUND: Elevated natriuretic peptide levels in asymptomatic individuals without heart failure are associated with increased risk of adverse cardiovascular outcomes and may reflect subclinical cardiac dysfunction. METHODS: In a sample of 313 asymptomatic individuals (51% women, mean age 61 years) with hypertension and diastolic dysfunction, we examined the association of plasma N terminal pro-B-type natriuretic peptide (NT-proBNP) with both conventional and advanced echocardiographic measures of systolic and diastolic function, including myocardial strain, using speckle-tracking-based analyses. RESULTS: In univariate analyses, higher NT-proBNP was associated with greater left ventricular mass index (P = 0.003), left atrial volume index (P = 0.007), lateral E' velocity (P < 0.0001), E/E' ratio (P < 0.0001), peak global longitudinal systolic strain (P = 0.015), systolic strain rate (P = 0.021), and early diastolic strain rate (P < 0.0001). In multivariable analyses, NT-proBNP remained associated with measures of diastolic dysfunction, including lateral E' velocity (P = 0.013) and the E/E' ratio (P = 0.008). However, early diastolic strain rate was the echocardiographic parameter most strongly associated with NT-proBNP (P = 0.003). CONCLUSIONS: In the setting of asymptomatic hypertensive heart disease and preserved ejection fraction, elevation in natriuretic peptide levels is predominantly associated with subclinical diastolic dysfunction. PMID- 23792242 TI - Social stress exacerbates the aversion to painful experiences in rats exposed to chronic pain: the role of the locus coeruleus. AB - Stressful experiences seem to negatively influence pain perception through as yet unknown mechanisms. As the noradrenergic locus coeruleus (LC) nucleus coordinates many components of the stress response, as well as nociceptive transmission, we evaluated whether the sensory and affective dimension of chronic neuropathic pain worsens in situations of stress due to adaptive changes of LC neurons. Accordingly, male rats were socially isolated for 5 weeks, and in the last 2 weeks, neuropathic pain was induced by chronic constriction injury. In this situation of stress, chronic pain selectively heightened the animal's aversion to painful experiences (affective pain), as measured in the place escape/avoidance test, although no changes were observed in the sensory dimension of pain. In addition, electrophysiological recordings of LC neurons showed a low tonic but exacerbated nociceptive-evoked activity when the injured paw was stimulated. These changes were accompanied by an increase in tyrosine hydroxylase and gephyrin expression in the LC. Furthermore, intra-LC administration of bicuculline, a gamma-aminobutyric acid-A receptor antagonist, attenuated the negative affective effects of pain. These data show that changes in the LC are greater than those expected from the simple summation of each independent factor (pain and stress), revealing mechanisms through which stressors may exacerbate pain perception without affecting the sensorial dimension. PMID- 23792243 TI - Children's selective attention to pain and avoidance behaviour: the role of child and parental catastrophizing about pain. AB - The present study investigated selective attention to pain in children, its implications for child avoidance behaviour, and the moderating role of dimensions comprising child and parental catastrophizing about pain (ie, rumination, magnification, and helplessness). Participants were 59 children (31 boys) aged 10 16 years and one of their parents (41 mothers). Children performed a dot-probe task in which child facial pain displays of varying pain expressiveness were presented. Child avoidance behaviour was indexed by child pain tolerance during a cold-pressor task. Children and parents completed measures of child and parent pain catastrophizing, respectively. Findings indicated that both the nature of child selective attention to pain and the impact of selective attention upon child avoidance behaviour were differentially sensitive to specific dimensions of child and parental catastrophizing. Specifically, findings showed greater tendency to shift attention away from pain faces (i.e.,, attentional avoidance) among children reporting greater pain magnification. A similar pattern was observed in terms of parental characteristics, such that children increasingly shifted attention away from pain with increasing levels of parental rumination and helplessness. Furthermore, child attentional avoidance was associated with greater avoidance behaviour (i.e., lower pain tolerance) among children reporting high levels of pain magnification and those whose parents reported greater rumination about pain. The current findings corroborate catastrophizing as a multidimensional construct that may differentially impact outcomes and attest to the importance of assessing both child and parental characteristics in relation to child pain-related attention and avoidance behaviour. Further research directions are discussed. PMID- 23792244 TI - Selective control of SNARE recycling by Golgi retention. AB - Two distinct sets of soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) catalyze membrane fusion in the cis-Golgi and trans-Golgi. The mechanism that controls Golgi localization of SNAREs remains largely unknown. Here we tested three potential mechanisms, including vesicle recycling between the Golgi and the endoplasmic reticulum, partitioning in Golgi lipid microdomains, and selective intra-Golgi retention. Recycling rates showed a linear relationship with intra-Golgi mobility of SNAREs. The cis-Golgi SNAREs had higher mobility than intra-Golgi SNAREs, whereas vesicle SNAREs had higher mobility than target membrane SNAREs. The differences in SNARE mobility were not due to preferential partitioning into detergent-resistant membrane microdomains. We propose that intra-Golgi retention precludes entropy-driven redistribution of SNAREs to the endoplasmic reticulum and endocytic compartments. PMID- 23792245 TI - Genotypic variations in field isolates of Theileria species infecting giraffes (Giraffa camelopardalis tippelskirchi and Giraffa camelopardalis reticulata) in Kenya. AB - Recently, mortalities among giraffes, attributed to infection with unique species of piroplasms were reported in South Africa. Although haemoparasites are known to occur in giraffes of Kenya, the prevalence, genetic diversity and pathogenicity of these parasites have not been investigated. In this study, blood samples from 13 giraffes in Kenya were investigated microscopically and genomic DNA extracted. PCR amplicons of the hyper-variable region 4 (V4) of Theileria spp. small subunit ribosomal RNA (18S rRNA) gene were hybridized to a panel of genus- and species specific oligonucleotide probes by reverse line blot (RLB). Two newly designed oligonucleotide probes specific for previously identified Theileria spp. of giraffes found single infections in eight of the specimens and mixed infections in the remaining five samples. Partial 18S rRNA genes were successfully amplified from 9 samples and the PCR amplicons were cloned. A total of 28 plasmid clones representing the Kenyan isolates were analyzed in the present study and compared with those of closely-related organisms retrieved from GenBank. In agreement with RLB results, the nucleotide sequence alignment indicated the presence of mixed infections in the giraffes. In addition, sequence alignment with the obtained 18S rRNA gene sequences revealed extensive microheterogeneities within and between isolates, characterized by indels in the V4 regions and point mutations outside this region. Phylogeny with 18S rRNA gene sequences from the detected parasites and those of related organisms places Theileria of giraffes into two major groups, within which are numerous clades that include the isolates reported in South Africa. Collectively, these data suggest the existence of at least two distinct Theileria species among giraffes, and extensive genetic diversity within the two parasite groups. PMID- 23792246 TI - Riparian swallows as integrators of landscape change in a multiuse river system: implications for aquatic-to-terrestrial transfers of contaminants. AB - Recent research has highlighted the transfer of contaminants from aquatic to terrestrial ecosystems via predation of aquatic emergent insects by riparian consumers. The influence of adjacent land use and land cover (LULC) on aquatic-to terrestrial contaminant transfer, however, has received limited attention. From 2010 to 2012, at 11 river reaches in the Scioto River basin (OH, USA), we investigated the relationships between LULC and selenium (Se) and mercury (Hg) concentrations in four species of riparian swallows. Hg concentrations in swallows were significantly higher at rural reaches than at urban reaches (t= 3.58, P<0.001, df=30), whereas Se concentrations were positively associated with adjacent land cover characterized by mature tree cover (R(2)=0.49, P=0.006). To an extent, these relationships appear to be mediated by swallow reliance on aquatic emergent insects. For example, tree swallows (Tachycineta bicolor) at urban reaches exhibited a higher proportion of aquatic prey in their diet, fed at a higher trophic level, and exhibited elevated Se levels. We also found that both Se and Hg concentrations in adult swallows were significantly higher than those observed in nestlings at both urban and rural reaches (Se: t=-2.83, P=0.033, df=3; Hg: t=-3.22, P=0.024, df=3). Collectively, our results indicate that riparian swallows integrate contaminant exposure in linked aquatic-terrestrial systems and that LULC may strongly regulate aquatic contaminant flux to terrestrial consumers. PMID- 23792247 TI - Soil biochemical properties and microbial resilience in agroforestry systems: effects on wheat growth under controlled drought and flooding conditions. AB - Agroforestry is increasingly viewed as an effective means of maintaining or even increasing crop and tree productivity under climate change while promoting other ecosystem functions and services. This study focused on soil biochemical properties and resilience following disturbance within agroforestry and conventional agricultural systems and aimed to determine whether soil differences in terms of these biochemical properties and resilience would subsequently affect crop productivity under extreme soil water conditions. Two research sites that had been established on agricultural land were selected for this study. The first site included an 18-year-old windbreak, while the second site consisted in an 8 year-old tree-based intercropping system. In each site, soil samples were used for the determination of soil nutrient availability, microbial dynamics and microbial resilience to different wetting-drying perturbations and for a greenhouse pot experiment with wheat. Drying and flooding were selected as water stress treatments and compared to a control. These treatments were initiated at the beginning of the wheat anthesis period and maintained over 10 days. Trees contributed to increase soil nutrient pools, as evidenced by the higher extractable-P (both sites), and the higher total N and mineralizable N (tree based intercropping site) found in the agroforestry compared to the conventional agricultural system. Metabolic quotient (qCO2) was lower in the agroforestry than in the conventional agricultural system, suggesting higher microbial substrate use efficiency in agroforestry systems. Microbial resilience was higher in the agroforestry soils compared to soils from the conventional agricultural system (windbreak site only). At the windbreak site, wheat growing in soils from agroforestry system exhibited higher aboveground biomass and number of grains per spike than in conventional agricultural system soils in the three water stress treatments. At the tree-based intercropping site, higher wheat biomass, grain yield and number of grains per spike were observed in agroforestry than in conventional agricultural system soils, but in the drought treatment only. Drought (windbreak site) and flooding (both sites) treatments significantly reduced wheat yield and 1000-grain weight in both types of system. Relationships between soil biochemical properties and soil microbial resilience or wheat productivity were strongly dependent on site. This study suggests that agroforestry systems may have a positive effect on soil biochemical properties and microbial resilience, which could operate positively on crop productivity and tolerance to severe water stress. PMID- 23792248 TI - Mercury and selenium concentrations in leatherback sea turtles (Dermochelys coriacea): population comparisons, implications for reproductive success, hazard quotients and directions for future research. AB - Leatherback sea turtles (Dermochelys coriacea) are long-distance migrants that travel thousands of km from foraging grounds to breeding and nesting grounds. These extensive journeys are fueled by ingestion of an estimated 300-400 kg of prey/d and likely result in exposure to high concentrations of environmental toxicants (e.g., mercury compounds). Increased bodily concentrations of mercury and its compounds in nesting female turtles may have detrimental effects on reproductive success. Leatherbacks have relatively low reproductive success compared with other sea turtles (global average hatching success ~50-60%). To assess toxicants and necessary nutrients as factors affecting leatherback turtle reproductive success at Sandy Point National Wildlife Refuge (SPNWR), St. Croix, U.S. Virgin Islands, we collected blood from nesting female leatherbacks and tissues from their hatchlings (blood from live turtles, liver and yolk sac from dead turtles). We compared the concentrations in those tissues to hatching and emergence success. We found that on SPNWR, hatching and emergence success were more closely related to seasonal factors than to total mercury and selenium concentrations in both nesting females and hatchlings. Selenium concentrations of nesting females were positively correlated with those of their hatchlings. Mercury and selenium in the liver of hatchlings were positively correlated with one another. Turtles with greater remigration intervals tended to have higher blood selenium concentrations, suggesting that selenium accumulates in leatherbacks through time. Through hazard quotients, we found evidence that selenium may be at or above concentrations that may cause physiologic harm to hatchlings. We also found evidence that population level differences exist for these trace elements. The concentrations of mercury and selenium established in this manuscript form a baseline for future toxicant studies. PMID- 23792249 TI - Environmental-benefit analysis of two urban waste collection systems. AB - Sustainable transportation infrastructure and travel policies aim to optimise the use of transportation systems to achieve economic and related social and environmental goals. To this end, a novel methodology based on life cycle assessment (LCA) has been developed in this study, with the aim of quantifying, in terms of CO2 emissions equivalent, the impact associated with different alternatives of waste collection systems in different urban typologies. This new approach is focussed on saving energy and raw materials and reducing the environmental impact associated with the waste collection system in urban areas, as well as allowing the design and planning of the best available technologies and most environment-friendly management. The methodology considers a large variety of variables from the point of view of sustainable urban transport such as the location and size of the urban area, the amount of solid waste generated, the level of social awareness on waste separation procedures, the distance between houses and waste collection points and the distance from the latter to the possible recovery plants and/or landfills, taking into account the material and energy recovery ratio within an integrated waste management system. As a case study, two different waste collection systems have been evaluated with this methodology in the ecocity Valdespartera located in Zaragoza, Spain, consisting of approximately 10,000 homes: (i) a system based on traditional truck transportation and manual collection, and (ii) a stationary vacuum waste collection system. Results show that, when operating at loads close to 100%, the stationary collection system has the best environmental performance in comparison with the conventional system. In contrast, when operating at load factors around 13% the environmental benefits in terms of net CO2-eq. emissions for the stationary collection system are around 60% lower in comparison with the conventional one. PMID- 23792250 TI - Decrease of concentration and colloidal fraction of organic carbon and trace elements in response to the anomalously hot summer 2010 in a humic boreal lake. AB - The colloidal distribution and size fractionation of organic carbon (OC), major elements and trace elements (TE) were studied in a seasonally stratified, organic rich boreal lake, Lake Svyatoe, located in the European subarctic zone (NW Russia, Arkhangelsk region). This study took place over the course of 4 years in both winter and summer periods using an in situ dialysis technique (1 kDa, 10 kDa and 50 kDa) and traditional frontal filtration and ultrafiltration (5, 0.22 and 0.025 MUm). We observed a systematic difference in dissolved elements and colloidal fractions between summer and winter periods with the highest proportion of organic and organo-ferric colloids (1 kDa-0.22 MUm) observed during winter periods. The anomalously hot summer of 2010 in European Russia produced surface water temperatures of approximately 30 degrees C, which were 10 degrees above the usual summer temperatures and brought about crucial changes in element speciation and size fractionation. In August 2010, the concentration of dissolved organic carbon (DOC) decreased by more than 30% compared to normal period, while the relative proportion of organic colloids decreased from 70-80% to only 20-30% over the full depth of the water column. Similarly, the proportion of colloidal Fe decreased from 90-98% in most summers and winters to approximately 60-70% in August 2010. During this hot summer, measurable and significant (>30% compared to other periods) decreases in the colloidal fractions of Ca, Mg, Sr, Ba, Al, Ti, Ni, As, V, Co, Y, all rare earth elements (REEs), Zr, Hf, Th and U were also observed. In addition, dissolved (<0.22 MUm) TE concentrations decreased by a factor of 2 to 6 compared to previously investigated periods. The three processes most likely responsible for such a crucial change in element biogeochemistry with elevated water temperature are 1) massive phytoplankton bloom, 2) enhanced mineralization (respiration) of allochthonous dissolved organic matter by heterotrophic aerobic bacterioplankton and 3) photo-degradation of DOM and photo chemical liberation of organic-bound TE. While the first process may have caused significant decreases in the total dissolved concentration of micronutrients (a factor of 2 to 5 for Cr, Mn, Fe, Ni, Cu, Zn and Cd and a factor of >100 for Co), the second and third factors could have brought about the decrease of allochthonous DOC concentration as well as the concentration and proportion of organic and organo-mineral colloidal forms of non-essential low-soluble trace elements present in the form of organic colloids (Al, Y, Ti, Zr, Hf, Th, Pb, all REEs). It can be hypothesized that climate warming in high latitudes capable of significantly raising surface water temperatures will produce a decrease in the colloidal fraction of most trace elements and, as a result, an increase in the most labile low molecular weight LMW(<1 kDa) fraction. PMID- 23792251 TI - Origin and fate of copper in a small Mediterranean vineyard catchment: new insights from combined chemical extraction and delta65Cu isotopic composition. AB - For centuries, many Mediterranean catchments were covered with vineyards in which copper was widely applied to protect grapevines against fungus. In the Mediterranean-type flow regime, brief and intense flood events increase the stream water discharge by up to 10 times and cause soil leaching and storm runoff. Because vineyards are primarily cultivated on steep slopes, high Cu fluxes are discharged by surface water runoff into the rivers. The purpose of this work was to investigate the riverine behavior and transport of anthropogenic Cu by coupling a sequential chemical extraction (SCE) procedure, used to determine Cu partitioning between residual and non-residual fractions, with delta(65)Cu isotopic measurements in each fraction. In the Baillaury catchment, France, we sampled soils (cultivated and abandoned), river bed sediments (BS), suspended particulate matter (SPM), and river water during the flash flood event of February 2009. Copper partitioning using SCE show that most of Cu in abandoned vineyard soil was in the residual phase (>60%) whereas in cultivated soil, BS and SPM, Cu was mostly (>25%) in non-residual fractions, mainly adsorbed onto iron oxide fractions. A small fraction of Cu was associated with organic matter (5 to 10%). Calculated enrichment factors (EF) are higher than 2 and the anthropogenic contribution was estimated between 50 to 85%. Values for delta(65)Cu in bulk samples were similar to bedrock therefore; delta(65)Cu on SCE fractions of superficial soils and SPM allowed for discrimination between Cu origin and distribution. Copper in residual fractions was of natural mineral origin (delta(65)Cu close to local bedrock, +0.070/00). Copper in water soluble fraction of SPM (delta(65)Cu=+0.260/00) was similar to dissolved river Cu (delta(65)Cu=+0.310/00). Copper from fungicide treatment (delta(65)Cu=-0.350/00) was bound to organic matter (delta(65)Cu=-0.200/00) without or with slight isotopic fractioning. A preferential adsorption of (65)Cu onto iron oxides (delta(65)Cu=+0.50/00) is shown. PMID- 23792252 TI - Biomarkers of human exposure to personal care products: results from the Flemish Environment and Health Study (FLEHS 2007-2011). AB - Personal care products (PCPs), such as soaps, perfumes, cosmetics, lotions, etc., contain a variety of chemicals that have been described as potentially hormone disrupting chemicals. Therefore, it is important to assess the internal exposure of these chemicals in humans. Within the 2nd Flemish Environment and Health Study (FLEHS II, 2007-2011), the human exposure to three classes of pollutants that are present in a wide variety of PCPs--i.e. polycyclic musks (galaxolide, HHCB and tonalide, AHTN in blood), parabens (urinary para-hydroxybenzoic acid, HBA) and triclosan (urinary TCS)--was assessed in 210 Flemish adolescents (14-15 years) and in 204 adults (20-40 years) randomly selected from the general population according to a stratified two stage clustered study design. The aim of this study was to define average levels of exposure in the general Flemish population and to identify determinants of exposure. Average levels (GM (95% CI)) in the Flemish adolescents were 0.717 (0.682-0.753) MUg/L for blood HHCB; 0.118 (0.108-0.128) MUg/L for blood AHTN; 1022 (723-1436) MUg/L for urinary HBA and 2.19 (1.64-2.92) MUg/L for urinary TCS. In the adults, levels of HBA were on average 634 (471-970) MUg/L. Inter-individual variability was small for HHCB and AHTN, intermediate for HBA, and large for TCS. All biomarkers were positively associated with the use of PCPs. Additionally, levels of HHCB and AHTN increased with higher educational level of the adolescents. Both in adults and adolescents, urinary HBA levels were negatively correlated with BMI. We define here Flemish exposure values for biomarkers of PCPs, which can serve as baseline exposure levels to identify exposure trends in future biomonitoring campaigns. PMID- 23792253 TI - Effects of different algaecides on the photosynthetic capacity, cell integrity and microcystin-LR release of Microcystis aeruginosa. AB - Bench scale tests were conducted to study the effects of four common algaecides, including copper sulfate, hydrogen peroxide, diuron and ethyl 2 methylacetoacetate (EMA) on the photosynthetic capacity, cell integrity and microcystin-LR (MC-LR) release of Microcystis aeruginosa. The release of potassium (K(+)) from cell membrane during algaecide exposure was also analyzed. The three typical photosynthetic parameters, including the effective quantum yield (Fe), photosynthetic efficiency (alpha) and maximal electron transport rate (rETRmax), were measured by a pulse amplitude modulated (PAM) fluorometry. Results showed that the photosynthetic capacity was all inhibited by the four algaecides, to different degrees, by limiting the energy capture in photosynthesis, and blocking the electron transfer chain in primary reaction. For example, at high diuron concentration (7.5 mg L(-1)), Fe, alpha and rETRmax decreased from 0.46 to 0.19 (p<0.01), from 0.20 to 0.01 (p<0.01) MUmol electrons m(-2) s(-1)/MUmol photons m(-2) s(-1), and from 160.7 to 0.1 (p<0.001) MUmol m( 2) s(-1) compared with the control group after 96 h of exposure, respectively. Furthermore, the increase of algaecide dose could lead to the cell lysis, as well as release of intracellular MC-LR that enhanced the accumulation of extracellular MC-LR. The order of MC-LR release potential for the four algaecides was CuSO4>H2O2>diuron>EMA. PMID- 23792254 TI - Transport of silver nanoparticles in saturated columns of natural soils. AB - With industrialization and urbanization soils are increasingly exposed to engineered nanoparticles (ENP), yet knowledge regarding the transport of ENP in natural soils is lacking, a process that was examined further in the current study. Saturated columns of 11 natural soils with varying physical and chemical properties were spiked with two pore volumes of a solution containing 1.7 mg Ag L(-1) as polyvinylpyrrolidone (PVP)-coated silver nanoparticles (AgNP) (40 nm actual diameter) and eluted at a constant flow rate of 1 ml min(-1). Breakthrough of Ag was analyzed using filtration theory and a HYDRUS-1D transport model that incorporated two-site kinetic attachment-detachment. Separate kinetic batch studies suggested fast heteroaggregation between negatively charged AgNP and positively charged sites on the common soil colloids maghemite or montmorillonite. The concentration of such sites in the soil correlates positively with the oxalate-extractable aluminum concentration of the soils, a measure that correlated positively with collision efficiency. This correlation thus suggested favorable deposition of AgNP and/or enhanced straining following heteroaggregation of AgNP with mobile soils colloids. Occurrence of heteroaggregation was supported by the batch studies, enhanced size-exclusion in the soil with the highest porosity, and reversible attachment-detachment predicted from HYDRUS modeling, whereas straining and favorable deposition were suggested by irreversible attachment. Our study suggests that under similar experimental conditions, PVP-coated AgNP would rapidly interact with natural colloids in soils significantly reducing their mobility and hence potential risk from off-site transport. PMID- 23792255 TI - Quantitative determination of metal and metalloid spatial distribution in hydrated and fresh roots of cowpea using synchrotron-based X-ray fluorescence microscopy. AB - Many metals and metalloids, jointly termed metal(loid)s, are toxic to plants even at low levels. This has limited the study of their uptake, distribution, and modes of action in plant roots grown at physiologically relevant concentrations. Synchrotron-based X-ray fluorescence microscopy was used to examine metal(loid)s in hydrated cowpea (Vigna unguiculata L.) roots exposed to Zn(II), Ni(II), Mn(II), Cu(II), Hg(II), Se(IV), Se(VI), As(III), or As(V). Development of a mathematical model enabled in situ quantitative determination of their distribution in root tissues. The binding strength of metals influenced the extent of their movement through the root cylinder, which influenced the toxic effects exerted-metals (e.g. Cu, Hg) that bind more strongly to hard ligands had high concentrations in the rhizodermis and caused this tissue to rupture, while other metals (e.g. Ni, Zn) moved further into the root cylinder and did not cause ruptures. When longitudinal distributions were examined, the highest Se concentration in roots exposed to Se(VI) was in the more proximal root tissues, suggesting that Se(VI) is readily loaded into the stele. This contrasted with other metal(loid)s (e.g. Mn, As), which accumulated in the apex. These differences in metal(loid) spatial distribution provide valuable quantitative data on metal(loid) physiology, including uptake, transport, and toxicity in plant roots. PMID- 23792256 TI - Aquatic photochemistry, abiotic and aerobic biodegradability of thalidomide: identification of stable transformation products by LC-UV-MS(n). AB - Thalidomide (TD), besides being notorious for its teratogenicity, was shown to have immunomodulating and anti-inflammatory activities. This is why recently TD became a promising drug for the treatment of different cancers and inflammatory diseases. Yet nothing is known about the environmental fate of TD, which therefore was assessed experimentally and by in silico prediction programs (quantitative structure activity relationship (QSAR) models) within this study. Photolytic degradation was tested with two different light sources (medium pressure mercury lamp; xenon lamp) and aerobic biodegradability was investigated with two OECD tests (Closed Bottle test (CBT), Manometric Respirometry test (MRT)). An additional CBT was performed for TD samples after 16 min of UV photolysis. The primary elimination of TD was monitored and the structures of its photo-, abiotic and biodegradation products were elucidated by HPLC-UV Fluorescence-MS(n). Furthermore, elimination of dissolved organic carbon was monitored in the photolysis experiment. LC-MS revealed that new photolytic transformation products (TPs) were identified, among them two isomers of TD with the same molecular mass. These TPs were different to the products formed by biodegradation. The experimental findings were compared with the results obtained from the in silico prediction programs where e.g. a good correlation for TD biodegradation in the CBT was confirmed. Moreover, some of the identified TPs were also structurally predicted by the MetaPC software. These results demonstrate that TD and its TPs are not readily biodegradable and not fully mineralized by photochemical treatment. They may therefore pose a risk to the aquatic environment due to the pharmacological activity of TD and unknown properties of its TPs. The applied techniques within this study emphasize the importance of QSAR models as a tool for estimating environmental risk assessments. PMID- 23792257 TI - The availability and mobility of arsenic and antimony in an acid sulfate soil pasture system. AB - The Macleay floodplain on the north coast of New South Wales, Australia, has surface soil concentrations of up to 40 mg kg(-1) arsenic (As) and antimony (Sb), due to historical mining practices in the upper catchment. The floodplain also contains areas of active and potential acid sulfate soils (ASS). Some of these areas are purposely re-flooded to halt oxidation processes, but the effect of this management on the metalloid mobility and phytoavailability of the metalloids present is unknown. This study investigated the changes to soil solution As and Sb, associations of metalloids with soil solid phases, and uptake into two common pasture species following 20 weeks of flooding in a controlled environment. The effect of an ASS subsoil was also investigated. The soil solution concentration and availability of the metalloids was in some instances higher in the floodplain soils than would generally be expected in soils with comparable contamination. There appeared to be few changes to soil solution concentrations or phase associations with flooding in this short term study, due to the high acid buffering and poise of the investigated soils. A strong relationship was found between the relative uptake of Sb into pastures and the oxalate extractable Fe in the soil, which was taken as a proxy for non-crystalline iron (Fe) hydroxides. This relationship was dependent on flooding and was absent for As. Further targeted investigations into metalloid speciation kinetics and the stability of soil solid phases with flooding management are recommended. PMID- 23792258 TI - Zebrafish locomotor capacity and brain acetylcholinesterase activity is altered by Aphanizomenon flos-aquae DC-1 aphantoxins. AB - Aphanizomenon flos-aquae (A. flos-aquae) is a source of neurotoxins known as aphantoxins or paralytic shellfish poisons (PSPs) that present a major threat to the environment and to human health. Generally, altered neurological function is reflected in behavior. Although the molecular mechanism of action of PSPs is well known, its neurobehavioral effects on adult zebrafish and its relationship with altered neurological functions are poorly understood. Aphantoxins purified from a natural isolate of A. flos-aquae DC-1 were analyzed by HPLC. The major analogs found in the toxins were the gonyautoxins 1 and 5 (GTX1 and GTX5; 34.04% and 21.28%, respectively) and the neosaxitoxin (neoSTX, 12.77%). Zebrafish (Danio rerio) were intraperitoneally injected with 5.3 and 7.61 MUg STXeq/kg (low and high dose, respectively) of A. flos-aquae DC-1 aphantoxins. The swimming activity was investigated by observation combined with video at 6 timepoints from 1 to 24 h post-exposure. Both aphantoxin doses were associated with delayed touch responses, reduced head-tail locomotory abilities, inflexible turning of head, and a tailward-shifted center of gravity. The normal S-pattern (or undulating) locomotor trajectory was replaced by a mechanical motor pattern of swinging the head after wagging the tail. Finally, these fish principally distributed at the top and/or bottom water of the aquarium, and showed a clear polarized distribution pattern at 12 h post-exposure. Further analysis of neurological function demonstrated that both aphantoxin doses inhibited brain acetylcholinesterase activity. All these changes were dose- and time-dependent. These results demonstrate that aphantoxins can alter locomotor capacity, touch responses and distribution patterns by damaging the cholinergic system of zebrafish, and suggest that zebrafish locomotor behavior and acetylcholinesterase can be used as indicators for investigating aphantoxins and blooms in nature. PMID- 23792259 TI - Mutation analysis in hyperphenylalaninemia patients from South Italy. AB - BACKGROUND: Mutations in the gene encoding phenylalanine hydroxylase (PAH, EC 1.14.16.1) are associated with various degrees of hyperphenylalaninemia (HPA), including classical phenylketonuria (PKU). OBJECTIVE: The aim of the study was to determine the mutations responsible for mild forms of HPA and to relate different clinical phenotypes of HPA patients to their PAH genotypes in order to better predict the clinical phenotype and implement optimal dietary therapy and prognosis in newborns with the disease. METHODS: Phenylalanine hydroxylase (PAH) gene mutations have been analyzed by direct DNA sequencing in 30 HPA patients (Phe levels ranging from 2 to 6mg/dL) from Southern Italy who were identified in a neonatal screening program and a genotype-phenotype correlation was performed. RESULTS: PAH gene mutation was identified in 39 out of 60 alleles with a mutation detection rate of 65%. Eighteen mutations, 2 undescribed, were observed (13 missense mutations, 1 deletion, 4 splice site mutations). Using the "in vitro" predicted residual activity, a good genotype-phenotype correlation was obtained also in a new mild HPA case, a PAH compound heterozygote, previously undetected. CONCLUSION: A marked genetic heterogeneity was found in HPA patients from Southern Italy and a good genotype-phenotype correlation was obtained. Identification of PAH gene mutations responsible for PAH deficiency will therefore be useful in the prediction of biochemical and clinical phenotypes in HPA patients. PMID- 23792260 TI - Serum sAPRIL: a potential tumor-associated biomarker to colorectal cancer. AB - OBJECTIVE: The purpose of our study was to investigate the serum levels of soluble a-proliferation-inducing ligand (sAPRIL) in patients with colorectal cancer (CRC), benign intestinal disease and healthy volunteers and explore the potential possibility of sAPRIL severing as a CRC biomarker. METHODS: Our investigation was conducted on 35 blood samples obtained from CRC patients, 32 blood samples from patients with benign intestinal diseases and 31 blood samples from healthy volunteers. The sAPRIL concentrations were examined by an enzyme linked immunosorbent assay (ELISA) and data were analyzed with non-parametric Mann-Whitney U-test and X2-test. The correlation relationship between sAPRIL and CEA, as well as sAPRIL and CA19-9 was assessed by non-parametric Spearmen's correlation test, respectively. RESULTS: The median value of sAPRIL in the malignant group was 10.43 ng/mL, compared with those of the benign group (4.89 ng/mL) and control group (3.30 ng/mL), respectively, which had an obvious significance (P<0.0003). Area under the receiver-operating characteristic (ROC) curve for sAPRIL was 0.854 (95% CI, 0.776-0.933). The optimal cut-off level of sAPRIL was 5.49 ng/mL. Serum sAPRIL had a positive correlation with CEA (r=0.637, P=0.000) and CA19-9 (r=0.357, P=0.008) in 35 patients with colorectal cancer. sAPRIL showed higher sensitivity (82.9%) than those of CEA (74.3%) and CA19-9 (65.7%) in CRC, respectively. CONCLUSION: The results indicated that serum sAPRIL, as a potential biomarker, had a positive diagnostic value for colorectal cancer. PMID- 23792261 TI - The predictive value of serum soluble E-cadherin levels in breast cancer patients undergoing preoperative systemic chemotherapy. AB - OBJECTIVES: To date, no reliable markers are available to predict response to or to assess prognosis after preoperative systemic chemotherapy (PST) in patients with locally advanced breast cancer. Previous studies demonstrated that elevated levels of soluble E-cadherin (sE-cadherin), a product of proteolytic cleavage of cell surface E-cadherin, are associated with higher risk for metastatic disease and poor prognosis in various tumor types. We, therefore, hypothesized that serum sE-cadherin levels measured before PST may correlate with pathological response. DESIGN AND METHODS: In a retrospective analysis, sE-cadherin levels were measured in sera of 108 female patients with histologically proven breast cancer before initiation of PST by using a commercially available quantitative sandwich enzyme immunoassay technique. Patients received a median number of 4 (range 3-6) cycles of anthracyline-based chemotherapy. The median patient age was 51.5 (range 21-71) years. Tumor size was measured clinically and translated into the tumor-node metastasis (TNM)-system before the start of chemotherapy. Histopathological response in surgically removed specimens was evaluated using a modified Sinn regression score. In univariate analyses the correlations between levels of sE cadherin and pathological response to PST were calculated. RESULTS: The histopathological regression scores correlated significantly with tumor grading (p=0.045), clinical lymph node status before PST (p=0.031) and sE-cadherin levels (p=0.039). No correlation was seen between histopathological regression scores and hormone receptor and menopausal status as well as Her2-neu status. CONCLUSION: sE-cadherin may be a marker predicting response to PST for patients with breast cancer. Our findings warrant further evaluation of sE-cadherin in a prospective trial. PMID- 23792262 TI - Systematical assessment of serum indices does not impair efficiency of clinical chemistry testing: a multicenter study. AB - OBJECTIVES: Despite manufacturers' claim that systematical assessment of serum indices does not impact on testing efficiency, there is widespread perception that this practice may increase the turnaround time (TAT). A multicenter investigation was planned to verify TAT and performance of serum indices on five different clinical chemistry analyzers. DESIGN AND METHODS: Twenty study samples prepared from pooled sera of outpatients, emergency department, intensive care unit and dialyzed patients were divided in aliquots and shipped to 5 different laboratories. According to local instrumentation (Beckman Coulter AU5800, Roche Cobas 6000, Siemens Dimension Vista 1500, Abbott Architect c 16000 and Ortho Vitros 5.1/FS) and reagents, 13 clinical chemistry parameters were assayed on all study samples, with or without contextual assessment of serum indices. RESULTS: The TAT with assessment of serum indices modestly or even negligibly increased, and varied from -0.2 to +5.0% (i.e., from -3 to +85 s). When using the lowest thresholds for sample acceptability, the agreement of hemolysis index (HI) among different instruments was comprised between 0.62 and 1.00 (all p<0.01), but was higher than 0.80 in only 4/10 cases. The agreement of icteric and lipaemic indices could not be estimated due to the low number of samples exceeding acceptability criteria. CONCLUSIONS: The results of this study confirm that systematical measurement of serum indices does not impair instrument efficiency. The comparison of HI also suggests that major harmonization may be advisable for this measure among different manufacturers and instrumentations. PMID- 23792263 TI - The OSIRIS Weight of Evidence approach: ITS for skin sensitisation. AB - Within the EU FP6 project OSIRIS approaches to Integrated Testing Strategies (ITSs) were developed, with the aim to facilitate the use of non-test and non animal testing information in regulatory risk assessment of chemicals. This paper describes an analytical Weight-of-Evidence (WoE) approach to an ITS for the endpoint of skin sensitisation. It specifically addresses the European chemicals legislation REACH, but the concept is readily applicable to ITS and WoE procedures in other regulatory frameworks, and for other toxicological endpoints. Bayesian statistics are applied to estimate the reliability of a conclusion on the sensitisation potential of a chemical, combining evidence from different information sources such as QSAR model predictions, in vitro and in vivo test results. The methodology allows for adaptation of the weight of individual information sources to account for the different levels of reliability of the individual ITS components. The calculated reliability of the WoE conclusion gives an objective, transparent and reproducible measure to decide if the information requirements for data evaluation are satisfied. Furthermore, in case the WoE is not sufficient, it gives the possibility to evaluate a priori if and how it will be possible to fulfil the information requirements with additional tests and/or model predictions. PMID- 23792264 TI - Involvement of pituitary gonadotropins, gonadal steroids and breeding season in sex change of protogynous dusky grouper, Epinephelus marginatus (Teleostei: Serranidae), induced by a non-steroidal aromatase inhibitor. AB - Two experiments were performed using the aromatase inhibitor (AI) letrozole (100mg/kg) to promote sex change, from female-to-male, in protogynous dusky grouper. One experiment was performed during the breeding season (spring) and the other at the end of the breeding season (summer). During the spring, AI promoted sex change after 9 weeks and the sperm produced was able to fertilize grouper oocytes. During the summer, the sex change was incomplete; intersex individuals were present and sperm was not released by any of the animals. Sex changed gonads had a lamellar architecture; cysts of spermatocytes and spermatozoa in the lumen of the germinal compartment. In the spring, after 4 weeks, 11ketotestosterone (11KT) levels were higher in the AI than in control fish, and after 9 weeks, coincident with semen release, testosterone levels increased in the AI group, while 11KT returned to the initial levels. Estradiol (E2) levels remained unchanged during the experimental period. Instead of decreasing throughout the period, as in control group, 17 alpha-OH progesterone levels did not change in the AI-treated fish, resulting in higher values after 9 weeks when compared with control fish. fshbeta and lhbeta gene expression in the AI animals were lower compared with control fish after 9 weeks. The use of AI was effective to obtain functional males during the breeding season. The increase in androgens, modulated by gonadotropins, triggered the sex change, enabling the development of male germ cells, whereas a decrease in E2 levels was not required to change sex in dusky grouper. PMID- 23792265 TI - Neural activity in the posterior superior temporal region during eye contact perception correlates with autistic traits. AB - The present study investigated the relationship between neural activity associated with gaze processing and autistic traits in typically developed subjects using magnetoencephalography. Autistic traits in 24 typically developed college students with normal intelligence were assessed using the Autism Spectrum Quotient (AQ). The Minimum Current Estimates method was applied to estimate the cortical sources of magnetic responses to gaze stimuli. These stimuli consisted of apparent motion of the eyes, displaying direct or averted gaze motion. Results revealed gaze-related brain activations in the 150-250 ms time window in the right posterior superior temporal sulcus (pSTS), and in the 150-450 ms time window in medial prefrontal regions. In addition, the mean amplitude in the 150 250 ms time window in the right pSTS region was modulated by gaze direction, and its activity in response to direct gaze stimuli correlated with AQ score. pSTS activation in response to direct gaze is thought to be related to higher-order social processes. Thus, these results suggest that brain activity linking eye contact and social signals is associated with autistic traits in a typical population. PMID- 23792266 TI - PACAP induces the dimerization of PAC1 on the nucleus associated with the cAMP increase in the nucleus. AB - PAC1 is PACAP (pituitary adenylate cyclase-activating polypeptide) preferring receptor belonging to class B G protein couple receptor (GPCR) mediating the most effects of PACAP. The dimerization of PAC1 has been proven by our previous research. The bimolecular fluorescence complementation (BiFC) combined with fluorescence confocal microscope image was used in this research to explore the profiles of PAC1 dimers during the activation by PACAP. Fluorescence metry and cAMP assays were both used to detect the functions of the dimerization of PAC1 on the nucleus induced by PACAP. It was found that PACAP in concentration lower than 10nM induced the de-dimerization of PAC1 on the plasma membranes and the re dimerization of PAC1 on the nucleus. While PACAP in concentration higher than 10nM, the nuclear localized PAC1 dimers were further translocated from outside/on the nucleus into the nucleus. In addition, it was also found that the more PAC1 dimers on the nucleus produced the higher cAMP level in the nucleus, and the levels of cAMP in the nucleus varied synchronously with functions of PACAP on the proliferation of PAC1-CHO cells. These results indicated the dimerization of PAC1 on the nucleus may be involved in the cell signals produced by PACAP. The finding and the research on the dimerization of PAC1 on the nucleus will help us to step forward to clarify the physiological and pharmacological role of PAC1. PMID- 23792267 TI - An alternative anterior tension free preperitoneal patch technique by help of the endoscope for femoral hernia repair. AB - BACKGROUND: Femoral hernias are relatively uncommon and have a higher risk for strangulation and incarceration. We introduce an alternative anterior tension free inlay patch technique by help of the endoscope for femoral hernia repair. METHOD: Characteristics of patients undergoing femoral hernia repair between March 2006-April 2011 and description of the surgical technique is presented. RESULTS: We analyzed our experience with this technique in 26 consecutive patients with femoral hernias (1 bilateral, 15 right, 10 left femoral hernia) in 5 year period. Seven of these 26 femoral hernias were recurrent and 2 of them were concomitant with inguinal hernia. Mean operation time was 30.0 +/- 12.1 min. Seroma was seen in 2 patients at postoperative 1st week. There were no; hematoma, wound infection and separation of wound edges and early recurrence at postoperative 1st week and 1st month. The mean follow up period was 41.8 +/- 18.2 months. All of 22 patients who were contacted were satisfied with the operation. There was no recurrence, chronic pain and foreign body feeling in any patient at the end of the follow-up period. CONCLUSION: This feasible and safe alternative anterior inlay patch repair might be used in all femoral hernias with the exception of the ones requiring intestinal resection. PMID- 23792268 TI - Should laparoscopic reversal of Hartmann's procedure be the first line approach in all patients? AB - BACKGROUND/AIMS: To assess if the laparoscopic reversal of Hartmann's can be attempted in all patients, without detriment to short or long-term outcomes if the patient is subsequently converted to open. METHODS: Retrospective review of a prospectively collected database of all reversals under 8 surgeons at a single unit over 105 months, two surgeons attempting laparoscopic reversal in all patients, two pre-selecting for the laparoscopic approach and four utilising the open approach. Long-term follow-up data for re-admissions, re-operations and incisional hernia rate obtained from a postal questionnaire. RESULTS: 45 laparoscopic and 50 primary open reversals were identified. There was no difference in the mean age or previous peritonitis rate in either group. Laparoscopic conversion rate was 29% (13 patients). On intention to treat analysis, a significant difference was identified in the overall 30-day post operative surgical morbidity (8.9% Laparoscopic-attempted vs 26.0% Open, p = 0.030). There was no difference in operating times (mean 164 vs 172 min, p = 0.896) despite the 13 patients converted to an open procedure. Mean length of stay was significantly lower in the laparoscopic-attempted group at 6.8 days (5.2 8.4) vs 14.9 days (6.4-23.7) in the open group (p = 0.001). Anastomotic leak rates were not statistically different. The median follow up was 27 months (range 6-105); 60% of patients completed a postal follow-up questionnaire. There was no difference in short-term or long-term re-admission or reoperation rates. CONCLUSIONS: Laparoscopic reversal of Hartamann's is associated with shorter hospital stay and lower morbidity even in unselected patients. Long-term outcomes are similar. PMID- 23792269 TI - Intraoperative rectal washout in rectal cancer surgery: a survey of current practice in the UK. AB - OBJECTIVES: Due to concerns about implantation of malignant cells during surgery for rectal cancer, traditionally, intraoperative rectal washout (IORW) has been performed to prevent local recurrence. But with the advent of laparoscopic surgery, many surgeons have abandoned this practice. The aim of this study was to assess current practice among colorectal surgeons in the UK. METHODS: A 10-item questionnaire was sent by email to 452 consultant surgeons, who were members of the Association of Coloproctology of Great Britain & Ireland, and had previously agreed to participate in research projects. RESULTS: The mean age of the 149 responders (n = 149, 33.0%) was 49.2 years. The mean number of years in independent practice was 12.1, and the mean number of rectal cancer cases performed per year was 20.3 and 20.6, in the years 2010 and 2011 respectively. 74.3% of the responders believed that there is an advantage in performing IORWs in rectal cancer resections. Of the 71.8% of all responders who performed laparoscopic rectal cancer resections, 54.8% routinely performed IORWs during laparoscopic resections. However, 87.2% of all responders performed IORWs in open resections for rectal cancer, and 79.2% had routinely performed IORWs before the advent of laparoscopic rectal cancer surgery. CONCLUSIONS: Most colorectal surgeons believe that there is an advantage in performing IORWs. Although, most surgeons would routinely perform IORWs in open resections, they do not routinely perform these in laparoscopic resections. PMID- 23792270 TI - Low levels of interleukin-1 receptor antagonist (IL-1RA) predict engraftment syndrome after autologous stem cell transplantation in POEMS syndrome and other plasma cell neoplasms. AB - A rare, multisystem, plasma cell neoplasm, POEMS (polyradiculoneuropathy, organomegaly, endocrinopathy, M-spike, skin changes) syndrome is characterized by an abundance of proinflammatory and angiogenic cytokines. Patients with POEMS are known to have a high incidence of engraftment syndrome after autologous stem cell transplantation. We conducted a pilot study assessing levels of 30 different pro- and anti-inflammatory cytokines before and serially after transplantation in 18 patients with plasma cell neoplasms: POEMS syndrome (n = 9), multiple myeloma (n = 4), and amyloidosis (n = 5). We show that POEMS patients have higher pretransplantation levels of IL-4, IL-10, IL-13, IFN-alpha, and EGF as compared with those with non-POEMS plasma cell neoplasms. Higher pre- and posttransplantation IL-13 levels correlated with delayed neutrophil engraftment in POEMS patients. Low posttransplantation IL-1RA levels correlated with engraftment syndrome in both POEMS and non-POEMS patients. We conclude that differences in the peri-transplantation cytokine milieu may explain the higher transplantation morbidity in patients with POEMS syndrome. Our results need validation in a larger cohort. PMID- 23792271 TI - The expression of Th17-associated cytokines in human acute graft-versus-host disease. AB - The role of Th17 cells and Th17-associated cytokines in the development of acute graft-versus-host disease (aGVHD) in clinical allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients is not well established. In the current study, a cohort of 69 allo-HSCT patients was examined for the percentages of Th17 and FoxP3(+) Treg cells and the expressions of RORgammat and FoxP3 in peripheral blood mononuclear cells (PBMCs). The Th17 percentage and RORgammat expression were significantly higher, whereas Treg percentage and FoxP3 expression were significantly lower in severe aGVHD (grade 3 to 4) and mild aGVHD (grade 1 to 2) patients than in patients without aGVHD (grade 0) and healthy donors. We then investigated the expressions of Th17-associated cytokines, including TGF-beta, IL 6, IL-1beta, IL-17, IL-21, IL-22, IL-23, as well as IL-23R in the PBMCs of patients after allo-HSCT. The expressions of IL-17 and IL-22 in CD4(+) T cells were also examined. The results showed that the expressions of IL-6, IL-1beta, IL 17, IL-21, IL-23, and IL-23R were all increased, whereas IL-22 expression was decreased in aGVHD patients. The changes were also correlated with the severity of aGVHD. We also investigated the dynamic changes of Th17/Treg cells and Th17 associated cytokines in patients during the onset and resolution of aGVHD. The results demonstrated a reciprocal relationship between Treg and Th17 cells. Th17 associated cytokine expressions, namely IL-17 and IL-23, were closely related to the occurrence and resolution of aGVHD. We conclude that the dynamic balance between the Th17 and FoxP3(+) Treg cells and the changes of Th17-associated cytokines could be the indicators of the disease progression and promising candidates of prognostic biomarkers of aGVHD. PMID- 23792272 TI - Exogenous bFGF promotes articular cartilage repair via up-regulation of multiple growth factors. AB - OBJECTIVE: To investigate the roles of exogenous basic fibroblast growth factor (bFGF) on the repair of full-thickness articular cartilage defects in rabbits. DESIGN: In the present study, a double-layered collagen membrane sandwiched with bFGF-loaded-nanoparticles between a dense layer and a loose layer was implanted into full-thickness articular cartilage defects in rabbits. By grafting the membrane in a different direction, the dense layer or the loose layer facing the surface of the subchondral bone, the effects of the released bFGF on the defects and the profiles of nine growth factors (GFs) in synovial fluid (SF) were investigated using histological methods and antibody arrays, respectively. RESULTS: In the group with the loose layer facing the surface of the subchondral bone, fast release of bFGF was observed, and early high levels of endogenous transforming growth factor-beta2 (TGF-beta2), vascular endothelial growth factor (VEGF), bFGF, bone morphogenetic protein 2 (BMP-2), BMP-3, and BMP-4 in SF were detected by antibody arrays, especially on day 3. Chondrocyte-like cells were also observed in this group at an early stage. As a result, this group showed better levels of repair, as compared to the other groups in which low GF levels were detected at an early stage, and chondrocyte-like cells appeared much later. CONCLUSIONS: Our study suggests that exogenous bFGF promotes articular cartilage repair by up-regulating the levels of multiple GFs, but administration at an early stage is required. PMID- 23792273 TI - Sequestosome1/p62: a regulator of redox-sensitive voltage-activated potassium channels, arterial remodeling, inflammation, and neurite outgrowth. AB - Sequestosome1/p62 (SQSTM1) is an oxidative stress-inducible protein regulated by the redox-sensitive transcription factor Nrf2. It is not an antioxidant but known as a multifunctional regulator of cell signaling with an ability to modulate targeted or selective degradation of proteins through autophagy. SQSTM1 implements these functions through physical interactions with different types of proteins including atypical PKCs, nonreceptor-type tyrosine kinase p56(Lck) (Lck), polyubiquitin, and autophagosomal factor LC3. One of the notable physiological functions of SQSTM1 is the regulation of redox-sensitive voltage gated potassium (Kv) channels which are composed of alpha and beta subunits: (Kvalpha)4 (Kvbeta)4. Previous studies have established that SQSTM1 scaffolds PKCzeta, enhancing phosphorylation of Kvbeta which induces inhibition of pulmonary arterial Kv1.5 channels under acute hypoxia. Recent studies reveal that Lck indirectly interacts with Kv1.3 alpha subunits and plays a key role in acute hypoxia-induced Kv1.3 channel inhibition in T lymphocytes. Kv1.3 channels provide a signaling platform to modulate the migration and proliferation of arterial smooth muscle cells and activation of T lymphocytes, and hence have been recognized as a therapeutic target for treatment of restenosis and autoimmune diseases. In this review, we focus on the functional interactions of SQSTM1 with Kv channels through two key partners aPKCs and Lck. Furthermore, we provide molecular insights into the functions of SQSTM1 in suppression of proliferation of arterial smooth muscle cells and neointimal hyperplasia following carotid artery ligation, in T lymphocyte differentiation and activation, and in NGF induced neurite outgrowth in PC12 cells. PMID- 23792275 TI - Free radical paradoxes. AB - Unlike bigger and more advanced animals, Caenorhabditis elegans does not generate NO, yet it was recently found that NO produced by chemical or biological sources exerts profound effects in that animal, leading to increased life span and thermotolerance. The biological source was Bacillus subtilis, a natural food for C. elegans. Yet once in the cell, NO might react with superoxide, leading to the production of the potentially toxic peroxynitrite. In this paper, a number of paradoxes that are involved in that situation are discussed. It is also argued that their solution might lead to a sizeable advancement of our knowledge of what constitutes oxidative stress and what role oxidative stress plays in the development of pathological processes and aging. PMID- 23792274 TI - Inhibition of Mycobacterium tuberculosis PknG by non-catalytic rubredoxin domain specific modification: reaction of an electrophilic nitro-fatty acid with the Fe S center. AB - PknG from Mycobacterium tuberculosis is a Ser/Thr protein kinase that regulates key metabolic processes within the bacterial cell as well as signaling pathways from the infected host cell. This multidomain protein has a conserved canonical kinase domain with N- and C-terminal flanking regions of unclear functional roles. The N-terminus harbors a rubredoxin-like domain (Rbx), a bacterial protein module characterized by an iron ion coordinated by four cysteine residues. Disruption of the Rbx-metal binding site by simultaneous mutations of all the key cysteine residues significantly impairs PknG activity. This encouraged us to evaluate the effect of a nitro-fatty acid (9- and 10-nitro-octadeca-9-cis-enoic acid; OA-NO2) on PknG activity. Fatty acid nitroalkenes are electrophilic species produced during inflammation and metabolism that react with nucleophilic residues of target proteins (i.e., Cys and His), modulating protein function and subcellular distribution in a reversible manner. Here, we show that OA-NO2 inhibits kinase activity by covalently adducting PknG remote from the catalytic domain. Mass spectrometry-based analysis established that cysteines located at Rbx are the specific targets of the nitroalkene. Cys-nitroalkylation is a Michael addition reaction typically reverted by thiols. However, the reversible OA-NO2 mediated nitroalkylation of the kinase results in an irreversible inhibition of PknG. Cys adduction by OA-NO2 induced iron release from the Rbx domain, revealing a new strategy for the specific inhibition of PknG. These results affirm the relevance of the Rbx domain as a target for PknG inhibition and support that electrophilic lipid reactions of Rbx-Cys may represent a new drug strategy for specific PknG inhibition. PMID- 23792276 TI - Novel self-emulsifying formulation of quercetin for improved in vivo antioxidant potential: implications for drug-induced cardiotoxicity and nephrotoxicity. AB - Quercetin (QT) was formulated into a novel self-emulsifying drug delivery system (SEDDS) to improve its oral bioavailability and antioxidant potential compared to free drug. Capmul MCM was selected as the oily phase on the basis of optimum solubility of QT in oil. Tween 20 and ethanol were selected as surfactant and cosurfactant from a large pool of excipients, depending upon their spontaneous self-emulsifying ability with the selected oily phase. Pseudoternary-phase diagrams were constructed to identify the efficient self-emulsification regions in various dilution media, viz., water, pH 1.2, and pH 6.8. The ratio of 40:40:20 w/w, Capmul MCM:QT (19:1)/Tween 20/ethanol was optimized based on its ability to form a spontaneous submicrometer emulsion in simulated gastrointestinal fluids. DPPH scavenging assay showed comparable antioxidant activity of QT-SEDDS to free QT. QT-SEDDS was robust in terms of stability against short-term excursion of freeze/thaw cycles and accelerated stability for 6 months as per International Conference on Harmonisation guidelines. A fluorescent dye-loaded SEDDS formulation showed rapid internalization within 1h of incubation with Caco-2 cells as evident by confocal laser scanning microscopy. QT-SEDDS showed a significant increase in cellular uptake by 23.75-fold in comparison with free QT cultured with Caco-2 cells. The SEDDS demonstrated ~5-fold enhancement in oral bioavailability compared to free QT suspension. The in vitro-in vivo relation between in vitro Caco-2 cell uptake and in vivo pharmacokinetics of QT-SEDDS showed a correlation coefficient of ~0.9961, as evident from a Levy plot. Finally, QT-SEDDS showed a significantly higher in vivo antioxidant potential compared to free QT when evaluated as a function of ability to combat doxorubicin and cyclosporin A-induced cardiotoxicity and nephrotoxicity, respectively. PMID- 23792277 TI - Bidirectional regulation of NF-kappaB by reactive oxygen species: a role of unfolded protein response. AB - Nuclear factor-kappaB (NF-kappaB) is a transcription factor that plays a crucial role in coordinating innate and adaptive immunity, inflammation, and apoptotic cell death. NF-kappaB is activated by various inflammatory stimuli including peptide factors and infectious microbes. It is also known as a redox-sensitive transcription factor activated by reactive oxygen species (ROS). Over the past decades, various investigators focused on the role of ROS in the activation of NF kappaB by cytokines and lipopolysaccharides. However, recent studies also suggested that ROS have the potential to repress NF-kappaB activity. Currently, it is not well addressed how ROS regulate activity of NF-kappaB in a bidirectional fashion. In this paper, we summarize evidence for positive and negative regulation of NF-kappaB by ROS, possible redox-sensitive targets for NF kappaB signaling, and mechanisms underlying biphasic and bidirectional influences of ROS on NF-kappaB, especially focusing on a role of ROS-mediated induction of endoplasmic reticulum stress. PMID- 23792278 TI - Systematic evaluation of phantom fluids for simultaneous PET/MR hybrid imaging. AB - With the recent advent of integrated PET/MR hybrid systems, the need for simultaneous PET and MR phantom measurements arises. Phantom fluids that are used in stand-alone MR systems, especially in larger phantoms and at a high magnetic field strength, are not necessarily applicable in PET imaging and vice versa. In this study, different approaches to fluid selection were considered and systematically evaluated with respect to their usability for simultaneous PET/MR phantom imaging. METHODS: Demineralized water, water with increased electrical conductivity, a water-oil emulsion, and monoethylene and triethylene glycol were investigated in MR and PET measurements using the most common PET tracer (18)F FDG. As an alternative to (18)F-FDG, a modified PET tracer ((18)F-fluoride Kryptofix 222 complex) was investigated toward its ability to dissolve in pure oil, which provides good signal homogeneity in MR imaging. Measurements were performed on a 3.0 T integrated PET/MR whole-body system using a National Electrical Manufacturers Association quality-standard phantom. RESULTS: All tested fluids dissolved the radiotracer (18)F-FDG homogeneously. Regarding their suitability for MR at 3.0 T, all fluids significantly improved the homogeneity compared to pure water (increase of excitation flip angle within the tested phantom by a factor of 2.0). When the use of (18)F-FDG was preferred, triethylene glycol provided the best compromise (flip angle increase by a factor of 1.13). The potential alternative tracer, (18)F-fluoride Kryptofix 222 complex, dissolved in pure oil; however, it is not optimal in its tested composition because it accumulates at the bottom of the phantom during the time of measurement. CONCLUSION: This study provides a systematic approach toward phantom fluid selection for imaging a given quality-standard body phantom--and phantoms of comparable size--at 3.0 T. For simultaneous PET/MR scans using the standard tracer (18)F-FDG, an alternative fluid to water and oil is proposed that serves as a viable option for both imaging modalities. Nevertheless, when water is preferred, ways to improve MR image homogeneity are presented. The tested alternative PET tracer enables the use of pure oil in combined scans, but the tracer composition needs to be optimized for phantom measurement applications. PMID- 23792279 TI - Phenotypic characterization and in vitro propagation and transplantation of the Nile tilapia (Oreochromis niloticus) spermatogonial stem cells. AB - In association with in vitro culture and transplantation, isolation of spermatogonial stem cells (SSCs) is an excellent approach for investigating spermatogonial physiology in vertebrates. However, in fish, the lack of SSC molecular markers represents a great limitation to identify/purify these cells, rendering it difficult to apply several valuable biotechnologies in fish-farming. Herein, we describe potential molecular markers, which served to phenotypically characterize, cultivate and transplant Nile tilapia SSCs. Immunolocalization revealed that Gfra1 is expressed exclusively in single type A undifferentiated spermatogonia (Aund, presumptive SSCs). Likewise, the expression of Nanos2 protein was observed in Aund cells. However, Nanos2-positive spermatogonia have also been identified in cysts with two to eight germ cells that encompass type A differentiated spermatogonia (Adiff). Moreover, we also established effective primary culture conditions that allowed the Nile tilapia spermatogonia to expand their population for at least one month while conserving their original undifferentiated (stemness) characteristics. The maintenance of Aund spermatogonial phenotype was demonstrated by the expression of early germ cell specific markers and, more convincingly, by their ability to colonize and develop in the busulfan-treated adult Nile tilapia recipient testes after germ cell transplantation. In addition to advancing our knowledge on the identity and physiology of fish SSCs, these findings provide the first step in establishing a system that will allow fish SSCs expansion in vitro, representing an important progress towards the development of new biotechnologies in aquaculture, including the possibility of producing transgenic fish. PMID- 23792280 TI - Remifentanil produces cross-desensitization and tolerance with morphine on the mu opioid receptor. AB - Remifentanil is a powerful mu-opioid (MOP) receptor agonist used in anaesthesia with a very short half-life. However, per-operative perfusion of remifentanil was shown to increase morphine consumption during post-operative period to relieve pain. In the present study, we aimed to describe the cellular mechanisms responsible for this apparent reduction of morphine efficacy. For this purpose, we first examined the pharmacological properties of both remifentanil and morphine at the MOP receptor, endogenously expressed in the human neuroblastoma SH-SY5Y cell line, to regulate adenylyl cyclase and the MAP kinase ERK1/2 pathway, their potency to promote MOP receptor phosphorylation, arrestin 3-CFP (cyan fluorescent protein) recruitment and receptor trafficking during acute and sustained exposure. In the second part of this work, we studied the effects of a prior exposure of remifentanil on morphine-induced inhibition of cAMP accumulation, activation of ERK1/2 and analgesia. We showed that sustained exposure to remifentanil promoted a rapid desensitization of opioid receptors on both signalling pathways and a pretreatment with this agonist reduced signal transduction produced by a second challenge with morphine. While both opioid agonists promoted Ser(375) phosphorylation on MOP receptor, remifentanil induced a rapid internalization of opioid receptors compared to morphine but without detectable arrestin 3-CFP translocation to the plasma membrane in our experimental conditions. Lastly, a cross-tolerance between remifentanil and morphine was observed in mice using the hot plate test. Our in vitro and in vivo data thus demonstrated that remifentanil produced a rapid desensitization and internalization of the MOP receptor that would reduce the anti-nociceptive effects of morphine. PMID- 23792281 TI - Neural underpinnings of behavioural strategies that prioritize either cognitive task performance or pain. AB - We previously discovered that when faced with a challenging cognitive task in the context of pain, some people prioritize task performance, while in others, pain results in poorer performance. These behaviours, designated respectively as A- and P-types (for attention dominates vs pain dominates), may reflect pain coping strategies, resilience or vulnerabilities to develop chronic pain, or predict the efficacy of treatments such as cognitive behavioural therapy. Here, we used a cognitive interference task and pain stimulation in 80 subjects to interrogate psychophysical, psychological, brain structure and function that distinguish these behavioural strategies. During concurrent pain, the A group exhibited faster task reaction times (RTs) compared to nonpain trials, whereas the P group had slower RTs during pain compared to nonpain trials, with the A group being 143 ms faster than the P group. Brain imaging revealed structural and functional brain features that characterized these behavioural strategies. Compared to the performance-oriented A group, the P group had (1) more gray matter in regions implicated in pain and salience (anterior insula, anterior midcingulate cortex, supplementary motor area, orbitofrontal cortex, thalamus, caudate), (2) greater functional connectivity in sensorimotor and salience resting-state networks, (3) less white matter integrity in the internal and external capsule, anterior thalamic radiation and corticospinal tract, but (4) were indistinguishable based on sex, pain sensitivity, neuroticism, and pain catastrophizing. These data may represent neural underpinnings of how task performance vs pain is prioritized and provide a framework for developing personalized pain therapy approaches that are based on behaviour-structure-function organization. PMID- 23792282 TI - Add-on therapy: when two are not better than one. PMID- 23792283 TI - Classification and definition of misuse, abuse, and related events in clinical trials: ACTTION systematic review and recommendations. AB - As the nontherapeutic use of prescription medications escalates, serious associated consequences have also increased. This makes it essential to estimate misuse, abuse, and related events (MAREs) in the development and postmarketing adverse event surveillance and monitoring of prescription drugs accurately. However, classifications and definitions to describe prescription drug MAREs differ depending on the purpose of the classification system, may apply to single events or ongoing patterns of inappropriate use, and are not standardized or systematically employed, thereby complicating the ability to assess MARE occurrence adequately. In a systematic review of existing prescription drug MARE terminology and definitions from consensus efforts, review articles, and major institutions and agencies, MARE terms were often defined inconsistently or idiosyncratically, or had definitions that overlapped with other MARE terms. The Analgesic, Anesthetic, and Addiction Clinical Trials, Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership convened an expert panel to develop mutually exclusive and exhaustive consensus classifications and definitions of MAREs occurring in clinical trials of analgesic medications to increase accuracy and consistency in characterizing their occurrence and prevalence in clinical trials. The proposed ACTTION classifications and definitions are designed as a first step in a system to adjudicate MAREs that occur in analgesic clinical trials and postmarketing adverse event surveillance and monitoring, which can be used in conjunction with other methods of assessing a treatment's abuse potential. PMID- 23792285 TI - Repetitive neonatal pain and neurocognitive abilities in ex-preterm children. PMID- 23792286 TI - Lack of endogenous opioid release during sustained visceral pain: a [11C]carfentanil PET study. AB - Opioidergic neurotransmission in the central nervous system is involved in somatic pain, but its role in visceral pain remains unknown. We aimed to quantify endogenous opioid release in the brain during sustained painful gastric distension. Therefore, 2 dynamic [11C]carfentanil positron emission tomography scans were performed in 20 healthy subjects during 2 conditions: sustained (20 minutes) painful proximal gastric balloon distension at predetermined individual discomfort threshold (PAIN) and no distension (NO PAIN), in counterbalanced order. Pain levels were assessed during scanning using visual analogue scales and after scanning using the McGill Pain Questionnaire. Emotional state was rated after scanning using the Positive and Negative Affect Schedule. Distribution volume ratios in 21 volumes of interest in the pain matrix were used to quantify endogenous opioid release. During the PAIN compared to the NO PAIN condition, volunteers reported a significantly higher increase in negative affect (5.50+/ 1.29 versus 0.10+/-1.08, P=.0147) as well as higher pain ratings (sensory: 74.05+/-9.23 versus 1.50+/-0.95, P<.0001; affective: 91.42+/-8.13 versus 4.33+/ 6.56, P<.0001). No difference in endogenous opioid release was demonstrated in any of the volumes of interest. Thus, contrary to its somatic counterpart, no opioid release is detected in the brain during sustained visceral pain, despite similar pain intensities. Endogenous opioids may play a less important role in visceral compared to somatic pain. PMID- 23792287 TI - Surface enhancement Raman scattering of tautomeric thiobarbituric acid. Natural bond orbitals and B3LYP/6-311+G (d, p) assignments of the Fourier Infrared and Fourier Raman Spectra. AB - Surface enhancement Raman scattering (SERS) of two tautomer of thiobarbituric acid was obtained using silver and gold nanoparticles. Large band enhancement in the region of the nu(C=S), nu(C=C), delta(CH2), and delta(CNH) vibrational modes was found. Natural bond analysis of the tautomer species revealed expressive values of charge transfer, principally from lone pair electron orbitals of the S, N, and O atoms. Complete vibrational assignment was done for the two tautomers using the B3LYP/6-311+G (d, p) procedure, band deconvolution analysis, and from a rigorous interpretation of the normal modes matrix. The calculated spectra agree well with the experimental ones. PMID- 23792288 TI - Raman spectroscopic study of the mineral qingheiite Na2(Mn2+,Mg,Fe2+)2(Al,Fe3+)(PO4)3, a pegmatite phosphate mineral from Santa Ana pegmatite, Argentina. AB - The pegmatite mineral qingheiite Na2(Mn(2+),Mg,Fe(2+))2(Al,Fe(3+))(PO4)3 has been studied by a combination of SEM and EMP, Raman and infrared spectroscopy. The studied sample was collected from the Santa Ana pegmatite, Argentina. The mineral occurs as a primary mineral in lithium bearing pegmatite, in association with beausite and lithiophilite. The Raman spectrum is characterized by a very sharp intense Raman band at 980 cm(-1) assigned to the PO4(3-) symmetric stretching mode. Multiple Raman bands are observed in the PO4(3-) antisymmetric stretching region, providing evidence for the existence of more than one phosphate unit in the structure of qingheiite and evidence for the reduction in symmetry of the phosphate units. This concept is affirmed by the number of bands in the nu4 and nu2 bending regions. No intensity was observed in the OH stretching region in the Raman spectrum but significant intensity is found in the infrared spectrum. Infrared bands are observed at 2917, 3195, 3414 and 3498 cm(-1) are assigned to water stretching vibrations. It is suggested that some water is coordinating the metal cations in the structure of qingheiite. PMID- 23792289 TI - Synthesis, characterization and vibrational spectra analysis of ethyl (2Z)-2-(2 amino-4-oxo-1,3-oxazol-5(4H)-ylidene)-3-oxo-3-phenylpropanoate. AB - In the present study, the experimental and theoretical vibrational spectra of ethyl (2Z)-2-(2-amino-4-oxo-1,3-oxazol-5(4H)-ylidene)-3-oxo-3-phenylpropanoate (AOX) were investigated. The experimental FT-IR (400-4000 cm(-1)) and Laser-Raman spectra (100-4000 cm(-1)) of the molecule in the solid phase were recorded. Theoretical vibrational frequencies and geometric parameters (bond lengths, bond angles and torsion angles) were calculated using ab initio Hartree Fock (HF), Density Functional Theory (B3LYP and B3PW91) methods with 6-311++G(d,p) basis set by Gaussian 03 program, for the first time. The computed values of frequencies are scaled using a suitable scale factor to yield good coherence with the observed values. The assignments of the vibrational frequencies were performed by potential energy distribution (PED) analysis by using VEDA 4 program. The theoretical optimized geometric parameters and vibrational frequencies were compared with the corresponding experimental X-ray diffraction data, and they were seen to be in a good agreement with each other. The hydrogen bonding geometry of the molecule was also simulated to evaluate the effect of intermolecular hydrogen bonding on the vibrational frequencies. Also, the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energies were found. PMID- 23792290 TI - Vibrational spectral investigations and density functional theory study of 4 Formylbenzoic acid. AB - An accurate assignment of the vibrational spectra of 4-Formylbenzoic acid in solid state was carried out. For this purpose density functional calculations (DFT) were performed to clarify wavenumber assignments of the experimentally observed bands for the first time. A scaling of the wavenumbers was carried out to improve the calculated values. Good reproduction of the experimental wavenumbers is obtained and the % error is very small in the majority of cases. The NBO analysis was carried out, and it reveals hyper conjugative interaction, ICT and stabilization of molecules. PMID- 23792291 TI - Experimental and theoretical FTIR and FT-Raman spectroscopic analysis of 1 pyrenecarboxylic acid. AB - The title molecule 1-pyrenecarboxylic acid (1PCA) has been characterized by FTIR, FT-Raman, NMR and UV-Vis spectral analyses. The molecular geometry, harmonic vibrational modes, the corresponding wavenumbers and IR intensities of 1PCA were calculated by DFT method with 6-311G(d,p) basis set. The assignments of the fundamentals were proposed on the basis of total energy distribution (TED) calculations. The calculated (13)C and (1)H NMR chemical shifts using gauge including atomic orbitals (GIAOs) approach are in good agreement with the observed chemical shifts. The polarizability and first order hyperpolarizability of the title molecule were calculated and interpreted. Using TD-DFT method, the electronic transitions have been compared with the experimental wavelengths. The molecular electrostatic potential map was used for prediction of possible hydrogen and oxygen bonding sites 1PCA molecule. PMID- 23792292 TI - Temperature-dependent microwave dielectric relaxation studies of hydrogen bonded polar binary mixtures of propan-1-ol and propionaldehyde. AB - The molecular interaction between the polar systems of propan-1-ol and propionaldehyde for various mole fractions at different temperatures were studied by determining the frequency dependent complex dielectric permittivity by using the open-ended coaxial probe technique method in the microwave frequency range from 20 MHz to 20 GHz. The geometries are optimized at HF, B3LYP and MP2 with 6 311G and 6-311G+ basis sets. Dipole moments of the binary mixtures are calculated from the dielectric data using Higasi's method and compared with the theoretical results. Conformational analysis of the formation of hydrogen bond between the propan-1-ol and propionaldehyde is supported by the FT-IR and molecular polarizability calculations. The average relaxation times are calculated from their respective Cole-Cole plots. The activation entropy, activation enthalpy and Kirkwood correlation 'g' factor, excess permittivity (epsilon(E)), excess inverse relaxation time (1/tau)(E), Bruggeman parameter (f(B)) have also been determined for propan-1-ol and propionaldehyde and the results were correlated. PMID- 23792284 TI - Glia and pain: is chronic pain a gliopathy? AB - Activation of glial cells and neuro-glial interactions are emerging as key mechanisms underlying chronic pain. Accumulating evidence has implicated 3 types of glial cells in the development and maintenance of chronic pain: microglia and astrocytes of the central nervous system (CNS), and satellite glial cells of the dorsal root and trigeminal ganglia. Painful syndromes are associated with different glial activation states: (1) glial reaction (ie, upregulation of glial markers such as IBA1 and glial fibrillary acidic protein (GFAP) and/or morphological changes, including hypertrophy, proliferation, and modifications of glial networks); (2) phosphorylation of mitogen-activated protein kinase signaling pathways; (3) upregulation of adenosine triphosphate and chemokine receptors and hemichannels and downregulation of glutamate transporters; and (4) synthesis and release of glial mediators (eg, cytokines, chemokines, growth factors, and proteases) to the extracellular space. Although widely detected in chronic pain resulting from nerve trauma, inflammation, cancer, and chemotherapy in rodents, and more recently, human immunodeficiency virus-associated neuropathy in human beings, glial reaction (activation state 1) is not thought to mediate pain sensitivity directly. Instead, activation states 2 to 4 have been demonstrated to enhance pain sensitivity via a number of synergistic neuro-glial interactions. Glial mediators have been shown to powerfully modulate excitatory and inhibitory synaptic transmission at presynaptic, postsynaptic, and extrasynaptic sites. Glial activation also occurs in acute pain conditions, and acute opioid treatment activates peripheral glia to mask opioid analgesia. Thus, chronic pain could be a result of "gliopathy," that is, dysregulation of glial functions in the central and peripheral nervous system. In this review, we provide an update on recent advances and discuss remaining questions. PMID- 23792293 TI - Raman spectroscopy as a tool for polyunsaturated compound characterization in gastropod and limnic terrestrial shell specimens. AB - The colours of mollusc shells were determined using the Raman spectroscopy and these analyses suggest that the conjugated polyenes (carotenoids) and psittacofulvins are the organic pigments incorporated into their skeletal structures responsible by their colorations. The symmetric stretching vibration of the carbonate ion gives rise to a very strong Raman band at ca. 1089 cm(-1) and a weak band at 705 cm(-1), for all samples; the second band characterizes the aragonite as the inorganic matrix and can be used as a marker. The specimens show bands at 1523-1500 and at 1130-1119 cm(-1), assigned to the nu1 and nu2 modes of the polyenic chain vibrations, respectively. Another band at 1293 cm(-1), assigned to the CH=CH in-plane rocking mode of the olefinic hydrogen is also observed in all samples, which reinforces the psittacofulvin compound as the main pigment present in the analyzed samples. PMID- 23792294 TI - Determination of torasemide by fluorescence quenching method with some dihalogenated fluorescein dyes as probes. AB - A novel fluorescence quenching method for the determination of torasemide (TOR) with some dihalogenated fluorescein dyes as fluorescence probes was developed. In acidulous medium, TOR could interact with some dihalogenated fluorescein dyes such as dichlorofluorescein (DCF), dibromofluorescein (DBF) and diiodofluorescein (DIF) to form binary complexes, which could lead to fluorescence quenching of above dihalogenated fluorescein dyes. The maximum fluorescence emission wavelengths were located at 532 nm (TOR-DCF), 535 nm (TOR-DBF) and 554 nm (TOR DIF). The relative fluorescence intensities (DeltaF=F0-F) were proportional to the concentration of TOR in certain ranges. The detection limits were 4.8 ng mL( 1) for TOR-DCF system, 9.8 ng mL(-1) for TOR-DBF system and 35.1 ng mL(-1) for TOR-DIF system. The optimum reaction conditions, influencing factors were studied; and the effect of coexisting substances was investigated owing to the highest sensitivity of TOR-DCF system. In addition, the reaction mechanism, composition and structure of the complex were discussed by quantum chemical calculation and Job's method. The fluorescence quenching of dihalogenated fluorescein dyes by TOR was a static quenching process judging from the effect of temperature and the Stern-Volmer plots. The method was satisfactorily applied to the determination of TOR in tablets and human urine samples. PMID- 23792295 TI - Dual therapy with infliximab and immunomodulator reduces one-year rates of hospitalization and surgery among veterans with inflammatory bowel disease. AB - BACKGROUND & AIMS: Effectiveness of early treatment with biologics and immunomodulator therapy on healthcare utilization remains poorly defined. We assessed rates of hospitalization and surgery within 1 year after initiation of infliximab and/or immunomodulator therapy in a United States cohort of patients with inflammatory bowel disease. METHODS: We conducted a retrospective, observational cohort study of veterans with Crohn's disease or ulcerative colitis by using administrative data from 176 Department of Veteran Affairs facilities (October 1, 2001 through September 30, 2009). Inpatient, outpatient, and death records were linked longitudinally with prescription fill data. Each person-day of follow-up was assessed for treatment with infliximab, immunomodulators, both (dual therapy), or neither. We calculated drug exposure time and used Poisson and logistic regression analyses to assess outcomes. RESULTS: The cohort of 20,474 patients included 8042 patients with Crohn's disease and 12,432 with ulcerative colitis (93.9% male; 72.5% white; mean age, 60.9 +/- 14.5 years) prescribed infliximab (0.17%), immunomodulator (1.3%), or dual therapy (1.5%). Adjusted models revealed 50% relative reductions in hospitalization among patients who received 9.2 months of immunomodulator monotherapy, 8 months of infliximab, or 7.7 months of dual therapy. A 50% relative reduction in surgery was observed among patients receiving 7 months of infliximab or 5 months of dual therapy. Analysis of dose-response data revealed 73.1% and 92% reductions in risk of hospitalization and surgery, respectively, after 9 months of dual therapy. CONCLUSIONS: On the basis of a retrospective cohort study, dual therapy with infliximab and an immunomodulator for <8 months is associated with significant reductions in hospitalization and surgery within 1 year of the start of therapy. These findings indicate that patients with IBD are more likely to benefit if dual therapy is initiated earlier in their first year of therapy. PMID- 23792296 TI - Alarmin HNP-1 promotes pyroptosis and IL-1beta release through different roles of NLRP3 inflammasome via P2X7 in LPS-primed macrophages. AB - Defensins are the first endogenous mediators to be characterized as alarmins and play multifunctional roles in immune response. Previous studies reported that human neutrophil peptide (HNP)-1, a member of the alpha-defensin subfamily, could regulate the IL-1beta post-translational process; however, the underlying mechanism remained unknown. Using an LPS-primed THP-1 macrophage model, we found that inhibition of P2X purinoceptor 7 (P2X7) suppressed HNP-1-initiated mature IL 1beta release. Confocal microscopy and glutathione S-transferase (GST) pull-down assay demonstrated that HNP-1 bound to P2X7 directly. HNP-1 treatment increased the activated level of caspase-1, and inhibition of caspase-1 abolished IL-1beta release. Incubation of LPS-primed macrophages with potassium chloride also prevented HNP-1-induced export of mature IL-1beta. Likewise, an ethidium bromide uptake test showed that the P2X7-K(+) efflux-caspase-1 signaling pathway triggered by HNP-1 contributed to pyroptotic pore formation. Furthermore, knock down of inflammasome adaptor Nod-like receptor family pyrin domain containing 3 (NLRP3) decreased activated caspase-1 level and reduced pore formation in macrophages, whereas IL-1beta release was not significantly impaired. These findings not only illustrated the mechanism for alarmin HNP-1 in enhancing inflammatory response, but also provided therapeutic targets for certain inflammatory diseases in which defensins play important roles. PMID- 23792297 TI - Social interactions modulate the virulence of avian malaria infection. AB - There is an increasing understanding of the context-dependent nature of parasite virulence. Variation in parasite virulence can occur when infected individuals compete with conspecifics that vary in infection status; virulence may be higher when competing with uninfected competitors. In vertebrates with social hierarchies, we propose that these competition-mediated costs of infection may also vary with social status. Dominant individuals have greater competitive ability than competing subordinates, and consequently may pay a lower prevalence mediated cost of infection. In this study we investigated whether costs of malarial infection were affected by the occurrence of the parasite in competitors and social status in domestic canaries (Serinus canaria). We predicted that infected subordinates competing with non-infected dominants would pay higher costs than infected subordinates competing with infected dominants. We also predicted that these occurrence-mediated costs of infection would be ameliorated in infected dominant birds. We found that social status and the occurrence of parasites in competitors significantly interacted to change haematocrit in infected birds. Namely, subordinate and dominant infected birds differed in haematocrit depending on the infection status of their competitors. However, in contrast to our prediction, dominants fared better with infected subordinates, whereas subordinates fared better with uninfected dominants. Moreover, we found additional effects of parasite occurrence on mortality in canaries. Ultimately, we provide evidence for costs of parasitism mediated by social rank and the occurrence of parasites in competitors in a vertebrate species. This has important implications for our understanding of the evolutionary processes that shape parasite virulence and group living. PMID- 23792298 TI - Chronic Opisthorchis felineus infection attenuates atherosclerosis--an autopsy study. AB - Previously, we proposed a hypothesis that chronic helminthic infection may have beneficial effects on the development of atherosclerosis. The aim of this study was to investigate an association between Opisthorchis felineus chronic helminthic infections with aortic atherosclerosis and serum total cholesterol. A series of medico-legal autopsy specimens collected in Khanty-Mansiisk (the region in Russia endemic for O. felineus) were studied to assess O. felineus worm burden in cadaver livers. The areas of atherosclerotic lesions in the cadaver aortas were measured by visual planimetry. A family history of cardiovascular disease, smoking, hypertension or diabetes was elicited, and serum total cholesterol levels examined. Three hundred and nineteen cadavers (280 (87.8%) males and 39 (12.2%) females) aged 20-72 years were divided into five age groups: (i) 20-29, (ii) 30-39, (iii) 40-49, (iv) 50-59 and (v) >60 years old. The O. felineus mean worm burden was 257+/-312 worms/liver. Infected subjects were categorised into three subgroups depending on the worm burden: mild (<100 worms), moderate (100 500 worms) and severe (>500 worms). Infected subjects had lower serum total cholesterol (mild worm burden, 186.4+/-25.6 mg/dl; moderate worm burden, 183.4+/ 23.1mg/dl, P=0.002; severe worm burden, 170.6+/-25.1mg/dl, P<0.001) than non infected subjects (201.1+/-21.2 mg/dl). The average percentage of aortic surface covered by fatty streaks, fibrotic plaques and complicated lesions was negatively related to worm burden in the infected subjects. Chronic helminthic infections was a negative predictor of aortic atherosclerosis; with an odds ratio of 1.72 (1.02-2.91), P=0.041 for all subjects; and 3.19 (1.35-7.58), P=0.008 for subjects aged >40 years old. Opisthorchis felineus chronic helminthic infectionswas found to be associated with lower serum total cholesterol levels and a significant attenuation of atherosclerosis. PMID- 23792299 TI - Magnetic and electric fields induce directional responses in Steinernema carpocapsae. AB - Entomopathogenic nematode species respond directionally to various cues including electrical stimuli. For example, in prior research Steinernema carpocapsae was shown to be attracted to an electrical current that was applied to an agar dish. Thus, we hypothesised that these nematodes may use electromagnetic reception to assist in navigating through the soil and finding a host. In this study we discovered that S. carpocapsae also responds to electrical fields (without current) and to magnetic fields; to our knowledge this is the first report of nematode directional movement in response to a magnetic field. Our research expands on the range of known stimuli that entomopathogenic nematodes respond to. The findings may have implications for foraging behavior. PMID- 23792300 TI - Indoxyl sulfate signals for rapid mRNA stabilization of Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2) and suppresses the expression of hypoxia-inducible genes in experimental CKD and uremia. AB - Chronic hypoxia in the tubulointerstitium serves as a final common pathway in progressive renal disease. Circumstantial evidence suggests that hypoxia inducible factor (HIF)-1 in the ischemic tubules may be functionally inhibited in a chronic kidney disease (CKD) milieu. In this study, we hypothesized that indoxyl sulfate (IS), a uremic toxin, impairs the cellular hypoxic response. In human kidney (HK-2) proximal tubular cells, IS reduced the hypoxic induction of HIF-1 target genes. This effect was not associated with quantitative changes in the HIF-1alpha protein, but with functional impairment of the HIF-1alpha C terminal transactivation domain (CTAD). Among factors that impeded the recruitment of transcriptional coactivators to the HIF-1alphaCTAD, IS markedly up regulated Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2) through a mechanism of post-transcriptional mRNA stabilization involving the extracellular signal-regulated kinase (ERK) 1/2 pathway. In vivo, disproportionate expression of HIF target genes was demonstrated in several CKD models, which was offset by an oral adsorbent, AST-120. Furthermore, administration of indole reduced the induction of angiogenic, hypoxia-inducible genes in rats with experimental heart failure. Results of these studies reveal a novel role of IS in modulating the transcriptional response of HIF-1 and provide insight into molecular mechanisms underlying progressive nephropathies as well as cardiovascular complications. PMID- 23792301 TI - Aspirin-triggered 15-epi-lipoxin A4 predicts cyclooxygenase-2 in the lungs of LPS treated mice but not in the circulation: implications for a clinical test. AB - Inhibition of cyclooxygenase (COX)-2 increases cardiovascular deaths. Identifying a biomarker of COX-2 is desirable but difficult, since COX-1 and COX-2 ordinarily catalyze formation of an identical product, prostaglandin H2. When acetylated by aspirin, however, COX-2 (but not COX-1) can form 15(R)-HETE, which is metabolized to aspirin-triggered lipoxin (ATL), 15-epi-lipoxin A4. Here we have used COX-1- and COX-2-knockout mice to establish whether plasma ATL could be used as a biomarker of vascular COX-2 in vivo. Vascular COX-2 was low but increased by LPS (10 mg/kg; i.p). Aspirin (10 mg/kg; i.v.) inhibited COX-1, measured as blood thromboxane and COX-2, measured as lung PGE2. Aspirin also increased the levels of ATL in the lungs of LPS-treated wild-type C57Bl6 mice (vehicle: 25.5+/-9.3 ng/ml; 100 mg/kg: 112.0+/-7.4 ng/ml; P<0.05). Despite this, ATL was unchanged in plasma after LPS and aspirin. This was true in wild-type as well as COX-1(-/-) and COX-2(-/-) mice. Thus, in mice in which COX-2 has been induced by LPS treatment, aspirin triggers detectable 15-epi-lipoxin A4 in lung tissue, but not in plasma. This important study is the first to demonstrate that while ATL can be measured in tissue, plasma ATL is not a biomarker of vascular COX-2 expression. PMID- 23792302 TI - Suboptimal nutrition in utero causes DNA damage and accelerated aging of the female reproductive tract. AB - Early life exposure to adverse environments can lead to a variety of metabolic and cardiovascular diseases in offspring. We hypothesize that female reproductive function may also be affected, with subsequent implications for fertility. We used an established maternal low-protein model where animals are born small but undergo rapid postnatal catch-up growth by suckling a control-fed dam (recuperated offspring). Markers of oxidative stress and cellular aging in reproductive tract tissues were assessed at 3 and 6 mo of age. Recuperated offspring had lower birth weight than controls (P<0.01) but caught up during lactation. 4-Hydroxynonenal (4HNE; an indicator of oxidative stress) was increased in recuperated animals compared with controls in both ovaries and oviducts at 6 mo. At 3 and 6 mo, ovaries and oviducts of recuperated offspring had increased mitochondrial (mt)DNA copy number (P<0.01). By contrast, germ-line cells showed no difference in mtDNA copy number, suggesting they were protected from suboptimal maternal nutrition. Oviduct and somatic ovarian telomere length declined more rapidly with age in recuperated animals. This accelerated cellular aging was associated with a declined ovarian reserve in developmentally programmed animals. These findings have significant clinical implications in light of worldwide trends to delayed childbearing. PMID- 23792303 TI - Novel insights into the function of Arabidopsis R2R3-MYB transcription factors regulating aliphatic glucosinolate biosynthesis. AB - Arabidopsis transcription factors, MYB28, MYB29 and MYB76, positively regulate aliphatic glucosinolate (AGSL) biosynthesis. Mutual transcriptional regulation among these MYB genes makes it difficult to elucidate their individual function simply by analyzing knock-out mutants or ectopically overexpressing lines of these genes. In this study, we constructed transgenic lines expressing each MYB gene driven by its own promoter in the myb28myb29 background, where the expression of the endogenous MYB28, MYB29 and MYB76 was repressed with no AGSL accumulation. In leaves, transgenic MYB28 expression activated AGSL biosynthetic genes and restored accumulation of AGSLs with short side chains. Transgenic MYB29 expression activated the same biosynthetic pathway, but induction of the genes involved in side chain elongation was weaker than that by MYB28, resulting in a weaker recovery of AGSLs. Neither MYB28 nor MYB29 recovered long-chain AGSL accumulation. MYB76 was considered to require both MYB28 and MYB29 for its normal level of expression in leaves, and could not activate AGSL biosynthesis on its own. Interestingly, the accumulation in seeds of long- and short-chain AGSLs was restored by transgenic expression of MYB28 and MYB76, respectively. A sulfur stress experiment indicated that MYB28 expression was induced by sulfur deficiency, while the expression levels of MYB29 and MYB76 were positively correlated with sulfur concentration. This study illustrated how the individual MYBs work in regulating AGSL biosynthesis when expressed alone under normal transcriptional regulation. PMID- 23792304 TI - Act now for a richer journal experience. PMID- 23792305 TI - Combined effect of comfort and adverse events on contact lens performance. AB - PURPOSE: To report the performance of various contact lenses and lens care solution combinations based on the combined response of subjective comfort and adverse events (AEs). METHODS: A retrospective analysis of 28 lens/solution combinations each tested on approximately 40 participants who wore their assigned combination on a daily wear basis and were followed for a 3-month period, with visits at baseline, 2 weeks, and 1 and 3 months. Lenses included frequent replacement and daily disposables. Solutions included hydrogen peroxide and multipurpose types. Subjective comfort (scale of 1 to 10) and AEs were collected and reported as a group mean and percentage, respectively. The data were converted into a ratio between 0 and 1 to represent the relative performance within the combination series, with a higher ratio indicating better performance in both AE rates and comfort. RESULTS: The overall AE rate was 3.6 events per 100 participant-months (95% confidence interval [95% CI], 2.7 to 4.7%). The rate was found to be lower in daily disposables compared with that in daily wear lenses (3.1 vs. 10.9%, p < 0.001). The overall comfort on insertion rating was 8.3 (95% CI, 8.1 to 8.4), and comfort at end of day was 7.2 (95% CI, 7.0 to 7.4). Based on the 28 lens/solution combinations, there was no significant correlation between overall AE rates and comfort on insertion or at end of day (Pearson correlation, 0.34, p = 0.08; and Pearson correlation, -0.23, p = 0.25, respectively). Less than 18% of the combinations tested combined good comfort with low AE rates. CONCLUSIONS: Both subjective comfort responses and AE rates varied according to the combination of lens type and care system in use. The combinations with the best comfort ratings did not necessarily have a favorable AE rate. Practitioners can maximize behavior with respect to both these factors by choosing an appropriate care system for the lenses they prescribe. PMID- 23792309 TI - Designing a medication cart and computerized chart on a budget. PMID- 23792308 TI - The morbidity of oral mucosal lesions in an adult Swedish population. AB - OBJECTIVE: To study the severity of symptoms and estimate the prevalence of oral mucosal lesions in a non-referral adult Swedish population, as registered by general dental practitioners. This study also aims to evaluate the possibility of dental practitioners collecting large quantities of reliable and accurate clinical data on oral mucosal lesions. STUDY DESIGN: Data from 6,448 adult Swedish patients were collected by general dental practitioners using a standardized registration method. A correlation analysis between a group with oral mucosal lesions and a control group, with no oral mucosal lesions, was performed for various parameters such as symptoms from the oral mucosa, systemic diseases, medication, allergy history, tobacco habits and the patient's own assessment of their general health. In addition, clinical photos were taken of all oral mucosal lesions in order to determine the degree of agreement between the diagnoses made by general dental practitioners and those made by oral medicine specialists. RESULTS: A total of 950 patients (14.7%) presented with some type of oral mucosal lesion and of these, 141 patients (14.8%) reported subjective symptoms. On a visual analogue scale, 43 patients (4.5%) scored their symptoms <30, 65 patients (6.8%) scored their symptoms >=30, and 28 patients (2.6%) scored their symptoms >=60. The most debilitating condition was aphthous stomatitis and the most common oral mucosal lesion was snuff dipper's lesion (4.8%), followed by lichenoid lesions (2.4%) and geographic tongue (2.2%). There was agreement between the oral medicine specialists and the general practitioners over the diagnosis of oral mucosal lesions on the basis of a clinical photograph in 85% of the cases (n=803). CONCLUSIONS: Nearly 15% of the patients with oral mucosal lesions reported symptoms. General practitioners could contribute significantly to the collection of large quantities of reliable and accurate clinical data, although there is a risk that the prevalence of oral mucosal lesions may be underestimated. PMID- 23792310 TI - Interview with Holly Miller, MS, BSN RN: Utah Nursing Informatics Network. Interview by Joyce Sensmeier. PMID- 23792312 TI - The administration of a polyvalent mechanical bacterial lysate in elderly patients with COPD results in serological signs of an efficient immune response associated with a reduced number of acute episodes. AB - The administration of a polyvalent mechanical bacterial lysate (PMBL) in elderly patients with COPD has been shown to reduce the number of exacerbation. This is largely related to the involvement of cells belonging to the innate and the adaptive immune system (including dendritic cells, granulocytes, T and B lymphocytes and NK cells) that actively cooperate inducing the production of specific opsonizing antibodies directed to the antigens of PMBL. We have evaluated the production of antibodies directed to respiratory and systemic pathogens in a group of elderly COPD patients, recruited in a clinical trial, ancillary to a larger multicenter double blind, placebo-controlled, parallel designed clinical trial in which patients were randomized to daily receive either PMBL or placebo. The treated group not only experienced a reduced number of seroconversion, but also, better controlled the number of infectious episodes and COPD exacerbations. It was thus evident that the administration of PMBL resulted not only effective in inducing the secretion of specific antibodies, but also effective in reducing the infectious episodes trough the potentiation of the antibody-mediated arm of the immune response. PMID- 23792314 TI - Species persistence in landscapes with spatial variation in habitat quality: a pair approximation model. AB - Habitat degradation has become a major threat to species persistence. Although several models have explicitly integrated habitat quality into metapopulation dynamics, we still lack knowledge of the spatial variability of species persistence which may result from the clustering of habitat patches of differing quality. Here we construct both pair approximation (PA) and cellular automaton (CA) models for species persistence in homogeneous versus heterogeneous landscapes. Heterogeneous landscapes are generated by varying the orthogonal neighbour correlation between two different-quality habitats. In our simulations, the PA model exhibits similar population dynamics to the CA model, though it overestimates species persistence due to the doublet approximation neglecting correlation beyond nearest neighbours. Generally, landscape heterogeneity enhances species persistence relative to landscape homogeneity, especially with enlarging habitat-quality difference. This indicates that models based on homogeneous landscapes may overestimate species extinction rate. In heterogeneous landscapes, habitat clumping does not influence global dispersers because of random establishment, although it does promote the persistence of local dispersers, especially under severe habitat degradation. However, habitat configurational fragmentation improves the persistence of global dispersers that are highly sensitive to local crowding, probably by reducing density dependence, but this positive fragmentation effect on local dispersers is overshadowed by the stronger negative border effect on impeding local extension. Furthermore, increasing density dependence promotes the extinction risk of local dispersers, while global dispersers are not influenced. For conservation and habitat management, our results suggest that minimising random anthropogenic disturbance should take priority over increasing the connectivity of good-quality habitat, as random habitat degradation poses a more serious threat to species persistence than clustered habitat degradation. Owing to species' diverse responses to habitat configurational fragmentation, landscapes with different properties may accommodate different species. PMID- 23792315 TI - Synthesis, self-aggregation and biological properties of alkylphosphocholine and alkylphosphohomocholine derivatives of cetyltrimethylammonium bromide, cetylpyridinium bromide, benzalkonium bromide (C16) and benzethonium chloride. AB - A series of alkylphosphocholine and alkylphosphohomocholine derivatives of cetyltrimethylammonium bromide, cetylpyridinium bromide, benzalkonium bromide (C16) and benzethonium chloride have been synthesized. Their physicochemical properties were also investigated. The critical micelle concentration (cmc), the surface tension value at the cmc (gammacmc), and the surface area at the surface saturation per head group (Acmc) were determined by means of surface tension measurements. The prepared compounds exhibit significant cytotoxic, antifungal and antiprotozoal activities. Alkylphosphocholines and alkylphosphohomocholines possess higher antifungal activity against Candida albicans in comparison with quaternary ammonium compounds in general. However, quaternary ammonium compounds exhibit significantly higher activity against human tumor cells and pathogenic free-living amoebae Acanthamoeba lugdunensis and Acanthamoeba quina compared to alkylphosphocholines. The relationship between structure, physicochemical properties and biological activity of the tested compounds is discussed. PMID- 23792316 TI - Design, synthesis and preliminary evaluation of a series of histone deacetylase inhibitors carrying a benzodiazepine ring. AB - A series of new histone deacetylase inhibitors were designed and synthesized based on hybridization between SAHA or oxamflatin and 5-phenyl-1,4 benzodiazepines. The compounds were tested for their enzyme inhibitory activity on HeLa nuclear extracts, and on human recombinant HDAC1 and HDAC6. Antiproliferative activity was tested on different cancer cells types, while proapoptotic activity was primarily tested on NB4 cells. The compounds showed IC50 values similar to those of SAHA. Compound (S)-8 displayed interesting activity against hematological and solid malignancies. PMID- 23792317 TI - Synthesis and bioevaluation of novel 4-aminoquinoline-tetrazole derivatives as potent antimalarial agents. AB - A series of novel tetrazole derivatives of 4-aminoquinoline were synthesized and screened for their antimalarial activities against both chloroquine-senstive (3D7) and chloroquine-resistant (K1) strains of Plasmodium falciparum as well as for cytotoxicity against VERO cell lines. Most of the synthesized compounds exhibited potent antimalarial activity as compared to chloroquine against K1 strain. Compounds with significant in vitro antimalarial activity were then evaluated for their in vivo efficacy in Swiss mice against Plasmodium yoelii following both intraperitoneal (ip) and oral administration, wherein compounds 20 and 23 each showed in vivo suppression of 99.99% parasitaemia on day 4. PMID- 23792318 TI - Nitric oxide donating anilinopyrimidines: synthesis and biological evaluation as EGFR inhibitors. AB - To search for potent nitric oxide (NO) donating epidermal growth factor receptor (EGFR) inhibitors, a series of phenylsulfonylfuroxan-based anilinopyrimidines 10a h were synthesized and biologically evaluated. Compounds 10f-h exhibited potent inhibitory activity against EGFR L858R/T790M and were as potent as WZ4002 in inhibition of H1975 cells harboring EGFR L858R/T790M. Additionally, 10h produced high levels of NO in H1975 cells but not in normal human cells, and its antiproliferative activity was diminished by hemoglobin, an NO scavenger. Furthermore, 10h inhibited EGFR activation and downstream signaling in H1975 cells. These results suggest that the strong antiproliferative activity of 10h could be attributed to the synergic effects of high levels of NO production and inhibition of EGFR and downstream signaling in the cancer cells. PMID- 23792319 TI - Synthesis and biological screening of 5-(alkyl(1H-indol-3-yl))-2-(substituted) 1,3,4-oxadiazoles as antiproliferative and anti-inflammatory agents. AB - A series of 5-(alkyl(1H-indol-3-yl))-2-(substituted)-1,3,4-oxadiazoles were efficiently synthesized by oxidative cyclisation of N'-benzylidene-(1H-indol-3 yl)alkane hydrazides using di(acetoxy)iodobenzene. N'-Benzylidene-(1H-indol-3 yl)alkane hydrazides themselves were derived from simple indole-3-carboxylic acids. The 5-(alkyl(1H-indol-3-yl))-2-(substituted)-1,3,4-oxadiazoles were evaluated for their anti-inflammatory and anti-proliferative activities. Based on the results obtained structure and activity relationship (SAR) was established and a correlation between the activities was observed. Compound 6i and 6t showed best activity against proliferation of human cancer cell lines and as well as inflammation of rat paw edema. PMID- 23792320 TI - Unveiling the mode of action of antibacterial labdane diterpenes from Alpinia nigra (Gaertn.) B. L. Burtt seeds. AB - The labdane diterpene, (E)-labda-8(17), 12-diene-15, 16-dial (compound A) and its epoxide analogue, (E)-8beta, 17-Epoxylabd-12-ene-15, 16-dial (compound B) were isolated from the seeds of Alpinia nigra for the first time. The antibacterial activities of both compounds were evaluated against three Gram-positive and four Gram-negative bacteria, and flow cytometric analysis revealed that these compounds caused significant damage to the bacterial cell membranes. Further, field emission scanning electron microscope imaging and cell leakage analysis confirmed that the labdane diterpenes were responsible for bacterial cell membrane damage and disintegration. Our findings provide new insight into the broad-spectrum effects of two natural labdane diterpenes that may be useful in the future development of herbal antibiotic products. PMID- 23792321 TI - Regioselective synthesis, characterization and antimicrobial evaluation of S glycosides and S,N-diglycosides of 1,2-Dihydro-5-(1H-indol-2-yl)-1,2,4-triazole-3 thione. AB - Glycosylation of 1,2-Dihydro-5-(1H-indol-2-yl)-1,2,4-triazole-3-thione with 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide, 2,3,4,6-tetra-O-acetyl alpha-D-galactopyranosyl bromide and 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-alpha D-glucopyranosyl chloride was investigated in the presence of Et3N and K2CO3 as acid scavengers. A regioselective S-glycosides were obtained by using Et3N whereas, using K2CO3 gave a mixtures of two hybrids having two glycosidic bonds. The two products of each mixture were separated and characterized as S,N(1)- and S,N(2)-bis(glycosylated) derivatives. The structures of the newly synthesized compounds were elucidated by (1)H NMR, (13)C NMR, 2D NMR and mass spectra. The compounds were screened for their antibacterial and antifungal activities. Some compounds exhibited strong inhibition activity compared with the reference drugs (chloramphenicol and baneocin). PMID- 23792322 TI - Neuroprotection of S-nitrosoglutathione against ischemic injury by down regulating Fas S-nitrosylation and downstream signaling. AB - S-nitrosoglutathione (GSNO) has been reported to protect against ischemic brain injury, however, the underlying mechanisms remain to be elucidated. In the present study, we aimed to investigate the effects of GSNO pre-treatment on the S nitrosylation of Fas and subsequent events in the Fas pathway, and reveal the correlation between Fas S-nitrosylation and nNOS activation in the rat hippocampal CA1 region after global cerebral ischemia. The results showed that GSNO pre-treatment not only facilitated the survival of hippocampal CA1 pyramidal neurons, but also abolished the activation of pro-apoptotic Caspase-8, Bid, Caspase-9 and Caspase-3. The S-nitrosylation of Fas increased sustainedly after global ischemia, and GSNO blocked such an increase. Global cerebral ischemia/reperfusion promoted the binding between neuronal nitric oxide synthase (nNOS) and postsynaptic density protein 95 that has been reported to activate nNOS, and GSNO inhibited the post-ischemic nNOS activation and NO release. A selective nNOS inhibitor 7-nitroindazole diminished the ischemia/reperfusion induced Fas S-nitrosylation, suggesting a critical role of endogenous NO from nNOS activation in Fas S-nitrosylation. In addition, pre-administration of GSNO decreased the translocation of Fas to membrane, the formation of CD95(hi) on the membrane, the internalization of Fas aggregates to plasma, as well as the assembly of DISC/hiDISC. These results indicate that GSNO-induced nNOS inactivation associates with the down-regulation of Fas S-nitrosylation and consequent Fas signal cascade, which is responsible for the GSNO-mediated neuronal survival after brain ischemia. The understanding of GSNO neuroprotection provides a novel strategy to find potential therapeutic targets for ischemic stroke. PMID- 23792323 TI - Differential effects of GH and GH-releasing peptide-6 on astrocytes. AB - GH and GH secretagogues (GHSs) are involved in many cellular activities such as stimulation of mitosis, proliferation and differentiation. As astrocytes are involved in developmental and protective functions, our aim was to analyse the effects of GH and GH-releasing hexapeptide on astrocyte proliferation and differentiation in the hypothalamus and hippocampus. Treatment of adult male Wistar rats with GH (i.v., 100 MUg/day) for 1 week increased the levels of glial fibrillary acidic protein (GFAP) and decreased the levels of vimentin in the hypothalamus and hippocampus. These changes were not accompanied by increased proliferation. By contrast, GH-releasing hexapeptide (i.v., 150 MUg/day) did not affect GFAP levels but increased proliferation in the areas studied. To further study the intracellular mechanisms involved in these effects, we treated C6 astrocytoma cells with GH or GH-releasing hexapeptide and the phosphatidylinositol 3'-kinase (PI3K) inhibitor, LY294002, and observed that the presence of this inhibitor reverted the increase in GFAP levels induced by GH and the proliferation induced by GH-releasing hexapeptide. We conclude that although GH-releasing hexapeptide is a GHS, it may exert GH-independent effects centrally on astrocytes when administered i.v., although the effects of both substances appear to be mediated by the PI3K/Akt pathway. PMID- 23792324 TI - The distribution of cigarette prices under different tax structures: findings from the International Tobacco Control Policy Evaluation (ITC) Project. AB - BACKGROUND: The distribution of cigarette prices has rarely been studied and compared under different tax structures. Descriptive evidence on price distributions by countries can shed light on opportunities for tax avoidance and brand switching under different tobacco tax structures, which could impact the effectiveness of increased taxation in reducing smoking. OBJECTIVE: This paper aims to describe the distribution of cigarette prices by countries and to compare these distributions based on the tobacco tax structure in these countries. METHODS: We employed data for 16 countries taken from the International Tobacco Control Policy Evaluation Project to construct survey-derived cigarette prices for each country. Self-reported prices were weighted by cigarette consumption and described using a comprehensive set of statistics. We then compared these statistics for cigarette prices under different tax structures. In particular, countries of similar income levels and countries that impose similar total excise taxes using different tax structures were paired and compared in mean and variance using a two-sample comparison test. FINDINGS: Our investigation illustrates that, compared with specific uniform taxation, other tax structures, such as ad valorem uniform taxation, mixed (a tax system using ad valorem and specific taxes) uniform taxation, and tiered tax structures of specific, ad valorem and mixed taxation tend to have price distributions with greater variability. Countries that rely heavily on ad valorem and tiered taxes also tend to have greater price variability around the median. Among mixed taxation systems, countries that rely more heavily on the ad valorem component tend to have greater price variability than countries that rely more heavily on the specific component. In countries with tiered tax systems, cigarette prices are skewed more towards lower prices than are prices under uniform tax systems. The analyses presented here demonstrate that more opportunities exist for tax avoidance and brand switching when the tax structure departs from a uniform specific tax. PMID- 23792325 TI - Euromonitor data on the illicit trade in cigarettes. PMID- 23792326 TI - Heavy metal hazards of Nigerian smokeless tobacco. AB - BACKGROUND: Interest is rising in smokeless tobacco as a safer alternative to smoking. Information on the heavy metal hazards of smokeless tobacco is sparse in Nigeria, as it is in most sub-Saharan Africa countries. This study assesses the heavy metal hazards of the smokeless tobacco types commonly available in Nigeria. METHODS: Using a market basket protocol 30 Nigerian smokeless tobacco types were studied. Digestion was performed by addition of 10 mL of a mix of nitric and hydrochloric acids (HCl:HNO3, 3:1); the mixture was then heated to dryness. Then, 20 mL deionised water was added, and the mixture stirred and filtered. The filtrate was made up in a standard volumetric flask and lead, cadmium, chromium, cobalt and nickel concentrations were assayed with atomic absorption spectrophotometry at 205 A. The daily intake and target hazard quotient (THQ) were calculated. RESULTS: Chromium, cobalt and nickel concentrations ranged from 2.77-11.40, 0.01-0.03 and 0.02-0.07 MUg/g, respectively, whereas lead and cadmium ranged from 0.00-2.48 and 0.01-0.17 MUg/g, respectively. The daily intake of chromium, cobalt and nickel ranged from 277-1140, 1-3 and 2 to 7 MUg/day, respectively. Lead and cadmium daily intakes ranged from 0-248 and 1-17 MUg/day, respectively. CONCLUSIONS: Although there was no apparent risk when each metal was analysed and considered individually, the potential risk could be multiplied when considering all heavy metals. The high heavy metal content in Nigerian smokeless tobacco may have public health implications. PMID- 23792327 TI - Species-specific effects of pigmentation negation on the neural response to faces. AB - Face processing is limited in scope as a function of experience - discrimination ability and face-specific behavioral effects are reduced in out-group faces. Nonetheless, other-species faces phylogenetically close to our own may be processed by similar mechanisms as human faces. Presently, we asked whether or not the well-known effect of contrast-negation on face recognition (Galper, 1970) was exclusive to human faces or generalized to monkey faces. Negation disrupts face pigmentation substantially, allowing us to examine species-specific use of surface cues as a function of expertise. We tested adult observers behaviorally and electrophysiologically: participants completed a 4AFC discrimination task subject to manipulations of face species and independent negation of image luminance and image chroma, and the same stimuli were used to collect event related potentials in a go/no-go task. We predicted that expertise for human faces would lead to larger deleterious effects of negation for human faces in both tasks, reflected in longer RTs for correct responses in the discrimination task and species-specific modulation of the N170 and P200 by contrast-negation. Our results however, indicate that behaviorally, luminance and chroma negation affect discrimination performance in a species-independent manner, while similar effects of contrast-negation effects are evident in each species at different components of the ERP response. PMID- 23792328 TI - Impaired vitality form recognition in autism. AB - Along with the understanding of the goal of an action ("what" is done) and the intention underlying it ("why" it is done), social interactions largely depend on the appraisal of the action from the dynamics of the movement: "how" it is performed (its "vitality form"). Do individuals with autism, especially children, possess this capacity? Here we show that, unlike typically developing individuals, individuals with autism reveal severe deficits in recognizing vitality forms, and their capacity to appraise them does not improve with age. Deficit in vitality form recognition appears, therefore, to be a newly recognized trait marker of autism. PMID- 23792329 TI - Dengue virus capsid protein interacts specifically with very low-density lipoproteins. AB - Dengue affects millions of people worldwide. No specific treatment is currently available, in part due to an incomplete understanding of the viral components' interactions with host cellular structures. We tested dengue virus (DENV) capsid protein (C) interaction with low- and very low-density lipoproteins (LDL and VLDL, respectively) using atomic force microscopy-based force spectroscopy, dynamic light scattering, NMR and computational analysis. Data reveal a specific DENV C interaction with VLDL, but not LDL. This binding is potassium-dependent and involves the DENV C N-terminal region, as previously observed for the DENV C lipid droplets (LDs) interaction. A successful inhibition of DENV C-VLDL binding was achieved with a peptide drug lead. The similarities between LDs and VLDL, and between perilipin 3 (DENV C target on LDs) and ApoE, indicate ApoE as the molecular target on VLDL. We hypothesize that DENV may form lipoviroparticles, which would constitute a novel step on DENV life cycle. FROM THE CLINICAL EDITOR: Using atomic force microscopy-based force spectroscopy, dynamic light scattering, NMR, and computational analysis, these authors demonstrate that dengue viral capsid proteins (DENV C) bind to very low density lipoprotein surfaces, but not to LDLs, in a potassium-dependent manner. This observation suggests the formation of lipo-viroparticles, which may be a novel step in its life cycle, and may offer potential therapeutic interventions directed to this step. PMID- 23792330 TI - In vitro angiogenic performance and in vivo brain targeting of magnetized endothelial progenitor cells for neurorepair therapies. AB - Endothelial progenitor cells (EPCs) represent a promising approach for cell-based therapies to induce tissue repair; however, their effective delivery into the brain has remained a challenge. We loaded EPCs with superparamagnetic iron oxide nanoparticles (SPIONs), assessed their angiogenic potential and evaluated their guidance to the brain using an external magnet. SPIONs were stored in the cytoplasm within endosomes/lysosomes as observed by transmission electron microscopy (TEM) and could be visualized as hypointense signals by magnetic resonance imaging (MRI) T2-weighted images. In vitro SPION-loaded EPCs were fully functional, forming vessel-like structures in Matrigel(r), and displayed enhanced migration and secretion of growth factors (VEGF and FGF), which was associated with a moderate increase in reactive oxygen species production. Furthermore, in vivo MRI of treated mice showed accumulated hypointense signals consistent with SPION-loaded EPCs engraftment. Thus, we demonstrate that loading EPCs with SPIONs represents a safe and effective strategy for precise cell guidance into specific brain areas. FROM THE CLINICAL EDITOR: This study investigates the potential role of endothelial progenitor cells in neuro-repair strategies of the central nervous system using SPION-loaded EPCs and magnetic guidance to the target organ. The authors demonstrate ex vivo cellular viability and maintained function following SPION load as well as successful guidance of the EPCs to the target site via MR imaging in a murine model. PMID- 23792331 TI - Design and development of nanocomposite scaffolds for auricular reconstruction. AB - Auricular reconstruction using sculpted autologous costal cartilage is effective, but complex and time consuming and may incur donor site sequelae and morbidity. Conventional synthetic alternatives are associated with infection and extrusion in up to about 15% of cases. We present a novel POSS-PCU nanocomposite auricular scaffold, which aims to reduce extrusion rates by mimicking the elastic modulus of human ears and by encouraging desirable cellular interactions. The fabrication, physicochemical properties (including nanoscale topography) and cellular interactions of these scaffolds were compared to Medpor(r), the current synthetic standard. Our scaffold had a more similar elastic modulus (5.73 +/- 0.17MPa) to ear cartilage (5.02 +/- 0.17MPa) compared with Medpor(r), which was much stiffer (140.9 +/- 0.04MPa). POSS-PCU supported fibroblast ingrowth and proliferation; significantly higher collagen production was also produced by cells on the POSS-PCU than those on Medpor(r). This porous POSS-PCU nanocomposite scaffold is therefore a promising alternative biomaterial for auricular surgical reconstruction. FROM THE CLINICAL EDITOR: In this paper, a novel POSS-PCU nanocomposite auricular scaffold is described to reduce extrusion rates by having a much closer elastic modulus of human ears than the currently available synthetic standard. Enabling desirable cellular interactions may lead to the successful clinical application of these novel scaffolds. PMID- 23792332 TI - Is feedback control effective for ecosystem-based fisheries management? AB - We investigate the effects of species interactions on the robustness of feedback control of the harvesting of prey species. We consider the consequences of feedback control of fishing effort. If a prey species is exploited, increasing fishing effort decreases predator abundance more than it does the prey abundance. Feedback control of fishing effort may cause the extinction of the predator, even if the prey population is well controlled. Even when fishing effort is controlled by predator density, it is difficult for the fishery and the predator to coexist, and, if they do so, the system exhibits complex dynamic behaviors. If the predator and fishery coexist, feedback control of fishing effort converges to a stable equilibrium, a synchronous cycle, or an asynchronous cycle. In the last case, the system undergoes more complex cycling with a longer period than that when the fishing effort is kept constant. These analyses suggest that there is no effective strategy that is robust against measurement errors, process errors and complex interactions in ecosystem dynamics. PMID- 23792333 TI - Epidural dirofilariosis in a paraparetic cat: case report of Dirofilaria immitis infection. AB - A 6-year-old neutered female cat was examined for chronic and progressive pelvic limb ataxia that progressed to non-ambulatory paraparesis over 1 month. Haematological and serum analyses were mainly within normal ranges. Thoracic and abdominal radiographs did not reveal any morphological abnormalities. Magnetic resonance imaging investigation of the thoraco-lumbar spine demonstrated a well defined, extradural mass that extended into the epidural space from the L2 to L3 vertebral bodies and expanded in the L2 to L3 left intervertebral foramen. During surgery, a long, narrow, white parasite which was weakly adherent to the phlogistic epidural fat tissue was gently removed from the spinal canal. Histological examination of the pathological tissue supported a diagnosis of epidural steatitis surrounding a female adult Dirofilaria immitis. This is a novel case of natural D immitis infection with spinal localisation in a cat, well documented with magnetic resonance investigation, and cytological and histological examinations, introducing a novel differential diagnosis for extradural spinal masses in cats. PMID- 23792334 TI - Molecular imaging in the development of a novel treatment paradigm for glioblastoma (GBM): an integrated multidisciplinary commentary. AB - Current therapeutic strategies against glioblastoma (GBM) have failed to prevent disease progression and recurrence effectively. The part played by molecular imaging (MI) in the development of novel therapies has gained increasing traction in recent years. For the first time, using expertise from an integrated multidisciplinary group of authors, herein we present a comprehensive evaluation of state-of-the-art GBM imaging and explore how advances facilitate the emergence of new treatment options. We propose a novel next-generation treatment paradigm based on the targeting of multiple hallmarks of cancer evolution that will heavily rely on MI. PMID- 23792335 TI - Evolution of cell culture systems for HCV. AB - Many challenges exist for the study of HCV in the laboratory. Therapy using interferon (IFN) is expensive, not well tolerated and ineffective for many patients. HCV research has been hampered by the lack of a robust tissue culture system, but recent advances have made virus growth in culture possible. Cell culture systems using genetically engineered viruses have been reviewed extensively, but here we review recent advances made in the use of natural isolates and the molecular challenges that have been used to overcome the limitations in their growth. Six major genotypes have been identified for HCV that are further divided into numerous subtypes. Combination therapy utilizing IFN-alpha and ribavirin is the standard of care, but is successful in only one half of patients. The reasons for IFN resistance may be viral- or host-related and may be due to multiple factors. Recently, telaprevir and boceprevir, together with IFN-alpha and ribavirin, have been added to the standard of care in patients infected with IFN-resistant genotypes. A major obstacle in the development of effective vaccines and improved therapeutics has been the lack of a reproducible and efficient tissue culture system for propagation of HCV. Many cell culture systems have used genetically-engineered viruses to gain growth in culture through the use of replicons, but recent advances using natural isolates may improve the outlook for progress in HCV research. PMID- 23792336 TI - Plasma leptin inhibits the response of nucleus of the solitary tract neurons to aortic baroreceptor stimulation. AB - Leptin receptors have been identified within the nucleus of the solitary tract (NTS) and leptin injections into the caudal NTS inhibit the baroreceptor reflex. However, whether plasma leptin alters the discharge of NTS neurons mediating aortic baroreceptor reflex activity is not known. A series of electrophysiological single unit recording experiments was done in the urethane chloralose anesthetized, paralyzed and artificially ventilated Wistar and Zucker obese rat with either their neuroaxis intact or with mid-collicular transections. Single units in NTS antidromically activated by electrical stimulation of depressor sites in the caudal ventrolateral medulla (CVLM) were found to display a cardiac cycle-related rhythmicity. These units were tested for their responses to stimulation of the aortic depressor nerve (ADN) and intra-carotid injections of leptin (50-200ng/0.1ml). Of 63 single units tested in NTS, 33 were antidromically activated by stimulation of CVLM depressor sites and 18 of these single units responded with a decrease in discharge rate after intracarotid injections of leptin. Thirteen of these leptin responsive neurons (~72%) were excited by ADN stimulation. Furthermore, the excitatory response of these single units to ADN stimulation was attenuated by about 50% after the intracarotid leptin injection. Intracarotid injections of leptin (200ng/0.1ml) in the Zucker obese rat did not alter the discharge rate of NTS-CVLM projecting neurons. These data suggest that leptin exerts a modulatory effect on brainstem neuronal circuits that control cardiovascular responses elicited during the reflex activation of arterial baroreceptors. PMID- 23792337 TI - Long-term testosterone supplementation is useful for ED with testosterone deficiency. PMID- 23792338 TI - Androgen receptors expressed by prostatic stromal cells obtained from younger versus older males exhibit opposite roles in prostate cancer progression. AB - Aging is a major risk factor for prostate cancer (PCa), and prostatic stromal cells may also promote PCa progression. Accordingly, stromal cells do not equally promote PCa in older males and younger males. Therefore, it is also possible that the expression of androgen receptors (ARs) by prostatic stromal cells in older versus younger males plays different roles in PCa progression. Using a gene knockdown technique and coculture system, we found that the knockdown of the AR in prostatic stromal cells obtained from younger males could promote the invasiveness and metastasis of cocultured PC3/LNCaP cells in vitro. By contrast, the invasiveness and metastasis of LNCaP cells was inhibited when cocultured with prostatic stromal cells from older males that when AR expression was knocked down. Moreover, after targeting AR expression with small hairpin RNA (shRNA), matrix metalloproteinase (MMP) expression in stromal cells was observed to increase in the younger group, but decreased or remained unchanged in the older group. One exception, however, was observed with MMP9. In vivo, after knocking down AR expression in prostatic stromal cells, the incidence of metastatic lymph nodes was observed to increase in the younger age group, but decreased in the older age group. Together, these data suggest that the AR in prostatic stromal cells played opposite roles in PCa metastasis for older versus younger males. Therefore, collectively, the function of the AR in prostatic stromal cells appears to change with age, and this may account for the increased incidence of PCa in older males. PMID- 23792339 TI - Resveratrol, an activator of SIRT1, restores erectile function in streptozotocin induced diabetic rats. AB - The high incidence of erectile dysfunction (ED) in diabetes highlights a need for effective treatment strategies. Resveratrol, an activator of silent information regulator 2-related enzymes 1 (sirtuin1, SIRT1), has received attention for its valuable effects in cancer, neurodegenerative diseases, longevity and cardiovascular disease. To explore the effects of resveratrol in diabetes-induced ED, resveratrol was administered to rats with streptozocin (65 mg kg(-1))-induced diabetes. Erectile function, cavernous structure, tissue protein expression of silent information regulator 2-related enzymes 1 (sirtuin1, SIRT1), p53 and forkhead transcription factor O 3a (FOXO3a), superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels in the corpora cavernosa were studied. We found that SIRT1 was expressed in cavernosal tissue, and it was downregulated in the corpora of diabetic rats. The administration of resveratrol upregulated the expression of SIRT1 and restored erectile function. In contrast, resveratrol downregulated the expression of p53 and FOXO3a, which regulate apoptosis and oxidative stress. Furthermore, the resveratrol-treated group showed an improvement in smooth muscle content, SOD activity and MDA levels when compared with the diabetic group. Therefore, the ability of resveratrol to improve diabetes-induced ED is likely related to its activation of SIRT1 expression, thus causing the suppression of apoptosis and resistance towards oxidative stress. PMID- 23792340 TI - Is V-Y plasty necessary for penile lengthening? Girth enhancement and increased length solely through circumcision: description of a novel technique. AB - Our objective is to describe a novel ligamentolysis approach using a subcoronal incision technique and to determine its safety and efficacy. During the last 7 years, 82 consecutive patients had penile augmentation surgery. Ligamentolysis, through a lower abdominal incision (V-Y plasty) in the first 35 males, was performed (Group A), followed by circumcision ligamentolysis in the next 47 males (Group B). The operation time, complications, and the preoperative and postoperative values of penile length and girth along with the self-esteem and relations questionnaire score as well as satisfaction score was calculated before and after the surgery, and a comparison was conducted between the groups. The mean age at presentation was 32 years (range: 18-56 years). Seventy-nine patients suffered from penile dysmorphophobia, and three patients had micropenises (length <7.5 cm). The mean surgical times were 150.7 and 125.2 min for Groups A and B, respectively (P=0.005). Postoperatively, four Group A patients and three Group B patients (11% versus 6%, respectively) experienced penile retraction (P=0.453). Hypertrophic scars were observed in 18 men (51%) in the former [corrected] group. In the circumcision group, no major wound complications were recorded. The length and girth improvements between the groups were similar. In terms of satisfaction and SEAR improvement, the resulting difference for both variables favored the circumcision group (P=0.007 and <0.001, respectively). With strict selection criteria, the circumcision ligamentolysis procedure compared to the V-Y plasty demonstrated improved results in terms of safety, operation time, retraction rate and cosmetic appearance without any compromise in the gained penile size. PMID- 23792341 TI - Obesity leads to higher risk of sperm DNA damage in infertile patients. AB - There has been a growing interest over the past few years in the impact of male nutrition on fertility. Infertility has been linked to male overweight or obesity, and conventional semen parameter values seem to be altered in case of high body mass index (BMI). A few studies assessing the impact of BMI on sperm DNA integrity have been published, but they did not lead to a strong consensus. Our objective was to explore further the relationship between sperm DNA integrity and BMI, through a 3-year multicentre study. Three hundred and thirty male partners in subfertile couples were included. Using the terminal uridine nick-end labelling (TUNEL) assay, we observed an increased rate of sperm DNA damage in obese men (odds ratio (95% confidence interval): 2.5 (1.2-5.1)). PMID- 23792343 TI - Prognostic factors for pain relief and functional improvement in chronic pain after inpatient rehabilitation. AB - OBJECTIVE: To determine the factors associated with pain relief and improved physical functioning in chronic pain patients during outpatient management in the first 5 months immediately after a standardized inpatient pain management program. METHODS: Prospective cohort study using standardized questionnaires on sociodemographic data, disease outcome, psychosocial factors, change in behavior, and outpatient therapies on discharge from inpatient rehabilitation and during the 5-month follow-up at home (observation period). Stepwise forward multivariate linear regression analysis examined the correlation of these factors with change in pain severity and change in physical functioning. RESULTS: The study included 80.1% female patients, 90.0% had at least 1 comorbidity and 62.9% had chronic pain for>=5 years. On average, pain intensity and depression worsened slightly during the observation period, but the other outcomes remained almost stable. Relief from anxiety (20.7% explained variance) and low baseline depression (5.5%) were the most important predictors for pain relief. Relief from anxiety (13.3%) and low baseline depression (7.1%) were most strongly associated with functional improvement. CONCLUSIONS: This study found a strong association of change in pain severity and physical functioning with change in baseline level of affective health and coping during the first outpatient management period after inpatient rehabilitation. As a consequence, it may be possible to improve the treatment of chronic pain by therapy of mood and coping. PMID- 23792342 TI - Effects of luteinizing hormone and androgen on the development of rat progenitor Leydig cells in vitro and in vivo. AB - Progenitor Leydig cells are derived from stem cells. The proliferation and differentiation of progenitor Leydig cells significantly contributes to Leydig cell number during puberty. However, the regulation of these processes remains unclear. The objective of the present study was to determine whether luteinizing hormone (LH) or androgen contributes to the proliferation and differentiation of progenitor Leydig cells. Fourteen-day-old male Sprague-Dawley rats were treated for 7 days with NalGlu, which is a gonadotropin-releasing hormone antagonist, to reduce the secretion of LH in the pituitary and thus, androgen in the testis. Rats were co-administered with LH or 7alpha-methyl-nortestosterone (MENT), which is an androgen resistant to metabolism by 5alpha-reductase 1 in progenitor Leydig cells, and the subsequent effects of LH or androgen were measured. (3)H-Thymidine was also intravenously injected into rats to study thymidine incorporation in progenitor Leydig cells. Progenitor Leydig cells were examined. NalGlu administration reduced progenitor Leydig cell proliferation by 83%. In addition, LH or MENT treatment restored Leydig cell proliferative capacity to 73% or 50% of control, respectively. The messenger RNA levels of proliferation-related genes were measured using real-time PCR. The expression levels of Igf1, Lifr, Pdgfra, Bcl2, Ccnd3 and Pcna were upregulated by MENT, and those of Pdgfra, Ccnd3 and Pcna were upregulated by LH. Both LH and MENT stimulated the differentiation of progenitor Leydig cells in vitro. We concluded that both LH and MENT were involved in regulating the development of progenitor Leydig cells. PMID- 23792344 TI - A disturbance in sensory processing on the affected side of the body increases limb pain in complex regional pain syndrome. AB - OBJECTIVES: The aim of this study was to determine whether a central disturbance in somatosensory processing contributes to limb pain in complex regional pain syndrome (CRPS). METHODS: In 37 patients with CRPS, the effect of cooling the ipsilateral forehead on pain in the affected limb was compared with the effect of cooling the contralateral forehead. In addition, symptoms associated with cold evoked limb pain were explored. RESULTS: Limb pain generally increased when the ipsilateral side of the forehead was cooled but did not change when the contralateral side of the forehead was cooled. Increases were greatest in patients with heightened sensitivity to cold, brushing, and pressure-pain in the ipsilateral forehead, in patients with heightened sensitivity to pressure-pain in the limbs, and in patients with chronic symptoms. In contrast, sensitivity to light touch was diminished in the CRPS-affected limb of patients whose limb pain remained unchanged or decreased during ipsilateral forehead cooling. CONCLUSIONS: These preliminary findings suggest that a central disturbance in sensory processing and pain modulation, which extends beyond the affected limb to the ipsilateral forehead, contributes to symptoms in a subgroup of patients with CRPS. PMID- 23792345 TI - Headache associated with temporomandibular disorders among young Brazilian adolescents. AB - OBJECTIVE: To verify whether headaches (HAs) are associated with temporomandibular disorders (TMD) in young Brazilian adolescents. METHODS: From a population sample, 3117 public school children (12 to 14 y) were randomly invited to participate in this study. TMD was assessed according to the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) Axis I, in addition to questions #3, #4, and #14 of Axis II history questionnaire. HAs were investigated with question #18 of RDC/TMD Axis II. Chronic TMD pain was considered as pain that has persisted for 6 months or more, as proposed by the International Association for the Study of Pain. The statistical analysis consisted of chi tests, odds ratio (OR), and logistic regression models, adopting a significance level of 5%. RESULTS: The sample included 1307 individuals (a response rate of 41.93%), and 56.8% (n=742) were girls. Overall, 330 adolescents (25.2%) were diagnosed with painful TMD and 595 (45.5%) presented with HAs. Individuals presenting with HAs were more likely to present painful TMD (OR=4.94; 95% confidence interval [CI], 3.73-6.54, P<0.001), especially combined muscle and joint painful TMD (OR=7.58; 95% CI, 4.77-12.05, P<0.001). HAs also increased the risk to a higher magnitude for chronic TMD pain (OR=6.12; 95% CI, 4.27-8.78, P<0.0001). All estimated ORs remained essentially unchanged after adjusting for sex. DISCUSSION: HAs were a potential risk factor for TMD in adolescents, and the risk was particularly higher for painful and chronic TMD. When HAs are present in young adolescents, a complete examination is strongly recommended with regard to the presence of painful TMD, and vice versa. PMID- 23792346 TI - Relationship between rheumatoid arthritis activity and antithyroid antibodies. AB - INTRODUCTION: Rheumatoid arthritis (RA) is known to be associated with a higher prevalence of antithyroid antibodies and autoimmune thyroid disease, but there have been few studies regarding the correlations between the presence of these antibodies and RA activity. OBJECTIVES: The aim of this study was to analyze the relationship between antithyroid antibody titers and selected parameters of RA activity. PATIENTS AND METHODS: A total of 75 consecutive hospitalized patients with RA were enrolled into the study. Levels of antithyroid peroxidase antibodies (aTPO), antithyroglobulin antibodies (aTG), and antithyrotropin receptor antibodies (aTSH-R) were measured. The analysis of disease activity was based on the disease activity score with 28-joint count (DAS28), duration of morning stiffness, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) and hemoglobin levels. RESULTS: Antithyroid antibodies were present in 13.3% of the patients (n = 10), aTPO in 9.3% (n = 7), aTG in 8% (n = 6), and aTPO and aTG in 4% (n = 3); aTSH-R was not detected in any of the patients. Significant positive correlations (P <0.05) were observed between aTPO and DAS28 (r = 0.35, P = 0.002), aTG and ESR (r = 0.25, P = 0.02), and aTG and CRP (r = 0.23, P = 0.04). There were significant differences in the mean DAS28 between the aTPO-positive and aTPO-negative groups (5.35; 95% confidence interval [CI], 4.39-6.3 vs. 4.12, respectively; 95% Cl, 3.81-4.43; P = 0.017) and between the aTG-positive and aTG negative groups (5.65; 95% Cl: 4.64-6.67 vs. 4.11; 95% Cl: 3.81-4.41; P = 0.005; respectively). CONCLUSIONS: Our results suggest that RA activity may be associated with the presence of antithyroid antibodies. This finding could be useful in the clinical evaluation of RA patients. PMID- 23792347 TI - Feasibility of reducing rabies immunoglobulin dosage for passive immunization against rabies: results of In vitro and In vivo studies. AB - Passive immunization is a crucial parameter for prevention of human rabies. Presently as World Health Organization (WHO) strongly advocates local infiltration of rabies immunoglobulin in and around the bite wound, we feel that there is no basis for calculating the dose of immunoglobulin based on body weight. Keeping this in view we conducted both in vitro and in vivo studies to know whether the dose of immunoglobulin can be reduced and still obtain complete neutralization of the virus. In vitro neutralization studies were conducted using CVS strain of virus and BHK 21 cells. In vivo experiments were conducted in 4 weeks old Swiss albino mice by initial challenge with CVS followed by infiltration with increasing dilutions of either human rabies immunoglobulin (HRIG) and equine rabies immunoglobulin (ERIG). In vitro studies showed that a dose of 100 FFD 50 of CVS was neutralized by increasing dilution of both HRIG and ERIG and 100% neutralization was observed with HRIG and ERIG in as low quantities as 0.025 IU. In mice studies there was 100% survival of mice infiltrated with 0.025 IU of both HRIG and ERIG compared with 100% mortality in mice infiltrated with normal saline. These results suggest that it is possible to reduce the dose of rabies immunoglobulins by at least 16 times the presently advocated dose. These findings needs to be further evaluated using larger animal models and street viruses prevalent in nature but cannot serve as recommendations for use of RIG for passive immunization in humans. PMID- 23792348 TI - Relationship satisfaction among mothers of children with congenital heart defects: a prospective case-cohort study. AB - OBJECTIVE: To assess the level of partner relationship satisfaction among mothers of children with different severity of congenital heart defects (CHD) compared with mothers in the cohort. METHODS: Mothers of children with mild, moderate, or severe CHD (n = 182) and a cohort of mothers of children without CHD (n = 46,782) from the Norwegian Mother and Child Cohort Study were assessed at 5 time points from pregnancy to 36 months postpartum. A 5-item version of the Relationship Satisfaction scale was used, and relevant covariates were explored. RESULTS: The trajectories of relationship satisfaction among mothers of children with varying CHD severity did not differ from the trajectories in the cohort. All women in the cohort experienced decreasing relationship satisfaction from 18 months after delivery up to 36 months after delivery. CONCLUSIONS: Having a child with CHD, regardless of severity, does not appear to exacerbate the decline in relationship satisfaction. PMID- 23792349 TI - Ligand/kappa-opioid receptor interactions: insights from the X-ray crystal structure. AB - During the past five years, the three-dimensional structures of 14 different G protein coupled receptors (GPCRs) have been resolved by X-ray crystallography. The most recently published structures, those of the opioid receptors (ORs), are remarkably important in pain modulation, drug addiction, and mood disorders. These structures, confirmed previously proposed key interactions conferring potency and antagonistic properties, including the well-known interaction with Asp138, conserved in all aminergic GPCRs. In addition, crystallization of the opioid receptors highlighted the potential function of the ECL2 and ICL2 loops. We have previously reported a set of potent and selective kappa opioid receptor peptide agonists, of which ff(D-nle)r-NH2 is among the most potent and selective ones. These peptides were identified from the deconvolution of a 6,250,000 tetrapeptide combinatorial library. A derivative of this set is currently the subject of a phase 2 clinical trial in the United States. In this work, we describe comparative molecular modeling studies of kappa-OR peptide agonists with the co-crystallized antagonist, JDTic, and also report structure-activity relationships of 23 tetrapeptides. The overall binding and contact interactions are sound and interactions known to favor selectivity and potency were observed. Additional modeling studies will reveal conformational changes that the kappa-OR undergoes upon binding to these peptide agonists. PMID- 23792350 TI - Synthesis and pharmacological evaluation of new N-phenylpiperazine derivatives designed as homologues of the antipsychotic lead compound LASSBio-579. AB - In an attempt to increase the affinity of our antipsychotic lead compound LASSBio 579 (1-((1-(4-chlorophenyl)-1H-pyrazol-4-yl)methyl)-4-phenylpiperazine; (2)) for the 5-HT(2A) receptor, we synthesized five new N-phenylpiperazine derivatives using a linear synthetic route and the homologation strategy. The binding profile of these compounds was evaluated for a series of dopaminergic, serotonergic and alpha-adrenergic receptors relevant for schizophrenia, using classical competition assays. Increasing the length of the spacer between the functional groups of (2) proved to be appropriated since the affinity of these compounds increased 3-10-fold for the 5-HT(2A) receptor, with no relevant change in the affinity for the D2-like and 5-HT(1A) receptors. A GTP-shift assay also indicated that the most promising derivative (1-(4-(1-(4-chlorophenyl)-1H-pyrazol-4-yl) butyl)-4-phenylpiperazine) (LASSBio-1635) (6) has the expected efficacy at the 5 HT(2A) receptors, acting as an antagonist. Intraperitoneal administration of (6) prevented apomorphine-induced climbing behavior and ketamine-induced hyperlocomotion in mice, in a dose dependent manner. Together, these results show that (6) could be considered as a new antipsychotic lead compound. PMID- 23792351 TI - Nonclassical antifolates, part 4. 5-(2-aminothiazol-4-yl)-4-phenyl-4H-1,2,4 triazole-3-thiols as a new class of DHFR inhibitors: synthesis, biological evaluation and molecular modeling study. AB - A new series of compounds possessing 5-(2-aminothiazol-4-yl)-4-phenyl-4H-1,2,4 triazole-3-thiol skeleton was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, antitumor and schistosomicidal activities. Four active compounds were allocated, the antibacterial 22 (comparable to gentamicin and ciprofloxacin), the schistosomicidal 29 (comparable to praziquantel), the DHFR inhibitor 34 (IC50 0.03 MUM, 2.7 fold more active than MTX), and the antitumor 36 (comparable to doxorubicin). Molecular modeling studies concluded that recognition with key amino acid Leu4 and Val1 is essential for DHFR binding. Flexible alignment and surface mapping revealed that the obtained model could be useful for the development of new class of DHFR inhibitors. PMID- 23792352 TI - Diversity-oriented synthesis of alpha-aminophosphonates: a new class of potential anticancer agents. AB - A small library of structurally diverse alpha-aminophosphonates has been synthesized by reacting alkyl/aryl aldehydes, alkyl/aryl amines and alkyl/aryl phosphites in one-pot catalyzed by Amberlite-IR 120 resin (acidic). All the synthesized alpha-aminophosphonates were assayed for their in vitro cytotoxic activities against a panel of five human cancer cell lines including A-549, NCI H23 (Lung), Colo 320DM (Colon), MG-63 (Bone marrow) and Jurkat (Blood T lymphocytes). Compound 4n having (R)-1-phenylethanamine was found to be the most active amongst all the synthesized alpha-aminophosphonates against all the five cancer cell lines, most prominent being against Jurkat cell line with an IC50 value of 4 MUM. Surprisingly, compound 4o having (S)-1-phenylethanamine was found to be devoid of any cytotoxicity. Our finding suggests that these chemical entities could further serve as interesting template for the design of potential anticancer agents. PMID- 23792353 TI - Exploring the space of histidine containing dipeptides in search of novel efficient RCS sequestering agents. AB - The study reports a set of forty proteinogenic histidine-containing dipeptides as potential carbonyl quenchers. The peptides were chosen to cover as exhaustively as possible the accessible chemical space, and their quenching activities toward 4-hydroxy-2-nonenal (HNE) and pyridoxal were evaluated by HPLC analyses. The peptides were capped at the C-terminus as methyl esters or amides to favor their resistance to proteolysis and diastereoisomeric pairs were considered to reveal the influence of configuration on quenching. On average, the examined dipeptides are less active than the parent compound carnosine (betaAla + His) thus emphasizing the unfavorable effect of the shortening of the betaAla residue as confirmed by the control dipeptide Gly-His. Nevertheless, some peptides show promising activities toward HNE combined with a remarkable selectivity. The results emphasize the beneficial role of aromatic and positively charged residues, while negatively charged and H-bonding side chains show a detrimental effect on quenching. As a trend, ester derivatives are slightly more active than amides while heterochiral peptides are more active than their homochiral diastereoisomer. Overall, the results reveal that quenching activity strongly depends on conformational effects and vicinal residues (as evidenced by the reported QSAR analysis), offering insightful clues for the design of improved carbonyl quenchers and to rationalize the specific reactivity of histidine residues within proteins. PMID- 23792354 TI - Managing and preventing outbreaks of Gram-negative infections in UK neonatal units. AB - De novo guidance on the management of Gram-negative bacteria outbreaks in UK neonatal units was developed in 2012 by a Department of Health, England Antimicrobial Resistance and Healthcare Associated Infection working group. The recommendations included activation of an organisational response and establishing a control team when an outbreak is suspected; screening for the specific organism only during an outbreak; undertaking multidisciplinary reviews of cleaning routines, hand hygiene and Gram-negative bacteria transmission risks; considering deep-cleaning; cohorting colonised and infected babies preferably but not necessarily in isolation cubicles; and considering reducing beds or closing a unit to new admissions as a way of improving spacing and staff:patient ratios until the outbreak is under control. The group advised establishing mechanisms to communicate effectively across the network; informing parents of the outbreak as early as possible, and providing prewritten 'infection outbreak' information sheets. For prevention of outbreaks, the group advised meeting national staffing and cot-spacing requirements; following a Water Action Plan; using infection reduction care bundles and benchmarking; and introducing breast milk early and limiting antibiotic use. PMID- 23792355 TI - Very preterm/very low birthweight infants' attachment: infant and maternal characteristics. AB - OBJECTIVE: To investigate whether there are differences in attachment security and disorganisation between very preterm or very low birthweight (VP/VLBW) (<32 weeks gestation or <1500 g birthweight) and full-term infants (37-42 weeks gestation) and whether the pathways to disorganised attachment differ between VP/VLBW and full-term infants. DESIGN: The sample with complete longitudinal data consisted of 71 VP/VLBW and 105 full-term children and their mothers matched for twin status, maternal age, income and maternal education. Infant attachment was assessed with the Strange Situation Assessment at 18 months of age. Maternal sensitivity in the VP/VLBW and full-term samples was rated by neonatal nurses and community midwives in the neonatal period, respectively, and mother-infant interaction was observed at 3 months. Infant difficultness was assessed by maternal report at 3 months and infant's developmental status was assessed with the Bayley Scales (BSID-II). RESULTS: Most VP/VLBW (61%) and full-term (72%) children were found to be securely attached. However, more VP/VLBW (32%) than full-term children (17%) had disorganised attachment. Longitudinal path analysis found that maternal sensitivity was predictive of attachment disorganisation in full-term children. In contrast, infant's distressing cry and infant's developmental delay, but not maternal sensitivity, were predictive of disorganised attachment in VP/VLBW children. CONCLUSIONS: A third of VP/VLBW children showed disorganised attachment. Underlying neurodevelopmental problems associated with VP/VLBW birth appear to be a common pathway to a range of social relationship problems in this group. Clinicians should be aware that disorganised attachment and relationship problems in VP/VLBW infants are frequent despite sensitive parenting. PMID- 23792362 TI - Assessment of depleted uranium in South-Western Iran. AB - Depleted uranium (DU) has been used in a number of conflicts most notably during the Gulf War in Iraq and existence of it has been reported in Kuwait by IAEA experts. Due to heavy sand storms prevailing into the direction to South West of Iran transporting sand originating from Iraq, the probability that DU could be moved is considered high. Therefore it was decided to take some air and soil samples near border line and some nearest cities. The study was focused on finding DU in air and soil of these south-west provinces. 22 air samples and 20 soil samples were collected and analyzed on their contents of uranium isotopes by alpha, beta and gamma spectrometry. The air and soil samples have been measured by use of an alpha-beta counter and by a gamma spectrometer, respectively. Results showed that there is no radiation impact from DU and so no DU has been transported via sand storms since all results were obtained below the detection limit. PMID- 23792363 TI - Revised Olweus Bully/Victim Questionnaire: evaluation in visually impaired. AB - PURPOSE: To explore the psychometric properties of the revised Olweus Bully/Victim Questionnaire (OBVQ) in children with visual impairment (VI) using Rasch analysis. METHODS: One hundred fifty Indian children with VI between 8 and 16 years (mean age, 11.6 years; 69% male; mean acuity in the better eye of 0.80 logMAR [Snellen, 20/126]) were administered the revised OBVQ. The 40-item revised OBVQ was developed to assess victimization (i.e., being bullied) and bullying (bullying others) in normally sighted schoolchildren. Only 16 items are used for Rasch analysis and are divided into two parts: I (victimization, eight items) and II (bullying others, eight items). Separate Rasch analysis was conducted for both parts, and the psychometric properties investigated included behavior of rating scale, extent to which the items measured a single construct (unidimensionality by fit statistics and principal component analysis [PCA] of residuals); ability to discriminate among participants' victimization and bullying behaviors (measurement precision as assessed by person separation reliability [PSR] minimum recommended value, 0.80); and targeting of items to participants' victimization and bullying. RESULTS: Response categories were misused for both parts I and II, which required repair before further analysis. Measurement precision was inadequate for both parts (PSR, 0.64 for part I and 0.19 for part II), indicating poor discriminatory ability. All items fit the Rasch model well in part I, indicating unidimensionality that was further confirmed using PCA of residuals. However, an item misfit in part II that required deletion following which the remaining items fit and PCA of residuals also supported unidimensionality. Targeting was -0.58 logits for part I, indicating that the items were matched well with the participants' victimization. By comparison, targeting was suboptimal for part II (-1.97 logits). CONCLUSIONS: In its current state, the revised OBVQ is not a valid psychometric instrument to assess victimization and bullying among children with VI. PMID- 23792360 TI - MSP-RON signalling in cancer: pathogenesis and therapeutic potential. AB - Since the discovery of MSP (macrophage-stimulating protein; also known as MST1 and hepatocyte growth factor-like (HGFL)) as the ligand for the receptor tyrosine kinase RON (also known as MST1R) in the early 1990s, the roles of this signalling axis in cancer pathogenesis has been extensively studied in various model systems. Both in vitro and in vivo evidence has revealed that MSP-RON signalling is important for the invasive growth of different types of cancers. Currently, small-molecule inhibitors and antibodies blocking RON signalling are under investigation. Substantial responses have been achieved in human tumour xenograft models, laying the foundation for clinical validation. In this Review, we discuss recent advances that demonstrate the importance of MSP-RON signalling in cancer and its potential as a therapeutic target. PMID- 23792364 TI - The Quality of Vision questionnaire: subscale interchangeability. AB - PURPOSE: The purpose of this study is to evaluate the interchangeability of the three subscales of the Quality of Vision (QoV) questionnaire: Frequency, Severity and Bothersome. This will indicate if any of the subscales are predictive of one another and whether respondents need to complete all three subscales. METHODS: Data from four studies were pooled together, totaling 1930 completed questionnaires. Patient groups consisted of spectacle wearers, contact lens wearers, post-laser refractive surgery (including laser in situ keratomileusis, laser-assisted subepithelial keratectomy, and photorefractive keratectomy surgeries for various refractive errors), patients with cataract, and patients having undergone lens implantation surgery (consisting of monofocal, multifocal, and pseudoaccommodative intraocular lenses). The Bland-Altman limits of agreement (LoA) method was used to assess the interchangeability between the three subscales of the QoV questionnaire. RESULTS: The mean difference, standard deviation of the differences, and the LoA for the Frequency versus Severity subscale was 2.8570, 6.784, and -10.4397 to 16.1537, respectively. The mean difference, standard deviation of the differences, and the LoA for the Frequency versus Bothersome subscale was 5.4674, 12.5768, and -19.1831 to 30.1179, respectively. The mean difference, standard deviation of the differences, and the LoA for the Severity versus Bothersome subscale was 2.6104, 9.4444, and -15.9006 to 21.1213, respectively. CONCLUSIONS: The wide LoA found in this study indicate that the three subscales of the QoV questionnaire (Frequency, Severity and Bothersome.) measure different aspects of the latent trait, quality of vision. Users should continue to use all three subscales of the questionnaire to achieve a comprehensive assessment of subjective quality of vision. PMID- 23792361 TI - Forkhead box proteins: tuning forks for transcriptional harmony. AB - Forkhead box (FOX) proteins are multifaceted transcription factors that are responsible for fine-tuning the spatial and temporal expression of a broad range of genes both during development and in adult tissues. This function is engrained in their ability to integrate a multitude of cellular and environmental signals and to act with remarkable fidelity. Several key members of the FOXA, FOXC, FOXM, FOXO and FOXP subfamilies are strongly implicated in cancer, driving initiation, maintenance, progression and drug resistance. The functional complexities of FOX proteins are coming to light and have established these transcription factors as possible therapeutic targets and putative biomarkers for specific cancers. PMID- 23792365 TI - Wafer-scale fabrication of nanoapertures using corner lithography. AB - Several submicron probe technologies require the use of apertures to serve as electrical, optical or fluidic probes; for example, writing precisely using an atomic force microscope or near-field sensing of light reflecting from a biological surface. Controlling the size of such apertures below 100 nm is a challenge in fabrication. One way to accomplish this scale is to use high resolution tools such as deep UV or e-beam. However, these tools are wafer-scale and expensive, or only provide series fabrication. For this reason, in this study a versatile method adapted from conventional micromachining is investigated to fabricate protruding apertures on wafer-scale. This approach is called corner lithography and offers control of the size of the aperture with diameter less than 50 nm using a low-budget lithography tool. For example, by tuning the process parameters, an estimated mean size of 44.5 nm and an estimated standard deviation of 2.3 nm are found. The technique is demonstrated--based on a theoretical foundation including a statistical analysis--with the nanofabrication of apertures at the apexes of micromachined pyramids. Besides apertures, the technique enables the construction of wires, slits and dots into versatile three dimensional structures. PMID- 23792366 TI - Collection and determination of nucleotide metabolites in neonatal and adult saliva by high performance liquid chromatography with tandem mass spectrometry. AB - Saliva contains a number of biochemical components which may be useful for diagnosis/monitoring of metabolic disorders, and as markers of cancer or heart disease. Saliva collection is attractive as a non-invasive sampling method for infants and elderly patients. We present a method suitable for saliva collection from neonates. We have applied this technique for the determination of salivary nucleotide metabolites. Saliva was collected from 10 healthy neonates using washed cotton swabs, and directly from 10 adults. Two methods for saliva extraction from oral swabs were evaluated. The analytes were then separated using high performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS). The limits of detection for 14 purine/pyrimidine metabolites were variable, ranging from 0.01 to 1.0MUM. Recovery of hydrophobic purine/pyrimidine metabolites from cotton tips was consistently high using water/acetonitrile extraction (92.7-111%) compared with water extraction alone. The concentrations of these metabolites were significantly higher in neonatal saliva than in adults. Preliminary ranges for nucleotide metabolites in neonatal and adult saliva are reported. Hypoxanthine and xanthine were grossly raised in neonates (49.3+/-25.4; 30.9+/-19.5MUM respectively) compared to adults (4.3+/-3.3; 4.6+/-4.5MUM); nucleosides were also markedly raised in neonates. This study focuses on three essential details: contamination of oral swabs during manufacturing and how to overcome this; weighing swabs to accurately measure small saliva volumes; and methods for extracting saliva metabolites of interest from cotton swabs. A method is described for determining nucleotide metabolites using HPLC with photodiode array or MS/MS. The advantages of utilising saliva are highlighted. Nucleotide metabolites were not simply in equilibrium with plasma, but may be actively secreted into saliva, and this process is more active in neonates than adults. PMID- 23792367 TI - Carrier mediated transport solvent bar microextraction for preconcentration and determination of dexamethasone sodium phosphate in biological fluids and bovine milk samples using response surface methodology. AB - In the current study, a fast and simple preconcentration and sample clean up procedure was developed based on carrier mediated three phase solvent bar liquid phase microextraction (TPSB-LPME) method prior to high performance liquid chromatography (HPLC) equipped with an ultraviolet (UV) absorbance detector for simultaneous extraction and determination of trace amounts of dexamethasone sodium phosphate (DSP) in human plasma, human urine and bovine milk. According to this procedure, dexamethasone sodium phosphate was extracted from an acidic aqueous sample (SP, 7.5mL with pH=6) into the organic solvent 1-octanol (containing 5%, w/v of Aliquat-336 as carrier) residing in the pores of a hollow fiber and then back extracted into an alkali receiving phase (RP, 5MUL of 0.65M NaClO4 with pH=10) was located inside the lumen of the fiber. After the extraction period, the receiving phase was directly injected into HPLC. The effect of different extraction conditions (i.e., pH of source and receiving phases, ionic strength, stirring rate, counter-ion concentration and extraction time) on the extraction efficiency of DSP was investigated and optimized using central composite design (CCD) as a powerful tool. Under the optimal conditions, preconcentration factor of 320, extraction recovery of 23%, dynamic linear range of 1-1000ngmL(-1) (r(2)=0.997) and limit of detection of 0.1ngmL(-1) were obtained. Eventually, applicability of the proposed method was successfully confirmed by extraction and determination of drug in plasma and urine samples and bovine milk with R.S.D.s<8%. Comparing to the traditional methods, the proposed method exhibits high sensitivity and high preconcentration factors as well as good precision. The extraction setup is simple and due to active transport of analytes, high cleanup effect and good selectivity are obtained in the extraction process. This extraction technique is also the most economical sample preparation and preconcentration technique as compared to traditional extraction techniques. PMID- 23792368 TI - Identification of honokiol metabolites in rats by the method of stable isotope cluster technique and ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometry. AB - Honokiol, a natural molecule isolated from Magnolia officinalis Rehd. et Wils., is widely known as an antitumor agent. In present work, an analysis of in vivo biotransformation and metabolites of honokiol has been performed by a combined method based on stable isotope cluster technique with honokiol-[(13)C6]-labeled and ultra-high performance liquid chromatography/quadrupole-time-of-flight-mass spectrometry (UHPLC/Q-TOF-MS). The metabolites could be easily identified by the determination of a chromatographically co-eluted pair of isotopomers (MS doublet peaks) with similar peak intensities and mass difference corresponding to that between isotope-labeled and non-isotope-labeled honokiol. A total of eighteen metabolites were detected and tentatively identified, fourteen of which were reported for the first time. The results indicated that the main metabolic pathways of honokiol in rats were hydroxylation, methylation, sulfation and glucuronidation. This study provided the first essential information on biotransformation and metabolites of honokiol in rats, which was very useful for further pharmacological and clinical studies of honokiol as a potent drug candidate. PMID- 23792369 TI - Impact of male-partner-focused interventions on breastfeeding initiation, exclusivity, and continuation. AB - Informal sources of support, particularly the male partner, have more influence on breastfeeding behaviors than formal support from health care providers. This systematic review examined the impact of male-partner-focused breastfeeding interventions on breastfeeding initiation, exclusivity, and continuation. Four unique interventions were identified that were tested through randomized controlled studies or quasi-experimental design. These 4 provided breastfeeding education to fathers, with breastfeeding outcomes reported by the mother. Three of the 4 studies compared initiation rates between intervention and control conditions, and 2 showed significantly higher rates of breastfeeding initiation in the intervention group. Although studies were inconsistent in their categorization and reporting of full, partial, or no breastfeeding, significantly higher rates of breastfeeding initiation, exclusivity, and/or continuation were seen for 2 interventions. Because all 4 interventions found at least 1 breastfeeding outcome to be superior in the treatment group, breastfeeding education should be offered to male partners. Future studies should test if intervention effectiveness can be increased if education is supplemented with other activities. Future studies also should use controlled designs and validated outcome measures. PMID- 23792370 TI - The euAP1 protein MPF3 represses MPF2 to specify floral calyx identity and displays crucial roles in Chinese lantern development in Physalis. AB - The Chinese lantern phenotype or inflated calyx syndrome (ICS) is a postfloral morphological novelty in Physalis. Its origin is associated with the heterotopic expression of the MADS box gene 2 from Physalis floridana (MPF2) in floral organs, yet the process underlying its identity remains elusive. Here, we show that MPF3, which is expressed specifically in floral tissues, encodes a core eudicot APETALA1-like (euAP1) MADS-domain protein. MPF3 was primarily localized to the nucleus, and it interacted with MPF2 and some floral MADS-domain proteins to selectively bind the CC-A-rich-GG (CArG) boxes in the MPF2 promoter. Downregulating MPF3 resulted in a dramatic elevation in MPF2 in the calyces and androecium, leading to enlarged and leaf-like floral calyces; however, the postfloral lantern was smaller and deformed. Starch accumulation in pollen was blocked. MPF3 MPF2 double knockdowns showed normal floral calyces and more mature pollen than those found in plants in which either MPF3 or MPF2 was downregulated. Therefore, MPF3 specifies calyx identity and regulates ICS formation and male fertility through interactions with MPF2/MPF2. Furthermore, both genes were found to activate Physalis floridana invertase gene 4 homolog, which encodes an invertase cleaving Suc, a putative key gene in sugar partitioning. The novel role of the MPF3-MPF2 regulatory circuit in male fertility is integral to the origin of ICS. Our results shed light on the evolution and development of ICS in Physalis and on the functional evolution of euAP1s in angiosperms. PMID- 23792372 TI - Predictors of sustainable work participation of young adults with developmental disorders. AB - For individuals with autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD) work participation is a challenge, as shown by their low employment rates. The aim of this study was to investigate which factors predict work participation, finding work as well as maintaining employment, of young adults with ASD as well as ADD. We obtained data on 563 individuals with ASD and/or ADD, aged 15-27 years. The follow-up period ranged from 1.25 to 2.75 years. Being male (for ADD), living independently (for ASD), expecting to be able to work fulltime (for ASD and ADD), high perceived support from parents and perceived positive attitude of parents regarding work (for ASD and ADD) and perceived positive attitude of social environment (for ADD) predicted finding work by the young adult, while being male (for ADD) and higher age (for ASD and ADD) and positive attitude of social environment regarding work (for ASD) predicted maintaining employment. Both personal and social factors predict work outcome and should be taken into account when supporting individuals with DD in their transition to work. PMID- 23792373 TI - Impaired theory of mind and symptoms of Autism Spectrum Disorder in children with Prader-Willi syndrome. AB - In order to evaluate the social cognitive functioning in children with Prader Willi syndrome (PWS), Theory of Mind (ToM) and symptoms of Autism Spectrum Disorder were evaluated. Sixty-six children with PWS aged 7-17 years were tested using the Theory of Mind test-R and the Diagnostic Interview for Social Communication disorders. We tested the correlation between Total ToM Standard Deviation Score (Total ToM SDS) and genetic subtype of paternal deletion or maternal uniparental disomy, and total IQ, verbal IQ and performal IQ. Prevalence and symptoms of Autism Spectrum Disorder were assessed. Median (interquartile range) of total ToM SDS of those aged 7-17 years was -3.84 (-5.73, -1.57). Their Total ToM SDS correlated with total IQ (beta=0.662, p<0.001, adj.R(2)=0.407), in particular with verbal IQ (beta=0.502, p=0.001, adj.R(2)=0.409), but not with performal IQ (beta=0.241, p>0.05, adj.R(2)=0.259). No difference in Total ToM SDS was found between children with deletion and maternal uniparental disomy (beta= 0.143, p>0.05, adj.R(2)=-0.016). Compared to the reference group of healthy children aged 7-12 years, children with PWS in the same age group had a median ToM developmental delay of 4 (3-5) years. One third of children with PWS scored positive for Autism Spectrum Disorder. Most prominent aberrations in Autism Spectrum Disorder were focused on maladaptive behavior. Our findings demonstrate a markedly reduced level of social cognitive functioning, which has consequences for the approach of children with PWS, i.e. adjustment to the child's level of social cognitive functioning. PMID- 23792371 TI - Arabidopsis BPM proteins function as substrate adaptors to a cullin3-based E3 ligase to affect fatty acid metabolism in plants. AB - Regulation of transcriptional processes is a critical mechanism that enables efficient coordination of the synthesis of required proteins in response to environmental and cellular changes. Transcription factors require accurate activity regulation because they play a critical role as key mediators assuring specific expression of target genes. In this work, we show that cullin3-based E3 ligases have the potential to interact with a broad range of ethylene response factor (ERF)/APETALA2 (AP2) transcription factors, mediated by Math-BTB/POZ (for Meprin and TRAF [tumor necrosis factor receptor associated factor] homolog)-Broad complex, Tramtrack, Bric-a-brac/Pox virus and Zinc finger) proteins. The assembly with an E3 ligase causes degradation of their substrates via the 26S proteasome, as demonstrated for the wrinkled1 ERF/AP2 protein. Furthermore, loss of Math BTB/POZ proteins widely affects plant development and causes altered fatty acid contents in mutant seeds. Overall, this work demonstrates a link between fatty acid metabolism and E3 ligase activities in plants and establishes CUL3-based E3 ligases as key regulators in transcriptional processes that involve ERF/AP2 family members. PMID- 23792374 TI - Interlaboratory trial of the rat Pig-a mutation assay using an erythroid marker HIS49 antibody. AB - The peripheral blood Pig-a assay has shown promise as a tool for evaluating in vivo mutagenicity. In this study five laboratories participated in a collaborative trial that evaluated the transferability and reproducibility of a rat Pig-a assay that uses a HIS49 antibody reacts with an antigen found on erythrocytes and erythroid progenitors. In preliminary work, flow cytometry methods were established that enabled all laboratories to detect CD59-negative erythrocyte frequencies (Pig-a mutant frequencies) of <10*10(-6) in control rats. Four of the laboratories (the in-life labs) then treated male rats with a single oral dose of N-nitroso-N-ethylurea, 7,12-dimethylbenz[a]anthracene (DMBA), or 4 nitroquinoline-1-oxide (4NQO). Blood samples were collected up to 4 weeks after the treatments and analyzed by flow cytometry for the frequency of CD59-negative cells among total red blood cells (RBCs; RBC Pig-a assay). RBC Pig-a assays were conducted in the four in-life laboratories, plus a fifth laboratory that received blood samples from the other laboratories. In addition, three of the five laboratories performed a Pig-a assay on reticulocytes (RETs; PIGRET assay), using blood from the rats treated with DMBA and 4NQO. The four in-life laboratories detected consistent, time- and dose-related increases in RBC Pig-a mutant frequency (MF) for all three test articles. Furthermore, comparable results were obtained in the fifth laboratory that received blood samples from other laboratories. The three laboratories conducting the PIGRET assay also detected consistent, time- and dose-related increases in Pig-a MF, with the RET MFs increasing more rapidly with time than RBC MFs. These results indicate that rat Pig-a assays using a HIS49 antibody were transferable between laboratories and that data generated by the assays were reproducible. The findings also suggest that the PIGRET assay may detect the in vivo mutagenicity of test compounds earlier than the RBC Pig-a assay. PMID- 23792375 TI - Epidemiological update of hepatitis B, C and delta in Latin America. AB - Viral hepatitis B, C and delta still remain a serious problem in Latin America. Data from the 1980s indicated that HBV and HDV infection are the main causes of chronic hepatitis. However, the spread of HBV infection could be controlled through the implementation of immunization programmes. Different countries from Mexico to Argentina display marked differences in terms of HBV genotype distribution. HBV genotype F has been identified as the most frequent in most Latin America countries, except for Mexico and Brazil, where genotypes H and A are the most frequent, respectively. In Latin America, the overall prevalence of HCV antibody is estimated to be 1.5%. Latin American countries have been very proactive in screening their blood supplies, thus minimizing risk of HCV transmission through transfusion. The number of diagnosed and treated patients is still low, thereby increasing the burden of complications such as liver cirrhosis or hepatocellular carcinoma. The most prevalent HCV genotype is 1, which is the genotype with the greatest worldwide spread, but it is a different genotype from other regions like Africa and Asia. HDV is present worldwide but its distribution pattern is not uniform. HDV was recently detected in novel geographic regions, reinforcing that it is a very serious health threat in under-developed countries. The main prevalence areas are the Mediterranean basin, the Middle East, central and northern Asia, western and central Africa, the Amazonian basin (Brazil, Peru, Venezuela and Colombia) and the Pacific islands. Novel strategies to increase HBV immunization in the Latin American population are needed to warrant thorough coverage in the rural areas. PMID- 23792376 TI - Falls prevention in persons with intellectual disabilities: development, implementation, and process evaluation of a tailored multifactorial fall risk assessment and intervention strategy. AB - In the general elderly population, multifactorial screening of fall risks has been shown to be effective. Although persons with intellectual disabilities (ID) fall more often, there appears to be no targeted screening for them. The aim of this study was to develop, implement, and evaluate a falls clinic for persons with ID. Based on guidelines, literature, and expert meetings, a falls clinic for persons with ID was developed. In total, 26 persons with ID and a fall history participated in the study. Process evaluation was conducted with evaluation forms and focus groups. Fifty interventions (0-8 per person) were prescribed. The (para)medical experts, clients, and caregivers described the falls clinic as useful. Advice for improvement included minor changes to clinic content. Logistics were the largest challenge for the falls clinic, for example organizing meetings, completing questionnaires prior to meetings, and ensuring that a personal caregiver accompanied the person with ID. Furthermore, the need for a screening tool to determine whether a person would benefit from the falls clinic was reported. In conclusion, the falls clinic for persons with ID was considered feasible and useful. Some minor content changes are necessary and there is a need for a screening tool. However, logistics concerning the falls clinic need improvement. More attention and time for multifactorial and multidisciplinary treatment of persons with ID is necessary. Implementation on a larger scale would also make it possible to investigate the effectiveness of the falls clinic with regard to the prevention of falls in this population. PMID- 23792377 TI - Quality and structure of variability in children during motor development: a systematic review. AB - Variability has been perceived to be beneficial to movement organization and execution, being essential to selection of movement patterns during motor development, to obtain flexible patterns and adaptability to different task demands. Human movement variability can be measured by linear and nonlinear tools. Recently, nonlinear techniques have been used successfully to give insight into motor skills control in children, and be able to discriminate pathologic and non-pathologic children. For that, this paper is the first to review systematically studies that used nonlinear measures in children. We intend to describe which mathematical tools are utilized to analyze quality and structure of variability, the factors that influence this variability and methodological procedures which are considered for its analysis, and how they are interpreted in child motor development field. A search was performed by one reviewer in relevant databases and the quality appraisal was conducted independently by two reviewers. In all, 27 articles were identified and 20 were selected for the present review. It was detected a large variation in sample characteristics and methodological issues among studies. In fact, the main importance of this review was due to the attempt to define some parameters and standardize some values for typical children and children with disabilities. It is noted that the results from nonlinear techniques depend on the task being analyzed, the age and the type of mathematical technique chosen. The presence of disability is associated to decreases in complexity and nonlinear tools were considered sensible to investigate the effectiveness of practice and intervention in typical children and children with cerebral palsy. Furthermore, future studies should be more careful in standardizing selection, recruitment and explaining missing data. Future reports also should present details of their results and limitations to favor comparisons and helping in formulating new research questions. PMID- 23792378 TI - Complete mitochondrial genomes of the Japanese pink coral (Corallium elatius) and the Mediterranean red coral (Corallium rubrum): a reevaluation of the phylogeny of the family Coralliidae based on molecular data. AB - Precious corals are soft corals belonging to the family Coralliidae (Anthozoa: Octocorallia: Alcyonacea) and class Anthozoa, whose skeletal axes are used for jewelry. The family Coralliidae includes ca. 40 species and was originally thought to comprise of the single genus Corallium. In 2003, Corallium was split into two genera, Corallium and Paracorallium, and seven species were moved to this newly identified genus on the bases of morphological features. Previously, we determined the complete mitochondrial genome sequence of two precious corals Paracorallium japonicum and Corallium konojoi, in order to clarify their systematic positions. The two genomes showed high nucleotide sequence identity, but their gene order arrangements were not identical. Here, we determined three complete mitochondrial genome sequences from the one specimen of Mediterranean Corallium rubrum and two specimens of Corallium elatius coming from Kagoshima (South Japan). The circular mitochondrial genomes of C. rubrum and C. elatius are 18,915bp and 18,969-18,970bp in length, respectively, and encode 14 typical octocorallian protein-coding genes (nad1-6, nad4L, cox1-3, cob, atp6, atp8, and mtMutS, which is an octocoral-specific mismatch repair gene homologue), two ribosomal RNA genes (rns and rnl), and one transfer RNA (trnM). The overall nucleotide differences between C. konojoi and each C. elatius haplotype (T2007 and I2011) are only 10 and 11 nucleotides, respectively; this degree of similarity indicates that C. elatius and C. konojoi are very closely related species. Notably, the C. rubrum mitochondrial genome shows more nucleotide sequence identity to P. japonicum (99.5%) than to its congeneric species C. konojoi (95.3%) and C. elatius (95.3%). Moreover, the gene order arrangement of C. rubrum was the same as that of P. japonicum, while that of C. elatius was the same as C. konojoi. Phylogenetic analysis based on three mitochondrial genes from 24 scleraxonian species shows that the family Coralliidae is separated into two distinct groups, recovering Corallium as a paraphyletic genus. Our results indicate that the currently accepted generic classification of Coralliidae should be reconsidered. PMID- 23792379 TI - New approaches to source-sink metapopulations decoupling demography and dispersal. AB - Source-sink systems are metapopulations of patches with different, and possibly temporally varying, habitat qualities, which are commonly used in ecology to study the fate of spatially extended populations. We propose new techniques that disentangle the respective contributions of demography and dispersal to the dynamics and fate of a single species in a source-sink system. Our approach is valid for a general class of stochastic, individual-based, stepping-stone models, with density-independent demography and dispersal, provided that the metapopulation is finite or else enjoys some transitivity property. We provide (1) a simple criterion of persistence, by studying the motion of a single random disperser until it returns to its initial position; (2) a joint characterization of the long-term growth rate and of the asymptotic occupancy frequencies of the ancestral lineage of a random survivor, by using large deviations theory. Both techniques yield formulas decoupling demography and dispersal, and can be adapted to the case of periodic or random environments, where habitat qualities are autocorrelated in space and possibly in time. In this last case, we display examples of coupled time-averaged sinks allowing survival, as was previously known in the absence of demographic stochasticity for fully mixing (Jansen and Yoshimura, 1998) or partially mixing (Evans et al., 2012; Schreiber, 2010) metapopulations. PMID- 23792380 TI - Oxidation of nonylphenol and octylphenol by manganese dioxide: kinetics and pathways. AB - Due to their potent estrogenicity and ubiquitous occurrence, non-ionic surfactant metabolites nonylphenol (NP) and octylphenol (OP) are of significant concern. Abiotic chemical oxidation by naturally abundant metal oxides may be an important route of their environmental attenuation, but is poorly understood. We investigated the reaction kinetics and pathways of NP and OP with MnO2. At pH 5.5 and 100 mg/L delta-MnO2, 92, 84 and 76% of 4-n-NP, 4-tert-OP and technical nonylphenol (tNP) was transformed in 90 min, respectively. A further experiment using a Mn-containing soil and Mn-removed soil confirmed that soil MnO2 caused NP removal. Multiple reaction products, including hydroquinone, hydroxylated products, dimers and trimers were identified through fragmentation analysis by GC MS/MS and UPLC-MS/MS, allowing the construction of tentative pathways. This study suggested that abiotic oxidation by MnO2 may contribute to the dissipation of tNP, 4-n-NP, 4-tert-OP and their analogues in the natural environment. PMID- 23792381 TI - Upwind impacts of ammonia from an intensive poultry unit. AB - This study investigated potential ammonia impacts on a sand dune nature reserve 600 m upwind of an intensive poultry unit. Ammonia concentrations and total nitrogen deposition were measured over a calendar year. A series of ammonia and nitrogen exposure experiments using dune grassland species were conducted in controlled manipulations and in the field. Ammonia emissions from the intensive poultry unit were detected up to 2.8 km upwind, contributing to exceedance of critical levels of ammonia 800 m upwind and exceedance of critical loads of nitrogen 2.8 km upwind. Emissions contributed 30% of the total N load in parts of the upwind conservation site. In the nitrogen exposure experiments, plants showed elevated tissue nitrogen contents, and responded to ammonia concentrations and nitrogen deposition loads observed in the conservation site by increasing biomass. Estimated long-term impacts suggest an increase in the soil carbon pool of 9% over a 50-year timescale. PMID- 23792382 TI - Contribution of a submerged membrane bioreactor in the treatment of synthetic effluent contaminated by Bisphenol-A: mechanism of BPA removal and membrane fouling. AB - A submerged membrane bioreactor has been operated at the laboratory scale for the treatment of a synthetic effluent containing Bisphenol-A (BPA). COD, NH4-N, PO4-P and BPA were eliminated respectively, at 99%, 99%, 61% and 99%. The increase of volumetric loading rate from 0 to 21.6 g/m(3)/d did not affect the performance of the MBR system. However, the removal rate decreased rapidly when the BPA loading rate increased above 21.6 g/m(3)/d. The adsorption process of BPA on the biomass was very well described by Freundlich and Langmuir isotherms. Subsequently, biodegradation of BPA occurred and followed the first order kinetic reaction, with a constant rate of 1.13 +/- 0.22 h(-1). During treatment, membrane fouling was reversible in the first 84 h of filtration, and then became irreversible. The membrane fouling was mainly due to the accumulation of suspended solid and development of biofilm on the membrane surface. PMID- 23792383 TI - An intermediate complexity dynamic model for predicting accumulation of atmospherically-deposited metals (Ni, Cu, Zn, Cd, Pb) in catchment soils: 1400 to present. AB - The Intermediate Dynamic Model for Metals (IDMM) is a model for prediction of the pools of metals (Ni, Cu, Zn, Cd, Pb) in topsoils of catchments resulting from deposition of metals from the atmosphere. We used the model to simulate soil metal pools from 1400 onwards in ten UK catchments comprising semi-natural habitats, and compared the results with present day observations of soil metal pools. Generally the model performed well in simulating present day pools, and further improvements were made to simulations of Ni, Cu, Zn and Cd by adjusting the strength of metal adsorption to the soils. Some discrepancies between observation and prediction for Pb appeared to be due either to underestimation of cumulative deposition, or to overestimation of the metal pool under 'pristine', pre-industrial conditions. The IDMM provides a potential basis for large scale assessment of metal dynamics in topsoils. PMID- 23792384 TI - Health effects of daily airborne particle dose in children: direct association between personal dose and respiratory health effects. AB - Air pollution is a widespread health problem associated with respiratory symptoms. Continuous exposure monitoring was performed to estimate alveolar and tracheobronchial dose, measured as deposited surface area, for 103 children and to evaluate the long-term effects of exposure to airborne particles through spirometry, skin prick tests and measurement of exhaled nitric oxide (eNO). The mean daily alveolar deposited surface area dose received by children was 1.35 * 10(3) mm(2). The lowest and highest particle number concentrations were found during sleeping and eating time. A significant negative association was found between changes in pulmonary function tests and individual dose estimates. Significant differences were found for asthmatics, children with allergic rhinitis and sensitive to allergens compared to healthy subjects for eNO. Variation is a child's activity over time appeared to have a strong impact on respiratory outcomes, which indicates that personal monitoring is vital for assessing the expected health effects of exposure to particles. PMID- 23792385 TI - Bridging the gap between traffic generated health stressors in urban areas: predicting xylene levels in EU cities. AB - Many citizens live, work, commute, or visit traffic intensive spaces and are exposed to high levels of chemical health stressors. However, urban conurbations worldwide present monitoring "shortage" - due to economical and/or practical constraints - for toxic stressors such as xylene isomers, which can pose human health risks. This "shortage" may be covered by the establishment of associations between rarely monitored substances such as xylenes and more frequently monitored (i.e. benzene) or usually monitored (i.e. CO). Regression analysis is used and strong statistical relationships are detected. The adopted models are applied to EU cities and comparison between measurements and predictions depicts their representativeness. The analysis provides transferability insights in an effort to bridge the gap between traffic-related stressors. Strong associations between substances of the air pollution mixture may be influential to interpret the complexity of the causal chain, especially if a synergetic exposure assessment in traffic intensive spaces is considered. PMID- 23792386 TI - Historical arsenic contamination of soil due to long-term phosphate fertiliser applications. AB - Archived samples from the Park Grass Experiment, established in 1856, were analysed to determine the impacts of long-term phosphate fertiliser applications on arsenic concentrations in soil and herbage. In plots receiving 35 kg P ha(-1) annually (+P), topsoil As concentrations almost doubled from an initial value of ~10 mg kg(-1) during 1888-1947 and remained stable thereafter. The phosphate fertilisers used before 1948 contained 401-1575 mg As kg(-1), compared to 1.6 20.3 mg As kg(-1) in the later samples. Herbage samples from the +P plots collected during 1888-1947 contained significantly more As than those from the -P plots, but later samples did not differ significantly. Mass-balance calculations show that the increase in soil As can be explained by the As input from P fertiliser applications before 1948. The results demonstrate that the P fertilisers used on the Park Grass Experiment before 1948 caused substantial As contamination of the soil. PMID- 23792387 TI - Soil contamination by phthalate esters in Chinese intensive vegetable production systems with different modes of use of plastic film. AB - The concentrations of six priority phthalic acid esters (PAEs) in intensively managed suburban vegetable soils in Nanjing, east China, were analyzed using gas chromatography-mass spectrometry (GC-MS). The total PAE concentrations in the soils ranged widely from 0.15 to 9.68 mg kg(-1) with a median value of 1.70 mg kg(-1), and di-n-butyl phthalate (DnBP), bis-(2-ethylhexyl) phthalate (DEHP) and di-n-octyl phthalate (DnOP) were the most abundant phthalate esters. Soil PAE concentrations depended on the mode of use of plastic film in which PAEs were incorporated as plasticizing agents and both the plastic film and poultry manure appeared to be important sources of soil PAEs. Vegetables in rotation with flooded rice led to lower concentrations of PAEs in soil. The results indicate that agricultural plastic film can be an important source of soil PAE contamination and further research is required to fully elucidate the mechanisms of PAE contamination of intensive agricultural soils with different use modes of use of plastic film. PMID- 23792388 TI - Quantitation of tetrabromobisphenol-A from dust sampled on consumer electronics by dispersed liquid-liquid microextraction. AB - Tetrabromobisphenol-A (TBBPA) is a brominated flame retardant used worldwide. Despite its widespread use, there are few data concerning environmental concentrations of TBBPA. Thus, the objective of this work was to optimize an ultrasound-assisted dispersed liquid-liquid microextraction (DLLME) method to analyze swabbed surfaces of consumer electronics to determine TBBPA concentrations. Upon sample preparation with DLLME, TBBPA was derivatized with acetic anhydride and then analyzed by gas chromatography-mass spectrometry (GC/MS). Using a (13)C12-TBBPA internal standard to improve precision and quantitation, a recovery study was performed. At concentrations of 250-1000 ng/mL, recoveries were 104-106%. Sample preparation with solid phase extraction had comparable recoveries, although overall, improved analyte recovery and precision were achieved with DLLME. In a small survey study, TBBPA concentrations in dust collected from 100 cm(2) areas on electronic surfaces (monitor, microwave, refrigerator, and TV) were determined to range from less than the LOQ to 523 ng/mL. PMID- 23792389 TI - Evaluation of reference genes for quantitative real-time RT-PCR analysis of gene expression in Nile tilapia (Oreochromis niloticus). AB - Quantitative real-time reverse-transcriptase polymerase chain reaction (RT-qPCR) has been used frequently to study gene expression related to fish immunology. In such studies, a stable reference gene should be selected to correct the expression of the target gene. In this study, seven candidate reference genes (glyceraldehyde-3-phosphate dehydrogenase (GADPH), ubiquitin-conjugating enzyme (UBCE), 18S ribosomal RNA (18S rRNA), beta-2-microglobulin (B2M), elongation factor 1 alpha (EF1A), tubulin alpha chain-like (TUBA) and beta actin (ACTB)), were selected to analyze their stability and normalization in seven tissues (liver, spleen, kidney, brain, heart, muscle and intestine) of Nile tilapia (Oreochromis niloticus) challenged with Streptococcus agalactiae or Streptococcus iniae, respectively. The results showed that all the candidate reference genes exhibited tissue-dependent transcriptional variations. With PBS injection as a control, UBCE was the most stable and suitable single reference gene in the intestine, liver, brain, kidney, and spleen after S. iniae infection, and in the liver, kidney, and spleen after S. agalactiae infection. EF1A was the most suitable in heart and muscle after S. iniae or S. agalactiae infection. GADPH was the most suitable gene in intestine and brain after S. agalactiae infection. In normal conditions, UBCE and 18S rRNA were the most stably expressed genes across the various tissues. These results showed that for RT-qPCR analysis of tilapia, selecting two or more reference genes may be more suitable for cross-tissue analysis of gene expression. PMID- 23792390 TI - Evidence Live 2013. PMID- 23792391 TI - Oral diseases affect some 3.9 billion people. AB - DATA SOURCES: Medline, Embase, Lilacs. STUDY SELECTION: Published and unpublished observational population-based studies presenting information on the prevalence, incidence, case fatality and cause-specific mortality related to untreated caries, severe periodontitis and severe tooth loss between January 1980 and December 2010. There were no language restrictions. Study quality was assessed using the STROBE checklist (http://www.strobe-statement.org/). DATA EXTRACTION AND SYNTHESIS: Prevalence estimates were calculated on the database for all age gender-country-year groups using a specifically developed Bayesian meta regression tool. Disability-adjusted life-years (DALYs) and years lived with disability (YLDs) metrics were used to quantify the disease burden. Disability weights were calculated based on population-based surveys in five countries (USA, Peru, Tanzania, Bangladesh and Indonesia) and an open Internet survey. Uncertainties in estimates were examined using Monte Carlo simulation techniques with uncertainty levels presented as the 2.5th and 97.5th centiles, which can be interpreted as a 95% UI. RESULTS: Oral diseases remain highly prevalent in 2010 affecting 3.9 billion people. Untreated caries in permanent teeth was the most prevalent condition evaluated for the entire GBD (Global Burden of Disease) 2010 Study with a global prevalence of 35% for all ages combined. Severe periodontitis and untreated caries in deciduous teeth were the 6th and 10th most prevalent conditions, affecting, respectively, 11% and 9% of the global population. Oral conditions combined accounted for 15 million DALYs globally (1.9% of all YLDs and 0.6% of all DALYs), implying an average health loss of 224 years per 100,000 people. DALYs due to oral conditions increased 20.8% between 1990 and 2010, mainly due to population growth and aging. While DALYs due to severe periodontitis and untreated caries increased, those due to severe tooth loss decreased. CONCLUSIONS: The findings highlight the challenge in responding to the diversity of urgent oral health needs world-wide, particularly in developing communities. PMID- 23792392 TI - Evidence of improved access to dental care with direct access arrangements. AB - DATA SOURCES: Medline, CINAHL, PsycINFO, SCI, SSCI, Cochrane Database of Systematic Reviews, Business Source Premier, Google scholar. STUDY SELECTION: Primary or secondary reports and studies, published in English, after 1993, likely to include data relevant to direct access, report on empirical data relating to the operation of that system. DATA EXTRACTION AND SYNTHESIS: After initial screening, titles and abstracts were assessed by two reviewers, and disagreements resolved by the third. Full texts of these eligible ones were then assessed by the team until consensus reached. Data extraction by one reviewer was checked by a second and disagreements resolved by discussion with the third. Study quality was assessed through reference to CASP or SIGN checklists. Descriptive analyses and synthesis of findings were given. RESULTS: From the 1,733 studies yielded from the search, over 100 research dental and other health related papers were identified as relevant. Thirty-five studies were eligible for inclusion under dental health care direct access and 57 under non-dental health care direct access literature. The quality of the evidence was varied but on the whole assessed as moderately good quality.There was no evidence of increased risk to patient safety in any of the included seven studies. Four studies on appropriateness of DCP referrals reported a high proportion of over-referral, one study found under-referral and one good agreement regarding referral decisions.Six of the seven studies looking at DCPs' knowledge or support to patients for smoking cessation, diabetes, child abuse and domestic violence found deficiencies in DCPs' knowledge or support to patients, but these studies didn't have evidence to suggest how this compared to dentists.Increasing access to dental therapists and hygienists (whether indirect, general or without supervision of a dentist) according to ten studies, resulted in greater access to and use of dental services by underserved populations. Three studies suggested variable and, at most, modest cost savings to patients and service providers. High levels of patient satisfaction were found in all eight studies reporting this, and DCP job satisfaction was reported to be higher with direct access. CONCLUSIONS: Although over-referral of patients to dentists was suggested and a need for training on assessment and referral skills, there was no evidence of significant issues of patient safety from the clinical activities of DCPs. There was strong evidence of improved access to dental care with direct access arrangements, cost benefits to patients/service providers and high levels of patient satisfaction. PMID- 23792393 TI - Only limited evidence available for the effectiveness and cost effectiveness of dental auxiliaries. AB - DATA SOURCES: Medline, Embase, CINAHL, LILACS, Cochrane Database of Systematic Reviews, OpenGrey (System for Information on Grey Literature in Europe [SIGLE] based), Scirus, Science.gov, Cost-Effective Analysis (CEA) Registry, European Network of Health Economics Evaluation Databases (EURON-HEED), ClinicalTrials.gov and Health Services Research Projects in Progress (HSRProj) databases. They also contacted 20 separate organisations. STUDY SELECTION: All study designs were considered with no limits on dates, age of study, language or country. Government reports, peer-reviewed publications, dissertations and theses were included. Editorials, opinion pieces, educational pieces, narrative reviews, abstracts without full-text availability and raw data such as those from national oral health surveys were excluded. Study quality and risk of bias was assessed. DATA EXTRACTION AND SYNTHESIS: Data extraction was conducted independently, and meta analysis was planned for the data, but only a qualitative synthesis could be conducted. RESULTS: Eighteen observational studies were included, 13 were considered to be at high risk of bias, five at moderate risk and one at low risk. They were conducted in Australia, Canada, Hong Kong, New Zealand and the United States. All the studies were related to dental caries with only studies involving dental nurses and therapists meeting the inclusion criteria. No studies regarding cost effectiveness, irreversible diagnostic procedures or diseases other than caries were in included. CONCLUSIONS: The authors concluded that the quality of the evidence was poor. They found that in select groups in which participants received irreversible dental treatment from teams that included midlevel providers, caries increment, caries severity or both decreased across time; however, there was no difference in caries increment, caries severity or both compared with those in populations in which dentists provided all irreversible treatment. In select groups in which participants had received irreversible dental treatment from teams that included midlevel providers, there was a decrease in untreated caries across time and a decrease in untreated caries compared with that in populations in which dentists provided all treatment. PMID- 23792394 TI - Early childhood caries. AB - DATA SOURCES: Medline and Embase electronic databases were searched. STUDY SELECTION: Papers published between 1996 and 2011 were initially identified by one reviewer, with 10% being independently reviewed by a second reviewer having predefined inclusion and exclusion criteria. DATA EXTRACTION AND SYNTHESIS: Data abstraction was conducted independently and meta-analysis was not attempted because of the heterogeneity of the studies. RESULTS: Inclusion criteria were met by four papers relating to the acquisition and colonisation of the oral cariogenic bacteria and caries outcome in infants, 13 papers were considered in relation to identifying possible determinants of early childhood caries (ECC) during the first year of life. CONCLUSIONS: The review confirmed that factors occurring during the first year of life affect ECC experience. Despite heterogeneity, findings indicated maternal factors influence bacterial acquisition, whereas colonisation was mediated by oral health behaviour and practices and feeding habits. PMID- 23792395 TI - Limited evidence available for the impact of school-based behavioural interventions on oral health. AB - DATA SOURCES: The Cochrane Oral Health Group's Trials Register, and Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, CINAHL, PsycINFO, Current Controlled Trials, ClinicalTrials.gov, Web of Science and Dissertations and Theses via Proquest databases were searched. A number of relevant journals, (Acta Odontologica Scandinavica, ASDC Journal of Dentistry for Children, British Dental Journal, Caries Research, Community Dental Health, Community Dentistry and Oral Epidemiology, Journal of the American Dental Association, Journal of Dental Research, Journal of Public Health Dentistry, Swedish Dental Journal, International Journal of Paediatric Dentistry) not already searched as part of the Cochrane Journal Handsearching Programme were handsearched. There were no restrictions regarding language or date of publication. STUDY SELECTION: Randomised controlled trials (RCTs) where randomisation occured at the level of the group (cluster by school and/or class) or individual children were included. Included studies had to include behavioural interventions addressing both toothbrushing and consumption of cariogenic foods or drinks and have a primary school as a focus for delivery of the intervention. DATA EXTRACTION AND SYNTHESIS: Two pairs of review authors independently extracted data related to methods, participants, intervention design including behaviour change techniques (BCTs) utilised, outcome measures and risk of bias. A qualitative synthesis was conducted. RESULTS: Four studies involving a total of 2302 children were included. One study was at unclear risk of bias and three were at high risk of bias. The studies were heterogeneous in both intervention and outcome measures and also suffered from poor reporting. Only one included study reported caries development as an outcome. This small study at unclear risk of bias showed a prevented fraction of 0.65 (95% confidence interval (CI) 0.12 to 1.18) in the intervention group. However, as this is based on a single study, this finding should be interpreted with caution. All three studies that reported plaque outcomes found statistically significant reduction in plaque in the intervention groups, but due to differences in plaque reporting between studies these could not be combined. Two of these studies included an active home component where parents were given tasks relating to the school oral health programme (games and homework), to complete with their children. Secondary outcome measures from one study reported that the intervention had a positive impact upon children's oral health knowledge. CONCLUSIONS: Currently, there is insufficient evidence for the efficacy of primary school-based behavioural interventions for reducing caries. There is limited evidence for the effectiveness of these interventions on plaque outcomes and on children's oral health knowledge acquisition. None of the included interventions were reported as being based on or derived from behavioural theory. There is a need for further high quality research to utilise theory in the design and evaluation of interventions for changing oral health related behaviours in children and their parents. PMID- 23792396 TI - Possible role for arginine-containing toothpastes in managing dentine hypersensitivity. AB - DATA SOURCES: The Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase and LILACS databases were searched. Reference lists of eligible studies and systematic reviews were cross-checked to identify additional studies. STUDY SELECTION: Randomised and controlled clinical trials conducted in adults with at least two hypersensitive teeth confirmed by evaporative stimulus or tactile hypersensitivity assessment comparing arginine-containing desensitising toothpastes to non-arginine-containing control toothpastes were included. DATA EXTRACTION AND SYNTHESIS: Data abstraction and risk of bias assessment were conducted independently by two reviewers and a qualitative summary presented. RESULTS: Two randomised trials met the criteria; both showed a positive effect on dentine hypersensitivity in response to tactile and air-blast stimuli. No subjective measures of sensitivity were reported. CONCLUSIONS: Data identified indicate a potential role for arginine-containing toothpastes in managing dentine hypersensitivity. However, this conclusion is based on small sample sizes and the studies identified did not follow patients up in the medium to long term. The authors recommend that there is a need for well-designed RCTs to be conducted prior to any definitive recommendations being made. PMID- 23792397 TI - Effectiveness of MTA pulpotomy in primary molars: a critical assessment of relevant studies. AB - DATA SOURCES: Medline. STUDY SELECTION: Studies that evaluated the efficacy of MTA as a pulpotomy medicament in primary teeth were included, abstracts, observational studies and case reports were excluded. Only English language studies were considered. DATA EXTRACTION AND SYNTHESIS: Studies were assessed and graded by two reviewers using a weighted criteria based system and a qualitative summary of the evidence provided. RESULTS: Twenty-two studies were included, 17 studies compared MTA with formocresol, four studies compared MTA with calcium hydroxide, ferric sulphate, Portland cement, calcium-enriched mixture cement (CEM) and one study compared white MTA with grey MTA. CONCLUSIONS: Based on the assessment criteria employed, there was no evidence that MTA was better than present materials and techniques as a pulpotomy medicament. PMID- 23792398 TI - All-ceramic tooth-supported single crowns have acceptable 5-year survival rates. AB - DATA SOURCES: The databases Medline/PubMed, EMBASE, the Cochrane Library, Chinese Biomedical Literature Database and the China National Knowledge Infrastructure were searched. Additional hand searches were conducted in the journals. STUDY SELECTION: Randomised controlled trials, prospective cohort studies and retrospective studies with follow-up of 36 months or longer were included. DATA EXTRACTION AND SYNTHESIS: Data were extracted independently in duplicate. The annual core and veneer fracture rates of various tooth types were estimated and compared using Poisson regression. RESULTS: 37 studies were included; two RCTs, 25 prospective cohorts and 10 retrospective studies. Based on the calculated results, all-ceramic crowns had an acceptable overall five-year fracture rate of 4.4% irrespective of the materials used. Five-year fracture rates were significantly higher for molar crowns (8.1%) compared to premolar crowns (3.0%), and the difference between anterior (3.0%) and posterior crowns (5.4%) also achieved significance. Core fracture rates had a five-year incidence of 2.5%, and a significantly higher core fracture rate was found in the posterior region (3.9%). The overall five-year incidence of veneer fracture was 3.0%, and no clear difference was found between restored tooth types, with incidences of 2.0%, 2.5%, 1.0%, and 3.0% for incisor, canine, premolar, and molar crowns, respectively. CONCLUSIONS: Within the limitations of this study's protocol, the current evidence suggests that dental ceramic materials demonstrated acceptable five-year core and veneer fracture incidences when used for tooth-supported single crowns in both anterior and posterior segments. Higher fracture tendency for posterior crowns was the trend for all-ceramic crowns, while molar crowns showed a significantly higher fracture rate than premolar crowns. Randomised controlled trials with large sample sizes be undertaken to obtain more definitive results. PMID- 23792399 TI - Trial suggests no difference between single-visit and two-visit root canal treatment. AB - DESIGN: Randomised controlled trial. INTERVENTION: Patients over the age of 16 with radiographic evidence of apical periodontitis and a diagnosis of pulpal necrosis confirmed by negative response to hot and cold tests were randomised to receive either a one or two visit root canal treatment (RoCT). OUTCOME MEASURE: Clinical and radiographic evaluation was undertaken at two years by masked examiners. RESULTS: Two hundred and eighty-seven patients (300 teeth) were randomised. One hundred and fifty-five teeth were allocated to the single visit group and 145 to two-visit treatment. Eighteen teeth were lost to follow up, nine from each group. At two years there were no significant differences between the groups, with 96.57% (141 of 146 teeth) in the single-visit group being classified as healed compared with 88.97% (121 of 136 teeth) in the two-visit group. CONCLUSIONS: This study provided evidence that a meticulously instrumented single visit root canal treatment can be as successful as a two-visit treatment. There was no significant difference in radiographic evidence of periapical healing between single-visit and two-visit root canal treatment. PMID- 23792400 TI - Four implant bar-connected implants sufficient to support a maxillary overdenture. AB - DESIGN: Randomised controlled trial. INTERVENTION: Edentulous patients aged at least 18 years with lack of retention and stability of the upper denture and lower denture were randomised to receive a maxillary overdenture supported by either four or six bar-connected implants. OUTCOME MEASURE: The primary outcome measure was change of radiographic bone level. Secondary outcome measures were implant survival, overdenture survival and soft tissue conditions (plaque index, presence of calculus, gingiva index, sulcus bleeding index and pocket probing depth). These were scored at placement of the overdenture and after 12 months of loading. Patient satisfaction was also scored at baseline and at 12 months. RESULTS: Forty-nine patients (one drop out) completed the one year follow-up. Mean marginal bone resorption was 0.24 +/- 0.32 mm in the four implants group and 0.25 +/- 0.29 mm in the six implants group. Implant survival was 100% in the four implants group and 99.3% in the six implants group (one implant lost). Overdenture survival was 100% in both groups. There were no differences in the soft tissue outcomes between the groups. Patient satisfaction had improved in both groups. CONCLUSIONS: After one year a bar-connected maxillary overdenture on four or six implants results in a comparable treatment outcome with high implant survival, healthy peri-implant tissues and high patient satisfaction. For reasons of cost-effectiveness, treatment with four bar-connected implants to support a maxillary overdenture is preferred. PMID- 23792401 TI - Debatable evidence for the adverse drug reactions to local anaesthetics. AB - DATA SOURCES: Medline, Embase, Chinese National Knowledge Infrastructure VIP Database for Chinese Technical Periodicals (and Chinese Biomedical Literature Database. STUDY SELECTION: Randomised controlled trials (RCTs), non-RCTs, case control studies, case reports, case series and cross-sectional studies that focused on adverse drug reactions of local anaesthetics were considered. DATA EXTRACTION AND SYNTHESIS: Data abstraction was conducted independently by two reviewers, and summary data and a meta-analysis presented. RESULTS: One hundred and one studies reporting 1645 events were included. Seven of these were deaths. Lidocaine (43.17%) and bupivacaine (16.32%) were the most often involved local anaesthetics. According to the meta-analysis, the risk of using LA alone was lower than when combined with epinephrine. CONCLUSIONS: The present study demonstrated that the adverse drug reactions of local anaesthetics could not be ignored, especially in oral and ophthalmologic treatments. Some adverse drug reactions could be avoided by properly evaluating the conditions of patients and correctly applying local anaesthetics. PMID- 23792402 TI - Weak evidence suggests higher risk for bracket bonding failure with self-etch primer compared to conventional acid etch over 12 months. AB - DATA SOURCES: Medline, Embase, Cochrane Oral Health Group's Trials Register and the Cochrane Central Register of Controlled Trials (CENTRAL). Unpublished data were sought by searching ClinicalTrials.gov, the National Research Register and Pro-Quest Dissertation Abstracts and Thesis database. There were no language restrictions. STUDY SELECTION: Randomised and controlled clinical trials (including split mouth) directly comparing self-etch and acid-etch primers including patients with full-arch, fixed and bonded orthodontic appliances (not banded) with follow-up periods of at least 12 months were included. DATA EXTRACTION AND SYNTHESIS: Two authors abstracted data independently, with disagreements being resolved by a third. The Cochrane Risk of Bias tool was used to assess study quality. A random effects meta-analysis was undertaken. RESULTS: Eleven studies were included in the qualitative summary with five studies contributing to a meta-analysis. These five studies (n =3444 brackets, 1721 acid etch, 1723 self-etch) had relatively low statistical and clinical heterogeneity. Meta-analysis demonstrated a tendency for a higher risk of failure (odds ratio 1.35; 95% CI, 0.99-1.83; P 5 0.06) with self-etch primers. The use of self-etch techniques was also associated with a small but statistically significant time saving (weighted mean difference 23.2 seconds per bracket; 95% CI, 20.7-25.8; P ?0.001). There was insufficient evidence to assess the effect of bonding modality on demineralisation rates. CONCLUSIONS: There is weak evidence indicating higher odds of failure with self-etch primer than acid-etch over 12 months in orthodontic patients, and there is strong evidence that a self-etch primer is likely to result in modest time savings (eight minutes for full bonding) compared with acid-etch. PMID- 23792403 TI - Systemic nucleoside antiviral agents may be effective in prevention of recurrent herpes labialis. AB - DATA SOURCES: The Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Medline and Embase databases were searched together with the reference lists of primary studies, commentaries and reviews. Grey literature resources including the System for Information on Grey Literature in Europe, the Scopus Web and Patent searches, Proquest Dissertations and Theses Fulltext, the Index to Scientific and Technical Proceedings and the clinical trials registry (http://clinicaltrials.gov) were also searched. STUDY SELECTION: Randomised controlled trials (RCTs) involving nucleoside antiviral agents for the prevention of recurrent oral herpes in healthy immunocompetent subjects >=12 years old were included. No language restrictions were applied. Study quality was assessed following Cochrane guidelines. DATA EXTRACTION AND SYNTHESIS: Data were abstracted using a standardised data extraction form and analysed with meta analysis carried out only with studies that reported the same outcome measure. RESULTS: Ten studies were included, only one study was considered to have a low risk of bias, five an unclear risk and four a high risk of bias. Oral acyclovir (800-1,600 mg daily) and valacyclovir (500 mg daily for four months) were shown to be effective in the prevention of RHL when taken prior to the appearance of any symptoms or exposure to triggers. CONCLUSIONS: This review found support for the use of systemic acyclovir and valacyclovir for the prevention of RHL. However, the findings from this review should be interpreted with caution, because the methodologic assessment of the quality of the included studies showed an unclear risk of bias in five out of the ten included papers, and a high risk of bias in four studies. PMID- 23792404 TI - Inconclusive results of a systematic review of efficacy of antidepressants on orofacial pain disorders. AB - DATA SOURCES: Medline. STUDY SELECTION: Single or double blinded randomised controlled trials (RCTs), in patients suffering from orofacial pain disorders, with pain intensity as main outcome measure and antidepressants as treatment modality were included. Study quality was assessed using a 15-item checklist. DATA EXTRACTION AND SYNTHESIS: Two independent investigators extracted the data and a qualitative summary was presented. RESULTS: Six trials were included; four studies were randomised placebo-controlled trials and two were randomised active controlled trials. All six trials were of high quality according to the 15-item criteria. Because of the heterogeneity of treatment modalities and the low number of trials per disorder there was limited evidence to support the effectiveness of antidepressants in orofacial pain disorders. CONCLUSIONS: More randomised controlled trials are needed to come to a firm conclusion for the use of antidepressants for orofacial pain disorders. PMID- 23792405 TI - Coronectomy may be a way of managing impacted third molars. AB - DATA SOURCES: TPubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL) and the grey literature database SIGLE. STUDY SELECTION: Randomised controlled trials (RCTs) and non-randomised controlled trials (CCTs) that compared coronectomy with total removal for third molar extractions with high risk of nerve injury were included. DATA EXTRACTION AND SYNTHESIS: Data were extracted independently and in duplicate by two reviewers. Risk of bias was assessed according to the Cochrane Reviewers' Handbook. Meta analysis and sensitivity analysis were performed. RESULTS: Four studies (two RCTs and two CCTs) involving 699 patients and 940 third molars were included. Pooled risk ratios for coronectomy compared with total removal are shown in table 1.Coronectomy was changed to total removal during surgery due to root loosening or mobilisation in 2.3% to 38.3% of cases. In 0% to 4.9% of cases reoperation was required in the coronectomy group due to persistent pain, root exposure or persistent apical infections. Root migration was only reported in three studies and ranged from 13.2% to 85.9%. CONCLUSIONS: We suggest that coronectomy can protect inferior alveolar nerves in the extraction of third molars with high risk of nerve injury as compared with total removal, and that the risk ratios of post operative infections were similar between the two surgical modalities. PMID- 23792406 TI - What is the role of topical fluoride application in preventing dental erosion? PMID- 23792409 TI - Clinical characteristics and autoantibody pattern in newly diagnosed adult-onset autoimmune diabetes. AB - INTRODUCTION: Autoimmune diabetes in adults comprises a broad spectrum of clinical phenotypes. OBJECTIVES: The aim of the study was to investigate clinical and biochemical features and anti-islet autoantibody pattern in adult patients with newly diagnosed autoimmune diabetes with regard to age and the number of autoantibodies detected at diagnosis. PATIENTS AND METHODS: We retrospectively evaluated 344 patients (aged >=18 years) with newly diagnosed diabetes and a positive anti-islet antibody titer. Patients were divided based on age (<35 and >=35 years of age) or the number of detected autoantibodies (1, 2, or 3). RESULTS: The studied age groups did not differ with respect to the majority of clinical and laboratory features (e.g., clinical presentation, metabolic status, or degree of insulin deficiency). Autoantibodies to islet cell cytoplasm and to glutamic acid decarboxylase 65 occurred more frequently in younger patients, while the prevalence of autoantibodies to intracytoplasmatic domain of the tyrosine phosphatase-like protein (IA-2A) was similar in both age groups. Single autoantibody positivity was observed more often in older patients. The most common isolated autoantibody in this group was IA-2A. The presence of multiple autoantibodies was associated with younger age, lower fasting and stimulated C peptide levels, and shorter duration of symptoms. CONCLUSIONS: The patient's age at diabetes onset does not determine clinical and biochemical characteristics at diagnosis but is associated with different autoantibody status. IA-2A antibodies may be useful in diagnosing autoimmune diabetes in adult patients. The assessment of the immune profile at diagnosis may help identify patients at a higher risk of significant insulin deficiency. PMID- 23792410 TI - Fetal rat hearts do not display acute cardiotoxicity in response to maternal Doxorubicin treatment. AB - Anthracyclines are used to treat cancers during the second and third trimester of pregnancy. The chemotherapeutic effect of anthracyclines is associated with a dose- and time-dependent cardiotoxicity that is well described for infants and adults. However, data regarding fetal anthracycline-related cardiotoxicity after administration of chemotherapeutics during pregnancy are limited. In this study, we analyzed the acute effect of doxorubicin, an anthracycline derivative, on fetal and maternal rat myocardium. We injected 10 or 20 mg/kg i.v. doxorubicin to pregnant Wistar rats at day 18 of pregnancy; age-matched pregnant rats injected with physiologic saline served as controls. Maternal echocardiography and fetal Doppler scanning were performed before the injection and before sacrifice. Cesarean operation was performed at day 19 or 20, and maternal and fetal blood samples and heart biopsies were collected to measure apoptosis, the impact on cell proliferation, and structural cardiac damage. Acute maternal cardiotoxicity is associated with loss of body weight, moderately deteriorated left ventricular function, induction of apoptosis, and a decrease in cell turnover. Despite a 30% lower fetal body weight and elevated plasma B-type natriuretic peptide concentrations after doxorubicin administration, the fetal hearts had intact microstructure, an unaltered number of apoptotic cells, and preserved cell proliferation compared with controls. Our study suggests that acute treatment using anthracyclines during pregnancy impairs maternal cardiac function, whereas fetal hearts are protected. PMID- 23792411 TI - Timing is everything: Rac1 controls Net1A localization to regulate cell adhesion. AB - Cell adhesion to the extracellular matrix elicits a temporal reorganization of the actin cytoskeleton that is regulated first by Rac1 and later by RhoA. The signaling mechanisms controlling late stage RhoA activation are incompletely understood. Net1A is a RhoA/RhoB-specific guanine nucleotide exchange factor that is required for cancer cell motility. The ability of Net1A to stimulate RhoA activation is negatively regulated by nuclear sequestration. However, mechanisms controlling the plasma membrane localization of Net1A had not previously been reported. Recently we have shown that Rac1 activation stimulates plasma membrane relocalization and activation of Net1A. Net1A relocalization is independent of its catalytic activity and does not require its C-terminal pleckstrin homology or PDZ interacting domains. Rac1 activation during cell adhesion stimulates a transient relocalization of Net1A that is terminated by proteasomal degradation of Net1A. Importantly, plasma membrane localization of Net1A is required for efficient myosin light chain phosphorylation, focal adhesion maturation, and cell spreading. These data show for the first time a physiological mechanism controlling Net1A relocalization from the nucleus. They also demonstrate a previously unrecognized role for Net1A in controlling actomyosin contractility and focal adhesion dynamics during cell adhesion. PMID- 23792413 TI - Re: "Correlation of computed tomography with histopathology in otosclerosis" Quesnel et al. Otol Neurotol 2013; 34(1):22-28. PMID- 23792412 TI - Were the mental health benefits of a housing mobility intervention larger for adolescents in higher socioeconomic status families? AB - Moving to Opportunity (MTO) was a social experiment to test how relocation to lower poverty neighborhoods influences low-income families. Using adolescent data from 4 to 7 year evaluations (aged 12-19, n=2829), we applied gender-stratified intent-to-treat and adherence-adjusted linear regression models, to test effect modification of MTO intervention effects on adolescent mental health. Low parental education, welfare receipt, unemployment and never-married status were not significant effect modifiers. Tailoring mobility interventions by these characteristics may not be necessary to alter impact on adolescent mental health. Because parental enrollment in school and teen parent status adversely modified MTO intervention effects on youth mental health, post-move services that increase guidance and supervision of adolescents may help support post-move adjustment. PMID- 23792414 TI - Distribution of viral hepatitis in indigenous populations of North America and the circumpolar Arctic. AB - The burden of viral hepatitis among indigenous populations of the United States, Canada and Greenland is greater than in non-indigenous populations. In particular, throughout the circumpolar Arctic regions, chronic hepatitis B infection is highly prevalent, although incidence rates have declined considerably in certain regions due to infant HBV vaccination. Unique HBV (sub)genotypes having distinct clinical outcomes and distribution patterns are also observed within this region. In conjunction with hepatitis B infection, hepatitis delta infection is also apparent within North American indigenous peoples, particularly with outbreaks in Greenlandic Inuit communities. Incidence rates for hepatitis C infection are higher for indigenous populations within the United States and Canada; however, some hepatitis C antibody-positive indigenous patients are more likely to be HCV RNA-negative compared to non-indigenous patients. Thus, an increased understanding of the epidemiology, clinical consequences and pathogenicity of viral hepatitis affecting the indigenous populations will help to address and balance the burden of infection. PMID- 23792415 TI - Determination of toxic elements (mercury, cadmium, lead, tin and arsenic) in fish and shellfish samples. Risk assessment for the consumers. AB - Although fish intake has potential health benefits, the presence of metal contamination in seafood has raised public health concerns. In this study, levels of mercury, cadmium, lead, tin and arsenic have been determined in fresh, canned and frozen fish and shellfish products and compared with the maximum levels currently in force. In a further step, potential human health risks for the consumers were assessed. A total of 485 samples of the 43 most frequently consumed fish and shellfish species in Andalusia (Southern Spain) were analyzed for their toxic elements content. High mercury concentrations were found in some predatory species (blue shark, cat shark, swordfish and tuna), although they were below the regulatory maximum levels. In the case of cadmium, bivalve mollusks such as canned clams and mussels presented higher concentrations than fish, but almost none of the samples analyzed exceeded the maximum levels. Lead concentrations were almost negligible with the exception of frozen common sole, which showed median levels above the legal limit. Tin levels in canned products were far below the maximum regulatory limit, indicating that no significant tin was transferred from the can. Arsenic concentrations were higher in crustaceans such as fresh and frozen shrimps. The risk assessment performed indicated that fish and shellfish products were safe for the average consumer, although a potential risk cannot be dismissed for regular or excessive consumers of particular fish species, such as tuna, swordfish, blue shark and cat shark (for mercury) and common sole (for lead). PMID- 23792416 TI - The cost effectiveness of radon reduction programmes in domestic housing in England and Wales: the impact of improved radon mapping and housing trends. AB - In the UK, excessive levels of radon gas have been detected in domestic housing. Areas where 1% of existing homes were found to be over the Action Level of 200Bq.m(-3) were declared to be Radon Affected Areas. Building Regulations have been introduced which require that, for areas where between 3% and 10% of existing houses are above the Action Level, new homes should be built with basic radon protection using a membrane, and that, where 10% or more of existing homes exceed this level, new homes should be built with full radon protection. Initially these affected areas followed administrative boundaries, known as Counties. However, with increasing numbers of measurements of radon levels in domestic homes recorded in the national database, these areas have been successively refined into smaller units - 5km grid squares in 1999, down to 1km grid squares in 2007. One result is the identification of small areas with raised radon levels within regions where previously no problem had been identified. In addition, some parts of areas that were previously considered radon affected are now considered low, or no, risk. Our analysis suggests that the net result of improved mapping is to increase the number of affected houses. Further, the process is more complex for local builders, and inspectors, who need to work out whether radon protection in new homes is appropriate. Our group has assessed the cost-effectiveness of radon remediation programmes, and has applied this analysis to consider the cost-effectiveness of providing radon protection in both new and existing homes. This includes modelling the potential failure rate of membranes, and whether testing radon levels in new homes is appropriate. The analysis concludes that it is more cost effective to provide targeted radon protection in high radon areas, although this introduces more complexity. The paper also considers the trend in housing to a greater proportion of apartments, the regional variations in types of housing and the decreasing average number of occupants in each dwelling, and concludes that data and methods are now available to respond to the health risks of radon at a local level, in keeping with a general initiative to prioritise responses to health and social welfare issues at a more local level. PMID- 23792417 TI - A method to derive the relationship between the annual and short-term air quality limits--analysis using the WHO Air Quality Guidelines for health protection. AB - The World Health Organization (WHO) Air Quality Guidelines (AQG) were launched in 2006, but gaps remain in evidence on health impacts and relationships between short-term and annual AQG needed for health protection. We tested whether relationships between WHO short-term and annual AQG for particulates (PM10 and PM2.5) and nitrogen dioxide (NO2) are concordant worldwide and derived the annual limits for sulfur dioxide (SO2) and ozone (O3) based on the short-term AQG. We obtained air pollutant data over seven years (2004-2010) in seven cities from Asia-Pacific, North America and Europe. Based on probability distribution concept using maximum as the short-term limit and arithmetic mean as the annual limit, we developed a new method to derive limit value one from another in each paired limits for each pollutant with capability to account for allowable exceedances. We averaged the limit derived each year for each city, then used meta-analysis to pool the limit values in all cities. Pooled mean short-term limit for NO2 (140.5MUg/m(3) [130.6-150.4]) was significantly lower than the WHO AQG of 200MUg/m(3) while for PM10 (46.4MUg/m(3) [95CI:42.1-50.7]) and PM2.5 (28.6MUg/m(3) [24.5-32.6]) were not significantly different from the WHO AQG of 50 and 25MUg/m(3) respectively. Pooled mean annual limits for SO2 and O3 were 4.6MUg/m(3) [3.7-5.5] and 27.0MUg/m(3) [21.7-32.2] respectively. Results were robust in various sensitivity analyses. The distribution relationships between the current WHO short-term and annual AQG are supported by empirical data from seven cities for PM10 and PM2.5, but not for NO2. The short-term AQG for NO2 should be lowered for concordance with the selected annual AQG for health protection. PMID- 23792418 TI - Long-range tropospheric transport of uranium and plutonium weapons fallout from Semipalatinsk nuclear test site to Norway. AB - A combination of state-of-the-art isotopic fingerprinting techniques and atmospheric transport modelling using real-time historical meteorological data has been used to demonstrate direct tropospheric transport of radioactive debris from specific nuclear detonations at the Semipalatinsk test site in Kazakhstan to Norway via large areas of Europe. A selection of archived air filters collected at ground level at 9 stations in Norway during the most intensive atmospheric nuclear weapon testing periods (1957-1958 and 1961-1962) has been screened for radioactive particles and analysed with respect to the concentrations and atom ratios of plutonium (Pu) and uranium (U) using accelerator mass spectrometry (AMS). Digital autoradiography screening demonstrated the presence of radioactive particles in the filters. Concentrations of (236)U (0.17-23nBqm(-3)) and (239+240)Pu (1.3-782MUBqm(-3)) as well as the atom ratios (240)Pu/(239)Pu (0.0517 0.237) and (236)U/(239)Pu (0.0188-0.7) varied widely indicating several different sources. Filter samples from autumn and winter tended to have lower atom ratios than those sampled in spring and summer, and this likely reflects a tropospheric influence in months with little stratospheric fallout. Very high (236)U, (239+240)Pu and gross beta activity concentrations as well as low (240)Pu/(239)Pu (0.0517-0.077), (241)Pu/(239)Pu (0.00025-0.00062) and (236)U/(239)Pu (0.0188 0.046) atom ratios, characteristic of close-in and tropospheric fallout, were observed in filters collected at all stations in Nov 1962, 7-12days after three low-yield detonations at Semipalatinsk (Kazakhstan). Atmospheric transport modelling (NOAA HYSPLIT_4) using real-time meteorological data confirmed that long range transport of radionuclides, and possibly radioactive particles, from Semipalatinsk to Norway during this period was plausible. The present work shows that direct tropospheric transport of fallout from atmospheric nuclear detonations periodically may have had much larger influence on radionuclide air concentrations and deposition than previously anticipated. PMID- 23792419 TI - Endocrine and immunological parameters in individuals involved in Prestige spill cleanup tasks seven years after the exposure. AB - In November 2002 the oil tanker Prestige spilled 63,000tonnes of heavy oil off the northwest coast of Spain, impacting more than 1000km of coastline. A general concern led to a huge mobilization of human and technical resources, and more than 300,000 people participated in cleanup activities, which lasted up to 10months. Some endocrine and immunological alterations were reported in Prestige oil exposed subjects for several months. Therefore, the objective of this study was to evaluate if these alterations are still present seven years after the exposure. Fifty-four individuals exposed for at least 2months were compared to 50 matched referents. Prolactin and cortisol plasma concentrations, percentages of lymphocyte subsets (CD3(+), CD4(+), CD8(+), CD19(+), and CD56(+)16(+)), plasma levels of circulating cytokines (interleukin (IL) 2, IL4, IL6, IL10, tumour necrosis factor alpha, and interferon gamma), and serum concentrations of neopterin, tryptophan and kynurenine were determined in peripheral blood samples. Results showed significant differences in exposed individuals vs. referents only in cortisol (increase), kynurenine and %CD16(+)56(+) lymphocytes (both decrease). Time of exposure to the oil or using protective clothes did not influence the results, but effect of using protective mask was observed on neopterin, %CD8(+), CD4(+)/CD8(+) ratio and IL4. Surveillance of the exposed individuals for early detection of possible health problems related to the endocrine or immunological systems is recommended. PMID- 23792420 TI - Cumulative health risk assessment of 17 perfluoroalkylated and polyfluoroalkylated substances (PFASs) in the Swedish population. AB - Humans are simultaneously exposed to a multitude of chemicals. Human health risk assessment of chemicals is, however, normally performed on single substances, which may underestimate the total risk, thus bringing a need for reliable methods to assess the risk of combined exposure to multiple chemicals. Per- and polyfluoroalkylated substances (PFASs) is a large group of chemicals that has emerged as global environmental contaminants. In the Swedish population, 17 PFASs have been measured, of which the vast majority lacks human health risk assessment information. The objective of this study was to for the first time perform a cumulative health risk assessment of the 17 PFASs measured in the Swedish population, individually and in combination, using the Hazard Index (HI) approach. Swedish biomonitoring data (blood/serum concentrations of PFASs) were used and two study populations identified: 1) the general population exposed indirectly via the environment and 2) occupationally exposed professional ski waxers. Hazard data used were publicly available toxicity data for hepatotoxicity and reproductive toxicity as well as other more sensitive toxic effects. The results showed that PFASs concentrations were in the low ng/ml serum range in the general population, reaching high ng/ml and low MUg/ml serum concentrations in the occupationally exposed. For those congeners lacking toxicity data with regard to hepatotoxicity and reproductive toxicity read-across extrapolations was performed. Other effects at lower dose levels were observed for some well-studied congeners. The risk characterization showed no concern for hepatotoxicity or reproductive toxicity in the general population except in a subpopulation eating PFOS-contaminated fish, illustrating that high local exposure may be of concern. For the occupationally exposed there was concern for hepatotoxicity by PFOA and all congeners in combination as well as for reproductive toxicity by all congeners in combination, thus a need for reduced exposure was identified. Concern for immunotoxicity by PFOS and for disrupted mammary gland development by PFOA was identified in both study populations as well as a need of additional toxicological data for many PFAS congeners with respect to all assessed endpoints. PMID- 23792421 TI - Highly selective and sensitive detection of neurotransmitters using receptor modified single-walled carbon nanotube sensors. AB - We present receptor-modified carbon nanotube sensors for the highly selective and sensitive detection of acetylcholine (ACh), one kind of neurotransmitter. Here, we successfully expressed the M1 muscarinic acetylcholine receptor (M1 mAChR), a family of G protein-coupled receptors (GPCRs), in E. coli and coated single walled carbon nanotube (swCNT)-field effect transistors (FETs) with lipid membrane including the receptor, enabling highly selective and sensitive ACh detection. Using this sensor, we could detect ACh at 100 pM concentration. Moreover, we showed that this sensor could selectively detect ACh among other neurotransmitters. This is the first demonstration of the real-time detection of ACh using specific binding between ACh and M1 mAChR, and it may lead to breakthroughs for various applications such as disease diagnosis and drug screening. PMID- 23792422 TI - Aging affects high-density lipoprotein composition and function. AB - Most coronary deaths occur in patients older than 65years. Age associated alterations in the composition and function of high-density lipoproteins (HDL) may contribute to cardiovascular mortality. The effect of advanced age on the composition and function of HDL is not well understood. HDL was isolated from healthy young and elderly subjects. HDL composition, cellular cholesterol efflux/uptake, anti-oxidant properties and paraoxonase activity were assessed. We observed a 3-fold increase of the acute phase protein serum amyloid A, an increased content of complement C3 and proteins involved in endopeptidase/protease inhibition in HDL of elderly subjects, whereas levels of apolipoprotein E were significantly decreased. HDL from elderly subjects contained less cholesterol but increased sphingomyelin. Most importantly, HDL from elderly subjects showed defective antioxidant properties, lower paraoxonase 1 activity and was more rapidly taken up by macrophages, whereas cholesterol efflux capability was not altered. These findings suggest that aging alters HDL composition, resulting in functional impairment that may contribute to the onset/progression of cardiovascular disease. PMID- 23792424 TI - Enhancer-derived RNAs: 'spicing up' transcription programs. PMID- 23792423 TI - Sex-specific differences in hyperoxic lung injury in mice: implications for acute and chronic lung disease in humans. AB - Sex-specific differences in pulmonary morbidity in humans are well documented. Hyperoxia contributes to lung injury in experimental animals and humans. The mechanisms responsible for sex differences in the susceptibility towards hyperoxic lung injury remain largely unknown. In this investigation, we tested the hypothesis that mice will display sex-specific differences in hyperoxic lung injury. Eight week-old male and female mice (C57BL/6J) were exposed to 72 h of hyperoxia (FiO2>0.95). After exposure to hyperoxia, lung injury, levels of 8-iso prostaglandin F2 alpha (8-iso-PGF 2alpha) (LC-MS/MS), apoptosis (TUNEL) and inflammatory markers (suspension bead array) were determined. Cytochrome P450 (CYP)1A expression in the lung was assessed using immunohistochemistry and western blotting. After exposure to hyperoxia, males showed greater lung injury, neutrophil infiltration and apoptosis, compared to air-breathing controls than females. Pulmonary 8-iso-PGF 2alpha levels were higher in males than females after hyperoxia exposure. Sexually dimorphic increases in levels of IL-6 (F>M) and VEGF (M>F) in the lungs were also observed. CYP1A1 expression in the lung was higher in female mice compared to males under hyperoxic conditions. Overall, our results support the hypothesis that male mice are more susceptible than females to hyperoxic lung injury and that differences in inflammatory and oxidative stress markers contribute to these sex-specific dimorphic effects. In conclusion, this paper describes the establishment of an animal model that shows sex differences in hyperoxic lung injury in a temporal manner and thus has important implications for lung diseases mediated by hyperoxia in humans. PMID- 23792425 TI - Ultra-deep profiling of alternatively spliced Drosophila Dscam isoforms by circularization-assisted multi-segment sequencing. AB - The Drosophila melanogaster gene Dscam (Down syndrome cell adhesion molecule) can generate thousands of different ectodomains via mutual exclusive splicing of three large exon clusters. The isoform diversity plays a profound role in both neuronal wiring and pathogen recognition. However, the isoform expression pattern at the global level remained unexplored. Here, we developed a novel method that allows for direct quantification of the alternatively spliced exon combinations from over hundreds of millions of Dscam transcripts in one sequencing run. With unprecedented sequencing depth, we detected a total of 18,496 isoforms, out of 19,008 theoretically possible combinations. Importantly, we demonstrated that alternative splicing between different clusters is independent. Moreover, the isoforms were expressed across a broad dynamic range, with significant bias in cell/tissue and developmental stage-specific patterns. Hitherto underappreciated, such bias can dramatically reduce the ability of neurons to display unique surface receptor codes. Therefore, the seemingly excessive diversity encoded in the Dscam locus might nevertheless be essential for a robust self and non-self discrimination in neurons. PMID- 23792426 TI - XIAP: inhibitor of two worlds. AB - Autophagy is a catabolic mechanism that selectively eliminates long-lived proteins, aggregates and damaged organelles and is thereby fundamental in maintaining cellular homeostasis. As a prosurvival mechanism, autophagy is carefully regulated and its dysfunction is associated with cancer development. Work of Huang et al (2013) in this issue of The EMBO Journal identifies the apoptosis inhibitor XIAP as a novel repressor of autophagy--a function that significantly contributes to its tumorigenecity. PMID- 23792427 TI - How two become one: HJURP dimerization drives CENP-A assembly. PMID- 23792429 TI - Determinants of physical health parameters in individuals with intellectual disability who use long-term antipsychotics. AB - Individuals with intellectual disability frequently use antipsychotics for many years. This may have detrimental health effects, including neurological symptoms and metabolic and hormonal dysregulation, the latter possibly affecting bone metabolism. There is large variability in the degree in which antipsychotic agents lead to these health problems. In the current study we investigated potential determinants of physical symptoms and biological parameters known to be associated with use of antipsychotics in a convenience sample of 99 individuals with intellectual disability who had used antipsychotics for more than one year for behavioural symptoms. We focused on extrapyramidal symptoms; on overweight and presence of components of the metabolic syndrome; and on elevated plasma prolactin and bone turnover parameters. As predictor variables, we used patient (sex, age, genetic polymorphisms, and severity of intellectual disability) and medication use (type and dosage) characteristics. We found extrapyramidal symptoms to be present in 53%, overweight or obesity in 46%, and the metabolic syndrome in 11% of participants. Hyperprolactineaemia and one or more elevated bone turnover markers were present in 17% and 25%, respectively. Higher age and more severe intellectual disability were associated with dyskinesia and a higher dosage of the antipsychotic drug was associated with parkinsonism. Less severe intellectual disability was related to higher Body Mass Index. Use of atypical antipsychotics was associated with higher diastolic blood pressure and elevated fasting glucose. Clinicians who prescribe antipsychotics in individuals with intellectual disability should carefully balance the potential benefits of prolonged treatment against the risk of health hazards associated with the use of antipsychotics. PMID- 23792428 TI - Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles. AB - The protease beta-secretase 1 (Bace1) was identified through its critical role in production of amyloid-beta peptides (Abeta), the major component of amyloid plaques in Alzheimer's disease. Bace1 is considered a promising target for the treatment of this pathology, but processes additional substrates, among them Neuregulin-1 (Nrg1). Our biochemical analysis indicates that Bace1 processes the Ig-containing beta1 Nrg1 (IgNrg1beta1) isoform. We find that a graded reduction in IgNrg1 signal strength in vivo results in increasingly severe deficits in formation and maturation of muscle spindles, a proprioceptive organ critical for muscle coordination. Further, we show that Bace1 is required for formation and maturation of the muscle spindle. Finally, pharmacological inhibition and conditional mutagenesis in adult animals demonstrate that Bace1 and Nrg1 are essential to sustain muscle spindles and to maintain motor coordination. Our results assign to Bace1 a role in the control of coordinated movement through its regulation of muscle spindle physiology, and implicate IgNrg1-dependent processing as a molecular mechanism. PMID- 23792430 TI - Parthenolide reverses doxorubicin resistance in human lung carcinoma A549 cells by attenuating NF-kappaB activation and HSP70 up-regulation. AB - Chemotherapy resistance represents a major problem for the treatment of patients with lung carcinomas. Parthenolide (PN), a naturally occurring small molecule found in herb feverfew, has been used in clinical treatment. Although its importance in treating the chemotherapy resistance has been shown, the pharmacological benefits of PN for lung cancer with multidrug resistance are underappreciated. Using human lung epithelial carcinoma A549 and A549 derived DOX resistant A549/DOX cell lines, we found that PN enhanced the apoptotic cytotoxicity of DOX in A549/DOX cells. PN inhibited P-glycoprotein (P-gp) up regulation and promoted the intracellular accumulation of DOX in A549/DOX cells. PN also exhibited inhibitory effect on NF-kappaB activation in A549/DOX cells, suggesting that inhibition of NF-kappaB was involved in attenuating P-gp expression by PN. Moreover, we found that PN could also effectively inhibit the HSP70 up-regulation in A549/DOX cells. Further studies revealed a positive correlation between HSP70 and P-gp expression. Overexpression of HSP70 upregulated P-gp expression independently of NF-kappaB activation in A549 cells, and knockdown of HSP70 caused a reduced expression of P-gp in A549/DOX cells. RT PCR experiments showed that HSP70 modulated the P-gp expression mainly at transcription level. Taken together, PN can reverse DOX resistance through suppressing P-gp expression by mechanisms involving attenuation of NF-kappaB activation and HSP70 up-regulation. Our results not only provide insight into potential use of PN in reversing P-gp mediated MDR to facilitate lung cancer chemotherapy, but also highlight a potential role of HSP70 in the development of drug resistance. PMID- 23792431 TI - The impact of prolonged cadmium exposure and co-exposure with polychlorinated biphenyls on thyroid function in rats. AB - Endocrine-disrupting chemicals currently represent one of the major concerns and this study was aimed to investigate the effects of different doses of cadmium, widespread toxic metal, on the levels of thyroid hormones and to calculate Benchmark doses for these effects. Furthermore, the effects of co-exposure to cadmium and polychlorinated biphenyls on thyroid function were investigated. Six orally-treated groups of rats were receiving 0.3, 0.6, 1.25, 2.5, 5 and 10mgCd/kgb.w./day, five groups were orally treated with 0.5, 1, 2, 4 and 8mgPCBs/kgb.w./day, while nine groups of rats were orally-treated with different dose combinations of Cd and PCBs (0.6, 1.25 and 2.5mgCd/kgb.w. and 2, 4 and 8mgPCBs/kgb.w./day), during 28 days. Thyroid hormones were adversely affected by cadmium, with most prominent effect observed on triiodothyroxine levels indicating Cd interference with thyroid function at extrathyroidal level. Calculated Benchmark doses for Cd effects on thyroid hormones indicate triiodothyroxine as the most sensitive one that can be used as a basis for risk assessment. This study also implicates possible synergistic effects of Cd and PCBs on thyroid function as a consequence of their interference at different levels of thyroid homeostasis. PMID- 23792432 TI - Lead concentration in plasma as a biomarker of exposure and risk, and modification of toxicity by delta-aminolevulinic acid dehydratase gene polymorphism. AB - Blood lead concentration (B-Pb), the main biomarker of lead exposure and risk, is curvi-linearily related to exposure. We assessed plasma lead (P-Pb) as a marker for both lead exposure and toxic effects. We examined claims that delta aminolevulinic acid dehydratase genotype (ALAD) can modify lead toxicity. In 290 lead-exposed and 91 unexposed Chinese workers, we determined P-Pb, B-Pb, urinary lead (U-Pb), ALAD polymorphism (rs1800435, ALAD1/2; TaqMan assay), and also toxic effects on heme synthesis (blood zinc protoporphyrin and hemoglobin, urinary delta-aminolevulic acid), on the kidneys (urinary albumin, beta2-microglobulin and N-acetyl-beta-d-glucosaminidase) and on the peripheral nervous system (sensory and motor conduction velocities). In exposed workers, median P-Pb was 4.10 (range 0.35-27)MUg/L, B-Pb 401 (110-950)MUg/L, and U-Pb 188 (22-590)MUg/g creatinine. P-Pb had a higher ratio between exposed and unexposed workers (median 39, range 18-110) than B-Pb (19, 15-36; p<0.001) and U-Pb (28, 15-36; p<0.001). All three biomarkers were associated with all toxic effects (P-Pb: rS=-0.10 to 0.79; B-Pb: rS=-0.08 to 0.75; all p<0.05). In the exposed workers, B-Pb and U-Pb were significantly higher (p=0.04) in ALAD2 carriers (7% in the exposed population) than in ALAD1 homozygotes. P-Pb values were similar; ALAD1 homozygotes suffered higher kidney toxicity at the same P-Pb. CONCLUSIONS: (i) P Pb has advantages over B-Pb as a biomarker of high Pb exposure, but it was not significantly better as an index of risk of toxicity. (ii) The ALAD genotype modifies toxicokinetics and toxicodynamics. PMID- 23792433 TI - A diverse induction of apoptosis by trabectedin in MCF-7 (HER2-/ER+) and MDA-MB 453 (HER2+/ER-) breast cancer cells. AB - Trabectedin (Yondelis, ET-743), a semi synthetic tetrahydroisoquinoline alkaloid that was originally derived from the marine tunicate Ecteinascidia turbinata. The objective of this study was to investigate whether trabectedin mediated apoptosis shows any diversity in human breast cancer cell lines with different genotypes. Trabectedin induced cytotoxicity and apoptosis in both breast cancer cells in a time and concentration-dependent manner. The expression levels of the death receptor pathway molecules, TRAIL-R1/DR4, TRAIL-R2/DR5, FAS/TNFRSF6, TNF RI/TNFRSF1A, and FADD were significantly increased by 2.6-, 3.1-, 1.7-, 11.2- and 4.0-fold by trabectedin treatment in MCF-7 cells. However, in MDA-MB-453 cells, the mitochondrial pathway related pro-apoptotic proteins Bax, Bad, Cytochrome c, Smac/DIABLO, and Cleaved Caspase-3 expressions were induced by 4.2-, 3.6-, 4.8-, 4.5-, and 4.4-fold, and the expression levels of anti-apoptotic proteins Bcl-2 and Bcl-XL were reduced by 4.8- and 5.2-fold in MDA-MB-453 cells. Moreover, trabectedin treatment increased the generation of ROS in both breast cancer cells. We have shown that trabectedin causes selective activation of extrinsic and intrinsic apoptotic pathways in two genotypically different breast cancer cells. This preliminary data might guide clinicians to choose appropriate combination agents with trabectedin based on different molecular subtypes of breast cancer. PMID- 23792434 TI - Megakaryocytes co-localise with hemopoietic stem cells and release cytokines that up-regulate stem cell proliferation. AB - We report transplanted hemopoietic stem cells (HSC) preferentially lodge within two cells of mature megakaryocytes (MM). With both populations comprising ~0.2% of bone marrow cells, this strongly suggests a key functional interaction. HSC isolated from the endosteum (eLSKSLAM) showed significantly increased hemopoietic cell proliferation while in co-culture with MM. Furthermore, eLSKSLAM progeny retained HSC potential, maintaining long-term multi-lineage reconstitution capacity in lethally ablated recipients. Increased hemopoietic cell proliferation was not MM contact dependent and could be recapitulated with media supplemented with two factors identified in MM-conditioned media: insulin-like growth factor binding protein-3 (IGFBP-3) and insulin-like growth factor-1 (IGF-1). We demonstrate that HSC express the receptor for IGF-1 and that IGF-1/IGFBP-3 induced increased hemopoietic cell proliferation can be blocked by an anti-IGF-1 neutralising antibody. However, co-cultures of 8N, 16N or 32N MM with eLSKSLAM showed that MM of individual ploidy did not significantly increase hemopoietic cell proliferation. Our data suggests that MM are an important component of the HSC niche and regulate hemopoietic cell proliferation through cytokine release. PMID- 23792435 TI - Global proteomic signature of undifferentiated human bone marrow stromal cells: evidence for donor-to-donor proteome heterogeneity. AB - The clinical application of human bone marrow stromal cells (hBMSCs) largely depends on their capacity to expand in vitro. We have conducted a comprehensive comparative proteomic analysis of culture-expanded hBMSCs obtained from different human donors. The data reveal extensive donor-to-donor proteomic heterogeneity. Processing and database-searching of the tandem MS data resulted in a most comprehensive to date proteomic dataset for hBMSC. A total of 7753 proteins including 712 transcription and translation regulators, 384 kinases, 248 receptor proteins, and 29 cytokines were confidently identified. The proteins identified are mainly nuclear (43.2%) and the share of proteins assigned to more than one subcellular location constitutes 10% of the identified proteome. Bioinformatics tools (IPA, DAVID, and PANTHER) were used to annotate proteins with respect to cellular locations, functions, and other physicochemical characteristics. We also compared the proteomic profile of hBMSCs to recently compiled datasets for human and mouse pluripotent stem cells. The result shows the extent of similarity between the three cell populations and also identified 253 proteins expressed uniformly by all lines of hBMSCs but not reported in the proteomic datasets of the two pluripotent stem cells. Overall, the proteomic database reported in this paper can serve as a reference map for extensive evaluation of hBMSC to explain their biology as well as identify possible marker candidates for further evaluation. PMID- 23792436 TI - Cardiolipin deficiency affects respiratory chain function and organization in an induced pluripotent stem cell model of Barth syndrome. AB - Barth syndrome (BTHS) patients carrying mutations in tafazzin (TAZ1), which is involved in the final maturation of cardiolipin, present with dilated cardiomyopathy, skeletal myopathy, growth retardation and neutropenia. To study how mitochondrial function is impaired in BTHS patients, we generated induced pluripotent stem cells (iPSCs) to develop a novel and relevant human model system for BTHS. BTHS-iPSCs generated from dermal fibroblasts of three patients with different mutations in TAZ1 expressed pluripotency markers, and were able to differentiate into cells derived from all three germ layers both in vitro and in vivo. We used these cells to study the impact of tafazzin deficiency on mitochondrial oxidative phosphorylation. We found an impaired remodeling of cardiolipin, a dramatic decrease in basal oxygen consumption rate and in the maximal respiratory capacity in BTHS-iPSCs. Simultaneous measurement of extra cellular acidification rate allowed us a thorough assessment of the metabolic deficiency in BTHS patients. Blue native gel analyses revealed that decreased respiration coincided with dramatic structural changes in respiratory chain supercomplexes leading to a massive increase in generation of reactive oxygen species. Our data demonstrate that BTHS-iPSCs are capable of modeling BTHS by recapitulating the disease phenotype and thus are important tools for studying the disease mechanism. PMID- 23792438 TI - Evaluation of possible error sources in corneal endothelial morphometry with a semiautomated noncontact specular microscope. AB - PURPOSE: To assess the corneal endothelium, particularly the polymegethism feature, using the Topcon SP-3000P specular microscope with newer center-dot software. METHODS: Forty-eight healthy, normal weight, noncontact lens wearers of Asian ethnicity were assessed. Single endothelial images from each subject were processed with center-dot software, reevaluated after correction of obvious errors, and then by manual border marking and planimetry. Endothelial cell density based on average cell area and the coefficient of variation (COV) of cell area (polymegethism) were calculated. RESULTS: Error sources are associated with erroneous location of cell borders (usually creating larger or smaller "cells") or failure to assign cell borders to a marked cell. On the initial application of the center-dot software, the endothelial cell density values ranged from 1822 to 3244 cells per square millimeter (mean, 2644 cells/mm); this range was reduced (eg, 1955-3054 cells/mm; mean 2690 cells/mm on editing or in manual planimetry). The COV values ranged from 17% to 39% (mean, 27.5% +/- 5.5%), with one third of the endothelia yielding COV values of greater than or equal to 30%. On editing or in manual planimetry, the COV values were reduced to between 17% and 29% (mean, 24.5% +/- 3.2%; P < 0.001). CONCLUSIONS: In the use of a center-dot endothelial analysis program with cell border identification, it is likely that at least 1 set of editing steps is required to produce reasonable results. PMID- 23792437 TI - Dysregulated heme oxygenase-ferritin system in pterygium pathogenesis. AB - PURPOSE: Cyclooxygenase (COX)-, lipoxygenase (LOX)-, and cytochrome P450 monooxygenase (CYP)-derived eicosanoids have been implicated in ocular surface inflammation and neovascularization. These eicosanoids are subjected to regulation by enzymes, such as heme oxygenases (HOs) and ferritin. METHODS: Quantitative polymerase chain reaction and lipidomics based on liquid chromatography-tandem mass spectrometry were performed on pterygia from patients undergoing surgical pterygium excision. Control tissues consisted of donor corneas. In addition, lipidomics based on liquid chromatography-tandem mass spectrometry was performed on tears collected from patients before the surgery. RESULTS: Messenger RNA (mRNA) expression of HO-2, the constitutive HO isoform, was upregulated by 40% in pterygia compared with control tissue, whereas the mRNA level of the inducible form, HO-1, was downregulated by more than 50%. Levels of CYP4B1 mRNA showed an approximate 2-fold increase in pterygia compared with control. Lipidomic analysis of tissues indicated a moderate elevation in Prostaglandin E2 and thromboxane B2 levels in pterygia compared with control. Among the LOX-derived metabolites, the antiinflammatory-hydroxyeicosatetraenoic acid (15-HETE) levels were significantly reduced in pterygia (79.3 +/- 48.11 pg/mg protein) compared with control (586.2 +/- 213.5 pg/mg protein), whereas the proinflammatory LOX- and CYP4B1-derived 12-HETE levels were 10-fold higher in pterygia (2768 +/- 832.3 pg/mg protein) compared with control (231.4 +/- 87.35 pg/mg protein). Prostaglandin E2 and HETEs were also present in tears from patients with pterygium but were not detected in tears from healthy volunteers. The mRNA expression levels of both light and heavy chain ferritin were 60% and 30% lower, respectively, in pterygia compared with control. CONCLUSIONS: We believe that a dysfunctional HO-ferritin system leads to increased levels of proinflammatory mediators, thus contributing to the inflammation characteristic of pterygia. PMID- 23792439 TI - Retrocorneal membrane after Descemet membrane endothelial keratoplasty. AB - PURPOSE: To describe a retrocorneal membrane after Descemet membrane endothelial keratoplasty (DMEK). METHODS: Case report and review of the medical literature. RESULTS: A 73-year-old woman diagnosed with bilateral pseudophakic bullous keratopathy underwent DMEK in her left eye. Her preoperative best-spectacle corrected visual acuity OD was 20/500 and OS was 20/500. After DMEK, graft detachment was found on the first and second postoperative days. Graft repositioning with air was performed 2 times. One month after DMEK, a membranous structure was identified behind the cornea by slit-lamp examination. The patient was applying topical levofloxacin 0.5% (Cravit; Santen, Japan) and prednisolone acetate 1% (Pred Forte; Allergan, Irvine, CA) 4 times per day. Two months after DMEK, the retrocorneal membrane disappeared, and the patient's best-corrected visual acuity OS improved to 20/40. CONCLUSIONS: We report the first case of retrocorneal membrane formation after DMEK surgery. PMID- 23792440 TI - Relationship between ultrasound features of nonalcoholic fatty liver disease and cardiometabolic risk factors in patients with newly diagnosed type 2 diabetes. AB - INTRODUCTION: It is suggested that nonalcoholic fatty liver disease (NAFLD) correlates with cardiometabolic risk factors in patients with newly diagnosed type 2 diabetes. OBJECTIVES: The aim of this study was to evaluate the prevalence of ultrasound features of NAFLD in patients with newly diagnosed type 2 diabetes and their relationship with cardiometabolic risk factors. PATIENTS AND METHODS: The study included 100 consecutive patients (mean age, 55.64 +/-13.42 years) with newly diagnosed type 2 diabetes, without other causes of hepatosteatosis. In each patient, medical history was taken, physical and abdominal ultrasound examinations were performed, and anthropometric and biochemical parameters were measured. Based on the results of an ultrasound examination, patients were assigned to 2 groups: with (n = 71) and without (n = 29) NAFLD. RESULTS: NAFLD was present in more than 70% of the patients with diabetes. In patients with NAFLD, significantly higher mean values of body weight, waist and hip circumferences, body mass index, liver enzyme activity, serum C-reactive protein, total cholesterol, and triglycerides and significantly lower levels of high-density lipoprotein (HDL) cholesterol were observed. There were no significant differences in the parameters of glycemic control between the groups. A correlation was observed between ultrasound features of NAFLD and some cardiovascular risk factors. Increased waist circumference and serum gamma glutamyltransferase level and decreased HDL-cholesterol levels were shown to be independent risk factors of NAFLD. CONCLUSIONS: Liver ultrasound should be performed in every patient with newly diagnosed type 2 diabetes. Our findings indicate a relationship between NAFLD and multiple cardiometabolic risk factors. The measurement of selected biochemical and anthropometric parameters may be used to assess the risk of NAFLD in this patient group. PMID- 23792441 TI - Recent developments in flexor tendon repair techniques and factors influencing strength of the tendon repair. AB - Over the last decade, both basic researchers and surgeons have sought to identify the most appropriate techniques to be applied in flexor tendon repairs. Recent developments in experimental tendon repairs and clinical outcomes of newer repair techniques have been reviewed in an attempt to comprehensively summarize the most critical mechanical factors affecting the performance of tendon repairs and the surgical factors influencing clinical outcomes. Among them, attention to annular pulleys, the purchase and tension of the core suture, and the direction and curvature of the path of tendon motion have been found to be determining factors in the results of tendon repair. PMID- 23792442 TI - Early rehabilitation after stable osteosynthesis of intra-articular fractures of the metacarpal base of the thumb. AB - The aim of this study was to investigate the radiological and functional results of anatomical reduction and stable fixation followed by an early rehabilitation programme in the treatment of fractures of the base of the thumb metacarpal. Sixteen consecutive patients (11 men and five women; mean age: 36.4 years) with intra-articular fractures of the thumb metacarpal base were treated with plate and/or screw fixation between April 2002 and March 2011 at our department. Patients were followed-up for an average period of 15.62 months. Bony healing was achieved in all cases and all patients were able to return to pre-trauma activity levels 12 weeks following surgery. Open reduction with stable internal fixation and an early active rehabilitation programme appears to be an efficient method in the treatment of trapeziometacarpal joint fractures with satisfactory functional and radiological results. PMID- 23792443 TI - Four years of immunization with OM-85 BV to prevent respiratory infections in HIV+ patients. AB - We report an interventional, non-randomized experience of OM-85 BV immunization in a group of 104 HIV-infected subjects presenting recurrent seasonal respiratory bacterial infections. We compared the number of respiratory events, the use of antibiotics and the cost related to antibiotics before (2005-2006) and after (2008-2011) the introduction of such intervention. The year 2007 was excluded from the analysis since half of the patients were immunized in that year in an exploratory approach. Respiratory infections dropped in all groups but in subjects with recurrent otitis, leading to a reduction in the use of antibiotics. This is the first report of the effect of OM-85 BV in vivo in HIV-infected subjects. PMID- 23792444 TI - The oncogenic GLI transcription factors facilitate keratinocyte survival and transformation upon exposure to genotoxic agents. AB - Ultraviolet B (UVB) light is the principal aetiological factor associated with non-melanoma skin cancer, the most prevalent group of malignancies in the Caucasian population. Exposure to environmental chemicals has also been shown to promote skin carcinogenesis and, as for UVB, this is associated with the acquisition of genomic DNA damage. Cells respond to DNA damage by inducing cell cycle arrest to facilitate DNA repair, although apoptosis will occur if the damage is excessive. Oncogenes may drive carcinogenesis by disrupting the balanced control of cell cycle progression, DNA repair and apoptosis, allowing for the propagation of cells with damaged DNA. The transcription factors GLI1 and GLI2 have been implicated in both the initiation and progression of several cancers, including basal cell carcinoma. Here we show that GLI1 and an active mutant of GLI2 (DeltaNGLI2) promote apoptotic resistance in N/TERT human keratinocytes upon exposure to UVB and the DNA-alkylating chemicals such as methyl methanesulphonate (MMS) and N-ethyl-N-nitrosurea. Compared with control and untreated N/TERT-GLI1 and -GLI2 cells, those that survived genotoxic insult formed significantly more colonies in soft agar and were significantly more invasive when grown in three-dimensional organotypic collagen gel cultures. Indeed, surviving N/TERT-GLI1 and -GLI2 cells expressed higher levels of the epithelial-to-mesenchymal transition markers Snail and vimentin, and a subpopulation of MMS-treated cells displayed an elongated fibroblast-like morphology with decreased levels of E-cadherin. Finally, whereas Bcl2 was strongly increased in N/TERT-GLI2 cells, the level of induction was weak in N/TERT-GLI1 cells, indicating that GLI1 may activate anti-apoptotic mechanisms(s) independently of Bcl2. In summary, our results show that GLI1 and GLI2 facilitate the propagation of cells with damaged DNA, and thus their expression may be naturally higher in cells that form the earliest precursor tumour lesions. PMID- 23792445 TI - Annexin A2 depletion delays EGFR endocytic trafficking via cofilin activation and enhances EGFR signaling and metastasis formation. AB - Enhanced epidermal growth factor receptor (EGFR) activity has been strongly linked to breast cancer progression and mediators of EGFR endocytosis may well be involved. We developed a semi-automated high-content fluorescence microscopy based EGFR endocytosis screen to identify proteins that mediate EGFR endocytosis in human HBL100 breast cancer cells. Knockdown of 172 individual endocytosis and actin-regulatory genes with small interfering RNAs led to the identification of 14 genes of which the contribution to EGFR endocytosis in breast cancer is until now poorly defined, including DNAJC6, GDI2, FGD6, HAX1, NECAP2 and AnxA2. We show that depletion of the actin and endocytosis regulatory protein annexin A2 (AnxA2) in a panel of four triple negative breast cancer (TNBC) cell lines affected EGFR endocytosis. Depletion of AnxA2 in the aggressive and highly metastatic MDA-MB 231 TNBC cell line resulted in the inhibition of EGFR transport beyond the early endosomes. This inhibition coincided with enhanced epidermal growth factor (EGF) induced cell migration and downstream signaling via c-Jun N-terminal kinase (JNK) and Akt. Moreover, AnxA2 knockdown increased lung metastasis formation in mice. The effect of AnxA2 knockdown on EGFR endocytosis in MDA-MB-231 was related to dephosphorylation/activation of the actin-severing protein cofilin, as re expression of an inactive S3E-cofilin mutant, but not an active S3A-cofilin mutant, re-established EGFR endocytosis to control levels. Together, our data provide evidence for AnxA2 as a mediator of EGFR endocytosis and signaling in breast cancer via regulation of cofilin activation. PMID- 23792446 TI - Whole chromosome instability resulting from the synergistic effects of pRB and p53 inactivation. AB - Whole chromosome instability (CIN) is a common feature of cancer cells and has been linked to increased tumor evolution and metastasis. Several studies have shown that the loss of the pRB tumor suppressor causes mitotic defects and chromosome mis-segregation. pRB is inactivated in many types of cancer and this raises the possibility that the loss of pRB may be a general cause of CIN in tumors. Paradoxically, retinoblastoma tumor cells have a relatively stable karyotype and currently the circumstances in which pRB inactivation causes CIN in human cancers are unclear. Here we utilize a fluorescence in situ hybridization based approach to score numerical heterogeneity in chromosome copy number as a readout of CIN. Using this technique, we show that high levels of CIN correlate with the combined inactivation of pRB and p53 and that this association is evident in two independent panels of cancer cell lines. Retinoblastoma cell lines characteristically retain a wild-type TP53 gene, providing an opportunity to test the relevance of this functional relationship. We show that retinoblastoma cell lines display mitotic defects similar to those seen when pRB is depleted from non transformed cells, but that the presence of wild-type p53 suppresses the accumulation of aneuploid cells. A similar synergy between pRB and p53 inactivation was observed in HCT116 cells. These results suggest that the loss of pRB promotes segregation errors, whereas loss of p53 allows tolerance and continued proliferation of the resulting, genomically unstable cancer cells. Hence, it is the cooperative effect of inactivation of both pRB and p53 tumor suppressor pathways that promotes CIN. PMID- 23792447 TI - Snail1-dependent transcriptional repression of Cezanne2 in hepatocellular carcinoma. AB - High malignancy and early metastasis are the hallmarks of hepatocellular carcinoma (HCC). Here, we report that Cezanne2 expression is downregulated in HCC cells and in HCC patients' tumorous tissues and that Cezanne2 is inversely associated with Snail1 expression in HCC patients' tumorous tissues. Chromatin immunoprecipitation assays and the reporter gene assay showed that Snail1 binds to the promoter of the Cezanne2 gene and mediates the direct consequence of Cezanne2 repression. Enhanced expression of Cezanne2 could suppress proliferation, migration and invasion in HCC cells. Further, Cezanne2 could regulate MMP (matrix metalloproteinase)2, MMP9 and ICAM1 (intercellular adhesion molecule) levels through modulation of the NF-kappaB (nuclear factor kappa-light chain-enhancer of activated B cell) signaling cascade. Co-immunoprecipitation and in vivo deubiquitination assay indicated that Cezanne2 interacts with TNF receptor-associated factor (TRAF)6 and cleaves the polyubiquitin from TRAF6 substrates. Our data reveal that Snail1-mediated suppression of Cezanne2 may have a key role in HCC malignancy. PMID- 23792448 TI - Targeting Myc in KSHV-associated primary effusion lymphoma with BET bromodomain inhibitors. AB - Primary effusion lymphoma (PEL) is an aggressive form of non-Hodgkin's B-cell lymphoma associated with infection by Kaposi's sarcoma-associated herpes virus (KSHV). (+)-JQ1 and I-BET151 are two recently described novel small-molecule inhibitors of BET bromodomain chromatin-associated proteins that have shown impressive preclinical activity in cancers in which MYC is overexpressed at the transcriptional level due to chromosomal translocations that bring the MYC gene under the control of a super-enhancer. PEL cells, in contrast, lack structural alterations in the MYC gene, but have deregulated Myc protein due to the activity of KSHV-encoded latent proteins. We report that PEL cell lines are highly sensitive to bromodomain and extra-terminal (BET) bromodomain inhibitors-induced growth inhibition and undergo G0/G1 cell-cycle arrest, apoptosis and cellular senescence, but without the induction of lytic reactivation, upon treatment with these drugs. Treatment of PEL cell lines with BET inhibitors suppressed the expression of MYC and resulted in a genome-wide perturbation of MYC-dependent genes. Silencing of BRD4 and MYC expression blocked cell proliferation and cell cycle progression, while ectopic expression of MYC from a retroviral promoter rescued cells from (+)-JQ1-induced growth arrest. In a xenograft model of PEL, (+)-JQ1 significantly reduced tumor growth and improved survival. Taken collectively, our results demonstrate that the utility of BET inhibitors may not be limited to cancers in which genomic alterations result in extremely high expression of MYC and they may have equal or perhaps greater activity against cancers in which the MYC genomic locus is structurally intact and c-Myc protein is deregulated at the post-translational level and is only modestly overexpressed. PMID- 23792449 TI - Infiltrating bone marrow mesenchymal stem cells increase prostate cancer stem cell population and metastatic ability via secreting cytokines to suppress androgen receptor signaling. AB - Although the contribution of the bone marrow mesenchymal stem cells (BM-MSCs) in cancer progression is emerging, their potential roles in prostate cancer (PCa) remain unclear. Here, we showed that PCa cells could recruit BM-MSCs and consequently the metastatic ability of PCa cells was increased. We also found that the increased metastatic ability of PCa cells could be due to the increased PCa stem cell population. Mechanism dissection studies found that the upregulation of Chemokine ligand 5 (CCL5) expression in BM-MSCs and PCa cells, after MSCs infiltrated into the PCa cells, subsequently downregulated androgen receptor (AR) signaling, which was due to inhibition of AR nuclear translocation. Interruption of such signaling led to suppression of the BM-MSCs-induced PCa stem cell population increase and thereby inhibited the metastatic ability of PCa cells. The PCa stem cell increase then led to the upregulation of matrix metalloproteinase 9, ZEB-1, CD133 and CXCR4 molecules, and enhanced the metastatic ability of PCa cells. Therefore, we conclude that the BM-MSCs-mediated increased metastatic ability of PCa cells can be due to the PCa stem cell increase via alteration of the CCL5-AR signaling pathway. Together, these results uncover the important roles of BM-MSCs as key components in the prostate tumor microenvironment to promote PCa metastasis and may provide a new potential target to suppress PCa metastasis by blocking BM-MSCs infiltration into PCa. PMID- 23792450 TI - Integrin alpha3beta1-CD151 complex regulates dimerization of ErbB2 via RhoA. AB - Integrin alpha3beta1 regulates adhesive interactions of cells with laminins and have a critical role in adhesion-dependent cellular responses. Here, we examined the role of alpha3beta1-integrin in ErbB2-dependent proliferation of breast cancer cells in three-dimensional laminin-rich extracellular matrix (3D lr-ECM). Depletion of alpha3beta1 in ErbB2-overexpressing breast cancer cells suppressed growth and restore cell polarity in 3D lr-ECM. The phenotype of alpha3beta1 depleted cells was reproduced upon depletion of tetraspanin CD151 and mirrored that of the cells treated with Herceptin, an established ErbB2 antagonist. Breast cancer cells expressing the alpha3beta1-CD151 complex have higher steady-state phosphorylation of ErbB2 and show enhanced dimerization of the protein when compared with alpha3beta1-/CD151-depleted cells. Furthermore, Herceptin-dependent dephosphorylation of ErbB2 was only observed in alpha3beta1-CD151-expressing cells. Importantly, the inhibitory activity of Herceptin was more pronounced when cells expressed both alpha3beta1 and CD151. We also found that the level of active RhoA was increased in alpha3beta1- and CD151-depleted cells and that Rho controls dimerization of ErbB2. Expression of alpha3beta1 alone did not have significant prognostic value in patients with invasive ductal carcinoma of the breast. However, expression of alpha3beta1 in combination with CD151 represented a more stringent indicator of poor survival than CD151 alone. Taken together, these results demonstrate that the alpha3beta1-CD151 complex has a critical regulatory role in ErbB2-dependent signalling and thereby may be involved in breast cancer progression. PMID- 23792452 TI - Linear B-cell epitopes in BthTX-1, BthTX-II and BthA-1, phospholipase A2's from Bothrops jararacussu snake venom, recognized by therapeutically neutralizing commercial horse antivenom. AB - The benefits from treatment with antivenom sera are indubitable. However, the mechanism for toxin neutralization has not been completely elucidated. A mixture of anti-bothropic and anti-crotalic horse antivenom has been reported to be more effective in neutralizing the effects of Bothrops jararacussu snake venom than anti-bothropic antivenom alone. This study determined which regions in the three PLA2s from B. jararacussu snake venom are bound by antibodies in tetravalent anti bothropic and monovalent anti-crotalic commercial horse antivenom. Mapping experiments of BthTX-I, BthTX-II and BthA-I using two small libraries of 69 peptides each revealed six major IgG-binding epitopes that were recognized by both anti-bothropic and anti-crotalic horse antivenom. Two epitopes in BthTX-I were only recognized by the anti-bothropic horse antivenom, while anti-crotalic horse antivenom recognized four unique epitopes across the three PLA2s. Our studies suggest that the harmful activities of the PLA2s present in the venom of B. jararacussu are neutralized by the combinatorial treatment with both antivenom sera through their complementary binding sites, which provides a wide coverage on the PLA2s. This is the first peptide microarray of PLA2s from B. jararacussu snake venom to survey the performance of commercial horse antiophidic antivenom. Regions recognized by the protective antivenom sera are prime candidates for improved venom cocktails or a chimeric protein encoding the multiple epitopes to immunize animals as well as for designing future synthetic vaccines. PMID- 23792453 TI - ADP is a vasodilator component from Lasiodora sp. mygalomorph spider venom. AB - Members of the spider genus Lasiodora are widely distributed in Brazil, where they are commonly known as caranguejeiras. Lasiodora spider venom is slightly harmful to humans. The bite of this spider causes local pain, edema and erythema. However, Lasiodora sp. spider venom may be a source of important pharmacological tools. Our research group has described previously that Lasiodora sp. venom produces bradycardia in the isolated rat heart. In the present work, we sought to evaluate the vascular effect of Lasiodora sp. venom and to isolate the vasoactive compounds from the venom. The results showed that Lasiodora spider venom induced a concentration-dependent vasodilation in rat aortic rings, which was dependent on the presence of a functional endothelium and abolished by the nitric oxide synthase (NOS) inhibitor L-NAME. Western blot experiments revealed that the venom also increased endothelial NOS function by increasing phosphorylation of the Ser1177 residue. Assay-directed fractionation isolated a vasoactive fraction from Lasiodora sp. venom. Mass spectrometry (MS) and nuclear magnetic resonance (NMR) assays identified a mixture of two compounds: adenosine diphosphate (ADP, approximately 90%) and adenosine monophosphate (AMP, approximately 10%). The vasodilator effects of Lasiodora sp. whole venom, as well as ADP, were significantly inhibited by suramin, which is a purinergic P2-receptor antagonist. Therefore, the results of the present work indicate that ADP is a main vasodilator component of Lasiodora sp. spider venom. PMID- 23792454 TI - High accuracy mass spectrometry comparison of Conus bandanus and Conus marmoreus venoms from the South Central Coast of Vietnam. AB - Cone snail (genus Conus) venoms provide a rich source of small bioactive peptides known as conopeptides or conotoxins, which are highly interesting in pharmacological studies for new drug discovery. Conus species have evolved expressing a variety of conopeptides, adapted to the biological targets of their own specific preys at their living environments. Therefore, the potential proteomic evaluation of Conus venom components, poorly studied, is of great interest. Early studies supposed about 5% overlap in venom peptides from different Conus species. In this study, we compare using nano-liquid chromatography coupled with electrospray ionisation-mass spectrometry and bioinformatics, the molluscivorous Conus bandanus venom to that of its close relative Conus marmoreus of the South Central Coast of Vietnam. With this approach, we demonstrate with high precision that 92 common conopeptides are present in the venom of the two mollusc-hunting cone snails, representing 24.4% (out of 376 peptides) and 18.4% (out of 499 peptides) of C. bandanus and C. marmoreus components, respectively. The proteomic comparison of the two close relative interspecies suggests both common and different strategies for mature conopeptide production in the two species. The overall estimation of putative conopeptide disulphide bridges reveals 75% and 61% of "disulphide-rich" peptides in C. bandanus and C. marmoreus venom components, respectively. The same amino acid sequence for Bn1.1 and Mr1.1, determined at the genomic level, was also found in the two venoms, besides other common conopeptides. Confidently, the broader distribution of C. bandanus compared to C. marmoreus guarantee new opportunities for discovering conopeptides with original pharmacological properties. PMID- 23792455 TI - An overall uncertainty approach for the validation of analytical separation methods. AB - The aim of this paper is to recommend a new strategy for the analytical validation based on the uncertainty profile as a graphical decision-making tool, and to exemplify a novel method to estimate the measurement uncertainty. Indeed, the innovative formula that we offer to assess the uncertainty is based on the calculation of the beta-content tolerance interval. Three chemometric methodologies are exposed to build the (beta, gamma) tolerance interval, namely: the Satterthwaite approximation, the GPQ method (generalized pivotal confidence) and the MLS procedure (modified large simple). Furthermore, we illustrate the applicability and flexibility of the uncertainty profile to assess the fitness of the purpose of chromatographic and electrophoretic analytical methods, which use different instrumental techniques such as liquid chromatography (LC-UV, LC-MS), gas chromatography (GC-FID, GC-MS) and capillary electrophoresis (CE, CE-MS). In addition, we demonstrate here that (beta, gamma) tolerance intervals will provide perfect estimates of the routine uncertainty. In particular, we show that there is no difference statistically between the uncertainties estimated by our methodology as of the validation stage with those obtained from the routine phase. PMID- 23792451 TI - Discovery of colorectal cancer PIK3CA mutation as potential predictive biomarker: power and promise of molecular pathological epidemiology. AB - Regular use of aspirin reduces incidence and mortality of various cancers, including colorectal cancer. Anticancer effect of aspirin represents one of the 'Provocative Questions' in cancer research. Experimental and clinical studies support a carcinogenic role for PTGS2 (cyclooxygenase-2), which is an important enzymatic mediator of inflammation, and a target of aspirin. Recent 'molecular pathological epidemiology' (MPE) research has shown that aspirin use is associated with better prognosis and clinical outcome in PIK3CA-mutated colorectal carcinoma, suggesting somatic PIK3CA mutation as a molecular biomarker that predicts response to aspirin therapy. The PI3K (phosphatidylinositol-4,5 bisphosphonate 3-kinase) enzyme has a pivotal role in the PI3K-AKT signaling pathway. Activating PIK3CA oncogene mutations are observed in various malignancies including breast cancer, ovarian cancer, brain tumor, hepatocellular carcinoma, lung cancer and colon cancer. The prevalence of PIK3CA mutations increases continuously from rectal to cecal cancers, supporting the 'colorectal continuum' paradigm, and an important interplay of gut microbiota and host immune/inflammatory reaction. MPE represents an interdisciplinary integrative science, conceptually defined as 'epidemiology of molecular heterogeneity of disease'. As exposome and interactome vary from person to person and influence disease process, each disease process is unique (the unique disease principle). Therefore, MPE concept and paradigm can extend to non-neoplastic diseases including diabetes mellitus, cardiovascular diseases, metabolic diseases, and so on. MPE research opportunities are currently limited by paucity of tumor molecular data in the existing large-scale population-based studies. However, genomic, epigenomic and molecular pathology testings (for example, analyses for microsatellite instability, MLH1 promoter CpG island methylation, and KRAS and BRAF mutations in colorectal tumors) are becoming routine clinical practices. In order for integrative molecular and population science to be routine practice, we must first reform education curricula by integrating both population and molecular biological sciences. As consequences, next-generation hybrid molecular biological and population scientists can advance science, moving closer to personalized precision medicine and health care. PMID- 23792456 TI - Shape effect on a single-nanoparticle-based plasmonic nanosensor. AB - Plasmonic refractometric nanosensors based on single nanostructures, i.e. spherical, nanorodand bipyramid-shaped gold nanoparticles, are investigated and compared numerically by employing the finite-difference time-domain method. The results show that the plasmonic sensing ability is distributed anisotropically around the nanorod and bipyramid, even for spherical nanoparticles when the illumination light is linearly polarized. To optimize nanosensor performance, some anisotropy in the shape of nanoparticles is required, this latter serving as an intrinsic light polarization filter to suppress the disturbance from localized surface plasmon resonance in other directions. The plasmonic near-field can be engineered by controlling the shape to achieve a concentrated and localized electromagnetic field, in direct relation with the sensing ability. Taking these factors into account, the gold bipyramid nanoconstruct which is easily available in experiment is proposed as an efficient plasmonic sensing platform. The bipyramid presents both highly localized sensitivity and high scattering cross section, thus avoiding the trade-off during the selection of the widely used nanorod-shaped sensors. The parameters of the bipyramid structure can be optimized by numerical simulation to improve the plasmonic sensing. Our findings permit a deeper understanding of single-nanoparticle-sensor behavior, and the study provides an opportunity to optimize the plasmonic sensor. PMID- 23792457 TI - CD164 and FCRL3 are highly expressed on CD4+CD26- T cells in Sezary syndrome patients. AB - Sezary syndrome (SS) cells express cell surface molecules also found on normal activated CD4 T cells. In an effort to find a more specific surface marker for malignant SS cells, a microarray analysis of gene expression was performed. Results showed significantly increased levels of mRNA for CD164, a sialomucin found on human CD34+ hematopoietic stem cells, and FCRL3, a molecule present on a subset of human natural T regulatory cells. Both markers were increased in CD4 T cells from SS patients compared with healthy donors (HD). Flow cytometry studies confirmed the increased expression of CD164 and FCRL3 primarily on CD4+CD26- T cells of SS patients. Importantly, a statistically significant correlation was found between an elevated percentage of CD4+CD164+ T cells and an elevated percentage of CD4+CD26- T cells in all tested SS patients but not in patients with mycosis fungoides and atopic dermatitis or HD. FCRL3 expression was significantly increased only in patients with high tumor burden. CD4+CD164+ cells displayed cerebriform morphology and their loss correlated with clinical improvement in treated patients. Our results suggest that CD164 can serve as a marker for diagnosis and for monitoring progression of cutaneous T-cell lymphoma (CTCL)/SS and that FCRL3 expression correlates with a high circulating tumor burden. PMID- 23792458 TI - Reduced susceptibility to two-stage skin carcinogenesis in mice with epidermis specific deletion of CD151. AB - Altered expression of the tetraspanin CD151 is associated with skin tumorigenesis; however, whether CD151 is causally involved in the tumorigenic process is not known. To evaluate its role in tumor formation, we subjected epidermis-specific Cd151 knockout mice to chemical skin carcinogenesis. Mice lacking epidermal Cd151 developed fewer and smaller tumors than wild-type mice after treatment with 7,12-dimethylbenzanthracene (DMBA)/12-O-tetradecanoylphorbol 13-acetate (TPA). Furthermore, Cd151-null epidermis showed a reduced hyperproliferative response to short-term treatment with TPA as compared with wild-type skin, whereas epidermal turnover was increased. Tumors were formed in equal numbers after DMBA-only treatment. We suggest that DMBA-initiated keratinocytes lacking Cd151 leave their niches in the epidermis and hair follicles in response to TPA treatment and subsequently are lost by differentiation. Because genetic ablation of Itga3 also reduced skin tumor formation, we tested whether reduced expression of alpha3 could further suppress tumor formation in epidermis-specific Cd151 knockout mice. Although DMBA/TPA induced formation of skin tumors was similar in compound heterozygotes for Cd151 and Itga3 to that in wild-type mice, heterozygosity for Itga3 on a Cd151-null background diminished tumorigenesis, suggesting genetic interaction between the two genes. We thus identify CD151 as a critical factor in TPA-dependent skin carcinogenesis. PMID- 23792459 TI - A signal transduction pathway from TGF-beta1 to SKP2 via Akt1 and c-Myc and its correlation with progression in human melanoma. AB - Both SKP2 (S-phase kinase-associated protein 2) and transforming growth factor beta1 (TGF-beta1) play important roles in cancer metastasis through different mechanisms: TGF-beta1 via induction of epithelial-mesenchymal transition (EMT) and SKP2 via downregulating p27(kip1). Recent studies indicated that c-Myc and Akt1 were active players in metastasis. In this study we demonstrated a crosstalk between these pathways. Specifically, we found that TGF-beta1 treatment increased SKP2 expression accompanied with increased phosphorylation of Akt1 and c-Myc protein accumulation during EMT. We demonstrated that Akt1 was required for TGF beta1-mediated SKP2 upregulation and that c-Myc transcription factor specifically bound to the promoter of SKP2 for its enhanced transcription. Analysis of 25 samples of normal human skin, nevi, and melanomas revealed a positive correlation between c-Myc and SKP2 accumulation. Furthermore, accumulation of SKP2 and c-Myc proteins was significantly higher in metastatic melanoma samples as compared with that in primary melanomas, which again was higher than that in normal skin or nevi. In summary, our results integrated TGF-beta1 signals to SKP2 via Akt1 and c Myc during EMT, and provided, to our knowledge, a previously unreported mechanistic molecular event for TGF-beta1-induced metastasis in human melanoma. PMID- 23792460 TI - RhoB promotes cancer initiation by protecting keratinocytes from UVB-induced apoptosis but limits tumor aggressiveness. AB - The role of UVB-induced apoptosis in the formation of squamous cell carcinoma (SCC) is recognized. We previously identified the small RhoB (Ras homolog gene family, member B) GTPase, an early response gene to cellular stress, as a critical protein controlling apoptosis of human keratinocytes after UVB exposure. Here we generated SKH1 (hairless immunocompetent mouse) mice invalidated for RhoB to evaluate its role in UVB-induced skin carcinogenesis in vivo. We show that rhob-/- mice have a lower risk of developing UVB-induced keratotic tumors and actinic keratosis that is associated with a higher sensitivity of UVB-exposed keratinocytes to apoptosis. We extend this observation to primary cultures of normal human keratinocytes in which RhoB was downregulated with small interfering RNA (siRNA) and further show that the hypersensitivity to apoptosis depends on B cell lymphoma 2 (Bcl-2) downregulation. In rhob-/- mice, the UVB-induced tumors were preferentially undifferentiated and highly proliferative. Finally, we show in humans an almost constant loss of RhoB expression in undifferentiated SCCs. These undifferentiated and RhoB-deficient tumors have elevated phosphorylated histone H2AX (gammaH2AX) and 53BP1, two markers of DNA double-strand breaks. Together, our results indicate that UVB-induced RhoB expression participates in in vivo SCC initiation by increasing keratinocyte survival. Conversely, RhoB may limit tumor aggressiveness as loss of RhoB expression in tumor cells is associated with tumor progression. PMID- 23792461 TI - Recombinant filaggrin is internalized and processed to correct filaggrin deficiency. AB - This study was designed to engineer a functional filaggrin (FLG) monomer linked to a cell-penetrating peptide (RMR) and to test the ability of this peptide to penetrate epidermal tissue as a therapeutic strategy for genetically determined atopic dermatitis (AD). A single repeat of the murine filaggrin gene (Flg) was covalently linked to a RMR motif and cloned into a bacterial expression system for protein production. Purified FLG+RMR (mFLG+RMR) was applied in vitro to HEK 293T cells and a reconstructed human epidermis (RHE) tissue model. Immunochemistry demonstrated RMR-dependent cellular uptake of FLG+RMR in a dose- and time-dependent manner in HEK cells. Immunohistochemical staining of the RHE model identified penetration of FLG+RMR to the stratum granulosum, the epidermal layer at which FLG deficiency is thought to be pathologically relevant. In vivo application of FLG+RMR to FLG-deficient flaky tail (ft/ft) mice skin demonstrated internalization and processing of recombinant FLG+RMR to restore the normal phenotype. These results suggest that topically applied RMR-linked FLG monomers are able to penetrate epidermal tissue, be internalized into the appropriate cell type, and be processed to a size similar to wild-type functional barrier peptides to restore necessary barrier function, and prove to be therapeutic for patients with AD. PMID- 23792462 TI - Loss of IL36RN function does not confer susceptibility to psoriasis vulgaris. PMID- 23792463 TI - Disrupted ectodermal organ morphogenesis in mice with a conditional histone deacetylase 1, 2 deletion in the epidermis. AB - Histone deacetylases (HDACs) are present in the epidermal layer of the skin, outer root sheath, and hair matrix. To investigate how histone acetylation affects skin morphogenesis and homeostasis, mice were generated with a K14 promoter-mediated reduction of Hdac1 or Hdac2. The skin of HDAC1 null (K14-Cre Hdac1(cKO/cKO)) mice exhibited a spectrum of lesions, including irregularly thickened interfollicular epidermis, alopecia, hair follicle dystrophy, claw dystrophy, and abnormal pigmentation. Hairs are sparse, short, and intermittently coiled. The distinct pelage hair types are lost. During the first hair cycle, hairs are lost and replaced by dystrophic hair follicles with dilated infundibulae. The dystrophic hair follicle epithelium is stratified and is positive for K14, involucrin, and TRP63, but negative for keratin 10. Some dystrophic follicles are K15 positive, but mature hair fiber keratins are absent. The digits form extra hyperpigmented claws on the lateral sides. Hyperpigmentation is observed in the interfollicular epithelium, the tail, and the feet. Hdac1 and Hdac2 dual transgenic mice (K14-Cre Hdac1(cKO/cKO) Hdac2(+/cKO)) have similar but more obvious abnormalities. These results show that suppression of epidermal HDAC activity leads to improper ectodermal organ morphogenesis and disrupted hair follicle regeneration and homeostasis, as well as indirect effects on pigmentation. PMID- 23792464 TI - Assessing the reliability of an automated dose-rounding algorithm. AB - OBJECTIVE: Pediatric dose rounding is a unique and complex process whose complexity is rarely supported by e-prescribing systems, though amenable to automation and deployment from a central service provider. The goal of this project was to validate an automated dose-rounding algorithm for pediatric dose rounding. METHODS: We developed a dose-rounding algorithm, STEPSTools, based on expert consensus about the rounding process and knowledge about the therapeutic/toxic window for each medication. We then used a 60% subsample of electronically-generated prescriptions from one academic medical center to further refine the web services. Once all issues were resolved, we used the remaining 40% of the prescriptions as a test sample and assessed the degree of concordance between automatically calculated optimal doses and the doses in the test sample. Cases with discrepant doses were compiled in a survey and assessed by pediatricians from two academic centers. The response rate for the survey was 25%. RESULTS: Seventy-nine test cases were tested for concordance. For 20 cases, STEPSTools was unable to provide a recommended dose. The dose recommendation provided by STEPSTools was identical to that of the test prescription for 31 cases. For 14 out of the 24 discrepant cases included in the survey, respondents significantly preferred STEPSTools recommendations (p<0.05, binomial test). Overall, when combined with the data from all test cases, STEPSTools either matched or exceeded the performance of the test cases in 45/59 (76%) of the cases. The majority of other cases were challenged by the need to provide an extremely small dose. We estimated that with the addition of two dose-selection rules, STEPSTools would achieve an overall performance of 82% or higher. CONCLUSIONS: Results of this pilot study suggest that automated dose rounding is a feasible mechanism for providing guidance to e-prescribing systems. These results also demonstrate the need for validating decision-support systems to support targeted and iterative improvement in performance. PMID- 23792465 TI - Synergistic co-delivery of doxorubicin and paclitaxel using multi-functional micelles for cancer treatment. AB - The main purposes of this study are to demonstrate the synergistic anticancer drug systems with the combined doxorubicin (D) and paclitaxel (P) via the aid of cell penetrating and cell targeting moieties for enhancing the cancer therapeutic effect. Firstly, the synergistic effect of combined free drugs (D/P) was investigated to obtain the suitable dose combination for subsequent studies. The combination of free drugs D/P at molar ratio of 1/0.2 shows synergistic therapeutic effect compared with the treatment of a free single drug D or P. Secondly, sustainable release systems of two single drug-loaded micelles, (i) co delivered D-FOL micelle & P-FOL micelle system and (ii) co-delivered D-TAT/FOL micelle & P-TAT/FOL micelle system, at D/P molar ratio of 1/0.2 were investigated. The results show synergistic effect with the higher efficacy of the TAT/FOL system compared to FOL only system. Finally, a dual D/P-loaded system with sustainable release rate, synergistic drug interaction, selective targeting to cancer cells and high cell penetrating ability was designed. The D/P-TAT/FOL micelles exhibit an IC50 value of 0.172 MUM D/0.043 MUM P, which is much lower than the IC50 values of the single drug-loaded micelles without functionalization (3.873 MUM for D-micelles and 0.790 MUM for P-micelles). Overall, this newly developed dual encapsulation of D and P in the multifunctional carrier would be a promising technology for cancer treatment. PMID- 23792466 TI - Polymeric micelles based on poly(methacrylic acid) block-containing copolymers with different membrane destabilizing properties for cellular drug delivery. AB - Poly(methacrylic acid)-b-poly(ethylene oxide) are double hydrophilic block copolymers, which are able to form micelles by complexation with a counter polycation, such as poly-l-lysine. A study was carried out on the ability of the copolymers to interact with model membranes as a function of their molecular weights and as a function of pH. Different behaviors were observed: high molecular weight copolymers respect the membrane integrity, whereas low molecular weight copolymers with a well-chosen asymmetry degree can induce a membrane alteration. Hence by choosing the appropriate molecular weight, micelles with distinct membrane interaction behaviors can be obtained leading to different intracellular traffics with or without endosomal escape, making them interesting tools for cell engineering. Especially micelles constituted of low molecular weight copolymers could exhibit the endosomal escape property, which opens vast therapeutic applications. Moreover micelles possess a homogeneous nanometric size and show variable properties of disassembly at acidic pH, of stability in physiological conditions, and finally of cyto-tolerance. PMID- 23792467 TI - Clotrimazole-loaded nanostructured lipid carrier hydrogels: thermal analysis and in vitro studies. AB - The aim of the present work is to design a new formulation containing clotrimazole (CTZ) loaded into nanostructured lipid carriers (NLC) for the treatment of fungal vaginal infections. In order to obtain formulations with suitable viscosity for mucosal application, NLC containing CTZ produced by the ultrasonication method were viscosized by the addition of poloxamer P407 in the NLC dispersion (CTZ-NLC-gel). These systems exhibit well-known thermogelling properties. The rheological characterization of the CTZ-NLC hydrogel using a controlled stress rheometer evidenced that the presence of NLC or CTZ did not affect gelling temperature (Tgel). Dilution with simulated vaginal fluid (SVF) increased the Tgel from 17.4 to 29.6 degrees C. For these thermogelling systems, micro-calorimetric assays conducted by a Micro-DSC III confirmed that the hydrogel-containing CTZ-NLC was able to change its structure with a rapid passage from non-crystalline (liquid) to crystalline (semi-solid) form. Furthermore, when a local application is considered, no drug should pass through the vaginal mucosa, limiting thus the systemic diffusion and toxicity. For this purpose, Franz cell has been employed to investigate the ex vivo permeation of CTZ through pig vaginal mucosa. The results showed no CTZ diffusion. The toxicological experiments performed on HeLa cells after a 24h incubation time confirmed that CTZ-NLC-gel at a concentration of 1mg/mL showed a low toxicity profile resulting in a cell vitality of 77.2%. Interestingly, anti-candida activity studies demonstrated that CTZ-NLC gel was 4-fold more active than Fungizone((r)) against Candida albicans. These encouraging results suggest that the hydrogel containing CTZ-NLC could be proposed as an innovative system to administer CTZ to treat vaginal infections. PMID- 23792468 TI - A Cognitive Attachment Model of prolonged grief: integrating attachments, memory, and identity. AB - Prolonged grief (PG), otherwise known as complicated grief, has attracted much attention in recent years as a potentially debilitating condition that affects approximately 10% of bereaved people. We propose a model of PG that integrates processes of attachment, self-identity, and autobiographical memory. The paper commences with a discussion of the PG construct and reviews current evidence regarding the distinctiveness of PG from other bereavement related-outcomes. We then review the evidence regarding the dysfunctional attachments, appraisals, and coping styles that people with PG display. Recent evidence pertaining to the patterns of autobiographical memory in PG is described in the context of the self memory system. This system provides a unifying framework to understand the roles of personal memories, identity, attachments, and coping responses in PG. The proposed model places emphasis on how one's sense of identity influences yearning, memories of the deceased, appraisals, and coping strategies, to maintain a focus on the loss. The model is discussed in relation to existing models of PG. The potential for shaping treatment strategies to shift perceptions of the self is then outlined. Finally, we outline future directions to test propositions stemming from the model and enhance our understanding of the mechanisms underlying PG. PMID- 23792469 TI - Pretrauma risk factors for posttraumatic stress disorder: a systematic review of the literature. AB - As it has become clear that most individuals exposed to trauma do not develop PTSD, it has become increasingly important to examine pretrauma risk factors. However, PTSD research has overwhelmingly relied on retrospective accounts of trauma, which is beleaguered by problems of recall bias. To further our understanding of PTSD's etiology, a systematic review of 54 prospective, longitudinal studies of PTSD published between 1991 and 2013 were examined. Inclusion criteria required that all individuals were assessed both before and after an index trauma. Results revealed six categories of pretrauma predictor variables: 1) cognitive abilities; 2) coping and response styles; 3) personality factors; 4) psychopathology; 5) psychophysiological factors; and 6) social ecological factors. The results indicated that many variables, previously considered outcomes of trauma, are pretrauma risk factors. The review considered these findings in the context of the extant retrospective PTSD literature in order to identify points of overlap and discrepancy. Pretrauma predictor categories were also used to conceptualize variable risk for PTSD. Limitations and directions for future research are discussed. PMID- 23792470 TI - Emotion regulation and other psychological models for body-focused repetitive behaviors. AB - The term body-focused repetitive behaviors (BFRBs) refers to a group of recurrent, problematic, destructive behaviors directed toward the body, including hair-pulling, skin-picking, and nail-biting. Individuals with BFRBs report diminished control over the behavior and a range of physical and psychological sequelae. Recent research on psychological models for BRFBs has investigated the role of emotion regulation (ER), and many authors in this area have conceptualized problematic body-focused behavior as a maladaptive ER mechanism. This article organizes and reviews the empirical research on the ER model for BRFBs. First, the three most common BFRBs are described, as are the conceptualization, phenomenological similarities and covariation, and psychological and physical impact of BFRBs. Next, psychodynamic models and several cognitive-behavioral (CB) models are described. The article focuses on the ER model, including a review of studies of comorbidity in BFRBs, naturalistic and experimental studies, studies of subtypes of BFRBs, and treatment trials. The implications of the findings are discussed and the authors make recommendations for future research. The article concludes with a discussion of the limitations of psychological models for BFRBs and the limitations of the review. PMID- 23792471 TI - An update on HDV: virology, pathogenesis and treatment. AB - Hepatitis delta is an inflammatory liver disease caused by infection with HDV. HDV is a single-stranded circular RNA pathogen with a diameter of 36 nm. HDV is classified in the genus Deltavirus and is still awaiting a final taxonomic classification up to the family level. HDV shares similarities with satellite RNA and viroids including a small circular single-stranded RNA with secondary structure that replicates through the 'double rolling circle' mechanism. The HDV RNA genome is capable of self-cleavage through a ribozyme and encodes only one structural protein, the hepatitis delta antigen (HDAg), from the antigenomic RNA. There are two forms of HDAg, a shorter (S; 22 kDa) and a longer (L; 24 kDa) form, the latter generated from an RNA editing mechanism. The S form is essential for viral genomic replication. The L form participates in the assembly and formation of HDV. For complete replication and transmission, HDV requires the hepatitis B surface antigen (HBsAg). Thus, HDV infection only occurs in HBsAg-positive individuals, either as acute coinfection in treatment-naive HBV-infected persons, or as superinfection in patients with pre-existing chronic hepatitis B (CHB). HDV is found throughout the world, but its prevalence, incidence, clinical features and epidemiological characteristics vary by geographic region. There are eight genotypes (1 to 8) distributed over different geographic areas: HDV-1 is distributed worldwide, whereas HDV-2 to 8 are seen more regionally. Levels of HDV viraemia change over the course of HDV infection, being significantly higher in patients with early chronic hepatitis than in cirrhosis. Chronic HDV infection leads to more severe liver disease than chronic HBV monoinfection with an accelerated course of fibrosis progression, an increased risk of hepatocellular carcinoma and early decompensation in the setting of established cirrhosis. Current treatments include pegylated interferon-alpha and liver transplantation; the latter of which can be curative. Further studies are needed to develop better treatment strategies for this challenging disease. PMID- 23792472 TI - Cognitive control and attentional functions. AB - Cognitive control is essential to flexible, goal-directed behavior under uncertainty, yet its underlying mechanisms are not clearly understood. Because attentional functions are known to allocate mental resources and prioritize the information to be processed, we propose that the attentional functions of alerting, orienting, and executive control and the interactions among them contribute to cognitive control in the service of uncertainty reduction. To test this hypothesis, we examined the relationship between cognitive control and attentional functions. We used the Majority Function Task (MFT) to manipulate uncertainty in order to evoke cognitive control along with the Revised Attention Network Test (ANT-R) to measure the efficiency and the interactions of attentional functions. A backwards, stepwise regression model revealed that performance on the MFT could be significantly predicted by attentional functions and their interactions as measured by the ANT-R. These results provide preliminary support for our theory that the attentional functions are involved in the implementation of cognitive control as required to reduce uncertainty, though further investigation is needed. PMID- 23792473 TI - Posture affects emotional responses: a Head Down Bed Rest and ERP study. AB - Body posture, mainly represented by horizontal bed rest, has been found to be associated with cortical inhibition, altered perceptual and cognitive processing. In the present research, the influence of Head Down Bed Rest (HDBR)--a condition also termed simulated microgravity--on emotional responses has been studied. Twenty-two male subjects were randomly assigned to either Sitting Control or HDBR group. After 3-h, subjects attended to a passive viewing emotional task in which 75 IAPS slides, divided into 25 pleasant, 25 neutral and 25 unpleasant, were presented in random order for 6s each, while EEG was recorded from F7, F8 and Pz locations. Results showed in Sitting Controls the expected greater P300 and Late Positive Potential (LPP) to pleasant and unpleasant compared with neutral slides, an effect which indicates greater processing of emotional arousing stimuli. The HDBR group showed smaller non-significant differences among all emotional conditions in both ERP components. Arousal and valence subjective evaluations, typically less sensitive to experimental manipulation, did not differentiate groups. The observed ability of HDBR to inhibit cortical emotional responses raises an important issue on the risk that astronauts underestimate a dangerous/threatening situation or that long-term bedridden inpatients develop depressive symptoms. PMID- 23792474 TI - Rare large cell neuroendocrine tumor of the endometrium: A case report and review of the literature. AB - INTRODUCTION: Large cell neuroendocrine carcinoma (LCNEC) of the endometrium is a rare malignancy with an aggressive course. Although data is limited to case reports, the prognosis appears to be poor, similar to other type II uterine cancers. A total of 12 cases of LCNEC of the uterus have been published to date. PRESENTATION OF CASE: A 71 year-old woman presented with postmenopausal vaginal bleeding. Endometrial biopsy was non-diagnostic for LCNEC. She underwent surgical debulking and staging of a 22cm endometrial tumor with omental metastasis and positive lymph nodes. Her final FIGO stage was IVB. DISCUSSION: We summarize all prior case reports of LCNEC of the endometrium and discuss the definition, presentation, imaging and surgical management. The pathology with immunohistochemical review, adjuvant therapy and prognosis of LCNEC of the endometrium are also reviewed. CONCLUSION: Pathologic findings and immunohistochemistry are essential in making a diagnosis of LCNEC of the endometrium. Primary debulking and surgical staging is typically performed, but if a diagnosis of LCNEC can be made preoperatively with immunohistochemistry, surgeons should consider neoadjuvant chemotherapy due to its high grade histology and aggressive course. Otherwise adjuvant chemotherapy is usually given. Even with early stage disease, the prognosis seems poor. Due to the rarity of this aggressive malignancy, more data is needed to establish incidence. PMID- 23792475 TI - Traumatic epistaxis: Skull base defects, intracranial complications and neurosurgical considerations. AB - INTRODUCTION: Endonasal procedures may be necessary during management of craniofacial trauma. When a skull base fracture is present, these procedures carry a high risk of violating the cranial vault and causing brain injury or central nervous system infection. PRESENTATION OF CASE: A 52-year-old bicyclist was hit by an automobile at high speed. He sustained extensive maxillofacial fractures, including frontal and sphenoid sinus fractures (Fig. 1). He presented to the emergency room with brisk nasopharyngeal hemorrhage, and was intubated for airway protection. He underwent emergent stabilization of his nasal epistaxis by placement of a Foley catheter in his left nare and tamponade with the Foley balloon. A six-vessel angiogram showed no evidence of arterial dissection or laceration. Imaging revealed inadvertent insertion of the Foley catheter and deployment of the balloon in the frontal lobe (Fig. 2). The balloon was subsequently deflated and the Foley catheter removed. The patient underwent bifrontal craniotomy for dural repair of CSF leak. He also had placement of a ventriculoperitoneal shunt for development of post-traumatic hydrocephalus. Although the hospital course was a prolonged one, he did make a good neurological recovery. DISCUSSION: The authors review the literature involving violation of the intracranial compartment with medical devices in the settings of craniofacial trauma. CONCLUSION: Caution should be exercised while performing any endonasal procedure in the settings of trauma where disruption of the anterior cranial base is possible. PMID- 23792476 TI - Lactobacillus fermentum, a pathogen in documented cholecystitis. AB - INTRODUCTION: Lactobacillus species are probiotics proven to exhibit various preventative as well as therapeutic properties. While lactobacillus species have been implicated in the formation of dental caries, endocarditis and bacteremia, their role as pathogens in cholecystitis has not been reported. We present a rare case of Lactobacillus fermentum working as a pathogen in cholecystitis. PRESENTATION OF CASE: An 81-year old male was admitted with right upper quadrant abdominal pain. His signs, symptoms, laboratory values and imaging were consistent with a diagnosis of cholecystitis with ascending cholangitis. In view of his co-morbidity and severe sepsis, the patient was treated non-operatively with antibiotics and cholecystostomy. L. fermentum, which was vancomycin resistant, was identified from the cholecystostomy aspirate and from anaerobic blood culture. The patient went into septic shock, developed multi-organ dysfunction syndrome and eventually died. DISCUSSION: Commensal bacteria such as L. fermentum are known to modulate immunity, reduce the pathogenicity of gastrointestinal organisms and play a therapeutic role in various disease processes. We isolated L. fermentum as a pathogen in a documented case of cholecystitis with ascending cholangitis. CONCLUSION: While the routine use lactobacillus species as a probiotic is supported in the literature, understanding its potential role as a pathogen may allow more judicious use of these bacteria and encourage research to elucidate the pathogenicity of lactobacillus species. PMID- 23792477 TI - Polymyositis as presenting manifestation of gallbladder carcinoma: A case report. AB - INTRODUCTION: Inflammatory myositis as a paraneoplastic presentation of gallbladder cancer is an extremely rare event. In this paper we reported the first case of gallbladder carcinoma presented as polymyositis. PRESENTATION OF CASE: A 68-year-old housewife presented with proximal muscles weakness, pain, significant decrease in force of proximal muscles, and globally decreased deep tendon reflexes. Laboratory studies revealed an anemia, increased acute phase reactants and increased serum creatine phosphokinase (CPK) levels. Electromyography (EMG) and nerve conduction velocity test (NCV) demonstrated mild myopathic changes. Muscle biopsy was suggestive for polymyositis. Corticosteroid therapy initiated and a meticulous search for probable underlying malignancy performed concurrently. Malignancy workup finally revealed a gallbladder tumor. Patient candidated for extended cholecystectomy. Pathologic evaluation of gallbladder tumor demonstrated a moderately differentiated carcinoma. Progressive improvement in clinical conditions and complete normalization of laboratory parameters occurred post-operatively. After 8 months of follow-up patient is still alive and in good state of health. There is no evidence of metastatic or local recurrence of tumor. Musculoskeletal complaints subsided completely. DISCUSSION: Gallbladder carcinoma is a rare and usually aggressive malignancy. Its primary presentation by paraneoplastic syndromes especially in the form of paraneoplastic neurological syndromes is an extremely rare event. Some believes that increased association between inflammatory myopathy and malignancy is limited to the dermatomyositis; however, presentation of our patient as polymyositis is contrary to this. This is the first reported case of gallbladder cancer who presented with polymyositis. CONCLUSION: Gallbladder cancer though rare, should be considered in patients with inflammatory myositis. PMID- 23792478 TI - Acute torsion of a wandering spleen in a post-partum female: A case report. AB - INTRODUCTION: Wandering spleen is a rare condition characterized by ectopic position of the spleen due to the absence or laxity of peritoneal ligaments that hold the organ within the left upper quadrant. Lower abdomen and pelvis are the most common locations of the wandering spleen. The disorder usually remains asymptomatic. PRESENTATION OF CASE: We present a case of acute abdomen due to torsion of a wandering spleen in a primiparus, healthy female shortly after delivery. Diagnosis was based on ultrasonography and computed tomography and was confirmed later on surgery. Total splenectomy was performed successfully. DISCUSSION: The rarity of the condition and the nonspecific clinical symptoms and signs make prompt diagnosis challenging. CONCLUSION: Prompt recognition and intervention are necessary in order to minimize the risk of complications. For this reason physicians have to include the condition in the differential diagnosis of acute abdominal pain especially when they encounter females in a pregnancy or post-natal period. PMID- 23792479 TI - Squamous cell carcinoma at an ileostomy site-Fifty-four years following colectomy for ulcerative colitis: A case report and literature review. AB - INTRODUCTION: Carcinoma arising at an ileostomy site is an extremely rare occurrence. The rate of malignancy arising at an ileostomy site is reported as being 2-4 of every 1000 cases. The development of squamous cell carcinoma at the mucocutaneous junction of an ileostomy is extremely rare. PRESENTATION OF CASE: We present a case of a 76-year-old male who developed squamous cell carcinoma at an ileostomy site fifty-four years after total colectomy as management for ulcerative colitis. DISCUSSION: Our literature review has identified only four similar cases previously published in English literature. All cases of squamous cell carcinoma developing in ileostomy have occurred after a minimum of twenty six years following ileostomy. This suggests that the etiology may be due to chronic factors. CONCLUSION: Patients with chronic stomal inflammation, bleeding or persistent induration and/or mass formation should be followed up closely and investigated for recurrence or development of a new malignancy. There should be a low threshold to obtain an early definitive tissue diagnosis by taking biopsies to prevent local or systemic invasion. PMID- 23792480 TI - Gastric outlet obstruction caused by focal nodular hyperplasia of the liver: A case report and literature review. AB - INTRODUCTION: Here, we present a case of gastric outlet obstruction due to focal nodular hyperplasia of the liver. PRESENTATION OF CASE: A 23-year-old female presented to our emergency clinic with nausea, vomiting, and abdominal pain. Endoscopy showed that the prepyloric region of the stomach was externally compressed by a lesion. Computed tomography and magnetic resonance imaging revealed a 70mm solid mass originating from the liver, extending caudally in an exophytic manner, and compressing the stomach. Laparotomy revealed an irregular and exophytic mass originating from the liver, which caused gastric outlet obstruction. The mass was resected with a 10mm safety margin. The histopathology report of the mass returned as focal nodular hyperplasia. DISCUSSION: Gastric outlet obstruction is a clinical syndrome characterized by abdominal pain, nausea, and postprandial vomiting. This clinical condition frequently develops as a result of peptic ulcer disease, pyloric stenosis, and obstruction of pylorus by foreign bodies including phytobezoars, congenital duodenal webs, malignant disorders, and various lesions externally compressing the stomach. Gastric outlet obstruction due to hepatic lesions is extremely rare; few cases have been reported. CONCLUSION: This is the first reported case of gastric outlet obstruction that developed due to focal nodular hyperplasia of the liver. PMID- 23792481 TI - FAP related periampullary adenocarcinoma. AB - INTRODUCTION: The risk of periampullary neoplasia in patients with familial adenomatous polyposis (FAP) is significantly increased compared to the general population. PRESENTATION OF CASE: We herein report the case of a 47-year-old woman with classic familial adenomatous polyposis with a history of total proctocolectomy for FAP who presented with an ulcerous ampullary lesion 8 years after primary colorectal surgery. Interestingly, the patient had not enrolled to optimal postoperative upper endoscopy follow-up. The patient underwent a Whipple procedure. Histology demonstrated a T2N0 ampullary adenocarcinoma. DISCUSSION: Periampullary disease in patients with familial adenomatous polyposis occurs increasingly, especially in the subset of patients without proper endoscopic follow-up. Current recommendations concerning upper endoscopy and appropriate management are herein discussed; the importance of optimal postoperative endoscopy after total proctocolectomy in the FAP setting is discussed. CONCLUSION: Periampullary cancer carries a significant risk in patients with FAP and proper endoscopic follow-up should be applied in this special patient group in order to manage ampullary manifestations of the disease in a timely manner. PMID- 23792482 TI - Adrenal metastasis of a phyllodes tumor of the breast: Case report and review of the literature. AB - INTRODUCTION: A phyllodes tumor is a neoplasm of mixed mesenchymal and epithelial origin affecting the breast. It may pursue a benign or malignant evolution with distant metastases in the latter case. Sites most commonly affected by metastases are the lungs and bones. Simple mastectomy is the mainstay of treatment. This article presents the first described case of metastasis to the adrenal gland after sarcomatous transformation of a phyllodes tumor. A review of the literature is presented afterwards. PRESENTATION OF CASE: A 57-year old female patient presented with a voluminous breast mass which was completely resected. Unfortunately she presented with malignant recurrence in the breast which was also resected. A later recurrence within the lung presented and was completely resected but showed aspects of sarcomatous changes. Finally a recurrence was pathologically documented within the adrenal gland. Unfortunately, disease later progressed and the patient refused further treatment at that point. DISCUSSION: While malignant transformation of breast phyllodes tumors and metastasis is relatively common, the prognosis for initially benign lesion that are completely excised is usually good. This case represents the first documented metastasis to the adrenal gland of a breast phyllodes tumor. CONCLUSION: We presented the first case of adrenal metastasis of a phyllodes tumor after sarcomatous degeneration. This is an unusual presentation of a relatively uncommon but well-recognized disease of variable malignant potential. PMID- 23792483 TI - Aspergilloma mimicking a lung cancer. AB - INTRODUCTION: Pulmonary aspergillosis occurs in the parenchymal cavities or ectatic airways. It rarely affects healthy people with an intact immune response. There have been few reports describing an aspergilloma mimicking a lung cancer. PRESENTATION OF CASE: We experienced the case of an asymptomatic healthy 71-year old female who was admitted with an abnormal lung shadow. Chest CT revealed an irregularly shaped solid lung nodule in the left upper lobe, which increased in size during the follow-up at a regional hospital. The pathology of the bronchial biopsy was negative for malignant cells, and the cultures were negative. Because a lung cancer was strongly suspected, video-assisted thoracic surgery was performed. Aspergillus was detected by a pathological study of the excised specimen, with no evidence of lung cancer. DISCUSSION: It is difficult to make an accurate diagnosis of aspergilloma by imaging findings in healthy people with an intact immune response, and therefore a surgical resection allows both the pathological diagnosis and treatment to be performed concurrently. CONCLUSION: An aspergilloma presenting a mass shadow on imaging may mimic a lung cancer in healthy people with intact immune response. PMID- 23792484 TI - Pancreatic cancer: Slow progression in the early stages. AB - INTRODUCTION: The rates of pancreatic cancer development in the early stages of growth remain unclear; but it is generally believed that they demonstrate a rapid degree of progression. There is evidence to suggest that pancreatic cancers measuring less than 1cm demonstrate better survival rates, hence it is clear that detecting pancreatic cancers less than 1cm in size is of paramount importance. However, to date, there has been no scientifically adequate research to show the growth rate of small pancreatic cancers less than 1cm in the early stages. PRESENTATION OF CASE: We present the case of a 65-year-old woman whose small pancreatic cancer possibly demonstrated a slow progressive rate as it grew to an invasive carcinoma measuring 1cm diameter from over the 29 months. DISCUSSION: It is reasonable to assume that the progression of some pancreatic cancers until 1cm size, can take up to 29 months. During this silent period, it is crucial to detect such a small pancreatic cancer by means of the initial US and subsequent EUS and ERCP. It is clear, therefore, that clinicians have to be aware of the growth rate of small pancreatic cancers and in particular high risk patients should be encouraged to monitor size of the main pancreatic duct by means of US on regular basis. CONCLUSION: This could give better outcomes for pancreatic cancer patients. Hopefully, by detecting these lethal, pancreatic cancers in their early stages, it will give us an extension of time to perform effective therapies. PMID- 23792485 TI - Microaneurysm formation rate as a predictive marker for progression to clinically significant macular edema in nonproliferative diabetic retinopathy. AB - PURPOSE: To evaluate the predictive value of microaneurysm (MA) formation rate concerning the development of clinically significant macular edema (CSME) in patients with mild-to-moderate nonproliferative diabetic retinopathy as evaluated by an automated analysis of central field fundus 30 degrees photographs. METHODS: Two hundred and eighty-seven eyes were included in the study. Photographs obtained at Day 0, at 6, and 12 months were analyzed using the RetmarkerDR software (Critical Health SA) in a masked manner, and the MA formation rate was documented. A threshold of a calculated MA formation rate of 2 or more was chosen to consider a patient "positive." The ability to predict CSME development was then calculated for a period of up to 5 years. HbA1c values, blood pressure, or duration of diabetes were also evaluated. RESULTS: The study population consisted of 89 male and 59 female patients with a mean age of 57.6 years, a mean HbA1c of 7.8, and a mean duration of diabetes of 12.3 years. Forty seven of 287 eyes (16.4%) developed CSME during follow-up. An increased MA formation rate of >2 MA was clearly associated with development of CSME. Using the automated analysis and a threshold of 2 or more new MA, the authors were able to identify 70.2% of the eyes that developed CSME during follow-up ("true positive") and using a threshold of up to 2 new MA, 71.7% of the patients that did not develop CSME ("true negative"). No significant differences concerning baseline and 1-year HbA1c levels within patient eyes that developed CSME compared with patient eyes below or over the calculated threshold of 2 MA (P = 0.554 and P = 0.890, respectively) were seen. The positive and negative predictive value was calculated to be 33% versus 92.5%, sensitivity was 70%, and specificity was 72%. CONCLUSION: Using the RetmarkerDR software, the authors were able to identify patients with higher risk to develop CSME during follow-up using a threshold of 2 or more MA formation rate. Together with the high negative predictive value, the automated analysis may help to determine the individual risk of a patient to develop sight-threatening complications related to diabetic retinopathy and schedule individual screening intervals. PMID- 23792486 TI - Green or yellow laser treatment for diabetic macular edema: exploratory assessment within the Diabetic Retinopathy Clinical Research Network. AB - PURPOSE: Explore differences in green compared with yellow focal/grid laser treatment on functional and anatomical endpoints in eyes with diabetic macular edema. METHODS: Data from two randomized clinical trials were evaluated for differences in visual acuity and optical coherence tomography parameters for eyes assigned to sham injection + prompt laser, ranibizumab + prompt laser, or prompt laser only: among subgroups of eyes treated exclusively and electively with either green or yellow laser. RESULTS: In the sham injection + prompt laser group, the mean visual acuity letter score change for eyes receiving green and yellow laser treatment, respectively, was +2.4 +/- 14 and +5.1 +/- 13 at the 52 week visit (P = 0.06) and +2.4 +/- 15 and +6.0 +/- 13 at the 104-week visit (P = 0.13), with no corresponding evidence of differences in optical coherence tomography thickness. When comparing wavelength groups in the ranibizumab + prompt laser and prompt laser-only groups, meaningful differences in visual acuity and optical coherence tomography thickness were not detected at 1 year or 2 years. CONCLUSION: A trend toward improved vision outcome with yellow laser observed in one trial was not corroborated by anatomical outcomes or by the other trial. In this study, without random assignment to different wavelengths controlling for bias and confounding, it is not possible to determine whether one wavelength is better than the other. PMID- 23792487 TI - Role of vitreoretinal surgery in maximizing treatment outcome following complications after proton therapy for uveal melanoma. AB - PURPOSE: To assess the role of vitreoretinal surgery in maximizing treatment outcome following complications after proton therapy for uveal melanoma and to evaluate its safety. METHODS: Retrospective chart study on 21 patients (2% of a total of 1,005 treated by proton therapy between January 2003 and August 2007) who had developed a complication requiring vitreoretinal surgery. Mean/median total follow-up after irradiation was 43/43 months (range, 12-70 months). RESULTS: Indications for surgery included vitreous hemorrhage (n = 13), epimacular membrane (n = 5), rhegmatogenous retinal detachment (n = 1), combined vitreous hemorrhage with total serous retinal detachment (n = 1), and vitritis (n = 1). Mean/median interval for vitreoretinal surgery after irradiation was 21/20 months (range, 4-45 months), and mean/median follow-up after pars plana vitrectomy was 22/23 months (range, 2-56 months). Pars plana vitrectomy was combined with retinal photocoagulation (n = 5), air/gas (n = 5), or silicone oil tamponade (n = 1). Mean Snellen visual acuity was 20/200 (0-20/40) before and 20/100 (0-20/25) after pars plana vitrectomy. A transient postoperative rise in intraocular pressure was measured in seven patients. Four patients developed phthisis bulbi. CONCLUSION: Vitreoretinal surgery was efficient in maximizing treatment outcome after proton therapy, as it allowed a better oncologic follow up. Pars plana vitrectomy permitted panretinal photocoagulation to avoid neovascular glaucoma or retinal detachment repair. Macular surgery improved visual acuity, especially in anterior melanoma, whereas repeated surgery may increase the risk of enucleation. PMID- 23792488 TI - Culprit for low aerobic fitness in down syndrome: is deconditioning guilty as charged? PMID- 23792489 TI - URI in athletes: are mucosal immunity and cytokine responses key risk factors? AB - Infection incidence among athletes is highest during periods of intensified training and competition and after strenuous long-distance events. Which aspects of depressed immune function are responsible for this increased infection risk are not known, but our hypothesis is that lower salivary immunoglobulin A (IgA) secretion and a higher antiinflammatory cytokine response to antigen exposure are key determinants of infection risk. PMID- 23792490 TI - Unraveling the complexities of SIRT1-mediated mitochondrial regulation in skeletal muscle. AB - Sirtuin 1 (SIRT1) is a purported central regulator of skeletal muscle mitochondrial biogenesis. Herein, we discuss our recent work using conditional mouse models, which highlight the complexities of SIRT1 biology in vivo, and question the role of SIRT1 in regulating mitochondrial function and mitochondrial adaptations to endurance exercise. Furthermore, we discuss the possible contribution of proposed SIRT1 substrates to muscle mitochondrial biogenesis. PMID- 23792491 TI - Euestrogenemia and metabolic dysfunction: a clinician's perspective. PMID- 23792492 TI - Response. PMID- 23792493 TI - Human umbilical-cord-blood mononucleated cells enhance the survival of lethally irradiated mice: dosage and the window of time. AB - The purpose of this study was to evaluate the window of time and dose of human umbilical-cord-blood (HUCB) mononucleated cells necessary for successful treatment of radiation injury in mice. Female A/J mice (27-30 weeks old) were exposed to an absorbed dose of 9-10 Gy of (137)Cs gamma-rays delivered acutely to the whole body. They were treated either with 1 * 10(8) or 2 * 10(8) HUCB mononucleated cells at 24-52 h after the irradiation. The antibiotic Levaquin was applied 4 h postirradiation. The increased dose of cord-blood cells resulted in enhanced survival. The enhancement of survival in animals that received 2 * 10(8) HUCB mononucleated cells relative to irradiated but untreated animals was highly significant (P < 0.01). Compared with earlier studies, the increased dose of HUCB mononucleated cells, coupled with early use of an antibiotic, extended the window of time for effective treatment of severe radiation injury from 4 to 24-52 h after exposure. PMID- 23792494 TI - VEGF significantly restores impaired memory behavior in Alzheimer's mice by improvement of vascular survival. AB - The functional impact of amyloid peptides (Abetas) on the vascular system is less understood despite these pathologic peptides are substantially deposited in the brain vasculature of Alzheimer's patients. Here we show substantial accumulation of Abetas 40 and 42 in the brain arterioles of Alzheimer's patients and of transgenic Alzheimer's mice. Purified Abetas 1-40 and 1-42 exhibited vascular regression activity in the in vivo animal models and vessel density was reversely correlated with numbers and sizes of amyloid plaques in human patients. A significant high number of vascular cells underwent cellular apoptosis in the brain vasculature of Alzheimer's patients. VEGF significantly prevented Abeta induced endothelial apoptosis in vitro. Neuronal expression of VEGF in transgenic mice restored memory behavior of Alzheimer's. These findings provide conceptual implication of improvement of vascular functions as a novel therapeutic approach for the treatment of Alzheimer's disease. PMID- 23792495 TI - Liver transplantation for intra- and extrahepatic cholangiocarcinoma. AB - Cholangiocarcinoma (CCA) is the second most frequent primary liver malignancy. Despite extensive surgical approaches and recently developed perioperative chemotherapeutic protocols the 5-year- survival rates range from 20-60%. Especially for central intrahepatic CCA resection is often impossible due to bilobar vascular and biliary invasion; patients with primary sclerosing cholangitis often present with small central tumors and significantly impaired liver function. For these patients liver transplantation (LT) has been discussed as a potential curative option. After a series of LT for CCA in the 1990s with high quotas of early tumor recurrence and very limited long-term survival CCA has widely been agreed upon as a contraindication for LT in times of universal organ shortage. However, in selected cases of patients with PSC and small CCA as well as irresectable Klatskin tumor without extrahepatic disease LT has been performed with acceptable recurrence-free survival rates. Modern, aggressive protocols of perioperative treatment have been established with promising results. This article provides an update and overview on the current status of LT as a potential option for patients with irresectable CCA. PMID- 23792496 TI - High graft protection and low incidences of infections, malignancies and other adverse effects with intra-operative high dose ATG-induction: a single centre cohort study of 760 cases. AB - BACKGROUND: In 1990 we introduced the intra-operative single high-dose induction (HDI) with ATG-Fresenius as a novel renal sparing concept. The aim of this analysis was to compare both the long-term patient and graft survival and the incidences of adverse effects in recipients treated with standard triple-drug therapy (TDT) alone or with an additional HDI with ATG-F. MATERIAL AND METHODS: A total of 760 renal transplant recipients receiving either TDT, consisting of steroids, azathioprine and cyclosporine (n=238) or TDT + 9mg/kg ATG-F intra operatively (n=522) were included in this retrospective analysis. RESULTS: Compared to the TDT cohort the graft and patient survival over the entire ten year period was significantly prolonged in the TDT+HDI cohort. In contrast, main adverse effects (TDT+HDI vs. TDT) such as malignancies (4.4 vs. 2.1%), PTLD (0.4 vs. 0.4%), CMV diseases (18.6 vs. 15.5%), Herpes zoster infections (2.9 vs. 1.3%), bacterial pneumonias (3.1 vs. 1.3%) and post-operative thrombocytopenia <50*103/ul (0.5 vs. 1.3%) did not significantly differ between the two immunosuppressive regimens. Only CMV-IgM seroconversions occurred significantly more in the HDI cohort (39.3 vs. 23.5%). The absolute numbers of CD3, CD4 and CD8 cell counts were significantly reduced in TDT+ATG-F HDI cohort only over a time period of about five days. CONCLUSIONS: This world-wide largest single-centre cohort analysis clearly shows the superiority of the HDI with ATG-F compared to TDT alone in improving long-term graft survival without increasing the risk for infections, malignancies or other adverse effects. PMID- 23792497 TI - Education in organ donation among students in Germany - results of an intervention study. AB - BACKGROUND: In Germany, organ donation remains low and is not sufficient to duly address all patients on the waiting lists. It is likely that lack of information and subsequent insecurity in the adult population relate to this imbalance. Virtually no data exist about teenagers' knowledge of organ donation. MATERIAL AND METHODS: A questionnaire-based survey was performed among all 11th and 12th grade students of secondary schools in Mainz, Germany. All students were subsequently offered an information event. The survey consisting of 17 questions was repeated later. The survey was voluntary and performed in class without the students using any information sources. RESULTS: 1165 (48%) students participated in the first survey, and 1491 (61.7%) in the second survey. 11.3% in the first and 19.55% in the second survey had an organ donor card. 38.83% reported having informed themselves within the last 12 months on organ donation. 56.56% would have filled out an organ donor card with an approval if they had had to decide at the time of survey. CONCLUSIONS: When young people discuss organ donation in their families or when they seek information themselves, the acceptance of organ donation greatly improves. Our data suggest that education on organ donation can double the number of carriers of an organ donor card among students. PMID- 23792498 TI - Development of nephrolithiasis in a renal transplant patient during treatment with Cinacalcet. AB - BACKGROUND: Secondary hyperparathyroidism often accompanies chronic kidney disease, which can result in severe bone abnormalities and nephrolithiasis. Renal transplantation can correct the mineral abnormalities associated with chronic kidney disease, but one year after transplantation many recipients continue to exhibit persistent hyperparathyroidism. CASE REPORT: Cinacalcet, a second generation calcimimetic, has been shown to be effective in decreasing serum calcium levels in post kidney transplant patients with hyperparathyroidism. However a question remains whether patients with hyperparathyroidism who take Cinacalcet may be at increased risk of renal calcium deposits due to hypercalciuria and subsequent renal transplant dysfunction. We report the first well-documented case in which Cinacalcet contributed to the development of new renal calculi in a post-transplant patient with hyperparathyroidism (PTH 346 pg/mL), hypercalcemia (11.3 mg/dL), and good renal function (1.45 mg/dL). Interval imaging tracks the new onset of renal allograft stone formation after initiating Cinacalcet up to 60mg daily, which was accompanied by persistent hypercalciuria (478.2 mg/24 hours). The nephrolithiases resolved after discontinuing Cinacalcet and a subtotal parathyroidectomy. CONCLUSIONS: This case supports the interval monitoring of urinary calcium excretion and imaging of the transplanted kidney for those recipients treated with Cinacalcet for hyperparathyroidism after renal transplantation. PMID- 23792499 TI - Safety and effects of prophylactic defibrotide for sinusoidal obstruction syndrome in hematopoietic stem cell transplantation. AB - BACKGROUND: Sinusoidal obstruction syndrome (SOS) is a serious complication of hematopoietic stem cell transplantation (HSCT), with a mortality rate of up to 90%. We report our experience on the use of defibrotide for SOS prophylaxis in HSCT. MATERIAL AND METHODS: We retrospectively reviewed data of 49 patients who received defibrotide as SOS prophylaxis during the course of HSCT at the National Cancer Center, Goyang, Korea, between August 2005 and July 2008. RESULTS: Thirty four patients (69.4%) were classified as a high-risk group for developing SOS. Defibrotide was well-tolerated, without any grade 3 or 4 toxicity. The median value of maximum total bilirubin within 100 days after HSCT was within the normal range. SOS was diagnosed in only 1 patient, who underwent autologous HSCT due to relapsed medulloblastoma. There was no day 100 treatment-related mortality in our study. CONCLUSIONS: Defibrotide appears to be a safe prophylaxis for SOS. This study suggests that it could be effective to use prophylactic defibrotide in advance to improve HSCT outcomes in patients at risk of SOS. PMID- 23792500 TI - Dose-normalization for exposure to mycophenolic acid and the early clinical outcome in patients taking tacrolimus after heart transplantation. AB - BACKGROUND: The early phase of MPA exposure has rarely been investigated after solid organ transplantation, especially in heart transplantation patients. We evaluated the association between exposure to mycophenolic acid (MPA), a main metabolite of mycophenolate mofetil (MMF), and clinical events within 3 months after heart transplantation. MATERIAL AND METHODS: Trough (C0) and area under the curve (AUC)0-12h levels of MPA and its metabolite, mycophenolic acid glucuronide (MPAG), were determined using high-performance liquid chromatography. Corresponding clinical endpoints included acute rejection or MMF-related adverse events (gastrointestinal symptoms, leucopenia, and anemia). AUC measurements (n=77) were collected from 21 patients. Dose-normalized C0 and AUC0-12h levels were used to evaluate the association between MPA or MPAG exposure and MMF related adverse events. RESULTS: No acute rejection or mortality occurred during the follow-up period. Twelve patients (57%) developed 13 MMF-related adverse events. The MMF dose was tapered from 2.50 g/day on D1 to 1.55+/-0.54 g/day on D90. Significantly higher levels of dose-normalized MPA C0 and AUC0-12h were associated with the events than with the absence of the events (C0: 1.04+/-0.42 vs. 0.84+/-0.85 ug/mL/g [p=0.047]; AUC0-12h: 20.37+/-3.21 vs. 14.97+/-1.13 ug * h/mL/g; [p=0.038]). Conclusions Dose-normalized MPA exposure may protect against MMF toxicity in the early stage after heart transplantation. The MMF dose can be decreased to near 1.5 g/day 3 months post-transplantation without jeopardizing patient safety; a well-planned, tapered MMF regimen should also be considered. PMID- 23792501 TI - Obstructive uropathy secondary to incisional herniation of a transplant ureter - case report and review of literature. AB - BACKGROUND: Herniation of transplant ureter into an incisional hernia is an uncommon and unreported cause of ureteric obstruction, which can lead to transplant dysfunction and diagnostic dilemmas. A report of our case and review of pertinent literature is presented. CASE REPORT: We report a 61-year-old lady, who presented with transplant dysfunction and hydronephrosis due to obstruction of the transplant ureter in an incisional hernia 8 years post-transplantation. An antegrade pyelogram and a computerised tomographic scan demonstrated an incisional hernia containing the obstructed transplant ureter. Antegrade stent insertion followed by an open mesh repair of the incision hernia restored normal alignment of the ureter and transplant renal function. CONCLUSIONS: Due to its rarity, awareness of this condition is important in its prevention and successful management. PMID- 23792502 TI - Insulin-like growth factor I correlates with MELD and returns to normal level after liver transplantation. AB - BACKGROUND: Insulin-like growth factor I (IGF-I) is produced almost entirely by the liver and is the main promoter of anabolic growth hormone (GH) effects on protein, carbohydrate, and lipid metabolism. IGF-I is significantly decreased in patients with liver cirrhosis. Our objective was to determine the relationship between circulating IGF-I and MELD (Model for End-stage Liver Disease) in cirrhotics subjected to orthotopic liver transplantation (OLT). We also assessed the changes of IGF-I and its major binding protein (IGF-binding protein-3 or IGFBP-3) after OLT. MATERIAL AND METHODS: In a prospective study, serum levels of IGF-I and IGFBP-3 of 25 male adult patients with end-stage liver disease were measured 2 to 4 hours before and 6 months after orthotopic liver transplantation. Seven age-matched healthy male volunteers with normal liver enzymes, albumin, and prothrombin time served as controls. MELD was determined on the day of OLT. For this analysis, extra points were not added for patients with hepatocarcinoma. RESULTS: The cirrhotic group had significantly lower IGF-I (46.7+/-21.6 ng/mL) and IGFBP-3 (1.0+/-0.9 ng/mL) levels in the pre-transplant period compared with the controls (208.6+/-76.5 ng/mL and 4.62+/-0.93 ng/mL, respectively) (p<0.05). There was a negative correlation between IGF-I or IGFBP-3 and MELD (p<0.001) (beta=-1.750; standard error =2.5054 and beta=-0.038; standard error <0.0001, respectively). IGF-I e IGFBP-3 increased to normal levels after OLT (207.7+/-82.8 and 4.14+/-1.1 ng/mL, respectively) (p<0.001). CONCLUSIONS: Low levels of IGF-I and IGFBP-3 observed in patients with advanced liver cirrhosis are corrected after OLT. IGF-I and IGFBP-3 correlate negatively with MELD. PMID- 23792503 TI - Children undergoing liver transplantation for treatment of inherited metabolic diseases are prone to higher oxidative stress, complement activity and transforming growth factor-beta1. AB - BACKGROUND: Main indications for liver transplantation in the pediatric population include biliary atresia and inherited metabolic diseases. The present study evaluated whether there are differences between pediatric patients undergoing living-related liver transplantation due to the two diseases in terms of their oxidative and immunological status during their regular outpatient follow-up visits. MATERIAL AND METHODS: A clinical outpatient study measuring serum oxidative stress index (calculated as serum oxidant/antioxidant ratio, in the form of serum total hydroperoxide/serum biological antioxidative potential), serum terminal complement component 5a, as an indicator of complement activity and immunological status, and transforming growth factor-beta1, as a marker of liver fibrosis, in 16 patients (6 males and 10 females, 2.5-15 years old) who received living-related liver transplantation due to inherited metabolic diseases (n=6; in the form of propionic acidemia [n=1], methylmalonic acidemia [n=1], arginase deficiency [n=1], tyrosinemia [n=2], and glycogen storage disease type 1b [n=1], with an age range of 2.4-14.6 years old) and due to biliary atresia ([n=10], with an age range of 2.9-14.5 years old). RESULTS: Serum oxidative stress index, complement component-5a, and transforming growth factor-beta1 were significantly higher in the inherited metabolic diseases group than in the biliary atresia group. In all patients, serum oxidative stress index correlated positively with complement component-5a and transforming growth factor-beta1. CONCLUSIONS: Patients who receive living-related liver transplantation due to inherited metabolic diseases are prone to higher oxidative stress, complement activity, and serum transforming growth factor-beta1. PMID- 23792504 TI - HTK preservative solution is associated with increased biliary complications among patients receiving DCD liver transplants: a single center experience. AB - BACKGROUND: This study compares biliary complication rates associated with use of two different preservative solutions, Histidine-Tryptophan-Ketoglutarate (HTK) and University of Wisconsin (UW), utilized in orthotopic liver transplantation (LT) with donations after cardiac death (DCDs). MATERIAL AND METHODS: Between 1997-2010, we retrospectively studied 35 LTs performed utilizing DCD donors, preserved either with HTK (n=17) or UW(n=18). Biliary complications were defined by the presence of anastomotic strictures, non-anastomotic strictures, and/or biliary leak on endoscopic retrograde cholangiopancreatography. RESULTS: HTK and UW cohorts were similar in terms of demographics as well as pre- and post operative biochemical profile. Donor age was significantly higher among HTK compared to UW recipients (41.5 +/- 11.9 vs. 26.2 +/- 8.8 years, p<0.001). The incidence of post-LT biliary complications was higher in the HTK group (76% vs. 39% in UW group, p=0.041). Hepatic arterial thrombosis (HAT) was observed among 3 HTK patients (17.7%) and 1 UW patient (5.6%), p=0.33. No patients underwent retransplantation in UW group, five recipients in HTK group underwent retransplantation (29%), p=0.019; 4 due to biliary complications and 1 due to HAT. CONCLUSIONS: This single-center study reveals that the use of HTK preservative among DCD donors is associated with an increased risk of biliary complications. Multicenter retrospective studies are suggested to further verify this observation. PMID- 23792505 TI - Role of platelets in the modulation of kidney allograft recipients' immune systems. AB - BACKGROUND: Renal transplantation is the most effective method of treatment in end-stage renal disease. Chronic allograft rejection still remains a challenge for transplant physicians. Despite a growing amount of data regarding the role of platelets (PLT) in immunological processes, few reports have correlated number of platelets with transplanted kidney function. We aimed to evaluate the correlation between number of circulating platelets and number of immune system cells, including lymphocytes CD 4+, CD8+, lymphocytes B, monocytes, NK cells, and lymphocytes T reg in kidney transplant recipients with stable graft function. MATERIAL AND METHODS: We enrolled 100 kidney transplant recipients (ages 20-78 years) 10 month to 10 years after transplantation. The numbers of platelets (using standard procedure) and immune blood cells were evaluated using flow cytometry. Statistical analysis was performed with Spearman rank correlation. RESULTS: We found a negative correlation between number of platelets and number of lymphocytes T reg, and a positive correlation between platelet count and number of other examined immunocompetent cells. CONCLUSIONS: The number of PLT correlates with number of cells responsible for induction and effector mechanisms of acquired cellular response. PMID- 23792506 TI - Program of laparoscopic living-donor nephrectomy with retroperitoneoscopic access - a Polish single-center experience - success or disappointment? AB - BACKGROUND: Laparoscopic living-donor nephrectomy (LLDN) is an attractive alternative to open approach and is a widely accepted method of kidney retrieval for transplantation. Here, we present the first Polish series of LLDN performed at a single center. MATERIAL AND METHODS: Between April 2008 and May 2012, we performed 8 LLDN with an immediate renal transplantation using classical surgical approach and technique. Four men and 4 women were operated on. In all cases of LLDN, left kidneys were retrieved and retroperitoneal approach with 3 trocars was used according to the technique we described previously. RESULTS: No intra- or postoperative complications were observed. The average "skin-to-skin" time of surgery was 138 minutes (min. 80; max. 210). The blood loss ranged from 0 to 280 ml (average, 80). Warm ischemia time did not exceed 3 minutes in any case. All organs were immediately implanted in the second operating room. Postoperative course was uneventful in all donors and recipients. CONCLUSIONS: Similar to many authors, at the beginning of our program we hoped that introduction of LLDN would increase the donor pool in Poland. Unfortunately, so far, these expectations have not been realized. However, we consider our program as a success regarding multidisciplinary cooperation and feasibility of LLDN in our country. PMID- 23792507 TI - Incidence of malignancies in cardiac allograft recipients - a single-center experience. AB - BACKGROUND: Most of the available data suggest that the risk of malignancy in solid organ recipients is higher than in the general population. In Poland, the prevalence rate for malignancy in the general population is about 1.02%. MATERIAL AND METHODS: At out Outpatient Clinic for patients after heart transplantation we analyzed all 324 patients transplanted from 1987-2011 for the presence of malignancies. The end-point of the analysis was determined by malignancy diagnosis, patient death, or end of the observation period (December 12, 2011). RESULTS: We detected 31 malignancies in 29 of 324 patients (8.95%). In 2 patients we found 2 types of malignancies. The dominant type of malignancy was pulmonary carcinoma, diagnosed in 11/29 (37.93%) patients. Skin carcinoma was recognized in 7 patients (24.14%). Fourteen (48.3%) patients died (12 men and 2 women): 5 of them in the course of pulmonary carcinoma (35.7%), 3 of skin carcinoma (21.4), 3 in the course of lymphoma, 1 in the course of renal carcinoma, 1 in the course of stomach carcinoma, 1 of colorectal carcinoma, and 1 of prostatic carcinoma. CONCLUSIONS: The risk of malignancy development is many times higher for HT patients than in the general population. The high incidence rate for pulmonary carcinoma in the analyzed group of patients was most likely related to smoking before transplantation and continuation of smoking after the procedure in the case of patients who received immunosuppressive therapy. PMID- 23792508 TI - Correlation between serum YKL-40 (chitinase-3-like protein 1) level and proteinuria in renal transplant recipients. AB - BACKGROUND: YKL-40 (chitinase-3-like protein 1) is a novel inflammation and endothelial dysfunction biomarker. Although YKL-40 is associated with albuminuria and predicts cardiovascular morbidity and mortality in a non-uremic population, it's status is not known in renal transplant recipients. The aim of this study was to investigate plausible links between serum YKL-40 and proteinuria. MATERIAL AND METHODS: A total of 110 renal transplant recipients were included in this study. The level of proteinuria was calculated from spot urine using the protein/creatinine ratio. The estimated glomerular filtration rate (GFR) was calculated using the Modification of Diet in Renal Disease (MDRD) formula. Serum YKL-40 was determined by ELISA (R&D Systems, USA). RESULTS: The mean patient age was 40.5 +/- 10 years. The mean YKL-40, GFR, and proteinuria levels were 66 +/- 46 ng/ml, 49 +/- 24 ml/min/1.73 m2, and 0.77 +/- 1.15 g/day, respectively. Increases in the YKL-40 tertiles were correlated with increases in proteinuria and C-reactive protein and decreases in the GFR and serum albumin. An adjusted linear regression analysis demonstrated that the YKL-40 level (t=3.28, P=0.001), GFR (t=-3.00, P=0.003), and systolic blood pressure (t=2.51, P=0.01) were independently associated with proteinuria. CONCLUSIONS: This is the first study to show that increased serum YKL-40 levels are independently associated with proteinuria in renal transplant recipients. YKL-40 may be responsible for the pathogenesis of cardiovascular injury in this patient population. PMID- 23792509 TI - Long-term outcome of en bloc pediatric kidney transplantation in adult recipients - up to 22 years of center experience. AB - BACKGROUND: Renal transplantation has been shown to be the best therapeutic option in end-stage renal disease patients. En bloc transplantation of pediatric kidneys into adult recipients (EBKT) is one strategy to increase the donor pool. We here report on 10 to 22 years of follow-up (median of 12.8 years) of patients receiving EBKT in a single-center, retrospective cohort study. MATERIAL AND METHODS: The mean donor age was 14 +/- 12 months and mean donor body weight was 8 +/- 3 kilograms. Thirteen recipients (6 females, 7 males) were followed for 10 to 22 years. The mean recipient age was 44 +/- 13 years at the time of transplantation. RESULTS: Two of 13 patients lost their grafts in the first week because of hemorrhagic infarction of the kidney transplants or sepsis (septic shock). Only 1 patient had an acute cellular rejection, which was successfully treated with steroids and anti-CD3 antibody. Eleven out of 13 patients after EBKT survived and had a functioning graft 10 to 22 years after successful EBKT. The serum creatinine was 1.34 +/- 0.6 mg/dl at 5 years (n=11), 1.37 +/- 0.7 mg/dl at 10 years (n=11), 1.40 +/- 0.6 mg/dl at 15 years (n=4), and 1.08 mg/dl at 20 years after EBKT (n=2). The eGFR, evaluated by using MDRD-2, was 66.5 +/- 22 ml/min/m2 at 5 years (n=11), 62 +/- 28 ml/min/m2 at 10 years (n=11), 56 +/- 23 ml/min/m2 at 15 years (n=4), and 61 ml/min/m2 at 20 years after EBKT (n=2). Proteinuria did not increase significantly within the observation period. CONCLUSIONS: In our experience, if the acute post-operative phase is uncomplicated, EBKT has excellent long-term graft and patient survival. PMID- 23792510 TI - Rapidly fatal disseminated acanthamoebiasis in a single lung transplant recipient. AB - BACKGROUND: Lung transplant recipients are at great risk for developing various infectious complications. These infections portend a significant morbidity and mortality throughout their lifetime following transplantation. At times, cutaneous manifestations are the only clues to systemic infection. CASE REPORT: A 62 year-old man with a history of idiopathic pulmonary fibrosis presented 6 months after receiving bilateral sequential cadaveric lung transplantation for anorexia, early satiety, weight loss, exertional dsypnea, arthralgia, and depression. On exam, two rapidly growing non-painful 1.5-3 centimeter erythematous nodules with purulent draining on the anterior chest wall were noted. On Hospital Day 7, the patent was found to be un-responsive, hypotensive, and febrile. Brain imaging revealed diffuse thick nodular enhancement of leptomeningeal surface and multiple areas of hypodenisty associated with mass effect in the bilateral vermis and cerebellar hemispheres with effacement of the fourth ventricle. CSF PCR analysis showed Acanthamoeba sp. confirmed by the Center for Disease Control. Despite multi-modal therapy, his clinical course deteriorated and resulted in brain death. CONCLUSION: Acanthamoeba infection is extremely rare in thoracic organ recipients. We report the fifth case of progressive disseminated acanthamoebiasis in a lung transplant recipient. PMID- 23792511 TI - Current approaches in national kidney paired donation programs. AB - Kidney transplantation is the treatment of choice for patients with end-stage renal disease. While living donors provide anywhere from a small to a large fraction of kidneys for transplantation in different countries, at least one third of these donors are incompatible with their potential recipients. To overcome these challenges, kidney paired donation (KPD) programs have been established that organize donor exchanges to find matches among the pool of incompatible pairs. Each program has developed its own features to accommodate local needs. Reasons for participating in KPD include blood group incompatibility, sensitization of the recipient against the donor, and the potential for improvement in transplant quality (e.g., age difference or graft size), and tissue compatibility. KPD programs use sophisticated algorithms to find matches among the pool of donor-recipient pairs to create simultaneous 2 way, 3-way, or 4-way exchanges or more complex non-simultaneous chains of transplants. These KPD allocation systems should be medically sound and ethically acceptable according to the principles of equity, utility, and justice. The variety of possible exchanges provided by these algorithms allows for maximizing the number of transplants, increasing the quality of transplants, and accommodating patients who are difficult to match. In this review, we describe several examples of successful KPD programs with diverse organizational approaches. By highlighting the strategies used by these programs to meet the needs of their patient populations, we aim to inspire improvements in existing programs and to provide a framework for expanding KPD to better serve international transplant communities. PMID- 23792512 TI - Treatment of cytomegalovirus infection after renal transplantation: experience from a single center in China. AB - BACKGROUND: We compared the efficacy and safety of 2 different treatments of CMV infection, including asymptomatic CMV replication and CMV disease. MATERIAL AND METHODS: 852 renal transplantation recipients, including asymptomatic CMV replication and CMV disease, received antiviral therapies of intravenous acyclovir or comprehensive anti-infection solution, mainly with intravenous ganciclovir. Effect, time, acute allograft rejection, and safety were analyzed during the antiviral therapy RESULTS: The total effective rates were higher with ganciclovir in both asymptomatic CMV replication (98.96% vs. 84.90%) and CMV disease (96.29% vs. 50.36%). Ganciclovir significantly shortened antiviral therapy duration in both asymptomatic CMV replication (15.0 +/- 2.3 days vs. 16.0 +/- 3.4 days) and CMV disease (19.7 +/- 3.1 days vs. 21.5 +/- 4.0 days). The acute allograft rejection incidences were significantly lower with ganciclovir in both asymptomatic CMV replication (8% vs. 14%) and CMV disease (11% vs. 22%). CMV IEA was detected in renal grafts of patients with acute rejection. There was more CMV-associated acute rejection using acyclovir than using ganciclovir. Except for the higher incidence of anemia leucopenia and anemia with ganciclovir, the safety profiles of both drugs were similar. CONCLUSIONS: Comprehensive anti-infection solution, mainly with intravenous ganciclovir, can effectively treat CMV infection, shorten duration of therapy, and decrease acute rejection. The few adverse effects had negligible effects on use of ganciclovir. PMID- 23792513 TI - Assessment of sexual function and conjugal satisfaction prior to and after liver transplantation. AB - BACKGROUND: The aims of this study were to assess sexual function and conjugal satisfaction in patients prior to and after liver transplantation, and in comparison to healthy individuals. MATERIAL AND METHODS: A cross-sectional cohort questionnaire assessment was performed in adult liver recipients, including the International Index of Erectile Function (IIEF) for men or the Female Sexual Function Index (FSFI) for women. Conjugal satisfaction was assessed with the Locke-Wallace Marital Adjustment Test. Waitlist candidates and age-matched healthy individuals were used as controls. RESULTS: Questionnaires of 136 patients were assessed (45 women/91 men, mean age: 57 +/- 11 years). Overall, sexual function improved after transplantation (male: p=0.065 and female: p=0.072), but remained lower than in aged-matched healthy individuals. The post transplant level of conjugal satisfaction was stable and similar to healthy controls in men, but improved significantly in women (p=0.008), with higher levels than in healthy subjects (p=0.05). CONCLUSIONS: The present study shows that sexual function improves after transplantation, yet not to the level of healthy controls. It also demonstrates, for the first time, that post-transplant conjugal satisfaction is at least similar to the one of healthy controls. PMID- 23792514 TI - Comparison of UW and Celsior: long-term results in kidney transplantation. AB - BACKGROUND: The aim of this study was to compare 2 preservation solutions in kidney transplant recipients in the same center during the same period since initiation of the use of High Na+; low K+ solution (Celsior). MATERIAL AND METHODS: From January 1999 to April 2011, 610 consecutive renal transplantations were done in our department with deceased donor kidneys. Data were collected prospectively. Organ procurement was performed in our center for 305 kidneys. We washed and preserved 409 kidneys in UW, and 201 in Celsior solution. RESULTS: Donors criteria were worse in the Celsior group for age, male sex, creatinemia, and cold ischemia. Populations of recipients were comparable. There were no differences at 1 and 12 months in creatinine levels (p=0.9 and 0.8, respectively) and in number of delayed graft functions (DGF) (p=0.8 and relative risk =0.9) between groups. There were no differences in post-transplantation outcomes for all variables. At 5 years, graft survival was 90.4% for UW and 93.5% for Celsior (p=0.44). CONCLUSIONS: Our retrospective study did not succeed in demonstrating superiority of a High Na+; low K+ solution compared to a UW type reference solution. Celsior has the same effectiveness as UW during kidney cold storage. PMID- 23792515 TI - Long-term survival rate of kidney graft and associated prognostic factors: a retrospective cohort study, 1994-2011. AB - BACKGROUND: Despite several studies conducted to detect predisposing factors of graft rejection, results are inconsistent and limited. This study was performed to estimate long-term survival rate of kidney transplantation and to detect associated prognostic factors. MATERIAL AND METHODS: This retrospective cohort study was conducted in Hamadan Province, in western Iran, enrolling 475 patients who had undergone kidney transplantation from 1994 to 2011. Data were extracted from patients' medical records using a checklist. Chronic nonreversible graft rejection was considered as the event of interest. The duration of time between kidney transplantation and rejection was considered as the survival time. Life table, Kaplan-Meier curve, log-rank test and Cox proportional hazard model were used for data analysis. RESULTS: Out of 475 transplantations, 55 episodes of rejection occurred. One-, 5-, 10-, 15-, and 18-year survival rates of transplantation were 97.1%, 92.3%, 86.2%, 77.6%, and 60.3%, respectively. The hazard ratio of graft rejection per 1-year increase in recipient age was 0.92 (P=0.001). The hazard ratio of graft rejection was 5.47 for grafts from deceased donors compared to grafts from living donors (P=0.025), and 3.54 (P=0.025) and 47.99 (P=0.001) in patients with episode of acute and hyperacute rejection compared to those without rejection episode, respectively. CONCLUSIONS: Rejection of kidney transplantation is shaped by several prognostic factors, the most important of which are recipient age, type of donor (living vs. deceased), and episode of post-transplantation acute and hyperacute rejection. PMID- 23792516 TI - D-MELD, a strong and accurate tool to guide donor-2-recipient matching. PMID- 23792517 TI - Risk factors and characteristics of post-transplant tuberculosis in an endemic area. AB - BACKGROUND: Tuberculosis (TB) is a major post-transplant concern in endemic areas. This report summarizes the clinical characteristics, risk factors, and effects of post-transplant TB on graft and patient survival at a single center in Korea. MATERIAL AND METHODS: We retrospectively analyzed data from 2799 kidney recipients at Yonsei University Health System between April 1979 and August 2008 to determine the incidence, outcome, and risk factors affecting the development of TB infections and the effect of TB on graft and patient survival rates. RESULTS: TB developed in 144 (109 males and 35 females; mean age, 37 +/- 12 years) out of 2799 (5.1%) recipients. Newly developed TB occurred in 116 recipients (81%) and recurrent TB occurred in 28 (19%) recipients with a pre transplant history of a mycobacterial infection. The mean interval to TB diagnosis was 55.6 +/- 47.9 months after transplantation without a peak interval incidence for 8 years after transplantation. Based on Cox regression analysis, a history of TB was the strongest risk factor (hazard ratio [HR] =11.618) affecting the development of TB. TB negatively affected graft and patient survival after kidney transplantation. Non-pleurisy extrapulmonary and miliary TB resulted in inferior treatment results and a poor prognosis in the early treatment period. CONCLUSIONS: A history of TB is the strongest predictor of post-transplant TB. Therefore, patients with a pre-transplant history of TB should be carefully monitored. PMID- 23792518 TI - Transplant nephrectomy: what are the surgical risks? AB - BACKGROUND: Whether or not to remove a failed renal graft has been the subject of much debate. One reason for a cautious approach to graft removal is its high morbidity and mortality rates. We analyzed the morbidity, mortality, and risk factors of transplant nephrectomy at our center. MATERIAL AND METHODS: We included 157 cases of transplant nephrectomy in 143 patients, performed between January 2000 and May 2012 at the Academic Medical Center, Amsterdam. Patient data were collected retrospectively. RESULTS: A total of 32 surgical complications occurred after transplant nephrectomy (20%) and 16 patients needed surgical re intervention (10%). Hemorrhage and infection are the most frequent causes of surgical complications (14%). The mortality rate was 3.2%. There were no significant differences in characteristics and timing of transplant nephrectomy between the group with surgical complications and the group without. A total of 59 re-transplantations were performed in 57 patients (38%). CONCLUSIONS: Transplant nephrectomy is associated with high morbidity and mortality rates. We found no significant risk factors for surgical complications following transplant nephrectomy and no significant association between timing of transplant nephrectomy and surgical complications. Steps to reduce these complications need further investigation. PMID- 23792519 TI - Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis in a liver graft recipient: a case report. AB - BACKGROUND: Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy is a potentially curative approach for peritoneal carcinomatosis of colonic origin. So far experience concerning the use of this treatment option in transplant recipients is lacking. CASE REPORT: We herein present the case of a 31 year-old man who had previously been liver transplanted for primary sclerosing cholangitis. Approximately 10 years after transplantation colon carcinoma with co existing peritoneal carcinomatosis was diagnosed. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy were conducted. Operative management under tacrolimus medication did not trigger infections, wound healing disorders or graft function impairment. At one year follow-up no tumor recurrence was detected. CONCLUSIONS: Recent literature suggests that proctocolectomy for colorectal cancer is considered feasible in liver graft recipients. Virtually all patients suffering from primary sclerosing cholangitis exhibit co-existing ulcerative colitis, rendering this subset of patient at risk for developing colonic malignancies. Furthermore chronic immunosuppression may facilitate malignant growth. The most feared complication in colorectal carcinomas is the occurence of peritoneal carcinomatosis, for which cytoreduction plus hyperthermic intraperitoneal chemotherapy may be a curative option. This, so far unique, case report suggests that even in this patient subset this treatment is feasible and for further cases this dual-approach for the management of PC in transplant recipients should be taken into account. PMID- 23792520 TI - Detection of transplant renal artery stenosis in the early postoperative period with analysis of parenchymal perfusion with ultrasound contrast agent. AB - BACKGROUND: Transplant renal artery stenosis (TRAS) is a serious vascular complication due to non-specific clinical manifestations, causing serious diagnostic difficulties. Contrast-enhanced ultrasound (CE-US) can complement standard sonographic examination in evaluation of TRAS. MATERIAL AND METHODS: Standard ultrasound B presentation, extended with color Doppler assessment of the flow spectrum and CE-US, was carried out in the early postoperative period in a group of 180 patients who underwent kidney transplantation. In CE-US analysis, the maximum contrast agent perfusion to the cortex and renal pyramids was evaluated. In 15 patients with sonographically diagnosed TRAS, magnetic resonance angiography and computer tomography angiography were performed to confirm the diagnosis. RESULTS: In patients with TRAS, significantly longer time of contrast agent (CE) inflow was observed in comparison to patients without perfusion disturbances (3.47 s vs. 1.5 s, p<0.000 for cortex; 6.01 vs. 2.09 s for pyramids, p<0.000). The rate of CE inflow was strongly positively correlated with severity of stenosis assessed on the basis of CTA/MRA examination (R=0.97 for cortex and 0.9 for pyramids; p<0.001). Six months after kidney transplantation, patients with a history of TRAS had significantly higher serum creatinine level than recipients with normal renal artery blood flow (1.76 mg/dL vs. 1.53 mg/dl, p<0.02). Estimated GFR was decreased to 35.9 ml/min vs. 46.5 ml/min, respectively (p<0.05). CONCLUSIONS: Contrast-enhanced ultrasound allows for quick and non invasive assessment of parenchymal kidney graft perfusion. It enables confirmation of TRAS diagnosis in the early postoperative period and helps assess the degree of stenosis. PMID- 23792521 TI - Urinary tract infections in kidney transplant recipients: role of gender, urologic abnormalities, and antimicrobial prophylaxis. AB - BACKGROUND: Urinary tract infections (UTI), the most common infectious complications after kidney transplantation, are associated with poor allograft survival. Identifying its predisposing factors is therefore remarkably important in order to optimize prevention strategies. MATERIAL AND METHODS: A retrospective study was performed in a cohort of patients who received kidney transplantation between June 2007 and June 2009. Factors associated with development of UTI were assessed. RESULTS: The population consisted of 301 patients, with majority receiving allograft from living donors (85%). A total of 101 patients (34%) developed at least one episode of UTI, and 25% of the episodes occurred during the first year after transplantation. Risk factors associated with increased risk of UTI were female gender, recurrent UTI prior to transplant, and presence of urological abnormalities. Trimethoprim-sulfamethoxazole (TMP-SMZ) use was associated with a lower risk of UTI, including a lower risk of recurrent UTI. CONCLUSIONS: In this cohort of predominantly living donor kidney transplant recipients, we report a high incidence of UTI, despite our practice of early ureteral and Foley catheter removal. Female gender and prior recurrent UTI or urological abnormalities were predisposing factors, while TMP-SMZ use had a protective role. These clinical relevant findings should guide clinicians in optimizing prevention strategies against UTI in kidney transplant recipients. PMID- 23792522 TI - Human albumin: old, new, and emerging applications. AB - Human serum albumin has been widely used in an array of clinical settings for nearly 7 decades. Although there is no evidence to support the use of albumin rather than crystalloid in acute volume resuscitation, many clinicians continue to use albumin because it has other important physiologic effects besides the oncotic function. In keeping with the improved understanding of albumin physiology and pathophysiology of many acute and chronic diseases, use of albumin for medical applications has increased in recent years. This, along with increased costs of manufacturing and lower production volume of medical-grade albumin, has lead to an ongoing shortage and rapid increase in albumin prices. This review is based on the analysis of major publications, related to albumin chemistry, physiology, and medical uses including guidelines developed by professional and governmental organizations. Results reflect current knowledge about the role of albumin in health and disease and relevance of albumin therapy in specific clinical settings. Albumin therapy is currently recommended in spontaneous bacterial peritonitis with ascites, refractory ascites not responsive to diuretics, large-volume paracentesis, post-paracentesis syndrome, and the treatment of hepatorenal syndrome as an adjunct to vasoconstrictors. New indications for albumin therapy are linked to the antioxidant activity of albumin and its effects on capillary integrity. In recent years, large-pore hemofiltration and albumin exchange have emerged as promising liver support therapies for liver failure and other toxic syndromes. They are designed to remove a broad range of blood-borne toxins and to restore normal functions of the circulating albumin by replacing defective forms of albumin and albumin molecules saturated with toxins with normal albumin. In view of the ongoing worldwide shortage and high cost of human albumin (native and recombinant), new usage criteria, protocols, and guidelines for appropriate utilization of albumin are needed. PMID- 23792523 TI - AST 17600 U/l after liver transplantation, what are you up to? - A case report. AB - BACKGROUND: Miscellaneous clinical classifications of liver function after liver transplantation are rested upon elevation of transaminases which represent damaging of hepatocytes and with it of the liver. CASE REPORT: We report the case of a 35-year-old man suffering from hepatocellular carcinoma in the setting of alcoholic liver cirrhosis. The patient underwent liver transplantation and developed an extreme peak of transaminases due to prolonged cold ischemia time and additional extended donor criteria. On the first postoperative day the laboratory results showed peak transaminases as follows: AST 17577 U/l and ALT 9884 U/l. Frequent ultrasound revealed no signs of vascular complications. In spite of the dramatically elevated transaminases the liver showed a good primary function and the patient was cardiopulmonary stable. The entire postoperative course was uneventful. We discharged the patient after three weeks in a very good general state of health, with normal laboratory values. CONCLUSIONS: Exclusive extreme elevation of transaminases after liver transplantation combined with adequate liver synthesis does not always require re-transplantation, if situation of the patient is stable. Nevertheless re-transplantation should be reconsidered in any case of clinical deterioration of the patient. PMID- 23792524 TI - Incidence, risk factors and management of incisional hernia in a high volume liver transplant center. AB - BACKGROUND: Incisional hernia after liver transplantation is a common complication with an incidence between 5% and 34%. This prospective study analyzed risk factors, surgical management and long-term results after hernia repair. MATERIAL AND METHODS: From February 2002 until August 2009, 810 liver transplantations were performed. 77 patients (9.5%) underwent incisional hernia repair after a median time of 21.1 months (4.6-76.7) following transplant. These patients were compared to patients without hernia (n=733). RESULTS: No statistically significant differences between the groups were observed with respect to gender, underlying liver disease, Child-Pugh classification, MELD Score and preoperative renal failure (p=NS). Multivariate analysis revealed advanced age (p=0.014), body mass index (p=0.016), and re-laparotomies (p<0.001) as independent risk factors for incisional hernias. Pre-existing diabetes mellitus and immunosuppression with mycophenolate mofetil reached significance only in the univariate analysis (p<0.001). Recurrent hernia was observed in 12 of 77 patients (15.6%) at a median time of 7.9 months (4.8-46.8) after primary surgical repair. The recurrence rate after intraperitoneal onlay mesh implantation was lower compared to other mesh techniques (7.7% vs. 21.4%). CONCLUSIONS: The risk factors for the development of incisional hernias in liver transplant patients are similar to patients with prior abdominal surgery for other reasons. Intraperitoneal onlay mesh implantation may lead to a decrease of hernia recurrences. The role of immunosuppression in the genesis of incisional hernias requires further elucidation. PMID- 23792525 TI - The impact of ICAM1 and VCAM1 gene polymorphisms on long-term renal transplant function and recipient outcomes. AB - BACKGROUND: Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are implicated in endothelial cell-leukocyte adhesion. Several functional polymorphisms that affect the expression of ICAM-1 and VCAM-1, and therefore post-transplant immunological response, have been found in genes of these molecules. The aim of this study was to examine the impact of ICAM1 and VCAM1 gene polymorphisms on long-term renal transplant function and recipient outcome during a 5-year follow-up period. MATERIAL AND METHODS: The study enrolled 269 Caucasian renal transplant recipients (165 males, 104 females, mean age 47.58 +/- 12.96 years) remaining under observation for 5 years. Genotyping of the c.1405A>G (Lys469Glu, rs5498) ICAM1, T(-1592)C (rs1041163), and T(-833)C (rs3170794) VCAM1 genes polymorphisms was performed using real-time PCR. RESULTS: The rs5498 ICAM1 GG genotype was an independent risk factor associated with increased creatinine concentration at 12, 24, 36, 48, and 60 months after transplantation (p=0.0004, p=0.02, p=0.01, p=0.01 and p=0.04, respectively). Creatinine concentrations 36 and 48 months after transplantation were higher among CC homozygotes of the rs1041163 VCAM1 (TT+CT vs. CC, p=0.049 and p=0.04, respectively). The C allele of the rs1041163 VCAM1 gene polymorphism was identified as a risk factor for dialysis after transplantation (HR=3.323, 95%CI=1.44-7.67, p=0.005). The C allele of the rs1041163 VCAM1 gene was at the border of statistical significance as a risk factor for death after transplantation (p=0.06). CONCLUSIONS: These results suggest that the rs5498 ICAM1 GG genotype is correlated with early and long-term allograft failure. The C allele of the rs1041163 VCAM1 gene may be associated with long-term allograft failure and graft loss, as well as increased morbidity after transplantation. PMID- 23792526 TI - Atypical presentation of invasive pulmonary aspergillosis in a liver transplant recipient. AB - BACKGROUND: Invasive pulmonary aspergillosis (IPA) occurs in 1% to 8% of liver transplant recipients. It is one of the most frequent life-threatening fungal infections in immunocompromised patients, with a reported mortality rate of approximately 60%. CASE REPORT: We present the case of an 18-year-old man who underwent liver transplantation (LT) in January 2004 due to multifocal hepatoblastoma (HBL) and was diagnosed with IPA 3 years after LT. Because of a single pulmonary nodule of the left lung found in chest computed tomography (CT) 4 weeks after LT, the patient received adjuvant chemotherapy. A control chest CT performed in September 2004 did not reveal any pathological changes. A subsequent examination in May 2006 demonstrated a pulmonary lesion situated in the 10th segment of the left lung, which was confirmed by PET in October 2006. In March 2007 the patient underwent videothoracoscopic complete resection of the lesion. Histopathological examination revealed IPA and subsequent 3-month antifungal treatment with voriconazole resulted in 5 years of recurrence-free survival. CONCLUSIONS: We conclude that any stable solitary pulmonary lesion in a transplant recipient needs to be resected in order to allow a definitive diagnosis and prevent disease dissemination such as IPA in our patient. PMID- 23792527 TI - Waiting time, not donor-risk-index, is a major determinant for beneficial outcome after liver transplantation in high-MELD patients. AB - BACKGROUND: Due to the increasing donor shortage, patients undergo liver transplantation actually mostly with high MELD-scores. In this study, we analyze high-MELD patients who underwent liver transplantation at a german single center. MATERIAL AND METHODS: Since implementation of the MELD-score within the Eurotransplant region (December 2006) up to May 2011, 45 patients with a lab-MELD score >= 36 underwent liver transplantation at our center. We correlated the 1 year-survival with donor data (especially the donor risk index, DRI), the time interval from reaching a lab-MELD-score >= 36 up to liver transplantation and the recipient's state prior transplantation. RESULTS: The overall 1-year-survival in our cohort is 68,8%. Waiting time of survivors was significantly shorter compared to non-survivors (MedianSurvivors: 2 days vs. MedianNon-survivors: 4 days; p=0.049). DRI showed no significant differences between both groups. Furthermore, the recipient's state prior transplantation (dialysis, mechanical ventilation, catecholamines) showed no significant association with the outcome. CONCLUSIONS: The outcome after liver transplantation in high-MELD patients is worse compared to that of patients with a marked lower MELD-score. Especially the time interval between reaching a lab-MELD score >= 36 to the transplantation is a major determinant for survival. Since the DRI is not associated with a worsened outcome, transplantation centers should accept even marginal organs for high-MELD patients to keep the waiting time as short as possible. PMID- 23792528 TI - Renal replacement therapy before, during, and after orthotopic liver transplantation. AB - Acute kidney injury (AKI) is a common complication of orthotopic liver transplantation (OLT) occurring both in the pre- and postoperative period. It significantly worsens prognosis. Performing renal replacement therapy (RRT) is difficult in these patients and may cause numerous problems. The patients usually remain in serious condition, are hemodynamically unstable, at risk of brain edema, and suffer from acidosis and electrolyte imbalance. They require multi drug treatment, parenteral nutrition, and use of life support devices. Here, we present the advantages and disadvantages of selected RRT methods, as well as problems associated with anticoagulation. We also discuss the possible extrarenal indications for RRT in liver transplant patients and the preliminary data on intraoperative RRT. PMID- 23792529 TI - The impact of apoptosis and inflammation gene polymorphisms on transplanted kidney function. AB - BACKGROUND: The progressive deterioration of kidney allograft function leads in most cases to transplant failure. Polymorphisms in genes encoding for inflammatory and apoptosis molecules may be one possible explanation for interindividual differences in kidney transplant outcomes. The objective of our work was to identify the possible effect of interleukin 6 (IL-6), transforming growth factor beta 1 (TGFB1), and Fas on graft function. MATERIAL AND METHODS: A case-control study was carried out to assess potential associations between polymorphisms in inflammation- and apoptosis-related genes and the risk for chronic impairment of kidney graft function. The study included 376 cadaveric kidney recipients, 256 of them with stable graft function and 120 who experienced renal deterioration during the follow-up period of 2.6 +/- 1.4 years. Genotyping of IL-6/G-174C, TGFB1/L10P, TGFB1/R25P, and Fas/G-670A polymorphisms was performed by PCR-RFLP and direct sequencing. RESULTS: Considering the single IL 6, TGFB1, and Fas polymorphisms, we found similar allelic and genotype frequencies between the 2 groups. To test the hypothesis of mutual effects of polymorphisms, multiple logistic regression was performed incorporating data for all the possible dual genotypic associations. The association of IL-6 high producer and Fas low producer genotype resulted in a protective effect against graft dysfunction (OR=0.79; 95% C.I.=0.72-0.86). CONCLUSIONS: This study did not find significant associations of apoptosis and inflammation gene polymorphisms with transplanted kidney function in Italian renal transplant recipients. However, our data seem to indicate that the carriage of IL-6 high producer/Fas low producer genotype has a protective effect against graft function loss. PMID- 23792530 TI - Day 1 post-operative fasting hyperglycemia may affect graft survival in kidney transplantation. AB - BACKGROUND: Early post-operative hyperglycemia is commonly encountered in patients without pre-existing diabetes mellitus who are undergoing kidney transplantation. The aim of this study was to determine the effect of early post operative hyperglycemia on graft and patient survival after kidney transplantation in our center. MATERIAL AND METHODS: This was a single-center retrospective review of solitary kidney recipients transplanted in our center between January 1998 and December 2007. Of a total of 432 patients, 377 were eligible for the study. Fasting plasma glucose (FPG) levels at day 1 (D1) and day 5 (D5) after transplantation were recorded. Hyperglycemia was defined as FPG >= 7.0 mmol/l. Outcome events recorded included deaths and graft failures. RESULTS: The mean age at transplantation was 43.2 +/- 9.5 years and 50.4% were male. The mean FPG levels at D1 and D5 were 7.5 +/- 1.3 mmol/L and 5.3 +/- 1.3 mmol/L, respectively; 64.2% of recipients had FPG >= 7.0 mmol/L on D1 and this was reduced to 8.5% on D5. Recipients with D1 FPG >= 7.0 mmol/L had significantly poorer graft survival (39 events) compared to those without D1 hyperglycemia (6 events), with a hazard ratio of 3.708 (95% CI, 1.568-8.766, P=0.003). There was a trend towards better patients survival in recipients with D1 FPG <7.0 mmol/L (P=0.056). CONCLUSIONS: D1 post-transplantation hyperglycemia may be associated with increased risk of graft failure. It is thus important to closely monitor glucose levels during the early post-transplantation period so that high risk patients can be identified and appropriate measures can be implemented to improve the long-term outcome. PMID- 23792531 TI - Pathologic response to non-surgical locoregional therapies as potential selection criteria for liver transplantation for hepatocellular carcinoma. AB - BACKGROUND: Preoperative locoregional treatments (PLT) are performed to avoid progression before liver transplantation for hepatocellular carcinoma (HCC). The objective of this study was to analyze the prognostic factors affecting the outcome in patients who received PLT. MATERIAL AND METHODS: A retrospective analysis of patients who underwent liver transplantation (LT) was performed. All patients who underwent PLT with confirmed pathological diagnosis of HCC were included. The rate of tumor necrosis (TN) was assessed by microscopic histological examination. RESULTS: From January 1997 to December 2010, PLT was performed in 154 patients ROC analysis individuated a TN cut-off value at 40%. Ninety-one patients (59.1%) of the patients presented TN>40%. At multivariate analysis, TN<40% (HR=1.76; p=0.04) and vascular invasion (VI) (HR=2.16; p<0.01) were associated with lower Overall Survival (OS). At multivariate analysis, TN<40% (HR=1.59; p=0.001) and VI (HR=2.51; p=0.001) were significant associated with lower Disease Free Survival (DFS). One, 3 and 5 years OS was 87.9%, 82.0% and 69.1% for patients with TN>40% and 82.5%, 64.2% and 53.2% for those with TN<40% (p=0.02). Tumour size <5 cm (p=0.02); age <55 years (p=0.02); absence of VI (p=0.02) and multiple procedures (p=0.04) were predictive factors for TN>40%. CONCLUSIONS: Response to preoperative locoregional treatment can be used as potential selection criteria for LT. PMID- 23792532 TI - Satisfactory outcomes with usage of extended criteria donor (ECD) kidneys in re transplant recipients. AB - BACKGROUND: The use of extended criteria donor (ECD) kidneys have increased substantially and the benefit recognized in certain populations. Our institution has maintained a policy of aggressively utilizing ECD kidneys, even among those who have failed a previous transplant. Previous reports on the benefit of ECD in re-transplants have shown equivocal outcomes. We sought to determine if our experience would support or refute this finding. MATERIAL AND METHODS: This is a retrospective study of 19 ECD re-transplants between 2002 and 2010. We compared 1 and 3 year outcomes with 95 patients with standard criteria donor (SCD) re transplant and 169 patients with first time transplant using ECD kidneys. Outcomes and demographics were evaluated including delayed graft function (DGF), HTN, DM, cold ischemia time (CIT), BMI, donor age and prior allograft nephrectomies using a Cox Proportional Hazard model. We compared patient and graft survival using the log rank test. RESULTS: Patient survival were similar among the first time ECD and ECD re-transplant groups at 1 year (p=0.9547) and at 3 years (p=0.8287). Graft survival was also similar between first time ECD and ECD re-transplant groups at 1 year (p=0.4781) and at 3 years (p=0.8519). As expected, SCD re-transplant had better outcomes than the other groups. CONCLUSIONS: 1 and 3 years graft and patient survival among first time ECD transplants and ECD re-transplants are similar. As the list of patients on dialysis is ever growing, it may be prudent to aggressively explore the utility of using ECD kidneys in re-transplant patients. PMID- 23792533 TI - Evaluation of immune function under conversion from Prograf to Advagraf in living donor liver transplantation. AB - BACKGROUND: Although some reports have shown the safety and efficacy of conversion from Prograf to Advagraf in liver transplantation, there have been no reports showing the change of immune function after conversion. The aim of this study is not only to analyze the safety and efficacy of conversion from Prograf to Advagraf, but also to evaluate the immune function using the ImmuKnow assay. MATERIAL AND METHODS: Of the 168 living donor liver transplantation (LDLT) patients, 21 recipients whose liver function was stable after discharge in outpatient clinic and who agreed to conversion from Prograf to Advagraf were enrolled in this study. Liver, renal, and immune functions were retrospectively reviewed. RESULTS: There were no significant differences in liver and renal function after conversion from Prograf to Advagraf. The intracellular adenosine triphosphate levels before and after conversion were 263+/-157 and 256+/-133 ng/ml, respectively, and there was also no significant difference in immune function. None of the recipients showed adverse effects, rejection, or severe infection during the study. It should be further noted that none of the recipients had to increase the dose of Advagraf, while five of 21 recipients (24%) were able to reduce the dose of Advagraf during this study. CONCLUSIONS: Conversion from Prograf to Advagraf in LDLT can be performed safely and effectively without affecting liver, renal, and immune function. PMID- 23792535 TI - Strategies targeted at motivating unrelated living kidney donation. AB - BACKGROUND: This paper aimed to assess the willingness of Malaysians with post secondary education to be living kidney donors. MATERIAL AND METHODS: From the total of 1,310 living kidney donor respondents in Kuala Lumpur and its suburbs, we focused on 688 respondents with post-secondary education. These 688 respondents were asked whether they were willing to become living kidney donors if the government provides a reasonable amount of financial incentive. Those who were not willing to be donors (490) were then asked the reasons for their unwillingness. Six options were given and respondents can choose more than 1 option. RESULTS: Malaysians with post-secondary education remain unconvinced to be living donors even when provided with monetized incentives. The main reason cited was they are not convinced that individuals can live with just 1 kidney. CONCLUSIONS: There is a need for the government to develop new ways to promote organ donation. These include strengthening government coordination of medical procedures and creating public awareness about the safety of living with 1 kidney. Setting up new institutions such as donor clinics, creating a living donor registry, and having independent donor advocates are also instrumental. PMID- 23792534 TI - Pretreatment of liver grafts in vivo by gamma-aminobutyric acid receptor regulation reduces cold ischemia/warm reperfusion injury in rat. AB - BACKGROUND: Gamma-aminobutyric acid (GABA) is found throughout the body. The regulation of GABA receptor (GABAR) reduces oxidative stress (OS). Ischemia/reperfusion injury after orthotopic liver transplantation (OLT) causes OS-induced graft damage. The effects of GABAR regulation in donors in vivo were investigated. MATERIAL AND METHODS: Donor rats received saline, a GABAR agonist or GABAR antagonist 4 h before surgery. Recipient rats were divided into four groups according to the donor treatments: laparotomy, OLT with saline, OLT with GABAR agonist and OLT with GABAR antagonist. Histopathological, biochemical and immunohistological examinations were performed at 6, 12 and 24 h after OLT. Protein assays were performed at 6 h after OLT. The 4-hydroxynonenal (4-HNE), ataxia-telangiectasia mutated kinase (ATM), phosphorylated histone H2AX (gammaH2AX), phosphatidylinositol-3 kinase (PI3K), Akt and superoxide dismutase (SOD) were assessed by western blot analysis. RESULTS: In the univariate analysis, histopathological and biochemical profiles verified that the GABAR agonist reduced graft damage. Immunohistology revealed that the GABAR agonist prevented the induction of apoptosis. Measurement of 4-4-HNE levels confirmed OS induced damage after OLT, and the GABAR agonist improved this damage. In the gammaH2AX, PI3K, Akt and antioxidant enzymes (SODs), ATM and H2AX were greatly increased after OLT, and were reduced by the GABAR agonist. In the multivariate analyses between multiple groups, histopathological assessment, aspartate aminotransferase level, immunohistological examinations for apoptotic induction and gammaH2AX showed statistical differences. CONCLUSIONS: A specific agonist demonstrated regulation of GABAR in vivo in the liver. This activation in vivo reduced OS after OLT via the ATM/H2AX pathway. PMID- 23792536 TI - Norepinephrine versus dopamine pretreatment of potential heart donors - impact on long-term outcome. AB - BACKGROUND: Current guidelines advocate administration of inotropic agents to stabilize potential deceased heart-beating donors. A consensus on the specific agent or combination therapy is lacking. We thus initiated a retrospective analysis of patients being transplanted at our center in a matched-pair study design focusing on survival after donor pre-treatment either with norepinephrine or dopamine. MATERIAL AND METHODS: 936 patients (759 male; 177 female; mean age: 47.5 +/- 15.4 years) were transplanted at our center between 8/1981 and 12/2010. An overall of 22 patient pairs (all male; mean age 55.4 +/- 7.5 years; range 23 67 years) were matched according to our strict criteria. During follow-up (5037 +/- 1791 days) 11 deaths occurred. Overall survival in both groups was not different (p=0.1438). RESULTS: In a sub-population analysis of all patient-pairs that completed 5-year follow-up (n=19), Kaplan-Meier analysis revealed significant superior survival of recipients that received hearts pre-treated with norepinephrine vs. dopamine pre-treatment (p=0.0368). CONCLUSIONS: Neither norepinephrine nor dopamine pre-treatment of potential heart donors showed superior overall survival. In a sub-population of long-term survivors norepinephrine pre-treatment was associated with better survival in a rather small cohort of heart transplant recipients. These findings underscore the urgent need of further prospective multicenter randomized trials to recommend a preferable adrenergic therapy. PMID- 23792537 TI - The 5'-3' exoribonuclease Pacman (Xrn1) regulates expression of the heat shock protein Hsp67Bc and the microRNA miR-277-3p in Drosophila wing imaginal discs. AB - Pacman/Xrn1 is a highly conserved exoribonuclease known to play a critical role in gene regulatory events such as control of mRNA stability, RNA interference and regulation via miRNAs. Although Pacman has been well studied in Drosophila tissue culture cells, the biologically relevant cellular pathways controlled by Pacman in natural tissues are unknown. This study shows that a hypomorphic mutation in pacman (pcm (5)) results in smaller wing imaginal discs. These tissues, found in the larva, are known to grow and differentiate to form wing and thorax structures in the adult fly. Using microarray analysis, followed by quantitative RT-PCR, we show that eight mRNAs were increased in level by>2-fold in the pcm5 mutant wing discs compared with the control. The levels of pre-mRNAs were tested for five of these mRNAs; four did not increase in the pcm (5) mutant, showing that they are regulated at the post-transcriptional level and, therefore, could be directly affected by Pacman. These transcripts include one that encodes the heat shock protein Hsp67Bc, which is upregulated 11.9-fold at the post-transcriptional level and 2.3-fold at the protein level. One miRNA, miR-277-3p, is 5.6-fold downregulated at the post-transcriptional level in mutant discs, suggesting that Pacman affects its processing in this tissue. Together, these data show that a relatively small number of mRNAs and miRNAs substantially change in abundance in pacman mutant wing imaginal discs. Since Hsp67Bc is known to regulate autophagy and protein synthesis, it is possible that Pacman may control the growth of wing imaginal discs by regulating these processes. PMID- 23792538 TI - Oxotremorine delays and scopolamine accelerates sexual exhaustion when applied to the preoptic area in male hamsters. AB - Acetylcholine (ACh) has not been tested for a role in the development of sexual exhaustion in males. However, male hamsters receiving infusions into the medial preoptic area (MPOA) of the muscarinic agonist oxotremorine (OXO) or antagonist scopolamine (SCO) show changes in the postejaculatory interval, one of the measures that changes most consistently as exhaustion approaches. In addition, central SCO treatments cause changes in the patterning of intromissions that resemble those signaling exhaustion. To extend these observations and more thoroughly test the dependence of sexual exhaustion on ACh, male hamsters received MPOA treatments of OXO, SCO or the combination of the two before mating to exhaustion. Relative to placebo, OXO infusions caused small but consistent increases in ejaculation frequency and long intromission latency, delaying the appearance of exhaustion. Scopolamine treatments did the reverse, dramatically accelerating the development of exhaustion. Consistent with and possibly responsible for these changes were effects on the quality of performance prior to exhaustion. These included differences in overall copulatory efficiency (e.g., ejaculations/intromission), which was increased by OXO and decreased by SCO. They also extended to several standard measures of copulatory behavior, including intromission frequency, ejaculation latency and the postejaculatory interval: Most of these were increased by SCO and decreased by OXO. Finally, whereas most or all effects of OXO were counteracted by SCO, most or all of the responses to SCO resisted change by added OXO. This asymmetry in the responses to combined treatment raises the possibility that the effects of these drugs on sexual exhaustion and other elements of male behavior are mediated by distinct muscarinic receptors. PMID- 23792539 TI - Effects of AS2586114, a soluble epoxide hydrolase inhibitor, on hyperlocomotion and prepulse inhibition deficits in mice after administration of phencyclidine. AB - Accumulating evidence suggests that soluble epoxide hydrolase (sEH) plays a key role in controlling levels of lipid signaling molecules, and that the potent sEH inhibitors may be potential therapeutic drugs for a number of diseases associated with metabolism of epoxyeicosatrienoic acids (EETs). This study was undertaken to examine whether the potent sEH inhibitor AS2586114 could attenuate behavioral abnormalities (e.g., hyperlocomotion and prepulse inhibition (PPI) deficits) in male ddY mice after a single administration of the N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine (PCP). A single oral administration of AS2586114 (10, 30, or 100 mg/kg) attenuated the hyperlocomotion in mice after the administration of PCP (3.0 mg/kg, s.c.), in a dose dependent manner. Furthermore, a single oral administration of AS2586114 (10, 30, or 100 mg/kg) improved the PPI deficits in mice after the administration of PCP (3.0 mg/kg, s.c.), in a dose dependent manner. In addition, the atypical antipsychotic drug clozapine (10 mg/kg, p.o.) significantly attenuated hyperlocomotion and PPI deficits after the administration of PCP (3.0 mg/kg, s.c.). In conclusion, this study suggests that AS2586114 may have antipsychotic activity in PCP models of schizophrenia. Therefore, it is likely that the sEH inhibitors may be potential therapeutic drugs for neuropsychiatric diseases such as schizophrenia. PMID- 23792541 TI - The effect of noradrenergic attenuation by clonidine on inhibition in the stop signal task. AB - Understanding the neuropharmacology of inhibition is of importance to fuel optimal treatment for disorders such as Attention Deficit/Hyperactivity Disorder. The aim of the present study was to assess the effect of noradrenergic antagonism by clonidine on behavioral-performance and brain-activity indices of inhibition. A placebo-controlled, double-blind, randomized, crossover design was implemented. Male (N=21) participants performed in a visual stop signal task while EEG was recorded under clonidine in one session and under placebo in another. We expected that 100 MUg clonidine would have a negative effect on EEG indices of inhibition, the Stop N2 and Stop P3. Furthermore, we expected that clonidine would negatively affect the behavioral measure of inhibition, the stop signal reaction time (SSRT). Behavioral analyses were performed on data of 17 participants, EEG analyses on a subset (N=13). Performance data suggested that clonidine negatively affected attention (response variability, omissions) without affecting inhibition as indexed by SSRT. Electrophysiological data show that clonidine reduced the Stop P3, but not the Stop N2, indicating a partial negative effect on inhibition. Results show that it is unlikely that the Stop P3 reduction was related to the effect of clonidine on lapses of attention and on peripheral cardiovascular functioning. In conclusion, the current dose of clonidine had a negative effect on attention and a partial effect on inhibitory control. This inhibitory effect was restricted to the dorsal region of the prefrontal cortex (presumably the superior frontal gyrus) as opposed to the ventral region of the prefrontal cortex (right inferior frontal gyrus). PMID- 23792540 TI - Adolescent binge-like ethanol exposure reduces basal alpha-MSH expression in the hypothalamus and the amygdala of adult rats. AB - Melanocortins (MC) are central peptides that have been implicated in the modulation of ethanol consumption. There is experimental evidence that chronic ethanol exposure reduces alpha-MSH expression in the limbic and hypothalamic brain regions and alters central pro-opiomelanocortin (POMC) mRNA activity in adult rats. Adolescence is a critical developmental period of high vulnerability in which ethanol exposure alters corticotropin releasing factor, neuropeptide Y, substance P and neurokinin neuropeptide activities, all of which have key roles in ethanol consumption. Given the involvement of MC and the endogenous inverse agonist AgRP in ethanol drinking, here we evaluate whether a binge-like pattern of ethanol treatment during adolescence has a relevant impact on basal and/or ethanol-stimulated alpha-MSH and AgRP activities during adulthood. To this end, adolescent Sprague-Dawley rats (beginning at PND25) were pre-treated with either saline (SP group) or binge-like ethanol exposure (BEP group; 3.0 g/kg given in intraperitoneal (i.p.) injections) of one injection per day over two consecutive days, followed by 2 days without injections, repeated for a total of 8 injections. Following 25 ethanol-free days, we evaluated alpha-MSH and AgRP immunoreactivity (IR) in the limbic and hypothalamic nuclei of adult rats (PND63) in response to ethanol (1.5 or 3.0 g/kgi.p.) and saline. We found that binge-like ethanol exposure during adolescence significantly reduced basal alpha-MSH IR in the central nucleus of the amygdala (CeA), the arcuate nucleus (Arc) and the paraventricular nucleus of the hypothalamus (PVN) during adulthood. Additionally, acute ethanol elicited AgRP IR in the Arc. Rats given the adolescent ethanol treatment required higher doses of ethanol than saline-treated rats to express AgRP. In light of previous evidence that endogenous MC and AgRP regulate ethanol intake through MC-receptor signaling, we speculate that the alpha-MSH and AgRP disturbances induced by binge-like ethanol exposure during adolescence may contribute to excessive ethanol consumption during adulthood. PMID- 23792542 TI - Selective cleavage of 3,5-bis-(trifluoromethyl)benzylcarbamate by SmI2-Et3N-H2O. AB - A novel electron poor protection group for amines has been developed. It undergoes rapid cleavage by SmI2-Et3N-H2O and its orthogonality towards the regular benzyl carbamate group (CBz) under reductive or transfer hydrogenolytic conditions is reported. PMID- 23792543 TI - Interaction of silver nanoparticles with proteins: a characteristic protein concentration dependent profile of SPR signal. AB - Silver nanoparticles are finding increasing applications in biological systems, for example as antimicrobial agents and potential candidates for control drug release systems. In all such applications, silver nanoparticles interact with proteins and other biomolecules. Hence, the study of such interactions is of considerable importance. While BSA has been extensively used as a model protein for the study of interaction with the silver nanoparticles, studies using other proteins are rather limited. The interaction of silver nanoparticles with light leads to collective oscillation of the conducting electrons giving rise to surface plasmon resonance (SPR). Here, we have studied the protein concentration dependence of the SPR band profiles for a number of proteins. We found that for all the proteins, with increase in concentration, the SPR band intensity initially decreased, reaching minima and then increased again leading to a characteristic "dip and rise" pattern. Minimum point of the pattern appeared to be related to the isoelectric point of the proteins. Detailed dynamic light scattering and transmission electron microscopy studies revealed that the consistency of SPR profile was dependent on the average particle size and state of association of the silver nanoparticles with the change in the protein concentration. Fluorescence spectroscopic studies showed the binding constants of the proteins with the silver nanoparticles were in the nano molar range with more than one nanoparticle binding to protein molecule. Structural studies demonstrate that protein retains its native-like structure on the nanoparticle surface unless the molar ratio of silver nanoparticles to protein exceeds 10. Our study reveals that nature of the protein concentration dependent profile of SPR signal is a general phenomena and mostly independent of the size and structure of the proteins. PMID- 23792544 TI - Physicochemical behaviour of WPI-stabilized emulsions in in vitro gastric and intestinal conditions. AB - Most studies on the in vitro lipid digestion of protein-stabilized emulsions have been carried out under simulated gastric and intestinal conditions. In this study, the digestion behaviour of whey protein isolate (WPI)-stabilized emulsions was examined under simulated intestinal fluid (SIF) conditions (pH 7.5, 2.5mg bile salts/mL and 0.8 mg pancreatin/mL) after the emulsions had been digested in a model simulated gastric fluid (SGF) containing pepsin (pH 1.6 and 3.2mg pepsin/mL) for different times. The droplet size, zeta-potential, microstructure, surface protein and amount of free fatty acids released were examined. The results indicated that WPI emulsions did not undergo pronounced changes in droplet size and microstructure during SGF digestion followed by coalescence during the subsequent SIF digestion. When WPI emulsions were treated with SGF, alpha-lactalbumin and a portion of beta-lactoglobulin proteins adsorbed at the interface were hydrolysed by pepsin, resulting in small peptides being produced as characterized by sodium dodecyl sulphate polyacrylamide gel electrophoresis. In general, digestion in SGF containing pepsin accelerated coalescence of the emulsion droplets during subsequent digestion in SIF containing pancreatic lipase. However, the changes in the size, the microstructure and the proteolysis of the interfacial proteins of the emulsions under gastric conditions did not influence the rate and the extent of lipid digestion in the subsequent intestinal environment. PMID- 23792545 TI - Nanoengineering of doxorubicin delivery systems with functionalized maghemite nanoparticles. AB - Superparamagnetic iron oxide nanoparticles are developing as promising candidates for biomedical applications such as targeted drug delivery. In particular, they represent an alternative to existing antitumor drug carriers, because of their ultra-fine size, low toxicity and magnetic characteristics. Nevertheless, there is a need to functionalize them in order to achieve good biocompatibility, efficient modification for further attachment of biomolecules, and improved stability. In this work we describe the functionalization of superparamagnetic maghemite nanoparticles encapsulated in a silica shell. After their chemical modification with positive (3-aminopropyl)trimethoxysilane, a gold layer was deposited in order to facilitate incorporation of the antitumor drug, doxorubicin (DOX), up to a maximum loading of 80 MUmol/g. In vitro cell uptake of nanocomposites was performed with DLD-1 colon cancer cells and PLC-PRF-5 liver cancer cells. Confocal microscopy photos illustrate that doxorubicin-loaded nanoparticles accumulate in both the cytoplasm and the cell nuclei. Cell survival efficiency with maghemite nanocomposites was determined via the MTT assay, and the cytotoxicity study proved that they exhibited significant toxicity against both types of cancer cells, although the improvement over free DOX treatment is more evident in the case of DLD-1 cancer cells when the most dilute drug and particle solutions are compared. PMID- 23792546 TI - Peptide decorated nano-hydroxyapatite with enhanced bioactivity and osteogenic differentiation via polydopamine coating. AB - To be better used as implant materials in bone graft substitutes, bioactivity and osteogenesis of nano-hydroxyapatite (nano-HA) need to be further enhanced. Inspired by adhesive proteins in mussels, here we developed a novel bone forming peptide decorated nano-HA material. In this study, nano-HA was coated by one-step pH-induced polymerization of dopamine, and then the peptide was grafted onto polydopamine (pDA) coated nano-HA (HA-pDA) through catechol chemistry. Our results demonstrated that the peptide-conjugated nano-HA crystals could induce the adhesion and proliferation of MG-63 cells. Moreover, the highly alkaline phosphatase activity of the functionalized nano-HA indicated that the grafted peptide could maintain its biological activity after immobilization onto the surface of HA-pDA, especially at the concentration of 100MUg/mL. These modified nano-HA crystals with better bioactivity and osteogenic differentiation hold great potential to be applied as bioactive materials in bone repairing, bone regeneration and bio-implant coating applications. PMID- 23792547 TI - Optimization and charaterization of repaglinide biodegradable polymeric nanoparticle loaded transdermal patchs: in vitro and in vivo studies. AB - Biodegradable polymeric nanoparticles loaded Repaglinide were prepared by solvent extraction method. In this method chitosan, PLA and PCL were employed to prepare Repaglinide polymeric nanoparticles. Some of the formulation parameters were optimized to obtain high quality nanoparticles. The particles were spherical shape with sizes of 108.6 +/- 3.4 nm to 220.6 +/- 1.2 nm and the poly dispersity indexes were in the range of 0.06 to 0.44. The zeta potential was in the range between - 16.48 +/- 2.02 and 30.52 +/- 3.20 mV. The percentage entrapment efficiency (EE%) was 81.4 +/- 1.8% to 92.7 +/- 1.4%. The drug release behavior was studied by externally sink method and the release pattern of drug was found to follow zero order, Higuchi and Peppas equations. The optimized PLA-Repaglinide nanoparticles were loaded in Methocel transdermal patches. These transdermal patches were evaluated by physiochemical parameters, in vitro, ex vivo and in vivo studies. Based on in vivo hypoglycemic results, bioavailability parameters like AUC, AUMC, Cmax, Tmax, MRT, t1/2 and relative bioavailability were found to be 2218.88 MUIU/mL/h, 381630.3 MUIU/mL/h, 41.88 MUIU/mL, 36 h, 83.24h, and 52.79 h respectively. The transdermal patch containing Repaglinide nanoparticles showed 76 fold effective than conventional oral administrations. PMID- 23792548 TI - Co-prescription of gastroprotective agents and their efficacy in elderly patients taking nonsteroidal anti-inflammatory drugs: a systematic review of observational studies. AB - BACKGROUND & AIMS: Guidelines recommend prescribing gastroprotective agents (proton pump inhibitors, misoprostol) to older patients (primarily >=65 years old) taking nonsteroidal anti-inflammatory drugs (NSAIDs) to prevent gastrointestinal ulcers. Older individuals are underrepresented in clinical trials of these agents. We systematically reviewed evidence from observational studies on the use of gastroprotective agents in elderly patients and their ability to prevent NSAID-related ulcers in this population. METHODS: We performed a systematic search of Embase and MEDLINE and identified 23 observational studies that focused on elderly patients and reported data on co-prescription of gastroprotective agents and NSAIDs and/or the effectiveness of the agents in preventing gastrointestinal events in NSAID users. We collected data on rates of co-prescription and NSAID-related gastrointestinal events in patients with and without gastroprotection. RESULTS: A median of 24% (range, 10%-69%) of elderly patients taking NSAIDs received a co-prescription for gastroprotective agents; this percentage was only slightly higher in the oldest age groups. All studies of efficacy showed a positive effect of gastroprotection. However, the adjusted results were not suitable for synthesis, and the 5 studies reporting unadjusted results were too heterogeneous for meta-analysis (I(2) = 97%). The studies differed in outcomes, definitions of co-prescription, and differences in baseline risk factors between patients with and without gastroprotection. None of the studies assessed adverse effects of gastroprotective agents. The 2 cost effectiveness studies reached opposing conclusions. CONCLUSIONS: In a systematic review, the observational evidence for the efficacy of gastroprotective agents in preventing NSAID-associated gastrointestinal events was in agreement with results of randomized controlled trials. However, because of heterogeneity of included studies, it is not clear what the effect would be if more patients were treated, or at what age gastroprotection should be recommended. We offer suggestions to facilitate comparison with other work and address the questions of risk and benefit in relation to age. PMID- 23792550 TI - India's poliomyelitis eradication: a milestone in public health. AB - India has recently completed 2 years without single case of poliomyelitis on 13 January 2013. This has brought South East Asian Region closer to eradication. Recently, India is being regarded as a role model for polio eradication efforts in other low-income endemic countries-Pakistan, Nigeria and Afghanistan. However, the near elimination of wild polio virus in India has set forth newer challenges. Stricter surveillance measures are now needed to check for importations spread of virus in migratory populations and rapid containment of newly found virus. India's battle against polio will soon be cited as biggest public health achievement or most expensive public health failure. PMID- 23792549 TI - Quantification of mRNA stability of stress-responsive yeast genes following conditional excision of open reading frames. AB - Eukaryotic cells rapidly adjust the levels of mRNAs in response to environmental stress primarily by controlling transcription and mRNA turnover. How different stress conditions influence the fate of stress-responsive mRNAs, however, is relatively poorly understood. This is largely due to the fact that mRNA half-life assays are traditionally based on interventions (e.g., temperature-shifts using temperature-sensitive RNA polymerase II alleles or treatment with general transcription inhibitory drugs), which, rather than blocking, specifically induce transcription of stress-responsive genes. To study the half-lives of the latter suite of mRNAs, we developed and describe here a minimally perturbing alternative method, coined CEO, which is based on discontinuance of transcription following the conditional excision of open reading frames. Using CEO, we confirm that the target of rapamycin complex I (TORC1), a nutrient-activated, central stimulator of eukaryotic cell growth, favors the decay of mRNAs that depend on the stress- and/or nutrient-regulated transcription factors Msn2/4 and Gis1 for their transcription. We further demonstrate that TORC1 controls the stability of these mRNAs via the Rim15-Igo1/2-PP2A(Cdc55) effector branch, which reportedly also controls Gis1 promoter recruitment. These data pinpoint PP2A(Cdc55) as a central node in homo-directional coordination of transcription and post-transcriptional mRNA stabilization of a specific array of nutrient-regulated genes. PMID- 23792551 TI - Diagnostic medical radiation in inflammatory bowel disease: how to limit risk and maximize benefit. AB - Diagnosis and management of inflammatory bowel disease (IBD) requires repeat diagnostic imaging for monitoring of disease activity. Recent evidence has suggested that patients with IBD are at increased risk of radiation exposure from repeat imaging. The aim of this article was to highlight risks associated with increasing radiation exposure and identify alternatives to minimize exposure. The increasing use of computed tomography (CT) in both Crohn's disease and ulcerative colitis has brought additional benefits to guiding management through non invasive measures. However, the massive increase in use of CT scans poses a risk of exposing patients with IBD to high levels of diagnostic medical radiation. High levels of diagnostic medical radiation are associated with an increased risk of malignancy in several studies. Numerous studies have identified particular risk factors in IBD associated with high levels of diagnostic medical radiation which are also associated with a more severe disease course. Imaging techniques such as magnetic resonance enterography, ultrasound, small bowel follow through, and capsule endoscopy are alternatives to CT scans as they do not utilize radiation. Gastroenterologists managing patients with IBD, particularly Crohn's disease, should be aware of the increased risk of high cumulative doses of radiation exposure, particularly from CT scanning. Alternative forms of imaging should be carefully considered when evaluating patients, in particularly those with identifiable risk factors for an aggressive disease course. PMID- 23792552 TI - A systematic review of economic studies on biological agents used to treat Crohn's disease. AB - BACKGROUND: Identifying clinical scenarios that maximize the cost-effectiveness of biological treatments can lead to optimized health care cost-saving and clinical effectiveness from a society's perspective. METHODS: Published articles between January 1995 and June 2012 were searched in PubMed, EMBASE, ABI/INFORM, Tuft's Cost-Effectiveness Analysis Registry Database, Cochrane National Health Service Economic Evaluation Database, International Pharmaceutical Abstracts, Web of Science, and Google Scholar. Studies of interest included the following: (1) cost studies, (2) economic evaluations, or (3) narrative or systematic reviews related to economic evaluations of biological treatments for moderate-to-severe Crohn's disease (CD). The primary outcomes of interest included costs associated with biological treatments and cost-effectiveness measures, including incremental cost-effectiveness ratios. A threshold of $100,000/quality-adjusted life year (L60,000/quality-adjusted life year) gained was used for treatment cost effectiveness. RESULTS: Thirty-eight studies were identified, including 15 economic evaluations and 23 cost studies or reviews of economic evaluations. Economic evaluations found that infliximab and adalimumab were more cost effective than standard therapy for luminal CD when provided as an induction therapy followed by episodic therapy over 5 or more years. The cost-effectiveness of infliximab and adalimumab versus standard therapy for luminal CD was less certain when used as 1-year maintenance treatment with or without previous induction therapy. Cost studies revealed that infliximab therapy reduced health care resource utilization and cost. Older reviews were inconclusive about the cost-effectiveness of biological treatments used for CD. CONCLUSIONS: Current evidence suggests that biological treatments may be cost-effective for CD under certain clinical scenarios. Future studies evaluating all biological treatments are needed to compare their respective benefits and costs. PMID- 23792553 TI - Concerns for low coverage of influenza vaccination in middle-aged adults. AB - A survey in Hong Kong on middle-aged adults revealed a low influenza vaccination uptake rate of 13%. As a heterogeneous population comprising individuals at different levels of risk for complications, effective development of strategy for improving vaccination coverage in middle-aged adults should be prioritized. PMID- 23792554 TI - Interaction of preosteoblasts with surface-immobilized collagen-based nanotubes. AB - In a previous work, we demonstrated the successful use of electrophoretic deposition (EPD) to immobilize collagen-based nanotubes onto indium-tin-oxide coated glass (ITO glass), leading to the creation of biointerfaces with protein based chemistry and topography [1]. In this work, we present a first study of preosteoblasts behavior in contact with surface-immobilized collagen-based nanotubes. Changes in cell morphology after their interaction with ITO glass modified with collagen-based nanotubes were studied using fluorescence microscopy and compared to those observed on virgin ITO glass as well as on ITO glass on which a collagen layer was simply adsorbed. Scanning electron microscopy (SEM) was used to study interactions of cell filopodias with the deposited nanotubes. Cytotoxicity of these biointerfaces was examined as well in short term cultures, using Alamar blue assay. Cells showed particular morphologies on ITO glass coated with nanotubes compared to virgin ITO glass or collagen adsorbed layer on ITO glass. High resolution SEM images suggest that apart from cell morphology, length and thickness of filopodias seem to be significantly affected by surface modification with collagen-based nanotubes. Moreover, nanotube-coated ITO glass did not show any obvious cytotoxicity in short term culture, opening new perspectives for the surface modification of biomaterials. We show the versatility of the proposed surface modification procedure by tailoring biointerfaces with a mixture of micro- and nanometer-scale collagen-based tubes. PMID- 23792555 TI - Microencapsulation of Traditional Chinese Herbs-PentaHerbs extracts and potential application in healthcare textiles. AB - In this work, Traditional Chinese Herbs (TCH)-PentaHerbs--was successfully microencapsulated in chitosan-sodium alginate (CSA) blend matrix using emulsion chemical cross-linking method and the final product was characterised with regard to structure, surface morphology, particle size, in vitro drug release and skin toxicity by means of Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), laser diffraction particle size analysis, high performance liquid chromatography (HPLC) and methyl thiazolyl tetrazolium (MTT) and lactate dehydrogenase (LDH) release assays respectively. Results showed that the microcapsules were in spherical form with diameter mostly in the range of 3 18 MUm and that the release performance of the microcapsules was influenced by pH value of phosphate buffer solution (PBS). The microcapsules had no toxic effects on cells and were successfully grafted onto the surface of cotton fabrics. These results indicated that PentaHerbs loaded CSA microcapsule may possess potential application in clinical treatment of atopic dermatitis (AD). PMID- 23792556 TI - Synthesis, characterization and applications of carboxylated and polyethylene glycolated bifunctionalized InP/ZnS quantum dots in cellular internalization mediated by cell-penetrating peptides. AB - Semiconductor nanoparticles, also known as quantum dots (QDs), are widely used in biomedical imaging studies and pharmaceutical research. Cell-penetrating peptides (CPPs) are a group of small peptides that are able to traverse cell membrane and deliver a variety of cargoes into living cells. CPPs deliver QDs into cells with minimal nonspecific absorption and toxic effect. In this study, water-soluble, monodisperse, carboxyl-functionalized indium phosphide (InP)/zinc sulfide (ZnS) QDs coated with polyethylene glycol lipids (designated QInP) were synthesized for the first time. The physicochemical properties (optical absorption, fluorescence and charging state) and cellular internalization of QInP and CPP/QInP complexes were characterized. CPPs noncovalently interact with QInP in vitro to form stable CPP/QInP complexes, which can then efficiently deliver QInP into human A549 cells. The introduction of 500nM of CPP/QInP complexes and QInP at concentrations of less than 1MUM did not reduce cell viability. These results indicate that carboxylated and polyethylene-glycolylated (PEGylated) bifunctionalized QInP are biocompatible nanoparticles with potential for use in biomedical imaging studies and drug delivery applications. PMID- 23792558 TI - Distribution of HBV genotypes in Latin America. AB - Approximately 2 billion people worldwide are infected with HBV, and 350 million people are chronic carriers. HBV is classified into nine genotypes (A to I). Genotype F is the most prevalent in the Spanish-speaking countries and in the Amerindian population in South America. HBV genotype F was primarily found in indigenous populations from South America and is divided into four subgenotypes (F1 to F4). Subgenotype F1 is further divided into F1a (found in Costa Rica and El Salvador) and F1b (found in in Alaska, Argentina and Chile). Subgenotypes F2 and F3 cocirculate in the north of South America: F2a is found in Brazil and Venezuela, F2b is described only in Venezuela, F3 is frequent in Colombia, Venezuela and Panama, and F4 is reported from the central and south areas of South America, including Bolivia, Argentina and southern Brazil. HBV genotypes and subgenotypes have distinct geographical distributions. It is currently under discussion whether they are associated with different prognoses, considering the patterns of severity of liver diseases in various populations. Furthermore, global human migrations affect the pattern of genotype distribution, introducing genotypes differing from those found in the original inhabitants. PMID- 23792557 TI - Chronic arsenic exposure and blood glutathione and glutathione disulfide concentrations in Bangladeshi adults. AB - BACKGROUND: In vitro and rodent studies have shown that arsenic (As) exposure can deplete glutathione (GSH) and induce oxidative stress. GSH is the primary intracellular antioxidant; it donates an electron to reactive oxygen species, thus producing glutathione disulfide (GSSG). Cysteine (Cys) and cystine (CySS) are the predominant thiol/disulfide redox couple found in human plasma. Arsenic, GSH, and Cys are linked in several ways: a) GSH is synthesized via the transsulfuration pathway, and Cys is the rate-limiting substrate; b) intermediates of the methionine cycle regulate both the transsulfuration pathway and As methylation; c) GSH serves as the electron donor for reduction of arsenate to arsenite; and d) As has a high affinity for sulfhydryl groups and therefore binds to GSH and Cys. OBJECTIVES: We tested the hypothesis that As exposure is associated with decreases in GSH and Cys and increases in GSSG and CySS (i.e., a more oxidized environment). METHODS: For this cross-sectional study, the Folate and Oxidative Stress Study, we recruited a total of 378 participants from each of five water As concentration categories: < 10 (n = 76), 10-100 (n = 104), 101-200 (n = 86), 201-300 (n = 67), and > 300 ug/L (n = 45). Concentrations of GSH, GSSG, Cys, and CySS were measured using HPLC. RESULTS: An interquartile range (IQR) increase in water As was negatively associated with blood GSH (mean change, -25.4 umol/L; 95% CI: -45.3, -5.31) and plasma CySS (mean change, -3.00 umol/L; 95% CI: -4.61, -1.40). We observed similar associations with urine and blood As. There were no significant associations between As exposure and blood GSSG or plasma Cys. CONCLUSIONS: The observed associations are consistent with the hypothesis that As may influence concentrations of GSH and other nonprotein sulfhydryls through binding and irreversible loss in bile and/or possibly in urine. PMID- 23792559 TI - Behaviour-dependent recruitment of long-range projection neurons in somatosensory cortex. AB - In the mammalian neocortex, segregated processing streams are thought to be important for forming sensory representations of the environment, but how local information in primary sensory cortex is transmitted to other distant cortical areas during behaviour is unclear. Here we show task-dependent activation of distinct, largely non-overlapping long-range projection neurons in the whisker region of primary somatosensory cortex (S1) in awake, behaving mice. Using two photon calcium imaging, we monitored neuronal activity in anatomically identified S1 neurons projecting to secondary somatosensory (S2) or primary motor (M1) cortex in mice using their whiskers to perform a texture-discrimination task or a task that required them to detect the presence of an object at a certain location. Whisking-related cells were found among S2-projecting (S2P) but not M1 projecting (M1P) neurons. A higher fraction of S2P than M1P neurons showed touch related responses during texture discrimination, whereas a higher fraction of M1P than S2P neurons showed touch-related responses during the detection task. In both tasks, S2P and M1P neurons could discriminate similarly between trials producing different behavioural decisions. However, in trials producing the same decision, S2P neurons performed better at discriminating texture, whereas M1P neurons were better at discriminating location. Sensory stimulus features alone were not sufficient to elicit these differences, suggesting that selective transmission of S1 information to S2 and M1 is driven by behaviour. PMID- 23792560 TI - Transport dynamics in a glutamate transporter homologue. AB - Glutamate transporters are integral membrane proteins that catalyse neurotransmitter uptake from the synaptic cleft into the cytoplasm of glial cells and neurons. Their mechanism of action involves transitions between extracellular (outward)-facing and intracellular (inward)-facing conformations, whereby substrate binding sites become accessible to either side of the membrane. This process has been proposed to entail transmembrane movements of three discrete transport domains within a trimeric scaffold. Using single-molecule fluorescence resonance energy transfer (smFRET) imaging, we have directly observed large-scale transport domain movements in a bacterial homologue of glutamate transporters. We find that individual transport domains alternate between periods of quiescence and periods of rapid transitions, reminiscent of bursting patterns first recorded in single ion channels using patch-clamp methods. We propose that the switch to the dynamic mode in glutamate transporters is due to separation of the transport domain from the trimeric scaffold, which precedes domain movements across the bilayer. This spontaneous dislodging of the substrate-loaded transport domain is approximately 100-fold slower than subsequent transmembrane movements and may be rate determining in the transport cycle. PMID- 23792561 TI - An siRNA screen for NFAT activation identifies septins as coordinators of store operated Ca2+ entry. AB - The STIM1-ORAI1 pathway of store-operated Ca(2+) entry is an essential component of cellular Ca(2+) signalling. STIM1 senses depletion of intracellular Ca(2+) stores in response to physiological stimuli, and relocalizes within the endoplasmic reticulum to plasma-membrane-apposed junctions, where it recruits and gates open plasma membrane ORAI1 Ca(2+) channels. Here we use a genome-wide RNA interference screen in HeLa cells to identify filamentous septin proteins as crucial regulators of store-operated Ca(2+) entry. Septin filaments and phosphatidylinositol-4,5-bisphosphate (also known as PtdIns(4,5)P2) rearrange locally at endoplasmic reticulum-plasma membrane junctions before and during formation of STIM1-ORAI1 clusters, facilitating STIM1 targeting to these junctions and promoting the stable recruitment of ORAI1. Septin rearrangement at junctions is required for PtdIns(4,5)P2 reorganization and efficient STIM1-ORAI1 communication. Septins are known to demarcate specialized membrane regions such as dendritic spines, the yeast bud and the primary cilium, and to serve as membrane diffusion barriers and/or signalling hubs in cellular processes such as vesicle trafficking, cell polarity and cytokinesis. Our data show that septins also organize the highly localized plasma membrane domains that are important in STIM1-ORAI1 signalling, and indicate that septins may organize membrane microdomains relevant to other signalling processes. PMID- 23792562 TI - Reversal of an ancient sex chromosome to an autosome in Drosophila. AB - Although transitions of sex-determination mechanisms are frequent in species with homomorphic sex chromosomes, heteromorphic sex chromosomes are thought to represent a terminal evolutionary stage owing to chromosome-specific adaptations such as dosage compensation or an accumulation of sex-specific mutations. Here we show that an autosome of Drosophila, the dot chromosome, was ancestrally a differentiated X chromosome. We analyse the whole genome of true fruitflies (Tephritidae), flesh flies (Sarcophagidae) and soldier flies (Stratiomyidae) to show that genes located on the dot chromosome of Drosophila are X-linked in outgroup species, whereas Drosophila X-linked genes are autosomal. We date this chromosomal transition to early drosophilid evolution by sequencing the genome of other Drosophilidae. Our results reveal several puzzling aspects of Drosophila dot chromosome biology to be possible remnants of its former life as a sex chromosome, such as its minor feminizing role in sex determination or its targeting by a chromosome-specific regulatory mechanism. We also show that patterns of biased gene expression of the dot chromosome during early embryogenesis, oogenesis and spermatogenesis resemble that of the current X chromosome. Thus, although sex chromosomes are not necessarily evolutionary end points and can revert back to an autosomal inheritance, the highly specialized genome architecture of this former X chromosome suggests that severe fitness costs must be overcome for such a turnover to occur. PMID- 23792565 TI - N-Terminal alpha-amino group modification of peptides by an oxime formation exchange reaction sequence. AB - A site-specific and efficient method for N-terminal modification of peptides using oxone for selective oxidation of N-terminal alpha-amino groups of peptides to oximes followed by transoximation with O-substituted hydroxylamines has been developed. PMID- 23792564 TI - Promoter directionality is controlled by U1 snRNP and polyadenylation signals. AB - Transcription of the mammalian genome is pervasive, but productive transcription outside of protein-coding genes is limited by unknown mechanisms. In particular, although RNA polymerase II (RNAPII) initiates divergently from most active gene promoters, productive elongation occurs primarily in the sense-coding direction. Here we show in mouse embryonic stem cells that asymmetric sequence determinants flanking gene transcription start sites control promoter directionality by regulating promoter-proximal cleavage and polyadenylation. We find that upstream antisense RNAs are cleaved and polyadenylated at poly(A) sites (PASs) shortly after initiation. De novo motif analysis shows PAS signals and U1 small nuclear ribonucleoprotein (snRNP) recognition sites to be the most depleted and enriched sequences, respectively, in the sense direction relative to the upstream antisense direction. These U1 snRNP sites and PAS sites are progressively gained and lost, respectively, at the 5' end of coding genes during vertebrate evolution. Functional disruption of U1 snRNP activity results in a dramatic increase in promoter-proximal cleavage events in the sense direction with slight increases in the antisense direction. These data suggest that a U1-PAS axis characterized by low U1 snRNP recognition and a high density of PASs in the upstream antisense region reinforces promoter directionality by promoting early termination in upstream antisense regions, whereas proximal sense PAS signals are suppressed by U1 snRNP. We propose that the U1-PAS axis limits pervasive transcription throughout the genome. PMID- 23792566 TI - Monitor tumor burden with circulating tumor DNA. AB - There is a need to identify better biomarkers to monitor diseases and/or assess therapeutic responses. For those with cancer, one can identify DNA fragments that contain somatic mutations originating in the tumor DNA in plasma or serum. There have been several early studies suggesting that advances in sequencing technologies will allow identification of somatic genomic alterations that can be used to monitor tumor dynamics. Dawson et.al. investigated circulating cell-free DNA carrying tumor specific alterations in patients with breast cancer. The authors compared CT imaging from 30 women with metastatic breast cancer receiving treatment, using two assays for circulating tumor DNA, CA 15-3, and CTCs. Taken the two methods together circulating tumor DNA was detected in 29 or 30 women (97%) and 115 of 141 plasma samples (82%). Circulating tumor DNA levels showed a greater dynamic range and greater correlation with changes in tumor burden than did CA 15-3 or CTC. The relatively small study showed that circulating tumor DNA has a superior sensitivity to other circulating biomarkers and a dynamic range that correlates with tumor burden. PMID- 23792567 TI - FOLFIRI plus dulanermin (rhApo2L/TRAIL) in a patient with BRAF-mutant metastatic colon cancer. AB - Colorectal cancer patients with BRAF-mutant tumors have a more aggressive, rapidly progressing disease that is in critical need of novel therapeutic approaches. Indeed, whereas the median overall survival (OS) of colorectal cancer (CRC) patients receiving standard-of-care therapy is approximately two years or more if their tumors express wild-type BRAF and wild-type KRAS, median OS is less than twelve months with tumors expressing V600E-mutant BRAF and wild-type KRAS. Pro-apoptotic receptor agonists are a class of biologic agents under development to induce tumor-specific apoptosis and are being combined with classical chemotherapy or targeted agents in clinical trials. Herein, we present the case of a patient with bulky V600E-mutant BRAF hepatic flexure colon carcinoma, treated initially with FOLFOX plus bevacizumab neoadjuvant therapy and surgery. The patient had a rapid tumor relapse with metastatic disease to the liver and lung, and was enrolled in a phase 1b open-label clinical study, where he received the FOLFIRI regimen in combination with the pro-apoptotic receptor agonist dulanermin (rhApo2L/TRAIL). The patient maintained stable disease through 25 doses administered every two weeks before his disease progressed. After coming off study, the patient underwent surgical debulking and received intraperitoneal hyperthermic chemotherapy. He subsequently relapsed and was treated with FOLFIRI plus cetuximab. At the time of this report, the patient remains on active treatment. It is unclear what effect dulanermin may have had on the course of his disease, but it is noteworthy that the patient remained on FOLFIRI plus dulanermin therapy for a period that exceeded the median OS for patients with advanced, aggressive BRAF-mutant CRC. It is also noteworthy that at the time of this report the patient's overall survival since diagnosis has exceeded 30 months, which is beyond what is generally observed even for patients with CRC harboring wild-type BRAF and wild-type KRAS. PMID- 23792568 TI - Off-label use of cetuximab plus sorafenib and panitumumab plus regorafenib to personalize therapy for a patient with V600E BRAF-mutant metastatic colon cancer. AB - Sorafenib, the first agent developed to target BRAF mutant melanoma, is a multi kinase inhibitor that was approved by the FDA for therapy of kidney and subsequently liver cancer, and is currently in clinical trials for thyroid, lung and brain cancer. Colorectal cancer with V600E BRAF mutation has shown relative resistance to standard chemotherapy regimens, as well as lack of efficacy to vemurafenib in clinical trials. New treatments are needed for BRAF-mutant colorectal cancer. We report a case of a patient with BRAF-mutant metastatic colon cancer whose disease had progressed on FOLFOX plus bevacizumab and subsequent FOLFIRI plus cetuximab. Based on preclinical data published in Nature in 2012 suggesting that successful therapeutic targeting of BRAF in colorectal cancer may require concomitant targeting of the EGFR, we offered this patient without other attractive options the combination of sorafenib plus cetuximab, in off-label use with informed consent. Sorafenib and cetuximab therapy led to a mixed radiographic response with some areas showing dramatic improvement and other areas showing stable disease over a 7-month period which is a notably long period of progression-free survival for V600E BRAF mutated colon cancer. The cetuximab plus sorafenib therapy was very well-tolerated by the patient who remained on it long enough until another therapy option, regorafenib, was approved in September 2012. The patient was offered single agent regorafenib at the time of progression. At the time of progression on single agent regorafenib, panitumumab was combined with regorafenib and this was also well-tolerated and appeared to slow disease progression. Further study of these approaches in the clinic as personalized treatment of BRAF-mutant advanced colorectal cancer is warranted. PMID- 23792569 TI - Focal adhesion kinase autophosphorylation inhibition decreases colon cancer cell growth and enhances the efficacy of chemotherapy. AB - Focal adhesion kinase (FAK) increasingly has been implicated in cancer growth and progression. 1,2,4,5-Benzenetetraamine tetrahydrochloride (Y15) is a small molecule FAK inhibitor that blocks the Y397 autophosphorylation site. FAK inhibitor, Y15 decreased Y397 FAK in different colon cancer cells lines in a dose dependent manner. In addition, Y15 decreased phosphorylated Src in SW480 and SW620 cells. Y15 decreased cell viability, increased detachment, and increased apoptosis in SW480 and SW620 cells in vitro. Combination of FAK inhibitor Y15 and Src inhibitor PP2 decreased colon cancer cell viability more effectively than each agent alone. In addition, when combined with 5-FU, oxaliplatin or 5-FU and oxaliplatin, colon cancer viability was decreased further, demonstrating that dual and triple therapy synergistically inhibits cell viability. In vivo, Y15 decreased subcutaneous SW620 tumor growth by 28%. Combination of oral Y15 with 5 FU/or oxaliplatin decreased tumor growth by 48% more effectively than each inhibitor alone. Finally, tumors treated with Y15 expressed less Y397 phosphorylation, Src phosphorylation and had greater apoptosis than controls. Thus, the small molecule FAK inhibitor, Y15, inhibits cell growth in vitro and in vivo and enhances the efficacy of chemotherapy, demonstrating that it can be an effective therapeutic inhibitor for treating colon cancer. PMID- 23792563 TI - Comprehensive molecular characterization of clear cell renal cell carcinoma. AB - Genetic changes underlying clear cell renal cell carcinoma (ccRCC) include alterations in genes controlling cellular oxygen sensing (for example, VHL) and the maintenance of chromatin states (for example, PBRM1). We surveyed more than 400 tumours using different genomic platforms and identified 19 significantly mutated genes. The PI(3)K/AKT pathway was recurrently mutated, suggesting this pathway as a potential therapeutic target. Widespread DNA hypomethylation was associated with mutation of the H3K36 methyltransferase SETD2, and integrative analysis suggested that mutations involving the SWI/SNF chromatin remodelling complex (PBRM1, ARID1A, SMARCA4) could have far-reaching effects on other pathways. Aggressive cancers demonstrated evidence of a metabolic shift, involving downregulation of genes involved in the TCA cycle, decreased AMPK and PTEN protein levels, upregulation of the pentose phosphate pathway and the glutamine transporter genes, increased acetyl-CoA carboxylase protein, and altered promoter methylation of miR-21 (also known as MIR21) and GRB10. Remodelling cellular metabolism thus constitutes a recurrent pattern in ccRCC that correlates with tumour stage and severity and offers new views on the opportunities for disease treatment. PMID- 23792570 TI - Antitumor and modeling studies of a penetratin-peptide that targets E2F-1 in small cell lung cancer. AB - E2F-1, a key transcription factor necessary for cell growth, DNA repair, and differentiation, is an attractive target for development of anticancer drugs in tumors that are E2F "oncogene addicted". We identified a peptide isolated from phage clones that bound tightly to the E2F-1 promoter consensus sequence. The peptide was coupled to penetratin to enhance cellular uptake. Modeling of the penetratin-peptide (PEP) binding to the DNA E2F-1 promoter demonstrated favorable interactions that also involved the participation of most of the penetratin sequence. The penetratin-peptide (PEP) demonstrated potent in vitro cytotoxic effects against a range of cancer cell lines, particularly against Burkitt lymphoma cells and small cell lung cancer (SCLC) cells. Further studies in the H 69 SCLC cell line showed that the PEP inhibited transcription of E2F-1 and also several important E2F-regulated enzymes involved in DNA synthesis, namely, thymidylate synthase, thymidine kinase, and ribonucleotide reductase. As the PEP was found to be relatively unstable in serum, it was encapsulated in PEGylated liposomes for in vivo studies. Treatment of mice bearing the human small cell lung carcinoma H-69 with the PEP encapsulated in PEGylated liposomes (PL-PEP) caused tumor regression without significant toxicity. The liposome encapsulated PEP has promise as an antitumor agent, alone or in combination with inhibitors of DNA synthesis. PMID- 23792571 TI - Amyloid precursor-like protein 2 suppresses irradiation-induced apoptosis in Ewing sarcoma cells and is elevated in immune-evasive Ewing sarcoma cells. AB - Despite surgery, chemotherapy, and radiotherapy treatments, the children, adolescents, and young adults who are diagnosed with metastasized Ewing sarcoma face a dismal prognosis. Amyloid precursor-like protein 2 (APLP2) has recently been implicated in the survival of cancer cells and in our current study, APLP2's contribution to the survival of Ewing sarcoma cells was examined. APLP2 was readily detected in all Ewing sarcoma cell lines analyzed by western blotting, with the TC71 Ewing sarcoma cells expressing the lowest level of APLP2 among the lines. While irradiation induces apoptosis in TC71 Ewing sarcoma cells (as we determined by quantifying the proportion of cells in the sub-G 1 population), transfection of additional APLP2 into TC71 decreased irradiation-induced apoptosis. Consistent with these findings, in parallel studies, we noted that isolates of the TC71 cell line that survived co-culture with lymphokine-activated killer (LAK) cells (which kill by inducing apoptosis in target cells) displayed increased expression of APLP2, in addition to smaller sub-G 1 cell populations after irradiation. Together, these findings suggest that APLP2 lowers the sensitivity of Ewing sarcoma cells to radiotherapy-induced apoptosis and that APLP2 expression is increased in Ewing sarcoma cells able to survive exposure to cytotoxic immune cells. PMID- 23792572 TI - Contradictory KRAS mutation test results in a patient with metastatic colon cancer: a clinical dilemma in the era of personalized medicine. AB - The KRAS oncogene is mutated in 40-50% of colorectal cancers and confers resistance to EGFR-targeted therapy. In the clinic, agents such as cetuximab or panitumumab target the EGFR receptor for therapeutic benefit. Cetuximab was approved by the FDA in 2012 as first-line therapy for KRAS mutation-negative (wild-type), EGFR-expressing metastatic colorectal cancer, in combination with FOLFIRI (5-fluorouracil, irinotecan, leucovorin). Herein we report a case of metastatic colon cancer with conflicting testing results for the KRAS oncogene from two different reference laboratories. The discordant reports complicated the decision-making process regarding the administration of targeted anti-EGFR personalized therapy. As the second test result was wild-type from the same original pathological specimen, the patient was treated with cetuximab-containing combination chemotherapy and appeared to have a response after prior disease progression. It is unclear whether the observed response was fully due to regression of wild-type KRAS-containing tumor or any component of antibody dependent cellular cytotoxicity to a heterogeneous tumor in this patient. PMID- 23792573 TI - Detection of DSS-induced gastrointestinal mucositis in mice by non-invasive optical near-infrared (NIR) imaging of cathepsin activity. AB - Approximately 1.4 million people of the US population suffer from Inflammatory Bowel Disease (IBD) of which the most common conditions are ulcerative colitis (UC) and Crohn disease (CD). Colonoscopy and small bowel follow through are considered the current gold standard in diagnosing IBD. However, improved imaging and increased diagnostic sensitivity could be beneficial. Optical molecular imaging has the potential to become a powerful and practical tool for early detection, image-guided biopsy, and surgery in diagnosing and treating patients with IBD. Here we used a well characterized chemical model to initiate experimental IBD in mice by feeding with dextran sulfate sodium (DSS) containing drinking water in an attempt to investigate the utility of non-invasive infrared (NIR) optical imaging in the detection gastrointestinal (GI) injury. We employed a "smart probe" (ProSense680) cleaved and fluorescently activated in the NIR spectrum by various forms of secreted cathepsins. This probe has previously been shown to serve as a biomarker for the homing of inflammatory cells to injury. Our investigation suggests that NIR optical imaging can detect cathepsin-dependent probe cleavage non-invasively in animals with DSS-induced IBD. Increased tissue probe-retention and fluorescence was associated with increased infiltration of inflammatory cells, epithelial atrophy and sterilization of the mucosa. Furthermore, using NIR-imaging ex vivo we were able to document regional "hot spots" of inflammatory damage to the large intestine suggesting this method potentially could be coupled with colonoscopy investigation to aid in the sampling and the diagnostics of IBD. PMID- 23792574 TI - "Selective cell death mediated by small conditional RNAs" is not selective. AB - Small conditional RNAs were used to kill cells selectively in a prior report. The method utilized the cellular innate immune response to dsRNA, causing PKR activation and cell death. We designed small conditional RNAs specific to a highly restricted transcript, that of the mesothelin gene expressed in various cancer lines and specific to a tpc/hpr fusion transcript expressed in a published "control" line. Hairpins of small conditional RNAs were functionally active in cell-free conditions. Hairpins were transfected into 6 types of cells. We observed non-specific killing of cells after transfection of the hairpins targeting the reported fusion transcript or of the mesothelin transcript. Thus when attempting to use this system for a special purpose, to target cancer mutations, the results were not satisfactory. Specifically when repeating the work described in the publication, we could not replicate the results using the methods described. Recently the publication was retracted but without comment on the validity of the reported method. Here we provide scientific basis to consider the method impaired or invalid. PMID- 23792575 TI - The renin angiotensin system regulates Kupffer cells in colorectal liver metastases. AB - Blockade of the renin angiotensin system (RAS) can inhibit tumor growth and this may be mediated via undefined immunomodulatory actions. This study investigated the effects of RAS blockade on liver macrophages (Kupffer cells; KCs) in an orthotopic murine model of colorectal cancer (CRC) liver metastases. Here we showed that pharmacological targeting of the RAS [ANG II (31.25 ug/kg/h i.p.), ANG-(1-7) (24 ug/kg/h i.p.) or the ACE inhibitor; captopril (750 mg/kg/d i.p.)] altered endogenous KC numbers in the tumor-bearing liver throughout metastatic growth. Captopril, and to a lesser extent ANG-(1-7), increased KC numbers in the liver but not tumor. KCs were found to express the key RAS components: ACE and AT1R. Treatment with captopril and ANG II increased the number of AT1R-expressing KCs, although total KC numbers were not affected by ANG II. Captopril (0.1 uM) also increased macrophage invasion in vitro. Additionally, captopril was administered with KC depletion before tumor induction (day 0) or at established metastatic growth (day 18) using gadolinium chloride (GdCl 3; 20 mg/kg). Livers were collected at day 21 and quantitative stereology used as a measure of tumor burden. Captopril reduced growth of CRC liver metastases. However, when captopril was combined with early KC depletion (day 0) tumor growth was significantly increased compared with captopril alone. In contrast, late KC depletion (day 18) failed to influence the anti-tumor effects of captopril. The result of these studies suggests that manipulation of the RAS can alter KC numbers and may subsequently influence progression of CRC liver metastases. PMID- 23792576 TI - Homologous recombination-based adenovirus vector system for tumor cell-specific gene delivery. AB - Cancer gene therapy requires tumor-specific delivery and expression of a transgene to maximize antitumor efficacy and minimize side effects. In this study, we developed a new tumor-targeting, homologous recombination-based adenovirus vector system, HRAVS. HRAVS is composed of two adenovirus vectors, Ad.CMV.IR containing reverse sequence (IR) and a CMV promoter and Ad.IR.EGFP comprising the report gene EGFP and IR. For improved viral DNA replication and transgene expression, the E1a gene was added to HRAVS to generate the enhanced HRAVS, EHRAVS, which consists of Ad.CMV.IR and Ad.IR.EGFP/E1a. The optimal vector composition ratio of Ad.CMV.IR to Ad.IR.EGFP or Ad.IR.EGFP/E1a was identified as 30:70 based on EGFP expression efficiency in tumor cells. The transgene expression of HRAVS and EHRAVS was efficiently and specifically activated in tumor cells only and not in normal cells. Moreover, compared with HRAVS, EHRAVS infection led to higher virus yields and transgene expression and higher toxicity to tumor cells, and these results could be related to the involvement of E1a genes. The results in present study suggest the need for in vivo antitumor study using these new dual-Ad vector systems based on the homologous recombination. PMID- 23792578 TI - Excessive activation of tissue plasminogen activator makes a mouse nervous. PMID- 23792579 TI - Why climate change will not dramatically decrease viticultural suitability in main wine-producing areas by 2050. PMID- 23792580 TI - Toba supereruption: age and impact on East African ecosystems. PMID- 23792581 TI - Comment on 'Temperature dependent optical properties of PbS nanocrystals'. AB - We address erroneous statements made by Nordin et al (2012 Nanotechnology 23 275701) claiming the inadequacy of an expression we, Ullrich et al (2011 Appl. Phys. Lett. 99 081901), used to fit the temperature dependence of the photoluminescence and the absorption of PbS quantum dots. We further correct a quote by Nordin et al, who, when referring to our work, mistakenly claimed temperature invariance of the Stokes shift. PMID- 23792582 TI - Obesity, physical fitness, and inflammatory markers in Polish children. AB - BACKGROUND: The relationship between obesity, physical fitness, and inflammation was analyzed in a Polish population aged 12 to 18 years. MATERIAL/METHODS: Body mass index measurements and Eurofit physical fitness tests were undertaken to assess the adiposity and physical fitness status, respectively, of subjects. Serum samples were collected to measure standard inflammatory markers, including interleukin 6; and the acute-phase proteins alpha1-acid glycoprotein and alpha1 antichymotrypsin. In addition, the glycosylation profiles of alpha1-acid glycoprotein and alpha1-antichymotrypsin were analyzed to further evaluate immune statuses. RESULTS: The physical fitness of individuals was negatively influenced by obesity. Obese subjects were characterized by an abnormal immune balance, including increased levels of alpha1-acid glycoprotein, as well as alpha1 antichymotrypsin, and altered glycosylation profiles indicative of an underlying inflammatory condition. Older age, male sex, and a large body mass index appeared to correlate with poor physical fitness scores and a disturbed immune status. CONCLUSIONS: Impaired physical fitness is indicative for non-compensated overweight and affects mainly males aged 15 to 18 years. Female subjects seemed to cope better with increased body mass. PMID- 23792583 TI - Socio-ecological predictors of the uptake of cycling for recreation and transport in adults: results from the RESIDE study. AB - OBJECTIVE: To examine the uptake of cycling for recreation and transport, and relate these behaviors to individual, social, and environmental exposures over time. METHOD: Data were drawn from 909 adults in Time 2 (T2) (2005-2006) and Time 3 (T3) (2007-2008) of the RESIDE study (Australia). Demographics, perceptions of self-efficacy and social support related to cycling, neighborhood environment perceptions, and objective measures of the neighborhood were measured at T2. These were compared with uptake of cycling for recreation and transport at T3. RESULTS: At T3, 54 (5.9%) had taken up cycling for recreation and 44 (4.8%) for transport. Positive perceptions of self-efficacy at T2 were consistently positively associated with the uptake of cycling for either purpose at T3. Respondents living in higher walkable neighborhoods (OR=1.63; 95% CI=1.02-2.62) or with higher objectively measured street connectivity (OR=1.80; 95% CI=1.05 3.07) were more likely to start cycling for recreation when compared with their reference groups. No significant relationships existed between objective measures of the neighborhood and uptake of cycling for transport. CONCLUSION: Interventions focusing on enhancing self-efficacy and generating social support will likely positively influence both cycling for recreation and transport; and providing infrastructure that creates physically supportive neighborhoods may increase cycling levels. PMID- 23792584 TI - Anti-inflammatory activity of Markhamia tomentosa (Benth.) K. Schum. Ex Engl. ethanolic leaf extract. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The leaves of Markhamia tomentosa (Benth.) K. Schum (Bignoniaceae) are used traditionally for the treatment of oedema and rheumatoid arthritis in Nigeria. AIM OF THE STUDY: The aim of the work was to investigate the anti-inflammatory activity of the ethanolic leaf extract of Markhamia tomentosa. MATERIALS AND METHODS: The extract was screened using the carrageenan-induced paw oedema in rats, xylene-induced oedema in mice and the formalin-induced oedema in mice at 50, 100, 200mg/kg doses p.o respectively. The mechanism by which the extract mediated the anti-inflammatory activity was assessed using the histamine-induced rat paw oedema and serotonin-induced rat paw oedema at the highest dose (200mg/kg). RESULTS: The results showed that the extract produced a significant dose-dependent inhibition in carrageenan-induced, xylene-induced and the formalin tests. The extract exerted a significant inhibition of 54.55% (P<0.0001) and 42.11% (P<0.01) at 90 min in the histamine induced and serotonin-induced rat paw oedema models respectively. CONCLUSIONS: These findings suggest that the ethanolic leaf extract of Markhamia tomentosa possesses anti-inflammatory activity possibly mediated by histamine. The results justify the use of the plant in the preparation of ethno medicines used in the treatment of ailments associated with inflammation. PMID- 23792585 TI - Deoxypodophyllotoxin: a promising therapeutic agent from herbal medicine. AB - BACKGROUND: Recently, biologically active compounds isolated from plants used in herbal medicine have been the center of interest. Deoxypodophyllotoxin (DPT), structurally closely related to the lignan podophyllotoxin, is a potent antitumor and anti-inflammatory agent. However, DPT has not been used clinically yet. Also, DPT from natural sources seems to be unavailable. Hence, it is important to establish alternative resources for the production of such lignan; especially that it is used as a precursor for the semi-synthesis of the cytostatic drugs etoposide phosphate and teniposide. AIMS AND OBJECTIVES: The update paper provides an overview of DPT as an effective anticancer natural compound and a leader for cytotoxic drugs synthesis and development in order to highlight the gaps in our knowledge and explore future research needs. APPROACH AND METHODS: The present review covers the literature available from 1877 to 2012. The information was collected via electronic search using Chinese papers and the major scientific databases including PubMed, Sciencedirect, Web of Science and Google Scholar using the keywords. All abstracts and full-text articles reporting database on the history and current status of DPT were gathered and analyzed. RESULTS: Plants containing DPT have played an important role in traditional medicine. In light of the in vitro pharmacological investigations, DPT is a high valuable medicinal agent that has anti-tumor, anti-proliferative, anti inflammatory and anti-allergic properties. Further, DPT is an important precursor for the cytotoxic aryltetralin lignan, podophyllotoxin, which is used to obtain semisynthetic derivatives like etoposide and teniposide used in cancer therapy. However, most studies have focused on the in vitro data. Therefore, DPT has not been used clinically yet. CONCLUSIONS: DPT has emerged as a potent chemical agent from herbal medicine. Therefore, in vivo studies are needed to carry out clinical trials in humans and enable the development of new anti-cancer agents. In addition, DPT from commercial sources seems to be unavailable due to its rarity from natural sources and cumbersome extraction procedures. Hence, it is important to establish alternative, cost-effective and renewable resources, such plant cell cultures and (semi-) synthesis strategies for the production of DPT. PMID- 23792586 TI - A common p53 mutation (R175H) activates c-Met receptor tyrosine kinase to enhance tumor cell invasion. AB - Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive forms of human cancer with poor prognosis due to late diagnosis and metastasis. Common genomic alterations in ESCC include p53 mutation, p120ctn inactivation, and overexpression of oncogenes such as cyclin D1, EGFR, and c-Met. Using esophageal epithelial cells transformed by the overexpression of EGFR and p53(R175H), we find novel evidence of a functional link between p53(R175H) and the c-Met receptor tyrosine kinase to mediate tumor cell invasion. Increased c-Met receptor activation was observed upon p53(R175H) expression and enhanced further upon subsequent EGFR overexpression. We inhibited c-Met phosphorylation, resulting in diminished invasion of the genetically transformed primary esophageal epithelial cells (EPC-hTERT-EGFR-p53(R175H)), suggesting that the mechanism of increased invasiveness upon EGFR and p53(R175H) expression may be the result of increased c Met activation. These results suggest that the use of therapeutics directed at c Met in ESCC and other squamous cell cancers. PMID- 23792588 TI - Combination treatment of PD98059 and DAPT in gastric cancer through induction of apoptosis and downregulation of WNT/beta-catenin. AB - gamma-secretase inhibitors (GSIs), the indirect inhibitors of Notch, are emerging as a new class of anticancer agents for the treatment of solid and hematological malignancies, but little is known about their effects on gastric cancer. In this study, we demonstrate that DAPT, a potent GSI, was effective to inhibit gamma secretase activity in gastric cancer (GC) cell lines that contained a fragment with approximately the size of the Notch1 intracellular domain (NICD), but was limited in their ability to induce apoptosis. However, activation of extracellular signal-regulated kinase (ERK)1/2 upon DAPT treatment was detected. Selective inhibition of ERK1/2 activation dramatically sensitized GC cells to apoptosis via downregulating beta-catenin signaling in these GC cells. Notably, in a xenograft mouse tumor model, combination therapy using ERK inhibitor PD98059 plus DAPT yielded additive antitumor effects as compared with either agent alone. Taken together, these data demonstrated that gamma-secretase inhibition combined with ERK1/2 inhibitor enhances cell death in GC cells partly through downregulation of WNT/beta-catenin pathways. PMID- 23792589 TI - Chromosomal structural variations during progression of a prostate epithelial cell line to a malignant metastatic state inactivate the NF2, NIPSNAP1, UGT2B17, and LPIN2 genes. AB - Prostate cancer is the second highest cause of male cancer deaths in the United States. A significant number of tumors advance to a highly invasive and metastatic stage, which is typically resistant to traditional cancer therapeutics. In order to identify chromosomal structural variants that may contribute to prostate cancer progression we sequenced the genomes of a HPV-18 immortalized nonmalignant human prostate epithelial cell line, RWPE1, and compared it to its malignant, metastatic derivative, WPE1-NB26. There were a total of 34 large (> 1 Mbp) and 38 small copy number variants (<100 kbp) in WPE1 NB26 that were not present in the precursor cell line. We also identified and validated 46 structural variants present in the two cell lines, of which 23 were unique to WPE1-NB26. Structural variants unique to the malignant cell line inactivated: (1) the neurofibromin2 (NF2) gene, a known tumor suppressor; (2) its neighboring gene NIPSNAP1, another putative tumor suppressor that inhibits TRPV6, an anti-apoptotic oncogene implicated in prostate cancer progression; (3) UGT2B17, a gene that inactivates dihydrotestosterone, a known activator of prostate cancer progression; and (4) LPIN2, a phosphatidic acid phosphatase and a co-factor of PGC1a that is important for lipid metabolism and for suppressing autoinflammation. Our results illustrate the value of comparing the genomes of defined related pairs of cell lines to discover chromosomal structural variants that may contribute to cancer progression. PMID- 23792590 TI - Daunomycin, an antitumor DNA intercalator, influences histone-DNA interactions. AB - Although daunomycin and adriamycin are considered effective antitumor drugs and have been used in the clinic for over 40 years, their mechanism of action is still a matter of debate. We investigated the influence of daunomycin on interaction between linker or core histones and DNA in live HeLa cells in vitro, using image and flow cytometry. Exposure to daunomycin at clinically relevant concentrations (25-250 nM) caused dissociation of wild-type H1.1 as well as 4 H1 point mutants from DNA, followed by their accumulation in nucleoli and aggregation of chromatin. A detectable dissociation of H2B core histones occurred only at much higher concentrations of the drug (500 nM). Replication of DNA and synthesis of RNA were not halted by daunomycin (up to 2500 nM); however the characteristic subnuclear distribution of sites of transcription and replication was lost. Dissociation of the H1.1 linker histones and subsequent loss of higher order chromatin structures may constitute an important component of the mechanism of cytotoxicity of daunomycin. PMID- 23792587 TI - Signaling pathways in the molecular pathogenesis of adenocarcinomas of the esophagus and gastroesophageal junction. AB - Esophageal adenocarcinoma develops in response to severe gastroesophageal reflux disease through the precursor lesion Barrett esophagus, in which the normal squamous epithelium is replaced by a columnar lining. The incidence of esophageal adenocarcinoma in the United States has increased by over 600% in the past 40 years and the overall survival rate remains less than 20% in the community. This review highlights some of the signaling pathways for which there is some evidence of a role in the development of esophageal adenocarcinoma. An increasingly detailed understanding of the biology of this cancer has emerged recently, revealing that in addition to the well-recognized alterations in single genes such as p53, p16, APC, and telomerase, there are interactions between the components of the reflux fluid, the homeobox gene Cdx2, and the Wnt, Notch, and Hedgehog signaling pathways. PMID- 23792591 TI - Dual kinin B1 and B2 receptor activation provides enhanced blood-brain barrier permeability and anticancer drug delivery into brain tumors. AB - The low permeability of the BBB is largely responsible for the lack of effective systemic chemotherapy against primary and metastatic brain tumors. Kinin B1R and B2R have been shown to mediate reversible tumor-selective BBB disruption in preclinical animal models. We investigated whether co-administration of two novel potent kinin B1R and B2R agonists offers an advantage over administering each agonist alone for enhancing BBB permeability and tumor targeting of drugs in the malignant F98 glioma rat model. A new covalent kinin heterodimer that equally stimulates B1R and B2R was also constructed for the purpose of our study. We found that co-administration of B1R and B2R agonists, or alternatively administration of the kinin heterodimer more effectively delivered the MRI contrast agent Gd-DTPA and the anticancer drug carboplatin to brain tumors and surrounding tissues than the agonists alone (determined by MRI and ICP-MS methods). Importantly, the efficient delivery of carboplatin by the dual kinin receptor targeting on the BBB translated into increased survival of glioma bearing rats. Thus, this report describes a potential strategy for maximizing the brain bioavailability and therapeutic efficacy of chemotherapeutic drugs. PMID- 23792592 TI - A Smac mimetic augments the response of urothelial cancer cells to gemcitabine and cisplatin. AB - Cisplatin-based chemotherapy is considered the gold standard for patients with advanced bladder cancer. However, despite initial response, many patients will relapse; therefore, novel salvage treatment strategies are desperately needed. Herein, we studied a mechanism based treatment combination using a Smac mimetic with standard chemotherapy. Using a panel of 10 urothelial cancer cell lines, we exposed them to a combination of gemcitabine, cisplatin, and a Smac mimetic. Sensitivity was determined using a DNA fragmentation assay. We determined that three cell lines (UMUC-3, UMUC-13, and RT4v6) were considered sensitive to the combination of gemcitabine and cisplatin and an additional three cell lines were sensitized to gemcitabine and cisplatin with the addition of the Smac mimetic (UMUC-6, UMUC-12, and UMUC-18). We next explored the constitutive expression of selected members of the IAP family (XIAP, cIAP-1, cIAP-2, and Survivin), the BCL family (BCL-2, BCLXL, and BAX) and Smac using gene expression profiling and western blotting. We determined that RNA and protein expression of SMAC, selected members of the IAP family and members of the BCL family did not correlate to drug sensitivity. Lastly, using an in vivo mouse model, we determined that treatment with the Smac mimetic in combination with gemcitabine and cisplatin resulted in increased apoptosis, decreased microvessel density and decreased cellular proliferation. This novel treatment strategy may be effective in patients with advanced urothelial carcinoma and warrants further investigation. PMID- 23792594 TI - Magnetocardiography in the diagnosis of fetal arrhythmias. PMID- 23792593 TI - Cold-induced RNA-binding proteins regulate circadian gene expression by controlling alternative polyadenylation. AB - The body temperature is considered a universal cue by which the master clock synchronizes the peripheral clocks in mammals, but the mechanism is not fully understood. Here we identified two cold-induced RNA-binding proteins (RBPs), Cirbp and Rbm3, as important regulators for the temperature entrained circadian gene expression. The depletion of Cirbp or Rbm3 significantly reduced the amplitudes of core circadian genes. PAR-CLIP analyses showed that the 3'UTR binding sites of Cirbp and Rbm3 were significantly enriched near the polyadenylation sites (PASs). Furthermore, the depletion of Cirbp or Rbm3 shortened 3'UTR, whereas low temperature (upregulating Cirbp and Rbm3) lengthened 3'UTR. Remarkably, we found that they repressed the usage of proximal PASs by binding to the common 3'UTR, and many cases of proximal/distal PAS selection regulated by them showed strong circadian oscillations. Our results suggested that Cirbp and Rbm3 regulated the circadian gene expression by controlling alternative polyadenylation (APA). PMID- 23792595 TI - Endocardial occlusion of incompletely surgically ligated left atrial appendage using an Amplatzer septal occluder device. PMID- 23792596 TI - Mechanisms, predictors, and trends of electrical failure of Riata leads. AB - BACKGROUND: Riata and Riata ST implantable cardioverter-defibrillator leads have been shown to be prone to structural and electrical failure. OBJECTIVE: To determine predictors, mechanisms, and temporal patterns of Riata/ST lead electrical failure. METHODS: All 314 patients who underwent Riata/ST lead implantation at our institution with greater than or equal to 90 days of follow up were studied. The Kaplan-Meier analysis of lead survival was performed. Results from the returned product analysis of explanted leads with electrical lead failure were recorded. RESULTS: During a median follow-up of 4.1 years, the Riata lead electrical failure rate was 6.6%. The rate of externalized conductors among failed leads was 57%. The engineering analysis of 10 explanted leads revealed 5 (50%) leads with electrical failure owing to breach of ethylene tetrafluoroethylene conductor coating. Female gender (hazard ratio 2.7; 95% confidence interval 1.1-6.7; P = .04) and age (hazard ratio 0.95; 95% confidence interval 0.92-0.97; P < .001) were multivariate predictors of lead failure. By using log-log analysis, we noted that the rate of Riata lead failure initially increased exponentially with a power of 2.1 but leads surviving past 4 years had a linear pattern of lead failure with a power of 1.0. CONCLUSIONS: Younger age and female gender are independent predictors of Riata lead failure. Loss of integrity of conductor cables with ethylene tetrafluoroethylene coating is an important mode of electrical failure of the Riata lead. Further study of Riata lead failure trends is warranted to guide lead management. PMID- 23792597 TI - Now available as an iPad app! PMID- 23792598 TI - Comments on "Effects of uterine manipulation on surgical outcomes in laparoscopic management of endometrial cancer: a prospective randomized clinical trial". PMID- 23792599 TI - Does extensive upper abdomen surgery during primary cytoreduction impact on long term quality of life? Baseline plus longitudinal quality-of-life assessment would have provided a better answer. PMID- 23792600 TI - Evolution in fertility-preserving options for early-stage cervical cancer: radical trachelectomy, simple trachelectomy, neoadjuvant chemotherapy. AB - Fertility preservation is of paramount importance for young women diagnosed with early-stage cervical cancer. The radical trachelectomy procedure was developed to preserve uterine/reproductive function. The procedure has evolved significantly over the last 25 years. This review focuses on the various surgical techniques (vaginal, abdominal, laparoscopic, and robotic), highlighting advantages and disadvantages of each in relation to their respective obstetrical and oncologic outcomes. A trend toward even more conservative surgery (simple trachelectomy/large cone) has recently been advocated for patients with low-risk early lesions. Conversely, the option of neoadjuvant chemotherapy followed by fertility-preserving surgery for patients with larger-size lesions has also been proposed. Emerging data are presented. PMID- 23792602 TI - Lacunae in International Federation of Gynecology and Obstetrics (FIGO) classification for cervical carcinoma: observational study using TNM classification as comparator. AB - PURPOSE: International Federation of Gynecology and Obstetrics (FIGO) staging for cervical cancer does not yet consider findings of cross-sectional imaging unlike clinical tumor, node, and metastasis (TNM) staging system. We compare the two with regard to accuracy in pretreatment staging and their reliability in the prediction of prognosis. MATERIALS AND METHODS: This was an observational study of patients with biopsy-proven nonmetastatic cervical carcinoma. Pretreatment evaluation of patients was done by clinical assessment and contrast-enhanced computed tomographic scan of the pelvis to stage the disease with FIGO and clinical TNM (cTNM) system, respectively. The extent of discordance between the 2 staging systems were studied in assessing stage of disease, correlation with histopathologic classification in patients who were operated on, and in prediction of prognosis. RESULTS: The study included 54 patients. Seventeen of 19 patients with early-stage disease underwent upfront radical surgery; and in 59% of these, FIGO did not match with final histopathologic TNM (pTNM), but only in 23% patients, cTNM did not match with histopathological TNM (P = 0.02). Sensitivity of computed tomographic scan to pick up lymph node metastasis was 85% in early disease. Stage migration rates to higher stage when considering imaging findings in stage I, stage IIA, and stage IIB were 25%, 71%, and 37%, respectively. Thirty-four percent of stage IIIB disease was downstaged with cTNM. Lymph node positivity by cTNM was a strong pointer of recurrence (P = 0.01). CONCLUSIONS: Pretreatment cross-sectional imaging may help avoid undue surgery in patients with cervical cancer with positive lymph nodes and may help in a more accurate assessment of prognosis. PMID- 23792601 TI - Inhibition of enhancer of zeste homolog 2 (EZH2) expression is associated with decreased tumor cell proliferation, migration, and invasion in endometrial cancer cell lines. AB - OBJECTIVE: To investigate the impact of enhancer of zeste homolog 2 (EZH2) expression on endometrial cancer cell line behavior. MATERIALS AND METHODS: Enhancer of zeste homolog 2 expression levels were compared between the nonmalignant endometrial cell line T-HESC and 3 endometrial cancer cell lines, ECC-1, RL95-2, and HEC1-A. Stable EZH2 knockdown cell lines were created, and the impact on cellular proliferation, migration, and invasion were determined. Fluorescent activated cell sorting was used to examine effects of EZH2 silencing on cell cycle progression. Enhancer of zeste homolog 2 expression in endometrial cancer tissue specimens was examined using immunohistochemistry. Comparison of differences between control and short-hairpin EZH2 cell lines was performed using the Student t test and the Fischer exact test. RESULTS: Enhancer of zeste homolog 2 protein expression was increased in all 3 cancer cell lines and human endometrial cancer tissue specimens relative to control. RNA interference of EZH2 expression in ECC-1, RL95-2, and HEC1-A significantly decreased cell proliferation, migration, and invasion. Down-regulation of EZH2 expression resulted in a significant increase in the proportion of cells arrested in the G2/M phase. RNA interference of EZH2 expression was associated with an increase in the expression of Wnt pathway inhibitors sFRP1 and DKK3 and a concomitant decrease in beta-catenin. Enhancer of zeste homolog 2 expression in human tissue samples was significantly associated with increased stage, grade, depth of invasion, and nodal metastasis. CONCLUSIONS: Enhancer of zeste homolog 2 expression is associated with tumor cell proliferation, migration, and invasion in 3 endometrial cancer cell lines as well as with increased stage, grade, depth of invasion, and nodal metastasis in human cancer tissue specimens. Further investigation into this potential therapeutic target is warranted. PMID- 23792603 TI - The impact of maximum rectal distention and tandem angle on rectal dose delivered in 3D planned gynecologic high dose-rate brachytherapy. AB - OBJECTIVE: Computed tomography-based treatment planning for cervical cancer has allowed investigation into the volumetric radiation dose delivered to the rectum. The goal of intracavitary brachytherapy is to maximize the tumor dose while decreasing the dose to normal tissue like the rectum. We investigated the effects of tandem angle and maximum rectal distention on rectal dose delivered in HDR brachytherapy for locally advanced cervical cancer. MATERIALS AND METHODS: Between July 2007 and January 2010, 97 brachytherapy treatment planning computed tomographic scans from the first and last implant of 51 patients with locally advanced cervical cancer were reviewed. The rectum was manually contoured from the ischial tuberosity to the bottom of the sacroiliac joint. The maximum rectal distention was determined by measuring the largest anterior-posterior diameter of the rectum superior to the tandem ring and inferior to the end of the applicator. A volumetric measurement of the maximum and mean rectal dose, dose to 2 cc (D2cc), dose to 1cc (D1cc) of the rectum was calculated. The tandem angle and the Internal Commission on Radiation Units and Measurement rectal point were recorded, and a dose volume histogram was referenced. RESULTS: The mean maximum rectal distention was 3.01 cm. The mean D1cc, D2cc, mean rectal dose, maximum rectal dose, and Internal Commission on Radiation Units and Measurement rectal dose were 3.03 Gy, 2.78 Gy, 4.19 cGy, 1.40 cGy, and 2.99 Gy per treatment, respectively. In a multivariate analysis controlling for surface area, tandem angle, and body mass index, there was a significant increase in D2cc with increasing rectal distention (P = 0.016). There were no significant findings when observing the effects of tandem angle on D2cc. CONCLUSION: Rectal distention significantly affects D2cc delivered in HDR brachytherapy. In contrast, tandem angle does not. Concerted efforts to decrease rectal distention should be considered during treatment planning and delivery. PMID- 23792604 TI - Absence of human papillomavirus infection and activation of PI3K-AKT pathway in cervical clear cell carcinoma. AB - OBJECTIVE: Cervical cancer is the second most common cancer in females worldwide, and the majority of squamous cell carcinomas and adenocarcinomas are associated with high-risk human papillomavirus (HPV) infection. However, the relationship between clear cell carcinoma of the cervix (CCCC) and HPV is unclear. In this study, we sought to determine if HPV infection is associated with CCCC and to elucidate the signaling pathways involved. METHODS: We collected samples from 13 CCCC patients and collated the relevant clinicopathologic data. We then evaluated the presence of HPV types 16, 18, 31, 33, 35, 52, and 58 by broad-spectrum amplification by polymerase chain reaction and HPV types 39, 45, 51, 56, 59, and 68 by nested polymerase chain reaction assay that combines degenerate E6/E7 consensus primers and type-specific primers from extracted genomic DNA. Immunohistochemistry was used to analyze the expression of EGFR (epidermal growth factor receptor), HER2, PTEN (phosphatase and tensin homolog), phospho-AKT, phospho-mTOR (mammalian target of rapamycin), p16, and p53. EGFR and HER2 gene amplification was determined by fluorescence in situ hybridization. RESULTS: Patients with stage IB CCCC had a better 3-year overall survival rate compared with those with advanced-stage cancer (100% vs 44%; P = 0.014). High-risk HPVs were not detected in any of the cases examined. EGFR immunostaining was observed in 9 (75%) of 12 patients, HER2 in 3 (25%) of 12, PTEN in 6 (50%) of 12, and phospho-AKT in 7 (58%) of 12, and phospho-mTOR in 6 (50%) of 12. EGFR amplification could not be detected, but HER2 amplification was identified in 1 of (12.5%) 8 cases. CONCLUSIONS: Patients with stage I CCCC demonstrated good overall survival and rare recurrence. Clear cell carcinoma of the cervix is unrelated to high-risk HPV infection; hence, current vaccines will not prevent the incidence of CCCC. However, increased EGFR or HER2 expression or activation of AKT or mTOR was observed in all cases, indicating that inhibitors of tyrosine kinases or the AKT-mTOR pathway may be suitable treatment regimens for CCCC. PMID- 23792605 TI - Prognostic value of pretreatment 18F-fluorodeoxyglucose uptake in patients with cervical cancer treated with definitive chemoradiotherapy. AB - OBJECTIVE: We analyzed the correlation of F-fluorodeoxyglucose (FDG) uptake into primary tumors using the maximum standardized uptake value (SUVmax) and clinicopathological factors of disease. The impact of the pretreatment SUVmax of the primary tumor on survival was investigated. MATERIALS AND METHODS: The records of 149 patients with biopsy-proven cervical cancer treated with definitive chemoradiotherapy (ChRT) were reviewed. All patients underwent pretreatment FDG positron emission tomography with computed tomography, and posttherapy FDG positron emission tomography with computed tomography was performed within a median interval of 4.2 months (range, 3.0-11.2 months) after the completion of chemoradiotherapy. RESULTS: The mean SUVmax in patients with lymph node metastasis was significantly higher than that in patients without metastasis (19.7 +/- 8.2 vs 16.4 +/- 8.2, respectively; P = 0.01). A significant difference existed between tumor size (<4 vs >=4 cm) and the primary tumor SUVmax (14.7 +/- 6.6 vs 18.7 +/- 8.5, respectively; P = 0.02). The primary tumor pretreatment SUVmax for patients with complete remission was significantly lower than that of patients with partial response or progressive disease (15.6 +/- 5.7 vs 28.0 +/- 9.9, respectively; P < 0.001). The relationship between primary tumor FDG uptake and survival was evaluated by the cutoff value determined by receiver operating characteristic curve analysis. The area under the curve was 0.901 (P < 0.001; 95% confidence interval, 0.848-0.954), and 15.6 was determined as the SUVmax cutoff value. The 4-year actuarial overall survival (OS) and disease-free survival for SUVmax of less than 15.6 compared with SUVmax of 15.6 or greater were 85% vs 34% (P < 0.001) and 80% vs 29%, respectively (P < 0.001). In multivariate analysis, age, SUVmax of 15.6 or greater, and lymph node metastasis were independent prognostic factors of OS, and International Federation of Gynecology and Obstetrics stage IIB or higher, SUVmax of 15.6 or greater, and lymph node metastasis were significant factors for disease-free survival. CONCLUSION: The primary tumor pretreatment SUVmax is correlated with increased tumor size and lymph node involvement at diagnosis, how well the primary tumor responds to treatment, the likelihood of disease recurrence, and OS. PMID- 23792606 TI - The need for more workshops in laparoscopic surgery and surgical anatomy for European gynaecological oncology trainees: a survey by the European Network of Young Gynaecological Oncologists. AB - OBJECTIVE: The objective of this study was to highlight the relative preference of European gynecologic oncology trainees for workshops that could support and supplement their training needs. METHODS: A Web-based survey was sent to 900 trainees on the European Network of Young Gynaecological Oncologists database in November 2011. Respondents were asked to rate a 13-item questionnaire (using a 1- to 5-point Likert scale) on workshop topics they felt would most benefit their training requirements. Free text space for additional topics was also provided. Descriptive analysis was used to describe the mean scores reported for different items. A complete linkage hierarchical cluster analysis with Dendron plot was used to assess any clustering of data, and Cronbach alpha was used to assess the internal reliability of the questionnaire. RESULTS: One hundred ninety trainees from 37 countries responded to the survey, giving a 21% response rate. The 3 most important topics reported were laparoscopic surgery; surgical anatomy, and imaging techniques in gynecologic oncology. The Dendron plot indicated 4 different clusters of workshops (research related skills, supportive ancillary skills, related nonsurgical subspecialties, and core surgical skills) reflecting different competencies trainees need to meet. There was no significant association between individual country of training and workshop preference. The mean duration of the workshop preferred by 71% of respondents was 2 days. Cronbach alpha of the 13-item questionnaire was 0.78, which suggests good internal consistency/reliability. CONCLUSIONS: This report for the first time highlights the relative importance and significance European trainees attach to some of their training needs in gynecologic oncology. Laparoscopic surgery, surgical anatomy, and imaging appear to be the 3 areas of greatest need. The European Society of Gynaecological Oncology, other national specialist societies, and institutions should direct additional training efforts at these areas. PMID- 23792607 TI - Robot-assisted total preservation of the pelvic autonomic nerve with extended systematic lymphadenectomy as part of nerve-sparing radical hysterectomy for cervical cancer. AB - OBJECTIVE: To evaluate our short-term clinical outcomes of robot-assisted autonomic nerve-sparing extended systematic lymphadenectomy as part of nerve sparing radical hysterectomy. METHODS: Between March 2011 and June 2012, we observed prospectively 28 consecutive patients who underwent robot-assisted autonomic nerve-sparing extended systematic lymphadenectomy, including the superior and inferior gluteal, presacral (subaortic), common iliac, and lower para-aortic nodes. RESULTS: The predominant International Federation of Gynecology and Obstetrics stage was IB1 (15 patients), followed by IB2 (5 patients), IA2 (3 patients), IIA1 (3 patients), and IIA2 (2 patients). The mean +/- SD total operating time was 308.8 +/- 54.9 minutes, and the mean +/- SD console time was 280.0 +/- 46.0 minutes. The mean +/- SD blood loss was 102.7 +/- 153.8 mL. The mean +/- SD acquired pelvic lymph node was 27.1 +/- 9.3, the mean +/- SD extended lymph node was 19.2 +/- 9.6, and the mean +/- SD total lymph node was 46.3 +/- 14.5. A total of 10 patients (35.7%) had nodal metastasis; among them, 6 patients (21.4%) had single pelvic nodal metastasis, 3 patients (10.7%) had concurrent pelvic and extended nodal metastasis, and one patient (3.6%) had single extended nodal metastasis. No intraoperative complications that required treatment occurred; however, ureterovaginal fistula was identified in 4 patients (14.3%) and ureter stricture in 4 patients (14.3%) after radiotherapy. After a median follow-up of 10 months (range, 1-16 months), there was no pelvic recurrence; however, one patient had recurrence at transposition site of ovary. CONCLUSIONS: With the advantage of delicate movement of robot instrument, robot assisted systematic extended lymphadenectomy with total preservation of pelvic autonomic nerves did not compromise the radicality, and its surgical technique was feasible and safe. By using this approach, we could harvest more lymph nodes and have a high rate of metastatic nodes without disturbing voiding function; however, there was increased rate of urological complications. Moreover, long term survival benefit after an extended systematic lymphadenectomy must be evaluated. PMID- 23792608 TI - Feasibility and outcomes of ureteroureterostomy and extravesical ureteroneocystostomy as part of radical surgery for infiltrating gynecologic disease. AB - OBJECTIVE: Abdominopelvic infiltrative disease may require aggressive surgical procedures. This study reports on our experience with distal ureterectomy, ureteroureterostomy, and extravesical ureteroneocystostomy as part of radical surgery for infiltrating gynecologic disease. PATIENTS AND METHODS: Twenty-one women required surgery to the distal ureter at the Queensland Centre for Gynecological Cancer, Australia, from January 2006 to September 2012. Details of the patient's history, operation record, inpatient notes, and follow-up data were obtained through chart review. RESULTS: Patients' median age was 57.8 +/- 14.7 years (range, 30-80 years). Seventeen patients had gynecologic cancer. Mean operating time was 3.9 +/- 0.9 hours (range, 2.5-5.5 hours). Restoration of continuity was achieved through extravesical ureteroneocystostomy and ureteroureterostomy in 18 and 3 patients, respectively. Boari flap was used in 3 patients, and psoas hitch was the technique chosen in 11 patients. Urinary tract infection was the most common clinical adverse event. Albeit clinically irrelevant, 38% of the patients showed structural renal tract changes postoperatively. CONCLUSIONS: To achieve maximal surgical radicalness, resection of the distal ureter with subsequent ureteroureterostomy or extravesical ureteroneocystostomy is feasible and safe. Radical surgery to the urinary tract should be considered as a legitimate part of a gynecologic oncologist's surgical armamentarium to increase a patient's probability of survival and its positive effect on kidney function. PMID- 23792609 TI - Preference-based utility scores for adverse events associated with the treatment of gynecologic cancers. AB - OBJECTIVE: Our goals were to (1) define a set of descriptive health states related to adverse events (AEs) associated with gynecologic cancer treatment with radical surgery and chemoradiation and (2) derive a set of quality of life related utility scores corresponding to these health states. METHODS: We developed a list of health states for grade 3/4 AEs related to gynecologic cancer treatment. Using the visual analog scale score and time trade-off (TTO) methods, valuation of each health state was obtained through interviews of 60 volunteers (15 cervical cancer survivors treated with surgery and/or chemoradiation and 45 women without a cancer diagnosis). Health states were ranked by mean/median TTO scores. Wilcoxon rank sum test was used to compare central tendencies related to patient and volunteer characteristics. RESULTS: Patients and volunteers agreed on their preference rankings, with highest preference given to infection (median TTO = 1.0) and thrombosis (median TTO = 0.97). Lowest preference was assigned to radiation proctitis (median TTO = 0.87) and gastrointestinal fistula formation (median TTO = 0.83). Utility scores for the majority of health states were not significantly associated with age, race, parity, patient or volunteer status, history of abnormal Pap smear, stage of cervical cancer diagnosis, or personal experience of a serious treatment-related AE. CONCLUSIONS: This study helps establish preferences and quality-of-life utility scores for health states related to toxicities from surgery, radiation, and chemotherapy for gynecologic cancer treatment. Such information can be used to inform medical decision making/counseling and may be applied to future comparative effectiveness models in which radical surgery and/or chemoradiation are considered. PMID- 23792610 TI - Design of motorcycle rider protection systems using numerical techniques. AB - The goal of this paper is the development of a design methodology, based on the use of finite elements numerical tools and dummies in order to study the damages and injuries that appear during a motorcyclist collision against a motorcyclist protection system (MPS). According to the existing regulation, a Hybrid III dummy FEM model has been used as a starting point and some modifications have been included. For instance a new finite element helmet model has been developed and later added to the dummy model. Moreover, some structural elements affecting the simulation results such as the connecting bolts or the ground have been adequately modeled. Finally there have been analyzed diverse types of current motorcyclists protection systems, for which it has been made a comparative numerical-experiment analysis to validate the numerical results and the methodology used. PMID- 23792611 TI - Modeling vehicle operating speed on urban roads in Montreal: a panel mixed ordered probit fractional split model. AB - Vehicle operating speed measured on roadways is a critical component for a host of analysis in the transportation field including transportation safety, traffic flow modeling, roadway geometric design, vehicle emissions modeling, and road user route decisions. The current research effort contributes to the literature on examining vehicle speed on urban roads methodologically and substantively. In terms of methodology, we formulate a new econometric model framework for examining speed profiles. The proposed model is an ordered response formulation of a fractional split model. The ordered nature of the speed variable allows us to propose an ordered variant of the fractional split model in the literature. The proposed formulation allows us to model the proportion of vehicles traveling in each speed interval for the entire segment of roadway. We extend the model to allow the influence of exogenous variables to vary across the population. Further, we develop a panel mixed version of the fractional split model to account for the influence of site-specific unobserved effects. The paper contributes substantively by estimating the proposed model using a unique dataset from Montreal consisting of weekly speed data (collected in hourly intervals) for about 50 local roads and 70 arterial roads. We estimate separate models for local roads and arterial roads. The model estimation exercise considers a whole host of variables including geometric design attributes, roadway attributes, traffic characteristics and environmental factors. The model results highlight the role of various street characteristics including number of lanes, presence of parking, presence of sidewalks, vertical grade, and bicycle route on vehicle speed proportions. The results also highlight the presence of site-specific unobserved effects influencing the speed distribution. The parameters from the modeling exercise are validated using a hold-out sample not considered for model estimation. The results indicate that the proposed panel mixed ordered probit fractional split model offers promise for modeling such proportional ordinal variables. PMID- 23792612 TI - Functional declines as predictors of risky street-crossing decisions in older pedestrians. AB - The experiment investigated the extent to which risky street-crossing decisions by older pedestrians can be explained by declines in functional abilities. Sixteen young (age 20-35), 17 younger-old (age 60-67), and 18 older-old (age 70 84) participants carried out a street-crossing task in a simulated two-way road environment and took a battery of tests assessing perceptual, cognitive, and motor abilities. Older-old pedestrians were more likely than young and younger old participants to make decisions that would have led to collisions with approaching cars, especially when traffic coming from two directions was approaching at a high speed. Regression analyses identified several functional performance measures as predictors of these dangerous choices. Walking speed, which determined the time needed to cross, was shown to play the most important role. Time-to-arrival estimate, which informed the pedestrians about the time available for crossing, was found to be the second most predictive factor. Visual processing speed and visual attention abilities assessed via the UFOV(r) Test also came into play, allowing participants to focus their attention on the relevant available information and to make timely, correct decisions. Attention shifting was the fourth significant predictor, allowing pedestrians to adapt their crossing strategy to the oncoming road-traffic information. The results suggest that the greater risk of being involved in a collision as age increases calls for a multi-dimensional explanation combining age-related physical, perceptual, and cognitive performance declines. These findings have implications for improving older pedestrians' safety in terms of speed limits, road design, and training. PMID- 23792613 TI - Revisiting the concept of the 'problem young driver' within the context of the 'young driver problem': who are they? AB - For decades there have been two young driver concepts: the 'young driver problem' where the driver cohort represents a key problem for road safety; and the 'problem young driver' where a sub-sample of drivers represents the greatest road safety problem. Given difficulties associated with identifying and then modifying the behaviour of the latter group, broad countermeasures such as graduated driver licensing (GDL) have generally been relied upon to address the young driver problem. GDL evaluations reveal general road safety benefits for young drivers, yet they continue to be overrepresented in fatality and injury statistics. Therefore it is timely for researchers to revisit the 'problem young driver' concept to assess its potential countermeasure implications. This is particularly relevant within the context of broader countermeasures that have been designed to address the 'young driver problem' Personal characteristics, behaviours and attitudes of 378 Queensland novice drivers aged 17-25 years were explored during their pre-, Learner and Provisional 1 (intermediate) licence as part of a larger longitudinal project. Self-reported risky driving was measured by the Behaviour of Young Novice Drivers Scale (BYNDS), and five subscale scores were used to cluster the drivers into three groups (high risk n=49, medium risk n=163, low risk n=166). High risk 'problem young drivers' were characterised by greater self reported pre-Licence driving, unsupervised Learner driving, and speeding, driving errors, risky driving exposure, crash involvement, and offence detection during the Provisional period. Medium risk drivers were also characterised by more risky road use than the low risk group. Interestingly problem young drivers appear to have some insight into their high-risk driving, since they report significantly greater intentions to bend road rules in future driving. The results suggest that tailored intervention efforts may need to target problem young drivers within the context of broad countermeasures such as GDL which address the young driver problem in general. Experiences such as crash-involvement could be used to identify these drivers as a preintervention screening measure. PMID- 23792614 TI - Burst fractures of the lumbar spine in frontal crashes. AB - BACKGROUND: In the United States, major compression and burst type fractures (>20% height loss) of the lumbar spine occur as a result of motor vehicle crashes, despite the improvements in restraint technologies. Lumbar burst fractures typically require an axial compressive load and have been known to occur during a non-horizontal crash event that involve high vertical components of loading. Recently these fracture patterns have also been observed in pure horizontal frontal crashes. This study sought to examine the contributing factors that would induce an axial compressive force to the lumbar spine in frontal motor vehicle crashes. METHODS: We searched the National Automotive Sampling System (NASS, 1993-2011) and Crash Injury Research and Engineering Network (CIREN, 1996 2012) databases to identify all patients with major compression lumbar spine (MCLS) fractures and then specifically examined those involved in frontal crashes. National trends were assessed based on weighted NASS estimates. Using a case-control study design, NASS and CIREN cases were utilized and a conditional logistic regression was performed to assess driver and vehicle characteristics. CIREN case studies and biomechanical data were used to illustrate the kinematics and define the mechanism of injury. RESULTS: During the study period 132 NASS cases involved major compression lumbar spine fractures for all crash directions. Nationally weighted, this accounted for 800 cases annually with 44% of these in horizontal frontal crashes. The proportion of frontal crashes resulting in MCLS fractures was 2.5 times greater in late model vehicles (since 2000) as compared to 1990s models. Belted occupants in frontal crashes had a 5 times greater odds of a MCLS fracture than those not belted, and an increase in age also greatly increased the odds. In CIREN, 19 cases were isolated as horizontal frontal crashes and 12 of these involved a major compression lumbar burst fracture primarily at L1. All were belted and almost all occurred in late model vehicles with belt pretensioners and buckets seats. CONCLUSION: Major compression burst fractures of the lumbar spine in frontal crashes were induced via a dynamic axial force transmitted to the pelvis/buttocks into the seat cushion/pan involving belted occupants in late model vehicles with increasing age as a significant factor. PMID- 23792615 TI - Dog safety in rural China: children's sources of safety information and effect on knowledge, attitudes, and practices. AB - Dog bites are a significant pediatric public health challenge in rural China. This study evaluated the effect of various sources of dog-safety information on children's knowledge, attitudes, beliefs and practices with dogs. A total of 1925 children (grade 3-6) between 6 and 15 years old in four rural regions across China participated between May and September 2012. Results showed that teachers and especially parents were effective information sources for children to learn about dog safety. Learning from peers and children teaching themselves were ineffective education strategies. Multi-source learning (from both parents and teachers) did not differ from single-source learning (from parents but not teachers) but did exceed learning from teachers but not parents or no learning from adults. Older age was associated with greater safety knowledge but also riskier practices with dogs. Girls generally held more safety knowledge, less risky attitudes/beliefs and safer practices than boys. Neither age nor gender interacted with information sources on outcome measures. In conclusion, parents appear to play a major role in educating children in rural China on dog safety. Future dog safety interventions might focus on changing cognition and behavior as well as delivering basic knowledge to youth through teachers and especially parents. PMID- 23792616 TI - Analysis of the minimum swerving distance for the development of a motorcycle autonomous braking system. AB - In the recent years the autonomous emergency brake (AEB) was introduced in the automotive field to mitigate the injury severity in case of unavoidable collisions. A crucial element for the activation of the AEB is to establish when the obstacle is no longer avoidable by lateral evasive maneuvers (swerving). In the present paper a model to compute the minimum swerving distance needed by a powered two-wheeler (PTW) to avoid the collision against a fixed obstacle, named last-second swerving model (Lsw), is proposed. The effectiveness of the model was investigated by an experimental campaign involving 12 volunteers riding a scooter equipped with a prototype autonomous emergency braking, named motorcycle autonomous emergency braking system (MAEB). The tests showed the performance of the model in evasive trajectory computation for different riding styles and fixed obstacles. PMID- 23792617 TI - Hybrid cadaveric/surrogate model of thoracolumbar spine injury due to simulated fall from height. AB - A fall from high height can cause thoracolumbar spine fracture with retropulsion of endplate fragments into the canal leading to neurological deficit. Our objectives were to develop a hybrid cadaveric/surrogate model for producing thoracolumbar spine injury during simulated fall from height, evaluate the feasibility and performance of the model, and compare injuries with those observed clinically. Our model consisted of a 3-vertebra human lumbar specimen (L3-L4-L5) stabilized with muscle force replication and mounted within an impact dummy. The model was subjected to a fall from height of 2.2 m with impact velocity of 6.6 m/s. Kinetic and kinematic time-history responses were determined using spinal and pelvis load cell data and analyses of high-speed video. Injuries to the L4 vertebra were evaluated by fluoroscopy, radiography, and detailed anatomical dissection. Peak compression forces during the fall from height occurred at 7 ms and reached 44.7 kN at the ground, 9.1 kN at the pelvis, and 4.5 kN at the spine. Pelvis acceleration peaks reached 209.9 g at 8 ms for vertical and 62.8 g at 12 ms for rearward. Tensile load peaks were then observed (spine: 657.0 N at 47 ms; pelvis: 569.4 N at 61 ms). T1/pelvis peak flexion of 68.3 degrees occurred at 38 ms as the upper torso translated forward while the pelvis translated rearward. Complete axial burst fracture of the L4 vertebra was observed including endplate comminution, retropulsion of bony fragments into the canal, loss of vertebral body height, and increased interpedicular distance due to fractures anterior to the pedicles and a vertical split fracture of the left lamina. Our dynamic injury model closely replicated the biomechanics of real-life fall from height and produced realistic, clinically relevant burst fracture of the lumbar spine. Our model may be used for further study of thoracolumbar spine injury mechanisms and injury prevention strategies. PMID- 23792618 TI - A test-based method for the assessment of pre-crash warning and braking systems. AB - In this paper, a test-based assessment method for pre-crash warning and braking systems is presented where the effectiveness of a system is measured by its ability to reduce the number of injuries of a given type or severity in car-to car rear-end collisions. Injuries with whiplash symptoms lasting longer than 1 month and MAIS2+ injuries in both vehicles involved in the crash are considered in the assessment. The injury reduction resulting from the impact speed reduction due to a pre-crash system is estimated using a method which has its roots in the dose-response model. Human-machine interaction is also taken into account in the assessment. The results reflect the self-protection as well as the partner protection performance of a pre-crash system in the striking vehicle in rear-end collisions and enable a comparison between two or more systems. It is also shown how the method may be used to assess the importance of warning as part of a pre crash system. PMID- 23792619 TI - The impact on alcohol-related collisions of the partial decriminalization of impaired driving in British Columbia, Canada. AB - INTRODUCTION: The purpose of this paper is to assess the impact of administrative sanctions introduced as part of a new law for drinking drivers in British Columbia, Canada. The new law, known as immediate roadside prohibitions (IRP), aimed to increase the efficiency of police and courts for processing drinking drivers, thereby increasing the certainty of their being apprehended and punished. However, in order to maintain these efficiencies, sanctions under this new law largely replaced laws under the Criminal Code of Canada for Driving While Impaired (DWI) by alcohol, which had more severe penalties but lower certainty of punishment. We examined whether the intervention was related to abrupt significant declines in three types of alcohol-related collisions (i.e. fatalities, injuries or property damage only) compared to the same type of collisions without alcohol involvement. METHODS: An interrupted time series design, with a non-equivalent control was used, testing for an intervention effect. Monthly rates of the three types of collisions with and without alcohol involvement were calculated for the 15-year period before and the 1-year period after implementation of the new law. ARIMA time series analysis was conducted controlling for trend effects, seasonality, autocorrelation, and collisions without alcohol. RESULTS: Significant average declines (p<0.05) in alcohol related collisions were found as follows: 40.4% for fatal collisions, 23.4% for injury collisions and 19.5% for property damage only collisions. No significant effects were found for any of the three comparable non-alcohol-related types of collisions. CONCLUSIONS: These results suggest that provincial law of administrative sanctions for drinking drivers and associated publicity was more effective for minimizing alcohol-related collisions than laws under the Canadian Criminal Code. PMID- 23792620 TI - "Single nickel source" in situ fabrication of a stable homochiral MOF membrane with chiral resolution properties. AB - A homochiral MOF membrane was successfully and facilely synthesized using an in situ growth method, which had the advantages of cheap raw materials, simple operation and high thermal stability. A diol isomer mixture was used to test the separation efficiency of the membrane at different temperatures and pressures. PMID- 23792621 TI - Size-resolved aerosol trace elements at a rural mountainous site in Northern China: importance of regional transport. AB - This paper presents an intensive field measurement campaign carried out at the rural mountainous site of Xinglong (960 m a.s.l.) in Northern China during Sep. 3 20 2008. Size-segregated samples were collected daily and analyzed for 25 trace elements (TEs). The majority of the TEs showed comparable concentrations in fine (<2.1 MUm) and coarse particles (2.1-9 MUm). In addition, elements like K, Mn, Cu, Se, Mo, Ag, Cd, Tl and Pb were accumulated in fine mode whereas Al, Co and Sb were concentrated in a coarse mode. For most of the TEs, their enrichment factor (EF) increased with decreasing particle size from large (>9 MUm) to coarse, and to fine, signifying influences by anthropogenic emissions. The observed concentrations of heavy metals in fine particles, with EF values higher than 100, were significantly higher than the historical data recorded in the 1980s and 1990s, reflecting the increasing emissions in the target area. One pronounced event occurred on Sep. 14 when all of the TEs showed a peak, which was associated with regional emissions from both southeast (SE) and southwest (SW) indicated by backward trajectory analysis. This is further supported by the measurements in upwind sites where the concentrations of TEs were several times higher than those in Xinglong, suggesting potential source regions. Episodes of heavy metals were generally characterized by significant enhancements of fine mode and air mass trajectories from SE or SW alone. Taking this finding and factor analysis results together, the metallic episodes were attributable to the long-range transport of regional plumes from coal consumption and nonferrous metal smelting. With the rapid urbanization and industrialization in Northern China, the increasing emissions of TEs will place a great strain on human health and the environment in the downwind regions, thus long-term and multi-site observation with high time resolution are necessary. PMID- 23792622 TI - Origin of HBV and its arrival in the Americas--the importance of natural selection on time estimates. AB - BACKGROUND: The strong geographic structure shown by the global pattern of HBV lineages suggests an ancient origin for this virus; however, estimates based on the molecular clock suggest a very recent origin for the Native American genotypes F and H. In this study, we contribute to this debate by estimating the divergence times of genotypes F and H and by discussing how evolutionary rates estimated from recent samples may underestimate the divergence time of more ancient nodes in HBV phylogenies. METHODS: A total of 108 complete HBV genotype F and H genomes were compared to 44 reference genomes from other genotypes. Time estimates were based on a Bayesian method with evolutionary rates taken from the literature. To assess the pattern of substitutions in recent versus old branches we mapped the phylogenetic distribution of all mutations occurring in genotypes F and H using a maximum likelihood approach and compared the number of synonymous and non-synonymous mutations in young and old branches of HBV genotype F and H phylogeny using a chi2 test. RESULTS: Estimated divergence times between genotypes F and H depend heavily on the evolutionary rate. While fast rates suggest a recent separation of these genotypes (approximately 800 years ago), slow rates suggest an earlier divergence (up to approximately 13,000 years ago). There is a clear excess of non-synonymous substitutions in the most recent branches of HBV phylogeny (P=4.87*10-15), most likely suggesting the action of purifying selection. CONCLUSIONS: These results suggest that rates estimated based on recent samples will overestimate the evolutionary rate and underestimate the coalescence times for ancient nodes in HBV phylogeny. PMID- 23792623 TI - Impedimetric immunosensor for the detection of circulating pro-inflammatory monocytes as infection markers. AB - Circulating blood monocytes belong to the first line of defense against pathogens and inflammation. Monocytes can be divided into three populations defined by the expression of the cell surface molecules, CD 14 and CD 16. The CD 14(++) CD 16(-) cells, called "classical" monocytes, represent 85% to 95% of the total monocytes in a healthy person whereas CD 14(-) CD 16(+), called "proinflammatory" monocytes, are found in greater numbers in the blood of patients with acute inflammation and infectious diseases. This increase in the concentration of proinflammatory monocytes can be a good indicator of an infectious state. This study presents an immunosensor based on impedance detection for specific cell trapping of classical and proinflammatory monocytes. The grafting of specific antibodies (CD 14 or CD 16) was based on the use of mixed SAM associated with protein G. Each step of the functionalization was characterized by electrochemical methods, quartz crystal microbalance and atomic force microscopy. Faradaic electrochemical impedance spectroscopy and voltametric analysis confirmed the success of the modification process with a surface coverage reaching 92% for the antibody layer. The increase in the deposited mass at each step of the modification process confirmed this results revealing that one protein G in two was bound to an antibody. The cell trapping capacity, evaluated by the variation in the film resistance using non-faradaic impedance spectroscopy revealed that the cell trapping is selective, depending on the specific antibody grafted and quantitative with the range of detection being 1000 to 30,000 infected cells. This range of detection is consistent with the application targeted. PMID- 23792624 TI - Fluorogenic substrate screening for G-quadruplex DNAzyme-based sensors. AB - Due to the inherent higher sensitivity of fluorescence detection than colorimetric detection, it is necessary to screen out a suitable fluorogenic substrate for G-quadruplex DNAzymes to improve the sensitivities of G-quadruplex DNAzyme-based sensors. Herein, seven candidates were tested to determine the possibilities of them as fluorogenic substrates. Among these candidates, tyramine hydrochloride gave the maximum signal-to-background ratio for the sensing systems with and without G-quadruplexes, and thus was recommended as the fluorogenic substrate for the sensors that are developed on the basis of target-triggered G quadruplex formation or destruction. 10-acetyl-3,7-dihydroxyphenoxazine gave the maximum fluorescence signal change between the sensing systems without and with H2O2, thus was recommended as the fluorogenic substrate for the sensors targeting the detection of H2O2 or H2O2-related analytes. In a model system of G-quadruplex DNAzyme-based Cu(2+) sensor, fluorescence detection using tyramine hydrochloride as fluorogenic substrate could decrease the detection limit from 4 nM to 0.7 nM compared with the colorimetric detection. PMID- 23792625 TI - Elevated cardiac troponin T is associated with higher mortality and amputation rates in patients with peripheral arterial disease. AB - OBJECTIVES: The aim of the present study was to evaluate whether elevated cardiac troponin T (cTnT) was independently associated with an increased all-cause mortality or risk of cardiovascular events and amputation among patients with peripheral arterial disease (PAD). BACKGROUND: PAD patients often have impaired renal function, and the blood concentration of cardiac troponin often increases with declining glomerular filtration rate. METHODS: The cohort consisted of 1,041 consecutive PAD patients (653 males, 388 females, age 70.7 +/- 10.8 years, Rutherford stages 2 to 5) undergoing endovascular peripheral revascularization. RESULTS: At baseline, measurable cTnT levels (>=0.01 ng/ml) were detected in 21.3% of individuals. Compared with patients who had undetectable cTnT levels, those with cTnT levels >=0.01 ng/ml had higher rates for mortality (31.7% vs. 3.9%, respectively; p < 0.001), myocardial infarction (4.1% vs. 1.1%, respectively; p = 0.003), and amputation (10.1% vs. 2.4%, respectively; p < 0.001) during a 1-year follow-up. In adjusted Cox regression models, cTnT levels >=0.01 ng/ml were associated with increased total mortality (hazard ratio [HR]: 8.14; 95% confidence interval [CI]: 3.77 to 17.6; p < 0.001) and amputation rates (HR: 3.71; 95% CI: 1.33 to 10.3; p = 0.012). CONCLUSIONS: cTnT is frequently elevated in PAD patients and is associated with higher event rates in terms of total mortality and amputation. Even small cTnT elevations predict a markedly increased risk that is independent of an impaired renal function. (Troponin T as Risk Stratification Tool in Patients With Peripheral Arterial Occlusive Disease; NCT01087385). PMID- 23792626 TI - Toxicity of environmental contaminants to fish spermatozoa function in vitro--a review. AB - In vitro techniques for investigating the toxic effects of environmental contaminants (EC) on fish spermatozoa motility kinetics and fertilizing ability are valuable tools to understand toxicity mechanisms and sites of action. In vitro techniques may also be well-suited to studies of endocrine disruption in male fertility in vivo. This review shows ECs to decrease or suppress spermatozoa motility kinetics and fertilizing ability in a dose-dependent manner, with toxic concentrations being much higher than those reported in the aquatic environment. Sites of action depend on EC concentration and duration of exposure. Both instant (immediate) and incubated exposure of spermatozoa to ECs results in damage to the plasma membrane and the axoneme, while disruption of energy metabolism appears only during incubated exposure. Spermatozoa lose fertilizing ability following exposure to ECs in vitro, not only due to inhibition or suppression of the initiation of motility, but also through damage to DNA. This review highlights the significant lack of information about disruption of spermatozoa function associated with exposure to water from polluted areas as well as combined effects of ECs. Specifics of alterations in intracellular signaling cascades involved in the initiation of spermatozoa motility following exposure to sublethal concentrations of ECs remain unknown. Further studies are also needed to elucidate in vitro EC effects during spermatozoa maturation, when spermatozoa acquire the potential for motility. PMID- 23792627 TI - Anti-androgens act jointly in suppressing spiggin concentrations in androgen primed female three-spined sticklebacks - prediction of combined effects by concentration addition. AB - Increasing attention is being directed at the role played by anti-androgenic chemicals in endocrine disruption of wildlife within the aquatic environment. The co-occurrence of multiple contaminants with anti-androgenic activity highlights a need for the predictive assessment of combined effects, but information about anti-androgen mixture effects on wildlife is lacking. This study evaluated the suitability of the androgenised female stickleback screen (AFSS), in which inhibition of androgen-induced spiggin production provides a quantitative assessment of anti-androgenic activity, for predicting the effect of a four component mixture of anti-androgens. The anti-androgenic activity of four known anti-androgens (vinclozolin, fenitrothion, flutamide, linuron) was evaluated from individual concentration-response data and used to design a mixture containing each chemical at equipotent concentrations. Across a 100-fold concentration range, a concentration addition approach was used to predict the response of fish to the mixture. Two studies were conducted independently at each of two laboratories. By using a novel method to adjust for differences between nominal and measured concentrations, good agreement was obtained between the actual outcome of the mixture exposure and the predicted outcome. This demonstrated for the first time that androgen receptor antagonists act in concert in an additive fashion in fish and that existing mixture methodology is effective in predicting the outcome, based on concentration-response data for individual chemicals. The sensitivity range of the AFSS assay lies within the range of anti-androgenicity reported in rivers across many locations internationally. The approach taken in our study lays the foundations for understanding how androgen receptor antagonists work together in fish and is essential in informing risk assessment methods for complex anti-androgenic mixtures in the aquatic environment. PMID- 23792628 TI - High-frequency off-target mutagenesis induced by CRISPR-Cas nucleases in human cells. AB - Clustered, regularly interspaced, short palindromic repeat (CRISPR) RNA-guided nucleases (RGNs) have rapidly emerged as a facile and efficient platform for genome editing. Here, we use a human cell-based reporter assay to characterize off-target cleavage of CRISPR-associated (Cas)9-based RGNs. We find that single and double mismatches are tolerated to varying degrees depending on their position along the guide RNA (gRNA)-DNA interface. We also readily detected off target alterations induced by four out of six RGNs targeted to endogenous loci in human cells by examination of partially mismatched sites. The off-target sites we identified harbored up to five mismatches and many were mutagenized with frequencies comparable to (or higher than) those observed at the intended on target site. Our work demonstrates that RGNs can be highly active even with imperfectly matched RNA-DNA interfaces in human cells, a finding that might confound their use in research and therapeutic applications. PMID- 23792629 TI - Efficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling. AB - Despite efforts to understand the interactions between nanoparticles and cells, the cellular processes that determine the efficiency of intracellular drug delivery remain unclear. Here we examine cellular uptake of short interfering RNA (siRNA) delivered in lipid nanoparticles (LNPs) using cellular trafficking probes in combination with automated high-throughput confocal microscopy. We also employed defined perturbations of cellular pathways paired with systems biology approaches to uncover protein-protein and protein-small molecule interactions. We show that multiple cell signaling effectors are required for initial cellular entry of LNPs through macropinocytosis, including proton pumps, mTOR and cathepsins. siRNA delivery is substantially reduced as ?70% of the internalized siRNA undergoes exocytosis through egress of LNPs from late endosomes/lysosomes. Niemann-Pick type C1 (NPC1) is shown to be an important regulator of the major recycling pathways of LNP-delivered siRNAs. NPC1-deficient cells show enhanced cellular retention of LNPs inside late endosomes and lysosomes, and increased gene silencing of the target gene. Our data suggest that siRNA delivery efficiency might be improved by designing delivery vehicles that can escape the recycling pathways. PMID- 23792631 TI - Studies on recombination processes in two Chlamydomonas reinhardtii endogenous genes, NIT1 and ARG7. AB - Integration of exogenous DNA in the unicellular green alga Chlamydomonas reinhardtii is principally carried out by mechanisms involving non-homologous recombination (NHR), rather than homologous recombination (HR). Homologous recombination is, however, the mechanism of choice when it comes to gene targeting. Unfortunately, attempts to establish this method in Chlamydomonas have had limited success. In this study we compared two endogenous genes, NIT1 and ARG7, and their HR/NHR ratios when different types of fragments were used as donors of homologous sequences. Transformation of the auxotrophic strain containing the inactivating point mutation arg7-8 with nonfunctional ARG7 gene fragments overlapping this mutation showed increased HR efficiencies when linearized plasmids were used. Efficiency went down rapidly with decreasing length of ARG7 homology. After identification of the inactivating 6726(G->A) point mutation in nit1-305 strains, an analogous set of experiments was performed. In the case of NIT1, overall efficiency of recombination was 10 to 100 fold lower than with ARG7. In order to better demonstrate HR we introduced three silent mutations close to the position of the point mutations in our transforming plasmids. Sequencing of transformants indicated homologous recombination over a short interval. PMID- 23792632 TI - Effects of age on lower extremity joint kinematics and kinetics during level walking with Masai barefoot technology shoes. AB - BACKGROUND: The age-associated loss of physical function engenders gait patterns which jeopardise the knee and hip to osteoarthritis. Masai Barefoot Technology (MBT) shoes have been shown to provide a facility to address specific needs for load modification in terms of musculoskeletal disease prevention in people with restricted proprioceptive or strength abilities. Therefore, a readjustment of lower extremity joint loading profiles in the elderly was hypothesised when using this type of footwear. AIM: The aim of this study was to evaluate the effects of MBT shoes on gait kinematics and kinetics in both an elderly and young cohort during walking. DESIGN: This was a cross-sectional study. SETTING: A 3 dimensional motion analysis laboratory. POPULATION: Eleven healthy elderly men and 11 healthy young men. METHODS: A conventional sport shoe served as control situation to MBT. Subjects were advised to walk eight trials per shoe at a criterion speed of 1.5 +/- 0.1 m.s(-1) in block-randomised order. Peak joint angles, moments and powers at the ankle, knee and hip were calculated through an inverse dynamic model. Data were compared by a two-way repeated measure ANOVA (alpha=0.05). RESULTS: MBT reduced external ankle joint moments and powers independent of age. At the hip, MBT footwear led to decreases in external hip flexion moments and concentric hip power output during early and late stance. Herein, no age-by-condition effects were present. Moreover, MBT reduced external knee flexion moments and concentric knee extensor powers at loading response, with the greater changes observed in the elderly. Additionally, a main effect of condition showing a general decrease in the MBT situation, but no interaction effect was noted for first peak external knee adduction moments. CONCLUSION: These results suggest that MBT shoes diminish joint loads among age groups, whereas compared to young adults, the elderly, in particular, benefited from MBT footwear with regard to relief stress on the knee joint region. CLINICAL REHABILITATION IMPACT: Based on these findings, the use of MBT shoes may attenuate the risk of developing knee and hip osteoarthritis in the elderly and may play an important role regarding pain avoidance and/or disability. PMID- 23792630 TI - Image-based analysis of lipid nanoparticle-mediated siRNA delivery, intracellular trafficking and endosomal escape. AB - Delivery of short interfering RNAs (siRNAs) remains a key challenge in the development of RNA interference (RNAi) therapeutics. A better understanding of the mechanisms of siRNA cellular uptake, intracellular transport and endosomal release could critically contribute to the improvement of delivery methods. Here we monitored the uptake of lipid nanoparticles (LNPs) loaded with traceable siRNAs in different cell types in vitro and in mouse liver by quantitative fluorescence imaging and electron microscopy. We found that LNPs enter cells by both constitutive and inducible pathways in a cell type-specific manner using clathrin-mediated endocytosis as well as macropinocytosis. By directly detecting colloidal-gold particles conjugated to siRNAs, we estimated that escape of siRNAs from endosomes into the cytosol occurs at low efficiency (1-2%) and only during a limited window of time when the LNPs reside in a specific compartment sharing early and late endosomal characteristics. Our results provide insights into LNP mediated siRNA delivery that can guide development of the next generation of delivery systems for RNAi therapeutics. PMID- 23792633 TI - Physicochemical properties and antioxidant activity of chitosan from the blowfly Chrysomya megacephala larvae. AB - In the present study, we extracted the chitosan from the larvae of blowfly Chrysomya megacephala, a new source of insect chitosan, using chemical methods. We evaluated the physical properties of the blowfly chitosan using a variety of approaches, including preliminary color-change identification, molecular weight determination, elemental analysis (EA), Fourier transform infrared spectroscopy (FTIR), solid-state (13)C cross-polarization and magic-angle-spinning nuclear magnetic resonance spectroscopy ((13)C CP/MAS NMR) and scanning electron microscopy (SEM). Its antioxidant property was examined through 2,2-diphenyl-1 picrylhydrazyl (DPPH) scavenging assays. The results showed that the molecular weight of the blowfly chitosan (501 kDa) was lower than that of the commercial chitosan (989 kDa), and its degree of deacetylation (DDA) (87.9-89.6%) was also higher than that of the commercial chitosan (83.8-85.8%). Furthermore, the blowfly chitosan exhibited excellent antioxidant activity and its IC50 value was 1.2 mg/ml. Therefore, the blowfly larvae could be a novel alternative source of chitosan and might be used as a natural antioxidant. PMID- 23792634 TI - Reply to comment on 'Temperature dependent optical properties of PbS nanocrystals'. PMID- 23792635 TI - Mesophilic anaerobic co-digestion of sewage sludge and a lixiviation of sugar beet pulp: optimisation of the semi-continuous process. AB - This study examine the effect of an increased organic loading rate on the efficiency of the stirred tank reactor treating sewage sludge and sugar beet pellets and to report on its steady-state performance. The digester was subjected to a program of steady-state operation over a range of hydraulic retention times (HRTs) of 30 to 6 days and organic loading rates (OLRs) of up to 1.7 kgCOD/m(3)d to evaluate its treatment capacity. The COD removal efficiency was found to be 84.23% COD in the digester when treating mixture sewage sludge/lixiviation of sugar beet pulp at 1.27 kgCOD/m(3)d (10-days SRT). The volumetric methane level produced in the digester reached 0.7 m(3)CH4/m(3)d and the methane yield was 0.64m(3)CH4/kgCODremoval. Therefore, anaerobic co-digestion of sewage sludge and lixiviation of sugar beet pulp improve the biogas productivity and the organic matter removal in addition to lowering solids retention times in the system. PMID- 23792636 TI - Paxillin mutations affect focal adhesions and lead to altered mitochondrial dynamics: relevance to lung cancer. AB - Cytoskeletal and focal adhesion abnormalities are observed in several types of cancer, including lung cancer. We have previously reported that paxillin (PXN) was mutated, amplified, and overexpressed in a significant number of lung cancer patient samples, that PXN protein was upregulated in more advanced stages of lung cancer compared with lower stages, and that the PXN gene was also amplified in some pre-neoplastic lung lesions. Among the mutations investigated, we previously found that PXN variant A127T in lung cancer cells enhanced cell proliferation and focal adhesion formation and colocalized with the anti-apoptotic protein B Cell Lymphoma 2 (BCL-2), which is known to localize to the mitochondria, among other sites. To further explore the effects of activating mutations of PXN on mitochondrial function, we cloned and expressed wild-type PXN and variants containing the most commonly occurring PXN mutations (P46S, P52L, G105D, A127T, P233L, T255I, D399N, E423K, P487L, and K506R) in a GFP-tagged vector using HEK 293 human embryonic kidney cells. Utilizing live-cell imaging to systematically study the effects of wild-type PXN vs. mutants, we created a model that recapitulates the salient features of the measured dynamics and conclude that compared with wild-type, some mutant clones confer enhanced focal adhesion and lamellipodia formation (A127T, P233L, and P487L) and some confer increased association with BCL-2, Dynamin-related Protein-1 (DRP-1), and Mitofusion-2 (MFN 2) proteins (P233L and D399N). Further, PXN mutants, through their interactions with BCL-2 and DRP-1, could regulate cisplatin drug resistance in human lung cancer cells. The data reported herein suggest that mutant PXN variants play a prominent role in mitochondrial dynamics with direct implications on lung cancer progression and hence, deserve further exploration as therapeutic targets. PMID- 23792637 TI - Cables1 is a tumor suppressor gene that regulates intestinal tumor progression in Apc(Min) mice. AB - The transformation of colonic mucosal epithelium to adenocarcinoma requires progressive oncogene activation and tumor suppressor gene inactivation. Loss of chromosome 18q is common in colon cancer but not in precancerous adenomas. A few candidate tumor suppressor genes have been identified in this region, including CABLES1 at 18q11.2-12.1. This study investigates the role of CABLES1 in an in vivo mouse model of intestinal adenocarcinoma and in human colon cancer cell culture. Apc(Min/+) mice were crossed with mice harboring targeted inactivation of the Cables1 gene (Cables1(-/-)). The intestinal tumor burden and tumor expression of beta-catenin and PCNA was compared in Cables1(+/+)Apc(Min/+) and Cables1(-/-)Apc(Min/+) mice. beta-catenin activity in human colon cancer cells with CABLES1 inactivation and intestinal progenitor cell function in Cables1(-/-) mice were assayed in vitro. The mean number of small intestinal tumors per mouse was 3.1 +/- 0.6 in Cables1(+/+)Apc(Min/+) mice, compared with 32.4 +/- 3.5 in the Cables1(-/-)Apc(Min/+) mice (P < 0.0001). Fewer colonic tumors were observed in Cables1(+/+)Apc(Min/+) mice (mean 0.6 +/- 0.1) compared with the Cables1(-/ )Apc(Min/+) mice (mean 1.3 +/- 0.3, P = 0.01). Tumors from Cables1(-/-)Apc(Min/+) mice demonstrated increased nuclear expression of beta-catenin and an increased number of PCNA-positive cells. In vitro studies revealed that CABLES1 deficiency increased beta-catenin dependent transcription and increased intestinal progenitor cell activity. Loss of Cables1 enhances tumor progression in the Apc(Min/+) mouse model and activates the Wnt/beta-catenin signaling pathway. Cables1 is a tumor suppressor gene on chromosome 18q in this in vivo mouse model and likely has a similar role in human colon cancer. PMID- 23792638 TI - Histone deacetylase inhibitors modulate miRNA and mRNA expression, block metaphase, and induce apoptosis in inflammatory breast cancer cells. AB - To develop new therapies for inflammatory breast cancer (IBC) we have compared the effects of two hydroxamic acid-based histone deacetylase (HDAC) inhibitors, CG-1521 and Trichostatin A (TSA) on the biology of two IBC cell lines: SUM149PT and SUM190PT. CG-1521 and TSA induce dose (0-10 uM) and time-dependent (0-96 h) increases in the proportion of cells undergoing cell cycle arrest and apoptosis in the presence or absence of 17beta-estradiol. In SUM 149PT cells, both CG-1521 and TSA increase the levels of acetylated alpha-tubulin; however the morphological effects are different: CG-1521 blocks mitotic spindle formation and prevents abscission during cytokinesis while TSA results in an increase in cell size. In SUM190PT cells CG-1521 does not cause an increase in acetylated-alpha tubulin and even though TSA significantly increases the levels of acetylated tubulin, neither inhibitor alters the morphology of the cells. Microarray analysis demonstrates that CG-1521 modulates the expression of 876 mRNAs and 63 miRNAs in SUM149PT cells, and 1227 mRNAs and 35 miRNAs in SUM190PT cells. Only 9% of the genes are commonly modulated in both cell lines, suggesting that CG-1521 and TSA target different biological processes in the two cell lines most likely though the inhibition of different HDACs in these cell lines. Gene ontology (GO) analysis reveals that CG-1521 affects the expression of mRNAs that encode proteins associated with the spindle assembly checkpoint, chromosome segregation, and microtubule-based processes in both cell lines and has cell-type specific effects on lipid biosynthesis, response to DNA damage, and cell death. PMID- 23792639 TI - In vitro targeting of Polo-like kinase 1 in bladder carcinoma: comparative effects of four potent inhibitors. AB - Despite the improvements in neoadjuvant chemotherapy, the outcome of patients with advanced bladder cancer has changed very little over the past 30 years. In the present study we tested and compared the in vitro antitumor activities of four different inhibitors of Polo-like kinase 1 (PLK1) (BI 2536, BI 6727, GW843682X, and GSK461364), against 3 bladder carcinoma cell lines RT4, 5637 and T24. The impact on radiosensitivity and drug interactions in simultaneous treatments with cisplatin, methotrexate, and doxorubicin were also investigated. Our results showed that PLK1 inhibition prevented cell proliferation and clonogenicity, causing significant inhibition of invasion of tumor cells, though modest differences were observed between drugs. Moreover, all PLK1 inhibitors induced G 2/M arrest, with the subsequent induction of death in all 3 cell lines. Drug interactions studies showed auspicious results for all PLK1 inhibitors when combined with the commonly used cisplatin and methotrexate, though combinations with doxorubicin showed mostly antagonistic effects. Comparably, the four PLK1 inhibitors efficiently sensitized cells to ionizing radiation. Our findings demonstrate that irrespective of the inhibitor used, the pharmacological inhibition of PLK1 constrains bladder cancer growth and dissemination, providing new opportunities for future therapeutic intervention. However, further laboratorial and pre-clinical tests are still needed to corroborate the usefulness of using them in combination with other commonly used chemotherapeutic drugs. PMID- 23792640 TI - Exposure to estrogen and ionizing radiation causes epigenetic dysregulation, activation of mitogen-activated protein kinase pathways, and genome instability in the mammary gland of ACI rats. AB - The impact of environmental mutagens and carcinogens on the mammary gland has recently received a lot of attention. Among the most generally accepted carcinogenic agents identified as factors that may increase breast cancer incidence are ionizing radiation and elevated estrogen levels. However, the molecular mechanisms of mammary gland aberrations associated with radiation and estrogen exposure still need to be further elucidated, especially the interplay between elevated hormone levels and radiation. Therefore, in the present study, we investigated molecular changes induced in rat mammary gland tissue by estrogen, ionizing radiation, and the combined action of these two carcinogens using a well-established ACI rat model. We found that continuous exposure of intact female ACI rats to elevated levels of estrogen or to both estrogen and radiation resulted in significant hyperproliferative changes in rat mammary glands. In contrast, radiation exposure alone did not induce hyperplasia. Interestingly, despite the obvious disparity in mammary gland morphology, we did not detect significant differences in the levels of genomic methylation among animals exposed to estrogen, radiation, or both agents together. Specifically, we observed a significant global genomic hypomethylation at 6 weeks of exposure. However, by 12 and 18 weeks, the levels of global DNA methylation returned to those of age-matched controls. We also found that combined exposure to radiation and estrogen significantly altered the levels of histone H3 and H4 methylation and acetylation. Most importantly, we for the first time demonstrated that estrogen and radiation exposure caused a significant induction of p42/44 MAPK and p38 pathways that was paralleled by elevated levels of H3S10 phosphorylation, a well-established biomarker of genome and chromosome instability. The precise role of MAPK pathways and their inter-relationship with H3S10 phosphorylation and genome instability in mammary gland tissues needs to be explored further. PMID- 23792641 TI - Phase 2 trial of erlotinib with or without PF-3512676 (CPG 7909, a Toll-like receptor 9 agonist) in patients with advanced recurrent EGFR-positive non-small cell lung cancer. AB - This phase 2 study assessed PF-3512676 plus erlotinib in patients with epidermal growth factor receptor-positive advanced non-small cell lung cancer after prior chemotherapy failure. Patients were randomized 1:1 to PF-3512676 (0.20 mg/kg injected subcutaneously once weekly) plus erlotinib (150 mg daily) or erlotinib alone. The primary objective was to estimate progression-free survival (PFS). Patients received PF-3512676 plus erlotinib (n = 18) or erlotinib alone (n = 21). The study was halted because an unplanned interim analysis indicated that large improvement in PFS with addition of PF-3512676 would be unlikely. In the PF 3512676-plus-erlotinib and erlotinib-alone arms, median PFS was 1.6 and 1.7 mo (hazard ratio, 1.00; 95% confidence interval, 0.5-2.0; P = 0.9335), respectively. Salient grade >= 3 adverse events in PF-3512676-plus-erlotinib and erlotinib alone arms were diarrhea (5/0), dyspnea (5/6), fatigue (4/1), other flu-like symptoms (2/0), anemia (2/1), and lymphocytopenia (based on laboratory values, 1/4). Adding PF-3512676 to erlotinib did not show potential for increased progression-free survival over erlotinib alone in patients with advanced recurrent epidermal growth factor receptor-positive non-small cell lung cancer. PMID- 23792642 TI - microRNA-17 regulates the expression of ATG7 and modulates the autophagy process, improving the sensitivity to temozolomide and low-dose ionizing radiation treatments in human glioblastoma cells. AB - ATG7 is a key autophagy-promoting gene that plays a critical role in the regulation of cell death and survival of various cell types. We report here that microRNAs (miRNAs), a class of endogenous 22-24 nucleotide noncoding RNA molecules able to affect stability and translation of mRNA, may represent a novel mechanism for regulating ATG7 expression and therefore autophagy. We demonstrated that ATG7 is a potential target for miR-17, and this miRNA could negatively regulate ATG7 expression, resulting in a modulation of the autophagic status in T98G glioblastoma cells. Treatment of these tumor cells with the miR-17 mimic decreased, and with the antagomir increased, the expression of ATG7 protein. Dual luciferase reporter assay confirmed that a specific miR-17 binding sequence in the 3'-UTR of ATG7 contributed to the modulation of the expression of the gene by miR-17. Interestingly, our results showed that anti-miR-17 administration activated autophagy through autophagosome formation, as resulted by LC3B and ATG7 protein expression increase, and by the analysis of GFP-LC3 positive autophagosome vesicles in living cells. Furthermore, the autophagy activation by anti-miR-17 resulted in a decrease of the threshold resistance at temozolomide doses in T98G cells, while miR-17 modulation in U373-MG glioblastoma cells resulted in a sensitization to low ionizing radiation doses. Our study of the role of miR-17 in regulating ATG7 expression and autophagy reveals a novel function for this miRNA sequence in a critical cellular event with significant impacts in cancer development, progression and treatment. PMID- 23792643 TI - Identification of repurposed small molecule drugs for chordoma therapy. AB - Chordoma is a rare, slow growing malignant tumor arising from remnants of the fetal notochord. Surgery is the first choice for chordoma treatment, followed by radiotherapy, although postoperative complications remain significant. Recurrence of the disease occurs frequently due to the anatomy of the tumor location and violation of the tumor margins at the initial surgery. Currently, there are no effective drugs available for patients with chordoma. Due to the rarity of the disease, there is limited opportunity to test agents in clinical trials and no concerted effort to develop agents for chordoma in the pharmaceutical industry. To rapidly and efficiently identify small molecules that inhibit chordoma cell growth, we screened the NCGC Pharmaceutical Collection (NPC) containing approximately 2800 clinically approved and investigational drugs at 15 different concentrations in chordoma cell lines, U-CH1 and U-CH2. We identified a group of drugs including bortezomib, 17-AAG, digitoxin, staurosporine, digoxin, rubitecan, and trimetrexate that inhibited chordoma cell growth, with potencies from 10 to 370 nM in U-CH1 cells, but less potently in U-CH2 cells. Most of these drugs also induced caspase 3/7 activity with a similar rank order as the cytotoxic effect on U-CH1 cells. Cantharidin, digoxin, digitoxin, staurosporine, and bortezomib showed similar inhibitory effect on cell lines and 3 primary chordoma cell cultures. The combination treatment of bortezomib with topoisomerase I and II inhibitors increased the therapeutic potency in U-CH2 and patient-derived primary cultures. Our results provide information useful for repurposing currently approved drugs for chordoma and potential approach of combination therapy. PMID- 23792644 TI - Level of Notch activation determines the effect on growth and stem cell-like features in glioblastoma multiforme neurosphere cultures. AB - BACKGROUND: Brain cancer stem-like cells (bCSC) are cancer cells with neural stem cell (NSC)-like properties found in glioblastoma multiforme (GBM) and they are assigned a central role in tumor initiation, progression and relapse. The Notch pathway is important for maintenance and cell fate decisions in the normal NSC population. Notch signaling is often deregulated in GBM and recent results suggest that this pathway plays a significant role in bCSC as well. We therefore wished to further elucidate the role of Notch activation in GBM-derived bCSC. METHODS: Human-derived GBM xenograft cells were cultured as NSC-like neurosphere cultures. Notch modulation was accomplished either by blocking the pathway using the gamma-secretase inhibitor DAPT or by activating it by transfecting the cells with the constitutive active Notch-1 receptor. RESULTS: GBM neurosphere cultures with high endogenous Notch activation displayed sensitivity toward Notch inhibition with regard to tumorigenic features as demonstrated by increased G0/G1 population and reduced colony formation capacity. Of the NSC-like characteristics, only the primary sphere forming potential was affected, while no effect was observed on self-renewal or differentiation. In contrast, when Notch signaling was activated a decrease in the G0/G1 population and an enhanced capability of colony formation was observed, along with increased self-renewal and de-differentiation. CONCLUSION: Based on the presented results we propose that active Notch signaling plays a role for cell growth and stem cell-like features in GBM neurosphere cultures and that Notch-targeted anti-bCSC treatment could be feasible for GBM patients with high endogenous Notch pathway activation. PMID- 23792645 TI - Non-hepatic tumors change the activity of genes encoding copper trafficking proteins in the liver. AB - To assess the statistical relationship between tumor growth and copper metabolism, we performed a metaanalysis of studies in which patients with neoplasms were characterized according to any of the copper status indexes (atomic copper serum concentration, serum oxidase activity, ceruloplasmin protein content). Our metaanalysis shows that in the majority of cases (more than 3100 patients), tumor growth positively correlates with the copper status indexes. Nude athymic CD-1 nu/nu mice with subcutaneous tumors of human origin, C57Bl/6J mice with murine melanoma and Apc(Min) mice with spontaneously developing adenomas throughout the intestinal tract were studied to experimentally determine the relationship between tumor progression, liver copper metabolism, and copper status indexes. We showed that the copper status indexes increased significantly during tumor growth. In the liver tissue of tumor-bearing mice, ceruloplasmin gene expression, as well as the expression of genes related to ceruloplasmin metallation (CTR1 and ATP7B), increased significantly. Moreover, the presence of an mRNA splice variant encoding a form of ceruloplasmin anchored to the plasma membrane by glycosylphosphatidyl inositol, which is atypical for hepatocytes, was also detected. The ATP7A copper transporter gene, which is normally expressed in the liver only during embryonic copper metabolism, was also activated. Depletion of holo-ceruloplasmin resulted in retardation of human HCT116 colon carcinoma cell growth in nude mice and induced DNA fragmentation in tumor cells. In addition, the concentration of cytochrome c increased significantly in the cytosol, while decreasing in the mitochondria. We discuss a possible trans-effect of developing tumors on copper metabolism in the liver. PMID- 23792646 TI - Bimodal role of Kupffer cells during colorectal cancer liver metastasis. AB - Kupffer cells (KCs) are resident liver macrophages that play a crucial role in liver homeostasis and in the pathogenesis of liver disease. Evidence suggests KCs have both stimulatory and inhibitory functions during tumor development but the extent of these functions remains to be defined. Using KC depletion studies in an orthotopic murine model of colorectal cancer (CRC) liver metastases we demonstrated the bimodal role of KCs in determining tumor growth. KC depletion with gadolinium chloride before tumor induction was associated with an increased tumor burden during the exponential growth phase. In contrast, KC depletion at the late stage of tumor growth (day 18) decreased liver tumor load compared with non-depleted animals. This suggests KCs exhibit an early inhibitory and a later stimulatory effect. These two opposing functions were associated with changes in iNOS and VEGF expression as well as T-cell infiltration. KC depletion at day 18 increased numbers of CD3 (+) T cells and iNOS-expressing infiltrating cells in the tumor, but decreased the number of VEGF-expressing infiltrating cells. These alterations may be responsible for the observed reduction in tumor burden following depletion of pro-tumor KCs at the late stage of metastatic growth. Taken together, our results indicate that the bimodal role of KC activity in liver tumors may provide the key to timing immunomodulatory intervention for the treatment of CRC liver metastases. PMID- 23792647 TI - A CDK4/6 inhibitor enhances cytotoxicity of paclitaxel in lung adenocarcinoma cells harboring mutant KRAS as well as wild-type KRAS. AB - The KRAS gain-of-function mutation confers intrinsic resistance to targeted anti cancer drugs and cytotoxic chemotherapeutic agents, ultimately leading to treatment failure. KRAS mutation frequency in lung adenocarcinoma is ~15-30%. Novel therapeutic strategies should be developed to improve clinical outcomes in these cases. Deregulation of the p16/cyclin-dependent kinase (CDK) 4/retinoblastoma (Rb) pathway is frequently observed in various cancers and it represents an attractive therapeutic target. We compared the anti-tumor efficacy of genetically knocked-down CDK4 and a pharmacological inhibitor of CDK4/6, CINK4, in KRAS mutation-positive lung adenocarcinoma cells. We also investigated changes in anti-proliferative activity and downstream molecules with these treatments in combination with paclitaxel. CDK4 short interfering RNA (siRNA) significantly increased paclitaxel sensitivity in KRAS mutation-positive H23 cells. CINK4 demonstrated concentration- and time-dependent anti-proliferative activity in 5 adenocarcinoma lines. CINK4 induced G 1 arrest by downregulating the p16/cyclin D1/Rb pathway, resulting in apoptotic induction via increased expression of cleaved caspase3, cleaved PARP and Bax. Combined CINK4 and paclitaxel produced synergistic anti-proliferative activity and increased apoptosis through reduced cyclin D1 and Bcl-2 in KRAS mutation-positive cancer cells. These data suggest CDK4 is a promising target for development of anti cancer drugs and CINK4 combined with paclitaxel may be an effective therapeutic strategy for enhancing anti-tumor efficacy in KRAS mutation-positive lung adenocarcinoma. PMID- 23792649 TI - Comparison of pharmacokinetics and pathology for low-dose tacrolimus once-daily and twice-daily in living kidney transplantation: prospective trial in once-daily versus twice-daily tacrolimus. AB - BACKGROUND: A prolonged-release formulation of tacrolimus (Tacrolimus QD) was developed to allow once-daily dosing and to have similar safety and efficacy profiles to twice-daily tacrolimus (Tacrolimus BID). This study compared the pharmacokinetics (PK) and renal pathology by protocol biopsy in de novo living kidney transplant recipients treated with either low-dose Tacrolimus QD or Tacrolimus BID. METHODS: Between November 2009 and January 2011, 102 consecutive adult patients were randomized to receive either low-dose Tacrolimus QD or Tacrolimus BID. All patients underwent PK study and protocol biopsy on postoperative day 14. Additional protocol biopsies were performed between 6 and 12 months after renal transplantation. RESULTS: During the 1-year follow up, the incidence of biopsy-proven acute rejection and toxic tubulopathy was low and similar in both groups. Twenty-four hours area under the curve (AUC0-24) was not different in both groups (285 +/- 78.7 and 281 +/- 62.4 ng hr/mL in Tacrolimus QD and Tacrolimus BID, respectively). C0 was well correlated with AUC0-24 in both groups and AUC0-24 between 260 and 280 in the Tacrolimus QD group was achieved by 6 to 8 ng/mL of C0. Acute nephrotoxicity was less than 10% in both groups without any clinical manifestation. CONCLUSION: Clinical efficacy, safety, and PK profile of Tacrolimus QD is same as those of Tacrolimus BID. PMID- 23792648 TI - Effect of doxorubicin, oxaliplatin, and methotrexate administration on the transcriptional activity of BCL-2 family gene members in stomach cancer cells. AB - Defective apoptosis comprises the main reason for tumor aggressiveness and chemotherapy tolerance in solid neoplasias. Among the BCL-2 family members, whose mRNA or protein expression varies considerably in different human malignancies, BCL2L12 is the one for which we have recently shown its propitious prognostic value in gastric cancer. The purpose of the current work was to investigate the expression behavior of BCL2L12, BAX, and BCL-2 in human stomach adenocarcinoma cells following their exposure to anti-tumor substances. The 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide and trypan blue methods assessed the impact of doxorubicin, oxaliplatin and methotrexate on AGS cells' viability and growth. Following isolation from cells, total RNA was reverse-transcribed to cDNA. Quantification of target genes' expression was performed with real-time PCR using SYBR Green detection system. The relative changes in their mRNA levels between drug-exposed and untreated cells were calculated with the comparative Ct method (2(-ddCt)). All three drugs, as a result of their administration to AGS cancer cells for particular time intervals, provoked substantial fluctuations in the transcriptional levels of the apoptosis-related genes studied. While BAX was principally upregulated, striking similar were the notable changes regarding BCL 2 and BCL2L12 expression in our cellular system. Our findings indicate the growth suppressive effects of doxorubicin, oxaliplatin and methotrexate treatment on stomach carcinoma cells and the implication of BCL2L12, BAX, and BCL-2 expression profiles in the molecular signaling pathways triggered by chemotherapy. PMID- 23792650 TI - Synthesis of heterogeneous enzyme-metal nanoparticle biohybrids in aqueous media and their applications in C-C bond formation and tandem catalysis. AB - The straightforward synthesis of novel enzyme-metalNP nanobiohybrids in aqueous medium was developed. These new nanobiohybrids were excellent multivalent catalysts combining both activities in various sets of synthetic reactions even at ultra-low concentrations (ppb amount). PMID- 23792651 TI - Exploiting design freedom in biaxial dielectrics to enable spatially overlapping optical instruments. AB - The optical behavior of gradient biaxial dielectrics has not been widely explored in the literature due to their complicated nature, but the extra degrees of freedom in the index tensor have the potential of yielding useful optical instruments which are otherwise unachievable. In this work, a design method is described in detail which allows one to combine the behavior of up to four totally independent isotropic optical instruments in an overlapping region of space. This is non-trivial because of the mixing of the index tensor elements in the Hamiltonians; previously known methods only handled uniaxial dielectrics (where only two independent isotropic optical functions could overlap). The biaxial method introduced also allows three-dimensional multi-faced Janus devices to be designed; these are worked out in an example of what is possible to design with the method. PMID- 23792652 TI - Donor site morbidity associated with autogenous bone harvesting from the ascending mandibular ramus. AB - PURPOSE: The objective of the present retrospective study was to assess long-term morbidity and postoperative complications after autogenous bone harvesting from the ascending mandibular ramus. MATERIALS AND METHODS: Bone harvesting from the ascending mandibular ramus was conducted in a consecutive case series, including 325 patients, at The Department of Oral and Maxillofacial Surgery, Aalborg University Hospital, Denmark from January 1, 2000 to December 31, 2010. Records and radiographs were retrospectively analyzed. RESULTS: Temporary neurosensory disturbances in the inferior alveolar nerve were found in 6.1% of the patients. Only 0.5% of the patients had permanent neurosensory disturbances. Severe hematoma occurred in 20 patients, while infection occurred in only 1 patient. CONCLUSIONS: Within the limitations of a retrospective case series study, the present study suggests that harvesting of autogenous bone from the ascending mandibular ramus is a safe surgical procedure with minimal donor site morbidity and few postoperative complications. PMID- 23792653 TI - Synthesis of mesoporous multiwall ZnO nanotubes by replicating silk and application for enzymatic biosensor. AB - A facial biotemplate-directed synthetic route for fabricating mesoporous multiwall ZnO nanotubes (ZnO-MMNTs) was proposed. Owing to the mesoporous multiwall based matrix, one dimensional (1D) tubes based channels and high isoelectric point (IEP), the prepared ZnO-MMNTs are wonderful platform to immobilize glucose oxidase (GOx) for glucose biosensing. Scale-adaptive cells are constructed to hold enzymes molecules, maintain enzymatic activity and keep stability. The prepared enzymatic electrode (chitosan/GOx/ZnO/Au) exhibits high sensitivity (47.2 MUA mM(-1)cm(-2)), very fast response (<2s), quite low KM(app) (1.09 mM), excellent selectivity and stability. Therefore, ZnO-MMNTs are promising material for enzyme assembly and other biological applications. PMID- 23792654 TI - Polyamidoamine dendrimers-capped carbon dots/Au nanocrystal nanocomposites and its application for electrochemical immunosensor. AB - In this work, polyamidoamine dendrimers capped-carbon dots (PAMAM-CDs) were fabricated by one-step microwave assisted pyrolysis of citric acid (CA) and PAMAM, where the formation of CDs and the surface passivation were accomplished simultaneously. The obtained graphitic PAMAM-CDs, with abundant amine groups, were employed as reducing and capping agents for the formation of PAMAM-CDs/Au nanocrystal nanocomposites. The resulting nanocomposites exhibited excellent conductivity, stability and biocompatibility on the surface of electrode and were designed as an immobilized matrix for sensitive immunosensing of alpha fetoprotein (AFP). The proposed immunosensor showed a wide linear detection range from 100 fg mL(-1) to 100 ng mL(-1). The detection limit for AFP was 0.025 pg mL( 1). Importantly, the immunosensor was evaluated for the analysis of clinical serum samples, obtaining a good correlation with enzyme-linked immunosorbent assay (ELISA). The results indicated that the immunosensor provided a possible application for the detection of AFP in clinical diagnosis. PMID- 23792655 TI - Antigen-loaded nanocarriers enhance the migration of stimulated Langerhans cells to draining lymph nodes and induce effective transcutaneous immunization. AB - This study aims to investigate the efficacy of chitosan nanoparticles (CS-NPs) as a vehicle for transcutaneous antigen delivery in anti-tumor therapy. Ovalbumin (OVA) or gp100 (melanocyte-associated antigen gp100 protein)-loaded CS-sodium tripolyphosphate (TPP)-grafted NPs were prepared by crosslinking low-molecular weight CS with TPP. Compared with the FITC-OVA solution, the encapsulated fluorescein isothiocyanate (FITC)-OVA-loaded NPs expressed much stronger cellular uptake ability in vitro and higher ability to migrate to lymph nodes in vivo. After transcutaneous administration, OVA-loaded NPs, with imiquimod as an adjuvant, increased the anti-OVA immunoglobulin G titer to levels similar to those induced by the OVA solution. The gp100-loaded NPs promoted the survival of tumor-bearing mice. These results provided evidence of CS-NPs as promising carriers for transcutaneous vaccine delivery, partly contributing to the increased uptake of NPs by skin antigen-presenting cells as well as their enhanced migration to the surrounding lymph nodes. FROM THE CLINICAL EDITOR: In this study the efficacy of chitosan nanoparticle based vehicles for transcutaneous antigen delivery is investigated in anti-tumor therapy. Authors demonstrate that such nanoparticles may be efficient carriers partly due to their increased uptake by antigen-presenting cells in the skin and their enhanced migration to surrounding lymph nodes. PMID- 23792656 TI - Simultaneous removal of organic matter and nitrogen by a heterotrophic nitrifying aerobic denitrifying bacterial strain in a membrane bioreactor. AB - A heterotrophic nitrifying-aerobic denitrifying bacterial strain, Bacillus methylotrophicus L7, was inoculated solely into a submerged membrane bioreactor (MBR) for continuous treatment of artificial sewage. The running conditions were also optimized for improvement of the treatment efficiency. The results indicated that inoculation of this single strain in a single reactor under constant aerobic conditions resulted in simultaneous removal of organic matter and nitrogen, in striking contrast to traditional aerobic nitrification-anaerobic denitrification treatment system and the sequencing batch reactor (SBR) systems. The optimal running conditions for the MBR were dissolved oxygen (DO) 4.5 mg/L, pH 7.5, loading ammonia <100 mg/L, and C/N ratio 3.5. Under these conditions, the removal percentages of chemical oxygen demand (COD), NH4(+)-N, and TN as high as 96%, 77.5% and 53%, respectively, were achieved without nitrite accumulation. PMID- 23792657 TI - Use of image analysis tool for the development of light distribution pattern inside the photobioreactor for the algal cultivation. AB - Light is one of the important parameters for the growth of photosynthetic microorganisms. In algal photobioreactors, pigmentation of algal cells has additional shading effect which reduces light penetration. Information on the local light intensity inside the photobioreactor is helpful for its efficient designs. Image analysis is based on trichromatic theory and it is used as a tool in studying the light distribution. Digital images of the top view of the photobioreactor were taken and processed using image processing tool in the MATLAB software. This was used to estimate the light intensity distribution in the externally radiating stirred tank photobioreactor across the radial path length. In addition, the effect of light tubes arrangement was studied. This was to find out the effect of light distribution along the periphery of culture suspension. Modified Beer-Lambert's law was found to fit the generated light intensity profile at various cell concentrations and light intensity. PMID- 23792658 TI - Reduced temperature hydrolysis at 134 degrees C before thermophilic anaerobic digestion of waste activated sludge at increasing organic load. AB - The performance of thermophilic digestion of waste activated sludge, either untreated or thermal pretreated, was evaluated through semi-continuous tests carried out at organic loading rates in the range of 1-3.7 kg VS/m(3)d. Although the thermal pretreatment at T=134 degrees C proved to be effective in solubilizing organic matter, no significant gain in organics degradation was observed. However, the digestion of pretreated sludge showed significant soluble COD removal (more than 55%) whereas no removal occurred in control reactors. The lower the initial sludge biodegradability, the higher the efficiency of thermal pretreated digestion was observed, in particular as regards higher biogas and methane production rates with respect to the parallel untreated sludge digestion. Heat balance of the combined thermal hydrolysis/thermophilic digestion process, applied on full-scale scenarios, showed positive values for direct combustion of methane. In case of combined heat and power generation, attractive electric energy recoveries were obtained, with a positive heat balance at high load. PMID- 23792659 TI - Evaluation of integrated anaerobic-aerobic biofilm reactor for degradation of azo dye methyl orange. AB - This study was to investigate the mineralization of wastewater containing methyl orange (MO) in integrated anaerobic-aerobic biofilm reactor with coconut fiber as bio-material. Different aeration periods (3h in phase 1 and 2; 3, 6 and 15 h in phase 3; 24 h in phase 4 and 5) in aerobic chamber were studied with different MO concentration 50, 100, 200, 200 and 300 mg/L as influent from phase 1-5. The color removals estimated from the standard curve of dye versus optical density at its maximum absorption wavelength were 97%, 96%, 97%, 97%, and 96% and COD removals were 75%, 72%, 63%, 81%, and 73% in phase 1-5, respectively. The MO decolorization and COD degradation followed first-order kinetic model and second order kinetic model, respectively. GC-MS analysis indicated the symmetrical cleavage of azo bond and the reduction in aromatic peak ensured the partial mineralization of MO. PMID- 23792660 TI - Simultaneous saccharification and co-fermentation of un-detoxified rice hull hydrolysate by Saccharomyces cerevisiae ICV D254 and Spathaspora arborariae NRRL Y-48658 for the production of ethanol and xylitol. AB - Co-fermentation and simultaneous saccharification of rice hull hydrolysate (RHH) were investigated for the production of ethanol and xylitol by Saccharomyces cerevisiae, Spathaspora arborariae, or the combination of both. In bioreactor cultures under oxygen limitation, S. cerevisiae was capable of metabolizing glucose from RHH, which contained small amounts of acetic acid, furfural, and hydroxymethylfurfural, achieving ethanol yields of 0.45 and concentrations of 10.5 g L(-1). In the co-culture of S. cerevisiae and S. arborariae pentoses and hexoses from RHH, were converted to ethanol and xylitol, with yields of 0.48 and 0.39, and concentrations of 11 g L(-1) and 3 g L(-1), respectively. The simultaneous saccharification and co-fermentation using both yeasts produced ethanol and xylitol to final concentrations of 14.5 g L(-1) and 3 g L(-1), respectively. Results showed good prospects to use co-cultures of S. cerevisiae and S. arborariae for the bioconversion of RHH into ethanol and xylitol without further detoxification. PMID- 23792661 TI - Optimizing the thermophilic hydrolysis of grass silage in a two-phase anaerobic digestion system. AB - Thermophilic hydrolysis of grass silage (GS) at 55 degrees C with organic loading rates (OLRs) of 6.5, 5, 2.5 and 1.0 kg VS m(-3) days(-1) and hydraulic retention times (HRT) of 10, 6, 4 and 2 days were evaluated in 12 glass bioreactors side by side. The hydrolytic process was measured by variation in pH, volatile solids (VS), VS destruction, soluble chemical oxygen demand (sCOD), hydrolysis and acidification yields. Biological methane potential (BMP) assays were carried out to measure the upper limit for methane production of grass silage with different hydrolytic pretreatments at mesophilic temperature (37 degrees C). The optimum methane yield of 368 LN CH4 kg(-1) VS was obtained at an OLR of 1 kg VS m(-3)days(-1) and a HRT of 4 days, showing an increase of 30% in the methane potential in comparison to non-hydrolysed GS. PMID- 23792662 TI - A one-pot glycerol-based additive-blended ethyl biodiesel production: a green process. AB - N-methyl-2-pyrrolidonium methyl sulfonate, a Bronsted acid ionic liquid, promoted the transesterification of soybean oil with ethanol giving a high quality fatty acid ethyl ester. At the end of the reaction, after distillation of excess of ethanol, spontaneous phase separation took place. While the clear upper phase corresponded to the ethyl ester, the lower phase was composed of a mixture of glycerol byproduct and the catalyst. By addition of a stoichiometric amount of appropriated reagents to the resulting mixture, a new ionic liquid-catalyzed process allows the conversion of the glycerol into less polar derivatives, and consequent migration to the ethyl esters phase. This work demonstrated that emulsion, phase separation and contamination problems were completely avoided and the glycerol could be incorporated into the biodiesel as additives in a single step. The whole process involves two renewable starting materials, ethanol and vegetable oil, allowing a total green additive-blended biodiesel production process. PMID- 23792663 TI - Short mechanical biological treatment of municipal solid waste allows landfill impact reduction saving waste energy content. AB - The aim of this work was to evaluate the effects of full scale MBT process (28 d) in removing inhibition condition for successive biogas (ABP) production in landfill and in reducing total waste impact. For this purpose the organic fraction of MSW was treated in a full-scale MBT plant and successively incubated vs. untreated waste, in simulated landfills for one year. Results showed that untreated landfilled-waste gave a total ABP reduction that was null. On the contrary MBT process reduced ABP of 44%, but successive incubation for one year in landfill gave a total ABP reduction of 86%. This ABP reduction corresponded to a MBT process of 22 weeks length, according to the predictive regression developed for ABP reduction vs. MBT-time. Therefore short MBT allowed reducing landfill impact, preserving energy content (ABP) to be produced successively by bioreactor technology since pre-treatment avoided process inhibition because of partial waste biostabilization. PMID- 23792664 TI - Hydrothermal carbonization: process water characterization and effects of water recirculation. AB - Poplar wood chips were treated hydrothermally and the increase of process efficiency by water recirculation was examined. About 15% of the carbon in the biomass was dissolved in the liquid phase when biomass was treated in de-ionized water at 220 degrees C for 4 h. The dissolved organic matter contained oxygen and was partly aerobically biodegradable. About 30-50% of the total organic carbon originated from organic acids. A polar and aromatic fraction was extracted and a major portion of the organic load was of higher molecular weight. By process water recirculation organic acids in the liquid phase concentrated and catalyzed dehydration reactions. As a consequence, functional groups in hydrothermally synthesized coal declined and dewaterability was enhanced. Recirculated reactive substances polymerized and formed additional solid substance. As a result, carbon and energetic yields of the produced coal rose to 84% and 82%, respectively. PMID- 23792665 TI - Oxalate degradation in a bioelectrochemical system: reactor performance and microbial community characterization. AB - The aim of this work was to investigate the feasibility of using oxalate at the anode in a continuous reactor. Complete oxalate removal was observed, albeit at a maximum coulombic efficiency of 33.9+/-0.4%. At the cathode side, there was an increase in pH from 8 to 11 showing production of caustic. Analysis of the microbial community demonstrated a clear shift during reactor start-up, resulting in enrichment of microorganisms belonging to Bacteroidetes, Firmicutes, Mollicutes, and beta and gamma-Proteobacteria. Methane was produced throughout the experiment; Archaea belonging to the Methanosarcinacea, Methanomicrobiaceae and Methanosaetaceae were identified as key representatives. PMID- 23792666 TI - Visual unimodal grouping mediates auditory attentional bias in visuo-spatial working memory. AB - Audiovisual links in spatial attention have been reported in many previous studies. However, the effectiveness of auditory spatial cues in biasing the information encoding into visuo-spatial working memory (VSWM) is still relatively unknown. In this study, we addressed this issue by combining a cuing paradigm with a change detection task in VSWM. Moreover, we manipulated the perceptual organization of the to-be-remembered visual stimuli. We hypothesized that the auditory effect on VSWM would depend on the perceptual association between the auditory cue and the visual probe. Results showed, for the first time, a significant auditory attentional bias in VSWM. However, the effect was observed only when the to-be-remembered visual stimuli were organized in two distinctive visual objects. We propose that these results shed new light on audio-visual crossmodal links in spatial attention suggesting that, apart from the spatio temporal contingency, the likelihood of perceptual association between the auditory cue and the visual target can have a large impact on crossmodal attentional biases. PMID- 23792667 TI - Attentional resource allocation during a cued saccade task. AB - Attentional selection of sensory information and motor output is critical for successful interaction with one's surroundings. However, organization of attentional processes involved in selection of salient visual information, decision making, and movement planning has not yet been fully elucidated. We hypothesized that attentional processes involved in these tasks can function independently and draw from separate resources. If true, challenging the capacity limit of one attentional process would not affect performance of others. Healthy participants performed a cued saccade task in which target cues were embedded in a central stream of letters in a Rapid Serial Visual Presentation (RSVP). Participants performed saccades as quickly and as accurately as possible to a peripheral target location based on cue presentation within the central letter stream. To challenge visual attention, we parametrically varied the duration at which each letter of the RSVP was presented (50-200ms). In a separate experiment we challenged motor attention by increasing the number of possible saccade trajectories (1-6 peripheral targets). As expected, increasing attentional load in one domain of the task negatively affected performance in that domain, while performance in other domains was unaffected. We interpret our results as support for the independent allocation of attentional resources, at least in the early stages of processing, required across components of a cued saccade task. Deciphering the contributions of attention during visuomotor tasks is a critical step to understanding how humans process information necessary to successfully interact with the environment. PMID- 23792668 TI - The middle of the road: perceiving intermediates. AB - This article aims to study the extension and immediacy of the perception of intermediates during the observation of images showing a variation in a spatial property from one extreme (e.g. at the top of a mountain) to the opposite extreme (e.g. at the bottom of a mountain). Three experiments were carried out: rating tasks were used in studies 1 and 3 and a classification task in study 2. Three main results emerged. The first result (concerning extension) is that people consistently recognize some instances of a dimension as intermediates (neither a... nor b) rather than as one or the other opposite pole (a, b). The number of these cases ranges from one to most of the experiences in between the two extremes, depending on the type of opposite considered. The second result (concerning immediacy) is that recognizing and rating intermediates did not take longer in most cases than recognizing and rating the two poles. The third result (concerning task influence) is that there were differences due to the type of task, i.e. rating and classification. The implications of these results are discussed within the framework of theories grounding cognition in perception. PMID- 23792669 TI - The effects of advice and "try more" instructions on improving realism of confidence. AB - This study investigated whether participants can improve the accuracy of their confidence judgments by making second-order judgments, and whether advice (attend both to correct and incorrect items and consider the remember/know quality of the item), and "try more" instructions can help increase participants' accuracy. The participants (n=220) made confidence judgments of their answers to 50 recall questions on a video clip. Next, all the participants were asked to try to increase the accuracy of their confidence judgments by modifying those they believed showed poor realism. Although the participants did increase the accuracy of their confidence judgments, neither the advice nor the "try more" instructions improved their accuracy. PMID- 23792670 TI - Viral hepatitis and HIV: update and management. AB - HCV-related liver disease is an important contributor to morbidity and mortality in the HIV-infected population. Successful treatment of HIV-HCV-coinfected patients is followed by favourable clinical outcomes. While the combination of pegylated interferon and ribavirin remains the mainstay in the treatment of non-1 HCV genotypes, the first generation of HCV protease inhibitors are being incorporated into existing HCV genotype-1 (HCV-1) treatment protocols. Although data are limited, the triple combination does improve the sustained virological response in HIV-HCV-1-coinfected subjects. However, with still very limited data in this setting, clinical decisions for triple therapy have to be individualized and made based on multiple considerations. Chronic HBV infection increases mortality in HIV-infected subjects. In the treatment of HIV-HBV coinfection, it is very important to coordinate HBV and HIV therapies. HBV-active HAART improves the outcome of patients with HIV-HBV coinfection and tenofovir has become a key component of the treatment for these patients, although a number of clinical situations require a case-by-case approach. PMID- 23792671 TI - Comparative study of deoxynivalenol, 3-acetyldeoxynivalenol, and 15 acetyldeoxynivalenol on intestinal transport and IL-8 secretion in the human cell line Caco-2. AB - The effects of the trichothecene mycotoxin deoxynivalenol (DON) and its acetylated derivatives, 3-acetyldeoxynivalenol (3ADON) and 15 acetyldeoxynivalenol (15ADON) on human intestinal cell Caco-2 were investigated by the studies of transepithelial transport, gene expression, and cytokine secretion. Permeability across a Caco-2 cell monolayer was evaluated by transport study. Transport rates were ranked as DON, 3ADON<15ADON in apical-basolateral direction. 15ADON showed the highest permeability, induced the highest decrease in transepithelial electrical resistance (TEER), and prompted significant Lucifer Yellow permeability. These results showed that 15ADON affect paracellular barrier function extremely. In addition, gene expressions induced by toxins were screened by DNA microarray for investigating cellular effect on Caco-2 cell. The most remarkable gene induced by DON and 15ADON was inflammatory chemokine IL-8 and thus mRNA expression and secretion of IL-8 were analyzed by PCR and ELISA. Both DON and acetylated DONs could induce mRNA expression and production of IL-8. In particular, ELISA assay showed that the ability to produce IL-8 was ranked as 3ADON75 cells for each of the nine age-region groups). The decay time of the Ca(2+) transient and the time required for 50% length relaxation both increased with age but not uniformly across the three regions (P < 0.02). Further analysis revealed a significant shift in the transmural distribution of these properties between 18 and 22 mo of age, with the largest changes occurring in epicardial myocytes. Computational modeling suggested that these changes were due in part to slower Ca(2+) dissociation from troponin in aging epicardial myocytes. Subsequent biochemical assays revealed a >50% reduction in troponin I phosphoprotein content in 22-mo old epicardium relative to the other regions. These data suggest that between 18 and 22 mo of age (before the onset of heart failure), F344 rats display epicardial-specific myofilament-level modifications that 1) break from the progression observed between 6 and 18 mo and 2) coincide with aberrant patterns of cardiac torsion. PMID- 23792679 TI - Strong linear relationship between heart rate and mean pulmonary artery pressure in exercising patients with severe precapillary pulmonary hypertension. AB - The contribution of heart rate (HR) to pulmonary artery hemodynamics has been suggested in pulmonary hypertension (PH). Our high-fidelity pressure, retrospective study tested the hypothesis that HR explained the majority of mean pulmonary artery pressure (mPAP) and pulse pressure (PApp) variation in 12 severe precapillary PH patients who performed incremental-load cycling while in the supine position. Seven idiopathic pulmonary arterial hypertension patients and five chronic thromboembolic PH patients were studied. Four to five PAP thermodilution cardiac output (CO) points (mean: 4.4) were obtained. At rest, mPAP was 57 +/- 9 mmHg, PApp was 51 +/- 11 mmHg, HR was 90 +/- 12 beats/min, and stroke volume (SV) was 50 +/- 22 ml. At peak exercise, mPAP was 76 +/- 10 mmHg, PApp was 67 +/- 11 mmHg, and HR was 123 +/- 18 beats/min (i.e., 71 +/- 10% of maximum HR, each P < 0.05), whereas SV was 51 +/- 20 ml (P = not significant). The input resistance did not change (mPAP/CO = 14.1 +/- 4.1 vs. 13.5 +/- 4.4 mmHg.min.l(-1)). The relative increase in mPAP was related to the relative increase in HR (n = 12, r(2) = 0.74) but not in CO. mPAP was linearly related to CO in 8 of 12 patients (median r(2) = 0.83) and to HR in 12 of 12 patients (median r(2) = 0.985). The parsimony principle favored the latter fit. PApp was linearly related to mPAP in 12 of 12 patients (median r(2) = 0.985), HR in 10 of 12 patients (median r(2) = 0.97), CO in 7 of 12 patients (median r(2) = 0.87), and SV in 1 of 12 patients. A strong linear relationship between HR and mPAP was consistently documented in severe precapillary PH patients who performed supine exercise. The limited value of thermodilution CO to predict mPAP could be explained by unavoidable precision errors in CO measurements, unchanged/decreased SV on exercise, curvilinearity of the mPAP-CO relationship at high flow, or flow independent additional mechanisms increasing mPAP on exercise. PMID- 23792680 TI - Endothelium-dependent control of cerebrovascular functions through age: exercise for healthy cerebrovascular aging. AB - Cognitive performances are tightly associated with the maximal aerobic exercise capacity, both of which decline with age. The benefits on mental health of regular exercise, which slows the age-dependent decline in maximal aerobic exercise capacity, have been established for centuries. In addition, the maintenance of an optimal cerebrovascular endothelial function through regular exercise, part of a healthy lifestyle, emerges as one of the key and primary elements of successful brain aging. Physical exercise requires the activation of specific brain areas that trigger a local increase in cerebral blood flow to match neuronal metabolic needs. In this review, we propose three ways by which exercise could maintain the cerebrovascular endothelial function, a premise to a healthy cerebrovascular function and an optimal regulation of cerebral blood flow. First, exercise increases blood flow locally and increases shear stress temporarily, a known stimulus for endothelial cell maintenance of Akt-dependent expression of endothelial nitric oxide synthase, nitric oxide generation, and the expression of antioxidant defenses. Second, the rise in circulating catecholamines during exercise not only facilitates adequate blood and nutrient delivery by stimulating heart function and mobilizing energy supplies but also enhances endothelial repair mechanisms and angiogenesis. Third, in the long term, regular exercise sustains a low resting heart rate that reduces the mechanical stress imposed to the endothelium of cerebral arteries by the cardiac cycle. Any chronic variation from a healthy environment will perturb metabolism and thus hasten endothelial damage, favoring hypoperfusion and neuronal stress. PMID- 23792681 TI - Size-dependent predilections of cardiogenic embolic transport. AB - While it is intuitively clear that aortic anatomy and embolus size could be important determinants for cardiogenic embolic stroke risk and stroke location, few data exist confirming or characterizing this hypothesis. The objective of this study is to use medical imaging and computational modeling to better understand if aortic anatomy and embolus size influence predilections for cardiogenic embolic transport and right vs. left hemisphere propensity. Anatomically accurate models of the human aorta and branch arteries to the head were reconstructed from computed tomography (CT) angiography of 10 patients. Blood flow was modeled by the Navier-Stokes equations using a well-validated flow solver with physiologic inflow and boundary conditions. Embolic particulate was released from the aortic root and tracked through the common carotid and vertebral arteries for a range of particle sizes. Cardiogenic emboli reaching the carotid and vertebral arteries appeared to have a strong size-destination relationship that varied markedly from expectations based on blood distribution. Observed trends were robust to modeling parameters. A patient's aortic anatomy appeared to significantly influence the probability a cardiogenic particle becomes embolic to the head. Right hemisphere propensity appeared dominant for cardiogenic emboli, which has been confirmed clinically. The predilections discovered through this modeling could represent an important mechanism underlying cardiogenic embolic stroke etiology. PMID- 23792682 TI - Insights into the arginine paradox: evidence against the importance of subcellular location of arginase and eNOS. AB - Reduced production of nitric oxide (NO) is one of the first indications of endothelial dysfunction and precedes overt cardiovascular disease. Increased expression of Arginase has been proposed as a mechanism to account for diminished NO production. Arginases consume l-arginine, the substrate for endothelial nitric oxide synthase (eNOS), and l-arginine depletion is thought to competitively reduce eNOS-derived NO. However, this simple relationship is complicated by the paradox that l-arginine concentrations in endothelial cells remain sufficiently high to support NO synthesis. One mechanism proposed to explain this is compartmentalization of intracellular l-arginine into distinct, poorly interchangeable pools. In the current study, we investigated this concept by targeting eNOS and Arginase to different intracellular locations within COS-7 cells and also BAEC. We found that supplemental l-arginine and l-citrulline dose dependently increased NO production in a manner independent of the intracellular location of eNOS. Cytosolic arginase I and mitochondrial arginase II reduced eNOS activity equally regardless of where in the cell eNOS was expressed. Similarly, targeting arginase I to disparate regions of the cell did not differentially modify eNOS activity. Arginase-dependent suppression of eNOS activity was reversed by pharmacological inhibitors and absent in a catalytically inactive mutant. Arginase did not directly interact with eNOS, and the metabolic products of arginase or downstream enzymes did not contribute to eNOS inhibition. Cells expressing arginase had significantly lower levels of intracellular l-arginine and higher levels of ornithine. These results suggest that arginases inhibit eNOS activity by depletion of substrate and that the compartmentalization of l arginine does not play a major role. PMID- 23792683 TI - Characterization of a cellular denitrase activity that reverses nitration of cyclooxygenase. AB - Protein 3-nitrotyrosine (3-NT) formation is frequently regarded as a simple biomarker of disease, an irreversible posttranslational modification that can disrupt protein structure and function. Nevertheless, evidence that protein 3-NT modifications may be site selective and reversible, thus allowing for physiological regulation of protein activity, has begun to emerge. We have previously reported that cyclooxygenase (COX)-1 undergoes heme-dependent nitration of Tyr(385), an internal and catalytically essential residue. In the present study, we demonstrate that nitrated COX-1 undergoes a rapid reversal of nitration by substrate-selective and biologically regulated denitrase activity. Using nitrated COX-1 as a substrate, denitrase activity was validated and quantified by analytic HPLC with electrochemical detection and determined to be constitutively active in murine and human endothelial cells, macrophages, and a variety of tissue samples. Smooth muscle cells, however, contained little denitrase activity. Further characterizing this denitrase activity, we found that it was inhibited by free 3-NT and may be enhanced by endogenous nitric oxide and exogenously administered carbon monoxide. Finally, we describe a purification protocol that results in significant enrichment of a discrete denitrase containing fraction, which maintains activity throughout the purification process. These findings reveal that nitrated COX-1 is a substrate for a denitrase in cells and tissues, implying that the reciprocal processes of nitration and denitration may modulate bioactive lipid synthesis in the setting of inflammation. In addition, our data reveal that denitration is a controlled process that may have broad importance for regulating cell signaling events in nitric oxide-generating systems during oxidative/nitrosative stress. PMID- 23792685 TI - Cytomegalovirus load in whole blood is more reliable for predicting and assessing CMV disease than pp65 antigenaemia. AB - CMV is a common cause of disease in immunocompromised patients. Because sampling of the diseased organ can be invasive, markers of systemic CMV reactivation such as pp65 and CMV viral load are commonly used to monitor patients at risk of CMV disease. In this retrospective analysis, the performance of these markers was compared in solid organ transplant recipients, patients with haematological malignancies and HIV infection. Both assays were sensitive markers of reactivation, however, the predictive value for disease of a positive result for both was low. Compared to viral load, the pp65 assay was a less sensitive marker of CMV reactivation. It was only positive when the viral load was greater than 3 log (10) copies/ml whole blood and was negative in 10 instances when the viral load was between 3 and 5 logs. In concordantly positive samples, the number of pp65 positive cells varied widely relative to the viral load and the number of positive cells counted could not be used to predict disease likelihood with any certainty. To conclude, CMV viral load provides a more consistent guide to determine likelihood of disease than pp65 count and is a more sensitive marker of CMV reactivation. PMID- 23792686 TI - Visualization and quantitation of abundant macroautophagy in virus-infected cells by confocal three-dimensional fluorescence imaging. AB - Varicella-zoster virus (VZV) is a human herpesvirus. Primary infection causes varicella (chickenpox), a viremic illness typified by an exanthem consisting of several hundred vesicles. When VZV reactivates from latency in the spinal ganglia during late adulthood, the emerging virus causes a vesicular dermatomal rash (herpes zoster or shingles). To expand investigations of autophagy during varicella and zoster, newer 3D imaging technology was combined with laser scanning confocal microscopy to provide animations of autophagosomes in the vesicular rash. First, the cells were immunolabeled with antibodies against VZV proteins and the LC3 protein, an integral autophagosomal protein. Antibody reagents lacking activity against the human blood group A1 antigen were selected. After laser excitation of the samples, optimized emission detection bandwidths were configured by Zeiss Zen control software. Confocal Z-stacks comprising up to 40 optical slices were reconstructed into 3D animations with the aid of Imaris software. With this imaging technology, individual autophagosomes were clearly detectable as spheres within each vesicular cell. To enumerate the number of autophagosomes, data sets from 50 cells were reconstructed as 3D fluorescence images and analyzed with MeasurementPro software. The mean number of autophagosomes per infected vesicular cell was >100, although over 200 autophagosomes were seen in a few cells. In summary, macroautophagy was easily quantitated within VZV-infected cells after immunolabeling and imaging by 3D confocal animation technology. These same 3D imaging techniques will be applicable for investigations of autophagy in other virus-infected cells. PMID- 23792684 TI - Astrocyte regulation of cerebral vascular tone. AB - Cerebral blood flow is controlled by two crucial processes, cerebral autoregulation (CA) and neurovascular coupling (NVC) or functional hyperemia. Whereas CA ensures constant blood flow over a wide range of systemic pressures, NVC ensures rapid spatial and temporal increases in cerebral blood flow in response to neuronal activation. The focus of this review is to discuss the cellular mechanisms by which astrocytes contribute to the regulation of vascular tone in terms of their participation in NVC and, to a lesser extent, CA. We discuss evidence for the various signaling modalities by which astrocytic activation leads to vasodilation and vasoconstriction of parenchymal arterioles. Moreover, we provide a rationale for the contribution of astrocytes to pressure induced increases in vascular tone via the vasoconstrictor 20-HETE (a downstream metabolite of arachidonic acid). Along these lines, we highlight the importance of the transient receptor potential channel of the vanilloid family (TRPV4) as a key molecular determinant in the regulation of vascular tone in cerebral arterioles. Finally, we discuss current advances in the technical tools available to study NVC mechanisms in the brain as it relates to the participation of astrocytes. PMID- 23792687 TI - Alterations in junctional proteins, inflammatory mediators and extracellular matrix molecules in eosinophilic esophagitis. AB - Eosinophilic esophagitis (EoE), an inflammatory atopic disease of the esophagus, causes massive eosinophil infiltration, basal cell hyperplasia, and sub epithelial fibrosis. To elucidate cellular and molecular factors involved in esophageal tissue damage and remodeling, we examined pinch biopsies from EoE and normal pediatric patients. An inflammation gene array confirmed that eotaxin-3, its receptor CCR3 and interleukins IL-13 and IL-5 were upregulated. An extracellular matrix (ECM) gene array revealed upregulation of CD44 & CD54, and of ECM proteases (ADAMTS1 & MMP14). A cytokine antibody array showed a marked decrease in IL-1alpha and IL-1 receptor antagonist and an increase in eotaxin-2 and epidermal growth factor. Western analysis indicated reduced expression of intercellular junction proteins, E-cadherin and claudin-1 and increased expression of occludin and vimentin. We have identified a number of novel genes and proteins whose expression is altered in EoE. These findings provide new insights into the molecular mechanisms of the disease. PMID- 23792688 TI - Single cell measurements of vacuolar rupture caused by intracellular pathogens. AB - Shigella flexneri are pathogenic bacteria that invade host cells entering into an endocytic vacuole. Subsequently, the rupture of this membrane-enclosed compartment allows bacteria to move within the cytosol, proliferate and further invade neighboring cells. Mycobacterium tuberculosis is phagocytosed by immune cells, and has recently been shown to rupture phagosomal membrane in macrophages. We developed a robust assay for tracking phagosomal membrane disruption after host cell entry of Shigella flexneri or Mycobacterium tuberculosis. The approach makes use of CCF4, a FRET reporter sensitive to beta-lactamase that equilibrates in the cytosol of host cells. Upon invasion of host cells by bacterial pathogens, the probe remains intact as long as the bacteria reside in membrane-enclosed compartments. After disruption of the vacuole, beta-lactamase activity on the surface of the intracellular pathogen cleaves CCF4 instantly leading to a loss of FRET signal and switching its emission spectrum. This robust ratiometric assay yields accurate information about the timing of vacuolar rupture induced by the invading bacteria, and it can be coupled to automated microscopy and image processing by specialized algorithms for the detection of the emission signals of the FRET donor and acceptor. Further, it allows investigating the dynamics of vacuolar disruption elicited by intracellular bacteria in real time in single cells. Finally, it is perfectly suited for high-throughput analysis with a spatio temporal resolution exceeding previous methods. Here, we provide the experimental details of exemplary protocols for the CCF4 vacuolar rupture assay on HeLa cells and THP-1 macrophages for time-lapse experiments or end points experiments using Shigella flexneri as well as multiple mycobacterial strains such as Mycobacterium marinum, Mycobacterium bovis, and Mycobacterium tuberculosis. PMID- 23792689 TI - A Bcl-xL-Drp1 complex regulates synaptic vesicle membrane dynamics during endocytosis. AB - Following exocytosis, the rate of recovery of neurotransmitter release is determined by vesicle retrieval from the plasma membrane and by recruitment of vesicles from reserve pools within the synapse, which is dependent on mitochondrial ATP. The anti-apoptotic Bcl-2 family protein Bcl-xL also regulates neurotransmitter release and recovery in part by increasing ATP availability from mitochondria. We now find, that Bcl-xL directly regulates endocytic vesicle retrieval in hippocampal neurons through protein-protein interaction with components of the clathrin complex. Our evidence suggests that, during synaptic stimulation, Bcl-xL translocates to clathrin-coated pits in a calmodulin dependent manner and forms a complex with the GTPase Drp1, Mff and clathrin. Depletion of Drp1 produces misformed endocytic vesicles. Mutagenesis studies suggest that formation of the Bcl-xL-Drp1 complex is necessary for the enhanced rate of vesicle endocytosis produced by Bcl-xL, thus providing a mechanism for presynaptic plasticity. PMID- 23792690 TI - Matrix geometry determines optimal cancer cell migration strategy and modulates response to interventions. AB - The molecular requirements and morphology of migrating cells can vary depending on matrix geometry; therefore, predicting the optimal migration strategy or the effect of experimental perturbation is difficult. We present a model of cell motility that encompasses actin-polymerization-based protrusions, actomyosin contractility, variable actin-plasma membrane linkage leading to membrane blebbing, cell-extracellular-matrix adhesion and varying extracellular matrix geometries. This is used to explore the theoretical requirements for rapid migration in different matrix geometries. Confined matrix geometries cause profound shifts in the relationship of adhesion and contractility to cell velocity; indeed, cell-matrix adhesion is dispensable for migration in discontinuous confined environments. The model is challenged to predict the effect of different combinations of kinase inhibitors and integrin depletion in vivo, and in confined matrices based on in vitro two-dimensional measurements. Intravital imaging is used to verify bleb-driven migration at tumour margins, and the predicted response to single and combinatorial manipulations. PMID- 23792692 TI - Role of TOMM40 rs10524523 polymorphism in onset of alzheimer's disease caused by the PSEN1 M146L mutation. AB - We investigated the association between TOMM40 rs10524523, age of onset, and memory performance in patients with the PSEN1 M146L mutation in a large familial Alzheimer's disease Calabrian kindred, with a wide variability of onset not attributable to APOE. APOE33/TOMM40VL/VL patients showed a tendency for an earlier age at onset compared to those with APOE33/TOMM40VL/S and APOE33/TOMM40S/S. Moreover, TOMM40VL/VL patients had better memory performance, when compared to TOMM40S/S but not to TOMM40VL/S patients, so there is not a dose dependent effect. Our results suggest that, in the presence of the PSEN1 mutation, the slight difference in age of onset together with memory performance could be influenced by TOMM40 genotypes. PMID- 23792693 TI - Word list and story recall elicit different patterns of memory deficit in patients with Alzheimer's disease, frontotemporal dementia, subcortical ischemic vascular disease, and Lewy body dementia. AB - BACKGROUND: Different roles have been attributed to mesio-temporal areas and frontal lobes in declarative memory functioning, and qualitative differences have been observed in the amnesic symptoms due to pathological damage of these two portions of the central nervous system. OBJECTIVE: The aim of the present study was to look for memory profiles related to pathological involvement in the temporal and frontal structures in patients with different dementia syndromes on word-list and prose memory tasks. METHODS: 20 patients with Alzheimer's disease (AD), 20 with frontal variant of FTD (fvFTD), 20 with subcortical ischemic vascular dementia (SIVD), and 20 with Lewy body dementia (LBD) and 34 healthy subjects (NCs) were submitted to word-list and prose memory tasks. RESULTS: All groups performed similarly on both the immediate and delayed recall of the word list. Conversely, AD patients performed worse than all the other dementia groups on the immediate prose recall. On delayed prose recall, AD patients performed worse than fvFTD and SIVD patients but similar to LBD patients. Differential scores between word-list and prose tests were minimal in the AD group and very pronounced in fvFTD and SIVD groups. CONCLUSION: The combined use of the prose and word-list tasks evidenced a "mesio-temporal" memory profile in AD patients as opposed to a "frontal" one in fvFTD and SIVD patients and a mixed profile in the LBD patients. In particular, a differential score between the two tests can be useful in differentiating AD patients from patients with other forms of dementia. PMID- 23792691 TI - TRF2 inhibits a cell-extrinsic pathway through which natural killer cells eliminate cancer cells. AB - Dysfunctional telomeres suppress tumour progression by activating cell-intrinsic programs that lead to growth arrest. Increased levels of TRF2, a key factor in telomere protection, are observed in various human malignancies and contribute to oncogenesis. We demonstrate here that a high level of TRF2 in tumour cells decreased their ability to recruit and activate natural killer (NK) cells. Conversely, a reduced dose of TRF2 enabled tumour cells to be more easily eliminated by NK cells. Consistent with these results, a progressive upregulation of TRF2 correlated with decreased NK cell density during the early development of human colon cancer. By screening for TRF2-bound genes, we found that HS3ST4--a gene encoding for the heparan sulphate (glucosamine) 3-O-sulphotransferase 4--was regulated by TRF2 and inhibited the recruitment of NK cells in an epistatic relationship with TRF2. Overall, these results reveal a TRF2-dependent pathway that is tumour-cell extrinsic and regulates NK cell immunity. PMID- 23792694 TI - The role of matrix metalloproteinases and tissue inhibitors of metalloproteinases in the pathophysiology of neurodegeneration: a literature study. AB - Matrix metalloproteinases (MMPs) and their natural tissue inhibitors (TIMPs) are involved in cell signaling processes and the release of extracellular matrix (ECM) and non-ECM molecules. Nonregulated MMP activity and an imbalance between metalloproteinases and their inhibitors might contribute to various disorders, including neurodegenerative diseases such as Alzheimer's disease (AD), which is the most common cause of dementia. There is a complex relationship between MMPs and TIMPs with AD. It has been shown that MMPs and TIMPs are localized in neuritic senile plaques and neurofibrillary tangles in the postmortem brains of patients with AD. Some MMPs have also been shown to induce tau aggregation and the formation of neurofibrillary tangles in vitro. Moreover, MMPs contribute to AD pathogenesis via the disruption of the blood-brain barrier and promotion of neurodegeneration. However, MMPs can degrade both soluble and fibrillar forms of amyloid-beta (Abeta). It has also been shown that Abeta enhances the expression of MMPs in neuroglial cultures and induces the release of TIMP-1 by brain cells. Inhibition of Abeta-induced MMP activity resulted in an improvement of performance tests in mice. Moreover, simultaneous examination of MMP-9, MMP-2, and TIMP-1 in the CSF contributed to the ability to differentiate between AD and other types of dementia. Thus, the aim of this literature study was to describe the role of MMPs and TIMPs in neurodegeneration, as well as their potential usefulness as CSF or plasma biomarkers in the diagnosis of AD as well as other neurodegenerative disorders and vascular dementia. PMID- 23792695 TI - Increased iron levels and decreased tissue integrity in hippocampus of Alzheimer's disease detected in vivo with magnetic resonance imaging. AB - BACKGROUND: Iron can catalyze damaging free radical reactions. With age, iron accumulates in brain gray matter regions and may contribute to the risk of developing age-related diseases such as Alzheimer's disease (AD). Prior MRI studies demonstrated increased iron deposits in basal ganglia regions; however, the hippocampus (Hipp), which is heavily damaged in AD, and comparator regions that are resistant to AD damage, such as thalamus (Th), have rarely been examined. OBJECTIVE: To assess iron levels and evidence of tissue damage in Hipp and Th of AD subjects and healthy controls. METHODS: Thirty-one AD and sixty eight healthy control subjects participated in this study. High- and low-field strength MRI instruments were used in combination to quantify iron content of ferritin molecules (ferritin iron) using the field dependent relaxation rate increase (FDRI) method. Decreased transverse relaxation rate (R2) was used as an index of tissue damage. RESULTS: Compared with healthy controls, AD subjects had increased ferritin iron in Hipp (p = 0.019) but not Th (p = 0.637), and significantly decreased R2 in Hipp (p < 0.001) but not Th (p = 0.37). In the entire sample, FDRI and R2 were negatively correlated. CONCLUSION: The data shows that in AD, Hipp damage occurs in conjunction with ferritin iron accumulation. Prospective studies are needed to evaluate how increasing iron levels may influence the trajectory of tissue damage and cognitive and pathologic manifestations of AD. PMID- 23792696 TI - Picoliter droplets developed as microreactors for ultrafast synthesis of multi color water-soluble CdTe quantum dots. AB - Picoliter droplets were developed as microreactors for ultrafast and continuous synthesis of multi-color, water-soluble CdTe quantum dots (QDs). Through a slight change in the local controllable reaction temperature of 1-2 degrees C, we could obtain a series of different colored fluorescent QDs in about 1 min. PMID- 23792697 TI - Impact of chlorine dioxide gas sterilization on nosocomial organism viability in a hospital room. AB - To evaluate the ability of ClO2 to decontaminate pathogens known to cause healthcare-associated infections in a hospital room strains of Acinetobacter baumannii, Escherichia coli, Enterococcus faecalis, Mycobacterium smegmatis, and Staphylococcus aureus were spot placed in duplicate pairs at 10 sites throughout a hospital room and then exposed to ClO2 gas. Organisms were collected and evaluated for reduction in colony forming units following gas exposure. Six sterilization cycles with varied gas concentrations, exposure limits, and relative humidity levels were conducted. Reductions in viable organisms achieved ranged from 7 to 10-log reductions. Two sterilization cycles failed to produce complete inactivation of organisms placed in a bathroom with the door closed. Reductions of organisms in the bathroom ranged from 6-log to 10-log reductions. Gas leakage between hospital floors did not occur; however, some minor gas leakage from the door of hospital room was measured which was subsequently sealed to prevent further leakage. Novel technologies for disinfection of hospital rooms require validation and safety testing in clinical environments. Gaseous ClO2 is effective for sterilizing environmental contamination in a hospital room. Concentrations of ClO2 up to 385 ppm were safely maintained in a hospital room with enhanced environmental controls. PMID- 23792698 TI - The current state of tuberculosis vaccines. AB - Tuberculosis continues to persist despite widespread use of BCG, the only licensed vaccine to prevent TB. BCG's limited efficacy coupled with the emergence of drug-resistant strains of Mycobacterium tuberculosis emphasizes the need for a more effective vaccine for combatting this disease. However, the development of a TB vaccine is hindered by the lack of immune correlates, suboptimal animal models, and limited funding. An adolescent/adult vaccine would have the greatest public health impact, but effective delivery of such a vaccine will require a better understanding of global TB epidemiology, improved infrastructure, and engagement of public health leaders and global manufacturers. Here we discuss the current state of tuberculosis vaccine research and development, including our understanding of the underlying immunology as well as the challenges and opportunities that may hinder or facilitate the development of a new and efficacious vaccine. PMID- 23792699 TI - Periodic architecture for high performance shock absorbing composites. AB - A novel composite architecture consisting of a periodic arrangement of closely spaced spheres of a stiff material embedded in a soft matrix is proposed for extremely high damping and shock absorption capacity. Efficacy of this architecture is demonstrated by compression loading a composite, where multiple steel balls were stacked upon each other in a polydimethylsiloxane (PDMS) matrix, at a low strain-rate of 0.05 s-1 and a very high strain-rate of >2400 s-1. The balls slide over each other upon loading, and revert to their original position when the load is removed. Because of imposition of additional strains into the matrix via this reversible, constrained movement of the balls, the composite absorbs significantly larger energy and endures much lesser permanent damage than the monolithic PDMS during both quasi-static and impact loadings. During the impact loading, energy absorbed per unit weight for the composite was ~8 times larger than the monolithic PDMS. PMID- 23792701 TI - Rac1 and cholesterol metabolism in macrophage. AB - In the early stages of atherosclerotic lesion development, cholesterol is mostly present as esterified cholesterol stored in macrophage cytoplasmic lipid droplets. However, when the lesion evolves, free cholesterol accumulates in other compartments, such as lysosomes and plasma membrane. A number of studies support a role for intracellular cholesterol content and distribution in regulating several cell functions. Particularly, membrane free cholesterol content has a specific effect on signaling pathways involved in regulating cell motility and organization of the actin cytoskeleton. These processes are regulated by several signaling pathways including the small GTPase Rac1. Rac1 belongs to the Rho GTPases of the Ras protein superfamily involved in the regulation of multiple cell functions, including cell proliferation, chemotaxis, phagocytosis, degranulation, and superoxide production. In this review, we discuss the role of Rac1 in macrophage with respect to cholesterol metabolism and trafficking as critical aspects for the development of atherosclerotic plaque. PMID- 23792702 TI - Puerarin accelerates re-endothelialization in a carotid arterial injury model: impact on vasodilator concentration and vascular cell functions. AB - Puerarin, a main isoflavone glucoside derived from the Chinese medicine Radix puerariae, has been employed clinically to prevent and treat various cardiovascular disorders. However, little research has been performed to identify the in vivo effects of puerarin on the re-endothelialization and neointimal hyperplasia of injured vessels, and its detailed mechanisms of action remain to be elucidated. In this study, Sprague-Dawley rats were treated with puerarin at the dosages of 0, 50, and 100 mg.kg(-1).day(-1) i.p. after balloon carotid denudation for 2 weeks. The results showed that puerarin accelerated re endothelialization after surgery, resulting in a significant reduction of neointima formation. Moreover, puerarin increased the serum levels of vasodilators, such as nitric oxide and prostaglandin I(2), in a dose-dependent manner. In vitro, puerarin exhibited protective effects on late endothelial progenitor cells and mature endothelial cells, and inhibitory effects on the migration of vascular smooth muscle cells. Taken together, these data indicate that puerarin accelerates re-endothelialization, inhibits neointima formation, and attenuates vascular remodeling at sites of arterial injury, possibly due to the cytoprotective effects on endothelial lineage and the suppression of vascular smooth muscle cell migration. PMID- 23792700 TI - Atherosclerosis in systemic lupus erythematosus. AB - Accelerated atherosclerosis and its long-term sequelae are a major cause of late mortality among patients with systemic lupus erythematosus (SLE). Traditional Framingham risk factors such as hypertension, hypercholesterolemia, diabetes, and smoking do not account in entirety for this risk. SLE specific factors like disease activity and duration, use of corticosteroids, presence of antiphospholipid antibodies, and others are important risk factors. SLE is considered a coronary heart disease; equivalent and aggressive management of all traditional risk factors is recommended. Despite their role in primary and secondary prevention in the general population, statins seem to have no effect on cardiovascular outcomes in adult or pediatric SLE populations. The use of hydroxychloroquine has a cardioprotective effect, and mycophenolate mofetil may reduce cardiovascular events based on basic science data and data from the transplant population. The role of vitamin D supplementation and treatment of hyperhomocysteinemia remain controversial, but due to the safety of therapy and the potential benefit, they remain as optional therapies. PMID- 23792703 TI - Recent insights into the role of the PD-1/PD-L1 pathway in immunological tolerance and autoimmunity. AB - Autoimmune diseases represent a heterogeneous group of conditions whose incidence is increasing worldwide. This has stimulated studies on their etiopathogenesis, derived from a complex interaction between genetic and environmental factors, in order to improve prevention and treatment of these disorders. The relevance of T regulatory cells and of the PD-1/PD-L1 pathway in controlling immune responses has been highlighted. Recent studies have in particular elucidated the putative role of the PD-1/PD-L1 pathway in regulating T cell responses and its effects on immunological tolerance and immune-mediated tissue damage. The role of the PD 1/PD-L1 pathway in autoimmunity has been already investigated in vivo in several experimental animal models including insulin-dependent diabetes mellitus, systemic lupus erythematosus, myocarditis, encephalomyelitis, rheumatoid arthritis and inflammatory bowel diseases. With the advent of candidate gene and genome-wide association studies, single nucleotide polymorphisms (SNPs) in PD-1 gene in humans have demonstrated relevant associations with a higher risk of developing autoimmune diseases in certain ethnic groups. In this review we present recent insights into the role of the PD-1/PD-L1 pathway in regulating lymphocyte activation, promotion of T regulatory cell development and function, breakdown of tolerance and development of autoimmunity. We finally speculate on the possible development of novel therapeutic treatments in human autoimmunity by modulating the PD-1/PD-L1 pathway. PMID- 23792705 TI - Fatal disseminated neurobrucellosis. PMID- 23792704 TI - The helical propensity of KLA amphipathic peptides enhances their binding to gel state lipid membranes. AB - The role and importance of the conformation of antimicrobial peptides for their binding and incorporation into lipid membranes as well as for their bioactivity are still not well understood. In this paper, we studied the interaction between four cationic alpha-helical KLA peptides, which differ primarily in their helical propensity, and the anionic gel-state lipid DPPG (1,2-dipalmitoyl-sn-glycero-3 phosphoglycerol). Of particular interest was the influence of the peptide conformation and membrane surface properties on the electrostatic binding process. Dynamic light scattering (DSL) showed that generally the KLA peptides possess high aggregation power but modest solubilization power. Circular dichroism spectroscopy (CD) spectra revealed that the KLA peptides with the low helical propensity tend to form beta-structures at low lipid/peptide ratios. Differential scanning calorimetry (DSC) thermograms showed that the helical KLA peptides stabilize the DPPG bilayer, whereas the beta-structured peptides induce pronounced membrane perturbations. Isothermal titration calorimetry (ITC) isotherms showed that the helical KLA peptides bind more efficiently to DPPG vesicles than the beta-structured KLA peptides, and that the binding affinity of the peptides is proportional to the peptide helical propensity and membrane negative surface charge. The stoichiometry values (N) deduced from the ITC isotherms suggest that the helical KLA peptides have a higher capacity to translocate the DPPG lipid bilayer. The new data presented in this study demonstrate the flexibility of KLA peptides in adopting various conformations in response to the surrounding and also how the peptide structuring controls the mode of peptide-membrane interaction. PMID- 23792706 TI - Isolation, identification and subtyping of Campylobacter: where to from here? AB - Campylobacter species are widely regarded as the most frequent bacterial cause of gastroenteritis in humans worldwide. Their main transmission routes are via contaminated food and water. For interventions to be effective, methods for the detection, identification and epidemiological subtyping must be sensitive, accurate and rapid. As yet, methods are not perfect, although several significant advances have been made in these areas in recent years. This paper provides a brief review and commentary on the current state of the art in the hope that it will help provide context for others in selecting, improving or developing these vital tools for research and diagnoses. PMID- 23792707 TI - High efficiency application of a mate-paired library from next-generation sequencing to postlight sequencing: Corynebacterium pseudotuberculosis as a case study for microbial de novo genome assembly. AB - With the advent of high-throughput DNA sequencing platforms, there has been a reduction in the cost and time of sequencing. With these advantages, new challenges have emerged, such as the handling of large amounts of data, quality assessment, and the assembly of short reads. Currently, benchtop high-throughput sequencers enable the genomes of prokaryotic organisms to be sequenced within two hours with a reduction in coverage compared with the SOLiD, Illumina and 454 FLX Titanium platforms, making it necessary to evaluate the efficiency of less expensive benchtop instruments for prokaryotic genomics. In the present work, we evaluate and propose a methodology for the use of the Ion Torrent PGM platform for decoding the gram-positive bacterium Corynebacterium pseudotuberculosis, for which 15 complete genome sequences have already been deposited based on fragment and mate-paired libraries with a 3-kb insert size. Despite the low coverage, a single sequencing run using a mate-paired library generated 39 scaffolds after de novo assembly without data curation. This result is superior to that obtained by sequencing using libraries generated from fragments marketed by the equipment's manufacturer, as well as that observed for mate-pairs sequenced by SOLiD. The generated sequence added an extra 91kb to the genome available at NCBI. PMID- 23792709 TI - Learning about Barriers to Care for People Living with HIV in Egypt: A Qualitative Exploratory Study. AB - The purpose of this study was to identify obstacles health care workers face in providing care for people living with HIV and AIDS (PLWHA). Based on these findings, health authorities can design interventions to support health care workers in providing better medical care for PLWHA. Thirty in-depth interviews were conducted with physicians and nurses in one 300-bed tertiary care public hospital in Giza, Egypt. Thematic analysis was conducted by 2 investigators. Five main themes were identified (1) fear of infection; (2) disbelief in effectiveness of infection control measures to protect against HIV; (3) misconceptions regarding medical care for PLWHA; (4) fear of secondary stigma; and (5) moral judgments toward PLWHA and negative connotations related to HIV. Interventions targeting health care workers should be multidimensional, including knowledge and skills building as well as value and attitude change. Reducing stigma among health care workers will improve access to care for PLWHA. PMID- 23792708 TI - Burden and Determinants of Severe Anemia among HIV-Infected Adults: Results from a Large Urban HIV Program in Tanzania, East Africa. AB - BACKGROUND AND METHODS: This cross-sectional study aimed at determining the prevalence and risk factors for severe anemia, severe microcytic anemia, and severe normocytic anemia among HIV-infected individuals aged >15 years. Univariate and multivariate analyses were performed to identify the risk factors for anemia. RESULTS: Data from 40 408 patients were analyzed, showing an overall prevalence of 22% for severe anemia. The risk of developing severe anemia increased by 49% among patients with a body mass index of <18.5 kg/m(2), by approximately 2-fold among patients with the World Health Organization (WHO) stage III, and by 3-fold among patients with WHO stage IV illness. Severe normocytic anemia was uniquely increased among patients aged >=50 years, among those with chronic diarrhea and Kaposi's sarcoma, and those taking cotrimoxazole. CONCLUSION: There was a high prevalence of severe anemia among adults infected with HIV. Focused identification of anemia should be based on the hemoglobin and mean corpuscular volume measurements. PMID- 23792710 TI - An evaluation of hepatitis B virus diagnostic methods and responses to antiretroviral therapy among HIV-infected women in Thailand. AB - Coinfection with HIV and hepatitis B virus (HBV) is common in resource-limited settings but is frequently not diagnosed. The authors retrospectively tested specimens for HBV in HIV-infected Thai women who had participated in an antiretroviral therapy (ART) clinical study. A substantial proportion (27 of 211; 13%) of HIV-infected women were HBV coinfected. Among HIV/HBV-coinfected women, the authors observed similar rates of antiretroviral-associated liver toxicity (despite nevirapine [NVP] use) and CD4 count reconstitution as observed in HIV monoinfected women. Hepatitis B surface antigen (HBsAg) screening detected the majority (81%) of HBV coinfections, including all 5 HBV-coinfected women who did not suppress HBV despite 48 weeks of lamivudine (3TC)-containing ART and could be used to tailor ART for patients diagnosed with HBV coinfection in accordance with World Health Organization guidelines. Although HBsAg screening did not diagnose 5 occult HBV coinfections, these women achieved HBV suppression on 3TC-containing ART, suggesting that not detecting occult HBV coinfection would have limited clinical impact. PMID- 23792712 TI - HBV genotype F: natural history and treatment. AB - The analysis of the HBV genome revealed the existence of 10 genotypes, named A-J. Evidence of the influence of the different genotypes in the natural history and treatment response to nucleoside/nucleotide analogues or interferon-based regimens is scant. HBV genotype F is one of the most prevalent circulating genotypes in South America and the Arctic Circle. Since most of the available information on HBV is from Asia, the US and Europe, it reflects their predominant genotypes: A, B, C and D. To date, the evidence is not fully confirmed, but it appears that genotype F chronic hepatitis B is associated with a more aggressive course of liver disease, reflected by higher histological indexes, a higher risk of development of hepatocellular carcinoma and a higher rate of liver-related mortality. In terms of treatment response, the available data is, unfortunately, even more limited; however, what data is available suggests acceptable and similar response rates to pegylated interferon-alpha2a in genotype F compared to genotype A. Response rates to nucleoside/nucleotide analogues is not influenced by genotype. The review of this limited data sheds light on the necessity to conduct further studies in South America and the Arctic Circle in order to better understand the different aspects of HBV genotype F, especially in relation to treatment response. PMID- 23792711 TI - Effects of Lifetime History of Use of Problematic Alcohol on HIV Medication Adherence. AB - BACKGROUND: The effects of previous alcohol abuse on antiretroviral therapy (ART) adherence have been less studied. MATERIALS AND METHODOLOGY: Participants were randomized to a 3-month group intervention or an individual-enhanced standard-of care condition and assessed over 6 months. Individual assessment at baseline, 3, and 6 months was done; interviews included lifetime history of problematic alcohol use. RESULTS: A total of 80 HIV-positive individuals on ART were recruited. In all, 35% of participants reported a history of problematic alcohol use, 37% had a detectable viral load, 55% were nonadherent, and 24% reporting skipping medication in the previous 3 months. There was no association between a history of problematic use and an adherence at any time point, that is, at baseline (t = -.7, P = .47), midpoint (t = -.39, P = .69), and 6-month follow-up (t = -1.2, P = .23). CONCLUSION: Results suggest that a history of problematic alcohol use may not impact ART adherence. PMID- 23792714 TI - Orals. PMID- 23792716 TI - Clinical Diabetes/Therapeutics. PMID- 23792715 TI - Behavioral Medicine, Clinical Nutrition, Education, and Exercise. PMID- 23792713 TI - Identification of G protein-coupled receptors in the pea aphid, Acyrthosiphon pisum. AB - GPCRs play crucial roles in the growth, development and reproduction of organisms. In insects, a large number of GPCRs have been reported for Holometabola but not Hemimetabola. The recently sequenced pea aphid genome provides us with the opportunity to analyze the evolution and potential functions of GPCRs in Hemimetabola. 82 GPCRs were identified from the representative model hemimetabolous insect Acyrthosiphon pisum, 37 of which have ESTs evidence, and 73 are annotated for the first time. A striking difference between A. pisum, Drosophila melanogaster and Tribolium castaneum is the duplication of the kinin and SIFamide receptors in A. pisum. Another divergence is the loss of the sulfakinin receptor in A. pisum. These duplications/losses are likely involved in the osmoregulation, reproduction and energy metabolism of A. pisum. Moreover, this work will promote functional analyses of GPCRs in A. pisum and may advance new drug target discovery for biological control of the aphid. PMID- 23792718 TI - Immunology/Transplantation. PMID- 23792717 TI - Epidemiology/Genetics. PMID- 23792719 TI - Insulin Action/Molecular Metabolism. PMID- 23792721 TI - Islet Biology/Insulin Secretion. PMID- 23792720 TI - Integrated Physiology/Obesity. PMID- 23792722 TI - Acute and Chronic Complications. PMID- 23792723 TI - Behavioral Medicine, Clinical Nutrition, Education, and Exercise. PMID- 23792724 TI - Clinical Diabetes/Therapeutics. PMID- 23792725 TI - Epidemiology/Genetics. PMID- 23792727 TI - Insulin Action/Molecular Metabolism. PMID- 23792726 TI - Immunology/Transplantation. PMID- 23792728 TI - Integrated Physiology/Obesity. PMID- 23792729 TI - Islet Biology/Insulin Secretion. PMID- 23792732 TI - Duality Info. PMID- 23792733 TI - Acute and Chronic Complications. PMID- 23792734 TI - A serine-substituted P450 catalyzes highly efficient carbene transfer to olefins in vivo. AB - Whole-cell catalysts for non-natural chemical reactions will open new routes to sustainable production of chemicals. We designed a cytochrome 'P411' with unique serine-heme ligation that catalyzes efficient and selective olefin cyclopropanation in intact Escherichia coli cells. The mutation C400S in cytochrome P450(BM3) gives a signature ferrous CO Soret peak at 411 nm, abolishes monooxygenation activity, raises the resting-state Fe(III)-to-Fe(II) reduction potential and substantially improves NAD(P)H-driven activity. PMID- 23792735 TI - Protein engineering: Chemistry gets the assist. AB - Integration of chemistry-based approaches into enzyme engineering provides a versatile strategy for biocatalyst development with the potential for improved performance and new catalytic activities. Application of this strategy led to the development of a whole-cell catalyst capable of converting olefins into cyclopropanes, synthetic intermediates used in the synthesis of more functionalized cycloalkanes and acyclic compounds. PMID- 23792738 TI - Stereotactic injection of microRNA-expressing lentiviruses to the mouse hippocampus ca1 region and assessment of the behavioral outcome. AB - MicroRNAs (miRNAs) are small regulatory single-stranded RNA molecules around 22 nucleotides long that may each target numerous mRNA transcripts and dim an entire gene expression pathway by inducing destruction and/or inhibiting translation of these targets. Several miRNAs play key roles in maintaining neuronal structure and function and in higher-level brain functions, and methods are sought for manipulating their levels for exploring these functions. Here, we present a direct in vivo method for examining the cognitive consequences of enforced miRNAs excess in mice by stereotactic injection of miRNA-encoding virus particles. Specifically, the current protocol involves injection into the hippocampal CA1 region, which contributes to mammalian memory consolidation, learning, and stress responses, and offers a convenient injection site. The coordinates are measured according to the mouse bregma and virus perfusion is digitally controlled and kept very slow. After injection, the surgery wound is sealed and the animals recover. Lentiviruses encoding silencers of the corresponding mRNA targets serve to implicate the specific miRNA/target interaction responsible for the observed effect, with naive mice, mice injected with saline and mice injected with "empty" lentivirus vectors as controls. One month post-injection, the animals are examined in the Morris Water Maze (MWM) for assessing their navigation learning and memory abilities. The MWM is a round tank filled with colored water with a small platform submerged 1 cm below the water surface. Steady visual cues around the tank allow for spatial navigation (sound and the earth's magnetic field may also assist the animals in navigating). Video camera monitoring enables measuring the route of swim and the time to find and amount the platform. The mouse is first taught that mounting the hidden platform offers an escape from the enforced swimming; it is then tested for using this escape and finally, the platform is removed and probe tests examine if the mouse remembers its previous location. Repeated tests over several consecutive days highlight improved performance of tested mice at shorter latencies to find and mount the platform, and as more direct routes to reach the platform or its location. Failure to show such improvement represents impaired learning and memory and/or anxiety, which may then be tested specifically (e.g. in the elevated plus maze). This approach enables validation of specific miRNAs and target transcripts in the studied cognitive and/or stress-related processes. PMID- 23792737 TI - Sugar administration is an effective adjunctive therapy in the treatment of Pseudomonas aeruginosa pneumonia. AB - Treatment of acute and chronic pulmonary infections caused by opportunistic pathogen Pseudomonas aeruginosa is limited by the increasing frequency of multidrug bacterial resistance. Here, we describe a novel adjunctive therapy in which administration of a mix of simple sugars-mannose, fucose, and galactose inhibits bacterial attachment, limits lung damage, and potentiates conventional antibiotic therapy. The sugar mixture inhibits adhesion of nonmucoid and mucoid P. aeruginosa strains to bronchial epithelial cells in vitro. In a murine model of acute pneumonia, treatment with the sugar mixture alone diminishes lung damage, bacterial dissemination to the subpleural alveoli, and neutrophil- and IL 8-driven inflammatory responses. Remarkably, the sugars act synergistically with anti-Pseudomonas antibiotics, including beta-lactams and quinolones, to further reduce bacterial lung colonization and damage. To probe the mechanism, we examined the effects of sugars in the presence or absence of antibiotics during growth in liquid culture and in an ex vivo infection model utilizing freshly dissected mouse tracheas and lungs. We demonstrate that the sugar mixture induces rapid but reversible formation of bacterial clusters that exhibited enhanced susceptibility to antibiotics compared with individual bacteria. Our findings reveal that sugar inhalation, an inexpensive and safe therapeutic, could be used in combination with conventional antibiotic therapy to more effectively treat P. aeruginosa lung infections. PMID- 23792739 TI - Draft Genome Sequences for Ten Salmonella enterica Serovar Typhimurium Phage Type 135 Variants. AB - Salmonella enterica serovar Typhimurium (S. Typhimurium) is a common cause of gastroenteritis in humans. Here, we report the draft genome sequences of 10 isolates of an S. Typhimurium phage type 135 variant that is linked to egg associated outbreaks in Tasmania, Australia. PMID- 23792740 TI - Complete Genome Sequences of Azotobacter vinelandii Wild-Type Strain CA and Tungsten-Tolerant Mutant Strain CA6. AB - We report the complete genome sequences of Azotobacter vinelandii mutant strain CA6 and its parent wild-type strain, CA. When fixing nitrogen, strain CA6 displays slow growth and impaired molybdate uptake, tolerance to tungstates, and production of hydrogen gas, compared to results for strain CA. Comparing these genome sequences may provide a genetic basis for these mutant phenotypes. PMID- 23792741 TI - Genome Sequences of a Novel HIV-1 Circulating Recombinant Form (CRF59_01B) Identified among Men Who Have Sex with Men in Northeastern China. AB - We report here a novel HIV-1 circulating recombinant form (CRF) (CRF59_01B) comprised of CRF01_AE and subtype B, with two recombination breakpoints in the pol and vpu-env regions, respectively. CRF59_01B was identified from three epidemiologically unlinked men who have sex with men (MSM) in northeast China. This represents the second CRF identified in the MSM population in China. PMID- 23792742 TI - Genome Sequence of an Environmental Isolate of the Bacterial Pathogen Legionella pneumophila. AB - We report here the genomic sequence of Legionella pneumophila strain LPE509 from the water distribution system of a hospital in Shanghai, China. This is the first complete genome sequence of an environmental L. pneumophila isolate. Genomic analyses identified approximately 600 genes unique to LPE509 compared to those of the 7 available L. pneumophila genomes. PMID- 23792743 TI - Genome Sequences of Industrially Relevant Saccharomyces cerevisiae Strain M3707, Isolated from a Sample of Distillers Yeast and Four Haploid Derivatives. AB - Saccharomyces cerevisiae strain M3707 was isolated from a sample of commercial distillers yeast, and its genome sequence together with the genome sequences for the four derived haploid strains M3836, M3837, M3838, and M3839 has been determined. Yeasts have potential for consolidated bioprocessing (CBP) for biofuel production, and access to these genome sequences will facilitate their development. PMID- 23792744 TI - Draft Genome Sequence of Leucobacter sp. Strain UCD-THU (Phylum Actinobacteria). AB - Here we present the draft genome of Leucobacter sp. strain UCD-THU. The genome contains 3,317,267 bp in 11 scaffolds. This strain was isolated from a residential toilet as part of an undergraduate project to sequence reference genomes of microbes from the built environment. PMID- 23792745 TI - Draft Genome Sequence of the Aeromonas diversa Type Strain. AB - We present here the first genome sequence of the Aeromonas diversa type strain (CECT 4254(T)). This strain was isolated from the leg wound of a patient in New Orleans (Louisiana) and was originally described as enteric group 501 and distinguished from A. schubertii by DNA-DNA hybridization and phenotypical characterization. PMID- 23792746 TI - Complete Genome Sequence of Staphylococcus aureus Strain M1, a Unique t024-ST8 IVa Danish Methicillin-Resistant S. aureus Clone. AB - We report the genome sequence, in five contigs, of a methicillin-resistant Staphylococcus aureus isolate designated M1. This clinical isolate was from the index patient of a methicillin-resistant Staphylococcus aureus (MRSA) outbreak in Copenhagen, Denmark, that started in 2003. This strain is sequence type 8 (ST8), spa type t024, and staphylococcal cassette chromosome mec element (SCCmec) type IVa. PMID- 23792747 TI - Complete Genome Sequence of Propionibacterium avidum Strain 44067, Isolated from a Human Skin Abscess. AB - Propionibacterium avidum is an anaerobic Gram-positive bacterium that forms part of the normal human cutaneous microbiota, colonizing moist areas such as the vestibule of the nose, axilla, and perineum. Here we present the complete genome sequence of P. avidum strain 44067, which was isolated from a carbuncle of the trunk. PMID- 23792748 TI - Draft Genome Sequence for Ralstonia sp. Strain OR214, a Bacterium with Potential for Bioremediation. AB - Ralstonia sp. strain OR214 belongs to the class Betaproteobacteria and was isolated from subsurface sediments in Oak Ridge, TN. A member of this genus has been described as a potential bioremediation agent. Strain OR214 is tolerant to various heavy metals, such as uranium, nickel, cobalt, and cadmium. We present its draft genome sequence here. PMID- 23792749 TI - Draft Genome Sequence for Caulobacter sp. Strain OR37, a Bacterium Tolerant to Heavy Metals. AB - Caulobacter sp. strain OR37 belongs to the class Alphaproteobacteria and was isolated from subsurface sediments in Oak Ridge, TN. Strain OR37 is noteworthy due to its tolerance to high concentrations of heavy metals, such as uranium, nickel, cobalt, and cadmium, and we present its draft genome sequence here. PMID- 23792750 TI - Genome Sequence of Proteus mirabilis Strain PR03, Isolated from a Local Hospital in Malaysia. AB - Proteus mirabilis is one of the pathogenic agents that commonly causes urinary tract infections among elderly individuals and long-term catheterized patients. Here, we report a draft genome sequence of Proteus mirabilis strain PR03 (3,932,623 bp, with a G+C content of 38.6%) isolated from a local hospital in Malaysia. PMID- 23792751 TI - New Volvovirus Isolates from Acheta domesticus (Japan) and Gryllus assimilis (United States). AB - A novel circular single-stranded DNA (ssDNA) virus, volvovirus, from the house cricket has been described recently. Here, we report the isolation of volvoviruses from Acheta domesticus in Japan and Gryllus assimilis in the United States. These Acheta domesticus volvovirus (AdVVV) isolates have genomes of 2,517 and 2,516 nucleotides (nt) and 4 large open reading frames (ORFs). PMID- 23792752 TI - Obsessing about intimate-relationships: testing the double relationship vulnerability hypothesis. AB - BACKGROUND AND OBJECTIVES: Obsessive preoccupation and doubts centering on one's intimate relationship may have a negative impact on the romantic dyad and lead to significant distress. In this research we investigated whether the co-occurrence of attachment anxiety and overreliance on intimate relationships for self-worth what we call double relationship-vulnerability-is linked with relationship centered obsessions and obsessive-compulsive tendencies. METHODS: Study 1 employed a correlational design to examine the link between double relationship vulnerability and relationship-centered obsessions. Study 2 employed an experimental design to assess response to subtle threats to the relationship self domain among individuals with double relationship-vulnerability. RESULTS: Study 1 supported the link between double relationship-vulnerability and relationship centered obsessions. Study 2 showed that when confronted with subtle threats to the relationship self-domain, individuals with double relationship-vulnerability are more likely to experience distress and engage in mitigating behavior in response to relationship doubts and fears. LIMITATIONS: Our studies were conducted with non-clinical samples. CONCLUSIONS: These findings suggest that double relationship-vulnerability may make individuals more susceptible to the development and maintenance of relationship-centered obsessions and compulsions. PMID- 23792753 TI - Symptom dimensions in obsessive-compulsive disorder: differences in distress, interference, appraisals and neutralizing strategies. AB - BACKGROUND AND OBJECTIVES: Cognitive proposals about the mediating role of misinterpretations, emotional reactions, and control strategies in the escalation of obsessional intrusive thoughts (OIT) to clinical obsessions have received only partial support. This study aims to examine these variables, taking into account the obsession/OIT contents and the severity of the obsessive-compulsive disorder (OCD). METHODS: After identifying their most upsetting OIT/obsession, 61 OCD patients and 61 non-clinical individuals assessed the associated distress, interference and appraisals, and the strategies used to control the obsession/OIT. RESULTS: Compared with the nonclinical subjects, OCD individuals scored higher on all variables. The obsession's severity was associated with high disturbance, interference and dysfunctional appraisals, whereas the compulsion's severity was related to specific control strategies. Different obsessional contents produced similar emotional disturbance and interference. However, obsessional contents influence the amount of adscription to different dysfunctional appraisals and the frequency of use of several control strategies. LIMITATIONS: Our conclusions are limited by the scarce number of patients representing the various obsessive contents, specially order. CONCLUSIONS: Overall, superstitious obsessions were more dysfunctionally appraised than the other obsessional contents, inducing both covert and overt neutralizing strategies, whereas contamination obsessions were less dysfunctionally appraised. PMID- 23792754 TI - Knockdown of PsbO leads to induction of HydA and production of photobiological H2 in the green alga Chlorella sp. DT. AB - Green algae are able to convert solar energy to H2 via the photosynthetic electron transport pathway under certain conditions. Algal hydrogenase (HydA, encoded by HYDA) is in charge of catalyzing the reaction: 2H(+)+2e(-)<->H2 but usually inhibited by O2, a byproduct of photosynthesis. The aim of this study was to knockdown PsbO (encoded by psbO), a subunit concerned with O2 evolution, so that it would lead to HydA induction. The alga, Chlorella sp. DT, was then transformed with short interference RNA antisense-psbO (siRNA-psbO) fragments. The algal mutants were selected by checking for the existence of siRNA-psbO fragments in their genomes and the low amount of PsbO proteins. The HYDA transcription and the HydA expression were observed in the PsbO-knockdown mutants. Under semi-aerobic condition, PsbO-knockdown mutants could photobiologically produce H2 which increased by as much as 10-fold in comparison to the wild type. PMID- 23792755 TI - Engineering strategies for improving the CO2 fixation and carbohydrate productivity of Scenedesmus obliquus CNW-N used for bioethanol fermentation. AB - Engineering strategies were applied to improve the cell growth, CO2 fixation ability, and carbohydrate productivity of a Scenedesmus obliquus CNW-N isolate. The resulting carbohydrate-rich microalgal biomass was subsequently utilized as feedstock for ethanol fermentation. The microalga was cultivated with 2.5% CO2 in a photobioreactor on different operation modes. Semi-batch operations with 50% replacement of culture medium resulted in the highest CO2 fixation rate (1546.7 mg L(-1) d(-1)), carbohydrate productivity (467.6 mg L(-1) d(-1)), and bioethanol yield (0.202 g/g biomass). This performance is better than most reported values in the literature. The microalgal biomass can accumulate nearly 50% carbohydrates, as glucose accounted for nearly 80% of the total carbohydrate content. This glucose-predominant carbohydrate composition of the microalga is well suited for fermentative bioethanol production. Therefore, using the proposed carbohydrate-rich microalgal biomass both as the carbon sink and as the feedstock provides a feasible alternative to current carbon-reduction and bioethanol production strategies. PMID- 23792756 TI - Membrane fouling related to microbial community and extracellular polymeric substances at different temperatures. AB - An anoxic-aerobic membrane bioreactor was established to investigate the role of microorganisms and microbial metabolites in membrane fouling at different temperatures. The results showed that the membrane fouling cycle at 303, 293, and 283 K were 30, 29, and 5.5 days, respectively. Polysaccharides dominated the extracellular polymeric substances (EPS) and soluble microbial products (SMP) at 303 and 293 K, instead, proteins was the predominant composition of metabolites at 283 K. The correlation coefficient (r(2)) was calculated to identify the relationship between temperature (T), filtration resistance (R) and compositions of EPS and SMP. In biocake, the EPS polysaccharides (EPSc) was the most correlative factor to temperature (T) and filtration resistance (R); in mixed liquor, the ratio of SMP polysaccharides to proteins (SMPc/p) was the most correlative factor. The microbial community structure and the dominant species was the major reason causing the change of EPS and SMP composition. PMID- 23792757 TI - Denitrification of simulated municipal wastewater treatment plant effluent using a three-dimensional biofilm-electrode reactor: operating performance and bacterial community. AB - A three-dimensional biofilm-electrode reactor (3D-BER) was applied for nitrate removal from simulated municipal wastewater treatment plant (WWTP) effluent. It was found that when the influent C/N ratio ranged from 1.0 to 2.0, both heterotrophic and autotrophic denitrifying microorganisms played important roles in nitrate removal. The extension of hydraulic retention time (HRT) could enhance nitrate removal, but too long HRT was not necessary. A phylogenetic tree of gene sequences in biofilm was established, and the biofilm was abundant with Thauera like and Enterobacter-like bacteria. The results illustrated that 3D-BER is a feasible and effective technology for the denitrification of WWTP effluent with poor organic carbon source. A nitrate removal of 98.3% was obtained with C/N ratio of 3.0 and HRT of 7h. About 85.0-90.0% of nitrate removal was found at a C/N ratio of 1.5 and HRT of 10h due to cooperative heterotrophic and autotrophic denitrification. PMID- 23792758 TI - Nitritation and denitrifying phosphorus removal via nitrite pathway from domestic wastewater in a continuous MUCT process. AB - Nitritation and denitrifying P removal under mode of nitritation and nitrification was investigated in continuous MUCT process treating domestic wastewater. Nitritation was established through short hydraulic retention time to 6 h and low dissolved oxygen concentration of 0.3-0.5 mg/L. Nitritation was stabilized for 95 days with average nitrite accumulation ratio over 90%. Ammonia and total nitrogen removal under nitritation reached 99% and 83%, respectively, much better than complete nitrification. Real-time quantitative PCR assays presented that cell numbers and percentages of ammonia oxidizing bacteria (AOB) population had a clear correlation with nitrite accumulation ratios. The highest percentage of AOB was 13% of total bacterial population. P removal was mainly completed by denitrifying P removal of about 90% occurring in anoxic zone. The P removal efficiency under nitritation was 30% higher than that under complete nitrification. Denitrifying P removal under nitritation was highly beneficial to the treatment of wastewater with limiting carbon source. PMID- 23792759 TI - Intensification of hemicellulose hot-water extraction from spruce wood in a batch extractor--effects of wood particle size. AB - The effect of five different wood particle size fractions between 0.5 and 12.5 mm on hot-water extraction of acetylated water-soluble hemicelluloses from spruce wood with a batch extraction setup at 170 degrees C was investigated. Extraction kinetics, with regard to particle size, was also studied. The purpose was to intensify the hemicellulose extraction for high molar mass hemicelluloses at high yield and purity. About 30% of the wood was dissolved and basically all the hemicelluloses could be extracted. The average molar masses of the extracted hemicelluloses decreased rapidly during the first 10 min of the extraction, but were not much affected by the difference in wood particle sizes. Smaller particles resulted in higher extraction rates. The reaction order was established to be of pseudo-first order for particles above 2mm and 1.5st order for particles smaller than 2mm. The effective diffusion coefficient was determined to be 9.11*10(-10) m(2)/s. PMID- 23792760 TI - The steady state anaerobic digestion of Laminaria hyperborea--effect of hydraulic residence on biogas production and bacterial community composition. AB - Methane production by anaerobic digestion (AD) of macroalgae (seaweed) is a promising algal bioenergy option. Work presented here is primarily based on the AD of Laminaria hyperborea using batch and continuously stirred tank reactors. Extrapolation of data from batch studies to long term continuous reactors was unreliable. A conservative organic loading rate (OLR) of 1 g L(-1) d(-1) was used due to difficulties experienced in achieving steady state performance at an OLR of 1.5 g L(-1) d(-1). Biogas composition and methane yields (60-70%) were near to values expected from terrestrial feedstocks. Biomass washout, as imposed by the dilution rate (i.e., hydraulic residence), had considerable bearing on the biogas generation profile, particularly at >3 hydraulic residences. Inhibition of methanogen growth was linked to nutrient deficiency and potentially antimicrobial compounds associated with the feedstock. Anaerobic digestion of L. hyperborea proved feasible over extended operational periods. PMID- 23792761 TI - Novel expanded porphyrin sensitized solar cells using boryl oxasmaragdyrin as the sensitizer. AB - Oxasmaragdyrin boron complexes were prepared and applied in DSSCs. The HOMO-LUMO energy gap analyses and theoretical calculations revealed that these expanded porphyrins are ideal sensitizers for DSSCs. A device containing oxasmaragdyrin BF2 as the sensitizer achieves an energy conversion efficiency of 5.7%. PMID- 23792762 TI - The role of T56 in controlling the flexibility of the distal histidine in dehaloperoxidase-hemoglobin from Amphitrite ornata. AB - The activation of dehaloperoxidase-hemoglobin (DHP) to form a ferryl intermediate requires the distal histidine, H55, to act as an acid base catalyst. The lack of ancillary amino acids in the distal pocket to assist in this process makes H55 even more important to the formation of active intermediates than in conventional peroxidases. Therefore, one can infer that the precise conformation H55 may greatly affect the enzymatic activity. Using site-direct mutagenesis at position T56, immediately adjacent to H55, we have confirmed that subtle changes in the conformation of H55 affect the catalytic efficiency of DHP. Mutating T56 to a smaller amino acid appears to permit H55 to rotate with relatively low barriers between conformations in the distal pocket, which may lead to an increase in catalytic activity. On the other hand, larger amino acids in the neighboring site appear to restrict the rotation of H55 due to the steric hindrance. In the case of T56V, which is an isosteric mutation, H55 appears less mobile, but forced to be closer to the heme iron than in wild type. Both proximity to the heme iron and flexibility of motion in some of the mutants can result in an increased catalytic rate, but can also lead to protein inactivation due to ligation of H55 to the heme iron, which is known as hemichrome formation. A balance of enzymatic rate and protein stability with respect to hemichrome formation appears to be optimum in wild type DHP (WT-DHP). PMID- 23792763 TI - Efficient synthesis and antiproliferative activity of novel thioether-substituted flavonoids. AB - As widely occurring natural products, flavonoids are an important source for drug discovery, due to their structural diversity and broad-spectrum biological activity. In this work, a library of novel, thioether-substituted flavonoids with diverse heterocyclic groups was synthesized via a microwave-assisted procedure with the advantages of good yields, short times, mild conditions and ready isolation of the products. Their antiproliferative activities were evaluated against six cancer cell lines, HCCLM-7, Hela, MDA-MB-435S, SW-480, Hep-2, and MCF 7 by the MTT-based assay. Compared with the positive control 5-fluorouracil, three compounds, 6a, 6b and 6j were successfully identified as the most promising candidates, due to their higher potency and broad-spectrum bioactivity with IC50 values in the range of 0.43 MUM-6.7 MUM. PMID- 23792764 TI - Efficient construction of novel D-ring modified steroidal dienamides and their cytotoxic activities. AB - Two series of steroidal dienamides 4a-q and 5a-f were designed, synthesized and evaluated for cytotoxic activities against five human cancer cell lines (MGC-803, EC109, PC-3, SMMC-7721 and MCF-7). The protocol developed efficiently achieved the construction of carbon-carbon double bond and selective conversion of nitrile group into carboxamide in one-pot procedure. Besides, compounds 4a-q and 5a-f showed moderate to excellent cytotoxic activities with the IC50 values ranging from 0.1 to 40 MUM and most of them were more potent than 5-fluorouracil. Particularly, four compounds 4d, 4e, 4q and 5a showed excellent selectivity against MGC-803 with the IC50 values less than 1 MUM. Flow cytometry analysis demonstrated that compound 4c caused the cellular early apoptosis and cell cycle arrest in G2/M phase in a concentration-independent manner. PMID- 23792765 TI - Design and synthesis of 2-phenyl-1,4-dioxa-spiro[4.5]deca-6,9-dien-8-ones as potential anticancer agents starting from cytotoxic spiromamakone A. AB - The spirocycle is a key structure found in many bioactive compounds. From the cytotoxic and spirocyclic natural product, spiromamakone A (1) and its analogues, a more synthetically accessible spiroacetal template 4 was designed based on structural similarity analysis. A total of 50 compounds were rapidly synthesized in only one or two synthetic steps from the starting compound, and their cytotoxicity was evaluated. As a result, (+/-)-(2R*,5R*)-2-(4-iodophenyl)-7 chloro-1,4-dioxa-spiro[4.5]deca-6,9-dien-8-one (7d-II) was discovered and found to be fifteen-fold more cytotoxic than 1. The easily accessible spiroacetal 7d-II appeared to act in a manner similar to the highly oxidized natural product, spiromamakone A (1). PMID- 23792766 TI - The hedgehog target Vlk genetically interacts with Gli3 to regulate chondrocyte differentiation during mouse long bone development. AB - Endochondral bone development is orchestrated by the spatially and temporally coordinated differentiation of chondrocytes along the longitudinal axis of the cartilage anlage. Initially, the slowly proliferating, periarticular chondrocytes give rise to the pool of rapidly dividing columnar chondrocytes, whose expansion determines the length of the long bones. The Indian hedgehog (IHH) ligand regulates both the proliferation of columnar chondrocytes and their differentiation into post-mitotic hypertrophic chondrocytes in concert with GLI3, one of the main transcriptional effectors of HH signal transduction. In the absence of Hh signalling, the expression of Vlk (vertebrate lonesome kinase, also called Pkdcc) is increased. We now show that the shortening of limb long bones in Vlk-deficient mouse embryos is aggravated by additional inactivation of Gli3. Our analysis establishes that Vlk and Gli3 synergize to control the temporal kinetics of chondrocyte differentiation during long bone development. Whereas differentiation of limb mesenchymal progenitors into chondrocytes and the initial formation of the cartilage anlagen of the limb skeleton are not altered, Vlk and Gli3 are required for the temporally coordinated differentiation of periarticular into columnar and ultimately hypertrophic chondrocytes in long bones. In limbs lacking both Vlk and Gli3, the appearance of columnar and hypertrophic chondrocytes is severely delayed and zones of morphologically distinct chondrocytes are not established until E16.5. At the molecular level, these morphological alterations are reflected by delayed activation and lowered expression of Ihh, Pth1r and Col10a1 in long bone rudiments of double mutant limbs. In summary, our genetic analysis establishes that VLK plays a role in the IHH/GLI3 interactions and that Vlk and Gli3 cooperate to regulate long bone development by modulating the temporal kinetics of establishing columnar and hypertrophic chondrocyte domains. PMID- 23792767 TI - Cynomolgus monkey induced pluripotent stem cells established by using exogenous genes derived from the same monkey species. AB - Induced pluripotent stem (iPS) cells established by introduction of the transgenes POU5F1 (also known as Oct3/4), SOX2, KLF4 and c-MYC have competence similar to embryonic stem (ES) cells. iPS cells generated from cynomolgus monkey somatic cells by using genes taken from the same species would be a particularly important resource, since various biomedical investigations, including studies on the safety and efficacy of drugs, medical technology development, and research resource development, have been performed using cynomolgus monkeys. In addition, the use of xenogeneic genes would cause complicating matters such as immune responses when they are expressed. In this study, therefore, we established iPS cells by infecting cells from the fetal liver and newborn skin with amphotropic retroviral vectors containing cDNAs for the cynomolgus monkey genes of POU5F1, SOX2, KLF4 and c-MYC. Flat colonies consisting of cells with large nuclei, similar to those in other primate ES cell lines, appeared and were stably maintained. These cell lines had normal chromosome numbers, expressed pluripotency markers and formed teratomas. We thus generated cynomolgus monkey iPS cell lines without the introduction of ecotropic retroviral receptors or other additional transgenes by using the four allogeneic transgenes. This may enable detailed analysis of the mechanisms underlying the reprogramming. In conclusion, we showed that iPS cells could be derived from cynomolgus monkey somatic cells. To the best of our knowledge, this is the first report on iPS cell lines established from cynomolgus monkey somatic cells by using genes from the same species. PMID- 23792769 TI - Achieving constancy in spoken word identification: time course of talker normalization. AB - This event-related potential (ERP) study examines the time course of context dependent talker normalization in spoken word identification. We found three ERP components, the N1 (100-220 ms), the N400 (250-500 ms) and the Late Positive Component (500-800 ms), which are conjectured to involve (a) auditory processing, (b) talker normalization and lexical retrieval, and (c) decisional process/lexical selection respectively. Talker normalization likely occurs in the time window of the N400 and overlaps with the lexical retrieval process. Compared with the nonspeech context, the speech contexts, no matter whether they have semantic content or not, enable listeners to tune to a talker's pitch range. In this way, speech contexts induce more efficient talker normalization during the activation of potential lexical candidates and lead to more accurate selection of the intended word in spoken word identification. PMID- 23792770 TI - Measuring naturally occurring uranium in soil and minerals by analysing the 352 keV gamma-ray peak of 214Pb using a NaI(Tl)-detector. AB - This article investigates the prospect of utilising the 351.9 keV gamma-ray of (214)Pb when determining the concentration of uranium. Soil samples were collected from various locations around South Africa and laboratory gamma ray spectra for each were obtained by means of a NaI(Tl)-detector (7.62*7.62 cm(2)). The potassium, uranium and thorium concentrations where extracted by analysing gamma ray peaks that are associated with these radionuclides. Two separate uranium concentrations were extracted; one by means of the (214)Pb decay and the other one by means of the (214)Bi decay. These uranium concentrations were compared in terms of accuracies and detection limits. PMID- 23792768 TI - Sex steroid receptor expression and localization in benign prostatic hyperplasia varies with tissue compartment. AB - Androgens and estrogens, acting via their respective receptors, are important in benign prostatic hyperplasia (BPH). The goals of this study were to quantitatively characterize the tissue distribution and staining intensity of androgen receptor (AR) and estrogen receptor-alpha (ERalpha), and assess cells expressing both AR and ERalpha, in human BPH compared to normal prostate. A tissue microarray composed of normal prostate and BPH tissue was used and multiplexed immunohistochemistry was performed to detect AR and ERalpha. We used a multispectral imaging platform for automated scanning, tissue and cell segmentation and marker quantification. BPH specimens had an increased number of epithelial and stromal cells and increased percentage of epithelium. In both stroma and epithelium, the mean nuclear area was decreased in BPH relative to normal prostate. AR expression and staining intensity in epithelial and stromal cells was significantly increased in BPH compared to normal prostate. ERalpha expression was increased in BPH epithelium. However, stromal ERalpha expression and staining intensity was decreased in BPH compared to normal prostate. Double positive (AR and ERalpha) epithelial cells were more prevalent in BPH, and fewer double negative (AR and ERalpha) stromal and epithelial negative cells were observed in BPH. These data underscore the importance of tissue layer localization and expression of steroid hormone receptors in the prostate. Understanding the tissue-specific hormone action of androgens and estrogens will lead to a better understanding of mechanisms of pathogenesis in the prostate and may lead to better treatment for BPH. PMID- 23792771 TI - Cafeteria diet induces obesity and insulin resistance associated with oxidative stress but not with inflammation: improvement by dietary supplementation with a melon superoxide dismutase. AB - Oxidative stress is involved in obesity. However, dietary antioxidants could prevent oxidative stress-induced damage. We have previously shown the preventive effects of a melon superoxide dismutase (SODB) on oxidative stress. However, the mechanism of action of SODB is still unknown. Here, we evaluated the effects of a 1-month curative supplementation with SODB on the liver of obese hamsters. Golden Syrian hamsters received either a standard diet or a cafeteria diet composed of high-fat, high-sugar, and high-salt supermarket products, for 15 weeks. This diet resulted in insulin resistance and in increased oxidative stress in the liver. However, inflammatory markers (IL-6, TNF-alpha, and NF-kappaB) were not enhanced and no liver steatosis was detected, although these are usually described in obesity-induced insulin resistance models. After the 1-month supplementation with SODB, body weight and insulin resistance induced by the cafeteria diet were reduced and hepatic oxidative stress was corrected. This could be due to the increased expression of the liver antioxidant defense proteins (manganese and copper/zinc superoxide dismutase, catalase, and glutathione peroxidase). Even though no inflammation was detected in the obese hamsters, inflammatory markers were decreased after SODB supplementation, probably through the reduction of oxidative stress. These findings suggest for the first time that SODB could exert its antioxidant properties by inducing the endogenous antioxidant defense. The mechanisms underlying this induction need to be further investigated. PMID- 23792772 TI - Mitochondrial superoxide mediates labile iron level: evidence from Mn-SOD transgenic mice and heterozygous knockout mice and isolated rat liver mitochondria. AB - Superoxide is the main reactive oxygen species (ROS) generated by aerobic cells primarily in mitochondria. It is also capable of producing other ROS and reactive nitrogen species (RNS). Moreover, superoxide has the potential to release iron from its protein complexes. Unbound or loosely bound cellular iron, known as labile iron, can catalyze the formation of the highly reactive hydroxyl radical. ROS/RNS can cause mitochondrial dysfunction and damage. Manganese superoxide dismutase (Mn-SOD) is the chief ROS-scavenging enzyme and thereby the primary antioxidant involved in protecting mitochondria from oxidative damage. To investigate whether mitochondrial superoxide mediates labile iron in vivo, the levels of labile iron were determined in the tissues of mice overexpressing Mn SOD and heterozygous Mn-SOD-knockout mice. Furthermore, the effect of increased mitochondrial superoxide generation on labile iron levels was determined in isolated rat liver mitochondria exposed to various electron transport inhibitors. The results clearly showed that increased expression of Mn-SOD significantly lowered the levels of labile iron in heart, liver, kidney, and skeletal muscle, whereas decreased expression of Mn-SOD significantly increased the levels of labile iron in the same organs. In addition, the data showed that peroxidative damage to membrane lipids closely correlated with the levels of labile iron in various tissues and that altering the status of Mn-SOD did not alter the status of other antioxidant systems. Results also showed that increased ROS production in isolated liver mitochondria significantly increased the levels of mitochondrial labile iron. These findings constitute the first evidence suggesting that mitochondrial superoxide is capable of releasing iron from its protein complexes in vivo and that it could also release iron from protein complexes contained within the organelle. PMID- 23792773 TI - Signaling pathways involved in isoprostane-mediated fibrogenic effects in rat hepatic stellate cells. AB - Despite evidence supporting a potential role for F2-isoprostanes (F2-IsoP's) in liver fibrosis, their signaling mechanisms are poorly understood. We have previously provided evidence that F2-IsoP's stimulate hepatic stellate cell (HSC) proliferation and collagen hyperproduction by activation of a modified form of isoprostane receptor homologous to the classic thromboxane receptor (TP). In this paper, we examined which signal transduction pathways are set into motion by F2 IsoP's to exert their fibrogenic effects. HSCs were isolated from rat liver, cultured to their activated myofibroblast-like phenotype, and then treated with the isoprostane 15-F2t-isoprostane (15-F2t-IsoP). Inositol trisphosphate (IP3) and adenosine 3',5'-cyclic monophosphate (cAMP) levels were determined using commercial kits. Mitogen-activated protein kinase (MAPK) and cyclin D1 expression was assessed by Western blotting. Cell proliferation and collagen synthesis were determined by measuring [(3)H]thymidine and [(3)H]proline incorporation, respectively. 15-F2t-IsoP elicited an activation of extracellular-signal regulated kinase (ERK), p38 MAPK, and c-Jun NH2-terminal kinase (JNK), which are known to be also regulated by G-protein-coupled receptors. Preincubation with specific ERK (PD98059), p38 (SB203580), or JNK (SP600125) inhibitors prevented 15 F2t-IsoP-induced cell proliferation and collagen synthesis. 15-F2t-IsoP decreased cAMP levels within 30 min, suggesting binding to the TPbeta isoform and activation of Gialpha protein. Also, 15-F2t-IsoP increased IP3 levels within a few minutes, suggesting that the Gq protein pathway is also involved. In conclusion, the fibrogenic effects of F2-IsoP's in HSCs are mediated by downstream activation of MAPKs, through TP binding that couples via both Gqalpha and Gialpha proteins. Targeting TP receptor, or its downstream pathways, may contribute to preventing oxidative damage in liver fibrosis. PMID- 23792774 TI - The effects of acetaldehyde and acrolein on muscle catabolism in C2 myotubes. AB - The toxic aldehydes acetaldehyde and acrolein were previously suggested to damage skeletal muscle. Several conditions in which exposure to acetaldehyde and acrolein is increased were associated with muscle wasting and dysfunction. These include alcoholic myopathy, renal failure, oxidative stress, and inflammation. A main exogenous source of both acetaldehyde and acrolein is cigarette smoking, which was previously associated with increased muscle catabolism. Recently, we have shown that exposure of skeletal myotubes to cigarette smoke stimulated muscle catabolism via increased oxidative stress, activation of p38 MAPK, and upregulation of muscle-specific E3 ubiquitin ligases. In this study, we aimed to investigate the effects of acetaldehyde and acrolein on catabolism of skeletal muscle. Skeletal myotubes differentiated from the C2 myoblast cell line were exposed to acetaldehyde or acrolein and their effects on signaling pathways related to muscle catabolism were studied. Exposure of myotubes to acetaldehyde did not promote muscle catabolism. However, exposure to acrolein caused increased generation of free radicals, activation of p38 MAPK, upregulation of the muscle specific E3 ligases atrogin-1 and MuRF1, degradation of myosin heavy chain, and atrophy of myotubes. Inhibition of p38 MAPK by SB203580 abolished acrolein induced muscle catabolism. Our findings demonstrate that acrolein but not acetaldehyde activates a signaling cascade resulting in muscle catabolism in skeletal myotubes. Although within the limitations of an in vitro study, these findings indicate that acrolein may promote muscle wasting in conditions of increased exposure to this aldehyde. PMID- 23792776 TI - How metalliferous brines line Mexican epithermal veins with silver. AB - We determined the composition of ~30-m.y.-old solutions extracted from fluid inclusions in one of the world's largest and richest silver ore deposits at Fresnillo, Mexico. Silver concentrations average 14 ppm and have a maximum of 27 ppm. The highest silver, lead and zinc concentrations correlate with salinity, consistent with transport by chloro-complexes and confirming the importance of brines in ore formation. The temporal distribution of these fluids within the veins suggests mineralization occurred episodically when they were injected into a fracture system dominated by low salinity, metal-poor fluids. Mass balance shows that a modest volume of brine, most likely of magmatic origin, is sufficient to supply the metal found in large Mexican silver deposits. The results suggest that ancient epithermal ore-forming events may involve fluid packets not captured in modern geothermal sampling and that giant ore deposits can form rapidly from small volumes of metal-rich fluid. PMID- 23792775 TI - Role of direct reactivity with metals in chemoprotection by N-acetylcysteine against chromium(VI), cadmium(II), and cobalt(II). AB - The antioxidant N-acetylcysteine (NAC) is widely used for the assessment of the role of reactive oxygen species (ROS) in various biological processes and adverse drug reactions. NAC has been found to effectively inhibit the toxicity of carcinogenic metals, which was attributed to its potent ROS-suppressive properties. However, the absence of redox activity among some metals and findings from genetic models suggested a more diverse, smaller role of oxidative stress in metal toxicity. Here, we examined mechanisms of chemoprotection by NAC against Cd(II), Co(II), and Cr(VI) in human cells. We found that NAC displayed a broad spectrum chemoprotective activity against all three metals, including suppression of cytotoxicity, apoptosis, p53 activation, and HSP72 and HIF-1alpha upregulation. Cytoprotection by NAC was independent of cellular glutathione. NAC strongly inhibited the uptake of all three metals in histologically different types of human cells, explaining its high chemoprotective potential. A loss of Cr(VI) accumulation by cells was caused by NAC-mediated extracellular reduction of chromate to membrane-impermeative Cr(III). Suppression of Co(II) uptake resulted from a rapid formation of Co(II)-NAC conjugates that were unable to enter cells. Our results demonstrate that NAC acts through more than one mechanism in preventing metal toxicity and its chemoprotective activity can be completely ROS-independent. Good clinical safety and effectiveness in Co(II) sequestration suggest that NAC could be useful in the prevention of tissue accumulation and toxic effects of Co ions released by cobalt-chromium hip prostheses. PMID- 23792777 TI - Distribution of HBV genotypes F and H in Mexico and Central America. AB - The distribution of HBV genotypes is associated with populations of specific geographical regions of the world. We show data from the GenBank sequence database and medical reports, which indicate that HBV genotype H (HBV/H) is mainly distributed in Mexico, whereas HBV genotype F (HBV/F) is distributed in countries from Central America. The phylogenetic analysis and historical records suggest that HBV/H has been present in Mexico even before the arrival of the Spaniards. Interestingly, occult hepatitis B is a common finding in both natives and patients with chronic liver disease in Mexico. This suggests that an immunogenic background could be important during the natural history of liver diseases. The estimated large number of HBV/H-infected patients in Mexico does not correlate with the total number of patients with chronic liver disease and cirrhosis reported in the country. This may be because of the fact that HBV infection is often masked by alcoholic liver disease, HCV coinfection and/or obesity. Here, we analyse the data concerning the distribution of HBV/F and HBV/H genotypes in Central America and Mexico. Specifically, we focus on the effect of molecular epidemiology and pathogenesis of HBV/H. These recent findings reveal new areas of study with therapeutic potential in viral liver diseases. PMID- 23792778 TI - Augmenting transcranial direct current stimulation with (D)-cycloserine for depression: a pilot study. AB - OBJECTIVES: Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that causes changes in cortical excitability. Recent double blind placebo-controlled clinical trials suggest that tDCS may be efficacious in the treatment of depression. Pharmacological agents that prolong the effects of tDCS could lead to greater cumulative changes in cortical excitability, producing greater and more prolonged efficacy. One agent shown to prolong the excitability enhancing effects of tDCS in healthy subjects is D-Cycloserine, a partial agonist at the glycine-binding site of N-methyl-D-aspartate receptors. We investigated whether combining prefrontal tDCS with D-Cycloserine could enhance and/or prolong the antidepressant effect of tDCS. METHODS: Five depressed subjects who had relapsed or failed to achieve remission after receiving a previous course of prefrontal tDCS were recruited. In this open-label pilot study, subjects ingested 100-mg D-Cycloserine 2 hours before tDCS sessions. Subjects received 20 minutes of tDCS at 2 mA on consecutive weekdays for a total of 20 sessions. The anode was placed at pF3 and the cathode at F8 (10/20 system). Clinical response was assessed using the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: The change in Montgomery-Asberg Depression Rating Scale scores was not greater with the combination of D-Cycloserine and tDCS than had previously been produced by tDCS alone. No significant additional adverse effects were reported. CONCLUSIONS: This pilot open-label study found that pretreatment with 100-mg D Cycloserine 2 hours before tDCS was well tolerated but did not enhance the antidepressant efficacy of anodal prefrontal tDCS. PMID- 23792779 TI - Postictal agitation after electroconvulsive therapy: incidence, severity, and propofol as a treatment option. AB - OBJECTIVES: Postictal agitation (PIA) after electroconvulsive therapy (ECT) is a major medical problem. This observational study investigated the incidence and severity of PIA and evaluated propofol as a treatment option in a patient population. METHODS: The study included 14 patients that underwent a series of ECTs performed either with or without an approximately 0.5-mg/kg propofol bolus after the end of an electroencephalography (EEG) seizure. Among other values, we documented PIA incidence and severity as rated by a simple score; orientation to person, time, place, and situation; transfer times to the postanesthesia care (PACU) and inpatient unit; nurses' and patients' rating of recovery period, and others and tested for significant differences. RESULTS: Five minutes after the end of ECT, the patients showed moderate to severe PIA in 8 of 37 ECT sessions. Incidence was significantly lower when patients had received propofol (3/37). Transfer time to the PACU was longer, but transfer time to the inpatient unit was shorter after administration of propofol. The recovery period was rated significantly better after propofol administration by nurses and patients. CONCLUSIONS: A single bolus of propofol administered after the end of the seizure reduced the incidence of post-ECT PIA. The PACU staff and patients rated the emergence period significantly better when propofol was administered. PMID- 23792780 TI - Enhancing thermo-induced recombinant protein production in Escherichia coli by temperature oscillations and post-induction nutrient feeding strategies. AB - Traditional strategies for production of thermo-induced recombinant protein in Escherichia coli consist of a two-phase culture, with an initial growth stage at low temperature (commonly 30 degrees C) followed by a production stage where temperature is increased stepwise (commonly up to 42 degrees C). A disadvantage of such strategies is that growth is inhibited upon temperature increase, limiting the duration of the production stage and consequently limiting recombinant protein production. In this work, a novel oscillatory thermo induction strategy, consisting on temperature fluctuations between 37 and 42 degrees C or 30 and 42 degrees C, was tested for improving recombinant protein production. In addition, the induction schemes were combined with one of three different nutrient feeding strategies: two exponential and one linear. Recombinant human preproinsulin (HPPI), produced under control of the lambdaP(L) cI857 system in the E. coli BL21 strain, was used as the model protein. Compared to the conventional induction scheme at constant temperature (42 degrees C), longer productive times were attained under oscillatory induction, which resulted in a 1.3- to 1.7-fold increase in maximum HPPI concentration. Temperature oscillations led to a 2.3- to 4.0-fold increase in biomass accumulation and a decrease of 48-62% in the concentration of organic acids, compared to conventional induction. Under constant induction, growth ceased upon temperature increase and the maximum concentration of HPPI was 3.9 g/L, regardless of the post-induction feeding strategy used. In comparison, the combination of temperature oscillations and a high nutrient-feeding rate allowed sustained growth after induction and reaching up to 5.8 g/L of HPPI. PMID- 23792781 TI - Development of cell-based assay system that utilizes a hyperactive channel mutant for high-throughput screening of BK(Ca) channel modulators. AB - Development of a cell-based functional assay for large-conductance calcium activated potassium (BK(Ca)) channels is challenging because of the unique requirement of both voltage and high concentrations of Ca2+ for activation of these channels. Here, we describe a new cell-based assay system that utilizes a hyperactive mutant BK(Ca) channel. The hyperactive mutant was generated by introducing two point-mutations into the cytosolic flexible interface between the two RCK domains of the wild-type BK(Ca) channel. The mutant channel exhibited a large negative shift in its conductance-voltage relationship, which indicates activation by modest depolarization at resting concentrations of intracellular Ca2+. Unlike the wild-type BK(Ca) channel, the hyperactive mutant did not require a concomitant increase of intracellular Ca2+ for activation. Despite the observed shift in its voltage activation profile, activity of the mutant channel was further potentiated by a known BK(Ca) channel activator. When tested in a commercially available cell-based K+ channel assay, cell-lines stably expressing the hyperactive BK(Ca) channel generated a strong fluorescence signal under conditions that are typical for voltage-gated K+ channels. In summary, cell-lines expressing the hyperactive mutant BK(Ca) channel represent a new cell-based assay system for investigation of BK(Ca) channels that can be used to screen for novel modulators of these channels. PMID- 23792782 TI - Dynamic protein phosphorylation during the growth of Xanthomonas campestris pv. campestris B100 revealed by a gel-based proteomics approach. AB - Xanthomonas campestris pv. campestris (Xcc) synthesizes huge amounts of the exopolysaccharide xanthan and is a plant pathogen affecting Brassicaceae, among them the model plant Arabidopsis thaliana. Xanthan is produced as a thickening agent at industrial scale by fermentation of Xcc. In an approach based on 2D gel electrophoresis, protein samples from different growth phases were characterized to initialize analysis of the Xanthomonas phosphoproteome. The 2D gels were stained with Pro-Q Diamond phosphoprotein stain to identify putatively phosphorylated proteins. Spots of putatively phosphorylated proteins were excised from the gel and analyzed by mass spectrometry. Three proteins were confirmed to be phosphorylated, the phosphoglucomutase/phosphomannomutase XanA that is important for xanthan and lipopolysaccharide biosynthesis, the phosphoenolpyruvate synthase PspA that is involved in gluconeogenesis, and an anti-sigma factor antagonist RsbR that was so far uncharacterized in xanthomonads. The growth phase in which the samples were collected had an influence on protein phosphorylation in Xcc, particular distinct in case of RsbR, which was phosphorylated during the transition from the late exponential growth phase to the stationary phase. PMID- 23792783 TI - Sex steroid hormone-mediated functional regulation of microglia-like BV-2 cells during hypoxia. AB - 17beta-estradiol (E2) and progesterone (P) are neuroprotective hormones in different neurological disorders and in particular under hypoxic conditions in the brain. Both hormones dampen brain-intrinsic immune responses and regulate local glial cell function. Besides astrocytes which are functionally regulated in a manifold and complex manner, especially microglial cells are in the focus of steroid-mediated neuroprotection. In previous studies using a transient brain artery occlusion model, we demonstrated that microglial characteristics are critically modified after the administration of either E2 or P. We here studied the influence of sex steroids on the murine BV-2 microglia cell line under hypoxic conditions. Hypoxia changed the cell morphology from an amoeboid-like phenotype with processes to a rounded shape of secreting cell type. BV-2 cells expressed both estrogen receptor-beta and progesterone receptors under each condition. Oxygen deprivation increased the expression of inducible nitric oxide synthetase (iNOS) and up-regulated selected cytokines and chemokines. Both hormones selectively prevented the induction of pro-inflammatory iNOS, interleukin IL-1beta, and chemokine ligand CCL5, whereas anti-inflammatory IL-10 and protective TREM 2 were up-regulated by sex steroids. Sex hormones abrogated hypoxia-dependent reduction of BV-2 phagocytic activity. We demonstrate that BV-2 microglia cells respond to hypoxia by enhanced pro-inflammatory cytokine secretion and reduced phagocytic activity. This effect is prevented by sex steroids resulting in a switch of BV-2 cells from a pro-inflammatory to a more anti-inflammatory phenotype. Anti-inflammatory effects of gonadal steroids might directly be mediated through hormone-microglia interactions in addition to known effects via astroglial regulation. PMID- 23792784 TI - Urinary profile of methylprednisolone and its metabolites after oral and topical administrations. AB - Methylprednisolone (MP) is prohibited in sports competitions when administered by systemic routes; however its use by topical administration is allowed. Therefore, analytical approaches to distinguish between these different administration pathways are required. A reporting level of 30ng/mL was established for this purpose. However, the suitability of that reporting level for MP is not known. In the present work, excretion profiles of MP and different metabolites after oral and topical administrations have been compared. A method for the quantification of MP and the qualitative detection of fifteen previously reported metabolites has been validated. The method involved an enzymatic hydrolysis, liquid-liquid extraction and analysis by liquid chromatography coupled to tandem mass spectrometry. The method was found to be linear, selective, precise and accurate. The high sensitivity (limit of detection 0.1ng/mL) and linear range (0.1 250ng/mL) achieved allowed for the quantification of MP at both the low concentrations present after topical administration and the high concentrations detected after oral intake. The method was applied to samples collected after oral (4 or 40mg) and topical administration (10mg of MP aceponate/day for 5 consecutive days) to healthy volunteers. After oral administration, MP and all metabolites were detected in urines collected up to at least 36h. Only MP and five metabolites were detected in samples obtained after topical treatment. As expected, concentrations of MP after topical administration were well below current reporting level (30ng/mL), however 3 out of 4 samples in range 8-24h after the low oral dose (4mg) were also below that concentration. Taking into account metabolites detected after both administration routes, metabolites 16beta,17alpha,21-trihydroxy-6alpha-methylpregna-1,4-diene-3,11,20-trione (M8) and 17alpha,20alpha,21-trihydroxy-6alpha-methylpregna-1,4-diene-3,11-dione (M11) are best markers to differentiate between topical and oral administrations. Their signals after topical administration were lower than those obtained in the first 48h after all oral doses. PMID- 23792786 TI - Purification and microRNA profiling of exosomes derived from blood and culture media. AB - Stable miRNAs are present in all body fluids and some circulating miRNAs are protected from degradation by sequestration in small vesicles called exosomes. Exosomes can fuse with the plasma membrane resulting in the transfer of RNA and proteins to the target cell. Their biological functions include immune response, antigen presentation, and intracellular communication. Delivery of miRNAs that can regulate gene expression in the recipient cells via blood has opened novel avenues for target intervention. In addition to offering a strategy for delivery of drugs or RNA therapeutic agents, exosomal contents can serve as biomarkers that can aid in diagnosis, determining treatment options and prognosis. Here we will describe the procedure for quantitatively analyzing miRNAs and messenger RNAs (mRNA) from exosomes secreted in blood and cell culture media. Purified exosomes will be characterized using western blot analysis for exosomal markers and PCR for mRNAs of interest. Transmission electron microscopy (TEM) and immunogold labeling will be used to validate exosomal morphology and integrity. Total RNA will be purified from these exosomes to ensure that we can study both mRNA and miRNA from the same sample. After validating RNA integrity by Bioanalyzer, we will perform a medium throughput quantitative real time PCR (qPCR) to identify the exosomal miRNA using Taqman Low Density Array (TLDA) cards and gene expression studies for transcripts of interest. These protocols can be used to quantify changes in exosomal miRNAs in patients, rodent models and cell culture media before and after pharmacological intervention. Exosomal contents vary due to the source of origin and the physiological conditions of cells that secrete exosomes. These variations can provide insight on how cells and systems cope with stress or physiological perturbations. Our representative data show variations in miRNAs present in exosomes purified from mouse blood, human blood and human cell culture media. Here we will describe the procedure for quantitatively analyzing miRNAs and messenger RNAs (mRNA) from exosomes secreted in blood and cell culture media. Purified exosomes will be characterized using western blot analysis for exosomal markers and PCR for mRNAs of interest. Transmission electron microscopy (TEM) and immunogold labeling will be used to validate exosomal morphology and integrity. Total RNA will be purified from these exosomes to ensure that we can study both mRNA and miRNA from the same sample. After validating RNA integrity by Bioanalyzer, we will perform a medium throughput quantitative real time PCR (qPCR) to identify the exosomal miRNA using Taqman Low Density Array (TLDA) cards and gene expression studies for transcripts of interest. These protocols can be used to quantify changes in exosomal miRNAs in patients, rodent models and cell culture media before and after pharmacological intervention. Exosomal contents vary due to the source of origin and the physiological conditions of cells that secrete exosomes. These variations can provide insight on how cells and systems cope with stress or physiological perturbations. Our representative data show variations in miRNAs present in exosomes purified from mouse blood, human blood and human cell culture media. PMID- 23792785 TI - Novel therapeutic approaches for the treatment of castration-resistant prostate cancer. AB - Prostate cancer is a leading cause of cancer death in men in developed countries. Once the tumor has achieved a castration-refractory metastatic stage, treatment options are limited with the average survival of patients ranging from two to three years only. Recently, new drugs for treatment of castration-resistant prostate cancer (CRPC) have been approved, and others are in an advanced stage of clinical testing. In this review we provide an overview of the new therapeutic agents that arrived in the clinical praxis or are tested in clinical studies and their mode of action including hormone synthesis inhibitors, new androgen receptor blockers, bone targeting and antiangiogenic agents, endothelin receptor antagonists, growth factor inhibitors, novel radiotherapeutics and taxanes, and immunotherapeutic approaches. Results and limitations from clinical studies as well as future needs for improvement of CRPC treatments are critically discussed. PMID- 23792787 TI - Dual functions of YF3:Eu3+ for improving photovoltaic performance of dye sensitized solar cells. AB - In order to enhance the photovoltaic performance of dye-sensitized solar cell (DSSC), a novel design is demonstrated by introducing rare-earth compound europium ion doped yttrium fluoride (YF3:Eu3+) in TiO2 film in the DSSC. As a conversion luminescence medium, YF3:Eu3+ transfers ultraviolet light to visible light via down-conversion, and increases incident harvest and photocurrent of DSSC. As a p-type dopant, Eu3+ elevates the Fermi level of TiO2 film and thus heightens photovoltage of the DSSC. The conversion luminescence and p-type doping effect are demonstrated by photoluminescence spectra and Mott-Schottky plots. When the ratio of YF3:Eu3+/TiO2 in the doping layer is optimized as 5 wt.%, the light-to-electric energy conversion efficiency of the DSSC reaches 7.74%, which is increased by 32% compared to that of the DSSC without YF3:Eu3+ doping. Double functions of doped rare-earth compound provide a new route for enhancing the photovoltaic performance of solar cells. PMID- 23792788 TI - White-matter microstructure and language lateralization in left-handers: a whole brain MRI analysis. AB - Most people are left-hemisphere dominant for language. However the neuroanatomy of language lateralization is not fully understood. By combining functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI), we studied whether language lateralization is associated with cerebral white-matter (WM) microstructure. Sixteen healthy, left-handed women aged 20-25 were included in the study. Left-handers were targeted in order to increase the chances of involving subjects with atypical language lateralization. Language lateralization was determined by fMRI using a verbal fluency paradigm. Tract-based spatial statistics analysis of DTI data was applied to test for WM microstructural correlates of language lateralization across the whole brain. Fractional anisotropy and mean diffusivity were used as indicators of WM microstructural organization. Right-hemispheric language dominance was associated with reduced microstructural integrity of the left superior longitudinal fasciculus and left sided parietal lobe WM. In left-handed women, reduced integrity of the left-sided language related tracts may be closely linked to the development of right hemispheric language dominance. Our results may offer new insights into language lateralization and structure-function relationships in human language system. PMID- 23792789 TI - The land value impacts of wetland restoration. AB - U.S. regulations require offsets for aquatic ecosystems damaged during land development, often through restoration of alternative resources. What effect does large-scale wetland and stream restoration have on surrounding land values? Restoration effects on real estate values have substantial implications for protecting resources, increasing tax base, and improving environmental policies. Our analysis focuses on the three-county Raleigh-Durham-Chapel Hill, North Carolina region, which has experienced rapid development and extensive aquatic ecological restoration (through the state's Ecosystem Enhancement Program [EEP]). Since restoration sites are not randomly distributed across space, we used a genetic algorithm to match parcels near restoration sites with comparable control parcels. Similar to propensity score analysis, this technique facilitates statistical comparison and isolates the effects of restoration sites on surrounding real estate values. Compared to parcels not proximate to any aquatic resources, we find that, 1) natural aquatic systems steadily and significantly increase parcel values up to 0.75 mi away, and 2) parcels <0.5 mi from EEP restoration sites have significantly lower sale prices, while 3) parcels >0.5 mi from EEP sites gain substantial amenity value. When we control for intervening water bodies (e.g. un-restored streams and wetlands), we find a similar inflection point whereby parcels <0.5 mi from EEP sites exhibit lower values, and sites 0.5-0.75 mi away exhibit increased values. Our work points to the need for higher public visibility of aquatic ecosystem restoration programs and increased public information about their value. PMID- 23792790 TI - Post-axial polydactyly type A2, overgrowth and autistic traits associated with a chromosome 13q31.3 microduplication encompassing miR-17-92 and GPC5. AB - Genomic rearrangements at chromosome 13q31.3q32.1 have been associated with digital anomalies, dysmorphic features, and variable degree of mental disability. Microdeletions leading to haploinsufficiency of miR17~92, a cluster of micro RNA genes closely linked to GPC5 in both mouse and human genomes, has recently been associated with digital anomalies in the Feingold like syndrome. Here, we report on a boy with familial dominant post-axial polydactyly (PAP) type A, overgrowth, significant facial dysmorphisms and autistic traits who carries the smallest germline microduplication known so far in that region. The microduplication encompasses the whole miR17~92 cluster and the first 5 exons of GPC5. This report supports the newly recognized role of miR17~92 gene dosage in digital developmental anomalies, and suggests a possible role of GPC5 in growth regulation and in cognitive development. PMID- 23792791 TI - The use of medical care and the prevalence of serious illness in an adult Prader Willi syndrome cohort. AB - INTRODUCTION: Adults with Prader-Willi syndrome (PWS) have an increased occurrence of several medical conditions. We report on the consequences of high morbidity rates such as prevalence rate of hospital admissions, medication use and surgery in a Dutch cohort of adults with PWS. Special attention is paid to causes and symptoms of serious illness. METHOD: Participants were contacted via the Dutch Prader-Willi Parent Association and through physicians specializing in persons with ID. The persons with PWS and their main caregivers were visited at home. Information was collected through semi-structured interviews on 102 adults with PWS. RESULTS: The need for medical care in the neonatal period is associated with hypotonia and feeding problems. Hospital admissions for respiratory tract infections are frequent. During childhood most hospital admissions were due to PWS syndrome specific surgery. During adolescence hospital admissions occurred for scoliosis surgery and endocrine evaluations. At adult age, hospitalization was associated with inguinal hernia surgery, diabetes mellitus, psychosis, erysipelas, water and drug intoxications. In the older group, respiratory infections were again the main reason for hospital admissions. Frequently used medications at adult age included psychotropics, laxatives, anti-diabetics and dermatologic preparations. Abnormal drinking patterns, problems with anesthesia, decreased ability to vomit, abnormal pain awareness and unpredictable fever responses were frequent and often lead to delayed diagnoses of serious conditions. DISCUSSION: People with PWS are frequent users of medical-care. Reasons for hospitalization and medication use are age specific. Knowledge on the different presentation of symptoms in people with PWS is needed. In case of unexplained illness, disturbances of consciousness and behavioral changes in people with PWS, an infection should be ruled out in the first place. Information from this study may help in preventing conditions and recognizing conditions in an early stage. Adequate preventive management and treatment of PWS related morbidity, could reduce medical care use in the long term and could improve quality adjusted life years. PMID- 23792792 TI - Genetic diversity of HCV in Brazil. AB - BACKGROUND: Many studies have documented the molecular epidemiological scenario of HCV within individual Brazilian states, but we still have an incomplete understanding of the dispersion dynamics of the virus in different regions throughout the country. METHODS: A total of 676 HCV NS5B gene sequences of subtypes 1a (n=321), 1b (n=170) and 3a (n=185), isolated from seven different Brazilian states covering four out of five regions were analysed in the present study. We also analysed 22 HCV NS5B gene sequences of minor genetic variants including genotype 2 (n=13), genotype 4 (n=6) and subtype 5a (n=3). Brazilian HCV sequences were aligned with sequences of non-Brazilian origin and subjected to maximum likelihood phylogenetic analyses. RESULTS: These analyses revealed that the Brazilian HCV epidemic resulted from multiple introductions and autochthonous transmission of subtypes 1a, 1b, 3a and genotypes 2, 4 and 5. Brazilian HCV subtype 1a epidemic is dominated by the dissemination of one major clade; while Brazilian HCV subtypes 1b and 3a epidemics are characterized by concurrent dissemination of several independent HCV lineages. Some HCV Brazilian lineages of subtypes 1a, 1b, 2b and 3a were successful in becoming established and disseminated through several regions in the country. Despite significant phylogenetic intermixing of Brazilian sequences, the distribution of HCV strains from different states across lineages was not completely homogeneous. CONCLUSIONS: These results demonstrate the existence of multiple introductions and local propagation of both prevalent and uncommon HCV genetic variants in Brazil and identify some major Brazilian HCV clades with nationwide dissemination. This study also suggests that the observed HCV diversity in Brazil has been shaped by both frequent viral migration among regions and in situ viral dissemination. PMID- 23792793 TI - Tracking technology: lessons learned in two health care sites. AB - The aim of this study is to describe the process of staff and patient adoption and compliance of a real-time locating system (RTLS) across two health care settings and present lessons learned. While previous work has examined the technological feasibility of tracking staff and patients in a health care setting in real-time, these studies have not described the critical adoption issues that must be overcome for deployment. The ability to track and monitor individual staff and patients presents new opportunities for improving workflow, patient health and reducing health care costs. A RTLS is introduced in both a long-term care and a polytrauma transitional rehabilitation program (PTRP) in a Veterans Hospital to track staff and patient locations and five lessons learned are presented from our experiences and responses to emergent technological, work related and social barriers to adoption. We conclude that successful tracking in a health care environment requires time and careful consideration of existing work, policies and stakeholder needs which directly impact the efficacy of the technology. PMID- 23792794 TI - A hybrid plaque characterization method using intravascular ultrasound images. AB - BACKGROUND: Intravascular ultrasound (IVUS) is an invasive imaging modality that provides high resolution cross-sectional images permitting detailed evaluation of the lumen, outer vessel wall and plaque morphology and evaluation of its composition. Over the last years several methodologies have been proposed which allow automated processing of the IVUS data and reliable segmentation of the regions of interest or characterization of the type of the plaque. OBJECTIVE: In this paper we present a novel methodology for the automated identification of different plaque components in grayscale IVUS images. METHODS: The proposed method is based on a hybrid approach that incorporates both image processing techniques and classification algorithms and allows classification of the plaque into three different categories: Hard Calcified, Hard-Non Calcified and Soft plaque. Annotations by two experts on 8 IVUS examinations were used to train and test our method. RESULTS: The combination of an automatic thresholding technique and active contours coupled with a Random Forest classifier provided reliable results with an overall classification accuracy of 86.14%. CONCLUSIONS: The proposed method can accurately detect the plaque using grayscale IVUS images and can be used to assess plaque composition for both clinical and research purposes. PMID- 23792795 TI - Robot services for elderly with cognitive impairment: testing usability of graphical user interfaces. AB - BACKGROUND: Socially assistive robotics for elderly care is a growing field. However, although robotics has the potential to support elderly in daily tasks by offering specific services, the development of usable interfaces is still a challenge. Since several factors such as age or disease-related changes in perceptual or cognitive abilities and familiarity with computer technologies influence technology use they must be considered when designing interfaces for these users. OBJECTIVE: This paper presents findings from usability testing of two different services provided by a social assistive robot intended for elderly with cognitive impairment: a grocery shopping list and an agenda application. The main goal of this study is to identify the usability problems of the robot interface for target end-users as well as to isolate the human factors that affect the use of the technology by elderly. METHODS: Socio-demographic characteristics and computer experience were examined as factors that could have an influence on task performance. A group of 11 elderly persons with Mild Cognitive Impairment and a group of 11 cognitively healthy elderly individuals took part in this study. Performance measures (task completion time and number of errors) were collected. RESULTS: Cognitive profile, age and computer experience were found to impact task performance. Participants with cognitive impairment achieved the tasks committing more errors than cognitively healthy elderly. Instead younger participants and those with previous computer experience were faster at completing the tasks confirming previous findings in the literature. CONCLUSIONS: The overall results suggested that interfaces and contents of the services assessed were usable by older adults with cognitive impairment. However, some usability problems were identified and should be addressed to better meet the needs and capacities of target end-users. PMID- 23792796 TI - Feasibility of using C-reactive protein for point-of-care testing. AB - BACKGROUND: C-reactive protein (CRP) point-of-care testing (POCT) can be a valuable tool for decision making in primary care. Very few studies have illustrated the utilization of CRP POCT. OBJECTIVE: To conduct a systematic review on the use of CRP POCT in primary care settings and to examine its feasibility and acceptability in an outpatient primary care setting. METHODS: The search was conducted via PubMed. Final articles in the systematic review met inclusion and exclusion criteria. For the feasibility and acceptability analysis, a convenience sample of 20 adult subjects was enrolled and CRP POCT was conducted. RESULTS: Antibiotic prescription was the most predominant outcome assessed, and antibiotic prescription reduction was the most common finding of CRP POCT effectiveness testing. CONCLUSION: CRP POCT can be used to detect inflammation and can reduce antibiotic prescription in primary care. It is a satisfactory procedure that should be available in the primary care setting. PMID- 23792797 TI - ART-ML: a new markup language for modelling and representation of biological processes in cardiovascular diseases. AB - BACKGROUND: With an ever increasing number of biological models available on the internet, a standardized modelling framework is required to allow information to be accessed and visualized. OBJECTIVE: In this paper we propose a novel Extensible Markup Language (XML) based format called ART-ML that aims at supporting the interoperability and the reuse of models of geometry, blood flow, plaque progression and stent modelling, exported by any cardiovascular disease modelling software. ART-ML has been developed and tested using ARTool. ARTool is a platform for the automatic processing of various image modalities of coronary and carotid arteries. METHODS: The images and their content are fused to develop morphological models of the arteries in 3D representations. All the above described procedures integrate disparate data formats, protocols and tools. ART ML proposes a representation way, expanding ARTool, for interpretability of the individual resources, creating a standard unified model for the description of data and, consequently, a format for their exchange and representation that is machine independent. More specifically, ARTool platform incorporates efficient algorithms which are able to perform blood flow simulations and atherosclerotic plaque evolution modelling. Integration of data layers between different modules within ARTool are based upon the interchange of information included in the ART ML model repository. ART-ML provides a markup representation that enables the representation and management of embedded models within the cardiovascular disease modelling platform, the storage and interchange of well-defined information. RESULTS: The corresponding ART-ML model incorporates all relevant information regarding geometry, blood flow, plaque progression and stent modelling procedures. All created models are stored in a model repository database which is accessible to the research community using efficient web interfaces, enabling the interoperability of any cardiovascular disease modelling software models. CONCLUSIONS: ART-ML can be used as a reference ML model in multiscale simulations of plaque formation and progression, incorporating all scales of the biological processes. PMID- 23792798 TI - Huge sciatic neuroma presented 40 years after traumatic above knee amputation. AB - BACKGROUND: An amount of 70,000 minor/major amputees are annually performed for different reasons such as tumor, trauma, perivascular diseases or diabetic ulcera yearly in Germany. Over the course of time a lot of patients get problems with their stump, which leads to an incompatible prosthetic treatment and immobilisation. OBJECTIVE: Handicapped patients are often characterized by a long history of pain. The fact that they often had comorbidities as diabetes, vascular diseases or other metabolic affection, leads to the situation that no other differential diagnoses are taken into account. PATIENTS AND METHODS: We present a case of a 62 year old patient with a history of burning pain with punctum maximum at the dorso-medial part of the distal femur stump 40 years after a traumatic above-knee amputation. He had sought different medical consultations and had a lot of modifications on his prosthesis shaft with partial benefit. The clinical examination confirmed the suspected diagnosis of a stump neuroma from the sciatic nerve, which has been verified in the MRI. Concerning the symptoms and the increasing immobilisation caused by the burning pain, we indicated a surgical revision which includes a resection from the neuroma and a local flap graft correction. RESULTS: Postoperatively he described a complete pain relief. After 6 weeks under weight bearing mobilisation he was 100% free of pain in his new custom-made shaft prosthesis and could mobilised under full bearing. CONCLUSION: We conclude that neurinoma needs to be considered in handicapped patients with such symptomatology and has to be surgically revised, even if that decision especially for handicapped patients is often difficult for the surgeon. PMID- 23792799 TI - Refractory adhesive capsulitis under acitretin therapy. AB - BACKGROUND: Adhesive capsulitis (AC) is characterized by a limited active and passive motion. Although the exact pathology remains unknown, a number of contributing factors are discussed. OBJECTIVE: AC has probably been caused by the Re-PUVA therapy (PUVA irradiation plus acitretin) of a cutaneous T-cell lymphoma, type mycosis fungoides. Acitretin belongs to the group of retinoids and is often used in cornification disorders. METHODS: After non-successful initial conservative therapy with intraarticular steroid injections and physical therapy, a significant improvement of shoulder joint mobility was finally achieved by an arthroscopic juxtaglenoid capsulotomy and adhesiolysis. RESULTS: A therapy with acitretin should be considered as a possible trigger of AC. CONCLUSIONS: Patient's medication should be checked carefully on possible triggers of AC. The athroscopic adhesiolysis is an effective method for a frustrating conservative treatment of AC. PMID- 23792800 TI - Computational tools for the analysis of mechanical functionality of gastrointestinal structures. AB - BACKGROUND AND OBJECTIVE: The gastrointestinal tract is a primary district of the living organism that shows a complex configuration in terms of biological tissues and structural conformation. The investigation of tissues mechanical functionality in healthy and degenerative conditions is mandatory to plan and design innovative diagnostic and surgical procedures. The aim of this work is to provide some tools for the mechanical analysis of gastrointestinal structures. METHODS: Computational methods allow for evaluating tissues behaviour and interaction phenomena between biomedical devices, prosthetic elements and tissues themselves. The approach envisages a strong integration of expertise from different areas, proceeding from medicine to bioengineering, computational and experimental biomechanics, bio-robotics and materials science. The development of computational models of gastrointestinal structures requires data from histological analysis and mechanical testing, together with engineering and mathematical skills for the definition of constitutive formulations and numerical procedures. RESULTS AND CONCLUSION: An outline of the computational mechanics approach to the investigation of the gastrointestinal tissues and structures response is reported. A general formulation is presented together with specific applications to oesophageal and colonic tissues. Preliminary results from the numerical analysis of interaction phenomena between colonoscopy devices and tissues are also proposed to address to aspects that allow for an evaluation of feasibility and reliability of the proposed approach. PMID- 23792801 TI - Transfusion-associated graft versus host disease in the immunocompetent patient: an ongoing problem. AB - Transfusion associated-graft versus host disease (TA-GVHD) is a rare complication of blood transfusion. It carries a very high mortality rate. Although the phenomenon has been well described in immunocompromised patients, this review focuses on the immunocompetent host. Cases of TA-GVHD continue to be reported following a variety of surgical procedures, especially cardiac procedures requiring cardiopulmonary bypass. Additional risk factors for TA-GVHD include blood component transfusion in populations with limited genetic diversity, the use of directed donations from family members, and the transfusion of fresh blood. As there is no effective treatment, the focus is on prevention. PMID- 23792802 TI - Argonaute 1 is indispensable for juvenile hormone mediated oogenesis in the migratory locust, Locusta migratoria. AB - Juvenile hormone (JH) is the primary hormone controlling vitellogenesis and oocyte maturation in the migratory locust Locusta migratoria, an evolutionarily primitive insect species with panoistic ovaries. However, molecular mechanisms of locust oogenesis remain unclear and the role of microRNA (miRNA) in JH mediated locust vitellogenesis and oocyte maturation has not been explored. Using miRNA sequencing and quantification with small RNA libraries derived from fat bodies of JH-deprived versus JH analog-exposed female adult locusts, we have identified 83 JH up-regulated and 60 JH down-regulated miRNAs. QRT-PCR validation has confirmed that transcription of selected miRNAs responded to JH administration and correlated with changes in endogenous hemolymph JH titers. Depletion of Argonaute 1 (Ago1), a key regulator of miRNA biogenesis and function by RNAi in female adult locusts dramatically decreased the expression of vitellogenin (Vg) and severely impaired follicular epithelium development, terminal oocyte maturation and ovarian growth. Our data indicate that Ago1 and Ago1-dependent miRNAs play a crucial role in locust vitellogenesis and egg production. PMID- 23792803 TI - Colorimetric visualization of acid-base equilibria in non-polar solvent. AB - Visualization of an acid-base equilibrium in a non-polar solvent (dichloromethane), which may be extended to other solvents, is reported. It is based on an oxoporphyrinogen as a multichromic indicator of prevailing acidity in solution and presents up to six distinct hues depending on degree of protonation, tautomeric state or presence of a basic guest. PMID- 23792804 TI - Web-based educational activities developed by the Society for Neuroscience in Anesthesiology and Critical Care (SNACC): the experience of process, utilization, and expert evaluation. AB - BACKGROUND: Web-based delivery of educational material by scientific societies appears to have increased recently. However, the utilization of such efforts by the members of professional societies is unknown. We report the experience with delivery of educational resources on the Web site of the Society for Neuroscience in Anesthesiology and Critical Care (SNACC), and utilization of those resources by members. METHODS: Three web-based educational initiatives were developed over 1 year to be disseminated through the SNACC Web site (http://www.snacc.org) for society members: (1) The SNACC Bibliography; (2) "Chat with the Author"; and (3) Clinical Case Discussions. Content experts and authors of important new research publications were invited to contribute. Member utilization data were abstracted with the help of the webmaster. RESULTS: For the bibliography, there were 1175 page requests during the 6-month period after its launch by 122/664 (19%) distinct SNACC members. The bibliography was utilized by 107/553 (19%) of the active members and 15/91 (16.5%) of the trainee members. The "Chats with the Authors" were viewed by 56 (9%) members and the Clinical Case Discussions by 51 (8%) members. CONCLUSIONS: Educational resources can be developed in a timely manner utilizing member contributions without additional financial implications. However, the member utilization of these resources was lower than expected. These are first estimates of utilization of web-based educational resources by members of a scientific society. Further evaluation of such utilization by members of other societies as well as measures of the effectiveness and impact of such activities is needed. PMID- 23792805 TI - Ontology-guided organ detection to retrieve web images of disease manifestation: towards the construction of a consumer-based health image library. AB - BACKGROUND: Visual information is a crucial aspect of medical knowledge. Building a comprehensive medical image base, in the spirit of the Unified Medical Language System (UMLS), would greatly benefit patient education and self-care. However, collection and annotation of such a large-scale image base is challenging. OBJECTIVE: To combine visual object detection techniques with medical ontology to automatically mine web photos and retrieve a large number of disease manifestation images with minimal manual labeling effort. METHODS: As a proof of concept, we first learnt five organ detectors on three detection scales for eyes, ears, lips, hands, and feet. Given a disease, we used information from the UMLS to select affected body parts, ran the pretrained organ detectors on web images, and combined the detection outputs to retrieve disease images. RESULTS: Compared with a supervised image retrieval approach that requires training images for every disease, our ontology-guided approach exploits shared visual information of body parts across diseases. In retrieving 2220 web images of 32 diseases, we reduced manual labeling effort to 15.6% while improving the average precision by 3.9% from 77.7% to 81.6%. For 40.6% of the diseases, we improved the precision by 10%. CONCLUSIONS: The results confirm the concept that the web is a feasible source for automatic disease image retrieval for health image database construction. Our approach requires a small amount of manual effort to collect complex disease images, and to annotate them by standard medical ontology terms. PMID- 23792806 TI - Cognitive constraints on constituent order: evidence from elicited pantomime. AB - To what extent does human cognition influence the structure of human language? Recent experiments using elicited pantomime suggest that the prevalence of Subject-Object-Verb (SOV) order across the world's languages may arise in part because SOV order is most compatible with how we conceptually represent transitive events (Goldin-Meadow, So, Ozyurek, & Mylander, 2008). However, this raises the question as to why non-SOV orders exist. Two recent studies (Meir, Lifshitz, Ilkbasaran, & Padden, 2010; Gibson et al., 2013) suggest that SOV might be suboptimal for describing events in which both the agent and patient are plausible agents (e.g. a woman pushing a boy); we call these "reversible" events. We replicate these findings using elicited pantomime and offer a new interpretation. Meir et al.'s (2010) account is framed largely in terms of constraints on comprehension, while Gibson et al.'s (2013) account involves minimizing the risk of information loss or memory degradation. We offer an alternative hypothesis that is grounded in constraints on production. We consider the implications of these findings for the distribution of constituent order in the world's spoken languages and for the structure of emerging sign languages. PMID- 23792807 TI - Functionalized nanospheres for targeted delivery of paclitaxel. AB - Targeted delivery of anti-cancer agents to cancer cells is a mature line of investigation that has yet to realize its full potential. In this study we report on the development of a delivery platform with the future goal of merging two thus far parallel methods for selective elimination of cancer cells: targeted nanospheres and pretargeted radioimmunotherapy. Several clinical trials have shown the promise of pretargeted radioimmunotherapy, which leverages the specificity of antibodies for targeted cell populations and delivers a localized dose of a biotinylated radionuclide that is most often administered following binding of a biotinylated antibody and streptavidin (StA) to the target cells. The work presented here describes the development of biotinylated nanospheres based on an ABA-type copolymer comprised of a tyrosine-derived oligomer as the B block and poly(ethylene glycol) (PEG) A-blocks. The biotinylated nanospheres encapsulate paclitaxel (PTX) to the same extent as unbiotinylated nanospheres. Efficacy of targeting was shown on CD44 positive cells in the SUM159 breast cancer cell line by incubating the cells sequentially with a biotinylated anti CD44 antibody, StA and the biotinylated nanospheres encapsulating PTX. Targeted nanospheres achieved the half maximal inhibitory concentration of PTX on SUM159 cells at a 5-10 fold lower concentration than that of PTX applied in either non targeted nanospheres or free drug approaches. Moreover, targeted nanospheres selectively eliminated CD44 positive SUM159 cells compared to free PTX and untargeted nanospheres. This new generation of nano-sized carrier offers a versatile platform that can be adopted for a wide variety of drug and target specific applications and has the potential to be combined with the clinically emerging method of pretargeted radioimmunotherapy. PMID- 23792808 TI - Application of time-resolved fluorescence for direct and continuous probing of release from polymeric delivery vehicles. AB - Though accurately evaluating the kinetics of release is critical for validating newly designed therapeutic carriers for in vivo applications, few methods yet exist for release measurement in real time and without the need for any sample preparation. Many of the current approaches (e.g. chromatographic methods, absorption spectroscopy, or NMR spectroscopy) rely on isolation of the released material from the loaded vehicles, which require additional sample purification and can lead to loss of accuracy when probing fast kinetics of release. In this study we describe the use of time-resolved fluorescence for in situ monitoring of small molecule release kinetics from biodegradable polymeric drug delivery systems. This method relies on the observation that fluorescent reporters being released from polymeric drug delivery systems possess distinct excited-state lifetime components, reflecting their different environments in the particle suspensions, i.e., confined in the polymer matrices or free in the aqueous environment. These distinct lifetimes enable real-time quantitative mapping of the relative concentrations of dye in each population to obtain precise and accurate temporal information on the release profile of particular carrier/payload combinations. We found that fluorescence lifetime better distinguishes subtle differences in release profiles (e.g. differences associated with dye loading) than conventional steady-state fluorescence measurements, which represent the averaged dye behavior over the entire scan. Given the method's applicability to both hydrophobic and hydrophilic cargo, it could be employed to model the release of any drug-carrier combination. PMID- 23792810 TI - Using chronic social stress to model postpartum depression in lactating rodents. AB - Exposure to chronic stress is a reliable predictor of depressive disorders, and social stress is a common ethologically relevant stressor in both animals and humans. However, many animal models of depression were developed in males and are not applicable or effective in studies of postpartum females. Recent studies have reported significant effects of chronic social stress during lactation, an ethologically relevant and effective stressor, on maternal behavior, growth, and behavioral neuroendocrinology. This manuscript will describe this chronic social stress paradigm using repeated exposure of a lactating dam to a novel male intruder, and the assessment of the behavioral, physiological, and neuroendocrine effects of this model. Chronic social stress (CSS) is a valuable model for studying the effects of stress on the behavior and physiology of the dam as well as her offspring and future generations. The exposure of pups to CSS can also be used as an early life stress that has long term effects on behavior, physiology, and neuroendocrinology. PMID- 23792809 TI - A small molecule modulates Jumonji histone demethylase activity and selectively inhibits cancer growth. AB - The pharmacological inhibition of general transcriptional regulators has the potential to block growth through targeting multiple tumorigenic signalling pathways simultaneously. Here, using an innovative cell-based screen, we identify a structurally unique small molecule (named JIB-04) that specifically inhibits the activity of the Jumonji family of histone demethylases in vitro, in cancer cells, and in tumours in vivo. Unlike known inhibitors, JIB-04 is not a competitive inhibitor of alpha-ketoglutarate. In cancer, but not in patient matched normal cells, JIB-04 alters a subset of transcriptional pathways and blocks viability. In mice, JIB-04 reduces tumour burden and prolongs survival. Importantly, we find that patients with breast tumours that overexpress Jumonji demethylases have significantly lower survival. Thus, JIB-04, a novel inhibitor of Jumonji demethylases in vitro and in vivo, constitutes a unique potential therapeutic and research tool against cancer, and validates the use of unbiased cellular screens to discover chemical modulators with disease relevance. PMID- 23792811 TI - Role of Engrailed-2 (EN2) as a prostate cancer detection biomarker in genetically high risk men. AB - Controversy surrounds the use of PSA as a biomarker for prostate cancer detection, leaving an unmet need for a novel biomarker in this setting; urinary EN2 may identify individuals with clinically relevant prostate cancer. Male BRCA1 and BRCA2 mutation carriers are at increased risk of clinically significant prostate cancer and may benefit from screening. Urine samples from 413 BRCA1 and BRCA2 mutation carriers and controls were evaluated. Subjects underwent annual PSA screening with diagnostic biopsy triggered by PSA > 3.0 ng/ml; 21 men were diagnosed with prostate cancer. Urinary EN2 levels were measured by ELISA and had a sensitivity of 66.7% and specificity of 89.3% for cancer detection. There was no statistically significant difference in EN2 levels according to genetic status or Gleason score. Urinary EN2 may be useful as a non-invasive early biomarker for prostate cancer detection in genetically high-risk individuals. PMID- 23792812 TI - Drug metabolites as cytochrome p450 inhibitors: a retrospective analysis and proposed algorithm for evaluation of the pharmacokinetic interaction potential of metabolites in drug discovery and development. AB - Understanding drug-drug interactions (DDIs) is a key component of clinical practice ensuring patient safety and efficacy of medicines. The role of drug metabolites in DDIs is a developing area of science, and has been recently highlighted in a draft regulatory guidance. The guidance states that metabolites representing >=25% of the parent drug's area under the plasma concentration/time curve and/or >10% of exposure of total drug-related material should trigger in vitro characterization of metabolites for cytochrome P450 inhibition and propensity for DDIs. The relationship between in vitro cytochrome P450 inhibitory potency, systemic exposure, and DDI potential of drug metabolites was examined using the Pfizer development database to identify compounds with pre-existing in vivo biotransformation data, where circulating metabolites were identified in humans. The database yielded 33 structurally diverse compounds with collectively 115 distinct circulating metabolites. Of these, 52% (60/115) achieved exposures >25% of parent drug levels as judged from mass balance/metabolite identification studies. It was noted that 14 metabolite standards for 12 parent drugs had been synthesized, monitored in clinical studies, and examined for cytochrome P450 inhibition. For the 14 metabolite/parent drug pairs, no clinically relevant DDIs were expected to occur against the major human cytochrome P450 isoforms. A review of the literature for parent/metabolite DDI information was also conducted to examine trends using a larger data set. Leveraging the analysis of both internal and literature-based data sets, an algorithm was devised for use in drug discovery/early development to assess cytochrome P450 inhibitory potential of drug metabolites and the propensity to cause a clinically relevant DDI. PMID- 23792813 TI - Critical review of preclinical approaches to investigate cytochrome p450-mediated therapeutic protein drug-drug interactions and recommendations for best practices: a white paper. AB - Drug-drug interactions (DDIs) between therapeutic proteins (TPs) and small molecule drugs have recently drawn the attention of regulatory agencies, the pharmaceutical industry, and academia. TP-DDIs are mainly caused by proinflammatory cytokine or cytokine modulator-mediated effects on the expression of cytochrome P450 enzymes. To build consensus among industry and regulatory agencies on expectations and challenges in this area, a working group was initiated to review the preclinical state of the art. This white paper represents the observations and recommendations of the working group on the value of in vitro human hepatocyte studies for the prediction of clinical TP-DDI. The white paper was developed following a "Workshop on Recent Advances in the Investigation of Therapeutic Protein Drug-Drug Interactions: Preclinical and Clinical Approaches" held at the Food and Drug Administration White Oak Conference Center on June 4 and 5, 2012. Results of a workshop poll, cross-laboratory data comparisons, and the overall recommendations of the in vitro working group are presented herein. The working group observed that evaluation of TP-DDI for anticytokine monoclonal antibodies is currently best accomplished with a clinical study in patients with inflammatory disease. Treatment-induced changes in appropriate biomarkers in phase 2 and 3 studies may indicate the potential for a clinically measurable treatment effect on cytochrome P450 enzymes. Cytokine mediated DDIs observed with anti-inflammatory TPs cannot currently be predicted using in vitro data. Future success in predicting clinical TP-DDIs will require an understanding of disease biology, physiologically relevant in vitro systems, and more examples of well conducted clinical TP-DDI trials. PMID- 23792814 TI - Bioinformatics methods for the analysis of hepatitis viruses. AB - HBV and HCV are the only hepatotropic viruses capable of establishing chronic infections. More than 500 million people worldwide are estimated to have chronic infections with HBV and/or HCV, and they have an increased risk of developing liver complications, such as cirrhosis or hepatocellular carcinoma. During the past decade, several antiviral agents including immune-modulatory drugs and nucleoside/nucleotide analogues have been approved for the treatment of HBV and HCV infections. In recent years, the focus has been on the development of new and better therapeutic agents for management of chronic HCV infections. Bioinformatics has only been applied recently to the field of viral hepatitis research. In addition to the wide range of general tools freely available for identification of open reading frames, gene prediction, homology searching, sequence alignment, and motif and epitope recognition, several public database systems designed specifically for HBV and HCV research have now been developed. The focus of these databases ranged from being viral sequence repositories for the provision of bioinformatics tools for viral genome analysis, as well as HBV or HCV drug resistance prediction. This review provides an overview of these public databases, which have integrated bioinformatics tools for HBV and HCV research. Properly managed and developed, these databases have the potential to have a broad effect on hepatitis research and treatment strategies. However, the effect will depend on the comprehensive collection of not only molecular sequence data, but also anonymous patient clinical and treatment data. PMID- 23792815 TI - Towards setting environmental water temperature guidelines: a South African example. AB - Water temperature is a primary factor affecting the number and kinds of species in a stream. A key step towards including water temperatures in environmental flow assessments is to develop metrics which describe natural variability in a river's thermal regime. This is best achieved using time series analyses, where metrics are defined based either on time series disaggregation, or shapes of regimes defined using agglomerative techniques. The aim of this paper was to refine approaches in setting environmental water temperature guidelines for inclusion in defining environmental flows assessments. Annual water temperature series from 82 sites sampled across 48 rivers (mainstems and tributaries) in ten catchments in the southern Cape region of South Africa were described using 39 metrics based on the magnitude, frequency, duration and timing of thermal events. Sites were classified into thermal groups using their similarity in multivariate temperature regime and variation amongst groups along important temperature gradients examined. Deviation from a natural range of variability using a thermal confidence envelope is a suitable approach for broad evaluation of thermal guidelines. The approach presented can be applied at multiple levels of complexity to assess which elements of a thermal time series fall outside of reference conditions. Further steps in this approach are to link thermal patterns to biotic metrics, and gain a clearer understanding of interactions between flows, temperatures and biota, particularly below impoundments. Research on improving approaches in defining thermal regions is recommended. PMID- 23792816 TI - The effects of fencing on carbon stocks in the degraded alpine grasslands of the Qinghai-Tibetan Plateau. AB - Quantifying the carbon storage of grasslands under different management strategies can help us understand how this ecosystem responds to different land management practices. To assess the C cycle and the importance of soil microbial biomass carbon, we measured the levels of soil organic carbon, biomass carbon (above- and underground) and soil microbial biomass carbon in areas with different grazing intensities and different management strategy (fenced and unfenced) in the Qinghai-Tibetan Plateau. We also calculated the ratio of soil microbial biomass carbon to soil organic carbon as an indicator of the soil organic matter availability and quality. Results showed that degradation had significant effects on the soil organic carbon, biomass carbon and microbial biomass carbon (P < 0.05). However, fencing only had a significant effect on the non-degraded and moderately degraded grasslands (P < 0.05). We also found that the level of soil microbial biomass carbon was positively correlated with the biomass carbon and soil organic carbon. From our research, we concluded that the level of soil microbial biomass carbon was crucial to the C cycle in the alpine grasslands and that fencing may be an important management strategy for restoring lightly or moderately degraded grassland in the Qinghai-Tibetan Plateau. PMID- 23792817 TI - Participatory modelling to support decision making in water management under uncertainty: two comparative case studies in the Guadiana river basin, Spain. AB - A participatory modelling process has been conducted in two areas of the Guadiana river (the upper and the middle sub-basins), in Spain, with the aim of providing support for decision making in the water management field. The area has a semi arid climate where irrigated agriculture plays a key role in the economic development of the region and accounts for around 90% of water use. Following the guidelines of the European Water Framework Directive, we promote stakeholder involvement in water management with the aim to achieve an improved understanding of the water system and to encourage the exchange of knowledge and views between stakeholders in order to help building a shared vision of the system. At the same time, the resulting models, which integrate the different sectors and views, provide some insight of the impacts that different management options and possible future scenarios could have. The methodology is based on a Bayesian network combined with an economic model and, in the middle Guadiana sub-basin, with a crop model. The resulting integrated modelling framework is used to simulate possible water policy, market and climate scenarios to find out the impacts of those scenarios on farm income and on the environment. At the end of the modelling process, an evaluation questionnaire was filled by participants in both sub-basins. Results show that this type of processes are found very helpful by stakeholders to improve the system understanding, to understand each other's views and to reduce conflict when it exists. In addition, they found the model an extremely useful tool to support management. The graphical interface, the quantitative output and the explicit representation of uncertainty helped stakeholders to better understand the implications of the scenario tested. Finally, the combination of different types of models was also found very useful, as it allowed exploring in detail specific aspects of the water management problems. PMID- 23792818 TI - Performance of a commercial industrial-scale UF-based process for treatment of oily wastewaters. AB - An evaluation was made of the performance of a commercial industrial-scale ultrafiltration (UF)-based process for treatment of highly concentrated oily wastewaters. Wastewater samples were gathered from two plants treating industrial wastewaters in 2008, and in 2011 (only from one of the plants), from three points of a UF-based treatment train. The wastewater samples were analyzed by measuring the BOD7, COD, TOC and total surface charge (TSC). The inorganic content and zeta potentials of the samples were analyzed and GC-FID/MS analyses were performed. The removal performances of BOD7, COD, TOC and TSC in 2008 and 2011 for both plants were very high. Initial concentrations of contaminants in 2011 were lower than in 2008, therefore the COD and TSC reductions were also lower in 2011 than three years before. Regardless of the high performance of UF-based processes in both plants, at times the residual concentrations were considerable. This could be explained by the high initial concentrations and also by the presence of the dissolved compounds that were characterized. Linear correlation was observed between COD and TOC, and between COD and TSC. The correlation between COD and TSC could be utilized for process control purposes. PMID- 23792819 TI - Removal of triazine herbicides from aqueous systems by a biofilm reactor continuously or intermittently operated. AB - The impact of pesticide movement via overland flow or tile drainage water on the quality of receiving water bodies has been a serious concern in the last decades; thus, for remediation of water contaminated with herbicides, bioreaction systems designed to retain biomass have been proposed. In this context, the aim of this study was to evaluate the atrazine and terbutryn biodegradation capacity of a microbial consortium, immobilized in a biofilm reactor (PBR), packed with fragments of porous volcanic stone. The microbial consortium, constituted by four predominant bacterial strains, was used to degrade a commercial formulation of atrazine and terbutryn in the biofilm reactor, intermittently or continuously operated at volumetric loading rates ranging from 44 to 306 mg L(-1) d(-1). The complete removal of both herbicides was achieved in both systems; however, higher volumetric removal rates were obtained in the continuous system. It was demonstrated that the adjuvants of the commercial formulation of the herbicide significantly enhanced the removal of atrazine and terbutryn. PMID- 23792820 TI - Wastewater disposal to landfill-sites: a synergistic solution for centralized management of olive mill wastewater and enhanced production of landfill gas. AB - The present paper focuses on a largely unexplored field of landfill-site valorization in combination with the construction and operation of a centralized olive mill wastewater (OMW) treatment facility. The latter consists of a wastewater storage lagoon, a compact anaerobic digester operated all year round and a landfill-based final disposal system. Key elements for process design, such as wastewater pre-treatment, application method and rate, and the potential effects on leachate quantity and quality, are discussed based on a comprehensive literature review. Furthermore, a case-study for eight (8) olive mill enterprises generating 8700 m(3) of wastewater per year, was conceptually designed in order to calculate the capital and operational costs of the facility (transportation, storage, treatment, final disposal). The proposed facility was found to be economically self-sufficient, as long as the transportation costs of the OMW were maintained at <=4.0 ?/m(3). Despite that EU Landfill Directive prohibits wastewater disposal to landfills, controlled application, based on appropriately designed pre-treatment system and specific loading rates, may provide improved landfill stabilization and a sustainable (environmentally and economically) solution for effluents generated by numerous small- and medium-size olive mill enterprises dispersed in the Mediterranean region. PMID- 23792821 TI - Thermo-chemical process with sewage sludge by using CO2. AB - This work proposed a novel methodology for energy recovery from sewage sludge via the thermo-chemical process. The impact of CO2 co-feed on the thermo-chemical process (pyrolysis and gasification) of sewage sludge was mainly investigated to enhance thermal efficiency and to modify the end products from the pyrolysis and gasification process. The CO2 injected into the pyrolysis and gasification process enhance the generation of CO. As compared to the thermo-chemical process in an inert atmosphere (i.e., N2), the generation of CO in the presence of CO2 was enhanced approximately 200% at the temperature regime from 600 to 900 degrees C. The introduction of CO2 into the pyrolysis and gasification process enabled the condensable hydrocarbons (tar) to be reduced considerably by expediting thermal cracking (i.e., approximately 30-40%); thus, exploiting CO2 as chemical feedstock and/or reaction medium for the pyrolysis and gasification process leads to higher thermal efficiency, which leads to environmental benefits. This work also showed that sewage sludge could be a very strong candidate for energy recovery and a raw material for chemical feedstock. PMID- 23792822 TI - Biofuels as a sustainable energy source: an update of the applications of proteomics in bioenergy crops and algae. AB - Sustainable energy is the need of the 21st century, not because of the numerous environmental and political reasons but because it is necessary to human civilization's energy future. Sustainable energy is loosely grouped into renewable energy, energy conservation, and sustainable transport disciplines. In this review, we deal with the renewable energy aspect focusing on the biomass from bioenergy crops to microalgae to produce biofuels to the utilization of high throughput omics technologies, in particular proteomics in advancing our understanding and increasing biofuel production. We look at biofuel production by plant- and algal-based sources, and the role proteomics has played therein. This article is part of a Special Issue entitled: Translational Plant Proteomics. PMID- 23792823 TI - Protein isoform-specific validation defines multiple chloride intracellular channel and tropomyosin isoforms as serological biomarkers of ovarian cancer. AB - New serological biomarkers for early detection and clinical management of ovarian cancer are urgently needed, and many candidates have been reported. A major challenge frequently encountered when validating candidates in patients is establishing quantitative assays that distinguish between highly homologous proteins. The current study tested whether multiple members of two recently discovered ovarian cancer biomarker protein families, chloride intracellular channel (CLIC) proteins and tropomyosins (TPM), were detectable in ovarian cancer patient sera. A multiplexed, label-free multiple reaction monitoring (MRM) assay was established to target peptides specific to all detected CLIC and TPM family members, and their serum levels were quantitated for ovarian cancer patients and non-cancer controls. In addition to CLIC1 and TPM1, which were the proteins initially discovered in a xenograft mouse model, CLIC4, TPM2, TPM3, and TPM4 were present in ovarian cancer patient sera at significantly elevated levels compared with controls. Some of the additional biomarkers identified in this homolog centric verification and validation approach may be superior to the previously identified biomarkers at discriminating between ovarian cancer and non-cancer patients. This demonstrates the importance of considering all potential protein homologs and using quantitative assays for cancer biomarker validation with well defined isoform specificity. BIOLOGICAL SIGNIFICANCE: This manuscript addresses the importance of distinguishing between protein homologs and isoforms when identifying and validating cancer biomarkers in plasma or serum. Specifically, it describes the use of targeted in-depth LC-MS/MS analysis to determine the members of two protein families, chloride intracellular channel (CLIC) and tropomyosin (TPM) proteins that are detectable in sera of ovarian cancer patients. It then establishes a multiplexed isoform- and homology-specific MRM assay to quantify all observed gene products in these two protein families as well as many of the closely related tropomyosin isoforms. Using this assay, levels of all detected CLICs and TPMs were quantified in ovarian cancer patient and control subject sera. These results demonstrate that in addition to the previously known CLIC1, multiple tropomyosins and CLIC4 are promising new ovarian cancer biomarkers. Based on these initial validation studies, these new ovarian cancer biomarkers appear to be superior to most previously known ovarian cancer biomarkers. PMID- 23792824 TI - Antioxidant and photosystem II responses contribute to explain the drought-heat contrasting tolerance of two forage legumes. AB - Identification of metabolic targets of environmental stress factors is critical to improve the stress tolerance of plants. Studying the biochemical and physiological responses of plants with different capacities to deal with stress is a valid approach to reach this objective. Lotus corniculatus (lotus) and Trifolium pratense (clover) are legumes with contrasting summer stress tolerances. In stress conditions, which are defined as drought, heat or a combination of both, we found that differential biochemical responses of leaves explain these behaviours. Lotus and clover showed differences in water loss control, proline accumulation and antioxidant enzymatic capacity. Drought and/or heat stress induced a large accumulation of proline in the tolerant species (lotus), whereas heat stress did not cause proline accumulation in the sensitive species (clover). In lotus, Mn-SOD and Fe-SOD were induced by drought, but in clover, the SOD-isoform profile was not affected by stress. Moreover, lotus has more SOD-isoforms and a higher total SOD activity than clover. The functionality and electrophoretic profile of photosystem II (PSII) proteins under stress also exhibited differences between the two species. In lotus, PSII activity was drastically affected by combined stress and, interestingly, was correlated with D2 protein degradation. Possible implications of this event as an adaption mechanism in tolerant species are discussed. We conclude that the stress-tolerant capability of lotus is related to its ability to respond to oxidative damage and adaption of the photosynthetic machinery. This reveals that these two aspects should be included in the evaluation of the tolerance of species to stress conditions. PMID- 23792825 TI - Glutathione and glutathione reductase: a boon in disguise for plant abiotic stress defense operations. AB - Abiotic stresses such as salinity, drought, clilling, heavy metal are the major limiting factors for crop productivity. These stresses induce the overproduction of reactive oxygen species (ROS) which are highly reactive and toxic, which must be minimized to protect the cell from oxidative damage. The cell organelles, particularly chloroplast and mitochondria are the major sites of ROS production in plants where excessive rate of electron flow takes place. Plant cells are well equipped to efficiently scavenge ROS and its reaction products by the coordinated and concerted action of antioxidant machinery constituted by vital enzymatic and non-enzymatic antioxidant components. Glutathione reductase (GR, EC 1.6.4.2) and tripeptide glutathione (GSH, gamma-Glutamyl-Cysteinyl-Glycine) are two major components of ascorbate-glutathione (AsA-GSH) pathway which play significant role in protecting cells against ROS and its reaction products-accrued potential anomalies. Both GR and GSH are physiologically linked together where, GR is a NAD(P)H-dependent enzymatic antioxidant and efficiently maintains the reduced pool of GSH - a cellular thiol. The differential modulation of both GR and GSH in plants has been widely implicated for the significance of these two enigmatic antioxidants as major components of plant defense operations. Considering recent informations gained through molecular-genetic studies, the current paper presents an overview of the structure, localization, biosynthesis (for GSH only), discusses GSH and GR significance in abiotic stress (such as salinity, drought, clilling, heavy metal)-exposed crop plants and also points out unexplored aspects in the current context for future studies. PMID- 23792826 TI - Dehydrin expression in soybean. AB - Soybean (Glycine max) is a relatively cold intolerant plant. In most stress tolerant plants the responsive expression of dehydrin proteins in vegetative tissues can be a significant contributor to protection against environmental stresses. The purpose of this study was to examine the expression of dehydrins in various organs and the cold-responses of dehydrin genes in vegetative tissues of soybean. Examination of the soybean genome indicated the presence of genes encoding ten distinct dehydrins. Levels of dehydrin proteins were probed with several antibodies specific to dehydrins or to the signature K-sequence. A single vegetatively expressed dehydrin protein was detected and the levels were insignificantly altered in response to cold, drought, or salt stress, nor was the transcript responsive to ABA. This SK2-type, acidic dehydrin family member (GmERD14) was purified, identified by mass spectroscopy, and shown to be in vivo phosphorylated; indicating characteristics similar to other known acidic dehydrins. The lack of cold stress-regulated acidic dehydrin expression may contribute to the inability of soybean to cold acclimate. While transcripts for all ten dehydrins could be detected in various tissues, only three accumulated to significant levels in vegetative tissues (two of the KS type and one of SK2 type). One of these transcripts, a KS dehydrin, was accumulated following cold treatments. The accumulation of the KS dehydrin was also responsive to exogenous ABA. PMID- 23792827 TI - Secondary metabolites from Penicillium pinophilum SD-272, a marine sediment derived fungus. AB - Two new secondary metabolites, namely, pinodiketopiperazine A (1) and 6,7 dihydroxy-3-methoxy-3-methylphthalide (2), along with alternariol 2,4-dimethyl ether (3) and L-5-oxoproline methyl ester (4), which were isolated from a natural source for the first time but have been previously synthesized, were characterized from the marine sediment-derived fungus Penicillium pinophilum SD 272. In addition, six known metabolites (5-10) were also identified. Their structures were elucidated by analysis of the NMR and mass spectroscopic data. The absolute configuration of compound 1 was determined by experimental and calculated ECD spectra. Compound 2 displayed potent brine shrimp (Artemia salina) lethality with LD50 11.2 MUM. PMID- 23792828 TI - Fully automated radiosynthesis of both enantiomers of [18F]Flubatine under GMP conditions for human application. AB - A fully automatized radiosynthesis of (+)- and (-)-[(18)F]Flubatine ((+)- and ( )NCFHEB) by means of a commercially available synthesis module (TRACERlab FX FN) under GMP conditions is reported. Radiochemical yields of 30% within an overall synthesis time of 40 min were achieved in more than 70 individual syntheses. Specific activities were approximately 3000 GBq/MUmol and radiochemical purity was determined to be at least 97%. PMID- 23792829 TI - A straightforward approach to oxide-free copper nanoparticles by thermal decomposition of a copper(I) precursor. AB - The synthesis of the novel copper(I) precursor [Cu(PPh3)2(O2CCH2OC2H4OC2H4OCH3)] and its application in the straightforward solution synthesis of oxide-free copper nanoparticles by mere thermal decomposition are reported; depending on the precursor concentration particles of sizes of 10 nm or 30 nm are obtained in narrow size distributions. PMID- 23792831 TI - The quest for active and healthy ageing: what cyberpsychology can offer. AB - The European Commission identified active and healthy ageing as a societal challenge common to all European countries, and an area which presents considerable potential for Europe to lead the world in providing innovative responses to this challenge (http://ec.europa.eu/active-healthy-ageing). To tackle the challenge of an ageing population, the European Commission launched the European Innovation Partnership (EIP) on Active and Healthy Ageing. What can cyberpsychology offer to this process? After presenting the main features of cyberpsychology, this paper identifies in patient engagement and positive technologies the key assets that will allow the technological innovations constantly being developed to provide greater help and care in enabling elderly people to live more normal, happier, fulfilling lives. PMID- 23792833 TI - Positive technology as a driver for health engagement. AB - Despite the fact that older adults are healthier than in the past, the current trend of an ageing population implies an increased risk and severity of chronic diseases. Low-resource healthcare systems face increased organizational healthcare costs, which is likely to result in an allocation of limited health resources. Healthcare organizations themselves must deal with patients' increasing need for a more active role in all the steps of the care & cure process. Technological advances may play a crucial role in sustaining people's health management in daily life, but only if it is "ecologically" designed and well-attuned to people's health needs and expectations. Healthcare is more and more called to orient innovative research approaches that recognize the crucial role of a person's engagement in health and well-being. This will enable patients to reach a higher quality of life and achieve a general psychophysical well being. Thus, positive technological innovation can sustain people's engagement in health and invoke community empowerment, as we shall discuss in this document. PMID- 23792835 TI - VR cue-exposure treatment for bulimia nervosa. AB - Several approaches to the treatment of bulimia nervosa have proved effective, including cognitive-behavioral therapy; however, not all patients improve. It is therefore necessary to explore the possibilities of increasing the efficacy of such treatments. One way to attempt this is to incorporate new technologies. This review explores the possibility of developing a new, empirically validated procedure for the treatment of bulimia nervosa patients that involves cue exposure via virtual reality. PMID- 23792836 TI - Sitting/setting on a fence: the use of (video)recording in producing data to study edge environments. AB - The presence of interactive technologies both in field and laboratory research settings makes new instruments and new methodological perspectives to have a complete view of the processes taking place in the setting. This contribution suggests that recording data and taking the researcher position in the setting into consideration may enrich the data production process. PMID- 23792838 TI - The German VR Simulation Realism Scale--psychometric construction for virtual reality applications with virtual humans. AB - Virtual training applications with high levels of immersion or fidelity (for example for social phobia treatment) produce high levels of presence and therefore belong to the most successful Virtual Reality developments. Whereas display and interaction fidelity (as sub-dimensions of immersion) and their influence on presence are well researched, realism of the displayed simulation depends on the specific application and is therefore difficult to measure. We propose to measure simulation realism by using a self-report questionnaire. The German VR Simulation Realism Scale for VR training applications was developed based on a translation of scene realism items from the Witmer-Singer-Presence Questionnaire. Items for realism of virtual humans (for example for social phobia training applications) were supplemented. A sample of N = 151 students rated simulation realism of a Fear of Public Speaking application. Four factors were derived by item- and principle component analysis (Varimax rotation), representing Scene Realism, Audience Behavior, Audience Appearance and Sound Realism. The scale developed can be used as a starting point for future research and measurement of simulation realism for applications including virtual humans. PMID- 23792839 TI - Virtual Multiple Errands Test: reliability, usability and possible applications. AB - Recently, many studies demonstrated the efficacy of using Virtual Reality (VR) in clinical setting, and in particular for neuropsychological assessment. However reliability and usability of the test developed within virtual reality paradigm are often neglect. In this study we test both reliability and usability using well-known psychometrics methods for the Virtual Multiple Errands Test (VMET). In a first experiment, for the reliability, two independent researchers scored the test through several videos. For the usability assessment we analyzed 21 healthy participants and 3 patients with Parkinson's disease. PMID- 23792840 TI - Validation of a low-cost EEG device for mood induction studies. AB - New electroencephalography (EEG) devices, more portable and cheaper, are appearing on the market. Studying the reliability of these EEG devices for emotional studies would be interesting, as these devices could be more economical and compatible with Virtual Reality (VR) settings. Therefore, the aim in this work was to validate a low-cost EEG device (Emotiv Epoc) to monitor brain activity during a positive emotional induction procedure. Emotional pictures (IAPS) were used to induce a positive mood in sixteen participants. Changes in the brain activity of subjects were compared between positive induction and neutral conditions. Obtained results were in accordance with previous scientific literature regarding frontal EEG asymmetry, which supports the possibility of using this low-cost EEG device in future mood induction studies combined with VR. PMID- 23792841 TI - Virtual reality as a method for evaluation and therapy after traumatic hand surgery. AB - In the last decade, Virtual Reality has encountered a continuous development concerning medical purposes and there are a lot of devices based on the classic "cyberglove" concept that are used as new therapeutic method for upper limb pathology, especially neurologic problems [1;2;3]. One of the VR devices is Pablo (Tyromotion), with very sensitive sensors that can measure the hand grip strenght and the pinch force, also the ROM (range of motion) for all the joints of the upper limb (shoulder, elbow, wrist) and offering the possibility of interactive games based on Virtual Reality concept with application in occupational therapy programs. We used Pablo in our study on patients with hand surgery as an objective tool for assessment and as additional therapeutic method to the classic Rehabilitation program [4;5]. The results of the study proved that Pablo represents a modern option for evaluation of hand deficits and dysfunctions, with objective measurement replacement of classic goniometry and dynamometry, with computerized data base of patients with monitoring of parameters during the recovery program and with better muscular and neuro-cognitive feedback during the interactive therapeutic modules. PMID- 23792842 TI - Methodology case study of the application of haptics to combat medic training programs. AB - Of the available training methods for emergency responders, including other methods based on computer technology, virtual reality video game training with haptics (tactile) features will be shown to provide the most effective transfer of skills to real-world emergency situations, providing a model for the development of new training products for combat medics and civilian first responders. This paper aims to provide a methodological case study of haptics use in medical training programs and highlight achievements in terms of performance. Review of these cases show that the addition of haptics to an existing simulation based training program increases user performance in terms of completion time, error rates, and learning rate. With this case study, haptics can be further incorporated into training programs designed for military combat medics. PMID- 23792843 TI - Clinical experiment to assess effectiveness of virtual reality teen smoking cessation program. AB - Smoking has increasingly become a burden on America's health and economic status. The fact that four out of every five adult smokers begins tobacco use before the age of eighteen indicates a need for teenage smoking cessation programs. The Virtual Reality Medical Center created an internet-based program that addresses the issue by utilizing cue exposure therapy in home and school environments to teach teens which cues trigger nicotine cravings and how to combat those cravings. The effectiveness of the program was measured through questionnaires administered before and after its use. Results indicated that the participants were engaged in the virtual environment, and that, in every aspect of the program, at least 8% more participants were knowledgeable about the subject than prior to the use of the program. Success of such a program could reduce teen smoking rates, ultimately leading to reduced smoking mortalities, complications, and costs overall. PMID- 23792845 TI - Psychophysiological correlates of flow during daily activities. AB - Flow is an optimal experience characterized by the perception of high challenges and high skills, positive affect, complete absorption in the activity carried out and intrinsic motivation. Although much research has examined the psychological features of flow, little is known about its biological underpinnings. The present study aimed at contributing to this gap by investigating the psychophysiological correlates of flow experience during daily routines. To this end, 15 university students took part in an experience sampling study, in which they provided real time information on daily activities and associated experience while cardiac activity was monitored. After seven days of observation, 32 flow events were identified among 10 participants. A multilevel regression analysis revealed a significant correlation between optimal experience and specific cardiovascular indexes. In particular, the experience of flow was associated with increased heart rate and increased LF/HF ratio, suggesting relative sympathetic enhancement. These findings are in line with those obtained by previous related studies and indicate the feasibility of investigating physiological correlates of subjective experience in ecological contexts. PMID- 23792846 TI - Designing a serious game for in-field interventions to promote nightlife well being. AB - Nightlife well-being interventions, although much needed, face several challenges related to the specificity of the context addressed. We argue that a game facilitated intervention helps with facing these challenges. The characteristics of a game developed to this goal and the results of user tests conducted in situ are presented. PMID- 23792847 TI - The impact of different perceptual cues on fear and presence in virtual reality. AB - The impact of perceptual visual cues on spider phobic reactions has been thoroughly investigated over the last years. Although the fear of being touched by a spider is part of the clinical picture of spider phobia, findings on the impact of tactile fear cues are rare. This study uses virtual reality to selectively apply visual and tactile fear cues. Self-reported fear and the experience of presence in VR were measured in 20 phobic and 20 non-phobic participants. All participants were repeatedly exposed to visual cues, tactile cues, the combination of both and no fear relevant perceptual cues. Participants were exposed in each condition for five times in random order. Results show that tactile fear cues have the power to trigger fear independent of visual cues. Participants experienced highest levels of presence in the combined and the control condition. Presence may not only be seen in association with the emotional impact of specific cues in VR but also appears to depend on the comparability of a virtual environment to a real life situation. PMID- 23792848 TI - The development of a haptic virtual reality environment to study body image and affect. AB - We report the results of a preliminary study testing the effect of participants' mood rating on visual motor performance using a haptic device to manipulate a cartoonish human body. Our results suggest that moods involving high arousal (e.g. happiness) produce larger movements whereas mood involving low arousal (e.g. sadness) produce slower speed of performance. Our results are used for the development of a new haptic virtual reality application that we briefly present here. This application is intended to create a more interactive and motivational environment to treat body image issues and for emotional communication. PMID- 23792849 TI - Cyberbullying in Cyprus--associated parenting style and psychopathology. AB - In this paper we present data from a cross-sectional study on cyberbullying experiences and cyberbullying perpetration in the Republic of Cyprus. Data were collected from a representative sample of the adolescent student population of the first and fourth grades of high school. Total sample was 2684 students, 48.5% of them male and 51.5% female. Research material included extended demographics, a detailed questionnaire on Internet activities, the Parental Bonding Index (PBI) and the Strengths and Difficulties Questionnaire (SDQ). We compared the results on psychometry for those students who did not report being bullied or having bullied others with those who were bullied, those who bullied others and those who were both sufferers and perpetrators of cyberbullying. Those students who reported being both victims and perpetrators tended to show similar or higher dysfunction than those students who only perpetrated cyberbullying. High maternal and paternal protection in combination with low maternal and paternal care ('affectionless control' parenting style) was associated with perpetrating cyberbullying, either with or without any experience of oneself being bullied as well. Results support a hypothesis that the perpetration of cyberbullying is associated with inefficient parenting styles. They also point to the existence of significant emotional symptoms for the involved adolescents and also general conduct problems, hyperactivity, peer problems and antisocial tendencies. It is important to note that perpetrators of cyberbullying were in most cases victims themselves at some point in time. PMID- 23792850 TI - The impact of Internet and PC addiction in school performance of Cypriot adolescents. AB - In this paper we present the results of a cross-sectional survey designed to ascertain Internet and personal computer (PC) addiction in the Republic of Cyprus. This is a follow-up to a pilot study conducted one year earlier. Data were collected from a representative sample of the adolescent student population of the first and fourth grades of high school. Total sample was 2684 students, 48.5% of them male and 51.5% female. Research material included extended demographics and an Internet security questionnaire, the Young's Diagnostic questionnaire (YDQ), the Adolescent Computer Addiction Test (ACAT). Results indicated that the Cypriot population had comparable addiction statistics with other Greek-speaking populations in Greece; 15.3% of the students were classified as Internet addicted by their YDQ scores and 16.3% as PC addicted by their ACAT scores. Those results are among the highest in Europe. Our results were alarming and have led to the creation of an Internet and PC addiction prevention program which will focus on high-school professor training and the creation of appropriate prevention material for all high-schools, starting immediately after the conclusion of the pan-Cypriot survey, focusing especially on those areas where the frequency of addictive behaviors will be highest. PMID- 23792851 TI - Priming to induce paranoid thought in a non clinical population. AB - Freeman et al. reported that a substantial minority of the general population has paranoid thoughts while exposed in a virtual environment. This suggested that in a development phase of a virtual reality exposure system for paranoid patients initially a non-clinical sample could be used to evaluate the system's ability to induce paranoid thoughts. To increase the efficiency of such an evaluation, this paper takes the position that when appropriately primed a larger group of a non clinical sample will display paranoid thoughts. A 2-by-2 experiment was conducted with priming for insecurity and vigilance as a within-subject factor and prior paranoid thoughts (low or high) as a between-subjects factor. Before exposure into the virtual world, participants (n=24) were shown a video and read a text about violence or about mountain animals. While exposed, participants were asked to comment freely on their virtual environment. The results of the experiment confirmed that exposure in a virtual environment could induce paranoid thought. In addition, priming with an aim to create a feeling of insecurity and vigilance increased paranoid comments in the non-clinical group that otherwise would less often exhibit ideas of persecution. PMID- 23792852 TI - Drugs don't work in patients who don't take them: Dr. Drin, the new ICT paradigm for chronic therapies. AB - Poor adherence to drug therapies still represents an unsolved problem. In order to provide a useful solution to chronic patients of all ages--with particular attention to the elderly--who are subjected to complex therapeutic regimen, an innovative ICT solution, called Dr.Drin, has been designed and tested. The aim of the developed framework is to assist the patient during the therapy and to enable and support a bidirectional communication between all healthcare stakeholders (doctors, caregivers and family members) and the patient. During the screening phase, patients were interviewed to understand what are the common practices they usually adopt to remember when and how to take a drug. The solutions which they rely the most on are the list of drugs, writing on the packaging, and setting up alarms. Patients who complained about difficulties of adherence and who had a smartphone were subsequently recruited to test Dr.Drin over a three-months period. In the following, preliminary results from the first twelve patients are presented and analyzed to prove the effectiveness of Dr.Drin in supporting patients adherence to therapies. PMID- 23792853 TI - Cue-elicited anxiety and craving for food using virtual reality scenarios. AB - Cue exposure therapy has been reported to be an effective intervention for reducing binge eating behavior in patients with eating disorders and obesity. However, in vivo food exposure conducted in the therapist's office presents logistical problems and lacks ecological validity. This study proposes the use of virtual reality technology as an alternative to in vivo exposure, and assesses the ability of different virtual environments to elicit anxiety and craving for food in a non-clinical sample. The results show that exposure to virtual environments provokes changes in reported craving for food. High-calorie food cues are the ones that elicit the highest increases in craving. PMID- 23792854 TI - Assessment of frontal brain functions in alcoholics following a health mobile cognitive stimulation approach. AB - The consequences of alcohol dependence syndrome are severe, ranging from physical diseases to neuropsychological deficits in several cognitive domains. Alcohol abuse has also been related to brain dysfunction specifically in the prefrontal cortex. We assessed these deficits and the effects of traditional (pen-and-paper) and novel (mobile technology) approaches to cognitive stimulation of alcoholics in a neuropsychological intervention program. Thirty alcoholics in treatment of alcohol dependence syndrome were assessed during four weeks on a three-day/week basis. The results showed an overall increase in frontal lobe function between the first and the final assessment, being more pronounced in alcoholics who were assigned to a treatment group with mobile technologies than to those assigned to a paper-and-pencil treatment and to a control group. These results support the use of ecologically sound and available approaches of neuropsychological stimulation to treat executive dysfunction in patients with alcohol dependence syndrome. PMID- 23792855 TI - Heart rate response to fear conditioning and virtual reality in subthreshold PTSD. AB - Posttraumatic stress disorder (PTSD) is a significant health concern for U.S. military service members (SMs) returning from Afghanistan and Iraq. Early intervention to prevent chronic disability requires greater understanding of subthreshold PTSD symptoms, which are associated with impaired physical health, mental health, and risk for delayed onset PTSD. We report a comparison of physiologic responses for recently deployed SMs with high and low subthreshold PTSD symptoms, respectively, to a fear conditioning task and novel virtual reality paradigm (Virtual Iraq). The high symptom group demonstrated elevated heart rate (HR) response during fear conditioning. Virtual reality sequences evoked significant HR responses which predicted variance of the PTSD Checklist Military Version self-report. Our results support the value of physiologic assessment during fear conditioning and combat-related virtual reality exposure as complementary tools in detecting subthreshold PTSD symptoms in Veterans. PMID- 23792856 TI - What do audiences do when they sit and listen? AB - Speech anxiety (SA) training may help subjects improve their skills on keeping audiences interested in the speech and on managing calm or restless audiences. Attention and lack of attention during speeches are displayed through several nonverbal cues. Such and other nonverbal behaviors can also spread throughout a group and engage whole audiences. The current study is an inquiry into the nonverbal markers of attention and lack of attention during lectures (e.g. note taking, eye gaze towards the speaker, conduct with electronic devices such as mobile phones or laptops). Additionally, the study tries to identify nonverbal behaviors that are diffused and their spatial and time diffusion characteristics. 37 university students at the Ilmenau University of Technology have been observed during a 40-minutes lecture. A quantitative content analysis is conducted to identify patterns of behaviors depicting attention and inattention. Afterwards a qualitative content analysis is carried out to identify contagious behaviors and their spreading characteristics. The findings are used to design virtual audiences (VA) whose members react to each other or display observable audience responses (OAR) and will be implemented into training scenarios for training university students against SA. PMID- 23792857 TI - The effect of military motion-assisted memory desensitization and reprocessing treatment on the symptoms of combat-related post traumatic stress disorder: first preliminary results. AB - Although the symptoms of Post-Traumatic Stress Disorder (PTSD) in the general and military population seem very similar, combat-related PTSD (cr-PTSD) is typically thought to be more severe due to the repeated and prolonged exposure of traumatic events. Therapeutic adherence is reported a problem in military populations compromising treatment efficacy. Therefore, a new potential supplementary treatment is specially designed for patients with cr-PTSD. This intervention is called Military Motion Memory Desensitization and Reprocessing (3MDR). The treatment incorporates key elements of successful treatments as Virtual Reality Exposure (VRE) and Eye Movement Desensitization Reprocessing (EMDR) and adds motion to the condition. We aimed at designing a treatment procedure that preserved dual task processing principle, yet introduced new engagement by performing the desensitization during motion by to walking on a treadmill. Moreover, we aimed at exposure to real high-affect pictures of deployment setting. Subjects walk a repetitive cycle while walking and viewing high affect pictures of deployment scenes. Dual task processing was maintained by an oscillating ball. Aspects of presence are adhered to, to maximize possible positive outcome. METHOD: Two veterans with chronic PTSD, received four weekly sessions of 3MDR therapy. The indicator of effectiveness was difference in CAPS (Clinical Administrated PTSD Scale)-score. The treatment was designed on the Computer Assisted Rehabilitation Environment (CAREN) facility. RESULTS: The 3MDR treatment did further decrease PTSD symptoms. Patients were highly satisfied about the treatment and had no attention to drop out. CONCLUSION: The results of the two cases suggest that the 3MDR treatment is a successful, more additional treatment that goes further into the patients affect where other treatment may stagnate. The presence was highly appreciated. Further research with more patients needs to be performed to obtain more reliable results. PMID- 23792859 TI - Evaluating virtual reality mood induction procedures with portable EEG devices. AB - Virtual Environments (VEs) have been used as mood induction procedures. In this context, it is necessary to have instruments to analyze the emotional state during VE exposure. Objective techniques such as EEG should be evaluated for this purpose. The aim in this work was to study the changes in the brain activity with a portable EEG device during a negative mood induction based on a VE. A virtual park was used to induce a negative mood (sadness) in ten participants. Changes in the brain activity of subjects were compared between two moments (before and after emotional induction). Obtained results were in accordance with previous scientific literature regarding frontal EEG asymmetry, which supports the possibility of using the portable EEG as a reliable instrument to measure emotions in VE. PMID- 23792860 TI - Measuring presence during the navigation in a virtual environment using EEG. AB - In the Virtual Reality field, presence refers to the sense of "being there" in the virtual world. Our aim in this work is to evaluate the usefulness of the Emotiv EPOC EEG device to measure the brain activations due to the sense of presence during the navigation in a Virtual Environment (VE), using for the analysis the sLORETA tool. We compare between two experimental conditions: free and automatic navigation through a VE. In this preliminary step, we monitored 9 healthy subjects, obtaining significant differences between the free and automatic navigation conditions in the activity of the right insula for the Theta and Alpha bands. The insula activation is related to stimulus attention and selfawareness processes, directly related with the sense of presence. PMID- 23792861 TI - Neurocognition, presence and acceptance of a VR programme for psychotic patients: a correlational study. AB - Patients with psychosis exhibit a wide range of cognitive deficits which are associated with poor functioning and poor outcomes in psychosocial interventions. Recently, virtual reality (VR) has been demonstrated to be a useful tool for treatment and rehabilitation of these patients. We have developed and applied an integrated VR programme to improve social skills in people with schizophrenia: the Soskitrain. The aim of the present study is to evaluate the relationship between patients' cognitive deficits, their sense of presence and their ratings of the programme's acceptability. Twelve clinically stabilized outpatients with a well-established diagnosis of schizophrenia or schizoaffective disorder underwent neuropsychological assessment prior to treatment, while after the intervention they completed a questionnaire about their sense of presence and the acceptability of the VR programme. Post-treatment results revealed a high sense of presence among patients, as well as good verisimilitude and high acceptance of the virtual environments. In addition, there were significant negative correlations between sense of presence and deficits in both delayed verbal learning and processing speed. The paper discusses the implications of cognitive impairment for the experience and acceptance of VR when treating psychotic patients. PMID- 23792863 TI - Contactless bio-behavioral technologies for virtual reality. AB - The use of biosensors in human experimental research has become one of the most reliable methods to objectively quantify participants' behavioral, psychological and physiological measures. Modern bio-behavioral technologies can be integrated in Virtual Reality platforms, for a contactless assessment of affective states. This manuscript proposes a paradigm to deeper reach accuracy in assessment and diagnostics of rehabilitation processes. PMID- 23792864 TI - Evaluation of a personal mobile coaching service for health tracking. AB - Yukendu is a personal mobile coaching service that supports people in reaching good levels of psychological and physical well-being. The aim of this contribution is to describe the peculiarities of Yukendu and its multi-step evaluation process. PMID- 23792865 TI - Cognitive rehabilitation of schizophrenia through NeuroVr training. AB - Cognitive difficulties are prevalent in people with diagnosis of schizophrenia and are associated with poor long-term functioning. In particular, memory, selective, divided and sustained attention and executive functions are altered by this disease. We used a Virtual Reality environment (developed via the NeuroVr2.0 software) for the rehabilitation of shifting, sustained attention and action planning functions using tasks reminiscent of daily life tasks. Test and retest showed significant differences in the assessed cognitive dimensions. PMID- 23792866 TI - Peak provoked craving after smoking cessation. AB - Peak provoked craving (PPC) is an alternative approach to cue-induced craving that focuses on the highest craving level experienced during the exposure to drug related cues. The main objective of this study was to assess the effect of abstinence on PPC in smokers and to determine whether PPC is altered by continuous abstinence. Results showed reductions on PPC levels only 24 hours after achieving abstinence and craving levels remain significantly lower after 7 days of abstinence. PMID- 23792867 TI - Designing virtual environments to measure behavioral correlates of state-level body satisfaction. AB - Virtual reality (VR) offers a unique method for eliciting state-variable fluctuations in body satisfaction and associated behaviors by allowing near perfect control over environmental factors. Greater variability in momentary body satisfaction is associated with more problematic eating behavior and cognitive styles predictive of eating disorders. The field currently lacks a model for understanding environmental variables and everyday events that tend to influence fluctuations in state body satisfaction. This study proposes a model of state level body satisfaction and presents a method for measuring changes as they occur. We aim to investigate body comparison, selective attention and body checking behaviors in relation to self-report levels of state body satisfaction. We additionally assess interpersonal correlates of state body satisfaction using VR to measure personal distance between subjects and avatars of varying body sizes. 80 female college students with varying levels of weight and shape concerns will be exposed to five virtual environments designed to elicit varying levels of body dissatisfaction: (a) an empty room; (b) an empty beach; (c) a beach populated with avatars; (d) an empty party scene; (e) a party scene populated with avatars. Self-report body satisfaction was measured immediately following each exposure. A tracking system automatically tracked subjects' head orientation and body translation to measure visual gaze and personal space behavior relative to each virtual human within the environment. Data collection is currently underway and expected to be completed by May 2013. Preliminary data and development of the VR model for state-variable assessment will be presented. PMID- 23792868 TI - The COST Action on cyberbullying: developing an international network. AB - The COST Action IS0801 on cyberbullying had the aim of a) sharing of developing expertise in knowledge base and measurement techniques across researchers, b) sharing of input from outside the research community; specifically, from legal experts as well as from mobile phone companies and internet service providers c) sharing of already nationally published guidelines, and recommended coping strategies, including positive uses of new technologies, and d) increasing awareness of the issue, as well as of the outcomes of the Action. Besides the conferences and Training schools organised, the Action has fostered or facilitated a considerable number of grant applications, publications as well as other outreach activities, and has established a fruitful international network. PMID- 23792869 TI - Estimation of usefulness of positron emission tomography (PET) in the diagnosis of post-traumatic stress disorders--preliminary report. AB - The aim of this study was to evaluate the possibility of using PET both in assessing the susceptibility to stress and in the diagnosis of post-traumatic stress disorders. Mentally and somatically healthy soldiers were subjected to PET CT head scan examinations before and after virtual reality stimulation with warfare scenarios. Despite stimulation of peripheral nervous system after 10 minutes, VR exposure in any of the examined soldiers simulation did not cause changes in any brain structure that was visualized in PET. PET-CT head scan was also performed in patients with typical symptoms of acute PTSD according to the criteria of DSM IV TR. In those patients no changes in any brain structure was found. Initially it was found that VR exposure techniques like clinically typical acute symptoms of PTSD do not leave changes in CNS, which could be visualized in PET. The preliminary hypothesis was put forward that exposure to stimuli like symptoms of PTSD must remain long enough to induce permanent damage of brain structure. PMID- 23792873 TI - How to escape the cancer attractor: rationale and limitations of multi-target drugs. AB - The increasingly evident limitations of target-selective cancer therapy has stimulated a flurry of ideas for overcoming the development of resistance and recurrence - the near universal reason for therapy failure from which target selective drugs are not exempt. A widely proposed approach to conquer therapy resistance is to depart from the myopic focus on individual causal pathways and instead target multiple nodes in the cancer cell's gene regulatory network. However, most ideas rely on a simplistic conceptualization of networks: utilizing solely their topology and treating it as a display of causal interactions, while ignoring the integrated dynamics in state space. Here, we review the more encompassing formal framework of global network dynamics in which cancer cells, like normal cell types, are high-dimensional attractor states. Then therapy is represented by the network perturbation that will promote the exit from such cancer attractors and reentering a normal attractor. We show in this qualitative and accessible discussion how the idea of a quasi-potential landscape and the theory of least-action-path offer a new formal understanding for computing the set of network nodes (molecular targets) that need to be targeted in concert in order to exit the cancer attractor. But targeting cancer cells based on the network configuration of an "average" cancer cell, however precise, may not suffice to eradicate all tumor cells because of the dynamic non-genetic heterogeneity of cancer cell populations that makes them moving targets and drives the replenishment of the cancer attractor with surviving, non-responsive cells from neighboring abnormal attractors. PMID- 23792874 TI - Call for neonatal nursing specialization in developing countries. AB - In an attempt to reach Millennium Development Goals, health facility births, which are births occurring in health centers, facilities, or institutions under the care of a skilled birth attendant, are increasing in developing countries. We examined the state of neonatal nursing care in the context of issues related to the capacity of these health facilities to provide quality care and the high facility mortality rates in those neonates admitted to hospital. Neonatal nursing as a specialty within a community-hospital-community network system is proposed as an effective scaling-up strategy to improve neonatal survival. Establishment of international competency standards for neonatal nursing together with regulatory processes with mechanisms to facilitate specialty education forms the basis for the specialty of neonatal nursing. We have identified a strategy to mobilize financial resources for the development of the specialty of neonatal nursing. Evaluation of trends in mortality and identification of process indicators will facilitate examination of the effectiveness of the introduction of the specialty of neonatal nursing as a scaling-up strategy. PMID- 23792875 TI - A practical approach to implementing new CDC GBS guidelines. AB - Group beta streptococcus (GBS) is a well-documented pathogen causing serious maternal and fetal morbidity and mortality. The CDC guidelines for managing clients who test positive for GBS in pregnancy were revised and published in 2010. However, CDC and extant literature provide limited guidance on implementation strategies for these new recommendations. Although several algorithms are included in the CDC (2010) document, none combine the maternal risk factors for practical and consistent implementation from pregnancy to newborn. In response to confusion upon initial education of these guidelines, we developed an algorithm for maternal intrapartum management. In addition, we clarified the CDC (2010) newborn algorithm in response to provider request. Without altering the recommendations, both algorithms provide clarification of the CDC (2010) guidelines. The nursing process provides an organizational structure for the discussion of our efforts to translate the complex guidelines into practice. This article could provide other facilities with tools for dealing with specific aspects of the complex clinical management of perinatal GBS. PMID- 23792877 TI - Flow cytometry makes all the difference. PMID- 23792876 TI - Antagonism between binding site affinity and conformational dynamics tunes alternative cis-interactions within Shp2. AB - Protein functions are largely affected by their conformations. This is exemplified in proteins containing modular domains. However, the evolutionary dynamics that define and adapt the conformation of such modular proteins remain elusive. Here we show that cis-interactions between the C-terminal phosphotyrosines and SH2 domain within the protein tyrosine phosphatase Shp2 can be tuned by an adaptor protein, Grb2. The competitiveness of two phosphotyrosines, namely pY542 and pY580, for cis-interaction with the same SH2 domain is governed by an antagonistic combination of contextual amino acid sequence and position of the phosphotyrosines. Specifically, pY580 with the combination of a favourable position and an adverse sequence has an overall advantage over pY542. Swapping the sequences of pY542 and pY580 results in one dominant form of cis-interaction and subsequently inhibits the trans-regulation by Grb2. Thus, the antagonistic combination of sequence and position may serve as a basic design principle for proteins with tunable conformations. PMID- 23792878 TI - Identification and comparative analysis of low phosphate tolerance-associated microRNAs in two maize genotypes. AB - Low phosphate (Pi) availability is a major constraint on maize growth and productivity. MicroRNAs (miRNAs) are known to play critical roles in plant responses to various environmental conditions. The identification of low Pi tolerance-associated miRNAs will accelerate the development of Pi starvation tolerant maize plants. However, miRNAs associated with low Pi tolerance have not been identified. In this study, we compared deep sequencing small RNA reads from two maize genotypes, the wild type, Qi319, and the low Pi tolerant mutant, 99038, under normal and low Pi conditions. Six known miRNA families and seven novel miRNAs were found differently expressed by the two genotypes. All these miRNAs were confirmed by sequencing a second batch of small RNA libraries constructed in the same way as those used in the first sequencing. The expression profiles of some of these miRNAs were further confirmed by real-time PCR. The predicted target genes of the low Pi tolerance-associated miRNAs were involved in root development or stress responses. Expression levels of some of target genes were significantly different between Qi319 and 99038. These findings suggested that miRNAs may play important roles in low Pi tolerance in maize and may be a key factor in determining the level of low Pi tolerance in different maize genotypes. This study provides an approach for identifying low Pi tolerance-associated miRNAs and can help in the selection and manipulation of high performing maize genotypes under low Pi conditions. PMID- 23792879 TI - The blind photographer. Observations on the bewildering nature of feigned vision loss. AB - The diagnosis of feigned vision loss in adults taxes the doctor-patient relationship because the relationship should be based on trust, honesty, and the mutual desire to improve the medical condition. Even under ideal circumstances, physicians rarely have a complete understanding of the factors that lead patients to simulate disease they do not have. We describe the historical figure of John Howard Griffin (1920-1980) who likely perpetuated feigned vision loss for a decade. His writings provide a unique perspective on motivation (or inspiration) behind factitious disease. PMID- 23792880 TI - Acute monocular visual loss in an elderly woman: a neuro-ophthalmologic emergency. PMID- 23792881 TI - Skyglow effects in UV and visible spectra: radiative fluxes. AB - Several studies have tried to understand the mechanisms and effects of radiative transfer under different night-sky conditions. However, most of these studies are limited to the various effects of visible spectra. Nevertheless, the invisible parts of the electromagnetic spectrum can pose a more profound threat to nature. One visible threat is from what is popularly termed skyglow. Such skyglow is caused by injudiciously situated or designed artificial night lighting systems which degrade desired sky viewing. Therefore, since lamp emissions are not limited to visible electromagnetic spectra, it is necessary to consider the complete spectrum of such lamps in order to understand the physical behaviour of diffuse radiation at terrain level. In this paper, the downward diffuse radiative flux is computed in a two-stream approximation and obtained ultraviolet spectral radiative fluxes are inter-related with luminous fluxes. Such a method then permits an estimate of ultraviolet radiation if the traditionally measured illuminance on a horizontal plane is available. The utility of such a comparison of two spectral bands is shown, using the different lamp types employed in street lighting. The data demonstrate that it is insufficient to specify lamp type and its visible flux production independently of each other. Also the UV emissions have to be treated by modellers and environmental scientists because some light sources can be fairly important pollutants in the near ultraviolet. Such light sources can affect both the living organisms and ambient environment. PMID- 23792882 TI - An in vitro model to study heterogeneity of human macrophage differentiation and polarization. AB - Monocyte-derived macrophages represent an important cell type of the innate immune system. Mouse models studying macrophage biology suffer from the phenotypic and functional differences between murine and human monocyte-derived macrophages. Therefore, we here describe an in vitro model to generate and study primary human macrophages. Briefly, after density gradient centrifugation of peripheral blood drawn from a forearm vein, monocytes are isolated from peripheral blood mononuclear cells using negative magnetic bead isolation. These monocytes are then cultured for six days under specific conditions to induce different types of macrophage differentiation or polarization. The model is easy to use and circumvents the problems caused by species-specific differences between mouse and man. Furthermore, it is closer to the in vivo conditions than the use of immortalized cell lines. In conclusion, the model described here is suitable to study macrophage biology, identify disease mechanisms and novel therapeutic targets. Even though not fully replacing experiments with animals or human tissues obtained post mortem, the model described here allows identification and validation of disease mechanisms and therapeutic targets that may be highly relevant to various human diseases. PMID- 23792883 TI - V-shaped dinuclear Pt(II) complexes: selective interaction with human telomeric G quadruplex and significant inhibition towards telomerase. AB - A quaternized trigeminal ligand, 4-[4,6-di(4-pyridyl)-1,3,5-(2-triazinyl)]-1 methylpyridine-1-ium hexafluorophosphate (dptmp.PF6), and two derivative V-shaped dinuclear Pt(II) complexes, {[Pt(dien)]2(dptmp)}(PF6)5 (1) and {[Pt(dpa)]2(dptmp)}(PF6)5 (2), were synthesized, characterized and applied to a series of biochemical studies. FRET and SPR analyses showed these compounds, especially Pt(II) complexes, bound more strongly to human telomeric (hTel) G quadruplex than to promoters (such as c-myc and bcl2) or to the duplex DNA. PCR stop assays revealed that the Pt(II) complexes could bind to and stabilize G quadruplex far more effectively than corresponding ligand. CD analyses further indicated the three compounds likely stabilized the formation of mixed-type parallel/antiparallel G-quadruplex structures. Their efficacy as telomerase inhibitors and potential anticancer drugs was explored via TRAP. The IC50 value was determined to be 0.113 +/- 0.019 MUM for 1, indicating that it is one of the strongest known telomerase inhibitors. These results confirm that both V-shaped dinuclear Pt(II) complexes act as selective G-quadruplex binders and significant telomerase inhibitors. PMID- 23792884 TI - The 'Red Queen' dilemma--running to stay in the same place: reflections on the evolutionary vector of HBV in humans. AB - BACKGROUND: Estimates for the evolutionary rate of HBV until now have been interpreted as showing that HBV is a relatively recent acquisition for mankind. The existence of defined HBV genotypes is thought to represent past founder effects. We have explored virus mutation in a group of 48 persistently infected blood donors sampled at two points in time and suggest otherwise. METHODS: HBV infected donors were detected by hepatitis B surface antigen (HBsAg) screening and staged by hepatitis B e markers. Serum DNA from those persistently infected with HBV was characterized by consensus sequencing and the amino acid sequences inferred. These were compared against consensus genotype sequences and divergence measured at two points in time. RESULTS: Rates of viral mutation were higher across both HBsAg and hepatitis B core antigen in the group of donors seropositive for hepatitis B e antibody (1.36*10-3 and 1.54*10-3 changes per residue per year, respectively) than in those seropositive for hepatitis B e antigen (4.59*10-4 and 6.62*10-4 changes per residue per year, respectively). Codon mutations reverting to the genotype consensus were commonly seen. Codon changes were clustered close to the C-terminal region of HBsAg and were accommodated in overlapping polymerase by synonymous substitutions. CONCLUSIONS: It is suggested that in vivo HBV behaves as a self-normalizing meme and mutational rates, although high, do not lead to significant change over time in a persistent infection. This would be compatible with co-evolution within its human host and introduction within humans being an ancient occurrence. PMID- 23792885 TI - Farmer decision-making and risk perceptions towards outwintering cattle. AB - Increasing financial pressures has led farmers to manage cattle outside for the winter months. In temperate areas the environmental risks of outwintering cattle are exacerbated by cooler and wetter weather and identifying how farmers perceive these risks is essential to understanding how potential hazards could be mitigated. A series of workshops were conducted with cattle producers in England and Wales to understand their perceptions of the risks, their decision-making with respect to outwintering and their options for mitigating these risks. A range of risks were identified, but emphasis was placed on environmentally related risks, such as soil damage, and on social risks, such as public perception of their treatment of the animals. The uncertainties due to the weather were highlighted as the most unmanageable risk. Another significant barrier to mitigating environmental impacts emerged from the lack of options towards choosing appropriate fields in which to conduct outwintering. We argue that the farmer-led nature of outwintering and the development of a wide range of systems is evidence of outwintering being a systems-innovation. We conclude that there is a role for Government intervention through the provision of information which clarifies cross-compliance breaches, but also encourages farmer-led innovation to develop more responsive outwintering systems. PMID- 23792886 TI - Phytoremediation potential of Brassica juncea in Cu-pyrene co-contaminated soil: comparing freshly spiked soil with aged soil. AB - A comparison was made between the dissipation of pyrene as well as the uptake of copper (Cu) in soil freshly spiked with Cu, pyrene or Cu + pyrene and in aged soil. The potential of B juncea for phytoremediation was also investigated. The biomass of Brassica juncea significantly decreased (>50% reduction) in freshly spiked soil when compared to aged soil in all treatments. However, the accumulation of Cu in shoot was significantly reduced (60-88%) in aged soil after 60 days of planting. The total removal of Cu from co-contaminated soil was always higher (>2-3 fold) in aged soil than in freshly spiked soil when lower Cu concentration (50 mg kg(-1)) was co-contaminated with 250 or 500 mg kg(-1) of pyrene while in other co-contaminated treatments, the total removal of Cu from aged soil were significantly lower. The level of pyrene in both planted and un planted freshly spiked soil decreased significantly (>67%) over the 60 days of plant trial. In aged soils, there were no significant differences in residual pyrene concentration between planted and unplanted soil. This suggests that the presence of B. juncea in aged soil did not enhance the dissipation of pyrene and that the prediction of pyrene dissipation in laboratory prepared soil may not have reflected the true situation in the fields. PMID- 23792887 TI - Dealing with fixed emissions ceilings in an uncertain future: Offsetting under environmental integrity. AB - National emission ceilings are a policy instrument to reduce adverse environmental impacts of transboundary air pollution. Such ceilings for SO2, NOx, NH3 and VOC are established, for example, in the Gothenburg Protocol of the Convention on Long-range Transboundary Air Pollution (UNECE, 1999) and the National Emission Ceilings (NEC) Directive of the European Union (EC, 2001a, b). They prescribe for each pollutant a fixed upper limit on emissions for a specific year. Flexibility in achieving them could lower implementation costs if reality develops differently from what was foreseen during negotiations. In this paper, we explore the conditions under which emission reductions for one pollutant (e.g., SO2) could be offset by additional cuts of another pollutant (e.g., NOx) within the same country, without compromising the environmental improvements that are envisaged from the original set of emission ceilings. We employ the impact module of the GAINS (Greenhouse gas - Air pollution Interactions and Synergies) model to examine possible exchange rates across pollutants for the 2012 negotiations on the revision of the Gothenburg Protocol in Europe. Our analysis shows that exchange rates that satisfy the environmental integrity condition can be established, but that their values vary substantially across countries. Extending the environmental integrity condition to downwind countries will require significantly higher exchange rates. We discuss aspects that decision makers would need to consider before adopting an offsetting schema for future international environmental agreements. PMID- 23792888 TI - Perception, demand and user contribution to ecosystem services in the Bilbao Metropolitan Greenbelt. AB - Peri-urban ecosystems are often managed as recreation areas or to enhance aesthetic value on the urban fringe. Scholars and land-use practitioners lack a current understanding of the supply of and the demands for these peri-urban ecosystem services (ES). In this study, we analysed the perceptions of 500 users and interest groups regarding the ES provided by the Bilbao Metropolitan Greenbelt (BMG) ecosystems in northern Spain, and we compared these perceptions to the demands for ES. The objective of this study is to understand user preferences and to thereby better orient land use planning. The results show that the demand for ES in the BMG did not correspond to what users perceived these ecosystems to provide. The respondents' perceptions appeared to be related to the management practices in the area, whereas their demand was related to the benefits they would like to obtain from the BMG. The interviewees were in favour of improvements to peri-urban rural areas, and the results suggested that the authorities should highlight the role of the BMG ecosystems with respect to regulating services and historic and cultural values to improve people's awareness of the ecosystems' capacity to provide benefits to society. Application of this framework also highlighted that there were differences in the perception of and demand for ES among different user groups. This holistic method of matching user demand with policy could be a useful tool to reorient ES-based land planning. PMID- 23792889 TI - Emergy evaluation of contrasting dairy systems at multiple levels. AB - Emergy accounting (EmA) was applied to a range of dairy systems, from low-input smallholder systems in South Mali (SM), to intermediate-input systems in two regions of France, Poitou-Charentes (PC) and Bretagne (BR), to high-input systems on Reunion Island (RI). These systems were studied at three different levels: whole-farm (dairy system and cropping system), dairy-system (dairy herd and forage land), and herd (animals only). Dairy farms in SM used the lowest total emergy at all levels and was the highest user of renewable resources. Despite the low quality of resources consumed (crop residues and natural pasture), efficiency of their use was similar to that of industrialised inputs by intensive systems in RI, PC and BR. In addition, among the systems studied, SM dairy farms lay closest to environmental sustainability, contradicting the usual image of high environmental impact of cattle production in developing countries. EmA also revealed characteristics of the three intensive systems. Systems from RI and PC had lower resource transformation efficiency and higher environmental impacts than those from BR, due mainly to feeding strategies that differed due to differing socio-climatic constraints. Application of EmA at multiple levels revealed the importance of a multi-level analysis. While the whole-farm level assesses the overall contribution of the system to its environment, the dairy system level is suitable for comparison of multi-product systems. In contrast, the herd level focuses on herd management and bypasses debates about definition of system boundaries by excluding land management. Combining all levels highlights the contribution of livestock to the global agricultural system and identifies inefficiencies and influences of system components on the environment. PMID- 23792890 TI - Cytoplasmic male sterility-associated chimeric open reading frames identified by mitochondrial genome sequencing of four Cajanus genotypes. AB - The hybrid pigeonpea (Cajanus cajan) breeding technology based on cytoplasmic male sterility (CMS) is currently unique among legumes and displays major potential for yield increase. CMS is defined as a condition in which a plant is unable to produce functional pollen grains. The novel chimeric open reading frames (ORFs) produced as a results of mitochondrial genome rearrangements are considered to be the main cause of CMS. To identify these CMS-related ORFs in pigeonpea, we sequenced the mitochondrial genomes of three C. cajan lines (the male-sterile line ICPA 2039, the maintainer line ICPB 2039, and the hybrid line ICPH 2433) and of the wild relative (Cajanus cajanifolius ICPW 29). A single, circular-mapping molecule of length 545.7 kb was assembled and annotated for the ICPA 2039 line. Sequence annotation predicted 51 genes, including 34 protein coding and 17 RNA genes. Comparison of the mitochondrial genomes from different Cajanus genotypes identified 31 ORFs, which differ between lines within which CMS is present or absent. Among these chimeric ORFs, 13 were identified by comparison of the related male-sterile and maintainer lines. These ORFs display features that are known to trigger CMS in other plant species and to represent the most promising candidates for CMS-related mitochondrial rearrangements in pigeonpea. PMID- 23792893 TI - Re: "obesity and US mortality risk over the adult life course". PMID- 23792895 TI - Re: "need for more individual-level meta-analyses in social epidemiology: example of job strain and coronary heart disease". PMID- 23792894 TI - Invited commentary: are dietary intakes and other exposures in childhood and adolescence important for adult cancers? AB - In this issue of the Journal, Nimptsch et al. (Am J Epidemiol. 2013;178(2):172 183) report significant associations between female adolescents' poultry consumption in high school and subsequent reduced risk of colorectal adenomas in adulthood. Consumption of red meat or fish was not related to risk, but replacement with poultry reduced the risk of later adenomas. Most epidemiologic studies of adult diseases lack exposure data from the distant past. By focusing on a cancer precursor lesion and using a variety of methods to assess data quality, the investigators address concerns about the quality of distant recall. These findings add to the growing evidence that links childhood and adolescent lifestyle and environmental exposures with subsequent risk of cancers arising in adulthood. Highlights of the literature on this topic and methodological challenges are summarized. Future studies would benefit from incorporating measures of lifestyle, diet, environmental exposures, and other risk factors from early in life and from validation and other data quality checks of such measurements. Sources of historical data on children's and adolescents' exposures should be sought and evaluated in conjunction with subsequent exposures in relationship to adult-onset cancers. PMID- 23792896 TI - Monoterpenoid indole alkaloids from Alstonia rupestris with cytotoxic, anti inflammatory and antifungal activities. AB - Phytochemical investigation of the 70% EtOH extract of the leaves of Alstonia scholaris afforded seven new monoterpenoid indole alkaloids: scholarisins I-VII (1-7), and three known compounds: (3R,5S,7R,15R,16R,19E)-scholarisine F (8), 3 epi-dihydro- corymine (9), and (E)-16-formyl-5alpha-methoxystrictamine (10). Structural elucidation of all the compounds was accomplished by spectral methods such as 1D- and 2D-NMR, IR, UV, and HRESIMS. The isolated compounds were tested in vitro for cytotoxicity against seven tumor cell lines, anti-inflammatory activities against Cox-1 and Cox-2, and antifungal potential against five species of fungi. Compounds 1, 6, and 10 exhibited significant cytotoxicities against all the tested tumor cell lines with IC50 values of less than 30 MUM and selective inhibition of Cox-2 comparable with the standard drug NS-398 (>90%). Additionally, 1, 2, 3 and 8 showed antifungal activity against two fungal strains (G. pulicaris and C. nicotianae). PMID- 23792897 TI - Herb-drug interaction of Epimedium sagittatum (Sieb. et Zucc.) maxim extract on the pharmacokinetics of sildenafil in rats. AB - Epimedium sagittatum (Sieb. et Zucc.) Maxim is one of the herbs used to treat erectile dysfunction in Traditional Chinese Medicine. Sildenafil is a phosphodiesterase 5 inhibitor used to treat erectile dysfunction in Western Medicine. This study evaluates the herbal-drug interaction of Epimedium sagittatum extract on the pharmacokinetics of sildenafil in rats by ultra performance liquid chromatography. The rat plasma was sampled from each anesthetized rat after pretreatment with 3-days Epimedium sagittatum extract (1/2 g/kg/day) and intravenous injection with sildenafil (10/30 mg/kg). The pharmacokinetic data demonstrate that the area under the concentration-time curve (AUC) of sildenafil (10 mg/kg) was significantly decreased in groups that received a high dose of Epimedium sagittatum extract. In conclusion, the study demonstrates that there was significant herb-drug interaction of Epimedium sagittatum extract on the pharmacokinetics of sildenafil at low and high daily doses, suggesting co-administration use of Epimedium sagittatum extract and sildenafil in clinical practice should be prevented due to possible herb-drug interactions. PMID- 23792898 TI - Calixarenes and cations: a time-lapse photography of the big-bang. AB - The outstanding cation complexation properties emerging from the pioneering studies on calixarene ligands during a five-year period in the early 1980s triggered a big-bang burst of publications on such macrocycles that is still lasting at a distance of more than 30 years. A time-lapse photography of this timeframe is proposed which allows the readers to pinpoint the contributions of the different research groups. PMID- 23792903 TI - Chlamydia trachomatis is present and metabolically active during the remitting phase in synovial tissues from patients with chronic Chlamydia-induced reactive arthritis. AB - BACKGROUND: Patients with chronic Chlamydia-induced reactive arthritis (ReA) often show a remitting-relapsing disease phenotype. Some information regarding bacterial and host responses to one another during active disease is available but no information for quiescence. This article presents the first molecular genetic insight into the behavior of bacterium and host during remitting ReA. METHODS: Synovial biopsies were procured from the knees of 4 patients with quiescent ReA by the Parker-Pearson technique. Nucleic acids prepared from them were analyzed by real-time polymerase chain reaction (PCR) and reverse transcription-PCR, and results were compared with data averaged from the knee synovial tissue samples of 10 patients with active ReA. RESULTS: Real-time PCR indicated that bacterial load in remitting samples was approximately 20% of that in active disease samples. Transcripts from the p60-encoding gene were equal to or higher than those seen in active disease. Messenger RNAs (mRNAs) from the paralog p60-encoding genes were equal to or lower than those of active disease. Host mRNAs encoding interleukin-10, tumor necrosis factor-alpha and interferon gamma were 4-fold lower than those in active disease samples, whereas monocyte chemotactic protein 1 and regulated upon activation, normal t-cell expressed, and secreted mRNA levels were equal to or higher. CONCLUSIONS: Bacterial load in synovial tissue of patients with remitting disease is lower than that of active disease, but mRNAs encoding proinflammatory proteins are equal to or higher than those of active disease. Transcription in the host is attenuated for cytokines and chemokines. These initial results demonstrate that organism is present and metabolically active in synovium during the remitting phase of chronic Chlamydia induced ReA and that the genetic events characterizing quiescence are complex. PMID- 23792904 TI - Evolutionary rates and HBV: issues of rate estimation with Bayesian molecular methods. AB - BACKGROUND: HBV infection is a public health problem affecting approximately 2 billion people and leading to >350 million chronic carriers of the virus worldwide. Phylogenetic analysis can give valuable insight to help in clarifying the history of viral infections around the world and in elucidating routes of transmission of the different viral strains present in the infected host population. These analyses rely on an accurate estimate of the rate of mutations. METHODS: In this study, we investigated the robustness of rate estimations based on Bayesian analysis obtained so far and examined, in particular, the choice of prior for the substitution rate. RESULTS: Most previous studies have concentrated on estimating the parameters of simple demographic models for HBV, such as exponential growth and constant population size. Here, we introduce a method that automatically partitions the genome in components that show a different rate of mutation and fit different substitution models. CONCLUSIONS: In conclusion, we find that, due to inaccuracy in the sampling dates from the samples where viral sequences were obtained, lack of a sufficiently large geographical and time spread of available and trustworthy sample dates, sensitivity to priors and model misspecification and rate estimation based on molecular methods, are not reliable. We suggest that rate estimates taking into account calibration points based on relevant historical events are more robust due to the lack of trustworthy sampling dates. For example, the known history of colonization of the Americas should be used to accurately study the current diversity of genotype F, which is the most frequent genotype in almost all Spanish speaking countries in South America. PMID- 23792905 TI - Adult cerebellar glioblastomas: a distinct entity or parcel of the whole? PMID- 23792906 TI - Mass-related inversion symmetry breaking and phonon self-energy renormalization in isotopically labeled AB-stacked bilayer graphene. AB - A mass-related symmetry breaking in isotopically labeled bilayer graphene (2LG) was investigated during in-situ electrochemical charging of AB stacked (AB-2LG) and turbostratic (t-2LG) layers. The overlap of the two approaches, isotopic labeling and electronic doping, is powerful tool and allows to tailor, independently and distinctly, the thermal-related and transport-related phenomena in materials, since one can impose different symmetries for electrons and phonons in these systems. Variations in the system's phonon self-energy renormalizations due to the charge distribution and doping changes could be analyzed separately for each individual layer. Symmetry arguments together with first-order Raman spectra show that the single layer graphene (1LG), which is directly contacted to the electrode, has a higher concentration of charge carriers than the second graphene layer, which is not contacted by the electrode. These different charge distributions are reflected and demonstrated by different phonon self-energy renormalizations of the G modes for AB-2LG and for t-2LG. PMID- 23792907 TI - Use of the Operant Orofacial Pain Assessment Device (OPAD) to measure changes in nociceptive behavior. AB - We present an operant system for the detection of pain in awake, conscious rodents. The Orofacial Pain Assessment Device (OPAD) assesses pain behaviors in a more clinically relevant way by not relying on reflex-based measures of nociception. Food fasted, hairless (or shaved) rodents are placed into a Plexiglas chamber which has two Peltier-based thermodes that can be programmed to any temperature between 7 degrees C and 60 degrees C. The rodent is trained to make contact with these in order to access a reward bottle. During a session, a number of behavioral pain outcomes are automatically recorded and saved. These measures include the number of reward bottle activations (licks) and facial contact stimuli (face contacts), but custom measures like the lick/face ratio (total number of licks per session/total number of contacts) can also be created. The stimulus temperature can be set to a single temperature or multiple temperatures within a session. The OPAD is a high-throughput, easy to use operant assay which will lead to better translation of pain research in the future as it includes cortical input instead of relying on spinal reflex-based nociceptive assays. PMID- 23792908 TI - Behavioural and metabolic characterisation of the low satiety phenotype. AB - Some individuals report weak appetite sensations and thus, have higher susceptibility to overeating. The aim of this study was (1) to evaluate the reliability of the satiety quotient (SQ), a marker of satiety efficiency; (2) to characterize the biopsychobehavioural profiles of individual presenting low satiety efficiency, i.e. the low satiety phenotype and (3) to document the impact of a weight loss program on these profiles. Sixty-nine obese men (BMI 33.6+/-3.0 kg/m2, age 41.5+/-5.7 years) participated in a 16-week, non-restrictive weight loss intervention. Visual analog scales for appetite sensations in response to a test-meal were completed twice at baseline. Blood samples were collected before and during one test-meal. Questionnaires were administered before and after the intervention. The mean SQ showed good reliability (ICC=0.67). Baseline SQ scores tended to be negatively correlated with external hunger, anxiety and night eating symptoms (p<0.10). Moreover, the low satiety phenotype showed a lower cortisol response to the test-meal (p<0.05). The SQ seems to be a reliable marker of weaker appetite sensation responses. Stress/anxiety could be involved in the low satiety phenotype but did not influence the biopsychobehavioural changes in response to the intervention. PMID- 23792909 TI - Consumer acceptance of the New Nordic Diet. An exploratory study. AB - With direct reference to New Nordic Cuisine and Nordic dietary recommendations, the OPUS Research Centre in Denmark is developing and testing a healthy, regional New Nordic Diet (NND) that promises to have outstanding gastronomic properties. The NND is disseminated to Danish consumers with a view to improving public health. To explore the acceptability of the NND to consumers, a qualitative study comprising focus groups, home-testing of NND prototype meals and personal interviews was conducted in urban and rural areas (N=38). Most participants, particularly women and residents in urban areas, are positive towards the ideas underlying the development of this new diet and enjoy the taste and appearance of NND meals. Barriers to acceptance include the untraditional formats of NND meals, the time needed to prepare them, the unfamiliarity of ingredients, perceived problems regarding product availability, reservations about the elitist character of this project and unwillingness to exclude non-Nordic dishes on an everyday basis. The study concludes that several social and cultural barriers must be overcome if the NND shall constitute a source of improved public health. The pursuit of this objective could more fruitfully take its point of departure in in depth consideration of existing food practices among Danish consumers. PMID- 23792910 TI - An argument against the use of the "patellar osteotomy technique". PMID- 23792911 TI - Organization and functionality of chlorophyll-protein complexes in thylakoid membranes isolated from Pb-treated Secale cereale. AB - In this study, Secale cereale seedlings cultivated under 0 (control), 2 or 5mM Pb(NO3)2 concentrations were used to examine alterations in the organization and functionality of chlorophyll-protein complexes in thylakoid membranes under Pb ion stress. The studies were conducted on whole leaves of rye seedlings or thylakoid membranes isolated from Pb-treated and control plants. Using non denaturing electrophoresis, it was assessed that increasing Pb concentrations resulted in an increase in the value of the ratio of the content of LHCII oligomers (mainly trimers) to the content of LHCII monomers. The parameters of chlorophyll fluorescence induction (q(p) and q(n)) indicated that the change in the LHCII supramolecular organization in the presence of Pb ions was connected with an increase in non-photochemical fluorescence quenching. Quantification of photosynthetic pigments showed that both Pb concentrations decreased the content of chlorophyll a, chlorophyll b, and carotenoids. The changes in the pigment content led to a significant reduction in light absorption by antenna complexes. However, the absorption spectra showed that red light was preferentially absorbed by antenna complexes in thylakoid membranes isolated from the Pb-treated plants. Examination of fluorescence emission spectra revealed that Pb ions decreased the fluorescence quantum yield of PSII. The emission spectra of thylakoids indicated a relative increase in the intensity of fluorescence emission from the trimeric and aggregated forms of the LHCII complexes in comparison to the intensity of fluorescence emission from PSI antenna complexes under excitation at 440 nm. Simultaneously, under excitation at 470 nm, we observed a rise in fluorescence intensity from the LHCII trimer after addition of 5mM Pb as well as a decrease in fluorescence intensity from the LHCII aggregates and PSI core and LHCI antenna complexes under both Pb concentrations. Pb treatments also reduced excitation energy absorbed by chlorophyll b and carotenoids within antenna complexes and transferred to chlorophyll a species emitting at 680 nm. PMID- 23792912 TI - Wheat Mds-1 encodes a heat-shock protein and governs susceptibility towards the Hessian fly gall midge. AB - Gall midges induce formation of host nutritive cells and alter plant metabolism to utilize host resources. Here we show that the gene Mayetiola destructor susceptibility-1 on wheat chromosome 3AS encodes a small heat-shock protein and is a major susceptibility gene for infestation of wheat by the gall midge M. destructor, commonly known as the Hessian fly. Transcription of Mayetiola destructor susceptibility-1 and its homoeologs increases upon insect infestation. Ectopic expression of Mayetiola destructor susceptibility-1 or induction by heat shock suppresses resistance of wheat mediated by the resistance gene H13 to Hessian fly. Silencing of Mayetiola destructor susceptibility-1 by RNA interference confers immunity to all Hessian fly biotypes on normally susceptible wheat genotypes. Mayetiola destructor susceptibility-1-silenced plants also show reduced lesion formation due to infection by the powdery mildew fungus Blumeria graminis f. sp. tritici. Modification of susceptibility genes may provide broad and durable sources of resistance to Hessian fly, B. graminis f. sp. tritici, and other pests. PMID- 23792913 TI - Synthesis, structure and antifungal activity of thiophene-2,3-dicarboxaldehyde bis(thiosemicarbazone) and nickel(II), copper(II) and cadmium(II) complexes: unsymmetrical coordination mode of nickel complex. AB - The reaction of nickel(II), copper(II) chlorides and cadmium(II) chloride and bromide with thiophene-2,3-dicarboxaldehyde bis(thiosemicarbazone) (2,3BTSTCH2) leads to a series of new complexes: [Ni(2,3BTSTCH)]Cl, [Cu(2,3BTSTC)], [CdCl2(2,3BTSTCH2)] and [CdBr2(2,3BTSTCH2)]. The crystal structures of the ligand and of [Ni(2,3BTSTCH)]Cl complex have been determined. In this case, we remark an unusual non-symmetrical coordination mode for the two functional groups: one acting as a thione and the second as a deprotonated thiolate. All compounds have been tested for their antifungal activity against human pathogenic fungi: Candida albicans, Candida glabrata and Aspergillus fumigatus, the cadmium complexes exhibit the highest antifungal activity. Cytotoxicity was evaluated using two biological methods: human MRC5 cultured cells and brine shrimp Artemia salina bioassay. PMID- 23792914 TI - Insights into the distal heme pocket of H-NOX using fluoride as a probe for H bonding interactions. AB - Nitric oxide (NO) and dioxygen (O2) are gases of similar size, shape, and electrostatic potential, but different physiological function. In aerobic organisms, the cellular concentration of O2 far exceeds that of NO; instead NO relies heavily on the ability of its receptor to discriminate against O2. In mammals, soluble guanylate cyclase (sGC) serves this role, binding NO with picomolar sensitivity and excluding O2 binding. Interestingly, some bacterial homologs of sGC, including the H-NOX (heme-nitric oxide/oxygen) domain from Thermoanaerobacter tengcongensis, tightly bind O2. Three distal pocket residues (Trp9, Asn74, and Tyr140) form a hydrogen-bonding network that stabilizes O2 binding to TtH-NOX. Therefore, a current hypothesis to explain sGC ligand specificity is that sGC lacks H-bond donors that preferentially stabilize O2 binding. The wavelength maximum of the charge-transfer band (CT1) in the electronic spectrum of the fluoride complex of ferric hemoproteins is a sensitive probe of H-bonding. Here, in order to gain further understanding of the distal pocket H-bonding network in TtH-NOX, we employ fluoride as a spectroscopic probe. As expected, our results indicate that Y140 donates a strong H-bond to the heme bound ligand. We find that an H-bond from Asn74 as well as distal pocket crowding contributes to positioning Tyr140 for a strong and directed H-bond to iron-bound ligands; indeed crowding may be the primary role for Trp9. We clarify the role of H-bonding in sGC ligand discrimination and suggest that sterics also regulate ligand binding in the H-NOX family. PMID- 23792915 TI - Understanding enabling capacities for managing the 'wicked problem' of nonpoint source water pollution in catchments: a conceptual framework. AB - Nonpoint source (NPS) water pollution in catchments is a 'wicked' problem that threatens water quality, water security, ecosystem health and biodiversity, and thus the provision of ecosystem services that support human livelihoods and wellbeing from local to global scales. However, it is a difficult problem to manage because water catchments are linked human and natural systems that are complex, dynamic, multi-actor, and multi-scalar in nature. This in turn raises questions about understanding and influencing change across multiple levels of planning, decision-making and action. A key challenge in practice is enabling implementation of local management action, which can be influenced by a range of factors across multiple levels. This paper reviews and synthesises important 'enabling' capacities that can influence implementation of local management action, and develops a conceptual framework for understanding and analysing these in practice. Important enabling capacities identified include: history and contingency; institutional arrangements; collaboration; engagement; vision and strategy; knowledge building and brokerage; resourcing; entrepreneurship and leadership; and reflection and adaptation. Furthermore, local action is embedded within multi-scalar contexts and therefore, is highly contextual. The findings highlight the need for: (1) a systemic and integrative perspective for understanding and influencing change for managing the wicked problem of NPS water pollution; and (2) 'enabling' social and institutional arenas that support emergent and adaptive management structures, processes and innovations for addressing NPS water pollution in practice. These findings also have wider relevance to other 'wicked' natural resource management issues facing similar implementation challenges. PMID- 23792916 TI - Foaming in membrane bioreactors: identification of the causes. AB - Membrane bioreactors (MBRs) represent by now a well established alternative for wastewater treatment. Their increasing development is undoubtedly related to the several advantages that such technology is able to guarantee. Nevertheless, this technology is not exempt from operational problems; among them the foaming still represents an "open challenge" of the MBR field, due to the high complexity of phenomenon. Unfortunately, very little work has been done on the foaming in MBRs and further studies are required. Actually, there is not a distinct difference between conventional activated system and MBR: the main difference is that the MBR plants can retain most Extracellular Polymeric Substances (EPSs) in the bioreactor. For these reason, unlike conventional activated sludge systems, MBRs have experienced foaming in the absence of foam-forming micro-organisms. Nevertheless, the actual mechanisms of EPS production and the role of bacteria in producing foam in activated sludge in MBRs are still unclear. In this paper, the authors investigated the roles of EPS and foam-forming filamentous bacteria by analyzing samples from different pilot plants using MBRs. In particular, in order to define the macroscopic features and the role of EPS and filamentous bacteria, a Modified Scum Index (MSI) test was applied and proposed. Based on the MSI and the foam power test, the causes of biological foaming were identified in terms of the potential for foaming, the quality and the quantity of the foam. The results indicated that the MBR foaming was influenced significantly by the concentration of bound EPSs in the sludge. In addition, the quantity and stability of MBR scum increased when both bound EPSs and foam-forming filamentous bacteria were present in the activated sludge. PMID- 23792918 TI - From placode to labyrinth: culture of the chicken inner ear. AB - The inner ear transduces the mechanical stimuli that are associated with sound and balance perception. Missteps during its formation often result in deafness, and thus understanding otic development has a profound clinical relevance. The intricate complexity of the inner ear is derived from a simple epithelial sheet during embryogenesis. Study of this process in vitro has provided insight into the mechanisms of otic induction, patterning and differentiation. This article details methods for the culture of otic placode, otocyst, and basilar papilla, providing a toolkit for the investigation of multiple facets of otic organogenesis, for regeneration studies and for setting up small molecule screens to identify possible therapeutic targets. PMID- 23792917 TI - Adoption of the Q transcriptional regulatory system for zebrafish transgenesis. AB - The Gal4-UAS regulatory system of yeast is widely used to modulate gene expression in Drosophila; however, there are limitations to its usefulness in transgenic zebrafish, owing to progressive methylation and silencing of the CpG rich multicopy upstream activation sequence. Although a modified, less repetitive UAS construct may overcome this problem, it is highly desirable to have additional transcriptional regulatory systems that can be applied independently or in combination with the Gal4/UAS system for intersectional gene expression. The Q transcriptional regulatory system of Neurospora crassa functions similarly to Gal4/UAS. QF is a transcriptional activator that binds to the QUAS upstream regulatory sequence to drive reporter gene expression. Unlike Gal4, the QF binding site does not contain essential CpG dinucleotide sequences that are subject to DNA methylation. The QS protein is a repressor of QF mediated transcriptional activation akin to Gal80. The functionality of the Q system has been demonstrated in Drosophila and Caenorhabditis elegans and we now report its successful application to a vertebrate model, the zebrafish, Danio rerio. Several tissue-specific promoters were used to drive QF expression in stable transgenic lines, as assessed by activation of a QUAS:GFP transgene. The QS repressor was found to dramatically reduce QF activity in injected zebrafish embryos; however, a similar repression has not yet been achieved in transgenic animals expressing QS under the control of ubiquitous promoters. A dual reporter construct containing both QUAS and UAS, each upstream of different fluorescent proteins was also generated and tested in transient assays, demonstrating that the two systems can work in parallel within the same cell. The adoption of the Q system should greatly increase the versatility and power of transgenic approaches for regulating gene expression in zebrafish. PMID- 23792919 TI - Mammalian cell display for the discovery and optimization of antibody therapeutics. AB - Recent advances are described for the isolation and affinity maturation of antibodies that couple in vitro somatic hypermutation (SHM) with mammalian cell display, replicating key aspects of the adaptive immune system. SHM is dependent on the action of the B cell specific enzyme, activation-induced cytidine deaminase (AID). AID-directed SHM in vitro in non-B cells, combined with mammalian display of a library of human antibodies, initially naive to SHM, can be used to isolate and affinity mature antibodies via iterative cycles of fluorescence-activated cell sorting (FACS) under increasingly stringent sort conditions. SHM observed in vitro closely resembles SHM observed in human antibodies in vivo in both mutation type and positioning in the antibody variable region. In addition, existing antibodies originating from mouse immunization, in vivo based libraries, or alternative display technologies such as phage can also be affinity matured in a similar manner. The display system has been developed to enable simultaneous high-level cell surface expression and secretion of the same protein through alternate splicing, where the displayed protein phenotype remains linked to genotype, allowing soluble secreted antibody to be simultaneously characterized in biophysical and cell-based functional assays. This approach overcomes many of the previous limitations of mammalian cell display, enabling direct selection and maturation of antibodies as full-length, glycosylated IgGs. PMID- 23792920 TI - RNA-seq in the tetraploid Xenopus laevis enables genome-wide insight in a classic developmental biology model organism. AB - Advances in sequencing technology have significantly advanced the landscape of developmental biology research. The dissection of genetic networks in model and non-model organisms has been greatly enhanced with high-throughput sequencing technologies. RNA-seq has revolutionized the ability to perform developmental biology research in organisms without a published genome sequence. Here, we describe a protocol for developmental biologists to perform RNA-seq on dissected tissue or whole embryos. We start with the isolation of RNA and generation of sequencing libraries. We further show how to interpret and analyze the large amount of sequencing data that is generated in RNA-seq. We explore the abilities to examine differential expression, gene duplication, transcript assembly, alternative splicing and SNP discovery. For the purposes of this article, we use Xenopus laevis as the model organism to discuss uses of RNA-seq in an organism without a fully annotated genome sequence. PMID- 23792921 TI - Quantitative assessment of in-solution digestion efficiency identifies optimal protocols for unbiased protein analysis. AB - The majority of mass spectrometry-based protein quantification studies uses peptide-centric analytical methods and thus strongly relies on efficient and unbiased protein digestion protocols for sample preparation. We present a novel objective approach to assess protein digestion efficiency using a combination of qualitative and quantitative liquid chromatography-tandem MS methods and statistical data analysis. In contrast to previous studies we employed both standard qualitative as well as data-independent quantitative workflows to systematically assess trypsin digestion efficiency and bias using mitochondrial protein fractions. We evaluated nine trypsin-based digestion protocols, based on standard in-solution or on spin filter-aided digestion, including new optimized protocols. We investigated various reagents for protein solubilization and denaturation (dodecyl sulfate, deoxycholate, urea), several trypsin digestion conditions (buffer, RapiGest, deoxycholate, urea), and two methods for removal of detergents before analysis of peptides (acid precipitation or phase separation with ethyl acetate). Our data-independent quantitative liquid chromatography tandem MS workflow quantified over 3700 distinct peptides with 96% completeness between all protocols and replicates, with an average 40% protein sequence coverage and an average of 11 peptides identified per protein. Systematic quantitative and statistical analysis of physicochemical parameters demonstrated that deoxycholate-assisted in-solution digestion combined with phase transfer allows for efficient, unbiased generation and recovery of peptides from all protein classes, including membrane proteins. This deoxycholate-assisted protocol was also optimal for spin filter-aided digestions as compared with existing methods. PMID- 23792922 TI - Chemical reactions catalyzed by metalloporphyrin-based metal-organic frameworks. AB - The synthetic versatility and the potential application of metalloporphyrins (MP) in different fields have aroused researchers' interest in studying these complexes, in an attempt to mimic biological systems such as cytochrome P-450. Over the last 40 years, synthetic MPs have been mainly used as catalysts for homogeneous or heterogeneous chemical reactions. To employ them in heterogeneous catalysis, chemists have prepared new MP-based solids by immobilizing MP onto rigid inorganic supports, a strategy that affords hybrid inorganic-organic materials. More recently, materials obtained by supramolecular assembly processes and containing MPs as building blocks have been applied in a variety of areas, like gas storage, photonic devices, separation, molecular sensing, magnets, and heterogeneous catalysis, among others. These coordination polymers, known as metal-organic frameworks (MOFs), contain organic ligands or complexes connected by metal ions or clusters, which give rise to a 1-, 2- or 3-D network. These kinds of materials presents large surface areas, Bronsted or redox sites, and high porosity, all of which are desirable features in catalysts with potential use in heterogeneous phases. Building MOFs based on MP is a good way to obtain solid catalysts that offer the advantages of bioinspired systems and zeolitic materials. In this mini review, we will adopt a historical approach to present the most relevant MP-based MOFs applicable to catalytic reactions such as oxidation, reduction, insertion of functional groups, and exchange of organic functions. PMID- 23792923 TI - Proinflammatory cytokines and the clinical features of dementia with lewy bodies. PMID- 23792924 TI - A novel nanometric DNA thin film as a sensor for alpha radiation. AB - The unexpected nuclear accidents have provided a challenge for scientists and engineers to develop sensitive detectors, especially for alpha radiation. Due to the high linear energy transfer value, sensors designed to detect such radiation require placement in close proximity to the radiation source. Here we report the morphological changes and optical responses of artificially designed DNA thin films in response to exposure to alpha radiation as observed by an atomic force microscope, a Raman and a reflectance spectroscopes. In addition, we discuss the feasibility of a DNA thin film as a radiation sensing material. The effect of alpha radiation exposure on the DNA thin film was evaluated as a function of distance from an 241Am source and exposure time. Significant reflected intensity changes of the exposed DNA thin film suggest that a thin film made of biomolecules can be one of promising candidates for the development of online radiation sensors. PMID- 23792925 TI - Photoacoustic cystography. AB - Conventional pediatric cystography, which is based on diagnostic X-ray using a radio-opaque dye, suffers from the use of harmful ionizing radiation. The risk of bladder cancers in children due to radiation exposure is more significant than many other cancers. Here we demonstrate the feasibility of nonionizing and noninvasive photoacoustic (PA) imaging of urinary bladders, referred to as photoacoustic cystography (PAC), using near-infrared (NIR) optical absorbents (i.e. methylene blue, plasmonic gold nanostructures, or single walled carbon nanotubes) as an optical-turbid tracer. We have successfully imaged a rat bladder filled with the optical absorbing agents using a dark-field confocal PAC system. After transurethral injection of the contrast agents, the rat's bladders were photoacoustically visualized by achieving significant PA signal enhancement. The accumulation was validated by spectroscopic PA imaging. Further, by using only a laser pulse energy of less than 1 mJ/cm(2) (1/20 of the safety limit), our current imaging system could map the methylene-blue-filled-rat-bladder at the depth of beyond 1 cm in biological tissues in vivo. Both in vivo and ex vivo PA imaging results validate that the contrast agents were naturally excreted via urination. Thus, there is no concern regarding long-term toxic agent accumulation, which will facilitate clinical translation. PMID- 23792926 TI - Effective removal of Ni(II) from aqueous solutions by modification of nano particles of clinoptilolite with dimethylglyoxime. AB - In this work an Iranian natural clinoptilolite tuff was pre-treated and changed to the micro (MCP) and nano (NCP) particles by mechanical method. Modification of micro and nano particles and also their Ni-exchanged forms were done by dimethylglyoxime (DMG). The raw and modified samples were characterized by XRD, FT-IR, SEM, BET, TG-DTG and energy dispersive analysis X-ray spectroscopy (EDAX). Removal of Ni(II) by modified and unmodified samples was investigated in batch procedure. It was found that NCP-DMG has higher capacity for removal of Ni(II). The effects of analytical parameters such as pH, dose of DMG, concentration of nickel solution, contact time and selectivity were studied and the optimal operation parameters were found as follows: pHPZC: 7.6, CNi(II): 0.01 M, contact time: 360 min and DMG dosage: 5mM. The results of selectivity experiments showed that the modified zeolite has a good selectivity for nickel in the presence of different multivalent cations. Langmuir and Freundlich isotherm models were adopted to describe the adsorption isotherms. Adsorption isotherms of Ni(II) ions could be best modelled by Langmuir equation, that indicate the monolayer sorption of Ni(II). Comparison of two kinetic models indicates that the adsorption kinetic can be well described by the pseudo-second-order rate equation that indicates that the rate limiting step for the process involves chemical reaction. The negative DeltaH and DeltaG indicate an exothermic and spontaneously process. The negative DeltaS indicates that the adsorption of nickel cations from solution occurs with lower amount ion replacement, thus chemisorptions due to complex formation are dominant process in nickel removal. PMID- 23792927 TI - Zeolite materials prepared using silicate waste from template synthesis of ordered mesoporous carbon. AB - Significant amount of silica waste is generated in the preparation of porous carbon materials using template synthesis. Industrial production of such porous carbon not only creates waste chemicals, but also poses significant environmental concerns and high waste treatment cost. Recycling is proposed as the best solution for tackling such chemical wastes. In this study, etched silica waste released from template synthesis of mesoporous carbon is recycled to produce precious functional microporous zeolite materials. The solid silica template is etched out with NaOH solution to produce silica-free mesoporous carbon. The collected silica waste is recycled to generate zeolites such as LTA and MFI type silica materials. The formation of zeolites is confirmed by FT-IR, XRD, (29)Si NMR, (27)Al NMR, and SEM. This straight forward green chemistry route not only recycles the waste chemicals, but also decreases environmental pollution for better improvement of our living. PMID- 23792928 TI - An investigation on the modelling of kinetics of thermal decomposition of hazardous mercury wastes. AB - The kinetics of mercury removal from solid wastes generated by chlor-alkali plants were studied. The reaction order and model-free method with an isoconversional approach were used to estimate the kinetic parameters and reaction mechanism that apply to the thermal decomposition of hazardous mercury wastes. As a first approach to the understanding of thermal decomposition for this type of systems (poly-disperse and multi-component), a novel scheme of six reactions was proposed to represent the behaviour of mercury compounds in the solid matrix during the treatment. An integration-optimization algorithm was used in the screening of nine mechanistic models to develop kinetic expressions that best describe the process. The kinetic parameters were calculated by fitting each of these models to the experimental data. It was demonstrated that the D1 diffusion mechanism appeared to govern the process at 250 degrees C and high residence times, whereas at 450 degrees C a combination of the diffusion mechanism (D1) and the third order reaction mechanism (F3) fitted the kinetics of the conversions. The developed models can be applied in engineering calculations to dimension the installations and determine the optimal conditions to treat a mercury containing sludge. PMID- 23792929 TI - Effects of chlorimuron-ethyl application with or without urea fertilization on soil ammonia-oxidizing bacteria and archaea. AB - Chlorimuron-ethyl (CE) has been widely used in modern agriculture, but little is known regarding the influence of CE on ammonia-oxidizing bacteria (AOB) and archaea (AOA) populations in soils. In this study, microcosm incubation of aquic brown soil was conducted for 60 d. Associated changes in the population sizes of AOB and AOA in response to CE application with or without urea fertilization were examined via quantitative real-time PCR (qPCR) assays of the ammonia monooxygenase gene (amoA). The half-life of CE ranged from 11.80 d to 14.54 d in the tested soil. Compared to the untreated control, the application of CE alone had no strong effects on soil pH, and urea fertilization temporarily increased soil pH in the first 7 days. The abundance of the AOA amoA gene was greater than the abundance of the AOB amoA gene in all treatments, but both were significantly suppressed by CE application in a dose-dependent manner. Urea fertilization generally increased AOB and AOA amoA gene abundances, except that the AOA amoA gene level was slightly reduced at the early stage of the incubation period. AOB and AOA preferred different N levels for growth, with AOB only growing significantly at high NH4(+) levels and AOA growing substantially at low NH4(+) levels. The stimulation effects of urea fertilization on AOA and AOB amoA gene abundances were strongly suppressed by the CE application. This study indicated that the CE application substantially suppressed soil nitrification via inhibiting the AOB and AOA population regardless of urea fertilization, which resulted in significant changes in the soil NH4(+)-N and NO3(-)-N levels. Furthermore, AOB and AOA inhabiting separate ecological niches with different NH4(+) levels played various roles in N cycling. PMID- 23792930 TI - Biochar properties regarding to contaminants content and ecotoxicological assessment. AB - The objective of the study was the determination of the content of contaminants and toxicity of four different biochars. The properties of the biochars, content of trace metals and polycyclic aromatic hydrocarbons (16 PAHs) were determined. Toxicological estimation of the biochars was performed on the basis of a battery of biotests with plants (Lepidium sativum), bacteria (Vibrio fischeri and 11 different strains from MARA), alga (Selenastrum capricornutum), protozoa (Tetrahymena thermophila) and crustaceans (Daphnia magna). The content of trace metals depended on the biochar and was comparable to uncontaminated soils. PAHs sum varied from 1124 to 28,339 MUg/kg. The toxicity of the biochars depended both on their kind and on the test applied. The most sensitive organism was D. magna. Relatively the least sensitive to extracts from the biochars proved to be S. capricornutum and T. thermophila. A significant correlation between the content of PAHs and toxicity was noted only in the case of D. magna. PMID- 23792931 TI - Experimental study on elemental mercury removal by diperiodatonickelate (IV) solution. AB - A novel method has been developed to remove elemental mercury from simulated flue gas by a diperiodatonickelate (IV) solution. The influencing factors, such as diperiodatonickelate (IV) concentration, reaction temperature, solution pH, the initial Hg(0) concentration, SO2 concentration and NO concentration were investigated at a bubbling reactor. In the presence of SO2 and NO, removal efficiency of 86.2% for elemental mercury was obtained. Meanwhile, 56.2% of NO and 98% of SO2 were simultaneously removed, under the optimal experimental conditions, in which diperiodatonickelate (IV) concentration was 6 * 10(-3)mol/L, reaction temperature was 50 degrees C, the initial Hg(0) concentration was 20 MUg/m(3) and pH was 8.5. Moreover, based on the research results of the hydrolyzing products of IO(4-), and the analysis of the removal products of Hg(0), the reaction mechanism of Hg(0) removal was proposed. PMID- 23792932 TI - Removal of emerging contaminants in sewage water subjected to advanced oxidation with ozone. AB - Advanced oxidation processes (AOP) based on ozone treatments, assisted by ultrasounds, have been investigated at a pilot-plant scale in order to evaluate the removal of emerging contaminants in sewage water. Around 60 emerging contaminants, mainly pharmaceuticals from different therapeutically classes and drugs of abuse, have been determined in urban wastewater samples (treated and untreated) by LC-MS/MS. In a first step, the removal efficiency of these contaminants in conventional sewage water treatment plants was evaluated. Our results indicate that most of the compounds were totally or partially removed during the treatment process of influent wastewater. Up to 30 contaminants were quantified in the influent and effluent samples analysed, being antibiotics, anti inflammatories, cholesterol lowering statin drugs and angiotensin II receptor antagonists the most frequently detected. Regarding drugs of abuse, cocaine and its metabolite benzoylecgonine were the most frequent. In a second step, the effectiveness of AOP in the removal of emerging contaminants remaining in the effluent was evaluated. Ozone treatments have been proven to be highly efficient in the removal, notably decreasing the concentrations for most of the emerging contaminants present in the water samples. The use of ultrasounds, alone or assisting ozone treatments, has been shown less effective, being practically unnecessary. PMID- 23792933 TI - The mechanism of inhibition by H2 of H2-evolution by hydrogenases. AB - By analysing the results of experiments carried out with two FeFe hydrogenases and several "channel mutants" of a NiFe hydrogenase, we demonstrate that whether or not hydrogen evolution is significantly inhibited by H2 is not a consequence of active site chemistry, but rather relates to H2 transport within the enzyme. PMID- 23792934 TI - A chronic high fat diet alters the homologous and heterologous control of appetite regulating peptide receptor expression. AB - Leptin, ghrelin and neuropeptide W (NPW) modulate vagal afferent activity, which may underlie their appetite regulatory actions. High fat diet (HFD)-induced obesity induces changes in the plasma levels of these peptides and alters the expression of receptors on vagal afferents. We investigated homologous and heterologous receptor regulation by leptin, ghrelin and NPW. Mice were fed (12 weeks) a standard laboratory diet (SLD) or HFD. Nodose ganglia were cultured overnight in the presence or absence of each peptide. Leptin (LepR), ghrelin (GHS R), NPW (GPR7) and cholecystokinin type-1 (CCK1R) receptor mRNA, and the plasma leptin, ghrelin and NPW levels were measured. SLD: leptin reduced LepR, GPR7, increased GHS-R and CCK1R mRNA; ghrelin increased LepR, GPR7, CCK1R, and decreased GHS-R. HFD: leptin decreased GHS-R and GPR7, ghrelin increased GHS-R and GPR7. NPW decreased all receptors except GPR7 which increased with HFD. Plasma leptin was higher and NPW lower in HFD. Thus, HFD-induced obesity disrupts inter-regulation of appetite regulatory receptors in vagal afferents. PMID- 23792935 TI - Subgenotype A1 of HBV--tracing human migrations in and out of Africa. AB - BACKGROUND: HBV subgenotype A1 is the dominant genotype A strain in Africa, with molecular characteristics differentiating it from A2, which prevails elsewhere. Outside Africa, A1 is confined to areas with migration history from Africa, including India and Latin America. The aim of this study was to reconstruct A1 phylogeny on a spatial scale in order to determine whether A1 can be used to track human migrations. METHODS: A phylogenetic comparison of A1 was established using neighbour-joining analysis of complete genomes, and the Bayesian method, implemented in BEAST, was performed on the S region of isolates from 22 countries. Migration events were estimated by ancestral state reconstruction using the criterion of parsimony. RESULTS: From the tree reconstruction, nucleotide divergence calculations and migration analysis, it was evident that Africa was the source of dispersal of A1 globally, and its dispersal to Asia and Latin America occurred at a similar time period. Strains from South Africa were the most divergent, clustering in both the African and Asian/American clades and a South African subclade was the origin of A1. The effect of the 9th to 19th century trade and slave routes on the dispersal of A1 was evident and certain unexpected findings, such as the co-clustering of Somalian and Latin American strains, and the dispersal of A1 from India to Haiti, correlated with historical evidence. CONCLUSIONS: Phylogeographic analyses of subgenotype A1 can be used to trace human migrations in and out of Africa and the plausible sites of origin and migration routes are presented. PMID- 23792936 TI - The association between insulin-like growth factor I and bone turnover markers in the general adult population. AB - OBJECTIVES: Growth hormone (GH) and its main mediator, insulin-like growth factor I (IGF-I), play a fundamental role in human metabolism. Previous epidemiological studies investigating the association of IGF-I and bone turnover markers (BTMs) yielded conflicting results and were limited by study design or sample size. Therefore, we aimed to investigate the associations between serum levels of IGF-I or the IGF-I/IGF binging protein 3 (IGFBP-3) ratio and levels of BTMs including procollagen type 1 N-terminal propeptide (PINP), C-terminal telopeptides of type 1 collagen (CTX), and bone-specific alkaline phosphatase (BAP). METHODS: Data from 1463 men and 1481 women who participated in the first follow-up of the Study of Health in Pomerania were used. IGF-I and IGFBP-3 levels were measured using chemiluminescent immunometric assays on an Immulite 2500 analyzer. BTM levels were measured on the IDS-iSYS Multi-Discipline Automated Analyser. Analyses of variance (ANOVA) and quantile regression models were calculated. RESULTS: In men <55 years and premenopausal women ANOVA and quantile regression analyses revealed positive associations between IGF-I or even stronger the IGF-I/IGFBP-3 ratio and PINP [per unit increase in IGF-I/IGFBP-3 ratio in men: beta (95%-CI) 2.33 ng/ml (0.91; 3.75), p < 0.01; women: 3.63 ng/ml (2.31; 4.95), p < 0.01] or CTX [men: 20.8 ng/l (3.5; 38.0), p = 0.02; women: 12.0 ng/l (-1.2; 25.2), p = 0.07]. Furthermore in postmenopausal women, IGF-I and the IGF-I/IGFBP-3 ratio were inversely related with CTX levels, whereas an inverse U-shaped relation between IGF-I/IGFBP-3 ratio and PINP was found. Regarding BAP, we observed borderline significant associations with IGF-I or the IGF-I/IGFBP-3 ratio in older subjects only. CONCLUSION: IGF-I levels and particularly free IGF-I, estimated by the IGF I/IGFBP-3 ratio, are positively related with PINP as a bone formation marker and CTX as a bone resorption marker in healthy adult men younger than 55 years and premenopausal women. In older subjects the found positive as well as negative relations with BTMs have to be further investigated. PMID- 23792937 TI - Calculated free and bioavailable vitamin D metabolite concentrations in vitamin D deficient hip fracture patients after supplementation with cholecalciferol and ergocalciferol. AB - We previously showed that oral cholecalciferol and ergocalciferol have comparable effects in decreasing circulating parathyroid hormone (PTH), despite a greater increase in total serum 25-hydroxyvitamin D (25OHD) concentration with cholecalciferol supplementation. However, the effects of cholecalciferol and ergocalciferol on total serum 1,25-dihydroxyvitamin D (1,25(OH)2D), vitamin D binding protein (DBP), free 25OHD and free 1,25(OH)2D concentrations have not been previously studied. We randomized 95 hip fracture patients (aged 83+/-8 years) with vitamin D deficiency (serum 25OHD <50 nmol/L) to oral supplementation with either cholecalciferol 1000 IU/day (n=47) or ergocalciferol 1000 IU/day (n=48) for three months. All were given matching placebos of the alternative treatment to maintain blinding. We measured serum 25OHD (high-pressure liquid chromatography), 1,25(OH)2D (Diasorin radioimmunoassay), DBP (immunonephelometry), ionized calcium (Bayer 800 ion-selective electrode) and albumin (bromocresol green) concentrations before and after treatment. We calculated free and bioavailable concentrations of the vitamin D metabolites using albumin and DBP, and calculated free vitamin D metabolite indices as the ratios between the molar concentrations of the vitamin D metabolites and DBP. Seventy participants (74%) completed the study with paired samples for analysis. Total serum 1,25(OH)2D did not change significantly with either treatment (p>0.05, post-treatment vs baseline). Both treatments were associated with comparable increases in DBP (cholecalciferol: +18%, ergocalciferol: +16%, p=0.32 between groups), albumin (cholecalciferol: +31%, ergocalciferol: +21%, p=0.29 between groups) and calculated free 25OHD (cholecalciferol: +46%, ergocalciferol: +36%, p=0.08), with comparable decreases in free 1,25(OH)2D (cholecalciferol: 17%, ergocalciferol: -19%, p=0.32 between groups). In the treatment-adherent subgroup the increase in ionized calcium was marginally greater with cholecalciferol compared with ergocalciferol (cholecalciferol: +8%, ergocalciferol: +5%, p=0.03 between groups). There were no significant differences between the treatments in their effects on the calculated bioavailable concentrations or free indices of the vitamin D metabolites (p>0.05 between groups). In vitamin D-deficient hip fracture patients, oral supplementation with cholecalciferol and ergocalciferol had no effect on total serum 1,25(OH)2D, and comparable effects on DBP and free vitamin D metabolite concentrations. This is despite cholecalciferol having greater effects than ergocalciferol in increasing total 25OHD, and in increasing ionized calcium in treatment-adherent subjects. These findings may explain why cholecalciferol and ergocalciferol supplementation result in similar magnitudes of PTH reduction, but implicate potential differences in other vitamin D metabolites, such as 24,25(OH)2D, that could explain their different effects on ionized calcium. PMID- 23792938 TI - The effect of loading and unloading on muscle activity during the jump squat. AB - The purpose of this study was to explore the effect of loading and unloading on lower-body muscle activity during the jump squat (JS). Thirteen strength-power trained male subjects completed JS with loads less than (10, 20, and 30% maximal dynamic strength [MDS]), equal to (35% MDS), and greater than (40, 50, and 60% MDS) their body mass. Loads less than body mass were accomplished with a custom designed unloading apparatus, and loads greater than body mass were accomplished with a barbell and weights. Surface electromyography was used to measure eccentric and concentric phase muscle activity of the vastus lateralis, vastus medialis, and biceps femoris during the JS. Data were analyzed using a 2-way repeated measures analysis of variance with 2 within-subjects factors (load condition and jump phase). A significant (p < 0.05) load condition * jump phase interaction was found for vastus lateralis, vastus medialis, and biceps femoris muscle activity. Post hoc pairwise comparisons revealed that eccentric phase activity for all muscles was significantly reduced during the 10 and 20% MDS load conditions (unloading) when compared with the 35% MDS condition (body mass). However, there were no significant changes in concentric phase activity for all muscles when compared with the body mass condition. These findings demonstrate that unloading during the JS causes significant reductions in eccentric phase muscle activity. Alterations in eccentric phase muscle activity during unloading may then have negative consequences on concentric phase JS kinetic and kinematic variables. Thus, assisted jump training with unloading is not recommended. PMID- 23792939 TI - Is the self-selected resistance exercise intensity by older women consistent with the American College of Sports Medicine guidelines to improve muscular fitness? AB - The purpose of this study was to verify the self-selected intensity during resistance training (RT) in older women. Twenty healthy women (mean age, 65.6 years) underwent a 2-week familiarization period followed by 3 experimental sessions. During the first session, anthropometric measurements were taken. The second session involved completion of a 1 repetition maximum (1RM) test for the following exercises: chest press, leg press, lat pull-down, leg extension, lateral shoulder raise, leg curl, biceps curl, and triceps pushdown. Last, a single RT session was performed at a self-selected intensity. During the RT session, participants were instructed to self-select a load for performing 3 sets of 10-15 repetitions. Data were analyzed by mean (SD) and analysis of variance with repeated measures (p < 0.05). Global mean of the 3 sets was bench press 41.0% 1RM (11.9), leg press 43.0% 1RM (17.2), lat pull-down 47.2% 1RM (11.1), leg extension 33.0% 1RM (8.1), lateral shoulder raise 51.1% 1RM (12.1), leg curl 43.5% 1RM (8.8), biceps curl 48.0% 1RM (15.5), and triceps pushdown 51.7% 1RM (13.3); there were no significant differences between the sets (p > 0.05). These results indicate that inactive older women self-selected an intensity exercise during RT below the recommendation for improvements on muscle fitness in apparently healthy older adults. However, this intensity is recommended for very deconditioned individuals. Nevertheless, the use of self-selection strategy during an exercise program can have greater advantages because of its easy applicability, its positive relation with exercise adherence, and for promoting initial muscle conditioning in older adults. Furthermore, it is crucial to gradually increase the RT load to guarantee better and sustainable effects on muscle fitness. Finally, future studies are needed to establish the chronic effects of RT at self-selected intensity on muscle fitness and the functional health of older adults. PMID- 23792940 TI - Text messaging interventions increase adherence to antiretroviral therapy and smoking cessation. PMID- 23792941 TI - Oral antibiotics confer small benefits and small harms in low-risk children with acute otitis media. PMID- 23792942 TI - Information for decision-making and stimulus identification is multiplexed in sensory cortex. AB - In recordings from anterior piriform cortex in awake behaving mice, we found that neuronal firing early in the olfactory pathway simultaneously conveyed fundamentally different information: odor value (is the odor rewarded?) and identity (what is the smell?). Thus, this sensory system performs early multiplexing of information reflecting stimulus-specific characteristics with that used for decision-making. PMID- 23792943 TI - Signals in inferotemporal and perirhinal cortex suggest an untangling of visual target information. AB - Finding sought visual targets requires our brains to flexibly combine working memory information about what we are looking for with visual information about what we are looking at. To investigate the neural computations involved in finding visual targets, we recorded neural responses in inferotemporal cortex (IT) and perirhinal cortex (PRH) as macaque monkeys performed a task that required them to find targets in sequences of distractors. We found similar amounts of total task-specific information in both areas; however, information about whether a target was in view was more accessible using a linear read-out or, equivalently, was more untangled in PRH. Consistent with the flow of information from IT to PRH, we also found that task-relevant information arrived earlier in IT. PRH responses were well-described by a functional model in which computations in PRH untangle input from IT by combining neurons with asymmetric tuning correlations for target matches and distractors. PMID- 23792944 TI - Prefrontal mechanisms of behavioral flexibility, emotion regulation and value updating. AB - Two ideas have dominated neuropsychology concerning the orbitofrontal cortex (OFC). One holds that OFC regulates emotion and enhances behavioral flexibility through inhibitory control. The other ascribes to OFC a role in updating valuations on the basis of current motivational states. Neuroimaging, neurophysiological and clinical observations are consistent with either or both hypotheses. Although these hypotheses are compatible in principle, we present results supporting the latter view of OFC function and arguing against the former. We found that excitotoxic, fiber-sparing lesions confined to OFC in monkeys did not alter either behavioral flexibility, as measured by object reversal learning, or emotion regulation, as assessed by fear of snakes. A follow up experiment indicated that a previously reported loss of inhibitory control resulted from damage to nearby fiber tracts and not from OFC dysfunction. Thus, OFC has a more specialized role in reward-guided behavior and emotion than has been thought, a function that includes value updating. PMID- 23792945 TI - Disruption of alcohol-related memories by mTORC1 inhibition prevents relapse. AB - Relapse to alcohol abuse is an important clinical issue that is frequently caused by cue-induced drug craving. Therefore, disruption of the memory for the cue alcohol association is expected to prevent relapse. It is increasingly accepted that memories become labile and erasable soon after their reactivation through retrieval during a memory reconsolidation process that depends on protein synthesis. Here we show that reconsolidation of alcohol-related memories triggered by the sensory properties of alcohol itself (odor and taste) activates mammalian target of rapamycin complex 1 (mTORC1) in select amygdalar and cortical regions in rats, resulting in increased levels of several synaptic proteins. Furthermore, systemic or central amygdalar inhibition of mTORC1 during reconsolidation disrupts alcohol-associated memories, leading to a long-lasting suppression of relapse. Our findings provide evidence that the mTORC1 pathway and its downstream substrates are crucial in alcohol-related memory reconsolidation and highlight this pathway as a therapeutic target to prevent relapse. PMID- 23792946 TI - SeeDB: a simple and morphology-preserving optical clearing agent for neuronal circuit reconstruction. AB - We report a water-based optical clearing agent, SeeDB, which clears fixed brain samples in a few days without quenching many types of fluorescent dyes, including fluorescent proteins and lipophilic neuronal tracers. Our method maintained a constant sample volume during the clearing procedure, an important factor for keeping cellular morphology intact, and facilitated the quantitative reconstruction of neuronal circuits. Combined with two-photon microscopy and an optimized objective lens, we were able to image the mouse brain from the dorsal to the ventral side. We used SeeDB to describe the near-complete wiring diagram of sister mitral cells associated with a common glomerulus in the mouse olfactory bulb. We found the diversity of dendrite wiring patterns among sister mitral cells, and our results provide an anatomical basis for non-redundant odor coding by these neurons. Our simple and efficient method is useful for imaging intact morphological architecture at large scales in both the adult and developing brains. PMID- 23792948 TI - Photophysical and calorimetric studies on the binding of 9-O-substituted analogs of the plant alkaloid berberine to double stranded poly(A). AB - This interaction of four novel 9-O-substituted analogs of the plant alkaloid berberine with double stranded poly(A) was studied using a variety of biophysical techniques. Remarkably higher binding of two 9-O-omega-amino alkyl ether analogs compared to the two 9-O-N-aryl/arylalkyl amino carbonyl methyl berberine analogs was observed. Quantum efficiency values suggested that energy was transferred from the adenine base pairs to the analogs on binding. Ferrocyanide quenching and viscosity studies revealed the binding mode to be intercalative for these analogs. Circular dichroism studies showed that these analogs induced significant conformational changes in the secondary structure of ds poly(A). Energetics of the binding suggested that 9-O-N-aryl/arylalkyl amino carbonyl methyl berberines bound very weakly to ds poly(A). The binding of 9-O-omega-amino alkyl ether analogs was entropy dominated with a smaller but favorable enthalpic contribution to the Gibbs energy. Increasing the temperature resulted in weaker binding; the enthalpic contribution increased and the entropic contribution decreased. A small negative heat capacity change with significant enthalpy-entropy compensation established the involvement of multiple weak noncovalent interactions in the binding process. PMID- 23792947 TI - A long noncoding RNA contributes to neuropathic pain by silencing Kcna2 in primary afferent neurons. AB - Neuropathic pain is a refractory disease characterized by maladaptive changes in gene transcription and translation in the sensory pathway. Long noncoding RNAs (lncRNAs) are emerging as new players in gene regulation, but how lncRNAs operate in the development of neuropathic pain is unclear. Here we identify a conserved lncRNA, named Kcna2 antisense RNA, for a voltage-dependent potassium channel mRNA, Kcna2, in first-order sensory neurons of rat dorsal root ganglion (DRG). Peripheral nerve injury increased Kcna2 antisense RNA expression in injured DRG through activation of myeloid zinc finger protein 1, a transcription factor that binds to the Kcna2 antisense RNA gene promoter. Mimicking this increase downregulated Kcna2, reduced total voltage-gated potassium current, increased excitability in DRG neurons and produced neuropathic pain symptoms. Blocking this increase reversed nerve injury-induced downregulation of DRG Kcna2 and attenuated development and maintenance of neuropathic pain. These findings suggest endogenous Kcna2 antisense RNA as a therapeutic target for the treatment of neuropathic pain. PMID- 23792949 TI - Genome-wide variation of cytosine modifications between European and African populations and the implications for complex traits. AB - Elucidating cytosine modification differences between human populations can enhance our understanding of ethnic specificity in complex traits. In this study, cytosine modification levels in 133 HapMap lymphoblastoid cell lines derived from individuals of European or African ancestry were profiled using the Illumina HumanMethylation450 BeadChip. Approximately 13% of the analyzed CpG sites showed differential modification between the two populations at a false discovery rate of 1%. The CpG sites with greater modification levels in European descent were enriched in the proximal regulatory regions, while those greater in African descent were biased toward gene bodies. More than half of the detected population specific cytosine modifications could be explained primarily by local genetic variation. In addition, a substantial proportion of local modification quantitative trait loci exhibited population-specific effects, suggesting that genetic epistasis and/or genotype * environment interactions could be common. Distinct correlations were observed between gene expression levels and cytosine modifications in proximal regions and gene bodies, suggesting epigenetic regulation of interindividual expression variation. Furthermore, quantitative trait loci associated with population-specific modifications can be colocalized with expression quantitative trait loci and single nucleotide polymorphisms previously identified for complex traits with known racial disparities. Our findings revealed abundant population-specific cytosine modifications and the underlying genetic basis, as well as the relatively independent contribution of genetic and epigenetic variations to population differences in gene expression. PMID- 23792950 TI - The jaw of the worm: GTPase-activating protein EAT-17 regulates grinder formation in Caenorhabditis elegans. AB - Constitutive transport of cellular materials is essential for cell survival. Although multiple small GTPase Rab proteins are required for the process, few regulators of Rabs are known. Here we report that EAT-17, a novel GTPase activating protein (GAP), regulates RAB-6.2 function in grinder formation in Caenorhabditis elegans. We identified EAT-17 as a novel RabGAP that interacts with RAB-6.2, a protein that presumably regulates vesicle trafficking between Golgi, the endoplasmic reticulum, and plasma membrane to form a functional grinder. EAT-17 has a canonical GAP domain that is critical for its function. RNA interference against 25 confirmed and/or predicted RABs in C. elegans shows that RNAi against rab-6.2 produces a phenotype identical to eat-17. A directed yeast two-hybrid screen using EAT-17 as bait and each of the 25 RAB proteins as prey identifies RAB-6.2 as the interacting partner of EAT-17, confirming that RAB-6.2 is a specific substrate of EAT-17. Additionally, deletion mutants of rab-6.2 show grinder defects identical to those of eat-17 loss-of-function mutants, and both RAB-6.2 and EAT-17 are expressed in the terminal bulb of the pharynx where the grinder is located. Collectively, these results suggest that EAT-17 is a specific GTPase-activating protein for RAB-6.2. Based on the conserved function of Rab6 in vesicular transport, we propose that EAT-17 regulates the turnover rate of RAB 6.2 activity in cargo trafficking for grinder formation. PMID- 23792951 TI - A DNA damage checkpoint pathway coordinates the division of dikaryotic cells in the ink cap mushroom Coprinopsis cinerea. AB - The fungal fruiting body or mushroom is a multicellular structure essential for sexual reproduction. It is composed of dikaryotic cells that contain one haploid nucleus from each mating partner sharing the same cytoplasm without undergoing nuclear fusion. In the mushroom, the pileus bears the hymenium, a layer of cells that includes the specialized basidia in which nuclear fusion, meiosis, and sporulation occur. Coprinopsis cinerea is a well-known model fungus used to study developmental processes associated with the formation of the fruiting body. Here we describe that knocking down the expression of Atr1 and Chk1, two kinases shown to be involved in the response to DNA damage in a number of eukaryotic organisms, dramatically impairs the ability to develop fruiting bodies in C. cinerea, as well as other developmental decisions such as sclerotia formation. These developmental defects correlated with the impairment in silenced strains to sustain an appropriated dikaryotic cell cycle. Dikaryotic cells in which chk1 or atr1 genes were silenced displayed a higher level of asynchronous mitosis and as a consequence aberrant cells carrying an unbalanced dose of nuclei. Since fruiting body initiation is dependent on the balanced mating-type regulator doses present in the dikaryon, we believe that the observed developmental defects were a consequence of the impaired cell cycle in the dikaryon. Our results suggest a connection between the DNA damage response cascade, cell cycle regulation, and developmental processes in this fungus. PMID- 23792952 TI - UP-TORR: online tool for accurate and Up-to-Date annotation of RNAi Reagents. AB - RNA interference (RNAi) is a widely adopted tool for loss-of-function studies but RNAi results only have biological relevance if the reagents are appropriately mapped to genes. Several groups have designed and generated RNAi reagent libraries for studies in cells or in vivo for Drosophila and other species. At first glance, matching RNAi reagents to genes appears to be a simple problem, as each reagent is typically designed to target a single gene. In practice, however, the reagent-gene relationship is complex. Although the sequences of oligonucleotides used to generate most types of RNAi reagents are static, the reference genome and gene annotations are regularly updated. Thus, at the time a researcher chooses an RNAi reagent or analyzes RNAi data, the most current interpretation of the RNAi reagent-gene relationship, as well as related information regarding specificity (e.g., predicted off-target effects), can be different from the original interpretation. Here, we describe a set of strategies and an accompanying online tool, UP-TORR (for Updated Targets of RNAi Reagents; www.flyrnai.org/up-torr), useful for accurate and up-to-date annotation of cell based and in vivo RNAi reagents. Importantly, UP-TORR automatically synchronizes with gene annotations daily, retrieving the most current information available, and for Drosophila, also synchronizes with the major reagent collections. Thus, UP-TORR allows users to choose the most appropriate RNAi reagents at the onset of a study, as well as to perform the most appropriate analyses of results of RNAi based studies. PMID- 23792953 TI - Why do more divergent sequences produce smaller nonsynonymous/synonymous rate ratios in pairwise sequence comparisons? AB - Several studies have reported a negative correlation between estimates of the nonsynonymous to synonymous rate ratio (omega = dN/dS) and the sequence distance d in pairwise comparisons of the same gene from different species. That is, more divergent sequences produce smaller estimates of omega. Explanations for this negative correlation have included segregating nonsynonymous polymorphisms in closely related species and nonlinear dynamics of the ratio of two random variables. Here we study the statistical properties of the maximum-likelihood estimates of omega and d in pairwise alignments and explore the possibility that the negative correlation can be entirely explained by those properties. We show that the omega estimate is positively biased for small d and that the bias decreases with the increase of d. We also show that the estimates of omega and d are negatively correlated when omega < 1 and positively correlated when omega > 1. However, the bias in estimates of omega and the correlation between estimates of omega and d are not enough to explain the much stronger correlation observed in real data sets. We then explore the behavior of the estimates when the model is misspecified and suggest that the observed correlation may be due to protein level selection that causes very different amino acids to be favored in different domains of the protein. Widely used models fail to account for such among-site heterogeneity and cause underestimation of the nonsynonymous rate and omega, with the bias being much stronger for distant sequences. We point out that tests of positive selection based on the omega ratio are invariant to the parameterization of the model and thus unaffected by bias in the omega estimates or the correlation between estimates of omega and d. PMID- 23792954 TI - Phospho-regulation pathways during egg activation in Drosophila melanogaster. AB - Egg activation is the series of events that transition a mature oocyte to an egg capable of supporting embryogenesis. Increasing evidence points toward phosphorylation as a critical regulator of these events. We used Drosophila melanogaster to investigate the relationship between known egg activation genes and phosphorylation changes that occur upon egg activation. Using the phosphorylation states of four proteins-Giant Nuclei, Young Arrest, Spindly, and Vap-33-1-as molecular markers, we showed that the egg activation genes sarah, CanB2, and cortex are required for the phospho-regulation of multiple proteins. We show that an additional egg activation gene, prage, regulates the phosphorylation state of a subset of these proteins. Finally, we show that Sarah and calcineurin are required for the Anaphase Promoting Complex/Cyclosome (APC/C) dependent degradation of Cortex following egg activation. From these data, we present a model in which Sarah, through the activation of calcineurin, positively regulates the APC/C at the time of egg activation, which leads to a change in phosphorylation state of numerous downstream proteins. PMID- 23792955 TI - Characterization of variant Creutzfeldt-Jakob disease prions in prion protein humanized mice carrying distinct codon 129 genotypes. AB - To date, all clinical variant Creutzfeldt-Jakob disease (vCJD) patients are homozygous for methionine at polymorphic codon 129 (129M/M) of the prion protein (PrP) gene. However, the appearance of asymptomatic secondary vCJD infection in individuals with a PRNP codon 129 genotype other than M/M and transmission studies using animal models have raised the concern that all humans might be susceptible to vCJD prions, especially via secondary infection. To reevaluate this possibility and to analyze in detail the transmission properties of vCJD prions to transgenic animals carrying distinct codon 129 genotype, we performed intracerebral inoculation of vCJD prions to humanized knock-in mice carrying all possible codon 129 genotypes (129M/M, 129M/V, or 129V/V). All humanized knock-in mouse lines were susceptible to vCJD infection, although the attack rate gradually decreased from 129M/M to 129M/V and to 129V/V. The amount of PrP deposition including florid/amyloid plaques in the brain also gradually decreased from 129M/M to 129M/V and to 129V/V. The biochemical properties of protease resistant abnormal PrP in the brain and transmissibility of these humanized mouse passaged vCJD prions upon subpassage into knock-in mice expressing bovine PrP were not affected by the codon 129 genotype. These results indicate that individuals with the 129V/V genotype may be more susceptible to secondary vCJD infection than expected and may lack the neuropathological characteristics observed in vCJD patients with the 129M/M genotype. Besides the molecular typing of protease-resistant PrP in the brain, transmission studies using knock-in mice carrying bovine PrP may aid the differential diagnosis of secondary vCJD infection, especially in individuals with the 129V/V genotype. PMID- 23792956 TI - Regulation of the human ether-a-go-go-related gene (hERG) channel by Rab4 protein through neural precursor cell-expressed developmentally down-regulated protein 4 2 (Nedd4-2). AB - The human ether-a-go-go-related gene (hERG) encodes the pore-forming alpha subunit of the rapidly activating delayed rectifier K(+) channel in the heart, which plays a critical role in cardiac action potential repolarization. Dysfunction of IKr causes long QT syndrome, a cardiac electrical disorder that predisposes affected individuals to fatal arrhythmias and sudden death. The homeostasis of hERG channels in the plasma membrane depends on a balance between protein synthesis and degradation. Our recent data indicate that hERG channels undergo enhanced endocytic degradation under low potassium (hypokalemia) conditions. The GTPase Rab4 is known to mediate rapid recycling of various internalized proteins to the plasma membrane. In the present study, we investigated the effect of Rab4 on the expression level of hERG channels. Our data revealed that overexpression of Rab4 decreases the expression level of hERG in the plasma membrane. Rab4 does not affect the expression level of the Kv1.5 or EAG K(+) channels. Mechanistically, our data demonstrate that overexpression of Rab4 increases the expression level of endogenous Nedd4-2, a ubiquitin ligase that targets hERG but not Kv1.5 or EAG channels for ubiquitination and degradation. Nedd4-2 undergoes self- ubiquitination and degradation. Rab4 interferes with Nedd4-2 degradation, resulting in an increased expression level of Nedd4-2, which targets hERG. In summary, the present study demonstrates a novel pathway for hERG regulation; Rab4 decreases the hERG density at the plasma membrane by increasing the endogenous Nedd4-2 expression. PMID- 23792957 TI - Parkinson disease protein DJ-1 binds metals and protects against metal-induced cytotoxicity. AB - The progressive loss of motor control due to reduction of dopamine-producing neurons in the substantia nigra pars compacta and decreased striatal dopamine levels are the classically described features of Parkinson disease (PD). Neuronal damage also progresses to other regions of the brain, and additional non-motor dysfunctions are common. Accumulation of environmental toxins, such as pesticides and metals, are suggested risk factors for the development of typical late onset PD, although genetic factors seem to be substantial in early onset cases. Mutations of DJ-1 are known to cause a form of recessive early onset Parkinson disease, highlighting an important functional role for DJ-1 in early disease prevention. This study identifies human DJ-1 as a metal-binding protein able to evidently bind copper as well as toxic mercury ions in vitro. The study further characterizes the cytoprotective function of DJ-1 and PD-mutated variants of DJ-1 with respect to induced metal cytotoxicity. The results show that expression of DJ-1 enhances the cells' protective mechanisms against induced metal toxicity and that this protection is lost for DJ-1 PD mutations A104T and D149A. The study also shows that oxidation site-mutated DJ-1 C106A retains its ability to protect cells. We also show that concomitant addition of dopamine exposure sensitizes cells to metal-induced cytotoxicity. We also confirm that redox-active dopamine adducts enhance metal-catalyzed oxidation of intracellular proteins in vivo by use of live cell imaging of redox-sensitive S3roGFP. The study indicates that even a small genetic alteration can sensitize cells to metal-induced cell death, a finding that may revive the interest in exogenous factors in the etiology of PD. PMID- 23792958 TI - Identification of PDCL3 as a novel chaperone protein involved in the generation of functional VEGF receptor 2. AB - Angiogenesis, a hallmark step in tumor metastasis and ocular neovascularization, is driven primarily by the function of VEGF ligand on one of its receptors, VEGF receptor 2 (VEGFR-2). Central to the proliferation and ensuing angiogenesis of endothelial cells, the abundance of VEGFR-2 on the surface of endothelial cells is essential for VEGF to recognize and activate VEGFR-2. We have identified phosducin-like 3 (PDCL3, also known as PhLP2A), through a yeast two-hybrid system, as a novel protein involved in the stabilization of VEGFR-2 by serving as a chaperone. PDCL3 binds to the juxtamembrane domain of VEGFR-2 and controls the abundance of VEGFR-2 by inhibiting its ubiquitination and degradation. PDCL3 increases VEGF-induced tyrosine phosphorylation and is required for VEGFR-2 dependent endothelial capillary tube formation and proliferation. Taken together, our data provide strong evidence for the role of PDCL3 in angiogenesis and establishes the molecular mechanism by which it regulates VEGFR-2 expression and function. PMID- 23792959 TI - Crystal structure of a human IkappaB kinase beta asymmetric dimer. AB - Phosphorylation of inhibitor of nuclear transcription factor kappaB (IkappaB) by IkappaB kinase (IKK) triggers the degradation of IkappaB and migration of cytoplasmic kappaB to the nucleus where it promotes the transcription of its target genes. Activation of IKK is achieved by phosphorylation of its main subunit, IKKbeta, at the activation loop sites. Here, we report the 2.8 A resolution crystal structure of human IKKbeta (hIKKbeta), which is partially phosphorylated and bound to the staurosporine analog K252a. The hIKKbeta protomer adopts a trimodular structure that closely resembles that from Xenopus laevis (xIKKbeta): an N-terminal kinase domain (KD), a central ubiquitin-like domain (ULD), and a C-terminal scaffold/dimerization domain (SDD). Although hIKKbeta and xIKKbeta utilize a similar dimerization mode, their overall geometries are distinct. In contrast to the structure resembling closed shears reported previously for xIKKbeta, hIKKbeta exists as an open asymmetric dimer in which the two KDs are further apart, with one in an active and the other in an inactive conformation. Dimer interactions are limited to the C-terminal six-helix bundle that acts as a hinge between the two subunits. The observed domain movements in the structures of IKKbeta may represent trans-phosphorylation steps that accompany IKKbeta activation. PMID- 23792960 TI - Amino-terminal domain tetramer organization and structural effects of zinc binding in the N-methyl-D-aspartate (NMDA) receptor. AB - N-Methyl-D-aspartate (NMDA) receptors mediate excitatory neurotransmission in the mammalian central nervous system. An important feature of these receptors is their capacity for allosteric regulation by small molecules, such as zinc, which bind to their amino-terminal domain (ATD). Zinc inhibition through high affinity binding to the ATD has been examined through functional studies; however, there is no direct measurement of associated conformational changes. We used luminescence resonance energy transfer to show that the ATDs undergo a cleft closure-like conformational change upon binding zinc, but no changes are observed in intersubunit distances. Furthermore, we find that the ATDs are more closely packed than the related AMPA receptors. These results suggest that the stability of the upper lobe contacts between ATDs allow for the efficient propagation of the cleft closure conformational change toward the ligand-binding domain and transmembrane segments, ultimately inhibiting the channel. PMID- 23792961 TI - Site-specific inhibitory mechanism for amyloid beta42 aggregation by catechol type flavonoids targeting the Lys residues. AB - The aggregation of the 42-residue amyloid beta-protein (Abeta42) is involved in the pathogenesis of Alzheimer disease (AD). Numerous flavonoids exhibit inhibitory activity against Abeta42 aggregation, but their mechanism remains unclear in the molecular level. Here we propose the site-specific inhibitory mechanism of (+)-taxifolin, a catechol-type flavonoid, whose 3',4'-dihydroxyl groups of the B-ring plays a critical role. Addition of sodium periodate, an oxidant, strengthened suppression of Abeta42 aggregation by (+)-taxifolin, whereas no inhibition was observed under anaerobic conditions, suggesting the inhibition to be associated with the oxidation to form o-quinone. Because formation of the Abeta42-taxifolin adduct was suggested by mass spectrometry, Abeta42 mutants substituted at Arg(5), Lys(16), and/or Lys(28) with norleucine (Nle) were prepared to identify the residues involved in the conjugate formation. (+)-Taxifolin did not suppress the aggregation of Abeta42 mutants at Lys(16) and/or Lys(28) except for the mutant at Arg(5). In addition, the aggregation of Abeta42 was inhibited by other catechol-type flavonoids, whereas that of K16Nle Abeta42 was not. In contrast, some non-catechol-type flavonoids suppressed the aggregation of K16Nle-Abeta42 as well as Abeta42. Furthermore, interaction of (+) taxifolin with the beta-sheet region in Abeta42 was not observed using solid state NMR unlike curcumin of the non-catechol-type. These results demonstrate that catechol-type flavonoids could specifically suppress Abeta42 aggregation by targeting Lys residues. Although the anti-AD activity of flavonoids has been ascribed to their antioxidative activity, the mechanism that the o-quinone reacts with Lys residues of Abeta42 might be more intrinsic. The Lys residues could be targets for Alzheimer disease therapy. PMID- 23792962 TI - Identification and characterization of a periplasmic aminoacyl phosphatidylglycerol hydrolase responsible for Pseudomonas aeruginosa lipid homeostasis. AB - Specific aminoacylation of the phospholipid phosphatidylglycerol (PG) with alanine (or with lysine) was shown to render various organisms less susceptible to antimicrobial agents and environmental stresses. In this study, we make use of the opportunistic pathogen Pseudomonas aeruginosa to decode ORF PA0919-dependent lipid homeostasis. Analysis of the polar lipid content of the deletion mutant DeltaPA0919 indicated significantly enlarged levels of alanyl-PG. The resulting phenotype manifested an increased susceptibility to several antimicrobial compounds when compared with the wild type. A pH-dependent PA0919 promoter located within the upstream gene PA0920 was identified. Localization experiments demonstrated that the PA0919 protein is anchored to the periplasmic surface of the inner bacterial membrane. The recombinant overproduction of wild type and several site-directed mutant proteins in the periplasm of Escherichia coli facilitated a detailed in vitro analysis of the enzymatic PA0919 function. A series of artificial substrates (p-nitrophenyl esters of various amino acids/aliphatic acids) indicated enzymatic hydrolysis of the alanine, glycine, or lysine moiety of the respective ester substrates. Our final in vitro activity assay in the presence of radioactively labeled alanyl-PG then revealed hydrolysis of the aminoacyl linkage, resulting in the formation of alanine and PG. Consequently, PA0919 was termed alanyl-PG hydrolase. The elucidated enzymatic activity implies a new regulatory circuit for the appropriate tuning of cellular alanyl-PG concentrations. PMID- 23792963 TI - Aggregatibacter actinomycetemcomitans leukotoxin utilizes a cholesterol recognition/amino acid consensus site for membrane association. AB - Aggregatibacter actinomycetemcomitans produces a repeats-in-toxin (RTX) leukotoxin (LtxA) that selectively kills human immune cells. Binding of LtxA to its beta2 integrin receptor (lymphocyte function-associated antigen-1 (LFA-1)) results in the clustering of the toxin.receptor complex in lipid rafts. Clustering occurs only in the presence of LFA-1 and cholesterol, and LtxA is unable to kill cells lacking either LFA-1 or cholesterol. Here, the interaction of LtxA with cholesterol was measured using surface plasmon resonance and differential scanning calorimetry. The binding of LtxA to phospholipid bilayers increased by 4 orders of magnitude in the presence of 40% cholesterol relative to the absence of cholesterol. The affinity was specific to cholesterol and required an intact secondary structure. LtxA contains two cholesterol recognition/amino acid consensus (CRAC) sites; CRAC(336) ((333)LEEYSKR(339)) is highly conserved among RTX toxins, whereas CRAC(503) ((501)VDYLK(505)) is unique to LtxA. A peptide corresponding to CRAC(336) inhibited the ability of LtxA to kill Jurkat (Jn.9) cells. Although peptides corresponding to both CRAC(336) and CRAC(503) bind cholesterol, only CRAC(336) competitively inhibited LtxA binding to this sterol. A panel of full-length LtxA CRAC mutants demonstrated that an intact CRAC(336) site was essential for LtxA cytotoxicity. The conservation of CRAC(336) among RTX toxins suggests that this mechanism may be conserved among RTX toxins. PMID- 23792964 TI - Efficient purification and reconstitution of ATP binding cassette transporter B6 (ABCB6) for functional and structural studies. AB - The mitochondrial ATP binding cassette transporter ABCB6 has been associated with a broad range of physiological functions, including growth and development, therapy-related drug resistance, and the new blood group system Langereis. ABCB6 has been proposed to regulate heme synthesis by shuttling coproporphyrinogen III from the cytoplasm into the mitochondria. However, direct functional information of the transport complex is not known. To understand the role of ABCB6 in mitochondrial transport, we developed an in vitro system with pure and active protein. ABCB6 overexpressed in HEK293 cells was solubilized from mitochondrial membranes and purified to homogeneity. Purified ABCB6 showed a high binding affinity for MgATP (Kd = 0.18 MUM) and an ATPase activity with a Km of 0.99 mM. Reconstitution of ABCB6 into liposomes allowed biochemical characterization of the ATPase including (i) substrate-stimulated ATPase activity, (ii) transport kinetics of its proposed endogenous substrate coproporphyrinogen III, and (iii) transport kinetics of substrates identified using a high throughput screening assay. Mutagenesis of the conserved lysine to alanine (K629A) in the Walker A motif abolished ATP hydrolysis and substrate transport. These results suggest a direct interaction between mitochondrial ABCB6 and its transport substrates that is critical for the activity of the transporter. Furthermore, the simple immunoaffinity purification of ABCB6 to near homogeneity and efficient reconstitution of ABCB6 into liposomes might provide the basis for future studies on the structure/function of ABCB6. PMID- 23792965 TI - The UDP-glucose dehydrogenase of Escherichia coli K-12 displays substrate inhibition by NAD that is relieved by nucleotide triphosphates. AB - UDP-glucose dehydrogenase (Ugd) generates UDP-glucuronic acid, an important precursor for the production of many hexuronic acid-containing bacterial surface glycostructures. In Escherichia coli K-12, Ugd is important for biosynthesis of the environmentally regulated exopolysaccharide known as colanic acid, whereas in other E. coli isolates, the same enzyme is required for production of the constitutive group 1 capsular polysaccharides, which act as virulence determinants. Recent studies have implicated tyrosine phosphorylation in the activation of Ugd from E. coli K-12, although it is not known if this is a feature shared by bacterial Ugd proteins. The activities of Ugd from E. coli K-12 and from the group 1 capsule prototype (serotype K30) were compared. Surprisingly, for both enzymes, site-directed Tyr -> Phe mutants affecting the previously proposed phosphorylation site retained similar kinetic properties to the wild-type protein. Purified Ugd from E. coli K-12 had significant levels of NAD substrate inhibition, which could be alleviated by the addition of ATP and several other nucleotide triphosphates. Mutations in a previously identified UDP glucuronic acid allosteric binding site decreased the binding affinity of the nucleotide triphosphate. Ugd from E. coli serotype K30 was not inhibited by NAD, but its activity still increased in the presence of ATP. PMID- 23792966 TI - The x-ray crystal structure of mannose-binding lectin-associated serine proteinase-3 reveals the structural basis for enzyme inactivity associated with the Carnevale, Mingarelli, Malpuech, and Michels (3MC) syndrome. AB - The mannose-binding lectin associated-protease-3 (MASP-3) is a member of the lectin pathway of the complement system, a key component of human innate and active immunity. Mutations in MASP-3 have recently been found to be associated with Carnevale, Mingarelli, Malpuech, and Michels (3MC) syndrome, a severe developmental disorder manifested by cleft palate, intellectual disability, and skeletal abnormalities. However, the molecular basis for MASP-3 function remains to be understood. Here we characterize the substrate specificity of MASP-3 by screening against a combinatorial peptide substrate library. Through this approach, we successfully identified a peptide substrate that was 20-fold more efficiently cleaved than any other identified to date. Furthermore, we demonstrated that mutant forms of the enzyme associated with 3MC syndrome were completely inactive against this substrate. To address the structural basis for this defect, we determined the 2.6-A structure of the zymogen form of the G666E mutant of MASP-3. These data reveal that the mutation disrupts the active site and perturbs the position of the catalytic serine residue. Together, these insights into the function of MASP-3 reveal how a mutation in this enzyme causes it to be inactive and thus contribute to the 3MC syndrome. PMID- 23792967 TI - Tolerance for high flavanol cocoa powder in semisweet chocolate. AB - Endogenous polyphenolic compounds in cacao impart both bitter and astringent characteristics to chocolate confections. While an increase in these compounds may be desirable from a health perspective, they are generally incongruent with consumer expectations. Traditionally, chocolate products undergo several processing steps (e.g., fermentation and roasting) that decrease polyphenol content, and thus bitterness. The objective of this study was to estimate group rejection thresholds for increased content of cocoa powder produced from under fermented cocoa beans in a semisweet chocolate-type confection. The group rejection threshold was equivalent to 80.7% of the non-fat cocoa solids coming from the under-fermented cocoa powder. Contrary to expectations, there were no differences in rejection thresholds when participants were grouped based on their self-reported preference for milk or dark chocolate, indicating that these groups react similarly to an increase in high cocoa flavanol containing cocoa powder. PMID- 23792968 TI - It just doesn't make good business sense. PMID- 23792970 TI - Zebrafish crypt neurons project to a single, identified mediodorsal glomerulus. AB - Crypt neurons are a third type of olfactory receptor neurons with a highly unusual "one cell type--one receptor" mode of expression, the same receptor being expressed by the entire population of crypt neurons. Attempts to identify the target region(s) of crypt neurons have been inconclusive so far. We report that TrkA-like immunoreactivity specifically labeled somata, axons, and terminals of zebrafish crypt neurons and reveal a single glomerulus, mdg2 of the dorsomedial group, as target glomerulus of crypt neurons. Injection of a fluorescent tracing dye into the mdg2 glomerulus retrogradely labeled mostly crypt neurons, as assessed by quantitative morphometry, whereas no crypt neurons were found after injections in neighboring glomeruli. Our data provide strong evidence that crypt neurons converge onto a single glomerulus, and thus form a labeled line consisting of a single sensory cell type, a single olfactory receptor and a single target glomerulus. PMID- 23792971 TI - Intersampler field comparison of Respicon(R), IOM, and closed-face 25-mm personal aerosol samplers during primary production of aluminium. AB - Intersampler field comparison of Respicon((r)), 25-mm closed-face 'total dust' cassette (CFC), and IOM inhalable aerosol sampler was conducted in pot rooms at seven aluminium smelters. The aerosol mass and water-soluble fluoride were selected as airborne contaminants for the comparisons. The aerosol masses of 889 sample pairs of IOM and Respicon((r)) inhalable aerosol sub-fraction, 165 of IOM and 25-mm CFC, and 194 of CFC and Respicon((r)) thoracic aerosol sub-fraction were compared. The number of sample pairs for the comparison of water-soluble fluoride was 906, 170, and 195, respectively. The geometric mean aerosol mass collected with the inhalable Respicon((r)) was 2.91 mg m(-3) compared with 3.38 mg m(-3) with the IOM. The overall ratio between IOM and Respicon((r)) inhalable sub-fraction was 1.16 [95% confidence interval (CI) = 1.11-1.21] for aerosol mass and 1.13 (95% CI = 1.08-1.18) for water-soluble fluoride. The results indicate that Respicon((r)) undersampled the aerosol mass and water-soluble fluoride in the inhalable sub-fraction compared with the IOM. The results indicated undersampling of the Respicon((r)) at mass concentrations higher than 1.35 mg m( 3) and oversampling at lower mass concentrations. The overall ratio between aerosol mass collected with IOM and CFC was 4.19 (95% CI = 3.79-4.64) and 1.61 (95% CI = 1.51-1.72) for water-soluble fluoride. Thus, for this industry, a correction factor of 4.2 is suggested for the conversion of CFC to inhalable aerosol masses and a conversion factor of 1.6 for water-soluble fluoride if wall deposits in the CFC are included. CFC and thoracic Respicon((r)) collected similar aerosol masses (ratio = 1.04; 95% CI = 0.97-1.12), whereas the ratio was 1.19 (95% CI = 1.11-1.28) for water-soluble fluoride. The variability of the exposure is substantial; thus, large data sets are required in sampler performance field comparisons. PMID- 23792972 TI - Comprehensive assessment of exposures to elongate mineral particles in the taconite mining industry. AB - Since the 1970s, concerns have been raised about elevated rates of mesothelioma in the vicinity of the taconite mines in the Mesabi Iron Range. However, insufficient quantitative exposure data have hampered investigations of the relationship between cumulative exposures to elongate mineral particles (EMP) in taconite dust and adverse health effects. Specifically, no research on exposure to taconite dust, which includes EMP, has been conducted since 1990. This article describes a comprehensive assessment of present-day exposures to total and amphibole EMP in the taconite mining industry. Similar exposure groups (SEGs) were established to assess present-day exposure levels and buttress the sparse historical data. Personal samples were collected to assess the present-day levels of worker exposures to EMP at six mines in the Mesabi Iron Range. The samples were analyzed using National Institute for Occupational Safety and Health (NIOSH) methods 7400 and 7402. For many SEGs in several mines, the exposure levels of total EMP were higher than the NIOSH Recommended Exposure Limit (REL). However, the total EMP classification includes not only the asbestiform EMP and their non asbestiform mineral analogs but also other minerals because the NIOSH 7400 cannot differentiate between these. The concentrations of amphibole EMP were well controlled across all mines and were much lower than the concentrations of total EMP, indicating that amphibole EMP are not major components of taconite EMP. The levels are also well below the NIOSH REL of 0.1 EMP cc(-1). Two different approaches were used to evaluate the variability of exposure between SEGs, between workers, and within workers. The related constructs of contrast and homogeneity were calculated to characterize the SEGs. Contrast, which is a ratio of between-SEG variability to the sum of between-SEG and between-worker variability, provides an overall measure of whether there are distinctions between the SEGs. Homogeneity, which is the ratio of the within-worker variance component to the sum of the between-worker and within-worker variance components, provides an overall measure of how similar exposures are for workers within an SEG. Using these constructs, it was determined that the SEGs are formed well enough when grouped by mine for both total and amphibole EMP to be used for epidemiological analysis. PMID- 23792973 TI - Exposure to inhalable dust and endotoxin among Danish pig farmers affected by work tasks and stable characteristics. AB - OBJECTIVE: To identify working tasks and stable characteristics that determine intensity and variability of personal exposure to dust and endotoxin among pig farmers. METHODS: Three hundred fifty-four personal full-shift measurements were performed in 231 farmers employed in 53 Danish pig farms. Filters were gravimetrically analysed for inhalable dust and for endotoxin by the Limulus amebocyte lysate assay. Information on working tasks and stable characteristics were collected using self-reported activity diaries and walk-through surveys performed in conjunction with the measurements. Associations between log transformed dust and endotoxin exposure and working tasks and stable characteristics were examined using linear mixed-effects analysis. In these models, worker and farm identity were treated as random effects and working tasks and stable characteristics as fixed effects. Both separate and combined models for tasks and stable characteristics were elaborated. RESULTS: Inhalable dust concentrations ranged between 0.1 and 48 mg m(-3) and endotoxin concentrations varied between 9.2 and 370,000 EU m(-3). Field work activities played a dominant role on the exposure variability. Indoor working tasks with intense animal activity or handling of feed materials increased exposure concentrations, whereas engagement in field work was associated with lower exposure concentrations. High pressure water cleaning increased endotoxin exposure but did not affect exposure to inhalable dust. Stable characteristics related to feeding practices and type of ventilation were determinants of exposure to inhalable dust. For endotoxin, the most important determinants were use of dry feed and slatted floor coverage. Feeding practices solely explained all between-farms variability in exposure to inhalable dust and endotoxin. CONCLUSIONS: These findings suggest feeding systems, flooring and ventilation to be potential areas where improved methods can reduce exposure to dust and endotoxin among pig farmers. Further, they highlight particular tasks involving feeding and intense animal handling as sources of very high levels of exposure. The pig farming industry is encouraged to focus on exposure reduction. Use of respirators during performance of working tasks where levels of exposure are particularly high ought to be considered until adequate hygienic solutions have been established. PMID- 23792974 TI - Detoxification of Jatropha curcas kernel cake by a novel Streptomyces fimicarius strain. AB - A huge amount of kernel cake, which contains a variety of toxins including phorbol esters (tumor promoters), is projected to be generated yearly in the near future by the Jatropha biodiesel industry. We showed that the kernel cake strongly inhibited plant seed germination and root growth and was highly toxic to carp fingerlings, even though phorbol esters were undetectable by HPLC. Therefore it must be detoxified before disposal to the environment. A mathematic model was established to estimate the general toxicity of the kernel cake by determining the survival time of carp fingerling. A new strain (Streptomyces fimicarius YUCM 310038) capable of degrading the total toxicity by more than 97% in a 9-day solid state fermentation was screened out from 578 strains including 198 known strains and 380 strains isolated from air and soil. The kernel cake fermented by YUCM 310038 was nontoxic to plants and carp fingerlings and significantly promoted tobacco plant growth, indicating its potential to transform the toxic kernel cake to bio-safe animal feed or organic fertilizer to remove the environmental concern and to reduce the cost of the Jatropha biodiesel industry. Microbial strain profile essential for the kernel cake detoxification was discussed. PMID- 23792975 TI - Fate of stable strontium in the sewage treatment process as an analog for radiostrontium released by nuclear accidents. AB - Radionuclides were widely released into the environment due to the nuclear accident at the Fukushima Daiichi Nuclear Power Plant. Some of these radionuclides have flowed into municipal sewage treatment plants through sewer systems. We have observed the fate of stable Sr in the sewage treatment process as a means to predict the fate of radiostrontium. Concentrations of stable Sr were determined in sewage influent, effluent, dewatered sludge, and incinerated sewage sludge ash collected from a sewage treatment plant once a month from July to December 2011. In the mass balance of Sr in the sewage treatment plant, 76% of the Sr entering the plant was discharged to the receiving water on average. Additionally, 14% of the Sr flowing through the plant was transferred to the sewage sludge and then concentrated in the sludge ash without being released to the atmosphere. We also investigated Sr sorption by activated sludge in a batch experiment. Measurements at 3 and 6h after the contact showed Sr was sorbed in the activated sludge; however, the measurements indicated Sr desorption from activated sludge occurred 48 h after the contact. PMID- 23792976 TI - Identification of silicon (Si) as an appropriate normaliser for estimating the heavy metals enrichment of an urban lake system. AB - Urbanisation has a profound influence on our environment, and its burden is often transferred to aquatic systems. The surface sediments of urban lake systems are severely threatened with major contamination on a daily basis. Empirical evidence gleaned from the study of Akkulam Veli, a tropical urban lake in Southern India, indicates the need to evaluate all factors defining the contamination status of lake systems, rather than the conventional procedure that use Al or Fe, and select normalisers to evaluate metal enrichment in contaminated lake systems. A two step correlation analysis was done using Fe, Al, Co, Mn, Ti and Si as normalisers for Cr, Co, Ni, Cu, Zn and Pb. However, Fe, Al, Co, Mn and Ti are found to be unsuitable as normalisers for various reasons, including the redox condition of the lake for Fe, the geological structure of the lake, with its laterite basin that is conducive to high concentrations of Al, the near detectable range in many stations that can magnify the enrichment for Co, the escalation in EF values for Mn, and the probability of effluent entry from the nearby titanium-based industry for Ti. Si, which is highly refractory, stable, associated with clay minerals, and unaffected by environmental factors such as reduction/oxidation, adsorption/desorption and other diagenic processes, appears to be the most appropriate normaliser in AV lake sediments. The average EF values calculated using Si as a normaliser are Pb (3.88) > Cr (1.77) > Zn (1.71) > Co (1.34) > Cu (1.29) > Ni (0.94). The results of the study show that this alternate method is more accurate at estimating EF values, which in turn can be employed more precisely to evaluate the extent of anthropogenic contamination in urban lake systems with highly contaminated surface sediments. PMID- 23792977 TI - Conscious recollection and binding among context features. AB - Recent research suggests that the subjective feeling of conscious recollection is uniquely characterized by joint memory for several context features while merely familiar memories lack this property (Meiser, Sattler, & Weisser, 2008). In the present research we took the novel approach of extending the dual task paradigm to the simultaneous study of subjective retrieval experience (using the remember/know procedure) and joint memory for two orthogonal context features. While dual task load during encoding lead to reductions in the frequency of the subjective experience of conscious recollection and reductions in overall context memory, joint context memory was not affected. Furthermore, the relation of higher overall context memory for consciously recollected items than for familiar items was preserved even under dual task load. These results have import implications for theories of long-term feature binding and the processes involved in producing the experience of conscious recollection. PMID- 23792978 TI - Resting state functional connectivity associated with trait emotional intelligence. AB - Previous neuroimaging studies have suggested that trait emotional intelligence (TEI) is associated with components of the neural network involved in social cognition (SCN) and somatic marker circuitry (SMC). Our study is the first to investigate the association of TEI with resting-state functional connectivity (RSFC) between the key nodes of SCN and SMC [medial prefromtal cortex (mPFC) and bilateral anterior insula (AI), respectively] and other brain regions. We found that (a) the intrapersonal factor of TEI was negatively correlated with RSFC between mPFC and the anterior part of the right dorsolateral prefrontal cortex (DLPFC), (b) the TEI interpersonal factor score was positively correlated with RSFC between mPFC and the lingual gyrus, and (c) total TEI was positively correlated with RSFC between mPFC and the precuneus as well as (d) between the left AI and the middle part of the right DLPFC. Taken together with previous study findings, our findings can be comprehensively understood as neural mechanisms of SCN and SMC components are associated with TEI. In particular, the fluent interaction between SCN's two key nodes (mPFC and precuneus/PCC) [as well as between DMN's two key nodes] is suggested to be crucial for total TEI. Our study also indicated that (a) a clear functional separation between the two key nodes of the two major intrinsic networks, DMN and the task-positive network (mPFC and DLPFC), is important for higher intrapersonal TEI, (b) brain interactions involving vision-related areas (lingual gyrus) and the key node of SCN (mPFC) are important for interpersonal TEI, and (c) control of DLPFC over the key node of SMC (AI) is important for total TEI. PMID- 23792979 TI - Human occipital cortices differentially exert saccadic suppression: Intracranial recording in children. AB - By repeating saccades unconsciously, humans explore the surrounding world every day. Saccades inevitably move external visual images across the retina at high velocity; nonetheless, healthy humans don't perceive transient blurring of the visual scene during saccades. This perceptual stability is referred to as saccadic suppression. Functional suppression is believed to take place transiently in the visual systems, but it remains unknown how commonly or differentially the human occipital lobe activities are suppressed at the large scale cortical network level. We determined the spatial-temporal dynamics of intracranially-recorded gamma activity at 80-150 Hz around spontaneous saccades under no-task conditions during wakefulness and those in darkness during REM sleep. Regardless of wakefulness or REM sleep, a small degree of attenuation of gamma activity was noted in the occipital regions during saccades, most extensively in the polar and least in the medial portions. Longer saccades were associated with more intense gamma-attenuation. Gamma-attenuation was subsequently followed by gamma-augmentation most extensively involving the medial and least involving the polar occipital region. Such gamma-augmentation was more intense during wakefulness and temporally locked to the offset of saccades. The polarities of initial peaks of perisaccadic event-related potentials (ERPs) were frequently positive in the medial and negative in the polar occipital regions. The present study, for the first time, provided the electrophysiological evidence that human occipital cortices differentially exert perisaccadic modulation. Transiently suppressed sensitivity of the primary visual cortex in the polar region may be an important neural basis for saccadic suppression. Presence of occipital gamma-attenuation even during REM sleep suggests that saccadic suppression might be exerted even without external visual inputs. The primary visual cortex in the medial region, compared to the polar region, may be more sensitive to an upcoming visual scene provided at the offset of each saccade. PMID- 23792980 TI - Disrupted cortico-cerebellar connectivity in older adults. AB - Healthy aging is marked by declines in a variety of cognitive and motor abilities. A better understanding of the aging brain may aid in elucidating the neural substrates of these behavioral effects. Investigations of resting state functional brain connectivity have provided insights into pathology, and to some degree, healthy aging. Given the role of the cerebellum in both motor and cognitive behaviors, as well as its known volumetric declines with age, investigating cerebellar networks may shed light on the neural bases of age related functional declines. We mapped the resting state networks of the lobules of the right hemisphere and the vermis of the cerebellum in a group of healthy older adults and compared them to those of young adults. We report disrupted cortico-cerebellar resting state network connectivity in older adults. These results remain even when controlling for cerebellar volume, signal-to-noise ratio, and signal-to-fluctuation noise ratio. Specifically, there was consistent disruption of cerebellar connectivity with both the striatum and the medial temporal lobe. Associations between connectivity strength and both sensorimotor and cognitive task performances indicate that cerebellar engagement with the default mode network and striatal pathways is associated with better performance for older adults. These results extend our understanding of the resting state networks of the aging brain to include cortico-cerebellar networks, and indicate that age differences in network connectivity strength are important for behavior. PMID- 23792981 TI - Heterogeneous impact of motion on fundamental patterns of developmental changes in functional connectivity during youth. AB - Several independent studies have demonstrated that small amounts of in-scanner motion systematically bias estimates of resting-state functional connectivity. This confound is of particular importance for studies of neurodevelopment in youth because motion is strongly related to subject age during this period. Critically, the effects of motion on connectivity mimic major findings in neurodevelopmental research, specifically an age-related strengthening of distant connections and weakening of short-range connections. Here, in a sample of 780 subjects ages 8-22, we re-evaluate patterns of change in functional connectivity during adolescent development after rigorously controlling for the confounding influences of motion at both the subject and group levels. We find that motion artifact inflates both overall estimates of age-related change as well as specific distance-related changes in connectivity. When motion is more fully accounted for, the prevalence of age-related change as well as the strength of distance-related effects is substantially reduced. However, age-related changes remain highly significant. In contrast, motion artifact tends to obscure age related changes in connectivity associated with segregation of functional brain modules; improved preprocessing techniques allow greater sensitivity to detect increased within-module connectivity occurring with development. Finally, we show that subject's age can still be accurately estimated from the multivariate pattern of functional connectivity even while controlling for motion. Taken together, these results indicate that while motion artifact has a marked and heterogeneous impact on estimates of connectivity change during adolescence, functional connectivity remains a valuable phenotype for the study of neurodevelopment. PMID- 23792982 TI - Locally linear embedding (LLE) for MRI based Alzheimer's disease classification. AB - Modern machine learning algorithms are increasingly being used in neuroimaging studies, such as the prediction of Alzheimer's disease (AD) from structural MRI. However, finding a good representation for multivariate brain MRI features in which their essential structure is revealed and easily extractable has been difficult. We report a successful application of a machine learning framework that significantly improved the use of brain MRI for predictions. Specifically, we used the unsupervised learning algorithm of local linear embedding (LLE) to transform multivariate MRI data of regional brain volume and cortical thickness to a locally linear space with fewer dimensions, while also utilizing the global nonlinear data structure. The embedded brain features were then used to train a classifier for predicting future conversion to AD based on a baseline MRI. We tested the approach on 413 individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) who had baseline MRI scans and complete clinical follow-ups over 3 years with the following diagnoses: cognitive normal (CN; n=137), stable mild cognitive impairment (s-MCI; n=93), MCI converters to AD (c-MCI, n=97), and AD (n=86). We found that classifications using embedded MRI features generally outperformed (p<0.05) classifications using the original features directly. Moreover, the improvement from LLE was not limited to a particular classifier but worked equally well for regularized logistic regressions, support vector machines, and linear discriminant analysis. Most strikingly, using LLE significantly improved (p=0.007) predictions of MCI subjects who converted to AD and those who remained stable (accuracy/sensitivity/specificity: =0.68/0.80/0.56). In contrast, predictions using the original features performed not better than by chance (accuracy/sensitivity/specificity: =0.56/0.65/0.46). In conclusion, LLE is a very effective tool for classification studies of AD using multivariate MRI data. The improvement in predicting conversion to AD in MCI could have important implications for health management and for powering therapeutic trials by targeting non-demented subjects who later convert to AD. PMID- 23792983 TI - She runs, the road runs, my mind runs, bad blood runs between us: literal and figurative motion verbs: an fMRI study. AB - The role of sensory-motor components in language processing is a central topic in cognitive neuroscience. Recent studies showed that the processing of action words recruits cortical motor regions involved in the planning and execution of the described actions. However, it remains unclear to what extent the abstract versus concrete nature of the described motion modulates the activation of premotor and motor areas and how the agent affects this modulation. Here, we contribute to this line of research by investigating the comprehension of motion verbs, used in a literal versus figurative context, in an fMRI study with normal subjects in which the somatotopy of activation was investigated by presenting motion verbs that involve upper vs. lower limbs. A set of sentences including a motion verb used in a literal, fictive (only lower limb), metaphorical, or idiomatic way was studied. Cognition verbs were also included as control. We found that figurative sentences compared to literal ones produced a greater activation of a bilateral fronto-temporal network, in line with previous studies. Moreover, fictive motion activated a more posterior region, involving primary visual areas and motion sensitive visual areas, but also the left middle frontal gyrus. Crucially, the left precentral gyrus was activated in the case of the upper limb for literal and metaphorical motion sentence types, but not idiomatic sentences. For fictive motion, we found a lower limb-related somatotopic effect, also present for literal sentences, while the evidence for metaphorical and idiomatic sentences was less strong. In conclusion, our results confirm that premotor areas are activated by language understanding, but to a different degree depending on the specific literal versus figurative context in which motion verbs appear. Therefore, they support weak embodied views suggesting that the motor system enhances the comprehension of linguistically encoded actions. PMID- 23792984 TI - A NIRS-fMRI investigation of prefrontal cortex activity during a working memory task. AB - Near-infrared spectroscopy (NIRS) is commonly used for studying human brain function. However, several studies have shown that superficial hemodynamic changes such as skin blood flow can affect the prefrontal NIRS hemoglobin (Hb) signals. To examine the criterion-related validity of prefrontal NIRS-Hb signals, we focused on the functional signals during a working memory (WM) task and investigated their similarity with blood-oxygen-level-dependent (BOLD) signals simultaneously measured by functional magnetic resonance imaging (fMRI). We also measured the skin blood flow with a laser Doppler flowmeter (LDF) at the same time to examine the effect of superficial hemodynamic changes on the NIRS-Hb signals. Correlation analysis demonstrated that temporal changes in the prefrontal NIRS-Hb signals in the activation area were significantly correlated with the BOLD signals in the gray matter rather than those in the soft tissue or the LDF signals. While care must be taken when comparing the NIRS-Hb signal with the extracranial BOLD or LDF signals, these results suggest that the NIRS-Hb signal mainly reflects hemodynamic changes in the gray matter. Moreover, the amplitudes of the task-related responses of the NIRS-Hb signals were significantly correlated with the BOLD signals in the gray matter across participants, which means participants with a stronger NIRS-Hb response showed a stronger BOLD response. These results thus provide supportive evidence that NIRS can be used to measure hemodynamic signals originating from prefrontal cortex activation. PMID- 23792986 TI - G8 ministers agree to collaborate on antimicrobial resistance. PMID- 23792987 TI - National Assembly to debate draft law to protect breeding dogs in Wales. PMID- 23792989 TI - Princess Royal draws attention to growing horse crisis. PMID- 23792985 TI - Multifaceted roles for low-frequency oscillations in bottom-up and top-down processing during navigation and memory. AB - A prominent and replicated finding is the correlation between running speed and increases in low-frequency oscillatory activity in the hippocampal local field potential. A more recent finding concerns low-frequency oscillations that increase in coherence between the hippocampus and neocortical brain areas such as prefrontal cortex during memory-related behaviors (i.e., remembering the correct location to visit). In this review, we tie together movement-related and memory related low-frequency oscillations in the rodent with similar findings in humans. We argue that although movement-related low-frequency oscillations, in particular, may have slightly different characteristics in humans than rodents, placing important constraints on our thinking about this issue, both phenomena have similar functional foundations. We review four prominent theoretical models that provide partially conflicting accounts of movement-related low-frequency oscillations. We attempt to tie together these theoretical proposals, and existing data in rodents and humans, with memory-related low-frequency oscillations. We propose that movement-related low-frequency oscillations and memory-related low-frequency oscillatory activity, both of which show significant coherence with oscillations in other brain regions, represent different facets of "spectral fingerprints," or different resonant frequencies within the same brain networks underlying different cognitive processes. Together, movement-related and memory-related low-frequency oscillatory coupling may be linked by their distinct contributions to bottom-up, sensorimotor driven processing and top-down, controlled processing characterizing aspects of memory encoding and retrieval. PMID- 23792990 TI - Time to get practical on anthelmintic resistance. PMID- 23792991 TI - Encouraging women to engage with veterinary politics. PMID- 23792992 TI - Simple concept that could have a massive impact. PMID- 23792994 TI - Northern Ireland disease surveillance, January to March 2013. PMID- 23792995 TI - Eradicating bovine viral diarrhoea virus. PMID- 23792996 TI - Learning about business. PMID- 23792997 TI - Adult polycystic liver disease in alpacas. PMID- 23792998 TI - Ensuring a sustainable profession. PMID- 23792999 TI - World Horse Welfare information pack. PMID- 23793000 TI - International Ruminant Digit Symposium. PMID- 23793001 TI - Can antipsychotic treatment contribute to drug addiction in schizophrenia? AB - Individuals with schizophrenia are at very high risk for drug abuse and addiction. Patients with a coexisting drug problem fare worse than patients who do not use drugs, and are also more difficult to treat. Current hypotheses cannot adequately account for why patients with schizophrenia so often have a co-morbid drug problem. I present here a complementary hypothesis based on evidence showing that chronic exposure to antipsychotic medications can induce supersensitivity within the brain's dopamine systems, and that this in turn can enhance the rewarding and incentive motivational effects of drugs and reward cues. At the neurobiological level, these effects of antipsychotics are potentially linked to antipsychotic-induced increases in the striatal levels of dopamine D2 receptors and D2 receptors in a high-affinity state for dopamine, particularly at postsynaptic sites. Antipsychotic-induced dopamine supersensitivity and enhanced reward function are not inevitable consequences of prolonged antipsychotic treatment. At least two parameters appear to promote these effects; the use of antipsychotics of the typical class, and continuous rather than intermittent antipsychotic exposure, such that silencing of dopaminergic neurotransmission via D2/3 receptors is unremitting. Thus, by inducing forms of neural plasticity that facilitate the ability of drugs and reward cues to gain control over behaviour, some currently used treatment strategies with typical antipsychotics might contribute to compulsive drug seeking and drug taking behaviours in vulnerable schizophrenia patients. PMID- 23793002 TI - One-pot one-step deracemization of amines using omega-transaminases. AB - In this study, we developed a one-pot one-step deracemization method for the production of various enantiomerically pure amines using two opposite enantioselective omega-TAs. Using this method, various aromatic amines were successfully converted to their (R)-forms (>99%) with good conversion. PMID- 23793003 TI - Cost-effectiveness: the menage a trois having a ratio with one denominator and one numerator. PMID- 23793004 TI - Numbers needed to treat (lives!) and numbers needed to save (money). PMID- 23793005 TI - Less invasive partial circulatory support: concept versus clinical utility. PMID- 23793006 TI - The current role of coronary artery bypass in diabetics with multivessel coronary disease. PMID- 23793009 TI - Ruptured plaque and large plaque burden are risks of distal embolisation during percutaneous coronary intervention: evaluation by angioscopy and virtual histology intravascular ultrasound imaging. AB - AIMS: Slow flow and no flow phenomena have been associated with distal embolisation, especially of plaque debris, and with unfavourable clinical outcomes. However, patients at high risk of distal embolisation for whom distal protection might be beneficial have not been adequately identified. We examined the frequency of distal embolisation and its predicting factors, including both ACS and non-ACS patients. METHODS AND RESULTS: Consecutive patients (n=98) with or without ACS who had received PCI with a filter-type distal protection device and successful angioscopic and VH-IVUS examination were prospectively enrolled. The presence of yellow plaque and plaque rupture was evaluated by angioscopy. Tissue classification and plaque burden was evaluated by VH-IVUS. Distal embolisation was evaluated by pathological examination of material collected in the filter. Distal embolisation of plaque debris was more frequently detected in patients with ACS (48% vs. 25%, p=0.02), in those with ruptured plaque (86% vs. 13%, p<0.001), in those with large (>75%) plaque burden (50% vs. 23%, p=0.006), and in those with grade 2/3 yellow plaque (52% vs. 7%, p<0.001), as compared to those without it. CONCLUSIONS: The presence of ruptured yellow plaque and of large plaque burden, rather than the setting of ACS, was highly predictive of distal embolisation of plaque debris. PMID- 23793010 TI - Stuck rotablator: the nightmare of rotational atherectomy. AB - AIMS: Rotational atherectomy (RA) is frequently performed to modify complex fibrocalcific coronary lesions with high procedural success. A stuck rotablator is a rare but life-threatening complication. However, its description remains sporadic and it has never been systematically analysed. The aim of this analysis is to present our experience and summarise the available literature about stuck rotablator, and to identify risk factors and possible management strategies for this complication. METHODS AND RESULTS: We analysed our experience of 442 RA procedures and identified four cases of stuck rotablator. Two of these cases were rotablations in freshly implanted stents. All cases were managed percutaneously. We further analysed the available literature and identified a total of 11 reports with 14 cases of a stuck rotablator burr; seven were managed surgically and seven with endovascular approaches. Based on our experience and the literature review we developed an algorithm to guide operators while managing this complication. CONCLUSIONS: Entrapment of a rotablation burr is a rare but very serious complication of RA. Operators performing RA should be aware of this risk and be prepared to manage it adequately. In our experience, the risk seems to be higher when rotablating freshly implanted underexpanded stents. PMID- 23793011 TI - Safety and feasibility of percutaneous delivery of a novel circulatory assist device (CircuLite(r) SYNERGY(r)) in the swine model. AB - AIMS: To demonstrate the feasibility and safety of percutaneous delivery of the novel inflow cannula of the CircuLite(r) SYNERGY(r) pocket Micro-pump via transseptal access in the swine model. METHODS AND RESULTS: After transseptal puncture, the inflow cannula system was advanced into the left atrium (LA) via the right external jugular vein and anchored onto the atrial septum under fluoroscopic and intracardiac echo guidance in 14 acute animals. Subsequently, chronic studies were performed to examine the long-term healing response to the cannula implantation with an artery-LA shunt (n=10) and overall safety of the Micro-pump components (n=6). Acute studies proved the concept of transcatheter delivery of the inflow cannula via superior venous access. The cannula tips were securely anchored in all chronic animals and appropriately endothelialised as early as two weeks. No thrombi or septal damage was observed. For the chronic pump group, device speed of 22,000 rpm (~2.0 L/min) was maintained without any adverse cardiac events. Plasma free haemoglobin assays confirmed the absence of clinically significant haemolysis. CONCLUSIONS: The transcatheter delivery of the inflow cannula via superior venous access to the LA is feasible and safe. This percutaneous delivery presents a significantly less invasive alternative to deliver partial circulatory support devices. PMID- 23793012 TI - Virtual fractional flow reserve by coronary computed tomography - hope or hype? AB - Studies evaluating the diagnostic performance of coronary computed tomography angiography (CTA) are consistent in demonstrating a high negative predictive accuracy, but only a modest positive predictive accuracy for the detection of significant coronary artery disease. Consequentially, there has been a considerable effort made to enhance the diagnostic capability of coronary CTA by developing scanner technology and also post-processing algorithms for coronary stenosis evaluation. Of these new developments, the proposition of being able to measure non-invasive fractional flow reserve by coronary computed tomography angiography (FFRct) has generated much recent interest. Initial reports indicate that the application FFRct not only correlates well with invasive fractional flow reserve but also has the potential to enhance substantially the positive predictive accuracy and overall accuracy of coronary CTA. Although it is theoretically possible to measure FFRct using complex computational fluid dynamics adapted from the aeronautical industry, this approach is likely to face a number of challenges prior to it being accepted into the mainstream as an adjunct to coronary CTA. The aim of the current review is to provide an overview of: 1) the fundamental engineering principles behind computational fluid dynamic modelling of coronary arterial blood flow; 2) the difficulties faced from an engineering perspective in developing a truly representative model; and 3) the challenges this technology is likely to face as it attempts to enter the clinical domain. PMID- 23793013 TI - How should I treat a left main spontaneous dissection involving left anterior descending artery, intermediate branch artery and left circumflex artery? AB - BACKGROUND: A 45-year-old woman presented to the emergency department with ST segment elevation myocardial infarction (STEMI). INVESTIGATION: Physical examination, electrocardiography, coronary angiography, echocardiography, cardiac computed tomography. DIAGNOSIS: STEMI due to spontaneous left main coronary artery dissection involving left anterior descending, intermediate and left circumflex arteries. TREATMENT: Percutaneous coronary intervention (PCI). PMID- 23793014 TI - Tools and techniques - clinical: catheter compatibility in CTO recanalisation. PMID- 23793015 TI - Percutaneous treatment of paravalvular leaks after transcatheter aortic valve implantation with the CoreValve self-expanding bioprosthesis. PMID- 23793016 TI - High-throughput, automated extraction of DNA and RNA from clinical samples using TruTip technology on common liquid handling robots. AB - TruTip is a simple nucleic acid extraction technology whereby a porous, monolithic binding matrix is inserted into a pipette tip. The geometry of the monolith can be adapted for specific pipette tips ranging in volume from 1.0 to 5.0 ml. The large porosity of the monolith enables viscous or complex samples to readily pass through it with minimal fluidic backpressure. Bi-directional flow maximizes residence time between the monolith and sample, and enables large sample volumes to be processed within a single TruTip. The fundamental steps, irrespective of sample volume or TruTip geometry, include cell lysis, nucleic acid binding to the inner pores of the TruTip monolith, washing away unbound sample components and lysis buffers, and eluting purified and concentrated nucleic acids into an appropriate buffer. The attributes and adaptability of TruTip are demonstrated in three automated clinical sample processing protocols using an Eppendorf epMotion 5070, Hamilton STAR and STARplus liquid handling robots, including RNA isolation from nasopharyngeal aspirate, genomic DNA isolation from whole blood, and fetal DNA extraction and enrichment from large volumes of maternal plasma (respectively). PMID- 23793017 TI - Identification of direct tyrosine kinase substrates based on protein kinase assay linked phosphoproteomics. AB - Protein kinases are implicated in multiple diseases such as cancer, diabetes, cardiovascular diseases, and central nervous system disorders. Identification of kinase substrates is critical to dissecting signaling pathways and to understanding disease pathologies. However, methods and techniques used to identify bona fide kinase substrates have remained elusive. Here we describe a proteomic strategy suitable for identifying kinase specificity and direct substrates in high throughput. This approach includes an in vitro kinase assay based substrate screening and an endogenous kinase dependent phosphorylation profiling. In the in vitro kinase reaction route, a pool of formerly phosphorylated proteins is directly extracted from whole cell extracts, dephosphorylated by phosphatase treatment, after which the kinase of interest is added. Quantitative proteomics identifies the rephosphorylated proteins as direct substrates in vitro. In parallel, the in vivo quantitative phosphoproteomics is performed in which cells are treated with or without the kinase inhibitor. Together, proteins phosphorylated in vitro overlapping with the kinase-dependent phosphoproteome in vivo represents the physiological direct substrates in high confidence. The protein kinase assay-linked phosphoproteomics was applied to identify 25 candidate substrates of the protein-tyrosine kinase SYK, including a number of known substrates and many novel substrates in human B cells. These shed light on possible new roles for SYK in multiple important signaling pathways. The results demonstrate that this integrated proteomic approach can provide an efficient strategy to screen direct substrates for protein tyrosine kinases. PMID- 23793019 TI - In China the use of analgesics and sedation following paediatric cardiac surgery is variable; average pain scores are reported to be good but over-sedation is common. PMID- 23793018 TI - Perturbations to the ubiquitin conjugate proteome in yeast deltaubx mutants identify Ubx2 as a regulator of membrane lipid composition. AB - Yeast Cdc48 (p97/VCP in human cells) is a hexameric AAA ATPase that is thought to use ATP hydrolysis to power the segregation of ubiquitin-conjugated proteins from tightly bound partners. Current models posit that Cdc48 is linked to its substrates through adaptor proteins, including a family of seven proteins (13 in human) that contain a Cdc48-binding UBX domain. However, few substrates for specific UBX proteins are known, and hence the generality of this hypothesis remains untested. Here, we use mass spectrometry to identify ubiquitin conjugates that accumulate in cdc48 and ubx mutants. Different ubx mutants exhibit unique patterns of conjugate accumulation that point to functional specialization of individual Ubx proteins. To validate our findings, we examined in detail the endoplasmic reticulum-bound transcription factor Spt23, which we identified as a putative Ubx2 substrate. Mutant ubx2Delta cells are deficient in both cleaving the ubiquitinated 120 kDa precursor of Spt23 to form active p90 and in localizing p90 to the nucleus, resulting in reduced expression of the target gene OLE1, which encodes fatty acid desaturase. Our findings provide a resource for future investigations on Cdc48, illustrate the utility of proteomics to identify ligands for specific ubiquitin receptor pathways, and uncover Ubx2 as a key player in the regulation of membrane lipid biosynthesis. PMID- 23793020 TI - Array of Hall Effect sensors for linear positioning of a magnet independently of its strength variation. a case study: monitoring milk yield during milking in goats. AB - In this study we propose an electronic system for linear positioning of a magnet independent of its modulus, which could vary because of aging, different fabrication process, etc. The system comprises a linear array of 24 Hall Effect sensors of proportional response. The data from all sensors are subject to a pretreatment (normalization) by row (position) making them independent on the temporary variation of its magnetic field strength. We analyze the particular case of the individual flow in milking of goats. The multiple regression analysis allowed us to calibrate the electronic system with a percentage of explanation R2 = 99.96%. In our case, the uncertainty in the linear position of the magnet is 0.51 mm that represents 0.019 L of goat milk. The test in farm compared the results obtained by direct reading of the volume with those obtained by the proposed electronic calibrated system, achieving a percentage of explanation of 99.05%. PMID- 23793021 TI - Sequential fuzzy diagnosis method for motor roller bearing in variable operating conditions based on vibration analysis. AB - A novel intelligent fault diagnosis method for motor roller bearings which operate under unsteady rotating speed and load is proposed in this paper. The pseudo Wigner-Ville distribution (PWVD) and the relative crossing information (RCI) methods are used for extracting the feature spectra from the non-stationary vibration signal measured for condition diagnosis. The RCI is used to automatically extract the feature spectrum from the time-frequency distribution of the vibration signal. The extracted feature spectrum is instantaneous, and not correlated with the rotation speed and load. By using the ant colony optimization (ACO) clustering algorithm, the synthesizing symptom parameters (SSP) for condition diagnosis are obtained. The experimental results shows that the diagnostic sensitivity of the SSP is higher than original symptom parameter (SP), and the SSP can sensitively reflect the characteristics of the feature spectrum for precise condition diagnosis. Finally, a fuzzy diagnosis method based on sequential inference and possibility theory is also proposed, by which the conditions of the machine can be identified sequentially as well. PMID- 23793022 TI - Extending the GMR current measurement range with a counteracting magnetic field. AB - Traditionally, current transformers are often used for current measurement in low voltage (LV) electrical networks. They have a large physical size and are not designed for use with power electronic circuits. Semiconductor-based current sensing devices such as the Hall sensor and Giant Magnetoresistive (GMR) sensor are advantageous in terms of small size, high sensitivity, wide frequency range, low power consumption, and relatively low cost. Nevertheless, the operational characteristics of these devices limit their current measurement range. In this paper, a design based on using counteracting magnetic field is introduced for extending the GMR current measurement range from 9 A (unipolar) to +/-45 A. A prototype has been implemented to verify the design and the linear operation of the circuit is demonstrated by experimental results. A microcontroller unit (MCU) is used to provide an automatic scaling function to optimize the performance of the proposed current sensor. PMID- 23793023 TI - Energy harvesting from the tail beating of a carangiform swimmer using ionic polymer-metal composites. AB - In this paper, we study energy harvesting from the beating of a biomimetic fish tail using ionic polymer-metal composites. The design of the biomimetic tail is based on carangiform swimmers and is specifically inspired by the morphology of the heterocercal tail of thresher sharks. The tail is constituted of a soft silicone matrix molded in the form of the heterocercal tail and reinforced by a steel beam of rectangular cross section. We propose a modeling framework for the underwater vibration of the biomimetic tail, wherein the tail is assimilated to a cantilever beam with rectangular cross section and heterogeneous physical properties. We focus on base excitation in the form of a superimposed rotation about a fixed axis and we consider the regime of moderately large-amplitude vibrations. In this context, the effect of the encompassing fluid is described through a hydrodynamic function, which accounts for inertial, viscous and convective phenomena. The model is validated through experiments in which the base excitation is systematically varied and the motion of selected points on the biomimetic tail tracked in time. The feasibility of harvesting energy from an ionic polymer-metal composite attached to the vibrating structure is experimentally and theoretically assessed. The response of the transducer is described using a black-box model, where the voltage output is controlled by the rate of change of the mean curvature. Experiments are performed to elucidate the impact of the shunting resistance, the frequency of the base excitation and the placement of the ionic polymer-metal composite on energy harvesting from the considered biomimetic tail. PMID- 23793024 TI - Large-scale fabrication of nanodimple arrays for surface-enhanced Raman scattering. AB - Here we report a simple bottom-up technology for scalably fabricating gold nanodimple arrays with tunable nanostructures for surface-enhanced Raman scattering (SERS). Double-layer silica colloidal crystal-polymer nanocomposites with an unusual non-close-packed structure created using a spin-coating technique are utilized as structural templates. A variety of nanodimple structures, including simple monolayer voids, nanoring-like nanodimples, and binary-void nanodimples, can be reproducibly templated over wafer-sized areas by simply controlling the conditions during an oxygen plasma etching process. Normal incidence specular reflection measurements show that the resulting gold nanodimple arrays exhibit tunable surface plasmon properties. The efficient electromagnetic coupling between neighboring nanodimples and inner-outer walls of nanoring-like nanodimples leads to high SERS enhancement factors (>10(8)). Numerical simulations based on a finite-difference time-domain model complement the experimental measurements, showing the spatial distribution of electromagnetic "hot spots" surrounding the periodic gold nanodimple arrays. PMID- 23793026 TI - Exome sequencing identifies recurrent somatic mutations in EIF1AX and SF3B1 in uveal melanoma with disomy 3. AB - Gene expression profiles and chromosome 3 copy number divide uveal melanomas into two distinct classes correlating with prognosis. Using exome sequencing, we identified recurrent somatic mutations in EIF1AX and SF3B1, specifically occurring in uveal melanomas with disomy 3, which rarely metastasize. Targeted resequencing showed that 24 of 31 tumors with disomy 3 (77%) had mutations in either EIF1AX (15; 48%) or SF3B1 (9; 29%). Mutations were infrequent (2/35; 5.7%) in uveal melanomas with monosomy 3, which are associated with poor prognosis. Resequencing of 13 uveal melanomas with partial monosomy 3 identified 8 tumors with a mutation in either SF3B1 (7; 54%) or EIF1AX (1; 8%). All EIF1AX mutations caused in-frame changes affecting the N terminus of the protein, whereas 17 of 19 SF3B1 mutations encoded an alteration of Arg625. Resequencing of ten uveal melanomas with disomy 3 that developed metastases identified SF3B1 mutations in three tumors, none of which targeted Arg625. PMID- 23793027 TI - A haplotype map of genomic variations and genome-wide association studies of agronomic traits in foxtail millet (Setaria italica). AB - Foxtail millet (Setaria italica) is an important grain crop that is grown in arid regions. Here we sequenced 916 diverse foxtail millet varieties, identified 2.58 million SNPs and used 0.8 million common SNPs to construct a haplotype map of the foxtail millet genome. We classified the foxtail millet varieties into two divergent groups that are strongly correlated with early and late flowering times. We phenotyped the 916 varieties under five different environments and identified 512 loci associated with 47 agronomic traits by genome-wide association studies. We performed a de novo assembly of deeply sequenced genomes of a Setaria viridis accession (the wild progenitor of S. italica) and an S. italica variety and identified complex interspecies and intraspecies variants. We also identified 36 selective sweeps that seem to have occurred during modern breeding. This study provides fundamental resources for genetics research and genetic improvement in foxtail millet. PMID- 23793028 TI - DNase I-hypersensitive exons colocalize with promoters and distal regulatory elements. AB - The precise splicing of genes confers an enormous transcriptional complexity to the human genome. The majority of gene splicing occurs cotranscriptionally, permitting epigenetic modifications to affect splicing outcomes. Here we show that select exonic regions are demarcated within the three-dimensional structure of the human genome. We identify a subset of exons that exhibit DNase I hypersensitivity and are accompanied by 'phantom' signals in chromatin immunoprecipitation and sequencing (ChIP-seq) that result from cross-linking with proximal promoter- or enhancer-bound factors. The capture of structural features by ChIP-seq is confirmed by chromatin interaction analysis that resolves local intragenic loops that fold exons close to cognate promoters while excluding intervening intronic sequences. These interactions of exons with promoters and enhancers are enriched for alternative splicing events, an effect reflected in cell type-specific periexonic DNase I hypersensitivity patterns. Collectively, our results connect local genome topography, chromatin structure and cis regulatory landscapes with the generation of human transcriptional complexity by cotranscriptional splicing. PMID- 23793025 TI - Genome-wide meta-analysis identifies new susceptibility loci for migraine. AB - Migraine is the most common brain disorder, affecting approximately 14% of the adult population, but its molecular mechanisms are poorly understood. We report the results of a meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine (cases) and 95,425 population-matched controls. We identified 12 loci associated with migraine susceptibility (P<5*10(-8)). Five loci are new: near AJAP1 at 1p36, near TSPAN2 at 1p13, within FHL5 at 6q16, within C7orf10 at 7p14 and near MMP16 at 8q21. Three of these loci were identified in disease subgroup analyses. Brain tissue expression quantitative trait locus analysis suggests potential functional candidate genes at four loci: APOA1BP, TBC1D7, FUT9, STAT6 and ATP5B. PMID- 23793029 TI - ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3. AB - Nephronophthisis is an autosomal recessive cystic kidney disease that leads to renal failure in childhood or adolescence. Most NPHP gene products form molecular networks. Here we identify ANKS6 as a new NPHP family member that connects NEK8 (NPHP9) to INVS (NPHP2) and NPHP3. We show that ANKS6 localizes to the proximal cilium and confirm its role in renal development through knockdown experiments in zebrafish and Xenopus laevis. We also identify six families with ANKS6 mutations affected by nephronophthisis, including severe cardiovascular abnormalities, liver fibrosis and situs inversus. The oxygen sensor HIF1AN hydroxylates ANKS6 and INVS and alters the composition of the ANKS6-INVS-NPHP3 module. Knockdown of Hif1an in Xenopus results in a phenotype that resembles loss of other NPHP proteins. Network analyses uncovered additional putative NPHP proteins and placed ANKS6 at the center of this NPHP module, explaining the overlapping disease manifestation caused by mutation in ANKS6, NEK8, INVS or NPHP3. PMID- 23793031 TI - Parametric spectro-temporal analyzer (PASTA) for real-time optical spectrum observation. AB - Real-time optical spectrum analysis is an essential tool in observing ultrafast phenomena, such as the dynamic monitoring of spectrum evolution. However, conventional method such as optical spectrum analyzers disperse the spectrum in space and allocate it in time sequence by mechanical rotation of a grating, so are incapable of operating at high speed. A more recent method all-optically stretches the spectrum in time domain, but is limited by the allowable input condition. In view of these constraints, here we present a real-time spectrum analyzer called parametric spectro-temporal analyzer (PASTA), which is based on the time-lens focusing mechanism. It achieves a frame rate as high as 100 MHz and accommodates various input conditions. As a proof of concept and also for the first time, we verify its applications in observing the dynamic spectrum of a Fourier domain mode-locked laser, and the spectrum evolution of a laser cavity during its stabilizing process. PMID- 23793030 TI - Massive genomic variation and strong selection in Arabidopsis thaliana lines from Sweden. AB - Despite advances in sequencing, the goal of obtaining a comprehensive view of genetic variation in populations is still far from reached. We sequenced 180 lines of A. thaliana from Sweden to obtain as complete a picture as possible of variation in a single region. Whereas simple polymorphisms in the unique portion of the genome are readily identified, other polymorphisms are not. The massive variation in genome size identified by flow cytometry seems largely to be due to 45S rDNA copy number variation, with lines from northern Sweden having particularly large numbers of copies. Strong selection is evident in the form of long-range linkage disequilibrium (LD), as well as in LD between nearby compensatory mutations. Many footprints of selective sweeps were found in lines from northern Sweden, and a massive global sweep was shown to have involved a 700 kb transposition. PMID- 23793032 TI - Cardiovascular health effects of internet-based encouragements to do daily workplace stair-walks: randomized controlled trial. AB - BACKGROUND: Although the hazardous health effects of a sedentary lifestyle are well known, many adults struggle with regular physical activity. Simple and efficient encouragements for increased physical activity are needed. OBJECTIVE: To determine the effect on cardiovascular health of email-based encouragements to do daily stair-walks at work together with colleagues among adults in sedentary occupations. METHODS: A single-blind randomized controlled trial was performed at a large administrative company in Copenhagen, Denmark. Participants were 160 office workers (125 women, 35 men; mean age 42 years, SD 10; sitting 89.5% of work time). At baseline, aerobic fitness was 37 mL/min/kg (SD 9), mean blood pressure was 118/79 mmHg (SD 14/9), and mean body mass index (BMI) was 23 kg/m(2) (SD 4). Participants were randomly assigned (2:1 ratio) to an email group receiving weekly email-based encouragements to walk the stairs for 10 minutes a day or to a control group receiving weekly reminders to continue their usual physical activities. The primary outcome was the change from baseline to 10-week follow-up in aerobic fitness determined from a maximal cycle test. The examiner was blinded to group allocation. RESULTS: Adherence to the email encouragements was fairly high with 82.7% of the participants performing at least 3 sessions of 10-minute stair-walks per week (mean 3.3, SD 1.3). Mean heart rate reached 167 beats/min (SD 10) during stair-walks. In the intention-to-treat analysis, aerobic fitness increased 1.45 mL/min/kg (95% CI 0.64-2.27) at 10-week follow-up in the email group compared with the control group. In participants with low aerobic fitness at baseline (n=56), aerobic fitness increased 1.89 mL/min/kg (95% CI 0.53 3.24), and systolic and diastolic blood pressure decreased 4.81 mmHg (95% CI 0.47 9.16) and 2.67 mmHg (95% CI 0.01-5.32), respectively, in the email group compared with the control group. Body weight decreased in the email group of those with low aerobic fitness compared with the control group, but this was not statistically significant. CONCLUSIONS: Simple and inexpensive email-based encouragements to do daily stair-walks together with colleagues at work improves cardiovascular health among adults in sedentary occupations. There exists an enormous potential to prevent the hazardous health effects of a sedentary lifestyle through the use of email-based encouragements to do short bouts of physical activity at the workplace. TRIAL REGISTRATION: Clinicaltrials.gov NCT01293253; http://clinicaltrials.gov/ct2/show/NCT01293253 (Archived by WebCite at http://www.webcitation.org/6HWG2jw68). PMID- 23793034 TI - Remarkable CO2/CH4 selectivity and CO2 adsorption capacity exhibited by polyamine decorated metal-organic framework adsorbents. AB - Solid porous dual amine-decorated metal-organic framework (MOF) adsorbents with tunable porosity have been prepared. The adsorbents exhibit remarkable CO2/CH4 selectivity and CO2 adsorption capacity at low pressures. PMID- 23793035 TI - Obesity, diabetes, and survival outcomes in a large cohort of early-stage breast cancer patients. AB - BACKGROUND: To determine the relationship between obesity, diabetes, and survival in a large cohort of breast cancer patients receiving modern chemotherapy and endocrine therapy. PATIENTS AND METHODS: We identified 6342 patients with stage I III breast cancer treated between 1996 and 2005. Patients were evaluated according to body mass index (BMI) category and diabetes status. RESULTS: In a multivariate model adjusted for body mass index, diabetes, medical comorbidities, patient- and tumor-related variables, and adjuvant therapies, relative to the normal weight, hazard ratios (HRs) for recurrence-free survival (RFS), overall survival (OS), and breast cancer-specific survival (BCSS) for the overweight were 1.18 [95% confidence interval (CI) 1.02-1.36], 1.20 (95% CI 1.00-1.42), and 1.21 (95% CI 0.98-1.48), respectively. HRs for RFS, OS, and BCSS for the obese were 1.13 (95% CI 0.98-1.31), 1.24 (95% CI 1.04-1.48), and 1.23 (95% CI 1.00-1.52), respectively. Subset analyses showed these differences were significant for the ER-positive, but not ER-negative or HER2-positive, groups. Relative to nondiabetics, HRs for diabetics for RFS, OS, and BCSS were 1.21 (95% CI 0.98 1.49), 1.39 (95% CI 1.10-1.77), and 1.04 (95% CI 0.75-1.45), respectively. CONCLUSIONS: In patients receiving modern adjuvant therapies, obesity has a negative impact on RFS, OS, and BCSS; and diabetes has a negative impact on RFS and OS. Control of both may be important to improving survival in obese and diabetic breast cancer patients. PMID- 23793036 TI - Nutrients and non-nutrients composition and bioactivity of wild and cultivated Coprinus comatus (O.F.Mull.) Pers. AB - Mushrooms have been reported as sources of biomolecules with various potential. Coprinus comatus was studied to obtain information about this species, comparing cultivated and wild samples. Free sugars, fatty acids, tocopherols, organic acids and phenolic acids were analyzed by chromatographic techniques coupled to different detectors. C. comatus methanolic extract was tested for its antioxidant potential (reducing power, radical scavenging activity and lipid peroxidation inhibition) and antimicrobial properties (tested towards Gram positive and negative bacteria, and microfungi). The toxicity for liver cells was tested in porcine liver primary cells. Both studied samples revealed similar nutritional value and energy contribution. The cultivated sample revealed the highest content in free sugars, monounsaturated fatty acids and tocopherols, while the wild mushroom was richer in saturated and polyunsaturated fatty acids, organic acids and phenolic compounds. The cultivated species also revealed the highest antioxidant potential and antimicrobial activity (with exception towards Gram negative bacteria and Aspergillus ochraceus). Both species revealed no toxicity towards porcine liver cells. The present study proved that cultivated and wild mushrooms from the same species could be excellent options as food and as sources of nutritional and bioactive compounds. Furthermore, differences in wild and cultivated samples were comparatively investigated for the first time. PMID- 23793037 TI - Assessment of the in vitro and in vivo genotoxicity of extracts and indole monoterpene alkaloid from the roots of Galianthe thalictroides (Rubiaceae). AB - Roots of Galianthe thalictroides K. Schum. (Rubiaceae) are used in folk medicine in the State of Mato Grosso do Sul, Brazil, for treating and preventing cancer. To gain information about the genotoxicity of extracts (aqueous and EtOH), the CHCl3 phase resulting from partition of the EtOH extract and the indole monoterpene alkaloid 1 obtained from this plant. The genotoxicity of 1 and extracts was evaluated in vivo through the Drosophila melanogaster wing Somatic Mutation and Recombination Test - SMART, while in vitro cytotoxic (MTT) and Comet assays were performed only with alkaloid 1. The results obtained with the SMART test indicated that the aqueous extract had no genotoxic activity. The EtOH extract was not genotoxic to ST descendants but genotoxic to HB ones. The CHCl3 phase was genotoxic and cytotoxic. Alkaloid 1 showed significant mutational events with SMART, in the cytotoxicity assay (MTT), it showed a high cytotoxicity for human hepatoma cells (HepG2), whereas for the Comet assay, not showing genotoxic activity. The ethanol extract was shown to be genotoxic to HB descendants in the SMART assay, while the results obtained in this test for the monoterpene indole alkaloid 1 isolated from this extract. PMID- 23793038 TI - Activation of the PI3K-AKT-mTOR signaling pathway promotes DEHP-induced Hep3B cell proliferation. AB - Hep3B cells were treated with DEHP at various concentrations (62.5, 125.0, 250.0, 500.0 and 1000.0 MUM). After 24 h exposure to DEHP only, increased Hep3B cell viability was observed (p<0.05 or p<0.01). However, after 24 h co-exposure to DEHP at indicated concentrations plus 50.0 MUM LY294002 (PI3K inhibitor), cell viability was significantly decreased compared to the corresponding DEHP treated groups. DEHP increased mitochondrial membrane potential level and induced oxidative DNA damage in Hep3B cells, DEHP also increased DNA replication rate and accelerated the cell cycle. The PI3K inhibitor LY294002 could recover the mitochondrial membrane potential and attenuate the oxidative stress in Hep3B cells; however, it could not protect the cells from oxidation of DNA damage. The findings showed that LY294002 attenuated DEHP-induced up-regulation of the selected genes (pi3k, akt, mtor and p70s6k) involved in PI3K-AKT-mTOR signaling pathway at both mRNA and protein levels thus inhibited the cell abnormal proliferation. PMID- 23793039 TI - Nuclear erythroid 2-related factor 2: a novel potential therapeutic target for liver fibrosis. AB - Hepatic stellate cells (HSC) are the key fibrogenic cells of the liver. HSC activation is a process of cellular transdifferentiation that occurs upon liver injury, but the mechanisms underlying liver fibrosis are unknown. Nuclear erythroid 2-related factor 2 (Nrf2) is an oxidative stress-mediated transcription factor with a variety of downstream targets aimed at cytoprotection. However, Nrf2 has recently been implicated as a new therapeutic target for the treatment of liver fibrosis. This review focuses on the transcriptional repressors that either control liver injury or regulate specific fibrogenic functions of liver fibrosis. We also show that Nrf2 may reveal significant gene expression changes, suggesting that Nrf2 activation may ameliorate liver fibrosis. PMID- 23793040 TI - Role of alpha-lipoic acid in dextran sulfate sodium-induced ulcerative colitis in mice: studies on inflammation, oxidative stress, DNA damage and fibrosis. AB - Ulcerative colitis affects many people worldwide. Inflammation and oxidative stress play a vital role in its pathogenesis. Previously, we reported that ulcerative colitis leads to systemic genotoxicity in mice. The present study was aimed at elucidating the role of alpha-lipoic acid in ulcerative colitis associated local and systemic damage in mice. Experimental colitis was induced using 3%w/v dextran sulfate sodium in drinking water for 2 cycles. alpha-Lipoic acid was administered in a co-treatment (20, 40, 80 mg/kg bw) and post-treatment (80 mg/kg bw) schedule. Various biochemical parameters, histological evaluation, comet and micronucleus assays, immunohistochemistry and western blot analysis were employed to evaluate the effect of alpha-lipoic acid in mice with ulcerative colitis. The protective effect of alpha-lipoic acid was mediated through the modulation of nuclear factor kappa B, cyclooxygenase-2, interleukin 17, signal transducer and activator of transcription 3, nuclear erythroid 2-related factor 2, NADPH: quinone oxidoreductase-1, matrix metalloproteinase-9 and connective tissue growth factor. Further, ulcerative colitis led to an increased gut permeability, plasma lipopolysaccharide level, systemic inflammation and genotoxicity in mice, which was reduced with alpha-lipoic acid treatment. The present study identifies the underlying mechanisms involved in alpha-lipoic acid mediated protection against ulcerative colitis and the associated systemic damage in mice. PMID- 23793041 TI - Using expired air carbon monoxide to determine smoking status during pregnancy: preliminary identification of an appropriately sensitive and specific cut-point. AB - BACKGROUND: Measurement of carbon monoxide in expired air samples (ECO) is a non invasive, cost-effective biochemical marker for smoking. Cut points of 6ppm-10ppm have been established, though appropriate cut-points for pregnant woman have been debated due to metabolic changes. This study assessed whether an ECO cut-point identifying at least 90% of pregnant smokers, and misidentifying fewer than 10% of non-smokers, could be established. METHODS: Pregnant women (N=167) completed a validated self-report smoking assessment, a urine drug screen for cotinine (UDS), and provided an expired air sample twice during pregnancy. RESULTS: Half of women reported non-smoking status early (51%) and late (53%) in pregnancy, confirmed by UDS. Using a traditional 8ppm+cut-point for the early pregnancy reading, only 1% of non-smokers were incorrectly identified as smokers, but only 56% of all smokers, and 67% who smoked 5+ cigarettes in the previous 24h, were identified. However, at 4ppm+, only 8% of non-smokers were misclassified as smokers, and 90% of all smokers and 96% who smoked 5+ cigarettes in the previous 24h were identified. False positives were explained by heavy second hand smoke exposure and marijuana use. Results were similar for late pregnancy ECO, with ROC analysis revealing an area under the curve of .95 for early pregnancy, and .94 for late pregnancy readings. CONCLUSIONS: A lower 4ppm ECO cut-point may be necessary to identify pregnant smokers using expired air samples, and this cut-point appears valid throughout pregnancy. Work is ongoing to validate findings in larger samples, but it appears if an appropriate cut-point is used, ECO is a valid method for determining smoking status in pregnancy. PMID- 23793042 TI - Smoking a virtual cigarette increases craving among smokers. AB - Previous studies have shown the efficacy of virtual reality (VR) environments that reproduce smoking-related stimuli for increasing self-reported craving and psychophysiological reactivity in smokers. However, no study to date has attempted to simulate smoking behavior itself by means of VR technology. The aim of this study was to assess the effect of smoking a virtual cigarette on self reported craving levels and heart rate (HR) in a sample of smokers. Participants were 45 smokers randomly assigned to three VR conditions built into a virtual pub: smoking a virtual cigarette, throwing virtual darts at a virtual dartboard or just being in the virtual pub. Results showed that smoking a virtual cigarette significantly increased self-reported craving and HR when compared to the other two conditions. These results reveal that simulation of smoking behavior in a VR environment functions as an efficacious proximal cue that can be used for triggering craving under the cue-exposure paradigm. PMID- 23793044 TI - Rate-gyro-integral constraint for ambiguity resolution in GNSS attitude determination applications. AB - In the field of Global Navigation Satellite System (GNSS) attitude determination, the constraints usually play a critical role in resolving the unknown ambiguities quickly and correctly. Many constraints such as the baseline length, the geometry of multi-baselines and the horizontal attitude angles have been used extensively to improve the performance of ambiguity resolution. In the GNSS/Inertial Navigation System (INS) integrated attitude determination systems using low grade Inertial Measurement Unit (IMU), the initial heading parameters of the vehicle are usually worked out by the GNSS subsystem instead of by the IMU sensors independently. However, when a rotation occurs, the angle at which vehicle has turned within a short time span can be measured accurately by the IMU. This measurement will be treated as a constraint, namely the rate-gyro-integral constraint, which can aid the GNSS ambiguity resolution. We will use this constraint to filter the candidates in the ambiguity search stage. The ambiguity search space shrinks significantly with this constraint imposed during the rotation, thus it is helpful to speeding up the initialization of attitude parameters under dynamic circumstances. This paper will only study the applications of this new constraint to land vehicles. The impacts of measurement errors on the effect of this new constraint will be assessed for different grades of IMU and current average precision level of GNSS receivers. Simulations and experiments in urban areas have demonstrated the validity and efficacy of the new constraint in aiding GNSS attitude determinations. PMID- 23793043 TI - A novel high-resolution in vivo imaging technique to study the dynamic response of intracranial structures to tumor growth and therapeutics. AB - We have successfully integrated previously established Intracranial window (ICW) technology (1-4) with intravital 2-photon confocal microscopy to develop a novel platform that allows for direct long-term visualization of tissue structure changes intracranially. Imaging at a single cell resolution in a real-time fashion provides supplementary dynamic information beyond that provided by standard end-point histological analysis, which looks solely at 'snap-shot' cross sections of tissue. Establishing this intravital imaging technique in fluorescent chimeric mice, we are able to image four fluorescent channels simultaneously. By incorporating fluorescently labeled cells, such as GFP+ bone marrow, it is possible to track the fate of these cells studying their long-term migration, integration and differentiation within tissue. Further integration of a secondary reporter cell, such as an mCherry glioma tumor line, allows for characterization of cell:cell interactions. Structural changes in the tissue microenvironment can be highlighted through the addition of intra-vital dyes and antibodies, for example CD31 tagged antibodies and Dextran molecules. Moreover, we describe the combination of our ICW imaging model with a small animal micro-irradiator that provides stereotactic irradiation, creating a platform through which the dynamic tissue changes that occur following the administration of ionizing irradiation can be assessed. Current limitations of our model include penetrance of the microscope, which is limited to a depth of up to 900 MUm from the sub cortical surface, limiting imaging to the dorsal axis of the brain. The presence of the skull bone makes the ICW a more challenging technical procedure, compared to the more established and utilized chamber models currently used to study mammary tissue and fat pads (5-7). In addition, the ICW provides many challenges when optimizing the imaging. PMID- 23793045 TI - Fifteen-minute consultation on the infant with a large head. AB - An infant with a large head (2.5 SDs above normal for weight and gender or above 99.6th centile for age) is a common clinical presentation. Usually, it is due to benign isolated macrocephaly or familial macrocephaly (FM) where some close family members are similarly affected(1); neither condition requires any further intervention. However, there are a few important underlying causes the clinician needs to actively consider and investigate when indicated before reassuring parents. These considerations include whether there is any associated developmental disorder or suggestion of a syndromic association or evidence of raised intracranial pressure (ICP). PMID- 23793046 TI - Detection of volatile biomarkers of therapeutic radiation in breath. AB - Breath testing could provide a rational tool for radiation biodosimetry because radiation causes distinct stress-producing molecular damage, notably an increased production of reactive oxygen species. The resulting oxidative stress accelerates lipid peroxidation of polyunsaturated fatty acids, liberating alkanes and alkane metabolites that are excreted in the breath as volatile organic compounds (VOCs). Breath tests were performed before and after radiation therapy over five days in 31 subjects receiving daily fractionated doses: 180-400 cGy d(-1) standard radiotherapy (n = 26), or 700-1200 cGy d(-1) high-dose stereotactic body radiotherapy (n = 5). Breath VOCs were assayed using comprehensive two dimensional gas chromatography time-of-flight mass spectrometry. Multiple Monte Carlo simulations identified approximately 50 VOCs as greater-than-chance biomarkers of radiation on all five days of the study. A consistent subset of 15 VOCs was observed at all time points. A radiation response function was built by combining these biomarkers and the resulting dose-effect curve was significantly elevated at all exposures ?1.8 Gy. Cross-validated binary algorithms identified radiation exposures ?1.8 Gy with 99% accuracy, and ?5 Gy with 78% accuracy. In this proof of principal study of breath VOCs, we built a preliminary radiation response function based on 15 VOCs that appears to identify exposure to localized doses of 1.8 Gy and higher. VOC breath testing could provide a new tool for rapid and non-invasive radiation biodosimetry. PMID- 23793048 TI - Lessons from the Electronic Data Methods Forum: collaboration at the frontier of comparative effectiveness research, patient-centered outcomes research, and quality improvement. AB - BACKGROUND: The Electronic Data Methods (EDM) Forum, with support from the Agency for Healthcare Research and Quality, exists to advance knowledge and practice on the use of electronic clinical data (ECD) for comparative effectiveness research, patient-centered outcomes research, and quality improvement (QI). The EDM Forum facilitates collaboration between the Prospective Outcome Systems using Patient specific Electronic data to Compare Tests and therapies, Scalable Distributed Research Network, and Enhanced registry projects funded by Agency for Healthcare Research and Quality. OBJECTIVES: This overview describes a second set of papers commissioned by the EDM Forum, published in this supplement to Medical Care. The papers that are included discuss challenges and innovations from the research and QI community using ECD. CONCLUSIONS: The papers in this supplement provide lessons learned based on experiences building transparent, scalable, reusable networks for research and QI. Through these papers, and a new open access e journal, eGEMs, the EDM Forum is working to advance the science of health research and QI using ECD to improve patient outcomes. PMID- 23793049 TI - Data quality assessment for comparative effectiveness research in distributed data networks. AB - BACKGROUND: Electronic health information routinely collected during health care delivery and reimbursement can help address the need for evidence about the real world effectiveness, safety, and quality of medical care. Often, distributed networks that combine information from multiple sources are needed to generate this real-world evidence. OBJECTIVE: We provide a set of field-tested best practices and a set of recommendations for data quality checking for comparative effectiveness research (CER) in distributed data networks. METHODS: Explore the requirements for data quality checking and describe data quality approaches undertaken by several existing multi-site networks. RESULTS: There are no established standards regarding how to evaluate the quality of electronic health data for CER within distributed networks. Data checks of increasing complexity are often used, ranging from consistency with syntactic rules to evaluation of semantics and consistency within and across sites. Temporal trends within and across sites are widely used, as are checks of each data refresh or update. Rates of specific events and exposures by age group, sex, and month are also common. DISCUSSION: Secondary use of electronic health data for CER holds promise but is complex, especially in distributed data networks that incorporate periodic data refreshes. The viability of a learning health system is dependent on a robust understanding of the quality, validity, and optimal secondary uses of routinely collected electronic health data within distributed health data networks. Robust data quality checking can strengthen confidence in findings based on distributed data network. PMID- 23793051 TI - Ethics and informed consent for comparative effectiveness research with prospective electronic clinical data. AB - BACKGROUND: Electronic clinical data (ECD) will increasingly serve as an important source of information for comparative effectiveness research (CER). Although many retrospective studies have relied on ECD, new study designs propose using ECD for prospective CER. These designs have great potential but they also raise important ethics questions. AIMS: Drawing on an ethics framework for learning health care systems, we identify morally relevant features of prospective CER-ECD studies by examining 1 case of an observational study and a second of a pragmatic, randomized trial. We focus only on questions of consent and assume research has been subject to appropriate ethics review and oversight. RESULTS AND CONCLUSIONS: We conclude that a CER-ECD observational study that imposes no or minimal additional risk to or burden on patients may proceed ethically without express informed consent from participants in settings where: (a) patients are regularly informed of the health care institution's commitment to learning through the integration of research and practice; and (b) there are appropriate protections for patients' rights and interests. In addition, where (a) and (b) apply, some pragmatic, randomized trials that similarly impose no or minimal additional risk to or burden on patients may also proceed ethically without express consent, when certain additional conditions are satisfied, including: (c) the trial does not negatively affect patients' prospects for good clinical outcomes; (d) physicians have the option of using an intervention other than the one assigned if they believe doing so is important for a particular patient; and (e) the trial does not engage preferences or values that are meaningful to patients. PMID- 23793050 TI - Knowledge management and informatics considerations for comparative effectiveness research: a case-driven exploration. AB - BACKGROUND: As clinical data are increasingly collected and stored electronically, their potential use for comparative effectiveness research (CER) grows. Despite this promise, challenges face those wishing to leverage such data. In this paper we aim to enumerate some of the knowledge management and informatics issues common to such data reuse. DESIGN: After reviewing the current state of knowledge regarding biomedical informatics challenges and best practices related to CER, we then present 2 research projects at our institution. We analyze these and highlight several common themes and challenges related to the conduct of CER studies. Finally, we represent these emergent themes. RESULTS: The informatics challenges commonly encountered by those conducting CER studies include issues related to data information and knowledge management (eg, data reuse, data preparation) as well as those related to people and organizational issues (eg, sociotechnical factors and organizational factors). Examples of these are described in further detail and a formal framework for describing these findings is presented. CONCLUSIONS: Significant challenges face researchers attempting to use often diverse and heterogeneous datasets for CER. These challenges must be understood in order to be dealt with successfully and can often be overcome with the appropriate use of informatics best practices. Many research and policy questions remain to be answered in order to realize the full potential of the increasingly electronic clinical data available for such research. PMID- 23793052 TI - Evidence generating medicine: redefining the research-practice relationship to complete the evidence cycle. AB - Accelerating clinical and translational science and improving healthcare effectiveness, quality, and efficiency are top priorities for the United States. Increasingly, the success of such initiatives relies on leveraging point-of-care activities, data, and resources to generate evidence through routine practice. At present, leveraging healthcare activities to advance knowledge is challenging. Underlying these challenges are a variety of persistent technological, regulatory, fiscal, and socio-organizational realities. Fundamentally, these result from the fact that the current healthcare system is designed around a paradigm that enables individual patient care and views the connection between research and practice as unidirectional (ie, research findings are applied to practice using evidence-based medicine) but does not support research-related activities during practice. We suggest that a fundamental paradigm shift is needed to redefine the relationship between research and practice as bidirectional rather than unidirectional and propose the concept of evidence generating medicine to provide a framework for realizing such a shift. We discuss how a transition toward evidence generating medicine would result in a range of much-needed system-level changes that would facilitate rather than frustrate the ongoing efforts of informaticians, health services researchers, and others working to accelerate research and improve healthcare. PMID- 23793053 TI - Synthesis, structures and magnetic properties of Fe(II) and Co(II) thiocyanato coordination compounds: on the importance of the diamagnetic counterparts for structure determination. AB - Reaction of Fe(NCS)2 and Co(NCS)2 with 2-methylpyrazine in different molar ratios and solvents at room temperature leads to the formation of five new coordination compounds of composition M(NCS)2(2-methylpyrazine)2(H2O)2 (M = Fe (1-Fe) , Co (1 Co)), Co(NCS)2(2-methylpyrazine)2(CH3OH)2 (2-Co) and Co(NCS)2(2 methylpyrazine)4.2-methylpyrazine solvate (3-Co). In all of these compounds, discrete complexes are found in which the metal cations are octahedrally coordinated by two terminal N-bonded thiocyanato anions and four N- or O-donor co ligands. On heating compounds 1-3 in a thermobalance new coordination polymers of composition M(NCS)2(2-methylpyrazine)2 (M = Co (4-Co) , Fe (4-Fe)) are obtained in the first step, which transform into M(NCS)2(2-methylpyrazine) (M = Co (5-Co) , Fe (5-Fe)) in the second. Because of the low chalcophilicity of these cations, compounds 4 and 5 are not accessible from solution. Further investigations prove that 4-Co and 4-Fe obtained by thermal decomposition are of low crystallinity, might be isotypic and might consist of metal cations, in which the anionic ligands are only terminal N-bonded. In contrast, 5-Co and 5-Fe are of good crystallinity but their structure cannot be solved from X-ray powder data. However, a compound of the same composition (5-Cd) based on the more chalcophilic cadmium can easily be crystallized from solution and characterized by single crystal X-ray diffraction. This compound is isotypic to 5-Co and 5-Fe and therefore their structures were determined by Rietveld refinements. In their crystal structures the metal atoms are linked by MU-1,3-bridging thiocyanato anions into a 2D network. Magnetic measurements reveal that compounds 1-4 show only Curie-Weiss paramagnetism and that for 5-Fe antiferromagnetic ordering is observed. In contrast, 5-Co shows metamagnetic behavior with a very large critical field. Finally, it was shown that 4-Co and 4-Fe are hygroscopic and transform within minutes into the hydrates 1-Co and 1-Fe. PMID- 23793054 TI - A conserved hydrolase responsible for the cleavage of aminoacylphosphatidylglycerol in the membrane of Enterococcus faecium. AB - Aminoacylphosphatidylglycerol synthases (aaPGSs) are enzymes that transfer amino acids from aminoacyl-tRNAs (aa-tRNAs) to phosphatidylglycerol (PG) to form aa-PG in the cytoplasmic membrane of bacteria. aa-PGs provide bacteria with resistance to a range of antimicrobial compounds and stress conditions. Enterococcus faecium encodes a triple-specific aaPGS (RakPGS) that utilizes arginine, alanine, and lysine as substrates. Here we identify a novel hydrolase (AhyD), encoded immediately adjacent to rakPGS in E. faecium, which is responsible for the hydrolysis of aa-PG. The genetic synteny of aaPGS and ahyD is conserved in >60 different bacterial species. Deletion of ahyD in E. faecium resulted in increased formation of Ala-PG and Lys-PG and increased sensitivity to bacitracin. Our results suggest that AhyD and RakPGS act together to maintain optimal levels of aa-PG in the bacterial membrane to confer resistance to certain antimicrobial compounds and stress conditions. PMID- 23793055 TI - Oligomerization of DHHC protein S-acyltransferases. AB - The formation of dimers or higher-order oligomers is a property of numerous integral membrane proteins, including ion channels, transporters, and receptors. In this study, we examined whether members of the DHHC-S-acyltransferase family oligomerize in intact cells and in vitro. DHHC-S-acyltransferases are integral membrane proteins that catalyze the addition of palmitate to cysteine residues on proteins at the cytoplasmic face of cell membranes. Bioluminescence resonance energy transfer (BRET) experiments revealed that DHHC2 or DHHC3 (Golgi-specific DHHC zinc finger protein (GODZ)) self-associate when expressed in HEK-293 cells. Homomultimer formation was confirmed by coimmunoprecipitation. Purified DHHC3 resolved predominately as a monomer and dimer on blue native polyacrylamide gels. In intact cells and in vitro, catalytically inactive DHHC proteins displayed a greater propensity to form dimers. BRET signals were higher for the catalytically inactive DHHC2 or DHHC3 than their wild-type counterparts. DHHC3 BRET in cell membranes was decreased by the addition of its lipid substrate palmitoyl-CoA, a treatment that results in autoacylation of the enzyme. Enzyme activity of a covalently linked DHHC3 dimer was less than that of the monomeric form, suggesting that enzyme activity may be modulated by the oligomerization status of the protein. PMID- 23793056 TI - Broadband homodecoupled NMR spectroscopy with enhanced sensitivity. AB - A new type of broadband homodecoupling technique is described, which is based on the original version of the Zangger-Sterk experiment, but results in a spectrum with higher sensitivity. The homodecoupling is performed by a combination of selective and non-selective 180 degrees RF pulses in the presence of weak rectangular pulsed field gradients in a pseudo 2D experiment. The proposed experiment uses a fast pulsing approach to increase the signal-to-noise ratio per unit time. The recycle delay is significantly shortened typically to about 100 ms. After each scan, the offset of the selective shaped pulse is changed to access fresh magnetisation from adjacent frequency/spatial regions. The physical acquisition time was limited to 40 ms to keep the total length of the pulse sequence as short as possible. Broadband inversion BIP pulses are used instead of 180 degrees hard pulses. They are used pairwise to cancel out unwanted phase shifts over the bandwidth. Reconstruction of the homodecoupled spectrum was done by concatenating the first 10 ms of the FID from each single increment to obtain the final homodecoupled proton FID followed by Fourier transformation. The new method can either be used to acquire broadband homodecoupled spectra in a shorter time or to increase the signal-to-noise ratio compared to the original Zangger Sterk experiment. Using eight different frequencies can thus lead to a signal to noise gain of a factor ?8 or a factor of eight in time. PMID- 23793057 TI - WURST-QCPMG sequence and "spin-lock" in 14N nuclear quadrupole resonance. AB - 14N nuclear quadrupole resonance (NQR) is a promising method for the analysis of pharmaceuticals or for the detection of nitrogen based illicit compounds, but so far, the technique is still not widely used, mostly due to the very low sensitivity. This problem is already acute in the preliminary NQR stage, when a compound is being examined for the first time and the NQR frequencies are being searched for, by scanning a wide frequency range step-by-step. In the present work, we experimentally show how to increase the efficiency of this initial stage by using a combination of a wideband excitation achieved with frequency swept pulses (WURST) and a "spin-lock" state obtained with a quadrupolar-CPMG (QCPMG) sequence. In the first part we show that WURST pulses provide a much larger excitation bandwidth compared to common rectangular pulses. This increased bandwidth allows to increase the frequency step and reduces the total number of steps in a scanning stage. In the second part we show that the "spin-lock" decay time T2eff obtained with the WURST-QCPMG combination is practically identical with the T2eff obtained with the most common "spin-lock" sequence, the SLSE, despite a very different nature and length of excitation pulses. This allows for a substantial S/N increase through echo averaging in every individual step and really allows to exploit all the advantages of the wider excitation in the NQR frequency scanning stage. Our experimental results were obtained on a sample of trinitrotoluene, but identical behavior is expected for all compounds where a "spin-lock" state can be created. PMID- 23793058 TI - Joint crisis plans and psychiatric advance directives in German psychiatric practice. AB - This study explores the attitude of German psychiatrists in leading positions towards joint crisis plans and psychiatric advance directives. This topic was examined by contacting 473 medical directors of German psychiatric hospitals and departments. They were asked to complete a questionnaire developed by us. That form contained questions about the incidence and acceptance of joint crisis plans and psychiatric advance directives and previous experiences with them. 108 medical directors of psychiatric hospitals and departments responded (response rate: 22.8%). Their answers demonstrate that in their hospitals these documents are rarely used. Among the respondents, joint crisis plans are more accepted than psychiatric advance directives. There is a certain uncertainty when dealing with these instruments. Our main conclusion is that German psychiatry needs an intensified discussion on the use of instruments for patients to constitute procedures for future critical psychiatric events. For this purpose it will be helpful to collect more empirical data. Furthermore, the proposal of joint crisis plans in psychiatric hospitals and departments should be discussed as well as the possibility of consulting an expert during the preparation of a psychiatric advance directive. PMID- 23793059 TI - Neuroenhancing public health. AB - One of the most fascinating issues in the emerging field of neuroethics is pharmaceutical cognitive enhancement (CE). The three main ethical concerns around CE were identified in a Nature commentary in 2008 as safety, coercion and fairness; debate has largely focused on the potential to help those who are cognitively disabled, and on the issue of 'cosmetic neurology', where people enhance not because of a medical need, but because they want to (as many as 25% of US students already use nootropic cognitive enhancers such as ritalin). However, the potential for CE to improve public health has been neglected. This paper examines the prospect of improving health outcomes through CE among sections of the population where health inequalities are particularly pronounced. I term this enhancement of the public's health through CE 'neuroenhancing health'. It holds great promise, but raises several ethical issues. This paper provides an outline of these issues and related philosophical problems. These include the potential effectiveness of CE in reducing health inequalities; issues concerning autonomy and free will; whether moral enhancement might be more effective than CE in reducing health inequalities; and the problem of how to provide such CE, including the issue of whether to provide targeted or universal coverage. PMID- 23793060 TI - Dual effects of resveratrol on arterial damage induced by insulin resistance in aged mice. AB - Aging leads to increased insulin resistance and arterial dysfunction, with oxidative stress playing an important role. This study explored the metabolic and arterial effects of a chronic treatment with resveratrol, an antioxidant polyphenol compound that has been shown to restore insulin sensitivity and decrease oxidative stress, in old mice with or without a high-protein diet renutrition care. High-protein diet tended to increase insulin resistance and atheromatous risk. Resveratrol improved insulin sensitivity in old mice fed standard diet by decreasing homeostasis model of assessment-insulin resistance and resistin levels. However, resveratrol did not improve insulin resistance status in old mice receiving the high-protein diet. In contrast, resveratrol exhibited deleterious effects by increasing inflammation state and superoxide production and diminishing aortic distensibility. In conclusion, we demonstrate that resveratrol has beneficial or deleterious effects on insulin sensitivity and arterial function, depending on nutritional status in our models. PMID- 23793061 TI - Signaling via the IL-20 receptor inhibits cutaneous production of IL-1beta and IL 17A to promote infection with methicillin-resistant Staphylococcus aureus. AB - Staphylococcus aureus causes most infections of human skin and soft tissue and is a major infectious cause of mortality. Host defense mechanisms against S. aureus are incompletely understood. Interleukin 19 (IL-19), IL-20 and IL-24 signal through type I and type II IL-20 receptors and are associated with inflammatory skin diseases such as psoriasis and atopic dermatitis. We found here that those cytokines promoted cutaneous infection with S. aureus in mice by downregulating IL-1beta- and IL-17A-dependent pathways. We noted similar effects of those cytokines in human keratinocytes after exposure to S. aureus, and antibody blockade of the IL-20 receptor improved outcomes in infected mice. Our findings identify an immunosuppressive role for IL-19, IL-20 and IL-24 during infection that could be therapeutically targeted to alter susceptibility to infection. PMID- 23793062 TI - The lymphoid lineage-specific actin-uncapping protein Rltpr is essential for costimulation via CD28 and the development of regulatory T cells. AB - Although T cell activation can result from signaling via T cell antigen receptor (TCR) alone, physiological T cell responses require costimulation via the coreceptor CD28. Through the use of an N-ethyl-N-nitrosourea-mutagenesis screen, we identified a mutation in Rltpr. We found that Rltpr was a lymphoid cell specific, actin-uncapping protein essential for costimulation via CD28 and the development of regulatory T cells. Engagement of TCR-CD28 at the immunological synapse resulted in the colocalization of CD28 with both wild-type and mutant Rltpr proteins. However, the connection between CD28 and protein kinase C-theta and Carma1, two key effectors of CD28 costimulation, was abrogated in T cells expressing mutant Rltpr, and CD28 costimulation did not occur in those cells. Our findings provide a more complete model of CD28 costimulation in which Rltpr has a key role. PMID- 23793064 TI - Endothelial progenitor cells in coronary artery disease. AB - In the last two decades a great deal of evidence has been collected on the key role of endothelial progenitor cells (EPC) in the mechanisms of vascular healing. The role of EPC as a marker of vascular health and prognosis of cardiovascular disease is already consolidated. This review aims to examine and evaluate recent data regarding EPC, as biomarkers, prognostic factor and potential therapy in cardiovascular disease. PMID- 23793065 TI - Index of clinical consequences of untreated dental caries (pufa) in primary dentition of children from north-east Poland. AB - PURPOSE: The purpose of this study was to evaluate the prevalence and experience of clinical consequences of untreated dental caries in primary dentition in 5 and 7 year-old children from north-east Poland and to find whether there is a correlation between dmft and pufa indices. MATERIAL/METHODS: Two hundred fifteen children aged 5 and 7 years living in the Podlaskie region were examined in the course of the Polish National Oral Health Survey 2011. Caries prevalence and experience in primary dentition was evaluated according to WHO criteria (dmft index). The clinical consequences of untreated dental caries were assessed by pufa index. RESULTS: The dmft index was 5.56 +/- 4.45 in 5-years-old children and 6.69 +/- 3.14 in 7-years-olds. The prevalence/experience of pufa index was 43.4%/2.20 +/- 3.43 and 72.4%/2.44 +/- 2.22, respectively. Children living in rural areas presented a worse dental condition. A statistical analysis revealed a strong relation between dmft and pufa in both age groups. CONCLUSION: The present study revealed negligence in the dental treatment of children from north-east Poland resulting in the high prevalence and experience of the pufa index in primary dentition. This index is a valuable measurement tool to record the clinical consequences of untreated dental caries. PMID- 23793066 TI - Magnetic ionic plastic crystal: choline[FeCl4]. AB - A novel organic ionic plastic crystal (OIPC) based on a quaternary ammonium cation and a tetrachloroferrate anion has been synthesized with the intention of combining the properties of the ionic plastic crystal and the magnetism originating from the iron incorporated in the anion. The thermal analysis of the obtained OIPC showed a solid-solid phase transition below room temperature and a high melting point above 220 degrees C, indicating their plastic crystalline behaviour over a wide temperature range, as well as thermal stability up to approximately 200 degrees C. The magnetization measurements show the presence of three-dimensional antiferromagnetic ordering below 4 K. The results from electrochemical characterization display a solid-state ionic conduction sufficiently high and stable (between 10(-2.7) and 10(-3.6) S cm(-1) from 20 to 180 degrees C) for electrochemical applications. PMID- 23793063 TI - Differences and similarities in the transcriptional profile of peripheral whole blood in early and late-onset preeclampsia: insights into the molecular basis of the phenotype of preeclampsiaa. AB - OBJECTIVE: Preeclampsia (PE) can be sub-divided into early- and late-onset phenotypes. The pathogenesis of these two phenotypes has not been elucidated. To gain insight into the mechanisms of disease, the transcriptional profiles of whole blood from women with early- and late-onset PE were examined. METHODS: A cross-sectional study was conducted to include women with: i) early-onset PE (diagnosed prior to 34 weeks, n=25); ii) late-onset PE (after 34 weeks, n=47); and iii) uncomplicated pregnancy (n=61). Microarray analysis of mRNA expression in peripheral whole blood was undertaken using Affymetrix microarrays. Differential gene expression was evaluated using a moderated t-test (false discovery rate <0.1 and fold change >1.5), adjusting for maternal white blood cell count and gestational age. Validation by real-time qRT-PCR was performed in a larger sample size [early PE (n=31), late PE (n=72) and controls (n=99)] in all differentially expressed genes. Gene ontology analysis and pathway analysis were performed. RESULTS: i) 43 and 28 genes were differentially expressed in early- and late-onset PE compared to the control group, respectively; ii) qRT-PCR confirmed the microarray results for early and late-onset PE in 77% (33/43) and 71% (20/28) of genes, respectively; iii) 20 genes that are involved in coagulation (SERPINI2), immune regulation (VSIG4, CD24), developmental process (H19) and inflammation (S100A10) were differentially expressed in early-onset PE alone. In contrast, only seven genes that encoded proteins involved in innate immunity (LTF, ELANE) and cell-to-cell recognition in the nervous system (CNTNAP3) were differentially expressed in late-onset PE alone. Thirteen genes that encode proteins involved in host defense (DEFA4, BPI, CTSG, LCN2), tight junctions in blood-brain barrier (EMP1) and liver regeneration (ECT2) were differentially expressed in both early- and late-onset PE. CONCLUSION: Early- and late-onset PE are characterized by a common signature in the transcriptional profile of whole blood. A small set of genes were differentially regulated in early- and late-onset PE. Future studies of the biological function, expression timetable and protein expression of these genes may provide insight into the pathophysiology of PE. PMID- 23793067 TI - Macroscopic motion of supramolecular assemblies actuated by photoisomerization of azobenzene derivatives. AB - Submillimetre size self-assemblies composed of oleate and azobenzene derivatives show forceful motions such as screw-type coiling-recoiling motion by photoirradiation. PMID- 23793068 TI - Ethical issues in family violence research in healthcare settings. AB - Research ethics is always important. However, it is especially crucial with sensitive research topics such as family violence. The aim of this article is to describe and discuss some crucial issues regarding intimate partner violence and child maltreatment, based on the authors' own research experiences. We focus on and discuss examples concerning the definition of family violence, research design, ethical approval, participant recruitment and safety and data collection and processing. During the research process, the significance of teamwork is emphasized. Support provided by the participants to each other and support given by experienced researchers within the team is very important for high ethical standards. PMID- 23793069 TI - Patient participation in special care units for persons with dementia: A losing principle? AB - The aim of this study was to explore the experience of nursing personnel with respect to patient participation in special care units for persons with dementia in nursing homes, with focus on everyday life. The study has an explorative grounded theory design. Eleven nursing personnel were interviewed twice. Patient participation is regarded as being grounded in the idea that being master of one's own life is essential to the dignity and self-esteem of all people. Patient participation was described at different levels as letting the resident make their own decisions, adjusting the choices, making decisions on behalf of the residents and forcing the residents. The educational level and commitment of the nursing personnel and how often they were on duty impacted the level that each person applied, as did the ability of the residents to make decisions, and organizational conditions, such as care culture, leadership and number of personnel. PMID- 23793070 TI - Nurses' perception of ethical climate, medical error experience and intent-to leave. AB - We examined nurses' perceptions of the ethical climate of their workplace and the relationships among the perceptions, medical error experience and intent to leave through a cross-sectional survey of 1826 nurses in 33 Korean public hospitals. Ethical climate was measured using the Hospital Ethical Climate Survey. Although the sampled nurses perceived their workplace ethical climate positively, 19% reported making at least one medical error during the previous year, and 25% intended to leave their jobs in the near future. Controlling for individual and organizational characteristics, we found that nurses with a more positive perception of the 'patient' dimension of ethical climate were less likely to have made medical errors. Nurses with a more positive perception of the 'patient', 'manager', 'hospital' and 'physician' dimensions of ethical climate were less likely to leave their current job. Enhancing workplace ethical climate could reduce medical errors and improve nurses' retention in public hospitals. PMID- 23793071 TI - Gender differences in neurotoxicity. PMID- 23793072 TI - Intestinal transport of methylmercury and inorganic mercury in various models of Caco-2 and HT29-MTX cells. AB - Food is the main pathway of exposure to mercury for most of the population. In food, mercury is generally present as inorganic mercury [Hg(II)] or methylmercury [MeHg]. Both chemical forms have some degree of toxicity, especially MeHg, which is considered a powerful neurotoxicant during development and is classified as a possible human carcinogen. Since the main exposure pathway is oral, gastrointestinal absorption is a decisive step in the process by which mercury reaches the systemic circulation. However, there are few studies that characterize this absorption process. The present work evaluates transport and cellular retention of Hg(II) and MeHg, using various models of the intestinal epithelium (Caco-2 monocultures and Caco-2/HT29-MTX co-cultures in various proportions). Additionally, a study was made of the influence of the mucus secreted by HT29-MTX cells and of substances normally present in the gastrointestinal tract (l-cysteine, bile salts and food components) on mercury transport and accumulation. The results show that incorporation of HT29-MTX reduces the permeability coefficient of Hg(II) and MeHg. This decrease coincides with an increase in cellular accumulation, since mercury is retained in the layer of mucus secreted by HT29-MTX cells [Hg(II): 40%; MeHg: 70%]. The presence of l cysteine, bile salts and food matrix components increases the percentage of both species that is not absorbed. It is noteworthy that in all the conditions assayed the intracellular accumulation of mercury was very high (37-77%). This study shows the importance of the cell model and assay conditions for an in vitro evaluation of intestinal transport of mercury species. PMID- 23793073 TI - Venous sinus thrombosis and subdural haematomas in infants--is there a causal link? PMID- 23793074 TI - Coculture analysis of extracellular protein interactions affecting insulin secretion by pancreatic beta cells. AB - Interactions between cell-surface proteins help coordinate the function of neighboring cells. Pancreatic beta cells are clustered together within pancreatic islets and act in a coordinated fashion to maintain glucose homeostasis. It is becoming increasingly clear that interactions between transmembrane proteins on the surfaces of adjacent beta cells are important determinants of beta-cell function. Elucidation of the roles of particular transcellular interactions by knockdown, knockout or overexpression studies in cultured beta cells or in vivo necessitates direct perturbation of mRNA and protein expression, potentially affecting beta-cell health and/or function in ways that could confound analyses of the effects of specific interactions. These approaches also alter levels of the intracellular domains of the targeted proteins and may prevent effects due to interactions between proteins within the same cell membrane to be distinguished from the effects of transcellular interactions. Here a method for determining the effect of specific transcellular interactions on the insulin secreting capacity and responsiveness of beta cells is presented. This method is applicable to beta cell lines, such as INS-1 cells, and to dissociated primary beta cells. It is based on coculture models developed by neurobiologists, who found that exposure of cultured neurons to specific neuronal proteins expressed on HEK293 (or COS) cell layers identified proteins important for driving synapse formation. Given the parallels between the secretory machinery of neuronal synapses and of beta cells, we reasoned that beta-cell functional maturation might be driven by similar transcellular interactions. We developed a system where beta cells are cultured on a layer of HEK293 cells expressing a protein of interest. In this model, the beta-cell cytoplasm is untouched while extracellular protein-protein interactions are manipulated. Although we focus here primarily on studies of glucose-stimulated insulin secretion, other processes can be analyzed; for example, changes in gene expression as determined by immunoblotting or qPCR. PMID- 23793076 TI - Electronic properties of four typical zigzag-edged graphyne nanoribbons. AB - The subband structures and edge magnetism of alpha-, beta-, gamma- and (6, 6, 12) graphyne nanoribbons with zigzag edges are studied by means of ab initio calculations. Dispersionless subbands and antiparallel edge magnetic ordering occur in these nanostructures, just like in zigzag-edged graphene nanoribbons. More importantly, a very simple tight-binding model is established which can accurately describe the subband structures of these ribbons. From such a model we find that beta-graphyne nanoribbon has many more transport modes than other graphyne and graphene nanoribbons, hence it can carry a much larger current. Such a tight-binding model provides a simple but effective way to study further the transport and optical properties of these graphyne nanoribbons. PMID- 23793075 TI - Computational design of peptide ligands for ochratoxin A. AB - In this paper, we describe a peptide library designed by computational modelling and the selection of two peptide sequences showing affinity towards the mycotoxin, ochratoxin A (OTA). A virtual library of 20 natural amino acids was used as building blocks to design a short peptide library against ochratoxin A template using the de novo design program, LeapFrog, and the dynamic modelling software, FlexiDock. Peptide sequences were ranked according to calculated binding scores in their capacity to bind to ochratoxin A. Two high scoring peptides with the sequences N'-Cys-Ser-Ile-Val-Glu-Asp-Gly-Lys-C' (octapeptide) and N'-Gly-Pro-Ala-Gly-Ile-Asp-Gly-Pro-Ala-Gly-Ile-Arg-Cys-C' (13-mer) were selected for synthesis from the resulting database. These synthesized peptides were characterized using a microtitre plate-based binding assay and a surface plasmon resonance biosensor (Biacore 3000). The binding assay confirmed that both de novo designed peptides did bind to ochratoxin A in vitro. SPR analysis confirmed that the peptides bind to ochratoxin A, with calculated K(D) values of ~15.7 MUM (13-mer) and ~11.8 MUM (octamer). The affinity of the peptides corresponds well with the molecular modelling results, as the 13-mer peptide affinity is about 1.3-times weaker than the octapeptide; this is in accordance with the binding energy values modelled by FlexiDock. This work illustrates the potential of using computational modelling to design a peptide sequence that exhibits in vitro binding affinity for a small molecular weight toxin. PMID- 23793077 TI - Extending the range of supercritical fluid chromatography by use of water-rich modifiers. AB - In this study we investigate the recently reported use of water-containing modifiers for separation and purification of hydrophilic compounds by supercritical fluid chromatography. Improved peak shape is obtained for a variety of glycosides and otherwise hydrophilic compounds when 5% water is added to the methanol co-solvent used in SFC separations, and examples of the use of this approach in preparative SFC purifications are presented. PMID- 23793078 TI - The future of meat: a qualitative analysis of cultured meat media coverage. AB - This study sought to explore the informational themes and information sources cited by the media to cover stories of cultured meat in both the United States and the European Union. The results indicated that cultured meat news articles in both the United States and the European Union commonly discuss cultured meat in terms of benefits, history, process, time, livestock production problems, and skepticism. Additionally, the information sources commonly cited in the articles included cultured meat researchers, sources from academia, People for the Ethical Treatment of Animals (PETA), New Harvest, Winston Churchill, restaurant owners/chefs, and sources from the opposing countries (e.g. US use some EU sources and vice versa). The implications of this study will allow meat scientists to understand how the media is influencing consumers' perceptions about the topic, and also allow them to strategize how to shape future communication about cultured meat. PMID- 23793079 TI - Determination of the myoglobin states in ground beef using non-invasive reflectance spectrometry and multivariate regression analysis. AB - Seventy-two samples of ground beef from M. semimembranosus of two 5 and two 1.5year old animals were prepared. Two types of fat tissues from either beef or pork were added to the ground beef. The samples were prepared to contain predominantly deoxymyoglobin (DMb), oxymyoglobin (OMb) and metmyoglobin (MMb) states on surfaces using selected methods based on chemical treatment (for MMb) and oxygen pressure packaging to induce the two other states. Reflectance spectra were measured on ground beef after three storage times. Partial least regression analysis was used to make calibration models of the desired myoglobin states. Validated models using leave-one-sample out cross validation gave, after correction and normalization, prediction errors of about 5%. Long term storage of ground beef was unsuitable for preparing pure MMb states due to gradual reduction of the pigment to DMb, presumably by bacteria. PMID- 23793080 TI - Inhibition of Listeria monocytogenes and Escherichia coli O157:H7 in liquid broth medium and during processing of fermented sausage using autochthonous starter cultures. AB - The antimicrobial effect of two autochthonous starter cultures of Lactobacillus sakei was evaluated in vitro (in liquid broth medium) and in situ assays. The inactivation of foodborne pathogens Listeria monocytogenes (serotype 4ab No 10) and Escherichia coli O157:H7 ATCC 43888 was investigated during the production of fermented sausage according to a typical Greek recipe using L. sakei strains as starter cultures. The inactivation kinetics were modeled using GInaFiT, a freeware tool to assess microbial survival curves. By the end of the ripening period, the inhibition of L. monocytogenes was significant in treatments with L. sakei 8416 and L. sakei 4413 compared to the control treatment. A 2.2-log reduction of the population of E. coli O157:H7 resulted from the autochthonous starter culture L. sakei 4413 during sausage processing. The use of the autochthonous starter cultures constitutes an additional improvement to the microbial safety by reducing foodborne pathogens. PMID- 23793081 TI - Oxidation in HiOx-packaged pork Longissimus muscle predisposes myofibrillar and sarcoplasmic proteins to N-nitrosamine formation in nitrite-curing solution. AB - The effect of meat protein in situ oxidation on the formation of N nitrosodiethylamine (NDEA) was investigated. Fresh minced pork was untreated (Con) or treated with 700mg/kg alpha-tocopherol (Toc) or 300mg/kg tea polyphenols (PPE), packaged in a HiOx atmosphere (78.8% O2, 18.8% CO2, 2.4% N2), then stored at 2+/-1 degrees C for up to 10days. Crude myofibrillar (MP) or sarcoplasmic (SP) protein (20mg/mL) extracted from stored meat was reacted with 43MUM sodium nitrite at 80 degrees C for 1h. Lipid oxidation was totally inhibited in PPE pork but increased in Con and Toc samples after 10days. There was significant protein oxidation (losses of sulfhydryls, formation of protein carbonyls) in both MP and SP in all samples during storage. However, the Con group suffered more extensive protein oxidation than Toc and PPE and produced more NDEA (P<0.05), indicating that protein oxidation promoted nitrosation. PMID- 23793082 TI - Small heat shock proteins and toughness in intermediate pHu beef. AB - Bull M. longissimus dorsi (n=94) categorised into high (n=28), intermediate (n=14) and low (n=52) ultimate pH (pHu) were aged at -1.5 degrees C for 28days. Shear force was higher and more variable (p<0.05) in intermediate pHu samples during ageing. Titin, filamin and desmin degradation was also less extensive in intermediate pHu samples compared to the other two pH categories. The extent of the decline of HSP20, HSP27 and alphabeta-crystallin concentrations during post mortem ageing was pHu related such that high pHu meat maintained the highest concentration of small heat shock proteins followed by intermediate and low pHu meat. MU-Calpain autolysis was slowest in intermediate pHu and cathepsin B activities remained consistently low during ageing in this group (p<0.05). Meat toughness in the intermediate pHu group may be attributed to the combination of a larger pool of sHSP with a sub-optimal cathepsin B activity and intermediary MU calpain activities. PMID- 23793083 TI - Relationship between commercially available DNA analysis and phenotypic observations on beef quality and tenderness. AB - Warner-Bratzler shear force values from 560 mixed breed heifers and steers were used to determine estimates of genetic selection. Cattle were marketed from 2008 to 2011, and included five feedlot based research projects at the North Dakota State University-Carrington Research Extension Center. Samples were collected for IGENITY(r) analysis providing information that included selection indices and estimated breeding values for carcass traits. DNA-based test results were compared with actual carcass measurements. Marbling accounted for over 10% of the variation in WBSF while hot carcass weight was the second most influential carcass trait accounting for 4% (P<0.01). Regression coefficients of IGENITY(r) molecular breeding value on phenotype for WBSF, marbling, ribeye area, yield grade, and fat thickness were low (R(2)=0.14, 0.02, 0.03, 0.03, and 0.02, respectively). Therefore selecting cattle for a higher degree of marbling and feeding a diet that meets or exceeds recommended nutrients for growth are the most important factors influencing beef tenderness and acceptability. PMID- 23793084 TI - Nutrient database improvement project: the influence of U.S.D.A. Quality and Yield Grade on the separable components and proximate composition of raw and cooked retail cuts from the beef rib and plate. AB - Beef nutrition is important to the worldwide beef industry. The objective of this study was to analyze proximate composition of eight beef rib and plate cuts to update the USDA National Nutrient Database for Standard Reference (SR). Furthermore, this study aimed to determine the influence of USDA Quality Grade on the separable components and proximate composition of the examined retail cuts. Carcasses (n=72) representing a composite of Yield Grade, Quality Grade, gender and genetic type were identified from six regions across the U.S. Beef plates and ribs (IMPS #109 and 121C and D) were collected from the selected carcasses and shipped to three university meat laboratories for storage, retail fabrication, cooking, and dissection and analysis of proximate composition. These data provide updated information regarding the nutrient content of beef and emphasize the influence of common classification systems (Yield Grade and Quality Grade) on the separable components, cooking yield, and proximate composition of retail beef cuts. PMID- 23793085 TI - Storage length, storage temperature, and lean formulation influence the shelf life and stability of traditionally packaged ground beef. AB - The effect of storage length and temperature on the shelf life of three ground beef formulations (lean:fat: 73:27, 81:19 and 91:9) was investigated. Coarsely ground beef was stored at -1.7 or 2.3 degrees C for up to 28d. Traditional overwrap packages were produced every 7d prior to retail display for 24h. Lipid oxidation (TBARS), subjective color, instrumental color, and aerobic bacteria were evaluated after 0 and 24h of display. Formulation influenced initial L* and subjective color values (P<0.05). Storage temperature did not affect initial color, but product stored at 2.3 degrees C was more discolored after 24h (P<0.05). Aerobic bacteria increased as storage d and temperature increased (P<0.05). Initial TBARS increased through d 21, but were lower after 28d. Overall, initial characteristics depended on formulation; however, ground beef shelf-life and stability were largely influenced by storage length and storage temperature. PMID- 23793086 TI - Prediction of fatty acids content in pig adipose tissue by near infrared spectroscopy: at-line versus in-situ analysis. AB - A handheld micro-electro-mechanical system (MEMS) based spectrometer working in the near infrared region (NIR) (1600-2400nm) was evaluated for in-situ and non destructive prediction of main fatty acids in Iberian pig (IP) carcasses. 110 IP carcasses were measured. Performance of the instrument was compared with at-line high-resolution NIRS monochromators working in two analysis modes: melted fat samples (transflectance cups) and intact adipose tissues (interactance fiber optic). Standard Error of Prediction (SEP) values obtained on the MEMS-NIRS device were: 0.68% (stearic), 1.30% (oleic), 0.55% (linoleic) and 1% (palmitic), explaining a variability of 83%, 84%, 81% and 78%, respectively. As expected, this represented a loss of predictive capability in comparison to at-line models, even with the same spectral characteristics as on the handheld device. However, the estimated total errors were at the same level for gas chromatography and NIRS analysis. This indicates that the MEMS-NIRS in-situ analysis of each individual carcass provides a cost-effective and real-time quality control system with suitable accuracy. PMID- 23793087 TI - Marbling in the longissimus thoracis muscle from lean cattle breeds. Computer image analysis of fresh versus stained meat samples. AB - One hundred eighty ribeye steaks from Charolais, Limousin and Retinta bulls were used to describe and compare the marbling fat between fresh and stained samples. Image analysis overestimated the intramuscular fat content (P<0.05) in relation to chemical analysis. Staining had a significant effect (P<0.05) on most of the marbling fleck traits, showing an increase in the number of marbling flecks and the proportion of marbling fleck area in the whole and in the ventral half of the longissimus m., and a decrease in the size, length and width of marbling flecks. Breed had a significant influence (P<0.05) on some quantity traits of marbling, but not in the distribution and structure of marbling flecks (P>0.05). Retinta breed was leaner than French breeds and showed fewer and smaller marbling flecks (P<0.05). The results showed a positive correlation (r=0.183 to 0.465) between USDA marbling score, and intramuscular fat by image and chemical analysis. PMID- 23793088 TI - Effects of transportation time, distance, stocking density, temperature and lairage time on incidences of pale soft exudative (PSE) and the physico-chemical characteristics of pork. AB - The study determined the effects of transportation time, distance, stocking density, temperature and lairage time on incidences of PSE and pork quality. Frequencies of PSE cases in stocking density categories within transport duration classes were determined. General linear models, regression and the principal component (PC) analysis were used to analyse the data. Highest incidences of PSE were recorded in autumn season while lowest incidences were recorded in the spring season. Transportation time and stocking density significantly affected pHu and ultimately PSE incidences although there were no interactive effects. Highest risks of PSE occurrence were observed with more space allowance. The highest incidences of PSE were observed for animals that had travelled for two hours while the PSE cases were lower in animals that travelled for longer times. Distance travelled and transportation time had significant effects (P<0.05) on thawing loss (TL) % of pork. No relationships were reported between the other pre slaughter variables and pork quality attributes. With the exception of transportation time and distance travelled which had a positive relationship with TL%, variation in other pre-slaughter variables did not affect meat quality variables. The risks of PSE occurrence were dependent on stocking density and transportation time. PMID- 23793089 TI - Teaching acupuncture to medical students: the experience of Rio Preto Medical School (FAMERP), Brazil. AB - Complementary and alternative medicine, and in particular acupuncture, has been practised and taught in recent years in many universities in the Western world. Here, we relate our experiences since 1997 in teaching acupuncture to medical students at Rio Preto Medical School (Faculty of Medicine of Sao Jose do Rio Preto (FAMERP)), Brazil. Classes are given in the third and fifth years. The main goals of understanding the mechanisms of action and being able to recognise patients who may benefit from treatment and referring them have been well achieved, scoring 3.6 and 4.1, respectively, on a scale of 1-5. Also using that scale, medical students believe that acupuncture is important in the curriculum (4.6), course time is not sufficient (2.7) and they would like more information (4.6). To overcome these concerns, many students join an undergraduate study group (Acupuncture League) where they have more time to learn. We also describe the presence of foreign medical students who, since 2000, have enrolled in a course of 150 h in an exchange programme. PMID- 23793090 TI - Acupuncture for primary hyperhidrosis: case series. AB - Three cases of primary hyperhidrosis of no known cause, with excess sweating day and night, were treated using the same acupuncture points. The patients reported that their sweating decreased and that they felt better after the treatment. PMID- 23793091 TI - Nitrite-embedded packaging film effects on fresh and frozen beef color development and stability as influenced by meat age and muscle type. AB - Muscles (Longissimus lumborum, LL; Psoas major, PM, semitendinosus, ST) were aged (2, 9d postmortem), cut into steaks, anaerobically packaged (nitrite-embedded film, NEF), and displayed (fresh, 19d; frozen, 39d). Fresh NEF increased (P<0.05) in redness (first 48h). Upon opening fresh NEF (d 6) and overwrapping in PVC film, redness declined (P<0.05). NEF cooked LL had more red surface compared to non-NEF. Meat age influenced NEF color. Intact NEF maintained acceptable red color throughout display. Residual nitrite and nitrate associated with fresh NEF and nitrate in NEF cooked LL were found (P<0.05) in the outer layer. Consideration should be given to providing sufficient time for nitric oxide myoglobin development when using NEF which may be influenced by meat age and muscle differences. NEF packaging has potential to extend fresh beef color display life. NEF appears to offer the opportunity to display bright red beef in frozen display by limiting typical effects of photooxidation. PMID- 23793092 TI - AMP-activated protein kinase (AMPK) alpha2 subunit mediates glycolysis in postmortem skeletal muscle. AB - Postmortem glycolysis is directly linked to the incidences of PSE (pale, soft and exudative) and DFD (dark, firm and dry) meats which cause significant loss to meat industry. AMP-activated protein kinase (AMPK) is a major regulator of postmortem glycolysis. However, there are two isoforms of the AMPKalpha catalytic subunit, and their roles in glycolysis of postmortem muscle remain unclear. The objective was to identify the isoform specific roles of AMPK in postmortem glycolysis. Wild type, AMPKalpha1, and AMPKalpha2 knockout (KO) mice were used in the current study. AMPK in Longissimus muscle was activated shortly after death. AMPKalpha2 but not AMPKalpha1 KO abolished the activity of AMPK in postmortem muscle. In addition, AMPKalpha2 KO reduced postmortem pH decline and the generation of lactate, while AMPKalpha1 KO had no significant effect. Finally, the glycogen content of skeletal muscle was reduced in AMPKalpha2 KO but not AMPKalpha1 KO mice. Data clearly demonstrate that AMPKalpha2 catalytic subunit mainly regulates postmortem glycolysis in muscle. PMID- 23793093 TI - Effect of long term dietary supplementation with plant extract on carcass characteristics meat quality and oxidative stability in pork. AB - The effects of dietary supplementation in pigs with plant extract (PE) from Lippia spp., titrated in verbascoside (5mg/kg feed), from weaning to slaughter (166days), on carcass characteristics, meat quality, collagen characteristics, oxidative stability and sensory attributes of Longissimus dorsi (LD) muscle were examined. Ten pigs per treatment were slaughter at a live weight of 109.5+/ 1.4kg. No influence on carcass characteristics, LD meat quality parameters and collagen characteristics were observed. Dietary PE increased (P<0.001) alpha tocopherol levels in LD muscle. Raw LD of pig fed PE showed lower (P<0.001) lipid oxidation levels than controls. A reduction (P=0.05) of fat odor and rancid flavor intensity in cooked LD muscle stored at 4 degrees C for 24h was observed in the treated group. This study shows that PE is an effective antioxidant in pork meat, enhancing oxidative status and sensory attributes, without affecting other meat quality parameters. PMID- 23793094 TI - Evaluation of management techniques to conserve water in a mechanical head wash blood removal system. AB - This research objectively evaluated methods to conserve water in a mechanical beef head wash system. Digital images of pre-wash and post-wash beef heads were analyzed to quantify the percentage change in red saturation of the image, which was used as an objective measure of cleanliness. Three types of nozzles (fan, three-hole, venturi) and three water pressures (344, 516, 689kPa) were evaluated in a two-way treatment structure. An interaction (P=0.07) was observed between water pressure and nozzle type; the change in red saturation increased as pressure decreased for fan and three-hole nozzles which contrasted with venturi nozzles. The fan nozzle*516kPa pressure treatment used 25L of water per head washed and was used to evaluate the effect of three water temperatures (15, 38, 57 degrees C). Water temperature did not impact (P=0.21) change in red saturation. Reducing water wastage and minimizing the use of heated water could have positive economic benefits to the beef processor. PMID- 23793095 TI - Structural and biochemical characteristics of bovine intramuscular connective tissue and beef quality. AB - The aim of the study was to evaluate the impact of structural and biochemical characteristics of muscle intramuscular connective tissue on beef quality. The experimental design was based on three muscles of three breeds sampled as fresh material and cooked at 55 degrees C (Longissimus thoracis and Semimembranosus) or at 70 degrees C (Semimembranosus and Biceps femoris) for quality assessment. The results showed that muscle characteristics influence beef quality differently from one muscle to another. In grilled LT, proteoglycan content contributed negatively to juiciness, and intramuscular lipids were linked positively to tenderness, flavour, residues and overall liking scores. In grilled SM, cross link and lipid contents were involved in beef quality. In BF cooked to 70 degrees C, perimysial branch points were negatively linked to tenderness. In SM cooked to 70 degrees C, perimysial area was involved in beef quality. These results should allow a better understanding of the factors involved in background toughness, in juiciness and flavour of meat. PMID- 23793096 TI - Impact of cardiac magnetic resonance imaging on human lymphocyte DNA integrity. AB - AIMS: Magnetic resonance (MR) imaging is widely used for diagnostic imaging in medicine as it is considered a safe alternative to ionizing radiation-based techniques. Recent reports on potential genotoxic effects of strong and fast switching electromagnetic gradients such as used in cardiac MR (CMR) have raised safety concerns. The aim of this study was to analyse DNA double-strand breaks (DSBs) in human blood lymphocytes before and after CMR examination. METHODS AND RESULTS: In 20 prospectively enrolled patients, peripheral venous blood was drawn before and after 1.5 T CMR scanning. After density gradient cell separation of blood samples, DNA DSBs in lymphocytes were quantified using immunofluorescence microscopy and flow cytometric analysis. Wilcoxon signed-rank testing was used for statistical analysis. Immunofluorescence microscopic and flow cytometric analysis revealed a significant increase in median numbers of DNA DSBs in lymphocytes induced by routine 1.5 T CMR examination. CONCLUSION: The present findings indicate that CMR should be used with caution and that similar restrictions may apply as for X-ray-based and nuclear imaging techniques in order to avoid unnecessary damage of DNA integrity with potential carcinogenic effect. PMID- 23793097 TI - Zn(II) coordination polymer of an in situ generated 4-pyridyl (4Py) attached bis(amido)phosphate ligand, [PO2(NH4Py)2]- showing preferential water uptake over aliphatic alcohols. AB - Two polymorphic 2D-coordination polymers of composition [ZnL(HCO2)]infinity were synthesized from an in situ generated ligand [PO2(NH(4)Py)2](-) (L(-)). The ligand L(-) was generated by a facile metal-assisted P-N bond hydrolysis reaction from the corresponding phosphonium salt 1, [P(NH(4)Py)4]Cl, or from the neutral phosphoric triamide 2, [PO(NH(4)Py)3]. The de-solvated sample of the polymer [ZnL(HCO2)]infinity features polar micropores and shows a type I isotherm for CO2 sorption whereas a type II behaviour was observed for N2. The vapour sorption isotherm of the de-solvated sample of [ZnL(HCO2)]infinity shows preferential adsorption of water vapour over aliphatic alcohols. PMID- 23793098 TI - Association of HLA-DRB1-restricted CD4+ T cell responses with HIV immune control. AB - The contribution of HLA class II-restricted CD4(+) T cell responses to HIV immune control is poorly defined. Here, we delineated previously uncharacterized peptide DRB1 restrictions in functional assays and analyzed the host genetic effects of HLA-DRB1 alleles on HIV viremia in a large cohort of HIV controllers and progressors. We found distinct stratifications in the effect of HLA-DRB1 alleles on HIV viremia, with HLA-DRB1*15:02 significantly associated with low viremia and HLA-DRB1*03:01 significantly associated with high viremia. Notably, a subgroup of HLA-DRB1 variants linked with low viremia showed the ability to promiscuously present a larger breadth of peptides with lower functional avidity when compared to HLA-DRB1 variants linked with high viremia. Our data provide systematic evidence that HLA-DRB1 variant expression has a considerable impact on the control of HIV replication, an effect that seems to be mediated primarily by the protein specificity of CD4(+) T cell responses to HIV Gag and Nef. PMID- 23793100 TI - Dietary phytoestrogen improves relaxant responses to 17-beta-estradiol in aged but not ovariectomised rat bladders. AB - This study examined the effect of age, ovariectomy and dietary phytoestrogen ingestion on 17-beta-estradiol-mediated relaxant responses and messenger RNA (mRNA) and protein expression of oestrogen receptor subtypes in the rat isolated bladder. Female Wistar rats (8 weeks) were anaesthetised, and the ovaries were removed (ovx) or left intact (sham). Rats were fed either normal rat chow (soy, phytoestrogens) or a non-soy (phytoestrogen free) diet. Isolated bladder from rats aged 12, 24 or 52 weeks were pre-contracted with 3 MUM carbachol prior to obtaining a concentration response curve to 17-beta-estradiol. Protein and mRNA expression of the oestrogen receptor subtypes was completed using immunohistochemistry and real-time PCR, respectively. Relatively moderate relaxant responses to 17-beta-estradiol were observed in bladders from all age and treatment groups. However, in soy-fed sham 52-week-old rats, the bladder exhibited enhanced relaxant responses to 17-beta-estradiol when compared to tissues from other age-matched rat treatment groups (P < 0.05). In bladders from female rats, the mRNA and protein expression of oestrogen receptors beta was significantly greater than the expression of the oestrogen receptor alpha. Oestrogen receptor alpha mRNA expression declined with age (P < 0.05), whereas oestrogen receptor beta expression did not change in any of the treatment groups (P > 0.05). Diet, overiectomy or age did not alter the protein expression of either oestrogen receptor subtype in the bladder (P > 0.05). While a soy diet improved relaxant effects to the 17-beta-estradiol with age, it did not alter relaxant responses in bladders from ovariectomised rats. PMID- 23793099 TI - BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1. AB - Here we show that glioblastoma express high levels of branched-chain amino acid transaminase 1 (BCAT1), the enzyme that initiates the catabolism of branched chain amino acids (BCAAs). Expression of BCAT1 was exclusive to tumors carrying wild-type isocitrate dehydrogenase 1 (IDH1) and IDH2 genes and was highly correlated with methylation patterns in the BCAT1 promoter region. BCAT1 expression was dependent on the concentration of alpha-ketoglutarate substrate in glioma cell lines and could be suppressed by ectopic overexpression of mutant IDH1 in immortalized human astrocytes, providing a link between IDH1 function and BCAT1 expression. Suppression of BCAT1 in glioma cell lines blocked the excretion of glutamate and led to reduced proliferation and invasiveness in vitro, as well as significant decreases in tumor growth in a glioblastoma xenograft model. These findings suggest a central role for BCAT1 in glioma pathogenesis, making BCAT1 and BCAA metabolism attractive targets for the development of targeted therapeutic approaches to treat patients with glioblastoma. PMID- 23793101 TI - Differential effects of glycogen synthase kinase 3 (GSK3) inhibition by lithium or selective inhibitors in the central nervous system. AB - Glycogen synthase kinase (GSK3) is a constitutively active serine-threonine kinase associated to neurological and psychiatric disorders. GSK3 inhibition is considered a mediator of the efficacy of the mood-stabiliser lithium. This study aimed at comparing the central nervous system effect of lithium with the selective GSK3 inhibitors AZ1080 and compound A in biochemical, cellular, and behavioural tests. Collapsin response mediator protein 2 is a neuron-specific GSK3 substrate. Lithium, AZ1080, and compound A inhibited its phosphorylation in rat primary neurons with different pIC50. After systemic treatments with lithium or GSK3 inhibitors to assess specific functional responses, phosphorylation was unchanged in adult rat brain, while it was strongly inhibited by GSK3 inhibitors in pups, differently from lithium. Lithium may exert neurotrophic effect by increasing brain-derived neurotrophic factor (BDNF) levels: in the present experimental conditions, lithium exerted opposite effects on plasma BDNF levels compared to GSK3 inhibitors, suggesting this effect might not be necessarily mediated by GSK3 inhibition alone. While plasma thyroid-stimulating hormone and luteinising hormone were not affected by lithium, they were decreased by selective inhibitors. GH and prolactin displayed similar responses towards reduction. Follicle-stimulating hormone levels were not altered by treatments, whereas melatonin was specifically increased by AZ1080. Lithium impaired mouse spontaneous locomotion and decreased amphetamine-induced hyper-locomotion. AZ1080 had no effects on locomotion, while compound A reduced spontaneous locomotor activity without effects on amphetamine-induced hyper-locomotion. The present results indicate that a broad correlation between the effects of lithium and selective GSK3 inhibitors could not be devised, suggesting alternative mechanisms, whereas overlapping results could be obtained in specific assays. PMID- 23793102 TI - Lack of specificity shown by P2Y6 receptor antibodies. AB - P2Y6 receptor in bladder smooth muscle responds to UDP by increasing muscle tone and augmenting bladder contractions. The exact cellular location of the receptor is however unknown. Three commercially available antibodies to P2Y6 receptor gave clean bands on Western blot which were eliminated by specific peptide competition. Two of the three also immunostained bladder smooth muscle cells while leaving adjacent interstitial cells of Cajal unstained. However, attempts to validate the specificity of these antibodies by performing the same assays on bladders from P2Y6 knockout mice were unsuccessful. In Western blots, all three antibodies bound similar proteins in both wild type and P2Y6 knockout tissue. Immunostaining of knockout tissue sections also showed no difference in staining patterns or intensity. We conclude that rigorous controls are required when using commercial reagents to this G-protein coupled receptor and perhaps to other members of the P2Y receptor family. PMID- 23793103 TI - Effect of mosapride on Kv4.3 potassium channels expressed in CHO cells. AB - Mosapride and cisapride are gastroprokinetic agents with 5-hydroxytryptamine4 receptor agonist activity and have been widely used in the treatment of a variety of gastrointestinal disorders. The effects of mosapride and cisapride on cloned Kv4.3 channels stably expressed in Chinese hamster ovary cells were investigated using the whole-cell patch-clamp technique. Mosapride and cisapride inhibited Kv4.3 in a concentration-dependent manner with IC50 values of 15.2 and 9.8 MUM, respectively. Mosapride accelerated the rate of inactivation and activation of Kv4.3 in a concentration-dependent manner and thereby decreased the time to peak. The rate constants of association (k +1) and dissociation (k -1) for mosapride were 9.9 MUM(-1) s(-1) and 151.3 s(-1), respectively. The K D (k -1/k +1) was 16.2 MUM, similar to the IC50 value calculated from the concentration-response curve. Voltage-dependent inhibition by mosapride was observed in the voltage range for channel opening but was not observed over a voltage range in which all Kv4.3 channels were open. Both the steady-state activation and inactivation curves of Kv4.3 were shifted in the hyperpolarizing direction in the presence of mosapride. Mosapride also caused a substantial acceleration in closed-state inactivation of Kv4.3. Mosapride produced use-dependent inhibition, which was consistent with a slow recovery from inactivation of Kv4.3. M1 and norcisapride, the major metabolites of mosapride and cisapride, respectively, had little or no effect on Kv4.3. These results indicate that mosapride inhibits Kv4.3 by both preferential binding to the open state of the channels during depolarization and acceleration of the closed-state inactivation at subthreshold potentials. PMID- 23793104 TI - Heterochromatin Protein 1a (HP1a) partner specificity is determined by critical amino acids in the chromo shadow domain and C-terminal extension. AB - Drosophila melanogaster Heterochromatin Protein 1a (HP1a) is an essential protein critical for heterochromatin assembly and regulation. Its chromo shadow domain (CSD) homodimerizes, a requirement for binding protein partners that contain a PXVXL motif. How does HP1a select among its many different PXVXL-containing partners? HP1a binds tightly to Heterochromatin Protein 2 (HP2), but weakly to PIWI. We investigated differences in homodimerization and the impact of the C terminal extension (CTE) by contrasting HP1a to its paralogue, HP1b. HP1a and HP1b differ in the dimerization interface, with HP1a having an Arg at position 188 rather than Glu. We find that while this substitution reduces the dimerization constant, it does not impact the binding surface as demonstrated by unchanged partner binding affinities. However, the CTE (only 4 residues in HP1a as compared with 87 residues in HP1b) is critical; the charged residues in HP1a are necessary for tight peptide binding. Examining a panel of amino acid substitutions in the HP1a CSD, we find that Leu-165 in HP1a interacts with HP2 but not PIWI, supporting the conclusion that different sites in the binding surface provide discrimination for partner selection. Partner sequence is also critical for affinity, as the remaining difference in binding between HP2 and PIWI polypeptides is eliminated by swapping the PXVXL motifs between the two. Taken together, these studies indicate that the binding surface of the HP1a CSD plus its short CTE provide the needed discrimination among HP1a's partners, and that the CTE is important for differentiating the interactions of the Drosophila HP1 paralogs. PMID- 23793105 TI - Comprehensive identification of high-frequency and co-occurring Mafa-DPA1, Mafa DQA1, Mafa-DRA, and Mafa-DOA alleles in Vietnamese cynomolgus macaques. AB - High-frequency alleles and/or co-occurring human leukocyte antigen alleles across loci appear to be more important than individual alleles as markers of disease risk and have clinical value as biomarkers for targeted screening or the development of new disease therapies. To better elucidate the major histocompatibility complex (MHC) background and to facilitate the experimental use of cynomolgus macaques, Mafa-DPA1, Mafa-DQA1, Mafa-DRA, and Mafa-DOA alleles were characterized, and their combinations were investigated in 30 Vietnamese macaques by gene cloning and sequencing. A total of 26 Mafa-DPA1, 18 Mafa-DQA1, 9 Mafa-DRA, and 15 Mafa-DOA alleles, including 7 high-frequency alleles, were identified in this study, respectively. In addition, 15 Mafa-DQA1, 17 Mafa-DPA1, 15 Mafa-DOA, and 2 Mafa-DRA alleles represented novel sequences that had not been documented in earlier studies. Our results also showed that the Vietnamese macaques might be valuable because no less than 30% of the test animals possessed Mafa-DRA*01:02:01 (90%), -DQA1*26:01:03 (37%), -DOA*01:02:07 (34%), and DQA1*01:03:03 (30%). We previously reported that the combinations of MHC class II alleles, including the combination of DOA*01:02:07-DPA1*02:09 and DOA*01:02:07 DQA1*01:03:03, were detected in 17 and 14% of the animals, respectively. Interestingly, more than two Mafa-DQA1 and Mafa-DPA1 alleles were detected in one animal in this study, which suggested that they might be caused by a chromosomal duplication. If our findings can be validated by other studies, it will further enrich the number of known Mafa-DPA1 and Mafa-DQA1 polymorphisms. Our results identified the co-occurring MHC alleles across loci in a cohort of Vietnamese cynomolgus macaques, which emphasized the value of this species as a model for biomedical research. PMID- 23793106 TI - An automated algorithm for extracting functional immunologic V-genes from genomes in jawed vertebrates. AB - Variable (V) domains of immunoglobulins (Ig) and T cell receptors (TCR) are generated from genomic V gene segments (V-genes). At present, such V-genes have been annotated only within the genome of a few species. We have developed a bioinformatics tool that accelerates the task of identifying functional V-genes from genome datasets. Automated recognition is accomplished by recognizing key V gene signatures, such as recombination signal sequences, size of the exon region, and position of amino acid motifs within the translated exon. This algorithm also classifies extracted V-genes into either TCR or Ig loci. We describe the implementation of the algorithm and validate its accuracy by comparing V-genes identified from the human and mouse genomes with known V-gene annotations documented and available in public repositories. The advantages and utility of the algorithm are illustrated by using it to identify functional V-genes in the rat genome, where V-gene annotation is still incomplete. This allowed us to perform a comparative human-rodent phylogenetic analysis based on V-genes that supports the hypothesis that distinct evolutionary pressures shape the TCRs and Igs V-gene repertoires. Our program, together with a user graphical interface, is available as open-source software, downloadable at http://code.google.com/p/vgenextract/. PMID- 23793107 TI - In situ switching layer-by-layer assembly: one-pot rapid layer assembly via alternation of reductive and oxidative electropolymerization. AB - In situ one-pot rapid layer-by-layer assembly of polymeric films as an active layer of a photoactive device via alternation of reductive and oxidative electropolymerization has been demonstrated. This novel fabrication without moving or changing experimental gears would be a powerful strategy to develop automated layer-by-layer machines. PMID- 23793108 TI - Race and association with disease manifestations and mortality in scleroderma: a 20-year experience at the Johns Hopkins Scleroderma Center and review of the literature. AB - Experience suggests that African Americans may express autoimmune disease differently than other racial groups. In the context of systemic sclerosis (scleroderma), we sought to determine whether race was related to a more adverse expression of disease. Between January 1, 1990, and December 31, 2009, a total of 409 African American and 1808 white patients with scleroderma were evaluated at a single university medical center. While the distribution by sex was virtually identical in both groups, at 82% female, African American patients presented to the center at a younger mean age than white patients (47 vs. 53 yr; p < 0.001). Two-thirds of white patients manifested the limited cutaneous subset of disease, whereas the majority of African American patients manifested the diffuse cutaneous subset (p < 0.001). The proportion seropositive for anticentromere antibody was nearly 3-fold greater among white patients, at 34%, compared to African American patients (12%; p < 0.001). Nearly a third of African American (31%) patients had autoantibodies to topoisomerase, compared to 19% of white patients (p = 0.001). Notably, African American patients experienced an increase in prevalence of cardiac (adjusted odds ratio [OR], 1.6; 95% confidence interval [CI], 1.3-2.2), renal (OR, 1.6; 95% CI, 1.2-2.1), digital ischemia (OR, 1.5; 95% CI, 1.4-2.2), muscle (OR, 1.7; 95% CI, 1.3-2.3), and restrictive lung (OR, 6.9; 95% CI, 5.1-9.4) disease. Overall, 700 (32%) patients died (159 African American; 541 white). The cumulative incidence of mortality at 10 years was 43% among African American patients compared to 35% among white patients (log-rank p = 0.0011). Compared to white patients, African American patients experienced an 80% increase in risk of mortality (relative risk [RR], 1.8; 95% CI, 1.4-2.2), after adjustment for age at disease onset and disease duration. Further adjustment by sex, disease subtype, and scleroderma-specific autoantibody status, and for the socioeconomic measures of educational attainment and health insurance status, diminished these risk estimates (RR, 1.3; 95% CI, 1.0-1.6). The heightened risk of mortality persisted in strata defined by age at disease onset, diffuse cutaneous disease, anticentromere seropositivity, decade of care at the center, and among women. These findings support the notion that race is related to a distinct phenotypic profile in scleroderma, and a more unfavorable prognosis among African Americans, warranting heightened diagnostic evaluation and vigilant care of these patients. Further, we provide a chronologic review of the literature regarding race, organ system involvement, and mortality in scleroderma; we furnish synopses of relevant reports, and summarize findings. PMID- 23793109 TI - Prevalence of the antiphospholipid syndrome and its effect on survival in 679 Chinese patients with systemic lupus erythematosus: a cohort study. AB - In this work we evaluate the prevalence of the antiphospholipid syndrome (APS) and its impact on survival in Chinese patients with systemic lupus erythematosus (SLE). We studied a prospective cohort of southern Chinese patients who fulfilled >=4 American College of Rheumatology criteria for SLE. The cumulative rate of survival over time was calculated by the Kaplan-Meier method. APS was defined by the 2006 updated consensus criteria. We evaluated the prevalence and manifestations of APS, and compared the survival of patients with and without APS. We followed 679 patients with SLE (92% women; age of onset, 32.5 +/- 14 yr) for 9.7 +/- 7.3 years. Sixty-eight (10%) patients died and 33 (4.9%) patients were lost to follow-up. Forty-four (6.5%) patients met the criteria for APS, manifested by the following: ischemic stroke (55%), deep venous thrombosis (32%), obstetric morbidity (14%), cardiovascular events (9%), and peripheral vascular disease (9%). Nine (9/44 [20%]) APS patients died, which was more frequent than the non-APS patients (59/635 [9%]; p = 0.02). The cumulative mortality of patients with APS was 4.6% at 5 years, 7.8% at 10 years, and 22.2% at 15 years, which was not significantly higher than that of non-APS patients (5.4% at 5 years, 9.2% at 10 years, and 11.3% at 15 years; p = 0.14). However, if we considered only patients with APS caused by arterial thrombosis, the presence of APS was significantly associated with mortality (hazard ratio, 2.29; 95% confidence interval, 1.13-4.64; p = 0.02). We conclude that the presence of APS increases the mortality risk of Chinese patients with SLE, which is mainly contributed by arterial thrombotic events. CLINICAL SIGNIFICANCE: 1) APS is infrequent in southern Chinese patients with SLE compared to white patients. 2) Arterial thrombosis is a more common manifestation of APS than venous thrombosis in Chinese SLE patients. 3) APS related to arterial thrombosis is associated with increased mortality in Chinese patients with SLE. PMID- 23793110 TI - IgG4-related disease and hypertrophic pachymeningitis. AB - Hypertrophic pachymeningitis (HP) is an inflammatory condition in which the dura mater of the cranium or spine becomes thickened, leading to symptoms that result from mass effect, nerve compression, or vascular compromise. The differential diagnosis of HP includes immune-mediated conditions such as rheumatoid arthritis and vasculitis, malignancies, and infections. Many times, no diagnosis is reached; in such cases, the disease has been described as idiopathic HP. IgG4 related disease (IgG4-RD) is a recently described inflammatory condition known to cause tumefactive lesions at myriad anatomical locations. Both IgG4-RD and idiopathic HP share similar demographics, histopathology, and natural history. We hypothesized that IgG4-RD is a common cause of idiopathic HP.To investigate this hypothesis, we identified all pathology specimens diagnosed as noninfectious HP during 25 years at our institution. Fourteen cases had stained slides and paraffin blocks to permit review of the original hematoxylin and eosin stained slides as well as immunostaining of cell blocks. Recently published consensus guidelines describing characteristic histopathology and the necessary quantity of IgG4+ plasma cell infiltrate were used to diagnose IgG4-RD.Four cases (66.6%) that had been regarded previously as representing idiopathic HP were diagnosed as IgG4-RD; of all the reviewed cases, IgG4-RD represented 29% of cases. Of the remaining cases, 3 cases were associated with granulomatosis with polyangiitis (GPA), 2 with lymphoma, and 1 each with rheumatoid arthritis, giant cell arteritis, and sarcoidosis. Two of the cases could not be diagnosed more precisely and were classified as undifferentiated HP. Clinical history, serologic tests, cerebrospinal fluid studies, and radiology alone could not identify the cause of HP. Rather, biopsy with histopathology and immunostaining was necessary to reach an accurate diagnosis. Significant IgG4+ plasma cell infiltrates were observed in rheumatoid arthritis, granulomatosis with polyangiitis, and lymphoma, underscoring the importance of histopathology in making the diagnosis of IgG4 RD.This case series demonstrates that IgG4-RD may be the most common etiology of noninfectious HP and highlights the necessity of biopsy for accurate diagnosis. PMID- 23793111 TI - Effect of tiger nut fibre addition on the quality and safety of a dry-cured pork sausage ("Chorizo") during the dry-curing process. AB - There is a growing interest in the revalorization of co-products from the food industry. Co-products from tiger nuts (Cyperus esculentus) milk production are a suitable fibre source. "Chorizo" is the most popular dry-cured meat product in Spain. The aim of this work was to study the effect of the tiger nut fibre addition (0, 5, and 7.5%) on the quality (composition, physicochemical, and sensorial properties) and safety (oxidation and microbial quality) of a Spanish dry-cured sausage, during the 28days of its dry-curing process. Tiger nut fibre (TNF) addition decreased fat and increased moisture content. The addition of TNF significantly increased (p<0.05) the total dietary fibre content of "Chorizo". Lightness (L*), yellowness (b*) and redness index (a*/b*) were significantly (p<0.05) affected by the fibre content. The addition of 5% and 7.5% TNF to chorizo provided rich fibre and a healthier product. Although there were slight changes in the physicochemical properties, its quality (traditional characteristics) and its safety remained. PMID- 23793112 TI - Describing curved-planar pi-pi interactions: modeled by corannulene, pyrene and coronene. AB - The specific pi-pi interactions between curved and planar structures, which are different from the general pi-pi interactions between planar arenes, have generated great attention due to their brand-new, unique, and fascinating photoelectric properties. Herein, the curved-planar (C-P) pi-pi interactions between corannulene, pyrene and coronene have been investigated using the DFT-D method. A series of structural and physical properties have been calculated including geometry, C-C distance, binding energy, population charge distribution, dipole moment, electrostatic potential (ESP), visualization of the interactions in real space, transfer integral, electronic transition behaviour and Raman shift. All the analyses indicate that the bowl-planar (C(B)-P) complexes are distinguishable from the mouth-tip-planar (C(M)-P) and planar-planar (P-P) packing motifs due to their coherent negative ESP, electronic attraction strength and Raman spectra. The C-P complexes are found to exhibit dominant electron transport characteristics. In addition, an unusual "negative Stokes shift" is found in the C-P pi-pi complexes, which is caused by state resonance. This provides a clue to help predict and explore the photoelectric properties of C-P pi-pi complexes. In particular, at the frequency of the out-of-plane CH bending vibration around 1400 cm(-1), the planar molecules in the C(B)-P complexes possess a smaller Raman peak shift than in the C(M)-P complexes, and vice versa for the curved molecules. This specific Raman shift can be utilized as characteristic signals to identify the C-P structures. PMID- 23793115 TI - The proof of the pudding is in the eating--health system preparedness for the February 2011 Canterbury Earthquake. PMID- 23793114 TI - Inheritance of gene expression level and selective constraints on trans- and cis regulatory changes in yeast. AB - Gene expression evolution can be caused by changes in cis- or trans-regulatory elements or both. As cis and trans regulation operate through different molecular mechanisms, cis and trans mutations may show different inheritance patterns and may be subjected to different selective constraints. To investigate these issues, we obtained and analyzed gene expression data from two Saccharomyces cerevisiae strains and their hybrid, using high-throughput sequencing. Our data indicate that compared with other types of genes, those with antagonistic cis-trans interactions are more likely to exhibit over- or underdominant inheritance of expression level. Moreover, in accordance with previous studies, genes with trans variants tend to have a dominant inheritance pattern, whereas cis variants are enriched for additive inheritance. In addition, cis regulatory differences contribute more to expression differences between species than within species, whereas trans regulatory differences show a stronger association between divergence and polymorphism. Our data indicate that in the trans component of gene expression differences genes subjected to weaker selective constraints tend to have an excess of polymorphism over divergence compared with those subjected to stronger selective constraints. In contrast, in the cis component, this difference between genes under stronger and weaker selective constraint is mostly absent. To explain these observations, we propose that purifying selection more strongly shapes trans changes than cis changes and that positive selection may have significantly contributed to cis regulatory divergence. PMID- 23793113 TI - NF-kappaB and IRF7 pathway activation by Epstein-Barr virus Latent Membrane Protein 1. AB - The principal Epstein-Barr virus (EBV) oncoprotein, Latent Membrane Protein 1 (LMP1), is expressed in most EBV-associated human malignancies. LMP1 mimics CD40 receptor signaling to provide infected cells with constitutive NF-kappaB, MAP kinase, IRF7, and PI3 kinase pathway stimulation. EBV-transformed B-cells are particularly dependent on constitutive NF-kappaB activity, and rapidly undergo apoptosis upon NF-kappaB blockade. Here, we review LMP1 function, with special attention to current understanding of the molecular mechanisms of LMP1-mediated NF-kappaB and IRF7 pathway activation. Recent advances include the elucidation of transmembrane motifs important for LMP1 trafficking and ligand-independent signaling, analysis of genome-wide LMP1 gene targets, and the identification of novel cell proteins that mediate LMP1 NF-kappaB and IRF7 pathway activation. PMID- 23793116 TI - Challenges of the New Zealand healthcare disaster preparedness prior to the Canterbury earthquakes: a qualitative analysis. AB - BACKGROUND: Disasters are a growing global phenomenon. New Zealand has suffered several major disasters in recent times. The state of healthcare disaster preparedness in New Zealand prior to the Canterbury earthquakes is not well documented. OBJECTIVE: To investigate the challenges of the New Zealand healthcare disaster preparedness prior to the Canterbury earthquakes. METHOD: Semi-structured interviews with emergency planners in all the District Health Boards (DHBs) in New Zealand in the period between January and March 2010. The interview protocol revolved around the domains of emergency planning adopted by the World Health Organization. RESULTS: Seventeen interviews were conducted. The main themes included disinterest of clinical personnel in emergency planning, the need for communication backup, the integration of private services in disaster preparedness, the value of volunteers, the requirement for regular disaster training, and the need to enhance surge capability of the New Zealand healthcare system to respond to disasters. CONCLUSION: Prior to the Canterbury earthquakes, healthcare disaster preparedness faced multiple challenges. Despite these challenges, New Zealand's healthcare response was adequate. Future preparedness has to consider the lessons learnt from the 2011 earthquakes to improve healthcare disaster planning in New Zealand. PMID- 23793117 TI - Disgust sensitivity and the 'non-rational' aspects of a career choice in surgery. AB - AIM: Fitting trainee physicians to career paths remains an ongoing challenge in a highly fluid health workforce environment. Studies attempting to explain low interest in surgical careers have typically examined the relative impact of career and lifestyle values. The current work argues that emotional proclivities are potentially more important and that disgust sensitivity may help explain both low surgical interest as well as the tendency for female students to avoid surgical careers. METHOD: 216 medical students attending a required course in human behaviour completed measures of career intention, traditional predictors of career intention and dispositional disgust sensitivity. RESULTS: As predicted, logistic regression showed that greater disgust sensitivity predicted lower surgical career intention even when controlling for traditional career values (OR=0.45, 95%CI=0.21-0.95). Additionally, the gender effect indexing low female interest in surgical careers was no longer significant once disgust sensitivity was added to the model. CONCLUSION: The impact of disgust sensitivity on surgical interest was substantial and on par with established predictors of career intention. Disgust sensitivity may represent a potentially modifiable factor impacting surgical career choice, particularly among female students who are typically more disgust sensitive. PMID- 23793118 TI - Factors related to postgraduate retention of medical graduates in New Zealand. AB - AIMS: To examine the influence of a number of variables, including age and medical school entrance category, on postgraduate retention of New Zealand (NZ) medical graduates. METHODS: An anonymised database was created of all graduates from the Otago School of Medicine (1999-2010), with demographic and entry category data. The NZ Medical Register was checked in January 2012 to identify which graduates remained in NZ. Risk Differences (RD) were calculated to compare retention between medical school entrance categories by year of graduation using the random effects Mantel-Haenszel method. The influence of covariates on remaining on the New Zealand Medical Register was evaluated using logistic regression. RESULTS: The odds of remaining on the NZ Medical Register increased by 7% for each additional year of age at graduation (Odds Ratio=1.070, 95%CI 1.038-1.113, p<0.001). Compared with students who entered medical school after a competitive first year exam, retention of students who entered after completion of a bachelor's degree was 7% higher, and 20% higher for "Other Category" (older, work experienced) students. Multiple logistic regression identified medical school entry category as the only significant predictor of higher retention. CONCLUSIONS: Admission policies favouring graduate entry and "Other Category" students could contribute to increased retention of NZ medical graduates. PMID- 23793119 TI - New Zealand's 2005 'no-fault' compensation reforms and medical professional accountability for harm. AB - AIMS: To discover the effect of the 2005 'no-fault' compensation reforms on medical professional accountability for harm in the context of overall trends in New Zealand's medical professional accountability processes 2001-2010. METHODS: Data for the 5 years before and after the 2005 reforms were compared including compensation claims to the Accident Compensation Corporation (ACC), ACC reporting to the authorities, patient complaints to the Health and Disability Commissioner and outcomes, referrals to the Medical Council and outcomes, and disciplinary proceedings and outcomes. RESULTS: Following the 2005 compensation reforms, claims for compensation increased, ACC reporting overall increased but ACC reporting to the Medical Council decreased; patient complaints increased but the Health and Disability Commissioner investigated fewer complaints and referred fewer doctors for discipline while maintaining steady referrals to the Medical Council; referrals to the Medical Council decreased, and the Medical Council conducted fewer performance reviews and referred fewer doctors for discipline; disciplinary proceedings decreased but more hearings ended in guilty findings. CONCLUSIONS: Accountability via compensation decreased following the 2005 'no fault' compensation reforms, contributing to an overall decrease in medical professional accountability for harm. PMID- 23793120 TI - A workforce survey of New Zealand medical oncologists. AB - AIM: There is wide recognition that the challenge of providing health care into the future requires planning for a sustainable workforce particularly in the context of increasing service demand. The Medical Oncology Work Group (MOWG) undertook a survey of vocationally registered medical oncologists which aimed to support future workforce planning and the development of models of care. METHODS: The survey was developed and carried out by the MOWG in conjunction with the Ministry of Health during 2009. Medical oncologists were sent the survey and forwarded unnamed completed responses to one of the authors (SB). RESULTS: A total of 33 out of 40 practising medical oncologists completed the survey, representing an 82% response rate. The survey found that there is an emerging movement from a male-dominated workforce largely working full time, to a workforce with a higher proportion of females and part-time workers. The median full-time medical oncologist in New Zealand was responsible for 220 first specialist assessments (FSAs) per annum, 40 more than the number considered reasonable by the surveyed practitioners. In qualitative responses, medical oncologists expressed frustration with lack of resources and high workloads that constrained their ability to appropriately deploy their skills and undertake teaching and research. Positive aspects included collegial collaboration and patient contact. Prominent suggestions for improving job satisfaction included use of skilled administrative staff or nurse specialists to free up time for oncologists to better use their skills. CONCLUSION: The survey highlights high clinical workload and frustration within the medical oncology workforce. In addition there is increasing service demand. This survey has formed the basis of work to develop new models of care in medical oncology. PMID- 23793121 TI - The New Zealand Vocational Trainee 2011 Survey: a national snapshot of vocational training. AB - AIM: To assess the opinions of New Zealand vocational trainees about the quality of their training. METHOD: We surveyed New Zealand vocational trainees using an online questionnaire based on the Australian Medical Association Specialist Trainee Survey, in September and October 2011. RESULTS: The response rate was 24.8% with representation across training programs. Trainees expressed a high level of satisfaction with most aspects of their training, and results compare favourably with Australia. Access to training in the private sector, and value for money emerged as areas of concern, but also highlight the importance of reimbursed costs in the satisfaction of New Zealand trainees. Work life balance is of increasing importance to young doctors, and an unmet desire for extended leave from medical practice may present an issue for workforce capacity and training flexibility in years to come. CONCLUSION: This survey provides a snapshot and a baseline, for future comparisons. PMID- 23793122 TI - Demography of medical students at the University of Otago, 2004-2008: a changing spectrum? AB - AIMS: To review the demography of University of Otago Year 2 medical students for the period 2004-2008 to determine whether our graduates reflect the changing demography of New Zealand society. METHOD: A demographic questionnaire was completed by students entering Year 2. This paper reviews data collected from 2004-2008 and compares the results with data collected between 1987-2000 and also with New Zealand census data. RESULTS: The demographic spectrum of the University of Otago Medical School Year 2 students does not show a general shift towards the demography of the New Zealand community. However, there have been specific positive changes for entrants with a rural background and the proportion of students who are New Zealand citizens. Of concern Maori and Pacific Island students and students from families with lower socioeconomic and educational status are under-represented in the reported period although there has been more recent improvement. In addition the proportion of students with a parent as a doctor has risen compared to the 1987-2000 cohort. CONCLUSIONS: Further initiatives are needed to improve the numbers of Maori and Pacific Island students and students from lower socioeconomic backgrounds. PMID- 23793123 TI - Kids in the cold: outcomes for New Zealand households with children using prepayment metering for electricity. AB - AIMS: Although fuel poverty is becoming increasingly researched, there is very limited information currently available on the experiences of and effects on children living in fuel poverty. This paper examines the consequences of using prepayment metering, a payment method typically used by low-income households, on households with children. METHODS: We present new results from two postal survey datasets, the Electricity Prepayment Meter Users' Survey undertaken in late 2010 and the follow-up survey undertaken in 2011, which explore the outcomes of prepayment metering and living on low-incomes for households with children. RESULTS: Among prepayment consumers, households with children experience greater levels of hardship. Households with children were statistically significantly more likely to cut back on grocery spending, and indicated greater levels of financial difficulty than childless households. Although there were no differences between the groups for most indicators of poor thermal comfort levels, households with children were statistically significantly more likely to report seeing their breath condensing indoors on at least one occasion during the winter. CONCLUSIONS: Policies to address fuel poverty should include protections for prepayment meter consumers, and households with children using this payment method who are especially vulnerable. PMID- 23793124 TI - Medical education--the next 40 years. AB - As the Christchurch campus of the Otago Medical School celebrates its 40th anniversary, this paper ponders where medical education might head in the next 40 years. The patient must remain at the centre of health care and health care education but such education needs to be placed within nurturing environments that value support and innovation. Synthesising evidence, weighing up options, considering the personal factors that a patient brings and the uniqueness of a person's particular illness will be increasingly important roles of a future doctor. This requires interpreting complex data, people skills, flexibility, redeployability and, at times even acting like the "Parish priest". Ultimately however, if we select the right people, create the right expectations, and give them the right learning opportunities, then the curriculum will look after itself. PMID- 23793125 TI - Bullosis diabeticorum: case report and review. AB - Assessment of the foot is an essential component of clinical examination of the patient with diabetes. As the prevalence of diabetes in New Zealand is increasing rapidly, a growing number of clinical encounters will involve individuals with diabetes. We present a case of bullosis diabeticorum, review the important clinical features and propose a management strategy for this rare dermatological complication of longstanding diabetes. PMID- 23793126 TI - Medical image. A murmur and a bleed: the Heyde syndrome. PMID- 23793127 TI - Endoscopic appendicectomy: can it be done? PMID- 23793128 TI - Families burdened by the cost of tongue-tie division. PMID- 23793129 TI - Zero-energy states in rotating trapped Bose-Einstein condensates. AB - We have calculated low-lying quasiparticle excitation spectra of rotating three dimensional Bose-Einstein condensates. We find, as opposed to the prediction of hydrodynamic continuum theories, a minimum in the Tkachenko mode spectrum at intermediate rotation frequencies of the harmonic trap. Such a minimum can harbour a Tkachenko quasiparticle with zero excitation energy. We discuss the experimental signatures of such a zero mode. PMID- 23793130 TI - SACE_0012, a TetR-family transcriptional regulator, affects the morphogenesis of Saccharopolyspora erythraea. AB - Saccharopolyspora erythraea, a mycelium-forming actinomycete, produces a clinically important antibiotic erythromycin. Extensive investigations have provided insights into erythromycin biosynthesis in S. erythraea, but knowledge of its morphogenesis remains limited. By gene inactivation and complementation strategies, the TetR-family transcriptional regulator SACE_0012 was identified to be a negative regulator of mycelium formation of S. erythraea A226. Detected by quantitative real-time PCR, the relative transcription of SACE_7115, the amfC homolog for an aerial mycelium formation protein, was dramatically increased in SACE_0012 mutant, whereas erythromycin biosynthetic gene eryA, a pleiotropic regulatory gene bldD, and the genes SACE_2141, SACE_6464, SACE_6040, that are the homologs to the sporulation regulators WhiA, WhiB, WhiG, were not differentially expressed. SACE_0012 disruption could not restore its defect of aerial development in bldD mutant, and also did not further accelerate the mycelium formation in the mutant of SACE_7040 gene, that was previously identified to be a morphogenesis repressor. Furthermore, the transcriptional level of SACE_0012 had not markedly changed in bldD and SACE_7040 mutant over A226. Taken together, these results suggest that SACE_0012 is a negative regulator of S. erythraea morphogenesis by mainly increasing the transcription of amfC gene, independently of the BldD regulatory system. PMID- 23793131 TI - Culture and motion analysis of diatom Bacillaria paradoxa on a microfluidic platform. AB - We proved the feasibility of using a microfluidic chip to culture diatom Bacillaria paradoxa, and analyzed the gliding characteristics of its self organized colony in detail. The optimal cultivation parameters of B. paradoxa for the designed chip made with polydimethylsiloxane are as follows: the preferable cells injecting rate for keeping the cells alive is 0.2 mL/h, the initial cell density for fast reproduction is 5.5 * 10(4) cells/mL, and the optimal replacement period of culture medium is 4 days. B. paradoxa tends to form a colony during their growth, and the colony can glide with a steady period of 29 +/- 3 s along its axial direction in a constant stream, the amplitude of the colony will not decay (e.g., 24 MUm of two-cell colony at 1.1 mm/s flow rate), and the colony rapidly adjusts its direction of gliding to the direction of water flow. The successful culture of diatoms on a microfluidic platform may be used for biosensing chips and the creation of gasoline-producing diatom solar panels. PMID- 23793132 TI - Global trends in neglected tropical disease control and elimination: impact on child health. AB - The neglected tropical diseases (NTDs) are a group of 17 lesser known chronic infections which predominantly affect poor and disenfranchised communities. There are a number of NTDs that cause significant global morbidity in children, including the three major soil transmitted helminth (STH) infections (ascariasis, trichuriasis and hookworm infection), schistosomiasis and trachoma. These NTDs, together with lymphatic filariasis and onchocerciasis, are currently being targeted for global control and elimination through mass drug administration (MDA) campaigns. They represent the most common NTDs and share significant geographical overlap. Additionally, many individuals are polyparasitised with more than a single NTD. Integrated NTD control and elimination MDA programmes offer safe and efficacious treatments for all seven NTDs. However, the current global level of MDA coverage for the leading childhood NTDs, that is, STH infections, schistosomiasis and trachoma, remains well under 50%. Limiting factors for global coverage include insufficient global financial support, drug donation capacity of pharmaceutical companies and targeting school age children to the exclusion of other age groups in need of treatment, such as preschool age children. There is also a need for development of novel prevention and treatment modalities, such as next-generation small molecule drugs and vaccines. Efforts are underway to harness the momentum of a 2012 London Declaration on NTDs and a 2013 World Health Assembly (WHA) resolution as a means to control or in some cases eliminate by 2020 these NTDs that affect children worldwide. PMID- 23793134 TI - C,C'-bis(benzodiazaborolyl)dicarba-closo-dodecaboranes: synthesis, structures, photophysics and electrochemistry. AB - Six new C,C'-bis(benzodiazaborolyl)dicarba-closo-dodecaboranes, 1,A-R2-1,A C2B10H10, where R represents the group 2-(1,3-Et2-1,3,2-N2BC6H4) or 2-(1,3-Ph2 1,3,2-N2BC6H4) and A is 2, 7 or 12, were synthesized from o-, m-, and p dicarbadodecaboranes (carboranes) by lithiation and subsequent treatment with the respective 2-bromo-1,3,2-benzodiazaboroles. UV-visible and fluorescence spectra of all carboranes display low energy charge transfer emissions. While such emissions with Stokes shifts between 17,330 and 21,290 cm(-1) are typical for C,C'-bis(aryl)-ortho-carboranes, the observed low-energy emissions with Stokes shifts between 8320 and 15,170 cm(-1) for the meta- and para-isomers are unusual as high-energy emissions are typical for meta- and para-dicarbadodecaboranes. Fluorescence quantum yields (phiF) for the novel 1,7- and 1,12 bis(benzodiazaborolyl)-carboranes depend on the substituents at the nitrogen atoms of the heterocycle. Thus, the para-carborane with N-ethyl substituents 1,12 (1',3'-Et2-1',3',2'-N2BC6H4)2-1,12-C2B10H10 has a phiF value of 41% in cyclohexane solution and only of 9% in the solid state, whereas the analogous 1,12-(1',3'-Ph2-1',3',2'-N2BC6H4)2-1,12-C2B10H10 shows quantum yields of 3% in cyclohexane solution and 72% in the solid state. X-ray crystallographic, computational and cyclic voltammetry studies for these carboranes are also presented. PMID- 23793133 TI - Effect of green tea on postprandial antioxidant capacity, serum lipids, C reactive protein and glucose levels in patients with coronary artery disease. AB - PURPOSE: Cardiovascular risk factors have been identified in the postprandial state, particularly in patients with coronary artery disease (CAD). Tea consumption has been linked to cardiovascular risk reduction, but the beneficial effect of tea has not been investigated under postprandial conditions. The objective was to examine the effect of green tea on postprandial levels of plasma total antioxidant capacity (TAC), serum lipids, C-reactive protein (CRP) and glucose in patients with CAD. METHODS: In a randomized controlled, parallel design with 2 arms, 43 patients with CAD were assigned to consume breakfast consisting of bread, butter and 330 ml water or tea (4.5 g green tea/330 ml, providing approximately 400 mg catechins). Blood samples were drawn immediately before and 1.5, 3 and 5 h after breakfast. TAC was measured in plasma with the ferric reducing antioxidant power of plasma and oxygen radical absorbance capacity assays. Total cholesterol, high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), triglycerides, glucose, CRP, uric acid and pancreatic lipase levels were measured in serum. RESULTS: Tested biomarkers did not differ between tea and water group at baseline, 1.5, 3 and 5 h (P > 0.05) postprandially. However, TAC increased 1.5 and 3 h after consumption of breakfast with tea (P < 0.005), but no change was observed after consumption of breakfast with water. Serum triglycerides levels significantly increased 3 h after breakfast with water (P = 0.031), but not after breakfast with tea. Serum uric acid decreased 1.5 h after breakfast with tea (P = 0.038). Pancreatic lipase, CRP, total cholesterol, HDL-C, LDL-C and glucose levels remained unchanged after breakfast with tea at any time point (P > 0.05). CONCLUSIONS: Tea consumption did not affect selected biomarkers at any postprandial time point in patients with CAD. PMID- 23793135 TI - Nursing leadership in addressing the social determinants of health. AB - Social determinants of health have a profound impact on health status and the prevalence of health disparities in the United States. Significant improvements in national health indices are not possible without addressing social determinants of health. Drawing on their historical legacy as patient advocates, patient care expertise, and community focused education, nurses are ideally positioned to lead the nation in strategies to promote health equity. Nurses can embrace this new leadership role through the use of interdisciplinary collaboration, advocacy, political involvement, and community partnerships. PMID- 23793136 TI - An empirical model of erythemal ultraviolet radiation in the city of Valencia, Spain. AB - This paper presents an improved empirical model that predicts ultraviolet erythemal radiation (UVER) and considers all aspects of atmospheric conditions in Valencia, Spain. The analyzed model is a potential function whose dependent variable is UVER radiation and independent variables are the clearness index and slant ozone column. A potential regression function with all the information contributed a small coefficient of determination and one chose to use a regression potential-exponential mathematical form which improved the coefficient of similar determination. A study was carried out on the influence of season on the regression parameters. This was found to be considerable due to the clearness index. The convergence between the values calculated by the model and the experimental values was analyzed using the mean bias error (MBE) and mean absolute bias error (MABE) statistical parameters. The clearness index and ozone column intervals were analyzed and found to give an improved prediction of the UVER clearness index using regression analysis. Also, a sensitivity analysis was performed on the regression coefficients and parameters. It is important to study the effects of UVER radiation predicted by the model on human health or on agriculture crop growth and yield. PMID- 23793137 TI - Visualization and analysis of mRNA molecules using fluorescence in situ hybridization in Saccharomyces cerevisiae. AB - The Fluorescence in situ Hybridization (FISH) method allows one to detect nucleic acids in the native cellular environment. Here we provide a protocol for using FISH to quantify the number of mRNAs in single yeast cells. Cells can be grown in any condition of interest and then fixed and made permeable. Subsequently, multiple single-stranded deoxyoligonucleotides conjugated to fluorescent dyes are used to label and visualize mRNAs. Diffraction-limited fluorescence from single mRNA molecules is quantified using a spot-detection algorithm to identify and count the number of mRNAs per cell. While the more standard quantification methods of northern blots, RT-PCR and gene expression microarrays provide information on average mRNAs in the bulk population, FISH facilitates both the counting and localization of these mRNAs in single cells at single-molecule resolution. PMID- 23793138 TI - Lack of value of midregional pro-adrenomedullin and C-terminal pro-endothelin-1 for prediction of severe bacterial infections in infants with fever without a source. AB - The study was performed to assess the usefulness of two new biomarkers, midregional pro-adrenomedullin (MR-pro-ADM) and C-pro-endothelin-1 (CT-pro-ET-1), in predicting bacterial infection (BI) and especially invasive bacterial infection (IBI) in well-appearing infants with fever without source (FWS). For this purpose, a multicenter prospective study was conducted between February 2008 and March 2009 including well-appearing infants less than 36 months of age with FWS. MR-pro-ADM, CT-pro-ET-1, procalcitonin (PCT), CRP, and WBC were measured and compared. Among the 1,035 infants included, a bacterial infection was diagnosed in 75 patients (7.2 %), and 16 (1.54 %) had an invasive bacterial infection (bacterial meningitis, 8; occult bacteremia, 6; and sepsis, 1). MR-pro-ADM and CT pro-ET-1 levels were less reliable for diagnosis than the other biomarkers. The area under receiver operating characteristic curve for infants with BI and IBI was 0.59 (95 % confidence interval (CI) 0.52-0.67) and 0.63 (95 % CI 0.46-0.80) for MR-pro-ADM and 0.58 (95 % CI 0.51-0.66) and 0.62 (95 % CI 0.47-0.67) for CT pro-ET-1, respectively. Multivariate analysis showed that PCT >= 0.5 ng/mL, CRP >= 40 mg/L, and CT-pro-ET-1 >= 105 pmol/mL were independent risk factors for having a BI (odds ratio (OR) 6.12, 3.61, and 2.84, respectively). PCT was the only independent risk factor for having an IBI (OR 17.53 if PCT >= 0.5 ng/mL). CONCLUSION: Although baseline MR-pro-ADM and CT-pro-ET-1 levels are significantly elevated in well-appearing febrile infants with a bacterial infection, their overall performance as diagnostic markers is very poor. PMID- 23793139 TI - Low maternal education is associated with increased growth velocity in the first year of life and in early childhood: the ABCD study. AB - The objective of this study is first to examine the relation of maternal education and growth velocity during the first year of life and early childhood (1-5 years). The second objective is to determine the potential explanatory role of standardized birth weight, maternal smoking during pregnancy, maternal prepregnancy body mass index (BMI), and infant feeding practice in this relation. We used longitudinal growth data of 1,684 participants with Dutch ethnicity participating in a population-based cohort study (Amsterdam Born Children and their Development study). Growth velocity of weight and of weight-for-length were calculated by subtracting the weight and weight-for-length standard deviation scores (SDS), respectively of two time periods. In the first year of life, children with low-educated mothers had an increase in SDS of 0.26 (95 % confidence interval (CI) 0.08-0.45) for weight compared to children with high educated mothers. In early childhood, children with low-educated mothers had a 0.27 SDS (95 % CI 0.11-0.42) increase for weight-for-length, compared to children with high-educated mothers. Using path analysis, these inequalities could partly be explained by maternal smoking, duration of breastfeeding, maternal age, and maternal BMI. CONCLUSION: Children with low-educated mothers had an increased weight gain during the first year of life and an increased weight-for-length gain in early childhood compared to children with high-educated mothers. Although underlying mechanisms were not completely clarified, an optimal duration of breastfeeding, cessation of maternal smoking, and reduction of maternal BMI seem to reduce these educational inequalities in early growth and possible adverse consequences of accelerated growth. PMID- 23793140 TI - Factors influencing breastfeeding duration: a survey in a Turkish population. AB - Breastfeeding provides perfect nutrition for infants and is a source of many health benefits for both mother and baby. To obtain the maximum beneficial effects of breast milk, it is necessary to prolong the breastfeeding duration. In this study, we investigated the factors influencing the duration of breastfeeding. We conducted a 32-question survey of mothers with children aged 2 4 years, who presented to our medical school's pediatric outpatient clinics. The questionnaire solicited information on demographics and breastfeeding attitudes. We found correlations between total duration of breastfeeding and the time the mother and baby spent together (sharing a room to sleep at night) and the father's engagement in breastfeeding. Breastfeeding duration inversely correlated with maternal employment. Total duration of breastfeeding did not correlate with breastfeeding education by health personnel, the mother's education level, the gender of the child, regular prenatal care visits, the use of a pacifier, the interval between birth and the onset of breastfeeding, gestational age, method of delivery, or the birth weight of the infant. CONCLUSION: Our findings suggest several strategies to increase the duration of breastfeeding, including educating fathers along with mothers, supporting a shared bedroom until the child is 2 years of age, and promoting measures that allow mothers to be with their children during working hours. PMID- 23793141 TI - Confirmation of genetic homogeneity of syndactyly type IV and triphalangeal thumb polysyndactyly syndrome in a Chinese family and review of the literature. AB - Syndactyly type IV (SD4) is inherited in an autosomal dominant fashion and characterized by complete cutaneous syndactyly of all fingers accompanied with polydactyly. Triphalangeal thumb-polysyndactyly syndrome (TPTPS) consists of a triphalangeal thumb, polydactyly, and syndactyly and is transmitted in an autosomal dominant manner with variable expression. Genomic duplications of the long-range limb-specific cis-regulator (ZRS) cause SD4 and TPTPS. Here, we report two individuals from a Chinese family with syndactyly. One individual had overlapping clinical symptoms of TPTPS and SD4, while the other had a typical SD4 with postaxial polydactyly of the toe. Results of quantitative PCR suggested that the duplication of ZRS involved all affected individuals, and array comparative genomic hybridization detected its size as 115.3 kb. CONCLUSION: This work confirms the genetic homogeneity of SD4 and TPTPS. Our result expands the spectrum of ZRS duplications. TPTPS and SD4 should be considered as a continuum of phenotypes. PMID- 23793142 TI - Usefulness of the PERFORM questionnaire to measure fatigue in cancer patients with anemia: a prospective, observational study. AB - BACKGROUND: The PERFORM Questionnaire is a 12-item scale developed for assessing fatigue in cancer patients in the clinical practice. It has advantages over other tools in that it is short and includes beliefs and attitudes of patients about fatigue. It was psychometrically validated in cancer patients with and without anemia. PURPOSE: We evaluated the usefulness of the PERFORM scale to measure fatigue in a large study focusing exclusively on anemic patients. METHODS: This was an observational, multicenter, prospective, 3-month study in cancer patients with hemoglobin (Hb)<=11 g/dl. Fatigue was assessed using the PERFORM questionnaire. The overall score ranges from 12 (no fatigue) to 60 (maximum fatigue). RESULTS: We included 667 patients: 54.1 % women, mean age 60 (standard deviation, 12) years. A highly significant, but mild correlation was observed between low baseline Hb and high patient perception of fatigue (r with PERFORM score=-0.215, p < 0.0001). Of the patients, 65.8 % improved Hb level during follow-up (increase of >=1 g/dL and/or achieving >11 g/dL), which translated into a significant improvement in the PERFORM score [mean (95 % confidence interval (CI)] change, -1.2 (-0.04 to -2.4), whereas more fatigue was observed in patients without improvement in Hb [change (95 % CI) in PERFORM, +3.3 (1.5 to 5)]. In a multivariate linear regression analysis, the independent factors associated to fatigue at 3 months were a low Hb level, a low Karnofsky index, active chemotherapy, cancer treatment with palliative intention, and transfusion need in the last 3 months. CONCLUSIONS: Minimal increases or decreases in Hb of >=1 g/dL were associated with meaningful changes in patient-perceived fatigue as measured with the PERFORM questionnaire. In addition to anemia severity, other factors such as active chemotherapy and advanced disease contribute to perception of fatigue by cancer patients. PMID- 23793143 TI - Bis(o-methylserotonin)-containing iridium(III) and ruthenium(II) complexes as new cellular imaging dyes: synthesis, applications, and photophysical and computational studies. AB - We report the synthesis, characterization, and scope of a new versatile emissive molecular probe functionalized with a 1,10-phenanthroline moiety containing methylserotonin groups as binding sites for metal ion recognition. The synthesis, characterization, and evaluation of the in vitro imaging capability of the iridium(III) and ruthenium(II) complexes [Ir(ppy)2(N-N)](+) and [Ru(bpy)2(N N)](2+), in which ppy is 2-phenylpyridine, bpy is 2,2'-bipyridine, and N-N is a 1,10-phenanthroline ligand functionalized with two methylserotonin groups to serve as binding sites for metal ion recognition, is reported. The uptake of these compounds by living freshwater fish (Carassius auratus) was studied by fluorescence microscopy, and the cytotoxicity of ligand N-N and [Ru(bpy)2(N N)](2+) in this species was also investigated. PMID- 23793144 TI - Data collection and processing. Introduction. PMID- 23793145 TI - Autoindexing diffraction images with iMosflm. AB - An overview of autoindexing diffraction images based on one-dimensional fast Fourier transforms is presented. The implementation of the algorithm in the Mosflm/iMosflm program suite is described with a discussion of practical issues that may arise and ways of assessing the success or failure of the procedure. Recent developments allow indexing of images that show multiple lattices, and several examples demonstrate the success of this approach in real cases. PMID- 23793146 TI - How good are my data and what is the resolution? AB - Following integration of the observed diffraction spots, the process of 'data reduction' initially aims to determine the point-group symmetry of the data and the likely space group. This can be performed with the program POINTLESS. The scaling program then puts all the measurements on a common scale, averages measurements of symmetry-related reflections (using the symmetry determined previously) and produces many statistics that provide the first important measures of data quality. A new scaling program, AIMLESS, implements scaling models similar to those in SCALA but adds some additional analyses. From the analyses, a number of decisions can be made about the quality of the data and whether some measurements should be discarded. The effective 'resolution' of a data set is a difficult and possibly contentious question (particularly with referees of papers) and this is discussed in the light of tests comparing the data-processing statistics with trials of refinement against observed and simulated data, and automated model-building and comparison of maps calculated with different resolution limits. These trials show that adding weak high resolution data beyond the commonly used limits may make some improvement and does no harm. PMID- 23793147 TI - Better models by discarding data? AB - In macromolecular X-ray crystallography, typical data sets have substantial multiplicity. This can be used to calculate the consistency of repeated measurements and thereby assess data quality. Recently, the properties of a correlation coefficient, CC1/2, that can be used for this purpose were characterized and it was shown that CC1/2 has superior properties compared with 'merging' R values. A derived quantity, CC*, links data and model quality. Using experimental data sets, the behaviour of CC1/2 and the more conventional indicators were compared in two situations of practical importance: merging data sets from different crystals and selectively rejecting weak observations or (merged) unique reflections from a data set. In these situations controlled 'paired-refinement' tests show that even though discarding the weaker data leads to improvements in the merging R values, the refined models based on these data are of lower quality. These results show the folly of such data-filtering practices aimed at improving the merging R values. Interestingly, in all of these tests CC1/2 is the one data-quality indicator for which the behaviour accurately reflects which of the alternative data-handling strategies results in the best quality refined model. Its properties in the presence of systematic error are documented and discussed. PMID- 23793148 TI - A Medipix quantum area detector allows rotation electron diffraction data collection from submicrometre three-dimensional protein crystals. AB - When protein crystals are submicrometre-sized, X-ray radiation damage precludes conventional diffraction data collection. For crystals that are of the order of 100 nm in size, at best only single-shot diffraction patterns can be collected and rotation data collection has not been possible, irrespective of the diffraction technique used. Here, it is shown that at a very low electron dose (at most 0.1 e(-) A(-2)), a Medipix2 quantum area detector is sufficiently sensitive to allow the collection of a 30-frame rotation series of 200 keV electron-diffraction data from a single ~100 nm thick protein crystal. A highly parallel 200 keV electron beam (lambda = 0.025 A) allowed observation of the curvature of the Ewald sphere at low resolution, indicating a combined mosaic spread/beam divergence of at most 0.4 degrees . This result shows that volumes of crystal with low mosaicity can be pinpointed in electron diffraction. It is also shown that strategies and data-analysis software (MOSFLM and SCALA) from X-ray protein crystallography can be used in principle for analysing electron diffraction data from three-dimensional nanocrystals of proteins. PMID- 23793149 TI - Crystallographic data processing for free-electron laser sources. AB - A processing pipeline for diffraction data acquired using the 'serial crystallography' methodology with a free-electron laser source is described with reference to the crystallographic analysis suite CrystFEL and the pre-processing program Cheetah. A detailed analysis of the nature and impact of indexing ambiguities is presented. Simulations of the Monte Carlo integration scheme, which accounts for the partially recorded nature of the diffraction intensities, are presented and show that the integration of partial reflections could be made to converge more quickly if the bandwidth of the X-rays were to be increased by a small amount or if a slight convergence angle were introduced into the incident beam. PMID- 23793150 TI - The use of a mini-kappa goniometer head in macromolecular crystallography diffraction experiments. AB - Most macromolecular crystallography (MX) diffraction experiments at synchrotrons use a single-axis goniometer. This markedly contrasts with small-molecule crystallography, in which the majority of the diffraction data are collected using multi-axis goniometers. A novel miniaturized kappa-goniometer head, the MK3, has been developed to allow macromolecular crystals to be aligned. It is available on the majority of the structural biology beamlines at the ESRF, as well as elsewhere. In addition, the Strategy for the Alignment of Crystals (STAC) software package has been developed to facilitate the use of the MK3 and other similar devices. Use of the MK3 and STAC is streamlined by their incorporation into online analysis tools such as EDNA. The current use of STAC and MK3 on the MX beamlines at the ESRF is discussed. It is shown that the alignment of macromolecular crystals can result in improved diffraction data quality compared with data obtained from randomly aligned crystals. PMID- 23793151 TI - Visualization of membrane protein crystals in lipid cubic phase using X-ray imaging. AB - The focus in macromolecular crystallography is moving towards even more challenging target proteins that often crystallize on much smaller scales and are frequently mounted in opaque or highly refractive materials. It is therefore essential that X-ray beamline technology develops in parallel to accommodate such difficult samples. In this paper, the use of X-ray microradiography and microtomography is reported as a tool for crystal visualization, location and characterization on the macromolecular crystallography beamlines at the Diamond Light Source. The technique is particularly useful for microcrystals and for crystals mounted in opaque materials such as lipid cubic phase. X-ray diffraction raster scanning can be used in combination with radiography to allow informed decision-making at the beamline prior to diffraction data collection. It is demonstrated that the X-ray dose required for a full tomography measurement is similar to that for a diffraction grid-scan, but for sample location and shape estimation alone just a few radiographic projections may be required. PMID- 23793152 TI - Decision making in xia2. AB - xia2 is an expert system for the automated reduction of macromolecular crystallography (MX) data employing well trusted existing software. The system can process a full MX data set consisting of one or more sequences of images at one or more wavelengths from images to structure-factor amplitudes with no user input. To achieve this many decisions are made, the rationale for which is described here. In addition, it is critical to support the testing of hypotheses and to allow feedback of results from later stages in the analysis to earlier points where decisions were made: the flexible framework employed by xia2 to support this feedback is summarized here. While the decision-making protocols described here were developed for xia2, they are equally applicable to interactive data reduction. PMID- 23793153 TI - New Python-based methods for data processing. AB - Current pixel-array detectors produce diffraction images at extreme data rates (of up to 2 TB h(-1)) that make severe demands on computational resources. New multiprocessing frameworks are required to achieve rapid data analysis, as it is important to be able to inspect the data quickly in order to guide the experiment in real time. By utilizing readily available web-serving tools that interact with the Python scripting language, it was possible to implement a high-throughput Bragg-spot analyzer (cctbx.spotfinder) that is presently in use at numerous synchrotron-radiation beamlines. Similarly, Python interoperability enabled the production of a new data-reduction package (cctbx.xfel) for serial femtosecond crystallography experiments at the Linac Coherent Light Source (LCLS). Future data-reduction efforts will need to focus on specialized problems such as the treatment of diffraction spots on interleaved lattices arising from multi-crystal specimens. In these challenging cases, accurate modeling of close-lying Bragg spots could benefit from the high-performance computing capabilities of graphics processing units. PMID- 23793154 TI - Collecting data in the home laboratory: evolution of X-ray sources, detectors and working practices. AB - While the majority of macromolecular X-ray data are currently collected using highly efficient beamlines at an ever-increasing number of synchrotrons, there is still a need for high-performance reliable systems for in-house experiments. In addition to crystal screening and optimization of data-collection parameters before a synchrotron trip, the home system allows the collection of data as soon as the crystals are produced to obtain the solution of novel structures, especially by the molecular-replacement method, and is invaluable in achieving the quick turnover that is often required for ligand-binding studies in the pharmaceutical industry. There has been a continuous evolution of X-ray sources, detectors and software developed for in-house use in recent years and a diverse range of tools for structural biology laboratories are available. An overview of the main directions of these developments and examples of specific solutions available to the macromolecular crystallography community are presented in this paper, showing that data collection 'at home' is still an attractive proposition complementing the use of synchrotron beamlines. PMID- 23793155 TI - How the ESRF helps industry and how they help the ESRF. AB - The ESRF has worked with, and provided services for, the pharmaceutical industry since the construction of its first protein crystallography beamline in the mid 1990s. In more recent times, industrial clients have benefited from a portfolio of beamlines which offer a wide range of functionality and beam characteristics, including tunability, microfocus and micro-aperture. Included in this portfolio is a small-angle X-ray scattering beamline dedicated to the study of biological molecules in solution. The high demands on throughput and efficiency made by the ESRF's industrial clients have been a major driving force in the evolution of the ESRF's macromolecular crystallography resources, which now include remote access, the automation of crystal screening and data collection, and a beamline database allowing sample tracking, experiment reporting and real-time at-a-distance monitoring of experiments. This paper describes the key features of the functionality put in place on the ESRF structural biology beamlines and outlines the major advantages of the interaction of the ESRF with the pharmaceutical industry. PMID- 23793156 TI - Microcrystal manipulation with laser tweezers. AB - X-ray crystallography is the method of choice to deduce atomic resolution structural information from macromolecules. In recent years, significant investments in structural genomics initiatives have been undertaken to automate all steps in X-ray crystallography from protein expression to structure solution. Robotic systems are widely used to prepare crystallization screens and change samples on synchrotron beamlines for macromolecular crystallography. The only remaining manual handling step is the transfer of the crystal from the mother liquor onto the crystal holder. Manual mounting is relatively straightforward for crystals with dimensions of >25 um; however, this step is nontrivial for smaller crystals. The mounting of microcrystals is becoming increasingly important as advances in microfocus synchrotron beamlines now allow data collection from crystals with dimensions of only a few micrometres. To make optimal usage of these beamlines, new approaches have to be taken to facilitate and automate this last manual handling step. Optical tweezers, which are routinely used for the manipulation of micrometre-sized objects, have successfully been applied to sort and mount macromolecular crystals on newly designed crystal holders. Diffraction data from CPV type 1 polyhedrin microcrystals mounted with laser tweezers are presented. PMID- 23793157 TI - Squeezing the most from every crystal: the fine details of data collection. AB - Modern synchrotron beamlines offer instrumentation of unprecedented quality, which in turn encourages increasingly marginal experiments, and for these, as much as ever, the ultimate success of data collection depends on the experience, but especially the care, of the experimenter. A representative set of difficult cases has been encountered at the Structural Genomics Consortium, a worldwide structural genomics initiative of which the Oxford site currently deposits three novel human structures per month. Achieving this target relies heavily on frequent visits to the Diamond Light Source, and the variety of crystal systems still demand customized data collection, diligent checks and careful planning of each experiment. Here, an overview is presented of the techniques and procedures that have been refined over the years and that are considered synchrotron best practice. PMID- 23793158 TI - Robust structural analysis of native biological macromolecules from multi-crystal anomalous diffraction data. AB - Structure determinations for biological macromolecules that have no known structural antecedents typically involve the incorporation of heavier atoms than those found natively in biological molecules. Currently, selenomethionyl proteins analyzed using single- or multi-wavelength anomalous diffraction (SAD or MAD) data predominate for such de novo analyses. Naturally occurring metal ions such as zinc or iron often suffice in MAD or SAD experiments, and sulfur SAD has been an option since it was first demonstrated using crambin 30 years ago; however, SAD analyses of structures containing only light atoms (Zmax <= 20) have not been common. Here, robust procedures for enhancing the signal to noise in measurements of anomalous diffraction by combining data collected from several crystals at a lower than usual X-ray energy are described. This multi-crystal native SAD method was applied in five structure determinations, using between five and 13 crystals to determine substructures of between four and 52 anomalous scatterers (Z <= 20) and then the full structures ranging from 127 to 1200 ordered residues per asymmetric unit at resolutions from 2.3 to 2.8 A. Tests were devised to assure that all of the crystals used were statistically equivalent. Elemental identities for Ca, Cl, S, P and Mg were proven by f'' scattering-factor refinements. The procedures are robust, indicating that truly routine structure determination of typical native macromolecules is realised. Synchrotron beamlines that are optimized for low-energy X-ray diffraction measurements will facilitate such direct structural analysis. PMID- 23793159 TI - Hybrid nanocolloids with programmed three-dimensional shape and material composition. AB - Tuning the optical, electromagnetic and mechanical properties of a material requires simultaneous control over its composition and shape. This is particularly challenging for complex structures at the nanoscale because surface energy minimization generally causes small structures to be highly symmetric. Here we combine low-temperature shadow deposition with nanoscale patterning to realize nanocolloids with anisotropic three-dimensional shapes, feature sizes down to 20 nm and a wide choice of materials. We demonstrate the versatility of the fabrication scheme by growing three-dimensional hybrid nanostructures that contain several functional materials with the lowest possible symmetry, and by fabricating hundreds of billions of plasmonic nanohelices, which we use as chiral metafluids with record circular dichroism and tunable chiroptical properties. PMID- 23793160 TI - Propulsion and navigation within the advancing monolayer sheet. AB - As a wound heals, or a body plan forms, or a tumour invades, observed cellular motions within the advancing cell swarm are thought to stem from yet to be observed physical stresses that act in some direct and causal mechanical fashion. Here we show that such a relationship between motion and stress is far from direct. Using monolayer stress microscopy, we probed migration velocities, cellular tractions and intercellular stresses in an epithelial cell sheet advancing towards an island on which cells cannot adhere. We found that cells located near the island exert tractions that pull systematically towards this island regardless of whether the cells approach the island, migrate tangentially along its edge, or paradoxically, recede from it. This unanticipated cell patterning motif, which we call kenotaxis, represents the robust and systematic mechanical drive of the cellular collective to fill unfilled space. PMID- 23793161 TI - Mobility engineering and a metal-insulator transition in monolayer MoS2. AB - Two-dimensional (2D) materials are a new class of materials with interesting physical properties and applications ranging from nanoelectronics to sensing and photonics. In addition to graphene, the most studied 2D material, monolayers of other layered materials such as semiconducting dichalcogenides MoS2 or WSe2 are gaining in importance as promising channel materials for field-effect transistors (FETs). The presence of a direct bandgap in monolayer MoS2 due to quantum mechanical confinement allows room-temperature FETs with an on/off ratio exceeding 10(8). The presence of high- kappa dielectrics in these devices enhanced their mobility, but the mechanisms are not well understood. Here, we report on electrical transport measurements on MoS2 FETs in different dielectric configurations. The dependence of mobility on temperature shows clear evidence of the strong suppression of charged-impurity scattering in dual-gate devices with a top-gate dielectric. At the same time, phonon scattering shows a weaker than expected temperature dependence. High levels of doping achieved in dual-gate devices also allow the observation of a metal-insulator transition in monolayer MoS2 due to strong electron-electron interactions. Our work opens up the way to further improvements in 2D semiconductor performance and introduces MoS2 as an interesting system for studying correlation effects in mesoscopic systems. PMID- 23793162 TI - Direct 2-acetoxylation of quinoline N-oxides via copper catalyzed C-H bond activation. AB - An efficient and direct 2-acetoxylation of quinoline N-oxides via copper(I) catalyzed C-H bond activation has been developed. This transformation was achieved using TBHP as an oxidant in the cross-dehydrogenative coupling (CDC) reaction of quinoline N-oxides with aldehydes, and provided a practical pathway to 2-acyloxyl quinolines. PMID- 23793163 TI - Functionalized 129Xe as a potential biosensor for membrane fluidity. AB - Using spin hyperpolarized xenon ((129)Xe) we investigate the impact of the local molecular environment on reversible host-guest interactions. We label Xe guest atoms that are temporarily bound to cryptophane-A hosts using the Hyper-CEST technique. By varying the length of the saturation pulse and utilizing an inverse Laplace transform we can determine depolarization times for the noble gas in different local environments, in this case biomembranes possessing different fluidity. We extend this technique to magnetic resonance imaging, mapping the spatial distribution of the different biomembranes. Such decays measured in biomembranes of 200 MUM 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) were characterized by mono exponential decays with time constants of tauPOPC = 3.00(-0.61)(+0.77) s and tauDPPC(-4.16)(+5.19) = 22.15 s. Analyzing both environments simultaneously yielded a bi-exponential decay. This approach may give further insights into saturation transfer dynamics of reversibly bound Xe with applications extending into biomedical diagnostics. PMID- 23793164 TI - Magnetic structure of the metallic triangular antiferromagnet Ag2NiO2. AB - The magnetic structure of the metallic antiferromagnet Ag2NiO2 with the Neel temperature TN = 56 K has been investigated by means of a neutron diffraction technique using a powder sample in the temperature range between 5 and 65 K. The antiferromagnetic (AF) diffraction peaks are clearly observed below TN and can be indexed with the propagation vector [Formula: see text]. Based on the results of both a representational analysis and a Rietveld refinement of the magnetic peaks, the AF spin structure is determined as an A-type AF structure with ml = m0cos(2pik ?l), where ml is the moment at the lth Ni(3+) site and m0 = (0.31,0,0.65) MUB at 5 K. PMID- 23793165 TI - Patterns of use of oral adjuvant endocrine therapy in Australian breast cancer survivors 5 years from diagnosis. AB - OBJECTIVE: Oral adjuvant endocrine therapy (OAET) substantially improves the survival of women with hormone receptor-positive (HR) breast cancer. However, we reported previously that at 3 to 4 years after diagnosis, 18% of affected women are not using OAET primarily because of estrogen deficiency symptoms. The aim of this study was to determine the use of OAET in women with HR breast cancer 5 to 6 years from diagnosis. METHODS: Analysis was carried out using data from the Bupa Health Foundation's Health and Wellbeing After Breast Cancer Study, a cohort study of 1,683 women with breast cancer who were recruited in Victoria, Australia between 2004 and 2006. All women completed an enrollment questionnaire within 12 months of diagnosis and an annual follow-up questionnaire (FQ) for 5 years. The fifth FQ was completed 5.7 years from the time of diagnosis. Use of OAET was self reported in response to a series of questions. RESULTS: A minimal exposure to OAET of at least 5 years (OAET in all six FQs) was reported by 19.7% of the women (n = 212), and another 46.7% (n = 503) received a minimal exposure of at least 4 years (OAET in five questionnaires). In total, 82.1% (n = 883) of the women would have received at least 3 years of treatment (OAET in at least four questionnaires). Only 7.8% (n = 84) reported never using OAET. CONCLUSIONS: Most women with HR breast cancer who survive at least 5 years have persisted with OAET despite the adverse effects of estrogen depletion. PMID- 23793166 TI - Spanish Menopause Society position statement: use of tibolone in postmenopausal women. AB - Tibolone is a drug with complex tissue-specific action that exhibits a combination of estrogenic, progestogenic, and slight androgenic activity. Its variable profile explains its clinical effects, depending on the target tissue where it is metabolized, its metabolites' affinity for and potency in hormone receptors, and probable enzymatic activity modulation.In recent reviews and clinical trials, the effectiveness of tibolone in alleviating different hot flush menopause symptoms, mainly in mood and sexuality disorders, has been noted. In Spain, tibolone is the most prescribed hormonal treatment, and one of the most common complaints among postmenopausal women is change in sexual drive. For such reason, a panel of experts from the Spanish Menopause Society met to develop usage recommendations based on the best evidence available. PMID- 23793167 TI - A randomized, double-blind, controlled trial of a Chinese herbal formula (Er-Xian decoction) for menopausal symptoms in Hong Kong perimenopausal women. AB - OBJECTIVE: The aim of this study is to investigate the effectiveness and safety of a Chinese herbal formula, Er-Xian decoction (EXD), in the treatment of menopausal symptoms among Hong Kong perimenopausal women. METHODS: A randomized, double-blind, controlled trial was conducted for 12 weeks among 108 Hong Kong perimenopausal women who reported Menopause Rating Scale (MRS) total scores of 28 or higher. Posttreatment follow-up was performed 3 months after the intervention. The primary outcome measure was the frequency and severity of hot flushes. The secondary outcome measures included the MRS, the Menopause-Specific Quality of Life questionnaire, and serum hormone levels. RESULTS: Among 108 participants, 101 participants finished the study. EXD significantly reduced the mean (SD) frequency of hot flushes from 5.8 (5.0) to 2.2 (3.0) in the treatment group and from 5.0 (3.8) to 2.4 (2.5) in the placebo group (P = 0.04). The mean (SD) hot flush score was also reduced from 19.6 (6.6) to 4.9 (7.8) in the treatment group and from 16.6 (5.4) to 7.0 (6.4) in the placebo group (P = 0.02). The superiority of EXD to placebo was also observed with greater improvement in the total scores for the MRS (P = 0.03) and the Menopause-Specific Quality of Life questionnaire (P < 0.01). There were no differences in serum hormone levels between the EXD group and the placebo group. There were no serious adverse events, and the safety indices of whole blood counts, renal function, and liver function were within the normal range before and after treatment. CONCLUSIONS: The Chinese herbal formula EXD is superior to placebo in reducing the frequency and severity of hot flushes and in improving menopausal symptoms in Hong Kong perimenopausal women. It is well tolerated, with no serious adverse events noted during the study period. PMID- 23793168 TI - Endometrial profile of bazedoxifene acetate alone and in combination with conjugated equine estrogens in a primate model. AB - OBJECTIVE: Concerns of breast cancer risk in postmenopausal women taking combined estrogen + progestin therapy have generated interest in the use of selective estrogen receptor modulators (SERMs) as potential progestin alternatives. Endometrial proliferation and cancer risk are major concerns, however, for estrogens and certain types of SERMs when given alone. The primary aim of this study was to evaluate the endometrial profile of bazedoxifene acetate (BZA), a third-generation SERM, alone and in combination with conjugated equine estrogens (CEE) in a postmenopausal primate model. METHODS: Ninety-eight ovariectomized cynomolgus monkeys (Macaca fascicularis) were randomized to receive no hormone treatment (controls), BZA 20 mg, CEE 0.45 mg, or the combination of BZA 20 mg + CEE 0.45 mg once daily for 20 months in a parallel-arm study design. The primary outcome measure was endometrial epithelial proliferation. RESULTS: BZA + CEE and BZA treatment resulted in significantly less endometrial epithelial area and Ki67 expression compared with CEE (P < 0.001 for all). The prevalence of endometrial hyperplasia and other estrogen-induced morphologic changes in the BZA + CEE and BZA groups was not significantly different from controls. The addition of BZA to CEE completely inhibited the expression of estrogen receptor-alpha-regulated genes (TFF1 and PGR), whereas BZA alone had no effect. BZA + CEE and BZA treatment also resulted in lower estrogen receptor-alpha protein expression in the endometrium compared with the control and CEE groups (P < 0.05 for all). CONCLUSIONS: BZA given at a clinically relevant dose inhibits estrogen effects on the endometrium and lacks uterotropic effects when given alone. PMID- 23793169 TI - Oral salmon calcitonin protects against impaired fasting glycemia, glucose intolerance, and obesity induced by high-fat diet and ovariectomy in rats. AB - OBJECTIVE: Oral salmon calcitonin (sCT) has demonstrated clinical efficacy in treating osteoporosis in postmenopausal women. The postmenopausal state is also associated with obesity-related insulin resistance (IR) and type 2 diabetes. The aim of this study was to investigate the preventive effects of oral sCT on energy and glucose homeostasis in high-fat diet (HFD)- and ovariectomy (OVX)-induced obese rats. Furthermore, the weight-regulatory and gluco-regulatory effects of short-term oral sCT intervention on HFD-induced obese rats were explored. METHODS: For prevention, female rats exposed to HFD with or without OVX were treated with oral sCT for 5 weeks. As intervention, HFD-induced obese male rats were treated with oral sCT for 4 days. Body weight, food intake, and plasma glucose, insulin, and leptin levels were measured, and the clinical homeostasis model assessment for insulin resistance (HOMA-IR) index was calculated. In addition, oral glucose tolerance was evaluated in the systemic and portal circulations. RESULTS: For prevention, oral sCT reduced body weight by ~16% to 19% (P < 0.001), reduced plasma insulin and leptin by ~50%, and improved impaired fasting glycemia (P < 0.05) concomitantly with amelioration of IR (HOMA-IR; P < 0.01) in HFD- and OVX-induced obesity. Furthermore, oral sCT significantly reduced the incremental area under the curve for plasma glucose and insulin by ~40% and ~70%, respectively, during glucose tolerance testing. As intervention in HFD-induced obese rats, oral sCT reduced body weight, fasting glycemia, and insulinemia in conjunction with HOMA-IR (P < 0.001). Finally, oral sCT alleviated glucose intolerance predominantly in the portal circulation. CONCLUSIONS: Oral sCT treatment displays weight-regulatory and glucoregulatory efficacy in HFD- and OVX-induced obese rats, indicating the clinical usefulness of oral sCT in postmenopausal obesity-related IR and type 2 diabetes. PMID- 23793171 TI - Drinking up rugby. PMID- 23793170 TI - Functional recovery and alterations in the expression and localization of protein kinase C following voluntary exercise in rat with cerebral infarction. AB - Recently, it has become widely known that rehabilitative training after stroke brings about some improvement of paralysis and disability; however, not much is known about the relationship between paralysis recovery and the participation of plasticity-related molecules. Hence, the localization and level of expression of several proteins in the cerebral cortex of rat groups with/without voluntary exercise using a running wheel after photo thrombotic infarction were examined in this study. In behavioral evaluation, the mean latency until falling from a rotating rod in the group with voluntary exercise at 6 days after infarction was significantly longer than that in the group without exercise. Immunohistochemical localization of c-Fos protein after behavioral test occurred in the area surrounding the infarction core in the exercise group. In protein expression analysis, protein kinase C (PKC), growth-associated protein 43 (GAP43) and phosphorylated at serine 41 GAP43 (p-GAP43) were significantly increased after voluntary exercise compared with those in rats without exercise. Expression of PKC immunoreactivity was observed in layer III of the perilesional cortex in rats with exercise, and the intracellular localization in the pyramidal neurons was mainly translocated to the plasma membrane. The expression and localization of these proteins may be related to the underlying mechanisms of exercise-induced paralysis recovery, that is, neuronal plasticity and remodeling of cortical connections through the phosphorylation of GAP43 by interaction with PKC. In the present study, the participation of at least some of the modulators associated with the improvement of motor deficit adjacent to the brain lesion might have been detected. PMID- 23793172 TI - Transient ischaemic attacks: "mini-strokes" with major but preventable consequences. PMID- 23793173 TI - Ambulance triage and treatment zones at major rugby events in Wellington, New Zealand: a sobering experience. AB - AIMS: A prospective analysis was undertaken of the workload of prehospital triage and treatment facilities established in Wellington for the 2011 and 2012 International Rugby Sevens, and the Rugby World Cup 2011 (RWC). The introduction of an alcohol intoxication pathway, the impact of the initiative on ambulance and Emergency Department (ED) workload, and its cost effectiveness were assessed. METHODS: A log of patients seen and their diagnoses and treatment was maintained. An alcohol questionnaire was completed when applicable. Patients intoxicated with alcohol were managed in accordance with a flowchart designed for paramedic use. Costs and savings were calculated. RESULTS: Half the patients were New Zealanders. The average age was 25 years with a slight female preponderance (52.9% female). 30% were students. Alcohol was a contributory or causative factor for the patient's attendance in 80-90% of cases. Approximately 60% of the 121 patients seen at the last two events would have had to be transferred to the ED in the absence of the treatment centre. Cost savings for the ambulance service and ED for the RWC and 2012 Sevens are estimated to be NZ$70,000. No adverse clinical event was identified. CONCLUSIONS: With minimal supervision, event medics and paramedics can safely care for the majority of patients attending large rugby events in New Zealand, easing the pressure on ambulances and the ED, and generating significant cost savings for those services. PMID- 23793174 TI - Who should manage transient ischemic attacks? A comparison between stroke experts, generalists, and electronic decision support. AB - AIMS: Rapid expert management of transient ischemic attacks (TIA) has been shown to reduce the incidence of stroke, but is not always achievable. This study aims to demonstrate that TIA management by stroke experts is indeed more guideline adherent than that of generalists and that a TIA/stroke electronic decision support (EDS) tool closely mimics expert advice and improves guideline adherence. METHODS: 11 general practitioners (GPs), 12 general physicians, and 12 stroke specialists assessed and provided management plans for 7 hypothetical patients with potential TIAs. Responses were compared with the advice provided when patient data was entered into a TIA/stroke EDS programme. RESULTS: Diagnosis and medical management was highly consistent and guideline adherent amongst stroke experts. Diagnostic accuracy was lower in the GP and general physician groups (76% and 79% respectively) and only one-third of generalists initiated best medical therapy when indicated. The TIA/stroke EDS consistently agreed with expert diagnosis, investigations, and medical management and provided most comprehensive lifestyle advice. COCNLUSION: This study (a) confirms that stroke expert care achieves higher guideline adherence and (b) provides validation that the TIA/stroke EDS tool is able to mimic expert advice and can reliably apply best practice guidelines. PMID- 23793175 TI - Progression of diabetic maculopathy in patients on the Wellington Diabetic Screening Programme initially graded M3. AB - AIM: To determine the likelihood of progression from M3 grade maculopathy, and therefore the safety of these patients remaining under the care of a primary screener. METHODS: Patients graded M3 at diabetic screening were selected from the Wellington screening database. Photographs for this visit and the subsequent visit were obtained, and graded by a consultant ophthalmologist. Photographs graded M3 were included and progression of maculopathy between visits, number of patients with a reduction in vision and duration between visits were determined. RESULTS: Mean duration between visits for all patients was 255 (plus or minus 59.5) days. Of the 54 eyes studied, 15 or 33.3% progressed to M4 maculopathy at the subsequent visit. Despite progressing from M3 to M4, none had a reduction of vision by more than one line of Snellen acuity at follow up due to diabetic maculopathy. CONCLUSIONS: Rates of progression of maculopathy from M3 to M4 were of clinical significance. Despite this none had worsening visual acuity due to diabetic eye disease. This suggests patients with M3 maculopathy could be maintained under a primary screening programme, as is the case in the United Kingdom. PMID- 23793176 TI - The future of the New Zealand plastic surgery workforce. AB - AIMS: The New Zealand (NZ) plastic and reconstructive surgery (PRS) workforce provides reconstructive plastic surgery (RPS) public services from six centres. There has been little analysis on whether the workforce is adequate to meet the needs of the NZ population currently or in the future. This study analysed the current workforce, its distribution and future requirements. METHODS: PRS manpower data, workforce activities, population statistics, and population modelling were analysed to determine current needs and predict future needs for the PRS workforce. The NZ PRS workforce is compared with international benchmarks. Regional variation of the workforce was analysed with respect to the population's access to PRS services. Future supply of specialist plastic surgeons is analysed. RESULTS: NZ has a lower number of plastic surgeons per capita than comparable countries. The current NZ PRS workforce is mal-distributed. Areas of current and emerging future need are identified. CONCLUSIONS: The current workforce mal-distribution will worsen with future population growth and distribution. Up to 60% of the NZ population will be at risk of inadequate access to PRS services by 2027. Development of PRS services must be coordinated to ensure that equitable and sustainable services are available throughout NZ. Strategies for ensuring satisfactory future workforce are discussed. PMID- 23793177 TI - A standardised and validated patient survey in primary care: introducing the New Zealand General Practice Assessment Questionnaire (NZGPAQ). AB - AIM: To determine whether the New Zealand adaptation of the UK developed General Practice Assessment Questionnaire (GPAQ) is a valid and reliable indicator of the quality of care in general practice in New Zealand and what the survey can tell us about patient satisfaction with general practice. METHOD: The Health Services Consumer Research Ltd Primary Care Patient Survey database which presently contains data from 184 medical practices (549 GPs) and responses from 50,000 enrolled patients was examined to determine the validity and reliability of the survey instrument. Data was briefly analysed to ascertain how survey results can best be employed to improve the quality of primary care. RESULTS: A check on representativeness showed that older, female and European patients are over represented. To determine validity and reliability, the "Cronbach alpha" statistic was calculated and shown to range between 0.85-0.96. Convergent validity was demonstrated by high correlations between items that measured closely related aspects of patient care. Discriminant validity was shown by very low correlations between variables that measured unrelated items. Further analyses show how patients' age, sex and ethnic group influence the level of satisfaction experienced. CONCLUSION: The NZGPAQ survey can be employed nationwide to improve the quality of primary care because these patient survey results emphasize where service delivery is good/excellent and identify where change is needed to improve patient satisfaction. PMID- 23793178 TI - The effect of Maori ethnicity misclassification on cervical screening coverage. AB - AIM: There is a large difference in the cervical screening coverage rate between Maori and European women in New Zealand. This paper examines the extent to which this difference is due to misclassification of ethnicity. METHODS: Data from Waitemata District Health Board's two Primary Health Organisations (PHOs) was used to identify the population of Waitemata domiciled women aged 25-69 years eligible for cervical screening. Their cervical screening status was obtained from the National Cervical Screening Programme register (NCPS-R). Data from Auckland and Waitemata DHBs was used to determine the women's ethnicity in the National Health Index (NHI). Women who had withdrawn from the NCSP-R, women who were deceased and women for whom an NHI ethnicity code could not be obtained were excluded from the analysis. Ethnicity codes from the three sources (PHO registers, NCSP-R and NHI) were compared to identify women classified as non Maori in the NCSP-R but Maori in either of the other two data sources. The effect on Maori cervical screening coverage rates of not counting these women was assessed. RESULTS: Within the study population there was a total of 6718 women identified as Maori on the NCSP of whom 5242 had been screened within the last 3 years and 1476 who had not. In addition to these, there were 2075 women identified as Maori in either the PHO or NHI databases but not in the NCSP-R who had been screened within the preceding 3 years, and a further 2094 who had not been screened. There were also 797 women identified as Maori in the NHI or PHO datasets who were not on the NCSP-R (and therefore were not screened). If all screened women classified as Maori from any source were counted, Waitemata DHB's Maori screening coverage rate would rise from 49.3% to 68.8% (or to 61.0% and 63.2% respective if just PHO and NHI Maori were counted). CONCLUSION: Misclassification of ethnicity could explain (in absolute terms) up to 19.5% of the 35.0% difference in cervical screening coverage rate between Maori and non Maori , non-Pacific, non-Asian coverage in Waitemata District. Misclassification is likely to have similar effects on coverage estimates throughout New Zealand. Without improving the accuracy of ethnicity data in the NCSP-R it will be impossible for the country to achieve the target coverage rate of 80% among Maori. PMID- 23793179 TI - Blood pressure and hypertension in New Zealand: results from the 2008/09 Adult Nutrition Survey. AB - AIMS: To report the blood pressure results from the 2008/09 New Zealand Adult Nutrition Survey (2008/09NZANS). METHODS: Blood pressure measurements were available for 4,407 adults who were part of a survey involving face-to-face interviews with 4,721 New Zealanders aged 15 years and over. Three measurements were taken one minute apart, and the mean of the second and third readings has been used for this analysis. Hypertension was defined as systolic blood pressure (SBP) greater than and equal to 140 mmHg or diastolic blood pressure (DBP) greater than and equal to 90 mmHg or self reported use of antihypertensive medications. Comparisons were made with previously published New Zealand population blood pressure estimates. RESULTS: Mean SBP for the New Zealand adult population was 126 mmHg. The prevalence of hypertension was 31%, with 15% reporting taking antihypertensive medication. Mean SBP has increased since 2002/03 for New Zealand European and others (NZEO) aged 35-54 years and Maori aged 35-74 years, reversing a downward trend observed in NZEO between 1982 and 2002. CONCLUSIONS: The increasing blood pressure levels are concerning. Given the importance of elevated blood pressure as a risk factor for cardiovascular disease, intensive screening, public health measures aimed at lowering population blood pressure, and further population monitoring are warranted. PMID- 23793180 TI - Palliative care patients' use of emergency departments. AB - AIM: To compare attendances of Maori with non-Maori palliative care patients at Emergency Departments (ED) and the outcome of their visits. METHOD: This was an observational study using record linkage. The study population was Waikato palliative care patients registered in a 12-month period, aged over 20 years. For each patient we recorded from the hospital records their age, gender, ethnicity, domicile (Hamilton or other), hospital visited and number of visits to the emergency department in the study period. We compared likelihood of attendance at ED and also looked at reasons for the visits and the outcome--including admit to hospital or place of discharge RESULTS: 1185 palliative care patients were identified from the palliative care register. There were 645 men (54.4%), 197 Maori (16.6%) and 18 Pacific (1.5%). The mean age overall was 70.8 years and mean length of time on the register during the year of interest was 120.7 (median 66) days. 449 (37.9%) of the study population visited ED at least once. A multivariate analysis revealed that men visited ED more than women (Odds Ratios [OR] 1.6, p=0.001) and women with a gynaecological cancer visited ED more often than other palliative care conditions (OR 3.3, p<0.001). No other factor including ethnicity was associated with the risk of visiting ED. CONCLUSION: This study has helped quantify the characteristics of palliative care patients utilising ED in a relatively rural population with a high proportion of Maori. It has shown that a significant proportion of palliative care patients will attend ED, that men with palliative care needs are more likely to attend ED but Maori are not more likely to utilise the services. We believe that New Zealand hospitals should consider the role of their ED in the management of palliative care patients. PMID- 23793181 TI - A rare cause of nasal septal abscess. AB - We describe a patient with mid-facial pain and nasal obstruction due to a nasal septal abscess (NSA) complicating an occult fungal ball of the sphenoid sinus. We highlight the importance of suspecting unusual pathology in patients with NSA and no trauma history. PMID- 23793182 TI - Hemifacial spasm leading to diagnosis of Moyamoya disease. AB - We present a case of Moyamoya disease presenting as hemifacial spasm due to compression of the facial nerve by a vascular loop related to compensatory enlargement of the posterior circulation vessels. PMID- 23793183 TI - Medical image. Liver parenchyma visible during gastroscopy. PMID- 23793184 TI - What does 'undiagnosed' diabetes really mean? PMID- 23793185 TI - The cost of non-funded vaccinations in New Zealand. PMID- 23793186 TI - The uptake rates of influenza vaccine in pregnant women in the Nelson region of New Zealand. PMID- 23793187 TI - Chiropractic manipulation of the neck. PMID- 23793188 TI - Hidradenitis suppurativa: retrospective study of 20 cases. AB - In this study, twenty cases of severe hidradenitis suppurativa are reported, mainly in non-white people and in axillary areas. Wide surgical excision has offered good results, although relapses have occurred at variable intervals in the follow-up period. PMID- 23793189 TI - Cartilaginous melanoma: case report and review of the literature. AB - Malignant melanoma can present a variety of histopathological patterns. Cartilaginous change in the absence of osteogenic differentiation is extremely rare in malignant melanoma, being among the least frequent of the wide range of melanoma histologic patterns. We report a case of a 47-year-old woman with a subungual nodule on her right great toe for many years. Histopathological examination of the lesion led to a diagnosis of malignant melanoma with cartilaginous differentiation devoid of concomitant osseous areas. It would appear that this unusual form of melanoma has a predilection for acral location, particularly the subungual region. Malignant melanoma with chondroid stroma should therefore be considered in the differential diagnosis of cartilaginous lesions of the toes and fingers. Careful examination of the overlying epidermis and identification of an in situ component of melanoma may be necessary in order to establish the correct diagnosis. PMID- 23793190 TI - Shiitake dermatitis: the first case reported in Brazil. AB - Shiitake Dermatitis is often presented as papules and erythemato-violaceous linear streaks. It can be associated with bleomycin treatment, dermatomyositis and shiitake mushroom (Lentinus edodes). There is not any previous report concerning this rare etiology in our country. Shiitake is the second most consumed mushroom worldwide and it can cause flagellate erythema when ingested raw or half cooked. It has a higher incidence in Oriental countries because of their eating habits, this is the first case reported in Brazil, in a male patient that presented a cutaneous rash after consuming this raw mushroom. PMID- 23793191 TI - Argyria -- case report. AB - A 70-year-old male rural worker was referred to our clinic with widespread grey pigmentation of the skin and nails. The condition had been asymptomatic for its entire duration (5 years). He reported past intranasal application of 10% Silver Vitellinate. A skin biopsy was performed and histology corroborated the clinical diagnosis of Argyria. This case represents a currently rare dermatological curiosity. Although silver colloids and salts have been withdrawn and/or banned by some drug surveillance agencies, they continue to be freely sold and unregulated as food supplements and as ingredients in alternative medicines, thereby risking the emergence of new cases of silver poisoning. PMID- 23793192 TI - Unilateral punctate porokeratosis -- case report. AB - This case report involves a 20-year-old man with unilateral punctate porokeratosis. The patient presented an 8-year history of numerous asymptomatic keratotic papules and pits with linear distribution on his left pal-mar surface and fifth finger of the left hand. Histopathological examination of the keratotic plug revealed findings of distinct epidermal depressions containing cornoid lamellae. This report review draws attention to differential diagnoses of punctate porokeratosis. PMID- 23793193 TI - Epidemiological aspects of melanoma at a university hospital dermatology center over a period of 20 years. AB - BACKGROUND: The incidence of melanoma has been steadily rising in past decades. Although it accounts for only 3% of all skin cancers, it is responsible for 75% of deaths. OBJECTIVE: to describe the epidemiological aspects of melanoma in a university hospital setting over a period of 20 years. METHODS: A total of 166 patients were analyzed between January 1990 and January 2010 for clinical and histological variables and correlations between them. A 5% level of significance was adopted. RESULTS: The majority of patients were Caucasians (74%), females (61%), with a mean age at diagnosis of 55. The predominant histological type was lentigo maligna/lentigo maligna melanoma (35.7%) and the head and neck was the most affected site (30.7%). Among non-Caucasians, the acral region was the most affected. Most tumors were in situ (41.1%). Growth of the lesion was the most frequent complaint (58.1%) and bleeding was most frequently associated with melanomas with a depth > 4mm. There were seven deaths (4.2%), with a high risk among men, non-Caucasians and those under 20 years of age, with a Breslow's depth > 2mm, with lentiginous acral melanoma and with a history of growth and bleeding. CONCLUSIONS: Our sample differs from most of the studies in the predominant location (head and neck), histological type (lentigo maligna/ lentigo maligna melanoma) and a major risk of death under the age of 20, which could be with a reflex of regional variation. Broader studies are necessary for validation of the results. PMID- 23793194 TI - Argyria mimicking a blue nevis: dermoscopy features. AB - Argyria is a rare disease caused by prolonged skin contact with silver. Localized cases have been described regarding the use of topical medications, and trauma with objects containing this metal such as acupuncture needles and jewelry. Clinically, a macule or a patch, round or oval, appears in the infected area, with a characteristic bluey-gray color. To our knowledge this is the first time that this clinical condition has been described through the use of dermoscopy. PMID- 23793195 TI - Identification of fungi species in the onychomycosis of institutionalized elderly. AB - BACKGROUND: Superficial fungal infections are caused by dermatophytes, yeasts or filamentous fungi. They are correlated to the etiologic agent, the level of integrity of the host immune response, the site of the lesion and also the injured tissue. OBJECTIVE: The purpose of this study is to isolate and to identify onychomycosis agents in institutionalized elderly (60 years old +). METHODS: The identification of the fungi relied upon the combined results of mycological examination, culture isolation and micro cultures observation under light microscopy from nail and interdigital scales, which were collected from 35 elderly with a clinical suspicion of onychomycosis and a control group (9 elderly with healthy interdigital space and nails). Both groups were institutionalized in two nursing homes in Sao Bernardo do Campo, SP, Brazil. RESULTS: The nail scrapings showed 51.40% positivity. Of these, dermatophytes were found in 44.40% isolates, 27.78% identified as Trichophyton rubrum and 5.56% each as Trichophyton tonsurans, Trichophyton mentagrophytes and Microsporum gypseum. The second more conspicuous group showed 38.89% yeasts: 16.67% Candida guilliermondii, 11.11% Candida parapsilosis, 5.56% Candida glabrata, and 5.56% Trichosporon asahii. A third group displayed 16.70% filamentous fungi, like Fusarium sp, Aspergillus sp and Neoscytalidium sp (5.56% each). The interdigital scrapings presented a positivity rate of 14.29%. The agents were coincident with the fungi that caused the onychomycosis. In the control group, Candida guilliermondii was found at interdigital space in one person. CONCLUSION: Employing a combination of those identification methods, we found no difference between the etiology of the institutionalized elderly onychomycosis from that reported in the literature for the general population. PMID- 23793196 TI - Study of dermatoses in kidney transplant patients. AB - BACKGROUND: The increasing in the number of kidney transplant recipients has favored, more frequently than before, the emergence of dermatoses and warranted their study through subsequent publications. OBJECTIVES: to evaluate the frequency of dermatoses in kidney transplant recipients. METHODS: kidney transplant recipients with suspected dermatoses between March 1st 2009 and June 30th 2010. RESULTS: 53 patients (28 males and 25 females), aged between 22 and 69 (mean age = 45 years) were evaluated. Most of them came from the cities of Ceilandia, Samambaia and Sao Sebastiao/DF, and had already been transplanted for 5 to 10 years before (37.7%); 62.3% were recipients of living donors and 83% were prednisone-treated. The most prevalent dermatoses were of fungal (45.3%) and viral (39.6%) etiologies. Among the non-melanoma malignant neoplasms, the basal cell carcinoma prevailed (six cases), in spite of the low incidence. Concerning fungal dermatoses, 12 cases of onychomycosis, five of pityriasis versicolor and four of pityrosporum folliculitis were reported. For diagnosis, in most cases (64.2%), laboratory examinations (mycological and histopathological) were performed. CONCLUSION: cutaneous manifestations in kidney transplant recipients are generally secondary to immunosuppression. The infectious dermatoses, especially those of fungal origin, are frequently found in kidney transplant recipients and their occurrence increases progressively according to the time elapsed from the transplantation, which makes follow-up important. PMID- 23793197 TI - Genitogluteal porokeratosis -- case report. AB - We report the case of a patient diagnosed with genitogluteal porokeratosis, a disorder of epidermal keratinization. The location described is extremely rare and very often late diagnosed or even misdiagnosed. Histopathology showed a typical cornoid lamella of great value to support this diagnosis. The importance of awareness of this entity by the specialist is emphasized as a differential diagnosis among genital diseases of chronic evolution and difficult treatment. PMID- 23793198 TI - Study on dermatoses and their prevalence in groups of confirmed alcoholic individuals in comparison to a non-alcoholic group of individuals. AB - BACKGROUND: The direct relationship between alcoholism and dermatoses has been evaluated in recent researches. However, there are few objective surveys that demonstrate and prove a direct relationship between alcohol and a specific dermatosis. OBJECTIVES: to verify the prevalence of dermatoses in alcoholics, analize the dermatological changes found in these patients and their evolution during alcoholic abstinence. Also, to compare the results obtained with a non alcoholic control group and with the data found in medical literature. METHODS: the dermatologic conditions of 278 alcoholic patients (250 men, 28 women) were studied over a period of 4 years, and compared to those of a control group of 271 non-alcoholic individuals (249 men, 22 women), members of the Military Police Force. The individuals in both groups were between 20 and 60 years old. RESULTS: Pellagra, nummular eczema, purpura pigmentosa chronica (also known as pigmented purpuric dermatosis) and psoriasis were more frequent in the group of alcoholics and, apparently, occurred in parallel with alcoholism that seems to play a role in the evolution of these dermatoses. The dermatopathies were more frequent before the age of forty, regardless of factors such as profession, race or gender. CONCLUSION: the association of dermatoses and alcoholism was extremely significant according to the statistical data. Alcoholism can be considered a risk factor for pellagra, psoriasis, nummular eczema and purpura pigmentosa chronica dermatoses, which can, as well, be considered alcoholism indicators. PMID- 23793199 TI - Translation into Brazilian Portuguese and validation of the psoriasis family index. AB - Psoriasis Family Index is a quality of life instrument for family members of patients with psoriasis developed in English. The aims of this study were to translate the Psoriasis Family Index into Brazilian Portuguese, culturally adapt it and verify its reliability and validity. The study followed these two steps: 1) Translation, linguistic and cultural adaptation, 2) Validation. The translated Psoriasis Family Index showed high internal consistency and high test-retest reliability, confirming its reproducibility. The Portuguese version of the Psoriasis Family Index was validated for our population and can be recommended as a reliable instrument to assess the QoL of family members and partners of patients with psoriasis. PMID- 23793200 TI - Behcet disease in association with Budd-Chiari syndrome and multiple thrombosis - case report. AB - Behcet's disease is a chronic inflammatory disease of unknown aetiology, characterized by recurrent oral and genital aphthous ulcerations, uveitis, skin lesions and other multisystem affections associated with vasculitis. Different types of vessels, predominantly veins, can be affected in Behcet's disease. The frequency of vascular lesions in Behcet's disease, such as superficial and deep venous thromboses, arterial aneurysms and occlusions, ranges between 7-29%. Budd Chiari syndrome is a rare and serious complication of Behcet's disease and implies thrombosis of the hepatic veins and/or the intrahepatic or suprahepatic inferior vena cava. We report a case of a 25-year-old man with Behcet's disease that developed Budd-Chiari syndrome. The correlation of dermatological, pathological and imaging studies confirmed the diagnosis. PMID- 23793202 TI - Results of a combination of bleomycin and triamcinolone acetonide in the treatment of keloids and hypertrophic scars. AB - While treatment of keloids and hypertrophic scars normally shows modest results, we found that treatment with bleomycin was more promising. The present study was divided into two parts. In the first part the aim was to show the results using a combination of bleomycin and triamcinolone acetonide per cm2 (BTA). In the second part the objective was to determine the response to both drugs in large keloids that were divided into 1 cm2 squares, treating each square with the dose previously used. In the first part of the study, the clinical response of 37 keloids ranging from 0.3 to 1.8 cm2 treated with BTA were followed up over a period of 1- 2 years. 0.375 IU bleomycin and 4 mg triamcinolone acetonide were injected every 3 months. In the second part of the study we reviewed the clinical response in six patients with large keloids. The monthly dose administered never exceeded 3 IU of bleomycin. The first study showed 36 keloids (97.29%) softening after the first dose. In the second study, 5 showed different responses (the response was complete in the four smaller keloids). The largest keloid needed 9 doses to achieve an improvement of 70%. In conclusion, combined treatment with 0.375 IU of bleomycin and 4mg of triamcinolone acetonide to 1 cm2 was considered to be an acceptable procedure for the treatment of keloids. The best results were obtained in keloids over 1 cm2 or when divided into 1 cm2 square areas. Larger series need to be performed in order to confirm these results.. PMID- 23793203 TI - Cutaneous neonatal lupus with cutis marmorata telangiectatica congenita-like lesions. AB - Neonatal lupus is a rare disease caused by the transplacental transfer of maternal autoantibodies to the foetus, characterized by transient clinical manifestations such as cutaneous, haematological, and hepatobiliary events or permanent such as congenital heart block. The typical cutaneous manifestations include erythematous, scaly, annular or arched lesions on the face, with slight central atrophy and photosensitivy, clinically and histologically similar to subacute cutaneous lupus. However, in some cases, the lesions may resemble those in cutis marmorata telangiectatica congenita, although this phenomenon is rare and only eight such cases have been reported to date. We report a case of cutaneous neonatal lupus with atypical lesions on the limbs, which had a reddish purple marbled appearance, resembling the lesions in cutis marmorata telangiectatica congenita. PMID- 23793204 TI - Cutaneous malakoplakia: case report and review. AB - Malakoplakia is a rare acquired disease that can affect many systems but is more common in the urogenital tract. Cutaneous malakoplakia is even rarer. It is far more frequent in immunodeficient patients. We report a case of cutaneous malakoplakia in a kidney transplant patient who had recently stopped receiving immunosuppressive therapy to illustrate a review of the relevant recent literature. PMID- 23793205 TI - Treatment of pityriasis versicolor with topical application of essential oil of Cymbopogon citratus (DC) Stapf - therapeutic pilot study. AB - BACKGROUND: Pityriasis versicolor is a fungal infection caused by Malassezia spp. that has frequent relapses. OBJECTIVES: The main objective of this research was to perform phase I and II clinical studies, using formulations containing essential oil of Cymbopogon citratus in patients with pityriasis versicolor. METHODS: Phase I study included twenty volunteers to ascertain the safety of the formulations. In phase II, 47 volunteers randomly received essential oil formulations at 1.25 MUL/mL concentration, for forty days. The shampoo should be applied three times a week and the cream twice a day. A control group in phase II, consisting of 29 volunteers, received the same formulations but with 2% ketoconazole as the active ingredient. RESULTS: No significant adverse events were observed in volunteers during Phase I. In Phase II, 30 (63.83%) volunteers using essential oil and 18 (62.07%) using ketoconazole remained until the end of the study. We observed a predominance of lesions in disseminated form, with M. sympodialis detected as the predominant agent identified in cultures. After 40 days of treatment, the rate of mycological cure was 60% (p <0.05) for the group treated with essential oil of C. citratus and over 80% (p <0.05) for the group treated with ketoconazole formulations. CONCLUSIONS: Notwithstanding the safety and antifungal effects observed in this study after application of formulations containing the essential oil of C. citratus, further studies with larger populations should be performed to confirm the actual potential of these formulations in the treatment of patients with Pityriasis versicolor. PMID- 23793206 TI - Case for diagnosis. AB - Pigmentary demarcation lines are physiologically abrupt transition lines from areas of deeper pigmentation to less pigmented areas. They are most often seen in African and Japanese individuals and rarely observed in Caucasians. There are eight types of pigmentary demarcation lines. The one described here, type B, is restricted to women and is associated with pregnancy in non-black patients. This type of pigmentary demarcation line occurs in the posterior aspect of the legs, extending from the perineum to the ankle. Its distribution follows the Voigt's lines, which define the distribution of peripheral nerves. Its pathogenesis remains unknown. Expectant treatment is used, and good results have been reported with the use of Q-switched Alexandrite laser. PMID- 23793207 TI - Evaluation of D-dimer serum levels among patients with chronic urticaria, psoriasis and urticarial vasculitis. AB - BACKGROUND: It has been demonstrated that neutrophils, eosinophils and monocytes, under appropriated stimulus, may express tissue factor and therefore, activate the extrinsic pathway of coagulation. We performed a transversal and case-control study of patients with chronic urticaria and patients with psoriasis, in our outpatient clinic to evaluate the production of D-dimer. OBJECTIVE: To evaluate D dimer serum levels in patients with chronic urticaria and its possible correlation with disease activity. PATIENTS AND METHODS: The study was conducted from October 2010 until March 2011. We selected 37 consecutive patients from our Allergy Unit and Psoriasis Unit, and divided them into three groups for statistical analysis: (i) 12 patients with active chronic urticaria (CU); (ii) 10 patients with chronic urticaria under remission and (iii) 15 patients with psoriasis (a disease with skin inflammatory infiltrate constituted by neutrophils, lymphocytes and monocytes). Another five patients with urticarial vasculitis were allocated in our study, but not included in statistical analysis. The serum levels of D-dimer were measured by Enzyme Linked Fluorescent Assay (ELFA), and the result units were given in ng/ml FEU. RESULTS: Patients with active chronic urticaria had the highest serum levels of D-dimer (p<0.01), when compared to patients with CU under remission and the control group (patients with psoriasis). CONCLUSIONS: Patients with active chronic urticaria have higher serum levels of D-dimer, when compared to patients with chronic urticaria under remission and patients with psoriasis. We found elevated serum levels of D-dimer among patients with urticarial vasculitis. PMID- 23793208 TI - Recurrent cutaneous leishmaniasis. AB - We present a case of an 18-year-old male patient who, after two years of inappropriate treatment for cutaneous leishmaniasis, began to show nodules arising at the edges of the former healing scar. He was immune competent and denied any trauma. The diagnosis of recurrent cutaneous leishmaniasis was made following positive culture of aspirate samples. The patient was treated with N methylglucamine associated with pentoxifylline for 30 days. Similar cases require special attention mainly because of the challenges imposed by treatment. PMID- 23793209 TI - Neurofibromatosis: chronological history and current issues. AB - Neurofibromatosis, which was first described in 1882 by Von Recklinghausen, is a genetic disease characterized by a neuroectodermal abnormality and by clinical manifestations of systemic and progressive involvement which mainly affect the skin, nervous system, bones, eyes and possibly other organs. The disease may manifest in several ways and it can vary from individual to individual. Given the wealth of information about neurofibromatosis, we attempted to present this information in different ways. In the first part of this work, we present a chronological history, which describes the evolution of the disease since the early publications about the disorder until the conclusion of this work, focusing on relevant aspects which can be used by those wishing to investigate this disease. In the second part, we present an update on the various aspects that constitute this disease. PMID- 23793211 TI - Case for diagnosis. AB - Granular cell tumor (Abrikossoff's tumor) is a rare benign disease that preferentially affects the cervicofacial segment. It is usually a solitary nodule that may ulcerate and present pearly infiltration on the borders, while keeping a clean background and a hyperchromic halo. This paper describes the case of an ulcerated granular cell tumor on an unusual location, which reinforces the necessity of including this tumor in the differential diagnosis of nodular ulcerative skin lesions. PMID- 23793210 TI - Use of potassium iodide in dermatology: updates on an old drug. AB - Potassium iodide, as a saturated solution, is a valuable drug in the dermatologist's therapeutic arsenal and is useful for the treatment of different diseases due to its immunomodulatory features. However, its prescription has become increasingly less frequent in dermatology practice. Little knowledge about its exact mechanism of action, lack of interest from the pharmaceutical industry, the advent of new drugs, and the toxicity caused by the use of high doses of the drug are some possible explanations for that. Consequently, there are few scientific studies on the pharmacological aspects, dosage and efficacy of this drug. Also, there is no conventional standard on how to manipulate and prescribe the saturated solution of potassium iodide, which leads to unawareness of the exact amount of the salt being delivered in grams to patients. Considering that dosage is directly related to toxicity and the immunomodulatory features of this drug, it is essential to define the amount to be prescribed and to reduce it to a minimum effective dose in order to minimize the risks of intolerance and thus improve treatment adherence. This review is relevant due to the fact that the saturated solution of potassium iodide is often the only therapeutic choice available for the treatment of some infectious, inflammatory and immune-mediated dermatoses, no matter whether the reason is specific indication, failure of a previous therapy or cost-effectiveness. PMID- 23793212 TI - Vibrio vulnificus infection in Southern Brazil -- case report. AB - The genus Vibrio is a member of the family Vibrionaceae, and among their disease causing species, Vibrio vulnificus, a lactose-positive gram-negative bacillus, is one of the most virulent pathogen of the noncholerae vibrios. We describe the case of a 39-year-old male patient, who was using immunosuppressive therapy, admitted to the hospital for liver transplantation. Twelve hours later, the patient presented high fever, myalgia, anuria and erythematous plaques on lower limbs, of rapid growth and proximal progression. The patient was treated with ceftriaxone, meropenem and oxacillin, however he expired within 30 hours. Blood cultures showed growth of a gram-negative bacillus, which was later identified as Vibrio vulnificus. PMID- 23793213 TI - General aspects of drug interactions with systemic antifungals in a retrospective study sample. AB - A retrospective study evaluating hepatic laboratory alterations and potential drug interactions in patients treated for onychomycosis. We evaluated 202 patients, 82% female. In 273 liver enzyme tests, there were changes in only 6%. Potential drug interactions were identified in 28% of patients for imidazole and 14% for terbinafine. The risk of potential interactions increased with the patient's age and use of multiple drugs. PMID- 23793214 TI - Desmoplastic melanoma associated with an intraepidermal lentiginous lesion: case report and literature review. AB - Desmoplastic melanoma tends to present as firm, amelanotic papules. Microscopically, it reveals a proliferation of fusiform cells in the dermis and variable collagen deposition, as well as intraepidermal melanocytic proliferation of lentiginous type in most cases. Biopsy in a 61-year-old white male patient, who had received a diagnosis of lentigo maligna on his face 10 years before, revealed a proliferation of dermal pigmented spindle cells and collagen deposition, reaching the deep reticular dermis, with a lentiginous component. Immunohistochemistry with S-100, Melan-A and WT1 showed positivity, but it was weak with HMB45. Desmoplastic melanoma associated with lentigo maligna was diagnosed. Several authors discuss whether desmoplastic melanoma represents a progression from the lentiginous component or arises "de novo". Desmoplastic melanoma represents a minority of cases of primary cutaneous melanoma (less than 4%). Identification of lentigo maligna indicates that desmoplastic melanoma should be carefully investigated. PMID- 23793215 TI - Proximal-type epithelioid sarcoma -- case report. AB - Epithelioid sarcoma, first described by Enzinger in 1970, is a rare soft-tissue sarcoma typically presenting as a subcutaneous or deep dermal mass in distal portions of the extremities of adolescents and young adults. In 1997, Guillou et al. described a different type of epithelioid sarcoma, called proximal-type epithelioid sarcoma, which is found mostly in the pelvic and perineal regions and genital tracts of young to middle-aged adults. It is characterized by a proliferation of epithelioid-like cells with rhabdoid features and the absence of a granuloma-like pattern. In this paper we present a case of proximal-type epithelioid sarcoma with an aggressive clinical course, including distant metastasis and death nine months after diagnosis. PMID- 23793216 TI - Follicular red dots: a normal trichoscopy feature in patients with pigmentary disorders? AB - Follicular red dots have been described as a trichoscopic feature of active discoid lupus erythematosus of the scalp and its presence associated with a better prognosis. We report five patients with pigmentary disorders in whom follicular red dots were detected during scalp examination. We suggest that this pattern is probably related to the rich vasculature that naturally envelops the normal hair follicle. The possible implications of such proposition in cases of discoid lupus erythematosus and other scalp disorders are also discussed. PMID- 23793217 TI - Do you know this syndrome? AB - Congenital Hypertrichosis Lanugionsa is a rare autosomal dominant genetic disorder, with fewer than 50 cases reported in the literature. It is characterized by excessive lanugo hair, sparing only the mucous membranes, palms and soles. It may be associated with other organic abnormalities and should form part of the dermatologist's current knowledge. We discuss some aspects of the syndrome in question arising from the case report of a 2-year-old female patient, black, with classic clinical presentation, with no other associated congenital abnormalities. PMID- 23793218 TI - Toxic epidermal necrolysis induced by Lansoprazole: pharmacologic considerations. PMID- 23793219 TI - Scanning electron microscopy of acantholysis in pemphigus foliaceus. AB - We performed scanning electron microscopy of an inverted blister roof in a case of pemphigus foliaceus. The loss of intercellular adherence could be easily seen with low magnification. The acantholytic keratinocytes displayed an irregular and sometimes polygonal contour. Round cells, typically seen in light microscopy, were also observed. The examination of a blister roof allows ultrastructural documentation of the acantholytic changes. PMID- 23793221 TI - Formation of a 1D-polymeric chain of Hg building blocks through C-C coupling under ambient conditions. AB - A novel C-C coupled 1D-polymeric chain (1) is obtained by reaction of HgCl2 and hmp-H (2-(2-hydroxymethyl pyridine)) (1 : 1) in MeOH at ambient temperature. However, a new class of MU-oxo and MU-chloro bridged polymers (2) has been obtained by altering the metal : ligand ratio to 1 : 2. PMID- 23793220 TI - Cutaneous histoplasmosis disclosing an HIV-infection. AB - Histoplasmosis is a systemic mycosis endemic in extensive areas of the Americas. The authors report on an urban adult male patient with uncommon oral-cutaneous lesions proven to be histoplasmosis. Additional investigation revealed unnoticed HIV infection with CD4+ cell count of 7/mm3. The treatment was performed with amphotericin B, a 2065 mg total dose followed by itraconazole 200mg/daily plus antiretroviral therapy with apparent cure. Histoplasmosis is an AIDS-defining opportunistic disease process; therefore, its clinical diagnosis must drive full laboratory investigation looking for unnoted HIV-infection. PMID- 23793222 TI - An isolated semi-intact preparation of the mouse vestibular sensory epithelium for electrophysiology and high-resolution two-photon microscopy. AB - Understanding vestibular hair cells function under normal conditions, or how trauma, disease, and aging disrupt this function is a vital step in the development of preventative approaches and/or novel therapeutic strategies. However, the majority of studies looking at abnormal vestibular function have not been at the cellular level but focused primarily on behavioral assays of vestibular dysfunction such as gait analyses and vestibulo-ocular reflex performance. While this work has yielded valuable data about what happens when things go wrong, little information is gleaned regarding the underlying causes of dysfunction. Of the studies that focus on the cellular and subcellular processes that underlie vestibular function, most have relied on acutely isolated hair cells, devoid of their synaptic connections and supporting cell environment. Therefore, a major technical challenge has been access to the exquisitely sensitive vestibular hair cells in a preparation that is least disrupted, physiologically. Here we demonstrate a semi-intact preparation of the mouse vestibular sensory epithelium that retains the local micro-environment including hair cell/primary afferent complexes. PMID- 23793223 TI - Non-redundant properties of IL-1alpha and IL-1beta during acute colon inflammation in mice. AB - OBJECTIVE: The differential role of the IL-1 agonists, IL-1alpha, which is mainly cell-associated versus IL-1beta, which is mostly secreted, was studied in colon inflammation. DESIGN: Dextran sodium sulfate (DSS) colitis was induced in mice globally deficient in either IL-1alpha or IL-1beta, and in wild-type mice, or in mice with conditional deletion of IL-1alpha in intestinal epithelial cells (IECs). Bone marrow transplantation experiments were performed to assess the role of IL-1alpha or IL-1beta of myeloid versus colon non-hematopoietic cells in inflammation and repair in acute colitis. RESULTS: IL-1alpha released from damaged IECs acts as an alarmin by initiating and propagating colon inflammation, as IL-1alpha deficient mice exhibited mild disease symptoms with improved recovery. IL-1beta is involved in repair of IECs and reconstitution of the epithelial barrier during the resolution of colitis; its deficiency correlates with disease exacerbation. Neutralisation of IL-1alpha in control mice during acute colitis led to alleviation of clinical and histological manifestations, whereas treatment with rIL-1Ra or anti-IL-1beta antibodies was not effective. Repair after colitis correlated with accumulation of CD8 and regulatory T cells in damaged crypts. CONCLUSIONS: The role of IL-1alpha and IL-1beta differs in DSS induced colitis in that IL-1alpha, mainly of colon epithelial cells is inflammatory, whereas IL-1beta, mainly of myeloid cell origin, promotes healing and repair. Given the dissimilar functions of each IL-1 agonistic molecule, an IL 1 receptor blockade would not be as therapeutically effective as specific neutralising of IL-1alpha, which leaves IL-1beta function intact. PMID- 23793224 TI - Colorectal cancers soon after colonoscopy: a pooled multicohort analysis. AB - OBJECTIVE: Some individuals are diagnosed with colorectal cancer (CRC) despite recent colonoscopy. We examined individuals under colonoscopic surveillance for colonic adenomas to assess possible reasons for diagnosing cancer after a recent colonoscopy with complete removal of any identified polyps. DESIGN: Primary data were pooled from eight large (>800 patients) North American studies in which participants with adenoma(s) had a baseline colonoscopy (with intent to remove all visualised lesions) and were followed with subsequent colonoscopy. We used an algorithm based on the time from previous colonoscopy and the presence, size and histology of adenomas detected at prior exam to assign interval cancers as likely being new, missed, incompletely resected (while previously an adenoma) or due to failed biopsy detection. RESULTS: 9167 participants (mean age 62) were included in the analyses, with a median follow-up of 47.2 months. Invasive cancer was diagnosed in 58 patients (0.6%) during follow-up (1.71 per 1000 person-years follow-up). Most cancers (78%) were early stage (I or II); however, 9 (16%) resulted in death from CRC. We classified 30 cancers (52%) as probable missed lesions, 11 (19%) as possibly related to incomplete resection of an earlier, non invasive lesion and 14 (24%) as probable new lesions. The cancer diagnosis may have been delayed in three cases (5%) because of failed biopsy detection. CONCLUSIONS: Despite recent colonoscopy with intent to remove all neoplasia, CRC will occasionally be diagnosed. These cancers primarily seem to represent lesions that were missed or incompletely removed at the prior colonoscopy and might be avoided by increased emphasis on identifying and completely removing all neoplastic lesions at colonoscopy. PMID- 23793226 TI - Acute effects of ayahuasca on neuropsychological performance: differences in executive function between experienced and occasional users. AB - BACKGROUND: Ayahuasca, a South American psychotropic plant tea containing the psychedelic 5-HT2A receptor agonist N,N-dimethyltryptamine, has been shown to increase regional cerebral blood flow in prefrontal brain regions after acute administration to humans. Despite interactions at this level, neuropsychological studies have not found cognitive deficits in abstinent long-term users. OBJECTIVES: Here, we wished to investigate the effects of acute ayahuasca intake on neuropsychological performance, specifically on working memory and executive function. METHODS: Twenty-four ayahuasca users (11 long-term experienced users and 13 occasional users) were assessed in their habitual setting using the Stroop, Sternberg, and Tower of London tasks prior to and following ayahuasca intake. RESULTS: Errors in the Sternberg task increased, whereas reaction times in the Stroop task decreased and accuracy was maintained for the whole sample following ayahuasca intake. Interestingly, results in the Tower of London showed significantly increased execution and resolution times and number of movements for the occasional but not the experienced users. Additionally, a correlation analysis including all subjects showed that impaired performance in the Tower of London was inversely correlated with lifetime ayahuasca use. CONCLUSIONS: Acute ayahuasca administration impaired working memory but decreased stimulus-response interference. Interestingly, detrimental effects on higher cognition were only observed in the less experienced group. Rather than leading to increased impairment, greater prior exposure to ayahuasca was associated with reduced incapacitation. Compensatory or neuromodulatory effects associated with long-term ayahuasca intake could underlie preserved executive function in experienced users. PMID- 23793228 TI - Group-theoretic models of the inversion process in bacterial genomes. AB - The variation in genome arrangements among bacterial taxa is largely due to the process of inversion. Recent studies indicate that not all inversions are equally probable, suggesting, for instance, that shorter inversions are more frequent than longer, and those that move the terminus of replication are less probable than those that do not. Current methods for establishing the inversion distance between two bacterial genomes are unable to incorporate such information. In this paper we suggest a group-theoretic framework that in principle can take these constraints into account. In particular, we show that by lifting the problem from circular permutations to the affine symmetric group, the inversion distance can be found in polynomial time for a model in which inversions are restricted to acting on two regions. This requires the proof of new results in group theory, and suggests a vein of new combinatorial problems concerning permutation groups on which group theorists will be needed to collaborate with biologists. We apply the new method to inferring distances and phylogenies for published Yersinia pestis data. PMID- 23793227 TI - Bromodomain proteins in HIV infection. AB - Bromodomains are conserved protein modules of ~110 amino acids that bind acetylated lysine residues in histone and non-histone proteins. Bromodomains are present in many chromatin-associated transcriptional regulators and have been linked to diverse aspects of the HIV life cycle, including transcription and integration. Here, we review the role of bromodomain-containing proteins in HIV infection. We begin with a focus on acetylated viral factors, followed by a discussion of structural and biological studies defining the involvement of bromodomain proteins in the HIV life cycle. We end with an overview of promising new studies of bromodomain inhibitory compounds for the treatment of HIV latency. PMID- 23793230 TI - Aggregation-induced emission on benzothiadiazole dyads with large third-order optical nonlinearity. AB - Two kinds of D-A molecular of (4-(4-(9H-carbazol-9-yl)phenyl))-7 nitrobenzothiadiazole (BSC) and 4-((4-(9H-carbazol-9-yl)phenyl)ethynyl)-7 nitrobenzothiadiazole (BEC) containing carbazole moieties as the donor were synthesized. X-ray crystal data elucidated the multiple intermolecular interactions. They exhibit distinctly different self-assembly behaviours. The nonlinear optical properties were studied using the top-hat Z-scan technique at 532 nm with a 21 ps pulse. The results indicate that they exhibit large third order nonlinear absorption effects. The nonlinear absorption coefficients alpha2 fitting the experimental data are 6.3 * 10(-12) m W(-1) for BSC and 3.6 * 10(-11) m W(-1) for BEC. The time-resolved pump-probe results show that both nonlinear absorption and nonlinear refraction of BEC in CH2Cl2 solution have rapid optical responses, which indicate the nonlinear absorption and nonlinear refraction mechanism are excited-state nonlinear. Moreover, both of these two compounds are observed to be aggregation-induced emission (AIE) active. The aggregates of the well-formed one-dimensional microrods of BEC and BSC endow the material with potential applications in the field of optical devices. PMID- 23793229 TI - Association of common gene variants in vitamin D modulating genes and colon cancer recurrence. AB - PURPOSE: Low concentrations of 25-hydroxyvitamin D3 (25(OH)D) have been associated with increased risk and poor prognosis of various cancer types, including colon cancer. Common genetic variants in genes that influence circulating 25(OH)D levels may affect vitamin D concentrations and risk of vitamin D insufficiency. In the present study, we investigated the association of three functional gene variants in GC (rs2282679 T>G), DHCR7 (rs12785878 G>T) and CYP2R1 (rs10741657 A>G) with time to recurrence (TTR) in patients with stages II and III colon cancer. METHODS: Two hundred and sixty-four patients were included in this retrospective study. Genomic DNA was genotyped for GC rs2282679 T>G, DHCR7 rs12785878 G>T and CYP2R1 rs10741657 A>G by 5'-exonuclease (TaqManTM) technology. RESULTS: In the univariate analysis, GC rs2282679 GG was significantly associated with decreased TTR (HR = 3.30, 95 % CI 1.09-9.97, p = 0.034) in patients with surgery alone and remained significantly associated in multivariate analysis including lymph node involvement and clinical stage (HR = 3.64, 95 % CI 1.16-11.46, p = 0.027). In patients with adjuvant chemotherapy, GC rs2282679 T>G was not significantly associated with TTR (HR = 1.02, 95 % CI 0.44 2.37, p = 0.964). Furthermore, we observed a trend toward decreased TTR in patients harboring the CYP2R1 rs10741657 A>G gene variant including all patients (HR = 1.50, 95 % CI 0.98-2.28, p = 0.060). No association was found between DHCR7 rs12785878 G>T and TTR in our study cohort. CONCLUSION: In conclusion, our results may indicate a prognostic effect of GC rs2282679 in stages II and III colon cancer patients with surgery alone. Larger studies have to be performed to validate our findings. PMID- 23793231 TI - Exercise dose, exercise adherence, and associated health outcomes in the TIGER study. AB - PURPOSE: To effectively evaluate activity-based interventions for weight management and disease risk reduction, objective and accurate measures of exercise dose are needed. This study examined cumulative exercise exposure defined by HR-based intensity, duration, and frequency as a measure of compliance with a prescribed exercise program and a predictor of health outcomes. METHODS: One thousand one-hundred fifty adults (21.3 +/- 2.7 yr) completed a 15-wk exercise protocol consisting of 30 min.d, 3 d.wk, at 65%-85% maximum HR reserve. Computerized HR monitor data were recorded at every exercise session (33,473 valid sessions). To quantify total exercise dose, duration for each session was adjusted for average exercise intensity (%HR reserve) to create a measure of intensity minutes for each workout, which were summed over all exercise sessions to formulate an HR physical activity score (HRPAS). Regression analysis was used to examine the relation between HRPAS and physiological responses to exercise training. Compliance with the exercise protocol based on achievement of the minimum prescribed HRPAS was compared with adherence defined by attendance. RESULTS: On the basis of HRPAS, 868 participants were empirically defined as compliant, and 282 were noncompliant. HRPAS-based and attendance-based classifications of compliance and adherence differed in approximately 9% of participants. Higher HRPAS was associated with significant positive changes in body mass (P < 0.001), body mass index (P < 0.001), waist and hip circumferences (P < 0.001), percent body fat (P < 0.001), systolic blood pressure (P < 0.011), resting HR (P < 0.003), fasting glucose (P < 0.001), and total cholesterol (P < 0.02). Attendance-based adherence was associated with body mass, hip circumference, percent body fat, resting HR, and cholesterol (P < 0.05). CONCLUSIONS: The HRPAS is a quantifiable measure of exercise dose associated with improvement in health indicators beyond that observed when adherence is defined as session attendance. PMID- 23793232 TI - Comparison of self-reported versus accelerometer-measured physical activity. AB - INTRODUCTION: The International Physical Activity Questionnaire (IPAQ) is one of the most widely used questionnaires to assess physical activity (PA). Validation studies for the IPAQ have been executed, but still there is a need for studies comparing absolute values between IPAQ and accelerometer in large population studies. PURPOSE: To compare PA and sedentary time from the self-administered, short version of the IPAQ with data from ActiGraph accelerometer in a large national sample. METHODS: A total of 1751 adults (19-84 yr) wore an accelerometer (ActiGraph GT1M) for seven consecutive days and completed the IPAQ-Short Form. Sedentary time, total PA, and time spent in moderate to vigorous activity were compared in relation to sex, age, and education. RESULTS: Men and women reported, on average, 131 min.d (SE = 4 min.d) less sedentary time compared with the accelerometer measurements. The difference between self-reported and measured sedentary time and vigorous-intensity PA was greatest among men with a lower education level and for men 65 yr and older. Although men reported 47% more moderate to vigorous physical activity (MVPA) compared with women, there were no differences between sexes in accelerometer-determined MVPA. Accelerometer determined moderate PA was reduced from 110 to 42 min.d (62%) when analyzed in blocks of 10 min (P < 0.0001) compared with 1-min blocks. The main correlation coefficients between self-reported variables and accelerometer measures of physical activity were between 0.20 and 0.46. CONCLUSIONS: The participants report through IPAQ-Short Form more vigorous PA and less sedentary time compared with the accelerometer. The difference between self-reported and accelerometer measured MVPA increased with higher activity and intensity levels. Associations between the methods were affected by sex, age, and education, but not body mass index. PMID- 23793233 TI - Pain relief after isometric exercise is not task-dependent in older men and women. AB - INTRODUCTION: This study assessed the effect of isometric contractions that varied in intensity and duration on pain perception in adults older than 60 yr. METHODS: Pain perception was measured in 24 men and women (mean +/- SD age = 72.2 +/- 6.2 yr) using a pressure pain device applied to the right index finger before and after isometric contractions of the left elbow flexor muscles of the following doses: 1) three brief maximal voluntary contractions (MVC), 2) 25% MVC held for 2 min, and 3) 25% MVC held to task failure. RESULTS: Older adults reported increased pain thresholds (58 s vs 49 s, P < 0.001) and decreased pain ratings (2.8 vs 3.4, P < 0.001) after exercise, and these changes were similar across all three tasks (P = 0.94 and P = 0.55, respectively). Sex differences were identified with older women reporting greater pain sensitivity (lower pain thresholds [P = 0.01] and higher pain ratings [P = 0.004]) and larger reductions in pain ratings than men (23% vs 9%, P = 0.003) after isometric contractions. CONCLUSIONS: Older adults experienced similar reductions in pain after several different intensities and durations of isometric contractions. Both older men and women experienced increases in pain threshold, but only older women experienced reductions in pain ratings. PMID- 23793234 TI - A randomized trial of exercise training in abdominal aortic aneurysm disease. AB - PURPOSE: Screening programs and greater public awareness have increased the recognition of early abdominal aortic aneurysm (AAA) disease. No medical therapy has proven effective in limiting AAA progression, and little is known regarding the safety and efficacy of exercise training in these patients. We evaluated the safety and efficacy of up to 3 yr of training in patients with early (<=5.5 cm) AAA disease. METHODS: One hundred and forty patients with small AAAs (72 +/- 8 yr) were randomized to exercise training (n = 72) or usual care (n = 68). Exercise subjects participated in a combination of in-house and home training for up to 3 yr. Cardiopulmonary exercise testing (CPX) was performed at baseline and 3, 12, 24, and 36 months. Comparisons were made for AAA expansion, safety, CPX responses, and weekly energy expenditure. RESULTS: The average duration of participation was 23.4 +/- 9.6 months; 81% of subjects completed >=1 year. No adverse clinical events or excessive AAA growth rates related to training occurred. Exercise subjects expended a mean 1999 +/- 1030 kcal.wk. Increases in peak exercise time and estimated METs occurred at the 3-month and 1-, 2-, and 3 yr evaluations (P < 0.01 between groups). A significant between-group interaction occurred for VO2 at the ventilatory threshold (P = 0.02), and submaximal heart rate was significantly reduced among exercise subjects. Neither exercise status nor level of fitness significantly influenced rate of AAA enlargement. CONCLUSIONS: These results support the safety and efficacy of training in patients with small AAA, a population for which few previous data are available. Despite advanced age and comorbidities, training up to 3 yr was well tolerated and sustainable in AAA patients. Training did not influence rate of AAA enlargement. PMID- 23793235 TI - The fatty acid amide hydrolase in lymphocytes from sedentary and active subjects. AB - PURPOSE: Endocannabinoids (eCB) and interleukin 6 (IL-6) levels change during physical activity, thus suggesting their involvement in the modulation of exercise-related processes like inflammation and energy homeostasis. To investigate whether lifestyle might affect the activity of the eCB-degrading enzyme fatty acid amide hydrolase (FAAH), active and sedentary subjects were enrolled. METHODS: Plasma IL-6 levels and lymphocyte FAAH activity of eight physically active male subjects (mean +/- SEM; age = 39.3 +/- 2.9 yr, body mass index = 21.1 +/- 0.4 kg.m), usually practicing aerobic exercise (8.1 +/- 1.2 h.wk), and eight sedentary subjects (38.8 +/- 3.7 yr, body mass index = 23.1 +/- 0.8 kg.m) were measured. Also, in vitro effect of IL-6 was tested on FAAH expression and activity and on FAAH promoter activity in lymphocytes from sedentary subjects. RESULTS: Under resting conditions (at least 12 h from the last exercise), the active group showed plasma IL-6 levels (2.74 +/- 0.73 pg.mL) and lymphocyte FAAH activity (215.7 +/- 38.5 pmol.min.mg protein) significantly higher than those measured in the sedentary group (0.20 +/- 0.02 pg.mL, and 42.0 +/- 4.2 pmol.min.mg protein). Increased IL-6 levels paralleled increased FAAH activity, and consistently, the in vitro treatment of lymphocytes from sedentary individuals with 10 ng.mL IL-6 for 48 h significantly increased FAAH expression and activity. Transient transfection experiments showed that IL-6 induced the expression of a reporter gene under the control of a cAMP response element-like region in the human FAAH promoter. A mutation in the same element abolished IL-6 up-regulation, demonstrating that this cytokine regulates FAAH activity at the transcriptional level. CONCLUSION: IL-6 leads to activation of the FAAH promoter, thus enhancing FAAH activity that modulates the eCB tone in physically active people. PMID- 23793236 TI - Does the environment around the H-cluster allow coordination of the pendant amine to the catalytic iron center in [FeFe] hydrogenases? Answers from theory. AB - [FeFe] hydrogenases are H2-evolving enzymes that feature a diiron cluster in their active site (the [2Fe]H cluster). One of the iron atoms has a vacant coordination site that directly interacts with H2, thus favoring its splitting in cooperation with the secondary amine group of a neighboring, flexible azadithiolate ligand. The vacant site is also the primary target of the inhibitor O2. The [2Fe]H cluster can span various redox states. The active-ready form (Hox) attains the Fe(II)Fe(I) state. States more oxidized than Hox were shown to be inactive and/or resistant to O2. In this work, we used density functional theory to evaluate whether azadithiolate-to-iron coordination is involved in oxidative inhibition and protection against O2, a hypothesis supported by recent results on biomimetic compounds. Our study shows that Fe-N(azadithiolate) bond formation is favored for an Fe(II)Fe(II) active-site model which disregards explicit treatment of the surrounding protein matrix, in line with the case of the corresponding Fe(II)Fe(II) synthetic system. However, the study of density functional theory models with explicit inclusion of the amino acid environment around the [2Fe]H cluster indicates that the protein matrix prevents the formation of such a bond. Our results suggest that mechanisms other than the binding of the azadithiolate nitrogen protect the active site from oxygen in the so-called H ox (inact) state. PMID- 23793237 TI - Multiplexed MS/MS for improved data-independent acquisition. AB - In mass spectrometry-based proteomics, data-independent acquisition (DIA) strategies can acquire a single data set useful for both identification and quantification of detectable peptides in a complex mixture. However, DIA data are noisy owing to a typical five- to tenfold reduction in precursor selectivity compared to data obtained with data-dependent acquisition or selected reaction monitoring. We demonstrate a multiplexing strategy, MSX, for DIA analysis that increases precursor selectivity fivefold. PMID- 23793238 TI - Tightly anchored tissue-mimetic matrices as instructive stem cell microenvironments. AB - A major obstacle in defining the exact role of extracellular matrix (ECM) in stem cell niches is the lack of suitable in vitro methods that recapitulate complex ECM microenvironments. Here we describe a methodology that permits reliable anchorage of native cell-secreted ECM to culture carriers. We validated our approach by fabricating two types of human bone marrow-specific ECM substrates that were robust enough to support human mesenchymal stem cells (MSCs) and hematopoietic stem and progenitor cells in vitro. We characterized the molecular composition, structural features and nanomechanical properties of the MSC-derived ECM preparations and demonstrated their ability to support expansion and differentiation of bone marrow stem cells. Our methodology enables the deciphering and modulation of native-like multicomponent ECMs of tissue-resident stem cells and will therefore prepare the ground for a more rational design of engineered stem cell niches. PMID- 23793239 TI - Biowire: a platform for maturation of human pluripotent stem cell-derived cardiomyocytes. AB - Directed differentiation protocols enable derivation of cardiomyocytes from human pluripotent stem cells (hPSCs) and permit engineering of human myocardium in vitro. However, hPSC-derived cardiomyocytes are reflective of very early human development, limiting their utility in the generation of in vitro models of mature myocardium. Here we describe a platform that combines three-dimensional cell cultivation with electrical stimulation to mature hPSC-derived cardiac tissues. We used quantitative structural, molecular and electrophysiological analyses to explain the responses of immature human myocardium to electrical stimulation and pacing. We demonstrated that the engineered platform allows for the generation of three-dimensional, aligned cardiac tissues (biowires) with frequent striations. Biowires submitted to electrical stimulation had markedly increased myofibril ultrastructural organization, elevated conduction velocity and improved both electrophysiological and Ca(2+) handling properties compared to nonstimulated controls. These changes were in agreement with cardiomyocyte maturation and were dependent on the stimulation rate. PMID- 23793242 TI - Translating community-based participatory research principles into practice. AB - BACKGROUND: Although academics are trained in research methods, few receive formal training in strategies for implementing equitable community engaged research. Academics and their community partners can benefit from such direction and assistance as they establish and maintain community-based participatory research (CBPR) partnerships. Research partners from the University of Pittsburgh, the Johns Hopkins Center for Injury Research and Policy, and the House of Ruth Maryland, one of the nation's leading domestic violence centers serving Baltimore and the surrounding areas, joined together to design, implement, and evaluate a series of activities to increase local CPBR capacity. OBJECTIVES: This article provides an overview of process and findings from two CBPR workshops jointly held for academic and community members and explores specific suggestions from the workshop participants about how to put the CBPR principles into practice to promote community engaged research to address intimate partner violence (IPV). METHODS: Twenty-four academic and community partners with experience addressing IPV participated in the two workshops. Facilitators led discussions based on the core CPBR principles. Participants were asked to interpret those principles, identify actions that could help to put the principles into practice, and discuss challenges related to CBPR approaches for IPV research. Observational notes and transcripts of the discussions and workshop evaluations are summarized. RESULTS: The CBPR principles were interpreted and revised through consensus into common language that reflected the group discussion of the core CBPR principles. Workshop participants provided a range of actions for putting the principles into practice and identified the need for sensitivity in relation to IPV research. A majority of participants felt that the workshop generated novel ideas about how they could use CPBR in their own work. CONCLUSIONS: Translating CBPR principles into common, action-oriented language is a useful first step when building a new academic-community research partnership. PMID- 23793244 TI - "Making a place of respect": lessons learned in carrying out consent protocol with First Nations elders. AB - BACKGROUND: This article explores the issue of informed consent by First Nations Elders modifying and implementing a substance abuse prevention program for youth, Nimi Icinohabi, among the Alexis Nakota Sioux Nation. The Elders who approved and guided the research maintained that informed consent procedures carried out by the Western academic institutions were redundant given adherence to their own culturally based protocol. OBJECTIVES: The objective of this article is to present lessons learned regarding the cultural basis of consent involving First Nations Elders to improve our own and other researchers' ethical practice in this context. METHODS: Two focus groups were held with our team of community and university-based researchers (n = 6) to discuss our experience of the Elder consent procedures used during the project. RESULTS: Elder involvement was integral to the success of the program. Using methods of consent originating from Western thought and given historical and ongoing issues of trust with Western institutions, signing consent forms was unacceptable to them and perceived as undermining their own ethical practices. An oral consent process utilizing cultural protocol and a tool to keep track of participation in this process was subsequently approved by our Research Ethics Board (REB) and used successfully. CONCLUSIONS: When researchers use standard informed consent practices, they risk losing the trust of community partners by undermining cultural values and practices. As academic researchers, it is our ethical responsibility, in the spirit of restorative justice, to honor the principles of beneficence and justice in research by ensuring consent within the context of cultural protocol. PMID- 23793243 TI - Exploring cancer screening in the context of unmet mental health needs: a participatory pilot study. AB - BACKGROUND: Cancer is the leading cause of preventable death in the Bronx, New York. Service providers in this mental health provider shortage area identified untreated mental illness as an important barrier to participation in cancer screening, a finding that supports existing literature. The Mental Health and Cancer (MHC) Connection partnership formed to investigate and address this issue. OBJECTIVES: We sought to use an ecological framework to examine barriers and facilitators to obtaining mental health services in the Bronx, and to explore how lack of access to mental healthcare affects cancer screening. METHODS: In this community-based participatory research (CBPR)-driven pilot study, semistructured, qualitative interviews based on an ecological framework were conducted with 37 Bronx-based service providers representing a range of professional perspectives. Data were analyzed using thematic content analysis and techniques from grounded theory. RESULTS: Similar barriers and facilitators were reported for mental healthcare and cancer screening utilization across ecological levels. Providers emphasized the impact of urban poverty-related stressors on the mental health of their clients, and affirmed that mental health issues were a deterrent for cancer screening. They also recognized their own inability to connect clients effectively to cancer screening services, and rarely saw this as part of their present role. CONCLUSIONS: Findings highlight how unmet mental health needs can affect cancer screening in impoverished urban contexts. Participants recommended improving linkages across healthcare and social service providers to address mental health and cancer screening needs simultaneously. Study results are being used to plan a collaborative intervention in the Bronx through the MHC Connection partnership. PMID- 23793245 TI - A community-based wellness program to reduce depression in African Americans: results from a pilot intervention. AB - BACKGROUND: African Americans are less likely than non-Hispanic Whites to find antidepressants acceptable or seek care for depression. OBJECTIVE: To develop and pilot test a culturally tailored, community-based, psychoeducational wellness and exercise promotion program to reduce depressive symptoms in African Americans. METHODS: Participants were African Americans with moderate depressive symptoms who were interested in exercise but were not exercising regularly. They attended a 6-week psychoeducational group program during which they set personal activity goals and learned depression self-management skills. We conducted pre- and postintervention surveys and postintervention feedback sessions. RESULTS: Twenty one African Americans participated in the intervention. The program had excellent attendance and satisfaction. We found a large reduction in depressive symptoms, with mean Patient Health Questionnaire-9 (PHQ-9) scores dropping from 14.8 to 7.1 (p < .0001), and increases in exercise and depression self-efficacy and behaviors. CONCLUSIONS: This pilot study offers promising preliminary evidence to inform further research on the use of community-based, culturally tailored wellness programs to address depression. PMID- 23793246 TI - Assessing follow-up care after prostate-specific antigen elevation in American Indian / Alaska Native Men: a partnership approach. AB - BACKGROUND: Although many studies conducted among American Indian and Alaska Native (AI/AN) populations may help to advance medical science and lead to improvements in health and health care, historically few have endeavored to share their findings, benefits, and/or expected outcomes with the communities in which they are conducted. This perceived lack of responsiveness has contributed to a perception in some AI/AN communities that researchers are disrespectful and may not make community needs a priority. OBJECTIVES: In the context of a study assessing the care received by AI/AN men with incident elevated prostate-specific antigen (PSA) levels, this paper describes our experience building collaborative relationships, planning, conducting analyses, and disseminating findings with four AI/AN communities. METHODS: We established formal partnerships with three Northern Plains AI communities and one AN tribal health organization, convened a 12-member Community Advisory Board (CAB), and obtained study approvals from all necessary tribal and institutional review bodies before implementing our study. A menu of options for study implementation was given to key collaborators at each site. CAB members and collaborating tribes contributed to each phase of the study. After data analysis, results were shared with tribal and institutional leaders. LESSONS LEARNED: Face-to-face communication, flexibility, and adaptability, as well as clearly defined, respectful roles contributed to the success of the study on the part of both the researchers and community partners. CONCLUSIONS: This study demonstrates the importance and feasibility of forging collaborative relationships with AI/AN community leaders in regions of Alaska and the Northern Plains in cancer control initiatives for AI/AN men. PMID- 23793247 TI - Heart of Hypertension Project: development of a community-based prevention program for young African American men. AB - BACKGROUND: Early-onset hypertension (HTN) is a major contributor to shortened life expectancy of African American men. Lifestyle changes are known to reduce blood pressure (BP); however, interventions tailored for young African American men have not been developed. OBJECTIVES: With a community partner, we developed and assessed a HTN education and lifestyle intervention for young African American men. METHODS: A preliminary plan was presented to experts and to 18- to 22-year-old African American men, and revised based on their feedback. The revised plan (health screening and 6-week intervention) was tested with the focal group. LESSONS LEARNED: Participants were enthusiastic about the program and suggested improvements included increasing individualized guidance, building on relationships, and defining the Heart of Hypertension community. CONCLUSIONS: The Heart of Hypertension Project holds promise for HTN prevention among young African American men. The next steps are to incorporate feedback from participants into the approach and evaluate the effectiveness of the intervention on lifestyle change and BP in young African American men with pre-HTN. PMID- 23793248 TI - Community-based participatory research and user-centered design in a diabetes medication information and decision tool. AB - BACKGROUND: Together, community-based participatory research (CBPR), user centered design (UCD), and health information technology (HIT) offer promising approaches to improve health disparities in low-resource settings. OBJECTIVES: This article describes the application of CBPR and UCD principles to the development of iDecide/Decido, an interactive, tailored, web-based diabetes medication education and decision support tool delivered by community health workers (CHWs) to African American and Latino participants with diabetes in Southwest and Eastside Detroit. The decision aid is offered in English or Spanish and is delivered on an iPad in participants' homes. METHODS: The overlapping principles of CBPR and UCD used to develop iDecide/Decido include a user-focused or community approach, equitable academic and community partnership in all study phases, an iterative development process that relies on input from all stakeholders, and a program experience that is specified, adapted, and implemented with the target community. RESULTS: Collaboration between community members, researchers, and developers is especially evident in the program's design concept, animations, pictographs, issue cards, goal setting, tailoring, and additional CHW tools. CONCLUSIONS: The principles of CBPR and UCD can be successfully applied in developing health information tools that are easy to use and understand, interactive, and target health disparities. PMID- 23793250 TI - Fall risk and prevention needs assessment in an older adult Latino population: a model community global health partnership. AB - BACKGROUND: The impact of falls in older adults presents a significant public health burden. Fall risk is not well-described in Latino populations nor have fall prevention programs considered the needs of this population. OBJECTIVES: The objectives of this study were to develop a needs assessment of falls in older adult Latinos at a community center (CC), determine fall prevention barriers and strengths in this population, determine the level of interest in various fall prevention methods, and provide medical students an opportunity for participation in a culturally diverse community project. METHODS: A cross-sectional survey was conducted with a convenience sample of older adult program participants. The survey was developed in collaboration with both partners. CC participants were approached by the interviewer and asked to participate. They were read the survey in their preferred language and their answers were recorded. Data were analyzed using descriptive statistics. RESULTS: We conducted 103 interviews. We found that 54% of participants had fallen in the last year, and of those 21% required medical care, 81% were afraid of falling again, and 66% considered themselves at risk for falling again. Of all respondents, 52% had 5 or more of the 10 surveyed risk factors for falling; 4% had no risk factors. Of all respondents, 75% were afraid of falling. Talking with health care providers and participating in an exercise class were the preferred methods of health information delivery (78% and 65%, respectively). CONCLUSION: Older adult Latinos in this selected population frequently fall and are worried about falling. Risk factors are prevalent. A fall prevention program is warranted and should include exercise classes and a connection with local primary care providers. A partnership between an academic organization and a CC is an ideal collaboration for the future development of prevention program. PMID- 23793251 TI - Assessment of oral health needs and barriers to care in a Gullah community: Hollywood smiles. AB - OBJECTIVES: To assess the oral health (OH) needs and barriers to OH care in Gullah African American communities. METHODS: A community advisory board (CAB) was formed to guide the research study. Five focus groups (n = 27 participants) were conducted to explore the OH needs/barriers. Participants completed demographic surveys and participated in discussions facilitated by open-ended questions. All sessions were audio-recorded, transcribed and analyzed using NVivo8. RESULTS: Facilitators of OH included positive experiences and modeling. Fear and access to care were the most cited barriers. Tooth extraction was the dental treatment of choice. Intervention recommendations included improving clinic access, using the churches to socially influence receipt of OH care, providing group educational sessions with OH specialists, and having local "lay people" to provide support and help to navigate OH care systems. CONCLUSIONS: The design of a multilevel, culturally and locally relevant intervention may lead to a decrease in OH disparities in Gullah communities. PMID- 23793252 TI - Building a navigation system to reduce cancer disparities among urban Black older adults. AB - BACKGROUND: Although cancer outcomes have improved in recent decades, substantial disparities by race, ethnicity, income, and education persist. Increasingly, patient navigation services are demonstrating success in improving cancer detection, treatment, and care and in reducing cancer health disparities. To advance progress in developing patient navigation programs, extensive descriptions of each component of the program must be made available to researchers and health service providers. OBJECTIVE: We sought to describe the components of a patient navigation program designed to improve cancer screening based on informed decision making on cancer screening and cancer treatment services among predominantly Black older adults in Baltimore City. METHODS: A community-academic participatory approach was used to develop a patient navigation program in Baltimore, Maryland. The components of the patient navigation system included the development of a community academic (advisory) committee (CAC); recruitment and selection of community health workers (CHWs)/navigators and supervisory staff, initial training and continuing education of the CHWs/navigators, and evaluation of CHWs/navigators. The study was approved by the Johns Hopkins Bloomberg School of Public Health Institutional Review Board. CONCLUSIONS: The incorporation of community-based participatory research principles into each facet of this patient navigation program facilitated the attainment of the intervention's objectives. This patient navigation program successfully delivered cancer navigation services to 1,302 urban Black older adults. Appropriately recruited, selected and trained CHWs monitored by an experienced supervisor and investigators are the key elements in a patient navigation program. This model has the potential to be adapted by research and health service providers. PMID- 23793253 TI - Training community health students to develop community-requested social marketing campaigns: an innovative partnership. AB - BACKGROUND: This paper describes a sustained partnership between a university community health program and local and regional community health agencies. As a key component of the Health Communication and Social Marketing course, the partnership involves undergraduate community health students working for and with community agencies and community members to design social marketing campaigns based on community-identified health needs. OBJECTIVES: The goals of the course are to (1) provide students with the opportunity to work within the community to apply their skills in program planning, evaluation, and communication and (2) provide community agencies with a tailored campaign that can be implemented in their communities. METHODS: Throughout the 10-week quarter, teams of students follow the principles of community participation in planning a social marketing campaign. These include (1) audience segmentation and formative assessment with the intended audience to determine campaign content and strategies and (2) pretesting and revisions of campaign messages and materials based on community feedback. CONCLUSION: This partnership contributes to the promotion of health in the local community and it builds the skills and competencies of future health educators. It demonstrates a successful and sustainable combination of community based participatory research and experiential learning. From 2005 to 2011, 35 campaigns have been developed, many which have been implemented. PMID- 23793255 TI - Can music lessons increase the performance of preschool children in IQ tests? AB - The impact of music on human cognition has a distinguished history as a research topic in psychology. The focus of the present study was on investigating the effects of music instruction on the cognitive development of preschool children. From a sample of 154 preschool children of Tehran kindergartens, 60 children aged between 5 and 6 were randomly assigned to two groups, one receiving music lessons and the other (matched for sex, age and mother's educational level) not taking part in any music classes. Children were tested before the start of the course of music lessons and at its end with 4 subtests of the Tehran-Stanford-Binet Intelligence Scale (TSB). The experimental group participated in twelve 75-min weekly music lessons. Statistical analysis showed significant IQ increase in participants receiving music lessons, specifically on the TSB verbal reasoning and short-term memory subtests. The numerical and visual/abstract reasoning abilities did not differ for the two groups after lessons. These data support studies that found similar skills enhancements in preschool children, despite vast differences in the setting in which the instruction occurred. These findings appear to be consistent with some neuroimaging and neurological observations which are discussed in the paper. PMID- 23793256 TI - BACTEC FX system as a tool for culturing gastric biopsies and Helicobacter pylori diagnosis. AB - Helicobacter pylori infection represents a key factor in the etiology of various gastrointestinal diseases. There are several acceptable methods to identify this microorganism. Some are invasive and some are noninvasive. This study demonstrates the use of BACTEC FX system for the growth and diagnosis of H. pylori isolated from gastric biopsy specimens, cut and placed in blood culture bottles, with subsequent incubation in the apparatus. Twenty-five positive and 15 negative biopsy samples tested using the quick urease technique, CUTest, were collected from 40 patients with confirmed chronic gastric inflammation. The biopsy samples were manually cut using a sterile scalpel and placed in tubes containing 5 ml of fetal bovine serum. The resulting suspensions were transferred using a syringe into anaerobic blood culture bottles. These bottles were incubated at 35 degrees C for a period of 7 days in the BACTEC FX system. All biopsy samples that reacted positive to the CUTest and one biopsy sample that reacted negative to the CUTest were confirmed as positive by the BACTEC FX system. In addition, there was a correlation between the positive culture and histology examination results. The use of BACTEC FX system significantly shortens the time needed for culturing, which makes the system more efficient in the identification of H. pylori. It should be emphasized that performing microbial culture testing has a significant role in monitoring antibiotic resistance, which cannot be done using other existing methods for H. pylori diagnosis. PMID- 23793257 TI - Isolation and characterization of Pseudoalteromonas sp. from fermented Korean food, as an antagonist to Vibrio harveyi. AB - The microbial intervention for sustainable management of aquaculture, especially use of probiotics, is one of the most popular and practical approaches towards controlling pathogens. Vibrio harveyi is a well-known pathogenic bacterium, which is associated to a huge economic loss in the aquaculture system by causing vibriosis. The present study is crafted for screening and characterization of anti-Vibrio strains, which were isolated from various traditional fermented Korean foods. A total of 196 strains have been isolated from soybean paste (78 strains), red chili paste (49 strains), soy sauce (18 strains), jeotgal-a salted fish (34 strains), and the gazami crab-Portunus trituberculatus (17 strains). Fifteen strains showed an inhibitory effect on the growth of V. harveyi when subjected to coculture condition. Among the strains isolated, one has been identified as a significant anti-Vibrio strain. Further biochemical characterization and 16S rDNA sequencing revealed it as Pseudoalteromonas aliena, which had been deposited at the Korean Culture Center of Microorganisms (KCCM), Korea and designated as KCCM 11207P. The culture supernatants did not have any antimicrobial properties either in pure or in coculture condition. The culture supernatant was not toxic when supplemented to the swimming crab, Zoea, and Artemia larvae in aquaculture system. The results were very encouraging and showed a significant reduction in accumulated mortality. Here, we reported that pathogenic vibriosis can be controlled by Pseudoalteromonas sp. under in vitro and in vivo conditions. The results indicated that the biotic treatment offers a promising alternative to the use of antibiotics in crab aquaculture. PMID- 23793258 TI - Bioinformatics and molecular biology for the quantification of closely related bacteria. AB - Molecular biological methods for mixed culture analysis outshine conventional culture-based techniques in terms of better sensitivity and reliability. The majority of these methods exploit the 16S rRNA sequences of the community DNA, which often fall short for the analysis of closely related microorganisms. This research details the development and validation of a comprehensive methodology to differentiate and quantitatively characterize two Pseudomonas species in a mixed culture. A bioinformatics tool based on whole-genome polymorphism comparison was used to identify marker sequences to differentiate the two bacteria using quantitative real-time PCR. The quantification of the two species was achieved through a correlation of the genomic DNA versus cell number (genomic DNA purification) and threshold cycle number versus genomic DNA (real-time PCR). Several factors including the limitation of genomic DNA purification, effects of substrate concentrations and growth phase on cellular DNA, and choice of simplex or duplex reaction for real-time PCR were considered and evaluated. The developed method was experimentally validated against synthetically constructed consortia. PMID- 23793259 TI - Ernst Chain: a great man of science. AB - This paper is a tribute to the scientific accomplishments of Ernst Chain and the influence he exerted over the fields of industrial microbiology and biotechnology. Chain is the father of the modern antibiotic era and all the benefits that these therapeutic agents have brought, i.e., longer life spans, greater levels of public health, widespread modern surgery, and control of debilitating infectious diseases, including tuberculosis, gonorrhea, syphilis, etc. Penicillin was the first antibiotic to become commercially available, and its use ushered in the age of antibiotics. The discovery of penicillin's bactericidal action had been made by Alexander Fleming in London in 1928. After publishing his observations in 1929, no further progress was made until the work was picked up in 1939 by scientists at Oxford University. The group was headed by Howard Florey, and Chain was the group's lead scientist. Chain was born and educated in Germany, and he fled in 1933 as a Jewish refugee from Nazism to England. Other important members of the Oxford research team were Norman Heatley and Edward Abraham. The team was able to produce and isolate penicillin under conditions of scarce resources and many technical challenges. Sufficient material was collected and tested on mice to successfully demonstrate penicillin's bactericidal action on pathogens, while being nontoxic to mammals. Chain directed the microbiological methods for producing penicillin and the chemical engineering methods to extract the material. This technology was transferred to US government facilities in 1941 for commercial production of penicillin, becoming an important element in the Allied war effort. In 1945, the Nobel Prize for medicine was shared by Fleming, Florey, and Chain in recognition of their work in developing penicillin as a therapeutic agent. After World War II, Chain tried to persuade the British government to fund a new national antibiotic industry with both research and production facilities. As resources were scarce in postwar Britain, the British government declined the project. Chain then took a post in 1948 at Rome's Instituto Superiore di Sanita, establishing a new biochemistry department with a pilot plant. During that period, his department developed important new antibiotics (including the first semisynthetic antibiotics) as well as improved technological processes to produce a wide variety of important microbial metabolites that are still in wide use today. Chain was also responsible for helping several countries to start up a modern penicillin industry following World War II, including the Soviet Union and the People's Republic of China. In 1964, Chain returned to England to establish a new biochemistry department and industrial scale fermentation pilot plant at Imperial College in London. Imperial College became the preeminent biochemical department in Europe. Chain was also a pioneer in changing the relationship between government, private universities, and private industry for collaboration and funding to support medical research. Ernst Chain has left a lasting impact as a great scientist and internationalist. PMID- 23793260 TI - Enhanced thermal stability of Pseudomonas aeruginosa lipoxygenase through modification of two highly flexible regions. AB - Lipoxygenase (LOX; EC 1.13.11.12) is an enzyme which is widely used in food industry to improve aroma and rheological or baking properties of foods. A series of studies have proven that the flexible regions negatively relates to the thermal stability of enzymes. In this study, two highly flexible regions, residues(20-49) and residues(201-206), were modified to improve the thermal stability of LOX from Pseudomonas aeruginosa. Deletion of the first 20 and 30 residues of the former region increased the thermal stability of the LOX by 1.3- and 2.1-fold, respectively. Although deletion of the residues(201-206) led to a sharp reduction of both thermal stability and catalytic activity of the enzyme, the residue substitutions with the glycines (G204P, G206P, and G204P/G206P) or even glycine-rich linker (L6/PT) within this region increased the thermal stability of LOX by values ranging from 0.46- to 3.45-fold. To be noted, over 85% of the specific activity was maintained in all thermally stabilized LOX mutants. Circular dichroism and fluorescence analysis showed that the overall secondary and tertiary structures were not significantly changed by these modifications. To the best of our knowledge, this is the first report on increasing the thermal stability of LOX by protein engineering without remarkably affecting the catalytic rate. PMID- 23793261 TI - Characterization of a newly synthesized carbonyl reductase and construction of a biocatalytic process for the synthesis of ethyl (S)-4-chloro-3-hydroxybutanoate with high space-time yield. AB - A carbonyl reductase (SCR2) gene was synthesized and expressed in Escherichia coli after codon optimization to investigate its biochemical properties and application in biosynthesis of ethyl (S)-4-chloro-3-hydroxybutanoate ((S)-CHBE), which is an important chiral synthon for the side chain of cholesterol-lowering drug. The recombinant SCR2 was purified and characterized using ethyl 4-chloro-3 oxobutanoate (COBE) as substrate. The specific activity of purified enzyme was 11.9 U mg(-1). The optimum temperature and pH for enzyme activity were 45 degrees C and pH 6.0, respectively. The half-lives of recombinant SCR2 were 16.5, 7.7, 2.2, 0.41, and 0.05 h at 30 degrees C, 35 degrees C, 40 degrees C, 45 degrees C, and 50 degrees C, respectively, and it was highly stable in acidic environment. This SCR2 displayed a relatively narrow substrate specificity. The apparent K m and V max values of purified enzyme for COBE are 6.4 mM and 63.3 MUmol min(-1) mg(-1), respectively. The biocatalytic process for the synthesis of (S)-CHBE was constructed by this SCR2 in an aqueous-organic solvent system with a substrate fed-batch strategy. At the final COBE concentration of 1 M, (S)-CHBE with yield of 95.3% and e.e. of 99% was obtained after 6-h reaction. In this process, the space-time yield per gram of biomass (dry cell weight, DCW) and turnover number of NADP(+) to (S)-CHBE were 26.5 mmol L(-1) h(-1) g(-1) DCW and 40,000 mol/mol, respectively, which were the highest values as compared with other works. PMID- 23793263 TI - RNA interference screens to uncover membrane protein biology. AB - In this review, we discuss the use of RNA interference screens to identify genes involved in the regulation and function of membrane proteins. Briefly, cells expressing the membrane protein of interest can be transduced with a pooled lentiviral short-hairpin RNA (shRNA) library containing tens of thousands of unique shRNAs. Transduced cells are then selected or fractionated based on specific critera, such as membrane protein expression or function. shRNAs from selected cell populations are then deconvoluted and quantified using microarray analyses or high-throughput sequencing technologies. This allows individual shRNAs to be scored and cutoffs can be made to generate a list of shRNA hits. Bioinformatic analyses of gene targets of shRNA hits can be used to identify pathways and processes associated with membrane protein biology. To illustrate this functional genomics approach, we discuss pooled lentiviral shRNA screens that were performed to identify genes that regulate the transcription and cell surface expression of the cancer stem cell marker CD133. This approach can be adapted to study other membrane proteins, as well as specific aspects of membrane proteins, such as their function or downstream signaling effects. PMID- 23793265 TI - Thermodynamic considerations for solubility and conformational transitions of poly-N-isopropyl-acrylamide. AB - Thermodynamic considerations based on the free energy of hydration, free energy of solvation and partition coefficient predictions of the monomer N-isopropyl acrylamide (NIPAM) determined using various intermolecular potentials are used to elucidate the origin of hydrophobicity/hydrophilicity across the lower critical solution temperature (LCST). Thermodynamic properties are predicted for NIPAM using adaptive bias force-molecular dynamics and various popular force-fields (AMBER, OPLS-AA, CHARMM and GROMOS) at four different temperatures: below the LCST (275 K and 300 K) and above the LCST (310 K and 330 K). The effect of changes in the thermodynamic properties of the monomer NIPAM at various temperatures below and above LCST on the kinetics of conformational transition of thermo-sensitive polymers is discussed. Our findings provide encouraging prospects for understanding the LCST transition in the hydrogel poly-N isopropylacrylamide which shows temperature-dependent conformational changes in part due to the complex interplay of hydrophilic/hydrophobic interactions. PMID- 23793264 TI - Functional genomics of Plasmodium falciparum using metabolic modelling and analysis. AB - Plasmodium falciparum is an obligate intracellular parasite and the leading cause of severe malaria responsible for tremendous morbidity and mortality particularly in sub-Saharan Africa. Successful completion of the P. falciparum genome sequencing project in 2002 provided a comprehensive foundation for functional genomic studies on this pathogen in the following decade. Over this period, a large spectrum of experimental approaches has been deployed to improve and expand the scope of functionally annotated genes. Meanwhile, rapidly evolving methods of systems biology have also begun to contribute to a more global understanding of various aspects of the biology and pathogenesis of malaria. Herein we provide an overview on metabolic modelling, which has the capability to integrate information from functional genomics studies in P. falciparum and guide future malaria research efforts towards the identification of novel candidate drug targets. PMID- 23793266 TI - Efficacy of sorafenib in patients with hepatocellular carcinoma refractory to transcatheter arterial chemoembolization. AB - BACKGROUND: The efficacy of sorafenib for hepatocellular carcinoma (HCC) patients refractory to transcatheter arterial chemoembolization (TACE) has not yet been clarified. We investigated the efficacy of sorafenib in HCC patients who were refractory to TACE (sorafenib group) and retrospectively compared the results with those of patients treated with hepatic arterial infusion chemotherapy using cisplatin (cisplatin group). METHODS: We evaluated the anti-tumor effect, the time to progression, and the overall survival in 48 patients in the sorafenib group and 66 patients in the cisplatin group. RESULTS: The disease control rate to sorafenib was 60.4 %, the median time to progression was 3.9 months, and the median survival time was 16.4 months in patients who were refractory to TACE. When compared with the cisplatin group, significant differences in the patient characteristics were not observed between the two groups with the exception of patient age; however, the disease control rate (cisplatin group 28.8 %, P = 0.001), time to progression (cisplatin group: median 2.0 months, hazard ratio 0.44, P < 0.01), and overall survival (cisplatin group: median 8.6 months, hazard ratio 0.57, P < 0.001) were significantly superior in the sorafenib group. The multivariate analysis also showed the sorafenib treatment to be the most significant factor contributing to prolongation of time to progression and overall survival. CONCLUSIONS: Sorafenib showed favorable treatment results in patients refractory to TACE. When compared with hepatic arterial infusion chemotherapy using cisplatin, sorafenib demonstrated a significantly higher disease control rate, a longer time to progression and increased overall survival. PMID- 23793267 TI - Health status, risk factors, and medical conditions among persons enrolled in Medicaid vs uninsured low-income adults potentially eligible for Medicaid under the Affordable Care Act. AB - IMPORTANCE: Under the Affordable Care Act (ACA), states can extend Medicaid eligibility to nearly all adults with income no more than 138% of the federal poverty level. Uncertainty exists regarding the scope of medical services required for new enrollees. OBJECTIVE: To document the health care needs and health risks of uninsured adults who could gain Medicaid coverage under the ACA. These data will help physicians, other clinicians, and state Medicaid programs prepare for the possible expansions. DESIGN, SETTING, AND PATIENTS: Data from the National Health and Nutrition Examination Survey 2007-2010 were used to analyze health conditions among a nationally representative sample of 1042 uninsured adults aged 19 through 64 years with income no more than 138% of the federal poverty level, compared with 471 low-income adults currently enrolled in Medicaid. MAIN OUTCOMES AND MEASURES: Prevalence and control of diabetes, hypertension, and hypercholesterolemia based on examinations and laboratory tests, measures of self-reported health status including medical conditions, and risk factors such as measured obesity status. RESULTS: Compared with those already enrolled in Medicaid, uninsured adults were less likely to be obese and sedentary and less likely to report a physical, mental, or emotional limitation. They also were less likely to have several chronic conditions. For example, 30.1% (95% CI, 26.8%-33.4%) of uninsured adults had hypertension, hypercholesterolemia, or diabetes compared with 38.6% (95% CI, 32.0%-45.3%) of those enrolled in Medicaid (P = .02). However, if they had these conditions, uninsured adults were less likely to be aware of them and less likely to have them controlled. For example, 80.1% (95% CI, 75.2%-85.1%) of the uninsured adults with at least 1 of these 3 conditions had at least 1 uncontrolled condition, compared with 63.4% (95% CI, 53.7%-73.1%) of adults enrolled in Medicaid. CONCLUSION AND RELEVANCE: Compared with adults currently enrolled in Medicaid, uninsured low-income adults potentially eligible to enroll in Medicaid under the ACA had a lower prevalence of many chronic conditions. A substantial proportion of currently uninsured adults with chronic conditions did not have good disease control; projections based on sample weighting suggest this may represent 3.5 million persons (95% CI, 2.9 million-4.2 million). These adults may need initial intensive medical care following Medicaid enrollment. PMID- 23793268 TI - Trypsin digest protocol to analyze the retinal vasculature of a mouse model. AB - Trypsin digest is the gold standard method to analyze the retinal vasculature (1 5). It allows visualization of the entire network of complex three-dimensional retinal blood vessels and capillaries by creating a two-dimensional flat-mount of the interconnected vascular channels after digestion of the non-vascular components of the retina. This allows one to study various pathologic vascular changes, such as microaneurysms, capillary degeneration, and abnormal endothelial to pericyte ratios. However, the method is technically challenging, especially in mice, which have become the most widely available animal model to study the retina because of the ease of genetic manipulations (6,7). In the mouse eye, it is particularly difficult to completely remove the non-vascular components while maintaining the overall architecture of the retinal blood vessels. To date, there is a dearth of literature that describes the trypsin digest technique in detail in the mouse. This manuscript provides a detailed step-by-step methodology of the trypsin digest in mouse retina, while also providing tips on troubleshooting difficult steps. PMID- 23793269 TI - FACS analysis of neuronal-glial interactions in the nucleus accumbens following morphine administration. AB - RATIONALE: Glia, including astrocytes and microglia, can profoundly modulate neuronal function and behavior; however, very little is known about the signaling molecules that govern neuronal-glial communication and in turn affect behavior. Morphine treatment activates microglia and astrocytes in the nucleus accumbens (NAcc) to induce the synthesis of cytokines and chemokines, and this has important implications for addictive behavior. Blocking morphine-induced glial activation using the nonspecific glial inhibitor, ibudilast, has no effect on the initial rewarding properties of morphine, but completely prevents the relapse of drug-seeking behavior months later. OBJECTIVES: We sought to determine the cellular source of these cytokines and chemokines in the NAcc in response to morphine, and the cell-type-specific expression pattern of their receptors to determine whether neurons have the capacity to respond to these immune signals directly. METHODS: We used fluorescence-activated cell sorting of neurons (Thy1+), astrocytes (GLT1+), and microglia (CD11b+) from the NAcc for the analysis of cell type specific gene expression following morphine or saline treatment. RESULTS: The results indicate that microglia and neurons each produce a subset of chemokines in response to morphine and that neurons have the capacity to respond directly to a select group of these chemokines via their receptors. In addition, we provide evidence that microglia are capable of responding directly to dopamine release in the NAcc. CONCLUSIONS: Future studies will examine the mechanism(s) by which neurons respond to these immune signals produced by microglia in an effort to understand their effect on addictive behaviors. PMID- 23793271 TI - DSM-5: the more it changes the more it is the same. PMID- 23793270 TI - Assessment of field portable X-ray fluorescence spectrometry for the in situ determination of heavy metals in soils and plants. AB - In soil pollution studies, large numbers of soil samples collected at random need to be processed and analyzed to determine their heavy metal contents. This study was designed to assess the use of a field portable X-ray fluorescence (FPXRF) spectrometry system for the in situ determination of heavy metal levels in both soil and plant samples. First, we optimised the method using 84 reference soil standards and soil samples from known polluted sites. The optimised method was then used to determine heavy metals at three abandoned mine sites and two sealed landfills in central Spain. Given that knowledge of heavy metal levels in plants is important for the ecotoxicological study of these sites, the FPXRF device was also used to determine heavy metals in plants. Our results indicate the acceptable to high quality of the data provided by the system especially for soil samples. The cost-benefits and sustainability of this instrument in relation to other techniques were also examined. The use of the FPXRF system for the study of potentially polluted sites was found to save on costs, time and materials. Results indicate its suitable use for the preliminary screening of heavy-metal polluted sites. PMID- 23793272 TI - Neuroathesetics and growing interest in "positive affect" in psychiatry: new evidence and prospects for the theory of informational needs. AB - What are the necessary and sufficient conditions to experience pleasure in interpersonal communication and dealing with art, science, and philosophy - this is what the theory of informational needs (TIN) suggested eleven years ago is about. At the same time, at the beginning of this century, several lines of research have emerged. Neuroaesthetics has been established; the discovery of the mirror neuron system and theories about its function have appeared; a growing interest in positive affect and pleasure has developed in psychiatry and medicine. The purpose of the present paper is to reconsider the TIN (Brankovic 2001) in the context of the advance in neuroscience during the last decade and to show how much conceptual clarity is gained when the recent empirical and theoretical findings are viewed from the standpoint of the TIN. A computational model of the aesthetic response based on the TIN's two-factor model of hedonic value of stimuli is delineated. PMID- 23793273 TI - Structural neuroimaging in patients with panic disorder: findings and limitations of recent studies. AB - BACKGROUND: Panic disorder, a relatively common anxiety disorder, is often associated to agoraphobia and may be disabling. Its neurobiological underpinnings are unknown, despite the proliferation of models and hypotheses concerning it; investigating its correlates could provide the means for better understanding its pathophysiology. Recent structural neuroimaging techniques may contribute to the identification of possible brain morphological alterations that could be possibly related to the clinical expression of panic disorder. METHODS: Through careful major database searches, using terms keen to panic, agoraphobia, structural magnetic neuroimaging and the like, we identified papers published in peer-review journals and reporting data on the brain structure of patients with panic disorder. Included papers were used comparatively to speculate about the nature of reported brain structural alterations. RESULTS: Anxiety, which is the core feature of the disorder, correlates with the function of the amygdala, which showed a smaller volume in patients, as compared to healthy subjects. Data also showed a volumetric decrease of the anterior cingulate along with increased fractional anisotropy, and increase of some brainstem nuclei, particularly of the rostral pons. Other structures with reported volumetric correlates of panic disorder are the hippocampus and the parahippocampal cortices, the insula, the putamen, and the pituitary gland. Volumetric changes in the anterior cingulate, frontal, orbitofrontal, insular, and temporal cortices have also been described in structural neuroimaging studies. Major methodological limitations are considered in context. CONCLUSIONS: Several data point to the existence of structural neuroanatomical alterations in panic disorder, consisting in significant volumetric reductions or increases in different brain areas. White matter alterations were shown also in the only diffusion tensor imaging study performed to date. Available data do not allow us to conclude about the possible progression of these alterations. PMID- 23793274 TI - Personality profiles of patients with dysthymic and panic disorder. AB - BACKGROUND: The research objective was to identify personality characteristics as well as similarities between, and differences in personality profiles of persons suffering from Dysthymic (DD) and Panic Disorder (with/without Agoraphobia) (PD/PDA). SUBJECTS AND METHODS: Three groups (N=120) were analysed: DD, PD/PDA, and a healthy control group, matched by socio-demographic characteristics and classified in sub-groups according to gender. Diagnoses were made using the Structured Clinical Interview for DSM-IV DD and PD/PDA, and the personality assessment was made using the Minnesota Multiphasic Personality Inventory 201 (MMPI-201). RESULTS: MMPI-201 profile of DD and PD/PDA groups has been characterised by a global increase of "neurotic triad" scales (Depression Hypochondriasis-Hysteria) (D-Hs-Hy), more expressed in the DD group. Sub-groups of women and men with DD, when compared to the healthy control group, have a significant (p<0.01) increase on the F, Hs, D, Pd, Pa, Pt and Sc scales, and sub groups with PD/PDA a significant (p<0.01) increase on the F, Hs, D, Hy, Pa, Pt and Sc scales. Scores on the F, D, Hy, Hs, Pt, and Sc scales were significantly higher (p<0.05), as well as on the scale Pa (p<0.01) in men suffering from DD than in the PD/PDA sub-group. Women suffering from DD, when compared to the PD/PDA women, showed a significant increase (p<0.05) on the F and Hy scales. CONCLUSION: Personality profiles of persons suffering from DD and PD/PDA are very similar, with differences being more dimensional than qualitative. Theoretical and practical implications of these findings have been discussed. PMID- 23793275 TI - Different serum BDNF levels in depression: results from BDNF studies in FYR Macedonia and Bulgaria. AB - BACKGROUND: A growing body of evidence shows that brain-derived neurotrophic factor (BDNF) plays a role in depressive disorder. Serum BDNF levels are lower in depressed patients and they increase after a long course of antidepressant treatment. Our study aims to test the effect of antidepressant treatment on serum BDNF levels in patients with a depressive episode, after they have achieved remission in two studies in Macedonia and Bulgaria. SUBJECTS AND METHODS: In the Macedonian study 23 patients were included (11 female, 12 male) diagnosed with a first depressive episode according to ICD-10, as well as 23 control subjects age- and sex-matched without a history of psychiatric disorder. In the Bulgarian study 10 female patients with depression and 10 control subjects were included. We have applied the Hamilton Depression Rating Scale (HDRS) to assess depression severity. Blood samples were collected before antidepressive treatment and after remission was achieved (decrease to 7 points or less on HDRS). RESULTS: In the Macedonian study, mean serum BDNF level at baseline was 13.15+/-6.75 ng/ml and the mean HDRS score was 28.52+/-4.02. Untreated depressed patients showed significantly lower serum BDNF levels compared to the control group (25.95+/-9.17 ng/ml). After remission was achieved, the mean serum BDNF level was 24.73+/-11.80 ng/ml whereas the mean HDRS score was 7.04+/-3.15. After 8 weeks of treatment there was no statistically significant difference in the serum BDNF levels between the two groups. In the Bulgarian study, baseline mean serum BDNF levels were 26.84+/-8.66 ng/ml, after 3 weeks treatment and remission was achieved mean serum BDNF levels were 30.33+/-9.25 ng/ml and in the control group mean serum BDNF levels were 25.04+/-2.88 ng/ml. Integrated results showed baseline mean serum BDNF levels of 17.30+/-9.66 ng/ml, after achieved remission 26.43+/-11.25 ng/ml and in the control group mean serum BDNF levels of 25.68+/-7.76 ng/ml. CONCLUSION: The Bulgarian results showed no statistical difference between the depressed group and controls. The Integrated results and the Macedonian study supported previous findings of low BDNF levels in untreated depressive patients compared to healthy controls, and that those levels increase after antidepressant treatment. These results may suggest that low serum levels of BDNF are a state abnormality that is evident during depression and normalizes during remission. PMID- 23793276 TI - Brain derived neurotrophic factor (BDNF) levels in depressed women treated with open-label escitalopram. AB - BACKGROUND: Recent studies suggest the important role of brain derived neurotrophic factor (BDNF) in the etiopathogenesis of major depressive disorder (MDD) and the mechanism of action of antidepressants. This study aimed to correlate serum levels of BDNF and clinical symptoms in patients with MDD before and after 6 months treatment with escitalopram. SUBJECTS AND METHODS: Twenty women diagnosed with MDD and 20 aged-matched healthy female controls were recruited. The patients received escitalopram 10-20 mg/day. BDNF serum levels were measured at inclusion, week 4, week 12 and week 24. The Montgomery-Asberg Depression Rating Scale (MADRS) was used to assess the severity of depressive symptoms and the clinical evolution of patients. Statistical analysis was performed using both observed cases and last observation carried forward. RESULTS: At baseline, low serum levels of BDNF were associated with MDD. In women with MDD, escitalopram seems to have a positive effect on BDNF serum levels in parallel with the clinical response. CONCLUSIONS: This study suggests that a good clinical evolution under treatment with escitalopram might be associated with increases of BDNF levels in female patients. PMID- 23793277 TI - Asperger Syndrome: a frequent comorbidity in first diagnosed adult ADHD patients? AB - BACKGROUND: Because adult ADHD is often accompanied by psychiatric comorbidities, the diagnostic process should include a thorough investigation for comorbid disorders. Asperger-Syndrome is rarely reported in adult ADHD and commonly little attention is paid to this possible comorbidity. SUBJECTS AND METHODS: We investigated 53 adult ADHD-patients which visited our out patient clinic for first ADHD-diagnosis (17 females, 36 males; range of age: 18-56 years) for the frequency of a comorbid Asperger-Syndrome. Diagnosis of this autism-spectrum disorder was confirmed by applying the appropriate DSM-IV-criteria. Additionally we tested the power of the two screening-instruments "Autism-spectrum quotient" (AQ) and "Empathy quotient" (EQ) by Baron-Cohen for screening Asperger-Syndrome in adult ADHD. RESULTS: Eight ADHD-patients were diagnosed with a comorbid Asperger-Syndrome (15.1%). The difference in AQ- and EQ-scores between pure ADHD patients and comorbid patients was analysed, showing significantly higher scores in AQ and significant lower scores in EQ in comorbid patients. CONCLUSIONS: Results show that the frequency of Asperger-Syndrome seems to be substantially increased in adult ADHD (versus the prevalence of 0.06% in the general population), indicating that investigators of adult ADHD should also be attentive to autism-spectrum disorders. Especially the AQ seems to be a potential screening instrument for Asperger-Syndrome in adult ADHD-patients. PMID- 23793278 TI - The dynamics of haemostatic parameters in acute psychotic patients: a one-year prospective study. AB - BACKGROUND: The primary goal of the present study was to replicate our previous finding of increased coagulation and thrombocytes activity in drug-naive psychotic patients in comparison with healthy controls and ascertain whether the blood levels of thrombogenesis markers further increase over the course of a consecutive one-year antipsychotic treatment. SUBJECTS AND METHODS: We investigated the plasma levels of markers indicating activation of coagulation (D dimers and Factor VIII) and platelets (soluble P-selectin, sP-selectin) in an antipsychotic-naive group of nineteen men and seventeen women with acute psychosis (age 28.1+/-8.0 years, body mass index 22.6+/-4.2), and thirty-seven healthy volunteers matched for age, gender and body mass index. In the patient group, we repeated these assessments after three months and again after one year of antipsychotic treatment. RESULTS: D-dimers (median 0.38 versus 0.19 mg/l; p=0.00008), factor VIII (median 141.5% versus 110%; p=0.02) and sP-selectin (median 183.6 versus 112.4 ng/ml; p=0.00005) plasma levels were significantly increased in the group of patients with acute psychosis prior to treatment compared with healthy volunteers. The plasma levels of sP-selectin varied significantly (p=0.016) in the course of the one-year antipsychotic treatment, mainly between 3 and 6 months after start of therapy. The plasma levels of D dimers and factor VIII did not change significantly, D-dimers remained elevated in contrast to the healthy controls. CONCLUSIONS: Patients with acute psychosis had increased levels of markers of thrombogenesis in comparison to the healthy volunteers. The haemostatic parameters also remained elevated during the one-year antipsychotic treatment. PMID- 23793279 TI - Origins of suicidality: compatibility of lay and expert beliefs - qualitative study. AB - BACKGROUND: Today there exist different views on origins of suicidal behaviour, which can influence the help-seeking behaviour and the adherence to the treatment of suicidal people. SUBJECTS AND METHODS: The beliefs lay people and patients have about the origins of suicidal behaviour as well as the compatibility of their beliefs with the views of the mental health personnel (general practitioners and psychiatrists) were assessed. 45 semi-structured interviews with the general population, suicide attempters, general practitioners and psychiatrists were conducted, audio typed, transcribed and a thematic analysis of the data was carried out. RESULTS: The results indicated the incompatibility of the views. The general population and the suicide attempters favoured psychological explanations of suicidal behaviour, whereas the general practitioners and psychiatrists promoted medical explanations. The only common theme was perception of the suicidal crisis as a crucial factor in suicidality. CONCLUSIONS: Lay people and experts believe that suicidal crisis is the main origin of suicidal behaviour. The awareness of this common denominator and also of the differences in opinions between lay people and experts should be kept in mind when planning and implementing prevention and treatment programmes if we wish to promote help-seeking behaviour and attain good adherence to treatment. PMID- 23793280 TI - Who identifies with suicidal film characters? Determinants of identification with suicidal protagonists of drama films. AB - BACKGROUND: Identification with a media character is an influential factor for the effects of a media product on the recipient, but still very little is known about this cognitive process. This study investigated to what extent identification of a recipient with the suicidal protagonist of a film drama is influenced by the similarity between them in terms of sex, age, and education as well as by the viewer's empathy and suicidality. SUBJECTS AND METHODS: Sixty adults were assigned randomly to one of two film groups. Both groups watched a drama that concluded with the tragic suicide of the protagonist. Identification, empathy, suicidality, as well as socio-demographic data were measured by questionnaires that were applied before and after the movie screening. RESULTS: Results indicated that identification was not associated with socio-demographic similarity or the viewer's suicidality. However, the greater the subjects' empathy was, the more they identified with the protagonist in one of the two films. CONCLUSIONS: This investigation provides evidence that challenges the common assumption that identification with a film character is automatically generated when viewer and protagonist are similar in terms of sex, age, education or attitude. PMID- 23793281 TI - Differences in the size of personal space between persons with anxious and persons with psychotic disorders. AB - BACKGROUND: Personal space is the area individuals maintain around themselves into which others cannot intrude without arousing discomfort. The purpose of this study was to establish whether patients with anxiety disorder and patients with psychotic disorder differ in personal space preferences according to experimenter sex. SUBJECTS AND METHODS: 82 patients who met the ICD- criteria for psychotic and anxiety disorder participated in the study. Personal space was assessed using stop-distance method in which all subjects were approached by female and male experimenter from four directions. RESULTS: Personal space zone was significantly larger in the patients with anxiety disorder than in the patients with psychotic disorder. CONCLUSION: The results of this research can be seen as possible tendencies, rather than firm indications; it is necessary to make a further research, on a larger sample, of different aspects of psychotic and anxiety patients' personal spaces in a quest for the significances in their behavior in space. PMID- 23793282 TI - The frequency of dyscalculia among primary school children. AB - BACKGROUND: Formal education, daily living activities and jobs require knowledge and application skills of counting and simple mathematical operations. Problems with mathematics start in primary school and persist till adulthood. This is known as dyscalculia and its prevalence in the school population ranges from 3 to 6.5%. SUBJECTS AND METHODS: The study included 1424 third-grade students (aged 9 10) of all primary schools in the City of Kragujevac, Serbia. Tests in mathematics were given in order to determine their mathematical achievement. 1078 students (538 boys and 540 girls) completed all five tests. RESULTS: The frequency of dyscalculia in the sample was 9.9%. The difference between boys and girls according to the total score on the test was statistically significant (p<0.005). The difference between students according to their school achievement (excellent, very good, good, sufficient and insufficient) was statistically significant for all tests (p<0.0005). The influence of place of residence/school was significant for all tests (p<0.0005). Independent prognostic variables associated with dyscalculia are marks in mathematics and Serbian language. CONCLUSION: Frequency of dyscalculia of 9.9% in the sample is higher than in the other similar studies. Further research should identify possible causes of such frequency of dyscalculia in order to improve students' mathematical abilities. PMID- 23793283 TI - Change in frequency of acute and subacute effects of ecstasy in a group of novice users after 6 months of regular use. AB - BACKGROUND: Recent research trends are to specify the relation between patterns of ecstasy use and side effects, possibility of dependency, tolerance and long term neurocognitive damage. The objective of this study was to assess the impact of regular ecstasy use on its acute and subacute effects. SUBJECTS AND METHODS: At the first stage, we recruited 120 subjects. If participants continued regular use of ecstasy in this period, they were asked to participate in the second stage of the research 6 months later. Thirty-five subjects attended the second stage of the study, 5 of which were excluded because they had less than 5 drug experiences during the last 6 months. At last, we recruited 30 novice ecstasy users by means of the snowball technique in Tehran, Iran. The pattern of use and experienced effects of ecstasy was documented at the beginning and after 6 months of regular consumption with a self administered questionnaire. RESULTS: Little or no change was observed in acute effects. Those subacute effects that had considerable increase in frequency were anxiety, depression, aggression, memory impairment, poor concentration and learning problems. CONCLUSION: Small change in acute effects suggests low possibility of tolerance after at least 6 months of regular use. Our results support long term neurocognitive damage and mood impairment with ecstasy use. PMID- 23793284 TI - Evaluation of psychotherapeutic effects on borderline personality disorder: a case report. PMID- 23793285 TI - Clomethiazole-induced hepatotoxicity - a case report. PMID- 23793286 TI - A near-hanging patient with PTSD and acute stroke - an unusual condition for "off label" thrombolysis. PMID- 23793287 TI - Experience of psychiatry teaching at medical school influences Croatian medical students' attitudes towards choosing psychiatry as a career. AB - BACKGROUND: Reports indicate that the number of students interested in choosing psychiatry as their future profession is constantly decreasing in the last decades. Our aim was to determine the proportion of medical students intending to pursue a career in psychiatry and to define undergraduate education-related factors influencing that choice. SUBJECTS AND METHODS: We report the preliminary findings of a cross sectional quantitative survey of final year Croatian medical students as part of the International Survey Of Student Career Choice In Psychiatry (ISOSCCIP). We surveyed medical students attending their final year at Zagreb School of Medicine in the academic year 2009/2010, using a structured questionnaire examining demographics, students' preferences on future career choice and their evaluations of undergraduate psychiatry teaching. RESULTS: The overall student evaluation of the compulsory psychiatry curriculum was "average". Significantly higher ratings were reported by students who felt more involved in the teaching of the subject. The possibility of psychiatry as a career choice correlated significantly with better evaluation grades of psychiatry lectures. Furthermore, poor evaluation grades predicted a higher likelihood that medical students completely ruled out choosing a career in psychiatry. CONCLUSION: This is the first survey of this kind in Croatia. Student ratings of medical school psychiatric education and perceived involvement in teaching appears to influence the likelihood of a stated career in psychiatry. Addressing these issues may increase the number of students motivated to pursue psychiatry as their future career choice. PMID- 23793288 TI - [Diagnosis of atrial fibrillation. From the standard ECG to analysis of electrograms]. AB - The early diagnosis of asymptomatic atrial fibrillation is important because of the associated risk for arterial embolism. Routine ECG recording, however, is not effective in asymptomatic patients. The goal of this article is to show the general practitioner and internist how the search for atrial fibrillation can be made more efficacious. For example, recording an ECG in patients older than 65 years with irregularities in their pulse or repeated ECG recording in patients older than 75 years with hypertension shows improved results in this regard. It is interesting that elements of the CHA2DS2-VASc score, which was developed to predict risk for arterial embolism, are also effective for defining populations to screen for atrial fibrillation. In the subgroup of patients with a pacemaker or implantable converter-defibrillator (ICD), histograms or intracardiac electrograms can be used to identify previously undiagnosed atrial fibrillation. The general practitioner should take these results which are usually obtained by a cardiologist into consideration in the follow-up treatment of his or her patients. PMID- 23793289 TI - [Primary Hodgkin's lymphoma of the colon]. AB - Primary Hodgkin's lymphoma of the colon is exceedingly rare. We report on the case of a 74-year-old female patient presenting with weight loss and hematochezia. Proctocolonoscopy revealed a bleeding tumor localized in the right colonic flexure. Histological examination of initial mucosal biopsies could not verify malignancy; however, explorative surgery was decided in an interdisciplinary conference setting and right-sided hemicolectomy was performed. Macroscopically, a tumor measuring 5.5 cm in maximum diameter was found. By means of histology and immunohistochemistry the diagnosis of classic Hodgkin's lymphoma was made. Mesenteric lymph nodes were not affected and postoperative staging revealed no systemic spread. Therefore, the tumor fulfilled the criteria of a primary colonic Hodgkin's lymphoma. Diagnosis of primary colonic lymphoma can be difficult as clinical symptoms are typically unspecific and, as shown in this case, even primary biopsy histology can be falsely negative. PMID- 23793290 TI - Potent inhibition of aldehyde dehydrogenase-2 by diphenyleneiodonium: focus on nitroglycerin bioactivation. AB - Aldehyde dehydrogenase-2 (ALDH2) catalyzes vascular bioactivation of the antianginal drug nitroglycerin (GTN) to yield nitric oxide (NO) or a related species that activates soluble guanylate cyclase (sGC), resulting in cGMP mediated vasodilation. Accordingly, established ALDH2 inhibitors attenuate GTN induced vasorelaxation in vitro and in vivo. However, the ALDH2 hypothesis has not been reconciled with early studies demonstrating potent inhibition of the GTN response by diphenyleneiodonium (DPI), a widely used inhibitor of flavoproteins, in particular NADPH oxidases. We addressed this issue and investigated the effects of DPI on GTN-induced relaxation of rat aortic rings and the function of purified ALDH2. DPI (0.3 uM) inhibited the high affinity component of aortic relaxation to GTN without affecting the response to NO, indicating that the drug interfered with GTN bioactivation. Denitration and bioactivation of 1-2 uM GTN, assayed as 1,2-glycerol dinitrate formation and activation of purified sGC, respectively, were inhibited by DPI with a half-maximally active concentration of about 0.2 uM in a GTN-competitive manner. Molecular modeling indicated that DPI binds to the catalytic site of ALDH2, and this was confirmed by experiments showing substrate-competitive inhibition of the dehydrogenase and esterase activities of the enzyme. Our data identify ALDH2 as highly sensitive target of DPI and explain inhibition of GTN-induced relaxation by this drug observed previously. In addition, the data provide new evidence for the essential role of ALDH2 in GTN bioactivation and may have implications to other fields of ALDH2 research, such as hepatic ethanol metabolism and cardiac ischemia/reperfusion injury. PMID- 23793292 TI - Popliteal artery occlusion secondary to exostosis of the femur. AB - Osteochondromas are the most common benign tumors of the bone and are usually asymptomatic. In rare cases, they can present as a cause of lower extremity vascular injury in young patients. We report a case of a 24-year-old man who presented with an acute onset of exercise-induced lower extremity claudication and was found to have a popliteal artery occlusion secondary to a femoral exostosis. The patient underwent an excision of the exostosis and resection of the occluded segment with primary reanastomosis of the popliteal and superficial femoral arteries. Successful treatment of patients with vascular complications secondary to osteochondromas has generally required early surgical intervention. PMID- 23793291 TI - Hits of a high-throughput screen identify the hydrophobic pocket of autotaxin/lysophospholipase D as an inhibitory surface. AB - Autotaxin (ATX), a lysophospholipase D, plays an important role in cancer invasion, metastasis, tumor progression, tumorigenesis, neuropathic pain, fibrotic diseases, cholestatic pruritus, lymphocyte homing, and thrombotic diseases by producing the lipid mediator lysophosphatidic acid (LPA). A high throughput screen of ATX inhibition using the lysophosphatidylcholine-like substrate fluorogenic substrate 3 (FS-3) and ~10,000 compounds from the University of Cincinnati Drug Discovery Center identified several small-molecule inhibitors with IC50 vales ranging from nanomolar to low micromolar. The pharmacology of the three most potent compounds: 918013 (1; 2,4-dichloro-N-(3 fluorophenyl)-5-(4-morpholinylsulfonyl) benzamide), 931126 (2; 4-oxo-4-{2-[(5 phenoxy-1H-indol-2-yl)carbonyl]hydrazino}-N-(4-phenylbutan-2-yl)butanamide), and 966791 (3; N-(2,6-dimethylphenyl)-2-[N-(2-furylmethyl)(4-(1,2,3,4 tetraazolyl)phenyl)carbonylamino]-2-(4-hydroxy-3-methoxyphenyl) acetamide), were further characterized in enzyme, cellular, and whole animal models. Compounds 1 and 2 were competitive inhibitors of ATX-mediated hydrolysis of the lysophospholipase substrate FS-3. In contrast, compound 3 was a competitive inhibitor of both FS-3 and the phosphodiesterase substrate p-nitrophenyl thymidine 5'-monophosphate. Computational docking and mutagenesis suggested that compounds 1 and 2 target the hydrophobic pocket, thereby blocking access to the active site of ATX. The potencies of compounds 1-3 were comparable to each other in each of the assays. All of these compounds significantly reduced invasion of A2058 human melanoma cells in vitro and the colonization of lung metastases by B16-F10 murine melanoma cells in C57BL/6 mice. The compounds had no agonist or antagonist effects on select LPA or sphingosine 1-phosphate receptors, nor did they inhibit nucleotide pyrophosphatase/phosphodiesterase (NPP) enzymes NPP6 and NPP7. These results identify the molecular surface of the hydrophobic pocket of ATX as a target-binding site for inhibitors of enzymatic activity. PMID- 23793293 TI - Peripheral vascular complications during transcatheter aortic valve replacement: management and potential role of chronic steroid use. AB - PURPOSE: To report a case of a major vascular complication during transcatheter aortic valve replacement (TAVR) and the endovascular management thereof. Additionally, we discuss a possible correlation with long-term steroid use. CASE REPORT: A 79-year-old woman with a history of critical aortic stenosis underwent elective TAVR. Her procedure was complicated by rupture of her right iliac artery, life-threatening retroperitoneal hemorrhage, and thrombus extending into the distal right lower extremity. This case was emergently managed by stent placement, thrombectomy, and tissue plasminogen activator via a percutaneous approach. CONCLUSIONS: Peripheral vascular complications are common during percutaneous TAVR, and chronic steroid use may predispose patients. Endovascular management is often possible and may potentially save valuable time in emergent situations. PMID- 23793294 TI - Specific interactions between the quaternary ammonium oligoether-based ionic liquid and water as a function of pressure. AB - The interactions between Ammoeng 100 and water are probed using high-pressure infrared measurements and DFT-calculations. The results of infrared absorption profiles suggest that the energetically favored approach for water molecules to interact with Ammoeng 100 is via the formation of anion-water interactions, whereas the alkyl C-H groups play much less important roles. After comparison with pure Ammoeng 100, it appears that no appreciable changes in band frequencies of alkyl C-H vibrations occurred as Ammoeng 100 was mixed with D2O. The presence of D2O has a red-shift effect on the peak frequency of the S=O stretching vibration under the pressures below 1 GPa in comparison to the absorption frequencies of pure Ammoeng 100. This observation is likely related to local structures of the S=O groups interacting with D2O molecules. DFT-calculations indicate that the most energetically favored conformation of ion pairs should be the species having only one hydrophilic hydrogen bonding. The results of calculations reveal that water addition may induce the partial replacement of C H...O interactions with strong hydrogen bonding between anions and water molecules. PMID- 23793295 TI - Impact of the neonicotinoid acetamiprid on immature stages of the predator Eriopis connexa (Coleoptera: Coccinellidae). AB - Eriopis connexa is a native coccinelid predator in the Neotropical Region. In Argentina it is commonly found associated to sucking pests in several crops and among them aphids and whiteflies. These pests are usually controlled with newly developed systemic insecticides, such as the neonicotinoids. However, the compatibility between selective pesticides and natural enemies is required before incorporating them in integrated pest management (IPM) packages. Within this frame, the objective of this study was to evaluate the side effect of various concentrations/doses of one commonly used neonicotinoid in vegetal crops, acetamiprid, on immature stages of E. connexa by dipping or topical exposure for eggs and larvae, respectively. Acetamiprid reduced egg hatching from 34 to 100 %. Moreover, the embryogenesis was disrupted by insecticide at early embryo stage at all tested concentrations. Second larval instar was more susceptible to acetamiprid than the fourth one and this susceptibility was positively related with the tested concentrations. On the other hand, the survival reduction at larval stage reached 100 % from 20 mg a.i./L (10 % of maximum field concentration). Besides, the reproduction of the females developed from topical bioassays on fourth instar larvae was strongly affected, with reduction in fecundity and fertility from 22 to 44 % and from 37 to 45 %, respectively. Overall the results showed a high toxicity of acetamiprid on immature stages of E. connexa, demonstrating that this broadly used insecticide could reduce biocontrol services provided by this predator and could also likely disturb IPM programs. PMID- 23793296 TI - Longer visits on familiar plants? Testing a regular visitor's tendency to probe more flowers than occasional visitors. AB - An individual pollinator may tend to consecutively probe more flowers on a plant to which it returns at shorter intervals than other plants. In a large net cage, I let individually marked bumble bees forage on flowering heads of red clovers arranged in 37 bottles (plants), each of which was monitored by an observer to record every visit and probe for 2.5 h on each of 3 days. The data of collective visits by marked individuals revealed that the bees had their own foraging areas, in which they visited a set of plants frequently and others less often, i.e., the same individual bee repeatedly returned to certain plants as a regular visitor while sampling others as an occasional visitor. I further found that as a regular visitor, an individual bee tended to probe more flowering heads on familiar plants while probing fewer on unfamiliar plants as an occasional visitor. The mean number of consecutive probes by a bee was also positively correlated with its activity (the total number of plant visits made during the observation period). The fact that each bee behaves differently on different plants indicates that the same individual pollinator can exert different influence on the reproductive success of each plant: apparently, a pollinator likely reduces the potential for geitonogamous self-pollination when foraging as an occasional visitor. Attracting occasional visitors therefore may be beneficial for plants to avoid geitonogamy. This study thus emphasizes the importance of paying attention to pollinator individuality in pollination ecology. PMID- 23793297 TI - A survey of DNA methylation across social insect species, life stages, and castes reveals abundant and caste-associated methylation in a primitively social wasp. AB - DNA methylation plays an important role in the epigenetic control of developmental and behavioral plasticity, with connections to the generation of striking phenotypic differences between castes (larger, reproductive queens and smaller, non-reproductive workers) in honeybees and ants. Here, we provide the first comparative investigation of caste- and life stage-associated DNA methylation in several species of bees and vespid wasps displaying different levels of social organization. Our results reveal moderate levels of DNA methylation in most bees and wasps, with no clear relationship to the level of sociality. Strikingly, primitively social Polistes dominula paper wasps show unusually high overall DNA methylation and caste-related differences in site specific methylation. These results suggest DNA methylation may play a role in the regulation of behavioral and physiological differences in primitively social species with more flexible caste differences. PMID- 23793298 TI - The devil's in the details. PMID- 23793299 TI - Caring for patients with burn injuries. PMID- 23793300 TI - Open the door for LGBTQ patients. PMID- 23793301 TI - Evolution of metallotionein isoforms complexes in hepatic cells of Mus musculus along cadmium exposure. AB - Characterization of Cd-binding proteins has great analytical interest due to the high toxicity of Cd to living organisms. Metallothioneins (MTs), as Cd(II) binding proteins are of increasing interest, since they form very stable Cd chelates and are involved in many detoxification processes. In this work, inductively coupled plasma octopole reaction cell mass spectrometry and nanospray ionization time-of-flight mass spectrometry were used in parallel and combined with two-dimensional chromatography: size exclusion followed by reversed-phase high performance liquid chromatography, to study metal complexes of MT isoforms produced in hepatic cytosols of Mus musculus during exposure experiments to Cd. Exposure experiments were carried out by subcutaneous injection of a growing dose of the toxic element ranging from 0.1 to 1.0 mg of Cd per kg of body weight per day during 10 days. A control group and three exposure groups at days 2, 6 and 10 of exposure were studied, and different cadmium, copper and zinc complexes with MTs isoforms were isolated and characterized from the two most exposed groups. The results allow gaining insight into the mechanisms involved in metal detoxification by MTs, showing the changes in the stoichiometry of metal complexes-MTs along cadmium exposure. PMID- 23793302 TI - Harnessing Photovoice for tuberculosis advocacy in Karachi, Pakistan. AB - In Pakistan, despite publically available free testing and treatment throughout the country, there were an estimated 58,000 deaths due to tuberculosis in 2010. Understanding the experiences of people affected by TB is essential in addressing barriers to effective treatment. The Indus Hospital used Photovoice to understand the experiences of people affected by TB in Karachi. Two hundred and thirty photographs and stories were collected from 55 people affected by TB. Five major themes and 12 sub-themes emerged from the data: the physical aspects of TB (weakness and the side effects of the medication), the social aspects of TB (loneliness, stigma, and the fear/guilt of infecting family members), the socio economic aspects of TB (financial difficulties/poverty and poor living conditions), supportive factors during treatment (support from family and friends, support from welfare organizations, prayer, visiting peaceful places), and recovery (happiness about getting better). The photographs, stories, and a Call for Action were shared at a Gallery event with patients, practitioners, and policy-makers. This study provides a look at the complexities surrounding TB and emphasizes the need for holistic interventions for TB that address all aspects of the disease, including its social determinants. It also highlights the potential of Photovoice as an effective means to bring much-needed attention to this disease. PMID- 23793303 TI - Prospective clinical comparisons of semitendinosus versus semitendinosus and gracilis tendon autografts for anatomic double-bundle anterior cruciate ligament reconstruction. AB - BACKGROUND: The data available from the previously reported clinical studies remains insufficient concerning the hamstring graft preparation in double-bundle anterior cruciate ligament (ACL) reconstruction. OBJECTIVE: To test the hypothesis that there are no significant differences between the semitendinosus tendon alone and the semitendinosus and gracilis tendon graft fashioning techniques concerning knee stability and clinical outcome after anatomic double bundle ACL reconstruction. METHODS: A prospective study was performed on 120 patients who underwent anatomic double-bundle ACL reconstruction according to the graft fashioning technique. The authors developed the protocol to use hamstring tendon autografts. When the harvested doubled semitendinosus tendon is thicker than 6 mm, each half of the semitendinosus tendon is doubled and used for the anteromedial (AM) and posterolateral (PL) bundle grafts (Group I). On the other hand, when the harvested semitendinosus tendon is under 6 mm in thickness, the gracilis tendon is harvested additionally. The distal half of the semitendinosus and gracilis tendons are doubled and used for the AM bundle graft, and the remaining proximal half of the semitendinosus tendon is doubled and used for the PL bundle grafts (Group II). Sixty-one patients were included in Group I, and 59 patients in Group II. The two groups were compared concerning knee stability and clinical outcome 2 years after surgery. RESULTS: The postoperative side-to-side anterior laxity averaged 1.3 mm in both groups, showing no statistical difference. There were also no significant differences between the two groups concerning the peak isokinetic torque of the quadriceps and the hamstrings, the Lysholm knee score, and the International Knee Documentation Committee evaluation. CONCLUSION: There were no significant differences between the two graft fashioning techniques after anatomic double-bundle ACL reconstruction concerning knee stability and postoperative outcome. The present study provided orthopedic surgeons with important information on double-bundle ACL reconstruction with hamstring tendons. LEVEL OF EVIDENCE: Level II; prospective comparative study. PMID- 23793304 TI - Atomic clock transitions in silicon-based spin qubits. AB - A major challenge in using spins in the solid state for quantum technologies is protecting them from sources of decoherence. This is particularly important in nanodevices where the proximity of material interfaces, and their associated defects, can play a limiting role. Spin decoherence can be addressed to varying degrees by improving material purity or isotopic composition, for example, or active error correction methods such as dynamic decoupling (or even combinations of the two). However, a powerful method applied to trapped ions in the context of atomic clocks is the use of particular spin transitions that are inherently robust to external perturbations. Here, we show that such 'clock transitions' can be observed for electron spins in the solid state, in particular using bismuth donors in silicon. This leads to dramatic enhancements in the electron spin coherence time, exceeding seconds. We find that electron spin qubits based on clock transitions become less sensitive to the local magnetic environment, including the presence of (29)Si nuclear spins as found in natural silicon. We expect the use of such clock transitions will be of additional significance for donor spins in nanodevices, mitigating the effects of magnetic or electric field noise arising from nearby interfaces and gates. PMID- 23793305 TI - Readout and control of a single nuclear spin with a metastable electron spin ancilla. AB - Electron and nuclear spins associated with point defects in insulators are promising systems for solid-state quantum technology. The electron spin is usually used for readout and addressing, and nuclear spins are used as exquisite quantum bits and memory systems. With these systems, single-shot readout of single nuclear spins as well as entanglement, aided by the electron spin, have been shown. Although the electron spin in this example is essential for readout, it usually limits the nuclear spin coherence, leading to a quest for defects with spin-free ground states. Here, we isolate a hitherto unidentified defect in diamond and use it at room temperature to demonstrate optical spin polarization and readout with exceptionally high contrast (up to 45%), coherent manipulation of an individual excited triplet state spin, and coherent nuclear spin manipulation using the triplet electron spin as a metastable ancilla. We demonstrate nuclear magnetic resonance and Rabi oscillations of the uncoupled nuclear spin in the spin-free electronic ground state. Our study demonstrates that nuclei coupled to single metastable electron spins are useful quantum systems with long memory times, in spite of electronic relaxation processes. PMID- 23793306 TI - Chickenpox: docile or deadly? PMID- 23793307 TI - An observational study of complications in chickenpox with special reference to unusual complications in an apex infectious disease hospital, Kolkata, India. AB - BACKGROUND: Chickenpox can cause serious complications and even death in persons without any risk factors. AIMS: To observe the different complications with special reference to unusual complications of chickenpox and their outcomes. MATERIALS AND METHODS: The present study was a prospective observational study where 300 patients suffering from chickenpox were evaluated with special reference to unusual complications and outcomes. RESULTS: The usual complications of chickenpox commonly observed were acute hepatitis in 30 (10%) and cerebellar ataxia in 22 patients (7.3%), whereas common unusual complications were acute pancreatitis in 45 (15%), hemorrhagic rash in 10 (3.3%), Guillain-Barriota syndrome in 4 (1.3%), disseminated intravascular coagulation in 4 (1.3%), necrotizing fasciitis in 4 (1.3%), and acute renal failure in 3 patients (1%). It had been observed that most of these unusual complications occurred in patients without any risk factor. A total of 18 patients (6%) died in this study and of them 12 patients (4%) died due to unusual complications. CONCLUSIONS: Compulsory childhood varicella vaccination including vaccination of risk groups and susceptible individuals are all essential to reduce the incidence of chickenpox, associated complications, and subsequent death. PMID- 23793308 TI - Acquired von Willebrand syndrome: a rare disorder of heterogeneous etiology. AB - CONTEXT: Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder that mimics the inherited form of von Willebrand disease (VWD) in terms of laboratory findings and clinical presentation. AIMS: To study the etiology of acquired VWD. SETTINGS AND DESIGN: The patients referred from various hospitals in and out of Mumbai were included in the study. MATERIALS AND METHODS: Six patients with AVWS diagnosed at this center over the last 10 years were analyzed against 171 patients with inherited VWD. The differential diagnosis of AVWS was made based on reduced levels of von Willebrand antigen and von Willebrand ristocetin cofactor, decrease in ristocetin induced platelet aggregation, absence of correction in mixing studies with no prior history of bleeding problems and a negative family history for bleeding disorders. RESULTS: In three patients, the disease was associated with systematic lupus erythematosus, out of which one was also associated with Kikuchi lymphadenitis and second with autoimmune hemolytic anemia. Fourth case was associated with hypothyroidism and fifth was a case of dermatitis and vitiligo. The last patient was a case of hemophilia A with Burkitts lymphoma, who developed autoantibodies to von Willebrand factor. Except two patients, all other patients responded to immune suppressive therapy with corticosteroids, while the patient with hypothyroidism responded to oral thyroxine. CONCLUSION: AVWS is a rare condition and may often be missed or diagnosed as inherited disease associated with heterogeneous disease conditions. PMID- 23793309 TI - Arterial bicarbonate may be a useful indicator of inadequate cortisol response in children with catecholamine resistant septic shock. AB - OBJECTIVE: To study the clinical and biochemical parameters that can predict cortisol insufficiency in children with septic shock. DESIGN: prospective, observational study. SETTING: Tertiary health-care center. PATIENTS/SUBJECTS: Fifty children admitted with the catecholamine resistant septic shock to a tertiary health-care center. MATERIALS AND METHODS: At the time of hospitalization all patients underwent detailed clinical evaluation including, history and physical examination, evaluation with the complete blood count, serum cortisol, renal function tests, liver function tests, prothrombin time activated partial thromboplastin time, arterial blood gas analysis, urine analysis, chest roentgenogram, ultrasonography of the abdomen and chest, urine, and blood culture for bacteria and fungi. RESULTS: Out of 50 children with the catecholamine resistant septic shock, seven had adrenal insufficiency (serum cortisol <18 MUg/dl). Of all parameters studied, only arterial bicarbonate at the time of admission to intensive care predicted adrenal insufficiency. On Receptor operative characteristic curve analysis, a bicarbonate level of 10.9 mEq/L had the best accuracy to predict adrenal insufficiency. CONCLUSION: Arterial bicarbonate may be used as a rapid test for provisional identification of adrenal insufficiency among children with the catecholamine resistant septic shock. PMID- 23793310 TI - Effect of fibromyalgia on bone mineral density in patients with fibromylagia and rheumatoid arthritis. AB - OBJECTIVES: Fibromyalgia (FM) may t cause a decrease in bone mineral density (BMD) because of decreased mobility. The condition is relatively frequent in rheumatoid arthritis (RA) and RA patients with FM have more disability than those without FM. We evaluated the effect of FM on BMD and investigated the effect of FM on BMD in RA patients. MATERIALS AND METHODS: We included age-matched 56 FM, 52 RA patients, and 37 healthy females as controls. Twenty three of all RA subjects met 1990 ACR FM criteria. Patients using the antiresorptive drugs, those on hormone replacement therapy, patients with thyroid or parathyroid dysfunction were excluded. Self-reported pain and fatigue severity, functional items of FM impact questionnaire were questioned in FM and RA patients. In all subjects, BMD of the lumbar spine and femur neck were determined by dual X-ray absorptiometry, and T-scores were recorded. RESULTS: Self-reported pain and fatigue scores in FM subjects were significantly higher than in RA patients (P<0.001). The mean lumbar spine and femur neck BMD and their T-scores in RA patients were significantly lower than in FM and control groups (P values<0.01). There was no difference in BMD between FM subjects and the control group. BMD in RA patients with and without FM were similar (P>0.05). There was a significant negative correlation between self-reported pain score and lumbar spine BMD in FM subjects (r=-0.41, P=0.006). CONCLUSIONS: In spite of functional disability, FM does not cause a decrease in BMD. The presence of FM in RA patients does not result in a change in BMD. PMID- 23793311 TI - HIV counseling and testing in a tertiary care hospital in Ganjam district, Odisha, India. AB - BACKGROUND: Human immunodeficiency virus (HIV) counseling and testing (HCT) conducted at integrated counseling and testing centers (ICTCs) is an entry point, cost-effective intervention in preventing transmission of HIV. OBJECTIVES: To study the prevalence of HIV among ICTC attendees, sociodemographic characteristics, and risk behaviors of HIV-seropositive clients. MATERIALS AND METHODS: It was hospital record-based cross-sectional study of 26,518 registered ICTC clients at a tertiary care hospital in Ganjam district, Odisha, India over a 4-year period from January 2009 to September 2012. RESULTS: A total of 1732 (7.5%) out of 22,897 who were tested for HIV were seropositive. Among HIV seropositives, 1138 (65.7%) were males, while 594 (34.3%) were females. Majority (88.3%) of seropositives were between the age group of 15-49 years. Client initiated HIV testing (12.1%) was more seropositive compared to provider initiated (2.9%). Among discordant couples, majority (95.5%) were male partner/husband positive and female partner/wife negative. Positives were more amongst married, less educated, low socioeconomic status, and outmigrants (P<0.0001). Risk factors included heterosexual promiscuous (89.3%), parent-to child transmission 5.8%, unknown 3.1%, infected blood transfusion 0.8%, homosexual 0.5%, and infected needles (0.5%). CONCLUSIONS: There is need to encourage activities that promote HCT in all health facilities. This will increase the diagnosis of new HIV cases. The data generated in ICTC provide an important clue to understand the epidemiology in a particular geographic region and local planning for care and treatment of those infected with HIV and preventive strategies for those at risk especially married, young adults, and outmigrants to reduce new infections. PMID- 23793312 TI - Transcription activity of MMP-2 and MMP-9 metalloproteinase genes and their tissue inhibitor (TIMP-2) in acute coronary syndrome patients. AB - BACKGROUND: Acute coronary syndromes (ACS) are a consequence of coronary vessel atherosclerosis and they are a leading cause of death in industrialized countries. One of the ACS causative factors is the deranged ratio equilibrium of the matrix metalloproteinase/tissue inhibitor of metalloproteinases (MMPs/TIMPs). AIMS: Assessment of transcriptional activity of metalloproteinase genes using Human Genome-U133A oligonucleotide microarrays and selection of candidate genes differentiating ACS patients from healthy subjects and finally, QRT-PCR (quantitative real time polymerase chain reaction) confirmation of the results. SETTINGS AND DESIGN: The study involved 67 ACS patients, admitted on a consecutive basis, to the Cardiology Clinic as well as 24 healthy subjects (control). MATERIALS AND METHODS: Ribonucleic acid isolated from peripheral blood mononuclear cells was analyzed by QRT-PCR. Transcriptional activity of the analyzed gene was assessed with TaqMan gene expression assays. STATISTICAL ANALYSIS: U Mann-Whitney test was used to compare the results. RESULTS: Homogeneity of the investigated group was assessed through hierarchical clusterization whereas the nine genes differentiating ACS patients from healthy persons were selected using the Bland-Altman technique. Among these genes three (platelet derived growth factor D, NUAK family SNF1-like kinase 1 and peroxisomal biogenesis factor 1) showed decreased transcriptional activity whereas the remaining six genes (MMP-2 and MMP-9, CDK5RAP3, transmembrane BAX inhibitor motif containing 1, adenylate cyclase-associated protein 1 and TIMP-2) were increased. MMP-2, MMP-9 and TIMP-2 were further characterized by QRT-PCR. CONCLUSIONS: The obtained results permit to conclude that the increased expression of MMP-2 and MMP-9 metalloproteinases and their tissue inhibitor (TIMP-2) is responsible for disturbed equilibrium of the metalloproteinase/tissue inhibitors system and as a consequence, for destabilization of atherosclerotic plaque and occurrence of the acute coronary syndrome in the investigated group of patients. PMID- 23793313 TI - Changing trends in the management of hypotension following spinal anesthesia in cesarean section. AB - Hypotension during cesarean section under spinal anesthesia remains a frequent scenario in obstetric practice. A number of factors play a role in altering the incidence and severity of hypotension. Counteracting aortocaval compression does not significantly prevent hypotension in most singleton pregnancies. Intravenous crystalloid pre-hydration is not very efficient. Thus, the focus has changed toward co-hydration and use of colloids. Among vasopressors, phenylephrine is now established as a first line drug, although there is limited data in high-risk patients. Though ephedrine crosses the placenta more than phenylephrine and can possibly cause alterations in the fetal physiology, it has not been shown to affect the fetal Apgar or neurobehavioral scores. PMID- 23793314 TI - Retapamulin: a newer topical antibiotic. AB - Impetigo is a common childhood skin infection. There are reports of increasing drug resistance to the currently used topical antibiotics including fusidic acid and mupirocin. Retapamulin is a newer topical agent of pleuromutilin class approved by the Food and Drug Administration for treatment of impetigo in children and has been recently made available in the Indian market. It has been demonstrated to have low potential for the development of antibacterial resistance and a high degree of potency against poly drug resistant Gram-positive bacteria found in skin infections including Staphylococcus aureus strains. The drug is safe owing to low systemic absorption and has only minimal side-effect of local irritation at the site of application. PMID- 23793315 TI - Cerebral demyelination in children with collagenous colitis. AB - Collagenous colitis (CC) is a form of microscopic colitis characterized by the presence of inflammatory infiltrate and subepithelial deposition of collagen in the colon and it is a rare condition with a predominant prevalence in the adult population. Only few cases have been reported in children. We report two children with the CC with concomitant neurological manifestations. Both cases demonstrated variable neurological symptoms clinically and significant cerebral demyelination. In both patients, the gastrointestinal manifestations drastically improved with a short course of prednisolone. However, the neurological symptoms were persistent and progressive. To the best of our knowledge, similar association has not been reported in children. PMID- 23793316 TI - Diffusion weighted MR imaging of 5-fluorouracil and oxaliplatin-induced leukoencephalopathy. AB - A 55-year-old man treated with 5-fluorouracil and oxaliplatin for advanced sigmoid colon cancer presented with seizures, progressive gait and balance difficulties with frequent falls and slurring of speech. After three cycles of chemotherapy, brain magnetic resonance imaging using diffusion-weighted imaging clearly revealed the presence of high signal intensity in the deep white matter of the bilateral cerebral hemispheres, including the corpus callosum symmetrically. A diagnosis of acute leukoencephalopathy was made based on these findings. His clinical symptoms normalized after the discontinuation of the chemotherapy. Early detection of drug-induced leukoencephalopathy is important as the clinical symptoms can be reversed by early discontinuation of the causative drug. Diffusion-weighted magnetic resonance imaging is a useful modality for the early detection and definitive diagnosis of this characteristic encephalopathy. PMID- 23793317 TI - Immature teratoma of the nose and paranasal sinuses masquerading as bilateral nasal polyposis: a unique presentation. AB - Teratomas are tumors of multipotent cells derived from all three germ cell layers and recapitulate normal organogenesis. Teratomas are hypothesized to arise by misplacement of multipotent germ cells. Teratoma is usually developmental and sometimes congenital neoplasm which displays both solid and cystic components with gross and microscopic differentiation into a wide variety of tissues representative of all three germ layers--ectoderm, mesoderm and endoderm. We are describing a case which was initially diagnosed as bilateral nasal polyposis clinically but histopathology report came out to be immature teratoma. This case is being reported to make aware all ENT surgeons of such unique presentation of sinonasal teratomas as such presentation of these tumors has not been reported in literature previously, and hence teratomas should be considered in the differential diagnosis of nasal polyposis in future. PMID- 23793318 TI - Acute myocardial infarction: can it be a complication of acute organophosphorus compound poisoning? AB - Organophosphorus compounds are used as pesticides and represent a common cause of poisoning in developing countries including India due to their widespread availability and use. Toxicity due to these agents can affect many organs including heart. Here, we report a case of acute organophosphorus poisoning (parathion), followed by acute myocardial infarction; documented by clinical features, electrocardiographic changes, and elevated cardiac enzymes. Myocardial infarction has been rarely reported with organophosphorus compounds exposure, thus awareness of this complication can reduce morbidity and mortality. PMID- 23793319 TI - Aspergilloma coexisting with idiopathic pulmonary fibrosis: a rare occurrence. AB - Fungal ball (mycetoma/aspergilloma) is a saprophytic fungal infection that colonizes pre-existing lung cavities. Reported literature suggests its development in cystic lesions/cavitation associated with tuberculosis, sarcoidosis, bronchiectasis, lung abscess, and cavitating neoplasm to name a few. Coexistence of aspergilloma with idiopathic pulmonary fibrosis (IPF) has not been reported in literature so far, to the best of our knowledge. We hereby report the case of a 55-year-old female with IPF having fungal ball. PMID- 23793320 TI - Low-grade Mullerian adenosarcoma with prominent decidualization, involving bilateral ovaries against a background of endometriosis: a diagnostic and treatment challenge. PMID- 23793321 TI - Heartburn literally: cardiac injury due to corrosive ingestion. PMID- 23793322 TI - Beware of "hook effect" giving false negative pregnancy test on point-of-care kits. PMID- 23793323 TI - Primary squamous cell carcinoma of breast presenting as a cystic mass. PMID- 23793324 TI - Autopsy findings and clinical diagnoses: a retrospective analysis of 641 cases in Greece. PMID- 23793325 TI - A traveler with hypothermia: twist in the tale. PMID- 23793326 TI - A critical look at the ophthalmological preparations in the national list of essential medicines of India 2011. PMID- 23793327 TI - Lung cavities in an infant: could it be only tuberculosis? PMID- 23793328 TI - Sustained paranoid psychosis in a patient with mast cell leukemia and decreased serotonin level. PMID- 23793329 TI - Clinical features scoring system for H1N1. PMID- 23793330 TI - EEG cerebral dysrhythmia in non-epileptic individuals as an incentive for seeking online health consultation. PMID- 23793331 TI - Fulminant hepatic failure secondary to diffuse melanoma infiltration in a patient with a breast cancer history. PMID- 23793332 TI - Body packer syndrome. PMID- 23793333 TI - Cardiac surgery in patients with sickle cell disease. PMID- 23793334 TI - Modern and postmodern medicine. PMID- 23793336 TI - Molecular characterization of Ascaridia galli infecting native chickens in Egypt. AB - Family: Ascaridae as a whole is distributed among Africa and adjacent regions and in many areas of the world. The nematode Ascaridia galli is one of the most pathogenic and economically important parasites of poultry. The adult affect the small intestine of the hosts feeding on digested food materials. Its control costs million dollars annually. The genomic DNA was extracted from nematode parasites, A. galli, from specific host, native chickens. The polymerase chain reaction (PCR) was applied to ensure that the DNA content aids in the further studies. Two primers were used in the PCR reactions. The two primers were screened, only the second primer gave total amplified fragment markers 818 bp. The gene sequences obtained from Egyptian A. galli was compared with another one of accession number (AY587609) showing that the sequence was similar in some points from 346 to 1244 sequence, to make a phylogenetic relationships of A. galli with other nematodes on the data base showing that it was to some extent similar to Heterorhabditis spp. PMID- 23793335 TI - In vivo schistosomicidal activity of three novels 8-hydroxyquinoline derivatives against adult and immature worms of Schistosoma mansoni. AB - Schistosomiasis control is widely dependent on a single drug, praziquantel (PZQ). The potential for development of resistance to PZQ has justified the search for new alternative chemotherapies. In a previous study, we have been reported that three of 8-hydroxyquinoline derivatives namely: 3-((8-hydroxyquinolin-5-yl) sulfonyl) pentane-2,4-dione (HQSP), 5-((2,4-diphenyl-3H-benzo[b][1,4]diazepin-3 yl) sulfonyl) quinolin-8-ol (HQBD), and 5-((2,4-diphenyl-3H-pyrido[3,4-b][1,4] diazepin-3-yl) sulfonyl) quinolin-8-ol (HQPD) possess a potent anti-schistosomal activity in vitro. The aim of the present study was to evaluate the in vivo schistosomicidal effect of these three compounds on adult and immature worms of Schistosoma mansoni and their induced pathology. Treatment of S. mansoni-infected mice with 1000, 250, 150, and 200 mg/kg body weight of PZQ, HQSP, HQBD, and HQPD, respectively, reduced adult and immature worm burden by 94.63 and 31.32%, 73.63 and 5.45%, 76.5 and 28.11%, and 81.25 and 56.84%, respectively, compared to infected untreated mice. Moreover, numbers of egg per gram liver and intestine were decreased by 84 and 95.51%, 47.84 and 46.28 %, 53.18 and 59.37 %, and 54.22 and 67.26 as a result of PZQ, HQSP, HQBD, and HQPD treatment, respectively. Hepatic granuloma volume was also reduced by 40.10, 42.96, 35.72, and 72.09% due to PZQ, HQSP, HQBD, and HQPD treatment, respectively. In addition, hepatic histopathological alterations and collagen fiber deposition that accompanied with S. mansoni infection were largely retrieved with different treatments, especially HQPD treatment. Furthermore, humoral immune response, especially IgG response against S. mansoni antigens, was augmented with different treatments. This study concluded that among the three tested 8-hydroxyquinoline derivatives, HQPD is the most effective compound against adult and pre-mature worms of S. mansoni and can be used for the development of a new schistosomicidal drug. PMID- 23793337 TI - Effect of Nd: YAG laser on the apical seal after root-end resection and MTA retrofill: a bacterial leakage study. AB - Laser irradiation has been investigated in terms of preventing leakage in retrofilled root canals. The aim of the present study was to evaluate the effect of neodymium-doped yttrium aluminum garnet (Nd: YAG) laser on the bacterial leakage of mineral trioxide aggregate (MTA)-retrofilled roots. In this ex vivo experimental study, 90 single-rooted incisor teeth were filled with gutta-percha and AH26 sealer. The apical 3 mm of all the roots were resected and 3-mm retrocavities were prepared by an ultrasonic device. The specimens were randomly divided into two experimental (n = 25), one positive control (n = 10), and two negative control (n = 10) groups. In the laser + MTA group, the cavity walls were irradiated by Nd: YAG laser prior to MTA placement. In the MTA group, MTA was placed without laser irradiation. The root surfaces were covered with two layers of nail varnish except for the apical 2 mm. The specimens were then embedded in a bacterial leakage test system and examined daily for 90 days. Contamination periods were recorded. Data were analyzed by Kaplan-Meier and Mann-Whitney U tests (alpha = 0.05). Five teeth with and five teeth without laser irradiation underwent scanning electron microscopic evaluation. The specimens in the laser + MTA group were contaminated earlier than those in the MTA group (p < 0.05). Comparison of survival times between the two groups showed significant differences (p < 0.05). Nd: YAG laser irradiation can decrease the sealing capacity of MTA in comparison to the apical seal achieved by MTA without laser irradiation. Further studies are recommended to provide a better seal for the MTA retrofilled teeth after laser irradiation. PMID- 23793338 TI - Ablative non-fractional lasers for atrophic facial acne scars: a new modality of erbium:YAG laser resurfacing in Asians. AB - Atrophic facial scars which commonly occur after inflammatory acne vulgaris can be extremely disturbing to patients both physically and psychologically. Treatment with fractional laser devices has become increasingly popular, but there has been disappointment in terms of effectiveness. The objective of this study was to assess the safety and efficacy of ablative full-face resurfacing on atrophic acne scars in the Korean population. A total of 22 patients, aged 25-44 years, underwent a new modality of resurfacing combining both short-pulsed and dual-mode erbium:yttrium-aluminum garnet (Er:YAG) laser. The patients had Fitzpatrick skin types ranging from III to V. Photographs were taken before and up to 6 months after treatment. Results were evaluated for the degree of clinical improvement and any adverse events. Degree of improvement was graded using a four point scale: poor (1) = <25%, fair (2) = 25-50%, good (3) = 51-75%, and excellent (4) = >75%. Based on the blinded photo assessments by two independent reviewers, clinically and statistically significant mean improvement of 3.41 was observed (one-sample Wilcoxon signed rank test, P < 0.001). Complete wound healing occurred between 6 and 9 days. Erythema occurred in all patients and lasted longer than 3 months in two patients (9.1%). Postinflammatory hyperpigmentation occurred in ten patients (45.5%) and lasted longer than 3 months in one patient (4.5%). One patient experienced mild hypopigmentation (4.5%). Mild to moderate acne flare-up occurred in five patients (22.7%). No other adverse effects were observed. A new modality of Er:YAG laser resurfacing combining short-pulsed and dual-mode Er:YAG laser is a safe and very effective treatment modality for atrophic facial acne scars in Asians with darker skin tones. PMID- 23793339 TI - Temperature rise in pulp and gel during laser-activated bleaching: in vitro. AB - The aim of this study was to evaluate the increase in temperature induced by various light sources during in-office bleaching treatment, under simulated blood microcirculation in pulp conditions. Ten freshly extracted human maxillary central incisors were used for the study. The roots of the teeth were removed from approximately 2 mm below the cementoenamel junction and fixed on an apparatus for the simulation of blood microcirculation in pulp. A J-type thermocouple wire was inserted into the pulp chamber through an artificial access at the lingual surfaces of the teeth, and another thermocouple wire was fixed on the labial surface of the teeth meanwhile. An in-office bleaching agent, intense red in color and with 30% water content, was applied to the labial surfaces of the teeth, and repeating measurements were made for each tooth using three different light sources: Er:YAG laser (40 mJ, 10 Hz, 20 s), 810-nm diode laser (4 W, 20 s, CW), and high-intensity light-emitting diodes (LED) (1,100 mW/cm(2), 20 s) as the control. Temperature increase in the pulp chamber and within the bleaching gel during light application were recorded and statistically evaluated. The highest pulp temperature increases were recorded for the diode laser group (2.61 degrees C), followed by the Er:YAG laser (1.86 degrees C) and LED (1.02 degrees C) groups (p < 0.05; analysis of variance (ANOVA), Tukey's honestly significant difference (HSD)). Contradictorily, the lowest gel temperature increases were recorded for diode laser (6.21 degrees C) and followed by LED (12.38 degrees C) and Er:YAG (20.11 degrees C) groups (p < 0.05; ANOVA, Tukey's HSD). Despite the significant differences among the groups, the temperature increases recorded for all groups were below the critical value of 5.6 degrees C that can cause irreversible harmful changes in pulp tissue. It can be concluded that, with regard to temperature increase, all the light sources evaluated in this study can be used safely for in-office bleaching treatment within the described parameters. PMID- 23793340 TI - Ankle dorsiflexor, not plantarflexor strength, predicts the functional mobility of people with spastic hemiplegia. AB - OBJECTIVE: To determine the relationships between affected ankle dorsiflexion strength, other ankle muscle strength measurements, plantarflexor spasticity, and Timed "Up & Go" (TUG) times in people with spastic hemiplegia after stroke. DESIGN: A cross-sectional study. SETTING: A university-based rehabilitation centre. PARTICIPANTS: Seventy-three subjects with spastic hemiplegia. MAIN OUTCOME MEASURES: Functional mobility was assessed using TUG times. Plantarflexor spasticity was measured using the Composite Spasticity Scale. Affected and unaffected ankle dorsiflexion and plantarflexion strength were recorded using a load-cell mounted on a foot support with the knee bent at 50o and subjects in supine lying. RESULTS: TUG times demonstrated strong negative correlation with affected ankle dorsiflexion strength (r = -0.67, p <= 0.001) and weak negative correlations with other ankle muscle strength measurements (r = -0.28 to -0.31, p <= 0.05), but no significant correlation with plantarflexor spasticity. A linear regression model showed that affected ankle dorsiflexion strength was independently associated with TUG times and accounted for 27.5% of the variance. The whole model explained 47.5% of the variance in TUG times. CONCLUSION: Affected ankle dorsiflexion strength is a crucial component in determining the TUG performance, which is thought to reflect functional mobility in subjects with spastic hemiplegia. PMID- 23793341 TI - Design and characterization of an efficient CYP105A1-based whole-cell biocatalyst for the conversion of resin acid diterpenoids in permeabilized Escherichia coli. AB - Cytochrome P450 enzymes exhibit a tremendous potential for biotechnological applications due to their ability to introduce oxygen into non-activated carbon atoms. Their catalytic diversity is complemented by a broad substrate range covering many natural compounds. Especially the functionalization of terpenoids by P450s becomes increasingly interesting due to the diverse biological effects of these compounds. The bacterial CYP105A1 from Streptomyces griseolus was recently identified to carry out a one-step hydroxylation of several abietane type resin acids. In this work, a whole-cell system for CYP105A1 with its heterologous electron transfer proteins Arh1 and Etp1(fd) from Schizosaccharomyces pombe was designed in Escherichia coli JM109 cells. Additionally, an enzyme-coupled cofactor regeneration system was integrated by co expression of alcohol dehydrogenase from Lactobacillus brevis. In order to overcome mass transfer limitations of substrate into the cell, different agents were tested towards their permeabilizing activity on the E. coli membrane. The peptide antibiotic polymyxin B proved to be the most effective permeabilizer. After optimising the expression and conversion conditions, the cells were able to completely convert 200 MUM of abietic acid into 15-hydroxyabietic acid within 2 h, exhibiting an initial conversion rate of 125 MUM/h. These results demonstrate the high potential of this whole-cell system for the synthesis of functionalized resin acid diterpenoids. PMID- 23793342 TI - Cytotoxic metabolites from the cultures of endophytic fungi from Panax ginseng. AB - Two strains of endophytic fungi, Penicillium melinii Yuan-25 and Penicillium janthinellum Yuan-27, with strong anti-Pyricularia oryzae activity, were obtained from the roots of Panax ginseng. Based on bioactivity-oriented isolation, a new benzaldehyde derivative, ginsenocin (1), together with six known compounds, methyl 2,4-dihydroxy-3,5,6-trimethylbenzoate (2), 3,4,5-trimethyl-1,2-benzenediol (3), penicillic acid (4), mannitol (5), ergosterol (6), and ergosterol peroxide (7), were separated from the EtOAc extract of Yuan-25 culture, while brefeldin A (8) was isolated as the major constituent from the EtOAc extract of Yuan-27 culture. The chemical structures were determined based on spectroscopic methods. All the isolated compounds 1-8 were evaluated for their cytotoxicity against six human cancer cell lines. Brefeldin A (8) was the most cytotoxic constituent against all the tested cell lines with IC50 values <0.12 MUg/ml, while ginsenocin (1) and penicillic acid (4) also exhibited potent cytotoxicity with IC50 values ranging from 0.49 to 7.46 MUg/ml. Our results suggest that endophytic fungi isolated from P. ginseng are a promising natural source of potential anticancer agents. PMID- 23793343 TI - Fatty alcohol production in engineered E. coli expressing Marinobacter fatty acyl CoA reductases. AB - Although successful production of fatty alcohols in metabolically engineered Escherichia coli with heterologous expression of fatty acyl-CoA reductase has been reported, low biosynthetic efficiency is still a hurdle to be overcome. In this study, we examined the characteristics of two fatty acyl-CoA reductases encoded by Maqu_2220 and Maqu_2507 genes from Marinobacter aquaeolei VT8 on fatty alcohol production in E. coli. Fatty alcohols with diversified carbon chain length were obtained by co-expressing Maqu_2220 with different carbon chain length-specific acyl-ACP thioesterases. Both fatty acyl-CoA reductases displayed broad substrate specificities for C12-C18 fatty acyl chains in vivo. The optimized mutant strain of E. coli carrying the modified tesA gene and fadD gene from E. coli and Maqu_2220 gene from Marinobacter aquaeolei VT8 produced fatty alcohols at a remarkable level of 1.725 g/L under the fermentation condition. PMID- 23793344 TI - Substrate profiling of cyclohexylamine oxidase and its mutants reveals new biocatalytic potential in deracemization of racemic amines. AB - A cyclohexylamine oxidase (CHAO) of bacterial origin was previously shown to be a potentially useful catalyst in the deracemization of racemic primary amines. To further explore the properties and application of this enzyme, five single-amino acid substitution mutants (L199A, M226A, Y321A, Y321F, and L353M) were created based on superimposition of the tertiary structure of CHAO and the monoamine oxidase (MAO) B homolog. The substrate specificity of the purified wild-type and five mutant enzymes were examined towards 38 structurally diverse amines. All the enzymes exhibited better activity for primary amines than secondary and tertiary amines and in general exhibited high stereoselectivity. Among the mutant enzymes, M226A displayed an enhanced activity (5-400%) towards most substrates, and L353M showed 7-445% higher activity towards primary aliphatic amines with cycloalkane or aromatic moieties. Kinetic parameters revealed that both Y321 mutants showed higher catalytic efficiency towards cyclooctanamine, whereas the wild-type CHAO (wt CHAO) was most efficient towards cyclohexylamine. The wt CHAO or variant L353M in combination with a borane-ammonia complex as reducing agent was applied to the deracemization of 1-aminotetraline to give the (R)-enantiomer, a precursor of an antidepressant drug Norsertraline, in good yield (73-76%), demonstrating their application potential in chiral amine synthesis. PMID- 23793345 TI - Comprehensive model of microalgae photosynthesis rate as a function of culture conditions in photobioreactors. AB - In this paper, the influence of culture conditions (irradiance, temperature, pH, and dissolved oxygen) on the photosynthesis rate of Scenedesmus almeriensis cultures is analyzed. Short-run experiments were performed to study cell response to variations in culture conditions, which take place in changing environments such as outdoor photobioreactors. Experiments were performed by subjecting diluted samples of cells to different levels of irradiance, temperature, pH, and dissolved oxygen concentration. Results demonstrate the existence of photoinhibition phenomena at irradiances higher than 1,000 MUE/m(2) s; in addition to reduced photosynthesis rates at inadequate temperatures or pH-the optimal values being 35 degrees C and 8, respectively. Moreover, photosynthesis rate reduction at dissolved oxygen concentrations above 20 mg/l is demonstrated. Data have been used to develop an integrated model based on considering the simultaneous influence of irradiance, temperature, pH, and dissolved oxygen. The model fits the experimental results in the range of culture conditions tested, and it was validated using data obtained by the simultaneous variation of two of the modified variables. Furthermore, the model fits experimental results obtained from an outdoor culture of S. almeriensis performed in an open raceway reactor. Results demonstrate that photosynthetic efficiency is modified as a function of culture conditions, and can be used to determine the proximity of culture conditions to optimal values. Optimal conditions found (T = 35 degrees C, pH = 8, dissolved oxygen concentration <20 mg/l) allows to maximize the use of light by the cells. The developed model is a powerful tool for the optimal design and management of microalgae-based processes, especially outdoors, where the cultures are subject to daily culture condition variations. PMID- 23793346 TI - Optical coherence tomographic findings of crystal deposits in the lens and cornea in Bietti crystalline corneoretinopathy associated with mutation in the CYP4V2 gene. AB - BACKGROUND: We report the optical coherence tomography (OCT) findings of crystalline deposits in the cornea and lens of a patient with Bietti crystalline dystrophy (BCD), thus providing evidence for a better understanding of the pathophysiology of BCD. PATIENT: A 49-year-old man showing typical chorioretinal degeneration with a CYP4V2 mutation was diagnosed with BCD. OBSERVATIONS: The anterior segment OCT images clearly showed flat hyperreflective plaques just beneath the corneal epithelium and in the lens epithelium. The crystals were not located on the outer surface of the lens capsule as previously described but on the inner surface of the anterior capsule. CONCLUSIONS: This finding suggests that the crystals in the lens of patients with BCD may be produced in the same way as corneal or retinal crystalline deposits and therefore result from a systemic abnormality of lipid metabolism rather than by previously considered possibilities, such as release from the retina adhering to the lens capsule. PMID- 23793347 TI - The use of feathers in monitoring bioaccumulation of metals and metalloids in the South African endangered African grass-owl (Tyto capensis). AB - Few studies have quantified metals in South African species and no published data on residues specifically in South African owl feathers exist. Tyto capensis is listed as vulnerable within South Africa, making it preferable to use a non invasive technique to determine metal bioaccumulation for this species. Comparisons are made with the cosmopolitan T. alba to determine whether this species could be used as a surrogate. Concentrations of various metals were thus determined in feathers of the two species and compared with liver and muscle samples. Samples were taken from 119 owls collected as road kill along a national road. A comparison of concentrations in feathers revealed similarly higher concentrations of aluminium, antimony, lead, nickel, and strontium, whereas concentrations of chromium, copper, iron, manganese, selenium, titanium and zinc were similarly higher in internal tissues for both species. Metal concentrations of owls were comparable to those reported in literature and below toxic levels, suggesting that these metals were not likely to impact the owls. Further regressions between feathers and corresponding livers were examined to determine if feathers were indicative of internal metal burdens. Significant positive relationships were found for aluminium, copper, lead, nickel and vanadium in T. alba and nickel, manganese and vanadium in T. capensis. Preliminary results support the feasibility of using feathers as non-destructive indicators of environmental contamination in T. capensis although caution needs to be taken when interpreting the results. PMID- 23793350 TI - Single atom alloy surface analogs in Pd0.18Cu15 nanoparticles for selective hydrogenation reactions. AB - We report a novel synthesis of nanoparticle Pd-Cu catalysts, containing only trace amounts of Pd, for selective hydrogenation reactions. Pd-Cu nanoparticles were designed based on model single atom alloy (SAA) surfaces, in which individual, isolated Pd atoms act as sites for hydrogen uptake, dissociation, and spillover onto the surrounding Cu surface. Pd-Cu nanoparticles were prepared by addition of trace amounts of Pd (0.18 atomic (at)%) to Cu nanoparticles supported on Al2O3 by galvanic replacement (GR). The catalytic performance of the resulting materials for the partial hydrogenation of phenylacetylene was investigated at ambient temperature in a batch reactor under a head pressure of hydrogen (6.9 bar). The bimetallic Pd-Cu nanoparticles have over an order of magnitude higher activity for phenylacetylene hydrogenation when compared to their monometallic Cu counterpart, while maintaining a high selectivity to styrene over many hours at high conversion. Greater than 94% selectivity to styrene is observed at all times, which is a marked improvement when compared to monometallic Pd catalysts with the same Pd loading, at the same total conversion. X-ray photoelectron spectroscopy and UV-visible spectroscopy measurements confirm the complete uptake and alloying of Pd with Cu by GR. Scanning tunneling microscopy and thermal desorption spectroscopy of model SAA surfaces confirmed the feasibility of hydrogen spillover onto an otherwise inert Cu surface. These model studies addressed a wide range of Pd concentrations related to the bimetallic nanoparticles. PMID- 23793349 TI - A student's perspective on medical ethics education. AB - Despite many efforts to increase ethics education in US medical schools, barriers continue to arise that impede the production of morally driven physicians who practice medicine with ideal empathy. Research has shown that, particularly during the clinical years, medical students lose the ability both to recognize ethical dilemmas and to approach such situations with compassionate reasoning. This article summarizes the current status of ethics education in US medical schools, described through the eyes of and alongside the story of a graduating medical student. PMID- 23793348 TI - Models and measurements of energy-dependent quenching. AB - Energy-dependent quenching (qE) in photosystem II (PSII) is a pH-dependent response that enables plants to regulate light harvesting in response to rapid fluctuations in light intensity. In this review, we aim to provide a physical picture for understanding the interplay between the triggering of qE by a pH gradient across the thylakoid membrane and subsequent changes in PSII. We discuss how these changes alter the energy transfer network of chlorophyll in the grana membrane and allow it to switch between an unquenched and quenched state. Within this conceptual framework, we describe the biochemical and spectroscopic measurements and models that have been used to understand the mechanism of qE in plants with a focus on measurements of samples that perform qE in response to light. In addition, we address the outstanding questions and challenges in the field. One of the current challenges in gaining a full understanding of qE is the difficulty in simultaneously measuring both the photophysical mechanism of quenching and the physiological state of the thylakoid membrane. We suggest that new experimental and modeling efforts that can monitor the many processes that occur on multiple timescales and length scales will be important for elucidating the quantitative details of the mechanism of qE. PMID- 23793351 TI - Fatty degeneration of the rotator cuff muscles on pre- and postoperative CT arthrography (CTA): is the Goutallier grading system reliable? AB - OBJECTIVES: To retrospectively evaluate fatty degeneration (FD) of rotator cuff muscles on CTA using Goutallier's grading system and quantitative measurements with comparison between pre- and postoperative states. MATERIALS AND METHODS: IRB approval was obtained for this study. Two radiologists independently reviewed pre and postoperative CTAs of 43 patients (24 males and 19 females, mean age, 58.1 years) with 46 shoulders confirmed as full-thickness tears with random distribution. FD of supraspinatus, infraspinatus/teres minor, and subscapularis was assessed using Goutallier's system and by quantitative measurements of Hounsfield units (HUs) on sagittal images. Changes in FD grades and HUs were compared between pre- and postoperative CTAs and analyzed with respect to preoperative tear size and postoperative cuff integrity. The correlations between qualitative grades and quantitative measurements and their inter-observer reliabilities were also assessed. RESULTS: There was statistically significant correlation between FD grades and HU measurements of all muscles on pre- and postoperative CTA (p < 0.05). Inter-observer reliability of fatty degeneration grades were excellent to substantial on both pre- and postoperative CTA in supraspinatus (0.8685 and 0.8535) and subscapularis muscles (0.7777 and 0.7972), but fair in infraspinatus/teres minor muscles (0.5791 and 0.5740); however, quantitative Hounsfield units measurements showed excellent reliability for all muscles (ICC: 0.7950 and 0.9346 for SST, 0.7922 and 0.8492 for SSC, and 0.9254 and 0.9052 for IST/TM). No muscle showed improvement of fatty degeneration after surgical repair on qualitative and quantitative assessments; there was no difference in changes of fatty degeneration after surgical repair according to preoperative tear size and post-operative cuff integrity (p > 0.05). The average dose-length product (DLP, mGy . cm) was 365.2 mGy . cm (range, 323.8-417.2 mGy . cm) and estimated average effective dose was 5.1 mSv. CONCLUSIONS: Goutallier grades correlated well with HUs of rotator cuff muscles. Reliability was excellent for both systems, except for FD grade of IST/TM muscles, which may be more reliably assessed using quantitative measurements. PMID- 23793352 TI - Transient pain and paresthesias in the hand--ulnar neuropathy secondary to compression from a low-lying medial triceps muscle and tendon insertion. PMID- 23793353 TI - Increased size of a gas-filled intradural cyst causing acute foot drop: a case report. AB - We describe the case of a 76-year-old man presenting with a gas-filled intradural cyst that increased in size over a 10-month period and caused acute bilateral foot drop. The gas-filled intradural cyst was resected from the adherent cauda equina, and histopathological examination identified cystic tissue with degenerated fibrocartilage. Leg pain disappeared immediately following surgery, and the bilateral foot drop resolved within 8 months. PMID- 23793354 TI - Copper(II)-human amylin complex protects pancreatic cells from amylin toxicity. AB - Human amylin-derived oligomers and aggregates are believed to play an important role in the pathogenesis of type II diabetes mellitus (T2DM). In addition to amylin-evoked cell attrition, T2DM is often accompanied by elevated serum copper levels. Although previous studies have shown that human amylin, in the course of its aggregation, produces hydrogen peroxide (H2O2) in solution, and that this process is exacerbated in the presence of copper(ii) ions (Cu(2+)), very little is known about the mechanism of interaction between Cu(2+) and amylin in pancreatic beta-cells, including its pathological significance. Hence, in this study we investigated the mechanism by which Cu(2+) and human amylin catalyze formation of reactive oxygen species (ROS) in cells and in vitro, and examined the modulatory effect of Cu(2+) on amylin aggregation and toxicity in pancreatic rat insulinoma (RIN-m5F) beta-cells. Our results indicate that Cu(2+) interacts with human and rat amylin to form metalo-peptide complexes with low aggregative and oxidative properties. Human and non-amyloidogenic rat amylin produced minute (nM) amounts of H2O2, the accumulation of which was slightly enhanced in the presence of Cu(2+). In a marked contrast to human and rat amylin, and in the presence of the reducing agents glutathione and ascorbate, Cu(2+) produced MUM concentrations of H2O2 surpassing the amylin effect by several fold. The current study shows that human and rat amylin not only produce but also quench H2O2, and that human but not rat amylin significantly decreases the amount of H2O2 in solution produced by Cu(2+) and glutathione. Similarly, human amylin was found to also decrease hydroxyl radical formation elicited by Cu(2+) and glutathione. Furthermore, Cu(2+) mitigated the toxic effect of human amylin by inhibiting activation of pro-apoptotic caspase-3 and stress-kinase signaling pathways in rat pancreatic insulinoma cells in part by stabilizing human amylin in its native conformational state. This sacrificial quenching of metal-catalyzed ROS by human amylin and copper's anti-aggregative and anti-apoptotic properties suggest a novel and protective role for the copper-amylin complex. PMID- 23793355 TI - Rimonabant precipitates anxiety in rats withdrawn from palatable food: role of the central amygdala. AB - The anti-obesity medication rimonabant, an antagonist of cannabinoid type-1 (CB(1)) receptor, was withdrawn from the market because of adverse psychiatric side effects, including a negative affective state. We investigated whether rimonabant precipitates a negative emotional state in rats withdrawn from palatable food cycling. The effects of systemic administration of rimonabant on anxiety-like behavior, food intake, body weight, and adrenocortical activation were assessed in female rats during withdrawal from chronic palatable diet cycling. The levels of the endocannabinoids, anandamide and 2 arachidonoylglycerol (2-AG), and the CB(1) receptor mRNA and the protein in the central nucleus of the amygdala (CeA) were also investigated. Finally, the effects of microinfusion of rimonabant in the CeA on anxiety-like behavior, and food intake were assessed. Systemic administration of rimonabant precipitated anxiety-like behavior and anorexia of the regular chow diet in rats withdrawn from palatable diet cycling, independently from the degree of adrenocortical activation. These behavioral observations were accompanied by increased 2-AG, CB(1) receptor mRNA, and protein levels selectively in the CeA. Finally, rimonabant, microinfused directly into the CeA, precipitated anxiety-like behavior and anorexia. Our data show that (i) the 2-AG-CB(1) receptor system within the CeA is recruited during abstinence from palatable diet cycling as a compensatory mechanism to dampen anxiety, and (ii) rimonabant precipitates a negative emotional state by blocking the beneficial heightened 2-AG-CB(1) receptor signaling in this brain area. These findings help elucidate the link between compulsive eating and anxiety, and it will be valuable to develop better pharmacological treatments for eating disorders and obesity. PMID- 23793357 TI - Evaluation of cognitive behaviors in young offspring of C57BL/6J mice after gestational nicotine exposure during different time-windows. AB - Gestational nicotine exposure is associated with cognitive abnormalities in young offspring. However, practical strategies for prevention or treatment of impaired cognitive behaviors of offspring are not available due to the lack of systematic investigation of underlying mechanism. Therefore, this study aimed at examining the effects of gestational and/or perinatal nicotine exposure (GPNE) on cognitive behaviors in offspring of C57BL/6J mice to provide systematic behavioral data. Pregnant mice were exposed to nicotine via sweetened drinking water during six time-windows, including gestational day 0 to day 13 (G0-G13), G14-postnatal day 0 (P0), G0-P0, G14-P7, G0-P7, and P0-P7. During P42-P56 days, both male and female offspring were given a battery of behavioral tests. Depending on the time of exposure, GPNE impaired working memory, object-based attention, and prepulse inhibition in male and female offspring to different extents. Nicotine exposure during G14-P0 also decreased norepinephrine turnover in the prefrontal cortex on P28 and P56. Overall results indicate that nicotine exposure during any time windows of development impairs cognitive behaviors in offspring, and suggest that certain time-windows, e.g., G14-P0, should be selected for further studies on the underlying neurochemical or molecular mechanisms. PMID- 23793356 TI - Neuroimaging in psychiatric pharmacogenetics research: the promise and pitfalls. AB - The integration of research on neuroimaging and pharmacogenetics holds promise for improving treatment for neuropsychiatric conditions. Neuroimaging may provide a more sensitive early measure of treatment response in genetically defined patient groups, and could facilitate development of novel therapies based on an improved understanding of pathogenic mechanisms underlying pharmacogenetic associations. This review summarizes progress in efforts to incorporate neuroimaging into genetics and treatment research on major psychiatric disorders, such as schizophrenia, major depressive disorder, bipolar disorder, attention deficit/hyperactivity disorder, and addiction. Methodological challenges include: performing genetic analyses in small study populations used in imaging studies; inclusion of patients with psychiatric comorbidities; and the extensive variability across studies in neuroimaging protocols, neurobehavioral task probes, and analytic strategies. Moreover, few studies use pharmacogenetic designs that permit testing of genotype * drug effects. As a result of these limitations, few findings have been fully replicated. Future studies that pre screen participants for genetic variants selected a priori based on drug metabolism and targets have the greatest potential to advance the science and practice of psychiatric treatment. PMID- 23793358 TI - Ancient pests: the season of the Santorini Minoan volcanic eruption and a date from insect chitin. AB - Attributing a season and a date to the volcanic eruption of Santorini in the Aegean has become possible by using preserved remains of the bean weevil, Bruchus rufipes, pests of pulses, from the storage jars of the West House, in the Bronze Age settlement at Akrotiri. We have applied an improved pre-treatment methodology for dating the charred insects, and this provides a date of 1744-1538 BC. This date is within the range of others obtained from pulses from the same context and confirms the utility of chitin as a dating material. Based on the nature of the insect material and the life cycle of the species involved, we argue for a summer eruption, which took place after harvest, shortly after this material was transported into the West House storeroom. PMID- 23793359 TI - Bird species migration ratio in East Asia, Australia, and surrounding islands. AB - Bird migration and its relationship with the contemporary environment have attracted long-term discussion. We calculated the avian migration ratio (the proportion of breeding species that migrate) in the areas from 70 degrees E to 180 degrees E and examined its relationship with the annual ranges of ambient temperature, primary productivity (estimated by the Enhanced Vegetation Index), and precipitation, along with island isolation and elevational range. The avian migration ratio increased with increasing latitude in general but varied greatly between the two hemispheres. Additionally, it showed minimal differences between continents and islands. Our analyses revealed that the seasonality of ambient temperature, which represents the energy expenditure of birds, is the dominant factor in determining bird species migration. Seasonality in primary productivity and other environmental factors play an indirect or limited role in bird species migration. The lower avian migration ratio in the Southern Hemisphere can be attributed to its paleogeographical isolation, stable paleoclimate, and warm contemporary environment. Under current trends of global warming, our findings should lead to further studies of the impact of warming on bird migration. PMID- 23793360 TI - Antimalarial activity of Bergenia ciliata (Haw.) Sternb. against Plasmodium berghei. AB - The emergence of resistance against most of the drugs in current use against malaria has aggravated the disease burden in endemic regions. Several plants species have been used for treatment of malaria in traditional/cultural health systems. Bergenia ciliata, used traditionally for treatment of fever by local communities in the Himalayan Region, was evaluated for its plausible role as an antimalarial. Phytochemical screening of the ethanolic leaf extract of B. ciliata (ELEBC) revealed the presence of phenols, flavonoids, steroids and diterpenes. The extract showed good in vitro antiplasmodial activity, with an IC50 <10 MUg/ml. Acute toxicity of the extract was observed to be >5 g/kg, which is considered toxicologically safe for oral administration. When tested in vivo, different concentrations of the extract (250 to 1,000 mg/kg) exhibited considerable chemosuppression on day 7, in a dose-dependent manner. Maximum chemosuppression was observed to be 87.50% at 1,000 mg/kg. Administration of ELEBC (750 and 1,000 mg/kg) significantly (p < 0.0005) enhanced the mean survival time of mice in comparison to infected control, which exhibited a mean survival time of 8.6 +/- 1.5 days. Study reports presence of considerable in vitro and in vivo antimalarial activity in ethanolic leaf extract of B. ciliata for first time. Hence, the ethnopharmacological usage of the plant for treating fever is confirmed with experimental evidence. PMID- 23793361 TI - Outcome and prognostic factors after adrenalectomy for patients with distant adrenal metastasis. AB - BACKGROUND: The purpose of this study was to describe a single-institution experience with adrenal metastasectomy and to elucidate factors that may bear prognostic significance. METHODS: This is a single-center, retrospective review of patients with adrenal metastasis who underwent adrenalectomy performed with curative intent between 2000 and 2012. The Kaplan-Meier method was used to evaluate overall survival from time of adrenalectomy to death or last follow-up. Primary endpoint was death from any cause. Clinical variables were examined for association with survival. RESULTS: The study included 62 patients with mean age of 60 (+/-12) years; 55 % (34 of 62) were male, 85 % (53 of 62) presented with isolated adrenal metastasis, and 82 % (51 of 62) had metachronous disease with median disease-free interval (DFI) of 22 months (range, 6-217 months). Non-small cell lung cancer (NSCLC) was the most common primary comprising 50 % of cases. Median survival for the study population was 30 months (range, 1-145 months) and 5-year survival was 31 %. Patients with NSCLC had significantly shortened survival compared with non-NSCLC with median and 5-year survival of 17 versus 47 months and 27 % versus 38 %, respectively (p = .033). Synchronous metastasis (p = .028) and DFI < 12 months (p = .038) were also associated with worse survival outcome, though male gender (p = .69) and oligometastatic disease (p = .62) were not. CONCLUSIONS: Adrenal metastasectomy resulted in median survival of 30 months and 5-year survival of 31 %. Shorter survival was associated with lung primary, short disease-free interval, and synchronous metastasis, but not with the presence of oligometastatic disease provided that the primary cancer and additional metastatic lesions were adequately controlled and amenable to resection. PMID- 23793362 TI - A systematic review and meta-analysis comparing laparoscopic versus open gastric resections for gastrointestinal stromal tumors of the stomach. AB - BACKGROUND: This study is a systematic review and meta-analysis that compares the short- and long-term outcomes of laparoscopic gastric resection (LR) versus open gastric resection (OR) for gastric gastrointestinal stromal tumors (GISTs). METHODS: Comparative studies reporting the outcomes of LR and OR for GIST were reviewed. RESULTS: A total of 11 nonrandomized studies reviewed 765 patients: 381 LR and 384 OR. A higher proportion of high-risk tumors and gastrectomies were in the OR compared with LR (odds ratio, 3.348; 95 % CI, 1.248-8.983; p = .016) and (odds ratio, .169; 95 % CI, .090-.315; p < .001), respectively. Intraoperative blood loss was significantly lower in the LR group [weighted mean difference (WMD), -86.508 ml; 95 % CI, -141.184 to -31.831 ml; p < .002]. The LR group was associated with a significantly lower risk of minor complications (odds ratio, .517; 95 % CI, .277-.965; p = .038), a decreased postoperative hospital stay (WMD, -3.421 days; 95 % CI, -4.737 to -2.104 days; p < .001), a shorter time to first flatus (WMD, -1.395 days; 95 % CI, -1.655 to -1.135 days; p < .001), and shorter time for resumption of oral intake (WMD, -1.887 days; 95 % CI, -2.785 to .989 days; p < .001). There was no statistically significant difference between the two groups with regard to operation time (WMD, 5.731 min; 95 % CI, -15.354 26.815 min; p = .594), rate of major complications (odds ratio, .631; 95 % CI, .202-1.969; p = .428), margin positivity (odds ratio, .501; 95 % CI, .157-1.603; p = .244), local recurrence rate (odds ratio, .629; 95 % CI, .208-1.903; p = .412), recurrence-free survival (RFS) (odds ratio, 1.28; 95 % CI, .705-2.325; p = .417), and overall survival (OS) (odds ratio, 1.879; 95 % CI, .591-5.979; p = .285). CONCLUSIONS: LR results in superior short-term postoperative outcomes without compromising oncological safety and long-term oncological outcomes compared with OR. PMID- 23793363 TI - Posterior approach for laparoscopic pancreaticoduodenectomy to prevent replaced hepatic artery injury. AB - BACKGROUND: Laparoscopic pancreaticoduodenectomy (PD) has become more popular despite its complexity and tendency for higher morbidity.1 Replaced right hepatic artery (RRHA) and replaced common hepatic artery (RCHA), both originating from the superior mesenteric artery (SMA), are the most significant and relatively common vascular anomalies in patients undergoing PD, occurring in 8.6-21 and 0.4 4.5% of cases, respectively.2,3 An inadvertent injury to theses arteries may result in an intra- or postoperative bleeding, hepatic or bile duct ischemia, and consequent leakage or delayed stricture in the bilioenteric anastomosis.2-4 Therefore, preservation of these aberrant hepatic arteries is essential unless their resection is oncologically indicated.2 We describe a posterior approach that can be advantageous in laparoscopic PD for patients with a RRHA or RCHA. METHODS: The posterior approach was used in 81 laparoscopic PDs at the Institute Mutualiste Montsouris between 1994 and 2012.5 In brief, retropancreatic dissection is performed to complete kocherization and expose the posterolateral aspect of the SMA. The origin of the RRHA or RCHA can then be identified and dissected. After division of the pancreatic neck, the portal vein and RRHA or RCHA are separated off the pancreatic neck. In case of the RCHA, the gastroduodenal artery originating from the RCHA is divided during this dissection. RESULTS: The video shows a secure procedure to preserve a RCHA in laparoscopic PD by early identification and dissection of the aberrant artery via the posterior approach. CONCLUSIONS: The posterior approach can help to prevent inadvertent RRHA or RCHA injury in laparoscopic PD. PMID- 23793364 TI - Consensus guidelines from The American Society of Peritoneal Surface Malignancies on standardizing the delivery of hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer patients in the United States. AB - BACKGROUND: The American Society of Peritoneal Surface Malignancies (ASPSM) is a consortium of cancer centers performing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). This is a position paper from the ASPSM on the standardization of the delivery of HIPEC. METHODS: A survey was conducted of all cancer centers performing HIPEC in the United States. We attempted to obtain consensus by the modified method of Delphi on seven key HIPEC parameters: (1) method, (2) inflow temperature, (3) perfusate volume, (4) drug, (5) dosage, (6) timing of drug delivery, and (7) total perfusion time. Statistical analysis was performed using nonparametric tests. RESULTS: Response rates for ASPSM members (n = 45) and non-ASPSM members (n = 24) were 89 and 33 %, respectively. Of the responders from ASPSM members, 95 % agreed with implementing the proposal. Majority of the surgical oncologists favored the closed method of delivery with a standardized dual dose of mitomycin for a 90-min chemoperfusion for patients undergoing cytoreductive surgery for peritoneal carcinomatosis of colorectal origin. CONCLUSIONS: This recommendation on a standardized delivery of HIPEC in patients with colorectal cancer represents an important first step in enhancing research in this field. Studies directed at maximizing the efficacy of each of the seven key elements will need to follow. PMID- 23793365 TI - [Breast cancer: current recommendations for pathologists on the basis of the S3 guidelines]. AB - Optimal management of breast cancer patients is based on efficient multidisciplinary cooperation. The role of pathologists is to survey those parameters that are crucial for the individually adopted therapy. Thereby, distinct quality criteria have to be considered concerning the handling of the tissue samples, including preparation and examination, as well as the analytical methods used. The interdisciplinary S3 guideline "Diagnosis, therapy and follow up of breast cancer" includes recommendations concerning these aspects based on current evidence. Its third edition was published in July 2012. In this article an overview of the topics relevant for pathologists that have been modified in the latest edition is provided. PMID- 23793366 TI - The hospital resource utilization associated with osteoporotic hip fractures in Kermanshah, Iran. AB - BACKGROUND: Hip fracture is the most serious complication of osteoporosis and imposes a significant financial burden on countries' economy. This study aimed to assess the hospitalization costs and length of stay associated with osteoporosis hip fractures and identify the major cost components in a referral hospital in Kermanshah city, Iran. METHODS: In a prospective study, from May 21 2007 to May 21 2008, all patients with osteoporotic hip fracture admitted to a referral hospital for operation were recruited as the study sample. For each patient, information such as age, gender, length of stay (LOS) in hospital and intensive care unit (ICU), medical and diagnostic procedures and cost of surgery and implant were collected both through interview with the patient or a family member and the patients' hospital records. RESULTS: A total of 103 patients (56 men and 47 women) were studied. The average hospital length of stay (LOS) for the patients was 9.7 days, ranging from 5 to 38 days. The average total hospitalization costs was 7,208,588 IRR (US$774). The main components of the costs were ward stay (16.3%), operative (54.6%), implant (26%) and medical and diagnostic procedures (3.1%). CONCLUSIONS: The results of this study demonstrate that the hospital resource burden associated with osteoporotic hip fractures in Iran is substantial and expected to rise with the projected increase of life expectancy and the number of elderly in Iran. Estimating the economic burden of osteoporotic hip fractures provide information that can be of importance in the planning and design of preventive strategies. PMID- 23793367 TI - Performance of a vertical subsurface flow (VSF) wetland treatment system using woodchips to treat livestock stormwater. AB - This study was conducted to develop a vertical subsurface flow (VSF) wetland remediation system packed with woodchips to control stormwater pollution arising from livestock agriculture. Three lab-scale VSF wetlands were operated with recirculation during the interval (Delta) between storms as 2, 4 and 8 days, respectively. The fed water was 100% recirculated one time per 24 h; the recirculation frequency was 1, 3 and 7 times at Delta of 2, 4 and 8 days, respectively. The constructed wetland systems proved to be effective in reducing total suspended solid (TSS), but also had potential for increasing TSS in the effluent due to the properties of the woodchips. The release of organic matter, especially in the dissolved form, occurred during the initial 60 days. The removal efficiencies of total nitrogen (TN) were 26.2%, 34.1% and 50.0% at Delta of 2, 4 and 8 days, respectively. Nitrification was promoted by the abundant oxygen supplied when the water in wetland was recirculated and fed into the wetland. Denitrification was stable and effective due to the availability of carbon sources. The influent total phosphorus (TP) was reduced from an average of 2.05 mg L(-1) to 1.79 mg L(-1), 1.36 mg L(-1) and 0.86 mg L(-1) at Delta as 2, 4 and 8 days, respectively. The result shows that woodchips can be used as substrate material for VSF wetland treatment systems to control nutrient influx from livestock stormwater. PMID- 23793368 TI - After Babel: language and the fundamental challenges of comparative aging research. AB - The rapid growth in comparative survey research carried out in multiple countries, or among different language communities within a single nation, has given rise to a renewed concern with problems of translation. The fundamental problem facing the comparative survey researcher relates to the complexity and subjectivity of language, and the fact that complete equivalence of concepts in different linguistic, cultural, and social class contexts may be in principle impossible to achieve. Yet language remains the only medium through which information concerning subjective states, values, and beliefs can be collected. That language and the subjective constructs to which it refers are influenced by a wide range of cultural and social factors. This fact has particular relevance for comparative aging research since older individuals are often monolingual in their native languages and more tied to traditional cultures than younger individuals. This paper consists of a review of basic issues related to the nature of language and communication, and discusses the possibility of a truly scientific translation process. It outlines current best practices, and also raises questions related to the common practice of using information collected with translated survey instruments in ways that assume it reflects a comparable and quantifiable latent construct. PMID- 23793369 TI - Laser treatment of dental ceramic/cement layers: transmitted energy, temperature effects and surface characterisation. AB - In the present paper, we investigate the behaviour of different dental materials under laser irradiation. We have used e.max Ceram, e.max ZirCAD, and e.max Press dental ceramics and glass ionomer cement Ketac Cem in the present study. The dental ceramics were prepared in the form of samples with thickness of 0.5-2 mm. We used two lasers [solid-state laser (Er:YAG, Fidelis III+, Fotona) and an 810- nm diode laser (FOX, A.R.C)] for the transillumination of ceramic samples. It has been shown that the laser energy transmitted through the ceramic material decreases to 30-40% of the original values along with an increase in the thickness of the irradiated sample. Pigmented ceramic samples show more laser energy loss compared to the samples containing no pigment. We investigated the temperature evolution in composite sandwiched ceramic/cement samples under laser treatment. The increase in the irradiation time and laser power led to a temperature increase of up to 80 degrees C. The surfaces of irradiated ceramic samples were examined with X-ray photoelectron spectroscopy to evaluate changes in chemical composition, such as a decrease in the C signal, accompanied by a strong increase in the Zr peak for the Er:YAG laser, while the 810-nm diode laser showed no change in the ratio of elements on the surface. PMID- 23793370 TI - Effect of agitation of EDTA with 808-nm diode laser on dentin microhardness. AB - The aim of this study is to analyze the effect of agitation of ethylenediaminetetraacetic acid (EDTA) with diode laser at different agitation times on root dentin microhardness. Eighty-four specimens were divided randomly into seven groups, as follows: (1) distilled water, (2) 17% EDTA, (3) EDTA with 60 s ultrasonic agitation, (4) EDTA with 10 s laser agitation, (5) EDTA with 20 s laser agitation, (6) EDTA with 30 s laser agitation, and (7) EDTA with 40 s laser agitation. All of the specimens were irrigated with 5% NaOCl and distilled water except the distilled water group. Microhardness values were calculated before and after the procedures. Statistical analyses were performed using one-way ANOVA and Tukey post hoc tests. Statistically significant differences were determined between the distilled water and other groups. Also, statistically significant differences were observed between EDTA with 40 s laser agitation and EDTA, and EDTA with 10 and 20 s laser agitations. Ultrasonic agitation of EDTA affected microhardness of root dentin similar to EDTA (p > .05). All applications decreased the microhardness of root dentin when compared with distilled water. Agitation of EDTA with diode laser for 40 s caused more reduction in microhardness of root dentin when compared with EDTA. PMID- 23793371 TI - Metastases from malignant melanoma after laser treatment of undiagnosed pigmented skin lesions. PMID- 23793372 TI - Enhanced hydrogen formation during the catalytic decomposition of H2O2 on metal oxide surfaces in the presence of HO radical scavengers. AB - Presently and for the foreseeable future, hydrogen peroxide and transition metal oxides are important constituents of energy production processes. In this work, the effect of the presence of HO radical scavengers on the product yield from the decomposition of H2O2 on metal oxide surfaces in aqueous solution was examined experimentally. Scavenging the intermediate product HO by means of Tris or TAPS buffer leads to enhanced formation of H2. In parallel, a decrease in the production of the main gaseous product O2 is observed. Under these conditions, H2 formation is a spontaneous process even at room temperature. The yields of both the H2 and O2 depend on the concentration of Tris or TAPS in the reaction media. We observed that TAPS has a higher affinity for the surface of ZrO2 than does Tris. The difference in adsorption of both scavengers is reflected by the difference in their influence on the product yields. The observed sensitivity of the system H2O2-ZrO2 towards the two different scavengers indicates that O2 and H2 are formed at different types of surface sites. PMID- 23793373 TI - Stroke prevention by percutaneous closure of patent foramen ovale: a systematic review and meta-analysis. AB - CONTEXT: The role of percutaneous closure of patent foramen oval (PFO) in patients with cryptogenic stroke has been very controversial for years due to a lack of clear evidence. OBJECTIVE: Systematic review and meta-analysis of the effect of percutaneous PFO closure for secondary prevention of cryptogenic strokes as compared to best medical therapy (BMT). DATA SOURCES: Trials were identified through a literature search until 28 May 2013. STUDY SELECTION: Controlled clinical trials (randomised and non-randomised) comparing percutaneous PFO closure with BMT. DATA EXTRACTION AND SYNTHESIS: Main end point of interest was stroke. A random effects model was used to calculate the pooled relative risks (RR) with 95% CIs. RESULTS: A total of 14 studies (three randomised controlled trials (RCT) and 11 non-randomised observational studies (non-RCT)), and a total of 4335 patients were included for this analysis. There was no significant treatment effect of PFO closure regarding stroke among the RCT (RR 0.66, 95% CI 0.37 to 1.19, p=0.171). However, among non-RCT stroke was reduced (RR 0.37, 95% CI 0.20 to 0.67, p<0.001) after PFO closure. A time-to-event (stroke) analysis, combining all three RCT and the two non-RCT which applied strict multivariate adjustments, showed a borderline significant risk reduction after PFO closure (HR 0.58, 95% CI 0.33 to 0.99, p=0.047). Neither risk of bleeding nor mortality differed significantly between the groups. However, there was a higher incidence of new onset atrial fibrillation in the closure group (RR 3.50, 95% CI 1.47 to 8.35, p=0.005). CONCLUSIONS: Percutaneous closure of PFO in patients with cryptogenic stroke does not appear superior to medical therapy according to currently available randomised data. Furthermore, it is associated with an increased incidence of atrial fibrillation. However, there are signals pointing towards a potential benefit and more research should be strongly encouraged. PMID- 23793374 TI - School-level variation in health outcomes in adolescence: analysis of three longitudinal studies in England. AB - School factors are associated with many health outcomes in adolescence. However, previous studies report inconsistent findings regarding the degree of school level variation for health outcomes, particularly for risk behaviours. This study uses data from three large longitudinal studies in England to investigate school level variation in a range of health indicators. Participants were drawn from the Longitudinal Study of Young People in England, the Me and My School Study and the Research with East London Adolescent Community Health Survey. Outcome variables included risk behaviours (smoking, alcohol/cannabis use, sexual behaviour), behavioural difficulties and victimisation, obesity and physical activity, mental and emotional health, and educational attainment. Multi-level models were used to calculate the proportion of variance in outcomes explained at school level, expressed as intraclass correlations (ICCs) adjusted for gender, ethnicity and socio-economic status of the participants. ICCs for health outcomes ranged from nearly nil to .28 and were almost uniformly lower than for attainment (.17-.23). Most adjusted ICCs were smaller than unadjusted values, suggesting that school level variation partly reflects differences in pupil demographics. School-level variation was highest for risk behaviours. ICCs were largely comparable across datasets, as well as across years within datasets, suggesting that school-level variation in health remains fairly constant across adolescence. School-level variation in health outcomes remains significant after adjustment for individual demographic differences between schools, confirming likely effects for school environment. Variance is highest for risk behaviours, supporting the utility of school environment interventions for these outcomes. PMID- 23793375 TI - Zinc regulates the activity of kinase-phosphatase pair (BasPrkC/BasPrpC) in Bacillus anthracis. AB - Bacillus anthracis Ser/Thr protein kinase PrkC (BasPrkC) is important for virulence of the bacterium within the host. Homologs of PrkC and its cognate phosphatase PrpC (BasPrpC) are the most conserved mediators of signaling events in diverse bacteria. BasPrkC homolog in Bacillus subtilis regulates critical processes like spore germination and BasPrpC modulates the activity of BasPrkC by dephosphorylation. So far, biochemical and genetic studies have provided important insights into the roles of BasPrkC and BasPrpC; however, regulation of their activities is not known. We studied the regulation of BasPrkC/BasPrpC pair and observed that Zn(2+) metal ions can alter their activities. Zn(2+) promotes BasPrkC kinase activity while inhibits the BasPrpC phosphatase activity. Concentration of Zn(2+) in growing B. anthracis cells was found to vary with growth phase. Zn(2+) was found to be lowest in log phase cells while it was highest in spores. This variation in Zn(2+) concentration is significant for understanding the antagonistic activities of BasPrkC/BasPrpC pair. Our results also show that BasPrkC activity is modulated by temperature changes and kinase inhibitors. Additionally, we identified Elongation Factor Tu (BasEf-Tu) as a substrate of BasPrkC/BasPrpC pair and assessed the impact of their regulation on BasEf-Tu phosphorylation. Based on these results, we propose Zn(2+) as an important regulator of BasPrkC/BasPrpC mediated phosphorylation cascades. Thus, this study reveals additional means by which BasPrkC can be activated leading to autophosphorylation and substrate phosphorylation. PMID- 23793378 TI - Preface: selected papers from SESEH 2012 Sino-European Symposium on Environment and Health. PMID- 23793376 TI - Tropomyosin de-phosphorylation in the heart: what are the consequences? AB - The focus of this review is on the very recent work we have conducted that addresses the molecular, morphological, and physiological significance of cardiac tropomyosin phosphorylation in the heart. We employ transgenic mice to address questions of how cardiomyocytes and the whole heart respond when the tropomyosin phosphorylation site (Ser283) is converted to a non-phosphorylatable amino acid (Ala). We address the phenotype of these mice during normal development and in response to acute cardiac stress (transaortic coarctation). In addition, we also examined how transgenic mice encoding the altered tropomyosin phosphorylation site (Ser283Ala) would respond to chronic cardiac stress through an encoded hypertrophic cardiomyopathy mutation (Glu180Gly). These studies are the first to address the in vivo significance of tropomyosin phosphorylation in the heart. In this review manuscript, we report the recent findings of these investigations. PMID- 23793379 TI - Clinical benefit of surgery for stage IV colorectal cancer with synchronous peritoneal metastasis. AB - BACKGROUND: Peritoneal metastasis is well-known as a poor prognostic factor in patients with colorectal cancer. It is important to improve the prognosis of patients with colorectal cancer and synchronous peritoneal metastasis. This study aimed to clarify the factors affecting R0 resection and the prognosis of colorectal cancer patients with synchronous peritoneal metastasis. METHODS: We investigated the data of patients with stage IV colorectal cancer between 1991 and 2007 in 16 hospitals that were members of the Japanese Society for Cancer of the Colon and Rectum. RESULTS: Of the 564 colorectal cancer patients with synchronous peritoneal metastases, 341 also had hematogenous metastases. The 5 year overall survival rates in patients with and without R0 resection were 32.4 and 4.7 %, respectively. A Cox proportional hazards model showed that histologic type of poorly differentiated adenocarcinoma, regional lymph node metastasis, liver metastasis, chemotherapy after surgery, R0 resection, the Japanese classification of peritoneal metastasis, and the size of peritoneal metastases were independent prognostic factors. Of the 564 patients, 28.4 % had R0 resection. The Japanese classification of peritoneal metastasis (P1-P2, p = 0.0024) and absence of hematogenous metastases (p < 0.0001) were associated with R0 resection. CONCLUSIONS: P1-P2 peritoneal metastasis and the absence of hematogenous metastasis were the most favorable factors benefiting from synchronous resection of peritoneal metastasis. In addition, chemotherapy after surgery was essential. PMID- 23793380 TI - Risk of second malignancies in patients with gastric marginal zone lymphomas of mucosa associate lymphoid tissue (MALT). AB - BACKGROUND: It is controversial whether patients with gastric marginal zone lymphomas of mucosa associated lymphoid tissue (MALT) have higher risk of second malignancies. The aim of this study was to define the risk of second malignancies in these patients. METHODS: We analyzed prospective follow-up data of 146 consecutive patients with gastric MALT lymphoma treated at Aichi Cancer Center Hospital and compared the incidence of second malignancies with that in the general population. We calculated the standardized incidence ratio (SIR), using age- and sex-specific incidence rates from the Aichi Cancer Registry. RESULTS: The median follow-up period was 74 months. A total of 27 tumors occurred in 22 patients (15.1%), including 19 solid tumors. Of these, nine tumors were detected concomitantly with, and 18 tumors following, the diagnosis of gastric MALT lymphoma. Four patients had two second malignancies each. For the entire group, the SIR of an additional malignancy was 3.39 (95% confidence interval [CI] 2.11 4.66). An increased incidence of solid tumors (SIR 2.91 [1.60-4.22]) and hematologic malignancies (SIR 5.54 [1.70-9.38]) were seen. In addition, there was increased risk for development of second malignancies during follow up (SIR 2.26 [1.21-3.30]). Chemotherapy for treatment of MALT was an independent risk factor for second malignancies (age-sex adjusted hazard ratio 3.98 [1.47-10.79]. CONCLUSIONS: Compared with the general population, patients with gastric MALT lymphoma are at increased risk for second malignancies, including gastric cancer. PMID- 23793381 TI - The NGS WikiBook: a dynamic collaborative online training effort with long-term sustainability. AB - Next-generation sequencing (NGS) is increasingly being adopted as the backbone of biomedical research. With the commercialization of various affordable desktop sequencers, NGS will be reached by increasing numbers of cellular and molecular biologists, necessitating community consensus on bioinformatics protocols to tackle the exponential increase in quantity of sequence data. The current resources for NGS informatics are extremely fragmented. Finding a centralized synthesis is difficult. A multitude of tools exist for NGS data analysis; however, none of these satisfies all possible uses and needs. This gap in functionality could be filled by integrating different methods in customized pipelines, an approach helped by the open-source nature of many NGS programmes. Drawing from community spirit and with the use of the Wikipedia framework, we have initiated a collaborative NGS resource: The NGS WikiBook. We have collected a sufficient amount of text to incentivize a broader community to contribute to it. Users can search, browse, edit and create new content, so as to facilitate self-learning and feedback to the community. The overall structure and style for this dynamic material is designed for the bench biologists and non bioinformaticians. The flexibility of online material allows the readers to ignore details in a first read, yet have immediate access to the information they need. Each chapter comes with practical exercises so readers may familiarize themselves with each step. The NGS WikiBook aims to create a collective laboratory book and protocol that explains the key concepts and describes best practices in this fast-evolving field. PMID- 23793383 TI - Irreversible thermochromism in copper chloride Imidazolium Nanoparticle Networks. AB - In this work Imidazolium Nanoparticle Networks (INNs) with chloride counter-ions were used to complex copper dichloride. This complexation reaction leads to the formation of a green material. The properties of the copper INN material were compared to: first, copper imidazolium complexes, without the presence of silica nanoparticles, which are not thermochromic; second, chloride-containing INN material. The copper INN material showed irreversible thermochromic behaviour, with a clear colour change from green to yellow at 180 degrees C, which is due to a configuration change of the copper complex from planar to tetragonal. This structural change was studied using DSC and in situ SAXS measurements during heat treatment. The thermochromic material is stable under air up to 250 degrees C. This preliminary study opens the door of optical sensors for INN materials. PMID- 23793384 TI - Cannabis use, employment, and income: fixed-effects analysis of panel data. AB - Uncertainty exists regarding the direction and magnitude of the association between cannabis use and labor market outcomes. Using panel data from waves 1 and 2 of the National Epidemiological Survey of Alcohol and Related Conditions, the current paper estimates the associations between several patterns of cannabis use during the past year, current employment, and annual personal income. In the single-equation models (wave 2 data), nearly all patterns of cannabis use are significantly associated with worse labor market outcomes (p < 0.05). However, when using fixed-effects techniques to address unobserved and time-invariant individual heterogeneity, the estimates are generally smaller in magnitude and less likely to be statistically significant vis-a-vis the benchmark estimates. These findings suggest that unobserved individual heterogeneity is an important source of bias in models of cannabis use and labor market outcomes. Moreover, cannabis use may be less detrimental in the labor market than other studies have reported. PMID- 23793385 TI - Implementation, testing and pilot clinical evaluation of superelastic splints that decrease joint stiffness. AB - The present work aims at demonstrating that a customised choice of shape memory alloy (SMA) composition, thermo-mechanical treatment and shaping can lead to effective rehabilitation devices applicable to sub-acute and chronic spastic paresis in paediatric patients. SMA pseudoelasticity is regarded as a means to implement a corrective action on posture without hindering residual voluntary or reflex mobility of the affected limb. Specific hinges containing NiTi or NiTiNb elements were designed and constructed to transfer pseudoelastic recovery force to fitted splints for the elbow or the ankle joint. The devices were mechanically tested and showed complete stability after 20-100 cycles, and unchanged characteristics after 1000 full-range deflections. Repositioning splints equipped with patient-specific pseudoelastic hinges were prescribed to 25 individuals (aged 7.75 +/- 5.40 years) with mild to severe spastic tetraparesis. Clinical and instrumental evaluations were carried out during crossover trials with traditional and pseudoelastic splints. The sequence of treatment steps was randomized for each subject. The results show that, compared to fixed-angle braces, pseudoelastic devices decrease passive joint stiffness while providing the same control on limb posture. Dynamic pseudoelastic braces are therefore an innovative treatment for spastic paresis, which may reduce joint stiffness. PMID- 23793386 TI - Finite element analysis of the multiple drilling technique for early osteonecrosis of the femoral head. AB - We used finite element (FE) method to investigate the effect of the drilling number and entry location of holes used in the multiple drilling technique on the stress and strain state in femur. Different three-dimensional FE models of a human hip joint with or without multiple drilling were fabricated using computed tomographic images obtained from the hip joint of a cadaver. The analysis technique was evaluated in a compression test using the cadaver specimen and FE analysis for the test using an FE model of the specimen. Von Mises stresses, principal stresses, and principal strains in the cancellous and cortical bone were calculated by using the different models, and changes in these values in relation to drilling number and entry hole locations were evaluated. Calculated peak values were much smaller than the yield strength, tensile strength, and yield strain of the cancellous and cortical bone for all cases of multiple drilling. Our results support that the multiple drilling technique for osteonecrosis of the femoral head is a stable operation technique. PMID- 23793382 TI - Fragile X-associated tremor/ataxia syndrome (FXTAS): pathology and mechanisms. AB - Since its discovery in 2001, our understanding of fragile X-associated tremor/ataxia syndrome (FXTAS) has undergone a remarkable transformation. Initially characterized rather narrowly as an adult-onset movement disorder, the definition of FXTAS is broadening; moreover, the disorder is now recognized as only one facet of a much broader clinical pleiotropy among children and adults who carry premutation alleles of the FMR1 gene. Furthermore, the intranuclear inclusions of FXTAS, once thought to be a CNS-specific marker of the disorder, are now known to be widely distributed in multiple non-CNS tissues; this observation fundamentally changes our concept of the disease, and may provide the basis for understanding the diverse medical problems associated with the premutation. Recent work on the pathogenic mechanisms underlying FXTAS indicates that the origins of the late-onset neurodegenerative disorder actually lie in early development, raising the likelihood that all forms of clinical involvement among premutation carriers have a common underlying mechanistic basis. There has also been great progress in our understanding of the triggering event(s) in FXTAS pathogenesis, which is now thought to involve sequestration of one or more nuclear proteins involved with microRNA biogenesis. Moreover, there is mounting evidence that mitochondrial dysregulation contributes to the decreased cell function and loss of viability, evident in mice even during the neonatal period. Taken together, these recent findings offer hope for early interventions for FXTAS, well before the onset of overt disease, and for the treatment of other forms of clinical involvement among premutation carriers. PMID- 23793387 TI - The RRM1 domain of the poly(A)-binding protein from Saccharomyces cerevisiae is critical to control of mRNA deadenylation. AB - The poly(A)-binding protein PAB1 from the yeast Saccharomyces cerevisiae plays an important role in controlling mRNA deadenylation rates. Deletion of either its RRM1 or proline-rich domain (P domain) severely restricts deadenylation and slows mRNA degradation. Because these large deletions could be having unknown effects on the structure of PAB1, different strategies were used to determine the importance of the RRM1 and P domains to deadenylation. Since the P domain is quite variable in size and sequence among eukaryotes, P domains from two human PABPCs and from Xenopus were substituted for that of PAB1. The resultant PAB1 hybrid proteins, however, displayed limited or no difference in mRNA deadenylation as compared with PAB1. In contrast to the P domain, the RRM1 domain is highly conserved across species, and a systematic mutagenesis of the RRM1 domain was undertaken to identify its functional regions. Several mutations along the RNA-binding surface of RRM1 inhibited deadenylation, whereas one set of mutations on its exterior non-RNA binding surface shifted deadenylation from a slow distributive process to a rapid processive deadenylation. These results suggest that the RRM1 domain is the more critical region of PAB1 for controlling deadenylation and consists of at least two distinguishable functional regions. PMID- 23793388 TI - Prediction of protein amidation sites by feature selection and analysis. AB - Carboxy-terminal alpha-amidation is a widespread post-translational modification of proteins found widely in vertebrates and invertebrates. The alpha-amide group is required for full biological activity, since it may render a peptide more hydrophobic and thus better be able to bind to other proteins, preventing ionization of the C-terminus. However, in particular, the C-terminal amidation is very difficult to detect because experimental methods are often labor-intensive, time-consuming and expensive. Therefore, in silico methods may complement due to their high efficiency. In this study, a computational method was developed to predict protein amidation sites, by incorporating the maximum relevance minimum redundancy method and the incremental feature selection method based on the nearest neighbor algorithm. From a total of 735 features, 41 optimal features were selected and were utilized to construct the final predictor. As a result, the predictor achieved an overall Matthews correlation coefficient of 0.8308. Feature analysis showed that PSSM conservation scores and amino acid factors played the most important roles in the alpha-amidation site prediction. Site specific feature analyses showed that features derived from the amidation site itself and adjacent sites were most significant. This method presented could be used as an efficient tool to theoretically predict amidated peptides. And the selected features from our study could shed some light on the in-depth understanding of the mechanisms of the amidation modification, providing guidelines for experimental validation. PMID- 23793391 TI - [Burnout]. PMID- 23793389 TI - A comparison of telephone and paper self-completed questionnaires of main patient related outcome measures in patients with ankylosing spondylitis and psoriatic arthritis. AB - A cross-sectional study was performed to assess the correlation between telephone and self-administration of patient-related outcomes (PROs) used in the assessment of ankylosing spondylitis (AS) patients. Participants underwent a telephone interview in which the following measures were evaluated: numerical rating scales (NRSs) for global health, pain intensity, global pain, back pain, and back pain at night; BASDI, BASFI, Health Assessment Questionnaire (HAQ), ASQoL, EuroQol, SF 12, and Work Productivity and Activity Impairment (WPAI) questionnaire. Within 48 h after the telephone interview, patients were appointed for a clinical visit in which the same questionnaires and in the same order were self-administered. The degree of correlation of outcomes measures between telephone interview and self administration was assessed with the intraclass correlation coefficient (ICC). The two modes of assessing PROs were highly reliable, with ICC of 0.81 for BASDAI, 0.82 for BASFI, and 0.75 for HAQ. NRSs for global health, global pain intensity, back pain, and back pain at night also showed ICCs between 0.51 and 0.70, and only NRS for global disease activity showed an ICC of 0.45. This results were similar in patients with AS and patients with psoriatic arthritis. Social functioning and mental health domains of the SF-12 as well as EuroQol had poor correlations. The ICCs for WPAI outcomes were very good or good. We conclude that PROs in AS patients are comparable in both self-administered paper questionnaires and via a telephone interview. Different modes of assessing PRO measures facilitate the assessment of patients with AS in routine practice. PMID- 23793392 TI - [Association between burnout and personality: results of the Zurich study]. AB - BACKGROUND: The causes of burnout can be mainly ascribed to stressful working conditions. Research results concerning the influence of personality characteristics on the risk of burnout are rare. Research addressing the interaction of the person and the environment on the risk of burnout is needed. METHODS: This study analysed data from the Zurich study. This study of a cohort from the general population started in 1978, when the participants were 19 and 20 years old and followed them until the age of 49 and 50. In the last interview (2008) several dimensions of burnout were assessed for the first time. The association between burnout and coping (mastery and self-confidence) on the one hand and personality characteristics as assessed in 1988 by means of the Freiburg Personality Inventory on the other were analysed. RESULTS: In a path-analytical model various associations between the variables under investigation were found. The results identify a complex interaction between a dysfunctional, maladaptive personality and burnout. CONCLUSIONS: More samples from the general population are needed to better understand the interaction between person and environment on the risk of burnout. PMID- 23793393 TI - [Pedophilia: etiology, diagnostics and therapy]. AB - Child sexual abuse is one of the most destructive events for healthy child development. Following psychiatric classification systems, pedophilia must be distinguished from child sexual abuse. Approximately only one half of all child abusers fulfill the diagnostic criteria for pedophilia which is defined as a persistent or dominating sexual preference for prepubescent children characterized by persistent thoughts, fantasies, urges, sexual arousal or behavior. This article describes the diagnostic criteria and potential differential diagnoses as well as epidemiological and etiological findings. From an etiological point of view multifactorial mechanisms are currently considered to be responsible especially genetic factors, learning theoretical and neurobiological factors. Psychotherapeutic and pharmaceutical treatment options will be discussed. According to the current state of knowledge cognitive behavioral psychotherapy is the method of choice in the treatment of pedophilia and has demonstrated positive treatment effects in meta-analyses regarding relapse prevention. Medicinal treatment of pedophilia is only indicated for severe forms of pedophilia. Important aspects of risk management in the treatment of pedophilia and aspects which must be considered in the forensic psychiatric assessment are presented. PMID- 23793394 TI - Low dimensional model of bursting neurons. AB - A computationally efficient, biophysically-based model of neuronal behavior is presented; it incorporates ion channel dynamics in its two fast ion channels while preserving simplicity by representing only one slow ion current. The model equations are shown to provide a wide array of physiological dynamics in terms of spiking patterns, bursting, subthreshold oscillations, and chaotic firing. Despite its simplicity, the model is capable of simulating an extensive range of spiking patterns. Several common neuronal behaviors observed in vivo are demonstrated by varying model parameters. These behaviors are classified into dynamical classes using phase diagrams whose boundaries in parameter space prove to be accurately delineated by linear stability analysis. This simple model is suitable for use in large scale simulations involving neural field theory or neuronal networks. PMID- 23793395 TI - Oligonucleotide optical switches for intracellular sensing. AB - Fluorescence imaging coupled with nanotechnology is making possible the development of powerful tools in the biological field for applications such as cellular imaging and intracellular messenger RNA monitoring and detection. The delivery of fluorescent probes into cells and tissues is currently receiving growing interest because such molecules, often coupled to nanodimensional materials, can conveniently allow the preparation of small tools to spy on cellular mechanisms with high specificity and sensitivity. The purpose of this review is to provide an exhaustive overview of current research in oligonucleotide optical switches for intracellular sensing with a focus on the engineering methods adopted for these oligonucleotides and the more recent and fascinating techniques for their internalization into living cells. Oligonucleotide optical switches can be defined as specifically designed short nucleic acid molecules capable of turning on or modifying their light emission on molecular interaction with well-defined molecular targets. Molecular beacons, aptamer beacons, hybrid molecular probes, and simpler linear oligonucleotide switches are the most promising optical nanosensors proposed in recent years. The intracellular targets which have been considered for sensing are a plethora of messenger-RNA-expressing cellular proteins and enzymes, or, directly, proteins or small molecules in the case of sensing through aptamer-based switches. Engineering methods, including modification of the oligonucleotide itself with locked nucleic acids, peptide nucleic acids, or L-DNA nucleotides, have been proposed to enhance the stability of nucleases and to prevent false-negative and high background optical signals. Conventional delivery techniques are treated here together with more innovative methods based on the coupling of the switches with nano-objects. PMID- 23793396 TI - Fragmentation pathways of O-alkyl methylphosphonothionocyanidates in the gas phase: toward unambiguous structural characterization of chemicals in the Chemical Weapons Convention framework. AB - The electron-impact (EI) mass spectra of a series of O-alkyl methylphosphonothionocyanidates were studied for Chemical Weapons Convention (CWC) purposes. General EI fragmentation pathways were constructed and discussed, and collision-induced dissociation studies of the major EI ions were performed to confirm proposed fragment structures by analyzing fragment ions of deuterated analogs and by use of density functional theory (DFT) calculations. Thiono-thiolo rearrangement, McLafferty-type rearrangement, and a previously unknown intramolecular electrophilic aromatic substitution reaction were observed and confirmed. The study also focused on differentiation of isomeric compounds. Retention indices for all compounds, and an electrophilicity index for several compounds, are reported and interpreted. PMID- 23793397 TI - Characterization of the structure of human skin substitutes by infrared microspectroscopy. AB - The skin acts mainly as a protective barrier from the external environment, thanks to the stratum corneum which is the outermost layer of the skin. As in vitro tests on skin are essential to elaborate new drugs, the development of skin models closer to reality becomes essential. It is now possible to produce in vitro human skin substitutes through tissue engineering by using the self assembly method developed by the Laboratoire d'Organogenese Experimentale. In the present work, infrared microspectroscopy imaging analyses were performed to get in-depth morpho-spectral characterization of the three characteristic layers of human skin substitutes and normal human skin, namely the stratum corneum, living epidermis, and dermis. An infrared spectral analysis of the skin is a powerful tool to gain information on the order and conformation of the lipid chains and the secondary structure of proteins. On one hand, the symmetric stretching mode of the lipid methylene groups (2,850 cm(-1)) is sensitive to the acyl chain conformational order. The evolution profile of the frequency of this vibrational mode throughout the epidermis suggests that lipids in the stratum corneum are more ordered than those in the living epidermis. On the other hand, the frequencies of the infrared components underneath the envelop of the amide I band provide information about the overall protein conformation. The analysis of this mode establishes that the proteins essentially adopt an alpha-helix conformation in the epidermis, probably associated with the presence of keratin, while modifications of the protein content are observed in the dermis (extracellular matrix made of collagen). Finally, the lipid organization, as well as the protein composition in the different layers, is similar for human skin substitutes and normal human skin, confirming that the substitutes reproduce essential features of real skin and are appropriate biomimetics. PMID- 23793398 TI - Micro- to nanostructured poly(pyrrole-nitrilotriacetic acid) films via nanosphere templates: applications to 3D enzyme attachment by affinity interactions. AB - We report the combination of latex nanosphere lithography with electropolymerization of N-substituted pyrrole monomer bearing a nitrilotriacetic acid (NTA) moiety for the template-assisted nanostructuration of poly(pyrrole NTA) films and their application for biomolecule immobilization. The electrodes were modified by casting latex beads (100 or 900 nm in diameter) on their surface followed by electropolymerization of the pyrrole-NTA monomer and the subsequent chelation of Cu(2+) ions. The dissolution of the nanobeads leads then to a nanostructured polymer film with increased surface. Thanks to the versatile affinity interactions between the (NTA)Cu(2+) complex and histidine- or biotin tagged proteins, both tyrosinase and glucose oxidase were immobilized on the modified electrode. Nanostructuration of the polypyrrole via nanosphere lithography (NSL) using 900- and 100-nm latex beads allows an increase in surface concentration of enzymes anchored on the functionalized polypyrrole electrode. The nanostructured enzyme electrodes were characterized by fluorescence microscopy, 3D laser scanning confocal microscopy, and scanning electron microscopy. Electrochemical studies demonstrate the increase in the amount of immobilized biomolecules and associated biosensor performances when achieving NSL compared to conventional polymer formation without bead template. In addition, the decrease in nanobead diameter from 900 to 100 nm provides an enhancement in biosensor performance. Between biosensors based on films polymerized without nanobeads and with 100-nm nanobeads, maximum current density values increase from 4 to 56 MUA cm(-2) and from 7 to 45 MUA cm(-2) for biosensors based on tyrosinase and glucose oxidase, respectively. PMID- 23793399 TI - Fate of Sb(V) and Sb(III) species along a gradient of pH and oxygen concentration in the Carnoules mine waters (Southern France). AB - The speciation and behaviour of antimony were investigated in surface waters downstream from the abandoned Pb-Zn Carnoules mine (Gard, France). These waters exhibit a permanent gradient of oxygen concentration and pH, ranging from acid suboxic in Reigous Creek at the outlet of sulfide tailings impoundment, to near neutral oxygenated at downstream sites along the rivers Amous and Gardon. The concentration of total dissolved (<0.22 MUm) antimony, acquired through a seven year monitoring, decreased from 7.7-409.9 MUg L(-1) at the source of Reigous Creek to 0.22-0.45 MUg L(-1) in the Gardon River, showing natural Sb attenuation. Speciation analysis carried out during three surveys indicated that Sb(III) represented up to 70% of the total dissolved Sb concentration at the source of Reigous Creek, while Sb(V) represented less than 50%. Field characterization showed that Sb(III) and Sb(V) species were attenuated through dilution and were also removed from the dissolved phase during downstream transport. Speciation analysis in suspended particulate matter extracts gave a distribution of particulate Sb into 70 to 100% of Sb(III) and less than 30% of Sb(V). The removal of Sb(III) and Sb(V) species from the dissolved phase was concordant with the oversaturation of Reigous Creek water relative to Sb(III)- and Sb(V)-oxides and Sb(III)- and Sb(V)-Fe oxides. Sb(III) was more efficiently removed than Sb(V) or As(III) and it was no more detectable in the dissolved phase at downstream sites in the rivers Amous and Gardon. Conversely, the concentration of Sb(V) in the rivers Amous and Gardon still denoted contamination arising from the Carnoules mine. The range of log Kd values, from 2.4 L kg(-1) to 4.9 L kg(-1), indicated that Sb was mainly transported in the dissolved phase downstream the Reigous Creek input. Altogether, these results give a better understanding of the fate of Sb downstream from sulfide-rich mining wastes. PMID- 23793400 TI - A crucial role of the RGS domain in trans-Golgi network export of AtRGS1 in the protein secretory pathway. AB - The secretory pathway is responsible for the transport of newly synthesized transmembrane proteins from the endoplasmic reticulum to their destinations via the Golgi/trans-Golgi network (TGN). Cargo proteins at each station are actively sorted by specific sorting signals on the cargo and the corresponding coat complexes. Here, we used the Arabidopsis regulator of G-protein signaling (AtRGS1), which contains an N-terminal potentially sensing glucose seven transmembrane domain and a C-terminal RGS domain, as a model to uncover sorting motifs required for its cell surface expression. Expression of wild-type and truncated or mutated AtRGS1 fluorescent fusion proteins identified two cysteine residues in the extracellular N-terminus that are essential for endoplasmic reticulum exit and/or correct folding of AtRGS1. The linker between the seven transmembrane and RGS domains contains an endoplasmic reticulum export signal, whereas the C-terminus is dispensable for the plasma membrane expression of AtRGS1. Interestingly, deletion of the RGS domain results in Golgi/TGN localization of the truncated AtRGS1. Further analysis using site-directed mutagenesis showed that a tyrosine-based motif embedded in the RGS domain is essential for Golgi/TGN export of AtRGS1. These results reveal a new role for the RGS domain in regulating AtRGS1 trafficking from the Golgi/TGN to the plasma membrane and explain the interaction between the seven-transmembrane and RGS domains. PMID- 23793401 TI - Community navigation to reduce institutional recidivism and promote recovery: initial evaluation of opening doors to recovery in Southeast Georgia. AB - New approaches for preventing repeated inpatient psychiatric stays, detention in jails and prisons, and homelessness among individuals with serious mental illnesses with established histories of such recidivism, while promoting recovery, are direly needed. We present findings from an initial program evaluation of a new community-based, recovery-oriented "community navigation" program in southeast Georgia, called Opening Doors to Recovery. Twenty-three in depth interviews were conducted with key stakeholders, program participants, community navigation specialist team members, and referring mental health professionals to identify hopes and strengths, challenges and weaknesses, and recommendations pertaining to the new program. Cited strengths included teamwork and pooling of resources from various partners, as well as the novel recovery based, community navigation team approach. An initial lack of fidelity processes across teams and an ongoing scarcity of safe and affordable housing were identified as weaknesses, with the latter seen as a liability of the overall mental health and social service systems rather than the program itself. Findings from this evaluation highlight strengths and opportunities of this new community navigation approach, including those related to the involvement of certified peer specialists and multiple community partners. PMID- 23793402 TI - Is recall of dreaming during anesthesia a sign of occurrence of postoperative nausea and vomiting? AB - We examined the relationships between recall of dreaming during anesthesia and postoperative nausea and vomiting (PONV). We found a relationship between PONV within 24 h and age <50 years, use of postoperative epidural analgesia with morphine, and female gender. We also found a relationship between PONV lasting more than 24 h and dream recall. As serotonin plays an important role for both inducing PONV and dream recall, results of the present study may suggest a possible relationship between dream recall and PONV. PMID- 23793403 TI - Sunlight-driven Ag-AgCl(1-x)Br(x) photocatalysts: enhanced catalytic performances via continuous bandgap-tuning and morphology selection. AB - The solid solution (SS) method is an effective way to design impactful photocatalysts, owing to its merit of continuous bandgap-tuning. A calcination, usually breaking the morphology of a material, has to be used to synthesize such catalysts, although the morphology is a critical issue affecting its catalytic behavior. It thus is strongly desired to construct SS-based catalysts with a shaped morphology. Here, we report that AgCl(1-x)Br(x) SS-based photocatalysts, Ag-AgCl(1-x)Br(x), with a shaped morphology, can be produced via an ion-exchange between nanostructured Ag-AgCl and KBr. It is found that when sphere-like Ag-AgCl is employed as a precursor, the Ag-AgCl(1-x)Br(x), maintains its morphology when x is in the range of 0-1. The bandgap, and the catalytic activities of these Ag AgCl(1-x)Br(x) for the degradation of methyl orange, display a monotonic narrowing and a continuous enhancement, respectively, with the increase of x. In contrast, when cube-like Ag-AgCl is used as a precursor, the Ag-AgCl(1-x)Br(x) preserves its morphological features when x <= 0.5, while a morphology distortion is observed when x >= 0.75. Fascinatingly, although the bandgap of thus constructed Ag-AgCl(1-x)Br(x) also exhibits a monotonic narrowing with the increase of x, they (x ? 0, 1) display enhanced catalytic activity compared with the two terminal materials, Ag-AgCl and Ag-AgBr, wherein Ag-AgCl0.5Br0.5, with a cube-like morphology, shows the highest catalytic performance. The synergistic effect of morphology selection and bandgap narrowing plays an important role for these intriguing new findings. Our work provides a unique forum for an optimized selection of SS-based photocatalysts in terms of morphology selection and bandgap tuning. PMID- 23793404 TI - Bacterial colonization of microbial biofilms in oral squamous cell carcinoma. AB - OBJECTIVES: The purpose of this prospective clinical study was to identify the bacterial spectra on the surface of oral squamous cell carcinomas (OSCC) in comparison to oral mucosa of patients with a higher risk to emerge an OSCC and a control group to determine their susceptibility to various common antibiotics. MATERIAL AND METHODS: Swabs from 90 patients, 30 patients of each group, were cultured on media for aerobes and anaerobes and tested with agar diffusion and Etest. RESULTS: The predominant pathogens of the normal healthy oral mucosa were aerobes. The ratio between aerobes and anaerobes was 2:1, balanced in risk patients and inverted in the OSCC group. Altogether, 1,006 isolates were cultured. The most frequent strains were 47 viridans streptococci, 30 Staphylococcus species, 14 Enterococcus faecalis, 36 Neisseria species, 14 Escherichia coli, and 23 other aerobes, 66 Peptostreptococcus species, 39 Fusobacterium species, and 34 Prevotella species. The resistance rates in the OSCC group were penicillin 40%, ampicillin 57%, doxycycline 23%, clindamycin 47%, and amoxicillin/clavulanic acid 20%, but up to 100% of pathogens were susceptible to azithromycin, telithromycin, levofloxacin, and moxifloxacin. CONCLUSION: Gram negative anaerobes play a decisive role in the development of postoperative infections in patients with OSCC. This tumor special type of colonization does not agree with the normal flora of the oral cavity. CLINICAL RELEVANCE: Biofilms on OSCC surfaces provide an important reservoir for anaerobic bacteria. As a consequence, a proposal for an antibiotic prophylactic regime should be given. PMID- 23793405 TI - Fracture toughness and hardness of a Y-TZP dental ceramic after mechanical surface treatments. AB - OBJECTIVES: The aim of the investigation was to evaluate the effects of surface mechanical treatments of all-Y-TZP restorations. In order to do that, surface roughness (Rs), fractal dimension (Df), fracture toughness (Ft), Vickers hardness (Hv), crack length (Cl), and opening (Co) were determined. MATERIALS AND METHODS: Y-TZP bar-shaped specimens (n = 30) were subdivided into three groups: as received by milling center (M), after coarse polishing (CP), and after fine polishing (FP). The specimens were examined under both confocal laser and electron scanning microscopes. One-way ANOVA and post hoc tests were used to analyze the data (alpha = 0.05). RESULTS: The FP group showed a significantly lesser amount of Rs (P < 0.05). The Df analysis confirmed the significantly lesser amount of surface complexity within the FP group (P < 0.05). The Hv values were not significantly different among the groups. The Ft was significantly lesser within the FP group (P < 0.05). At the same time, both Cl and Co were significantly higher within the FP group (P < 0.05). Likewise, the FP treatment showed a significant decrease in roughness and surface complexity associated to a decrease of fracture toughness with a significant microcrack increase. CONCLUSIONS: The present study suggests that the fine polishing procedure in all YTZP restorations produces surface embrittlement. CLINICAL RELEVANCE: Because of the surface embrittlement, mechanical surface polishing of all-zirconia restorations should be avoided. PMID- 23793406 TI - Trial quality checklists: on the need to multiply (not add) scores. PMID- 23793408 TI - [Association of work load and mental disorders: review of the data]. AB - Currently, the two faces of work as described by Kurt Lewin (The socialization of the Taylor system. A fundamental examination of work and vocational psychology 1920) are clearly pronounced. Thus, work can be beneficial to personal development and well-being as work is a possible source of learning opportunities, motivation and positive emotional states. On the other hand there are a growing number of complaints about stress and exhaustion because of high work load and working days lost due to incapacity to work because of mental ill health are increasing. The question arises whether there is a relationship between work load and mental health. This article presents information on the data and tries to clarify if the relationship between work load and mental health results more due to bad job design than a distorted response behavior due to mental illness. PMID- 23793409 TI - [Alemtuzumab for relapsing-remitting multiple sclerosis. Results of two randomized controlled phase III studies]. AB - In November 2012 the results of 2 clinical phase III trials were published which addressed the effects of alemtuzumab in patients with relapsing-remitting multiple sclerosis (MS). In the CARE-MS-I study patients with early untreated MS (EDSS <= 3.0, disease duration < 5 years) were included, whereas CARE-MS-II investigated the effects of alemtuzumab in patients with persisting disease activity under standard disease-modifying treatment (EDSS <= 5.0, disease duration < 10 years). These groups were compared to patients under treatment with frequently applied interferon beta 1a (3 times 44 ug subcutaneous). Both studies clearly demonstrated a superiority of alemtuzumab compared to interferon in terms of reduction of relapse rate as well as the number of new or enlarging T2 lesions and gadolinium-enhancing lesions. Moreover, the CARE-MS-II study showed a significant delay in disease progression by alemtuzumab. The portfolio and the frequency of relevant side effects, such as infusion-related reactions, development of secondary autoimmunity or infections were within the expected range. Taken together these studies confirm the high anti-inflammatory efficacy of alemtuzumab and hence provide the first evidence of superiority of a monotherapy in direct comparison to standard disease-modifying treatment in two phase III trials in relapsing-remitting MS. These data in the context of the mode of action of alemtuzumab provide evidence for the relevance of immune cells, especially T cells, in the pathophysiology of MS. Experience with long-term effects of alemtuzumab, e.g. from the phase II extension trial as well as the side effect profile argue in favor of a sustained reprogramming of the immune system as a consequence of immune cell depletion by alemtuzumab. PMID- 23793410 TI - Imaging bile duct tumors: staging. AB - Cholangiocarcinoma (CC) is the most frequent neoplasm of the biliary system. According to its anatomic origin in the biliary tree it is usually classified as intrahepatic, perihilar, or extrahepatic distal CC. Tumors originated in these areas differ in biological behavior and management. The stratification of the patients aligned to therapeutic options and prognosis is a key point in the management of CC. Thus, specific staging systems have been designed for each anatomical location. They are precise for surgical planning, to establish prognosis after surgery, or to compare the benefits of different therapeutic approaches, but they are less accurate to stratify patients into a therapeutic decision algorithm. Imaging tools, mainly multidetector computed tomography and magnetic resonance imaging (MRI), allow full assessment of the diagnosis and extension of the tumor. They are especially useful in establishing the correct diagnosis and determining resectability, which reaches a high negative predictive value, identifying those patients in whom surgery will not be effective. We will discuss the different staging systems for CC, the radiologic characteristics with classical and recently described signs that allow a confident diagnosis of the disease and the criteria for resectability of biliary tract malignancies. PMID- 23793411 TI - Renal transplant complications. AB - Clinical monitoring and appropriate imaging have played an important role to ensure a successful outcome for renal transplant patients. A variety of imaging options now exist, and they are routinely used in these patients. Ultrasound is the most frequent first-line imaging method in the post-operative period and for long-term follow-up. For specific indications, magnetic resonance imaging, computed tomography, and nuclear medicine examinations are often helpful. This article will review the imaging findings of the most commonly encountered complications of renal transplantation. PMID- 23793412 TI - Using vocally inspired mechanical conditioning to enhance the synthesis of a cell derived biomaterial. AB - The collection of cell-derived extracellular matrix (ECM) to form implantable biomaterials has therapeutic potential. However, a significant challenge to the creation of these biomaterials is the ability to produce an adequate quantity of ECM from cells in culture. Mechanical stimulation has long been viewed as a practical means to enhance cellular matrix production. In this study we explored the influence of vocally inspired mechanical stimulation, a unique combination of high frequency vibration and low frequency strain, on the production of ECM. Using a custom fabricated vocal bioreactor, tracheal fibroblast seeded sacrificial foams were treated for 3 weeks using either isolated cyclic strain, combined cyclic strain and vibration (dual mode), or static conditioning. When compared to static controls, ECM production was significantly increased for samples conditioned with either cyclic strain or dual mode stimulation. The quantity of ECM harvested from sacrificial foams increased from 25 +/- 1 mg for statically conditioned control foams, to 34 +/- 3 and 52 +/- 10 mg for cyclic strain and dual mode conditioned samples respectively. Furthermore, mechanical conditioning significantly increased the elastic modulus of ECM biomaterials collected from sacrificial foams. Static control modulus increased from 40 +/- 2 to 63 +/- 7 kPa and 92 +/- 7 kPa following isolated cyclic strain and dual mode conditioning, respectively. These results indicate that cyclic strain conditioning can be used to accelerate the production of ECM by human tracheal cells during growth in culture, and that the addition of high frequency vibration to the conditioning program further enhances ECM production. PMID- 23793413 TI - Two-micron thulium laser resection of the distal ureter and bladder cuff during nephroureterectomy for upper urinary tract urothelial carcinoma. AB - The thulium laser (Tm-laser) technique has been used in the management of many urologic conditions. The present study aimed to evaluate the use of this technique for distal ureter and bladder cuff (DUBC) excision during nephroureterectomy for upper urinary tract urothelial carcinoma (UUT-UC). Fifty eight patients with UUT-UC who underwent radical nephroureterectomy were included in this retrospective study. DUBC was managed by open excision in 24 cases, by transurethral electrosurgery in 17 cases, and by transurethral Tm-laser in 17 cases. Perioperative measures and oncologic outcomes were compared among the three groups. Furthermore, 11 human ureteral segments were collected to measure the burst pressure and show physical pressure tolerance, and six ureteral segments were assessed histologically to investigate the sealing effect. Operative time and hospital stay were significantly longer, and intraoperative blood loss was significantly greater in the open excision group than in the electrosurgery and Tm-laser groups (P < 0.05 for all). There were no significant differences in these parameters between the electrosurgery and Tm-laser groups. In addition, there were no significant differences in the incidences of bladder tumors and retroperitoneal recurrence of urothelial carcinoma among the three groups. The coagulation time and resection time were significantly shorter in the Tm-laser group than in the electrosurgery group. The mean burst pressure did not differ significantly between the tissues sealed by electrosurgery and by Tm laser. Histopathological analyses showed that distal ureters were completely sealed by both electrosurgery and Tm-laser. The Tm-laser technique is superior to open excision and comparable to transurethral electrosurgery in the management of DUBC during nephroureterectomy for UUT-UC, offering an alternative treatment option for this condition. PMID- 23793414 TI - Photodynamic antimicrobial therapy of curcumin in biofilms and carious dentine. AB - Photodynamic therapy (PDT) is a technique that involves the activation of photosensitizers by light in the presence of oxygen, resulting in the production of reactive radicals that are capable of inducing cell death. The present study evaluated the susceptibility of Streptococcus mutans and Lactobacillus acidophilus to PDT grown as multi-species in the biofilm phase versus in dentine carious lesions. A brain-heart infusion culture medium supplemented with 1% glucose, 2% sucrose, and 1% young primary culture of L. acidophilus 10(8) CFU/mL and S. mutans 10(8) CFU/mL was used to develop multi-species biofilms and to induce caries on human dentine slabs. Five different concentrations of curcumin (0.75, 1.5, 3.0, 4.0, and 5.0 g/L) were used associated with 5.7 J/cm(2) light emission diode. Four different groups were analyzed L-D- (control group), L-D+ (drug group), L+D- (light group), and L+D+ (PDT group). ANOVA/Tukey's tests were conducted to compare groups. A significant reduction (p <0.05) in cell viability was observed in the biofilm phase following photosensitization with all curcumin concentrations tested. To achieve significant bacterial reduction (p <0.05) in carious dentine, it was necessary to utilize 5.0 g/L of curcumin in association with blue light. No significant reduction was found for L-D+, supporting the absence of the drug's dark toxicity. S. mutans and L. acidophilus were susceptible to curcumin in the presence of blue light. However, due to light penetration and drug diffusion difficulties, these microorganisms within dentine carious lesions were less affected than they were in the biofilm phase. PMID- 23793415 TI - A report on the use of Er:YAG laser for pilot hole drilling prior to miniscrew insertion. AB - The aim of the present in vitro study was to investigate the required time period of the Er:YAG laser that is used for drilling through cortical bone when pilot hole drilling is needed before miniscrew insertion. Even though Er:YAG laser is used in various in vivo and in vitro studies, there is no accepted procedure of laser for depth control during drilling through cortical bone. The study sample consisted of 120 cortical bone segments having 1.5 and 2.0 mm of cortical bone thickness. An Er:YAG laser, with a spot size of 1.3 mm and an air-water spray of 40-50 ml/min, was used. The laser was held 2 mm away from and perpendicular to the bone surface with different laser settings. Twelve specimens were prepared for each subgroup. As the cortical bone thickness increased, the time needed to drill through the bone increased. Frequency increase directly caused a decrease in irradiation duration. When three different frequency, three different energy, and four different power values were tested for both the 1.5- and 2-mm cortical bone thicknesses, the shortest duration needed to drill through cortical bone was seen in the 3.6-W (300 mJ-12 Hz) setting. When pilot holes are drilled prior to miniscrew placement in 1.5 to 2 mm of cortical bone using Er:YAG laser, the most appropriate value is found with the 3.6-W (300 mJ-12 Hz) setting. PMID- 23793416 TI - Long-duration epilepsy affects cell morphology and glutamatergic synapses in type IIB focal cortical dysplasia. AB - To investigate hypothesized effects of severe epilepsy on malformed cortex, we analyzed surgical samples from eight patients with type IIB focal cortical dysplasia (FCD) in comparison with samples from nine non-dysplastic controls. We investigated, using stereological quantification methods, where appropriate, dysplastic neurons, neuronal density, balloon cells, glia, glutamatergic synaptic input, and the expression of N-methyl-D-aspartate (NMDA) receptor subunits and associated membrane-associated guanylate kinase (MAGUK). In all FCD patients, the dysplastic areas giving rise to epileptic discharges were characterized by larger dysmorphic neurons, reduced neuronal density, and increased glutamatergic inputs, compared to adjacent areas with normal cytology. The duration of epilepsy was found to correlate directly (a) with dysmorphic neuron size, (b) reduced neuronal cell density, and (c) extent of reactive gliosis in epileptogenic/dysplastic areas. Consistent with increased glutamatergic input, western blot revealed that NMDA regulatory subunits and related MAGUK proteins were up-regulated in epileptogenic/dysplastic areas of all FCD patients examined. Taken together, these results support the hypothesis that epilepsy itself alters morphology-and probably also function-in the malformed epileptic brain. They also suggest that glutamate/NMDA/MAGUK dysregulation might be the intracellular trigger that modifies brain morphology and induces cell death. PMID- 23793417 TI - A liposome-based ion release impedance sensor for biological detection. AB - Low-cost detection of pathogens and biomolecules at the point-of-care promises to revolutionize medicine through more individualized monitoring and increased accessibility to diagnostics in remote and resource-limited areas. While many approaches to biosensing are still limited by expensive components or inadequate portability, we present here an ELISA-inspired lab-on-a-chip strategy for biological detection based on liposome tagging and ion-release impedance spectroscopy. Ion-encapsulating dipalmitoylphosphatidylcholine (DPPC) liposomes can be functionalized with antibodies and are stable in deionized water yet permeabilized for ion release upon heating, making them ideal reporters for electrical biosensing of surface-immobilized antigens. We demonstrate the quantification of these liposomes by real-time impedance measurements, as well as the qualitative detection of viruses as a proof-of-concept toward a portable platform for viral load determination which can be applied broadly to the detection of pathogens and other biomolecules. PMID- 23793418 TI - Proportional hazards regression in the presence of missing study eligibility information. AB - We consider the study of censored survival times in the situation where the available data consist of both eligible and ineligible subjects, and information distinguishing the two groups is sometimes missing. A complete-case analysis in this context would use only subjects known to be eligible, resulting in inefficient and potentially biased estimators. We propose a two-step procedure which resembles the EM algorithm but is computationally much faster. In the first step, one estimates the conditional expectation of the missing eligibility indicators given the observed data using a logistic regression based on the complete cases (i.e., subjects with non-missing eligibility indicator). In the second step, maximum likelihood estimators are obtained from a weighted Cox proportional hazards model, with the weights being either observed eligibility indicators or estimated conditional expectations thereof. Under ignorable missingness, the estimators from the second step are proven to be consistent and asymptotically normal, with explicit variance estimators. We demonstrate through simulation that the proposed methods perform well for moderate sized samples and are robust in the presence of eligibility indicators that are missing not at random. The proposed procedure is more efficient and more robust than the complete case analysis and, unlike the EM algorithm, does not require time consuming iteration. Although the proposed methods are applicable generally, they would be most useful for large data sets (e.g., administrative data), for which the computational savings outweigh the price one has to pay for making various approximations in avoiding iteration. We apply the proposed methods to national kidney transplant registry data. PMID- 23793419 TI - A pool-adjacent-violators type algorithm for non-parametric estimation of current status data with dependent censoring. AB - A likelihood based approach to obtaining non-parametric estimates of the failure time distribution is developed for the copula based model of Wang et al. (Lifetime Data Anal 18:434-445, 2012) for current status data under dependent observation. Maximization of the likelihood involves a generalized pool-adjacent violators algorithm. The estimator coincides with the standard non-parametric maximum likelihood estimate under an independence model. Confidence intervals for the estimator are constructed based on a smoothed bootstrap. It is also shown that the non-parametric failure distribution is only identifiable if the copula linking the observation and failure time distributions is fully-specified. The method is illustrated on a previously analyzed tumorigenicity dataset. PMID- 23793420 TI - Nanoimprint lithography with a focused laser beam for the fabrication of nanopatterned microchannel molds. AB - We present a process based on nanoimprint lithography for the fabrication of a microchannel mold having nanopatterns formed at the bottoms of its microchannels. A focused laser beam selectively cures the resist in the micrometer scale during nanoimprint lithography. Nanopatterns within the microchannels may be used to control microfluidic behavior. PMID- 23793421 TI - Human biology of taste. AB - Taste or gustation is one of the 5 traditional senses including hearing, sight, touch, and smell. The sense of taste has classically been limited to the 5 basic taste qualities: sweet, salty, sour, bitter, and umami or savory. Advances from the Human Genome Project and others have allowed the identification and determination of many of the genes and molecular mechanisms involved in taste biology. The ubiquitous G protein-coupled receptors (GPCRs) make up the sweet, umami, and bitter receptors. Although less clear in humans, transient receptor potential ion channels are thought to mediate salty and sour taste; however, other targets have been identified. Furthermore, taste receptors have been located throughout the body and appear to be involved in many regulatory processes. An emerging interplay is revealed between chemical sensing in the periphery, cortical processing, performance, and physiology and likely the pathophysiology of diseases such as diabetes. PMID- 23793422 TI - Correlation of hemochromatosis gene mutations and cardiovascular disease in hemodialysis patients. AB - BACKGROUND AND OBJECTIVES: Cardiovascular disease (CVD) is a major cause of death in hemodialysis (HD) patients. Hemochromatosis (HFE) gene mutations are reported to be associated with CVD. The present study aims to investigate the association of HFE gene polymorphism with CVD in HD patients. DESIGN AND SETTINGS: Cross sectional case-control. METHODS: C282Y/H63D mutations of HFE gene were evaluated in 560 HD patients and 480 healthy controls from 4 HD centers in North China. The results obtained from this evaluation process were correlated with biochemical parameters including iron status (serum iron, ferritin, and transferrin concentration), cardiovascular disease, and inflammation marker CRP, IL-6, TNF-a. RESULTS: No C282Y mutations were detected in HD patients or healthy controls in this study. The genotype of H63D heterozygous mutation was similar in HD patients with CVD, HD patients without CVD, and controls. H63D homozygous mutation was 7.4% (19/257), 3.1% (9/303), and 1.0% (5/480) for the 3 groups, respectively. Compound heterozygosity was not found in this study. The relative risk for CVD in HD patients with H63D homozygous mutation was 2.59 (95% CI: 1.15-5.84). H63D homozygous mutation had significantly higher serum ferritin concentrations compared with wild-type individuals. Moreover, HD patients had significantly higher levels of inflammatory biomarkers such as CRP, IL-6, and TNF-a. The multivariate logistic regression analysis revealed that H63D mutation instead of ferritin level was an independent risk factor of CVD for HD patients. CONCLUSIONS: Our study demonstrates for the first time that there was an association between H63D homozygous mutations and CVD in HD patients. Elevated serum CRP, IL-6, and TNF-a levels were also related to CVD in HD patients. PMID- 23793423 TI - Association of HLA-DRB1*15 and HLADQB1*06 with SLE in Saudis. AB - BACKGROUND AND OBJECTIVES: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by humoral autoimmunity. The etiology of SLE is thought to be multifactorial including environmental, hormonal, and genetic factors. The human leukocyte antigen (HLA) has extensively been associated with the susceptibility to SLE; however, the association is heterogeneous among different ethnic groups. The aim of this study was to determine the association of HLA-A, HLA-B, HLA-DRB1, and HLA-DQB1 with SLE susceptibility in the Saudi population. DESIGN AND SETTINGS: A total of 86 consecutive SLE patients attending the rheumatology clinic at King Abdulaziz Medical City, Riyadh, were recruited for this study. METHODS: HLA types were determined by the polymerase chain reaction sequence-specific oligonucleotide (PCR-SSP) method in 86 patients and 356 control subjects. RESULTS: The following HLA alleles were found to be positively associated with SLE: HLA-A*29 (OR=2.70; 95% CI=1.03-7.08; P=.0035), HLA-B*51 (OR=1.81; 95% CI=1.17-2.79; P=.0066), HLA-DRB1*15 (OR=1.45; 95% CI=0.98 2.29; P=.063), and HLA-DQB1*06 (OR=1.67; 95% CI=1.19-2.36; P=.0032), whereas HLA DRB1*16 was negatively associated with the disease (OR=0.18; 95% CI=0.02-1.3; P=.055). HLA-DRB1*15 haplotypes were significantly associated with SLE (OR=2.01, 95% CI=1.20-3.68, P=.008); this was mainly due to the HLADRB1*15-DQB1*06 association. CONCLUSIONS: Our data suggest an association between MHC class I and class II (HLA-A*29, HLA-B*51, HLA-DRB1*15, and HLA-DQB1*06) and susceptibility to SLE in the Saudi population. HLA-DRB1*15-DQB1*06 haplotype showed the highest risk factor for the disease that is similar to what was seen in the African American patients, suggesting shared susceptibility genetic factors among these ethnic groups. PMID- 23793424 TI - Assisted reproductive technique outcomes in hypogonadotropic hypogonadism women. AB - BACKGROUND AND OBJECTIVES: To evaluate the outcomes of using in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI cycle) techniques in hypogonadotropic hypogonadism (HH) women and comparing them to women with tubal factor infertility. DESIGN AND SETTINGS: Retrospective cohort study in Royan Institute, Iran. PATIENTS AND METHODS: Data from 81 HH patients treated with IVF/ICSI in the period from early 2009 until the end of 2010 were analyzed and compared with treatment results from 89 patients with tubal factor infertility. Moreover, data from the HH patients were analyzed with respect to the age factor. P value < .05 was considered statistically significant. The main outcome measures were implantation, fertilization, pregnancy, and live birth rates. RESULTS: Despite a higher fertilization rate and higher number of grade A/B embryos transferred in the tubal factor group, the implantation, pregnancy, and live birth rates were found to be similar between the 2 groups (P=.3, P=.1, P=.1, respectively). When the HH patients were evaluated according to the age factor, no significant difference was found regarding outcome parameters (P=.2). CONCLUSIONS: HH women that were treated with IVF/ICSI cycles seem to have a sound potential for pregnancy, even in advanced age patients. PMID- 23793425 TI - The burden of Rotavirus gastroenteritis among hospitalized pediatric patients in a tertiary referral hospital in Jeddah. AB - BACKGROUND AND OBJECTIVES: To evaluate the burden of Rotavirus gastroenteritis (GE) among pediatric hospital admissions. DESIGN AND SETTINGS: This is a retrospective observational study, in which all pediatric cases admitted to one of the biggest tertiary hospitals in Jeddah, with the diagnosis of GE, in the year 2010, were enrolled. PATIENTS AND METHODS: This is a retrospective observational study in which all pediatric cases admitted with the diagnosis of GE in the year 2010 were enrolled. Clinical data and laboratory findings were compared between Rota positive and Rota negative cases. The data was statistically analyzed. RESULTS: GE cases represented 8.8% of all pediatric hospital admissions in 2010. Almost 43% (42.9%) of these cases proved to have Rotavirus GE. Rotavirus infection alone, adenovirus infection alone, combined Rotavirus and adenovirus infection, and other causes of GE were present in 101 (33.6%), 21 (7%), 28 (9.3%), and 151 (50.2%) patients respectively. Coinfection with adenovirus was higher in Rota-positive GE (RPG; P=.039). Vaccination against Rotavirus was protective against Rotavirus GE (P=.042). CONCLUSIONS: Rotavirus infection is the most important causative organism of GE in our community that accounted for 42.9% of children hospitalized for GE in our study, either alone or with other infections. Among our patients, vaccination against Rotavirus appeared to be protective against Rotavirus GE. In view of the high disease prevalence among children, locally and worldwide, we recommend routine Rotavirus vaccination as the most effective available means of control despite improvement in sanitation and hygiene. PMID- 23793426 TI - Mortality among tuberculosis patients in Saudi Arabia (2001-2010). AB - BACKGROUND AND OBJECTIVES: Tuberculosis (TB) still contributes to deaths in Saudi Arabia, among both Saudis and non-Saudis. Exploring the trend of deaths caused by TB and determinants associated with high fatality rate among TB patients is considered as a part of monitoring and evaluation of the performance of National Tuberculosis Control Program to help planners improve policies and procedures used to achieve the targets of TB control. DESIGN AND SETTINGS: The current study is a retrospective one, which used the official notifications of NTP in Saudi Arabia over a period of 10 years (2001-2010). METHODS: A 10-year retrospective study included all TB cases registered in Saudi Arabia with known outcome of survival or death while under anti-TB therapy covering the period January 1, 2001, to December 31, 2010. RESULTS: Mortality among TB patients show a declining trend among Saudis starting from the year 2003 (7.2%6.1%) and a stagnant trend among non-Saudis. Saudi nationality was associated with higher fatality rate compared to non-Saudis (6.4% and 5.4%, respectively). Mortality was positively correlated with advancing age, male sex among Saudis (7.3% compared to 5.3% among females), and female sex among non-Saudis (6% compared to 5% among males), prior history of anti-TB therapy, smear positivity, and human immunodeficiency virus (HIV) seropositivity. CONCLUSIONS: We recommend WHO to modify the definition of death among TB patients. We recommend NTP in Saudi Arabia to adopt and implement International Classification of Diseases (ICD10) for TB patients' registration, improve health care services provided for elderly, monitor and strengthen NTP performance to decrease defaulter and early detect and treat patients, initiate a collaborative TB/HIV activities, and screen all suspected TB patients for HIV. In addition to these, more extended research has to be initiated concerning delayed diagnosis and comorbidities with TB. PMID- 23793427 TI - Thyroid dysfunctions and sonographic characteristics in northern Turkey: a population-based study. AB - BACKGROUND AND OBJECTIVES: In this study, it was aimed to investigate thyroid functions, sonographic characteristics of thyroid gland, relation of thyroid functions, and cardiovascular risk factors in adult population living in northern Turkey. DESIGN AND SETTINGS: The study was conducted in 70 areas (12 urban and 58 rural) in the province of Tokat in northern Turkey from 2005 to 2006. PATIENTS AND METHODS: The study included about 530000 inhabitants of 18 years and older. Demographic characteristics and thyroid sonographic findings were noted for each subject, and blood samples were collected for measuring serum lipids and thyroid function tests. RESULTS: A total of 1095 subjects (541 males, 554 females) were included, and their mean age (SD) was 41.4 (17) years. Mean thyrotropin (TSH) and free T4 levels (SD) were 1.5 (1.6) micro IU/mL and 1.2 (0.1) ng/dL, respectively, in males, and 2.2 (6.6) micro IU/mL and 1.2 (0.3) ng/dL, respectively, in females (P < .05). According to mean TSH levels, the prevalence of overt hypothyroidism, overt hyperthyroidism, subclinical hypothyroidism, and subclinical hyperthyroidism was detected as 1.6%, 0.5%, 2.7%, and 4.9%, respectively. Nodular goiter, multi-nodular goiter, and thyroid heterogeneity were determined as 13.8, 32.1, and 15.6%, respectively. The correlation between cardiovascular risk factors and serum TSH levels was not statistically significant (P > .05). The age was independently and significantly associated with serum TSH levels (P < .0001). CONCLUSION: In terms of high prevalence of thyroid dysfunction and nodular goiter, thyroid diseases must be concluded as a public health problem, and accurate and effective strategies must be identified. PMID- 23793428 TI - Incidence and outcomes of antenatally detected congenital hydronephrosis. AB - BACKGROUND AND OBJECTIVES: Antenatally detected urinary tract abnormalities (ADUTA) are increasingly recognized. Our aims were to determine the incidence and outcomes of antenatally diagnosed congenital hydronephrosis in a large cohort. DESIGN AND SETTINGS: We recorded the number of total deliveries over 4 years at King Abdulaziz University Hospital (KAUH) between January 2008 and December 2011 from the number of nursery and neonatal intensive care unit (NICU) admissions. PATIENTS AND METHODS: We reviewed the records of 18 853 deliveries between January 2008 and December 2011 at KAUH, Saudi Arabia. ADUTA were recorded, and their postnatal medical records were reviewed for demographic and radiological data. RESULTS: ADUTA were diagnosed in 327 fetuses (1.7%). The commonest pathology was congenital hydronephrosis (n=313, 95.7%). Cystic renal anomalies were reported in 4 babies (1.2%), and 10 children (3.1%) were reported to have other renal anomalies, including duplex kidneys or a single kidney. A total of 240 babies with congenital hydronephrosis were followed up. Hydronephrosis resolved in 99 children (41.2%) within 2 months of birth. A total of 29 subjects had underlying renal anomalies (12.1%), including vesicoureteral reflux (n=12, 5%), pelvi-ureteric junction obstruction (n=14, 5.8%), and posterior urethral valve (n=3, 1.3%). The best predictor for nonresolving congenital hydronephrosis and underlying anatomical abnormalities was the anteroposterior diameter on the first postnatal scan. A cut-off point of 5 mm was found to be 83% sensitive in predicting nonresolving hydronephrosis, while 7 mm was 88% sensitive and 10 mm was 94% sensitive. CONCLUSIONS: Congenital hydronephrosis is the commonest ADUTA. A large percentage resolved within 2 months of birth, but underlying anatomical abnormalities were found in 12.1%. All babies with antenatally detected hydronephrosis should be examined by ultrasound postnatally but further radiological investigations should only be performed for persistent significant AP dilatation >=10 mm. PMID- 23793429 TI - Grading adenoid utilizing flexible nasopharyngoscopy. AB - BACKGROUND AND OBJECTIVES: To assess the possibility of adenoid size asymmetry in both nasal sides by nasopharyngoscopy. DESIGN AND SETTINGS: This is a prospective study involving 100 children, with age ranging between 1 and 12 years, performed in Saudi Arabia between January 2010 and December 2011. METHODS: Adenoid was examined and graded I-IV in relation to posterior choana bilaterally by flexible nasopharyngoscopy. The adenoid grade was compared with the other side in each child. RESULTS: The findings from endoscopy were analyzed: there was a high degree of agreement in grading both sides, that was 92% with kappa=0.868. Moreover, there was grade asymmetry in 8% of the cases. CONCLUSION: Adenoid grading using flexible nasopharyngoscopy through one side of the nose may not represent the adenoid grade of the other side in all cases. PMID- 23793430 TI - Outcome after ileal pouch-anal anastomosis for familial adenomatous polyposis compared to mucosal ulcerative colitis in a Middle Eastern population. AB - BACKGROUND AND OBJECTIVES: To compare the complications and outcome after ileal pouch-anal anastomosis (IPAA) for mucosal ulcerative colitis (MUC) and familial adenomatous polyposis (FAP). DESIGN AND SETTINGS: This is a retrospective study. The study was conducted at a single tertiary referral center. METHODS: All patients who underwent restorative proctocolectomy with IPAA at a tertiary center in Saudi Arabia from 2001 till 2009 were retrieved. Data was obtained regarding preoperative status, postoperative complications, and functional outcome. RESULTS: A total of 40 patients underwent IPAA, of which 21 cases were of FAP and 19 cases of MUC. Median age at operation for FAP and MUC was 31 (range: 16-45) and 43 (range: 15-65) years, respectively (P < .05). Median length of stay was 10 days (range: 6-42) for FAP and 12 days (range: 9-27) for MUC (P=.1). Postoperative morbidity was noted in 4 cases of FAP and 6 cases of MUC (P=.36). Specifically, wound infection was noted in 2 cases of FAP compared to 3 cases of MUC (P=.55); 1 MUC case had an anastomotic leak (P=.29). One mortality was recorded among the FAP cases (P=.35). The time between the creation of IPAA and the closure of ileostomy was 4.5 and 5 months for FAP and MUC, respectively (P=.87). Median follow-up was 36 months. Median bowel frequency per 24 hours was 6 (range: 3-24) for FAP and 7 (range 3-17) for MUC (P=.54). Intestinal obstruction was reported in 3 cases of FAP and 5 cases of MUC (P=.38). One pouch was excised in a FAP patient. One case of MUC developed pouchitis. CONCLUSIONS: The outcome after IPAA was inferior for MUC compared to FAP, but it was not statistically significant due to the small sample size. The morbid status of the MUC cases and their older age contributed to the minor differences. PMID- 23793431 TI - Risk factors for congenital hypothyroidism in Egypt: results of a population case control study (2003-2010). AB - BACKGROUND AND OBJECTIVES: Although the prevention of the neuropsychological consequences of congenital hypothyroidism (CH) through the use of replacement therapy represents an important public health success, knowledge about the modifiable risk factors could reduce the number of infants affected by this disease. This study was carried out to identify risk factors for CH at Fayoum Governorate, Egypt. DESIGN AND SETTINGS: This was a population-based case-control study, which started in 2003 and was carried out for 8 years through Fayoum center of the Egyptian Ministry of Health and Population screening program for CH. METHODS: This study was a population-based case-control study carried out by using national project for CH. One control was enrolled for each new CH infant; 320 cases and 320 controls were enrolled in 8 years. Maternal and neonatal influences were investigated. RESULTS: A statistically significant association of CH was observed with birth defects, female gender, gestational age > 40 weeks, and gestational diabetes. An increased risk for CH was detected in twins by a multivariate analysis. CONCLUSION: Our results suggest a multifactorial origin of CH in which genetic (high frequency of additional malformations) and environmental factors (especially maternal diabetes) play a role in the development of the disease. PMID- 23793432 TI - Curative effect of pleural lavage on open chest trauma caused by seawater immersion. AB - BACKGROUND AND OBJECTIVES: Open chest trauma with seawater immersion can lead systematic inflammatory response and multiple organ dysfunction syndromes (MODS). Early intervention of seawater immersion significantly decreases mortality. This study aims to explore the curative effect of pleural lavage in the treatment of open chest trauma caused by seawater immersion on dogs. DESIGN AND SETTINGS: An in vivo experimental study was performed in healthy cross-breeding adult dogs (n=20). SUBJECTS AND METHODS: A dog model of open chest trauma caused by seawater immersion was established. All experimental dogs were divided into control group and pleural lavage group, with 10 dogs in each group. In the control group, dogs were performed ventilator-assisted breathing, and thoracic tube was kept open for adequate chest water drainage; in the pleural lavage group, dogs were further injected with 0.9% sodium chloride (35 mL/kg) immediately into the right side of the chest after the pleural effusion was drained off. The internal environment, oxygen partial pressure, and pathological changes of the lung tissue were observed and recorded. RESULTS: Following open chest trauma caused by seawater immersion, both groups showed obviously increased serum sodium and plasma osmolality and sharply decreased oxygen partial pressure. After treatment, the serum sodium and plasma osmolality decreased, whereas oxygen partial pressure increased in both groups. The pleural lavage group showed better improvement than the conventional treatment group. The pathological changes in the pleural group were lighter than in the conventional treatment group. CONCLUSION: Compared with conventional treatment, repeated pleural lavage shows improved treatment in the correction of blood hypertonic state and hypoxemia in seawater-immersed open chest trauma. PMID- 23793433 TI - The use of and out-of-pocket spending on complementary and alternative medicine in Qassim province, Saudi Arabia. AB - BACKGROUND AND OBJECTIVES: The current picture of the Saudis' use of complementary and alternative medicine (CAM) has not yet been developed. The aim of this study was to assess the feasibility of using the international questionnaire to measure use of complementary and alternative medicine (I-CAM-Q) in Saudi Arabia to evaluate the use of and out-of-pocket spending on CAM. DESIGN AND SETTINGS: It was a cross-sectional study, conducted in 2011, in primary health care centers in Qassim. METHODS: In a multistage sampling technique, 12 primary health care centers were selected randomly in the Al-Qassim province in Saudi Arabia. From each center, 100 attendants were interviewed for a total of 1160 completed questionnaires. RESULTS: A total of 74% of subjects had visited CAM providers in 12 months before the survey. This percentage decreased to 47.6% when spiritual healers were excluded. The specific CAM providers who were visited were spiritual healers (26.7%), herbalists (23.2%), providers of honeybee products (14.9%), and hijama (wet cupping; 13%). Chronic illnesses were the main reason for the visits. A total of 50% of subjects were satisfied with their visit. Physicians were the providers of CAM for 11.3% of the participants. More than 75% of the subjects used herbs in the previous 12 months for medical and health reasons, while only 25% used vitamins or minerals. Self-help was used in 26% of the participants. Relaxation (10.3%) was the most common self-CAM practice followed by meditation (6.7%). The subjects spent 350000 (US$) on CAM visits and 300000 (US$) purchasing CAM products. CONCLUSIONS: I-CAM-Q can be used in different populations and cultures in the East including Saudi Arabia after customization to overcome its limitations, as the questionnaire was developed in Western societies. PMID- 23793434 TI - The distribution of cagA and dupA genes in Helicobacter pylori strains in Kurdistan region, northern Iraq. AB - BACKGROUND AND OBJECTIVES: Helicobacter pylori is a Gram negative bacteria that causes peptic ulceration and gastric adenocarcinoma. H pylori virulence factors, such as cagA and dupA, are important to study in populations as they contribute to disease risk. This study aimed to look at the distribution of the cagA and dupA genes in H pylori strains isolated from patients suffering from gastroduodenal diseases in Kurdistan region, Iraq. DESIGN AND SETTINGS: A cross sectional study conducted between June 2011 and January 2012. Biopsies were collected from the Endoscopy Department in Duhok and Sulaimania hospitals, Kurdistan region, northern Iraq. PATIENTS AND METHODS: Upper gastrointestinal (GI) endoscopy examination was performed and 4 gastric biopsies (2 from the antrum and 2 from the corpus) were obtained from 204 patients. H pylori positivity was examined by CLO test; then the association between disease status and virulence factors was assessed by polymerase chain reaction. RESULTS: 154 (75%) of our samples were found to be H pylori + by CLO test. Endoscopic diagnoses for those who were positive were as follows: peptic ulcer disease (PUD) including duodenal ulcer, 45; gastric ulcer, 23; and no ulcer (NPUD), 86. The overall prevalence rates of cagA and dupA were 72.7% and 18.8%, respectively. While a significant association between cagA and PUD was observed (P. <=.017; OR=0.4; CI=0.18-0.85), no relationship between dupA and PUD could be seen. CONCLUSION: These data suggested that the presence of cagA may be a predictor of clinical outcome in Kurdistan region, northern Iraq. PMID- 23793435 TI - Heterosexual precocity: rare manifestation of virilizing adrenocortical oncocytoma. AB - Adrenocortical oncocytomas are extremely rare, and most of the tumors are benign and nonfunctioning. To our knowledge, only 30 cases have been reported in English published studies, and most patients are 40 to 60 years of age. So far, in the pediatric age group, only three cases of functioning adrenocortical oncocytoma have been reported. We report a case of functioning adrenocortical oncocytoma in a 3 1/2-year-old female child who presented with premature pubarche, clitoromegaly, and increased serum dehydroepiandrosterone sulfate and testosterone. She was managed successfully with right adrenalectomy, and the tumor histology was consistent with adrenal oncocytoma. PMID- 23793436 TI - Acute fibrinous and organizing pneumonia. AB - A 45-year-old man presented with malaise, arthralgia, and dyspnea. The chest CT scan showed bilateral patchy consolidation in the lower lobes. A lung biopsy revealed intra-alveolar fibrin "balls" deposits and focal features of organizing pneumonia, both of which are typical pathological features of acute fibrinous and organizing pneumonia (AFOP). The patient had a good clinical course after treatment with prednisone. We report this case of idiopathic AFOP and review the published studies on this newly recognized clinicopathological entity that is still underdiagnosed and underreported. PMID- 23793437 TI - Malignant melanoma and basal cell carcinoma of the face: a rare coexistence. AB - The simultaneous presence of two disparate neoplasms occurring in the same specimen has been well documented, albeit uncommonly. The juxtaposition of malignant melanoma (MM) and basal cell carcinoma (BCC) as collision tumors has been rarely reported, with most cases describing melanoma in situ and BCC. We report a case of a 20-year-old male presenting with three papillomatous growths on the face, localized over the left frontotemporal region, below the right eye and over the right eyebrow. On histopathology and immunohistochemistry the lesions were diagnosed as pigmented MM and BCC. MM and BCC presenting at different sites on the face in the same patient along with a focus of metastasis in the same anatomical region as the primary tumor is quite rare. To the best of our knowledge this is the first report of such a case. PMID- 23793438 TI - Endovascular embolization of a giant aneurysm in medial posterior choroidal artery with associated arteriovenous malformation. AB - A 16-year-old male adolescent who presented with vomiting and headache and in the emergency department had a loss of consciousness, was discovered to have a large mass compressing the brainstem. CT scan showed two adjacent mass lesions. Digital subtraction angiography (DSA) revealed a giant aneurysm in the posterior medial choroidal artery, subsequently embolized with Guglielmi detachable coils (GDCs). Ten GDCs were used to embolize the aneurysm and the distal aspect of its parent artery. Postembolization DSA confirmed complete embolization of the aneurysm. Endovasular embolization of giant aneurysms in the medial posterior choroidal artery with GDCs is technically feasible and represents a successful therapeutic option. In unruptured giant intracranial aneurysms, simultaneous packing of the aneurysm with coils and occlusion of the distal parent artery can have a good outcome. PMID- 23793439 TI - Local recurrence of primary central nervous system lymphoma due to tumor seeding. PMID- 23793441 TI - Parkinson disease loci in the mid-western Amish. AB - Previous evidence has shown that Parkinson disease (PD) has a heritable component, but only a small proportion of the total genetic contribution to PD has been identified. Genetic heterogeneity complicates the verification of proposed PD genes and the identification of new PD susceptibility genes. Our approach to overcome the problem of heterogeneity is to study a population isolate, the mid-western Amish communities of Indiana and Ohio. We performed genome-wide association and linkage analyses on 798 individuals (31 with PD), who are part of a 4,998 member pedigree. Through these analyses, we identified a region on chromosome 5q31.3 that shows evidence of association (p value < 1 * 10( 4)) and linkage (multipoint HLOD = 3.77). We also found further evidence of linkage on chromosomes 6 and 10 (multipoint HLOD 4.02 and 4.35 respectively). These data suggest that locus heterogeneity, even within the Amish, may be more extensive than previously appreciated. PMID- 23793442 TI - A novel rearrangement of occludin causes brain calcification and renal dysfunction. AB - Pediatric intracranial calcification may be caused by inherited or acquired factors. We describe the identification of a novel rearrangement in which a downstream pseudogene translocates into exon 9 of OCLN, resulting in band-like brain calcification and advanced chronic kidney disease in early childhood. SNP genotyping and read-depth variation from whole exome sequencing initially pointed to a mutation in the OCLN gene. The high degree of identity between OCLN and two pseudogenes required a combination of multiplex ligation-dependent probe amplification, PCR, and Sanger sequencing to identify the genomic rearrangement that was the underlying genetic cause of the disease. Mutations in exon 3, or at the 5-6 intron splice site, of OCLN have been reported to cause brain calcification and polymicrogyria with no evidence of extra-cranial phenotypes. Of the OCLN splice variants described, all make use of exon 9, while OCLN variants that use exons 3, 5, and 6 are tissue specific. The genetic rearrangement we identified in exon 9 provides a plausible explanation for the expanded clinical phenotype observed in our individuals. Furthermore, the lack of polymicrogyria associated with the rearrangement of OCLN in our patients extends the range of cranial defects that can be observed due to OCLN mutations. PMID- 23793443 TI - The use of focus groups to develop a culturally relevant quality of life tool for lymphatic filariasis in Bangladesh. AB - PURPOSE: The purpose of this study was to conduct focus groups to operationalise the construct of quality of life (QOL) for people living with lymphatic filariasis (LF) in Bangladesh to develop culturally valid items for a Bangladeshi LF QOL tool. METHODS: Ten focus groups were conducted with a stratified purposeful sample (n = 60) of LF patients (3 focus groups, n = 17), doctors (1 focus group, n = 5), nurses (1 focus group, n = 6) and other hospital staff (1 focus group, n = 5), community leaders (2 focus groups, n = 14), community volunteer health workers (1 focus group, n = 5) and Bangladeshi LF researchers and planners (1 focus group, n = 8). Focus group methodology was informed by local culture in consultation with cultural mentors and local advisors, often going against standard focus group procedures. Data were collected through note taking, audio taping, transcripts, observational notes and a reflection diary. Open coding of transcript data was completed until data saturation was achieved. RESULTS: Forty-three constructs were identified through the focus groups that had not previously been identified in the literature, including constructs relating to environmental supports and barriers, activities, participation and psychological impacts. There were marked differences between the impacts reported by different groups, highlighting the need for a comprehensive purposive sample. In particular, contributions from participants who would not traditionally be viewed as "experts" were vital. CONCLUSIONS: The use of focus groups strongly contributed to the operationalisation of the concept of QOL in Bangladesh for people living with LF. Use of literature review or expert opinion alone would have missed vital constructs. PMID- 23793444 TI - Left atrial pressure as predictor for recurrence of atrial fibrillation after pulmonary vein isolation. AB - PURPOSE: Identification of reliable risk factors for recurrence of atrial fibrillation (AF) after pulmonary vein isolation (PVI) has important implications. Left atrial (LA) pressure is a largely observator-independent parameter that can easily be determined after transseptal puncture. The purpose of this study was to investigate the predictive value of LA pressure for AF recurrence after PVI. METHODS: Two hundred five consecutive patients with paroxysmal or persistent AF scheduled for first PVI were included. Baseline clinical data were collected. During PVI, LA pressure was determined invasively after transseptal puncture. PVI was performed with radiofrequency or cryoenergy, and patients were followed for 25 +/- 7 months. RESULTS: One hundred five (51 %) patients had AF recurrence. Patients with persistent AF prior to ablation had significantly more recurrences than patients with paroxysmal AF (70.1 vs. 42.0 %, p < 0.001). Mean LA pressure was significantly higher in patients with recurrence of AF (13.4 +/- 7.1 vs. 11.0 +/- 5.2 mmHg, p = 0.007), as was mean LA volume index (40.1 +/- 18.5 vs. 33.0 +/- 11.2 mL/m(2), p < 0.001). In the multivariate analysis, mean LA pressure was predictive in patients with normal or mildly enlarged LA, while AF type was not predictive. For each 1-mmHg increase in LA pressure, the risk of AF recurrence increased by 11 % in this subgroup. In patients with moderately or severely enlarged LA, AF type was predictive whereas LA pressure was not. CONCLUSION: LA pressure, AF type, and LA volume index are independent predictors for recurrence of AF after PVI. LA pressure may be helpful especially in patients with small atria, where AF type is not predictive. PMID- 23793445 TI - The role of anticipatory postural adjustments in interlimb coordination of coupled arm movements in the parasagittal plane: II. Postural activities and coupling coordination during cyclic flexion-extension arm movements, ISO- and ANTI-directionally coupled. AB - When coupling cyclic adduction-abduction movements of the arms in the transverse (horizontal) plane, isodirectional (ISO) coupling is less stable than antidirectional (ANTI) coupling. We proposed that such deficiency stems from the disturbing action that anticipatory postural adjustments exert on ISO coupling. To ascertain if postural adjustments differentiate ISO versus ANTI coupling coordination in other types of cyclic arm movements, we examined flexion extension oscillations in the parasagittal plane. Oscillations of the right arm alone elicited cyclic Postural Adjustments (PAs) in the left Anterior Deltoid and Posterior Deltoid, which replicated the excitation-inhibition pattern of the prime movers right Anterior Deltoid, right Posterior Deltoid. Cyclic PAs also developed symmetrically in Erector Spinae (RES and LES) and in phase opposition in Ischiocruralis (RIC and LIC), so as to discharge to the ground both an anteroposterior force, Fy, and a moment about the vertical axis, Tz. Oscillations of both arms in ISO coupling induced symmetric PAs in both ES and IC muscles, thus generating a large Fy but no Tz. In ANTI coupling, PAs in RES and LES remained symmetric but smaller in size, while PAs in RIC and LIC were large and opposite in phase, resulting in a large Tz and small Fy. Altogether, PAs would thus favour ISO and hamper ANTI parasagittal movements because (1) in the motor pathways to the prime movers of either arm, a convergence would occur between the voluntary commands and the commands for PAs linked to the movement of the other arm, the two commands having the same sign (excitatory or inhibitory) during ISO and an opposite sign during ANTI; (2) the postural effort of trunk and leg muscles would be higher for generating Tz in ANTI than Fy in ISO. These predictions fit with the finding that coupling stability was lower in ANTI than in ISO, i.e., opposite to horizontal movements. In conclusion, in both parasagittal and horizontal arm movements, the less coordinated coupling mode was the one constrained by postural adjustments through the two above mechanisms. PMID- 23793447 TI - Correlation analysis as a tool to investigate the bioaccessibility of nickel, vanadium and zinc in Northern Ireland soils. AB - Correlation analyses were conducted on nickel (Ni), vanadium (V) and zinc (Zn) oral bioaccessible fractions (BAFs) and selected geochemistry parameters to identify specific controls exerted over trace element bioaccessibility. BAFs were determined by previous research using the unified BARGE method. Total trace element concentrations and soil geochemical parameters were analysed as part of the Geological Survey of Northern Ireland Tellus Project. Correlation analysis included Ni, V and Zn BAFs against their total concentrations, pH, estimated soil organic carbon (SOC) and a further eight element oxides. BAF data were divided into three separate generic bedrock classifications of basalt, lithic arenite and mudstone prior to analysis, resulting in an increase in average correlation coefficients between BAFs and geochemical parameters. Sulphur trioxide and SOC, spatially correlated with upland peat soils, exhibited significant positive correlations with all BAFs in gastric and gastro-intestinal digestion phases, with such effects being strongest in the lithic arenite bedrock group. Significant negative relationships with bioaccessible Ni, V and Zn and their associated total concentrations were observed for the basalt group. Major element oxides were associated with reduced oral trace element bioaccessibility, with Al2O3 resulting in the highest number of significant negative correlations followed by Fe2O3. spatial mapping showed that metal oxides were present at reduced levels in peat soils. The findings illustrate how specific geology and soil geochemistry exert controls over trace element bioaccessibility, with soil chemical factors having a stronger influence on BAF results than relative geogenic abundance. In general, higher Ni, V and Zn bioaccessibility is expected in peat soil types. PMID- 23793448 TI - Arsenic removal using natural biomaterial-based sorbents. AB - Arsenic contamination of water is a major problem worldwide. A possible solution can be approached through developing new sorbents based on cost-effective and environmentally friendly natural biomaterials. We have developed new sorbents based on biomaterial impregnation with iron oxyhydroxide. In this study, raw peat material, iron-modified peat, iron-modified biomass (shingles, straw, sands, cane and moss) as well as iron humate were used for the removal of arsenate from contaminated water. The highest sorption capacity was observed in iron-modified peat, and kinetic studies indicated that the amount of arsenic sorbed on this material exceeds 90 % in 5 h. Arsenate sorption on iron-modified peat is characterised by the pseudo-second-order mechanism. The results of arsenic sorption in the presence of competing substances indicated that sulphate, nitrate, chloride and tartrate anions have practically no influence on As(V) sorption onto Fe-modified peat, whereas the presence of phosphate ions and humic acid significantly lowers the arsenic removal efficiency. PMID- 23793449 TI - Comparison of inflammatory cytokine profiles in plasma of patients undergoing otorhinological surgery with propofol or isoflurane anesthesia. AB - OBJECTIVE AND DESIGN: The effects of anesthetics on cytokine release in patients without comorbidities who undergo minor surgery are not well defined. We compared inflammatory cytokine profiles in adult patients undergoing minimally invasive surgery who received isoflurane or propofol anesthesia. METHODS: Thirty-four patients without comorbidities undergoing minor surgery were randomly assigned to receive an inhaled anesthetic (isoflurane; n = 16) or an intravenous anesthetic (propofol; n = 18). Blood samples were drawn before premedication and anesthesia (T1), 120 min after anesthesia induction (T2), and on the first post-operative day (T3). Plasma concentrations of interleukins (IL-) 1beta, 6, 8, 10 and 12 and tumor necrosis factor (TNF)-alpha were measured using flow cytometry. RESULTS: The pro-inflammatory cytokine IL-6 was increased in the isoflurane group at T2 and T3 compared to T1 (P < 0.01). In the propofol group, IL-6 and IL-8 were significantly increased at T3 compared to T1. However, there were no significant differences in cytokine concentrations between the isoflurane and propofol groups. CONCLUSION: An inflammatory response occurred earlier in patients who received an inhaled agent compared with an intravenous anesthetic, but no differences in plasma cytokine profiles were evident between isoflurane and propofol anesthesia in patients without comorbidities undergoing minimally invasive surgeries. PMID- 23793450 TI - Synthesis of In2O3-In2S3 core-shell nanorods with inverted type-I structure for photocatalytic H2 generation. AB - In2O3-In2S3 core-shell nanostructures were prepared via a simple hydrothermal process at low temperatures. Ultraviolet photoelectron spectroscopy (UPS) shows that the In2O3-In2S3 nanorod is an inverted type I nanostructure. The energy potential in this structure would drive both the photo-generated holes and electrons towards the shell to facilitate photocatalytic H2 generation. Such inverted type-I nanostructure is firstly used for hydrogen generation. Comparing with reported indium-based photocatalysts upon UV-Vis illumination, the core shell In2O3-In2S3 nanostructure obtained here exhibits a good H2 evolution rate of 61.4 MUmol h(-1) g(-1). PMID- 23793452 TI - [Female patient with depressive psychosis and visual disturbances]. PMID- 23793451 TI - Targeting the PDGF signaling pathway in the treatment of non-malignant diseases. AB - Platelet-derived growth factor (PDGF) is a family of mesenchymal mitogens with important functions during the embryonal development and in the control of tissue homeostasis in the adult. The PDGF isoforms exert their effects by binding to alpha-and beta-tyrosine kinase receptors. Overactivity of PDGF signaling has been linked to the development of certain malignant and non-malignant diseases, including atherosclerosis and various fibrotic diseases. Different types of PDGF antagonists have been developed, including inhibitory monoclonal antibodies and DNA aptamers against PDGF isoforms and receptors, and receptor tyrosine kinase inhibitors. Beneficial effects have been recorded using such inhibitors in preclinical models and in patients with certain malignant as well as non malignant diseases. The present communication summarizes the use of PDGF antagonists in the treatment of non-malignant diseases. PMID- 23793453 TI - Rootstock scion somatogenetic interactions in perennial composite plants. AB - The ancient plant production practice of grafting which instantly imparts new physiological properties to the desirable scion still remains shrouded in mystery. Yet, grafting remains a widely used technique in the production of several horticultural species. In a composite grafted plant, rootstocks control many aspects of scion growth and physiology including yield and quality attributes as well as biotic and abiotic stress tolerance. Broadly, physical, physiological, biochemical and molecular mechanisms have been reviewed to develop an integrated understanding of this enigmatic process that challenges existing genetic paradigms. This review summarizes the reported mechanisms underlying some of the economically important traits and identifies several key points to consider when conducting rootstock scion interaction experiments. Study of the somatogenetic interactions between rootstock and scion is a field that is ripe for discovery and vast improvements in the coming decade. Further, utilization of rootstocks based on a better understanding of the somatogenetic interactions is highly relevant in the current agricultural environment where there is a need for sustainable production practices. Rootstocks may offer a non-transgenic approach to rapidly respond to the changing environment and expand agricultural production of annual and perennial crops where grafting is feasible in order to meet the global food, fiber and fuel demands of the future. PMID- 23793455 TI - The predictive ability of the STarT Back Screening Tool in a Danish secondary care setting. AB - INTRODUCTION: The predictive ability of the STarT Back Tool (SBT) in secondary care settings has not been investigated. The aim of this study was to determine the SBT's predictive ability in a Danish secondary care setting and compare this to a Danish primary care setting. METHODS: Poor clinical outcome at 6 months (>30 points on a 0-100 Roland Morris Disability Scale) was calculated in secondary care (n = 960) and primary care (n = 172) cohorts. The cohorts were stratified into SBT subgroups and estimates of additional risk for poor outcome were calculated [relative risk (RR), unadjusted and adjusted odds ratios]. The discriminative ability was determined using the area under the curve statistic. RESULTS: In secondary care 69.0 % and in primary care 40.2 % had poor outcome on activity limitation. Although significant, the predictive ability of the SBT in secondary care (medium-risk RR 1.5, high-risk RR 1.7) was not as strong as in primary care (medium-risk RR 2.3, high-risk RR 3.5). Adjusting for episode duration and pain intensity only changed the predictive ability marginally in secondary care. The discriminative ability of the SBT was similar in both cohorts despite differences in the predictive ability. CONCLUSION: The SBT had less predictive ability in a Danish secondary care setting compared to a Danish primary care setting for persistent activity limitation at 6 months follow-up. SBT-targeted treatment implications in secondary care were not investigated in this study. PMID- 23793454 TI - Mechanical loading of the intervertebral disc: from the macroscopic to the cellular level. AB - PURPOSE: Mechanical loading represents an integral part of intervertebral disc (IVD) homeostasis. This review aims to summarise recent knowledge on the effects of mechanical loads on the IVD and the disc cells, taking into consideration the changes that IVDs undergo during ageing and degeneration, from the macroscopic to the cellular and subcellular level. METHODS: Non-systematic literature review. RESULTS: Several scientific papers investigated the external loads that act on the spine and the resulting stresses inside the IVD, which contribute to estimate the mechanical stimuli that influence the cells that are embedded within the disc matrix. As disc cell responses are also influenced by their biochemical environment, recent papers addressed the role that degradation pathways play in the regulation of (1) cell viability, proliferation and differentiation and (2) matrix production and turnover. Special emphasis was put on the intracellular signalling pathways, as mechanotransduction pathways play an important role in the maintenance of normal disc metabolism and in disc degenerative pathways. CONCLUSIONS: Disc cells are exposed to a wide range of mechanical loads, and the biochemical environment influences their responses. Degeneration-associated alterations of the disc matrix change the biochemical environment of disc cells and also the mechanical properties of the disc matrix. Recent studies indicate that these factors interact and regulate disc matrix turnover. PMID- 23793456 TI - An in vivo and in vitro investigation of the use of ICDAS, DIAGNOdent pen and CarieScan PRO for the detection and assessment of occlusal caries in primary molar teeth. AB - OBJECTIVES: The aim of this study was to investigate the in vivo and in vitro validity of International Caries Detection and Assessment System (ICDAS), DIAGNOdent pen and CarieScan PRO in the detection and assessment of occlusal caries in primary teeth. METHODS: Sixty-four molars were assessed using all three systems under standardised in vivo conditions. They were then extracted and assessed by two examiners in vitro along with an additional 38 teeth (102 teeth in total from 45 children). Downer's histological scoring criterion was the validation gold standard. Sensitivity, specificity, positive and negative likelihood ratios and area under the receiver-operator curves were calculated for all caries and dentine caries. Repeatability was analysed using Cohen's Kappa and the performance of the systems between in vivo and in vitro settings by the same examiner were compared. RESULTS: ICDAS showed the highest validity and repeatability. The DIAGNOdent pen's overall clinical validity was comparable to that of ICDAS, but it demonstrated only moderate repeatability. CarieScan PRO had negligible validity in vivo, and there was no relationship between in vivo and in vitro parameters. CONCLUSIONS: The in vivo results of ICDAS and DIAGNOdent pen were satisfactory and comparable to those obtained in vitro, with ICDAS performing better. The CarieScan PRO performed poorly under both conditions. CLINICAL RELEVANCE: ICDAS should be the index of choice when detecting and assessing occlusal caries in the primary dentition, and in vitro data can be safely extrapolated in vivo. The DIAGNOdent pen must be employed with caution. Currently, the CarieScan PRO is unsuitable for use in the primary dentition. PMID- 23793457 TI - Host cell reactivation of gene expression for an adenovirus-encoded reporter gene reflects the repair of UVC-induced cyclobutane pyrimidine dimers and methylene blue plus visible light-induced 8-oxoguanine. AB - Previously, we have reported the use of a recombinant adenovirus (Ad)-based host cell reactivation (HCR) assay to examine nucleotide excision repair (NER) of UVC induced DNA lesions in several mammalian cell types. The recombinant non replicating Ad expresses the Escherichia coli beta-galactosidase (beta-gal) reporter gene under control of the cytomegalovirus immediate-early enhancer region. We have also used methylene blue plus visible light (MB + VL) to induce the major oxidative lesion 7,8-dihydro-8-oxoguanine (8-oxoG) in the recombinant Ad-encoded reporter gene in order to study base excision repair (BER). The reported variability regarding 8-oxoG's potential to block transcription by RNA polymerase II and data demonstrating that a number of factors play a role in transcriptional bypass of the lesion led us to examine the repair of 8-oxoG in the Ad reporter and its relationship to HCR for expression of the reporter gene. We have used Southern blotting to examine removal of UVC- and MB + VL-induced DNA damage by loss of endonuclease-sensitive sites from the Ad-encoded beta-gal reporter gene in human and rodent cells. We show that repair of MB + VL-induced 8 oxoG via BER and UVC-induced cyclobutane pyrimidine dimers (CPDs) via NER is substantially greater in human SV40-transformed GM637F skin fibroblasts compared to hamster CHO-AA8 cells. We also show that HCR for expression of the MB + VL damaged and the UVC-damaged reporter gene is substantially greater in human SV40 transformed GM637F skin fibroblasts compared to hamster CHO-AA8 cells. The difference between the human and rodent cells in the removal of both 8-oxoG and CPDs from the damaged reporter gene was comparable to the difference in HCR for expression of the damaged reporter gene. These results suggest that the major factor for HCR of the MB + VL-treated reporter gene in mammalian cells is DNA repair in the Ad rather than lesion bypass. PMID- 23793458 TI - Insights into MLC pathogenesis: GlialCAM is an MLC1 chaperone required for proper activation of volume-regulated anion currents. AB - Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of leukodystrophy caused by mutations in either MLC1 or GLIALCAM genes and is associated with myelin and astrocyte vacuolation. It has been suggested that MLC is caused by impaired cell volume regulation as a result of defective activation of astrocytic volume-regulated anion currents (VRAC). GlialCAM brings MLC1 and the ClC-2 Cl(-) channel to cell-cell junctions, even though the role of ClC-2 in MLC disease remains incompletely understood. To gain insights into the biological role of GlialCAM in the pathogenesis of MLC disease, here we analyzed the gain- and loss-of-function phenotypes of GlialCAM in Hela cells and primary astrocytes, focusing on its interaction with the MLC1 protein. Unexpectedly, GlialCAM ablation provoked intracellular accumulation and reduced expression of MLC1 at the plasma membrane. Conversely, over-expression of GlialCAM increased the cellular stability of mutant MLC1 variants. Reduction in GlialCAM expression resulted in defective activation of VRAC and augmented vacuolation, phenocopying MLC1 mutations. Importantly, over-expression of GlialCAM together with MLC1 containing MLC-related mutations was able to reactivate VRAC currents and to reverse the vacuolation caused in the presence of mutant MLC1. These results indicate a previously unrecognized role of GlialCAM in facilitating the biosynthetic maturation and cell surface expression of MLC1, and suggest that pharmacological strategies aimed to increase surface expression of MLC1 and/or VRAC activity may be beneficial for MLC patients. PMID- 23793459 TI - HRG regulates tumor progression, epithelial to mesenchymal transition and metastasis via platelet-induced signaling in the pre-tumorigenic microenvironment. AB - Mice lacking histidine-rich glycoprotein (HRG) display an accelerated angiogenic switch and larger tumors-a phenotype caused by enhanced platelet activation in the HRG-deficient mice. Here we show that platelets induce molecular changes in the pre-tumorigenic environment in HRG-deficient mice, promoting cell survival, angiogenesis and epithelial-to-mesenchymal transition (EMT) and that these effects involved signaling via TBK1, Akt2 and PDGFRbeta. These early events subsequently translate into an enhanced rate of spontaneous metastasis to distant organs in mice lacking HRG. Later in tumor development characteristic features of pathological angiogenesis, such as decreased perfusion and pericyte coverage, are more pronounced in HRG-deficient mice. At this stage, platelets are essential to support the larger tumor volumes formed in mice lacking HRG by keeping their tumor vasculature sufficiently functional. We conclude that HRG-deficiency promotes tumor progression via enhanced platelet activity and that platelets play a dual role in this process. During early stages of transformation, activated platelets promote tumor cell survival, the angiogenic switch and invasiveness. In the more progressed tumor, platelets support the enhanced pathological angiogenesis and hence increased tumor growth seen in the absence of HRG. Altogether, our findings strengthen the notion of HRG as a potent tumor suppressor, with capacity to attenuate the angiogenic switch, tumor growth, EMT and subsequent metastatic spread, by regulating platelet activity. PMID- 23793460 TI - Healing of osteotomy sites applying either piezosurgery or two conventional saw blades: a pilot study in rabbits. AB - PURPOSE: The purpose of this study was to compare bone healing of experimental osteotomies applying either piezosurgery or two different oscillating saw blades in a rabbit model. METHODS: The 16 rabbits were randomly assigned into four groups to comply with observation periods of one, two, three and five weeks. In all animals, four osteotomy lines were performed on the left and right nasal bone using a conventional saw blade, a novel saw blade and piezosurgery. RESULTS: All three osteotomy techniques revealed an advanced gap healing starting after one week. The most pronounced new bone formation took place between two and three weeks, whereby piezoelectric surgery revealed a tendency to faster bone formation and remodelling. Yet, there were no significant differences between the three modalities. CONCLUSIONS: The use of a novel as well as the piezoelectric bone cutting instrument revealed advanced bone healing with a favourable surgical performance compared to a traditional saw. PMID- 23793461 TI - Surgical resection and radiation therapy of desmoid tumours of the extremities: results of a supra-regional tumour centre. AB - PURPOSE: Desmoid tumours of the extremity have a high recurrence rate. The purpose of this study was to analyse the outcome after resection of these tumours with special emphasis on recurrent disease and adjuvant therapeutic strategies. METHODS: In this retrospective study we evaluated prognostic factors for recurrence-free survival after surgical treatment of desmoid tumours of the extremity in 27 patients with an average age of 41 years treated from 1997 to 2009. Adjuvant radiotherapy (50-60 Gy) was given in five cases with primary and in nine patients with recurrent disease. The average follow-up was 64 months. RESULTS: The five-year recurrence-free survival in patients with primary disease was 33%. Patients with negative resection margins tended to have a better outcome than patients with positive resection margins, but the difference between both groups was not significant (56 vs 14%, p = 0.145). In patients with positive margins, adjuvant radiotherapy did not significantly improve recurrence-free survival (40 vs 14%, p = 0.523). Patients with local recurrence had a five-year further recurrence-free survival of 47%. In those patients further recurrence free survival was significantly better after adjuvant radiation (89 vs 25%, p = 0.015). Two thirds of all patients suffered moderate or severe complications due to the treatment regimen. CONCLUSIONS: Compared to desmoids of the trunk or the head and neck region, desmoids affecting the limbs show by far the worst outcome in terms of relapse or treatment-related morbidity. The importance of negative resection margins is still not clear. Particularly in recurrent desmoids adjuvant radiotherapy appears to reduce the further recurrence rate. Therefore, a general use of radiation should be considered for this high-risk group. PMID- 23793462 TI - The acromial index is not predictive for failed rotator cuff repair. AB - BACKGROUND: The main objective of this study was to evaluate the association between the acromial index (AI) and the incidence of recurrent tears of the rotator cuff (RC) in a cohort of patients with full thickness tears who underwent arthroscopic primary repair. METHODS: A prognostic study of a prospective case series of 103 patients with full thickness RC tears was undertaken. The average age was 59.5 years (39-74) and follow-up was 30.81 months (12-72). True anterior posterior X-rays were obtained during the pre-operative evaluation. Pre and post operative magnetic resonance imaging (MRI) were recorded. RESULTS: Eighteen cases with recurrent tears (17.4%) were seen on post-operative MRI. The average AI for patients with recurrent tears was 0.711 +/- 0.065 and for patients without recurrent tears 0.710 +/- 0.064 (p < 0.05). A positive association between age and recurrent tears of the RC was noted (average ages: recurrent tears group 63 +/- 5.9 years; group without recurrent tears 58.8 +/- 7.5 years) (r = -0.216; p = 0.029). We did not find an association between size of the primary tear and recurrent tears (r = -0.075; p < 0.05) or between degrees of retraction of the primary and recurrent tears of the cuff (r = -0.073; p < 0.05). We observed that 38.9% of the recurrent tears cases presented with more than one tendon affected before the arthroscopy. At follow-up, none of these recurrent tears showed more than one tendon affected on MRI evaluation. CONCLUSION: In this study, we found that the AI radiological measurement is not a predictor for recurrent tears of the RC after primary arthroscopic repair. PMID- 23793463 TI - Inappropriate requests for magnetic resonance scans of the shoulder. AB - PURPOSE: Magnetic resonance imaging (MRI) scans are a useful investigation for some shoulder pathology. They are costly however and a significant burden on radiology departments. In most cases clinical examination, plain radiography or ultrasound scan (USS) are sufficient for a diagnosis. There are no current UK guidelines regarding MRI shoulder scan requests. METHODS: We reviewed 100 consecutive MRI shoulder scan requests and the associated formal reports; other investigations were also assessed. RESULTS: Overall, 56% of MRI scans were ordered inappropriately. Shoulder consultant's requests were more appropriate than other groups (70% vs. 38%. p = 0.04). Excluding shoulder consultants 63 % of scans were inappropriately ordered. Shoulder consultants were more likely to order a preceding X-ray (80% vs. 53% respectively, p = 0.03). Of those with a clinical diagnosis of cuff pathology only 29% had an USS. CONCLUSION: A high percentage of MRI shoulder scans are performed inappropriately. Shoulder consultants are more appropriate in their ordering than other groups. If all groups performed as well 50 % less MRI scans would need to be performed. PMID- 23793464 TI - Comment on Liu et al.: Operative versus non-operative treatment for clavicle fracture: a meta-analysis. PMID- 23793465 TI - The mini postero-postero-lateral mini incision in total hip arthroplasty. AB - PURPOSE: Mini invasive incisions in THA and femoral hip prostheses tend to minimise healing and recovery time. We have used a very posterior approach with technical modifications and precise skin landmarks to decrease surgical complexity, and we describe this experience here. METHODS: From 2010 to 2012, 140 patients aged 79 years (range 53-93 years) were operated upon by the same surgeon in a continuous series using the same minimally invasive skin incision and six different types of implants. The incision was very posterior in the hip allowing direct visualisation of the acetabulum in the hip flexion position and visualisation of the femoral shaft extremity in a leg flexion position. RESULTS: The mean operating time was 100 minutes (range 75-110 min). Estimated blood loss was 385 cc (20-585 cc). Twenty-six patients had blood transfusion. The mean hospital stay was 6.8 days (5-20 days) including the time waiting for a rehabilitation centre. No operative complications related to the technique were recorded. On the postoperative radiograph, the femoral stem was aligned with the femoral axis within 3 degrees in all patients. The mean acetabular angle to the ground plane was 40 degrees (35-48 degrees ). No patient had a leg length discrepancy of more than four millimetres. The mean skin incision length was seven centimetres (six to eight centimetres). All patients were seen at the clinic after six weeks and the data were unchanged at this time point. CONCLUSION: The method and skin landmarks we describe appear to be a safe way to perform minimally invasive total hip replacement. PMID- 23793466 TI - Comment on Gagala et al.: Clinical and radiological outcomes of avascular necrosis of the femoral head using autologous osteochondral transfer (mosaicplasty). Preliminary report. PMID- 23793467 TI - Attendance at a survivorship clinic: impact on knowledge and psychosocial adjustment. AB - PURPOSE: Due to their heightened risk of developing late-occurring adverse outcomes, pediatric cancer survivors are advised to receive follow-up care in specialized Survivor Clinics. However, little is known about the impact of attending such clinics on psychosocial adjustment, knowledge, and morbidity. This study assesses the differences between those who attended a Survivorship Clinic and those who did not on knowledge, perception of risk, and psychosocial adjustment. METHODS: We assessed 102 survivors who attended our Long-Term Follow Up (LTFU) Clinic and 71 survivors never seen in a specialized clinic (non-LTFU). Participants were diagnosed at least 5 years prior to the assessment, were at least 20 years old, and had no evidence of active disease. Groups were matched on gender, age at cancer diagnosis, diagnosis, and race. RESULTS: On average, participants were currently 30 years of age and had been diagnosed with cancer around age 12. Most common reasons that non-LTFU survivors did not attend the clinic were "not aware" (71 %) or "not interested" (16 %). Survivors in each group were able to accurately report their cancer diagnosis, but few knew specific treatment information. There were no significant differences regarding survivors' perceptions of risk of future health problems with both groups similarly underestimating their risks. A significant minority in each group reported psychological or emotional problems (16-18 %), post-traumatic stress disorder (4.2-6.9 %), and/or psychological distress (7.8-19.7 %). CONCLUSIONS: Survivors are in need of continued education about their specific cancer treatments, recommended follow-up practices, the importance of survivorship care, and their specific risks for late effects. IMPLICATIONS FOR CANCER SURVIVORS: Among those childhood cancer survivors who do attend a Survivor clinic, a majority are in need of continued education about their specific cancer treatments, recommended follow-up practices, and risk of late effects. As many survivors of pediatric cancer appear to be unaware of the existence of Survivor clinics, improved methods of transitioning survivors after completion of treatment are needed. PMID- 23793468 TI - Trends in modifiable lifestyle-related risk factors following diagnosis in breast cancer survivors. AB - PURPOSE: Evidence suggests that high-risk lifestyle behaviors exacerbate the health of cancer survivors and increase cancer mortality. This study examined the prevalence of lifestyle-related risk factors among female breast cancer survivors by duration of survivorship in the United States. METHODS: We analyzed data from 7,443 women aged >=18 years who participated in the 2009 Behavioral Risk Factor Surveillance System and reported having ever-diagnosed breast cancer. Adjusted prevalence with 95 % confidence interval for lifestyle-related risk factors (including current smoking, excessive alcohol drinking, obesity, engaging in physical activity >=150 min/week, and consuming fruits and vegetables >=5 times/day) was estimated using log-linear regression while controlling for confounders. RESULTS: Overall, the prevalence estimates for lifestyle-related risk factors were 10.2 % for current smoking, 6.8 % for excessive alcohol drinking, 24.7 % for obesity, 53.8 % for engaging in physical activity >=150 min/week, and 33.9 % for consuming fruits and vegetables >=5 times/day among female breast cancer survivors. After adjustment for covariates, with increasing years of survivorship, a linearly increasing trend was observed for current smoking (P = 0.038), and quadratic trends were observed for excessive alcohol drinking (P < 0.001) and obesity (P = 0.048). The adjusted prevalence estimates for engaging in physical activity >=150 min/week and consuming fruits and vegetables >=5 times/day did not vary significantly by duration of survivorship. CONCLUSION: Continuing efforts on counseling and encouraging breast cancer survivors to adopt healthy lifestyles are needed to improve their health. IMPLICATIONS FOR CANCER SURVIVORS: Understanding the trends of modifiable lifestyle-related risk factors among breast cancer survivors with varying duration of survivorship may assist health care providers to provide appropriate counseling for breast cancer patients to improve their health. Clinical and public health intervention programs should seek to maximize the number of recommended healthy behaviors especially in those women who are at high risk for failing to comply with the healthy lifestyle guidelines. PMID- 23793469 TI - hESC-secreted proteins can be enriched for multiple regenerative therapies by heparin-binding. AB - This work builds upon our findings that proteins secreted by hESCs exhibit pro regenerative activity, and determines that hESC-conditioned medium robustly enhances the proliferation of both muscle and neural progenitor cells. Importantly, this work establishes that it is the proteins that bind heparin which are responsible for the pro-myogenic effects of hESC-conditioned medium, and indicates that this strategy is suitable for enriching the potentially therapeutic factors. Additionally, this work shows that hESC-secreted proteins act independently of the mitogen FGF-2, and suggests that FGF-2 is unlikely to be a pro-aging molecule in the physiological decline of old muscle repair. Moreover, hESC-secreted factors improve the viability of human cortical neurons in an Alzheimer's disease (AD) model, suggesting that these factors can enhance the maintenance and regeneration of multiple tissues in the aging body. PMID- 23793470 TI - Differential regulation of brain-derived neurotrophic factor in term and preterm preeclampsia. AB - Our earlier studies in preeclampsia (PE) suggest a causal relationship between altered angiogenic factors and birth outcomes. Recent studies suggest that brain derived neurotrophic factor (BDNF) can stimulate angiogenesis. The present study examines the levels of maternal and cord BDNF in women with PE (n = 106; full term [n = 60] and preterm [n = 46]) and normotensive women (n = 95; control) delivering at term. Maternal BDNF levels were lower (P < .05) in women with PE when compared to normotensive women. Cord BDNF levels were higher (P < .01) in women with PE delivering at term, while it was lower (P < .01) in women delivering preterm. Maternal BDNF levels were negatively associated with systolic and diastolic blood pressure (P < .01 for both). Our data for the first time suggest a possible role for BDNF in the pathophysiology of PE. Differential regulation of cord BDNF levels in preterm PE suggests a need to follow-up children to assess the neurodevelopmental effects in later life. PMID- 23793471 TI - Risks for donors in uterus transplantation. AB - Uterus transplantation (UTx) is an alternative to gestational surrogacy and adoption for patients with absolute uterine infertility. Studies have been conducted in animals, and UTx is now within the reach of clinical application in humans. Procedures in humans have been published, but many medical, ethical, and social problems and risks of UTx require discussion prior to widespread clinical application, from the perspectives of donors, recipients, families, and newborns. In this article, we summarize the burdens and risks of UTx, with a focus on donors who provide the uterus. PMID- 23793472 TI - Expression patterns of progesterone receptor membrane components 1 and 2 in endometria from women with and without endometriosis. AB - Endometriosis is a hormone-dependent inflammatory condition associated with pain and infertility. A growing body of evidence supports attenuated secretory-phase progesterone responsiveness in women with this disease. Herein, we compare the expression of progesterone receptor membrane components (PGRMC) 1 and 2 in eutopic endometrium from 11 women with laparoscopically and/or histologically proven stage III/IV endometriosis and 23 disease-free women. Menstrual cycle phase was determined using a combination of reported cycle day, serum hormone profile, and endometrial histologic dating. The PGRMC-1 (fold change -3.3; P < .05) and PGRMC-2 (fold-change -8.8; P < .05) gene expression were significantly downregulated in secretory phase, eutopic endometrium from women with endometriosis. Immunohistochemistry demonstrated decreased PGRMC-1 and PGRMC-2 protein expression in the secretory phase endometrial stroma cells of women with endometriosis. Consistent with the preclinical work of others, our results reflect downregulation of endometrial PGRMC-1 and PGRMC-2 expression in secretory phase endometrium from women with advanced stage endometriosis. Understanding the molecular mechanisms of attenuated progesterone action in endometriosis has important diagnostic and therapeutic implications. PMID- 23793473 TI - Antenatal allopurinol reduces hippocampal brain damage after acute birth asphyxia in late gestation fetal sheep. AB - Free radical-induced reperfusion injury is a recognized cause of brain damage in the newborn after birth asphyxia. The xanthine oxidase inhibitor allopurinol reduces free radical synthesis and crosses the placenta easily. Therefore, allopurinol is a promising therapeutic candidate. This study tested the hypothesis that maternal treatment with allopurinol during fetal asphyxia limits ischemia-reperfusion (I/R) damage to the fetal brain in ovine pregnancy. The I/R challenge was induced by 5 repeated measured compressions of the umbilical cord, each lasting 10 minutes, in chronically instrumented fetal sheep at 0.8 of gestation. Relative to control fetal brains, the I/R challenge induced significant neuronal damage in the fetal hippocampal cornu ammonis zones 3 and 4. Maternal treatment with allopurinol during the I/R challenge restored the fetal neuronal damage toward control scores. Maternal treatment with allopurinol offers potential neuroprotection to the fetal brain in the clinical management of perinatal asphyxia. PMID- 23793474 TI - 1,25-Dihydroxyvitamin D deficiency is associated with preterm birth in African American and Caucasian women. AB - Vitamin (vit) D deficiency and preterm birth (PTB) are more prevalent among African American (AA) women compared to caucasian (Cau) women. Because vit D is important in regulating cell-mediated immune responses, vit D insufficiency or deficiency during pregnancy may enhance inflammation in pregnant women and increase the risk of PTB. In this study, circulatory levels of 25-hydroxy (OH) and 1,25-dihydroxy (OH)2 vit D were measured using chemiluminescence and radioimmunoassay techniques, respectively, in AA (n = 108) and Cau (n = 84) women who delivered at term and preterm. The results from this study suggest that the serum levels of the 25-(OH) vit D concentrations tend to decrease (P = .06) in the Cau women who delivered at preterm compared to those delivering at term. However, the 25-(OH) vit D levels in Cau and AA between term and preterm deliveries were not significantly different. The serum levels of 1,25-(OH)2 vit D were found to be significantly lower in AA women compared to Cau women (P < .02) at term, and in the Cau (P < .01) and AA (P < .04) women delivering at preterm compared to those delivering at term. One-way analysis of variance demonstrated that 1,25-(OH)2 vit D levels were significantly lower in participants delivering at preterm (<34 weeks and between 34 and 37 weeks) compared to those delivering at term (>37 weeks).These results suggest that low levels of serum 1,25-(OH)2 vit D are associated with PTB, and vit D can potentially be used as a novel diagnostic marker in the detection of PTB. PMID- 23793475 TI - Antiapoptotic agent sphingosine-1-phosphate protects vitrified murine ovarian grafts. AB - Significant follicle loss from frozen ovarian grafts is unavoidable. The authors evaluated the protective effects of the antiapoptotic agent sphingosine-1 phosphate (S1P) on vitrified ovarian grafts. Three-week-old sexually immature female FVB mice were divided into 4 groups, fresh, control without S1P, 0.5 mmol/L S1P, and 2 mmol/L S1P. The ovaries were pretreated with S1P for 1 hour and then cryopreserved by modified vitrification. The frozen-thawed ovaries were autotransplanted under the back muscles of mice for 10 days. Expression of apoptosis-related genes encoding caspase 3 and c-Myc was analyzed in the vitrified ovaries and 10 days after transplantation using real-time quantitative polymerase chain reaction. To quantify the ovarian reserve, anti-Mullerian hormone (AMH) levels and follicles were measured in the 10-day vitrified ovarian grafts. Caspase 3 and c-Myc messenger RNA did not differ significantly in the 4 groups after vitrification but was significantly upregulated in the control group after transplantation. The AMH levels and primordial follicle pool were significantly higher in the S1P-treated groups than in the control group but lower than that in the fresh group. The S1P protects vitrified ovarian grafts from ischemic reperfusion injury rather than from vitrification-associated process. PMID- 23793476 TI - Rapid imaging protocol in trauma: a whole-body dual-source CT scan. AB - The purpose of this study is to determine whether a single acquisition whole-body trauma multi-detector CT scan is able to reduce resuscitation time, scan time, and effective radiation dose without compromising diagnostic quality in the setting of polytrauma. Retrospective analysis of 33 trauma patients undergoing single acquisition whole-body CT with injury severity scores of >= 16 was compared to 34 patients imaged with a segmented whole-body CT protocol. Time spent in the emergency department, effective radiation dose, image quality, and mortality rates were compared. The single acquisition group spent 53.7 % less time in the emergency department prior to imaging (p=0.0044) and decreased scanning time by 25 %. The protocol yielded a 24.5 % reduction in mean effective radiation dose (24.66 mSv vs. 32.67 mSv, p<0.0001). The image noise was similar in both groups. Standardized mortality ratios were comparable. The single acquisition protocol significantly reduces time spent in the emergency department by allowing faster imaging at a lower radiation dose while maintaining image quality. Other contributors to reduction in radiation dose include use of dual source CT technology, removal of delayed CT intravenous pyelogram, and arm positioning. PMID- 23793477 TI - Electrical field manipulation of cancer cell behavior monitored by whole cell biosensing device. AB - All living cells possess electrical characteristics and are thus responsive to, and even generate electric fields and currents. It has been shown that the electrical properties of cancer cells differ from normal proliferating cells, thus electric fields may induce differential effects in normal and cancer cells. Manipulation of these electrical properties may provide a powerful direct and/or adjuvant therapeutic option for cancer. A whole cell impedance-based biosensor to monitor the effects of a range of different frequencies (50 kHz-2 MHz) at low intensity (<2 V/cm) on the growth rate of human SKOV3 ovarian cancer cells versus non-cancerous HUVECs is reported. Rapid real-time monitoring of the SKOV3 behavior was observed as the alternating electric fields were applied and the impedimetric response of the cells was recorded. The cells were also labeled with propidium iodide to examine morphological changes and cell viability with fluorescence microscopy with trypan blue for comparison. A noticeable decrease in the growth profile of the SKOV3 was observed with the application of 200 kHz alternating electric fields indicating specific inhibitory effects on dividing cells in culture in contrast to the HUVECs. The outcome of this research will improve our fundamental understanding of the behavior of cancer cells when exposed to alternating electric fields at specific frequencies and foster the development strategies and optimal parameters for alternating electric field therapies for clinical and drug delivery applications. PMID- 23793478 TI - Graft failure versus graft fixation in ACL reconstruction: histological and immunohistochemical studies in rabbits. AB - The causes of graft failure after anterior cruciate ligament (ACL) reconstruction are multifactorial including the methods of graft fixation. The purpose of this study was to examine the ACL graft failure in three different methods of graft fixations including interference screw fixation, suture-post fixation and combined interference screw and suture-post fixation. We hypothesized that the fixation method after ACL reconstruction can affect the graft healing in tibial tunnel. Eighteen New Zealand white rabbits were categorized into three groups according to the method of fixation in unilateral ACL reconstruction with long digital extensor autograft. Histological examination demonstrated that the combined fixation and suture-post fixation groups showed significantly better integration between tendon and bone (P = 0.04). In immunohistochemical analysis, the combined fixation and suture-post fixation groups showed significantly higher BMP-2 and VEGF expressions than interference screw (P < 0.01). The tendon-bone healing after ACL reconstruction was affected by the method of graft fixation. Combined fixation with interference screw and suture-post reduced graft-tunnel micromotion and improved the graft healing in tibial tunnel. PMID- 23793479 TI - Autologous double-barrel vascularized fibula bone graft for arthrodesis of the shoulder after tumor resection. AB - INTRODUCTION: Arthrodesis of the shoulder is a straightforward and established alternative to reconstruct the shoulder function after tumor resection of the proximal humerus. In most cases, some kind of intercalary bone graft is used to bridge the bony defect. However, due to low stability of a single fibula autograft and disadvantages of exogenous graft material when performing combined allo- and autograft reconstruction, efforts to develop new surgical techniques, with the intention to lower the complication rates, are ongoing. MATERIALS AND METHODS: We present a detailed description of the surgical technique and the outcome of three patients with osteosarcomas of the proximal humerus, which were treated with tumor resection and autologous double-barrel vascularized fibula bone graft for arthrodesis of the shoulder. The construct was stabilized using a 4.5-mm pelvic reconstruction plate positioned on the scapular spine and the lateral aspect of the humerus. RESULTS: A wide surgical margin was achieved in all patients. Two of them could be reintegrated and are able to work with excellent shoulder function. In one patient, who developed metastasis, a deep infection under chemotherapy 16 months after index surgery complicated the postoperative course. CONCLUSION: The fibula's unique dual endosteal and periosteal blood supply makes it effective as a double-barrel bone graft for major long bone defects, which requires extra bone volume to prevent fractures until bone hypertrophy occurs. Additional bone and scar formation between the two struts are believed to provide a stable and long lasting construct, as seen in our patients. PMID- 23793480 TI - The functional outcome of acute scapholunate ligament repair in patients with intraarticular distal radius fractures treated by internal fixation. AB - BACKGROUND: Intra-articular fractures of the distal radius (DRF) are associated with a twofold increase in the risk of scapholunate ligament injury (SLI). The aim of this study was to compare functional outcome, pain, and disability between patients with operatively treated DRF and either an acute, repaired scapholunate ligament injury or no ligament injury. METHODS: We retrospectively analyzed 18 patients with an intraarticular DRF and SLI that was diagnosed and treated (Group I) and compared them with 20 patients with DRF without associated ligament injury (Group II) (20 women, 18 men; average age 55 years, range 19-72). The two cohorts were analyzed for differences in motion, grip strength, pain, Mayo wrist score, and Quick Disabilities of the Arm, Shoulder, and Hand (DASH) score an average of 43 months (range 12-73) after surgery. Radiographic assessment included fracture union, palmar tilt, radial inclination, ulnar variance, intercarpal angles, and arthrosis (according to Knirk and Jupiter). We used T-tests to compare range of motion, grip strength, pain (visual analog scale), DASH scores, and radiographic alignment between cohorts. A Chi-squared analysis was used to determine radiographic differences of arthritis. RESULTS: There were no significant differences in mean range of motion, grip strength, Quick DASH score, Mayo wrist score, pain level, or radiographic arthrosis between cohorts. There was no correlation between radiographic signs of osteoarthritis and the QuickDASH score, and pain level. CONCLUSION: The outcomes of intraarticular fractures of the distal radius with operatively treated associated SLI are comparable with the outcomes of intraarticular fractures of the distal radius without associated SLI. PMID- 23793481 TI - Exploring U.S. men's birth intentions. AB - While recently there have been renewed interest in women's childbearing intentions, the authors sought to bring needed research attention to understanding men's childbearing intentions. Nationally representative data from the 2006-2010 National Survey of Family Growth (NSFG) was used to examine pregnancy intentions and happiness for all births reported by men in the 5 years preceding the interview. We used bivariate statistical tests of associations between intention status, happiness about the pregnancy, and fathers' demographic characteristics, including joint race/ethnicity and union status subgroups. Multivariate logistic regressions were used to calculate adjusted odds ratios of a birth being intended, estimated separately by father's union status at birth. Using comparable data and measures from the male and female NSFG surveys, we tested for gender differences intentions and happiness, and examined the sensitivity of our results to potential underreporting of births by men. Nearly four out of ten of births to men were reported as unintended, with significant variation by men's demographic traits. Non-marital childbearing was more likely to be intended among Hispanic and black men. Sixty-two percent of births received a 10 on the happiness scale. Happiness about the pregnancy varied significantly by intention status. Men were significantly happier than women about the pregnancies, with no significant difference in intention status. Potential underreporting of births by men had little impact on these patterns. This study brings needed focus to men's childbearing intentions and improves our understanding of the context of their role as fathers. Men need to be included in strategies to prevent unintended pregnancy. PMID- 23793482 TI - Are gestational diabetes mellitus and preconception diabetes mellitus less common in non-Hispanic black women than in non-Hispanic white women? AB - Based on their higher risk of type 2 diabetes, non-Hispanic blacks (NHBs) would be expected to have higher gestational diabetes mellitus (GDM) risk compared to non-Hispanic whites (NHWs). However, previous studies have reported lower GDM risk in NHBs versus NHWs. We examined whether GDM risk was lower in NHBs and NHWs, and whether this disparity differed by age group. The cohort consisted of 462,296 live singleton births linked by birth certificate and hospital discharge data from 2004 to 2007 in Florida. Using multivariable regression models, we examined GDM risk stratified by age and adjusted for body mass index (BMI) and other covariates. Overall, NHBs had a lower prevalence of GDM (2.5 vs. 3.1%, p < 0.01) and a higher proportion of preconception DM births (0.5 vs. 0.3%, p <= 0.01) than NHWs. Among women in their teens (risk ratio 0.56, p < 0.01) and 20-29 years of age (risk ratio 0.85, p < 0.01), GDM risk was lower in NHBs than NHWs. These patterns did not change with adjustment for BMI and other covariates. Among women 30-39 years (risk ratio 1.18, p < 0.01) and >=40 years (risk ratio 1.22, p < 0.01), GDM risk was higher in NHBs than NHWs, but risk was higher in NHWs after adjustment for BMI. Associations between BMI and GDM risk did not vary by race/ethnicity or age group. NHBs have lower risk of GDM than NHWs at younger ages, regardless of BMI. NHBs had higher risk than NHWs at older ages, largely due to racial/ethnic disparities in overweight/obesity at older ages. PMID- 23793483 TI - The effects of CenteringPregnancy group prenatal care on gestational age, birth weight, and fetal demise. AB - We examined the effects of CenteringPregnancy group prenatal care versus individually delivered prenatal care on gestational age, birth weight, and fetal demise. We conducted a retrospective chart review and used propensity score matching to form a sample of 6,155 women receiving prenatal care delivered in a group or individual format at five sites in Tennessee. Compared to the matched group of women receiving prenatal care in an individual format, women in CenteringPregnancy group prenatal care had longer weeks of gestation (b = .35, 95 % CI [.29, .41]), higher birth weight in grams (b = 28.6, 95 % CI [4.8, 52.3]), lower odds of very low birth weight (OR = .21, 95 % CI [.06, .70]), and lower odds of fetal demise (OR = .12, 95 % CI [.02, .92]). Results indicated no evidence of differences in the odds of preterm birth or low birth weight for participants in group versus individual prenatal care. CenteringPregnancy group prenatal care had statistically and clinically significant beneficial effects on very low birth weight and fetal demise outcomes relative to traditional individually delivered prenatal care. Group prenatal care had statistically significant beneficial effects on gestational age and birth weight, although the effects were relatively small in clinical magnitude. PMID- 23793484 TI - Descriptive epidemiology of chronic hypertension, gestational hypertension, and preeclampsia in New York State, 1995-2004. AB - We examined social, demographic, and behavioral predictors of specific forms of hypertensive disorders in pregnancy in New York State. Administrative data on 2.3 million births over the period 1995-2004 were available for New York State, USA, with linkage to birth certificate data for New York City (964,071 births). ICD-9 hospital discharge diagnosis codes were used to assign hypertensive disorders hierarchically as chronic hypertension, chronic hypertension with superimposed preeclampsia, preeclampsia (eclampsia/severe or mild), or gestational hypertension. Sociodemographic and behavioral predictors of these outcomes were examined separately for upstate New York and New York City by calculating adjusted odds ratios. The most commonly diagnosed conditions were preeclampsia (2.57 % of upstate New York births, 3.68 % of New York City births) and gestational hypertension (2.46 % of upstate births, 1.42 % of New York City births). Chronic hypertension was much rarer. Relative to non-Hispanic Whites, Hispanics in New York City and Black women in all regions had markedly increased risks for all hypertensive disorders, whereas Asian women were at consistently decreased risk. Pregnancy-associated conditions decreased markedly with parity and modestly among smokers. A strong positive association was found between pre pregnancy weight and risk of hypertensive disorders, with slightly weaker associations among Blacks and stronger associations among Asians. While patterns of chronic and pregnancy-induced hypertensive disorders differed, the predictors of gestational hypertension and both mild and severe preeclampsia were similar to one another. The increased risk for Black and some Hispanic women warrants clinical consideration, and the markedly increased risk with greater pre pregnancy weight suggests an opportunity for primary prevention among all ethnic groups. PMID- 23793485 TI - Building Economic Security Today: making the health-wealth connection in Contra Costa county's maternal and child health programs. AB - In recent years, maternal and child health professionals have been seeking approaches to integrating the Life Course Perspective and social determinants of health into their work. In this article, we describe how community input, staff feedback, and evidence from the field that the connection between wealth and health should be addressed compelled the Contra Costa Family, Maternal and Child Health (FMCH) Programs Life Course Initiative to launch Building Economic Security Today (BEST). BEST utilizes innovative strategies to reduce inequities in health outcomes for low-income Contra Costa families by improving their financial security and stability. FMCH Programs' Women, Infants, and Children Program (WIC) conducted BEST financial education classes, and its Medically Vulnerable Infant Program (MVIP) instituted BEST financial assessments during public health nurse home visits. Educational and referral resources were also developed and distributed to all clients. The classes at WIC increased clients' awareness of financial issues and confidence that they could improve their financial situations. WIC clients and staff also gained knowledge about financial resources in the community. MVIP's financial assessments offered clients a new and needed perspective on their financial situations, as well as support around the financial and psychological stresses of caring for a child with special health care needs. BEST offered FMCH Programs staff opportunities to engage in non-traditional, cross-sector partnerships, and gain new knowledge and skills to address a pressing social determinant of health. We learned the value of flexible timelines, maintaining a long view for creating change, and challenging the traditional paradigm of maternal and child health. PMID- 23793486 TI - Feasibility and acceptability of alternate methods of postnatal data collection. AB - This study was done in preparation for the launch of the National Children's Study (NCS) main study. The goal of this study was to examine the feasibility (completion rates and completeness of data), acceptability, staff time and cost effectiveness of three methods of data collection for the postnatal 3- and 9 month questionnaires completed as part of NCS protocol. Eligible NCS participants who were scheduled to complete a postnatal questionnaire at three and nine months were randomly assigned to receive either: (a) telephone data collection (b) web based data collection, or (c) self-administered (mailed) questionnaires. Event completion rates and satisfaction across the three data collection methods were compared and the influence of socio-demographic factors on completion rates and satisfaction rates was examined. Cost data were compared to data for completion and satisfaction for each of the delivery methods. Completion rates and satisfaction did not differ significantly by method, but completeness of data did, with odds of data completeness higher among web than phone (p < 0.001) or mail (p < 0.001). Costs were highest for the phone, followed by mail and web methods (p < 0.001). No significant differences in participant time (i.e. burden) across the three data collection methods were seen. Mail and phone data collection were the least complete of the three methods and were the most expensive. Mailed data collection was neither complete nor exceptionally economical. Web-based data collection was the least costly and provided the most complete data. Participants without web access could complete the questionnaire over the phone. PMID- 23793487 TI - Six-month outcomes from a randomized controlled trial to prevent perinatal depression in low-income home visiting clients. AB - Perinatal depression (PD) has negative consequences for mothers and children and is more prevalent among women of low socioeconomic status. Home visitation programs serve low-income pregnant women at risk for PD. This study tested the efficacy of a group-based cognitive behavioral intervention (Mothers and Babies Course; MB) in reducing depressive symptoms and preventing the onset of perinatal depression among low-income women enrolled in home visitation. A randomized controlled trial was conducted. Seventy-eight women who were pregnant or had a child less than 6 months of age and who were assessed as at risk for PD were randomized to the MB intervention or usual home visiting services. Depressive symptoms were assessed at baseline and 1-week, 3- and 6-months post-intervention; depressive episodes were assessed with a clinical interview at the 6-month follow up. Depressive symptoms declined at a significantly greater rate for intervention participants than usual care participants between baseline and 1-week, 3 and 6 months post-intervention. At the 6-month follow-up, 15 % of women who received the MB intervention had experienced a major depressive episode as compared with 32 % of women receiving usual care. Integrating mental health interventions into home visitation appears to be a promising approach for preventing PD. Cognitive behavioral techniques can be effective in preventing depression in perinatal populations and treating it. PMID- 23793488 TI - What does it mean when we screen? A closer examination of perinatal depression and psychosocial risk screening within one MCH home visiting program. AB - Perinatal depression screening has become an imperative for maternal and child health (MCH) home visitation programs. However, contextual life experiences and situational life stress may be equally important in determining program response. As one component of a larger research study with an urban MCH home visitation program, we examined the results from multiple measures of depression and anxiety symptoms, social support and stressful life events in a sample of 30 newly enrolled program participants. We compared commonly used tools in identifying women who were "at risk" for perinatal depression. The analysis used published and agency practice cut-off scores, examined correlations between measures, and reflected on the role of stressful life events in this assessment. In this low income, predominantly African-American sample, the assessed tools were inconsistent in identifying "at risk" women for perinatal depression, ranging from 22 % (Edinburgh Perinatal Depression Scale) to 75 % (Center for Epidemiological Studies, Depression Scale) depending on the instrument. Depression and anxiety were correlated across most measures, although provider collected data did not correlate as anticipated with other measures. The combination of screening for perinatal depression and stressful life events offered an additional perspective on possible symptom alleviation and psychosocial intervention that could occur within the home visiting program. Our experience suggests that introducing a brief inventory of stressful life events accompanying perinatal depression screening allowed for a more comprehensive understanding of women's experiences than perinatal depression screening alone. We encourage psychosocial risk screening which integrates assessment of social support, stressful life events and perinatal depression symptoms. PMID- 23793489 TI - Epidemiology of unintentional injuries among children under six years old in floating and residential population in four communities in Beijing: a comparative study. AB - To explore and compare the epidemiological characteristics of non-fatal unintentional injury among children in floating and residential population. Using a structured survey, quantitative data were collected on a total of 352 floating and 201 residential families. Some potential influencing factors were questioned, such as socio-demographic characteristics, injury-related family environment, knowledge, attitude and behavior, and child's character. The self-reported incidence of non-fatal unintentional injuries was 11.9 % in the floating group and 12.9 % in the residential group. Unintentional injuries were more serious and caused more disease burden in floating children than residential children, with the average medical cost being over ten times in the floating group than in the residential group. Results of multiple regression analysis showed that children living in floating families have more risk of unintentional injuries than those children in residential families. Older children and children with extroverted character were more vulnerable to unintentional injuries. Risky family environment was also an important risk factor of unintentional injuries. Better household economic status and having more siblings appeared to reduce the probability of unintentional injuries among children. Floating children are more vulnerable to unintentional injuries comparing with residential children. These findings can be used as preliminary data supporting intervention strategies and activities to promote safe living environment and decrease injury incidence among floating children. PMID- 23793490 TI - Parental pregnancy wantedness and child social-emotional development. AB - To examine how maternal and paternal pregnancy wantedness and couple concordance regarding pregnancy wantedness predict children's social-emotional development in kindergarten. We used data from nationally representative US sample from the Early Childhood Longitudinal Study Birth Cohort. Exposures of interest were maternal and paternal pregnancy wantedness, and couple concordance regarding pregnancy wantedness. Children's social-emotional development was evaluated by the child's kindergarten teacher using an adapted version of the Preschool and Kindergarten Behavior Scales. We examined bivariate associations between pregnancy wantedness and key socio-demographic variables in relation to children's social-emotional development. Multiple linear regression was used to assess the relationship between each pregnancy wantedness predictor and children's social-emotional development scores. Items related to child concentration and attention appeared to be the components driving almost all the associations with social-emotional development. Maternal report of unwanted pregnancy, resident father's report of mistimed pregnancy, and discordance of parental pregnancy wantedness (specifically when the mother wanted but the father did not want the pregnancy) predicted lower children's social-emotional development scores. Results suggest that maternal unwanted pregnancy and couple discordance in pregnancy wantedness were associated with poorer social-emotional development, especially in the area of concentration and attention, in kindergarten. PMID- 23793491 TI - Comparison of a SiO2-CaO-ZnO-SrO glass polyalkenoate cement to commercial dental materials: ion release, biocompatibility and antibacterial properties. AB - Ion Release and biocompatibility of a CaO-SrO-ZnO-SiO2 (BT 101) based glass polyalkenoate cement (GPC) was compared against commercial GPCs, Fuji IX and Ketac Molar. The radiopacity (R) was similar for each material, 2.0-2.8. Ion release was evaluated on each material over 1, 7, 30 and 90 days. BT 101 release included Ca (23 mg/L), Sr (23 mg/L) Zn (13 mg/L), Si (203 mg/L). Fuji IX release includes Ca (0.7 mg/L), Al (3 mg/L) Si (26 mg/L), Na (60 mg/L) and P (0.5 mg/L) while Ketac Molar release includes Ca (1 mg/L), Al (0.6 mg/L) Si (23 mg/L), Na (76 mg/L) and P (0.7 mg/L). Simulated body fluid trials revealed CaP surface precipitation on BT 101. No evidence of precipitation was found on Fuji IX or Ketac Molar. Cytotoxicity testing found similar cell viability values for each material (~60 %, P = 1.000). Antibacterial testing determined a reduced CFU count with BT 101 (2.5 * 103) when compared to the control bacteria (2.4 * 104), Fuji IX (1.5 * 104) and Ketac Molar (1.2 * 104). PMID- 23793492 TI - Silver-doped self-assembling di-phenylalanine hydrogels as wound dressing biomaterials. AB - Chronic and acute wounds can be quickly contaminated and infected by microorganisms such as bacteria, multi-resistant organisms or fungi. The introduction of silver as anti-microbial agent into wound management has widely been demonstrated to be effective and contribute to wound healing. As a consequence, many approaches and different materials have been employed to synthesize antibacterial silver-hydrogels. In this work the introduction of silver particles into the fibrillar structure of self-assembling aromatic di phenylalanine derivatives modified with aromatic groups such as 9 fluorenylmethoxycarbonyl is proposed to produce antibacterial wound dressings. Hydrogels doped with increasing amounts of silver were tested and adopted to modify flax textiles. The influence of silver on the structure of hydrogels was studied using light and confocal microscopy, while SEM-EDX allowed the characterization of the hydrogel coating on the surface of the textile substrates as well as the identification and distribution of silver nanoparticles. The antibacterial potential of the treated flax was demonstrated through microbiological tests on Staphylococcus aureus. The combination of the physico chemical and anti-bacterial properties, together with the ease of preparation of these biomaterials, fulfils the requirement of clinically-effective wound dressings. PMID- 23793493 TI - Coating NiTi archwires with diamond-like carbon films: reducing fluoride-induced corrosion and improving frictional properties. AB - This study aims to coat diamond-like carbon (DLC) films onto nickel-titanium (NiTi) orthodontic archwires. The film protects against fluoride-induced corrosion and will improve orthodontic friction. 'Mirror-confinement-type electron cyclotron resonance plasma sputtering' was utilized to deposit DLC films onto NiTi archwires. The influence of a fluoride-containing environment on the surface topography and the friction force between the brackets and archwires were investigated. The results confirmed the superior nature of the DLC coating, with less surface roughness variation for DLC-coated archwires after immersion in a high fluoride ion environment. Friction tests also showed that applying a DLC coating significantly decreased the fretting wear and the coefficient of friction, both in ambient air and artificial saliva. Thus, DLC coatings are recommended to reduce fluoride-induced corrosion and improve orthodontic friction. PMID- 23793494 TI - Allopsoroptoides galli n. g., n. sp., a new genus and species of feather mites (Acari: Analgoidea: Psoroptoididae) causing mange in commercially raised domestic chicken in Brazil. AB - A new feather mite, Allopsoroptoides galli n. g., n. sp. (Psoroptoididae: Pandalurinae), is described from the domestic chicken, Gallus gallus (Linnaeus) (Galliformes: Phasianidae), from Brazil. This is the first record of a representative of the feather mite family Psoroptoididae from an avian host of the order Galliformes. The new genus is closely related to the genus Cygnocoptes Fain & Bochkov, 2003 but clearly differs from the latter and all other genera of the family by the loss of four median pairs of hysteronotal setae (c1, d1, e1, and h1) in both sexes and by the unique shape of the male opisthosoma. Instead of the bilobate opisthosoma, the male opisthosoma in this genus has a narrow and long median projection, ending with a pair of semi-ovate terminal lamellae. These mites were first detected during a mange outbreak in several commercial poultry facilities in the state of Sao Paulo, Brazil. PMID- 23793495 TI - A new genus of quill mites of the family Syringophilidae (Acari: Cheyletoidea) associated with mousebirds (Aves: Coliiformes). AB - A new monotypic genus Colisyringophilus n. g. is established for C. tanzanicus n. sp., quill mites parasitising two mouse bird species from Tanzania, Colius striatus Gmelin and Urocolius macrourus (Linnaeus). This new genus is closely related to Neoaulobia Fain, Bochkov & Mironov, 2000, but differs from it by the following features: the stylophore is rounded posteriorly, the propodonotal shield is reduced to triangular sclerite bearing bases of setae vi and ve, the hysteronotal shield is absent, legs I are longer than legs II, and apodemes I are distinctly elongated. This is the first record of syringophilid mites from hosts of the order Coliiformes. PMID- 23793496 TI - Morphological and molecular characterisation of Steinernema costaricense Uribe Lorio, Mora & Stock, 2007 (Panagrolaimorpha: Steinernematidae) isolate from Bush Augusta State Park, Missouri, USA. AB - A new isolate of Steinernema costaricense Uribe-Lorio, Mora & Stock, 2007 (Panagrolaimorpha: Steinernematidae) was discovered from the Bush Augusta State Park, Missouri, USA, and its morphological and molecular examination was carried out. Morphologically, adults of the Missouri isolate are very close to S. costaricense from Costa Rica. Infective juveniles (IJs) from Missouri are characterised by mean body length of 843 MUm, mean body width of 33 MUm, mean tail length of 80 MUm, mean pharynx length of 143 MUm, excretory pore at 62 MUm from anterior extremity, high cephalic papillae, and lateral field formula 2-6-2 with two central ridges less prominent. They resemble IJs of S. costaricense from Costa Rica in having high cephalic papillae, similar lateral field pattern and pharynx length, but are twice shorter. Based on the nearly complete identity between the sequence of D2-D3 domains of LSU rDNA of the Missouri isolate and those of S. costaricense retrieved from GenBank and the high similarity of their bacterial symbionts, the new isolate was identified as S. costaricense. The phylogenetic affinities among S. costaricense and the species of the "bicornutum" group proposed by the authors of its original description based on LSU rDNA analysis, is debated. In the present study, all three methods of analysis for the ITS region showed that four species of Steinernema from the Americas (S. rarum de Doucet, 1986, S. scarabaei Stock & Koppenhofer, 2003, S. unicornum Edgington, Buddie, Tymo, France, Merino & Hunt, 2009 and S. costaricense Missouri isolate) formed a weakly supported clade although bootstrap support for the sister-group relationship between the new isolate and S. scarabaei was always high. In phylogenies inferred from D2-D3 LSU rDNA S. costaricense never formed a clade with S. rarum and S. unicornum. PMID- 23793497 TI - Doridicola indistinctus n. sp. (Copepoda: Poecilostomatoida: Rhynchomolgidae) associated with the soft coral Gersemia fruticosa Sars (Octocorallia: Alcyonacea: Nephtheidae) from the White Sea. AB - A new species of poecilostomatoid copepod, Doridicola indistinctus n. sp. (Rhynchomolgidae), is described from specimens found in association with the soft coral Gersemia fruticosa Sars (Alcyonacea: Nephtheidae), collected from the White Sea. The new species is distinguished from its congeners by the combination of the following features in the female: (i) antenna tipped, with two subequal large claws which are about as long as the segment bearing them; (ii) two naked, extremely unequal setae on the middle segment of the maxilliped, the short, medial seta less than half-length of the outer seta; and (iii) free segment of leg 5 bears the basal swelling and is ornamented with spinules on the outer surface. This is the first report of a copepod occurring in symbiosis with nephtheid corals from the Arctic Zone. It also constitutes the northernmost record for a species of Doridicola Leydig, 1853, which is the largest genus of the Rhynchomolgidae Burmeister, 1835 comprising 52 species, including the present new species. PMID- 23793498 TI - Morphometric and molecular characterisation of specimens of Lepidapedon Stafford, 1904 (Digenea: Lepidapedidae) from the deep-sea fish Mora moro (Risso) (Teleostei: Moridae) in the western Mediterranean. AB - In a study of the parasites of the deep-sea fish Mora moro (Risso) (Gadiformes: Moridae) off the Mediterranean coasts of Catalonia and the Balearic Islands (Spain), we were able to distinguish two morphs of specimens belonging to Lepidapedon Stafford, 1904 (Digenea: Lepidapedidae). This material is herein described and illustrated. Comparative sequence analyses using partial mitochondrial nad1 sequences revealed that the material assigned to one of these morphs can be considered conspecific with the material identified as Lepidapedon desclersae Bray & Gibson, 1995 from the same host. However, the published nad1 sequence for L. desclersae was generated from a specimen ex M. moro from the North East Atlantic. Examination of the voucher specimens associated with this sequence revealed that both the North East Atlantic and the Mediterranean specimens ex M. moro differ from L. desclersae as described from its type-host, Lepidion eques (Gunther), in the anterior extent of the vitelline fields which is further posterior, reaching only to the posterior margin of the external seminal vesicle in L. desclersae, versus being at the mid-level of this organ and reaching the posterior margin of the ventral sucker. Therefore, we have tentatively assigned the material characterised here, both morphologically and molecularly as Lepidapedon sp. Acquisition of additional sequences for both nad1 mitochondrial and 28S rRNA genes of L. desclersae from material ex Lepidion spp. is required in order to determine whether the observed morphometric variation reflects host-related or inter-specific differences. The second morph of Lepidapedon from M. moro is described and distinguished on morphometric grounds, such as the position of the most anterior vitelline follicles, which reach to the anterior margin of the ventral sucker. Its identity is commented upon, but, in view of the fact that there were few specimens and no molecular data available, it is not named. PMID- 23793499 TI - A new species and two new records of Minicopenaeon Bourdon, 1981 (Crustacea: Isopoda: Bopyridae) from China. AB - Three species of the parasitic isopod genus Minicopenaeon Bourdon, 1981 (Crustacea: Isopoda: Bopyridae) are reported from China, one new to science and two new records from mainland China. Minicopenaeon crosnieri (Bourdon, 1979) formerly known from Madagascar, the Philippines and Taiwan, is recorded from Zhejiang province. Minicopenaeon intermedium Bourdon, 1981 previously recorded from the Philippines and Japan, is recorded from China for the first time. The new species Minicopenaeon liuruiyui n. sp. is recorded from the East and South China Seas. As with other species of the genus, females of the new species have rudimentary coxal plates on the second pereomeres on the short side. The new species can be distinguished from other species by the presence of a widely open brood pouch, head with bilobate anterior edge and median concave groove, and male head with curved posterior margin of the pleon. A key to species of Minicopenaeon is provided and the subspecies M. intermedium curvatum Bourdon, 1981 is synonymised with M. intermedium Bourdon, 1981. Metapenaeopsis philippii (Bate, 1881) and M. coniger (Wood-Mason, 1891) are newly recorded as host species for bopyrids. PMID- 23793500 TI - Redescription of Heliconema africanum (Linstow, 1899) n. comb. (Nematoda: Physalopteridae), a nematode parasite of freshwater eels (Anguilla spp.) in South Africa. AB - The little-known nematode species Heliconema africanum (Linstow, 1899) n. comb. (Physalopteridae) is redescribed based on light and scanning electron microscopical examinations of specimens collected from the stomach of the African longfin eel Anguilla mossambica (Peters) in the Nahoon River, Eastern Cape Province, South Africa. This species, previously misidentified as Heliconema longissimum (Ortlepp, 1922), is a common parasite of eels in South Africa. The systematic status of H. longissimum, a species originally described from unidentified Australian snakes, is unclear and probably several morphologically closely related species have been included under this name. PMID- 23793501 TI - Trypanorhynch cestodes from elasmobranchs from the Gulf of Oman, with the description of Prochristianella garshaspi n. sp. (Eutetrarhynchidae). AB - In a study on the order Trypanorhyncha Diesing, 1863, a total of 35 specimens belonging to nine species of elasmobranch in the Gulf of Oman, was examined. The following trypanorhynch species were identified: Pterobothrium lesteri Campbell & Beveridge, 1996, Otobothrium carcharidis (Shipley & Hornell, 1906), Eutetrarhynchus platycephali Palm, 2004, Parachristianella indonesiensis Palm, 2004, Pa. monomegacantha Kruse, 1959 and Prochristianella mooreae Beveridge, 1990. Prochristianella garshaspi n. sp. is described from Pastinachus sephen (Forsskal) and Rhinoptera sp. The new species is allocated to the genus Prochristianella Dollfus, 1946 on the basis of the presence of two bothria, prebulbar organs, and a heteroacanthous typical tentacular armature with relatively few hooks in each principal row, hollow hooks increasing in size from antibothrial and then decreasing towards the bothrial surface of the tentacle, hooks 1 and 1' being separated, and a basal swelling with characteristic billhooks increasing in size towards the bothrial surface. The lack of microscopically visible microtriches on the scolex distinguishes the new species from P. hispida (Linton, 1890), P. clarkeae Beveridge, 1990, P. thalassia (Kovaks & Schmidt, 1980), P. multidum Friggens & Duszynski, 2005 and P. cairae Schaeffner & Beveridge, 2012. Prochristianella garshaspi n. sp. can be distinguished from the remaining species within the genus by a combination of the following morphological features: the presence of numerous gland-cells within the tentacular bulbs, the number of rows on the basal swelling, the number of hooks per half spiral row, the size of the principal hooks, the number of the testes and the presence of an external seminal vesicle. PMID- 23793502 TI - Evaluation of latex subclinical sensitization by way of the basophil activation test and specific IgE to latex recombinant allergens. PMID- 23793503 TI - Translation and linguistic validation of the Allergy-CONTROL-ScoreTM for use in Japan. AB - BACKGROUND: Symptom and medication scores are recommended to measure the primary outcome on allergies. The Allergy Control Score was proved to be a valid and reliable instrument to assess allergy severity in clinical trials and may be used in observational studies of respiratory allergic diseases in many countries. We translated the Allergy Control Score and adapted it for use in Japan. METHODS: We translated the original English version into Japanese according to the Mapi approach to linguistic validation: conceptual definition, forward translation by two native Japanese speakers, reconciliation, back-translation by an independent translator, review in consultation with original developer, and pilot testing on 12 patients of an allergy clinic and 3 volunteers with seasonal/non-seasonal allergic rhinitis and/or asthma. RESULTS: Two of the ten back-translated items needed slight modifications and some words were revised. In the pilot test, the average time required to complete the questionnaire was 55 seconds for the section on symptoms and 25 seconds for the section on medication. All participants were able to self-complete the questionnaire. CONCLUSIONS: By applying the Mapi approach to linguistic validation, we ensured a close match between the Japanese and English versions of the Allergy Control Score. The Allergy Control Score Japanese version is accessible and acceptable to persons with respiratory allergic symptoms in Japan. PMID- 23793504 TI - Age-specific characteristics of inpatients with severe asthma exacerbation. AB - BACKGROUND: The characteristics of inpatients with severe asthma exacerbation remain unclear. It is considered that the characteristics of inpatients with severe asthma vary depending on age. However, these are rarely investigated. The objective of this study is to investigate the differences in characteristics among different age groups. We considered that it is necessary to understand the characteristics of each age group so that we can establish strategies in preventing severe asthma exacerbation. METHODS: All asthma inpatients who were hospitalized between 2004 and 2011 with SpO2 <90% (in room air), were breathless at rest, and showed increased respiratory rate and pulse rate were examined. We compared the characteristics among the young age group, middle age group, and advanced age group. RESULTS: The total number of patients was 204. In the young age group, the percentages of patients with irregular visits and non visits to a medical institution were high. This group showed high percentages of smokers and pet owners. The percentage of continuous ICS users in this group was 25.9%. The middle age group had high rates of aspirin-intolerant asthma. The percentage of continuous ICS users in this group was 60.2%. In the advanced age group, the percentages of patients with hypertension/heart disease, diabetes mellitus, and COPD were high. This group showed good treatment adherence. The percentage of continuous ICS users in this group was 77.4%. CONCLUSIONS: The characteristics of inpatients with severe asthma vary depending on age. We need to establish countermeasures for asthma exacerbation according to the characteristics of patients depending on age. PMID- 23793505 TI - The role of tumor necrosis factor-alpha and interferon-gamma in regulating angiomotin-like protein 1 expression in lung microvascular endothelial cells. AB - BACKGROUND: Angiogenesis in the alveolar septa is thought be a critical factor in pulmonary emphysema. Angiomotin-like protein 1 (AmotL1) is involved in angiogenesis via regulating endothelial cell function. However, the role of AmotL1 in the pathogenesis of pulmonary emphysema has not been elucidated. The objective of this study is to evaluate the expression of AmotL1 in lung tissues from a murine model with emphysema, as well as from patients with chronic obstructive pulmonary disease (COPD). Furthermore, we analyzed the regulation of AmotL1 expression by TNF-alpha and IFN-gamma in endothelial cells in vitro. METHODS: Nrf2 knockout mice were exposed to cigarette smoke (CS) for 4 weeks, and the down-regulated genes affecting vascularity in the whole lung were identified by microarray analysis. This analysis revealed that the mRNA expression of AmotL1 decreased in response to CS when compared with air exposure. To confirm the protein levels that were indicated in the microarray data, we determined the expression of AmotL1 in lung tissues obtained from patients with COPD and also determined the expression of AmotL1, NFkappaB and IkappaBalpha in cultured normal human lung microvascular endothelial cells (HLMVECs) that were stimulated by TNF alpha and IFN-gamma. RESULTS: We found that the number of AmotL1-positive vessels decreased in the emphysema lungs compared with the normal and bronchial asthmatic lungs. IFN-gamma pretreatment diminished the TNF-alpha-induced AmotL1 in the cultured HLMVECs by blocking the degradation of IkappaBalpha. CONCLUSIONS: These results suggested that IFN-gamma exhibits anti-angiogenesis effects by regulating the expression of TNF-alpha-induced AmotL1 via NFkappaB in emphysema lungs. PMID- 23793506 TI - The Asthma Control Test, Japanese version (ACT-J) as a predictor of Global Initiative for Asthma (GINA) guideline-defined asthma control: analysis of a questionnaire-based survey. AB - BACKGROUND: The 2006 Global Initiative for Asthma (GINA 2006) guidelines emphasize the importance of evaluating the control rather than the severity of asthma. The Asthma Control Test (ACT) is well known to be an excellent tool for evaluating asthma control in the clinical setting. This study aimed to evaluate the ACT, Japanese version (ACT-J) as a predictor of asthma control as defined by the GINA 2006 guidelines in actual clinical practice. METHODS: A cross-sectional analysis comparing the ACT-J score and GINA classification of asthma control among 419 patients of primary care physicians and specialists was performed using the data from a 2010 questionnaire-based survey conducted by the Niigata Asthma Treatment Study Group. RESULTS: The optimal cut-off point of the ACT-J score for predicting GINA-defined asthma control was 23, with ACT-J scores of >=23 and <=22 predicting controlled and uncontrolled asthma with area under the receiver operating characteristics curve values of 0.76 [95% confidence interval (CI): 0.72-0.81] and 0.93 [95% CI: 0.90-0.97], respectively. CONCLUSIONS: ACT scores of >=23 and <=22 are useful for identifying patients with controlled and uncontrolled asthma, respectively, as defined by GINA 2006, and the latter is more strongly predictive than the former. The reason for the higher cut-off point of the ACT-J relative to other versions of the ACT is unclear and warrants further investigation. PMID- 23793507 TI - A new on-chip whole blood/plasma separator driven by asymmetric capillary forces. AB - A new on-chip whole blood/plasma separator driven by asymmetric capillary forces, which are produced through a microchannel with sprayed nanobead multilayers, has been designed, fabricated and fully characterized. The silica nanobead multilayers revealing as superhydrophilic surfaces have been fabricated using a spray layer-by-layer (LbL) nano-assembly method. This new on-chip blood plasma separator has been targeted for a sample-to-answer (S-to-A) microfluidic lab-on-a chip (LOC) toward point-of-care clinical testing (POCT). Effective plasma separation from undiluted whole blood was achieved through the microchannel which was composed of asymmetric superhydrophilic surfaces with a 10 mm hydrophobic patch. Blood cells were continuously accumulated over the hydrophobic patch while the blood plasma was able to flow over the patch. Therefore, the blood plasma was successfully separated from the whole blood throughout the accumulated blood cells which worked as a so-called 'self-built-in blood cell microfilter'. The separated plasma was approximately 102 nL from a single drop of 3 MUL whole blood within 10 min, which is very suitable for single-use disposable POCT devices. PMID- 23793508 TI - The influence of target context and early and late vision on goal-directed reaching. AB - The online visual control of movement involves contributions from 2 processes: a process early in the trajectory concerned with comparisons between actual and expected sensory consequences and another process late in the trajectory that reduces the discrepancy between the position of the hand and the target. This experiment was designed to determine how early and late visual controls are impacted by the illusory characteristics of the target in a rapid reaching task. Participants performed 500 ms movements to the vertices of Muller-Lyer figures with the availability of full vision on the majority of trials. However, on a fraction of the trials, movements to the targets were performed with either early vision (first 200 ms of movement), late vision (last 200 ms of movement) or no vision. Although participants undershoot the targets under all target and visual conditions, the impact of the target configuration was greatest when vision was available during only the final portion of the movement trajectory and least when only early vision was available for limb regulation. Aiming bias under full vision and no-vision conditions was intermediate. These findings indicate that visual context has a greater impact on late discrete limb regulation than on early dynamic control of the limb trajectory. PMID- 23793509 TI - Pollution characteristics and potential health risk of polychlorinated dibenzo-p dioxins and dibenzofurans (PCDD/Fs) in soil/sediment from Baiyin City, North West, China. AB - In order to better understand the environmental behaviors of persistent organic pollutants, the characteristics of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) were investigated in twenty-three soil/sediment samples from Baiying City, Northwest China, in 2008. The possible sources and potential health risk of PCDD/Fs were also discussed. The concentrations of PCDD/Fs in nineteen soil samples varied between 20.13 and 496.26 pg/g dry weight (dw.), with an average value of 125.59 pg/g dw. The highest International Toxic Equivalent (I TEQ) of PCDD/Fs (8.34 pg/g dw.) in soil was found at sample S1 collected from proximity to a copper metallurgy plant. The concentrations of PCDD/Fs in four sediment samples ranged from 37.69 to 491.49 pg/g dw., with an average value of 169.95 pg/g dw. The highest I-TEQ of PCDD/Fs (8.56 pg/g dw.) in sediment was found at sample S12 collected from the East big ditch with waste water discharged into the Yellow River. The results indicated that PCDD/Fs contamination of soil/sediment is originated from three sources: chlorine-containing chemicals, non-ferrous metal industrial PCDD/Fs emission and coal burning. The health risk exposure to PCDD/Fs through soil, dust ingestion and dermal absorption ranged from 0.0006 to 0.0134 pg/kg/day Word Health Organization's toxic equivalent in 1998 (WHO1998-TEQ) with mean values 0.0032 pg WHO1998-TEQ for adults and varied between 0.0012 and 0.0256 pg/kg/day WHO1998-TEQ with mean values 0.006 pg/kg/day WHO1998-TEQ for children, respectively. These results indicated that health risk of PCDD/Fs for children should be paid more attention. PMID- 23793510 TI - Gypsum addition to soils contaminated by red mud: implications for aluminium, arsenic, molybdenum and vanadium solubility. AB - Red mud is highly alkaline (pH 13), saline and can contain elevated concentrations of several potentially toxic elements (e.g. Al, As, Mo and V). Release of up to 1 million m(3) of bauxite residue (red mud) suspension from the Ajka repository, western Hungary, caused large-scale contamination of downstream rivers and floodplains. There is now concern about the potential leaching of toxic metal(loid)s from the red mud as some have enhanced solubility at high pH. This study investigated the impact of red mud addition to three different Hungarian soils with respect to trace element solubility and soil geochemistry. The effectiveness of gypsum amendment for the rehabilitation of red mud contaminated soils was also examined. Red mud addition to soils caused a pH increase, proportional to red mud addition, of up to 4 pH units (e.g. pH 7 -> 11). Increasing red mud addition also led to significant increases in salinity, dissolved organic carbon and aqueous trace element concentrations. However, the response was highly soil specific and one of the soils tested buffered pH to around pH 8.5 even with the highest red mud loading tested (33 % w/w); experiments using this soil also had much lower aqueous Al, As and V concentrations. Gypsum addition to soil/red mud mixtures, even at relatively low concentrations (1 % w/w), was sufficient to buffer experimental pH to 7.5-8.5. This effect was attributed to the reaction of Ca(2+) supplied by the gypsum with OH(-) and carbonate from the red mud to precipitate calcite. The lowered pH enhanced trace element sorption and largely inhibited the release of Al, As and V. Mo concentrations, however, were largely unaffected by gypsum induced pH buffering due to the greater solubility of Mo (as molybdate) at circumneutral pH. Gypsum addition also leads to significantly higher porewater salinities, and column experiments demonstrated that this increase in total dissolved solids persisted even after 25 pore volume replacements. Gypsum addition could therefore provide a cheaper alternative to recovery (dig and dump) for the treatment of red mud-affected soils. The observed inhibition of trace metal release within red mud affected soils was relatively insensitive to either the percentage of red mud or gypsum present, making the treatment easy to apply. However, there is risk that over-application of gypsum could lead to detrimental long-term increases in soil salinity. PMID- 23793511 TI - Localization of coherent sources by simultaneous MEG and EEG beamformer. AB - Simultaneous magnetoencephalography (MEG) and electroencephalography (EEG) analysis is known generally to yield better localization performance than a single modality only. For simultaneous analysis, MEG and EEG data should be combined to maximize synergistic effects. Recently, beamformer for simultaneous MEG/EEG analysis was proposed to localize both radial and tangential components well, while single modality analyses could not detect them, or had relatively higher location bias. In practice, most interesting brain sources are likely to be activated coherently; however, conventional beamformer may not work properly for such coherent sources. To overcome this difficulty, a linearly constrained minimum variance (LCMV) beamformer may be used with a source suppression strategy. In this work, simultaneous MEG/EEG LCMV beamformer using source suppression was formulated firstly to investigate its capability over various suppression strategies. The localization performance of our proposed approach was examined mainly for coherent sources and compared thoroughly with the conventional simultaneous and single modality approaches, over various suppression strategies. For this purpose, we used numerous simulated data, as well as empirical auditory stimulation data. In addition, some strategic issues of simultaneous MEG/EEG analysis were discussed. Overall, we found that our simultaneous MEG/EEG LCMV beamformer using a source suppression strategy is greatly beneficial in localizing coherent sources. PMID- 23793513 TI - Triage of mass casualties in war conditions: realities and lessons learned. AB - PURPOSE: The authors made a retrospective analysis of three triage situations of war wounded in Chad and Rwanda in which mass casualties overwhelmed available medical facilities. METHODS: The triage classification is based on the waiting period for surgery. The categories are: extreme, first, second and third emergencies, expectant, walking wounded. RESULTS: In Chad, 23 wounded adults were received in 24 hours, and 19 were operated up on within 48 hours. In Rwanda 1, 94 wounded were received in two hours, of whom 68 were operated upon, 23 on the first day. In Rwanda 2, 59 wounded were received in 12 hours, treatment of extreme and first emergencies required 48 hours, while second and third emergencies were treated during the three following days. CONCLUSIONS: These episodes were very different when considering the setting, the number of casualties, the type of wounds, the logistical and medical difficulties. The authors report the difficulties faced and the lessons learned. "Il faut toujours commencer par le plus douloureusement blesse sans avoir egard aux rangs et aux distinctions." You must always begin with those who are most seriously wounded without regard to rank or other distinction. Baron Larrey (1766-1842), surgeon to Napoleon's Imperial Guard. PMID- 23793512 TI - Transcriptional control of CD4 and CD8 coreceptor expression during T cell development. AB - The differentiation and function of peripheral helper and cytotoxic T cell lineages is coupled with the expression of CD4 and CD8 coreceptor molecules, respectively. This indicates that the control of coreceptor gene expression is closely linked with the regulation of CD4/CD8 lineage decision of DP thymocytes. Research performed during the last two decades revealed comprehensive mechanistic insight into the developmental stage- and subset/lineage-specific regulation of Cd4, Cd8a and Cd8b1 (Cd8) gene expression. These studies provided important insight into transcriptional control mechanisms during T cell development and into the regulation of cis-regulatory networks in general. Moreover, the identification of transcription factors involved in the regulation of CD4 and CD8 significantly advanced the knowledge of the transcription factor network regulating CD4/CD8 cell-fate choice of DP thymocytes. In this review, we provide an overview of the identification and characterization of CD4/CD8 cis-regulatory elements and present recent progress in our understanding of how these cis regulatory elements control CD4/CD8 expression during T cell development and in peripheral T cells. In addition, we describe the transcription factors implicated in the regulation of coreceptor gene expression and discuss how these factors are integrated into the transcription factor network that regulates CD4/CD8 cell-fate choice of DP thymocytes. PMID- 23793514 TI - Platelet-rich plasma for the treatment of patellar tendinopathy: clinical and imaging findings at medium-term follow-up. AB - PURPOSE: The purpose of this study was to evaluate the efficacy of multiple platelet-rich plasma (PRP) injections on the healing of chronic refractory patellar tendinopathy, and report the quality and duration of the clinical improvement up to a medium-term follow-up. METHODS: Forty-three patients (mean age, 30.6 years; mean BMI, 24.7; 42 men, one woman) affected by chronic patellar proximal tendinopathy were enrolled in this trial. Eleven patients were affected by bilateral tendinopathy. They underwent three ultrasound guided intra-tendinous injections of five millilitres PRP, two weeks apart from each other. Patients were prospectively evaluated initially, then after two, six, and up to mean 48.6 +/- 8.1 months of follow-up (minimum evaluation at 36 months). The following evaluation tools were used: Blanzina, VISA-P, EQ-VAS for general health, and Tegner scores. Patients' overall satisfaction and time to return to sport were also reported. RESULTS: Good and stable results were documented over time, with the VISA-P score increasing from 44.1 +/- 15.6 at baseline to 61.4 +/- 22.2 at two months, 76.6 +/- 25.4 at six months, and 84.3 +/- 21.6 at four years' follow up. The same trend was confirmed by the other scores used, and 80 % of the patients were satisfied and returned to previous sports activities. Significantly poorer results were obtained in patients with a longer history of symptoms, and poor results were also observed in bilateral lesions. No correlation between ultrasonographic and clinical findings could be found. CONCLUSIONS: Multiple injections of PRP provided a good clinical outcome for the treatment of chronic recalcitrant patellar tendinopathy with stable results up to medium-term follow up. Patients affected by bilateral pathology and presenting a long history of pain obtained significantly poorer results. PMID- 23793515 TI - The adaptive variant EDARV370A is associated with straight hair in East Asians. AB - Hair straightness/curliness is a highly heritable trait amongst human populations. Previous studies have reported European specific genetic variants influencing hair straightness, but those in East Asians remain unknown. One promising candidate is a derived coding variant of the ectodysplasin A receptor (EDAR), EDARV370A (370A), associated with several phenotypic changes of epidermal appendages. One of the strongest signals of natural selection in human genomes, 370A, has risen to high prevalence in East Asian and Native American populations, whilst being almost absent in Europeans and Africans. This striking frequency distribution and the pleiotropic nature of 370A led us to pursue if hair straightness, another epidermal appendage-related phenotype, is affected by this variant. By studying 1,718 individuals from four distinctive East Asian populations (Han, Tibetan, Mongolian, and Li), we found a significant association between 370A and the straight hair type in the Han (p = 2.90 * 10(-6)), Tibetan (p = 3.07 * 10(-2)), and Mongolian (p = 1.03 * 10(-5)) populations. Combining all the samples, the association is even stronger (p = 5.18 * 10(-10)). The effect of 370A on hair straightness is additive, with an odds ratio of 2.05. The results indicate very different biological mechanisms of straight hair in Europe and Asia, and also present a more comprehensive picture of the phenotypic consequences of 370A, providing important clues into the potential adaptive forces shaping the evolution of this extraordinary genetic variant. PMID- 23793517 TI - Nano-dimensional CeO2 nanorods for high Ni loading catalysts: H2 production by autothermal steam reforming of methanol reaction. AB - CeO2 nanorods were synthesized by a hydrothermal method and used as the support for preparing a series of Ni/CeO2 nanorod catalysts. The surface area of the catalysts decreased when the Ni percent over the CeO2 nanorods was increased. SEM results showed that the CeO2 is formed by nanorods approximately 1 MUm in length. TEM and HREM revealed that the width of the nanorods is about 8 nm and it grew along the [1 1 1-] axis. The catalytic activity of the catalysts was improved as the Ni was loaded onto CeO2 nanorods. The exposed planes of the CeO2 nanorod structure along the zone axis [0 1 1] for Ni impregnation were (1- 1- 1), (1 1 1 ), (1 1- 1), (1- 1 1-), (2 0 0) and (2- 0 0) and they were more reactive for methanol conversion than (2- 2- 0), (2- 0 2-), (0 2 2-), (0 2- 2), (2 0 2) and (2 2 0) planes from the [1 1 1-] axis (growth direction of the nanorod). This finding is mainly ascribed to the synergistic effect of the CeO2 nanorods and the Ni. PMID- 23793516 TI - MuPIT interactive: webserver for mapping variant positions to annotated, interactive 3D structures. AB - Mutation position imaging toolbox (MuPIT) interactive is a browser-based application for single-nucleotide variants (SNVs), which automatically maps the genomic coordinates of SNVs onto the coordinates of available three-dimensional (3D) protein structures. The application is designed for interactive browser based visualization of the putative functional relevance of SNVs by biologists who are not necessarily experts either in bioinformatics or protein structure. Users may submit batches of several thousand SNVs and review all protein structures that cover the SNVs, including available functional annotations such as binding sites, mutagenesis experiments, and common polymorphisms. Multiple SNVs may be mapped onto each structure, enabling 3D visualization of SNV clusters and their relationship to functionally annotated positions. We illustrate the utility of MuPIT interactive in rationalizing the impact of selected polymorphisms in the PharmGKB database, somatic mutations identified in the Cancer Genome Atlas study of invasive breast carcinomas, and rare variants identified in the exome sequencing project. MuPIT interactive is freely available for non-profit use at http://mupit.icm.jhu.edu . PMID- 23793518 TI - Mid-term clinical efficacy of a volumetric magnetic resonance-guided high intensity focused ultrasound technique for treatment of symptomatic uterine fibroids. AB - OBJECTIVE: To assess the mid-term efficacy of magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) using a volumetric ablation technique for treating uterine fibroids. METHODS: Forty-six premenopausal women with 58 symptomatic uterine fibroids were prospectively included for MR-HIFU. After treatment, CE-MRI allowed measurement of the non-perfused volume (NPV) ratio, defined as the non-enhancing part of the fibroid divided by fibroid volume. Clinical symptoms and fibroid size on T2W-MRI were quantified at 3 and 6 months' follow-up. The primary endpoint was a clinically relevant improvement in the transformed Symptom Severity Score (tSSS) of the Uterine Fibroid Symptom and Quality of Life questionnaire, defined as a 10-point reduction. RESULTS: Volumetric ablation resulted in a mean NPV ratio of 0.40 +/- 0.22, with a mean NPV of 141 +/- 135 cm(3). Mean fibroid volume was 353 +/- 269 cm(3) at baseline, which decreased to 271 +/- 225 cm(3) at 6 months (P < 0.001), corresponding to a mean volume reduction of 29 % +/- 20 %. Clinical follow-up showed that 54 % (25/46) of the patients reported a more than 10-point reduction in the tSSS. Mean tSSS improved from 50.9 +/- 18.4 at baseline to 34.7 +/- 20.2 after 6 months (P < 0.001). CONCLUSION: Volumetric MR-HIFU is effective for patients with symptomatic uterine fibroids. At 6 months, significant symptom improvement was observed in 54 % of patients. KEY POINTS: * Volumetric MR-guided high-intensity focused ultrasound is a novel ablation technique for leiomyomatosis. * We prospectively evaluated the outcome of volumetric MR-HIFU ablation for symptomatic fibroids. * This study showed that volumetric MR-HIFU results in an effective treatment. * A randomised controlled trial would set this technique in an appropriate context. PMID- 23793519 TI - Non-hyperfunctioning neuroendocrine tumours of the pancreas: MR imaging appearance and correlation with their biological behaviour. AB - OBJECTIVE: To describe MR imaging features of non-hyperfunctioning neuroendocrine pancreatic tumours by comparing them to histopathology and to determine the accuracy of MR imaging in predicting biological behaviour. MATERIALS AND METHODS: After institutional review board approval, we retrospectively reviewed 45 patients with pathologically proven NF-NET of the pancreas and >=1 preoperative MR/MRCP examinations. Of the NF-NETS, 29/45 (64.4 %) were G1 and 16/45 (35.5 %) were G2. Image analysis included the lesion maximum diameter, vascular encasement, extrapancreatic spread, signal intensity on T1- and T2-weighted, contrast enhancement features, and presence of metastases. Tumour vessel density was calculated on the histological specimen using a grid. RESULTS: The median maximum diameter of NF-NETs was 20 mm (range 5-200 mm). Eighty per cent of the NF NETs were hypointense on T1-weighted images, 82.2 % were hyperintense on T2 weighted images, and 75.6 % were hypervascular. Overall MRI accuracy showed a mean AUC of 0.86 compared to pathology. Lesions with a maximum diameter of 30 mm irregular margins, absence of a cleavage plane with the main pancreatic duct, vascular encasement, extrapancreatic spread and abdominal metastases were significantly associated with malignant NF-NETs. No correlation was found between the tumour vessel density and contrast-enhanced MR imaging pattern. CONCLUSIONS: Hyperintensity on T2-weighted images and iso-/hypervascularity occurred in 27/45 (60.0 %) of NF-NETs. MRI identifies malignant NF-NETs with a sensitivity of 93.3 % and a specificity of 76.9 % (AUC = 0.85). KEY POINTS: * Non-hyperfunctioning neuroendocrine pancreatic tumours (NF-NET) pose a difficult diagnostic challenge. * On T2-weighted MRI, 82.2 % of neuroendocrine tumours appeared hyperintense. * MR imaging showed 0.94 sensitivity and 0.77 specificity in predicting biological behaviour. * The hyper-/isointensity during dynamic MRI did not correlate with vessel density at pathology. PMID- 23793520 TI - Effective dose estimates for cone beam computed tomography in interventional radiology. AB - OBJECTIVES: To compare radiation doses in cone beam computed tomography (CBCT) with those of multi-detector computed tomography (MDCT) using manufacturers' standard protocols. METHODS: Dose-levels in head and abdominal imaging were evaluated using a dosimetric phantom. Effective dose estimates were performed by placing thermoluminescent dosimeters in the phantom. Selected protocols for two CBCT systems and comparable protocols for one MDCT system were evaluated. Organ doses were measured and effective doses derived by applying the International Commission on Radiological Protection 2007 tissue weighting factors. RESULTS: Effective doses estimated for the head protocol were 4.4 and 5.4 mSv for the two CBCT systems respectively and 4.3 mSv for MDCT. Eye doses for one CBCT system and MDCT were comparable (173.6 and 148.4 mGy respectively) but significantly higher compared with the second CBCT (44.6 mGy). Two abdominal protocols were evaluated for each system; the effective doses estimated were 15.0 and 18.6 mSv, 25.4 and 37.0 mSv, and 9.8 and 13.5 mSv, respectively, for each of the CBCT and MDCT systems. CONCLUSIONS: The study demonstrated comparable dose-levels for CBCT and MDCT systems in head studies, but higher dose levels for CBCT in abdominal studies. There was a significant difference in eye doses observed between the CBCT systems. KEY POINTS: * Cone beam computed tomography (CBCT) is increasingly utilised in interventional radiology. * Effective doses for selected CBCT and MDCT protocols were estimated and compared. * Dose levels in CBCT and MDCT were comparable for head studies. * Dose levels were higher in CBCT for abdominal studies. PMID- 23793521 TI - Clinical relationship between cervical spinal canal stenosis and traumatic cervical spinal cord injury without major fracture or dislocation. AB - PURPOSE: The purpose of the study was to evaluate the clinical relationship between cervical spinal canal stenosis (CSCS) and incidence of traumatic cervical spinal cord injury (CSCI) without major fracture or dislocation, and to discuss the clinical management of traumatic CSCI. METHODS: Forty-seven patients with traumatic CSCI without major fracture or dislocation (30 out of 47 subjects; 63.83 %, had an injury at the C3-4 segment) and 607 healthy volunteers were measured the sagittal cerebrospinal fluid (CSF) column diameter at five pedicle and five intervertebral disc levels using T2-weighted midsagittal magnetic resonance imaging. We defined the sagittal CSF column diameter of less than 8 mm as CSCS based on the previous paper. We evaluated the relative and absolute risks for the incidence of traumatic CSCI related with CSCS. RESULTS: Using data from the Spinal Injury Network of Fukuoka, Japan, the relative risk for the incidence of traumatic CSCI at the C3-4 segment with CSCS was calculated as 124.5:1. Moreover, the absolute risk for the incidence of traumatic CSCI at the C3-4 segment with CSCS was calculated as 0.00017. CONCLUSIONS: In our results, the relative risk for the incidence of traumatic CSCI with CSCS was 124.5 times higher than that for the incidence without CSCS. However, only 0.017 % of subjects with CSCS may be able to avoid developing traumatic CSCI if they undergo decompression surgery before trauma. Our results suggest that prophylactic surgical management for CSCS might not significantly affect the incidence of traumatic CSCI. PMID- 23793523 TI - Platelet distribution width and the risk of periprocedural myocardial infarction in patients undergoing percutaneous coronary intervention. AB - Periprocedural myocardial infarction (PMI) still occurs in a large amount of percutaneous coronary interventions (PCI), mainly due to increased platelet activation. Platelet size has been suggested as an indicator of enhanced reactivity and platelet distribution width (PDW) could reflect morphologic changes in platelets, therefore affecting their function and potentially increasing the risk of complications after coronary stenting. Aim of the present study was to evaluate the relationship between PDW and PMI. We included 1,300 consecutive patients undergoing PCI. Myonecrosis biomarkers were dosed at intervals from 6 to 48 h after PCI. Periprocedural myonecrosis was defined as troponin I increase by three times the ULN or by 50 % of an elevated baseline value, whereas PMI as CKMB increase by three times the ULN or 50 % of baseline. We grouped patients according to tertiles values of PDW (<12.1; >=13.9). Higher PDW was associated with age (p = 0.03), diabetes (p < 0.001), previous cerebrovascular accidents (p = 0.04), therapy with statins (p = 0.001) and ARBs (p < 0.001), ASA (p = 0.02), nitrates (p = 0.006), calcium antagonists (p = 0.05) and lower pre-procedural clopidogrel bolus (p = 0.005). PDW related with haemoglobin levels (p < 0.001), while inversely to platelet count (p < 0.001) and glycaemia (p = 0.003). Patients with larger PDW had lower presence of coronary thrombus (p < 0.001), higher rate of coronary calcifications (p = 0.02), higher stenting rate (p = 0.03) and lower rate of distal embolization (p = 0.03). Larger PDW did not increase risk of PMI (p = 0.11; adjusted OR [95 % CI] = 0.94 [0.78 1.1], p = 0.55) or periprocedural myonecrosis (p = 0.73; adjusted OR [95 % CI] = 0.95 [0.82-1.1], p = 0.51). Results were confirmed even in higher-risk subgroups of patients. In patients undergoing coronary stenting, PDW does not increase the risk of periprocedural MI and therefore should not be considered a risk factor for thrombotic periprocedural complications after PCI. PMID- 23793522 TI - Will there ever be a universal Staphylococcus aureus vaccine? AB - Developing a universal vaccine for S. aureus is a top priority but to date we have only had failures in human clinical trials. Given the plethora of bacterial virulence factors, broad range of the health of humans at-risk for infections, lack of any information regarding immune effectors mediating protection for any manifestation of S. aureus infection and overall competence of this organism as a colonizer, commensal and pathogen, we may just simply have to accept the fact that we will not get a universal vaccine. Antigenic variation is a major challenge for some vaccine targets and for many conserved targets the organism can easily decrease or even eliminate expression to avoid immune effectors without compromise to infectivity and ability to cause disease. Studies of human immune responses similarly have been unable to identify any clear mediators of immunity and data from such studies can only eliminate those found not to be associated with protection or that might serve as a marker for individuals with a higher level of resistance to infection. Animal studies are not predictive of success in humans and unlikely will be except in hindsight if and when we develop an efficacious vaccine. Successful vaccines for other bacteria based on capsular polysaccharides have not worked to date for S. aureus, and laboratory studies combining antibody to the major capsular serotypes and the other S. aureus surface polysaccharide, poly-N-acetyl glucosamine, unexpectedly showed interference not augmentation of immunity. Potential pathways toward vaccine development do exist but for the foreseeable future will be based on empiric approaches derived from laboratory-based in vitro and animal tests and not on inducing a known immune effector that predicts human resistance to infection. PMID- 23793525 TI - Rhythmic affects on stroke-induced joint synergies across a range of speeds. AB - Joint synergies are one among several diminished motor capabilities that are associated with stroke. These synergies are characterized by a stereotypical combination of involuntary joint coactivations. This research measured the synergistic rotations of the shoulder in response to voluntary rhythmic motion of the elbow across a range of speeds. The experimental protocol included a total of 22 subjects divided into two groups: (1) stroke survivors and (2) neurologically intact controls. Rhythmic motion in stroke survivors resulted in comparable synergies to discrete movement. It was found that hemiparetic subjects had greater synergy than neurologically intact individuals for all speeds. Synergy was quantified using a synergy ratio. This ratio uses elbow rotation as an input in the denominator and shoulder rotation as an output in the numerator. The amount of shoulder synergy varied with the subject's level of impairment as measured by a modified Fugl-Meyer assessment. As rhythmic speeds increased, the synergy ratios became higher for stroke subjects. This effect was especially pronounced for subjects with higher impairment. The relationships between synergies that arise from rhythmic and discrete movements are also discussed. The results of this study may have implications for therapeutic interventions, robotic rehabilitation approaches, and for the design of orthotic devices. More generally, these results shed light on the role of central pattern generators in hemiparetic motion. PMID- 23793524 TI - Treatment of borderline resectable pancreatic cancer. AB - OPINION STATEMENT: Borderline resectable pancreatic adenocarcinoma represents a subset of localized cancers that are at high risk for a margin-positive resection and early treatment failure when resected de novo. Although several different anatomic definitions for this disease stage exist, there is agreement that some degree of reconstructible mesenteric vessel involvement by the tumor is the critical anatomic feature that positions borderline resectable between anatomically resectable and unresectable (locally advanced) tumors in the spectrum of localized disease. Consensus also exists that such cancers should be treated with neoadjuvant chemotherapy and/or chemoradiation before resection; although the optimal algorithm is unknown, systemic chemotherapy followed by chemoradiation is a rational approach. Although gemcitabine-based systemic chemotherapy with either 5-FU or gemcitabine-based chemoradiation regimens has been used to date, newer regimens, including FOLFIRINOX, should be evaluated on protocol. Delivery of neoadjuvant therapy necessitates durable biliary decompression for as many as 6 months in many patients with cancers of the pancreatic head. Patients with no evidence of metastatic disease following neoadjuvant therapy should be brought to the operating room for pancreatectomy, at which time resection of the superior mesenteric/portal vein and/or hepatic artery should be performed when necessary to achieve a margin-negative resection. Following completion of multimodality therapy, patients with borderline resectable pancreatic cancer can expect a duration of survival as favorable as that of patients who initially present with resectable tumors. Coordination among a multidisciplinary team of physicians is necessary to maximize these complex patients' short- and long-term oncologic outcomes. PMID- 23793526 TI - Analysis of serum metabolites for the discovery of amino acid biomarkers and the effect of galangin on cerebral ischemia. AB - Ischemic stroke, a devastating disease with a complex pathophysiology, is a leading cause of death and disability worldwide. In our previous study, we reported that galangin provided direct protection against ischemic injury and acted as a potential neuroprotective agent. However, its associated neuroprotective mechanism has not yet been clarified. In this paper, we explored the potential AA biomarkers in the acute phase of cerebral ischemia and the effect of galangin on those potential biomarkers. In our study, 12 AAs were quantified in rat serum and found to be impaired by middle cerebral artery occlusion (MCAO)-induced focal cerebral ischemia. Using partial least squares discriminate analysis (PLS-DA), we identified the following amino acids as potential biomarkers of cerebral ischemia: glutamic acid (Glu), homocysteine (Hcy), methionine (Met), tryptophan (Trp), aspartic acid (Asp), alanine (Ala) and tyrosine (Tyr). Moreover, four amino acids (Hcy, Met, Glu and Trp) showed significant change in galangin-treated (100 and 50 mg kg(-1)) groups compared to vehicle groups. Furthermore, we identified three pathway-related enzymes tyrosine aminotransferase (TAT), glutamine synthetase (GLUL) and monocarboxylate transporter (SLC16A10) by multiplex interactions with Glu and Hcy, which have been previously reported to be closely related to cerebral ischemia. Through an analysis of the metabolite-protein network analysis, we identified 16 proteins that were associated with two amino acids by multiple interactions with three enzymes; five of them may become potential biomarkers of galangin for acute ischemic stroke as the result of molecule docking. Our results may help develop novel strategies to explore the mechanism of cerebral ischemia, discover potential targets for drug candidates and elucidate the related regulatory signal network. PMID- 23793527 TI - Niemann-Pick type C Suspicion Index tool: analyses by age and association of manifestations. AB - OBJECTIVE: The Suspicion Index (SI) screening tool was developed to identify patients suspected of having Niemann-Pick disease type C (NP-C). The SI provides a risk prediction score (RPS) based on NP-C manifestations within and across domains (visceral, neurological, and psychiatric). The aim of these subanalyses was to further examine the discriminatory power of the SI by age and manifestation-associations by NP-C suspicion-level and leading manifestations. METHODS: The original retrospectively collected data were split into three patient age groups, where NP-C-positive cases were >16 years (n = 30), 4-16 years (n = 18), and <4 years (n = 23), and patients' RPS were analyzed by logistic regression. Co-occurrence of manifestations within groups of suspicion level (low, medium, high) and leading manifestations (presence/absence of ataxia, cognitive decline, psychosis, and splenomegaly) were analyzed descriptively. RESULTS: NP-C-positive cases versus controls showed strong discriminatory power of RPS. Area under the receiver operating characteristic curve was 0.964 (>16 years) and 0.981 (4-16 years) but weaker 0.562 for infants (<4 years). Patients with RPS <70 were characterized by a lack of psychiatric manifestations and low levels of neurological involvement, suggestive of a preneurological phase of the disease. In patients >4 years, prominent leading manifestation-associations were ataxia with dystonia, dysarthria/dysphagia, and cognitive decline. Psychosis was associated with dysarthria/dysphagia but also with cognitive decline and treatment-resistant psychiatric symptoms. CONCLUSIONS: The SI tool maintains strong discriminatory power in patients >4 years but is not as useful for infants <4 years. The SI is also informative regarding the association and co-occurrence of manifestations in patients with NP-C. PMID- 23793528 TI - Liver trauma grading and biochemistry tests. AB - Among solid organ blunt traumas, the liver and spleen are mostly subject to injury. In addition, the liver is also commonly injured in penetrating traumas because of its size, location, and the ease of injury to the "Glisson Capsule". Several enzymes are known to be elevated following trauma. In our study, we evaluated the correlation between the levels of serum aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and gamma-glutamyl transpeptidase in 57 patients with blunt trauma to the liver and compared these values to the American Association for the Surgery of Trauma trauma grading system. Additionally, we compared the enzyme level elevations in these patients to the enzyme levels of 29 healthy subjects. As expected, we found significant elevations in enzyme levels of trauma patients compared to the control group. The calculated point estimates were not significantly different between grades 1 and 2 trauma. However, grade 3 trauma group showed a significant increase in enzyme levels. PMID- 23793529 TI - Mortality prediction of rats in acute hemorrhagic shock using machine learning techniques. AB - This study sought to determine a mortality prediction model that could be used for triage in the setting of acute hemorrhage from trauma. To achieve this aim, various machine learning techniques were applied using the rat model in acute hemorrhage. Thirty-six anesthetized rats were randomized into three groups according to the volume of controlled blood loss. Measurements included heart rate (HR), systolic and diastolic blood pressures (SBP and DBP), mean arterial pressure, pulse pressure, respiratory rate, temperature, blood lactate concentration (LC), peripheral perfusion (PP), shock index (SI, SI = HR/SBP), and a new hemorrhage-induced severity index (NI, NI = LC/PP). NI was suggested as one of the good candidates for mortality prediction variable in our previous study. We constructed mortality prediction models with logistic regression (LR), artificial neural networks (ANN), random forest (RF), and support vector machines (SVM) with variable selection. The SVM model showed better sensitivity (1.000) and area under curve (0.972) than the LR, ANN, and RF models for mortality prediction. The important variables selected by the SVM were NI and LC. The SVM model may be very helpful to first responders who need to make accurate triage decisions and rapidly treat hemorrhagic patients in cases of trauma. PMID- 23793530 TI - Critical hopefulness: a person-centered analysis of the intersection of cognitive and emotional empowerment. AB - Leaders in struggles for social justice agree on the importance and the difficulty of maintaining hopefulness while developing critical awareness of social issues. Research has indicated that the analogous components of psychological empowerment (emotional and cognitive) often do not co-vary across populations. This study used a person-centered analytic approach, latent class analysis, to identify subpopulations of participants (n = 1,322) according to the cognitive and emotional components of psychological empowerment. Four distinct sub-groups emerged: those who were relatively (1) critical but alienated, (2) uncritical but hopeful, (3) uncritical and alienated, or (4) critical and hopeful. These clusters were then examined for demographic differences and relationships with a set of conceptually relevant variables including social capital, psychological sense of community, openness, organizational participation and mental wellbeing. Results shed light on the complexity of empowerment processes and yield implications for ongoing community research and action. PMID- 23793531 TI - Voluntary versus involuntary hospital admission in child and adolescent psychiatry: a German sample. AB - Involuntary psychiatric admission is a central issue in mental health care, especially in the treatment of children and adolescents. Its legal regulations do not only differ between European countries, but also on a federal level. Only few studies so far dealt with rates of involuntary admission (RIA), mainly focusing on adults, rather than children and adolescents. None of the studies analyzed this topic in a large cohort. The aim of this regional cross-sectional study was to compare voluntary and involuntary admissions in child and adolescent psychiatry (CAP) regarding personal and admission characteristics. Furthermore, risk factors and predictors of involuntary admission should be identified. A retrospective analysis of hospital admission registers from three major German CAP hospitals over a period of 6 years (2004-2009) was conducted (N = 10,547 inpatients). Group comparisons between involuntarily and voluntarily treated minors and a logistic regression to determine predictors of legal status were performed. Information on harm to self or others prior to the admission, medication and clinical outcome was not available due to data structure. 70.8 % of patients were voluntarily and 29.2 % involuntarily admitted. Both subsamples comprised more males. The RIA decreased consistently over the years, ranging from 25.7 to 32.4 %. The strongest predictor of being admitted involuntarily was suffering from mental retardation (OR = 15.74). Adolescence, substance abuse, psychotic disorders and admission on duty time were also strongly associated (OR > 3). In this first large cohort study on involuntary treatment of children and adolescents in Germany, about every fourth patient was treated involuntarily. Certain personal and disease-related factors increased the risk. Commitment laws and other legal instruments for regulating involuntary placements are inconsistent and a standardized description or systematic analysis is needed. The influence of demographic, institutional variables and care and health services aspects should also be investigated. PMID- 23793532 TI - Biotribological properties of UHMWPE grafted with AA under lubrication as artificial joint. AB - Osteolysis caused by wear particles from polyethylene in the artificial hip joints is a serious issue. In order to endow the low friction and wear of the bearing surface of ultra-high molecular weight polyethylene (UHMWPE) artificial joint for a longer term, hydrophilic acrylic acid (AA) was grafted on UHMWPE powders with the method of ultraviolet irradiation and then the modified powders were hot pressed. The tribological properties of modified UHMWPE sliding against CoCrMo metallic plate on reciprocating tribometer under calf serum, saline and distilled water lubrication during a long-term friction were investigated. The measurement of Fourier-transform infrared spectroscopy indicates that AA is successfully grafted on the surface of UHMWPE powders by photo-induced graft polymerization. Contact angles of UHMWPE are decreased from 83 degrees to 35 degrees by grafting and the surface wettability is effectively improved. The tensile strength of modified sample decreases. The friction coefficient and wear rate of UHMWPE-g-PAA under calf serum, saline and distilled water lubrication are lower than that of untreated UHMWPE. With the increase of grafting ratio, the wear rate of UHMWPE-g-PAA decreases firstly and then increases. The modified UHMWPE with grafting ratio of 3.5 % has the lowest wear rate, which is just quarter of the untreated UHMWPE. The hydrated PAA polymer brushes enclosed in the UHMWPE bulk material provide continuous lubrication during long term sliding. PMID- 23793533 TI - The relationship between the medical home and unmet needs for children with autism spectrum disorders. AB - The purpose of this study was to examine the relationship between having access to a medical home and unmet needs for specialty care services for children with autism spectrum disorders (ASD). Parents of children enrolled in a national autism registry were invited to complete an online Access to Care Questionnaire. The resulting sample consisted of 371 parents-child dyads. Bivariate and hierarchical regression analyses were conducted to determine whether having a medical home was associated with the number of unmet needs for specialty care. Less than one in five children with ASD had a medical home (18.9%). Nearly all parents reported that their child had a personal doctor or nurse as well as a usual source of care, but less than one-third received coordinated care (29.9%) and less than one-half received family-centered care (47.1%). Many children had unmet needs (63%), and the highest unmet need was for behavioral therapy. Having a medical home was associated with fewer unmet specialty care needs, even after demographic, child and family characteristics were taken into account. Children with ASD who have a medical home are more likely to have adequate access to needed services. Unfortunately, relatively few children have a medical home that includes family-centered and coordinated care. Enhancements in the delivery of primary care for children with ASD may make a real difference in access to needed specialty care services, potentially improving child and family outcomes. PMID- 23793534 TI - 2009 H1N1 and seasonal influenza immunization among pregnant women: a comparison of different sources of immunization information. AB - Validity of prenatal immunization data from different sources has not been assessed. We evaluated prenatal 2009 H1N1 and seasonal influenza (FLU) data obtained from state immunization information systems (IIS), medical record abstraction (MRA), and participant recall using medical care logs (NCS-MCL). 2009 H1N1 and FLU data were obtained from IIS and MRA for 325 pregnant women participating in the National Children's Study at three locations (SD/MN, NC, WI). Women recalled immunizations at first pregnancy visit and at 16-17 and 36 weeks' gestation (NCS-MCL). The proportion of women with vaccine information obtainable from each data source was determined, and proportions immunized as determined using different data sources were compared. IIS data were available for 82%, MRA for 97%, and NCS-MCL for 93% of women. No mention of either vaccine occurred in 29% (range 4-48%) of IIS, 40% of MRA (25-59%), and 59% (43-82%) in NCS-MCL. Best agreement between sources was 2009 H1N1 vaccine in MRA versus IIS [kappa (95% CI) of 0.44 (0.32-0.55)], with poorest agreement for FLU in IIS versus NCS-MCL [0.11 (-0.03 to 0.25)]. IIS was the most sensitive method for identifying women receiving 2009 H1N1 vaccine (92%); MRA was most sensitive for FLU vaccine (81%). IIS provided the most complete and sensitive data for 2009 H1N1 immunizations and MRA the most complete and sensitive data for FLU; IIS data were available for a smaller percent of population than MRA. NCS-MCL was the least sensitive method for identifying vaccinated women. PMID- 23793535 TI - Examining the links between perceived impact of pregnancy, depressive symptoms, and quality of life during adolescent pregnancy: the buffering role of social support. AB - The aims of the current study were to examine the indirect effect of the perceived impact of pregnancy on quality of life (QoL) through the severity of depressive symptoms among a sample of pregnant adolescents, and to explore whether adolescents' satisfaction with support from their mothers (SM) or partners (SP) was a buffer of this effect. Demographic and pregnancy-related data were collected for 395 pregnant adolescents age 12-19 and were controlled for testing the proposed indirect effect. SM and SP were tested as moderators of the links between perceived impact of pregnancy and depressive symptoms and between depressive symptoms and QoL. A computational tool for path analysis-based moderation and mediation analysis as well as their combination was used to test indirect and interaction effects (PROCESS). A significant indirect effect of the perceived impact of pregnancy on QoL through the severity of depressive symptoms was found (0.51, CI = 0.29/0.78). There was no significant direct effect of the perceived impact of pregnancy on QoL after controlling for the severity of depressive symptoms. SM and SP buffered the indirect effect by weakening the association between a negative perception of the impact of pregnancy and higher severity of depressive symptoms. Identifying adolescents with a negative perception of the impact of pregnancy, improving the quality of their relations with their mothers and partners, and promoting satisfactory support from these figures may be extremely important to prevent and treat depressive symptoms and, in so doing, improve adolescents' QoL during pregnancy. PMID- 23793536 TI - Care coordination impacts on access to care for children with special health care needs enrolled in Medicaid and CHIP. AB - Children with special health care needs (CSHCN) often require services from multiple health care providers. This study's objective is to evaluate whether CSHCN, enrolled in Medicaid or the Children's Health Insurance Program (CHIP) and receiving care coordination services, experience improved access to mental and specialty health care services. Using data from the 2009-2010 National Survey of Children with Special Health Care Needs, two separate outcomes are used to evaluate children's access to care: receipt of needed mental and specialty care and timely access to services. Using propensity score matching, CSHCN propensity for receiving care coordination services is derived and an assessment is made of care coordination's impact on the receipt of health care and whether care is delayed. Results demonstrate that care coordination is positively associated with whether a child receives the mental and specialty care that they need, regardless of whether or not that coordination is perceived to be adequate by parents. However, receiving care coordination services that parents perceive to be adequate has a larger impact on the timeliness in which care is received. This study indicates that care coordination is associated with an increased ability for CSHCN to access needed mental and specialty care. States should consider offering care coordination services that support provider communication and fulfill families' coordination needs to the CSHCN enrolled in their Medicaid and CHIP programs. PMID- 23793537 TI - Caregiver burden and preventive dental care use for US children with special health care needs: a stratified analysis based on functional limitation. AB - The objectives of this study were to evaluate the association between caregiver burden and preventive dental care use for children with special health care needs (CSHCN) and assess if caregiver burden explains the relationship between child- and family-level characteristics and preventive dental care use. Samples of US CSHCN ages 3-17 years with a functional limitation (n = 7,559) and those without (n = 26,345) were derived from the 2005-2006 National Survey of CSHCN. We generated structural equation models, stratified by functional limitation, to describe the relationships between caregiver burden and preventive dental utilization. We measured caregiver burden using six items on whether the child's health condition impacted work, time spent on health management, and finances. About 80.9 % of CSHCN used preventive dental care. Higher levels of caregiver burden were associated with significantly lower odds of preventive dental care use for CHSCN with a functional limitation (beta = -0.06; P < 0.001) and those without (beta = -0.07; P < 0.001). For CSHCN with a functional limitation, family poverty and being uninsured were significantly associated with greater caregiver burden and less preventive dental use. Findings were similar for CSHCN without a functional limitation, except that lower caregiver education was also associated with greater caregiver burden and less preventive dental care use. Caregiver burden is potential barrier to preventive dental care use for CSHCN and explains the relationship between child- and family-level characteristics and preventive dental care use. Interventions to improve the oral health of CSHCN should include strategies to reduce caregiver burden, especially within socioeconomically vulnerable families. PMID- 23793538 TI - Dissipation and residues of bispyribac-sodium in rice and environment. AB - The dissipation and residues of bispyribac-sodium in rice cropping system were studied. Bispyribac-sodium residues were extracted by a simple analytical method based on QuEChERs and detected by LC-MS/MS. The limit of detection for bispyribac sodium of this method was 0.375 * 10(-3) ng. The limit of quantification (LOQ) was 5.0 MUg/kg for rice plant samples, 2.0 MUg/kg for rice hull, 0.2 MUg/kg for water, and 0.1 MUg/kg for soil and husked rice samples. The average recoveries of bispyribac-sodium ranged from 74.7 to 108%, with relative standard deviations less than 13%. The half-lives of bispyribac-sodium in rice plant, water, and soil were in the range of 1.4-5.6 days. More than 90% of bispyribac-sodium residue dissipated within 5 days. The final residues of bispyribac-sodium in rice were all below LOQ at harvest time. PMID- 23793539 TI - Early-season agricultural drought: detection, assessment and monitoring using Shortwave Angle and Slope Index (SASI) data. AB - Early season or crop-planting-period (ES/CPP) drought conditions have become a recurrent phenomenon in tropical countries like India, due to fluctuations in the time of onset and progression of monsoon rains. ES/CPP agricultural drought assessment is a major challenge because of the difficulties in the generation of operational products on soil moisture at larger scales. The present study analyzed the Shortwave Angle Slope Index (SASI) derived from Near Infrared and Shortwave Infrared data of Moderate Resolution Imaging Spectroradiometer, for tracking surface moisture changes and assessing the agricultural drought conditions during ES/CPP, over Andhra Pradesh state, India. It was found that in season progression of SASI was well correlated with rainfall and crop planting patterns in different districts of the study area state in both drought and normal years. Rainfall occurrence, increase in crop planted area, and decrease in SASI were in chronological synchronization in the season. Change in SASI from positive to negative values is a unique indication of dryness to wetness shift in the season. Duration of positive SASI values indicated the persistence of agricultural drought in the crop planting period. Mean SASI values were able to discriminate an area which was planted in normal year and unplanted in drought year. SASI thresholds provide an approximate and rapid estimate of the crop planting favorable area in a region which is useful to assess the impact of drought. Thus, SASI is a potential index to strengthen the existing operational drought monitoring systems. Further work needs to be on the integration of multiple parameters-SASI, soil texture, soil depth, rainfall and cropping pattern, to evolve a geospatial product on crop planting favorable areas. Such products pave the way for quantification of drought impact on agriculture in the early part of the season, which is a major inadequacy in the current drought monitoring system. PMID- 23793540 TI - Heavy metal bioaccumulation and risk assessment for wild and farmed beluga sturgeon caviar. AB - Because of over-exploitation of sturgeon for caviar production, they have been listed worldwide in annex II of the Convention on International Trade in Endangered Species regulations; so caviar production using aquaculture is increasingly seen as a feasible way to reduce overfishing. The accumulation of the nonessential metals As, Ba, Cd, Hg, Pb, and Sn was determined in the caviar of farmed and wild Beluga sturgeon (Huso huso). The levels of As in both and Cd in wild samples were less than 0.01 mg kg(-1) wet weight, and the comparison for all of the metals studied did not show large fluctuations in metal concentrations between farmed and wild caviar samples. The average for each toxic metal was below the permissible limits proposed by the UK's Ministry of Agriculture, Fisheries and Foods (2000). The maximum allowable daily consumption rate of caviar was calculated; however, the health risks from caviar consumption are uncertain because the amount of caviar consumed by heavy users is not known. PMID- 23793541 TI - Assessment of hydraulic redistribution on desert riparian forests in an extremely arid area. AB - The roots of Populus euphratica, a plant that grows in the lower reaches of the Tarim River, Northwest China, exhibit a significant level of hydraulic redistribution; however, quantitative assessments of the water-sharing process and its ecological effects are limited. This study was designed to obtain such data using an assessment model based on field observation parameters, including soil water content (soil water potential), root distribution, and stable isotope delta(18)O values of soil and plant samples during the entire growing season. The results showed that hydraulic redistribution in P. euphratica can be detected in 0-120 cm soil layers, with the amount of hydraulically redistributed water (HRW) in the soil found at different depths as follows: 60-80 > 40-60 > 20-40 > 0-20 > 80-100 > 100-120 cm. The variations in HRW in soil layers can be partly attributed to the vertical distribution of roots. The denser roots found at greater depths positively influenced the amount of redistributed water in lower soil layers. During the growing season, the amount of HRW reached a daily average of 0.27 mm, which allowed increased transpiration and provided an adequate water supply to herbs. Based on the stable isotope (delta(18)O) data, the amount of HRW provided by the roots of P. euphratica could meet 22-41% of its water demand. PMID- 23793542 TI - Octahedral tin dioxide nanocrystals as high capacity anode materials for Na-ion batteries. AB - Single crystalline SnO2 nanocrystals (~60 nm in size) with a uniform octahedral shape were synthesised using a hydrothermal method. Their phase and morphology were characterized by XRD and FESEM observation. TEM and HRTEM analyses identified that SnO2 octahedral nanocrystals grow along the [001] direction, consisting of dominantly exposed {221} high energy facets. When applied as anode materials for Na-ion batteries, SnO2 nanocrystals exhibited high reversible sodium storage capacity and excellent cyclability (432 mA h g(-1) after 100 cycles). In particular, SnO2 nanocrystals also demonstrated a good high rate performance. Ex situ TEM analysis revealed the reaction mechanism of SnO2 nanocrystals for reversible Na ion storage. It was found that Na ions first insert into SnO2 crystals at the high voltage plateau (from 3 V to ~0.8 V), and that the exposed (1 * 1) tunnel-structure could facilitate the initial insertion of Na ions. Subsequently, Na ions react with SnO2 to form NaxSn alloys and Na2O in the low voltage range (from ~0.8 V to 0.01 V). The superior cyclability of SnO2 nanocrystals could be mainly ascribed to the reversible Na-Sn alloying and de-alloying reactions. Furthermore, the reduced Na2O "matrix" may help retard the aggregation of tin nanocrystals, leading to an enhanced electrochemical performance. PMID- 23793543 TI - Absence of a robust innate immune response in rat neurons facilitates persistent infection of Borna disease virus in neuronal tissue. AB - Borna disease virus (BDV) persistently infects neurons of the central nervous system of various hosts, including rats. Since type I IFN-mediated antiviral response efficiently blocks BDV replication in primary rat embryo fibroblasts, it has been speculated that BDV is not effectively sensed by the host innate immune system in the nervous system. To test this assumption, organotypical rat hippocampal slice cultures were infected with BDV for up to 4 weeks. This resulted in the secretion of IFN and the up-regulation of IFN-stimulated genes. Using the rat Mx protein as a specific marker for IFN-induced gene expression, astrocytes and microglial cells were found to be Mx positive, whereas neurons, the major cell type in which BDV is replicating, lacked detectable levels of Mx protein. In uninfected cultures, neurons also remained Mx negative even after treatment with high concentrations of IFN-alpha. This non-responsiveness correlated with a lack of detectable nuclear translocation of both pSTAT1 and pSTAT2 in these cells. Consistently, neuronal dissemination of BDV was not prevented by treatment with IFN-alpha. These data suggest that the poor innate immune response in rat neurons renders this cell type highly susceptible to BDV infection even in the presence of exogenous IFN-alpha. Intriguingly, in contrast to rat neurons, IFN-alpha treatment of mouse neurons resulted in the up regulation of Mx proteins and block of BDV replication, indicating species specific differences in the type I IFN response of neurons between mice and rats. PMID- 23793544 TI - Understanding human-landscape interactions in the "Anthropocene". AB - This article summarizes the primary outcomes of an interdisciplinary workshop in 2010, sponsored by the U.S. National Science Foundation, focused on developing key questions and integrative themes for advancing the science of human-landscape systems. The workshop was a response to a grand challenge identified recently by the U.S. National Research Council (2010a)--"How will Earth's surface evolve in the "Anthropocene?"--suggesting that new theories and methodological approaches are needed to tackle increasingly complex human-landscape interactions in the new era. A new science of human-landscape systems recognizes the interdependence of hydro-geomorphological, ecological, and human processes and functions. Advances within a range of disciplines spanning the physical, biological, and social sciences are therefore needed to contribute toward interdisciplinary research that lies at the heart of the science. Four integrative research themes were identified--thresholds/tipping points, time scales and time lags, spatial scales and boundaries, and feedback loops--serving as potential focal points around which theory can be built for human-landscape systems. Implementing the integrative themes requires that the research communities: (1) establish common metrics to describe and quantify human, biological, and geomorphological systems; (2) develop new ways to integrate diverse data and methods; and (3) focus on synthesis, generalization, and meta-analyses, as individual case studies continue to accumulate. Challenges to meeting these needs center on effective communication and collaboration across diverse disciplines spanning the natural and social scientific divide. Creating venues and mechanisms for sustained focused interdisciplinary collaborations, such as synthesis centers, becomes extraordinarily important for advancing the science. PMID- 23793545 TI - An application of remote sensing data in mapping landscape-level forest biomass for monitoring the effectiveness of forest policies in northeastern China. AB - Monitoring the dynamics of forest biomass at various spatial scales is important for better understanding the terrestrial carbon cycle as well as improving the effectiveness of forest policies and forest management activities. In this article, field data and Landsat image data acquired in 1999 and 2007 were utilized to quantify spatiotemporal changes of forest biomass for Dongsheng Forestry Farm in Changbai Mountain region of northeastern China. We found that Landsat TM band 4 and Difference Vegetation Index with a 3 * 3 window size were the best predictors associated with forest biomass estimations in the study area. The inverse regression model with Landsat TM band 4 predictor was found to be the best model. The total forest biomass in the study area decreased slightly from 2.77 * 10(6) Mg in 1999 to 2.73 * 10(6) Mg in 2007, which agreed closely with field-based model estimates. The area of forested land increased from 17.9 * 10(3) ha in 1999 to 18.1 * 10(3) ha in 2007. The stabilization of forest biomass and the slight increase of forested land occurred in the period following implementations of national forest policies in China in 1999. The pattern of changes in both forest biomass and biomass density was altered due to different management regimes adopted in light of those policies. This study reveals the usefulness of the remote sensing-based approach for detecting and monitoring quantitative changes in forest biomass at a landscape scale. PMID- 23793546 TI - Role of regucalcin in cell nuclear regulation: involvement as a transcription factor. AB - Regucalcin (RGN/SMP30) was discovered in 1978 as a calcium (Ca(2+))-binding protein that contains no EF-hand motif of the Ca(2+)-binding domain. The name of regucalcin was proposed for this Ca(2+)-binding protein, which can regulate various Ca(2+)-dependent enzyme activations in liver cells. The regucalcin gene is localized on the X chromosome. Regucalcin plays a multifunctional role in cell regulation through maintaining intracellular Ca(2+) homeostasis and suppressing signal transduction in various cell types. The cytoplasmic regucalcin is translocated into the nucleus and inhibits nuclear Ca(2+)-dependent and independent protein kinases and protein phosphatases, Ca(2+)-activated deoxyribonucleic acid (DNA) fragmentation and DNA and ribonucleic acid (RNA) synthesis. Moreover, overexpression of endogenous regucalcin regulates the gene expression of various proteins that are related to cell proliferation and apoptosis. This review will discuss the role of regucalcin in the regulation of cell nuclear function and an involvement in gene expression as a novel transcription factor. PMID- 23793547 TI - Spatial memory tasks in rodents: what do they model? AB - The analysis of spatial learning and memory in rodents is commonly used to investigate the mechanisms underlying certain forms of human cognition and to model their dysfunction in neuropsychiatric and neurodegenerative diseases. Proper interpretation of rodent behavior in terms of spatial memory and as a model of human cognitive functions is only possible if various navigation strategies and factors controlling the performance of the animal in a spatial task are taken into consideration. The aim of this review is to describe the experimental approaches that are being used for the study of spatial memory in rats and mice and the way that they can be interpreted in terms of general memory functions. After an introduction to the classification of memory into various categories and respective underlying neuroanatomical substrates, I explain the concept of spatial memory and its measurement in rats and mice by analysis of their navigation strategies. Subsequently, I describe the most common paradigms for spatial memory assessment with specific focus on methodological issues relevant for the correct interpretation of the results in terms of cognitive function. Finally, I present recent advances in the use of spatial memory tasks to investigate episodic-like memory in mice. PMID- 23793548 TI - Differentiation of malignant and benign pulmonary nodules with first-pass dual input perfusion CT. AB - OBJECTIVE: To assess diagnostic performance of dual-input CT perfusion for distinguishing malignant from benign solitary pulmonary nodules (SPNs). METHODS: Fifty-six consecutive subjects with SPNs underwent contrast-enhanced 320-row multidetector dynamic volume CT. The dual-input maximum slope CT perfusion analysis was employed to calculate the pulmonary flow (PF), bronchial flow (BF), and perfusion index [Formula: see text]. Differences in perfusion parameters between malignant and benign tumours were assessed with histopathological diagnosis as the gold standard. Diagnostic value of the perfusion parameters was calculated using the receiver-operating characteristic (ROC) curve analysis. RESULTS: Amongst 56 SPNs, statistically significant differences in all three perfusion parameters were revealed between malignant and benign tumours. The PI demonstrated the biggest difference between malignancy and benignancy: 0.30 +/- 0.07 vs. 0.51 +/- 0.13 , P < 0.001. The area under the PI ROC curve was 0.92, the largest of the three perfusion parameters, producing a sensitivity of 0.95, specificity of 0.83, positive likelihood ratio (+LR) of 5.59, and negative likelihood ratio (-LR) of 0.06 in identifying malignancy. CONCLUSIONS: The PI derived from the dual-input maximum slope CT perfusion analysis is a valuable biomarker for identifying malignancy in SPNs. PI may be potentially useful for lung cancer treatment planning and forecasting the therapeutic effect of radiotherapy treatment. KEY POINTS: * Modern CT equipment offers assessment of vascular parameters of solitary pulmonary nodules (SPNs) * Dual vascular supply was investigated to differentiate malignant from benign SPNs. * Different dual vascular supply patterns were found in malignant and benign SPNs. * The perfusion index is a useful biomarker for differentiate malignancy from benignancy. PMID- 23793549 TI - Phylogeny and systematics of demospongiae in light of new small-subunit ribosomal DNA (18S) sequences. AB - The most diverse and species-rich class of the phylum Porifera is Demospongiae. In recent years, the systematics of this clade, which contains more than 7000 species, has developed rapidly in light of new studies combining molecular and morphological observations. We add more than 500 new, nearly complete 18S sequences (an increase of more than 200%) in an attempt to further enhance understanding of the phylogeny of Demospongiae. Our study specifically targets representation of type species and genera that have never been sampled for any molecular data in an effort to accelerate progress in classifying this diverse lineage. Our analyses recover four highly supported subclasses of Demospongiae: Keratosa, Myxospongiae, Haploscleromorpha, and Heteroscleromorpha. Within Keratosa, neither Dendroceratida, nor its two families, Darwinellidae and Dictyodendrillidae, are monophyletic and Dictyoceratida is divided into two lineages, one predominantly composed of Dysideidae and the second containing the remaining families (Irciniidae, Spongiidae, Thorectidae, and Verticillitidae). Within Myxospongiae, we find Chondrosida to be paraphyletic with respect to the Verongida. We amend the latter to include species of the genus Chondrosia and erect a new order Chondrillida to contain remaining taxa from Chondrosida, which we now discard. Even with increased taxon sampling of Haploscleromorpha, our analyses are consistent with previous studies; however, Haliclona species are interspersed in even more clades. Haploscleromorpha contains five highly supported clades, each more diverse than previously recognized, and current families are mostly polyphyletic. In addition, we reassign Janulum spinispiculum to Haploscleromorpha and resurrect Reniera filholi as Janulum filholi comb. nov. Within the large clade Heteroscleromorpha, we confirmed 12 recently identified clades based on alternative data, as well as a sister-group relationship between the freshwater Spongillida and the family Vetulinidae. We transfer Stylissa flabelliformis to the genus Scopalina within the family Scopalinidae, which is of uncertain position. Our analyses uncover a large, strongly supported clade containing all heteroscleromorphs other than Spongillida, Vetulinidae, and Scopalinidae. Within this clade, there is a major division separating Axinellidae, Biemnida, Tetractinellida, Bubaridae, Stelligeridae, Raspailiidae, and some species of Petromica, Topsentia, and Axinyssa from Agelasida, Polymastiidae, Placospongiidae, Clionaidae, Spirastrellidae, Tethyidae, Poecilosclerida, Halichondriidae, Suberitidae, and Trachycladus. Among numerous results: (1) Spirophorina and its family Tetillidae are paraphyletic with respect to a strongly supported Astrophorina within Tetractinellida; (2) Agelasida is the earliest diverging lineage within the second clade listed above; and (3) Merlia and Desmacella appear to be the earliest diverging lineages of Poecilosclerida. PMID- 23793550 TI - Usefulness of 10 genomic regions in soybean associated with sudden death syndrome resistance. AB - Sudden death syndrome (SDS) is an important soybean [Glycine max (L) Merrill] disease caused by the soilborne fungus Fusarium virguliforme. Currently, 14 quantitative trait loci (QTL) had been confirmed associated with resistance or tolerance to SDS. The objective of the study was to evaluate usefulness of 10 of these QTL in controlling disease expression. Six populations were developed providing a total of 321 F2-derived lines for the study. Recombinant inbred lines (RIL) used as parents were obtained from populations of 'Essex' * 'Forrest' (EF), 'Flyer' * 'Hartwig' (FH), and 'Pyramid' * 'Douglas' (PD). Disease resistance was evaluated in the greenhouse at three different planting times, each with four replications, using sorghum infested with F. virguliforme homogeneously mixed in the soil (Luckew et al., Crop Sci 52:2215-2223, 2012). Four disease assessment criteria-foliar disease incidence (DI), foliar leaf scorch disease severity (DS), area under the disease progress curve (AUDPC), and root rot severity-were used. QTL were identified in more than one of the disease assessment criteria, mainly associated with lines in the most resistant categories. Five QTL (qRfs4, qRfs5, qRfs7, qRfs12, and Rfs16) were associated with at least one of the disease assessments across multiple populations. Of the five, qRfs4 was associated with DI, AUDPC, and root rot severity, and Rfs16 with AUDPC and root rot severity. The findings suggest it may be possible for plant breeders to focus on stacking a subset of the previously identified QTL to improve resistance to SDS in soybean. PMID- 23793551 TI - Ectopic pregnancy: a review. AB - PURPOSE: Ectopic pregnancy (EP) presents a major health problem for women of child-bearing age. EP refers to the pregnancy occurring outside the uterine cavity that constitutes 1.2-1.4 % of all reported pregnancies. All identified risk factors are maternal: pelvic inflammatory disease, Chlamydia trachomatis infection, smoking, tubal surgery, induced conception cycle, and endometriosis. These developments have provided the atmosphere for trials using methotrexate as a non-surgical treatment for EP. The diagnosis measure of EP is serum human chorionic gonadotropin, urinary hCGRP/i-hCG, progesterone measurement, transvaginal ultrasound scan, computed tomography, vascular endothelial growth factor, CK, disintegrin and metalloprotease-12 and hysterosalpingography. The treatment option of EP involves surgical treatment by laparotomy or laparoscopy, medical treatment is usually systemic or through local route, or by expectant treatment. RESULTS: It was concluded that review data reflect a decrease in surgical treatment and not an actual decline in EP occurrence so that further new avenues are needed to explore early detection of the EP. PMID- 23793552 TI - Hierarchical neural encoding of temporal regularity in the human auditory cortex. AB - Temporal regularity provides an important cue for the identification of natural sounds. Here, we measured auditory evoked cortical magnetic fields to investigate the neural processing of temporal regularity that cannot be tonotopically represented in the auditory periphery. Auditory steady state responses (ASSR) and sustained fields (SF) elicited by 40 Hz amplitude modulated periodic and non periodic noises were analyzed. Periodic noises of 40-, 20-, and 5-Hz were prepared in the form of repeating frozen noises where the same noise segment appears at either each period (40 Hz), every second period (20 Hz), or every eighth period (5 Hz) of amplitude modulation. Compared to non-periodic white noises, periodic noises with repetition rates of 5-, 20-, and 40-Hz caused significantly increased SF amplitudes in both hemispheres. ASSR amplitudes were significantly enhanced for 20- and 40-Hz periodic noises in the right hemisphere while no enhancement was observed for periodic noises in the left hemisphere. The observed variation of the regularity effect between evoked response components and hemispheres may reflect the differences in the temporal integration window lengths adopted between ASSR and SF generators and also between the right and left auditory pathways. PMID- 23793553 TI - Negative BOLD response to interictal epileptic discharges in focal epilepsy. AB - In EEG-fMRI studies, BOLD responses related to interictal epileptic discharges (IEDs) are most often the expected positive response (activation) but sometimes a surprising negative response (deactivation). The significance of deactivation in the region of IED generation is uncertain. The aim of this study was to determine if BOLD deactivation was caused by specific IED characteristics. Among focal epilepsy patients who underwent 3T EEG-fMRI from 2006 to 2011, those with negative BOLD having a maximum t-value in the IED generating region were selected. As controls, subjects with maximum activation in the IED generating region were selected. We established the relationship between the type of response (activation/deactivation) and (1) presence of slow wave in the IEDs, (2) lobe of epileptic focus, (3) occurrence as isolated events or bursts, (4) spatial extent of the EEG discharge. Fifteen patients with deactivation and 15 with activation were included. The IEDs were accompanied by a slow wave in 87 % of patients whose primary BOLD was a deactivation and only in 33 % of patients with activation. In the deactivation group, the epileptic focus was more frequently in the posterior quadrant and involved larger cortical areas, whereas in the activation group it was more frequently temporal. IEDs were more frequently of long duration in the deactivation group. The main factor responsible for focal deactivations is the presence of a slow wave, which is the likely electrographic correlate of prolonged inhibition. This adds a link to the relationship between electrophysiological and BOLD activities. PMID- 23793554 TI - Resveratrol repressed viability of U251 cells by miR-21 inhibiting of NF-kappaB pathway. AB - Resveratrol (RSV), a polyphenol, is known to play an important role in inhibiting proliferation and inducing apoptosis of glioma cells. The aim of this study was to explore the mechanism of RSV on U251 cells apoptosis. RSV showed a dose dependent decrease in U251 cell viability. It could reduce IkappaB phosphorylation, nuclear P65 protein levels and NF-kappaB transcriptional activity, which suggested that signaling pathway are involved in RSV-induced apoptosis. In addition, RSV could inhibit miR-21 expression and down-regulation of miR-21 expression could suppress NF-kappaB activity. Interestingly, over expression of miR-21 can reverse the effect of RSV on NF-kappaB activity and apoptosis in U251 cells. These results suggest that RSV can effectively induce apoptosis of U251 cells and modulation of miR-21 possibly contributes to this antitumor action. PMID- 23793556 TI - Studying and addressing urban immigrant restaurant worker health and safety in San Francisco's Chinatown district: a CBPR case study. AB - With its emphasis on empowerment, individual and community capacity building, and translating research findings into action, community-based participatory research (CBPR) may be particularly advantageous in work with urban immigrant populations. This paper highlights eight ways in which CBPR has been shown to add value to work with urban underserved communities. It then describes the background, context, and methods of an ecological CBPR project, the Chinatown Restaurant Worker Health and Safety Study, conducted in San Francisco, California, and draws on study processes and outcomes to illustrate each of the eight areas identified. Challenges of using CBPR, particularly with urban immigrant populations, briefly are described, drawing again on the Chinatown study to provide illustrative examples. We discuss lessons learned, through this and other studies, for the effective use of CBPR with urban immigrant populations. We conclude that despite its challenges, this transdisciplinary, community-partnered and action-oriented approach to inquiry can make substantial contributions to both the processes and the outcomes of the research. PMID- 23793555 TI - Understanding plant defence responses against herbivore attacks: an essential first step towards the development of sustainable resistance against pests. AB - Plant-herbivore relationships are complex interactions encompassing elaborate networks of molecules, signals and strategies used to overcome defences developed by each other. Herbivores use multiple feeding strategies to obtain nutrients from host plants. In turn, plants respond by triggering defence mechanisms to inhibit, block or modify the metabolism of the pest. As part of these defences, herbivore-challenged plants emit volatiles to attract natural enemies and warn neighbouring plants of the imminent threat. In response, herbivores develop a variety of strategies to suppress plant-induced protection. Our understanding of the plant-herbivore interphase is limited, although recent molecular approaches have revealed the participation of a battery of genes, proteins and volatile metabolites in attack-defence processes. This review describes the intricate and dynamic defence systems governing plant-herbivore interactions by examining the diverse strategies plants employ to deny phytophagous arthropods the ability to breach newly developed mechanisms of plant resistance. A cornerstone of this understanding is the use of transgenic tools to unravel the complex networks that control these interactions. PMID- 23793557 TI - Prognosis of chronic low back pain in patients presenting to a private community based group exercise program. AB - PURPOSE: To examine the prognosis and prognostic factors for patients with chronic low back pain presenting to a private, community-based, group exercise program. METHODS: A total of 118 consecutive patients with chronic LBP were recruited. Baseline assessments included socio-demographic characteristics, back pain history and clinical examination findings. Primary outcome measures were pain intensity and disability at 3, 6 and 12 months. Potential prognostic factors to predict pain intensity and disability at 12 months were assessed using a multivariate regression model. RESULTS: 112 (95 %) participants were followed up at 12 months. The majority of participants were female (73 %), had high educational levels (82 %) and resided in suburbs with a high socio-economic status (99 %). Pain intensity improved markedly during the first 6 months (35 %) with further minimal reductions up to 12 months (39 %). Interestingly, disability improved to a greater degree than pain (48 % improvement at 6 months) and continued to improve throughout the 12 months (60 %). Baseline pain intensity accounted for 10 % of the variance in the 1 year pain outcomes. Duration of current episode, baseline disability and educational level accounted for 15 % of the variation in disability at 12 months. CONCLUSIONS: During a period of 12 months, patients with chronic LBP presenting to a private, community-based, group exercise program improved markedly, with greater improvements in disability than pain. The predictors investigated accounted for only 10 and 15 % of pain and disability outcomes, respectively. PMID- 23793558 TI - Systematic review of microendoscopic discectomy for lumbar disc herniation. AB - STUDY DESIGN: Systematic review. OBJECTIVE: To search and analyse randomised controlled trials (RCTs) published since the Cochrane review by Gibson and Waddell (2007) comparing microendoscopic discectomy (MED) with open discectomy (OD) or microdiscectomy (MD) and to assess whether MED improves patient-reported outcomes. Discectomy for symptomatic herniated lumbar discs is an effective operative treatment. A number of operative techniques exist including OD, MD, and MED. A 2007 Cochrane review identified OD as an effective treatment for symptom improvement, and found sufficient evidence for MD. However, evidence for MED was lacking. METHODS: A systematic review of Medline and Embase was carried out. Aiming to identify RCTs carried out after 2007, which compared OD with MD and MED which reported the Oswestry disability index (ODI) as an outcome. RESULTS: Four RCTs were identified. None of the studies found a significant difference in the ODI scores between study groups at any time point. Three studies compared MED to OD and one compared OD, MD, and MED. The largest study reported an increased number of severe complications in the MED group. CONCLUSIONS: There is some evidence to suggest that MED performed by surgeons skilled in the technique in tertiary referral centres is as effective as OD. PMID- 23793559 TI - Pervasive refusal syndrome (PRS) 21 years on: a re-conceptualisation and a renaming. AB - Twenty-one years ago, Lask and colleagues first described pervasive refusal syndrome (PRS) as a child's "dramatic social withdrawal and determined refusal to walk, talk, eat, drink, or care for themselves in any way for several months" in the absence of an organic explanation. PRS has been conceptualised in a variety of ways since then. These have included a form of post-traumatic stress disorder, learnt helplessness, 'lethal mothering', loss of the internal parent, apathy or the 'giving-up' syndrome, depressive devitalisation, primitive 'freeze', severe loss of activities of daily living and 'manipulative' illness, meaning the possibility that the children have been drugged to increase chances of asylum in asylum-seeking families. Others have insisted that PRS is simply depression, conversion disorder, catatonia or a factitious condition. This paper reviews these conceptualisations, explores some of the central complexities around PRS and proposes a neurobiological explanatory model, based upon autonomic system hyper-arousal. It touches upon the clinical implications and suggests a new name for the condition reflecting what we believe to be a more sophisticated understanding of the disorder than was available when it was first described. PMID- 23793560 TI - Comment on the paper "Pervasive Refusal Syndrome (PRS) 21 years on-a reconceptualization and renaming" by Ken Nunn, Bryan Lask and Isabel Owen. PMID- 23793561 TI - Walking in the woods with quantum chemistry--applications of quantum chemical calculations in natural products research. AB - This Highlight describes applications of quantum chemical calculations to problems in natural products chemistry, including the elucidation of natural product structures (distinguishing between constitutional isomers, distinguishing between diastereomers, and assigning absolute configuration) and determination of reasonable mechanisms for their formation. PMID- 23793562 TI - Health care disparities in the treatment of colorectal cancer. AB - OPINION STATEMENT: Treatment of colorectal carcinoma remains challenging, especially in patients with recurrent or metastatic disease. Despite advances in screening and treatment of this cancer, health care disparities remain one of the major yet amendable factors that can lead to differences in outcomes. As clinicians, we need to be aware of such disparities to better tailor our screening and treatment interventions for our patients. Knowing that socioeconomic status, educational status, and personal beliefs contribute to racial disparities in this disease, as clinicians we should strive to know our patients and their beliefs to help minimize this discrepancy. Additionally, we need to maintain and advance our knowledge by keeping up with all clinical and translational research in the field and create strategies to increase enrollment of racial minorities in clinical trials. While conventional chemotherapies continue to play a vital role, it is becoming more and more evident that treatment strategies need to be personalized. Understanding the molecular biology of cancer has changed the landscape of new therapies. Future research needs to be directed towards understanding genetic, biological, and pharmacogenetic and genomic contributors to the development of disease and treatment responses. PMID- 23793563 TI - Rothia marina sp. nov., isolated from an intertidal sediment of the South China Sea. AB - A novel non-sporulating, non-motile, catalase-positive, oxidase-negative, facultatively anaerobic, Gram-positive coccus, designated strain JSM 078151(T), was isolated from an intertidal sediment sample collected from Naozhou Island in the South China Sea, China. Growth was found to occur in the presence of 0-15 % (w/v) NaCl (optimum 0.5-3 % (w/v) NaCl), at pH 6.5-10.5 (optimum pH 7.0-8.0) and at 5-35 degrees C (optimum 25-30 degrees C). The peptidoglycan type was determined to be A3a, containing lysine, glutamic acid and alanine. The major cellular fatty acid identified was anteiso-C15:0 and the predominant menaquinones are MK-7 and MK-8. The polar lipids were found to consist of diphosphatidylglycerol, phosphatidylglycerol, glycolipid and one unidentified phospholipid. The genomic DNA G+C content of strain JSM 078151(T) was determined to be 55.2 mol%. A phylogenetic analysis based on 16S rRNA gene sequence comparisons revealed that strain JSM 078151(T) should be assigned to the genus Rothia, and was most closely related to Rothia nasimurium CCUG 35957(T) (98.3 % sequence similarity), followed by Rothia amarae J18(T) (97.5 %) and Rothia terrae L-143(T) (97.3 %). A combination of phylogenetic analysis, DNA-DNA relatedness values, phenotypic characteristics and chemotaxonomic data supports the suggestion that strain JSM 078151(T) represents a novel species of the genus Rothia, for which the name Rothia marina sp. nov. is proposed. The type strain is JSM 078151(T) (= DSM 21080(T) = KCTC 19432(T)). PMID- 23793564 TI - Short-term effect of magnesium implantation on the osteomyelitis modeled animals induced by Staphylococcus aureus. AB - Pure magnesium (Mg) granules were implanted into the tibial medullary cavity of osteomyelitis modeled animals after debridement, and the animals without implant were taken as the control group. The antibacterial and osteogenic effects on bone tissue during Mg degradation were evaluated through detecting Mg ions, counting bacteria culture in peripheral blood, histology and iconography. The results showed that there was no significant difference for the concentration of serum Mg between the preoperative and postoperative animals within 5 weeks, maintaining in the normal range, and the number of bacteria in bone tissue of the Mg implant group was significantly lower than that of the control group. Mg implantation showed good biocompatibility no harmful to the liver, spleen, kidney and other organs in the modeled animals. In addition, the formation rate of new bone tissues around the implanted Mg was faster, indicating that the degradation of Mg could also promote the osteogenic process with good biocompatibility. PMID- 23793565 TI - Adipose-derived stem cells could sense the nano-scale cues as myogenic differentiating factors. AB - Microenvironmental cues, such as surface topography and substrate stiffness, may affect stem cells adhesion, morphology, alignment, proliferation and differentiation. Adipose derived stem cells (ASCs) have attracted considerable interest in regenerative medicine due to their easy isolation, extensive in vitro expandability and ability to differentiate along a number of different tissue specific lineages. The aim of this work was to investigate ASCs adhesion, alignment and differentiation into myogenic lineage on nanofibrous polymeric scaffolds with anisotropic topography. Nanostructured scaffolds with randomized or parallel fibers were fabricated by electrospinning using polycaprolactone (PCL) and the polycarbonate-urethane ChronoFlex AL 80A (CFAL). Cells expressed myosin (fast skeletal) and tropomyosin in all surface topographies 7 days after seeding but myotube formation was only observed on CFAL scaffolds and only few myotubes were formed on PCL scaffolds. The different cell behavior could be ascribed to two main parameters: fibers dimensions and fibers orientation of the substrates that could result in a better myotube formation on CFAL scaffolds. PMID- 23793566 TI - Transferrin-conjugated, fluorescein-loaded magnetic nanoparticles for targeted delivery across the blood-brain barrier. AB - The blood-brain barrier (BBB) restricts the delivery of many potentially important therapeutic agents for the treatment of brain disorders. An efficient strategy for brain targeted delivery is the utilization of the targeting ligand conjugated nanoparticles to trigger the receptor-mediated transcytosis. In this study, transferrin (Tf) was employed as a brain targeting ligand to functionalize the fluorescein-loaded magnetic nanoparticles (FMNs). The Tf conjugated FMNs (Tf FMNs) were characterized by transmission electron microscopy, thermal gravimetric analysis, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy. Using fluorescein as an optical probe, the potential of Tf-FMNs as brain targeting drug carriers was explored in vivo. It was demonstrated that Tf FMNs were able to cross the intact BBB, diffuse into brain neurons, and distribute in the cytoplasm, dendrites, axons, and synapses of neurons. In contrast, magnetic nanoparticles without Tf conjugation cannot cross the BBB efficiently under the same conditions. Therefore, Tf-FMNs hold great potential in serving as an efficient multifunctional platform for the brain-targeted theranostics. PMID- 23793567 TI - Monitoring the impact of urban effluents on mineral contents of water and sediments of four sites of the river Ravi, Lahore. AB - We assessed the impact of urban effluents on the concentrations of selected minerals (Cd, Cr, Cu, Fe, Pb, Zn, Mn, Ni, and Hg) in river Ravi before and after its passage through Lahore city. Water and sediment samples were collected from three lowly to highly polluted downstream sites (Shahdera (B), Sunder (C), and Balloki (D)) alongside the least polluted upstream site (Siphon (A)) during high and low river flow seasons. All the mineral concentrations increased up to site C but stabilized at site D, showing some recovery as compared to the third sampling site. The trend of mean mineral concentration was significantly higher during the low than the high flow season at all the sites. The mean Hg concentrations approached 0.14 and 0.12 mg/l at site A which increased (%) up to 107 and 25% at site B, 1,700 and 1,317% at site C, and 1,185 and 1,177% at site D during low and high river flows, respectively. All mineral concentrations were much higher in the sediment than the water samples. Mean Cd (917%), Cr (461%), Cu (300%), Fe (254%), Pb (179%), Zn (170%), Mn (723%), Ni (853%), and Hg (1,699%) concentrations were higher in riverbed sediments sampled from site C in comparison with the sample collected at site A during low flow season. The domestic and industrial discharges from Lahore city have created undesirable water qualities during the low river flow season. As majority of the mineral levels in the river Ravi were higher than the permissible and safe levels, this is of immediate concern for riverine fish consumers and the users of water for recreation and even irrigation. The use of these waters may pose health risks, and therefore, urgent intervention strategies are needed to minimize river water pollution and its impact on fish-consuming communities of this study area and beyond. PMID- 23793568 TI - Sensible guidelines for clinical trials: are current European regulations 'a gift to America'? Interview by Barry Shurlock. PMID- 23793570 TI - Age-related micro-RNA abundance in individual C. elegans. AB - Non-coding small RNAs of the micro-RNA class (miRNA) are conserved regulators of gene function with a broad impact on biological processes. We screened miRNA levels for age-related changes in individual worms and investigated their influence on the lifespan of the nematode C. elegans. We measured the abundance of 69 miRNAs expressed in individual animals at different ages with over thirty five thousand discrete quantitative nano-fluidic polymerase chain reactions. We found that miRNA abundance was highly variable between individual worms raised under identical conditions and that expression variability generally increased with age. To identify expression differences associated with either reproductive or somatic tissues, we analyzed wild type and mutants that lacked germlines. miRNAs from the mir-35-41 cluster increased in abundance with age in wild type animals, but were nearly absent from mutants lacking a germline, suggesting their age-related increase originates from the germline. Most miRNAs with age-dependent levels did not have a major effect on lifespan, as corresponding deletion mutants exhibited wild-type lifespans. The major exception to this was mir-71, which increased in abundance with age and was required for normal longevity. Our genetic characterization indicates that mir-71 acts at least partly in parallel to insulin/IGF like signals to influence lifespan. PMID- 23793571 TI - Seroprevalence of antibodies against measles, rubella, mumps, varicella-zoster, and B. Pertussis in young adults of Madrid, Spain. AB - In recent years, there has been an increase in the number of cases of certain immunopreventable diseases in our country. A high proportion of these have been recorded among the young adult population. The aim of this study was to determine the seroprevalence of antibodies against immunopreventable diseases with the greatest health impacts on the young adult population (19-39 y of age) in Madrid. We collected a total of 1,153 serum samples from healthy volunteers undergoing routine medical visits and used ELISA to determine the presence of IgG antibodies against measles, rubella, mumps, and varicella zoster, as well as Bordetella pertussis. The Pearson's chi(2) test was used to compare prevalences, the Mann Whitney U test was used to compare means, and the Kruskal-Wallis test was applied for variables with more than 2 categories. Statistical significance was achieved with p values of<0.05. The global prevalence of antibodies was 92.1% for measles, 94.4% for rubella, 88.3% for mumps, 92.8% for varicella zoster, and 70.2% for B. pertussis. No statistically significant differences were found between genders. The prevalence of antibodies against measles was more than 95% in the group of individuals born after 1986, and the percentage of individuals susceptible to rubella was less than 5% in women born after 1986. In spite of adequate vaccination coverage, in our region, a population of young adults exists who have not achieved the objectives of the WHO for the elimination of measles and congenital rubella syndrome. PMID- 23793573 TI - How the EEA came to America. AB - Surgical stapling instruments, a revolutionary concept in surgical technique, were introduced in the United States in 1967. Notably absent in the new family of American instruments was the circular stapler (EEA) for end-to-end intestinal anastomosis. This strange omission was corrected a decade later. The EEA is now one of the most widely used stapling instruments in the surgical armamentarium. PMID- 23793572 TI - Identifying genetic diversity of avirulence genes in Leptosphaeria maculans using whole genome sequencing. AB - Next generation sequencing technology allows rapid re-sequencing of individuals, as well as the discovery of single nucleotide polymorphisms (SNPs), for genomic diversity and evolutionary analyses. By sequencing two isolates of the fungal plant pathogen Leptosphaeria maculans, the causal agent of blackleg disease in Brassica crops, we have generated a resource of over 76 million sequence reads aligned to the reference genome. We identified over 21,000 SNPs with an overall SNP frequency of one SNP every 2,065 bp. Sequence validation of a selection of these SNPs in additional isolates collected throughout Australia indicates a high degree of polymorphism in the Australian population. In preliminary phylogenetic analysis, isolates from Western Australia clustered together and those collected from Brassica juncea stubble were identical. These SNPs provide a novel marker resource to study the genetic diversity of this pathogen. We demonstrate that re sequencing provides a method of validating previously characterised SNPs and analysing differences in important genes, such as the disease related avirulence genes of L. maculans. Understanding the genetic characteristics of this devastating pathogen is vital in developing long-term solutions to managing blackleg disease in Brassica crops. PMID- 23793574 TI - Modified trocar with laser diode for instrument guidance. AB - Laparoscopic instruments that are newly inserted into trocars are initially outside the surgeon's endoscopic field of view. This can make it difficult to accurately position the instrument at the operative site and presents a potential risk to patients since the tip of the instrument could potentially perforate organs and blood vessels while it is advanced blindly. To solve this problem, I have designed a trocar that incorporates a laser pointer to guide laparoscopic instruments while they are outside the endoscopic field of view. The laser dot is projected along the long axis of the trocar. This allows the surgeon to instantly determine the direction and target of the introduced instrument. Furthermore, the projected laser dot serves as evidence of an unobstructed path from the trocar to the target. This modification improves safety in laparoscopic surgery. PMID- 23793575 TI - Temporary endoscopic metallic stent for idiopathic esophageal achalasia. AB - Idiopathic achalasia is a motor disorder of the esophagus of unknown etiology caused by loss of motor neurons determining an altered motility. It may determine severe symptoms such as progressive dysphagia, regurgitations, and pulmonary aspirations. Many therapeutic options may be offered to patients with achalasia, from surgery to endoscopic treatments such as pneumatic dilation, botulinum injection, peroral endoscopic myotomy, or endoscopic stenting. Recently, temporary placement of a stent was proposed by Cheng as therapy for achalasia disorders, whereas no Western authors have dealt with it up to date. The present study reports our preliminary experience in 7 patients with achalasia treated with a temporary stent. Partially covered self-expanding metallic stents (Micro Tech, Nanjin, China) 80 mm long and 30 mm wide were placed under fluoroscopic control and removed after 6 days. Clinical follow-up was scheduled to check endoscopic success, symptoms release, and complications. The placement and the removal of the stents were obtained in all patients without complications. Mean clinical follow-up was 19 months. Five out of 7 patients referred total symptoms release and 2 experienced significant improvement of dysphagia. The procedure was not time consuming and was safe; no mild or severe complications were registered. In conclusion, our results may suggest a possible safe and effective endoscopic alternative treatment in patients with achalasia; however, further larger studies are necessary to confirm these promising, but very preliminary, data. PMID- 23793576 TI - Hybrid video-assisted thoracic surgery with segmental-main bronchial sleeve resection for non-small cell lung cancer. AB - BACKGROUND: The purpose of the current study is to present the clinical and surgical results in patients who underwent hybrid video-assisted thoracic surgery with segmental-main bronchial sleeve resection. METHODS: Thirty-one patients, 27 men and 4 women, underwent segmental-main bronchial sleeve anastomoses for non small cell lung cancer between May 2004 and May 2011. RESULTS: Twenty-six (83.9%) patients had squamous cell carcinoma, and 5 patients had adenocarcinoma. Six patients were at stage IIB, 24 patients at stage IIIA, and 1 patient at stage IIIB. Secondary sleeve anastomosis was performed in 18 patients, and Y-shaped multiple sleeve anastomosis was performed in 8 patients. Single segmental bronchiole anastomosis was performed in 5 cases. The average time for chest tube removal was 5.6 days. The average length of hospital stay was 11.8 days. No anastomosis fistula developed in any of the patients. The 1-, 2-, and 3-year survival rates were 83.9%, 71.0%, and 41.9%, respectively. CONCLUSION: Hybrid video-assisted thoracic surgery with segmental-main bronchial sleeve resection is a complex technique that requires training and experience, but it is an effective and safe operation for selected patients. PMID- 23793577 TI - Prospective evaluation of intra-observer variability of the hydronephrosis index in sonographic examination of 44 patients with acute renal colic. AB - PURPOSE: The aim of our prospective designed study was to confirm the intra observer agreement of assessments of the hydronephrosis index (HI) with a sonographic technique that potentially provides additional information in patients with acute renal colic (ARC). METHODS: Sonographic measurement of HI and valuation of common clinical criteria were performed in 44 consecutive patients presenting with unilateral stone-related ARC. HI of colic side was recorded twice in predefined time intervals. Intra-observer agreement was evaluated with the Spearman's rank correlation/rho (rho) for attributive-metric characteristics. Data of HI-measurement on the colic side were compared with data of the unaffected side using t test. RESULTS: Intra-observer agreement was significant for HI in the colic side (rho = 0.918, p < 0.001) and in the unaffected side (rho = 0.826, p < 0.001). The mean HI between colic and unaffected side differed significantly on the first evaluation (85.2 vs. 93.7, respectively; p < 0.001) and on the second evaluation (85.1 vs. 93.6, respectively; p < 0.001) as well. CONCLUSIONS: The HI method is a slightly feasible examination method in patients presenting with stone-related renal colic. Moreover, it offers a solid discrimination between obstruction and non-obstruction. Our prospective trial illustrates HI as a reproducible method with a high-grade intra-observer agreement. However, potential change of values under medical expulsive therapy and coherency with the functionality of the obstructed kidney may lead to bias and therefore remain to be analyzed. Further studies to specify exact thresholds for this method and to state our findings are required. PMID- 23793578 TI - Field-level financial assessment of contour prairie strips for enhancement of environmental quality. AB - The impacts of strategically located contour prairie strips on sediment and nutrient runoff export from watersheds maintained under an annual row crop production system have been studied at a long-term research site in central Iowa. Data from 2007 to 2011 indicate that the contour prairie strips utilized within row crop-dominated landscapes have greater than proportionate and positive effects on the functioning of biophysical systems. Crop producers and land management agencies require comprehensive information about the Best Management Practices with regard to performance efficacy, operational/management parameters, and the full range of financial parameters. Here, a farm-level financial model assesses the establishment, management, and opportunity costs of contour prairie strips within cropped fields. Annualized, depending on variable opportunity costs the 15-year present value cost of utilizing contour prairie strips ranges from $590 to $865 ha(-1) year(-1) ($240-$350 ac(-1) year(-1)). Expressed in the context of "treatment area" (e.g., in this study 1 ha of prairie treats 10 ha of crops), the costs of contour prairie strips can also be viewed as $59 to about $87 per treated hectare ($24-$35 ac(-1)). If prairie strips were under a 15-year CRP contract, total per acre cost to farmers would be reduced by over 85 %. Based on sediment, phosphorus, and nitrogen export data from the related field studies and across low, medium, and high land rent scenarios, a megagram (Mg) of soil retained within the watershed costs between $7.79 and $11.46 mg(-1), phosphorus retained costs between $6.97 and $10.25 kg(-1), and nitrogen retained costs between $1.59 and $2.34 kg(-1). Based on overall project results, contour prairie strips may well become one of the key conservation practices used to sustain US Corn Belt agriculture in the decades to come. PMID- 23793579 TI - Metallosupramolecular grid complexes: towards nanostructured materials with high tech applications. AB - Metallosupramolecular grid complexes (hereafter referred to as metallogrids) are well-defined oligonuclear metal ion complexes involving essentially planar arrays of the metal ions sited at the points of intersection of square or rectangular metallogrids and possess a variety of interesting optical, electronic, magnetic and supramolecular properties. Herein I aim to give the reader an overview of the synthesis, properties and potential for a variety of high-tech applications of metallogrids. PMID- 23793580 TI - Evaluation of the potential for interspecific hybridization between Camelina sativa and related wild Brassicaceae in anticipation of field trials of GM camelina. AB - Camelina (Camelina sativa (L.) Crantz) is a re-emergent oilseed crop that is also becoming important as a model for applied projects based on studies in Arabidopsis thaliana, since the two species are closely related members of the tribe Camelineae of the Brassicaeae. Since camelina can be transformed genetically by floral dip, genetically modified (GM) camelina is being created in many laboratories, and small-scale field trials are already being conducted in the US and Canada. Although camelina does not cross-fertilize Brassica crop species, such as oilseed rape, nothing was known about its ability to cross with other members of the tribe Camelineae, which in addition to arabidopsis includes the widespread weed, shepherd's purse (Capsella bursa-pastoris). We have tested the ability of camelina to cross with arabidopsis and C. bursa-pastoris, as well as with the more distantly related Cardamine hirsuta, tribe cardamineae. No seeds were produced in crosses with arabidopsis, and a few seeds were obtained in crosses with C. hirsuta, but the embryos aborted at an early stage of development. A few seeds were also obtained in crosses with C. bursa-pastoris, which germinated to produce plants of a phenotype intermediate to that of the parents, but the hybrids were both male and female sterile. Therefore, the likelihood of pollen-mediated gene flow from camelina to these related species is low. PMID- 23793581 TI - Caveolin-1 deficiency protects against mesangial matrix expansion in a mouse model of type 1 diabetic nephropathy. AB - AIMS/HYPOTHESIS: Glomerular matrix protein accumulation, mediated largely by resident mesangial cells (MCs), is central to the pathogenesis of diabetic nephropathy. We previously showed that caveolin (CAV)-1/caveolae mediate matrix upregulation by MCs in response to high glucose and TGFbeta, two important pathogenic mediators of diabetic glomerular sclerosis. Here, we evaluated the in vivo role of CAV-1/caveolae in the development of diabetic nephropathy. METHODS: Diabetes was induced in Cav1-knockout (KO) mice and their wild-type (WT) counterparts by streptozotocin injection. After 10 months, kidneys were evaluated for the development of nephropathy, including glomerular sclerosis and upregulation of matrix proteins. Parallel experiments assessing glucose-induced matrix upregulation were carried out in MCs isolated from KO mice. RESULTS: KO diabetic mice developed hyperglycaemia and renal hypertrophy, but were protected from developing albuminuria and glomerular sclerosis compared with WT mice. KO mice were significantly protected from the upregulation of glomerular collagen I, fibronectin, connective tissue growth factor (CTGF) and TGFbeta. In vitro, glucose induced collagen I A1 promoter activation and collagen I, fibronectin and CTGF protein upregulation in WT but not KO MCs. Re-expression of Cav1 in KO cells restored this response. CONCLUSIONS/INTERPRETATION: Cav1 deletion rendered significant protection from glomerular matrix accumulation and albuminuria in a mouse model of type 1 diabetes. These studies provide a foundation for the development of renal-targeted interference with CAV-1/caveolae as a novel approach to the treatment of diabetic nephropathy. PMID- 23793582 TI - Impacts of simulated climate change and fungal symbionts on survival and growth of a foundation species in sand dunes. AB - For many ecosystems, one of the primary avenues of climate impact may be through changes to foundation species, which create habitats and sustain ecosystem services. For plants, microbial symbionts can often act as mutualists under abiotic stress and may mediate foundational plant responses to climate change. We manipulated the presence of endophytes in Ammophila breviligulata, a foundational sand dune species, to evaluate their potential to influence plant responses to climate change. We simulated projected climate change scenarios for temperature and precipitation using a growth chamber experiment. A 5 degrees C increase in temperature relative to current climate in northern Michigan reduced A. breviligulata survival by 45 %. Root biomass of A. breviligulata, which is critical to dune stabilization, was also strongly reduced by temperature. Plants inoculated with the endophyte had 14 % higher survival than endophyte-free plants. Contrary to our prediction, endophyte symbiosis did not alter the magnitude or direction of the effects of climate manipulations on A. breviligulata survival. However, in the absence of the endophyte, an increase in temperature increased the number of sand grains bound by roots by 80 %, while in symbiotic plants sand adherence did not significantly respond to temperature. Thus, plant-endophyte symbiosis actually negated the benefits in ecosystem function gained under a warmer climate. This study suggests that heat stress related to climate change in the Great Lakes may compromise the ability of A. breviligulata to stabilize dune ecosystems and reduce carbon storage and organic matter build-up in these early-successional systems due to reduced plant survival and root growth. PMID- 23793583 TI - A novel mutation of the LMNA gene in a family with dilated cardiomyopathy, conduction system disease, and sudden cardiac death of young females. AB - The LMNA gene, which encodes the nuclear envelope protein lamin A/C, is considered to be the most common autosomal disease gene associated with familial dilated cardiomyopathy. To date, each mutation of the LMNA gene has been associated with a specific disease phenotype. Clinical data, family histories, and blood samples were collected from 27 biological members of a family with dilated cardiomyopathy, prominently occurring as heart failure and conduction system disease with a high incidence of sudden cardiac death in young females. Twelve exons of the LMNA gene were screened for nucleotide alterations. A novel insertion mutation (nucleotide 1526insA, amino acid T510Y) in exon nine of the LMNA gene was identified in seven subjects (7/27, 25.9%). This reveals that the LMNA gene insertion mutation (T510Y frameshift mutation) can cause dilated cardiomyopathy, conduction system disease, and sudden cardiac death without skeletal myopathy, clinically manifested with early onset, severe symptoms, and poor prognosis. PMID- 23793584 TI - Requirements for the structured recording of surgical device data in the digital operating room. AB - PURPOSE: Due to the increasing complexity of the surgical working environment, increasingly technical solutions must be found to help relieve the surgeon. This objective is supported by a structured storage concept for all relevant device data. METHODS: In this work, we present a concept and prototype development of a storage system to address intraoperative medical data. The requirements of such a system are described, and solutions for data transfer, processing, and storage are presented. In a subsequent study, a prototype based on the presented concept is tested for correct and complete data transmission and storage and for the ability to record a complete neurosurgical intervention with low processing latencies. In the final section, several applications for the presented data recorder are shown. RESULTS: The developed system based on the presented concept is able to store the generated data correctly, completely, and quickly enough even if much more data than expected are sent during a surgical intervention. CONCLUSIONS: The Surgical Data Recorder supports automatic recognition of the interventional situation by providing a centralized data storage and access interface to the OR communication bus. In the future, further data acquisition technologies should be integrated. Therefore, additional interfaces must be developed. The data generated by these devices and technologies should also be stored in or referenced by the Surgical Data Recorder to support the analysis of the OR situation. PMID- 23793585 TI - A single-cell perspective on non-growing but metabolically active (NGMA) bacteria. AB - A long-standing and fundamental problem in microbiology is the non-trivial discrimination between live and dead cells. The existence of physically intact and possibly viable bacterial cells that fail to replicate during a more or less protracted period of observation, despite environmental conditions that are ostensibly propitious for growth, has been extensively documented in many different organisms. In clinical settings, non-culturable cells may contribute to non-apparent infections capable of reactivating after months or years of clinical latency, a phenomenon that has been well documented in the specific case of Mycobacterium tuberculosis. The prevalence of these silent but potentially problematic bacterial reservoirs has been highlighted by classical approaches such as limiting culture dilution till extinction of growing cells, followed by resuscitation of apparently "viable but non-culturable" (VBNC) subpopulations. Although these assays are useful to demonstrate the presence of VBNC cells in a population, they are effectively retrospective and are not well suited to the analysis of non-replicating cells per se. Here, we argue that research on a closely related problem, which we shall refer to as the "non-growing but metabolically active" state, is poised to advance rapidly thanks to the recent development of novel technologies and methods for real-time single-cell analysis. In particular, the combination of fluorescent reporter dyes and strains, microfluidic and microelectromechanical systems, and time-lapse fluorescence microscopy offers tremendous and largely untapped potential for future exploration of the physiology of non-replicating cells. PMID- 23793586 TI - Science to Practice: periprocedural myocardial injury: is there a role for cardiac MR imaging? PMID- 23793587 TI - To disclose or not to disclose radiologic errors: should "patient-first" supersede radiologist self-interest? PMID- 23793588 TI - Lung cancer diagnosis: radiologic imaging, histology, and genetics. PMID- 23793589 TI - Breast intervention: how I do it. AB - Breast imaging has undergone many changes since the early years of mammography. Screening mammography is credited with contributing to the substantial decrease in breast cancer mortality through early detection. Screening mammography programs allow depiction of nonpalpable, suspicious findings requiring histologic evaluation, but most of which eventually are proved benign. Widespread acceptance of percutaneous breast biopsy techniques represents the most important practice changing development in breast imaging. The radiologist now plays a vital role not only in the detection and evaluation of breast disease, but also in the diagnosis and management of breast cancer. Descriptions of the advantages of percutaneous breast biopsy and the techniques of performing breast intervention are the focus of this review. PMID- 23793590 TI - MR imaging of cardiac tumors and masses: a review of methods and clinical applications. AB - Cardiac masses are usually first detected at echocardiography. In their further evaluation, cardiac magnetic resonance (MR) imaging has become a highly valuable technique. MR imaging offers incremental value owing to its larger field of view, superior tissue contrast, versatility in image planes, and unique ability to enable discrimination of different tissue characteristics, such as water and fat content, which give rise to particular signal patterns with T1- and T2-weighted techniques. With contrast material-enhanced MR imaging, additional tissue properties such as vascularity and fibrosis can be demonstrated. MR imaging can therefore contribute to the diagnosis of a cardiac mass as well as be used to detail its relationship to other cardiac and extracardiac structures. These assessments are important to plan therapy, such as surgical intervention. In addition, serial MR studies can be used to monitor tumor regression after surgery or chemotherapy. Primary cardiac tumors are very rare; metastases and pseudotumors (eg, thrombus) are much more common. This article provides an overview of cardiac masses and reviews the optimal MR imaging techniques for their assessment. PMID- 23793591 TI - ABR examinations: the why, what, and how. AB - The American Board of Radiology (ABR) has provided certification for diagnostic radiologists and other specialists and subspecialists for more than 75 years. The Board certification process is a tangible expression of the social contract between the profession and the public by which the profession enjoys the privilege of self-regulation and the public is assured that it can expect medical professionals to put patients' interests first, guarantees the competence of practitioners, and guards the public health. A primary tool used by the ABR in fulfilling this responsibility is the secure proctored examination. This article sets forth seven standards based on authoritative sources in the field of psychometrics (the science of mental measurements), and explains in each case how the ABR implements that standard. Readers are encouraged to understand that, despite the multiple opinions that may be held, these standards developed over decades by experts using the scientific method should be the central feature in any discussion or critique of examinations given for the privilege of professional practice and for safeguarding the public well-being. PMID- 23793593 TI - Case 195: chondrosarcoma of the posterior mediastinum. PMID- 23793594 TI - Diagnostic accuracy of CT angiography, intravascular US, and optical frequency domain imaging in the differentiation of advanced coronary plaques. PMID- 23793595 TI - Measurement of solid component in part-solid lesions with a mediastinal window setting? PMID- 23793596 TI - Management of part-solid nodules. PMID- 23793597 TI - The location of the mastoid portion of the facial nerve in patients with congenital aural atresia. AB - In order to investigate the location of the mastoid portion of the facial nerve in patients with congenital aural atresia and to assess its effect on the round window middle ear implant (MEI) transducer implantation approach, 70 patients with unilateral congenital aural atresia were examined by computer tomography (CT). The patients were divided into two groups based on their ages: 44 patients in Group A (2-12 years) and 26 patients in Group B (13-29 years). CT scans were reviewed for each patient. Based on the CT findings, the mastoid portion of the facial nerve's spatial configuration with respect to the oval and round windows was qualitatively recorded. Additionally, the exact location of the facial nerve was measured quantitatively. The results suggested that of the 70 deformed ears, 57 had facial nerves located at the round window, six at the oval window, and seven at the normal site. Of the 70 normal opposite ears, 63 had facial nerves located at the normal site, and the other seven had facial nerves located at the round window. Based on the quantitative measurements, the mastoid portion of the facial nerve was more anteriorly positioned in the deformed ears: 3.44-6.09 mm more anteriorly located in Group A and 4.35-7.41 mm more anteriorly located in Group B. In conclusion, in patients with congenital aural atresia, the dislocation of the facial nerve could have significant effects on the surgical approach to round window MEI transducer implantation. PMID- 23793598 TI - Aqua splint suture technique in isolated zygomatic arch fractures. AB - Various methods have been used to treat zygomatic arch fractures, but no optimal modality exists for reducing these fractures and supporting the depressed bone fragments without causing esthetic problems and discomfort for life. We developed a novel aqua splint and suture technique for stabilizing isolated zygomatic arch fractures. The objective of this study is to evaluate the effect of novel aqua splint and suture technique in isolated zygomatic arch fractures. Patients with isolated zygomatic arch fractures were treated by a single surgeon in a single center from January 2000 through December 2012. Classic Gillies approach without external fixation was performed from January 2000 to December 2003, while the novel technique has been performed since 2004. 67 consecutive patients were included (Classic method, n = 32 and Novel method, n = 35). An informed consent was obtained from all patients. The novel aqua splint and suture technique was performed by the following fashion: first, we evaluated intraoperatively the bony alignment by ultrasonography and then, reduced the depressed fracture surgically using the Gillies approach. Thereafter, to stabilize the fracture and obtain the smooth facial figure, we made an aqua splint that fit the facial contour and placed monofilament nonabsorbable sutures around the fractured zygomatic arch. The novel aqua splint and suture technique showed significantly correlated with better cosmetic and functional results. In conclusion, the aqua splint suture technique is very simple, quick, safe, and effective for stabilizing repositioned zygomatic arch fractures. The aqua splint suture technique can be a good alternative procedure in isolated zygomatic arch fractures. PMID- 23793599 TI - Plasma level of homocysteine associated with severe vertebral fracture in postmenopausal women. AB - The aim of this cross-sectional cohort study was to clarify risk factors for severe vertebral fractures in postmenopausal Japanese women. Subjects were ambulatory volunteers age over 50 years who were recruited from a population of outpatients at a primary care institute. At registration, age, body mass index (BMI), bone mineral density (BMD), and present illness were investigated. Biochemical parameters including urinary levels of type I collagen cross-linked N telopeptides (NTXs), and pentosidine and plasma levels of homocysteine were measured. Values were compared with different fracture grades (grade 0-3). A total of 1,475 postmenopausal women (66.6 +/- 9.0 years) were included in the present study. Distributions of vertebral fracture grades were grade 1, 137 cases (9.3 %); grade 2, 124 cases (8.4 %); and grade 3, 162 cases (11.0 %). Age, BMI, BMD, NTX, pentosidine, and homocysteine were significantly associated with vertebral fracture in unadjusted analysis. In addition, a higher prevalence of hypertension was observed in patients with severe fracture. When comparing vertebral fracture grade 0 versus grade 2-3 by multiple regression analysis, pentosidine and homocysteine levels were a significant risk for moderate/severe vertebral fracture (odds ratio [OR] = 1.17, 95 % confidence interval [CI] 1.00 1.38, p = 0.049; OR = 1.22, 95 % CI 1.03-1.46, p = 0.013). Homocysteine levels were also a significant risk when comparing vertebral fracture grade 0 versus grade 3 (OR = 1.27, 95 % CI 1.04-1.58, p = 0.021). Plasma level of homocysteine was an independent risk for severe vertebral fractures. PMID- 23793600 TI - Unimolecular amplifier: principles of a three-terminal device with power gain. AB - A single molecule composed of three linked moieties can function as an amplifier of electrical current, when certain conditions are met by the molecular orbitals of the three component parts. This device should exhibit power gain at appropriate voltages. In this work, we will explain a plausible mechanism by which this device should work, and present its operating characteristics. In particular, we find that a fundamental requirement for current amplification is to have the LUMO of the central moiety more strongly coupled to a control electrode than it is to the other orbitals in the molecule, while the HOMO of this moiety should be more strongly coupled to the orbitals in the other moieties than it is to the control electrode. PMID- 23793601 TI - Providing access to risk prediction tools via the HL7 XML-formatted risk web service. AB - Cancer risk prediction tools provide valuable information to clinicians but remain computationally challenging. Many clinics find that CaGene or HughesRiskApps fit their needs for easy- and ready-to-use software to obtain cancer risks; however, these resources may not fit all clinics' needs. The HughesRiskApps Group and BayesMendel Lab therefore developed a web service, called "Risk Service", which may be integrated into any client software to quickly obtain standardized and up-to-date risk predictions for BayesMendel tools (BRCAPRO, MMRpro, PancPRO, and MelaPRO), the Tyrer-Cuzick IBIS Breast Cancer Risk Evaluation Tool, and the Colorectal Cancer Risk Assessment Tool. Software clients that can convert their local structured data into the HL7 XML-formatted family and clinical patient history (Pedigree model) may integrate with the Risk Service. The Risk Service uses Apache Tomcat and Apache Axis2 technologies to provide an all Java web service. The software client sends HL7 XML information containing anonymized family and clinical history to a Dana-Farber Cancer Institute (DFCI) server, where it is parsed, interpreted, and processed by multiple risk tools. The Risk Service then formats the results into an HL7 style message and returns the risk predictions to the originating software client. Upon consent, users may allow DFCI to maintain the data for future research. The Risk Service implementation is exemplified through HughesRiskApps. The Risk Service broadens the availability of valuable, up-to-date cancer risk tools and allows clinics and researchers to integrate risk prediction tools into their own software interface designed for their needs. Each software package can collect risk data using its own interface, and display the results using its own interface, while using a central, up-to-date risk calculator. This allows users to choose from multiple interfaces while always getting the latest risk calculations. Consenting users contribute their data for future research, thus building a rich multicenter resource. PMID- 23793602 TI - Long-term follow-up of axillary recurrences after negative sentinel lymph node biopsy: effect on prognosis and survival. AB - As axillary recurrence (AR) after a negative sentinel lymph node biopsy (SLNB) is rare, the prognosis of these patients is unknown. Since treatment paradigms for patients with breast cancer are shifting toward less axillary surgery, the number of ARs might increase. In this study, we evaluated primary and salvage treatment as well as long-term survival of patients diagnosed with an AR. A retrospective analysis of the cancer registry of 16 breast cancer units in the Netherlands was used to identify patients who developed an AR after a negative SLNB performed between 2002 and 2004. Using local hospital records we recorded primary patient-, tumor-, and treatment-characteristics, as well as salvage treatment. We identified 54 patients with an AR, median 30 months (range 3-79) after SLNB. Eighteen patients (33 %) were initially treated with breast conserving therapy, 15 of whom received external beam radiation therapy (EBRT). Thirty-three patients (61 %) did not receive adjuvant systemic treatment. In 45 of the 54 (83 %) patients, a salvage axillary lymph node dissection was performed showing a median of three positive nodes (range 1-24). Nine patients (17 %) were not treated surgically: three were treated with salvage EBRT and six with salvage systemic therapy only. At time of detection of the AR, a total of 7 patients (13 %) had proven distant metastases. After a median follow-up of 47 months (range 3-118), the 5-year "post-recurrence" distant metastasis free survival was 50 % and overall survival was 58 %. Significant negative predictors of survival were negative estrogen receptor (ER) status and receiving adjuvant chemotherapy at initial treatment. AR following a negative SLNB is associated with a 58 % 5-year OS. Prognostic factors are ER- primary tumor and receiving adjuvant chemotherapy as a part of initial treatment, reflecting an aggressive phenotype. Adequate regional and systemic salvage therapy constitute a chance for long-term survival after AR. PMID- 23793603 TI - ROLL versus RSL: toss of a coin? AB - The safety and benefits of radio-guided localization (RGL) versus wire-guided localization (WGL) surgery in the treatment of non-palpable breast cancers have been confirmed through several meta-analyses. RGL has become the standard of care in several institutions, although overall uptake has been slow. In view of this evidence supporting RGL, we believe that the future discussion is not of RGL versus WGL, but rather of what form of RGL will constitute best practice of care going forward. We therefore discuss the case for radio-guided occult lesion localization versus radioactive seed localization in the treatment of non palpable breast cancers, is it really a toss of a coin? PMID- 23793604 TI - Functional MDM4 rs4245739 genetic variant, alone and in combination with P53 Arg72Pro polymorphism, contributes to breast cancer susceptibility. AB - The oncoprotein MDM4 plays an essential role in P53 tumor suppressor pathway through negative regulation of P53 function. It has been reported that the rs4245739 A > C polymorphism located in the MDM4 3'-untranslated region creates a miR-191 target site and results in decreased MDM4 expression. Therefore, we investigated the association of the MDM4 rs4245739 polymorphism as well as the P53 Arg72Pro genetic variant with the breast cancer risk. Genotypes were determined in two independent case-control sets consisting of 1100 breast cancer cases and 1400 controls from two regions of China. Odds ratios (ORs) and 95 % confidence intervals (CIs) were estimated by logistic regression. Our results demonstrated that the MDM4 rs4245739 AC and CC genotypes were significantly associated with decreased breast cancer risk compared to the AA genotype in both the case-control sets (Jinan set: OR = 0.55, 95 % CI 0.40-0.76, P = 2.3 * 10(-4); Huaian set: OR = 0.41, 95 % CI 0.25-0.67, P = 3.1 * 10(-4)). The P53 Arg/Pro genotype or Pro/Pro genotype was significantly associated with an increased risk of developing breast cancer, compared to the P53 Arg/Arg genotype in both the case-control sets (all P < 0.05). Interestingly, we observed a combinational effect between MDM4 rs4245739 and P53 Arg72Pro variants in attenuating breast cancer risk, highlighting the importance of the P53 tumor suppressor pathway genes during malignant transformation. Our results also support the hypothesis that genetic variants interrupting miRNA-mediated gene regulation might be important genetic modifiers of breast cancer risk. PMID- 23793605 TI - Solution structure of monomeric human FAM96A. PMID- 23793606 TI - Cryogenic solid state NMR studies of fibrils of the Alzheimer's disease amyloid beta peptide: perspectives for DNP. AB - Dynamic Nuclear Polarization solid-state NMR holds the potential to enable a dramatic increase in sensitivity by exploiting the large magnetic moment of the electron. However, applications to biological solids are hampered in uniformly isotopically enriched biomacromolecules due to line broadening which yields a limited spectral resolution at cryogenic temperatures. We show here that high magnetic fields allow to overcome the broadening of resonance lines often experienced at liquid nitrogen temperatures. For a fibril sample of the Alzheimer's disease beta-amyloid peptide, we find similar line widths at low temperature and at room temperature. The presented results open new perspectives for structural investigations in the solid-state. PMID- 23793607 TI - Coexisting lumbar and cervical stenosis (tandem spinal stenosis): an infrequent presentation. Retrospective analysis of single-stage surgery (53 cases). AB - STUDY DESIGN: Retrospective analysis of 53 patients who underwent single stage simultaneous surgery for tandem spinal stenosis (TSS) at single centre. OBJECTIVE: To discuss the presentation of combined cervical and lumbar (tandem) stenosis and to evaluate the safety and efficacy of single-stage simultaneous surgery. Combined stenosis is an infrequent presentation with mixed presentation of upper motor neuron and lower motor neuron signs. Scarce literature on its presentation and management is available. There is a controversy in the surgical strategy of these patients. Staged surgeries are frequently recommended and only few single-stage surgeries reported. METHODS: All the patients were clinico radiologically diagnosed TSS. Surgeries were performed in single stage by two teams. Results were evaluated with Nurick grade, modified Japanese Orthopedic Association score (mJOA), oswestry disability index (ODI), patient satisfaction index, mJOA recovery rate, blood loss and complication. RESULTS: The mJOA cervical and ODI score improved from a mean 8.86 and 68.15 preoperatively to 13.00 and 30.11, respectively, at 12 months and to 14.52 and 24.03 at final follow-up. The average mJOA recovery rate was 48.23 +/- 26.90 %. Patient satisfaction index was 2.13 +/- 0.91 at final follow-up. Estimated blood loss of <=400 ml and operating room time of <150 min showed improvement of scores and lessened the complications. In the age group below 60 years, the improvement was statistically significant in ODI (p = 0.02) and Nurick's grade (p = 0.03) with average improvement in mJOA score. CONCLUSION: Short-lasting surgery, single anaesthesia, reduced morbidity and hospital stay as well as costs, an early return to function, high patient satisfaction rate with encouraging results justify single-stage surgery in TSS. Age, blood loss and duration of surgery decide the complication rate and outcome of surgery. Staged surgery is recommended in patients above the age of 60 years. PMID- 23793608 TI - Identification of hepatoma-derived growth factor as a potential prognostic and diagnostic marker for extrahepatic cholangiocarcinoma. AB - BACKGROUND: Hepatoma-derived growth factor (HDGF) has been reported to play a pivotal role in the development and progression of several tumors. The aim of the present study was to analyze whether HDGF is a potential prognostic and diagnostic marker for extrahepatic cholangiocarcinoma (EHCC). METHODS: The immunostaining of HDGF was analyzed by immunohistochemistry for 65 pathologically confirmed EHCC, and its correlation with clinicopathologic factors and prognosis was investigated. Meanwhile, to evaluate the diagnostic value of HDGF, an enzyme linked immunosorbent assay (ELISA) was performed to measure HDGF levels in the serum samples of 83 EHCC patients and 51 healthy controls. RESULTS: Positive expression of HDGF was detected in 30 (46.2 %) patients with EHCC and correlated with poor tumor differentiation (P = 0.024). Univariate analysis showed that the positive HDGF expression group had a significantly poorer survival rate than the negative HDGF expression group did (P < 0.001). Multivariate analysis demonstrated that HDGF expression and N stage were independent prognostic factors. The mean serum HDGF level in EHCC patients was 2.39-fold higher than that in healthy controls (P = 0.002). The optimal cut-off value for HDGF was 122.15 pg/mL, providing a sensitivity of 66.27 % and a specificity of 88.24 %. The area under the curve (AUC) of HDGF was 0.807 (95 % confidence interval 0.730 0.870), demonstrating that HDGF was a potential biomarker for EHCC. CONCLUSIONS: HDGF was a valuable independent prognostic factor after curative resection in EHCC, and it provided an important basis for screening/treating high-risk patients. Meanwhile, our study indicated that serum HDGF levels can be used as a noninvasive and potential diagnostic marker for EHCC. PMID- 23793609 TI - Identification of innate immune response endotypes in asthma: implications for personalized medicine. AB - Asthma is an idiopathic disease characterized by episodic inflammation and reversible airway obstruction triggered by exposure to environmental agents. Because this disease is heterogeneous in onset, exacerbations, inflammatory states, and response to therapy, there is intense interest in developing personalized approaches to its management. Of focus in this review, the recognition that a component of the pathophysiology of asthma is mediated by inflammation has implications for understanding its etiology and individualizing its therapy. Despite understanding how Th2 polarization mediates asthma exacerbations by aeroallergen exposure, we do not yet fully understand how RNA virus infections produce asthmatic exacerbations. This review will summarize the explosion of information that has revealed how patterns produced by RNA virus infection trigger the innate immune response (IIR) in sentinel airway cells. When the IIR is triggered, these cells elaborate inflammatory cytokines and protective mucosal interferons whose actions activate long-lived adaptive immunity and limit organismal replication. Recent work has shown the multifaceted way that dysregulation of the IIR is linked to viral-induced exacerbation, steroid insensitivity, and T helper polarization of adaptive immunity. New developments in quantitative proteomics now enable accurate identification of subgroups of individuals that demonstrate activation of IIR ("innate endotype"). Potential applications to clinical research are proposed. Together, these developments open realistic prospects for how identification of the IIR endotype may inform asthma therapy in the future. PMID- 23793610 TI - Hepatic genotoxicity and toxicogenomic responses in MutaTMMouse males treated with dibenz[a,h]anthracene. AB - Dibenz[a,h]anthracene (DB[a,h]A) is a polycyclic aromatic hydrocarbon that is a by-product of combustion and a potent carcinogen. Few studies have investigated the effects of DB[a,h]A on mRNA and microRNA expression to dissect the mechanisms involved in carcinogenesis. In this study, mature male mice (Muta(TM)Mouse) were exposed to 6.25, 12.5 and 25mg/kg/day DB[a,h]A by oral gavage for 28 consecutive days. Results were compared with mice similarly exposed to benzo[a]pyrene (B[a]P) in our previous work. Liver DNA adduct levels and lacZ mutant frequency increased dose dependently for both chemicals. Aryl hydrocarbon receptor (AhR) potency was greater for DB[a,h]A than B[a]P using the chemical-activated luciferase expression assay. Microarray analysis revealed 19 up-regulated and 22 down regulated genes (false discovery rate-adjusted P <= 0.05; fold change >= 1.5) following treatment with 6.25 mg/kg/day DB[a,h]A. Thirteen transcripts were up regulated and 32 down-regulated in the 12.5mg/kg/day group. The 25mg/kg/day dose had major effects on mRNA expression with 135 up-regulated and 104 down-regulated genes. Overall, perturbations were greater for DB[a,h]A than for B[a]P; in vitro chemical-activated luciferase expression supports that this may be driven by the AhR. Many of the DB[a,h]A-affected genes are implicated in cancer and are essential in vital biological functions including circadian rhythm, glucose metabolism, lipid metabolism, immune response, cell cycle and apoptosis. Although a number of functional groups were similarly affected by B[a]P and DB[a,h]A, in general the responses generated by each chemical were quite distinct. Commonalities included a DNA damage response leading to induction of cell cycle arrest and apoptosis in both Tp53-dependent and Tp53-independent manners. MicroRNA expression was identical for both chemicals, with only miR-34a showing a dose-dependent increase in treated mice. PMID- 23793611 TI - Development of a screening system for DNA damage and repair of potential carcinogens based on dual luciferase assay in human HepG2 cell. AB - At present, different methods are used for the detection of early biological effects of DNA-damaging agents in environment. Some sensitive testing methods employing DNA damage-inducing genes RNR3, RAD51, RAD54 or growth-arrested and DNA damage-inducible gene 153 (Gadd 153) are used to detect the DNA damage. The host cell reactivation (HCR) assay is a functional assay that is based on the independent transfection of cells with either damaged or undamaged plasmid DNA and allows the identification of the genes responsible for DNA repair-deficient syndromes. In this study, we combined the gadd153-luc test system and HCR assay to measure the DNA damage and DNA repair by dual luciferase assay. We used 16 DNA damaging agents all of which were detected by a positive dual luciferase reporter test system. The sensitivity of the dual luciferase assay system to detect DNA damage/repair was same as the gadd153-luc test system and/or the HCR assay. Since DNA repair is important to maintain genetic stability, DNA damage and repair have been good biomarkers of early biological effects of DNA-damaging agents. Accordingly, the measurement of DNA repair capacity should be a valued tool in molecular epidemiology studies. The dual luciferase assay described in this study is rapid, convenient, stable and standard. PMID- 23793612 TI - Exposure of insect cells to ionising radiation in vivo induces persistent phosphorylation of a H2AX homologue (H2AvB). AB - The response of eukaryotic cells to ionising radiation (IR)-induced double-strand DNA breaks is highly conserved and involves a DNA repair mechanism characterised by the early phosphorylation of histone protein H2AX (producing the active form gammaH2AX). Although the expression of an induced gammaH2AX variant has been detected in Drosophila melanogaster, the expression and radiation response of a gammaH2AX homologue has not been reported in economically important fruit flies. We use Bactrocera tryoni (Diptera: Tephritidae, Queensland fruit fly or 'Q-fly') to investigate this response with a view to developing molecular assays to detect/quantify exposure of fruit flies to IR and consequent DNA damage. Deep sequencing confirmed the presence of a H2AX homologue that we have termed H2AvB (i.e. variant Bactrocera) and has an identical sequence to a histone reported from the human disease vector Glossina morsitans. A linear dose-response of gammaH2AvB (0-400 Gy IR) was observed in whole Q-fly pupal lysates 24h post-IR and was detected at doses as low as 20 Gy. gammaH2AvB signal peaked at ~20min after IR exposure and at 24h post-IR the signal remained elevated but declined significantly by 5 days. Persistent and dose-dependent gammaH2AvB signal could be detected and quantified either by western blot or by laser scanning cytometry up to 17 days post-IR exposure in histone extracts or isolated nuclei from adult Q flies (irradiated as pupae). We conclude that IR exposure in Q-fly leads to persistent gammaH2AvB signals (over a period of days) that can easily be detected by western blot or quantitative immunofluorescence techniques. These approaches have potential as the basis for assays for detection and quantification of prior IR exposure in pest fruit flies. PMID- 23793613 TI - Beryllium chloride-induced oxidative DNA damage and alteration in the expression patterns of DNA repair-related genes. AB - Beryllium metal has physical properties that make its use essential for very specific applications, such as medical diagnostics, nuclear/fusion reactors and aerospace applications. Because of the widespread human exposure to beryllium metals and the discrepancy of the genotoxic results in the reported literature, detail assessments of the genetic damage of beryllium are warranted. Mice exposed to beryllium chloride at an oral dose of 23mg/kg for seven consecutive days exhibited a significant increase in the level of DNA-strand breaking and micronuclei formation as detected by a bone marrow standard comet assay and micronucleus test. Whereas slight beryllium chloride-induced oxidative DNA damage was detected following formamidopyrimidine DNA glycosylase digestion, digestion with endonuclease III resulted in considerable increases in oxidative DNA damage after the 11.5 and 23mg/kg/day treatment as detected by enzyme-modified comet assays. Increased 8-hydroxydeoxyguanosine was also directly correlated with increased bone marrow micronuclei formation and DNA strand breaks, which further confirm the involvement of oxidative stress in the induction of bone marrow genetic damage after exposure to beryllium chloride. Gene expression analysis on the bone marrow cells from beryllium chloride-exposed mice showed significant alterations in genes associated with DNA damage repair. Therefore, beryllium chloride may cause genetic damage to bone marrow cells due to the oxidative stress and the induced unrepaired DNA damage is probably due to the down regulation in the expression of DNA repair genes, which may lead to genotoxicity and eventually cause carcinogenicity. PMID- 23793614 TI - The influence on DNA damage of glycaemic parameters, oral antidiabetic drugs and polymorphisms of genes involved in the DNA repair system. AB - The hyperglycaemia seen in type 2 diabetes mellitus (DM2) is associated with increased oxidative stress and production of reactive oxygen species, both of which are factors that can provoke DNA damage. Notwithstanding, other factors, including medications and individual susceptibility, can also induce this type of DNA lesion. The objective of this study was, therefore, to investigate the influence of glycaemic control, oral antidiabetic drugs (metformin and glibenclamide) and polymorphisms of the XRCC1 and XRCC3 genes on the frequency of DNA damage in DM2 patients, which was accessed by the cytokinesis-block micronucleus cytome and the comet assays on the ex vivo mitogenically stimulated lymphocytes. The 53 people recruited to take part in the study were already on treatment with metformin and were followed for 5 months. Ten of these patients were put on combined treatment with the addition of glibenclamide. It was observed that the greater the plasma metformin concentration, the lower the frequency of micronuclei (MN) in the sample total (P = 0.009) and also that the subset of patients using combined treatment including glibenclamide had a significantly higher MN rate 90 days after starting combined treatment (P = 0.024). In the subset who only took metformin, the rate of MN was significantly higher among carriers of the 399Gln allele on the XRCC1 gene (P = 0.008). In addition, homozygotes for the 241Thr allele exhibited a significant increase in MN in the combined treatment group (P = 0.008). Our results suggest that different combinations of oral antidiabetic drugs and polymorphisms on genes involved in the DNA damage repair system could influence the frequency of this type of chromosome lesion, which can be a useful biomarker for assessing the risk of developing cancer. PMID- 23793615 TI - A decline in PABPN1 induces progressive muscle weakness in oculopharyngeal muscle dystrophy and in muscle aging. AB - Oculopharyngeal muscular dystrophy (OPMD) is caused by trinucleotide repeat expansion mutations in Poly(A) binding protein 1 (PABPN1). PABPN1 is a regulator of mRNA stability and is ubiquitously expressed. Here we investigated how symptoms in OPMD initiate only at midlife and why a subset of skeletal muscles is predominantly affected. Genome-wide RNA expression profiles from Vastus lateralis muscles human carriers of expanded-PABPN1 at pre-symptomatic and symptomatic stages were compared with healthy controls. Major expression changes were found to be associated with age rather than with expression of expanded-PABPN1, instead transcriptomes of OPMD and elderly muscles were significantly similar (P<0.05). Using k-means clustering we identified age-dependent trends in both OPMD and controls, but trends were often accelerated in OPMD. We report an age-regulated decline in PABPN1 levels in Vastus lateralis muscles from the fifth decade. In concurrence with severe muscle degeneration in OPMD, the decline in PABPN1 accelerated in OPMD and was specific to skeletal muscles. Reduced PABPN1 levels (30% to 60%) in muscle cells induced myogenic defects and morphological signatures of cellular aging in proportion to PABPN1 expression levels. We suggest that PABPN1 levels regulate muscle cell aging and OPMD represents an accelerated muscle aging disorder. PMID- 23793617 TI - Application of pseudo-two phase partitioning bioreactor (P-TPPB) to the production of biodiesel. AB - Pseudo-two phase partitioning bioreactor (P-TPPB) was newly proposed as an extension of the application of TPPB to bioprocesses in which hydrophilic substrates and/or products are involved. The feasibility of P-TPPB was demonstrated in enzymatic biodiesel production, where methanol completely inhibits the enzymes. Unlike conventional TPPB, the P-TPPB comprises a hydrophobic first phase (soybean oil) and hydrophilic second phase. n-Pentanol was found to be the optimum for the second phase, since P-TPPB containing n pentanol showed the greatest total biodiesel conversion and highest fatty acid methyl ester content. The enzyme was repeatedly used to produce biodiesel in P TPPB, while maintaining its activity at over 95% relative to that of the intact enzyme. PMID- 23793616 TI - Carotid artery stenting using the proximal or dual protection method for near occlusion of the cervical internal carotid artery. AB - The treatment for patients with near occlusion of the cervical internal carotid artery (ICA) is controversial. The aim of this study was to examine the results of carotid artery stenting (CAS) as a surgical treatment for ICA near occlusion. Between April 2008 and September 2012, 14 patients (all men; mean age, 75.4 years) with ICA near occlusion were treated with CAS. This represents 5.2% of a total of 267 patients treated with CAS during the study period. All patients were treated with CAS using an embolic protection device. The proximal balloon protection method was performed in five patients, and the dual protection method using a proximal balloon and distal filter protection was used in nine patients. We examined the change of stenotic lesion, hyperintensity spot in diffusion weighted imaging (DWI), and perioperative complications after CAS. All near occlusions were successfully dilated. Among 2 of 14 patients, DWI showed 1 and 4 hyperintensity spots. Transient and persistent complications, including neurological deficits, did not occur in any patients. In this small number of cases, CAS using the proximal or dual embolic protection method seems to be a safe and beneficial treatment for ICA near occlusion. PMID- 23793618 TI - Validity of malnutrition scores for predicting mortality in chronic hemodialysis patients. AB - PURPOSE: Malnutrition is a strong predictor of mortality in hemodialysis patients. Several scoring systems for evaluating nutritional status have been proposed. However, they rely on different sets of anthropometric and laboratory markers to make a diagnosis of malnutrition and assess its impact on prognosis. To validate them, nutritional scores should be compared with clinical outcomes. Thus, the purpose of this study was to assess malnutrition by three different nutrition scoring systems and determine which best predicts mortality in hemodialysis patients. METHODS: This prospective study included 106 adult chronic hemodialysis patients. Their mean age was 56.3 +/- 14.9 years and mean body mass index 24.8 (21.8-28.9); 52 % were men and they had been on dialysis for 24 (5-55) months. Nutritional status was classified according to the diagnostic systems proposed by Wolfson et al. (Am J Clin Nutr 39(4):547-555, 1984), International Society of Renal Nutrition and Metabolism (ISRNM) (Fouque et al. in Kidney Int 73(4):391-398, 2008), and Beberashvili et al. (Nephrol Dial Transplant 25(8):2662 2671, 2010). During about 2 years of follow-up, mortality was assessed by Kaplan Meier curves, log-rank, and Cox's models adjusted for diabetes, sex, C-reactive protein, time on dialysis, age, and fractional urea clearance. RESULTS: Twenty three deaths (21.5 %) occurred during the study period. According to the systems of Wolfson, Beberashvili, and the ISRNM, 54, 32, and 20 % of patients, respectively, had malnutrition. Both univariate and multivariate analyses showed that the ISRNM system was the only one that predicted poorer survival (fourfold higher death risk) in malnourished patients. CONCLUSIONS: The scoring system proposed by the ISRNM most accurately identifies patients at higher risk of death. PMID- 23793619 TI - Pulmonary hypertension as an independent predictor of cardiovascular mortality and events in hemodialysis patients. AB - BACKGROUND: Hemodialysis patients are at an increased risk of cardiovascular (CV) morbidity and mortality. Pulmonary hypertension (PH) has been recently reported as a new entity and unrecognized threat in maintenance hemodialysis (MHD) patients, whether PH predicts CV mortality and events in this population remains unknown. The aim of the present study was to determine the value of PH in predicting CV mortality and events in a prospective cohort of MHD patients. METHODS: We studied 278 MHD patients (98 with and 180 without PH) in Guangdong General Hospital Blood Purification Center, Guangzhou, China. All patients had been followed up for 2 years, and in survival analysis, we considered time to death or first cardiovascular event. The endpoints were all-cause mortality, CV mortality and CV events. PH was defined as systolic pulmonary artery pressure (SPAP) >= 35 mmHg as determined by Doppler echocardiographic evaluation. RESULTS: Of the 278 MHD patients, 53 (19.1 %) died as a result of all causes, 28 (10.1 %) died from CV events (52.8 % of causes of death), and 87 (31.3 %) had new-onset CV events. The survival curve showed that all-cause and CV mortality and new-onset CV events were higher in PH group than the non-PH group. In a multivariate Cox proportional hazard model, the adjusted HR for all-cause mortality, CV mortality and CV events was 1.85 [95 % confidence interval (CI) 1.03-3.34], 2.36 (95 % CI 1.05-5.31) and 2.27 (95 % CI 1.44-3.58), respectively. CONCLUSIONS: Our study showed that PH was an independent predictor of all-cause mortality and CV mortality and events in MHD patients. We suggest to evaluate SPAP in MHD patients in order to stratify risk of death and CV events. PMID- 23793620 TI - Association between TNF-alpha -308G/A polymorphism and diabetic nephropathy risk: a meta-analysis. AB - PURPOSE: TNF-alpha -308G/A polymorphism has been implicated in the susceptibility of diabetic nephropathy, but studies have reported inconclusive results. The present study investigated the relationship between -308G/A polymorphism in the TNF-alpha gene and diabetic nephropathy risk by meta-analysis. METHODS: Data from PubMed, Embase, Ovid, Cochrane Library, China National Knowledge Infrastructure, Wanfang, VIP and China Biology Medicine disc databases were evaluated and analyzed. Statistical analysis was performed using RevMan 4.2 and Stata 10.0 software. RESULTS: A total of 1,277 diabetic nephropathy cases and 1,740 controls in eight case-controlled studies were identified for data analysis. The results suggested that A allele carriers (GA + AA) may not have an altered risk of diabetic nephropathy when compared with homozygote GG carriers with boarder-line statistical significance (OR = 0.84, 95 % CI = 0.71-1.00, p = 0.05 for GA + AA vs. GG). However, in Asian subgroup analysis, the A allele variant was associated with a decreased diabetic nephropathy risk (OR = 0.69, 95 % CI = 0.51-0.94, p = 0.02 for GA + AA vs. GG) CONCLUSIONS: Meta-analysis suggests that the A allele of TNF-alpha -308G/A polymorphism might be protective against diabetic nephropathy with ethnic selectivity. Future studies are needed to validate these findings. PMID- 23793621 TI - Phylogenetic and morphologic complexity of giant sulphur bacteria. AB - The large sulphur bacteria, first discovered in the early nineteenth century, include some of the largest bacteria identified to date. Individual cells are often visible to the unaided eye and can reach 750 MUm in diameter. The cells usually feature light-refracting inclusions of elemental sulphur and a large internal aqueous vacuole, which restricts the cytoplasm to the outermost periphery. In some taxa, it has been demonstrated that the vacuole can also serve for the storage of high millimolar concentrations of nitrate. Over the course of the past two centuries, a wide range of morphological variation within the family Beggiatoaceae has been found. However, representatives of this clade are frequently recalcitrant to current standard microbiological techniques, including 16S rRNA gene sequencing and culturing, and a reliable classification of these bacteria is often complicated. Here we present a summary of the efforts made and achievements accomplished in the past years, and give perspectives for investigating the heterogeneity and possible evolutionary developments in this extraordinary group of bacteria. PMID- 23793622 TI - Cholesterol regulates HERG K+ channel activation by increasing phospholipase C beta1 expression. AB - Human ether-a-go-go-related gene (HERG) K(+) channel underlies the rapidly activating delayed rectifier K(+) conductance (IKr) during normal cardiac repolarization. Also, it may regulate excitability in many neuronal cells. Recently, we showed that enrichment of cell membrane with cholesterol inhibits HERG channels by reducing the levels of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] due to the activation of phospholipase C (PLC). In this study, we further explored the effect of cholesterol enrichment on HERG channel kinetics. When membrane cholesterol level was mildly increased in human embryonic kidney (HEK) 293 cells expressing HERG channel, the inactivation and deactivation kinetics of HERG current were not affected, but the activation rate was significantly decelerated at all voltages tested. The application of PtdIns(4,5)P2 or inhibitor for PLC prevented the effect of cholesterol enrichment, while the presence of antibody against PtdIns(4,5)P2 in pipette solution mimicked the effect of cholesterol enrichment. These results indicate that the effect of cholesterol enrichment on HERG channel is due to the depletion of PtdIns(4,5)P2. We also found that cholesterol enrichment significantly increases the expression of beta1 and beta3 isoforms of PLC (PLCbeta1, PLCbeta3) in the membrane. Since the effects of cholesterol enrichment on HERG channel were prevented by inhibiting transcription or by inhibiting PLCbeta1 expression, we conclude that increased PLCbeta1 expression leads to the deceleration of HERG channel activation rate via downregulation of PtdIns(4,5)P2. These results confirm a crosstalk between two plasma membrane-enriched lipids, cholesterol and PtdIns(4,5)P2, in the regulation of HERG channels. PMID- 23793623 TI - Roles of the Yap1 transcription factor and antioxidants in Saccharomyces cerevisiae's tolerance to furfural and 5-hydroxymethylfurfural, which function as thiol-reactive electrophiles generating oxidative stress. AB - Development of the tolerance of Saccharomyces cerevisiae strains to furfural and 5-hydroxymethylfurfural (HMF) is an important issue for cellulosic ethanol production. Although furfural and HMF are known to induce oxidative stress, the underlying mechanisms are largely unknown. In this study, we show that both furfural and HMF act as thiol-reactive electrophiles, thus directly activating the Yap1 transcription factor via the H2O2-independent pathway, depleting cellular glutathione (GSH) levels, and accumulating reactive oxygen species in Saccharomyces cerevisiae. However, furfural showed higher reactivity than did HMF toward GSH in vitro and in vivo. In line with such toxic mechanisms, overexpression of YAP1(C620F), a constitutively active mutant of YAP1, and Yap1 target genes encoding catalases (CTA1 and CTT1) increased tolerance to furfural and HMF. However, increasing GSH levels by overexpression of genes for GSH biosynthesis (GSH1 and GLR1) or by the exogenous addition of GSH to the culture medium enhanced tolerance to furfural but not to HMF. PMID- 23793624 TI - Development of a dual-index sequencing strategy and curation pipeline for analyzing amplicon sequence data on the MiSeq Illumina sequencing platform. AB - Rapid advances in sequencing technology have changed the experimental landscape of microbial ecology. In the last 10 years, the field has moved from sequencing hundreds of 16S rRNA gene fragments per study using clone libraries to the sequencing of millions of fragments per study using next-generation sequencing technologies from 454 and Illumina. As these technologies advance, it is critical to assess the strengths, weaknesses, and overall suitability of these platforms for the interrogation of microbial communities. Here, we present an improved method for sequencing variable regions within the 16S rRNA gene using Illumina's MiSeq platform, which is currently capable of producing paired 250-nucleotide reads. We evaluated three overlapping regions of the 16S rRNA gene that vary in length (i.e., V34, V4, and V45) by resequencing a mock community and natural samples from human feces, mouse feces, and soil. By titrating the concentration of 16S rRNA gene amplicons applied to the flow cell and using a quality score based approach to correct discrepancies between reads used to construct contigs, we were able to reduce error rates by as much as two orders of magnitude. Finally, we reprocessed samples from a previous study to demonstrate that large numbers of samples could be multiplexed and sequenced in parallel with shotgun metagenomes. These analyses demonstrate that our approach can provide data that are at least as good as that generated by the 454 platform while providing considerably higher sequencing coverage for a fraction of the cost. PMID- 23793625 TI - Population structure of Salmonella enterica serovar 4,[5],12:b:- strains and likely sources of human infection. AB - Salmonella enterica serovar 4,[5],12:b:- is a monophasic serovar not able to express the second-phase flagellar antigen (H2 antigen). In Germany, the serovar is occasionally isolated from poultry, reptiles, fish, food, and humans. In this study, a selection of 67 epidemiologically unrelated Salmonella enterica serovar 4,[5],12:b:- strains isolated in Germany between 2000 and 2011 from the environment, animal, food, and humans was investigated by phenotypic and genotypic methods to better understand the population structure and to identify potential sources of human infections. Strains of this monophasic serovar were highly diverse. Within the 67 strains analyzed, we identified 52 different pulsed field gel electrophoresis XbaI profiles, 12 different multilocus sequence types (STs), and 18 different pathogenicity array types. The relatedness of strains based on the pathogenicity gene repertoire (102 markers tested) was in good agreement with grouping by MLST. S. enterica serovar 4,[5],12:b:- is distributed across multiple unrelated eBurst groups and consequently is highly polyphyletic. Two sequence types (ST88 and ST127) were linked to S. enterica serovar Paratyphi B (d-tartrate positive), two single-locus variants of ST1583 were linked to S. enterica serovar Abony, and one sequence type (ST1484) was associated with S. enterica serovar Mygdal, a recently defined, new serovar. From the characterization of clinical isolates and those of nonhuman origin, it can be concluded that the potential sources of sporadic human infections with S. enterica serovar 4,[5],12:b:- most likely are mushrooms, shellfish/fish, and poultry. PMID- 23793626 TI - Characterization of a feruloyl esterase from Lactobacillus plantarum. AB - Lactobacillus plantarum is frequently found in the fermentation of plant-derived food products, where hydroxycinnamoyl esters are abundant. L. plantarum WCFS1 cultures were unable to hydrolyze hydroxycinnamoyl esters; however, cell extracts from the strain partially hydrolyze methyl ferulate and methyl p-coumarate. In order to discover whether the protein Lp_0796 is the enzyme responsible for this hydrolytic activity, it was recombinantly overproduced and enzymatically characterized. Lp_0796 is an esterase that, among other substrates, is able to efficiently hydrolyze the four model substrates for feruloyl esterases (methyl ferulate, methyl caffeate, methyl p-coumarate, and methyl sinapinate). A screening test for the detection of the gene encoding feruloyl esterase Lp_0796 revealed that it is generally present among L. plantarum strains. The present study constitutes the description of feruloyl esterase activity in L. plantarum and provides new insights into the metabolism of hydroxycinnamic compounds in this bacterial species. PMID- 23793627 TI - Bacterially induced weathering of ultramafic rock and its implications for phytoextraction. AB - The bioavailability of metals in soil is often cited as a limiting factor of phytoextraction (or phytomining). Bacterial metabolites, such as organic acids, siderophores, or biosurfactants, have been shown to mobilize metals, and their use to improve metal extraction has been proposed. In this study, the weathering capacities of, and Ni mobilization by, bacterial strains were evaluated. Minimal medium containing ground ultramafic rock was inoculated with either of two Arthrobacter strains: LA44 (indole acetic acid [IAA] producer) or SBA82 (siderophore producer, PO4 solubilizer, and IAA producer). Trace elements and organic compounds were determined in aliquots taken at different time intervals after inoculation. Trace metal fractionation was carried out on the remaining rock at the end of the experiment. The results suggest that the strains act upon different mineral phases. LA44 is a more efficient Ni mobilizer, apparently solubilizing Ni associated with Mn oxides, and this appeared to be related to oxalate production. SBA82 also leads to release of Ni and Mn, albeit to a much lower extent. In this case, the concurrent mobilization of Fe and Si indicates preferential weathering of Fe oxides and serpentine minerals, possibly related to the siderophore production capacity of the strain. The same bacterial strains were tested in a soil-plant system: the Ni hyperaccumulator Alyssum serpyllifolium subsp. malacitanum was grown in ultramafic soil in a rhizobox system and inoculated with each bacterial strain. At harvest, biomass production and shoot Ni concentrations were higher in plants from inoculated pots than from noninoculated pots. Ni yield was significantly enhanced in plants inoculated with LA44. These results suggest that Ni-mobilizing inoculants could be useful for improving Ni uptake by hyperaccumulator plants. PMID- 23793628 TI - Substantial within-animal diversity of Salmonella isolates from lymph nodes, feces, and hides of cattle at slaughter. AB - Lymph nodes (mandibular, mesenteric, mediastinal, and subiliac; n = 68) and fecal (n = 68) and hide (n = 35) samples were collected from beef carcasses harvested in an abattoir in Mexico. Samples were analyzed for Salmonella, and presumptive colonies were subjected to latex agglutination. Of the isolates recovered, a subset of 91 was characterized by serotyping, pulsed-field gel electrophoresis (PFGE), and antimicrobial susceptibility phenotyping. Salmonella was isolated from 100% (hide), 94.1% (feces), 91.2% (mesenteric), 76.5% (subiliac), 55.9% (mandibular), and 7.4% (mediastinal) of samples. From the 87 typeable isolates, eight Salmonella enterica serotypes, including Kentucky (32.2%), Anatum (29.9%), Reading (17.2%), Meleagridis (12.6%), Cerro (4.6%), Muenster (1.1%), Give (1.1%), and Mbandaka (1.1%), were identified. S. Meleagridis was more likely (P = 0.03) to be recovered from lymph nodes than from feces or hides, whereas S. Kentucky was more likely (P = 0.02) to be recovered from feces and hides than from lymph nodes. The majority (59.3%) of the Salmonella isolates were pansusceptible; however, multidrug resistance was observed in 13.2% of isolates. Typing by PFGE revealed that Salmonella strains generally clustered by serotype, but some serotypes (Anatum, Kentucky, Meleagridis, and Reading) were comprised of multiple PFGE subtypes. Indistinguishable PFGE subtypes and, therefore, serotypes were isolated from multiple sample types, and multiple PFGE subtypes were commonly observed within an animal. Given the overrepresentation of some serotypes within lymph nodes, we hypothesize that certain Salmonella strains may be better at entering the bovine host than other Salmonella strains or that some may be better adapted for survival within lymph nodes. Our data provide insight into the ecology of Salmonella within cohorts of cattle and offer direction for intervention opportunities. PMID- 23793629 TI - Longitudinal study of distributions of similar antimicrobial-resistant Salmonella serovars in pigs and their environment in two distinct swine production systems. AB - The aim of this longitudinal study was to determine and compare the prevalences and genotypic profiles of antimicrobial-resistant (AR) Salmonella isolates from pigs reared in antimicrobial-free (ABF) and conventional production systems at farm, at slaughter, and in their environment. We collected 2,889 pig fecal and 2,122 environmental (feed, water, soil, lagoon, truck, and floor swabs) samples from 10 conventional and eight ABF longitudinal cohorts at different stages of production (farrowing, nursery, finishing) and slaughter (postevisceration, postchill, and mesenteric lymph nodes [MLN]). In addition, we collected 1,363 carcass swabs and 205 lairage and truck samples at slaughter. A total of 1,090 Salmonella isolates were recovered from the samples; these were isolated with a significantly higher prevalence in conventionally reared pigs (4.0%; n = 66) and their environment (11.7%; n = 156) than in ABF pigs (0.2%; n = 2) and their environment (0.6%; n = 5) (P < 0.001). Salmonella was isolated from all stages at slaughter, including the postchill step, in the two production systems. Salmonella prevalence was significantly higher in MLN extracted from conventional carcasses than those extracted from ABF carcasses (P < 0.001). We identified a total of 24 different serotypes, with Salmonella enterica serovar Typhimurium, Salmonella enterica serovar Anatum, Salmonella enterica serovar Infantis, and Salmonella enterica serovar Derby being predominant. The highest frequencies of antimicrobial resistance (AR) were exhibited to tetracycline (71%), sulfisoxazole (42%), and streptomycin (17%). Multidrug resistance (resistance to >= 3 antimicrobials; MDR) was detected in 27% (n = 254) of the Salmonella isolates from the conventional system. Our study reports a low prevalence of Salmonella in both production systems in pigs on farms, while a higher prevalence was detected among the carcasses at slaughter. The dynamics of Salmonella prevalence in pigs and carcasses were reciprocated in the farm and slaughter environment, clearly indicating an exchange of this pathogen between the pigs and their surroundings. Furthermore, the phenotypic and genotypic fingerprint profile results underscore the potential role played by environmental factors in dissemination of AR Salmonella to pigs. PMID- 23793630 TI - Direct assessment of viral diversity in soils by random PCR amplification of polymorphic DNA. AB - Viruses are the most abundant and diverse biological entities within soils, yet their ecological impact is largely unknown. Defining how soil viral communities change with perturbation or across environments will contribute to understanding the larger ecological significance of soil viruses. A new approach to examining the composition of soil viral communities based on random PCR amplification of polymorphic DNA (RAPD-PCR) was developed. A key methodological improvement was the use of viral metagenomic sequence data for the design of RAPD-PCR primers. This metagenomically informed approach to primer design enabled the optimization of RAPD-PCR sensitivity for examining changes in soil viral communities. Initial application of RAPD-PCR viral fingerprinting to soil viral communities demonstrated that the composition of autochthonous soil viral assemblages noticeably changed over a distance of meters along a transect of Antarctic soils and across soils subjected to different land uses. For Antarctic soils, viral assemblages segregated upslope from the edge of dry valley lakes. In the case of temperate soils at the Kellogg Biological Station, viral communities clustered according to land use treatment. In both environments, soil viral communities changed along with environmental factors known to shape the composition of bacterial host communities. Overall, this work demonstrates that RAPD-PCR fingerprinting is an inexpensive, high-throughput means for addressing first order questions of viral community dynamics within environmental samples and thus fills a methodological gap between narrow single-gene approaches and comprehensive shotgun metagenomic sequencing for the analysis of viral community diversity. PMID- 23793631 TI - Haloarchaeal-type beta-ketothiolases involved in Poly(3-hydroxybutyrate-co-3 hydroxyvalerate) synthesis in Haloferax mediterranei. AB - The key enzymes for poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) biosynthesis in haloarchaea have been identified except the beta-ketothiolase(s), which condense two acetyl coenzyme A (acetyl-CoA) molecules to acetoacetyl-CoA, or one acetyl-CoA and one propionyl-CoA to 3-ketovaleryl-CoA. Whole-genome analysis has revealed eight potential beta-ketothiolase genes in the haloarchaeon Haloferax mediterranei, among which the PHBV-specific BktB and PhaA were identified by gene knockout and complementation analysis. Unlike all known bacterial counterparts encoded by a single gene, the haloarchaeal PhaA that was involved in acetoacetyl-CoA generation, was composed of two different types of subunits (PhaAalpha and PhaAbeta) and encoded by the cotranscribed HFX_1023 (phaAalpha) and HFX_1022 (phaAbeta) genes. Similarly, the BktB that was involved in generation of acetoacetyl-CoA and 3-ketovaleryl-CoA, was also composed of two different types of subunits (BktBalpha and BktBbeta) and encoded by cotranscribed HFX_6004 (bktBalpha) and HFX_6003 (bktBbeta). BktBalpha and PhaAalpha were the catalytic subunits and determined substrate specificities of BktB and PhaA, respectively. Their catalytic triad "Ser-His-His" was distinct from the bacterial "Cys-His-Cys." BktBbeta and PhaAbeta both contained an oligosaccharide-binding fold domain, which was essential for the beta-ketothiolase activity. Interestingly, BktBbeta and PhaAbeta were functionally interchangeable, although PhaAbeta preferred functioning with PhaAalpha. In addition, BktB showed biotechnological potential for the production of PHBV with the desired 3 hydroxyvalerate fraction in haloarchaea. This is the first report of the haloarchaeal type of PHBV-specific beta-ketothiolases, which are distinct from their bacterial counterparts in both subunit composition and catalytic residues. PMID- 23793632 TI - Novel, oxygen-insensitive group 5 [NiFe]-hydrogenase in Ralstonia eutropha. AB - Recently, a novel group of [NiFe]-hydrogenases has been defined that appear to have a great impact in the global hydrogen cycle. This so-called group 5 [NiFe] hydrogenase is widespread in soil-living actinobacteria and can oxidize molecular hydrogen at atmospheric levels, which suggests a high affinity of the enzyme toward H2. Here, we provide a biochemical characterization of a group 5 hydrogenase from the betaproteobacterium Ralstonia eutropha H16. The hydrogenase was designated an actinobacterial hydrogenase (AH) and is catalytically active, as shown by the in vivo H2 uptake and by activity staining in native gels. However, the enzyme does not sustain autotrophic growth on H2. The AH was purified to homogeneity by affinity chromatography and consists of two subunits with molecular masses of 65 and 37 kDa. Among the electron acceptors tested, nitroblue tetrazolium chloride was reduced by the AH at highest rates. At 30 degrees C and pH 8, the specific activity of the enzyme was 0.3 MUmol of H2 per min and mg of protein. However, an unexpectedly high Michaelis constant (Km) for H2 of 3.6 +/- 0.5 MUM was determined, which is in contrast to the previously proposed low Km of group 5 hydrogenases and makes atmospheric H2 uptake by R. eutropha most unlikely. Amperometric activity measurements revealed that the AH maintains full H2 oxidation activity even at atmospheric oxygen concentrations, showing that the enzyme is insensitive toward O2. PMID- 23793633 TI - Application of denaturing high-performance liquid chromatography for monitoring sulfate-reducing bacteria in oil fields. AB - Sulfate-reducing bacteria (SRB) participate in microbially induced corrosion (MIC) of equipment and H2S-driven reservoir souring in oil field sites. Successful management of industrial processes requires methods that allow robust monitoring of microbial communities. This study investigated the applicability of denaturing high-performance liquid chromatography (DHPLC) targeting the dissimilatory sulfite reductase beta-subunit (dsrB) gene for monitoring SRB communities in oil field samples from the North Sea, the United States, and Brazil. Fifteen of the 28 screened samples gave a positive result in real-time PCR assays, containing 9 * 10(1) to 6 * 10(5) dsrB gene copies ml(-1). DHPLC and denaturing gradient gel electrophoresis (DGGE) community profiles of the PCR positive samples shared an overall similarity; both methods revealed the same samples to have the lowest and highest diversity. The SRB communities were diverse, and different dsrB compositions were detected at different geographical locations. The identified dsrB gene sequences belonged to several phylogenetic groups, such as Desulfovibrio, Desulfococcus, Desulfomicrobium, Desulfobulbus, Desulfotignum, Desulfonatronovibrio, and Desulfonauticus. DHPLC showed an advantage over DGGE in that the community profiles were very reproducible from run to run, and the resolved gene fragments could be collected using an automated fraction collector and sequenced without a further purification step. DGGE, on the other hand, included casting of gradient gels, and several rounds of rerunning, excising, and reamplification of bands were needed for successful sequencing. In summary, DHPLC proved to be a suitable tool for routine monitoring of the diversity of SRB communities in oil field samples. PMID- 23793634 TI - Polysaccharide-degrading thermophiles generated by heterologous gene expression in Geobacillus kaustophilus HTA426. AB - Thermophiles have important advantages over mesophiles as host organisms for high temperature bioprocesses, functional production of thermostable enzymes, and efficient expression of enzymatic activities in vivo. To capitalize on these advantages of thermophiles, we describe here a new inducible gene expression system in the thermophile Geobacillus kaustophilus HTA426. Six promoter regions in the HTA426 genome were identified and analyzed for expression profiles using beta-galactosidase reporter assay. This analysis identified a promoter region upstream of a putative amylose-metabolizing gene cluster that directed high-level expression of the reporter gene. The expression was >280-fold that without a promoter and was further enhanced 12-fold by maltose addition. In association with a multicopy plasmid, this promoter region was used to express heterologous genes. Several genes, including a gene whose product was insoluble when expressed in Escherichia coli, were successfully expressed as soluble proteins, with yields of 0.16 to 59 mg/liter, and conferred new functions to G. kaustophilus strains. Remarkably, cellulase and alpha-amylase genes conferred the ability to degrade cellulose paper and insoluble starch at high temperatures, respectively, generating thermophiles with the potential to degrade plant biomass. Our results demonstrate that this novel expression system expands the potential applications of G. kaustophilus. PMID- 23793635 TI - Serotypes, virulence factors, and antimicrobial susceptibilities of vaginal and fecal isolates of Escherichia coli from giant pandas. AB - Although Escherichia coli typically colonizes the intestinal tract and vagina of giant pandas, it has caused enteric and systemic disease in giant pandas and greatly impacts the health and survival of this endangered species. In order to understand the distribution and characteristics of E. coli from giant pandas, 67 fecal and 30 vaginal E. coli isolates from 21 giant pandas were characterized for O serogroups, phylogenetic groups, antimicrobial susceptibilities, and pulsed field gel electrophoresis (PFGE) profiles. In addition, these isolates were tested for the presence of extraintestinal pathogenic E. coli (ExPEC) and diarrheagenic E. coli (DEC) by multiplex PCR detection of specific virulence genes. The most prevalent serogroups for all E. coli isolates were O88, O18, O167, O4, and O158. ExPEC isolates were detected mostly in vaginal samples, and DEC isolates were detected only in fecal samples. Phylogenetic group B1 predominated in fecal isolates, while groups B2 and D were frequently detected in vaginal isolates. Resistance to trimethoprim-sulfamethoxazole was most frequently observed, followed by resistance to nalidixic acid and tetracycline. All except five isolates were typeable by using XbaI and were categorized into 74 PFGE patterns. Our findings indicate that panda E. coli isolates exhibited antimicrobial resistance, and potentially pathogenic E. coli isolates were present in giant pandas. In addition, these E. coli isolates were genetically diverse. This study may provide helpful information for developing strategies in the future to control E. coli infections of giant pandas. PMID- 23793636 TI - Saccharification of cellulose by recombinant Rhodococcus opacus PD630 strains. AB - The noncellulolytic actinomycete Rhodococcus opacus strain PD630 is the model oleaginous prokaryote with regard to the accumulation and biosynthesis of lipids, which serve as carbon and energy storage compounds and can account for as much as 87% of the dry mass of the cell in this strain. In order to establish cellulose degradation in R. opacus PD630, we engineered strains that episomally expressed six different cellulase genes from Cellulomonas fimi ATCC 484 (cenABC, cex, cbhA) and Thermobifida fusca DSM43792 (cel6A), thereby enabling R. opacus PD630 to degrade cellulosic substrates to cellobiose. Of all the enzymes tested, five exhibited a cellulase activity toward carboxymethyl cellulose (CMC) and/or microcrystalline cellulose (MCC) as high as 0.313 +/- 0.01 U . ml(-1), but recombinant strains also hydrolyzed cotton, birch cellulose, copy paper, and wheat straw. Cocultivations of recombinant strains expressing different cellulase genes with MCC as the substrate were carried out to identify an appropriate set of cellulases for efficient hydrolysis of cellulose by R. opacus. Based on these experiments, the multicellulase gene expression plasmid pCellulose was constructed, which enabled R. opacus PD630 to hydrolyze as much as 9.3% +/- 0.6% (wt/vol) of the cellulose provided. For the direct production of lipids from birch cellulose, a two-step cocultivation experiment was carried out. In the first step, 20% (wt/vol) of the substrate was hydrolyzed by recombinant strains expressing the whole set of cellulase genes. The second step was performed by a recombinant cellobiose-utilizing strain of R. opacus PD630, which accumulated 15.1% (wt/wt) fatty acids from the cellobiose formed in the first step. PMID- 23793637 TI - Structure-activity relationship of synthetic variants of the milk-derived antimicrobial peptide alphas2-casein f(183-207). AB - Template-based studies on antimicrobial peptide (AMP) derivatives obtained through manipulation of the amino acid sequence are helpful to identify properties or residues that are important for biological activity. The present study sheds light on the importance of specific amino acids of the milk-derived alphas2-casein f(183-207) peptide to its antibacterial activity against the food borne pathogens Listeria monocytogenes and Cronobacter sakazakii. Trimming of the peptide revealed that residues at the C-terminal end of the peptide are important for activity. Removal of the last 5 amino acids at the C-terminal end and replacement of the Arg at position 23 of the peptide sequence by an Ala residue significantly decreased activity. These findings suggest that Arg23 is very important for optimal activity of the peptide. Substitution of the also positively charged Lys residues at positions 15 and 17 of the alphas2-casein f(183-207) peptide also caused a significant reduction of the effectiveness against C. sakazakii, which points toward the importance of the positive charge of the peptide for its biological activity. Indeed, simultaneous replacement of various positively charged amino acids was linked to a loss of bactericidal activity. On the other hand, replacement of Pro residues at positions 14 and 20 resulted in a significantly increased antibacterial potency, and hydrophobic end tagging of alphas2-casein f(193-203) and alphas2-casein f(197-207) peptides with multiple Trp or Phe residues significantly increased their potency against L. monocytogenes. Finally, the effect of pH (4.5 to 7.4), temperature (4 degrees C to 37 degrees C), and addition of sodium and calcium salts (1% to 3%) on the activity of the 15-amino-acid alphas2-casein f(193-207) peptide was also determined, and its biological activity was shown to be completely abolished in high-saline environments. PMID- 23793638 TI - Adjustment of trehalose metabolism in wine Saccharomyces cerevisiae strains to modify ethanol yields. AB - The ability of Saccharomyces cerevisiae to efficiently produce high levels of ethanol through glycolysis has been the focus of much scientific and industrial activity. Despite the accumulated knowledge regarding glycolysis, the modification of flux through this pathway to modify ethanol yields has proved difficult. Here, we report on the systematic screening of 66 strains with deletion mutations of genes encoding enzymes involved in central carbohydrate metabolism for altered ethanol yields. Five of these strains showing the most prominent changes in carbon flux were selected for further investigation. The genes were representative of trehalose biosynthesis (TPS1, encoding trehalose-6 phosphate synthase), central glycolysis (TDH3, encoding glyceraldehyde-3 phosphate dehydrogenase), the oxidative pentose phosphate pathway (ZWF1, encoding glucose-6-phosphate dehydrogenase), and the tricarboxylic acid (TCA) cycle (ACO1 and ACO2, encoding aconitase isoforms 1 and 2). Two strains exhibited lower ethanol yields than the wild type (tps1Delta and tdh3Delta), while the remaining three showed higher ethanol yields. To validate these findings in an industrial yeast strain, the TPS1 gene was selected as a good candidate for genetic modification to alter flux to ethanol during alcoholic fermentation in wine. Using low-strength promoters active at different stages of fermentation, the expression of the TPS1 gene was slightly upregulated, resulting in a decrease in ethanol production and an increase in trehalose biosynthesis during fermentation. Thus, the mutant screening approach was successful in terms of identifying target genes for genetic modification in commercial yeast strains with the aim of producing lower-ethanol wines. PMID- 23793639 TI - Relationship between presence of cows with milk positive for Mycobacterium avium subsp. paratuberculosis-specific antibody by enzyme-linked immunosorbent assay and viable M. avium subsp. paratuberculosis in dust in cattle barns. AB - Paratuberculosis, or Johne's disease, in cattle is caused by Mycobacterium avium subsp. paratuberculosis, which has recently been suspected to be transmitted through dust. This longitudinal study on eight commercial M. avium subsp. paratuberculosis-positive dairy farms studied the relationship between the number of cows with M. avium subsp. paratuberculosis antibody-positive milk and the presence of viable M. avium subsp. paratuberculosis in settled-dust samples, including their temporal relationship. Milk and dust samples were collected in parallel monthly for 2 years. M. avium subsp. paratuberculosis antibodies in milk were measured by enzyme-linked immunosorbent assay (ELISA) and used as a proxy for M. avium subsp. paratuberculosis shedding. Settled-dust samples were collected by using electrostatic dust collectors (EDCs) at six locations in housing for dairy cattle and young stock. The presence of viable M. avium subsp. paratuberculosis was identified by liquid culture and PCR. The results showed a positive relationship (odds ratio [OR], 1.2) between the number of cows with ELISA-positive milk and the odds of having positive EDCs in the same airspace as the adult dairy cattle. Moreover, the total number of lactating cows also showed an OR slightly above 1. This relationship remained the same for settled-dust samples collected up to 2 months before or after the time of milk sampling. The results suggest that removal of adult cows with milk positive for M. avium subsp. paratuberculosis-specific antibody by ELISA might result in a decrease in the presence of viable M. avium subsp. paratuberculosis in dust and therefore in the environment. However, this decrease is likely delayed by several weeks at least. In addition, the data support the notion that M. avium subsp. paratuberculosis exposure of young stock is reduced by separate housing. PMID- 23793640 TI - Increases in the amounts of Vibrio spp. in oysters upon addition of exogenous bacteria. AB - The bacterial pathogen Vibrio vulnificus is found naturally in brackish coastal waters but can be greatly concentrated by filter-feeding organisms such as shellfish. Numerous experiments in which exogenous V. vulnificus cells are added to oysters in an attempt to measure uptake and depuration have been performed. In nearly all cases, results have shown that laboratory-grown bacteria are rapidly taken up by the oysters but ultimately eliminated, while naturally present Vibrio populations in oysters are resistant to depuration. In this study, oysters harvested during winter months, with low culturable Vibrio concentrations, were incubated in aquaria supplemented with strains of V. vulnificus that were either genotypically or phenotypically distinct from the background bacteria. These exogenous cells were eliminated from the oysters, as previously seen, but other vibrios already inhabiting the oysters responded to the V. vulnificus inoculum by rapidly increasing in number and maintaining a large stable population. The presence of such an oyster-adapted Vibrio population would be expected to prevent colonization by exogenous V. vulnificus cells, thus explaining the rapid depuration of these added bacteria. PMID- 23793641 TI - Facility-specific "house" microbiome drives microbial landscapes of artisan cheesemaking plants. AB - Cheese fermentations involve the growth of complex microbial consortia, which often originate in the processing environment and drive the development of regional product qualities. However, the microbial milieus of cheesemaking facilities are largely unexplored and the true nature of the fermentation facility relationship remains nebulous. Thus, a high-throughput sequencing approach was employed to investigate the microbial ecosystems of two artisanal cheesemaking plants, with the goal of elucidating how the processing environment influences microbial community assemblages. Results demonstrate that fermentation associated microbes dominated most surfaces, primarily Debaryomyces and Lactococcus, indicating that establishment of these organisms on processing surfaces may play an important role in microbial transfer, beneficially directing the course of sequential fermentations. Environmental organisms detected in processing environments dominated the surface microbiota of washed-rind cheeses maturing in both facilities, demonstrating the importance of the processing environment for populating cheese microbial communities, even in inoculated cheeses. Spatial diversification within both facilities reflects the functional adaptations of microbial communities inhabiting different surfaces and the existence of facility-specific "house" microbiota, which may play a role in shaping site-specific product characteristics. PMID- 23793642 TI - Exploring environmental control of cyclic di-GMP signaling in Vibrio cholerae by using the ex vivo lysate cyclic di-GMP assay (TELCA). AB - Vibrio cholerae senses its environment, including the surrounding bacterial community, using both the second messenger cyclic di-GMP (c-di-GMP) and quorum sensing (QS) to regulate biofilm formation and other bacterial behaviors. Cyclic di-GMP is synthesized by diguanylate cyclase (DGC) enzymes and degraded by phosphodiesterase (PDE) enzymes. V. cholerae encodes a complex network of 61 enzymes predicted to mediate changes to the levels of c-di-GMP in response to extracellular signals, and the transcription of many of these enzymes is influenced by QS. Because of the complexity of the c-di-GMP signaling system in V. cholerae, it is difficult to determine if modulation of intracellular c-di-GMP in response to different stimuli is driven primarily by changes in c-di-GMP synthesis or hydrolysis. Here, we describe a novel method, named the ex vivo lysate c-di-GMP assay (TELCA), that systematically measures total DGC and PDE cellular activity. We show that V. cholerae grown in different environments exhibits significantly different intracellular levels of c-di-GMP, and we used TELCA to determine that these differences correspond to changes in both c-di-GMP synthesis and hydrolysis. Furthermore, we show that the increased concentration of c-di-GMP at low cell density is primarily due to increased DGC activity due to the DGC CdgA. Our findings highlight the idea that modulation of both total DGC and PDE activity alters the intracellular concentration of c-di-GMP, and we present a new method that is widely applicable to the systematic analysis of complex c-di-GMP signaling networks. PMID- 23793644 TI - The benzazole scaffold: a SWAT to combat Alzheimer's disease. AB - Neurodegenerative disorders including Alzheimer's disease (AD) are drawing scientists' attention within various fields, being one of the most serious diseases mankind will have to fight against in the very near future. AD is multi factorial and is characterized by two histopathological hallmarks: the senile plaques made of amyloid-beta (Abeta) peptide fibrils which also contain high levels of transition metal ions and the neurofibrillary tangles of Tau protein. Abeta aggregation, possibly modulated by metal ions, is now considered as an important factor in AD aetiology. Hence, chemists are studying the details of molecular features at the origin of the disease with special interest in Abeta aggregation and in the design of new molecules for the early diagnosis of AD or with curative properties. In this context, the benzazole molecular scaffold, included for instance in Thioflavin-T, an Abeta fibril specific dye, or the PIB imaging agent, appears to be very attractive and exhibits multiple uses. In the present review, we have thus focused our interest on the applications of benzazole derivatives for understanding, diagnosing and curing AD. After having analysed the synthetic access to 2-arylbenzazoles, we have described a selection of recent applications of such compounds aiming to combat AD. They include the use of Thioflavin-T for the monitoring of Abeta aggregation, the investigations of new PET and SPECT imaging agents for the detection of the senile plaques, the development of bi-functional molecules, encompassing the 2-arylbenzazole moiety for Abeta binding and a chelating unit for metal ions coordination for instance. PMID- 23793643 TI - Tracking down biotransformation to the genetic level: identification of a highly flexible glycosyltransferase from Saccharothrix espanaensis. AB - Saccharothrix espanaensis is a member of the order Actinomycetales. The genome of the strain has been sequenced recently, revealing 106 glycosyltransferase genes. In this paper, we report the detection of a glycosyltransferase from Saccharothrix espanaensis which is able to rhamnosylate different phenolic compounds targeting different positions of the molecules. The gene encoding the flexible glycosyltransferase is not located close to a natural product biosynthetic gene cluster. Therefore, the native function of this enzyme might be not the biosynthesis of a secondary metabolite but the glycosylation of internal and external natural products as part of a defense mechanism. PMID- 23793645 TI - The temporal changes in road stormwater runoff quality and the implications to first flush control in Chongqing, China. AB - This study investigates the quality of stormwater runoff from a driveway in the southwest mountainous urban area of Chongqing, China, from 2010 to 2011. The results showed that the mean concentrations of chemical oxygen demand (COD), total nitrogen (TN), and total phosphorus (TP) were 4.1, 2.4, and 2.2 times the grade V levels of the national surface water standard of China. The pollutant concentration peak preceded or synchronized with the rainfall intensity peak and occurred 10 min after the runoff started. The significant high pollutant concentration in the initial stage of the rainfall suggested that first flush control is necessary, especially for the most polluted constitutes, such as total suspended solids, COD, and TN. Three potential pollution sources were identified: the atmospheric dry and wet deposition (TN, NO3(-)-N, NH4(+)-N, and DCu), the road sediment and materials (total suspended solids, COD, and TP), and the vehicle emissions (DPb and DZn). Therefore, this study indicates that reductions in road sediments and material pollution and dry and wet deposition should be the priority factors for pollution control of road stormwater runoff in mountainous urban areas. PMID- 23793646 TI - What factors determine trace metal contamination in Lake Tonga (Algeria)? AB - A study of trace metal (TM) contamination was conducted at Lake Tonga (Algeria), a site surrounded by several indirect contamination point sources such as an abandoned mine and steelworks. Studying two sampling sites over four seasons, we were able to depict the spatial and temporal variability of TM contamination in the lake. Among the seven TM examined (Pb, Cd, Fe, Zn, Ni, Cu, and Cr), only Fe, Pb, and Cd showed concentrations significantly higher than the site's geological background. The contamination index (sediment concentration/background concentration) calculated for these three TM (Cd = 1.9 +/- 1.6, Fe = 6.8 +/- 1.8, and Pb = 3.3 +/- 2.6) clearly indicated anthropogenic contamination. Sediment TM contamination differed both between sampling sites and seasons despite environmental variables (e.g., oxygen and pH) being similar, thus suggesting different TM contamination sources. Fe contamination was high at the two sampling sites and over all studied seasons, possibly indicating general lake-scale Fe contamination, probably related to atmospheric deposition of steelworks emissions both on the lake and within the watershed. Lake tributaries were further suspected of channeling Fe contamination from the watershed into the lake. On the other hand, the sampling site close to the outlet was especially rich in Cd and Pb typically reflecting contamination by mine wastes. The indirect connection between the abandoned mine and the lake indicates that runoff of mine leachates through groundwater was likely a candidate in explaining the specificity of the TM contamination in this part of the lake. This study provides insights for management of TM contamination by addressing both spatial and temporal variability within the lake as well as differences in contamination sources. PMID- 23793647 TI - Residents' concerns and attitudes toward a municipal solid waste landfill: integrating a questionnaire survey and GIS techniques. AB - The ever-growing industry of municipal solid waste (MSW) disposal appeals to the growing need for disposal facilities, and MSW treatment facilities are increasingly an environmental and public health concern. Residents living near MSW management facilities are confronted with various risk perceptions, especially odour. In this study, in an effort to assist responsible decision makers in better planning and managing such a project, a structured questionnaire was designed and distributed to assess the nearby residents' concerns and attitudes surrounding the Laogang Landfill in Shanghai. Geographic information system techniques and relevance analysis were employed to conduct the spatial analysis of physical perceptions, especially odour annoyance. The findings of the research indicate that a significant percentage of the responding sample was aware of the negative impacts of landfills on the environment and public health, and residents in close proximity preferred to live farther from the landfill. The results from the spatial analysis demonstrated a definite degree of correlation between odour annoyance and distance to the facility and proved that the benefits of the socially disadvantaged have been neglected. The research findings also direct attention to the important role of public participation, information disclosure, transparency in management, and mutual communication to avoid conflicts and build social trust. PMID- 23793648 TI - Impact of Zn and Cu on the development of phenanthrene catabolism in soil. AB - Mixtures of polycyclic aromatic hydrocarbons (PAHs) and heavy metals are of major concern in contaminated soil. Biodegradation of PAHs in metal-contaminated soils is complicated because metals are toxic and cannot be degraded by biological processes. This investigation considered the effects of Zn and Cu (50, 100, 500 and 1,000 mg/kg) on (14)C-phenanthrene biodegradation in soil over 60-day contact time. The presence of Zn at all concentrations and low concentrations of Cu (50 and 100 mg/kg) had no significant effect (p > 0.05) on the development of phenanthrene catabolism; however, at higher Cu concentrations, the development of phenanthrene catabolism and bacterial cell numbers were significantly reduced (p < 0.05). This suggests that Cu is more toxic than Zn to soil microbial PAH catabolic activity. Metal/PAH-contaminated soils represent one of the most difficult remedial challenges and insights into PAH biodegradation in the presence of metals is necessary in order to assess the potential for bioremediation. PMID- 23793649 TI - Experiences of patients and professionals participating in the HITS home blood pressure telemonitoring trial: a qualitative study. AB - OBJECTIVES: To explore the experiences of patients and professionals taking part in a randomised controlled trial (RCT) of remote blood pressure (BP) telemonitoring supported by primary care. To identify factors facilitating or hindering the effectiveness of the intervention and those likely to influence its potential translation to routine practice. DESIGN: Qualitative study adopting a qualitative descriptive approach. PARTICIPANTS: 25 patients, 11 nurses and 9 doctors who were participating in an RCT of BP telemonitoring. A maximum variation sample of patients from within the trial based on age, sex and deprivation status of the practice was sought. SETTING: 6 primary care practices in Scotland. METHOD: Data were collected via taped semistructured interviews. Initial thematic analysis was inductive. Multiple strategies were employed to ensure that the analysis was credible and trustworthy. RESULTS: Prior to the trial, both patients and professionals were reluctant to increase the medication based on single BP measurements taken in the surgery. BP measurements based on multiple electronic readings were perceived as more accurate as a basis for action. Patients using telemonitoring became more engaged in the clinical management of their condition. Professionals reported that telemonitoring challenged existing roles and work practices and increased workload. Lack of integration of telemonitoring data with the electronic health record was perceived as a drawback. CONCLUSIONS: BP telemonitoring in a usual care setting can provide a trusted basis for medication management and improved BP control. It increases patients' engagement in the management of their condition, but supporting telemetry and greater patient engagement can increase professional workloads and demand changes in service organisation. Successful service design in practice would have to take account of how additional roles and responsibilities could be realigned with existing work and data management practices. The embedded qualitative study was included in the protocol for the HITS trial registered with ISRCTN no. 72614272. PMID- 23793650 TI - Telemonitoring-based service redesign for the management of uncontrolled hypertension (HITS): cost and cost-effectiveness analysis of a randomised controlled trial. AB - OBJECTIVES: To compare the costs and cost-effectiveness of managing patients with uncontrolled blood pressure (BP) using telemonitoring versus usual care from the perspective of the National Health Service (NHS). DESIGN: Within trial post hoc economic evaluation of data from a pragmatic randomised controlled trial using an intention-to-treat approach. SETTING: 20 socioeconomically diverse general practices in Lothian, Scotland. PARTICIPANTS: 401 primary care patients aged 29 95 with uncontrolled daytime ambulatory blood pressure (ABP) (>=135/85, but <210/135 mm Hg). INTERVENTION: Participants were centrally randomised to 6 months of a telemonitoring service comprising of self-monitoring of BP transmitted to a secure website for review by the attending nurse/doctor and patient, with optional automated patient decision-support by text/email (n=200) or usual care (n-201). Randomisation was undertaken with minimisation for age, sex, family practice, use of three or more hypertension drugs and self-monitoring history. MAIN OUTCOME MEASURES: Mean difference in total NHS costs between trial arms and blinded assessment of mean cost per 1 mm Hg systolic BP point reduced. RESULTS: Home telemonitoring of BP costs significantly more than usual care (mean difference per patient L115.32 (95% CI L83.49 to L146.63; p<0.001)). Increased costs were due to telemonitoring service costs, patient training and additional general practitioner and nurse consultations. The mean cost of systolic BP reduction was L25.56/mm Hg (95% CI L16.06 to L46.89) per patient. CONCLUSIONS: Over the 6-month trial period, supported telemonitoring was more effective at reducing BP than usual care but also more expensive. If clinical gains are maintained, these additional costs would be very likely to be compensated for by reductions in the cost of future cardiovascular events. Longer-term modelling of costs and outcomes is required to fully examine the cost-effectiveness implications. TRIAL REGISTRATION: International Standard Randomised Controlled Trials, number ISRCTN72614272. PMID- 23793651 TI - Suicide risk in relation to air pollen counts: a study based on data from Danish registers. AB - OBJECTIVES: Since the well-observed spring peak of suicide incidents coincides with the peak of seasonal aeroallergens as tree-pollen, we want to document an association between suicide and pollen exposure with empirical data from Denmark. DESIGN: Ecological time series study. SETTING: Data on suicide incidents, air pollen counts and meteorological status were retrieved from Danish registries. PARTICIPANTS: 13 700 suicide incidents over 1304 consecutive weeks were obtained from two large areas covering 2.86 million residents. PRIMARY AND SECONDARY OUTCOME MEASURES: Risk of suicide associated with pollen concentration was assessed using a time series Poisson-generalised additive model. RESULTS: We noted a significant association between suicide risk and air pollen counts. A change of pollen counts levels from 0 to '10-<30' grains/m(3) air was associated with a relative risk of 1.064, that is, a 6.4% increase in weekly number of suicides in the population, and from 0 to '30-100' grains, a relative risk of 1.132. The observed association remained significant after controlling for effects of region, calendar time, temperature, cloud cover and humidity. Meanwhile, we observed a significant sex difference that suicide risk in men started to rise when there was a small increase of air pollen, while the risk in women started to rise until pollen grains reached a certain level. High levels of pollen had slightly stronger effect on risk of suicide in individuals with mood disorder than those without the disorder. CONCLUSIONS: The observed association between suicide risk and air pollen counts supports the hypothesis that aeroallergens, acting as immune triggers, may precipitate suicide. PMID- 23793652 TI - Premature retirement due to ill health and income poverty: a cross-sectional study of older workers. AB - OBJECTIVES: To assess the income-poverty status of Australians who were aged between 45 and 64 years and were out of the labour force due to ill health. DESIGN: A cross-sectional study using a microsimulation model of the 2009 Australian population (Health&WealthMOD). SETTING: 2009 Australian population. PARTICIPANTS: 9198 people aged between 45 and 64 years surveyed for the 2003 Survey of Disability, Ageing and Carers. PRIMARY OUTCOME MEASURES: 50% of the median equivalised income-unit-income poverty line. RESULTS: It was found that individuals who had retired early due to other reasons were significantly less likely to be in income poverty than those retired due to ill health (OR 0.43 95% CI 0.33 to 0.51), and there was no significant difference in the likelihood of being in income poverty between these individuals and those unemployed. Being in the same family as someone who is retired due to illness also significantly increases an individual's chance of being in income poverty. CONCLUSIONS: It can be seen that being retired due to illness impacts both the individual and their family. PMID- 23793653 TI - Professionalisation and social attitudes: a protocol for measuring changes in HIV/AIDS-related stigma among healthcare students. AB - INTRODUCTION: HIV/AIDS-related stigma affects the access and utilisation of health services. Although HIV/AIDS-related stigma in the health services has been studied, little work has attended to the relationship between professional development and stigmatising attitudes. Hence, in this study, we will extend earlier research by examining the relationship between the stage of professional development and the kinds of stigmatising attitudes held about people living with HIV/AIDS. METHODS AND ANALYSIS: A serial cross-sectional design will be combined with a two-point in time longitudinal design to measure the levels of stigma among healthcare students from each year of undergraduate and graduate courses in Malaysia and Australia. In the absence of suitable measures, we will carry out a sequential mixed methods design to develop such a tool. The questionnaire data will be analysed using mixed effects linear models to manage the repeated measures. ETHICS AND DISSEMINATION: We have received ethical approval from the Monash MBBS executive committee as well as the Monash University Human Research Ethics Committee. We will keep the data in a locked filing cabinet in the Monash University (Sunway campus) premises for 5 years, after which the information will be shredded and disposed of in secure bins, and digital recordings will be erased in accordance with Monash University's regulations. Only the principal investigator and the researcher will have access to the filing cabinet. We aim to present and publish the results of this study in national and international conferences and peer-reviewed journals, respectively. PMID- 23793654 TI - Neonatal complications in public and private patients: a retrospective cohort study. AB - OBJECTIVE: To use propensity score methods to create similar groups of women delivering in public and private hospitals and determine any differences in mode of delivery and neonatal outcomes between the matched groups. DESIGN: Population based, retrospective cohort study. SETTING: Public and private hospitals in Western Australia. PARTICIPANTS: Included were 93 802 public and 66 479 private singleton, term deliveries during 1998-2008, from which 32 757 public patients were matched with 32 757 private patients on the propensity score of maternal characteristics. MAIN OUTCOME MEASURES: Neonatal outcomes were compared in the propensity score-matched cohorts using conditional logistic regression, adjusted for antenatal risk factors and mode of delivery. Outcomes included Apgar score <7 at 5 min, neonatal resuscitation (endotracheal intubation or external cardiac massage) and admission to a neonatal special care unit. RESULTS: No significant differences in maternal characteristics were found between the propensity score matched groups. Private patients were more likely than their matched public counterparts to undergo prelabour caesarean section (25.2% vs 18%, p<0.0001). Public patients had lower rates of neonatal unit admission (AOR 0.67, 95% CI 0.62 to 0.73) and neonatal resuscitation (AOR 0.73, 95% CI 0.56 to 0.95), but higher rates of low Apgar scores at 5 min (AOR 1.31, 95% CI 1.06 to 1.63) despite adjustment for antenatal factors. Additional adjustment for mode of delivery reduced the resuscitation risk (AOR 0.86, 95% CI 0.63 to 1.18) but did not significantly alter the other estimates. CONCLUSIONS: Propensity score methods can be used to generate comparable groups of public and private patients. Despite the rates of low Apgar scores being higher in public patients, the rates of special care admission were lower. Whether these findings stem from differences in paediatric services or clinical factors is yet to be determined. PMID- 23793655 TI - The influence of pregnancy termination on the outcome of subsequent pregnancies: a retrospective cohort study. AB - OBJECTIVE: To compare the incidences of preterm delivery, cervical incompetence treated by cerclage, placental implantation or retention problems (ie, placenta praevia, placental abruption and retained placenta) and postpartum haemorrhage between women with and without a history of pregnancy termination. DESIGN: A retrospective cohort study using aggregated data from a national perinatal registry. SETTING: All midwifery practices and hospitals in the Netherlands. PARTICIPANTS: All pregnant women with a singleton pregnancy without congenital malformations and a gestational age of >=20 weeks who delivered between January 2000 and December 2007. MAIN OUTCOME MEASURES: Preterm delivery, cervical incompetence treated by cerclage, placenta praevia, placental abruption, retained placenta and postpartum haemorrhage. RESULTS: A previous pregnancy termination was reported in 16 000 (1.2%) deliveries. The vast majority of these (90-95%) were performed by surgical methods. The incidence of all outcome measures was significantly higher in women with a history of pregnancy termination. Adjusted ORs (95% CI) for cervical incompetence treated by cerclage, preterm delivery, placental implantation or retention problems and postpartum haemorrhage were 4.6 (2.9 to 7.2), 1.11 (1.02 to 1.20), 1.42 (1.29 to 1.55) and 1.16 (1.08 to 1.25), respectively. Associated numbers needed to harm were 1000, 167, 111 and 111, respectively. For any listed adverse outcome, the number needed to harm was 63. CONCLUSIONS: In this large nationwide cohort study, we found a positive association between surgical termination of pregnancy and subsequent preterm delivery, cervical incompetence treated by cerclage, placental implantation or retention problems and postpartum haemorrhage in a subsequent pregnancy. Absolute risks for these outcomes, however, remain small. Medicinal termination might be considered first whenever there is a choice between both methods. PMID- 23793657 TI - Correction. PMID- 23793656 TI - Inattention and hyperactivity in children at risk of obesity: a community cross sectional study. AB - OBJECTIVE: There is a link between the symptoms of hyperactivity/inattention and overweight in children. Less is known about the factors which might influence this relationship, such as physical and sedentary activity levels or exercise self-efficacy. The aim of this study is to examine the associations between the symptoms of hyperactivity/inattention and risk factors for adult obesity in a sample of children with barriers to exercise. DESIGN: Children aged 9-11 years were recruited from 24 primary schools that participated in the Steps to Active Kids (STAK) physical activity intervention study. Study inclusion criteria were low exercise self-efficacy, teacher-rated overweight or asthma. Children with high levels of physical activity were excluded. Measures included parent and teacher-rated behavioural and emotional well-being using the Strengths and Difficulties Questionnaire, physical and sedentary activity levels, BMI (body mass index) and exercise self-efficacy. RESULTS: Of 424 participating children, 62% were girls and 39% were classified as overweight or obese. As compared with population norms, boys in this at-risk sample were more likely to receive an abnormal teacher-rated hyperactivity/inattention score (OR 1.48, 95% CI 1.01 to 2.17). Children with teacher-rated abnormal hyperactivity/inattention scores reported higher levels of sedentary activity (OR 1.13, 95% CI 1.02 to 1.17), but not physically active activity. The pattern of findings was similar for children with hyperactivity/inattention problems as rated by both parent and teacher (pervasive hyperactivity and impairment). CONCLUSIONS: Although BMI was not directly related to hyperactivity/inattention, children with risk factors for adult obesity have more hyperactivity/inattention problems. In particular, hyperactivity/inattention is associated with higher levels of sedentary activity. Higher rates of pervasive hyperactivity and impairment were apparent in this at risk group. PMID- 23793658 TI - Microbleeds as a predictor of intracerebral haemorrhage and ischaemic stroke after a TIA or minor ischaemic stroke: a cohort study. AB - OBJECTIVES: We examined whether patients with cerebral microbleeds on MRI, who started and continued antithrombotic medication for years, have an increased risk of symptomatic intracerebral haemorrhage (ICH). DESIGN: Prospective cohort study. SETTINGS: Multicentre outpatient clinics in the Netherlands. PARTICIPANTS: We followed 397 patients with newly diagnosed transient ischaemic attack (TIA) or minor ischaemic stroke receiving anticoagulants or antiplatelet drugs. 58% were men. The mean age was 65.3 years. 395 (99%) patients were white Europeans. MRI including a T2*-weighted gradient echo was performed within 3 months after start of medication. 48 (12%) patients had one or more microbleeds. They were followed every 6 months by telephone for a mean of 3.8 years. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was a symptomatic ICH. Secondary outcome were all strokes, ischaemic stroke, myocardial infarct, death from all vascular causes, death from non-vascular causes and death from all causes. RESULTS: Five patients (1%) suffered from a symptomatic ICH. One ICH occurred in a patient with microbleeds at baseline (adjusted HR 2.6, 95% CI 0.3 to 27). The incidence of all strokes during follow-up was higher in patients with than without microbleeds (adjusted HR 2.3, 95% CI 1.0 to 5.3), with a dose-response relationship. The incidences of ischaemic stroke, vascular death, non-vascular death and death of all causes were higher in patients with microbleeds, but not statistically significant. CONCLUSIONS: In our cohort of patients using antithrombotic drugs after a TIA or minor ischaemic stroke, we found that microbleeds on MRI are associated with an increased risk of future stroke in general, but we did not find an increased risk of symptomatic ICH. PMID- 23793659 TI - Endoscopic retrograde cholangiopancreatography: utilisation and outcomes in a 10 year population-based cohort. AB - OBJECTIVE: To determine utilisation of endoscopic retrograde cholangiopancreatography (ERCP); incidence of inpatient admissions for complications occurring within 30 days of ERCP and risk factors for procedural related complications, in a population-based study. DESIGN: Retrospective cohort study. SETTING: Olmsted County, Minnesota. PARTICIPANTS: All adult residents of Olmsted County, Minnesota, who underwent ERCP from 1997 to 2006. INTERVENTIONS: Diagnostic and therapeutic ERCPs were assessed. PRIMARY AND SECONDARY OUTCOME MEASURES: Patient and procedural characteristics and complications within 30 days; and rates of ERCP utilisation and unplanned admissions and risk factors for admissions. RESULTS: In 10 years, 1072 ERCPs were performed on 827 individual patients. Average utilisation of ERCP was 83.1 ERCPs/100 000 persons/year, with an increase from 58 to 104.8 ERCPs/100 000 persons/year over time, driven by increases in therapeutic procedures. Within 30 days after 236 procedures, 62 admissions were definitely related to the index ERCP. The complication rate was 5.3%, including pancreatitis (26, 2.4%), infection/cholangitis (16, 1.5%), bleeding (15, 1.4%) and perforation (4, 0.37%). 30-day mortality was 2.4%, none of which was directly related to the ERCP or complications thereof. Risk factors identified through multivariate analysis to be associated with adverse events included: age <45 years (p=0.0498); body mass index >=35 (p=0.0024); pancreatic duct cannulation (p=0.0026); outpatient procedure (p<0.0001); intraprocedure sphincterotomy bleeding (p<0.0001); difficulty grade (p=0.115) and patient's first ERCP (p=0.0394). LIMITATIONS: Retrospective study. CONCLUSIONS: Population utilisation of ERCP rose during the study period, specifically in therapeutic procedures. Admissions within 30 days of ERCP are common but often unrelated. Complications of ERCP remain infrequent and deaths quite unusual. PMID- 23793660 TI - Influence of the US President's Emergency Plan for AIDS Relief (PEPfAR) on career choices and emigration of health-profession graduates from a Ugandan medical school: a cross-sectional study. AB - OBJECTIVE: The purpose of this study was to determine the current work distribution of health professionals from a public Ugandan medical school in a period of major donor funding for HIV programmes. We explore the hypothesis that programmes initiated under unprecedented health investments from the US President's Emergency Plan for AIDS Relief have possibly facilitated the drain of healthcare workers from the public-health system of countries like Uganda. DESIGN: Cross-sectional study conducted between January and December 2010 to survey graduates, using in-person, phone or online surveys using email and social networks. Logistic regression analysis was applied to determine ORs for association between predictors and outcomes. SETTING: Located rurally, Mbarara University of Science and Technology (MUST) is one of three government supported medical schools in Uganda. PARTICIPANTS: Graduates who completed a health-related degree at MUST. MAIN OUTCOME MEASURE: Location of health profession graduates (Uganda or abroad) and main field of current job (HIV-related non-governmental organisation (NGO) or others). RESULTS: We interviewed 85.4% (n=796) of all MUST alumni since the university opened in 1989. 78% (n=618) were physicians and 12% (n=94) of graduates worked outside Uganda. Over 50% (n=383) of graduates worked for an HIV-related NGO whether in Uganda or abroad. Graduates receiving their degree after 2005, when large HIV programmes started, were less likely to leave the country, OR=0.24 (95% CI 0.1 to 0.59) but were more likely to work for an HIV related NGO, OR=1.53 (95% CI 1.06 to 2.23). CONCLUSIONS: A majority of health professionals surveyed work for an HIV-related NGO. The increase in resources and investment in HIV-treatment capacity is temporally associated with retention of medical providers in Uganda. Donor funds should be channelled to develop and retain healthcare workers in disciplines other than HIV and broaden the healthcare workforce to other areas. PMID- 23793661 TI - Primary healthcare costs associated with sleep problems up to age 7 years: Australian population-based study. AB - OBJECTIVES: In Australian 0-7-year olds with and without sleep problems, to compare (1) type and costs to government of non-hospital healthcare services and prescription medication in each year of age and (2) the cumulative costs according to persistence of the sleep problem. DESIGN: Cross-sectional and longitudinal data from a longitudinal population study. SETTING: Data from two cohorts participating in the first two waves of the nationally representative Longitudinal Study of Australian Children. PARTICIPANTS: Baby cohort at ages 0-1 and 2-3 (n=5107, 4606) and Kindergarten cohort at ages 4-5 and 6-7 (n=4983, 4460). MEASUREMENTS: Federal Government expenditure on healthcare attendances and prescription medication from birth to 8 years, calculated via linkage to Australian Medicare data, were compared according to parent report of child sleep problems at each of the surveys. RESULTS: At both waves and in both cohorts, over 92% of children had both sleep and Medicare data. The average additional healthcare costs for children with sleep problems ranged from $141 (age 5) to $43 (age 7), falling to $98 (age 5) to $18 (age 7) per child per annum once family socioeconomic position, child gender, global health and special healthcare needs were taken into account. This equates to an estimated additional $27.5 million (95% CI $9.2 to $46.8 million) cost to the Australian federal government every year for all children aged between 0 and 7 years. In both cohorts, costs were higher for persistent than transient sleep problems. CONCLUSIONS: Higher healthcare costs were sustained by infants and children with sleep problems. This supports ongoing economic evaluations of early prevention and intervention services for sleep problems considering impacts not only on the child and family but also on the healthcare system. PMID- 23793662 TI - Are emergency admissions in palliative cancer care always necessary? Results from a descriptive study. AB - OBJECTIVES: Patients with advanced cancer are often admitted to hospital as emergency cases. This may not always be medically indicated. Study objectives were to register the reasons for the emergency admissions, to examine interventions performed during hospitalisation and self-reported symptom intensity at admission and discharge, and to assess patients' opinions about the admission. DESIGN: This was a descriptive before-and-after study. Participating patients completed the Edmonton Symptom Assessment System (ESAS) twice, upon hospital admission and prior to discharge. All patients underwent a structured interview assessing their opinion about the emergency admission. Medical data were obtained from the hospital records. SETTING: The study was performed in two Norwegian acute care secondary hospitals with urban catchment areas. PARTICIPANTS: 44 patients with cancer (men 27 and women 17; mean age 69.2, SD 9.2) representing 50 emergency admissions were included. RESULTS: Median length of stay was 7 days (95% CI 7.4 to 11.4). Median survival was 50 days (95% CI 51 to 115). 90% were admitted from home, and 46% had been hospitalised less than 1 month earlier. Lung and gastrointestinal symptoms and pain were the most frequent reasons for admissions. Mean pain scores on ESAS were reduced by 50% from admission to discharge (p<0.01). Simple interventions such as hydration, bladder catheterisation and oxygen therapy were most frequent. Nearly one-third would have preferred treatment at another site, provided that the quality of care was similar. Home visits by the family doctor and specialised care teams were perceived by patients as important to prevent hospitalisation. CONCLUSIONS: In most emergency admissions, relatively simple medical interventions are necessary. Specialised care teams with palliative care physicians, easier access to the family doctor and better lines of cooperation between hospitals and the primary care sector may make it possible to perform more of these procedures at home, thereby reducing the need for emergency admissions. PMID- 23793663 TI - Surgery versus prolonged conservative treatment for sciatica: 5-year results of a randomised controlled trial. AB - OBJECTIVE: This study describes the 5 years' results of the Sciatica trial focused on pain, disability, (un)satisfactory recovery and predictors for unsatisfactory recovery. DESIGN: A randomised controlled trial. SETTING: Nine Dutch hospitals. PARTICIPANTS: Five years' follow-up data from 231 of 283 patients (82%) were collected. INTERVENTION: Early surgery or an intended 6 months of conservative treatment. MAIN OUTCOME MEASURES: Scores from Roland disability questionnaire, visual analogue scale (VAS) for leg and back pain and a Likert self-rating scale of global perceived recovery were analysed. RESULTS: There were no significant differences between groups on the 5 years' primary outcome scores. Despite at least 6 months of conservative treatment 46% of the conservatively allocated patients were treated surgically because of severe leg pain and disability. Forty-nine (21%) patients had an unsatisfactory recovery at 5 years and the recovery pattern showed that there was a variable group of 66 patients (31%) with at least one unsatisfactory outcome at 1, 2 or 5 years of follow-up. Multivariate logistic regression showed that age (>40; OR 2.42 (95% CI 1.16 to 5.02)), severity of leg pain (VAS >70; OR 3.32 (95% CI 1.69 to 6.54)) and the Mc Gill affective score (score >3; OR 6.23 (95% CI 2.23 to 17.38)) were the only significant predictors for an unsatisfactory outcome at 5 years. CONCLUSIONS: In the long term, 8% of the patients with sciatica never showed any recovery and in at least 23%, sciatica appears to result in ongoing complaints, which fluctuate over time, irrespective of treatment. Prolonged conservative care might give patients a fair chance for pain and disability to resolve without surgery, but with the risk to receive delayed surgery after prolonged suffering of sciatica. Age above 40 years, severe leg pain at baseline and a higher affective Mc Gill pain score were predictors for unsatisfactory recovery. Trial Registry ISRCT No 26872154. PMID- 23793664 TI - Asthma mortality in Australia in the 21st century: a case series analysis. AB - OBJECTIVE: As previous asthma mortality studies were undertaken between 1986 and 1997, and treatments have evolved since that time, in order to direct future asthma interventions, we investigated the reasons for asthma deaths between 2005 and 2009. DESIGN: We undertook a case series analysis by searching the National Coroners' Information System using the most recent International Classification of Diseases-10 codes J45 and J46 and the keyword 'asthma' as the underlying cause of death. SETTING: Records for 283 cases aged 70 years and under were retrieved from each Australian state and territory. Coroner's findings, autopsy, toxicology and police reports were reviewed to determine: if the team agreed the death was due to asthma and whether the death was preventable or modifiable factors existed? Owing to the likelihood of comorbidities or alternative diagnoses contributing to deaths in those over 70 years of age, this group was excluded. RESULTS: Examination of available data in those aged under 70 years identified risk factors associated with asthma death. These included physical barriers (rural and remote location, institutionalised care), psychosocial issues (social disengagement, mental illness, living alone, being unemployed), smoking, drug and alcohol dependence, allergies, respiratory tract infections, inadequate treatment and delay in seeking help. CONCLUSIONS: Our study provides a current assessment of death from asthma across Australia. Further reductions in the rate of asthma deaths will require interventions targeted at the personal, practice and policy levels. Asthma-related health literacy needs to be improved especially among those with episodic asthma. Reforms are also needed to address inequity in healthcare delivery to 'reach the unreached'. Our study points to the dangers associated with smoking, drug and alcohol use and the consequences of delay in seeking care among those with asthma. PMID- 23793665 TI - A nationwide Danish cohort study challenging the categorisation into right-sided and left-sided colon cancer. AB - OBJECTIVES: The categorisation of colon cancer (CC) into right-sided (RCC) and left-sided (LCC) disease may not capture more subtle variances in aetiology and prognosis. In a nationwide study, we investigated differences in clinical characteristics and survival of RCC versus LCC and of the complete range of CC subsites. DESIGN: Prospective nationwide cohort study. SETTING: The database of the Danish Colorectal Cancer Group (DCCG). PARTICIPANTS: 23 487 CC patients. OUTCOME MEASURES: Overall survival (Kaplan-Meier plots) and mortality (HR from Cox proportional hazards regression analysis) according to CC localisation. For adjustment and stratification, we used age, sex, ASA score (the American Society of Anaesthesiologists score), tumour location and stage, number of lymph nodes harvested at operation, number of lymph nodes with metastases and presence of distant metastases. RESULTS: Patients with RCC had a higher median age at diagnosis (74.3 years) than patients with LCC (71.8 years; p<0.0001). Overall, the proportion of patients who were women increased the closer the tumour site was to the small intestine. Although RCC patients had higher ASA scores than LCC patients (p<0.0001), the highest ASA scores were observed in patients with cancer in the transverse and descending colon and at both colon flexures. While RCCs overall were more advanced than LCCs (p<0.0001), the most advanced CCs were those of the descending colon, splenic flexure and caecum. RCC mortality was higher than LCC mortality only during the first 2 years (women: HR 1.13; 95% CI 1.06 to 1.20; men: HR 1.27; 95% CI 1.20 to 1.35), and relative to mortality from sigmoid CC, the highest mortality was observed from splenic flexure cancer (HR 1.75; 95% CI 1.54 to 2.00). CONCLUSIONS: The present data challenge the simple categorisation of CC into RCC and LCC. PMID- 23793666 TI - Risk factors for hand injury in hurling: a cross-sectional study. AB - OBJECTIVES: Hurling is Ireland's national sport, played with a stick and ball; injury to the hand is common. A decrease in the proportion of head injury among emergency department (ED) presentations for hurling-related injury has coincided with voluntary use of helmet and face protection since 2003. A similar decrease in proportions has not occurred in hand injury. We aim to quantify hurling related ED presentations and examine variables associated with injury. In particular, we were interested in comparing the occurrence of hand injury in those using head and face protection versus those who did not. DESIGN: This study utilised a retrospective cross-sectional study design. SETTING: This study took place at a university hospital ED over a 3-month period. OUTCOME MEASURES: A follow-up telephone interview was performed with 163 players aged >=16 years to reflect voluntary versus obligatory helmet use. RESULTS: The hand was most often injured (n=85, 52.1%). Hand injury most commonly occurred from a blow of a hurley (n=104, 65%), and fracture was confirmed in 62% of cases. Two-thirds of players (66.3%) had multiple previous (1-5) hand injuries. Most patients 149 (91.4%) had tried commercially available hand protection, but only 4.9% used hand protection regularly. Univariate analysis showed a statistically significant association between wearing a helmet and faceguard and hand injury; OR 2.76 (95% CI 1.42 to 5.37) p=0.003. On further analysis adjusting simultaneously for age, prior injury, foul play and being struck by a hurley, this relationship remained significant (OR 3.15 95% CI 1.51 to 6.56, p=0.002). CONCLUSIONS: We report that hurling-related hand injury is common. We noted the low uptake of hand protection. We found that hand injury was significantly associated with the use of helmet and faceguard protection, independent of the other factors studied. Further studies are warranted to develop strategies to minimise the occurrence of this injury. PMID- 23793667 TI - Effects of train noise and vibration on human heart rate during sleep: an experimental study. AB - OBJECTIVES: Transportation of goods on railways is increasing and the majority of the increased numbers of freight trains run during the night. Transportation noise has adverse effects on sleep structure, affects the heart rate (HR) during sleep and may be linked to cardiovascular disease. Freight trains also generate vibration and little is known regarding the impact of vibration on human sleep. A laboratory study was conducted to examine how a realistic nocturnal railway traffic scenario influences HR during sleep. DESIGN: Case-control. SETTING: Healthy participants. PARTICIPANTS: 24 healthy volunteers (11 men, 13 women, 19 28 years) spent six consecutive nights in the sleep laboratory. INTERVENTIONS: All participants slept during one habituation night, one control and four experimental nights in which train noise and vibration were reproduced. In the experimental nights, 20 or 36 trains with low-vibration or high-vibration characteristics were presented. PRIMARY AND SECONDARY OUTCOME MEASURES: Polysomnographical data and ECG were recorded. RESULTS: The train exposure led to a significant change of HR within 1 min of exposure onset (p=0.002), characterised by an initial and a delayed increase of HR. The high-vibration condition provoked an average increase of at least 3 bpm per train in 79% of the participants. Cardiac responses were in general higher in the high-vibration condition than in the low-vibration condition (p=0.006). No significant effect of noise sensitivity and gender was revealed, although there was a tendency for men to exhibit stronger HR acceleration than women. CONCLUSIONS: Freight trains provoke HR accelerations during sleep, and the vibration characteristics of the trains are of special importance. In the long term, this may affect cardiovascular functioning of persons living close to railways. PMID- 23793668 TI - An observational study of malaria in British travellers: Plasmodium ovale wallikeri and Plasmodium ovale curtisi differ significantly in the duration of latency. AB - OBJECTIVES: Ovale malaria is caused by two closely related species of protozoan parasite: Plasmodium ovale curtisi and Plasmodium ovale wallikeri Although clearly distinct genetically, there have been no studies comparing the morphology, life cycle or epidemiology of these parasites. We tested the hypothesis that the two species differ in the duration of latency prior to presentation with symptoms of blood-stage infection. DESIGN: PCR was used to identify P ovale curtisi and P ovale wallikeri infections among archived blood from UK malaria patients. Latency periods, estimated as the time between entry into the UK and diagnosis of malaria, were compared between the two groups. SETTING: UK National Reference Laboratory. PARTICIPANTS: None. Archived parasite material and surveillance data for 74 P ovale curtisi and 60 P ovale wallikeri infections were analysed. Additional epidemiological data were taken from a database of 1045 imported cases. OUTCOMES: None. RESULTS: No differences between the two species were identified by a detailed comparison of parasite morphology (N=9, N=8, respectively) and sex ratio (N=5, N=4) in archived blood films. The geometric mean latency period in P ovale wallikeri was 40.6 days (95% CI 28.9 to 57.0), whereas that for P ovale curtisi was more than twice as long at 85.7 days (95% CI 66.1 to 111.1; p=0.002). Further, the proportion of ovale malaria sensu lato which occurred in patients reporting chemoprophylaxis use was higher than for Plasmodium falciparum (OR 7.56; p<0.0001) or P vivax (OR 1.82; p<0.0001). CONCLUSIONS: These findings provide the first difference of epidemiological significance observed between the two parasites which cause ovale malaria, and suggest that control measures aimed at P falciparum may not be adequate for reducing the burden of malaria caused by P ovale curtisi and P ovale wallikeri. PMID- 23793669 TI - Evidence-based commissioning in the English NHS: who uses which sources of evidence? A survey 2010/2011. AB - OBJECTIVES: To investigate types of evidence used by healthcare commissioners when making decisions and whether decisions were influenced by commissioners' experience, personal characteristics or role at work. DESIGN: Cross-sectional survey of 345 National Health Service (NHS) staff members. SETTING: The study was conducted across 11 English Primary Care Trusts between 2010 and 2011. PARTICIPANTS: A total of 440 staff involved in commissioning decisions and employed at NHS band 7 or above were invited to participate in the study. Of those, 345 (78%) completed all or a part of the survey. MAIN OUTCOME MEASURES: Participants were asked to rate how important different sources of evidence (empirical or practical) were in a recent decision that had been made. Backwards stepwise logistic regression analyses were undertaken to assess the contributions of age, gender and professional background, as well as the years of experience in NHS commissioning, pay grade and work role. RESULTS: The extent to which empirical evidence was used for commissioning decisions in the NHS varied according to the professional background. Only 50% of respondents stated that clinical guidelines and cost-effectiveness evidence were important for healthcare decisions. Respondents were more likely to report use of empirical evidence if they worked in Public Health in comparison to other departments (p<0.0005, commissioning and contracts OR 0.32, 95%CI 0.18 to 0.57, finance OR 0.19, 95%CI 0.05 to 0.78, other departments OR 0.35, 95%CI 0.17 to 0.71) or if they were female (OR 1.8 95% CI 1.01 to 3.1) rather than male. Respondents were more likely to report use of practical evidence if they were more senior within the organisation (pay grade 8b or higher OR 2.7, 95%CI 1.4 to 5.3, p=0.004 in comparison to lower pay grades). CONCLUSIONS: Those trained in Public Health appeared more likely to use external empirical evidence while those at higher pay scales were more likely to use practical evidence when making commissioning decisions. Clearly, National Institute for Clinical Excellence (NICE) guidance and government publications (eg, National Service Frameworks) are important for decision-making, but practical sources of evidence such as local intelligence, benchmarking data and expert advice are also influential. New Clinical Commissioning Groups will need a variety of different evidence sources and expert involvement to ensure that effective decisions are made for their populations. PMID- 23793670 TI - Parental comprehension of the benefits/risks of first-line randomised clinical trials in children with solid tumours: a two-stage cross-sectional interview study. AB - OBJECTIVES: To analyse the parental understanding of informed consent information in first-line randomised clinical trials (RCTs) including children with malignant solid tumours and to assess parents' needs for decision-making. DESIGN: Observational prospective study. SETTING: 3 paediatric oncology centres in the Parisian region in France. PARTICIPANTS: 53 parents were approached to participate in a RCT for their child with malignant solid tumour, over a 1-year period. 40 parents have been interviewed in our study. PRIMARY AND SECONDARY OUTCOME MEASURES: Parental understanding of information in RCTs, parents' needs for decision-making. Parents were questioned by a psychologist, independent of the paediatric oncology teams, using a semidirected interview, 1 (M1) and 6 months (M6) after the consent was sought. RESULTS: 18 parents (45%) did not understand the concept of randomisation. Half of the parents could explain neither the aim of the clinical trial nor the potential benefit to their child of inclusion. 35 parents (87.5%) expressed very few specific risks related to the trial. Being mostly French-speaking (p=0.03) and the reading of the information sheet by the parents (p=0.0025) improved their understanding. The parental comprehension did not differ between M1 and M6. The principal factors underlying their decision were confidence in the medical team (39%), wish to access to the best treatment (37%) and the best quality of life (37%). CONCLUSIONS: Despite medical explanations, parents have limited knowledge in some areas in first-line RCTs and improvements of information process are required. The risks specific to the randomised trial are underestimated by parents and the unproven nature of the treatment is not well-known or understood. PMID- 23793671 TI - Prevalence and factors associated with asymptomatic gonococcal and chlamydial infection among US Navy and Marine Corps men infected with the HIV: a cohort study. AB - OBJECTIVES: Neisseria gonorrhoeae (GC) and Chlamydia trachomatis (CT) can facilitate transmission of HIV. Men who have sex with men (MSM) may harbour infections at genital and extragenital sites. Data regarding extragenital GC and CT infections in military populations are lacking. We examined the prevalence and factors associated with asymptomatic GC and CT infection among this category of HIV-infected military personnel. DESIGN: Cross-sectional cohort study (pilot). SETTING: Infectious diseases clinic at a single military treatment facility in San Diego, CA. PARTICIPANTS: Ninety-nine HIV-positive men were evaluated-79% men who had sex with men, mean age 31 years, 36% black and 33% married. INCLUSION CRITERIA: male, HIV-infected, Department of Defense beneficiary. EXCLUSION CRITERIA: any symptom related to the urethra, pharynx or rectum. PRIMARY OUTCOME MEASURES: GC and CT screening results. RESULTS: Twenty-four per cent were infected with either GC or CT. Rectal swabs were positive in 18% for CT and 3% for GC; pharynx swabs were positive in 8% for GC and 2% for CT. Only one infection was detected in the urine (GC). Anal sex (p=0.04), male partner (OR 7.02, p=0.04) and sex at least once weekly (OR 3.28, p=0.04) were associated with infection. Associated demographics included age <35 years (OR 6.27, p=0.02), non Caucasian ethnicity (p=0.03), <3 years since HIV diagnosis (OR 2.75, p=0.04) and previous sexually transmitted infection (STI) (OR 5.10, p=0.001). CONCLUSIONS: We found a high prevalence of extragenital GC/CT infection among HIV-infected military men. Only one infection was detected in the urine, signalling the need for aggressive three-site screening of MSM. Clinicians should be aware of the high prevalence in order to enhance health through comprehensive STI screening practices. PMID- 23793672 TI - 'The body we leave behind': a qualitative study of obstacles and opportunities for increasing uptake of male circumcision among Tanzanian Christians. AB - OBJECTIVES: Male circumcision (MC) reduces HIV infection by approximately 60% among heterosexual men and is recommended by the WHO for HIV prevention in sub Saharan Africa. In northwest Tanzania, over 60% of Muslims but less than 25% of Christian men are circumcised. We hypothesised that the decision to circumcise may be heavily influenced by religious identity and that specific religious beliefs may offer both obstacles and opportunities to increasing MC uptake, and conducted focus group discussions to explore reasons for low rates of MC among Christian church attenders in the region. DESIGN: Qualitative study using focus group discussions and interpretative phenomenological analysis. SETTING: Discussions took place at churches in both rural and urban areas of the Mwanza region of northwest Tanzania. PARTICIPANTS: We included 67 adult Christian churchgoers of both genders in a total of 10 single-gender focus groups. RESULTS: Christians frequently reported perceiving MC as a Muslim practice, as a practice for the sexually promiscuous, or as unnecessary since they are taught to focus on 'circumcision of the heart'. Only one person had ever heard MC discussed at church, but nearly all Christian parishioners were eager for their churches to address MC and felt that MC could be consistent with their faith. CONCLUSIONS: Christian religious beliefs among Tanzanian churchgoers provide both obstacles and opportunities for increasing uptake of MC. Since half of adults in sub Saharan Africa identify themselves as Christians, addressing these issues is critical for MC efforts in this region. PMID- 23793673 TI - The neurophysiological effects of dry needling in patients with upper trapezius myofascial trigger points: study protocol of a controlled clinical trial. AB - INTRODUCTION: Dry needling (DN) is an effective method for the treatment of myofascial trigger points (MTrPs). There is no report on the neurophysiological effects of DN in patients with MTrPs. The aim of the present study will be to assess the immediate neurophysiological efficacy of deep DN in patients with upper trapezius MTrPs. METHODS AND ANALYSIS: A prospective, controlled clinical trial was designed to include patients with upper trapezius MTrPs and volunteered healthy participants to receive one session of DN. The primary outcome measures are neuromuscular junction response and sympathetic skin response. The secondary outcomes are pain intensity and pressure pain threshold. Data will be collected at baseline and immediately after intervention. ETHICS AND DISSEMINATION: This study protocol has been approved by the Research Council, School of Rehabilitation and the Ethics Committee of Tehran University of Medical Sciences. The results of the study will be disseminated in a peer-reviewed journal and presented at international congresses. PMID- 23793674 TI - Development of an economic evaluation of diagnostic strategies: the case of monogenic diabetes. AB - OBJECTIVES: To describe the development process for defining an appropriate model structure for the economic evaluation of test-treatment strategies for patients with monogenic diabetes (caused by mutations in the GCK, HNF1A or HNF4A genes). DESIGN: Experts were consulted to identify and define realistic test-treatment strategies and care pathways. A systematic assessment of published diabetes models was undertaken to inform the model structure. SETTING: National Health Service in England and Wales. PARTICIPANTS: Experts in monogenic diabetes whose collective expertise spans the length of the patient care pathway. PRIMARY AND SECONDARY OUTCOMES: A defined model structure, including the test-treatment strategies, and the selection of a published diabetes model appropriate for the economic evaluation of strategies to identify patients with monogenic diabetes. RESULTS: Five monogenic diabetes test-treatment strategies were defined: no testing of any kind, referral for genetic testing based on clinical features as noted by clinicians, referral for genetic testing based on the results of a clinical prediction model, referral for genetic testing based on the results of biochemical and immunological tests, referral for genetic testing for all patients with a diagnosis of diabetes under the age of 30 years. The systematic assessment of diabetes models identified the IMS CORE Diabetes Model (IMS CDM) as a good candidate for modelling the long-term outcomes and costs of the test treatment strategies for monogenic diabetes. The short-term test-treatment events will be modelled using a decision tree which will feed into the IMS CDM. CONCLUSIONS: Defining a model structure for any economic evaluation requires decisions to be made. Expert consultation and the explicit use of critical appraisal can inform these decisions. Although arbitrary choices have still been made, decision modelling allows investigation into such choices and the impact of assumptions that have to be made due to a lack of data. PMID- 23793675 TI - A population-based cross-sectional study of the association between facial morphology and cardiometabolic risk factors in adolescence. AB - OBJECTIVE: To determine whether facial morphology is associated with fasting insulin, glucose and lipids independent of body mass index (BMI) in adolescents. DESIGN: Population-based cross-sectional study. SETTING: Avon Longitudinal Study of Parents and Children (ALSPAC), South West of England. PARTICIPANTS: From the ALSPAC database of 4747 three-dimensional facial laser scans, collected during a follow-up clinic at the age of 15, 2348 white British adolescents (1127 males and 1221 females) were selected on the basis of complete data on cardiometabolic parameters, BMI and Tanner's pubertal stage. MAIN OUTCOME MEASURES: Fasting insulin, glucose and lipids (triglycerides, high-density lipoprotein cholesterol (HDLc) and low-density lipoprotein cholesterol (LDLc)). RESULTS: On the basis of the collection of 63 x, y and z coordinates of 21 anthropometric landmarks, 14 facial principal components (PCs) were identified. These components explained 82% of the variation in facial morphology and were used as exposure variables. With adjustment for age, gender and pubertal stage, seven PCs were associated with fasting insulin, none with glucose, three with triglycerides, three with HDLc and four with LDLc. After additional adjustment for BMI, four PCs remained associated with fasting insulin, one with triglycerides and two with LDLc. None of these associations withstood adjustment for multiple comparisons. CONCLUSIONS: These initial hypotheses generating analyses provide no evidence that facial morphology is importantly related to cardiometabolic outcomes. Further examination might be warranted. Facial morphology assessment may have value in identifying other areas of disease risk. PMID- 23793676 TI - Validation of a questionnaire measuring preschool children's reactions to and coping with noise in a repeated measurement design. AB - OBJECTIVES: The aim of the study was to explore and describe the reliability and validity of an instrument to measure preschool children's reactions to and coping with indoor noise at preschools or day care centres. DESIGN: Data were derived from an acoustical before and after intervention study providing repeated measurements. SETTING: The study was performed at seven preschools in Molndal, Sweden. PARTICIPANTS: Children were recruited from these preschools and the final sample comprised 61 and 59 preschool children aged 4-5 years, with a response rate of 98% and 48% girls and 52% boys. Two children were excluded from analysis because they fell outside the age range. PRIMARY AND SECONDARY OUTCOME MEASURES: The instrument was developed based on a qualitative study performed in Swedish preschools. Questions pertained to preschool children's perception of noise when at school, their bodily and emotional reactions to it, non-specific symptoms and the coping strategies used by them to diminish the detrimental effects of the noise. RESULTS: Confirmative factor analysis yielded a three-factor model fitted to 10 items pertaining to angry reactions, symptoms and coping. The model fit was moderate to good (standardised root mean square residual=0.08, 0.12; adjusted goodness of fit=0.97/0.91) in the before and after conditions, respectively. The scales showed moderate to good reliability in terms of internal consistency, with an alpha ranging between 0.52 and 0.67, and was stronger in the before condition. Concurrent validity was strongest for symptoms by comparing groups based on bodily reaction (general and sound specific). CONCLUSIONS: Young children's emotional and bodily reactions to coping with noise can be reliably measured with this instrument. Like adults and older children, young children are able to distinguish between emotional reactions, bodily reactions, coping and unwell being. Future research on larger groups of preschool children is needed to further refine the questions, in particular the questions pertaining to well being. PMID- 23793677 TI - Identifying HIV most-at-risk groups in Malawi for targeted interventions. A classification tree model. AB - OBJECTIVES: To identify HIV-socioeconomic predictors as well as the most-at-risk groups of women in Malawi. DESIGN: A cross-sectional survey. SETTING: Malawi PARTICIPANTS: The study used a sample of 6395 women aged 15-49 years from the 2010 Malawi Health and Demographic Surveys. INTERVENTIONS N/A PRIMARY AND SECONDARY OUTCOME MEASURES: Individual HIV status: positive or not. RESULTS: Findings from the Pearson chi(2) and chi(2) Automatic Interaction Detector analyses revealed that marital status is the most significant predictor of HIV. Women who are no longer in union and living in the highest wealth quintiles households constitute the most-at-risk group, whereas the less-at-risk group includes young women (15-24) never married or in union and living in rural areas. CONCLUSIONS: In the light of these findings, this study recommends: (1) that the design and implementation of targeted interventions should consider the magnitude of HIV prevalence and demographic size of most-at-risk groups. Preventive interventions should prioritise couples and never married people aged 25-49 years and living in rural areas because this group accounts for 49% of the study population and 40% of women living with HIV in Malawi; (2) with reference to treatment and care, higher priority must be given to promoting HIV test, monitoring and evaluation of equity in access to treatment among women in union disruption and never married or women in union aged 30-49 years and living in urban areas; (3) community health workers, households-based campaign, reproductive-health services and reproductive-health courses at school could be used as canons to achieve universal prevention strategy, testing, counselling and treatment. PMID- 23793679 TI - Correction. PMID- 23793678 TI - Adjusting the obesity thresholds for self-reported BMI in Ireland: a cross sectional analysis. AB - OBJECTIVE: To investigate the optimal adjustment to be made to obesity thresholds when using self-reported body mass index (BMI). DESIGN: A cross-sectional study. SETTING: Data from the Survey of Lifestyle, Attitudes and Nutrition in Ireland, a nationally representative dataset using the Geodirectory (a listing of all residential addresses in Ireland compiled by the postal service) as the sampling frame. PARTICIPANTS: A nationally representative sample of 10 364 adults aged 18+, carried out by face-to-face interview with clinical measurement applied to a number of outcomes to a representative subsample of 2174. After discarding the observations with missing values and errors, the eventual sample was 1874. PRIMARY AND SECONDARY OUTCOME MEASURES: BMI based on measured and self-reported weight and height. BACKGROUND: It is generally found that self-reported BMI understates true or measured BMI and accordingly revised obesity thresholds have been suggested. METHODS: Data from the 2007 Survey of Lifestyles, Attitudes and Nutrition in Ireland were used to analyse self-reported and measured BMI. The self-reported BMI threshold was adjusted to obtain the optimal signal for measured BMI using different criteria viz. efficiency (maximum number of correct classifications), maximisation of Youden's J, maximisation of OR, minimisation of cost of misclassification and constrained optimisation. RESULTS: The optimal threshold differed substantially depending on the criterion adopted for choosing it, with thresholds of 29.1 (efficiency criterion), 27.5 (Youden's J) and 26.0 (FN rate of 5%). Standard criteria such as Youden's J index were shown to implicitly impose relative costs of false-negatives and false-positives which may not always correspond to the values of the analyst. CONCLUSIONS: When adjusting self-reported BMI thresholds in order to obtain the optimal signal for 'true' obesity, analysts should explicitly choose the relative costs of false-positives and false-negatives. PMID- 23793680 TI - Correction. PMID- 23793681 TI - The incidence of eating disorders in the UK in 2000-2009: findings from the General Practice Research Database. AB - OBJECTIVES: Few studies have investigated the incidence of eating disorders (EDs). Important questions about changes in the incidence of diagnosed disorders in recent years, disorder and gender-specific onset and case detection remain unanswered. Understanding changes in incidence is important for public health, clinical practice and service provision. The aim of this study was to estimate the annual (age-specific, gender-specific and subtype-specific) incidence of diagnosed ED: anorexia nervosa (AN), bulimia nervosa (BN) and eating disorder not otherwise specified (EDNOS) in primary care over a 10-year period in the UK (2000 2009); to examine the changes within the study period; and to describe peak age at diagnosis. DESIGN: Register-based study. SETTING: Primary care. Data were obtained from a primary care register, the General Practice Research Database, which contains anonymised records representing about 5% of the UK population. PARTICIPANTS: All patients with a first-time diagnosis of AN, BN and EDNOS were identified. PRIMARY OUTCOME: Annual crude and age-standardised incidence rates were calculated. RESULTS: A total of 9072 patients with a first-time diagnosis of an ED were identified. The age-standardised annual incidence rate of all diagnosed ED for ages 10-49 increased from 32.3 (95% CI 31.7 to 32.9) to 37.2 (95% CI 36.6 to 37.9) per 100 000 between 2000 and 2009. The incidence of AN and BN was stable; however, the incidence of EDNOS increased. The incidence of the diagnosed ED was highest for girls aged 15-19 and for boys aged 10-14. CONCLUSIONS: The age-standardised incidence of ED increased in primary care between 2000 and 2009. New diagnoses of EDNOS increased, and EDNOS is the most common ED in primary care. PMID- 23793682 TI - Error rates in a clinical data repository: lessons from the transition to electronic data transfer--a descriptive study. AB - OBJECTIVE: Data errors are a well-documented part of clinical datasets as is their potential to confound downstream analysis. In this study, we explore the reliability of manually transcribed data across different pathology fields in a prostate cancer database and also measure error rates attributable to the source data. DESIGN: Descriptive study. SETTING: Specialist urology service at a single centre in metropolitan Victoria in Australia. PARTICIPANTS: Between 2004 and 2011, 1471 patients underwent radical prostatectomy at our institution. In a large proportion of these cases, clinicopathological variables were recorded by manual data-entry. In 2011, we obtained electronic versions of the same printed pathology reports for our cohort. The data were electronically imported in parallel to any existing manual entry record enabling direct comparison between them. OUTCOME MEASURES: Error rates of manually entered data compared with electronically imported data across clinicopathological fields. RESULTS: 421 patients had at least 10 comparable pathology fields between the electronic import and manual records and were selected for study. 320 patients had concordant data between manually entered and electronically populated fields in a median of 12 pathology fields (range 10-13), indicating an outright accuracy in manually entered pathology data in 76% of patients. Across all fields, the error rate was 2.8%, while individual field error ranges from 0.5% to 6.4%. Fields in text formats were significantly more error-prone than those with direct measurements or involving numerical figures (p<0.001). 971 cases were available for review of error within the source data, with figures of 0.1-0.9%. CONCLUSIONS: While the overall rate of error was low in manually entered data, individual pathology fields were variably prone to error. High-quality pathology data can be obtained for both prospective and retrospective parts of our data repository and the electronic checking of source pathology data for error is feasible. PMID- 23793683 TI - A brief intervention for drug use, sexual risk behaviours and violence prevention with vulnerable women in South Africa: a randomised trial of the Women's Health CoOp. AB - OBJECTIVE: To assess the impact of the Women's Health CoOp (WHC) on drug abstinence among vulnerable women having HIV counselling and testing (HCT). DESIGN: Randomised trial conducted with multiple follow-ups. SETTING: 15 communities in Cape Town, South Africa. PARTICIPANTS: 720 drug-using women aged 18-33, randomised to an intervention (360) or one of two control arms (181 and 179) with 91.9% retained at follow-up. INTERVENTIONS: The WHC brief peer facilitated intervention consisted of four modules (two sessions), 2 h addressing knowledge and skills to reduce drug use, sex risk and violence; and included role playing and rehearsal, an equal attention nutrition intervention, and an HCT-only control. PRIMARY OUTCOME MEASURES: Biologically confirmed drug abstinence measured at 12-month follow-up, sober at last sex act, condom use with main and casual sex partners, and intimate partner violence. RESULTS: At the 12-month endpoint, 26.9% (n=83/309) of the women in the WHC arm were abstinent from drugs, compared with 16.9% (n=27/160) in the Nutrition arm and 20% (n=31/155) in the HCT only control arm. In the random effects model, this translated to an effect size on the log odds scale with an OR of 1.54 (95% CI 1.07 to 2.22) comparing the WHC arm with the combined control arms. Other 12-month comparison measures between arms were non-significant for sex risk and victimisation outcomes. At 6-month follow-up, women in the WHC arm (65.9%, 197/299) were more likely to be sober at the last sex act (OR1.32 (95% CI 1.02 to 1.84)) than women in the Nutrition arm (54.3%, n=82/152). CONCLUSIONS: This is the first trial among drug-using women in South Africa showing that a brief intervention added to HCT results in greater abstinence from drug use at 12 months and a larger percentage of sexual activity not under the influence of substances. TRIAL REGISTRATION NUMBER: NCT00729391 ClinicalTrials.gov. PMID- 23793684 TI - Contributions of body mass index and exercise habits on inflammatory markers: a cohort study of middle-aged adults living in the USA. AB - OBJECTIVES: Determine whether body mass index (BMI) and physical activity (PA) above, at or below MET minute per week (MMW) levels recommended in the 2008 Physical Activity Guidelines interact or have additive effects on interleukin (IL)-6, C reactive protein (CRP), fibrinogen, interleukin6 (IL-6) soluble receptor (IL-6sr), soluble E-selectin and soluble intracellular adhesion molecule (sICAM)-1. DESIGN: Archived cohort data (n=1254, age 54.5+/-11.7 year, BMI 29.8+/ 6.6 kg/m(2)) from the National Survey of Midlife Development in the USA (MIDUS) Biomarkers Study were analysed for concentrations of inflammatory markers using general linear models. MMW was defined as no regular exercise, <500 MMW, 500-1000 MMW, >1000 MMW and BMI was defined as <25, 25-29.9, >=30 kg/m(2). Analyses were adjusted for age, sex, smoking and relevant medication use. SETTING: Respondents reported to three centres to complete questionnaires and provide blood samples. PARTICIPANTS: Participants were men and women currently enroled in the MIDUS Biomarker Project (n=1254, 93% non-Hispanic white, average age 54.5 years). PRIMARY OUTCOME MEASURES: Concentration of serum IL-6, CRP, fibrinogen, IL-6sr, sE-selectin and sICAM. RESULTS: Significant interactions were found between BMI and MMW for CRP and sICAM-1 (p<0.05). CRP in overweight individuals was similar to that in obese individuals when no PA was reported, but it was similar to normal weight when any level of regular PA was reported. sICAM-1 was differentially lower in obese individuals who reported >1000 MMW compared to obese individuals reporting less exercise. CONCLUSIONS: The association of exercise with CRP and sICAM-1 differed by BMI, suggesting that regular exercise may buffer weight-associated elevations in CRP in overweight individuals while higher levels of exercise may be necessary to reduce sICAM-1 or CRP in obese individuals. PMID- 23793685 TI - Doctors' understanding of individualisation of drug treatments: a qualitative interview study. AB - OBJECTIVE: To explore doctors' understanding of individualisation of drug treatments, and identify the methods used to achieve individualisation. DESIGN: In this exploratory study, we used in-depth qualitative interviews with doctors to gain insight into their understanding of the term 'individualised treatments' and the methods that they use to achieve it. PARTICIPANTS: 16 general practitioners in 6 rural and 10 urban practices, 2 geriatricians and 2 clinical academics were recruited. SETTING: Primary and secondary care in South West of England. RESULTS: Understanding of individualisation varied between doctors, and their initial descriptions of individualisation were not always consistent with subsequent examples of the patients they had treated. Understandings of, and methods used to achieve, individualised treatment were frequently discussed in relation to making drug treatment decisions. Few doctors spoke of using strategies to support patients to individualise their own treatments after the consultation. CONCLUSIONS: Despite its widespread use, variation in doctors' understanding of the term individualisation highlights the need for it to be defined. Efforts are needed to develop effective methods that would offer a structured approach to support patients to manage their treatments after consultations. PMID- 23793686 TI - Factors affecting patients' trust and confidence in GPs: evidence from the English national GP patient survey. AB - OBJECTIVES: Patients' trust in general practitioners (GPs) is fundamental to effective clinical encounters. Associations between patients' trust and their perceptions of communication within the consultation have been identified, but the influence of patients' demographic characteristics on these associations is unknown. We aimed to investigate the relative contribution of the patient's age, gender and ethnicity in any association between patients' ratings of interpersonal aspects of the consultation and their confidence and trust in the doctor. DESIGN: Secondary analysis of English national GP patient survey data (2009). SETTING: Primary Care, England, UK. PARTICIPANTS: Data from year 3 of the GP patient survey: 5 660 217 questionnaires sent to patients aged 18 and over, registered with a GP in England for at least 6 months; overall response rate was 42% after adjustment for sampling design. OUTCOME MEASURES: We used binary logistic regression analysis to investigate patients' reported confidence and trust in the GP, analysing ratings of 7 interpersonal aspects of the consultation, controlling for patients' sociodemographic characteristics. Further modelling examined moderating effects of age, gender and ethnicity on the relative importance of these 7 predictors. RESULTS: Among 1.5 million respondents (adjusted response rate 42%), the sense of 'being taken seriously' had the strongest association with confidence and trust. The relative importance of the 7 interpersonal aspects of care was similar for men and women. Non-white patients accorded higher priority to being given enough time than did white patients. Involvement in decisions regarding their care was more strongly associated with reports of confidence and trust for older patients than for younger patients. CONCLUSIONS: Associations between patients' ratings of interpersonal aspects of care and their confidence and trust in their GP are influenced by patients' demographic characteristics. Taking account of these findings could inform patient-centred service design and delivery and potentially enhance patients' confidence and trust in their doctor. PMID- 23793687 TI - Material, psychosocial and behavioural factors associated with self-reported health in the Republic of Ireland: cross-sectional results from the SLAN survey. AB - OBJECTIVES: To explore the associations between various material, psychosocial and behavioural factors and self-reported health (SRH), and to determine whether these associations varied according to educational level. DESIGN: Representative national cross-sectional survey. SETTING: Republic of Ireland. PARTICIPANTS: 4369 men and 5995 women aged 18 or more (Survey of Lifestyle, Attitudes and Nutrition (SLAN) 2007). METHODS: SRH was measured using one single item. Three groups of factors were studied: material, psychosocial and behavioural factors. Statistical analyses were performed using logistic regression analysis and interaction testing, the sample design being taken into account. All results were adjusted for age and educational level and stratified on gender. RESULTS: When each group of factors was studied separately, non-working status, no private health insurance, inability to afford enough food, no car, being non-married, low social participation, serious neighbourhood problems, low social support, smoking, no alcohol consumption, illicit drug use, low physical activity and obesity were associated with poor SRH. When studied together, some material and psychosocial factors were no longer significant. Four significant interaction terms were found, suggesting that some factors might have a stronger association with SRH among low-educated people. CONCLUSIONS: Various types of factors were found to be associated with SRH, and most of these associations were similar according to educational level. Behavioural factors might be intermediate factors in the causal pathways from material and psychosocial factors to SRH. Prevention policies should integrate a large number of factors comprehensively to improve SRH. PMID- 23793688 TI - Trends and risk factors for severe perineal trauma during childbirth in New South Wales between 2000 and 2008: a population-based data study. AB - OBJECTIVES: To determine trends and risk factors for severe perineal trauma between 2000 and 2008. DESIGN: This was a population-based data study. SETTING: New South Wales, Australia. PARTICIPANTS: 510 006 women giving birth to a singleton baby during the period 2000-2008. MAIN OUTCOME MEASURES: Rates of severe perineal trauma between 2000 and 2008 and associated demographic, fetal, antenatal, labour and delivery events and factors. RESULTS: There was an increase in the overall rate of severe perineal trauma from 2000 to 2008 from 1.4% to 1.9% (36% increase). Compared with women who were intact or had minor perineal trauma (first-degree tear, vaginal graze/tear), women who were primiparous (adjusted OR (AOR) 1.8 CI (1.65 to 1.95), were born in China or Vietnam (AOR 1.1 CI (1.09 to 1.23), gave birth in a private hospital (AOR 1.1 CI (1.03 to 1.20), had an instrumental birth (AOR 1.8 CI (1.65 to 1.95) and male baby (AOR 1.3 CI (1.27 to 1.34) all had a significantly higher risk of severe perineal trauma. Only giving birth to a male baby, adjusted for birth weight (AOR 1.5 CI (1.44 to 1.58), remained significant, when women with severe perineal trauma were compared with all other women not experiencing severe perineal trauma. This association increased over the study period. CONCLUSIONS: To our knowledge, this is the first time that having a male baby has been found to exert such a strong independent risk for severe perineal trauma and the increasing significance of this in recent years needs further exploration. PMID- 23793689 TI - Social determinants of syphilis in South China: the effect of sibling position on syphilis and sexual risk behaviours. AB - OBJECTIVE: This study evaluated the relationship between sibling position and sexual risk based on behavioural and syphilis infection data from sexually transmitted infection (STI) patients in South China. DESIGN: A cross-sectional study examining sexual behaviours and syphilis infection. SETTING: 4 STI clinics in the Pearl River Delta of South China. PARTICIPANTS: 1792 Chinese men and women attending STI clinics. PRIMARY OUTCOME MEASURES: STI history, syphilis infection defined as positive non-treponemal and treponemal tests. RESULTS: Among all clinic patients, 824 (46.3%) were first-born, 354 (19.9%) were middle-born and 602 (33.8%) were final-born. Middle-born individuals had a higher percentage of reported STI history (44.7% compared to 34.7%, p<0.001) and syphilis infection (9.7% compared to 4.9%, p=0.01) among men (n=1163) compared to other sibling positions in bivariate analyses, but not in the final multivariate model. The relationship between sibling position and syphilis was independent of income and education level. There was no trend observed between middle-born position and female sexual risk behaviours (n=626). Higher education was significantly associated with syphilis among women and men in respective multivariate models. CONCLUSIONS: This study suggests that middle-born men in China may have an increased sexual risk compared to other sibling positions. As Chinese family and social structures change, a more thorough understanding of how demographic factors influence sexual risk behaviours is needed. PMID- 23793690 TI - An exploratory study of cannabis withdrawal among Indigenous Australian prison inmates: study protocol. AB - INTRODUCTION: Cannabis use and dependence is a serious health and criminal justice issue among incarcerated populations internationally. Upon abrupt, enforced cessation of cannabis, prisoners may suffer irritability and anger that can lead to threatening behaviour, intimidation, violence, sleep disturbances and self-harm. Cannabis withdrawal syndrome, proposed for inclusion in the Diagnostic and Statistical Manual of Mental Disorders in 2013, has not been examined in Indigenous populations. Owing to the exceptionally high rates of cannabis use in the community, high proportions of Australian Indigenous prisoners may suffer from withdrawal upon entry to custody. METHODS AND ANALYSIS: 60 male and 60 female Indigenous prisoners (18-40 years) at a high risk of cannabis dependence will be recruited upon entry to custody. A pictorial representation of the standard Cannabis Withdrawal Scale will be tested for reliability and validity. Cortisol markers will be measured in saliva, as the indicators of onset and severity of cannabis withdrawal and psychological distress. The characteristics will be described as percentages and mean or median values with 95% CI. Receiver operator curve analysis will determine an ideal cut-off of the Cannabis Withdrawal Scale and generalised estimating equations modelling will test changes over time. The acceptability and efficacy of proposed resources will be assessed qualitatively using thematic analysis. OUTCOMES: A valid and reliable measure of cannabis withdrawal for use with Indigenous populations, the onset and time course of withdrawal symptoms in this population and the development of culturally acceptable resources and interventions to identify and manage cannabis withdrawal. ETHICS AND DISSEMINATION: The project has been approved by the James Cook University Human Research Ethics Committee (approval number H4651).The results will be reported via peer reviewed publications, conference, seminar presentations and on-line media for national and international dissemination. PMID- 23793691 TI - Bed sharing when parents do not smoke: is there a risk of SIDS? An individual level analysis of five major case-control studies. AB - OBJECTIVE: To resolve uncertainty as to the risk of Sudden Infant Death Syndrome (SIDS) associated with sleeping in bed with your baby if neither parent smokes and the baby is breastfed. DESIGN: Bed sharing was defined as sleeping with a baby in the parents' bed; room sharing as baby sleeping in the parents' room. Frequency of bed sharing during last sleep was compared between babies who died of SIDS and living control infants. Five large SIDS case-control datasets were combined. Missing data were imputed. Random effects logistic regression controlled for confounding factors. SETTING: Home sleeping arrangements of infants in 19 studies across the UK, Europe and Australasia. PARTICIPANTS: 1472 SIDS cases, and 4679 controls. Each study effectively included all cases, by standard criteria. Controls were randomly selected normal infants of similar age, time and place. RESULTS: In the combined dataset, 22.2% of cases and 9.6% of controls were bed sharing, adjusted OR (AOR) for all ages 2.7; 95% CI (1.4 to 5.3). Bed sharing risk decreased with increasing infant age. When neither parent smoked, and the baby was less than 3 months, breastfed and had no other risk factors, the AOR for bed sharing versus room sharing was 5.1 (2.3 to 11.4) and estimated absolute risk for these room sharing infants was very low (0.08 (0.05 to 0.14)/1000 live-births). This increased to 0.23 (0.11 to 0.43)/1000 when bed sharing. Smoking and alcohol use greatly increased bed sharing risk. CONCLUSIONS: Bed sharing for sleep when the parents do not smoke or take alcohol or drugs increases the risk of SIDS. Risks associated with bed sharing are greatly increased when combined with parental smoking, maternal alcohol consumption and/or drug use. A substantial reduction of SIDS rates could be achieved if parents avoided bed sharing. PMID- 23793692 TI - Psychometric properties of the WHO Violence Against Women instrument in a female population-based sample in Sweden: a cross-sectional survey. AB - OBJECTIVE: To explore psychometric properties of the Violence Against Women instrument in a randomly selected national sample of women (N=573) aged 18-65 years and residing in Sweden. DESIGN: Cross-sectional survey study. SETTING: Sweden. PARTICIPANTS: A postal survey was sent to 1006 women between January and March 2009, during which 624 women (62%) returned the questionnaire. 51 women who did not answer any of the violence items were excluded from the analyses, resulting in a final sample of 573 women. PRIMARY AND SECONDARY OUTCOME MEASURES: Self-reported exposure to psychological, physical and sexual intimate partner violence. RESULTS: Cronbach's alpha coefficients were 0.79 (psychological scale), 0.80 (physical scale), 0.72 (sexual scale) and 0.88 (total scale). A predetermined three-component solution largely replicated the explored three component conceptual model of the Violence Against Women instrument. The instrument was able to discriminate between groups known from previous studies to differ in exposure to physical and/or sexual violence, that is, respondents with poor versus good self-rated health and witnessed versus not witnessed physical violence at home when growing up. Past-year prevalence of physical (8.1%; 95% CI 5.9 to 10.3) and sexual (3%; 1.6 to 4.4) violence was similar to that reported in other Nordic studies; however, earlier-in-life prevalence was lower in the current study (14.3%; 95% CI 11.4 to 17.2 and 9.2%; 95% CI 6.8 to 11.6, respectively). Reported exposure rates were higher than those obtained from a concurrently administered instrument (NorVold Abuse Questionnaire). CONCLUSIONS: The Violence Against Women instrument demonstrated good construct validity and internal reliability in an adult female population in Sweden. However, further studies examining these and other psychometric properties need to be conducted in other countries. PMID- 23793693 TI - INterpreting the Processes of the UMPIRE Trial (INPUT): protocol for a qualitative process evaluation study of a fixed-dose combination (FDC) strategy to improve adherence to cardiovascular medications. AB - INTRODUCTION: This paper describes a planned process evaluation of the Use of a Multidrug Pill In Reducing Cardiovascular Events (UMPIRE) trial, one of several randomised clinical trials taking place globally to assess the potential of cardiovascular drugs as a fixed-dose combination (polypill) in cardiovascular disease prevention. A fixed-dose combination may be a promising strategy for promoting adherence to medication; alleviating pill burden through simplifying regimens and reducing cost. This process evaluation will complement the UMPIRE trial by using qualitative research methods to inform understanding of the complex interplay of factors that underpin trial outcomes. METHODS: A series of semistructured, in-depth interviews with local health professionals and UMPIRE trial participants in India and the UK will be undertaken. The aim is to understand their views and experiences of the trial context and of day-to-day use of medications more generally. The grounded theory approach will be used to analyse data and help inform the processes of the UMPIRE trial. ETHICS AND DISSEMINATION: The study has received ethical approval for all sites in the UK and India where trial participant interviews will be undertaken. The process evaluation will help inform and enhance the understanding of the UMPIRE trial results and its applicability to clinical practice as well as shaping policy regarding strategies for improving cardiovascular medication adherence. PMID- 23793694 TI - Doctors' willingness to give honest answers about end-of-life practices: a cross sectional study. AB - OBJECTIVES: We aimed to (1) evaluate the extent to which doctors in New Zealand would be willing to answer honestly questions about their care of patients at the end of their lives and (2) identify the assurances that would encourage this. Results were compared with findings from a previous pilot study from the UK. DESIGN: Survey study involving a mailed questionnaire. SETTING: New Zealand hospital and community-based medical care settings. PARTICIPANTS: The questionnaire was mailed to a random sample of 800 doctors in New Zealand who were vocationally registered with the Medical Council of New Zealand in disciplines involving caring for patients at the end of their lives. PRIMARY AND SECONDARY OUTCOME MEASURES: Willingness to provide honest answers about various aspects of end-of-life care; assurances that might increase willingness to provide honest answers to questions about end-of-life practices. RESULTS: Completed questionnaires were returned by 436 doctors. The majority of respondents (59.9-91.5%) indicated willingness to provide honest answers to such questions. However, more than a third of doctors were unwilling to give honest answers to certain questions regarding euthanasia. These results are comparable with the UK data. Complete anonymity was the assurance most likely to encourage honest answering, with most of the respondents preferring the use of anonymous written replies. Respondents were less reassured by survey endorsements from regulatory bodies. Themes in free comments included the deterrent effect of medicolegal consequences, fear of censure from society, peers and the media and concerns about the motivations and potential uses of such research. CONCLUSIONS: Many New Zealand doctors were willing to give honest answers to questions about end-of-life practices, particularly if anonymity was guaranteed; others, however, expressed doubts or indicated that they would not be willing to provide honest answers to questions of this sort. PMID- 23793695 TI - Exercise referral for drug users aged 40 and over: results of a pilot study in the UK. AB - OBJECTIVES: To test whether older drug users (aged 40 and over) could be recruited to an exercise referral (ER) scheme, to evaluate the feasibility and acceptability and measure the impact of participation on health. DESIGN: Observational pilot. SETTING: Liverpool, UK. PARTICIPANTS: (1) 12 men and 5 women recruited to ER. (2) 7 specialist gym instructors. OUTCOME MEASURES: Logistic feasibility and acceptability of ER and associated research, rate of recruitment, level of participation over 8 weeks and changes in health. RESULTS: 22 gym inductions were arranged (recruitment time: 5 weeks), 17 inductions were completed and 14 participants began exercising. Attendance at the gym fluctuated with people missing weeks then re-engaging; in week 8, seven participants were in contact with the project and five of these attended the gym. Illness and caring responsibilities affected participation. Participants and gym instructors found the intervention and associated research processes acceptable. In general, participants enjoyed exercising and felt fitter, but would have welcomed more support and the offer of a wider range of activities. Non-significant reductions in blood pressure and heart rate and improvements in metabolic equivalents (METs; a measure of fitness) and general well-being were observed for eight participants who completed baseline and follow-up assessments. The number of weeks of gym attendance was significantly associated with a positive change in METs. CONCLUSIONS: It is feasible to recruit older drug users into a gym-based ER scheme, but multiple health and social challenges affect their ability to participate regularly. The observed changes in health measures, particularly the association between improvements in METs and attendance, suggest further investigation of ER for older drug users is worthwhile. Measures to improve the intervention and its evaluation include: better screening, refined inclusion/exclusion criteria, broader monitoring of physical activity levels, closer tailored support, more flexible exercise options and the use of incentives. PMID- 23793696 TI - Mathematical modelling to restore circulating IGF-1 concentrations in children with Crohn's disease-induced growth failure: a pharmacokinetic study. AB - OBJECTIVES: Children with Crohn's disease grow poorly, and inflammation depresses the response of insulin-like growth factor-1 (IGF-1) to growth hormone. Correcting the inflammation normalises growth velocity; however, removing inflammation cannot be achieved in all children. Our lack of understanding of IGF 1 kinetics has hampered its use, particularly as high IGF-1 concentrations over long periods may predispose to colon cancer. We hypothesised that mathematical modelling of IGF-1 would define dosing regimes that return IGF-1 concentrations into the normal range, without reaching values that risk cancer. DESIGN: Pharmacokinetic intervention study. SETTING: Tertiary paediatric gastroenterology unit. PARTICIPANTS: 8 children (M:F; 4:4) entered the study. All completed: 5 South Asian British; 2 White British; 1 African British. INCLUSION CRITERIA: Children over 10 years with active Crohn's disease (C reactive protein >10 mg/l or erythrocyte sedimentation rate >25 mm/h) and height velocity <-2 SD score. EXCLUSION CRITERIA: closed epiphyses; corticosteroids within 3 months; neoplasia or known hypersensitivity to recombinant human IGF-1 (rhIGF-1). INTERVENTIONS: Subcutaneous rhIGF-1 (120 MUg/kg) per dose over two admissions: the first as a single dose and the second as twice daily doses over 5 days. PRIMARY OUTCOME: Significant increase in circulating IGF-1. SECONDARY OUTCOMES: Incidence of side effects of IGF-1. A mathematical model of circulating IGF-1 (Ac) was developed to include parameters of endogenous synthesis (Ksyn); exogenous uptake (Ka) from the subcutaneous dose (As): and IGF-1 clearance: where dAc/dt=Ksyn - Kout*Ac+Ka*As. RESULTS: Subcutaneous IGF-1 increased concentrations, which were maintained on twice daily doses. In covariate analysis, disease activity reduced Ksyn (p<0.001). Optimal dosing was derived from least squares regression fitted to a dataset of 384 Crohn's patients, with model parameters assigned by simulation. CONCLUSIONS: By using age, weight and disease activity scaling in IGF-1 dosing, over 95% of children will have normalised IGF-1 concentrations below +2.5 SDs of the normal population mean, a level not associated with cancer risk. PMID- 23793697 TI - Underage alcohol drinking and medical services use in Hong Kong: a cross sectional study. AB - OBJECTIVES: To investigate the association of underage alcohol drinking with medical consultation and hospitalisation in Hong Kong. DESIGN: Cross-sectional study. SETTING: Secondary schools in Hong Kong. PARTICIPANTS: A total of 33 300 secondary 1 (US grade 7) to secondary 5 students (47.6% boys; mean age 14.6 years, SD 1.6) in 85 randomly selected schools. OUTCOME MEASURES: An anonymous questionnaire was used to obtain information about medical consultation in the past 14 days, hospitalisation in the past 12 months, drinking alcohol, smoking, illicit drug use, physical activity, secondhand smoke exposure, feeling depressed, feeling anxious and sociodemographic characteristics. Drinking alcohol was categorised as non-drinking (reference), <1, 1-2 and 3-7 days/week. Logistic regression yielded adjusted ORs (AORs) of medical consultation and hospitalisation for drinking, adjusting for different potential confounders. Subgroup analysis was conducted among adolescents who did not report feeling anxious or depressed. RESULTS: More than one-fourth (27.6%) of adolescents drank alcohol, 15.9% had medical consultation and 5.1% had been hospitalised. In the fully adjusted model, the AORs (95% CI) for medical consultation were 1.14 (1.06 to 1.23) for <1 day/week, 1.30 (1.13 to 1.50) for 1-2 days/week and 1.70 (1.41 to 2.06) for 3-7 days/week of drinking compared with non-drinking (p for trend <0.001). The corresponding AORs (95% CI) for hospitalisation were 1.14 (1.02 to 1.28), 1.68 (1.32 to 2.14) and 2.38 (1.90 to 2.98) (p for trend <0.001). Similar associations were observed among students who did not feel anxious or depressed. CONCLUSIONS: Alcohol consumption was associated with medical services use in Chinese adolescents. More rigorous alcohol control policies and health promotion programmes are needed to reduce alcohol drinking and related harms in adolescents. PMID- 23793698 TI - Pulmonary metastasectomy in colorectal cancer: a prospective study of demography and clinical characteristics of 543 patients in the Spanish colorectal metastasectomy registry (GECMP-CCR). AB - OBJECTIVES: To capture an accurate contemporary description of the practice of pulmonary metastasectomy for colorectal carcinoma in one national healthcare system. DESIGN: A national registry set up in Spain by Grupo Espanol de Cirugia Metastasis Pulmonares de Carcinoma Colo-Rectal (GECMP-CCR). SETTING: 32 Spanish thoracic units. PARTICIPANTS: All patients with one or more histologically proven lung metastasis removed by surgery between March 2008 and February 2010. INTERVENTIONS: Pulmonary metastasectomy for one or more pulmonary nodules proven to be metastatic colorectal carcinoma. PRIMARY AND SECONDARY OUTCOME MEASURES: The age and sex of the patients having this surgery were recorded with the number of metastases removed, the interval between the primary colorectal cancer operation and the pulmonary metastasectomy, and the carcinoembryonic antigen level. Also recorded were the practices with respect to mediastinal lymphadenopathy and coexisting liver metastases. RESULTS: Data were available on 543 patients from 32 units (6-43/unit). They were aged 32-88 (mean 65) years, and 65% were men. In 55% of patients, there was a solitary metastasis. The median interval between the primary cancer resection and metastasectomy was 28 months and the serum carcinoembryonic antigen was low/normal in the majority. Liver metastatic disease was present in 29% of patients at some point prior to pulmonary metastasectomy. Mediastinal lymphadenectomy varied from 9% to 100% of patients. CONCLUSIONS: The data represent a prospective comprehensive national data collection on pulmonary metastasectomy. The practice is more conservative than the impression gained when members of the European Society of Thoracic Surgeons were surveyed in 2006/2007 but is more inclusive than would be recommended on the basis of recent outcome analyses. Further analyses on the morbidity associated with this surgery and the correlation between imaging studies and pathological findings are being published separately by GECMP-CCR. PMID- 23793699 TI - Mapping the 12-item multiple sclerosis walking scale to the EuroQol 5-dimension index measure in North American multiple sclerosis patients. AB - OBJECTIVE: To map the 12-item Multiple Sclerosis Walking Scale (MSWS-12) onto the EuroQol 5-dimension (EQ-5D) health-utility index in multiple sclerosis (MS) patients participating in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry. DESIGN: Cross-sectional MSWS-12 to EQ-5D cross walking analysis. SETTING: NARCOMS registry spring 2010 biannual update and supplemental survey. PARTICIPANTS: North American patients completing both the MSWS-12 and the EQ-5D randomly split into derivation and validation cohorts. OUTCOME MEASURES: Ordinary least squares regression was performed within the derivation cohort, with participants' EQ-5D as the dependent variable. Results of the MSWS-12 were input as independent variable(s) into six regression models. Model goodness-of-fit was subsequently assessed in the validation cohort using the mean absolute error (MAE), root mean square error (RMSE) and the adjusted R(2). The best performing model was refined in the entire cohort and utilised for additional analyses. RESULTS: A total of 3505 NARCOMS participants were included. Their mean+/-SD EQ-5D and MSWS-12 scores were 0.74+/-0.18 and 50.8+/-33.5, respectively, and these assessments were found to be moderately correlated (r= 0.553, p<0.001). The model using all individual MSWS-12 item scores as independent variables was found to have the best fit (MAE=0.109+/-0.096, RMSE=0.145, adjusted R(2)=0.329). The percentage of EQ-5D estimates within 0.05 and 0.10 of the actual value were 30% and 61%, respectively. This mapping equation was more precise in patients with moderate mobility impairment (MAE=0.087+/-0.061 at patient-determined disease step (PDDS) of 3-6) and less precise in patients with no (MAE=0.141+/-0.128 at PDDS of 0-2) or severe mobility impairment (MAE=0.121+/-0.049 at PDDS >=7). CONCLUSIONS: The EQ-5D scores can be predicted using the MSWS-12 item scores with reasonable precision in North American patients with MS. Prediction estimates were more precise in patients with moderate mobility impairment. PMID- 23793700 TI - On the time spent preparing grant proposals: an observational study of Australian researchers. AB - OBJECTIVE: To estimate the time spent by the researchers for preparing grant proposals, and to examine whether spending more time increase the chances of success. DESIGN: Observational study. SETTING: The National Health and Medical Research Council (NHMRC) of Australia. PARTICIPANTS: Researchers who submitted one or more NHMRC Project Grant proposals in March 2012. MAIN OUTCOME MEASURES: Total researcher time spent preparing proposals; funding success as predicted by the time spent. RESULTS: The NHMRC received 3727 proposals of which 3570 were reviewed and 731 (21%) were funded. Among our 285 participants who submitted 632 proposals, 21% were successful. Preparing a new proposal took an average of 38 working days of researcher time and a resubmitted proposal took 28 working days, an overall average of 34 days per proposal. An estimated 550 working years of researchers' time (95% CI 513 to 589) was spent preparing the 3727 proposals, which translates into annual salary costs of AU$66 million. More time spent preparing a proposal did not increase the chances of success for the lead researcher (prevalence ratio (PR) of success for 10 day increase=0.91, 95% credible interval 0.78 to 1.04) or other researchers (PR=0.89, 95% CI 0.67 to 1.17). CONCLUSIONS: Considerable time is spent preparing NHMRC Project Grant proposals. As success rates are historically 20-25%, much of this time has no immediate benefit to either the researcher or society, and there are large opportunity costs in lost research output. The application process could be shortened so that only information relevant for peer review, not administration, is collected. This would have little impact on the quality of peer review and the time saved could be reinvested into research. PMID- 23793701 TI - Exploring adaptations to the modified shuttle walking test. AB - OBJECTIVE: The 10 m modified shuttle walking test (MSWT) is recommended to determine the functional capacity in older individuals and for patients entering cardiac rehabilitation. Participants are required to negotiate around cones set 1 m from the end markers. However, consistent comments indicate that for some individuals manoeuvring around the cones can be quite difficult. Therefore, the objective of this study was to explore differences within and between non-cardiac and postmyocardial infarction (MI) males during MSWT with and without the cones. DESIGN: Comparative study. PARTICIPANTS: 20 post-MI (64.8+/-6.6, range 51-74 years) and 20 non-cardiac male controls (64.1+/-5.7, range 52-74 years) participated. METHODS: Participants performed MSWT with and without cones. Throughout, the participants expired air, and the heart rate (bpm) (HR) and ratings of perceived exertion (RPE) were measured. Participant protocol preference was recorded verbatim. RESULTS: One-way analysis of variance found no significant difference in VO2 peak (cones 20.4+/-5.1 vs no-cones 21.9+/-4.8 ml/kg/min, p=0.197) or distance ambulated (cones 631.8+/-132.9 m vs no-cones 662.4+/-164.1 m, p=0.371) between protocols or groups. Analysis comparing lines of regression showed a significant trajectory difference in VO2 (ml/kg/min) (p<0.01) between protocols with higher HR (p<0.01) and respiratory exchange ratio (RER, p<0.001) values during cones. RPEs were higher for post-MIs versus controls during both protocols (p<0.05). Post-MIs taking beta-blockers produce significantly lower HR values. The chi(2) analysis found no significant difference in protocol preference (no-cones: all n=25, 63%; post-MIs n=13, 65%; and controls n=12, 60%). CONCLUSIONS: Post-MIs found both protocols subjectively harder than controls with no significant difference in the VO2 peak. However, both groups worked at a lesser percentage of their anaerobic threshold during no cones protocol as indicated by lower RER values. Importantly, for the post-MIs, this would reduce their risk of functional impairment. Therefore, though more research is required, indicators at present are more favourable for the use of the no-cones with post-MIs. PMID- 23793702 TI - Early life bereavement and childhood cancer: a nationwide follow-up study in two countries. AB - OBJECTIVE: Childhood cancer is a leading cause of child deaths in affluent countries, but little is known about its aetiology. Psychological stress has been suggested to be associated with cancer in adults; whether this is also seen in childhood cancer is largely unknown. We investigated the association between bereavement as an indicator of severe childhood stress exposure and childhood cancer, using data from Danish and Swedish national registers. DESIGN: Population based cohort study. SETTING: Denmark and Sweden. PARTICIPANTS: All live-born children born in Denmark between 1968 and 2007 (n=2 729 308) and in Sweden between 1973 and 2006 (n=3 395 166) were included in this study. Exposure was bereavement by the death of a close relative before 15 years of age. Follow-up started from birth and ended at the first of the following: date of a cancer diagnosis, death, emigration, day before their 15th birthday or end of follow-up (2007 in Denmark, 2006 in Sweden). OUTCOME MEASURES: Rates and HRs for all childhood cancers and specific childhood cancers. RESULTS: A total of 1 505 938 (24.5%) children experienced bereavement at some point during their childhood and 9823 were diagnosed with cancer before the age of 15 years. The exposed children had a small (10%) increased risk of childhood cancer (HR 1.10; 95% CI 1.04 to 1.17). For specific cancers, a significant association was seen only for central nervous system tumours (HR 1.14; 95% CI 1.02 to 1.28). CONCLUSIONS: Our data suggest that psychological stress in early life is associated with a small increased risk of childhood cancer. PMID- 23793703 TI - Effect of low-protein diet on kidney function in diabetic nephropathy: meta analysis of randomised controlled trials. AB - OBJECTIVE: To evaluate the effect of low-protein diet on kidney function in patients with diabetic nephropathy. DESIGN: A systematic review and a meta analysis of randomised controlled trials. DATA SOURCES: MEDLINE, EMBASE, Cochrane Library, ClinicalTrials.gov, International Standard Randomised Controlled Trial Number (ISRCTN) Register and University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) from inception to 10 December 2012. Internet searches were also carried out with general search engines (Google and Google Scholar). STUDY SELECTION: Randomised controlled trials that compared low-protein diet versus control diet and assessed the effects on kidney function, proteinuria, glycaemic control or nutritional status. PRIMARY AND SECONDARY OUTCOME MEASURES AND DATA SYNTHESIS: The primary outcome was a change in the glomerular filtration rate (GFR). The secondary outcomes were changes in proteinuria, post-treatment value of glycated haemoglobin A1C (HbA1c) and post treatment value of serum albumin. The results were summarised as the mean difference for continuous outcomes and pooled by the random effects model. Subgroup analyses and sensitivity analyses were conducted regarding patient characteristics, intervention period, methodological quality and assessment of diet compliance. The assessment of diet compliance was performed based on the actual protein intake ratio (APIR) of the low-protein diet group to the control group. RESULTS: We identified 13 randomised controlled trials enrolling 779 patients. A low-protein diet was associated with a significant improvement in GFR (5.82 ml/min/1.73 m(2), 95% CI 2.30 to 9.33, I(2)=92%; n=624). This effect was consistent across the subgroups of type of diabetes, stages of nephropathy and intervention period. However, GFR was improved only when diet compliance was fair (8.92, 95% CI 2.75 to 15.09, I(2)=92% for APIR <0.9 and 0.03, 95% CI -1.49 to 1.56, I(2)=90% for APIR >=0.9). Proteinuria and serum albumin were not differed between the groups. HbA1c was slightly but significantly decreased in the low protein diet group (-0.26%, 95% CI -0.35 to -0.18, I(2)=0%; n=536). CONCLUSIONS: Low-protein diet was significantly associated with improvement of diabetic nephropathy. The adverse effects of low-protein diet were not apparent such as worsening of glycaemic control and malnutrition. PMID- 23793704 TI - Mobile phone text messages for improving adherence to antiretroviral therapy (ART): a protocol for an individual patient data meta-analysis of randomised trials. AB - INTRODUCTION: Mobile phone text messaging is emerging as an important tool in the care of people living with HIV; however, reports diverge on its efficacy in improving adherence to antiretroviral therapy (ART), and little is known about which patient groups may benefit most from phone-based adherence interventions. We will conduct an individual patient data meta-analysis to investigate the overall and subgroup effects of text messaging in three recently published text messaging randomised controlled trials. METHODS AND ANALYSIS: Data from two Kenyan and one Cameroonian trial will be verified, reformatted and merged. We will determine pooled effect sizes for text messaging versus standard care for improving adherence to ART using individual patient random-effects meta-analysis. We will test for the interaction effects of age, gender, level of education and duration on ART. Sensitivity analyses will be conducted with regard to thresholds for adherence, methods of handling missing data and fixed-effects meta-analysis. Only anonymised data will be collected from the individual studies. ETHICS AND DISSEMINATION: Ethical approval was obtained for the individual studies. The results of this paper will be disseminated as peer-reviewed publications, at conferences and as part of a doctoral thesis. This individual patient data meta analysis may provide important insights into the effects of text messaging on ART adherence in different subpopulations, with important implications for programme implementation involving such interventions and future research. PMID- 23793705 TI - An observational study of the hand hygiene initiative: a comparison of preintervention and postintervention outcomes. AB - OBJECTIVES: To evaluate the impact of implementing a simple, user-friendly eLearning module on hand hygiene (HH) compliance and infection rates. DESIGN: Preintervention and postintervention observational study. PARTICIPANTS: All neonates admitted to the neonatal intensive care unit (NICU) over the study period were eligible for participation and were included in the analyses. A total of 3422 patients were admitted over a 36-month span (July 2009 to June 2012). INTERVENTIONS: In the preintervention and postintervention periods (phases I and II), all healthcare providers were trained on HH practices using an eLearning module. The principles of the '4 moments of HH' and definition of 'baby space' were incorporated using interactive tools. The intervention then extended into a long-term sustainability programme (phase III), including the requirement of an annual recertification of the module and introduction of posters and screensavers throughout the NICU. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was HH compliance rates among healthcare providers in the three phases. The secondary outcome was healthcare-associated infection rates in the NICU. RESULTS: HH compliance rates declined initially in phase II then improved in phase III with the addition of a long-term sustainability programme (76%, 67% and 76% in phases I, II and III, respectively (p<0.01). Infection rates showed an opposing, but concomitant trend in the overall population as well as in infants <1500 g and were 4%, 6% and 4% (p=0.02), and 11%, 21% and 16% (p<0.01), respectively, during the three phases. CONCLUSIONS: Interventions to improve HH compliance are challenging to implement and sustain with the need for ongoing reinforcement and education. PMID- 23793706 TI - Muscle strength in adolescent men and future musculoskeletal pain: a cohort study with 17 years of follow-up. AB - OBJECTIVES: Musculoskeletal pain is highly prevalent throughout adulthood with a major impact on health, function and participation in the society. Still, the association between muscle strength and development of musculoskeletal pain is unclear. We aimed to study whether overall muscle strength in adolescent men is inversely associated with self-reported musculoskeletal pain in adulthood. DESIGN: Cohort study with baseline data from the Swedish Conscription Register and outcome information from the random population-based Swedish Living Conditions Surveys. SETTING: Sweden, 1970-2005. PARTICIPANTS: 5489 men who at age 17-19 years tested their isometric muscle strength (hand grip, arm flexion and knee extension) during the compulsory conscription. OUTCOME MEASURES: The men were surveyed regarding self-reported musculoskeletal pain; mean follow-up time of 17 (range 1-35) years. Our primary outcome was a self-report of musculoskeletal pain, and secondary outcomes were a report of 'severe pain', 'pain in back/hips', 'pain in neck/shoulders' or 'pain in arms/legs', respectively. We categorised muscle strength into three groups: low, average and high, using the 25th-75th percentile to define the reference category (average). We estimated relative risks using log binomial regression with adjustment for smoking, body mass index, education and physical activity. RESULTS: In the adjusted model, men with low overall muscle strength had decreased risk of self reported musculoskeletal pain (0.93, 95% CI 0.87 to 0.99). We observed no such association in men with high strength (0.99, 0.93 to 1.05). Furthermore, no statistically significant increase or decrease in risk was observed for any of the secondary outcomes. CONCLUSIONS: In men, low overall isometric muscle strength in youth was not associated with an increased risk of future musculoskeletal pain. Contrarily, we observed a slightly decreased risk of self reported musculoskeletal pain in adulthood. Our results do not support a model in which low muscle strength is a risk factor for future musculoskeletal pain. PMID- 23793707 TI - Assessment of blood clot formation and platelet receptor function ex vivo in patients with primary Sjogren's syndrome. AB - OBJECTIVES: Primary Sjogren's syndrome (pSS) shares clinical features and pathogenetic mechanisms with systemic lupus erythematosus (SLE). SLE is associated with an increased thromboembolic risk; however, it is unclear whether pSS patients are susceptible to thromboembolic diseases. In this study, we examined ex vivo blood clot formation (clot strength, rates of clot formation and lysis) in pSS using thromboelastography (TEG) and platelet aggregation to common agonists using multiple electrode aggregometry (MEA). We also investigated the relationship between TEG/MEA parameters and clinical/laboratory features of pSS. DESIGN: Case control. SETTING: Secondary care, single centre. PARTICIPANTS: 34 pSS patients, 11 SLE patients and 13 healthy volunteers (all women) entered and completed the study. PRIMARY AND SECONDARY OUTCOME MEASURES: PRIMARY OUTCOMES: TEG and MEA parameters between three subject groups. SECONDARY OUTCOMES: The relationships between TEG/MEA and clinical/laboratory parameters analysed using bivariate correlation analysis with corrections for multiple testing. RESULTS: All TEG and MEA parameters were similar for the three subject groups. After corrections for multiple testing, interleukin (IL)-1alpha and Macrophage inflammatory proteins (MIP)-1alpha remain correlated inversely with clot strength (r=-0.686, p=0.024 and r=-0.730, p=0.012, respectively) and overall coagulability (r=-0.640, p=0.048 and r=-0.648, p=0.048). Stepwise regression analysis revealed that several cytokines such as MIP-1alpha, IL-17a, IL-1alpha and Interferon (IFN) gamma may be key predictors of clot strength and overall coagulability in pSS. CONCLUSIONS: Clot kinetics and platelet receptor function are normal in pSS. Several cytokines correlate with clot strength and overall coagulability in pSS. PMID- 23793708 TI - Clinical implementation of a new antibiotic prophylaxis regimen for percutaneous endoscopic gastrostomy. AB - OBJECTIVES: This study was undertaken to test the extent to which a new antibiotic prophylaxis regimen for percutaneous endoscopic gastrostomy (PEG), identified as a justified and simpler alternative to conventional regimen in a randomised clinical trial, has been adopted in clinical practice. DESIGN: A Swedish nationwide implementation survey, conducted in February 2013, assessed the level of clinical implementation of a 20 ml dose of oral solution of sulfamethoxazole and trimethoprim deposited in the PEG catheter immediately after insertion. All hospitals inserting at least five PEGs annually were identified from the Swedish Patient Registry. A clinician involved in the PEG insertions at each hospital participated in a structured telephone interview addressing their routine use of antibiotic prophylaxis. SETTING: All Swedish hospitals inserting PEGs (n=60). PARTICIPANTS: Representatives of PEG insertions at each of the 60 eligible hospitals participated (100% participation). MAIN OUTCOME MEASURES: Use of routine antibiotic prophylaxis for PEG. RESULTS: A total of 32 (53%) of the 60 hospitals had adopted the new regimen. It was more frequently adopted in university hospitals (67%) than in community hospitals (41%). An annual total of 1813 (70%) of 2573 patients received the new regimen. Higher annual hospital volume was associated with a higher level of adoption of the new regimen (80% in the highest vs 31% in the lowest). CONCLUSIONS: The clinical implementation of the new antibiotic prophylaxis regimen for PEG was high and rapid (70% of all patients within 3 years), particularly in large hospitals. PMID- 23793709 TI - Impact of occult renal impairment on early and late outcomes following coronary artery bypass grafting. AB - OBJECTIVES: High serum creatinine is considered an independent risk factor for poor outcomes following coronary artery bypass grafting (CABG). However, the impact of occult renal impairment (ORI), defined as an impaired glomerular filtration rate (GFR) with a normal serum creatinine (SCr) level, remains unclear. Thus, we sought to investigate the impact of ORI on outcomes after CABG. METHODS: Among patients undergoing their first percutaneous coronary intervention (PCI) or CABG enrolled in the CREDO-Kyoto Registry (a registry of first-time PCI and CABG patients in Japan), 1842 patients with normal SCr levels undergoing CABG were enrolled in the study. Patients were divided into two groups based on preoperative estimated GFR calculated by the Cockcroft-Gault equation: 1339 patients with estimated GFR of >= 60 ml/min/1.73 m(2) (normal group) and 503 with estimated GFR of <60 ml/min/1.73 m(2) (ORI group). RESULTS: Preoperative estimated GFR differed between the groups (51.3 +/- 6.6 vs 85.8 +/- 23.0 ml/min/1.73 m(2), P < 0.01). ORI was associated with high in-hospital mortality (3.2 vs 1.0%, P < 0.01) and need for dialysis (2.0 vs 0.2%, P < 0.01). In terms of long-term outcomes, ORI was associated with high mortality compared with the normal (hazard ratio [95% confidence interval]: 1.72 [1.16-2.54], P < 0.01) and high incidence of composite cardiovascular events (death, stroke or myocardial infarction: 1.53 [1.16-2.02], P < 0.01). CONCLUSIONS: ORI was an independent risk factor for early and late death as well as cardiovascular events in patients undergoing CABG with normal SCr levels. A more accurate evaluation of renal function through a combination of SCr and estimated GFR is needed in patients with normal SCr levels. PMID- 23793710 TI - Mid-term outcome after surgical repair of congenital supravalvular aortic stenosis by extended aortoplasty. AB - OBJECTIVES: Congenital supravalvular aortic stenosis (SVAS) is a rare arteriopathy associated with the Williams-Beuren syndrome (WBS) and other elastin gene deletions. Our objective was to review the mid-term outcomes of SVAS repair with extended aortoplasty. METHODS: Congenital SVAS repairs from 2001 to 2010 were retrospectively reviewed. The follow-up records, reintervention and reoperation data and most recent echocardiograms were obtained. RESULTS: From 2001 to 2010, 21 patients (15 males) underwent surgical repair of SVAS by extended aortoplasty with autologous pretreated pericardium, which is a modification of the Doty technique. The mean age was 3.1 +/- 4.2 years. WBS was diagnosed in 14 of the patients. There was no early mortality, but one late death was observed. At the latest follow-up (mean follow-up, 4.3 +/- 2.9 years; range, 1-108 months), echocardiograms revealed a peak Doppler gradient across the aortic outflow tract of 15 +/- 8 mmHg. The majority of the patients had minimal to mild aortic insufficiency. No reoperation or reintervention was required. CONCLUSIONS: Extended aortoplasty provides excellent mid-term relief of SVAS and, in addition, reshapes the aortic root geometry to a much more favourable anatomical configuration. It can be performed without any increase in operative risks. The mid-term results are excellent. PMID- 23793711 TI - Tuberculous ascending aortic pseudoaneurysm. AB - Pseudoaneurysms of the ascending aorta due to infective organisms are a rare but challenging entity with a risk of high morbidity and mortality. Previous cardiac surgery is an attributing factor, but they can present without previous surgical interventions. Various micro-organisms are responsible for this pathology. Tuberculous pseudoaneurysms of the ascending aorta are extremely rare. We report a case of a 25-year old man who presented to us with shortness of breath and recurrent haemoptysis. After preoperative evaluation including clinical and radiological assessment and echocardiography, he underwent successful repair of a pseudoaneurysm of the ascending aorta by excision and replacement of the diseased aorta with a Dacron tube graft using cardiopulmonary bypass. Postoperatively, he was started on antituberculous chemotherapy based on histological findings. PMID- 23793712 TI - MRE11 is required for homologous synapsis and DSB processing in rice meiosis. AB - Mre11, a conserved protein found in organisms ranging from yeast to multicellular organisms, is required for normal meiotic recombination. Mre11 interacts with Rad50 and Nbs1/Xrs2 to form a complex (MRN/X) that participates in double-strand break (DSB) ends processing. In this study, we silenced the MRE11 gene in rice and detailed its function using molecular and cytological methods. The OsMRE11 deficient plants exhibited normal vegetative growth but could not set seed. Cytological analysis indicated that in the OsMRE11-deficient plants, homologous pairing was totally inhibited, and the chromosomes were completely entangled as a formation of multivalents at metaphase I, leading to the consequence of serious chromosome fragmentation during anaphase I. Immunofluorescence studies further demonstrated that OsMRE11 is required for homologous synapsis and DSB processing but is dispensable for meiotic DSB formation. We found that OsMRE11 protein was located on meiotic chromosomes from interphase to late pachytene. This protein showed normal localization in zep1, Oscom1 and Osmer3, as well as in OsSPO11 1(RNAi) plants, but not in pair2 and pair3 mutants. Taken together, our results provide evidence that OsMRE11 performs a function essential for maintaining the normal HR process and inhibiting non-homologous recombination during meiosis. PMID- 23793714 TI - Retracted article: Mortality trends in patients with and without diabetes in Ontario, Canada and the UK from 1996 to 2009: a population-based study. PMID- 23793713 TI - UKPDS outcomes model 2: a new version of a model to simulate lifetime health outcomes of patients with type 2 diabetes mellitus using data from the 30 year United Kingdom Prospective Diabetes Study: UKPDS 82. AB - AIMS/HYPOTHESIS: The aim of this project was to build a new version of the United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model (UKPDS-OM1), a patient level simulation tool for predicting lifetime health outcomes of people with type 2 diabetes mellitus. METHODS: Data from 5,102 UKPDS patients from the 20 year trial and the 4,031 survivors entering the 10 year post-trial monitoring period were used to derive parametric proportional hazards models predicting absolute risk of diabetes complications and death. We re-estimated the seven original event equations and estimated new equations for diabetic ulcer and some second events. The additional data permitted inclusion of new risk factor predictors such as estimated GFR. We also developed four new equations for all-cause mortality. Internal validation of model predictions of cumulative incidence of all events and death was carried out and a contemporary patient-level dataset was used to compare 10 year predictions from the original and the new models. RESULTS: Model equations were based on a median 17.6 years of follow-up and up to 89,760 patient-years of data, providing double the number of events, greater precision and a larger number of significant covariates. The new model, UKPDS OM2, is internally valid over 25 years and predicts event rates for complications, which are lower than those from the existing model. CONCLUSIONS/INTERPRETATION: The new UKPDS-OM2 has significant advantages over the existing model, as it captures more outcomes, is based on longer follow-up data, and more comprehensively captures the progression of diabetes. Its use will permit detailed and reliable lifetime simulations of key health outcomes in people with type 2 diabetes mellitus. PMID- 23793715 TI - Continuous hypothalamic K(ATP) activation blunts glucose counter-regulation in vivo in rats and suppresses K(ATP) conductance in vitro. AB - AIMS/HYPOTHESIS: Acute systemic delivery of the sulfonylurea receptor (SUR)-1 specific ATP-sensitive K(+) channel (K(ATP)) opener, NN414, has been reported to amplify glucose counter-regulatory responses (CRRs) in rats exposed to hypoglycaemia. Thus, we determined whether continuous NN414 could prevent hypoglycaemia-induced defective counter-regulation. METHODS: Chronically catheterised male Sprague-Dawley rats received a continuous infusion of NN414 into the third ventricle for 8 days after implantation of osmotic minipumps. Counter-regulation was examined by hyperinsulinaemic-hypoglycaemic clamp on day 8 after three episodes of insulin-induced hypoglycaemia (recurrent hypoglycaemia [RH]) on days 5, 6 and 7. In a subset of rats exposed to RH, NN414 infusion was terminated on day 7 to wash out NN414 before examination of counter-regulation on day 8. To determine whether continuous NN414 exposure altered K(ATP) function, we used the hypothalamic glucose-sensing GT1-7 cell line, which expresses the SUR-1 containing K(ATP) channel. RESULTS: Continuous exposure to NN414 in the setting of RH increased, rather than decreased, the glucose infusion rate (GIR), as exemplified by attenuated adrenaline (epinephrine) secretion. Termination of NN414 on day 7 with subsequent washout for 24 h partially diminished the GIR. The same duration of exposure of GT1-7 cells to NN414 substantially reduced K(ATP) conductance, which was also reversed on washout of the agonist. The suppression of K(ATP) current was not associated with reduced channel subunit mRNA or protein levels. CONCLUSIONS/INTERPRETATION: These data indicate that continuous K(ATP) activation results in suppressed CRRs to hypoglycaemia in vivo, which in vitro is associated with the reversible conversion of KATP into a stable inactive state. PMID- 23793716 TI - Deficiency of APPL1 in mice impairs glucose-stimulated insulin secretion through inhibition of pancreatic beta cell mitochondrial function. AB - AIMS/HYPOTHESIS: Adaptor protein, phosphotyrosine interaction, pleckstrin homology domain and leucine zipper containing 1 (APPL1) is an adapter protein that positively mediates adiponectin signalling. Deficiency of APPL1 in the target tissues of insulin induces insulin resistance. We therefore aimed, in the present study, to determine its role in regulating pancreatic beta cell function. METHODS: A hyperglycaemic clamp test was performed to determine insulin secretion in APPL1 knockout (KO) mice. Glucose- and adiponectin-induced insulin release was measured in islets from APPL1 KO mice or INS-1(832/13) cells with either APPL1 knockdown or overproduction. RT-PCR and western blotting were conducted to analyse gene expression and protein abundance. Oxygen consumption rate (OCR), ATP production and mitochondrial membrane potential were assayed to evaluate mitochondrial function. RESULTS: APPL1 is highly expressed in pancreatic islets, but its levels are decreased in mice fed a high-fat diet and db/db mice compared with controls. Deletion of the Appl1 gene leads to impairment of both the first and second phases of insulin secretion during hyperglycaemic clamp tests. In addition, glucose-stimulated insulin secretion (GSIS) is significantly decreased in islets from APPL1 KO mice. Conversely, overproduction of APPL1 leads to an increase in GSIS in beta cells. In addition, expression levels of several genes involved in insulin production, mitochondrial biogenesis and mitochondrial OCR, ATP production and mitochondrial membrane potential are reduced significantly in APPL1-knockdown beta cells. Moreover, suppression or overexproduction of APPL1 inhibits or stimulates adiponectin-potentiated GSIS in beta cells, respectively. CONCLUSIONS/INTERPRETATION: Our study demonstrates the roles of APPL1 in regulating GSIS and mitochondrial function in pancreatic beta cells, which implicates APPL1 as a therapeutic target in the treatment of type 2 diabetes. PMID- 23793717 TI - Non-attendance at diabetic eye screening and risk of sight-threatening diabetic retinopathy: a population-based cohort study. AB - AIMS/HYPOTHESIS: This study evaluated whether repeated non-attendance for diabetic eye screening is associated with the risk of sight-threatening diabetic retinopathy (STDR). METHODS: This was a cohort study of 6,556 residents with diabetes who were invited for screening between 2008 and 2011 in a population based eye screening programme in inner London and who attended for their first ever screen in 2008. The proportion of participants with STDR was evaluated in relation to the number of years in which screening was missed. RESULTS: The proportion of participants who did not attend screening decreased between 2009 and 2011 (annual reduction 1.6% [95% CI 0.9%, 2.3%]). The adjusted relative odds of STDR for 210 participants who did not attend two consecutive years of screening were 3.76 (95% CI 2.14, 6.61; p < 0.001), compared with participants who were screened annually. In 605 participants with mild non-proliferative retinopathy at the first screen, the adjusted relative odds of developing proliferative or moderate to severe non-proliferative retinopathy were 5.72 (95% CI 7.43, 22.83; p = 0.013) for 53 participants who missed two screens. CONCLUSIONS/INTERPRETATION: Patients who do not attend diabetic eye screening are at increased risk of developing STDR. Tracing of non-attenders with evidence of established retinopathy should be an important fail-safe procedure. PMID- 23793718 TI - The symmetric and asymmetric thiophene-fused benzocarborane: structures and first hyperpolarizabilities. AB - The unusual properties of thiophene-fused benzocarborane have attracted a lot of interest in recent years due to their wide applications in photonics and optoelectronics. In the present work, nine molecules [M, N] (M, N are labeled as the number of thiophene rings on the left and right part, respectively) on the basis of thiophene-fused benzocarborane were considered. The first hyperpolarizability (beta tot) values of three synthesized symmetric molecules [1, 1], [2, 2], [3, 3] (M=N, Chem. Eur. J 2012. 18, 11251-11257) and six asymmetric molecules [1, 2], [1, 3], [1, 4], [1, 5], [2, 3], [2, 4] (M?N) were investigated, beta tot values of symmetric molecules show the order: 39 of [1, 1]< 800 of [2, 2]< 903 au of [3, 3], which indicate that beta tot value increases with increasing the number of thiophene ring for symmetric molecules. The other order of beta tot values can be observed: 39 of [1, 1]< 800 of [1, 2]< 3553 of [1, 3]< 7998 of [1, 4]< 13049 au of [1, 5] and 66 of [2, 2]< 3240 of [2, 3]< 8029 au of [2, 4]. Interestingly, when sum of M and N is constant, larger difference between M and N is, larger beta tot value is: 800 au of [2, 2]< 3553 au of [1, 3]; 3240 au of [2, 3] < 7998 au of [1, 4]; 903 au of [3, 3]< 8029 au of [2, 4]< 13049 au of [1, 5]. Significantly, [1, 5] with six thiophene rings has the largest beta tot value (13049 au) which is greatly larger than 903 au of [3, 3] with six thiophene rings. Furthermore, the natural bond orbital (NBO) charge populations, the nucleus-independent chemical shift (NICS), the bond length alternation (BLA) of the nine molecules and crucial transition were studied in our work. We hope that the present work will be beneficial for future theoretical and experimental studies on the electro-optical properties of thiophene-fused benzocarborane molecules. PMID- 23793719 TI - DFT studies of acrolein molecule adsorption on pristine and Al-doped graphenes. AB - The ability of pristine graphene (PG) and Al-doped graphene (AlG) to detect toxic acrolein (C3H4O) was investigated by using density functional calculations. It was found that C3H4O molecule can be adsorbed on the PG and AlG with adsorption energies about -50.43 and - v30.92 kcal mol(-1) corresponding to the most stable configurations, respectively. Despite the fact that interaction of C3H4O has no obvious effects on the of electronic properties of PG, the interaction between C3H4O and AlG can induce significant changes in the HOMO/LUMO energy gap of the sheet, altering its electrical conductivity which is beneficial to sensor designing. Thus, the AlG may be sensitive in the presence of C3H4O molecule and might be used in its sensor devices. Also, applying an external electric filed in an appropriate orientation (almost stronger than 0.01 a.u.) can energetically facilitate the adsorption of C3H4O molecule on the AlG. PMID- 23793720 TI - The effect of cross linking density on the mechanical properties and structure of the epoxy polymers: molecular dynamics simulation. AB - Recently, great attention has been focused on using epoxy polymers in different fields such as aerospace, automotive, biotechnology, and electronics, owing to their superior properties. In this study, the classical molecular dynamics (MD) was used to simulate the cross linking of diglycidyl ether of bisphenol-A (DGEBA) with diethylenetriamine (DETA) curing agent, and to study the behavior of resulted epoxy polymer with different conversion rates. The constant-strain (static) approach was then applied to calculate the mechanical properties (Bulk, shear and Young's moduli, elastic stiffness constants, and Poisson's ratio) of the uncured and cross-linked systems. Estimated material properties were found to be in good agreement with experimental observations. Moreover, the dependency of mechanical properties on the cross linking density was investigated and revealed improvements in the mechanical properties with increasing the cross linking density. The radial distribution function (RDF) was also used to study the evolution of local structures of the simulated systems as a function of cross linking density. PMID- 23793721 TI - Intensity-based hierarchical elastic registration using approximating splines. AB - PURPOSE: We introduce a new hierarchical approach for elastic medical image registration using approximating splines. In order to obtain the dense deformation field, we employ Gaussian elastic body splines (GEBS) that incorporate anisotropic landmark errors and rotation information. Since the GEBS approach is based on a physical model in form of analytical solutions of the Navier equation, it can very well cope with the local as well as global deformations present in the images by varying the standard deviation of the Gaussian forces. METHODS: The proposed GEBS approximating model is integrated into the elastic hierarchical image registration framework, which decomposes a nonrigid registration problem into numerous local rigid transformations. The approximating GEBS registration scheme incorporates anisotropic landmark errors as well as rotation information. The anisotropic landmark localization uncertainties can be estimated directly from the image data, and in this case, they represent the minimal stochastic localization error, i.e., the Cramer-Rao bound. The rotation information of each landmark obtained from the hierarchical procedure is transposed in an additional angular landmark, doubling the number of landmarks in the GEBS model. RESULTS: The modified hierarchical registration using the approximating GEBS model is applied to register 161 image pairs from a digital mammogram database. The obtained results are very encouraging, and the proposed approach significantly improved all registrations comparing the mean square error in relation to approximating TPS with the rotation information. On artificially deformed breast images, the newly proposed method performed better than the state-of-the-art registration algorithm introduced by Rueckert et al. (IEEE Trans Med Imaging 18:712-721, 1999). The average error per breast tissue pixel was less than 2.23 pixels compared to 2.46 pixels for Rueckert's method. CONCLUSION: The proposed hierarchical elastic image registration approach incorporates the GEBS approximation scheme extended with anisotropic landmark localization uncertainties as well as rotation information. Our experimental results show that the proposed scheme improved the registration result significantly. PMID- 23793722 TI - Hybrid method for the detection of pulmonary nodules using positron emission tomography/computed tomography: a preliminary study. AB - PURPOSE: In this study, an automated scheme for detecting pulmonary nodules using a novel hybrid PET/CT approach is proposed, which is designed to detect pulmonary nodules by combining data from both sets of images. METHODS: Solitary nodules were detected on CT by a cylindrical filter that we developed previously, and in the PET imaging, high-uptake regions were detected automatically using thresholding based on standardized uptake values along with false-positive reduction by means of the anatomical information obtained from the CT images. Initial candidate nodules were identified by combining the results. False positives among the initial candidates were eliminated by a rule-based classifier and three support vector machines on the basis of the characteristic features obtained from CT and PET images. RESULTS: We validated the proposed method using 100 cases of PET/CT images that were obtained during a cancer-screening program. The detection performance was assessed by free-response receiver operating characteristic (FROC) analysis. The sensitivity was 83.0% with the number of false positives/case at 5.0, and it was 8% higher than the sensitivity of independent detection systems using CT or PET images alone. CONCLUSION: Detection performance indicates that our method may be of practical use for the identification of pulmonary nodules in PET/CT images. PMID- 23793723 TI - Electrode localization for planning surgical resection of the epileptogenic zone in pediatric epilepsy. AB - PURPOSE: In planning for a potentially curative resection of the epileptogenic zone in patients with pediatric epilepsy, invasive monitoring with intracranial EEG is often used to localize the seizure onset zone and eloquent cortex. A precise understanding of the location of subdural strip and grid electrodes on the brain surface, and of depth electrodes in the brain in relationship to eloquent areas is expected to facilitate pre-surgical planning. METHODS: We developed a novel algorithm for the alignment of intracranial electrodes, extracted from post-operative CT, with pre-operative MRI. Our goal was to develop a method of achieving highly accurate localization of subdural and depth electrodes, in order to facilitate surgical planning. Specifically, we created a patient-specific 3D geometric model of the cortical surface from automatic segmentation of a pre-operative MRI, automatically segmented electrodes from post operative CT, and projected each set of electrodes onto the brain surface after alignment of the CT to the MRI. Also, we produced critical visualization of anatomical landmarks, e.g., vasculature, gyri, sulci, lesions, or eloquent cortical areas, which enables the epilepsy surgery team to accurately estimate the distance between the electrodes and the anatomical landmarks, which might help for better assessment of risks and benefits of surgical resection. RESULTS: Electrode localization accuracy was measured using knowledge of the position of placement from 2D intra-operative photographs in ten consecutive subjects who underwent intracranial EEG for pediatric epilepsy. Average spatial accuracy of localization was 1.31 +/- 0.69 mm for all 385 visible electrodes in the photos. CONCLUSIONS: In comparison with previously reported approaches, our algorithm is able to achieve more accurate alignment of strip and grid electrodes with minimal user input. Unlike manual alignment procedures, our algorithm achieves excellent alignment without time-consuming and difficult judgements from an operator. PMID- 23793724 TI - Evolution of educational inequalities in mortality among young adults in an urban setting. AB - OBJECTIVES: To gain insight into the evolution in educational inequalities in adolescent and young adult all-cause and cause-specific mortality in the urban setting of the Brussels-Capital Region. METHODS: Data were derived from record linkage between the censuses of 1991 and 2001 and register data on all-cause and cause-specific mortality and emigration in the respective periods of 1st October 1991 to 1st January 1996 and 1st October 2001 to 1st January 2006. Both directly and indirectly standardised mortality rates and the relative index of inequality (RII) were computed. RESULTS: Mortality rates among adolescents and young adults have dropped significantly, especially infections and traffic accidents. However, educational inequalities among men have slightly increased: men with a maximum primary education are four times more likely to die than those who are higher educated [RII = 4.09 (2.78-6.03)]. Among women, no social gradient is observed in either period, but a clear split between the lowest educated and other educational groups is apparent in the 2000s. CONCLUSIONS: There is a positive evolution towards lower mortality among adolescents and young adults, but educational inequalities remain a public health concern. PMID- 23793725 TI - The effects of quercetin protect cardiomyocytes from A/R injury is related to its capability to increasing expression and activity of PKCepsilon protein. AB - Quercetin is a ubiquitous flavonoid found in vegetable foods. Epidemiological and animal studies have reported an inverse association between quercetin intakes and occurrence and development of various cardiovascular diseases. Some researchers have inferred that the mechanisms of quercetin to protect cardiomyocytes from ischemia/reperfusion injury may be involved in modulation of intracellular signal pathways and regulation of proteins expression beyond its antioxidant activity. The aim of this study was to investigate whether quercetin protect cardiomyocytes from anoxia/reoxygenation injury through PKCepsilon pathway. Neonatal rat primary cardiomyocytes were pretreated with quercetin or quercetin plus epsilonV1-2, a selective PKCepsilon inhibitor, prior to A/R treatment. Western blotting analysis showed that the level of PKCepsilon and phosphor-PKCepsilon Ser297 in the quercetin pretreatment group were all increased significantly compared to the control or A/R group. Subsequent assays showed that pretreated with quercetin could increase the viability of neonatal rat primary cardiomyocytes suffered A/R, decrease the apoptosis and ROS and alleviate the loss of mitochondrial membrane potential induced by A/R injury. However, the protective effects of quercetin disappeared in the group pretreated with epsilonV1-2. Thus, for the first time, we revealed that one of the mechanisms of quercetin protecting cardiomyocytes from A/R injury might be increase the expression of PKCepsilon protein and then enhance the activity of its downstream pathway. PMID- 23793726 TI - Negative emotions and risk for type 2 diabetes among Korean immigrants. AB - PURPOSE: The purpose of this study is to examine the relationship between negative emotions and bio-behavioral risk factors among Korean immigrants at risk for type 2 diabetes (T2DM). METHODS: Data were collected from 148 Korean immigrant adults who are "at risk" for T2DM as defined by having family history of T2DM in first-degree relatives, body mass index greater than 23, or history of gestational diabetes in women. Participants completed questionnaires and underwent biological measures. Negative emotions included feeling nervous, hopeless, restless, anxious, and stressed as well as depressive symptoms. RESULTS: High percentages of participants had T2DM risk factors including overweight, greater than normal waist to hip ratio, and blood glucose readings that are indicative of T2DM. Feeling stressed was the most commonly reported negative emotion (66%), followed by feeling anxious (51%), restless (38%), nervous (30%), and hopeless (13%). Experience of negative emotions was significantly related to behavioral risk factors; higher levels of experiencing negative emotions were related to increased soda intake and a decreased likelihood of doing at least 10 minutes of moderate exercise. Stress and anxiety were each negatively related to moderate exercise, and depressive symptoms were negatively related to both moderate and vigorous exercise. No significant relationship was found between negative emotions and biological risk factors. CONCLUSIONS: Findings suggest that negative emotions, individually and taken together, may be related to T2DM risk behaviors in high-risk Korean immigrants. Behavioral interventions to prevent T2DM in this population should consider assessing and addressing negative emotions. PMID- 23793727 TI - Preprocedural coronary CT angiography significantly improves success rates of PCI for chronic total occlusion. AB - Chronic total occlusions of coronary arteries occur in about 20% of patients with suspected coronary artery disease and are more frequent with increasing age. The success rate of interventions is lower (55-80%) compared to conventional lesions (>90%). Coronary CT angiography (coronary CTA) provides information about the occluded segment, which cannot be obtained from invasive angiograms (XA). We therefore hypothesized that preprocedural coronary CTA may improve success rates of percutaneous coronary intervention (PCI) for coronary arteries (CTO). 30 patients with chronic total coronary artery occlusions (mean age 73 years, 26 men) and predicted high complexity were imaged by coronary CTA prior to PCI for CTO. CT data sets were acquired with a 64 detector row dual source scanner and retrograde ECG gating, 0.6 mm collimation and z-flying focal spot, yielding isovoxel spatial resolution of about 0.4 mm. Based on the CT data sets, established complexity criteria for CTO (Euro CTO club, Di Mario et al. in EuroIntervention 3(1):30-43, 2007) were evaluated and compared to invasive coronary angiography. Three-dimensional volume-rendered images of the occluded coronary artery were displayed in the catheterization lab during PCI to guide the advancement of the wire. PCI success, defined as the ability to advance the guide wire into the distal lumen with thrombolysis in myocardial infarction III flow was compared to 43 controls without coronary CTA using propensity score matching based on established criteria of procedural success. The course of the occluded segments was visualized by coronary CTA in all cases. Calcification, lesion length, stump morphology and presence of side branches were underestimated by invasive angiograms when compared to coronary CTA. PCI success rate in 30 patients who underwent pre-procedural CTA was significantly higher than in patients without prior coronary CTA [unmatched: CT 90% (27/30) vs. no CT 63% (27/43), p = 0.009; matched: CT 88% (22/25) vs. no CT 64% (16/25) p = 0.03]. Through information not readily seen on invasive coronary angiography, coronary CTA can significantly enhance success rates of PCI for CTO. PMID- 23793729 TI - Interface interaction induced ultra-dense nanoparticles assemblies. AB - We demonstrate a simple and clean physical methodology for fabricating such nanoparticle assemblies (dense arrays and/or dendrites) related to the interfacial interaction between the constructed materials and the anodized aluminum oxide (AAO) porous templates. The interfacial interaction can be regulated by the surface tension of the constructed materials and the AAO membrane, and the AAO-template structure, such as pore size, membrane thickness and surface morphologies. Depending on the interfacial interaction between the constructed materials and the AAO templates, NP arrays with mean particle diameters from 3.8 +/- 1.0 nm to 12.5 +/- 2.9 nm, mean inter-edge spacings from 3.5 +/- 1.4 nm to 7.9 +/- 3.4 nm and areal densities from 5.6 * 10(11) NPs per cm(2) to 1.5 * 10(12) NPs per cm(2) are fabricated over large areas (currently ~2 cm * 3 cm). The fabrication process includes firstly thermal evaporation of metal layers no more than 10 nm thick on the pre-coated Si wafer by AAO templates with a thickness of less than 150 nm and mean pore sizes no more than 12 nm, and then removal of the AAO templates. The NP arrays can be stable for hours at a temperature slightly below the melting point of the constructed materials (e.g., ~800 degrees C for Au NPs for 4 hours) with little change in size and inter particle separation. Using one of them (e.g., 11.8 nm Au NPs) as growth-oriented catalysts, ultra-thin (12.1 +/- 2.3 nm) dense nanowires can be conveniently obtained. Furthermore, dendrite superstructures can be generated easily from eutectic alloy NPs with diameters of ~10 nm pre-formed by thermal evaporation of metal layers more than 20 nm thick on surface-patterned thick AAO templates (e.g., 500 nm). The resulting dendrites, dense arrays and other superstructures (i.e., nanorods and nanowires) formed using NP arrays as catalysts, should have broad applications in catalysis, information technology, photovoltaics and biomedical engineering. PMID- 23793730 TI - Risk factors for and complications of distraction osteogenesis. AB - PURPOSE: Distraction osteogenesis is commonly used for limb deformities and reconstruction of bone defects with satisfactory outcome for the patients. However, it is associated with a risk of complications. The present study aims to assess the incidence of complications and to identify the risk factors that may predict distraction osteogenesis-related complications. MATERIALS AND METHODS: We retrospectively studied 63 patients (mean age 13.5 years; range 3-57 years) who had 74 distraction osteogenesis procedures from 2004 to 2009. A circular external fixator was used in 58 procedures, and a monolateral in 16 procedures. Fixator's time, days of treatment, lengthening percentage, bone healing index, distraction regenerate length and index, risk factors and complications were evaluated. The mean follow-up was 5 years (range 2-7 years). RESULTS: Complications occurred in 57 of the 74 procedures (77%); 70% were major complications and 30% were minor. Complications were more common in adults. Bone healing index, days of treatment and fixator's time were univariate predictors of complications. Bone healing index and adult age were the only multivariate predictors of complications. CONCLUSION: Adult age and bone healing index are the most important multivariate predictors of distraction osteogenesis-related complications. Routine follow-up after implant removal, selection of younger patients with minor risk factors and shorter fixator's time are necessary to reduce the rate of distraction osteogenesis-related complications. PMID- 23793731 TI - A critical analysis of clinical outcomes reported in stem cell trials for acute myocardial infarction: some thoughts for design of future trials. AB - The purpose of stem cell therapy for myocardial infarction is to improve clinical outcomes, and detailed information on clinical outcomes is critical to appropriate planning of phase III trials. We have examined data from select phase II trials using autologous bone-marrow-derived stem cells in patients with acute myocardial infarction. We have extracted available definitions and outcome data, and have generated standardized estimates of events to permit summary comparisons. Nine trials (1,040 patients) with results for 6 months to 5 years were evaluated. Adverse outcomes differed widely, and there was a general lack of details in the definitions of these outcomes. Heart-failure-related hospitalizations occurred in only 16 patients (1.5 %) and death occurred in only 43 patients (4.1 %). Ischemia-related outcomes outnumbered heart failure outcomes more than tenfold. Uniform criteria need to be developed to better define clinical outcomes of interest. Furthermore, a refocus from heart failure outcomes to ischemia-related outcomes seems appropriate. PMID- 23793733 TI - [Bullous keratopathy]. PMID- 23793732 TI - Primary angiitis of the central nervous system and reversible cerebral vasoconstriction syndrome. AB - Primary angiitis of the central nervous system (PACNS) is one of the most devastating pathologic processes that affect the central nervous system (CNS). It results in exclusive inflammation and destruction of CNS blood vessels. Progressive debilitating unexplained neurological deficit associated with abnormal cerebrospinal fluid (CSF) analysis findings is the typical picture of the disease. CNS biopsy is the gold standard diagnostic test. Immunosuppressive therapy is the core treatment. Reversible cerebral vasoconstriction syndrome (RCVS) is a main mimic of PACNS. RCVS is characterized clinically by recurrent thunderclap headache with or without neurological deficit and normal CSF analysis findings and angiographically by reversible diffuse segmental vasospasm of intracranial vessels. A stepwise diagnostic approach should be followed to differentiate PACNS from RCVS and exclude the other clinical, radiographic, and angiographic mimics. PMID- 23793734 TI - [Intraoperative inhibition of fibrosis in modern trabeculectomy]. PMID- 23793735 TI - Cardiac autonomic function associated with treatment adherence after a brief intervention in patients with chronic pain. AB - The goal of this study was to investigate psychophysiological characteristics in chronic pain patients during a pain stressor (cold pressor test) and after a brief diaphragmatic breathing intervention. Laboratory procedures were designed to quantify the effects of diaphragmatic breathing training at six breaths per minute on cardiac autonomic reactivity as indexed by root mean square of successive differences (RMSSD) and sequential baroreflex sensitivity (sBRS). Participants (n = 22) completed an initial laboratory assessment including the diaphragmatic breathing training session and were instructed to practice the technique for three ten-minute sessions daily. Self-monitoring of the use of the technique along with daily pain and fatigue scores was accomplished with hand held computers. Participants returned to the lab for a second assessment after two-weeks. Participants demonstrating improved resting physiological status as indexed by change in RMSSD and sBRS after training (improvers) were compared to those not demonstrating any change in these variables (non-improvers). After two weeks of training, the improvers showed higher tolerance (p < .05) and lower blood pressure reactivity to the cold pressor test (p < .05) compared to the non improvers. Time spent practicing the breathing technique was significantly different between the groups with the improvers maintaining daily practice close to the intervention recommendations. These results suggest the potential for significant improvements in autonomic functioning and inhibitory response to stress after a single intervention session and two weeks of practice. PMID- 23793736 TI - Surgical technique: Muscle transfer restores extensor function after failed patella-patellar tendon allograft. AB - BACKGROUND: Extensor mechanism allograft provides an effective remedy for severe quadriceps deficiency caused by loss of the patella, patellar tendon, and quadriceps tendon in TKA. Late failure is common, however, and major quadriceps deficiency occurs after removal of the allograft material. DESCRIPTION OF TECHNIQUE: Six human cadaver specimens were dissected to evaluate the feasibility of transferring the vastus medialis, vastus lateralis, and medial head of the gastrocnemius muscle to fill the defect caused by loss of the patella and extensor tendon mechanism after failure and removal of allograft material. Transfer of the medial and lateral vastus muscles with their distal attachments into the tibia achieved closure of the defect but did not provide robust tendon material to fill the defect in the anterior knee. The medial gastrocnemius muscle reached easily to the muscular portion of the vastus medialis and lateralis flaps and provided secure closure of the anterior knee and strong attachment of viable muscle and tendon. METHODS: Five knees (five patients) with failed patella patellar tendon allograft between August 2008 and April 2010 were repaired using this technique. RESULTS: Mean extensor lag was 47 degrees (range, 35 degrees -62 degrees ) before surgery and improved to 12 degrees (range, 5 degrees -15 degrees ) 1 year after surgery. CONCLUSIONS: These preliminary results suggest that the described muscle transfer technique may provide an approach to salvage the failed extensor mechanism allograft after TKA. PMID- 23793737 TI - CORR Insights (r): High prevalence of adverse reactions to metal debris in small headed ASRTM hips. PMID- 23793738 TI - Surveillance biopsy and active treatment during active surveillance for low-risk prostate cancer. AB - BACKGROUND: The goals of the study were to examine surveillance biopsy and active treatment in patients under active surveillance (AS) for low-risk prostate cancer and to determine the active treatment-free survival rate. METHODS: The subjects were 87 patients with low-risk prostate cancer who were under AS between 2000 and 2010. The eligibility criteria for AS were T1c, Gleason score <= 6, prostate specific antigen level <= 10 ng/ml, one or two positive biopsies, maximum cancer involvement <= 50 %, and age <= 80 years old. RESULTS: Of the 87 patients, 48 underwent the first surveillance biopsy (55.2 %). In this biopsy, no cancer was found in 33.3 % of cases, 27.1 % remained eligible for AS, and 39.6 % did not meet the AS criteria (up-grade 22.9 %, up-volume 16.7 %). A second surveillance biopsy was performed at 1.9 years after the first biopsy. No cancer was found in 20.0 % of cases, 40.0 % remained eligible for AS, and 40.0 % did not meet the AS criteria (up-grade 26.7 %, up-volume 13.3 %). A total of 50 patients received treatment by 1.7 years after starting AS, mainly due to an up-grade or up-volume. However, some patients underwent radiotherapy despite biopsy results indicating no cancer or eligibility for AS. The active treatment-free survival rate was 64.1 % after 2 years. CONCLUSIONS: Surveillance biopsy is important for identifying patients who require active treatment. The results in this study allowed determination of the active treatment-free survival rate and are informative for making treatment decisions. PMID- 23793740 TI - Electron density reactivity indexes of the tautomeric/ionization forms of thiamin diphosphate. AB - The generation of the highly reactive ylide in thiamin diphosphate catalysis is analyzed in terms of the nucleophilicity of key atoms, by means of density functional calculations at X3LYP/6-31++G(d,p) level of theory. The Fukui functions of all tautomeric/ionization forms are calculated in order to assess their reactivity. The results allow to conclude that the highly conserved glutamic residue does not protonate the N1' atom of the pyrimidyl ring, but it participates in a strong hydrogen bonding, stabilizing the eventual negative charge on the nitrogen, in all forms involved in the ylide generation. This condition provides the necessary reactivity on key atoms, N4' and C2, to carry out the formation of the ylide required to initiate the catalytic cycle of ThDP dependent enzymes. This study represents a new approach for the ylide formation in ThDP catalysis. PMID- 23793739 TI - Effects of organic solvents and substrate binding on trypsin in acetonitrile and hexane media. AB - In this work, we used molecular dynamic (MD) simulation to study trypsin with and without a six-amino-acid peptide bound in three different solvents (water, acetonitrile and hexane) in order to provide molecular information for well understanding the structure and function of enzymes in non-aqueous media. The results show that the enzyme is more compact and less native-like in hexane than in the other two polar solvents. The substrate could stabilize the native protein structure in the two polar media, but not in the non-polar hexane. There are no significant differences in the conformation of the S1 pocket upon the substrate binding in water and acetonitrile media while a reverse behavior is observed in hexane media, implying a possible induced fit binding mechanism in the non-polar media. The substrate binding enhances the stability of catalytic H-bond network since it could expel the solvent molecules from the active site. The enzyme and the substrate appear to be more appropriate to the reactive conformation in the organic solvents compared with aqueous solution. There is much greater substrate binding strength in hexane media than the water and acetonitrile ones since the polar solvent significantly weakens electrostatic interactions, which are observed to be the main driving force to the binding. In addition, some residues of the S1 pocket could remain favorable contribution to the binding despite the solvent change, but with differences in the contribution extent, the number and the type of residues between the three media. PMID- 23793741 TI - Revealing substitution effects on the strength and nature of halogen-hydride interactions: a theoretical study. AB - A quantum chemistry study was carried out to investigate the strength and nature of halogen bond interactions in HXeH...XCCY complexes, where X = Cl, Br and Y = H, F, Cl, Br, CN, NC, C2H, CH3, OH, SH, NH2. Examination of the electrostatic potentials V(r) of the XCCY molecules reveals that the addition of substituents has a significant effect upon the most positive electrostatic potential on the surface of the interacting halogen atom. We found that the magnitude of atomic charges and multipole moments depends upon the halogen atom X and is rather sensitive to the electron-withdrawing/donating power of the remainder of the molecule. An excellent correlation was found between the most positive electrostatic potentials on the halogen atom and the interaction energies. For either HXeH...ClCCY or HXeH...BrCCY complexes, an approximate linear correlation between the interaction energies and halogens multipole moments are established, indicating that the electrostatic and polarization interactions are responsible for the stability of the complexes. According to energy decomposition analysis, it is revealed that the electrostatic interactions are the major source of the attraction in the HXeH...XCCY complexes. Furthermore, the changes in the electrostatic term are mainly responsible for the dependence of interaction energy on the halogen atom. PMID- 23793743 TI - NH3 on a BC3 nanotube: effect of doping and decoration of aluminum. AB - The adsorption of the NH3 molecule was investigated on pristine, Al-doped and Al decorated BC3 nanotubes (BC3NT) using density functional theory calculations. It was found that NH3 prefers to be adsorbed on a B atom of the tube wall, releasing energy of 1.02 eV. Al-doping increases the acidity of the tube surface and, therefore, its reactivity toward NH3 so that the released energy in this case is about 1.62 eV, while decorating the BC3NT with Al atom decreases the acidity and reactivity. Although Al-doping has no significant effect on the electronic properties of the BC3NT, Al-decoration significantly reduces its HOMO/LUMO energy gap from 2.37 to 1.16 eV so that the tube becomes an n-type semiconductor. However, we believe that the acidity of the BC3NTs may be controlled by doping or decoration of Al atoms. PMID- 23793742 TI - Structural and phylogenetic basis for the classification of group III phospholipase A2. AB - Secretory phospholipase A2 (PLA2) catalyses the hydrolysis of the sn-2 position of glycerophospholipids to liberate arachidonic acid, a precursor of eicosanoids, that are known mediators of inflammation. The group III PLA2 enzymes are present in a wide array of organisms across many species with completely different functions. A detailed understanding of the structure and evolutionary proximity amongst the enzymes was carried out for a meaningful classification of this group. Fifty protein sequences from different species of the group were considered for a detailed sequence, structural and phylogenetic studies. In addition to the conservation of calcium binding motif and the catalytic histidine, the sequences exhibit specific 'amino acid signatures'. Structural analysis reveals that these enzymes have a conserved globular structure with species specific variations seen at the active site, calcium binding loop, hydrophobic channel, the C-terminal domain and the quaternary conformational state. Character and distance based phylogenetic analysis of these sequences are in accordance with the structural features. The outcomes of the structural and phylogenetic analysis lays a convincing platform for the classification the group III PLA2s into (1A) venomous insects; (IB) non-venomous insects; (II) mammals; (IIIA) gila monsters; (IIIB) reptiles, amphibians, fishes, sea anemones and liver fluke, and (IV) scorpions. This classification also helps to understand structure function relationship, enzyme-substrate specificity and designing of potent inhibitors against the drug target isoforms. PMID- 23793744 TI - Patients with early arthritis consume less alcohol than controls, regardless of the type of arthritis. AB - OBJECTIVES: There are conflicting reports concerning the association between alcohol consumption and RA. We performed a case-control study to investigate the association of alcohol consumption with RA as well as with other forms of arthritis. To assess whether alcohol consumption affects long-term disease outcome, we also investigated its association with radiographic progression and sustained drug-free remission in RA. METHODS: Patients with arthritis and various diagnoses including RA, OA, ReA, SpA and PsA were compared with 5868 controls from the general population. The association of disease with alcohol consumption was analysed by logistic regression analysis. RESULTS: Alcohol consumption was inversely associated with not only RA [odds ratio (OR) 0.28, 95% CI 0.23, 0.35] but also OA (OR 0.31, 95% CI 0.16, 0.62) and other forms of arthritis (OR 0.34, 95% CI 0.24, 0.48). A higher degree of systemic inflammation, reflected by the ESR and CRP level, was associated with a smaller proportion of patients consuming alcohol. There was no dose-response relationship between the amount of alcohol consumed and the presence of arthritis. The extent of joint destruction and the rate of sustained drug-free remission were not affected by alcohol consumption. CONCLUSION: Arthritis patients report less alcohol consumption than controls, regardless of the type of arthritis. This suggests that alcohol may either protect against different kinds of arthritis or that the inverse association between alcohol and arthritis may be secondary to disease development, with arthritis patients being less inclined to consume alcohol due to their decreased general well-being. PMID- 23793745 TI - Single-session aspiration thrombectomy of lower extremity deep vein thrombosis using large-size catheter without pharmacologic thrombolysis. AB - PURPOSE: To retrospectively evaluate the efficacy of single-session aspiration thrombectomy using large catheters without pharmacologic thrombolysis to treat acute and subacute lower extremity deep vein thrombosis (DVT). METHODS: From January 2008 to December 2011, single-session aspiration thrombectomy using large, 11F introducer catheters to treat acute and subacute lower extremity DVT was performed in 74 limbs of 74 patients (M/F = 23/51, age range 36-88 years), and clinical and imaging follow-up of over 6 months were obtained in 26 patients. Causes of DVT were May-Thurner syndrome (n = 65), malignancy related (n = 6), and pelvic mass (n = 3). A 14F introducer sheath was inserted through the popliteal vein, followed by rotational thrombus maceration and aspiration thrombectomy. Angioplasty and stent placement were performed when needed. Radiological images and medical records were reviewed for immediate and midterm results, complications, and recurrences. RESULTS: Initial technical success rate was 89.2% (66 patients). Stenting was performed in 55 patients. The failures were due to underlying chronic thrombi/DVT (n = 7) and stent failure due to huge pelvic mass (n = 1). There was no procedure-related complication. In the 26 midterm follow-up patients for a duration of 6-48 months, there was no recurrence (n = 20), stent occlusion (n = 3), or femoral vein occlusion (n = 3). One-year primary patency rate in stent/iliac vein, femoral vein, and popliteal/infrapopliteal vein were 88.5, 88.5, and 96.2%, respectively. CONCLUSION: Single-session aspiration thrombectomy for acute and subacute lower extremity DVT using large introducer catheters without pharmacologic thrombolysis is feasible with acceptable immediate and midterm results, excluding complications related to pharmacologic thrombolysis. PMID- 23793746 TI - Co-regulation in embryonic stem cells via context-dependent binding of transcription factors. AB - MOTIVATION: With the accumulation of genome-wide binding data for many transcription factors (TFs) in the same cell type or cellular condition, it is of great current interest to systematically infer the complex regulatory logic among multiple TFs. In particular, ChIP-Seq data have been generated for 14 core TFs critical to the maintenance and reprogramming of mouse embryonic stem cells (ESCs). This provides a great opportunity to study the regulatory collaboration and interaction among these TFs and with other unknown co-regulators. RESULTS: In combination with liquid association among gene expression profiles, we develop a computational method to predict context-dependent (CD) co-egulators of these core TFs in ESCs from pairwise binding datasets. That is, co-occupancy between a core TF and a predicted co-regulator depends on the presence or absence of binding sites of another core TF, which is regarded as a binding context. Unbiased external validation confirms that the predicted CD binding of a co-regulator is reliable. Our results reveal a detailed CD co-regulation network among the 14 core TFs and provide many other potential co-regulators showing strong agreement with the literature. AVAILABILITY: See www.stat.ucla.edu/~zhou/CMF for software and source code. PMID- 23793747 TI - Linc2GO: a human LincRNA function annotation resource based on ceRNA hypothesis. AB - Large numbers of long intergenic non-coding RNA (lincRNA) have been detected through high-throughput sequencing technology. However, currently we still know very little about their functions. Therefore, a lincRNA function annotation database is needed to facilitate the study in this field. In this article, we present Linc2GO, a web resource that aims to provide comprehensive functional annotations for human lincRNA. MicroRNA-mRNA and microRNA-lincRNA interaction data were integrated to generate lincRNA functional annotations based on the 'competing endogenous RNA hypothesis'. To the best of our knowledge, Linc2GO is the first database that makes use of the 'competing endogenous RNA hypothesis' to predict lincRNA functions. AVAILABILITY: Freely available at http://www.bioinfo.tsinghua.edu.cn/~liuke/Linc2GO/index.html PMID- 23793748 TI - The human genome contracts again. AB - The number of human genomes that have been sequenced completely for different individuals has increased rapidly in recent years. Storing and transferring complete genomes between computers for the purpose of applying various applications and analysis tools will soon become a major hurdle, hindering the analysis phase. Therefore, there is a growing need to compress these data efficiently. Here, we describe a technique to compress human genomes based on entropy coding, using a reference genome and known Single Nucleotide Polymorphisms (SNPs). Furthermore, we explore several intrinsic features of genomes and information in other genomic databases to further improve the compression attained. Using these methods, we compress James Watson's genome to 2.5 megabytes (MB), improving on recent work by 37%. Similar compression is obtained for most genomes available from the 1000 Genomes Project. Our biologically inspired techniques promise even greater gains for genomes of lower organisms and for human genomes as more genomic data become available. AVAILABILITY: Code is available at sourceforge.net/projects/genomezip/ PMID- 23793749 TI - Mechanistic insights into mutually exclusive splicing in dynamin 1. AB - SUMMARY: Mutually exclusive splicing is a strictly regulated pattern of alternative splicing. A specific group of mutually exclusive splicing events has been shown to be regulated by the formation of specific RNA secondary structures. This type of regulation has been shown to exist only in arthropods. The present study involved a detailed sequence analysis of human gene structures that undergo mutually exclusive splicing, which showed that this type of regulation may also occur in dynamin 1 in mammals. A phylogenetic analysis revealed that the dynamin 1 orthologs in invertebrates did not share the same sequence features, which suggests that the regulatory mechanism has independently evolved in the mammalian lineage. Therefore, the emergence of this elaborate mechanism for mutually exclusive splicing may be attributable to mechanistic convergence. PMID- 23793750 TI - cisExpress: motif detection in DNA sequences. AB - MOTIVATION: One of the major challenges for contemporary bioinformatics is the analysis and accurate annotation of genomic datasets to enable extraction of useful information about the functional role of DNA sequences. This article describes a novel genome-wide statistical approach to the detection of specific DNA sequence motifs based on similarities between the promoters of similarly expressed genes. This new tool, cisExpress, is especially designed for use with large datasets, such as those generated by publicly accessible whole genome and transcriptome projects. cisExpress uses a task farming algorithm to exploit all available computational cores within a shared memory node. We demonstrate the robust nature and validity of the proposed method. It is applicable for use with a wide range of genomic databases for any species of interest. AVAILABILITY: cisExpress is available at www.cisexpress.org. PMID- 23793751 TI - Differential gene expression analysis using coexpression and RNA-Seq data. AB - MOTIVATION: RNA-Seq is increasingly being used for differential gene expression analysis, which was dominated by the microarray technology in the past decade. However, inferring differential gene expression based on the observed difference of RNA-Seq read counts has unique challenges that were not present in microarray based analysis. The differential expression estimation may be biased against low read count values such that the differential expression of genes with high read counts is more easily detected. The estimation bias may further propagate in downstream analyses at the systems biology level if it is not corrected. RESULTS: To obtain a better inference of differential gene expression, we propose a new efficient algorithm based on a Markov random field (MRF) model, called MRFSeq, that uses additional gene coexpression data to enhance the prediction power. Our main technical contribution is the careful selection of the clique potential functions in the MRF so its maximum a posteriori estimation can be reduced to the well-known maximum flow problem and thus solved in polynomial time. Our extensive experiments on simulated and real RNA-Seq datasets demonstrate that MRFSeq is more accurate and less biased against genes with low read counts than the existing methods based on RNA-Seq data alone. For example, on the well-studied MAQC dataset, MRFSeq improved the sensitivity from 11.6 to 38.8% for genes with low read counts. AVAILABILITY: MRFSeq is implemented in C and available at http://www.cs.ucr.edu/~yyang027/mrfseq.htm PMID- 23793752 TI - Multilabel classification for exploiting cross-resistance information in HIV-1 drug resistance prediction. AB - MOTIVATION: Antiretroviral treatment regimens can sufficiently suppress viral replication in human immunodeficiency virus (HIV)-infected patients and prevent the progression of the disease. However, one of the factors contributing to the progression of the disease despite ongoing antiretroviral treatment is the emergence of drug resistance. The high mutation rate of HIV can lead to a fast adaptation of the virus under drug pressure, thus to failure of antiretroviral treatment due to the evolution of drug-resistant variants. Moreover, cross resistance phenomena have been frequently found in HIV-1, leading to resistance not only against a drug from the current treatment, but also to other not yet applied drugs. Automatic classification and prediction of drug resistance is increasingly important in HIV research as well as in clinical settings, and to this end, machine learning techniques have been widely applied. Nevertheless, cross-resistance information was not taken explicitly into account, yet. RESULTS: In our study, we demonstrated the use of cross-resistance information to predict drug resistance in HIV-1. We tested a set of more than 600 reverse transcriptase sequences and corresponding resistance information for six nucleoside analogues. Based on multilabel classification models and cross-resistance information, we were able to significantly improve overall prediction accuracy for all drugs, compared with single binary classifiers without any additional information. Moreover, we identified drug-specific patterns within the reverse transcriptase sequences that can be used to determine an optimal order of the classifiers within the classifier chains. These patterns are in good agreement with known resistance mutations and support the use of cross-resistance information in such prediction models. CONTACT: dominik.heider@uni-due.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23793753 TI - Sipros/ProRata: a versatile informatics system for quantitative community proteomics. AB - SUMMARY: Sipros/ProRata is an open-source software package for end-to-end data analysis in a wide variety of community proteomics measurements. A database searching program, Sipros 3.0, was developed for accurate general-purpose protein identification and broad-range post-translational modification searches. Hybrid Message Passing Interface/OpenMP parallelism of the new Sipros architecture allowed its computation to be scalable from desktops to supercomputers. The upgraded ProRata 3.0 performs label-free quantification and isobaric chemical labeling quantification in addition to metabolic labeling quantification. Sipros/ProRata is a versatile informatics system that enables identification and quantification of proteins and their variants in many types of community proteomics studies. AVAILABILITY: Both programs are freely available under the GNU GPL license at Sipros.omicsbio.org and ProRata.omicsbio.org. PMID- 23793754 TI - Optimizing multiple sequence alignments using a genetic algorithm based on three objectives: structural information, non-gaps percentage and totally conserved columns. AB - MOTIVATION: Multiple sequence alignments (MSAs) are widely used approaches in bioinformatics to carry out other tasks such as structure predictions, biological function analyses or phylogenetic modeling. However, current tools usually provide partially optimal alignments, as each one is focused on specific biological features. Thus, the same set of sequences can produce different alignments, above all when sequences are less similar. Consequently, researchers and biologists do not agree about which is the most suitable way to evaluate MSAs. Recent evaluations tend to use more complex scores including further biological features. Among them, 3D structures are increasingly being used to evaluate alignments. Because structures are more conserved in proteins than sequences, scores with structural information are better suited to evaluate more distant relationships between sequences. RESULTS: The proposed multiobjective algorithm, based on the non-dominated sorting genetic algorithm, aims to jointly optimize three objectives: STRIKE score, non-gaps percentage and totally conserved columns. It was significantly assessed on the BAliBASE benchmark according to the Kruskal-Wallis test (P < 0.01). This algorithm also outperforms other aligners, such as ClustalW, Multiple Sequence Alignment Genetic Algorithm (MSA-GA), PRRP, DIALIGN, Hidden Markov Model Training (HMMT), Pattern-Induced Multi-sequence Alignment (PIMA), MULTIALIGN, Sequence Alignment Genetic Algorithm (SAGA), PILEUP, Rubber Band Technique Genetic Algorithm (RBT-GA) and Vertical Decomposition Genetic Algorithm (VDGA), according to the Wilcoxon signed-rank test (P < 0.05), whereas it shows results not significantly different to 3D COFFEE (P > 0.05) with the advantage of being able to use less structures. Structural information is included within the objective function to evaluate more accurately the obtained alignments. AVAILABILITY: The source code is available at http://www.ugr.es/~fortuno/MOSAStrE/MO-SAStrE.zip. PMID- 23793755 TI - Modelling the nitrification in a full-scale tertiary biological aerated filter unit. AB - A wastewater biofiltration model is used to assess its capacity to reproduce the treatment behaviour of a plant-sized tertiary nitrifying biofilter unit. It is calibrated on two different types of datasets collected at the Seine-Aval biofiltration plant (Acheres, France): grab samples at several heights inside the media bed and a long-term daily plant monitoring over a 1-year period. The model parameters are first calibrated to fit the dynamics observed in the media bed, after which the model is compared to the second dataset. Further parameter changes are then made if necessary and the model is once again compared to both datasets to ensure its ability to predict the treatment behaviour on both size scales. The calibrated model provides correct predictions for most observed nutrient variables for both datasets. An overestimation of the oxygen transfer under a summer, low ammonia load period however leads to a slight underestimation of the nitrifying efficiency of the biofilters. Statistical score computation corroborates the model accuracy as the mean error scores usually remain low. They also point to a certain weakness of the model regarding the suspended solids filtration. Both datasets are overall correctly modelled using a single parameter set. Most of this parameter set is close to or contained in value ranges found in the literature. The parameters related to aeration, however, seem to be slightly higher than what is reported elsewhere. PMID- 23793756 TI - [Current perspectives in molecular biology applied to uro-oncology]. PMID- 23793757 TI - [New concepts in molecular biology applied to traslational research]. AB - This chapter intends to introduce the new concepts that have been established in molecular biology over the last years and are being applied in translational research. The chapter is divided in four big blocks, which treat the molecular biology concepts and techniques in relation to DNA, RNA, proteins and metabolites, respectively. Moreover, we give examples of translational application of these new methodologies described. PMID- 23793758 TI - [Which molecular biology techniques must conform to the armamentarium for basic research in uro-oncology?]. AB - Molecular biology has been one of the scientific disciplines in which there has been more advances in the last years. The first impulse in the study of genetic alterations came from the discovery of DNA structure, followed by elucidation of the genetic code, the discovery of restriction enzymes and subsequently the invention of PCR, not forgetting the exponential development of computer science. All of them have allowed us to know much more about our genome and its regulation than we could imagine. The impulse in proteomics has been especially in tune up of soft methods of ionization coupled with mass spectrometry. Nevertheless, this seems to be only the beginning since today there are continuous methodological advances that will increase more, without doubt, the knowledge and applications in this discipline. PMID- 23793759 TI - [Biobanking: the basis for molecular research in uro-oncology]. AB - OBJECTIVES: The advances in cancer translational research, as well as the study of its changes and interactions, depend basically on the procurement of case series (individuals affected and non affected controls) which supply high quality samples and other associated data. Biobanks have shown they are indispensable tools for the advance of uro-oncological research. METHODS: Bibliographic review based on biobanks with focus on Urology. RESULTS AND CONCLUSIONS: Well-organized, large biobanks are a key element in research in Uro-oncology. The integration of theses resources with molecular sciences and various "omics", together with powerful available bioinformatic tools enable the advance in the knowledge of development of uro-oncological diseases, with strong implications at the time of very advanced therapeutic strategies. However,in Spain, these valuable collections of tissue material and biological fluids are usually not much in use, mainly due to fragmentation, low accessibility, lack of proper management strategies (such as lack of consensus about standard operative procedures), limited specific policies of use and distribution, as well as lack of a comprehensive base in which the research needs are reflected under interdisciplinar and multi-institutional focus. We must add the frequent ignorance of the high scientific potential of these institutions in the urological world. The development of the Spanish National Plan of Biobanks brings light for the better use of these materials by the uro-oncological community. We present a general view on the biobank topic, which may serve as a model for future debates about their use in uro-oncology. This approach is based in data from the literature and results of discussions in various international forums. PMID- 23793760 TI - [Basic principles for the development of biomarkers in oncology]. AB - The accelerated expansion of the knowledge of genetic and molecular basics of cancer, together with the recent development of molecular biology techniques, have had a significant impact in the field of oncology, among other medical disciplines. So, over the last few years, we are crossing from an empiricism based model to an evidence-based model in which drugs are adapted depending of the molecular alterations which result crucial for tumor development (both for carcinogenesis and acquisition of an aggressive phenotype leading to tumor invasion and resistance to therapy). The molecular alterations /variations offer the possibility of being detected and used as biomarkers in clinical practice. Biomarkers may have multiple applications in the field of oncology, from determining the risk to suffer the disease to prediction of response to therapy, including diagnosis, prognosis and disease monitoring, with the final aim of performing a more personalized medicine and achieving greater efficacy for the therapies selected, diminishing each therapy's own adverse events. Considering the importance biomarkers may get to have in clinical decision making, it is basic that their development is performed under straight evaluation and validation rules. In this article we review the various types of biomarkers and the basic methodological principles for their development, validation and subsequent clinical application. PMID- 23793761 TI - The role of methylation in urological tumours. AB - Alterations in DNA methylation have been described in human cancer for more than thirty years now. Since the last decade DNA methylation gets more and more important in cancer research. In this review the different alterations of DNA methylation are discussed in testicular germ cell tumours, Wilms'tumours, renal cell carcinomas, urothelial cell carcinomas of the bladder and adenocarcinomas of the prostate. Eventually, the potential use in diagnostics, prognostics and therapy are discussed. PMID- 23793762 TI - [Non-invasive diagnosis of prostate cancer: serum and urine markers]. AB - The great number of biomarkers basic research is presenting in different clinical scenarios of prostate cancer demands the scientific community rigor in their molecular and clinical development for the selection of those which could supply diagnostic and prognostic information for the established nomograms of clinical pathological factors. Prostate cancer, due to its prevalence and heterogeneity, needs a more directed diagnosis, characterization of malignant potential and monitoring of its multiple therapies. In this review article we try to go over the recent incorporation of new serum and urine markers in the clinical management of this tumor, emphasizing those with greater clinical development. PMID- 23793763 TI - Molecular biology of castration-resistant prostate cancer: basis for the novel therapeutic targets. AB - Prostate cancer cells express the androgen receptor (AR) and need the presence of androgens to survive. Androgen suppression is the gold standard first-line therapy for metastatic disease. Almost all prostate cancer patients initially respond to hormonal therapy, but most of them gradually develop castration resistant progression. Recent evidence has shown that progression at the castration resistant prostate cancer (CRPC) stage is often mediated by AR signalling. Importantly, subsequent AR androgen inhibition, by abiraterone acetate or enzalutamide, has shown to improve patients' survival. Several mechanisms that enhance AR signalling in an androgen-depleted environment have been elucidated:(1) AR mutations that allow activation by low androgen levels or by other endogenous steroids, (2) AR amplification and/or overexpression,(3)increased local intracrine synthesis of androgens, (4) changes in AR cofactors and (5) cross-talk with cytokines and growth factors. Today, there are under development a number of novel agents targeting the AR signaling pathway. This article reviews the postulated mechanisms of AR-driven resistance to androgen suppression that have contributed to the development of new hormonal therapeutic strategies in prostate cancer. PMID- 23793764 TI - [Molecular biology of bone metastases]. AB - Bone metastases are a frequent and devastating complication in cancer patients. Recently, significant advances in our understanding of the molecular mechanisms responsible for both osteolytic and osteoblastic bone metastases have occurred. The use of OMICS and the availability of appropriate preclinical animal models of bone metastasis have permitted the identification of factors produced by the tumor or by the host stroma in response to the tumor. These types of studies should result in a decrease of the serious skeletal morbidities associated with metastatic prostate cancer and may in the future improve overall survival. In this review the next generation of molecular targets in bone metastasis will be summarized. PMID- 23793765 TI - Stem cells in prostate cancer. AB - Tumors constitute complex ecosystems with multiple interactions among neoplastic cells displaying various phenotypes and functions and where the tumoral niche is built with an active participation of the host environment that also impacts the malignant progression of the tumor cells. Irrespective of the cell of origin of prostate adenocarcinoma, mounting evidences support the existence of a hierarchy within neoplastic prostate cells that contributes to the heterogeneity of these tumors. At the origin of this hierarchy are small populations of tumor cells with high self-renewal potential and also capable of generating progeny tumor cells that lose self-renewal properties as they acquire more differentiated phenotypes. These cancer stem cells (CSC) depend on active gene networks that confer them with their self-renewal capacity through symmetrical divisions whereas they can also undergo asymmetrical division and differentiation either as stochastic events or in response to environmental cues. Although new experimental evidences indicate that this is can be a reversible process, thus blurring the distinction between CSCs and non-CSCs, the former are considered as the drivers of tumor growth and evolution, and thus a prime target for therapeutic intervention. Of particular importance in prostate cancer, CSCs may constitute the repository population of androgen-insensitive and chemotherapy-resistant tumor cells responsible for castration-resistant and chemotherapy-insensitive tumors, thus their identification and quantification in primary and metastatic neoplasms could play important roles in the management of this disease. PMID- 23793766 TI - [Non-invasive diagnosis bladder cancer: new molecular markers and future perspectives]. AB - Bladder cancer represents a very important entity in the field of urologic oncology. At the time of diagnosis 70% of them are non muscle-invasive tumors with a very variable risk of recurrence and progression. These patients will require a periodic follow up, at least for 5 years, performing multiple cystoscopies and urine cytologies throughout their lifes. These diagnostic tests are either invasive or have a low sensitivity, a fact that has stimulated the search of non-invasive markers with high sensitivity for the diagnosis of bladder cancer. The great advantage in this neoplasia is the availability of a biologic sample such as urine, which being in close contact with the urothelium collects exfoliated cells, representing a valuable non invasive tool for the diagnosis and follow up of this neoplasias. In this article we try to perform a review of those markers for bladder cancer already marketed and under development, as well as future diagnostic perspectives. PMID- 23793767 TI - Biomarkers for assessing therapeutic response in bladder cancer. AB - Reliable markers for assessing therapeutic response are needed to select the most effective treatment strategy for bladder cancer patients. We analyzed the role of biomarkers predicting response of non-muscle invasive bladder cancer (NMIBC) on BCG induction, and of non-organ confined muscle invasive bladder cancer (MIBC) on neoadjuvant chemotherapy. A critical, non-structured review of the literature was conducted. For assessing BCG therapy outcome, measurement of urinary IL-2 levels seems to be the most potent marker of all the clinical parameters reviewed. Measurements of urinary interleukins IL-8, IL-18, and tumour necrosis factor apoptosis-inducing ligand levels seem promising as well. Immunohistochemical markers (ie, TP53, Ki-67, and Rb)display contradictory results and seem unsuitable. Gene polymorphisms need to be studied more thoroughly before their clinical relevance can be determined. Regarding assessing and predicting response of MIBC to neoadjuvant chemotherapy, a set of potent markers has been studied. However, no conclusive evidence is yet available on their additional value over the established clinicopathological variables. Prospective trials are needed to validate the clinical benefit of molecular markers to predict response to BCG (NMIBC) and neoadjuvant chemotherapy (MIBC) before predictive biomarkers can become part of clinical practice. PMID- 23793768 TI - Diagnosis and treatment of small renal masses: the role for molecular biology. AB - Renal cell carcinoma (RCC), the most common type of kidney cancer, is increasing in incidence and is the most lethal genitourinary cancer. Due to the increasing use of abdominal imaging, incidentally detected, asymptomatic small renal masses (SRMs), most of which are RCC, have become the most common presentation of kidney cancer. Most RCC SRMs initially grow slowly or not at all, but others progress to advanced and metastatic cancer. Several diagnostic and prognostic genomic, transcriptomic and proteomic studies have been completed in RCC, however signatures for SRM progression have not been identified. In the absence of useful factors to distinguish those tumors requiring treatment for progression from those that can be managed by active surveillance alone, most SRMs are treated as RCC with surgery. Currently, the only prognostic factor at diagnosis is tumor size. Tumor growth rate also appears to identify potential progressive tumours. Identifying signatures for progression and the utilization of needle biopsies will be important for SRM patients and will guide therapy. PMID- 23793769 TI - [Molecular biology of renal cancer: bases for genetic directed therapy in advanced disease]. AB - There has been expansion of therapeutic options in the management of metastatic renal cell carcinoma due to a better knowledge of the molecular biology of kidney cancers. There are different tumors grouped under the term renal cell carcinoma, being clear cell cancer the most frequent and accounting for 80% of kidney tumors. Mutations in the Von Hippel-Lindau gene can be identified in up to 80% of sporadic clear cell cancer, linking a genetically inheritable disease where vascular tumors are frequent, with renal cell cancer. Other histologic types present specific alterations in molecular pathways, like c-MET in papillary type I tumors, and Fumarase Hydratase in papillary type II tumors. Identification of the molecular alteration for a specific tumor may offer an opportunity for treatment selection based on biomarkers, and, in the future, for developing an engineering designed genetic treatment. PMID- 23793770 TI - [Molecular bases of platinum-resistance in testicular cancer]. AB - Cisplatin has been the cornerstone of germ cell testicular tumors therapy since its introduction more tan 30 years ago, and a basic part of the schemes given to multiple ovarian, lung, head and neck, and bladder tumors among others. Some tumors present primary resistance to this drug, others will develop it despite good initial response. In the case of testicular germ cell tumors most of them are very sensitive to this drug but up to 20% of patients with metastatic disease will present resistance, most of them secondary after a very good initial response. Cisplatin acts by binding to DNA to activate genetic damage recognition mechanisms and apoptosis through the mitochondrial pathway. Resistance mechanisms to cisplatin have been classified in those that happen (1) before its binding to DNA and (2) once it binds to DNA. Most advances in their discovery have used other neoplasias as models, mainly ovarian and lung tumors. In this review we will describe the biological mechanisms behind resistance to cisplatin from the global perspective but trying to focus in testicular germ cell tumors. PMID- 23793771 TI - How could molecular biology modify the management of upper urinary tract tumours? AB - BACKGROUND: Upper urinary tract urothelial carcinomas (UUT-UCs) account for only 5-10% of urothelial carcinomas and the gold standard treatment is open radical nephroureterectomy. Strong differences exist regarding tumor behaviour between the upper and the lower urinary tract. OBJECTIVE: To demonstrate how the current knowledge in molecular biology of UUT-UCs is likely to modify the management of these tumours. ACQUISITION OF EVIDENCE: A MEDLINE search was performed on UUT-UC using the following terms: urinary tract cancer; urothelial carcinomas; upper urinary tract; molecular markers; renal pelvis; ureter; ureteroscopy; nephroureterectomy; adjuvant treatment; neoadjuvant treatment; recurrence; risk factors and survival. EVIDENCE SYNTHESIS: Conservative surgery for low-risk UUT UCs allows for preservation of the upper urinary renal unit, while sparing the patient the morbidity associated with open surgery. Such surgical strategy might be more appropriate in tumors displaying certain molecular markers: microsatellite instability, E-cadherin, MET, Aurora-A, and Ki-67. These markers could help to identify more candidates to nephron-sparing treatment without compromising the oncologic outcome. Susceptibility means an increase in risk conferred by one or more polymorphisms (allele types) of a given gene or genes, which expose the individual to the genotoxic effects of environmental carcinogens. The variant allele SULT1A1*2 with reduced sulfotransferase activity and the T allele of rs9642880 on chromosome 8q24 enhance the risk of UUT-UCs. If an at-risk genetic profile could be established, it might be possible to prevent urothelial carcinomas in some patients. CONCLUSIONS: Surgical practice is gradually moving towards minimally invasive techniques which spare the functional unity of the kidney and urinary tract. The ongoing identification of distinct carcinogenic mechanisms for UUT-UCs might open the way to specific treatments adapted to the molecular pattern of each tumor. The next era might hopefully be that of chemoprevention. PMID- 23793772 TI - Cystoscopically guided percutaneous suprapubic cystolitholapaxy in children. AB - PURPOSE: To evaluate the safety and efficacy of endoscopically guided percutaneous suprapubic artery forceps litholapaxy for pediatric vesical and posterior urethral stone <1 cm in diameter. MATERIALS AND METHODS: A retrospective series study of 73 children (68 boys and 5 girls) with vesical and urethral stones less than 1 cm in diameter with an average age of 3.5 years (range 1-9 years) were included in this study. Cases with previous suprapubic surgery, stones of more than 1 cm in diameter, multiple bladder or urethral stone, anterior urethral stones and cases with neurological or anatomical abnormalities were excluded from our study. The bladder was filled and punctured suprapubically by an artery forceps under the vision of the pediatric cystoscopy then the stone is completely crushed. All intraoperative and postoperative complications were recorded. The stone-free rate status was evaluated 2 weeks postoperatively using plain X-ray/ultrasonography. RESULTS: All cases were successful, and the stones were completely crushed to smaller insignificant fragments in a single session. No intraoperative bladder perforation or bleeding was recorded. The mean operative time was 12.5 min (ranging from 9 to 17 min). There were no postoperative complications apart from 2 cases of persistent suprapubic leakage postoperatively for 24 h and the leakage stopped after 48 h with the insertion of 8 Fr Foley catheter. In all cases, no significant stone fragments were found 2 weeks postoperatively. CONCLUSION: Our technique for management of pediatric vesical and posterior urethral stone less than 1 cm is an easy and safe with no intraoperative or postoperative significant complications. PMID- 23793773 TI - Extracting curvature preferences of lipids assembled in flat bilayers shows possible kinetic windows for genesis of bilayer asymmetry and domain formation in biological membranes. AB - Studies on the assembly of pure lipid components allow mechanistic insights toward understanding the structural and functional aspects of biological membranes. Molecular dynamic (MD) simulations on membrane systems provide molecular details on membrane dynamics that are difficult to obtain experimentally. A large number of MD studies have remained somewhat disconnected from a key concept of amphipathic assembly resulting in membrane structures- shape parameters of lipid molecules in those structures in aqueous environments. This is because most of the MD studies have been done on flat lipid membranes. With the above in view, we analyzed MD simulations of 26 pure lipid patches as a function of (1) lipid type(s) and (2) time of MD simulations along with 35-40 ns trajectories of five pure lipids. We report, for the first time, extraction of curvature preferences of lipids from MD simulations done on flat bilayers. Our results may lead to mechanistic insights into the possible origins of bilayer asymmetries and domain formation in biological membranes. PMID- 23793774 TI - Luminescent probes and sensors for temperature. AB - Temperature (T) is probably the most fundamental parameter in all kinds of science. Respective sensors are widely used in daily life. Besides conventional thermometers, optical sensors are considered to be attractive alternatives for sensing and on-line monitoring of T. This Review article focuses on all kinds of luminescent probes and sensors for measurement of T, and summarizes the recent progress in their design and application formats. The introduction covers the importance of optical probes for T, the origin of their T-dependent spectra, and the various detection modes. This is followed by a survey on (a) molecular probes, (b) nanomaterials, and (c) bulk materials for sensing T. This section will be completed by a discussion of (d) polymeric matrices for immobilizing T sensitive probes and (e) an overview of the various application formats of T sensors. The review ends with a discussion on the prospects, challenges, and new directions in the design of optical T-sensitive probes and sensors. PMID- 23793775 TI - DNA methylation in monozygotic quadruplets affected by type 1 diabetes. PMID- 23793776 TI - Volumetric low-tube-voltage CT imaging for evaluating hypervascular hepatocellular carcinoma; effects on radiation exposure, image quality, and diagnostic performance. AB - OBJECTIVES: To assess the value of hepatic arterial-phase (HAP) imaging with a low tube voltage (80 kVp), using non-helical, volumetric acquisition with a 320 detector-rows area-detector CT (ADCT) scanner for evaluating hypervascular hepatocellular carcinoma (HCC) compared with routine 120-kVp HAP imaging. METHODS: This study enrolled 128 patients with 148 HCCs. Seventy-six patients with 79 HCCs underwent HAP imaging with 80 kVp obtained using a 320-detector-rows ADCT scanner. The remaining 52 patients with 69 HCCs underwent routine HAP imaging with 120 kVp obtained by 64-slice helical acquisition. Image noise and tumor to liver contrast-to-noise ratio (CNR) of the two sets of images were compared. Three radiologists evaluated both sets of images using receiver operating characteristic analyses. RESULTS: Although there was a two-fold increase in the mean image noise with 80 kVp over that with 120 kVp (p < 0.001), no significant differences were observed in CNR among the two sets. The mean area under the curve (Az value) and the sensitivity for detecting HCC with 80 kVp (0.980, 78/79, respectively) were higher than that of 120 kVp (0.892, 55/69, respectively). CONCLUSIONS: HAP imaging with 80 kVp obtained by an ADCT scanner significantly improves the diagnostic performance for evaluating hypervascular HCC. PMID- 23793778 TI - Hydrogeochemical features of groundwater of semi-confined coastal aquifer in Amol Ghaemshahr plain, Mazandaran Province, Northern Iran. AB - Hydrogeochemical data of groundwater from the semi-confined aquifer of a coastal two-tier aquifer in Amol-Ghaemshahr plain, Mazandaran Province, Northern Iran reveal salinization of the fresh groundwater (FGW). The saline groundwater zone is oriented at an angle to both Caspian Sea coastline and groundwater flow direction and extends inland from the coastline for more than 40 km. Spearman's rank correlation coefficient matrices, factor analysis data, and values of C ratio, chloro-alkaline indices, and Na(+)/Cl(-) molar ratio indicate that the ionic load in the FGW is derived essentially from carbonic acid-aided weathering of carbonates and aluminosilicate minerals, relict connate saline water, and ion exchange reactions. Saline groundwater samples (SGWS) (n = 20) can be classified into two groups. SGWS of group 1 (n = 17) represent the saline groundwater zone below the Caspian Sea level, and salinization is attributed essentially to (1) lateral intrusion of Caspian seawater as a consequence of (a) excessive withdrawal of groundwater from closely spaced bore wells located in the eastern part of the coastal zone and (b) imbalance between recharge and discharge of the two-tier aquifer and (2) upconing of paleobrine (interfaced with FGW) along deep wells. SGWS of this group contain, on average, 7.9% of saltwater, the composition of which is similar to that of Caspian seawater. SGWS of group 2 (n = 3) belong to the saline groundwater zone encountered above the Caspian Sea level, and salinization of the groundwater representing these samples is attributed to irrigation return flow (n = 2) and inflow of saline river water (n = 1). PMID- 23793777 TI - Novel potential agents for ulcerative colitis by molecular topology: suppression of IL-6 production in Caco-2 and RAW 264.7 cell lines. AB - Ulcerative colitis (UC) is an immune-mediated chronic and relapsing intestinal inflammatory disease. Interleukin (IL)-6, a pro-inflammatory cytokine, plays a key role in the uncontrolled intestinal inflammatory process, which is a main characteristic of UC. In this work, a quantitative structure-activity relationship model based on molecular topology (MT) has been built up to predict the IL-6 mediated anti-UC activity. After an external validation of the model, a virtual screening of the MicroSource Pure Natural Products Collection and Sigma Aldrich databases was carried out looking for potential new active compounds. From the entire set of compounds labeled as active by the model, four of them, namely alizarin-3-methylimino-N,N-diacetic acid (AMA), Calcein, (+)-dibenzyl-L tartrate (DLT), and Ro 41-0960, were tested in vitro by determination of IL-6 production in two cell lines (RAW 264.7 and Caco-2). The results demonstrate that three of them were able to significantly reduce IL-6 levels in both cell lines and particularly one, namely Ro 41-0960. These results confirm MT's efficacy as a tool for the selection of compounds potentially active in UC. PMID- 23793779 TI - Wrapped omentum with periosteum concurrent with adipose derived adult stem cells for bone tissue engineering in dog model. AB - Adipose derived adult stem cells (ASCs) are multipotent cells that are able to differentiate into osteoblasts in presence of certain factors. The histological characteristics of periosteum makes it a specific tissue with a unique capacity to be engineered. Higher flexibility of the greater omentum is useful for reconstructive surgery. These criteria make it suitable for tissue engineering. The present study was designed to evaluate bone tissue engineering with periosteal free graft concurrent with ASCs and pedicle omentum in dog model. Twelve young female indigenous dogs were used in this experiment. In omental group (n = 4), end of omentum was wrapped by periosteum of the radial bone in abdomen of each dog. In omental-autogenously ASCs group (n = 4), 1 ml of ASCs was injected into the wrapped omentum with periosteum while in omental-allogenously ASCs group (n = 4), 1 ml of allogenous ASCs was injected. Lateral view radiographs were taken from the abdominal cavity postoperatively at the 2nd, 4th, 6th and 8th weeks post-surgery. Eight weeks after operation the dogs were re anesthetized and the wrapped omenum by periosteum in all groups was found and removed for histopathological evaluation. Our results showed that omentum periosteum, omental-periosteum-autogenous ASCs and omental-periosteum-allogenous ASCs groups demonstrated bone tissue formation in the abdominal cavity in dog model. The radiological, macroscopical and histological findings of the present study by the end of 8 weeks post-surgery indicate bone tissue engineering in all three groups in an equal level. The present study has shown that the wrapped omentum with periosteum concurrent with ASCs (autogenous or allogenous ASCs) lead to a favorable bone tissue formation. We suggested that it may be useful when pedicle graft omentum used concurrent with periosteum in the bone defect reconstruction, and this phenomenon should be studied in future. PMID- 23793780 TI - Appropriateness of percutaneous coronary intervention: a review. AB - The appropriateness of coronary revascularization for various clinical scenarios has been reviewed formally by several specialty and subspecialty societies resulting in the formulation of scored appropriateness criteria. The goal of the appropriateness criteria is to guide physician decision-making and future research as well as to label coronary revascularization more clearly for patients and payors in regards to its expected benefits in certain situations. The appropriateness criteria were formulated from a standardized process and are intended to be updated at regular intervals as new data further elucidates the clinical roles of revascularization. Since its last iteration in early 2012, several studies have been published that may further expand scenarios or impact the appropriateness of revascularization in already-established scenarios. The differentiation of appropriateness with particular forms of revascularization has been reserved for specific clinical scenarios where revascularization is generally considered necessary and appropriate. The goals of this review are 1) to highlight aspects of the methodology and development of the coronary revascularization appropriateness criteria, and 2) to focus on the role established specifically for percutaneous coronary intervention within the criteria. Important data published in 2012 that further evaluates the role of percutaneous coronary intervention will also be reviewed with a focus on its potential impact on future iterations of the appropriateness criteria. PMID- 23793781 TI - Maturation of CD4+ regulatory T lymphocytes and of cytokine secretions in infants born prematurely. AB - PURPOSE: To characterize the maturation of CD4(+) regulatory T lymphocytes (Treg) and of cytokine productions in preterm infants during their first 16 months of life. METHODS: The proportions of CD4(+) Treg cells, their phenotypic characteristics, and the mitogen-induced cytokine productions by peripheral blood mononuclear cells (PBMC) were analysed in 26 very-preterm infants from 2 to 16 months of age, and compared to results obtained for 17 cord blood mononuclear cells (CBMC) from very-preterm infants, 12 from term infants and to blood samples from 40 adults. RESULTS: High proportion of CD25(+/high)CD4(+) Treg cells was found at birth in preterm CB with a gradual decreased afterwards. However, their percentage at 16 months of age was still higher than in term CB. In contrast to adults, preterm infants were characterized by excellent linear correlations between the proportions of CD25(+/high)CD4(+) and CD25(+/high)FoxP3(+) CD4(+) or CD25(+/high)CD127(low) CD4(+) or CD25(+/high)FoxP3(+)CD127(low) CD4(+)T lymphocytes. CD45RO(+) and HLA-DR(+) expressions were very low on preterm Treg and progressively increased with age. Functionally, preterm compared to term CBMC secreted in response to phytohaemagglutinin lower IFN-gamma, higher IL-5 and similar IL-12p70, IL-10, IL-2 and IL-13 concentrations. IFN-gamma, IL-12p70 and IL-10 productions were at 16 months still lower than those obtained for adults CONCLUSION: Preterm differed from term CBMC both by their proportion and phenotype of CD4(+) Treg lymphocytes and by their cytokine secretions. Maturation occurred during infancy with similar IFN-gamma secretion but with persistently higher proportion of CD4(+) Treg cells in 1 year preterm infants compared to term neonates. PMID- 23793783 TI - Social and custodial needs of older adults in prison. AB - BACKGROUND: older prisoners are a fast-growing group but there is limited evidence for how well their needs are being met. OBJECTIVES: to quantify the social and custodial needs of older prisoners and suggest improvements for service provision. DESIGN: cross-sectional study. SETTING: twelve prisons holding adult males in North West England. SUBJECTS: two hundred and sixty-two prisoners; 97 aged between 50 and 59, 165 aged 60 and over. METHODS: interview and case-note review for issues of social and custodial need and quality of life in prison, including Forensic Camberwell Assessment of Need and Lubben Scale for social networks. RESULTS: many had problems mixing with younger prisoners, accommodation and activities, and limited contact with friends and family. A small group had personal care needs which were not well managed in prison. CONCLUSION: older prisoners have distinct social and custodial needs which need to be addressed by a national strategy for their care and management. PMID- 23793782 TI - Socioeconomic inequalities in mental health and health-related quality of life (HRQOL) in children and adolescents from 11 European countries. AB - OBJECTIVES: To assess the presence and magnitude of social inequalities in mental health and health-related quality of life (HRQOL) in the population aged 8-18 years in 11 European countries. METHODS: Cross-sectional surveys were carried out in representative samples of children/adolescents (8-18 years) from the participating countries of the KIDSCREEN project. Mental health was assessed using the Strengths and Difficulties Questionnaire (SDQ), and HRQOL by means of the KIDSCREEN-10. Socioeconomic status (SES) was assessed using the Family Affluence Scale and parental level of education. The association between health outcomes and SES was analyzed with the regression-based relative index of inequalities (RII) and population attributable risk. RESULTS: A total of 16,210 parent-child pairs were included. The SDQ showed inequalities in mental health according to family level of education in all countries (RII = 1.45; 1.37-1.53). The RII for HRQOL was 2.15 (1.79-2.59) in the whole sample, with less consistent results by age and country. CONCLUSIONS: Socioeconomic inequalities in mental health were consistently found across Europe. Future research should clarify the causes of these inequalities and define initiatives which prevent them continuing into adulthood. PMID- 23793784 TI - Necrotising sialometaplasia in the floor of mouth. AB - INTRODUCTION: Necrotising sialometaplasia is a benign self-limiting inflammatory process which occurs in the salivary gland tissue. The condition is a diagnostic challenge mimicking malignancy both clinically and histopathologically. Commonly, it presents in the hard palate. CASE REPORT: Here, we report an unusual case in a 56-year-old man which presented in the floor of the mouth. PMID- 23793785 TI - Free-standing and binder-free lithium-ion electrodes based on robust layered assembly of graphene and Co3O4 nanosheets. AB - Free-standing and binder-free Co3O4/graphene films were fabricated through vacuum filtration and thermal treatment processes, in which sheet-like Co3O4 and graphene were assembled into a robust lamellar hierarchical structure via electrostatic interactions. The morphological compatibility coupled with strong interfacial interactions between Co3O4 and graphene significantly promoted the interfacial electron and lithium ion transport. When used as a binder-less and free-standing electrode for lithium-ion batteries, the hybrid film delivered a high specific capacity (~1400 mA h g(-1) at 100 mA g(-1) based on the total electrode weight), enhanced rate capability and excellent cyclic stability (~1200 mA h g(-1) at 200 mA g(-1) after 100 cycles). This effective strategy will provide new insight into the design and synthesis of many other composite electrodes for high-performance lithium-ion batteries. PMID- 23793786 TI - Making God real and making God good: some mechanisms through which prayer may contribute to healing. AB - Many social scientists attribute the health-giving properties of religious practice to social support. This paper argues that another mechanism may be a positive relationship with the supernatural, a proposal that builds upon anthropological accounts of symbolic healing. Such a mechanism depends upon the learned cultivation of the imagination and the capacity to make what is imagined more real and more good. This paper offers a theory of the way that prayer enables this process and provides some evidence, drawn from experimental and ethnographic work, for the claim that a relationship with a loving God, cultivated through the imagination in prayer, may contribute to good health and may contribute to healing in trauma and psychosis. PMID- 23793787 TI - Distinctive clinical and neuroimaging characteristics of longitudinally extensive transverse myelitis associated with aquaporin-4 autoantibodies. AB - Longitudinally extensive transverse myelitis (LETM) is a characteristic feature of Neuromyelitis Optica (NMO), but it can also occur in several other inflammatory diseases of the central nervous system (CNS). An IgG autoantibody that binds to aquaporin-4 (AQP4), the predominant water channel of the CNS, is a reliable biomarker of the NMO spectrum disorders, and if detected predicts the recurrence of the myelitis. In this study, we compared the clinical and neuroimaging characteristics of AQP4-IgG+ and AQP4-IgG- LETM patients. Thirty seven first-ever LETM patients were retrospectively evaluated and divided into two groups according to the presence of AQP4 autoantibodies. AQP4-IgG was detected in the serum and in the cerebrospinal fluid of sixteen patients. The female to male ratio was higher in AQP4-IgG+ patients. Intractable nausea and vomiting and paroxysmal tonic spasms often accompanied the LETM in AQP4-IgG+ patients. T2-weighted spinal cord MRI revealed that inflammatory lesions extending into the brainstem and involving the central grey matter occurred more frequently in AQP4-IgG+ LETM patients. Hypointense lesions on T1-weighted spinal cord MRI were detected more frequently in the seropositive group, and their presence correlated with attack severity. In conclusion, this study provides clinical and spinal cord neuroimaging clues that can help distinguishing AQP4 IgG+ LETM patients. PMID- 23793788 TI - Measurement accuracy of foramen of vesalius for safe percutaneous techniques using computer-assisted three-dimensional landmarks. AB - The presence and description of anatomical findings about the foramen of Vesalius (FV) is important in the surgical procedure on the trigeminal nerve and/or trigeminal ganglion. This is an evaluation area for percutaneous techniques. A morphological analysis of the FVs was made in a total of 344 sides of the basis cranii of adult skulls by computerized photogrammetry using standardized digital photographs. The FV was identified in 60 specimens (34.8%). The FV was observed to be present bilaterally in 16 specimens (9.3%). The incidence of unilateral FV was 25.5% of the skulls, of which in 26 specimens (15.1%) it occurred on the left side, and in 18 specimens (10.4%) on the right side. The FV was observed to present a double opening in two specimens. The diameters of the FV were found to be 0.86 +/- 0.21 (right) and 1.07 +/- 0.37 mm (left). The incidence of openings with a diameter of FV 0.5 mm or more was found to be 45%. The area of the FV was calculated as 1.09 +/- 0.51, and 1.4 +/- 0.83 mm(2) on the right and the left, respectively. The mean distances of FV to the foramen ovale were measured as 2.30 +/- 1.14 mm (right) and 2.46 +/- 0.89 mm (left). The mean distances of FV to foramen spinosum were found to be 10.76 +/- 1.26 mm (right) and 10.42 +/- 1.29 mm (left). The findings suggest that the diameter of FV as <0.5 mm was safer to work with, while the opening types bigger than 0.5 mm opening types were highly risky for percutaneous techniques on the foramen ovale. In our study, a clear standardization has been achieved. The findings were the data obtained through computer-assisted three dimensional landmarks, appropriate for use in three dimensional planning. PMID- 23793789 TI - Investigation of the mechanical properties of the human crural fascia and their possible clinical implications. AB - The mechanical properties of deep fasciae strongly affect muscular actions, development of pathologies, such as acute and chronic compartment syndromes, and the choice of the various fascial flaps. Actually, a clear knowledge of the mechanical characterization of these tissues still lacks. This study focuses attention on experimental tests of different regions of human crural fascia taken from an adult frozen donor. Tensile tests along proximal-distal and medial lateral direction at a strain rate of 120 %/s were performed at the purpose of evaluating elastic properties. Viscous phenomena were investigated by applying incremental relaxation tests at total strain of 7, 9 and 11 % and observing stress decay for a time interval of 240 s. The elastic response showed that the fascia in the anterior compartment is stiffer than in the posterior compartment, both along the proximal-distal and medial-lateral directions. This result can explain why the compartment syndromes are more frequent in this compartment with respect to posterior one. Furthermore, the fascia is stiffer along the proximal distal than along medial-lateral direction. This means that the crural fascia can adapt to the muscular variation of volume in a transversal direction, while along the main axis it could be considered as a structure that contributes to transmitting the muscular forces at a distance and connecting the different segments of the limb. The stress relaxation tests showed that the crural fascia needs 120 s to decrease stress of 40 %, suggesting a similar time also in the living so that the static stretching could have an effect on the fascia. PMID- 23793790 TI - Left gastric vein on the dorsal side of the splenic artery: a rare anatomic variant revealed during gastric surgery. AB - PURPOSE: The left gastric vein (LGV) is an important blood vessel requiring dissection during gastric surgery. We describe a rare anatomic variant of the LGV. METHODS: The LGV drainage pattern was analyzed relative to intraoperative vascular anatomy in 2,111 patients with gastric cancer who underwent radical resection from May 2007 to September 2012. The incidence of the anatomic variant was determined, and the diameter and length of the LGV and the distances from the end of the LGV to the splenoportal confluence and the root of the left gastric artery (LGA) were measured by abdominal CT reconstruction. RESULTS: In 6 of the 2,111 (0.28%) gastric cancer patients who underwent radical resection, the LGV descended on the left side of the gastropancreatic fold, ran across the dorsal side of the splenic artery and drained into the splenic vein. The mean diameter and length of the LGV were 5.10 +/- 0.40 and 37.40 +/- 5.19 mm, respectively, and the mean distance from the end of the LGV to the splenoportal confluence was 13.05 +/- 0.86 mm. The closer the LGV and LGA were to the root, the greater the distance between them, with a mean 13.85 +/- 1.02 mm between the end of the LGV and the root of the LGA. CONCLUSIONS: In this rare anatomic variant, the LGV descends along the gastropancreatic fold, runs across the dorsal side of the splenic artery and drains into the splenic vein. Knowledge of this rare anatomic variant will help avoid damage to the LGV during gastric surgery. PMID- 23793791 TI - CORR Insights(r): restoration of the hip center during THA performed for protrusio acetabuli is associated with better implant survival. PMID- 23793792 TI - Mites associated with stored grain commodities in Benin, West Africa. AB - After insects, mites are the major arthropod pests that inhabit stored agricultural products worldwide. To determine the acarofauna that infests cowpea, maize, paddy rice and sorghum in Benin (West Africa), surveys were conducted in some principal markets (Dantokpa, Glazoue and Parakou) of this country. A total of 555 samples of grains and debris were collected in May and September 2011. More than 56 species belonging to 24 mite families were recorded in the four products. These mite species included predators, parasites, fungivorous, phytophagous and other groups whose feeding habits are not well known. The family Cheyletidae was the most prevalent and the most diverse predatory mite family encountered, in which Cheyletus malaccensis Oudemans was the most abundant species. Several families of mite pests and mites responsible for allergies (Acaridae, Glycyphagidae, Pyroglyphidae, Pyemotidae and Saproglyphidae) were also detected. The three most dominant and frequent species were C. malaccensis, Suidasia nesbitti (Hughes) and Suidasia sp. Statistical analysis showed that densities of these three mite species were higher in Parakou than in Glazoue and Dantokpa, on one hand, and higher in debris than in grains, on the other hand. The densities of S. nesbitti and Suidasia sp. decreased significantly during the dry season, whereas C. malaccensis remained stable throughout the two samplings. Of all grains, sorghum was the least infested with mites. This study shows that in Benin mites are present in stored agricultural products to which they cause serious damage, and may cause various allergies to people. PMID- 23793793 TI - Recent advances in the Willgerodt-Kindler reaction. AB - The Willgerodt-Kindler reaction has, in recent years, received limited attention and application in synthetic organic chemistry. With the advent of new technology such as microwave-assisted heating, several new, high-yielding, practical, and more environmentally friendly reaction protocols have been developed. This review aims to once again draw attention to this relatively underutilised process by highlighting the recent developments in the Willgerodt-Kindler reaction in the synthesis of (thio)amides, carboxylic acids, and heterocycles. PMID- 23793794 TI - Nitrofurantoin, phenazopyridine, and the superoxide-response regulon soxRS of Escherichia coli. AB - Nitrofurantoin and phenazopyridine are two drugs commonly used against urinary tract infections. Both compounds exert oxidative damage in patients deficient in glucose-6-phosphate dehydrogenase. This study was done to assess the interactions of these drugs with the soxRS regulon of Escherichia coli, a superoxide-defense system (that includes a nitroreductase that yields the active metabolite of nitrofurantoin) involved in antibiotic multi-resistance. The effects of either nitrofurantoin or phenazopyridine, upon strains with different soxRS genotypes, were measured as minimum inhibitory concentrations (MICs) and growth curves. Also, the ability of these drugs to induce the expression of a soxS'::lacZ gene fusion was assessed. The effect of antibiotics in the presence of phenazopyridine, paraquat (a known soxRS inducer), or an efflux inhibitor, was measured using the disk diffusion method. A strain constitutively expressing the soxRS regulon was slightly more susceptible to nitrofurantoin, and more resistant to phenazopyridine, compared to wild-type and soxRS-deleted strains, during early treatment, but 24-h MICs were the same (8 mg/l nitrofurantoin, 1,000 mg/l phenazopyridine) for all strains. Both compounds were capable of inducing the expression of a soxS'::lacZ fusion, but less than paraquat. Subinhibitory concentrations of phenazopyridine increased the antimicrobial effect of ampicillin, chloramphenicol, tetracycline, and nitrofurantoin. The induction or constitutive expression of the soxRS regulon seems to be a disadvantage for E. coli during nitrofurantoin exposure; but might be an advantage during phenazopyridine exposure, indicating that the latter compound could act as a selective pressure for mutations related to virulence and antibiotic multi resistance. PMID- 23793795 TI - High resolution melting curve assay for rapid detection of drug-resistant Mycobacterium tuberculosis. AB - We developed and evaluated a high resolution melting (HRM) curve assay by using real-time PCR for the detection of the most frequent mutations of Mycobacterium tuberculosis, which are responsible for the resistance of four anti-TB drugs: rifampicin, isoniazid, ethambutol, and streptomycin. The HRM assay was successfully used for the detection of dominant mutations: A516V, H526A, H526T, S531L, L533P, and A516G/S531L in rpoB; S315T, and S315A in katG; -15C/T, and 8T/C in mab-inhA; M306I in embB; K88Q and K43R in rpsL; and 513A/C in rrs. We were able to discriminate the mutant from the wild type by analyzing the melting curve shape in 40 clinical M. tuberculosis isolates, and the results of the HRM assay were completely consistent with those of DNA sequencing. This HRM assay is a simple, rapid, and cost-effective method that can be performed in a closed tube. Therefore, our assay is a potentially useful tool for the rapid detection of drug-resistant M. tuberculosis. PMID- 23793796 TI - Clinical and epidemiological aspects of hepatocellular carcinoma in Brazil. AB - The global hepatocellular carcinoma (HCC) incidence is widely variable, depending on geographic region and the prevalence of major risk factors. In Brazil, two large multicentre retrospective studies were performed to investigate clinical and epidemiological aspects of HCC. In the first study, performed in 1997, HCC was found in cirrhotic livers in 71% of cases. Chronic alcoholism was present in 36% of cases, chronic hepatitis B in 35% and hepatitis C in 25%. In a 2010 survey, cirrhosis was present in 98% of cases and HCV was the main aetiology (54%). Differences in HBV prevalence were found among regions. Selection of HCC treatment depends on tumour burden, liver function and performance status. Liver transplantation (LT) is the best available curative treatment for HCC in its early stage and with compromised liver function. After modifications in priority policy, the number of patients with early HCC submitted for LT has increased in the past 5 years in Brazil. Chemoembolization is the most common initial HCC therapy in early and intermediate stages of HCC in Brazil. PMID- 23793797 TI - The neuroprotective ability of polyethylene glycol is affected by temperature in ex vivo spinal cord injury model. AB - Immediate membrane sealing after spinal cord injury (SCI) can prevent further degradation and result in ultimate functional recovery. It has been reported that polyethylene glycol (PEG) can repair membrane damage caused by mechanical insults to the spinal cord. Furthermore, membrane fluidity and its sealing process vary at different temperatures. Here, we have assessed the possible synergistic effects of PEG and temperature on the repair of neural membranes in an SCI model. The effects of PEGs (400, 1,000 and 2,000 Da) were studied at different temperatures (25, 37 and 40 degrees C) by means of compound action potential (CAP) recovery and a lactate dehydrogenase (LDH) assay. Isolated spinal cords were mounted in a double sucrose gap chamber, where the amplitude and area of CAPs were recorded after implementing injury, in the presence and absence of PEG. Moreover, the LDH assay was used to assess the effects of PEG on membrane resealing. Data showed that the least CAP recovery occurred at 25 degrees C, followed by 37 and 40 degrees C, in all treated groups. Moreover, maximum CAP amplitude recovery, 65.46 +/- 5.04 %, was monitored in the presence of PEG400 at 40 degrees C, followed by 41.49 +/- 2.41 % in PEG1000 and 37.36 +/- 1.62 % in PEG2000. Furthermore, raising the temperature from 37 to 40 degrees C significantly increased CAP recovery in the PEG2000 group. Similar recovery patterns were obtained by CAP area measurements and LDH assay. The results suggest that application of low-molecular weight PEG (PEG400) in mild hyperthermia conditions (40 degrees C) provides the optimum condition for membrane sealing in SCI model. PMID- 23793798 TI - Perception of floral volatiles involved in host-plant finding behaviour: comparison of a bee specialist and generalist. AB - Specialist and generalist bees use olfactory and visual cues to find and recognise flowering plants. Specialised (oligolectic) bees rely on few host plants for pollen collection. These bee species are suggested to use specific volatiles, but it is unknown whether they have dedicated adaptations for these particular compounds compared to bees not specialised on the same plants. In the present study, we investigated the perception of host odorants and its neuronal substrate with regard to host-plant finding behaviour in oligolectic bees. We reconstructed the antennal lobes (AL) in the Salix specialist, Andrena vaga, and counted about 135 glomeruli and thereby less than the approximately 160 in honeybees. Using calcium imaging experiments to measure neural activity in the bee brain, we recorded odorant-evoked activity patterns in the AL of A. vaga and, for comparison, in the generalist honeybee, Apis mellifera. Our physiological experiments demonstrated that A. vaga bees were particularly sensitive to 1,4 dimethoxybenzene, a behaviour-mediating odorant of Salix host flowers. We found more sensitive glomeruli in the specialised bees as compared to generalist honeybees. This neural adaptation might allow oligolectic A. vaga bees to effectively locate host plants from distances. PMID- 23793799 TI - Effects of petroleum hydrocarbon contaminated soil on germination, metabolism and early growth of green gram, Vigna radiata L. AB - The objective of the present study was to evaluate effects of petroleum hydrocarbon contaminated soil on the leguminous plant, Vigna radiata L. Seed germination, metabolism and early growth performance of V. radiata L. were studied as parameters by applying a combined approach. The employed combined method which included microcalorimetry and analysis of the root cross section revealed dose dependent effects of petroleum hydrocarbon contaminated soil on V. radiata L. for most parameters. Although significant reductions in measured parameters were observed even at low total petroleum hydrocarbon (TPH) levels such as 1 % and 1.5 %, calculated inhibitions, IC50 values and metabolic heat emission-time curves inferred that substantial negative effects can be expected on V. radiata L. in soils with comparatively high contamination levels, such as 2.5 % TPH and higher. PMID- 23793800 TI - Effect of moisture, organic matter, microbial population and fortification level on dissipation of pyraclostrobin in soils. AB - The dissipation of pyraclostrobin, a strobilurin fungicide, in soil was found to be influenced by soil moisture, organic matter content and microbial population. Among the different moisture regimes, dissipation was faster under submerged condition (T1/2 10 days) followed by field capacity (T1/2 28.7 days) and in dry soil (T1/2 41.8 days). Use of sludge at 5 % level to Inceptisol favoured a faster dissipation of pyraclostrobin, whereas a slower rate of dissipation was observed in partial organic matter removed soil as compared to normal soil. Slower rate of dissipation was also observed in sterile soil (T1/2 47 days) compared to normal soil. Pyraclostrobin dissipated faster in Vertisol (T1/2 21.8 days) than in Inceptisol (T1/2 28.7 days). No significant difference in the dissipation rate was observed at 1 and 10 MUg g(-1) fortification levels. PMID- 23793801 TI - ERCP via gastrostomy vs. double balloon enteroscopy in patients with prior bariatric Roux-en-Y gastric bypass surgery. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) is the most common bariatric surgery. The performance of ERCP in bariatric RYGB is challenging due to the long Roux limb. We herein compared the indications and technical outcomes of ERCP via percutaneous gastrostomy (GERCP) and double balloon enteroscopy (DBERCP) for patients with prior bariatric RYGB anatomy. METHODS: Between December 2005 and November 2011, consecutive ERCP patients who had undergone RYGB were identified using a prospectively maintained electronic ERCP database. Medical records were abstracted for ERCP indications and outcomes. In most cases, the gastrostomy was done by either laparoscopic or open surgery and allowed to mature at least 1 month before performing ERCP. The choice of route for ERCP was at discretion of managing physician. RESULTS: Forty-four patients (F = 42) with GERCP and 28 patients (F = 26) with DBERCP were identified. The mean age was younger in GERCP than DBERCP (44.8 vs. 56.1, p < 0.001). GERCP patients were more likely to have suspected sphincter of Oddi dysfunction (77 %) as the primary indication whereas DBERCP was suspected CBD stone (57 %). The mean total number of sessions/patient in GERCP and DBERCP was 1.7 +/- 1.0 and 1.1 +/- 0.4, respectively (p = 0.004). GERCP access to the major papilla was successful in all but two (97 %), whereas duct cannulation and interventions were successful in all. In DBERCP, the success rate of accessing major papilla, cannulation and therapeutic intervention was 78, 63, 56 %, respectively. There was one (3.1 %) post-ERCP pancreatitis in DBERCP. Complications occurred in 11 GERCP procedures (14.5 %) and 10 were related to the gastrostomy. This was significantly higher than that of DBERCP (p = 0.022). CONCLUSIONS: GERCP is more effective than DBERCP in gaining access to the pancreatobiliary tree in patients with RYGB, but it is hindered by the gastrostomy maturation delay and a higher morbidity. Technical improvements in each method are needed. PMID- 23793802 TI - Laparotomy versus retroperitoneal laparoscopy in debridement and drainage of retroperitoneal infected necrosis in severe acute pancreatitis. AB - BACKGROUND: The aim of this study was to compare laparotomy and retroperitoneal laparoscopy in debridement and drainage of retroperitoneal infected necrosis of severe acute pancreatitis (SAP), and to evaluate the curative efficacy and the timing of retroperitoneal laparoscopic debridement drainage (RLDD) for SAP patients. METHODS: We performed a retrospective analysis of 50 SAP cases, including 18 patients in the RLDD group and 32 patients in the laparotomy group. Observed indices included gender, age, CT severity index, Ranson score, APACHE II score, preoperative course, length of stay, operation time, mortality, postoperative complications, drainage tube indwelling time, and change of body temperature and peripheral white blood cell (PWBC) count between the time before the operation and at 48 h after surgery. RESULTS: Between the RLDD group and the laparotomy group, there was a significant difference in operation time (130 +/- 15 vs. 148 +/- 25 h; P = 0.007), length of stay [40.8 (6-121) vs. 55.9 (28-133) days; P = 0.053], and preoperative course [14.7 (5-31) vs. 18.3 (6-31) days; P = 0.05], but no significant difference in average drainage tube indwelling time [44.4 (2-182) vs. 49.8 (2-175) days; P = 0.663]. More improvement in body temperature and PWBC count was observed in the patients of the RLDD group. There was one death (1/18) in the RLDD group and four (4/32) in the laparotomy group. Fourteen cases (14/32) in the laparotomy group had postoperative complications, including pancreatic fistula (n = 11), intestinal fistula (n = 2), retroperitoneal hemorrhage (n = 2), infection of incision (n = 9), and 5 cases (5/18) in the RLDD group, including pancreatic fistula (n = 4) and retroperitoneal hemorrhage (n = 1). CONCLUSIONS: RLDD, as minimally invasive surgery, is technically feasible, safe, and effective in the treatment of retroperitoneal infected necrosis in SAP patients, in contrast to the laparotomy technique, and can be performed in the early phase of SAP to prevent the deterioration of the disease. PMID- 23793803 TI - Endoscopic submucosal dissection using a carbon dioxide laser with submucosally injected laser absorber solution (porcine model). AB - BACKGROUND: Recently, endoscopic submucosal dissection (ESD) has been performed to treat early gastric cancer. The en bloc resection rate of ESD has been reported to be higher than that of conventional endoscopic mucosal resection (EMR), and ESD can resect larger lesions than EMR. However, ESD displays a higher complication rate than conventional EMR. Therefore, the development of devices that would increase the safety of ESD is desired. Lasers have been extensively studied as a possible alternative to electrosurgical tools. However, laser by itself easily resulted in perforation upon irradiation of the gastrointestinal tract. We hypothesized that performing ESD using a CO2 laser with a submucosal laser absorber could be a safe and simple treatment for early gastric cancer. To provide proof of concept regarding the feasibility of ESD using a CO2 laser with submucosally injected laser absorber solution, an experimental study in ex vivo and in vivo porcine models was performed. METHODS: Five endoscopic experimental procedures using a carbon dioxide (CO2) laser were performed in a resected porcine stomach. In addition, three endoscopic experimental procedures using a CO2 laser were performed in living pigs. RESULTS: In the ex vivo study, en bloc resections were all achieved without perforation and muscular damage. In addition, histological evaluations could be performed in all of the resected specimens. In the in vivo study, en bloc resections were achieved without perforation and muscular damage, and uncontrollable hemorrhage did not occur during the procedures. CONCLUSIONS: Endoscopic submucosal dissection using a CO2 laser with a submucosal laser absorber is a feasible and safe method for the treatment of early gastric cancer. PMID- 23793804 TI - Mesh in laparoscopic large hiatal hernia repair: a systematic review of the literature. AB - BACKGROUND: The use of mesh is becoming more popular for large hiatal hernia (type II-IV) repair to reduce the recurrence rate. The aim of this study was to outline the currently available literature on the use of mesh in laparoscopic large hiatal hernia repair, emphasizing objective outcome. METHODS: A structured search of the literature was performed in the Medline, Embase, and Cochrane Central Register of Controlled Trials databases. RESULTS: A total of 26 studies met the inclusion criteria. There were three randomized controlled trials, seven prospective and five retrospective cohort studies, and five prospective and one retrospective case-control study. The study design was not reported in the remaining studies. In the included studies, laparoscopic hiatal hernia repair was performed with mesh in 924 patients (mesh group) and without mesh in 340 patients (nonmesh group). The type of mesh used was very different: polypropylene in six, biomesh in nine, polytetrafluoroethylene (PTFE) in two, expanded PTFE (ePTFE) in two, and composite polypropylene-PTFE in another two. At least two different kinds of mesh were used in five studies. Radiological and/or endoscopic follow-up was performed after a mean (+/- SEM) period of 25.2 +/- 4.0 months. There was no or only a small recurrence (recurrent hiatal hernia <2 cm) in 385 of the 451 available patients (85.4 %) in the mesh group and in 182 of 247 (73.7 %) in the nonmesh group. CONCLUSIONS: The use of mesh in the repair of large hiatal hernias is promising with respect to the reduction of anatomical recurrences. However, many different kinds and configurations of mesh are available. This systematic review of the literature is a basis for high-quality randomized controlled trials to obtain the most effective and safe mesh in the long term. PMID- 23793805 TI - Long-term outcomes of laparoscopy-assisted distal gastrectomy for early gastric cancer: result of a randomized controlled trial (COACT 0301). AB - BACKGROUND: The purpose of this study was to evaluate laparoscopy-assisted distal gastrectomy (LADG) compared to open distal gastrectomy (ODG) in the treatment of early gastric cancer with respect to survival, surgical outcomes, complications, and quality of life (QOL). METHODS: One hundred sixty-four patients with cT1N0M0 and cT1N1M0 distal gastric cancer were randomly assigned to either the LADG group or the ODG group. The primary end point was the 5-year disease-free survival (DFS) rate. Complications were classified using the accordion severity classification of postoperative complications scheme. QOL was measured using the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-STO22 preoperatively and postoperatively during regular follow-up visits. This trial is registered at ClinicalTrials.gov (NCT00546468). RESULTS: The median (range) follow-up period was 74.3 (24.8-90.8) months. The LADG and ODG groups showed similar survival [5-year DFS rate: 98.8 % vs. 97.6 %, respectively (P = 0.514), 5 year overall survival (OS) rate: 97.6 vs. 96.3 %, respectively (P = 0.721)] or overall complication rate (29.3 vs. 42.7 %, respectively; P = 0.073). Mild complications were significantly less frequent in the LADG group than in the ODG group (23.2 vs. 41.5 %; P = 0.012). The rates of moderate, severe, and long-term complications (i.e., 31 days to 5 years after surgery) did not differ significantly between groups. No clinically meaningful differences were detected between the two groups in long-term QOL. CONCLUSION: LADG showed similar DFS and OS compared to ODG in treating early gastric cancer. Marginal benefits in mild complications were observed with LADG. LADG did not show advantages over ODG regarding other complications and long-term QOL. PMID- 23793806 TI - Short-term outcome of total laparoscopic distal gastrectomy for overweight and obese patients with gastric cancer. AB - BACKGROUND: Laparoscopic distal gastrectomy for gastric cancer has been firmly established in recent decades but still is a difficult procedure, especially for obese patients, as with open surgery. This study aimed to evaluate the perioperative outcome of total laparoscopic distal gastrectomy (TLDG) for early gastric cancer patients with a body mass index (BMI) exceeding 25 kg/m(2) and to consider countermeasures to this. METHODS: Perioperative outcomes were compared between 42 patients with a BMI exceeding 25 kg/m(2) [overweight or obese group (OWG)] and 174 patients with a BMI lower than 25 kg/m(2) [normal or underweight group (NWG)] who underwent TLDG between September 2010 and December 2012. RESULTS: The BMI was 26.0 +/- 1.4 kg/m(2) in the OWG group and 22.0 +/- 2.1 kg/m(2) in the NWG group (P < 0.001). The groups did not differ in terms of age, sex, American Society of Anesthesiologists score, presence of diabetes, number of retrieved lymph nodes, number of metastatic lymph nodes, or metastatic lymph node ratio. The two groups did not differ significantly with respect to the extent of lymph node dissection [OWG: D1 (11.9 %), D1+ (66.7 %), D2 (21.4 %) vs NWG: D1 (5.2 %), D1+ (51.7 %), D2 (43.1 %); P = 0.020] or tumor size (OWG: 25.5 +/- 20.2 mm vs NWG: 33.0 +/- 17.2 mm; P = 0.037). Differences in operation time (OWG: 212 +/- 31 min vs NWG: 200 +/- 35 min; P = 0.005) and estimated blood loss (OWG: 15 +/- 22 ml vs NWG: 10 +/- 34 ml; P = 0.013) seemed to have a minimal impact clinically. Postoperative complications including infectious complications and recovery after surgery did not differ between the two groups. CONCLUSIONS: For overweight and obese patients, TLDG was managed safely. The procedure was considered to be difficult but sufficiently feasible. PMID- 23793807 TI - Endoluminal surgical triangulation: overcoming challenges of colonic endoscopic submucosal dissections using a novel flexible endoscopic surgical platform: feasibility study in a porcine model. AB - BACKGROUND: Colonic endoscopic submucosal dissection (ESD) is challenging as a result of the limited ability of conventional endoscopic instruments to achieve traction and exposure. The aim of this study was to evaluate the feasibility of colonic ESD in a porcine model using a novel endoscopic surgical platform, the Anubiscope (Karl Storz, Tuttlingen, Germany), equipped with two working channels for surgical instruments with four degrees of freedom offering surgical triangulation. METHODS: Nine ESDs were performed by a surgeon without any ESD experience in three swine, at 25, 15, and 10 cm above the anal verge with the Anubiscope. Sixteen ESDs were performed by an experienced endoscopist in five swine using conventional endoscopic instruments. Major ESD steps included the following for both groups: scoring the area, submucosal injection of glycerol, precut, and submucosal dissection. Outcomes measured were as follows: dissection time and speed, specimen size, en bloc dissection, and complications. RESULTS: No perforations occurred in the Anubis group, while there were eight perforations (50 %) in the conventional group (p = 0.02). Complete and en bloc dissections were achieved in all cases in the Anubis group. Mean dissection time for completed cases was statistically significantly shorter in the Anubis group (32.3 +/- 16.1 vs. 55.87 +/- 7.66 min; p = 0.0019). Mean specimen size was higher in the conventional group (1321 +/- 230 vs. 927.77 +/- 229.96 mm(2); p = 0.003), but mean dissection speed was similar (35.95 +/- 18.93 vs. 23.98 +/- 5.02 mm(2)/min in the Anubis and conventional groups, respectively; p = 0.1). CONCLUSIONS: Colonic ESDs were feasible in pig models with the Anubiscope. This surgical endoscopic platform is promising for endoluminal surgical procedures such as ESD, as it is user-friendly, effective, and safe. PMID- 23793808 TI - Can laparoscopy for colon resection reduce the need for discharge to skilled care facility? AB - BACKGROUND: A significant proportion of patients, especially the elderly undergoing colon resections, are likely to be discharged to a skilled care facility. This study aims to examine whether the technique of colectomy, open versus laparoscopic, contributed to their discharge to a skilled care facility. METHODS: This was a retrospective analysis using discharge data from the Nationwide Inpatient Sample (NIS), Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality. Adult patients who underwent colectomy in 2009 were evaluated. SAS and SUDAAN software were used to provide weighted estimates and to account for the complex sampling design of the NIS. We compared routine discharge to nonroutine discharge, defined as transfer to short term hospital, skilled nursing facility, intermediate care, home health, or another type of facility. RESULTS: A weighted total of 221,294 adult patients underwent colectomy in 2009 and had the primary outcome of discharge available. Of these colon resections, 70,361 (32 %) were performed laparoscopically and 150,933 (68 %) by open technique. A total of 139,047 (62.8 %) patients had routine discharge and 73,572 (33.3 %) nonroutine. A total of 8,445 (3.8 %) patients died while in the hospital, and 229 (0.1 %) left against medical advice and were excluded from further analysis. On univariate analysis, age >= 65 years, female gender, Black/Hispanic race, open technique (compared to laparoscopic), Medicare/Medicaid insurance status, comorbidity index of >= 1, and malignant primary diagnosis predicted nonroutine discharge. A multivariate logistic model was then used to predict nonroutine discharge in these patients using variables significant in the univariate analysis at the alpha = 0.05 significance level. In the multivariate analysis, open compared to laparoscopic technique was independently associated with increased likelihood of discharge to skilled care facilities (odds ratio 2.85, 95 % confidence interval 2.59-3.14). CONCLUSIONS: In addition to the expected factors like advancing age, female gender, and increasing comorbidity index, open compared to laparoscopic technique for colectomy is associated with an increased likelihood of discharge to skilled care facilities. When feasible, the laparoscopic technique should be considered as an option, especially in the elderly patients who require colon resection, because it may reduce their likelihood of discharge to a skilled care facility. PMID- 23793809 TI - Peritoneal dialysis outcomes in a modern cohort of overweight patients. AB - BACKGROUND: The incidence of obesity is increasing both in the general population and in incident dialysis patients. While there is evidence that being overweight is associated with good outcomes in hemodialysis, the evidence in peritoneal dialysis (PD) patients is not very clear. We studied a modern cohort of PD patients to examine outcomes in large patients. METHODS: Forty-three patients who started PD, who weighed more than 90 kg at dialysis initiation, between January/2000 and June/2010 were matched with 43 control patients who weighed less than 90 kg. Detailed review of the charts was undertaken. RESULTS: The mean weight and body mass index of the wt < 90 kg group were 69.3 +/- 11.3 kg and 25.0 +/- 3.9 kg/m(2). The number of peritonitis episodes per year was 0.33 +/- 0.6 (wt < 90 kg) and 0.82 +/- 1.7 (wt >= 90 kg) (p = 0.26). The median time to first peritonitis showed a trend toward earlier peritonitis in larger patients [9.5 (4.3, 27) months in wt >= 90 kg, 19.1(7.9, 30.8) months in wt < 90 kg] but did not reach statistical significance (p = 0.12). Surprisingly, hernias and leaks were more common in the weight <90 kg group (44 vs. 18.6 % p = 0.02). There was no difference in total number of hospitalizations or the number of days hospitalized. Kaplan-Meier analysis of survival on PD showed no differences between the two groups (logrank p = 0.99). Cox regression analysis using age, race, cause of ESRD due to diabetes and Charlson comorbidity index as the covariates did not show weight to be associated with survival on PD. CONCLUSIONS: Large patients tend to do just as well on PD, with survival on PD being no different compared to individuals with lower weight and body mass index. PMID- 23793810 TI - PKM2 and ACVR 1C are prognostic markers for poor prognosis of gallbladder cancer. AB - PURPOSE: To identify biological markers related to the progression and prognosis of GBC. METHODS: The expressions of pyruvate kinase isoenzyme type M2 (PKM2) and activin A receptor type IC (ACVR 1C) in 46 squamous cell/adenosquamous carcinomas (SC/ASC) and 80 adenocarcinomas (AC) were examined using immunohistochemistry. RESULTS: Positive PKM2 and negative ACVR 1C expressions were significantly associated with lymph node metastasis, invasion and TNM stage of SC/ASCs and ACs. Univariate Kaplan-Meier analysis showed that either elevated PKM2 or loss of ACVR 1C expression significantly correlated with shorter average survival times in both SC/ASC and AC patients. Multivariate Cox regression analysis showed that positive PKM2 expression and loss of ACVR 1C expression were poor prognosis biomarkers in both SC/ASC and AC patients. CONCLUSIONS: Our study suggested that PKM2 overexpression is a marker of metastasis, invasion and poor prognosis of GBC. ACVR 1C is a tumor suppressor, and lowered ACVR 1C expression is an important marker for the metastasis, invasion, and prognosis of GBC. PMID- 23793811 TI - To evaluate the accuracy of dynamic versus static IMRT delivery using portal dosimetry. AB - INTRODUCTION: To evaluate the delivery accuracy of dynamic (DMLC) and static (SMLC) intensity modulated radiation therapy (IMRT) techniques using portal dosimetry (PD) in Varian Eclipse Treatment Planning System. MATERIALS AND METHODS: Seven DMLC IMRT Head and Neck plans were retrospectively generated for the study using SMLC mode at 20, 10 and 5 levels of intensity (SMLC20, SMLC10, SMLC5). Dosimetric verifications performed by PD on a total of 107 fields were evaluated using the gamma index (maximum (gammamax), average (gammaavg), percentage of points with (gamma%) <= 1). The images were acquired at a source detector distance of 100 cm at gantry zero degree and also at clinically planned gantry angles. RESULTS: For both modes, measurements are within acceptable criteria. (gamma%) <= 1 improves by increasing SMLC levels (+3.4 % from SMLC5 to SMLC20, p < 0.001) and using DMLC (+3.9 % and +0.6 % compared to SMLC5 and SMLC20, respectively, p < 0.001). Also (gammamax) parameter improves significantly by increasing SMLC levels (+22 % from SMLC5 to SMLC20) and using DMLC (+34 % and +16 % compared to SMLC5 and SMLC20, respectively). The effect of the gantry rotation influences the delivery accuracy by up to -7 % (p < 0.05). The effect of leaves travelling direction was almost negligible (1 %). CONCLUSIONS: A good agreement between calculated and measured fluences was obtained for DMLC and SMLC techniques at higher intensity levels; however, DMLC delivery ensures the best reproduction of computed fluence maps. The gantry rotation influences the delivery accuracy in particular for SMLC modes at lower intensity levels. PMID- 23793812 TI - The clinical significance of memory T cells and its subsets in gastric cancer. AB - BACKGROUND: Long life of memory T cell (Tm) determines its crucial role in the carcinogenesis and carcinogenic progression which usually take long time. The Tm compartment contains two populations, central memory T cells (Tcm) and effector memory T cells (Tem), based on their phenotypic markers, functional attributes, and migratory properties. METHODS: We investigated the subsets of the Tm in peripheral blood and tumor microenvironments in patients with gastric cancer by flow cytometry, and aimed to explore the correlation between the Tm and clinicopathologic features of gastric cancer. RESULTS: The percentages of CD4(+)/CD8(+) Tm and CD4(+)/CD8(+) Tcm in peripheral blood from gastric cancer patients were statistically lower, whereas the percentages of CD4(+)/CD8(+) Tem were significantly higher than healthy controls. The proportion of CD4(+)/CD8(+) Tcm increased after tumor resection, while the percentage of the CD4(+)/CD8(+) Tem decreased significantly. Significant associations were detected between the peripheral CD4(+)/CD8(+) Tm and clinical stage, as well as the CD8(+) Tcm and clinical stage and nodal involvement. Tumor infiltrating CD8(+) Tm expressed both central and effector memory phenotypes, whereas CD4(+) Tm displayed predominantly an effector memory phenotype. Higher percentages of tumor infiltrating CD4(+)/CD8(+) Tm were significantly associated with the early disease stage. CONCLUSIONS: Tm and its subsets were good immune indicators for the disease stage of gastric cancer. The proportion of Tm subsets may reflect the immune suppressive and immune response to the tumor associated antigen. PMID- 23793813 TI - Should we continue temozolomide beyond six cycles in the adjuvant treatment of glioblastoma without an evidence of clinical benefit? A cost analysis based on prescribing patterns in Spain. AB - PURPOSE: The standard adjuvant treatment for glioblastoma is temozolomide concomitant with radiotherapy, followed by a further six cycles of temozolomide. However, due to the lack of empirical evidence and international consensus regarding the optimal duration of temozolomide treatment, it is often extended to 12 or more cycles, even in the absence of residual disease. No clinical trial has shown clear evidence of clinical benefit of this extended treatment. We have explored the economic impact of this practice in Spain. MATERIALS AND METHODS: Spanish neuro-oncologists completed a questionnaire on the clinical management of glioblastomas in their centers. Based on their responses and on available clinical and demographic data, we estimated the number of patients who receive more than six cycles of temozolomide and calculated the cost of this extended treatment. RESULTS: Temozolomide treatment is continued for more than six cycles by 80.5 % of neuro-oncologists: 44.4 % only if there is residual disease; 27.8 % for 12 cycles even in the absence of residual disease; and 8.3 % until progression. Thus, 292 patients annually will continue treatment beyond six cycles in spite of a lack of clear evidence of clinical benefit. Temozolomide is covered by the National Health Insurance System, and the additional economic burden to society of this extended treatment is nearly 1.5 million euros a year. CONCLUSIONS: The optimal duration of adjuvant temozolomide treatment merits investigation in a clinical trial due to the economic consequences of prolonged treatment without evidence of greater patient benefit. PMID- 23793814 TI - Osteopontin expressions correlate with WHO grades and predict recurrence in meningiomas. AB - Recurrence of meningiomas is a major prognostic issue. Although World Health Organization (WHO) histopathological grading correlates strongly with recurrence, it has some limitations, and predicting the biological behavior of grade I meningiomas is particularly difficult. Osteopontin (OPN) is a protein known to be involved in tumor progression. The purpose of this study is to determine expression of OPN in meningiomas and to investigate its correlation with WHO grades and tumor recurrence. Immunohistochemical (IHC) evaluation of expression of OPN was performed by two different methods to ensure reliability. OPN IHC and Allred scores were calculated on the basis of intensity and extent of staining. Both scores were in agreement and correlated significantly with meningioma grade and Ki-67 index. OPN scores were also significantly correlated with recurrence of WHO grade I meningiomas. Cut-off values for OPN IHC and OPN Allred scores between non-recurrent and recurrent grade I meningiomas were calculated as 70 and 5.5 respectively. We concluded that OPN is a valuable marker for grading meningiomas and for predicting the recurrence in WHO grade I tumors. PMID- 23793815 TI - Cone-beam computed tomography analysis of the shape, height, and location of the mandibular lingula. AB - OBJECTIVES: The precise anatomic location of the lingula is clinically significant because it is subject to injury during a variety of oral and maxillofacial surgical procedures. This is the first study to identify and classify the different morphological shapes of the mandibular lingula using cone beam computed tomography. MATERIALS AND METHODS: A retrospective study was performed to evaluate the shape, height, and location of the lingula in relation to surrounding structures using cone-beam computed tomographic images. The shape of the lingula was classified into triangular, truncated, nodular, and assimilated types. The location was determined by five distances from the lingular tip to: the anterior and the posterior borders of the mandibular ramus, the mandibular notch, the distal surface of the mandibular second molar, and the occlusal plane. RESULTS: Nodular shape of the lingula was most commonly found [51.2% (422)] followed by truncated [32% (264)]. The mean height of the lingula was 7.97 +/- 1.84 mm. The mean distance of lingula from the anterior and posterior borders of mandibular ramus was 16.7 +/- 2.7 and 13.0 +/- 2.3 mm, respectively. The lingula was located at 15.3 +/- 2.4 mm from the mandibular notch and 29.4 +/- 3.9 mm from the distal side of alveolar socket of mandibular second molar tooth. CONCLUSION: The present study provides new information to the literature concerning the shape, height, and location of the lingula in the Turkish population. This finding may assist surgeons to localize the lingula and avoid intraoperative complications. PMID- 23793816 TI - Loss of heterozygosity preferentially occurs in early replicating regions in cancer genomes. AB - Erroneous repair of DNA double-strand breaks by homologous recombination (HR) leads to loss of heterozygosity (LOH). Analysing 22,392 and 74,415 LOH events in 363 glioblastoma and 513 ovarian cancer samples, respectively, and using three different metrics, we report that LOH selectively occurs in early replicating regions; this pattern differs from the trends for point mutations and somatic deletions, which are biased toward late replicating regions. Our results are independent of BRCA1 and BRCA2 mutation status. The LOH events are significantly clustered near RNA polII-bound transcription start sites, consistent with the reports that slow replication near paused RNA polII might initiate HR-mediated repair. The frequency of LOH events is higher in the chromosomes with shorter inter-homolog distance inside the nucleus. We propose that during early replication, HR-mediated rescue of replication near paused RNA polII using homologous chromosomes as template leads to LOH. The difference in the preference for replication timing between different classes of genomic alterations in cancer genomes also provokes a testable hypothesis that replicating cells show changing preference between various DNA repair pathways, which have different levels of efficiency and fidelity, as the replication progresses. PMID- 23793817 TI - Peptide-binding dependent conformational changes regulate the transcriptional activity of the quorum-sensor NprR. AB - The transcriptional regulator NprR controls the expression of genes essential for the adaptative response of Bacillus cereus. NprR belongs to the RNPP family of directly regulated quorum sensors from Gram-positive bacteria. It is activated by the re-imported signaling peptide NprX. To elucidate the activation mechanism of this quorum-sensing system, we analyzed the conformation changes induced on binding of NprX. We solved the crystal structure of the NprR/NprX binary complex and characterized the apo form of NprR in solution. We demonstrated that apo NprR is a dimer that switches to a tetramer in the presence of NprX. Mutagenesis, and functional analysis allowed us to identify the protein and peptide residues directly involved in the NprR activation process. Based on the comparison with the Rap proteins, we propose a model for the peptide-induced conformational change allowing the apo dimer to switch to an active tetramer specifically recognizing target DNA sequences. PMID- 23793818 TI - Behavioural and emotional symptoms of apathy are associated with distinct patterns of brain atrophy in neurodegenerative disorders. AB - Apathy is a neurocognitive syndrome of reduced goal-directed behaviour and is an important cause of disability in neurodegenerative disorders. Frontal-subcortical dysfunction is thought to be important in apathy, but the contribution of individual brain regions to different aspects of the apathy syndrome is poorly understood. We aimed to test the hypotheses that apathy in two distinct neurodegenerative disorders would be associated with frontal lobe atrophy and that reduced initiative and emotional blunting would be associated with distinct patterns of atrophy in functionally relevant brain areas. Seventeen patients with progressive supranuclear palsy (PSP) and 17 patients with Alzheimer's disease (AD) underwent structural MRI scanning at 3 T to provide data for voxel based morphometric analysis. Apathy was defined using Robert's 2009 diagnostic criteria and specific symptoms were assessed with the Apathy Inventory. Patients with and without apathy were matched for important demographic and clinical characteristics. Apathy was associated with atrophy of the ventromedial orbitofrontal cortex and left insula in both AD and PSP. Reduced initiative was specifically associated with atrophy of the anterior cingulate and ventrolateral orbitofrontal cortex whilst emotional blunting was specifically associated with atrophy of the left insula. These findings provide further support for the role of medial frontal regions and insular cortex in apathy and suggest that behavioural and emotional aspects of the apathy syndrome may have distinct neuroanatomical bases. PMID- 23793819 TI - A parkinsonian movement disorder with brain iron deposition and a haemochromatosis mutation. PMID- 23793820 TI - Sir Francis Walshe (1885-1973). PMID- 23793821 TI - Pentacoordinate silicon complexes with dynamic motion resembling a pendulum on the S(N)2 reaction pathway. AB - A series of glutarimide derivatives which has two carbonyl coordination sites for intramolecular pentacoordination at silicon with a X(1+n)SiC(3-n)O moiety have been synthesised and characterized. The substituent (leaving group) effects on the Si-O bond exchange between the two coordination sites (resembling a pendulum) have been studied by comparison of the differently substituted (X = F, Cl, OTf, Br and I) structures. The activation parameters for the Si-O bond exchange process were measured by NMR and separately computed and are consistent with the strength of Si-O bond coordination and the nature of the leaving group, X. The temperature-dependent (29)Si NMR spectroscopy is supported by X-ray crystallography and shows that the tetrahedral reactant is converted into pentacoordinate intermediates by intramolecular O-Si association followed by reversion to a tetrahedral geometry by Si-X dissociation. The two association/dissociation patterns offer a model for nucleophilic substitution at a silicon atom. A continuum of structures on the S(N)2 reaction profile from the glutarimide derivatives correlates reasonably well with the structural data obtained from derivatives of lactams, diketopiperazines and quinolones. PMID- 23793822 TI - Fat suppression strategies in MR imaging of breast cancer at 3.0 T: comparison of the two-point Dixon technique and the frequency selective inversion method. AB - PURPOSE: To compare two fat suppression methods in contrast-enhanced MR imaging of breast cancer at 3.0 T: the two-point Dixon method and the frequency selective inversion method. MATERIALS AND METHODS: Forty female patients with breast cancer underwent contrast-enhanced three-dimensional T1-weighted MR imaging at 3.0 T. Both the two-point Dixon method and the frequency selective inversion method were applied. Quantitative analyses of the residual fat signal-to-noise ratio and the contrast noise ratio (CNR) of lesion-to-breast parenchyma, lesion-to-fat, and parenchyma-to-fat were performed. Qualitative analyses of the uniformity of fat suppression, image contrast, and the visibility of breast lesions and axillary metastatic adenopathy were performed. RESULTS: The signal-to-noise ratio was significantly lower in the two-point Dixon method (P < 0.001). All CNR values were significantly higher in the two-point Dixon method (P < 0.001 and P = 0.001, respectively). According to qualitative analysis, both the uniformity of fat suppression and image contrast with the two-point Dixon method were significantly higher (P < 0.001 and P = 0.002, respectively). Visibility of breast lesions and metastatic adenopathy was significantly better in the two-point Dixon method (P < 0.001 and P = 0.03, respectively). CONCLUSION: The two-point Dixon method suppressed the fat signal more potently and improved contrast and visibility of the breast lesions and axillary adenopathy. PMID- 23793824 TI - Lentinan: clinical benefit in the management of systemic malignancies. PMID- 23793823 TI - Cardiovascular disease and HIV infection. AB - The emergence of chronic disease complications in controlled HIV disease has changed the landscape of HIV clinical care. HIV infection confers an increased cardiovascular disease risk, which is thought to be due to a complex interplay of mechanistic factors. While traditional cardiovascular risk factors likely play a role, recent evidence suggests that HIV-associated inflammation and immune activation are important mediators of cardiovascular risk. It is unclear whether established preventative interventions for the general population are applicable to HIV-infected patients, and the need to translate mechanistic knowledge into HIV-specific clinical interventions represents an important priority. Developing strategies to prevent cardiovascular disease in HIV-infected individuals calls for a multidisciplinary approach and represents an opportunity to exert a major public health impact in an at-risk population. PMID- 23793825 TI - Altered expression of O-GlcNAc-modified proteins in a mouse model whose glycemic status is controlled by a low carbohydrate ketogenic diet. AB - Abnormal modification of proteins by O-linked N-acetylglucosamine (O-GlcNAc) is known to be associated with the pathology induced by hyperglycemia. However, the dynamic mechanism of O-GlcNAc modification under hyperglycemic conditions in vivo has not been fully characterized. To understand the mechanism, we established an animal model in which the glycemic status is controlled by the diet. A mutant mouse (ob/ob) which exhibits diet-induced hyperglycemia when fed a regular chow (chow) was used to establish this model; the mice were fed a very low carbohydrate ketogenic diet (KD) to improve hyperglycemia. Using this model, we evaluated the levels of O-GlcNAc-modified proteins in tissues under a hyperglycemic or its improved condition. ELISA and Western blot analyses revealed that altered expression of certain proteins modified by O-GlcNAc were found in the mice tissues, although global O-GlcNAc levels in the tissues remained unaltered by improvement of hyperglycemia. We also found the Akt protein kinase was modified by O-GlcNAc in the liver of ob/ob mice, and the modification levels were decreased by improvement of hyperglycemia. Furthermore, aberrant phosphorylation of Akt was found in the liver of ob/ob mice under hyperglycemic condition. In conclusion, our established mouse model is useful for evaluating the dynamics of O-GlcNAc-modified proteins in tissues associated with glycemic status. This study revealed that the expression level of certain proteins modified by O-GlcNAc is altered when KD improves the hyperglycemia. These proteins could be prospective indexes for nutritional therapy for hyperglycemia associated diseases, such as diabetes mellitus. PMID- 23793826 TI - Pretreatment for simultaneous production of total lipids and fermentable sugars from marine alga, Chlorella sp. AB - The goal of this study was to determine the optimal pretreatment process for the extraction of lipids and reducing sugars to facilitate the simultaneous production of biodiesel and bioethanol from the marine microalga Chorella sp. With a single pretreatment process, the optimal ultrasonication pretreatment process was 10 min at 47 KHz, and extraction yields of 6.5 and 7.1 (percentage, w/w) of the lipids and reducing sugars, respectively, were obtained. The optimal microwave pretreatment process was 10 min at 2,450 MHz, and extraction yields of 6.6 and 7.0 (percentage, w/w) of the lipids and reducing sugars, respectively, were obtained. Lastly, the optimal high-pressure homogenization pretreatment process was two cycles at a pressure of 20,000 psi, and extraction yields of 12.5 and 12.8 (percentage, w/w) of the lipids and reducing sugars, respectively, were obtained. However, because the single pretreatment processes did not markedly improve the extraction yields compared to the results of previous studies, a combination of two pretreatment processes was applied. The yields of lipids and reducing sugars from the combined application of the high-pressure homogenization process and the microwave process were 24.4 and 24.9 % (w/w), respectively, which was up to three times greater than the yields obtained using the single pretreatment processes. Furthermore, the oleic acid content, which is a fatty acid suitable for biodiesel production, was 23.39 % of the fatty acids (w/w). The contents of glucose and xylose, which are among the fermentable sugars useful for bioethanol production, were 77.5 and 13.3 % (w/w) of the fermentable sugars, respectively, suggesting the possibility of simultaneously producing biodiesel and bioethanol. Based on the results of this study, the combined application of the high-pressure homogenization and microwave pretreatment processes is the optimal method to increase the extraction yields of lipids and reducing sugars that are essential for the simultaneous production of biodiesel and bioethanol. PMID- 23793827 TI - Gentamicin palmitate as a new antibiotic formulation for mixing with bone tissue and local release. AB - During surgery with bone grafting, the impaction of bone tissue creates an avascular area where local circulation is disrupted. If infections arise, they may prevent systemically administered antibiotics from reaching the infected bone. In this study we evaluated gentamicin palmitate (GP) mixed with gentamicin sulfate (GS) as a coating for bone chips (BCh). The efficacy of the coated BCh was measured by gentamicin base release tests using B. subtilis, S. epidermidis and S. aureus. Gentamicin base release was evaluated in phosphate-buffered saline for up to 7 days using B. subtilis bioassay. Antimicrobial efficacy was tested with S. aureus and S. epidermidis. A significant difference on the release of gentamicin base between GS and GS + GP was observed. S. epidermidis are significantly more susceptible to GS + GP and GS than S. aureus. BCh can act as gentamicin carriers and showed efficacy against S. aureus and S. epidermidis. PMID- 23793828 TI - Role of microRNA-21 in regulating 3T3-L1 adipocyte differentiation and adiponectin expression. AB - MicroRNAs are endogenous small RNAs with a high degree of conservation, participating in a variety of vital activities. In present study, to explore the effect of microRNAs on 3T3-L1 adipocyte differentiation and adiponectin expression, the adipo-related microRNAs were screened and identified by micorRNA microarray. The highly expression plasmid of microRNA-21 with obvious expression up-regulation (miR-21) and its anti-sense (miR-21 inhibitor) were constructed and transfected into 3T3-L1 preadipocytes. The effect of miR-21 on 3T3-L1 adipocyte differentiation was observed, and the protein and mRNA expression level of adiponectin and AP-1 were analyzed. Results showed that, the expression profiles of microRNAs significantly changed during 3T3-L1 adipocyte differentiation. The expression of miR-21 was obviously up-regulated. miR-21 could significantly promote adipocyte differentiation, increase adiponectin mRNA and protein expression, while decrease AP-1 protein level. Meanwhil, miR-21 inhibitor blocked the effects of miR-21 mentioned above. The overexpression of AP-1 could absolutely reverse the stimulatory effect of miR-21 on adiponectin. miR-21 plays an important role in regulating adipocyte differentiation and adiponectin expression by inhibiting AP-1 expression. PMID- 23793830 TI - Computer simulation of diffusion in silica liquid under temperature and pressure. AB - We have studied the diffusion mechanism in silica liquid following a new approach where the diffusion rate is estimated via the rate of SiO(x) -> SiO(x+/-1) and the mean square displacement of Si particles per SiO(x) -> SiO(x+/-1). Molecular dynamics simulation has been conducted for a model consisting of 1998 particles over a wide range of temperatures (3000-4500 K) and pressure (from 0 to 25.75 GPa). Our results show that the rate of SiO(x) -> SiO(x+/-1) increases either with increasing the temperature or pressure. Further, we find that SiO(x) -> SiO(x+/-1) is heterogeneously distributed through the network structure of the liquid. In particular, it is concentrated on a small section of Si particles in a low-temperature regime and at ambient pressure. The spatial localisation of SiO(x) -> SiO(x+/-1) originates from the fact that the stable unit in low- and high-pressure regime is SiO4 and SiO6, respectively. The major change in the diffusion mechanism under pressure or temperature concerns the change in the distribution of SiO(x) -> SiO(x+/-1) through the network structure. It is finally shown that the spatial localisation of SiO(x) -> SiO(x+/-1) is responsible for the dynamics heterogeneity and the diffusion anomaly for silica liquid. This finding supports the concept that as the temperature approaches the glass transition point, SiO(x) -> SiO(x+/-1) spatially localises such that the diffusivity drops and the dynamics are anomalously slow. PMID- 23793829 TI - The association of SNPs in Hsp90beta gene 5' flanking region with thermo tolerance traits and tissue mRNA expression in two chicken breeds. AB - Thermo stress induces heat shock proteins (HSPs) expression and HSP90 family is one of them that has been reported to involve in cellular protection against heat stress. But whether there is any association of genetic variation in the Hsp90beta gene in chicken with thermo tolerance is still unknown. Direct sequencing was used to detect possible SNPs in Hsp90beta gene 5' flanking region in 3 chicken breeds (n = 663). Six mutations, among which 2 SNPs were chosen and genotypes were analyzed with PCR-RFLP method, were found in Hsp90beta gene in these 3 chicken breeds. Association analysis indicated that SNP of C.-141G>A in the 5' flanking region of the Hsp90beta gene in chicken had some effect on thermo tolerance traits, which may be a potential molecular marker of thermo tolerance, and the genotype GG was the thermo tolerance genotype. Hsp90beta gene mRNA expression in different tissues detected by quantitative real-time PCR assay were demonstrated to be tissue dependent, implying that different tissues have distinct sensibilities to thermo stress. Besides, it was shown time specific and varieties differences. The expression of Hsp90beta mRNA in Lingshan chickens in some tissues including heart, liver, brain and spleen were significantly higher or lower than that of White Recessive Rock (WRR). In this study, we presume that these mutations could be used in marker assisted selection for anti-heat stress chickens in our breeding program, and WRR were vulnerable to tropical thermo stress whereas Lingshan chickens were well adapted. PMID- 23793831 TI - Tuning the wettability of an aluminum surface via a chemically deposited fractal dendrite structure. AB - We have developed a straightforward method to tune the wettability of an aluminum substrate within a contact angle (CA) range from 2( degrees ) to 170( degrees ) by chemical deposition in CuCl2 solution and fluoroalkylsilane (FAS) modification. The CA of the as-deposited surface decreases with deposition time due to the growth of fractal copper dendrites, which enhance the surface roughness significantly. After subsequent modification with FAS, a superhydrophobic surface with CA 170( degrees ) and sliding angle less than 5( degrees ) has been obtained. With the increase of CA, the maximum spreading of water droplets is reduced. A bouncing behavior is observed for droplets impinging on the superhydrophobic substrate, suggesting its potential application as a self cleaning surface. PMID- 23793832 TI - Gravity-driven thin liquid films over topographical substrates. AB - We investigate the time-dependent evolution of thin liquid films over inclined substrates using a multi-component lattice Boltzmann algorithm. Substrates with and without grooves are considered and the effects of the inclination angle on the dynamics and the coating of the substrates are studied. Our results indicate that the dynamics is enhanced and the ridge height and its displacement are increased by increasing the inclination angle. However, by increasing the inclination angle the maximum depth that can be successfully coated is reduced. Also, although for any given groove depth the width should be larger than a critical value for successful coating, the critical width decreases for smaller inclination angles. For different inclination angles we derive and report the critical sizes of the grooves for successful coating of the substrates. PMID- 23793833 TI - Graphene oxide-based benzimidazole-crosslinked networks for high-performance supercapacitors. AB - The synthesis of graphene oxide (GO)-based benzimidazole-crosslinked network (GOBIN) materials is presented. These materials are prepared by the covalent crosslinking of GO sheets using a condensation reaction between the carboxylic acid moieties on the GO surface and the o-aminophenyl end groups of 3,3' diaminobenzidine (or 1,2,4,5-benzenetetraamine tetrahydrochloride). An efficient one-pot catalyst- and template-free synthesis was performed. The obtained porous GO-based materials possess a Brunauer-Emmett-Teller specific surface area ranging from 260 to 920 m(2) g(-1). Electrochemical testing indicates that the GOBIN materials display a specific capacitance up to 370 F g(-1) at a current density of 0.1 A g(-1) and about 90% of the original capacitance is retained after 5000 cycles at a current density of 3 A g(-1). Therefore, GOBIN materials can be employed as promising electrode materials for high-performance supercapacitors with outstanding cycling stability. Furthermore, owing to their significantly high specific surface area, these materials also show hydrogen uptake (up to 1.24 wt%, at 77 K and 1.0 bar) and carbon dioxide capture (up to 14.2 wt%, at 273 K and 1.0 bar) properties. As a result, these GO-based porous materials improve both the supercapacitor performance and gas sorption property, which demonstrate an excellent performance in the practical application of energy storage. PMID- 23793834 TI - Multimodality imaging of a left atrial appendage thrombus. PMID- 23793835 TI - Myocarditis patient with left ventricular, right atrial, and pericardial thrombi. Successful treatment with warfarin. PMID- 23793836 TI - Simplified detection of myocardial ischemia by seismocardiography. Differentiation between causes of altered myocardial function. AB - Seismocardiography (SCG) is a noninvasive technique for recording cardiac vibrations. Changes in these waves have been correlated with chronic and acute alterations in myocardial function. This analysis is complex and clinical integration limited. The current study aimed to simplify the utilization of SCG by fast Fourier transformation for a reliable discrimination between different intra- and postoperative causes of hypotension (i.e., myocardial ischemia or hypovolemia). We operated on nine pigs and recorded SCG at baseline, at hypovolemia (occlusion of the inferior vena cava), and at ischemia (occlusion of the right coronary artery). In conclusion, SCG enables detection and differentiation of ischemia and hypovolemia as important causes of altered myocardial function during and after surgery. Thus, this simple and noninvasive diagnostic tool may be used intra- and postoperatively to identify patients at risk. PMID- 23793837 TI - Nephroprotective action of sirtuin 1 (SIRT1). AB - Sirtuins, silent information regulator 2 (Sir 2) proteins, belong to the family of NAD(+)-dependent enzymes with deacetylase or mono-ADP-ribosyltransferase activity. These enzymes are responsible for processes of DNA repair or recombination, chromosomal stability and gene transcription. In mammals, sirtuins occur in seven varieties, from 1 to 7 (SIRT1-SIRT7), differing among themselves with location. SIRT1, the best known variety, exerts its effects on proteins via NAD(+) coenzymes, being thus associated with cellular energetic metabolism and the 'red-ox' state. Its deficits are, among others, concomitant with stressful situations and associated with pathophysiologies of many medical conditions, including diabetes mellitus, cardiovascular diseases, neurodegenerative syndromes and kidney diseases. In kidney disorders, it promotes (stimulates) the survival of cells in an affected kidney by modulating their responses to various stress stimuli, takes part in arterial blood pressure control, protects against cellular apoptosis in renal tubules by catalase induction and triggers autophagy. More and more available in vitro and in vivo data indicate SIRT1 activity to be oriented, among others, towards nephroprotection. Thus, SIRT1 may become a novel element in the therapy of age-related renal diseases, including diabetic nephropathy. PMID- 23793838 TI - A fluorescence 'turn-on' chemodosimeter for selective detection of Nb5+ ions in mixed aqueous media. AB - Based on the mechanism of hydrolytic cleavage of Schiff bases, a 1-aminopyrene based fluorescent chemodosimeter, 3, is reported for the selective detection of Nb(5+) ions in solution. Among the 21 metal ions tested, the chemodosimeter shows a selective fluorogenic 'turn-on' response toward Nb(5+) ions in mixed aqueous media. PMID- 23793840 TI - An exploration of family problem-solving and affective involvement as moderators between disease severity and depressive symptoms in adolescents with inflammatory bowel disease. AB - Little is known about how family functioning relates to psychosocial functioning of youth with inflammatory bowel disease (IBD). The study aim was to examine family problem solving and affective involvement as moderators between adolescent disease severity and depressive symptoms. Participants were 122 adolescents with IBD and their parents. Measures included self-reported and parent-reported adolescent depressive symptoms, parent-reported family functioning, and physician completed measures of disease severity. Disease severity was a significant predictor of adolescent-reported depressive symptoms, but not parent-reported adolescent depressive symptoms. Family affective involvement significantly predicted parent-reported adolescent depressive symptoms, while family problem solving significantly predicted adolescent self-report of depressive symptoms. Neither affective involvement nor problem-solving served as moderators. Family affective involvement may play an important role in adolescent emotional functioning but may not moderate the effect of disease severity on depressive symptoms. Research should continue to examine effects of family functioning on youth emotional functioning and include a sample with a wider range of disease severity to determine if interventions aimed to enhance family functioning are warranted. PMID- 23793841 TI - [Differential indications for current endoprosthesis systems of the shoulder]. AB - Modern shoulder prostheses adapt to the size, inclination, posterior offset and retrotorsion of the shoulder anatomy. Typical implants are cup prostheses for surface replacement, stemless prostheses that anchor in metaphyseal bone, anatomical prostheses using stems of different lengths, and last but not least reverse prostheses. The main reasons for implantation of shoulder prostheses are primary osteoarthritis, posttraumatic and rheumatoid arthritis, avascular necrosis, arthritis of instability and cuff defect arthropathy.Anatomical hemiprostheses should be used only if the glenoid is intact as total prostheses are functionally better as soon as the arthritis involves the glenoid. Conventional stems are cemented most of the time and cemented glenoids that are convex on the back are standard. Stemless prostheses were developed for posttraumatic indications and can often replace stemmed designs if the bone quality is good. Reverse prostheses were developed for the treatment of cuff tear arthropathies but if used as a revision implant complication rates rise and survival time is shorter. PMID- 23793842 TI - [Endoprosthesis infections of the shoulder: diagnosis and therapy algorithm]. AB - Periprosthetic shoulder joint infections are encountered by orthopedic surgeons mainly as complex situations which are highlighted by difficult treatment modalities. In a confirmed infection the general therapeutic principle is a surgical procedure. Several strategies orientate on the cause of an infection, the time course of postoperative symptoms, the pathogenicity of the isolated species and the specific comorbidities of the patient. An arthroscopic joint lavage with open debridement and component change may suffice in selected acute cases whereas a two-stage revision augmented by an articulating antibiotic spacer is mandatory in chronic infections. Early recognition is of paramount importance in order to prevent further spread, sepsis or even fatal outcome. Low grade infections are challenging conditions in terms of diagnosis and treatment. This article summarizes the principles of current classification, detection and treatment strategies for periprosthetic shoulder joint infections. PMID- 23793843 TI - [Glenoid replacement for omarthritis : indications, technique, results and new developments]. AB - In anatomical shoulder arthroplasty glenoid replacement is a critical point. Although total shoulder arthroplasty (TSA) provides better functional and pain results than hemi shoulder arthroplasty (HSA) there is great reluctance to implant a glenoid. For successful glenoid replacement it is necessary to preoperatively evaluate clear indications for glenoid replacement. Planning is a crucial point and has to be done thoroughly. The gold standard is an all polyethylene cemented glenoid. The implantation technique is most important to obtain an excellent and long-term result without complications. Significant key factors are preservation of the subchondral bone and an anatomical reconstruction of the glenoid. It seems that after a period of 10 years the loosening rate of glenoids increases and revisions rates rise. Therefore there is a high demand to develop new implants and a need for improved and convertible glenoids with better modularity and alternative options for fixation. PMID- 23793844 TI - Smad1 stabilization and delocalization in response to the blockade of BMP activity. AB - Signaling at the plasma membrane receptors is generally terminated by some form of feedback regulation, such as endocytosis and/or degradation of the receptors. BMP-Smad1 signaling can also be attenuated by BMP-induced expression of the inhibitory Smads, which are negative regulators of Smad1 transactivation activity and/or BMP antagonists. Here, we report on a novel Smad1 regulation mechanism that occurs in response to the blockade of BMP activity. Lowering the serum levels or antagonizing BMPs with noggin led to upregulation of Smad1 at the protein level in several cell lines, but not to upregulation of Smad5, Smad8 or Smad2/3. The Smad1 upregulation occurs at the level of protein stabilization. Upregulated Smad1 was relocalized to the perinuclear region. These alterations seem to affect the dynamics and amplitude of BMP2-induced Smad1 reactivation. Our findings indicate that depleting or antagonizing BMPs leads to Smad1 stabilization and relocalization, thus revealing an unexpected regulatory mechanism for BMP-Smad1 signaling. PMID- 23793845 TI - Role of inflammasomes and their regulators in prostate cancer initiation, progression and metastasis. AB - Prostate cancer is one of the main cancers that affect men, especially older men. Though there has been considerable progress in understanding the progression of prostate cancer, the drivers of its development need to be studied more comprehensively. The emergence of resistant forms has also increased the clinical challenges involved in the treatment of prostate cancer. Recent evidence has suggested that inflammation might play an important role at various stages of cancer development. This review focuses on inflammasome research that is relevant to prostate cancer and indicates future avenues of study into its effective prevention and treatment through inflammasome regulation. With regard to prostate cancer, such research is still in its early stages. Further study is certainly necessary to gain a broader understanding of prostate cancer development and to create successful therapy solutions. PMID- 23793846 TI - Incidence and etiology of acute kidney injury in Southern India: correspondence. PMID- 23793847 TI - A HPLC-based glycoanalytical protocol allows the use of natural O-glycans derived from glycoproteins as substrates for glycosidase discovery from microbial culture. AB - Many disorders are characterised by changes in O-glycosylation, but analysis of O glycosylation has been limited by the availability of specific endo- and exo glycosidases. As a result chemical methods are employed. However, these may give rise to glycan degradation, so therefore novel O-glycosidases are needed. Artificial substrates do not always identify every glycosidase activity present in an extract. To overcome this, an HPLC-based protocol for glycosidase identification from microbial culture was developed using natural O-glycans and O glycosylated glycoproteins (porcine stomach mucin and fetuin) as substrates. O glycans were released by ammonia-based beta-elimination for use as substrates, and the bacterial culture supernatants were subjected to ultrafiltration to separate the proteins from glycans and low molecular size molecules. Two bacterial cultures, the psychrotroph Arthrobacter C1-1 and a Corynebacterium isolate, were examined as potential sources of novel glycosidases. Arthrobacter C1-1 culture contained a beta-galactosidase and N-acetyl-beta-glucosaminidase when assayed using 4-methylumbelliferyl substrates, but when defucosylated O glycans from porcine stomach mucin were used as substrate, the extract did not cleave beta-linked galactose or N-acetylglucosamine. Sialidase activity was identified in Corynebacterium culture supernatant, which hydrolysed sialic acid from fetuin glycans. When both culture supernatants were assayed using the glycoproteins as substrate, neither contained endoglycosidase activity. This method may be applied to investigate a microbial or other extract for glycosidase activity, and has potential for scale-up on high-throughput platforms. PMID- 23793848 TI - LGR5 is a proneural factor and is regulated by OLIG2 in glioma stem-like cells. AB - The biological functional roles of LGR5 (leucine-rich repeat containing G protein coupled receptor 5, also known as GPR49), a novel potential marker for stem-like cells in glioblastoma (GSCs), is poorly acknowledged. Here, we demonstrated that LGR5 was detected in glioblastoma tissues and GSCs. Bioinformatics analysis revealed that LGR5 is closely related to neurogenesis and neuronal functions, and preferentially expressed in Proneural subtype of GBMs. Furthermore, LGR5 is regulated by Proneural factor OLIG2, which is important for both neurogenesis and GSC maintenance. Biological experiments in GSC cells validated the bioinformatics analysis results and revealed that LGR5 regulated the tumor sphere formation capacity, an important stem cell property for GSCs. Therefore, LGR5 expression may be functionally correlated with the neurogenic competence, and be regulated by OLIG2 in GSCs. PMID- 23793850 TI - Presumed air by vitrectomy embolisation (PAVE) a potentially fatal syndrome. AB - BACKGROUND: Since first being reported in the ophthalmology literature in 2010, three cases (one fatal) of suspected venous air embolism (VAE) during vitrectomy have received little notice, and the vitrectomy/VAE connection has been described as unproven. We investigated the ability of air to exit the eye through vortex veins after accidental suprachoroidal air infusion. METHODS: Vitrectomy was performed on four donor eyes. Unsutured cannulas were partially withdrawn during air fluid exchange, producing choroidal detachments that emulated accidental suprachoroidal air infusion from a slipping cannula. Eyes with and without clamping of the vortex vein stumps were partially submerged in a water bath. RESULTS: Extensive choroidal detachment was created in all eyes during air infusion. All eyes with open vortex veins demonstrated rapid air extravasation/bubbling. An eye with clamped vortex vein stumps showed no air extravasation until the clamps were removed. CONCLUSIONS: When combined with existing clinical reports of suspected VAE in the eyes of living patients during ocular air fluid exchange, this experiment justifies recognition of presumed air by vitrectomy embolisation (PAVE) as a rare but potentially fatal vitrectomy complication. Simple surgical precautions can change PAVE from a 'rare event' to a 'never event', beginning with acknowledgment of its existence. PMID- 23793851 TI - Surgical and functional outcomes in bilateral exotropic Duane's retraction syndrome. AB - AIMS: To evaluate the outcomes following surgery on patients with bilateral Duane's Retraction Syndrome (DRS) associated with exotropia or exophoria. METHODS: Eleven consecutive patients with exotropic DRS were identified in a 10 year period. The case notes were reviewed, and data was analysed to evaluate the results following surgery. The preoperative and postoperative outcomes were evaluated for the angle of deviation in primary position, abnormal head posture, stereovision for near-fixation and horizontal ocular ductions. RESULTS: All patients had a significant improvement in their angle of deviation in primary position, and 82% had a residual angle within 10 prism dioptres of orthotropia/phoria (p<0.001). For those patients with abnormal head posture, 86% resolved or improved. The postoperative cumulative horizontal ocular ductions measured less in nine patients by an average of 1.5 units. Pre-existing near stereovision improved in 83% of the patients by an average of 40" arc. CONCLUSIONS: Surgery for bilateral exotropic DRS resulted in an improvement in the primary position angle and abnormal head posture. Patients demonstrated reduced cumulative horizontal ocular ductions restrictions and enhanced near stereovision. This case series on exotropic bilateral DRS provides further evidence into successful postoperative surgical and functional outcomes. PMID- 23793849 TI - Fructose-containing sugars, blood pressure, and cardiometabolic risk: a critical review. AB - Excessive fructose intake from high-fructose corn syrup (HFCS) and sucrose has been implicated as a driving force behind the increasing prevalence of obesity and its downstream cardiometabolic complications including hypertension, gout, dyslidpidemia, metabolic syndrome, diabetes, and non-alcoholic fatty liver disease (NAFLD). Most of the evidence to support these relationships draws heavily on ecological studies, animal models, and select human trials of fructose overfeeding. There are a number of biological mechanisms derived from animal models to explain these relationships, including increases in de novo lipogenesis and uric acid-mediated hypertension. Differences between animal and human physiology, along with the supraphysiologic level at which fructose is fed in these models, limit their translation to humans. Although higher level evidence from large prospective cohorts studies has shown significant positive associations comparing the highest with the lowest levels of intake of sugar sweetened beverages (SSBs), these associations do not hold true at moderate levels of intake or when modeling total sugars and are subject to collinearity effects from related dietary and lifestyle factors. The highest level of evidence from controlled feeding trials has shown a lack of cardiometabolic harm of fructose and SSBs under energy-matched conditions at moderate levels of intake. It is only when fructose-containing sugars or SSBs are consumed at high doses or supplement diets with excess energy that a consistent signal for harm is seen. The available evidence suggests that confounding by excess energy is an important consideration in assessing the role of fructose-containing sugars and SSBs in the epidemics of hypertension and other cardiometabolic diseases. PMID- 23793852 TI - Comparison of the Heller-Toupet procedure with the Heller-Dor procedure in patients who underwent laparoscopic surgery for achalasia. AB - PURPOSE: We compared the outcomes of Toupet fundoplication with those of Dor fundoplication in patients with achalasia who underwent laparoscopic Heller myotomy. METHODS: Seventy-two patients with achalasia and dysphagia underwent laparoscopic Heller myotomy with fundoplication performed by a single surgeon. Heller-Toupet fundoplication (HT) was performed in 30 patients, and Heller-Dor fundoplication (HD) was done in 42. The symptoms and esophageal function were retrospectively assessed in both groups. RESULTS: The dysphagia scores significantly decreased after both the HT and HD procedures, and did not differ significantly between them. The incidence of reflux symptoms was significantly higher after HT (26.7%) than after HD (7.1%). The lower esophageal sphincter (LES) resting pressure significantly decreased after both HT and HD. Upon endoscopic examination, the incidence of reflux esophagitis was significantly higher after HT (38.5%) than after HD (8.8%). During esophageal pH monitoring, the fraction time at pH <4 was similar in the patients who underwent HT and HD. CONCLUSIONS: Laparoscopic Heller myotomy provided significant improvements in the dysphagia symptoms of achalasia patients, regardless of the type of fundoplication. The incidences of reflux symptoms and reflux esophagitis were higher after HT than after HD. However, the results of pH monitoring did not differ between the procedures. PMID- 23793853 TI - Polysaccharide K and its rapidly emerging role in the treatment of systemic malignancies. PMID- 23793854 TI - Comment on women in surgery: little change in gender equality in Japanese medical societies over the past 3 years. PMID- 23793855 TI - Gluconacetobacter tumulisoli sp. nov., Gluconacetobacter takamatsuzukensis sp. nov. and Gluconacetobacter aggeris sp. nov., isolated from Takamatsuzuka Tumulus samples before and during the dismantling work in 2007. AB - Ten strains of Gram-stain-negative, rod-shaped, non-spore-forming bacteria were isolated from the burial mound soil collected before the dismantling and samples collected during the dismantling work on the Takamatsuzuka Tumulus in Asuka village, Nara Prefecture, Japan in 2007. On the basis of the 16S rRNA gene sequence analysis of the isolates, they were accommodated in the genus Gluconacetobacter (class Alphaproteobacteria) and can be separated into four groups within the cluster containing the genus Gluconacetobacter. One of the groups demonstrated a phylogenetic position identical to that of Gluconacetobacter asukensis, which was isolated from small holes on plaster walls of the stone chamber interior of Kitora Tumulus in Asuka village, Nara Prefecture, Japan. The remaining three groups consisted of novel lineages within the genus Gluconacetobacter. A total of four isolates were selected from each group and carefully identified using a polyphasic approach. The isolates were characterized on the basis of their possessing Q-10 as the major ubiquinone system and C18 : 1omega7c (58.5-65.2 %) as the predominant fatty acid. A DNA-DNA hybridization test was used to determine that the three lineages represented novel species, for which the names Gluconacetobacter tumulisoli sp. nov., Gluconacetobacter takamatsuzukensis sp. nov. and Gluconacetobacter aggeris sp. nov. are proposed. The type strains are T611xx-1-4a(T) ( = JCM 19097(T) = NCIMB 14861(T)), T61213-20-1a(T) ( = JCM 19094(T) = NCIMB 14859(T)) and T6203-4-1a(T) ( = JCM 19092(T) = NCIMB 14860(T)), respectively. PMID- 23793856 TI - Planktomarina temperata gen. nov., sp. nov., belonging to the globally distributed RCA cluster of the marine Roseobacter clade, isolated from the German Wadden Sea. AB - Four heterotrophic bacterial strains belonging to the globally distributed marine RCA (Roseobacter clade-affiliated) cluster (family Rhodobacteraceae, class Alphaproteobacteria) were obtained from coastal seawater samples. Strain RCA23(T) was isolated from a 10(-7) dilution culture inoculated with seawater from the German Wadden Sea (southern North Sea), reflecting the high abundance of RCA bacteria in this habitat. Strains IMCC1909, IMCC1923 and IMCC1933 were isolated from diluted seawater (10(-3)) of the Yellow Sea, South Korea. Based on 16S rRNA gene sequence comparison, Octadecabacter antarcticus 307(T) is the closest described relative of the RCA strains, with 95.4-95.5 % sequence similarity. Cells of RCA23(T), IMCC1909, IMCC1923 and IMCC1933 are small motile rods requiring sodium ions. Optimal growth of RCA23(T) occurs at 25 degrees C and within a very narrow pH range (pH 7-8, optimum pH 7.5). The DNA G+C base content of RCA23(T) is 53.67 mol%. The major respiratory lipoquinone is ubiquinone-10 (Q 10) and the dominant fatty acids (>1 %) are 12 : 1 3-OH, 16 : 1omega7c, 16 : 0, 18 : 1omega7c, 18 : 0 and 11-methyl 18 : 1omega7c. The polar lipid pattern indicated the presence of phosphatidylglycerol, two unidentified aminolipids and two unidentified phospholipids. On marine agar, RCA23(T) forms non-pigmented, transparent to light beige, small (<1 mm), circular, convex colonies. Strain RCA23(T) harbours all genes for the production of bacteriochlorophyll a (BChl a). Genes encoding the light-harvesting reaction centre of BChl a (pufM) were identified in all RCA strains. No visible pigmentation was observed for any of the strains under laboratory conditions, but spectrophotometric analysis revealed weak production of BChl a by RCA23(T). Morphological, physiological and genotypic features of strain RCA23(T) suggest that it represents a novel species of a new genus within the Rhodobacteraceae, for which we propose the name Planktomarina temperata gen. nov., sp. nov., described previously by Giebel et al. [ISME J 5 (2011), 8-19] as 'Candidatus Planktomarina temperata'. The type strain of Planktomarina temperata is RCA23(T) ( = DSM 22400(T) = JCM 18269(T)). PMID- 23793857 TI - Prevotella jejuni sp. nov., isolated from the small intestine of a child with coeliac disease. AB - Five obligately anaerobic, Gram-stain-negative, saccharolytic and proteolytic, non-spore-forming bacilli (strains CD3 : 27, CD3 : 28(T), CD3 : 33, CD3 : 32 and CD3 : 34) are described. All five strains were isolated from the small intestine of a female child with coeliac disease. Cells of the five strains were short rods or coccoid cells with longer filamentous forms seen sporadically. The organisms produced acetic acid and succinic acid as major metabolic end products. Phylogenetic analysis based on comparative 16S rRNA gene sequence analysis revealed close relationships between CD3 : 27, CD3 : 28(T) and CD3 : 33, between CD3 : 32 and Prevotella histicola CCUG 55407(T), and between CD3 : 34 and Prevotella melaninogenica CCUG 4944B(T). Strains CD3 : 27, CD3 : 28(T) and CD3 : 33 were clearly different from all recognized species within the genus Prevotella and related most closely to but distinct from P. melaninogenica. Based on 16S rRNA, RNA polymerase beta-subunit (rpoB) and 60 kDa chaperonin protein subunit (cpn60) gene sequencing, and phenotypic, chemical and biochemical properties, strains CD3 : 27, CD3 : 28(T) and CD3 : 33 are considered to represent a novel species within the genus Prevotella, for which the name Prevotella jejuni sp. nov. is proposed. Strain CD3 : 28(T) ( = CCUG 60371(T) = DSM 26989(T)) is the type strain of the proposed novel species. All five strains were able to form homologous aggregates, in which tube-like structures were connecting individual bacteria cells. The five strains were able to bind to human intestinal carcinoma cell lines at 37 degrees C. PMID- 23793858 TI - Nationwide prospective study on readmission after umbilical or epigastric hernia repair. AB - PURPOSE: The primary aim of the present study was to investigate risk factors for readmission after elective umbilical and epigastric hernia repair and secondarily to evaluate causes for readmission. METHODS: All patients with elective umbilical or epigastric hernias registered in The Danish Hernia Database during January 2007-January 2011 were included. A 100 % 30-day follow-up was obtained by merging with administrative data from The Danish National Patient Register. RESULTS: A total of 6,783 umbilical and epigastric hernia repairs were included (open = 5,634; laparoscopic = 1,149). Readmissions caused by surgical and medical complications related to the hernia repair were observed in 3.6 and 1.5 % of patients, respectively. Surgical complications were mainly due to pain and wound complications, whereas medical complications were mainly cardiovascular, pulmonary, and renal complications. There were no significant differences in surgical or medical complication rates and in risk factors for readmission between open and laparoscopic repair, P >= 0.229. After open repair, independent risk factors for readmission were umbilical hernia repair (vs epigastric repair) (OR = 1.5, 95 % CI 1.1-2.1), hernia defects >2 cm (OR = 1.7, 95 % CI 1.2-2.5), mesh reinforcement (OR = 1.3, 95 % CI 1.0-1.7), and tacked mesh fixation (OR = 2.6, 95 % CI 1.1-6.0). After laparoscopic repair, female gender was the only independent risk factor for readmission (OR = 1.7, 95 % CI 1.1-2.7). CONCLUSION: The risk for 30-day readmission after umbilical or epigastric hernia repairs was mainly because of surgical complications. Open mesh repair reduced the risk for readmission in open repairs; no specific approach was found to reduce readmission after laparoscopic repair. PMID- 23793859 TI - An unusual cause of chronic anemia and abdominal pain caused by transmural mesh migration in the small bowel after laparoscopic incisional hernia repair. AB - Mesh repair of incisional hernia is recommended to reduce recurrence. Recognized complications include mesh infection and fistula. Composite meshes with antiadhesive barriers were designed for intraperitoneal placement to reduce adhesion formation and fistulization to the viscera. Transmural mesh migration is a rare complication of hernia repair with composite mesh and can be present with a variety of symptoms. We report an interesting case of transmural mesh migration into the small bowel presenting with chronic microcytic anemia and abdominal pain 5 years after laparoscopic incisional hernia repair with a composite polypropylene/ePTFE mesh. PMID- 23793860 TI - Post-operative internal hernia through an orifice underneath the right common iliac artery after Dargent's operation. AB - We report the case of a 39-year-old woman with ileus resulting from a small bowel incarceration underneath the right common iliac artery. The patient had a history of a radical trachelectomy with laparoscopic pelvic lymphadenectomy ("Dargent's operation") for cervical carcinoma. After dissection of the iliac vessels, a small bowel loop could slide underneath the common iliac artery. The hernia was closed by gluing a collagen patch over the right common iliac artery onto the retroperitoneal cavity. To our knowledge, such a case has not previously been reported in the medical literature. PMID- 23793861 TI - Dissecting aneurysms of posterior communicating artery itself: anatomical, diagnostic, clinical, and therapeutical considerations. AB - Posterior communicating artery (PCoA) itself is an unusual location for intracranial aneurysms in that isolated dissections or dissecting aneurysms are extremely rare. In the way of correct diagnosis of dissecting aneurysms of PCoA itself, a proper understanding of (1) the anatomy of the PCoA and its perforator branches, (2) some particular diagnostic features, and (3) related clinical aspects is of significant importance. Although there are no established treatment strategies for this particular type of aneurysms, the endovascular approach might be considered as a plausible one. In this paper, our scope was to report five cases with dissecting aneurysm of the PCoA itself and to discuss this rare vascular pathology from anatomical, diagnostic, clinical, and therapeutical perspectives. PMID- 23793863 TI - Antifungal activities of diphenyl diselenide alone and in combination with fluconazole or amphotericin B against Candida glabrata. AB - Here, we evaluated combinations of diphenyl diselenide [(PhSe)2] with fluconazole and amphotericin B in a checkerboard assay against clinical Candida glabrata strains. Minimal inhibitory concentration (geometric mean) ranged from 0.25 to >64 (5.16 MUg/mL) for (PhSe)2, 1 to 32 (5.04 MUg/mL) for fluconazole and 0.06 to 0.5 (0.18 MUg/mL) for amphotericin B. Synergistic (76.66 %) and indifferent (23.34 %) interactions were observed for (PhSe)2 + amphotericin B combination. (PhSe)2 + fluconazole combination demonstrated indifferent (50 %) and antagonistic (40 %) interactions, whereas synergistic interactions were observed in 10 % of the isolates. New experimental in vivo protocols are necessary and will promote a better understanding of the antimicrobial activity of (PhSe)2 against C. glabrata and its use as an adjuvant therapy with antifungal agents. PMID- 23793864 TI - Selective production of 2,3-butanediol and acetoin by a newly isolated bacterium Klebsiella oxytoca M1. AB - A newly isolated bacterium, designated as Klebsiella oxytoca M1, produced 2,3 butanediol (2,3-BDO) or acetoin selectively as a major product depending on temperature in a defined medium. K. oxytoca M1 produced 2,3-BDO mainly (0.32~0.34 g/g glucose) at 30 degrees C while acetoin was a major product (0.32~0.38 g/g glucose) at 37 degrees C. To investigate factors affecting product profiles according to temperature, the expression level of acetoin reductase (AR) that catalyzes the conversion of acetoin to 2,3-BDO was analyzed using crude protein extracted from K. oxytoca M1 grown at 30 and 37 degrees C. The AR expression at 37 degrees C was 12.8-fold lower than that at 30 degrees C at the stationary phase and reverse transcription PCR (RT-PCR) analysis of the budC (encoding AR) was also in agreement with the AR expression results. When AR was overexpressed using K. oxytoca M1 harboring pUC18CM-budC, 2,3-BDO became a major product at 37 degrees C, indicating that the AR expression level was a key factor determining the major product of K. oxytoca M1 at 37 degrees C. The results in this study demonstrate the feasibility of using K. oxytoca M1 for the production of not only 2,3-BDO but also acetoin as a major product. PMID- 23793862 TI - Relationship between thrombus attenuation and different stroke subtypes. AB - INTRODUCTION: More insights in the etiopathogenesis of thrombi could be helpful in the treatment of patients with acute ischemic stroke. The aim of our study was to determine the relationship between presence of a hyperdense vessel sign and thrombus density with different stroke subtypes. METHODS: We included 123 patients with acute ischemic anterior circulation stroke and a visible occlusion on CT-angiography caused by cardioembolism (n = 53), large artery atherosclerosis (n = 55), or dissection (n = 15). Presence or absence of a hyperdense vessel sign was assessed and thrombus density was measured in Hounsfield Units (HU) on non contrast 1 mm thin slices CT. Subsequently, occurrence of hyperdense vessel sign and thrombus density (absolute HU and rHU (=HU thrombus/HU contralateral)) were related with stroke subtypes. RESULTS: The presence of hyperdense vessel signs differed significantly among subtypes and was found in 45, 64 and 93 % of patients with cardioembolism, large artery atherosclerosis and dissection, respectively (p = 0.003). The mean HU and rHU (+95 % CI) of the thrombi in all vessels were respectively 56.1 (53.2-59.0) and 1.39 (1.33-1.45) in cardioembolism, 64.6 (62.2-66.9) and 1.59 (1.54-1.64) in large artery atherosclerosis and 76.4 (73.0-79.8) and 1.88 (1.79-1.97) in dissection (p < 0.0001). We found the same significant ranking order in the density of thrombi with hyperdense vessel signs (mean HU and rHU (+95 % CI), respectively): cardioembolism 61.3 (57.4-65.3) and 1.49 (57.4-65.3); large artery atherosclerosis 67.3 (64.9-69.7) and 1.65 (1.58-1.71); dissection 76.4 (72.6 80.1) and 1.89 (1.79-1.99, p < 0.0001). CONCLUSION: Presence of a hyperdense vessel sign and thrombus density are related to stroke subtype. PMID- 23793865 TI - Dichloroacetate induces tumor-specific radiosensitivity in vitro but attenuates radiation-induced tumor growth delay in vivo. AB - BACKGROUND: Inhibition of pyruvate dehydrogenase kinase (PDK) by dichloroacetate (DCA) can shift tumor cell metabolism from anaerobic glycolysis to glucose oxidation, with activation of mitochondrial activity and chemotherapy-dependent apoptosis. In radiotherapy, DCA could thus potentially enhance the frequently moderate apoptotic response of cancer cells that results from their mitochondrial dysfunction. The aim of this study was to investigate tumor-specific radiosensitization by DCA in vitro and in a human tumor xenograft mouse model in vivo. MATERIALS AND METHODS: The interaction of DCA with photon beam radiation was investigated in the human tumor cell lines WIDR (colorectal) and LN18 (glioma), as well as in the human normal tissue cell lines HUVEC (endothelial), MRC5 (lung fibroblasts) and TK6 (lymphoblastoid). Apoptosis induction in vitro was assessed by DAPI staining and sub-G1 flow cytometry; cell survival was quantified by clonogenic assay. The effect of DCA in vivo was investigated in WIDR xenograft tumors growing subcutaneously on BALB/c-nu/nu mice, with and without fractionated irradiation. Histological examination included TUNEL and Ki67 staining for apoptosis and proliferation, respectively, as well as pinomidazole labeling for hypoxia. RESULTS: DCA treatment led to decreased clonogenic survival and increased specific apoptosis rates in tumor cell lines (LN18, WIDR) but not in normal tissue cells (HUVEC, MRC5, TK6). However, this significant tumor-specific radiosensitization by DCA in vitro was not reflected by the situation in vivo: The growth suppression of WIDR xenograft tumors after irradiation was reduced upon additional DCA treatment (reflected by Ki67 expression levels), although early tumor cell apoptosis rates were significantly increased by DCA. This apparently paradoxical effect was accompanied by a marked DCA-dependent induction of hypoxia in tumor-tissue. CONCLUSION: DCA induced tumor specific radiosensitization in vitro but not in vivo. DCA also induced development of hypoxia in tumor tissue in vivo. Further investigations relating to the interplay between tumor cell metabolism and tumor microenvironment are necessary to explain the limited success of metabolic targeting in radiotherapy. PMID- 23793866 TI - [Risk of venous thromboembolism in patients with cancer treated with cisplatin: A systematic review and meta-analysis]. PMID- 23793867 TI - Picomolar detection of mercuric ions by means of gold-silver core-shell nanorods. AB - We report an ultrasensitive and selective probe for detection of mercuric ions using gold-silver core-shell nanorods as the substrate of surface-enhanced Raman scattering. The detection limit of this probe for mercuric ions can be as low as 1 pM. The efficiency of this probe in complex samples was evaluated by allowing detection of spiked mercuric ions in river water and fish samples. PMID- 23793868 TI - Apoptotic process in cystic fibrosis cells. AB - Cystic fibrosis (CF) is a recessively inherited disease caused by genetic lesions in CF transmembrane conductance regulator (CFTR) gene. CF is characterized by exaggerated inflammation, progressive tissue damage, and chronic bacterial colonization, mainly in the respiratory tract. The mechanisms underlying these pathological changes are increasingly well understood. However, apoptotic dysfunction in CF disease is still debated since studies report controversial results. Nonetheless, it is clear that apoptosis participates to onset of pathology and concerns various types of cells with variable susceptibility. Apoptosis is a physiological process necessary for the preservation of homeostasis of epithelial organization and function for clearance of inflammatory cells. Increased susceptibility to apoptosis in epithelial cells and failed apoptosis in neutrophils would contribute to the self-perpetuating inflammatory cycle in CF. Also, retention of mutated CFTR in the endoplasmic reticulum participates to inflammation which may trigger apoptosis. Independently of the sensibility to apoptosis of CF cells, it has been shown that clearance of apoptotic cells, due in part to decrease in efferocytosis, is flawed and that accumulation of such cells may contribute to ongoing inflammation in CF patients. Despite great advance in understanding CF pathophysiology, there is still no cure for the disease. The most recent therapeutic strategies are directed to target CFTR protein using cell and gene therapy as well as pharmacotherapy. PMID- 23793869 TI - Genome-wide transcriptional analysis of apoptosis-related genes and pathways regulated by H2AX in lung cancer A549 cells. AB - Histone H2AX is a novel tumor suppressor protein and plays an important role in apoptosis of cancer cells. However, the role of H2AX in lung cancer cells is unclear. The detailed mechanism and epigenetic regulation by H2AX remain elusive in cancer cells. We showed that H2AX was involved in apoptosis of lung cancer A549 cells as in other tumor cells. Knockdown of H2AX strongly suppressed apoptosis of A549 cells. We clarified the molecular mechanisms of apoptosis regulated by H2AX based on genome-wide transcriptional analysis. Microarray data analysis demonstrated that H2AX knockdown in A549 cells affected expression of 3,461 genes, including upregulation of 1,435 and downregulation of 2,026. These differentially expressed genes were subjected to bioinformatic analysis for exploring biological processes regulated by H2AX in lung cancer cells. Gene ontology analysis showed that H2AX affected expression of many genes, through which, many important functions including response to stimuli, gene expression, and apoptosis were involved in apoptotic regulation of lung cancer cells. Pathway analysis identified the mitogen-activated protein kinase signaling pathway and apoptosis as the most important pathways targeted by H2AX. Signal transduction pathway networks analysis and chromatin immunoprecipitation assay showed that two core genes, NFKB1 and JUN, were involved in apoptosis regulated by H2AX in lung cancer cells. Taken together, these data provide compelling clues for further exploration of H2AX function in cancer cells. PMID- 23793870 TI - The effects of rebate contracts on the health care system. AB - Group purchasing organizations gain increasing importance with respect to the supply of pharmaceutical products and frequently use multiple, exclusive or partially exclusive rebate contracts to exercise market power. Based on a Hotelling model of horizontal and vertical product differentiation, we examine the controversy around whether a superior rebate scheme exists, as far as consumer surplus, firms' profits and total welfare are concerned. We find that firms clearly prefer partially exclusive over multiple, and multiple over exclusive rebate contracts. In contrast, no rebate form exists that lowers total costs per se for the consumers or maximizes total welfare. PMID- 23793871 TI - [Neurological disorders related to vitamin B12 deficiency in prisons in Guinea: a 22-case study]. AB - Neurological disorders related to vitamin B12 deficiency are common in prisons of tropical Africa. We collected 22 cases (20 men and 2 women). They all showed vitamin B12 deficiency associated with neurological signs that were represented by sclerosis combined with bone marrow (n = 9), peripheral neuropathy (n = 6), cerebellar syndrome (n = 2), a pyramidal syndrome of the lower limbs (n = 4) and optic neuropathy (n = 1). Laboratory tests showed a mean hemoglobin concentration of 7.2 +/- 1.5 g/dl, mean 104 +/- 28 fl, macrocytic anemia in 10 patients. Biermer's disease was identified in 9 patients, 3 patients showed the syndrome of non dissociation of vitamin B12, a gastrectomy in 2 patients and no etiology was identified in 8 patients. PMID- 23793873 TI - Fractional flow reserve as the reference standard for myocardial perfusion studies: fool's gold? PMID- 23793872 TI - Subbasal nerve morphology, corneal sensation, and tear film evaluation after refractive femtosecond laser lenticule extraction. AB - BACKGROUND: The purpose of this study was to compare corneal subbasal nerve morphology, corneal sensation, and tear film parameters after femtosecond lenticule extraction (FLEX) and small-incision lenticule extraction (SMILE). METHODS: A prospective, randomized, single-masked, paired-eye design clinical trial of 35 patients treated for moderate to high myopia with FLEX in one eye and SMILE in the other. In both techniques, an intrastromal lenticule was cut by a femtosecond laser and manually extracted. In FLEX, a LASIK-like flap allowed removal of the lenticule, whereas in SMILE, it was removed through a small incision. In-vivo confocal microscopy was used to acquire images of the central corneal subbasal nerve plexus, from which nerve density, total nerve number, and nerve tortuosity were analyzed. Corneal sensation was measured using Cochet Bonnet esthesiometry. A visual analog scale, tear osmolarity, non-invasive tear film break-up time (keratograph) tear meniscus height (anterior segment OCT), Schirmer's test, and fluorescein tear film break-up time were used to evaluate tear film and ocular surface symptoms. Patients were examined before and 6 months after surgery. RESULTS: There were no statistically significant differences in baseline parameters between FLEX and SMILE (p > 0.050). With regard to changes from before to 6 months after surgery, mean reduction in subbasal nerve density was 14.22 +/- 6.24 mm/mm(2) in FLEX eyes, and 9.21 +/- 7.80 mm/mm(2) in SMILE eyes (p < 0.05). The total number of nerves decreased more in FLEX eyes than in SMILE eyes (p < 0.05). No change was found when comparing tortuosity (p > 0.05). Corneal sensation was reduced with 0.38 +/- 0.49 cm in FLEX eyes, and 0.10 +/- 0.34 cm in SMILE eyes (p < 0.01). No differences were found between FLEX and SMILE in tear film evaluation tests (p > 0.05). Significantly more patients felt postoperative foreign body sensation in the FLEX eye within the first days after surgery, as compared to the SMILE eye. CONCLUSIONS: Six months after surgery, the less invasive SMILE technique seemed better at sparing the central corneal nerves as compared to FLEX. Corneal sensation was only significantly reduced in FLEX eyes. There were no differences between FLEX and SMILE when comparing tear film evaluation tests 6 months after surgery. PMID- 23793874 TI - Supra-valvular aortic stenosis in a patient with homozygous familial hypercholesterolaemia. PMID- 23793875 TI - Left ventricular twist in left ventricular noncompaction. AB - AIMS: Left ventricular (LV) twist is an important component of systolic function. The effect of abnormal LV twist on adverse remodelling of the heart in left ventricular noncompaction (LVNC) is unknown. This study used speckle-tracking echocardiography to evaluate LV twist in patients with LVNC and determine whether abnormal LV twist is associated with more adverse LV remodelling. METHODS AND RESULTS: Clinical, echocardiographic, and myocardial deformation characteristics were prospectively compared between 60 subjects diagnosed with LVNC and 59 age matched healthy controls. Net instantaneous twist was defined as: peak apical rotation minus isochronous basal rotation. Normal rotation during systole was defined based on the 2010 ASE/EAE consensus document. Rigid body rotation (RBR) was determined present if the apex and base moved in the same direction during ejection. Rigid body rotation was found in 32 (53.3%) subjects with LVNC. The 28 subjects with LVNC and normal LV rotation had diminished apical rotation, basal rotation, and net twist compared with normal controls (P < 0.0001). Patients with LVNC and RBR had worse NYHA functional status (P < 0.0001), but similar echocardiographic indices of remodelling, ejection fraction, and strain parameters as those with LVNC and normal LV rotation. CONCLUSION: Left ventricular twist is diminished in subjects with LVNC and normal LV rotation. Rigid body rotation occurs in 53.3% of subjects with LVNC and is not associated with more adverse remodelling than subjects with LVNC and normal LV rotation. PMID- 23793876 TI - Changes in multidirectional LV strain in asymptomatic patients with type 2 diabetes mellitus: a 2-year follow-up study. AB - AIMS: Asymptomatic patients with diabetes mellitus (DM) and normal left ventricular (LV) ejection fraction (EF) may have LV dysfunction as assessed with speckle tracking echocardiography. Whether this subtle LV dysfunction may progress or not over time remains unknown. The present evaluation assessed changes in LV function with two-dimensional (2D) speckle tracking analysis in asymptomatic clinically stable patients with type 2 DM and normal LVEF after 2 year follow-up. METHODS AND RESULTS: A total of 112 asymptomatic patients with type 2 DM and normal LVEF (53 +/- 10 years, 59% men) were evaluated. Patients remained clinically stable between baseline and follow-up echocardiography. Conventional and 2D speckle tracking echocardiographic measurements were performed. Circumferential strain (CS) and longitudinal strain (LS) were measured to assess systolic function and strain rate during isovolumetric relaxation time (SR IVR) and peak transmitral early diastolic inflow strain rate (SR E) to assess diastolic function. After 2-year follow-up, a significant increase in the LV mass index and significant decrease in the E/A ratio were observed. Left ventricular ejection fraction remained unchanged (59 to 60%, P = 0.4). In contrast, 2D speckle tracking analysis demonstrated a significant impairment in CS (-19.7 +/- 4.0 to -18.9 +/- 3.8%, P < 0.001), LS (-17.2 +/- 2.3 to -16.9 +/- 2.7%, P = 0.022), and SR E (from 1.02 +/- 0.28 to 0.94 +/- 0.25 S(-1), P < 0.001). After adjusting for changes in the LV mass index, only changes in CS and SR E remained significant (P < 0.001 and P = 0.013, respectively). CONCLUSION: Asymptomatic patients with type 2 DM and normal LVEF may show mild progression of subclinical LV function assessed with 2D speckle tracking echocardiography. The prognostic implications of these mild changes warrant prospective evaluation. PMID- 23793877 TI - Acute myocardial ischemia due to septal branch occlusion of LAD: detection by computed tomography angiography. PMID- 23793878 TI - Prodromal angina is associated with myocardial salvage in acute ST-segment elevation myocardial infarction. AB - AIMS: Previous studies have shown that prodromal angina (PA) occurs frequently in acute myocardial infarction (MI) patients. However, the potential benefits of PA on ischaemic myocardial damage remain unknown. METHODS AND RESULTS: One-hundred and fifty-four patients with acute ST-segment elevation MI successfully treated with primary percutaneous coronary intervention (PPCI) were prospectively evaluated for new-onset PA in the week preceding infarction and other factors known to influence myocardial salvage. Cardiovascular magnetic resonance was performed 8 +/- 3 days after MI for the assessment of area-at-risk (AAR), MI size, myocardial haemorrhage (MH), microvascular obstruction (MO), and myocardial salvage index (MSI). Patients with PA (n = 60) compared with those without PA (n = 94) showed similar AAR but significantly smaller MI size leading to larger MSI (0.53 +/- 0.27 vs. 0.32 +/- 0.26, P < 0.001). Additionally, patients with PA had lower incidence of MH (18 vs. 33%) and MO (22 vs. 46%) than non-PA patients (both P < 0.05). At univariate analysis, higher MSI was associated with new-onset PA, lower myocardial oxygen consumption before PPCI, shorter time-to-PPCI, and higher post-procedural TIMI flow-grade. Neither collateral circulation nor medications administered before PPCI were associated to MSI. After correction for other covariates by multivariate analysis, new-onset PA remained significantly associated with MSI (beta-value: 0.352, P < 0.001). CONCLUSION: In acute MI patients, new-onset PA is associated with higher MSI independent of others factors known to influence jeopardized myocardium, as well as with less microvascular damage. PMID- 23793879 TI - Polymetallic complexes linked to a single-frame ligand: cooperative effects in catalysis. AB - In an eco-friendly development, catalysis represents the key approach for converting raw materials into valuable products, particularly convenient for multi-step transformations. Mimicking Nature seems the smartest way to design poly-functional assemblies leading to the design of "synergic" catalysts. This perspective focuses on the advances in the conception of polymetallic catalysts bonded to a single ligand frame. PMID- 23793880 TI - Mutational analysis of BCORL1 in the leukemic transformation of chronic myeloproliferative neoplasms. PMID- 23793881 TI - Difference in neointimal coverage at chronic stage between bare metal stent and sirolimus-eluting stent evaluated at stent-strut level by optical coherence tomography. AB - Compared with the bare metal stent (BMS), suppression of neointimal growth in the sirolimus-eluting stent (SES) reduced restenosis at the cost of more exposed struts that could impose the risk of stent thrombosis. The present study was conducted to analyze neointimal coverage patterns of stents at a strut-level after implantation of BMS or SES with the use of optical coherence tomography (OCT). We enrolled 35 patients and analyzed neointimal coverage of every strut from 41 stents (BMS: n = 8, SES: n = 33) by using OCT at follow-up of the stent implantation. All of the 371 struts from eight BMSs were covered with >=100 MUm of neointima, while 19.8 and 3.5% of 3,478 struts from 33 SESs were uncovered (neointimal thickness of <10 MUm) and malapposed, respectively. The histogram of neointimal thickness showed basically normal distribution in BMS but skewed in SES. No regional difference in neointimal thickness was observed in BMS (proximal, 535.7 +/- 25.2 MUm; body, 532.4 +/- 17.0 MUm; distal, 485.8 +/- 27.0 MUm). In SES, however, the body segment showed thinner neointima [median 40 MUm (interquartile range (IQR) 10-90 MUm)] than proximal [60 MUm (IQR 10-140 MUm), p < 0.001] or distal [50 MUm (IQR 10-110 MUm), p < 0.001] segment, while uncovered and malapposed struts were more frequent in the proximal and body segments. In conclusion, SES, compared with BMS, showed more suppressed neointimal growth with regional variation: neointimal thickness was the least in the body part while the ratio of exposed and malapposed struts was minimal in the distal segment. OCT was useful for a strut-level analysis of neointimal coverage over the whole stent. PMID- 23793882 TI - Methylmalonic acidemia and kidney transplantation. PMID- 23793883 TI - Effect of galactose on glomerular permeability and proteinuria in steroid resistant nephrotic syndrome. AB - BACKGROUND: Idiopathic steroid-resistant nephrotic syndrome (SRNS) has been associated with the presence of a circulating focal sclerosis permeability factor (FSPF) thought to damage the glomerular barrier and increase permeability to albumin. Galactose binds and inactivates FSPF in vitro, but its effect in vivo is uncertain. METHODS: A prospective clinical trial was conducted to investigate the effect of oral galactose on FSPF and proteinuria in children with SRNS. Seven pediatric subjects with idiopathic SRNS and positive FSPF activity (>0.5) were treated with oral galactose (0.2 gm/kg/dose twice daily) for 16 weeks. Post treatment FSPF and proteinuria were measured. RESULTS: Focal sclerosis permeability factor activity of the seven subjects decreased from 0.69 +/- 0.11 to 0.35 +/- 0.21 (p = 0.009) in response to galactose. The two subjects with post transplant recurrence of focal segmental glomerulosclerosis (FSGS) demonstrated the most significant improvement in FSPF (p = 0.006). Despite this decrease in FSPF, the pre- and post-treatment urine protein:creatinine ratio remained unchanged and no subject achieved remission. CONCLUSIONS: Galactose decreases FSPF in children with SRNS, with the most significant improvement in those with post-transplant FSGS recurrence, but it fails to improve proteinuria. At the present time there is no evidence to support the use of galactose in children with FSGS, either pre- or post-transplant. Future studies to investigate the role of galactose as preemptive therapy to decrease the risk of post-transplant FSGS recurrence may be useful. PMID- 23793884 TI - Growth in children on renal replacement therapy: a shrinking problem? AB - Growth failure has been almost inextricably linked with chronic kidney disease (CKD) and end-stage renal disease (ESRD) since initial reports of renal dwarfism dating back to the turn of the twentieth century. Growth failure in CKD has been associated with both increased morbidity and mortality. Growth failure in the setting of kidney disease is multifactorial and is related to poor nutritional status as well as comorbidities, such as anemia, bone and mineral disorders, and alterations in hormonal responses, as well as to aspects of treatment such as steroid exposure. In this issue of Pediatric Nephrology, Franke et al. report on the gains made in growth and maturation in pediatric patients with ESRD in recent decades, particularly in Germany. Through advances in the care of CKD and ESRD over recent decades, the prevalence of growth failure appears to be decreasing. These findings, along with a recent report demonstrating decreases in mortality in childhood ESRD in the United States Renal Data System (USRDS), suggest overall improvements in the outcomes of care, perhaps reflecting improvements in the quality of care for children with kidney disease worldwide. PMID- 23793885 TI - Neurally adjusted ventilatory assist: letting the respiratory center take over control of ventilation. PMID- 23793887 TI - Rash, organ dysfunction, and eosinophiles: it is a DRESS. PMID- 23793888 TI - Strong words, but still a step back for researchers in emergency and critical care research? The proposed revision of the Declaration of Helsinki. PMID- 23793889 TI - Autonomic dysfunction in ICU-acquired weakness: a prospective observational pilot study. AB - PURPOSE: Intensive care unit-acquired weakness (ICU-AW) is a frequent complication of critical illness. It is unknown if patients with ICU-AW also have autonomic dysfunction, another frequent neurological complication of critical illness. We hypothesized that patients who develop ICU-AW also develop autonomic dysfunction. Furthermore, we hypothesized that patients with ICU-AW are more prone to develop autonomic dysfunction compared to patients without ICU-AW. METHODS: This was an observational cohort study of patients newly admitted to the ICU. Autonomic dysfunction was measured daily using heart rate variability (HRV) to a maximum of 15 days after admission. ICU-AW was diagnosed using the Medical Research Council score. Abnormal HRV was defined using age-matched reference values. The association between ICU-AW and HRV was analyzed using linear mixed effects models. RESULTS: We included 83 patients, 15 (18 %) of whom were diagnosed with ICU-AW. Of 279 HRV measurements, 204 could be analyzed. Abnormal HRV was found in all critically ill patients irrespective of the presence of ICU AW (ICU-AW 100 % (IQR 71-100) vs. no ICU-AW 100 % (IQR 40-100); p = 0.40). Mechanical ventilation, sedation, norepinephrine, heart rate, and HRV artifacts were identified as confounders for HRV. ICU-AW was not associated with HRV. CONCLUSION: Abnormal HRV is frequent in critically ill patients, both with and without ICU-AW. It is unlikely that patients with ICU-AW are more prone to develop abnormal HRV. However, we found that abnormal HRV may not be an accurate indicator of autonomic dysfunction because of confounders. PMID- 23793890 TI - Microparticles are new biomarkers of septic shock-induced disseminated intravascular coagulopathy. AB - PURPOSE: Septic shock-induced disseminated intravascular coagulopathy (DIC) contributes to multiple organ failure. Mechanisms governing vascular responses to open occurrence of DIC have not yet been established. Circulating plasma microparticles (MPs), released upon cell stress, constitute a catalytic procoagulant surface and are surrogates of vascular cell activation/injury. Herein, MPs were assessed as possible markers of haemostatic and vascular dysfunction in the DIC time course. METHODS: One hundred patients with septic shock from three ICUs were enrolled and their haemostatic status evaluated at admission (D1), D2, D3 and D7. Circulating procoagulant MPs were isolated, quantified by prothrombinase assay and their cellular origin determined. DIC diagnosis was made according to the JAAM 2006 score. RESULTS: Ninety-two patients were analysed and 40 had DIC during the first 24 h. Routine clotting times and factor/inhibitor activity did not allow assessing vascular cell involvement. At admission, thrombin generation and fibrinolysis were observed in both groups while impaired fibrin polymerisation was evidenced only in DIC patients. Sustained thrombin generation persisted over time in both groups at D7. While total microparticle concentrations were in the same range regardless of DIC diagnosis, specific phenotypes were already detected at admission in DIC patients. Endothelial- and leucocyte-derived MPs were higher in DIC while an increased soluble glycoprotein V/platelet ratio was delayed, underscoring the first involvement of endothelial cells and leucocytes whereas platelet activation was delayed. Endothelium-derived CD105-MPs (OR 6.55) and CD31-MPs (OR 0.49) were strongly associated with early DIC in multivariate analysis. CONCLUSION: Endothelial-derived microparticles are relevant biomarkers of septic shock induced DIC and could be used to evaluate early vascular injury. PMID- 23793892 TI - Enzyme engineering through evolution: thermostable recombinant group II intron reverse transcriptases provide new tools for RNA research and biotechnology. AB - Current investigation of RNA transcriptomes relies heavily on the use of retroviral reverse transcriptases. It is well known that these enzymes have many limitations because of their intrinsic properties. This commentary highlights the recent biochemical characterization of a new family of reverse transcriptases, those encoded by group II intron retrohoming elements. The novel properties of these enzymes endow them with the potential to revolutionize how we approach RNA analyses. PMID- 23793891 TI - The nuclear cap-binding complex interacts with the U4/U6.U5 tri-snRNP and promotes spliceosome assembly in mammalian cells. AB - The nuclear cap-binding complex (CBC) binds to the 7-methyl guanosine cap present on every RNA polymerase II transcript. CBC has been implicated in many aspects of RNA biogenesis; in addition to roles in miRNA biogenesis, nonsense-mediated decay, 3'-end formation, and snRNA export from the nucleus, CBC promotes pre-mRNA splicing. An unresolved question is how CBC participates in splicing. To investigate CBC's role in splicing, we used mass spectrometry to identify proteins that copurify with mammalian CBC. Numerous components of spliceosomal snRNPs were specifically detected. Among these, three U4/U6.U5 snRNP proteins (hBrr2, hPrp4, and hPrp31) copurified with CBC in an RNA-independent fashion, suggesting that a significant fraction of CBC forms a complex with the U4/U6.U5 snRNP and that the activity of CBC might be associated with snRNP recruitment to pre-mRNA. To test this possibility, CBC was depleted from HeLa cells by RNAi. Chromatin immunoprecipitation and live-cell imaging assays revealed decreased cotranscriptional accumulation of U4/U6.U5 snRNPs on active transcription units, consistent with a requirement for CBC in cotranscriptional spliceosome assembly. Surprisingly, recruitment of U1 and U2 snRNPs was also affected, indicating that RNA-mediated interactions between CBC and snRNPs contribute to splicing. On the other hand, CBC depletion did not impair snRNP biogenesis, ruling out the possibility that decreased snRNP recruitment was due to changes in nuclear snRNP concentration. Taken together, the data support a model whereby CBC promotes pre mRNA splicing through a network of interactions with and among spliceosomal snRNPs during cotranscriptional spliceosome assembly. PMID- 23793893 TI - Unexpected expansion of tRNA substrate recognition by the yeast m1G9 methyltransferase Trm10. AB - N-1 Methylation of the nearly invariant purine residue found at position 9 of tRNA is a nucleotide modification found in multiple tRNA species throughout Eukarya and Archaea. First discovered in Saccharomyces cerevisiae, the tRNA methyltransferase Trm10 is a highly conserved protein both necessary and sufficient to catalyze all known instances of m1G9 modification in yeast. Although there are 19 unique tRNA species that contain a G at position 9 in yeast, and whose fully modified sequence is known, only 9 of these tRNA species are modified with m1G9 in wild-type cells. The elements that allow Trm10 to distinguish between structurally similar tRNA species are not known, and sequences that are shared between all substrate or all nonsubstrate tRNAs have not been identified. Here, we demonstrate that the in vitro methylation activity of yeast Trm10 is not sufficient to explain the observed pattern of modification in vivo, as additional tRNA species are substrates for Trm10 m1G9 methyltransferase activity. Similarly, overexpression of Trm10 in yeast yields m1G9 containing tRNA species that are ordinarily unmodified in vivo. Thus, yeast Trm10 has a significantly broader tRNA substrate specificity than is suggested by the observed pattern of modification in wild-type yeast. These results may shed light onto the suggested involvement of Trm10 in other pathways in other organisms, particularly in higher eukaryotes that contain up to three different genes with sequence similarity to the single TRM10 gene in yeast, and where these other enzymes have been implicated in pathways beyond tRNA processing. PMID- 23793894 TI - A miRNA-responsive cell-free translation system facilitates isolation of hepatitis C virus miRNP complexes. AB - Micro(mi)RNAs are 21- to 23-nt RNAs that regulate multiple biological processes. In association with Argonaute (Ago) proteins and other factors that form the RNA induced silencing complex (RISC), miRNAs typically bind mRNA 3' untranslated regions (UTRs) and repress protein production through antagonizing translation and transcript stability. For a given mRNA-miRNA interaction, cis-acting RNA elements and trans-acting RNA-binding proteins (RBPs) may influence mRNA fate. This is particularly true of the hepatitis C virus (HCV) genome which interacts with miR-122, an abundant liver miRNA. miR-122 binding to HCV RNA considerably stimulates virus replication in cultured cells and primates, but the mechanism(s) and associated host factors required for enhancement of HCV replication have not been fully elucidated. We recapitulated miR-122-HCV RNA interactions in a cell free translation system derived from cells that express miR-122. Specifically, lysates produced from HEK-293 cells that inducibly transcribe and process pri-miR 122 were characterized alongside those from isogenic cells lacking miR-122 expression. We observed a stimulatory effect of miR-122 on HCV reporter mRNAs in a manner that depended on expression of miR-122 and intact target sites within the HCV 5' UTR. We took advantage of this system to affinity-purify miR-122-HCV RNP complexes. Similar to functional assays, we found that association of immobilized HCV internal ribosome entry site (IRES) RNA with endogenous Ago2 requires both miR-122 expression and intact miR-122 target sites in cis. This combined approach may be generalizable to affinity purification of miRNP complexes for selected target mRNAs, allowing identification of miRNP components and RBPs that may contribute to regulation. PMID- 23793895 TI - HIV epidemic control-a model for optimal allocation of prevention and treatment resources. AB - With 33 million people living with human immunodeficiency virus (HIV) worldwide and 2.7 million new infections occurring annually, additional HIV prevention and treatment efforts are urgently needed. However, available resources for HIV control are limited and must be used efficiently to minimize the future spread of the epidemic. We develop a model to determine the appropriate resource allocation between expanded HIV prevention and treatment services. We create an epidemic model that incorporates multiple key populations with different transmission modes, as well as production functions that relate investment in prevention and treatment programs to changes in transmission and treatment rates. The goal is to allocate resources to minimize R 0, the reproductive rate of infection. We first develop a single-population model and determine the optimal resource allocation between HIV prevention and treatment. We extend the analysis to multiple independent populations, with resource allocation among interventions and populations. We then include the effects of HIV transmission between key populations. We apply our model to examine HIV epidemic control in two different settings, Uganda and Russia. As part of these applications, we develop a novel approach for estimating empirical HIV program production functions. Our study provides insights into the important question of resource allocation for a country's optimal response to its HIV epidemic and provides a practical approach for decision makers. Better decisions about allocating limited HIV resources can improve response to the epidemic and increase access to HIV prevention and treatment services for millions of people worldwide. PMID- 23793896 TI - Characterization of volatile organic compounds emitted by barley (Hordeum vulgare L.) roots and their attractiveness to wireworms. AB - Root volatile organic compounds (VOCs), their chemistry and ecological functions have garnered less attention than aboveground emitted plant VOCs. We report here on the identification of VOCs emitted by barley roots (Hordeum vulgare L.). Twenty nine VOCs were identified from isolated 21-d-old roots. The detection was dependent on the medium used for root cultivation. We identified 24 VOCs from 7-d old roots when plants were cultivated on sterile Hoagland gelified medium, 33 when grown on sterile vermiculite, and 34 on non-sterile vermiculite. The major VOCs were fatty acid derived compounds, including hexanal, methyl hexanoate, (E) hex-2-enal, 2-pentylfuran, pentan-1-ol, (Z)-2-(pentenyl)-furan, (Z)-pent-2-en-1 ol, hexan-1-ol, (Z)-hex-3-en-1-ol, (E)-hex-2-en-1-ol, oct-1-en-3-ol, 2-ethylhexan 1-ol (likely a contaminant), (E)-non-2-enal, octan-1-ol, (2E,6Z)-nona-2,6-dienal, methyl (E)-non-2-enoate, nonan-1-ol, (Z)-non-3-en-1-ol, (E)-non-2-en-1-ol, nona 3,6-dien-1-ol, and nona-2,6-dien-1-ol. In an olfactometer assay, wireworms (larvae of Agriotes sordidus Illiger, Coleoptera: Elateridae) were attracted to cues emanating from barley seedlings. We discuss the role of individual root volatiles or a blend of the root volatiles detected here and their interaction with CO2 for wireworm attraction. PMID- 23793897 TI - Microbial brokers of insect-plant interactions revisited. AB - Recent advances in sequencing methods have transformed the field of microbial ecology, making it possible to determine the composition and functional capabilities of uncultured microorganisms. These technologies have been instrumental in the recognition that resident microorganisms can have profound effects on the phenotype and fitness of their animal hosts by modulating the animal signaling networks that regulate growth, development, behavior, etc. Against this backdrop, this review assesses the impact of microorganisms on insect-plant interactions, in the context of the hypothesis that microorganisms are biochemical brokers of plant utilization by insects. There is now overwhelming evidence for a microbial role in insect utilization of certain plant diets with an extremely low or unbalanced nutrient content. Specifically, microorganisms enable insect utilization of plant sap by synthesizing essential amino acids. They also can broker insect utilization of plant products of extremely high lignocellulose content, by enzymatic breakdown of complex plant polysaccharides, nitrogen fixation, and sterol synthesis. However, the experimental evidence for microbial-mediated detoxification of plant allelochemicals is limited. The significance of microorganisms as brokers of plant utilization by insects is predicted to vary, possibly widely, as a result of potentially complex interactions between the composition of the microbiota and the diet and insect developmental age or genotype. For every insect species feeding on plant material, the role of resident microbiota as biochemical brokers of plant utilization is a testable hypothesis. PMID- 23793899 TI - Middle East Respiratory Syndrome coronavirus (MERS CoV): Update 2013. AB - Middle East Respiratory Syndrome coronavirus (MERS CoV) came to attention as an emerging pathogen causing severe respiratory illness in patients from the Middle East in September 2012. As of 14 June 2013, 58 human cases of MERS CoV infection have been confirmed, including 33 deaths (case fatality rate of 57%). MERS CoV is a beta-coronavirus, in the same family as SARS-CoV, and shares a probable origin from bats. No animal reservoir or intermediates have been definitely implicated in transmission. Limited human-to-human transmission has occurred within several clusters, as individuals without a recent travel history have become infected after exposure to an ill returned traveler. PMID- 23793898 TI - Induced dicentric chromosome formation promotes genomic rearrangements and tumorigenesis. AB - Chromosomal rearrangements can radically alter gene products and their function, driving tumor formation or progression. However, the molecular origins and evolution of such rearrangements are varied and poorly understood, with cancer cells often containing multiple, complex rearrangements. One mechanism that can lead to genomic rearrangements is the formation of a "dicentric" chromosome containing two functional centromeres. Indeed, such dicentric chromosomes have been observed in cancer cells. Here, we tested the ability of a single dicentric chromosome to contribute to genomic instability and neoplastic conversion in vertebrate cells. We developed a system to transiently and reversibly induce dicentric chromosome formation on a single chromosome with high temporal control. We find that induced dicentric chromosomes are frequently damaged and mis segregated during mitosis, and that this leads to extensive chromosomal rearrangements including translocations with other chromosomes. Populations of pre-neoplastic cells in which a single dicentric chromosome is induced acquire extensive genomic instability and display hallmarks of cellular transformation including anchorage-independent growth in soft agar. Our results suggest that a single dicentric chromosome could contribute to tumor initiation. PMID- 23793900 TI - Skin as marker for collagen type I/III ratio in abdominal wall fascia. AB - PURPOSE: An altered collagen metabolism could play an important role in hernia development. This study compared collagen type I/III ratio and organisation between hernia and control patients, and analysed the correlation in collagen type I/III ratio between skin and abdominal wall fascia. METHODS: Collagen organisation was analysed in Haematoxylin-Eosin sections of anterior rectus sheath fascia, and collagen type I/III ratio, by crosspolarisation microscopy, in Sirius-Red sections of skin and anterior rectus sheath fascia, of 19 control, 10 primary inguinal, 10 recurrent inguinal, 13 primary incisional and 8 recurrent incisional hernia patients. RESULTS: Compared to control patients [7.2 (IQR = 6.8 7.7) and 7.2 (IQR = 5.8-7.9)], collagen type I/III ratio was significantly lower in skin and anterior rectus sheath fascia of primary inguinal [5.2 (IQR = 3.8 6.3) and 4.2 (IQR = 3.8-4.7)], recurrent inguinal [3.2 (IQR = 3.1-3.6) and 3.3 (IQR = 3-3.7)], primary incisional [3.5 (IQR = 3-3.9) and 3.4 (IQR = 3.3-3.6)] and recurrent incisional hernia [3.2 (IQR = 3.1-3.9) and 3.2 (IQR = 2.9-3.2)] patients; also incisional and recurrent inguinal hernia had lower ratio than primary inguinal hernia patients. Furthermore, collagen type I/III ratio was significantly correlated (r = 0.81; P < 0.001) between skin and anterior rectus sheath fascia. Finally, collagen organisation was comparable between hernia and control patients. CONCLUSIONS: Furthermore, in both skin and abdominal wall fascia of hernia patients, collagen type I/III ratio was lower compared to control patients, with more pronounced abnormalities in incisional and recurrent inguinal hernia patients. Importantly, collagen type I/III ratio in skin was representative for that in abdominal wall fascia. PMID- 23793901 TI - Person-environment interactions and the shaping of resilience. PMID- 23793902 TI - Individual and collective dimensions of resilience within political violence. AB - Research has documented a link between political violence and the functioning of individuals and communities. Yet, despite the hardships that political violence creates, evidence suggests remarkable fortitude and resilience within both individuals and communities. Individual characteristics that appear to build resilience against political violence include demographic factors such as gender and age, and internal resources, such as hope, optimism, determination, and religious convictions. Research has also documented the protective influence of individuals' connection to community and their involvement in work, school, or political action. Additionally, research on political violence and resilience has increasingly focused on communities themselves as a unit of analysis. Community resilience, like individual resilience, is a process supported by various traits, capacities, and emotional orientations toward hardship. This review addresses various findings related to both individual and community resilience within political violence and offers recommendations for research, practice, and policy. PMID- 23793903 TI - Role of telomerase reverse transcriptase in glial scar formation after spinal cord injury in rats. AB - The study aims to determine the expression of telomerase reverse transcriptase (TERT) in the glial scar following spinal cord injury in the rat, and to explore its relationship with glial scar formation. A total of 120 Sprague-Dawley rats were randomly divided into three groups: SCI only group (without TERT interference), TERT siRNA group (with TERT interference), and sham group. The TERT siRNA and SCI only groups received spinal cord injury induced by the modified Allen's weight drop method. In the sham group, the vertebral plate was opened to expose the spinal cord, but no injury was modeled. Five rats from each group were sacrificed under anesthesia at days 1, 3, 5, 7, 14, 28, 42, and 56 after spinal cord injury. Specimens were removed for observation of glial scar formation using hematoxylin-eosin staining and immunofluorescence detection. mRNA and protein expressions of TERT and glial fibrillary acidic protein (GFAP) were detected by reverse-transcription (RT)-PCR and western blotting, respectively. Hematoxylin-eosin staining showed evidence of gliosis and glial scarring in the spinal cord injury zone of the TERT siRNA and SCI only groups, but not in the sham group. Immunofluorescence detection showed a significant increase in GFAP expression at all time points after spinal cord injury in the SCI only group (81 %) compared with the TERT siRNA group (67 %) and sham group (2 %). In contrast, the expression of neurofilament protein 200 (NF-200) was gradually reduced and remained at a stable level until 28 days in the SCI only group. There were no NF 200-labeled cells in the spinal cord glial scar and cavity at day 56 after spinal cord injury. NF-200 expression at each time point was significantly lower in the SCI only group than the TERT siRNA group, while there was no change in the sham group. Western blotting showed that TERT and GFAP protein expressions changed dynamically and showed a linear relationship in the SCI only group (r = 0.765, P < 0.01), while there was no obvious linear relationship in the sham group (r = 0.208, P = 0.121). RT-PCR results showed a dynamic expression of TERT and GFAP mRNA in the SCI only group, exhibiting a linear relationship (r = 0.722, P < 0.01), while there was no linear relationship in the sham group (r = 0.206, P = 0.180). Our data indicate that TERT has a dynamic expression in the spinal cord glial scar, which positively correlates to GFAP expression, and may be important for promoting glial scar formation. PMID- 23793904 TI - Effect of HDAC inhibitors on neuroprotection and neurite outgrowth in primary rat cortical neurons following ischemic insult. AB - Histone deacetylase inhibitors (HDACi)-valproic acid (VPA) and trichostatin A (TSA) promote neurogenesis, neurite outgrowth, synaptic plasticity and neuroprotection. In this study, we investigated whether VPA and TSA promote post ischemic neuroprotection and neuronal restoration in rat primary cortical neurons. On 6 days in vitro (DIV), cortical neurons were exposed to oxygen glucose deprivation for 90 min. Cells were returned to normoxic conditions and cultured for 1, 3, or 7 days with or without VPA and TSA. Control cells were cultured in normoxic conditions only. On 7, 9, and 13 DIV, cells were measured neurite outgrowth using the Axiovision program and stained with Tunel staining kit. Microtubule associated protein-2 immunostaining and tunel staining showed significant recovery of neurite outgrowth and post-ischemic neuronal death by VPA or TSA treatment. We also determined levels of acetylated histone H3, PSD95, GAP 43 and synaptophysin. Significant increases in all three synaptic markers and acetylated histone H3 were observed relative to non-treated cells. Post-ischemic HDACi treatment also significantly raised levels of brain derived neurotrophic factor (BDNF) expression and secreted BDNF. Enhanced BDNF expression by HDACi treatment might have been involved in the post-ischemic neuroprotection and neuronal restorative effects. Our findings suggest that both VPA and TSA treatment during reoxygenation after ischemia may help post-ischemic neuroprotection and neuronal regeneration via increased BDNF expression and activation. PMID- 23793905 TI - SARS: a timely reminder. PMID- 23793906 TI - LXV Meeting of the Italian Society for Veterinary Sciences (SISVet), Tropea Drapia 2011-selected papers : Full papers will be available in Pugliese A, Ferlazzo A, Gaiti A, Boiti C (2013) Trends in Veterinary Sciences-Current Aspects in Veterinary Morphophysiology, Biochemistry, Animal Production, Food Hygiene and Clinical Sciences. Springer-Verlag, Berlin Heidelberg. PMID- 23793907 TI - A comparison of particulate and Onyx embolization in preoperative devascularization of carotid body tumors. AB - INTRODUCTION: Preoperative embolization of a carotid body tumor (CBT) is a useful adjunct prior to surgical excision because it decreases operative blood loss and improves surgical outcomes. Traditionally, this is performed by transarterial particulate embolization (TAPE). More recently, direct percutaneous embolization (DPE) with Onyx is recognized as a promising technique for preoperative embolization. We compared these two techniques in patients treated for CBTs at our institution. METHODS: We retrospectively reviewed cases of preoperative devascularization of CBT from 1 January 1995 through 1 September 2012. Patient cases were placed into two groups: TAPE and DPE. Operative blood loss, operative length, angiographic devascularization, embolization procedure complications, operative transfusion requirements, postoperative hospital stay, intensive care unit (ICU) stay, and procedure-related mortalities were compared. RESULTS: A total of 17 patients underwent preoperative devascularization of their CBT with TAPE technique and ten patients using the DPE technique with Onyx. Average operative blood loss was significantly higher in the TAPE group (Mann-Whitney U test, p = 0.04). Operative time was also higher, although this difference was not significant. Two patients required intraoperative blood transfusions in the TAPE group while none required transfusions in the DPE group. There was no significant difference in ICU stay or length of hospitalization. One serious embolization procedure complication occurred in the TAPE group and none in the DPE group. CONCLUSION: Operative blood loss in the DPE group was significantly less than the TAPE group. Blood transfusion requirement, operative time, and complications were less in the DPE group, although they did not reach statistical significance. PMID- 23793908 TI - Freedom of conscience in health care: distinctions and limits. AB - The widespread emergence of innumerable technologies within health care has complicated the choices facing caregivers and their patients. The escalation of knowledge and technical innovation has been accompanied by an erosion of moral and ethical consensus among health providers that is reflected in the abandonment of the Hippocratic Oath as the immutable bedrock of medical ethics. Ethical conflicts arise when the values of health professionals collide with the expressed wishes of patients or the dictates of regulatory bodies and administrators. Increasing attempts by groups outside of the medical profession to limit freedom of conscience for health providers has raised concern and consternation among some health professionals. The personal and professional impact of health professionals surrendering freedom of conscience and participating in actions they deem malevolent or unethical has not been adequately studied and may not be inconsequential when considering the recognized impact of other circumstances of coerced complicity. We argue that the distinction between the two ways that freedom of conscience is exercised (avoiding a perceived evil and seeking a perceived good) provides a rational basis for a principled limitation of this fundamental freedom. PMID- 23793910 TI - What features of images affect parents' appraisal of safety messages? Examining images from the A Million Messages programme in Canada. AB - BACKGROUND: Enhancing caregivers' awareness of children's injury risks and increasing knowledge about strategies for injury prevention often involve presenting parents with written materials and accompanying images. OBJECTIVES: To assess parents' appraisals of different variations of images and identify those features that enhance their attention to safety messages. METHODS: Eight images showing risk situations were taken from the A Million Messages safety education parent-directed programme in Canada and modified to create a corresponding image that clearly showed negative consequences for the child, and facial expressions of fear and/or upset. Mothers with young children were presented with the eight pairs of images (negative consequence vs risk situation) and asked to select the best accompaniment to a safety message and to provide an explanation for their choice. Each image was then also rated for fit to the safety message, communication of danger, emotional arousal and attention elicitation. RESULTS: The images depicting negative consequences were chosen for most comparisons (78%) and higher scores were assigned to these images for all four features rated by parents (danger communicated, emotions evoked, attention elicitation and fit to the safety message). Moreover, ratings of danger, emotions and attention predicted 'fit to safety message' scores. CONCLUSIONS: Depicting negative consequences and showing negative emotions is important to maximise the effectiveness of images in communicating danger and evoking attention and concern when targeting parents with child-safety messaging. PMID- 23793911 TI - Combined foldable artificial iris with foldable IOL implantation through 5-mm incisions--still to be verified in practice. PMID- 23793912 TI - Simultaneous correction of post-traumatic aphakia and aniridia with the use of artificial iris and IOL implantation. PMID- 23793913 TI - An approach to quality and security of supply for single-use bioreactors. AB - Single-use systems (also referred to as disposables) have become a huge part of the bioprocessing industry, which raised concern in the industry regarding quality and security of supply. Processes must be in place to assure the supply and control of outsourced activities and quality of purchased materials along the product life cycle. Quality and security of supply for single-use bioreactors (SUBs) are based on a multidisciplinary approach. Developing a state-of-the-art SUB-system based on quality by design (QbD) principles requires broad expertise and know-how including the cell culture application, polymer chemistry, regulatory requirements, and a deep understanding of the biopharmaceutical industry. Using standardized products reduces the complexity and strengthens the robustness of the supply chain. Well-established supplier relations including risk mitigation strategies are the basis for achieving long-term security of supply. Well-developed quality systems including change control approaches aligned with the requirements of the biopharmaceutical industry are a key factor in supporting long-term product availability. This chapter outlines the approach to security of supply for key materials used in single-use production processes for biopharmaceuticals from a supplier perspective. PMID- 23793914 TI - Biomining: metal recovery from ores with microorganisms. AB - Biomining is an increasingly applied biotechnological procedure for processing of ores in the mining industry (biohydrometallurgy). Nowadays the production of copper from low-grade ores is the most important industrial application and a significant part of world copper production already originates from heap or dump/stockpile bioleaching. Conceptual differences exist between the industrial processes of bioleaching and biooxidation. Bioleaching is a conversion of an insoluble valuable metal into a soluble form by means of microorganisms. In biooxidation, on the other hand, gold is predominantly unlocked from refractory ores in large-scale stirred-tank biooxidation arrangements for further processing steps. In addition to copper and gold production, biomining is also used to produce cobalt, nickel, zinc, and uranium. Up to now, biomining has merely been used as a procedure in the processing of sulfide ores and uranium ore, but laboratory and pilot procedures already exist for the processing of silicate and oxide ores (e.g., laterites), for leaching of processing residues or mine waste dumps (mine tailings), as well as for the extraction of metals from industrial residues and waste (recycling). This chapter estimates the world production of copper, gold, and other metals by means of biomining and chemical leaching (bio /hydrometallurgy) compared with metal production by pyrometallurgical procedures, and describes new developments in biomining. In addition, an overview is given about metal sulfide oxidizing microorganisms, fundamentals of biomining including bioleaching mechanisms and interface processes, as well as anaerobic bioleaching and bioleaching with heterotrophic microorganisms. PMID- 23793915 TI - Unrelated cord blood transplantation for central nervous system relapse in high risk childhood acute lymphoblastic leukemia. AB - Few clinical studies have investigated the role of unrelated cord blood transplantation (CBT) for central nervous system (CNS) relapse of childhood acute lymphoblastic leukemia (ALL) patients with high-risk factors. The aim of this report is to identify the potential benefits of unrelated CBT in high-risk childhood ALL with CNS relapse who has been treated on CNS-directed treatment strategies. Eleven childhood ALL patients with CNS relapse who underwent unrelated CBT enrolled in our study between 2001 and 2011, and all of the patients had features associated with poor outcomes, such as high white blood cells at diagnosis, ph + chromosome, or a history of bone marrow relapse. All transplants were performed with myeloablative-conditioning therapy (BU/cyclophosphamide (CY2) or total body irradiation/CY) plus highly CNS-active agents (carmustine or high-dose cytarabine). All patients achieved neutrophil engraftment and platelet engraftment. A total of nine patients (81.8 %) developed pre-engraftment syndrome at a median of 7 days, and three patients developed acute graft-vs-host disease at a median of 21 days. The median follow-up after CBT was 28.5 months. The probability of overall survival at 9 years was 63.6 %, and no patient experienced a CNS relapse. Our experience suggests that unrelated CBT appears to be an effective treatment option for CNS relapse of childhood ALL patients associated with poor outcome features. PMID- 23793916 TI - ABCB6 RNA expression in leukemias--expression is low in acute promyelocytic leukemia and FLT3-ITD-positive acute myeloid leukemia. PMID- 23793917 TI - IgA monoclonal gammopathy accompanying extranodal B cell lymphomas. PMID- 23793918 TI - Clinical features and surgical outcomes of primary cauda equina tumours. AB - BACKGROUND: To identify clinical features, radiological findings and surgical outcomes of primary cauda equina tumours. METHODS: A consecutive series of 64 operations in 60 patients with primary cauda equina tumours from April 1999 to May 2009 at one institution comprised the study. The cases were divided into tumours of neural sheath origin (TNS, n = 48) and tumours of non-neural sheath origin (TNNS, n = 22). We analysed pain intensity, neurological abnormalities, MRI findings, surgical extent and functional outcome. RESULTS: The TNS group showed more leg pain (76 % vs. 44 %, p = 0.019) with higher intensity (6.1 +/- 1.5 vs. 4.6 +/- 1.9, p = 0.04). Motor weakness and bladder dysfunction were more common in the TNNS group (p = 0.028 and p = 0.00 in each). Flow voids of MRI were more frequently observed in TNNS (50 % vs. 4 %, p = 0.01). The TNS group achieved total removal in all operations compared with total removal in 77 % in the TNNS group (p = 0.001). The TNNS group showed higher recurrence rates (18 % vs. 0 %, p = 0.009). The TNS group showed higher improvement of JOA scores postoperatively (p = 0.049). Surgical complications were observed less frequently in the TNS group (19 % vs. 78 %, p = 0.000). CONCLUSIONS: TNS differs from TNNS by causing more frequent leg pain, higher pain intensity and more frequent flow voids. TNS has better surgical outcomes than TNNS in terms of higher rates of total removal, fewer surgical complications, better functional outcomes and less recurrence. PMID- 23793919 TI - Conjunctival oedema as a potential objective sign of intracranial hypertension: a short illustrated review and three case reports. AB - Periorbital and conjunctival oedema has been reported anecdotally by patients with raised intracranial pressure states. We present three clinical cases of this phenomenon and discuss the current evidence for pathways by which cerebrospinal fluid (CSF) drains in relation to conjunctival oedema. We reviewed the available literature using PubMed, in regards to conjunctival oedema as it relates to intracranial hypertension, and present the clinical history, radiology and orbital photographs of three cases we have observed. Only one previous publication has linked raised intracranial pressure (ICP) to conjuctival oedema. The weight of evidence supports the observation that the majority of CSF drains along the cranial nerves as opposed to via the arachnoid projections. Conjunctival oedema may be a clinical manifestation of CSF draining via the optic nerve in elevated ICP states. PMID- 23793920 TI - Changes of blue mussels Mytilus edulis L. lipid composition under cadmium and copper toxic effect. AB - The lipid and fatty acid composition of the blue mussels Mytilus edulis L. gills and digestive glands was evaluated after 24 and 72 h of cadmium (Cd) and copper (Cu) exposure. Mussels were exposed to different cadmium (10, 100, and 500 MUg/L) and copper (5, 50, and 250 MUg/L) concentrations. Similar stress response of predominant membrane phospholipids level as well as polyenoic and non-methylene interrupted (NMI) fatty acids content was observed in mussel gills under both cadmium and copper effects. Increased NMI fatty acids level after 24 h, the metal ions treatment suggests that these acids contribute to the protective response to the membrane oxidative stress caused by accumulation of the metals. The content of cholesterol, some minor membrane phospholipids, and storage lipids (triacylglycerols, TAG) in the mussels' organs alter significantly under the cadmium and copper effect. A two-step response at the digestive glands TAG level depends on the duration of the cadmium and copper treatments (24 and 72 h) on the mussels. The results demonstrate that Cd and Cu impact has adverse effects on gills and digestive glands lipid and fatty acids composition. The type of observed effects varies with the nature and concentration of the metal ions and depends on the role of the metals in the mussels' life activity. PMID- 23793921 TI - Isomerisation and controlled condensation in an aqueous medium of allyl alcohol catalysed by new water-soluble rhodium complexes with 1,3,5-triaza-7 phosphaadamantane (PTA). AB - New aqua-soluble rhodium(I) [Rh(CO)(PTA)4]Cl (1) (PTA = 1,3,5-triaza-7 phosphaadamantane) and rhodium(III) [RhCl2(PTA)4]Cl (2) complexes have been synthesized via the reaction of [{Rh(CO)2(MU-Cl)}2] or RhCl3.3H2O, respectively, with stoichiometric amounts of PTA in ethanol. Compound 1 is also obtained upon reduction of 2 in an H2/CO atmosphere. They have been characterized by IR, (1)H and (31)P{H} NMR spectroscopies, elemental and single crystal X-ray diffraction analyses. While compound 1 shows distorted square-pyramid geometry (tau5 = 0.09) with a P3C-type basal plane, compound 2 is octahedral with the chloro ligands in the cis position. The hydride rhodium(I) complex [RhH(PTA)4] (3) is formed upon the addition of NaBH4 to an aqueous solution of 1 or 2. Compounds 1-3 (in the case of 2 upon reduction by H2) act as homogeneous catalysts, or catalyst precursors, in the isomerisation and condensation of allyl alcohol at room temperature and in an aqueous medium. The product selectivity is easily controlled by changing the concentration of the base in the reaction mixture, thus resulting in the exclusive formation of either 3-hydroxy-2-methylpentanal (HP) or 2-methyl-2-pentenal (MP) in quantitative yields. PMID- 23793922 TI - Diagnosis of Alport syndrome--search for proteomic biomarkers in body fluids. AB - BACKGROUND: The hereditary kidney disease Alport syndrome (AS) has become a treatable disease: intervention with angiotensin-converting enzyme (ACE) inhibitors delays end stage renal failure by years. The efficiency of ACE inhibition depends on the onset of therapy-the earlier the better. Therefore, early diagnosis has become increasingly important. To date, robust diagnosis requires renal biopsy and/or expensive genetic analysis, which is mostly performed late after onset of the profound clinical symptoms of this progressive renal disease. Thus, disease biomarkers enabling low-invasive screening are urgently required. METHODS: Fourteen potential proteomic candidate markers (proteins) identified in a previous study in sera from patients exhibiting manifest AS were evaluated in the plasma, serum, and urine collected from a cohort of 132 subjects, including patients with AS and other nephropathies and healthy controls. Quantitation was performed by immunoassays. RESULTS: The serum and plasma levels of none of the 14 proteins evaluated were significantly different among the three groups and therefore could not be used to discriminate between the groups. In contrast, the levels of various biomarker combinations in the urine were significantly different between AS patients and healthy controls. Importantly, some combinations had the potential to discriminate between AS and other nephropathies. CONCLUSIONS: These findings open a window of opportunity for the sensitive and specific early diagnosis of AS. Our results increase the potential for larger scale evaluation of an increased number of patients. PMID- 23793923 TI - Rituximab in idiopathic nephrotic syndrome: does it make sense? AB - Idiopathic nephrotic syndrome (INS) includes three different entities: minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and mesangial proliferative glomerulonephritis. Historically, this condition has been attributed to a T-cell disorder resulting in the secretion of a circulating factor that increases glomerular permeability to plasma proteins. The therapeutic approach to control the proteinuria of INS remains the use of drugs that have been considered to suppress the production of the "circulating factor" secreted by T cells. Recently, rituximab (RTX), a chimeric monoclonal antibody directed against the CD20 cell surface receptor expressed on B cells, has emerged as potential therapeutic agent. The number of publications reporting clinical experience with RTX in the treatment of nephrotic syndrome has greatly increased in the last few years. However, there is currently no good evidence from clinical or experimental studies that support a role of RTX in the treatment of MCD and FSGS proteinuria. In summary, there is the need for a better understanding of the pathogenesis of the proteinuria in INS and the potential role of RTX in this condition. PMID- 23793924 TI - Intracranial metastasis of neuroblastoma: in two different areas at the same time. AB - INTRODUCTION: Neuroblastoma (NB) is the most common extracranial solid malignancy in children. The major cause of death from this cancer is metastasis of tumors, and metastasis can be seen in different areas of the body. Metastasis of NB occurs by hematogenous and lymphatic routes. Generally, brain metastases have been reported in only one area of the brain parenchyma. CASE REPORT: A 4-year-old male patient was treated in our clinic due to the NB that settled in the intra abdominal region, but the patient presented with headache and nausea approximately 5 months after completion of the treatment. Whereupon, cranial imaging was performed and two masses were detected in the bilateral frontal lobe, and then the patient underwent surgery. Metastatic NB diagnosis was confirmed histopathologically. The patient's chemotherapy treatment is still ongoing. CONCLUSION: We report the case of a male patient with two separate metastatic masses in the brain parenchyma, which occurred in two different areas at the same time. PMID- 23793925 TI - Decreased expression and aberrant methylation of Gadd45G is associated with tumor progression and poor prognosis in esophageal squamous cell carcinoma. AB - The growth arrest DNA damage-inducible gene (Gadd45) family, which is composed of Gadd45A, Gadd45B, and Gadd45G, is involved in DNA damage response and cell growth arrest. The present study was to detect the role of Gadd45 gene family in esophageal cancer and the relationship of Gadd45G methylation to a series of pathological parameters in a large esophageal squamous cell carcinoma (ESCC) sample, in order to elucidate more information on the role of Gadd45 gene family with regard to the pathogenesis of ESCC. Frequent silencing of Gadd45G but not Gadd45A and Gadd45B were found in esophageal cancer cell lines and the silencing of Gadd45G may be reversed by 5-Aza-dC or TSA treatment in Eca109 cell line. The aberrant proximal promoter methylation of Gadd45G induces silencing of Gadd45G expression in Eca109 cell line. Gadd45A mRNA and protein expression in ESCC tumor tissues was significantly different compared to corresponding normal tissues. Decreased mRNA and protein expression of Gadd45G was observed in ESCC tumor tissues and was associated with Gadd45G proximal promoter methylation. Gadd45A or Gadd45B expression was not correlated with ESCC patients survival, while Gadd45G methylation status and protein expression were independently associated with ESCC patients' survival. These data indicated that Gadd45G may be a functional tumor suppressor and its inactivation through proximal promoter methylation may play an important role in ESCC carcinogenesis and reactivation of Gadd45G gene may has therapeutic potential and may be used as a prognostic marker for ESCC patients. PMID- 23793926 TI - Do clinical characteristics and metabolic markers detected on positron emission tomography/computerized tomography associate with persistent disease in patients with in-operable cervical cancer? AB - The objective of this retrospective study was to evaluate the prognostic significance of volume-based metabolic markers of PET/CT along with clinical characteristics in patients with in-operable cervical carcinoma. METHODS: Fifty eight patients with cervical carcinoma (stage IIB-IVB) underwent FDG PET/CT for pretreatment evaluation and included in this study. Patients were staged according to International Federation of Gynecology and Obstetrics [FIGO] system. After chemoradiation therapy, patients were evaluated for persistent disease (PD) by clinical examinations, smear tests, pelvic MRI and PET/CT. Based upon follow up results, clinical characteristics (patient age, tumor histology, FIGO stage) and PET/CT findings such as presence of PET-positive pelvic/para-aortic lymph nodes (LN), metabolic tumor volume (MTV), total lesion glycolysis (TLG), maximum standardized uptake values (SUVmax) of tumor and lymph nodes were analyzed for disease persistence. Survival analysis for disease-free survival and overall survival was performed with Kaplan-Meier method using PET findings and clinical characteristics. RESULTS: At the time of last follow-up (mean: 22 +/- 12.6 months, range 6-48), 38 patients (65 %) had PD, 20 patients (35 %) had no evidence of disease (NED). Patient age, tumor histology, MTV, TLG and tumor SUVmax did not differ between groups. The frequency of PET-positive pelvic/para aortic lymph nodes (84 vs. 60 %, p = 0.03), LN SUVmax (10.2 vs. 6.5, p = 0.02), and FIGO stage differed significantly between PD and NED groups. Cox proportional hazards model demonstrated advanced FIGO stage and the presence of PET-positive para-aortic LN were independent predictors for PD. Both disease-free survival and overall survival curves showed progressive worsening as the disease advanced, p = 0.015. PET LN status was the most important prognostic indicator for disease-free survival and overall survival. The worst outcome curves were detected for patients with PET-positive para-aortic lymph nodes among all patients, p = 0.03. CONCLUSION: Advanced FIGO stage and the presence of FDG-avid para-aortic lymph nodes on pretreatment PET/CT are significant prognostic biomarkers for PD and decreased overall survival in patients with in-operable cervical carcinoma independent from MTV, TLG, tumor and lymph node SUVmax. PMID- 23793927 TI - False-positive iodine-131 whole body scan due to a benign dermal lesion; intradermal nevus ((131)I uptake in a benign nevus). AB - Whole body radioiodine scanning (WBS), along with plasma thyroglobulin level, remains a reference method for detecting residual or metastatic differentiated thyroid cancer, however, false-positive WBS is not uncommon. External contaminations by body secretions or excretions, inflammation, and cystic structures mimicking metastases in WBS have been reported. Various benign and malignant tumors having different histopathological natures accumulate radioiodine, but intradermal melanocytic nevus was not previously described in the literature, as far as we know. This report describes an unusual cause of false-positive WBS after radioablation therapy due to an intradermal nevus, and the possible mechanisms are discussed. PMID- 23793929 TI - Umbilical hernia management during liver transplantation. AB - PURPOSE: Patients with liver cirrhosis scheduled for liver transplantation often present with a concurrent umbilical hernia. Optimal management of these patients is not clear. The objective of this study was to compare the outcomes of patients who underwent umbilical hernia correction during liver transplantation through a separate infra-umbilical incision with those who underwent correction through the same incision used to perform the liver transplantation. METHODS: In the period between 1990 and 2011, all 27 patients with umbilical hernia and liver cirrhosis who underwent hernia correction during liver transplantation were identified in our hospital database. In 17 cases, umbilical hernia repair was performed through a separate infra-umbilical incision (separate incision group) and 10 were corrected from within the abdominal cavity without a separate incision (same incision group). Six patients died during follow-up; no deaths were attributable to intraoperative umbilical hernia repair. All 21 patients who were alive visited the outpatient clinic to detect recurrent umbilical hernia. RESULTS: One recurrent umbilical hernia was diagnosed in the separate incision group (6 %) and four (40 %) in the same incision group (p = 0.047). Two patients in the same incision group required repair of the recurrent umbilical hernia; one of whom underwent emergency surgery for bowel incarceration. The one recurrent hernia in the separate incision group was corrected electively. CONCLUSION: In the event of liver transplantation, umbilical hernia repair through a separate infra-umbilical incision is preferred over correction through the same incision used to perform the transplantation. PMID- 23793928 TI - Chronic pain and quality of life (QoL) after transinguinal preperitoneal (TIPP) inguinal hernia repair using a totally extraperitoneal, parietalized, Polysoft (r) memory ring patch : a series of 622 hernia repairs in 525 patients. AB - INTRODUCTION: Little is known about both incidence of chronic pain and quality of life (QoL) after the transinguinal preperitoneal (TIPP) technique using a totally extraperitoneal, parietalized, memory ring patch. MATERIALS AND METHODS: Among 622 (428 unilateral and 194 bilateral) hernia repairs (HR) in 525 patients, 92 % had a postoperative clinical control. Thereafter, two sets of postal self assessed questionnaires were sent. RESULTS: A total of 531 HR were studied with a mean follow-up of 17 +/- 8 months. Only one recurrence was detected. In 151 (28.4 %) HR the patients alleged various symptoms, but in only 10 (1.9 %) HR they considered their discomfort more bothersome than the hernia they had before, and in just 2 (0.4 %) HR they judged their result as bad (one patch removal for sepsis and one for hematoma). Only mild pain (including no painful discomfort such as a foreign body sensation) or moderate pain was frequent. Pain was self graded as severe in four cases. None of them reported any regular consumption of antalgics. None of them judged their result as bad. Dysesthesia (numbness 19, paresthesia 20) mentioned in 39 HR (7 %), associated with pain in 16 HR, was said to be more bothersome than the hernia treated in just 3 HR (0.6 %). The results of the entire series were self-assessed as good or excellent in 97 % of the HR. CONCLUSION: In our TIPP series, both the incidence of recurrences (0.2 %) and that of severe chronic pain (<=0.7 %) were very low, as well as patients' QoL was excellent. In our experience, the postoperative course was as painless as that of laparoscopic TEP we had been performing previously, but TIPP appeared more suited to day-case surgery. PMID- 23793930 TI - Homogenized stiffness matrices for mineralized collagen fibrils and lamellar bone using unit cell finite element models. AB - Mineralized collagen fibrils have been usually analyzed like a two-phase composite material where crystals are considered as platelets that constitute the reinforcement phase. Different models have been used to describe the elastic behavior of the material. In this work, it is shown that when Halpin-Tsai equations are applied to estimate elastic constants from typical constituent properties, not all crystal dimensions yield a model that satisfy thermodynamic restrictions. We provide the ranges of platelet dimensions that lead to positive definite stiffness matrices. On the other hand, a finite element model of a mineralized collagen fibril unit cell under periodic boundary conditions is analyzed. By applying six canonical load cases, homogenized stiffness matrices are numerically calculated. Results show a monoclinic behavior of the mineralized collagen fibril. In addition, a 5-layer lamellar structure is also considered where crystals rotate in adjacent layers of a lamella. The stiffness matrix of each layer is calculated applying Lekhnitskii transformations, and a new finite element model under periodic boundary conditions is analyzed to calculate the homogenized 3D anisotropic stiffness matrix of a unit cell of lamellar bone. Results are compared with the rule-of-mixtures showing in general good agreement. PMID- 23793931 TI - Recent advances in the genetic etiology of brain malformations. AB - In the past few years, the increasing accessibility of next-generation sequencing technology has translated to a number of significant advances in our understanding of brain malformations. Genes causing brain malformations, previously intractable due to their complex presentation, rarity, sporadic occurrence, or molecular mechanism, are being identified at an unprecedented rate and are revealing important insights into central nervous system development. Recent discoveries highlight new associations of biological processes with human disease including the PI3K-AKT-mTOR pathway in brain overgrowth syndromes, the trafficking of cellular proteins in microcephaly-capillary malformation syndrome, and the role of the exosome in the etiology of pontocerebellar hypoplasia. Several other gene discoveries expand our understanding of the role of mitosis in the primary microcephaly syndromes and post-translational modification of dystroglycan in lissencephaly. Insights into polymicrogyria and heterotopias show us that these 2 malformations are complex in their etiology, while recent work in holoprosencephaly and Dandy-Walker malformation suggest that, at least in some instances, the development of these malformations requires "multiple-hits" in the sonic hedgehog pathway. The discovery of additional genes for primary microcephaly, pontocerebellar hypoplasia, and spinocerebellar ataxia continue to impress upon us the significant degree of genetic heterogeneity associated with many brain malformations. It is becoming increasingly evident that next generation sequencing is emerging as a tool to facilitate rapid and cost effective molecular diagnoses that will be translated into routine clinical care for these rare conditions in the near future. PMID- 23793932 TI - Written language production disorders: historical and recent perspectives. AB - Written language production is often the least examined neuropsychological function, yet it provides a sensitive and subtle sign to a variety of different behavioral disorders. The dissociation between written and spoken language and reading and writing first came to clinical prominence in the nineteenth century, with respect to ideas about localization of function. Twentieth century aphasiology research focused primarily on patients with unifocal lesions from cerebrovascular accidents, which have provided insight into the various levels of processing involved in the cognitively complex task of producing written language. Recent investigations have provided a broader perspective on writing impairments in a variety of disorders, including progressive and diffuse brain disorders, and functional brain imaging techniques have been used to study the underlying processes in healthy individuals. PMID- 23793933 TI - Interaction between graphene layers and the mechanisms of graphite's superlubricity and self-retraction. AB - Graphene layer-layer interaction is explored as a function of the misorientation angle. A stepwise potential energy surface (PES), where the optimized commensurate configuration (AB stacking) corresponds to the global minimum and all incommensurate configurations correspond to nearly equal energies, is shown. The stepwise behavior is attributed to the alternating appearance of AB and AA stacking-like areas and the transition areas between them. Further, the PES of most incommensurate configurations is found to be ultra-smooth. Based on this, the puzzling experimental observation of graphite flake self-retraction is successfully explained. PMID- 23793934 TI - Identification of miR-7 as an oncogene in renal cell carcinoma. AB - MicroRNA-7 (miR-7) has been described as a tumor suppressor in several human cancers, but the results of a study to identify miRNAs associated with metastatic capability in breast cancer suggested that miR-7 may be characterized as an oncogene. The present study was to determine the expression and function of miR-7 in renal cell carcinoma. Quantitative real-time polymerase chain reaction was used to validate the expressions of miR-7 in 48 paired renal cell carcinomas (RCC) and normal tissues, based on the preliminary sequencing results of miRNAs. Furthermore, the impacts of miR-7 on cell migration, proliferation and apoptosis were analyzed using wound scratch assay, MTT and flow cytometry, respectively. The results demonstrated that miR-7 was up-regulated in RCC compared with normal tissues (p = 0.001). Down-regulation of miR-7 with synthesized inhibitor inhibited cell migration in vitro, suppressed cell proliferation and induced renal cancer cell apoptosis, prompting that miR-7 could be characterized as an oncogene in RCC. The present study was the first to reveal that miR-7 was up regulated in RCC and it played an important role in RCC by affecting cellular migration, proliferation and apoptosis. Further researches should be conducted to explore the roles and target genes of miR-7 in RCC and other cancers. PMID- 23793935 TI - Performance of a multi-disciplinary emergency department observation protocol for acetaminophen overdose. AB - The availability of 20-h N-acetylcysteine (NAC) infusion for low-risk acetaminophen (APAP) overdose enabled our center to implement an Emergency Department observation unit (OU) protocol as an alternative to hospitalization. Our objective was to evaluate our early experience with this protocol. This retrospective cohort study included all patients treated for low-risk APAP overdose in our academic hospital between 2006 and 2011. Cases were identified using OU and pharmacy records. Successful OU discharge was defined as disposition with no inpatient admission. Differences in medians with 95 % confidence intervals were used for comparisons. One hundred ninety-six patients received NAC for APAP overdose with a mean age of 35 years (SD 14); 73 % were white, and 43 % were male. Twenty (10 %) received care in the OU; 3/20(15 %) met criteria for inclusion in the OU protocol and 13/20(65 %) were discharged successfully. Out of the 196 patients, 10 met criteria for inclusion in the OU protocol but instead received care in the inpatient setting. The median total length of stay from presentation to ED discharge was 41 h for all patients treated in the OU, compared to 68 h for ten patients who met criteria for inclusion in the OU protocol but who were admitted (difference 27 h, 95 % CI 18-72 h). ED observation for APAP overdose can be a viable alternative to inpatient admission. Most patients were successfully discharged from the OU. This evaluation identified both over- and under-utilization of the OU. OU treatment resulted in shorter median length of stay than inpatient admission. PMID- 23793936 TI - Nurses' responses to initial moral distress in long-term care. AB - While researchers have examined the types of ethical issues that arise in long term care, few studies have explored long-term care nurses' experiences of moral distress and fewer still have examined responses to initial moral distress. Using an interpretive description approach, 15 nurses working in long-term care settings within one city in Canada were interviewed about their responses to experiences of initial moral distress, resources or supports they identified as helpful or potentially helpful in dealing with these situations, and factors that hindered nurses in their responses. Using a thematic analysis process, three major themes were identified from the nurses' experiences: (i) the context of the situation matters; (ii) the value of coming together as a team; and (iii) looking for outside direction. The work of responding to initial moral distress was more fruitful if opportunities existed to discuss conflicts with other team members and if managers supported nurses in moving their concerns forward through meetings or conversations with the team, physician, or family. Access to objective others and opportunities for education about ethics were also identified as important for dealing with value conflicts. PMID- 23793937 TI - Low doses of radiation can enhance insect lifespans. AB - This paper assesses the capacity of ionizing radiation to extend the lifespans of experimental insect models based on the peer-reviewed literature. Ionizing radiation biphasically affects the lifespans of adult males and females for a broad range of insect models with high doses reducing lifespan whereas lower doses can enhance lifespan, typically in the 20-60 % range. The average adult insect lifespan can be increased when ionizing radiation exposure is administered during early developmental stages or during the adult stage. The effective dose inducing the average adult insect lifespan enhancement may vary considerably depending upon which life stage is exposed. Recent findings have identified specific genes affecting anti-oxidant defenses, DNA repair, apoptosis and heat shock proteins as well as several cell signaling pathways that mediate the longevity enhancing hormetic response. PMID- 23793938 TI - Potential pitfalls in MALDI-TOF MS analysis of abiotically synthesized RNA oligonucleotides. AB - Demonstration of the abiotic polymerization of ribonucleotides under conditions consistent with conditions that may have existed on the prebiotic Earth is an important goal in "RNA world" research. Recent reports of abiotic RNA polymerization with and without catalysis rely on techniques such as HPLC, gel electrophoresis, and MALDI-TOF MS to analyze the reaction products. It is essential to understand the limitations of these techniques in order to accurately interpret the results of these analyses. In particular, techniques that rely on mass for peak identification may not be able to distinguish between a single, linear RNA oligomer and stable aggregates of smaller linear and/or cyclic RNA molecules. In the case of MALDI-TOF MS, additional complications may arise from formation of salt adducts and MALDI matrix complexes. This is especially true for abiotic RNA polymerization reactions because the concentration of longer RNA chains can be quite low and RNA, as a polyelectrolyte, is highly susceptible to adduct formation and aggregation. Here we focus on MALDI-TOF MS analysis of abiotic polymerization products of imidazole activated AMP in the presence and absence of montmorillonite clay as a catalyst. A low molecular weight oligonucleotide standard designed for use in MALDI-TOF MS and a 3'-5' polyadenosine monophosphate reference standard were also run for comparison and calibration. Clay-catalyzed reaction products of activated GMP and UMP were also examined. The results illustrate the ambiguities associated with assignment of m/z values in MALDI mass spectra and the need for accurate calibration of mass spectra and careful sample preparation to minimize the formation of adducts and other complications arising from the MALDI process. PMID- 23793939 TI - Plant uptake and translocation of inorganic and organic forms of selenium. AB - Selenium (Se) plays a role in human health: It is an essential trace element but can be toxic if too much is consumed. The aim of this study was to determine which species of Se are most rapidly taken up and translocated to above-ground plant tissues. Specifically, we wished to determine if organic forms of Se in an exposure solution can contribute to the amount of Se found in shoot tissue. Durum wheat (Triticum turgidum) and spring canola (Brassica napus) were grown hydroponically, and young seedlings were exposed to 0.5 or 5.0 MUM Se as selenate, selenite, seleno-methionione, or seleno-cystine for <=300 min. Canola accumulated more Se than wheat, although the difference depended on Se speciation of the exposure solution. Organic forms of Se were taken up at a greater rate than inorganic forms. When exposed to 5.0 MUM Se, the rate of uptake of selenite was 1.5- (canola) or 5-fold (wheat) greater than the rate of uptake of selenate, whereas seleno-methionine was taken up 40- (canola) or 100-fold (wheat) faster and seleno-cystine 2- (wheat) to 20-fold (canola) faster. Plants exposed to seleno-methionine had the highest shoot concentrations of Se even though selenate was more mobile once taken up; in plants exposed to selenate >50% of accumulated Se was translocated to shoot tissue. Because organic forms of Se (especially seleno-methionine) can be readily taken up and translocated to above-ground tissues of wheat and canola, these Se species should be considered when attempting to predict Se accumulation in above-ground plant tissues. PMID- 23793940 TI - Diversity of the intestinal microbiota in different patterns of feeding infants by Illumina high-throughput sequencing. AB - The gastrointestinal microbiota plays a crucial role in the health and disease of the host through its impact on nutrition. Gut microbial composition is related to different diets, but an association of microbiota with different diets in infant has not yet been shown. In this work, we compared the fecal microbiota of breast fed (BF) and formula-fed infants (FF). By using Illumina high-throughput sequencing and biochemical analyses, we found differences in gut microbiota between the two groups. BF infants showed a significant enrichment of Actinobacteria and Firmicutes and depletion of Proteobacteria (P < 0.05), the abundance of Bacteroidetes in the two groups was very low (P > 0.05). Enterobacteriaceae (Proteobacteria) were the dominant bacteria in FF infant fecal microbiota, and Veillonellaceae (Firmicutes) and Enterobacteriaceae (Proteobacteria) were the dominant bacteria in the BF infant fecal microbiota. The number of genera (percentage of sequences >0.1 %) in BF and FF infants was 17 and 15 respectively, and Streptococcus was the dominant bacterial genus in both groups. PMID- 23793941 TI - Sodium houttuyfonate, a potential phytoanticipin derivative of antibacterial agent, inhibits bacterial attachment and pyocyanine secretion of Pseudomonas aeruginosa by attenuating flagella-mediated swimming motility. AB - Pseudomonas aeruginosa is a well-known clinical pathogen for its recalcitrant infection caused by biofilm formation which are initiated by flagella-mediated attachment. Sodium houttuyfonate (SH) is a natural phytoanticipin derivative of houttuynin and has anti-pathogenic effect on P. aeruginosa biofilm formation. In this paper, when using 1/2 * MIC SH, the diameter of P. aeruginosa swimming motility was sharply shortened to 36 % in 24 h incubation, and the fold changes of fliC required for swimming motility was 0.36 in 24 h cultivation, the adherence inhibition accounted for about 46 %, and the pyocyanin production decreased to 47 % after 1-day treatment and 56 % after 3-day treatment with obvious visual changes from dark green to light green, compared with the negative control. With the help of mass spectra and scanning electronic microscope, 1/2 * MIC SH was further testified to be enough to eradicate flagella and inhibit pyocyanin secretion of P. aeruginosa. The results do not only re-affirm the close interplay of attachment and virulence (i.e. swimming motility and pyocyanin), but also unravel the potential mechanism of SH on anti-biofilm of P. aeruginosa. PMID- 23793942 TI - Immuno capture PCR for rapid and sensitive identification of pathogenic Bacillus anthracis. AB - Immuno capture PCR (IPCR) is a technique capable of detecting the pathogens with high specificity and sensitivity. Rapid and accurate detection of Bacillus anthracis was achieved using anti-EA1 antibodies to capture the cells and two primer sets targeting the virulence factors of the pathogen i.e., protective antigen (pag) and capsule (cap) in an IPCR format. Monoclonal antibodies specific to B. anthracis were generated against extractable antigen 1 protein and used as capture antibody onto 96 well polystyrene plates. Following the binding of the pathogen, the DNA extraction was carried out in the well itself and further processed for PCR assay. We compared IPCR described here with conventional duplex PCR using the same primers and sandwich ELISA using the monoclonal antibodies developed in the present study. IPCR was capable of detecting as few as 10 and 100 cfu ml-1 of bacterial cells and spores, respectively. IPCR was found to be 2 3 logs more sensitive than conventional duplex PCR and the sandwich ELISA. The effect of other bacteria and any organic materials on IPCR was also analyzed and found that this method was robust with little change in the sensitivity in the presence of interfering agents. Moreover, we could demonstrate a simple process of microwave treatment for spore disruption which otherwise are resistant to chemical treatments. Also, the IPCR could clearly distinguish the pathogenic and nonpathogenic strains of B. anthracis in the same assay. This can help in saving resources on unnecessary decontamination procedures during false alarms. PMID- 23793943 TI - Bacillus megaterium mediated mineralization of calcium carbonate as biogenic surface treatment of green building materials. AB - Microbially induced calcium carbonate precipitation is a biomineralization process that has various applications in remediation and restoration of range of building materials. In the present study, calcifying bacteria, Bacillus megaterium SS3 isolated from calcareous soil was applied as biosealant to enhance the durability of low energy, green building materials (soil-cement blocks). This bacterial isolate produced high amounts of urease, carbonic anhydrase, extra polymeric substances and biofilm. The calcium carbonate polymorphs produced by B. megaterium SS3 were analyzed by scanning electron microscopy, confocal laser scanning microscopy, X-ray diffraction and Fourier transmission infra red spectroscopy. These results suggested that calcite is the most predominant carbonate formed by this bacteria followed by vaterite. Application of B. megaterium SS3 as biogenic surface treatment led to 40 % decrease in water absorption, 31 % decrease in porosity and 18 % increase in compressive strength of low energy building materials. From the present investigation, it is clear that surface treatment of building materials by B. megaterium SS3 is very effective and eco friendly way of biodeposition of coherent carbonates that enhances the durability of building materials. PMID- 23793944 TI - Characterization, cloning and functional expression of novel xylanase from Thermomyces lanuginosus SS-8 isolated from self-heating plant wreckage material. AB - Extracellular cellulase free xylanase from Thermomyces lanuginosus sp. SS-8, isolated from self heating plant wreckage material was identified as beta-1,4 endo-xylanase precursor, a monomer of 21.3 kDa with no carbohydrate residue. This xylanase retained 80 % activity at 60 degrees C for 96 h, was active at a wide pH range of 3-11 and uniquely hydrolyzed xylan to xylose without production of xylo-oligosaccharides. Gene xynSS8 encoding xylanase from T. lanuginosus SS-8 was cloned and functionally expressed in Escherichia coli XL1 Blue using pTZ57R/T plasmid and xynSS8/pQE-9 expression vector construct respectively. Gene xynSS8 was of 777 bp and deduced amino acid sequence was a mature xylanase of 258 amino acids. XynSS8 has extra 33 amino acids compared to its nearest homolog and was thermo-alkali tolerant as that of native protein. The xylanase could degrade pulp and release substantial chromophoric materials and lignin derived compounds indicating its effective utility in pulp bleaching. Novel characteristics of the enzyme may contribute to its wide industrial usage. This is first report of cloning and functional expression of the novel xylanase from T. lanuginosus SS-8. PMID- 23793946 TI - Comparison of three techniques using the Parkland Formula to aid fluid resuscitation in adult burns. AB - We performed a randomised study to compare the accuracy and speed of three different techniques (pen and paper, electronic calculator and a novel graphic device: 'nomogram') for calculation of resuscitation fluid requirements for adults in the first 24 h of burn injury, based on the Parkland Formula. We also assessed acceptability of each technique using visual analogue scores and qualitative analysis of free text responses. 28 participants performed 252 calculations using a series of computer generated simulated patient data. For nomogram, electronic calculator, pen and paper: Magnitude of error [low (>=25%), medium (>=50%), high (>=75%)]: [6.0%, 1.2%, 0%], [17.9%, 14.3%, 8.3%], [25%, 16.7%, 9.5%]; p<0.002. Calculation time: [sec: mean (SD)]: 94(34), 73(31), 214(103); p<0.001. The mean (SD) of the difficulty scores for each method were 23(17), 17(14) and 70(21) out of 100. Of the 28 participants 15 preferred the calculator, 12 preferred the nomogram and 1 scored the calculator and nomogram equally (table 3). The nomogram was significantly more accurate at all levels, almost as fast as an electronic calculator, and deemed easy to use. It is low cost and robust, and provides a rapid means of detecting and preventing the large errors that we have shown can occur when an electronic device is used as the only method of calculation. We therefore suggest that the Parkland Formula nomogram is a suitable method for calculation of resuscitation fluid requirements in adult burns. Fluid requirement should, however, be reviewed frequently, and adjusted to ensure adequate organ perfusion. PMID- 23793945 TI - Clinical effects and safety of different strategies for administering intravenous diuretics in acutely decompensated heart failure: a randomised clinical trial. AB - BACKGROUND: The mainstay of treatment for acutely decompensated heart failure (ADHF) is intravenous diuretic therapy either as a bolus or via continuous infusion. OBJECTIVES: We evaluated the clinical effects and safety of three strategies of intravenous furosemide administration used in emergency departments (EDs) for ADHF. METHODS: We performed a multicentre, randomised, parallel-group study. Patients with ADHF were randomised within 2 h of ED arrival to receive furosemide by continuous infusion (10 mg/h, group 1) or boluses (20 mg/6 h, group 2; or 20 mg/8 h, group 3). The primary end point was total diuresis, and secondary end points were dyspnoea, orthopnoea, extension of rales and peripheral oedema, blood pressure, respiratory and heart rates, and pulse oximetry, which were measured at arrival and 3, 6, 12 and 24 h after treatment onset. We also measured serum creatinine, sodium and potassium levels at arrival and after 24 h. RESULTS: Group 1 patients (n=36) showed greater 24 h diuresis (3705 mL) than those in groups 2 (n=37) and 3 (n=36) (3093 and 2670 mL, respectively; p<0.01), and this greater diuretic effect was observed earlier. However, no differences were observed among groups in the nine secondary clinical end points evaluated. Creatinine deterioration developed in 15.6% of patients, hyponatraemia in 9.2%, and hypokalaemia in 19.3%, with the only difference among groups observed in hypokalaemia (group 1, 36.3%; group 2, 13.5%; group 3, 8.3%; p<0.01). CONCLUSIONS: In patients with ADHF attending the ED, boluses of furosemide have a smaller diuretic effect but provide similar clinical relief, similar preservation of renal function, and a lower incidence of hypokalaemia than continuous infusion. TRIAL REGISTRATION NUMBER: This randomised trial was registered in the European Clinical Trial Database (EudraCT) with the reference number 2008-004488 20. PMID- 23793947 TI - Clonal chromosomal abnormalities in Philadelphia-negative cells in chronic myeloid leukemia patients treated with nilotinib used in first-line therapy. AB - Nilotinib is an effective option for the first-line treatment of chronic myeloid leukemia (CML) patients in chronic phase (CP). In CML patients, clonal cytogenetic abnormalities (CAs) in Philadelphia-negative (Ph-) metaphases have been widely observed after treatment with imatinib, or dasatinib/nilotinib following failure with imatinib. However, such abnormalities in CML patients treated with nilotinib as the first-line therapy have not been reported. Thirteen CML CP patients with Philadelphia-positive (Ph+) cells were initially diagnosed in our hospital from December 2010 to July 2011. Patients were followed up by clinical assessment, cytogenetic analysis, and BCR-ABL transcriptional level every 3 to 6 months. Retrospective fluorescence in situ hybridization was performed on stored bone marrow specimens of patients when the cytogenetic analysis showed CAs. During nilotinib therapy, 12 (92.3 %), 5 (38.5 %), and 2 (15.4 %) patients achieved complete cytogenetic response, major molecular response, and complete molecular response at 18 months, respectively. Two patients developed CAs in Ph- cells, including trisomy 8 and monosomies 20 and 21. Monosomies 20 and 21 appeared in the same patient simultaneously. Our data confirmed that clonal CAs in Ph- cells is a general phenomenon in Ph+ CML patient treated with tyrosine kinase inhibitors (TKIs), including nilotinib. The clinical significance of these CAs that arise in Ph+ CML patient treated with TKIs and whether these CAs exist before or after treatment of TKIs are not clear. PMID- 23793948 TI - Primary alveolar soft part sarcoma arising from the cerebellopontine angle. AB - INTRODUCTION: Alveolar soft part sarcoma (ASPS), a rare soft tissue malignant neoplasm, frequently metastasizes to the brain. However, primary intracranial ASPS is extremely rare. We present a case of primary intracranial ASPS arising from the cerebellopontine angle (CPA) without demonstrable systemic lesions. CASE REPORT: An 11-year-old girl presented with a recurrent tumor in the right CPA after a partial resection and radiation therapy (RT). Near-total resection with a minimal tumor left in the jugular foramen was performed. The pathological diagnosis was ASPS. There was no evidence of primary extracranial tumors. She underwent adjuvant chemotherapy and gamma knife surgery. At 29 months after the second surgery, magnetic resonance imaging revealed multifocal enhancing lesions at the prepontine cistern, right CPA and medulla oblongata, despite intensive treatment. However, extracranial metastasis was not noted. This case suggested a poor outcome of primary intracranial ASPS, similar to extracranial ASPS. PMID- 23793949 TI - Radiological findings in relation to the neurodevelopmental outcome in hydrocephalic children treated with shunt insertion or endoscopic third ventriculostomy. AB - PURPOSE: The aim of the study was to compare the radiological indicators of effectiveness for hydrocephalus treatment in children operated on under the third year of age with the use of shunt insertion (SI) and endoscopic third ventriculostomy (ETV). The effectiveness was considered in terms of postoperative neurodevelopment in correlation to pre- and postoperative radiological findings. METHODS: The examined group consisted of 46 children operated on for hydrocephalus in the Division of Pediatric Neurosurgery in Katowice, Poland. There were 21 children treated with SI and 25 with ETV. The radiographic assessment was carried out on the basis of MRI and CT examinations with the use of a linear estimate known as frontal and occipital horn ratio (FOR). The FOR values were calculated for the entire group and in correlation to the treatment method and to the children neurodevelopment evaluated with The Denver Developmental Screening Test. RESULTS: No differences were recognized between initial FOR value in terms of the postoperative children neurodevelopment. In the successful ETV-treated subgroup, the mean change in FOR was 0.05 and in the SI treated subgroup, the mean change in FOR 0.13. The patients with BFOR >0.1, developed normally more often than those in whom BFOR was lower than 0.1. CONCLUSIONS: The initial FOR value probably does not affect the postoperative developmental outcome. Long-term change in ventricles size after surgery can correlate with psychomotor development of hydrocephalic children. Presumably, there are no differences between two treatment options according to initial FOR values and to changes in FOR values. PMID- 23793950 TI - Use of the human calvaria and skull as alms bowls and drinking vessels by Aghori ascetics in present-day India. AB - INTRODUCTION: The purpose of this article is to discuss the use of the human calvaria and skull as alms bowls and drinking vessels by a sect of Hindu ascetics in present-day India known as the Aghoris. The authors attempt to explain the rationale behind the Aghoris' use of the human calvaria and skull in this manner. METHODS: A review of the literature using standard search engines was conducted to obtain information about the history and philosophy of the Aghori ascetics. RESULTS: Multiple academic references confirm the persistence of the practice of using the human calvaria and skull as alms bowls and drinking vessels among Aghori ascetics in present-day India. This practice is inspired by the Aghoris' monistic philosophy, a principle of which is that observance of social convention deters the individual soul in its journey towards liberation from the cycle of death and rebirth. CONCLUSION: Certain anatomical features of the human body have had religious significance in the past. Multiple academic references concerning the Aghoris argue that religious significance continues to be ascribed to certain components of human anatomy. In the case of the Aghoris, these components are the calvaria and skull. PMID- 23793951 TI - Research on products such as artificial turf is potentially exposed to the same types of industry bias as research on pharmaceuticals. PMID- 23793952 TI - Topographic regulation of neuronal intermediate filaments by phosphorylation, role of peptidyl-prolyl isomerase 1: significance in neurodegeneration. AB - The neuronal cytoskeleton is tightly regulated by phosphorylation and dephosphorylation reactions mediated by numerous associated kinases, phosphatases and their regulators. Defects in the relative kinase and phosphatase activities and/or deregulation of compartment-specific phosphorylation result in neurodegenerative disorders. The largest family of cytoskeletal proteins in mammalian cells is the superfamily of intermediate filaments (IFs). The neurofilament (NF) proteins are the major IFs. Aggregated forms of hyperphosphorylated tau and phosphorylated NFs are found in pathological cell body accumulations in the central nervous system of patients suffering from Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. The precise mechanisms for this compartment-specific phosphorylation of cytoskeletal proteins are not completely understood. In this review, we focus on the mechanisms of neurofilament phosphorylation in normal physiology and neurodegenerative diseases. We also address the recent breakthroughs in our understanding the role of different kinases and phosphatases involved in regulating the phosphorylation status of the NFs. In addition, special emphasis has been given to describe the role of phosphatases and Pin1 in phosphorylation of NFs. PMID- 23793953 TI - Detection of MAPK signal transduction proteins in an ischemia/reperfusion model of mouse intestine using in vivo cryotechnique. AB - Intestinal ischemia and ischemia-reperfusion rapidly progress to tissue destruction and reconstruction of functional organs. To date, precise immunolocalizations and the timing of appearance of cell signaling components under such conditions have not been well visualized. Mitogen-activated protein kinase (MAPK) signal transduction pathways have been reported to be activated under various types of cell damage, and cyclic AMP response element-binding protein (CREB) was directly phosphorylated with various cellular stimuli. In this study, both the expression and the immunolocalization of ERK1/2, a member of the MAPK family, were examined in mouse intestinal tissues by in vivo cryotechnique, which is useful to retain soluble molecules including cell signaling molecules. Under normal conditions, although ERK was widely immunolocalized in the cytoplasm of epithelial cells, phosphorylated (p) ERK1/2 was slightly detected in a small amount of epithelial cells in crypt and top parts of the villi. In 5 min ischemia, more pERK1/2 immunolocalization was detected in epithelial cells of the crypt part. Up to 60 min, the pERK1/2 immunoreactivity was remarkably increased in wide areas of epithelial cells. In the 20 and 60 min ischemia groups, phosphorylated CREB was also immunostained in the nuclei of the same epithelial cell areas of pERK1/2. In 20 min ischemia with 60 min reperfusion experiments, pERK1/2 immunointensity was reduced in the crypt areas. In 60 min ischemia with 60 min reperfusion, however, it was still strongly immunolocalized in epithelial cells of the crypts. Thus, rapidly changing ERK1/2 phosphorylation was visualized in the intestinal epithelial stem cells of mouse small intestine. PMID- 23793955 TI - Climate change effect on Betula (birch) and Quercus (oak) pollen seasons in the United States. AB - Climatic change is expected to affect the spatiotemporal patterns of airborne allergenic pollen, which has been found to act synergistically with common air pollutants, such as ozone, to cause allergic airway disease (AAD). Observed airborne pollen data from six stations from 1994 to 2011 at Fargo (North Dakota), College Station (Texas), Omaha (Nebraska), Pleasanton (California), Cherry Hill and Newark (New Jersey) in the US were studied to examine climate change effects on trends of annual mean and peak value of daily concentrations, annual production, season start, and season length of Betula (birch) and Quercus (oak) pollen. The growing degree hour (GDH) model was used to establish a relationship between start/end dates and differential temperature sums using observed hourly temperatures from surrounding meteorology stations. Optimum GDH models were then combined with meteorological information from the Weather Research and Forecasting (WRF) model, and land use land coverage data from the Biogenic Emissions Land use Database, version 3.1 (BELD3.1), to simulate start dates and season lengths of birch and oak pollen for both past and future years across the contiguous US (CONUS). For most of the studied stations, comparison of mean pollen indices between the periods of 1994-2000 and 2001-2011 showed that birch and oak trees were observed to flower 1-2 weeks earlier; annual mean and peak value of daily pollen concentrations tended to increase by 13.6%-248%. The observed pollen season lengths varied for birch and for oak across the different monitoring stations. Optimum initial date, base temperature, and threshold GDH for start date was found to be 1 March, 8 degrees C, and 1,879 h, respectively, for birch; 1 March, 5 degrees C, and 4,760 h, respectively, for oak. Simulation results indicated that responses of birch and oak pollen seasons to climate change are expected to vary for different regions. PMID- 23793954 TI - Microbial volatile emissions as insect semiochemicals. AB - We provide a synthesis of the literature describing biochemical interactions between microorganisms and insects by way of microbial volatile organic compound (MVOC) production. We evaluated the functionality and ecological context of MVOC signals, and explored important metabolic pathways involved in MVOC production. The cosmopolitan distribution of microorganisms creates a context for frequent, and frequently overlooked, insect responses to microbial emissions. There are numerous instances of MVOCs being closely associated with insect feeding behaviors, but some MVOCs are also powerful repellants. Emissions from microorganisms in situ may signal aspects of habitat suitability or potential exposure to entomopathogens. In some ecosystems, bacterial or fungal volatiles can also incite insect aggregations, or MVOCs can resemble sexual pheromones that elicit mating and oviposition behaviors from responding insects. A single microorganism or MVOC can have different effects on insect behaviors, especially across species, ontogenies, and habitats. There appears to be a multipartite basis for insect responses to MVOCs, and complex tritrophic interactions can result from the production of MVOCs. Many biochemical pathways for behaviorally active volatile production by microbial species are conserved across large taxonomic groupings of microorganisms. In addition, there is substantial functional redundancy in MVOCs: fungal tissues commonly produce polyketides and short-chain alcohols, whereas bacterial tissues tend to be more commonly associated with amines and pyrazines. We hypothesize that insect olfactory responses to emissions from microorganisms inhabiting their sensory environment are much more common than currently recognized, and that these signals represent evolutionarily reliable infochemicals. Insect chemoreception of microbial volatiles may contribute to the formation of neutral, beneficial, or even harmful symbioses and provide considerable insight into the evolution of insect behavioral responses to volatile compounds. PMID- 23793956 TI - Poaceae pollen in the air depending on the thermal conditions. AB - The relationship between the meteorological elements, especially the thermal conditions and the Poaceae pollen appearance in the air, were analysed as a basis to construct a useful model predicting the grass season start. Poaceae pollen concentrations were monitored in 1991-2012 in Krakow using the volumetric method. Cumulative temperature and effective cumulative temperature significantly influenced the season start in this period. The strongest correlation was seen as the sum of mean daily temperature amplitudes from April 1 to April 14, with mean daily temperature>15 degrees C and effective cumulative temperature>3 degrees C during that period. The proposed model, based on multiple regression, explained 57% of variation of the Poaceae season starts in 1991-2010. When cumulative mean daily temperature increased by 10 degrees C, the season start was accelerated by 1 day. The input of the interaction between these two independent variables into the factor regression model caused the increase in goodness of model fitting. In 2011 the season started 5 days earlier in comparison with the predicted value, while in 2012 the season start was observed 2 days later compared to the predicted day. Depending on the value of mean daily temperature from March 18th to the 31st and the sum of mean daily temperature amplitudes from April 1st to the 14th, the grass pollen seasons were divided into five groups referring to the time of season start occurrence, whereby the early and moderate season starts were the most frequent in the studied period and they were especially related to mean daily temperature in the second half of March. PMID- 23793957 TI - Meteorological factors are associated with hemorrhagic fever with renal syndrome in Jiaonan County, China, 2006-2011. AB - This study examined the effect of meteorological factors on the occurrence of hemorrhagic fever with renal syndrome (HFRS) using a generalized additive model with penalized smoothing splines in Jiaonan, China, from 2006 to 2011. The dose response relationship was first examined, and then the association between daily meteorological variables and HFRS occurrence was investigated according to the dose-response curves. There were two linear segments in the temperature-HFRS relationship curve. When daily temperature was lower than 17 degrees C, a positive association was found [with excessive risk (ER) for 1 degrees C increase on the current day being 2.56 %, 95 % confidence interval (CI): 0.36 % to 4.80 %]. An inverse association was found when daily temperature was higher than 17 degrees C [ER for 1 degrees C increase on the current day was -12.82 % (95 % CI: -17.51 % to -7.85 %)]. Inverse associations were observed for relative humidity [ER for 1 % increase on lag day 4 was -1.21 % (95 % CI: -1.63 % to -0.79 %)] and rainfall [ER for 1 mm increase on lag day 1 was -2.20 % (95 % CI: -3.56 % to -0.82 %)]. Meteorological factors might be important predictor of HFRS epidemics in Jiaonan County. PMID- 23793958 TI - Precise reconstruction of veins and bile ducts in rat liver transplantation. AB - Rat orthotopic liver transplantation (ROLT) remains a technically demanding procedure, especially regarding the reconstruction of the suprahepatic vena cava (SHVC). In this study, a new microsuture technique was developed for anastomosis of the SHVC, and a special single-groove cuff and blade-cut stent were introduced. With these modified techniques, we aimed to make a precise anastomosis of the SHVC and to provide optimal cuffs and stents for the reconstruction of the veins and bile ducts. According to different microsuture techniques for the SHVC and different types of cuffs and stents, three ROLT groups were created to compare the operation times and prognoses. Sham operations were performed as controls in the fourth group. The time expenditures with each step were compared among the transplantation groups. Biochemical parameters were tested at the end of a 1-month observation period. The short- and long-term survival rates of the transplantation groups were recorded and compared. Our new microsuture technique was faster than the conventional continuous suture technique for SHVC anastomosis (P < 0.05). The use of a single-groove cuff for reconstruction of the portal vein and the infrahepatic vena cava shortened the anastomotic time (P < 0.05). The use of blade-cut stents resulted in fewer biliary complications and better survival over the short and long terms (P < 0.05). Our new microsuture technique and the single-groove cuffs proved to be a precise method for venous reconstruction which shortened the anhepatic time and the anastomotic time significantly. The blade-cut stents apparently reduced the incidence of biliary complications. In summary, with this precise microsuture technique and delicate cuffs and stents, excellent long-term survival can be achieved easily and stably for ROLT. PMID- 23793959 TI - Biophysical characterization of bladder cancer cells with different metastatic potential. AB - Specific membrane capacitance (SMC) and Young's modulus are two important parameters characterizing the biophysical properties of a cell. In this work, the SMC and Young's modulus of two cell lines, RT4 and T24, corresponding to well differentiated (low grade) and poorly differentiated (high grade) urothelial cell carcinoma (UCC), respectively, were quantified using microfluidic and AFM measurements. Quantitative differences in SMC and Young's modulus values of the high-grade and low-grade UCC cells are, for the first time, reported. PMID- 23793960 TI - Resveratrol induces pro-oxidant effects and time-dependent resistance to cytotoxicity in activated hepatic stellate cells. AB - Resveratrol (RSV) is known for its antioxidant properties; however, this compound has been proposed to have cytotoxic and pro-oxidant effects depending on its concentration and time of exposure. We previously reported the cell cycle arrest effect of low doses of RSV in GRX cells, an activated hepatic stellate cell model. Here, we evaluated the effects of RSV treatment (0.1-50 MUM) for 24 and 120 h on GRX viability and oxidative status. Only treatment with 50 MUM of RSV reduced the amount of live cells. However, even low doses of RSV induced an increased reactive species production at both treatment times. While being diminished within 24 h, RSV induced an increase in the SOD activity in 120 h. The cellular damage was substantially increased at 24 h in the 50 MUM RSV-treated group, as indicated by the high lipoperoxidation, which may be related to the significant cell death and low proliferation. Paradoxically, this cellular damage and lipoperoxidation were considerably reduced in this group after 120 h of treatment while the surviving cells proliferated. In conclusion, RSV induced a dose-dependent pro-oxidant effect in GRX cells. The highest RSV dose induced oxidative-related damage, drastically reducing cell viability; but this cytotoxicity seems to be attenuated during 120 h of treatment. PMID- 23793961 TI - Extracapsular dissection technique with the cotton swab for pituitary adenomas through an endoscopic endonasal approach -- how I do it. AB - BACKGROUND: Pituitary adenomas are often encased in a histological pseudocapsule that separates the tumor from the normal gland. Transsphenoidal adenoma resection may be performed either in an intra- or an extracapsular technique. The extracapsular fashion offers anatomical orientation, removal of a security margin, reduced risk of opening the arachnoid layer with subsequent CSF flow and identification of invasion. METHOD: The sella turcica is approached through the classic endoscopic endonasal route. After opening the dura of the sellar floor, the interface between the compressed tissue and the normal gland is used as a surgical plane for dissection. Performing slight counter-traction with the suction tube, the cleavage plane is identified and stepwise unsealed in an atraumatic fashion with the cotton swab. Once the cleavage plane is partially loosened, repeated twisting movements are performed with the cotton swab to enucleate the pseudocapsule and adenoma. CONCLUSION: Both micro- and macroadenomas presenting a pseudocapsule may be resected in the extracapsular dissection technique with the cotton swab. Operating in an endoscopic three- to four hands technique enables to visualize the anatomic planes and perform twisting movements with the cotton swab separating pseudocapsule and tumor in order to enucleate the adenoma. PMID- 23793962 TI - Cerebellar pilocytic astrocytoma in adults: a management paradigm for a rare tumour. AB - BACKGROUND: Pilocytic astrocytoma is one of the commonest subtypes of glioma to affect children. However, they are rarely diagnosed in patients over the age of 18 years. In adults, these tumours appear more frequently supra-tentorially than in the cerebellum and some reports suggest a different clinical course in adults. We reviewed ten patients aged 18 or over who had been operated on for cerebellar pilocytic astrocytoma to assess the impact of tumour biology and extent of resection on outcome in adults. METHOD: Patients were identified from a neuropathology database and a retrospective chart review of ten patients was performed. Recorded data included patient demographics, tumour location, presenting features, radiological appearance, extent of surgical resection, tumour recurrence and Ki-67 proliferation index. RESULTS: Nine patients were men and one patient was a woman. Median follow up is 41.5 months (range 15-334 months). Complete surgical resection was achieved in nine of the patients operated in our institution. One patient had prior subtotal resection elsewhere. Tumour recurrence was seen only in the two patients with subtotal resection, at 7 and 25 years. Ki-67 ranged from <1 to 10% and appears to have no correlation to recurrence. No patients in this series had adjuvant treatment. CONCLUSIONS: Cerebellar pilocytic astrocytomas in adults should be treated with macroscopic complete surgical resection whenever possible. If this is achieved, long-term survival rates are excellent, whereas subtotal resection carries a high risk of tumour recurrence. Ki-67 is less important prognostically than the extent of initial resection. PMID- 23793963 TI - Opinions from the experts: exploring what prostate cancer patients should know about post-operative radiotherapy. AB - The present study investigated health professionals' opinions about important questions that should be discussed with patients who may require post prostatectomy radiotherapy. A 74-question survey was conducted among radiation oncologists, urologists, nurses, and radiation therapists involved in the care of prostate cancer patients. Survey questions covered six domains: understanding my situation and prostate cancer diagnosis, making a decision, radiotherapy: procedures involved, potential benefits, side effects, and my support network during radiation treatment. Respondents rated the importance of addressing these questions as either essential, important, no opinion, or avoid with a hypothetical post-prostatectomy case. The majority of questions were rated as either essential or important. There was disagreement between professions on essential questions, mostly between nurses and urologists in the side-effects domain. There was agreement between all professions regarding which questions should be avoided. PMID- 23793964 TI - A crash course in medical writing for health profession students. AB - The production of publications is a key component of one's career advancement in medicine. The goal of this piece is to discuss five tips to help health profession students get started in medical writing. First, students should take full advantage of the time-saving resources at the local academic biomedical library. Second, outlining a manuscript is one of the essential first steps for producing a successful, high-quality publication. Third, planning the manuscript and writing efficiently is critical since many young authors are either in medical school or residency and do not have ample time to devote to the writing process. Fourth, communicating complex concepts, thoughts, ideas, and observations in a simple way is important and helps limit redundancies, awkward passages, and improves reader comprehension. Lastly, a student can maximize their chances at publication if they are persistent in how they approach manuscript submission. The chances for successful publication of a project can be increased if young authors consider the tips supplied here. PMID- 23793965 TI - Fluorescein for vascular and oncological neurosurgery. PMID- 23793966 TI - Long-term outcome of surgical treatment of patients with intractable epilepsy associated with schizencephaly. AB - BACKGROUND: Schizencephaly is a developmental anomaly of the brain that is sometimes associated with intractable seizures. Patients that suffer from medically refractory seizures may be considered for surgical treatment. METHOD: Five patients with intractable epilepsy associated with schizencephaly were studied. Evaluation methods included medical history assessment, neurological examination, magnetic resonance imaging (MRI) with three-dimensional (3D) surface rendering, positron emission tomography (PET), video-electroencephalogram (EEG) monitoring with surface electrodes and subdural grid electrodes, sodium amobarbital test, and neuropsychological assessments. Topectomy was performed close to the schizencephalic cleft in two patients, and at an area distant from the cleft in one under the guidance of electrocorticography (ECoG). Temporal lobectomy was performed in two patients. RESULTS: MRI revealed unilateral schizencephaly in all five patients. Video-EEG monitoring recorded simple partial seizures in two patients and complex partial seizures in three patients. The epileptogenic zone was localized close to the schizencephalic cleft in two patients, distant to the cleft in one patient, and in the temporal lobe in two patients. Postoperatively, one of two patients with temporal lobectomy and one of three patients with topectomy were seizure-free at 1-year follow-up. Three patients experienced marked seizure reduction but were not seizure-free at 1 year; however, at the follow-up periods of 2.5 years and 6.5 years, two of these three patients were seizure free. One patient who underwent temporal lobectomy began to have very brief losses of consciousness lasting 1-3 s (3-4 times per year). Neurological complications included temporary upper monoparesis in one and hemiparesis in one. CONCLUSIONS: The abnormal cortex lining schizencephalic clefts and cortical tissues near the cleft may be epileptogenic. Areas distant to the cleft may also be the source of seizures. Careful evaluation should be performed to define the epileptogenic zone in patients with intractable epilepsy associated with schizencephaly, and meticulous resection of the epileptogenic zone can lead to good seizure control. PMID- 23793967 TI - To operate or not--the impact of a lecture on radical glioblastoma surgery and different treatment options on decision-making for oneself and patients. AB - BACKGROUND: Clinical decision-making involves a complex interaction between patients and caregivers. The medical knowledge and values of caregivers are essential for treatment recommendations. This study was undertaken to evaluate treatment recommendations by a group of Scandinavian neurosurgeons before and after an expert lecture on glioblastoma surgery. METHOD: An interactive voting system was used to record responses to four questions regarding glioblastoma management before and after a 25-min lecture on the benefit of radical glioblastoma surgery. RESULTS: The majority of the audience aimed at radical surgery combined with radiotherapy before (76%) and after (88%) the lecture. The proportion who recommended immediate postoperative follow-up by MRI increased from 34% to 75%. Fourteen percent (before) and 45% (after) recommended renewed surgery to remove small residuals in patients, while 52% (before) and 60% (after) would have wanted to be re-operated if they themselves had been patients. CONCLUSION: The views on optimum management differed widely in a relatively homogeneous group of neurosurgeons. The lecture had a major impact on decision making. A large proportion of the attendees recommended different management strategies for themselves and for their patients. The findings indicated the need to analyze the evaluation of medical knowledge, discuss the ethics of decision making and encourage second opinions for serious neurosurgical decisions. PMID- 23793968 TI - The transnational alliance for genetic counseling: promoting international communication and collaboration. AB - The Transnational Alliance for Genetic Counseling seeks to promote communication and collaboration among genetic counselor educators, internationally. Connecting and building global relationships among colleagues also promotes the development of the genetic counseling profession. Genetic counselors everywhere can achieve deeper understanding of their work by seeking international perspectives. PMID- 23793969 TI - Use of genetic tests among neurologists and psychiatrists: knowledge, attitudes, behaviors, and needs for training. AB - This study explores neurologists' and psychiatrists' knowledge, attitudes, and practices concerning genetic tests. Psychiatrists (n = 5,316) and neurologists (n = 2,167) on the American Medical Association master list who had agreed to receive surveys were sent an email link to a survey about their attitudes and practices regarding genetic testing; 372 psychiatrists and 163 neurologists responded. A higher proportion of neurologists (74%) than psychiatrists (14%) who responded to the survey had ordered genetic testing in the past 6 months. Overall, most respondents thought that genetic tests should be performed more frequently, but almost half believed genetic tests could harm patients psychologically and considered legal protections inadequate. Almost half of neurologists (49%) and over 75% of psychiatrists did not have a genetics professional to whom to refer patients; those who had ordered genetic tests were more likely than those who did not do so to have access to a genetic counselor. Of respondents, 10% had received patient requests not to document genetic information and 15% had received inquiries about direct-to-consumer genetic testing. Neurologists reported themselves to be relatively more experienced and knowledgeable about genetics than psychiatrists. These data, the first to examine several important issues concerning knowledge, attitudes and behaviors of neurologists and psychiatrists regarding genetic tests, have important implications for future practice, research, and education. PMID- 23793970 TI - Treatment for ischial tuberosity avulsion fractures in adolescent athletes. AB - PURPOSE: Avulsion fractures of the ischial tuberosity are rare sports injuries typically occurring in young athletes. Their misdiagnosis may lead to chronic pain or disability. The aim of this study is to report a retrospective series of patients sustaining a fracture of the ischial tuberosity and to propose decision guidelines. METHODS: The mechanism of accident, the diagnostic management, the mode of treatment and outcome after avulsion fractures of the ischial tuberosity in adolescents were analysed. RESULTS: Thirteen patients (1 female and 12 males) with a median age of 15 years (range 13-16 years) with an avulsion fracture of the ischial tuberosity were included. Twelve of these patients suffered from sports injuries leading to the avulsion fracture. Five of our patients with a displacement of >15 mm were treated operatively. The outcome was excellent in cases of acute presentation and osteosynthesis. Eight patients were treated conservatively: four of them showed a displacement of <15 mm and had an excellent outcome; and the other four patients had a displacement of >15 mm. Two of those patients had excellent outcome with regular bone healing, the remaining two patients developed pseudarthrosis associated with a good outcome. CONCLUSION: The present paper shows that in patients with displacement of <15 mm, conservative treatment yields excellent results and early operative intervention should be considered in physically active patients with displacement of >15 mm. PMID- 23793971 TI - Chondrotoxic effect of intraarticular bupivacaine administration. PMID- 23793972 TI - Letter regarding "The effects of arthroscopic joint debridement in the knee osteoarthritis: results of a meta-analysis". PMID- 23793973 TI - [Basic algorithm for Point-of-Care based hemotherapy: perioperative treatment of coagulopathic patients]. AB - During perioperative treatment of coagulopathic patients the so-called Point-of Care (POC) analyses enable more rapidly available and more comprehensive hemostatic analyses compared to routinely performed conventional coagulation testing, such as activated partial thromboplastin time (aPTT), international normalized ratio (INR), fibrinogen concentration and platelet count. In this review article a hemotherapy algorithm is presented which is based on viscoelastic and aggregometric POC measurements. The algorithm was designed double sided and consists of a general and a special part. The general part contains boxes and fields for sociodemographic data and gives general recommendations for coagulation management and therapy specifications for particular patient collectives and presents proposals for emergency reversal of anticoagulation therapy. The special part refers to basic physiological conditions for hemostasis and asks for measurement results of clot initiation, clot firmness, clot stability and platelet function analyses. Reference values were defined for each parameter and therapeutic options are presented. In cases of persistent coagulopathy despite algorithm-conform therapy, the algorithm could be run through once again. Finally, the algorithm presents therapeutic options for an ultima ratio therapy approach. PMID- 23793974 TI - CAY10593 inhibits the human P2X7 receptor independently of phospholipase D1 stimulation. AB - The P2X7 receptor is a trimeric ATP-gated cation channel important in health and disease. We have observed that the specific phospholipase D (PLD)1 antagonist, CAY10593 impairs P2X7-induced shedding of the 'low affinity' IgE receptor, CD23. The current study investigated the mode of action of this compound on P2X7 activation. Measurements of ATP-induced ethidium(+) uptake revealed that CAY10593 impaired P2X7-induced pore formation in human RPMI 8226 B cells, P2X7-transfected HEK-293 cells and peripheral blood mononuclear cells. Concentration response curves demonstrated that CAY10593 impaired P2X7-induced pore formation in RPMI 8226 cells more potently than the PLD2 antagonist CAY10594 and the non-specific PLD antagonist halopemide. Electrophysiology measurements demonstrated that CAY10593 also inhibited P2X7-induced inward currents. Notably, RT-PCR demonstrated that PLD1 was absent in RPMI 8226 cells, while choline-Cl medium or 1-butanol, which block PLD stimulation and signalling respectively did not impair P2X7 activation in these cells. This data indicates that CAY10593 impairs human P2X7 independently of PLD1 stimulation and highlights the importance of ensuring that compounds used in signalling studies downstream of P2X7 activation do not affect the receptor itself. PMID- 23793975 TI - Preparation of carboxylated Ag nanoparticles as a coating material for medical devices and control of antibacterial activity. AB - Carboxyl group-donated silver (Ag) nanoparticles for coating on medical devices were prepared by a two-phase reduction system in situ. AgNO3 was the Ag ion source, tetraoctylammonium bromide [N(C8H17)4Br] the phase-transfer agent, sodium tetrahydroborate (NaBH4) the reducing agent and 10-carboxy-1-decanthiol (C11H22O2S, CDT) the capping agent. The characterizations of the Ag nanoparticles were conducted by diffuse reflectance Fourier transform infrared (FT-IR) spectroscopy, thermogravimetric differential thermal analysis (TG/DTA) and transmission electron microscope. With CDT capped on Ag nanoparticles, we found that the band around 3,100 cm(-1) was attributed to COO-H stretching vibration, two adsorptions at 2,928 and 2,856 cm(-1) to C-H symmetric/anti-symmetric stretching vibration, and at 1,718 cm(-1) to C=O stretching vibration in the FT IR spectra. The organic components of the carboxylated Ag nanoparticles were 5.8 25.9 wt%, determined by TG/DTA. The particle sizes of the carboxylated Ag nanoparticles were well controlled by the addition of the capping agent, CDT, into the reaction system. The antimicrobial activity of the Ag nanoparticles covered with different contents of CDT against E. coli was evaluated. Smaller size Ag nanoparticles showed higher antibacterial activity, which depended on a surface area that attached easily to a microorganism cell membrane. PMID- 23793976 TI - Laser Doppler imaging evaluation of adipogenesis after adipose tissue-derived stem cell implantation. AB - We need a better method of assessing adipose tissue formation non-invasively than the current one, which requires resecting tissue samples in vivo. The aim of this study was to establish a system to evaluate adipogenesis using laser Doppler imaging (LDI) to measure subcutaneous microcirculation. CGSs containing adipose stem cells with or without bFGF were implanted in the backs of 30 mice. Once per week after implantation, LDI was used to evaluate blood flow at the implantation site. The implantation sites were resected at 6 weeks, and the tissue was weighed. Six weeks after implantation, LDI showed that mice who received CGS with 1 MUg/cm(2) bFGF had the greatest mean blood flow, and these mice had the heaviest resected specimens, which contained the most newly formed adipose tissue. The findings for LDI and the weight findings were compatible. This study indicates that LDI could be used to assess subcutaneous tissue regeneration in vivo in a real-time, non-invasive manner. PMID- 23793977 TI - Responses of phytoplankton and Hyalella azteca to agrichemical mixtures in a constructed wetland mesocosm. AB - We assessed the capability of a constructed wetland to mitigate toxicity of a variety of possible mixtures, such as nutrients only (NO) (nitrogen [N], phosphorus [P]), pesticides only (PO) (atrazine, S-metolachlor, permethrin), and nutrients + pesticides on phytoplankton chlorophyll-a, on 48-h aqueous Hyalella azteca survival and 10-day sediment H. azteca survival and growth. Water and sediment were collected at 10-, 20-, and 40-m distances from inflow and analyzed for nutrients, pesticides, chlorophyll-a, and H. azteca laboratory bioassays. Phytoplankton chlorophyll-a increased 4- to 10 -fold at 7 days after NO treatment. However, responses of chlorophyll-a to PO and nutrients + pesticides were more complex with associated decreases at only 20 m for pesticides only and 10 and 40 m for nutrients + pesticides treatments. H. azteca aqueous survival decreased within the first 48 h of dosing at 10- and 20-m distances during PO and nutrients + pesticides treatments in association with permethrin concentrations. H. azteca sediment survival was unaffected, whereas 10-day growth decreased within 1 day of dosing at all sites during nutrients + pesticides treatment. Constructed wetlands were shown to be an effective agricultural best-management tool for trapping pollutants and mitigating ecological impacts of run-off in agricultural watersheds. PMID- 23793978 TI - Dynamics of organochlorine contaminants in surface water and in Myriophyllum aquaticum plants of the River Xanaes in central Argentina during the annual dry season. AB - The dynamics of organochlorine pesticides (OCPs) and their major metabolites were studied in surface waters and plants of the River Xanaes (province of Cordoba, Argentina) during the annual dry season. The results of the 5-month monitoring study (April to August 2010) showed similar low contamination levels in nonagricultural mountain and agricultural areas in both water and plants. The concentrations of compounds detected in the surface water were <4.5 ng L(-1), whereas concentrations of these substances in Myriophyllum aquaticum plants were <5 MUg kg(-1) (dry weight) with the exception of trans-permethrin (17.6 MUg kg( 1), dry weight). Because no notable differences in the contamination level between samples from the mountain and the agricultural area were observed, it was assumed that OCPs may not play an important role in today's pesticide use in this area. Furthermore, the concentration-time trends for OCPs in the submerged plants showed a generally similar elimination behaviour independent of compound and sampling site, thus indicating an integral rather then a substance-specific process, such as partitioning between the plant and the ambient water. As known, rooted macrophytes can take up contaminants by way of roots, so sediments may be the principal source. To understand the dynamics of these compounds in the river area more deeply, thus further research should include study of the river sediment. PMID- 23793979 TI - Molecular characterization and functional analysis of "fruit-weight 2.2-like" gene family in rice. AB - Tomato fruit-weight 2.2 (FW2.2) was reported to control up to 30 % fruit weight. Recent studies demonstrated that FW2.2-like (FWL) genes also play important roles in plant growth and development. For instance, a maize homolog of FW2.2, named cell number regulator 1 (CNR1), negatively regulates plant and organ size. However, FWL genes in rice have not been characterized yet. In this study, eight FWL genes were identified in rice genome and designated as OsFWL1-8. The chromosome location, gene structure, protein motif, and phylogenetic relationship of OsFWL genes were analyzed. RT-PCR result and microarray data revealed that OsFWL genes exhibited diverse expression patterns and the detailed expression patterns of OsFWL5, 6, and 7 negatively correlated with leaf growth activity. Rice protoplast transient transformation experiment showed that most OsFWL proteins locate at cell membrane but OsFWL8 is present in the nucleus. In addition, the functions of OsFWL genes were investigated by analyzing two T-DNA insertion lines for OsFWL3 and 5. Compared with wild type, the grain weight of osfwl3 mutant and the plant height of osfwl5 mutant were increased by 5.3 and 12.5 %, respectively. We also found that the increase in grain length of osfwl3 mutant was due chiefly to incremental cell number, not cell size and the expression of OsFWL3 negatively correlated with glume growth activity. These results provide a comprehensive foundation for further study of OsFWL functions in rice. PMID- 23793980 TI - Electrically conductive lines on cellulose nanopaper for flexible electrical devices. AB - Highly conductive circuits are fabricated on nanopapers composed of densely packed 15-60 nm wide cellulose nanofibers. Conductive materials are deposited on the nanopaper and mechanically sieved through the densely packed nanofiber networks. As a result, their conductivity is enhanced to the level of bulk silver and LED lights are successfully illuminated via these metallic conductive lines on the nanopaper. Under the same deposition conditions, traditional papers consisting of micro-sized pulp fibers produced very low conductivity lines with non-uniform boundaries because of their larger pore structures. These results indicate that advanced, lightweight and highly flexible devices can be realized on cellulose nanopaper using continuous deposition processes. Continuous deposition on nanopaper is a promising approach for a simple roll-to-roll manufacturing process. PMID- 23793981 TI - [The current state of research in bright light therapy]. AB - The significance of light for the human organism and especially for the mental health is well-established for a long time. Therefore, the impact of light on mood and the use of bright light as a treatment-option for affective disorders have been studied extensively by scientists. Today bright light therapy is the treatment of choice for saisonal affective disorders. In the last years several clinical trials could demonstrate the therapeutic efficacy of bright light therapy for different neurological and psychiatric disorders such as sleep disorders, non-seasonal affective disorders or dementia. This article will give an overview about the neurobiological basis for light therapy and discuss different disorders responsive to light therapy. Finally a short overview about technical aspects of light therapy and new developments in light engineering will be presented. PMID- 23793983 TI - Chemotherapy-induced amenorrhea: a prospective study of brain activation changes and neurocognitive correlates. AB - Chemotherapy-induced amenorrhea (CIA) often occurs in pre- and peri-menopausal BC patients, and while cancer/chemotherapy and abrupt estrogen loss have separately been shown to affect cognition and brain function, studies of the cognitive effects of CIA are equivocal, and its effects on brain function are unknown. Functional MRI (fMRI) during a working memory task was used to prospectively assess the pattern of brain activation and deactivation prior to and 1 month after chemotherapy in BC patients who experienced CIA (n = 9), post-menopausal BC patients undergoing chemotherapy (n = 9), and pre- and post-menopausal healthy controls (n = 6 each). Neurocognitive testing was also performed at both time points. Repeated measures general linear models were used to assess statistical significance, and age was a covariate in all analyses. We observed a group-by time interaction in the combined magnitudes of brain activation and deactivation (p = 0.006): the CIA group increased in magnitude from baseline to post-treatment while other groups maintained similar levels over time. Further, the change in brain activity magnitude in CIA was strongly correlated with change in processing speed neurocognitive testing score (r = 0.837 p = 0.005), suggesting this increase in brain activity reflects effective cognitive compensation. Our results demonstrate prospectively that the pattern of change in brain activity from pre- to post-chemotherapy varies according to pre-treatment menopausal status. Cognitive correlates add to the potential clinical significance of these findings. These findings have implications for risk appraisal and development of prevention or treatment strategies for cognitive changes in CIA. PMID- 23793982 TI - Survey of encoding and decoding of visual stimulus via FMRI: an image analysis perspective. AB - A variety of exciting scientific achievements have been made in the last few decades in brain encoding and decoding via functional magnetic resonance imaging (fMRI). This trend continues to rise in recent years, as evidenced by the increasing number of published papers in this topic and several published survey papers addressing different aspects of research issues. Essentially, these survey articles were mainly from cognitive neuroscience and neuroimaging perspectives, although computational challenges were briefly discussed. To complement existing survey articles, this paper focuses on the survey of the variety of image analysis methodologies, such as neuroimage registration, fMRI signal analysis, ROI (regions of interest) selection, machine learning algorithms, reproducibility analysis, structural and functional connectivity, and natural image analysis, which were employed in previous brain encoding/decoding research works. This paper also provides discussions of potential limitations of those image analysis methodologies and possible future improvements. It is hoped that extensive discussions of image analysis issues could contribute to the advancements of the increasingly important brain encoding/decoding field. PMID- 23793985 TI - Understanding and combating age-related muscle weakness: MYOAGE challenge. PMID- 23793984 TI - Localization of Beclin1 in mouse developing tooth germs: possible implication of the interrelation between autophagy and apoptosis. AB - Our previous study identified the appearance of autophagy in developing tooth germs, and suggested its possible association with apoptosis in odontogenesis. Beclin1 was recently indicated to play a central role in bridging autophagy and apoptosis, and occupied a key position in the process of development. This study hypothesized that Beclin1 may be involved, and act as the molecular basis of the connection between autophagy and apoptosis in odontogenesis. Immunohistochemical analysis showed the spatiotemporal expression pattern of Beclin1 in odontogenesis from embryonic (E) day 13.5 to postnatal (P) day 5.5. At E stages, Beclin1 was mainly immunolocalized in the cytoplasm of the cells in the enamel organ. Meanwhile, the nucleus localization of Beclin1 was detected in part of the stellate reticulum, outer and inner enamel epithelium, especially at E16.5 and E18.5. At P stages, Beclin1 was detected in the cytoplasm of the odontoblasts, besides the dental epithelium cells. Triple immunofluorescence analysis showed the partial colocalization of Beclin1, autophagic marker LC3, or activated caspase-3 in the E14.5 tooth germs, especially the Beclin1(+)LC3(+)Caspase-3(+) cells in the PEK. Furthermore, western blot analysis revealed that the full length (60 kDa) and/or cleaved (50, 37, and 35 kDa) Beclin1 in the developing tooth germs. Taken together, our findings indicate that Beclin1 is involved, and might be responsible for the crosstalk between autophagy and apoptosis in mouse odontogenesis. PMID- 23793986 TI - Predictive factors for successful balloon catheter extraction of esophageal foreign bodies. AB - INTRODUCTION: Foreign bodies in the esophagus are common in children. Time from ingestion to presentation is variable, and may not be known. Our center usually performs Foley catheter balloon extraction under fluoroscopy as the first step to attempt removal to prevent all patients from going to the operating room. The efficacy of this procedure has been reported. However, information is lacking about the relationship between presentation variables and the likelihood of success. METHODS: After IRB approval, we performed a retrospective single-center review from January 1988 to August 2011 of children with an esophageal foreign body. Pearson's correlation was used to evaluate the relationship between variables and successful balloon extraction for P < 0.05. A logistic regression was done to evaluate for independence. RESULTS: 819 patients presented with esophageal foreign bodies, with a mean age of 3.3 years. 572 patients underwent balloon extraction, 83 % successful. Mean ingestion duration was 16.6 h with fluoroscopy time of 2.3 min and mean number of attempts was 1.5. Successful balloon extraction had a negative correlation with refusal to eat, respiratory distress, cough, wheeze, upper respiratory infection symptoms, stridor, fever, duration of ingestion >1 day, unwitnessed ingestion, fluoroscopy time and number of balloon catheter attempts. There was a positive correlation between success and both age and duration of ingestion <1 day. Independent predictive factors were number of balloon catheter attempts. CONCLUSIONS: Patients with longer duration of ingestion, symptoms from the foreign body and increased number of removal attempts have a decreased likelihood of success with balloon catheter extraction and should not undergo prolonged efforts of removal. PMID- 23793987 TI - Systematic review and meta-analysis of studies comparing the perimeatal-based flap and tubularized incised-plate techniques for primary hypospadias repair. AB - PURPOSE: To conduct a systematic review and meta-analysis of studies comparing the perimeatal-based flap (PBF) and tubularized incised-plate (TIP) techniques for primary hypospadias repair and determine whether the two techniques had similar reported outcomes. METHODS: The PubMed, Embase and Cochrane databases were searched using the terms: hypospadias, Snodgrass, TIP*, tubularized incised plate, tubularized incised-plate, Mathieu*, perimeatal-based flap, perimeatal flap, meatal-based flap and meatal based flap. No other limits were used. Inclusion criteria included: primary hypospadias repair only; both including the PBF and TIP techniques; at least one of the quantitative outcomes obtainable from study; comparative studies. RESULTS: Twelve studies fulfilled the inclusion criteria and were included in the final analysis. Meta-analysis showed that there were no significant differences between the two techniques when comparing fistula (OR = 1.47; 95 % CI: 0.82-2.63; P = 0.20), meatal stenosis (OR = 0.53; 95 % CI: 0.24-1.16; P = 0.11), and wound dehiscence (OR = 0.82; 95 % CI: 0.24-2.84; P = 0.76). Both the studies which assessed cosmesis objectively showed a consistent better cosmetic result of the TIP technique (P < 0.05). CONCLUSION: There were no significant differences of complication rates between the two techniques, and the TIP technique was usually of better cosmesis. Given the large clinical heterogeneity among studies, future more well-designed studies with full data and uniform criterion were awaited. PMID- 23793988 TI - Targeting myofascial taut bands by ultrasound. AB - Myofascial pain syndrome (MPS) is a frequent diagnosis in chronic pain and is characterized by tender, taut bands known as trigger points. The trigger points are painful areas in skeletal muscle that are associated with a palpable nodule within a taut band of muscle fibers. Despite the prevalence of myofascial pain syndrome, diagnosis is based on clinical criteria alone. A growing body of evidence that suggests that taut bands are readily visualized under ultrasound guided exam, especially when results are correlated with elastography, multidimensional imaging, and physical exam findings such as local twitch response. The actual image characteristic in B mode appears to be controversial. Ultrasonography provides an objective modality to assist with diagnosis and treatment of trigger points in the future. PMID- 23793989 TI - Host pigment epithelium-derived factor (PEDF) prevents progression of liver metastasis in a mouse model of uveal melanoma. AB - Uveal melanoma (UM) has a 30 % 5-year mortality rate, primarily due to liver metastasis. Both angiogenesis and stromagenesis are important mechanisms for the progression of liver metastasis. Pigment epithelium-derived factor (PEDF), an anti-angiogenic and anti-stromagenic protein, is produced by hepatocytes. Exogenous PEDF suppresses metastasis progression; however, the effects of host produced PEDF on metastasis progression are unknown. We hypothesize that host PEDF inhibits liver metastasis progression through a mechanism involving angiogenesis and stromagenesis. Mouse melanoma cells were injected into the posterior ocular compartment of PEDF-null mice and control mice. After 1 month, the number, size, and mean vascular density (MVD) of liver metastases were determined. The stromal component of hepatic stellate cells (HSCs) and the type III collagen they produce was evaluated by immunohistochemistry. Host PEDF inhibited the total area of liver metastasis and the frequency of macrometastases (diameter >200 MUm) but did not affect the total number of metastases. Mice expressing PEDF exhibited significantly lower MVD and less type III collagen production in metastases. An increase in activated HSCs was seen in the absence of PEDF, but this result was not statistically significant. In conclusion, host PEDF inhibits the progression of hepatic metastases in a mouse model of UM, and loss of PEDF is accompanied by an increase in tumor blood vessel density and type III collagen. PMID- 23793990 TI - Lipid absorption triggers drug supersaturation at the intestinal unstirred water layer and promotes drug absorption from mixed micelles. AB - PURPOSE: To evaluate the potential for the acidic intestinal unstirred water layer (UWL) to induce drug supersaturation and enhance drug absorption from intestinal mixed micelles, via the promotion of fatty acid absorption. METHODS: Using a single-pass rat jejunal perfusion model, the absorptive-flux of cinnarizine and (3)H-oleic acid from oleic acid-containing intestinal mixed micelles was assessed under normal acidic microclimate conditions and conditions where the acidic microclimate was attenuated via the co-administration of amiloride. As a control, the absorptive-flux of cinnarizine from micelles of Brij(r) 97 (a non-ionizable, non-absorbable surfactant) was assessed in the absence and presence of amiloride. Cinnarizine solubility was evaluated under conditions of decreasing pH and decreasing micellar lipid content to assess likely changes in solubilization and thermodynamic activity during micellar passage across the UWL. RESULTS: In the presence of amiloride, the absorptive flux of cinnarizine and (3)H-oleic acid from mixed micelles decreased 6.5-fold and 3.0-fold, respectively. In contrast, the absorptive-flux of cinnarizine from Brij(r) 97 micelles remained unchanged by amiloride, and was significantly lower than from the long-chain micelles. Cinnarizine solubility in long-chain micelles decreased under conditions where pH and micellar lipid content decreased simultaneously. CONCLUSIONS: The acidic microclimate of the intestinal UWL promotes drug absorption from intestinal mixed micelles via the promotion of fatty acid absorption which subsequently stimulates drug supersaturation. The observations suggest that formulations (or food) containing absorbable lipids (or their digestive precursors) may outperform formulations that lack absorbable components since the latter do not benefit from lipid absorption-induced drug supersaturation. PMID- 23793991 TI - Omeprazole and PGC-formulated heparin binding epidermal growth factor normalizes fasting blood glucose and suppresses insulitis in multiple low dose streptozotocin diabetes model. AB - PURPOSE: Our objective was to develop novel nanocarriers (protected graft copolymer, PGC) that improve the stability of heparin binding EGF (HBEGF) and gastrin and then to use PGC-formulated HBEGF (PGC-HBEGF) and Omeprazole (+/- PGC gastrin) for normalizing fasting blood glucose (FBG) and improving islet function in diabetic mice. METHODS: HBEGF, PGC-HBEGF, Omeprazole, Omeprazole + PGC-HBEGF, Omeprazole + PGC-gastrin + PGC-HBEGF and epidermal growth factor (EGF) + gastrin were tested in multiple low dose streptozotocin diabetic mice. RESULTS: Omeprazole + PGC-HBEGF normalized FBG and is better than EGF + gastrin at improving islet function and decreasing insulitis. Groups treated with Omeprazole, Omeprazole + PGC-HBEGF, or EGF + gastrin have significantly improved islet function versus saline control. All animals that received PGC-HBEGF had significantly reduced islet insulitis versus saline control. Non-FBG was lower for Omeprazole + PGC-gastrin + PGC-HBEGF but Omeprazole + PGC-HBEGF alone showed better FBG and glucose tolerance. CONCLUSIONS: Omeprazole + PGC-HBEGF provides a sustained exposure to both EGFRA and gastrin, improves islet function, and decreases insulitis in multiple low dose streptozotocin diabetic mice. Although HBEGF or EGF elevates non-FBG, it facilitates a reduction of insulitis and, in the presence of Omeprazole, provides normalization of FBG at the end of treatment. The study demonstrates Omeprazole and PGC-HBEGF is a viable treatment for diabetes. PMID- 23793992 TI - Superoxide dismutase administration, a potential therapy against oxidative stress related diseases: several routes of supplementation and proposal of an original mechanism of action. AB - Oxidative stress, involved in many diseases, is defined as an impaired balance between reactive oxygen species (ROS) production and antioxidant defences. Antioxidant enzymes such as superoxide dismutase (SOD) play a key role in diminishing oxidative stress. Thus, the removal of ROS by exogenous SODs could be an effective preventive strategy against various diseases. The poor bioavailability of exogenous SODs has been criticized. However, improvements in SOD formulation may overcome this limitation and boost interest in its therapeutic properties. Here, we provide a review of animal and human studies about SODs supplementation in order to evaluate their therapeutic value. Protective effects have been observed against irradiation, carcinogenesis, apoptosis and neurodegeneration. SODs administration has also been reported to alleviate inflammatory, infectious, respiratory, metabolic and cardiovascular diseases and genitourinary and fertility disorders, raising the question of its mechanism of action in these diverse situations. Some authors have shown an increase in endogenous antioxidant enzymes after exogenous SODs administration. The induction of endogenous antioxidant defence and, consequently, a decrease in oxidative stress, could explain all the effects observed. Further investigations need to be carried out to test the hypothesis that SODs supplementation acts by inducing an endogenous antioxidant defence. PMID- 23793993 TI - Bioactive lipids-based pH sensitive micelles for co-delivery of doxorubicin and ceramide to overcome multidrug resistance in leukemia. AB - PURPOSE: Construction of a novel PEGylated bioactive lipids-based micelle system for co-delivery of doxorubicin (DOX) and short chain ceramide (C6-ceramide) to overcome multidrug resistance in leukemia. METHODS: The PEGylated bioactive lipids-based micelle system was constructed via electrostatic and hydrophobic interactions among DOX, bioactive lipids PazPC and C6-ceramide. The micellar formulation was characterized in terms of size, zeta potential, stability and release behavior, etc., and in vitro cytotoxicity, in vivo antitumor efficacy and the underlying mechanism were further evaluated. RESULTS: This novel micellar system showed small size (~15 nm), high drug encapsulation efficiency (>90%), good stability and endosomal acid-triggered release of DOX. Synergistic cytotoxic effects between DOX and bioactive lipid C6-ceramide in P-gp overexpressing drug resistant leukemia P388/ADR cells were observed. The mechanistic studies demonstrated that modulation of drug efflux system and induction of apoptotic effects by lipids were responsible for the synergistic effects between DOX and C6 ceramide in drug resistant leukemia P388/ADR cells. Using an in-vivo P388/ADR leukemia mouse model, the median survival time of the DOX-loaded PEGylated micelles with PazPC and C6-ceramide as major components was significantly greater than that of free DOX and control group. CONCLUSIONS: We developed a novel pH sensitive bioactive lipids-based micellar formulation which could potentially be useful in delivering chemotherapeutic drug DOX and provide a novel strategy to increase the therapeutic index for drug resistant leukemia treatment. PMID- 23793994 TI - Dual physiologically based pharmacokinetic model of liposomal and nonliposomal amphotericin B disposition. AB - PURPOSE: To investigate the biodistribution of amphotericin B (AmB) in mice and rats following administration of liposomal AmB (AmBisome(r)) using a physiologically-based pharmacokinetic (PBPK) modeling framework and to utilize this approach for predicting AmBisome(r) pharmacokinetics in human tissues. METHODS: AmB plasma and tissue concentration-time data, following single and multiple intravenous administration of nonliposomal and liposomal AmB to mice and rats, were extracted from literature. The whole-body PBPK model was constructed and incorporated nonliposomal and liposomal subcompartments. Various structural models for individual organs were evaluated. Allometric relationships were incorporated into the model to scale parameters based on species body weight. RESULTS: A non-Michaelis-Menten mechanism was included into the structure of the liver and spleen liposomal compartments to describe saturable uptake of particles by the reticuloendothelial system. The model successfully described plasma and tissue pharmacokinetics of AmB after administration of AmBisome(r) to rats and mice. CONCLUSIONS: The dual PBPK model demonstrated good predictive performance by reasonably simulating AmB exposure in human tissues. This modeling framework can be potentially utilized for optimizing AmBisome(r) therapy in humans and for investigating pathophysiological factors controlling AmB pharmacokinetics and pharmacodynamics. PMID- 23793995 TI - Use of alpha1-microglobulin for diagnosing chronic interstitial nephropathy. AB - alpha1-Microglobulin (alpha1M) is a low molecular weight protein and has been best characterized for detecting acute lesions of proximal tubules (Bonventre in Contrib Nephrol 156:213-219, 2007). This study has tried to evaluate the use of alpha1M for the differential diagnosis of chronic interstitial nephropathy. 145 patients were recruited [81 men and 64 women, mean age 61.8 +/- 16.7 years, 64.8 % have an estimated glomerular filtration (GFR) <60 ml/min]. Urinary alpha1M was evaluated using an immunonephelometric assay. 82 patients were diagnosed as having chronic interstitial nephritis (CIN), and 46 patients have been previously diagnosed of glomerulonephritis (GN). A group of hypertensive patients without renal disease was used as control (n = 17). Patients in GN group had the highest alpha1M excretion (15.05 mg/24 h). When the alpha1M/albuminuria rates were calculated, the CIN group had the highest rate (1.03 mg/mg) and the GN group had the lowest rate (0.04 mg/mg) (p < 0.001). When the alpha1M/proteinuria rates were calculated, the results were rather similar. The AUC for CIN group was 0.785, and the one for GN group was 0.139. Patients with estimated GFR <60 ml/min showed a higher excretion of alpha1M (18.75, 8.75-40.00 mg/24 h). Nevertheless, alpha1M/albuminuria and alpha1M/proteinuria rates were still higher in CIN patients with GFR >=60 ml/min. alpha1M urinary excretion is increased in chronic interstitial nephropathy and glomerulonephritis as well as in patients with GFR <60 ml/min. The alpha1M/albuminuria rate and the alpha1M/proteinuria quotient are increased in chronic interstitial nephropathies but decreased in glomerular diseases. PMID- 23793996 TI - Guest editorial: Pathophysiology and management of thrombocytopenia: possible clinical application of TPO receptor agonists. PMID- 23793997 TI - Biotherapeutics for the treatment of multiple sclerosis: hopes and hazards. AB - Multiple sclerosis (MS), the most common cause of neurological disability in young adults, represents the prototypic inflammatory autoimmune disorder of the central nervous system. Increased understanding of the immunopathological processes underlying this disease, advances in biotechnology, development of powerful magnetic resonance imaging technologies together with improvements in clinical trial design have translated into a variety of new and innovative therapeutic avenues. In this review, we will highlight recent therapeutic developments in MS and critically discuss new challenges associated with these new treatment options. PMID- 23793998 TI - Heat- and cold-stress effects on cardiovascular mortality and morbidity among urban and rural populations in the Czech Republic. AB - Several studies have examined the relationship of high and low air temperatures to cardiovascular mortality in the Czech Republic. Much less is understood about heat-/cold-related cardiovascular morbidity and possible regional differences. This paper compares the effects of warm and cold days on excess mortality and morbidity for cardiovascular diseases (CVDs) in the city of Prague and a rural region of southern Bohemia during 1994-2009. Population size and age structure are similar in the two regions. The results are evaluated for selected population groups (men and women). Excess mortality (number of deaths) and morbidity (number of hospital admissions) were determined as differences between observed and expected daily values, the latter being adjusted for long-term changes, annual and weekly cycles, and epidemics of influenza/acute respiratory infections. Generally higher relative excess CVD mortality on warm days than on cold days was identified in both regions. In contrast to mortality, weak excess CVD morbidity was observed for both warm and cold days. Different responses of individual CVDs to heat versus cold stress may be caused by the different nature of each CVD and different physiological processes induced by heat or cold stress. The slight differences between Prague and southern Bohemia in response to heat versus cold stress suggest the possible influence of environmental and socioeconomic factors such as the effects of urban heat island and exposure to air pollution, lifestyle differences, and divergence in population structure, which may result in differing vulnerability of urban versus rural population to temperature extremes. PMID- 23794000 TI - The NLRP3 inflammasome activation in human or mouse cells, sensitivity causes puzzle. PMID- 23794001 TI - Structure and receptor-binding properties of an airborne transmissible avian influenza A virus hemagglutinin H5 (VN1203mut). AB - Avian influenza A virus continues to pose a global threat with occasional H5N1 human infections, which is emphasized by a recent severe human infection caused by avian-origin H7N9 in China. Luckily these viruses do not transmit efficiently in human populations. With a few amino acid substitutions of the hemagglutinin H5 protein in the laboratory, two H5 mutants have been shown to obtain an air-borne transmission in a mammalian ferret model. Here in this study one of the mutant H5 proteins developed by Kawaoka's group (VN1203mut) was expressed in a baculovirus system and its receptor-binding properties were assessed. We herein show that the VN1203mut had a dramatically reduced binding affinity for the avian alpha2,3 linkage receptor compared to wild type but showed no detectable increase in affinity for the human alpha2,6-linkage receptor, using Surface Plasmon Resonance techonology. Further, the crystal structures of the VN1203mut and its complexes with either human or avian receptors demonstrate that the VN1203mut binds the human receptor in the same binding manner (cis conformation) as seen for the HAs of previously reported 1957 and 1968 pandemic influenza viruses. Our receptor binding and crystallographic data shown here further confirm that the ability to bind the avian receptor has to decrease for a higher human receptor binding affinity. As the Q226L substitution is shown important for obtaining human receptor binding, we suspect that the newly emerged H7N9 binds human receptor as H7 has a Q226L substitution. PMID- 23794002 TI - Effects of a genetic counseling model on mothers of children with down syndrome: a Brazilian pilot study. AB - Down syndrome occurs in approximately 1:600 live births. Genetic counseling is indicated for these families and may be beneficial for adaptation to the challenges that accompany by this diagnosis. Although the basic counseling goals are similar, there are many models of genetic counseling practiced around the world. The aim of this article is to report the results of a pilot study that evaluated the level of satisfaction with a model of service delivery of genetic counseling practiced in Brazil, the knowledge assimilated about Down syndrome and whether this process resulted in a feeling of well-being and psychological support. Thirty mothers of under 6-month-old children with Down syndrome were interviewed after having two sessions of genetic counseling in a public healthcare service within a period of 30 days. A semi-structured questionnaire was developed by the researchers to collect identification, socioeconomic and demographic data and to assess the client's satisfaction with the model of genetic counseling. Data were collected using both open and closed questions. The reported level of satisfaction was high. The knowledge assimilated about Down syndrome after only two sessions was considered technically vague by raters in 44 % of cases. Most mothers (96.7 %) reported that genetic counseling was beneficial and provided psychological support. The model was considered satisfactory, but further research is needed to identify ways to improve knowledge retention by this population. These results highlight the utility of referring families for genetic counseling when there is a suspicion of a diagnosis of Down syndrome. PMID- 23794003 TI - Periprosthetic supracondylar femoral fractures above total knee arthroplasty: comparison of the locking and non-locking plating methods. AB - PURPOSE: The purpose of this study was to compare the results and complications of periprosthetic supracondylar femoral fracture treatment using locking or non locking plates. METHODS: A locking compression plate was used in 14 patients, and a non-locking condylar buttress plate was used in 19 patients. There were no significant differences in the demographic data between the two groups. The primary healing rate and bone union time were compared. The Knee Society knee score and range of motion (ROM) were reviewed. The femorotibial angle and alpha and gamma angles were measured using the Knee Society radiological evaluation method. The clinical and radiographic results, complications, and additional surgeries were compared between the two groups. RESULTS: Thirteen of 14 locking plating patients and 11 of 19 non-locking plating patients healed without any additional surgeries. There were no differences in the average bone union time, knee score, or ROM between the two groups. The alignment and position of the implants were better without a loss in the reduction angle of >3 degrees in the locking plating group compared with the non-locking plating group. Locking plate fixation reduced the incidence of overall complications, non-union, malunion, loss of reduction, and additional surgeries compared with non-locking plate fixation. CONCLUSION: Fixation of periprosthetic supracondylar femoral fractures with a locking plate provided satisfactory results with a low risk of complications and additional surgeries compared with fixation with a non-locking plate. LEVEL OF EVIDENCE: III. PMID- 23794004 TI - Influence of the anterior-posterior femoral translation on the range of motion in cruciate-retaining total knee arthroplasty. AB - PURPOSE: The purpose of this study is to evaluate the post-operative range of motion (ROM) of the knee related to the anterior-posterior femoral translation on the tibia observed during surgery in cruciate-retaining total knee arthroplasty (TKA) using a navigation system. Our hypothesis is that the intraoperative anterior-posterior femoral translation is correlated with the post-operative ROM in patients undergoing cruciate-retaining TKA. METHODS: The subjects were 20 patients involving 23 joints. The passive maximum ROM was measured before and 1 year after surgery. In addition, we evaluated the intraoperative anterior posterior femoral translation that was measured after inserting a tensor device from 10 degrees to 120 degrees of knee flexion. The starting point of the anterior-posterior femoral translation was defined as when the femur started to move posteriorly. The anterior-posterior femoral translation 120 was set as the amount of femoral movement from 10 degrees to 120 degrees . RESULTS: The subjects were divided into those with an increased or maintained ROM (group A) and those with a decreased ROM (group B). There were no significant differences between the two groups in terms of the age or pre-operative ROM. The starting point of the anterior-posterior femoral translation was significantly earlier in group B (58.0 +/- 5.7 degrees for group A, 48.7 +/- 3.2 degrees for group B) (P < 0.05). Regarding the anterior-posterior femoral translation 120, Group B showed a larger amount of femoral movement posteriorly than group A (13.0 +/- 6.5 mm for group A, 19.0 +/- 6.2 mm for group B) (P < 0.05). CONCLUSIONS: The present study shows that intraoperative anterior-posterior femoral translation has a significant correlation with the post-operative ROM in patients undergoing cruciate-retaining TKA. If the starting point of the anterior-posterior femoral translation is early and the anterior-posterior femoral translation 120 is large, there is likely to be a decrease in the post-operative ROM. LEVEL OF EVIDENCE: III. PMID- 23794005 TI - Joint line changes after primary total knee arthroplasty: navigated versus non navigated. AB - PURPOSE: Navigation has been introduced to achieve more accurate positioning of the implants after TKA. The scientific attention was mainly paid on limb alignment rather than restoration of the natural joint line. The aim of our study was to compare the accuracy of the joint line restoration in primary TKA with and without navigation. We hypothesized that joint line reconstruction in navigated TKA is more accurate. METHODS: A total of 493 primary TKAs operated in a single medical centre were consecutively selected and divided into two groups. 206 cases were performed computer assisted (BrainLab CI-System), whereas 287 knees were implanted conventionally. For both groups, the joint line position of the knee was determined on standardized calibrated standing pre- and postoperative digital radiographs in ap view by a modified method of Kawamura et al. A joint line shift of more than 8 mm was defined as outlier. RESULTS: In the conventional group, the joint line shift averaged 0.7 mm (+/-4.4 mm), whereas the findings in the computer-assisted cases were in average 0.6 mm (+/-4.5 mm). The joint line was located above 8 mm in 6 % of non-navigated versus 6.8 % of navigated primary TKAs. There were no statistically significant differences of joint line shift between the different component types. A statistically significant relation was not found between joint line shift and leg alignment changes. CONCLUSIONS: Conventional surgical technique allows a precise joint line reconstruction in primary TKA. Navigation did not improve the joint line reconstruction. LEVEL OF EVIDENCE: Diagnostic study, Level III. PMID- 23794006 TI - As a new inflammatory marker for familial Mediterranean fever: neutrophil-to lymphocyte ratio. AB - Familial Mediterranean fever (FMF), which is an autosomal recessive disease, is characterised by recurrent febrile episodes in association with peritonitis, pleuritis and arthritis and has ongoing subclinical inflammation during attack free period. In this study, we aimed to investigate the relationship between FMF with neutrophil-to-lymphocyte ratio (NLR), which is determined in many chronic inflammations as a new potential inflammatory mediator. We included 62 patients and 41 healthy subjects who were similar in terms of age and sex. We found that the NLR values of the patients were significantly higher than those of the control group, and C-reactive protein values were correlated with NLR. Another finding was the NLR values were significantly higher in the FMF patient with M694V mutation than with other mutations. As a result, NLR might be used in the FMF patient as an indicator of the subclinical inflammation, and the FMF patients with M694V mutation should be followed up closely because of increased subclinical inflammation risk. PMID- 23794007 TI - Asparaginase Erwinia chrysanthemi (Erwinaze(r)): a guide to its use in acute lymphoblastic leukemia in the USA. AB - Asparaginase Erwinia chrysanthemi (Erwinaze(r)) is approved in the USA for use in patients with acute lymphoblastic leukemia (ALL) who have developed hypersensitivity to Escherichia coli-derived asparaginase. The approved regimen of intramuscular Erwinaze(r) was associated with sustained, clinically meaningful asparaginase activity in patients with ALL who had to discontinue treatment with pegaspargase (a pegylated formulation of E. coli asparaginase) because of hypersensitivity. Another study revealed that development of E. coli-derived asparaginase allergy and a switch to Erwinaze(r) maintained event-free survival in pediatric patients with newly diagnosed ALL. In a multicenter, compassionate use trial, Erwinaze(r) was generally well tolerated, with the most commonly occurring adverse events including hypersensitivity, pancreatitis, fever, hyperglycemia, and increased transaminase levels. Subclinical hypersensitivity may result in the inactivation of asparaginase and affect treatment outcome; monitoring of serum asparaginase levels may be used to identify subclinical hypersensitivity. PMID- 23794008 TI - Genetic diversity of kenaf (Hibiscus cannabinus) evaluated by inter-simple sequence repeat (ISSR). AB - Understanding genetic diversity is very useful for scientific utilization for breeding. In this study, we estimated the genetic distances in a panel of 84 kenaf accessions collected from 26 countries and regions using ISSR markers. The results of UPGMA analysis showed that kenaf germplasm had abundant genetic variation, with genetic dissimilarity coefficients ranging from 0.01 to 0.62. The in-group dissimilarity coefficient (0.29) was observed in 84 kenaf accessions, and all the accessions could be divided into three groups: cultivars (L1-1), relatively wild species (L1-2 and L1-3), and wild species (the others). Further in-group analysis in group L1-1 (0.19) revealed that the kenaf cultivars could be divided into five subgroups with distinct regional characteristics. It is imperative that genes be exchanged among all kinds of tested varieties from different origins. The results provide a useful basis for kenaf germplasm research and breeding. PMID- 23794009 TI - miR-146a polymorphism influences levels of miR-146a, IRAK-1, and TRAF-6 in young patients with coronary artery disease. AB - Modulation of nuclear factor KappaB (NF-kappaB) activation may play a role in regulating inflammatory conditions associated with coronary artery disease (CAD). MicroRNA-146a (miR-146a) primarily targets interleukin-1 receptor-associated kinase 1 (IRAK-1) and tumour necrosis factor receptor associated factor 6 (TRAF 6), which results in inhibition of NF-kappaB via the TLR pathway. This study investigated the influence of the miR-146a GC rs2910164 on miR-146a expression in young South African Indians with CAD. CAD patients and controls were genotyped by PCR-RFLP and miRNA-146a levels were measured by qPCR. IRAK-1, TRAF-6 and NF kappaB expression was determined by Western blot. No differences in genotypic frequency was found (GG: 45 vs. 47%, GC: 46 vs. 41%, CC: 9 vs. 12%) in controls and patients respectively (odds ratio = 1.025; 95% confidence interval 0.6782 1.550; p = 0.9164). Significantly higher levels of miR-146a was associated with CAD patients with the CC genotype (6.25-fold increase relative to controls and patients with the wildtype variant, p < 0.0001). Significantly lower levels of IRAK-1 (0.38 +/- 0.02; p = 0.0072) and TRAF-6 (0.44 +/- 0.02; p = 0.0146) was found in CAD patients with the CC genotype. The lowest levels of NF-kappaB and C reactive protein were found in patients with the homozygous C allele compared to the heterozygous GC and wildtype variants. We propose a role for miR-146a in TLR signalling through a negative feedback mechanism involving the attenuation of NF kappaB by down-regulation of IRAK-1 and TRAF-6. Our observations implicate miR 146a as a target for lowering inflammation in CAD patients. PMID- 23794010 TI - Insight into the oseltamivir resistance R292K mutation in H5N1 influenza virus: a molecular docking and molecular dynamics approach. AB - H5N1 is a subtype of the influenza A virus that can cause disease in humans and many other animal species. Oseltamivir (Tamiflu) is a potent and selective antiviral drug employed to fight the flu virus in infected individuals by inhibiting neuraminidase (NA), a flu protein responsible for the release and spread of the progeny virions. However, oseltamivir resistance has become a critical problem. In particular, influenza strains with a R292K NA mutation are highly resistant to the oseltamivir. Though the biological functions of the mutations have previously been characterized, the structural basis behind the reduced catalytic activity and reduced protein level is not clear. In this study, molecular docking and molecular dynamics (MD) approach were employed to investigate the structural and dynamical effects throughout the protein structure and specifically, at the drug-binding pocket. Furthermore, potential of mean force was analyzed using explicit solvent MD simulations with the umbrella sampling method to explore the free energy of binding. It is believed that this study provides valuable guidance for the resistance management of oseltamivir and designing of more potent antiviral inhibitor. PMID- 23794011 TI - Adrenal insufficiency in children undergoing heart surgery does not correlate with more complex postoperative course. AB - Although some evidence suggests benefit of steroid supplementation after pediatric cardiac surgery, data correlating adrenal function with the postoperative course is scarce. This study sought to determine if adrenal insufficiency (AI) after cardiac surgery is associated with a more complicated postoperative course in children. A prospective study was performed during a 6 month period at a pediatric medical center. Included were 119 children, 3 months and older, who underwent heart surgery with cardiopulmonary bypass. Cortisol levels were measured before and 18 h after surgery. Patients were divided into two groups by procedure complexity (low or high), and clinical and laboratory parameters were compared between patients with and without AI within each complexity group. In the low-complexity group, 45 of the 65 patients had AI. The normal adrenal function (NAF) subgroup had greater inotropic support at 12, 24, and 36 h after surgery and a higher lactate level at 12 and 24 h after surgery. There were no significant differences between subgroups in duration of ventilation, sedation, intensive care unit (ICU) stay, or urine output. In the high-complexity group, 27 patients had AI, and 27 did not. There were no significant differences between subgroups in inotropic support or urine output during the first 36 h or in mechanical ventilation, sedation, or ICU stay duration. Children with AI after heart surgery do not have a more complex postoperative course than children with NAF. The adrenal response of individual patients seems to be appropriate for their cardiovascular status. PMID- 23794012 TI - Screening for aortic aneurysm after treatment of coarctation. AB - Isolated coarctation of the aorta (CoA) occurs in 6-8 % of patients with congenital heart disease. After successful relief of obstruction, patients remain at risk for aortic aneurysm formation at the site of the repair. We sought to determine the diagnostic utility of echocardiography compared with advanced arch imaging (AAI) in diagnosing aortic aneurysms in pediatric patients after CoA repair. The Congenital Heart Databases from 1996 and 2009 were reviewed. All patients treated for CoA who had AAI defined by cardiac magnetic resonance imaging (MRI), computed tomography (CT), or catheterization were identified. Data collected included the following: type, timing, and number of interventions, presence and time to aneurysm diagnosis, and mortality. Patients were subdivided into surgical and catheterization groups for analysis. Seven hundred and fifty nine patients underwent treatment for CoA during the study period. Three hundred and ninety-nine patients had at least one AAI. Aneurysms were diagnosed by AAI in 28 of 399 patients at a mean of 10 +/- 8.4 years after treatment. Echocardiography reports were available for 380 of 399 patients with AAI. The sensitivity of echocardiography for detecting aneurysms was 24 %. The prevalence of aneurysms was significantly greater in the catheterization group (p < 0.05) compared with the surgery group. Aneurysm was also diagnosed earlier in the catheterization group compared with the surgery group (p = 0.02). Multivariate analysis showed a significantly increased risk of aneurysm diagnosis in patients in the catheterization subgroup and in patients requiring more than three procedures. Aortic aneurysms continue to be an important complication after CoA repair. Although serial echocardiograms are the test of choice for following-up most congenital cardiac lesions in pediatrics, our data show that echocardiography is inadequate for the detection of aneurysms after CoA repair. Because the time to aneurysm diagnosis was shorter and the risk greater in the catheterization group (particularly for patients requiring more than one procedure), surveillance with cardiac MRI or CT should begin earlier in these patients. PMID- 23794013 TI - Ambulatory blood pressure and subclinical cardiovascular disease in children with turner syndrome. AB - Patients with Turner syndrome (TS) have an increased risk of cardiovascular morbidity. 29 TS and 25 healthy control subjects (CS) were included in the study. We investigated body mass index, waist circumference, fasting glucose and insulin, homeostatic model assessment (HOMA) index, serum lipids, oral glucose tolerance test, 24-h ambulatory blood pressure (BP) monitoring, and carotid intima-media thickness (CIMT) and compared them with CS. 28 % (N = 7) of TS had insulin resistance (IR), and 36 % (N = 9) had IGT. Mean systolic BP and diastolic BP (DBP) dip were 7.24 +/- 3.97 % and 11.84 +/- 6.2 %, respectively. CIMT was greater in TS than in CS (p = 0.00). CIMT was correlated positively with fasting insulin, HOMA index, and insulin-sensitivity check index (r = 0.563, p = 0.015; r = 0.603, p = 0.008; and r = 0.623, p = 0.006, respectively) and negatively with fasting glucose-to-insulin ratio and DBP dipping (r = -0.534, p = 0.022; r = 0.534, p = 0.00, respectively) in the two groups combined. These results provide additional evidence for the presence of subclinical cardiovascular disease and its relation to hypertension in TS. They also indicate a significant relation between DBP dipping and increased arterial stiffness. It is also important to note that our findings show significant relationships between insulin sensitivity and cardiovascular changes and underline the importance of insulin resistance for predicting cardiovascular disease. PMID- 23794014 TI - Root colonization and phytostimulation by phytohormones producing entophytic Nostoc sp. AH-12. AB - Nostoc, a nitrogen-fixing cyanobacterium, has great potential to make symbiotic associations with a wide range of plants and benefit its hosts with nitrogen in the form of nitrates. It may also use phytohormones as a tool to promote plant growth. Phytohormones [cytokinin (Ck) and IAA] were determined in the culture of an endophytic Nostoc isolated from rice roots. The strain was able to accumulate as well as release phytohormones to the culture media. Optimum growth conditions for the production of zeatin and IAA were a temperature of 25 degrees C and a pH of 8.0. Time-dependent increase in the accumulation and release of phytohormones was recorded. To evaluate the impact of cytokinins, an ipt knockout mutant in the background of Nostoc was generated by homologous recombination method. A sharp decline (up to 80 %) in the zeatin content was observed in the culture of mutant strain Nostoc AHM-12. Association of the mutant and wild type strain with rice and wheat roots was studied under axenic conditions. The efficacy of Nostoc to colonize plant root was significantly reduced (P < 0.05) as a result of ipt inactivation as evident by low chlorophyll a concentration in the roots. In contrast to the mutant strain, wild type strain showed good association with the roots and enhanced several growth parameters, such as fresh weight, dry weight, shoot length, and root length of the crop plants. The study clearly demonstrated that Ck is a tool of endophytic Nostoc to colonize plant root and promote its growth. PMID- 23794015 TI - Distribution of the entomopathogenic fungus Beauveria bassiana in rice ecosystems and its effect on soil enzymes. AB - Fungal entomopathogens, especially Beauveria bassiana, are often studied within the context of their use in biological pest control; however, there is limited knowledge of their distributions in host plants and soil ecosystem. We examined the distribution of B. bassiana and its influence on rice plants and paddy soils. B. bassiana could only be detected on the foliar surfaces of rice plants within 15 days under Bb-4 (7.5 * 10(4) conidia/mL) and Bb-7 (7.5 * 10(7) conidia/mL) treatments. The endophytic colonization of B. bassiana could not be found in stems, roots, or seeds of rice plants under Bb-4 and Bb-7 treatments. The fungus was found only in the leaves of rice plants under Bb-4 and Bb-7 treatments at 15 days after inoculation. Moreover, B. bassiana was absent from paddy soils under Bb-4 and Bb-7 treatments at all times. Enzyme activity (urease and phosphatase) in the paddy soils of Bb-4 and Bb-7 treatments showed no significant difference from the control. It is possible that B. bassiana was not able to colonize paddy soil. Detailed understanding of distribution and ecological interactions of B. bassiana is helpful for understanding and predicting the effects of fungal entomopathogens on host populations, and the interactions among fungal entomopathogens and other organisms in the community. PMID- 23794016 TI - Cutaneous mycosis in a Barbastelle bat (Barbastella barbastellus) caused by Hyphopichia burtonii. AB - A rare barbastelle bat (Barbastella barbastellus) died shortly after being found in emaciated condition in Devon, England. The skin over the muzzle and face was grossly thickened, crusty, and in places was sloughing and ulcerated. There were numerous nodules up to 3 mm in diameter on both wings and ear pinnae. Histologically, multiple foci of epidermal hyperplasia, hyperkeratosis, and crateriform erosions containing masses of fungal spores and septate hyphae were found in the wing. Epidermal hyperplasia and follicular hyperkeratosis, with fungal masses within keratinized follicles and also in fissured stratum corneum, were found in the pinna. Hyphae did not invade the dermis, and there was no inflammation, but there was multifocal serous exudation and crusting. No parasites or other significant organisms were identified. Microscopic and multiple cultural analyses of face and wing lesions demonstrated (10/10) a fine, septate fungus bearing laterally oval to clavate conidia; morphologically and culturally this was entirely consistent with Hyphopichia burtonii, and polymerase chain reaction analysis and sequencing gave 100% identity with the type strain. The organism isolated was morphologically consistent with that repeatedly seen in histology sections and demonstrates that although H. burtonii has not previously been recognized as a dermatophyte, it clearly has the ability to invade the skin of live bats. Although not identical, the lesions in this case show similarity with those of white nose syndrome and therefore H. burtonii should be considered as a potential pathogen of bats. PMID- 23794017 TI - A retrospective study of brain lesions in goats submitted to three veterinary diagnostic laboratories. AB - A retrospective study of brain lesions in goats was conducted to identify the range of lesions and diseases recognized and to make recommendations regarding the best tissues to examine and tests to conduct in order to maximize the likelihood of making a definitive diagnosis in goats that may have had clinical signs referable to the brain. One hundred thirty-nine goats with a brain lesion were identified. The most common lesion, in 52.5% of the goats, was suppurative inflammation. Approximately two-thirds of these goats had encephalitic listeriosis. Other goats were found to have suppurative inflammation in association with septicemia, pituitary abscesses, dehorning injury, and otitis. Thirty goats (21.6%) were diagnosed with polioencephalomalacia. Twenty-one goats (15.1%) were diagnosed with nonsuppurative inflammation. In more than half of these goats, no definitive diagnosis was made, while 8 were infected with Caprine arthritis encephalitis virus and 1 with Rabies virus. However, few goats were tested for rabies. Based on these findings, it is recommended that, in addition to appropriate handling of the brain, the head should be examined with attention paid to the sella turcica and the temporal bones for evidence of a pituitary abscess and otitis, respectively. Histologic examination should include multiple areas of the brain, including the brainstem, for lesions of encephalic listeriosis; the cerebral cortex, for lesions of polioencephalomalacia; and the hippocampus, for Negri bodies associated with Rabies virus infection. Consideration should be given to collecting samples of other tissues including, but not limited to, the spinal cord and liver for ancillary testing if warranted. PMID- 23794018 TI - [Effects of pancreatectomy on nutritional state, pancreatic function and quality of life]. PMID- 23794020 TI - Metabolic roles of AMPK and metformin in cancer cells. AB - Metformin is one of the most widely used anti-diabetic agents in the world, and a growing body of evidence suggests that it may also be effective as an anti-cancer drug. Observational studies have shown that metformin reduces cancer incidence and cancer-related mortality in multiple types of cancer. These results have drawn attention to the mechanisms underlying metformin's anti-cancer effects, which may include triggering of the AMP-activated protein kinase (AMPK) pathway, resulting in vulnerability to an energy crisis (leading to cell death under conditions of nutrient deprivation) and a reduction in circulating insulin/IGF-1 levels. Clinical trials are currently underway to determine the benefits, appropriate dosage, and tolerability of metformin in the context of cancer therapy. This review highlights fundamental aspects of the molecular mechanisms underlying metformin's anti-cancer effects, describes the epidemiological evidence and ongoing clinical challenges, and proposes directions for future translational research. PMID- 23794019 TI - Aggregation formation in the polyglutamine diseases: protection at a cost? AB - Mutant protein aggregation is a hallmark of many neurodegenerative diseases, including the polyglutamine disorders. Although the correlation between aggregation formation and disease pathology originally suggested that the visible inclusions seen in patient tissue might directly contribute to pathology, additional studies failed to confirm this hypothesis. Current opinion in the field of polyglutamine disease research now favors a model in which large inclusions are cytoprotective and smaller oligomers or misfolded monomers underlie pathogenesis. Nonetheless, therapies aimed at reducing or preventing aggregation show promise. This review outlines the debate about the role of aggregation in the polyglutamine diseases as it has unfolded in the literature and concludes with a brief discussion on the manipulation of aggregation formation and clearance mechanisms as a means of therapeutic intervention. PMID- 23794021 TI - Three-decade metabolic outcome of neonatal gastrectomy and early Roux-en-Y. AB - Little information is available about long-term outcomes of major gastric surgery when performed very early in life and adverse consequences in growing children might be expected. In this case, gastrectomy with Roux-en-Y esophagojejunostomy was performed in early childhood. Despite stomach loss, growth velocity paralleled the third percentile for age during development. Maintained on a daily multivitamin and monthly B12 injections, no overt nutritional deficiencies were detected in adulthood. However, dual energy X-ray absorptiometry scan at age 31 revealed that the patient had abnormally low bone mineral density. This case study demonstrates that even after gastrectomy and reconstruction early in life, linear growth can be achieved. However, bone density can be adversely affected, even in the face of normal serum calcium and vitamin D levels. PMID- 23794022 TI - Variations in biliary ductal and hepatic vascular anatomy and their relevance to the surgical management of choledochal cysts. AB - PURPOSE: An aberrant biliary ductal and vascular anatomy presents a technical challenge for choledochal cyst (CDC) surgery. Mismanagement may have unfavourable implications. This study highlights the spectrum, approach to their identification and management. METHODS: Forty of 117 (34 %) cases were identified to have an aberrant biliary ductal (n = 17) or arterial (n = 26) anatomy; 3 had both. The pancreaticobiliary anatomy was defined by an intraoperative cholangiogram (IOC) before January 2005 and a preoperative magnetic resonance cholangiopancreatogram (MRCP) subsequently. RESULTS: IOC missed 3 of 4 aberrant biliary ducts, while an MRCP accurately delineated 10 of 13 aberrant bile ducts. The significant biliary anomalies were: an aberrant right sectoral/segmental duct joining the common hepatic duct (CHD) or the cyst itself (n = 14), cystic duct (n = 1) and cystic duct-CHD junction (n = 1). The aberrant duct was incorporated into the biliary-enteric anastomosis (B-EA) by: (i) double ostia B-EA (n = 1), (ii) ductoplasty with single ostium B-EA for aberrant duct and CHD (n = 2), and (iii) transection of the CHD/cyst distal to the aberrant duct orifice with a single ostium B-EA (n = 13). The arterial anomalies were (i) replaced or accessory right hepatic artery (RHA) (n = 11) and (ii) RHA crossing anterior to the cyst (n = 15), which was repositioned posterior to the B-EA. CONCLUSION: It is important to consciously look for, appropriately identify and manage aberrant biliovascular anatomy. MRCP facilitates accurate preoperative delineation of aberrant duct anatomy. All major aberrant ducts need to be incorporated into the B-EA and aberrant arteries should not be ligated. PMID- 23794023 TI - Clinical characteristics and outcome of hepatocellular carcinoma in children and adolescents. AB - PURPOSE: Hepatocellular carcinoma (HCC) rarely occurs in children and adolescents and has been reported to be highly hepatitis B related more than 10 years ago. However, after global vaccination for hepatitis B virus (HBV), the characteristics and outcome of pediatric HCC remain undefined. METHODS: Patients with HCC admitted from 2004 to 2010 were retrospectively reviewed in a large tertiary hospital. RESULTS: 45 (1.97 %) pediatric HCC were diagnosed (age <=18 years), with predominantly male patients (93.3 %). 32 (71.1 %) children were HBV positive, 30 of whom had vertical transmission from their mothers. HBV positivity was associated with liver cirrhosis and portal vein invasion, and thus compromised survival. Advanced disease prevented surgical resection due to large tumor size (>10 cm, 66.7 %), early metastasis (24.4 %), bilateral involvement (57.8 %) and portal vein invasion (46.7 %). The median survival for resectable, transarterial chemotherapy and embolization and untreated patients was 28.6, 4 and 5 months, respectively (p < 0.001). Patients with distal metastasis had significantly poorer survival rate than those without metastasis (p < 0.001). CONCLUSION: Screening of children whose mothers are HBV carriers is important in early detection of pediatric HCC. HBV-associated HCC in pediatric patients, especially in endemic areas, should be detected earlier for more resectability and improvement of surgical prognosis. PMID- 23794024 TI - Extrarenal testicular Wilms' tumor in a 3-year-old child. AB - We report an extremely rare case of extrarenal testicular Wilms' tumor in a 3 year-old boy with intrabdominal undescended left testis. The patient was admitted because of pain and vomiting, with evidence of a huge abdominal mass. At surgery a large tumor arising from the intrabdominal testis was found. Histology showed the classical triphasic Wilms' tumor elements: epithelial, mesenchymal and blastemal areas. Extrarenal Wilms' tumors account for only 3% of all Wilms' tumors and just -100 cases have been reported in literature. Testicular origin is anecdotic. We present histomorphological, histogenetic, clinical, diagnostic, prognostic and therapeutic features of this rare tumor. PMID- 23794025 TI - Visible light plasmonic heating of Au-ZnO for the catalytic reduction of CO2. AB - Plasmonic excitation of Au nanoparticles attached to the surface of ZnO catalysts using low power 532 nm laser illumination leads to significant heating of the catalyst and the conversion of CO2 and H2 reactants to CH4 and CO products. Temperature-calibrated Raman spectra of ZnO phonons show that intensity-dependent plasmonic excitation can controllably heat Au-ZnO from 30 to ~600 degrees C and simultaneously tune the CH4 : CO product ratio. The laser induced heating and resulting CH4 : CO product distribution agrees well with predictions from thermodynamic models and temperature-programmed reaction experiments indicating that the reaction is a thermally driven process resulting from the plasmonic heating of the Au-ZnO. The apparent quantum yield for CO2 conversion under continuous wave (cw) 532 nm laser illumination is 0.030%. The Au-ZnO catalysts are robust and remain active after repeated laser exposure and cycling. The light intensity required to initiate CO2 reduction is low (~2.5 * 10(5) W m(-2)) and achievable with solar concentrators. Our results illustrate the viability of plasmonic heating approaches for CO2 utilization and other practical thermal catalytic applications. PMID- 23794026 TI - Root transcriptome analysis of Arabidopsis thaliana exposed to beneficial Bacillus subtilis FB17 rhizobacteria revealed genes for bacterial recruitment and plant defense independent of malate efflux. AB - Our previous work has demonstrated that Arabidopsis thaliana can actively recruit beneficial rhizobacteria Bacillus subtilis strain FB17 (hereafter FB17) through an unknown shoot-to-root long-distance signaling pathway post a foliar bacterial pathogen attack. However, it is still not well understood which genetic targets FB17 affects in plants. Microarray analysis of A. thaliana roots treated with FB17 post 24 h of treatment showed 168 and 129 genes that were up- and down regulated, respectively, compared with the untreated control roots. Those up regulated include auxin-regulated genes as well as genes involved in metabolism, stress response, and plant defense. In addition, other defense-related genes, as well as cell-wall modification genes were also down-regulated with FB17 colonization. Expression patterns of 20 selected genes were analyzed by semi quantitative RT-PCR, validating the microarray results. A. thaliana insertion mutants were used against FB17 to further study the functional response of the differentially expressed genes. Five mutants for the up-regulated genes were tested for FB17 colonization, three (at3g28360, at3g20190 and at1g21240) mutants showed decreased FB17 colonization on the roots while increased FB17 titers was seen with three mutants of the down-regulated genes (at3g27980, at4g19690 and at5g56320). Further, these mutants for up-regulated genes and down-regulated genes were foliar infected with Pseudomonas syringae pv. tomato (hereafter PstDC3000) and analyzed for Aluminum activated malate transporter (ALMT1) expression which showed that ALMT1 may be the key regulator for root FB17 colonization. Our microarray showed that under natural condition, FB17 triggers plant responses in a manner similar to known plant growth-promoting rhizobacteria and to some extent also suppresses defense-related genes expression in roots, enabling stable colonization. The possible implication of this study opens up a new dialogin terms of how beneficial microbes regulate plant genetic response for mutualistic associations. PMID- 23794027 TI - Palliative care psychiatry: update on an emerging dimension of psychiatric practice. AB - Palliative care psychiatry is an emerging subspecialty field at the intersection of Palliative Medicine and Psychiatry. The discipline brings expertise in understanding the psychosocial dimensions of human experience to the care of dying patients and support of their families. The goals of this review are (1) to briefly define palliative care and summarize the evidence for its benefits, (2) to describe the roles for psychiatry within palliative care, (3) to review recent advances in the research and practice of palliative care psychiatry, and (4) to delineate some steps ahead as this sub-field continues to develop, in terms of research, education, and systems-based practice. PMID- 23794028 TI - Application of endoscopic techniques in orbital blowout fractures. AB - Minimally invasive surgical techniques, particularly endoscopic techniques, have revolutionized otolaryngeal surgery. Endoscopic techniques have been gradually applied in orbital surgery through the sinus inferomedial to the orbit and the orbital subperiosteal space. Endoscopic techniques help surgeons observe fractures and soft tissue of the posterior orbit to precisely place implants and protect vital structures through accurate, safe, and minimally invasive approaches. We reviewed the development of endoscopic techniques, the composition of endoscopic systems for orbital surgery, and the problems and developmental prospects of endoscopic techniques for simple orbital wall fracture repair. PMID- 23794029 TI - Understanding channel tropism in traditional Chinese medicine in the context of systems biology. AB - Channel tropism is investigated and developed through long-term clinical practice. In recent years, the development of channel tropism theory has attracted increasing attention. This study analyzed channel tropism theory and the problems associated with it. Results showed that this theory and systems biology have a similar holistic viewpoint. Systems biology could provide novel insights and platform in the study of channel tropism. Some problems in channel tropism theory, including pharmacology and action mechanism, were investigated. PMID- 23794030 TI - Role of mesenchymal stem cells in leukaemia: Dr. Jekyll or Mr. Hyde? AB - Mesenchymal stem cells (MSCs) have captured the attention of researchers today due to their multipotent differentiation capacity. Also, they have been successfully applied clinically, in the treatment of various diseases of the heart and musculoskeletal systems, with encouraging results. Their supportive role in haematopoiesis and their anti-inflammatory and immunomodulatory properties have enhanced their contribution towards the improvement of engraftment and the treatment of graft-versus-host disease in patients receiving haematopoietic stem cell transplantation. However, there is a growing body of research that supports the involvement of MSCs in leukaemogenesis with several genetic and functional abnormalities having been detected in the MSCs of leukaemia patients. MSCs also exert leukaemia-enhancing effects and induce chemotherapy resistance in leukaemia cells. This paper addresses the key issues in the therapeutic value as well as the harmful effects of the MSCs in leukaemia with a sharp focus on the recent updates in the published literature. PMID- 23794031 TI - Structure of the catalytic domain of a state transition kinase homolog from Micromonas algae. AB - Under natural environments, plants and algae have evolved various photosynthetic acclimation mechanisms in response to the constantly changing light conditions. The state transition and long-term response processes in photosynthetic acclimation involve remodeling and composition alteration of thylakoid membrane. A chloroplast protein kinase named Stt7/STN7 has been found to have pivotal roles in both state transition and long-term response. Here we report the crystal structures of the kinase domain of a putative Stt7/STN7 homolog from Micromonas sp. RCC299 (MsStt7d) in the apo form and in complex with various nucleotide substrates. MsStt7d adopts a canonical protein kinase fold and contains all the essential residues at the active site. A novel hairpin motif, found to be a conserved feature of the Stt7/STN7 family and indispensable for the kinase stability, interacts with the activation loop and fixes it in an active conformation. We have also demonstrated that MsStt7d is a dualspecifi city kinase that phosphorylates both Thr and Tyr residues. Moreover, preliminary in vitro data suggest that it might be capable of phosphorylating a consensus N-terminal pentapeptide of light-harvesting proteins Micromonas Lhcp4 and Arabidopsis Lhcb1 directly. The potential peptide/protein substrate binding site is predicted based on the location of a pseudo-substrate contributed by the adjacent molecule within the crystallographic dimer. The structural and biochemical data presented here provide a framework for an improved understanding on the role of Stt7/STN7 in photosynthetic acclimation. PMID- 23794032 TI - Co-evolution of plant LTR-retrotransposons and their host genomes. AB - Transposable elements (TEs), particularly, long terminal repeat retrotransposons (LTR-RTs), are the most abundant DNA components in all plant species that have been investigated, and are largely responsible for plant genome size variation. Although plant genomes have experienced periodic proliferation and/or recent burst of LTR-retrotransposons, the majority of LTR-RTs are inactivated by DNA methylation and small RNA-mediated silencing mechanisms, and/or were deleted/truncated by unequal homologous recombination and illegitimate recombination, as suppression mechanisms that counteract genome expansion caused by LTR-RT amplification. LTR-RT DNA is generally enriched in pericentromeric regions of the host genomes, which appears to be the outcomes of preferential insertions of LTR-RTs in these regions and low effectiveness of selection that purges LTR-RT DNA from these regions relative to chromosomal arms. Potential functions of various TEs in their host genomes remain blurry; nevertheless, LTR RTs have been recognized to play important roles in maintaining chromatin structures and centromere functions and regulation of gene expressions in their host genomes. PMID- 23794033 TI - Effects of afferent and efferent denervation of vagal nerve on endotoxin-induced oxidative stress in rats. AB - This study investigated the role of vagal innervation in oxidative stress after systemic administration of lipopolysaccharide (LPS) endotoxin. Control rats and rats subjected to bilateral subdiaphragmatic vagotomy, perivagal capsaicin application (5 mg/ml) or cholinergic receptor blockade with subcutaneous atropine (1 mg/kg), were intraperitoneally injected with 300 MUg/kg of LPS and euthanized 4 h later. Results indicated that; (1) surgical vagotomy and sensory denervation by perivagal capsaicin increased brain oxidative stress and decreased reduced glutathione in basal condition (saline-treated rats) and following endotoxin challenge; (2) oxidative stress decreased after cholinergic blockade with atropine in endotoxemic rats; (3) nitric oxide decreased by abdominal vagotomy, sensory deafferentation and cholinergic blockade after endotoxin injection; (4) liver lipid peroxidation decreased after surgical vagotomy and cholinergic blockade but increased after sensory deafferentation; (5) liver reduced glutathione decreased following vagotomy and sensory denervation in basal state and by cholinergic blockade in basal state and during endotoxemia; (6) nitric oxide increased by vagotomy in basal state and by sensory denervation and cholinergic blockade in basal state and during endotoxemia; (7) liver histological damage increased by subdiaphragmatic vagotomy, sensory denervation or cholinergic blockade. These findings suggest that: (1) sensory fibers (signals from the periphery) running in the vagus nerves are important in maintaining the redox status of the brain; (2) capsaicin vagal sensory nerves are likely to maintain nitric oxide tone in basal conditions; (3) the vagus nerve modulates liver redox status and nitric oxide release, (4) the vagus nerve mediates protective role in the liver with both cholinergic and capsaicin-sensitive mechanisms being involved. PMID- 23794034 TI - Changes in the expression of smooth muscle contractile proteins in TNBS- and DSS induced colitis in mice. AB - Thin filament-associated proteins such as calponin, caldesmon, tropomyosin, and smoothelin are thought to regulate acto-myosin interaction and thus, muscle contraction. However, the effect of inflammation on the expression of thin filament-associated proteins is not known. The aim of the present study is to determine the changes in the expression of calponin, caldesmon, tropomyosin, and smoothelin in colonic smooth muscle from trinitrobenzene sulphonic acid (TNBS)- and dextran sodium sulphate (DSS)-induced colitis in mice. Expression of h caldesmon, h2-calponin, alpha-tropomyosin, and smoothelin-A was measured by qRT PCR and Western blot. Contraction in response to acetylcholine in dispersed muscle cells was measured by scanning micrometry. mRNA and protein expression of alpha-actin, h2-calponin, h-caldesmon, smoothelin, and alpha-tropomyosin in colonic muscle strips from mice with TNBS- or DSS-induced colitis was significantly increased compared to control animals. Contraction in response to acetylcholine was significantly decreased in muscle cells isolated from inflamed regions of TNBS- or DSS-treated mice compared to control mice. Our results show that increase in the expression of thin filament-associated contractile proteins, which inhibit acto-myosin interaction, could contribute to decrease in smooth muscle contraction in inflammation. PMID- 23794035 TI - Protective effects of sivelestat in a caerulein-induced rat acute pancreatitis model. AB - In the present study, we investigated the protective effects of sivelestat on acute pancreatitis (AP) in a rat model. Sivelestat is a specific neutrophil elastase inhibitor, which has been developed in Japan in 1991. Varying doses of sivelestat in normal saline were infused continuously in sivelestat-treated groups through osmotic pumps. Blood and pancreas samples were collected for serological and histopathological studies, and ten rats in each group were taken for survival observation. Increasing doses of sivelestat inhibits the expression of lipase, amylase, corticosterone, IL-1beta, TNF-alpha, and nuclear factor kappaB. Furthermore, sivelestat reduces the inflammatory cells infiltration, histological damage, and mortality rate. Meanwhile, the total antioxidant power and serum level of IL-4 in high-dose sivelestat-treated groups were increased. Our findings suggest that the increasing doses of sivelestat protect against caerulein-induced AP in rats, and this protection is possibly associated with the anti-inflammatory ability of sivelestat. PMID- 23794036 TI - Drug interactions with the newer antiepileptic drugs (AEDs)--Part 2: pharmacokinetic and pharmacodynamic interactions between AEDs and drugs used to treat non-epilepsy disorders. AB - Since antiepileptic drugs (AEDs) are prescribed to treat various non-epilepsy related disorders in addition to the fact that patients with epilepsy may develop concurrent disorders that will need treatment, the propensity for AEDs to interact with non-AEDs is considerable and indeed can present a difficult clinical problem. The present review details the pharmacokinetic and pharmacodynamic interactions that have been reported to occur with the new AEDs (eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, pregabalin, retigabine (ezogabine), rufinamide, stiripentol, tiagabine, topiramate, vigabatrin and zonisamide) and drugs used to treat non-epilepsy disorders. Interaction study details are described, as necessary, so as to allow the reader to take a view as to the possible clinical significance of particular interactions. Pharmacokinetic interactions relate to hepatic enzyme induction or inhibition and involved a variety of drugs including psychoactive drugs, cardioactive drugs, oral contraceptives, antituberculous agents, analgesics and antineoplastic drugs. A total of 68 pharmacokinetic interactions have been described, with lamotrigine (n = 22), topiramate (n = 18) and oxcarbazepine (n = 7) being associated with most, whilst lacosamide, pregabalin, stiripentol and vigabatrin are associated with none. Overall, only three pharmacodynamic interactions have been described and occur with oxcarbazepine, perampanel and pregabalin. PMID- 23794037 TI - A solid-state NMR study of amorphous ezetimibe dispersions in mesoporous silica. AB - PURPOSE: The purpose of this work is to examine the ability of methods based on multinuclear and multidimensional solid-state NMR (SSNMR) to perform detailed characterization of amorphous dispersions of ezetimibe adsorbed on mesoporous silica. METHODS: Ezetimibe was loaded into two types of mesoporous silica with average pore sizes of 2.5 and 21 nm. The mesoporous materials were characterized by powder X-ray diffraction (PXRD), vibrational spectroscopy, differential scanning calorimetry, and (1)H, (13)C, (19)F, and (29)Si SSNMR analysis including relaxation time measurements. Interactions between the drug and silica were investigated using 1D and 2D SSNMR methods based on dipolar correlation using cross-polarization (CP) and spin diffusion. RESULTS: PXRD was used to show the absence of crystalline ezetimibe in the mesoporous materials, and (19)F SSNMR was used to assess drug physical state and study mobility. (19)F-(29)Si CP methods were used to directly detect adsorbed ezetimibe. (1)H-(13)C, (1)H-(19)F, and (1)H (29)Si, and heteronuclear correlation and (1)H homonuclear correlation experiments were used to investigate interactions between the drug and silica through (1)H environments. CONCLUSIONS: SSNMR methods were able to detect interactions between the drug and the silica substrate. Differences between the drug loaded onto silica with two different pore sizes were observed, including differences in hydrogen bonding environment and molecular mobility. These methods should be useful for characterization of similar systems. PMID- 23794038 TI - Engineering of an inhalable DDA/TDB liposomal adjuvant: a quality-by-design approach towards optimization of the spray drying process. AB - PURPOSE: The purpose of this study was to identify and optimize spray drying parameters of importance for the design of an inhalable powder formulation of a cationic liposomal adjuvant composed of dimethyldioctadecylammonium (DDA) bromide and trehalose-6,6'-dibehenate (TDB). METHODS: A quality by design (QbD) approach was applied to identify and link critical process parameters (CPPs) of the spray drying process to critical quality attributes (CQAs) using risk assessment and design of experiments (DoE), followed by identification of an optimal operating space (OOS). A central composite face-centered design was carried out followed by multiple linear regression analysis. RESULTS: Four CQAs were identified; the mass median aerodynamic diameter (MMAD), the liposome stability (size) during processing, the moisture content and the yield. Five CPPs (drying airflow, feed flow rate, feedstock concentration, atomizing airflow and outlet temperature) were identified and tested in a systematic way. The MMAD and the yield were successfully modeled. For the liposome size stability, the ratio between the size after and before spray drying was modeled successfully. The model for the residual moisture content was poor, although, the moisture content was below 3% in the entire design space. Finally, the OOS was drafted from the constructed models for the spray drying of trehalose stabilized DDA/TDB liposomes. CONCLUSIONS: The QbD approach for the spray drying process should include a careful consideration of the quality target product profile. This approach implementing risk assessment and DoE was successfully applied to optimize the spray drying of an inhalable DDA/TDB liposomal adjuvant designed for pulmonary vaccination. PMID- 23794039 TI - Altered brain uptake of therapeutics in a triple transgenic mouse model of Alzheimer's disease. AB - PURPOSE: The purpose of this study was to systematically assess the impact of Alzheimer's disease (AD)-associated blood-brain barrier (BBB) alterations on the uptake of therapeutics into the brain. METHODS: The brain uptake of probe compounds was measured in 18-20 month old wild type (WT) and triple transgenic (3*TG) AD mice using an in situ transcardiac perfusion technique. These results were mechanistically correlated with immunohistochemical and molecular studies. RESULTS: The brain uptake of the paracellular marker, [(14)C] sucrose, did not differ between WT and 3*TG mice. The brain uptake of passively diffusing markers, [(3)H] diazepam and [(3)H] propranolol, decreased 54-60% in 3*TG mice, consistent with a 33.5% increase in the thickness of the cerebrovascular basement membrane in 3*TG mice. Despite a 42.4% reduction in P-gp expression in isolated brain microvessels from a sub-population of 3*TG mice (relative to WT mice), the brain uptake of P-gp substrates ([(3)H] digoxin, [(3)H] loperamide and [(3)H] verapamil) was not different between genotypes, likely due to a compensatory thickening in the cerebrovascular basement membrane counteracting any reduced efflux of these lipophilic substrates. CONCLUSION: These studies systematically assessed the impact of AD on BBB drug transport in a relevant animal model, and have demonstrated a reduction in the brain uptake of passively-absorbed molecules in this mouse model of AD. PMID- 23794041 TI - Genistein-induced G2/M cell cycle arrest of human intestinal colon cancer Caco-2 cells is associated with Cyclin B1 and Chk2 down-regulation. AB - Genistein is an isoflavonic phyto-oestrogen contained in soya beans. It is thought to display anti-cancer effects. This study was designed to investigate its effect on human intestinal colon cancer Caco-2 cells. MTT assay, flow cytometric analysis and western blotting were used to investigate the effect of genistein on cell proliferation, cell cycle progression and protein alterations of selected cell cycle-related proteins in Caco-2 cells. Our results showed that genistein and daidzein significantly suppressed cell proliferation. Genistein treatment was demonstrated to modulate cell cycle distribution through accumulation of cells at G2/M phase, with a significant decreasing effect of Cyclin B1 and Serine/threonine-protein kinase 2 (Chk2) proteins expression. However, daidzein did not alter the cell cycle progression in Caco-2 cells. All these observation strongly indicate that genistein has anti-proliferative effect in human intestinal colon cancer Caco-2 cells through the down-regulation of cell cycle check point proteins, Cyclin B1 and Chk2. PMID- 23794040 TI - IL-1Ra and its delivery strategies: inserting the association in perspective. AB - Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring anti inflammatory antagonist of interleukin-1 family of pro-inflammatory cytokines. The broad spectrum anti-inflammatory effects of IL-1Ra have been investigated against various auto-immune diseases such as diabetes mellitus, rheumatoid arthritis. Despite of its outstanding broad spectrum anti-inflammatory effects, IL-1Ra has short biological half-life (4-6 h) and to cope with this problem, up till now, many delivery strategies have been applied either to extend the half life and/or prolong the steady-state sustained release of IL-1Ra from its target site. Here in our present paper, we have provided an overview of all approaches attempted to prolong the duration of therapeutic effects of IL-1Ra either by fusing IL-1Ra using fusion protein technology to extend the half-life and/or development of new dosage forms using various biodegradable polymers to prolong its steady-state sustained release at the site of administration. These approaches have been characterized by their intended impact on either in vitro release characteristics and/or pharmacokinetic and pharmacodynamic parameters of IL-1Ra. We have also compared these delivery strategies with each other on the basis of bioactivity of IL-1Ra after fusion with fusion protein partner and/or encapsulation with biodegradable polymer. PMID- 23794042 TI - Pseudomonas prosekii sp. nov., a novel psychrotrophic bacterium from Antarctica. AB - During Czech expeditions at James Ross Island, Antarctica, in the years 2007 2009, the bacterial diversity of the genus Pseudomonas was studied. Twelve fluorescent Pseudomonas strains were isolated from various samples and were subjected to a detailed taxonomic study. A polyphasic approach included genotypic and phenotypic analyses. The genotypic analysis involved sequencing of rrs, rpoB and rpoD genes, DNA-DNA hybridization (DDH) studies as well as manual ribotyping using HindIII endonuclease. The phenotypic characterization included conventional tests as well as biotyping using the Biolog system, protein profiling by SDS PAGE, and MALDI-TOF MS analysis. Our taxonomic study revealed that all isolates belonged to the same Pseudomonas species with psychrotrophic growth not exceeding 37 degrees C. The cultures showed a unique position among the phylogenetically related pseudomonads. DDH experiment between the proposed type strain of the antarctic isolates and the closest neighbour P. arsenicoxydans CCM 8423(T) showed only 40.9-50.1 % similarity, thus confirming that the characterized strains do not belong to the P. arsenicoxydans species. According to the results obtained we propose the name P. prosekii sp. nov. for this novel Pseudomonas taxon with type strain AN/28/1(T) (=CCM 7990(T) and LMG 26867(T)). PMID- 23794043 TI - Discontinuation of leisure time impact-loading exercise is related to reduction of a calcaneus quantitative ultrasound parameter in young adult Japanese females: a 3-year follow-up study. AB - A 3-year follow-up study on 334 young Japanese females enrolled in a university at the age of 18 years revealed that discontinuation of leisure time impact loading exercises performed in junior high and/or high school was associated with increased risk of reduction in calcaneus osteo-sono assessment index (OSI). INTRODUCTION: Bone strength rapidly increases during puberty and reaches its peak by the end of adolescence. The aim of this study was to determine the lifestyle factors that influence the maintenance of calcaneus OSI in young adult females around the time when peak bone mass is attained. METHODS: Annual health checkups including OSI measurements, anthropometrics, lifestyle analysis, and blood examination were performed 4 times on 334 Japanese females enrolled in a university at the age of 18 years. According to the slope of OSI change during the 3-year follow-up, the subjects were grouped into two categories: OSI loss (the lowest tertile) and OSI gain/stable (the second and third tertiles). RESULTS: At the baseline assessment, the OSI loss group had higher OSI and height and an earlier menarche age than the OSI gain/stable group. Performing leisure time impact-loading exercise in junior high and/or high school but discontinuing it at university was associated with increased risk of OSI loss, independent of OSI, height and weight at the age of 18 years, weight change during follow-up, age of menarche, energy-adjusted nutrient intake, and alcohol drinking; the odds ratios were 4.1-4.9 compared with those performing impact-loading exercise at university. In particular, duration, frequency, and subjective intensity of impact-loading exercise during high school were positively associated with OSI loss. CONCLUSION: Discontinuation of leisure time impact-loading exercises performed during late adolescence is associated with an increased risk of OSI loss in young adult females during the 3-year follow-up period. PMID- 23794044 TI - Factors influencing the pharmacological management of osteoporosis after fragility fracture: results from the Ontario Osteoporosis Strategy's fracture clinic screening program. AB - Potential mediating factors in the pathway to initiation of osteoporosis treatment following a fragility fracture were evaluated. Patients' perceived need for treatment, mediated by their perception of bone density test results, was central to treatment initiation. Interventions focusing on patients' perceptions of need and test results may improve treatment rates. INTRODUCTION: We tested a hypothesized pathway to osteoporosis (OP) pharmacotherapy initiation in fragility fracture patients. We hypothesized that bone mineral density (BMD) testing is strongly associated with treatment initiation and perception of BMD test results would inform patients' perceived need for treatment, which would mediate the effect between BMD testing and treatment initiation. METHODS: A longitudinal cohort study followed patients, >=50 years of age, screened for fragility fracture in 31 fracture clinics in Ontario, Canada who had no prior diagnosis of or treatment for OP. At screening, OP risk factors, baseline-patient perception of OP risk, OP knowledge, and perceived benefits of medication were reported by patients. Patients were followed up within 6 months of fracture to determine BMD testing and prescription of and adherence to first-line OP pharmacotherapy. Structural equation modeling tested the hypothesized pathway. Significance and magnitude of the coefficients and indicators of overall model fit were used to test our model. RESULTS: The direct path from BMD testing to OP treatment initiation was non-significant. The pathway to treatment initiation was mediated by patients' perception of their need, which was influenced by their self reported BMD results. Baseline fracture risk factors, knowledge of OP, and perceived benefits of treatment-predicted patient-perceived need for treatment at follow-up and initiation of OP treatment. CONCLUSIONS: Patient perceptions were central factors in the path to initiation of OP pharmacotherapy. Interventions to facilitate accurate patient perceptions of BMD test results and OP risk status could prove helpful in improving OP treatment initiation. PMID- 23794046 TI - Enhanced aldehyde dehydrogenase activity by regenerating NAD+ in Klebsiella pneumoniae and implications for the glycerol dissimilation pathways. AB - In Klebsiella pneumoniae, 3-hydroxypropaldehyde is converted to 3 hydroxypropionic acid (3-HP) by aldehyde dehydrogenase (ALDH) with NAD(+) as a cofactor. Although ALDH overexpression stimulates the formation of 3-HP, it ceases to accumulate when NAD(+) is exhausted. Here we show that NAD(+) regeneration, together with ALDH overexpression, facilitates 3-HP production and benefits cell growth. Three distinct NAD(+)-regenerating enzymes: NADH oxidase and NADH dehydrogenase from K. pneumoniae, and glycerol-3-phosphate dehydrogenase (GPD1) from Saccharomyces cerevisiae, were individually expressed in K. pneumoniae. In vitro assay showed their higher activities than that of the control, indicating their capacities to regenerate NAD(+). When they were respectively co-expressed with ALD4, an ALDH from S. cerevisiae, the activities of ALD4 were significantly elevated compared with that expressing ALD4 alone, suggesting that the regenerated NAD(+) enhanced the activity of ALD4. More interestingly, the growth rates of all NAD(+)-regenerating strains were prolonged in comparison with the control, indicating that NAD(+) regeneration stimulated cell proliferation. This study not only reveals the reliance of ALD4 activity on NAD(+) availability but also provides a method for regulating the dha regulon. PMID- 23794047 TI - Preparation of an osteochondral composite with mesenchymal stem cells as the single-cell source in a double-chamber bioreactor. AB - A double-chamber bioreactor has been developed to generate a tissue-engineered osteochondral composite (TEOC). However, a TEOC generally requires two types of cells (i.e. chondrogenic and osteogenic cells). Therefore, the capacity of mesenchymal stem cells (MSCs) as a single-cell source to work within a double chamber bioreactor and biphasic scaffolds for generating TEOC was investigated. Compared with static culture, the double-chamber bioreactor not only can promote faster cellular proliferation, indicated by the PicoGreen dsDNA assay, SEM and confocal imaging, but also can trigger efficient chondrogenic and osteogenic differentiation of MSCs in biphasic scaffolds simultaneously, evidenced by gene expression. Thus MSCs are promising as the ideal single-cell source and the double-chamber bioreactor is an advanced culture system to generate TEOC. PMID- 23794048 TI - Specific primer design for the polymerase chain reaction. AB - The design of primers has a major impact on the success of PCR in relation to the specificity and yield of the amplified product. Here, we introduce the applications of PCR as well as the definition and characteristics for PCR primer design. Recent primer design tools based on Primer3, along with several computational intelligence-based primer design methods which have been applied in primer design, are also reviewed. In addition, characteristics of population based methods used in primer design are discussed in detail. PMID- 23794049 TI - Degradation of a xenobiotic textile dye, Disperse Brown 118, by Brevibacillus laterosporus. AB - The toxic textile dye, Disperse Brown 118, was degraded by Brevibacillus laterosporus. 96% decolorization was achieved within 48 h at pH 7, 40 degrees C at 50 mg dye l(-1) accompanied by significant increases in the activities of veratryl alcohol oxidase, tyrosinase and NADH-DCIP reductase. HPTLC and FT-IR spectroscopy confirmed biodegradation after dye decolorization. As identified by GC-MS, biodegradation products of Disperse Brown 118 were N-carbamoyl-2-[(8 chloroquinazolin-4-yl)oxy] acetamide and N-carbamoyl-2-(quinazolin-4 yloxy)acetamide which were much less toxic than parent dye as evidenced by phytotoxicity tests. PMID- 23794050 TI - Directed evolution of cytochrome P450 for sterol epoxidation. AB - 16,17-Epoxysterol plays an important role in pharmaceutical steroid synthesis. To investigate the potential application of cytochrome P450 for epoxysterol synthesis, an approach to the epoxidation of 16,17-epoxysterol, based on directed evolution of cytochrome P450 BM-3, was developed. This comprised random gene mutagenesis for optimizing the activity of P450 BM-3 for epoxidation of hydrophobic sterol, followed by the 7-ethoxycoumarin de-ethylation assay for general enzyme activity detection and the modified picric acid assay for epoxidation activity screening. By the two-step screening, one mutant from 792 clones showed specific substrate activity of converting progesterone to 16,17 epoxysterol, which validated the possibility to evolve the cytochrome P450 for the synthesis of steroidal epoxides. PMID- 23794051 TI - Improving the thermostability of Escherichia coli phytase, appA, by enhancement of glycosylation. AB - A codon-optimized Escherichia coli appA phytase gene was synthesized and expressed in Pichia pastoris. Two residue substitutions (Q258N, Q349N) were sequentially introduced to enhance its glycosylation activity. Secretion of appA Q258N/Q349N was approx. 0.3 mg ml(-1) and enzyme activity reached 1,030 U ml(-1). Purified appA-Q258N/Q349N had a specific activity of 3,137 U mg(-1) with an MW of approx. 53 kDa. Compared with appA-WT, appA-Q258N/Q349N showed over 40 % enhancement in thermostability (85 degrees C for 10 min) and 4-5 degrees C increases in the melting temperatures (Tm). The Km and Kcat of appA-Q258N/Q349N were 0.43 mM and 3,058 s(-1), respectively, which are similar with that of appA WT. The mutant appA-Q258N/Q349N obtained in this study could be used for the large-scale commercial production of phytase. PMID- 23794052 TI - Distinguishing snoring sounds from breath sounds: a straightforward matter? AB - BACKGROUND: Although snoring is a common problem, no unequivocal definition yet exists for this acoustic phenomenon. The primary study objective was to investigate whether snoring sounds can be distinguished at all clearly from breath sounds. Our secondary objective was to evaluate whether the sound pressure level in common use and psychoacoustic parameters are suitable for making this distinction. METHODS: Twenty-five subjects exposed to 55 sound sequences were asked to decide whether these were breath sounds or snoring sounds, and to indicate how certain they were about their decision. The sound pressure level and the psychoacoustic parameters of loudness, sharpness, roughness, and fluctuation strength were then analyzed, and psychoacoustic annoyance was calculated from these parameters. RESULTS: Sixteen percent of the sound sequences could not be classified unequivocally, although the individual raters stated that they were still moderately certain about their decision. The sound pressure level and psychoacoustic parameters were capable of distinguishing between breath sounds and snoring sounds. The optimum for sensitivity and specificity was 76.9 and 78.8 %, respectively. CONCLUSIONS: Because snoring appears to be a subjective impression, at least in part, a generally valid acoustic definition therefore seems to be impossible. The sound pressure level and psychoacoustic parameters are suitable for distinguishing between breath sounds and snoring sounds. Nevertheless, when interpreting results, the only moderate validity of these parameters due to the absence of a universally valid definition of snoring should be taken into account. PMID- 23794053 TI - Analysis of the SDS-PAGE patterns of outer membrane proteins from Escherichia coli strains that have lost the ability to form K1 antigen and varied in the susceptibility to normal human serum. AB - We used SDS-polyacrylamide gel electrophoresis to investigate the outer membrane proteins (OMPs) band composition of 19 Escherichia coli K1 strains that have spontaneously lost the ability to form K1 polysaccharide capsule (E. coli K1-) and demonstrated different degrees of susceptibility to the bactericidal action of normal human serum. Presented results showed that there were differences between E. coli K1- strains in OMPs expressing capacity. The analysis performed on OMPs has not revealed a direct association between the different OMPs band composition and the susceptibility of these strains to the serum. PMID- 23794054 TI - Preterm infants' early growth and brain white matter maturation at term age. AB - BACKGROUND: Normal intrauterine conditions are essential to normal brain growth and development; premature birth and growth restriction can interrupt brain maturation. Maturation processes can be studied using diffusion tensor imaging. OBJECTIVE: The aim of this study was to use tract-based spatial statistics to assess the effect that early postnatal growth from birth to 40 gestational weeks has on brain white matter maturation. MATERIALS AND METHODS: A total of 36 preterm infants were accepted in the study. Postnatal growth was assessed by weight, length and head circumference. Birth weight z-score and gestational age were used as confounding covariates. RESULTS: Head circumference catch-up growth was associated with less mature diffusion parameters (P < 0.05). No significant associations were observed between weight or length growth and diffusion parameters. CONCLUSION: Growth-restricted infants seem to have delayed brain maturation that is not fully compensated at term, despite catch-up growth. PMID- 23794055 TI - Multiplanar CT assessment of femoral head displacement in slipped capital femoral epiphysis. AB - BACKGROUND: With recent changing approaches to the management of slipped capital femoral epiphysis (SCFE), the accurate radiographic assessment of maximum extent of displacement is crucial for planning surgical treatment. OBJECTIVE: To determine what plane best represents the maximum SCFE displacement as quantified by the head-neck angle difference (HNAD), whether HNAD can quantitatively differentiate the SCFE cohort from the normal cohort, based on CT, and how Southwick slip angle (SSA) compares to HNAD. MATERIALS AND METHODS: We reviewed 19 children with SCFE (23 affected hips) with preoperative CT scans and 27 age- and sex-matched children undergoing abdominal CT for non-orthopedic problems. Head-neck angle (HNA), the angle between the femoral epiphysis and the neck axis, was measured in three planes on each hip and the HNAD (affected - unaffected hip) was determined. SSA was measured on radiographs. RESULTS: The coronal HNAD (mean 8.7 degrees ) was less than both the axial-oblique (mean 30.7 degrees ) and sagittal (mean 37.4 degrees ) HNADs, which were also greater than the HNADs of the normal cohort. Grouping HNAD measurements by SSA severity classification did not consistently distinguish between SCFE severity levels. CONCLUSION: Axial oblique and sagittal planes best represent the maximum SCFE displacement while biplanar radiograph may underestimate the extent of the displacement, thereby potentially altering the management between in situ pinning and capital realignment. PMID- 23794056 TI - Titania nanorods curve to lower their energy. AB - Spontaneous formation of curved nanorods is generally unexpected, since curvature introduces strain energy. However, electron microscopy shows that under hydrothermal conditions, some nanorods grown by oriented attachment of small anatase particles on {101} surfaces are curved and dislocation free. Molecular dynamics simulations show that the lattice energy of a curved anatase rod is actually lower than that of a linear rod due to more attractive long-range interatomic Coulombic interactions among atoms in the curved rod. The thermodynamic driving force stemming from lattice energy could be harnessed to produce asymmetric morphologies unexpected from classical Ostwald ripening with unusual shapes and properties. PMID- 23794057 TI - Suppression of malignancy by Smad3 in mouse embryonic stem cell formed teratoma. AB - Disease associated gene deficient embryonic stem cells can serve as valuable in vitro models to study disease mechanisms and screen drugs. Smad3 mediated TGF beta/Activin/Nodal signaling plays important roles in many biological processes. Despite numerous studies regarding Smad3 function, the role of Smad3 in mouse ES cells is not well studied. To understand the function of Smad3 in mouse ES cells, we derived Smad3-/- ES cells and wild type ES cells. Smad3-/- ES cells display no defect on self-renewal. They express similar level of pluripotent genes and lineage genes compared to wild type ES cells. However, Smad3 ablation results in transient difference in germ layer marker expression during embryoid body formation. Mesoderm lineage marker expression is significantly reduced in the embryoid body formed by Smad3-/- ES cells compared to wild type ES cells. Intriguingly, subcutaneous injection of Smad3-/- ES cells into nude mice leads to formation of malignant immature teratomas, whilst wild type ES cells tend to form mature teratomas. Smad3-/- ES cell formed teratomas can therefore provide a new model for the study of the mechanism of malignant teratomas. PMID- 23794058 TI - Capacity of human umbilical cord-derived mesenchymal stem cells to differentiate into sweat gland-like cells: a preclinical study. AB - Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) possess various advantageous properties, including self-renewal, extended proliferation potential, multi-lineage differentiation potential and capacity for differentiating into sweat gland-like cells in certain conditions. However, little is known about the effect of clinical-grade culture conditions on these properties and on the differentiative potential of hUC-MSCs. In this study, we sought to investigate the properties of hUC-MSCs expanded with animal serum free culture media (ASFCM) in order to determine their potential for differentiation into sweat gland-like cells. We found that primary cultures of hUC-MSCs could be established with ASFCM. Moreover, cells cultured in ASFCM showed vigorous proliferation comparable to those of cells grown in classical culture conditions containing fetal bovine serum (FBS). Morphology of hUC-MSCs cultured in ASFCM was comparable to those of cells grown under classical culture conditions, and hUC MSCs grown in both of the two culture conditions tested showed the typical antigen profile of MSCs-positive for CD29, CD44, CD90, and CD105, and negative for CD34 and CD45, as expected. Chromosomal aberration assay revealed that the cells were stable after long-term culture under both culture conditions. Like normal cultured MSCs, hUC-MSCs induced under ASFCM conditions exhibited expression of the same markers (CEA, CK14 and CK19) and developmental genes (EDA and EDAR) that are characteristic of normal sweat gland cells. Taken together, our findings indicate that the classical culture medium used to differentiate hUC MSCs into sweat gland-like cells can be replaced safely by ASFCM for clinical purposes. PMID- 23794059 TI - Extraction of electron beam dose parameters from EBT2 film data scored in a mini phantom. AB - Quality assurance of medical linear accelerators includes dosimetric parameter measurement of therapeutic electron beams e.g. relative dose at a depth of 80% (R80). This parameter must be within a tolerance of 0.2 cm of the declared value. Cumbersome water tank measurements can be regarded as a benchmark to measure electron depth dose curves. A mini-phantom was designed and built, in which a strip of GAFCHROMIC(r) EBT2 film could be encased tightly for electron beam depth dose measurement. Depth dose data were measured for an ELEKTA Sl25 MLC, ELEKTA Precise, and ELEKTA Synergy (Elekta Oncology Systems, Crawley, UK) machines. The electron beam energy range was between 4 and 22 MeV among the machines. A 10 * 10 cm2 electron applicator with 95 cm source-surface-distance was used on all the machines. 24 h after irradiation, the EBT2 film strips were scanned on Canon CanoScan N670U scanner. Afterwards, the data were analysed with in-house developed software that entailed optical density to dose conversion, and optimal fitting of the PDD data to de-noise the raw data. From the PDD data R80 values were solved for and compared with acceptance values. A series of tests were also carried out to validate the use of the scanner for film Dosimetry. These tests are presented in this study. It was found that this method of R80 evaluation was reliable with good agreement with benchmark water tank measurements using a commercial parallel plate ionization chamber as the radiation detector. The EBT2 film data yielded R80 values that were on average 0.06 cm different from benchmark water tank measured R80 values. PMID- 23794060 TI - [Rosacea: Clinical features and classification]. AB - Rosacea is a frequent chronic dermatological disorder mainly affecting the face. Since it affects the appearance, it can be very distressing for the patient leading to psychosocial disturbances. Rosacea occurs in adults, peaking between 40 and 50 years of age. The course of rosacea is quite variable and the disease may stop at any stage. Generally, three main stages are differentiated: erythemato-teleangiectatic rosacea (rosacea stage I), papulopustular rosacea (rosacea stage II), hyperglandular-hypertrophic rosacea (rosacea stage III). Besides these main manifestations numerous special forms exist, which often lead to difficulties in the differential diagnoses and require specific therapeutic strategies. These include rosacea conglobata, rosacea fulminans, granulomatous rosacea, persisting edema, (Morbihan disease), gram negative rosacea, ocular rosacea, and steroid rosacea. Recently increasing numbers of patients have been observed, whose rosacea was were induced by inhibitors of epidermal growth factors (cetuximab, geftinib) used as chemotherapy in patients with different malignancies. These side effects have been described as acneiform eruptions but at least some of the described patients have a rosacea-like appearance; therefore, this form can be classified as a subset of drug induced rosacea. PMID- 23794061 TI - Parenteral monofluorophosphate (MFP) is a more potent inducer of enamel fluorotic defects in neonatal hamster molars than sodium fluoride. AB - Supra-optimal intake of sodium fluoride (NaF) during early childhood results in formation of irreversible enamel defects. Monofluorophosphate (MFP) was considered as less toxic than NaF but equally cariostatic. We compared the potency of MFP and NaF to induce pre-eruptive sub-ameloblastic cysts and post eruptive white spots and pits in developing hamster enamel. Hamster pups were injected subcutaneously with either NaF or MFP in equimolar doses of either 9 mg or 18 mg F/kg body weight. At 9 mg F/kg, MFP induced more but smaller sub ameloblastic cysts with a collective cyst volume twice as large as that induced by NaF. Eight days after F injection, all F-injected groups had formed 4-6 white spots per molar, with an additional 2 pits per molar in the low MFP group. Twenty eight days after injection, most white spots had turned into pits (5-6 per molar) and only the high MFP group still contained 2 white spots per molar. We conclude that parenterally applied MFP is more potent in inducing enamel defects than NaF. Most white spots formed turn into pits by functional use of the dentition. The higher potency of parenteral MFP may be associated with sustained elevated F levels in the enamel organ by enzymatic hydrolysis of MFP by alkaline phosphatase activity. PMID- 23794062 TI - Atrial fibrillation, elevated troponin, ischemic stroke and adverse outcomes: understanding the connection. AB - Cardiac troponin is widely used for the diagnosis of acute myocardial infarction. In addition to this indication, the elevation of troponin has been found to play a prognostic role in ischemic stroke. It is hypothesized that approximately 15-20 % of all ischemic strokes are associated with atrial fibrillation and that these events are more often fatal. Recent studies have demonstrated that troponin elevation can also be used as a prognosticator in patients with atrial fibrillation and for risk stratification to predict which patients are more prone to stroke or other thromboembolic events. Therefore, troponin appears to play a pivotal role in the overlap of atrial fibrillation and ischemic stroke and the subsequent development of an adverse outcome. The different aspects of this association will be addressed and novel explanations will be proposed to better clarify the underlying mechanisms. PMID- 23794063 TI - The anti-inflammatory effect of diclofenac is considerably augmented by topical capsaicinoids-containing patch in carrageenan-induced paw oedema of rat. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most used drugs in musculoskeletal disorders, but their systemic adverse effects limit their therapeutic benefit in local inflammation. On the other hand, topical preparations of capsaicinoids are widely used for musculoskeletal disorders as a complementary therapy. In this study, the effects of both topical capsaicinoids containing patch and local subcutaneous capsaicin application on the anti inflammatory action of NSAID were examined. Carrageenan-induced paw oedema of rats was used as the inflammation model. The volume and weight of the paw oedema and plasma extravasation in the paw were determined after carrageenan injection. The systemic application of diclofenac (3 mg/kg), which is an NSAID, significantly decreased the volume and weight of the paw oedema. Topical capsaicinoids-containing patch application or local capsaicin injection (2, 10, 20 MUg/paw) alone did not cause any effect on oedema volume and weight. However, the combination of diclofenac with topical capsaicinoids-containing patch significantly increased the effectiveness of diclofenac on inflammation. Evans blue content of the paws that represents plasma extravasation was decreased by capsaicinoids-containing patch with and without diclofenac and diclofenac combination with the lowest dose of capsaicin injection. The results of this study indicate that topical application of capsaicinoids-containing patch enhances the anti-inflammatory effect of diclofenac and its beneficial effect may not purely relate to its capsaicin content. In the treatment of local inflammatory disorders, the combination of NSAID with topical capsaicinoids containing patch could increase the anti-inflammatory efficiency of drug without systemic side effects. PMID- 23794064 TI - Unraveling the complexity of tyrosine kinase inhibitor-resistant populations by ultra-deep sequencing of the BCR-ABL kinase domain. AB - In chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia, tyrosine kinase inhibitor (TKI) therapy may select for drug-resistant BCR-ABL mutants. We used an ultra-deep sequencing (UDS) approach to resolve qualitatively and quantitatively the complexity of mutated populations surviving TKIs and to investigate their clonal structure and evolution over time in relation to therapeutic intervention. To this purpose, we performed a longitudinal analysis of 106 samples from 33 patients who had received sequential treatment with multiple TKIs and had experienced sequential relapses accompanied by selection of 1 or more TKI-resistant mutations. We found that conventional Sanger sequencing had misclassified or underestimated BCR-ABL mutation status in 55% of the samples, where mutations with 1% to 15% abundance were detected. A complex clonal texture was uncovered by clonal analysis of samples harboring multiple mutations and up to 13 different mutated populations were identified. The landscape of these mutated populations was found to be highly dynamic. The high degree of complexity uncovered by UDS indicates that conventional Sanger sequencing might be an inadequate tool to assess BCR-ABL kinase domain mutation status, which currently represents an important component of the therapeutic decision algorithms. Further evaluation of the clinical usefulness of UDS-based approaches is warranted. PMID- 23794065 TI - C1galt1-deficient mice exhibit thrombocytopenia due to abnormal terminal differentiation of megakaryocytes. AB - C1galt1 is essential for synthesis of the core 1 structure of mucin-type O glycans. To clarify the physiological role of O-glycans in adult hematopoiesis, we exploited the interferon-inducible Mx1-Cre transgene to conditionally ablate the C1galt(flox) allele (Mx1-C1). Mx1-C1 mice exhibit severe thrombocytopenia, giant platelets, and prolonged bleeding times. Both the number and DNA ploidy of megakaryocytes in Mx1-C1 bone marrow were similar to those in wild-type (WT) mice. However, there were few proplatelets in Mx1-C1 primary megakaryocytes. Conversely, bone marrow transplanted from Mx1-C1 to WT and splenectomized Mx1-C1 mice gave rise to observations similar to those described above. The expression of GPIbalpha messenger RNA was unchanged in Mx1-C1 bone marrow, whereas flow cytometric and western blot analyses using megakaryocytes and platelets revealed that the expression of GPIbalpha protein was significantly reduced in Mx1-C1 mice. Moreover, circulating Mx1-C1 platelets exhibited an increase in the number of microtubule coils, despite normal levels of alpha- and beta-tubulin. Our observations suggest that O-glycan is required for terminal megakaryocyte differentiation and platelet production and that the decrease in GPIbalpha in cells lacking O-glycan might be caused by increased proteolysis. PMID- 23794066 TI - Human CD1c+ dendritic cells secrete high levels of IL-12 and potently prime cytotoxic T-cell responses. AB - Dendritic cells (DC) have the unique capacities to induce primary T-cell responses. In mice, CD8alpha(+)DC are specialized to cross-prime CD8(+) T cells and produce interleukin-12 (IL-12) that promotes cytotoxicity. Human BDCA-3(+)DC share several relevant characteristics with CD8alpha(+)DC, but the capacities of human DC subsets to induce CD8(+) T-cell responses are incompletely understood. Here we compared CD1c(+) myeloid DC (mDC)1, BDCA-3(+)mDC2, and plasmacytoid DC (pDC) in peripheral blood and lymphoid tissues for phenotype, cytokine production, and their capacities to prime cytotoxic T cells. mDC1 were surprisingly the only human DC that secreted high amounts of IL-12p70, but they required combinational Toll-like receptor (TLR) stimulation. mDC2 and pDC produced interferon-lambda and interferon-alpha, respectively. Importantly, mDC1 and mDC2 required different combinations of TLR ligands to cross-present protein antigens to CD8(+) T cells. pDC were inefficient and also expressed lower levels of major histocompatibility complex and co-stimulatory molecules. Nevertheless, all DC induced CD8(+) memory T-cell expansions upon licensing by CD4(+) T cells, and primed naive CD8(+) T cells following appropriate TLR stimulation. However, because mDC1 produced IL-12, they induced the highest levels of cytotoxic molecules. In conclusion, CD1c(+)mDC1 are the relevant source of IL-12 for naive T cells and are fully equipped to cross-prime cytotoxic T-cell responses. PMID- 23794067 TI - The CXCR4 mutations in WHIM syndrome impair the stability of the T-cell immunologic synapse. AB - WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) syndrome is a rare disease characterized by diverse symptoms indicative of aberrantly functioning immunity. It is caused by mutations in the chemokine receptor CXCR4, which impair its intracellular trafficking, leading to increased responsiveness to chemokine ligand and retention of neutrophils in bone marrow. Yet WHIM symptoms related to adaptive immunity, such as delayed IgG switching and impaired memory B-cell function, remain largely unexplained. We hypothesized that the WHIM-associated mutations in CXCR4 may affect the formation of immunologic synapses between T cells and antigen-presenting cells (APCs). We show that, in the presence of competing external chemokine signals, the stability of T-APC conjugates from patients with WHIM-mutant CXCR4 is disrupted as a result of impaired recruitment of the mutant receptor to the immunologic synapse. Using retrogenic mice that develop WHIM-mutant T cells, we show that WHIM-mutant CXCR4 inhibits the formation of long-lasting T-APC interactions in ex vivo lymph node slice time lapse microscopy. These findings demonstrate that chemokine receptors can affect T-APC synapse stability and allow us to propose a novel mechanism that contributes to the adaptive immune response defects in WHIM patients. PMID- 23794068 TI - Hepatitis E virus: an underestimated opportunistic pathogen in recipients of allogeneic hematopoietic stem cell transplantation. AB - Hepatitis E virus (HEV) is increasingly acknowledged as a cause of hepatitis in healthy individuals as well as immunocompromised patients. Little is known of HEV infection in recipients of allogeneic hematopoietic stem cell transplantation (alloHSCT). Therefore, we set out to study the incidence and sequelae of HEV as a cause of hepatitis in a recent cohort of 328 alloHSCT recipients. HEV RNA was tested in episodes of liver enzyme abnormalities. In addition, HEV RNA and HEV serology were assessed pre- and post-alloHSCT. We found 8 cases (2.4%) of HEV infection, of which 5 had developed chronic HEV infection. Seroprevalence pre alloHSCT was 13%. Four patients died with HEV viremia, with signs of ongoing hepatitis, having a median time of infection of 4.1 months. The 4 surviving patients cleared HEV after a median period of 6.3 months. One patient was diagnosed with HEV reactivation after a preceding infection prior to alloHSCT. Although the incidence of developing acute HEV post-alloHSCT is relatively low, the probability of developing chronic hepatitis in severely immunocompromised patients is high. Therefore, alloHSCT recipients should be screened pretransplantation by HEV serology and RNA. Furthermore, a differential diagnosis including hepatitis E is mandatory in all alloHSCT patients with severe liver enzyme abnormalities. PMID- 23794069 TI - Herpes simplex virus type 2 cross-sectional seroprevalence and the estimated rate of neonatal infections among a cohort of rural Malawian female adolescents. AB - OBJECTIVE: To assess herpes simplex virus type 2 (HSV-2) seroprevalence among rural Malawian adolescent women and estimate the number of neonatal herpes infections among infants of these adolescents. METHODS: A longitudinal cohort study of adolescents (14-16 years at entry) residing in rural Malawi was initiated in 2007 with annual observation. HSV-2 testing was introduced in 2010. In this study, we (1) determined, using cross-sectional analysis, risk factors for positive serostatus, (2) adjusted for non-response bias with imputation methods and (3) estimated the incidence of neonatal herpes infection using mathematical models. RESULTS: A total of 1195 female adolescents (age 17-20 years) were interviewed in 2010, with an observed HSV-2 seroprevalence of 15.2% among the 955 women tested. From a multivariate analysis, risk factors for HSV-2 seropositivity include older age (p=0.037), moving from the baseline village (p=0.020) and report of sexual activity with increasing number of partners (p<0.021). Adjusting for non-response bias, the estimated HSV-2 seroprevalence among the total female cohort (composed of all women interviewed in 2007) was 18.0% (95% CI 16.0% to 20.2%). HSV-2 seropositivity was estimated to be 25.6% (95% CI 19.6% to 32.5%) for women who refused to provide a blood sample. The estimated number of neonatal herpes infections among the total female cohort was 71.8 (95% CI 57.3 to 86.3) per 100 000 live births. CONCLUSIONS: The risk of HSV 2 seroconversion is high during adolescence, when childbearing is beginning, among rural Malawian women. Research on interventions to reduce horizontal and vertical HSV-2 transmission during adolescence in resource-limited settings is needed. PMID- 23794070 TI - Seroprevalence of rubella in northeastern Turkey. AB - AIM: The aim of this study was to search rubella prevalence and compare the results with national and international data. MATERIALS AND METHODS: The presence of anti-rubella immunoglobulin G (IgG) and anti-rubella immunoglobulin M (IgM) antibodies were studied in the sera obtained from cases with fever in last week and applied to the Microbiology Laboratory in the period between February 2010 and December 2010. No clinical sign or symptom regarding rubella infection has been evaluated for cases to obtain blood samples. IgM and IgG antibodies were tested with ELISA (Vitros ECI Q (J&J) Company Ortho Clinical Diagnostic Macro) method. The data obtained were assessed with SPSS statistical package using chi square trend analysis method. RESULTS: Anti-rubella IgM positivity was found 8/68 (8.8 %) of males and 3/138 (2.2 %) of females who are under 18 years-old (p = 0.028). Meanwhile 47/65 (72.3 %) of males and 99/122 (81.8 %) of females under 18 years-old were presented with anti-rubella IgG positivity (p = 0.164). In all, 2/8 (25 %) males and 28/1,181 (2.4 %) females older than 18 years-old were anti rubella IgM positive (p = 0.013). Anti-rubella IgG antibodies were found positive in 862/1,181 (73 %) of females and all males (8/8) older than 18-years-old (p = 0.086). CONCLUSION: In spite of the active immunization programme commenced after 2006, rubella infection is still a risk in Turkey without discriminating the gender. PMID- 23794071 TI - Oral bullous eruption after taking lisinopril--case report and literature review. AB - Drug-induced lesions of oral mucosa are well-established side effect of different commonly used drugs. A female patient under treatment for hypertension with an angiotensin-converting enzyme inhibitor (ACE inhibitor), lisinopril, developed blisters and ulcerations on oral mucosa 3 weeks after lisinopril intake. Due to clinical finding drug-induced pemphigus was considered. However, direct and indirect immunofluorescence anal-ysis revealed no autoantibodies that are commonly present in pemphigus while histological study suggested allergic reaction. Lisinopril was discontinued from further therapy and after a month after her first arrival patient has experienced complete remission of the disease. This case raises the question, whether the term pemphigus in drug induced reactions could be used when immunopathological criteria for pemphigus are not fulfilled. PMID- 23794072 TI - A cost analysis of a community health worker program in rural Vermont. AB - Studies have shown that community health workers (CHWs) can improve the effectiveness of health care systems; however, little has been reported about CHW program costs. We examined the costs of a program staffed by three CHWs associated with a small, rural hospital in Vermont. We used a standardized data collection tool to compile cost information from administrative data and personal interviews. We analyzed personnel and operational costs from October 2010 to September 2011. The estimated total program cost was $420,348, a figure comprised of $281,063 (67%) for personnel and $139,285 (33%) for operations. CHW salaries and office space were the major cost components. Our cost analysis approach may be adapted by others to conduct cost analyses of their CHW program. Our cost estimates can help inform future economic studies of CHW programs and resource allocation decisions. PMID- 23794073 TI - Repeated acquisition and discrimination reversal in the squirrel monkey (Saimiri sciureus). AB - Repeated acquisition and discrimination reversal tasks are often used to examine behavioral relations of, respectively, learning and cognitive flexibility. Surprisingly, despite their frequent use in cognitive neuroscience and behavioral pharmacology, variables that control performance under these two tasks have not been widely studied. The present studies were conducted to directly investigate the controlling variables in nonhuman primates. Squirrel monkeys were trained with a touchscreen variant of the repeated acquisition task in which a novel pair of S(+)/S(-) stimuli was presented daily. Subjects learned to discriminate the two stimuli (acquisition) and, subsequently, with the contingencies switched (reversal). Results indicate that rates of both acquisition and reversal learning increased across successive sessions, but that rate of reversal learning remained slower than acquisition learning, i.e., more trials were needed for mastery. Subsequent experiments showed this difference between the rate of learning novel discriminations and reversal was reliable for at least 5 days between acquisition and reversal and notwithstanding the interpolation of additional discriminations. Experimental analysis of the S(+)/S(-) elements of the tasks revealed that the difference in the rate of learning could not be attributed to a relatively aversive quality of the S(-) or to a relatively appetitive quality of the S(+), but, rather, to contextual control by the S(+)/S(-) stimulus complex. Thus, if either element (S(+) or S(-)) of the stimulus complex was replaced by a novel stimulus, the rate of acquisition approximated that expected with a novel stimulus pair. These results improve our understanding of fundamental features of discrimination acquisition and reversal. PMID- 23794074 TI - Knowing your audience affects male-male interactions in Siamese fighting fish (Betta splendens). AB - Aggressive interactions between animals often occur in the presence of third parties. By observing aggressive signalling interactions, bystanders may eavesdrop and gain relevant information about conspecifics without the costs of interacting. On the other hand, interactants may also adjust their behaviour when an audience is present. This study aimed to test how knowledge about fighting ability of an audience affects aggressive interactions in male Siamese fighting fish. Subjects were positioned between two dyads of non-interacting males and allowed to observe both dyads shortly before the view to one of the dyads was blocked, and the dyads were allowed to interact. Subjects were subsequently exposed to an unknown opponent in the presence of either the winner or the loser of the seen or unseen interaction. The results suggest a complex role of the characteristic of an audience in the agonistic behaviours of a subject engaged in an interaction. The presence of a seen audience elicited more aggressive displays towards the opponent if the audience was a loser. This response was different in the presence of an unseen audience. Subjects then directed a higher aggressiveness against their opponent if the audience was a winner. These results also suggest a potentially more complex and interesting process allowing individuals to gain information about the quality and threat level of an unknown audience while it is interacting with a third party. The importance of information acquisition for an individual to adapt its behaviour and the role of communication networks in shaping social interactions are discussed. PMID- 23794075 TI - Effects of hepatitis B virus X gene on apoptosis and expression of immune molecules of human proximal tubular epithelial cells. AB - The hepatitis B virus X protein (HBx) is the most important determinant in viral pathogenesis. HBx regulates HBV replication, cellular transcription, signal transduction, proteasome activity and cell cycle progression. In this study, HK-2 cells were transiently transfected with the HBx gene using a eukaryotic vector, pcDNA3.1/myc-HBx. Transfection with the HBx gene increased the number of apoptotic cells. In addition, cultured HK-2 cells became irregular in shape. The expression of alpha-SMA and E-cadherin, TLR4, MHC-II and CD40 was increased. The transfection resulted in increased IL-1, IL-6, TNF-alpha and IFN-gamma levels in the supernatant and decreased IL-4 in the supernatant. In conclusion, overexpression of the HBx gene in renal tubular epithelial cells induces apoptosis of HK-2 cells and promotes epithelial-mesenchymal transdifferentiation. HBx transfection upregulates the expression of immune molecules in renal tubular epithelial cells and induces an imbalance in cytokine levels. PMID- 23794076 TI - Therapeutic protein drug-drug interactions: navigating the knowledge gaps highlights from the 2012 AAPS NBC Roundtable and IQ Consortium/FDA workshop. AB - The investigation of therapeutic protein drug-drug interactions has proven to be challenging. In May 2012, a roundtable was held at the American Association of Pharmaceutical Scientists National Biotechnology Conference to discuss the challenges of preclinical assessment and in vitro to in vivo extrapolation of these interactions. Several weeks later, a 2-day workshop co-sponsored by the U.S. Food and Drug Administration and the International Consortium for Innovation and Quality in Pharmaceutical Development was held to facilitate better understanding of the current science, investigative approaches and knowledge gaps in this field. Both meetings focused primarily on drug interactions involving therapeutic proteins that are pro-inflammatory cytokines or cytokine modulators. In this meeting synopsis, we provide highlights from both meetings and summarize observations and recommendations that were developed to reflect the current state of the art thinking, including a four-step risk assessment that could be used to determine the need (or not) for a dedicated clinical pharmacokinetic interaction study. PMID- 23794077 TI - Risk of medication safety incidents with antibiotic use measured by defined daily doses. AB - BACKGROUND: Medication incidents (MIs) account for 11.3 % of all reported patient safety incidents in England and Wales. Approximately one-third of inpatients are prescribed an antibiotic at some point during their hospital stay. The WHO has identified incident reporting as one solution to reduce the recurrence of adverse incidents. OBJECTIVES: The aim of this study was to determine the number and nature of reported antibiotic-associated MIs occurring in inpatients and to use defined daily doses (DDDs) to calculate the incident rate for the antibiotics most commonly associated with MIs at each hospital. SETTING: Two UK acute NHS teaching hospitals. METHODS: Retrospective quantitative analysis was performed on antibiotic-associated MIs reported to the risk management system over a 2-year period. Quality-assurance measures were undertaken before analysis. The study was approved by the clinical audit departments at both hospitals. Drug consumption data from each hospital were used to calculate the DDD for each antibiotic. MAIN OUTCOME MEASURES: The number of antibiotic-related MIs reported and the incident rate for the 10 antibiotics most commonly associated with MIs at each hospital. RESULTS: Healthcare staff submitted 6,756 reports, of which 885 (13.1 %) included antibiotics. This resulted in a total of 959 MIs. Most MIs occurred during prescribing (42.4 %, n = 407) and administration (40.0 %, n = 384) stages. Most common types of MIs were omission/delay (26.3 %, n = 252), and dose/frequency (17.9 %, n = 172). Penicillins (34.5 %, n = 331) and aminoglycosides (16.6 %, n = 159) were the most frequently reported groups with co-amoxiclav (16.8 %, n = 161) and gentamicin (14.1 %, n = 135) the most frequently reported drugs. Using DDDs to assess the incident rate showed that cefotaxime (105.4/10,000 DDDs), gentamicin (25.7/10,000 DDDs) and vancomycin (23.7/10,000 DDDs) had the highest rates. CONCLUSIONS: This study highlights that detailed analysis of data from reports is essential in understanding MIs and developing strategies to prevent their recurrence. Using DDDs in the analysis of MIs allowed determination of an incident rate providing more useful information than the absolute numbers alone. It also highlighted the disproportionate risk associated with less commonly prescribed antibiotics not identified using MI reporting rates alone. PMID- 23794078 TI - Blood concentrations of cefuroxime in cardiopulmonary bypass surgery. AB - OBJECTIVES: Patients with coronary artery bypass graft (CABG) surgery are at risk for severe postoperative infections. Prophylactic cefuroxime may help to reduce this risk, however sufficient concentrations, i.e. above the breakpoint (32 mg/L), are mandatory. The aim of this study is to evaluate the blood concentrations of cefuroxime during and after CABG surgery with cardiopulmonary bypass (CPB) and hypothermia, to determine the concentration of cefuroxime in sternum fluid and to evaluate possible factors of influence. METHODS: Seventeen patients were enrolled in this study, given 1.5 g cefuroxime at anaesthesia induction and an additional 1.5 g at start CPB. Blood samples were collected at skin incision, start CPB, every 30 min on CPB, end CPB, at wound closure and 1 h after surgery. Cefuroxime concentrations were determined by high performance liquid chromatography. RESULTS: In 47 % of the patients the cefuroxime concentration was below the breakpoint at some point during the operation and in 59 % of the patients 1 h after surgery. A statistically significant inverse correlation between estimated glomerular filtration rate and plasma cefuroxime concentrations was found (P = 0.034). Cefuroxime levels in the sternum are not significantly different from blood levels from the radial artery catheter, taken at approximately the same time (P = 0.30). CONCLUSIONS: The current antibiotic regimen used did not maintain cefuroxime concentrations above the breakpoint throughout the operation, suggesting insufficient antibiotic prophylaxis. Further research to other antibiotic regimes is therefore necessary. PMID- 23794079 TI - [Use of standardized patients in the psycho-social subjects of medical studies- applicability of standardized patients in postgraduate psychotherapy training curricula?]. AB - Due to the successful use of standardized patients (SPs) in medical studies, possible fields of application for SPs in postgraduate psychotherapy training were examined on the basis of a systematic literature research (ranging from 1982 to 2011) on the use of SPs in the fields of psychotherapy, medical psychology, psychosomatic medicine, and psychiatry. The results show that SPs are used predominantly for teaching communication and counseling techniques, history taking, and assessment of psychopathology and are commonly used to portray patients with affective disorders, neurotic, stress and somatoform disorders and schizophrenia, as well as schizotypal and delusional disorders. The use of SPs is generally rated positively with regard to subjective learning effects, satisfaction, and authenticity. Hence, the results suggest that postgraduate psychotherapy training curricula might benefit from the implementation of SPs. PMID- 23794080 TI - Temporal variations of benthic diatom community and its main influencing factors in a subtropical river, China. AB - Benthic diatoms are the main component in many aquatic ecosystems such as streams, creeks and rivers, and they function as important primary producers and chemical modulators for other organisms in the ecosystems. In this study, the composition of benthic diatoms was investigated and further explored the primary physicals and chemicals affecting their temporal variations in the upper Han River, China. There were seasonal variations in physical and chemical variables in waters over the sampling period of 2007-2010. Water temperature (t), chemical oxygen demand, total nitrogen, dissolved organic carbon (DOC), silica and fluoride were much higher in the high flow season (i.e., July or August) than these in the base flow season. Three species Achnanthidium minutissimum (composed of 10.7% of the total diatom abundance), Achnanthidium pyrenaicum (11.9%), and Achnanthidium subatomus (12.7%) accounting for more than 5% of the total diatom abundance were persistently dominant in all seasons, while the other two prostrate and motile species including Eolimna minima and Nitzschia dissipata also dominant in the base flow season. The species richness always peaked in autumn with significant difference with summer (p < 0.01), and density of benthic diatom varied and peaked in April. Analyses indicated that the temporal variation in benthic diatom communities was strongly related to t, nitrogen, organic pollutants (indicated by COD and DOC), and hydrological regime. The research will expand the understanding of water chemistry monitoring, and improve watershed- scale management and conservation efforts in the upper Han River, China. PMID- 23794081 TI - Aquatic biomonitoring of Giardia cysts and Cryptosporidium oocysts in peninsular Malaysia. AB - An aquatic biomonitoring of Giardia cysts and Cryptosporidium oocysts in river water corresponding to five villages situated in three states in peninsular Malaysia was determined. There were 51.3% (20/39) and 23.1% (9/39) samples positive for Giardia and Cryptosporidium (oo)cysts, respectively. Overall mean concentration between villages for Giardia cysts ranged from 0.10 to 25.80 cysts/l whilst Cryptosporidium oocysts ranged from 0.10 to 0.90 oocysts/l. Detailed results of the river samples from five villages indicated that Kuala Pangsun 100% (9/9), Kemensah 77.8% (7/9), Pos Piah 33.3% (3/9) and Paya Lebar 33.3% (1/3) were contaminated with Giardia cysts whilst Cryptosporidium (oo)cysts were only detected in Kemensah (100 %; 9/9) and Kuala Pangsun (66.6%; 6/9). However, the water samples from Bentong were all negative for these waterborne parasites. Samples were collected from lower point, midpoint and upper point. Midpoint refers to the section of the river where the studied communities are highly populated. Meanwhile, the position of the lower point is at least 2 km southward of the midpoint and upper point is at least 2 km northward of the midpoint. The highest mean concentration for (oo)cysts was found at the lower points [3.15 +/- 6.09 (oo)cysts/l], followed by midpoints [0.66 +/- 1.10 (oo)cysts/l] and upper points [0.66 +/- 0.92 (oo)cysts/l]. The mean concentration of Giardia cysts was highest at Kuala Pangsun (i.e. 5.97 +/- 7.0 cysts/l), followed by Kemensah (0.83 +/- 0.81 cysts/l), Pos Piah (0.20 +/- 0.35 cysts/l) and Paya Lebar (0.10 +/- 0.19 cysts/l). On the other hand, the mean concentration of Cryptosporidium oocysts was higher at Kemensah (0.31 +/- 0.19 cysts/l) compared to Kuala Pangsun (0.03 +/- 0.03cysts/l). All the physical and chemical parameters did not show significant correlation with both protozoa. In future, viability status and molecular characterisation of Giardia and Cryptosporidium should be applied to identify species and genotypes/subgenotypes for better understanding of the epidemiology of these waterborne parasites. PMID- 23794082 TI - IgG4-associated vasculitis. AB - Elevated IgG4 is characteristic of cases of IgG4-RD, a newly recognized systemic disease. However, several chronic inflammatory conditions, including rheumatic diseases, can also be associated with increased levels of IgG4. There have also recently been several reports describing an increased IgG4 immune response to some vasculitis syndromes, in particular Churg-Strauss syndrome and granulomatosis with polyangiitis. To avoid misdiagnosis, clinicians must be aware that the clinical manifestations of IgG4-RD and ANCA-associated vasculitis may overlap. The meaning of these observations is not yet understood, and more studies are needed to determine the true significance of the increased IgG4 response to vasculitis syndromes, especially anti-neutrophil cytoplasmatic antibodies (ANCA)-associated vasculitis. PMID- 23794083 TI - An optimised 3 M KCl salt-bridge technique used to measure and validate theoretical liquid junction potential values in patch-clamping and electrophysiology. AB - Accurate potential measurements in electrophysiological experiments require correction for liquid junction potentials (LJPs), and, in patch-clamping especially, these can often be ~5-10 mV or more. They can be either calculated, if ion mobilities are known, or measured directly. We describe an optimised system to directly measure LJPs with a patch-clamp amplifier, using as a reference electrode, a freshly-cut 3 M KCl-agar salt-bridge (in polyethylene tubing) with its tip cut off by at least 5 mm during solution changes to eliminate its solution-history-dependent effects. We quantify such history dependent effects and complement this with a de-novo theoretical analysis of salt diffusion to and from the salt-bridge. Our analysis and experimental results validate the optimised methodology for measuring LJPs, and the use of the Henderson equation for accurately calculating them. The use of this equation is also assessed and generally validated in the light of rigorous Nernst-Planck Poisson and other numerical simulations and analytical studies of LJPs over recent decades. Digitizing, recording and amplifying the measured potentials increases their accuracy. The measured potentials still need correction for small, well-defined calculable, shifts in LJPs at the 3 M KCl-agar reference. Using this technique, we have measured changes in LJPs for diluted solutions of NaCl, LiCl, KCl, CsCl and NaF, obtaining excellent agreement within +/-0.1 mV of predicted values, calculated using ion activities. Our de novo LJP measurements of biionic combinations of the above undiluted salts, and NaI and NaF (with halide anions I- and F-), generally also gave excellent agreement with predicted values. PMID- 23794084 TI - The hepatoprotective effects of Hypericum perforatum L. on hepatic ischemia/reperfusion injury in rats. AB - Little is known about the effective role of Hypericum perforatum on hepatic ischemia-reperfusion (I/R) injury in rats. Hence, albino rats were subjected to 45 min of hepatic ischemia followed by 60 min of reperfusion period. Hypericum perforatum extract (HPE) at the dose of 50 mg/kg body weight (HPE50) was intraperitonally injected as a single dose, 15 min prior to ischemia. Rats were sacrificed at the end of reperfusion period and then, biochemical investigations were made in serum and liver tissue. Liver tissue homogenates were used for the measurement of malondialdehyde (MDA), catalase (CAT) and glutathione peroxidase (GPx) levels. At the same time alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) were assayed in serum samples and compared statistically. While the ALT, AST, LDH activities and MDA levels were significantly increased, CAT and GPx activities significantly decreased in only I/R-induced control rats compared to normal control rats (p < 0.05). Treatment with HPE50 significantly decreased the ALT, AST, LDH activities and MDA levels, and markedly increased activities of CAT and GPx in tissue homogenates compared to I/R-induced rats without treatment-control group (p < 0.05). In oxidative stress generated by hepatic ischemia-reperfusion, H. perforatum L. as an antioxidant agent contributes an alteration in the delicate balance between the scavenging capacity of antioxidant defence systems and free radicals in favour of the antioxidant defence systems in the body. PMID- 23794085 TI - Assessment of concomitant testicular dose with radiochromic film. AB - To assess the suitability of EBT2 and XRQA2 Gafchromic film for measuring low doses in the periphery of treatment fields, and to measure the accumulative concomitant dose to the contralateral testis resulting from CT imaging, pre treatment imaging (CBCT) and seminoma radiotherapy with and without gonadal shielding. Superficial peripheral dose measurements made using EBT2 Gafchromic film on the surface of water equivalent material were compared to measurements made with an ionisation chamber in a water phantom to evaluate the suitability and accuracy of the film dosimeter for such measurements. Similarly, XRQA2 was used to measure surface doses within a kilovoltage beam and compared with ionisation chamber measurements. Gafchromic film was used to measure CT, CBCT and seminoma treatment related testicular doses on an anthropomorphic phantom. Doses were assessed for two clinical plans, both with and without gonadal shielding. Testicular doses resulting from the treatment of up to 0.83 +/- 0.17 Gy were measured per treatment. Additional doses of up to 0.49 +/- 0.01 and 2.35 +/- 0.05 cGy were measured per CBCT and CT image, respectively. Reductions in the testicular dose in the order of 10, 36 and 78% were observed when gonadal shielding was fitted for treatment, CT and CBCT imaging, respectively. Gafchromic film was found to be suitable for measuring dose in the periphery of treatment fields. The dose to the testis should be limited to minimise the risk of radiation related side effects. This can be achieved by using appropriate gonadal shielding, irrespective of the treatment fields employed. PMID- 23794086 TI - Near-infrared fluorescence-guided resection of colorectal liver metastases. AB - BACKGROUND: The fundamental principle of oncologic surgery is the complete resection of malignant cells. However, small tumors are often difficult to find during surgery using conventional techniques. The objectives of this study were to determine if optical imaging, using a contrast agent already approved for other indications, could improve hepatic metastasectomy with curative intent, to optimize dose and timing, and to determine the mechanism of contrast agent accumulation. METHODS: The high tissue penetration of near-infrared (NIR) light was exploited by use of the FLARE (Fluorescence-Assisted Resection and Exploration) image-guided surgery system and the NIR fluorophore indocyanine green in a clinical trial of 40 patients undergoing hepatic resection for colorectal cancer metastases. RESULTS: A total of 71 superficially located (< 6.2 mm beneath the liver capsule) colorectal liver metastases were identified and resected using NIR fluorescence imaging. Median tumor-to-liver ratio was 7.0 (range, 1.9-18.7) and no significant differences between time points or doses were found. Indocyanine green fluorescence was seen as a rim around the tumor, which is shown to be entrapment around cytokeratin 7-positive hepatocytes compressed by the tumor. Importantly, in 5 of 40 patients (12.5%, 95% confidence interval = 5.0-26.6), additional small and superficially located lesions were detected using NIR fluorescence, and were otherwise undetectable by preoperative computed tomography, intraoperative ultrasound, visual inspection, and palpation. CONCLUSIONS: NIR fluorescence imaging, even when used with a nontargeted, clinically available NIR fluorophore, is complementary to conventional imaging and able to identify missed lesions by other modalities. PMID- 23794087 TI - Cloning, production, and functional expression of the bacteriocin sakacin A (SakA) and two SakA-derived chimeras in lactic acid bacteria (LAB) and the yeasts Pichia pastoris and Kluyveromyces lactis. AB - Mature sakacin A (SakA, encoded by sapA) and its cognate immunity protein (SakI, encoded by sapiA), and two SakA-derived chimeras mimicking the N-terminal end of mature enterocin P (EntP/SakA) and mature enterocin A (EntA/SakA) together with SakI, were fused to different signal peptides (SP) and cloned into the protein expression vectors pNZ8048 and pMG36c for evaluation of their production and functional expression by different lactic acid bacteria. The amount, antimicrobial activity, and specific antimicrobial activity of SakA and its chimeras produced by Lactococcus lactis subsp. cremoris NZ9000 depended on the SP and the expression vector. Only L. lactis NZ9000 (pNUPS), producing EntP/SakA, showed higher bacteriocin production and antimicrobial activity than the natural SakA-producer Lactobacillus sakei Lb706. The lower antimicrobial activity of the SakA-producer L. lactis NZ9000 (pNUS) and that of the EntA/SakA-producer L. lactis NZ9000 (pNUAS) could be ascribed to secretion of truncated bacteriocins. On the other hand, of the Lb. sakei Lb706 cultures transformed with the pMG36c derived vectors only Lb. sakei Lb706 (pGUS) overproducing SakA showed a higher antimicrobial activity than Lb. sakei Lb706. Finally, cloning of SakA and EntP/SakA into pPICZalphaA and pKLAC2 permitted the production of SakA and EntP/SakA by recombinant Pichia pastoris X-33 and Kluyveromyces lactis GG799 derivatives although their antimicrobial activity was lower than expected from their production. PMID- 23794088 TI - Differential expression of STAT1 and IFN-gamma in primary and invasive or metastatic wilms tumors. AB - BACKGROUND AND OBJECTIVES: IFN/STAT1 signaling has been found to be not only associated with an aggressive tumor phenotype but also activated and functional during metanephric development. This study was undertaken to evaluate STAT1 and IFN-gamma expression and its relation to histopathological features of primary and invasive/metastatic Wilms tumors. METHODS: Immunohistochemistry was used to determine the expression and cellular distribution of STAT1 and IFN-gamma in 18 pairs of primary and corresponding invasive/metastatic Wilms tumors and 40 primary tumors without invasion or metastasis. RESULTS: Positive rate of STAT1/IFN-gamma expression was 66.7%/61.1% and 72.2%/77.8% in 18 pairs of primary and associated invasive/metastatic Wilms tumor tissues, while 35.0%/27.5% in 40 primary tumors without invasion or metastasis. The expression of STAT1 and IFN gamma was significantly associated with invasion/metastasis (P = 0.025; P = 0.015). There was a positive correlation between STAT1 and IFN-gamma expression in all Wilms tumor tissues (chi(2) = 23.408, P = 0.05, r = 0.555). The expression of STAT1 and IFN-gamma between primary and matched invasive/metastatic tissues was concordance, respectively (P = 0.710 and P = 0.375). CONCLUSIONS: These results suggest that IFN-gamma/STAT1 signaling might have clinical potential as a promising predictor to identify individuals with poor prognostic potential and as a possible novel target molecule of therapy for Wilms tumor. PMID- 23794089 TI - Dual role of PPAR-gamma in induction and expression of behavioral sensitization to cannabinoid receptor agonist WIN55,212-2. AB - Behavioral sensitization (B.S.) is a pathophysiological animal model for stimulant-induced psychosis and addiction. Accumulated evidence indicates that inflammatory processes are involved in psychostimulants effects in the CNS. Cannabinoids like WIN55,212-2 act as potential activators of PPAR-gamma and affects the inflammatory status of the CNS. The purpose of this study is to determine PPAR-gamma role in induction and expression of B.S. and the coincident inflammatory responses developed by WIN55,212-2 (WIN). Using open-field test, locomotor activity was monitored in animals treated with intraperitoneal low-dose WIN single or repeated injections. Concurrent striatal COX-2 and TNF-alpha levels and PPAR-gamma activity were determined by immunoblotting assay. Effects of concomitant chronic or acute PPAR-gamma pharmacological inhibition (with GW9662) were then investigated on behavioral and biochemical variables. WIN enhanced locomotor activity and while administered chronically augmented cytosolic COX-2 and TNF-alpha and also PPAR-gamma nuclear levels. GW9662 co-administration completely prevented the induction of sensitizing effects of chronic WIN and altered the inflammatory responses. However, the expression of B.S. was intensified with GW9662 as assessed by increased locomotion after WIN challenge following 48 h withdrawal. Neuroinflammation and locomotor excitability in animals received just a single-dose WIN were also escalated with GW9662. Our findings conclude that PPAR-gamma could play different key roles during B.S. development by WIN. Although PPAR-gamma is mostly known for neuroprotective and anti-inflammatory effects, our data indicate that it mediates the B.S. induction by chronic WIN. However, while the B.S. was induced, PPAR-gamma could play a homeostatic role opposing the expressed B.S. escalation. PMID- 23794090 TI - Cardiac glutaminolysis: a maladaptive cancer metabolism pathway in the right ventricle in pulmonary hypertension. AB - The rapid growth of cancer cells is permitted by metabolic changes, notably increased aerobic glycolysis and increased glutaminolysis. Aerobic glycolysis is also evident in the hypertrophying myocytes in right ventricular hypertrophy (RVH), particularly in association with pulmonary arterial hypertension (PAH). It is unknown whether glutaminolysis occurs in the heart. We hypothesized that glutaminolysis occurs in RVH and assessed the precipitating factors, transcriptional mechanisms, and physiological consequences of this metabolic pathway. RVH was induced in two models, one with PAH (Monocrotaline-RVH) and the other without PAH (pulmonary artery banding, PAB-RVH). Despite similar RVH, ischemia as determined by reductions in RV VEGFalpha, coronary blood flow, and microvascular density was greater in Monocrotaline-RVH versus PAB-RVH. A sixfold increase in (14)C-glutamine metabolism occurred in Monocrotaline-RVH but not in PAB-RVH. In the RV working heart model, the glutamine antagonist 6-diazo-5-oxo-L norleucine (DON) decreased glutaminolysis, caused a reciprocal increase in glucose oxidation, and elevated cardiac output. Consistent with the increased glutaminolysis in RVH, RV expressions of glutamine transporters (SLC1A5 and SLC7A5) and mitochondrial malic enzyme were elevated (Monocrotaline-RVH > PAB-RVH > control). Capillary rarefaction and glutamine transporter upregulation also occurred in RVH in patients with PAH. cMyc and Max, known to mediate transcriptional upregulation of glutaminolysis, were increased in Monocrotaline RVH. In vivo, DON (0.5 mg/kg/day * 3 weeks) restored pyruvate dehydrogenase activity, reduced RVH, and increased cardiac output (89 +/- 8, vs. 55 +/- 13 ml/min, p < 0.05) and treadmill distance (194 +/- 71, vs. 36 +/-7 m, p < 0.05) in Monocrotaline-RVH. Glutaminolysis is induced in the RV in PAH by cMyc-Max, likely as a consequence of RV ischemia. Inhibition of glutaminolysis restores glucose oxidation and has a therapeutic benefit in vivo. KEY MESSAGE: Patients with pulmonary artery hypertension (PAH) have evidence of cardiac glutaminolysis. Cardiac glutaminolysis is associated with microvascular rarefaction/ischemia. As in cancer, cardiac glutaminolysis results from activation of cMyc-Max. The specific glutaminolysis inhibitor DON regresses right ventricular hypertrophy. DON improves cardiac function and exercise capacity in an animal model of PAH. PMID- 23794091 TI - Lack of induction of direct protection or cross-protection in Staphylococcus aureus by sublethal concentrations of Origanum vulgare L. essential oil and carvacrol in a meat-based medium. AB - The capacity of Origanum vulgare L. essential oil (OVEO) and its majority compound, carvacrol (CAR), to induce direct tolerance and cross-tolerance in Staphylococcus aureus against high temperature (45 degrees C), lactic acid (pH 5.2) and NaCl (10 g/100 mL) was assessed. Overnight exposure of S. aureus to sublethal concentrations (1/2 MIC, 1/4 MIC) of either OVEO or CAR in meat broth revealed no induction of direct protection. S. aureus cells pre-adapted to OVEO or CAR showed no induction of cross-protection to high temperature, lactic acid or NaCl. Cells subjected to 24 h cycles of adaptation in increasing amounts (1/2 MIC to 2 * MIC) of OVEO or CAR showed no increase in direct tolerance. These results revealed a lack of induction of direct protection or cross-protection in S. aureus exposed to sublethal amounts of OVEO or CAR in meat-based broth, as determined by monitoring cell survival and growth behavior. PMID- 23794092 TI - The impact of laparoscopic sleeve gastrectomy on plasma ghrelin levels: a systematic review. AB - Within the last decade, several authors have proposed laparoscopic sleeve gastrectomy (LSG) as a potential definitive treatment for morbid obesity. While initially perceived as being a solely restrictive procedure, it is now theorized to have additional hormonal effects (primarily the reduction of circulating levels of plasma ghrelin). However, there is limited supporting evidence for this claim. Therefore, the purpose of our study is to conduct a systematic review of the literature to clarify the effects of LSG on modulation of postoperative ghrelin concentrations. A comprehensive literature search for published or unpublished studies of sleeve gastrectomy (SG) and ghrelin written in English prior to February 2013 was performed using Pubmed, EMBASE, the Cochrane database, and Scopus. Gray literature was also searched through Google. Inclusion criteria for searches were: randomized controlled trials, non-randomized clinical trials, retrospective and prospective cohort studies, or case series. Seven studies were deemed suitable for analysis. The mean patient age was 43 +/- 8.8 years and female percentage was 74.4 +/- 15.3 %. The mean initial BMI was 46.2 +/- 7.8 and mean follow-up time was 9.5 +/- 15 months. The mean postoperative BMI was 37.3 +/ 5.8 over the same follow-up period. Pooled mean preoperative ghrelin levels were 698.4 +/- 312.4 pg/ml and postoperative levels were 414.1 +/- 226.3 pg/ml (P < 0.0001). Pooled analysis of ghrelin levels at 3, 6, and 12 months showed a significant reduction in circulating levels. Our systematic review shows that LSG has a significant effect on ghrelin levels, leading to considerable reduction in circulation levels following surgery. Further research and standardization is necessary to clearly establish a causative relationship between LSG and reduction of circulating ghrelin levels. PMID- 23794093 TI - Low hemoglobin concentration is associated with poor outcome after peripheral arterial surgery. AB - OBJECTIVE: To assess the influence of low hemoglobin (Hb) concentration on major adverse cardiac events (MACE) and mortality in patients undergoing peripheral arterial surgery. METHODS: This was a retrospective cohort study of patients undergoing peripheral arterial reconstructive surgery at a tertiary vascular center. Preoperative factors linked with the occurrence of MACE and death on univariate analysis (P <= .1) were included in a multivariate model to confirm the independent association with the outcome variables. RESULTS: A total of 360 consecutive patients (238 men) with a mean (standard deviation) age of 69 (10.7) years and Hb of 13.0 (2.12) g/dL treated under the care of a single specialist between January 2004 and December 2011 were included in the analysis. Of these, 193 (53.6%) were anemic. In all, 26 (7%) had a postoperative MACE and 18 (5%) died. On multivariate analysis, age > 80 years (odds ratio [OR] = 3; 95% confidence interval [CI] [1.2-7.5]; P = .025), renal impairment (OR = 3.2; 95% CI [.99-10.2]; P = .053), coronary disease (OR = 3.6; 95% CI [1.5-8.7]; P = .005), and low Hb (OR for each 1 g/dL drop below the mean = 1.4 [1.13-1.7]; P = .002) were independent risk factors for MACE. Unplanned surgery (OR = 4.5; 95% CI [1.2 16.9]; P = .025) and low Hb (OR for each 1 g/dL drop below the mean = 1.5; 95% CI [1.14-1.86]; P = .002) were independent risk factors for death. CONCLUSION: In peripheral arterial surgery, preoperative low Hb is associated with MACE and death. Further investigation is necessary to elucidate whether this relationship is causal. Meanwhile, consideration should be given to treating preoperative anemia as a significant risk factor for adverse outcome in this setting. PMID- 23794094 TI - A TP53 founder mutation, p.R337H, is associated with phyllodes breast tumors in Brazil. AB - A few studies have reported phyllodes tumors (PT) of the breast with germline TP53 mutations. Given this potential association and the high frequency of the TP53 p.R337H in southern and southeastern Brazil, the aim of this study was to assess whether p.R337H occurs among women diagnosed with such rare tumors in this region. Benign, borderline, and malignant breast PT were retrieved from eight pathology laboratories, and DNA was extracted from tumor tissue to perform p.R337H analysis. Overall, 128 cases classified as benign, 7 as borderline, and 13 as malignant PT were included in the study. The TP53 p.R337H mutation was identified in tumor cells of eight (5.4 %) cases. Analysis of DNA from non tumoral tissue was possible in two of these, and both were p.R337H carriers in the germline. In addition, haplotype analysis was done in these two p.R337H carriers showing the presence of the founder haplotype previously reported in Brazilian mutation-positive individuals. Mutation frequency was significantly higher among malignant (3 of 13; 23 %) compared to benign tumors (5 of 128; 3.4 %) (p = 0.004). Mean age at PT diagnosis was not significantly different between mutation carriers and non-carriers. However, when subgroups where analyzed, the difference in age at diagnosis of carriers versus non-carriers within the group of benign tumors reached borderline significance. Our findings reinforce previous evidence that TP53 mutations have an important role in the development of both benign and malignant PT of the breast. PMID- 23794095 TI - The behaviour of young children with social communication disorders during dyadic interaction with peers. AB - Children with social communication disorders are known to experience more problematic peer relations than typically-developing children. However, detailed observation of their behaviour and communication during interaction with peers has not previously been undertaken. Micro-analytic observational methods were used to analyse the audio-taped interaction of children (N = 112) selected from mainstream schools (ages 5-6 years-old) on a computerised dyadic collaborative task. Comparisons were made between children with average-to-high- and low pragmatic language skill as measured by the Test of Pragmatic Skills. Dyads were composed of an average-to-high-skilled child plus a low-skilled child (32 dyads), or of two average-to-high-skilled children (24 dyads). Consistently with their pragmatic language scores, low-skilled children were more likely to ignore other children's questions and requests than were average-to-high-skilled children. When average-to-high-skilled children worked with low-skilled children, as opposed to with other average-to-high-skilled children, they showed some sensitivity and adaptation to these children's difficulties; they used significantly more directives, clarification and provided more information. However, there was a cost in terms of the emotional tone of these interactions; when working with low-skilled children, the average-to-high-skilled children expressed considerably more negative feelings towards their partners than with another average-to-high-skilled child. In conclusion, observation of the interaction of average-to-high- and low-skilled children suggests promise for peer-assisted interventions and specifies which communicative behaviours could be targeted. However, care should be taken to manage the affective climate of these interactions for the benefit of all children involved. PMID- 23794096 TI - Transgenic expression of plant chitinases to enhance disease resistance. AB - Crop plants have evolved an array of mechanisms to counter biotic and abiotic stresses. Many pathogenesis-related proteins are expressed by plants during the attack of pathogens. Advances in recombinant DNA technology and understanding of plant-microbe interactions at the molecular level have paved the way for isolation and characterization of genes encoding such proteins, including chitinases. Chitinases are included in families 18 and 19 of glycosyl hydrolases (according to www.cazy.org ) and they are further categorized into seven major classes based on their aminoacid sequence homology, three-dimensional structures, and hydrolytic mechanisms of catalytic reactions. Although chitin is not a component of plant cell walls, plant chitinases are involved in development and non-specific stress responses. Also, chitinase genes sourced from plants have been successfully over-expressed in crop plants to combat fungal pathogens. Crops such as tomato, potato, maize, groundnut, mustard, finger millet, cotton, lychee, banana, grape, wheat and rice have been successfully engineered for fungal resistance either with chitinase alone or in combination with other PR proteins. PMID- 23794097 TI - Should patients with dementia who wander be electronically tagged? No. PMID- 23794098 TI - Emerging applications of metabolomics in studying chemopreventive phytochemicals. AB - Phytochemicals from diet and herbal medicines are under intensive investigation for their potential use as chemopreventive agents to block and suppress carcinogenesis. Chemical diversity of phytochemicals, together with complex metabolic interactions between phytochemicals and biological system, can overwhelm the capacity of traditional analytical platforms, and thus pose major challenges in studying chemopreventive phytochemicals. Recent progresses in metabolomics have transformed it to become a robust systems biology tool, suitable for examining both chemical and biochemical events that contribute to the cancer prevention activities of plant preparations or their bioactive components. This review aims to discuss the technical platform of metabolomics and its existing and potential applications in chemoprevention research, including identifying bioactive phytochemicals in plant extracts, monitoring phytochemical exposure in humans, elucidating biotransformation pathways of phytochemicals, and characterizing the effects of phytochemicals on endogenous metabolism and cancer metabolism. PMID- 23794100 TI - Palliative and oncologic co-management: symptom management for outpatients with cancer. AB - PURPOSE: Although outpatient palliative care clinics are increasingly common, evidence for their efficacy remains limited. METHODS: We conducted an observational study at the palliative care clinic of an academic cancer center to assess the association between palliative care co-management and symptoms and quality of life. Two hundred sixty-six adult outpatients were seen for a minimum of two palliative care visits within 120 days. A subset of 142 patients was seen for a third visit within 240 days. Patients completed a questionnaire containing validated symptom, quality of life, and spiritual wellbeing questions at each visit. RESULTS: The first follow-up visit was on average 41 days after the initial visit; the second follow-up visit was on average 81 days after the initial visit. Between the initial and first follow-up visits, there was significant improvement in pain (p < 0.001), fatigue (p < 0.001), depression (p < 0.001), anxiety (p < 0.001), quality of life (p = 0.002), and spiritual wellbeing (p < 0.001), but not nausea (p = 0.14). For the subset of patients seen for a second follow-up visit, the improvements in pain, fatigue, depression, anxiety, quality of life, and spiritual wellbeing persisted (p <= 0.005 for trend of each symptom). Patients had similar improvement regardless of their gender, age, ethnicity, disease stage, disease progression, and concurrent oncologic treatments. CONCLUSIONS: Palliative care was associated with significant improvement in nearly all the symptoms evaluated. A sustained change in symptoms was observed in the subset of patients seen for a second follow-up visit. Members of all subgroups improved. PMID- 23794101 TI - A policy of free access to asthma medicines in Brazil: an opportunity for pharmacists to optimize asthma treatment. AB - Asthma is a chronic inflammatory disorder of the airways that is characterized by recurrent symptoms associated with airflow limitation and by bronchial hyper responsiveness. Free asthma treatment has been guaranteed in Brazil since 2003, notably after the Brazilian government decided to support drugs for the most serious forms of the disease. The asthma treatment access policy in Brazil offers a new opportunity for pharmacists to work closely with patients, and for caregivers and health care teams to promote educational activities and patient counselling about asthma. Pharmacists have an important role in the management of drug therapy within the health care team. Pharmacists should be prepared to engage with the latest concept of health care delivery proposed for Brazilian Unified Health System. These are centred on forming health care networks and strengthening multidisciplinary teams to integrate all professionals who are in charge of patient care. PMID- 23794104 TI - [Cartilage biopsy for autologous chondrocyte implantation (ACI)]. AB - Autologous chondrocyte implantation (ACI) is an established two-step procedure for the treatment of full-thickness cartilage defects of the knee. Cartilage harvest from the affected knee joint represents the first step of this procedure and is essential for further in vitro expansion of autologous chondrocytes. Nevertheless, the cartilage biopsy process itself is underrepresented in the scientific literature and currently there is only a limited amount of data available addressing this process. Biopsy location as well as the technique itself and instruments used for cartilage collection are not well defined and only little standardisation can be found. The article describes the relevant aspects of the biopsy in the context of ACI with regard to the literature available. Follow-up studies to better define and standardise the cartilage biopsy process are thus required. PMID- 23794103 TI - The sub-cellular localisation of the potato (Solanum tuberosum L.) carotenoid biosynthetic enzymes, CrtRb2 and PSY2. AB - Carotenoids are isoprenoids with important biological roles both for plants and animals. The yellow flesh colour of potato (Solanum tuberosum L.) tubers is a quality trait dependent on the types and levels of carotenoids that accumulate. The carotenoid biosynthetic pathway is well characterised, facilitating the successful engineering of carotenoid content in numerous crops including potato. However, a clear understanding concerning the factors regulating carotenoid accumulation and localisation in plant storage organs, such as tubers, is lacking. In the present study, the localisation of key carotenoid biosynthetic enzymes was investigated, as one of the unexplored factors that could influence the accumulation of carotenoids in potato tubers. Stable transgenic potato plants were generated by over-expressing beta-CAROTENE HYDROXYLASE 2 (CrtRb2) and PHYTOENE SYNTHASE 2 (PSY2) genes, fused to red fluorescent protein (RFP). Gene expression and carotenoid levels were both significantly increased, confirming functionality of the fluorescently tagged proteins. Confocal microscopy studies revealed different sub-organellar localisations of CrtRb2-RFP and PSY2-RFP within amyloplasts. CrtRb2 was detected in small vesicular structures, inside amyloplasts, whereas PSY2 was localised in the stroma of amyloplasts. We conclude that it is important to consider the location of biosynthetic enzymes when engineering the carotenoid metabolic pathway in storage organs such as tubers. PMID- 23794105 TI - Drug library screening against metronidazole-sensitive and metronidazole resistant Trichomonas vaginalis isolates. AB - OBJECTIVES: Metronidazole and tinidazole are effective treatments for most patients with trichomoniasis but not for individuals who are infected with very resistant strains of Trichomonas vaginalis or persons with hypersensitivity to the 5-nitroimidazole drugs. Thus, there is a need for additional oral therapies to treat trichomoniasis. METHODS: We screened the US Drug Collection Library against metronidazole-susceptible and resistant strains of T vaginalis. Activity was measured by incubating parasites and drugs for 48 h in the presence of tritiated thymidine. Growth inhibition was determined by the reduction of incorporated radioactivity by compounds at 20 MUM in comparison to media control. Drugs that showed good initial activity were further tested to calculate IC50 values. Drugs with the most promise were tested together with metronidazole to see if there was any combinatorial effect. RESULTS: Of the 1040 drugs in the library, 83 (8%) reduced growth of a metronidazole-susceptible T vaginalis strain by at least 20%. Of these, IC50 values were calculated for 27 compounds and 8 drugs were evaluated in combination with metronidazole. Disulfiram and nithiamide were non-5-nitroimidazole drugs that showed the best activity against parasites when used alone. Albendazole and coenzyme B12 were the most promising compounds to boost the efficacy of metronidazole. CONCLUSIONS: No one drug was as effective as any of the 5-nitroimidazole compounds. However, disulfiram and nithiamide may be useful to treat individuals with hypersensitivity to 5-nitroimidazole drugs and albendazole and coenzyme B12 may be helpful in combination with metronidazole or tinidazole for treatment of persons with highly resistant T vaginalis infections. PMID- 23794106 TI - Clinical heterogeneity and outcomes of antisynthetase syndrome. AB - The autoimmune connective tissue disease antisynthetase syndrome (ASS) is an inflammatory myopathy associated with myositis-specific autoantibodies, e.g. anti tRNA-synthetase antibodies (ASA). Since 1976 eight different ASA have been rigorously identified, of which anti-hystidyl-tRNA synthetase (anti-Jo1) is the most prevalent. Other phenotype features of ASS include interstitial lung disease (ILD), Raynaud's phenomenon, polyarthritis, fever, and mechanic's hands. The clinical presentation of ASS varies greatly, as does the severity of involvement of different organs-both among patients and/or over the course of the disease. ILD has been associated with poor outcomes, but in general the heterogeneity of ASS prevents identification of robust prognosis indicators. Early identification of patients requiring aggressive immunosuppressive treatment is very challenging, and there are very few prospective trials available to help match treatment management to ASS clinical characteristics. This review will focus on the biological, clinical, functional, and morphological features of ASS associated with patient outcome. Our objective is to use compiled data on these subjects to discuss the usefulness of patient stratification in developing future prospective therapeutic trials. PMID- 23794107 TI - Effect of tolcapone on brain activity during a variable attentional control task: a double-blind, placebo-controlled, counter-balanced trial in healthy volunteers. AB - BACKGROUND: Attention is the capacity to flexibly orient behaviors and thoughts towards a goal by selecting and integrating relevant contextual information. The dorsal cingulate (dCC) and prefrontal (PFC) cortices play critical roles in attention. Evidence indicates that catechol-O-methyltransferase (COMT) modulates dopaminergic tone in the PFC and dCC. OBJECTIVE: In this study, we explored the effect of tolcapone, a CNS penetrant COMT inhibitor that increases cortical dopamine levels, on brain activity during a Variable Attentional Control (VAC) task. STUDY DESIGN: We performed a double-blinded, placebo-controlled, counter balanced trial with tolcapone (Tasmar, tablets, 100 mg three times a day for 1 day and then 200 mg three times a day for 6 days; ClinicalTrials.gov identifier: NCT00044083). SETTING: The study was conducted in the Clinical Center of the National Institute of Mental Health from 2005 to 2009. PATIENTS: Twenty healthy volunteers (11 males; mean age = 32.7 years) with good imaging and performance data on both arms of the study were investigated. INTERVENTION: Participants underwent 3T blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) while performing the event-related VAC task, which varies attention over three levels of load: LOW, INT (intermediate), and HIGH. MAIN OUTCOME MEASURE: Changes in behavioral data and individual contrast images were analyzed using ANOVA with drug and task load as co-factors. RESULTS: There was a significant main effect of increasing task load, with resulting decreased accuracy and increased reaction time. While there was no significant effect of tolcapone on these behavioral measures, the neuroimaging data showed a significant effect on load-related changes in dCC, with significantly lower dCC activation on tolcapone compared with placebo. Further, neural activity in dCC correlated positively with COMT enzyme activity (i.e., lower COMT activity and presumably more dopamine was associated with lower activation in dCC, i.e., more efficient information processing). CONCLUSION: Our results show that pharmacological reduction of COMT activity modulates the engagement of attentional mechanisms, selectively enhancing the efficiency of dCC processing in healthy volunteers, reflected as decreased activity for the same level of performance. PMID- 23794109 TI - Abstracts of the 9th EBSA (European Biophysical Societies' Association) European Biophysics Congress. July 13-17, 2013. Lisbon, Portugal. PMID- 23794110 TI - In reference to Determinants of bilateral audiometric notches in noise-induced hearing loss. PMID- 23794108 TI - The art of dying as an art of living: historical contemplations on the paradoxes of suicide and the possibilities of reflexive suicide prevention. AB - The main aim of this paper is to reconstruct different aspects of the history of ideas of suicide, from antiquity to late modernity, and contemplate their dialectical tension. Reflexive suicide prevention, drawing on the ancient wisdom that the art of living is inseparable from the art of dying, takes advantage, it is argued, of the contradictory nature of suicide, and hence embraces, rather than trying to overcome, death, pain, grief, fear, hopelessness and milder depressions. This approach might facilitate the transformation of inner shame to inter-personal guilt, which is the precondition for coping with losses through grieving that is shared with others. The traditional projection of suicide on the 'Other', reinforced by modernity's bio-political suppression of death, has inhibited development of good suicide prevention. Awareness of the ambiguity and ambivalence found in suicide may work as a resource when measures are taken to address as many causal mechanisms as possible, and bringing special emphasis to external factors. PMID- 23794111 TI - TRAF6 promoted the tumorigenicity of esophageal squamous cell carcinoma. AB - Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide. It is very urgent to understand the underlying molecular mechanism and develop new therapeutic strategy. Tumor necrosis factor receptor-associated factor (TRAF6), initially identified as a regulator of NF-kappaB, recently has been found to be involved in cancer by modulating various signaling pathways. However, the function of TRAF6 in ESCC is poorly understood. Here, we found that the expression of TRAF6 was upregulated in ESCC cell lines and clinical samples. Moreover, over-expression of TRAF6 in ESCC cells promoted cell proliferation, while downregulation of TRAF6 impaired the tumorigenicity of ESCC cells in vitro and in vivo. Mechanistically, TRAF6 inhibited cell apoptosis by downregulation of activated caspase 3 and cleaved poly ADP ribose polymerase and upregulation of c Jun, Bcl2, and c-Myc. Taken together, our study suggested the oncogenic role of TRAF6 in ESCC, and TRAF6 might be an important therapeutic target for ESCC. PMID- 23794112 TI - The -137G>C polymorphism in interleukin-18 promoter region and cancer risk: evidence from a meta-analysis of 21 studies. AB - Interleukin-18 (IL-18) is a key cytokine responsible for immune response and involved in the process of cancer development. The association of -137G>C polymorphism in the promoter region of IL-18 with cancer risk is still elusive based on current genetic association studies. We performed this meta-analysis to determine whether the -137G>C polymorphism is associated with cancer risk. A comprehensive search was conducted for databases of PubMed, EMBASE, and China National Knowledge Infrastructure. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the association strength. Publication bias was detected by Egger's and Begg's test. Twenty-one eligible studies including 3,498 cancer patients and 5,222 controls were identified and analyzed. In the overall analysis, no significant association between -137G>C polymorphism and cancer risk was observed. In the sub-group analyses of ethnicities, the 137G>C polymorphism significantly increased cancer risk in Asian population (GC/CC vs. GG: OR = 1.313, 95% CI = 1.053-1.638, heterogeneity P < 0.001) but not in Caucasian population. Further stratified analyses showed that the variant 137C allele was significantly associated with increased risk of nasopharyngeal carcinoma (C vs. G: OR = 1.484, 95% CI = 1.193-1.847, heterogeneity P = 0.213). No publication bias was detected. We provide evidence that the -137G>C polymorphism in IL-18 promoter region significantly increases cancer risk in Asian population but not in Caucasian population, and the variant -137C allele is associated with increased risk of nasopharyngeal carcinoma. PMID- 23794102 TI - Do we age because we have mitochondria? AB - The process of aging remains a great riddle. Production of reactive oxygen species (ROS) by mitochondria is an inevitable by-product of respiration, which has led to a hypothesis proposing the oxidative impairment of mitochondrial components (e.g., mtDNA, proteins, lipids) that initiates a vicious cycle of dysfunctional respiratory complexes producing more ROS, which again impairs function. This does not exclude other processes acting in parallel or targets for ROS action in other organelles than mitochondria. Given that aging is defined as the process leading to death, the role of mitochondria-based impairments in those organ systems responsible for human death (e.g., the cardiovascular system, cerebral dysfunction, and cancer) is described within the context of "garbage" accumulation and increasing insulin resistance, type 2 diabetes, and glycation of proteins. Mitochondrial mass, fusion, and fission are important factors in coping with impaired function. Both biogenesis of mitochondria and their degradation are important regulatory mechanisms stimulated by physical exercise and contribute to healthy aging. The hypothesis of mitochondria-related aging should be revised to account for the limitations of the degradative capacity of the lysosomal system. The processes involved in mitochondria-based impairments are very similar across a large range of organisms. Therefore, studies on model organisms from yeast, fungi, nematodes, flies to vertebrates, and from cells to organisms also add considerably to the understanding of human aging. PMID- 23794113 TI - Postural control in restless legs syndrome with medication intervention using pramipexole. AB - Central dopamine regulation is involved in postural control and in the pathophysiology of restless legs syndrome (RLS) and Parkinson's disease (PD). Postural control abnormalities have been detected in PD, but there are no earlier studies with regard to RLS and postural control. Computerized force platform posturography was applied to measure the shift and the velocity (CPFV) of center point of forces (CPF) with eyes open (EO) and eyes closed (EC) in controls (n = 12) and prior and after a single day intervention with pramipexole in RLS subjects (n = 12). CPFV (EO) was significantly lower in the RLS group (p < 0.05) than in controls. After pramipexole intake, the difference disappeared and the subjective symptom severity diminished. Pramipexole did not significantly influence CPFV (EC) or CPF shift direction. Subjects with RLS used extensively visual mechanisms to control vestibule-spinal reflexes to improve or compensate the postural stability. Further research is needed to clarify altered feedback in the central nervous system and involvement of dopamine and vision in the postural control in RLS. PMID- 23794115 TI - Depression-like behavior in subclinical hypothyroidism rat induced by hemi thyroid electrocauterization. AB - The purpose of this study was to investigate the depression-like behavior performances of subclinical hypothyroidism (SCH) rat. SCH rat model was induced by hemi-thyroid electrocauterization, and the behavior performances were measured by sucrose preference test, force swimming test (FST), and tail suspension test (TST). SCH rat model was established successfully by hemi-thyroid electrocauterization. In the behavior tasks, SCH rats displayed depression-like behavior were indicated as a significant elevation of immobility time in both the TST and FST, though the sucrose preference was not significantly decreased. The index of left adrenal cortex in both SCH and clinical hypothyroidism (CH) group significantly increased, and many large lipid vacuoles were observed in the zona fasciculata cells. The serum corticosterone concentration and hypothalamic corticotropin-releasing hormone mRNA expression 2 h after behavior test was markedly up-regulated in CH rats, but not SCH rats, indicated that SCH induced a less impairment of HPA axis than CH did. The important finding of this study was that the concentration of hippocampal T3 was lower in SCH group than that of the sham group. Furthermore, the results of Pearson correlation test showed that the immobility behaviors in TST and FST were both negatively correlated with hippocampal T3 concentration. Taking together, our results indicated that SCH could result in depression-like behavior, accompanied with subtle hyperactivity of HPA axis. The reduced hippocampal T3 prior to the reduction of thyroid hormone in serum might be taken as an early sign of hippocampus impairment in the progression from SCH to CH. PMID- 23794117 TI - Bioprocess development for nicotinic acid hydroxamate synthesis by acyltransferase activity of Bacillus smithii strain IITR6b2. AB - In this work, acyltransferase activity of a new bacterial isolate Bacillus smithii strain IITR6b2 was utilized for the synthesis of nicotinic acid hydroxamate (NAH), a heterocyclic class of hydroxamic acid. NAH is an important pyridine derivative and has found its role as bioligand, urease inhibitor, antityrosinase, antioxidant, antimetastatic, and vasodilating agents. Amidase having acyltransferase activity with nicotinamide is suitable for nicotinic acid hydroxamate production. However, amidase can also simultaneously hydrolyze nicotinamide and nicotinic acid hydroxamate to nicotinic acid. Nicotinic acid is an undesirable by-product and thus any biocatalytic process involving amidase for nicotinic acid hydroxamate production needs to have high ratios of acyltransferase to amide hydrolase and acyltransferase to nicotinic acid hydroxamate hydrolase activity. Isolate Bacillus smithii strain IITR6b2 was found to have 28- and 12.3-fold higher acyltransferase to amide and hydroxamic acid hydrolase activities, respectively. This higher ratio resulted in a limited undesirable by-product, nicotinic acid (NA) synthesis. The optimal substrate/co substrate ratio, pH, temperature, incubation time, and resting cells concentration were 200/250 mM, 7, 30 degrees C, 40 min, and 0.7 mg(DCW) ml(-1), respectively, and 94.5 % molar conversion of nicotinamide to nicotinic acid hydroxamate was achieved under these reaction conditions. To avoid substrate inhibition effect, a fed-batch process based on the optimized parameters with two feedings of substrates (200/200 mM) at 40-min intervals was developed and a molar conversion yield of 89.4 % with the productivity of 52.9 g h(-1) g (DCW) (-1) was achieved at laboratory scale. Finally, 6.4 g of powder containing 58.5 % (w/w) nicotinic acid hydroxamate was recovered after lyophilization and further purification resulted in 95 % pure product. PMID- 23794116 TI - Growth hormone values after an oral glucose load do not add clinically useful information in patients with acromegaly on long-term somatostatin receptor ligand treatment. AB - The optimal method of assessing GH status in acromegalic patients receiving medical therapy with somatostatin analogs (SSA) has been matter of debate. The aim of the study has been to investigate whether OGTT may add information in patients with discordant random GH (GHr) and IGF values. Moreover, we evaluated the association of GH nadir with the prevalence of co-morbidities observed in acromegalic patients on SSA therapy. We evaluated 130 patients with proven diagnosis of acromegaly on SSA. The patients were subdivided in three groups: patients with controlled disease (both safe random GH and normal IGF-I, group A, 20.0 %), patients with uncontrolled disease (both high random GH and IGF-I, group B, 34.6 %), and patients with discordant random GH and IGF-I values (group C, 35.4 %). A high concordance rate for GH nadir with random GH and IGF-I was observed in group B, while a significant reduced concordance rate has been observed in group A (100 % sensitivity, 64.5 % specificity). By contrast, in group C, we observed concordant results between GH nadir and IGF-I only in 14/59 patients. In group A, the prevalence of diabetes was lower than in group B or C. Safe random GH was the only single criteria associated with a lower prevalence of diabetes. Discrepant IGF-I and either GH nadir or random GH values are frequently observed in acromegalic patients treated with SSA. Concordant IGF-I and random GH may influence the prevalence of metabolic complications. GH nadir measurement may help to interpret discrepancies between random GH and IGF-I data only in few cases. PMID- 23794114 TI - Genetic variants associated with insulin signaling and glucose homeostasis in the pathogenesis of insulin resistance in polycystic ovary syndrome: a systematic review. AB - BACKGROUND: Polycystic ovary syndrome must be recognized as a serious issue due to its implication on long term health regardless of an individual's age. PCOS and insulin resistance are interlinked, as approximately 40 % of women with PCOS are insulin resistant. However, the detailed molecular basis for insulin resistance that is coupled with PCOS remains poorly understood. OBJECTIVE: To review the published evidence that polymorphisms in genes that are involved in insulin secretion and action are associated with an increased risk of PCOS. METHODS: We reviewed articles published through November 2012 which concerned polymorphisms of genes related to insulin signaling and glucose homeostasis as well as their associations with PCOS. The articles were identified via Medline searches. CONCLUSIONS: No consistent evidence emerged of a strong association between the risk of PCOS and any known gene that is related to insulin signaling and glucose homeostasis. Moreover, recent genome-wide association studies are inconsistent in identifying the associations between PCOS and insulin metabolism genes. Many of the studies reviewed were limited by heterogeneity in the PCOS diagnosis and by not have having a sufficient number of study participants. Further studies are warranted to determine predisposing risk factors which could modify environmental factors and thus reduce the risk of PCOS. Large genome-wide association studies devoted solely to PCOS will be necessary to identify new candidate genes and proteins that are involved in PCOS risk. PMID- 23794119 TI - Upregulation of extrinsic apoptotic pathway in curcumin-mediated antiproliferative effect on human pancreatic carcinogenesis. AB - Pancreatic cancer is one of the most lethal human cancers, with almost identical incidence and mortality rates. Curcumin, derived from the rhizome of Curcuma longa, has a long history of use as coloring agent and for a wide variety of disorders. Here, the antiproliferative activity of curcumin and its modulatory effect on gene expression of pancreatic cancer cell lines were investigated. The effect of curcumin on cellular proliferation and viability was monitored by sulphurhodamine B assay. Apoptotic effect was evaluated by flow cytometry and further confirmed by measuring amount of cytoplasmic histone-associated DNA fragments. Analysis of gene expression was performed with and without curcumin treatment using microarray expression profiling techniques. Array results were confirmed by real-time PCR. ingenuity pathway analysis (IPA) has been used to classify the list of differentially expressed genes and to indentify common biomarkergenes modulating the chemopreventive effect of curcumin. Results showed that curcumin induces growth arrest and apoptosis in pancreatic cancer cell lines. Its effect was more obvious on the highly COX-2 expressing cell line. Additionally, the expression of 366 and 356 cancer-related genes, involved in regulation of apoptosis, cell cycle, metastasis, was significantly altered after curcumin treatment in BxPC-3 and MiaPaCa-2 cells, respectively. Our results suggested that up-regulation of the extrinsic apoptotic pathway was among signaling pathways modulating the growth inhibitory effects of curcumin on pancreatic cancer cells. Curcumin effect was mediated through activation of TNFR, CASP 8, CASP3, BID, BAX, and down-regulation of NFkappaB, NDRG 1, and BCL2L10 genes. PMID- 23794118 TI - Weight loss expectations of laparoscopic sleeve gastrectomy candidates compared to clinically expected weight loss outcomes 1-year post-surgery. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) results in significant, sustainable weight loss in obese individuals (body mass index (BMI) >= 40 kg/m(2) or BMI 35.0-39.9 kg/m(2) with major comorbidity). Average clinically expected % excess weight loss (%EWL) has been reported to be 56.1 % 1 year after LSG. Unrealistic weight loss expectations are purported to negatively impact treatment adherence and weight loss outcomes. This study examined the weight loss expectations of LSG candidates in Newfoundland and Labrador, Canada. METHODS: The Goals and Relative Weights Questionnaire was administered before the start of a bariatric surgery education session to 84 consecutive LSG candidates. Patients reported postoperative weight loss expectations in four categories: "dream", "happy", "acceptable", and "disappointed". RESULTS: Participants included 69 women and 15 men with an average age and weight of 43.7 years and 136.7 kg. The patients reported average postoperative "dream" and "happy" weights as 71.1 and 80.0 kg, respectively. Patients reported a weight of 86.2 kg as "acceptable" but would be "disappointed" with a weight of 105.6 kg. To achieve the desired amount of weight loss for each category, patients would have to achieve %EWLs of 88.7, 76.4, 68.2, and 40.6 %, respectively. CONCLUSIONS: Patients have higher weight loss expectations than those that are clinically expected within 1 year after LSG. PMID- 23794120 TI - Microstructural organization of axons in the human corpus callosum quantified by diffusion-weighted magnetic resonance spectroscopy of N-acetylaspartate and post mortem histology. AB - Diffusion-weighted magnetic resonance spectroscopy of brain metabolites offers unique access to compartment-specific microstructural information on neural tissue. Here, we investigated in detail the diffusion characteristics of the neuronal/axonal markers N-acetylaspartate + N-acetyl aspartyl glutamate (tNAA) in a small region of the human corpus callosum at 7 T. The diffusion-weighted spectroscopy data were analyzed by fitting to a model in which information about cross-callosal tract orientation within the spectroscopy volume, obtained from diffusion tensor imaging data, was incorporated. We estimated the microscopic misalignment of axons (sigma phi = 18.6 degrees +/- 3.0 degrees ) in excellent agreement with independent histological results (sigma phi = 18.1 degrees +/- 4.6 degrees ) obtained from microscopic analysis of axonal orientations in the body of the corpus callosum from post-mortem human brain slices. We also robustly quantified the diffusion coefficient of tNAA (0.51 +/- 0.06 * 10(-3) mm(2)/s) in axonal cytoplasm, unbiased by the tract curvature. This work supports the notion that microscopic axonal misalignment is a dominant microstructural property in white matter tracts and has a strong impact on the evaluation of tissue microstructure using diffusion information, and should therefore be taken into consideration in the evaluation of white matter microstructure. Additionally, this study enabled robust and unbiased assessment of the cytosolic diffusion coefficient of tNAA, a potential biomarker for axonopathy and neuronal degeneration. PMID- 23794121 TI - European non-invasive trisomy evaluation (EU-NITE) study: a multicenter prospective cohort study for non-invasive fetal trisomy 21 testing. AB - OBJECTIVE: To evaluate the performance of a directed non-invasive prenatal testing method of cell-free DNA analysis for fetal trisomy 21 (T21) by shipping the whole blood samples from Europe to a laboratory in the USA. METHODS: A European multicenter prospective, consecutive cohort study was performed enrolling pregnant women from Sweden and the Netherlands. Blood samples were drawn just prior to a planned of invasive diagnostic procedure in a population at increased risk for fetal T21 and then shipped to the USA without any blood processing. Chromosome-selective sequencing was carried out on chromosome 21 with reporting high risk or low risk of T21. Karyotyping or rapid aneuploidy detection was used as the clinical reference standard. RESULTS: Of the 520 eligible study subjects, a T21 test result was obtained in 504/520 (96.9%). Risk assessment was accurate in 503/504 subjects (99.8%). There was one false negative result for T21 (sensitivity 17/18, 94.4%, and specificity 100%). CONCLUSION: This is the first prospective European multicenter study showing that non-invasive prenatal testing using directed sequencing of cell-free DNA applied to blood samples shipped across the Atlantic Ocean, is highly accurate for assessing risk of fetal T21. PMID- 23794122 TI - Osteomalacia induced by vitamin D deficiency in hemodialysis patients: the crucial role of vitamin D correction. AB - Vitamin D deficiency/insufficiency is significantly prevalent in chronic kidney disease. Data in the literature are however scarce about the effects of this deficiency on bone metabolism in hemodialysis (HD) patients. Moreover, it is still debated whether low vitamin D levels should be normalized in HD patients. In this paper, we report two cases showing the deleterious consequences of vitamin D deficiency in HD patients which is characterised by hypophosphatemia, hypocalcemia and osteomalacia (OM) leading to bone fractures. As vitamin D repletion is an easy way to treat OM, this report underlines the importance of monitoring and correction of vitamin D deficiency in this population. PMID- 23794123 TI - Hypophysitis due to IgG4-related disease responding to treatment with azathioprine: an alternative to corticosteroid therapy. AB - PURPOSE: Fifteen cases of lymphocytic hypophysitis due to IgG4-related disease have been reported demonstrating marked improvement with corticosteroid therapy. This is the first case of IgG4-related hypophysitis demonstrating improvement with azathioprine, where corticosteroids were initially tried but ceased due to concern regarding enlargement of the pituitary infiltrate. METHODS: Case description and review of 15 cases reported in the literature. A 40 year old male was diagnosed with IgG-4 related disease based on pituitary and lacrimal gland biopsies associated with raised serum concentration of IgG4. The patient was commenced on prednisolone 30 mg/day, as rapid response to prednisolone treatment has been described in the literature for other cases of IgG4-related hypophysitis. Over the next 3 months, prednisolone treatment resulted in a reduction of serum IgG4 levels, but repeat MRI scan showed an enlarging pituitary mass with new optic nerve compression. Azathioprine 75 mg twice daily was commenced and in the subsequent 3 months, IgG4 levels normalised (0.58 g/L) and MRI scan showed 50% shrinkage of the pituitary mass. After 10 months of azathioprine treatment the MRI showed a normal sized pituitary but persistence of the infraorbital nerve thickening. CONCLUSIONS: Hypophysitis due to IgG4-related disease usually demonstrates prompt response to corticosteroids. This case highlights the need to image promptly after starting treatment to exclude an enlarging pituitary mass despite corticosteroid treatment. Alternative therapy with azathioprine can result in marked improvement. It should be remembered that IgG-4 related hypophysitis is part of a multi-organ disease. PMID- 23794124 TI - Measuring the capacity of staff culture to further recovery from psychiatric disabilities. AB - Three linked instruments for measuring the recovery-orientation of mental health program culture are introduced as the Recovery Centered Measures (RCM). Two scales assess the views of staff and of consumers, respectively, regarding staff consumer interactions. A third scale measures staff culture. The RCM scales are quick, easy to understand (reading level of grade 5.4), and internally consistent. Test-retest correlations ranged from 0.81 to 0.67. Convergent validity with three related instruments was appropriate. The scales discriminate ACT from residential programs. The RCM scales show strong potential to be useful to program administrators and researchers working to increase the recovery orientation of programs. PMID- 23794125 TI - Urethral lift for benign prostatic hyperplasia: a comprehensive review of the literature. AB - Current treatments for benign prostatic hyperplasia (BPH) include watchful waiting, medical therapy, and interventional procedures. The post-surgical complication profile and the early discontinuation of medical therapy are significant drawbacks of the established approach and stimulate the search for less-invasive approaches. Our aim is to provide a comprehensive review all available literature on prostatic urethral lift (PUL), presenting an overview of safety, indications, surgical technique and results of the procedure, and to evaluate the potential role it could play in the treatment of BPH. A comprehensive search was conduct on PubMed and Scopus database to identify original articles in English dealing with PUL without any limit to publication date. Keywords used were prostatic urethral lift, urethral lifting, Urolift, benign prostatic hyperplasia and minimally invasive therapy. The PUL seems to offer a better IPSS improvement when compared to medical therapy, but the result is inferior when compared to surgical therapy. Published studies report an absence of degradation of erectile or ejaculatory function after treatment, which appears a noteworthy benefit of PUL. Additional advantages of the PUL are a better complication profile in comparison to other surgical therapies and the use of a local anesthesia, sometimes without postoperative catheterization. The PUL, a novel, minimally invasive treatment option for men affected by BPH, presents a promising potential although it is clear that PUL is not a substitute for traditional ablative surgical approach, as this procedure requires a scrupulous selection of the patient. PMID- 23794127 TI - Mitigate B1+ inhomogeneity using spatially selective radiofrequency excitation with generalized spatial encoding magnetic fields. AB - PURPOSE: High-field magnetic resonance imaging (MRI) has the challenge of inhomogeneous B(1)(+), and consequently inhomogeneous flip angle distribution, which causes spatially dependent contrast and makes clinical diagnosis difficult. METHOD: We propose a two-step pulse design procedure in which (1) a combination of linear and nonlinear spatial encoding magnetic fields (SEMs) is used to remap the B(1)(+) map in order to reduce the dimensionality of the problem, (2) the locations, amplitudes, and phases of spoke pulses are estimated in one dimension. The advantage of this B(1)(+) remapping is that when the isointensity contours of a linear combination of SEMs are similar to the isointensity contours of B(1)(+), a simple pulse sequence design using time-varying SEMs can achieve a homogenous flip-angle distribution efficiently. RESULTS: We demonstrate that spatially selective radiofrequency (RF) excitation with generalized SEMs (SAGS) using both linear and quadratic SEMs in a multi-spoke k-space trajectory can mitigate the B(1)(+) inhomogeneity at 7T efficiently. Numerical simulations based on experimental data suggest that, compared with other methods, SAGS provide a formulation allowing multiple-pulse design, a similar average flip-angle distribution with less RF power, and/or a more homogeneous flip-angle distribution. CONCLUSION: Without using multiple RF coils for parallel transmission, SAGS can be used to mitigate the B(1)(+) inhomogeneity in high field MRI experiments. PMID- 23794126 TI - Two global conformation states of a novel NAD(P) reductase like protein of the thermogenic appendix of the Sauromatum guttatum inflorescence. AB - A novel NAD(P) reductase like protein (RL) belonging to a class of reductases involved in phenylpropanoid synthesis was previously purified to homogeneity from the Sauromatum guttatum appendix. The Sauromatum appendix raises its temperature above ambient temperature to ~30 degrees C on the day of inflorescence opening (D-day). Changes in the charge state distribution of the protein in electrospray ionization-mass spectrometry spectra were observed during the development of the appendix. RL adopted two conformations, state A (an extended state) that appeared before heat-production (D - 4 to D - 2), and state B (a compact state) that began appearing on D - 1 and reached a maximum on D-day. RL in healthy leaves of Arabidopsis is present in state A, whereas in thermogenic sporophylls of male cones of Encephalartos ferox is present in state B. These conformational changes strongly suggest an involvement of RL in heat-production. The biophysical properties of this protein are remarkable. It is self-assembled in aqueous solutions into micrometer sizes of organized morphologies. The assembly produces a broad range of cyclic and linear morphologies that resemble micelles, rods, lamellar micelles, as well as vesicles. The assemblies could also form network structures. RL molecules entangle with each other and formed branched, interconnected networks. These unusual assemblies suggest that RL is an oligomer, and its oligomerization can provide additional information needed for thermoregulation. We hypothesize that state A controls the plant basal temperature and state B allows a shift in the temperature set point to above ambient temperature. PMID- 23794128 TI - Homogeneous catalytic hydrogenation of amides to amines. AB - Hydrogenation of amides in the presence of [Ru(acac)3] (acacH=2,4-pentanedione), triphos [1,1,1-tris- (diphenylphosphinomethyl)ethane] and methanesulfonic acid (MSA) produces secondary and tertiary amines with selectivities as high as 93% provided that there is at least one aromatic ring on N. The system is also active for the synthesis of primary amines. In an attempt to probe the role of MSA and the mechanism of the reaction, a range of methanesulfonato complexes has been prepared from [Ru(acac)3], triphos and MSA, or from reactions of [RuX(OAc)(triphos)] (X=H or OAc) or [RuH2(CO)(triphos)] with MSA. Crystallographically characterised complexes include: [Ru(OAc kappa(1)O)2(H2O)(triphos)], [Ru(OAc-kappa(2)O,O')(CH3SO3-kappa(1)O)(triphos)], [Ru(CH3SO3-kappa(1)O)2(H2O)(triphos)] and [Ru2(MU-CH3SO3)3(triphos)2][CH3SO3], whereas other complexes, such as [Ru(OAc-kappa(1)O)(OAc-kappa(2)O,O')(triphos)], [Ru(CH3SO3-kappa(1)O)(CH3SO3-kappa(2)O,O')(triphos)], H[Ru(CH3SO3 kappa(1)O)3(triphos)], [RuH(CH3SO3-kappa(1)O)(CO)(triphos)] and [RuH(CH3SO3 kappa(2)O,O')(triphos)] have been characterised spectroscopically. The interactions between these various complexes and their relevance to the catalytic reactions are discussed. PMID- 23794130 TI - Three-dimensional contrast-enhanced magnetic resonance venography for detection of renal vein thrombosis: comparison with multidetector CT venography. AB - BACKGROUND: Renal vein thrombosis is not uncommon, however, there have been few reports on the diagnostic accuracy of three-dimensional contrast-enhanced magnetic resonance venography (3D-CE-MRV) in the detection of renal vein thrombosis (RVT). PURPOSE: To evaluate the value of 3D-CE-MRV for detecting RVT with multidetector computed tomography (CT) venography as reference standard. MATERIAL AND METHODS: Thirty-two patients with nephrotic syndrome underwent renal CT venography and gradient echo pulse sequence (FLASH 3D) 3D-CE-MRV in a clinical 3-T whole-body MR scanner for suspected RVT with time interval of 0-5 days. RVT was recorded on a per-patient and per-vessel (left renal vein, right renal vein, and inferior vena cava) basis. The diagnostic accuracy of 3D-CE-MRV for detection of RVT was calculated with CT venography as reference standard. Inter-reader agreement for RVT detection was evaluated using Kappa statistics. RESULTS: Of 32 patients, CT venography detected 22 vessels with thrombosis in 17 patients, including five in right renal veins, 14 in left renal veins, and three in inferior vena cava, while 15 patients had no RVT. 3D-CE-MRV detected 21 vessels (21/96, 21.9%) with thrombosis in 16 patients (6/32, 50%), including five in right renal veins, 13 in left renal veins, and three in inferior vena cava, while 16 patients (16/32, 50%) had no RVT. With CT venography as reference standard, the sensitivities and specificities of 3D-CE-MRV for RVT detection were 94.1%, 100%; 95.5%, 100% on a per-patient and a per-vessel basis, respectively. Excellent inter-reader agreement (Kappa value = 0.969, P < 0.001) was observed for RVT detection. CONCLUSION: 3D-CE-MRV has a high diagnostic accuracy in the detection of RVT, which is optimal alternative imaging modality in the detection of RVT. PMID- 23794129 TI - Vaccine development for tuberculosis: current progress. AB - Very substantial efforts have been made over the past decade or more to develop vaccines against tuberculosis. Historically, this began with a view to replace the current vaccine, Bacillus Calmette Guerin (BCG), but more recently most candidates are either new forms of this bacillus, or are designed to boost immunity in children given BCG as infants. Good progress is being made, but very few have, as yet, progressed into clinical trials. The leading candidate has advanced to phase IIb efficacy testing, with disappointing results. This article discusses the various types of vaccines, including those designed to be used in a prophylactic setting, either alone or BCG-boosting, true therapeutic (post exposure) vaccines, and therapeutic vaccines designed to augment chemotherapy. While there is no doubt that progress is still being made, we have a growing awareness of the limitations of our animal model screening processes, further amplified by the fact that we still do not have a clear picture of the immunological responses involved, and the precise type of long-lived immunity that effective new vaccines will need to induce. PMID- 23794131 TI - FID modulus: a simple and efficient technique to phase and align MR spectra. AB - OBJECT: The post-processing of MR spectroscopic data requires several steps more or less easy to automate, including the phase correction and the chemical shift assignment. First, since the absolute phase is unknown, one of the difficulties the MR spectroscopist has to face is the determination of the correct phase correction. When only a few spectra have to be processed, this is usually performed manually. However, this correction needs to be automated as soon as a large number of spectra is involved, like in the case of phase coherent averaging or when the signals collected with phased array coils have to be combined. A second post-processing requirement is the frequency axis assignment. In standard mono-voxel MR spectroscopy, this can also be easily performed manually, by simply assigning a frequency value to a well-known resonance (e.g. the water or NAA resonance in the case of brain spectroscopy). However, when the correction of a frequency shift is required before averaging a large amount of spectra (due to B 0 spatial inhomogeneities in chemical shift imaging, or resulting from motion for example), this post-processing definitely needs to be performed automatically. MATERIALS AND METHODS: Zero-order phase and frequency shift of a MR spectrum are linked respectively to zero-order and first-order phase variations in the corresponding free induction decay (FID) signal. One of the simplest ways to remove the phase component of a signal is to calculate the modulus of this signal: this approach is the basis of the correction technique presented here. RESULTS: We show that selecting the modulus of the FID allows, under certain conditions that are detailed, to automatically phase correct and frequency align the spectra. This correction technique can be for example applied to the summation of signals acquired from combined phased array coils, to phase coherent averaging and to B 0 shift correction. CONCLUSION: We demonstrate that working on the modulus of the FID signal is a simple and efficient way to both phase correct and frequency align MR spectra automatically. This approach is particularly well suited to brain proton MR spectroscopy. PMID- 23794132 TI - The present/null polymorphism in the GSTT1 gene and the risk of lung cancer in Chinese population. AB - The present/null polymorphism in the GSTT1 gene has been implicated in susceptibility to lung cancer in Chinese population. A large number of studies have reported inconclusive results. The aim of the current study was to investigate the relationship between the present/null polymorphism in the GSTT1 gene and lung cancer risk in Chinese population by meta-analysis. The Pubmed, Embase, CNKI, and Wanfang databases were searched. The statistical analysis was performed by using Revman4.2 and Stata10.0. In summary, a total of 2,211 lung cancer cases and 3,115 controls in 18 case-control studies were included for data analysis. The results suggested that the null genotype carriers may contribute to increased risk of lung cancer in Chinese population when compared with the present genotype carriers (odds ratio = 1.24, 95% confidence interval = 1.02 1.49). The current meta-analysis suggested that the present/null polymorphism in the GSTT1 gene might contribute to the risk of lung cancer in Chinese population. Future studies are needed to validate these results. PMID- 23794133 TI - CYP1B1 C4326G polymorphism and susceptibility to cervical cancer in Chinese Han women. AB - Cytochrome P450 1B1 (CYP1B1) is a key P450 enzyme, which could catalyze the formation of 4-hydroxy estrogen metabolites and play a role in estrogen-dependent cancers. We hypothesized that genetic variant in CYP1B1 may modify individual susceptibility to cervical cancer. The aim of this study was to evaluate the association between CYP1B1 C4326G polymorphism and cervical cancer risk in Chinese women. We extracted the peripheral blood samples in 250 patients with cervical cancer and 250 female controls. The matrix-assisted laser desorption ionization time-of-flight mass spectrometry method and direct DNA sequencing were performed to detect the polymorphism. The frequencies of CC, CG, and GG genotypes of CYP1B1 C4326G in cases and controls were 66.0, 26.8, 7.2% and 75.2, 21.6, and 3.2%, respectively, and there was a significant difference between the two groups (P = 0.034). Compared with the wild-type CC genotype, the variant GG genotype was associated with a significantly increased risk of cervical cancer (adjusted OR = 2.30; 95% CI = 1.02, 5.50). Moreover, stratification analysis by age, smoking, drinking, human papillomaviruses (HPV) 16 or 18 carrier status, and family history of cervical cancer, we found that the variant genotypes containing the G allele were associated with a significantly increased risk of cervical cancer among HPV 16 or 18-positive individuals (adjusted OR = 2.85; 95% CI = 1.45, 5.62) and among women younger than 45 years old (adjusted OR = 1.87; 95% CI = 1.03, 3.37). These results suggest that CYP1B1 C4326G polymorphism may increase risk of cervical cancer in Chinese women, especially among young individuals with high risk HPV infection. PMID- 23794135 TI - In response to Determinants of bilateral audiometric notches in noise-induced hearing loss. PMID- 23794134 TI - Angiosarcoma of the thyroid: a case report with review of the literature. AB - Angiosarcoma is a rare and aggressive tumor of the thyroid gland, mainly seen in the Alpine regions. We present such a case with literature review. We present the case of a 60-year-old man with cough, dyspnea, and hemoptysis along with slow increase in the size of his long-standing goiter. Computed tomography of the neck showed a large thyroid mass and chest imaging revealed multiple pulmonary nodules. Fine needle aspiration cytology and tru-cut biopsy of the thyroid were notable for poorly differentiated malignant cells. Diagnosis of angiosarcoma of the thyroid was made after total thyroidectomy. Patient died of continued hemoptysis and respiratory failure 3 weeks after admission. We searched the literature for previous case reports using Pubmed and Ovid. Forty-seven reported cases were identified and our case was added to make a database of 48 cases. Demographic and tumor characteristics were analyzed. Angiosarcoma was found to be more common in females and at age of 60 or above. Results were consistent with previously reported series of 14 and 17 cases from Austria. This review provides information on various characteristics angiosarcoma of the thyroid which can be used as baseline data for future reference and research studies for this cancer. PMID- 23794136 TI - Socioeconomic status and the cerebellar grey matter volume. Data from a well characterised population sample. AB - The cerebellum is highly sensitive to adverse environmental factors throughout the life span. Socioeconomic deprivation has been associated with greater inflammatory and cardiometabolic risk, and poor neurocognitive function. Given the increasing awareness of the association between early-life adversities on cerebellar structure, we aimed to explore the relationship between early life (ESES) and current socioeconomic status (CSES) and cerebellar volume. T1-weighted MRI was used to create models of cerebellar grey matter volumes in 42 adult neurologically healthy males selected from the Psychological, Social and Biological Determinants of Ill Health study. The relationship between potential risk factors, including ESES, CSES and cerebellar grey matter volumes were examined using multiple regression techniques. We also examined if greater multisystem physiological risk index-derived from inflammatory and cardiometabolic risk markers-mediated the relationship between socioeconomic status (SES) and cerebellar grey matter volume. Both ESES and CSES explained the greatest variance in cerebellar grey matter volume, with age and alcohol use as a covariate in the model. Low CSES explained additional significant variance to low ESES on grey matter decrease. The multisystem physiological risk index mediated the relationship between both early life and current SES and grey matter volume in cerebellum. In a randomly selected sample of neurologically healthy males, poorer socioeconomic status was associated with a smaller cerebellar volume. Early and current socioeconomic status and the multisystem physiological risk index also apparently influence cerebellar volume. These findings provide data on the relationship between socioeconomic deprivation and a brain region highly sensitive to environmental factors. PMID- 23794137 TI - In vitro TNF-alpha- and noradrenaline-stimulated lipolysis is impaired in adipocytes from growing rats fed a low-protein, high-carbohydrate diet. AB - The aim of this study was to investigate tumor necrosis factor alpha (TNF-alpha)- and noradrenaline (NE)-stimulated lipolysis in retroperitoneal (RWAT) and epididymal (EAT) white adipose tissue as a means of understanding how low protein, high-carbohydrate (LPHC) diet-fed rats maintain their lipid storage in a catabolic environment (marked by increases in serum TNF-alpha and corticosterone and sympathetic flux to RWAT and EAT), as previously observed. Adipocytes or tissues from the RWAT and EAT of rats fed an LPHC diet and rats fed a control (C) diet for 15 days were used in the experiments. The adipocytes from both tissues of the LPHC rats exhibited lower TNF-alpha- stimulated lipolysis compared to adipocytes from the C rats. The intracellular lipolytic agents IBMX, DBcAMPc and FSK increased lipolysis in both tissues from rats fed the C and LPHC diets compared to basal lipolysis; however, the effect was approximately 2.5-fold lower in adipocytes from LPHC rats. The LPHC diet induced a marked reduction in the beta3 and alpha2-AR, adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) content in RWAT and EAT. The LPHC diet did not affect TNF-alpha receptor 1 content but did induce a reduction in ERK p44/42 in both tissues. The present work indicates that RWAT and EAT from LPHC rats have an impairment in the lipolysis signaling pathway activated by NE and TNF-alpha, and this impairment explains the reduced response to these lipolytic stimuli, which may be fundamental to the maintenance of lipid storage in LPHC rats. PMID- 23794139 TI - Fatty acid profile of cardiac muscle phospholipid and triacylglycerol in MDX mice and C57BL/10ScSnJ controls. AB - The mdx mouse is a model for Duchenne muscular dystrophy (DMD), a debilitating disease affecting striated muscle. It is established that the fatty acid (FA) composition of skeletal muscle phospholipid (PL) is altered in mdx mice, but it is not known if cardiac muscle is similarly affected by dystrophin-deficiency. We tested FA profiles in PL and triacylglycerol (TAG) in cardiac muscle of 12-week old mdx and control (con) mice. Of 22 different FA, similar to our previous finding for skeletal muscle, the most abundant FA in heart PL were palmitic, stearic, cis-vaccenic, linoleic, and docosahexaenoic acid, while for TAG the most abundant FA were palmitic, oleic, cis-vaccenic, and linoleic acid. In comparing mdx and con, no significant group differences were detected for any FA in PL or TAG. Thus, unlike skeletal muscle, FA composition in cardiac muscle PL is not different between mdx and con at the age studied. The results can be understood in the context of tissue-specific disease severity in mdx mice, as pathology is quite modest in cardiac compared with skeletal muscle. PMID- 23794138 TI - Hydrolysis products generated by lipoprotein lipase and endothelial lipase differentially impact THP-1 macrophage cell signalling pathways. AB - Macrophages express lipoprotein lipase (LPL) and endothelial lipase (EL) within atherosclerotic plaques; however, little is known about how lipoprotein hydrolysis products generated by these lipases might affect macrophage cell signalling pathways. We hypothesized that hydrolysis products affect macrophage cell signalling pathways associated with atherosclerosis. To test our hypothesis, we incubated differentiated THP-1 macrophages with products from total lipoprotein hydrolysis by recombinant LPL or EL. Using antibody arrays, we found that the phosphorylation of six receptor tyrosine kinases and three signalling nodes--most associated with atherosclerotic processes--was increased by LPL derived hydrolysis products. EL derived hydrolysis products only increased the phosphorylation of tropomyosin-related kinase A, which is also implicated in playing a role in atherosclerosis. Using electrospray ionization-mass spectrometry, we identified the species of triacylglycerols and phosphatidylcholines that were hydrolyzed by LPL and EL, and we identified the fatty acids liberated by gas chromatography-mass spectrometry. To determine if the total liberated fatty acids influenced signalling pathways, we incubated differentiated THP-1 macrophages with a mixture of the fatty acids that matched the concentrations of liberated fatty acids from total lipoproteins by LPL, and we subjected cell lysates to antibody array analyses. The analyses showed that only the phosphorylation of Akt was significantly increased in response to fatty acid treatment. Overall, our study shows that macrophages display potentially pro atherogenic signalling responses following acute treatments with LPL and EL lipoprotein hydrolysis products. PMID- 23794140 TI - Systematic assignment of NMR spectra of 5-substituted-4-thiopyrimidine nucleosides. AB - Unambiguous characterization of 5-substituted-4-thiopyrimidine nucleosides (ribonucleosides and 2'-deoxynucleosides) was performed using NMR spectroscopy. Assignments of all proton and carbon signals of 5-bromo-4-thiouridine and related nucleosides were systematically carried out and firmly established by COSY and HMQC techniques. The NMR data of various 4-thiopyrimidine nucleosides are compared, and the key contributing factors discussed. The approach presented here is applicable to other modified nucleosides and nucleotides, as well as nucleobases. PMID- 23794141 TI - Using microbubbles as an MRI contrast agent for the measurement of cerebral blood volume. AB - The susceptibility differences at the gas-liquid interface of microbubbles (MBs) allow their use as an intravascular susceptibility contrast agent for in vivo MRI. However, the characteristics of MBs are very different from those of the standard gadolinium-diethylenetriaminepentaacetic acid (Gd-DPTA) contrast agent, including the size distribution and hemodynamic properties, which could influence MRI outcomes. Here, we investigate quantitatively the correlation between the relative cerebral blood volume (rCBV) derived from Gd-DTPA (rCBV(Gd)) and the MB induced susceptibility effect (DeltaR(2*MB)) by conventional dynamic susceptibility contrast MRI (DSC-MRI). Custom-made MBs had a mean diameter of 0.92 um and were capable of inducing 4.68 +/- 3.02% of the maximum signal change (MSC). The MB-associated DeltaR(2*MB) was compared with rCBV(Gd) in 16 rats on 4.7-T MRI. We observed a significant effect of the time to peak (TTP) on the correlation between DeltaR(2*MB) and rCBV(Gd), and also found a noticeable dependence between TTP and MSC. Our findings suggest that MBs with longer TTPs can be used for the estimation of rCBV by DSC-MRI, and emphasize the critical effect of TTP on MB-based contrast MRI. PMID- 23794142 TI - Overexpression of AtWRKY30 enhances abiotic stress tolerance during early growth stages in Arabidopsis thaliana. AB - AtWRKY30 belongs to a higher plant transcription factor superfamily, which responds to pathogen attack. In previous studies, the AtWRKY30 gene was found to be highly and rapidly induced in Arabidopsis thaliana leaves after oxidative stress treatment. In this study, electrophoretic mobility shift assays showed that AtWRKY30 binds with high specificity and affinity to the WRKY consensus sequence (W-box), and also to its own promoter. Analysis of the AtWRKY30 expression pattern by qPCR and using transgenic Arabidopsis lines carrying AtWRKY30 promoter-beta-glucuronidase fusions showed transcriptional activity in leaves subjected to biotic or abiotic stress. Transgenic Arabidopsis plants constitutively overexpressing AtWRKY30 (35S::W30 lines) were more tolerant than wild-type plants to oxidative and salinity stresses during seed germination. The results presented here show that AtWRKY30 is responsive to several stress conditions either from abiotic or biotic origin, suggesting that AtWRKY30 could have a role in the activation of defence responses at early stages of Arabidopsis growth by binding to W-boxes found in promoters of many stress/developmentally regulated genes. PMID- 23794144 TI - Rapid prenatal diagnosis of common beta-thalassemia mutations in Southeast Asia using pyrosequencing. AB - OBJECTIVE: Current methods of prenatal diagnosis to detect beta-thalassemia are Sanger sequencing and reverse dot blot. These methods are time-consuming and can prolong assay turnaround time. We aim to develop a sensitive and rapid method to detect 27 beta-thalassemia mutations using pyrosequencing. METHOD: Pyrosequencing primer pairs and sequencing primers were designed to detect 27 most common beta thalassemia mutations found in Singapore. Pyrosequencing was performed on 191 DNA samples with known beta-thalassemia mutations isolated from 143 peripheral blood and 48 prenatal samples (seven chorionic villus biopsies, 26 cultured amniocytes, 15 uncultured amniocytes). All mutations were validated with Sanger sequencing. RESULTS: Pyrosequencing identified 210 alleles with beta-thalassemia mutations and 82 alleles without mutations with 100% sensitivity (lower 95% confidence interval [CI], 97.8%) and 100% specificity (lower 95% CI, 94.4%). All pyrosequences were concordant with Sanger-based sequences. Pyrosequencing was able to detect DNA concentrations as low as 2 ng, obviating the need for cell culture in volume-restricted samples. Sample receipt-to-report assay turnaround times were 16 to 18 h (Sanger sequencing) and 4 to 6 h (pyrosequencing). CONCLUSION: Pyrosequencing is a rapid and sensitive method to detect common beta thalassemia mutations without the need for cell culture, thus reducing the assay turnaround time. PMID- 23794143 TI - The yeast two-hybrid and related methods as powerful tools to study plant cell signalling. AB - One basic property of proteins is their ability to specifically target and form non-covalent complexes with other proteins. Such protein-protein interactions play key roles in all biological processes, extending from the formation of cellular macromolecular structures and enzymatic complexes to the regulation of signal transduction pathways. Identifying and characterizing protein interactions and entire interaction networks (interactomes) is therefore prerequisite to understand these processes on a molecular and biophysical level. Since its original description in 1989, the yeast two-hybrid system has been extensively used to identify protein-protein interactions from many different organisms, thus providing a convenient mean to both screen for proteins that interact with a protein of interest and to characterize the known interaction between two proteins. In these years the technique has improved to overcome the limitations of the original assay, and many efforts have been made to scale up the technique and to adapt it to large scale studies. In addition, variations have been introduced to enlarge the range of proteins and interactors that can be assayed by hybrid-based approaches. Several groups studying molecular mechanisms that underlie plant cell signal transduction pathways have successfully used the yeast two-hybrid system or related methods. In this review we provide a brief description of the technology, attempt to point out some of the pitfalls and benefits of the different systems that can be employed, and mention some of the areas, within the plant cell signalling field, where hybrid-based interaction assays have been particularly informative. PMID- 23794145 TI - MicroRNA-212 inhibits proliferation of gastric cancer by directly repressing retinoblastoma binding protein 2. AB - Retinoblastoma binding protein 2 (RBP2), a newly found histone demethylase, is overexpressed in gastric cancer. We examined the upstream regulatory mechanism of RBP2 at the microRNA (miRNA) level and the role in gastric carcinogenesis. We used bioinformatics to predict that microRNA-212 (miR-212) might be a direct upstream regulator of RBP2 and verified the regulation in gastric epithelial derived cell lines. Overexpression of miR-212 significantly inhibited the expression levels of RBP2, whereas knockdown of miR-212 promoted RBP2 expression. Furthermore, we identified the putative miR-212 targeting sequence in the RBP2 3' UTR by luciferase assay. MiR-212 inhibited the colony formation ability of cells by repressing RBP2 expression and increasing that of P21(CIP1) and P27(kip1), both critical in cell cycle arrest. In addition, the expression of RBP2 and miR 212 in tumor tissue and matched normal tissue from 18 patients further supported the results in vivo. MiR-212 directly regulates the expression of RBP2 and inhibits cell growth in gastric cancer, which may provide new clues to treatment. PMID- 23794146 TI - Lost productivity and burden of illness in cancer survivors with and without other chronic conditions. AB - BACKGROUND: Cancer survivors may experience long-term and late effects from treatment that adversely affect health and limit functioning. Few studies examine lost productivity and disease burden in cancer survivors compared with individuals who have other chronic conditions or by cancer type. METHODS: We identified 4960 cancer survivors and 64,431 other individuals from the 2008-2010 Medical Expenditure Panel Survey and compared multiple measures of disease burden, including health status and lost productivity, between conditions and by cancer site for cancer survivors. All analyses controlled for the effects of age, sex, race/ethnicity, and number of comorbid conditions. RESULTS: Overall, in adjusted analyses in multiple models, cancer survivors with another chronic disease (heart disease or diabetes) experienced higher levels of burden compared with individuals with a history of cancer only, chronic disease only, and neither cancer, heart disease, nor diabetes across multiple measures (P < .05). Among cancer survivors, individuals with short survival cancers and multiple cancers consistently had the highest levels of burden across multiple measures (P < .0001). CONCLUSIONS: Cancer survivors who have another chronic disease experience more limitations and higher levels of burden across multiple measures. Limitations are particularly severe in cancer survivors with short survival cancer and multiple cancers. PMID- 23794147 TI - Targeted gene delivery with noncovalent electrostatic conjugates of sgc-8c aptamer and polyethylenimine. AB - BACKGROUND: Several strategies have been shown to improve the transfection efficiency of polyethylenimine (PEI) as a nonviral gene delivery vector. In the present study, a nucleic acid aptamer specific for protein tyrosine kinase 7 (PTK7) surface marker, sgc-8c, was conjugated electrostatically to pre-formed 10 kDa PEI/plasmid DNA polyplexes, and the ability of the conjugate to transfer genetic material was evaluated in MOLT-4 human acute lymphoblastic leukemia T cells, which express PTK7 on their surface. METHODS: Polyplexes (plasmid DNA vector conjugates), prepared using PEI-sgc-8c conjugate and pCMVLuc as a reporter gene, were characterized in terms of particle size, surface charge and the extent of DNA condensation. Polyplexes were also evaluated for cytotoxicity using the MTS colorimetric assay, as well as for transfection efficiency in MOLT-4 cells, and compared with the results obtained in U266 cells, which lack cell surface PTK7. RESULTS: Relative to pDNA/PEI, the size of pDNA/PEI/sgc-8c aptamer polyplexes increased with decreasing zeta potential. In MOLT-4 cells, pDNA/PEI/sgc-8c aptamer polyplexes exhibited an almost six- to eight-fold increase in transfection efficiency compared to that of pDNA/PEI polyplex, indicating that conjugation of sgc-8c aptamer to pre-formed 10-kDa PEI/plasmid DNA polyplexes achieved effective targeting without covalent attachment, whereas receptor-mediated conducted transfection was confirmed by performing a competitive transfection experiment and a cellular uptake study. CONCLUSIONS: The results of the present study provide an example of the usefulness of a nucleic acid aptamer in the form of noncovalent, electrostatic conjugates as an approach for enhancing the transfection efficiency of a polycation vector such as PEI without significant induced cytotoxicity. PMID- 23794148 TI - Histologic characteristics and KIT staining patterns of equine cutaneous mast cell tumors. AB - Mast cell tumors are uncommon in horses and typically have a benign clinical course, but there are occasional reports of more aggressive behavior. The objective of this study was to review histologic features and KIT expression patterns of 72 previously diagnosed equine cutaneous mast cell tumors to determine if either is associated with clinical outcomes. Biopsy specimens were reviewed using histologic criteria derived from grading schemes, and KIT antibody expression patterns used in canine tumors and surveys were sent to referring veterinarians for follow-up clinical data. Arabians were overrepresented relative to the reference population. Most tumors were well differentiated with low mitotic rates (96%), and aberrant KIT staining patterns, as described in dogs, were uncommonly identified (12%). Associated clinical disease was uncommon and no tumors exhibited malignant behavior. Overall, KIT staining pattern and histologic features were not associated with poor clinical outcome or abnormal tumor behavior. PMID- 23794149 TI - Cardiac lesions in 30 dogs naturally infected with Leishmania infantum chagasi. AB - The hearts of 30 dogs naturally infected with Leishmania infantum chagasi were evaluated histologically and immunohistochemically. Myocardial lesions were detected in all dogs, including lymphoplasmacytic myocarditis (27/30), myonecrosis (24/30), increased interstitial collagen (22/30), lepromatous-type granulomatous myocarditis (7/30), fibrinoid vascular change (3/30), and vasculitis (1/30). The parasite was detected in the hearts of 20 of 30 dogs. The number of parasitized cells correlated with the intensity of the inflammation and with the number of granulomas. The results indicate that cardiac lesions are prevalent in dogs with naturally occurring leishmaniasis even in the absence of clinical signs of cardiac disease. PMID- 23794150 TI - Clinical, morphologic, and immunohistochemical features of canine orbital hibernomas. AB - Hibernomas are uncommon benign tumors of brown fat that occur in humans and various animal species. They have not been observed in the orbit of dogs, humans, or other animals. Here we report clinical, light and electron microscopic, and immunohistochemical features of a series of 7 hibernomas arising in the orbital region of dogs. These neoplasms occurred in adult dogs with no breed predilection. The mean age of the affected dogs was 10.4 years (range, 8-13 years). All neoplasms presented as soft lobular masses composed of predominantly round or polygonal neoplastic cells with granular eosinophilic and vacuolated cytoplasm resembling adipocytes. The cytoplasm contained large numbers of pleomorphic mitochondria with dense matrices and indistinct cristae. Immunohistochemical evaluation confirmed positive labeling of neoplastic cells from all cases with uncoupling protein 1 (UCP-1) consistent with brown fat differentiation. Interestingly, rare neoplastic cells also expressed myogenin and myoD, possibly suggesting a common progenitor cell for neoplastic brown adipose and skeletal muscle cells. PMID- 23794151 TI - Domino catalysis: palladium-catalyzed carbonylation of allylic alcohols to beta,gamma-unsaturated esters. PMID- 23794152 TI - Using genetic testing to guide therapeutic decisions in cardiomyopathy. AB - OPINION STATEMENT: Genetic analysis of human cardiomyopathy has rapidly transitioned from a strictly research endeavor to a diagnostic tool readily available to clinicians across the globe. In contemporary practice, genetic testing improves the efficiency of family evaluations and clarifies the etiology of ambiguous clinical presentations. The great promise of genetic diagnosis is to enable preventative therapies for individuals at high risk of future disease development, a strategy that is under active clinical investigation. However, in the present and future, careful interpretation of DNA sequence variation is critical, and can be ensured by referral to a specialized cardiovascular genetics clinic. PMID- 23794153 TI - Aromaticity effects on the profiles of the lowest triplet-state potential-energy surfaces for rotation about the C=C bonds of olefins with five-membered ring substituents: an example of the impact of Baird's rule. AB - A density functional theory study on olefins with five-membered monocyclic 4n and 4n+2 pi-electron substituents (C4H3X; X=CH(+), SiH(+), BH, AlH, CH2, SiH2, O, S, NH, and CH(-)) was performed to assess the connection between the degree of substituent (anti)aromaticity and the profile of the lowest triplet-state (T1) potential-energy surface (PES) for twisting about olefinic C=C bonds. It exploited both Huckel's rule on aromaticity in the closed-shell singlet ground state (S0) and Baird's rule on aromaticity in the lowest pipi* excited triplet state. The compounds CH2=CH(C4H3X) were categorized as set A and set B olefins depending on which carbon atom (C2 or C3) of the C4H3X ring is bonded to the olefin. The degree of substituent (anti)aromaticity goes from strongly S0 antiaromatic/T1 -aromatic (C5H4 (+)) to strongly S0 -aromatic/T1- antiaromatic (C5H4(-)). Our hypothesis is that the shapes of the T1 PESs, as given by the energy differences between planar and perpendicularly twisted olefin structures in T1 [DeltaE(T1)], smoothly follow the changes in substituent (anti)aromaticity. Indeed, correlations between DeltaE(T1) and the (anti)aromaticity changes of the C4 H3 X groups, as measured by the zz-tensor component of the nucleus-independent chemical shift DeltaNICS(T1;1)zz , are found both for sets A and B separately (linear fits; r(2) =0.949 and 0.851, respectively) and for the two sets combined (linear fit; r(2) =0.851). For sets A and B combined, strong correlations are also found between DeltaE(T1) and the degree of S0 (anti)aromaticity as determined by NICS(S0,1)zz (sigmoidal fit; r(2) =0.963), as well as between the T1 energies of the planar olefins and NICS(S0,1)zz (linear fit; r(2) =0.939). Thus, careful tuning of substituent (anti)aromaticity allows for design of small olefins with T1 PESs suitable for adiabatic Z/E photoisomerization. PMID- 23794154 TI - Liver resection for hepatocellular carcinoma in patient with situs inversus viscerum. PMID- 23794155 TI - Experiences with the OECD 308 transformation test: a human pharmaceutical perspective. AB - The Organisation for Economic Co-operation and Development (OECD) 308 water sediment transformation test has been routinely conducted in Phase II Tier A testing of the environmental risk assessment (ERA) for all human pharmaceutical marketing authorization applications in Europe, since finalization of Environmental Medicines Agency (EMA) ERA guidance in June 2006. In addition to the "Ready Biodegradation" test, it is the only transformation test for the aquatic/sediment compartment that supports the classification of the drug substance for its potential persistence in the environment and characterizes the fate of the test material in a water-sediment environment. Presented is an overview of 31 OECD 308 studies conducted by 4 companies with a focus on how pharmaceuticals behave in these water-sediment systems. The geometric mean (gm) parent total system half-life for the 31 pharmaceuticals was 30 days with 10th/90th percentile (10/90%ile) of 14.0/121.6 d respectively, with cationic substances having a half-life approximately 2 times that of neutral and anionic substances. The formation of nonextractable residues (NER) was considerable, with gm (10/90%ile) of 38% (20.5/81.4) of the applied radioactivity: cationic substances 50.8% (27.7/87.6), neutral substances 31.9% (15.3/52.3), and anionic substances 16.7% (9.5/30.6). In general, cationic substances had fewer transformation products and more unchanged parent remaining at day 100 of the study. A review of whether a simplified 1-point analysis could reasonably estimate the parent total system half-life showed that the total amount of parent remaining in the water and sediment extracts at day 100 followed first-order kinetics and that the theoretical half-life and the measured total system half life values agreed to within a factor of 1.68. Recommendations from this 4 company collaboration addressed: 1) the need to develop a more relevant water sediment transformation test reflecting the conditions of the discharge scenario more representative of human pharmaceuticals, 2) potential use of a 1-point estimate of parent total system half-life in the EMA ERA screening phase of testing, 3) the need for a more consistent and transparent interpretation of the results from the transformation study; consistent use of terminology such as dissipation, transformation, depletion, and degradation in describing their respective processes in the ERA, 4) use of the parent total system dissipation half-life in hazard classification schemes and in revising predicted environmental concentration in ERA, and 5) further research into cationic pharmaceuticals to assess whether their classification as such serves as a structural alert to high levels of NER; and whether this results in reduced bioavailability of those residues. PMID- 23794156 TI - Clinical research must include more older people. PMID- 23794157 TI - Should antibiotic prophylaxis after urinary catheter removal be standard practice? PMID- 23794158 TI - Saying no to chemotherapy. PMID- 23794159 TI - Care Quality Commission reveals names of people involved in alleged cover-up decision. PMID- 23794160 TI - Disruption of Phthorimaea operculella (Lepidoptera: Gelechiidae) oviposition by the application of host plant volatiles. AB - BACKGROUND: Phthorimaea operculella is a key pest of potato. The authors characterised the P. operculella olfactory system, selected the most bioactive host plant volatiles and evaluated their potential application in pest management. The electrophysiological responses of olfactory receptor neurons (ORNs) housed in long sensilla trichodea of P. operculella to plant volatiles and the two main sex pheromone components were evaluated by the single-cell recording (SCR) technique. The four most SCR-active volatiles were tested in a laboratory oviposition bioassay and under storage warehouse conditions. RESULTS: The sensitivity of sensilla trichodea to short-chained aldehydes and alcohols and the existence of ORNs tuned to pheromones in females were characterised. Male recordings revealed at least two types of ORN, each of which typically responded to one of the two pheromone components. Hexanal, octanal, nonanal and 1-octen-3 ol significantly disrupted the egg-laying behaviour in a dose-dependent manner. Octanal reduced the P. operculella infestation rate when used under storage conditions. CONCLUSIONS: This work provides new information on the perception of plant volatiles and sex pheromones by P. operculella. Laboratory and warehouse experiments show that the use of hexanal, octanal, nonanal and 1-octen-3-ol as host recognition disruptants and/or oviposition deterrents for P. operculella control appears to be a promising strategy. PMID- 23794161 TI - Delayed presentation of melanoma-associated retinopathy and subsequent resolution with cytoreduction surgery. AB - BACKGROUND: To present a case of melanoma-associated retinopathy (MAR) which manifested 26 months prior to a formal diagnosis of melanoma. METHODS: Case report. RESULTS: A 72-year-old female presented with bilateral continuous photopsia consistent with MAR of 7-months duration. At this point, visual function appeared normal with the exception of mildly impaired colour vision (10/17 Ishihara plates). The flash electroretinographic (ERG) revealed extinguished rod responses, a normal a-wave and reduced b-wave (electronegative ERG) on the maximal combined response, absent oscillatory potentials and broadened a-wave trough on the cone response. Multifocal ERG (mfERG) responses were delayed and demonstrated atypical morphology. Nineteen months after the initial presentation, her visual symptoms had progressed significantly with constant debilitating photopsia in combination with 13 kg weight loss. Biopsy of a now evident left axillary mass demonstrated a metastatic high-grade malignant melanoma. No primary was detected, and an axillary lymph node clearance was undertaken. Subsequently, visual symptoms resolved with corresponding improvement in the ERG over the next 18 months. Rod responses recovered such that the amplitude was at the lower limit of normal and the mfERG response delay lessened. Unfortunately, the melanoma recurred and the patient passed away 6 months later. Visual symptoms did not recur. CONCLUSION: We present a case which demonstrates MAR may precede the formal diagnosis of melanoma by up to 26 months. The potential for improvement in the rod visual function persists over a period of years with normalisation of an electronegative waveform. In this case, cytoreductive surgery resulted in complete resolution of the MAR, which did not return even with a recurrence of the tumour. PMID- 23794162 TI - Parental participation in religious services and parent and child well-being: findings from the National Survey of America's Families. AB - Using data from the 1999 and 2002 National Survey of America's Families, a large scale nationally representative sample, this study finds that parental religious attendance is positively associated with parent self-rated health, parent mental well-being, positive parenting attitudes, child health, and child school engagement. Although the strength of these associations varies to some extent according to socio-demographic factors, the interactive patterns are not consistently predictable. Moreover, parental health and well-being and positive attitudes toward parenting appear to be important pathways linking parental religious attendance to child well-being. These findings suggest that opportunities for participation in local religious services offered by faith based organizations may be fruitful avenues through which the government and society can help American families enhance parent and child well-being. PMID- 23794163 TI - Grasping the world through words: from action to linguistic production of verbs in early childhood. AB - We investigated whether the bodily-mediated production of verbs emerges earlier than verb recognition and oral production during early language acquisition. Children (aged 18-22, 23-27, 28-32, and 33-37 months) viewed animated pictures representing actions related to transitive and intransitive verbs and were asked to (i) orally indicate the verb presented, (ii) recognize the target verb among other verbs, and (iii) perform the actions corresponding to the target verb enunciated by the experimenter. Children 18-22 months showed a capacity to enact the verbs, while their recognition and oral production abilities were not comparably developed. Until 27 months of age, children produced more transitive than intransitive verbs across tasks. The gap between verb recognition and verb oral production was found in all ages tested. This is the first study to directly demonstrate that the ability to produce verbs, especially transitive verbs, via overt body actions emerges ontogenetically earlier than recognition and oral production. PMID- 23794164 TI - Secondary voice prosthesis insertion in patients without direct access to the upper esophagus. PMID- 23794165 TI - Registry. PMID- 23794166 TI - Synthesis, structural analysis, and properties of [8]circulenes. AB - Polygons: [8]Circulenes were easily prepared by Pd-catalyzed annulations of tetraiodotetraphenylenes with alkynes. Their saddle-shaped structure with an [8]radialene character was identified by X-ray crystallography. Similar to 1,3,5,7-cyclooctatetraene, they have a tub-shaped eight-membered ring, but all of the bond lengths and bond angles are almost equal. Variable-temperature NMR investigations showed interesting dynamic behavior. PMID- 23794167 TI - Pharmacokinetics, distribution and excretion of PNA in rat by liquid chromatography mass spectrometry method. AB - The pharmacokinetic profiles, tissue distribution and excretion patterns of PNA in healthy male and female Sprague-Dawley rats following a single intra-duodenum administration were investigated by previously established LC-MS method. Absorption was rapid in rats as evidenced by a short time to maximum concentration (Cmax) of 0.050 +/- 0.021, 0.072 +/- 0.017 and 0.067 +/- 0.018 h at the 25, 50 and 100 mg/kg dose level, respectively. The Cmax were 754.9 +/- 196.1, 1187.8 +/- 642.1 and 2082.1 +/- 1,278.5 ng/mL and the AUC0-4 were 71.8 +/- 25.9, 135.2 +/- 69.9 and 303.3 +/- 198.3 ug/L h, which showed linear with the intra duodenum administration range from 25-100 mg/kg. Tissues were collected at 4 time points (3, 10 min, 1 and 3 h) after dosing at 50 mg/kg. Compare to the concentrations of plasma and other tissues, the level was particularly high in the liver and brain during 3 h. Bile/urine and feces samples were collected before dosing and till 24/48 h post-dosing. The mean cumulative excretion of unchanged PNA in bile amounted to 0.021% of the dose up to 24 h. The mean recoveries of unchanged PNA were 0.0095% and 0.043% of the dose up to 48 h in urine and feces, respectively. There was no significant difference in PNA concentration observed between male and female rats during the experiments. PMID- 23794169 TI - Production of reactive oxygen species in decoupled, Ca(2+)-depleted PSII and their use in assigning a function to chloride on both sides of PSII. AB - Extraction of Ca(2+) from the oxygen-evolving complex of photosystem II (PSII) in the absence of a chelator inhibits O2 evolution without significant inhibition of the light-dependent reduction of the exogenous electron acceptor, 2,6 dichlorophenolindophenol (DCPIP) on the reducing side of PSII. The phenomenon is known as "the decoupling effect" (Semin et al. Photosynth Res 98:235-249, 2008). Extraction of Cl(-) from Ca(2+)-depleted membranes (PSII[-Ca]) suppresses the reduction of DCPIP. In the current study we investigated the nature of the oxidized substrate and the nature of the product(s) of the substrate oxidation. After elimination of all other possible donors, water was identified as the substrate. Generation of reactive oxygen species HO, H2O2, and O 2 (.-) , as possible products of water oxidation in PSII(-Ca) membranes was examined. During the investigation of O 2 (.-) production in PSII(-Ca) samples, we found that (i) O 2 (.-) is formed on the acceptor side of PSII due to the reduction of O2; (ii) depletion of Cl(-) does not inhibit water oxidation, but (iii) Cl(-) depletion does decrease the efficiency of the reduction of exogenous electron acceptors. In the absence of Cl(-) under aerobic conditions, electron transport is diverted from reducing exogenous acceptors to reducing O2, thereby increasing the rate of O 2 (.-) generation. From these observations we conclude that the product of water oxidation is H2O2 and that Cl(-) anions are not involved in the oxidation of water to H2O2 in decoupled PSII(-Ca) membranes. These results also indicate that Cl(-) anions are not directly involved in water oxidation by the Mn cluster in the native PSII membranes, but possibly provide access for H2O molecules to the Mn4CaO5 cluster and/or facilitate the release of H(+) ions into the lumenal space. PMID- 23794168 TI - Excitonic connectivity between photosystem II units: what is it, and how to measure it? AB - In photosynthetic organisms, light energy is absorbed by a complex network of chromophores embedded in light-harvesting antenna complexes. In photosystem II (PSII), the excitation energy from the antenna is transferred very efficiently to an active reaction center (RC) (i.e., with oxidized primary quinone acceptor Q(A)), where the photochemistry begins, leading to O2 evolution, and reduction of plastoquinones. A very small part of the excitation energy is dissipated as fluorescence and heat. Measurements on chlorophyll (Chl) fluorescence and oxygen have shown that a nonlinear (hyperbolic) relationship exists between the fluorescence yield (Phi(F)) (or the oxygen emission yield, (Phi(O2)) and the fraction of closed PSII RCs (i.e., with reduced Q(A)). This nonlinearity is assumed to be related to the transfer of the excitation energy from a closed PSII RC to an open (active) PSII RC, a process called PSII excitonic connectivity by Joliot and Joliot (CR Acad Sci Paris 258: 4622-4625, 1964). Different theoretical approaches of the PSII excitonic connectivity, and experimental methods used to measure it, are discussed in this review. In addition, we present alternative explanations of the observed sigmoidicity of the fluorescence induction and oxygen evolution curves. PMID- 23794170 TI - Getting the most out of natural variation in C4 photosynthesis. AB - C4 photosynthesis is a complex trait that has a high degree of natural variation, involving anatomical and biochemical changes relative to the ancestral C3 state. It has evolved at least 66 times across a variety of lineages and the evolutionary route from C3 to C4 is likely conserved but not necessarily genetically identical. As such, a variety of C4 species are needed to identify what is fundamental to the C4 evolutionary process in a global context. In order to identify the genetic components of C4 form and function, a number of species are used as genetic models. These include Zea mays (maize), Sorghum bicolor (sorghum), Setaria viridis (Setaria), Flaveria bidentis, and Cleome gynandra. Each of these species has different benefits and challenges associated with its use as a model organism. Here, we propose that RNA profiling of a large sampling of C4, C3-C4, and C3 species, from as many lineages as possible, will allow identification of candidate genes necessary and sufficient to confer C4 anatomy and/or biochemistry. Furthermore, C4 model species will play a critical role in the functional characterization of these candidate genes and identification of their regulatory elements, by providing a platform for transformation and through the use of gene expression profiles in mesophyll and bundle sheath cells and along the leaf developmental gradient. Efforts should be made to sequence the genomes of F. bidentis and C. gynandra and to develop congeneric C3 species as genetic models for comparative studies. In combination, such resources would facilitate discovery of common and unique C4 regulatory mechanisms across genera. PMID- 23794171 TI - Abatacept: a review of its use in the management of rheumatoid arthritis. AB - The biological disease-modifying antirheumatic drug abatacept (Orencia) has a novel mechanism of action; its activity is mediated via the selective modulation of T cell co-stimulation. This article reviews the clinical efficacy and tolerability of intravenous and subcutaneous abatacept in patients with rheumatoid arthritis (RA) and intravenous abatacept in patients with juvenile idiopathic arthritis (JIA), as well as summarizing its pharmacological properties. In patients with RA, the beneficial effects of intravenous or subcutaneous abatacept on signs and symptoms, disease activity, the progression of structural damage, physical function and/or health-related quality of life were seen in a number of well-designed trials, including in methotrexate-naive patients with early RA and poor prognostic factors and in patients with established RA and an inadequate response to either methotrexate or anti-tumour necrosis factor therapy. Subcutaneous abatacept plus methotrexate was also noninferior to subcutaneous adalimumab plus methotrexate in patients with active RA who were naive to biological therapy and had an inadequate response to methotrexate. In paediatric patients with JIA, intravenous abatacept improved signs and symptoms and delayed the time to flare. Abatacept was generally well tolerated in RA and JIA and was associated with low rates of immunogenicity. In conclusion, abatacept is an important option for use in the treatment of RA and JIA. PMID- 23794172 TI - Compositional shifts in Costa Rican forests due to climate-driven species migrations. AB - Species are predicted to shift their distributions upslope or poleward in response to global warming. This prediction is supported by a growing number of studies documenting species migrations in temperate systems but remains poorly tested for tropical species, and especially for tropical plant species. We analyzed changes in tree species composition in a network of 10 annually censused 1-ha plots spanning an altitudinal gradient of 70-2800 m elevation in Costa Rica. Specifically, we combined plot data with herbarium records (accessed through GBIF) to test if the plots' community temperature scores (CTS, average thermal mean of constituent species weighted by basal area) have increased over the past decade as is predicted by climate-driven species migrations. In addition, we quantified the contributions of stem growth, recruitment, and mortality to the observed patterns. Supporting our a priori hypothesis of upward species migrations, we found that there have been consistent directional shifts in the composition of the plots, such that the relative abundance of lowland species, and hence CTS, increased in 90% of plots. The rate of the observed compositional shifts corresponds to a mean thermal migration rate (TMR) of 0.0065 degrees C yr(-1) (95% CI = 0.0005-0.0132 degrees C yr(-1) ). While the overall TMR is slower than predicted based on concurrent regional warming of 0.0167 degrees C yr(-1) , migrations were on pace with warming in 4 of the 10 plots. The observed shifts in composition were driven primarily by mortality events (i.e., the disproportionate death of highland vs. lowland species), suggesting that individuals of many tropical tree species will not be able to tolerate future warming and thus their persistence in the face of climate change will depend on successful migrations. Unfortunately, in Costa Rica and elsewhere, land area inevitably decreases at higher elevations; hence, even species that are able to migrate successfully will face heightened risks of extinction. PMID- 23794173 TI - Anomalous congenital band and intestinal obstruction: report of a fatal case in a child. PMID- 23794174 TI - Structures and interligand interaction pattern of phosphoramidite Pd complexes by NMR spectroscopy: modulations in extended interaction surfaces as stereoselection mode of a privileged class of ligands. AB - During the last decade, phosphoramidites have been established as a so-called privileged class of ligands in various transition metal catalyses. However, the interactions responsible for their favorable properties have hitherto remained elusive. To address this issue, the formation trends, structural features, and interligand interaction patterns of several trans- and cis-[PdLL'Cl2] complexes have been investigated by NMR spectroscopy. The energetic contribution of their interligand interactions has been measured experimentally using the supramolecular balance for transition-metal complexes. The resulting energetics combined with an analysis of the electrostatic potential surfaces reveal that in phosphoramidites not only the aryl groups but the complete (CH)CH3 Ph moieties of the amine side chains form extended quasi-planar CH-pi and pi-pi interaction surfaces. Application of the supramolecular balance has shown that modulations in these extended interaction surfaces cause energetic differences that are relevant to enantioselective catalysis. In addition, the energetics of these interligand interactions are quite independent of the actual structures of the complexes. This is shown by similar formation and aggregation trends of complexes with the same ligand but different structures. The extended quasi-planar electrostatic interaction surface of the (CH)CH3 Ph moiety explains the known pattern of successful ligand modulation and the substrate specificity of phosphoramidites. Thus, we propose modulations in these extended CH-pi and pi-pi interaction areas as a refined stereoselection mode for these ligands. Based on the example of phosphoramidites, this study reveals three general features potentially applicable to various ligands in asymmetric catalysis. First, specific combinations of alkyl and aryl moieties can be used to create extended anisotropic interaction areas. Second, modulations in these interaction surfaces cause energetic differences that are relevant to catalytic applications. Third, bulky substituents with matching complementary interaction surfaces should not only be considered in terms of steric hindrance but also in terms of attractive and repulsive interactions, a feature that may often be underestimated in asymmetric catalysis. PMID- 23794175 TI - Hemifacial microsomia in cat-eye syndrome: 22q11.1-q11.21 as candidate loci for facial symmetry. AB - Cat-Eye syndrome (CES), (OMIM 115470) also known as chromosome 22 partial tetrasomy or inverted duplicated 22q11, was first reported by Haab [1879] based on the primary features of eye coloboma and anal atresia. However, >60% of the patients lack these primary features. Here, we present a 9-month-old female who at birth was noted to have multiple defects, including facial asymmetry with asymmetric retrognathia, bilateral mandibular hypoplasia, branchial cleft sinus, right-sided muscular torticollis, esotropia, and an atretic right ear canal with low-to-moderate sensorineural hearing loss, bilateral preauricular ear tag/pits, and two skin tags on her left cheek. There were no signs of any colobomas or anal atresia. Hemifacial microsomia (HFM) was suspected clinically. Chromosome studies and FISH identified an extra marker originated from 22q11 consistent with CES, and this was confirmed by aCGH. This report expands the phenotypic variability of CES and includes partial tetrasomy of 22q11.1-q11.21 in the differential diagnosis of HFM. In addition, our case as well as the previous association of 22q11.2 deletions and duplications with facial asymmetry and features of HFM, supports the hypothesis that this chromosome region harbors genes important in the regulation of body plan symmetry, and in particular facial harmony. PMID- 23794176 TI - The increasing importance of herbicides in worldwide crop production. AB - Herbicide use is increasingly being adopted around the world. Many developing countries (India, China, Bangladesh) are facing shortages of workers to hand weed fields as millions of people move from rural to urban areas. In these countries, herbicides are far cheaper and more readily available than labor for hand weeding. History shows that in industrializing countries in the past, including the United States, Germany, Japan and South Korea, the same phenomenon has occurred-as workers have left agriculture, herbicides have been adopted. It is inevitable that herbicide use will increase in sub-Saharan Africa, not only because millions of people are leaving rural areas, creating shortages of hand weeders, but also because of the need to increase crop yields. Hand weeding has never been a very efficient method of weed control-often performed too late and not frequently enough. Uncontrolled weeds have been a major cause of low crop yields in sub-Saharan Africa for a long time. In many parts of the world, herbicides are being increasingly used to replace tillage in order to improve environmental conditions. In comparison with tillage, herbicide use reduces erosion, fuel use, greenhouse gas emissions and nutrient run-off and conserves water. PMID- 23794177 TI - A strong consensus has emerged around the role of protein misfolding and aggregation in the pathogenesis of neurodegeneration. Introduction. PMID- 23794178 TI - Visual attention during neonatal imitation in newborn macaque monkeys. AB - Previous studies suggest that about 50% of rhesus macaque infants engage in neonatal imitation of facial gestures. Here we measured whether individual differences in newborn macaques' (n = 49) visual attention may explain why some infants imitate lipsmacking (LPS) and tongue protrusion (TP) gestures. LPS imitators, but not TP imitators, looked more to a human experimenter's face and to a control stimulus compared to nonimitators (p = .017). LPS imitation was equally accurate when infants were looking at faces and when they were looking away (p = .221); TP imitation was more accurate when infants were looking at faces (p = .001). Potentially, less attention is necessary for LPS imitation compared to TP imitation, as LPS is part of macaques' natural communicative repertoire. These findings suggest that facial gestures may differentially engage imitators and nonimitators, and infants' visual attention during neonatal assessments may uncover the conditions that support this skill. PMID- 23794179 TI - Selection of Medications to Prevent Stroke Among Individuals With Atrial Fibrillation : Update on Prevention of Stroke in Patients with AF. AB - OPINION STATEMENT: Vitamin K antagonists have been the only available orally active anticoagulants for decades. Although effective, their numerous limitations have driven the introduction of new oral anticoagulants (NOAs) that showed effectiveness at fixed doses without the need for routine coagulation monitoring. However, the safety and efficacy observed in controlled clinical trials may be hard to translate in clinical practice. Clinical conditions as well as drug interactions may considerably impact on patient outcomes. Moreover, the inability to monitor the pharmacological activity of NOAs and the absence of any antidote in the setting of bleeding or emergent invasive procedures may limit their use. Vitamin K antagonists will be still used in many circumstances, including patients with an optimal control of the INR, with mechanical heart valves, and other indications for which these new agents have not been investigated. Nevertheless, these new agents will reduce the burden of anticoagulation management at the patient as well as Health Care level. PMID- 23794180 TI - The Schedule for Nonadaptive and Adaptive Personality for Youth (SNAP-Y): a new measure for assessing adolescent personality and personality pathology. AB - The Schedule for Nonadaptive and Adaptive Personality-Youth Version (SNAP-Y) is a new, reliable self-report questionnaire that assesses 15 personality traits relevant to both normal-range personality and the alternative DSM-5 model for personality disorder. Community adolescents, 12 to 18 years old (N = 364), completed the SNAP-Y; 347 also completed the Big Five Inventory-Adolescent, 144 provided 2-week retest data, and 128 others completed the Minnesota Multiphasic Personality Inventory-Adolescent. Outpatient adolescents (N = 103) completed the SNAP-Y, and 97 also completed the Minnesota Multiphasic Personality Inventory Adolescent. The SNAP-Y demonstrated strong psychometric properties, and structural, convergent, discriminant, and external validities. Consistent with the continuity of personality, results paralleled those in adult and college samples using the adult Schedule for Nonadaptive and Adaptive Personality-Second Edition (SNAP-2), from which the SNAP-Y derives and which has established validity in personality-trait assessment across the normal-abnormal continuum. The SNAP-Y thus provides a new, clinically useful instrument to assess personality traits and personality pathology in adolescents. PMID- 23794181 TI - Development and validation of the mindfulness-based interventions - teaching assessment criteria (MBI:TAC). AB - BACKGROUND: The assessment of intervention integrity is essential in psychotherapeutic intervention outcome research and psychotherapist training. There has been little attention given to it in mindfulness-based interventions research, training programs, and practice. AIMS: To address this, the Mindfulness Based Interventions: Teaching Assessment Criteria (MBI:TAC) was developed. This article describes the MBI:TAC and its development and presents initial data on reliability and validity. METHOD: Sixteen assessors from three centers evaluated teaching integrity of 43 teachers using the MBI:TAC. RESULTS: Internal consistency (alpha = .94) and interrater reliability (overall intraclass correlation coefficient = .81; range = .60-.81) were high. Face and content validity were established through the MBI:TAC development process. Data on construct validity were acceptable. CONCLUSIONS: Initial data indicate that the MBI:TAC is a reliable and valid tool. It can be used in Mindfulness-Based Stress Reduction/Mindfulness-Based Cognitive Therapy outcome evaluation research, training and pragmatic practice settings, and in research to assess the impact of teaching integrity on participant outcome. PMID- 23794182 TI - Bone marrow composition, diabetes, and fracture risk: more bad news for saturated fat. PMID- 23794183 TI - Critical assessment of proteome-wide label-free absolute abundance estimation strategies. AB - There is a great interest in reliable ways to obtain absolute protein abundances at a proteome-wide scale. To this end, label-free LC-MS/MS quantification methods have been proposed where all identified proteins are assigned an estimated abundance. Several variants of this quantification approach have been presented, based on either the number of spectral counts per protein or MS1 peak intensities. Equipped with several datasets representing real biological environments, containing a high number of accurately quantified reference proteins, we evaluate five popular low-cost and easily implemented quantification methods (Absolute Protein Expression, Exponentially Modified Protein Abundance Index, Intensity-Based Absolute Quantification Index, Top3, and MeanInt). Our results demonstrate considerably improved abundance estimates upon implementing accurately quantified reference proteins; that is, using spiked in stable isotope labeled standard peptides or a standard protein mix, to generate a properly calibrated quantification model. We show that only the Top3 method is directly proportional to protein abundance over the full quantification range and is the preferred method in the absence of reference protein measurements. Additionally, we demonstrate that spectral count based quantification methods are associated with higher errors than MS1 peak intensity based methods. Furthermore, we investigate the impact of miscleaved, modified, and shared peptides as well as protein size and the number of employed reference proteins on quantification accuracy. PMID- 23794184 TI - IL-33/IL-31 axis: a new pathological mechanisms for EGFR tyrosine kinase inhibitors-associated skin toxicity. AB - The dermatologic side effects are the most common adverse effects associated with Epidermal Growth Factor Receptor tyrosine kinase inhibitors. Although the mechanisms underlying the development of the skin toxicity remain unclear, immunological mechanisms are considered to be involved. A possible correlation between plasma levels of certain cytokines and development of skin toxicity has been reported. The aim of this work was to investigate the possible contribution of IL-31 and IL-33, cytokines involved in disorders associated with itching, in the pathogenesis of pruritus in patients undergoing EGFR-TK inhibitors. We report a significant increase of IL-31 and IL-33 serum levels in a patient with a bronchioalveolar carcinoma, who had showed previous skin rash, xerosis, and pruritus during treatment with different EGFR-TK inhibitors. She developed intense iching during gefitinib therapy. Therefore, we had collected patient blood sample to evaluate IL-31 and IL-33 serum levels compared to controls, reporting a significant increase in serum of patient. In the light of these findings, EGFR-TK inhibitors-related symptoms of dermatologic toxicities might be related to the release of IL-31 and IL-33. In particular, it is supposable that EGFR-TK inhibitors could cause keratinocytes injury, the release of IL-33 and the consequent interaction with its receptor on mast cells, that induces the secretion of several factors capable to cause skin manifestations, included IL 31, a known pruritus-inducing cytokine. This report, to the best of our knowledge, is the first work describing a possible involvement of IL-31/IL-33 axis in the pathogenesis of skin side effects related to EGFR-TK inhibitors treatment. PMID- 23794185 TI - Canine fossa puncture for severe maxillary disease in unilateral chronic sinusitis with nasal polyp. AB - OBJECTIVES/HYPOTHESIS: To evaluate the efficacy of canine fossa puncture (CFP) by comparing patients with unilateral chronic rhinosinusitis (CRS) accompanying nasal polyposis (NP) who underwent CFP with those who underwent maxillary sinus clearance through a middle meatal antrostomy (MMA). STUDY DESIGN: Prospective randomized study. METHODS: Twenty-nine patients were randomly assigned to the CFP and MMA groups. Preoperative computed tomography (CT) established that all patients had severely diseased maxillary sinuses. Subjective outcomes were evaluated preoperatively and at 3, 6, and 12 months postoperatively using the Sino-Nasal Outcome Test 20 (SNOT-20) and a visual analogue scale (VAS). Additionally, mucosal thickening was measured as a percentage of total maxillary sinus volume on CT images taken 12 months postoperatively. RESULTS: Twenty-five patients who completed the follow-up, questionnaires, and postoperative CT evaluation were included in the analysis. SNOT-20 and VAS scores improved significantly at 3, 6, and 12 months postprocedure in both groups. However, significant improvement of SNOT-20 at 12 months and VAS scores for purulent discharge, foul odor, and postnasal drip at 6 and 12 months were observed in the CFP group compared with the MMA group. In addition, the volume of mucosal thickening was significantly greater in the MMA group than in the CFP group on postoperative CT images. CONCLUSIONS: CFP is a useful method for the removal of severe maxillary mucosal disease that cannot be reached through MMA, and is superior to conventional MMA for improving subjective and objective outcomes in patients with unilateral CRS accompanying NP. PMID- 23794186 TI - Hydrocyanative cyclization and three-component cross-coupling reaction between allenes and alkynes under nickel catalysis. PMID- 23794187 TI - Screening for lung cancer. AB - BACKGROUND: This is an updated version of the original review published in The Cochrane Library in 1999 and updated in 2004 and 2010. Population-based screening for lung cancer has not been adopted in the majority of countries. However it is not clear whether sputum examinations, chest radiography or newer methods such as computed tomography (CT) are effective in reducing mortality from lung cancer. OBJECTIVES: To determine whether screening for lung cancer, using regular sputum examinations, chest radiography or CT scanning of the chest, reduces lung cancer mortality. SEARCH METHODS: We searched electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 5), MEDLINE (1966 to 2012), PREMEDLINE and EMBASE (to 2012) and bibliographies. We handsearched the journal Lung Cancer (to 2000) and contacted experts in the field to identify published and unpublished trials. SELECTION CRITERIA: Controlled trials of screening for lung cancer using sputum examinations, chest radiography or chest CT. DATA COLLECTION AND ANALYSIS: We performed an intention-to-screen analysis. Where there was significant statistical heterogeneity, we reported risk ratios (RRs) using the random-effects model. For other outcomes we used the fixed effect model. MAIN RESULTS: We included nine trials in the review (eight randomised controlled studies and one controlled trial) with a total of 453,965 subjects. In one large study that included both smokers and non-smokers comparing annual chest x-ray screening with usual care there was no reduction in lung cancer mortality (RR 0.99, 95% CI 0.91 to 1.07). In a meta-analysis of studies comparing different frequencies of chest x-ray screening, frequent screening with chest x-rays was associated with an 11% relative increase in mortality from lung cancer compared with less frequent screening (RR 1.11, 95% CI 1.00 to 1.23); however several of the trials included in this meta-analysis had potential methodological weaknesses. We observed a non-statistically significant trend to reduced mortality from lung cancer when screening with chest x-ray and sputum cytology was compared with chest x-ray alone (RR 0.88, 95% CI 0.74 to 1.03). There was one large methodologically rigorous trial in high-risk smokers and ex smokers (those aged 55 to 74 years with >= 30 pack-years of smoking and who quit <= 15 years prior to entry if ex-smokers) comparing annual low-dose CT screening with annual chest x-ray screening; in this study the relative risk of death from lung cancer was significantly reduced in the low-dose CT group (RR 0.80, 95% CI 0.70 to 0.92). AUTHORS' CONCLUSIONS: The current evidence does not support screening for lung cancer with chest radiography or sputum cytology. Annual low dose CT screening is associated with a reduction in lung cancer mortality in high risk smokers but further data are required on the cost effectiveness of screening and the relative harms and benefits of screening across a range of different risk groups and settings. PMID- 23794188 TI - Special issue on long-term ecotoxicological effects: an introduction. PMID- 23794189 TI - Metal accumulation in wild nine-banded armadillos. AB - Nine-banded armadillos (Dasypus novemcinctus) are widespread and abundant New World mammals with a lifestyle that entails prolonged, intimate contact with soils. Thus, armadillos would seem a promising candidate as a sentinel species to monitor chemical contamination in terrestrial ecosystems. Surprisingly, there have been virtually no toxicology studies on armadillos. Here, we provide the first analysis of metal contaminants for wild armadillos. Liver tissues were obtained from 302 armadillos collected at 6 sites in Georgia and Florida, USA that varied in their extent of human disturbance, from rural pine plantations to highly modified military/space installations. Data were stratified by age (juvenile and adult), sex, and site. Temporal (yearly) variation was examined at two of the sites that were sampled over three consecutive years. Concentrations of aluminum, cadmium, copper, nickel, lead, and zinc were measured in liver samples from each site. Although reference levels are not available for armadillos, accumulated metal concentrations were comparable to those reported for other mammals. We found no evidence of sex or age differences in the concentrations of any metal, except for Cd (age) and Pb (sex and age). However, concentrations of most metals varied substantially across sites and over time. Finally, concentrations of many metals were positively correlated with one another, suggesting that they likely co-occurred in some areas. Collectively, this study indicates the utility of armadillos as a sentinel species for studies of metal contamination in terrestrial systems, and highlights the need for further studies of other toxicants in these animals. PMID- 23794190 TI - The number needed to treat provides additional insight on the performance of detection points of asthma exacerbations in self-management plans: authors' response on behalf of the BIOAIR consortium. PMID- 23794191 TI - Moving from the Oslerian paradigm to the post-genomic era: are asthma and COPD outdated terms? AB - In the majority of cases, asthma and chronic obstructive pulmonary disease (COPD) are two clearly distinct disease entities. However, in some patients there may be significant overlap between the two conditions. This constitutes an important area of concern because these patients are generally excluded from randomised controlled trials (mostly because of smoking history in the case of asthma or because of significant bronchodilator reversibility in the case of COPD). As a result, their pathobiology, prognosis and response to therapy are largely unknown. This may lead to suboptimal management and can limit the development of more personalised therapeutic options. Emerging genetic and molecular information coupled with new bioinformatics capabilities provide novel information that can pave the way towards a new taxonomy of airway diseases. In this paper we question the current value of the terms 'asthma' and 'COPD' as still useful diagnostic labels; discuss the scientific and clinical progress made over the past few years towards unravelling the complexity of airway diseases, from the definition of clinical phenotypes and endotypes to a better understanding of cellular and molecular networks as key pathogenic elements of human diseases (so-called systems medicine); and summarise a number of ongoing studies with the potential to move the field towards a new taxonomy of airways diseases and, hopefully, a more personalised approach to medicine, in which the focus will shift from the current goal of treating diseases as best as possible to the so-called P4 medicine, a new type of medicine that is predictive, preventive, personalised and participatory. PMID- 23794192 TI - A non-interventional study of extended-release methylphenidate in the routine treatment of adolescents with ADHD: effectiveness, safety and adherence to treatment. AB - This multi-centre, open-label, non-interventional study evaluates effectiveness, safety and adherence to treatment of a specific extended-release methylphenidate with a 50 % immediate and a 50 % extended-release component (Medikinet((r)) retard) in the clinical routine treatment of 381 adolescents with ADHD and a mean age of 14.0 +/- 1.9 years. ADHD and associated psychiatric symptoms, medication status and dosage frequency, treatment adherence and adverse events were assessed at baseline and after a median treatment length with Medikinet((r)) retard of 70 days. Primary outcome criterion was the change of ADHD symptom severity from baseline to endpoint according to the ADHD-KGE (German: ADHS-Klinische Gesamteinschatzung) change score. At baseline, 4.2 % of the patients were treatment naive, 92.7 % had previously received different methylphenidate formulations and 3.1 % had received atomoxetine or amphetamine. During the study, patients received a mean daily dose of 35.7 +/- 15.1 mg Medikinet((r)) retard. At endpoint, in 78 % of patients, the total ADHD symptom severity was reduced, in 20.4 %, it remained unchanged and in 1.6 %, it was worsened. The mean ADHD-KGE total ADHD symptom score was reduced from 1.8 +/- 0.7 (moderate) at baseline to 0.8 +/- 0.5 (mild; p < 0.001) at endpoint; the mean ADHD-KGE total-associated symptom score was reduced from 1.9 +/- 0.7 (moderate) at baseline to 1.0 +/- 0.6 (mild; p < 0.0001) at endpoint. After the medication switch from previous methylphenidate formulation to Medikinet((r)) retard, multiple dosing with >=3 daily medication intakes was reduced from 12.9 % at baseline to 3.1 % at endpoint (p < 0.001). Adherence to treatment was improved in 37 % of patients. Most frequent adverse events were loss of appetite and gastrointestinal problems. The findings suggest that pharmacologically treated adolescents with ADHD and insufficient symptom reduction and/or treatment adherence benefit from switching to Medikinet((r)) retard and that it is well tolerated when given in clinical routine care. PMID- 23794193 TI - The use of computed tomography in determining developmental changes, anomalies, and trauma of the thyroid cartilage. AB - Recognition of injury to the hyoid bone and thyroid and cricoid cartilages is intrinsic to post-mortem examination. Due to its increasing brittleness with age the thyroid cartilage is particularly susceptible to injury following neck trauma, although there is inconsistency in the patterns of injury reported. In this study computed tomography scans of the head and neck of 431 deceased persons (235 males and 196 females) between the ages of 1 day and 100 years (mean age 35.93 +/- 24.15), and including 25 victims of hangings, were examined to reveal the pattern of age-related change and the types of injury that occurred. Thyroid cartilage anomalies likely to cause confusion and be misinterpreted as trauma related are documented. Angulation of the thyroid cartilage horns was found to change with age, and it is suggested this may be a significant factor in traumatic neck injury. Unlike in previous reports, the average age of hanging victims with fractures to the thyroid cartilage was 34 years. The base of the superior horn was the most common fracture site and in 50 % of hanging cases was associated with a ligature positioned on the thyrohyoid membrane or thyroid lamina. Although an age-related relationship exists it was not possible to establish narrow age-prediction ranges from calcification of the thyroid cartilage. PMID- 23794194 TI - Pm50: a new powdery mildew resistance gene in common wheat derived from cultivated emmer. AB - Fungal diseases of wheat, including powdery mildew, cause significant crop, yield and quality losses throughout the world. Knowledge of the genetic basis of powdery mildew resistance will greatly support future efforts to develop and cultivate resistant cultivars. Studies were conducted on cultivated emmer-derived wheat line K2 to identify genes involved in powdery mildew resistance at the seedling and adult plant growth stages using a BC(1) doubled haploid population derived from a cross between K2 and susceptible cultivar Audace. A single gene was located distal to microsatellite marker Xgwm294 on the long arm of chromosome 2A. Quantitative trait loci (QTL) analysis indicated that the gene was also effective at the adult plant stage, explaining up to 79.0 % of the variation in the progeny. Comparison of genetic maps indicated that the resistance gene in K2 was different from Pm4, the only other formally named resistance gene located on chromosome 2AL, and PmHNK54, a gene derived from Chinese germplasm. The new gene was designated Pm50. PMID- 23794195 TI - Bio-inspired materials science at its best--flexible mesocrystals of calcite. PMID- 23794196 TI - Subcutaneous cholera toxin exposure induces potent CD103+ dermal dendritic cell activation and migration. AB - CD103+ dermal dendritic cells (dDCs) are a recently described DC subset of the skin shown to be the principal migratory DCs capable of efficiently cross presenting antigens and activating CD8+ T cells. Harnessing their activity would promote vaccine efficacy, but it has been unclear how this can be achieved. We tested a panel of adjuvants for their ability to affect dDCs. In comparison to the other adjuvants tested, the capacity of cholera toxin (CT) to induce the migration of dDCs was unique. Within 24 h of CT injection, large numbers of highly activated dDCs (including CD103+ dDCs) migrated to the draining lymph nodes and cross-presented coinjected antigens, potently activating naive CD8+ T cells. Peptide vaccines adjuvanted with CT induced T-cell responses uniquely characterized by dynamic cytokine responses including the production of IL-2, and such vaccines were protective in situations reliant on CD8+ T-cell responses, including liver-stage Plasmodium challenge, or tumor challenge. This study is the first to examine the effects of adjuvants on CD103+ dDCs and identifies CT as a prototypical adjuvant for the activation of CD103+ dDCs, opening the way to development of vaccines and adjuvants that specifically target dDCs and generate effective CD8+ T-cell responses. PMID- 23794197 TI - A new method for protection from shower embolism during TEVAR on a shaggy aorta. AB - The case of a patient with a thoracoabdominal aortic aneurysm accompanied by a shaggy aorta, in whom embolism was prevented by a graft used in debranching and placement of an extracorporeal shunt during thoracic endovascular aortic repair, called the "block and trap method", is presented. Two-staged operations were performed using Y graft replacement, debranching bypass, and thoracic endovascular aortic repair during which a temporary shunt line with a blood filter was made involving the femoral artery and vein. The method of trapping emboli in a filter in an external shunt appears effective. PMID- 23794198 TI - Risk factors for treatment failure with antiosteoporosis medication: the global longitudinal study of osteoporosis in women (GLOW). AB - Antiosteoporosis medication (AOM) does not abolish fracture risk, and some individuals experience multiple fractures while on treatment. Therefore, criteria for treatment failure have recently been defined. Using data from the Global Longitudinal Study of Osteoporosis in Women (GLOW), we analyzed risk factors for treatment failure, defined as sustaining two or more fractures while on AOM. GLOW is a prospective, observational cohort study of women aged >=55 years sampled from primary care practices in 10 countries. Self-administered questionnaires collected data on patient characteristics, fracture risk factors, previous fractures, AOM use, and health status. Data were analyzed from women who used the same class of AOM continuously over 3 survey years and had data available on fracture occurrence. Multivariable logistic regression was used to identify independent predictors of treatment failure. Data from 26,918 women were available, of whom 5550 were on AOM. During follow-up, 73 of 5550 women in the AOM group (1.3%) and 123 of 21,368 in the non-AOM group (0.6%) reported occurrence of two or more fractures. The following variables were associated with treatment failure: lower Short Form 36 Health Survey (SF-36) score (physical function and vitality) at baseline, higher Fracture Risk Assessment Tool (FRAX) score, falls in the past 12 months, selected comorbid conditions, prior fracture, current use of glucocorticoids, need of arms to assist to standing, and unexplained weight loss >=10 lb (>=4.5 kg). Three variables remained predictive of treatment failure after multivariable analysis: worse SF-36 vitality score (odds ratio [OR] per 10-point increase, 0.85; 95% confidence interval [CI], 0.76 0.95; p = 0.004); two or more falls in the past year (OR, 2.40; 95% CI, 1.34 4.29; p = 0.011), and prior fracture (OR, 2.93; 95% CI, 1.81-4.75; p < 0.0001). The C statistic for the model was 0.712. Specific strategies for fracture prevention should therefore be developed for this subgroup of patients. PMID- 23794199 TI - Richieri-costa and Pereira syndrome: severe phenotype. AB - Richieri-Costa and Pereira syndrome, described in 1992, comprises short stature, Robin sequence, cleft mandible, limb malformations, and short larynx, deformed or lack of epiglottis, and abnormal aryepiglottic folds. There are 32 reported cases, only one described outside Brazil. We describe a 4-month-old boy with the most severe phenotype yet reported. PMID- 23794200 TI - T-tube drainage versus primary closure after open common bile duct exploration. AB - BACKGROUND: Between 5% and 11% of people undergoing cholecystectomy have common bile duct stones. Stones may be removed at the time of cholecystectomy by opening and clearing the common bile duct. The optimal technique is unclear. OBJECTIVES: The aim is to assess the benefits and harms of T-tube drainage versus primary closure without biliary stent after open common bile duct exploration for common bile duct stones. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until April 2013. SELECTION CRITERIA: We included all randomised clinical trials comparing T-tube drainage versus primary closure after open common bile duct exploration. DATA COLLECTION AND ANALYSIS: Two of four authors independently identified the studies for inclusion and extracted data. We analysed the data with both the fixed-effect and the random-effects model using Review Manager (RevMan) analyses. For each outcome we calculated the risk ratio (RR), rate ratio (RaR), or mean difference (MD) with 95% confidence interval (CI) based on intention-to-treat analysis. MAIN RESULTS: We included six trials randomising 359 participants, 178 to T-tube drainage and 181 to primary closure. All trials were at high risk of bias. There was no significant difference in mortality between the two groups (4/178 (weighted percentage 1.2%) in the T-tube group versus 1/181 (0.6%) in the primary closure group; RR 2.25; 95% CI 0.55 to 9.25; six trials). There was no significant difference in the serious morbidity rate between the two groups (24/136 (weighted serious morbidity rate, 145 events per 1000 patients) in the T-tube group versus 9/136 (weighted serious morbidity rate, 66 events per 1000 patients) in the primary closure group; RaR 2.19; 95% CI 0.98 to 4.91; four trials). Quality of life and return to work were not reported in any of the trials. The operating time was significantly longer in the T-tube drainage group compared with the primary closure group (MD 28.90 minutes; 95% CI 17.18 to 40.62 minutes; one trial). The hospital stay was significantly longer in the T-tube drainage group compared with the primary closure group (MD 4.72 days; 95% CI 0.83 days to 8.60 days; five trials). AUTHORS' CONCLUSIONS: T-tube drainage appeared to result in significantly longer operating time and hospital stay compared with primary closure without any apparent evidence of benefit on clinically important outcomes after open common bile duct exploration. Based on the currently available evidence, there is no justification for the routine use of T-tube drainage after open common bile duct exploration in patients with common bile duct stones. T-tube drainage should not be used outside well designed randomised clinical trials. More randomised trials comparing the effects of T tube drainage versus primary closure after open common bile duct exploration may be needed. Such trials should be conducted with low risk of bias and assessing the long-term beneficial and harmful effects of T-tube drainage, including long term complications such as bile stricture and recurrence of common bile duct stones. PMID- 23794201 TI - T-tube drainage versus primary closure after laparoscopic common bile duct exploration. AB - BACKGROUND: T-tube drainage may prevent bile leak from the biliary tract following bile duct exploration and it offers post-operative access to the bile ducts for visualisation and exploration. Use of T-tube drainage after laparoscopic common bile duct (CBD) exploration is controversial. OBJECTIVES: To assess the benefits and harms of T-tube drainage versus primary closure after laparoscopic common bile duct exploration. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until April 2013. SELECTION CRITERIA: We included all randomised clinical trials comparing T-tube drainage versus primary closure after laparoscopic common bile duct exploration. DATA COLLECTION AND ANALYSIS: Two of four authors independently identified the studies for inclusion and extracted data. We analysed the data with both the fixed-effect and the random-effects model meta-analyses using Review Manager (RevMan) Analysis. For each outcome we calculated the risk ratio (RR), rate ratio (RaR), or mean difference (MD) with 95% confidence intervals (CI) based on intention-to treat analysis. MAIN RESULTS: We included three trials randomising 295 participants: 147 to T-tube drainage versus 148 to primary closure. All trials had a high risk of bias. No one died during the follow-up period. There was no significant difference in the proportion of patients with serious morbidity (17/147 (weighted percentage 11.3%) in the T-tube drainage versus 9/148 (6.1%) in the primary closure group; RR 1.86; 95% CI 0.87 to 3.96; three trials), and no significant difference was found in the serious morbidity rates (weighted serious morbidity rate = 97 events per 1000 patients) in participants randomised to T tube drainage versus serious morbidity rate = 61 events per 1000 patients in the primary closure group; RR 1.59; 95% CI 0.66 to 3.83; three trials). Quality of life was not reported in any of the trials. The operating time was significantly longer in the T-tube drainage group compared with the primary closure group (MD 21.22 minutes; 95% CI 12.44 minutes to 30.00 minutes; three trials). The hospital stay was significantly longer in the T-tube drainage group compared with the primary closure group (MD 3.26 days; 95% CI 2.49 days to 4.04 days; three trials). According to one trial, the participants randomised to T-tube drainage returned to work approximately eight days later than the participants randomised to the primary closure group (P < 0.005). AUTHORS' CONCLUSIONS: T-tube drainage appears to result in significantly longer operating time and hospital stay as compared with primary closure without any evidence of benefit after laparoscopic common bile duct exploration. Based on currently available evidence, there is no justification for the routine use of T-tube drainage after laparoscopic common bile duct exploration in patients with common bile duct stones. More randomised trials comparing the effects of T-tube drainage versus primary closure after laparoscopic common bile duct exploration may be needed. Such trials should be conducted with low risk of bias, assessing the long-term beneficial and harmful effects including long-term complications such as bile stricture and recurrence of common bile duct stones. PMID- 23794204 TI - Reactions templated by nucleic acids: more ways to translate oligonucleotide based instructions into emerging function. AB - The programmability of oligonucleotide recognition offers an attractive platform to direct the assembly of reactive partners that can engage in chemical reactions. Recently, significant progress has been made in both the breadth of chemical transformations and in the functional output of the reaction. Herein we summarize these recent progresses and illustrate their applications to translate oligonucleotide instructions into functional materials and novel architectures (conductive polymers, nanopatterns, novel oligonucleotide junctions); into fluorescent or bioactive molecule using cellular RNA; to interrogate secondary structures or oligonucelic acids; or a synthetic oligomer. PMID- 23794205 TI - Ultrafast solvent-assisted electronic level crossing in 1-naphthol. PMID- 23794206 TI - Outcome measurements in obstructive sleep apnea: beyond the apnea-hypopnea index. AB - OBJECTIVES/HYPOTHESIS: The apnea-hypopnea index (AHI) is overwhelmingly used as the main therapeutic metric in the assessment of obstructive sleep apnea (OSA) in surgical studies. However, using AHI as the sole measure is problematic. This study investigates the utility of other outcome measures for patients with OSA undergoing surgery. STUDY DESIGN: Systematic review of cohort and review studies. METHODS: A review was performed using the PubMed database. English articles focusing on outcome measures in adults with OSA were included. Studies in pediatric populations, those combining obstructing and central sleep apnea, and those without the use of outcome measures were excluded. Articles were categorized according to level of evidence. The Downs and Black scale and AMSTAR scale were used to assess quality. RESULTS: Of a total of 10,454 retrieved articles, 21 studies met inclusion and exclusion criteria. Most articles related to continuous positive airway pressure outcomes. Many categories of outcome measures were found: general quality of life, OSA-specific quality of life, measurements of sleepiness, performance, and physiological. Subjects with OSA scored differently in measurement tools in all categories compared to control populations or after treatment, and generally a poor correlation with AHI was seen. CONCLUSIONS: The literature shows a range of tools based on symptoms and physiology of OSA that can assess effects of treatment. Assessment of surgical treatment for OSA should neither be limited to AHI as an outcome, nor should this be the only outcome stressed. PMID- 23794207 TI - Migration of CXCR4 gene-modified bone marrow-derived mesenchymal stem cells to the acute injured kidney. AB - Bone marrow-derived mesenchymal stem cells (BMSCs) can migrate to the injured kidney after acute kidney injury (AKI) with limited efficiency. This study investigated the effect of CXCR4 overexpression on BMSC migration to the AKI kidney and the possible mechanisms. CXCR4 gene-modified BMSCs (CXCR4-BMSCs) and null-BMSCs were prepared and transplanted into the AKI mice. Blood indicators, histology, expression of stromal cell-derived factor 1 (SDF-1), and BMSC migration were investigated. Hypoxia/re-oxygenation-pretreated renal tubular epithelial cells (HR-RTECs) were prepared to generate AKI in vitro. The chemotaxis experiment was performed using the transwell chamber. The phosphorylation of AKT and MAPK in the BMSCs was also investigated. The CXCR4 BMSCs showed a remarkable expression of CXCR4. The SDF-1 expression in the AKI renal tissue was increased. CXCR4-BMSCs transplantation sharply increased the accumulation of BMSCs in the renal tissue, which was consistent with a greater improvement of renal function. The in vitro experiments showed that the migration of BMSCs to the HR-RTEC culturing chamber was CXCR4-dependent, and could be fully inhibited by AMD3100, a CXCR4-specific antagonist. The migration could also be partly blocked by either LY294002 (PI3K inhibitor) or PD98059 (MAPK inhibitor). Phosphorylated Akt and MAPK were increased in the BMSCs co-cultured with HR-RTECs and their expression was the highest in the CXCR4-BMSCs, which could be recovered by AMD3100. Overexpression of CXCR4 gene could enhance BMSC migration to the kidney area after AKI. The SDF-1/CXCR4 axis via its activation of PI3K/AKT and MAPK in BMSCs could be the possible mechanisms underlying this function. PMID- 23794208 TI - Ultrahigh pressure fast size exclusion chromatography for top-down proteomics. AB - Top-down MS-based proteomics has gained a solid growth over the past few years but still faces significant challenges in the LC separation of intact proteins. In top-down proteomics, it is essential to separate the high mass proteins from the low mass species due to the exponential decay in S/N as a function of increasing molecular mass. SEC is a favored LC method for size-based separation of proteins but suffers from notoriously low resolution and detrimental dilution. Herein, we reported the use of ultrahigh pressure (UHP) SEC for rapid and high resolution separation of intact proteins for top-down proteomics. Fast separation of intact proteins (6-669 kDa) was achieved in < 7 min with high resolution and high efficiency. More importantly, we have shown that this UHP-SEC provides high resolution separation of intact proteins using a MS-friendly volatile solvent system, allowing the direct top-down MS analysis of SEC-eluted proteins without an additional desalting step. Taken together, we have demonstrated that UHP-SEC is an attractive LC strategy for the size separation of proteins with great potential for top-down proteomics. PMID- 23794209 TI - Metallothionein 3: an androgen-upregulated gene enhances cell invasion and tumorigenesis of prostate carcinoma cells. AB - BACKGROUND: Metallothioneins (MT1, MT2, MT3, and MT4) are regarded as modulators regulating a number of biological processes including cell proliferation, differentiation, and invasion. We determined the effects of androgen, cadmium, and arsenic on MT1/2 and MT3 in prostate carcinoma cells, and evaluated the functional effects of MT3 on cell proliferation, invasion, and tumorigenesis. METHODS: We determined the expression of MT1/2 and MT3 in prostate carcinoma cells by immunoblotting assays or real-time reverse transcription-polymerase chain reactions. The effects of ectopic MT3 overexpression or MT3-knockdown on cell proliferation, invasion, and tumorigenesis were determined by (3) H thymidine incorporation, matrigel invasion, and murine xenograft studies. The effects of androgen, cadmium, and arsenic on target genes were assessed using immunoblotting and reporter assays. RESULTS: Androgen, cadmium, and arsenic treatments enhanced gene expression of MT1/2 and MT3 in prostate carcinoma LNCaP cells. Results of immunohistochemical staining indicated MT3 overexpression was found predominantly in the nuclear areas of PC-3 cells overexpressing MT3. Overexpression of MT3 significantly increased cell proliferation, invasion, and tumorigenic activities in PC-3 cells in vitro and in vivo. MT3 overexpression downregulated the gene expressions of N-myc downstream regulated gene 1 (Ndrg1) and maspin, and attenuated blocking effects of doxorubicin in PC-3 cells on cell proliferation. MT3-knockdown enhanced Ndrg1 and maspin expressions in LNCaP cells. CONCLUSIONS: The experiments indicate that MT3 is an androgen-upregulated gene, and promotes tumorigenesis of prostate carcinoma cells. The downregulation of Ndrg1 and maspin gene expressions appears to account for the enhancement of proliferative and invasive functions of MT3 in PC-3 cells. PMID- 23794210 TI - Visual discrimination thresholds for time to arrival. AB - In a seminal article, Todd (Journal of Experimental Psychology: Human Perception and Performance 7:795-810, 1981) reported a difference threshold of about 50 ms to discriminate the times of arrival of two differently sized objects that simultaneously approached head-on at constant but different velocities. Subsequent investigators, however, have often found much higher thresholds. We did one complete replication of Todd's experiment, and then modified his stimuli and experimental regime, which we hypothesized may have been responsible for some of the discrepancies reported in the literature. Unlike Todd and most other researchers, we exclusively used untrained observers. Several of our participants performed almost as well as the trained observers used by Todd and others, but the performance of most of our participants fell short of this standard. Furthermore, thresholds were affected by the experimental regimes, with large differences between objects' sizes and speeds compromising performance. Analyses of the response patterns revealed that the responses were driven mainly by the objects' relative apparent sizes. PMID- 23794212 TI - Tetraaryl ZnII porphyrinates substituted at beta-pyrrolic positions as sensitizers in dye-sensitized solar cells: a comparison with meso-disubstituted push-pull Zn(II) porphyrinates. AB - A facile and fast approach, based on microwave-enhanced Sonogashira coupling, has been employed to obtain in good yields both mono- and, for the first time, disubstituted push-pull Zn(II) porphyrinates bearing a variety of ethynylphenyl moieties at the beta-pyrrolic position(s). Furthermore, a comparative experimental, electrochemical, and theoretical investigation has been carried out on these beta-mono- or disubstituted Zn(II) porphyrinates and meso-disubstituted push-pull Zn(II) porphyrinates. We have obtained evidence that, although the HOMO LUMO energy gap of the meso-substituted push-pull dyes is lower, so that charge transfer along the push-pull system therein is easier, the beta-mono- or disubstituted push-pull porphyrinic dyes show comparable or better efficiencies when acting as sensitizers in DSSCs. This behavior is apparently not attributable to more intense B and Q bands, but rather to more facile charge injection. This is suggested by the DFT electron distribution in a model of a beta monosubstituted porphyrinic dye interacting with a TiO2 surface and by the positive effect of the beta substitution on the incident photon-to-current conversion efficiency (IPCE) spectra, which show a significant intensity over a broad wavelength range (350-650 nm). In contrast, meso-substitution produces IPCE spectra with two less intense and well-separated peaks. The positive effect exerted by a cyanoacrylic acid group attached to the ethynylphenyl substituent has been analyzed by a photophysical and theoretical approach. This provided supporting evidence of a contribution from charge-transfer transitions to both the B and Q bands, thus producing, through conjugation, excited electrons close to the carboxylic anchoring group. Finally, the straightforward and effective synthetic procedures developed, as well as the efficiencies observed by photoelectrochemical measurements, make the described beta-monosubstituted Zn(II) porphyrinates extremely promising sensitizers for use in DSSCs. PMID- 23794214 TI - Effects of obesity on functional capacity. AB - OBJECTIVE: To assess the relationships between BMI and walking speed, balance control, sit-to-stand performance (a measure of mass specific lower limb power), and endurance. DESIGN AND METHODS: Thirty-six women with a BMI >= 30 kg/m(2) and 10 women with normal body weight (BMI between 18 kg/m(2) and 25 kg/m(2) ) were enrolled in this observational study. The obese group comprised 12 persons with a BMI >= 30 and <35 (obese), 14 subjects with a BMI >= 35 and <40 (severe obesity) and 10 people with a BMI >= 40 kg/m(2) (morbid obesity). All subjects underwent a clinical examination, a gait test, an endurance test (6 minutes walking test), a mass specific lower limb power test (five times sit-to-stand) and a balance test. RESULTS: Obese women exhibited slower fast gait speeds (P < 0.05) with correspondingly shorter stride lengths, poorer sit-to-stand performance (P < 0.05), and endurance (P < 0.05). However, once the state of severe obesity was reached, additional weight gain (morbid obesity) does not seem to decrease these functional capacities any further. CONCLUSION: This study underlines the importance of assessing obese patients' related physical problems in an early stage of obesity in order to focus exercise regimens and promote appropriate health behaviors. PMID- 23794213 TI - Complications of varicella zoster virus reactivation. AB - OPINION STATEMENT: Varicella zoster virus (VZV) is an exclusively human neurotropic alphaherpesvirus. Primary infection causes varicella (chickenpox), after which virus becomes latent in ganglionic neurons along the entire neuraxis. With advancing age or immunosuppression, cell-mediated immunity to VZV declines and virus reactivates to cause zoster (shingles), which can occur anywhere on the body. Skin lesions resolve within 1-2 weeks, while complete cessation of pain usually takes 4-6 weeks. Zoster can be followed by chronic pain (postherpetic neuralgia), cranial nerve palsies, zoster paresis, meningoencephalitis, cerebellitis, myelopathy, multiple ocular disorders and vasculopathy that can mimic giant cell arteritis. All of the neurological and ocular disorders listed above may also develop without rash. Diagnosis of VZV-induced neurological disease may require examination of cerebrospinal fluid (CSF), serum and/ or ocular fluids. In the absence of rash in a patient with neurological disease potentially due to VZV, CSF should be examined for VZV DNA by PCR and for anti VZV IgG and IgM. Detection of VZV IgG antibody in CSF is superior to detection of VZV DNA in CSF to diagnose vasculopathy, recurrent myelopathy, and brainstem encephalitis. Oral antiviral drugs speed healing of rash and shorten acute pain. Immunocompromised patients require intravenous acyclovir. First-line treatments for post-herpetic neuralgia include tricyclic antidepressants, gabapentin, pregabalin, and topical lidocaine patches. VZV vasculopathy, meningoencephalitis, and myelitis are all treated with intravenous acyclovir. PMID- 23794215 TI - Reversible dihydrogen activation in cationic rare-earth-metal polyhydride complexes. PMID- 23794216 TI - Thymoquinone attenuates astrogliosis, neurodegeneration, mossy fiber sprouting, and oxidative stress in a model of temporal lobe epilepsy. AB - Temporal lobe epilepsy (TLE) is a rather common and difficult-to-treat variant of epilepsy. Nearly one third of people with epilepsy do not respond effectively to currently available anticonvulsants. In this study, we evaluated the protective effect of thymoquinone (TQ), the main constituent of black seed with antioxidant and anti-inflammatory effects, in the intrahippocampal kainate model of TLE in rat. Following kainate injection, seizure activity was observed that was significantly diminished by TQ pretreatment at a dose of 10 mg/kg, p.o. Intrahippocampal kainate also increased malondialdehyde (MDA), nitrite, and nitrate levels and decreased activity of superoxide dismutase and TQ only significantly attenuated MDA. In addition, intrahippocampal kainate caused a significant reduction of neurons in CA1, CA3 and the hilar regions, and TQ significantly attenuated these changes. Timm histochemistry showed a marked mossy fiber sprouting (MFS) in the dentate gyrus of kainate-lesioned rats, and TQ significantly lowered MFS intensity. Meanwhile, a number of reactive astrocytes (astrogliosis) increased significantly in the kainate group, and TQ pretreatment significantly decreased it. These data suggest that TQ pretreatment could attenuate seizure activity and lipid peroxidation, lower hippocampal neuronal loss and MFS, and mitigate astrogliosis in kainate model of TLE. PMID- 23794217 TI - Genome-wide pathway analysis in major depressive disorder. AB - The aims of this study were: (1) to identify candidate single-nucleotide polymorphisms (SNPs) and mechanisms of major depressive disorder (MDD) and (2) to generate SNP-to-gene-to-pathway hypotheses. An MDD genome-wide association study (GWAS) data set that included 365,419 SNPs in 1,821 MDD cases and 1,822 controls of European descent was used in this study. Identify Candidate Causal SNPs and Pathway (ICSNPathway) analysis was applied to the GWAS dataset. ICSNPathway analysis identified 21 candidate SNPs, 16 genes, and 5 pathways, which provided 16 hypothetical biological mechanisms. The strongest hypothetical biological mechanism was that rs3213764 alters the role of ATF7IP in the context of the pathways of negative regulation of transcription, negative regulation of nucleobase, nucleoside, nucleotide, and nucleic acid metabolic processes and negative regulation of gene expression (nominal p < 0.001, FDR = 0.043, 0.044, and 0.046, respectively). Five of 16 candidate genes are known to be associated with inflammatory or immune response that may be associated with MDD: ANPEP, PRDM1, ZBTB32, MMP8, and ENPEP. By applying the ICSNPathway analysis to the MDD GWAS data, 21 candidate SNPs, 16 genes that included ATF7IP, ANPEP, PRDM1, ZBTB32, MMP8, and ENPEP, and 5 pathways that involved negative regulation of transcription and nucleic acid metabolism were identified that may contribute to MDD susceptibility. PMID- 23794218 TI - A versatile fiber-optic fluorescence sensor based on molecularly imprinted microstructures polymerized in situ. PMID- 23794219 TI - Resveratrol attenuates radiation-induced salivary gland dysfunction in mice. AB - OBJECTIVES/HYPOTHESIS: In our study we investigated the radioprotective effect of resveratrol (RES) in a murine model of radiation-induced salivary gland dysfunction. STUDY DESIGN: Ninety-six Institute of Cancer Research mice were randomly divided into four groups: solvent (group I), RES treated (group II; 20 mg/kg/d), 15 Gy irradiation with solvent treatment (group III), and 15 Gy irradiation with RES treatment (group IV; 15 Gy and 20 mg/kg/d RES). RES (group II and IV) was administered intraperitoneally 3 days prior to irradiation through the conclusion of the experiment. METHODS: Saliva and submandibular gland tissues were obtained for biochemical, morphological, immunohistochemical, and Western blot analyses at 8 hours, 24 hours, and 30 days after localized irradiation. RESULTS: Radiation caused a reduction of saliva secretion, salivary amylase activity, superoxide dismutase, and an elevation of malondialdehyde. Administration of RES reversed the reduction of saliva secretion induced by irradiation and restored salivary amylase and superoxide dismutase activity. In addition, RES could inhibit increases in transforming growth factor-beta1 expression induced by radiation. CONCLUSIONS: RES can protect salivary glands against the negative effects of irradiation and has great potential as a treatment for successful radiotherapy in clinical practice. PMID- 23794220 TI - GAPO syndrome associated with vestibular dysfunction and hearing loss. PMID- 23794221 TI - Autophagy and senescence in cancer therapy. AB - Autophagy and senescence have multiple and often overlapping and complementary functions in cancer, both in terms of influencing tumor development and in modulating the response to chemotherapy and/or radiation. However, while there is evidence that autophagy induction may accelerate the development of senescence, other studies suggest precisely the opposite, that autophagy inhibition is permissive for senescence. Furthermore, even in those cases where autophagy and senescence appear to occur in tandem, it is clear that the two responses are not interdependent. An additional attribute of senescent cells, both tumor cells and fibroblasts, is the secretion of factors that may influence the growth and/or survival of other cells through paracrine mechanisms. The nature of the secreted factors which mediate these bystander effects remain to be conclusively determined, particularly since senescent fibroblasts and senescent tumor cells appear to exhibit different paracrine functions. Tumor cells tend to secrete factors that promote senescence in "bystander" tumor cells while, conversely, different molecules discharged from tumor-associated fibroblasts can accelerate tumor growth and metastasis. An understanding of the relationship between autophagy induction and the senescence secretory phenotype in both tumor cells and fibroblasts is likely to be relevant to current clinical efforts to exploit autophagy inhibition as a therapeutic strategy for enhancing the response of malignancies to chemotherapy or radiotherapy. PMID- 23794222 TI - Effects of metal binding on solubility and resistance of physiological prions depend on tissues and glycotypes. AB - Prion diseases entail the conversion of a normal host-encoded prion protein (PrP(C)) into an infectious isoform (PrP(Sc)). Various PrP(C) types differing in banding profiles and detergent solubility are present in different tissues, but only few PrP(Sc) types have been generated although PrP(C) acts as substrate. We hypothesize that distinct PrP(C) subtypes may be converted more efficiently to PrP(Sc) than others. One prerequisite for the analysis is the identification of the PrP(C) subtypes present in the protein complexes. Metal binding to PrP(C) is one of the most prominent features of the protein which induces increased proteolysis resistance and structural changes which might play an important role in the conversion process. Here we analyzed the metal-induced structural PrP(C) transformation of two different Triton X-100 soluble PrP(C) types derived from human platelets and brains by changes in protein solubility. We found that zinc and copper rendered approximately half of total PrP(C) and mainly un- and low glycosylated PrP(C) to the Triton insoluble fraction. Our results indicate the presence of at least two distinct PrP(C) subtypes by metal interactions. The differentiation of high and low soluble metal bound PrP(C) offers precious information about PrP(C) protein composition and provides approaches for analyzing the transformation efficiency to PrP(Sc). PMID- 23794223 TI - Common versus noble Bacillus subtilis differentially responds to air and argon gas plasma. AB - The applications of low-temperature plasma are not only confined to decontamination and sterilization but are also found in the medical field in terms of wound and skin treatment. For the improvement of already established and also for new plasma techniques, in-depth knowledge on the interactions between plasma and microorganism is essential. In an initial study, the interaction between growing Bacillus subtilis and argon plasma was investigated by using a growth chamber system suitable for low-temperature gas plasma treatment of bacteria in liquid medium. In this follow-up investigation, a second kind of plasma treatment-namely air plasma-was applied. With combined proteomic and transcriptomic analyses, we were able to investigate the plasma-specific stress response of B. subtilis toward not only argon but also air plasma. Besides an overlap of cellular responses due to both argon and air plasma treatment (DNA damage and oxidative stress), a variety of gas-dependent cellular responses such as growth retardation and morphological changes were observed. Only argon plasma treatments lead to a phosphate starvation response whereas air plasma induced the tryptophan operon implying damage by photooxidation. Biological findings were supported by the detection of reactive plasma species by optical emission spectroscopy and Fourier transformed infrared spectroscopy measurements. PMID- 23794224 TI - Gain of employment and depressive symptoms among previously unemployed workers: a longitudinal cohort study in South Korea. AB - BACKGROUND: The goal of this study is to examine the association between gain of employment and depressive symptoms among previously unemployed workers in South Korea. METHODS: Using data from the on-going Korean Welfare Panel Study, we determined four different employment statuses (i.e., unemployment, part-time precarious, full-time precarious, full-time permanent employment) at follow up (2008 or 2010) among the unemployed at baseline (2007 or 2009) and examined their association with depressive symptoms after excluding the people with depressive symptoms at baseline (N = 308). Depressive symptoms were assessed annually using the 11-item Center for Epidemiologic Studies Depression Scale. RESULTS: After adjusting for covariates including health-related variables, unemployed individuals who gained full-time permanent employment (RR: 0.38, 95% CI: 0.18, 0.83) and those who gained full-time precarious employment (RR: 0.26, 95% CI: 0.11, 0.63) were less likely to have depressive symptoms compared to those with persistent unemployment. In a subpopulation analysis conducted after additionally excluding the people with depressive symptoms 1 year before baseline, only the association between gaining full-time permanent employment and depressive symptoms was significant (RR: 0.27, 95% CI: 0.08, 0.86). CONCLUSIONS: Our findings highlight the benefits of full-time permanent employment on worker's mental health. PMID- 23794226 TI - School-based obesity prevention programs: a meta-analysis of randomized controlled trials. AB - OBJECTIVE: Attempts have been made to reduce childhood obesity through school based programs. Systematic reviews of studies until 2006 reported a lack of consistency about effectiveness of such programs. Presented is an updated systematic review and meta-analysis. DESIGN AND METHODS: Replication of methodology used in previous comprehensive systematic review and meta-analysis of randomized controlled trials of school-based obesity prevention programs covering studies until 2006 to review studies thru January 2012. RESULTS: Based on 32 studies (n = 52,109), programs were mildly effective in reducing BMI relative to controls not receiving intervention. Studies of children had significant intervention effects, those of teenagers did not, though the difference between the two groups was not statistically significant. Meta-regression showed a significant linear hierarchy of studies with the largest effects for comprehensive programs more than 1 year long that aimed to provide information on nutrition and physical activity, change attitudes, monitor behavior, modify environment, involve parents, increase physical activity and improve diet, particularly among children. CONCLUSIONS: Unlike earlier studies, more recent studies showed convincing evidence that school-based prevention interventions are at least mildly effective in reducing BMI in children, possibly because these newer studies tended to be longer, more comprehensive and included parental support. PMID- 23794225 TI - Femoral and vertebral strength improvements in postmenopausal women with osteoporosis treated with denosumab. AB - In the randomized, placebo-controlled FREEDOM study of women aged 60 to 90 years with postmenopausal osteoporosis, treatment with denosumab once every 6 months for 36 months significantly reduced hip and new vertebral fracture risk by 40% and 68%, respectively. To gain further insight into this efficacy, we performed a nonlinear finite element analysis (FEA) of hip and spine quantitative computed tomography (QCT) scans to estimate hip and spine strength in a subset of FREEDOM subjects (n = 48 placebo; n = 51 denosumab) at baseline, 12, 24, and 36 months. We found that, compared with baseline, the finite element estimates of hip strength increased from 12 months (5.3%; p < 0.0001) and through 36 months (8.6%; p < 0.0001) in the denosumab group. For the placebo group, hip strength did not change at 12 months and decreased at 36 months (-5.6%; p < 0.0001). Similar changes were observed at the spine: strength increased by 18.2% at 36 months for the denosumab group (p < 0.0001) and decreased by -4.2% for the placebo group (p = 0.002). At 36 months, hip and spine strength increased for the denosumab group compared with the placebo group by 14.3% (p < 0.0001) and 22.4% (p < 0.0001), respectively. Further analysis of the finite element models indicated that strength associated with the trabecular bone was lost at the hip and spine in the placebo group, whereas strength associated with both the trabecular and cortical bone improved in the denosumab group. In conclusion, treatment with denosumab increased hip and spine strength as estimated by FEA of QCT scans compared with both baseline and placebo owing to positive treatment effects in both the trabecular and cortical bone compartments. These findings provide insight into the mechanism by which denosumab reduces fracture risk for postmenopausal women with osteoporosis. PMID- 23794227 TI - Short-term in vitro culturing improves transplantability of type A spermatogonia in rainbow trout (Oncorhynchus mykiss). AB - Continuous production of sperm within the testes is supported by spermatogonial stem cells capable of both self-renewal and the production of numerous differentiated germ cells. We previously demonstrated that a subpopulation of trout type A spermatogonia transplanted into the body cavity of a recipient embryo incorporated into the genital ridge, where they produced functional gametes within the gonads. Various cell-surface proteins could have played a role in the incorporation of spermatogonia into recipient genital ridges. During the preparation of cell suspensions for transplantation in our experimental protocol, however, dissociation of testis by strong proteases was unavoidable. This was problematic as cell-surface proteins may have been at least partially digested by protease activity. In the present study, recovery of spermatogonial surface proteins using short-term culture prior to transplantation was attempted. It was found that spermatogonia cultured in vitro could be harvested by ethylenediaminetetraacetic acid (EDTA) instead of protease treatment. Furthermore, when cultured spermatogonia collected by EDTA treatment were maintained for 24 hr in vitro, they exhibited high adhesiveness. These cultured spermatogonia also possessed higher survival of transplantation compared to spermatogonia newly dispersed by trypsin treatment. These results indicated that spermatogonia possess a reduced ability to migrate toward, adhere to, and/or be incorporated into the recipient genital ridge immediately after protease treatment. Short-term in vitro culturing, however, could allow spermatogonia to recover the surface proteins required for successful incorporation into the recipient genital ridge. PMID- 23794228 TI - Investigation of electron behavior in Nano-TiO2 photocatalysis by using in situ open-circuit voltage and photoconductivity measurements. AB - The in situ open-circuit voltages (Voc ) and the in situ photoconductivities have been measured to study electron behavior in photocatalysis and its effect on the photocatalytic oxidation of methanol. It was observed that electron injection to the conduction band (CB) of TiO2 under light illumination during photocatalysis includes two sources: from the valence band (VB) of TiO2 and from the methanol molecule. The electron injection from methanol to TiO2 is slower than that directly from the VB, which indicates that the adsorption mode of methanol on the TiO2 surface can change between dark and illuminated states. The electron injection from methanol to the CB of TiO2 leads to the upshift of the Fermi level of electrons in TiO2 , which is the thermodynamic driving force of photocatalytic oxidation. It was also found that the charge state of nano-TiO2 is continuously changing during photocatalysis as electrons are injected from methanol to TiO2 . Combined with the apparent Langmuir-Hinshelwood kinetic model, the relation between photocatalytic kinetics and electrons in the TiO2 CB was developed and verified experimentally. The photocatalytic rate constant is the variation of the Fermi level with time, based on which a new method was developed to calculate the photocatalytic kinetic rate constant by monitoring the change of Voc with time during photocatalysis. PMID- 23794229 TI - Workplace psychosocial factors associated with work-related injury absence: a study from a nationally representative sample of Korean workers. AB - BACKGROUND: Little is known about the association between psychosocial factors and injury absence in the workplace. PURPOSE: This study aims to assess the association of comprehensive workplace psychosocial factors with work-related injury absence among Korean workers. METHODS: The data (n = 7,856) were derived from the First Korean Working Conditions Survey conducted in 2006 with a representative sample (n = 10,043) of the Korean working population. The survey instrument contained questions about hours of work, physical risk factors, work organization, and the effect of work on health/injury. Work-related injury absence was indicated by a dichotomous variable with at least 1 day absence during the preceding 12 months. Logistic regression models were used to calculate odds ratio and confidence interval (CI). Incremental adjustments for sociodemographic, health behavior, and occupational confounding variables were employed in the models. RESULTS: The overall 1-year prevalence of work-related injury absence in this study was 1.37 % (95 % CI, 1.11-1.63 %). Those who experienced violence at work (adjusted odds ratio (aOR), 7.05 (95 % CI, 2.69 18.5)), threat of violence at work (aOR, 4.25 (95 % CI, 1.32-13.64)), low job autonomy (aOR, 1.79 (95 % CI, 1.17-2.74)), and high job strain (aOR, 2.38 (95 % CI, 1.29-4.42) had an increased risk of injury absence, compared with their respective counterparts (p < 0.05). Among all job types, skilled workers in Korea were at a near fourfold risk of work absence due to occupational injuries, compared with managers in low-risk jobs. CONCLUSION: Workplace violence and increased job strain were two key workplace psychosocial factors associated with work-related injury absence. PMID- 23794230 TI - Combined percutaneous ultrasound and fluoroscopic-guided recanalization of Stensen's duct. PMID- 23794231 TI - Generation of organolithium compounds bearing super silyl ester and their application to Matteson rearrangement. PMID- 23794232 TI - Heparanase expression correlates with poor survival in oral mucosal melanoma. AB - Oral mucosal melanoma (OMM) is a lethal cancer with a poor prognosis. Despite the great interest in heparanase (HPSE) as a potential anticancer therapy target, the prognostic role of HPSE in oral mucosal melanoma has not been elucidated. In this study, we investigated HPSE expression in OMM tissues and examined its association with clinical outcome. A total of 81 patients with OMM were enrolled in this study. We examined the expression of HPSE in OMM, and its staining extent, intensity and cellular localization were analyzed for clinical significance. HPSE staining was positive in 81 % of tumors (66 of 81 patients) and was negative in the remaining 19 % (15 patients). The median survival time and the 5-year survival rate were 12 months and 7.0 % in the high-heparanase group, 35 months and 36.4 % in the low-heparanase group and 62 months and 53.3 % in the none-heparanase group (P = 0.001). In univariate survival analysis of oral mucosal melanoma, AJCC Stage, heparanase level, heparanase location and tumor size were the clinical parameters related to overall survival. In Cox analysis, overall survival time was significantly dependent on AJCC stage and heparanase level, but not tumor size and heparanase location. Heparanase is frequently expressed in oral mucosal melanoma, and its expression levels inversely correlate with the survival rates of OMM patients, clearly indicating that heparanase is a reliable prognostic factor for this malignancy and an attractive target for anticancer drug development. PMID- 23794233 TI - Noncovalent interactions in organocatalysis: modulating conformational diversity and reactivity in the MacMillan catalyst. PMID- 23794234 TI - Retraction note to: Local and global effects of motivation on cognitive control. Cognitive, Affective, & Behavioral Neuroscience, 12(4): 2012, 692-718. PMID- 23794235 TI - Shared knowledge or shared affordances? Insights from an ecological dynamics approach to team coordination in sports. AB - Previous research has proposed that team coordination is based on shared knowledge of the performance context, responsible for linking teammates' mental representations for collective, internalized action solutions. However, this representational approach raises many questions including: how do individual schemata of team members become reformulated together? How much time does it take for this collective cognitive process to occur? How do different cues perceived by different individuals sustain a general shared mental representation? This representational approach is challenged by an ecological dynamics perspective of shared knowledge in team coordination. We argue that the traditional shared knowledge assumption is predicated on 'knowledge about' the environment, which can be used to share knowledge and influence intentions of others prior to competition. Rather, during competitive performance, the control of action by perceiving surrounding informational constraints is expressed in 'knowledge of' the environment. This crucial distinction emphasizes perception of shared affordances (for others and of others) as the main communication channel between team members during team coordination tasks. From this perspective, the emergence of coordinated behaviours in sports teams is based on the formation of interpersonal synergies between players resulting from collective actions predicated on shared affordances. PMID- 23794236 TI - Interstitial 6q microdeletion syndrome and epilepsy: a new patient and review of the literature. AB - Interstitial deletions of the long arm of chromosome 6 represent a rare genomic disorder. Variable phenotypes has been reported in patients carrying this deletion, including facial dysmorphisms, intellectual disability/developmental delay, growth retardation and hypotonia, upper limb and cardiac malformations, and Prader-Willi (PWS)-like features. We describe a new patient with an interstitial 6q deletion of 11.58 Mb detected by CGH-Array, who showed facial dysmorphic features, small hands and feet, and severe dorsal scoliosis. Ataxic gait and frequent hand stereotypies were also noted. She started having seizures at 14 years, characterized by loss of consciousness, clonic jerks of the limbs, roaring breathing, fixed gaze, and generalized hypotonia. In the course of the disease she experienced cluster of seizures requiring intensive treatment. The electroencephalographic recording showed slowing of the background activity and bilateral paroxysmal activity over the posterior regions. Review of the literature done to pinpoint the epileptological features of the syndrome identified heterogeneous descriptions of the electro-clinical picture in patients with interstitial 6q deletions. Genotype-phenotype correlations of this syndrome have been lacking until recently, when patients can be characterized with microarray-based comparative genomic hybridization. Description of additional patients with interstitial 6q deletions will help to delineate candidate genes associated with particular phenotypes. PMID- 23794237 TI - Specially formulated foods for treating children with moderate acute malnutrition in low- and middle-income countries. AB - BACKGROUND: Moderate acute malnutrition, also called moderate wasting, affects around 10% of children under five years of age in low- and middle-income countries. There are different approaches to addressing malnutrition with prepared foods in these settings; for example, providing lipid-based nutrient supplements or blended foods, either a full daily dose or in a low dose as a complement to the usual diet. There is no definitive consensus on the most effective way to treat children with moderate acute malnutrition. OBJECTIVES: To evaluate the safety and effectiveness of different types of specially formulated foods for children with moderate acute malnutrition in low- and middle-income countries, and to assess whether foods complying or not complying with specific nutritional compositions, such as the WHO technical specifications, are safe and effective. SEARCH METHODS: In October 2012, we searched CENTRAL, MEDLINE, LILACS, CINAHL, BIBLIOMAP, POPLINE, ZETOC, ICTRP, mRCT, and ClinicalTrials.gov. In August 2012, we searched Embase. We also searched the reference lists of relevant papers and contacted nutrition-related organisations and researchers in this field. SELECTION CRITERIA: We planned to included any relevant randomised controlled trials (RCTs), controlled clinical trials (CCTs), controlled before-and-after studies (CBAs), and interrupted time series (ITS) that evaluated specially formulated foods for the treatment of moderate acute malnutrition in children aged between six months and five years in low- and middle-income countries. DATA COLLECTION AND ANALYSIS: Two authors assessed trial eligibility and risk of bias, and extracted and analysed the data. We summarised dichotomous outcomes using risk ratios (RR) and continuous outcomes using mean differences (MD) with 95% confidence intervals (CI). Where appropriate, we combined data in meta-analyses using the random-effects model and assessed heterogeneity. The quality of evidence was assessed using GRADE methods. MAIN RESULTS: Eight randomised controlled trials, enrolling 10,037 children, met our inclusion criteria. Seven of the trials were conducted in Africa. In general, the included studies were at a low risk of bias. There may have been a risk of performance bias as trial participants were aware which intervention group they were in, but we did not consider this likely to have biased the outcome measurement. We were unable to assess the risk of reporting bias in half of the trials and two trials were at high risk of attrition bias. Any specially formulated food versus standard care - the provision of food increased the recovery rate by 29% (RR 1.29, 95% CI 1.20 to 1.38; 2152 children, two trials; moderate quality evidence), decreased the number dropping out by 70% (RR 0.30, 95% CI 0.22 to 0.39; 1974 children, one trial; moderate quality evidence), and improved weight-for-height (MD 0.20 z-score, 95% CI 0.03 to 0.37; 1546 children, two trials; moderate quality evidence). The reduction in mortality did not reach statistical significance (RR 0.44; 95% CI 0.14 to 1.36; 1974 children, one trial; low quality evidence). Lipid-based nutrient supplements versus any blended foods (dry food mixtures, without high lipid content), at full doses - there was no significant difference in mortality (RR 0.93, 95% CI 0.54 to 1.62; 6367 children, five trials; moderate quality evidence), progression to severe malnutrition (RR 0.88, 95% CI 0.72 to 1.07; 4537 children, three trials; high quality evidence), or the number of dropouts from the nutritional programme (RR 1.14, 95% CI 0.62 to 2.11; 5107 children, four trials; moderate quality evidence). However, lipid-based nutrient supplements significantly increased the number of children recovered (RR 1.10, 95% CI 1.04 to 1.16; 6367 children, five trials; moderate quality evidence), and decreased the number of non-recovering children (RR 0.53, 95% CI 0.40 to 0.69; 4537 children, three trials; high quality evidence). LNS also improved weight gain, weight-for height, and mid-upper arm circumference, although for these outcomes, the improvement was modest (moderate quality evidence). One trial observed more children with vomiting in the lipid-based nutrient supplements group compared to those receiving blended food (RR 1.43, 95% CI 1.11 to 1.85; 2712 children, one trial; low quality evidence). Foods at complementary doses - no firm conclusion could be drawn on the comparisons between LNS at complementary dose and blended foods at complementary or full dose (low quality evidence). Lipid-based nutrient supplements versus specific types of blended foods - a recently developed enriched blended food (CSB++) resulted in similar outcomes to LNS (4758 children, three trials; moderate to high quality evidence). Different types of blended foods - in one trial, CSB++ did not show any significant benefit over locally made blended food, for example, Misola, in number who recovered, number who died, or weight gain (moderate to high quality evidence). Improved adequacy of home diet - no study evaluated the impact of improving adequacy of local diet, such as local foods prepared at home according to a given recipe or of home processing of local foods (soaking, germination, malting, fermentation) in order to increase their nutritional content. AUTHORS' CONCLUSIONS: In conclusion, there is moderate to high quality evidence that both lipid-based nutrient supplements and blended foods are effective in treating children with MAM. Although lipid-based nutrient supplements (LNS) led to a clinically significant benefit in the number of children recovered in comparison with blended foods, LNS did not reduce mortality, the risk of default or progression to SAM. It also induced more vomiting. Blended foods such as CSB++ may be equally effective and cheaper than LNS. Most of the research so far has focused on industrialised foods, and on short-term outcomes of MAM. There are no studies evaluating interventions to improve the quality of the home diet, an approach that should be evaluated in settings where food is available, and nutritional education and habits are the main determinants of malnutrition. There are no studies from Asia, where moderate acute malnutrition is most prevalent. PMID- 23794239 TI - Vascular endothelial growth factor does not accelerate endothelial differentiation of human mesenchymal stem cells. AB - For clinical applications of engineered vascular replacements, endothelial cells may not be available in sufficient quantities due to limited harvesting sites and slow in vitro expansion rates. Soluble vascular endothelial growth factor (VEGF) is often added to differentiate mesenchymal stem cells (MSCs) into endothelial cells; however, recent studies demonstrate that VEGF is not required to upregulate endothelial markers. In contrast to previous assumptions, this study demonstrates that exogenous VEGF does not enhance or accelerate the upregulation of common endothelial markers during endothelial differentiation of human MSCs. MSCs were cultured at confluence for up to 3 weeks in either basal medium or medium containing VEGF. Cells were examined for gene and protein expression as well as the ability to internalize acetylated low density lipoprotein. With either treatment, endothelial differentiation occurred as evidenced by upregulation of gene and protein expression of typical endothelial markers and the ability to internalize acetylated low density lipoproteins. Interestingly, the addition of VEGF at typical or high concentrations (50 or 100 ng/ml) did not result in differences in gene or protein expression levels of many typical endothelial markers. However, high concentrations of VEGF did significantly increase protein expression of the arterial marker Ephrin-B1. Thus, VEGF did not accelerate or enhance differentiation of human MSCs towards endothelial cells but was vital for specification of arterial fate. PMID- 23794238 TI - Gene-by-age effects on BMI from birth to adulthood: the Fels Longitudinal Study. AB - OBJECTIVES: Genome wide association studies have shown 32 loci to influence BMI in European-American adults but replication in other studies is inconsistent and may be attributed to gene-by-age effects. The aims of this study were to determine if the influence of the summed risk score of these 32 loci (GRS) on BMI differed across age from birth to 40 years, and to determine if additive genetic effects other than those in the GRS differed by age. METHODS: Serial measures of BMI were calculated at 0, 1, 3, 6, 9, 12, 18, and 28 months, and 4, 7, 11, 15, 19, 23, 30, and 40 years for 1,176 (605 females, 571 males) European-American participants in the Fels Longitudinal Study. SOLAR was used for genetic analyses. RESULTS: GRS was significant (P < 0.05) at ages: 6, 9 months, 4-15 years, and 23 40 years. Remaining additive genetic effects independently influenced BMI (P < 5.3 * 10(-5) , 0.40 < h(2) < 0.76). Some genetic correlations between ages were not significant. Differential GRS effects did not retain significance after multiple comparisons adjustments. CONCLUSIONS: While well-known BMI variants do not appear to have significant differential effects, other additive genes differ over the lifespan. PMID- 23794240 TI - From solar cells to nanoparticles and lots of organic synthesis in between: the 48th Burgenstock conference. PMID- 23794241 TI - Forced bonding and QTAIM deficiencies: a case study of the nature of interactions in He@adamantane and the origin of the high metastability. AB - Calculations within the framework of the interacting quantum atoms (IQA) approach have shown that the interactions of the helium atom with both tertiary, tC, and secondary, sC, carbon atoms in the metastable He@adamantane (He@adam) endohedral complex are bonding in nature, whereas the earlier study performed within the framework of Bader's quantum theory of atoms in molecules (QTAIM) revealed that only He---tC interactions are bonding. The He---tC and He---sC bonding interactions are shown to be forced by the high pressure that the helium and carbon atoms exert upon each other in He@adam. The occurrence of a bonding interaction between the helium and sC atoms, which are not linked by a bond path, clearly shows that the lack of a bond path between two atoms does not necessarily indicate the lack of a bonding interaction, as is asserted by QTAIM. IQA calculations showed that not only the destabilization of the adamantane cage, but also a huge internal destabilization of the helium atom, contribute to the metastability of He@adam, these contributions being roughly equal. This result disproves previous opinions based on QTAIM analysis that only the destabilization of the adamantane cage accounts for the endothermicity of He@adam. Also, it was found that there is no homeomorphism of the rho(r) and -v(r) fields of He@adam. Comparison of the IQA and QTAIM results on the interactions in He@adam exposes other deficiencies of the QTAIM approach. The reasons for the deficiencies in the QTAIM approach are analyzed. PMID- 23794242 TI - Insulin induces C2C12 cell proliferation and apoptosis through regulation of cyclin D1 and BAD expression. AB - Insulin is a secreted peptide hormone identified in human pancreas to promote glucose utilization. Insulin has been observed to induce cell proliferation and myogenesis in C2C12 cells. The precise mechanisms underlying the proliferation of C2C12 cells induced by insulin remain unclear. In this study, we observed for the first time that 10 nM insulin treatment promotes C2C12 cell proliferation. Additionally, 50 and 100 nM insulin treatment induces C2C12 cell apoptosis. By utilizing real-time PCR and Western blotting analysis, we found that the mRNA levels of cyclinD1 and BAD are induced upon 10 and 50 nM/100 nM insulin treatment, respectively. The similar results were observed in C2C12 cells expressing GATA-6 or PPARalpha. Our results identify for the first time the downstream targets of insulin, cyclin D1, and BAD, elucidate a new molecular mechanism of insulin in promoting cell proliferation and apoptosis. PMID- 23794243 TI - Characterization of the stereochemical structures of 2H-thiazolo[3,2-a]pyrimidine compounds and their binding affinities for anti-apoptotic Bcl-2 family proteins. AB - In a previous study we reported a class of compounds with a 2H-thiazolo[3,2 a]pyrimidine core structure as general inhibitors of anti-apoptotic Bcl-2 family proteins. However, the absolute stereochemical configuration of one carbon atom on the core structure remained unsolved, and its potential impact on the binding affinities of compounds in this class was unknown. In this study, we obtained pure R and S enantiomers of four selected compounds by HPLC separation and chiral synthesis. The absolute configurations of these enantiomers were determined by comparing their circular dichroism spectra to that of an appropriate reference compound. In addition, a crystal structure of one selected compound revealed the exocyclic double bond in these compounds to be in the Z configuration. The binding affinities of all four pairs of enantiomers to Bcl-xL , Bcl-2, and Mcl-1 proteins were measured in a fluorescence-polarization-based binding assay, yielding inhibition constants (Ki values) ranging from 0.24 to 2.20 MUM. Interestingly, our results indicate that most R and S enantiomers exhibit similar binding affinities for the three tested proteins. A binding mode for this compound class was derived by molecular docking and molecular dynamics simulations to provide a reasonable interpretation of this observation. PMID- 23794245 TI - Global harmonization of food safety regulation from the perspective of Korea and a novel fast automatic product recall system. AB - Efforts have been made for global harmonization of food safety regulations among countries through international organizations such as WTO and WHO/FAO. Global harmonization of food safety regulations is becoming increasingly important for Korean consumers because more than half of food and agricultural products are imported and consumed. Through recent reorganization of the Korean government, a consolidated national food safety authority-the Ministry of Food and Drug Safety (MFDS)-has been established for more efficient food safety control and better communication with consumers. The Automatic Sales Blocking System (ASBS), which blocks the sales of the recalled food products at the point of sale, has been implemented at over 40,000 retail food stores around the nation using state-of the art information and communication technology (ICT) for faster recall of adulterated food products, and the e-Food Safety Control System has been developed for more efficient monitoring of national food safety surveillance situations. The National Food Safety Information Service was also established for monitoring and collecting food safety information and incidents worldwide, and shares relevant information with all stakeholders. The new approaches adopted by the Korean Food Safety Authority are expected to enhance public trust with regard to food safety issues and expedite the recall process of adulterated products from the market. PMID- 23794244 TI - Transoral partial epiglottidectomy to treat dysphagia in post-treatment head and neck cancer patients: a preliminary report. AB - OBJECTIVES: To determine symptoms and findings in patients with dysphagia related to epiglottic dysfunction. To analyze outcomes in patients who underwent partial epiglottidectomy due to dysphagia related to epiglottic dysfunction. STUDY DESIGN: Review and analysis of clinical data obtained as part of the diagnosis and treatment of patients with dysphagia related to epiglottic dysfunction. METHODS: A retrospective review was performed of all post-treatment head and neck cancer patients who underwent epiglottidectomy at a single tertiary care referral center. Objective pre- and postprocedure swallow findings, endoscopic evaluation, and subjective improvement based on patient self-reports were reviewed. RESULTS: Seven patients were identified based on endoscopic evaluation and modified barium swallow study (MBSS) as having epiglottic pathology leading to dysphagia. Specific anatomic and functional findings included thickening of the epiglottis, absence of epiglottic deflection, vallecular bolus retention during and after the swallow, and bolus backflow from the pharynx to the oral or nasal cavity. Partial epiglottidectomy was performed in these patients. Postoperative MBSS was analyzed for changes in swallow efficiency and safety. Nearly all patients demonstrated improved pharyngeal bolus passage with little to no added swallowing morbidity. CONCLUSIONS: Preliminary findings suggest a role for partial epiglottidectomy in post-treatment head and neck cancer patients with swallowing disorders. Ideal candidates have intact tongue base contraction and poor retroflexion of the epiglottis, which results in bolus obstruction at the level of the valleculae. Partial epiglottic resection enables improved bolus passage in the pharyngeal phase. Minimal postoperative morbidity occurs in the appropriately selected patient. PMID- 23794246 TI - Plasma choline, nicotine exposure, and risk of low bone mineral density and hip fracture: the Hordaland health study. AB - Choline, obtained from diet and formed by biosynthesis, is the immediate precursor of betaine. Animal studies suggest an impact of choline on bone metabolism. We examined the associations of plasma choline and betaine with bone mineral density (BMD), the risk of hip fractures, and possible effect modification by nicotine exposure. The Hordaland Health Study (1998 to 2000) included 7074 women and men (ages 46 to 49 or 71 to 74 years). In 5315, BMD was measured. The oldest (n = 3311) were followed for hip fractures through 2009. Risk associations were studied by logistic and Cox regression by comparing the lowest and middle tertiles with the highest, as well as trends across tertiles of plasma choline and betaine. In analyses adjusted for sex and age, participants in the lowest (odds ratio [OR] = 2.00, 95% confidence interval [CI] 1.69-2.37) and middle (OR = 1.39, CI 1.17-1.66) tertiles of plasma choline had an increased risk of low BMD (lowest quintile) (p trend < 0.001). Separate analyses for sex and age groups revealed the strongest relations in elderly women (lowest tertile: OR = 2.84, CI 1.95-4.14; middle tertile: OR = 1.80, CI 1.22-2.67, p trend < 0.001), and highest OR among those in the lowest tertile who were exposed to nicotine (OR = 4.56, CI 1.87-11.11). Low plasma choline was also associated with an increased risk of hip fracture in elderly women and men (lowest tertile: hazard ratio [HR] = 1.45, CI 1.08-1.94; middle tertile: HR = 1.13, CI 0.83-1.54, p trend = 0.012). In elderly women, the HR for hip fracture was 1.90 (CI 1.32-2.73) and 1.36 (CI 0.92-1.99) (p trend < 0.001) for lowest and middle tertiles of choline, and the highest HR was found among women in the lowest tertile exposed to nicotine (HR = 2.68, CI 1.16-6.19). Plasma betaine was not related to BMD or hip fracture. Low plasma choline was associated with low BMD in both sexes and increased the risk of hip fracture in elderly women. These results should motivate further studies on choline, nicotine exposure, and bone metabolism. PMID- 23794247 TI - Beryllium disease among construction trade workers at Department of Energy nuclear sites. AB - BACKGROUND: A medical surveillance program was developed to identify current and former construction workers at significant risk for beryllium related disease from work at the DOE nuclear weapons facilities, and to improve surveillance among beryllium exposed workers. METHODS: Medical examinations included a medical history and a beryllium blood lymphocyte proliferation test (BeLPT). Stratified and multivariate logistic regression analyses were used to explore the risk of disease by age, race, trade, and reported work in buildings where beryllium was used. After adjusting for covariates, the risk of BeS was significantly higher among boilermakers, roofers, and sheet metal workers, as suggested in the stratified analyses. Workers identified as sensitized to beryllium were interviewed to determine whether they had been subsequently diagnosed with chronic beryllium disease. RESULTS: Between 1998 and December 31, 2010 13,810 workers received a BeLPT through the BTMed program; 189 (1.4%) were sensitized to beryllium, and 28 reported that they had had a compensation claim accepted for CBD. CONCLUSIONS: These data on former construction workers gives us additional information about the predictive value of the blood BeLPT test for detection of CBD in populations with lower total lifetime exposures and more remote exposures than that experienced by current workers in beryllium machining operations. Through this surveillance program we have identified routes of exposures to beryllium and worked with DOE site personnel to identity and mitigate those exposures which still exist, as well as helping to focus attention on the risk for beryllium exposure among current demolition workers at these facilities. PMID- 23794248 TI - Psychotropic drugs and their impact on the treatment of paediatric dental patients. AB - In the past 10-15 years, the diagnosis of mental diseases in the paediatric and adolescent population has risen significantly. This has resulted in paediatric dentists caring for a large number of children suffering from these conditions. For the safe care of these children, paediatric dentists need to be aware of not only the characteristics of mental diseases but also the medications used for their treatment. Becoming familiar with the plethora of psychoactive agents and their complex pharmacological properties and interactions poses a daunting but necessary challenge as they are likely to influence dental treatment. To help with this understanding, the present paper provides a comprehensive but simplified review of the major paediatric psychotropic drugs in terms of basic pharmacology, common indications, general and oral health-related adverse effects and interactions with other medications which may be prescribed in the course of dental treatment. PMID- 23794249 TI - Reversible effects of oxygen partial pressure on genes associated with placental angiogenesis and differentiation in primary-term cytotrophoblast cell culture. AB - Timely regulated changes in oxygen partial pressure are important for placental formation. Disturbances could be responsible for pregnancy-related diseases like preeclampsia and intrauterine growth restriction. We aimed to (i) determine the effect of oxygen partial pressure on cytotrophoblast differentiation; (ii) measure mRNA expression and protein secretion from genes associated with placental angiogenesis; and (iii) determine the reversibility of these effects at different oxygen partial pressures. Term cytotrophoblasts were incubated at 21% and 2.5% O2 for 96 hr, or were switched between the two oxygen concentrations after 48 hr. Real-time PCR and enzyme-linked immunosorbent assays (ELISAs) were used to evaluate cell fusion and differentiation, measuring transcript levels for those genes involved in cell fusion and placental angiogenesis, including VEGF, PlGF, VEGFR1, sVEGFR1, sENG, INHA, and GCM1. Cytotrophoblasts underwent fusion and differentiation in 2.5% O2 . PlGF expression was inhibited while sVEGFR1 expression increased. VEGF and sENG mRNA expressions increased in 2.5% compared to 21% O2 , but no protein was detected in the cell supernatants. Finally, GCM1 mRNA expression increased during trophoblast differentiation at 21% O2 , but was inhibited at 2.5% O2 . These mRNA expression effects were reversed by returning the cells to 21% O2 . Thus, low-oxygen partial pressure does not inhibit term cytotrophoblast cell fusion and differentiation in vitro. Lowering the oxygen partial pressure from 21% to 2.5% caused normal-term trophoblasts to reversibly modify their expression of genes associated with placental angiogenesis. This suggests that modifications observed in pregnancy diseases such as preeclampsia or growth retardation are probably due to an extrinsic effect on trophoblasts. PMID- 23794250 TI - Further delineation of genotype-phenotype correlation in homozygous 2p21 deletion syndromes: first description of patients without cystinuria. AB - Homozygous contiguous gene deletion syndromes are rare. On 2p21, however, several overlapping homozygous gene deletion syndromes have been described, all presenting with cystinuria but otherwise distinct phenotypes. Hypotonia cystinuria syndrome (HCS, OMIM606407) is characterized by infantile hypotonia, poor feeding, and growth hormone deficiency. Affected individuals carry homozygous deletions including the cystinuria gene SLC3A1 and the adjacent PREPL gene. Larger homozygous deletions in this region encompassing the PPM1B, SLC3A1, PREPL, and C2orf34 (CAMKMT) genes result in a more severe phenotype, the 2p21 deletion syndrome. A phenotype intermediate to HCS and the 2p21 deletion syndrome is termed atypical HCS and is caused by deletion of SLC3A1, PREPL, and C2orf34 (CAMKMT). Using high resolution SNP array molecular karyotyping we identified two siblings with a homozygous deletion of 83 kb partially encompassing the genes PREPL and C2orf34 (CAMKMT), but not the SLC3A1 gene. The affected siblings display a recognizable phenotype which is similar to atypical HCS with regard to growth failure and neuro-muscular features, but is characterized by lack of cystinuria. The patients also exhibit features which have not been reported to date such as cleft palate and genital abnormalities. In conclusion, we report the first patients with a homozygous 2p21 deletion syndrome without cystinuria and further delineate the complex genotype-phenotype correlations of homozygous microdeletion syndromes of this region. PMID- 23794251 TI - Association of tumor-associated fibroblasts with progression of hepatocellular carcinoma. AB - Interaction between tumor and stromal cells plays an important role in cancer progression. The aim of this study was to explore the effects of tumor-associated fibroblasts on regulation of hepatocellular carcinoma (HCC) progression. Sixty five cases of HCC and the corresponding normal liver tissues were recruited for immunohistochemical assessment of alpha-smooth muscle actin (alpha-SMA) expression, a biomarker for activated fibroblasts. Clinicopathological data were also collected from HCC patients for association with alpha-SMA expression. Primary cell culture of fibroblasts from HCC tissues was used to generate conditioned medium for testing the effect on regulation of HCC cell migration capacity in the transwell cell migration assay. alpha-SMA protein was expressed in 84.0 % (21 out 25 cases) of the fibroblasts from the metastatic HCCs, 45 % (18/40) from HCCs without metastasis, and 19.2 % (5/26) from normal liver tissues, difference of which was statistically significant (P < 0.01). The expression of alpha-SMA protein in HCC tissues was associated with tumor thrombosis, poor pathology grade, advanced clinical stages, and lymph node metastasis. The conditioned medium from the primary cultured fibroblasts with alpha-SMA expression significantly promoted the migration capacity of HCC Hep3B cells compared to the heat-inactivated conditioned medium. The data from the current study demonstrated that expression of alpha-SMA protein in HCC fibroblasts associated with tumor metastasis and advanced clinical stages and that the conditioned medium from alpha-SMA-positive fibroblasts enhanced HCC cell migration. This study indicates that alpha-SMA protein might serve as a biomarker to predict HCC progression. PMID- 23794252 TI - Cancer relating symptoms in homecare cancer patients: which impact in daily clinical practice? PMID- 23794253 TI - Potential clinical significance of ERbeta ON promoter methylation in sporadic breast cancer. AB - The aim of the study was to assess how hypermethylation of the ON promoter of the estrogen receptor beta (ERbeta) gene affects its expression (at the mRNA and protein level) and to correlate these with some clinical and histopathological parameters. A total of 131 samples of frozen breast cancer tissue was analyzed. A custom-designed, two-step PCR method was used to measure the methylation index of the ERbeta gene ON promoter region. Quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was performed to quantify mRNA of the ERbeta1 isoform, while ERbeta1 protein was determined using the Western blot method. There was a significant difference in the methylation index of the ERbeta gene ON promoter between the groups of patients with negative and positive axillary lymph node status (P = 0.03). In addition, the methylation index of the ON promoter was positively correlated with estrogen receptor alfa (ERalpha) protein levels (rho = 0.31, P = 0.02). There was a significant difference in the methylation index of the ON promoter between the progesterone receptor (PR)-negative and PR-positive groups of patients (P = 0.01). ERbeta1 protein levels were negatively correlated with ERalpha protein (rho = -0.27, P < 0.01). The methylation index of the ON promoter could be a more reliable additional parameter for prediction and/or prognosis in breast cancer than ERbeta1-mRNA and/or protein levels. PMID- 23794254 TI - Ecological rationality or nested sets? Individual differences in cognitive processing predict Bayesian reasoning. AB - The presentation of a Bayesian inference problem in terms of natural frequencies rather than probabilities has been shown to enhance performance. The effect of individual differences in cognitive processing on Bayesian reasoning has rarely been studied, despite enabling us to test process-oriented variants of the two main accounts of the facilitative effect of natural frequencies: The ecological rationality account (ERA), which postulates an evolutionarily shaped ease of natural frequency automatic processing, and the nested sets account (NSA), which posits analytical processing of nested sets. In two experiments, we found that cognitive reflection abilities predicted normative performance equally well in tasks featuring whole and arbitrarily parsed objects (Experiment 1) and that cognitive abilities and thinking dispositions (analytical vs. intuitive) predicted performance with single-event probabilities, as well as natural frequencies (Experiment 2). Since these individual differences indicate that analytical processing improves Bayesian reasoning, our findings provide stronger support for the NSA than for the ERA. PMID- 23794255 TI - Oxytocin versus no treatment or delayed treatment for slow progress in the first stage of spontaneous labour. AB - BACKGROUND: Slow progress in the first stage of spontaneous labour is associated with an increased caesarean section rate and fetal and maternal morbidity. Oxytocin has long been advocated as a treatment for slow progress in labour but it is unclear to what extent it improves the outcomes for that labour and whether it actually reduces the caesarean section rate or maternal and fetal morbidity. This review will address the use of oxytocin and whether it improves the outcomes for women who are progressing slowly in labour compared to situations where it is not used or where its administration is delayed. OBJECTIVES: To determine if the use of oxytocin for the treatment of slow progress in the first stage of spontaneous labour is associated with a reduction in the incidence of caesarean sections, or maternal and fetal morbidity compared to situations where it is not used or where its administration is delayed. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (23 February 2013) and bibliographies of relevant papers. SELECTION CRITERIA: Randomised controlled trials which compared oxytocin with either placebo, no treatment or delayed oxytocin in the active stage of spontaneous labour in low-risk women at term. DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for inclusion, assessed risk of bias and extracted data. We sought additional information from trial authors. MAIN RESULTS: We included eight studies in the review involving a total of 1338 low-risk women in the first stage of spontaneous labour at term. Two comparisons were made; 1) the use of oxytocin versus placebo or no treatment (three trials); 2) the early use of oxytocin versus its delayed use (five trials). There were no significant differences in the rates of caesarean section or instrumental vaginal delivery in either comparison. Early use of oxytocin resulted in an increase in uterine hyperstimulation associated with fetal heart changes. However, the early use of oxytocin versus its delayed use resulted in no significant differences in a range of neonatal and maternal outcomes. Use of early oxytocin resulted in a statistically significant reduction in the mean duration in labour of approximately two hours but did not increase the normal delivery rate. There was significant heterogeneity for this analysis and we carried out a random-effects meta-analysis; however, all of the trials are strongly in the same direction so it is reasonable to conclude that this is the true effect. We also performed a random-effects meta-analysis for the four other analyses which showed substantial heterogeneity in the review. AUTHORS' CONCLUSIONS: For women making slow progress in spontaneous labour, treatment with oxytocin as compared with no treatment or delayed oxytocin treatment did not result in any discernable difference in the number of caesarean sections performed. In addition there were no detectable adverse effects for mother or baby. The use of oxytocin was associated with a reduction in the time to delivery of approximately two hours which might be important to some women. However, if the primary goal of this treatment is to reduce caesarean section rates, then doctors and midwives may have to look for alternative options. PMID- 23794256 TI - Clinical utility and reproducibility of visceral adipose tissue measurements derived from dual-energy X-ray absorptiometry in White and African American adults. AB - OBJECTIVE: The purpose of this study was to determine reproducibility and clinical thresholds for DXA-derived visceral adipose tissue (VAT). DESIGN AND METHODS: The sample included 2317 white and African American adults 18-74 years of age. VAT areas (cm(2) ) were measured using a Hologic DXA scanner equipped with APEX 4.0 software. Reproducibility was assessed using repeated measurements on 101 participants scanned 14 days apart. Receiver Operating Characteristic (ROC) curves were used to assess clinical utility and select thresholds that identified elevated cardiometabolic risk, defined as the presence of >=2 risk factors. RESULTS: Reproducibility of DXA-VAT was 8.1%. The areas under the ROC curves ranged from 0.754 in African American men to 0.807 in white women. The thresholds were higher in white men (154 cm(2) ) and women (143 cm(2) ) compared to African American men (101 cm(2) ) and women (114 cm(2) ). CONCLUSION: The results demonstrated that DXA VAT is a useful clinical marker of cardiometabolic risk; however, further research is required to determine associations with health outcomes using longitudinal studies. PMID- 23794257 TI - Ahp cyclodepsipeptides: the impact of the Ahp residue on the "canonical inhibition" of S1 serine proteases. AB - S1 serine proteases are by far the largest and most diverse family of proteases encoded in the human genome. Although recent decades have seen an enormous increase in our knowledge, the biological functions of most of these proteases remain to be elucidated. Chemical inhibitors have proven to be versatile tools for studying the functions of proteases, but this approach is hampered by the limited availability of inhibitor scaffold structures with the potential to allow rapid discovery of selective, noncovalent small-molecule protease inhibitors. The natural product class of Ahp cyclodepsipeptides is an unusual class of small molecule canonical inhibitors; the incorporation of protease cleavage sequences into their molecular scaffolds enables the design of specific small-molecule inhibitors that simultaneously target the S and S' subsites of the protease through noncovalent mechanisms. Their synthesis is tedious, however, so in this study we have investigated the relevance of the Ahp moiety for achieving potent inhibition. We found that although the Ahp residue plays an important role in inhibition potency, appropriate replacement with beta-hydroxy amino acids results in structurally less complex derivatives that inhibit serine proteases in the low micromolar range. PMID- 23794258 TI - Assembly of cerium(III)-stabilized polyoxotungstate nanoclusters with SeO3(2 )/TeO3(2-) templates: from single polyoxoanions to inorganic hollow spheres in dilute solution. AB - A versatile one-pot strategy was employed to synthesize three cerium(III) stabilized polyoxotungstates nanoclusters by combining cerium linkers and SeO3(2 )/TeO3(2-) heteroanion templates: K32Na16[{(XO3)W10O34}8{Ce8(H2O)20}(WO2)4(W4O12)].nH2O [X=Se, n=81 (1); X=Te, n=114 (2)] and K12Na22[{(SeO3)W10O34}8{Ce8(H2O)20}(WO2)4{(W4O6)Ce4(H2O)14(SeO3)4(NO3)2}]. 79H2O (3), which are the first lanthanide-containing polyoxotungstates with selenium or tellurium heteroatoms. The three clusters were characterized by single-crystal X ray structure analysis, IR spectroscopy, thermogravimetric/differential thermal analysis, UV/Vis spectroscopy, ESI-MS, and X-ray photoelectron spectroscopy. Their electrochemical, photoluminescence, and magnetic properties were investigated. Their behavior in solution was studied by transmission electron microscopy, which showed that their single polyoxoanions assemble into intact, uniform-sized, purely inorganic hollow spheres in dilute water/acetone solution. PMID- 23794259 TI - Circulating miR-22, miR-24 and miR-34a as novel predictive biomarkers to pemetrexed-based chemotherapy in advanced non-small cell lung cancer. AB - Pemetrexed has been widely used in patients with advanced non-small cell lung cancer (NSCLC). The clinical relevance of polymorphisms of folate pathway genes for pemetrexed metabolism have not been fully elucidated yet. The aim of this study was to evaluate the expression levels of circulating miR-22, miR-24, and miR-34a, possibly involved in folate pathway, in NSCLC patients treated with pemetrexed compared with healthy controls and to investigate their impact on patient clinical outcomes. A total of 22 consecutive patients with advanced NSCLC, treated with pemetrexed-based chemotherapy and 27 age and sex matched healthy controls were included in this preliminary analysis. miR-22, miR-24, and miR-34a targets were identified by TargetScan 6.2 algorithm, validating the involvement of these microRNAs in folate pathway. MicroRNAs were isolated from whole blood and extracted with miRNAeasy Mini Kit (Qiagen). miRNA profiling was performed using Real-Time PCR. SPSS 17 was used to data analysis. miR-22, miR-24, and miR-34a were found upregulated (P<0.05) in NSCLC patients versus healthy controls. Higher expression levels were recorded for miR-34a. Nevertheless, significantly higher miR-22 expression was observed in patients developing progressive disease (P=0.03). No significant associations with clinical outcome were recorded for miR-24 and miR-34a. Albeit preliminary, these data support the involvement of miR-22, miR-24, and miR-34a in advanced NSCLC. The correlation between high expression of miR-22 in whole blood and the lack of response in pemetrexed treated NSCLC patients indicates that miR-22 could represent a novel predictive biomarker for pemetrexed-based treatment. PMID- 23794261 TI - Ruthenium-NHC-catalyzed asymmetric hydrogenation of indolizines: access to indolizidine alkaloids. PMID- 23794260 TI - Selective and brain-permeable polo-like kinase-2 (Plk-2) inhibitors that reduce alpha-synuclein phosphorylation in rat brain. AB - Polo-like kinase-2 (Plk-2) has been implicated as the dominant kinase involved in the phosphorylation of alpha-synuclein in Lewy bodies, which are one of the hallmarks of Parkinson's disease neuropathology. Potent, selective, brain penetrant inhibitors of Plk-2 were obtained from a structure-guided drug discovery approach driven by the first reported Plk-2-inhibitor complexes. The best of these compounds showed excellent isoform and kinome-wide selectivity, with physicochemical properties sufficient to interrogate the role of Plk-2 inhibition in vivo. One such compound significantly decreased phosphorylation of alpha-synuclein in rat brain upon oral administration and represents a useful probe for future studies of this therapeutic avenue toward the potential treatment of Parkinson's disease. PMID- 23794262 TI - Epiglottopexy with and without lingual tonsillectomy. PMID- 23794263 TI - Willingness to participate in genomics research and desire for personal results among underrepresented minority patients: a structured interview study. AB - Patients from traditionally underrepresented communities need to be involved in discussions around genomics research including attitudes towards participation and receiving personal results. Structured interviews, including open-ended and closed-ended questions, were conducted with 205 patients in an inner-city hospital outpatient clinic: 48 % of participants self-identified as Black or African American, 29 % Hispanic, 10 % White; 49 % had an annual household income of <$20,000. When the potential for personal results to be returned was not mentioned, 82 % of participants were willing to participate in genomics research. Reasons for willingness fell into four themes: altruism; benefit to family members; personal health benefit; personal curiosity and improving understanding. Reasons for being unwilling fell into five themes: negative perception of research; not personally relevant; negative feelings about procedures (e.g., blood draws); practical barriers; and fear of results. Participants were more likely to report that they would participate in genomics research if personal results were offered than if they were not offered (89 vs. 62 % respectively, p < 0.001). Participants were more interested in receiving personal genomic risk results for cancer, heart disease and type 2 diabetes than obesity (89, 89, 91, 80 % respectively, all p < 0.001). The only characteristic consistently associated with interest in receiving personal results was disease-specific worry. There was considerable willingness to participate in and desire for personal results from genomics research in this sample of predominantly low income, Hispanic and African American patients. When returning results is not practical, or even when it is, alternatively or additionally providing generic information about genomics and health may also be a valuable commodity to underrepresented minority and other populations considering participating in genomics research. PMID- 23794265 TI - Occupation held at the time of asthma symptom development. AB - BACKGROUND: Examining occupations other than those held when asthma symptoms first developed may not correctly identify occupations with higher risk of asthma onset. METHODS: To determine the occupation held when individuals first developed asthma symptoms, we examined 2010 National Health Interview Survey data for working adults with current asthma. RESULTS: Overall 37.1% of working adults with current asthma developed asthma while employed. Of these, the highest proportions of individuals identified office and administrative support (13.3%), sales and related (9.4%), and management (8.5%) as the occupation held when asthma first developed; 37.8% had a different current occupation than at asthma onset, and estimates of a change in occupation were highest for those who developed asthma while working in business and financial operations (49.3%), sales and related (48.6%), and healthcare support (43.8%) occupations. CONCLUSION: Future population-based studies should further examine associations between asthma and occupation held at time of asthma onset. PMID- 23794264 TI - TBK1 mediates critical effects of measles virus nucleocapsid protein (MVNP) on pagetic osteoclast formation. AB - Paget's disease of bone (PDB) is characterized by abnormal osteoclasts with unique characteristics that include increased sensitivity of osteoclast progenitors to 1,25(OH)2 D3 , receptor activator of NF-kappaB ligand (RANKL), and TNF-alpha; increased osteoclast numbers; and increased expression of IL-6 and several transcription factors. We recently reported that measles virus nucleocapsid protein (MVNP) plays a key role in the development of these abnormal osteoclasts. MVNP can induce the pagetic osteoclast phenotype in vitro and in vivo in TRAP-MVNP transgenic mice. However, the molecular mechanisms by which MVNP generates pagetic osteoclasts have not been determined. TANK-binding kinase 1 (TBK1) and IkappaB kinase-epsilon (IKKepsilon) are IKK family members that complex with MVNP and activate both IRF3 and NF-kappaB pathways. MVNP increases the amount of TBK1 protein in bone marrow monocytes (BMM). Interestingly, we found that RANKL increased TBK1 and IKKepsilon early in osteoclast differentiation, suggesting a possible role in normal osteoclastogenesis. However, only TBK1 is further increased in osteoclasts formed by TRAP-MVNP BMM owing to increased TBK1 protein stability. TBK1 overexpression induced IL6 promoter reporter activity, and elevated endogenous IL6 mRNA and p65 NF-kappaB, TAF12, and ATF7 proteins in several cell lines. Overexpression of TBK1 was insufficient to induce pagetic osteoclasts from WT BMM but synergized with MVNP to increase pagetic osteoclast formation from TRAP-MVNP BMM. BX795 inhibition of TBK1 impaired MVNP-induced IL-6 expression in both NIH3T3 cells and BMM, and shRNA knockdown of Tbk1 in NIH3T3 cells impaired IL-6 secretion induced by MVNP and decreased TAF12 and ATF7, factors involved in 1,25(OH)2 D3 hypersensitivity of pagetic osteoclasts. Similarly, Tbk1 knockdown in BMM from TRAP-MVNP and WT mice specifically impaired development of the MVNP-induced osteoclast pagetic phenotype. These results demonstrate that TBK1 plays a critical role in mediating the effects of MVNP on osteoclast differentiation and on the expression of IL-6, a key contributor to the pagetic osteoclast phenotype. PMID- 23794266 TI - Exogenous polyamines promote osteogenic differentiation by reciprocally regulating osteogenic and adipogenic gene expression. AB - Polyamines are naturally occurring organic polycations that are ubiquitous in all organisms, and are essential for cell proliferation and differentiation. Although polyamines are involved in various cellular processes, their roles in stem cell differentiation are relatively unexplored. In this study, we found that exogenous polyamines, putrescine, spermidine, and spermine, promoted osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs) without inducing cell death or apoptosis. Alkaline phosphatase (ALP) activity and the mRNA level of osteogenic genes, including Runx2, ALP, osteopontin, and osteocalcin, were up-regulated by exogenous polyamines. When hBMSCs were cultured at high cell density favoring adipocyte formation, exogenous polyamines resulted in down-regulation of adipogenic genes such as PPARgamma, aP2, and adipsin. Extracellular matrix mineralization, a marker for osteoblast maturation, was enhanced in the presence of exogenous polyamines, while lipid accumulation, an indication of adipogenic differentiation, was attenuated. Exogenous polyamines increased the mRNA expression of polyamine-modulated factor 1 (PMF-1) and its downstream effector, spermidine/spermine N(1)-acetyltransferase (SSAT), while that of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis, was suppressed. These results lead to possible connections between polyamine metabolism and osteogenic differentiation pathways. To summarize, this study provides evidence for the involvement of polyamines in osteogenic differentiation of hBMSCs, and is the first to demonstrate that osteogenic and adipogenic differentiation are reciprocally regulated by exogenous polyamines. PMID- 23794267 TI - SGEBP, a giant protein from starfish oocytes able to interact with ERK. AB - The mitogen-activated protein kinase (MAPK) pathway is a key regulator of animal meiotic divisions. It involves cascades of kinases whose specificity has been shown to depend on binding proteins acting as scaffolds. We searched for proteins interacting with starfish extracellular signal-regulated kinase (ERK) using the yeast two-hybrid system. An interacting clone was found to encode the 5' region of a giant 16.7-kb transcript encoded by an intronless gene. The corresponding 630-kDa protein could not be detected by Western blot, but the meiotic spindle was labelled by immunolocalization with an antibody against the ERK-binding domain. A related gene was found in the genome of another starfish species, and similarities were also found to a 42.9-kb open reading frame in the sea urchin genome. Yet, no conserved protein-binding domain was detected in the amino acid sequence(s) compared to all the known motifs. Structure prediction software indicated that the encoded proteins are probably disordered while a query of the disordered protein database indicated some similarity with vertebrates microtubule-associated protein 2 (MAP2). This predicts that SGEBP may function as a space-filling polymer, having a role in both cytoskeleton organization and ERK targeting. PMID- 23794268 TI - Single dose oral ibuprofen plus paracetamol (acetaminophen) for acute postoperative pain. AB - BACKGROUND: Combining two different analgesics in fixed doses in a single tablet can provide better pain relief than either drug alone in acute pain. This appears to be broadly true across a range of different drug combinations, in postoperative pain and migraine headache. Some combinations of ibuprofen and paracetamol are available for use without prescription in some acute pain situations. OBJECTIVES: To assess the efficacy and adverse effects of single dose oral ibuprofen plus paracetamol for acute postoperative pain using methods that permit comparison with other analgesics evaluated in standardised trials using almost identical methods and outcomes. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (Issue 4 of 12, 2013), MEDLINE (1950 to May 21st 2013), EMBASE (1974 to May 21st 2013), the Oxford Pain Database, ClinicalTrials.gov, and reference lists of articles. SELECTION CRITERIA: Randomised, double-blind clinical trials of single dose, oral ibuprofen plus paracetamol compared with placebo or the same dose of ibuprofen alone for acute postoperative pain in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently considered trials for inclusion in the review, assessed quality, and extracted data. We used validated equations to calculate the area under the pain relief versus time curve and derive the proportion of participants with at least 50% of maximum pain relief over six hours. We calculated relative risk (RR) and number needed to treat to benefit (NNT) for ibuprofen plus paracetamol, ibuprofen alone, or placebo. We used information on use of rescue medication to calculate the proportion of participants requiring rescue medication and the weighted mean of the median time to use. We also collected information on adverse events. MAIN RESULTS: Searches identified three studies involving 1647 participants. Each of them examined several dose combinations. Included studies provided data from 508 participants for the comparison of ibuprofen 200 mg + paracetamol 500 mg with placebo, 543 participants for the comparison of ibuprofen 400 mg + paracetamol 1000 mg with placebo, and 359 participants for the comparison of ibuprofen 400 mg + paracetamol 1000 mg with ibuprofen 400 mg alone.The proportion of participants achieving at least 50% maximum pain relief over 6 hours was 69% with ibuprofen 200 mg + paracetamol 500 mg, 73% with ibuprofen 400 mg + paracetamol 1000 mg, and 7% with placebo, giving NNTs of 1.6 (1.5 to 1.8) and 1.5 (1.4 to 1.7) for the lower and higher doses respectively compared with placebo. For ibuprofen 400 mg alone the proportion was 52%, giving an NNT for ibuprofen 400 mg + paracetamol 1000 mg compared with ibuprofen alone of 5.4 (3.5 to 12).Ibuprofen + paracetamol at the 200/500 mg and 400/1000 mg doses resulted in longer times to remedication than placebo. The median time to use of rescue medication was 7.6 hours for ibuprofen 200 mg + paracetamol 500 mg, 8.3 hours with ibuprofen 400 mg + paracetamol 1000 mg, and 1.7 hours with placebo. Fewer participants needed rescue medication with ibuprofen + paracetamol combination than with placebo or ibuprofen alone. The proportion was 34% with ibuprofen 200 mg + paracetamol 500 mg, 25% with ibuprofen 400 mg + paracetamol 1000 mg, and 79% with placebo, giving NNTs to prevent use of rescue medication of 2.2 (1.8 to 2.9) and 1.8 (1.6 to 2.2) respectively compared with placebo. The proportion of participants using rescue medication with ibuprofen 400 mg was 48%, giving an NNT to prevent use for ibuprofen 400 mg + paracetamol 1000 mg compared with ibuprofen alone of 4.3 (3.0 to 7.7).The proportion of participants experiencing one or more adverse events was 30% with ibuprofen 200 mg + paracetamol 500 mg, 29% with ibuprofen 400 mg + paracetamol 1000 mg, and 48% with placebo, giving NNT values in favour of the combination treatment of 5.4 (3.6 to 10.5) and 5.1 (3.5 to 9.5) for the lower and higher doses respectively. No serious adverse events were reported in any of the included studies. Withdrawals for reasons other than lack of efficacy were fewer than 5% and balanced across treatment arms. AUTHORS' CONCLUSIONS: Ibuprofen plus paracetamol combinations provided better analgesia than either drug alone (at the same dose), with a smaller chance of needing additional analgesia over about eight hours, and with a smaller chance of experiencing an adverse event. PMID- 23794269 TI - Duplication of AKT3 as a cause of macrocephaly in duplication 1q43q44. AB - Somatic and germline duplications of AKT3 and activating mutations of this gene have been reported in individuals with megalencephaly and hemimegalencephaly. We report on a patient with macrocephaly and a 3 Mb duplication on 1q43q44 that includes AKT3. This duplication was detected by array comparative genomic hybridization. The patient presented with moderate developmental delays in gross motor movements and speech. She also had macrocephaly, frontal bossing, hypertelorism, wide nasal bridge, small alae nares, short philtrum, prominent upper lip, and low-set, protruding ears. The 3 Mb duplicated region contained 15 genes including AKT3. The observation of megalencephaly in a child with 1q43q44 duplication provides further evidence of involvement of AKT3 dosage imbalances in brain growth disturbance. PMID- 23794270 TI - Capturing and testing perceptual-cognitive expertise: a comparison of stationary and movement response methods. AB - Numerous methods have been used to study expertise and performance. In the present article, we compare the cognitive thought processes of skilled soccer players when responding to film-based simulations of defensive situations involving two different experimental conditions. Participants either remained stationary in a seated position (n = 10) or were allowed to move (n = 10) in response to life-size film sequences of 11 versus 11 open-play soccer situations viewed from a player's perspective. Response accuracy and retrospective verbal reports of thinking were collected across the two task conditions. In the movement-based response group, participants generated a greater number of verbal report statements, including a higher proportion of evaluation, prediction, and action planning statements, than did participants in the stationary group. Findings suggest that the processing strategies employed during performance differ depending on the nature of the response required of participants. Implications for behavioral methods and experimental design are discussed. PMID- 23794271 TI - Identification of residues essential for the activity and substrate affinity of L carnitine dehydrogenase. AB - Recently, two L-carnitine dehydrogenases from soil isolates Rhizobium sp. (Rs CDH) and Xanthomonas translucens (Xt-CDH) have demonstrated to exhibit mutually differing affinities toward L-carnitine. To identify residues important for affinity to the substrate, we compared the primary structure of Xt-CDH and Rs-CDH with the recognized 3D structure of 3-hydroxyacyl-CoA dehydrogenase (PDB code: 1F0Y). Then, six residues of Xt-CDH (Phe143, Gly188, Ile190, Ala191, Gly223, and Ala224) and the corresponding residues of Rs-CDH (Tyr140, Ala185, Val187, Gly188, Ser220, and Phe221) were selected for further mutagenesis. The residues of Xt-CDH were replaced with that of Rs-CDH at the corresponding position and vice versa. All Rs-CDH mutants exhibited slight effects on substrate affinity, except for the double mutants Rs-V187I/G188A, which was devoid of enzyme activity. All Xt-CDH mutants showed different K m values. Xt-F143Y caused a higher increase in the K m value. Furthermore, the kinetic parameters of 10 mutants at Xt-F143 and Rs-Y140 were investigated. All Rs-Y140 mutants, except aromatic residues (Phe, Trp), produced proteins that were almost entirely devoid of enzyme activity and with disrupted affinity to L-carnitine. All Xt-F143 variants showed a marked reduction (P <= 0.05) in enzyme activity. Overall, our results suggest that the aromatic rings of Tyr140 in Rs-CDH and Phe143 of Xt-CDH are essential for substrate recognition. PMID- 23794272 TI - Comparative profiling analysis of woody flavouring from vine-shoots and oak chips. AB - BACKGROUND: Woody liquid flavourings extracted from different varieties of vine shoots and oak chips have been characterized by gas chromatography-mass spectrometry to compare the profile of compounds as potential contributors to the organoleptical properties of wine and spirits aged in oak barrels. Oak chips are frequently added to barrels to accelerate the ageing process, while vine shoots are produced in high amounts in wine-producing countries. RESULTS: The extracts were isolated by superheated liquid extraction (SHLE) after optimization of extraction variables. The SHLE protocol was performed using ethanol-water mixtures (pH 3) at 220 degrees C for 60 min. Compounds were identified using NIST databases, and the resulting profile was used as a dataset for qualitative and semi-quantitative comparison between extracts obtained from different varieties of vine shoots and oak chips. CONCLUSION: Statistical analysis enabled demonstration of the similarity among extracts from vine shoots and oak wood, providing the first study on this subject. The special role of phenols and furanic derivatives has been described. This study is the first stage for characterization of vine shoots as a by-product with potential for use in the oenological field. PMID- 23794273 TI - Daily iron during pregnancy improves birth weight. PMID- 23794274 TI - Failure to innovate is "high risk" option for UK healthcare, conference hears. PMID- 23794275 TI - People in mental health crises are treated like criminals, says report. PMID- 23794276 TI - A&E doctor is suspended for nine months after series of incidents that alarmed colleagues. PMID- 23794277 TI - Suicidal memes. PMID- 23794278 TI - Novartis found to be in breach of code over drug brochure. PMID- 23794279 TI - UK needs 10,000 more GPs by 2022 to meet needs, report says. PMID- 23794281 TI - Relationship between reflux and laryngeal cancer. AB - Gastroesophageal reflux disease (GERD), or its variation known as laryngopharyngeal reflux (LPR), has been recognized as a potential cause of several laryngeal disorders. Patients with laryngeal cancer have lifestyle risk factors, especially tobacco and alcohol consumption, that play an etiological role in the development of their cancer but also places them at risk for reflux. The question then arises whether there is merely an association or a causal relationship between laryngeal cancer and reflux. However, despite a number of studies, a causal relationship with laryngeal cancer is uncertain. In this article, we address the current literature in a critical manner to evaluate the relationship between reflux and laryngeal cancer. From the review of the literature, we conclude that there is insufficient evidence to support a causal role of reflux in laryngeal cancer, mainly because of the confounding effect of tobacco and alcohol consumption and the inaccuracies in the diagnosis of reflux. PMID- 23794280 TI - Circulating and tissue resident endothelial progenitor cells. AB - Progenitor cells for the endothelial lineage have been widely investigated for more than a decade, but continue to be controversial since no unique identifying marker has yet been identified. This review will begin with a discussion of the basic tenets originally proposed for proof that a cell displays properties of an endothelial progenitor cell. We then provide an overview of the methods for putative endothelial progenitor cell derivation, expansion, and enumeration. This discussion includes consideration of cells that are present in the circulation as well as cells resident in the vascular endothelial intima. Finally, we provide some suggested changes in nomenclature that would greatly clarify and demystify the cellular elements involved in vascular repair. PMID- 23794282 TI - Altered lipid metabolism in gastroschisis: a novel hypothesis. AB - Gastroschisis is a congenital abdominal wall defect where there is herniation of abdominal organs. Optimal maternal nutritional intake, in particular, fatty acids, are vital for proper growth and development of the fetus. This pilot case control study explored the association of several biomarkers of fatty acids and gastroschisis. Between 2008 and 2011, we recruited 13 pregnant women in mid gestation who were referred to the UCSD Prenatal Center for evaluation of an abnormal maternal serum alpha-fetoprotein (MSAFP) test and subsequently identified as carrying a baby with gastroschisis. Nine controls were selected from a false positive MSAFP or from the UCSD prenatal clinic. At enrollment, maternal blood was drawn for analysis of fatty acids. Mann-Whitney-Wilcoxon tests were used to test for mean differences between erythrocyte fatty acid biomarkers and the fatty acid lipogenic (palmitic acid: linoleic acid) and desaturation (palmitoleic acid: palmitic acid) indices and gastroschisis. Mothers carrying a baby with gastroschisis and gastroschisis babies had consistently higher levels of palmitoleic acid (all P's < 0.05), gastroschisis mothers had lower levels of oleic acid during pregnancy and at delivery, and higher levels of DHA at delivery (all P's < 0.05). The lipogenic index was significantly lower at delivery for gastroschisis mothers (P < 0.05) and the desaturation index was consistently higher in gastroschisis mothers and babies (all P's < 0.01). These findings suggest that early maternal inflammation possibly resulting from an imbalance of fatty acids, leading to a vascular disruption, may be the underlying mechanism responsible for at least some cases of gastroschisis. PMID- 23794283 TI - GPNMB enhances bone regeneration by promoting angiogenesis and osteogenesis: potential role for tissue engineering bone. AB - Bone regeneration is a coordinated process involving the connection between blood vessels and bone cells. Glycoprotein non-metastatic melanoma protein B (GPNMB) is known to be vital in bone formation. However, the effect of GPNMB on bone regeneration and the underlying molecular mechanism are still undefined. Fibroblast growth factor receptor (FGFR)-mediating signaling is pivotal in bone formation and angiogenesis. Therefore, we assessed GPNMB function as a communicating molecule between osteoblasts and angiogenesis, and the possible correlation with FGFR-1 signaling. Recombinant GPNMB dose-dependently increased the differentiation of human bone marrow stromal cells (hBMSCs) into osteoblasts, as well as the mRNA levels of osteoblasts marker alkaline phosphatase (ALP) and osteocalcin (OCN). Furthermore, these increases depended on the activation of FGFR-1 signaling, as pretreatment with FGFR-1 siRNA or its inhibitor SU5402 dramatically dampened GPNMB-induced osteogenesis. Additionally, GPNMB triggered dose-dependently the proliferation and migration of human umbilical vein endothelial cells (hUVECs), FGFR-1 phosphorylation, as well as capillary tube and vessels formation in vitro and in vivo. Blocking FGFR-1 signaling dampened GPNMB induced angiogenic activity. Following construction of a rodent cranial defect model, scaffolds delivering GPNMB resulted in an evident increase in blood vessels and new bone formation; however, combined delivery of GPNMB and SU5402 abated these increase in defect sites. Taken together, these results suggest that GPNMB stimulates bone regeneration by inducing osteogenesis and angiogenesis via regulating FGFR-1 signaling. Consequently, our findings will clarify a new explanation about how GPNMB induces bone repair, and provide a potential target for bone regeneration therapeutics and bone engineering. PMID- 23794284 TI - Chemoselective oxidation by electronically tuned nitroxyl radical catalysts. PMID- 23794285 TI - Interventions for treating cholestasis in pregnancy. AB - BACKGROUND: Obstetric cholestasis has been linked to adverse maternal and fetal/neonatal outcomes. As the pathophysiology is poorly understood, therapies have been empiric. The first version of this review, published in 2001, and including nine randomised controlled trials involving 227 women, concluded that there was insufficient evidence to recommend any of the interventions alone or in combination. This is the first update. OBJECTIVES: To evaluate the effectiveness and safety of therapeutic and delivery interventions in women with cholestasis of pregnancy. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (20 February 2013) and reference lists of identified studies. SELECTION CRITERIA: Randomised controlled trials that compared two intervention strategies for women with a clinical diagnosis of obstetric cholestasis. DATA COLLECTION AND ANALYSIS: The review authors independently assessed trials for eligibility and risk of bias. We independently extracted data and checked these for accuracy. MAIN RESULTS: We included 21 trials with a total of 1197 women. They were mostly at moderate to high risk of bias. They assessed 11 different interventions resulting in 15 different comparisons.Compared with placebo, ursodeoxycholic acid (UDCA) showed improvement in pruritus in five (228 women) out of seven trials. There were no significant differences in instances of fetal distress in the UDCA groups compared with placebo (average risk ratio (RR) 0.67; 95% confidence interval (CI) 0.22 to 2.02; five trials, 304 women; random effects analysis: T2 = 0.74; I2 = 48%). There were significantly fewer total preterm births with UDCA (RR 0.46; 95% CI 0.28 to 0.73; two trials, 179 women). The difference for spontaneous preterm births was not significant (RR 0.99; 95% CI 0.41 to 2.36, two trials, 109 women).Two trials (48 women) reported lower (better) pruritus scores for S-adenosylmethionine (SAMe) compared with placebo, while two other trials of 34 women reported no significant differences between groups.UDCA was more effective in improving pruritus than either SAMe (four trials; 133 women) or cholestyramine (one trial; 84 women), as was combined UDCA+SAMe when compared with placebo (one trial; 16 women) and SAMe alone (two trials; 68 women). However, combined UDCA+SAMe was no more effective than UDCA alone in regard to pruritus improvement (one trial; 53 women) and two trials (80 women) reported data were insufficient to draw any conclusions from. In one trial comparing UDCA and dexamethasone (83 women), a significant improvement with UDCA was seen only in a subgroup of women with severe obstetric cholestasis (23 women).Danxiaoling significantly improved pruritus in comparison to Yiganling. No significant differences were seen in pruritus improvement with other interventions.Eight trials reported fetal or neonatal deaths, with two deaths reported overall (both in the placebo groups).Women receiving UDCA and cholestyramine experienced nausea, vomiting and diarrhoea. Guar gum caused mild abdominal distress, diarrhoea and flatulence during the first days of treatment. Women found charcoal suspension unpleasant to swallow. Dexamethasone caused nausea, dizziness and stomach pain in one woman.One trial (62 women) looked at the timing of delivery intervention. There were no stillbirths or neonatal deaths in 'early delivery' or the 'await spontaneous labour' group. There were no significant differences in the rates of caesarean section, meconium passage or admission to neonatal intensive care unit between the two groups. AUTHORS' CONCLUSIONS: Different approaches to assessing and reporting pruritus precluded pooling of trials comparing the effects of UDCA versus placebo on pruritus, but examination of individual trials suggests that UDCA significantly improves pruritus, albeit by a small amount. Fewer instances of fetal distress/asphyxial events were seen in the UDCA groups when compared with placebo but the difference was not statistically significant. Large trials of UDCA to determine fetal benefits or risks are needed.A single trial was too small to rule in or out a clinically important effect of early term delivery on caesarean section.There is insufficient evidence to indicate that SAMe, guar gum, activated charcoal, dexamethasone, cholestyramine, Salvia, Yinchenghao decoction (YCHD), Danxioling and Yiganling, or Yiganling alone or in combination are effective in treating women with cholestasis of pregnancy. PMID- 23794286 TI - Interventions for cutaneous Bowen's disease. AB - BACKGROUND: Bowen's disease is the clinical term for in situ squamous cell carcinoma of the skin. Cutaneous lesions present as largely asymptomatic, well defined, scaly erythematous patches on sun-exposed skin. In general, people with Bowen's disease have an excellent prognosis because the disease is typically slow growing and responds favourably to treatment. Lesions are persistent and can be progressive, with a small potential (estimated to be 3%) to develop into invasive squamous cell carcinoma. The relative effectiveness of the available treatments is not known for Bowen's disease, and this review attempts to address which is the most effective intervention, with the least side-effects, for cutaneous Bowen's disease. OBJECTIVES: To assess the effects of therapeutic interventions for cutaneous Bowen's disease. SEARCH METHODS: We searched the following databases up to September 2012: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2012, Issue 9), MEDLINE (from 1946), EMBASE (from 1974), PsycINFO (from 1806), and LILACS (from 1982). We also searched online trials registers. We checked the bibliographies of included and excluded studies and reviews, for further references to relevant randomised controlled trials (RCTs). SELECTION CRITERIA: We included all randomised controlled trials assessing interventions used in Bowen's disease, preferably histologically proven. DATA COLLECTION AND ANALYSIS: Two authors independently carried out study selection and assessment of methodological quality. MAIN RESULTS: The primary outcome measures were complete clearance of lesions after the first treatment cycle and recurrence rate at 12 months. Our secondary outcomes included the number of lesions that cleared after each treatment cycle, the number of treatment cycles needed to achieve clearance, the recurrence rates at > 12 months, cosmetic outcome, quality of life assessment, and adverse outcomes as reported by both participant and clinician.We included 9 studies, with a total of 363 participants. One study demonstrated statistically significantly greater clearance of lesions of Bowen's disease with MAL-PDT (methyl aminolevulinate with photodynamic therapy) when compared with placebo-PDT (RR (risk ratio) 1.68, 95% CI (confidence interval) 1.12 to 2.52; n = 148) or cryotherapy (RR 1.17, 95% CI 1.01 to 1.37; n = 215), but there was no significant difference when MAL-PDT was compared to 5-FU (5-fluorouracil). One study demonstrated statistically significantly greater clearance of lesions with ALA-PDT (5-aminolevulinic acid with photodynamic therapy) versus 5-FU (RR 1.83, 95% CI 1.10 to 3.06; n = 66), but no statistically significant difference in recurrence rates at 12 months (RR 0.33, 95% CI 0.07 to 1.53).Cryotherapy showed no statistically significant difference in clearance rates (RR 0.99, 95% CI 0.78 to 1.26) or recurrences at 1 year (RR 1.48, 95% CI 0.53 to 4.17) when compared to 5-FU in 1 study of 127 participants.One study compared imiquimod to placebo and demonstrated statistically significantly greater clearance rates in the imiquimod group (9/15 lesions) compared to placebo (0/16) (Fisher's Exact P value < 0.001). The imiquimod group did not report any recurrences at 12 months, but at 18 months, 2/16 participants in the placebo group had developed early invasive squamous cell carcinoma. AUTHORS' CONCLUSIONS: Overall, there has been very little good-quality research on treatments for Bowen's disease. There is limited evidence from single studies to suggest MAL-PDT is an effective treatment. Although cosmetic outcomes appear favourable with PDT, five-year follow-up data are needed. Significantly more lesions cleared with MAL-PDT compared to cryotherapy. No significant difference in clearance was seen when MAL-PDT was compared with 5-FU, but one study found a significant difference in clearance in favour of ALA-PDT when compared to 5-FU. There was no significant difference in clearance when cryotherapy was compared to 5-FU.The lack of quality data for surgery and topical cream therapies has limited the scope of this review to one largely about PDT studies. The age group, number, and size of lesions and site(s) affected may all influence therapeutic choice; however, there was not enough evidence available to provide guidance on this. More studies are required in the immunosuppressed populations as different therapeutic options may be preferable. Specific recommendations cannot be made from the data in this review, so we cannot give firm conclusions about the comparative effectiveness of treatments. PMID- 23794288 TI - Fluorescent gold nanoparticles: synthesis of composite materials of two-component disulfide gels and gold nanoparticles. AB - Pseudoenantiomeric ethynylhelicene oligomers containing a disulfide group formed two-component gels, which showed different solvent properties from gels without the disulfide group. The disulfide gels reacted with gold nanoparticles, and the resulting organic-inorganic composite materials exhibited fluorescence emission between 600-800 nm, along with emission from the oligomers at 450 nm. The disulfide gels and isolated gold nanoparticles loaded with the oligomers did not show the former emission. The 600-800 nm emission reversibly disappeared upon sol formation with heating, which was accompanied by an enhancement of the emission at 450 nm. The novel emission was also observed in the solid state. PMID- 23794287 TI - Presenilin-1 regulates the expression of p62 to govern p62-dependent tau degradation. AB - Mutations in presenilin-1 (PS1) are tightly associated with early-onset familial Alzheimer's disease (FAD), which is characterized by extracellular amyloid plaques and the accumulation of intracellular Tau. In addition to being the catalytic subunit of gamma-secretase, PS1 has been shown to regulate diverse cellular functions independent of its proteolytic activity. We found that cells deficient in PS1 exhibit reduced levels of p62 protein, a cargo-receptor shuttling Tau for degradation. The downregulation of PS1 led to a significant decrease in both the protein and mRNA transcript of p62, concomitant with attenuated p62 promoter activity. This PS1-dependent regulation of p62 expression was mediated through an Akt/AP-1 pathway independent of the proteolytic activity of PS1/gamma-secretase. This p62-mediated Tau degradation was significantly impaired in PS1-deficient cells, which can be rescued by ectopic expression of either p62 or wild-type PS1 but not mutant PS1 containing FAD-linked mutations. Our study suggests a novel function for PS1 in modulating p62 expression to control the proteostasis of Tau. PMID- 23794289 TI - Factors influencing referral of patients with voice disorders from primary care to otolaryngology. AB - OBJECTIVES/HYPOTHESIS: To evaluate the frequency, timing, and factors that influence referral of patients with laryngeal/voice disorders to otolaryngology following initial evaluation by a primary care physician (PCP). STUDY DESIGN: Retrospective analysis of a large, national administrative US claims database. METHODS: Patients with a laryngeal disorder based on International Classification of Diseases, Ninth Revision, Clinical Modification codes from January 1, 2004 to December 31, 2008, seen by a PCP as an outpatient (with or without otolaryngology involvement), and continuously enrolled for 12 months were included. Patient age, gender, geographic region, last PCP laryngeal diagnosis, comorbid conditions, time from first PCP visit to first otolaryngology visit, number of PCP outpatient visits, and number of PCP laryngeal diagnoses were collected. Cox and generalized linear regressions were performed. RESULTS: A total of 149,653 unique patients saw a PCP as an outpatient for a laryngeal/voice disorder, with 136,152 (90.9%) only seeing a PCP, 6,013 (4.0%) referred by a PCP to an otolaryngologist, and 3,820 (2.6%) self-referred to an otolaryngologist. Acute laryngitis had a lower hazard ratio (HR) for otolaryngology referral than chronic laryngitis, nonspecific dysphonia, and laryngeal cancer. Having multiple comorbid conditions was associated with a greater HR for otolaryngology referral than having no comorbidities. Patient age, gender, and geographic region also affected otolaryngology referral. The time to otolaryngology evaluation ranged from <1 month to >3 months. PCP-referred patients had less time to the otolaryngology evaluation than self-referred patients. CONCLUSIONS: Multiple factors affected otolaryngology referral for patients with laryngeal/voice disorders. Further education of PCPs regarding appropriate otolaryngology referral for laryngeal/voice disorders is needed. PMID- 23794290 TI - Salimyxins and enhygrolides: antibiotic, sponge-related metabolites from the obligate marine myxobacterium Enhygromyxa salina. AB - Unlike their terrestrial counterparts, marine myxobacteria are hardly investigated for their secondary metabolites. This study describes three new compounds (1-3), named salimyxins and enhygrolides, obtained from the obligate marine myxobacterium Enhygromyxa salina. These are the first natural products obtained from Enhygromyxa species. Their structures were elucidated by spectroscopic analysis, including NMR and CD spectroscopy. Enhygrolides are closely related to the nostoclides, which were initially isolated from a cyanobacterium of the genus Nostoc. The salimyxins, representing structurally most unusual degraded sterols, are close to identical to demethylincisterol from the sponge Homaxinella sp. Salimyxin B and enhygrolide A inhibit the growth of the Gram-positive bacterium Arthrobacter cristallopoietes (MIC salimyxin B, 8 MUg mL-1; enhygrolide A, 4 MUg mL-1). PMID- 23794291 TI - QTc interval and electrocardiographic changes by type of shift work. AB - BACKGROUND: We conducted a cross sectional survey of electrocardiographic changes among shift-workers. METHODS: We classified the electrocardiogram morphology, and measured the QTc interval in 91 male workers engaged in regular daily work shifts, 32 in 24 hr work-shift (h24), and 93 in irregular 6 hr work-shift (h6). RESULTS: With reference to daily workers, the QTc interval was prolonged among h6 workers (P < 0.001) and h24 workers (P < 0.005). The age- and obesity-adjusted standardized prevalence ratio (SPR) of a borderline/prolonged QTc was 2.2-fold among h6 workers (95% CI 1.2, 4.2); conduction disorders (SPR = 2.6; 95% CI 1.3, 5.2) and repolarization disorders (SPR = 1.9; 95% CI 1.0, 3.5) were also more frequently observed among h6 workers. Excluding 19 subjects with risk factors for prolonged QTc did not change the results. CONCLUSIONS: Our study reveals significant changes in the ECG morphology in relation to shift-work, especially in unpredictable and non-standard working hours. PMID- 23794292 TI - Relation of respiratory muscle strength, cachexia and survival in severe chronic heart failure. AB - BACKGROUND: Respiratory muscle (RM) function predicts prognosis in non-cachectic patients with chronic heart failure (CHF). We hypothesized that weakness of RM (maximum inspiratory mouth occlusion pressure, Pimax) is a function of body mass index, and that outcome is more a function of BMI than of Pimax or ventilatory drive (P0.1). SUBJECTS AND METHODS: We enrolled 249 CHF patients (11.2 % female, median age 54.2 years) at the German Heart Institute Berlin. Patients were in NYHA classes I/II/III/IV by n = 16/90/108/35. All patients underwent tests of pulmonary function, RM (Pimax, P0.1), cardiopulmonary exercise testing (peakVO2, VE/VCO2-slope), and right heart catheterization. RESULTS: Mean follow-up time was 18 (1-36) months, 47 patients (18.9 %) died or underwent cardiac assist implantation. Pimax correlated weakly with BMI (r = 0.19), peakVO2 (r = 0.15), and FEV1 (r = 0.34, all p < 0.02), and was lower in females compared to males (3.9 +/- 1.7 vs. 6.6 +/- 2.7 kPa; p < 0.001). P0.1 correlated with pulmonary pressure (rho = 0.2; p < 0.01) and peakVO2 (rho = -0.14; p < 0.02). Neither Pimax [hazard ratio (HR) 0.98; confidence interval (CI) 0.88-1.08] nor P0.1 (HR 0.52; 0.06-4.6) predicted survival. Multivariate regression analysis revealed gender, BMI, and FEV1 as cofactors of Pimax, with only BMI (HR 0.87; CI 0.80-0.95) predicting survival independently. The lowest quintile in BMI had the worst outcome (log-rank chi2 = 13.5, p = 0.009). In CHF patients including cachexia and NYHA IV, Pimax does not predict survival. Pimax depends on gender, BMI, FEV1, and peakVO2, with only BMI and peakVO2 predicting survival. The impaired Pimax in CHF might be a result of catabolism and weight loss and is not a predictive factor in itself. PMID- 23794293 TI - Design, synthesis and biological evaluation of rose bengal analogues as SecA inhibitors. AB - SecA, a key component of bacterial Sec-dependent secretion pathway, is an attractive target for exploring novel antimicrobials. Rose bengal (RB), a polyhalogenated fluorescein derivative, was found from our previous study as a potent SecA inhibitor. Here we describe the synthesis and structure-activity relationships (SAR) of 23 RB analogues that were designed by systematical dissection of RB. Evaluation of these analogues allowed us to establish an initial SAR in SecA inhibition. The antimicrobial effects of these SecA inhibitors are confirmed in experiments using E. coli and B. subtilis. PMID- 23794294 TI - Food matrix and cooking process affect mineral bioaccessibility of enteral nutrition formulas. AB - BACKGROUND: When enteral formulas (EF) are administered orally as a supplement to the normal diet, they are often mixed with conventional foods or included in recipes in order to seek new flavors and textures and avoid monotony. The aims of this work were to study the bioaccessibility of Fe, Zn and Ca from commercial EF and the impact upon their incorporation into sweet preparations. Twenty commercial EF, before and after inclusion in sweet food (rice pudding, RP; banana smoothie, BS; tea, T; chocolate dessert, CD) were evaluated regarding Fe, Zn and Ca dialyzability (%DFe , %DZn , %DCa ) as an estimator of mineral bioaccessibility. RESULTS: Fe, Zn and Ca dialyzability from EF was variable and generally low. Heating during EF-sweet food preparation (T and CD) lowered values to 44.1 %DFe , possibly due to degradation of vitamin C, and 52.7 %DZn and 25.3 %DCa , due to the interaction with food components. CONCLUSION: EF and EF-sweet foods did not represent a good supply of Fe, Zn and Ca as recommended. This study demonstrated how the bioaccessibility of these minerals is affected by the food matrix in which EF is included as well as heating during food preparation. PMID- 23794295 TI - Is mda-7/IL-24 a potential target and biomarker for enhancing drug sensitivity in human glioma U87 cell line? AB - Gliomas are the most common form of primary brain tumor with the highest mortality rates. Drug resistance is a major cause of treatment failure in patients with glioma. Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) has been demonstrated to play an important role in drug resistance in human cancer cell lines. However, the reversing effect of mda-7/IL-24 on drug resistance of human glioma is not fully clear. Here, we investigated the effects of overexpression of the mda-7/IL-24 gene in human glioma. We established a cisplatin-resistant U87 glioma cell line and found that mda-7/IL-24 was highly correlated with drug resistance. Furthermore, we investigated the apoptotic rate, intracellular accumulation of Rhodamine-123, and expression of glutathione and P glycoprotein. The over-expression of mda-7/IL-24 enhanced cisplatin cytotoxicity and reversal of drug resistance in glioma cells. The reversing effect of mda-7/IL 24 on drug resistance was induced mainly through the regulation of drug resistance-related genes and efflux drug pumps. Thus, mda-7/IL-24 can be used as a promising predictive biomarker and potential therapeutic target for chemotherapy in glioma. PMID- 23794296 TI - Ineffective esophageal motility and gastroesophageal reflux disease: a close relationship? AB - BACKGROUND/AIMS: An association between ineffective esophageal motility and gastroesophageal reflux disease is already known, but there are also some conflicting data. We evaluated the association between ineffective esophageal motility and gastroesophageal reflux disease in patients who underwent ambulatory pH monitoring for the evaluation of reflux symptoms at Gazi University, Gastroenterology Clinic. MATERIALS AND METHODS: A total of 239 patients who underwent endoscopy, esophageal manometry and ambulatory 24-h pH monitoring due to reflux symptoms were enrolled. Of them, we selected patients who had normal esophageal motility and ineffective esophageal motility. The endoscopy and ambulatory pH monitoring findings were compared between the two groups. RESULTS: Of the 239 patients who presented with reflux symptoms, pathologic acid reflux or endoscopic esophagitis was found in 114 (48%). Ineffective esophageal motility was found in 18 (16%) in the pathologic reflux group and in 4 (3%) in the functional reflux group (p=0.01). Ambulatory pH, manometric and demographic findings were compared in ineffective esophageal motility and normal motility groups. Lower esophageal sphincter (LES) pressures were lower in the ineffective esophageal motility group (19.7 versus 16.2; p=0.01), and total reflux times in both supine and upright position were higher (10.3 versus 4.9; p=0.01) inthe ineffective esophageal motility group. Ineffective esophageal motility patients were older and more obese than normal motility group patients. CONCLUSIONS: This study points to a clear association between ineffective esophageal motility and gastroesophageal reflux disease as defined by ambulatory pH monitoring. PMID- 23794297 TI - Gastroesophageal reflux in children with functional constipation. AB - BACKGROUND/AIMS: Functional constipation and gastroesophageal reflux disease are two major and commonly encountered components of childhood functional gastrointestinal disorders. Epidemiological studies in the adult population support that there is a significant overlap between the different functional disorders of the digestive tract. Therefore, we aimed to investigate the frequency of gastroesophageal reflux disease in children with functional constipation and to compare clinical findings and 24-h esophageal pH monitoring with a group of patients with suspected gastroesophageal reflux disease. MATERIALS AND METHODS: Children between 4 and 16 years old with functional constipation (based on Rome III criteria, Group 1; n=38) were prospectively evaluated. A control group was composed of patients with symptoms suggesting gastroesophageal reflux disease (Group 2; n= 40). All patients included in the study were asked about reflux-related symptoms, and then all cases underwent 24-h esophageal pH monitoring analysis. RESULTS: Delayed gastric emptying symptoms such as belching and hiccups were more common in patients in Group 1 (p=0.002, p=0.021, respectively), whereas chronic cough was more common in patients in Group 2 (p=0.012). According to the 24-h esophageal pH monitoring, pathologic acid reflux in the lower and/or laryngopharyngeal portion of the esophagus was determined in 39.5% of the patients in Group 1 and in 42.5% of the patients in Group 2 (p=0.96). No significant difference was found in terms of age, gender and duration of constipation in patients with and without acid reflux in Group 1 patients. Pyrosis (66.6 vs. 0%, p=0.00001)was more common in Group 1 patients with acid reflux, but hiccups (20 vs. 69.5%, p=0.007) and belching (33.3 vs. 60.8%, p=0.184) were more common in patients in Group 1 without acid reflux. CONCLUSIONS: Gastroesophageal reflux disease should be considered in the treatment and monitoring of patients with functional constipation. Further studies are needed using 24-h pH multichannel impedance. PMID- 23794298 TI - The dual modulatory effect of folic acid supplementation on indomethacin-induced gastropathy in the rat. AB - BACKGROUND/AIMS: Folic acid modulates several disorders in humans. We investigated the effects of folic acid supplementation at varying doses on ulcer formation in the rat. MATERIALS AND METHODS: Male Wistar rats were treated with 1 mg/kg, 2 mg/kg and 3 mg/kg diet of folic acid for 21 days. Gastric ulceration was induced by indomethacin, scored, and assayed to determine the concentration of mucus, malondialdehyde, catalase, and superoxide dismutase in homogenized samples. Normal saline- and ranitidine-treated groups served as negative and positive control, respectively. RESULTS: Indomethacin caused severe damage to the glandular portion of the rats' stomachs with increase in malondialdehyde concentration and reduction in mucus, catalase and superoxide dismutase concentration (p < 0.001). Folic acid supplementation at 2 mg/kg diet reduced significantly the formation of gastric lesions by indomethacin, while at 3 mg/kg, potentiation of the lesions was observed (p < 0.05). Malondialdehyde concentration significantly decreased and superoxide dismutase activity increased in the 2 mg/kg folic acid pre-treated group, while 3 mg/kg folic acid significantly increased the malondialdehyde concentration and decreased both catalase and superoxide dismutase. Mucus concentration was increased in the 2 mg/kg folic acid pretreated group, but decreased in the 3 mg/kg folic acid pretreated group when compared with controls. Pre-treatment with 1 mg/kg diet of folic acid produced no significant changes. Histopathological studies underlined differences in the indomethacin-induced alterations in gastric mucosal structure following pre-treatment with a 2 mg/kg or 3 mg/kg diet of folic acid. CONCLUSIONS: Folic acid is gastroprotective at the basal requirement supplemental dose; high dose may be dangerous to the integrity of the stomach. PMID- 23794299 TI - The assessment of carotid intima-media thickness, lipid profiles and oxidative stress markers in Helicobacter pylori-positive subjects. AB - BACKGROUND/AIMS: Helicobacter pylori infection has been suggested to be associated with atherosclerosis. The issue is still controversial. It is well known that abnormal lipid profile and oxidative stress are related to atherosclerosis and the measurement of carotid intima-media thickness. The aim of this study was to investigate carotid intima-media thickness and oxidative stress along with lipid parameters in Helicobacter pylori-positive and -negative subjects. MATERIALS AND METHODS: Thirty Helicobacter pylori-positive subjects and 31 Helicobacter pylori-negative subjects were enrolled. Helicobacter pylori infection was diagnosed by noninvasive tests. Serum total oxidant status and total antioxidant capacity levels were measured. Oxidative stress index was calculated based on total oxidant status/total antioxidant capacity ratio. Traditional cardiovascular risk factors were recorded, and laboratory analysis included measurement of serum triglycerides, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol. carotid intima media thickness was assessed by high-resolution ultrasound. RESULTS: We found that the mean and maximum values of right and overall carotid intima-media thickness in Helicobacter pylori-positive subjects were significantly thicker than in Helicobacter pylori-negatives (p < 0.05). Serum triglycerides levels of Helicobacter pylori-positive subjects were significantly higher than in Helicobacter pylori-negatives (p < 0.05). Total oxidant status, total antioxidant capacity and oxidative stress index values were significantly higher in Helicobacter pylori-positive subjects compared with negatives (p < 0.05). No significant correlation was observed between oxidative stress markers and carotid intima-media thickness values. CONCLUSIONS: Carotid intima-media thickness, total oxidant status, total antioxidant capacity, oxidative stress index, and triglycerides values are increased in Helicobacter pylori-positive subjects compared to Helicobacter pylori-negatives. These data indicated that Helicobacter pylori infection may have a role in atherosclerotic processes. PMID- 23794300 TI - T85C polymorphisms of the dihydropyrimidine dehydrogenase gene detected in gastric cancer tissues by high-resolution melting curve analysis. AB - BACKGROUND/AIMS: Dihydropyrimidine dehydrogenase is a key enzyme acting on the metabolic pathway of medications for gastric cancer. High-resolution melting curve technology, which was developed recently, can distinguish the wild-type dihydropyrimidine dehydrogenase gene from multiple polymorphisms by fluorescent quantitative polymerase chain reaction products in a direct and effective manner. MATERIALS AND METHODS: T85C polymorphisms of dihydropyrimidine dehydrogenase in the peripheral blood of 112 Chinese gastric cancer patients were detected by real time polymerase chain reaction combined with high-resolution melting curve technology. Primer design, along with the reaction system and conditions, was optimized based on the GenBank sequence. RESULTS: Seventy nine cases of wild-type (TT, [70.5%]), 29 cases of heterozygous (TC, [25.9%]), and 4 cases of homozygous mutant (CC, [3.6%]) were observed. The result was completely consistent with the results of the sequencing. CONCLUSIONS: Real-time polymerase chain reaction combined with high-resolution melting curve technology is a rapid, simple, reliable, direct-viewing, and convenient method for the detection and screening of polymorphisms. PMID- 23794301 TI - Mouse forestomach carcinoma cells immunosuppress macrophages through TGF-beta1. AB - BACKGROUND/AIMS: Peritoneal implantation metastasis of gastric cancer cells is associated with poor prognosis. Peritoneal macrophages are the most important immune cells in the abdominal cavity to control tumor metastasis. In the present study, the immunosuppressive effects of mouse forestomach cells on macrophages were examined. MATERIALS AND METHODS: Conditioned medium from mouse forestomach cell cultures were used to treat isolated peritoneal macrophages. A colorimetry based phagocytosis assay was performed to investigate the functional change of macrophages. The alternation in cytokine secretion by macrophages was measured by enzyme-linked immunosorbent assay. Specific markers of macrophage polarization were analyzed by real-time reverse transcription polymerase chain reaction. The transforming growth factor-beta1 signaling was evaluated by Western blotting. Neutralization experiments were performed by using transforming growth factor beta1 antibody. RESULTS: The conditioned medium reduced the phagocytotic capability of macrophages. Lower tumor necrosis factor-alpha and interleukin 1beta levels and higher interleukin-10 and vascular endothelial growth factor levels were observed. Real-time reverse transcription polymerase chain reaction showed increased mRNA levels of M2 macrophage markers. Further study revealed that transforming growth factor-beta1 was significantly elevated in the conditioned medium and transforming growth factor-beta1 signaling was activated in the macrophages with treatment with conditioned medium. Neutralization of transforming growth factor-beta1 reversed the immunosuppressive effects on macrophages. CONCLUSIONS: Immunosuppressive macrophages can be induced by conditioned medium from mouse forestomach cell cultures. These effects seemed to be through the production of transforming growth factor-beta1 by the tumor cells. Targeting transforming growth factor-beta1 intervention might help in the control of peritoneal metastasis of gastric cancers. PMID- 23794302 TI - Peptic ulcer disease in children: an uncommon disorder with subtle symptomatology. AB - BACKGROUND/AIMS: Data concerning peptic and infectious ulcers in children are limited. The aim of the study was to investigate the prevalence, presenting symptoms and significance of symptomatology in ulcer diagnosis in the pediatric age group. MATERIALS AND METHODS: Between January 2000 and 2009, upper gastrointestinal endoscopy charts were examined retrospectively. All children in whom a diagnosis of ulcer was established were included in the study. Demographic, clinical, endoscopic, and histopathologic data were obtained from the patients' records. Peptic ulcer disease prevalence, presenting symptoms and symptomatology were evaluated. RESULTS: Ulcer disease was observed in 31 (3.4%) of 902 patients. The mean age was 10.85 +/- 4.25 (range: 2-17 years), and the male to female ratio was 2:1. The most common symptom was chronic abdominal pain (68%), hematemesis and melena (55%) and vomiting (39%). Helicobacter pylori was identified in 19 patients (61%) with ulcer. In the Helicobacter pylori-positive group, upper intestinal bleeding and pain were the major symptoms. Symptom frequency was not different between Helicobacter pylori-positive and -negative patients (p>0.05). CONCLUSIONS: Ulcer disease is an uncommon disorder in children with nonspecific clinical symptoms. Unlike the adult population, symptoms fail to diagnose peptic ulcer disease before gastrointestinal bleeding occurs. PMID- 23794303 TI - Route selection for double balloon enteroscopy in patients with obscure gastrointestinal bleeding: experience from a single center. AB - BACKGROUND/AIMS: This study was performed to clarify the best insertion route of double-balloon enteroscopy and to report the characteristics and proportions of small bowel pathologies detected by double-balloon enteroscopy in our patients with obscure gastrointestinal bleeding. MATERIALS AND METHODS: Between January 2006 and December 2009, 75 patients with obscure gastrointestinal bleeding were enrolled into this study. The procedure was performed by oral route in 60 patients, anal route in 5 patients and both in 10 patients. Mean age of the patients was 50.8 years, and 57.3% of them were male. The main outcome measurements were total length of insertion, total time of double-balloon enteroscopy, diagnostic rates, anatomic location of the lesions, and final diagnosis of lesions detected. RESULTS: Double-balloon enteroscopy was diagnostic in 75% of the patients. This rate was significantly higher in overt bleeding (91.7%). The source of bleeding could not be detected in 19 patients. Mean times of procedures were 119, 144 and 154 minutes for oral route, anal route and both, respectively. The mean insertion length was 310.65 cm (beyond the pylorus)for oral and 166.8 cm (beyond the ileocecal valve) for anal route. The most frequent pathologies were vascular malformations (n=20) and tumors (n=19). All malignant lesions were detected in the proximal part of the small intestine. Vascular malformations were distributed equally through the small intestine. Endoscopic treatment was performed in 30% of patients. CONCLUSIONS: Double-balloon enteroscopy is a safe and feasible examination for obscure gastrointestinal bleeding. Most lesions were localized in the proximal part of the small intestine. The oral route may be preferred as a first choice, if the imaging modalities including capsuleendoscopy cannot detect the lesion. PMID- 23794304 TI - The effect of narrowed segment length on the degree of early postoperative dysphagia in laparoscopic Nissen fundoplication. AB - BACKGROUND/AIMS: Although laparoscopic Nissen fundoplication is the gold standard in the surgical treatment of gastroesophageal reflux disease, it may cause troublesome complications like dysphagia. In this study, we demonstrated the effect of narrowed segment length on early dysphagia in patients. MATERIALS AND METHODS: Forty-one patients who underwent laparoscopic Nissen fundoplication by a single surgeon between January 2007 and November 2008 were reviewed. Dysphagia scores were assessed by a question in the Gastrointestinal Quality of Life Index questionnaire and recorded preoperatively and at 1 month and 6 months. Barium esophagogram was performed for all patients at 1 month. Narrowed segment length was measured on esophagogram. Patients were divided into two groups (Group 1, <=30 mm; Group 2, >30 mm). Dysphagia scores preoperatively and at 1 month and 6 months were compared between the two groups. RESULTS: The two groups were homogeneous in age, gender, body mass index, and preoperative dysphagia score. We were unable to demonstrate any difference in preoperative and postoperative dysphagia scores between the two groups. CONCLUSIONS: In this study, we used subjective data for grade of dysphagia and esophagogram for wrap length instead of manometric data. In our opinion, there is no effect of narrowed segment length on the degree of early postoperative dysphagia in patients undergoing laparoscopic Nissen fundoplication. PMID- 23794305 TI - Does Helicobacter pylori treatment improve the symptoms of globus hystericus? AB - BACKGROUND/AIMS: Globus hystericus is a feeling of tension in the throat, irrelevant of swallowing, persisting for at least 12 weeks. Since the cause of globus hystericus is not fully described, the treatment is controversial. We aimed in this study to determine the symptoms of gastroesophageal reflux disease, upper gastrointestinal endoscopic findings, prevalence of Helicobacter pylori,and post-treatment symptoms (symptoms of gastroesophageal reflux and/or Helicobacter pylori) in patients with a diagnosis of globus hystericus. MATERIALS AND METHODS: One hundred twenty three patients were recruited from the archives of the Department of Gastroenterology and Endoscopy at Celal Bayar University Medical School between January 2009 and August 2010. RESULTS: Helicobacter pylori was positive in 75 (60%) of 123 patients with globus hystericus. Helicobacter pylori (+) patients had significantly more heartburn, regurgitation, and inlet patch in upper esophagus than Helicobacter pylori (-) patients. Significantly more Helicobacter pylori (-) patients had normal endoscopy findings when compared to Helicobacter pylori (+) patients. While 27 (50%) of Helicobacter pylori eradicated patients had regressing globus symptoms, 12 (17.3%) of them did not have any regression in globus symptoms. Improvement in symptoms showed a positive correlation with Helicobacter pylori eradication (p=0.001). CONCLUSIONS: Helicobacter pylori rate among cases with globus sensation was similar to values in the general population. Helicobacter pylori eradication was found to decrease globus symptoms. PMID- 23794306 TI - Clinical and molecular characterization of colorectal cancer in young Moroccan patients. AB - BACKGROUND/AIMS: Early-onset colorectal cancers are relatively rare. About 20% of colorectal cancers are familial or hereditary. Two autosomal dominantly inherited cancer syndromes are more studied: Lynch syndrome accounts for 2-5% of colorectal cancers and familial adenomatous polyposis represents 1% of total colorectal cancers. Unlike the familial adenomatous polyposis syndrome, there are no clinical features that help in easily recognizing Lynch syndrome. The young age of cancer occurrence could be a criterion that should raise a suspicion of Lynch syndrome. In Morocco, the average age at diagnosis of colorectal cancers according to the register of cancers of Casablanca is 56 years, which is 10 years earlier than in European countries. Our study aimed to assess the frequency and molecular characteristics of the Lynch syndrome in Moroccan early-onset colorectal cancers patients. MATERIALS AND METHODS: The population analyzed included 70 patients. The criteria for inclusion of patients in this study were a colorectal cancers before age 50 and the exclusion of familial adenomatous polyposis. We started by searching for microsatellite instability, first by immunohistochemistry of 3 mismatch repair proteins (MLH1, MSH2 and MSH6) and with second confirmation using 4 monomorphic markers (BAT25, BAT26, NR21, and CAT25). RESULTS: We found instability in 10/70 (15%) of the cases. The loss of expression affects more often the MLH1 protein, with 8 cases, versus 2 cases of altered MSH2. None of the 70 patients of the series fulfilled the Amsterdam II criteria, indicative of Lynch syndrome. CONCLUSIONS: Further work needs to be done to discriminate hereditary cases from sporadic ones, but testing for microsatellite instability as a first step is important. PMID- 23794307 TI - Effects of glucagon-like peptide-2 on bacterial translocation in rat models of colitis. AB - BACKGROUND/AIMS: The aim of this trial was to study the role of glucagon-like peptide-2 in reducing bacterial translocation by virtue of its anti-inflammatory effects and ability to decrease intestinal permeability in rat models of inflammatory bowel diseases. On the basis of our results and those of other recent studies, we suggest a new treatment modality for colitis. To our knowledge, this is the first study of the effectiveness of glucagon-like peptide 2 on bacterial translocation, in treating an experimental colitis model. METHODS: Rats were randomized into 3 groups of 7 rats each-the control group, colitis group, and treatment group. On the 7 th day after induction of colitis, the levels of tissue myeloperoxidase, serum tumor necrosis factor-alpha, and plasma endotoxin were measured. Tissue samples were obtained from the liver, spleen, and mesenteric lymph nodes for evaluating bacterial translocation. RESULTS: Bacterial translocation in samples of the liver, spleen, mesenteric lymph nodes, and portal and systemic blood obtained from the treatment group was lower than that in samples obtained from the colitis group (p < 0.05). The levels of tissue myeloperoxidase, serum tumor necrosis factor-alpha, and plasma endotoxin in the treatment group were significantly lower than those in the colitis group (p < 0.05). CONCLUSIONS: In experimental colitis models, which were induced using trinitrobenzene sulfonic acid in ethanol, glucagon-like peptide-2 treatment reduced inflammation and bacterial translocation from the intestinal mucosa. Our results indicate that glucagon-like peptide-2 is a potential agent for treating colitis; however, extensive trials are needed to confirm our results. PMID- 23794308 TI - Relationship between serum aminotransferase levels and metabolic disorders in northern China. AB - BACKGROUND/AIMS: Increasing evidence suggests an association between elevated serum aminotransferase levels and metabolic disorders (metabolic syndrome, hyperlipidemia and diabetes mellitus). However, the significance of relatively low levels of aminotransferases in relation to metabolic disorders has not been fully investigated in the general population. We investigated the association between serum aminotransferase levels and metabolic disorders using data from a survey in Jilin Province, China. MATERIALS AND METHODS: In 2007, a prospective survey was conducted throughout Jilin, China, covering both urban and rural areas. A total of 3835 people, 18-79 years old, were undergoing real-time ultrasonography, blood tests, and interviews with a structured questionnaire. RESULTS: Serum aminotransferase levels within the normal range were associated with metabolic syndrome independent of age, occupation, cultural and educational level, income, body mass index, waist circumference, smoking, and alcohol intake. Compared with the lowest level (< 20 IU/L), the adjusted odds ratios for alanine aminotransferase levels of 20-29, 30-39, 40-49, and >50 IU/L were 1.92, 2.50, 2.97, and 3.52 in men, and 1.38, 1.54, 3.06, and 2.62 in women, respectively. Near-normal serum aminotransferase levels associated with hyperlipidemia, non alcoholic fatty liver disease, and diabetes mellitus were also found in the study. CONCLUSIONS: Normal to near-normal serum aminotransferase levels are associated with metabolic disorders. Serum alanine aminotransferase levels of 21 25 IU/L for men and 17-22 IU/L for women are suggested as cut-off levels that detect metabolic disorders affecting the liver. PMID- 23794309 TI - Selective transitional zone sampling approach versus random biopsy in cases with malignant liver masses: is there any superiority? AB - BACKGROUND/AIMS: Currently, the diagnostic sensitivity of malignant liver mass biopsies is an important problem in the definitive diagnosis. In this study, we aimed to investigate the role of selective peripheral approach to lesion biopsies for diagnostic sensitivity of liver masses. MATERIALS AND METHODS: Between June 2007 and March 2011, totally 88 patients (50 male, 38 female), referred to our Interventional Radiology Department for sonographically guided Tru-cut biopsies for liver lesions, were examined.All biopsies were performed by an experienced radiologist with an 18-gauge Tru-cut biopsy needle with a spring-loaded biopsy gun under sonographic guidance. We describe two locations (peripheral and central) for liver lesions, with the inner 2/3 part of the mass as central and the outer 1/3 part as peripheral. We obtained biopsy from both of these locations, and samples were transferred to the Pathology Department separately. RESULTS: According to pathological and immunohistochemistry studies, there were 42 hepatocellular carcinomas and 46 metastases. All of the metastatic tumors were stained by cytokeratin (10 lung adenocarcinoma, 15 breast adenocarcinoma, 16 gastrointestinal tract, 4 prostate, and 1 malignant melanoma of these 46 metastases were reported as primary). According to histopathological results, diagnostic sensitivity was 97.7% in peripherally located biopsies and 86.3% in biopsies taken from the center of the masses (p=0.0063). CONCLUSIONS: Selective peripheral biopsy approach in Tru-cut biopsies of liver lesions has better sensitivity rates for histopathologic diagnosis compared to the centrally located and random biopsies. PMID- 23794310 TI - Molecular characterization of hepatitis A virus isolated from acute infections in Turkey. AB - BACKGROUND/AIMS: Hepatitis A virus is a global public health problem, especially in developing countries, and the most common cause of hepatitis in childhood. Hepatitis A virus is a single- stranded positive RNA virus subdivided to 6 genotypes (3 human,3 simian). The aim of this study was to determine the prevalent genotype in Turkey using sera of acute hepatitis A virus-infected patients from different geographical regions of the country. MATERIALS AND METHODS: Sera of 137 patients with acute hepatitis A virus from different geographical regions were collected for phylogenetic analysis. The VP1-2A region of the hepatitis A virus genome was amplified by real-time-polymerase chain reaction in 76 patients where possible. Amplified polymerase chain reaction fragments were sequenced, and phylogenetic analysis was done together with other reference hepatitis A virus sequences obtained from GenBank database. RESULTS: Sequencing and phylogenetic analysis of the VP1-2A junction of hepatitis A virus showed that the most prevalent genotype in Turkey is IB (100%). Comparison of Turkish isolates and reference sequences of genotype IB showed a similarity of 94.9%. The same comparison was done between Turkish isolates and reference hepatitis A virus genotype IB and HM175, and it was found that similarity between them ranged from 93.0-95.9%. When Turkish isolates were compared according to Mean Percentage Nucleotide Distance analysis, similarity ranged between 95.3% 100%. CONCLUSIONS: Phylogenetic analysis pointed out that all Turkish isolates belong to genotype IB. Sequence analysis is a useful tool in revealing hepatitis A outbreaks, and allows us to detect and distinguish the presence of epidemic and small outbreaks. PMID- 23794311 TI - Measurement of the coronary flow velocity reserve in patients with non-alcoholic fatty liver disease. AB - BACKGROUND/AIMS: Endothelial dysfunction is an early and reversible feature in the pathogenesis of atherosclerosis. Coronary flow velocity reserve is a noninvasive test showing endothelial function of epicardial coronary arteries and coronary microcirculatory function. This study was designed to evaluate the carotid intima-media thickness and myocardial microvascular circulation in patients with non-alcoholic fatty liver disease. MATERIALS AND METHODS: Twenty four patients with non-alcoholic fatty liver disease and 28 healthy subjects were studied. According to the pathology of liver biopsies, patients with non alcoholic fatty liver disease were divided into non-alcoholic fatty liver and nonalcoholic steatohepatitis groups. Coronary diastolic peak flow velocities were measured at baseline, and then dipyridamole infusion was measured by transthoracic Doppler echocardiography. The ratio of hyperemic to baseline diastolic peak velocities was calculated and the intima-media thicknesss of the carotid arteries were measured. RESULTS: Baseline average diastolic peak and diastolic mean flow velocities were similar between non-alcoholic fatty liver disease patients and healthy subjects. However, hyperemic average diastolic peak and diastolic mean flow velocities were significantly lower in the patient groups compared to those in the controls (p=0.005 and p=0.002). Coronary flow velocity reserve was 1.65 +/- 0.36 and 2.67 +/- 0.81 in patients and healthy subjects, respectively (p < 0.001). The intima-media thickness was similar between the patients with non-alcoholic fatty liver disease and healthy subjects. The comparison of patients with non-alcoholic fatty liver and non-alcoholic steatohepatitis within the non-alcoholic fatty liver disease group with respect to coronary flow velocity reserve and intima-media thickness yielded no statistical differences. CONCLUSIONS: The present study showed that coronary flow velocity reserve, which establishes coronary microvascular and endothelial functions noninvasively, is significantly impaired in patients with non-alcoholic fatty liver disease. The impaired coronary flow velocity reserve-like early atherosclerotic changes may have value in the prediction of coronary artery disease in patients with non-alcoholic fatty liver disease. PMID- 23794312 TI - Solid pseudopapillary tumor of the pancreas: a case series of 9 patients. AB - BACKGROUND/AIMS: Solid pseudopapillary tumor is a rare exocrine tumor of the pancreas. There is no clear consensus on its etiology, origin and treatment. In this study, the clinical, pathological and immunohistochemical features of nine patients with solid pseudopapillary tumor were re-evaluated in view of the current literature findings. MATERIALS AND METHODS: We studied nine cases diagnosed with solid pseudopapillary tumor between 2005 and 2010. The clinical, pathological and laboratory data were analyzed. RESULTS: On microscopy, all tumors had well-defined borders and were separated from surrounding pancreatic tissue by a thick fibrous capsule. The tumor consisted mainly of pseudopapillary structures with focal solid areas accompanied by wide hemorrhagic and cystic regions. The typical morphological features were present to varying degrees. Of the nine cases, one relapsed approximately two years after the diagnosis, and our laboratory also evaluated the surgical specimen of local recurrence. CONCLUSIONS: While some new light has been shed on the clinicopathological features of solid pseudopapillary tumor concerning its etiology, origin and treatment methods, there is much to be understood. Further studies focusing on genetics, pathogenesis and prognosis are needed for a better understanding of this entity. PMID- 23794313 TI - Prognostic value of somatostatin receptor-2 positivitiy in gastroenteropancreatic neuroendocrine tumors in reference to known prognostic factors. AB - BACKGROUND/AIMS: Identification of the predictive factors for the prognosis of gastroenteropancreatic neuroendocrine tumors is important but rather challenging due to the rarity of the condition. This study aimed to examine the association between somatostatin receptor-2 positivity and known prognostic factors for gastroenteropancreatic neuroendocrine tumor to identify the value of somatostatin receptor-2 positivity itself as a predictive factor for prognosis. MATERIALS AND METHODS: Records of 41 gastroenteropancreatic neuroendocrine tumor patients (24 females, 17 males) were retrospectively reviewed. The relations between somatostatin receptor-2 positivity and known prognostic factors including tumor stage, Ki-67 positivity, vascular or perineural invasion, lymph node metastasis, presence of necrosis, and soft tissue extension were analyzed. RESULTS: Sixty percent of the patients had histologically confirmed somatostatin receptor-2 positivity with 45% exhibiting focal and 15% showing diffuse staining characteristic. No significant relation was found between somatostatin receptor-2 positivity and any of the known prognostic factors for gastroenteropancreatic neuroendocrine tumor: versus stage, p=0.67; vs. lymph node metastasis, p=0.51; vs. vascular invasion, p=0.11; vs. extension to surrounding soft tissue, p=0.54; vs. necrosis, p=0.23; vs. lymphatic invasion, p=0.25; and vs. perineural invasion, p=0.42. CONCLUSIONS: Somatostatin receptor-2 positivity, either focal or diffuse, does not seem to predict prognosis in gastroenteropancreatic neuroendocrine tumors. However, growing evidence supports the benefits of somatostatin analogues as adjunctive treatment in this group of patients. PMID- 23794314 TI - Health needs assessment for medical genetic services for congenital disorders in middle- and low-income nations. AB - Medical genetic services for the care and prevention of congenital disorders have received little attention in most middle- and low-income countries to date. In 2010, the World Health Organisation prioritized services for the care and prevention of birth defects in these nations, emphasising their importance in assisting such countries to reach their Millennium Development Goals. Health Needs Assessment is an inclusive, rational, epidemiological-assisted approach for providing information to plan, introduce and beneficially change health care services to improve the health of populations. It is intrinsic to much of the development of health care systems in industrialised nations. Its use by middle- and low-income countries to introduce and develop medical genetic services commensurate with their needs and circumstances would be beneficial. An approach to applying Health Needs Assessment in these circumstances is described. PMID- 23794315 TI - Salvia divinorum: from Mazatec medicinal and hallucinogenic plant to emerging recreational drug. AB - Salvia divinorum is a sage endemic to a small region of Mexico and has been traditionally used by the Mazatec Indians for divination and spiritual healing. Recently, it has gained increased popularity as a recreational drug, used by adolescents and young adults as an alternative to marijuana and LSD. Salvinorin A, the major active ingredient of the plant, is considered to be the most potent known hallucinogen of natural origin. This review surveys the current state of knowledge on the neurochemical, pharmacokinetic, and pharmacological properties of salvinorin A, the trends and motivation behind S. divinorum use, and the health problems among users of the plant's products. S. divinorum induces intense, but short-lived, psychedelic-like changes in mood and perception, with concomitant hallucinations and disorientation. Many websites have misinterpreted the limited existing research-based information on the side effects of salvia as evidence for its safety. However, data accumulated over the last few years indicate that potential health risks are associated with the use of S. divinorum, especially by teenagers, users of other substances of abuse, and individuals with underlying psychotic disturbances. Taken together, the data presented in this review point to the need for further basic and clinical studies to create a basis for the development of well-addressed prevention and treatment strategies. PMID- 23794317 TI - Is there a family profile of addictive behaviors? Family functioning in anorexia nervosa and drug dependence disorder. AB - OBJECTIVES: The objective of the study was to determine whether family profiles differ between patients with anorexia nervosa or drug dependence disorder. METHOD: 25 families of patients with anorexia nervosa and 26 families of patients with drug dependence disorder responded to a battery of self-reports (Interpersonal Dependence Inventory, Family Adaptability and Cohesion Evaluation Scales, and Family Questionnaire). RESULTS: A lack of social self-confidence was observed in patients with anorexia nervosa or drug dependence disorder and their parents. Family disturbances characterized by low cohesion and emotional reliance on another person were observed in the families of patients with anorexia nervosa or drug dependence disorder. CONCLUSIONS: The present study suggests that there are differing levels of severity of family disturbances among fathers, mothers, and patients in both anorexia nervosa and drug dependence disorder. PMID- 23794318 TI - High-molecular-weight regular alternating diketopyrrolopyrrole-based terpolymers for efficient organic solar cells. PMID- 23794319 TI - Autosomal dominant oculoauriculovertebral spectrum and 14q23.1 microduplication. AB - Oculoauriculovertebral spectrum (OAVS; OMIM 164210) is characterized by anomalies derived from an abnormal development of the first and second branchial arches, with marked inter and intra-familial phenotypic variability. Main clinical features are defects on aural, oral, mandibular, and vertebral development. Cardiac, pulmonary, renal, skeletal, and central nervous system anomalies have also been described. Most affected individuals are isolated cases in otherwise normal families. Autosomal dominant inheritance has been observed in about 2-10% of cases and linkage analysis as well as array-CGH analysis have detected candidate loci for OAVS offering new insights into the understanding of pathogenesis of this entity. We describe a family with clinical diagnosis of OAVS, autosomal dominant inheritance pattern, and detection of a 14q23.1 duplication of 1.34 Mb in size which segregates with the phenotype. This region contains OTX2, which is involved in the development of the forebrain, eyes, and ears, and appears to be a good candidate gene for OAVS. PMID- 23794316 TI - Anaemia, prenatal iron use, and risk of adverse pregnancy outcomes: systematic review and meta-analysis. AB - OBJECTIVES: To summarise evidence on the associations of maternal anaemia and prenatal iron use with maternal haematological and adverse pregnancy outcomes; and to evaluate potential exposure-response relations of dose of iron, duration of use, and haemoglobin concentration in prenatal period with pregnancy outcomes. DESIGN: Systematic review and meta-analysis DATA SOURCES: Searches of PubMed and Embase for studies published up to May 2012 and references of review articles. STUDY SELECTION CRITERIA: Randomised trials of prenatal iron use and prospective cohort studies of prenatal anaemia; cross sectional and case-control studies were excluded. RESULTS: 48 randomised trials (17 793 women) and 44 cohort studies (1 851 682 women) were included. Iron use increased maternal mean haemoglobin concentration by 4.59 (95% confidence interval 3.72 to 5.46) g/L compared with controls and significantly reduced the risk of anaemia (relative risk 0.50, 0.42 to 0.59), iron deficiency (0.59, 0.46 to 0.79), iron deficiency anaemia (0.40, 0.26 to 0.60), and low birth weight (0.81, 0.71 to 0.93). The effect of iron on preterm birth was not significant (relative risk 0.84, 0.68 to 1.03). Analysis of cohort studies showed a significantly higher risk of low birth weight (adjusted odds ratio 1.29, 1.09 to 1.53) and preterm birth (1.21, 1.13 to 1.30) with anaemia in the first or second trimester. Exposure-response analysis indicated that for every 10 mg increase in iron dose/day, up to 66 mg/day, the relative risk of maternal anaemia was 0.88 (0.84 to 0.92) (P for linear trend<0.001). Birth weight increased by 15.1 (6.0 to 24.2) g (P for linear trend=0.005) and risk of low birth weight decreased by 3% (relative risk 0.97, 0.95 to 0.98) for every 10 mg increase in dose/day (P for linear trend<0.001). Duration of use was not significantly associated with the outcomes after adjustment for dose. Furthermore, for each 1 g/L increase in mean haemoglobin, birth weight increased by 14.0 (6.8 to 21.8) g (P for linear trend=0.002); however, mean haemoglobin was not associated with the risk of low birth weight and preterm birth. No evidence of a significant effect on duration of gestation, small for gestational age births, and birth length was noted. CONCLUSIONS: Daily prenatal use of iron substantially improved birth weight in a linear dose-response fashion, probably leading to a reduction in risk of low birth weight. An improvement in prenatal mean haemoglobin concentration linearly increased birth weight. PMID- 23794320 TI - Adverse drug reactions in patients with Alzheimer's disease and related dementia in France: a national multicentre cross-sectional study. AB - PURPOSE: To assess the prevalence of adverse drug reactions (ADRs) occurring in patients with Alzheimer's disease (AD) or other dementia in France. METHODS: A cross-sectional multicentre study was conducted by the French network of the 31 regional pharmacovigilance centres on a given day. The subjects were selected by random draw to be a representative sample of French patients with dementia: consultations of dementia clinics, nursing-homes, acute and long care geriatric units, rehabilitation care geriatric units. The staff of each medical structure together with that of the pharmacovigilance centre defined a day for including the patients. Socio-demographic data, history, ADR and drugs given were registered. RESULTS: There were 1332 subjects included, 51.1% living at home, 48.8% in institutions, aged 82.0 +/- 8.0 years (46-108); 61.3% suffered from AD. Mean number of drugs was 6.3 +/- 3.1. Anti-dementia drugs were given to 66.4% subjects. ADR prevalence was 5.0% (95% CI: 3.9-6.2) without a significant difference between at home and institutionalized patients. ADR consisted of gastro-intestinal (23.2%), central nervous system (17.4%) and psychiatric disorders (8.7%). Of the ADR, 31.9% were serious, and 47.8% preventable. The drugs most often involved were anti-dementia (28.9%), cardio-vascular (28.9%) and psychotropic drugs (26.4%, anxiolytics, hypnotics, antidepressants, neuroleptics). CONCLUSION: This national scale study showed that iatrogenesis in patients with AD and related dementia can at times be serious and preventable. Therefore, special attention is required when prescribing psychotropic and anti dementia drugs, as they are frequently used and induce half of the ADR in this population. PMID- 23794322 TI - Oral steroids for long-term use in cystic fibrosis. AB - BACKGROUND: In cystic fibrosis (CF) airway obstruction and recurrent respiratory infection lead to inflammation, long-term lung damage, respiratory failure and death. Anti-inflammatory agents, e.g. oral corticosteroids are used since inflammation occurs early in disease. OBJECTIVES: To assess the effectiveness of oral corticosteroids in respiratory complications in CF, particularly lung function and adverse events. We examined long-term use (over 30 days) only. SEARCH METHODS: We searched the Cochrane CF and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Most recent search: 15 May 2013. SELECTION CRITERIA: Randomised trials comparing oral corticosteroids given for more than 30 days with placebo or no additional therapy in people with CF. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study eligibility and quality. MAIN RESULTS: Of eleven studies identified, three (354 participants) were included: two with four year follow up and one with 12-weeks follow up. Data were lacking on predefined outcomes; common outcomes were examined at different time-points and presented differently. Meta-analyses were not possible.In one study, oral corticosteroids at prednisolone-equivalent dose of 1 mg/kg alternate days slowed progression of lung disease; at two and four years, % predicted FEV1 in the 1 mg/kg group changed significantly more than in the placebo group (P < 0.02). During the first two years, the 2 mg/kg group was not significantly different from the placebo group. Linear growth retardation was observed from six months in the 2 mg/kg alternate days prednisolone group and from 24 months in the 1 mg/kg alternate days prednisolone group.Adverse events terminated one four-year study early. Year 10 follow up showed catch-up growth started two years after treatment ceased. Alternate-day treatment with oral corticosteroids may have impaired growth until adulthood in boys. AUTHORS' CONCLUSIONS: Oral corticosteroids at prednisolone equivalent dose of 1 to 2 mg/kg alternate days appear to slow progression of lung disease in CF; benefit should be weighed against occurrence of adverse events. Risk-benefit analysis of low-dose alternate days corticosteroids is important and the short-term use of oral corticosteroids should be better evaluated. PMID- 23794323 TI - Reply to letter by Nolan and colleagues--re: the carcinogenicity of New York state talc dusts in humans. PMID- 23794321 TI - New approaches to the problem of generating coherent, reproducible phenotypes. AB - Fundamental, unresolved questions in biology include how a bacterium generates coherent phenotypes, how a population of bacteria generates a coherent set of such phenotypes, how the cell cycle is regulated and how life arose. To try to help answer these questions, we have developed the concepts of hyperstructures, competitive coherence and life on the scales of equilibria. Hyperstructures are large assemblies of macromolecules that perform functions. Competitive coherence describes the way in which organisations such as cells select a subset of their constituents to be active in determining their behaviour; this selection results from a competition between a process that is responsible for a historical coherence and another process responsible for coherence with the current environment. Life on the scales of equilibria describes how bacteria depend on the cell cycle to negotiate phenotype space and, in particular, to satisfy the conflicting constraints of having to grow in favourable conditions so as to reproduce yet not grow in hostile conditions so as to survive. Both competitive coherence and life on the scales deal with the problem of reconciling conflicting constraints. Here, we bring together these concepts in the common framework of hyperstructures and make predictions that may be tested using a learning program, Coco, and secondary ion mass spectrometry. PMID- 23794324 TI - Prevalence of radiologic superior canal dehiscence in normal ears and ears with chronic otitis media. AB - OBJECTIVES/HYPOTHESIS: Although labyrinth fistulae are caused mostly by cholesteatoma, they can occur in long-standing chronic otitis media (COM) without cholesteatoma. We aimed to compare the prevalence of radiologic SCD on computed tomography (CT) between normal ears and contralateral COM ears in patients with unilateral COM and to assess the prevalence of superior canal dehiscence (SCD) according to the age. STUDY DESIGN: Case series with comparison performed at a tertiary care academic referral center. METHODS: We retrospectively reviewed consecutive temporal bone CT scans of 759 patients with unilateral COM between 2009 and 2011. The mean (+/- standard deviation) age was 48 years (+/-14 years). Images were independently evaluated by two otologists, and the bone overlying the superior canal was characterized as normal, suspicious, or definite SCD. RESULTS: The prevalence (3.4%) of definite SCD in COM ears was significantly higher than that (0.3%) in normal ears. The prevalence (6.6%) of suspicious or definite SCD in COM ears was also higher than that (1.2%) in normal ears. There was no correlation between the prevalence of SCD and age in either normal or COM ears. All of the normal ears with suspicious or definite SCD also showed contralateral suspicious or definite SCD (bilateral involvement). CONCLUSIONS: Our present findings suggest that the COM is related to the presence of SCD. The roof of the temporal bone may become thin by the failure of postnatal bone development and susceptible to chronic brain pulsation and pressure exerted by the temporal lobe in COM ears. PMID- 23794325 TI - An electrochemical route to quantitative oxidation of graphene frameworks with controllable C/O ratios and added pseudocapacitances. AB - We report an electrochemical oxidation route to tunable C/O ratios in the graphene framework, creating enhanced pseudocapacitance with increasing oxygen content. Controlled surface functionalities on graphene enable a high specific capacitance and negligible electric conductivity loss. A specific capacitance of up to 279 F g(-1) was achieved for the functionalized graphene at a discharge current of 1 A g(-1) in 1 M H2SO4 electrolyte; this capacitance remained as high as 152 F g(-1) at 100 A g(-1). These values are much higher than those of non oxidized graphene. These excellent performances of the functionalized graphene signify the importance of precise control of the surface chemistry of graphene based materials. PMID- 23794326 TI - Synthesis, structure and gas-phase reactivity of a silver hydride complex [Ag3{(PPh2)2CH2}3(MU3-H)(MU3-Cl)]BF4. PMID- 23794328 TI - Change and continuity: reflections on editing the AJPA, 2007-2013. PMID- 23794329 TI - Viewpoints. PMID- 23794330 TI - Viewpoints: diet and dietary adaptations in early hominins: the hard food perspective. AB - Recent biomechanical analyses examining the feeding adaptations of early hominins have yielded results consistent with the hypothesis that hard foods exerted a selection pressure that influenced the evolution of australopith morphology. However, this hypothesis appears inconsistent with recent reconstructions of early hominin diet based on dental microwear and stable isotopes. Thus, it is likely that either the diets of some australopiths included a high proportion of foods these taxa were poorly adapted to consume (i.e., foods that they would not have processed efficiently), or that aspects of what we thought we knew about the functional morphology of teeth must be wrong. Evaluation of these possibilities requires a recognition that analyses based on microwear, isotopes, finite element modeling, and enamel chips and cracks each test different types of hypotheses and allow different types of inferences. Microwear and isotopic analyses are best suited to reconstructing broad dietary patterns, but are limited in their ability to falsify specific hypotheses about morphological adaptation. Conversely, finite element analysis is a tool for evaluating the mechanical basis of form-function relationships, but says little about the frequency with which specific behaviors were performed or the particular types of food that were consumed. Enamel chip and crack analyses are means of both reconstructing diet and examining biomechanics. We suggest that current evidence is consistent with the hypothesis that certain derived australopith traits are adaptations for consuming hard foods, but that australopiths had generalized diets that could include high proportions of foods that were both compliant and tough. PMID- 23794331 TI - Viewpoints: feeding mechanics, diet, and dietary adaptations in early hominins. AB - Inference of feeding adaptation in extinct species is challenging, and reconstructions of the paleobiology of our ancestors have utilized an array of analytical approaches. Comparative anatomy and finite element analysis assist in bracketing the range of capabilities in taxa, while microwear and isotopic analyses give glimpses of individual behavior in the past. These myriad approaches have limitations, but each contributes incrementally toward the recognition of adaptation in the hominin fossil record. Microwear and stable isotope analysis together suggest that australopiths are not united by a single, increasingly specialized dietary adaptation. Their traditional (i.e., morphological) characterization as "nutcrackers" may only apply to a single taxon, Paranthropus robustus. These inferences can be rejected if interpretation of microwear and isotopic data can be shown to be misguided or altogether erroneous. Alternatively, if these sources of inference are valid, it merely indicates that there are phylogenetic and developmental constraints on morphology. Inherently, finite element analysis is limited in its ability to identify adaptation in paleobiological contexts. Its application to the hominin fossil record to date demonstrates only that under similar loading conditions, the form of the stress field in the australopith facial skeleton differs from that in living primates. This observation, by itself, does not reveal feeding adaptation. Ontogenetic studies indicate that functional and evolutionary adaptation need not be conceptually isolated phenomena. Such a perspective helps to inject consideration of mechanobiological principles of bone formation into paleontological inferences. Finite element analysis must employ such principles to become an effective research tool in this context. PMID- 23794332 TI - A calcaneus attributable to the primitive late Eocene anthropoid Proteopithecus sylviae: phenetic affinities and phylogenetic implications. AB - A well-preserved calcaneus referrable to Proteopithecus sylviae from the late Eocene Quarry L-41 in the Fayum Depression, Egypt, provides new evidence relevant to this taxon's uncertain phylogenetic position. We assess morphological affinities of the new specimen using three-dimensional geometric morphometric analyses with a comparative sample of primate calcanei representing major extinct and extant radiations (n = 58 genera, 106 specimens). Our analyses reveal that the calcaneal morphology of Proteopithecus is most similar to that of the younger Fayum parapithecid Apidium. Principal components analysis places Apidium and Proteopithecus in an intermediate position between primitive euprimates and crown anthropoids, based primarily on landmark configurations corresponding to moderate distal elongation, a more distal position of the peroneal tubercle, and a relatively "unflexed" calcaneal body. Proteopithecus and Apidium are similar to cercopithecoids and some omomyiforms in having an ectal facet that is more tightly curved, along with a larger degree of proximal calcaneal elongation, whereas other Fayum anthropoids, platyrrhines and adapiforms have a more open facet with less proximal elongation. The similarity to cercopithecoids is most plausibly interpreted as convergence given the less tightly curved ectal facets of stem catarrhines. The primary similarities between Proteopithecus and platyrrhines are mainly in the moderate distal elongation and the more distal position of the peroneal tubercle, both of which are not unique to these groups. Proteopithecus and Apidium exhibit derived anthropoid features, but also a suite of primitive retentions. The calcaneal morphology of Proteopithecus is consistent with our cladistic analysis, which places proteopithecids as a sister group of Parapithecoidea. PMID- 23794333 TI - Patterns of astragalar fibular facet orientation in extant and fossil primates and their evolutionary implications. AB - A laterally sloping fibular facet of the astragalus (=talus) has been proposed as one of few osteological synapomorphies of strepsirrhine primates, but the feature has never been comprehensively quantified. We describe a method for calculating fibular facet orientation on digital models of astragali as the angle between the planes of the fibular facet and the lateral tibial facet. We calculated this value in a sample that includes all major extant primate clades, a diversity of Paleogene primates, and nonprimate euarchontans (n = 304). Results show that previous characterization of a divide between extant haplorhines and strepsirrhines is accurate, with little overlap even when individual data points are considered. Fibular facet orientation is conserved in extant strepsirrhines despite major differences in locomotion and body size, while extant anthropoids are more variable (e.g., low values for catarrhines relative to non-callitrichine platyrrhines). Euprimate outgroups exhibit a mosaic of character states with Cynocephalus having a more obtuse strepsirrhine-like facet and sampled treeshrews and plesiadapiforms having more acute haplorhine-like facets. Surprisingly, the earliest species of the adapiform Cantius have steep haplorhine-like facets as well. We used a Bayesian approach to reconstruct the evolution of fibular facet orientation as a continuous character across a supertree of living and extinct primates. Mean estimates for crown Primatomorpha (97.9 degrees ), Primates (99.5 degrees ), Haplorhini (98.7 degrees ), and Strepsirrhini (108.2 degrees ) support the hypothesis that the strepsirrhine condition is derived, while lower values for crown Anthropoidea (92.8 degrees ) and Catarrhini (88.9 degrees ) are derived in the opposite direction. PMID- 23794334 TI - CCN2: a master regulator of the genesis of bone and cartilage. AB - CCN family member 2 (CCN2), also known as connective tissue growth factor (CTGF), has been suggested to be an endochondral ossification genetic factor that has been termed "ecogenin", because in vitro studies revealed that CCN2 promotes the proliferation and differentiation of growth-plate chondrocytes, osteoblasts, and vascular endothelial cells, all of which play important roles in endochondral ossification. In addition to its action toward these three types of cells, CCN2 was recently found to promote the formation of osteoclasts in vitro, which cells play an important role in the replacement of cartilage by bone during endochondral ossification, thus strengthening the "ecogenin" hypothesis. For confirmation of this hypothesis, transgenic mice over-expressing CCN2 in cartilage were generated. The results proved the hypothesis; i.e., the over expression of CCN2 in cartilage stimulated the proliferation and differentiation of growth-plate chondrocytes, resulting in the promotion of endochondral ossification. In addition to its "ecogenin" action, CCN2 had earlier been shown to promote the differentiation of various cartilage cells including articular cartilage cells. In accordance with these findings, cartilage-specific overexpression of CCN2 in the transgenic mice was shown to protect against the development of osteoarthritic changes in aging articular cartilage. Thus, CCN2 may also play a role as an anti-aging (chondroprotective) factor, stabilizing articular cartilage. CCN2 also had been shown to promote intramembranous ossification, regenerate cartilage and bone, and induce angiogenesis in vivo. For understanding of the molecular mechanism underlying such multifunctional actions, yeast two-hybrid analysis, protein array analysis, solid-phase binding assay, and surface plasmon resonance (SPR) analysis have been used to search for binding partners of CCN2. ECMs such as fibronectin and aggrecan, growth factors including BMPs and FGF2 and their receptors such as FGFR1 and 2 and RANK, as well as CCN family members themselves, were shown to bind to CCN2. Regarding the interaction of CCN2 with some of them, various binding modules in the CCN2 molecule have been identified. Therefore, the numerous biological actions of CCN2 would depend on what kinds of binding partners and what levels of them are present in the microenvironment of different types of cells, as well as on the state of differentiation of these cells. Through this mechanism, CCN2 would orchestrate various signaling pathways, acting as a signal conductor to promote harmonized skeletal growth and regeneration. PMID- 23794335 TI - Optimizing the kinetics and thermodynamics of DNA i-motif folding. AB - Under slightly acidic conditions, single cytidine-rich DNA strands can form four stranded structures called i-motifs. The stability of the i-motif structure is based on the intercalation of hemiprotonated C-C(+) base pairs. In addition, the stability of these structures is influenced by pH, temperature, salt concentration, number of cytidines per C-rich stretch, and length of sequence; it also depends on the nucleotides in the connecting loop regions. Here, we investigated the influence of the loop nucleotides on i-motif stability, structure, and kinetics of folding, in five structures with the same loop-size but different adenosine and thymidine residues within the loop. The stabilities of the i-motif structures were determined by CD melting, and structure and kinetics of folding were studied by static and time-resolved NMR experiments. PMID- 23794336 TI - What is the future of research for hereditary hemochromatosis in Turkey. PMID- 23794337 TI - Characterization of 23S rRNA gene mutation in primary and secondary clarithromycin-resistant Helicobacter pylori strains from East China. AB - BACKGROUND/AIMS: Clarithromycin is an effective antibiotic for treating Helicobacter pylori; however, the development clarithromycin- resistance by multiple strains prevents the eradication of Helicobacter pylori. We aimed to characterize mutations in the 23S rRNA gene of primary clarithromycin-sensitive, primary clarithromycin-resistant and secondary clarithromycin-resistant Helicobacter pylori strains that were collected in East China and elucidate the mechanisms of clarithromycin resistance. MATERIALS AND METHODS: The disk diffusion test and E-test method were used to determine the clarithromycin susceptibility of clinical Helicobacter pylori strains. The 23S rRNA gene fragments were amplified by polymerase chain reaction from 18 primary clarithromycin- resistant strains, 15 primary sensitive strains and 8 secondary clarithromycin-resistant strains. Polymerase chain reaction-products were sequenced to determine mutations of the 23S rRNA gene. RESULTS: We found an A2143G (8 strains) mutation in primary clarithromycin-resistant strains, an A2143T (5 strains) mutation in secondary clarithromycin-resistant strains; but no mutations were found in position 2143 of sensitive strains. A T2182C mutation in primary clarithromycin-sensitive, primary clarithromycinresistant and secondary clarithromycin-resistant strains was found with a prevalence of 86.7% (13 strains), 72.2% (13 strains) or 87.5% (7 strains), respectively. In addition, we found a G2254T (8 strains) and a G2172T (7 strains) mutation in secondary clarithromycin- resistant strains. These point mutations were absent in primary clarithromycin-resistant and -sensitive strains. CONCLUSION: The gene mutation in position 2143 was associated with resistance to clarithromycin, but the mutation was different between primary and secondary clarithromycin-resistant strains. The T2182C mutation was not associated with clarithromycin resistance. Two new hotspot mutations: G2254T and G2172T, in 23S rRNA were discovered in secondary clarithromycin-resistant strains. PMID- 23794338 TI - Azithromycin based triple therapy versus standard clarithromycin based triple therapy in eradication of Helicobacter pylori infection in Iran: a randomized controlled clinical trial. AB - BACKGROUND/AIMS: In regarding to azithromycin's high tissue concentration, long biologic half life, low cost, and excellent anti bacterial profile for Helicobacter pylori in Iran, we sought to compare an azithromycin-based regimen with an already established clarithromycinbased regimen in regards to the eradication of Helicobacter pylori infection. MATERIAL AND METHODS: A prospective, open label, randomized controlled trial was conducted on 165 patients who presented to gastrointestinal clinics of QOM Medical University Clinics, with complaint of dyspepsia. All patients received upper gastrointestinal endoscopy, and underwent rapid urease test to confirm Helicobacter pylori infection. Patients were randomized to a treatment arm, which consisted of, clarithromycin, amoxicillin, and omeprazole, or another treatment arm consisting of azithromycin, amoxicillin, and omeprazole. Informed consent was obtained from all patients participating in the trial. Urease breath test was performed in patients 6 weeks after end of treatment to assess eradication. All side effects were recorded. Comparison between the two groups was made using a chi-square test. RESULT: Seventy six and 89 patients received regimen clarithromycin, amoxicillin, and omeprazole and azithromycin, amoxicillin, and omeprazole, respectively, and completed the study course. Per protocol, eradication rate was 83% with clarithromycin, amoxicillin, and omeprazole and 75% with azithromycin, amoxicillin, and omeprazole (p =0.158). Eradication rate for a subgroup of patients with peptic ulcer disease in two groups were 83% and 74%, respectively (p=0.134). Only one patient in each group was compelled to stop the treatment due to a severe skin hypersensitivity reaction. Other lesser side effects were comparable within the two groups. CONCLUSION: The results of this study suggest that azithromycin, amoxicillin, and omeprazole at best is as effective as clarithromycin, amoxicillin, and omeprazole; and this new therapy could be considered as an alternative choice for Helicobacter pylori eradication, especially in geographic areas with lower economic status. PMID- 23794339 TI - Ongoing symptoms after eradication of Helicobacter pylori: psychiatric disorders may accompany. AB - BACKGROUND/AIMS: The precise mechanism of functional dyspepsia is yet to be elucidated. Helicobacter pylori infection and psychiatric disorders are implicated in the etiology. We aimed to determine the prevalence of psychiatric co-morbid disorders in patients with Helicobacter pylori-positive functional dyspepsia and the impact of existing psychiatric disorders on symptomatic response following eradication treatment. MATERIAL AND METHODS: Patients with Helicobacter pylori-positive functional dyspepsia and no previous diagnosis of any psychiatric disorder were included in the study. All patients' symptoms were evaluated with a visual analog scale and Likert scale. The Composite International Diagnostic Interview was applied to all patients by an experienced psychiatric nurse. RESULTS: At least one psychiatric disorder was diagnosed in 22 of 54 patients. The most common disorder was depression, found in 13 patients. Symptomatic response to treatment was significantly higher in functional dyspepsia patients with no psychiatric disorder compared to those with at least one psychiatric co-morbid disorder (84% vs. 50%; p=0.007). CONCLUSION: Psychiatric co-morbid disorders are common in patients with functional dyspepsia and affect symptomatic response to Helicobacter pylori eradication treatment. Psychiatric disorders should be considered in patients who fail to achieve sufficient symptomatic relief after Helicobacter pylori eradication treatment. PMID- 23794340 TI - What is the diagnostic utility of endoscopic scoring systems in children? AB - BACKGROUND/AIMS: The aim of this study was to evaluate the consistency of the Savary-Miller, the Hetzel-Dent and the Los Angeles endoscopic classification systems and to compare them with the esophageal histopathology in children. MATERIAL AND METHODS: Children between the ages of 5-17 years who underwent esophagogastroduodenoscopy were included in the study. The endoscopic reports and the still images of the esophagus were reclassified by the same gastroenterologist according to the Savary-Miller, Hetzel- Dent and Los Angeles scoring systems. The esophageal biopsies were also reevaluated by the same pathologist and the consistency between endoscopic and histopathologic esophagitis was evaluated. RESULTS: A total of 113 out of 192 pediatric patients were included in the study. Seventy-three patients (64.6%) had esophagitis according to the Hetzel-Dent classification, whereas only 20 (17.7%) patients were defined as having esophagitis according to the other two classification systems. The consistency between the Savary-Miller and Los Angeles classifications was excellent (kappa: 0.92) but the agreement between the Hetzel Dent and Savary-Miller and between the Hetzel-Dent and Los Angeles classifications were poor. A total of 82 patients (72.6%) had histopathological esophagitis, and there was a weak consistency between all 3 endoscopic scoring systems and the histopathology. CONCLUSIONS: Since pediatric patients have milder esophagitis than in adults, the use of endoscopic scoring systems developed for adults seems to be inapplicable for children. The inclusion of minimal endoscopic changes in endoscopic scoring systems by using more sensitive and novel endoscopic techniques would increase the sensitivity of these scoring systems in children. PMID- 23794341 TI - Protective effect of tryptophan against dextran sulfate sodium- induced experimental colitis. AB - BACKGROUND/AIMS: Little is known about the anti-colitis effect of tryptophan or its metabolites. Here, the protective effect and its mechanism of tryptophan administration on dextran sulfate sodium -induced colitis in mice was studied. MATERIALS AND METHODS: Twenty C57black6 female mice were equally divided into the control group, and treatment group. The control group received a standard CE-2 diet, while the tryptophan group received a CE-2 diet containing 0.5% l tryptophan. After one week on this diet, all mice were orally administered a solution of 3.5% dextran sulfate sodium for 12 days to induce colitis. Changes in body weight and bloody stool frequency were monitored during dextran sulfate sodium administration. At 12 days post initial dextran sulfate sodium administration, all mice were sacrificed and the histology of their colonic tissue was examined. The nitrotyrosine levels in colonic tissues in both groups, and nitrate and nitrite levels in the urine of the control group, the tryptophan group and the group of mice without dextran sulfate sodium administration was measured. RESULTS: The tryptophan group showed significantly attenuated body weight loss, bloody stool frequency and ameliorated histological changes of colitis. While tryptophan treatment significantly reduced nitrotyrosine level in the colonic tissues, there was no significant reduction in urine nitrate and nitrite levels compared with the (dextran sulfate sodium-induced) control group. CONCLUSION: Tryptophan treatment ameliorated dextran sulfate sodium-induced colitis in this study. One of the anti-colitis mechanisms of tryptophan treatment is attributable to an anti-nitration effect, and may not be via the suppression of nitric oxide generation. PMID- 23794342 TI - Diagnostic and prognostic value of tumor M2-pyruvate kinase levels in patients with colorectal canhcer. AB - BACKGROUND/AIMS: Screening for precancerous lesions is important for the diagnosis and treatment of colorectal tumors. We investigated M2-pyruvate kinase levels in patients with colorectal polyps and carcinoma and assessed factors affecting M2-pyruvate kinase levels. MATERIALS AND METHODS: Eighty-five patients who had undergone colonoscopic examination and who were diagnosed with a neoplastic lesion were included. Patients were divided into two groups according to the macroscopic diagnosis of polyp or carcinoma. According to histopathological evaluation, specimens were grouped as nonneoplastic lesions, tubular adenoma, tubulovillous adenoma and adenocarcinoma. M2-pyruvate kinase levels were measured with the Tumor M2-pyruvate kinase ELISA kit. RESULTS: Mean M2-pyruvate kinase levels were 76.1+/-57.73 (13.1-288.22) IU/ml. We did not find a correlation between M2-pyruvate kinase levels and age, gender, smoking, alcohol and aspirin consumption and colorectal cancer family history. There was a relationship between body mass index and M2-pyruvate kinase level (p=0.022). The carcinoma group had the highest levels of M2-pyruvate kinase both endoscopically and histopathologically (p=0.009, p=0.019 respectively). M2-pyruvate kinase levels of patients who died were significantly higher than patients who survived (p=0.001). Enzyme values were significantly lower in diabetic patients than nondiabetics (p=0.04); and chronic renal failure patients had higher levels (p=0.045). CONCLUSION: Serum M2-pyruvate kinase levels may be useful in distinguishing malignant and benign lesions of the colon and may provide insight in terms of survival. PMID- 23794343 TI - The prevalence of primary hereditary hemochromatosis in central Anatolia. AB - BACKGROUND/AIMS: Hereditary hemochromatosis is an autosomal recessive disorder associated with the HFE genes. Early identification and diagnosis is important as end stage organ damage may occur if treatment is delayed.. This study aimed to identify the prevalence of hereditary hemochromatosis in Kayseri and surroundings known as Central Anatolia. MATERIALS AND METHODS: 2304 participants (1220 males, 1084 females) who were older then the age of 17 were included in the study conducted between December 2005 and December 2006 in Kayseri, Turkey. Transferin saturation was measured from overnight fasting blood samples. Serum iron, total iron binding capacity, and transferin saturation were measured. Serum ferritin levels and hereditary hemochromatosis genetic analysis were also performed after an overnight fasting blood samples from participants whose transferin saturation results were more than 50% in man and more than 45% in women. RESULTS: The homozygote C282Y mutation and heterozygote C282Y mutation prevalences were found as 0.08% (1/1220) and 0.08% (1/1220) in male participants, respectively. The heterozygote H63D mutation prevalence was found in 0.09% (1/1084) of female participants. Calculated prevalences in general population are as follows; The homozygote C282Y mutation prevalence is 0.043% (1/2304), the heterozygote C282Y mutation prevalence is 0.043% (1/2304) and the heterozygote H63D mutation prevalence is 0.043% (1/2304). CONCLUSIONS: The prevalence of hereditary hemochromatosis in Central Anatolia is 0.043% (1/2304). Because of the relatively low frequency, population screening studies are not cost-effective. PMID- 23794344 TI - The protective effect of L-carnitine on hepatic ischemia-reperfusion injury in rats. AB - BACKGROUND/AIMS: Ischemia-reperfusion injury may occur during liver transplantation and remains a serious concern in clinical practice. This study was designed to study the potential benefit of L-carnitine on experimental warm hepatic ischemia-reperfusion injury in rats. MATERIALS AND METHODS: Forty-five male Wistar Albino rats were divided into three groups; Group 1 sham-operation without ischemia-reperfusion (n=15); Group 2, ischemia-reperfusion (n=15); and Group 3, which was administered L-carnitine (200 mg/kg, intraperitoneal, for 4 days) prior to ischemia-reperfusion (n=15). The study animals were then sacrificed to obtain hepatic tissue and serum samples. Tissue levels of malondialdehyde and reduced glutathione and serum levels for aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase were assessed. RESULTS: Mean aspartate aminotransferase levels were significantly higher in Group 2 (405.2 U/L) when compared to Groups 1 (137.1 U/L) and 3 (267.6 U/L). Mean alanine aminotransferase levels were significantly higher in Group 2 (257.1 U/L) when compared to Groups 1 (37.2 U/L), and 3 (118.1 U/L) (p< 0.001 for each). Mean lactate dehydrogenase levels were significantly higher in Group 2 (2943.8 U/L) when compared to Groups 1 (1496.5 U/L), and 3 (2185.3U/L) (p < 0.001 for each). Mean malondialdehyde levels were significantly higher in Group 2 (54.3 nmol/g) compared to Groups 1 (41.0 nmol/g) and 3 (42.1 nmol/g) (p < 0.001 for each). Mean reduced glutathione levels were significantly lower in Group 2 (5.9 nmol/mg) and Group 3 (7.4 nmol/mg) compared to Group 1 (9.1 nmol/mg) (p < 0.001 for each). CONCLUSIONS: In conclusion, our data supports a protective effect of L carnitine against oxidative damage in hepatic ischemia-reperfusion injury in rats. This is evidenced by improvement of the antioxidant defense system and lipid peroxidation levels. PMID- 23794345 TI - Two juvenile polyps, hereditary hemorrhagic telangiectasia and SMAD4 mutation. AB - An adolescent girl with recurrent iron deficiency anemia, epistaxis, cyanosis, hypoxemia, clubbing, two juvenile polyps in the colon, oro-naso-pharyngeal telangiectasias, multiple arterio-venous malformations of the lungs, and a new homozygous mutation in SMAD4 gene is reported. Patients with juvenile polyps should be examined carefully for mucocutaneus findings and digital clubbing. When a combination of these signs is noted, a genetic testing is warranted inspite of low polyp count in order to prevent potential risk of malignancy and other complications. PMID- 23794346 TI - Successful management of severe acute liver disease related with adult-onset Still's disease in a pregnant patient. AB - Adult-onset Still's disease is a rare systemic inflammatory disease, which is characterized by varying degrees of liver involvement. Herein we present a rare case of pregnancy onset adult onset Still's disease with severe acute liver disease which worsened after labor. The patient was successfully managed with medical treatment preventing acute liver failure, and is currently in remission from adult onset Still's disease with liver tests that have returned to normal. PMID- 23794347 TI - Diagnosis of tuberculous peritonitis using endoscopic ultrasound-guided fine needle aspiration biopsy of the peritoneum. AB - BACKGROUND/AIMS: Tuberculous peritonitis is prevalent in developing countries and its diagnosis is still challenging due to the lack of specific clinical characteristics and the difficulty in obtaining tissue from the peritoneum without laparoscopy. Endoscopic ultrasound - guided fine needle aspiration is emerging as the most effective and safe method for obtaining tissue from the structures surrounding the gut lumen. Our study aimed to elucidate the efficacy of endoscopic ultrasound-fine needle aspiration of the peritoneum in the diagnosis of tuberculous peritonitis. MATERIALS AND METHODS: Three patients (2 male and 1 female; aged 38, 25, and 65 years, respectively) suspected of having tuberculous peritonitis were recruited into the study. Clinical evaluation including computed tomography imaging and analysis of ascitic fluid were performed. Endoscopic ultrasound-fine needle aspiration biopsy of the peritoneum was performed trans-gastrically with a 19-gauge ProCore needle in all patients. At least two different areas of the peritoneum suspected to be involved were sampled and paraffin-embedded cell blocks were prepared for each biopsy specimen. RESULTS: Biopsy specimens were positive for Mycobacterium tuberculosis by polimerase chain reaction in 2 patients and positive for multinucleated giant cells in all patients. Treatment for tuberculosis resulted in the resolution of symptoms and ascites. No procedure- related complications occured. CONCLUSIONS: Endoscopic ultrasound-fine needle aspiration is an efficacious and safe method to obtain tissue from the peritoneum to use in the diagnosis of tuberculous peritonitis. PMID- 23794348 TI - Dental findings of gastroesophageal reflux disease and treatment planning. PMID- 23794349 TI - Coexistence of Behcet's disease and colonic diverticulitis: is it causal or just a coincidence? PMID- 23794350 TI - Germ cell tumor in duodenum. PMID- 23794351 TI - HLA subtypes and Helicobacter pylori infection in an infant with celiac crisis. PMID- 23794352 TI - A rare cause of elevated liver enzymes: Addison's disease. PMID- 23794353 TI - Adult intussusception and gastrointestinal bleeding due to an isolated heterotopic pancreas. PMID- 23794354 TI - An unusual cause of ascites in a young patient. PMID- 23794355 TI - Isolated Crohn's disease of the esophagus. PMID- 23794356 TI - Albendazole-induced toxic hepatitis: A case report. PMID- 23794357 TI - Electrochemical magnetoimmunosensing approach for the sensitive detection of H9N2 avian influenza virus particles. AB - A novel electrochemical magnetoimmunosensor for fast and ultrasensitive detection of H9N2 avian influenza virus particles (H9N2 AIV) was designed based on the combination of high-efficiency immunomagnetic separation, enzyme catalytic amplification, and the biotin-streptavidin system. The reusable, homemade magneto Au electrode (M-AuE) was designed and used for the direct sensing. Immunocomplex coated magnetic beads (IMBs) were easily accumulated on the surface of the M-AuE to obtain the catalytically reduced electrochemical signal of H2 O2 after the immunoreaction. The transducer was regenerated through a simple washing procedure, which made it possible to detect all the samples on a single electrode with higher reproducibility. The magnetic-bead-based electrochemical immunosensor showed better analytical performance than the planar-electrode-based immunosensor with the same sandwich construction. Amounts as low as 10 pg mL(-1) H9N2 AIV could be detected even in samples of chicken dung. This electrochemical magnetoimmunosensor not only provides a simple platform for the detection of the virus with high sensitivity, selectivity, and reproducibility but also shows great potential in the early diagnosis of diseases. PMID- 23794358 TI - "Love hurts": romantic attachment and depressive symptoms in pregnant adolescent and young adult couples. AB - OBJECTIVE: The current study investigates the relationship between romantic attachment style and depressive symptoms between both members of pregnant adolescent and young adult couples. METHOD: Participants were 296 pregnant young females (mean age = 18.7) and their male partners (mean age = 21.3; 592 total participants) who were recruited from obstetrics and gynecology clinics in Connecticut. The dimensions of avoidant and anxious romantic attachment were assessed using the Experiences in Close Relationships Inventory. Depressive symptoms were measured using the Center for Epidemiological Studies-Depression Scale. RESULTS: Results showed that avoidant attachment and anxious attachment were significantly positively related to depressive symptoms. Multilevel modeling for partner effects revealed that anxious attachment and depressive symptoms in partners were significantly positively associated with depressive symptoms CONCLUSION: Findings underscore the importance of considering couples-based approaches to supporting the transition to parenthood and developing the necessary self and relationship skills to manage attachment needs and relationship challenges. PMID- 23794359 TI - Characterization of synthetic routes to 'Bromo-DragonFLY' and benzodifuranyl isopropylamine homologues utilizing ketone intermediates. Part 1: synthesis of ketone precursors. AB - Bromo-DragonFLY (BDF) and many of its analogues are misused as recreational drugs due to their potency as psychoactive substances. To date, none of the published routes to these designer amphetamines have exploited a ketone intermediate. It is well known that benzyl methyl ketone (BMK) can be employed as a precursor in the synthesis of amphetamine. Similarly, it is reasonable to assume that ketone precursors may potentially be utilized in the clandestine synthesis of BDF and its homologues. This paper describes the multifaceted synthesis of novel precursor ketones structurally related to BDF, namely benzodifuranyl propanone 16, its tetrahydrobenzodifuranyl homologue 8, and their brominated analogues 12 and 20. Their characterization by Fourier transform infrared spectroscopy (FTIR), proton nuclear magnetic resonance spectroscopy ((1) H-NMR), carbon nuclear magnetic resonance spectroscopy ((13) C-NMR), high performance liquid chromatography (HPLC), gas chromatography (GC) and mass spectrometry (MS) is also described. PMID- 23794361 TI - Further delineation of the clinical spectrum in RNU4ATAC related microcephalic osteodysplastic primordial dwarfism type I. AB - We describe five patients from three different families with microcephalic osteodysplastic primordial dwarfism type I (MOPD I), which was molecularly confirmed by homozygosity for the g.51G >A and g.55G >A mutations in RNU4ATAC, respectively. The patients showed the classical phenotype and demonstrated in addition variable degrees of gyration abnormalities and malformations of the callosal body with an interhemispheric cyst. One patient also showed underdevelopment of the cerebellar vermis. This confirms that cortical malformations should be considered cardinal manifestations of MOPD I. Oculocutaneous albinism, brain hemorrhage and chilblains have been found to be associated with MOPD I. The present study showed lack of retinal pigmentation in three patients of whom two had an unusually fair complexion of hair and skin. One patient was found to have a hematoma in the left thalamus. This may indicate that both pigmentary abnormalities and vascular anomalies may be part of the phenotype of MOPD I as well. PMID- 23794362 TI - Income and the use of prescription drugs for near retirement individuals. AB - In this paper, we estimate how demand for prescription drugs varies with income for a sample of near retirement individuals. The analysis is based on a novel panel data set with information about the purchase of prescription drugs for a large number of Danish individuals over the period 1995-2003. Our preferred model performs better in an external validation test than models that can be estimated on cross section data. Results indicate that demand does respond to variations in income and that reforms affecting income will therefore affect the use of prescription drugs. PMID- 23794360 TI - Role of omega-3 fatty acids in obesity, metabolic syndrome, and cardiovascular diseases: a review of the evidence. AB - The present review aims to illustrate current knowledge about the efficacy of omega-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs) in treating/preventing several metabolic pathologies. We reviewed systematically the published evidence on the effectiveness of n-3 LC-PUFAs fish consumption or n-3 LC-PUFAs supplementation on prevention/treatment of obesity, metabolic syndrome, and cardiovascular diseases. Most of the reviewed studies were randomized controlled interventional trials, although some relevant prospective and cross sectional studies as well as some meta-analysis were also reviewed. Supplementation with n-3 LC-PUFAs might improve some obesity-associated metabolic syndrome features such as insulin resistance, hypertension and dyslipidemia by decreasing plasma triglycerides. Moreover, the blood pressure-lowering and anti inflammatory properties of these fatty acids and their benefits in vascular function might confer cardioprotection. However, the efficacy of n-3 LC-PUFA on reducing myocardial infarction, arrhythmia, cardiac and sudden death, or stroke is controversial. Due to the beneficial actions of n-3 LC-PUFAs, several worldwide government and health organizations have established some recommendations of n-3 LC-PUFAs intake for groups of population. In general, the recommended levels for diseases prevention are lower than those advised for particular treatments. However, more clinical trials are necessary to recommend the most effective dosages and formulas (type of n-3 LC-PUFA, EPA/DHA ratio) for specific pathologies. PMID- 23794363 TI - A large ApoE epsilon4/epsilon4 homozygous cohort reveals no association with Parkinson's disease. AB - To investigate the correlation between cognitive impairment, Parkinson's disease (PD) symptoms and ApoE epsilon4/epsilon4 homozygosity an ApoE epsilon4/epsilon4 homozygous cohort was compared with an ApoE epsilon3/epsilon3 homozygous comparison group. A total of 696 outpatients with memory complaints had undergone comprehensive neuropsychiatric assessment including interview and examination by clinical psychiatrists and neurologists as well as laboratory blood testing (including ApoE genotyping). Patients also underwent the Consortium to Establish a Registry on Alzheimer's Disease (CERAD) test battery and the Clock-Drawing Test (Shulman scoring). Of the 623 selected individuals 258 were homozygous for ApoE epsilon3 and 133 were homozygous for ApoE epsilon4, while 232 were heterozygous for ApoE epsilon3/epsilon4. Thirty patients in the entire sample were diagnosed with PD (4.8 %). In the ApoE epsilon4/epsilon4 group seven persons had PD (5.3 %), while in the ApoE epsilon3/epsilon3 comparison group nine persons were diagnosed with PD (3.5 %). In the ApoE epsilon3/epsilon4 heterozygous group we found 14 (6.03 %) subjects meeting criteria for PD, P = 0.406. This is to our knowledge the largest retrospective cohort study to date of ApoE epsilon4 homozygous carriers. In comparison with the ApoE epsilon3 homozygous carriers in our study, subjects who were homozygous for ApoE epsilon4 demonstrated a slightly but statistically insignificant higher prevalence of PD, while in the ApoE epsilon3/epsilon4 heterozygous group we detected the highest rate of probands diagnosed with PD. We conclude that there is no correlation between allele combinations of ApoE epsilon3 and ApoE epsilon4 in their heterozygote and homozygote composition and prevalence of PD. PMID- 23794364 TI - Impact of season on the chemical composition of male and female blesbok (Damaliscus pygargus phillipsi) muscles. AB - BACKGROUND: The harvesting and consumption of game meat in South Africa is not limited to season. The study was thus aimed at investigating the seasonal impact on the chemical composition (moisture, protein, fat and ash contents) of male and female blesbok muscles (N = 32; longissimus dorsi, biceps femoris, semimembranosus, semitendinosus, infraspinatus and supraspinatus). RESULTS: A significant interaction (P <= 0.01) existed between season and muscle type. Selected muscles had higher (P <= 0.01) mean protein contents with a higher plane of nutrition (spring of 2009), while longissimus dorsi muscles had the highest (P <= 0.01) mean intramuscular fat content (33.52 g kg-1). A strong negative correlation (r = -0.82; P <= 0.01) existed between the muscles' moisture and protein content. The chemical composition of blesbok semimembranosus muscles was significantly different between seasons, while the other muscles were least affected by seasonal differences in blesbok plane of nutrition and activity levels. CONCLUSION: The seasonal and muscle differences were statistically significant, but numerically small. It is therefore debatable whether this is of biological relevance relating to human nutrition. PMID- 23794365 TI - Comorbid persistent lower respiratory symptoms and posttraumatic stress disorder 5-6 years post-9/11 in responders enrolled in the World Trade Center Health Registry. AB - BACKGROUND: Co-occurrence of lower respiratory symptoms (LRS) and posttraumatic stress disorder (PTSD) has been increasingly recognized among responders and survivors of the World Trade Center (WTC) disaster. Information is limited on the degree which comorbidity intensifies symptoms and compromises quality of life across exposed groups. METHODS: Among responders who completed the first and second Registry surveys, measures of respiratory illness, psychological distress, and diminished quality of life were compared between responders comorbid for LRS and PTSD and responders with only LRS or PTSD. RESULTS: Of 14,388 responders, 40% of those with LRS and 57% of those with PTSD were comorbid. When demographic and WTC exposure-related factors were controlled, comorbid responders compared to those with LRS alone were twice as likely to have frequent dyspnea and to have sought care for dyspnea. Compared to responders with PTSD alone, comorbid responders were 2.1 times more likely to report intense re-experiencing of the disaster, 2.5 times more likely to express feelings of significant non-specific psychological distress, and 1.4 times more likely to have received mental health care. Comorbid responders were approximately three times more likely to report only fair or poor general health and more than twice as likely to report being unable to perform usual activities for >=14 of 30 days before interview. CONCLUSIONS: Outcomes in comorbid responders were similar to or more severe than in comorbid survivors. Health care and disaster relief providers must suspect comorbid illness when evaluating responders' respiratory or mental illnesses and consider treatment for both. PMID- 23794366 TI - Chiral thin films of metal oxide. AB - In this paper, we describe for the first time the synthesis of new chiral nanosized metal oxide surfaces based on chiral self-assembled monolayers (SAMs) coated with metal oxide (TiO2) nanolayers. In this new type of nanosize chiral surface, the metal oxide nanolayers enable the protection of the chiral self assembled monolayers while preserving their enantioselective nature. The chiral nature of the SAM/TiO2 films was characterized by variety of unique techniques, such as second-harmonic generation circular dichroism (SHG-CD), quartz crystal microbalance, and chiral adsorption measurements with circular dichroism spectroscopy. The chiral resolution abilities of the SAMs coated with metal oxide (TiO2) nanolayers were investigated in the crystallization of a racemic mixture of threonine and glutamic acid. Our proposed methodology for the preparation of nanoscale chiral surfaces described in this article could open up opportunities in other fields of chemistry, such as chiral catalysis. PMID- 23794367 TI - Utility and cost analysis of cholesteatoma histopathologic evaluation. AB - OBJECTIVES/HYPOTHESIS: To evaluate the correlation between the surgeon's intraoperative findings and histopathologic diagnosis of cholesteatoma specimens and the associated health care cost in requesting pathologic evaluation. STUDY DESIGN: Retrospective chart analysis. METHODS: Chart data were collected at a tertiary neurotology referral center from patients undergoing tympanomastoidectomy for chronic otitis media, with specimens submitted for pathologic review between 2010 and 2011. Correlation between the surgeon's intraoperative findings and the pathologic diagnosis was evaluated using a kappa statistic. Cost analysis for pathologic consultation was also reviewed. RESULTS: A Cohen's kappa value of 0.93 (P < .01) was found between the surgeon's intraoperative findings and pathologic diagnosis. Using accepted kappa magnitude guidelines, there is perfect agreement between the surgeon's intraoperative findings and pathologic diagnosis of cholesteatoma after tympanomastoidectomy. The average cost for microscopic evaluation of cholesteatoma (current procedural terminology code 88304) as estimated per 2012 Medicare reimbursement rates is $61.95. CONCLUSIONS: In the absence of concern for other pathology, intraoperative findings of cholesteatoma are adequate to confirm diagnosis in patients undergoing tympanomastoidectomy for chronic otitis media without the use of histopathology. The increased cost of routine cholesteatoma histopathologic evaluation should be considered in future health care cost-containing measures, as clinical utility appears to be low. LEVEL OF EVIDENCE: 4. PMID- 23794368 TI - The effects of the formation of Stone-Wales defects on the electronic and magnetic properties of silicon carbide nanoribbons: a first-principles investigation. AB - Detailed first-principles density functional theory (DFT) computations were performed to investigate the geometries, the electronic, and the magnetic properties of both armchair-edged silicon carbide nanoribbons (aSiCNRs) and zigzag-edged silicon carbide nanoribbons (zSiCNRs) with Stone-Wales (SW) defects. SW defects in the center of aSiCNRs can remarkably reduce their band gaps, irrespective of the orientation of the defect, whereas zSiCNRs with SW defects in the center or at the edges exhibit degenerate energies of their ferromagnetic (FM) and antiferromagnetic (AFM) states, in which metallic and half-metallic behavior can be observed, respectively; half-metallic behavior can even be observed in both the FM and AFM states simultaneously. Further, it was shown that the formation energies of the SW defects in SiCNRs are orientation dependent, and the formation of edge defects is always favored over the formation of interior defects in zSiCNRs. The possible existence of SW defects in SiCNRs was further validated through exploring the kinetic process of their formation. These findings can be anticipated to provide valuable information in promoting the potential applications of SiC-based nanomaterials in multifunctional and spintronic nanodevices. PMID- 23794369 TI - Nanosegregation and neighbor-cation control of photoluminescence in carbidonitridosilicate phosphors. PMID- 23794370 TI - Peptide contour length determines equilibrium secondary structure in protein analogous micelles. AB - This work advances bottom-up design of bioinspired materials built from peptide amphiphiles, which are a class of bioconjugates in which a biofunctional peptide is covalently attached to a hydrophobic moiety that drives self-assembly in aqueous solution. Specifically, this work highlights the importance of peptide contour length in determining the equilibrium secondary structure of the peptide as well as the self-assembled (i.e., micelle) geometry. Peptides used here repeat a seven-amino acid sequence between one and four times to vary peptide contour length while maintaining similar peptide-peptide interactions. Without a hydrophobic tail, these peptides all exhibit a combination of random coil and alpha-helical structure. Upon self-assembly in the crowded environment of a micellar corona, however, short peptides are prone to beta-sheet structure and cylindrical micelle geometry while longer peptides remain helical in spheroidal micelles. The transition to beta-sheets in short peptides is rapid, whereby amphiphiles first self-assemble with alpha-helical peptide structure, then transition to their equilibrium beta-sheet structure at a rate that depends on both temperature and ionic strength. These results identify peptide contour length as an important control over equilibrium peptide secondary structure and micelle geometry. Furthermore, the time-dependent nature of the helix-to-sheet transition opens the door for shape-changing bioinspired materials with tunable conversion rates. PMID- 23794371 TI - Hydrodynamical properties of recombinant spider silk proteins: Effects of pH, salts and shear, and implications for the spinning process. AB - We have investigated the effect of pH, salts and shear on the hydrodynamical diameter of recombinant major ampullate (MA) rMaSpI silk proteins in solution as a function of time using (1) H solution NMR spectroscopy. The results indicate that the silk proteins in solution are composed of two diffusing populations, a high proportion of "native" solubilized proteins and a small amount of high molecular weight oligomers. Similar results are observed with the MA gland content. Salts help maintaining the proteins in a compact form in solution over time and inhibit aggregation, the absence of salts triggering protein assembly leading to a gel state. Moreover, the aggregation kinetics of rMaSpI at low salt concentration accelerates as the pH is close to the isoelectric point of the proteins, suggesting that the pH decrease tends to slow down aggregation. The data also support the strong impact of shear on the spinning process and suggest that the assembly is driven by a nucleation conformational conversion mechanism. Thus, the adjustment of the physicochemical conditions in the ampulla seems to promote a stable, long term storage. In addition, the optimization of protein conformation as well as their unfolding and aggregation propensity in the duct leads to a specifically organized structure. PMID- 23794374 TI - Comparing the interpersonal behavior of distressed couples with and without depression. AB - OBJECTIVE: This study compared the interpersonal behavior of distressed couples with depression in one partner (n = 23) to distressed couples without depression in either partner (n = 38). METHOD: Participants (mean age = 44 years old) were recruited at an urban outpatient mental health center. Couples discussed the three best things in their relationship, and their interactions were coded using Structural Analysis of Social Behavior (Benjamin, 1987). RESULTS: Self- and partner-focused hostility were associated with actors' and partners' relationship distress. Actors' hostility towards partners was positively associated with partners' depression status, but negatively associated with partners' depression symptoms. Actors' control behavior was positively associated with their relationship distress. Whereas the behavior of depressed individuals did not differ from a control sample of nondepressed individuals, partners of depressed individuals displayed more partner-focused hostility and submissiveness than controls. CONCLUSIONS: Results underscore the importance of considering partner effects when conceptualizing depression within distressed relationships. PMID- 23794375 TI - Two unusual 3D POM-Ag frameworks with tetragonal and dodecagonal helical channels. AB - Two new hybrid compounds with tetragonal and dodecagonal helical channels, K[Ag14(pyttz)4(H2O)2][PW12O40]2?(OH)?5 H2O (1) and K[Ag14(pyttz)4(H2O)4][HSiW12O40]2?H2O (2), have been hydrothermally synthesized and structurally characterized by using routine techniques. X-ray diffraction analysis shows that compounds 1 and 2 are isostructural and crystallize in the monoclinic space group P2(1)/c. A fascinating structural feature of these compounds is that they form 3D POM-Ag frameworks with helical channels, which are the first examples of helical channels that are constructed from POMs and metal atoms. Notably, there are two types of spatial orientation of the POMs, which result in the formations of left- and right-handed helical chains. Furthermore, these different helical chains are perfectly enclosed through shared POMs, thereby forming tetragonal and dodecagonal helical channels. In addition, the photocatalytic degradation of RhB by these compounds was also investigated. PMID- 23794376 TI - Myoclonic epilepsy in a child with 17q22-q23.1 deletion. AB - Interstitial deletions of the long arm of the chromosome 17 are relatively rare. Up to 17 cases involving the q22-q23.3 band have been reported so far. A common phenotype has not yet been delineated and epilepsy has been reported in only 2 out of 17 cases. We describe a clinical phenotype of epilepsy characterized by myoclonic atonic and absence seizures in a 6-year-old boy carrying a de novo 17q22q23 deletion detected by oligonucleotide array comparative genomic hybridization (aCGH). PMID- 23794377 TI - [37-year-old woman with weight loss and periocular papules and nodules]. PMID- 23794378 TI - Delineation of key XRCC4/Ligase IV interfaces for targeted disruption of non homologous end joining DNA repair. AB - Efficient DNA repair mechanisms frequently limit the effectiveness of chemotherapeutic agents that act through DNA damaging mechanisms. Consequently, proteins involved in DNA repair have increasingly become attractive targets of high-throughput screening initiatives to identify modulators of these pathways. Disruption of the XRCC4-Ligase IV interaction provides a novel means to efficiently halt repair of mammalian DNA double strand break repair; however; the extreme affinity of these proteins presents a major obstacle for drug discovery. A better understanding of the interaction surfaces is needed to provide a more specific target for inhibitor studies. To clearly define key interface(s) of Ligase IV necessary for interaction with XRCC4, we developed a competitive displacement assay using ESI-MS/MS and determined the minimal inhibitory fragment of the XRCC4-interacting region (XIR) capable of disrupting a complex of XRCC4/XIR. Disruption of a single helix (helix 2) within the helix-loop-helix clamp of Ligase IV was sufficient to displace XIR from a preformed complex. Dose dependent response curves for the disruption of the complex by either helix 2 or helix-loop-helix fragments revealed that potency of inhibition was greater for the larger helix-loop-helix peptide. Our results suggest a susceptibility to inhibition at the interface of helix 2 and future studies would benefit from targeting this surface of Ligase IV to identify modulators that disrupt its interaction with XRCC4. Furthermore, helix 1 and loop regions of the helix-loop helix clamp provide secondary target surfaces to identify adjuvant compounds that could be used in combination to more efficiently inhibit XRCC4/Ligase IV complex formation and DNA repair. PMID- 23794379 TI - Tracking context-specific transcription factors regulating hox activity. AB - BACKGROUND: Hox proteins are key developmental regulators involved in almost every embryonic tissue for specifying cell fates along longitudinal axes or during organ formation. It is thought that the panoply of Hox activities relies on interactions with tissue-, stage-, and/or cell-specific transcription factors. High-throughput approaches in yeast or cell culture systems have shown that Hox proteins bind to various types of nuclear and cytoplasmic components, illustrating their remarkable potential to influence many different cell regulatory processes. However, these approaches failed to identify a relevant number of context-specific transcriptional partners, suggesting that these interactions are hard to uncover in non-physiological conditions. Here we discuss this problematic. RESULTS: In this review, we present intrinsic Hox molecular signatures that are probably involved in multiple (yet specific) interactions with transcriptional partners. We also recapitulate the current knowledge on Hox cofactors, highlighting the difficulty to tracking context-specific cofactors through traditional large-scale approaches. CONCLUSION: We propose experimental approaches that will allow a better characterisation of interaction networks underlying Hox contextual activities in the next future. PMID- 23794380 TI - Oxidation-triggered ring-opening metathesis polymerization. AB - Eight new N-Hoveyda-type complexes were synthesized in yields of 67-92 % through reaction of [RuCl2 (NHC)(Ind)(py)] (NHC=1,3-bis(2,4,6-trimethylphenylimidazolin) 2-ylidene (SIMes) or 1,3-bis(2,6-diisopropylphenylimidazolin)-2-ylidene (SIPr), Ind=3-phenylindenylid-1-ene, py=pyridine) with various 1- or 1,2-substituted ferrocene compounds with vinyl and amine or imine substituents. The redox potentials of the respective complexes were determined; in all complexes an iron centered oxidation reaction occurs at potentials close to E=+0.5 V. The crystal structures of the reduced and of the respective oxidized Hoveyda-type complexes were determined and show that the oxidation of the ferrocene unit has little effect on the ruthenium environment. Two of the eight new complexes were found to be switchable catalysts, in that the reduced form is inactive in the ring-opening metathesis polymerization of cis-cyclooctene (COE), whereas the oxidized complexes produce polyCOE. The other complexes are not switchable catalysts and are either inactive or active in both reduced and oxidized states. PMID- 23794381 TI - A new multiresponsive drug delivery system using smart nanogels. AB - This paper addresses the synthesis and characterization of a novel temperature- and pH-responsive nanogel system based on poly(vinylcaprolactam-co-2 dimethylaminoethyl methacrylate) [P(VCL-co-DMAEMA)] by using a surfactant-free emulsion polymerization procedure for the multiresponsive drug delivery of hydrophobic drugs. The effects of solvent, monomer, pH, and temperature were studied to tailor the average particle hydrodynamic diameters and the polydispersity index of the final particles. According to dynamic light scattering measurements, the obtained nanogels show a narrow particle-size distribution and their hydrodynamic diameters can be varied from 81 to 368 nm. The nanogels display a re-entrant phase-transition state, and the equilibrium volume swelling ratio of the nanogels decreases drastically down to 47 degrees C and then increases up to 65 degrees C. In addition, the nanogels show pH dependent behavior. They exhibit a maximum size at pH 5.0. Rhodamine B (RhB) was chosen as a model compound for drug loading and release studies from P(VCL-co DMAEMA) on the basis of particles in different phosphate buffer solutions at different temperatures. The temperature/pH-dependent cumulative release and ultrasound-enhanced pulsatile release properties were investigated for RhB-loaded nanogels for long-term and one-shot delivery. The nanogels display efficient delivery for both long-term and one-shot delivery systems. We provide here a proof of concept for the novel use of multiresponsive nanogels having an overall size below 200 nm as a cargo system for hydrophobic drugs and for controlled release mediated by temperature/pH and ultrasound. PMID- 23794382 TI - Corticosteroids in peritonsillar abscess treatment: a blinded placebo-controlled clinical trial. AB - OBJECTIVES/HYPOTHESIS: Sore throat is a common, benign emergency department (ED) presentation; however, peritonsillar abscess (PTA) is a complication that requires aggressive management. Use of systemic corticosteroids (SCSs) in PTA is occurring without clear evidence of benefit. This study examined the efficacy and safety of SCS treatment for patients with PTA. STUDY DESIGN: Randomized, double blind, placebo-controlled trial. METHODS: A controlled trial with concealed allocation and double-blinding was conducted at two Canadian EDs. Following written informed consent, eligible patients received 48 hours of intravenous clindamycin and a single dose of the study drug (dexamethasone [DEX] or placebo [PLAC], intravenously [IV]). Follow-up occurred at 24 hours, 48 hours, and 7 days. The primary outcome was pain; other outcomes were side effects and return to normal activities/diet. RESULTS: A total of 182 patients were screened for eligibility; 41 patients were enrolled (21 DEX; 20 PLAC). At 24 hours, those receiving DEX reported lower pain scores (1.4 vs. 5.1; P = .009); however, these differences disappeared by 48 hours (P = .22) and 7 days (P = .4). At 24 hours, more patients receiving DEX returned to normal activities (33% vs. 11%) and dietary intake (38% vs 25%); however, these differences were not significant and disappeared by 48 hours and 7 days. Side effects were rare and did not differ between groups (P > .05). CONCLUSIONS: Combined with PTA drainage and IV antibiotics, 10 mg IV DEX resulted in less pain at 24 hours when compared to PLAC, without any serious side effects. This effect is short-lived, and further research is required on factors associated with PTA treatment success. PMID- 23794383 TI - Developing fruit-based nutritious snack bars. AB - BACKGROUND: Marolo (Annona crassiflora Mart) is a typical savannah fruit that is very nutritious and highly appreciated. However, its consumption has been limited to fresh fruit. The objective of this study was to evaluate the potential use of marolo flour in the production of healthy snack bars to valorise this fruit and provide an alternative ready-to-eat nutritious product. Snack bars containing increasing amounts of marolo flour (5 g 100 g(-1), 10 g 100 g(-1), 15 g 100 g( 1), 20 g 100 g(-1), expressed in w/w) were produced and the physico-chemical and sensory characteristics were determined. RESULTS: Levels up to 20% marolo flour can be incorporated in snack bars with some minor changes in pH and moisture content but with an increase of 2.4-fold in dietary fibre content and also 1.3 fold of vitamin C, minerals and antioxidant activity. In addition, up to 10% marolo flour improves significantly the sensory properties of the snack bars, namely appearance, taste, texture and overall acceptance. CONCLUSION: Marolo flour can be considered an alternative flour for obtaining healthy snack bars, with increased nutritional and sensory quality. PMID- 23794384 TI - Catalytic Z-selective cross-metathesis with secondary silyl- and benzyl-protected allylic ethers: mechanistic aspects and applications to natural product synthesis. PMID- 23794385 TI - Subcontractors and increased risk for work-related diseases and absenteeism. AB - BACKGROUND: Despite increasing reliance on subcontracting in many economic sectors, there is little information available on occupational health and safety issues among subcontractor employees. The purpose of this study was to investigate the effect of subcontracting on self-reported health problems and absences due to occupational accidents and sickness using a nationally representative sample from South Korea. METHODS: The data used were sampled from the second wave of the Korean Working Conditions Survey [2010]. Information on 3,282 parent firm employees and 728 subcontractor employees was obtained. For the logistic regression model, the outcomes were work-related health problems and absenteeism. The independent variables were personal and occupational characteristics, job aspects, and working hazards. RESULTS: Subcontractor employees were significantly more likely to experience health problems than the employee at parent firms. In particular, subcontractors' risk of injuries and anxiety/depression increased twofold (odd ratios, OR=2.01, 95% confidence interval, CIs, 1.24-3.26) and threefold (OR=2.95, 95% CIs 1.52-5.73), respectively, after controlling for potential variables. In addition, subcontractor employees were three times more likely than employees at parent firms to miss work due to illness (OR=3.56; 95% CIs 2.02-6.26). Working conditions, especially those related to job aspects and workplace exposures, attenuated these risks. CONCLUSION: Subcontracting workers were found to have a higher risk of work-related diseases and a higher absenteeism rate than parent firm workers. Our study highlights the need to protect and improve the occupational health and safety of subcontractor employees. PMID- 23794386 TI - Solvent-dependent reversible ligand exchange in nickel complexes of a monosulfide bis(diphenylphosphino)(N-thioether)amine. AB - The coordination chemistry of the DPPA-type functional phosphine bis(diphenylphosphino)(N-thioether)amine N(PPh2)2(CH2)3SMe () and its monosulfide derivative, (Ph2P)N{P(S)Ph2}(CH2)3SMe (1.S), towards Ni(II) precursors has been investigated. The crystal structures of N{P(S)Ph2}2(CH2)3SMe (1.S2), [NiCl2{(Ph2P)2N(CH2)3SMe-P,P}] (2), [NiCl2((Ph2P)N{P(S)Ph2}(CH2)3SMe-P,S)] (3), [Ni((Ph2P)N{P(S)Ph2}(CH2)3SMe-P,S)2]NiCl4 (3'), [Ni((Ph2P)N{P(S)Ph2}(CH2)3SMe P,S)2](BF4)2 (4), and [Ni((Ph2P)NH{P(S)Ph2}-P,S)2]Cl2 (5) have been determined by single-crystal X-ray diffraction. In all of the complexes with the hybrid ligand 1.S, P,S-chelation to the Ni(II) center is observed. Despite the stability generally associated with five-membered ring chelation, easy migration of this LL'-type P,S-chelating ligand from one metal center to another was observed, which accounts for the reversible ligand-redistribution reaction occurring in the equilibrium between the neutral, diamagnetic complex [NiCl2LL'] and the paramagnetic ion-pair [Ni(LL')2][NiCl4]. Detailed investigations by multinuclear NMR, UV/Vis, and FTIR spectroscopic methods and DFT calculations are reported. Each of the formula isomers 3 and 3' can be selectively obtained, depending on the experimental conditions. PMID- 23794387 TI - The Metacognitions about Desire Thinking Questionnaire: development and psychometric properties. AB - OBJECTIVES: Recent research has suggested that specific metacognitions may play a role in the activation and escalation of desire thinking and craving. The goal of this research project was to develop the first self-report instrument of metacognitions about desire thinking. METHOD: We conducted three studies with nonclinical samples (N = 213, N = 279, N = 60) to construct the Metacognitions about Desire Thinking Questionnaire (MDTQ) and test its structure and psychometric properties. A fourth study was added to test the predictive validity of MDTQ in a sample of alcohol abusers (N = 75). RESULTS: Explorative and confirmatory factor analysis supported a 3-factor solution: positive metacognitions about desire thinking, negative metacognitions about desire thinking, and need to control desire related thoughts. Internal consistency, divergent validity, temporal stability were also examined in a community sample and predictive validity was confirmed even in a sample of alcohol abusers. CONCLUSIONS: The MDTQ was shown to possess good psychometric properties, as well as divergent and predictive validity within the populations that were tested. PMID- 23794388 TI - Juvenile idiopathic arthritis, mitral valve prolapse and a familial variant involving the integrin-binding fragment of FBN1. AB - Mutations in Fibrillin 1 (FBN1) are associated with Marfan syndrome and in some instances with the MASS phenotype (myopia, mitral valve prolapse, borderline non progressive aortic root dilatation, skeletal features, and striae). Potential confusion over diagnosis and management in patients with borderline features has been addressed through the revised Ghent nosology, which emphasizes the importance of aortic root dilatation and ectopia lentis as features of Marfan syndrome. The overlapping and more common mitral valve prolapse syndrome is precluded by ectopia lentis or aortic dilatation. Among these clinically related conditions, there is no compelling evidence that genotype predicts phenotype, with the exception of neonatal Marfan syndrome, mutations in which cluster within FBN1 exons 24-32. Recent reports also link two very different phenotypes to changes in FBN1. Heterozygous mutations in transforming growth factor beta binding protein-like domain 5 (TB5) can cause acromicric or geleophysic dysplasias-and mutations in the TB4 domain, which contains an integrin binding RGD loop, have been found in congenital scleroderma/stiff skin syndrome. We report on a variant in an evolutionarily conserved residue that stabilizes the integrin binding fragment of FBN1, associated with juvenile idiopathic arthritis, mitral valve prolapse or apparently normal phenotype in different family members. PMID- 23794390 TI - Effects of deformation on transmural dispersion of repolarization using in silico models of human left ventricular wedge. AB - Mechanical deformation affects the electrical activity of the heart through multiple feedback loops. The purpose of this work is to study the effect of deformation on transmural dispersion of repolarization and on surface electrograms using an in silico human ventricular wedge. To achieve this purpose, we developed a strongly coupled electromechanical cell model by coupling a human left ventricle electrophysiology model and an active contraction model reparameterized for human cells. This model was then embedded in tissue simulations on the basis of bidomain equations and nonlinear solid mechanics. The coupled model was used to evaluate effects of mechanical deformation on important features of repolarization and electrograms. Our results indicate an increase in the T-wave amplitude of the surface electrograms in simulations that account for the effects of cardiac deformation. This increased T-wave amplitude can be explained by changes to the coupling between neighboring myocytes, also known as electrotonic effect. The thickening of the ventricular wall during repolarization contributes to the decoupling of cells in the transmural direction, enhancing action potential heterogeneity and increasing both transmural repolarization dispersion and T-wave amplitude of surface electrograms. The simulations suggest that a considerable percentage of the T-wave amplitude (15%) may be related to cardiac deformation. PMID- 23794391 TI - Replication of mesoporous silica films from block copolymer films through a chemical vapor approach. PMID- 23794392 TI - Solvent- and achiral-guest-triggered chiral inversion in a planar chiral pseudo[1]catenane. PMID- 23794393 TI - High-dimensional NMR spectra for structural studies of biomolecules. AB - Recent developments in the acquisition and processing of NMR data sets facilitate the recording of ultra-high-resolution NMR spectra in a reasonable time. The new experiments allow easy resonance assignment for folded and unfolded proteins, as well as the precise determination of spectral parameters, for example, chemical shifts, NOE contacts, coupling constants or cross-correlated relaxation rates. Owing to exceptional resolution of 4D-6D spectroscopy, detailed studies of biomolecules of unprecedented complexity are now possible. Herein, the principles of acquisition and processing methods are presented. The main applications of high-dimensional NMR experiments, including backbone and side-chain resonance assignment in proteins, as well as heteronuclear edited NOE techniques are reviewed. PMID- 23794394 TI - Traditional food and tourism: French tourist experience and food heritage in rural spaces. AB - Tourist interest in different food cultures is a factor for local development in the fields of agro-food and crafts, whilst also contributing to the enhancement of food culture and heritage. As part of the tourist experience, eating local cuisine is a way of breaking with standardised, everyday routine by taking the tourist off into unknown culinary realms. This distancing from daily life is already possible in the home country through eating exotic food at home, or in so called 'ethnic' restaurants. It takes on another dimension when travelling. This paper therefore aims to examine the role of food and eating in the tourist experience. To be more precise, we shall first attempt to assess its importance in visitors' representations, notably as a motive for travel, or in the images deployed regarding eating and drinking during their stay, as they relate to perceptions of the place visited. As well as studying tourist food perceptions, we shall also examine tourist behaviour as regards food purchase and consumption, together with behaviour relating to food souvenirs. PMID- 23794395 TI - Versatile eco-friendly pickering emulsions based on substrate/native cyclodextrin complexes: a winning approach for solvent-free oxidations. AB - Solvent-less Pickering emulsions were developed and applied to catalytic oxidation. These systems are stabilized by inclusion complexes between cyclodextrins and substrates, forming a 3D network among the dispersed phase. In the presence of hydrogen peroxide as a green oxidant and [Na]3 [PW12 O40 ] as a catalyst, they provide particularly efficient reaction media for the oxidation of olefins, organosulfurs, and alcohols. The reactions proceed at competitive rates (up to 400 h(-1) ) with straightforward separation of the phases by centrifugation or heating. Moreover, these new eco-friendly systems work at a preparative scale (up to 2.5 M) and are recycled without loss of activity. PMID- 23794396 TI - Ebstein anomaly associated with left ventricular noncompaction: an autosomal dominant condition that can be caused by mutations in MYH7. AB - Left ventricular noncompaction (LVNC) is a relatively common genetic cardiomyopathy, characterized by prominent trabeculations with deep intertrabecular recesses in mainly the left ventricle. Although LVNC often occurs in an isolated entity, it may also be present in various types of congenital heart disease (CHD). The most prevalent CHD in LVNC is Ebstein anomaly, which is a rare form of CHD characterized by apical displacement and partial fusion of the septal and posterior leaflet of the tricuspid valve with the ventricular septum. Several reports of sporadic as well as familial cases of Ebstein anomaly associated with LVNC have been reported. Recent studies identified mutations in the MYH7 gene, encoding the sarcomeric beta-myosin heavy chain protein, in patients harboring this specific phenotype. Here, we will review the association between Ebstein anomaly, LVNC and mutations in MYH7, which seems to represent a subtype of Ebstein anomaly with autosomal dominant inheritance and variable penetrance. PMID- 23794397 TI - Impact of social discrimination, job concerns, and social support on Filipino immigrant worker mental health and substance use. AB - BACKGROUND: The personal and social impact of mental health problems and substance use on workforce participation is costly. Social determinants of health contribute significantly to health disparities beyond effects associated with work. Guided by a theory-driven model, we identified pathways by which social determinants shape immigrant worker health. METHOD: Associations between known social determinants of mental health problems and substance use (social discrimination, job and employment concerns, and social support) were examined using structural equation modeling in a sample of 1,397 immigrants from the Filipino American Community Epidemiological Study. RESULTS: Social discrimination and low social support were associated with mental health problems and substance use (P < 0.05). Job and employment concerns were associated with mental health problems, but not substance use. CONCLUSIONS: The integration of social factors into occupational health research is needed, along with prevention efforts designed for foreign-born ethnic minority workers. PMID- 23794398 TI - Recurrent deletion of 3p13 targets multiple tumour suppressor genes and defines a distinct subgroup of aggressive ERG fusion-positive prostate cancers. AB - Deletion of 3p13 has been reported from about 20% of prostate cancers. The clinical significance of this alteration and the tumour suppressor gene(s) driving the deletion remain to be identified. We have mapped the 3p13 deletion locus using SNP array analysis and performed fluorescence in situ hybridization (FISH) analysis to search for associations between 3p13 deletion, prostate cancer phenotype and patient prognosis in a tissue microarray containing more than 3200 prostate cancers. SNP array analysis of 72 prostate cancers revealed a small deletion at 3p13 in 14 (19%) of the tumours, including the putative tumour suppressors FOXP1, RYBP and SHQ1. FISH analysis using FOXP1-specific probes revealed deletions in 16.5% and translocations in 1.2% of 1828 interpretable cancers. 3p13 deletions were linked to adverse features of prostate cancer, including advanced stage (p < 0.0001), high Gleason grade (p = 0.0125), and early PSA recurrence (p = 0.0015). In addition, 3p13 deletions were linked to ERG(+) cancers and to PTEN deletions (p < 0.0001 each). A subset analysis of ERG(+) tumours revealed that 3p13 deletions occurred independently from PTEN deletions (p = 0.3126), identifying tumours with 3p13 deletion as a distinct molecular subset of ERG(+) cancers. mRNA expression analysis confirmed that all 3p13 genes were down regulated by the deletion. Ectopic over-expression of FOXP1, RYBP and SHQ1 resulted in decreased colony-formation capabilities, corroborating a tumour suppressor function for all three genes. In summary, our data show that deletion of 3p13 defines a distinct and aggressive molecular subset of ERG(+) prostate cancers, which is possibly driven by inactivation of multiple tumour suppressors. PMID- 23794399 TI - VEGFA, FLT1, KDR and colorectal cancer: assessment of disease risk, tumor molecular phenotype, and survival. AB - Angiogenesis is essential for tumor progression. Vascular endothelial growth factor (VEGFA) and its receptors 1 (FLT1) and 2 (KDR), have been identified as major mediators of this process. We hypothesized that genetic variation in FLT1 (38 SNPs), KDR (22 SNPS), and VEGFA (11 SNPs) would be associated with colon and rectal cancer development and survival. Data from a case-control study of 1555 colon cancer cases and 1956 controls and 754 rectal cancer cases and 959 controls were used. An adaptive rank truncation product (ARTP), based on 10,000 permutations, was used to determine the statistical significance of the candidate genes and angiogenesis pathway. Based on ARTP results, FLT1 was significantly associated with risk of colon cancer (P(ARTP) = 0.045) and VEGFA was significantly associated with rectal cancer (P(ARTP) = 0.036). After stratifying by tumor molecular subtype, SNP associations observed for colon cancer were: VEGFA rs2010963 with CIMP+ colon tumors; FLT1 rs4771249 and rs7987649 with TP53; FLT1 rs3751397, rs7337610, rs7987649, and rs9513008 and KDR rs10020464, rs11941492, and rs12498529 with MSI+ and CIMP+/KRAS2-mutated tumors. FLT1 rs2296189 and rs600640 were associated with CIMP+ rectal tumors and FLT1 rs7983774 was associated with TP53-mutated rectal tumors. Four SNPs in FLT1 were associated with colon cancer survival while three SNPs in KDR were associated with survival after diagnosis with rectal cancer. Aspirin/NSAID use, smoking cigarettes, and BMI modified the associations. These findings suggest the importance of inflammation and angiogenesis in the etiology of colorectal cancer and that genetic and lifestyle factors may be targets for modulating disease risk. PMID- 23794400 TI - Acute metabolic, hormonal, and psychological responses to different endurance training protocols. AB - In the last years, mainly 2 high-intensity-training (HIT) protocols became common: first, a Wingate-based "all-out" protocol and second, a 4*4 min protocol. However, no direct comparison between these protocols exists, and also a comparison with high-volume-training (HVT) is missing. Therefore, the aim of the present study was to compare these 3 endurance training protocols on metabolic, hormonal, and psychological responses. Twelve subjects performed: 1) HVT [130 min at 55% peak power output (PPO)]; 2) 4*4 min at 95% PPO; 3) 4*30 s all-out. Human growth hormone (hGH), testosterone, and cortisol were determined before (pre) and 0', 30', 60', 180' after each intervention. Metabolic stimuli and perturbations were characterized by lactate, blood gas (pH, BE, HCO3-, pO2, PCO2), and spirometric analysis. Furthermore, changes of the person's perceived physical state were determined. The 4*30 s training caused the highest increases in cortisol and hGH, followed by 4 * 4 min and HVT. Testosterone levels were significantly increased by all 3 exercise protocols. Metabolic stress was highest during and after 4*30 s, followed by 4*4 min and HVT. The 4*30 s training was also the most demanding intervention from an athlete's point of view. In conclusion, the results suggest that 4*30 s and 4*4 min promote anabolic processes more than HVT, due to higher increases of hGH, testosterone, and the T/C ratio. It can be speculated that the acute hormonal increase and the metabolic perturbations might play a positive role in optimizing training adaptation and in eliciting health benefits as it has been shown by previous long term training studies using similar exercise protocols. PMID- 23794401 TI - Bone: an acute buffer of plasma sodium during exhaustive exercise? AB - Both hyponatremia and osteopenia separately have been well documented in endurance athletes. Although bone has been shown to act as a "sodium reservoir" to buffer severe plasma sodium derangements in animals, recent data have suggested a similar function in humans. We aimed to explore if acute changes in bone mineral content were associated with changes in plasma sodium concentration in runners participating in a 161 km mountain footrace. Eighteen runners were recruited. Runners were tested immediately pre- and post-race for the following main outcome measures: bone mineral content (BMC) and density (BMD) via dual energy X-ray absorptiometry (DEXA); plasma sodium concentration ([Na+]p), plasma arginine vasopressin ([AVP]p), serum aldosterone concentration ([aldosterone]s), and total sodium intake. Six subjects finished the race in a mean time of 27.0+/ 2.3 h. All subjects started and finished the race with [Na+]p within the normal range (137.7+/-2.3 and 136.7+/-1.6 mEq/l, pre- and post-race, respectively). Positive correlations were noted between change (Delta; post-race minus pre-race) in total BMC (grams) and [Na+]p (mEq/l) (r=0.99; p<0.0001), and between total sodium intake (mEq/kg) and %Delta lumbar spine BMD (r=0.94; p<0.001). Change in [aldosterone]s was positively correlated with: rate of total sodium intake (r=0.84; p<0.05); Delta total BMC (r=0.82; p<0.05); and Delta [Na+]p (r=0.88; p<0.05). No significant pre- to post-race mean differences were noted in BMC or BMD. Robust associations between Delta BMC and Delta [Na+]p suggest that sodium status and bone density may be inter-related during endurance exercise and should be considered in future investigations of athletic osteopenia. PMID- 23794402 TI - 17beta-Estradiol reduces nitric oxide production in the Guinea pig cochlea. AB - Intense noise exposure and the application of ototoxic substances result in increased levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS), such as nitric oxide (NO). In order to reduce the free NO concentration in the inner ear under pathological conditions, the use of natural cytoprotective substances such as 17beta-estradiol is a promising therapeutic concept. In male guinea pigs the organ of Corti and the lateral wall were isolated from the cochlea and afterwards incubated for 6 h in cell-culture medium. 17beta-Estradiol was adjusted in 2 concentrations to organ cultures of the right ears (12 animals per concentration). The left ears were used as controls. The NO production was quantified in the supernatant by chemiluminescence after incubation. Depending on the concentration, 17beta-estradiol reduced NO in the organ of Corti by 43% (p=0.015) and 46% (p=0.026), respectively. In the lateral wall, the NO concentration was reduced by 24%, but without statistical significance (p=0.86). However, when analyzing the association between the 2 cochlear regions for each animal separately, the NO concentrations were lower in nearly all 17beta estradiol-treated ears compared to controls. In order to demonstrate the flexibility of the organ culture system, the NO donor DETA NONOate and the nitric oxide synthase inhibitors L-NAME and L-NMMA were applied. The electron microscopic analysis revealed a well-preserved cochlear cell morphology after incubation. The ability of 17beta-estradiol to influence the NO production preferentially in the organ of Corti might offer new therapeutic perspectives for inner ear protection. PMID- 23794403 TI - Energetic N-trinitroethyl-substituted mono-, di-, and triaminotetrazoles. AB - A series of dense energetic N-trinitroethyl-substituted mono-, bis-, and tri-5 aminotetrazoles were obtained by reacting primary amines with in situ generated cyanogen azide, followed by the trinitroethyl functionalization that involves a condensation of a hydroxymethyl intermediate (prepared by a reaction with formaldehyde) with trinitromethane. These compounds were fully characterized by using multinuclear NMR spectroscopy, IR, elemental analysis, differential scanning calorimetry (DSC), and, in one case with 9, with single-crystal XRD analysis. The heats of formation for all compounds were calculated with Gaussian 03 and then combined with experimental densities to determine the detonation pressures (P) and velocities (D(v)) of the energetic materials. Interestingly, most of them exhibited high density, good thermal stability, acceptable oxygen balance, positive heat of formation, low impact sensitivity, and excellent detonation properties, which highlighted their practical application potentials as a fascinating class of highly energetic materials. PMID- 23794405 TI - Caution regarding the choice of standard deviations to guide sample size calculations in clinical trials. AB - BACKGROUND: The method used to determine choice of standard deviation (SD) is inadequately reported in clinical trials. Underestimations of the population SD may result in underpowered clinical trials. PURPOSE: This study demonstrates how using the wrong method to determine population SD can lead to inaccurate sample sizes and underpowered studies, and offers recommendations to maximize the likelihood of achieving adequate statistical power. METHODS: We review the practice of reporting sample size and its effect on the power of trials published in major journals. Simulated clinical trials were used to compare the effects of different methods of determining SD on power and sample size calculations. RESULTS: Prior to 1996, sample size calculations were reported in just 1%-42% of clinical trials. This proportion increased from 38% to 54% after the initial Consolidated Standards of Reporting Trials (CONSORT) was published in 1996, and from 64% to 95% after the revised CONSORT was published in 2001. Nevertheless, underpowered clinical trials are still common. Our simulated data showed that all minimal and 25th-percentile SDs fell below 44 (the population SD), regardless of sample size (from 5 to 50). For sample sizes 5 and 50, the minimum sample SDs underestimated the population SD by 90.7% and 29.3%, respectively. If only one sample was available, there was less than 50% chance that the actual power equaled or exceeded the planned power of 80% for detecting a median effect size (Cohen's d = 0.5) when using the sample SD to calculate the sample size. The proportions of studies with actual power of at least 80% were about 95%, 90%, 85%, and 80% when we used the larger SD, 80% upper confidence limit (UCL) of SD, 70% UCL of SD, and 60% UCL of SD to calculate the sample size, respectively. When more than one sample was available, the weighted average SD resulted in about 50% of trials being underpowered; the proportion of trials with power of 80% increased from 90% to 100% when the 75th percentile and the maximum SD from 10 samples were used. Greater sample size is needed to achieve a higher proportion of studies having actual power of 80%. LIMITATIONS: This study only addressed sample size calculation for continuous outcome variables. CONCLUSIONS: We recommend using the 60% UCL of SD, maximum SD, 80th-percentile SD, and 75th percentile SD to calculate sample size when 1 or 2 samples, 3 samples, 4-5 samples, and more than 5 samples of data are available, respectively. Using the sample SD or average SD to calculate sample size should be avoided. PMID- 23794404 TI - Overcoming co-product inhibition in the nicotinamide independent asymmetric bioreduction of activated C=C-bonds using flavin-dependent ene-reductases. AB - Eleven flavoproteins from the old yellow enzyme family were found to catalyze the disproportionation ("dismutation") of conjugated enones. Incomplete conversions, which were attributed to enzyme inhibition by the co-product phenol could be circumvented via in situ co-product removal by scavenging the phenol using the polymeric adsorbent MP-carbonate. The optimized system allowed to reduce an alkene activated by ester groups in a "coupled-substrate" approach via nicotinamide-free hydrogen transfer with >90% conversion and complete stereoselectivity. PMID- 23794406 TI - Gynecologic oncology group strategies to improve timeliness of publication. AB - BACKGROUND: The Gynecologic Oncology Group (GOG) is a multi-institution cooperative group funded by the National Cancer Institute to conduct clinical trials encompassing clinical and basic scientific research in gynecologic malignancies. These results are disseminated via publication in peer-reviewed journals. This process requires collaboration of numerous investigators located in diverse cancer research centers. Coordination of manuscript development is positioned within the Statistical and Data Center (SDC), thus allowing the SDC personnel to manage the process and refine strategies to promote earlier dissemination of results. A major initiative to improve timeliness utilizing the assignment, monitoring, and enforcement of deadlines for each phase of manuscript development is the focus of this investigation. PURPOSE: Document improvement in timeliness via comparison of deadline compliance and time to journal submission due to expanded administrative and technologic initiatives implemented in 2006. METHODS: Major steps in the publication process include generation of first draft by the First Author and submission to SDC, Co-author review, editorial review by Publications Subcommittee, response to journal critique, and revision. Associated with each step are responsibilities of First Author to write or revise, collaborating Biostatistician to perform analysis and interpretation, and assigned SDC Clinical Trials Editorial Associate to format/revise according to journal requirements. Upon the initiation of each step, a deadline for completion is assigned. In order to improve efficiency, a publications database was developed to track potential steps in manuscript development that enables the SDC Director of Administration and the Publications Subcommittee Chair to assign, monitor, and enforce deadlines. They, in turn, report progress to Group Leadership through the Operations Committee. The success of the strategies utilized to improve the GOG publication process was assessed by comparing the timeliness of each potential step in the development of primary Phase II manuscripts during 2003-2006 versus 2007-2010. RESULTS: Improvement was noted in 10 of 11 identified steps resulting in a cumulative average improvement of 240 days from notification of data maturity to First Author through first submission to a journal. Moreover, the average time to journal acceptance has improved by an average of 346 days. LIMITATIONS: The investigation is based on only Phase II trials to ensure comparability of manuscript complexity. Nonetheless, the procedures employed are applicable to the development of any clinical trials manuscript. CONCLUSIONS: The assignment, monitoring, and enforcement of deadlines for all stages of manuscript development have resulted in increased efficiency and timeliness. The positioning and support of manuscript development within the SDC provide a valuable resource to authors in meeting assigned deadlines, accomplishing peer review, and complying with journal requirements. PMID- 23794407 TI - Clinician-trialist rounds: 17. Mind your explanatory and pragmatic attitudes! Part 2: How? PMID- 23794408 TI - Are bile acids the new gut hormones? Lessons from weight loss surgery models. PMID- 23794409 TI - Do not turn to the hypothalamus for feedback on stress if you are growth restricted. PMID- 23794410 TI - Adiponectin to the rescue: how the embryo maintains glucose uptake in a diabetic mother. PMID- 23794411 TI - Firing up brown fat with brain amylin. PMID- 23794412 TI - Opening the black box: revealing the molecular basis of thyroid hormone transport. PMID- 23794413 TI - Rigid DNA beams for high-resolution single-molecule mechanics. AB - Bridging the gap: Rigid DNA linkers (blue, see picture) between microspheres (green) for high-resolution single-molecule mechanical experiments were constructed using DNA origami. The resulting DNA helical bundles greatly reduce the noise generated in studies of conformation changes using optical tweezers and were applied to study small DNA secondary structures. PMID- 23794414 TI - Population pharmacokinetics of tolvaptan in healthy subjects and patients with hyponatremia secondary to congestive heart failure or hepatic cirrhosis. AB - Tolvaptan is a selective V2 -receptor antagonist used to treat hypervolemic and euvolemic hyponatremia. A population pharmacokinetic (PK) analysis was performed for tolvaptan in NONMEM(r) based upon data obtained from three trials conducted in 93 healthy subjects and six trials conducted in 628 congestive heart failure (CHF) patients or 24 hepatic cirrhosis patients receiving oral tolvaptan (5 to 240 mg). A two-compartment model with first-order absorption and elimination best described tolvaptan PK. Relative oral bioavailability was modeled relative to 100% for a 30 mg dose and ranged from 79.4% to 122%. Body weight and the impact of CHF or hepatic cirrhosis relative to healthy subjects were statistically significant (p < 0.001) predictors of both the apparent oral clearance (CL/F) and apparent central volume of distribution (Vc /F). The CL/F was reduced to 58.2% for New York Heart Association (NYHA) Class 1 or 2 CHF, 45.5% for NYHA Class 3 or 4 CHF, and 58.0% for hepatic cirrhosis relative to healthy subjects. Vc /F was reduced to 59.9% for NYHA Class 1 or 2 CHF and 51.3% for NYHA Class 3 or 4 CHF, and was 64.8% larger for severe hepatic cirrhosis (Child-Pugh score >= 10) relative to healthy subjects. A slight additional decrease in CL/F of 18.3% was also detected for patients with moderate hyponatremia (serum sodium of 115-130 mEq/l) after adjusting for CHF or cirrhosis (p < 0.001). This population PK model enabled assessment of tolvaptan PK with varying degrees of CHF and hepatic cirrhosis with fluid overload and may be used to explore PK-PD relationships with respect to fluid and electrolyte balance. PMID- 23794415 TI - Metabolite profiling and quantification of phytochemicals in potato extracts using ultra-high-performance liquid chromatography-mass spectrometry. AB - BACKGROUND: Potatoes contain a diverse range of phytochemicals which have been suggested to have health benefits. Metabolite profiling and quantification were conducted on plant extracts made from a white potato cultivar and 'Urenika', a purple potato cultivar traditionally consumed by New Zealand Maori. There is limited published information regarding the metabolite profile of Solanum tuberosum cultivar 'Urenika'. RESULTS: Using ultra-high- performance liquid chromatography-mass spectrometry (UHPLC-MS), a total of 31 compounds were identified and quantified in the potato extracts. The majority of the compounds were identified for the first time in 'Urenika'. These compounds include several types of anthocyanins, hydroxycinnamic acid (HCA) derivatives, and hydroxycinnamic amides (HCAA). Six classes of compounds, namely organic acids, amino acids, HCA, HCAA, flavonols and glycoalkaloids, were present in both extracts but quantities varied between the two extracts. CONCLUSIONS: The unknown plant metabolites in both potato extracts were assigned with molecular formulae and identified with high confidence. Quantification of the metabolites was achieved using a number of appropriate standards. High-resolution mass spectrometry data critical for accurate identification of unknown phytochemicals were achieved and could be added to potato or plant metabolomic database. PMID- 23794416 TI - Carbon nanofibers grafted on activated carbon as an electrode in high-power supercapacitors. AB - A hybrid electrode material for high-power supercapacitors was fabricated by grafting carbon nanofibers (CNFs) onto the surface of powdered activated carbon (AC) through catalytic chemical vapor deposition (CCVD). A uniform thin layer of disentangled CNFs with a herringbone structure was deposited on the carbon surface through the decomposition of propane at 450 degrees C over an AC supported nickel catalyst. CNF coating was controlled by the reaction time and the nickel content. The superior CNF/AC composite displays excellent electrochemical performance in a 0.5 mol L(-1) solution of K2 SO4 due to its unique structure. At a high scan rate (100 mV s(-1) ) and current loading (20 A g(-1) ), the capacitance values were three- and fourfold higher than those for classical AC/carbon black composites. Owing to this feature, a high energy of 10 Wh kg(-1) was obtained over a wide power range in neutral medium at a voltage of 0.8 V. The significant enhancement of charge propagation is attributed to the presence of herringbone CNFs, which facilitate the diffusion of ions in the electrode and play the role of electronic bridges between AC particles. An in situ coating of AC with short CNFs (below 200 nm) is a very attractive method for producing the next generation of carbon composite materials with a high power performance in supercapacitors working in neutral medium. PMID- 23794418 TI - Review and comparison of ROC curve estimators for a time-dependent outcome with marker-dependent censoring. AB - To quantify the ability of a marker to predict the onset of a clinical outcome in the future, time-dependent estimators of sensitivity, specificity, and ROC curve have been proposed accounting for censoring of the outcome. In this paper, we review these estimators, recall their assumptions about the censoring mechanism and highlight their relationships and properties. A simulation study shows that marker-dependent censoring can lead to important biases for the ROC estimators not adapted to this case. A slight modification of the inverse probability of censoring weighting estimators proposed by Uno et al. (2007) and Hung and Chiang (2010a) performs as well as the nearest neighbor estimator of Heagerty et al. (2000) in the simulation study and has interesting practical properties. Finally, the estimators were used to evaluate abilities of a marker combining age and a cognitive test to predict dementia in the elderly. Data were obtained from the French PAQUID cohort. The censoring appears clearly marker-dependent leading to appreciable differences between ROC curves estimated with the different methods. PMID- 23794417 TI - Selective modulation through the glucocorticoid receptor ameliorates muscle pathology in mdx mice. AB - The over-expression of NF-kappaB signalling in both muscle and immune cells contribute to the pathology in dystrophic muscle. The anti-inflammatory properties of glucocorticoids, mediated predominantly through monomeric glucocorticoid receptor inhibition of transcription factors such as NF-kappaB (transrepression), are postulated to be an important mechanism for their beneficial effects in Duchenne muscular dystrophy. Chronic glucocorticoid therapy is associated with adverse effects on metabolism, growth, bone mineral density and the maintenance of muscle mass. These detrimental effects result from direct glucocorticoid receptor homodimer interactions with glucocorticoid response elements of the relevant genes. Compound A, a non-steroidal selective glucocorticoid receptor modulator, is capable of transrepression without transactivation. We confirm the in vitro NF-kappaB inhibitory activity of compound A in H-2K(b) -tsA58 mdx myoblasts and myotubes, and demonstrate improvements in disease phenotype of dystrophin deficient mdx mice. Compound A treatment in mdx mice from 18 days of post-natal age to 8 weeks of age increased the absolute and normalized forelimb and hindlimb grip strength, attenuated cathepsin-B enzyme activity (a surrogate marker for inflammation) in forelimb and hindlimb muscles, decreased serum creatine kinase levels and reduced IL-6, CCL2, IFNgamma, TNF and IL-12p70 cytokine levels in gastrocnemius (GA) muscles. Compared with compound A, treatment with prednisolone, a classical glucocorticoid, in both wild-type and mdx mice was associated with reduced body weight, reduced GA, tibialis anterior and extensor digitorum longus muscle mass and shorter tibial lengths. Prednisolone increased osteopontin (Spp1) gene expression and osteopontin protein levels in the GA muscles of mdx mice and had less favourable effects on the expression of Foxo1, Foxo3, Fbxo32, Trim63, Mstn and Igf1 in GA muscles, as well as hepatic Igf1 in wild-type mice. In conclusion, selective glucocorticoid receptor modulation by compound A represents a potential therapeutic strategy to improve dystrophic pathology. PMID- 23794419 TI - Effects of oriented surface dipole on photoconversion efficiency in an alkane/lipid-hybrid-bilayer-based photovoltaic model system. AB - When a phospholipid monolayer containing a zinc-coordinated porphyrin species formed atop a self-assembled monolayer of heptadecafluoro-1-decanethiol (CF3(CF2)7(CH2)2SH) is subjected to photoelectrochemical current generation, a significant modulation effect is observed. Compared with devices that contain similar photoactive lipid monolayers but formed on 1-dodecanethiol SAMs, these fluorinated hybrid bilayers produce a >60% increase in cathodic currents and a similar decrease in anodic currents. Photovoltages recorded from these hybrid bilayers are found to vary in the same fashion. The modulation of photovoltaic responses in these hybrid-bilayer-based devices is explained by the opposite surface dipoles associated with the thiols employed in this study, which in one case (fluorothiol) increase and in another (alkanethiol) decrease the work function of the underlying gold substrates. A similar trend of photovoltage/photocurrent modulation is also observed if fullerene is used as the photoagent in these devices. Our results reveal the intricacy of orientated surface dipole in influencing the photovoltaic processes, and its subtle interplay with other factors related to the photoagents, such as their location and orientation within the organic matrix. PMID- 23794420 TI - What is evolutionary novelty? Process versus character based definitions. AB - With the rise of EvoDevo, the topic of evolutionary novelty has received renewed attention. Indeed, it has been argued that one of the major contributions of EvoDevo to evolutionary theory is the explanation of phenotypic novelty. Despite such assertions, dispute continues over what exactly a novelty is and whether the term applies to a unique type of evolutionary phenomenon or whether it merely has informal meaning. In a recent special issue of J. Exp. Zool. (Mol. Dev. Evol.) dedicated to novelty, a new definition was introduced, linking novelty exclusively with adaptation and developmental constraint. In our commentary, we discuss how defining novelty in this process oriented manner leads to heightened difficulties with the application of the term and the identification of novelties. At the same time it conceals important implications for evolutionary studies. In contrast, we argue for a character based definition that is independent from adaptive necessities and promotes the integration of evolutionary factors not included in the standard theory. The implications of approaching novelty in this manner take the issue beyond definitional debates. PMID- 23794421 TI - Importance of size and distribution of Ni nanoparticles for the hydrodeoxygenation of microalgae oil. AB - Improved synthetic approaches for preparing small-sized Ni nanoparticles (d=3 nm) supported on HBEA zeolite have been explored and compared with the traditional impregnation method. The formation of surface nickel silicate/aluminate involved in the two precipitation processes are inferred to lead to the stronger interaction between the metal and the support. The lower Bronsted acid concentrations of these two Ni/HBEA catalysts compared with the parent zeolite caused by the partial exchange of Bronsted acid sites by Ni(2+) cations do not influence the hydrodeoxygenation rates, but alter the product selectivity. Higher initial rates and higher stability have been achieved with these optimized catalysts for the hydrodeoxygenation of stearic acid and microalgae oil. Small metal particles facilitate high initial catalytic activity in the fresh sample and size uniformity ensures high catalyst stability. PMID- 23794422 TI - [Highlights from yesterday's Klinische Monatsblatter fur Augenheilkunde]. PMID- 23794423 TI - [Highlights on today's new possibilities of digital photo documentation in clinical practice for ophthalmologists]. PMID- 23794424 TI - [Paediatric cornea: diagnostics and therapy]. PMID- 23794425 TI - [CD34 and alpha-smooth muscle actin expression of keratocytes following photodynamic inactivation (PDI)]. AB - PURPOSE: Photodynamic inactivation (PDI) may be a potential treatment alternative in therapy-resistant infectious keratitis. PDI may eliminate the microorganisms from the infected cornea by damage caused through free oxygen radicals, or even by supporting different stages of activation of keratocytes and inflammatory cell response. The purpose of this study was to determine the impact of PDI on activation of human keratocytes in culture. METHODS: Primary human keratocytes were isolated by digestion in collagenase A (1 mg/mL) from human corneal buttons, and cultured in DMEM/Ham's culture medium supplemented with 10% foetal calf serum. Keratocytes underwent illumination (670 nm) for 13 minutes following exposure to 0, 50, 150 and 250 nMol/ml concentrations of the photosensitizer chlorin e6 (Ce6) in the culture medium. Twenty-four hours after treatment CD34 and alpha-smooth-muscle actin expression of the cells was analysed using flow cytometry (FACS). RESULTS: Using Ce6 or illumination only, alpha-smooth-muscle actin expression of the cells did not change significantly. Twenty-four hours after PDI the percentage of CD34-positive keratocytes did not change significantly using 50-250 nM Ce6, however, the percentage of alpha-smooth-muscle actin-positive keratocytes decreased significantly at 250 nM Ce6 (p = 0.01). CONCLUSIONS: As a short-term effect, PDI seems to inhibit myofibroblastic transformation of keratocytes, but does not have an impact on activation of CD34 positive keratocytes.With this impact PDI possibly may reduce the antimicrobial defence of keratocytes. PMID- 23794426 TI - [Therapy for systemic metabolic disorders based on the detection of basic corneal landmarks in childhood]. AB - Many systemic lysosomal storage disorders show basic corneal opacities already in childhood. The lysosome is a cell organelle, produced by Golgi's apparatus, that is surrounded by a membrane and contains hydrolytic enzymes that break down food molecules, especially proteins and other complex molecules. The ophthalmologist's precise diagnosis of corneal clouding at the slit-lamp may reveal the correct interpretation of the specific lysosomal storage disorder. It is very important to diagnose such diseases as soon as possible because today the development of systemic enzymatic therapies has broadened the therapeutic armamentarium for the current standard of care. The following corneal landmarks of systemic storage diseases and of the modern systemic therapy are presented: cornea verticillata in Fabry's disease, periodic infusion of alpha-galactosidase a; Kayser-Fleischer's ring in Wilson's disease, zinc, trienetin, low copper diet; multiple, punctiform crystals in cystinosis, cysteamine, Raptor RP 103(DR cysteamine) that reduces the cytotoxity in form of continous dissolving of cystine from lysosome, renal transplantation, haematopoietic stem cell transplantation; peripheral ring, but not true lipid arc, and moderate stromal haze in LCAT-deficiency, injection of recombinant enzyme or of encapsulated LCAT-secreting cells; diffuse stromal haze in mucopolysaccharidoses (MPS). Enzyme replacement therapy is currently indicated for MPS I, MPS II, and MPS VI, haematopoietic stem cell transplantation; painful, bilateral pseudo-dendritic opacities in tyrosinemia type II (eponym: Richner Hanhart syndrome), low phenylalanine and tyrosine diet result in complete disappearance of corneal alterations with a consecutive painfree period. Strict diet during the whole life is necessary to prevent corneal recurrences and the occurrence of palmo-plantar keratoses. Such therapies can enable the patient to lead an otherwise normal life for decades. PMID- 23794427 TI - [Corneal dystrophy (CD)-induced pain and visual impairment in childhood]. AB - Many forms of the 25 corneal dystrophies (CD) manifest already in childhood with bilateral corneal opacities without any visual impairment in most cases. Pain attacks due to recurrent erosion with red eye and epiphora can occur in combination with the first dystrophy-specific corneal opacities, e.g., nest-like lattice lines + corneal erosion in lattice CD. Often we can observe a joint occurrence. The parents accompany their child to consult the ophthalmologist concerning the recurrent and joint pain attacks. The ophthalmologist can also diagnose in such a situation subtle corneal opacities on the painless, contralateral eye, e.g., those of lattice, granular, macular or Reis-Bucklers CD. The correct interpretation of this combination does not lead the ophthalmologist to an inflammatory-, but to a dystrophy-induced interpretation of this entity. In a further group of CD, e.g., in Franceschetti CD, the typical history of this entity is a dominant disorder with recurrent epithelial erosions starting in the first decade, declining in frequency and severity at a later age, and associated with a central, disk-like haze of the subepithelial cornea from middle age. The recurrent erosions in childhood lasted 3-5 days and were followed by complete recovery. Congenital corneal clouding in the form of a milky ground-glass appearance can be observed in the rare endothelial CD, such as in congenital hereditary endothelial dystrophy 1 and 2 (CHED 1 and 2), X-linked endothelial CD (XECD), and in posterior polymorphous CD (PPCD). The differential diagnosis for congenital glaucoma is of essential importance. The parents of babies with congenital corneal opacification should be examined at the slit-lamp to in- or exclude the appearance of mooncrater-like endothelial changes. PMID- 23794428 TI - [Keratoplasty in children--still a dilemma]. AB - BACKGROUND: Penetrating keratoplasty (PKP) in children is associated with specific age-related problems. In contrast to adults, children can be examined less easily and they are not readily complaining about symptoms. Thus, the rate of intra- and postoperative complications is higher than in adults. In addition, amblyopia is a major issue before the age of seven years potentially resulting in irreversible reduction of visual acuity. PATIENTS AND METHODS: Potential indications for surgery are classified as follows: (i) congenital cloudiness (e.g., congenital hereditary endothelial dystrophy--CHED), (ii) acquired traumatic scars, (iii) acquired non-traumatic scars (e.g., infections, keratoconus) and (iv) irreversible graft failure. Our experience concerning 126 paediatric PKPs between 1980 and 2002 in children under age 16 is reported. Five case reports of PKPs performed in Homburg/Saar from 2006 are added. RESULTS: To minimise the risk of immunological graft rejection and chronic endothelial cell loss, we prefer PTK, lamellar keratoplasty or ipsilateral autologous rotational keratoplasty whenever possible. In cases of sclerocornea we feel that PKP should be avoided in view of the histopathology, in cases of Peters' anomaly an optical sector iridectomy may be considered as a valid alternative to high-risk PKP. In cases of buphthalmos the IOP must be controlled before PKP (e.g., previous trabeculotomy). In cases of central penetrating cornea and lens injuries we advocate simultaneous PKP and IOL implantation in the quiet interval after primary wound closure to achieve quick optical rehabilitation. We prefer smaller grafts and interrupted sutures in children. In addition, early suture removal is attempted, especially in cases of progressive corneal neovascularisation threatening the graft. If in doubt, examinations are performed in general anaesthesia readily. CONCLUSIONS: Corneal grafting in children should be performed as soon as necessary (less amblyopia!), but as late as possible (better cooperation!). In children, critical indication, repeated in-depth counselling of the parents, good cooperation with the anaesthetist and excellent cooperation with the paediatric ophthalmologist are indispensable in order to achieve good morphological and functional results after PKP. PMID- 23794429 TI - [Therapeutic excimer laser treatment of the cornea]. AB - Concomitant with new innovations in the field of refractive surgery, therapeutic excimer laser applications like phototherapeutic keratectomy (PTK) and topography guided customised ablation treatment are gaining high importance and undergoing rapid evolution. Nowadays, PTK is an effective treatment modality for superficial corneal pathologies. Primary indications are decreased epithelial adherence, superficial opacifications and an irregular corneal surface. For the right indication and successful treatment of corneal pathologies with PTK, a knowledge of the size, depth and nature of the pathology, as well as the refractive status of both eyes is important. Next to slit-lamp examination, objective measuring systems like the topography, confocal microscopy and the anterior segment OCT facilitate presurgical planning. Regarding the treatment procedure the surgeon can choose between a variety of methods. PTK can be combined with manual epithelial debridement or done by only using the excimer laser. In the case of an irregular corneal surface, depending on the pathology, masking fluids or topography-guided custom ablation protocols can increase the visual outcome. To avoid recurrence of the underlying pathology (e.g., corneal dystrophy, haze), the topical application of 0.02% mitomycin C for 20-60 seconds has proved to be a safe and effective procedure. If the surgeon considers all the patient-related factors carefully and manages to combine the available treatment options correctly, PTK embodies an effective and minimally invasive alternative to lamellar or penetrating keratoplasty. PMID- 23794430 TI - [Statement of the German Ophthalmological Society, the Retina Society and the Professional Association of German Ophthalmologists: treatment of diabetic maculopathy (April 2013)]. PMID- 23794431 TI - [Current Statement of the German Ophthalmological Society, the Retina Society and the Professional Association of German Ophthalmologists for therapeutic intravitreal application of Ocriplasmin (JETREA (r)) in ophthalmology (May 2013)]. PMID- 23794432 TI - Salicylic acid and analogues as diaCEST MRI contrast agents with highly shifted exchangeable proton frequencies. PMID- 23794434 TI - Low cerebrospinal fluid concentration of mitochondrial DNA in preclinical Alzheimer disease. AB - OBJECTIVE: To identify a novel biochemical marker that precedes clinical symptoms in Alzheimer disease (AD). METHODS: Using quantitative polymerase chain reaction techniques, we measured circulating cell-free mitochondrial DNA (mtDNA) in cerebrospinal fluid (CSF) from study participants, selected from a cohort of 282 subjects, who were classified according to their concentrations of amyloid beta1 42, total tau, and phosphorylated tau and by the presence or absence of dementia, into asymptomatic subjects at risk of AD, symptomatic patients diagnosed with sporadic AD, presymptomatic subjects carrying pathogenic PSEN1 mutations, and patients diagnosed with frontotemporal lobar degeneration (FTLD). We performed equivalent studies in a separate validation cohort of sporadic AD and FTLD patients. In addition, we measured mtDNA copy number in cultured cortical neurons from mutant amyloid precursor protein/presenilin1 (APP/PS1) transgenic mice. RESULTS: Asymptomatic patients at risk of AD and symptomatic AD patients, but not FTLD patients, exhibit a significant decrease in circulating cell-free mtDNA in the CSF. These observations were confirmed in the validation cohort. In addition, presymptomatic subjects carrying pathogenic PSEN1 gene mutations show low mtDNA content in CSF before the appearance of AD-related biomarkers in CSF. Moreover, mtDNA content in CSF discriminates with high sensitivity and specificity AD patients from either controls or patients with FTLD. Furthermore, cultured cortical neurons from APP/PS1 transgenic mice have fewer mtDNA copies before the appearance of altered synaptic markers. INTERPRETATION: Low content of mtDNA in CSF may be a novel biomarker for the early detection of preclinical AD. These findings support the hypothesis that mtDNA depletion is a characteristic pathophysiological factor of neurodegeneration in AD. PMID- 23794433 TI - Validating retinal fundus image analysis algorithms: issues and a proposal. AB - This paper concerns the validation of automatic retinal image analysis (ARIA) algorithms. For reasons of space and consistency, we concentrate on the validation of algorithms processing color fundus camera images, currently the largest section of the ARIA literature. We sketch the context (imaging instruments and target tasks) of ARIA validation, summarizing the main image analysis and validation techniques. We then present a list of recommendations focusing on the creation of large repositories of test data created by international consortia, easily accessible via moderated Web sites, including multicenter annotations by multiple experts, specific to clinical tasks, and capable of running submitted software automatically on the data stored, with clear and widely agreed-on performance criteria, to provide a fair comparison. PMID- 23794435 TI - Quality parameters, bioactive compounds and their correlation with antioxidant capacity of commercial fruit-based baby foods. AB - Comprehensive research is required to achieve the optimization of the antioxidant protection through baby foods, in particular, the commercially available fruit based baby foods. This study investigated the physicochemical properties, ascorbic acid (AA), total carotenoids (TC), total phenolic content (TPC), trolox equivalent antioxidant capacity (TEAC) and oxygen radical absorbance capacity (ORAC) of 23 different commercially available fruit-based baby foods. The main contribution to the total antioxidant capacity (trolox equivalent antioxidant capacity and oxygen radical absorbance capacity) was provided by ascorbic acid, followed by phenolic compounds, in accordance with a mathematical equation obtained from the data: TEAC = 245.906 + 7.727 * (AA) + 1.988 * (TPC) - 0.008 * (TC) and ORAC = 318.662 + 2.775 * (AA) - 0.531 * (TPC) - 0.073 * (TC). Moreover, a positive correlation (r = 0.346, p < 0.05) was found for oxygen radical absorbance capacity and trolox equivalent antioxidant capacity methods. Baby foods with different kind of fruits used as ingredients showed higher antioxidant capacity. Among the commercial baby foods analysed in this work, that treated by gentle steam cooking process had high levels of bioactive compounds and antioxidant capacity. PMID- 23794436 TI - Nanowires and nanostructures that grow like polymer molecules. AB - Unique properties (e.g., rubber elasticity, viscoelasticity, folding, reptation) determine the utility of polymer molecules and derive from their morphology (i.e., one-dimensional connectivity and large aspect ratios) and flexibility. Crystals do not display similar properties because they have smaller aspect ratios, they are rigid, and they are often too large and heavy to be colloidally stable. We argue, with the support of recent experimental studies, that these limitations are not fundamental and that they might be overcome by growth processes that mimic polymerization. Furthermore, we (i) discuss the similarities between crystallization and polymerization, (ii) critically review the existing experimental evidence of polymer-like growth kinetic and behavior in crystals and nanostructures, and (iii) propose heuristic guidelines for the synthesis of "polymer-like" crystals and assemblies. Understanding these anisotropic materials at the boundary between molecules and solids will determine whether we can confer the unique properties of polymer molecules to crystals, expanding them with topology, dynamics, and information and not just tuning them with size. PMID- 23794437 TI - Pathways mediating resolution of inflammation: when enough is too much. AB - Patients with critical illness, and in particular sepsis, are now recognized to undergo unifying, pathogenic disturbances of immune function. Whilst scientific and therapeutic focus has traditionally been on understanding and modulating the initial pro-inflammatory limb, recent years have witnessed a refocusing on the development and importance of immunosuppressive 'anti-inflammatory' pathways. Several mechanisms are known to drive this phenomenon; however, no overriding conceptual framework justifies them. In this article we review the contribution of pro-resolution pathways to this phenotype, describing the observed immune alterations in terms of either a failure of resolution of inflammation or the persistence of pro-resolution processes causing inappropriate 'injurious resolution'-a novel hypothesis. The dysregulation of key processes in critical illness, including apoptosis of infiltrating neutrophils and their efferocytosis by macrophages, are discussed, along with the emerging role of specialized cell subtypes Gr1(+) CD11b(+) myeloid-derived suppressor cells and CD4(+) CD25(+) FoxP3(+) T-regulatory cells. PMID- 23794438 TI - Biochemical characterization and crystal structure of a GH10 xylanase from termite gut bacteria reveal a novel structural feature and significance of its bacterial Ig-like domain. AB - Bacterial Ig-like (Big) domains are commonly distributed in glycoside hydrolases (GH), but their structure and function remains undefined. Xylanase is a GH, and catalyzes the hydrolysis of the internal beta-xylosidic linkages of xylan. In this study, we report the molecular cloning, biochemical and biophysical characterization, and crystal structure of a termite gut bacterial xylanase, Xyl ORF19, which was derived from gut bacteria of a wood-feeding termite (Globitermes brachycerastes). The protein architecture of Xyl-ORF19 reveals that it has two domains, a C-terminal GH10 catalytic domain and an N-terminal Big_2 non-catalytic domain. The catalytic domain folds in an (alpha/beta)8 barrel as most GH10 xylanases do, but it has two extra beta-strands. The non-catalytic domain is structurally similar to an immunoglobulin-like domain of intimins. The recombinant enzyme without the non-catalytic domain has fairly low catalytic activity, and is different from the full-length enzyme in kinetic parameters, pH and temperature profiles, which suggests the non-catalytic domain could affect the enzyme biochemical and biophysical properties as well as the role for enzyme localization. This study provides a molecular basis for future efforts in xylanase bioengineering. PMID- 23794439 TI - Differential expression of ISG20 in chronic hepatitis B patients and relation to interferon-alpha therapy response. AB - The 20 kDa exonuclease encoded by the interferon-stimulated gene, ISG20, can inhibit the replication of hepatitis B virus (HBV), and may represent a clinically useful prognostic marker for response to interferon-alpha (IFN-alpha) antiviral therapy. The present study was designed to investigate the differential expression patterns of ISG20 in liver biopsy samples from treatment-naive patients with chronic hepatitis B and non-HBV infected controls and to determine the relation between the differential expression and IFN-alpha treatment outcome (responders vs. non-responders). HBV infection status was determined by measuring levels of hepatitis B surface antigen (HBsAg) by chemoluminescence immunoassay and of HBV DNA by real-time quantitative (q)PCR. ISG20 protein and mRNA expressions were assessed by immunohistochemistry and qPCR, respectively. Chronic hepatitis B responders showed significantly higher levels of ISG20 protein and mRNA expressions than either the chronic hepatitis B non-responders or the controls. Moreover, increased expression of ISG20 in both the nucleus and cytoplasm was correlated with positive response to IFN-alpha treatment. Thus, active transcription and translation of ISG20 may represent a marker to identify chronic hepatitis B patients likely to respond to IFN-alpha therapy. Prognostic clinical strategies based upon this marker may include genomic screening methods and immunohistochemical staining of liver biopsies. PMID- 23794440 TI - Molecular characterization of alpha-keratins in comparison to associated beta proteins in soft-shelled and hard-shelled turtles produced during the process of epidermal differentiation. AB - The tough corneous layer in the carapace and plastron of hard-shelled turtles derives from the accumulation of keratin-associated beta-proteins (KAbetaPs, formerly called beta-keratins) while these proteins are believed to be absent in soft-shelled turtles. Our bioinformatics and molecular study has instead shown that the epidermis of the soft-shelled turtle Apalone spinifera expresses beta proteins like or even in higher amount than in the hard-shelled turtle Pseudemys nelsoni. The analysis of a carapace cDNAs library has allowed the identification and characterization of three alpha-keratins of type I and of ten beta-proteins (beta-keratins). The acidic alpha-keratins probably combine with the basic beta proteins but the high production of beta-proteins in A. spinifera is not prevalent over that of alpha-keratin so that their combination does not determine the formation of hard corneous material. Furthermore the presence of a proline and cisteine in the beta-sheet region of beta-proteins in A. spinifera may be unsuited to form hard masses of corneous material. The higher amount of beta proteins over alpha-keratins instead occurs in keratinocytes of the hard and inflexible epidermis of P. nelsoni determining the deposition of hard corneous material. The study suggests that the hardness of the corneous layer derives not exclusively from the interactions between alpha-keratins with KAbetaPs but also from the different dynamic of accumulation and loss of corneocytes in the corneous layer of the hard shelled turtles where a prevalent accumulation and piling of corneocytes takes place versus the soft shelled turtle where a rapid turnover of the stratum corneum occurs. PMID- 23794441 TI - Oxo-group-14-element bond formation in binuclear uranium(V) Pacman complexes. AB - Simple and versatile routes to the functionalization of uranyl-derived U(V)-oxo groups are presented. The oxo-lithiated, binuclear uranium(V)-oxo complexes [{(py)3LiOUO}2(L)] and [{(py)3LiOUO}(OUOSiMe3)(L)] were prepared by the direct combination of the uranyl(VI) silylamide "ate" complex [Li(py)2][(OUO)(N")3] (N" = N(SiMe3)2) with the polypyrrolic macrocycle H4L or the mononuclear uranyl (VI) Pacman complex [UO2(py)(H2L)], respectively. These oxo-metalated complexes display distinct U-O single and multiple bonding patterns and an axial/equatorial arrangement of oxo ligands. Their ready availability allows the direct functionalization of the uranyl oxo group leading to the binuclear uranium(V) oxo stannylated complexes [{(R3Sn)OUO}2(L)] (R = nBu, Ph), which represent rare examples of mixed uranium/tin complexes. Also, uranium-oxo-group exchange occurred in reactions with [TiCl(OiPr)3] to form U-O-C bonds [{(py)3LiOUO}(OUOiPr)(L)] and [(iPrOUO)2(L)]. Overall, these represent the first family of uranium(V) complexes that are oxo-functionalised by Group 14 elements. PMID- 23794442 TI - CO adsorption on N2-precovered NaY faujasite: a FTIR analysis of the resulting adsorbed species. AB - To productively complete the information regarding the reversible adsorption of a gas mixture on the micropores of cationic zeolites, the adsorption of the two gases N2 and CO on NaY faujasite is taken as a model case study. We analyze herein CO adsorption (77 K) on two distinct N2-precovered NaY sets (low and medium). We outline the continuous desorption of N2 adducts during CO admittance to full N2 desorption for the highest CO loadings. These features contrast with preceding results obtained for N2 loading on CO-precovered NaY. By comparing these results with the sole CO admission and combining both studies regarding the co-adsorption sets, we demonstrate the influence of the basic strength of the two gases regarding the nature of the surface-adsorbed species formed. We also propose and discuss a hypothesis regarding the formation of adsorbed mixed species having both N2 and CO as ligands. These new findings strengthen the statistical response of IR signatures as a helpful proposal for analyzing adsorbed species and their assignments. This survey completes the molecular understanding of gas-mixture adsorption that lacks experimental data to date. PMID- 23794443 TI - An approach to the phytochemical profiling of rocket [Eruca sativa (Mill.) Thell]. AB - BACKGROUND: Eruca sativa (rocket) contains a wide range of compounds with nutraceutical and organoleptical properties. This research aimed to characterise the nutraceutical interest of four rocket accessions by analysis of glucosinolates, isothiocyanates, phenolics, carotenoids and carbohydrates. Different methods based on chromatographic separation with ultraviolet absorbance or mass spectrometry detection were used. RESULTS: The total content of glucosinolates ranged from 14.02 to 28.24 umol g(-1) of dry weight. Glucoraphanin represented up to 52% of the total glucosinolates in leaves of one accession. Accessions showed differences in the hydrolysis of glucoraphanin to the isothiocyanate sulforaphane. No correlation between these compounds was observed, which insisted differences in the myrosinase activity within accessions. Rocket leaves had variable phenolic profiles represented by quercetin-3-glucoside, rutin, myricetin, quercetin and ferulic and p-coumaric acids. A high variability was observed for the total carotenoids ranged from 16.2 to 275 ug g(-1) with lutein as the main carotenoid. Glucose was the predominant sugar, representing >70% of the total soluble carbohydrates. CONCLUSIONS: Some accessions could be candidates for future breeding programmes because of their pattern of beneficial compounds for human health. However, further research is essential to evaluate the biological activity of these accessions before designing functional food. PMID- 23794444 TI - Highly selective hydrogenolysis of glycerol to 1,3-propanediol over a boehmite supported platinum/tungsten catalyst. PMID- 23794445 TI - Self-reported quality of life and depressive symptoms in children, adolescents, and adults with Duchenne muscular dystrophy: a cross-sectional survey study. AB - AIM: We aimed to address the impact of Duchenne muscular dystrophy (DMD) on self reported health-related quality of life (HRQOL) and depressive symptoms in different age groups of patients to discern a possible need for improved psychosocial support or counseling. METHODS: In a German clinic for pediatric neurology, we performed a cross-sectional questionnaire survey in a total of 50 patients with DMD (i.e., n = 15 children aged 8 to 12 years; n = 11 adolescents aged 13 to 16 years; n = 24 young adults aged 17 to 23 years). We assessed self reported HRQOL and symptoms of depression using validated, age-appropriate instruments. RESULTS: In children with DMD, virtually all aspects of HRQOL were significantly impaired when compared with published normative data for boys with other chronic illnesses. On the contrary, adolescents and adults with DMD did not differ from published normative data in psychosocial areas of HRQOL, despite significant reductions in physical aspects of HRQOL. Clinically relevant depressive symptoms were not observed in either age group. INTERPRETATION: DMD may not always be associated with impaired psychosocial HRQOL and clinical depression, although progressive physical impairment leads to reduced physical aspects of HRQOL. Only children with DMD demonstrated marked impairments in psychosocial aspects of HRQOL calling for psychosocial interventions tailored to this age group. PMID- 23794446 TI - Mycoplasma pneumoniae intrathecal antibody responses in Bickerstaff brain stem encephalitis. AB - The pathogenesis of Mycoplasma pneumoniae encephalitis is not established. We report, for the first time, the case of a patient with severe Bickerstaff brain stem encephalitis in whom we detected intrathecal production of M. pneumoniae specific antibodies, contrasting the findings in another patient with less severe encephalitis in whom we detected intrathecal M. pneumoniae DNA but no specific antibodies. Our observations suggest that intrathecal M. pneumoniae-specific antibody responses may contribute to a more severe course of M. pneumoniae encephalitis. PMID- 23794447 TI - Reversible splenic lesion in a patient with Febrile Infection-Related Epilepsy Syndrome (FIRES). AB - Febrile infection-related epilepsy syndrome (FIRES) is a severe epileptic syndrome that manifests with refractory seizures or status epilepticus in previously healthy children after banal febrile illness. The neuroimaging findings in the acute phase of FIRES are nonspecific or normal. We report the case of a 7-year-old boy with FIRES who presented with a reversible lesion in the splenium of the corpus callosum on brain magnetic resonance imaging (MRI). The patient developed clusters of clonic seizures with a deviation of the eyes after a 3-day history of fever. A reversible splenial lesion was observed on brain MRI and, therefore, the initial diagnosis was mild encephalitis/encephalopathy with a reversible splenial lesion (MERS). However, the intractable complex partial seizures necessitated a long-term midazolam infusion, indicating that FIRES was a more likely diagnosis than MERS. All other findings of this patient met the diagnostic criteria for FIRES. With this diagnosis, a high-dose phenobarbital was administrated, and the seizures were successfully controlled. This case indicated that FIRES should be considered even in patients with a reversible splenial lesion associated with encephalitis/encephalopathy. PMID- 23794449 TI - Antifungal and anticancer effects of a polysaccharide-protein complex from the gut bacterium Raoultella ornithinolytica isolated from the earthworm Dendrobaena veneta. AB - The polysaccharide-protein complex (PPC) isolated from metabolites of gut bacteria Raoultella ornithinolytica from Dendrobaena veneta earthworms exhibits activity against Candida albicans, in breast ductal carcinoma (line T47D) and in the endometrioid ovarian cancer line (TOV-112D) in vitro. The action against C. albicans was analyzed using light, SEM, TEM, and AFM microscopes. The changes observed indicated two directions of the action of the complex, that is, disturbance of metabolic activity and cell wall damage. The PPC is an adhesion promoting complex inducing death of C. albicans cells by necrosis. Owing to its significant effect on C. albicans, the complex is a promising source of antifungal compounds. The PPC showed a minimal cytotoxic effect against human skin fibroblasts; however, the cytotoxicity against the T47D line was determined at 20% and 15% against the TOV-112D line. The action of the PPC against the T47D line exerted a cytopathic effect, whereas in the TOV-112D line, it caused a reduction in the cell number. The PPC induced death of tumor cells by apoptosis and necrosis. In view of the negligible cytotoxicity on fibroblasts, the PPC will be subjected to chemical modifications to increase its antitumor activity for prospective medical applications. PMID- 23794448 TI - Amylin deposition in the brain: A second amyloid in Alzheimer disease? AB - OBJECTIVE: Hyperamylinemia, a common pancreatic disorder in obese and insulin resistant patients, is known to cause amylin oligomerization and cytotoxicity in pancreatic islets, leading to beta-cell mass depletion and development of type 2 diabetes. Recent data has revealed that hyperamylinemia also affects the vascular system, heart, and kidneys. We therefore hypothesized that oligomerized amylin might accumulate in the cerebrovascular system and brain parenchyma of diabetic patients. METHODS: Amylin accumulation in the brain of diabetic patients with vascular dementia or Alzheimer disease (AD), nondiabetic patients with AD, and age-matched healthy controls was assessed by quantitative real time polymerase chain reaction, immunohistochemistry, Western blot, and enzyme-linked immunosorbent assay. RESULTS: Amylin oligomers and plaques were identified in the temporal lobe gray matter from diabetic patients, but not controls. In addition, extensive amylin deposition was found in blood vessels and perivascular spaces. Intriguingly, amylin deposition was also detected in blood vessels and brain parenchyma of patients with late onset AD without clinically apparent diabetes. Mixed amylin and amyloid beta (Abeta) deposits were occasionally observed. However, amylin accumulation leads to amyloid formation independent of Abeta deposition. Tissues infiltrated by amylin showed increased interstitial space, vacuolation, spongiform change, and capillaries bent at amylin accumulation sites. Unlike the pancreas, there was no evidence of amylin synthesis in the brain. INTERPRETATION: Metabolic disorders and aging promote accumulation of amylin amyloid in the cerebrovascular system and gray matter, altering microvasculature and tissue structure. Amylin amyloid formation in the wall of cerebral blood vessels may also induce failure of elimination of Abeta from the brain, thus contributing to the etiology of AD. PMID- 23794450 TI - Ruthenium-containing phosphinesulfonate chelate for the hydrogenation of aryl ketones. AB - Various ruthenium(II) complexes that contain phosphinesulfonate chelate have been synthesized. Arene-free complexes were found to be efficient in the base-free hydrogenation of various aryl ketones, whereas the arene-containing precatalysts required the presence of an amine as an additive. The seminal asymmetric hydrogenation reaction by using the new Sulfo-Binepine ligand was also investigated for the possible intervention of a dihydride species. PMID- 23794451 TI - A chemo-enzymatic approach for site-specific modification of the RNA cap. AB - Capped and gowned: A two-step approach can be used to site-specifically modify the 5'-cap of eukaryotic mRNAs. First, a trimethylguanosinesynthase variant recognizes the m(7)G cap structure and introduces bioorthogonal groups using S adenosyl-L-methionine-based cosubstrates. Then, the enzymatically introduced reporter groups are further modified by thiol-ene or CuAAC click chemistry (see scheme). PMID- 23794452 TI - Metabolic signatures of GS-CHO cell clones associated with butyrate treatment and culture phase transition. AB - Chinese hamster ovary (CHO) cells are preferred hosts for the production of recombinant biopharmaceuticals. Efforts to optimize these bioprocesses have largely relied on empirical experience and our knowledge of cellular behavior in culture is incomplete. More recently, comprehensive investigations of metabolic network operation have started to be used to uncover traits associated with optimal growth and recombinant protein production. In this work, we used (1) H nuclear magnetic resonance ((1) H-NMR) to analyze the supernatants of glutamine synthetase (GS)-CHO cell clones expressing variable amounts of an IgG4 under control and butyrate-treated conditions. Exometabolomic data revealed accumulation of several metabolic by-products, indicating inefficiencies at different metabolic nodes. These data were contextualized in a detailed network and the cellular fluxomes estimated through metabolic flux analysis. This approach allowed comparing metabolic activity across different clones, growth phases and culture conditions, in particular the efficiency pertaining to carbon lost to glycerol and lactate accumulation and the characteristic nitrogen metabolism involving high asparagine and serine uptake rates. Importantly, this study shows that early butyrate treatment has a marked effect on sustaining high nutrient consumption along culture time, being more pronounced during the stationary phase when extra energy generation and biosynthetic activity is fueled to increase IgG formation. Collectively, the information generated contributes to deepening our understanding of CHO cells metabolism in culture, facilitating future design of improved bioprocesses. PMID- 23794453 TI - Conformational propensities of intrinsically disordered proteins from NMR chemical shifts. AB - The realization that a protein can be fully functional even in the absence of a stable three-dimensional structure has motivated a large number of studies describing the conformational behaviour of these proteins at atomic resolution. Here, we review recent advances in the determination of local structural propensities of intrinsically disordered proteins (IDPs) from experimental NMR chemical shifts. A mapping of the local structure in IDPs is of paramount importance in order to understand the molecular details of complex formation, in particular, for IDPs that fold upon binding or undergo structural transitions to pathological forms of the same protein. We discuss experimental strategies for the spectral assignment of IDPs, chemical shift prediction algorithms and the generation of representative structural ensembles of IDPs on the basis of chemical shifts. Additionally, we highlight the inherent degeneracies associated with the determination of IDP sub-state populations from NMR chemical shifts alone. PMID- 23794454 TI - Anti-inflammatory and immunomodulatory activities of stevioside and steviol on colonic epithelial cells. AB - BACKGROUND: Stevioside is a natural non-caloric sweetener isolated from Stevia rebaudiana Bertoni leaves. We have proposed its effect on attenuation of tumour necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta) release in lipopolysaccharide (LPS)-stimulated monocytes. In this study, the anti inflammatory and immunomodulatory activities of stevioside and its metabolite, steviol, on human colon carcinoma cell line (Caco-2) were evaluated. RESULTS: Stevioside and steviol, in the doses used in this study, had no cytotoxicity on Caco-2 cells. Anti-inflammatory activities of these two compounds were observed by potentially suppressed LPS-mediated TNF-alpha, IL-1beta and IL-6 release. In addition, stevioside and steviol showed immunomodulatory effects on IkappaBalpha activation and nuclear factor kappa B (NF-kappaB) suppression in western blotting. CONCLUSION: Stevioside and steviol attenuate LPS-induced pro inflammatory cytokine productions by affecting cytokine gene expression via IkappaBalpha/NF-kappaB signalling pathway. PMID- 23794455 TI - Counting fluorescent dye molecules on DNA origami by means of photon statistics. AB - Obtaining quantitative information about molecular assemblies with high spatial and temporal resolution is a challenging task in fluorescence microscopy. Single molecule techniques build on the ability to count molecules one by one. Here, a method is presented that extends recent approaches to analyze the statistics of coincidently emitted photons to enable reliable counting of molecules in the range of 1-20. This method does not require photochemistry such as blinking or bleaching. DNA origami structures are labeled with up to 36 dye molecules as a new evaluation tool to characterize this counting by a photon statistics approach. Labeled DNA origami has a well-defined labeling stoichiometry and ensures equal brightness for all dyes incorporated. Bias and precision of the estimating algorithm are determined, along with the minimal acquisition time required for robust estimation. Complexes containing up to 18 molecules can be investigated non-invasively within 150 ms. The method might become a quantifying add-on for confocal microscopes and could be especially powerful in combination with STED/RESOLFT-type microscopy. PMID- 23794456 TI - Ammoniation-dehydration of fatty acids into nitriles: heterogeneous or homogeneous catalysis? AB - Fatty nitriles have lately become of interest in the framework of biofuels and for the valorization of the oil part of biomass to form fine chemicals or polymers. The production of long-chain fatty nitriles by the direct reaction of acids with NH3 has not been extensively studied, although several catalysts have been developed and published as patents. The characterization of this reaction with and without catalyst is, to the best of our knowledge, performed for the first time in this study. Several catalysts with various acid-base features were tested, and the best catalysts at 250 degrees C (Zn- and In-based catalysts) were further studied. Catalytically active forms and models are proposed for the Zn- and In-based catalysts, and the kinetic parameters for the amide to nitrile reaction are evaluated. PMID- 23794457 TI - A systematic approach toward stabilization of CagL, a protein antigen from Helicobacter pylori that is a candidate subunit vaccine. AB - An important consideration in the development of subunit vaccines is the loss of activity caused by physical instability of the protein. Such instability often results from suboptimal solution conditions related to pH and temperature. Excipients can help to stabilize vaccines, but it is important to screen and identify excipients that adequately contribute to stabilization of a given formulation. CagL is a protein present in strains of Helicobacter pylori (H. pylori) that possess type IV secretion systems. It contributes to bacterial adherence via alpha5beta1 integrin, thereby making it an attractive subunit vaccine candidate. We characterized the stability of CagL in different pH and temperature conditions using a variety of spectroscopic techniques. Stability was assessed in terms of transition temperature with the accumulated data, and then incorporated into an empirical phase diagram (EPD) that provided an overview of CagL physical stability. These analyses indicated maximum CagL stability at pH 4 6 up to 40 degrees C in the absence of excipient. Using this EPD analysis, aggregation assays were developed to screen a panel of excipients with some found to inhibit CagL aggregation. Candidate stabilizers were selected to confirm their enhanced stabilizing effect. These analyses will help in the formulation of a stable vaccine against H. pylori. PMID- 23794458 TI - The use of the probiotic Lactobacillus rhamnosus GG and viral findings in the nasopharynx of children attending day care. AB - Limited data are available on the effects of probiotics on the nasopharyngeal presence of respiratory viruses in children attending day care. In this substudy of a randomized, double-blinded, placebo-controlled 28-week intervention study, nasopharyngeal swab samples were collected, on visits to a physician due to symptoms of infection, from children receiving control milk (N = 97) and children receiving the same milk supplemented with probiotic Lactobacillus rhamnosus GG (N = 97). The presence of 14 respiratory viruses was assessed by PCR methods, and viral findings were compared with symptom prevalences in the intervention groups. Rhinovirus was identified in 28.6% of 315 swab samples, followed by respiratory syncytial virus (12.4%), parainfluenza virus 1 (12.1%), enterovirus (8.9%), influenza A(H1N1)pdm09 (7.9%), human bocavirus 1 (3.8%), parainfluenza virus 2 (3.2%), adenovirus (2.9%), and influenza A(H3N2) (0.6%). The children in the probiotic group had less days with respiratory symptoms per month than the children in the control group (6.48 [95% CI 6.28-6.68] vs. 7.19 [95% CI 6.98 7.41], P < 0.001). Probiotic intervention did not reduce significantly the occurrence of the examined respiratory viruses, or have an effect on the number of respiratory symptoms observed at the time of a viral finding. Rhinovirus, respiratory syncytial virus, and parainfluenza virus 1 were the most common respiratory viruses in symptomatic children. Children receiving Lactobacillus rhamnosus GG had fewer days with respiratory symptoms than children in the control group, although probiotic intervention was not effective in reducing the amount of viral findings or the respiratory symptoms associated with viral findings. PMID- 23794459 TI - A healable, semitransparent silver nanowire-polymer composite conductor. AB - A quick recovery: A semitransparent composite conductor comprising a layer of silver nanowire percolation network inlaid in the surface layer of a Diels-Alder based healable polymer film is fabricated. The composite is flexible and highly conductive, and is capable of both structural and electrical healing via heating. Cut samples that completely lose their conductivity can recover 97% of it within 5 minutes of heating at 110 degrees C. The cutting and healing can be repeated at the same location for multiple cycles. PMID- 23794460 TI - Pituitary dysfunction after blast traumatic brain injury: The UK BIOSAP study. AB - OBJECTIVE: Pituitary dysfunction is a recognized consequence of traumatic brain injury (TBI) that causes cognitive, psychological, and metabolic impairment. Hormone replacement offers a therapeutic opportunity. Blast TBI (bTBI) from improvised explosive devices is commonly seen in soldiers returning from recent conflicts. We investigated: (1) the prevalence and consequences of pituitary dysfunction following moderate to severe bTBI and (2) whether it is associated with particular patterns of brain injury. METHODS: Nineteen male soldiers with moderate to severe bTBI (median age = 28.3 years) and 39 male controls with moderate to severe nonblast TBI (nbTBI; median age = 32.3 years) underwent full dynamic endocrine assessment between 2 and 48 months after injury. In addition, soldiers had structural brain magnetic resonance imaging, including diffusion tensor imaging (DTI), and cognitive assessment. RESULTS: Six of 19 (32.0%) soldiers with bTBI, but only 1 of 39 (2.6%) nbTBI controls, had anterior pituitary dysfunction (p = 0.004). Two soldiers had hyperprolactinemia, 2 had growth hormone (GH) deficiency, 1 had adrenocorticotropic hormone (ACTH) deficiency, and 1 had combined GH/ACTH/gonadotrophin deficiency. DTI measures of white matter structure showed greater traumatic axonal injury in the cerebellum and corpus callosum in those soldiers with pituitary dysfunction than in those without. Soldiers with pituitary dysfunction after bTBI also had a higher prevalence of skull/facial fractures and worse cognitive function. Four soldiers (21.1%) commenced hormone replacement(s) for hypopituitarism. INTERPRETATION: We reveal a high prevalence of anterior pituitary dysfunction in soldiers suffering moderate to severe bTBI, which was more frequent than in a matched group of civilian moderate to severe nbTBI subjects. We recommend that all patients with moderate to severe bTBI should routinely have comprehensive assessment of endocrine function. PMID- 23794461 TI - Minimal killing unit of the mitochondrial targeting domain of Noxa. AB - Noxa is a key player in p53-induced cell death via mitochondrial dysfunction, and the mitochondrial-targeting domain (MTD) of Noxa is responsible for the translocation of Noxa to mitochondria and for the induction of necrotic cell death. The purpose of this study was to define the minimal killing unit of MTD in vitro and in vivo. It was found that the peptides R8:MTD(10), R8:MTD(9), and R8:MTD(8) can kill various human tumor cells (HCT116, HeLa, MCF-7, BJAB), but that R8:MTD(7) abolishes the killing activity of MTD mainly because of the loss of mitochondrial targeting activity. We find it interesting that R8:MTD(8) was found to kill tumor cells but showed a limited killing activity on normal peritoneal macrophages. Furthermore, R8:MTD(10), R8:MTD(9), and R8:MTD(8) limitedly suppressed tumor growth when injected i.v. into BalB/C mice bearing CT26 cell-derived tumors. These results indicate that MTD(8) is the minimal killing unit of MTD. PMID- 23794462 TI - Cell fate conversion by conditionally switching the signal-transducing domain of signalobodies. AB - Conditionally and strictly controlling cell fates is important for biomedical applications including cell therapies. Although previous studies have been based on regulating the expression or activation of signaling molecules, the techniques therein require improvement in terms of reducing leakiness and complexity. In this study, we propose a novel cell fate converting system using our previously developed antibody/receptor chimeras named "signalobodies" in combination with a Cre/loxP recombination system. We designed a "switch vector" where a growth signalobody gene was flanked by two loxP sites and a death signalobody gene was placed downstream of the floxed cassette. Cells transduced with the switch vector showed superior growth activity in the presence of a specific antigen. Subsequent expression of Cre induced the death signalobody, leading to conditional cell death. This technology could be applicable for other cell fate conversion systems including differentiation and migration, by using appropriate signal-transducing domains. PMID- 23794463 TI - Disseminated, large-sized neonatal pneumatoceles: the wait-and-see strategy. AB - Pulmonary pneumatoceles are thin-walled, air-filled cysts that develop within the lung parenchyma. Most often, they occur as a sequel of acute pneumonia, commonly caused by Staphylococcus aureus in children. Limited data are available about infective pulmonary cysts in newborns. We report a case of a newborn, who developed multiple pneumatoceles after Escherichia coli pneumonia. PMID- 23794464 TI - Differences in plasma and sputum biomarkers between COPD and COPD-asthma overlap. AB - The pathophysiological features of chronic obstructive pulmonary disease (COPD) asthma overlap are poorly understood and there has been no study of plasma or sputum biomarkers in overlap patients. In order to clarify the similarity and differences between overlap and COPD or asthma, we have investigated four potential biomarkers of COPD: surfactant protein A (SP-A), soluble receptor for advanced glycation end-products (sRAGE), myeloperoxidase (MPO) and neutrophil gelatinase-associated lipocalin (NGAL). SP-A and sRAGE are pneumocyte-derived markers. MPO and NGAL are neutrophil-derived molecules, but NGAL can also be expressed by respiratory epithelial cells. Plasma levels of SP-A and sRAGE and induced sputum levels of MPO and NGAL were measured by enzyme immunoassay/ELISA in 134 subjects: nonsmokers (n=26), smokers (n=23), asthma (n=32), COPD (n=39) and COPD-asthma overlap patients (n=14). In patients with COPD-asthma overlap, sputum MPO and plasma SP-A were significantly elevated whereas plasma sRAGE levels were reduced compared with asthma patients. Only sputum NGAL was significantly elevated in COPD-asthma overlap compared with COPD (p=0.00016) and could be used to differentiate patients with overlap from those with COPD. Increased induced sputum levels of NGAL might be a characteristic feature of overlap, suggesting enhanced neutrophilic airway inflammation and/or airway epithelial injury in COPD-asthma overlap. PMID- 23794465 TI - Prednisone in COPD exacerbation requiring ventilatory support: an open-label randomised evaluation. AB - Recommendation of the use of systemic steroids in chronic obstructive disease (COPD) exacerbation rely on trials that excluded patients requiring ventilatory support. In an open-label, randomised evaluation of oral prednisone administration, 217 patients with acute COPD exacerbation requiring ventilatory support were randomised (with stratification on the type of ventilation) to usual care (n=106) or to receive a daily dose of prednisone (1 mg.kg(-1)) for up to 10 days (n=111). There was no difference regarding the primary end-point, intensive care unit mortality, which was 17 (15.3%) deaths versus 15 (14%) deaths in the steroid-treated and control groups, respectively (relative risk 1.08, 95% CI 0.6 2.05). Analysis according to ventilation modalities showed similar mortality rates. Noninvasive ventilation failed in 15.7% and 12.7% (relative risk 1.25, 95% CI 0.56-2.8; p=0.59), respectively. Both study groups had similar median mechanical ventilation duration and intensive care unit length of stay, which were 6 (interquartile range 6-12) days versus 6 (3.8-12) days and 9 (6-14) days versus 8 (6-14) days, respectively. Hyperglycaemic episodes requiring initiation or alteration of current insulin doses occurred in 55 (49.5%) patients versus 35 (33%) patients in the prednisone and control groups, respectively (relative risk 1.5, 95% CI 1.08-2.08; p=0.015). Prednisone did not improve intensive care unit mortality or patient-centred outcomes in the selected subgroup of COPD patients with severe exacerbation but significantly increased the risk of hyperglycaemia. PMID- 23794466 TI - The effect of peroxisome proliferator-activated receptor-gamma ligands on in vitro and in vivo models of COPD. AB - Peroxisome proliferator-activated receptor (PPAR)-gamma is expressed in alveolar macrophages. The anti-inflammatory potential of the PPAR-gamma ligands rosiglitazone and pioglitazone were investigated using in vitro alveolar macrophage models and in vivo animal models relevant to chronic obstructive pulmonary disease (COPD). PPAR-gamma protein and gene expression in COPD alveolar macrophages was compared with control smokers and never-smokers. COPD macrophages were used to investigate the effects of PPAR-gamma ligands and corticosteroids on lipopolysaccharide-induced cytokine production, alternative macrophage activation (M2) gene expression and efferocytosis. The effects of PPAR-gamma ligands in a subchronic tobacco smoke model in mice were investigated. PPAR-gamma protein expression was similar in COPD patients compared to controls, although increased gene expression levels were observed in COPD patients and control smokers compared to never-smokers. PPAR-gamma ligands reduced tumour necrosis factor alpha and CC chemokine ligand-5, but not CXC chemokine ligand-8, in COPD alveolar macrophages; these effects were generally less than those of the corticosteroid dexamethasone. Rosiglitazone increased M2 gene expression and enhanced efferocytosis of apoptotic neutrophils. Rosiglitazone and pioglitazone attenuated airway neutrophilia in a corticosteroid-resistant mouse model of pulmonary inflammation. We show biological actions of PPAR-gamma agonists on corticosteroid resistant disease, tobacco smoke-induced pulmonary inflammation, skewing of macrophage phenotype and clearance of apoptotic neutrophils. PMID- 23794467 TI - Predicting Mycobacterium tuberculosis in patients with community-acquired pneumonia. AB - The 22 risk factors suggested by the Centers for Disease Control and Prevention (CDC) to predict patients at risk for Mycobacterium tuberculosis have not been evaluated in hospitalised patients with community-acquired pneumonia (CAP). We evaluated which of the CDC risk factors best predict M. tuberculosis in these patients. To our knowledge, this is the first time a score has been developed assessing these risk factors. This was a secondary analysis of 6976 patients hospitalised with CAP enrolled in the Community-Acquired Pneumonia Organization International Cohort Study. Using Poisson regression, we selected the subset of risk factors that best predicted the presence of CAP due to M. tuberculosis. This subset was compared to the CDC risk factors using receiver operating characteristic (ROC) curve analysis. Five risk factors were found to best predict CAP due to M. tuberculosis: night sweats, haemoptysis, weight loss, M. tuberculosis exposure and upper lobe infiltrate. The area under the ROC curve for all CDC risk factors was 71% and 89% for the subset of five risk factors. The CDC suggested risk factors are poor at predicting the presence of M. tuberculosis in hospitalised patients with CAP. With a subset of five risk factors identified in this study, we developed a new score, which will improve our capacity to isolate patients at risk of CAP due to M. tuberculosis at the time of hospitalisation. PMID- 23794468 TI - Zero reference level for right heart catheterisation. AB - Although in the pulmonary circulation small pressure differences may alter the categorisation of patients, there is no consensus on a standard zero reference level (ZRL). In the supine position, ZRL is mostly set at "5 cm below anterior thorax surface", "1/3 thoracic diameter below anterior thorax surface", "mid thoracic level" or "10 cm above table level". We retrospectively assessed the distance of these four ZRLs from computed tomography-derived right and left atrial centre levels and from one another in patients undergoing right heart catheterisation and calculated the respective differences in pressure readings. We included 196 consecutive patients. The ZRL at "1/3 thoracic diameter" was most often (98.5%) level with the right atrium, and the ZRL at "mid-thoracic level" was level with the left atrium (97.4%), revealing a median (range) pressure difference of -0.3 (-3.0-1.3) and 0.2 (-2.0-1.3) mmHg from the right and left atrial centre level, respectively. The largest differences (8.0 (2.0-15.4) mmHg) were found between the ZRLs "5 cm below anterior thorax surface" and "10 cm above table level". Accordingly, 59% versus 80% of patients would be classified with pulmonary hypertension and 7% versus 38% with elevated left heart pressures. The choice of ZRL strongly influences pulmonary pressure readings and pulmonary hypertension classification. 1/3 thoracic diameter mostly represents the right atrium while the left atrium is best represented by the mid-thoracic level. PMID- 23794469 TI - Adrenomedullin refines mortality prediction by the BODE index in COPD: the "BODE A" index. AB - The BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity) index is well-validated for mortality prediction in chronic obstructive pulmonary disease (COPD). Concentrations of plasma pro-adrenomedullin, a surrogate for mature adrenomedullin, independently predicted 2-year mortality among inpatients with COPD exacerbation. We compared accuracy of initial pro-adrenomedullin level, BODE and BODE components, alone or combined, in predicting 1-year or 2-year all cause mortality in a multicentre, multinational observational cohort with stable, moderate to very severe COPD. Pro-adrenomedullin was significantly associated (p<0.001) with 1-year mortality (4.7%) and 2-year mortality (7.8%) and comparably predictive to BODE regarding both (C statistics 0.691 versus 0.745 and 0.635 versus 0.679, respectively). Relative to using BODE alone, adding pro adrenomedullin significantly improved 1-year and 2-year mortality prognostication (C statistics 0.750 and 0.818, respectively; both p<0.001). Pro-adrenomedullin plus BOD was more predictive than the original BODE including 6-min walk distance. In multivariable analysis, pro-adrenomedullin (likelihood ratio Chi squared 13.0, p<0.001), body mass index (8.5, p=0.004) and 6-min walk distance (7.5, p=0.006) independently foretold 2-year survival, but modified Medical Research Council dyspnoea score (2.2, p=0.14) and forced expiratory volume in 1 s % predicted (0.3, p=0.60) did not. Pro-adrenomedullin plus BODE better predicts mortality in COPD patients than does BODE alone; pro-adrenomedullin may substitute for 6-min walk distance in BODE when 6-min walk testing is unavailable. PMID- 23794470 TI - Amination of heteroaryl chlorides: palladium catalysis or SN Ar in green solvents? AB - The reaction of heteroaryl chlorides in the pyrimidine, pyrazine and quinazoline series with amines in water in the presence of KF results in a facile SN Ar reaction and N-arylation. The reaction is less satisfactory with pyridines unless an additional electron-withdrawing group is present. The results showed that the transition-metal-free SN Ar reaction not only compares favourably to palladium catalysed coupling reactions but also operates under environmentally acceptable ("green") conditions in terms of the base and solvent. PMID- 23794471 TI - Electron transition-based optical activity (ETOA) of achiral metal oxides derived from chiral mesoporous silica. PMID- 23794472 TI - Can the affected semicircular canal be predicted by the initial provoking position in benign paroxysmal positional vertigo? AB - OBJECTIVES/HYPOTHESIS: The study evaluated the relationship between the position that initially provoked vertigo and the affected semicircular canal (SCC) in patients with benign paroxysmal positional vertigo (BPPV), and aimed to predict the side affected by BPPV through history taking regarding the provoking position. STUDY DESIGN: Prospective study at a tertiary hospital. METHODS: A total of 521 patients with BPPV involving the posterior or horizontal SCCs performed questionnaires at initial visit asking to choose the initial provoking position among the 10 positions corresponding to one of the three planes (roll, pitch, or yaw). After excluding 45 patients showing signs of simultaneous multiple canal or anterior canal involvement, the frequency of the provoking positions and the correlation between the side of the provoking position and the ear affected by BPPV were analyzed. RESULTS: There were 239 patients with posterior SCC BPPV (p-BPPV) and 237 patients with horizontal SCC BPPV (h-BPPV). The waking-up position was the most common provoking position in both types of BPPV. Statistically significant correlation was demonstrated between the side of the provoking position at the onset of vertigo and the affected side by BPPV (P < .01) in patients with p-BPPV as well as h-BPPV (geotropic type [Geo]), but not in patients with h-BPPV (apogeotropic type [Apo]). CONCLUSIONS: History taking regarding the side of provoking position at the onset of vertigo may help predict the side affected by BPPV in p-BPPV and h-BPPV (Geo). When h-BPPV (Apo) is suspected, further detailed examinations using additional localization methods should be performed. PMID- 23794473 TI - Tuning the emission colors of semiconductor nanocrystals beyond their bandgap tunability: all in the dope. AB - Adopting the concept of one dopant for one color, all the prominent emitting colors in the visible windows are obtained by doping selective dopants (Ag, Cu, Ni, and Cu) in an appropriate host (alloy of Cdx Zn1-x S) with fixed size/composition and bandgap. Analyzing the origin of these emissions the relative position of respective dopant states are correlated. PMID- 23794474 TI - Microdialysis sampling coupled to microchip electrophoresis with integrated amperometric detection on an all-glass substrate. AB - The development of an all-glass separation-based sensor using microdialysis coupled to microchip electrophoresis with amperometric detection is described. The system includes a flow-gated interface to inject discrete sample plugs from the microdialysis perfusate into the microchip electrophoresis system. Electrochemical detection was accomplished with a platinum electrode in an in channel configuration using a wireless electrically isolated potentiostat. To facilitate bonding around the in-channel electrode, a fabrication process was employed that produced a working and a reference electrode flush with the glass surface. Both normal and reversed polarity separations were performed with this sensor. The system was evaluated in vitro for the continuous monitoring of the production of hydrogen peroxide from the reaction of glucose oxidase with glucose. Microdialysis experiments were performed using a BASi loop probe with an overall lag time of approximately five minutes and a rise time of less than 60 seconds. PMID- 23794475 TI - Fluorescent nanoparticle delivered dsRNA toward genetic control of insect pests. AB - A fluorescent cationic core-shell nanoparticle efficiently enters into cells with high transfection efficacy. A FNP/CHT10-dsRNA complex is orally fed to insect pests and knocks down a midgut-specific chitinase gene of the Asian corn borer, which leads to death. This is the first report on the genetic control of insect pests through a non-viral gene delivery system to knock down key developmental gene expression. PMID- 23794476 TI - Structural basis of DNA quadruplex-duplex junction formation. PMID- 23794478 TI - Multiple antigen peptide mimetics containing gp41 membrane-proximal external region elicit broad neutralizing antibodies against human immunodeficiency virus type 1 in guinea pigs. AB - Eliciting a broadly neutralizing antibody response against the HIV-1 membrane proximal external region (MPER) mimicking the activity of 4E10 and 2F5 monoclonal antibodies remains a major challenge. In this study, two novel tetra-branched peptide immunogens, 4E10- and 2F5-MAP4, were designed and synthesized using a MAP system. Guinea pigs were immunized with either of these two synthetic immunogens emulsified in an oil-phase adjuvant at 3-week intervals. After four immunizations, epitope-specific antibody responses were induced successfully, and moderate neutralizing activities against tier 1 (clades B, BC, AE) and tier 2 (clade C) HIV-1 pseudoviruses were detectable in unfractionated sera and purified IgGs. The synthetic gp41 membrane-proximal external region peptide mimetics, 4E10 and 2F5-MAP4, assisted by an appropriate adjuvant, are promising prophylactic vaccine candidates potentially capable of eliciting broadly neutralizing antibody responses against HIV-1. PMID- 23794477 TI - Preconditioning mesenchymal stem cells with caspase inhibition and hyperoxia prior to hypoxia exposure increases cell proliferation. AB - Myocardial infarction is a leading cause of mortality and morbidity worldwide. Occlusion of a coronary artery produces ischemia and myocardial necrosis that leads to left ventricular (LV) remodeling, dysfunction, and heart failure. Stem cell therapy may decrease infarct size and improve LV function; the hypoxic environment, however, following a myocardial infarction may result in apoptosis, which in turn decreases survival of transplanted stem cells. Therefore, the effects of preconditioned mesenchymal stem cells (MSC) with hyperoxia (100% oxygen), Z-VAD-FMK pan-caspase inhibitor (CI), or both in a hypoxic environment in order to mimic conditions seen in cardiac tissue post-myocardial infarction were studied in vitro. MSCs preconditioned with hyperoxia or CI significantly decreased apoptosis as suggested by TUNEL assay and Annexin V analysis using fluorescence assisted cell sorting. These effects were more profound when both, hyperoxia and CI, were used. Additionally, gene and protein expression of caspases 1, 3, 6, 7, and 9 were down-regulated significantly in MSCs preconditioned with hyperoxia, CI, or both, while the survival markers Akt1, NF kappaB, and Bcl-2 were significantly increased in preconditioned MSCs. These changes ultimately resulted in a significant increase in MSC proliferation in hypoxic environment as determined by BrdU assays compared to MSCs without preconditioning. These effects may prove to be of great clinical significance when transplanting stem cells into the hypoxic myocardium of post-myocardial infarction patients in order to attenuate LV remodeling and improve LV function. PMID- 23794479 TI - An unusual case of biphenotypic, bigenotypic mature lymphoma. PMID- 23794480 TI - EGFR mutation detection by microfluidic technology: a validation study. AB - Advanced non-small cell lung cancer samples are tested for epidermal growth factor receptor (EGFR) gene mutations. Their detection by direct sequencing is time-consuming. Conversely, the length analysis of fluorescently labelled PCR products is easier. To avoid labelled primers and the automated capillary electrophoresis apparatus, we validated a fast and sensitive chip-based microfluidic technology. The limit of detection of fragment length assay on microfluidic device was 5%, more sensitive than direct sequencing (12.5%). The novel methodology showed high accuracy in the analysis of samples whose mutational status was known. The accuracy in quantifying mutated alleles (mA) was evaluated by PCR products subcloning; the mA% provided by direct sequencing of subcloned PCR products showed a close correlation with the mA% provided by the microfluidic technology for both exon 19 (R(2)=0.9) and 21 (R(2)=0.9). Microfluidic-based on-chip electrophoresis makes EGFR testing more rapid, sensitive and cost-effective. PMID- 23794481 TI - Virus infections among young children--the first year of the INDIS study. AB - The frequencies of early childhood infections were studied in healthy children with increased genetic risk for type 1 diabetes participating in the ongoing prospective high intensive infection follow-up Study, INDIS, started in 2009 in Turku, Finland. Here the results obtained from 160 stool to 160 nasal swab specimens collected in parallel at times of infectious symptoms in 2009-2010 from 45 children at the age of 24 months or younger are reported. The specimens were analyzed for enteric (human enterovirus, norovirus, rotavirus, sapovirus, astrovirus) and respiratory RNA viruses (human enterovirus and rhinovirus) common in early childhood, respectively, using highly validated virus-specific real-time PCR methods. According to the results 96% of the children had at least one virus infection during the study period and one or several viral agents were detected in 76% of sample sets. The most prevalent viral agents were human rhinovirus, enterovirus, parechovirus, and norovirus (genotype GII) with positive specimens 57.5%, 28.8%, 19.4%, and 6.9%, respectively. Other intestinal viruses were found in less than 2% of stool specimens. Single infections covered 40.0% of the specimens while multiple infections with two or more infectious agents were detected in 36.3% of specimens and altogether 11 combinations of viruses were included in the mixed infections. Although human enterovirus is known to be a frequent finding in stool specimens, especially during early childhood, it was found in this study more frequently in nasal swab specimens. Whether this is true, more general, in countries with the high hygiene level remains to be shown. PMID- 23794482 TI - Application of quantitative (19) F nuclear magnetic resonance spectroscopy in tape-stripping experiments with natural microemulsions. AB - The skin penetration of flufenamic acid (Fluf) and fluconazole (Fluc) from innovative natural microemulsions was investigated in tape-stripping experiments on pig ears. The formulations were based on the eudermic surfactants lecithin, sucrose laurate, alkylpolyglycoside or a mixture thereof. The quantification of the penetrated drug amounts was executed by (19) F nuclear magnetic resonance (NMR) in comparison with high-performance liquid chromatography (HPLC). The data obtained by the (19) F NMR method were confirmed by additional quantitative studies using HPLC. An excellent linear correlation was found for Fluf as well as for Fluc between (19) F NMR and HPLC data. This work presents a strategy outlining the use of (19) F NMR to selectively monitor the skin penetration routes of fluorinated compounds. Fluc penetrated generally well into the stratum corneum with the significantly highest amounts from the sucrose laurate microemulsion on the tape strips 1-5. Similarly, the highest amounts of penetrated Fluf could be observed from the formulation based on sucrose laurate. In addition, NMR self-diffusion studies were conducted and revealed a bicontinuous microstructure of the investigated microemulsions. The skin penetration results are in good agreement with the obtained (19) F NMR self diffusion coefficients of the active compounds in the microemulsion systems. PMID- 23794483 TI - Enhanced performance of p-type dye-sensitized solar cells based on ultrasmall Mg doped CuCrO2 nanocrystals. AB - Herein, we present ultrasmall delafossite-type Mg-doped CuCrO2 nanocrystals prepared by using hydrothermal synthesis and their first application as photocathodes in efficient p-type dye-sensitized solar cells. The short-circuit current density (Jsc ) is notably increased by approximately 27% owing to the decreased crystallite size and the enhanced optical transmittance associated with Mg doping of the CuCrO2 nanocrystalline sample. An open-circuit voltage (Voc ) of 201 mV, Jsc of 1.51 mA cm(-2) , fill factor of 0.449, and overall photoconversion efficiency of 0.132% have been achieved with the CuCr0.9 Mg 0.1 O2 dye photocathode sensitized with the P1 dye under optimized conditions. This efficiency is nearly three times higher than that of the NiO-based reference device, which is attributed to the largely improved Voc and Jsc . The augmentation of Voc and Jsc can be attributed to the lower valance band position and the faster hole diffusion coefficient of CuCr0.9 Mg 0.1 O2 compared to those of the NiO reference, respectively, which leads to a higher hole collection efficiency. PMID- 23794484 TI - The influence on cell cycle and cell division by various cadmium-containing quantum dots. AB - Quantum dots (QDs) have attracted great attention because of their favorable optical properties and have been widely applied in biomedical fields. However, in recent years, there have been an increasing number of reports about the cytotoxicity of QDs, especially cadmium-containing QDs, which may release cadmium ions to induce cytotoxicity. Importantly, the chemical composition and surface modifications of cadmium-based QDs determine the amount of Cd(2+) released inside the cell. Thus, there is an urgent need for more systematic work to study the relationship between cytotoxicity and the surface properties of QDs. In this article, the cytotoxicity of seven cadmium-containing QDs with different constituent elements and surface chemistries are compared. The results show that the cytotoxicity of QDs is closely related to their constituent elements and surface properties: First, CdTe@ZnS core-shell QDs show much lower cytotoxicity than naked ones when they have similar surface modifications; second, the positively charged QDs are more toxic than the negatively charged ones. Moreover, both positively and negatively charged QDs without ZnS coatings lead to multipolar spindles, misaligned chromosomes, and G2/M checkpoint failures. Interestingly, although CdSe QDs with a PEG coating cause no apparent cytotoxicity in any of the cell lines studied, they can localize near the contractile ring during cytokinesis and then block contractile ring disassembly. The cellular effect of CdTe QDs comes not only from the release of cadmium ions but also the intracellular distribution of QD nanoparticles in cells and the associated nanoscale effects. It is also found that QD-caused cytokinesis failure is closely related to the decreased expression of Cyclin A and Cyclin B. Taken together, the above findings provide new insight into the dynamic fate of QDs during cell mitosis, and are important for understanding the intracellular effects of QDs on the mitotic spindle and chromosomes during cell division. Furthermore, this kind of cytotoxicity evaluation method should be applicable to studies of the biological effects and health impacts of other nanomaterials. PMID- 23794486 TI - Gold carbenes from substituted propargyl acetates: intramolecular ene-type reactions to 2-acetoxynaphthalene derivatives. PMID- 23794487 TI - Interaction of synthetic peptide octarphin (TPLVTLFK) with human blood lymphocytes. AB - The synthetic peptide octarphin (TPLVTLFK) corresponding to the sequence 12-19 of beta-endorphin, a selective agonist of non-opioid beta-endorphin receptor, was labeled with tritium to specific activity of 29 Ci/mmol. The analysis of [(3) H]octarphin binding to human T and B lymphocytes separated from normal human blood revealed the existence of one type of high-affinity binding sites (receptors): Kd 3.0 and 3.2 nM, respectively. Besides unlabeled octarphin, unlabeled beta-endorphin possessed the ability to inhibit the specific binding of [(3) H]octarphin to T and B lymphocytes (Ki 1.9 and 2.2 nM, respectively). Tests of the specificity of the receptors revealed that they are not sensitive to naloxone, alpha-endorphin, gamma-endorphin, [Met(5) ]enkephalin, and [Leu(5) ]enkephalin. Thus, both T and B lymphocytes from normal human blood express non opioid receptor for beta-endorphin. Binding of the hormone to the receptor provides a fragment 12-19. PMID- 23794488 TI - Characterization of human dental pulp cells-derived spheroids in serum-free medium: stem cells in the core. AB - Spheroid models have led to an increased understanding of differentiation, tissue organization and homeostasis. In the present study, we have observed that under a serum-free medium, human dental pulp cells (DPCs) spontaneously formed spheroids, and could survive over 15 weeks. To characterize these spheroids, we investigated their dynamics, microenvironment, cell distribution, molecular profiles, and neuronal/osteogenic potential. Cell tracking assay showed that cells inside the spheroids have very slow cycling. Although the spheroids had hypoxia microenvironments, there were not any massive cell die-offs even after long-term cultivation. Whole mount immunofluorescence staining and histological analysis showed a distribution of stem cells in the central/intermediate zones of spheroids. qRT-PCR analysis demonstrated that the expression of stemness markers NANOG, TP63, and CD44 in the spheroids were much higher than within the monolayer cultures. Gene expression levels of neural markers CDH2, NFM, TUBB3, and CD24 in the spheroids were much higher than the monolayer DPCs and increased in a culture time-dependent manner. Without any neural induction, spheroid-derived cells spontaneously converted into neuron-like cells with positive staining of neural markers HuC/D and P75 under the serum-free medium for about 2 weeks. When the spheroids were transferred into osteogenic medium, they rapidly differentiated into osteo/odontogenic cells, especially the central original cells. Compared to the monolayer DPCs, mineralization in spheroids were significantly increased. This spheroid model offers a study tool to explore the molecular bases of stem cell homeostasis and tissue organization, and can be wildly used for nerve tissue and bone regeneration. PMID- 23794489 TI - Higher homocysteine and lower betaine increase the risk of microangiopathy in patients with diabetes mellitus carrying the GG genotype of PEMT G774C. AB - BACKGROUND: Diabetes represents one of the greatest medical and socioeconomic threats worldwide. The pathogenesis involved is complicated. The effect of methyl donors and genetic polymorphisms in metabolic enzymes on the risk of microangiopathy in patients with diabetes is not well understood. This study investigates the association of homocysteine, choline and betaine levels and phosphatidylethanolamine N-methyltransferase (PEMT) G774C (rs12325817) genotypes with the risk of diabetes and its related microangiopathic complications. METHODS: Between January 2009 and June 2010, 184 diabetic patients and 188 non diabetic control subjects were enrolled in the hospital-based case-control study. Serum concentrations of betaine and choline were determined by high-performance liquid chromatography (HPLC)-mass spectrometry. Serum concentrations of homocysteine were assayed using HPLC. PEMT gene mutations were detected by polymerase chain reaction and restriction fragment length polymorphism. RESULTS: After adjustment for potential confounders, serum total homocysteine had a significant dose-dependent positive association, and serum choline had an inverse association with the risks of diabetes and its microangiopathic complications (both p < 0.001). Although serum betaine was not associated with the risk of diabetes, it had a significant inverse association with diabetic microangiopathy. Compared with GG genotype, the CC genotype of PEMT G774C was associated with a decreased risk of diabetes (OR 0.559, 95% CI 0.338, 0.926) and its microangiopathy (OR 0.452, 95% CI 0.218, 0.937). CONCLUSION: The GG genotype of the PEMT G774C polymorphism, higher levels of serum homocysteine and lower levels of serum betaine are associated with an increased risk of microangiopathy in patients with diabetes. PMID- 23794491 TI - Propargyl amides as irreversible inhibitors of cysteine proteases--a lesson on the biological reactivity of alkynes. PMID- 23794490 TI - Fluorescent multiblock pi-conjugated polymer nanoparticles for in vivo tumor targeting. AB - Highly fluorescent multiblock conjugated polymer nanoparticles with folic acid surface ligands are highly effective for bioimaging and in vivo tumor targeting. The targeted nanoparticles were preferentially localized in tumor cells in vivo, thereby illustrating their potential for diagnostic and therapeutic applications. PMID- 23794492 TI - Immunohistochemical profiling of ALK fusion gene-positive adenocarcinomas of the lung. AB - Our aim was to determine whether or not non-small-cell lung cancer is squamous cell carcinoma (SQCC); even in small samples, it is essential in view of the side effects attendant on new therapeutics. Lung adenocarcinoma (ADC) with the EML4 ALK fusion gene has been described as demonstrating mucinous cribriform/acinar growth and signet-ring cells, sometimes partially simulating SQCC. We investigated the relation among morphology, anaplastic lymphoma kinase (ALK) rearrangement, and immunophenotype in 321 ADCs by tissue microarray using SQCC markers cytokeratin (CK)5/6, CK14, desmocollin-3, desmoglein-3, p40, p63 versus ADC markers thyroid transcription factor (TTF)-1 and napsin A. Unlike 312 ALK negative ADCs, 9 ALK-positive cases were negative for 4 SQCC markers. Only 1 ALK positive ADC showing assertive morphology was positive for CK5/6 and p63 as well as for TTF-1 and napsin A. Coexpression of TTF-1/p40 was not observed, unlike that of TTF-1/p63 reported previously. There was no statistically significant difference between ALK-negative and ALK-positive ADC by immunohistochemical profiling. PMID- 23794493 TI - Metastatic Malignant Melanoma to Urinary Bladder: A Potential Pitfall for High Grade Urothelial Carcinoma. AB - We present a case of a 61-year-old female presenting with a bladder tumor that occurred 7 years after her previous diagnosis of Clark's level III mid-back melanoma. The bladder tumor was submitted to histopathology without accompanying clinical history, and an initial diagnosis of high-grade urothelial carcinoma was rendered based on epithelioid and sarcomatoid appearing pleomorphic histopathology. We present this case to highlight the diagnostic challenge presented by the rare occurrence of metastatic melanoma to the urinary bladder and the potential pitfall of this lesion being diagnosed as high-grade urothelial carcinoma in the presence of limited clinical history. PMID- 23794494 TI - Plexiform fibromyxoma (plexiform angiomyxoid myofibroblastic tumor) of stomach: an unusual presentation as a fistulating abscess. AB - Plexiform fibromyxoma (plexiform angiomyxoid myofibroblastic tumor) is a rare benign mesenchymal tumor of stomach. The plexiform growth of bland-looking spindly cells in a richly vascularized fibromyxoid stroma is distinctive. The described cases are solid tumors associated with ulceration, with the patients presenting with symptoms related to the ulcer or mass effect of the tumor. We report an unusual case presenting as a fistulating abscess. A 42-year-old woman presented with abdominal pain, fever, and elevated white cell count. Computed tomography scan revealed a 12-cm cavitating mass in the gastric antrum, with fistulation to the gastric lumen through an ulcer. Histologic examination showed transmural involvement of the stomach by plexiform islands of fibromyxoid tumor with interspersed delicate capillaries. There was a pseudocyst-like component. The unusual presentation therefore broadens the clinical and pathologic spectrum of this rare tumor type. PMID- 23794495 TI - Hamlet by william shakespeare presented by surgical pathology. PMID- 23794496 TI - Subangulomaxillary cyst containing vestigeal remnants with thymic and parathyroid differentiation in an adult HIV1-positive patient. PMID- 23794497 TI - Hernia sacs: is histological examination necessary? AB - The hernia sac is a common surgical pathology specimen which can occasionally yield unexpected diagnoses. The College of American Pathologists recommends microscopic examination of abdominal hernias, but leaves submission of inguinal hernias for histology to the discretion of the pathologist. To validate this approach at a tertiary care centre, we retrospectively reviewed 1426 hernia sacs derived from inguinal, femoral and abdominal wall hernias. The majority of pathologies noted were known to the clinician, including herniated bowel, lipomas and omentum. A malignancy was noted in three of 800 inguinal hernias and seven of 576 abdominal wall hernias; five of these lesions were not seen on gross examination. Other interesting findings in hernia sacs included appendices, endometriosis, a perivascular epithelioid cell tumour, and pseudomyxoma peritoneii. All hernia sacs should be examined grossly as most pathologies are grossly visible. The decision to submit inguinal hernias for histology may be left to the discretion of the pathologist, but abdominal and femoral hernias should be submitted for histology. PMID- 23794498 TI - Design and synthesis of 3D ordered macroporous CeO2-supported Pt@CeO(2-delta) core-shell nanoparticle materials for enhanced catalytic activity of soot oxidation. PMID- 23794499 TI - Use of an anti-apoptotic CHO cell line for transient gene expression. AB - Transient gene expression in mammalian cells allows for rapid production of recombinant proteins for research and preclinical studies. Here, we describe the development of a polyethylenimine (PEI) transient transfection system using an anti-apoptotic host cell line. The host cell line, referred to as the Double Knockout (DKO), was generated by deleting two pro-apoptotic factors, Bax and Bak, in a CHO-K1 cell line using zinc finger nuclease mediated gene disruption. Optimized DNA and PEI volumes for DKO transfections were 50% and 30% lower than CHO-K1, respectively. During transfection DKO cells produced relatively high levels of lactate, but this was mitigated by a temperature shift to 31 degrees C which further enhanced productivity. DKO cells expressed ~3- to 4-fold higher antibody titers than CHO-K1 cells. As evidence of their anti-apoptotic properties post-transfection, DKO cells maintained higher viability and had reduced levels of active caspase-3 compared to CHO-K1 cells. Nuclear plasmid DNA copy numbers and message levels were significantly elevated in DKO cells. Although DNA uptake levels, as early as 40 min post-transfection, were higher in DKO cells this was not due to differences in cell surface heparan sulfate (HS) or initial endocytosis mechanism as both cell types utilized caveolae- and clathrin-mediated endocytosis to internalize DNA:PEI complexes. These results suggest that the increased transfection efficiency and titers from DKO cells are attributed to their resistance to transfection-induced apoptosis and not differences in endocytosis mechanism. PMID- 23794500 TI - Lanthanide oxide clusters: from tetrahedral [Dy4(MU4-O)](10+) to supertetrahedral [Ln20(MU4-O)11]38+ (Ln = Tb, Dy, Ho, Er). AB - Supertetrahedral clusters: A family of lanthanide oxide supertetrahedral T3{Ln20} clusters (Ln = Tb, Dy, Ho, Er; see figure) were obtained from the solvothermal reaction of lanthanide(III) salts with polytriazolate ligands that could be methylated and oxidized in situ. PMID- 23794501 TI - Major active components in grapefruit, orange, and apple juices responsible for OATP2B1-mediated drug interactions. AB - We aimed to explore the major active components in grapefruit juice (GFJ), orange juice (OJ), and apple juice (AJ) that are responsible for OATP2B1-mediated drug interactions, by means of in vitro studies using Xenopus oocytes expressing OATP2B1 with a typical OATP2B1 substrate, estrone-3-sulfate. All three juices inhibited OATP2B1-mediated estrone-3-sulfate uptake with half-maximum inhibition (IC50 ) values of 0.222% (GFJ), 0.807% (OJ), and 2.27% (AJ). Eight major flavonoids (naringin, naringenin, hesperidin, hesperetin, phloridzin, phloretin, quercetin, and kaempferol) contained in the juices inhibited OATP2B1-mediated estrone-3-sulfate uptake with IC50 values of 4.63, 49.2, 1.92, 67.6, 23.2, 1.31, 9.47, and 21.3 MUM, respectively. When the concentration-IC50 ratios ([C]/IC50 ) of these flavonoids in GFJ, OJ, and AJ were calculated, values of [C]/IC50 >= 100 were obtained for naringin in GFJ and hesperidin in OJ. No flavonoid in AJ showed a ratio higher than unity. However, significant inhibition of OATP2B1 was observed with a mixture of phloridzin, phloretin, hesperidin, and quercetin at the concentrations present in AJ. In conclusion, our results indicate that naringin and hesperidin are the major OATP2B1 inhibitors in GFJ and OJ, respectively, whereas a combination of multiple components appears to be responsible for OATP2B1 inhibition by AJ. PMID- 23794508 TI - Recombinant production of TEV cleaved human parathyroid hormone. AB - The parathyroid hormone, PTH, is responsible for calcium and phosphate ion homeostasis in the body. The first 34 amino acids of the peptide maintain the biological activity of the hormone and is currently marketed for calcium imbalance disorders. Although several methods for the production of recombinant PTH(1-34) have been reported, most involve the use of cleavage conditions that result in a modified peptide or unfavorable side products. Herein, we detail the recombinant production of (15) N-enriched human parathyroid hormone, (15) N PTH(1 34), generated via a plasmid vector that gives reasonable yield, low-cost protease cleavage (leaving the native N-terminal serine in its amino form), and purification by affinity and size exclusion chromatography. We characterize the product by multidimensional, heteronuclear NMR, circular dichroism, and LC/MS. PMID- 23794509 TI - Active hydrocarbon biosynthesis and accumulation in a green alga, Botryococcus braunii (race A). AB - Among oleaginous microalgae, the colonial green alga Botryococcus braunii accumulates especially large quantities of hydrocarbons. This accumulation may be achieved more by storage of lipids in the extracellular space rather than in the cytoplasm, as is the case for all other examined oleaginous microalgae. The stage of hydrocarbon synthesis during the cell cycle was determined by autoradiography. The cell cycle of B. braunii race A was synchronized by aminouracil treatment, and cells were taken at various stages in the cell cycle and cultured in a medium containing [(14)C]acetate. Incorporation of (14)C into hydrocarbons was detected. The highest labeling occurred just after septum formation, when it was about 2.6 times the rate during interphase. Fluorescent and electron microscopy revealed that new lipid accumulation on the cell surface occurred during at least two different growth stages and sites of cells. Lipid bodies in the cytoplasm were not prominent in interphase cells. These lipid bodies then increased in number, size, and inclusions, reaching maximum values just before the first lipid accumulation on the cell surface at the cell apex. Most of them disappeared from the cytoplasm concomitant with the second new accumulation at the basolateral region, where extracellular lipids continuously accumulated. The rough endoplasmic reticulum near the plasma membrane is prominent in B. braunii, and the endoplasmic reticulum was often in contact with both a chloroplast and lipid bodies in cells with increasing numbers of lipid bodies. We discuss the transport pathway of precursors of extracellular hydrocarbons in race A. PMID- 23794510 TI - Mutual cross talk between the regulators Hac1 of the unfolded protein response and Gcn4 of the general amino acid control of Saccharomyces cerevisiae. AB - Hac1 is the activator of the cellular response to the accumulation of unfolded proteins in the endoplasmic reticulum. Hac1 function requires the activity of Gcn4, which mainly acts as a regulator of the general amino acid control network providing Saccharomyces cerevisiae cells with amino acids. Here, we demonstrate novel functions of Hac1 and describe a mutual connection between Hac1 and Gcn4. Hac1 is required for induction of Gcn4-responsive promoter elements in haploid as well as diploid cells and therefore participates in the cellular amino acid supply. Furthermore, Hac1 and Gcn4 mutually influence their mRNA expression levels. Hac1 is also involved in FLO11 expression and adhesion upon amino acid starvation. Hac1 and Gcn4 act through the same promoter regions of the FLO11 flocculin. The results indicate an indirect effect of both transcription factors on FLO11 expression. Our data suggest a complex mutual cross talk between the Hac1- and Gcn4-controlled networks. PMID- 23794511 TI - Unisexual reproduction enhances fungal competitiveness by promoting habitat exploration via hyphal growth and sporulation. AB - Unisexual reproduction is a novel homothallic sexual cycle recently discovered in both ascomycetous and basidiomycetous pathogenic fungi. It is a form of selfing that induces the yeast-to-hyphal dimorphic transition in isolates of the alpha mating type of the human fungal pathogen Cryptococcus neoformans. Unisexual reproduction may benefit the pathogen by facilitating sexual reproduction in the absence of the opposite a mating type and by generating infectious propagules called basidiospores. Here, we report an independent potential selective advantage of unisexual reproduction beyond genetic exchange and recombination. We competed a wild-type strain capable of undergoing unisexual reproduction with mutants defective in this developmental pathway and found that unisexual reproduction provides a considerable dispersal advantage through hyphal growth and sporulation. Our results show that unisexual reproduction may serve to facilitate access to both nutrients and potential mating partners and may provide a means to maintain the capacity for dimorphic transitions in the environment. PMID- 23794513 TI - Affinity of a galactose-specific legume lectin from Dolichos lablab to adenine revealed by X-ray cystallography. AB - Crystal structure analysis of a galactose-specific lectin from a leguminous food crop Dolichos lablab (Indian lablab beans) has been carried out to obtain insights into its quaternary association and lectin-carbohydrate interactions. The analysis led to the identification of adenine binding sites at the dimeric interfaces of the heterotetrameric lectin. Structural details of similar adenine binding were reported in only one legume lectin, Dolichos biflorus, before this study. Here, we present the structure of the galactose-binding D. lablab lectin at different pH values in the native form and in complex with galactose and adenine. This first structure report on this lectin also provides a high resolution atomic view of legume lectin-adenine interactions. The tetramer has two canonical and two DB58-like interfaces. The binding of adenine, a non carbohydrate ligand, is found to occur at four hydrophobic sites at the core of the tetramer at the DB58-like dimeric interfaces and does not interfere with the carbohydrate-binding site. To support the crystallographic observations, the adenine binding was further quantified by carrying out isothermal calorimetric titration. By this method, we not only estimated the affinity of the lectin to adenine but also showed that adenine binds with negative cooperativity in solution. PMID- 23794515 TI - Preapproval of sinus computed tomography for otolaryngologic evaluation of chronic rhinosinusitis does not save health care costs. AB - OBJECTIVES/HYPOTHESIS: To evaluate the cost-effectiveness of preapproval requirements for computed tomography (CT) of the sinuses in the evaluation and management of chronic rhinosinusitis (CRS). STUDY DESIGN: Retrospective analysis of prospectively collected data. METHODS: Over a 6-month period, all sinus CT scans ordered by an otolaryngology practice and requiring preapproval by a third party payor were tabulated. Characteristics of the preapproval process that were recorded and analyzed included time spent by office administrative staff, need for peer-to-peer review, and time spent by the ordering physician. RESULTS: All 111 sinus CT scans ordered during the 6-month time period required preapproval based on insurer requirements-38 performed by computer, 71 by telephone, and two required both-costing an average of 8.1 minutes per scan by administrative staff (range, 2.0-20.0 minutes). Thirteen preapprovals required peer-to-peer telephone interaction by the ordering physician, utilizing an average of 7.7 minutes (range, 5-12 minutes). In no case was the insurance company peer an otolaryngologist. Ultimately, no sinus CT scan request was rejected by a third party payor. CONCLUSIONS: Preapprovals for sinus CTs ordered by otolaryngologists are unlikely to save costs for third-party payors, as sinus CT for the evaluation of CRS is well established and therefore unlikely to be rejected. Preapproval in this context comes at the expense of practice administrative and physicians' time. Based on our results, preapproval for sinus CT scans ordered by an otolaryngologist for evaluation of CRS appears to be an unnecessary and costly requirement. LEVEL OF EVIDENCE: N/A. PMID- 23794512 TI - The regulation and function of microRNAs in kidney diseases. AB - MicroRNAs (miRNA) are endogenous short noncoding RNAs, which regulate virtually all major cellular processes by inhibiting target gene expression. In kidneys, miRNAs have been implicated in renal development, homeostasis, and physiological functions. In addition, miRNAs play important roles in the pathogenesis of various renal diseases, including renal carcinoma, diabetic nephropathy, acute kidney injury, hypertensive nephropathy, polycystic kidney disease, and others. Furthermore, miRNAs may have great values as biomarkers in different kidney diseases. PMID- 23794516 TI - "Focused introspection" during naturally increased diuresis: description and repeatability of a method to study bladder sensation non-invasively. AB - OBJECTIVE: To present and describe a non-invasive method to study the origin and development of bladder filling sensation and to evaluate the repeatability of the method. METHOD: Eighteen volunteers participated in the study and were given a water loading protocol consisting of 1,000 ml water intake 1 hr before the session and 200 ml every 10 min during the session. Protocol 1: To evaluate diuresis rate, seven participants were asked to void every 15 min and the voided volume was measured. Protocol 2: Eleven volunteers graded bladder sensation on regular time points, on an empty graph with time on the X-axis and intensity of sensation on the Y-axis. The protocol ended at absolute need to void (maximal intensity) and voided volumes were measured. This protocol was conducted three times with a 10 days interval. RESULTS: Protocol 1: The diuresis rate was not different during the sessions and showed no variation over the studied time period (P = 0.2). Protocol 2: For an individual, the diuresis rate was not different between the sessions. The curves in all patients showed a continuously increasing bladder intensity. In seven participants the curve was convex, in the other four, the curve was sigmoidal. For each individual the pattern was constant during the three sessions. CONCLUSION: A strict water loading protocol induces a constant diuresis. This allows individuals to draw an introspection bladder sensation curve with a specific shape, which can be used as a method to study the development of bladder sensation non-invasively. PMID- 23794517 TI - Functional antibody CDR3 fusion proteins with enhanced pharmacological properties. PMID- 23794518 TI - Autophagy stimulates apoptosis in HER2-overexpressing breast cancers treated by lapatinib. AB - HER2-overexpressing breast cancers often show hyperactivation of the HER2/AKT/mTOR signaling pathway. Lapatinib is an oral dual tyrosine kinase inhibitor (TKI) that targets both EGFR and HER2 to inhibit the proliferation of breast cancer cells. However, it is obscure whether and how lapatinib could induce autophagy in breast cancer cells, an important cell response with drug treatment. In this study, we investigated the apoptosis and the autophagy in the HER2-overexpressing breast cancer cells BT474 and AU565 treated with lapatinib, and further examined their relationship. Lapatinib inhibited the proliferation and the rate of DNA synthesis in HER2-positive cells, as observed by MTT, colony formation and EDU assays. Lapatinib not only induced apoptosis accompanied by an increased expression of cleaved Caspase-3 and cleaved PARP, but it also induced autophagy in vitro, as confirmed by electron microscopy (EM), acridine orange (AO) staining and LC3-II expression. Meanwhile, lapatinib inhibited the phosphorylation of HER2, AKT, mTOR, and p70S6K, whereas that of AMPK was activated. When the cells were pre-incubated with 3-Methyladenine (3-MA), the specific autophagy inhibitor, the growth inhibitory ratio and apoptosis rate were frustrated, whereas colony formation and DNA synthesis ability were encouraged. In addition, 3-MA application could up-regulate Caspase-3 and PARP expression, compared with the treatment with lapatinib alone. The addition of 3-MA could attenuate the inhibitory role on HER2/AKT/mTOR pathway and the active role on AMPK that was raised by lapatinib. Therefore, lapatinib simultaneously induced both apoptosis and autophagy in the BT474 and AU565 cells, and in these settings, autophagy facilitates apoptosis. PMID- 23794519 TI - Comparison of pharmacological and electrical cardioversion in permanent atrial fibrillation after prosthetic cardiac valve replacement: a prospective randomized trial. AB - OBJECTIVE: To compare the efficacy of electrical versus pharmacological cardioversion following prosthetic cardiac valve replacement in patients with permanent atrial fibrillation (AF). METHODS: Patients with permanent AF who had undergone prosthetic cardiac valve replacement, who had a cardiothoracic ratio <= 0.5 and a left atrial diameter <= 50 mm for >= 6 months after surgery were randomly divided to receive either electrical or pharmacological cardioversion. Patients in the electrical cardioversion group were given direct-current synchronized electrical defibrillation under general anaesthesia. Patients in the pharmacological cardioversion group were given oral combination therapy with amiodarone, captopril and simvastatin for 3 months. RESULTS: A total of 115 patients received either electrical cardioversion (n = 59) or pharmacological cardioversion (n = 56); reversion to sinus rhythm occurred in 98.3% and 26.8%, respectively. Recurrence rates were similar in the two groups (3.4% and 6.7% for electrical and pharmacological cardioversion, respectively). No deaths or severe complications were reported. CONCLUSION: Electrical cardioversion has a favourable safety profile and appears to be a more effective method than pharmacological cardioversion for the treatment of permanent AF after cardiac valve replacement, once the heart has returned close to its normal size. PMID- 23794521 TI - Enhancing the [13C]bicarbonate signal in cardiac hyperpolarized [1-13C]pyruvate MRS studies by infusion of glucose, insulin and potassium. AB - A change in myocardial metabolism is a known effect of several diseases. MRS with hyperpolarized (13)C-labelled pyruvate is a technique capable of detecting changes in myocardial pyruvate metabolism, and has proven to be useful for the evaluation of myocardial ischaemia in vivo. However, during fasting, the myocardial glucose oxidation is low and the fatty acid oxidation (beta-oxidation) is high, which complicates the interpretation of pyruvate metabolism with the technique. The aim of this study was to investigate whether the infusion of glucose, insulin and potassium (GIK) could increase the myocardial glucose oxidation in the citric acid cycle, reflected as an increase in the [(13)C]bicarbonate signal in cardiac hyperpolarized [1-(13)C]pyruvate MRS measurements in fasted rats. Two groups of rats were infused with two different doses of GIK and investigated by MRS after injection of hyperpolarized [1 (13)C]pyruvate. No [(13)C]bicarbonate signal could be detected in the fasted state. However, a significant increase in the [(13)C]bicarbonate signal was observed by the infusion of a high dose of GIK. This study demonstrates that a high [(13)C]bicarbonate signal can be achieved by GIK infusion in fasted rats. The increased [(13)C]bicarbonate signal indicates an increased flux of pyruvate through the pyruvate dehydrogenase enzyme complex and an increase in myocardial glucose oxidation through the citric acid cycle. PMID- 23794522 TI - A systematic multitechnique approach for detection and characterization of reversible self-association during formulation development of therapeutic antibodies. AB - In addition to controlling typical instabilities such as physical and chemical degradations, understanding monoclonal antibodies' (mAbs) solution behavior is a key step in designing and developing process and formulation controls during their development. Reversible self-association (RSA), a unique solution property in which native, reversible oligomeric species are formed as a result of the noncovalent intermolecular interactions has been recognized as a developability risk with the potential to negatively impact manufacturing, storage stability, and delivery of mAbs. Therefore, its identification, characterization, and mitigation are key requirements during formulation development. Considering the large number of available analytical methods, choice of the employed technique is an important contributing factor for successful investigation of RSA. Herein, a multitechnique (dynamic light scattering, multiangle static light scattering, and analytical ultracentrifugation) approach is employed to comprehensively characterize the self-association of a model immunoglobulin G1 molecule. Studies herein discuss an effective approach for detection and characterization of RSA during biopharmaceutical development based on the capabilities of each technique, their complementarity, and more importantly their suitability for the stage of development in which RSA is investigated. PMID- 23794523 TI - Metabolic engineering and transhydrogenase effects on NADPH availability in Escherichia coli. AB - The synthesis of several industrially useful compounds are cofactor-dependent, requiring reducing equivalents like NADPH in enzymatic reactions leading up to the synthesis of high-value compounds like polymers, chiral alcohols, and antibiotics. However, NADPH is costly and has limited intracellular availability. This study focuses on the study of the effect of the two transhydrogenase enzymes of Escherichia coli, PntAB and UdhA (SthA) on reducing equivalents-dependent biosynthesis. The production of (S)-2-chloropropionate from 2-chloroacrylate is used as a model system for monitoring NADPH availability because 2-haloacrylate reductase, the enzyme catalyzing the one-step conversion to (S)-2 chloropropionate in the synthesis pathway, requires NADPH as a cofactor. Results suggest that the presence of UdhA increases product yield and NADPH availability while the presence of PntAB has the opposite effect. A maximum product yield of 1.4 mol product/mol glucose was achieved aerobically in a pnt-deletion strain with udhA overexpression, a 150% improvement over the wild-type control strain. PMID- 23794524 TI - Molecular dynamics simulations of certain mutant peptide models from staphylococcal nuclease reveal that initial hydrophobic collapse associated with turn propensity drives beta-hairpin folding. AB - An important nucleation event during the folding of staphylococcal nuclease involves the formation of a beta-hairpin by the sequence (21) DTVKLMYKGQPMTFR(35) . Earlier studies show that the turn sequence 'YKGQP' has an important role in the folding of this beta-hairpin. To understand the active or passive nature of the turn sequence 'YKGQP' in the folding of the aforementioned beta-hairpin sequence, we studied glycine mutant peptides Ac-(2) DTVKLMYGGQPMTFR(16) -NMe (K9G:15), Ac-(2) DTVKLMYKGGPMTFR(16) -NMe (Q11G:15), Ac-(2) DTVKLMYGGGPMTFR(16) NMe (K9G/Q11G:15), and Ac-(2) DTVKLMGGGGGMTFR(16) -NMe (penta-G:15) by using molecular dynamics simulations, starting with two different unfolded states, polyproline II and extended conformational forms. Further, 5mer mutant turn peptides Ac-(2) YGGQP(6) -NMe (K3G:5), Ac-(2) YKGGP(6) -NMe (Q5G:5), Ac-(2) YGGGP(6) -NMe (K3G/Q5G:5), and Ac-(2) GGGGG(6) -NMe (penta-G:5) were also studied individually. Our results show that an initial hydrophobic collapse and loop closure occurs in all 15mer mutants, but only K9G:15 mutant forms a stable native like beta-hairpin. In the other 15mer mutants, the hydrophobic collapsed state would not proceed to beta-hairpin formation. Of the different simulations performed for the penta-G:15 mutant, in only one simulation a nonnative beta hairpin conformation is sampled with highly flexible loop region ((8) GGGGG(12) ), which has no specific conformational preference as a 5mer. While the sequence 'YGGQP' in the K3G:5 simulation shows relatively higher beta-turn propensity, the presence of this sequence in K9G:15 peptide seems to be driving the beta-hairpin formation. Thus, these results seem to suggest that for the formation of a stable beta-hairpin, the initial hydrophobic collapse is to be assisted by a turn propensity. Initial hydrophobic collapse alone is not sufficient to guide beta hairpin formation. PMID- 23794525 TI - Convergent chemical synthesis of histone H2B protein for the site-specific ubiquitination at Lys34. PMID- 23794527 TI - Comparison of endoscopic techniques designed for posterior glottic stenosis--a cadaver morphometric study. AB - OBJECTIVES/HYPOTHESIS: Posterior glottic stenosis may cause more or less severe dyspnea. The popular endoscopic procedures have only a limited role in the treatment. Considering our clinical experiences, endoscopic arytenoid abduction lateropexy (EAAL) after proper mobilization of the fixed joints provides an effective option even in high-grade stenoses. STUDY DESIGN: To confirm these clinical observations, a morphometric study was performed in 100 cadaver larynges (50 male, 50 female) to objectively compare the endoscopic glottis-widening procedures. METHODS: The postoperative measurements of the posterior commissure following EAAL, classic vocal cord laterofixation (VCL), transverse cordotomy (TC), and arytenoidectomy (AE) were assessed by a digital image analyzer program. The distance between the vocal process of the lateralized vocal fold and the midline, the angle between the axis of the posterior commissure midpoint, and the vocal process and laryngeal median sagittal line were measured. RESULTS: EAAL was found to be more effective in improving the posterior glottis configuration; however, AE and VCL were beneficial as well. CONCLUSIONS: Our morphometric study proved that organ-preserving EAAL provided more space in the posterior glottic area. Fibrous reconnection and contraction of the scar can be minimized in this way, which may be the clinical efficacy explanation. PMID- 23794526 TI - Increasing both CoCrMo-alloy particle size and surface irregularity induces increased macrophage inflammasome activation in vitro potentially through lysosomal destabilization mechanisms. AB - Recent investigations indicate that innate immune "danger-signaling" pathways mediate metal implant debris induced-inflammatory responses, for example, NALP3 inflammasome. How the physical characteristics of particles (size, shape, and chemical composition) affect this inflammatory reactivity remains controversial. We examined the role of Cobalt-Chromium-Molybdenum (CoCrMo) alloy particle shape and size on human macrophage phagocytosis, lysosomal destabilization, and inflammasome activation. Round/smooth versus irregularly shaped/rough CoCrMo alloy particles of ~1 and 6-7 um diameter were investigated for differential lysosomal damage and inflammasome activation in human monocytes/macrophages. While spherical/smooth 1 um CoCrMo-alloy particles did not measurably affect macrophage IL-1beta production, irregular 1 um CoCrMo-alloy particles induced significant IL-1beta increases over controls. Both round/smooth particles and irregular CoCrMo-alloy particles that were 6-7 um in size induced >10-fold increases in IL-1beta production compared to similarly shaped smaller particles (p < 0.05). Larger irregular particles induced a greater degree of intracellular lysosomal damage and a >3-fold increase in IL-1beta versus similarly sized round/smooth particles (at an equal dose, particles/cell). CoCrMo-alloy particle size-induced IL-1beta production was dependent on the lysosomal protease Cathepsin B, further supporting lysosomal destabilization as causative in inflammation. Phagocytosable larger/irregular shaped particles (6 um) demonstrated the greatest lysosomal destabilization (observed immunofluorescently) and inflammatory reactivity when compared on an equal dose basis (particles/cell) to smaller/spherical 1 um particles in vitro. PMID- 23794528 TI - Interactions between L-arginine/L-arginine derivatives and lysozyme and implications to their inhibition effects on protein aggregation. AB - L-arginine (Arg), L-homoarginine (HArg), L-arginine ethylester (ArgEE), and L arginine methylester (ArgME) were found effective in inhibiting protein aggregation, but the molecular mechanisms are not clear. Herein, stopped-flow fluorescence spectroscopy, isothermal titration calorimetry, and mass spectroscopy were used to investigate the folding kinetics of lysozyme and the interactions of the additives with lysozyme. It was found that the interactions of ArgME and ArgEE with lysozyme were similar to that of guanidine hydrochloride and were much stronger than those of Arg and HArg. The binding forces were all mainly hydrogen bonding and cation-pi interaction from the guanidinium group, but their differences in molecular states led to the significantly different binding strengths. The additives formed molecular clusters in an increasing order of ArgEE, ArgME, HArg, and Arg. Arg and HArg mainly formed annular clusters with head-to-tail bonding, while ArgME and ArgEE formed linear clusters with guanidinium groups stacking. The interactions between the additives and lysozyme were positively related to the monomer contents. That is, the monomers were the primary species that participated in the direct interactions due to their intact guanidinium groups and small sizes, while the clusters performed as barriers to crowd out the protein-protein interactions for aggregation. Thus, it is concluded that the effects of Arg and its derivatives on protein aggregation stemmed from the direct interactions by the monomers and the crowding effects by the clusters. Interplay of the two effects led to the differences in their inhibition effects on protein aggregation. PMID- 23794529 TI - Preparation of unconventional dendrimers that contain rigid NH-triazine linkages and peripheral tert-butyl moieties for CO2 -selective adsorption. AB - Three unconventional dendrimers that contained rigid NH-triazine linkages and peripheral tert-butyl moieties were prepared by using a convergent approach and characterized by (1)H and (13)C NMR spectroscopy, mass spectrometry, and elemental analysis. Based on a thermogravimetric analysis study, these dendrimers were observed to display thermal stability at about 300 degrees C. The NH triazine moiety, which possessed protonated and proton-free nitrogen sites (like the imidazole unit), displayed the capture of polarizable CO2 molecules through hydrogen-bond and/or dipole-quadrupole interactions. In addition, the adsorption of various amounts of CO2 and N2 at different pressures suggests that the dendritic pores, which arise from the stacking of the middle co-planar and rim protuberant dendrimers, Gn -N~N-Gn (n=1-3), either swell or shrink at high pressure, thus indicating that these dendrimers may have a breathing ability. PMID- 23794531 TI - Mediators of longitudinal changes in measures of adiposity in teenagers using parallel process latent growth modeling. AB - OBJECTIVE: The aim of the study was to evaluate mediating effects of energy balance-related behaviors on measures of adiposity in the Dutch Obesity Intervention in Teenagers-study (DOiT). DESIGN AND METHODS: DOiT was an 8-month behavioral intervention program consisting of educational and environmental components and evaluated in 18 prevocational secondary schools in the Netherlands (n = 1,108, baseline age 12.7 years, 50% girls). Outcome measures were changes in body mass index (BMI), waist circumference, and sum of skinfold thickness. Self reported consumption of sugar-containing beverages and high caloric snacks, active transport to/from school, and screen-viewing behaviors were the hypothesized mediators. Data were collected at 0, 8, 12, and 20 months. For the data analysis, parallel process latent growth modeling was used. RESULTS: Total sugar-containing beverages consumption mediated the intervention effects on BMI (ab = -0.01, 95%CI = -0.20, -0.001). The intervention group lowered their sugar containing beverages consumption more than controls (B = -0.14, 95%CI = -0.22, 0.11) and this, in turn, led to smaller increases in BMI. No significant mediated effect by the targeted behaviors was found for waist circumference or sum of skinfolds. CONCLUSIONS: Future school-based overweight prevention interventions may target decreasing sugar-containing beverages consumption. PMID- 23794532 TI - Highly active catalysts for the transfer dehydrogenation of alkanes: synthesis and application of novel 7-6-7 ring-based pincer iridium complexes. AB - A series of Ir-PCP pincer precatalysts [(7-6-7-(R) PCP)Ir(H)(Cl)] and [(7-6-7 (Ar) PCP)Ir(H)(Cl)(MeCN)] bearing a novel "7-6-7" fused-ring skeleton have been synthesized based upon the postulate that the catalytic species would have durability due to their rather rigid structure and high activity owing to the low but sufficient flexibility of their backbones, which are not completely fixed. Treatment of these precatalysts with NaOtBu gave rise to the active 14 electron (14e) species [(7-6-7-(iPr) PCP)Ir] and [(7-6-7-(Ph) PCP)Ir], which can trap hydrogen and were spectroscopically characterized as the tetrahydride complexes. Both [(7-6-7-(iPr) PCP)Ir] and [(7-6-7-(Ph) PCP)Ir] were found to be highly effective in the transfer dehydrogenation of cyclooctane with tert-butylethylene as the hydrogen acceptor, the initial reaction rate at high temperature (230 degrees C) being higher for [(7-6-7-(iPr) PCP)Ir] than [(7-6-7-(Ph) PCP)Ir], and the turnover number (TON) of the overall hydrogen transfer being higher for the latter. Nonetheless, the estimated TONs were as high as 4600 and 4820 for the two complexes at this temperature, respectively, which are unprecedented absolute values. In terms of durability, the [(7-6-7-(Ph) PCP)Ir] complex is the catalyst of choice for this reaction. Structural analysis and computational studies support the importance of the low flexibility of the ligand core. PMID- 23794533 TI - Analysis and correction of gradient nonlinearity bias in apparent diffusion coefficient measurements. AB - PURPOSE: Gradient nonlinearity of MRI systems leads to spatially dependent b values and consequently high non-uniformity errors (10-20%) in apparent diffusion coefficient (ADC) measurements over clinically relevant field-of-views. This work seeks practical correction procedure that effectively reduces observed ADC bias for media of arbitrary anisotropy in the fewest measurements. METHODS: All inclusive bias analysis considers spatial and time-domain cross-terms for diffusion and imaging gradients. The proposed correction is based on rotation of the gradient nonlinearity tensor into the diffusion gradient frame where spatial bias of b-matrix can be approximated by its Euclidean norm. Correction efficiency of the proposed procedure is numerically evaluated for a range of model diffusion tensor anisotropies and orientations. RESULTS: Spatial dependence of nonlinearity correction terms accounts for the bulk (75-95%) of ADC bias for FA = 0.3-0.9. Residual ADC non-uniformity errors are amplified for anisotropic diffusion. This approximation obviates need for full diffusion tensor measurement and diagonalization to derive a corrected ADC. Practical scenarios are outlined for implementation of the correction on clinical MRI systems. CONCLUSIONS: The proposed simplified correction algorithm appears sufficient to control ADC non uniformity errors in clinical studies using three orthogonal diffusion measurements. The most efficient reduction of ADC bias for anisotropic medium is achieved with non-lab-based diffusion gradients. PMID- 23794534 TI - Creation of ternary multicomponent crystals by exploitation of charge-transfer interactions. AB - Four new ternary crystalline molecular complexes have been synthesised from a common 3,5-dinitrobenzoic acid (3,5-dnda) and 4,4'-bipyridine (bipy) pairing with a series of amino-substituted aromatic compounds (4-aminobenzoic acid (4-aba), 4 (N,N-dimethylamino)benzoic acid (4-dmaba), 4-aminosalicylic acid (4-asa) and sulfanilamide (saa)). The ternary crystals were created through the application of complementary charge transfer and hydrogen-bonding interactions. For these systems a dimer was created through a charge-transfer interaction between two of the components, while hydrogen bonding between the third molecule and this dimer completed the construction of the ternary co-crystal. All resulting structures display the same acid???pyridine interaction between 3,5-dnba and bipy. However, changing the third component causes the proton of this bond to shift from neutral OH???N to a salt form, O(-) ???HN(+) , as the nature of the group hydrogen bonding to the carboxylic acid was changed. This highlights the role of the crystal environment on the level of proton transfer and the utility of ternary systems for the study of this process. PMID- 23794535 TI - MRI acquisition and analysis protocol for in vivo intraorbital optic nerve segmentation at 3T. AB - PURPOSE: To present a new acquisition and analysis protocol for reliable and reproducible segmentation of the entire intraorbital optic nerve (ION) mean cross sectional area by means of magnetic resonance imaging (MRI) at 3 tesla (T). METHODS: Eight healthy volunteers (mean age 31, five were male) gave written informed consent and both of their IONs were imaged individually using a coronal oblique T2-weighted fast multidynamic image acquisition scheme; the proposed acquisition scheme has its rationale in combining separately acquired volumes and registering them to account for motion-related artifacts commonly associated with longer acquisitions. Mean cross-sectional area of each ION was measured using a semiautomated image analysis protocol that was based on an active surface model previously described and used for spinal cord imaging. Reproducibility was assessed for repeated scans (scan-rescan) and repeated image analysis performance (intraobserver). RESULTS: Mean and SD values of the left ION cross-sectional area for the eight healthy volunteers were 5.0 (+/-0.7) mm2 and for the right ION were 5.3 (+/-0.8) mm2. Mean scan-rescan coefficient of variation (COV) for the left ION was 4.3% and for the right was 4.4%. Mean intraobserver COV for the left ION was 2.1% and for the right was 1.8%. CONCLUSIONS: This study presents a new MRI acquisition and analysis protocol for reliable and reproducible in vivo measurement of the entire ION mean cross-sectional area as demonstrated in a pilot study of healthy subjects. The protocol presented here can be used in future studies of the ION in disease state. PMID- 23794536 TI - Clinical implications of acanthamoeba affinity for electric fields. PMID- 23794537 TI - Adding metabolomics to the toolbox for studying retinal disease. PMID- 23794538 TI - Selective reporting of outcomes in randomised controlled trials in systematic reviews of cystic fibrosis. AB - BACKGROUND: Outcome reporting bias (ORB) in randomised trials has been identified as a threat to the validity of systematic reviews. Previous work highlighting this problem is limited to considering a single primary review outcome. The aim of this study was to assess ORB across all efficacy outcomes in the Cochrane systematic reviews of cystic fibrosis. METHODS: Systematic reviews of interventions for cystic fibrosis published on the Cochrane Library by the Cochrane Cystic Fibrosis and Genetic Disorders Group before 2010 were assessed for discrepancies in outcomes between review protocol and full review. ORB in eligible trials was also assessed for all efficacy review outcomes. Two authors independently classified each outcome using a nine-point classification system developed by the Outcome Reporting Bias In Trials study. These classifications were used to inform the assessment of the risk of bias for selective outcome reporting for each trial. RESULTS: -46 Cochrane cystic fibrosis systematic reviews were included. The median number of primary outcomes, number of trials and participants per trial in the reviews were 3 (IQR 2, 3), 4 (IQR 2, 8) and 21 (IQR 14, 41), respectively. 18 reviews (39%, 18/46) had a discrepancy in outcomes between protocol and full review. 37 reviews were eligible to be included in the ORB assessment. When considering review primary outcomes and all review outcomes, ORB was suspected in at least one trial in 86% and 100%, respectively. CONCLUSIONS: Assessment of ORB within a systematic review of a single primary outcome underestimates the risk of ORB in comparison to the assessment of multiple primary and secondary outcomes. ORB in trials is highly prevalent within systematic reviews of cystic fibrosis when assessed across all outcomes. This could be reduced by the development of a core outcome set for trials and systematic reviews in cystic fibrosis. PMID- 23794539 TI - Undergraduate teaching on biological weapons and bioterrorism at medical schools in the UK and the Republic of Ireland: results of a cross-sectional study. AB - OBJECTIVE: To determine if individual undergraduate schools of medicine in the UK and the Republic of Ireland provide any teaching to medical students about biological weapons, bioterrorism, chemical weapons and weaponised radiation, if they perceive them to be relevant issues and if they figure them in their future plans. DESIGN: A cross-sectional study utilising an internet-based questionnaire sent to key figures responsible for leading on the planning and delivery of undergraduate medical teaching at all schools of medicine in the UK and Ireland. SETTING: All identified undergraduate schools of medicine in the UK and Ireland between August 2012 and December 2012. OUTCOME MEASURES: Numerical data and free text feedback about relevant aspects of undergraduate teaching. RESULTS: Of the 38 medical schools approached, 34 (28 in UK, 6 in Ireland) completed the questionnaire (89.47%). 4 (all in UK) chose not to complete it. 6/34 (17.65%) included some specific teaching on biological weapons and bioterrorism. 7/34 (20.59%) had staff with bioterrorism expertise (mainly in microbiological and syndromic aspects). 4/34 (11.76%) had plans to introduce some specific teaching on bioterrorism. Free text responses revealed that some felt that because key bodies (eg, UK's General Medical Council) did not request teaching on bioterrorism, then it should not be included, while others regarded this field of study as a postgraduate subject and not appropriate for undergraduates, or argued that the curriculum was too congested already. 4/34 (11.76%) included some specific teaching on chemical weapons, and 3/34 (8.82%) on weaponised radiation. CONCLUSIONS: This study provides evidence that at the present time there is little teaching at the undergraduate level in the UK and Ireland on the subjects of biological weapons and bioterrorism, chemical weapons and weaponised radiation and signals that this situation is unlikely to change unless there were to be high-level policy guidance. PMID- 23794540 TI - Potentially preventable complications of urinary tract infections, pressure areas, pneumonia, and delirium in hospitalised dementia patients: retrospective cohort study. AB - OBJECTIVES: To identify rates of potentially preventable complications for dementia patients compared with non-dementia patients. DESIGN: Retrospective cohort design using hospital discharge data for dementia patients, case matched on sex, age, comorbidity and surgical status on a 1 : 4 ratio to non-dementia patients. SETTING: Public hospital discharge data from the state of New South Wales, Australia for 2006/2007. PARTICIPANTS: 426 276 overnight hospital episodes for patients aged 50 and above (census sample). MAIN OUTCOME MEASURES: Rates of preventable complications, with episode-level risk adjustment for 12 complications that are known to be sensitive to nursing care. RESULTS: Controlling for age and comorbidities, surgical dementia patients had higher rates than non-dementia patients in seven of the 12 complications: urinary tract infections, pressure ulcers, delirium, pneumonia, physiological and metabolic derangement (all at p<0.0001), sepsis and failure to rescue (at p<0.05). Medical dementia patients also had higher rates of these complications than did non dementia patients. The highest rates and highest relative risk for dementia patients compared with non-dementia patients, in both medical and surgical populations, were found in four common complications: urinary tract infections, pressure areas, pneumonia and delirium. CONCLUSIONS: Compared with non-dementia patients, hospitalised dementia patients have higher rates of potentially preventable complications that might be responsive to nursing interventions. PMID- 23794541 TI - Hypogonadism and low bone mineral density in patients on long-term intrathecal opioid delivery therapy. AB - OBJECTIVES: This study aimed to investigate the hypothalamic-pituitary-gonadal axis in a sample of male patients undertaking intrathecal opioid delivery for the management of chronic non-malignant pain and the presence of osteopaenia and/or osteoporosis in those diagnosed with hypogonadism. DESIGN: Observational study using health data routinely collected for non-research purposes. SETTING: Department of Pain Management, Russells Hall Hospital, Dudley, UK. PATIENTS: Twenty consecutive male patients attending follow-up clinics for intrathecal opioid therapy had the gonadal axis evaluated by measuring their serum luteinising hormone, follicle stimulating hormone, total testosterone, sex hormone binding globulin and calculating the free testosterone level. Bone mineral density was measured by DEXA scanning in those patients diagnosed with hypogonadism. RESULTS: Based on the calculated free testosterone concentrations, 17 (85%) patients had biochemical hypogonadism with 15 patients (75%) having free testosterone <180 pmol/L and 2 patients (10%) between 180 and 250 pmol/L. Bone mineral density was assessed in 14 of the 17 patients after the exclusion of 3 patients. Osteoporosis (defined as a T score <=-2.5 SD) was detected in three patients (21.4%) and osteopaenia (defined as a T score between -1.0 and -2.5 SD) was observed in seven patients (50%). Five of the 14 patients (35.7%) were at or above the intervention threshold for hip fracture. CONCLUSIONS: This study suggests an association between hypogonadism and low bone mass density in patients undertaking intrathecal opioid delivery for the management of chronic non-malignant pain. Surveillance of hypogonadism and the bone mineral density levels followed by appropriate treatment may be of paramount importance to reduce the risk of osteoporosis development and prevention of fractures in this group of patients. PMID- 23794542 TI - What can qualitative research do for randomised controlled trials? A systematic mapping review. AB - OBJECTIVE: To develop an empirically based framework of the aspects of randomised controlled trials addressed by qualitative research. DESIGN: Systematic mapping review of qualitative research undertaken with randomised controlled trials and published in peer-reviewed journals. DATA SOURCES: MEDLINE, PreMEDLINE, EMBASE, the Cochrane Library, Health Technology Assessment, PsycINFO, CINAHL, British Nursing Index, Social Sciences Citation Index and ASSIA. ELIGIBILITY CRITERIA: Articles reporting qualitative research undertaken with trials published between 2008 and September 2010; health research, reported in English. RESULTS: 296 articles met the inclusion criteria. Articles focused on 22 aspects of the trial within five broad categories. Some articles focused on more than one aspect of the trial, totalling 356 examples. The qualitative research focused on the intervention being trialled (71%, 254/356); the design, process and conduct of the trial (15%, 54/356); the outcomes of the trial (1%, 5/356); the measures used in the trial (3%, 10/356); and the target condition for the trial (9%, 33/356). A minority of the qualitative research was undertaken at the pretrial stage (28%, 82/296). The value of the qualitative research to the trial itself was not always made explicit within the articles. The potential value included optimising the intervention and trial conduct, facilitating interpretation of the trial findings, helping trialists to be sensitive to the human beings involved in trials, and saving money by steering researchers towards interventions more likely to be effective in future trials. CONCLUSIONS: A large amount of qualitative research undertaken with specific trials has been published, addressing a wide range of aspects of trials, with the potential to improve the endeavour of generating evidence of effectiveness of health interventions. Researchers can increase the impact of this work on trials by undertaking more of it at the pretrial stage and being explicit within their articles about the learning for trials and evidence-based practice. PMID- 23794543 TI - Sedentary behaviours and obesity in adults: the Cardiovascular Risk in Young Finns Study. AB - OBJECTIVE: Sedentary behaviour may contribute to the development of obesity. We investigated the relations between different types of sedentary behaviour and adiposity markers in a well-characterised adult population after controlling for a wide range of potential confounders. DESIGN: Cross-sectional study. SETTING: The Cardiovascular Risk in Young Finns Multicenter Study. Participants Sedentary time (TV viewing, computer time, reading, music/radio listening and other relaxation) was assessed with a questionnaire for 1084 women and 909 men aged 30 45 years. Other study variables included occupational and leisure-time physical activity, sleep duration, socioeconomic status, smoking, alcohol consumption, energy intake, adherence to the recommended diet, multiple individual food items, age and genetic variants associated with body mass index (BMI). Primary outcome measures BMI in kg/m(2) and waist circumference (WC in cm). RESULTS: Of the different sedentary behaviour types, TV viewing was most consistently related to higher BMI and WC, both in men and women. One additional daily TV hour was associated with a 1.81+/-0.44 cm larger WC in women and 2 cm+/-0.44 cm in men (both p<0.0001). The association with TV was diluted, but remained highly significant after adjustments with all measured covariates, including several potentially obesogenic food items associated with TV viewing. The intakes of food items such as sausage, beer and soft drinks were directly associated with TV viewing, while the intakes of oat and barley, fish, and fruits and berries were associated indirectly. After these adjustments, non-TV sedentary behaviour remained associated with adiposity indices only in women. CONCLUSIONS: Out of the different types of sedentary behaviour, TV viewing was most consistently associated with adiposity markers in adults. Partial dilution of these associations after adjustments for covariates suggests that the obesogenic effects of TV viewing are partly mediated by other lifestyle factors. PMID- 23794544 TI - The role of gender in housing for individuals with severe mental illness: a qualitative study of the Canadian service context. AB - OBJECTIVE: This study was undertaken to examine the role of gender as it relates to access to housing among individuals with severe mental illness (SMI) in Canada. DESIGN: An exploratory, qualitative approach was used to assess the perspectives of Canadian housing experts. The focus of inquiry was on the role of gender and associated intersections (eg, ethnicity) in pathways to housing access and housing needs for individuals with SMI. SETTING: A purposeful sampling strategy was undertaken to access respondents across all Canadian geographic regions, with diversity across settings (urban and rural) and service sectors (hospital based and community based). PARTICIPANTS: -29 individuals (6 men and 23 women) considered to be experts in a housing service context as it pertains to SMI were recruited. On average, participants had worked for 15 years in services that specialised in the support and delivery of housing services to people with SMI. MEASURES: Semistructured interviews with participants focused on the role gender plays in access to housing in their specific context. Barriers and facilitators were examined as were intersections with other relevant factors, such as ethnicity, poverty and parenthood. Quantitative ratings of housing accessibility as a function of gender were also collected. RESULTS: Participants across geographic contexts described a lack of shelter facilities for women, leading to a reliance on exploitative circumstances. Other findings included a compounding of discrimination for ethnic minority women, the unique resource problems faced in rural contexts, and the difficulties that attend access to shelter and housing for parents with SMI. CONCLUSIONS: These findings suggest that, along with a generally poor availability of housing stock for individuals with SMI, access problems are compounded by a lack of attention to the unique needs and illness trajectories that attend gender. PMID- 23794545 TI - Corifollitropin alpha followed by menotropin for poor ovarian responders' trial (COMPORT): a protocol of a multicentre randomised trial. AB - BACKGROUND: Poor response to ovarian stimulation affects a significant proportion of infertile couples undergoing in vitro fertilisation (IVF) treatment. Recently, the European Society of Human Reproduction and Embryology developed new criteria to define poor ovarian response, the so-called Bologna criteria. Although preliminary studies in these patients demonstrated very low pregnancy rates, a recent pilot study has shown promising results in women <40 years old fulfilling the criteria, after treatment with corifollitropin alpha followed by highly purified menotropin (hpHMG) in a gonadotropin-releasing hormone (GnRH) antagonist setting. Corifollitropin alpha followed by menotropin for poor ovarian responders' trial (COMPORT) is a randomised trial aiming to investigate whether this novel protocol is superior to treatment with recombinant follicle stimulating hormone (FSH) in an antagonist setting for young poor responders. METHODS/DESIGN: COMPORT is a multicentre, open label, phase III randomised trial using a parallel two-arm design. 150 patients <40 years old fulfilling the 'Bologna criteria' will be randomised to corifollitropin alpha followed by hpHMG (group A) or recombinant FSH (group B) in a GnRH antagonist protocol for IVF/intracytoplasmic sperm injection (ICSI). The primary outcome is the ongoing pregnancy rate (defined as the presence of intrauterine gestational sac with an embryonic pole demonstrating cardiac activity at 9-10 weeks of gestation). Secondary outcomes are clinical and biochemical pregnancy rates and number of oocytes retrieved. Central randomisation will be performed using a computer generated list and allocation concealment will be secured with the use of sealed opaque envelopes. A sample size of 150 women is essential to detect a difference of 19.5% in ongoing pregnancy rates between group A (28%) and group B (8.5%) with a power of 85% and a level of significance at 0.05 using a two-sided Fisher's exact test. PMID- 23794546 TI - Home telemonitoring study for Japanese patients with heart failure (HOMES-HF): protocol for a multicentre randomised controlled trial. AB - INTRODUCTION: Despite the encouraging results from several randomised controlled trials (RCTs) and meta-analyses, the ability of home telemonitoring for heart failure (HF) to improve patient outcomes remains controversial as a consequence of the two recent large-scale RCTs. However, it has been suggested that there is a subgroup of patients with HF who may benefit from telemonitoring. The aim of the present study was to investigate whether an HF management programme using telemonitoring could improve outcomes in patients with HF under the Japanese healthcare system. METHODS AND ANALYSIS: The Home Telemonitoring Study for Japanese Patients with Heart Failure (HOMES-HF) study is a prospective, multicentre RCT to investigate the effectiveness of home telemonitoring on the primary composite endpoint of all-cause death and rehospitalisation due to worsening HF in recently admitted HF patients (aged 20 and older, New York Heart Association classes II-III). The telemonitoring system is an automated physiological monitoring system including body weight, blood pressure and pulse rate by full-time nurses 7 days a week. Additionally, the system was designed to make it a high priority to support patient's self-care instead of an early detection of HF decompensation. A total sample size of 420 patients is planned according to the Schoenfeld and Richter method. Eligible patients are randomly assigned via a website to either the telemonitoring group or the usual care group by using a minimisation method with biased-coin assignment balancing on age, left ventricular ejection fraction and a history of ischaemic heart disease. Participants will be enrolled until August 2013 and followed until August 2014. Time to events will be estimated using the Kaplan-Meier method, and HRs and 95% CIs will be calculated using the Cox proportional hazards models with stratification factors. TRIAL REGISTRATION: The study is registered at UMIN Clinical Trials Registry (UMIN000006839). PMID- 23794547 TI - Are there sleep-specific phenotypes in patients with chronic fatigue syndrome? A cross-sectional polysomnography analysis. AB - OBJECTIVES: Despite sleep disturbances being a central complaint in patients with chronic fatigue syndrome (CFS), evidence of objective sleep abnormalities from over 30 studies is inconsistent. The present study aimed to identify whether sleep-specific phenotypes exist in CFS and explore objective characteristics that could differentiate phenotypes, while also being relevant to routine clinical practice. DESIGN: A cross-sectional, single-site study. SETTING: A fatigue clinic in the Netherlands. PARTICIPANTS: A consecutive series of 343 patients meeting the criteria for CFS, according to the Fukuda definition. MEASURES: Patients underwent a single night of polysomnography (all-night recording of EEG, electromyography, electrooculography, ECG and respiration) that was hand-scored by a researcher blind to diagnosis and patient history. RESULTS: Of the 343 patients, 104 (30.3%) were identified with a Primary Sleep Disorder explaining their diagnosis. A hierarchical cluster analysis on the remaining 239 patients resulted in four sleep phenotypes being identified at saturation. Of the 239 patients, 89.1% met quantitative criteria for at least one objective sleep problem. A one-way analysis of variance confirmed distinct sleep profiles for each sleep phenotype. Relatively longer sleep onset latencies, longer Rapid Eye Movement (REM) latencies and smaller percentages of both stage 2 and REM characterised the first phenotype. The second phenotype was characterised by more frequent arousals per hour. The third phenotype was characterised by a longer Total Sleep Time, shorter REM Latencies, and a higher percentage of REM and lower percentage of wake time. The final phenotype had the shortest Total Sleep Time and the highest percentage of wake time and wake after sleep onset. CONCLUSIONS: The results highlight the need to routinely screen for Primary Sleep Disorders in clinical practice and tailor sleep interventions, based on phenotype, to patients presenting with CFS. The results are discussed in terms of matching patients' self-reported sleep to these phenotypes in clinical practice. PMID- 23794548 TI - Prognostication of recovery time after acute peripheral facial palsy: a prospective cohort study. AB - OBJECTIVE: Owing to a lack of prospective studies, our aim was to evaluate diagnostic factors, in particular, motor and non-motor function tests, for prognostication of recovery time in patients with acute facial palsy (AFP). DESIGN: Prospective cohort study. SETTING: University hospital. PARTICIPANTS: 259 patients with AFP. MEASUREMENTS: Clinical data, facial grading, electrophysiological motor function tests and other non-motor function tests were assessed for their contribution to recovery time. RESULTS: The predominant origin of AFP was idiopathic (59%) and traumatic (21%). At baseline, the House-Brackmann scale (HB) was >III in 46% of patients. Follow-up time was 5.6+/-9.8 months with a complete recovery rate of 49%. The median recovery time was 3.5 months (95% CI 2.2 to 4.7 months). The following variables were associated with faster recovery: Interval between onset of AFP and treatment <6 days versus >=6 days (median recovery time in months 2.1 vs 6.5; p<0.0001); HB <=III vs >III (2.2 vs 4.6; p=0.001); no versus presence of pathological spontaneous activity in first electromyography (EMG; 2.8 vs probability of recovery <50%; p<0.0001); no versus voluntary activity in EMG (probability of recovery <50% vs 3.1; p<0.0001); normal versus pathological ipsilateral electroneurography (1.9 vs 6.5; p=0.008), normal versus pathological stapedius reflexes (1.6 vs 3.3; p=0.003). CONCLUSIONS: Start of treatment and grading, but most importantly EMG evaluated for pathological spontaneous activity and the stapedius reflex test are powerful prognosticators for estimating the recovery time from AFP. These results need confirmation in larger datasets. PMID- 23794549 TI - From never to daily smoking in 30 months: the predictive value of tobacco and non tobacco advertising exposure. AB - OBJECTIVE: To test the specificity of the association between tobacco advertising and youth smoking initiation. DESIGN: Longitudinal survey with a 30 month interval. SETTING: 21 public schools in three German states. PARTICIPANTS: A total of 1320 sixth-to-eighth grade students who were never-smokers at baseline (age range at baseline, 10-15 years; mean, 12.3 years). EXPOSURES: Exposure to tobacco and non-tobacco advertisements was measured at baseline with images of six tobacco and eight non-tobacco advertisements; students indicated the number of times they had seen each ad and the sum score over all advertisements was used to represent inter-individual differences in the amount of advertising exposure. PRIMARY AND SECONDARY OUTCOME MEASURES: Established smoking, defined as smoked >100 cigarettes during the observational period, and daily smoking at follow-up. Secondary outcome measures were any smoking and smoking in the last 30 days. RESULTS: During the observation period, 5% of the never-smokers at baseline smoked more than 100 cigarettes and 4.4% were classified as daily smokers. After controlling for age, gender, socioeconomic status, school performance, television screen time, personality characteristics and smoking status of peers and parents, each additional 10 tobacco advertising contacts increased the adjusted relative risk for established smoking by 38% (95% CI 16% to 63%; p<0.001) and for daily smoking by 30% (95% CI 3% to 64%; p<0.05). No significant association was found for non-tobacco advertising contact. CONCLUSIONS: The study confirms a content specific association between tobacco advertising and smoking behaviour and underlines that tobacco advertising exposure is not simply a marker for adolescents who are generally more receptive or attentive towards marketing. PMID- 23794550 TI - Confidence in the future, health-related behaviour and psychological distress: results from a web-based cross-sectional study of 101 257 Finns. AB - OBJECTIVES: To investigate the role of socioeconomic status and psychological stress to potential associations between confidence in the future and a wide range of health-related behaviours. DESIGN: Web-based cross-sectional study including an 'Electronic Health Check' at the Finnish Happiness-Flourishing Study website linked to a TV programme on happiness and depression. SETTING: The Finnish population with access to the internet. PARTICIPANTS: 101 257 Finns aged 18 and above (21 365 men; 79 892 women). Participants who were under the age of 18 and who did not provide information about their gender were excluded. PRIMARY OUTCOME MEASURES: As planned, we assessed smoking, weekly alcohol consumption and binge drinking, daily intake of fruits and vegetables and regular exercise. RESULTS: Compared with participants with low confidence in the future, those with high confidence were less likely to be daily smokers (men OR 0.58, 95% CI 0.52 to 0.65; women 0.57, 95% CI 0.53 to 0.61) and binge drinkers (men 0.57; 0.52 to 0.63; women 0.54; 0.50 to 0.57). Participants with high confidence in the future were more likely to exercise regularly (men OR 2.82, 95% CI 2.55 to 3.13; women 2.57, 95% CI 2.44 to 2.71) and consume vegetables (men OR 2.48, 95% CI 2.25 to 2.74; women 2.13, 95% CI 2.03 to 2.24) and fruits (men OR 2.09, 95% CI 1.86 to 2.35; women 1.83, 95% CI 1.74 to 1.93) daily. Adjustment for current psychological distress and satisfaction for income attenuated the results. CONCLUSIONS: Having confidence in the future is strongly associated with a healthy lifestyle, as assessed by a healthy diet, physical exercise and substance abuse. Health-related interventions may benefit from tailoring interventions according to the target population's level of confidence in the future as well as their level of psychological distress. PMID- 23794551 TI - Reduction in inequality in antenatal-care use and persistence of inequality in skilled birth attendance in the Philippines from 1993 to 2008. AB - OBJECTIVE: To assess changes in the inequalities associated with maternal healthcare use according to economic status in the Philippines. DESIGN: An analysis of four population-based data sets that were conducted between 1993 and 2008. SETTING: Philippines. PARTICIPANTS: Women aged 15-49 years who had a live birth within 1 year in 1993 (n=1707), 1998 (n=1513), 2003 (n=1325) and 2008 (n=1209). OUTCOMES: At least four visits of antenatal care, skilled birth attendance and delivery in a medical facility. RESULTS: The adjusted OR for antenatal-care use when comparing the highest wealth-index quintile with the lowest quintile declined from 1993 to 2008: 3.43 (95% CI 2.22 to 5.28) to 2.87 (95% CI 1.31 to 6.29). On the other hand, the adjusted OR for the other two outcome indicators by the wealth index widened from 1993 to 2008: 9.92 (95% CI 5.98 to 16.43) to 15.53 (95% CI 6.90 to 34.94) for skilled birth attendance and 7.74 (95% CI 4.22 to 14.21) to 16.00 (95% CI 7.99 to 32.02) for delivery in a medical facility. The concentration indices for maternal health utilisation in 1993 and 2008 were 0.19 and 0.09 for antenatal care; 0.26 and 0.24 for skilled birth attendance and 0.41 and 0.35 for delivery in a medical facility. CONCLUSIONS: Over a 16-year period, gradients in antenatal-care use decreased and the high level of inequalities in skilled birth attendance and delivery in a medical facility persisted. The results showed a disproportionate use of institutional care at birth among disadvantaged Filipino women. PMID- 23794552 TI - Cost of illness of patient-reported adverse drug events: a population-based cross sectional survey. AB - OBJECTIVES: To estimate the cost of illness (COI) of individuals with self reported adverse drug events (ADEs) from a societal perspective and to compare these estimates with the COI for individuals without ADE. Furthermore, to estimate the direct costs resulting from two ADE categories, adverse drug reactions (ADRs) and subtherapeutic effects of medication therapy (STE). DESIGN: Cross-sectional study. SETTING: The adult Swedish general population. PARTICIPANTS: The survey was distributed to a random sample of 14 000 Swedish residents aged 18 years and older, of which 7099 responded, 1377 reported at least one ADE and 943 reported an ADR or STE. MAIN OUTCOME MEASURES: Societal COI, including direct and indirect costs, for individuals with at least one self reported ADE, and the direct costs for prescription drugs and healthcare use resulting from self-reported ADRs and STEs were estimated during 30 days using a bottom-up approach. RESULTS: The economic burden for individuals with ADEs were (95% CI) 442.7 to 599.8 international dollars (Int$), of which direct costs were Int$ 279.6 to 420.0 (67.1%) and indirect costs were Int$ 143.0 to 199.8 (32.9%). The average COI was higher among those reporting ADEs compared with other respondents (COI: Int$ 442.7 to 599.8 versus Int$ 185.8 to 231.2). The COI of respondents reporting at least one ADR or STE was Int$ 468.9 to 652.9. Direct costs resulting from ADRs or STEs were Int$ 15.0 to 48.4. The reported resource use occurred both in hospitals and outside in primary care. CONCLUSIONS: Self reported ADRs and STEs cause resource use both in hospitals and in primary care. Moreover, ADEs seem to be associated with high overall COI from a societal perspective when comparing respondents with and without ADEs. There is a need to further examine this relationship and to study the indirect costs resulting from ADEs. PMID- 23794553 TI - Salpingectomy as standard at hysterectomy? A Danish cohort study, 1977-2010. AB - OBJECTIVE: To assess if the risk of first-time salpingectomy was affected by prior hysterectomy with retained fallopian tubes and by prior sterilisation. DESIGN: A historical cohort study. SETTING: Denmark. PARTICIPANTS: 170 000 randomly selected women born 1947-1963 (10 000/year) were followed from 1977 until the end of 2010. MAIN OUTCOME MEASURES: Effect of hysterectomy with retained fallopian tubes or sterilisation on the risk of salpingectomy. Both were modelled in a Cox proportional hazards model as time-dependent covariates, analysing time to first salpingectomy. End of follow-up period was 31 December 2010. RESULTS: Of 9591 hysterectomies, 6456 (67.3%) had both fallopian tubes retained. HRs for salpingectomy after hysterectomy with retained fallopian tubes and sterilisation were 2.13 (95% 1.88 to 2.42) and 2.42 (2.21 to 2.64), as compared with those for non-hysterectomised and non-sterilised women. CONCLUSIONS: Women undergoing hysterectomy with retained fallopian tubes or sterilisation have at least a doubled risk of subsequent salpingectomy. Removal of the fallopian tubes at hysterectomy should therefore be recommended. PMID- 23794555 TI - Patients' subjective concepts about primary healthcare utilisation: the study protocol of a qualitative comparative study between Norway and Germany. AB - BACKGROUND: In Germany, utilisation of ambulatory healthcare services is high compared with other countries: While a study based on the process data of German statutory health insurances showed an average of 17.1 physician-patient-contacts per year, the comparable figure for Norway is about five. The usual models of healthcare utilisation, such as Rosenstock's Health Belief Model and Andersen's Behavioural Model, cannot explain these differences adequately. Organisational factors of the healthcare system, such as gatekeeping, do not explain the magnitude of the differences. Our hypothesis is that patients' subjective concepts about primary healthcare utilisation play a major role in explaining different healthcare utilisation behaviour in different countries. Hence, the aim of this study is to explore these subjective concepts comparatively, between Germany and Norway. METHODS/DESIGN: With that aim in mind, we chose a comparative qualitative study design. In Norway and Germany, we are going to interview 20 patients each with qualitative episodic interviews. In addition, we are going to conduct participant observation in four German and four Norwegian primary care practices. The data will be analysed by thematic coding. Using selected categories, we are going to conduct comparative case and group analyses. ETHICS AND DISSEMINATION: The study adheres to the Declaration of Helsinki. All interviewees will sign informed consent forms and all patients will be observed during consultation. Strict rules for data security will apply. Developed theory and policy implications are going to be disseminated by a workshop, presentations for experts and laypersons and publications. PMID- 23794554 TI - Canadian Study of Determinants of Endometabolic Health in ChIlDrEn (CanDECIDE study): a cohort study protocol examining the mechanisms of obesity in survivors of childhood brain tumours. AB - BACKGROUND: Childhood obesity has reached epidemic proportions and is impacting children's health globally. In adults, obesity is associated with chronic low grade inflammation that leads to insulin resistance, which is one of the important mechanisms through which dysregulation of metabolism occurs. There is limited information available about the contribution of inflammation to metabolic health in obese children, and how individual and lifestyle factors impact this risk. One of the paediatric groups at risk of higher rates of obesity includes the survivors of childhood brain tumours. The aim of this study was to evaluate the mechanisms that contribute to inflammation in obese survivors of childhood brain tumours. METHODS AND ANALYSIS: This is a prospective cohort study. We will recruit lean and obese survivors of childhood brain tumours, and a control group composed of lean and obese children with no history of tumours. We will measure circulating and urinary cytokine levels and cytokine gene expression in monocytes. In addition, the methylation patterns of cytokine genes and that of toll-like receptor genes will be evaluated. These will be correlated with individual and lifestyle factors including age, sex, ethnicity, puberty, body mass index, fasting lipid levels, insulin sensitivity, diet, exercise, sleep, stress and built environment. The sample size calculation showed that we need 25 participants per arm ETHICS AND DISSEMINATION: This study has received ethics approval from the institutional review board. Once completed, we will publish this work in peer-reviewed journals and share the findings in presentations and posters in meetings. DISCUSSION: This study will permit the interrogation of inflammation as a contributor to obesity and its complications in obese survivors of childhood brain tumours and compare them with lean survivors and lean and obese controls with no history of tumours, which may help identify therapeutic and preventative interventions to combat the rising tide of obesity. PMID- 23794556 TI - Prenatal alcohol exposure and childhood balance ability: findings from a UK birth cohort study. AB - OBJECTIVE: To investigate the association of prenatal alcohol exposure with balance in10-year-old children. DESIGN: Population-based prospective longitudinal study. SETTING: Former Avon region of UK (Southwest England). PARTICIPANTS: 6915 children from the Avon Longitudinal Study of Parents and Children who had a balance assessment at age 10 and had data on maternal alcohol consumption. OUTCOME MEASURES: 3 composite balance scores: dynamic balance (beam-walking), static balance eyes open, static balance eyes closed (heel-to-toe balance on a beam and standing on one leg, eyes open or closed). RESULTS: Most mothers (95.5%) consumed no-to-moderate amounts (3-7 glasses/week) of alcohol during pregnancy. Higher total-alcohol consumption was associated with maternal-social advantage, whereas binge drinking (>=4 units/day) and abstinence were associated with maternal social disadvantage. No evidence was found of an adverse effect of maternal-alcohol consumption on childhood balance. Higher maternal-alcohol use during pregnancy was generally associated with better offspring outcomes, with some specific effects appearing strong (static balance eyes open and moderate total alcohol exposure at 18 weeks, adjusted OR 1.23 (95% CI 1.01 to 1.49); static balance eyes closed and moderate total alcohol exposure at 18 weeks, adjusted OR 1.25 (95% CI 1.06 to 1.48). Similar results were found for both paternal and postnatal maternal alcohol exposure. A Mendelian-randomization approach was used to estimate the association between maternal genotype and offspring balance using the non-synonymous variant rs1229984*A (ADH1B) to proxy for lower maternal alcohol consumption; no strong associations were found between this genotype/proxy and offspring balance. CONCLUSIONS: No evidence was found to indicate that moderate maternal alcohol consumption in this population sample had an adverse effect on offspring balance at age 10. An apparent beneficial effect of higher total maternal alcohol consumption on offspring balance appeared likely to reflect residual confounding. PMID- 23794557 TI - The use of glucosamine for chronic low back pain: a systematic review of randomised control trials. AB - OBJECTIVES: To ascertain whether the use of oral glucosamine influences symptoms or functional outcomes in patients with chronic low back pain (LBP) thought to be related to spinal osteoarthritis (OA). DESIGN: Systematic review of randomised control trials. Searches were performed up to March 2011 on Medline, AMED, CINHAL, Cochrane and EMBASE with subsequent reference screening of retrieved studies. In addition, the grey literature was searched via opensigle. Included studies were required to incorporate at least one of the Cochrane Back Pain Review Group's outcome measures as part of their design. Trials with participants over 18 years with a minimum of 12 weeks of back pain, in combination with radiographic changes of OA in the spine, were included. Studies were rated for risk-of-bias and graded for quality. RESULTS: 148 studies were identified after screening and meeting eligibility requirements, and three randomised controlled trials (n=309) were included in the quantitative synthesis. The review found that there was low quality but generally no evidence of an effect from glucosamine on function, with no change in the Roland-Morris Disability Questionnaire score in all studies. Conflicting evidence was demonstrated with pain scores with two studies showing no difference and one study with a high risk-of-bias showing both a statistically and clinically significant improvement from taking glucosamine. CONCLUSIONS: On the basis of the current research, any clinical benefit of oral glucosamine for patients with chronic LBP and radiographic changes of spinal OA can neither be demonstrated nor excluded based on insufficient data and the low quality of existing studies. PMID- 23794558 TI - An enhanced exercise and cognitive programme does not appear to reduce incident delirium in hospitalised patients: a randomised controlled trial. AB - OBJECTIVE: To determine if a programme of progressive resistance exercise, mobilisation and orientation, in addition to usual care, was superior to usual care alone in the prevention of incident delirium in older hospitalised patients. DESIGN: A randomised controlled trial. SETTING: The study was performed at a secondary referral hospital in Melbourne, Australia between May 2005 and December 2007. PARTICIPANTS: 648 consecutive medical inpatients aged 65 years or older who had been in hospital for less than 48 h and who did not have delirium. INTERVENTION: Participants were randomly allocated to a twice-daily programme of progressive resistance exercise tailored to individual ability, mobilisation and orientation in addition to usual care or to usual care alone. MEASUREMENTS: Delirium was measured using the Confusion Assessment Method at baseline and every 48 h until discharge. Secondary outcome measures were severity and duration of delirium, discharge destination and length of stay. RESULTS: Delirium occurred in 4.9% (95% CI 2.3% to 7.3%) of the intervention group (15/305) and in 5.9% (20/339; 95% CI 3.8% to 9.2%) of the group receiving usual care. No difference was observed between groups (chi(2); p=0.5). The intervention had no effect on delirium duration, severity, discharge destination or length of stay. CONCLUSION: A programme of progressive resistance exercise and orientation was not effective in reducing incident delirium in hospitalised elderly patients. PMID- 23794559 TI - Individual-level, network-level and city-level factors associated with HIV prevalence among people who inject drugs in eight Russian cities: a cross sectional study. AB - OBJECTIVES: To ascertain HIV prevalence among people who inject drug (injection drug users (IDUs)) in the Russian Federation and identify explanations for the disparity in different cities. DESIGN: Cross-sectional survey with serological testing for HIV and hepatitis C virus prevalent infections. SETTING: 8 Russian cities-Irkutsk, Omsk, Chelyabinsk, Yekaterinburg, Naberezhnye Chelny, Voronezh, Orel and St Petersburg. PARTICIPANTS: In 2007-2009 active IDUs were recruited by respondent-driven sampling with a target sample size of 300 or more in each city. MAIN OUTCOME MEASURES: Participants were administered a questionnaire covering sociodemographics, injection risk and protective behaviours, sexual behaviours, HIV knowledge, experiences with drug treatment and harm reduction programmes and social networks. Participants were tested for HIV and hepatitis C by enzyme immunoassay. Data were analysed to identify individual-level, network-level and city-level characteristics significantly associated with HIV prevalence. Factors significant at p<=0.1 were entered into a hierarchical regression model to control for multicollinearity. RESULTS: A total of 2596 active IDUs were recruited, interviewed and tested for HIV and hepatitis C virus infection. HIV prevalence ranged from 3% (in Voronezh) to 64% (in Yekaterinburg). Although individual-level and network-level variables explain some of the difference in prevalence across the eight cities, the over-riding variable that seems to account for most of the variance is the emergence of commercial, as opposed to homemade, heroin as the predominant form of opioid injected. CONCLUSIONS: The expansion of commercial heroin markets to many Russian cities may have served as a trigger for an expanding HIV epidemic among IDUs in that country. PMID- 23794560 TI - Changes in smoking behaviours following a smokefree legislation in parks and on beaches: an observational study. AB - OBJECTIVE: To examine the effect of an outdoor smokefree law in parks and on beaches on observed smoking in selected venues. METHODS: The study involved repeated observations in selected parks and beaches in Vancouver, British Columbia, Canada. The main outcome measure was changes in observed smoking rates in selected venues from prelaw to 12 months postlaw. RESULTS: No venue was 100% smokefree at the 12-month postlaw observation time point. There was a significant decrease in observed smoking rates in all venues from prelaw to 12-month postlaw (prelaw mean smoking rate=20.5 vs 12-month mean smoking rate=4.7, p=0.04). In stratified analysis by venue, the differences between the prelaw and 12-month smoking rates decreased significantly in parks (prelaw mean smoking rate=37.1 vs 12-month mean smoking rate=6.5, p=0.01) but not in beaches (prelaw mean smoking rate=2.9 vs 12-month mean smoking rate=1.0, p=0.1). CONCLUSIONS: Smokefree policies in outdoor recreational venues have the potential to decrease smoking in these venues. The effectiveness of such policies may differ by the type and usage of the venue; for instance, compliance may be better in venues that are used more often and have enforcement. Future studies may further explore factors that limit and foster the enforcement of such policies in parks and beaches. PMID- 23794561 TI - Predictors of good functional outcome in counterpulsation-treated recent ischaemic stroke patients. AB - OBJECTIVES: External counterpulsation (ECP) is a non-invasive method being investigated for ischaemic stroke. We aimed to explore predictors of good functional outcome for ECP-treated ischaemic stroke patients who completed a minimum of 10 sessions. METHODS: We analysed our ECP registry of ischaemic stroke patients with cerebral large artery stenosis who underwent ECP therapy at the Prince of Wales Hospital from 2004 to 2010. We included 155 patients who completed at least 10 sessions of ECP and had 3-month follow-up data as well as 52 medical controls. Functional outcomes were dichotomised into good outcome (modified Rankin Scale (mRS) 0-2) and bad outcome (mRS 3-6). We compared the differences in two groups in terms of demographics, medical history and parameters of ECP treatment. RESULTS: At 3 months after stroke, 70.5% of patients who finished the whole course of ECP had a good outcome (only 46.5% in the unfinished group and 38.5% in the medical group). Among all 207 recruited cases, 119 (57.5%) patients had a good outcome at 3 months after stroke. Compared with the bad outcome group, patients in the good outcome group were younger and had a lower baseline National Institutes of Health Stroke Scale (NIHSS) and longer ECP therapy duration. Multivariate logistic regression showed that ECP duration (OR 1.032), baseline NIHSS (OR 0.734) and age (OR 0.961) were independent predictors for a favourable outcome. CONCLUSIONS: Duration of ECP therapy is first found to be an important predictor for good outcome of ECP-treated ischaemic stroke patients, in addition to the well-known prognostic factors such as age and NIHSS. PMID- 23794562 TI - Would increasing centre volumes improve patient outcomes in peritoneal dialysis? A registry-based cohort and Monte Carlo simulation study. AB - OBJECTIVE: To estimate the association between centre volume and patient outcomes in peritoneal dialysis, explore robustness to residual confounding and predict the impact of policies to increase centre volumes. DESIGN: Registry-based cohort study with probabilistic sensitivity analysis and Monte Carlo simulation of (hypothetical) intervention effects. SETTING: 112 secondary-care centres in France. PARTICIPANTS: 9602 adult patients initiating peritoneal dialysis. MAIN OUTCOME MEASURES: Technique failure (ie, permanent transfer to haemodialysis), renal transplantation and death while on peritoneal dialysis within 5 years of initiating treatment. Associations with underlying risk measured by cause specific HRs (cs-HRs) and with cumulative incidence by subdistribution HRs (sd HRs). Intervention effects measured by predicted mean change in cumulative incidences. RESULTS: Higher volume centres had more patients with diabetes and were more frequently academic centres or associative groupings of private physicians. Patients in higher volume centres had a reduced risk of technique failure (>60 patients vs 0-10 patients: adjusted cs-HR 0.46; 95% CI 0.43 to 0.69), with no changed risk of death or transplantation. Sensitivity analyses mitigated the cs-HRs without changing the findings. In higher volume centres, the cumulative incidence was reduced for technique failure (>60 patients vs 0-10 patients: adjusted sd-HR 0.49; 95% CI 0.29 to 0.85) but was increased for transplantation and death (>60 patients vs 0-10 patients: transplantation adjusted sd-HR 1.53; 95% CI 1.04 to 2.24; death-adjusted sd-HR 1.28; 95% CI 1.00 to 1.63). The predicted reduction in cumulative incidence of technique failure was largest under a scenario of shifting all patients to the two highest volume centre groups (0.091 reduction) but lower for three more realistic interventions (around 0.06 reduction). CONCLUSIONS: Patients initiating peritoneal dialysis in high-volume centres had a considerably reduced risk of technique failure but simulations of interventions to increase exposure to high-volume centres yielded only modest improvements. PMID- 23794563 TI - Antitubercular specific activity of ibuprofen and the other 2-arylpropanoic acids using the HT-SPOTi whole-cell phenotypic assay. AB - OBJECTIVES: Lead antituberculosis (anti-TB) molecules with novel mechanisms of action are urgently required to fuel the anti-TB drug discovery pipeline. The aim of this study was to validate the use of the high-throughput spot culture growth inhibition (HT-SPOTi) assay for screening libraries of compounds against Mycobacterium tuberculosis and to study the inhibitory effect of ibuprofen (IBP) and the other 2-arylpropanoic acids on the growth inhibition of M tuberculosis and other mycobacterial species. METHODS: The HT-SPOTi method was validated not only with known drugs but also with a library of 47 confirmed anti-TB active compounds published in the ChEMBL database. Three over-the-counter non-steroidal anti-inflammatory drugs were also included in the screening. The 2-arylpropanoic acids, including IBP, were comprehensively evaluated against phenotypically and physiologically different strains of mycobacteria, and their cytotoxicity was determined against murine RAW264.7 macrophages. Furthermore, a comparative bioinformatic analysis was employed to propose a potential mycobacterial target. RESULTS: IBP showed antitubercular properties while carprofen was the most potent among the 2-arylpropanoic class. A 3,5-dinitro-IBP derivative was found to be more potent than IBP but equally selective. Other synthetic derivatives of IBP were less active, and the free carboxylic acid of IBP seems to be essential for its anti-TB activity. IBP, carprofen and the 3,5-dinitro-IBP derivative exhibited activity against multidrug-resistant isolates and stationary phase bacilli. On the basis of the human targets of the 2-arylpropanoic analgesics, the protein initiation factor infB (Rv2839c) of M tuberculosis was proposed as a potential molecular target. CONCLUSIONS: The HT-SPOTi method can be employed reliably and reproducibly to screen the antimicrobial potency of different compounds. IBP demonstrated specific antitubercular activity, while carprofen was the most selective agent among the 2-arylpropanoic class. Activity against stationary phase bacilli and multidrug-resistant isolates permits us to speculate a novel mechanism of antimycobacterial action. Further medicinal chemistry and target elucidation studies could potentially lead to new therapies against TB. PMID- 23794564 TI - Identifying admitted patients at risk of dying: a prospective observational validation of four biochemical scoring systems. AB - OBJECTIVES: Risk assessment is an important part of emergency patient care. Risk assessment tools based on biochemical data have the advantage that calculation can be automated and results can be easily provided. However, to be used clinically, existing tools have to be validated by independent researchers. This study involved an independent external validation of four risk stratification systems predicting death that rely primarily on biochemical variables. DESIGN: Prospective observational study. SETTING: The medical admission unit at a regional teaching hospital in Denmark. PARTICIPANTS: Of 5894 adult (age 15 or above) acutely admitted medical patients, 205 (3.5%) died during admission and 46 died (0.8%) within one calendar day. INTERVENTIONS: None. MAIN OUTCOME MEASURES: The main outcome measure was the ability to identify patients at an increased risk of dying (discriminatory power) as area under the receiver-operating characteristic curve (AUROC) and the accuracy of the predicted probability (calibration) using the Hosmer-Lemeshow goodness-of-fit test. The endpoint was all-cause mortality, defined in accordance with the original manuscripts. RESULTS: Using the original coefficients, all four systems were excellent at identifying patients at increased risk (discriminatory power, AUROC >=0.80). The accuracy was poor (we could assess calibration for two systems, which failed). After recalculation of the coefficients, two systems had improved discriminatory power and two remained unchanged. Calibration failed for one system in the validation cohort. CONCLUSIONS: Four biochemical risk stratification systems can risk-stratify the acutely admitted medical patients for mortality with excellent discriminatory power. We could improve the models for use in our setting by recalculating the risk coefficient for the chosen variables. PMID- 23794565 TI - 'I can't be an addict. I am.' Over-the-counter medicine abuse: a qualitative study. AB - OBJECTIVES: Over-the-counter (OTC) pharmacy medicines are considered relatively safe in contrast to prescribed and illicit substances, but their abuse and addiction potential is increasingly recognised. Those affected represent a hard to reach group, with little known about their experiences. Study objectives were to describe the experiences and views of those self-reporting OTC medicine abuse, and why medicines were taken, how they were obtained and associated treatment and support sought. DESIGN: Qualitative study using in-depth mainly telephone interviews. PARTICIPANTS: A purposive sample of 25 adults, aged 20-60s, 13 women. SETTING: UK, via two internet support groups. RESULTS: Individuals considered themselves 'addicted', but socially and economically active and different from illicit substance misusers. They blamed themselves for losing control over their medicine use, which usually began for genuine medical reasons and not experimentation and was often linked to the cessation of, or ongoing, medical prescribing. Codeine, in compound analgesics, was the main medicine implicated with three distinct dose ranges emerging with decongestant and sedative antihistamine abuse also being reported. Subsequent use was for the 'buzz' or similar effects of the opiate, which was obtained unproblematically by having lists of pharmacies to visit and occasionally using internet suppliers. Perceived withdrawal symptoms were described for all three dose ranges, and work and health problems were reported with higher doses. Mixed views about different treatment and support options emerged with standard drug treatment services being considered inappropriate for OTC medicines and concerns that this 'hidden addiction' was recorded in medical notes. Most supported the continued availability of OTC medicines with appropriate addiction warnings. CONCLUSIONS: Greater awareness of the addiction potential of OTC medicines is needed for the public, pharmacists and medical prescribers, along with appropriate communication about, and reviews of, treatment and support options, for this distinct group. PMID- 23794566 TI - Protocol for a longitudinal qualitative interview study: maintaining psychological well-being in advanced cancer--what can we learn from patients' and carers' own coping strategies? AB - INTRODUCTION: People with advanced cancer and their carers experience stress and uncertainty which affects the quality of life and physical and mental health. This study aims to understand how patients and carers recover or maintain psychological well-being by exploring the strategies employed to self-manage stress and uncertainty. METHODS AND ANALYSIS: A longitudinal qualitative interview approach with 30 patients with advanced cancer and 30 associated family or informal carers allows the exploration of contexts, mechanisms and outcomes at an individual level. Two interviews, 4-12 weeks apart, will not only enable the exploration of individuals' evolving coping strategies in response to changing contexts but also how patients' and carers' strategies inter-relate. Patient and Carer focus groups will then consider how the findings may be used in developing an intervention. Recruiting through two major tertiary cancer centres in the North West and using deliberately broad and inclusive criteria will enable the sample to capture demographic and experiential breadth. ETHICS AND DISSEMINATION: The research team will draw on their considerable experience to ensure that the study is sensitive to a patient and carer group, which may be considered vulnerable but still values being able to contribute its views. Public and patient involvement (PPI) is integral to the design and is evidenced by: a research advisory group incorporating patient and carers, prestudy consultations with the PPI group at one of the study sites and a user as the named applicant. The study team will use multiple methods to disseminate the findings to clinical, policy and academic audiences. A key element will be engaging health professionals in patient and carer ideas for promoting self-management of psychological well-being. The study has ethical approval from the North West Research Ethics Committee and the appropriate NHS governance clearance. REGISTRATION: National Institute for Health Research (NIHR) Clinical Studies Portfolio, UK Clinical Research Network (UKCRN) Study number 11725. PMID- 23794567 TI - Surveys of the salt content in UK bread: progress made and further reductions possible. AB - OBJECTIVES: To explore the salt reductions made over time in packaged bread sold in the UK, the biggest contributor of salt to the UK diet. STUDY DESIGN: Cross sectional surveys were carried out on the salt content of breads available in UK supermarkets in 2001(40 products), 2006 (138) and 2011 (203). MAIN OUTCOME MEASURES: The primary outcome measure was the change in salt content per 100 g over time. Further measures included the proportion of products meeting salt targets and differences between brands and bread types. RESULTS: The average salt level of bread was 1.23+/-0.19 g/100 g in 2001, 1.05+/-0.16 in 2006 and 0.98+/ 0.13 in 2011. This shows a reduction in salt/100 g of ~20% between 2001 and 2011. In the 18 products which were surveyed in all 3 years, there was a significant reduction of 17% (p<0.05). Supermarket own brand bread was found to be lower in salt compared with branded bread (0.95 g/100 g compared with 1.04 g/100 g in 2011). The number of products meeting the 2012 targets increased from 28% in 2001 to 71% in 2011 (p<0.001). CONCLUSIONS: This study shows that the salt content of bread has been progressively reduced over time, contributing to the evidence base that a target-based approach to salt reduction can lead to reductions being made. A wide variation in salt levels was found with many products already meeting the 2012 targets, indicating that further reductions can be made. This requires further progressive lower targets to be set, so that the UK can continue to lead the world in salt reduction and save the maximum number of lives. PMID- 23794568 TI - An assessment of the iPad as a testing platform for distance visual acuity in adults. AB - OBJECTIVES: Visual acuity is a common measurement in general practice, and the advent of new technology such as tablet computers offers a change in the way in which these tests are delivered. The aim of this study was to assess whether measurements of distance visual acuity using LogMAR letter charts displayed on an iPad tablet computer were in agreement with standard clinical tests of visual acuity in adults with normal vision. DESIGN: Blinded, diagnostic test study. SETTING: Single centre (University) in Auckland, New Zealand. PARTICIPANTS: University staff and students (n=85). Participants were required to have visual acuity better than 6/60 and wear habitual refractive correction during testing. Participants were excluded if there was any history of ocular pathology. PRIMARY AND SECONDARY OUTCOME MEASURES: Visual acuity measured under a number of conditions. RESULTS: The iPad tablet with its glossy screen was highly susceptible to glare resulting in acuity measurements that were significantly poorer (approximately 2 LogMAR lines) than those made using an ETDRS chart and a standard computerised testing system (n=56). However, fitting the iPad with an antiglare screen and positioning the device away from sources creating reflected (veiling) glare resulted in acuity measurements that were equivalent those made using gold standard charts (n=29). CONCLUSIONS: Tablet computers are an attractive option for visual acuity measurement due to portability, the ability to randomise letters, automated scoring of acuity and the ability to select from a range of charts. However, these devices are only suitable for use in situations where sources of glare can be eliminated. PMID- 23794569 TI - The effects of a multisite aerobic exercise intervention on asthma morbidity in sedentary adults with asthma: the Ex-asthma study randomised controlled trial protocol. AB - OBJECTIVE: Aerobic exercise can improve cardiovascular fitness and does not seem to be detrimental to patients with asthma, though its role in changing asthma control and inflammatory profiles is unclear. The main hypothesis of the current randomised controlled trial is that aerobic exercise will be superior to usual care in improving asthma control. Key secondary outcomes are asthma quality of life and inflammatory profiles. DESIGN: A total of 104 sedentary adults with physician-diagnosed asthma will be recruited. Eligible participants will undergo a series of baseline assessments including: the asthma control questionnaire; the asthma quality-of-life questionnaire and the inflammatory profile (assessed from both the blood and sputum samples). On completion of the assessments, participants will be randomised (1:1 allocation) to either 12-weeks of usual care or usual care plus aerobic exercise. Aerobic exercise will consist of three supervised training sessions per week. Each session will consist of taking a short-acting bronchodilator, 10 min of warm-up, 40 min of aerobic exercise (50 75% of heart rate reserve for weeks 1-4, then 70-85% for weeks 5-12) and a 10 min cool-down. Within 1 week of completion, participants will be reassessed (same battery as at baseline). Analyses will assess the difference between the two intervention arms on postintervention levels of asthma control, quality of life and inflammation, adjusting for age, baseline inhaled corticosteroid prescription, body weight change and pretreatment dependent variable level. Missing data will be handled using standard multiple imputation techniques. ETHICS AND DISSEMINATION: The study has been approved by all relevant research ethics boards. Written consent will be obtained from all participants who will be able to withdraw at any time. RESULTS: The result will be disseminated to three groups of stakeholder groups: (1) the scientific and professional community; (2) the research participants and (3) the general public. REGISTRATION DETAILS CLINICALTRIALSGOV IDENTIFIER: NCT00953342. PMID- 23794570 TI - The developmental origins of ageing: study protocol for the Dutch famine birth cohort study on ageing. AB - INTRODUCTION: Evidence from animal studies suggest that the rate of ageing may be influenced not only by genetic and lifestyle factors, but also by the prenatal environment. We have previously shown that people who were exposed to famine during early gestation performed worse on a selective attention task, which may be a first sign of cognitive decline, and were on average 3 years younger at the time of coronary artery disease diagnosis. Women in this group seem to die at a younger age. We hypothesise that an accelerated ageing process, set in motion by the poor prenatal environment, underlies these findings. METHODS AND ANALYSIS: The Dutch Famine Birth Cohort consists of 2414 men and women born in Amsterdam as term singletons around the time of the Dutch famine. In a subsample of 150 cohort members, who now are about 68 years of age, we are currently measuring cognitive decline and the incidence of white matter hyperintensities and cerebral microbleeds (through MRI), incidence of fractures, grip strength and physical performance, visual acuity and incidence of cataract operations. In this same subgroup, we will assess telomere length, oxidative stress and inflammatory status as potential underlying mechanisms. Furthermore, in the entire cohort, we will assess mortality as well as hospital admissions for age-related diseases up to the age of 68 years. ETHICS AND DISSEMINATION: The study was approved by the local medical ethics committee (Academic Medical Centre, University of Amsterdam) and is being carried out in agreement with the Declaration of Helsinki. All participants give written informed consent. Study findings will be widely disseminated to the scientific public as well as to the medical society and general public. PMID- 23794571 TI - Female sex work interventions and changes in HIV and syphilis infection risks from 2003 to 2008 in India: a repeated cross-sectional study. AB - OBJECTIVES: We examined if increased spending and coverage of female sex worker (FSW) interventions were associated with declines in HIV or syphilis risk among young pregnant women (as a proxy for new infections in the general population) in the high-burden southern states of India. DESIGN: Repeated cross-sectional analysis. SETTING: We used logistic regression to relate district-level spending, number of sexually transmitted infections (STIs) treated, FSWs reached or condoms distributed to the declines in the annual risk of HIV and syphilis from 2003 to 2008 among prenatal clinic attendees in the four high-HIV burden states of Andhra Pradesh, Karnataka, Maharashtra and Tamil Nadu. PARTICIPANTS: 386 961 pregnant women aged 15-24 years (as a proxy for incident infections in the adult population). INTERVENTIONS: We examined National AIDS Control Organisation (NACO) data on 868 FSW intervention projects implemented between 1995 and 2008. PRIMARY AND SECONDARY OUTCOME MEASURES: HIV or syphilis infection. RESULTS: HIV and syphilis prevalence declined substantially among young pregnant women. Each additional STI treated (per 1000 people) reduced the annual risk of HIV infection by -1.7% (95% CI -3.3 to -0.1) and reduced the annual risk of syphilis infection by -10.9% (95%CI -15.9 to -5.8). Spending, FSWs reached or condoms distributed did not reduce HIV risk, but each was significantly associated with reduced annual risk of syphilis infection. There were no major differences between the NACO-funded and Avahan-funded districts in the annual risk of either STI. CONCLUSIONS: Targeted FSW interventions are associated with reductions in syphilis risk and STI treatment is associated with reduced HIV risk. Both more and less costly FSW interventions have comparable effectiveness. PMID- 23794572 TI - MRI and cerebrospinal fluid biomarkers for predicting progression to Alzheimer's disease in patients with mild cognitive impairment: a diagnostic accuracy study. AB - OBJECTIVES: To assess the incremental value of MRI and cerebrospinal fluid (CSF) analysis after a short memory test for predicting progression to Alzheimer's disease from a pragmatic clinical perspective. DESIGN: Diagnostic accuracy study in a multicentre prospective cohort study. SETTING: Alzheimer Disease Neuroimaging Initiative participants with complete data on neuropsychological assessment, MRI of the brain and CSF analysis. PARTICIPANTS: Patients with mild cognitive impairment (MCI; n=181) were included. Mean follow-up was 38.9 months (range 5.5-75.9). MAIN OUTCOME MEASURES: Diagnostic accuracy of individual instruments and incremental value of entorhinal cortex volume on MRI and p tau/Abeta ration in CSF after administration of Rey's Auditory Verbal Learning Memory Test are calculated and expressed as the 'Net Reclassification Improvement' (NRI), which is the change in the percentage of individuals that are correctly diagnosed as Alzheimer or non-Alzheimer case. RESULTS: Tested in isolation, a short memory test, MRI and CSF all substantially contribute to the differentiation of those MCI patients who remain stable during follow-up from those who progress to develop Alzheimer's disease. The memory test, MRI and CSF improved the diagnostic classification by 21% (95% CI 15.1 to 26.9), 22.1% (95% CI 16.1 to 28.1) and 18.8% (95% CI 13.1 to 24.5), respectively. After administration of a short memory test, however, the NRI of MRI is +1.1% (95% CI 0.1 to 3.9) and of CSF is -2.2% (95% CI -5.6 to -0.6). CONCLUSIONS: After administration of a brief test of memory, MRI or CSF do not substantially affect diagnostic accuracy for predicting progression to Alzheimer's disease in patients with MCI. The NRI is an intuitive and easy to interpret measure for evaluation of potential added value of new diagnostic instruments in daily clinical practice. PMID- 23794573 TI - Objectively measured sedentary time and physical activity in women with fibromyalgia: a cross-sectional study. AB - OBJECTIVES: To characterise levels of objectively measured sedentary time and physical activity in women with fibromyalgia. DESIGN: Cross-sectional study. SETTING: Local Association of Fibromyalgia (Granada, Spain). PARTICIPANTS: The study comprised 94 women with diagnosed fibromyalgia who did not have other severe somatic or psychiatric disorders, or other diseases that prevent physical loading, able to ambulate and to communicate and capable and willing to provide informed consent. PRIMARY OUTCOME MEASURES: Sedentary time and physical activity were measured by accelerometry and expressed as time spent in sedentary behaviours, average physical activity intensity (counts/minute) and amount of time (minutes/day) spent in moderate intensity and in moderate-to-vigorous intensity physical activity (MVPA). RESULTS: The proportion of women meeting the physical activity recommendations of 30 min/day of MVPA on 5 or more days a week was 60.6%. Women spent, on average, 71% of their waking time (approximately 10 h/day) in sedentary behaviours. Both sedentary behaviour and physical activity levels were similar across age groups, waist circumference and percentage body fat categories, years since clinical diagnosis, marital status, educational level and occupational status, regardless of the severity of the disease (all p>0.1). Time spent on moderate-intensity physical activity and MVPA was, however, lower in those with greater body mass index (BMI) (-6.6 min and -7 min, respectively, per BMI category increase, <25, 25-30, >30 kg/m(2); p values for trend were 0.056 and 0.051, respectively). Women spent, on average, 10 min less on MVPA (p<0.001) and 22 min less on sedentary behaviours during weekends compared with weekdays (p=0.051). CONCLUSIONS: These data provide an objective measure of the amount of time spent on sedentary activities and on physical activity in women with fibromyalgia. PMID- 23794574 TI - The Crohn's disease: associated ATG16L1 variant and Salmonella invasion. AB - OBJECTIVE: A common genetic coding variant in the core autophagy gene ATG16L1 is associated with increased susceptibility to Crohn's disease (CD). The variant encodes an amino acid change in ATG16L1 such that the threonine at position 300 is substituted with an alanine (ATG16L1 T300A). How this variant contributes to increased risk of CD is not known, but studies with transfected cell lines and gene-targeted mice have demonstrated that ATG16L1 is required for autophagy, control of interleukin-1-beta and autophagic clearance of intracellular microbes. In addition, studies with human cells expressing ATG16L1 T300A indicate that this variant reduces the autophagic clearance of intracellular microbes. DESIGN/RESULTS: We demonstrate, using somatically gene-targeted human cells that the ATG16L1 T300A variant confers protection from cellular invasion by Salmonella. In addition, we show that ATG16L1-deficient cells are resistant to bacterial invasion. CONCLUSIONS: These results suggest that cellular expression of ATG16L1 facilitates bacterial invasion and that the CD-associated ATG16L1 T300A variant may confer protection from bacterial infection. PMID- 23794575 TI - Lay perspectives of successful ageing: a systematic review and meta-ethnography. AB - OBJECTIVES: The aim of the current study was to conduct a systematic review of lay perspectives of successful ageing (SA), synthesise these data using a metaethnographic framework and to provide a snapshot of extant lay perspectives of SA. DESIGN: A systematic review of layperson perspectives of SA was conducted across MEDLINE, PsycInfo, CINAHL, EMBASE and ISI Web of Knowledge. PARTICIPANTS: Peer-reviewed studies conducting qualitative investigations of lay perspectives of SA were included. Included studies were coded and analysed using NVivo V.9 to examine underlying themes of SA. RESULTS: The search strategy identified 7285 articles; 26 articles met the inclusion criteria. Laypersons identified psychosocial components, notably engagement (eg, social engagement), and personal resources (eg, attitude) as integral components of SA more often than 'physiological' components, such as longevity or physical functioning. These results also highlight the profound under-representation of non-Western countries and the cultural homogeneity of research participants. CONCLUSIONS: The current study reveals the importance laypersons place on incorporating psychosocial components into multidimensional models of SA, as well as highlighting the need for increased research with under-represented populations. PMID- 23794576 TI - A 12-month incidence of exercise-related injuries in previously sedentary community-dwelling older adults following an exercise intervention. AB - OBJECTIVES: Fear of injury is reported as a barrier to exercise by older adults. However, the literature is limited in describing exercise injuries in older adults. DESIGN: This study prospectively evaluated the 12-month incidence of exercise-related injuries to community-dwelling older adults (n=167 respondents; 63 men, 104 women; mean age 69+/-5 year). METHODS: A questionnaire developed for use in older adults was administered to document self-reported injuries. Linear regression analysis was conducted to identify covariates related to injury outcomes. RESULTS: 23 people (14%) reported injuries. 41% of injuries were to the lower extremities, where the most common type was overuse muscle strains (32%, n=7). Overexertion was the most common cause of injury (n=9) and walking accounted for half of the activities during which injury occurred. 70% of injuries required medical treatment. 44% were not able to continue exercising after injury and return-to-activity time varied from 1 to 182 days. Sex, age and exercise volume were not significantly associated with injury occurrence. CONCLUSIONS: These results showed similar, or lower, exercise-related injury rates as compared with previous reports on younger and middle-aged adults; however, the definition of, and criteria for, 'injury' reporting varies in the literature. This study indicates that older adults taking up exercise are not at increased risk of injury versus younger age groups. PMID- 23794577 TI - Azithromycin and survival in Streptococcus pneumoniae pneumonia: a retrospective study. AB - OBJECTIVE: Streptococcus pneumoniae (SP) represents a major pathogen in pneumonia. The impact of azithromycin on mortality in SP pneumonia remains unclear. Recent safety concerns regarding azithromycin have raised alarm about this agent's role with pneumonia. We sought to clarify the relationship between survival and azithromycin use in SP pneumonia. DESIGN: Retrospective cohort. SETTING: Urban academic hospital. PARTICIPANTS: Adults with a diagnosis of SP pneumonia (January-December 2010). The diagnosis of pneumonia required a compatible clinical syndrome and radiographic evidence of an infiltrate. INTERVENTION: None. PRIMARY AND SECONDARY OUTCOME MEASURES: Hospital mortality served as the primary endpoint, and we compared patients given azithromycin with those not treated with this. Covariates of interest included demographics, severity of illness, comorbidities and infection-related characteristics (eg, appropriateness of initial treatment, bacteraemia). We employed logistic regression to assess the independent impact of azithromycin on hospital mortality. RESULTS: The cohort included 187 patients (mean age: 67.0+/-8.2 years, 50.3% men, 5.9% admitted to the intensive care unit). The most frequently utilised non-macrolide antibiotics included: ceftriaxone (n=111), cefepime (n=31) and moxifloxacin (n=22). Approximately two-thirds of the cohort received azithromycin. Crude mortality was lower in persons given azithromycin (5.6% vs 23.6%, p<0.01). The final survival model included four variables: age, need for mechanical ventilation, initial appropriate therapy and azithromycin use. The adjusted OR for mortality associated with azithromycin equalled 0.26 (95% CI 0.08 to 0.80, p=0.018). CONCLUSIONS: SP pneumonia generally remains associated with substantial mortality while azithromycin treatment is associated with significantly higher survival rates. The impact of azithromycin is independent of multiple potential confounders. PMID- 23794578 TI - The effect of weekly short message service communication on patient retention in care in the first year after HIV diagnosis: study protocol for a randomised controlled trial (WelTel Retain). AB - INTRODUCTION: Interventions to improve retention in care after HIV diagnosis are necessary to optimise the timely initiation of antiretroviral therapy (ART) and HIV/AIDS control outcomes. Widespread mobile phone use presents new opportunities to engage patients in care. A randomised controlled trial (RCT), WelTel Kenya1, demonstrated that weekly text messages led to improved ART adherence and viral load suppression among those initiating ART. The aim of this study was to determine whether the WelTel intervention is an effective and cost-effective method of improving retention in care in the first year of care following HIV diagnosis. METHODS AND ANALYSIS: WelTel Retain is an open, parallel group RCT that will be conducted at the Kibera Community Health Centre in Nairobi, Kenya. Over a 1-year period, we aim to recruit 686 individuals newly diagnosed with HIV who will be randomly allocated to an intervention or control arm (standard care) at a 1:1 ratio. Intervention arm participants will receive the weekly WelTel SMS 'check-in' to which they will be instructed to respond within 48 h. An HIV clinician will follow-up and triage any problems that are identified. Participants will be followed for 1 year, with a primary endpoint of retention in care at 12 months. Secondary outcomes include retention in stage 1 HIV care (patients return to the clinic to receive their first CD4 results) and timely ART initiation. Cost-effectiveness will be analysed through decision-analytic modelling. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the University of British Columbia and the African Medical and Research Foundation. This trial will test the effectiveness and cost-effectiveness of the WelTel intervention to engage patients during the first year of HIV care. Trial results and economic evaluation will help inform policy and practice on the use of WelTel in the early stages of HIV care. TRIAL REGISTRATION: ClinicalTrials.gov NCT01630304. PMID- 23794579 TI - Serum perfluoroalkyl acids concentrations and memory impairment in a large cross sectional study. AB - OBJECTIVES: To examine the cross-sectional association between serum perfluorooctanate (PFOA), perfuorooctane sulfonate (PFOS), perfluorononanoic acid (PFNA) and perfluorohexane sulfonate (PFHxS) concentrations with self-reported memory impairment in adults and the interaction of these associations with diabetes status. DESIGN: Cross-sectional study. SETTING: Population-based in Mid Ohio Valley, West Virginia following contamination by a chemical plant. PARTICIPANTS: The C8 Health Project collected data and measured the serum level of perfluoroalkyl acids (PFAAs) of 21 024 adults aged 50+ years. PRIMARY OUTCOME MEASURE: Self-reported memory impairment as defined by the question 'have experienced short-term memory loss?' RESULTS: A total of 4057 participants self reported short-term memory impairment. Inverse associations between PFOS and PFOA and memory impairment were highly statistically significant with fully adjusted OR=0.93 (95% CI 0.90 to 0.96) for doubling PFOS and OR=0.96 (95% CI 0.94 to 0.98) for doubling PFOA concentrations. Comparable inverse associations with PFNA and PFHxS were of borderline statistical significance. Inverse associations of PFAAs with memory impairment were weaker or non-existent in patients with diabetes than overall in patients without diabetes. CONCLUSIONS: An inverse association between PFAA serum levels and self-reported memory impairment has been observed in this large population-based, cross-sectional study that is stronger and more statistically significant for PFOA and PFOS. The associations can be potentially explained by a preventive anti-inflammatory effect exerted by a peroxisome proliferator-activated receptor agonist effect of these PFAAs, but confounding or even reverse causation cannot be excluded as an alternative explanation. PMID- 23794580 TI - Are depressive symptoms more common among British South Asian patients compared with British White patients with cancer? A cross-sectional survey. AB - OBJECTIVES: This cross-sectional survey investigated whether there were ethnic differences in depressive symptoms among British South Asian (BSA) patients with cancer compared with British White (BW) patients during 9 months following presentation at a UK Cancer Centre. We examined associations between depressed mood, coping strategies and the burden of symptoms. DESIGN: Questionnaires were administered to 94 BSA and 185 BW recently diagnosed patients with cancer at baseline and at 3 and 9 months. In total, 53.8% of the BSA samples were born in the Indian subcontinent, 33% in Africa and 12.9% in the UK. Three screening tools for depression were used to counter concerns about ethnic bias and validity in linguistic translation. The Hospital Anxiety and Depression Scale (HADS-D), Patient Health Questionnaire-9 (both validated in Gujarati), Emotion Thermometers (including the Distress Thermometer (DT), Mini-MAC and the newly developed Cancer Insight and Denial questionnaire (CIDQ) were completed. SETTING: Leicestershire Cancer Centre, UK. PARTICIPANTS: 94 BSA and 185 BW recently diagnosed patients with cancer. RESULTS: BSA self-reported significantly higher rates of depressive symptoms compared with BW patients longitudinally (HADS-D >=8: baseline: BSA 35.1% vs BW 16.8%, p=0.001; 3 months BSA 45.6% vs BW 20.8%, p=0.001; 9 months BSA 40.6% vs BW 15.3%, p=0.004). BSA patients used potentially maladaptive coping strategies more frequently than BW patients at baseline (hopelessness/helplessness p=0.005, fatalism p=0.0005, avoidance p=0.005; the CIDQ denial statement 'I do not really believe I have cancer' p=0.0005). BSA patients experienced more physical symptoms (DT checklist), which correlated with ethnic differences in depressive symptoms especially at 3 months. CONCLUSIONS: Health professionals need to be aware of a greater probability of depressive symptomatology (including somatic symptoms) and how this may present clinically in the first 9 months after diagnosis if this ethnic disparity in mental well being is to be addressed. PMID- 23794581 TI - What are the factors associated with HIV testing among male injecting and non injecting drug users in Lashio, Myanmar: a cross-sectional study. AB - OBJECTIVES: HIV testing is an effective intervention for reducing HIV risk and providing information on HIV status. However, uptake of HIV testing is a major challenge within the drug-using population due to the stigma and discrimination associated with their illegal drug use behaviours. This study thus aimed to identify factors associated with HIV testing among injecting drug users (IDUs) and non-injecting drug users (NIDUs) in Lashio, Myanmar. DESIGN: A cross sectional study was conducted from January 2010 to February 2010. SETTING: This study was carried out in Lashio city, Northern Shan State, Myanmar. PARTICIPANTS: In total, 158 male IDUs and 210 male NIDUs were recruited using a respondent driven sampling method. PRIMARY OUTCOME MEASURES: Proportion of both drug users who were ever tested for HIV and factors associated with HIV testing. RESULTS: Approximately 77% of IDUs and 46% of NIDUs were ever tested for HIV. The multivariate analysis revealed that having ever received drug treatment was positively associated with HIV testing among both IDUs (adjusted OR (AOR) 13.07; 95% CI 3.38 to 50.53) and NIDUs (AOR 3.58; 95% CI 1.38 to 9.24). IDUs who were married (AOR 0.24; 95% CI 0.06 to 0.94) and who injected at least twice daily (AOR 0.30; 95% CI 0.09 to 0.97) were less likely to undergo HIV testing. Among NIDUs, those who belonged to Shan (AOR 0.30; 95% CI 0.11 to 0.84) or Kachin (AOR 0.30; 95% CI 0.10 to 0.87) ethnicities were less likely to test for HIV. CONCLUSIONS: IDUs and NIDUs who have received drug treatment are more likely to test for HIV. Integrating HIV testing into drug treatment programmes alongside general expansion of HIV testing services may be effective in increasing HIV testing uptake among both IDUs and NIDUs in the Northern Shan State of Myanmar. PMID- 23794582 TI - Results from the Upper Limb International Spasticity Study-II (ULISII):a large, international, prospective cohort study investigating practice and goal attainment following treatment with botulinum toxin A in real-life clinical management. AB - OBJECTIVE: To describe real-life practice and person-centred outcomes in the treatment of poststroke upper limb spasticity with botulinum toxin A (BoNT-A). DESIGN: Observational, prospective study. SETTING: 84 secondary care centres in 22 countries. PARTICIPANTS: 456 adults (>=18 years) with poststroke upper limb spasticity treated with one cycle of BoNT-A. METHODS/OUTCOMES: Muscle selection, BoNT-A preparation, injection technique and timing of follow-up were conducted according to routine practice for each centre. PRIMARY OUTCOME: achievement of the patient's primary goal for treatment using goal-attainment scaling (GAS). Measurements of spasticity, standardised outcome measures and global benefits were also recorded. RESULTS: The median number of injected muscles was 5 (range 1 15) and the most frequently injected muscles were the long finger flexors, followed by biceps and brachioradialis. The median (range) follow-up time was 14 (2.6 to 32.3) weeks. The common primary treatment goals were passive function (132 (28.9%)), active function (104 (22.8%)), pain (61 (13.4%)), impairment (105 (23%)), involuntary movement (41 (9%)) and mobility (10 (2.2%)). Overall, 363 (79.6%) (95% CI 75.6% to 83.2%) patients achieved (or overachieved) their primary goal and 355 (75.4%) (95% CI 71.2% to 79.2%) achieved their secondary goal. Mean (SD) change from baseline in GAS T-scores was 17.6 (11.0) (95% CI 16.4 to 18.8; p<0.001). GAS T-scores were strongly correlated with global benefit and other standard measures (correlations of 0.38 and 0.63, respectively; p<0.001). CONCLUSIONS: BoNT-A demonstrated a clinically significant effect on goal attainment for the real-life management of upper-limb spasticity following stroke. The study confirms the feasibility of a common international data set to collect systematic prospective data, and of using GAS to capture person-centred outcomes relating to passive and active functions and to pain. REGISTRATION: ClinicalTrials.gov identifier: NCT01020500. PMID- 23794583 TI - The long-term effects of occupational exposure to vinyl chloride monomer on microcirculation: a cross-sectional study 15 years after retirement. AB - OBJECTIVES: To assess residual long-term microcirculation abnormalities by capillaroscopy, 15 years after retiring from occupational exposure to vinyl chloride monomer (VCM). DESIGN: Cross-sectional study. SETTING: Allier, one of the major areas of polyvinyl chloride production in France. PARTICIPANTS: We screened 761 (97% men) retired workers exposed to chemical toxics. Exposure to chemicals other than VCM excluded potential participants. PRIMARY AND SECONDARY OUTCOME MEASURES: These participants underwent a medical examination including a capillaroscopy, symptoms of Raynaud and comorbidities, as well as a survey to determine exposure time, direct or indirect contact, type of occupation, smoking status and time after exposure. A double blind analysis of capillaroscopic images was carried out. A control group was matched in age, sex, type of occupation. RESULTS: 179/761 retired workers were only exposed to VCM at their work, with 21 meeting the inclusion criteria and included. Exposure time was 29.8+/-1.9 years and time after exposure was 15.9+/-2.4 years. Retired workers previously exposed to VCM had significantly higher capillaroscopic modifications than the 35 controls: enlarged capillaries (19% vs 0%, p<0.001), dystrophy (28.6% vs 0%, p=0.0012) and augmented length (33% vs 0%, p<0.001). Time exposure was linked (p<0.001) with enlarged capillaries (R(2)=0.63), dystrophy (R(2)=0.51) and capillary length (R(2)=0.36). They also had higher symptoms of Raynaud (19% vs 0%, p=0.007) without correlation with capillaroscopic modifications. CONCLUSIONS: Although VCM exposure was already known to affect microcirculation, our study demonstrates residual long-term abnormalities following an average of 15 years' retirement, with a time-related exposure response. Symptoms of Raynaud, although statistically associated with exposure, were not related to capillaroscopic modifications; its origin remains to be determined. PMID- 23794584 TI - Characteristics of paid malpractice claims settled in and out of court in the USA: a retrospective analysis. AB - OBJECTIVE: An analysis of paid malpractice claims judged in court compared with those settled out of court may help explain perceptions of malpractice risk. DESIGN: A retrospective analysis and cross-sectional comparison of malpractice claims. Evaluated trends in the number and proportion of paid claims, and mean payment amount by resolution type; identified patient, physician and claim characteristics associated with each resolution type. Examined the effects of resolution type on payment amount and time to claim resolution. SETTING: Claims paid on behalf of US physicians reported in the National Practitioner Data Bank (NPDB) from 2005 to 2009. MAIN OUTCOME MEASURES: Type of resolution, claim characteristics, payment amount and time to resolution. RESULTS: Between 2005 and 2009, there were 58 667 claims paid on behalf of US physicians. Of these paid claims, 56 850 (96.9%) were settled outside court, and 1817 (3.1%) were judged in court. There was no significant change in the proportion of paid claims resolved by settlement versus judgement over time (p=0.83); nor was there a significant change in the mean payment amount in either resolution group (settlement, p=0.94; judgement, p=0.36). The claims in which the physicians were under 50, had prior malpractice reports, which were paid by a state malpractice programme, for adverse events to a fetus, and for surgical or obstetric error were more likely to be judged in court. The mean payment amount (US$592 283 vs US$317 447, p<0.01), per cent of payments over US$1 million (41.82% vs 15.43%, p<0.01), and time to decision (6.50 years vs 4.93 years, p<0.01) were significantly higher in judged claims. CONCLUSIONS: Although only a very small percentage of paid malpractice claims in the USA are judged in court, a number of characteristics differ between settled and judged claims. Such differences may influence perceptions of malpractice risk and future reform efforts. PMID- 23794585 TI - Genotyping Chlamydia trachomatis strains among men who have sex with men from a Northern Spain region: a cohort study. AB - OBJECTIVES: To determine the prevalence of anorectal Chlamydia trachomatis serovars in a group of men who have sex with men (MSM) with high risk sexual behaviour, attendees at a sexually transmitted infection (STI) unit from a region in Northwest Spain. DESIGN: Retrospective and descriptive study of all swabs obtained from all MSM attendees at an STI unit, from 2007 to 2011. Retrospective ethical approval was granted by the Ethical Regional Committee of Clinical Investigation of the Principality of Asturias. SETTING: The STI clinic in Oviedo, Spain, offers screening and free-of-charge treatment to about 3646 patients per year. PARTICIPANTS: 303 symptomatic and asymptomatic consecutive and unselected MSM patients (mean age 36.7 and range 21-55 years) were evaluated for anorectal chlamydial infection. MAIN OUTCOME MEASURES: C trachomatis DNA extraction and detection in all rectal and in 36 urethral swabs. Characterisation of C trachomatis genotypes through sequencing of ompA gene amplicons and further phylogenetic tree analysis. RESULTS: We found 40 (13. 2%) positive rectal samples. The distribution of genotypes was E (37. 5%) followed by G (25%), D (12. 5%), J (10%) and L2b (5%).25 (62.5%, 95% CI 46.2 to 78.7) of the chlamydia infected MSM showed clinical manifestations while 15 (37.5%, 95% CI 21.25 to 53.75) reported no symptoms. Concurrent infection with other STIs was documented in 27 (67.5%, 95% CI 51.7 to 83.2) patients. The most frequently reported clinical symptom was anal ulcer (7 cases, 17.5%; 95% CI 4.47 to 30.52). E genotype was mostly detected in asymptomatic patients. There were non-E genotypes detected in 21 (84%, 95% CI 63.9 to 95.5) of 25 symptomatic patients (p<0.001). CONCLUSIONS: The first two confirmed cases of lymphogranuloma venereum (LGV) in MSM in Asturias are reported, probably indicating the increase of this infection. The Spanish C trachomatis laboratory-based surveillance system may underlie an underestimated number of chlamydial infections. Whenever mild and atypical symptoms exist, laboratory evaluation would contribute to the early implementation of appropriate therapy and prevent LGV dissemination. PMID- 23794586 TI - Vitamin C may alleviate exercise-induced bronchoconstriction: a meta-analysis. AB - OBJECTIVE: To determine whether vitamin C administration influences exercise induced bronchoconstriction (EIB). DESIGN: Systematic review and meta-analysis. METHODS: MEDLINE and Scopus were searched for placebo-controlled trials on vitamin C and EIB. The primary measures of vitamin C effect used in this study were: (1) the arithmetic difference and (2) the relative effect in the postexercise forced expiratory volume in 1 s (FEV1) decline between the vitamin C and placebo periods. The relative effect of vitamin C administration on FEV1 was analysed by using linear modelling for two studies that reported full or partial individual-level data. The arithmetic differences and the relative effects were pooled by the inverse variance method. A secondary measure of the vitamin C effect was the difference in the proportion of participants suffering from EIB on the vitamin C and placebo days. RESULTS: 3 placebo-controlled trials that studied the effect of vitamin C on EIB were identified. In all, they had 40 participants. The pooled effect estimate indicated a reduction of 8.4 percentage points (95% CI 4.6 to 12) in the postexercise FEV1 decline when vitamin C was administered before exercise. The pooled relative effect estimate indicated a 48% reduction (95% CI 33% to 64%) in the postexercise FEV1 decline when vitamin C was administered before exercise. One study needed imputations to include it in the meta-analyses, but it also reported that vitamin C decreased the proportion of participants who suffered from EIB by 50 percentage points (95% CI 23 to 68); this comparison did not need data imputations. CONCLUSIONS: Given the safety and low cost of vitamin C, and the positive findings for vitamin C administration in the three EIB studies, it seems reasonable for physically active people to test vitamin C when they have respiratory symptoms such as cough associated with exercise. Further research on the effects of vitamin C on EIB is warranted. PMID- 23794587 TI - Identification of acute myocardial infarction from electronic healthcare records using different disease coding systems: a validation study in three European countries. AB - OBJECTIVE: To evaluate positive predictive value (PPV) of different disease codes and free text in identifying acute myocardial infarction (AMI) from electronic healthcare records (EHRs). DESIGN: Validation study of cases of AMI identified from general practitioner records and hospital discharge diagnoses using free text and codes from the International Classification of Primary Care (ICPC), International Classification of Diseases 9th revision-clinical modification (ICD9 CM) and ICD-10th revision (ICD-10). SETTING: Population-based databases comprising routinely collected data from primary care in Italy and the Netherlands and from secondary care in Denmark from 1996 to 2009. PARTICIPANTS: A total of 4 034 232 individuals with 22 428 883 person-years of follow-up contributed to the data, from which 42 774 potential AMI cases were identified. A random sample of 800 cases was subsequently obtained for validation. MAIN OUTCOME MEASURES: PPVs were calculated overall and for each code/free text. 'Best-case scenario' and 'worst-case scenario' PPVs were calculated, the latter taking into account non-retrievable/non-assessable cases. We further assessed the effects of AMI misclassification on estimates of risk during drug exposure. RESULTS: Records of 748 cases (93.5% of sample) were retrieved. ICD-10 codes had a 'best-case scenario' PPV of 100% while ICD9-CM codes had a PPV of 96.6% (95% CI 93.2% to 99.9%). ICPC codes had a 'best-case scenario' PPV of 75% (95% CI 67.4% to 82.6%) and free text had PPV ranging from 20% to 60%. Corresponding PPVs in the 'worst case scenario' all decreased. Use of codes with lower PPV generally resulted in small changes in AMI risk during drug exposure, but codes with higher PPV resulted in attenuation of risk for positive associations. CONCLUSIONS: ICD9-CM and ICD-10 codes have good PPV in identifying AMI from EHRs; strategies are necessary to further optimise utility of ICPC codes and free-text search. Use of specific AMI disease codes in estimation of risk during drug exposure may lead to small but significant changes and at the expense of decreased precision. PMID- 23794588 TI - Variation in severe maternal morbidity according to socioeconomic position: a UK national case-control study. AB - OBJECTIVES: This study aimed to explore the independent association between socioeconomic position, defined by occupation, and severe maternal morbidity among women in the UK. DESIGN: Case-control study. SETTING: The analysis was conducted as a case-control analysis, using data from a series of studies of direct causes of severe maternal morbidity undertaken through the UK Obstetric Surveillance System (UKOSS), with data collected throughout all consultant-let obstetric units in the UK. PARTICIPANTS: The analysis included 1144 cases and 2256 comparison women (controls). UKOSS studies from which data on case women were obtained included amniotic fluid embolism, acute fatty liver of pregnancy, eclampsia, peripartum hysterectomy, therapies for peripartum haemorrhage and uterine rupture. PRIMARY OUTCOME MEASURE: Odds of severe maternal morbidity by socioeconomic group, independent of ethnicity, maternal age, smoking, pre existing medical condition, body mass index (BMI), multiple pregnancy and past pregnancy complications. Occupation was used to classify different socioeconomic groups. SECONDARY OUTCOME MEASURE: Odds of morbidity related to ethnic group, maternal age, smoking, pre-existing medical condition, BMI, multiple pregnancy and past pregnancy complications. RESULTS: Across the socioeconomic groups, compared with the 'managerial/professional' group, adjusted ORs were 1.17 (95% CI 0.94 to 1.45) for the 'intermediate group', 1.16 (95% CI 0.93 to 1.45) for 'routine/manual', 1.22 (95% CI 0.92 to 1.61) for 'unemployed' women and 1.51 (95% CI 1.18 to 1.94) for women with missing socioeconomic information. Women of non white ethnicity, older maternal age (>=35 years), BMI >=25 kg/m(2) and those with pre-existing medical condition/s, multiple pregnancy or past pregnancy complications were shown to have a significantly increased odds of severe maternal morbidity. CONCLUSIONS: This study suggests that socioeconomic position may be independently associated with an increased risk of severe maternal morbidity, although the observed association was not statistically significant. Further research is warranted to confirm this and investigate why this association might exist in a country where healthcare is universal and free at the point of access. PMID- 23794589 TI - Violence, HIV risk behaviour and depression among female sex workers of eastern Nepal. AB - OBJECTIVES: The primary objective of the study was to estimate the prevalence of depression among female sex workers (FSWs) of eastern Nepal. The secondary objective was to search for an association between depression, violence and HIV risk behaviour. DESIGN: Cross-sectional/observational study. STUDY SETTING: This study was carried out in five cities of eastern Nepal (Dharan, Itahari, Biratnagar, Damak and Birtamode). Both restaurant-based and street-based FSWs were recruited in the study. PARTICIPANTS: Women who had been involved in commercial sex activity in the past 6 months and gave informed consent were included in the study. PRIMARY OUTCOME MEASURE: A score of more than or equal to 16 on the Centre for Epidemiological Studies Depression (CESD) scale was considered as depression. METHODOLOGY: Face-to-face interviews were conducted with respondents who were sought through a snowball sampling technique. Information regarding their depression status, HIV high-risk behaviour and violence was recorded. The estimated sample size was 210. RESULTS: We interviewed 210 FSWs (both restaurant-based and street-based). The prevalence of depression among respondents was 82.4%. FSWs who had experienced violence were five times more likely to be depressed than those who were not victims of violence. The odds of depression were six times higher among respondents who were involved in any HIV risk behaviour compared with those who were not involved. CONCLUSIONS: The present study reports a high prevalence of depression, HIV risk behaviours and violence among FSWs of eastern Nepal. The mental health of FSWs should also be regarded as an important aspect of HIV prevention efforts which can help to promote the overall health of this population. PMID- 23794590 TI - Factors associated with breastfeeding in England: an analysis by primary care trust. AB - OBJECTIVES: To identify the sociodemographic factors associated with variation in area-based breastfeeding in England; to calculate the predicted breastfeeding rates adjusted for sociodemographic variations. DESIGN: Ecological analysis of routine data using random effects logistic regression. SETTING: All 151 primary care trusts (PCTs) in England 2010-2011. OUTCOME MEASURES: PCT level data on breastfeeding: initiation, any and exclusive breastfeeding at 6-8 weeks. RESULTS: There was considerable variation in breastfeeding across PCTs (breastfeeding initiation mean 72%, range 39-93%; any breastfeeding at 6-8 weeks mean 45%, range 19-83%; exclusive breastfeeding at 6-8 weeks mean 32%, range 14-58%), with London PCTs reporting markedly higher rates. Maternal age was strongly associated with area-based breastfeeding, with a 4-6% increase in odds of breastfeeding associated with a unit increase in the percentage of older mothers. Outside London, the proportion of the local population from a Black and Minority Ethnic (BME) background, compared with those from a White British background, was associated with higher breastfeeding (1-3% increase in odds per unit increase in the proportion from a BME background). Area-based deprivation was associated with reduced odds of breastfeeding (21-32% reduced odds comparing most deprived quintile to least deprived quintile). Weaker associations were observed between sociodemographic factors and breastfeeding in London PCTs. Very few PCTs reported breastfeeding figures substantially above or below the national average, having adjusted for variations in sociodemographic factors. CONCLUSIONS: Our results show striking associations between sociodemographic factors and breastfeeding at the area level, with much of the variation in breastfeeding rates explained by the sociodemographic profile. The sociodemographic context of breastfeeding is clearly important at the area level as well as the individual level. Our findings can be used to inform decision-making relating to local priorities and service provision. PMID- 23794591 TI - Costs of surgical procedures in Indian hospitals. AB - OBJECTIVE: Despite a growing volume of surgical procedures in low-income and middle-income countries, the costs of these procedures are not well understood. We estimated the costs of 12 surgical procedures commonly conducted in five different types of hospitals in India from the provider perspective, using a microcosting method. DESIGN: Cost and utilisation data were collected retrospectively from April 2010 to March 2011 to avoid seasonal variability. SETTING: For this study, we chose five hospitals of different types: a 57-bed charitable hospital, a 200-bed private hospital, a 400-bed district hospital, a 655-bed private teaching hospital and a 778-bed tertiary care teaching hospital based on their willingness to cooperate and data accessibility. The hospitals were from four states in India. The private, charitable and tertiary care hospitals serve urban populations, the district hospital serves a semiurban area and the private teaching hospital serves a rural population. RESULTS: Costs of conducting lower section caesarean section ranged from rupees 2469 to 41 087; hysterectomy rupees 4124 to 57 622 and appendectomy rupees 2421 to 3616 (US$1=rupees 52). We computed the costs of conducting lap and open cholecystectomy (rupees 27 732 and 44 142, respectively); hernia repair (rupees 13 204); external fixation (rupees 8406); intestinal obstruction (rupees 6406); amputation (rupees 5158); coronary artery bypass graft (rupees 177 141); craniotomy (rupees 75 982) and functional endoscopic sinus surgery (rupees 53 398). CONCLUSIONS: Estimated costs are roughly comparable with rates of reimbursement provided by the Rashtriya Swasthya Bima Yojana (RSBY)-India's government-financed health insurance scheme that covers 32.4 million poor families. Results from this type of study can be used to set and revise the reimbursement rates. PMID- 23794592 TI - Effect of occupation on risk of developing MS: an insurance cohort study. AB - OBJECTIVE: The aim of this study was to estimate the occupational risks in relation to multiple sclerosis (MS). The immediate background for this research was our finding that there had been a high number of critical illness insurance claims by patients diagnosed with MS within the agricultural segment of a Danish pension fund. DESIGN: An open insurance cohort. All payouts for the critical illness insurance from 2002 to 2011 were continuously registered. SETTINGS: PensionDanmark; one of Denmark's largest pension funds. PARTICIPANTS: PensionDanmark insures more than 300 000 members of the Danish Confederation of Trade Unions against critical illness. All members are insured, and all policies are identical. The total exposure is 3.3 million person-years. PRIMARY OUTCOME MEASURES: The incidence of MS. RESULTS: During the 10-year period, 389 persons were diagnosed with MS. The crude incidence rate for men was 10.2/100 000; the corresponding figure for women was 16.1/100 000. We found signs of an overall effect of occupation on the risk of developing MS, and the high frequency found within the agricultural segment was attributed to dairy operators, who had an incidence of MS 2.0 times higher than the rest of the study's population (95% CI=1.2 to 3.0). CONCLUSIONS: Our results indicate some occupational risk factors in MS, and this should be investigated further. PMID- 23794593 TI - Evidence of overtesting for vitamin D in Australia: an analysis of 4.5 years of Medicare Benefits Schedule (MBS) data. AB - OBJECTIVE: To comprehensively examine pathology test utilisation of 25 hydroxyvitamin D (25(OH)D) testing in each state of Australia to determine the cost impact and value and to add evidence to enable the development of vitamin D testing guidelines. DESIGN: Longitudinal analysis of all 25(OH)D pathology tests in Australia. SETTING: Primary and Tertiary Care. MEASUREMENTS: The frequency of 25(OH)D testing between 1 April 2006 and 30 October 2010 coded for each individual by provider, state and month between 2006 and 2010. Rate of tests per 100 000 individuals and benefit for 25(OH)D, full blood count (FBC) and bone densitometry by state and quarter between 2000 and 2010. RESULTS: 4.5 million tests were performed between 1 April 2006 and 30 October 2010. 42.9% of individuals had more than one test with some individuals having up to 79 tests in that period. Of these tests, 80% were ordered by general practitioners and 20% by specialists. The rate of 25(OH)D testing increased 94-fold from 2000 to 2010. Rate varied by state whereby the most southern state represented the highest increase and northern state the lowest increase. In contrast, the rate of a universal pathology test such as FBC remained relatively stable increasing 2.5 fold. Of concern, a 0.5-fold (50%) increase in bone densitometry was seen. CONCLUSIONS: The marked variation in the frequency of testing for vitamin D deficiency indicates that large sums of potentially unnecessary funds are being expended. The rate of 25(OH)D testing increased exponentially at an unsustainable rate. Consequences of such findings are widespread in terms of cost and effectiveness. Further research is required to determine the drivers and cost benefit of such expenditure. Our data indicate that adoption of specific guidelines may improve efficiency and effectiveness of 25(OH)D testing. PMID- 23794594 TI - What is the best strategy for investigating abnormal liver function tests in primary care? Implications from a prospective study. AB - OBJECTIVE: Evaluation of predictive value of liver function tests (LFTs) for the detection of liver-related disease in primary care. DESIGN: A prospective observational study. SETTING: 11 UK primary care practices. PARTICIPANTS: Patients (n=1290) with an abnormal eight-panel LFT (but no previously diagnosed liver disease). MAIN OUTCOME MEASURES: Patients were investigated by recording clinical features, and repeating LFTs, specific tests for individual liver diseases, and abdominal ultrasound scan. Patients were characterised as having: hepatocellular disease; biliary disease; tumours of the hepato-biliary system and none of the above. The relationship between LFT results and disease categories was evaluated by stepwise regression and logistic discrimination, with adjustment for demographic and clinical factors. True and False Positives generated by all possible LFT combinations were compared with a view towards optimising the choice of analytes in the routine LFT panel. RESULTS: Regression methods showed that alanine aminotransferase (ALT) was associated with hepatocellular disease (32 patients), while alkaline phosphatase (ALP) was associated with biliary disease (12 patients) and tumours of the hepatobiliary system (9 patients). A restricted panel of ALT and ALP was an efficient choice of analytes, comparing favourably with the complete panel of eight analytes, provided that 48 False Positives can be tolerated to obtain one additional True Positive. Repeating a complete panel in response to an abnormal reading is not the optimal strategy. CONCLUSIONS: The LFT panel can be restricted to ALT and ALP when the purpose of testing is to exclude liver disease in primary care. PMID- 23794595 TI - The effect of multiple chronic conditions on self-rated health, disability and quality of life among the older populations of Northern Ireland and the Republic of Ireland: a comparison of two nationally representative cross-sectional surveys. AB - OBJECTIVES: Multimorbidity is common in the older population, but the impact of combinations of chronic conditions on disability and quality of life (QoL) is not well known. This analysis explores the effect of specific combinations of chronic diseases on disability, QoL and self-rated health (SRH). DESIGN: We used data from two population representative cross-sectional studies, the Northern Ireland Health and Social Wellbeing Survey (NIHSWS) 2005 and the Survey of Lifestyle, Attitudes and Nutrition (SLAN) 2007 (conducted in the Republic of Ireland). SETTING: Randomly selected community-living participants were interviewed at home. PARTICIPANTS: A total of 6159 participants aged 50 years and older were included in the analysis. OUTCOME MEASURES: Chronic conditions were classified as cardiovascular disease, chronic pain, diabetes or respiratory disease. Interaction terms estimated by logistic regression were used to examine the effects of multiple chronic conditions on disability, SRH and QoL. RESULTS: Each chronic condition group was correlated with each of the others after adjusting for sociodemographic factors. Those from Northern Ireland were more likely to report a limitation in daily activities (45%) compared to those from the Republic of Ireland (21%). Each condition had an independent effect on disability, SRH and QoL, and those with multiple chronic conditions reported the worst outcomes. However, there were no statistically significant positive interactions between chronic condition groups with respect to any outcome. CONCLUSIONS: Chronic conditions affect individuals largely independent of each other with respect to their effect on disability, SRH and QoL. However, a significant proportion of the population aged 50 years and over across the island of Ireland lives with multimorbidity, and this group is at the highest risk of disability, poor SRH and poor QoL. PMID- 23794596 TI - Gender differences in the association of individual social class and neighbourhood unemployment rate with prevalent type 2 diabetes mellitus: a cross sectional study from the DIAB-CORE consortium. AB - OBJECTIVE: To analyse gender differences in the relationship of individual social class, employment status and neighbourhood unemployment rate with present type 2 diabetes mellitus (T2DM). DESIGN: Five cross-sectional studies. SETTING: Studies were conducted in five regions of Germany from 1997 to 2006. PARTICIPANTS: The sample consisted of 8871 individuals residing in 226 neighbourhoods from five urban regions. PRIMARY AND SECONDARY OUTCOME MEASURES: Prevalent T2DM. RESULTS: We found significant multiplicative interactions between gender and the individual variables--social class and employment status. Social class was statistically significantly associated with T2DM in men and women, whereby this association was stronger in women (lower vs higher social class: OR 2.68 (95% CIs 1.66 to 4.34)) than men (lower vs higher social class: OR 1.78 (95% CI 1.22 to 2.58)). Significant associations of employment status and T2DM were only found in women (unemployed vs employed: OR 1.73 (95% CI 1.02 to 2.92); retired vs employed: OR 1.77 (95% CI 1.10 to 2.84); others vs employed: OR 1.64 (95% CI 1.01 to 2.67)). Neighbourhood unemployment rate was associated with T2DM in men (high vs low tertile: OR 1.52 (95% CI 1.18 to 1.96)). Between-study and between neighbourhood variations in T2DM prevalence were more pronounced in women. The considered covariates helped to explain statistically the variation in T2DM prevalence among men, but not among women. CONCLUSIONS: Social class was inversely associated with T2DM in both men and women, whereby the association was more pronounced in women. Employment status only affected T2DM in women. Neighbourhood unemployment rate is an important predictor of T2DM in men, but not in women. PMID- 23794597 TI - Does smoking cessation with varenicline worsen vascular endothelial function? AB - OBJECTIVES: A meta-analysis suggested that the use of varenicline, which is a partial agonist of nicotinic acetylcholine receptors and is effective in smoking cessation, increases the risk of cardiovascular events within 52 weeks of starting treatment. Defining these events as occurring during drug treatment (usually for 12 weeks) or within 30 days of discontinuation, another meta analysis showed that the risk was statistically insignificant. In the present study, we aimed to clarify the effect of varenicline-assisted smoking cessation on vascular endothelial function assessed by flow-mediated vasodilation (FMD). DESIGN: Before-after and time-series. SETTING: Tochigi Prefecture, Japan. PARTICIPANTS: Data of 85 participants who visited nicotine-dependent outpatient services were reviewed. FMD was repeatedly measured in 33 of the 85 participants. INCLUSION CRITERIA: 20 years and older, Brinkman index >=200, Tobacco Dependence Screener >=5 and stated motivation to quit smoking. INTERVENTIONS: Each participant was treated with varenicline titrated up to 1.0 mg twice daily (for 12 weeks in total). PRIMARY AND SECONDARY OUTCOME MEASURES: Participants were evaluated by FMD prior to, and 3 months after, complete smoking cessation. Follow up FMD measurements were carried out every 3 months if possible. Changes in FMD during varenicline use were also evaluated. RESULTS: FMD was significantly increased from 4.0+/-1.8% to 5.5+/-2.2% (p<0.01, n=22) 3 months after complete cessation. Although the timecourse of FMD in most of the cases showed an increase with fluctuations, there was an exceptional case where FMD decreased over the 9 months following complete cessation. Although statistically insignificant, FMD also increased during varenicline use (from 3.7+/-2.7% to 4.3+/-2.8%, n=11). CONCLUSIONS: Our observations suggest that in ceasing smokers, varenicline and smoking cessation do not lead to a worsening of the vascular endothelial function. TRIAL REGISTRATION: FK-79 (International University of Health and Welfare). PMID- 23794598 TI - Effects of amphotericin B on Aspergillus flavus clinical isolates with variable susceptibilities to the polyene in an experimental model of systemic aspergillosis. AB - OBJECTIVES: The aim of the present study was to evaluate the effects of amphotericin B (AMB) on clinical isolates of Aspergillus flavus. METHODS: MICs of both standard AMB and liposomal AMB (L-AMB) were determined using a broth dilution method for seven isolates of A. flavus. AMB MICs were also determined using the Etest. The activity of the polyene was then investigated in a murine model of systemic aspergillosis in which animals were infected intravenously, treated intravenously with several doses of the polyene (1-10 mg/kg/day) and observed for survival. RESULTS: Broth dilution AMB, broth dilution L-AMB and Etest AMB MICs ranged from 0.5 to 2.0 mg/L, 0.06 to >16 mg/L and 1.0 to >32 mg/L, respectively. There were two isolates for which all doses were effective at prolonging the survival. Their AMB MICs were <=1.0 mg/L, regardless of the method/drug formulation utilized for testing. There were four isolates for which no regimen was effective. Their broth dilution AMB, broth dilution L-AMB and Etest AMB MICs ranged from 1.0 to 2.0 mg/L, 0.06 to >16 mg/L and 2.0 to >32 mg/L, respectively. There was one isolate for which only L-AMB given at 10 mg/kg/day was effective; broth dilution MICs of AMB and L-AMB were 0.5 mg/L, while the Etest MIC of AMB was 2.0 mg/L. CONCLUSIONS: Our data indicate that not all isolates of A. flavus should be considered resistant to AMB. The Etest represented the in vitro method that best correlated with the experimental infection. Finally, a clinical isolate showing an MIC >=2.0 mg/L may be reasonably considered resistant in vivo to any dose/formulation of the polyene. PMID- 23794599 TI - Cefazolin high-inoculum effect in methicillin-susceptible Staphylococcus aureus from South American hospitals. AB - OBJECTIVES: Clinical failures with cefazolin have been described in high-inoculum infections caused by methicillin-susceptible Staphylococcus aureus (MSSA) producing type A beta-lactamase. We investigated the prevalence of the cefazolin inoculum effect (InE) in MSSA from South American hospitals, since cefazolin is used routinely against MSSA due to concerns about the in vivo efficacy of isoxazolyl penicillins. METHODS: MSSA isolates were recovered from bloodstream (n = 296) and osteomyelitis (n = 68) infections in two different multicentre surveillance studies performed in 2001-02 and 2006-08 in South American hospitals. We determined standard-inoculum (10(5)cfu/mL) and high-inoculum (10(7) cfu/mL) cefazolin MICs. PFGE was performed on all isolates that exhibited a cefazolin InE. Multilocus sequence typing (MLST) and sequencing of part of blaZ were performed on representative isolates. RESULTS: The overall prevalence of the cefazolin InE was 36% (131 isolates). A high proportion (50%) of MSSA isolates recovered from osteomyelitis infections exhibited the InE, whereas it was observed in 33% of MSSA recovered from bloodstream infections. Interestingly, Ecuador had the highest prevalence of the InE (45%). Strikingly, 63% of MSSA isolates recovered from osteomyelitis infections in Colombia exhibited the InE. MLST revealed that MSSA isolates exhibiting the InE belonged to diverse genetic backgrounds, including ST5, ST8, ST30 and ST45, which correlated with the prevalent methicillin-resistant S. aureus clones circulating in South America. Types A (66%) and C (31%) were the most prevalent beta-lactamases. CONCLUSIONS: Our results show a high prevalence of the cefazolin InE associated with type A beta-lactamase in MSSA isolates from Colombia and Ecuador, suggesting that treatment of deep-seated infections with cefazolin in those countries may be compromised. PMID- 23794600 TI - An engineered HIV-1 gp41 trimeric coiled coil with increased stability and anti HIV-1 activity: implication for developing anti-HIV microbicides. AB - OBJECTIVES: We previously constructed a trimeric coiled coil, N28Fd, based on the N-heptad repeat (NHR) sequence of HIV-1 gp41, as a promising HIV-1 entry inhibitor. Here, we attempted to engineer a stabilized trimeric coiled coil, ccN28Fd, by adding interchain disulphide bonds at the N terminus of N28Fd to improve its biophysical properties and anti-HIV-1 efficacy. METHODS: Molecular biology techniques were applied to engineer ccN28Fd. Circular dichroism and sedimentation velocity analysis were used to determine its secondary structure and thermostability and polymeric states, respectively. The anti-HIV-1 activity was assessed by p24 or luciferase expression. Its cytotoxicity was evaluated by XTT assay. RESULTS: At low pH, ccN28Fd and N28Fd were in trimeric and monomeric conformation, respectively. ccN28Fd showed higher thermostability and much stronger antiviral activity against HIV-1 IIIB (X4) and Bal (R5) strains than N28Fd. ccN28Fd was effective in inhibiting infection by a broad spectrum of primary HIV-1 isolates and enfuvirtide-resistant strains and blocking cell-to cell HIV-1 transmission. A combination of ccN28Fd with tenofovir, a nucleoside reverse transcriptase inhibitor-based microbicide, exhibited potent synergistic anti-HIV-1 activity. ccN28Fd was highly resistant to digestion by proteinase K at pH 7.2 and pepsin at pH 1.5, and its anti-HIV-1 activity was not significantly affected by the presence of hydroxyethyl cellulose gel, seminal fluid or vaginal fluid simulant. It possessed no significant in vitro cytotoxicity. CONCLUSIONS: The engineered ccN28Fd maintains high stability in a low pH environment and exhibits potent and broad anti-HIV-1 activity, suggesting good potential for development as an effective and safe vaginal microbicide to prevent HIV sexual transmission. PMID- 23794601 TI - Interactions between tenofovir and nevirapine in CD4+ T cells and monocyte derived macrophages restrict their intracellular accumulation. AB - OBJECTIVES: There is no pharmacokinetic interaction between tenofovir and nevirapine, but a higher emergence rate of resistance mutations has been reported when these drugs are coadministered. We sought to examine if there is a potential intracellular interaction that may account for the emergence of resistant virus. METHODS: Primary CD4+ and CD14+ cells were isolated from healthy volunteer blood. Monocyte-derived macrophages were differentiated from CD14+ cells. Accumulation of radiolabelled tenofovir and nevirapine was then assessed in these cells. RESULTS: We show here that tenofovir and nevirapine immune cell intracellular concentrations are lower when coincubated in CD4+ cells and monocyte-derived macrophages, but not in CD14+ cells. CONCLUSIONS: These data indicate a potential intracellular drug-drug interaction between these drugs that warrants further investigation. PMID- 23794602 TI - Characterization of a major facilitator superfamily (MFS) tripartite efflux pump EmrCABsm from Stenotrophomonas maltophilia. AB - OBJECTIVES: To characterize the emrRCABsm operon of Stenotrophomonas maltophilia. METHODS: The presence of the emrRCABsm operon was verified by RT-PCR. The regulatory role of EmrRsm was investigated by DeltaemrRsm mutant construction and promoter transcriptional fusion assay. A susceptibility test was employed to assess the substrate spectrum of the EmrCABsm efflux pump. The requirement for each component of the EmrCABsm pump was assessed by individual mutant construction and susceptibility testing. The expression of the emrRCABsm operon was evaluated by an induction assay, using different compounds as inducers. RESULTS: emrRsm, emrCsm, emrAsm and emrBsm formed a four-member operon that was negatively regulated by the MarR-type transcriptional regulator EmrRsm. The emrRCABsm operon was intrinsically poorly expressed and the EmrCAB pump favoured extrusion of the uncoupling agents carbonyl cyanide 3-chlorophenylhydrazone (CCCP) and tetrachlorosalicylanilide (TCS), and the hydrophobic antibiotics nalidixic acid and erythromycin. However, the emrRCABsm operon could not be derepressed by CCCP, nalidixic acid, TCS, 2-chlorophenylhydrazine hydrochloride or salicylate, which are known to be possible inducers for MarR-type regulons. Each component of the EmrCABsm pump was apparently essential for pump function. CONCLUSIONS: The EmrRsm-regulated EmrCABsm efflux pump is involved in the extrusion of hydrophobic compounds. PMID- 23794603 TI - Primary resistance of CCR5-tropic HIV-1 to maraviroc cannot be predicted by the V3 sequence. AB - OBJECTIVES: Resistance of HIV-1 to CCR5 antagonists can occur without coreceptor switching by mutations in envelope glycoproteins that enable virus entry using the inhibitor-bound form of CCR5. We investigated whether mutations in the V3 region of HIV-1 from subjects naive to maraviroc could be associated with primary resistance to this drug. METHODS: The frequency of CCR5-tropic HIV-1 subtype B isolates harbouring putative V3 maraviroc resistance mutations was assessed among the HIV tropism database of Toulouse University Hospital, France. Phenotypic assessment of maraviroc susceptibility was performed for 14 isolates representative of the main mutation patterns and 14 controls. V3 mutations were reversed or introduced by site-directed mutagenesis. RESULTS: Ninety-three of 951 (9.8%) isolates harboured V3 mutations assumed to be associated with maraviroc resistance. Maraviroc completely blocked virus entry for all but 1 of the 14 isolates harbouring V3 mutations [IC50 8.6 nM; 95% CI (6.6-47.4)], as in the 14 control isolates [IC50 13.4 nM; 95% CI (7.7-50.3)] (P = 0.24). Primary resistance to maraviroc, with a plateau in entry inhibition, was found in one isolate (harbouring a 20F/21I genotype). Site-directed mutagenesis showed that V3 mutations are necessary but not sufficient to induce maraviroc resistance. CONCLUSIONS: The impact of V3 mutations depended on the env context in which they occurred. Simple assessment of the V3 genotype thus cannot accurately predict maraviroc resistance. Rather, phenotypic assessment of virus particles expressing the envelope glycoprotein as a whole is required. This approach revealed that primary resistance of CCR5-tropic HIV-1 subtype B isolates to maraviroc seems uncommon. PMID- 23794605 TI - The neurology of itch. AB - Research over the past 15 years has helped to clarify the anatomy and physiology of itch, the clinical features of neuropathic itch syndromes and the scientific underpinning of effective treatments. Two itch-sensitive pathways exist: a histamine-stimulated pathway that uses mechanically insensitive C-fibres, and a cowhage-stimulated pathway primarily involving polymodal C-fibres. Interactions with pain continue to be central to explaining various aspects of itch. Certain spinal interneurons (Bhlhb5) inhibit itch pathways within the dorsal horn; they may represent mediators between noxious and pruritic pathways, and allow scratch to inhibit itch. In the brain, functional imaging studies reveal diffuse activation maps for itch that overlap, but not identically, with pain maps. Neuropathic itch syndromes are chronic itch states due to dysfunction of peripheral or central nervous system structures. The most recognized are postherpetic itch, brachioradial pruritus, trigeminal trophic syndrome, and ischaemic stroke-related itch. These disorders affect a patient's quality of life to a similar extent as neuropathic pain. Treatment of neuropathic itch focuses on behavioural interventions (e.g., skin protection) followed by stepwise trials of topical agents (e.g., capsaicin), antiepileptic drugs (e.g., gabapentin), injection of other agents (e.g., botulinum A toxin), and neurostimulation techniques (e.g., cutaneous field stimulation). The involved mechanisms of action include desensitization of nerve fibres (in the case of capsaicin) and postsynaptic blockade of calcium channels (for gabapentin). In the future, particular histamine receptors, protease pathway molecules, and vanilloids may serve as targets for novel antipruritic agents. PMID- 23794604 TI - Vancomycin MIC as a predictor of outcome in MRSA bacteraemia in the UK context. AB - Received 29 November 2012; returned 20 February 2013; revised 16 May 2013; accepted 18 May 2013 OBJECTIVES: Raised vancomycin MICs have been associated with poor outcomes for methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia in the USA and mainland Europe. We investigated if this also applies in the UK, where EMRSA-15 (clonal complex 22) dominates. METHODS: Isolates from UK patients receiving vancomycin therapy for MRSA bacteraemia in 2008-10 were collected, along with clinical details. Outcomes (i.e. patient survival or bacteraemia resolution) were reported 28 days after vancomycin therapy ended. The relationship between clinical outcome and MIC--as determined by CLSI and BSAC agar dilution methods--was assessed. RESULTS: Among 228 MRSA bacteraemias, 82% were caused by EMRSA-15; 65% of the patients were male and the median age was 70.5 years. MICs correlated between methods, but CLSI agar dilution testing gave a mode at 1 mg/L with only 12% of results either side, whereas the BSAC method gave a mode straddling 0.7-1 mg/L with <4% outliers. Twenty-three percent of patients died, with MRSA contributory in half; another 17% had unresolved bacteraemia at 28 days. Neither death nor unresolved bacteraemia was significantly associated with higher vancomycin MICs by either method. Rifampicin co-therapy had no quantifiable effect on outcome. The patient's age was the only significant correlate of patient outcome (P < 0.01); the underlying medical condition of the patient was important for the resolution of bacteraemia (P < 0.01), though not for overall mortality. CONCLUSIONS: Subtle vancomycin MIC differences did not correlate with worse outcomes for vancomycin monotherapy or for vancomycin/rifampicin co-therapy in MRSA bacteraemia. Regardless of the exact MIC-outcome relationship, detecting such small MIC differences seems unlikely to be reliable in routine laboratories. PMID- 23794606 TI - Pioglitazone halts axonal degeneration in a mouse model of X-linked adrenoleukodystrophy. AB - X-linked adrenoleukodystrophy is a neurometabolic disorder caused by inactivation of the peroxisomal ABCD1 transporter of very long-chain fatty acids. In mice, ABCD1 loss causes late onset axonal degeneration in the spinal cord in association with locomotor disability resembling the most common phenotype in patients, adrenomyeloneuropathy. Increasing evidence indicates that oxidative stress and bioenergetic failure play major roles in the pathogenesis of X-linked adrenoleukodystrophy. In this study, we aimed to evaluate whether mitochondrial biogenesis is affected in X-linked adrenoleukodystrophy. We demonstrated that Abcd1 null mice show reduced mitochondrial DNA concomitant with downregulation of mitochondrial biogenesis pathway driven by PGC-1alpha/PPARgamma and reduced expression of mitochondrial proteins cytochrome c, NDUFB8 and VDAC. Moreover, we show that the oral administration of pioglitazone, an agonist of PPARgamma, restored mitochondrial content and expression of master regulators of biogenesis, neutralized oxidative damage to proteins and DNA, and reversed bioenergetic failure in terms of ATP levels, NAD+/NADH ratios, pyruvate kinase and glutathione reductase activities. Most importantly, the treatment halted locomotor disability and axonal damage in X-linked adrenoleukodystrophy mice. These results lend support to the use of pioglitazone in clinical trials with patients with adrenomyeloneuropathy and reveal novel molecular mechanisms of action of pioglitazone in neurodegeneration. Future studies should address the effects of this anti-diabetic drug on other axonopathies in which oxidative stress and mitochondrial dysfunction are contributing factors. PMID- 23794607 TI - Metallic profile of whole blood and plasma in a series of 106 healthy volunteers. AB - In 2003, we simultaneously quantified 27 metals by inductively coupled plasma mass spectrometry (ICP-MS) in the whole blood, plasma and urine of 100 healthy volunteers. We again determined the metallic profile in whole blood and plasma during 2012. ICP-MS validated multielementary method was performed for metals in whole blood and plasma. Whole blood vanadium and chromium were quantified using ICP-MS collision cell technology. The aims of the study were to compare and assess any changes in this profile, particularly due to the environment. Healthy male/female staff volunteers (n = 106) with no professional exposure to metals, or medication containing lithium, strontium; or food supplements with trace elements and vitamins and with no metal prosthesis were included. Tobacco consumption and the number of dental amalgams were recorded. Our results demonstrated a blood lead level that had drastically decreased, i.e. reduced by half, during this period (12.5 versus 26.3 ug/L, P < 0.0001). Known differences were observed between males and females for copper and zinc; cadmium and lead were higher in smokers. Median plasmatic mercury, a specific test for dental amalgam exposure, did not significantly increase (0.38 versus 0.28 ug/L, P = 0.11). The ICP-MS metallic profile is a very practical concept that is useful for clinical, forensic and environmental toxicology, including industrial hygiene monitoring. PMID- 23794608 TI - Monitoring iron therapy in chronic heart failure. PMID- 23794609 TI - No association of G-protein-coupled receptor kinase 5 or beta-adrenergic receptor polymorphisms with Takotsubo cardiomyopathy in a large Australian cohort. AB - AIMS: Takotsubo cardiomyopathy (TC) is an increasingly recognized syndrome in which patients present with chest pain and ST changes, and are observed to have reversible LV apical ballooning in the absence of angiographically significant coronary artery stenosis. Although the pathophysiology remains unclear, the syndrome occurs almost exclusively in women, and is often triggered by stress. Recent small studies have reported association of TC with functional variants in the G-protein-coupled receptor kinase 5 (GRK5) gene, as well as in the beta1 adrenergic receptor (beta1AR) and beta2AR. METHODS AND RESULTS: We tested these associations in a larger cohort of 92 TC patients. In addition we examined for the association of polymorphisms in the oestrogen receptor alpha (ERalpha) and catechol-O-methyl transferase (COMT) with the occurrence of TC, by comparing the allele frequency of these variants in the TC cohort with that in previously genotyped large Caucasian cohorts. Ninety-two patients with TC were recruited from four Australian centres; they had an age range of 41-90 years (mean +/- SD = 66.3 +/- 9) and 89/92 were female. There were no significant differences in allelic frequency in the TC group vs. the historic control database for any of the loci. CONCLUSION: In the largest genotyped TC cohort in the literature, we have found no association of genetic variants in the ERalpha, beta1AR, beta2AR, or COMT genes, or with the previously implicated GRK5, with occurrence of the syndrome. PMID- 23794610 TI - Road traffic accidents in Greece: have we benefited from the financial crisis? PMID- 23794611 TI - Sports facilities in Madrid explain the relationship between neighbourhood economic context and physical inactivity in older people, but not in younger adults: a case study. AB - BACKGROUND: Neighbourhood characteristics may contribute to differences in physical inactivity. PURPOSE: To evaluate whether the availability of sports facilities helps explain the differences in physical inactivity according to the economic context of the neighbourhood. METHODS: 6607 participants representative of the population aged 16-74 years, resident in Madrid (Spain) in 2005, were analysed. Using ORs calculated by multilevel logistic regression, the association between per capita income of the neighbourhood of residence and physical inactivity was estimated, after adjusting for age, population density, individual socioeconomic characteristics and the availability of green spaces. The analysis was repeated after further adjustment for the availability of sports facilities to determine if this reduced the magnitude of the association. RESULTS: Residents in the neighbourhoods with the lowest per capita income had the highest OR for the prevalence of physical inactivity. In participants aged 16-49 years, after adjusting for the availability of sports facilities, the magnitude of the OR in the poorest neighbourhoods with respect to the richest neighbourhoods increased in men (from 2.22 to 2.35) and declined by 13% in women (from 2.13 to 1.98). In contrast, in the population aged 50-74 years, this adjustment reduced the magnitude of the OR by 21% in men (from 2.00 to 1.80) and by 53% in women (from 2.03 to 1.48). CONCLUSIONS: The poorest neighbourhoods show the highest prevalence of physical inactivity. The availability of sports facilities explains an important part of this excess prevalence in participants aged 50-74 years, but not in younger individuals. PMID- 23794612 TI - Successful ablation of idiopathic ventricular fibrillation by targeting Purkinje potentials from right ventricle. PMID- 23794613 TI - A novel electrocardiographic predictor of clinical response to cardiac resynchronization therapy. AB - AIMS: A wide QRS with left bundle branch block pattern is usually required for cardiac resynchronization therapy (CRT) in patients with dilated cardiomyopathy. However, ~30% of patients do not benefit from CRT. We evaluated whether a detailed analysis of QRS complex can improve prediction of CRT success. METHODS AND RESULTS: We studied 51 patients (67.3 + 9.5 years, 36 males) with classical indication to CRT. Twelve-lead electrocardiogram (ECG) (50 mm/s, 0.05 mV/mm) was obtained before and 3 months after CRT. The following ECG intervals were measured in leads V1 and V6: (i) total QRS duration; (ii) QRS onset-R wave peak; (iii) R wave peak-S wave peak (RS-V1 and RS-V6); (iv) S wave peak-QRS end; and (v) difference between QR in V6 and in V1. Patients were considered as responder when left ventricular ejection fraction (LVEF) increased by >=5% and New York Heart Association class by >=1 after 3 months of CRT. Of ECG intervals, only basal RS V1 was longer in responders (n = 36) compared with non-responders (52.9 +/- 11.8 vs. 44.0 +/- 12.6 ms, P = 0.021). Among patients with RS-V1 >=45 ms 83% responded to CRT vs. 33% of those with RS-V1 < 45 ms (P < 0.001). RS-V1 >= 45 ms was independently associated with response to CRT in multivariable analysis (odds ratio 9.8; P = 0.002). A reduction of RS-V1 >= 10 ms by CRT also significantly predicted clinical response. RS-V1 shortening correlated with improvement in LVEF (r = -0.45; P < 0.001) and in MS (r = 0.46; P < 0.001). CONCLUSION: Our data point out that RS-V1 interval and its changes with CRT may help to identify patients who are most likely to benefit from CRT. PMID- 23794614 TI - Laser lead extraction to facilitate cardiac implantable electronic device upgrade and revision in the presence of central venous obstruction. AB - AIMS: The number of procedures involving upgrade or revision of cardiac implantable electronic devices (CIEDs) is increasing and the risks of adding additional leads are significant. Central venous occlusion in patients with pre existing devices is often asymptomatic and optimal management of such patients in need of device revision/upgrade is not clear. We sought to assess our use of laser lead extraction in overcoming venous obstruction. METHODS AND RESULTS: Patients in need of device upgrade/revision underwent pre-procedure venography to assess venous patency. In patients with venous occlusion or stenosis severe enough to preclude passage of a hydrophilic guide wire, laser lead extraction with retention of the outer sheath in the vasculature was performed with the aim of maintaining a patent channel through which new leads could be implanted. Data were recorded on a dedicated database and patient outcomes were assessed. Between July 2004 and April 2012, laser lead extractions were performed in 71 patients scheduled for device upgrade/revision who had occluded or functionally obstructed venous anatomy. New leads were successfully implanted across the obstruction in 67 (94%) cases. There were two major complications (infection) and four minor complications with no peri-procedural mortality. Device follow-up was satisfactory in 65 (92%) cases with mean follow-up up to 26 +/- 19 months. CONCLUSION: Laser lead extraction is a safe and effective option when managing patients with central venous obstruction in need of CIED revision or upgrade. PMID- 23794615 TI - A conditional model for estimating the increase in suicides associated with the 2008-2010 economic recession in England. AB - BACKGROUND: Although evidence of the effects of the economic crisis on suicides is quite low, a recent article shows that the increase in suicides in England between 2008 and 2010 could be associated with the rise in unemployment. Our study analysed whether this effect was the same for all regions of England, using a conditional model which explicitly allows estimation of regional time trends and the effects of unemployment on suicides at the regional level. METHODS: Hierarchical mixed models were used to assess both, suicides attributable to the financial crisis and the association between unemployment and suicides. The number and the (age-standardised) rate of suicides, for men and women separately, were the dependent variables. We considered the nine English regions based on the NUTS 2 level. RESULTS: There was an (not statistically significant) increase in the number of suicides between 2008 and 2010. The variation in rates was not statistically significant in England as a whole but there were statistically significant increases and decreases in some regions. Statistically significant associations between unemployment and suicides were only found at regional level. For men, statistically significant unemployment rates were positively associated with age-standardised suicide rates in the South West (0.384), North West (0.260) and North East (0.136), and negatively associated in the East of England ( 0.444), East Midlands (-0.236) and London (-0.168). CONCLUSIONS: The study provides evidence that, even with statistically significant associations, finding variability, but no clear pattern, between trends and associations and/or numbers and rates might in fact suggest relatively spurious relationships; this is a result of not controlling for confounders. PMID- 23794616 TI - Evolutionary dynamics of the prokaryotic adaptive immunity system CRISPR-Cas in an explicit ecological context. AB - A stochastic, agent-based mathematical model of the coevolution of the archaeal and bacterial adaptive immunity system, CRISPR-Cas, and lytic viruses shows that CRISPR-Cas immunity can stabilize the virus-host coexistence rather than leading to the extinction of the virus. In the model, CRISPR-Cas immunity does not specifically promote viral diversity, presumably because the selection pressure on each single proto-spacer is too weak. However, the overall virus diversity in the presence of CRISPR-Cas grows due to the increase of the host and, accordingly, the virus population size. Above a threshold value of total viral diversity, which is proportional to the viral mutation rate and population size, the CRISPR-Cas system becomes ineffective and is lost due to the associated fitness cost. Our previous modeling study has suggested that the ubiquity of CRISPR-Cas in hyperthermophiles, which contrasts its comparative low prevalence in mesophiles, is due to lower rates of mutation fixation in thermal habitats. The present findings offer a complementary, simpler perspective on this contrast through the larger population sizes of mesophiles compared to hyperthermophiles, because of which CRISPR-Cas can become ineffective in mesophiles. The efficacy of CRISPR-Cas sharply increases with the number of proto-spacers per viral genome, potentially explaining the low information content of the proto-spacer-associated motif (PAM) that is required for spacer acquisition by CRISPR-Cas because a higher specificity would restrict the number of spacers available to CRISPR-Cas, thus hampering immunity. The very existence of the PAM might reflect the tradeoff between the requirement of diverse spacers for efficient immunity and avoidance of autoimmunity. PMID- 23794617 TI - PdeB, a cyclic Di-GMP-specific phosphodiesterase that regulates Shewanella oneidensis MR-1 motility and biofilm formation. AB - Shewanella oneidensis MR-1, a gammaproteobacterium with respiratory versatility, forms biofilms on mineral surfaces through a process controlled by the cyclic dinucleotide messenger c-di-GMP. Cellular concentrations of c-di-GMP are maintained by proteins containing GGDEF and EAL domains, which encode diguanylate cyclases for c-di-GMP synthesis and phosphodiesterases for c-di-GMP hydrolysis, respectively. The S. oneidensis MR-1 genome encodes several GGDEF and EAL domain proteins (50 and 31, respectively), with a significant fraction (~10) predicted to be multidomain (e.g., GGDEF-EAL) enzymes containing an additional Per-Arnt-Sim (PAS) sensor domain. However, the biochemical activities and physiological functions of these multidomain enzymes remain largely unknown. Here, we present genetic and biochemical analyses of a predicted PAS-GGDEF-EAL domain-containing protein, SO0437, here named PdeB. A pdeB deletion mutant exhibited decreased swimming motility and increased biofilm formation under rich growth medium conditions, which was consistent with an increase in intracellular c-di-GMP. A mutation inactivating the EAL domain also produced similar swimming and biofilm phenotypes, indicating that the increase in c-di-GMP was likely due to a loss in phosphodiesterase activity. Therefore, we also examined the enzymatic activity of purified PdeB and found that the protein exhibited phosphodiesterase activity via the EAL domain. No diguanylate cyclase activity was observed. In addition to the motility and biofilm phenotypes, transcriptional profiling by DNA microarray analysis of biofilms of pdeB (in-frame deletion and EAL) mutant cells revealed that expression of genes involved in sulfate uptake and assimilation were repressed. Addition of sulfate to the growth medium resulted in significantly less motile pdeB mutants. Together, these results indicate a link between c-di GMP metabolism, S. oneidensis MR-1 biofilm development, and sulfate uptake/assimilation. PMID- 23794618 TI - Two ATP-binding cassette transporters involved in (S)-2-aminoethyl-cysteine uptake in thermus thermophilus. AB - Thermus thermophilus exhibits hypersensitivity to a lysine analog, (S)-2 aminoethyl-cysteine (AEC). Cosmid libraries were constructed using genomes from two AEC-resistant mutants, AT10 and AT14, and the cosmids that conferred AEC resistance on the wild-type strain were isolated. When the cosmid library for mutant AT14 was screened, two independent cosmids, conferring partial AEC resistance to the wild type, were obtained. Two cosmids carried a common genomic region from TTC0795 to TTC0810. This region contains genes encoding an ATP binding cassette (ABC) transporter consisting of TTC0806/TTC0795, using TTC0807 as the periplasmic substrate-binding protein. Sequencing revealed that AT14 carries mutations in TTC0795 and TTC0969, causing decreases in the thermostability of the products. TTC0969 encodes the nucleotide-binding protein of a different ABC transporter consisting of TTC0967/TTC0968/TTC0969/TTC0970 using TTC0966 as the periplasmic substrate-binding protein. By similar screening for cosmids constructed for the mutant AT10, mutations were found at TTC0807 and TTC0969. Mutation in either of the transporter components gave partial resistance to AEC in the wild-type strain, while mutations of both transporters conferred complete AEC resistance. This result indicates that both transporters are involved in AEC uptake in T. thermophilus. To elucidate the mechanism of AEC uptake, crystal structures of TTC0807 were determined in several substrate binding forms. The structures revealed that TTC0807 recognizes various basic amino acids by changing the side-chain conformation of Glu19, which interacts with the side-chain amino groups of the substrates. PMID- 23794619 TI - Characterization of Chlamydia trachomatis plasmid-encoded open reading frames. AB - The recent success in transformation of Chlamydia trachomatis represents a major advancement in Chlamydia research. Plasmid-free C. trachomatis serovar L2 organisms can be transformed with chlamydial plasmid-based shuttle vectors pGFP::SW2 and pBRCT. Deletion of plasmid genes coding for Pgp1 to Pgp8 in pBRCT led to the identification of Pgp1, -2, -6, and -8 as plasmid maintenance factors; Pgp4 as a transcriptional regulator of chlamydial virulence-associated gene expression; and Pgp3, -5, and -7 as being dispensable for chlamydial growth in vitro. Using the pGFP::SW2 vector system, we confirmed these findings in the current report. To further dissect the roles of pgp coding sequences and Pgp proteins in plasmid maintenance, we introduced premature stop codons into the pgp genes. Stable transformants were obtained with pGFP::SW2 derivatives carrying premature stop codons in pgp8 but not in pgp1, pgp2, and pgp6, suggesting that the pgp8 coding sequence but not the Pgp8 protein is required for maintaining the plasmid, while Pgp1, -2, and -6 proteins are necessary for plasmid maintenance. We also found that a minimum of 30 nucleotides in the pgp3 coding region was required for pgp4 expression. Finally, mCherry red fluorescent protein was successfully expressed when the mCherry gene was used to replace the pgp3, pgp4, or pgp5 coding region, indicating that these regions can be used to express nonchlamydial genes in chlamydial organisms. These novel observations have provided information for further use of chlamydial plasmid shuttle vectors as genetic tools to understand chlamydial biology and pathogenicity as well as to develop attenuated chlamydial vaccines. PMID- 23794620 TI - Role for ferredoxin:NAD(P)H oxidoreductase (FprA) in sulfate assimilation and siderophore biosynthesis in Pseudomonads. AB - Pyridine-2,6-bis(thiocarboxylate) (PDTC), produced by certain pseudomonads, is a sulfur-containing siderophore that binds iron, as well as a wide range of transition metals, and it affects the net hydrolysis of the environmental contaminant carbon tetrachloride. The pathway of PDTC biosynthesis has not been defined. Here, we performed a transposon screen of Pseudomonas putida DSM 3601 to identify genes necessary for PDTC production (Pdt phenotype). Transposon insertions within genes for sulfate assimilation (cysD, cysNC, and cysG [cobA2]) dominated the collection of Pdt mutations. In addition, two insertions were within the gene for the LysR-type transcriptional activator FinR (PP1637). Phenotypic characterization indicated that finR mutants were cysteine bradytrophs. The Pdt phenotype of finR mutants could be complemented by the known target of FinR regulation, fprA (encoding ferredoxin:NADP(+) oxidoreductase), or by Escherichia coli cysJI (encoding sulfite reductase). These data indicate that fprA is necessary for effective sulfate assimilation by P. putida and that the effect of finR mutation on PDTC production was due to deficient expression of fprA and sulfite reduction. fprA expression in both P. putida and P. aeruginosa was found to be regulated by FinR, but in a manner dependent upon reduced sulfur sources, implicating FinR in sulfur regulatory physiology. The genes and phenotypes identified in this study indicated a strong dependence upon intracellular reduced sulfur/cysteine for PDTC biosynthesis and that pseudomonads utilize sulfite reduction enzymology distinct from that of E. coli and possibly similar to that of chloroplasts and other proteobacteria. PMID- 23794621 TI - Expression in Haloferax volcanii of 3-hydroxy-3-methylglutaryl coenzyme A synthase facilitates isolation and characterization of the active form of a key enzyme required for polyisoprenoid cell membrane biosynthesis in halophilic archaea. AB - Enzymes of the isoprenoid biosynthetic pathway in halophilic archaea remain poorly characterized, and parts of the pathway remain cryptic. This situation may be explained, in part, by the difficulty of expressing active, functional recombinant forms of these enzymes. The use of newly available expression plasmids and hosts has allowed the expression and isolation of catalytically active Haloferax volcanii 3-hydroxy-3-methylglutaryl coenzyme A (CoA) synthase (EC 2.3.310). This accomplishment has permitted studies that represent, to the best of our knowledge, the first characterization of an archaeal hydroxymethylglutaryl CoA synthase. Kinetic characterization indicates that, under optimal assay conditions, which include 4 M KCl, the enzyme exhibits catalytic efficiency and substrate saturation at metabolite levels comparable to those reported for the enzyme from nonhalophilic organisms. This enzyme is unique in that it is the first hydroxymethylglutaryl CoA synthase that is insensitive to feedback substrate inhibition by acetoacetyl-CoA. The enzyme supports reaction catalysis in the presence of various organic solvents. Haloferax 3-hydroxy-3 methylglutaryl CoA synthase is sensitive to inactivation by hymeglusin, a specific inhibitor known to affect prokaryotic and eukaryotic forms of the enzyme, with experimentally determined Ki and kinact values of 570 +/- 120 nM and 17 +/- 3 min(-1), respectively. In in vivo experiments, hymeglusin blocks the propagation of H. volcanii cells, indicating the critical role that the mevalonate pathway plays in isoprenoid biosynthesis by these archaea. PMID- 23794622 TI - Genes required for and effects of alginate overproduction induced by growth of Pseudomonas aeruginosa on Pseudomonas isolation agar supplemented with ammonium metavanadate. AB - Pseudomonas aeruginosa is an opportunistic pathogen that can adapt to changing environments and can secrete an exopolysaccharide known as alginate as a protection response, resulting in a colony morphology and phenotype referred to as mucoid. However, how P. aeruginosa senses its environment and activates alginate overproduction is not fully understood. Previously, we showed that Pseudomonas isolation agar supplemented with ammonium metavanadate (PIAAMV) induces P. aeruginosa to overproduce alginate. Vanadate is a phosphate mimic and causes protein misfolding by disruption of disulfide bonds. Here we used PIAAMV to characterize the pathways involved in inducible alginate production and tested the global effects of P. aeruginosa growth on PIAAMV by a mutant library screen, by transcriptomics, and in a murine acute virulence model. The PA14 nonredundant mutant library was screened on PIAAMV to identify new genes that are required for the inducible alginate stress response. A functionally diverse set of genes encoding products involved in cell envelope biogenesis, peptidoglycan remodeling, uptake of phosphate and iron, phenazine biosynthesis, and other processes were identified as positive regulators of the mucoid phenotype on PIAAMV. Transcriptome analysis of P. aeruginosa cultures growing in the presence of vanadate showed differential expression of genes involved in virulence, envelope biogenesis, and cell stress pathways. In this study, it was observed that growth on PIAAMV attenuates P. aeruginosa in a mouse pneumonia model. Induction of alginate overproduction occurs as a stress response to protect P. aeruginosa, but it may be possible to modulate and inhibit these pathways based on the new genes identified in this study. PMID- 23794623 TI - Novel archaeal adhesion pilins with a conserved N terminus. AB - Type IV pili play important roles in a wide array of processes, including surface adhesion and twitching motility. Although archaeal genomes encode a diverse set of type IV pilus subunits, the functions for most remain unknown. We have now characterized six Haloferax volcanii pilins, PilA[1-6], each containing an identical 30-amino-acid N-terminal hydrophobic motif that is part of a larger highly conserved domain of unknown function (Duf1628). Deletion mutants lacking up to five of the six pilin genes display no significant adhesion defects; however, H. volcanii lacking all six pilins (DeltapilA[1-6]) does not adhere to glass or plastic. Consistent with these results, the expression of any one of these pilins in trans is sufficient to produce functional pili in the DeltapilA[1 6] strain. PilA1His and PilA2His only partially rescue this phenotype, whereas DeltapilA[1-6] strains expressing PilA3His or PilA4His adhere even more strongly than the parental strain. Most surprisingly, expressing either PilA5His or PilA6His in the DeltapilA[1-6] strain results in microcolony formation. A hybrid protein in which the conserved N terminus of the mature PilA1His is replaced with the corresponding N domain of FlgA1 is processed by the prepilin peptidase, but it does not assemble functional pili, leading us to conclude that Duf1628 can be annotated as the N terminus of archaeal PilA adhesion pilins. Finally, the pilin prediction program, FlaFind, which was trained primarily on archaeal flagellin sequences, was successfully refined to more accurately predict pilins based on the in vivo verification of PilA[1-6]. PMID- 23794624 TI - Inactivation of cyclic Di-GMP binding protein TDE0214 affects the motility, biofilm formation, and virulence of Treponema denticola. AB - As a ubiquitous second messenger, cyclic dimeric GMP (c-di-GMP) has been studied in numerous bacteria. The oral spirochete Treponema denticola, a periodontal pathogen associated with human periodontitis, has a complex c-di-GMP signaling network. However, its function remains unexplored. In this report, a PilZ-like c di-GMP binding protein (TDE0214) was studied to investigate the role of c-di-GMP in the spirochete. TDE0214 harbors a PilZ domain with two signature motifs: RXXXR and DXSXXG. Biochemical studies showed that TDE0214 binds c-di-GMP in a specific manner, with a dissociation constant (Kd) value of 1.73 MUM, which is in the low range compared to those of other reported c-di-GMP binding proteins. To reveal the role of c-di-GMP in T. denticola, a TDE0214 deletion mutant (TdDelta214) was constructed and analyzed in detail. First, swim plate and single-cell tracking analyses showed that TdDelta214 had abnormal swimming behaviors: the mutant was less motile and reversed more frequently than the wild type. Second, we found that biofilm formation of TdDelta214 was substantially repressed (~6.0-fold reduction). Finally, in vivo studies using a mouse skin abscess model revealed that the invasiveness and ability to induce skin abscesses and host humoral immune responses were significantly attenuated in TdDelta214, indicative of the impact that TDE0214 has on the virulence of T. denticola. Collectively, the results reported here indicate that TDE0214 plays important roles in motility, biofilm formation, and virulence of the spirochete. This report also paves a way to further unveil the roles of the c-di-GMP signaling network in the biology and pathogenicity of T. denticola. PMID- 23794625 TI - DR1769, a protein with N-terminal beta propeller repeats and a low-complexity hydrophilic tail, plays a role in desiccation tolerance of Deinococcus radiodurans. AB - The Deinococcus radiodurans genome encodes five putative quinoproteins. Among these, the Deltadr2518 and Deltadr1769 mutants became sensitive to gamma radiation. DR2518 with beta propeller repeats in the C-terminal domain was characterized as a radiation-responsive serine/threonine protein kinase in this bacterium. DR1769 contains beta propeller repeats at the N terminus, while its C terminal domain is a proline-rich disordered structure and constitutes a low complexity hydrophilic region with aliphatic-proline dipeptide motifs. The Deltadr1769 mutant showed nearly a 3-log cycle sensitivity to desiccation at 5% humidity compared to that of the wild type. Interestingly, the gamma radiation and mitomycin C (MMC) resistance in mutant cells also dropped by ~1-log cycle at 10 kGy and ~1.5-fold, respectively, compared to those in wild-type cells. But there was no effect of UV (254 nm) exposure up to 800 J . m(-2). These cells showed defective DNA double-strand break repair, and the average size of the nucleoid in desiccated wild-type and Deltadr1769 cells was reduced by approximately 2-fold compared to that of respective controls. However, the nucleoid in wild-type cells returned to a size almost similar to that of the untreated control, which did not happen in mutant cells, at least up to 24 h postdesiccation. These results suggest that DR1769 plays an important role in desiccation and radiation resistance of D. radiodurans, possibly by protecting genome integrity under extreme conditions. PMID- 23794626 TI - Molecular characterization of PauR and its role in control of putrescine and cadaverine catabolism through the gamma-glutamylation pathway in Pseudomonas aeruginosa PAO1. AB - Pseudomonas aeruginosa PAO1 grows on a variety of polyamines as the sole source of carbon and nitrogen. Catabolism of polyamines is mediated by the gamma glutamylation pathway, which is complicated by the existence of multiple homologous enzymes with redundant specificities toward different polyamines for a more diverse metabolic capacity in this organism. Through a series of markerless gene knockout mutants and complementation tests, specific combinations of pauABCD (polyamine utilization) genes were deciphered for catabolism of different polyamines. Among six pauA genes, expression of pauA1, pauA2, pauA4, and pauA5 was found to be inducible by diamines putrescine (PUT) and cadaverine (CAD) but not by diaminopropane. Activation of these promoters was regulated by the PauR repressor, as evidenced by constitutively active promoters in the pauR mutant. The activities of these promoters were further enhanced by exogenous PUT or CAD in the mutant devoid of all six pauA genes. The recombinant PauR protein with a hexahistidine tag at its N terminus was purified, and specific bindings of PauR to the promoter regions of most pau operons were demonstrated by electromobility shift assays. Potential interactions of PUT and CAD with PauR were also suggested by chemical cross-linkage analysis with glutaraldehyde. In comparison, growth on PUT was more proficient than that on CAD, and this observed growth phenotype was reflected in a strong catabolite repression of pauA promoter activation by CAD but was completely absent as reflected by activation by PUT. In summary, this study clearly establishes the function of PauR in control of pau promoters in response to PUT and CAD for their catabolism through the gamma-glutamylation pathway. PMID- 23794627 TI - The Clostridium difficile exosporium cysteine (CdeC)-rich protein is required for exosporium morphogenesis and coat assembly. AB - Clostridium difficile is an important nosocomial pathogen that has become a major cause of antibiotic-associated diarrhea. There is a general consensus that C. difficile spores play an important role in C. difficile pathogenesis, contributing to infection, persistence, and transmission. Evidence has demonstrated that C. difficile spores have an outermost layer, termed the exosporium, that plays some role in adherence to intestinal epithelial cells. Recently, the protein encoded by CD1067 was shown to be present in trypsin exosporium extracts of C. difficile 630 spores. In this study, we renamed the CD1067 protein Clostridium difficile exosporium cysteine-rich protein (CdeC) and characterized its role in the structure and properties of C. difficile spores. CdeC is expressed under sporulation conditions and localizes to the C. difficile spore. Through the construction of an DeltacdeC isogenic knockout mutant derivative of C. difficile strain R20291, we demonstrated that (i) the distinctive nap layer is largely missing in DeltacdeC spores; (ii) CdeC is localized in the exosporium-like layer and is accessible to IgGs; (iii) DeltacdeC spores were more sensitive to lysozyme, ethanol, and heat treatment than wild type spores; and (iv) despite the almost complete absence of the exosporium layer, DeltacdeC spores adhered at higher levels than wild-type spores to intestinal epithelium cell lines (i.e., HT-29 and Caco-2 cells). Collectively, these results indicate that CdeC is essential for exosporium morphogenesis and the correct assembly of the spore coat of C. difficile. PMID- 23794628 TI - Intra-amniotic IL-1beta induces fetal inflammation in rhesus monkeys and alters the regulatory T cell/IL-17 balance. AB - Very low birth weight preterm newborns are susceptible to the development of debilitating inflammatory diseases, many of which are associated with chorioamnionitis. To define the effects of chorioamnionitis on the fetal immune system, IL-1beta was administered intra-amniotically at ~80% gestation in rhesus monkeys. IL-1beta caused histological chorioamnionitis, as well as lung inflammation (infiltration of neutrophils or monocytes in the fetal airways). There were large increases in multiple proinflammatory cytokine mRNAs in the lungs at 24 h postadministration, which remained elevated relative to controls at 72 h. Intra-amniotic IL-1beta also induced the sustained expression of the surfactant proteins in the lungs. Importantly, IL-1beta significantly altered the balance between inflammatory and regulatory T cells. Twenty-four hours after IL 1beta injection, the frequency of CD3(+)CD4(+)FOXP3(+) T cells was decreased in lymphoid organs. In contrast, IL-17A-producing cells (CD3(+)CD4(+), CD3(+)CD4(-), and CD3(-)CD4(-) subsets) were increased in lymphoid organs. The frequency of IFN gamma-expressing cells did not change. In this model of a single exposure to an inflammatory trigger, CD3(+)CD4(+)FOXP3(+) cells rebounded quickly, and their frequency was increased at 72 h compared with controls. IL-17 expression was also transient. Interestingly, the T cell profile alteration was confined to the lymphoid organs and not to circulating fetal T cells. Together, these results suggest that the chorioamnionitis-induced IL-1/IL-17 axis is involved in the severe inflammation that can develop in preterm newborns. Boosting regulatory T cells and/or controlling IL-17 may provide a means to ameliorate these abnormalities. PMID- 23794629 TI - Macrophage scavenger receptor 1 (Msr1, SR-A) influences B cell autoimmunity by regulating soluble autoantigen concentration. AB - The class A macrophage scavenger receptor Msr1 (SR-A, CD204) has been reported to participate in the maintenance of immunological tolerance. We investigated the role of Msr1 in a mouse model of autoantibody-dependent arthritis. Genetic deficiency of Msr1 in K/BxN TCR transgenic mice decreased the incidence and severity of arthritis because of decreased autoantibody production. Despite normal initial activation of autoreactive CD4(+) T cells, potentially autoreactive B cells in Msr1(-/-) K/BxN mice retained a naive phenotype and did not expand. This was not due to an intrinsic B cell defect. Rather, we found that macrophages lacking Msr1 were inefficient at taking up the key autoantigen glucose-6-phosphate isomerase and that Msr1-deficient mice had elevated serum concentrations of glucose-6-phosphate isomerase. Arthritis developed normally when bone marrow from Msr1(-/-) K/BxN mice was transplanted into hosts whose macrophages did express Msr1. Thus, Msr1 can regulate the concentration of a soluble autoantigen. In this model, the absence of Msr1 led to higher levels of soluble autoantigen and protected mice from developing pathogenic autoantibodies, likely because of altered cognate interactions of autoreactive T and B cells with impaired differentiation of follicular Th cells. PMID- 23794630 TI - Essential requirements of zoledronate-induced cytokine and gammadelta T cell proliferative responses. AB - The potent nitrogen-containing bisphosphonate zoledronate inhibits farnesyl pyrophosphate synthase, a key enzyme of the mevalonate pathway that is often hyperactive in malignant cells. Zoledronate activates human Vgamma9Vdelta2 T cells, which are immune sentinels of cell stress and tumors, through upstream accumulation of the cognate Ag isopentenyl pyrophosphate. IL-18 was shown to enhance zoledronate-induced gammadelta T cell activation. Although monocytes have been considered important accessory cells that provide the Ag isopentenyl pyrophosphate, CD56(bright)CD11c(+) NK cells were postulated to mediate the costimulatory effects of IL-18. We report in this article that downstream depletion of geranylgeranyl pyrophosphate (GGPP), which is required for protein prenylation, caused cell stress in monocytes, followed by caspase-1-mediated maturation and release of IL-18, which, in turn, induced gammadelta T cell CCL2. Likewise, zoledronate caused a substantial delay in gammadelta T cell expansion, which could be skipped by GGPP supplementation. Moreover, repletion of GGPP, which prevented acute zoledronate toxicity, and supplementation with IL-18, which strongly upregulated IL-2Ralpha (CD25) and favored the central memory phenotype, were sufficient to enable zoledronate-induced expansion of highly purified gammadelta T cells, even when starting cell numbers were as low as 10(4) gammadelta T cells. Our study reveals essential components of gammadelta T cell activation and indicates that exogenous IL-18, which can directly costimulate gammadelta T cells, eliminates the need for any accessory cells. Our findings will facilitate the generation of robust gammadelta T cells from small blood or tissue samples for cancer immunotherapy and immune-monitoring purposes. PMID- 23794632 TI - Cutting edge: Heterosubtypic influenza infection antagonizes elicitation of immunological reactivity to hemagglutinin. AB - Influenza-specific immunity in humans is unique because there are repeated exposures to viral strains containing genetically conserved epitopes recruiting memory CD4 T cells and novel epitopes stimulating naive CD4 T cells, possibly resulting in competition between memory and naive lymphocytes. In this study, we evaluated the effect of this competition on CD4 T cell and B cell response specificity using a murine model of sequential influenza infection. We found striking and selective decreases in CD4 T cell reactivity to nonconserved hemagglutinin (HA) epitopes following secondary influenza infection. Surprisingly, this shift in CD4 T cell specificity was associated with dramatic decreases in HA-specific Ab. These results suggest that repeated exposure to influenza viruses and vaccines containing conserved internal proteins may have unintended and negative consequences on the ability to induce HA-specific Ab to novel pandemic strains of influenza. These finding could have important implications on pandemic influenza preparedness strategies. PMID- 23794631 TI - Th17 cells induce Th1-polarizing monocyte-derived dendritic cells. AB - In chronically inflamed tissues, such as those affected by autoimmune disease, activated Th cells often colocalize with monocytes. We investigate in this study how murine Th cells influence the phenotype and function of monocytes. The data demonstrate that Th1, Th2, and Th17 subsets promote the differentiation of autologous monocytes into MHC class II(+), CD11b(+), CD11c(+) DC that we call DCTh. Although all Th subsets induce the formation of DCTh, activated Th17 cells uniquely promote the formation of IL-12/IL-23-producing DCTh (DCTh17) that can polarize both naive and Th17 cells to a Th1 phenotype. In the inflamed CNS of mice with Th17-mediated experimental autoimmune encephalomyelitis, Th cells colocalize with DC, as well as monocytes, and the Th cells obtained from these lesions drive the formation of DCTh that are phenotypically indistinguishable from DCTh17 and polarize naive T cells toward a Th1 phenotype. These results suggest that DCTh17 are critical in the interplay of Th17- and Th1-mediated responses and may explain the previous finding that IL-17-secreting Th cells become IFN-gamma-secreting Th1 cells in experimental autoimmune encephalomyelitis and other autoimmune disorders. PMID- 23794633 TI - Thymocyte selection regulates the homeostasis of IL-7-expressing thymic cortical epithelial cells in vivo. AB - Thymic epithelial cells (TECs) help orchestrate thymopoiesis, and TEC differentiation relies on bidirectional interactions with thymocytes. Although the molecular mediators that stimulate medullary thymic epithelial cell (mTEC) maturation are partially elucidated, the signals that regulate cortical thymic epithelial cell (cTEC) homeostasis remain elusive. Using IL-7 reporter mice, we show that TECs coexpressing high levels of IL-7 (Il7(YFP+) TECs) reside within a subset of CD205(+)Ly51(+)CD40(low) cTECs that coexpresses Dll4, Ccl25, Ccrl1, Ctsl, Psmb11, and Prss16 and segregates from CD80(+)CD40(high) mTECs expressing Tnfrsf11a, Ctss, and Aire. As the frequency of Il7(YFP+) TECs gradually declines as mTEC development unfolds, we explored the relationship between Il7(YFP+) TECs and mTECs. In thymic organotypic cultures, the thymocyte-induced reduction in Il7(YFP+) TECs dissociates from the receptor activator of NF-kappaB-mediated differentiation of CD80(+) mTECs. Still, Il7(YFP+) TECs can generate some CD80(+) mTECs in a stepwise differentiation process via YFP(-)Ly51(low)CD80(low) intermediates. Il7(YFP+) TECs are sustained in Rag2(-/-) mice, even following in vivo anti-CD3epsilon treatment that mimics the process of pre-TCR beta-selection of thymocytes to the double positive (DP) stage. Using Marilyn-Rag2(-/-) TCR transgenic, we find that positive selection into the CD4 lineage moderately reduces the frequency of Il7(YFP+) TECs, whereas negative selection provokes a striking loss of Il7(YFP+) TECs. These results imply that the strength of MHC/peptide-TCR interactions between TECs and thymocytes during selection constitutes a novel rheostat that controls the maintenance of IL-7-expressing cTECs. PMID- 23794635 TI - GeneMANIA prediction server 2013 update. AB - GeneMANIA (http://www.genemania.org) is a flexible user-friendly web interface for generating hypotheses about gene function, analyzing gene lists and prioritizing genes for functional assays. Given a query gene list, GeneMANIA extends the list with functionally similar genes that it identifies using available genomics and proteomics data. GeneMANIA also reports weights that indicate the predictive value of each selected data set for the query. GeneMANIA can also be used in a function prediction setting: given a query gene, GeneMANIA finds a small set of genes that are most likely to share function with that gene based on their interactions with it. Enriched Gene Ontology categories among this set can sometimes point to the function of the gene. Seven organisms are currently supported (Arabidopsis thaliana, Caenorhabditis elegans, Drosophila melanogaster, Mus musculus, Homo sapiens, Rattus norvegicus and Saccharomyces cerevisiae), and hundreds of data sets have been collected from GEO, BioGRID, IRefIndex and I2D, as well as organism-specific functional genomics data sets. Users can customize their search by selecting specific data sets to query and by uploading their own data sets to analyze. PMID- 23794636 TI - I. Managing pain: recent advances and new challenges. PMID- 23794637 TI - II. No need for translation when the same language is spoken. PMID- 23794638 TI - III. Pain research: what have we learned and where are we going. PMID- 23794639 TI - IV. Persistent post-surgery pain: research agenda for mechanisms, prevention, and treatment. PMID- 23794640 TI - Chronic pain epidemiology and its clinical relevance. AB - Chronic pain affects ~20% of the European population and is commoner in women, older people, and with relative deprivation. Its management in the community remains generally unsatisfactory, partly because of lack of evidence for effective interventions. Epidemiological study of chronic pain, through an understanding of its distribution and determinants, can inform the development, targeting, and evaluation of interventions in the general population. This paper reviews current knowledge of risk markers associated with chronic pain and considers how these might inform management and prevention. Risk factors include socio-demographic, clinical, psychological, and biological factors. These are relevant to our understanding of chronic pain mechanisms and the nature of, and responses to, current and future treatments. PMID- 23794642 TI - Neuroinflammation and the generation of neuropathic pain. AB - Inflammation is the process by which an organism responds to tissue injury involving both immune cell recruitment and mediator release. Diverse causes of neuropathic pain are associated with excessive inflammation in both the peripheral and central nervous system which may contribute to the initiation and maintenance of persistent pain. Chemical mediators, such as cytokines, chemokines, and lipid mediators, released during an inflammatory response have the undesired effect of sensitizing and stimulating nociceptors, their central synaptic targets or both. These changes can promote long-term maladaptive plasticity resulting in persistent neuropathic pain. This review aims to provide an overview of inflammatory mechanisms at differing levels of the sensory neuroaxis with a focus on neuropathic pain. We will compare and contrast neuropathic pain states such as traumatic nerve injury which is associated with a vigorous inflammatory response and chemotherapy induced pain in which the inflammatory response is much more modest. Targeting excessive inflammation in neuropathic pain provides potential therapeutic opportunities and we will discuss some of the opportunities but also the clinical challenges in such an approach. PMID- 23794641 TI - Assessment of patients with chronic pain. AB - Chronic pain is a public health concern affecting 20-30% of the population of Western countries. Although there have been many scientific advances in the understanding of the neurophysiology of pain, precisely assessing and diagnosing a patient's chronic pain problem is not straightforward or well-defined. How chronic pain is conceptualized influences how pain is evaluated and the factors considered when making a chronic pain diagnosis. There is no one-to-one relationship between the amount or type of organic pathology and pain intensity, but instead, the chronic pain experience is shaped by a myriad of biomedical, psychosocial (e.g. patients' beliefs, expectations, and mood), and behavioural factors (e.g. context, responses by significant others). Assessing each of these three domains through a comprehensive evaluation of the person with chronic pain is essential for treatment decisions and to facilitate optimal outcomes. This evaluation should include a thorough patient history and medical evaluation and a brief screening interview where the patient's behaviour can be observed. Further assessment to address questions identified during the initial evaluation will guide decisions as to what additional assessments, if any, may be appropriate. Standardized self-reported instruments to evaluate the patient's pain intensity, functional abilities, beliefs and expectations, and emotional distress are available, and can be administered by the physician, or a referral for in depth evaluation can be made to assist in treatment planning. PMID- 23794643 TI - Challenges in design and interpretation of chronic pain trials. AB - The process of systematic review has shone a light on the methodology of randomized controlled trials. Notably, a range of potential biases hinders the interpretation of chronic pain trials. These include a consistent bias favouring active over placebo in trials that are small and of short duration. The use of the 'last observation carried forward' imputation method is known to inflate results, often generating statistically significance when adverse event withdrawals are high; in clinical practice terms, this is the wrong answer. Patients want outcomes of low pain scores, large reductions in pain and relief from associated symptoms, with improvements in ability to function and in quality of life. Some patients achieve this, but many do not. The distribution of benefit is skewed and the use of average pain scores, or change in pain, can be misleading compared with responder analysis in which withdrawal is regarded as non-response. Historically, chronic pain trials have had a simple classic or a crossover design. They have been small and short, and used inappropriate imputation and outcomes unconnected to the experiences of most patients. While these designs are useful for answering some questions, they may be insensitive for many interventions. Newer designs, like enriched enrolment randomized withdrawal (EERW) trials or clinical effectiveness trials, are potentially more interesting and informative. PMID- 23794644 TI - Targeting novel peripheral mediators for the treatment of chronic pain. AB - Research efforts over the past two decades have helped us better understand the biological mechanisms that lead to chronic pain. Despite this, there has been limited progress in developing novel analgesics to treat sufferers of persistent pain conditions, who may account for as many as one-fifth of the population. A re evaluation of the strategies used to discover pain-relieving drugs is needed to meet this widespread clinical need. Here, we discuss the merits of pursuing peripherally acting pain mediators. We review the significant clinical evidence that neuronal activity from the periphery is a major contributor to painful symptom production and that peripheral mediators play a substantial role in this aberrant nociceptor activity. We discuss the clinical benefits of blocking individual known mediators and describe our own approach to identify novel mediators. PMID- 23794646 TI - Psychological approaches to chronic pain management: evidence and challenges. AB - Psychological interventions are a mainstay of modern pain management practice and a recommended feature of a modern pain treatment service. Systematic reviews for the evidence of psychological interventions are reviewed in this article. The evidence for effectiveness is strongest for cognitive behavioural therapy with a focus on cognitive coping strategies and behavioural rehearsal. Most evidence is available for treatments of adult pain, although adolescent chronic pain treatments are also reviewed. It is clear that treatment benefit can be achieved with cognitive behavioural methods. It is possible to effect change in pain, mood, and disability, changes not achieved by chance or by exposure to any other treatment. However, the overall effect sizes of treatments for adults, across all trials, are modest. Reasons for the relatively modest treatment effects are discussed within the context of all treatments for chronic pain being disappointing when measured by the average. Suggestions for improving both trials and evidence summaries are made. Finally, consideration is given to what can be achieved by the pain specialist without access to specialist psychology resource. PMID- 23794645 TI - Sex differences in pain: a brief review of clinical and experimental findings. AB - Recent years have witnessed substantially increased research regarding sex differences in pain. The expansive body of literature in this area clearly suggests that men and women differ in their responses to pain, with increased pain sensitivity and risk for clinical pain commonly being observed among women. Also, differences in responsivity to pharmacological and non-pharmacological pain interventions have been observed; however, these effects are not always consistent and appear dependent on treatment type and characteristics of both the pain and the provider. Although the specific aetiological basis underlying these sex differences is unknown, it seems inevitable that multiple biological and psychosocial processes are contributing factors. For instance, emerging evidence suggests that genotype and endogenous opioid functioning play a causal role in these disparities, and considerable literature implicates sex hormones as factors influencing pain sensitivity. However, the specific modulatory effect of sex hormones on pain among men and women requires further exploration. Psychosocial processes such as pain coping and early-life exposure to stress may also explain sex differences in pain, in addition to stereotypical gender roles that may contribute to differences in pain expression. Therefore, this review will provide a brief overview of the extant literature examining sex-related differences in clinical and experimental pain, and highlights several biopsychosocial mechanisms implicated in these male-female differences. The future directions of this field of research are discussed with an emphasis aimed towards further elucidation of mechanisms which may inform future efforts to develop sex-specific treatments. PMID- 23794648 TI - Neuropathic pain: a pathway for care developed by the British Pain Society. AB - Neuropathic pain is a common chronic pain condition that can be challenging to treat, particularly for non-specialists. The development of the Map of Medicine care pathway for the management of neuropathic pain was led by the British Pain Society. Focusing on treatment by non-specialists, this pathway is based on new evidence, consensus, and the interests of service users. This paper presents the care pathway and accompanying evidence base, highlighting its salient features, and discussing important treatment points. After initial assessment, the pathway progresses through first-, second-, and third-line drug treatment, includes advice on topical treatment and opioids (in specific circumstances), and describes non-pharmacological approaches. Importantly, timely review of patients and referral to specialist secondary or tertiary care must be considered as vital components of the pathway. Although the emphasis was not on specialist treatment, advice is given on existing interventions, including neural stimulation and multi disciplinary care. These, and other steps on the pathway, will be subject to further review as more evidence becomes available. In the meantime, the pathway represents a straightforward, valuable and accessible approach for healthcare professionals managing the distress and impact of neuropathic pain. PMID- 23794647 TI - Imaging pain: a potent means for investigating pain mechanisms in patients. AB - Chronic pain is a state of physical suffering strongly associated with feelings of anxiety, depression and despair. Disease pathophysiology, psychological state, and social milieu can influence chronic pain, but can be difficult to diagnose based solely on clinical presentation. Here, we review brain neuroimaging research that is shaping our understanding of pain mechanisms, and consider how such knowledge might lead to useful diagnostic tools for the management of persistent pain in individual patients. PMID- 23794649 TI - Opioids and immune modulation: more questions than answers. AB - Opioid addicts are more likely to present with infections suggesting opioids are immune modulators. The potential sites/mechanism(s) for this modulation are controversial and on close inspection not well supported by the current literature. It has long been assumed that opioid-induced immune modulation occurs via a combination of direct actions on the immune cell itself, via the hypothalamic-pituitary-adrenal (HPA) axis, or both. Opioid receptors are classified as MOP (MU, mu), DOP (delta, delta), and KOP (kappa, kappa)--classical naloxone sensitive receptors--or NOP (the receptor for nociceptin/orphanin FQ), which is naloxone insensitive. Opioids currently used in clinical practice predominantly target the MOP receptor. There do not appear to be classical opioid receptors present on immune cells. The evidence for HPA activation is also poor and shows some species dependence. Most opioids used clinically or as drugs of abuse do not target the NOP receptor. Other possible target sites for immune modulation include the sympathetic nervous system and central sites. We are currently unable to accurately define the cellular target for immune modulation and suggest further investigation is required. Based on the differences observed when comparing studies in laboratory animals and those performed in humans we suggest that further studies in the clinical setting are needed. PMID- 23794650 TI - Psychosocial interventions for managing pain in older adults: outcomes and clinical implications. AB - Interest in the use of psychosocial interventions to help older adults manage pain is growing. In this article, we review this approach. The first section reviews the conceptual background for psychosocial interventions with a special emphasis on the biopsychosocial model of pain. The second section highlights three psychosocial interventions used with older adults: cognitive behavioural therapy, emotional disclosure, and mind-body interventions (specifically mindfulness-based stress reduction and yoga). The final section of the paper highlights important future directions for work in this area. PMID- 23794651 TI - Differential diagnosis of facial pain and guidelines for management. AB - The diagnosis and management of facial pain below the eye can be very different dependant on whether the patient visits a dentist or medical practitioner. A structure for accurate diagnosis is proposed beginning with a very careful history. The commonest acute causes of pain are dental and these are well managed by dentists. Chronic facial pain can be unilateral or bilateral and continuous or episodic. The commonest non-dental pains are temporomandibular disorders (TMDs), especially musculoskeletal involving the muscles of mastication either unilaterally or bilaterally; they may be associated with other chronic pains. A very wide range of treatments are used but early diagnosis, reassurance and some simple physiotherapy is often effective in those with good coping strategies. Dentists will often make splints to wear at night. Neuropathic pain is usually unilateral and of the episodic type; the most easily recognized is trigeminal neuralgia. This severe electric shock like pain, provoked by light touch, responds best to carbamazepine, and neurosurgery in poorly controlled patients. Trauma, either major or because of dental procedures, results in neuropathic pain and these are then managed as for any other neuropathic pain. Red flags include giant cell arteritis which much be distinguished from temporomandibular disorders (TMD), especially in >50 yr olds, and cancer which can present as a progressive neuropathic pain. Burning mouth syndrome is rarely recognized as a neuropathic pain as it occurs principally in peri-menopausal women and is thought to be psychological. Chronic facial pain patients are best managed by a multidisciplinary team. PMID- 23794652 TI - Neuropathic pain in cancer. AB - Cancer-related neuropathic pain is common; it can be disease related or related to the acute or chronic effects of cancer treatment. For example, chemotherapy induced peripheral neuropathy occurs in 90% of patients receiving neurotoxic chemotherapy. Cancer treatments have become more effective; patients are living longer with cancer and there are more cancer survivors. However, side-effects (particularly neuropathy) have become more problematic. The key to management of cancer-related neuropathy is a considered assessment, remembering not to miss the opportunity of reversing the cause of the pain with appropriate oncological management. An increasing range of oncological therapies are available, including radiotherapy, chemotherapy, hormonal therapy, or one of the evolving approaches (e.g. immune therapies). Patients are often elderly and with comorbidities; therefore, all treatment decisions have to be made carefully and reviewed appropriately. Cancer pain is often of mixed aetiology or, if purely neuropathic, may be one of several pains experienced by a patient. For these reasons, opioids are used more frequently in patients with cancer-related neuropathic pain. Standard guidelines for the use of anticonvulsants (e.g. pregabalin and gabapentin), antidepressants (e.g. duloxetine and tricyclics), and topical treatments (e.g. capsaicin and lidocaine) may be applicable, but there is a lack of good-quality clinical trials in cancer-related neuropathic pain. Choice is dictated not just by age, drug interactions, and comorbidities, but also by the coexistence of many symptoms in patients with cancer. Treating more than one symptom with a particular neuropathic pain agent can avoid polypharmacy. PMID- 23794653 TI - Low back and radicular pain: a pathway for care developed by the British Pain Society. AB - These consensus guidelines aim to provide an overview of best practice for managing chronic spinal pain reflecting the heterogeneity of low back pain. Most guidelines have covered only one aspect of spinal care and thus have been divisive and potentially worsened the quality of care. Additionally, some of the evidence base is subjective and of poor quality. The British Pain Society low back pain pathway has reached across all disciplines and involved input from patients. It is recognized, however, that there is an urgent need for further good-quality clinical research in this area to underpin future guidelines. Considerable work is still needed to clarify the evidence; however, foundations have been laid with this pathway. Key features include: risk stratification; clarification of intensity of psychological interventions; a logical progression for the management of sciatica; and decision points for considering structural interventions such as spinal injections and surgery. PMID- 23794654 TI - Comparison of propofol and fentanyl for preventing emergence agitation in children. PMID- 23794655 TI - Emergence agitation after sevoflurane anaesthesia in children. PMID- 23794656 TI - Differences in study results. PMID- 23794657 TI - Dexmedetomidine as adjuvant for peripheral nerve blocks. PMID- 23794658 TI - Alternative methods to improve probability of CVC catheter placement. PMID- 23794659 TI - Alternative methods to improve the probability of correct central venous catheter placement. PMID- 23794660 TI - Control group bias: a potential cause of over-estimating the benefit of videolaryngoscopy on laryngeal view. PMID- 23794661 TI - Use of transabdominal ultrasound to enhance safety during oesophageal dilatation. PMID- 23794662 TI - Internal leaks into anaesthesia machines: an unaddressed problem. PMID- 23794663 TI - Rescuing direct laryngoscopy: is it enough for the surgeon? PMID- 23794669 TI - Blockade of CCL2/CCR2 signalling ameliorates diabetic nephropathy in db/db mice. AB - BACKGROUND: CCL2/C-C chemokine receptor 2 (CCR2) signalling is suggested to play a significant role in various kidney diseases including diabetic nephropathy. We investigated the renoprotective effect of a CCR2 antagonist, RS102895, on the development of diabetic nephropathy in a type 2 diabetic mouse model. METHODS: Six-week-old diabetic db/db and non-diabetic db/m mice were fed either normal chow or chow mixed with 2 mg/kg/day of RS102895 for 9 weeks. We investigated the effects of CCR2 antagonism on blood glucose, blood pressure, albuminuria and the structure and ultrastructure of the kidney. RESULTS: Diabetes-induced albuminuria was significantly improved after CCR2 antagonist treatment, and glucose intolerance was improved in the RS102895-treated diabetic mice. RS102895 did not affect blood pressure, body weight or kidney weight. Mesangial expansion, glomerular basement membrane thickening and increased desmin staining in the diabetic kidney were significantly improved after RS102895 treatment. The up regulation of vascular endothelial growth factor mRNA expression and the down regulation of nephrin mRNA expression were markedly improved in the kidneys of RS102895-treated diabetic mice. Increased renal CD68 and arginase II and urinary malondialdehyde in diabetes were effectively attenuated by RS102895 treatment. CONCLUSION: Blockade of CCL2/CCR2 signalling by RS102895 ameliorates diabetic nephropathy not only by improving blood glucose levels but also by preventing CCL2/CCR2 signalling from altering renal nephrin and VEGF expressions through blocking macrophage infiltration, inflammation and oxidative stress in type 2 diabetic mice. PMID- 23794670 TI - Haemodilution-induced changes in coagulation and effects of haemostatic components under flow conditions. AB - BACKGROUND: Blood flow patterns are important modifiers of platelet interactions with plasma coagulation factors. However, it is not feasible to evaluate rheological effects of haemodilution on coagulation using conventional coagulation testing. METHODS: We evaluated thrombus formation with a microchip based flow-chamber system using whole blood from 12 healthy volunteers (with/without 40% dilution with saline), and 15 cardiac patients [before/after cardiopulmonary bypass (CPB)] in parallel with thromboelastometry. The in vitro additions of von Willebrand factor (vWF, 1.5 U ml(-1)), prothrombin complex concentrate (PCC, 0.3 U ml(-1)), fibrinogen (2 g litre(-1)), or combined PCC (0.3 U ml(-1)) and fibrinogen (1 g litre(-1)) were examined. Recalcified whole-blood samples were perfused over the microchip coated with collagen and tissue thromboplastin at flow rates of 10 and 3 ul min(-1). RESULTS: Dilution of whole blood led to delayed onset of thrombus formation (Ton), and thrombus growth (T80). Changes relative to baseline values were more extensive at 10 ul min(-1) (>=85% prolongation for Ton and T80) than at 3 ul min(-1) (>=40% prolongation for Ton and T80). Adding vWF accelerated thrombus formation only at 10 ul min(-1), while PCC increased thrombin generation in the thrombus at both flow rates. Fibrinogen increased mural thrombus formation at 3 ul min(-1). Decreased clot strength after dilution was restored by fibrinogen, but not by vWF or PCC on thromboelastometry. Additive effects of fibrinogen and PCC in post-CPB blood were demonstrated by both flow chamber and thromboelastometry. CONCLUSIONS: Blood flow affects thrombus formation after haemodilution and subsequent haemostatic component interventions, with differential effects at low and high flow. PMID- 23794671 TI - Comparison of techniques for double-lumen endobronchial intubation: 90 degrees or 180 degrees rotation during advancement through the glottis. AB - BACKGROUND: During endobronchial intubation with a double-lumen endobronchial tube (DLT), the DLT is conventionally rotated through 90 degrees when the bronchial tip is just past the vocal cords. This study was performed to investigate if rotation of the DLT through 180 degrees decreases postoperative hoarseness, sore throat, or vocal cord injuries. METHODS: Patients (n=164) undergoing thoracic surgery were randomized into two groups. Just after the bronchial tip passed the glottis, left-sided DLTs were rotated 90 degrees (Group 90, n=84) or 180 degrees (Group 180, n=80) counterclockwise and advanced. In the Group 180, DLTs were re-rotated 90 degrees clockwise after the tracheal tip passed the glottis. Resistance during the advance of DLTs was assessed. Hoarseness and sore throat were evaluated for three postoperative days. Vocal cords were examined on the first postoperative day. RESULTS: In nine patients allocated to Group 90, the DLT could not be advanced past the glottis because of severe resistance. There was less resistance to advancement of the DLT in Group 180 compared with Group 90 (P<0.001). The incidence of hoarseness was comparable between the two groups. Sore throat and vocal cord injuries occurred less frequently in Group 180 compared with Group 90 (20 vs 40%, P=0.008; 19 vs 47%, P=0.032). CONCLUSIONS: Rotation of a DLT through 180 degrees facilitated its passage through the glottis and reduced the incidence of postoperative sore throat and vocal cord injuries. PMID- 23794672 TI - Screening and risk evaluation for sudden cardiac death in ischaemic and non ischaemic cardiomyopathy: results of the European Heart Rhythm Association survey. AB - The purpose of this EHRA survey was to examine the current clinical practice of screening and risk evaluation for sudden cardiac death in ischaemic and non ischaemic cardiomyopathy with a focus on selection of candidates for implantable cardioverter-defibrillator (ICD) therapy, timing of ICD implantation, and use of non-invasive and invasive diagnostic tests across Europe. A systematic screening programme for sudden cardiac death existed in 19 out of 31 centres (61.3%). Implantation of ICDs according to the inclusion criteria of MADIT-II and SCD-HeFT trials was reported in 30 and 29% of centres, respectively, followed by MADIT-CRT (18%), COMPANION (16%), and combined MADIT and MUSTT (7%) indications. In patients with severe renal impairment, ICD implantation for primary prevention of sudden death was always avoided in 8 centres (33.3%), was not used only if creatinine level was >2.5 mg/dL in 10 centres (32.2%), and in patients with permanent dialysis in 8 centres (33.3%). Signal-averaged electrocardiography and heart rate variability were never considered as risk stratification tools in 23 centres (74.2%). Implantation of a loop recorder was performed in patients with borderline indications for ICD therapy in 6 centres (19.4%), for research purposes in 5 (16.1%), and was never performed in 20 (64.5%) centres. In conclusion, the majority of participating European centres have a screening programme for sudden cardiac death and the selection of candidates for ICD therapy was mainly based on the clinical risk stratification and not on non invasive and invasive diagnostic tests or implantable loop recorder use. PMID- 23794673 TI - Carotid artery stenting outcomes: do they correlate with antiplatelet response assays? AB - OBJECTIVE: Limited data exist regarding the use of antiplatelet response assays during neuroendovascular intervention. We report outcomes after carotid artery stenting (CAS) based on aspirin and P2Y12 assays. METHODS: We retrospectively identified patients who had aspirin and P2Y12 assays at the time of stenting. Aspirin (325 mg) and clopidogrel (75 mg) were started 7-10 days pre-intervention. If not possible, aspirin (650 mg) and clopidogrel (600 mg) loading doses were given pre-intervention. Assays were checked on postoperative day 0/1. Outcomes included neurological ischemic sequela at 30 days, 1 and 2 years, as well as 30 day death/hemorrhage/myocardial infarction. RESULTS: 449 patients were included. Mean P2Y12 reaction unit (PRU) values were higher in patients with an ipsilateral ischemic event (stroke/transient ischemic attack (TIA)) or stroke (alone) at 1 and 2 years than in patients with no events: ischemic event versus no event at 1 year, 252 vs 202 (p=0.008); stroke versus no stroke at 1 year, 252 versus 203(p=0.029); ischemic event versus no event at 2 years, 244 vs 203 (p=0.047); stroke versus no stroke at 2 years, 243 versus 203 (p=0.082). Ischemic event free survival (stroke/TIA, p=0.0268) and overall survival (p=0.0291) post-CAS were longer in patients with PRU <=198 compared with an initial threshold of PRU <=237. Mean PRU values were higher in patients who died from all causes at 30 days than in survivors (p=0.031). No correlation was found between lower PRU values and hemorrhage. Aspirin reaction units did not correlate with outcome. CONCLUSIONS: PRU <=198 may be associated with a lower incidence of ischemic neurological sequela and death post-CAS. Prospective studies are needed to validate the relationship between antiplatelet assays and outcomes post-CAS. PMID- 23794674 TI - Reporting standards for balloon test occlusion. PMID- 23794675 TI - Y stenting assisted coiling using a new low profile visible intraluminal support device for wide necked basilar tip aneurysms: a technical report. AB - Many endovascular techniques have been described in recent years for the management of wide necked aneurysms. The Y stent assisted technique has been generally used for coil embolization of wide necked bifurcation aneurysms. This technique was first described for the treatment of basilar tip aneurysms in combination with several different devices, demonstrating encouraging results. We report the results of the first two cases of wide necked basilar tip aneurysms treated with Y stent assisted coil embolization using a new low profile visible intraluminal stent (LVIS Jr; MicroVention, Tustin, California, USA) delivered through a 0.017 inch microcatheter. We also reviewed the literature comparing other endovascular techniques (coiling alone, stent assisted coiling, and Y stent assisted coiling) for wide necked aneurysms. The LVIS Jr device offers a new option for the treatment of these challenging lesions, with clear advantages over currently available intracranial stents. Larger series and long term results are needed to confirm the applicability and durability of this technique/technology. PMID- 23794676 TI - An examination of the association between premature mortality and life expectancy among men in Europe. AB - BACKGROUND: A feature of the health of men across Europe is their higher rates of premature mortality and shorter life expectancy at birth than women. Following the publication of the first State of Men's Health in Europe report, we sought to explore possible reasons. METHOD: We analyzed trends in life expectancy at birth in 19 European Union member states (EU19) between 1999 and 2008 using mortality data obtained from Eurostat. We then used Pollard's decomposition method to identify the contribution of deaths from different causes and at different age groups to differences in life expectancy. RESULTS: Between 1999 and 2008, life expectancy at birth in the EU19 increased by 2.74 years for men and by 2.09 years for women. Most of these improvements were due to reductions in mortality at ages >60, with cardiovascular disease accounting for approximately half these improvements for men. In 2008, life expectancy of men in the EU19 was 5.92 years lower than that of women. Deaths from all major groups of causes, and at all ages, contributed to this gap, with external causes contributing 0.96 years, cardiovascular disease 1.80 years and neoplasms 1.61 years. CONCLUSION: Improvements in the life expectancy at birth of men and women have mostly occurred at older ages. There has been little improvement in the high rate of premature death in younger men, suggesting a need for interventions to tackle their high death rate. PMID- 23794677 TI - Cold-related cardiorespiratory symptoms among subjects with and without hypertension: the National FINRISK Study 2002. AB - BACKGROUND: Exposure to cold weather increases blood pressure (BP) and may aggravate the symptoms and influence the prognosis of subjects with a diagnosis of hypertension. We tested the hypothesis that subjects with hypertension alone or in combination with another cardiovascular disease (CVD) experience cold related cardiorespiratory symptoms more commonly than persons without hypertension. This information is relevant for proper treatment and could serve as an indicator for predicting wintertime morbidity and mortality. METHODS: A self-administered questionnaire inquiring of cold-related symptoms was obtained from 6591 men and women aged 25-74 yrs of the FINRISK Study 2002 population. BP was measured in association with clinical examinations. Symptom prevalence was compared between subjects with diagnosed hypertensive disease with (n = 395) or without (n = 764) another CVD, untreated diagnosed hypertension (n = 1308), measured high BP (n = 1070) and a reference group (n = 2728) with normal BP. RESULTS: Hypertension in combination with another CVD was associated with increased cold-related dyspnoea (men: adjusted odds ratio 3.94, 95% confidence interval 2.57-6.02)/women: 4.41, 2.84-6.86), cough (2.64, 1.62-4.32/4.26, 2.60 6.99), wheezing (2.51, 1.42-4.43/;3.73, 2.08-6.69), mucus excretion (1.90, 1.24 2.91/2.53, 1.54-4.16), chest pain (22.5, 9.81-51.7/17.7, 8.37-37.5) and arrhythmias (43.4, 8.91-211/8.99, 3.99-20.2), compared with the reference group. Both diagnosed treated hypertension and untreated hypertension and measured high BP resulted in increased cardiorespiratory symptoms during the cold season. CONCLUSION: Hypertension alone and together with another CVD is strongly associated with cold-related cardiorespiratory symptoms. As these symptoms may predict adverse health events, hypertensive patients need customized care and advice on how to cope with cold weather. PMID- 23794678 TI - Preload-adjusted left ventricular dP/dtmax: a sensitive, continuous, load independent contractility index. AB - The classical indicators of left ventricular (LV) performances have been derived from pressure-volume (PV) and stroke work-volume plots obtained during various loading or pharmacological interventions. More recently, the preload-adjusted maximal change in pressure over time (PAdP/dtmax), derived from single beat PV analysis, has been shown to reflect the LV systolic performance accurately in varying conditions of inotropy and afterload. The objective of this study was to address whether PAdP/dtmax is a valid indicator of LV function in the setting of large preload variations, compared with the classical dP/dtmax-end-diastolic volume (EDV) and stroke work-EDV (preload recruitable stroke work) relationships. Nine anaesthetized and mechanically ventilated rats were instrumented with a ventricular conductance catheter. Stepwise preload reduction was achieved by repeated blood withdrawals (up to a total of 5 ml). Steady-state and dynamic PV loops were recorded during brief occlusion of the inferior vena cava, and LV function parameters were derived from these recordings. Our results demonstrate that PAdP/dtmax behaved in a similar manner to preload recruitable stroke work, reflecting well-maintained LV contractility during controlled haemorrhage until mean arterial pressure decreased below 40 mmHg. In contrast, dP/dtmax-EDV increased significantly and exhibited a curvilinear response that was associated with a large inter- and intra-animal variability. In a model of acute preload reduction, PAdP/dtmax was found to be the best indicator of systolic LV function. Given its simplicity, this real-time index derived from single beat analysis should be tested further in clinical settings. PMID- 23794679 TI - Rasmussen encephalitis treated with natalizumab. PMID- 23794680 TI - Electrographic seizures in pediatric ICU patients: cohort study of risk factors and mortality. AB - OBJECTIVES: We aimed to determine the incidence of electrographic seizures in children in the pediatric intensive care unit who underwent EEG monitoring, risk factors for electrographic seizures, and whether electrographic seizures were associated with increased odds of mortality. METHODS: Eleven sites in North America retrospectively reviewed a total of 550 consecutive children in pediatric intensive care units who underwent EEG monitoring. We collected data on demographics, diagnoses, clinical seizures, mental status at EEG onset, EEG background, interictal epileptiform discharges, electrographic seizures, intensive care unit length of stay, and in-hospital mortality. RESULTS: Electrographic seizures occurred in 162 of 550 subjects (30%), of which 61 subjects (38%) had electrographic status epilepticus. Electrographic seizures were exclusively subclinical in 59 of 162 subjects (36%). A multivariable logistic regression model showed that independent risk factors for electrographic seizures included younger age, clinical seizures prior to EEG monitoring, an abnormal initial EEG background, interictal epileptiform discharges, and a diagnosis of epilepsy. Subjects with electrographic status epilepticus had greater odds of in-hospital death, even after adjusting for EEG background and neurologic diagnosis category. CONCLUSIONS: Electrographic seizures are common among children in the pediatric intensive care unit, particularly those with specific risk factors. Electrographic status epilepticus occurs in more than one third of children with electrographic seizures and is associated with higher in hospital mortality. PMID- 23794682 TI - Evolution of mild cognitive impairment in Parkinson disease. AB - OBJECTIVE: We examined the development of Parkinson disease (PD)-mild cognitive impairment (MCI) in patients with newly diagnosed PD over 5 years using recently proposed consensus criteria, and we assessed the reliability of the criteria. METHODS: Patients with PD (n = 123) underwent extensive neuropsychological testing at baseline and after 3 (n = 93) and 5 years (n = 59). Two neuropsychologists independently applied the PD-MCI criteria to examine the interrater and intrarater reliability. RESULTS: At baseline, 35% of patients had PD-MCI. Three years later, 53% of the patients had PD-MCI. At 5-year follow-up, 20 patients who had PD-MCI at an earlier assessment had converted to PD dementia and 50% of the remaining patients without dementia had MCI. The interrater reliability (kappa) was 0.91. The intrarater reliabilities were 0.85 and 0.96. CONCLUSION: Approximately one-third of patients with newly diagnosed PD fulfill the consensus criteria for PD-MCI; after 5 years, this proportion is approximately 50% of patients without dementia. The criteria have good interrater and intrarater reliability. PMID- 23794681 TI - Differentiating primary progressive aphasias in a brief sample of connected speech. AB - OBJECTIVE: A brief speech expression protocol that can be administered and scored without special training would aid in the differential diagnosis of the 3 principal forms of primary progressive aphasia (PPA): nonfluent/agrammatic PPA, logopenic variant PPA, and semantic variant PPA. METHODS: We used a picture description task to elicit a short speech sample, and we evaluated impairments in speech-sound production, speech rate, lexical retrieval, and grammaticality. We compared the results with those obtained by a longer, previously validated protocol and further validated performance with multimodal imaging to assess the neuroanatomical basis of the deficits. RESULTS: We found different patterns of impaired grammar in each PPA variant, and additional language production features were impaired in each: nonfluent/agrammatic PPA was characterized by speech-sound errors; logopenic variant PPA by dysfluencies (false starts and hesitations); and semantic variant PPA by poor retrieval of nouns. Strong correlations were found between this brief speech sample and a lengthier narrative speech sample. A composite measure of grammaticality and other measures of speech production were correlated with distinct regions of gray matter atrophy and reduced white matter fractional anisotropy in each PPA variant. CONCLUSIONS: These findings provide evidence that large-scale networks are required for fluent, grammatical expression; that these networks can be selectively disrupted in PPA syndromes; and that quantitative analysis of a brief speech sample can reveal the corresponding distinct speech characteristics. PMID- 23794683 TI - GFPT1-myasthenia: clinical, structural, and electrophysiologic heterogeneity. AB - OBJECTIVE: To identify patients with GFPT1-related limb-girdle myasthenia and analyze phenotypic consequences of the mutations. METHODS: We performed genetic analysis, histochemical, immunoblot, and ultrastructural studies and in vitro electrophysiologic analysis of neuromuscular transmission. RESULTS: We identified 16 recessive mutations in GFPT1 in 11 patients, of which 12 are novel. Ten patients had slowly progressive limb-girdle weakness responsive to cholinergic agonists with onset between infancy and age 19 years. One patient (no. 6) harbored a nonsense mutation and a second mutation that disrupts the muscle specific GFPT1 exon. This patient never moved in utero, was apneic and arthrogrypotic at birth, and was bedfast, tube-fed, and barely responded to therapy at age 6 years. Histochemical studies in 9 of 11 patients showed tubular aggregates in 6 and rimmed vacuoles in 3. Microelectrode studies of intercostal muscle endplates in 5 patients indicated reduced synaptic response to acetylcholine in 3 and severely reduced quantal release in patient 6. Endplate acetylcholine receptor content was moderately reduced in only one patient. The synaptic contacts were small and single or grape-like, and quantitative electron microscopy revealed hypoplastic endplate regions. Numerous muscle fibers of patient 6 contained myriad dilated and degenerate vesicular profiles, autophagic vacuoles, and bizarre apoptotic nuclei. Glycoprotein expression in muscle was absent in patient 6 and reduced in 5 others. CONCLUSIONS: GFPT1-myasthenia is more heterogeneous than previously reported. Different parameters of neuromuscular transmission are variably affected. When disruption of muscle specific isoform determines the phenotype, this has devastating clinical, pathologic, and biochemical consequences. PMID- 23794684 TI - Reduced postmovement cortical inhibition in patients with paroxysmal kinesigenic dyskinesia. AB - OBJECTIVE: To characterize movement-related neural oscillatory activity and to clarify its neurophysiologic role in paroxysmal kinesigenic dyskinesia (PKD). METHODS: We recorded neuromagnetic event-related desynchronization (ERD) and event-related synchronization (ERS) activities in response to a self-paced finger lifting task in 16 patients with PKD and 17 healthy controls. RESULTS: The amplitude of alpha-ERD was comparable between the healthy controls and patients with PKD, whereas either the contralateral or ipsilateral beta-ERS was decreased. The peak latency of contralateral beta-ERS was delayed in patients with PKD. Patients with less frequent dyskinetic attacks demonstrated a larger ipsilateral beta-ERS. Moreover, some patients with PKD revealed a lesser degree of contralateral preponderance of beta-ERS generation. CONCLUSIONS: The present data imply a decreased postmovement inhibition of motor cortex in patients with PKD, and the inhibitory function in the contralateral hemisphere is more affected than that in the ipsilateral hemisphere. PMID- 23794685 TI - Olfactory dysfunction in patients with idiopathic intracranial hypertension. AB - OBJECTIVE: Although accumulating evidence suggests that a malfunction of the CSF system in idiopathic intracranial hypertension (IIH) may give rise to olfactory dysfunction, little objective knowledge is available at present about the olfactory capacity of patients with this condition. METHODS: Seventeen patients with IIH and 17 age- and sex-matched controls were included. The extended Sniffin' Sticks procedure was used to test odor threshold, discrimination, and identification (TDI). RESULTS: Median (interquartile range) values of the composite TDI score (29 [26.5-35.5] vs 35 [34-37], p = 0.003) were reduced in patients with IIH. Furthermore, Spearman correlation revealed reduced TDI values in patients with a recent clinical deterioration of IIH (r = 0.66, p = 0.004). CONCLUSIONS: Our pilot study provides new evidence that olfaction is impaired in patients with IIH, especially in those who have been newly diagnosed or who have experienced a recent clinical deterioration. PMID- 23794687 TI - Use of emergency contraceptive pills among female sex workers in Swaziland. AB - OBJECTIVES: Female sex workers (FSW) often have unprotected sex. Emergency contraceptive pills (ECP) are an important back-up method to prevent unwanted pregnancy among FSW. We examine ECP use among FSW in Swaziland. METHODS: Using data from a 2011 respondent-driven sampling survey of 325 Swazi FSW, we explored the association between individual characteristics and ever having used ECP. RESULTS: In weighted analyses, 27.5% of FSW had ever used ECP. Most (77.8%) had ever been pregnant, among whom 48.7% had had an unwanted pregnancy and 11.7% had had an abortion. Nearly half (47.5%) had experienced condom failure in the past month. Significant independent correlates of ECP use were younger age, higher education, higher income, having two or more children, and never having been married. CONCLUSIONS: FSW who are older or of lower socioeconomic status may not have adequate access to ECP. By better addressing these women's family planning needs, the dual goals of preventing unwanted pregnancy and preventing vertical transmission of HIV can be achieved. PMID- 23794688 TI - Open access orthodontics. PMID- 23794689 TI - Clinical trial design for orthodontists. AB - High-quality research should form the basis of all clinical practice. Randomized controlled trials currently provide the gold standard for investigating the effectiveness of treatment interventions and these are increasingly being used in orthodontics. Here we discuss the reasons why this form of investigation provides the most useful evidence for assessing treatment outcome. The methods available to achieve true randomization, a fundamental component in the design of these trials, are also discussed. In addition, we focus on how to minimize bias in clinical research, not only during the design and management of a trial, but also when disseminating results. We focus on the importance of using control groups correctly and describe methods that are available to adequately power a trial. Finally, we emphasise the importance of accurate and transparent reporting, which facilitates correct communication and assessment of the evidence. PMID- 23794690 TI - Setting up a randomized clinical trial in the UK: approvals and process. AB - Randomized clinical trials are considered the 'gold standard' in primary research for healthcare interventions. However, they can be expensive and time-consuming to set up and require many approvals to be in place before they can begin. This paper outlines how to determine what approvals are required for a trial, the background of each approval and the process for obtaining them. PMID- 23794691 TI - Great expectations: what do patients expect and how can expectations be managed? AB - Patients' expectations of their treatment are a key determinant in their satisfaction with treatment. Expectations may encompass not only notions of the outcome of treatment, but also the process of treatment. This article explores the processes by which expectations are formed, differences in expectations across patient groups, and the psychopathology of individuals with unrealistic expectations of treatment manifest in body dysmorphic disorder. PMID- 23794692 TI - The impact of tooth agenesis on oral health-related quality of life in children. AB - OBJECTIVE: The purpose of this cross-sectional survey was to evaluate the psychosocial impact of tooth agenesis in children and to investigate the potential influence of gender, socioeconomic status, severity of tooth absence, and the number of retained primary teeth on their quality of life. MATERIALS AND METHODS: A total of 86 children (36 male, 50 female) with tooth agenesis, aged 11 14 years were recruited from the Birmingham Dental Hospital, United Kingdom. Thirty subjects with a complete dentition and having a low treatment need acted as controls. Children completed the validated Child Perceptions Questionnaire (CPQ) and their parents completed the Parental-Caregiver Perceptions Questionnaire (P-CPQ). RESULTS: The median number of missing teeth in the sample population was 6. There were significant differences in the oral symptoms, functional limitations and the social and emotional well-being reported between the agenesis and control groups. The overall CPQ scores were significantly higher in children with tooth agenesis (P<0.001). No significant correlation was detected between the number of missing teeth and the quality of life score. There was no influence found on the CPQ score from gender, socioeconomic status, the site of agenesis or the presence of retained primary teeth. There was moderate correlation between parental and child reported quality of life. CONCLUSIONS: Tooth agenesis can have a significant impact on the quality of life of children, resulting in oral symptoms, functional limitation and also affecting emotional and social well-being. This does not appear to be related to the number of missing teeth. This study has implications for our understanding of the effect of tooth absence on the quality of life of children and their parents and addressing these reported impacts may help to improve patient satisfaction. PMID- 23794693 TI - The effects of face mask and tongue plate on maxillary deficiency in growing patients: a randomized clinical trial. AB - OBJECTIVE: The purpose of this randomized clinical trial was to compare the effects of facemask and tongue plate therapy in the treatment of class III malocclusion associated with maxillary deficiency in growing patients. DESIGN: Prospective, randomized clinical trial. SETTING: Department of Orthodontics, SB University of Medical Sciences Dental School, Tehran, Iran. METHODS: Fifty patients with maxillary deficiency were randomly allocated to two groups. One group was treated with a removable facemask and the other with a tongue plate. Three patients dropped out of the study leaving a final number of 47 that were analysed. The face mask group included 24 patients (12 males, 12 females) with a mean age of 9 (SD 1.2) years; while the tongue plate group included 23 patients (10 males, 13 females) with a mean age of 9.1 (SD 0.9) years. The patients lateral cephalograms obtained at the beginning and end of the study were analysed. RESULTS: Paired t-tests showed that SNA increased by 1 degrees (SD 1.5 degrees ) in the facemask group (P<0.001) and by 2.2 degrees (SD 1.5 degrees ) in the tongue plate group (P<0.001). With the exception of SNA and GoGn, Mann Whitney testing showed that there were no statistically significant differences between the two groups. IMPA was found to decrease significantly in both groups. CONCLUSION: Both treatment modalities were successful in moving the maxilla forward, proclining the maxillary incisors and retroclining the mandibular incisors. The more simple design of the tongue plate might therefore confer some advantages to this system in comparison with a facemask. PMID- 23794694 TI - Initial and fatigue bond strengths of nanofilled and conventional composite bonding adhesives. AB - AIM: To compare the initial and fatigue shear bond strengths of a nanofilled adhesive with a conventional light-cured adhesive in an ex vivo laboratory study. METHODS: Fifty hydroxyapatite discs were prepared by cold pressing. Using a standardized bonding protocol, 100 Victory series upper left central incisor brackets were bonded to discs with TransbondTM Supreme LV nanofilled composite resin and 100 brackets were bonded to discs with Transbond XT. Fifty brackets from each group were subjected to cyclic loading (5000 cycles at 2 Hz) at 50% of the mean bond strength in a Dartec Series HC10 Testing Machine. Initial (unfatigued) and fatigued bond strengths were determined by applying a shear force at the bracket/substrate interface using a custom-made metal jig in an Instron Universal Testing Machine. RESULTS AND STATISTICAL ANALYSIS: One-way analysis of variance showed that Transbond Supreme LV exhibited higher initial mean bond strength than Transbond XT (P = 0.001). No statistically significant difference was found between the fatigue bond strengths of Transbond Supreme LV and Transbond XT (P = 0.323). Two-way analysis of variance demonstrated statistically significant differences when the effect of the composite resin (P = 0.013) and fatigue (P = 0.017) were considered individually. However, when considered in combination there was no statistical significance (P = 0.09). Kaplan-Meier survival analysis showed superior survival of unfatigued brackets with Transbond Supreme LV, but there was no significant difference between the adhesives after fatiguing. CONCLUSIONS: The initial bond strength of Transbond Supreme LV was significantly higher than Transbond XT, while the fatigue bond strengths of both resins were comparable. Overall, Transbond Supreme LV demonstrated superior survival under loading than Transbond XT. However, while this was statistically significant for the initial loading, it was not significant after fatiguing. Although these laboratory findings are useful as indicators of potential clinical performance, extrapolation of these results should be carried out with caution. PMID- 23794695 TI - A Scottish cost analysis of interceptive orthodontics for thumb sucking habits. AB - OBJECTIVE: There is a potential cost saving to be made within the NHS by providing simple interceptive treatment rather than comprehensive treatment at a later date. The focus of this study is to determine the size of this potential cost by looking at the cost to NHS Tayside for the provision of interceptive treatment for cessation of thumb sucking and where this has been unsuccessful (or not provided) the costs of correction of the associated malocclusion. DESIGN: A cost analysis is described, investigating the costs of treatment solely to the NHS, both in the primary and secondary setting. METHODS: Three potential treatment pathways are identified with the costs calculated for each pathway. The actual cost of providing this treatment in NHS Tayside, and the potential cost saving in Tayside if there was a change in clinical practice are calculated. Both discounting of costs and a sensitivity analysis are performed. RESULTS: The cost to NHS Tayside of current practice was calculated to be between L123,710 and L124,930 per annum. Change in practice to replace use of a removable with a fixed habit breaker for the interceptive treatment of thumb sucking reduced the calculated cost to between L99,581 and L105,017. CONCLUSION: A saving could be made to the NHS, both locally and nationally, if the provision of a removable habit breaker was changed to a fixed habit breaker. In addition, increasing the proportion receiving active treatment, in the form of a fixed habit breaker, rather than monitoring, would appear to further reduce the cost to the NHS considerably. PMID- 23794696 TI - Does the bracket-ligature combination affect the amount of orthodontic space closure over three months? A randomized controlled trial. AB - OBJECTIVE: To investigate the effect of bracket-ligature combination on the amount of orthodontic space closure over three months. DESIGN: Randomized clinical trial with three parallel groups. SETTING: A hospital orthodontic department (Chesterfield Royal Hospital, UK). PARTICIPANTS: Forty-five patients requiring upper first premolar extractions. METHODS: Informed consent was obtained and participants were randomly allocated into one of three groups: (1) conventional pre-adjusted edgewise brackets and elastomeric ligatures; (2) conventional pre-adjusted edgewise brackets and Super Slick((r)) low friction elastomeric ligatures; (3) Damon 3MX((r)) passive self-ligating brackets. Space closure was undertaken on 0.019*0.025-inch stainless steel archwires with nickel titanium coil springs. Participants were recalled at four weekly intervals. Upper alginate impressions were taken at each visit (maximum three). The primary outcome measure was the mean amount of space closure in a 3-month period. RESULTS: A one-way ANOVA was undertaken [dependent variable: mean space closure (mm); independent variable: group allocation]. The amount of space closure was very similar between the three groups (1 mm per 28 days); however, there was a wide variation in the rate of space closure between individuals. The differences in the amount of space closure over three months between the three groups was very small and non-significant (P = 0.718). CONCLUSION: The hypothesis that reducing friction by modifying the bracket/ligature interface increases the rate of space closure was not supported. The major determinant of orthodontic tooth movement is probably the individual patient response. PMID- 23794697 TI - A systematic review of etiological and risk factors associated with bruxism. AB - OBJECTIVE: The aim of the present work was to systematically review the literature and identify all peer-reviewed papers dealing with etiological and risk factors associated with bruxism. DATA SOURCES: Data extraction was carried out according to the standard Cochrane systematic review methodology. The following databases were searched for randomized clinical trials (RCT), controlled clinical trials (CCT) or cohort studies: Cochrane Library, Medline, and Embase from 1980 to 2011. Unpublished literature was searched electronically using ClinicalTrials.gov. DATA SELECTION: The primary outcome was bruxism etiology. Studies should have a standardized method to assess bruxism. DATA EXTRACTION: Screening of eligible studies, assessment of the methodological quality and data extraction were conducted independently and in duplicate. Two reviewers inspected the references using the same search strategy and then applied the same inclusion criteria to the selected studies. They used criteria for methodological quality that was previously described in the Cochrane Handbook. Among the 1247 related articles that were critically assessed, one randomized clinical trial, one controlled clinical trial and seven longitudinal studies were included in the critical appraisal. Of these studies, five were selected, but reported different outcomes. DATA SYNTHESIS: There is convincing evidence that (sleep-related) bruxism can be induced by esophageal acidification and also that it has an important relationship with smoking in a dose-dependent manner. Disturbances in the central dopaminergic system are also implicated in the etiology of bruxism. PMID- 23794698 TI - Triplets with bilateral palatally displaced canines in association with third molar agenesis: an example of biologically related dental anomaly patterns? AB - This case series shows male triplets with similarly positioned palatally displaced canines and agenesis of third molars. It supports findings reported previously in the literature suggesting a genetic origin for the palatally displaced canine and other dental anomalies which may be biologically related. PMID- 23794699 TI - Working to fill the boss's shoes. PMID- 23794700 TI - Genome engineering with Cre-loxP. PMID- 23794701 TI - Independent control of immunoglobulin switch recombination at individual switch regions evidenced through Cre-loxP-mediated gene targeting. PMID- 23794703 TI - The dormancy dilemma: quiescence versus balanced proliferation. AB - Metastatic dissemination with subsequent clinical outgrowth leads to the greatest part of morbidity and mortality from most solid tumors. Even more daunting is that many of these metastatic deposits silently lie undetected, recurring years to decades after primary tumor extirpation by surgery or radiation (termed metastatic dormancy). As primary tumors are frequently curable, a critical focus now turns to preventing the lethal emergence from metastatic dormancy. Current carcinoma treatments include adjuvant therapy intended to kill the cryptic metastatic tumor cells. Because such standard therapies mainly kill cycling cells, this approach carries an implicit assumption that metastatic cells are in the mitogenic cycle. Thus, the pivotal question arises as to whether clinically occult micrometastases survive in a state of balanced proliferation and death, or whether these cells undergo at least long periods of quiescence marked by cell cycle arrest. The treatment implications are thus obvious--if the carcinoma cells are cycling then therapies should target cycling cells, whereas if cells are quiescent then therapies should either maintain dormancy or be toxic to dormant cells. Because this distinction is paramount to rational therapeutic development and administration, we investigated whether quiescence or balanced proliferation is the most likely etiology underlying metastatic dormancy. We recently published a computer simulation study that determined that balanced proliferation is not the likely driving force and that quiescence most likely participates in metastatic dormancy. As such, a greater emphasis on developing diagnostics and therapeutics for quiescent carcinomas is needed. PMID- 23794702 TI - Reciprocal relationship between myeloid-derived suppressor cells and T cells. AB - Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of myeloid cells that play a major role in the regulation of immune responses in many pathological conditions. These cells have a common myeloid origin, relatively immature state, common genetic and biochemical profiles, and, most importantly, the ability to inhibit immune responses. Although initial studies of MDSCs were almost exclusively performed in tumor-bearing mice or cancer patients, in recent years, it became clear that MDSCs play a critical role in the regulation of different types of inflammation that are not directly associated with cancer. In this review we discuss the nature of the complex relationship between MDSCs and the different populations of CD4(+) T cells. PMID- 23794705 TI - EGF receptor activates MET through MAPK to enhance non-small cell lung carcinoma invasion and brain metastasis. AB - MET amplification as a mechanism of acquired resistance to EGF receptor (EGFR) targeted therapies in non-small cell lung carcinoma (NSCLC) led to investigation of novel combinations of EGFR and MET kinase inhibitors. However, promiscuous interactions between MET and ERBB family members have made it difficult to evaluate the effects of MET on EGFR signaling, both independent of drug treatment and in the context of drug resistance. We addressed this issue by establishing a 32D model cell system wherein ERBBs or MET are expressed alone and in combination. Using this model, we determined that EGFR signaling is sufficient to induce MET phosphorylation, although MET activation is enhanced by coexpression of ERBB3. EGFR-MET cross-talk was not direct, but occurred by a combined regulation of MET levels and intermediary signaling through mitogen-activated protein kinases (MAPK). In NSCLCs harboring either wild-type or mutant EGFR, inhibiting EGFR or MAPK reduced MET activation and protein levels. Furthermore, MET signaling promoted EGFR-driven migration and invasion. Finally, EGFR-MET signaling was enhanced in a highly metastatic EGFR-mutant cell subpopulation, compared with the indolent parental line, and MET attenuation decreased the incidence of brain metastasis. Overall, our results establish that EGFR-MET signaling is critical for aggressive behavior of NSCLCs and rationalize its continued investigation as a therapeutic target for tumors harboring both wild type and mutant EGFR at early stages of progression. PMID- 23794706 TI - Targeting transmembrane TNF-alpha suppresses breast cancer growth. AB - TNF antagonists may offer therapeutic potential in solid tumors, but patients who have high serum levels of TNF-alpha fail to respond to infliximab, suggesting consumption of the circulating antibody and loss of transmembrane TNF-alpha (tmTNF-alpha) on tumors by ectodomain shedding. Addressing this possibility, we developed a monoclonal antibody (mAb) that binds both full-length tmTNF-alpha and its N-terminal truncated fragment on the membrane after tmTNF-alpha processing but does not cross-react with soluble TNF-alpha. We documented high levels of tmTNF-alpha expression in primary breast cancers, lower levels in atypical hyperplasia or hyperplasia, but undetectable levels in normal breast tissue, consistent with the notion that tmTNF-alpha is a potential therapeutic target. Evaluations in vitro and in vivo further supported this assertion. tmTNF-alpha mAb triggered antibody-dependent cell-mediated cytotoxicity against tmTNF-alpha expressing cells but not to tmTNF-alpha-negative cells. In tumor-bearing mice, tmTNF-alpha mAb delayed tumor growth, eliciting complete tumor regressions in some mice. Moreover, tmTNF-alpha mAb inhibited metastasis and expression of CD44v6, a prometastatic molecule. However, the antibody did not activate tmTNF alpha-mediated reverse signaling, which facilitates tumor survival and resistance to apoptosis, but instead inhibited NF-kappaB activation and Bcl-2 expression by decreasing tmTNF-alpha-positive cells. Overall, our results established that tmTNF-alpha mAb exerts effective antitumor activities and offers a promising candidate to treat tmTNF-alpha-positive tumors, particularly in patients that are nonresponders to TNF antagonists. PMID- 23794708 TI - Optimal targeting of HER2-PI3K signaling in breast cancer: mechanistic insights and clinical implications. AB - The combination of a PI3K inhibitor with trastuzumab has been shown to be effective at overcoming trastuzumab resistance in models of HER2(+) breast cancer by inhibiting HER2-PI3K-FOXO-survivin signaling. In this review the potential clinical implications of these findings are discussed. PMID- 23794709 TI - Modulation of granulocyte kinetics by GM-CSF/IFN-gamma in a human LPS rechallenge model. AB - Inflammation in response to infection or trauma can lead to CARS, which is characterized by leukocyte dysfunction. In this study, we used a human model system for CARS to study the effect of GM-CSF and IFN-gamma treatment on this immunoparalyzed state. Healthy human volunteers were treated with GM-CSF (4 MUg/kg), IFN-gamma (100 MUg), or placebo in between two challenges with Escherichia coli LPS/endotoxin (2 ng/kg). Serial leukocyte blood counts were measured. Neutrophil subsets were discriminated using CD16 and CD62L expression. LPS rechallenge resulted in increased mobilization of mature neutrophils, whereas banded neutrophils decreased. GM-CSF and IFN-gamma treatment did not restore these changes. GM-CSF treatment did, however, increase the number of CD16(bright)/CD62L(dim) neutrophils that were previously shown be able to suppress T cell proliferation. IFN-gamma treatment decreased neutrophilia seen after LPS rechallenge. Our study shows that LPS rechallenge was associated with changes in the distribution of neutrophil subsets, whereas no additional changes in kinetics of other granulocyte populations were observed. GM-CSF and IFN-gamma treatment induced a shift in granulocyte composition toward an anti-inflammatory direction by increasing CD16(bright)/CD62L(dim) cells or decreasing neutrophil counts, respectively. PMID- 23794711 TI - Mannose receptor and macrophage galactose-type lectin are involved in Bordetella pertussis mast cell interaction. AB - Mast cells are crucial in the development of immunity against Bordetella pertussis, and the function of TLRs in this process has been investigated. Here, the interaction between mast cells and B. pertussis with an emphasis on the role of CLRs is examined. In this study, two CLRs, MGL and MR, were detected for the first time on the surface of mast cells. The involvement of MR and MGL in the stimulation of mast cells by heat-inactivated BP was investigated by the use of blocking antibodies and specific carbohydrate ligands. The cell wall LOS of BP was also isolated to explore its role in this interaction. Mast cells stimulated with heat-inactivated BP or BP LOS induced TNF-alpha, IL-6, and IFN-gamma secretion, which was suppressed by blocking MR or MGL. Inhibition of CLRs signaling during BP stimulation affected the ability of mast cells to promote cytokine secretion in T cells but had no effect on the cell-surface expression of ICAM1. Blocking MR or MGL suppressed BP-induced NF-kappaB expression but not ERK phosphorylation. Syk was involved in the CLR-mediated activation of mast cells by BP. Bacterial recognition by immune cells has been predominantly attributed to TLRs; in this study, the novel role of CLRs in the BP-mast cell interaction is highlighted. PMID- 23794710 TI - RIP2 activity in inflammatory disease and implications for novel therapeutics. AB - The role of NOD2 and RIP2 in inflammatory disease has been paradoxical. Whereas loss-of-function NOD2 polymorphisms cause CD, a granulomatous disease of the gastrointestinal tract, gain-of-function mutations cause EOS-a granulomatous disease primarily affecting the skin, joints, and eyes. Thus, gain-of-function mutations and loss-of-function polymorphisms cause granulomatous inflammatory disease, only in different anatomic locations. The situation is complicated further by the fact that WT NOD2 and WT RIP2 activity has been implicated in diseases such as asthma, inflammatory arthritis and MS. This article reviews the role that the NOD2:RIP2 complex plays in inflammatory disease, with an emphasis on the inhibition of this signaling pathway as a novel pharmaceutical target in inflammatory disease. PMID- 23794712 TI - Technical advance: actin CytoFRET, a novel FRET flow cytometry method for detection of actin dynamics in resting and activated T cell. AB - Actin cytoskeleton plays a critical role in regulating T cell motility and activation. However, the lack of a real-time quantitative method to analyze actin assembly has limited the progress toward understanding actin regulation. Here, we describe a novel approach to probe actin dynamics on living T cells using FRET combined with flow cytometry. We have first generated a Jurkat T cell line stably coexpressing EGFP and mOrange FPs fused to actin. The real-time variation of actin monomer assembly or disassembly into filaments was quantified using a ratiometric flow cytometry method measuring changes in the mOrange/EGFP emission ratio. The method was validated on resting T cells by using chemical compounds with known effects on actin filaments and comparison with conventional microscopy imaging. Our method also detected the rapid and transient actin assembly in T cells stimulated by anti-CD3/CD28-coated beads, demonstrating its robustness and high sensitivity. Finally, we provide evidence that lentiviral-mediated transduction of shRNAs in engineered Jurkat cells could be used as a strategy to identify regulators of actin remodeling. In conclusion, the flow cytometric FRET analysis of actin polymerization represents a new technical advance to study the dynamics of actin regulation in intact cells. PMID- 23794713 TI - Accelerated direct reprogramming of fibroblasts into cardiomyocyte-like cells with the MyoD transactivation domain. AB - AIMS: Fibroblasts can be directly reprogrammed to cardiomyocyte-like cells by introducing defined genes. However, the reprogramming efficiency remains low, delaying the clinical application of this strategy to regenerative cardiology. We previously showed that fusion of the MyoD transactivation domain to the pluripotency transcription factor Oct4 facilitated the transcriptional activity of Oct4, resulting in highly efficient production of induced pluripotent stem cells. We examined whether the same approach can be applied to cardiac transcription factors to facilitate cardiac reprogramming. METHODS AND RESULTS: We fused the MyoD domain to Mef2c, Gata4, Hand2, and Tbx5 and transduced these genes in various combinations into mouse non-cardiac fibroblasts. Transduction of the chimeric Mef2c with the wild-types of the other three genes produced much larger beating clusters of cardiomyocyte-like cells faster than the combination of the four wild-type genes, with an efficiency of 3.5%, >15-fold greater than the wild-type genes. CONCLUSION: Fusion of a powerful transactivation domain to heterologous factors can increase the efficiency of direct reprogramming of fibroblasts to cardiomyocytes. PMID- 23794714 TI - Serum IF1 concentration is independently associated to HDL levels and to coronary heart disease: the GENES study. AB - HDL is strongly inversely related to cardiovascular risk. Hepatic HDL uptake is controlled by ecto-F1-ATPase activity, and potentially inhibited by mitochondrial inhibitor factor 1 (IF1). We recently found that IF1 is present in serum and correlates with HDL-cholesterol (HDL-C). Here, we have evaluated the relationship between circulating IF1 and plasma lipoproteins, and we determined whether IF1 concentration is associated with the risk of coronary heart disease (CHD). Serum IF1 was measured in 648 coronary patients ages 45-74 and in 669 matched male controls, in the context of a cross-sectional study on CHD. Cardiovascular risk factors were documented for each participant, including life-style habits and biological and clinical markers. In controls, multivariate analysis demonstrated that IF1 was independently positively associated with HDL-C and apoA-I (r = 0.27 and 0.28, respectively, P < 0.001) and negatively with triglycerides (r = -0.23, P < 0.001). Mean IF1 concentration was lower in CHD patients than in controls (0.43 mg/l and 0.53 mg/l, respectively, P < 0.001). In multivariate analyses, following adjustments on cardiovascular risk factors or markers, IF1 was negatively related to CHD (P < 0.001). This relationship was maintained after adjustment for HDL-C or apoA-I. This study identifies IF1 as a new determinant of HDL-C that is inversely associated with CHD. PMID- 23794715 TI - Direct evidence for attention-dependent influences of the frontal eye-fields on feature-responsive visual cortex. AB - Voluntary selective attention can prioritize different features in a visual scene. The frontal eye-fields (FEF) are one potential source of such feature specific top-down signals, but causal evidence for influences on visual cortex (as was shown for "spatial" attention) has remained elusive. Here, we show that transcranial magnetic stimulation (TMS) applied to right FEF increased the blood oxygen level-dependent (BOLD) signals in visual areas processing "target feature" but not in "distracter feature"-processing regions. TMS-induced BOLD signals increase in motion-responsive visual cortex (MT+) when motion was attended in a display with moving dots superimposed on face stimuli, but in face-responsive fusiform area (FFA) when faces were attended to. These TMS effects on BOLD signal in both regions were negatively related to performance (on the motion task), supporting the behavioral relevance of this pathway. Our findings provide new causal evidence for the human FEF in the control of nonspatial "feature"-based attention, mediated by dynamic influences on feature-specific visual cortex that vary with the currently attended property. PMID- 23794716 TI - The IkappaB family member Bcl-3 stabilizes c-Myc in colorectal cancer. PMID- 23794717 TI - Associations of common variants in HFE and TMPRSS6 with iron parameters are independent of serum hepcidin in a general population: a replication study. AB - BACKGROUND: Genome-wide association studies have convincingly shown that single nucleotide polymorphisms (SNPs) in HFE and TMPRSS6 are associated with iron parameters. It was commonly thought that these associations could be explained by the intermediate effect on hepcidin concentration. A recent study in an isolated Italian population, however, concluded that these associations were not exclusively dependent on hepcidin values. We report here the second study to investigate the role of hepcidin in the associations between common variants in HFE and TMPRSS6 with iron parameters. METHODS: We extracted 101 SNPs in HFE and TMPRSS6 from genome-wide imputed SNP data of 1832 individuals from the general population (Nijmegen Biomedical Study). Single locus and haplotype associations with serum iron parameters and hepcidin were studied using linear regression analyses. RESULTS: We found that HFE rs1800562 and TMPRSS6 rs855791 are the main determinants of HFE and TMPRSS6 related variation in serum iron, ferritin, transferrin saturation, and total iron binding capacity. These SNPs are associated with the ratios hepcidin/ferritin (p<1*10(-5)) and hepcidin/transferrin saturation (p<1*10(-3)), but not with serum hepcidin (p>0.2). Adjustment for hepcidin or the ratio hepcidin/ferritin did not decrease the strength of the SNP-iron parameter associations. CONCLUSIONS: Our results do not support an intermediate role for hepcidin in the SNP-iron parameter associations, which confirms previous findings, and indicate a pleiotropic SNP effect on the hepcidin ratios and the iron parameters. Taken together, this suggests that there might be other, yet unknown, serum hepcidin independent mechanisms which play a role in the association of HFE and TMPRSS6 variants with serum iron parameters. PMID- 23794718 TI - Significance of arterial hyperoxia and relationship with case fatality in traumatic brain injury: a multicentre cohort study. AB - OBJECTIVE: In this retrospective multi-centre cohort study, we tested the hypothesis that hyperoxia was not associated with higher in-hospital case fatality in ventilated traumatic brain injury (TBI) patients admitted to the intensive care unit (ICU). METHODS: Admissions of ventilated TBI patients who had arterial blood gases within 24 h of admission to the ICU at 61 US hospitals between 2003 and 2008 were identified. Hyperoxia was defined as PaO2 >=300 mm Hg (39.99 kPa), hypoxia as any PaO2 <60 mm Hg (7.99 kPa) or PaO2/FiO2 ratio <=300 and normoxia, not defined as hyperoxia or hypoxia. The primary outcome was in hospital case fatality. RESULTS: Over the 5-year period, we identified 1212 ventilated TBI patients, of whom 403 (33%) were normoxic, 553 (46%) were hypoxic and 256 (21%) were hyperoxic. The case-fatality was higher in the hypoxia group (224/553 [41%], crude OR 2.3, 95% CI 1.7-3.0, p<.0001) followed by hyperoxia (80/256 [32%], crude OR 1.5, 95% CI 1.1-2.5, p=.01) as compared to normoxia (87/403 [23%]). In a multivariate analysis adjusted for other potential confounders, the probability of being exposed to hyperoxia and hospital-specific characteristics, exposure to hyperoxia was independently associated with higher in-hospital case fatality adjusted OR 1.5, 95% CI 1.02-2.4, p=0.04. CONCLUSIONS: In ventilated TBI patients admitted to the ICU, arterial hyperoxia was independently associated with higher in-hospital case fatality. In the absence of results from clinical trials, unnecessary oxygen delivery should be avoided in critically ill ventilated TBI patients. PMID- 23794719 TI - High-throughput determination of nicotine in plasma by ultrasonication enhanced hollow fiber liquid-phase microextraction prior to gas chromatography. AB - In high-throughput ultrasonication enhanced hollow-fiber liquid-phase microextraction (H-U-HF-LPME), ultrasonication was introduced into HF-LPME to enhance the mass transfer rate of the analytes in the two immiscible liquid phases, which resulted in a very short time for extraction equilibrium and a high throughput analysis. Several parameters were investigated and optimized (such as extraction solvent, temperature of sample, frequency and intensity of ultrasonication, volume of extractant, extraction time, ionic strength of the sample and sample concentration). Based on the results of this study, nicotine was first extracted from a 1.5 mL sample solution under the optimum conditions (ultrasonic power of 50 W with a frequency of 60 kHz, extraction time of 10 min, sodium chloride concentration of 5 mol/L and temperature of 37 degrees C). Next, 0.5 uL of acceptor solution inside the hollow fiber was automatically injected into a gas chromatograph with a flame ionization detector. The results of this study illustrated that the limit of detection, relative standard deviation (n = 6), relative recovery and enrichment factor of nicotine were 0.06 ug/L, 3%, 99.8% and 16.6, respectively. Finally, H-U-HF-LPME was successfully applied for the determination of nicotine in plasma. PMID- 23794720 TI - Determination of three phthalate esters in environmental samples by coal cinder extraction and cyclodextrin modified micellar electrokinetic chromatography. AB - A new micellar electrokinetic chromatography (MEKC) method using beta cyclodextrin (beta-CD) as the electrophoresis additive has been developed for the simultaneous determination of dimethyl phthalate (DMP), diethyl phthalate (DEP) and di(2-ethylhexyl) phthalate (DEHP) in environmental samples. To improve the sensitivity of cyclodextrin-modified MEKC (CD-MEKC), a flow injection procedure using a microcolumn packed with coal cinder as the solid-phase extractant was also investigated for the preconcentration and separation of DMP, DEP and DEHP in environmental samples. Parameters affecting CD-MEKC separation and coal cinder flow injection solid-phase extraction were systematically researched. In the presence of the running buffer [5 mmol/L of borax, 5% (v/v) methanol and 25 mmol/L of sodium dodecyl sulfate at pH 9.5], the addition of 14 mmol/L beta-CD greatly improved the separation efficiency. The analytes were quantitatively adsorbed by coal cinders and readily desorbed quantitatively with 0.2 mL of 10% (v/v) methanol-10 mmol/L disodium hydrogen phosphate. Under the optimum conditions, the enrichment factor of coal cinder was 60, and the determination limits of DMP, DEP and DEHP were 3.07, 2.07 and 4.06 ng/mL, respectively. The presented procedure was successfully applied to determine DMP, DEP and DEHP in landfill leachate and water samples with satisfactory results. PMID- 23794721 TI - HPLC method for naproxen determination in human plasma and its application to a pharmacokinetic study in Turkey. AB - A simple high-performance liquid chromatography method has been developed for the determination of naproxen in human plasma. The method was validated on an Ace C18 column using ultraviolet detection. The mobile phase consisted of 20 mM phosphate buffer (pH 7) containing 0.1% trifluoroacetic acid-acetonitrile (65:35, v/v). The calibration curve was linear between the concentration ranges of 0.10 and 5.0 ug/mL. Intra-day and inter-day precision values for naproxen in plasma were less than 4.84, and accuracy (relative error) was better than 3.67%. The extraction recovery values of naproxen from human plasma were between 91.0 and 98.9%. The limits of detection and quantification of naproxen were 0.03 and 0.10 ug/mL, respectively. Also, this assay was applied to determine the pharmacokinetic parameters of naproxen in six healthy Turkish volunteers who had been given 220 mg of naproxen. PMID- 23794722 TI - Molecular epidemiology linking multihospital clusters of opportunistic Pneumocystis jirovecii pneumonia. PMID- 23794723 TI - Evolution from acute Q fever to endocarditis is associated with underlying valvulopathy and age and can be prevented by prolonged antibiotic treatment. AB - BACKGROUND: The prevention of Q fever endocarditis through the use of systematic echocardiography and antibiotic prophylaxis in patients with acute Q fever and valvulopathy has never been validated in a cohort study. METHODS: From 2007 to 2012, all patients followed at the French National Referral Center for acute Q fever were included in a cohort study. The prevention of endocarditis included a systematic transthoracic echocardiography (TTE) and a 12-month course of doxycycline and hydroxychloroquine prophylaxis in patients with significant valvulopathy. Transesophageal echocardiography (TEE) was performed in patients with a negative TTE and a rapid rise of phase I immunoglobulin G titers. RESULTS: Seventy-two patients were included with a median follow-up time of 22 months. A valvulopathy was identified in 31 patients (43%), being previously unknown in 24 (33%) and diagnosed only upon TEE or a second TTE in 7 (10%). The major determinants associated with endocarditis were age (hazard ratio [HR], 1.07; 95% confidence interval [CI], 1.006-1.13; P = .03), aortic regurgitation (HR, 10.2; 95% CI, 3.2-32.2; P < .001), and mitral regurgitation (HR, 4.78; 95% CI, 1.4 16.0; P = .01). Antibiotic prophylaxis was highly effective (HR, 0.002; 95% CI, .00-.77; P = .04) for the 31 patients with valvulopathy. CONCLUSIONS: Acute Q fever could be associated with an increased prevalence of valvulopathy. The evolution from acute Q fever to endocarditis is associated with age and valvulopathy and can be entirely prevented by antibiotic prophylaxis. Although the name "chronic Q fever" suggests otherwise, rapid evolution (<1 month) was observed. PMID- 23794725 TI - The emergence of influenza A (H3N2)v virus: what we learned from the first wave. PMID- 23794726 TI - Estimates of the number of human infections with influenza A(H3N2) variant virus, United States, August 2011-April 2012. AB - BACKGROUND: Thirteen human infections with an influenza A(H3N2) variant (H3N2v) virus containing a combination of gene segments not previously associated with human illness were identified in the United States from August 2011 to April 2012. Because laboratory confirmation of influenza virus infection is only performed for a minority of ill persons and routine clinical tests may not identify H3N2v virus, the count of laboratory-confirmed H3N2v virus infections underestimates the true burden of illness. METHODS: To account for this underascertainment, we adapted a multiplier model created at the beginning of the influenza A(H1N1) 2009 pandemic to estimate the true burden of H3N2v illness. Data to inform each of these parameters came from the literature and from special projects conducted during the 2009 H1N1 pandemic and the 2010-2011 influenza season. The multipliers were calculated as the simple inverses of the proportions at each step, and we accounted for variability and uncertainty in model parameters by using a probabilistic or Monte Carlo approach. RESULTS: We estimate that the median multiplier for children was 200 (90% range, 115-369) and for adults was 255 (90% range, 152-479) and that 2055 (90% range, 1187-3800) illnesses from H3N2v virus infections may have occurred from August 2011 to April 2012, suggesting that the new virus was more widespread than previously thought. CONCLUSIONS: Illness from this variant influenza virus was more frequent than previously thought. Continued surveillance is needed to ensure timely detection and response to H3N2v virus infections. PMID- 23794727 TI - Transmissibility of variant influenza from Swine to humans: a modeling approach. AB - BACKGROUND: Respiratory illness was reported among humans and swine at an agricultural fair in 2011; 3 human infections with an influenza A(H3N2) variant (H3N2v) virus were confirmed. Using epidemiologic investigation data, we sought to estimate H3N2v transmissibility from swine to humans. METHODS: We developed a model of H3N2v transmission among swine and humans and fit it to data from a cohort of 100 agricultural club members reporting swine contact to estimate transmissibility. A sensitivity analysis was performed varying H3N2v prevalence in the club cohort. Using the best-fit transmission probability, we simulated the number of swine-acquired infections among all fair attendees. RESULTS: We estimated the best-fit probability of swine-to-human H3N2v transmission per minute of swine contact. Applying this probability to 14 910 people with swine contact at the fair, we estimate that there were 80 (95% confidence interval [CI], 40-133) H3N2v infections among persons aged <20 years and 58 (95% CI, 29 96) H3N2v infections among person aged >=20 years. CONCLUSIONS: Using early data from investigation of a new virus with unclear transmission properties, we estimated the transmissibility of H3N2v from swine to humans and the burden of H3N2v among fair attendees. Although the risk of H3N2v virus infection is small for fair attendees with minimal swine contact, large populations attend agricultural events each year, and human cases will likely occur when infected swine are present. PMID- 23794728 TI - Multiple contributory factors to the age distribution of disease cases: a modeling study in the context of influenza A(H3N2v). AB - BACKGROUND: In late 2011 and early 2012, 13 cases of human influenza resulted from infection with a novel triple reassortant swine-origin influenza virus, influenza A (H3N2) variant. This variant was notable for its inclusion of the matrix gene from the 2009 influenza A(H1N1) pandemic virus. While most of these confirmed cases were among children, the transmission potential and likely age dependent susceptibility to the virus was unknown. Preliminary serologic studies indicated that very young children have less protection than older children and adults. METHODS: We construct a mathematical transmission model of influenza transmission that allows for external zoonotic exposure to infection and show how exposure and susceptibility-related factors contribute to the observed case distribution. RESULTS AND CONCLUSIONS: Age-dependent susceptibility to infection strongly influences epidemic dynamics. The result is that the risk of an outbreak in a highly susceptible age group may be substantially higher than in an older age group with less susceptibility, but exposure-related factors must also be accounted for when interpreting case data. PMID- 23794730 TI - Acute rheumatic fever and rheumatic heart disease: incidence and progression in the Northern Territory of Australia, 1997 to 2010. AB - BACKGROUND: Although acute rheumatic fever (ARF) and its sequel, rheumatic heart disease (RHD), continue to cause a large burden of morbidity and mortality in disadvantaged populations, most studies investigating the effectiveness of control programs date from the 1950s. A control program, including a disease register, in the Northern Territory of Australia where the Indigenous population has high rates of ARF and RHD allowed us to examine current disease incidence and progression. METHODS AND RESULTS: ARF and RHD incidence rates, ARF recurrence rates, progression rates from ARF to RHD to heart failure, and RHD survival and mortality rates were calculated for Northern Territory residents from 1997 to 2010. For Indigenous people, ARF incidence was highest in the 5- to 14-year age group (males, 162 per 100,000; females, 228 per 100,000). There was little evidence that the incidence of ARF or RHD had declined. The ARF recurrence rate declined by 9% per year after diagnosis. After a first ARF diagnosis, 61% developed RHD within 10 years. After RHD diagnosis, 27% developed heart failure within 5 years. For Indigenous RHD patients, the relative survival rate was 88.4% at 10 years after diagnosis and the standardized mortality ratio was 1.56 (95% confidence interval, 1.23-1.96). CONCLUSIONS: For Indigenous Australians in the Northern Territory, ARF and RHD incidence and associated mortality remain very high. The reduction in ARF recurrence indicates that the RHD control program has improved secondary prophylaxis; a decline in RHD incidence is expected to follow. PMID- 23794729 TI - Human infections with influenza A(H3N2) variant virus in the United States, 2011 2012. AB - BACKGROUND. During August 2011-April 2012, 13 human infections with influenza A(H3N2) variant (H3N2v) virus were identified in the United States; 8 occurred in the prior 2 years. This virus differs from previous variant influenza viruses in that it contains the matrix (M) gene from the Influenza A(H1N1)pdm09 pandemic influenza virus. METHODS. A case was defined as a person with laboratory confirmed H3N2v virus infection. Cases and contacts were interviewed to determine exposure to swine and other animals and to assess potential person-to-person transmission. RESULTS. Median age of cases was 4 years, and 12 of 13 (92%) were children. Pig exposure was identified in 7 (54%) cases. Six of 7 cases with swine exposure (86%) touched pigs, and 1 (14%) was close to pigs without known direct contact. Six cases had no swine exposure, including 2 clusters of suspected person-to-person transmission. All cases had fever; 12 (92%) had respiratory symptoms, and 3 (23%) were hospitalized for influenza. All 13 cases recovered. CONCLUSIONS. H3N2v virus infections were identified at a high rate from August 2011 to April 2012, and cases without swine exposure were identified in influenza like illness outbreaks, indicating that limited person-to-person transmission likely occurred. Variant influenza viruses rarely result in sustained person-to person transmission; however, the potential for this H3N2v virus to transmit efficiently is of concern. With minimal preexisting immunity in children and the limited cross-protective effect from seasonal influenza vaccine, the majority of children are susceptible to infection with this novel influenza virus. PMID- 23794731 TI - Contribution of ABCC4-mediated gastric transport to the absorption and efficacy of dasatinib. AB - PURPOSE: Several oral multikinase inhibitors are known to interact in vitro with the human ATP-binding cassette transporter ABCC4 (MRP4), but the in vivo relevance of this interaction remains poorly understood. We hypothesized that host ABCC4 activity may influence the pharmacokinetic profile of dasatinib and subsequently affect its antitumor properties. EXPERIMENTAL DESIGN: Transport of dasatinib was studied in cells transfected with human ABCC4 or the ortholog mouse transporter, Abcc4. Pharmacokinetic studies were done in wild-type and Abcc4-null mice. The influence of Abcc4 deficiency on dasatinib efficacy was evaluated in a model of Ph(+) acute lymphoblastic leukemia by injection of luciferase-positive, p185(BCR-ABL)-expressing Arf(-/-) pre-B cells. RESULTS: Dasatinib accumulation was significantly changed in cells overexpressing ABCC4 or Abcc4 compared with control cells (P < 0.001). Deficiency of Abcc4 in vivo was associated with a 1.75 fold decrease in systemic exposure to oral dasatinib, but had no influence on the pharmacokinetics of intravenous dasatinib. Abcc4 was found to be highly expressed in the stomach, and dasatinib efflux from isolated mouse stomachs ex vivo was impaired by Abcc4 deficiency (P < 0.01), without any detectable changes in gastric pH. Abcc4-null mice receiving dasatinib had an increase in leukemic burden, based on bioluminescence imaging, and decreased overall survival compared with wild-type mice (P = 0.048). CONCLUSIONS: This study suggests that Abcc4 in the stomach facilitates the oral absorption of dasatinib, and it possibly plays a similar role for other orally administered substrates, such as acetylsalicylic acid. This phenomenon also provides a mechanistic explanation for the malabsorption of certain drugs following gastric resection. PMID- 23794732 TI - Effective activity of cytokine-induced killer cells against autologous metastatic melanoma including cells with stemness features. AB - PURPOSE: We investigate the unknown tumor-killing activity of cytokine-induced killer (CIK) cells against autologous metastatic melanoma and the elusive subset of putative cancer stem cells (mCSC). EXPERIMENTAL DESIGN: We developed a preclinical autologous model using same patient-generated CIK cells and tumor targets to consider the unique biology of each patient/tumor pairing. In primary tumor cell cultures, we visualized and immunophenotypically defined a putative mCSC subset using a novel gene transfer strategy that exploited their exclusive ability to activate the promoter of stemness gene Oct4. RESULTS: The CIK cells from 10 patients with metastatic melanoma were successfully expanded (median, 23 fold; range, 11-117). Primary tumor cell cultures established and characterized from the same patients were used as autologous targets. Patient-derived CIK cells efficiently killed autologous metastatic melanoma [up to 71% specific killing (n = 26)]. CIK cells were active in vivo against autologous melanoma, resulting in delayed tumor growth, increased necrotic areas, and lymphocyte infiltration at tumor sites. The metastatic melanoma cultures presented an average of 11.5% +/- 2.5% putative mCSCs, which was assessed by Oct4 promoter activity and stemness marker expression (Oct4, ABCG2, ALDH, MITF). Expression was confirmed on mCSC target molecules recognized by CIK cells (MIC A/B; ULBPs). CIK tumor killing activity against mCSCs was intense (up to 71%, n = 4) and comparable with results reported against differentiated metastatic melanoma cells (P = 0.8). CONCLUSIONS: For the first time, the intense killing activity of CIK cells against autologous metastatic melanoma, including mCSCs, has been shown. These findings move clinical investigation of a new immunotherapy for metastatic melanoma, including mCSCs, closer. PMID- 23794733 TI - From art to science: oligosaccharide analysis by maldi-tof mass spectrometry finally replaces 1-dimensional thin-layer chromatography. PMID- 23794734 TI - Glycemic control in the 12 months following a change to SI hemoglobin A1c reporting units. AB - BACKGROUND: Many countries have implemented, or are considering, a change in hemoglobin A1c (Hb A1c) units from traditional percentage values [Diabetes Control and Complications Trial (DCCT)] to the new Systeme International d'Unites (SI) unit in millimoles per mole. Concern exists that such a large alteration in numeric values might lead, through confusion, to a deterioration in patients' glycemia. This study has assessed Hb A1c in the year before and after the change of units in a UK diabetes population. METHODS: The Hb A1c in the 12 months immediately before the unit change (October 2010 to September 2011) was compared with the 12 months after (October 2011 to September 2012). Also, the subsequent change in Hb A1c in patients who had poor glycemic control [Hb A1c >8% (64 mmol/mol)], either before or after the unit change, was compared. RESULTS: Over the 2 years, 44 721 Hb A1c measurements were requested on 13,197 (7247 male, 5950 female) known diabetes patients. The population Hb A1c was no different between years, with a median [interquartile range (IQR)] value of 7.5% (6.6%-8.7%) after the change and 7.5% (6.5-8.7) before (P = 0.34). The subsequent change in Hb A1c following a raised (>8%) result was the same regardless of whether the initial value reported was in DCCT or SI units [median (IQR) change in Hb A1c -0.2% ( 0.9% to 0.3%), n = 4316, following a DCCT result, vs -0.2% (-0.8% to 0.3%), n = 4396, following SI; P = 0.44]. CONCLUSIONS: In this UK diabetes population, a move to SI Hb A1c reporting did not lead to any marked short-term deterioration in glycemia or a different Hb A1c outcome in patients with initial poor glucose control. PMID- 23794735 TI - The CARLSBAD database: a confederated database of chemical bioactivities. AB - Many bioactivity databases offer information regarding the biological activity of small molecules on protein targets. Information in these databases is often hard to resolve with certainty because of subsetting different data in a variety of formats; use of different bioactivity metrics; use of different identifiers for chemicals and proteins; and having to access different query interfaces, respectively. Given the multitude of data sources, interfaces and standards, it is challenging to gather relevant facts and make appropriate connections and decisions regarding chemical-protein associations. The CARLSBAD database has been developed as an integrated resource, focused on high-quality subsets from several bioactivity databases, which are aggregated and presented in a uniform manner, suitable for the study of the relationships between small molecules and targets. In contrast to data collection resources, CARLSBAD provides a single normalized activity value of a given type for each unique chemical-protein target pair. Two types of scaffold perception methods have been implemented and are available for datamining: HierS (hierarchical scaffolds) and MCES (maximum common edge subgraph). The 2012 release of CARLSBAD contains 439 985 unique chemical structures, mapped onto 1,420 889 unique bioactivities, and annotated with 277 140 HierS scaffolds and 54 135 MCES chemical patterns, respectively. Of the 890 323 unique structure-target pairs curated in CARLSBAD, 13.95% are aggregated from multiple structure-target values: 94 975 are aggregated from two bioactivities, 14 544 from three, 7 930 from four and 2214 have five bioactivities, respectively. CARLSBAD captures bioactivities and tags for 1435 unique chemical structures of active pharmaceutical ingredients (i.e. 'drugs'). CARLSBAD processing resulted in a net 17.3% data reduction for chemicals, 34.3% reduction for bioactivities, 23% reduction for HierS and 25% reduction for MCES, respectively. The CARLSBAD database supports a knowledge mining system that provides non-specialists with novel integrative ways of exploring chemical biology space to facilitate knowledge mining in drug discovery and repurposing. Database URL: http://carlsbad.health.unm.edu/carlsbad/. PMID- 23794736 TI - ESCAPE: database for integrating high-content published data collected from human and mouse embryonic stem cells. AB - High content studies that profile mouse and human embryonic stem cells (m/hESCs) using various genome-wide technologies such as transcriptomics and proteomics are constantly being published. However, efforts to integrate such data to obtain a global view of the molecular circuitry in m/hESCs are lagging behind. Here, we present an m/hESC-centered database called Embryonic Stem Cell Atlas from Pluripotency Evidence integrating data from many recent diverse high-throughput studies including chromatin immunoprecipitation followed by deep sequencing, genome-wide inhibitory RNA screens, gene expression microarrays or RNA-seq after knockdown (KD) or overexpression of critical factors, immunoprecipitation followed by mass spectrometry proteomics and phosphoproteomics. The database provides web-based interactive search and visualization tools that can be used to build subnetworks and to identify known and novel regulatory interactions across various regulatory layers. The web-interface also includes tools to predict the effects of combinatorial KDs by additive effects controlled by sliders, or through simulation software implemented in MATLAB. Overall, the Embryonic Stem Cell Atlas from Pluripotency Evidence database is a comprehensive resource for the stem cell systems biology community. Database URL: http://www.maayanlab.net/ESCAPE PMID- 23794738 TI - Personal and collective evaluations of the 2010 health care reform. AB - The 2010 health care reform law has been as controversial as any piece of American legislation in recent memory. Although numerous polls have been conducted on the public's views of the reform, we do not know much about how citizens evaluated the policy alternatives. Are citizens more focused on how policy affects them personally or how it affects the nation as a whole? Further, are these evaluations made more on the basis of past experience or assessments of how the policy will affect the future? Using an original survey of public opinion administered during the 2009 congressional debate, we examine how these evaluative dimensions (and several other factors) shaped public support for overall reform, for associated policy goals, and for available policy tools. We find evidence that retrospective and prospective collective evaluations mattered most, as did personal prospective assessments, but evidence on personal retrospective factors is somewhat mixed. PMID- 23794737 TI - Analysis of disease-associated objects at the Rat Genome Database. AB - The Rat Genome Database (RGD) is the premier resource for genetic, genomic and phenotype data for the laboratory rat, Rattus norvegicus. In addition to organizing biological data from rats, the RGD team focuses on manual curation of gene-disease associations for rat, human and mouse. In this work, we have analyzed disease-associated strains, quantitative trait loci (QTL) and genes from rats. These disease objects form the basis for seven disease portals. Among disease portals, the cardiovascular disease and obesity/metabolic syndrome portals have the highest number of rat strains and QTL. These two portals share 398 rat QTL, and these shared QTL are highly concentrated on rat chromosomes 1 and 2. For disease-associated genes, we performed gene ontology (GO) enrichment analysis across portals using RatMine enrichment widgets. Fifteen GO terms, five from each GO aspect, were selected to profile enrichment patterns of each portal. Of the selected biological process (BP) terms, 'regulation of programmed cell death' was the top enriched term across all disease portals except in the obesity/metabolic syndrome portal where 'lipid metabolic process' was the most enriched term. 'Cytosol' and 'nucleus' were common cellular component (CC) annotations for disease genes, but only the cancer portal genes were highly enriched with 'nucleus' annotations. Similar enrichment patterns were observed in a parallel analysis using the DAVID functional annotation tool. The relationship between the preselected 15 GO terms and disease terms was examined reciprocally by retrieving rat genes annotated with these preselected terms. The individual GO term-annotated gene list showed enrichment in physiologically related diseases. For example, the 'regulation of blood pressure' genes were enriched with cardiovascular disease annotations, and the 'lipid metabolic process' genes with obesity annotations. Furthermore, we were able to enhance enrichment of neurological diseases by combining 'G-protein coupled receptor binding' annotated genes with 'protein kinase binding' annotated genes. Database URL: http://rgd.mcw.edu PMID- 23794739 TI - Attitudes toward reciprocity systems for organ donation and allocation for transplantation. AB - Many of those who support organ donation do not register to become organ donors. The use of reciprocity systems, under which some degree of priority is offered to registered donors who require an organ transplant, is one suggestion for increasing registration rates. This article uses a combination of survey and focus group methodologies to explore the reaction of Canadians to a reciprocity proposal. Our results suggest that the response is mixed. Participants are more convinced of the efficacy than they are of the fairness of a reciprocity system. Those more positive about donation (decided donors and those leaning toward donation) rate the system more positively. Although there is general endorsement of the notion that those who wish to receive should be prepared to give (the Golden Rule), this does not translate into universal support for a reciprocity system. In discussions of efficacy, decided donors focus on the positive impact of reciprocity, whereas undecided donors also reflect on the limits of reciprocity for promoting registration. The results demonstrate divided support for reciprocity systems in the Canadian context, with perceptions of efficacy at the cost of fairness. Further studies are warranted prior to considering a reciprocity system in Canada. PMID- 23794740 TI - Privatizing the English National Health Service: an irregular verb? AB - This article explores different stakeholder perspectives of "privatization" in the English National Health Service (NHS). Much of the academic literature makes empirical claims about privatization on the basis of absent or shaky definitions of the term, resulting in much of the debate on this issue largely being a "non debate," where opponents talk past rather than to each other. We aim to throw light on privatization by applying the lens of the "three-dimensional" approach (ownership, finance, and regulation) of the mixed economy of welfare to the views of key voices within these debates. These stakeholder perspectives are political (parliamentary debates), public (opinion polls), clinical provider (British Medical Association and Royal College of Nursing), and campaigning groups. We argue that in terms of grammar, "privatize" seems to be an irregular verb: I want more private-sector involvement; you wish to privatize the NHS. The term privatization is multidimensional, and definitions and operationalizations of the term are often implicit, unclear, and conflicting, resulting in differing accounts of the occurrence, chronology, and degree of privatization in the NHS. Stakeholders have divergent interests, and they use "privatization" as a way to express them, resulting in a Tower of Babel. PMID- 23794741 TI - Why states expand Medicaid: party, resources, and history. AB - After the passage of the Patient Protection and Affordable Care Act in March 2010 and the affirmation of its constitutionality by the Supreme Court in 2012, key decisions about the implementation of health care reform are now in the hands of states. But our understanding of these decisions is hampered by simplistic sortings of state directions into two or three simple, rigid categories. This article takes a different approach--it tracks the variations in relative state progress in implementing Medicaid expansion across a continuum of activities and steps in the decision-making process. This new measure reveals wide variation not only among states that have adopted Medicaid expansion but also among those that have rejected it but have also made progress. We use this new measure to spotlight cross-pressured Republican states that have adopted Medicaid expansion or have prepared to move forward and to explore possible explanations for implementation that extend beyond a simple focus on party control. PMID- 23794742 TI - What moves public opinion on health care? Individual experiences, system performance, and media framing. AB - Although Canadians generally support their health care "model," dissatisfaction with health care policy and demands for fundamental changes in the system often surface in public opinion surveys. We seek to explain variations in levels of dissatisfaction and demands for health care reform with a series of micro- and macro-level analyses that account for a combination of individual experiences with health care delivery, broader measures of system performance, and media framing. Empirical analyses are guided by a model of opinion on policy that distinguishes between personal and collective, and prospective and retrospective assessments. This view helps make sense of the fact that those who use the system can have generally positive experiences even as there is decreasing confidence in the system's ability to meet future needs, and increasing demand for reform. What drives these divergent perceptions? We suggest that system performance plays a role in driving the long-term trend, but media content may also be an important driver as well, particularly for collective attitudes. PMID- 23794743 TI - Alcohol control in the news: the politics of media representations of alcohol policy in South Africa. AB - Media coverage of the "problems" associated with alcohol is widespread in countries of the global North and now, increasingly, in those of the global South. However, despite this mounting ubiquity, there have been very few analyses either of newspaper coverage of alcohol or of media coverage of alcohol policy, especially outside Europe and North America. This article argues that given international concern with the long-term health, economic, social, and developmental consequences of risky drinking in the global South, an exploration of newspaper coverage of nascent alcohol policy in such a context is both timely and valuable. Indeed, such analyses bring to the fore the deeply contextual and contingent nature of alcohol's problematization in politics, policy, and public life. To examine these assertions, we explore the "attention allocation" processes of two South African alcohol control policies--the Western Cape Liquor Bill and the city of Cape Town's liquor bylaws--in two regional English-language newspapers between 2007 and 2011. In so doing, the article highlights the particularities of the political valence of alcohol in the South African context. Furthermore, it also draws out the tensions between alcohol as a source of livelihoods in a context of endemic unemployment and chronic poverty and alcohol as a causal factor in poverty, crime, violence, and social disintegration. In contrast to media coverage of alcohol policy in Europe and North America, this analysis of the South African press suggests that liquor consumption is far less likely to be framed as an express health risk, forcing us to question how preventative policy efforts should best proceed. PMID- 23794744 TI - Liver Resection for Primary Hepatic Neoplasms. AB - Subtotal hepatic resection was performed in 356 patients; 87 had primary hepatic malignancies, 108 had metastatic tumors, and 161 had benign lesions including 8 traumatic injuries. The global mortality was 4.2%. The experience has elucidated the role of subtotal hepatic resection both for benign and malignant neoplasms. PMID- 23794745 TI - The Pursuit of Happiness and Its Relationship to the Meta-experience of Emotions and Culture. AB - In this commentary, I provide a brief background of the meta-experience of emotions, the philosophical and psychological literature on happiness, and further discuss the influence of culture on happiness. The meta-experience of emotions implies that there are primary and secondary emotions (i.e., emotions about emotions), similar to the concept of meta-cognitions. Primary and secondary emotions are closely associated with one's cultural background and happiness. Most scholars throughout history believe that happiness per se cannot be taught. However, it is possible to teach practices that lead to the path toward happiness. Promising strategies include loving-kindness and compassion meditation. These strategies are based on Buddhist teachings, which are deeply rooted in a collectivistic culture. This illustrates the close association between emotions, approaches towards happiness, and cultural background. PMID- 23794746 TI - Efficiency Loss Caused by Linearity Condition in Dimension Reduction. AB - Linearity, sometimes jointly with constant variance, is routinely assumed in the context of sufficient dimension reduction. It is well understood that, when these conditions do not hold, blindly using them may lead to inconsistency in estimating the central subspace and the central mean subspace. Surprisingly, we discover that even if these conditions do hold, using them will bring efficiency loss. This paradoxical phenomenon is illustrated through sliced inverse regression and principal Hessian directions. The efficiency loss also applies to other dimension reduction procedures. We explain this empirical discovery by theoretical investigation. PMID- 23794747 TI - First through Eighth Grade Retention Rates for All 50 States: A New Method and Initial Results. AB - How many students repeat a grade each year? How do retention rates vary across states and over time? Despite extensive research on the predictors and consequences of grade retention, there is no systematic way to quantify state level retention rates; even national estimates rely on imperfect proxy measures. We present a conceptually simple method-based on publicly available data that are routinely collected each year-that describes retention rates at the state and national levels. After describing and validating this method, we employ it to report first through eighth grade public school retention rates for 2002-003 through 2008-09 for the entire country and for each state. PMID- 23794748 TI - The efficiency of the second-order nonlinear least squares estimator and its extension. AB - We revisit the second-order nonlinear least square estimator proposed in Wang and Leblanc (Anne Inst Stat Math 60:883-900, 2008) and show that the estimator reaches the asymptotic optimality concerning the estimation variability. Using a fully semiparametric approach, we further modify and extend the method to the heteroscedastic error models and propose a semiparametric efficient estimator in this more general setting. Numerical results are provided to support the results and illustrate the finite sample performance of the proposed estimator. PMID- 23794749 TI - A multiscale MDCT image-based breathing lung model with time-varying regional ventilation. AB - A novel algorithm is presented that links local structural variables (regional ventilation and deforming central airways) to global function (total lung volume) in the lung over three imaged lung volumes, to derive a breathing lung model for computational fluid dynamics simulation. The algorithm constitutes the core of an integrative, image-based computational framework for subject-specific simulation of the breathing lung. For the first time, the algorithm is applied to three multi-detector row computed tomography (MDCT) volumetric lung images of the same individual. A key technique in linking global and local variables over multiple images is an in-house mass-preserving image registration method. Throughout breathing cycles, cubic interpolation is employed to ensure C1 continuity in constructing time-varying regional ventilation at the whole lung level, flow rate fractions exiting the terminal airways, and airway deformation. The imaged exit airway flow rate fractions are derived from regional ventilation with the aid of a three-dimensional (3D) and one-dimensional (1D) coupled airway tree that connects the airways to the alveolar tissue. An in-house parallel large-eddy simulation (LES) technique is adopted to capture turbulent-transitional-laminar flows in both normal and deep breathing conditions. The results obtained by the proposed algorithm when using three lung volume images are compared with those using only one or two volume images. The three-volume-based lung model produces physiologically-consistent time-varying pressure and ventilation distribution. The one-volume-based lung model under-predicts pressure drop and yields un physiological lobar ventilation. The two-volume-based model can account for airway deformation and non-uniform regional ventilation to some extent, but does not capture the non-linear features of the lung. PMID- 23794750 TI - ASSESSING CAUSALITY AND PERSISTENCE IN ASSOCIATIONS BETWEEN FAMILY DINNERS AND ADOLESCENT WELL-BEING. AB - Adolescents who share meals with their parents score better on a range of well being indicators. Using three waves of the National Longitudinal Survey of Adolescent Health (N = 17,977), we assessed the causal nature of these associations and the extent to which they persist into adulthood. We examined links between family dinners and adolescent mental health, substance use, and delinquency at wave 1, accounting for detailed measures of the family environment to test whether family meals simply proxy for other family processes. As a more stringent test of causality, we estimated fixed effects models from waves 1 and 2, and we used wave 3 to explore persistence in the influence of family dinners. Associations between family dinners and adolescent well-being remained significant, net of controls, and some held up to stricter tests of causality. Beyond indirect benefits via earlier well-being, however, family dinners associations did not persist into adulthood. PMID- 23794751 TI - Profiles of Risk: Maternal Health, Socioeconomic Status, and Child Health. AB - Child health is fundamental to well-being and achievement throughout the life course. Prior research has demonstrated strong associations between familial socioeconomic resources and children's health outcomes, with especially poor health outcomes among disadvantaged youth who experience a concentration of risks, yet little is known about the influence of maternal health as a dimension of risk for children. This research used nationally representative U.S. data from the National Health Interview Surveys in 2007 and 2008 (N = 7,361) to evaluate the joint implications of maternal health and socioeconomic disadvantage for youth. Analyses revealed that maternal health problems were present in a substantial minority of families, clustered meaningfully with other risk factors, and had serious implications for children's health. These findings support the development of health policies and interventions aimed at families. PMID- 23794752 TI - "What did you say, and who do you think you are?" How Power Differences Affect Emotional Reactions to Prejudice. AB - Three studies examine how power differences between targets and sources of prejudice affect targets' emotional reactions to prejudice. Study 1 first demonstrates that people do not expect powerful others to be prejudiced. Studies 2 and 3 then examine what happens when targets encounter prejudice, as a function of the source's power. Targets notice and recall prejudiced statements from powerful sources, irrespective of whether or not they are personally dependent on the source. However, results also demonstrate that personal dependency on the source determines how much targets attend to and are emotionally affected by prejudice. Emotional reactions to prejudice as a function of source power were mediated by negative expectations about future interactions. PMID- 23794753 TI - A facile glovebox-free strategy to significantly accelerate the syntheses of well defined polypeptides by N-carboxyanhydride (NCA) ring opening polymerizations. AB - A facile N2 flow-accelerated N-carboxyanhydride ring opening polymerization (NCA ROP) is demonstrated, herein, with rigorous kinetic studies to evaluate the methodology in detail. By using n-hexylamine as initiator and gamma-benzyl-L glutamate N-carboxyanhydride (BLG-NCA) as monomer, the NCA ROP via a normal amine mechanism (NAM) reached 90% conversion in 2 h under N2 flow at room temperature in a fume hood, much shorter than the time required for the same polymerization conducted in a glove box (14 h). The efficient removal of CO2 from the reaction by N2 flow drove the carbamic acid-amine equilibrium toward the formation of active nucleophilic amino termini and promoted polymerization. The detailed kinetic studies of the polymerization with different feed ratios and N2 flow rates were conducted, demonstrating the living feature of the NCA ROP and the tuning of the polymerization rate by simply changing the flow rate of N2. Maintenance of the reactivity of the amino omega-chain terminus and control during a subsequent polymerization were confirmed by performing chain extension reactions. The N2 flow method provides a new straightforward strategy to synthesize well-defined polypeptides with predictable molecular weights and narrow molecular weight distributions (PDI < 1.19). PMID- 23794754 TI - Ethics, Cultural Competence, and the Changing Face of America. AB - The population in the United States is increasingly multicultural. So, too, is the U.S. physician workforce. The combination of these diversity dynamics sets up the potential for various types of cultural conflict in the nation's examining rooms, including the relationship between religion and medicine. To address the changing patient-physician landscape, we argue for a broad scale intervention: interdisciplinary bioethics training for physicians and other health professionals. This approach seeks to promote a common procedural expectation and language which can lead to an improved, patient-centered approach resulting in better patient-physician relationships that contribute to better health outcomes across the U.S. population. The authors illustrate their thesis and solution using a well-known case of cross-cultural dynamics taken from religion and medicine-Anne Fadiman's The Spirit Catches You And You Fall Down. PMID- 23794755 TI - De novo asymmetric synthesis of oligo-rhamno di- and tri-saccharides related to the anthrax tetrasaccharide. AB - An asymmetric synthesis of the di- and trisaccharide portion of the naturally occurring anthrax tetrasaccharide from acetylfuran has been developed. The construction of the di- and trisaccharide subunits is based upon our previously disclosed route to anthrax tetrasaccharide. The approach uses iterative diastereoselective palladium-catalyzed glycosylations, Luche reductions, diastereoselective dihydroxylations, and regioselective protections for the assembly of the rhamno- di- and tri-saccharide. The route was also modified for the preparation of the mixed D-/L-disaccharide analogue. PMID- 23794756 TI - Total synthesis of taxane terpenes: cyclase phase. AB - A full account of synthetic efforts toward a lowly oxidized taxane framework is presented. A non-natural taxane, dubbed "taxadienone", was synthesized as our first entry into the taxane family of diterpenes. The final synthetic sequence illustrates a seven-step, gram-scale and enantioselective route to this tricyclic compound in 18% overall yield. This product was then modified further to give (+) taxadiene, the lowest oxidized member of the taxane family of natural products. PMID- 23794757 TI - Development of a palladium-catalyzed decarboxylative cross-coupling of (2 azaaryl)carboxylates with aryl halides. AB - A catalytic method for the decarboxylative coupling of 2-(azaaryl)carboxylates with aryl halides is described. The decarboxylative cross-coupling presented is mediated by a system catalytic in both palladium and copper without requiring stoichiometric amounts of organometallic reagents or organoboronic acids. This method circumvents additional synthetic steps required to prepare 2-azaaryl organometallics and organoborates as nucleophilic coupling partners, which are prone to protodemetallation and protodeborylation and produce potentially toxic byproducts. PMID- 23794758 TI - Synthesis of benzyl substituted naphthalenes from benzylidene tetralones. AB - A convenient and efficient synthesis of novel highly substituted dimethoxybenzylnaphthalenes, which are precursors to several dihydroxynaphthoic acids, is described. The approach involves the use of aldol chemistry to provide a number of benzylidene tetralones, which are converted to the target naphthalenes in three steps, with good to excellent yields. Grignard reaction of intermediate benzyl tetralones provided 1-substituted benzyl naphthalenes. The reported synthesis is flexible and scalable and provides access to naphthalenes having a variety of substitution patterns. These benzyl substituted naphthalenes are being converted to naphthoic acids and the bioactivities of these compounds are currently being investigated. PMID- 23794759 TI - Efficient microwave-assisted solid phase coupling of nucleosides, small library generation and mild conditions for release of nucleoside derivatives. AB - Nucleosides are essential bio-molecules that participate in a wide array of biological processes involved in maintaining physiologic homeostasis. Recent efforts geared towards the synthesis of nucleoside analogues and development of nucleoside combinatorial libraries using solid phase synthesis has contributed invaluable information towards drug design and development. These studies have provided information concerning the structural requirements of substrate binding pockets of enzymes and evaluation of enzyme kinetics. However, the synthesis of nucleosides and its corresponding analogues remains a challenging and time consuming process. Herein, we report an efficient, microwave assisted solid phase coupling of nucleosides, combinatorial chemistry on the coupled nucleosides to generate small library and mild cleavage conditions to release nucleoside derivatives from its solid support. We anticipate these findings will accelerate the development of synthetic methods or combinatorial library design of nucleoside analogues in similar settings. PMID- 23794760 TI - An E/Z conformational behaviour study on the trypanocidal action of lipophilic spiro carbocyclic 2,6-diketopiperazine-1-acetohydroxamic acids. AB - An explanation for the vast difference observed in the trypanocidal activity between the new secondary (N-methylated) hydroxamic acids 5 and 6, and their primary (nonmethylated) congeners 1a and 2, based on their E/Z conformational behaviour in DMSO, is presented. PMID- 23794761 TI - Cross-Shear in Metal-on-Polyethylene Articulation of Orthopaedic Implants and its Relationship to Wear. AB - Wear of polyethylene (UHMWPE) is dependent on cross-shear. The aim of the present study was: 1) to develop a theoretical description of cross-shear, 2) to experimentally determine the relationship between cross-shear motion and UHMWPE wear using a wheel-on-flat apparatus, and 3) to calculate the work it takes to remove a unit volume of wear for the use in advanced computational models of wear. The theoretical description of cross-shear has been based on the previously reported finding that cross-shear is maximal when movement occurs perpendicular to fibril orientation. Here, cross-shear is described with a double-sinusoidal function that uses the angle between fibril orientation and velocity vector as input, and maximum cross-shear occurs at 90 degrees and 270 degrees . In the experimental part of the study, friction and wear of polyethylene were plotted against increasing sliding velocity vector angles, i.e. increasing cross-shear. It was found that wear intensified with increasing cross-shear, and wear depth could be predicted well using the double-sinusoidal function for cross-shear (r2=0.983). The friction data were then used to calculate the work to remove a unit particle by integrating the frictional force over the directional sliding distance. Using the wear volumes, determined for both longitudinal and perpendicular motion directions, the work to remove a unit volume of material was qy = 8.473 * 108 J/mm3 and qx = 1.321 * 108 J/mm3, respectively. Hence, 6.4 times more work was necessary to remove a unit wear volume in the direction of principal motion (i.e. along the molecular fibril orientation) than 90 degrees perpendicular to it. In the future, these findings will be implemented in computational models to assess wear. PMID- 23794762 TI - Influence of numerical model decisions on the flow-induced vibration of a computational vocal fold model. AB - Computational vocal fold models are often used to study the physics of voice production. In this paper the sensitivity of predicted vocal fold flow-induced vibration and resulting airflow patterns to several modeling selections is explored. The location of contact lines used to prevent mesh collapse and assumptions of symmetry were found to influence airflow patterns. However, these variables had relatively little effect on the vibratory response of the vocal fold model itself. Model motion was very sensitive to Poisson's ratio. The importance of these parameter sensitivities in the context of vocal fold modeling is discussed. PMID- 23794763 TI - Adaptive mesh refinement techniques for the immersed interface method applied to flow problems. AB - In this paper, we develop an adaptive mesh refinement strategy of the Immersed Interface Method for flow problems with a moving interface. The work is built on the AMR method developed for two-dimensional elliptic interface problems in the paper [12] (CiCP, 12(2012), 515-527). The interface is captured by the zero level set of a Lipschitz continuous function phi(x, y, t). Our adaptive mesh refinement is built within a small band of |phi(x, y, t)| <= delta with finer Cartesian meshes. The AMR-IIM is validated for Stokes and Navier-Stokes equations with exact solutions, moving interfaces driven by the surface tension, and classical bubble deformation problems. A new simple area preserving strategy is also proposed in this paper for the level set method. PMID- 23794764 TI - The place of punishment: Variation in the provision of inmate services staff across the punitive turn. AB - : Despite the growing literature on the punitive turn, knowledge of how the experience of American imprisonment varied across time and place remain limited. This article begins to fill that gap, providing a more nuanced portrayal of rehabilitation during the punitive turn. PURPOSE: To examine how one aspect of the rehabilitative ideal in practice-the provision of staff dedicated to inmate services-varied across time and place over the past 30 years. METHODS: The article presents statistics on the inmate-to-staff ratios for inmate services staff (including teachers, counselors, doctors, etc.) between the years 1979 and 2005 for all 50 U.S. states. RESULTS: The analyses reveal that, while there was a substantial decline in the services staff ratio during the 1990s and 2000s, this shift across time paled in comparison to variation across place. Northeastern prison systems, for example, maintained higher inmate services staff ratios in 2005 than Southern states in any year. In addition, results suggest state variation is related to differences in prison crowding, inmates' racial composition, and political cultures. CONCLUSIONS: The findings suggest the punitive turn was more variegated and partial than is often assumed and highlight the importance of exploring state variation in penal practices. PMID- 23794765 TI - Submarine Groundwater Discharge as a Source of Mercury in the Bay of Puck, the Southern Baltic Sea. AB - Both groundwater flow and mercury concentrations in pore water and seawater were quantified in the groundwater seeping site of the Bay of Puck, southern Baltic Sea. Total dissolved mercury (HgTD) in pore water ranged from 0.51 to 4.90 ng l 1. Seawater samples were characterized by elevated HgTD concentrations, ranging from 4.41 to 6.37 ng l-1, while HgTD concentrations in groundwater samples ranged from 0.51 to 1.15 ng l-1. High HgTD concentrations in pore water of the uppermost sediment layers were attributed to seawater intrusion into the sediment. The relationship between HgTD concentrations and salinity of pore water was non conservative, indicating removal of dissolved mercury upon mixing seawater with groundwater. The mechanism of dissolved mercury removal was further elucidated by examining its relationships with both dissolved organic matter, dissolved manganese (Mn II), and redox potential. The flux of HgTD to the Bay of Puck was estimated to be 18.9 +/- 6.3 g year-1. The submarine groundwater discharge derived mercury load is substantially smaller than atmospheric deposition and riverine discharge to the Bay of Puck. Thus, groundwater is a factor that dilutes the mercury concentrations in pore water and, as a result, dilutes the mercury concentrations in the water column. PMID- 23794766 TI - Surface excitations in electron spectroscopy. Part I: dielectric formalism and Monte Carlo algorithm. AB - The theory describing energy losses of charged non-relativistic projectiles crossing a planar interface is derived on the basis of the Maxwell equations, outlining the physical assumptions of the model in great detail. The employed approach is very general in that various common models for surface excitations (such as the specular reflection model) can be obtained by an appropriate choice of parameter values. The dynamics of charged projectiles near surfaces is examined by calculations of the induced surface charge and the depth- and direction-dependent differential inelastic inverse mean free path (DIIMFP) and stopping power. The effect of several simplifications frequently encountered in the literature is investigated: differences of up to 100% are found in heights, widths, and positions of peaks in the DIIMFP. The presented model is implemented in a Monte Carlo algorithm for the simulation of the electron transport relevant for surface electron spectroscopy. Simulated reflection electron energy loss spectra are in good agreement with experiment on an absolute scale. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 23794767 TI - Cognitions and Insomnia Subgroups. AB - PURPOSE: This study explored cognitive predictors of multiple symptoms of insomnia (difficulty with sleep initiation, maintenance, and early morning awakenings) among a sample of individuals seeking cognitive-behavior therapy for insomnia. METHODS: Participants consisted of 146 clinical patients with insomnia of which 67 (45.89%) were classified as Single Symptoms subgroup and 79 (54.11%) as Combined subgroup. A receiver operating curve (ROC) analysis was conducted to identify predictors of Combined versus Single Symptom subgroups. The set of predictor variables included demographics, sleep-related cognitions, circadian preferences, depression symptoms, and self-report sleep parameters with insomnia subgroups (Combined versus Single Symptom only) as the dependent variable. RESULTS: The ROC analysis identified two significant predictors: Self Efficacy Scale (SES) < 23 and a 3-item subscale of the Glasgow Content of Thoughts Inventory (GCTI) assessing "thoughts about the environment" with scores >= 5. Post-hoc comparisons revealed that individuals with combined symptoms who had SES score < 23 had significantly longer sleep onset latency (SOL) and more number of nights with SOL>30 minutes, poorer sleep quality, higher insomnia severity, less morningness tendency, higher depression symptom severity, and more anxiety about anxiety and about sleep compared to individuals with SES score >= 23. CONCLUSIONS: These findings indicate that low self-efficacy and increased thoughts about the environment are associated with having multiple symptoms of insomnia. Further research should examine the specific role of self-efficacy and thought content in the etiology of individuals who suffer from multiple symptoms of insomnia. PMID- 23794768 TI - Predictors of Stability and Change in Private Safety Nets of Unmarried Mothers. AB - Although the importance of social supports for single mothers in times of crisis is widely recognized, little is known about the stability of such "private safety nets" over time, as children age and maternal and household characteristics change. This study uses multilevel models and 4 waves of data from the Fragile Families and Child Wellbeing Study to describe trajectories of social support perceptions for 3,065 unmarried mothers. Results suggest that, following a birth, most unmarried mothers perceive the availability of support, but these support perceptions disintegrated somewhat in subsequent years. Mothers who appeared to have the greatest need for support-those without stable employment or a stable partner-experienced more rapid deterioration of their perceived safety nets than more advantaged mothers. Future research should examine network composition and conditions for support provision among the most vulnerable single mothers and consider how safety net stability influences maternal and child health and well being. PMID- 23794770 TI - HISPANIC FERTILITY, RELIGION AND RELIGIOUSNESS IN THE U.S. PMID- 23794769 TI - Intrinsic Regression Models for Medial Representation of Subcortical Structures. AB - The aim of this paper is to develop a semiparametric model for describing the variability of the medial representation of subcortical structures, which belongs to a Riemannian manifold, and establishing its association with covariates of interest, such as diagnostic status, age and gender. We develop a two-stage estimation procedure to calculate the parameter estimates. The first stage is to calculate an intrinsic least squares estimator of the parameter vector using the annealing evolutionary stochastic approximation Monte Carlo algorithm and then the second stage is to construct a set of estimating equations to obtain a more efficient estimate with the intrinsic least squares estimate as the starting point. We use Wald statistics to test linear hypotheses of unknown parameters and establish their limiting distributions. Simulation studies are used to evaluate the accuracy of our parameter estimates and the finite sample performance of the Wald statistics. We apply our methods to the detection of the difference in the morphological changes of the left and right hippocampi between schizophrenia patients and healthy controls using medial shape description. PMID- 23794771 TI - Class-Level Spectral Features for Emotion Recognition. AB - The most common approaches to automatic emotion recognition rely on utterance level prosodic features. Recent studies have shown that utterance level statistics of segmental spectral features also contain rich information about expressivity and emotion. In our work we introduce a more fine-grained yet robust set of spectral features: statistics of Mel-Frequency Cepstral Coefficients computed over three phoneme type classes of interest-stressed vowels, unstressed vowels and consonants in the utterance. We investigate performance of our features in the task of speaker-independent emotion recognition using two publicly available datasets. Our experimental results clearly indicate that indeed both the richer set of spectral features and the differentiation between phoneme type classes are beneficial for the task. Classification accuracies are consistently higher for our features compared to prosodic or utterance-level spectral features. Combination of our phoneme class features with prosodic features leads to even further improvement. Given the large number of class-level spectral features, we expected feature selection will improve results even further, but none of several selection methods led to clear gains. Further analyses reveal that spectral features computed from consonant regions of the utterance contain more information about emotion than either stressed or unstressed vowel features. We also explore how emotion recognition accuracy depends on utterance length. We show that, while there is no significant dependence for utterance-level prosodic features, accuracy of emotion recognition using class-level spectral features increases with the utterance length. PMID- 23794772 TI - Two algorithms for fitting constrained marginal models. AB - The two main algorithms that have been considered for fitting constrained marginal models to discrete data, one based on Lagrange multipliers and the other on a regression model, are studied in detail. It is shown that the updates produced by the two methods are identical, but that the Lagrangian method is more efficient in the case of identically distributed observations. A generalization is given of the regression algorithm for modelling the effect of exogenous individual-level covariates, a context in which the use of the Lagrangian algorithm would be infeasible for even moderate sample sizes. An extension of the method to likelihood-based estimation under L1-penalties is also considered. PMID- 23794773 TI - Implications of New Marriages and Children for Coparenting in Nonresident Father Families. AB - Prior research has noted that although cooperative coparenting between resident and nonresident parents is beneficial to children, this form of shared parenting is relatively uncommon. Relying on nationally representative data from two waves of the National Survey of Families and Households (N = 628), we examine the importance of nonresident fathers' and resident mothers' new marriages and new children for levels of cooperative coparenting and test whether changes in coparenting are linked to changes in parents' marital or fertility statuses. Consistent with prior studies, our data suggest that cooperative coparenting does not occur in most nonresident father families. Results suggest that changes to the nonresident father's family structure are of primary importance for cooperative coparenting, but that mother's family structure is relatively unimportant. PMID- 23794774 TI - The Relationship between Neighborhood Characteristics and Effective Parenting Behaviors: The Role of Social Support. AB - Neighborhood characteristics have been linked to healthy behavior, including effective parenting behaviors. This may be partially explained through the neighborhood's relation to parents' access to social support from friends and family. The current study examined associations of neighborhood characteristics with parenting behaviors indirectly through social support. The sample included 614 mothers of 11-12 year old youths enrolled in a health care system in the San Francisco area. Structural equations modeling shows that neighborhood perceptions were related to parenting behaviors, indirectly through social support, while archival census neighborhood indicators were unrelated to social support and parenting. Perceived neighborhood social cohesion and control were related to greater social support, which was related to more effective parenting style, parent-child communication, and monitoring. Perceived neighborhood disorganization was unrelated to social support. Prevention strategies should focus on helping parents build a social support network that can act as a resource in times of need. PMID- 23794775 TI - Tracing Metabolite Footsteps of Escherichia coli Along the Time Course of Recombinant Protein Expression by Two-Dimensional NMR Spectroscopy. AB - The recombinant expression of proteins has been the method of choice to meet the demands from proteomics and structural genomics studies. Despite its successful production of many heterologous proteins, Escherichia coli failed to produce many other proteins in their native forms. This may be related to the fact that the stresses resulting from the overproduction interfere with cellular processes. To better understand the physiological change during the overproduction phase, we profiled the metabolites along the time course of the recombinant protein expression. We identified 32 metabolites collected from different time points in the protein production phase. The stress induced by protein production can be characterized by (A) the increased usage of aspartic acid, choline, glycerol, and N-acetyllysine; and (B) the accumulation of adenosine, alanine, oxidized glutathione, glycine, N-acetylputrescine, and uracil. We envision that this work can be used to create a strategy for the production of usable proteins in large quantities. PMID- 23794776 TI - Parental Involvement and Work Schedules: Time with Children in the United States, Germany, Norway, and the United Kingdom. AB - We examine variation in parents' time with children by work schedule in two parent families, utilizing time use surveys from the United States (2003), Germany (2001), Norway (2000), and the United Kingdom (2000) (N = 6,835). We find that American fathers working the evening shift spend more time alone with children regardless of mothers' employment status, whereas this association is conditional on mothers' employment in the United Kingdom and Germany. We find no evidence that Norwegian fathers working the evening shift spend more time alone with children. We conclude that a consequence of evening work often viewed as positive for children - fathers spending more time with children - is sensitive to both household employment arrangements and country context. PMID- 23794777 TI - Evaluation of the Fluids Mixing Enclosure System for Life Science Experiments During a Commercial Caenorhabditis elegans Spaceflight Experiment. AB - The Student Spaceflight Experiments Program (SSEP) is a United States national science, technology, engineering, and mathematics initiative that aims to increase student interest in science by offering opportunities to perform spaceflight experiments. The experiment detailed here was selected and flown aboard the third SSEP mission and the first SSEP mission to the International Space Station (ISS). Caenorhabditis elegans is a small, transparent, self fertilizing hermaphroditic roundworm that is commonly used in biological experiments both on Earth and in Low Earth Orbit. Past experiments have found decreased expression of mRNA for several genes whose expression can be controlled by the FOXO transcription factor DAF-16. We flew a daf-16 mutant and control worms to determine if the effects of spaceflight on C. elegans are mediated by DAF-16. The experiment used a Type Two Fluids Mixing Enclosure (FME), developed by Nanoracks LLC, and was delivered to the ISS aboard the SpaceX Dragon and returned aboard the Russian Soyuz. The short time interval between experiment selection and the flight rendered preflight experiment verification tests impossible. In addition, published research regarding the viability of the FME in life science experiments was not available. The experiment was therefore structured in such a way as to gather the needed data. Here we report that C. elegans can survive relatively short storage and activation in the FME but cannot produce viable populations for post-flight analysis on extended missions. The FME appears to support short-duration life science experiments, potentially on supply or crew exchange missions, but not on longer ISS expeditions. Additionally, the flown FME was not properly activated, reportedly due to a flaw in training procedures. We suggest that a modified transparent FME could prevent similar failures in future flight experiments. PMID- 23794778 TI - Synthesis and Characterization of Hydrido Carbonyl Molybdenum and Tungsten PNP Pincer Complexes. AB - In the present study the Mo(0) and W(0) complexes [M(PNP)(CO)3] as well as seven coordinate cationic hydridocarbonyl Mo(II) and W(II) complexes of the type [M(PNP)(CO)3H]+, featuring PNP pincer ligands based on 2,6-diaminopyridine, have been prepared and fully characterized. The synthesis of Mo(0) complexes [Mo(PNP)(CO)3] was accomplished by treatment of [Mo(CO)3(CH3CN)3] with the respective PNP ligands. The analogous W(0) complexes were prepared by reduction of the bromocarbonyl complexes [W(PNP)(CO)3Br]+ with NaHg. These intermediates were obtained from the known dinuclear complex [W(CO)4(MU-Br)Br]2, prepared in situ from W(CO)6 and stoichiometric amounts of Br2. Addition of HBF4 to [M(PNP)(CO)3] resulted in clean protonation at the molybdenum and tungsten centers to generate the Mo(II) and W(II) hydride complexes [M(PNP)(CO)3H]+. The protonation is fully reversible, and upon addition of NEt3 as base the Mo(0) and W(0) complexes [M(PNP)(CO)3] are regenerated quantitatively. All heptacoordinate complexes exhibit fluxional behavior in solution. The mechanism of the dynamic process of the hydrido carbonyl complexes was investigated by means of DFT calculations, revealing that it occurs in a single step. The structures of representative complexes were determined by X-ray single-crystal analyses. PMID- 23794779 TI - Monoaryloxide Pyrrolide (MAP) Imido Alkylidene Complexes of Molybdenum and Tungsten That Contain 2,6-Bis(2,5-R2-pyrrolyl)phenoxide (R = i-Pr, Ph) Ligands and an Unsubstituted Metallacyclobutane on Its Way to Losing Ethylene. AB - We report the synthesis of Mo and W MAP complexes that contain O-2,6-(2,5-R2 pyrrolyl)2C6H3 (2,6-dipyrrolylphenoxide or ODPPR) ligands in which R = i-Pr, Ph. W(NAr)(CH-t-Bu)(Pyr)(ODPPPh) (4a; Ar = 2,6-disopropylphenyl, Pyr = pyrrolide) reacts readily with ethylene to yield a metallacyclobutane complex, W(NAr)(C3H6)(Pyr)(ODPPPh) (5). The structure of 5 in the solid state shows that it is approximately a square pyramid with the WC4 ring spanning apical and basal positions. This SP' structure, which has never been observed as an actual intermediate, must now be regarded as an integral feature of the metathesis reaction. PMID- 23794780 TI - Work Stress and Well-being in the Hotel Industry. AB - Employee stress is a significant issue in the hospitality industry, and it is costly for employers and employees alike. Although addressing and reducing stress is both a noble goal and is capable of resulting in expense reductions for employers, the nature and quantity of hospitality employee stress is not fully understood. The first aim of this study was to identify common work stressors in a sample of 164 managerial and hourly workers employed at 65 different hotels who were each interviewed for eight consecutive days. The two most common stressors were interpersonal tensions at work and overloads (e.g., technology not functioning). The second aim was to determine whether there were differences in the types and frequency of work stressors by job type (i.e., managers v. non managers), gender, and marital status. Hotel managers reported significantly more stressors than hourly employees. There were no significant differences by gender or marital status. The third aim was to investigate whether the various stressors were linked to hotel employee health and work outcomes. More employee and coworker stressors were linked to more negative physical health symptoms. Also, interpersonal tensions at work were linked to lower job satisfaction and greater turnover intentions. PMID- 23794781 TI - Limit Theory for Panel Data Models with Cross Sectional Dependence and Sequential Exogeneity. AB - The paper derives a general Central Limit Theorem (CLT) and asymptotic distributions for sample moments related to panel data models with large n. The results allow for the data to be cross sectionally dependent, while at the same time allowing the regressors to be only sequentially rather than strictly exogenous. The setup is sufficiently general to accommodate situations where cross sectional dependence stems from spatial interactions and/or from the presence of common factors. The latter leads to the need for random norming. The limit theorem for sample moments is derived by showing that the moment conditions can be recast such that a martingale difference array central limit theorem can be applied. We prove such a central limit theorem by first extending results for stable convergence in Hall and Hedye (1980) to non-nested martingale arrays relevant for our applications. We illustrate our result by establishing a generalized estimation theory for GMM estimators of a fixed effect panel model without imposing i.i.d. or strict exogeneity conditions. We also discuss a class of Maximum Likelihood (ML) estimators that can be analyzed using our CLT. PMID- 23794782 TI - A Review on Dimension Reduction. AB - Summarizing the effect of many covariates through a few linear combinations is an effective way of reducing covariate dimension and is the backbone of (sufficient) dimension reduction. Because the replacement of high-dimensional covariates by low-dimensional linear combinations is performed with a minimum assumption on the specific regression form, it enjoys attractive advantages as well as encounters unique challenges in comparison with the variable selection approach. We review the current literature of dimension reduction with an emphasis on the two most popular models, where the dimension reduction affects the conditional distribution and the conditional mean, respectively. We discuss various estimation and inference procedures in different levels of detail, with the intention of focusing on their underneath idea instead of technicalities. We also discuss some unsolved problems in this area for potential future research. PMID- 23794783 TI - A fractal Richards' equation to capture the non-Boltzmann scaling of water transport in unsaturated media. AB - The traditional Richards' equation implies that the wetting front in unsaturated soil follows Boltzmann scaling, with travel distance growing as the square root of time. This study proposes a fractal Richards' equation (FRE), replacing the integer-order time derivative of water content by a fractal derivative, using a power law ruler in time. FRE solutions exhibit anomalous non-Boltzmann scaling, attributed to the fractal nature of heterogeneous media. Several applications are presented, fitting the FRE to water content curves from previous literature. PMID- 23794784 TI - Youden index and Associated Cut-points for Three Ordinal Diagnostic Groups. AB - Directly relating to sensitivity and specificity and providing an optimal cut point which maximizes overall classification effectiveness for diagnosis purpose, the Youden index has been frequently utilized in biomedical diagnosis practice. Current application of the Youden index is limited to two diagnostic groups. However, there usually exists a transitional intermediate stage in many disease processes. Early recognition of this intermediate stage is vital to open an optimal window for therapeutic intervention. In this paper, we extend the Youden index to assess diagnostic accuracy when there are three ordinal diagnostic groups. Parametric and nonparametric methods are presented to estimate the optimal Youden index, the underlying optimal cut-points and the associated confidence intervals. Extensive simulation studies covering representative distributional assumptions are reported to compare performance of the proposed methods. A real example illustrates the usefulness of the Youden index in evaluating discriminating ability of diagnostic tests. PMID- 23794785 TI - Basic Fibroblast Growth Factor Modulates the Expression of PDZ Domain-containing Proteins in Cultured Cortical Neurons. AB - Different cytokines and growth factors, together with their receptors, are expressed in brain tissue. One such molecule is the basic fibroblast growth factor (bFGF) that has recently been shown to promote survival following insults to neurons in vivo or in vitro. In this study, we found that repeated treatment of neocortical cultures with bFGF modulated the expression of various PDZ domain containing proteins (SAP97, GRIP1, Pick1, and PSD-93) and that the patterns of their immunostaining matched the bFGF effects on their total protein expression. For instance, bFGF decreased the expression of SAP97, GRIP1, and Pick1 (PDZ proteins that interact with the AMPA-type glutamate receptor subunits GluR1 and GluR2/3). PSD-93, which associates with the NMDA-type glutamate receptor, was increased by bFGF. Moreover, the interactions of GluR1 with SAP97 and GluR2 with GRIP1 were down-regulated by the repeated bFGF stimulation, as revealed by co immunoprecipitation. Together, these results describe a novel function of bFGF in the regulation of expression of PDZ proteins. PMID- 23794786 TI - Effectiveness of a Feedback-Based Brief Intervention to Reduce Alcohol Use in Community Substance Use Disorders. AB - Feedback brief interventions for alcohol use problems have been highly effective with undergraduate populations. However, there has been little research on the effectiveness of administering feedback alone to community treatment populations. The goal of the current study was to assess the effectiveness of a feedback brief intervention in a community treatment setting with patients characterized largely by dependence on alcohol and drugs, ethnic diversity, and low socioeconomic status. It was hypothesized that pre-treatment brief individualized feedback would reduce alcohol consumption and increase participation in subsequent treatment for a substance use disorder (SUD). Participants were recruited from a public hospital's SUD clinic. After the intake but prior to entry into the treatment as usual, 121 participants were randomized to receive personalized feedback or a condition without feedback. Eighty-seven participants completed post-intervention follow-up interviews and were included in the final analyses. Repeated measures ANOVAs and MANCOVAs were used to examine variables obtained from the Addiction Severity Index (ASI; McLellan et al., 1992) of drinking quantity and frequency, and motivation for treatment. Results indicated that personalized feedback delivered no benefit beyond that of pre-treatment assessment procedures (phone screening and intake interview) alone. Intervention conditions did not differ on other outcomes at follow-up, including days of heavy drinking, motivation for treatment, or drug use frequency. Therefore, feedback based brief interventions may be not helpful in reducing the drinking frequency and intensity of individuals presenting to community-based substance use treatment. PMID- 23794787 TI - A structured population modeling framework for quantifying and predicting gene expression noise in flow cytometry data. AB - We formulated a structured population model with distributed parameters to identify mechanisms that contribute to gene expression noise in time-dependent flow cytometry data. The model was validated using cell population-level gene expression data from two experiments with synthetically engineered eukaryotic cells. Our model captures the qualitative noise features of both experiments and accurately fit the data from the first experiment. Our results suggest that cellular switching between high and low expression states and transcriptional re initiation are important factors needed to accurately describe gene expression noise with a structured population model. PMID- 23794788 TI - Primary and Reversible Pisa Syndrome in Juvenile Normal Pressure Hydrocephalus. AB - OBJECTIVE: To report a case of Pisa syndrome in a patient with idiopathic normal pressure hydrocephalus, who had never been exposed to psychotropic medications. METHODS: A 26 years-old, Colombian, male patient, was referred because he had cognitive abnormalities, gait disturbances and urinary incontinence. This patient also displayed pleurothotonos. Neurofunctional evaluation of sensory and motor integration at peripheral and central nervous system levels were done. RESULTS: Pisa syndrome disappeared after spinal tap drainage with further gait, balance and behavioral improvement. A brainstem-thalamocortical deregulation of the central sensory and motor programming, due to the chaotic enlargement of brain ventricles was thought to be the pathophysiological mechanism underlying this case. CONCLUSION: NPH must not be longer considered as an exclusive geriatric disorder. Further, uncommon movement disorders may appear with this disorder, which should be carefully approached to avoid iatrogenic and deleterious pharmacological interventions. PMID- 23794789 TI - Winter peridermal conductance of apple trees: lammas shoots and spring shoots compared. AB - Lammas shoots are flushes formed by some woody species later in the growing season. Having less time to develop, tissue formation is suggested to be incomplete leading to a higher peridermal water loss during consecutive months. In this study, we analysed morphological and anatomical parameters, peridermal conductance to water vapour and the level of native embolism in mid-winter and late-winter of lammas shoots and normal spring shoots of the apple varieties Malus domestica 'Gala' and 'Nicoter'. Lammas shoots showed a significantly higher shoot cross-sectional area due to larger pith and corticular parenchyma areas. In contrast, phloem was significantly thicker in spring shoots. No pronounced differences were observed in xylem and collenchyma thickness or mean hydraulic conduit diameter. The phellem of spring shoots was composed of more suberinised cells compared to lammas shoots, which led to a significantly higher peridermal conductance in the latter. The amount of native embolism in mid-winter did not differ between shoot types, but in late-winter lammas shoots were more embolised than spring shoots. Data show that the restricted vegetation period of lammas shoots affects their development and, in consequence, their transpiration shield. This may also pose a risk for winter desiccation. PMID- 23794790 TI - Infrared Studies on Bimetallic Copper/Nickel Catalysts Supported on Zirconia and Ceria/Zirconia. AB - ABSTRACT: Infrared spectroscopy has been employed for a detailed characterization of ZrO2 and CeO2/ZrO2 supported nickel and copper/nickel catalysts to be utilized for methane decomposition. Adsorption of CO at 303 K was performed in order to determine the surface composition and accessible adsorption sites. Alloy formation occurred during reduction, as indicated by a red-shift of the vibrational band of CO on Ni: by 27 cm-1 on nickel-rich CuNi alloy, by 34 cm-1 on 1:1 Cu:Ni and by 36 cm-1 on copper-rich CuNi alloy. CuNi alloy formation was confirmed by X-ray absorption spectroscopy during reduction revealing a considerably lower reduction temperature of NiO in the bimetallic catalyst compared to the monometallic one. However, hydrogen chemisorption indicated that after reduction at 673 K copper was enriched at the surface of the all bimetallic catalysts, in agreement with IR spectra of adsorbed CO. In situ IR studies of methane decomposition at 773 K demonstrated that the addition of Cu to Ni strongly reduced coking occurring preferentially on nickel, while maintaining methane activation. Modification of the zirconia by ceria did not have much effect on the adsorption and reaction properties. Ceria-zirconia and zirconia supported samples exhibited very similar properties and surface chemistry. The main difference was an additional IR band of CO adsorbed on metallic copper pointing to an interaction of part of the Cu with the ceria. GRAPHICAL ABSTRACT: PMID- 23794791 TI - THE CHALLENGING ROLE OF A READING COACH, A CAUTIONARY TALE. AB - The purpose of this case study is to describe the challenges one coach faced during the initial implementation of a coaching initiative involving 33 teachers in an urban, high-poverty elementary school. Reading coaches are increasingly expected to play a key role in the professional development efforts to improve reading instruction in order to improve reading achievement for struggling readers. Data sources included initial reading scores for kindergarten and first graders, pretest and posttest scores of teachers' knowledge, a teacher survey, focus group interviews, project documents, and field notes. Data were analyzed using a mixed methods approach. Findings revealed several challenges that have important implications for research and practice: that teachers encountered new information about teaching early reading that conflicted with their current knowledge, this new information conflicted with their core reading program, teachers had differing perceptions of the role of the reading coach that affected their feelings about the project, and reform efforts are time-intensive. PMID- 23794792 TI - Factors Associated with Growth in Daily Smoking among Indigenous Adolescents. AB - North American Indigenous adolescents smoke earlier, smoke more, and are more likely to become regular smokers as adults than youth from any other ethnic group yet we know very little about their early smoking trajectories. We use multilevel growth modeling across five waves of data from Indigenous adolescents (aged 10 to 13 years at Wave 1) to investigate factors associated with becoming a daily smoker. Several factors, including number of peers who smoked at Wave 1 and meeting diagnostic criteria for major depressive episode and conduct disorder were associated with early daily smoking. Only age and increases in the number of smoking peers were associated with increased odds of becoming a daily smoker. PMID- 23794793 TI - Choice theories: What are they good for? AB - Simonson et al. present an ambitious sketch of an integrative theory of context. Provoked by this thoughtful proposal, I discuss what is the function of theories of choice in the coming decades. Traditionally, choice models and theory have attempted to predict choices as a function of the attributes of options. I argue that to be truly useful, they need to generate specific and quantitative predictions of the effect of the choice environment upon choice probability. To do this, we need to focus on rigorously modeling and measuring the underlying processes causing these effects, and use the Simonson et al. proposal to provide some examples. I also present some examples from research in decision-making and decision neuroscience, and argue that models that fail, and fail spectacularly are particularly useful. I close with a challenge: How would consumer researcher aid the design of real world choice environments such as the health exchanges under the Patient Protection and Affordable Care Act? PMID- 23794794 TI - Wavelet-based LASSO in functional linear regression. AB - In linear regression with functional predictors and scalar responses, it may be advantageous, particularly if the function is thought to contain features at many scales, to restrict the coefficient function to the span of a wavelet basis, thereby converting the problem into one of variable selection. If the coefficient function is sparsely represented in the wavelet domain, we may employ the well known LASSO to select a relatively small number of nonzero wavelet coefficients. This is a natural approach to take but to date, the properties of such an estimator have not been studied. In this paper we describe the wavelet-based LASSO approach to regressing scalars on functions and investigate both its asymptotic convergence and its finite-sample performance through both simulation and real-data application. We compare the performance of this approach with existing methods and find that the wavelet-based LASSO performs relatively well, particularly when the true coefficient function is spiky. Source code to implement the method and data sets used in the study are provided as supplemental materials available online. PMID- 23794795 TI - Girls' Tobacco and Alcohol Use During Early Adolescence: Prediction from Trajectories of Depressive Symptoms Across Two Studies. AB - Associations between trajectories of depressive symptoms and subsequent tobacco and alcohol use were examined in two samples of girls assessed at age 11.5 (T1), 12.5 (T2), and 13.5 (T3). Two samples were examined to ascertain if there was generalizability of processes across risk levels and cultures. Study 1 comprised a United States-based sample of 100 girls in foster care; Study 2 comprised 264 girls in a United Kingdom community-based sample. Controlling for T1 aggression and T1 substance use, individual variation in intercept and slope of depressive symptoms was associated with tobacco use at T3 in both samples: greater intercept and increases in depressive symptoms increased the risk for T3 tobacco use. A similar pattern of associations was found for alcohol use in Study 1. The replicability of findings for the prediction of tobacco use from trajectories of depressive symptoms suggests potential benefit in identifying girls with elevated depressive symptoms for tobacco use prevention programs prior to the transition to secondary school. PMID- 23794797 TI - Alcohols Effect on Critic Micelle Concentration of Polysorbate 20 and Cetyl Trimethyl Ammonium Bromine Mixed Solutions. AB - In this research, the micellar behavior of a cationic surfactant, cetyl trimethyl ammonium bromide (CTAB) and an nonionic surfactant, polysorbate 20 (Polyoxyethylene (20) sorbitan monolaurate) in different alcohol solutions media was investigated over the temperature range 293.15-313.15 K. The interaction between two surfactants in binary systems can be determined by calculating the values of their beta parameters. The critical micelle concentrations (CMC) of the micelles were determined from the surface tension, the conductivity at different temperatures. The CMC behavior of CTAB and polysorbate 20 was analyzed in terms of the effect of temperature and the increase in the alcohol carbon chain. Changes in the critical micelle concentration of mixed surfactant systems of different alcohol solutions were measured. The CMC decreased sharply as the hydrocarbon chain length of the alcohols becomes larger. This shows that the more hydrophobic alcohols are, the more marked a decrease in CMC is observed. PMID- 23794796 TI - Asymmetric Preparation of prim-, sec-, and tert-Amines Employing Selected Biocatalysts. AB - This account focuses on the application of omega-transaminases, lyases, and oxidases for the preparation of amines considering mainly work from our own lab. Examples are given to access alpha-chiral primary amines from the corresponding ketones as well as terminal amines from primary alcohols via a two-step biocascade. 2,6-Disubstituted piperidines, as examples for secondary amines, are prepared by biocatalytical regioselective asymmetric monoamination of designated diketones followed by spontaneous ring closure and a subsequent diastereoselective reduction step. Optically pure tert-amines such as berbines and N-methyl benzylisoquinolines are obtained by kinetic resolution via an enantioselective aerobic oxidative C-C bond formation. PMID- 23794798 TI - In Vivo Replication and Pathogenesis of Vesicular Stomatitis Virus Recombinant M40 Containing Ebola Virus L-Domain Sequences. AB - The M40 VSV recombinant was engineered to contain overlapping PTAP and PPxY L domain motifs and flanking residues from the VP40 protein of Ebola virus. Replication of M40 in cell culture is virtually indistinguishable from that of control viruses. However, the presence of the Ebola PTAP motif in the M40 recombinant enabled this virus to interact with and recruit host Tsg101, which was packaged into M40 virions. In this brief report, we compared replication and the pathogenic profiles of M40 and the parental virus M51R in mice to determine whether the presence of the Ebola L-domains and flanking residues altered in vivo characteristics of the virus. Overall, the in vivo characteristics of M40 were similar to those of the parental M51R virus, indicating that the Ebola sequences did not alter pathogenesis of VSV in this small animal model of infection. PMID- 23794799 TI - The Impact of Model Uncertainty on Benchmark Dose Estimation. AB - We study the popular benchmark dose (BMD) approach for estimation of low exposure levels in toxicological risk assessment, focusing on dose-response experiments with quantal data. In such settings, representations of the risk are traditionally based on a specified, parametric, dose-response model. It is a well known concern, however, that uncertainty can exist in specification and selection of the model. If the chosen parametric form is in fact misspecified, this can lead to inaccurate, and possibly unsafe, lowdose inferences. We study the effects of model selection and possible misspecification on the BMD, on its corresponding lower confidence limit (BMDL), and on the associated extra risks achieved at these values, via large-scale Monte Carlo simulation. It is seen that an uncomfortably high percentage of instances can occur where the true extra risk at the BMDL under a misspecified or incorrectly selected model can surpass the target BMR, exposing potential dangers of traditional strategies for model selection when calculating BMDs and BMDLs. PMID- 23794800 TI - Discovery of steninae from ningxia, northwest china (coleoptera, staphylinidae). AB - A study on the Steninae of Ningxia Autonomous Region is presented. Sixteen species are recognized, including new province records for 11 species and four new species: Stenus biwenxuani sp. n., Stenus liupanshanus sp. n., Dianous yinziweii sp. n., Dianous ningxiaensis sp. n. Habitus photos of the new species, illustrations of diagnostic characters of all species and a key to species of the Steninae recorded from Ningxia are provided. PMID- 23794801 TI - A new species of Myrmozercon Berlese (Acari, Mesostigmata, Laelapidae) associated with ant from Iran. AB - This paper report on a new species of mites of the genus Myrmozercon associated with ant in Iran - Myrmozercon cyrusi Ghafarian and Joharchi sp. n. was collected associated of the Monomorium sp. in Kenevist Rural District in the Central District of Mashhad County, Khorasan Razavi Province, Iran. This new species is described and illustrations provided. Myrmozercon ovatum Karawajew, 1909 is suspected to be a junior synonym of Myrmozercon brevipes Berlese, 1902 and host specificity and host range of Myrmozercon are also reviewed. PMID- 23794802 TI - Sinularia leptoclados (Ehrenberg, 1834) (Cnidaria, Octocorallia) re-examined. AB - Sinularia leptoclados (Ehrenberg, 1834) is re-described. Sinularia leptoclados var. gonatodes Kolonko, 1926 is synonymized with Sinularia maxima Verseveldt, 1977. Two new species of Sinularia with digitiform lobules, leptoclados-type surface clubs and unbranched interior spindles, are described. An updated maximum likelihood tree of Sinularia species with leptoclados-type clubs (clade 5C) based on two mitochondrial genes (mtMutS, COI) and a nuclear gene (28S rDNA) is presented. PMID- 23794803 TI - Heptageniidae (insecta, ephemeroptera) of Thailand. AB - Nine genera and twenty-two species of heptageniid mayflies from Thailand are defined in this present work as well as one suggested further subgenus, Compsoneuria (Siamoneuria) kovaci (species "incertae sedis") including some particular characters. Taxonomic remarks, diagnoses, line drawings of key characters, distribution, habitat and biological data, and a larval key to the genera and species are provided. The chorionic eggs of eight genera and eight species were observed and shown using a scanning electron microscope. PMID- 23794804 TI - New record of the cockroach genus Pseudophoraspis (Blaberidae, Epilamprinae) from China with descriptions of three new species. AB - The genus Pseudophoraspis Kirby, 1903 with three new species, Pseudophoraspis clavellata sp. n., Pseudophoraspis recurvata sp. n. and Pseudophoraspis incurvata sp. n., are reported from China for the first time. This extends the range of this genus northward from Vietnam. Species studied in the present paper are illustrated and described, and a key to these species based on males is provided. PMID- 23794805 TI - The subtribes and genera of the tribe Listroderini (Coleoptera, Curculionidae, Cyclominae): Phylogenetic analysis with systematic and biogeographical accounts. AB - The phylogenetic relationships of the genera of Listroderini LeConte, 1876 are analyzed based on 58 morphological characters. The genera are grouped in four clades, which are given subtribal status: Macrostyphlina new subtribe (Adioristidius, Amathynetoides, Andesianellus, Macrostyphlus, Nacodius and Puranius), Palaechthina Brinck, 1948 (Anorthorhinus, Gunodes, Haversiella, Inaccodes, Listronotus, Neopachytychius, Palaechthus, Palaechtodes, Steriphus and Tristanodes), Falklandiina new subtribe (Falklandiellus, Falklandiopsis, Falklandius, Gromilus, Lanteriella, Liparogetus, Nestrius and Telurus), and Listroderina (Acroriellus, Acrorius, Acrostomus, Antarctobius, Germainiellus, Hyperoides, Lamiarhinus, Listroderes, Methypora, Philippius, Rupanius and Trachodema). The subtribes are characterized and keys to identify them and their genera are provided. Listroderini have four main biogeographical patterns: Andean (Macrostyphlina), Andean-New Zealand (Falklandiina), Andean-Neotropical Australian (Listroderina) and Andean-Neotropical-Australian-New Zealand-Nearctic Tristan da Cunha-Gough islands (Palaechthina). Geographical paralogy, particularly evident in the Subantarctic subregion of the Andean region, suggests that Listroderini are an ancient Gondwanic group, in which several extinction events might have obscured relationships among the areas. PMID- 23794806 TI - A review of the genus Berosus Leach of Cuba (Coleoptera, Hydrophilidae). AB - The Cuban fauna of the genus Berosus Leach, 1817 is reviewed based on newly collected material as well as historical and type specimens. Nine species are recognized, including three recorded from Cuba for the first time: Berosus infuscatus LeConte, 1855, Berosus interstitialis Knisch, 1924 (= Berosus stribalus Orchymont, 1946 syn. n.) and Berosus metalliceps Sharp, 1882. Only one of the nine Cuban species, Berosus chevrolati, remains endemic to Cuba, as two other species previously considered as endemic to Cuba are recorded from elsewhere: Berosus quadridens from Mexico and Central America and Berosus trilobus from the Dominican Republic. Notes on biology and Cuban distribution are provided for all nine species. Berosus quadridens Chevrolat, 1863, stat. restit. is removed from synonym with Berosus truncatipennis and considered a valid species. PMID- 23794807 TI - A preliminary study on the insect fauna of Al-Baha Province, Saudi Arabia, with descriptions of two new species. AB - A preliminary study was carried out on the insect fauna of Al-Baha Province, south-western part of Saudi Arabia. A total number of 582 species and subspecies (few identified only to the genus level) belonging to 129 families and representing 17 orders were recorded. Two of these species are described as new, namely: Monomorium sarawatensis Sharaf & Aldawood, sp. n. [Formicidae, Hymenoptera] and Anthrax alruqibi El-Hawagry sp. n. [Bombyliidae, Diptera]. Another eight species are recorded for the first time in Saudi Arabia, namely: Xiphoceriana arabica (Uvarov, 1922) [Pamphagidae, Orthoptera], Pyrgomorpha conica (Olivier, 1791) [Pyrgomorphidae, Orthoptera], Catopsilia florella (Fabricius, 1775) [Pieridae, Lepidoptera], Anthrax chionanthrax (Bezzi, 1926) [Bombyliidae, Diptera], Spogostylum near tripunctatum Pallas in Wiedemann, 1818 [Bombyliidae, Diptera], Cononedys dichromatopa (Bezzi, 1925) [Bombyliidae, Diptera], Mydas sp. [Mydidae, Diptera], and Hippobosca equina Linnaeus, 1758 [Hippoboscidae, Diptera]. Al-Baha Province is divided by huge and steep Rocky Mountains into two main sectors, a lowland coastal plain at the west, known as "Tihama", and a mountainous area with an elevation of 1500 to 2450 m above sea level at the east, known as "Al-Sarat or Al-Sarah" which form a part of Al-Sarawat Mountains range. Insect species richness in the two sectors (Tihama and Al-Sarah) was compared, and the results showed that each of the two sectors of Al-Baha Province has a unique insect community. The study generally concluded that the insect faunal composition in Al-Baha Province has an Afrotropical flavor, with the Afrotropical elements predominant, and a closer affiliation to the Afrotropical region than to the Palearctic region or the Eremic zone. Consequently, we tend to agree with those biogeographers who consider that parts of the Arabian Peninsula, including Al-Baha Province, should be included in the Afrotropical region rather than in the Palaearctic region or the Eremic zone. PMID- 23794808 TI - Redescription and anatomy of Diplodonta portesiana (d'Orbigny, 1846) (Bivalvia, Ungulinidae) from Brazil. AB - The present redescription of Diplodonta portesiana (d'Orbigny, 1846) is the first part of the revision of this genus in the East Atlantic. This species, despite being common in the Atlantic coast, remains poorly known. A detailed shell and anatomical study was conducted based not only on specimens from the type locality's vicinities but also on samples from other regions. Diagnostic characters for Diplodonta portesiana includes: rounded shell with a small ligament; triangular, short and deep nymph; external micro ornamentation composed of small concavities in a concentric pattern; small adductor muscles; reduced pedal gape; pair of long hemipalps with a large area covered by folds; stomach with four ducts leading to digestive diverticula; and long intestine length. Our study suggests at least two new diagnostic characters to the genus: the two pair of muscles that controls the incurrent and excurrent openings and a residual ring like tissue surrounding the anterior half of the posterior foot retractor muscle. PMID- 23794809 TI - Description of Pella maoershanensis sp. n. (Coleoptera, Staphylinidae, Aleocharinae) associated with Lasius spathepus from Guangxi, South China. AB - Pellamaoershanensis Song & Li, sp. n., collected from a colony of Lasius (Dendrolasius) spathepus in Maoershan Natural Reserve, Guangxi, is diagnosed, described and illustrated. The discovery represents the first record of the genus in South China. PMID- 23794810 TI - Further studies on the Pselaphodes complex of genera from China (Coleoptera, Staphylinidae, Pselaphinae). AB - New data on the Pselaphodes complex of genera (Pselaphitae: Tyrini) from China is presented. The generic limits of Labomimus Sharp and Pselaphodes Westwood are discussed and expanded. A revised key to the genera of the Pselaphodes complex is provided. New geographic evidence suggests that previously believed wide-spread species Pselaphodes tianmuensis Yin, Li & Zhao contains a number of related species, resulting in a division of the species to nine separate taxa. Fourteen new species belonging to three genera are diagnosed, described and illustrated: Dayao emeiensis Yin & Li, sp. n. (Sichuan), Labomimus fimbriatus Yin & Hlavac, sp. n. (Yunnan), Labomimus jizuensis Yin & Hlavac, sp. n. (Yunnan), Labomimus simplicipalpus Yin & Hlavac, sp. n. (Sichuan), Pselaphodes anhuianus Yin & Li, sp. n. (Anhui), Pselaphodes daii Yin & Hlavac, sp. n. (Sichuan), Pselaphodes grebennikovi Yin & Hlavac, sp. n. (Yunnan), Pselaphodes hainanensis Yin & Li, sp. n. (Hainan), Pselaphodes kuankuoshuiensis Yin & Li, sp. n. (Guizhou), Pselaphodes longilobus Yin & Hlavac, sp. n. (Hunbei, Yunnan), Pselaphodes monoceros Yin & Hlavac, sp. n. (Xizang), Pselaphodes pengi Yin & Li, sp. n. (Sichuan), Pselaphodes tiantongensis Yin & Li, sp. n. (Zhejiang) and Pselaphodes wrasei Yin & Li, sp. n. (Yunnan). Labomimus sichuanicus Hlavac, Nomura & Zhou (Sichuan) is redescribed and illustrated based on a paratype and the material from the type locality. Two recently described species, Pselaphodes tibialis Yin & Li (Yunnan), and Pselaphodes venustus Yin & Li (Yunnan), are transferred to Labomimus (comb. n.) due to the presence of a median metaventral fovea. New locality data is provided for Pselaphodes aculeus Yin, Li & Zhao (Anhui, Fujian, Guangxi, Hainan, Yunnan), Pselaphodes maoershanus Yin & Li (Guangxi, Guizhou), Pselaphodes tianmuensis (Zhejiang, Anhui, Fujian, Jiangxi, Guangxi) and Pselaphodes pectinatus Yin, Li & Zhao (Hainan), with the aedeagus newly illustrated for the latter species. PMID- 23794811 TI - One new and seven newly recorded Callichromatini species from China (Coleoptera, Cerambycidae, Cerambycinae). AB - One new species, Schwarzerium yunnanum sp. n. is described from Yunnan Province, China. And a new subgenus Rugosochroma subgen. n. is erected for it. Additionally, Seven species of the tribe Callichromatini are newly recorded from China: Aphrodisium niisatoi Vives & Bentanachs, 2007, Aphrodisium tricoloripes Pic, 1925, Chelidonium violaceimembris Gressitt & Rondon, 1970 (new from Vietnam too), Chloridolum grossepunctatum Gressitt & Rondon, 1970 (new from Vietnam too), Chloridolum semipunctatum Gressit & Rondon 1970, Embrikstrandia vivesi Bentanachs, 2005 and Laosaphrodisium subplicatum (Pic, 1937). PMID- 23794812 TI - Description of a new species of Distenia (Coleoptera, Disteniidae, Disteniini) from Southeastern China, with records and diagnoses of similar species. AB - A new species, Distenia orientalis sp. n. is described from Southeastern China. It was misidentified as Distenia gracilis (Blessig, 1872) but can be separated from the latter by the color of antennae and legs, structure differences on scape, maxillary palp, pronotum, tibiae, punctures on elytra, etc. Three related species are carefully diagnosed and treated. PMID- 23794813 TI - A new species of Haplothrips from southern Iran (Thysanoptera, Phlaeothripidae). AB - Haplothrips herajius sp. n. is described from leaves and flowers of a species of Suaeda in the south of Fars Province, Iran. This is the second Iranian species of Haplothrips with the unusual character state of extra setae on the metanotum. Information on variation in color and structure of the new species is provided. The similarities and host plant associations of this new species and Haplothrips kermanensis are discussed,as both are phytophagous on species of Chenopodiaceae. PMID- 23794814 TI - A revision of the continental species of Copa Simon, 1885 (Araneae, Corinnidae) in the Afrotropical Region. AB - The cryptic ground-dwelling castianeirine genus Copa Simon, 1885 (Araneae: Corinnidae) is revised in the continental Afrotropical Region. The type species of the genus, Copa flavoplumosa Simon, 1885, is redescribed and considered a senior synonym of Copa benina Strand, 1916 syn. n. and Copa benina nigra Lessert, 1933 syn. n. It is widespread throughout the Afrotropical Region but has not been introduced to any of the associated regional islands. A new species, Copa kei sp. n., is described from South Africa. Copa agelenina Simon, 1910, originally described from a subadult female from southern Botswana, is considered a nomen dubium. Copa flavoplumosa is a characteristic species of leaf litter spider assemblages and is particularly prevalent in savanna habitats on the continent, but also occurs in various forest types, grasslands, fynbos and semi-arid Nama Karoo habitats. In contrast, Copa kei sp. n. has only been recorded from Afromontane and coastal forests in south-eastern South Africa. PMID- 23794815 TI - A new species of Newportia Gervais, 1847 from Puerto Rico, with a revised key to the species of the genus (Chilopoda, Scolopendromorpha, Scolopocryptopidae). AB - A new species of the centipede genus Newportia, Newportia stoevi sp. n., is described from Rio Encantado Cave, Puerto Rico. It differs from all congeners by having sternites distinctly margined laterally and ultimate legs bearing 4 spinous processes on both prefemur and femur, and 2 on tibia. The value of some terms used in the taxonomy of the genus have been analyzed and an amended identification key to the species of Newportia is provided. PMID- 23794816 TI - Distinguishing Bolboceras inaequale Westwood, 1848 and two new relatives from India (Coleoptera, Geotrupidae, Bolboceratinae). AB - The taxonomy of the Bolboceras inaequale group of species is discussed. The group as here conceived comprises three species in the Indian subcontinent: Bolboceras inaequale Westwood, 1848 (reputedly also ranging into sub-Saharan Africa), and two new species: Bolboceras duplicatum, and Bolboceras orissicum, both from India. All three are keyed, diagnosed, and illustrated; variability and potential taxonomic obstacles are briefly discussed. PMID- 23794817 TI - A curious abnormally developed embryo of the pill millipede Glomeris marginata (Villers, 1789). AB - This paper reports on an abnormally developed embryo (ADE) of the common pill millipede Glomeris marginata. This ADE represents a modified case of Duplicitas posterior, in which two posterior ends are present, but only one anterior end. While the major posterior germ band of the embryo appears almost normally developed, the minor posterior germ band is heavily malformed, has no clear correlation to the single head, little or no ventral tissue, and a minute amount of yolk. The anterior end of the minor germ band is fused to the ventral side of the major germ band between the first and second trunk segment. At least one appendage of the second trunk segment appears to be shared by the two germ bands. Morphology and position of the minor germ band suggest that the ADE may be the result of an incorrectly established single cumulus [the later posterior segment addition zone (SAZ)]. This differs from earlier reports on Duplicitas posterior type ADEs in Glomeris marginata that are likely the result of the early formation of two separate cumuli. PMID- 23794818 TI - Morphometric measurements of dragonfly wings: the accuracy of pinned, scanned and detached measurement methods. AB - Large-scale digitization of museum specimens, particularly of insect collections, is becoming commonplace. Imaging increases the accessibility of collections and decreases the need to handle individual, often fragile, specimens. Another potential advantage of digitization is to make it easier to conduct morphometric analyses, but the accuracy of such methods needs to be tested. Here we compare morphometric measurements of scanned images of dragonfly wings to those obtained using other, more traditional, methods. We assume that the destructive method of removing and slide-mounting wings provides the most accurate method of measurement because it eliminates error due to wing curvature. We show that, for dragonfly wings, hand measurements of pinned specimens and digital measurements of scanned images are equally accurate relative to slide-mounted hand measurements. Since destructive slide-mounting is unsuitable for museum collections, and there is a risk of damage when hand measuring fragile pinned specimens, we suggest that the use of scanned images may also be an appropriate method to collect morphometric data from other collected insect species. PMID- 23794819 TI - Alburnoides manyasensis (Actinopterygii, Cyprinidae), a new species of cyprinid fish from Manyas Lake basin, Turkey. AB - Alburnoides manyasensis, sp. n., is described from the Koca Stream (Lake Manyas drainage, Marmara Sea basin) in Anatolia. It is distinguished from all species of Alburnoides in Turkey and adjacent regions, Alburnoides tzanevi (Rezovska [Rezve], Istranca and Terkos streams in the western Black Sea drainage), Alburnoides cf. smyrnae (Banaz Stream, a drainage of Buyuk Menderes River, Aegean Sea basin), Alburnoides fasciatus (streams and rivers in the eastern Black Sea drainage) and Alburnoides eichwaldii (Kura and Aras rivers [a drainage of Kura River], Caspian Sea basin) by a combination of the following characters (none unique to the species):marked hump at nape, especially in specimens larger than 60 mm SL; partly developed ventral keel between pelvic fin and anal fin, scaleless 1/2 to 2/3 its length; body depth at dorsal-fin origin 29-32% SL; caudal peduncle depth 11-12% SL; 45-52+ 2-3 lateral-line scales; 9-12 scale rows between lateral line and dorsal-fin origin; 4-5 scale rows between lateral line and anal-fin origin, 101/2-121/2 branched anal-fin rays; 40-42 total vertebrae. PMID- 23794820 TI - A new species of the genus Gaeolaelaps (Acari, Mesostigmata, Laelapidae) from Iran. AB - The Genus Gaeolaelaps Evans & Till, 1966 is currently one of the largest genera of the family Laelapidae Berlese. The known representatives of this genus are active predators of small invertebrates such as other mites, insect eggs and nematodes. Gaeolaelaps iranicus Kavianpour & Nemati sp. n., was collected from soil and litter in various parts of Iran. The description and figures of this species are given. A key to the Gaeolaelaps species of Iran is provided. PMID- 23794821 TI - A preliminary checklist of the ants (Hymenoptera, Formicidae) of Andorra. AB - Within the last decade, checklists of the ant fauna of several European countries have been published or updated. Nevertheless, no ant checklists have hitherto been published for the principality of Andorra, a small landlocked country located in the eastern part of the Pyrenees. This work presents a critical list of the ant species of Andorra based on a review of the literature and on the biological material we collected during several field campaigns conducted in Andorra since the year 2005. Seventy-five species belonging to 21 genera of Formicidae were recorded. Nine species were recorded for the first time in Andorra: Aphaenogaster gibbosa (Latreille, 1798), Camponotus lateralis (Olivier, 1792), Camponotus piceus (Leach, 1825), Formica exsecta Nylander, 1846, Lasius piliferus Seifert, 1992, Tapinoma madeirense Forel, 1895, Temnothorax lichtensteini (Bondroit, 1918), Temnothorax niger (Forel, 1894), Temnothorax nigriceps (Mayr, 1855). The most speciose genera were Formica Linnaeus, 1758 and Temnothorax Forel, 1890 with 14 and 12 species, respectively. The ant fauna of Andorra is mostly dominated by Central European species (some are typical cold climate specialists); however species belonging to the Mediterranean ant fauna were also found. This can be explained by the particular geographic situation of Andorra which is characterized by a high mountain Mediterranean climate. PMID- 23794822 TI - Barucynips panamensis , a new genus and species of oak gallwasps (Hymenoptera, Cynipidae, Cynipini) from Panama, and description of one new species of Coffeikokkos. AB - Barucynips panamensis Medianero & Nieves-Aldrey, a new genus and species of oak gallwasps (Hymenoptera: Cynipidae: Cynipini), is described from adults reared from galls on Quercus bumelioides in Panama. The new genus is taxonomically close to the recently described Coffeikokkos from Costa Rica, but differs from it and all of the described genera of Cynipini, by the shape and setation of the projecting part of the ventral spine of the hypopygium and by the sculpture of the propodeum. A new species of Coffeikokkos is also described from the same area, the Volcan Baru in Panama. Diagnostic characters, gall description, distribution, and biological data of the new genus and the two new species are given. The new genus is the first genus of oak gallwasps of the tribe Cynipini described in Panama. PMID- 23794823 TI - On the Lathrobium fauna of the Emei Shan, Sichuan, China (Coleoptera, Staphylinidae, Paederinae). AB - Six species of Lathrobium Gravenhorst, 1802 from the Emei Shan, Sichuan, are described and illustrated: Lathrobium iunctum Assing & Peng sp. n., Lathrobium coniunctum Assing & Peng sp. n., Lathrobium conexum Assing & Peng sp. n., Lathrobium ensigerum Assing & Peng sp. n., Lathrobium hastatum Assing & Peng sp. n., and Lathrobium bisinuatum Assing & Peng sp. n. Based on their primary and secondary sexual characters, they represent two distinct lineages, each of them comprising three species. A key to the species recorded from the Emei Shan is provided. PMID- 23794824 TI - Two sympatric new species of woodlizards (Hoplocercinae, Enyalioides ) from Cordillera Azul National Park in northeastern Peru. AB - We report the discovery of two sympatric new species of Enyalioides from a montane rainforest of the Rio Huallaga basin in northeastern Peru. Among other characters, the first new species is distinguishable from other Enyalioides by the combination of the following characters: strongly keeled ventral scales, more than 37 longitudinal rows of dorsals in a transverse line between the dorsolateral crests at midbody, low vertebral crest on the neck with vertebrals on neck similar in size to those between hind limbs, projecting scales on body or limbs absent, 96 mm maximum SVL in both sexes, and caudals increasing in size posteriorly within each autotomic segment. The second new species differs from other species of Enyalioides in having strongly keeled ventral scales, scales posterior to the superciliaries forming a longitudinal row of strongly projecting scales across the lateral edge of the skull roof in adults of both sexes, 31 or fewer longitudinal rows of strongly keeled dorsals in a transverse line between the dorsolateral crests at midbody, vertebrals on neck more than five times the size of vertebrals between hind limbs in adult males, projecting scales on body or limbs absent, and caudals increasing in size posteriorly within each autotomic segment. We also present an updated molecular phylogenetic tree of hoplocercines including new samples of Enyalioides rudolfarndti, Enyalioides rubrigularis, both species described in this paper, as well as an updated identification key for species of Hoplocercinae. PMID- 23794825 TI - Alien molluscan species established along the Italian shores: an update, with discussions on some Mediterranean "alien species" categories. AB - The state of knowledge of the alien marine Mollusca in Italy is reviewed and updated. Littorina saxatilis (Olivi, 1792), Polycera hedgpethi Er. Marcus, 1964 and Haminoea japonica Pilsbry, 1895are here considered as established on the basis of published and unpublished data, and recent records of the latter considerably expand its known Mediterranean range to the Tyrrhenian Sea. COI sequences obtained indicate that a comprehensive survey of additional European localities is needed to elucidate the dispersal pathways of Haminoea japonica.Recent records and interpretation of several molluscan taxa as alien are discussed both in light of new Mediterranean (published and unpublished) records and of four categories previously excluded from alien species lists. Within this framework, ten taxa are no longer considered as alien species, or their records from Italy are refuted. Furthermore, Trochocochlea castriotae Bellini, 1903 is considered a new synonym for Gibbula albida (Gmelin, 1791). Data provided here leave unchanged as 35 the number of alien molluscan taxa recorded from Italy as well as the percentage of the most plausible vectors of introduction, but raise to 22 the number of established species along the Italian shores during the 2005 2010 period, and backdate to 1792 the first introduction of an alien molluscan species (Littorina saxatilis) to the Italian shores. PMID- 23794826 TI - Nomenclatural changes in Cicadellidae: Typhlocybinae and Delphacidae (Homoptera). AB - New replacement names are proposed for seven species of the subfamily Typhlocybinae; one new synonym is recognized in the family Delphacidae. The following changes are proposed: Empoasca (Empoasca) angustata nom.nov. for Empoasca angusta Linnavuori & DeLong (not Dworakowska); Empoasca (Empoasca) chilensis nom.nov. for Empoasca diversa Linnavuori & DeLong (not Vilbaste); Austroasca verdensis nom.nov. for Empoasca artemisiae Lindberg (not Lethierry); Kropka vidanoi Dworakowska for Erythroneura unipunctata Dlabola (not Cerutti); Zyginella vietnamica nom. nov. for Zyginella melichari Dworakowska (not Kirkaldy); Eupteryx (Eupteryx) dlabolai nom. nov. for Eupteryx octonotata Dlabola (not Hardy); Baaora ahmedi nom. nov. for Baaora spinosa (Ahmed) (not Beamer); Paradelphacodes insolitus Dmitriev is synonymized with Paradelphacodes gvosdevi (Mitjaev), syn. nov. PMID- 23794827 TI - Phylogeny and host-plant relationships of the Australian Myrtaceae leafmining moth genus Pectinivalva (Lepidoptera, Nepticulidae), with new subgenera and species. AB - The phylogeny of the mainly Australian nepticulid genus Pectinivalva Scoble, 1983 is investigated on the basis of morphology, and a division into three monophyletic subgenera is proposed on the basis of these results. These subgenera (Pectinivalva, Casanovula Hoare, subgen. n. and Menurella Hoare, subgen. n. ) are described and diagnosed, the described species of Pectinivalva are assigned to them, and representative new species are described in each: Pectinivalva (Pectinivalva) mystaconota Hoare, sp. n., Pectinivalva (Casanovula) brevipalpa Hoare, sp. n., Pectinivalva (Casanovula) minotaurus Hoare, sp. n., Pectinivalva (Menurella) scotodes Hoare, sp. n., Pectinivalva (Menurella) acmenae Hoare, sp. n., Pectinivalva (Menurella) xenadelpha Van Nieukerken & Hoare, sp. n., Pectinivalva (Menurella) quintiniae Hoare & Van Nieukerken, sp. n., and Pectinivalva (Menurella) tribulatrix Van Nieukerken & Hoare, sp. n. Pectinivalva (Menurella) quintiniae (from Quintinia verdonii, Paracryphiaceae) is the first known member of the genus with a host-plant not belonging to Myrtaceae. Pectinivalva (Menurella) xenadelpha from Mt Gunung Lumut, Kalimantan, Borneo, is the first pectinivalvine reported from outside Australia. Keys to the subgenera of Nepticulidae known from Australia, based on adults, male and female genitalia, and larvae, are presented. Host-plant relationships of Pectinivalva are discussed with relation to the phylogeny, and a list of known host-plants of Pectinivalva, including hosts of undescribed species, is presented. DNA barcodes are provided for most of the new and several unnamed species. PMID- 23794828 TI - Cockroaches of genus Muzoa: morphology of the male genital sclerites and description of one new species (Dictyoptera, Blattodea, Ectobiidae, Nyctiborinae). AB - The male genital sclerites of cockroaches of genus Muzoa Hebard 1921 are described for first time and the new species Muzoa curtalata sp. n. is described and ilustrated. A dichotomous key to identify the species of genus Muzoa is given. PMID- 23794829 TI - Four new species of Unixenus Jones, 1944 (Diplopoda, Penicillata, Polyxenida) from Australia. AB - Unixenus carnarvonensis sp. n., Unixenus corringlensis sp. n., Unixenus barrabaensis sp. n. and Unixenus myallensis sp. n. are described from Australia. A revised diagnosis of Unixenus karajinensis and new details on the distribution of the species are given. A key is presented to 10 of all 11 currently known species of the genus. PMID- 23794830 TI - A new species of the genus Duvalius sg. Neoduvalius from Montenegro with taxonomical remarks on the genus Duvalius (Coleoptera, Carabidae, Trechini). AB - Duvalius (sg. Neoduvalius) gejzadunayi sp. n. from Pecina u Dubokom potoku cave ( Donje Bisevo village near Rozaje, Montenegro), the first known representative of this subgenus from the territory of Montenegro is described, illustrated and compared with the related species of the subgenus Neoduvalius Muller, 1913. This new species is characterised by depigmented, medium sized body, totally reduced eyes, deep and complete frontal furrows, 3-4 pairs of discal setae in third elytral stria, as well as by the shape of aedeagus. Data on the distribution and the ecology of this remarkable species, as well as a check-list of the subgenus Neoduvalius are also provided. Recently described genera Serboduvalius Curcic, S. B. Pavicevic & Curcic, B.P.M., 2001, Rascioduvalius Curcic, S. B. Brajkovic, Mitic & Curcic, B.P.M., 2003, Javorella Curcic, S. B. Brajkovic, Curcic, B.P.M. & Mitic, 2003 and Curcicia Curcic, S. B. & Brajkovic, 2003 are regarded as junior synonyms of the genus Duvalius Delarouzee. PMID- 23794831 TI - Annotated type catalogue of the Orthalicoidea (Mollusca, Gastropoda) in the Museum fur Naturkunde, Berlin. AB - The type status is described of 96 taxa classified within the superfamily Orthalicoidea and present in the Mollusca collection of the Museum fur Naturkunde der Humboldt-Universitat zu Berlin. Lectotypes are designated for the following taxa: Orthalicus elegans Rolle, 1895; Bulimus maranhonensis Albers, 1854; Orthalicus nobilis Rolle, 1895; Orthalichus tricinctus Martens, 1893. Orthalicus sphinx tresmariae is introduced as new name for Zebra sphinx turrita Strebel, 1909, not Zebra quagga turrita Strebel, 1909. The following synonyms are established: Zebra crosseifischeri Strebel, 1909 = Orthalicus princeps fischeri Martens, 1893; Orthalicus isabellinus Martens, 1873 = Orthalicus bensoni (Reeve, 1849); Zebra zoniferus naesiotes Strebel, 1909 = Orthalicus undatus (Bruguiere, 1789); Porphyrobaphe (Myiorthalicus) dennisoni pallida Strebel, 1909 = Hemibulimus dennisoni (Reeve, 1848); Zebra delphinus pumilio Strebel, 1909 = Orthalicus delphinus (Strebel, 1909); Orthalicus (Laeorthalicus) reginaeformis Strebel, 1909 = Corona perversa (Swainson, 1821); Bulimus (Eurytus) corticosus Sowerby III, 1895 = Plekocheilus (Eurytus) stuebeli Martens, 1885. The taxon Bulimus (Eudioptus) psidii Martens, 1877 is now placed within the family Sagdidae, tentatively in the genus Platysuccinea. Appendices are included with an index to all the types of Orthalicoidea extant (including those listed by Kohler 2007) and a partial list of letters present in the correspondence archives. PMID- 23794832 TI - One hundred and one new species of Trigonopterus weevils from New Guinea. AB - A species discovery and description pipeline to accelerate and improve taxonomy is outlined, relying on concise expert descriptions, combined with DNA sequencing, digital imaging, and automated wiki species page creation from the journal. One hundred and one new species of Trigonopterus Fauvel, 1862 are described to demonstrate the feasibility of this approach: Trigonopterus aeneipennis sp. n., Trigonopterus aeneus sp. n., Trigonopterus agathis sp. n., Trigonopterus agilis sp. n., Trigonopterus amplipennis sp. n., Trigonopterus ancoruncus sp. n., Trigonopterus angulatus sp. n., Trigonopterus angustus sp. n., Trigonopterus apicalis sp. n., Trigonopterus armatus sp. n., Trigonopterus ascendens sp. n., Trigonopterus augur sp. n., Trigonopterus balimensis sp. n., Trigonopterus basalis sp. n., Trigonopterus conformis sp. n., Trigonopterus constrictus sp. n., Trigonopterus costatus sp. n., Trigonopterus costicollis sp. n., Trigonopterus crassicornis sp. n., Trigonopterus cuneipennis sp. n., Trigonopterus cyclopensis sp. n., Trigonopterus dentirostris sp. n., Trigonopterus discoidalis sp. n., Trigonopterus dromedarius sp. n., Trigonopterus durus sp. n., Trigonopterus echinus sp. n., Trigonopterus edaphus sp. n., Trigonopterus eremitus sp. n., Trigonopterus euops sp. n., Trigonopterus ferrugineus sp. n., Trigonopterus fusiformis sp. n., Trigonopterus glaber sp. n., Trigonopterus gonatoceros sp. n., Trigonopterus granum sp. n., Trigonopterus helios sp. n., Trigonopterus hitoloorum sp. n., Trigonopterus imitatus sp. n., Trigonopterus inflatus sp. n., Trigonopterus insularis sp. n., Trigonopterus irregularis sp. n., Trigonopterus ixodiformis sp. n., Trigonopterus kanawiorum sp. n., Trigonopterus katayoi sp. n., Trigonopterus koveorum sp. n., Trigonopterus kurulu sp. n., Trigonopterus lekiorum sp. n., Trigonopterus lineatus sp. n., Trigonopterus lineellus sp. n., Trigonopterus maculatus sp. n., Trigonopterus mimicus sp. n., Trigonopterus monticola sp. n., Trigonopterus montivagus sp. n., Trigonopterus moreaorum sp. n., Trigonopterus myops sp. n., Trigonopterus nangiorum sp. n., Trigonopterus nothofagorum sp. n., Trigonopterus ovatus sp. n., Trigonopterus oviformis sp. n., Trigonopterus parumsquamosus sp. n., Trigonopterus parvulus sp. n., Trigonopterus phoenix sp. n., Trigonopterus plicicollis sp. n., Trigonopterus politoides sp. n., Trigonopterus pseudogranum sp. n., Trigonopterus pseudonasutus sp. n., Trigonopterus ptolycoides sp. n., Trigonopterus punctulatus sp. n., Trigonopterus ragaorum sp. n., Trigonopterus rhinoceros sp. n., Trigonopterus rhomboidalis sp. n., Trigonopterus rubiginosus sp. n., Trigonopterus rubripennis sp. n., Trigonopterus rufibasis sp. n., Trigonopterus scabrosus sp. n., Trigonopterus scissops sp. n., Trigonopterus scharfi sp. n., Trigonopterus signicollis sp. n., Trigonopterus simulans sp. n., Trigonopterus soiorum sp. n., T sordidus sp. n., Trigonopterus squamirostris sp. n., Trigonopterus striatus sp. n., Trigonopterus strigatus sp. n., Trigonopterus strombosceroides sp. n., Trigonopterus subglabratus sp. n., Trigonopterus sulcatus sp. n., Trigonopterus taenzleri sp. n., Trigonopterus talpa sp. n., Trigonopterus taurekaorum sp. n., Trigonopterus tialeorum sp. n., Trigonopterus tibialis sp. n., Trigonopterus tridentatus sp. n., Trigonopterus uniformis sp. n., Trigonopterus variabilis sp. n., Trigonopterus velaris sp. n., Trigonopterus verrucosus sp. n., Trigonopterus violaceus sp. n., Trigonopterus viridescens sp. n., Trigonopterus wamenaensis sp. n., Trigonopterus wariorum sp. n., Trigonopterus zygops sp. n.. All new species are authored by the taxonomist-in charge, Alexander Riedel. PMID- 23794833 TI - An overview of the Mediterranean cave-dwelling horny sponges (Porifera, Demospongiae). AB - The present synthesis focuses on the so called 'horny sponges' recorded from marine caves of the Mediterranean Sea. The main aim is to provide a list of all recorded species, diagnostic keys to their identification up to family and genus level, and exhaustive, formally uniform descriptions at the species level contributing to sharing of information on the faunistics and taxonomy of Mediterranean cave-dwelling species, including habitat preferences. The majority of species was recorded in 105 Mediterranean marine caves hosting four orders of horny sponges belonging to 9 families, 19 genera and 40 species. Species endemic to the Mediterranean Sea harboured in marine caves are 14 with an endemicity value of 35%. For each species morphological descriptions are supported by illustrations both original and from the literature, including the diagnostic traits of the skeleton by light and scanning electron microscopy giving further characterization at the specific level. A detailed map together with a list of all caves harbouring horny sponges is also provided with geographic coordinates. PMID- 23794834 TI - A new freshwater snail genus (Hydrobiidae, Gastropoda) from Montenegro, with a discussion on gastropod diversity and endemism in Skadar Lake. AB - Karucia sublacustrina a new species of freshwater snails (Hydrobiidae, Gastropoda) is described based on material collected from Skadar Lake (Montenegro, Albania). The new species belongs to monotypic genus Karucia gen. n. The shell morphology and body shape of the new genus resembles Radomaniola Szarowska, 2006 and Grossuana Radoman, 1973, from which it differs in the larger shells with relatively slim and a slightly, but clearly shouldered body whorl. The number of gastropods from Skadar Lake basin tallies now 50 species. The adjusted rate of gastropod endemicity for Skadar Lake basin is estimated to be 38%. By compiling faunal and taxonomic data we also aim to provide information of relevance as to conservation efforts. PMID- 23794835 TI - A new species of Euscorpius Thorell, 1876 (Scorpiones, Euscorpiidae) from Marmara Region of Turkey. AB - A new species of the genus Euscorpius Thorell, 1876 is described based on specimens collected from Bursa Province, in Marmara Region of Turkey. It is characterized by a mesotrichous trichobothrial pattern (Pv= 8, et= 6, em=4, eb= 4), medium size and light coloration. Euscorpius (Euscorpius) rahsenae sp. n. is the second species of the subgenus Euscorpius recognizedin Turkey. PMID- 23794836 TI - The genera in the second catalogue (1833-1836) of Dejean's Coleoptera collection. AB - All genus-group names listed in the second edition of the catalogue (1833-1836) of Dejean's beetle collection are recorded. For each new genus-group name the originally included available species are listed and for generic names with at least one available species, the type species and the current status are given. Names available prior to the publication of Dejean's second catalogue (1833-1836) are listed in an appendix. THE FOLLOWING NEW SYNONYMIES ARE PROPOSED: Cyclonotum Dejean, 1833 (= Dactylosternum Wollaston, 1854) [Hydrophilidae], Hyporhiza Dejean, 1833 (= Rhinaspis Perty, 1830) [Scarabaeidae], Aethales Dejean, 1834 (= Epitragus Latreille, 1802) [Tenebrionidae], Arctylus Dejean, 1834 (= Praocis Eschscholtz, 1829) [Tenebrionidae], Euphron Dejean, 1834 (= Derosphaerus Thomson, 1858) [Tenebrionidae], Hipomelus Dejean, 1834 (= Trachynotus Latreille, 1828) [Tenebrionidae], Pezodontus Dejean, 1834 (= Odontopezus Alluaud, 1889) [Tenebrionidae], Zygocera Dejean, 1835 (= Disternopsis Breuning, 1939) [Cerambycidae], and Physonota Chevrolat, 1836 (= Anacassis Spaeth, 1913) [Chrysomelidae]. Heterogaster pilicornis Dejean, 1835 [Cerambycidae] and Labidomera trimaculata Chevrolat, 1836 [Chrysomelidae] are placed for the first time in synonymy with Anisogaster flavicans Deyrolle, 1862 and Chrysomela clivicollis Kirby, 1837 respectively. Type species of the following genus-group taxa are proposed: Sphaeromorphus Dejean, 1833 (Sphaeromorphus humeralis Erichson, 1843) [Scarabaeidae], Adelphus Dejean, 1834 (Helops marginatus Fabricius, 1792) [Tenebrionidae], Cyrtoderes Dejean, 1834 (Tenebrio cristatus DeGeer, 1778) [Tenebrionidae], Selenepistoma Dejean, 1834 (Opatrum acutum Wiedemann, 1823) [Tenebrionidae], Charactus Dejean, 1833 (Lycus limbatus Fabricius, 1801) [Lycidae], Corynomalus Chevrolat, 1836 (Eumorphus limbatus Olivier, 1808) [Endomychidae], Hebecerus Dejean, 1835 (Acanthocinus marginicollis Boisduval, 1835) [Cerambycidae], Pterostenus Dejean, 1835 (Cerambyx abbreviatus Fabricius, 1801) [Cerambycidae], Psalicerus Dejean, 1833 (Lucanus femoratus Fabricius, 1775) [Lucanidae], and Pygolampis Dejean, 1833 (Lampyris glauca Olivier, 1790) [Lampyridae]. A new name, Neoeutrapela Bousquet and Bouchard [Tenebrionidae], is proposed for Eutrapela Dejean, 1834 (junior homonym of Eutrapela Hubner, 1809). The following generic names, made available in Dejean's catalogue, were found to be older than currently accepted valid names: Catoxantha Dejean, 1833 over Catoxantha Solier, 1833 [Buprestidae], Pristiptera Dejean, 1833 over Pelecopselaphus Solier, 1833 [Buprestidae], Charactus Dejean, 1833 over Calopteron Laporte, 1836 [Lycidae], Cyclonotum Dejean, 1833 over Dactylosternum Wollaston, 1854 [Hydrophilidae], Ancylonycha Dejean, 1833 over Holotrichia Hope, 1837 [Scarabaeidae], Aulacium Dejean, 1833 over Mentophilus Laporte, 1840 [Scarabaeidae], Sciuropus Dejean, 1833 over Ancistrosoma Curtis, 1835 [Scarabaeidae], Sphaeromorphus Dejean, 1833 over Ceratocanthus White, 1842 [Scarabaeidae], Psalicerus Dejean, 1833 over Leptinopterus Hope, 1838 [Lucanidae], Adelphus Dejean, 1834 over Praeugena Laporte, 1840 [Tenebrionidae], Amatodes Dejean, 1834 over Oncosoma Westwood, 1843 [Tenebrionidae], Cyrtoderes Dejean, 1834 over Phligra Laporte, 1840 [Tenebrionidae], Euphron Dejean, 1834 over Derosphaerus Thomson, 1858 [Tenebrionidae], Pezodontus Dejean, 1834 over Odontopezus Alluaud, 1889 [Tenebrionidae], Anoplosthaeta Dejean, 1835 over Prosopocera Blanchard, 1845 [Cerambycidae], Closteromerus Dejean, 1835 over Hylomela Gahan, 1904 [Cerambycidae], Hebecerus Dejean, 1835 over Ancita Thomson, 1864 [Cerambycidae], Mastigocera Dejean, 1835over Mallonia Thomson, 1857 [Cerambycidae], Zygocera Dejean, 1835 over Disternopsis Breuning, 1939 [Cerambycidae], Australica Chevrolat, 1836 over Calomela Hope, 1840 [Chrysomelidae], Edusa Chevrolat, 1836 over Edusella Chapuis, 1874 [Chrysomelidae], Litosonycha Chevrolat, 1836 over Asphaera Duponchel and Chevrolat, 1842 [Chrysomelidae], and Pleuraulaca Chevrolat, 1836 over Iphimeis Baly, 1864 [Chrysomelidae]. In each of these cases, Reversal of Precedence (ICZN 1999: 23.9) or an applicationto the International Commission on Zoological Nomenclature will be necessary to retain usage of the younger synonyms. PMID- 23794837 TI - The genera in the third catalogue (1836-1837) of Dejean's Coleoptera collection. AB - All genus-group names first proposed or made available for the first time in the third edition of Dejean's catalogue of his beetle collection are recorded. The following 18 names are made available for the first time in Dejean's third catalogue: Batoscelis Dejean [Carabidae], Laphyra Dejean [Carabidae], Sauriodes Dejean [Staphylinidae], Abrobapta Dejean [Buprestidae], Selagis Dejean [Buprestidae], Eurhipis Dejean [Eucnemidae], Anaeretes Dejean [Scarabaeidae], Doryscelis Dejean [Scarabaeidae], Epilissus Dejean [Scarabaeidae], Hoploscelis Dejean [Scarabaeidae], Brachygenius Dejean [Tenebrionidae], Capnisa Dejean [Tenebrionidae], Heterocheira Dejean [Tenebrionidae], Selenomma Dejean [Tenebrionidae], Dactylocrepis Dejean [Curculionidae], Lophodes Dejean [Curculionidae], Heterarthron Dejean [Bostrichidae] and Homalopus Chevrolat [Chrysomelidae]. Eurhipis Dejean, 1836 is considered a junior synonym of Phyllocerus Lepeletier and Audinet-Serville, 1825 for the first time. Abrobapta Dejean, 1836 has precedence over Torresita Harold, 1869. PMID- 23794838 TI - "First" abyssal record of Stenosemus exaratus (G.O. Sars, 1878) (Mollusca, Polyplacophora) in the North-Atlantic Ocean. AB - The first proven abyssal record of Stenosemus exaratus (G.O. Sars, 1878) is presented on the basis of an ROV study in the Irish Sea. For the first time in situ images of the species and data on the environmental parameters are provided. PMID- 23794839 TI - Bellisotoma, a new genus of Isotomidae from North America (Hexapoda, Collembola). AB - A new genus of Isotomidae, Bellisotoma gen. n., is described. The new genus is a member of the Proisotoma genus complex and is characterized by a combination of having a bidentate mucro with wide dorsal lamellae that join clearly before the end of mucronal axis without forming a tooth and one strong ventral rib with basal notch that articulates with dens; having abundant chaetotaxy on both faces of dens; and abundant tergal sensilla. Bellisotoma gen. n. shows a furcula adapted to a neustonic mode of life, and may be a Isotopenola-like derivative adapted to neustonic habitats. Subisotoma joycei Soto-Adames & Giordano, 2011 and Ballistura ewingi James, 1933 are transferred to the new genus. PMID- 23794840 TI - New taxa and revisionary systematics of alcyonacean octocorals from the Pacific coast of North America (Cnidaria, Anthozoa). AB - A taxonomic assessment of four species of octocorals from the northeastern Pacific Ocean (British Columbia to California) is provided. Included here are a new species of clavulariid stolonifieran Cryptophyton, a new species of the nephtheid soft coral Gersemia, an undetermined species of soft coral in the genus Alcyonium that has been referred in the literature by several other names, and a new genus is named for a plexaurid sea fan originally described in the Indo Pacific genus Euplexaura. Discussions are included that compare the species to related taxa, or provide revisionary assessments. PMID- 23794841 TI - A new species of Megachile Latreille subgenus Megachiloides (Hymenoptera, Megachilidae). AB - A new species of leafcutter bee, Megachile (Megachiloides) chomskyi, is described from Texas, United States. Megachile chomskyi is one of the four known species of the oenotherae species group of Megachiloides, all members sharing the long tongue, and is most similar to Megachile (Megachiloides) amica Cresson. Like other members of the oenotherae species group, this species probably shows oligolecty with Onagraceae (Evening-Primrose Family). A diagnosis, full description of both sexes and a key to the species of the oenotherae species group are provided. PMID- 23794842 TI - The extinct Baltic amber genus Propelma Trjapitzin, a valid genus of Neanastatinae (Hymenoptera, Eupelmidae). AB - The extinct Eocene Baltic amber genus Propelma Trjapitzin 1963 is removed from synonymy under Eupelmus Dalman 1820 (Hymenoptera, Eupelmidae, Eupelminae) and treated as a valid genus within Neanastatinae Kalina 1984 based on examination of the holotype female of Propelma rohdendorfi Trjapitzin. Propelma rohdendorfi is redescribed, illustrated by photomacrographs, and compared to other described extant and extinct genera of Neanastatinae. Taxonomic, morphological and geological diversity of Neanastatinae relative to Eupelminae and Calosotinae is also discussed relative to potential age of the subfamily. PMID- 23794843 TI - Taxonomic synopsis of the subtribe Physoderina (Coleoptera, Carabidae, Lebiini), with species revisions of eight genera. AB - Ten genera of Physoderina from the Oriental Region are diagnosed and described, and twenty six species representing eight genera (Paraphaea Bates, Anchista Nietner, Metallanchista gen. n., Diamella nom. n., Allocota Motschulsky, Orionella Jedlicka, Endynomena Chaudoir and Dasiosoma Britton (Oriental species only)) are revised. Keys to genera and species are provided, along with distribution maps, habitus images, photographs of the name-bearing types, and illustrations of male and female genitalia of available species. The female internal reproductive system is illustrated for fourteen species. Two genera, Anchista and Taicona, previously placed in Calleidina, are moved into Physoderina. One new genus is described: Metallanchista, gen. n. (type species Metallanchista laticollis, sp. n.). Two new generic synonyms are proposed: Taicona Bates, 1873, junior synonym of Allocota Motschulsky, 1859; Teradaia Habu, 1979a, junior synonym of Dasiosoma Britton, 1937. A new generic replacement name is proposed: Diamella, nom. n. for Diamella Jedlicka, 1952 (junior homonym of Diamella Gude, 1913). The status of Paraphaea Bates, 1873 is resurrected from synonym of Anchista Nietner, 1856. Five new species are described: Paraphaea minor Shi & Liang, sp. n. (Hoa-Binh, Tonkin, Vietnam), Anchista pilosa Shi & Liang, sp. n. (Chikkangalur, Bangalore, India), Metallanchista laticollis Shi & Liang, sp. n. (PhaTo env., Chumphon prov., Thailand), Allocota bicolor Shi & Liang, sp. n. (Dengga to Mafengshan, Ruili, Yunnan, China), Dasiosoma quadraticolle Shi & Liang, sp. n. (Menglun Botanical Garden, Yunnan, China). Fourteen new combinations are proposed: Paraphaea binotata (Dejean, 1825), comb. n. from Anchista; Paraphaea formosana (Jedlicka, 1946), comb. n. from Anchista; Paraphaea philippinensis (Jedlicka, 1935b), comb. n. from Allocota; Metallanchista perlaeta (Kirschenhofer, 1994), comb. n. from Allocota; Physodera andrewesi (Jedlicka, 1934), comb. n. from Allocota; Diamella cupreomicans (Oberthur, 1883), comb. n. from Physodera; Diamella arrowi (Jedlicka, 1935a), comb. n. from Allocota; Allocota aurata (Bates, 1873), comb. n. from Taicona; Dasiosoma bellum (Habu, 1979a), comb. n. from Teradaia; Dasiosoma indicum (Kirschenhofer, 2011), comb. n. from Diamella; Dasiosoma maindroni (Tian & Deuve, 2001), comb. n. from Lachnoderma; Dasiosoma hirsutum (Bates, 1873), comb. n. from Lachnoderma; Orionella discoidalis (Bates, 1892), comb. n. from Anchista; Orionella kathmanduensis (Kirschenhofer, 1994), comb. n. from Lachnoderma. Five names are newly placed as junior synonyms: Paraphaea eurydera (Chaudoir, 1877), junior synonym of Paraphaea binotata (Dejean, 1825); Anchista glabra Chaudoir, 1877, and Anchista nepalensis Kirschenhofer, 1994, junior synonyms of Anchista fenestrata (Schmidt-Gobel, 1846); Allocota caerulea Andrewes, 1933, junior synonym of Allocota viridipennis Motschulsky, 1859; Allocota perroti (Jedlicka, 1963), junior synonym of Allocota aurata (Bates, 1873). One new replacement name is proposed: Dasiosoma basilewskyi, nom. n. for Dasiosoma hirsutum Basilewsky, 1949 (secondary junior homonym of Dasiosoma hirsutum (Bates, 1892)). One species is downgraded to subspecies rank: Anchista fenestrata subpubescens Chaudoir, 1877, new rank. PMID- 23794844 TI - Revision of sternaspis otto, 1821 (polychaeta, sternaspidae). AB - To the memory of William Ronald Sendall Sternaspid polychaetes are common and often abundant in soft bottoms in the world oceans. Some authors suggest that only one species should be recognized, whereas others regard a few species as widely distributed in many seas and variable depths from the low intertidal to about 4400 m. There are some problems with species delineation and the distinctive ventro-caudal shield has been disregarded or barely used for identifying species. In order to clarify these issues, the ventral shield is evaluated in specimens from the same locality and its diagnostic potential is confirmed. On this basis, a revision of Sternaspis Otto, 1821 (Polychaeta: Sternaspidae) is presented based upon type materials, or material collected from type localities. The sternaspid body, introvert hooks and shield show three distinct patterns, two genera have seven abdominal segments and tapered introvert hooks, and one genus has eight abdominal segments and spatulate introvert hooks. The ventro-caudal shield has three different patterns: stiff with ribs, and sometimes concentric lines, stiff with feebly-defined ribs but no concentric lines, and soft with firmly adhered sediment particles. Sternaspis is restricted to include species with seven abdominal segments, falcate introvert hooks, and stiff shields, often exhibiting radial ribs, concentric lines or both. Sternaspis includes, besides the type species, Sternaspis thalassemoides Otto, 1821 from the Mediterranean Sea, Sternaspis affinis Stimpson, 1864 from the Northeastern Pacific, Sternaspis africana Augener, 1918, stat. n. from Western Africa, Sternaspis andamanensis sp. n. from the Andaman Sea, Sternaspis costata von Marenzeller, 1879 from Japan, Sternaspis fossor Stimpson, 1853 from the Northwestern Atlantic, Sternaspis islandica Malmgren, 1867 from Iceland, Sternaspis maior Chamberlin, 1919 from the Gulf of California, Sternaspis princeps Selenka, 1885 from New Zealand, Sternaspis rietschi Caullery, 1944 from abyssal depths around Indonesia, Sternaspis scutata (Ranzani, 1817) from the Mediterranean Sea, Sternaspis spinosa Sluiter, 1882 from Indonesia, and Sternaspis thorsoni sp. n. from the Iranian Gulf. Two genera are newly proposed to incorporate the remaining species: Caulleryaspis and Petersenaspis. Caulleryaspis gen. n. is defined by the presence of falcate introvert hooks, seven abdominal segments, and soft shields with sediment particles firmly adhered on them; it includes two species: Caulleryaspis gudmundssoni sp. n. from Iceland and Caulleryaspis laevis (Caullery, 1944) comb. n. from Indonesia. Petersenaspis gen. n. is defined by the presence of spatulate introvert hooks, eight abdominal segments, and stiff shields with poorly defined ribs but no concentric line; it includes Petersenaspis capillata (Nonato, 1966) from Brazil and Petersenaspis palpallatoci sp. n. from the Philippines. Neotypes are proposed for eight species: Sternaspis thalassemoides, Sternaspis affinis, Sternaspis africana, Sternaspis costata, Sternaspis fossor, Sternaspis maior, Sternaspis scutata and Sternaspis spinosa, to stabilize these species-group names, and a lectotype is designated for Sternaspis laevis which is transferred to Caulleryaspis gen. n. The geographic range of most species appears to be much smaller than previously indicated, and for some species additional material in good condition is needed to clarify their distributions. Keys to genera and to all species are also included. PMID- 23794845 TI - A new species of Metacyclops Kiefer, 1927 (Copepoda, Cyclopidae, Cyclopinae) from the Chihuahuan desert, northern Mexico. AB - A new species of the freshwater cyclopoid copepod genus Metacyclops Kiefer, 1927 is described from a single pond in northern Mexico, within the binational area known as the Chihuahuan Desert. This species belongs to a group of Metacyclops species with a 3443 spine formula of swimming legs. It is morphologically similar to Metacyclops lusitanus Lindberg, 1961 but differs from this and other congeners by having a unique combination of characters, including a caudal rami length/width proportion of 3.5-3.8, a innermost terminal seta slightly longer than the outermost terminal seta, intercoxal sclerites of legs 1-4 naked, a strong apical spine of the second endopodal segment of leg 1 and one row of 6-8 small spinules at the insertion of this spine. The finding of this species represents also the first record of the genus in Mexico and the third in North America, where only two other species, Metacyclops gracilis (Lilljeborg, 1853)and Metacyclops cushae Reid, 1991 have been hitherto reported. This is also the first continental record of a species of Metacyclops from an arid environment in the Americas. This species appears to be endemic to the Chihuahuan Desert, thus emphasizing the high endemicity of this area. PMID- 23794846 TI - Taxonomic revision of the Elephant Pupinid snail genus Pollicaria Gould, 1856 (Prosobranchia, Pupinidae). AB - The status of species currently assigned to the Southeast Asian Elephant Pupinid snail genus Pollicaria Gould, 1856 is reassessed. Shell, radular and reproductive morphology are investigated and analysed with reference to karyotype patterns previously reported and to distribution patterns among the species. Six previously described species are recognised: Pollicaria gravida (Benson, 1856), Pollicaria myersii (Haines, 1855), Pollicaria mouhoti (Pfeiffer, 1862), Pollicaria elephas (Morgan, 1885), Pollicaria crossei (Dautzenberg & d'Hamonville, 1887) and Pollicaria rochebruni (Mabille, 1887). A new subspecies, Pollicaria mouhoti monochroma ssp. n.,is proposed and a dichotomous key to species is provided. PMID- 23794847 TI - Three new species of the carnivorous snail genus Perrottetia Kobelt, 1905 from Thailand (Pulmonata, Streptaxidae). AB - Three new species of the streptaxid snail genus Perrottetia are described from north and northeastern Thailand, Perrottetia aquilonaria sp. n., Perrottetia dermapyrrhosa sp. n. and Perrottetia phuphamanensis sp. n. Each species is endemic to a single or a few limestone mountain ranges. The species are characterized by the morphology of their genital organs, as well as by shell characters. Perrottetia aquilonaria sp. n. has a club shaped distal penis and large penial hooks are present and penial papillae cover almost the entire penial hook portion; adjacent areas possess low reticulated folds. Perrottetia dermapyrrhosa sp. n. has a long genital atrium and the penial sheath is about two thirds of the penis length. Penial hooks are long, scattered and sunken into deep ovate hollows; vaginal hooks are present. Perrottetia phuphamanensis sp. n. has a rounded and protruded shell periphery. The aperture is subcircular, peristome is thick and the second parietal lamella is adjacent to the first parietal lamella; a basal lamella is the smaller than in the other Thai species. PMID- 23794848 TI - The New Caledonian genus Caledonotrichia Sykora (Trichoptera, Insecta) reviewed, with descriptions of 6 new species. AB - The New Caledonian endemic hydroptilid genus Caledonotrichia Sykora (Trichoptera) is reviewed and 6 new species are described: Caledonotrichia bifida, Caledonotrichia capensis, Caledonotrichia minuta, Caledonotrichia ouinnica, Caledonotrichia sykorai and Caledonotrichia vexilla. Together with the established species for which revised diagnoses are given, these raise to 11 the number of species known in this genus. The new species, females of 3 species, and several unusual larval cases are examined and described for further insight into relationships of this enigmatic genus. A key to species is provided. PMID- 23794849 TI - A new species of sublittoral marine gastrotrich, Lepidodasys ligni sp. n. (Macrodasyida, Lepidodasyidae), from the Atlantic coast of Florida. AB - A new species of Lepidodasys is described from sublittoral sandy sediments off the Atlantic coast of Florida. Lepidodasys ligni sp. n. is a small species (<= 450 um) with a crossed-helical pattern of small, non-keeled, non-imbricated scales on the dorsal and lateral body surfaces, two columns of ventral, interciliary scales that form a herringbone pattern, and a series of anterior, lateral, dorsal and posterior adhesive tubes. Similar to Lepidodasys castoroides from the Faroe Islands, the new species possesses a caudal constriction that demarcates the posterior end containing the caudal organ. The frontal organ lies within the posterior constriction, which is heavily invested with somatic circular muscles. These muscles are also present throughout the trunk and represent a novel condition for species of Lepidodasys,which were previously considered to lack somatic circular muscles. Posterior of the caudal constriction is a large, barrel-shaped caudal organ that is wrapped in a series of interdigitating, spindle-shaped, incomplete circular muscle fibers. The caudal organ contains a sclerotized central canal, but the absence of distal cuticular endpieces distinguishes the new species from its morphologically similar congener, Lepidodasys castoroides. PMID- 23794850 TI - A new non-naked species of Ptychostomella (Gastrotricha) from Brazil. AB - A new species of marine Gastrotricha from Brazil is described and discussed. Ptychostomella lamelliphora sp. n. is one of the several new taxa that were found during an extensive survey of the gastrotrich fauna carried out in 2002 and 2003 along the coastline of the State of Sao Paulo. The new species is unique in that it possesses cuticular ornamentations in the form of plate-like structures (scales) along the lateral borders of the body and two massive clusters of densely packed adhesive tubes on the ventral surface, near the ano-genital opening. Both these features appear to be adaptations to challenge the high energy waters that characterize the species' microhabitat: the coarse sublittoral sand in the channel between the mainland and the largest island in the State, Ihlabela. Additionally, a key to the described Ptychostomella species of the world is provided. PMID- 23794851 TI - New taxonomic data on the genus Ypsolopha Latreille (Lepidoptera, Ypsolophidae) with descriptions of two new species from the Russian Far East. AB - Two new species of the genus Ypsolopha Latreille, 1796 are described from Far East of Russia: Ypsolopha melanofuscella sp. n. and Ypsolopha straminella sp. n. Two new synomymies are proposed: Ypsolopha ulingensis Yang, 1977, a new junior synonym of Ypsolopha costibasella (Caradja, 1939); and Cerostoma falculella Erschoff, 1877, a new junior synonym of Ypsolopha asperella Linnaeus, 1761. The species Ypsolopha costibasella Caradja, 1939, Ypsolopha nigrofasciata Yang, 1977 and Ypsolopha nigrimaculata Byun et Park, 2001 are recorded from Far East of Russia for the first time. The male genitalia of Ypsolopha nigrofasciata are described and illustrated for the first time, diagnostic genital characters are given. PMID- 23794852 TI - Notes on black elytron species of Pyrrhalta Joannis and the description of a new species from China (Coleoptera, Chrysomelidae, Galerucinae). AB - Thirteen species of Pyrrhalta Joannis, 1865 with black elytron are reviewed. A key to species, photographs of aedeagus and habitus are provided. Pyrrhalta qianana sp. n. is described from Guizhou, China. Pyrrhalta martensi Medvedev & Sprecher-Uebersax, 1999 is newly recorded from China (Tibet). PMID- 23794853 TI - A new species of Tarsonops (Araneae, Caponiidae) from southern Belize, with a key to the genera of the subfamily Nopinae. AB - A new species of Caponiidae, Tarsonops irataylori sp. n. is described from southern Belize, and a key to the genera of the subfamily Nopinae is provided. PMID- 23794854 TI - An opiine Braconidae (Hymenoptera) reared from Richardiidae (Diptera) and recognition of a new species group of Opius s. l. AB - A new species of opiine Braconidae, Opius rojam Daniels & Wharton, is described from Trinidad. The description is based in part on two individuals reared from Sepsisoma erythrocephalum infesting shoots of the grass Paspalum fasciculatum. This is the first record of members of the Opiinae attacking species in the dipteran family Richardiidae. The Opius ingenticornis species group is proposed and delineated to accommodate this and several putatively related species formerly included in Opius (Merotrachys), Opius (Pendopius), and Opius (Ilicopius). A key to the species of this group is provided. Descriptions and diagnoses are referenced to the Hymenoptera Anatomy Ontology. PMID- 23794855 TI - A review of the Western Australian keeled millipede genus Boreohesperus (Diplopoda, Polydesmida, Paradoxosomatidae). AB - A taxonomic review of the endemic Western Australian millipede genus Boreohesperus Shear is presented in which six species are recognized: the type species, Boreohesperus capensis Shear, 1992, from North-West Cape, one new species, Boreohesperus dubitalis, from Barrow Island and four more new species from the Pilbara region, Boreohesperus curiosus, Boreohesperus delicatus, Boreohesperus furcosus and Boreohesperus undulatus. All six species have highly localized distributions, consistent with being short-range endemics. The nomenclature of the branches of the male gonopod is revised. PMID- 23794856 TI - Two new species of Neoperla (Plecoptera, Perlidae) from China. AB - Two species of the genus Neoperla from China are described as new: Neoperla furcostyla sp. n., and Neoperla similidella sp. n. The new species are compared to similar taxa. PMID- 23794857 TI - New synonymies and new combinations of Muscidae from China (Diptera, Muscoidea). AB - New synonymies and new combinations are proposed, based mainly on the study of type materials. They are as follows: Helina sarmentosa Fang & Fan, 1993 = Helina dianica Qian & Feng, 2005, syn. n.; Helina dianxiia Xue and Li, 2002 = Helina aureolicolorata Feng & Xue, 2002, syn. n.; Myospila lenticeps (Thomson, 1869) = Helina magnimaculata Feng, 1995, syn. n.; Spilogona angulisurstyla (Xue & Xiang, 1998), comb. n.; Spilogona apicicauda (Xue, Wang & Tong, 2003), comb. n.; Hebecnema arcuatiabdomina (Feng & Fan, 2001), comb. n. PMID- 23794858 TI - Three new species of Bolbochromus Boucomont (Coleoptera, Geotrupidae, Bolboceratinae) from Southeast Asia. AB - Three new species of the Oriental bolboceratine genus Bolbochromus Boucomont 1909, Bolbochromus minutus Li and Krikken, sp. n. (Thailand), Bolbochromus nomurai Li and Krikken, sp. n. (Vietnam), and Bolbochromus malayensis Li and Krikken, sp. n. (Malaysia), are described from continental Southeast Asia with diagnoses, distributions, remarks and illustrations. The genus is discussed with emphasis on continental Southeast Asia. A key to species known from Indochina and Malay Penisula is presented. An annotated checklist of Bolbochromus species is presented. PMID- 23794859 TI - Chinese species of the genus Aptesis Forster (Hymenoptera, Ichneumonidae) parasitizing sawflies, with descriptions of three new species and a key to species. AB - Six species of the genus Aptesis Forster 1850 belonging to the tribe Hemigastrini of the subfamily Cryptinae (Hymenoptera, Ichneumonidae) are reported from China. Three of them, Aptesis elongata Li & Sheng, sp. n., Aptesis melana Li & Sheng, sp. n. and Aptesis nigricoxa Li & Sheng, sp. n. reared from sawflies in China, are new to science. The biology of Aptesis melana is described. A key to the species of Aptesis known from China is provided. PMID- 23794860 TI - A new Brazilian Passiflora leafminer: Spinivalva gaucha, gen. n., sp. n. (Lepidoptera, Gracillariidae, Gracillariinae), the first gracillariid without a sap-feeding instar. AB - Male, female, pupa, larva and egg of a new genus and species of Gracillariidae (Gracillariinae), Spinivalva gaucha Moreira and Vargas from southern Brazil are described and illustrated with the aid of optical and scanning electron microscopy. A preliminary analysis of mitochondrial DNA sequences including members of related lineages is also provided. The immature stages are associated with Passiflora actinia, Passiflora misera and Passiflora suberosa (Passifloraceae), and build mines on the adaxial leaf surface. Initially the mines are serpentine in shape, but later in larval ontogeny become a blotch type. Although the larvae are hypermetamorphic as in other Gracillariidae, there is no sap-feeding instar in Spinivalva gaucha; the larva feeds on the palisade parenchyma, thus producing granular frass during all instars. Pupation occurs outside the mine; prior to pupating, the larva excretes numerous bubbles that are placed in rows on the lateral margins of the cocoon external surface. This is the second genus of gracillariid moth described for the Atlantic Rain Forest, and the second gracillariid species known to be associated with Passifloraceae. PMID- 23794861 TI - Phylogenetic systematics of Schacontia Dyar with descriptions of eight new species (Lepidoptera, Crambidae). AB - The Neotropical genus SchacontiaDyar (1914) is reviewed and revised to include eleven species. Schacontia replica Dyar, 1914, syn. n. and Schacontia pfeifferi Amsel, 1956, syn. n. are synonymized with Schacontia chanesalis (Druce, 1899) and eight new species are described: Schacontia umbra,sp. n., Schacontia speciosa,sp. n., Schacontia themis, sp. n., Schacontia rasa, sp. n., Schacontia nyx,sp. n., Schacontia clotho, sp. n., Schacontia lachesis, sp. n., and Schacontia atropos, sp. n. Three species, Schacontia medalba, Schacontia chanesalis, and Schacontia ysticalis, are re-described. An analysis of 64 characters (56 binary, 8 multistate; 5 head, 13 thoracic, 13 abdominal, 25 male genitalic, and 8 female genitalic) scored for all Schacontia and three outgroup species (Eustixia pupula Hubner, 1823, Glaphyria sesquistrialis Hubner, 1823, and Hellula undalis (Fabricius, 1781)) retrieved 8 equally most parsimonious trees (L=102, CI=71, RI=84) of which the strict consensus is: [[[[medalba + umbra] + chanesalis] + speciosa] + [ysticalis + [rasa + themis + [atropos + lachesis + nyx + clotho]]]]. The relevance of male secondary sexual characters to the diagnosis of Schacontia species is discussed. PMID- 23794862 TI - Descriptions of eleven Opatrini pupae (Coleoptera, Tenebrionidae) from China. AB - The pupal stage of eleven Opatrini species occuring in the northern China are described and a key for their identifiaction is provided. The species are Scleropatrum horridum horridum Reitter, Gonocephalum reticulatum Motschulsky, Opatrum (Opatrum) subaratum Faldermann, Eumylada potanini (Reitter), Eumylada punctifera (Reitter), Penthicus (Myladion) alashanicus (Reichardt), Penthicus (Myladion) nojonicus (Kaszab), Myladina unguiculina Reitter, Melanesthes (Opatronesthes) rugipennis Reitter, Melanesthes (Melanesthes) maxima maxima Menetries and Melanesthes (Melanesthes) jintaiensis Ren. PMID- 23794863 TI - Systematics of the parasitic wasp genus Oxyscelio Kieffer (Hymenoptera, Platygastridae s.l.), Part I: Indo-Malayan and Palearctic fauna. AB - The Indo-Malayan and Palearctic species of Oxyscelio (Hymenoptera: Platygastridae s.l.) are revised. A total of 90 species are recognized as valid, 19 of which are redescribed - Oxyscelio acutiventris (Kieffer), Oxyscelio brevinervis (Kieffer), Oxyscelio carinatus (Kieffer), Oxyscelio ceylonensis (Dodd), Oxyscelio consobrinus (Kieffer), Oxyscelio crassicornis (Kieffer), Oxyscelio cupularis (Kieffer), Oxyscelio dorsalis (Kieffer), Oxyscelio excavatus (Kieffer), Oxyscelio flavipennis (Kieffer), Oxyscelio florus Kononova, Oxyscelio foveatus Kieffer, Oxyscelio kiefferi Dodd, Oxyscelio magnus (Kieffer), Oxyscelio marginalis (Kieffer), Oxyscelio naraws Kozlov & Le, Oxyscelio perpensus Kononova, Oxyscelio rugosus (Kieffer) and Oxyscelio spinosiceps (Kieffer), and 71 which are described as new - Oxyscelio aclavae Burks, sp. n., Oxyscelio amrichae Burks, sp. n., Oxyscelio anguli Burks, sp. n., Oxyscelio angustifrons Burks, sp. n., Oxyscelio angustinubbin Burks, sp. n., Oxyscelio arcus Burks, sp. n., Oxyscelio arvi Burks, sp. n., Oxyscelio asperi Burks, sp. n., Oxyscelio aureamediocritas Burks, sp. n., Oxyscelio bipunctuum Burks, sp. n., Oxyscelio brevidentis Burks, sp. n., Oxyscelio caesitas Burks, sp. n., Oxyscelio capilli Burks, sp. n., Oxyscelio capitis Burks, sp. n., Oxyscelio cavinetrion Burks, sp. n., Oxyscelio chimaerae Burks, sp. n., Oxyscelio codae Burks, sp. n., Oxyscelio convergens Burks, sp. n., Oxyscelio cordis Burks, sp. n., Oxyscelio crateris Burks, sp. n., Oxyscelio crebritas Burks, sp. n., Oxyscelio crustum Burks, sp. n., Oxyscelio cuculli Burks, sp. n., Oxyscelio cyrtomesos Burks, sp. n., Oxyscelio dasymesos Burks, sp. n., Oxyscelio dasynoton Burks, sp. n., Oxyscelio dermatoglyphes Burks, sp. n., Oxyscelio doumao Burks, sp. n., Oxyscelio fistulae Burks, sp. n., Oxyscelio flabellae Burks, sp. n., Oxyscelio flaviventris Burks, sp. n., Oxyscelio fodiens Burks, sp. n., Oxyscelio fossarum Burks, sp. n., Oxyscelio fossularum Burks, sp. n., Oxyscelio genae Burks, sp. n., Oxyscelio granorum Burks, sp. n., Oxyscelio granuli Burks, sp. n., Oxyscelio greenacus Burks, sp. n., Oxyscelio halmaherae Burks, sp. n., Oxyscelio intermedietas Burks, sp. n., Oxyscelio jaune Burks, sp. n., Oxyscelio jugi Burks, sp. n., Oxyscelio kramatos Burks, sp. n., Oxyscelio labis Burks, sp. n., Oxyscelio lacunae Burks, sp. n., Oxyscelio latinubbin Burks, sp. n., Oxyscelio latitudinis Burks, sp. n., Oxyscelio limae Burks, sp. n., Oxyscelio longiventris Burks, sp. n., Oxyscelio mesiodentis Burks, sp. n., Oxyscelio mollitia Burks, sp. n., Oxyscelio nasolabii Burks, sp. n., Oxyscelio nodorum Burks, sp. n., Oxyscelio noduli Burks, sp. n., Oxyscelio nubbin Burks, sp. n., Oxyscelio obsidiani Burks, sp. n., Oxyscelio ogive Burks, sp. n., Oxyscelio operimenti Burks, sp. n., Oxyscelio peludo Burks, sp. n., Oxyscelio planocarinae Burks, sp. n., Oxyscelio praecipitis Burks, sp. n., Oxyscelio reflectens Burks, sp. n., Oxyscelio regionis Burks, sp. n., Oxyscelio sinuum Burks, sp. n., Oxyscelio spinae Burks, sp. n., Oxyscelio striarum Burks, sp. n., Oxyscelio tecti Burks, sp. n., Oxyscelio unguis Burks, sp. n., Oxyscelio vadorum Burks, sp. n., Oxyscelio vittae Burks, sp. n. and Oxyscelio zeuctomesos. Neotypes are designated for nine species, including the type species O. foveatus Kieffer, Oxyscelio brevinervis (Kieffer), Oxyscelio bifurcatus (Kieffer), Oxyscelio frontalis (Kieffer), Oxyscelio crassicornis (Kieffer), Oxyscelio cupularis (Kieffer), Oxyscelio foveatus Kieffer, Oxyscelio kiefferi Dodd, Oxyscelio magnus (Kieffer) and Oxyscelio marginalis (Kieffer). Oxyscelio bifurcatus (Kieffer) syn. n. and Oxyscelio frontalis (Kieffer) syn. n. are synonymized under Oxyscelio consobrinus (Kieffer). The fauna is divided into 13 species groups, with six species unplaced to a group. A phylogenetic analysis employing 73 morphological characters did not find most of these groups to be monophyletic, but they are retained to aid in specimen identification. Potential biogeographical patterns are discussed, including regional variation in surface sculpture and a morphological link between Sri Lankan and Australian species. PMID- 23794864 TI - A specialist's audit of aggregated occurrence records. AB - Occurrence records for named, native Australian millipedes from the Global Biodiversity Information Facility (GBIF) and the Atlas of Living Australia (ALA) were compared with the same records from the Millipedes of Australia (MoA) website, compiled independently by the author. The comparison revealed some previously unnoticed errors in MoA, and a much larger number of errors and other problems in the aggregated datasets. Errors have been corrected in MoA and in some data providers' databases, but will remain in GBIF and ALA until data providers have supplied updates to these aggregators. An audit by a specialist volunteer, as reported here, is not a common occurrence. It is suggested that aggregators should do more, or more effective, data checking and should query data providers when possible errors are detected, rather than simply disclaim responsibility for aggregated content. PMID- 23794865 TI - On the cicada genus Nipponosemia Kato, with description of one new species from China (Hemiptera, Cicadidae). AB - The cicada genus Nipponosemia Kato is reviewed. Four species are illustrated, photographed and described, including three known species and one new species. A key to all species of this genusis presented, and information on the biology of Nipponosemia are provided. The systematic status of the tribe Cicadatrini and biogeography of Nipponosemia are discussed. PMID- 23794866 TI - Revision of Australian Matini diving beetles based on morphological and molecular data (Coleoptera, Dytiscidae, Matinae), with description of a new species. AB - Morphological characters and mitochondrial DNA sequence data were used to revise the Australian diving beetles in the genera Allomatus Mouchamps, 1964 and Batrachomatus Clark, 1863. As a result of these studies Allomatus syn. n. is synonymised with Batrachomatus, and Allomatus nannup Watts, 1978 from SW Australia and Allomatus wilsoni Mouchamps, 1964 from SE Victoria are transferred to Batrachomatus. The four Australian Matini species knownso far are re described, and Batrachomatus larsoni sp. n. from the Windsor Tableland in NE Queensland is described. After more than 40 years Batrachomatus wilsoni has been re-discovered in two rivers in Victoria. We delineate the species using traditionally employed morphological structures such as in the male genitalia and body size, shape and colour pattern, as well as mitochondrial cox1 sequence data for 20 individuals. Important species characters (median lobes, parameres and colour patterns) were illustrated. We provide an identification key and outline distribution and habitat preferences of each species. All Australian Matini are lotic, inhabiting permanent and intermittent streams, creeks and rivers. PMID- 23794867 TI - Description of Phradonoma blabolili sp. n. (Coleoptera, Dermestidae, Megatominae), with notes on the dermestid beetles from Angola. AB - Phradonoma blabolili sp. n. from Angola is described and illustrated. Key to the Afrotropical "Phradonoma nobile species group" to which the newly described species belongs, as well as key to genera of dermestid beetles occurring in Angola is given. List of all species of Dermestidae known to occur in Angola hitherto is provided. PMID- 23794868 TI - Did the genus Parandrocephalus Heller, 1916 (Coleoptera, Cerambycidae, Callichromatini) cross the Wallace line? The taxonomic status of Parandrocephalus blairi Bentanachs & Vives 2009 and a new subgenus of Hexamitodera Heller, 1896, with notes on convergent evolution and secondary sexual characters. AB - The genera Parandrocephalus Heller, 1916 and Hexamitodera Heller, 1896 are reviewed and redescribed. Based on the combination of chromatic sexual dimorphism, velvety pubescence on the whole dorsal body and distinctly developed carina on the elytra, Parandrocephalus blairi Bentanachs & Vives, 2009 is transferred to Hexamitodera. A new subgenus, Sulcognatha Perger, is instituted to accommodate mandible, head and metasternal modifications in Hexamitodera blairi comb. n. that are lacking in the type species of Hexamitodera, Hexamitodera semivelutina. As indicated by fundamental structural differences in the mandibles of Parandrocephalus and Hexamitodera (Sulcognatha) blairi comb. n., the exaggerated secondary sexual traits and open procoxal cavities in both taxa are presumably the result of convergent evolution. Contrary to Bentanachs & Vives (2009), the presence of the two Parandrocephalus species in Sundaland and the endemism of Hexamitodera on Sulawesi agree well with the zoogeographical separation of both areas by the Wallace line. PMID- 23794869 TI - Amundsen Sea Mollusca from the BIOPEARL II expedition. AB - Information regarding the molluscs in this dataset is based on the epibenthic sledge (EBS) samples collected during the cruise BIOPEARL II / JR179 RRS James Clark Ross in the austral summer 2008. A total of 35 epibenthic sledge deployments have been performed at five locations in the Amundsen Sea at Pine Island Bay (PIB) and the Amundsen Sea Embayment (ASE) at depths ranging from 476 to 3501m. This presents a unique and important collection for the Antarctic benthic biodiversity assessment as the Amundsen Sea remains one of the least known regions in Antarctica. Indeed the work presented in this dataset is based on the first benthic samples collected with an EBS in the Amundsen Sea. However we assume that the data represented are an underestimation of the real fauna present in the Amundsen Sea. In total 9261 specimens belonging to 6 classes 55 families and 97 morphospecies were collected. The species richness per station varied between 6 and 43. Gastropoda were most species rich 50 species followed by Bivalvia (37), Aplacophora (5), Scaphopoda (3) and one from each of Polyplacophora and Monoplacophora. PMID- 23794870 TI - Taxonomic revision of the genus Callimerus Gorham s. l. (Coleoptera, Cleridae). Part I. latifrons species-group. AB - The latifrons species-group (=Brachycallimerus sensu Chapin 1924, Corporaal 1950; = flavofasciatus-group sensu Kolibac 1998) of Callimerus Gorham is redefined and revised. Five species are recognized including one new species Callimerus cacuminis Yang & Yang sp. n. (type locality: Yunnan, China). Callimerus flavofasciatus Schenkling, 1902 is newly synonymized with Callimerus latifrons Gorham, 1876. Callimerus trifasciatus Schenkling, 1899a is transferred to the genus Corynommadius Schenkling, 1899a. Callimerus gorhami Corporaal, 1949 and Callimerus pallidus Gorham, 1892 are excluded from the latifrons species-group (their assignment to a species-group will be dealt with in a subsequent paper). A key to species of the latifrons species-group is given and habitus of each type specimen, male terminalia, and other diagnostic characters are illustrated. PMID- 23794871 TI - On the identity of Liolaemus nigromaculatus Wiegmann, 1834 (Iguania, Liolaemidae) and correction of its type locality. AB - In the current study, we review the taxonomic status of Liolaemus nigromaculatus. Despite being the nominal species of the nigromaculatus group and being the second species of the genus Liolaemus that was described, this species is of uncertain type locality and its true identification is a matter of discussion. After carefully analyzing several digital pictures of the holotype (juvenile male), reviewing all of the literature concerning the issue, examining specimens of nearly all recognized species of the nigromaculatus group, and determining the locations visited by the specimen collector, we are able to point out the following: 1) Liolaemus nigromaculatus was collected between Puerto Viejo and Copiapo of the Atacama region in Chile, and not in Huasco 2) Liolaemus bisignatus is a nomen nudum, and populations attributed to Liolaemus bisignatus should be referred to as Liolaemus nigromaculatus. 3) There is agreement that Liolaemus copiapoensis is indistinguishable from populations currently referred to as Liolaemus bisignatus (= Liolaemus nigromaculatus), 4) Populations found in Huasco (currently considered the type locality of Liolaemus nigromaculatus) are very similar to those found in Caldera (currently considered Liolaemus bisignatus) and should be designated as Liolaemus nigromaculatus, and 5) Liolaemus oxycephalus and Liolaemus inconspicuus are not synonymous with Liolaemus nigromaculatus, although their true identities are difficult to determine. We also detail several characteristic based on the holotype of Liolaemus nigromaculatus, in addition to drawing diagnostic comparisons between this species and others belonging to the nigromaculatus group. PMID- 23794872 TI - Afroprinus cavicola gen. et sp. n. from the Afrotropical region with notes on cave-dwelling Saprininae (Coleoptera, Histeridae). AB - A new genus and species from Kenya, Afroprinus cavicola is herein described and illustrated and its systematic position is discussed. By the prosternal pre apical foveae connected by marginal prosternal stria it resembles most of the Afrotropical species of the genus Chalcionellus Reichardt, 1932, or some species of the genus Pholioxenus Reichardt, 1932 from South Africa and Namibia. Afroprinus can be distinguished from Chalcionellus chiefly by the lack of pronotal depressions and a coarsely sculptured, non-metallic dorsum; from Afrotropical species of Pholioxenus it can be most easily distinguished by the asetose pronotal hypomeron. The new taxon was discovered in a cave, but lacks obvious troglophilic adaptations. Notes on other Saprininae taxa found in caves are given. An identification key to the genera of Afrotropical Saprininae is provided. PMID- 23794873 TI - Description and scanning electron microscopic observation of a new species of the genus Polycopetta (Crustacea, Ostracoda, Cladocopina) from an interstitial habitat in Japan. AB - A new species of the genus Polycopetta Chavtur, 1981, Polycopetta quadrispinata sp. n. is described from the interstitial environment of Mihomasaki Beach in Japan. These observations showed some morphological peculiarities of Polycopetta quadrispinata sp. n. compared with its congeners; Polycopetta monneroni Chavtur, 1979, Polycopetta curva Chavtur, 1979, Polycopetta bransfieldensis (Hartmann, 1987), and Polycopetta pax Kornicker and Harrison-Nelson, 2005. Three characteristics are described for the first time: (1) a seta with serrated tip on the male antennula, (2) the endopodite of the fifth limb consisting of two podomeres, (3) the long spermatozoa in the male posterior body. More detailed observations of the type species are needed in order to update the generic diagnosis. PMID- 23794874 TI - Revision of the Middle American clade of the ant genus Stenamma Westwood (Hymenoptera, Formicidae, Myrmicinae). AB - Stenamma is a cryptic "leaf-litter" ant genus that occurs in mesic forest habitats throughout the Holarctic region, Central America, and part of northwestern South America (Colombia and Ecuador). The genus was thought to be restricted primarily to the temperate zone, but recent collecting efforts have uncovered a large radiation of Neotropical forms, which rival the Holarctic species in terms of morphological and behavioral diversity. By inferring a broad scale molecular phylogeny of Stenamma, Branstetter (2012) showed that all Neotropical species belong to a diverse Middle American clade (MAC), and that this clade is sister to an almost completely geographically separated Holarctic clade (HOC). Here, the Middle American clade of Stenamma is revised to recognize 40 species, of which 33 are described as new. Included in the revision are a key to species based on the worker caste, and for each species where possible, descriptions and images of workers and queens, images of males, information on geographic distribution, descriptions of intraspecific variation, and notes on natural history. Several species groups are defined, but the majority of species remain unassigned due to a lack of diagnostic morphological character states for most molecular clades. The following species are redescribed: Stenamma alas Longino, Stenamma diversum Mann, Stenamma expolitum Smith, Stenamma felixi Mann, Stenamma huachucanum Smith, Stenamma manni Wheeler, and Stenamma schmidti Menozzi. The following are described as new: Stenamma andersoni sp. n., Stenamma atribellum sp. n., Stenamma brujita sp. n., Stenamma callipygium sp. n., Stenamma catracho sp. n., Stenamma connectum sp. n., Stenamma crypticum sp. n., Stenamma cusuco sp. n., Stenamma excisum sp. n., Stenamma expolitico sp. n., Stenamma hojarasca sp. n., Stenamma ignotum sp. n., Stenamma lagunum sp. n., Stenamma llama sp. n., Stenamma leptospinum sp. n., Stenamma lobinodus sp. n., Stenamma longinoi sp. n., Stenamma maximon sp. n., Stenamma megamanni sp. n., Stenamma monstrosum sp. n., Stenamma muralla sp. n., Stenamma nanozoi sp. n., Stenamma nonotch sp. n., Stenamma ochrocnemis sp. n., Stenamma pelophilum sp. n., Stenamma picopicucha sp. n., Stenamma saenzae sp. n., Stenamma sandinista sp. n., Stenamma stictosomum sp. n., Stenamma tiburon sp. n., Stenamma tico sp. n., Stenamma vexator sp. n., and Stenamma zelum sp. n. Although many of the newly defined species consist of challenging species complexes, this study establishes a robust baseline that will guide future work on the systematics of MAC Stenamma. The total global diversity of Stenamma now includes 84 extant species. PMID- 23794875 TI - Morphological and acoustic characters of Cicadatra platyptera Fieber, 1876. AB - Acoustic and morphological characters are very important to distinguish species of Cicadidae. In this study, the morphological and acoustic characters of Cicadatra platyptera Fieber, 1876 (Hemiptera, Cicadidae) collected from Turkey were analysed. The external morphological structures of two species were drawn and photographs of some specimens were taken. We evaluated taxonomically important morphological characters such as body shape, colors, patterns, structure, and genital structure. We evaluated measurements of external morphological structures and acoustics characters of Cicadatra platyptera from Turkey, partly with statistical analyses. Morphological characters were compared and differentiated from the closely related species, Cicadatra atra. The distribution in Turkey including previous records and the material examined were shown on a map, and the distribution in Palearctic Region was given. PMID- 23794876 TI - The species of the genus Hypodynerus de Saussure (Hymenoptera, Vespidae, Eumeninae) occurring in Brazil. AB - An identification table and descriptions are given to recognize the two species of Hypodynerus (Hymenoptera: Vespidae: Eumeninae) recorded from Brazil: Hypodynerus arechavaletae (Brethes) and Hypodynerus duckei (Bertoni) comb. n. The lectotype is designated and the male is described for Hypodynerus duckei, its presence being recorded from Brazil for the first time. PMID- 23794877 TI - Diversity and distribution of amphibians in Romania. AB - Nineteen species of amphibians inhabit Romania, 9 of which reach their range limit on this territory. Based on published occurrence reports, museum collections and our own data we compiled a national database of amphibian occurrences. We georeferenced 26779 amphibian species occurrences, and performed an analysis of their spatial patterns, checking for hotspots and patterns of species richness. The results of spatial statistic analyses supported the idea of a biased sampling for Romania, with clear hotspots of increased sampling efforts. The sampling effort is biased towards species with high detectability, protected areas, and large cities. Future sampling efforts should be focused mostly on species with a high rarity score in order to accurately map their range. Our results are an important step in achieving the long-term goals of increasing the efficiency of conservation efforts and evaluating the species range shifts under climate change scenarios. PMID- 23794878 TI - Pogonophryne neyelovi , a new species of Antarctic short-barbeled plunderfish (Perciformes, Notothenioidei, Artedidraconidae) from the deep Ross Sea. AB - This paper continues descriptions of new deep-water Antarctic barbeled plunderfishes of the poorly known and the most speciose notothenioid genus Pogonophryne. It is based on a comprehensive collection obtained by the authors in 2009-2010 during an Antarctic toothfish (Dissostichus mawsoni) fishing trip. A new species, the hopbeard plunderfish Pogonophryne neyelovi, the twenty-second species of the genus, is described. The new species belongs to dorsally-spotted short-barbeled species forming the "Pogonophryne mentella" group. Pogonophryne neyelovi sp. n. is characterized by the following combination of characters: a very short and small mental barbel with an ovaloid and short terminal expansion covered by flattened scale-like processes that are mostly bluntly palmate; a moderately protruding lower jaw; a high second dorsal fin almost uniformly black and lacking a sharply elevated anterior lobe; pectoral fins striped anteriorly and uniformly light posteriorly; the anal and pelvic fins light; the dorsal surface of the head and the area anterior to the first dorsal fin covered with large, irregular dark brown blotches and spots; the ventral surface of the head, breast and belly without sharp dark markings. The new species is compared to the closest species Pogonophryne brevibarbata, Pogonophryne tronio, and Pogonophryne ventrimaculata. English vernacular names are proposed for all species of the genus. PMID- 23794879 TI - Two new Mallinella species from southern China (Araneae, Zodariidae). AB - Two new species of the spider genus Mallinella Strand, 1906 are reported from China: Mallinella sphaerica sp. n. (male, female) from Tianmu Mountain, Zhejiang Province and Mallinella pluma sp. n. (male) from Daming Mountain, Guangxi Zhuang Autonomous Region. PMID- 23794880 TI - The soapberry bug, Jadera haematoloma (Insecta, Hemiptera, Rhopalidae): First Asian record, with a review of bionomics. AB - The soapberry bug, Jadera haematoloma (Herrich-Schaffer, 1847) (Insecta: Hemiptera: Heteroptera: Rhopalidae: Serinethinae), a species native in tropical and subtropical regions of the New World and accidentally introduced to Hawaii, is reported for the first time from Asia (Taiwan). This record represents the first occurrence of the species in Asia. Stable populations composed of hundreds of specimens were found in seven localities of Kaohsiung City and one locality in Tainan City, and a single specimen was observed in Chiayi County. Aggregating adults and larvae fed in large numbers on the sapindacean plants Cardiospermum halicacabum L. and Koelreuteria elegans (Seem.) A. C. Smith ssp. formosana (Hayata) F. G. Meyer. Diagnostic characters of adults and larvae of Jadera haematoloma are discussed. A review of its bionomics and a bibliography are provided. Initial observations on the populations in southern Taiwan are presented. The species is potentially invasive, and further extension of its range is anticipated in Southeast Asia. PMID- 23794881 TI - New Spanish Dinotrema species with propodeal areola or mainly sculptured propodeum (Hymenoptera, Braconidae, Alysiinae). AB - The illustrated descriptions of eight new species of the genus Dinotrema with either the propodeum mainly sculptured or having a large propodeal areola from Spain are provided, viz. Dinotrema amparoae sp. n., Dinotrema benifassaense sp. n., Dinotrema lagunasense sp. n., Dinotrema pilarae sp. n., Dinotrema robertoi sp. n., Dinotrema teresae sp. n., Dinotrema tinencaense sp. n., and Dinotrema torreviejaense sp. n.. PMID- 23794882 TI - Three new species of the genus Philopteroides Mey, 2004 (Phthiraptera, Ischnocera, Philopteridae) from New Zealand. AB - We describe and illustrate three new species of chewing lice in the genus Philopteroides parasitic on passerines (Order Passeriformes, families Acanthizidae, Rhipiduridae and Petroicidae) from New Zealand. They are: Philopteroides pilgrimi sp. n. from Gerygone igata igata; Philopteroides fuliginosus sp. n. from Rhipidura fuliginosa placabilis and Rhipidura fuliginosa fuliginosa; and Philopteroides macrocephalus sp. n. from Petroica macrocephala macrocephala and Petroica macrocephala dannefaerdi. The identity of Docophorus lineatus Giebel, 1874 is discussed based on its morphology and host association. We also transfer Tyranniphilopterus beckeri to the genus Philopteroides, and provide a key to identify adults of 12 of the 13 species now included in Philopteroides. PMID- 23794883 TI - Taxonomy and distribution pattern of the African rain forest butterfly genus Euphaedra Hubner sensu stricto with the description of three new subspecies of Euphaedra cyparissa (Cramer) and one of E. sarcoptera (Butler) (Lepidoptera, Nymphalidae, Limenitidinae, Adoliadini). AB - Updated data on the distribution, ecology and taxonomy of Euphaedra cyparissa (Cramer) and Euphaedra sarcoptera (Butler) are presented. Three new subspecies of Euphaedra cyparissa and one of Euphaedra sarcoptera are described and their geographic distribution is presented. The monophyly of the genus Euphaedra sensu Hecq is assessed based on morphological, in particular male and female genitalia, and behavioural traits. Possible evolutionary reasons for the convergence of colour pattern between the sympatric subspecies of Euphaedra cyparissa and Euphaedra sarcoptera are discussed. PMID- 23794884 TI - Revision of the genus Placospongia (Porifera, Demospongiae, Hadromerida, Placospongiidae) in the Indo-West Pacific. AB - Species of the genus Placospongia are common within the tropical Indo-West Pacific, demonstrating a wide variety of colors and either branching or encrusting growth forms. A revision of Indo-West Pacific Placospongia was undertaken based on a redescription of the holotypes of species of Placospongia from the Indian Ocean and Western Pacific and an examination of an additional 103 specimens of Placospongia ssp. collected from Indonesia (including Vosmaer and Vernhout 1902 material), Seychelles, India, Singapore and Micronesia. One mitochondrial (COI) and one nuclear (ITS) marker were subsequently used to differentiate species. All Placospongia species are characterized by selenasters and tylostyles in two size classes. The combination of microsclere diversity and morphology as well as megasclere size were shown to be informative morphometric characters, supported by molecular evidence. Live coloration and growth form is shown to be unreliable for diagnoses. The study of holotypes found that Placospongia mixta is a valid species and that two genus transfers are necessary: Geodinella anthosigma is a Placospongia and Placospongia labyrinthica is a Geodia. A new species is also described from an anchialine pool in Indonesia, Placospongia santodomingoae sp. n.; bringing the total fauna of Placospongia species in the Indo-West Pacific to five: Placospongia anthosigma, Placospongia carinata, Placospongia mixta, Placospongia melobesioides, and Placospongia santodomingoae sp. n. An identification key is given. Two additional species, possibly morphologically cryptic, have been identified by molecular markers. PMID- 23794885 TI - A relict lineage and new species of green palm-pitviper (Squamata, Viperidae, Bothriechis) from the Chortis Highlands of Mesoamerica. AB - A new species of palm-pitviper of the genus Bothriechis is described from Refugio de Vida Silvestre Texiguat in northern Honduras. The new species differs from congeners by having 19 dorsal scale rows at midbody, a bright green dorsal coloration in adults, the prelacunal scale fused to the second supralabial, and in representing a northern lineage that is sister to Bothriechis lateralis, which is distributed in Costa Rica and western Panama and is isolated from the new taxon by the Nicaraguan Depression. This represents the 15th endemic species occurring in Refugio de Vida Silvestre Texiguat, one of the richest herpetofaunal sites in Honduras, itself being the country with the highest degree of herpetofaunal endemism in Central America. We name this new species in honor of a Honduran conservationist slain in fighting against illegal logging, highlighting the sacrifices of rural activists in battling these issues and the critical importance of conservation in these areas. PMID- 23794886 TI - The genus Myrmarachne (Araneae, Salticidae) in Flores, Indonesia. AB - Two new species of the genus Myrmarachne are described (Myrmarachne acutidens sp. n., Myrmarachne epigealis sp. n.), and Myrmarachne macrognatha and Myrmarachne melanocephala are redescribed from Flores specimens. The females of Myrmarachne macrognatha are recorded for the first time. PMID- 23794887 TI - Torrenticolid water mites from Korea and the Russian Far East. AB - New records of water mites of the family Torrenticolidae Piersig, 1902 (Acari: Hydrachnidia) from streams in South Korea and the Russian Far East are presented. Detailed descriptions or redescrptions are provided for eight species of the genera Torrenticola Piersig, 1896 and Monatractides K. Viets 1926. Two species are described as new to science: Torrenticola kimichungi sp. n. and Monatractides abei sp. n. Five species are reported as first records from Korea: Torrenticola brevirostris (Halbert, 1911); Torrenticola dentifera Wiles, 1991; Torrenticola recentis Tuzovskij, 2003; Torrenticola ussuriensis (Sokolow, 1934); and Torrenticola turkestanica (Sokolow, 1926). Torrenticola nipponica (Enami, 1940) is reported for the first time from Russia. PMID- 23794888 TI - Six new species of Cymatodera from Mexico and Central America and the retention of Cymatodera obliquefasciata as a valid name (Cleridae, Tillinae). AB - Six new Cymatodera speciesfrom the Mexican states of Jalisco and Chiapas, and the Central American countries of El Salvador, Honduras, Costa Rica and Panama are described: Cymatodera rosalinae sp. n., Cymatodera capax sp. n., Cymatodera sinuosa sp. n., Cymatodera vittata sp. n., Cymatodera rubida sp. n. and Cymatodera limatula sp. n. Justification for retaining Cymatodera obliquefasciata within Cymatodera instead of transferring it to Bogcia is provided. Male genitalia and other characters of taxonomic value are illustrated. PMID- 23794889 TI - The Tetramorium tortuosum species group (Hymenoptera, Formicidae, Myrmicinae) revisited - taxonomic revision of the Afrotropical T. capillosum species complex. AB - In this study we revise the taxonomy of the Tetramorium tortuosum species group members encountered in the Afrotropical region, which we have placed in its own subgroup: the Tetramorium capillosum species complex. We re-describe the two previously known species Tetramorium capillosum Bolton and Tetramorium tabarum Bolton, and describe the new species Tetramorium hecate sp. n. The geographic distribution of the three species appears to be restricted to the equatorial rainforests of Central Africa. We provide a diagnosis of the Tetramorium capillosum species complex, an illustrated identification key to species level, and worker-based species descriptions, which include diagnoses, discussions, high quality montage images, and distribution maps. Furthermore, we discuss biogeography and composition of the globally distributed Tetramorium tortuosum group. PMID- 23794890 TI - The genus Macroteleia Westwood (Hymenoptera, Platygastridae s. l., Scelioninae) from China. AB - The genus Macroteleia Westwood (Hymenoptera: Platygastridaes. l., Scelioninae) from China is revised. Seventeen species are recognized based on 502 specimens, all of which are new records for China. Seven new species are described: Macroteleia carinigena sp. n. (China), Macroteleia flava sp. n. (China), Macroteleia gracilis sp. n. (China), Macroteleia salebrosa sp. n. (China), Macroteleia semicircula sp. n. (China), Macroteleia spinitibia sp. n. (China) and Macroteleia striatipleuron sp. n. (China). Ten species are redescribed: Macroteleia boriviliensis Saraswat (China, India, Thailand), Macroteleia crawfordi Kiefer, stat. n. (China, Philippines, Thailand, Vietnam), Macroteleia dolichopa Sharma (China, India, Vietnam), Macroteleia emarginata Dodd (China, Malaysia), Macroteleia indica Saraswat & Sharma (China, India, Vietnam), Macroteleia lamba Saraswat & Sharma (China, India, Thailand, Vietnam), Macroteleia livingstoni Saraswat (China, India), Macroteleia peliades Kozlov & Le (China, Vietnam), Macroteleia rufa Szelenyi (China, Egypt, Georgia, Russia, Thailand, Ukraine) and Macroteleia striativentris Crawford (China, Philippines, Thailand, Vietnam). The following five new synonyms are proposed: Macroteleia crates Kozlov & Le syn. n. and Macroteleia demades Kozlov & Le syn. n. of Macroteleia crawfordi Kieffer; Macroteleia cebes Kozlov & Le syn. n. and Macroteleia dones Kozlov & Le syn. n. of Macroteleia indica Saraswat & Sharma; Macroteleia dores Kozlov & Le syn. n. of Macroteleia lamba Saraswat & Sharma. A key to the Chinese species of the genus is provided. PMID- 23794891 TI - Immature Stages and Hosts of Two Plesiomorphic, Antillean Genera of Membracidae (Hemiptera) and a new species of Antillotolania from Puerto Rico. AB - The nymphs of Antillotolania Ramos and Deiroderes Ramos are described for the first time, along with the first host record for the genus Antillotolania, represented by Antillotolania myricae, sp. n. Nymphal features of both genera, such as a ventrally fused, cylindrical tergum IX (anal tube), the presence of abdominal lamellae, and heads with foliaceous ventrolateral lobes confirm their placement in Membracidae and are consistent with phylogenetic analyses placing them in Stegaspidinae but in conflict with a cladistic analysis showing a closer relationship to Nicomiinae. Head processes and emarginate forewing pads in the last instars of both genera support an earlier estimate, based on nuclear genes, that the two genera form a monophyletic group in Stegaspidinae. Distinguishing features of the four species of Antillotolania are tabulated. PMID- 23794892 TI - Cardiocondyla pirata sp. n. - a new Philippine ant with enigmatic pigmentation pattern (Hymenoptera, Formicidae). AB - A new species of the ant genus Cardiocondyla Emery, 1869 - Cardiocondyla pirata sp. n. - is described from the Philippines. The species belongs to an Indo Malayan group of six species that is characterized by workers having a strongly bilobate postpetiolar sternite and a thickset mesosoma with strongly convex dorsal profile as well as wingless, ergatoid males with sickle-shaped mandibles. The female castes show a pigmentation pattern not known from any ant worldwide. If having any adaptive value, a possible function of this structure is supposed to be visual dissolution of body shape in order to irritate predators. PMID- 23794893 TI - Subgeneric division of the genus Orcula Held 1837 with remarks on Romanian orculid data (Gastropoda, Pulmonata, Orculidae). AB - The genital anatomy of Orcula jetschini (Romania), Orcula zilchi (Bulgaria), and Orcula wagneri (Albania) is described. Based on anatomical features (morphology of the penial caecum) shell characters (sculpture and shape) and unpublished molecular data the genus Orcula is subdivided into three subgenera. Orcula zilchi was classified within the monotypic subgenus Orcula (Hausdorfia) subgen. n.; Orcula jetschini, Orcula wagneri, and Orcula schmidtii were classified to Orcula (Illyriobanatica) subgen. n. (type species: Pupa schmidtii) whereas the other Orcula species remain in the nominotypical subgenus. Orcula (Hausdorfia) is known from South-Eastern Bulgaria and North-Western Turkey, Orcula (Illyriobanatica) inhabits Western Romania, North-Western Greece, Albania, Macedonia, Kosovo, and Montenegro. The nine species of Orcula (Orcula) are known mainly from the Alps and the Western Carpathians (from Eastern France to Eastern Hungary and Slovakia). The occurrence of only one Orcula species namely Orcula jetschini is verified from Romania. Available information suggests that data on the Romanian occurrence of Orcula dolium and Orcula gularis were based on wrongly identified specimens. Sphyradium dobrogicum (=Orcula dobrogica) is considered as a synonym of Sphyradium doliolum. PMID- 23794894 TI - Notes on the scorpions (Arachnida, Scorpiones) from Xizang with the redescription of Scorpiops jendeki Kovarik, 2000 (Scorpiones, Euscorpiidae) from Yunnan (China). AB - Until now, there are 26 scorpion species of 7 genera of 5 families recorded in Xizang (China). Xizang Autonomous Region (Tibet) is the scorpion biodiversity richest area in China (53 scorpion species of 12 genera of 5 families), also the highest altitude habitat of scorpions in the world. We present information of type specimens, an identification key of the scorpion species from Xizang, the distribution, updated feature pictures, and discussion on the disputed species. The redescriptions of Scorpiops jendeki Kovarik, 2000 (Yunnan) and Scorpiops tibetanus Hirst, 1911 (Xizang), comments and feature figures of species of genus Scorpiops are provided for identification. PMID- 23794895 TI - First record of Tyrodes Raffray (Coleoptera, Staphylinidae, Pselaphinae) in China, with description of T. jenisi sp. n. from Yunnan Province. PMID- 23794896 TI - Notes on Michael Schulke's pselaphine collections from China. - Tyrini. II. Genus Megatyrus Hlavac & Nomura (Coleoptera, Staphylinidae, Pselaphinae). AB - Two new species of the tyrine genus Megatyrus Hlavac & Nomura, Megatyrus schuelkei Yin & Li, sp. n. (based on two males) and Megatyrus tengchongensis Yin & Li, sp. n. (based on one female), from Yunnan, Southwest China are described, illustrated and distinguished from allied species. The body size, form of maxillary palpi, male and female genital structures, and distributional patterns are used to separate the new species. PMID- 23794897 TI - A new Ingolfiellid (Crustacea, Amphipoda, Ingolfiellidae) from an anchialine pool on Abd al Kuri Island, Socotra Archipelago, Yemen. AB - Ingolfiella arganoi sp. n. from Abd al Kuri Island in the Arabian Sea is described from two specimens, a male and a female. The western shore of the Indian Ocean was hitherto a vacant spot in the distribution of circumtropical shallow marine interstitial ingolfiellids and therefore the location of the new species fills a meaningful gap in the geography of the family. Morphologically, the new species shows close affinities with Ingolfiella xarifae from the Maldives. PMID- 23794898 TI - Review of the millipede family Opisotretidae (Diplopoda, Polydesmida), with descriptions of new species. AB - The small, basically Oriental family Opisotretidae is rediagnosed, reclassified, and shown to comprise the following seven genera, all keyed: Carlotretus Hoffman, 1980, with two species, including Carlotretus triramus sp. n. from southern China; Corypholophus Attems, 1938, with two species, one in Vietnam, the other in the Ryukyus, Japan; Martensodesmus Golovatch, 1987, with eight species, all keyed, including Martensodesmus cattienensis sp. n. from southern Vietnam, as well as Martensodesmus bedosae sp. n. and Martensodesmus spiniger sp. n. from southern China; Opisotretus Attems, 1907, with seven species, all keyed, including Opisotretus beroni sp. n. and Opisotretus hagen sp. n., both from Papua New Guinea, Opisotretus deharvengi sp. n. from Sulawesi, Indonesia, and Opisotretus spinosus sp. n. from Nusakambangan Island, off Java, Indonesia; Opisthoporodesmus Silvestri, 1899, with six nominate species; Retrodesmus Chamberlin, 1945, with two species, i.e. the type-species Retrodesmus dammermani Chamberlin, 1945, from Java, Indonesia, revised from the holotype, and Retrodesmus cavernicola sp. n., from Papua New Guinea; and Solaenaulus Attems, 1940, with two species. Comments are presented on the family's possible relationships and palaeogeographic history. Instead of being considered as the sole component of the superfamily Opisotretoidea, the Opisotretidae is believed here to form one of the families of the diverse superfamily Trichopolydesmoidea, perhaps the sister-group to, if not immediately derived from, the pantropical family Fuhrmannodesmidae. The origin of Opisotretidae, previously dated as far back as the Triassic (220 Ma) in relation to the fragmentation of eastern Gondwanaland, mainly in the region of present-day Indonesia, could have had nothing to do with Gondwanaland. Opisotretids might have originated in mainland Southeast Asia well within the Cenozoic, with subsequent dispersals along the Himalayas in the West and across Indonesia (including New Guinea) in the East, also reaching as far north as the Ryukyus, Japan and Guangxi, southern China. PMID- 23794899 TI - Three new species in the genus Wilkinsonellus (Braconidae, Microgastrinae) from the Neotropics, and the first host record for the genus. AB - The genus Wilkinsonellus Mason is a poorly sampled but widely distributed tropical genus of Microgastrinae (Braconidae), parasitoid wasps that exclusively attack caterpillars (Lepidoptera). Currently, species of Wilkinsonellus have been described only from the Palaeotropics, but the genus was known to occur in the Neotropics. Here we describe the first three species from Central and South America: Wilkinsonellus alexsmithi sp. n., Wilkinsonellus kogui sp. n.,and Wilkinsonellus panamaensis sp. n. These species descriptions confirm that Wilkinsonellus is a Pantropical genus. A dichotomous key for the three new Neotropical species is given. The first recorded host for the genus, Microthyris prolongalis (Crambidae), is also reported, for Wilkinsonellus alexsmithi. PMID- 23794900 TI - Eight new apterous Lathrobium species (Coleoptera, Staphylinidae) from Sichuan, Southwest China. AB - Eight apterous species of the paederine genus Lathrobium Gravenhorst, 1802 from the Chinese province Sichuan are described, illustrated, and distinguished from closely related and/or geographically close congeners: Lathrobium erlangense Peng & Li sp. n. (Erlang Shan), Lathrobium blandum Peng & Li sp. n. (Labahe N. R.), Lathrobium yelense Peng & Li sp. n. (Yele), Lathrobium obscurum Peng & Li sp. n. (Yele), Lathrobium yinziweii Peng & Li sp. n. (Yele), Lathrobium illustre Peng & Li sp. n. (Yele), Lathrobium micangense Peng & Li sp. n. (Micang Shan) and Lathrobium agglutinatum Assing & Peng sp. n. (Qingcheng Shan). The total number of described Lathrobium species from Sichuan now stands at 39, that of mainland China at 165. PMID- 23794901 TI - Two new species of oribatid mites of the genus Truncozetes (Acari, Oribatida, Epactozetidae) from Ecuador. AB - Two new oribatid mite species of the genus Truncozetes (Oribatida, Epactozetidae), Truncozetes ecuadoriensis sp. n. and Truncozetes monodactylus sp. n., are described from the Ecuadorian soils. The morphology of the gnathosoma and the legs is presented in detail for the first time for the species of Truncozetes. An identification key to all known species of the family Epactozetidae is given. PMID- 23794902 TI - Two new species of the genera Mysmena and Trogloneta (Mysmenidae, Araneae) from Southwestern China. AB - Two new spider species of the family Mysmenidae Petrunkevitch, 1928 are reported from Southwestern China, i.e., Mysmena wawuensis sp. n. (male and female) from Sichuan and Trogloneta yuensis sp. n. (male) from Chongqing. Diagnoses and illustrations of the new species are provided. PMID- 23794903 TI - A food plant specialist in Sparganothini: A new genus and species from Costa Rica (Lepidoptera, Tortricidae). AB - Sparganocosma docsturnerorum Brown, new genus and new species, is described and illustrated from Area de Conservacion (ACG) in northwestern Costa Rica. The new genus shares a long, crescent- or ribbon-shaped signum in the corpus bursae of the female genitalia with Aesiocopa Zeller, 1877, Amorbia Clemens, 1860, Amorbimorpha Kruse, 2011, Coelostathma Clemens, 1860, Lambertiodes Diakonoff, 1959, Paramorbia Powell & Lambert, 1986, Rhynchophyllus Meyrick, 1932, Sparganopseustis Powell & Lambert, 1986, Sparganothina Powell, 1986, and Sparganothoides Lambert & Powell, 1986. Putative autapomorphies for Sparganocosma include the extremely short uncus; the smooth (unspined) transtilla; and the upturned, free, distal rod of the sacculus. Adults of Sparganocosma docsturnerorum have been reared numerous times (>50) from larvae collected feeding on rain forest Asplundia utilis (Oerst.) Harling and Asplundia microphylla (Oerst.) Harling (Cyclanthaceae) at intermediate elevations (375-500 m) in ACG. Whereas most Sparganothini are generalists, typically feeding on two or more plant families, Sparganocosma docsturnerorum appears to be a specialist on Asplundia, at least in ACG. The solitary parasitoid wasp Sphelodon wardae Godoy & Gauld (Ichneumonidae; Banchinae) has been reared only from the larvae of Sparganocosma docsturnerorum. PMID- 23794904 TI - First cytogenetic information for Drymoreomys albimaculatus (Rodentia, Cricetidae), a recently described genus from Brazilian Atlantic Forest. AB - The recently described taxon Drymoreomys albimaculatus is endemic to the Brazilian Atlantic Forest and its biology and genetics are still poorly known. Herein, we present, for the first time, the karyotype of the species using classical and molecular cytogenetics, which showed 2n=62, FN=62, and interstitial telomeric signals at the sex chromosomes. Nuclear and mitochondrial DNA sequences from the two karyotyped individuals verify the taxonomic identity as the recently described Drymoreomys albimaculatus and confirm the relationship of the species with other Oryzomyini. Additionally, external morphological information is provided. PMID- 23794905 TI - Two new species of the genus Ancistrocerus Wesmael (Hymenoptera, Vespidae, Eumeninae) from China, with a key to the Oriental species. AB - Two new species, namely Ancistrocerus transpunctatus You and Li, sp. n. and Ancistrocerus deqinensis You and Li, sp. n. are described and illustrated from Yunnan, China. A key to the Oriental species of the genus Ancistrocerus is provided. PMID- 23794906 TI - Taxonomy of the Cryptopygus complex. I. Pauropygus - a new worldwide littoral genus (Collembola, Isotomidae). AB - In this paper, we describe the new genus Pauropygus gen. n. which includes three minute species, blind and unpigmented, living in interstitial littoral habitats in tropical or subtropical countries. Two of these species are new to science (type species Pauropygus projectus sp. n. from New Caledonia and Pauropygus pacificus sp. n. from China); the third one, originally described in the genus Cryptopygus (Cryptopygus caussaneli Thibaud, 1996), has a larger pantropical distribution. We synonymize here Cryptopygus riebi Barra, 1997 from South Africa with Pauropygus caussaneli. Two paratypes of the Mexican species Cryptopygus axayacatl Palacios & Thibaud, 2001 turned also to be Pauropygus caussaneli, while the holotype and remaining paratypes of this species support its placement in Proisotomodes. Among the Cryptopygus complex, Pauropygus gen. n. is easily recognized by characters of mouthparts (presence of two large projections on pleural fold, basolateral field with 6 chaetae, modified mouthparts) and reduced sensillar chaetotaxy (tergal sensilla 2-3,0-1/0-1,0-1,1-2,1-2,1-3, microsensilla reduced in number: 00/0-100, with sensilla situated in p-row on the abdomen). Small size, absence of eyes and pigment are also shared by all its species. The three species belonging to the genus differ by sensillar chaetotaxy. PMID- 23794907 TI - A study on the Neotropical Anthaxiini (Coleoptera, Buprestidae, Buprestinae). AB - Revision of the Neotropical genera of the subtribe Anthaxiina Gory & Laporte, 1839 (Coleoptera, Buprestidae, Buprestinae, Anthaxiini). Five new genera are described: Anthaxita gen. n., Charlesina gen. n., Cobosina gen. n., Marikia gen. n. and Sanchezia gen. n. Genus Agrilaxia Kerremans, 1903 is divided into two subgenera: Agrilaxia and Costiptera subgen. n. and the genus Bilyaxia Holynski, 1989 is divided into three subgenera: Bilyaxia, Paraguayetta subgen. n. and Tomasia subgen. n. One new species is described: Anthaxita peruviana sp. n., and two informal species-groups are suggested within Agrilaxia (Costiptera subgen. n.): Agrilaxia (Costiptera) modesta (Kerremans, 1897) species-group and Agrilaxia (Costiptera) occidentalis (Kerremans, 1900) species-group. Lectotype is designated for Agrilaxia mrazi Obenberger, 1932. A key of all genera/subgenera is provided and all treated taxa are illustrated. PMID- 23794908 TI - New species and records of Lobrathium Mulsant & Rey (Coleoptera, Staphylinidae, Paederinae) from China. AB - Seven new species of the genus Lobrathium Mulsant & Rey from China are described and illustrated: Lobrathium anatinum Li & Li, sp. n. (Guangxi), Lobrathium diaoluoense Li & Li, sp. n. (Hainan), Lobrathium dufui Li & Li, sp. n. (Hubei), Lobrathium lirunyui Li & Li, sp. n. (Guizhou), Lobrathium pengi Li & Li, sp. n. (Guangxi), Lobrathium quyuani Li & Li, sp. n. (Hubei) and Lobrathium uncinatum Li & Li, sp. n. (Qinghai). A recent key to the species of mainland China is modified to accommodate the new species. New locality data are provided for eleven species. PMID- 23794909 TI - Exocelina baliem sp. n., the only known pond species of New Guinea Exocelina Broun, 1886 (Coleoptera, Dytiscidae, Copelatinae). AB - Exocelina baliem sp. n. is described from the Baliem Valley in the Central Mountain Range of New Guinea (Papua Province, Indonesia). Having striolate elytra, different structure and setation of the male and female genitalia and tarsomeres, and inhabiting swampy ponds, the new species differs from all known New Guinea species, which have smooth elytra and are stream associated. It forms a monophyletic group with the Australian Exocelina ferruginea (Sharp, 1882) and New Caledonian Exocelina inexspectata Wewalka, Balke & Hendrich, 2010, based on shape of the paramere and structure of the male tarsi. Habitus, protarsomeres, and male and female genitalia are illustrated, comparing some structures with Exocelina ferruginea and two New Guinea stream species. We briefly discuss the biogeographic relevance of this discovery. PMID- 23794910 TI - A butterfly with olive green eyes discovered in the United States and the Neotropics (Lepidoptera, Lycaenidae, Eumaeini). AB - We describe Ministrymon janevicroy Glassberg, sp. n., from the United States (Texas). Its wing pattern closely resembles that of the widespread and well-known lycaenid, Ministrymon azia (Hewitson). The new species is distinguished by the structure of its male and female genitalia, by the patterning of the ground color on the basal half of the ventral hindwing surface, and by the color of its eyes. Adults of Ministrymon janevicroy in nature have olive green eyes in contrast to the dark brown/black eyes of Ministrymon azia. Ministrymon janevicroy occurs in dry deciduous forest and scrub from the United States (Texas) to Costa Rica (Guanacaste) with disjunct populations on Curacao and Isla Margarita (Venezuela). In contrast, Ministrymon azia occurs from the United States to southern Brazil and Chile in both dry and wet lowland habitats. Nomenclaturally, we remove the name Electrostrymon grumus K. Johnson & Kroenlein, 1993, from the synonymy of Ministrymon azia (where it had been listed as a synonym of Ministrymon hernandezi Schwartz & K. Johnson, 1992). We accord priority to Angulopis hernandezi K. Johnson & Kroenlein, 1993 over Electrostrymon grumus K. Johnson & Kroenlein, 1993, syn. n., which currently is placed in Ziegleria K. Johnson, 1993. The English name Vicroy's Ministreak is proposed for Ministrymon janevicroy. We update biological records of dispersal and caterpillar food plants, previously attributed to Ministrymon azia, in light of the new taxonomy. PMID- 23794911 TI - Seladonia (Pachyceble) henanensis sp. n. (Hymenoptera, Halictidae) from China. AB - Seladonia (Pachyceble) henanensis sp. n., is described from Henan Province, the eastern-central part of China. This species is separated from its allied species by a combination of the following morphological characters: head broad in female, inner hind tibial spur of female with 7-8 slender teeth, T1 basolaterally with appressed hair tuft in both sexes, and genitalia with long and large lower gonostylus in male. Important taxonomic characters are illustrated with photographs, scanning electron micrographs, and line drawings. PMID- 23794912 TI - Synopsis of Acanthocerini (Hemiptera, Coreidae) from Argentina. AB - Eight genera and 13 species of the tribe Acanthocerini are recorded in Argentina, i.e., Athaumastus haematicus (Stal), Athaumastus macer Brailovsky, Athaumastus subcarinatus (Stal), Athaumastus subterlineatus Bergroth, Beutelspacoris sanchezi Brailovsky, Beutelspacoris dilatata Casini, Camptischium clavipes (Fabricius), Crinocerus sanctus (Fabricius), Dersagrena flaviventris (Berg), Dersagrena lacerdae (Signoret), Dersagrena subfoveolata (Berg), Thlastocoris hernandezi Brailovsky and Zoreva dentipes Fabricius. Redescriptions are given for Athaumastus haematicus, Athaumastus subcarinatus and Dersagrena flaviventris with photographs of male and female genitalia of Dersagrena subfoveolata. Zoreva recorded from Argentina the first time. New locality records are given for Buenos Aires, Chaco, Formosa, Misiones, and Tucuman. PMID- 23794913 TI - Photosymbiotic ascidians in Singapore: turbid waters may reduce living space. AB - The photosymbiotic ascidian fauna at Changi Beach, Pulau Semakau, Sentosa and St. John's Island, Singapore were surveyed. A total of five species, Diplosoma simile, Lissoclinum bistratum, Lissoclinum punctatum, Lissoclinum timorense and Trididemnum cyclops, were recorded, with Lissoclinum timorense and Trididemnum cyclops being newly recorded in Singapore. However, no photosymbiotic species were found at Changi Beach probably due to the polluted waters in the region. Coastal development has caused Singapore waters to become turbid, leading to decrease in suitable habitats for photosymbiotic ascidians. Clean waters in Pulau Semakau probably provide a better environment for the growth of photosymbiotic ascidians and this area has a greater variety of these ascidians than the other areas in Singapore. Each of the five species has also been recorded in the Ryukyu Archipelago (Japan) and three species (Diplosoma simile, Lissoclinum bistratum and Trididemnum cyclops) have also been recorded in Taiwan. PMID- 23794914 TI - A specialist's audit of aggregated occurrence records: An 'aggregator's' perspective. AB - A recent ZooKeys' paper (Mesibov, 2013: http://www.pensoft.net/journal_home_page.php?journal_id=1&page=article&SESID=df7b b35b02603283dcb83ee0e0af0c9&type=show&article_id=5111) has highlighted data quality issues in aggregated data sets, but did not provide a realistic way to address these issues. This paper provides an aggregator's perspective including ways that the whole community can help to address data quality issues. The establishment of GBIF and national nodes (national aggregators) such as the Atlas of Living Australia (ALA) have integrated and exposed a huge diversity of biological observations along with many associated issues. Much of the admirable work by Mesibov (2013) was enabled by having the data exposed. Data quality, one of the highest priorities for GBIF, the national nodes and other aggregators, depends on both automatic methods and community experts to detect and correct data issues. Not all issues can however be automatically detected or corrected, so community assistance is needed to help improve the quality of exposed biological data. We do need to improve the infrastructure and associated processes to more easily identify data issues and document all changes to ensure a full record is permanently and publicly available. PMID- 23794915 TI - Identification of the terebrantian thrips (Insecta, Thysanoptera) associated with cultivated plants in Java, Indonesia. AB - An illustrated identification key is provided to 49 species of Thysanoptera, Terebrantia that have been found in association with cultivated plants in Java. This is the first published identification system to this group of insects from Indonesia, and includes 15 species not previously recorded from Indonesia, and a further three species not previously recorded from Java. A table is provided indicating the plants from which thrips were taken. PMID- 23794916 TI - A review of the genus Monema Walker in China (Lepidoptera, Limacodidae). AB - Four species and one subspecies of the genus Monema Walker, 1855 are recognized from China, in which Monema tanaognatha Wu & Pan sp. n. is described as new, Monema coralina Dudgeon, 1895 and Monema meyi Solovyev & Witt, 2009 are newly recorded for China. The female of Monema meyi is reported for the first time. Monema nigrans de Joannis, 1901 and Monema melli Hering, 1931 are synonymized with Monema flavescens Walker, 1855. Cnidocampa rubriceps Matsumura, 1931 is regarded here as a subspecies of Monema flavescens Walker, 1855. The photographs of moths and their genitalia are given. A key to the species of the genus is provided. PMID- 23794917 TI - Iberian Odonata distribution: data of the BOS Arthropod Collection (University of Oviedo, Spain). AB - Odonata are represented from the Iberian Peninsula by 79 species. However, there exists a significant gap in accessible knowledge about these species,especially regarding their distribution. This data paper describes the specimen-based Odonata data of the Arthropod Collection of the Department of Biologia de Organismos y Sistemas (BOS), University of Oviedo, Spain. The specimens were mainly collected from the Iberian Peninsula (98.63% of the data records), especially the northern region. The earliest specimen deposited in the collection dates back to 1950, while the 1980's and 2000's are the best-represented time periods. Between 1950 and 2009, 16, 604 Odonata specimens were deposited and are documented in the dataset. Approximately 20% of the specimens belong to the families Coenagrionidae and Calopterygidae. Specimens include the holotype and paratypes of the Iberian subspecies Calopteryx haemorrhoidalis asturica Ocharan, 1983 and Sympetrum vulgatum ibericum Ocharan, 1985. The complete dataset is also provided in Darwin Core Archive format. PMID- 23794918 TI - FORMIDABEL: The Belgian Ants Database. AB - FORMIDABEL is a database of Belgian Ants containing more than 27.000 occurrence records. These records originate from collections, field sampling and literature. The database gives information on 76 native and 9 introduced ant species found in Belgium. The collection records originated mainly from the ants collection in Royal Belgian Institute of Natural Sciences (RBINS), the 'Gaspar' Ants collection in Gembloux and the zoological collection of the University of Liege (ULG). The oldest occurrences date back from May 1866, the most recent refer to August 2012. FORMIDABEL is a work in progress and the database is updated twice a year. THE LATEST VERSION OF THE DATASET IS PUBLICLY AND FREELY ACCESSIBLE THROUGH THIS URL: http://ipt.biodiversity.be/resource.do?r=formidabel. The dataset is also retrievable via the GBIF data portal through this link: http://data.gbif.org/datasets/resource/14697 A dedicated geo-portal, developed by the Belgian Biodiversity Platform is accessible at: http://www.formicidae atlas.be PURPOSE: FORMIDABEL is a joint cooperation of the Flemish ants working group "Polyergus" (http://formicidae.be) and the Wallonian ants working group "FourmisWalBru" (http://fourmiswalbru.be). The original database was created in 2002 in the context of the preliminary red data book of Flemish Ants (Dekoninck et al. 2003). Later, in 2005, data from the Southern part of Belgium; Wallonia and Brussels were added. In 2012 this dataset was again updated for the creation of the first Belgian Ants Atlas (Figure 1) (Dekoninck et al. 2012). The main purpose of this atlas was to generate maps for all outdoor-living ant species in Belgium using an overlay of the standard Belgian ecoregions. By using this overlay for most species, we can discern a clear and often restricted distribution pattern in Belgium, mainly based on vegetation and soil types. PMID- 23794919 TI - A new Haptoclinus blenny (Teleostei, Labrisomidae) from deep reefs off Curacao, southern Caribbean, with comments on relationships of the genus. AB - A second species of the blenniiform genus Haptoclinus is described from deep reefs off Curacao, southern Caribbean. Haptoclinus dropi sp. n. differs from the northwestern Caribbean Haptoclinus apectolophus Bohlke and Robins, 1974, in having 29 total dorsal-fin elements-III-I-XIII, 12 (vs. 31-III-I-XIV, 13 or III-I XIII, 14); 19 anal-fin soft rays (vs. 20-21); 12 pectoral-fin rays (vs. 13); 12 precaudal vertebrae (vs. 13); and the first dorsal-fin spine longer than the second (vs. the second longer than the first). It further differs from Haptoclinus apectolophus in lacking scales (vs. three-quarters of body densely scaled), in having a distinctive pattern of spotting on the trunk and fins in preservative (vs. no spotting), and in lacking a fleshy flap on the anterior rim of the posterior nostril (vs. flap present). Color in life is unknown for Haptoclinus apectolophus, and the color description presented for the new species constitutes the first color information for the genus. Familial placement of Haptoclinus remains questionable, but the limited relevant information obtained from morphological examination of the new species provides additional support for a close relationship with the Chaenopsidae. Haptoclinus dropi represents one of numerous new teleost species emerging from sampling to 300 m off Curacao as part of the Smithsonian Institution's Deep Reef Observation Project (DROP). PMID- 23794920 TI - The remarkable scorpion diversity in the Ecuadorian Andes and description of a new species of Tityus C. L. Koch, 1836 (Scorpiones, Buthidae). AB - A new species of Tityus, subgenus Atreus (Scorpiones: Buthidae) is described from the Province of Pichincha in the Ecuadorian Andes. Ecuadorian scorpion fauna remains one of the less well studied among those of South America. Nevertheless, some comments are addressed about its remarkable diversity and high level of endemic elements. PMID- 23794921 TI - Maeropsis paphavasitae and Rotomelita longipropoda, two new species (Crustacea, Amphipoda) from Lower Gulf of Thailand. AB - Two new species of maerid and melitid Amphipoda, Maeropsis paphavasitae and Rotomelita longipropoda, respectively, collected from a seagrassbed of the Lower Gulf of Thailand, are described. Maeropsis paphavasitae is characterized by it seven teeth on the palm of gnathopod 2 and Rotomelita longipropoda can be recognized by its long gnathopod 1 propodus. Their characters are described and illustrated. All specimens are deposited at Princess Maha Chakri Sirindhorn Natural History Museum, Prince of Songkla University, Thailand and the Museum fur Naturkunde, Berlin. PMID- 23794922 TI - Two new Korean earthworms (Annelida, Oligochaeta, Megadrilacea, Megascolecidae). AB - Two Korean endemic pheretimoid Amynthas Kinberg, 1867 species belonging in family Megascolecidae s. stricto are sketched, dissected and described. Amynthas daeari Blakemore sp. n. has spermathecae in 6/7/8 complying with an Amynthas tokioensis spp-group, whilst Amynthas jinburi Blakemore sp. n. has spermathecal pores in 5 & 6 strictly complying with Sims and Easton's (1972)Amynthas canaliculatus-group. A definitive COI gene barcode is provided for the holotype of Amynthas daeari but the age since collection or preservation of the Amynthas jinburi type in 2000 precluded its mtDNA extraction at this time. PMID- 23794923 TI - A taxonomic guide to the brittle-stars (Echinodermata, Ophiuroidea) from the State of Paraiba continental shelf, Northeastern Brazil. AB - We provide the first annotated checklist of ophiuroids from the continental shelf of the State of Paraiba, northeastern Brazil. Identification keys and taxonomic diagnoses for 23 species, belonging to 14 genera and 8 families, are provided. The material is deposited in the Invertebrate Collection Paulo Young, at the Federal University of Paraiba. Ophiopsila hartmeyeri represents the first record for the northeastern region of Brazil, while Ophiolepis impressa, Ophiolepis paucispina, Amphiura stimpsoni, Amphiodia riisei, Ophiactis quinqueradia, Ophiocoma wendtii and Ophionereis olivaceae are new records for the State of Paraiba. The number of species known for the state was increased from 16 to 23, representing approximately 17% of the species known for Brazil and 54% of the species known for northeastern Brazil. The recorded fauna has a large geographical and bathymetrical distribution. PMID- 23794924 TI - Revision of the genus Neometopina (Hemiptera, Fulgoromorpha, Delphacidae) from China. AB - The planthopper genus Neometopina Yang (Hemiptera: Fulgoroidea: Delphacidae: Delphacinae: Delphacini) is revised to include 2 species: Neometopina penghuensis Yang, 1989 (China: Guizhou: Maolan), and Neometopina orientalis (Qin & Zhang) comb. n. (China: Hainan: Bawangling) (transferred from Laminatopina Qin & Zhang). The included species are described and illustrated, and a key to species is provided. PMID- 23794925 TI - Taxonomic review of the Ornithocheirus complex (Pterosauria) from the Cretaceous of England. AB - Over a decade after the last major review of the Cambridge Greensand pterosaurs, their systematics remains one of the most disputed points in pterosaur taxonomy. Ornithocheiridae is still a wastebasket for fragmentary taxa, and some nomenclatural issues are still a problem. Here, the species from the Cretaceous of England that, at some point, were referred in Ornithocheirus, are reviewed. Investigation of the primary literature confirmed that Criorhynchus should be considered an objective junior synonym of Ornithocheirus. Taxonomic review of more than 30 species known from fragmentary remains showed that 16 of them are undiagnosable (nomina dubia): Palaeornis cliftii, Cimoliornis diomedeus, Pterodactylus compressirostris, Pterodactylus fittoni, Pterodactylus woodwardi, Ornithocheirus brachyrhinus, Ornithocheirus carteri, Ornithocheirus crassidens, Ornithocheirus dentatus, Ornithocheirus enchorhynchus, Ornithocheirus eurygnathus, Ornithocheirus oxyrhinus, Ornithocheirus scaphorhynchus, Ornithocheirus tenuirostris, Ornithocheirus xyphorhynchus, and Pterodactylus sagittirostris. Fourteen species are considered valid, and diagnoses are provided to all of them: Ornithocheirus simus, Lonchodraco giganteus comb. n., Lonchodraco machaerorhynchus comb. n., Lonchodraco(?) microdon comb. n., Coloborhynchus clavirostris, 'Ornithocheirus' capito, Camposipterus nasutus comb. n., Camposipterus(?) sedgwickii comb. n., Camposipterus(?) colorhinus comb. n., Cimoliopterus cuvieri comb. n., 'Ornithocheirus' polyodon, 'Ornithocheirus' platystomus, 'Pterodactylus' daviesii, and 'Ornithocheirus' denticulatus. These species are referred in the genera Ornithocheirus, Lonchodraco gen. n., Coloborhynchus, Cimoliopterus gen. n., and Camposipterus gen. n., but additional genera are probably present, as indicated by the use of single quotation marks throughout the text. A cladistic analysis demonstrates that Anhangueridae lies within a newly recognized clade, here named Anhangueria, which also includes the genera Cearadactylus, Brasileodactylus, Ludodactylus, and Camposipterus. The anhanguerian 'Cearadactylus' ligabuei belongs to a different genus than Cearadactylus atrox. Lonchodraconidaefam. n. (more or less equivalent to LonchodectidaesensuUnwin 2001) is a monophyletic entity, but its exact phylogenetic position remains uncertain, as is the case of Ornithocheirus simus. Therefore, it is proposed that Ornithocheiridae should be constricted to its type species and thus is redundant. Other taxa previously referred as "ornithocheirids" are discussed in light of the revised taxonomy. PMID- 23794926 TI - Two new species of Itagonia Reitter (Coleoptera, Tenebrionidae, Blaptini) from China. AB - Two new species of Itagonia Reitter, 1887, Itagonia tibialis sp. n. and Itagonia litangensis sp. n. are described from Sichuan, China. A key to the known species of Itagonia from China is given. PMID- 23794927 TI - New Curculionoidea (Coleoptera) records for Canada. AB - The following species of Curculionoidea are recorded from Canada for the first time, in ten cases also representing new records at the generic level: Ischnopterapion (Ischnopterapion) loti (Kirby, 1808); Stenopterapion meliloti (Kirby, 1808) (both Brentidae); Atrichonotus taeniatulus (Berg, 1881); Barinus cribricollis (LeConte, 1876); Caulophilus dubius (Horn, 1873); Cionus scrophulariae (Linnaeus, 1758); Cryptorhynchus tristis LeConte, 1876; Cylindrocopturus furnissi Buchanan, 1940; Cylindrocopturus quercus (Say, 1832); Desmoglyptus crenatus (LeConte, 1876); Pnigodes setosus LeConte, 1876; Pseudopentarthrum parvicollis (Casey, 1892); Sibariops confinis (LeConte, 1876); Sibariops confusus (Boheman, 1836); Smicronyx griseus LeConte, 1876; Smicronyx lineolatus Casey, 1892; Euwallacea validus (Eichhoff, 1875); Hylocurus rudis (LeConte, 1876); Lymantor alaskanus Wood, 1978; Phloeotribus scabricollis (Hopkins, 1916); Scolytus oregoni Blackman, 1934; Xyleborus celsus Eichhoff, 1868; Xyleborus ferrugineus (Fabricius, 1801); Xylosandrus crassiusculus (Motschulsky, 1866) (all Curculionidae). In addition the following species were recorded for the first time from these provinces and territories: Yukon - Dendroctonus simplex LeConte, 1868; Phloetribus piceae Swaine, 1911 (both Curculionidae); Northwest Territories - Loborhynchapion cyanitinctum (Fall, 1927) (Brentidae); Nunavut - Dendroctonus simplex LeConte, 1868 (Curculionidae); Alberta - Anthonomus tectus LeConte, 1876; Promecotarsus densus Casey, 1892; Dendroctonus ponderosae Hopkins, 1902; Hylastes macer LeConte, 1868; Rhyncolus knowltoni (Thatcher, 1940); Scolytus schevyrewi Semenov Tjan-Shansky, 1902 (all Curculionidae); Saskatchewan - Phloeotribus liminaris (Harris, 1852); Rhyncolus knowltoni (Thatcher, 1940); Scolytus schevyrewi Semenov Tjan-Shansky, 1902 (all Curculionidae); Manitoba - Cosmobaris scolopacea Germar, 1819; Listronotus maculicollis (Kirby, 1837); Listronotus punctiger LeConte, 1876; Scolytus schevyrewi Semenov Tjan-Shansky, 1902; Tyloderma foveolatum (Say, 1832); (all Curculionidae); Ontario - Trichapion nigrum (Herbst, 1797); Nanophyes marmoratus marmoratus (Goeze, 1777) (both Brentidae); Asperosoma echinatum (Fall, 1917); Micracis suturalis LeConte, 1868; Orchestes alni (Linnaeus, 1758); Phloeosinus pini Swaine, 1915; Scolytus schevyrewi Semenov Tjan-Shansky, 1902; Xyleborinus attenuatus (Blandford, 1894) (all Curculionidae); Quebec - Trigonorhinus alternatus (Say, 1826); Trigonorhinus tomentosus tomentosus (Say, 1826) (both Anthribidae); Trichapion nigrum (Herbst, 1797); Trichapion porcatum (Boheman, 1839); Nanophyes marmoratus marmoratus (Goeze, 1777) (all Brentidae); Lissorhoptrus oryzophilus Kuschel, 1952 (Brachyceridae); Acalles carinatus LeConte, 1876; Ampeloglypter ampelopsis (Riley, 1869); Anthonomus rufipes LeConte, 1876; Anthonomus suturalis LeConte, 1824; Ceutorhynchus hamiltoni Dietz, 1896; Curculio pardalis (Chittenden, 1908); Cyrtepistomus castaneus (Roelofs, 1873); Larinus planus (Fabricius, 1792); Mecinus janthinus (Germar, 1821); Microhyus setiger LeConte, 1876; Microplontus campestris (Gyllenhal, 1837); Orchestes alni (Linnaeus, 1758); Otiorhynchus ligustici (Linnaeus, 1758); Rhinusa neta (Germar, 1821); Trichobaris trinotata (Say, 1832); Tychius liljebladi Blatchley, 1916; Xyleborinus attenuatus (Blandford, 1894); Xyleborus affinis Eichhoff, 1868 (all Curculionidae); Sphenophorus incongruus Chittenden, 1905 (Dryophthoridae); New Brunswick - Euparius paganus Gyllenhal, 1833; Allandrus populi Pierce, 1930; Gonotropis dorsalis (Thunberg, 1796); Euxenus punctatus LeConte, 1876 (all Anthribidae); Loborhynchapion cyanitinctum (Fall, 1927) (Brentidae); Pseudanthonomus seriesetosus Dietz, 1891; Curculio sulcatulus (Casey, 1897); Lignyodes bischoffi (Blatchley, 1916); Lignyodes horridulus (Casey, 1892); Dietzella zimmermanni (Gyllenhal, 1837); Parenthis vestitus Dietz, 1896; Pelenomus squamosus LeConte, 1876; Psomus armatus Dietz, 1891; Rhyncolus macrops Buchanan, 1946; Magdalis inconspicua Horn, 1873; Magdalis salicis Horn, 1873 (all Curculionidae); Nova Scotia - Dryocoetes autographus (Ratzeburg, 1837); Ips perroti Swaine, 1915; Xyleborinus attenuatus (Blandford, 1894) (all Curculionidae); Prince Edward Island - Dryocoetes caryi Hopkins, 1915 (Curculionidae); Newfoundland - Scolytus piceae (Swaine, 1910) (Curculionidae). Published records of Dendroctonus simplex LeConte, 1868 from Northwest Territories should be reassigned to Nunavut, leaving no documented record for NWT. Collection data are provided for eight provincial and national records published without further information previously. PMID- 23794928 TI - An annotated update of the scale insect checklist of Hungary (Hemiptera, Coccoidea). AB - The number of scale insect species (Hemiptera: Coccoidea) known from Hungary has increased in the last 10 years by 39 (16.6 %), to a total of 274 species belonging to 112 genera in10 families. The family Pseudococcidae is the most species rich, with 101 species in 34 genera; Diaspididae contains 59 species in 27 genera; Coccidae contains 54 species in 27 genera; and the Eriococcidae contains 33 species in 8 genera. The other 6 coccoid families each contain only a few species: Asterolecaniidae (7 species in 3 genera); Ortheziidae (7 species in 4 genera); Margarodidaesensu lato (5 species in 5 genera); Cryptococcidae (3 species in 2 genera); Kermesidae (4 species in 1genus); and Cerococcidae (1 species). Of the species in the check list, 224 were found in outdoor conditions, while 50 species occurred only in indoor conditions. This paper contains 22 species recorded for the first time in the Hungarian fauna. PMID- 23794929 TI - Two new replacement names for the planthopper genera in Dictyopharidae (Hemiptera, Fulgoromorpha). AB - New replacement names are proposed for two genera of the family Dictyopharidae (Hemiptera: Fulgoromorpha). The following changes are proposed: Neonotostrophia nom. n. for Notostrophia Emeljanov (not Waterhouse); Emeljanovina nom. n. for Glochina Emeljanov (not Meigen); Neonotostrophia nigrosuturalis (Melichar, 1912) comb. n. from Notostrophia nigrosuturalis (Melichar, 1912) = Dictyophara nigrosuturalis Melichar, 1912 and Emeljanovina dixoni (Distant, 1906) comb. n. from Glochina dixoni (Distant, 1906) = Dictyophara dixoni Distant, 1906. PMID- 23794930 TI - Disregarding ZooBank registration results in the unavailability of Hemicaloosia graminis Zeng et al., 2012 (Nematoda, Tylenchida) under the ICZN Code. PMID- 23794931 TI - Ampelocissus asekii J. Wen, R. Kiapranis & M. Lovave, a new species of Vitaceae from Papua New Guinea. AB - A new species Ampelocissus asekii J.Wen, R.Kiapranis & M.Lovave of Vitaceae is described from Morobe Province of Papua New Guinea. It is a close relative of Ampelocissus muelleriana Planch., another endemic of New Guinea and differs from the latter by its densely woolly tomentose lower leaflet surface and much thicker leaflets. The new species is from the mid montane forests, whereas Ampelocissus muelleriana occurs in the lowland rain forests. PMID- 23794932 TI - Axonopus graniticola, a new species of A. ser. Suffulti (Poaceae, Panicoideae, Paspaleae) from Minas Gerais, Brazil. AB - A new species of Axonopus ser. Suffulti from Minas Gerais, Brazil, is described and illustrated. Comparison with morphologically related species, as well as comments on the ecology and the conservation status are provided. PMID- 23794933 TI - Pyropia plicata sp. nov. (Bangiales, Rhodophyta): naming a common intertidal alga from New Zealand. AB - A commonly found red alga of the upper intertidal zone of New Zealand rocky coasts is described for the first time as Pyropia plicata sp. nov. This species has been incorrectly known as Porphyra columbina Mont. (now Pyropia columbina (Mont.) W.A.Nelson) for many years. Pyropia plicata is widespread and common, and it is readily distinguished from other species of bladed Bangiales in New Zealand by its distinctive morphology, with pleated blades attached by a central rhizoidal holdfast. PMID- 23794934 TI - Allium formosum Sennikov & Lazkov (Amaryllidaceae), a new species from Kyrgyzstan. AB - Allium formosum Sennikov & Lazkov sp. nov. is described as new to science and illustrated. This species is the second member of Allium sect. Spathulata F.O.Khass. & R.M.Fritsch, being different from Allium spathulatum F.O.Khass. & R.M.Fritsch in larger, broader, obtuse and more intensely purple-coloured tepals, and in a more robust habit. It is a local endemic of Babash-Ata Mt. Range situated east of Fergana Valley in Kyrgyzstan, recommended for legal protection as Endangered because of the very small population size in its only locality. PMID- 23794935 TI - A synopsis of Harperocallis (Tofieldiaceae, Alismatales) with ten new combinations. AB - Ten new combinations from Asagraea, Isidrogaliva, and Tofieldia are proposed in the previously monospecific genus Harperocallis (Tofieldiaceae, Alismatales). As circumscribed here, the genus is restricted to the Americas. The majority of species occur in the Andes or the Guayana region of northern South America; more than half have restricted distributions, and Harperocallis flava is narrowly endemic in the Coastal Plain of the southeastern United States. A key to species, synonymies, distributions, representative specimens, and salient notes are presented. Populations of the species are mapped and Harperocallis robustior is illustrated. A neotype is selected for Tofieldia frigida, here considered a synonym of Harperocallis falcata. Several recent records of Harperocallis longiflora, previously known only from the type collected in 1902, are reported. PMID- 23794936 TI - Reinterpretation of the nomenclatural type of Pseudobombax heteromorphum (Malvaceae, Bombacoideae) reveals an overlooked new species from Bolivia. AB - In the course of a taxonomic revision of Pseudobombax Dugand, one of us (JGCS) frequently has observed herbarium specimens of Bombacoideae that comprise a mixture of different Angiosperm families. In particular, Pseudobombax heteromorphum (Kuntze) A. Robyns, a frequent name in checklists of the Bolivian flora, is based on type material of Bombax heteromorphum Kuntze that is clearly a mixture of Pseudobombax flowers and Tabebuia Gomes ex DC. (Bignoniaceae) leaves. We herein designate as the lectotype of Bombax heteromorphum the flowers of an herbarium sheet deposited in NY and as epitype a complete specimen (leaves, flowers, and fruit) in HUEFS. We consider Bombax heteromorphum to be a synonym of Pseudobombax longiflorum (Mart.) A. Robyns, a species widespread in Neotropical seasonally dry forest of Bolivia, Brazil, Paraguay, and Peru. Furthermore, we describe a new species, Pseudobombax pulchellum Carv.-Sobr., apparently endemic to seasonally dry tropical forest (SDTF) in Bolivia (Chiquitano dry forest), based on specimens commonly but incorrectly identified as Pseudobombax heteromorphum.We also comment on the morphology, distribution, and conservation status of this new species. PMID- 23794937 TI - A revision of the Dulcamaroid Clade of Solanum L. (Solanaceae). AB - The Dulcamaroid clade of Solanum contains 45 species of mostly vining or weakly scandent species, including the common circumboreal weed Solanum dulcamara L. The group comprises members of the previously recognised infrageneric groupings sect. Andropedas Rusby, sect. Californisolanum A. Child, sect. Dulcamara (Moench) Dumort., sect. Holophylla (G.Don) Walp., sect. Jasminosolanum (Bitter) Seithe, sect.Lysiphellos (Bitter) Seithe, subsect. Nitidum A.Child and sect. Subdulcamara Dunal. These infrageneric groups are not monophyletic as traditionally recognised, and the complex history of the classification of the dulcamaroid solanums is reviewed. Many of the species in the clade are quite variable morphologically; plants are shrubs, herbaceous vines or woody canopy lianas, and habits can vary between these states in a single locality. Variation in leaf shape and pubescence density and type is also extreme and has lead to the description of many minor morphological variants as distinct species. The flowers of members of the group are generally very showy, and several species (e.g., Solanum crispum Ruiz & Pav., Solanum laxum Spreng., Solanum seaforthianum Andrews) are popular ornamental plants that have occasionally escaped from cultivation and become naturalised. The clade is here divided into five morphologically and geographically delimited species groups to facilitate further study. One new species from southern Ecuador, Solanum agnoston S.Knapp sp. nov., is described here. Full descriptions and synonymies (including designations of lectotypes or neotypes), preliminary conservation assessments, illustrations, distribution maps, and an extensive list of localities are provided for all species. PMID- 23794938 TI - New lepidium (brassicaceae) from new zealand. AB - A revision of the New Zealand endemic Lepidium oleraceum and allied species is presented. Sixteen species are recognised, 10 of these are new. The new species are segregated on the basis of morphological characters supported by molecular data obtained from three DNA markers (two rDNA and one cpDNA). One species, Lepidium castellanum sp. nov., is endemic to the Kermadec Islands where it is sympatric with Lepidium oleraceum. The North Island of New Zealand supports four species, with two of them, Lepidium amissum sp. nov. and Lepidium obtusatum, now extinct. The South Island supports six species, that, aside from Lepidium banksii, Lepidium flexicaule and Lepidium oleraceum, are all confined to the south-eastern half of the island (Lepidium aegrum sp. nov., Lepidium crassum sp. nov. and Lepidium juvencum sp. nov.). One of these, Lepidium juvencum sp. nov., extends to Stewart Island. The Chatham Islands support six species (Lepidium flexicaule, Lepidium oblitum sp. nov., Lepidium oleraceum, Lepidium oligodontum sp. nov., Lepidium panniforme sp. nov., and Lepidium rekohuense sp. nov.), one of which, Lepidium oligodontum sp. nov., extends to the Antipodes Islands group. The remote, subantarctic Bounty Islands group supports one endemic, Lepidium seditiosum sp. nov., which is the only vascular plant to be recorded from there. Lepidium limenophylax sp. nov. is known from islands off the south-western side of Stewart Island/Rakiura, The Snares and Auckland islands. Lepidium naufragorum, although not related to Lepidium oleraceum and its allies, is also treated because populations with entire leaves are now known. Typification is undertaken for Lepidium banksii, Lepidium oleraceum, Lepidium oleraceum var. acutidentatum, var. frondosum and var. serrulatum. PMID- 23794939 TI - Identification of the predominant nonrestoring allele for Owen-type cytoplasmic male sterility in sugar beet (Beta vulgaris L.): development of molecular markers for the maintainer genotype. AB - Hybrid seed production in sugar beet relies on cytoplasmic male sterility (CMS). As time-consuming and laborious test crosses with a CMS tester are necessary to identify maintainer lines, development of a marker-assisted selection method for the rf gene (the nonrestoring allele of restorer-of-fertility locus) is highly desirable for sugar-beet breeding. To develop such a method, we investigated genetic variation at the Rf1 locus, one of two Rf loci known in sugar beet. After HindIII-digestion, genomic DNAs from beet plants known to have a restoring Rf1 allele yielded a range of hybridization patterns on agarose gels, indicating that Rf1 is a multi-allelic locus. However, the hybridization patterns of 22 of 23 maintainer lines were indistinguishable. The nucleotide sequences of the rf1 coding regions of these 22 maintainer lines were found to be identical, confirming that the lines had the same rf1 allele. Two PCR markers were developed that targeted a downstream intergenic sequence and an intron of Rf1. The electrophoretic patterns of both markers indicated multiple Rf1 alleles, one of which, named the dd(L) type, was associated with the maintainer genotype. To test the validity of marker-assisted selection, 147 sugar beet plants were genotyped using these markers. Additionally, the 147 sugar beet plants were crossed with CMS plants to determine whether they possessed the maintainer genotype. Analysis of 5038 F1 offspring showed that 53 % of the dd(L) plants, but none of the plants with other alleles, had the maintainer genotype. Thus, selection for the dd(L) type considerably enriched the proportion of plants with the maintainer genotype. PMID- 23794940 TI - Quantitative trait loci for leaf chlorophyll fluorescence parameters, chlorophyll and carotenoid contents in relation to biomass and yield in bread wheat and their chromosome deletion bin assignments. AB - Relatively little is known of the genetic control of chlorophyll fluorescence (CF) and pigment traits important in determining efficiency of photosynthesis in wheat and its association with biomass productivity. A doubled haploid population of 94 lines from the wheat cross Chinese Spring * SQ1 was trialled under optimum glasshouse conditions for 4 years to identify quantitative trait loci (QTL) for CF traits including, for the first time in wheat, JIP-test parameters per excited cross section (CSm): ABS/CSm, DIo/CSm, TRo/CSm, RC/CSm and ETo/CSm, key parameters determining efficiency of the photosynthetic apparatus, as well as chlorophyll and carotenoid contents to establish associations with biomass and grain yield. The existing genetic map was extended to 920 loci by adding Diversity Arrays Technology markers. Markers and selected genes for photosynthetic light reactions, pigment metabolism and biomass accumulation were located to chromosome deletion bins. Across all CF traits and years, 116 QTL for CF were located on all chromosomes except 7B, and 39 QTL were identified for pigments on the majority of chromosomes, excluding 1A, 2A, 4A, 3B, 5B, 1D, 2D, 5D, 6D and 7D. Thirty QTL for plant productivity traits were mapped on chromosomes 3A, 5A, 6A, 7A, 1B, 2B, 4B, 6B, 7B, 3D and 4D. A region on chromosome 6B was identified where 14 QTL for CF parameters coincided with QTL for chlorophyll content and grain weight per ear. Thirty-five QTL regions were coincident with candidate genes. The environment was shown to dominate in determining expression of genes for those traits. PMID- 23794941 TI - Convenient Synthesis and Evaluation of Heptadentate Bifunctional Ligand for Radioimmunotherapy Applications. AB - An efficient synthetic route to a bifunctional chelating agent C-NE3TA-NCS for antibody-targeted radioimmunotherapy (RIT) applications was developed. Various synthetic methods centered on the key reaction steps including bimolecular cyclization, ring opening reactions of aziridine and aziridinium cations, and reductive aminiation were explored to optimize the preparation of a tetraaza based chelate TANPA and C-NE3TA analogues. Heptadentate C-NE3TA-NCS was conjugated to a tumor targeting antibody and compared to hexadentate C-NOTA-NCS for radiolabeling reaction kinetics with lanthanides for RIT. C-NE3TA-antibody conjugate displayed significantly enhanced complexation kinetics with 90Y as compared to C-NOTA-antibody conjugate. The synthetic methods for TANPA and C NE3TA-NCS reported herein have broad applications for preparation of bifunctioanl macrocyclic chelating agents. PMID- 23794942 TI - Synthesis of CuO and Cu3N Nanoparticles in and on Hollow Silica Spheres. AB - Copper oxide nanoparticles within hollow mesoporous silica spheres were prepared by binding/adsorbing Cu2+ or [Cu(NH3)4(H2O)2]2+ ions on the surface of carbon spheres, followed by formation of a mesoporous silica shell by sol-gel processing and calcination in air. The CuO nanoparticles can subsequently be converted into Cu3N nanoparticles by nitridation with ammonia. The effect of the different copper precursors, i.e. Cu2+ and [Cu(NH3)4(H2O)2]2+, on the nanocomposites was studied. CuO nanoparticles on the outer surface of hollow silica spheres were obtained by thermal treatment of hollow CuSiO3 spheres in air. Nitridation of the CuSiO3 spheres with ammonia resulted in Cu3N@SiO2 composites, with aggregated Cu3N nanoparticles on hollow silica spheres. PMID- 23794943 TI - Data mining of the public version of the FDA Adverse Event Reporting System. AB - The US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS, formerly AERS) is a database that contains information on adverse event and medication error reports submitted to the FDA. Besides those from manufacturers, reports can be submitted from health care professionals and the public. The original system was started in 1969, but since the last major revision in 1997, reporting has markedly increased. Data mining algorithms have been developed for the quantitative detection of signals from such a large database, where a signal means a statistical association between a drug and an adverse event or a drug associated adverse event, including the proportional reporting ratio (PRR), the reporting odds ratio (ROR), the information component (IC), and the empirical Bayes geometric mean (EBGM). A survey of our previous reports suggested that the ROR provided the highest number of signals, and the EBGM the lowest. Additionally, an analysis of warfarin-, aspirin- and clopidogrel-associated adverse events suggested that all EBGM-based signals were included in the PRR based signals, and also in the IC- or ROR-based ones, and that the PRR- and IC based signals were in the ROR-based ones. In this article, the latest information on this area is summarized for future pharmacoepidemiological studies and/or pharmacovigilance analyses. PMID- 23794944 TI - Areca nut chewing and risk of atrial fibrillation in Taiwanese men: a nationwide ecological study. AB - BACKGROUND: Areca nut chewing is associated with the risk of obesity, metabolic syndrome, hypertension, and cardiovascular mortality. Although a few case reports or case series have suggested the link between areca nut chewing and cardiac arrhythmias, information about the relationship between areca nut chewing and atrial fibrillation (AF) is lacking. Thus, a nationwide ecological study was conducted to investigate this. METHODS: Two national datasets, the nationwide population-based 2005 Taiwan National Health Insurance Research dataset (NHIRD) and the 2005 National Health Interview Survey (NHIS), were used for analyses. The clinical characteristics, inhabited area and medical histories for 375,360 eligible males were retrieved from the 2005 NHIRD. Health related behaviors including areca nut chewing, cigarette smoking, infrequent vegetable eating, and exercise habit were collected from the 2005 NHIS. The prevalence of AF and the areca nut chewing rate were evaluated by multivariate analysis. RESULTS: Of the 375,360 males (mean age, 44 years old), 1,326 (0.35%) were diagnosed with AF. The higher areca nut chewing rate, the higher prevalence rate of AF in Taiwan (Spearman correlation coefficient r=0.558, p=0.007). After adjusting for other covariates, the current areca nut chewing rate was found to be independently associated with the prevalence of AF. The adjusted odd ratio for areca nut chewing was 1.02 (95% CI=1.00-1.04) in risk of AF prevalence. CONCLUSIONS: Areca nut chewing is independently associated with the prevalence of AF in Taiwanese men. However, further exploration of the underlying mechanisms is necessary. PMID- 23794945 TI - Angiotensin receptor blockers and statins could alleviate atrial fibrosis via regulating platelet-derived growth factor/Rac1/nuclear factor-kappa B Axis. AB - AIMS: To investigate whether the administration of renin-angiotensin system (RAS) inhibitors and statins could alleviate atrial fibrosis via platelet-derived growth factor (PDGF)/Rac1 /nuclear factor-kappa B (NF-kappaB) axis. METHODS AND RESULTS: In human left atrium, the degree of atrial fibrosis, as well as the expression levels of PDGF, Rac1 and NF-kappaB increased 1.5 to 2.9 folds in patients with atrial fibrillation compared to that with sinus rhythm, (P<0.0001). There were strongly positive correlations between angiotensin II (Ang II) or procollagen type III-alpha-1 (COL3A1) with PDGF, Rac1, NF-kappaB, and among PDGF, Rac1 and NF-kappaB (all P<0.05). At 3 weeks after the transverse aorta constriction (TAC) operation in rat model and with intervention of irbesartan or/and simvastatin, the collagen volume fraction (CVF) and atrial natriuretic peptide (ANP) values respectively increased 6-folds and 3.5-folds in the TAC group compared to SHAM group (P<0.0001), but these levels decreased by 16% to 63% with following drug intervention (all P<0.0001), the combined treatment was the lowest. Accordingly, the expression levels of PDGF (3-folds), Rac1 (1.6-folds), NF-kappaB (7-folds) and AngII (12-folds) significantly increased in the TAC group compared to the SHAM group, and these levels were also reduced by 25% to 64% with following drug intervention. The highest reduction could be seen after treatment with irbesartan and simvastatin in combination (all P<0.001).There were strongly positive correlations between AngII or CVF with PDGF, Rac1, NF-kappaB, and among PDGF, Rac1 and NF-kappaB (all P<0.05). CONCLUSIONS: Irbesartan or/and simvastatin can improve atrial fibrosis by regulating PDGF/Rac1/NF-kappaB axis. PMID- 23794946 TI - A systematic review and meta-analysis of randomized trials and prospective studies comparing covered and bare self-expandable metal stents for the treatment of malignant obstruction in the digestive tract. AB - BACKGROUND: Self-expandable metal stents (SEMS) are widely used for the palliative treatment of malignant gastrointestinal obstruction. Our aim was to evaluate the evidence comparing covered and bare SEMS in the digestive tract using meta-analytical techniques. METHODS: A literature search was performed using PubMed, Cochrane Library, and Embase databases for comparative studies assessing the two types of stents. The primary outcomes of interest were stent patency and patient survival; second outcomes included technical success, clinical success, tumor ingrowth, tumor overgrowth, and stent migration. A random effects model was conducted. Pooled analysis was done separately based on the different segments of the digestive tract. RESULTS: Eleven studies (8 randomized controlled trials and 3 prospective cohort studies) including a total of 1376 patients were identified. Covered SEMS were equivalent to bare SEMS in terms of technical success, clinical success, stent patency (gastroduodenal obstruction: HR =0.87, 95% CI 0.53-1.42; colorectal obstruction: HR =0.89, 95% CI 0.18-4.45; biliary obstruction: HR =0.73, 95% CI 0.41-1.32) and survival rates (esophageal obstruction: HR =1.80, 95% CI 0.73-4.44; gastroduodenal obstruction: HR =0.83, 95% CI 0.55-1.26; biliary obstruction: HR =0.99, 95% CI 0.77-1.28), although bare stents were more prone to tumor ingrowth (esophageal obstruction: RR =0.10, 95% CI 0.01-0.77; gastroduodenal obstruction: RR =0.12, 95% CI 0.03-0.55; colorectal obstruction: RR =0.21, 95% CI 0.06-0.70; biliary obstruction: RR =0.21, 95% CI 0.06-0.69), whereas covered stents had the higher risk of stent migration (gastroduodenal obstruction: RR =5.01, 95% CI 1.53-16.43; colorectal obstruction: RR =11.70, 95% CI 2.84-48.27; biliary obstruction: RR =8.11, 95% CI 1.47-44.76) and tumor overgrowth (biliary obstruction: RR =2.03, 95% CI 1.08-3.78). CONCLUSION: Both covered and bare SEMS are comparable in efficacy for the palliative treatment of malignant obstruction in the digestive tract. Each type of the stents has its own merit and demerit relatively. PMID- 23794947 TI - Increased levels of macrophage migration inhibitory factor in patients with familial mediterranean Fever. AB - OBJECTIVE: To determine the level of macrophage migration inhibitory factor (MIF), its relationship with Mediterranean fever (MEFV) gene mutations and oxidative stress in familial Mediterranean fever (FMF). METHODS: Fifty one unrelated attack free FMF patients (24 M and 27 F, 32.8+/-8.7 years) and 30 healthy controls (16 M and 14 F, 32.7+/-7 years) were included in the study. Serum MIF, total oxidant status (TOS) and total anti-oxidant status (TAS) were studied. RESULTS: Age, sex distribution, anthropometrical indices, smoking status, serum lipids and TAS concentrations were similar between the patients and controls. However; erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), MIF, and TOS were significantly higher in the patients' group compared with healthy subjects. MIF, TOS and TAS levels were not different between patients with or without M694V mutations. CONCLUSION: We found increased concentrations of MIF in patients with FMF. Increased MIF levels were significantly correlated with oxidative stress and in regression analysis MIF concentrations were independent from the inflammatory activity as assessed by ESR and CRP. M694V mutations seem no effect on MIF and oxidative stress. PMID- 23794948 TI - Associations of MMP1, 3, 9 and TIMP3 genes polymorphism with isolated systolic hypertension in Chinese Han population. AB - BACKGROUND AND AIMS: Large artery stiffness and endothelial dysfunction are the predominant characteristic of isolated systolic hypertension. Recently studies have revealed MMP1, 3, 9 and TIMP3 Genes polymorphism were associated with arterial stiffness, but the relationship with isolated systolic hypertension were not further studied. This study was to investigate the associations of MMP1,3,9 and TIMP3 Genes polymorphism with isolated systolic hypertension. METHODS: We identified the genotype of the genes in 503 patients with isolated systolic hypertension, 481 essential hypertension patients with elevated diastolic blood pressure and 244 age-matched normotensive controls for 5 SNPs and detected the brachial-ankle pulse wave velocity, flow-mediated dilatation, endothelin-1 and nitric oxide among the participants. RESULTS: Multinomial logistic analyses showed that the 5A allele of rs3025058(5A/6A) in MMP3 and the T allele of rs3918242(C-1562T) in MMP9 were significantly associated with isolated systolic hypertension after adjusted by age, triglyceride, low-density lipoprotein (P<0.001, Pcorr<0.003; P=0.009, Pcorr=0.027). The 5A/G/C and 6A/A/T haplotypes were significantly associated with isolated systolic hypertension (Permutation p=0.0258; Permutation p=0.000002). In addition, the brachial-ankle pulse wave velocity of different genotypes for the 5A/6A and C-1562T polymorphisms was significantly highest in 5A or T homozygotes (P<0.01), however, the flow-mediated dilatation and nitric oxide were markedly lowest in 5A or T homozygotes (P<0.01). CONCLUSION: MMP3 and MMP9 genes variant seem to contribute to the development of isolated systolic hypertension by affecting arterial stiffness and endothelial function. PMID- 23794949 TI - Hemodynamic reactivity to laboratory stressors in healthy subjects: influence of gender and family history of cardiovascular diseases. AB - Although laboratory stressor tests have been applied as a preliminary protocol in some cardiovascular studies, there is a lack of data comparing the pressor and chronotropic responses among the main stressor tests. Therefore, the aim of this study was to evaluate the variability in hemodynamic responsiveness to the main stressor tests, establish a hyperresponsiveness cutoff criterion and analyze the influence of gender and family history of cardiovascular diseases (CVDs) in healthy subjects. We examined hemodynamic responses to physical (cold pressor and handgrip tests) and mental (Stroop color-word test) stressors in 98 subjects (48 males and 50 females) without CVDs. All stressor tests resulted in increased blood pressure (BP) levels, which were lower and less dispersed in the handgrip test compared to the cold pressor test. Adopting the 75(th) percentile as the cutoff in our data, we classified subjects exhibiting absolute pressor changes equal to or higher than 14, 24 and 36 mmHg in systolic and 9, 13 and 24 mmHg in diastolic BP during the handgrip, Stroop and cold pressor test, respectively, as hyperresponsives. Males exhibited greater (p<0.05) increases in systolic BP in the handgrip (11% vs. 8%) and cold pressor (25% vs. 21%) tests and in diastolic BP in the handgrip (12% vs. 7%) and Stroop (22% vs. 19%) tests than females. A positive association between family history of CVDs and pressor hyperreactivity to stressor tests was observed. We propose using the 75(th) percentile of hemodynamic sample values as a cutoff criterion to classify individuals as pressor or chronotropic hyperreactives. We conclude that hemodynamic responsiveness to stressor tests in healthy subjects is positively influenced by male gender and family history of CVDs. PMID- 23794950 TI - Influence of the forest caterpillar hunter Calosoma sycophanta on the transmission of microsporidia in larvae of the gypsy moth Lymantria dispar. AB - The behaviour of predators can be an important factor in the transmission success of an insect pathogen. We studied how Calosoma sycophanta influences the interaction between its prey [Lymantria dispar (L.) (Lepidoptera, Lymantriidae)] and two microsporidian pathogens [Nosema lymantriae (Microsporidia, Nosematidae) and Vairimorpha disparis (Microsporidia, Burellenidae)] infecting the prey.Using laboratory experiments, C. sycophanta was allowed to forage on infected and uninfected L. dispar larvae and to disseminate microsporidian spores when preying or afterwards with faeces.The beetle disseminated spores of N. lymantriae and V. disparis when preying upon infected larvae, as well as after feeding on such prey. Between 45% and 69% of test larvae became infected when C. sycophanta was allowed to disseminate spores of either microsporidium.Laboratory choice experiments showed that C. sycophanta did not discriminate between Nosema infected and uninfected gypsy moth larvae. Calosoma sycophanta preferred Vairimorpha-infected over uninfected gypsy moth larvae and significantly influenced transmission.When C. sycophanta was allowed to forage during the latent period on infected and uninfected larvae reared together on caged, potted oak saplings, the percentage of V. disparis infection among test larvae increased by more than 70%. The transmission of N. lymantriae was not affected significantly in these experiments.Beetles never became infected with either microsporidian species after feeding on infected prey.We conclude that the transmission of N. lymantriae is not affected. Because no V. disparis spores are released from living larvae, feeding on infected larvae might enhance transmission by reducing the time to death and therefore the latent period. PMID- 23794951 TI - Coaching Competency and (Exploratory) Structural Equation Modeling: A Substantive Methodological Synergy. AB - OBJECTIVES: The purpose of this manuscript was to provide a substantive methodological synergy of potential importance to future research in the psychology of sport and exercise. DESIGN: The substantive focus was the emerging role for, and particularly the measurement of, athletes' evaluations of their coach's competency within conceptual models of effective coaching. The methodological focus was exploratory structural equation modeling (ESEM), a methodology that integrates the advantages of exploratory factor analysis and confirmatory factor analysis (CFA) within the general structural equation model. METHOD: The synergy was a demonstration of when a new and flexible methodological framework, ESEM, may be preferred as compared to a more familiar and restrictive methodological framework, CFA, by reanalyzing existing data. RESULTS: ESEM analysis on extant datasets suggested that for responses to the Athletes' Perceptions of Coaching Competency Scale II - High School Teams (APCCS II-HST), a CFA model based on the relevant literature plus one post hoc modification, offered a viable alternative to a more complex ESEM model. For responses to the Coaching Competency Scale (CCS), a CFA model based on the relevant literature did not offer a viable alternative to a more complex ESEM model. CONCLUSIONS: The ESEM framework should be strongly considered in subsequent studies validity studies - for new and/or existing instruments in the psychology of sport and exercise. A key consideration for deciding between ESEM and the accompanying rotation criterion and CFA in future validity studies should be level of a priori measurement theory. PMID- 23794952 TI - Should bilingual children learn reading in two languages at the same time or in sequence? AB - Is it best to learn reading in two languages simultaneously or sequentially? We observed 2nd and 3rd grade children in two-way dual-language learning contexts: (i) 50:50 or Simultaneous dual-language (two languages within same developmental period) and (ii) 90:10 or Sequential dual-language (one language, followed gradually by the other). They were compared to matched monolingual English-only children in single-language English schools. Bilinguals (home language was Spanish only, English-only, or Spanish and English in dual-language schools), were tested in both languages, and monolingual children were tested in English using standardized reading and language tasks. Bilinguals in 50:50 programs performed better than bilinguals in 90:10 programs on English Irregular Words and Passage Comprehension tasks, suggesting language and reading facilitation for underlying grammatical class and linguistic structure analyses. By contrast, bilinguals in 90:10 programs performed better than bilinguals in the 50:50 programs on English Phonological Awareness and Reading Decoding tasks, suggesting language and reading facilitation for surface phonological regularity analysis. Notably, children from English-only homes in dual-language learning contexts performed equally well, or better than, children from monolingual English-only homes in single-language learning contexts. Overall, the findings provide tantalizing evidence that dual-language learning during the same developmental period may provide bilingual reading advantages. PMID- 23794953 TI - Seven-Month-Old Infants Selectively Reproduce the Goals of Animate But Not Inanimate Agents. PMID- 23794954 TI - In-law Relationships Before and After Marriage. AB - Relationships with in-laws play an important role in individuals' lives, but we do not know how these ties are formed. We considered two pathways through which early relationships with mothers-in-laws may affect subsequent in-law relationship qualities: a) dimensions of the early relationship and, b) beliefs and expectations of the future relationship. Sixty men and women engaged to be married and their mothers (N = 240) completed interviews prior to, and 6 to 8 months following the wedding. Measures at Time 1 assessed three dimensions of the in-law relationship: a) behavioral (contact by phone, in person), b) emotional (positive and negative relationship qualities), and c) cognitive (knowledge about the other person). Participants also described positive and negative expectations of their future tie. Multilevel models revealed that dimensions of the tie prior to the marriage were associated with post-wedding in-law relationship qualities. When the parties had individual contact with one another and positive feelings before the wedding, ties were stronger following the wedding. Data from open ended descriptions of negative expectations obtained before the wedding predicted negative relationship qualities after the wedding. Husbands, wives, and mothers in-law showed similar patterns with regard to relationship qualities. Discussion focuses on the role of early emotional qualities of the in-law tie for subsequent in-law relationships. PMID- 23794955 TI - Post-LASIK ectasia treated with intrastromal corneal ring segments and corneal crosslinking. AB - Corneal ectasia is a serious complication of laser in situ keratomileusis (LASIK). We report the case of a 29-year-old man who underwent LASIK in both eyes and in whom corneal ectasia developed in the left eye 3 years after surgery. He was treated sequentially with intraocular pressure-lowering medication, intrastromal corneal ring segment (ICRS) implants, and collagen cross-linking. Vision improved and the ectasia stabilized following treatment. Combined ICRS implantation and collagen cross-linking should be considered early in the management of post-LASIK ectasia. PMID- 23794956 TI - A 64-year-old woman with dilated right pupil, nausea, and headache. PMID- 23794957 TI - Iatrogenic choroidal neovascularization following idiopathic epiretinal membrane peel. AB - Choroidal neovascularization is an uncommon complication of macular surgery. The functional outcome is poor despite various treatment options, including laser photocoagulation, photodynamic therapy, and a variety of surgical procedures. We report a case of iatrogenic choroidal neovascularization in a 69-year-old woman at the site of inadvertent retinal trauma 5 weeks after an epiretinal membrane peel. Visual acuity was 6/15 at the time of diagnosis. Four intravitreal bevacizumab injections were administered over a period of 6 months; treatment was discontinued when a disciform scar was noted. At last follow-up, 21 months after surgery, the patient's visual acuity was counting fingers. PMID- 23794958 TI - Subperiosteal hematoma in multiple settings. AB - Most reports of orbital hemorrhage do not distinguish among intraconal, extraconal, and subperiosteal hemorrhages, although several reports describe isolated subperiosteal hematomas as a separate entity. We report 3 cases of subperiosteal hematoma with different etiologies but similar progression of signs and symptoms. Each patient presented with spontaneous proptosis, rarely caused by orbital subperiosteal hematoma, measuring approximately 5 mm. Over the course of 4-10 days their conditions worsened and warranted intervention. All 3 cases were treated with anterior orbitotomy, and visual acuity returned to baseline following surgery in all. PMID- 23794959 TI - Stress Analysis at the Molecular Level: A Forced Cucurbituril-Guest Dissociation Pathway. AB - Changes in mechanical stresses in a tight-binding host-guest system were computed and visualized as the cationic was computationally pulled out of the cucurbituril host in a series of steps. A sharp conformational transition was observed as one of the guest's ammonium groups jumped through the center of the host to the opposite portal. The conformation immediately prior to this transition was found to possess high levels of Lennard-Jones and electrostatic stress. This observation, along with the specific distribution of Lennard-Jones stress around the portals, suggested that the conformational transition resulted from steric constriction, which had been expected, and electrostatics, which was not expected. An important role for electrostatics, at least at the level of these calculations, was confirmed by a comparative computational pulling study of another guest molecule lacking the critical ammonium group. These calculations suggest that the binding kinetics of diammonium guests that position an ammonium at each cucurbituril portal will be found to be slower than the kinetics of monoammonium guests. More generally, the results suggest that computational stress analysis can provide mechanistic insight into supramolecular systems. It will be of considerable interest to extend such applications to biomolecules, for which the mechanisms of conformational change are of great scientific and practical interest. PMID- 23794960 TI - Standard binding free energies from computer simulations: What is the best strategy? AB - Accurate prediction of standard binding free energies describing protein:ligand association remains a daunting computational endeavor. This challenge is rooted to a large extent in the considerable changes in conformational, translational and rotational entropies underlying the binding process that atomistic simulations cannot easily capture. In spite of significant methodological advances, reflected in a continuously improving agreement with experiment, a characterization of alternate strategies aimed at measuring binding affinities, notably their respective advantages and drawbacks, is somewhat lacking. Here, two distinct avenues to determine the standard binding free energy are compared in the case of a short, proline-rich peptide associating to the Src homology domain 3 of tyrosine kinase Abl. These avenues - one relying upon alchemical transformations and the other on potentials of mean force (PMFs) - invoke a series of geometrical restraints acting on collective variables designed to alleviate sampling limitations inherent to classical molecular dynamics simulations. The experimental binding free energy of DeltaGbind = -7.99 kcal/mol is well reproduced by the two strategies developed herein, with DeltaGbind = -7.7 for the alchemical route and DeltaGbind = -7.8 kcal/mol for the alternate PMF based route. In detailing the underpinnings of these numerical strategies devised for the accurate determination of standard binding free energies, many practical elements of the proposed rigorous, conceptual framework are clarified, thereby paving way to tackle virtually any recognition and association phenomenon. PMID- 23794961 TI - The Association of Chronic Back Pain and Stress Urinary Incontinence: A Cross Sectional Study. AB - OBJECTIVE: The objective of this study was to investigate the association between chronic back pain and urinary incontinence in women. STUDY DESIGN: This study was a cross-sectional, observational study. BACKGROUND: There are numerous factors associated with the development of back pain, yet little consideration has been given to the pelvic floor musculature and dysfunction of this musculature which may also cause urinary incontinence. Currently, limited research exists evaluating the relationship between back pain and urinary incontinence. METHODS AND MEASURES: Data from a sample of 2,341 women from the Kentucky Women's Health Registry were used for analysis. The primary variables of interest were self reported chronic back pain (CBP) and stress urinary incontinence (SUI), with stress urinary incontinence serving as the primary dependent variable. Simple comparisons were performed using chi-square tests and two-sample t-tests, and multivariable associations were assessed using binary logistic regression. RESULTS: Reports of stress urinary incontinence were higher in women reporting CBP than those not reporting CBP (49.0% vs. 35.2%, p<0.01). After controlling for potential confounders, the adjusted SUI odds ratio for CBP versus not was 1.44 (95% CI 1.11, 1.86). CONCLUSION: Women who report CBP have an increased odds of having SUI. Therefore, clinicians must consider this association and the relationship of relevant trunk muscles, including pelvic floor musculature, in patients presenting with CBP and/or UI. PMID- 23794963 TI - Water soluble poly(1-vinyl-1,2,4-triazole) as novel dielectric layer for organic field effect transistors. AB - Water soluble poly(1-vinyl-1,2,4-triazole) (PVT) as a novel dielectric layer for organic field effect transistor is studied. Dielectric spectroscopy characterization reveals it has low leakage current and rather high breakdown voltage. Both n-channel and p-channel organic field effect transistors are fabricated using pentacene and fullerene as active layers. Both devices show device performances with lack of hysteresis, very low threshold voltages and high on/off ratios. Excellent film formation property is utilized to make AlO x and thin PVT bilayer in order to decrease the operating voltage of the devices. All solution processed ambipolar device is fabricated with simple spin coating steps using poly(2-methoxy-5-(2-ethyl-hexyloxy)-1,4-phenylenevinylene) (MEH-PPV) end capped with polyhedral oligomeric silsesquioxanes (POSS) as active layer. Our investigations show that PVT can be a very promising dielectric for organic field effect transistors. PMID- 23794962 TI - Molecular diversity of fungal communities in agricultural soils from Lower Austria. AB - A culture-independent survey of fungal diversity in four arable soils and one grassland in Lower Austria was conducted by RFLP and sequence analysis of clone libraries of the partial ITS/LSU-region. All soils were dominated by the ascomycetous orders Sordariales, Hypocreales and Helotiales, taxa that are known from traditional cultivation approaches to occur in agricultural soils. The most abundant genus in the investigated soils was Tetracladium, a hyphomycete which has been described as occurring predominantly in aquatic habitats, but was also found in agricultural soils. Additionally, soil clone group I (SCGI), a subphylum at the base of the Ascomycota with so far no cultivated members, was identified at high frequency in the grassland soil but was below detection limit in the four arable fields. In addition to this striking difference, general fungal community parameters like richness, diversity and evenness were similar between cropland and grassland soils. The presented data provide a fungal community inventory of agricultural soils and reveal the most prominent species. PMID- 23794964 TI - (Thio-cyanato-kappaS)-tris-(thio-urea-kappaS)mercury(II) chloride. AB - In the title salt, [Hg(NCS)(CH4N2S)3]Cl, the Hg(2+) ion is coordinated in a severely distorted tetra-hedral manner by three thio-urea groups and one thio cyanate anion through their S atoms. The S-Hg-S angles vary widely from 87.39 (5) to 128.02 (4) degrees . Weak intra-molecular N-H?S hydrogen bonds are observed, which form S(6) ring motifs. In the crystal, the ions are linked by N-H?N and weak N-H?Cl inter-actions, generating a three-dimensional network. PMID- 23794965 TI - Synchrotron powder study of Na3V(PO3)3N. AB - Polycrystalline tris-odium vanadium(III) nitridotriphosphate, Na3V(PO3)3N, was prepared by thermal nitridation of a mixture of NaPO3 and V2O5. The title compound is isotypic with Na3Al(PO3)3N. In the crystal, the P-atom and the three O-atom sites are on general positions, whereas the Na-, V- and N-atom sites are located on threefold rotation axes. The P atom is coordinated by three O atoms and one N atom in form of a slightly distorted tetra-hedron. Three PO3N tetra hedra build up a nitridotriphosphate group, (PO3)3N, by sharing a common N atom. The V atom is coordinated by six O atoms in form of a slightly distorted octa hedron. The Na(+) ions occupy three crystallographically distinct sites. One Na(+) ion is situated in an irregular polyhedral coordination environment composed of six O atoms and one N atom, while the other two Na(+) cations are surrounded by six and nine O atoms, respectively. PMID- 23794966 TI - Poly[tri-MU-aqua-di-aqua-MU-phosphono-formato-cobalt(II)sodium]. AB - The title complex, [CoNa(CO5P)(H2O)5]n, was obtained by reacting sodium phosphono formate with cobalt nitrate. The complex contains cobalt(II) and sodium ions, which are bridged by the O atoms of two aqua ligands. The Co(II) ion is octahedrally coordinated by three phosphonoformato ligands (one bi- and the other monodentate) and by two O atoms from the bridging aqua ligands. The sodium cation is hexa-coordinated by six O atoms from four bridging and two terminal aqua ligands. The complex mol-ecules are linked to give a three-dimensional structure by phosphono-formate ligands bridging Co(II) atoms and water mol-ecules establishing cobalt-sodium bridges. O-H?O hydrogen bonding between the aqua ligands and all O atoms of the phosphono-formato ligand and neighbouring aqua ligands help to consolidate the packing. PMID- 23794967 TI - The low-symmetry lanthanum(III) oxotellurate(IV), La10Te12O39. AB - Single crystals of deca-lanthanum(III) dodeca-oxotellurate(IV), La10Te12O39, were obtained by reacting La2O3 and TeO2 in a CsCl flux. Its crystal structure can be viewed as a three-dimensional network of corner- and edge-sharing LaO8 polyhedra with Te(IV) atoms filling the inter-stitial sites. The Te(IV) atoms with their 5s (2) electron lone pairs distort the LaO8 polyhedra through variable Te-O bonds. Among the six unique Te sites, four of them define empty channels extending parallel to the a axis. The formation of these channels is a result of the stereochemically active electron lone pairs on the Te(IV) atoms. The atomic arrangement of the Te-O units can be understood on the basis of the valence shell electron pair repulsion (VSEPR) model. A certain degree of disorder is observed in the crystal structure. As a result, one of the five different La sites is split into two positions with an occupancy ratio of 0.875 (2):0.125 (2). Also, one of the oxygen sites is split into two positions in a 0.559 (13):0.441 (13) ratio, and one O site is half-occupied. Such disorder was observed in all measured La10Te12O39 crystals. PMID- 23794968 TI - K(MoO2)4O3(AsO4). AB - A new compound with a non-centrosymmetric structure, potassium tetra-kis [dioxomolybdenum(IV)] arsenate trioxide, K(MoO2)4O3(AsO4), has been synthesized by a solid-state reaction. The [(MoO2)4O3(AsO4)](+) three-dimensional framework consists of single arsenate AsO4 tetra-hedra, MoO6 octa-hedra, MoO5 bipyramids and bi-octa-hedral units of edge-sharing Mo2O10 octa-hedra. The [Mo2O8]infinity octa-hedral chains running along the a-axis direction are connected through their corners to the AsO4 tetra-hedra, MoO6 octa-hedra and MoO5 bipyramids, so as to form large tunnels propagating along the a axis in which the K(+) cations are located. This structure is compared with compounds containing M 2O10 (M = Mo, V, Fe) dimers and with those containing M 2O8 (M = V) chains. PMID- 23794969 TI - Na2.9KMo12S14: a novel quaternary reduced molybdenum sulfide containing Mo12 clusters with a channel structure. AB - The crystal structure of tris-odium potassium dodeca-molybdenum tetra-deca sulfide, Na2.9 (2)KMo12S14, consists of Mo12S14S6 cluster units inter-connected through inter-unit Mo-S bonds and delimiting channels in which the Na(+) cations are disordered. The cluster units are centered at Wyckoff positions 2d and have point-group symmetry 3.2. The K atom lies on sites with 3.2 symmetry (Wyckoff site 2c) between two consecutive Mo12S14S6 units. One of the three independent S atoms and one Na atom lie on sites with 3.. symmetry (Wyckoff sites 4e and 4f). The other Na atom occupies a 2b position with -3.. symmetry. The crystal studied was a merohedral twin with refined components of 0.4951 (13) and 0.5049 (13). PMID- 23794970 TI - LiCo2As3O10: une nouvelle structure a tunnels inter-connectes. AB - The title compound, lithium dicobalt(II) triarsenate, LiCo2As3O10, was synthesized by a solid-state reaction. The As atoms and four out of seven O atoms lie on special positions, all with site symmetry m. The Li atoms are disordered over two independent special (site symmetry -1) and general positions with occupancies of 0.54 (7) and 0.23 (4), respectively. The structure model is supported by bond-valence-sum (BVS) and charge-distribution (CHARDI) methods. The structure can be described as a three-dimensional framework constructed from bi octahedral Co2O10 dimers edge-connected to As3O10 groups. It delimits two sets of tunnels, running parallel to the a and b axes, the latter being the larger. The Li(+) ions are located within the inter-sections of the tunnels. The possible motion of the alkali cations has been investigated by means of the BVS model. This simulation shows that the Li(+) motion appears to be easier mainly along the b-axis direction and that this material may possess inter-esting conduction properties. PMID- 23794971 TI - Pyridinium bis-(pyridine-kappaN)tetra-kis-(thio-cyanato-kappaN)ferrate(III). AB - In the title compound, (C5H6N)[Fe(NCS)4(C5H5N)2], the Fe(III) ion is coordinated by four thio-cyanate N atoms and two pyridine N atoms in a trans arrangement, forming an FeN6 polyhedron with a slightly distorted octa-hedral geometry. Charge balance is achieved by one pyridinium cation bound to the complex anion via N-H?S hydrogen bonding. The asymmetric unit consists of one Fe(III) cation, four thio cyanate anions, two coordinated pyridine mol-ecules and one pyridinium cation. The structure exhibits pi-pi inter-actions between pyridine rings [centroid centroid distances = 3.7267 (2), 3.7811 (2) and 3.8924 (2) A]. The N atom and a neighboring C atom of the pyridinium cation are statistically disordered with an occupancy ratio of 0.58 (2):0.42 (2). PMID- 23794972 TI - Bis{2-[2,5-bis-(pyridin-2-yl)-1H-imidazol-4-yl]pyridinium} tetra cyanidoplatinate(II) tetra-hydrate. AB - The asymmetric unit of the title hydrated complex salt, (C18H14N5)2[Pt(CN)4].4H2O, consists of one 2-[2,5-bis-(pyridin-2-yl)-1H-imidazol 4-yl]pyridinium cation, half a tetra-cyanidoplatinate(II) dianion, which is located about a crystallographic inversion center, and two water mol-ecules of crystallization. The Pt(II) atom has a square-planar coordination environment, with Pt-CCN distances of 1.992 (4) and 2.000 (4) A. In the cation, there is an N H?N hydrogen bond linking adjacent pyridinium and pyridine rings in positions 4 and 5. Despite this, the organic component is non-planar, as shown by the dihedral angles of 10.3 (2), 6.60 (19) and 15.66 (18) degrees between the planes of the central imidazole ring and the pyridine/pyridinium substituents in the 2-, 4- and 5-positions. In the crystal, cations and anions are linked via O-H?O, O H?N and N-H?O hydrogen bonds, forming a three-dimensional network. Additional pi pi, C-H?O and C-H?N contacts provide stabilization to the crystal lattice. PMID- 23794973 TI - 2-Amino-5-bromo-pyridin-1-ium (2-amino-5-bromo-pyridine-kappaN (1))trichloridozincate. AB - The structure of the title salt, (C5H6BrN2)[ZnCl3(C5H5BrN2)], consists of discrete 2-amino-5-bromo-pyridin-1-ium cations and distorted tetra-hedral (2 amino-5-bromo-pyridine)-tri-chlorido-zincate anions. In the crystal, the complex anions and cations are linked via N-H?Cl hydrogen bonds into layers parallel to (101). Short Br?Cl contacts of 3.4239 (11) and 3.4503 (12) A are observed, as well as pi-pi stacking inter-actions between the pyridine and pyridinium rings, with alternating centroid-to-centroid distances of 3.653 (2) and 3.845 (2) A. PMID- 23794974 TI - Poly[1H-imidazol-3-ium [di-MU-nitrato-sodium]]. AB - In the title compound {(C3H5N2)[Na(NO3)2]} n , the Na(I) ion is coordinated by eight O atoms from three bidentate nitrate anions and two O atoms from two monodentate nitrate anions, displaying a bicapped trigonal-prismatic geometry. The imidazolium cation is essentially planar (r.m.s. deviation for all non-H atoms = 0.0018 A). In the crystal, the Na(I) ions are connected by bridging nitrate ligands, forming layers parallel to (010). The imidazolium cations are sandwiched between these layers. Weak C-H?O hydrogen bonds link the layers into a three-dimensional network. In addtion, pi-pi inter-actions between the imidazolium rings [centroid-centroid distance = 3.588 (3) A] are observed. PMID- 23794975 TI - Poly[bis-(piperazine-1,4-diium) [(MU4-cyclo-hexa-phosphato)dilithium] tetra hydrate]. AB - In the title compound, {(C4H12N2)2[Li2(P6O18)].4H2O} n , the phosphate ring anion, located around an inversion center, adopts a chair conformation. Adjacent P6O18 rings are linked via corner-sharing by LiO4 tetra-hedra, generating anionic porous {[Li2(P6O18)](4-)} n layers parallel to (101). The piperazine-1,4-diium cations occupy the pores and develop hydrogen bonds with the inorganic framework. An extensive network of N-H?O and O-H?O hydrogen-bonding inter-actions link the components into a three-dimensional network and additional stabilization is provided by weak C-H?O hydrogen bonds. PMID- 23794976 TI - Sodium bis-(ethyl-enedi-amine)-copper(II) tetra-cyanido-cuprate(I). AB - The title compound, Na[Cu(en)2][Cu(CN)4], where en represents ethyl-enedi-amine, NH2CH2CH2NH2, crystallizes as a salt with two distinct cations, Na(+) and [Cu(II)en2](2+), and discrete [Cu(I)(CN)4](3-) anions. The anion geometry is tetra-hedral, with angles at the copper atom ranging from 105.0 (1) to 115.4 (1) degrees . The Cu-C distances are in the range 1.976 (3) to 1.993 (3) A. The divalent copper atom is coordinated by four N atoms of the two bidentate en ligands in a slightly distorted square-planar geometry. In the crystal, each sodium ion inter-acts with cyanide N atoms of four different anions, with Na-N distances lying in the narrow range of 2.344 (3) to 2.367 (3) A, and an approximately tetra-hedral arrangement around the sodium ions. The inter-acting sodium ions and [Cu(I)(CN)4](3-) anions form a three-dimensional network with channels which contain the [Cu(en)2](2+) cations. One of the chelate rings in the cation shows partial disorder between two different conformations and the C atoms were refined with occupancies in the ratio 0.817 (15):0.183 (15). PMID- 23794977 TI - Bis(3-amino-pyrazine-2-carboxyl-ato-kappa(2) N (1),O)di-aqua-nickel(II) dihydrate. AB - In the title compound, [Ni(C5H4N3O2)2(H2O)2].2H2O, the Ni(II) ion lies on an inversion center and is coordinated in an slightly distorted octa-hedral environment by two N,O-chelating 3-amino-pyrazine-2-carboxyl-ate (APZC) ligands in the equatorial plane and two trans-axial aqua ligands. In the crystal, O-H?O, N-H?O and O-H?N hydrogen bonds involving the solvent water mol-ecules, aqua and APZC ligands form layers parallel to (010). These layers are linked further via O H?O, N-H?O and C-H?O hydrogen bonds involving the axial aqua ligands, amino groups and the carboxyl-ate groups of the APZC ligands, forming a three dimensional network. PMID- 23794978 TI - Tris(N,N-di-methyl-anilinium) hexa-bromido-stannate(IV) bromide. AB - In the title compound, (C8H12N)3[SnBr6]Br, the anilinium N atom of one of the three unique cations exhibits flip-flop disorder with an 0.60:0.40 occupancy ratio. In the crystal, N-H?Br hydrogen bonds link the N,N-di-methyl-anilinium cations and both Br(-) anions and [SnBr6](2-) dianions into a layered arrangement parallel to (001). PMID- 23794979 TI - 1,1'-(Ethane-1,2-di-yl)dipyridinium bis-(1,2-di-cyano-ethene-1,2-di-thiol-ato kappa(2) S,S')cuprate(II). AB - In the title ion-pair complex, (C12H14N2)[Cu(C4N2S2)2], the complex anion exhibits a highly twisted coordination environment around the tetra-coordinated Cu(II) atom. The dihedral angles between the 1,2-di-cyano-ethene-1,2-di-thiol-ato ligands and between the two pyridine rings in the cation are 37.49 (3) and 29.18 (10) degrees , respectively. Weak C-H?N and C-H?S hydrogen bonds link the cations and anions into a three-dimensional network. PMID- 23794980 TI - Aqua-trimeth-yl[2-(4-methyl-pyrimidin-2-ylsulfan-yl)acetato-kappaO]tin(IV). AB - In the title compound, [Sn(CH3)3(C7H7N2O2S)(H2O)], the Sn(IV) atom has a distorted trigonal-bipyramidal coordination geometry, with one carboxyl-ate O atom of the 2-(4-methyl-pyrimidine-2-sulfan-yl)acetate ligand and the O atom of a water mol-ecule in axial positions, and three methyl groups in equatorial positions. In the crystal, mol-ecules are linked via O-H?O and O-H?N hydrogen bonds, forming double-stranded chains propagating along [010]. PMID- 23794981 TI - [Di-aqua-sesqui(nitrato-kappaO)hemi(perchlorato-kappaO)copper(II)]-MU-{bis-[5 methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl] selenide}-[tri-aqua-(perchlorato kappaO)copper(II)] nitrate monohydrate. AB - In the binuclear title complex, [Cu2(ClO4)1.5(NO3)1.5(C18H16N6Se)(H2O)5]NO3.H2O, both Cu(II) ions are hexa-coordinated by O and N atoms, thus forming axially elongated CuO4N2 octa-hedra. The equatorial plane of each octa-hedron is formed by one chelating pyrazole-pyridine fragment of the organic ligand and two water mol-ecules. The axial positions in one octa-hedron are occupied by a water mol ecule and a monodentately coordinated perchlorate anion, while those in the other are occupied by a nitrate anion and a disordered perchlorate/nitrate anion with equal site occupancy. The pyrazole-pyridine units of the organic selenide are trans-oriented to each other with a C-Se-C angle of 96.01 (14) degrees . In the crystal, uncoordinated nitrate anions and the coordinating water mol-ecules are involved in O-H?O and N-H?O hydrogen bonds, forming a bridge between the pyrazole group and the coordinating water mol-ecules. Further O-H?O hydrogen bonds between the complex mol-ecules and a pi-pi stacking inter-action with a centroid-centroid distance of 3.834 (4) A are also observed. PMID- 23794982 TI - (O-Methyl di-thio-carbonato-kappaS)tri-phenyl-tin(IV). AB - In the title compound, [Sn(C6H5)3(C2H3OS2)], the Sn(IV) atom adopts a distorted SnC3S tetra-hedral coordination geometry. A short Sn?O contact [2.988 (4) A] is also present. The phenyl rings are each disordered over two sets of sites with an occupancy ratio of 0.550 (8):0.450 (8). The crystal studied was found to be a racemic twin with a twin component ratio of 0.57 (18):0.43 (18). PMID- 23794983 TI - catena-Poly[[[di-aqua-bis-[1,2-bis-(pyridin-4-yl)diazene]copper(II)]-MU-1,2-bis (pyridin-4-yl)diazene] bis-(perchlorate)]. AB - In the title compound, {[Cu(C10H8N4)3(H2O)2](ClO4)2} n , the coordination environment of the cationic Cu(II) atom is distorted octa-hedral, formed by pairs of symmetry-equivalent 1,2-bis-(pyridin-4-yl)diazene ligands, bridging 1,2-bis (pyridin-4-yl)diazene ligands and two non-equivalent water mol-ecules. The 1,2 bis-(pyridin-4-yl)diazene mol-ecules form polymeric chains parallel to [-101] via azo bonds which are situated about inversion centres. Since the Cu(II) atom is situated on a twofold rotation axis, the monomeric unit has point symmetry 2. The perchlorate anions are disordered in a 0.536 (9):0.464 (9) ratio and are acceptors of water H atoms in medium-strong O-H?O hydrogen bonds with graph set R 4 (4)(12). The water mol-ecules, which are coordinated to the Cu(II) atom and are hydrogen-bonded to the perchlorate anions, form columns parallel to [010]. A pi pi inter-action [centroid-centroid distance = 3.913 (2) A] occurs between pyridine rings, and weak C-H?O inter-actions also occur. PMID- 23794984 TI - catena-Poly[[[bis-(methanol-kappaO)bis-(seleno-cyanato-kappaN)manganese(II)]-MU 1,2-bis-(pyridin-4-yl)eth-ene-kappa(2) N:N'] 1,2-bis-(pyridin-4-yl)eth-ene mono solvate]. AB - In the crystal structure of the title compound, {[Mn(NCSe)2(C12H10N2)(CH3OH)2].C12H10N2} n , the Mn(II) cation is coordin-ated by two terminal N-bonded seleno-cyanate anions, two methanol mol-ecules and two 1,2 bis-(pyridin-4-yl)eth-ene (bpe) ligands within a slightly distorted octahedral geometry. The Mn(II) cations are linked into chains along the c-axis direction by the bpe ligands, which are further connected by inter-molecular O-H?N hydrogen bonding between the methanol H atoms and additional bpe mol-ecules that are not coordinated to the metal atoms. The Mn(II) cation and both crystallographically independent bpe ligands are located on centers of inversion, whereas the seleno cyanate and methanol ligands occupy general positions. PMID- 23794985 TI - catena-Poly[[[di-aqua-bis-(seleno-cyanato-kappaN)iron(II)]-MU-1,2-bis-(pyridin-4 yl)ethane-kappa(2) N:N'] 1,2-bis-(pyridin-4-yl)ethane disolvate dihydrate]. AB - The title compound, {[Fe(NCSe)2(C12H12N2)(H2O)2].2C12H12N2.2H2O} n , was obtained by the reaction of iron(II) sulfate hepta-hydrate and potassium seleno-cyanate with 1,2-bis-(pyridin-4-yl)ethane (bpa) in water. The Fe(II) cation is coordinated by two N-bonded seleno-cyanate anions, two water mol-ecules and two 1,2-bis-(pyridin-4-yl)ethane (bpa) ligands in a slightly distorted octa-hedral geometry. In addition, two non-coordinating bpa mol-ecules and two water mol ecules are present. The Fe(II) cation is located on a center of inversion while the coordinating bpa ligand is located on a twofold rotation axis. The Fe(II) cations are linked by the bpa ligands into chains along the b-axis direction, which are further connected into layers perpedicular to the c axis by O-H?N and O H?O hydrogen bonds to the non-coordin-ating bpa and the water mol-ecules. The crystal studied was twinned by pseudo-merohedry (180 degrees rotation along c*; contribution of the minor twin component 3.7%). PMID- 23794986 TI - [Hexane-2,5-dione bis-(thio-semi-carba-zon-ato)]nickel(II). AB - In the title compound, [Ni(C8H14N6S2)], the Ni(II) ion is coordinated by N2S2 donor atoms of the tetradentate thio-semicarbazone ligand, and has a slightly distorted square-planar geometry. In the crystal, inversion-related mol-ecules are linked via pairs of N-H?N and N-H?S hydrogen bonds, forming R 2 (2)(8) ring motifs. Mol-ecules are further linked by slightly weaker N-H?N, N-H?S and C-H?S hydrogen bonds, forming two-dimensional networks which lie parallel to the bc plane. PMID- 23794987 TI - Bis{(Z)-[(E)-2-(pyridin-2-yl-methyl-idene)hydrazin-1-yl-idene][(pyridin-2 yl)methyl-sulfan-yl]methane-thiol-ato}nickel(II). AB - The title compound, [Ni(C13H11N4S2)2], was obtained by the reaction of S-2 picolyldi-thio-carbazate and pyridine-2-carbaldehyde with nickel(II) acetate. The Ni(II) atom is located on a twofold rotation axis and is bonded to four N atoms at distances of 2.037 (8) and 2.109 (9) A, and to two S atoms at a distance of 2.406 (3) A, leading to a distorted octa-hedral coordination. The angle between the mean planes of the coordinating moieties of the two symmetry-related tridentate ligands is 83.3 (2) degrees . In the crystal, complex mol-ecules are linked by weak C-H?S hydrogen bonds, pi-pi inter-actions between the pyridine rings [centroid-centroid distance = 3.775 (9) A] and C-H?pi inter-actions. The hydrogen-bonding inter-actions lead to the formation of layers parallel to (010); pi-pi inter-actions link these layers into a three-dimensional network. PMID- 23794988 TI - Bis(2,2',2''-nitrilo-triacetamide-kappa(3) O,N,O')cobalt(II) dinitrate tetra hydrate. AB - In the centrosymmetric title compound, [Co(C6H12N4O3)2](NO3)2.4H2O, the Co(II) ion, lying on an inversion center, is O,N,O'-chelated by two nitrilo-triacetamide mol-ecules, forming a distorted octa-hedral geometry. In the crystal, extensive O H?O and N-H?O hydrogen bonds link the complex cations, nitrate anions and lattice water mol-ecules into a three-dimensional network. PMID- 23794989 TI - catena-Poly[[manganese(III)-bis-{MU-2-[(2-hy-droxy-eth-yl)imino-meth-yl]-6-meth oxy-phenolato-kappa(3) O (1),N:O (2);kappa(3) O (2):N,O (1)}] iodide]. AB - In the title one-dimensional coordination polymer, {[Mn(C10H12NO3)2]I} n , the potentially tetra-dentate (O,O,O,N) 2-[(2-hy-droxy-eth-yl)imino-meth-yl]-6-meth oxy-phenol (H2 L) ligands are mono-deprotonated (as HL (-)) and coordinated by the metal ions in a tridentate chelate-bridging fashion [2.0111112]. The Mn(III) atom possesses a distorted trans-MnO4N2 octa-hedral coordination environment. The bridging ligands lead to [010]-chain polymeric cations {[Mn(HL)2](+)} n in the crystal. The charge-balancing iodide ions are disordered over two sites in a 0.690 (2):0.310 (2) ratio and a weak O-H?I hydrogen bond occurs. The crystal studied was found to be a racemic twin. PMID- 23794990 TI - Tetra-phenyl-phospho-nium [MU3-(4-methyl-phen-yl)tellurolato]tris-[tetra-carbonyl iron(0)]. AB - In the anion of the title compound, (C24H20P)[Fe3(C7H7Te)(CO)12], each Fe(0) atom is coordinated by four CO ligands and a Te atom, resulting in a trigonal bipyramidal coordination environment. The Te atom is coordinated by a 4-methyl phenyl group and the Fe(0) atoms in a distorted tetra-hedral geometry. The average Te-Fe bond length is 2.574 (4) A. PMID- 23794991 TI - cis-Tetra-kis(MU-N-phenyl-acetamidato)-kappa(4) N:O;kappa(4) O:N-bis-[(benzo nitrile-kappaN)rhodium(II)](Rh-Rh). AB - The complex molecule of the title compound, [Rh2{N(C6H5)COCH3}4(C6H5CN)2], exhibits crystallographically imposed centrosymmetry. The four acetamide ligands bridging the dirhodium core are arranged in a 2,2-cis manner, with two N atoms and two O atoms coordinating to the unique Rh(II) atom cis to one another. The Neq-Rh-Rh-Oeq torsion angles on the acetamide bridges vary between 1.62 (4) and 1.78 (4) degrees . The Rh-Rh bond length is 2.4319 (3) A. The axial nitrile ligand completes the distorted octahedral coordination sphere and shows a non linear coordination with an Rh-N-C bond angle of 167.14 (15) degrees , while the N-C bond length is 1.135 (3) A. PMID- 23794992 TI - Bis(1,4-diazo-niabi-cyclo-[2.2.2]octa-ne) di-MU-chlorido-bis-[tetra-chlorido-anti monate(III)] dihydrate. AB - The title salt, (C6H14N2)2[Sb2Cl10].2H2O, was obtained by slow evaporation of an acidic solution of 1,4-di-aza-bicyclo-[2.2.2]octane and SbCl3. The crystal structure consists of (C6H14N2)(2+) cations, [Sb2Cl10](4-) double octa-hedra and lattice water mol-ecules. All mol-ecular components are situated on special positions. The cation and the lattice water mol-ecule exhibit mirror symmetry, whereas the anion has site symmetry 2/m. The cations, anions and water mol-ecules are alternately arranged into columns along [010]. Individual columns are joined into layers extending along (001). Intra-layer N-H?O and inter-layer N-H?Cl hydrogen-bonding inter-actions lead to the formation of a three-dimensional network. PMID- 23794993 TI - trans-Dichloridobis{2-chloro-6-[(3-fluoro-benz-yl)amino]-9-isopropyl-9H-purine kappaN (7)}platinum(II). AB - In the title compound, trans-[PtCl2(C15H15ClFN5)2], the Pt(II) atom, located on an inversion centre, is coordinated by the purine N atoms of the 2-chloro-6-[(3 fluoro-benz-yl)amino]-9-isopropyl-9H-purine ligands and two Cl atoms in a slightly distorted trans-square-planar coordination geometry [N-Pt-Cl angles = 89.91 (5) and 90.09 (5) degrees ]. Weak intra-molecular N-H?Cl contacts occur. In the crystal, C-H?Cl and C-H?F contacts, as well as weak pi-pi stacking inter actions [centroid-centroid distances = 3.5000 (11) and 3.6495 (12) A] connect the mol-ecules into a three-dimensional architecture. PMID- 23794994 TI - Tris(ethyl-enedi-amine)-cobalt(II) dichloride. AB - The title compound, [Co(II)(C2H8N2)3]Cl2, was obtained unexpectedly as the product of an attempted solvothermal synthesis of cobalt selenide from the elements in the presence of NH4Cl in ethyl-enedi-amine solvent. The three chelate rings of the distorted octa-hedral [Co(C2H8N2)3](2+) complex cation adopt twisted conformations about their C-C bonds. The spread of cis-N-Co-N bond angles [80.17 (6)-98.10 (6) degrees ] in the title compound is considerably greater than the equivalent data for [Co(III)(C2H8N2)3]Cl3 [Takamizawa et al. (2008 ?). Angew. Chem. Int. Ed. 47, 1689-1692]. In the crystal, the components are linked by numerous N-H?Cl hydrogen bonds, generating a three-dimensional network in which the cationic complexes are stacked in columns along [010] and separated by columns of chloride anions. PMID- 23794995 TI - Bis(but-2-enoato-kappaO)tri-phenyl-bis-muth(V). AB - In the title mol-ecule, [Bi(C6H5)3(C4H5O2)2], the Bi(V) atom is in a distorted trigonal-bipyramidal environment with carboxyl-ate O atoms in axial positions and phenyl C atoms in the equatorial plane. The Bi-O bond lengths are 2.283 (3) and 2.309 (2) A, but as a result of additional long Bi?O inter-actions [2.787 (3) and 2.734 (3) A], one of the C-Bi-C angles is 148.62 (13) degrees . In the crystal, weak C-H?O hydrogen bonds connect pairs of mol-ecules into inversion dimers. These dimers are further connected by weak C-H?pi inter-actions into chains along [100] . PMID- 23794996 TI - (Cyclo-butane-1,1-di-carboxyl-ato-kappa(2) O,O')(1,10-phenanthroline-kappa(2) N,N')platinum(II) dihydrate. AB - The title compound, [Pt(C6H6O4)(C12H8N2)].2H2O, which crystallizes as two independent formula units, has the metal atom in a square-planar geometry defined by two O atoms of the chelating cyclo-butane-1,1-di-carboxyl-ate dianion and two N atoms of the chelating 1,10-phenanthroline mol-ecule (r.m.s. deviations of the PtO2N2 units = 0.026 and 0.026 A). Adjacent complex and water mol-ecules are connected through inter-molecular O-H?O hydrogen bonds and C-H?O, C?O [shortest C?O distance = 3.140 (5) A], pi-pi [shortest C?C distances = 3.234 (6) and 3.347 (6) A] and Pt?pi [shortest Pt?C distance = 3.358 (4) A] inter-actions into a three-dimensional network. PMID- 23794997 TI - (Adipato-kappa(2) O,O')di-aqua-[bis-(pyridin-2-yl-kappaN)amine]-cobalt(II) trihydrate. AB - In the monomeric title complex, [Co(C6H8O4)(C10H9N3)(H2O)2].3H2O, the distorted octa-hedral CoN2O4 coordination environment comprises two N-atom donors from the bidentate di-pyridyldi-amine ligand, two O-atom donors from one of the carboxyl ate groups of the bidentate chelating adipate ligand and two water mol-ecules. In addition, there are three solvent water mol-ecules which are involved in both intra- and inter-unit O-H?O hydrogen-bonding inter-actions, which together with an amine-water N-H?O hydrogen bond produce a three-dimensional framework. PMID- 23794998 TI - Di-MU-azido-di-azidodi-MU-oxalato-di-histamine-tetra-copper(II) 0.9-hydrate. AB - The title compound, [Cu4(C2O4)2(N3)4(C5H9N3)2].0.9H2O, contains a tetranuclear Cu(II)-based molecule composed of two oxalate-bridged Cu(II) dimers linked through end-on azide ions and related by an inversion center. The tetranuclear unit contains two crystallographically independent Cu(II) ions. One Cu(II) ion coordinates to two N atoms of a histamine mol-ecule, two O atoms of a bridging oxalate ligand, and an N atom of an end-on bridging azide ligand, leading to an elongated square-pyramidal coordination geometry in which the azide ion occupies the axial position. The other Cu(II) ion, which has a square-planar coordination geometry, is coordinated by two O atoms of a bridging oxalate ligand and two N atoms of two different azide ligands, one which is bridging. In the crystal, a two-dimensional network parallel to (010) is formed by N-H?N and N-H?O hydrogen bonds. A partially occupied solvent water mol-ecule refined to an occupancy of 0.447 (5). Two of the azide ligands were refined as disordered over two sets of sites with refined occupancies in the ratios 0.517 (8):0.483 (8) and 0.553 (5):0.447 (5). PMID- 23794999 TI - Bis[MU-1,3-bis-(di-phenyl-phosphan-yl)propane-kappa(2) P:P']digold(I) tetra chloridonickelate(II) diethyl ether monosolvate. AB - The title compound, [Au2(C27H26P2)2][NiCl4].C4H10O, consists of a digold(I) complex cation, an [NiCl4](2-) complex anion and a diethyl ether solvent mol ecule. Two 1,3-bis-(di-phenyl-phosphan-yl)propane (dppp) ligands bridge two Au(I) atoms, forming a metallacycle in which each of the Au(I) atoms is coordinated in a slightly distorted linear environment by two P atoms. In the complex anion, the Ni(II) atom is coordinated by four chloride ligands in a distorted tetra-hedral geometry. The complex cation and the complex anion form a cation-anion pair through two Au?Cl contacts of 3.040 (1) and 3.021 (2) A. One of the phenyl groups of the dppp ligand is disordered over two positions with equal occupancies. PMID- 23795000 TI - Tris(aceto-nitrile-kappaN)dichlorido(tri-phenyl-phosphane-kappaP)ruthenium(II) aceto-nitrile monosolvate. AB - In the title complex, [RuCl2(CH3CN)3(C18H15P)].CH3CN, the coordination geometry of the Ru(II) atom is distorted octa-hedral, defined by one P atom from a tri phenyl-phosphane ligand, three N atoms from three aceto-nitrile ligands and two Cl atoms. The three acetronitile ligands linearly bind to the Ru(II) atom, with Ru-N-C angles of 172.6 (2), 179.9 (2) and 171.4 (2) degrees . PMID- 23795001 TI - Tris(diisopropyl di-thio-phosphato-kappa(2) S,S')ruthenium(III). AB - In the title complex, [Ru(C6H14O2PS2)3], the coordination environment of the Ru(III) atom is distorted octa-hedral, defined by six S atoms from three S,S' bidentate diisopropyl di-thio-phosphate ligands. The average Ru-S bond length is 2.41 (1) A and the average S-Ru-S bite angle is 81.13 (19) degrees . PMID- 23795002 TI - catena-Poly[[(tri-phenyl-phosphane-kappaP)silver(I)]-MU-4,4'-bi-pyridine-kappa(2) N:N'-[(tri-phenyl-phosphane-kappaP)silver(I)]-di-MU-chlorido]. AB - In the title coordination polymer, [Ag2Cl2(C10H8N2)(C18H15P)2] n , the Ag(I) cation is coordinated by a 4,4'-bi-pyridine N atom, a tri-phenyl-phosphane P atom and two Cl(-) anions in a distorted tetra-hedral geometry. The 4,4-bi-pyridine and Cl(-) anions bridge the Ag(I) cations, forming polymeric chains running along [21-1]. In the crystal, weak C-H?Cl inter-actions link the polymeric chains into a three-dimensiona supra-molecular architecture. PMID- 23795003 TI - Aqua-carbon-yl(ferrocenyldi-thio-phos-phon-ato-kappa(2) S,S')bis-(tri-phenyl phosphane-kappaP)ruthenium(II) dichloromethane mono-solvate. AB - The structure of the title complex, [FeRu(C5H5)(C5H4OPS2)(CO)(C18H15P)2(H2O)].CH2Cl2, consists of one neutral [{FcP(O)S2}Ru(CO)(H2O)(PPh3)2] complex [Fc = Fe(eta(5)-C5H4)(eta(5)-C5H5)] and one CH2Cl2 solvent mol-ecule. The geometry around the Ru(II) atom is pseudo-octa hedral, with two cis-binding PPh3 ligands and one chelating bidentate [Fc(O)PS2](2-) ligand via two S atoms. The average Ru-S and Ru-P bond lengths are 2.434 (1) and 2.398 (1) A, and the Ru-O and Ru-C bond lengths are 2.157 (3) and 1.826 (4) A, respectively. In the crystal, pairs of O-H?O hydrogen bonds link adjacent mol-ecules into dimers. PMID- 23795004 TI - Tetra-ethyl-ammonium trichlorido(N,N'-di-methyl-formamide-kappaO)zinc. AB - The title complex salt, (C8H20N)[ZnCl3(C3H7NO)], contains one [Et4N](+) cation (Et is ethyl) and one [ZnCl3(DMF)](-) anion (DMF is di-methyl-formamide). In the anion, the zinc atom is tetra-hedrally coordinated by a DMF ligand via the O atom and by three terminal Cl atoms. The average Zn-Cl bond length and Cl-Zn-Cl angle are 2.243 (11) A and 114 (3) degrees , respectively. PMID- 23795005 TI - catena-Poly[[bis-(pyridine-kappaN)zinc]-MU-5-carb-oxy-benzene-1,3-di-carboxyl-ato kappa(2) O (1):O (3)]. AB - The title one-dimensional coordination polymer, [Zn(C9H4O6)(C5H5N)2] n or [Zn(HBTC)(py)2] n , (I), where BTC is benzene-1,3,5-tricarboxylate and py is pyridine, is a solvent-free polymorph of [Zn(HBTC)(py)2].2C2H5OH [Yaghi et al. (1997 ?). Chem. Mater. 9, 1074-1076]. Differences in the spatial arrangements and supra-molecular packing of the [Zn(HBTC)(py)2] n chains in the two structures are described. The chain in (I) extends parallel to [100] and is severely puckered, with a Zn?Zn distance of 8.3599 (3) A and a Zn?Zn?Zn angle of 107.516 (3) degrees , as a result of hydrogen-bonding inter-actions of the types O-H?O and C-H?O. There is no evidence for pi-pi inter-actions in (I). The differences between the solvent-free and solvent-containing structures can be accounted for by the absence of the ethanol solvent mol-ecule and the use of the converging pair of O atoms in the bis-monodentate bridging HBTC(2-) ligand in (I). PMID- 23795006 TI - {N,N-Bis[bis-(2,2,2-tri-fluoro-eth-oxy)phosphan-yl]methyl-amine-kappa(2) P,P'}bis (eta(5)-cyclo-penta-dien-yl)titanium(II). AB - The title compound, [Ti(C5H5)2(C9H11F12NO4P2)], is a four-membered titanacycle obtained from the reaction of Cp2Ti(eta(2)-Me3SiC2SiMe3) and CH3N[P(OCH2CF3)2]2 {N,N-bis-[bis-(tri-fluoro-eth-oxy)phosphan-yl]methyl-amine, tfepma}. The Ti(II) atom is coordinated by two cyclo-penta-dienyl (Cp) ligands and the chelating tfepma ligand in a strongly distorted tetra-hedral geometry. The mol-ecule is located on a mirror plane. PMID- 23795007 TI - Bis(2,2'-bipyridyl-kappa(2) N,N')(sulfato-kappa(2) O,O')nickel(II) 2.5-hydrate. AB - The title compound, [Ni(SO4)(C10H8N2)2].2.5H2O, is a nickel(II) complex with a distorted octa-hedral coordination geometry. The Ni(II) atom is bonded by two O atoms of the bidentate chelating sulfate ligand and the four N atoms of two chelating 2,2'-bi-pyridine ligands. The Ni-N bond lengths range from 2.059 (3) to 2.075 (3) A and the Ni-O bond lengths are 2.098 (3) and 2.123 (3) A. The bipyridyl ligands are both close to planar (r.m.s. deviations of 0.254 and 0.0572 A) and are almost orthogonal, making a dihedral angle of 82.77 (1) degrees . In the crystal, the complex and water mol-ecules are connected by O-H?O hydrogen bonds. Inter-estingly, six water mol-ecules form a chain linking two complex mol ecules via sulfate O atoms. There are also stacking inter-actions between the aromatic rings of neighbouring 2,2'-bi-pyridine ligands with shortest non covalent contacts of 3.268 (6), 3.393 (6) and 3.435 (5) A. One of the three unique water molecules shows half-occupation. PMID- 23795008 TI - Di-aqua-bis-(3-chloro-benzoato-kappaO)bis-(nicotinamide-kappaN (1))cobalt(II). AB - In the title complex, [Co(C7H4ClO2)2(C6H6N2O)2(H2O)2], the Co(II) atom is located on an inversion center and is coordinated by two 3-chloro-benzoate (CB) anions, two nicotinamide (NA) ligands and two water mol-ecules. The four O atoms in the equatorial plane form a slightly distorted square-planar arrangement, while the slightly distorted octa-hedral coordination is completed by the two N atoms of the NA ligands in the axial positions. The dihedral angle between the carboxyl ate group and the adjacent benzene ring is 9.14 (9) degrees , while the pyridine and benzene rings are oriented at a dihedral angle of 82.18 (8) degrees . In the crystal, N-H?O and O-H?O hydrogen bonds link the mol-ecules into a two dimensional network lying parallel to (101). pi-pi stacking between parallel pyridine rings of adjacent mol-ecules [centroid-centroid distance = 3.7765 (8) A] further stabilizes the crystal structure. PMID- 23795009 TI - Bis[MU-2,5-bis-(pyridin-2-yl)-1,3,4-thia-diazole-kappa(4) N (2),N (3):N (4),N (5)]bis-[(nitrato-kappaO)silver(I)] tetra-hydrate. AB - The self-assembly of an angular 2,5-bis-(pyridin-2-yl)-1,3,4-thia-diazole ligand (L) with silver nitrate (AgNO3) produced a new dinuclear silver(I) coordination complex, [Ag2(C12H8N4S)2(NO3)2].4H2O, which crystallizes with two Ag atoms bridged by two L ligands. The Ag atom is surrounded by four N atoms of L and by one O from the nitrate anion defining a distorted square pyramid. The atoms comprising the dication are nearly coplanar, with an r.m.s. deviation of 0.1997 A. Mol-ecules are linked by C-H?O and O-H?O hydrogen bonds through nitrate anions and water mol-ecules, forming a two-dimensional porous network. The overall structure involves stacking of Ag complex layers along the b axis. The cohesion in the three-dimensional architecture is ensured by O?Ag inter-actions. PMID- 23795010 TI - 1,3-Bis(2-methyl-prop-2-eno-yl)-1H-benz-imidazol-2(3H)-one. AB - The mol-ecules of the title compound, C15H14N2O3, possesses crystallographically imposed twofold rotational symmetry, so the asymmetric unit contains one half-mol ecule. The fused-ring system deviates significantly from planarity; the planes of the five- and six-membered rings are twisted with respect to each other by 3.0 (1) degrees . In the crystal, weak C-H?O hydrogen bonds link mol-ecules related by translation in [010] into chains. PMID- 23795011 TI - 2-Meth-oxy-4-(prop-2-en-1-yl)phenyl 4-meth-oxy-benzoate. AB - In the title compound, C18H18O4, the planes of the benzene rings are twisted by 81.60 (5) degrees . In the crystal, weak C-H?O hydrogen bonds link the mol-ecules into supra-molecular chains extending along the a axis. PMID- 23795012 TI - 2-(4-Fluoro-phen-yl)-5-iodo-7-methyl-3-phenyl-sulfinyl-1-benzo-furan. AB - In the title compound, C21H14FIO2S, the dihedral angles between the mean plane [r.m.s. deviation = 0.007 (1) A] of the benzo-furan fragment and the pendant 4 fluoro-phenyl and phenyl rings are 3.66 (7) and 82.37 (6) degrees , respectively. In the crystal, mol-ecules are linked by pairs of C-H?I hydrogen bonds into centrosymmetric dimers, which are further packed into stacks along the b axis by C-H?O hydrogen bonds. In addition, the stacked mol-ecules exhibit inversion related S?O contacts [2.9627 (14) A] involving the sulfinyl groups. PMID- 23795013 TI - 3-(2-Fluoro-phenyl-sulfin-yl)-2,5,7-tri-methyl-1-benzo-furan. AB - In the title compound, C17H15FO2S, the benzo-furan ring system, being essentially planar, with an r.m.s. deviation from the least-squares plane of 0.009 (2) A, makes a dihedral angle of 79.02 (5) degrees with the plane of the 2-fluoro phenyl group. In the crystal, mol-ecules are linked by pairs of weak C-H?O hydrogen bonds into centrosymmetric dimers. PMID- 23795014 TI - Ethyl 1''-benzyl-1'-methyl-2''-oxodi-spiro-[indeno-[1,2-b]quinoxaline-11,3' pyrrolidine-2',3''-indoline]-4'-carboxyl-ate. AB - In the title compound, C36H30N4O3, the quinoxaline-indene system is roughly planar, with a maximum deviation from the mean plane of 0.218 A for the C atom shared with the central pyrrolidine ring. This latter ring forms dihedral angles of 84.54 (7) and 83.91 (8) degrees with the quinoxaline-indene system and the indole ring, respectively. The central pyrrolidine ring has an envelope conformation with the N atom as the flap, while the pyrrolidine and five-membered rings of the indole group adopt twisted conformation and envelope (with the C atom bearing the quinoxaline-indene system as the flap) conformations, respectively. In the crystal, mol-ecules are linked via weak C-H?N hydrogen bonds, forming a chain running along [100]. PMID- 23795015 TI - Methyl (3S,10b'S)-5-chloro-9'-fluoro-1-methyl-2-oxo-5'-phenyl-10b'H-spiro [indoline-3,1'-pyrazolo-[3,2-a]iso-quinoline]-2'-carboxyl-ate. AB - In the title compound, C27H19ClFN3O3, the pyrazole ring has a twist conformation and the six-membered ring to which it is fused has a screw-boat conformation. The mean plane of the pyrazole ring is inclined to the 2-methyl-indoline ring by 85.03 (9) and by 28.17 (8) degrees to the mean plane of the iso-quinoline ring system. In the crystal, mol-ecules are linked by pairs of C-H?F hydrogen bonds, forming inversion dimers. These dimers are linked via C-H?O hydrogen bonds, forming a two-dimensional network lying parallel to (10-1). PMID- 23795016 TI - Methyl 5''-chloro-1',1''-dimethyl-2,2''-dioxodi-spiro-[indoline-3,2'-pyrrolidine 3',3''-indoline]-4'-carboxyl-ate. AB - In the title compound, C22H20ClN3O4, the central pyrrolidine ring adopts an envelope conformation on the N atom. The indolinone systems are individually roughly planar, with maximum deviations from their mean planes of 0.130 A for the spiro C atom of the indolinone unit and 0.172 A for the carbonyl C atom of the 5 chloro-1-methyl-indolinone unit. They make dihedral angles of 77.7 (8) and 86.1 (8) degrees with the mean plane through the central pyrrolidine ring. In the crystal, mol-ecules are linked by N-H?O hydrogen bonds supported by C-H?O contacts into chains along the ab diagonal. The structure also features C-H?O hydrogen bonds, forming R 2 (2)(8) and R 2 (2)(16) rings and generating a three dimensional array. PMID- 23795017 TI - 3-Nitro-phenol-1,3,5-triazine-2,4,6-tri-amine (2/1). AB - The asymmetric unit of the title compound, C3H6N6.2C6H5NO3, contains one melamine and two 3-nitro-phenol mol-ecules. The mean planes of the 3-nitro-phenol mol ecules are almost orthogonal to the plane of melamine, making dihedral angles of 82.77 (4) and 88.36 (5) degrees . In the crystal, mol-ecules are linked via O H?N, N-H?N and N-H?O hydrogen bonds, forming a three-dimensional network. The crystal also features weak C-H?pi and pi-pi inter-actions [centroid-centroid distance = 3.9823 (9) A]. PMID- 23795018 TI - 9-[3-(Carbazol-9-yl)-5-methyl-phen-yl]carbazole. AB - The title compound, C31H22N2, crystallizes with two symmetry-independent mol ecules in the asymmetric unit. The mol-ecules have slightly different conformations, the dihedral angles between the central phenyl ring and the carbazolyl groups being 56.29 (4) and 59.57 (4) degrees in one mol-ecule and 48.71 (4) and 65.47 (4) degrees in the other. In the crystal, mol-ecules are linked by weak C-H?pi and pi-pi [centroid-centroid distances = 3.7698 (10), 3.8292 (9), 3.9429 (10) and 3.9431 (10) A]. PMID- 23795019 TI - N-(2-Bromo-4-methyl-phen-yl)-2-(5-methyl-2-phenyl-pyrazolo-[1,5-a]pyrimidin-7 yl)acetamide. AB - The fused pyrazole and pyrimidine rings in the title compound, C22H19BrN4O, are almost coplanar, their planes being inclined to one another by 2.08 (13) degrees . The dihedral angles formed by the mean plane of the fused ring system and the phenyl and benzene rings are 16.21 (4) and 82.84 (4) degrees , respectively. An intra-molecular N-H?N hydrogen bond is observed. In the crystal, mol-ecules form inversion dimers via pairs of C-H?O hydrogen bonds. pi-pi inter-actions, with centroid-centroid distances of 3.4916 (9) A, connect the dimers into a three dimensional network. PMID- 23795020 TI - (1S,3R,8R)-2,2-Di-chloro-3,7,7,10-tetra-methyl-tri-cyclo-[6.4.0.0(1,3)]dodec-9-en 11-one. AB - The title compound, C16H22Cl2O, was synthesized from beta-himachalene (3,5,5,9 tetra-methyl-2,4a,5,6,7,8-hexa-hydro-1H-benzo-cyclo-heptene), which was isolated from the essential oil of the Atlas cedar (Cedrus Atlantica). The mol-ecule is built up from fused six- and seven-membered rings and an additional three membered ring arising from the reaction of himachalene with di-chloro-carbene. The six-membered ring has an envelope conformation, with the C atom belonging to the three-membered ring forming the flap, whereas the seven-membered ring displays a screw-boat conformation; the dihedral angle between the rings (all atoms) is 59.65 (14) degrees . PMID- 23795021 TI - 10-Methyl-2-oxo-4-phenyl-2,11-di-hydro-pyrano[2,3-a]carbazole-3-carbo-nitrile. AB - In the title mol-ecule, C23H14N2O2, the atoms in the carbazole unit deviate from planarity [maximum deviation from mean plane = 0.1018 (8) A]. The pyrrole ring makes dihedral angles of 4.44 (5), 3.84 (5), 2.18 (5) and 56.44 (5) degrees with the pyran, fused benzene rings and phenyl ring, respectively. In the crystal, pairs of N-H?O hydrogen bonds generate R 2 (2)(14) loops and a C-H?N inter-action is also found. Mol-ecules are further linked by a number of pi-pi interactions [centroid-centroid distances vary from 3.5702 (5) to 3.7068 (6) A], forming a three-dimensional network. PMID- 23795022 TI - 2-Chloro-6-(2,3-di-chloro-benzene-sulfonamido)-benzoic acid. AB - In the title compound, C13H8Cl3NO4S, the aromatic rings are oriented at a dihedral angle of 68.94 (1) degrees and the mol-ecule adopts a V-shape. An intra molecular N-H?O inter-action generates a six-membered S(6) ring motif. In the crystal, pairs of O-H?O hydrogen bonds involving the carb-oxy group link the mol ecules into inversion dimers with an R 2 (2)(8) motif. N-H?O and non-classical C H?O inter-actions connect the mol-ecules, forming sheets propagating in (100). PMID- 23795023 TI - 15-Meth-oxy-14,15-di-hydro-andranginine. AB - The title polycyclic alkaloid, C22H26N2O3, an indole derivative obtained from Melodinus yunnanensis, comprises three chiral C atoms and crystallizes as a racemate. Its seven-membered heterocyclic ring has a twisted conformation, with the N atom within the plane of the indole moiety and with two adjacent C atoms deviating in opposite directions from its plane by 0.756 (3) (methyl-ene C) and 0.802 (3) A (methine C). In the crystal, pairs of N-H?O hydrogen bonds connect the mol-ecules into centrosymmetric dimers. PMID- 23795024 TI - 2-Bromo-1,6,6-trimethyl-6,7,8,9-tetra-hydro-phenanthro[1,2-b]furan-10,11-dione. AB - In the title compound, C19H17BrO3, the ring skeleton is located on a crystallographic mirror plane; two C atoms of the cyclo-hexene ring are disordered over the two locations to satisfy the preferred ring conformation. In the crystal, C-H?O hydrogen bonds link the mol-ecules into chains along the a axis. pi-pi stacking inter-actions between benzo-quinone rings, with a centroid centroid distance of 3.7225 (4) A, are also observed, which connect the chains into a two-dimensional networkparallel to the ab plane. PMID- 23795025 TI - 4-Hy-droxy-1,2,6-tri-methyl-pyridinium chloride monohydrate. AB - In the crystal of the title hydrated mol-ecular salt, C8H12NO(+).Cl(-).H2O, the water mol-ecule makes two O-H?Cl hydrogen bonds, generating [010] zigzag chains of alternating water mol-ecules and chloride ions. The cation is bonded to the chain by an O-H?O hydrogen bond and two weak C-H?Cl inter-actions. Weak aromatic pi-pi stacking [centroid-centroid separation = 3.5175 (15) A] occurs between the chains. PMID- 23795026 TI - Methyl 2-(2-methyl-4-nitro-1H-imidazol-1-yl)acetate. AB - In the crystal of the title compound, C7H9N3O4, mol-ecules are linked by weak C H?O hydrogen bonds into chains along the a-axis direction. The dihedral angle between the ring and the nitro group is 3.03 (6), while that between the ring and the acetate group is 85.01 (3) degrees . PMID- 23795027 TI - 1-Methyl-3-(2-oxo-2H-chromen-3-yl)-1H-imidazol-3-ium picrate. AB - The title salt, C13H11N2O2 (+).C6H2N3O7 (-), is the unexpected product of a domino reaction of 3-cyano-methyl-1-methyl-imidazolium chloride with salicylic aldehyde in the presence of picric acid. In the cation, the 1H-imidazole ring is twisted by 63.2 (1) degrees from the 2H-chromen plane. In the crystal, cations and anions are alternately stacked along the a axis through pi-pi stacking inter actions between the almost parallel aromatic rings [centroid-centroid distances = 3.458 (2) and 3.678 (2) A]. The stacks are further linked by C-H?O hydrogen bonds into a two-tier layer parallel to (001). PMID- 23795028 TI - 1-[3-(2-Benz-yloxy-6-hy-droxy-4-methyl-phen-yl)-5-[3,5-bis-(tri-fluoro-meth yl)phen-yl]-4,5-di-hydro-1H-pyrazol-1-yl]propane-1-one. AB - In the title compound, C28H24F6N2O3, the mean plane of the central pyrazoline ring forms dihedral angles of 2.08 (9) and 69.02 (16) degrees with the 2-benz yloxy-6-hy-droxy-4-methyl-phenyl and 3,5-bis-(tri-fluoro-meth-yl)phenyl rings, respectively. The dihedral angle between the mean planes of the pyrazoline and 3,5-bis-(tri-fluoro-meth-yl)phenyl rings is 68.97 (9) degrees . An intra molecular O-H?N hydrogen bond is observed, which forms an S(6) graph-set motif. In the crystal, pairs of weak C-H?F halogen inter-actions link the mol-ecules into inversion dimers while molecular chains along [100] are formed by C-H?O contacts. PMID- 23795029 TI - 2-Amino-5-nitro-pyridinium tri-fluoro-acetate. AB - The title salt, C5H6N3O2 (+).C2F3O2 (-), crystallizes with two cations and two anions in the asymmetric unit. In the crystal, the acetate and pyridine groups are linked by a pair of N-H?O hydrogen bonds, forming loops described by the graph-set motif R 2 (2)(8). These loops are linked via N-H?O hydrogen bonds, forming chains along [001]. The chains are in turn linked by C-H?O and C-H?F hydrogen bonds, generating a three-dimensional supra-molecular network. In both anions, the O and F atoms are disordered over two sites, with occupancy ratios of 0.852 (3):0.148 (3) and 0.851 (3):0.149 (3). PMID- 23795030 TI - 3-(Ammonio-methyl)-pyridinium bis-(perchlorate). AB - In the title molecular salt, C6H10N2 (2+).2ClO4 (-), the Cl-O bond lengths [anion 1: 1.369 (3)-1.415 (3); anion 2: 1.420 (2)-1.441 (2) A] and the O-Cl-O angles [anion 1: 105.4 (2)-111.8 (4); anion 2: 107.8 (1)-110.3 (1) degrees ] indicate a slight distortion of the perchlorate anions from regular tetra-hedral symmetry. In the crystal, the components are linked into columns along the a-axis direction via N-H?O and C-H?O hydrogen bonds, with stacks of the organic mol-ecules being surrounded by stacks of perchlorate anions. PMID- 23795031 TI - 3-Amino-5,6-dimethyl-1,2,4-triazin-2-ium nitrate. AB - In the title compound, C5H9N4 (+).NO3 (-), the organic cations and the nitrate anions have both crystallographically imposed mirror symmetry and are linked via N-H?O hydrogen bonds, forming infinite chains running along the c-axis direction. The values of the N-O bond lengths [1.2256 (19)-1.2642 (18) A] and O-N-O angles [118.39 (16)-121.64 (15) degrees ] indicate that the nitrate anion exhibits a slightly distorted C3h geometry. The N atom of the NH2 group has sp (2) character. PMID- 23795032 TI - 3,5-Dimethyl-1-{2-[(5-methyl-1,3,4-thia-diazol-2-yl)sulfan-yl]acet-yl}-2,6 diphenylpiperidin-4-one. AB - In the title compound, C24H25N3O2S2, the piperidine ring adopts a distorted boat conformation. The phenyl rings subtend angles of 75.6 (1) degrees and 86.3 (1) degrees with the mean plane of the piperidine ring. In the crystal, mol-ecules are linked through a network C-H?N hydrogen bonds, forming zigzag chains along [100]. The thia-diazol ring methyl group is disordered over two positions with an occupancy ratio of 0.69 (4):0.31 (4). PMID- 23795033 TI - 2-(2,6-Di-chloro-phen-yl)-1-pentyl-4,5-diphenyl-1H-imidazole. AB - The title compound, C26H24Cl2N2, crystallizes with two independent mol-ecules (1 and 2) in the asymmetric unit. In mol-ecule 1, the two phenyl and 2,6-di-chloro phenyl rings are inclined to the imidazole ring at angles of 74.12 (14), 26.13 (14) and 67.30 (14) degrees , respectively. In mol-ecule 2, due to the different mol-ecular environment in the crystal, the corresponding angles are different, viz. 71.72 (15), 16.14 (15) and 80.41 (15) degrees , respectively. In the crystal, mol-ecules 1 and 2 are linked by C-H?Cl inter-actions, and inversion related 2 mol-ecules are linked by C-H?pi inter-actions. There are no other significant inter-molecular inter-actions present. PMID- 23795034 TI - Ethyl 3-bromo-4-cyano-5-[(2-eth-oxy-2-oxoeth-yl)sulfan-yl]thio-phene-2-carboxyl ate. AB - The title compound, C12H12BrNO4S2, was obtained by the Sandmeyer reaction from ethyl 3-amino-4-cyano-5-[(2-eth-oxy-2-oxoeth-yl)sulfan-yl]thio-phene-2-carboxyl ate. The dihedral angle between the thiophene ring and linked CO2 ester group is 2.0 (5) degrees . PMID- 23795035 TI - (E)-9-(But-2-en-1-yl)-6-chloro-9H-purine. AB - The asymmetric unit of the title compound, C9H9ClN4, contains two mol-ecules. In the crystal, the mol-ecules are ordered in a chain-like fashion along the a axis, and form layers offset relative to the C plane by approximately 30 degrees . This ordering does not, however, appear to be directed by classical hydrogen bonding.The allylic side chains of both independent mol-ecules are disordered, with occupancies of 0.870 (4) and 0.934 (3) for the major components. The disorder components represent two possible spatial orientations of the atoms around the C=C double bond. PMID- 23795036 TI - 1-{(E)-[(2-Fluoro-5-nitro-phen-yl)imino]-meth-yl}naphthalen-2-ol. AB - The title mol-ecule, C17H11FN2O3, is nearly planar [maximum deviation = 0.197 (1) A] and the mol-ecular conformation is stabilized by an N-H?O hydrogen bond forming an S(6) ring motif. The H atom of the intra-molecular hydrogen bond was found to be disordered over two sites and thus both the hy-droxy and keto tautomers are simultaneously present in the solid. Refinement of the occupancy of this site suggests that the hy-droxy form is the major component [occupancy refined to 0.59 (3):0.41 (3)]. Bond lengths are also largely consistent with dominance of the hy-droxy form. In the crystal, mol-ecules are linked by C-H?O hydrogen bonds, forming layers parallel to (101). pi-pi stacking inter-actions [centroid-centroid distances = 3.5649 (9) and 3.7579 (9) A] inter-connect these layers. PMID- 23795037 TI - Methyl (2Z)-2-bromo-meth-yl-3-(3-chloro-phen-yl)prop-2-enoate. AB - There are two independent mol-ecules (A and B) in the asymmetric unit of the title compound C11H10BrClO2, which represents the Z isomer. The methyl-acrylate moieties are essentially planar, within 0.084 (2) and 0.027 (5) A in mol-ecules A and B, respectively. The benzene ring makes dihedral angles of 13.17 (7) and 27.89 (9) degrees with the methyl-acrylate moiety in mol-ecules A and B, respectively. The methyl-bromide moiety is almost orthogonal to the benzene ring, making dihedral angles of 81.46 (16) degrees in mol-ecule A and 79.61 (16) degrees in mol-ecule B. The methyl-acrylate moiety exhibits an extended trans conformation in both mol-ecules. In the crystal, pairs of C-H?O hydrogen bonds result in the formation of quasi-centrosymmetric R 2 (2)(14) AB dimers. PMID- 23795038 TI - 5-Methyl-N-(1,3-thia-zol-2-yl)isoxazole-4-carboxamide. AB - In the title compound, C8H7N3O2S, the dihedral angle between the thia-zol and isoxazole rings is 34.08 (13) degrees . In the crystal, the mol-ecules are linked by pairs of N-H?N hydrogen bonds, forming inversion dimers, and C-H?O inter actions, resulting in chains along the b-axis direction. PMID- 23795039 TI - Ethyl 1''-benzyl-2''-oxo-2',3',5',6',7',7a'-hexa-hydro-1'H-di-spiro-[indeno-[1,2 b]quinoxaline-11,2'-pyrrolizine-3',3''-indoline]-1'-carboxyl-ate monohydrate. AB - In the title compound, C38H32N4O3.H2O, the quinoxaline-indene and pyrrolizine systems are essentially planar, with maximum deviations from their mean planes of 0.162 and 0.563 A, respectively. The pyrrolizine ring forms dihedral angles of 88.53 (5) and 89.95 (8) degrees with the quinoxaline-indene system and the indoline ring, respectively. The central pyrrolidine ring has an envelope conformation with the C atom bearing the quinoxaline-indene system as the flap. The pyrrolidine ring of the indole system adopts an envelope conformation with the C atom bonded to the pyrrolizine ring N atom as the flap. The five-membered ring attached to the central pyrolidine ring adopts a twisted conformation. In the crystal, O-H?N and O-H?O hydrogen bonds between water mol-ecules and pyrrolizine N and carbonyl O atoms together with C-H?O inter-actions result in chains along [100]. PMID- 23795040 TI - Methyl 2-(5-chloro-1-methyl-2-oxo-2,3-di-hydro-1H-indol-3-ylidene)acetate. AB - The title compound, C12H10ClNO3, the indoline ring system is essentially planar, with a maximum deviation of 0.009 A for the N atom. The indoline ring and acetate group are essentially coplanar, with a maximum deviation of 0.086 A for the O atom. The mean plane through the methoxy-carbonyl-methyl group forms a dihedral angle of 3.68 (5) degrees with the plane of the indoline ring system. The mol ecular structure is stabilized by an intra-molecular C-H?O hydrogen-bond inter action. In the crystal, pi-pi stacking inter-actions [centroid-centroid distance = 3.7677 (8) A] occur between benzene rings, forming a chain running along the c axis direction. PMID- 23795041 TI - 6'-(1,3-Diphenyl-1H-pyrazol-4-yl)-7'-(1H-indol-3-ylcarbon-yl)-2-oxo-1-(prop-2-en 1-yl)-5',6',7',7a'-tetra-hydro-1'H-spiro-[indoline-3,5'-pyrrolo-[1,2-c][1,3]thia zole]-7'-carbo-nitrile. AB - In the title compound, C41H32N6O2S, the pyrrolo-thia-zole ring system is folded about the bridging N-C bond. The thia-zolidine and pyrrolidine rings adopt envelope (with the fused C atom as the flap) and twisted conformations, respectively. The two phenyl rings attached to the pyrazole ring are twisted from the plane of the latter by 6.8 (1) and 52.8 (1) degrees . The allyl group is disordered over two conformations in a 0.805 (6):0.195 (6) ratio. In the crystal, pairs of N-H?O hydrogen bonds link the mol-ecules into centrosymmetric dimers. PMID- 23795042 TI - (2E)-1-(5-Bromothiophen-2-yl)-3-(4-chloro-phen-yl)prop-2-en-1-one. AB - In the title compound, C13H8BrClOS, the thio-phene and phenyl rings are inclined by 40.69 (11) degrees to each other. The crystal structure is characterized by C H?pi inter-actions, which link the mol-ecules into broad layers parallel to (100). Short Br?Cl contacts [3.698 (1) A] link these layers along [100]. PMID- 23795043 TI - Ammonium 2-(3,4-di-methyl-benzo-yl)benzoate dihydrate. AB - In the anion of the title compound, NH4 (+).C16H13O3 (-).2H2O, the benzene rings are twisted with respect to each other by 73.56 (10) degrees . In the crystal, extensive N-H?O and O-H?O hydrogen bonds link the cations, anions and lattice water mol-ecules into a three dimensional supra-molecular structure. PMID- 23795044 TI - 4',4',6',6'-Tetra-chloro-2-(6-methyl-pyridin-2-yl)-1H,2H-spiro-[naphtho-[1,2 e][1,3,2]oxaza-phosphinine-3,2'-[1,3,5,2,4,6]tri-aza-triphosphinine]. AB - The title compound, C17H14Cl4N5OP3, is a spiro-phosphazene derivative with bulky naphthalene and pyridine rings. The phosphazene and the six-membered N/O rings are in flattened-boat and twisted-boat conformations, respectively. The naphthalene ring system and the pyridine ring are oriented at a dihedral angle of 18.06 (8) degrees . In the crystal, weak pi-pi stacking between the pyridine rings and between the pyridine rings and the naphthalene ring system [centroid centroid distances = 3.594 (2) and 3.961 (2) A, respectively] occur. Weak C-H?pi inter-actions are also observed. These interactions link the molecules into a three-dimensional supramolecular network. PMID- 23795045 TI - N,N-Diethyl-2-hy-droxy-ethanaminium 5-(2,4-di-nitro-phen-yl)barbiturate sesquihydrate. AB - In the title hydrated mol-ecular salt, C6H16NO(+).C10H5N4O7 (-).1.5H2O [systematic name: N,N-diethyl-2-hy-droxy-ethan-am-in-ium 5-(2,4-di-nitro-phen-yl) 2,6-di-oxo-1,2,3,6-tetra-hydro-pyrim-idin-4-olate sesquihydrate], the dihedral angle between the six-membered rings in the anion is 37.66 (11) degrees . The nitro groups ortho and para to the ring junction are rotated from their attached ring by 40.8 (3) and 23.5 (3) degrees , respectively. The ethanol group is disordered over two of the 'arms' of the cation in a statistical ratio. In the crystal, [010] chains of anions occur, linked by N-H?O and O-H?O hydrogen bonds, which generate R 2 (2)(8) loops. Further N-H?O and O-H?O hydrogen bonds link the components into a three-dimensional network. One of the water O atoms lies near an inversion centre and is 50% occupied. PMID- 23795046 TI - Tetra-phenyl-phospho-nium iodide-1,3,5-tri-fluoro-2,4,6-tri-iodo-benzene-methanol (3/4/1). AB - The crystallization of a 1:1 molar solution of 1,3,5-tri-fluoro-2,4,6-di-iodo benzene (TFTIB) and tetra-phenyl-phosponium iodide (TPPI) from methanol produced tetra-gonal needles of pure TPPI and tabular pseudo-hexa-gonal truncated bipyramids of the title compound, 3C24H20P(+).3I(-).4C6F3I3.CH4O or (TPPI)3(TFTIB)4.MeOH. The asymmetric unit is composed of six TPPI mol-ecules, eight TFTIB mol-ecules and two methanol mol-ecules, overall 16 constituents. The formation of the architecture is essentially guided by a number of C-I?I(-) halogen bonds (XB), whose lengths are in the range 3.276 (1)-3.625 (1) A. Layers of supra-molecular polyanions are formed parallel to (10-1) wherein iodide anions function as penta-, tetra- or bidentate XB acceptors. The structure is not far from being P21/n, but the centrosymmetry is lost due to a different conformation of a single couple of cations and the small asymmetry in the formed supra molecular anion. One methanol mol-ecule is hydrogen bonded to an iodide anion, while the second is linked to the first one via an O-H?O contact. This second methanol mol-ecule is more loosely pinned in its position than the first and presents very high anisotropic displacement parameters and a seeming shortening of the C-O bond length. The crystal studied was refined as a perfect inversion twin. PMID- 23795047 TI - 1-(4-Hy-droxy-phen-yl)-2-(2-oxidonaphthalen-1-yl)diazen-1-ium methanol hemisolvate. AB - In the title compound, C16H12N2O2.0.5CH3OH, the H atom of the -OH group has been transfered to the N atom in the azo group, forming a zwitterion. Hence, there is an intra-molecular N-H?O, rather than an O-H?N, hydrogen bond in the mol-ecule. The mol-ecule is almost planar, the dihedral angle between the benzene ring and the mean plane of the naphthalene ring system being 4.51 (6) degrees . In the crystal, mol-ecules are linked to and bridged by O-H?O hydrogen bonds involving the methanol mol-ecule, which is located about a twofold rotation axis, and hence half-occupied, forming zigzag chains along [001]. Mol-ecules are also linked via C-H?pi and pi-pi inter-actions, the latter involving adjacent benzene and naphthalene rings and having a centroid-centroid distance of 3.6616 (13) A, forming a three-dimensional network. PMID- 23795048 TI - 2-(Pyridin-4-yl)-1H-benzimidazole. AB - The title compound, C12H9N3, is an unhydrated analogue of the previously reported trihydrate. The mol-ecule is essentially planar, with a 3.62 (11) degrees angle between the pyridine and benzimidazole planes. In the crystal, N-H?N hydrogen bonds result in chains of mol-ecules parallel to [010], which are additionally linked by weak pi-pi stacking inter-actions [centroid-centroid distance = 3.7469 (17) A], resulting in extended sheets of molecules parallel to (103). PMID- 23795049 TI - Bis(2,3-dimeth-oxy-10-oxostrychni-din-ium) phthalate nonahydrate. AB - The asymmetric unit of the title compound 2C23H27N2O4 (+).C8H4O4 (2-).9H2O, contains a cation, an anionon a twofold axis and four and half mol-ecules of water, one of which is located on the twofold axis. In the cation, both fused pyrrolidine rings exhibit twisted conformations, while the piperidine rings adopt screw-boat and boat conformations. In the crystal, the components are linked by N H?O and O-H?O hydrogen bonds. The brucinium cations form typical undulating head to-tail ribbon structuresalong the a-axis direction, which associate with the carb-oxy phthalate and the water mol-ecules. PMID- 23795050 TI - 6-[(2,4-Di-methyl-anilino)methyl-idene]-2-hy-droxy-cyclo-hexa-2,4-dienone. AB - In the title compound, C15H15NO2, the dihedral angle between the aromatic rings is 5.86 (6) degrees , and an intra-molecular N-H?O hydrogen bond generates an S(6) motif, which helps to stabilize the enamine-keto tautomer. An intra molecular O-H?O hydrogen bond also occurs. In the crystal, inversion dimers linked by pairs of O-H?O hydrogen bonds generate R 2 (2)(10) loops. A C-H?O inter action links the dimers into [010] chains and aromatic pi-pi stacking [centroid centroid separation = 3.6131 (9) A] also occurs. PMID- 23795051 TI - Alternariol 9-O-methyl ether dimethyl sulfoxide monosolvate. AB - THE TITLE COMPOUND (SYSTEMATIC NAME: 3,7-dihy-droxy-9-meth-oxy-1-methyl-6H benzo[c]chromen-6-one dimethyl sulfoxide monosolvate), C15H12O5.C2H6OS, was isolated from an unidentified endophytic fungus (belonging to class Ascomycetes) of Taxus sp. In the crystal, both the alternariol 9-O-methyl ether (AME) and the dimethyl sulfoxide (DMSO) mol-ecules exhibit crystallographic mirror symmetry. One of the hy-droxy groups makes bifurcated hydrogen bonds, viz. an intra molecular bond with the carbonyl group and an inter-molecular bond with the carbonyl group in an inversion-related AME mol-ecule. In the crystal, the AME mol ecules are organized into stacks parallel with the b axis by pi-pi inter-actions between centrosymmetrically related mol-ecules [the distance between the centroid of the central ring and the centroid of the meth-oxy-substituted benzene ring in the next mol-ecule of the stack is 3.6184 (5) A]. Pairs of DMSO mol-ecules, linked via centrosymmetric C-H?O contacts, are inserted into the voids created by the AME mol-ecules, making O-H?O and C-H?O contacts with the hosts. PMID- 23795052 TI - 2-Chloro-1-(2,4,4-trimethyl-2,3,4,5-tetra-hydro-1H-1,5-benzodiazepin-1 yl)ethanone. AB - In the title compound, C14H19ClN2O, the diazepine ring adopts a boat conformation. The Cl atom of the chloro-acetyl group is trans to the N atom of the diazepine ring. In the crystal, the mol-ecules form chains running along the diagonal of the ac plane through N-H?O hydrogen bonds. PMID- 23795053 TI - 2-(4-Chloro-phen-yl)-4,5-diphenyl-1-(prop-2-en-1-yl)-1H-imidazole. AB - The title compound, C24H19ClN2, crystallizes with two independent mol-ecules in the asymmetric unit. The prop-2-enyl substituents on the imidazole rings adopt similar conformations in the two mol-ecules. The 4-and 5-substituted phenyl rings and the benzene ring make dihedral angles of 67.06 (8), 5.61 (8) and 41.09 (8) degrees , respectively, with the imadazole ring in one mol-ecule and 71.53 (8), 28.85 (8) and 41.87 (8) degrees , respectively, in the other. The crystal structure features C-H?pi inter-actions and weak pi-pi stacking inter-actions [centroid-centroid distances = 3.6937 (10) and 4.0232 (10) A] between the chloro phenyl rings, which form a three-dimensional supramolecular structure. PMID- 23795054 TI - 6,8-Di-bromo-3-nitro-2-phenyl-2H-chromene. AB - In the title compound, C15H9Br2NO3, the chromene unit is not quite planar (r.m.s. deviation from planarity = 0.0888 A). The di-hydro-pyran ring adopts an envelope conformation with the phenyl-substituted C atom fused to the di-hydro-pyran ring as the flap. The dihedral angle between the plane defined by this C atom and the adjacent C and O atoms and the mean plane of the di-hydro-pyran ring excluding the phenyl-substituted C atom is 25.1 (3) degrees . The dihedral angle between the mean plane of the chromene unit and the phenyl ring is 85.7 (1) degrees . The crystal structure features C-H?O hydrogen bonds and Br?O contacts [3.289 (3) A] involving the nitro O atoms. PMID- 23795055 TI - Ethyl 2,5-di-tert-butyl-5-eth-oxy-4-oxo-4,5-di-hydro-1H-pyrrole-3-carboxyl-ate. AB - The title compound, C17H29NO4, contains a chiral center and crystallizes as a racemate. The asymmetric unit consists of two non-equivalent mol-ecules, in which the carbeth-oxy groups have markedly different orientations [C(=O)CC(OEt)=O torsion angles = 59.3 (2) and 156.0 (2) degrees ]. In the crystal, mol-ecules form chains along [101] through N-H?O hydrogen bonds. PMID- 23795056 TI - 3beta,6beta-Diacet-oxy-5,9alpha-dihy-droxy-5alpha-cholest-7-en-11-one acetic acid 0.04-solvate. AB - The title compound, C31H48O7.0.04CH3COOH, is a polyoxy-genated steroid obtained by selective chemical oxidation of 7-de-hydro-cholesteryl acetate. The asymmetric unit comprises three mol-ecules of the steroid (Z' = 3) and a mol-ecule of acetic acid which has occupancy factor 0.131 (5). The geometric parameters of the independent mol-ecules do not reveal significant differences. In one mol-ecule, the terminal isopropyl group is disordered over two sets of sites with occupancy ratio 0.869 (5):0.131 (5). The three mol-ecules reveal different hydrogen-bonding patterns. Each of them is involved in an intra-molecular S(6) hydrogen-bonding motif, involving hy-droxy groups as donor and acceptor. In the crystal, two independent mol-ecules form dimers through hydrogen bonding between an OH donor and an acetate carbonyl acceptor, giving rise to R 2 (2)(16) ring patterns. A single hydrogen bond between the OH group and a ketone carbonyl group is observed between two symmetry-independent mol-ecules. PMID- 23795057 TI - N'-[(E)-2-Hy-droxy-5-meth-oxy-benzyl-idene]pyridine-4-carbohydrazide monohydrate. AB - The title compound, C14H13N3O3.H2O, adopts an E conformation with respect to the azomethine bond and crystallizes in the amide form. An intra-molecular O-H?N hydrogen bond occurs. In the crystal, the lattice water molecule plays a major role in the supramolecular architecture by interconnecting adjacent molecules into a three-dimensional netwrok by means of O-H?O, O-H?N and N-H?O hydrogen bonding inter-actions. The structure also features two non-classical C-H?O inter actions. PMID- 23795058 TI - 4-(Adamantan-1-yl)-2-(4-fluoro-phen-yl)quinoline. AB - In the mol-ecule of the title compound, C25H24FN, the dihedral angle between the best planes of the quinoline fragment (rings A and B) and the benzene ring (C) is 9.51 (4) degrees . In the crystal, mol-ecules are linked into centrosymmetric dimers via pairs of weak C-H?F inter-actions. The mol-ecules are stacked into chains along the a axis by weak off-set pi-pi inter-actions between the A and C rings of translation-related mol-ecules with a centroid-centroid distance of 3.6440 (2) A. PMID- 23795059 TI - 8-{(E)-[(4-Chloro-phen-yl)imino]-meth-yl}-1,1,7,7-tetra-methyl-1,2,3,5,6,7-hexa hydro-pyrido[3,2,1-ij]quinolin-9-ol. AB - The title Schiff base, C23H27ClN2O adopts the phenol-imine tautomeric form, with an intra-molecular O-H?N hydrogen bond, which generates an S(6) ring motif. Three C atoms of the heterocyclic moiety of the hexa-hydro-pyrido-quinoline unit, as well as the two methyl groups bonded to one of these C atoms, are disordered over two set of sites, with anoccupancy ratio of 0.740 (4):0.260 (4). PMID- 23795060 TI - 1-Allyl-2-amino-pyridin-1-ium bromide. AB - In the cation of the title salt, C8H11N2 (+).Br(-), the dihedral angle between the planes of the pyridinium ring and the allyl group is 79.4 (3) degrees . In the crystal, N-H?Br and weak C-H?Br hydrogen bonds link the cations and anions, forming chains of alternating R 2 (1)(7) and R 4 (2)(8) rings, which run parallel to the c-axis direction. The crystal studied was an inversion twin with components in a 0.753 (12):0.247 (12) ratio. PMID- 23795061 TI - Pyrimidine-4-carb-oxy-lic acid. AB - The crystal structure of the title compound, C5H4N2O2, is built of acid mol ecules located on a mirror plane. They form sheets stacked along the b-axis direction. The mol-ecules inter-act via O-H?N hydrogen bonds, forming [001] chains, and weak van der Waals inter-actions. PMID- 23795062 TI - Ethyl 2-[4-(di-methyl-amino)-phen-yl]-1-phenyl-1H-benzimidazole-5-carboxyl-ate. AB - In the title compound, C24H23N3O2, the benzimidazole ring system makes dihedral angles of 7.28 (5) and 67.17 (5) degrees , respectively, with the planes of the benzene and phenyl rings, which in turn make a dihedral angle of 69.77 (6) degrees . In the crystal, mol-ecules are connected by C-H?N and C-H?O inter actions, forming a layer parallel to the bc plane. A pi-pi inter-action, with a centroid-centroid distance of 3.656 (1) A, is observed in the layer. PMID- 23795063 TI - 5-Cyclo-hexyl-2-(2-fluoro-phen-yl)-3-methyl-sulfinyl-1-benzo-furan. AB - In the title compound, C21H21FO2S, the cyclo-hexyl ring adopts a chair conformation. The 2-fluoro-benzene ring makes a dihedral angle of 38.68 (6) degrees with the mean plane [r.m.s. deviation = 0.018 (2) A] of the benzo-furan fragment. In the crystal, mol-ecules are linked by pairs of C-H?O hydrogen bonds into dimers, which are further packed into stacks along the c axis by C-H?O hydrogen bonds. In addition, the stacked mol-ecules exhibit S?O contacts [3.1733 (13) A] involving the sulfinyl groups. The F atom is disordered over two positions, with site-occupancy factors of 0.961 (3) and 0.039 (3). PMID- 23795064 TI - 2-(1-Amino-4-tert-butyl-cyclo-hex-yl)acetic acid (tBu-beta(3,3)-Ac6c) hemihydrate. AB - The title compound, C12H23NO2.0.5H2O, crystallized with two 2-(1-amino-4-tert butylcyclohexyl)acetic acid mol-ecules, which are present as zwitterions, and one water mol-ecule in the asymmetric unit. The mol-ecular structure of each zwitterion is stabilized by an intra-molecular six-membered (C 6 ) N-H?O hydrogen bond. In the crystal, the two independent zwitterions are linked head-to-head by N-H?O hydrogen bonds. Further O-H?O and N-H?O hydrogen bonds link the zwitterions and the water molecules, forming sandwich-like layers, with a hydrophilic filling and a hydrophobic exterior, lying parallel to the ab plane. PMID- 23795065 TI - 2-{[3-Chloro-4-(4-chloro-phen-oxy)phen-yl]imino-meth-yl}-4-nitro-phenol. AB - In the title compound, C19H12Cl2N2O4, the imine bond length of 1.257 (6) A is typical of a double bond. The dihedral angle between the para-nitro benzene ring and the central benzene ring is 12.06 (3) degrees and that between the central benzene and the para-chloro benzene ring is 73.81 (2) degrees . An intra molecular O-H?N hydrogen bond generates an S(6) ring motif. In the crystal, mol ecules are linked together by two pairs of C-H?O interactions (to the same O atom acceptor), forming inversion dimers. A short Cl?Cl contact [3.232 (4) A] is observed. PMID- 23795066 TI - 6,12-Bis[(tri-cyclo-hexyl-sil-yl)ethyn-yl]indeno-[1,2-b]fluorene. AB - The title compound, C60H76Si2, a formally anti-aromatic system containing 20-pi electrons, contains a rare p-xylylene motif. This is displayed by the alternating short and long bonds. The outer rings possess nearly homogenous bond lengths. In the crystal, the molecules forms layers perpendicular to the c axis and within these layers there are two one-dimensional stacks with one stack that has a sp (2) carbon contact of 3.283 (6) A, less than the sum of the van der Waals radii. The center of the mol-ecule sits on an inversion center. PMID- 23795067 TI - 2-(4-Bromo-phen-yl)-N-(pyrazin-2-yl)acetamide. AB - In the title compound, C12H10BrN3O, the dihedral angle between the mean planes of the 4-bromo-phenyl and pyrazin-2-yl rings is 54.6 (3) degrees . An intra molecular C-H?O hydrogen bond generates an S(6) graph-set motif. In the crystal, weak N-H?N hydrogen bonds link the mol-ecules into chains along [100]. The chains are linked via C-H?N and C-H?O hydrogen bonds, forming two-dimensional networks lying parallel to the ab plane. PMID- 23795068 TI - 8,13,26-Trioxa-23-thia-21-aza-penta-cyclo-[18.6.0.0(2,7).0(14,19).0(21,25)]hexa cosa-2(7),3,5,14,16,18-hexa-ene. AB - In the title compound, C21H23NO3S, both the thia-zole and oxazolidine rings adopt twist conformations. The mean plane of the thia-zole ring makes a dihedral angle of 61.02 (7) degrees with the oxazolidine ring mean plane, and dihedral angles of 22.72 (6) and 75.07 (6) degrees with the benzene rings. The benzene rings are almost perpendicular to one another, making a dihedral angle of 89.14 (6) degrees . There are bifurcated intra-molecular C-H?O hydrogen bonds in the mol-ecular structure. In the crystal, mol-ecules are linked via C-H?pi inter-actions, forming chains propagating along [100]. PMID- 23795069 TI - 4-(2-Hy-droxy-phen-yl)-3,5-di-thia-hepta-ne-dioic acid. AB - In the crystal of the title compound, C11H12O5S2, mol-ecules are linked by O-H?O hydrogen bonds and C-H?O inter-actions, forming a three-dimensional network. PMID- 23795070 TI - 5-Cyclo-hexyl-3-(2-fluoro-phenyl-sulfin-yl)-2-methyl-1-benzo-furan. AB - In the title compound, C21H21FO2S, the cyclo-hexyl ring adopts a chair conformation. The 2-fluoro-phenyl ring makes a dihedral angle of 88.47 (4) degrees with the mean plane [r.m.s. deviation = 0.013 (1) A] of the benzo-furan fragment. In the crystal, mol-ecules are linked by weak C-H?O and C-H?pi inter actions, forming chains propagating along [100]. The crystal structure also exhibits slipped pi-pi inter-actions between the furan rings of neighboring mol ecules [centroid-to-centroid distance = 3.397 (2) A, inter-planar distance = 3.346 (2) A and slippage = 0.586 (2) A]. PMID- 23795071 TI - 2-(4-Hy-droxy-phen-yl)-3-meth-oxy-4H-chromen-4-one. AB - In the title compound, C16H12O4, the substituent benzene ring and meth-oxy group are twisted relative to the 4H-chromene skeleton by 24.1 (1) and 61.3 (1) degrees , respectively. In the crystal, mol-ecules are connected by classical O-H?O and weak C-H?O hydrogen bonds, forming chains parallel to [201]. The 4H-chromene ring systems of adjacent mol-ecules are either parallel or inclined at an angle of 28.9 (1) degrees . PMID- 23795072 TI - 1,2-Bis{2-[(4-meth-oxy-benzyl-idene)amino]-phen-yl}disulfane. AB - The asymmetric unit of the title compound, C28H24N2O2S2, contains one-half mol ecule, which is completed by twofold rotation symmetry with the twofold axis passing through the mid-point of the central S-S bond. The planes of the two benzene rings linked by the di-sulfide chain form a dihedral angle of 76.1 (1) degrees , while the planes of the two benzene rings in the benzyl-ideneaniline fragment form a dihedral angle of 48.9 (1) degrees . The crystal packing exhibits no significantly short inter-molecular contacts. PMID- 23795073 TI - 5-Methyl-3-phenyl-isoxazole-4-carb-oxy-lic acid. AB - In the title compound, C11H9NO3, the phenyl and isoxazole rings form a dihedral angle of 56.64 (8) degrees . The carb-oxy group is almost in the same plane as the isoxazole ring with a C-C-C-O torsion angle of -3.3 (2) degrees . In the crystal, pairs of O-H?O hydrogen bonds link the mol-ecules into head-to-head dimers. C-H?N hydrogen bonds and pi-pi stacking inter-actions between phenyl rings [centroid-centroid distance = 3.9614 (17)A] link the dimers into a three dimensional network. PMID- 23795074 TI - 8,11,24-Trioxa-21-thia-19-aza-penta-cyclo-[16.6.0.0(2,7).0(12,17).0(19,23)]tetra cosa-2(7),3,5,12,14,16-hexa-ene. AB - In the title compound, C19H19NO3S, the thia-zole and oxazolidine rings each adopt an envelope conformation, with the S and O atoms as the respective flap atoms. The thia-zole and oxazolidine rings (all atoms) make a dihedral angle of 66.39 (11) degrees while the phenyl rings subtend a dihedral angle of 22.71 (10) degrees . PMID- 23795075 TI - N-[3-(Benzyl-dimethyl-aza-nium-yl)prop-yl]-N',N',N'',N''-tetra-methyl-guanidinium bis-(tetra-phenyl-borate). AB - In the crystal structure of the title salt, C17H32N4 (2+).2C24H20B(-), the C-N bond lengths in the CN3 unit of the guanidinium ion are 1.323 (4), 1.336 (5) and 1.337 (5) A, indicating partial double-bond character in each. The C atom of this unit is bonded to the three N atoms in a nearly ideal trigonal-planar geometry [N C-N angles = 117.7 (4), 120.9 (3) and 121.4 (3) degrees ] and the positive charge is delocalized in the CN3 plane. The bonds between the N atoms and the terminal C methyl groups of the guanidinium moiety all have values close to a typical single bond [1.452 (5)-1.484 (6) A]. In the crystal, C-H?pi inter-actions are present between guanidinium H atoms and the phenyl rings of both tetra-phenyl-borate ions. This leads to the formation of a two-dimensional supramolecular pattern along the ab plane. PMID- 23795076 TI - 2-(4-Bromo-phen-yl)-N-(3,4-di-fluoro-phen-yl)acetamide. AB - In the title compound, C14H10BrF2NO, the dihedral angle between the mean planes of the 4-bromo-phenyl and 3,4-di-fluoro-phenyl rings is 66.4 (1) degrees . These two planes are twisted by 40.0 (5) and 86.3 (2) degrees , respectively, from that of the acetamide group. In the crystal, N-H?O hydrogen bonds and weak C-H?O and C H?F inter-actions form infinite chains along [100]. PMID- 23795077 TI - (Z)-N-tert-Butyl-2-(4-meth-oxy-anilino)-N'-(4-meth-oxy-phen-yl)-2-phenyl acetimidamide. AB - In the crystal of the title compound, C26H31N3O2, pairs of N-H?O hydrogen bonds link molecules, forming inversion dimers, which enclose an R 2 (2)(20) ring motif. One N atom does not form hydrogen bonds and lies in a hydro-phobic pocket with closest inter-molecular contacts of 4.196 (2) and 4.262 (2) A. PMID- 23795078 TI - 4-[(E)-(4-Eth-oxy-benzyl-idene)amino]-phenol. AB - The mol-ecule of the title compound, C15H15NO2, adopts a trans conformation with respect to the methyl-idene C=N bond and is twisted with a dihedral angle of 26.31 (5) degrees between the two substituted benzene rings. The eth-oxy group is almost coplanar with the bound benzene ring with a C-O-C-C torsion angle of 179.08 (9) degrees . In the crystal, mol-ecules are linked by O-H?N hydrogen bonds and weak C-H?O inter-actions into chains propagating in the [011] and [01 1] directions. C-H?pi inter-actions are also present. PMID- 23795079 TI - N-[4-(Di-methyl-amino)-benzyl-idene]-4-methyl-aniline. AB - The mol-ecules of the title compound, C16H18N2, exists in a trans conformation with respect to the C=N bond [1.270 (3) A]. The least-squares plane of the di methyl-amino group makes a dihedral angle of 1.3 (2) degrees with the ring to which it is attached. The dihedral angle between the two aromatic rings is 11.70 (2) degrees . The crystal structure features weak C-H?pi inter-actions. PMID- 23795080 TI - 1-[4-(Di-methyl-amino)-benzyl-idene]-4-o-tolyl-thio-semicarbazide. AB - The asymmetric unit of the title compound, C17H20N4S, contains two independent mol-ecules, the main difference between them being the dihedral angles between the benzene rings [19.99 (17) and 9.72 (17) degrees ]. The mol-ecules both have a trans conformation about the C=N double bond and intra-molecular C-H?S and N-H?N hydrogen bonds are observed in both mol-ecules. In the crystal, mol-ecules are linked by weak N-H?S hydrogen bonds with graph-set motif R 2 (2)(8). In each mol ecule, all but one of the N atoms and both the S atoms are involved in hydrogen bonding. PMID- 23795081 TI - 5,5'-(Ethyne-1,2-di-yl)diisophthalic acid dimethyl sulfoxide tetra-solvate. AB - In the title compound, C18H10O8.4C2H6OS, the mid-point of the triple bond of the main mol-ecule is located on a special position, i.e. about an inversion center. The carboxyl groups are twisted slightly out of the planes of the aromatic rings to which they are attached, making dihedral angles of 24.89 (1) and 7.40 (2) degrees . The cystal packing features strong O-H?O hydrogen bonds, weaker C-H?O inter-actions and O?S contacts [3.0981 (11) A] and displays channel-like voids extending along the a-axis direction which contain the dimethyl sulfoxide solvent mol-ecules. PMID- 23795082 TI - 2-Amino-4-methyl-pyridinium 2-nitro-benzoate. AB - In the title mol-ecular salt, C6H9N2 (+).C7H4NO4 (-), the original pyridine N atom of 2-amino-4-methyl-pyridine is protonated and the carb-oxylic acid group of nitro-benzoic acid is deprotonated. In the crystal, the ions are linked by N-H?O hydrogen bonds, forming chains propagating along [001]. The chains are linked via C-H?O hydrogen bonds, forming two-dimensional networks lying parallel to the bc plane. PMID- 23795083 TI - (E)-1,5-Di-phenyl-pent-2-en-4-yn-1-one. AB - The title compound, C17H12O, has an E conformation about the C=C bond. The C-C C C torsion angle is 7.7 (2) degrees , and the mean planes of the phenyl-ethyl enone [r.m.s. deviation = 0.059 (1) A] and phenyl-acetyl-ene [r.m.s. deviation = 0.023 (1) A] fragments form a dihedral angle of 14.16 (7) degrees . In the crystal, weak C-H?O inter-actions link the mol-ecules into zigzag chains propagated in [010]. PMID- 23795084 TI - 5-(Naphthalen-1-yl)isophthalic acid-dimethyl sulfoxide-water (2/1/2). AB - The asymmetric unit of the title compound, 2C18H12O4.C2H6OS.2H2O, consists of four crystallographically independent mol-ecules of 5-(naphthalen-1 yl)isophthalic acid, two dimethyl sulfoxide and four water mol-ecules. The dihedral angles formed by the the planes of the aromatic fragments of the organic mol-ecules range from 57.4 (1) to 59.1 (1) degrees . In the crystal, multiple O H?O hydrogen bonds link the water mol-ecules with the carbonyl and sulfoxide groups, giving rise to double ribbons along the b-axis direction. PMID- 23795085 TI - 3,3'-{[(Biphenyl-2,2'-di-yl)bis-(methyl-ene)]bis-(-oxy)}bis-[N-(4-chloro-phen yl)benzamide]. AB - In the title compound, C40H30Cl2N2O4, the two benzene rings of the biphenyl unit are twisted with respect to each other, making a dihedral angle of 73.07 (4) degrees . The benzene rings of the benzamide groups form dihedral angles of 77.09 (5) and 55.48 (6) degrees with the central biphenyl moiety. In the crystal, mol ecules are linked through N-H?O hydrogen bonds to form a fused R 2 (2)(38) ring motif which forms a supermolecular ribbon network extending along the [100] plane. In the two 4-chloro-phenyl rings, the five C atoms and their attached H atoms are disordered over two sets of sites, with site-occupancy factors of 0.657 (15):0.343 (15) and 0.509 (13):0.491 (13). PMID- 23795086 TI - Thio-phene-2-carbaldehyde azine. AB - The asymmetric unit of the title compound, C10H8N2S2, is composed of two independent half-mol-ecules, each residing on a center of symmetry. In the crystal, weak C-H?pi inter-actions join the two symmetry-independent molecules together into interlinked chains parallel to [011]. The crystal structure was refined as a two-component pseudo-merohedral twin using the twin law 001 0-10 100. The refined domain fractions are 0.516 (3) and 0.484 (3). PMID- 23795087 TI - 2-Acetyl-amino-1,3,4,6-tetra-O-(tri-methyl-silyl)-2-de-oxy-alpha-d-gluco-pyran ose. AB - The title compound, C20H47NO6Si4, was synthesized by per-O-tri-methyl-silylation of N-acetyl-d-glucosa-mine using chloro-tri-methyl-silane in the presence of hexa methyl-disiloxane. The tri-methyl-silyl group and acetamido group are located on the same side of the pyran ring, showing an alpha-configuration glycoside. One of the tri-methyl-silyl groups is disordered over two orientations, with site occupancy factors of 0.625 (9) and 0.375 (9). In the crystal, N-H?O hydrogen bonds link the mol-ecules into supra-molecular chains along the a-axis direction. PMID- 23795088 TI - 1-[2-(Trit-yloxy)phen-yl]ethanone. AB - In the title compound, C27H22O2, the acetyl group is nearly coplanar with the the ring to which it attacted [O-C-C-C torsion angle = -5.5 (3) degrees ]. The three phenyl groups of the tri-phenyl-methyl substituent are mutually nearly perpendicular, making dihedral angles of 89.87 (11) and 78.29 (11) and 60.34 (11) degrees . Two intra-molecular C-H? O hydrogen bonds occur. In the crystal, C-H? O hydrogen bonds link the moleclues into chains along the b-axis direction. PMID- 23795089 TI - Dimethyl 2-(4-methyl-benzyl-idene)malonate. AB - In the mol-ecule of the title compound, C13H14O4, the benzene ring forms dihedral angles of 18.60 (7) and 81.36 (8) degrees with the two arms of the malonate moiety. The crystal structure features C-H?O inter-actions, which form chains running parallel to the b axis. PMID- 23795090 TI - 5-Chloro-2-(4-fluoro-phen-yl)-7-methyl-3-methyl-sulfinyl-1-benzo-furan. AB - In the title compound, C16H12ClFO2S, the 4-fluoro-phenyl ring makes a dihedral angle of 16.43 (4) degrees with the mean plane [r.m.s. deviation = 0.012 (1) A] of the benzo-furan fragment. In the crystal, mol-ecules are linked by pairs of Cl?O contacts [3.1839 (12) A] into inversion dimers, which are further packed into stacks along the b axis by weak C-H?O hydrogen bonds. PMID- 23795091 TI - 1-Ethyl-2-phenyl-3-[2-(tri-methyl-sil-yl)ethyn-yl]-1H-indole. AB - The title compound, C21H23NSi, was synthesized by Sonogashira-type reaction of 1 ethyl-3-iodo-2-phenyl-1H-indole with tri-methyl-silyl-acetyl-ene. The indole ring system is nearly planar [maximum atomic deviation = 0.0244 (15) A] and is oriented at a dihedral angle of 51.48 (4) degrees with respect to the phenyl ring. The supramolecular aggregation is completed by weak C-H?pi inter-actions of the methylene and phenyl groups with the benzene and pyrrole rings of the indole ring system. The methyl groups of the tri-methyl-silyl unit are equally disordered over two sets of sites. PMID- 23795092 TI - 3-Benzoyl-1-[4-(methyl-sulfan-yl)phen-yl]thio-urea. AB - The title compound, C15H14N2OS2, adopts a helix conformation. An intra-molecular N-H?O hydrogen bond leads to a six-membered pseudo-ring [r.m.s. deviation = 0.0212 A, maximum deviation = 0.033 (1) A for the N atom bearing the benzoyl group] in the central unit. The benzene and (methyl-sulfan-yl)benzene ring [r.m.s = 0.0028 A and largest deviation of 0.067 (3) A for the methyl-sulfanyl C atom] make dihedral angles of 31.76 (8) and 54.68 (6) degrees , respectively, with the pseudo-ring plane. The dihedral angle between the benzene rings is 85.71 (8) degrees . In the crystal, pairs of weak N-H?S inter-actions form inversion dimers and mediate a linear chain along [001]. PMID- 23795093 TI - 3,4-Bis[1-(prop-2-yn-yl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione. AB - In the title mol-ecule, C26H17N3O2, both indole ring systems are essentially planar, with maximum deviations of 0.019 (2) and 0.033 (1) A for the N atoms, and form dihedral angles of 34.40 (9) and 45.06 (8) degrees with the essentially planar pyrrole ring [maximum deviation = 0.020 (2) A]. The dihedral angle between the two indole ring systems is 58.78 (6) degrees . In the crystal, mol-ecules are connected by pairs of N-H?O hydrogen bonds, forming inversion dimers and generating R 2 (2)(8) rings. Weak pi-pi stacking inter-actions, with a centroid centroid distance of 3.983 (2) A, are also observed. PMID- 23795094 TI - 2-Tosyl-2,3,3a,4,9,9a-hexa-hydro-1H-benzo[f]isoindol-1-one. AB - The title compound, C19H19NO3S, was produced by the self-reaction of N-cinnamyl-N tosyl-acryl-amide in the presence of palladium(II) acetate via an intra-molecular C-C coupling reaction and C-H activation. There are two chiral C atoms in the mol ecule, but the crystal is a racemic system due to a lack of chiral separation. The five-membered ring is twisted about the methyl-ene-methane bond, and the cyclo-hexa-1,4-diene ring has a boat conformation. The dihedral angle between the benzene rings is 88.27 (14) degrees , indicating an almost orthogonal relationship and an approximate L-shape for the mol-ecule. In the crystal, the presence of C-H?pi inter-actions leads to inversion dimers. PMID- 23795095 TI - [(2R,3R)-3-(4-Nitro-phen-yl)aziridin-2-yl]methanol monohydrate. AB - The title monohydrate, C9H10N2O3.H2O, contains an aziridine ring including two contiguous stereocenters, both of which exhibit an R configuration. The methyl hydroxy and nitro-phenyl groups are cis-disposed about the aziridine ring. The mean plane of the benzene ring is tilted to the aziridine ring by 66.65 (8) degrees . The nitro group is nearly coplanar with the benzene ring [dihedral angle = 2.5 (2) degrees ]. In the crystal, the components are linked by N-H?O, O H?N and O-H?O hydrogen bonds, generating supra-molecular layers parallel to (001). PMID- 23795096 TI - 4-Di-phenyl-phosphanyl-8-methyl-1,5-naphthyridine. AB - In the title compound, C21H17N2P, the dihedral angles between the 1,5 naphthyridine ring system (r.m.s. deviation = 0.005 A) and the phenyl rings are 89.18 (8) and 77.39 (8) degrees . The phenyl rings are almost perpendicular, making a dihedral angle of 88.12 (8) degrees . The only possible inter-molecular inter-action is a very weak aromatic pi-pi stacking inter-action [centroid centroid separation = 3.898 (2) A]. PMID- 23795097 TI - 6-Amino-2-methyl-8-phenyl-1,2,3,4-tetra-hydro-iso-quinoline-5,7-dicarbo-nitrile. AB - In the title compound, C18H16N4, the dihedral angle between the benzene and phenyl rings is 61.40 (4) degrees . In the crystal, mol-ecules are linked by N H?N(nitrile) hydrogen bonds, forming inversion dimers. The dimers are further linked by N-H?N(amine) hydrogen bonds, and both units are arranged almost perpendicular to each other [angle between dimer mean planes = 84.43 (12) degrees ]. This arrangement is extended to form a ladder-like structure parallel to the c axis. PMID- 23795098 TI - N-(2-Meth-oxy-phen-yl)phthalamic acid. AB - The title compound, C14H13NO3, adopts a twisted conformation in the crystal, with an inter-planar angle between the two benzene rings of 87.30 (5) degrees . Mol ecules within the structure are linked via O-H?O inter-actions, forming a hydrogen-bonded chain motif with graph set C(7) along the glide plane in the [001] direction. PMID- 23795099 TI - 4-(4-Bromo-phen-yl)-2-methyl-amino-3-nitro-5,6,7,8-tetra-hydro-4H-chromen-5-one. AB - In the title compound, C16H15BrN2O4, the six-membered carbocyclic ring of the chromene moiety adopts an envelope conformation with the disordered methyl-ene C atom as the flap. The pyran ring is almost orthogonal to the chloro-phenyl ring, making a dihedral angle of 87.11 (12) degrees . The amine-group N atom deviates significantly from the pyran ring [0.238 (3) A]. The mol-ecular structure is stabilized by an intra-molecular N-H?O hydrogen bond, which generates an S(6) ring motif. In the crystal, mol-ecules are linked via C-H?O hydrogen bonds, which generate C(8) chains running parallel to the b axis. The chains are linked by C H?pi inter-actions. The methyl-ene-group C atom of the chromene system that is disordered, along with its attached H atoms and the H atoms on the two adjacent C atoms, has an occupancy ratio of 0.791 (7):0.209 (7). PMID- 23795100 TI - (1S,3S,8R,9S,11R)-10,10-Di-chloro-3,7,7,11-tetra-methyl-tetra cyclo[6.5.0.0(1,3).0(9,11)]trideca-ne. AB - The title compound, C17H26Cl2, was synthesized from beta-himachalene (3,5,5,9 tetra-methyl-2,4a,5,6,7,8-hexa-hydro-1H-benzo-cyclo-heptene), which was isolated from the essential oil of the Atlas cedar (Cedrus Atlantica). The asymmetric unit contains two independent mol-ecules with similar conformations. Each mol-ecule is built up from fused six- and seven-membered rings and two three-membered rings from the reaction of beta-himachalene with di-chloro-carbene. In both mol-ecules, the six-membered ring has a half-chair conformation, whereas the seven-membered ring displays a boat conformation. The absolute configuration was established from anomalous dispersion effects. PMID- 23795101 TI - tert-Butyl N-[(3R,4R)-1-(2-cyano-acet-yl)-4-methyl-piperidin-3-yl]-N-methyl carbamate. AB - The piperidine ring of the title compound, C15H25N3O3, adopts a slightly distorted chair conformation with the cis substituents displaying an N-C-C-C torsion angle of 43.0 (3) degrees . The cyano group (plane defined by C-C-C N atoms) is bent slightly out of the plane of the amide group by 13.3 (2) degrees . The carbamate group is oriented at a dihedral angle of 60.3 (5) degrees relative to the amide group. PMID- 23795102 TI - 3-{[5-(4-Chloro-phen-yl)-3-methyl-1H-pyrazol-1-yl]meth-yl}-4-m-tolyl-1H-1,2,4 triazole-5(4H)-thione. AB - In the title compound, C20H18ClN5S, the toluene and triazole rings are oriented almost perpendicular to each other, making a dihedral angle of 89.97 (9) degrees , whereas the dihedral angle between cholorophenyl and pyrazole rings is 54.57 (11) degrees . In the crystal, pairs of N-H?N hydrogen bonds link the mol-ecules into inversion dimers. Weaker C-H?S and C-H?Cl inter-actions are also present. PMID- 23795103 TI - (1R,2S,4S,4aS,8S,8aS)-4-Hy-droxy-8,8a-dimethyl-10-oxo-2,3,4,7,8,8a-hexa-hydro-1H 4a,1-(ep-oxy-methano)-naphthalen-2-yl acetate. AB - The title compound, C15H20O5, presents a bis-norsesquiterpene skeleton, with a trans-deca-line backbone constrained by the lactone bridge. The alpha-hy-droxy substituent and the methyl group belonging to the two deca-line rings are in axial positions, whereas the other methyl group and the acyl group occupy the sterically preferred equatorial positions. The mol-ecular structure is stabilized by an intra-molecular C-H?O hydrogen bond. In the crystal, mol-ecules are linked into chains along [010] by O-H?O hydrogen bonds. PMID- 23795104 TI - Pyridine-4-carbaldehyde-fumaric acid (2/1). AB - In the title co-crystal, 2C6H5NO.C4H4O4, two crystallographically different hydrogen-bonded trimers are formed, one in which the components occupy general positions, and one generated by an inversion centre. This results in the uncommon situation of Z = 3 for a triclinic crystal. In the formula units, mol-ecules are linked by O-H?N hydrogen bonds. PMID- 23795105 TI - 4-Hy-droxy-1,2,6-tri-methyl-pyridinium bromide monohydrate. AB - The title salt, C8H12NO(+).Br(-).H2O, is isomorphous with the chloride analogue [Seethalakshmi et al. (2013). Acta Cryst. E69, o835-o836]. In the solid state, the cations, anions and water mol-ecules are inter-linked by a network of O-H?O, O-H?Br and C-H?Br inter-actions. The water mol-ecule makes two O-H?Br hydrogen bonds, generating [010] zigzag chains of alternating water mol-ecules and bromide anions. The cation is involved in two inter-molecular C-H?Cl inter-actions in the chloride salt, whereas three inter-molecular C-H?Br inter-actions are observed in the title bromide salt. This additional inter-molecular C-H?Br inter-action links the adjacent water and bromide zigzag chains via cationic mol-ecules. In addition, weak pi-pi stacking inter-actions are observed between pyridinium rings [centroid-centroid distance = 3.5664 (13) A]. PMID- 23795106 TI - N-(5-Nitro-1,3-thia-zol-2-yl)-4-(tri-fluoro-meth-yl)benzamide. AB - There are two independent and conformationally dissimilar mol-ecules (A and B) in the asymmetric unit of the title compound, C11H6F3N3O3S; the dihedral angles between the benzene and thia-zole rings are 33.8 (2) degrees in A and 59.7 (2) degrees in B. The similarity of the C-N bond lengths in the amide group [1.379 (5) and 1.358 (5) A for A, and 1.365 (5) and 1.363 (5) A for B] indicates the presence of conjugation between the two rings. In the crystal, mol-ecules are linked by N-H?N hydrogen bonds, forming chains extending along [010]; weak N H?Oamide inter-actions are also present in the structure. PMID- 23795108 TI - 1-(Prop-2-en-1-yl)-3-{[3-(pyridin-4-yl)-4,5-di-hydro-isoxazol-5-yl]meth-yl}-1H anthra[1,2-d]imidazole-2,6,11(3H)-trione. AB - The fused five- and three six-membered rings of the anthra[1,2-d]imidazole-trione part of the title compound, C27H20N4O4, show two different substituents at the imidazole N atoms, viz. an allyl group and a [3-(pyridin-4-yl)-4,5-di-hydro isoxazol-5-yl]methyl group. The fused-ring system is approximately planar [r.m.s. deviation = 0.232 (2) A], but is slightly buckled along the common edge of the two pairs of adjacent rings, with a dihedral angle between them of 11.17 (6) degrees . The isoxazole ring makes dihedral angles of 27.2 (2) and 12.7 (2) degrees with the imidazole and pyridine rings, respectively. Weak C-H?O and C H?N hydrogen bonds ensure the cohesion of the crystal structure, forming a three dimensional network. PMID- 23795107 TI - 1,3-Bis(prop-2-yn-1-yl)-1H-anthra[1,2-d]imidazole-2,6,11(3H)-trione. AB - In the title compound, C21H12N2O3, the fused-ring system is roughly planar, the largest deviation from the mean plane being 0.084 (2) A. The two prop-2-yn-1-yl groups are almost perpendicular to the fused ring plane, making C-C-N-C torsion angles of -103.4 (2) and -105.3 (2) degrees , and point in opposite directions with respect to the plane. In the crystal, mol-ecules are linked by weak C-H?O hydrogen bonds, forming a three-dimensional network. PMID- 23795109 TI - Ethyl 4-anilino-2,6-bis-(4-chloro-phen-yl)-1-phenyl-1,2,5,6-tetra-hydro-pyridine 3-carboxyl-ate. AB - The title compound, C32H28Cl2N2O2, was synthesized by a multicomponent reaction of 4-chloro-benzaldehyde, aniline and ethyl aceto-acetate. The central 1,2,5,6 tetra-hydro-pyridine ring exhibits a distorted boat conformation and the two chloro-phenyl rings attached to the central ring at positions 2 and 6 are oriented in opposite directions. The two O atoms of the eth-oxy-carbonyl group are involved in intra-molecular N-H?O and C-H?O hydrogen bonds. In the crystal, weak C-H?O hydrogen bonds link mol-ecules related by translation along the b axis into chains. PMID- 23795110 TI - N-tert-Butyl-2-(2,6-di-chloro-phen-yl)imidazo[1,2-a]pyrazin-3-amine. AB - In the title compound, C16H16Cl2N4, the imidazole ring mean plane makes a dihedral angle of 70.01 (1) degrees with the phenyl ring. The Cl atoms deviate by -0.0472 (6) and 0.0245 (8) A from the plane of their attached benzene ring. In the crystal, mol-ecules are linked via pairs of C-H?N hydrogen bonds, forming inversion dimers. PMID- 23795111 TI - Dimethyl 1,8-bis-(4-methyl-phen-yl)-11-oxatri-cyclo-[6.2.1.0(2,7)]undeca-2,4,6,9 tetra-ene-9,10-di-carboxyl-ate. AB - The title compound, C28H24O5, consists of a fused tricyclic system containing two five-membered rings and one six-membered ring. The five-membered rings both exhibit an envelope conformation with the O atom at the flap, whereas the six membered ring adopts a boat conformation. The dihedral angle between the 4-methyl phenyl rings at the 1,8-positions is 76.4 (1) degrees . In the crystal, mol ecules are stacked in columns along the a axis through C-H?O inter-actions. PMID- 23795112 TI - Acet-oxy-gamma-valerolactone. AB - Levulinyl cellulose esters have been produced as an effective renewable binder for architectural coatings. The title compound, C7H10O4 (systematic name: 2 methyl-5-oxo-tetra-hydro-furan-2-yl acetate), assigned as the esterifying species, was isolated and crystallized to confirm the structure. In the crystal, the mol-ecules pack in layers parallel to (102) utilizing weak C-H?O inter actions. PMID- 23795113 TI - 5-Isopropyl-5-methyl-2-sulfanylidene-imidazolidin-4-one. AB - In the title compound, C7H12N2OS, the 2-sulfanylideneimidazolidin-4-one moiety is nearly planar, with a maximum deviation of 0.054 (2) A. In the crystal, a pair of N-H?O hydrogen bonds and a pair of N-H?S hydrogen bonds each form a centrosymmetric ring with an R 2 (2)(8) graph-set motif. The enanti-omeric R and S mol-ecules are alternately linked into a tape along [1-10] via these pairs of hydrogen bonds. PMID- 23795114 TI - N-Benzyl-9-isopropyl-9H-purin-6-amine. AB - The asymmetric unit of the title compound, C15H17N5, consists of two mol-ecules in which the dihedral angles between the best planes of the purine ring system (r.m.s. deviations = 0.0060 and 0.0190 A) and the benzene ring are 89.21 (3) and 82.14 (4) degrees . The mol-ecules within the asymmetric unit are linked into dimers by pairs of N-H?N hydrogen bonds. Weak C-H?pi contacts and pi-pi inter actions [centroid-centroid = 3.3071 (1) A] further connect the mol-ecules into a three-dimensional network. PMID- 23795115 TI - 2-(4-Bromo-phen-yl)-4-(4-meth-oxy-phen-yl)-6,7,8,9-tetra-hydro-5H-cyclo-hepta [b]pyridine. AB - In the title compound, C23H22BrNO, the cyclo-heptane ring adopts a chair conformation. The pyridine ring makes dihedral angles of 58.63 (15) and 8.27 (16) degrees with the benzene rings. The dihedral angle between the benzene rings is 56.68 (17) degrees . The crystal packing features C-Br?pi inter-actions [Br?centroid distances= 3.813 (2) and 3.839 (2) A; C-Br?centroid = 126.25 (10) and 138.31 (10) degrees , respectively, forming a three dimensional supramolecular architecture. PMID- 23795116 TI - l-Histidinium dipicrate dihydrate. AB - In the title mol-ecular salt, C6H11N3O2 (2+).2C6H2N3O7 (-).2H2O, the histidine mol-ecule exists as a histidinium dication, being protonated at the N atom of the imidazole ring. The charges are balanced by two picrate anions and the compound crystallizes as a dihydrate. In the crystal, the components are linked via N-H?O and O-H?O hydrogen bonds and weak C-H?O inter-actions, forming a three dimensional supermolecular structure. PMID- 23795117 TI - N,N-Di-methyl-dehydro-abietyl-ammonium chloride ethanol monosolvate. AB - The title compound {systematic name: 1-[(1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl 1,2,3,4,4a,9,10,10a-octa-hydro-phenan-thren-1-yl]-N,N-di-methyl-methanaminium chloride ethanol monosolvate}, C22H36N(+).Cl(-).C2H6O, was synthesized from dehydroabietylamine by N-methyl-ation with formaldehyde/formic acid and transformation into the hydro-chloride. The de-hydro-abietyl moiety exhibits the usual conformation with the two cyclo-hexane rings in chair and half-chair conformations and a trans-ring junction. The crystal structure is built up from columns of the de-hydro-abietyl moieties stacked along the a axis. These columns are held together by the chloride ions via N-H?Cl and C-H?Cl inter-actions, which establish a two-dimensional network parallel to (010). The ethanol solvent mol ecules are located between the columns and anchored via O-H?Cl hydrogen bonds. PMID- 23795118 TI - (E)-3-(3,4-Di-fluoro-phen-yl)-1-(3,4-di-meth-oxy-phen-yl)prop-2-en-1-one. AB - In the title compound, C17H14F2O3, the dihedral angle between the benzene rings is 20.56 (8) degrees and the H atoms at the central propenone group are trans configured. One of the F atoms is disordered over two positions (occupancy ratio 0.57:0.43) and was refined using a split model. In the crystal, the molecules are linked into centrosymmetrical dimers and are further connected into a three dimensional network via weak C-H?O interactions. PMID- 23795119 TI - 2-[(3,4-Di-chloro-benzyl-idene)amino]-4-methyl-phenol. AB - In the title compound, C14H11Cl2NO, the dihedral angle between the benzene rings is 15.36 (8) degrees . A phenol-imine-type intra-molecular O-H?N hydrogen bond generates an S(5) ring motif. In the crystal, a pair of weak C-H?O hydrogen bonds form an R 2 (1)(7) ring motif involving glide-plane-related mol-ecules. The mol ecules linked via these inter-actions form chains along [101]. PMID- 23795120 TI - 3-Benzyl-6-bromo-1H-imidazo[4,5-b]pyridin-2(3H)-one. AB - The fused imidazole and pyridine rings in the title compound, C13H10BrN3O, are linked to a benzyl group. The fused ring system is essentially planar, the largest deviation from the mean plane being 0.006 (2) A. The phenyl ring is not coplanar with the fused ring system, as indicated by the dihedral angle of 67.04 (12) degrees . In the crystal, mol-ecules are linked by pairs of N-H?O hydrogen bonds, forming inversion dimers. PMID- 23795121 TI - 2-(9H-Fluoren-9-yl)-4-(4-fluoro-anilino)-4-oxo-butanoic acid. AB - In the title compound, C23H18FNO3, the tricyclic 9-fluorenyl system is approximately planar (r.m.s. deviation = 0.0279 A). The N-C(=O) bond length is comparatively short [1.359 (3) A], which is typical for such conjugated systems. The N atom has a planar configuration [sum of bond angles= 359.8 degrees ] due to conjugation of its lone pair with the pi-system of the carbonyl group. In the crystal, a three-dimensional network is formed through N-H?O and O-H?O hydrogen bonds between the amide and carb-oxy-lic acid groups and carbonyl O-atom acceptors. PMID- 23795122 TI - 2-[(Di-methyl-phenyl-phosphanyl-idene)aza-nium-yl]-5-methyl-benzene-sulfonate benzene monosolvate. AB - The title compound, C15H18NO3PS.C6H6, is a rare example of a crystallographically characterized exocyclic phosphiniminium-arene-sulfonate zwitterion, which crystallises as its benzene solvate. The crystal structure shows that the N atom is protonated and that the iminium H atom forms both intra- and inter-molecular hydrogen bonds to the single-bonded sulfonate O atom in an R 2 (2)(4) graph-set motif. The dihedral angle between the aromatic rings in the main molecule is 89.49 (8) degrees . PMID- 23795123 TI - 2,4,6-Tri-nitro-phenyl 3-chloro-benzoate. AB - In the title benzoate derivative, C13H6ClN3O8, the planes of the benzene rings form a dihedral angle of 73.59 (7) degrees . The central ester unit forms an angle of 20.38 (12) degrees with the chloro-substituted benzene ring. In the crystal, mol-ecules are linked by weak C-H?O inter-actions, forming helical chains along [101] and [100]. PMID- 23795124 TI - N-[(2,6-Di-ethyl-phen-yl)carbamo-thio-yl]-2,2-di-phenyl-acetamide. AB - In the title compound, C25H26N2OS, the diethyl-substituted benzene ring forms dihedral angles of 67.38 (9) and 55.32 (9) degrees with the terminal benzene rings. The mol-ecule adopts a trans-cis conformation with respect to the orientations of the di-phenyl-methane and 1,3-di-ethyl-benzene groups with respect to the S atom across the C-N bonds. This conformation is stabilized by an intra-molecular N-H?O hydrogen bond, which generates an S(6) ring. In the crystal, pairs of N-H?S hydrogen bonds link the mol-ecules into inversion dimers, forming R 2 (2)(6) loops. The dimer linkage is reinforced by a pair of C-H?S hydrogen bonds, which generate R 2 (2)(8) loops. Weak C-H?pi and pi-pi [centroid centroid seperation = 3.8821 (10) A] inter-actions also occur in the crystal structure. PMID- 23795125 TI - 6-(4-Methyl-phen-yl)-1,3,5-triazine-2,4-di-amine-benzoic acid (1/1). AB - The benzoic acid mol-ecule of the title adduct, C10H11N5.C7H6O2, is approximately planar, with a dihedral angle of 7.2 (3) degrees between the carb-oxy-lic acid group and the benzene ring. In the triazine mol-ecule, the plane of the triazine ring makes a dihedral angle of 28.85 (9) degrees with that of the adjacent benzene ring. In the crystal, the two components are linked by N-H?O and O-H?N hydrogen bonds with an R 2 (2)(8) motif, thus generating a 1 + 1 unit of triazine and benzoic acid mol-ecules. The acid-base units are further connected by N-H?N hydrogen bonds with R 2 (2)(8) motifs, forming a supra-molecular ribbon along [101]. The crystal structure also features weak pi-pi [centroid-centroid distances = 3.7638 (12) and 3.6008 (12) A] and C-H?pi inter-actions. PMID- 23795126 TI - 6-(4-Methyl-phen-yl)-1,3,5-triazine-2,4-di-amine-4-methyl-benzoic acid (1/1). AB - The 4-methyl-benzoic acid mol-ecule of the title adduct, C10H11N5.C8H8O2, is approximately planar with a dihedral angle of 6.3 (2) degrees between the carb oxy-lic acid group and the benzene ring. In the triazine mol-ecule, the plane of the triazine ring makes a dihedral angle of 29.2 (2) degrees with that of the adjacent benzene ring. In the crystal, the acid and base mol-ecules are linked via N-H?O and O-H?N hydrogen bonds with an R 2 (2)(8) motif, and the acid-base pairs are further connected via N-H?N hydrogen bonds with R 2 (2)(8) motifs, forming a supra-molecular ribbon along [101]. Between the tapes, a weak C-H?pi inter-action is observed. PMID- 23795127 TI - 1-(4-Chloro-phen-yl)-2-(1,3-diazepan-2-yl-idene)ethanone. AB - In the title compound, C13H15ClN2O, there are two crystallographically independent but conformationally similar (E)-mol-ecules in the asymmetric unit [dihedral angles between the phenyl ring and a common planar fragment of the 1,3 diazepane moiety = 47.34 (16) and 48.00 (16) degrees ]. The seven-membered ring system adopts a chair conformation in both molecules. In the crystal, N-H?O hydrogen bonds lead to chains extending along the b-axis direction. PMID- 23795129 TI - 5-(6-Amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetra-hydropyrimidin-5-yl)-1,3-dimethyl 1H-chromeno[2,3-d]pyrim-idine-2,4(3H,5H)-dione 3.5-hydrate. AB - The title compound, C19H19N5O5.3.5H2O, crystallizes with 3.5 mol-ecules of water in the asymmetric unit, one of which lies on a mirror plane. One of the water mol ecules links the mol-ecules, forming centrosymmetric dimers. These dimers are then linked through further N-H?O and O-H?O hydrogen bonding, leading to the observed three-dimensional structure. PMID- 23795128 TI - 6-[3-(p-Tolyl-sulfonyl-amino)-prop-yl]diquino-thia-zine. AB - In the title mol-ecule {systematic name: N-[3-(diquino[3,2-b;2',3'-e][1,4]thia zin-6-yl)prop-yl]-4-methyl-benzene-sulfon-amide}, C28H24N4O2S2, the penta-cyclic system is relatively planar [maximum deviation from the mean plane = 0.242 (1) A]. The dihedral angle between two quinoline ring systems is 8.23 (2) degrees and that between the two halves of the 1,4-thia-zine ring is 5.68 (3) degrees . The conformation adopted by the 3-(p-tolyl-sulfonyl-amino)-propyl substituent allows for the formation of an intra-molecular N-H?N hydrogen bond and places the benzene ring of this substituent above one of the quinoline fragments of the penta-cyclic system. In the crystal, mol-ecules are arranged via pi-pi stacking inter-actions into (0-11) layers [centroid-centroid distances = 3.981 (1)-4.320 (1) A for the rings in the penta-cyclic system and 3.645 (1) A for the tolyl benzene rings]. In addition, mol-ecules are involved in weak C-H?O, which connect the layers, and C-H?S hydrogen bonds. The title compound shows promising anti cancer activity against renal cancer cell line UO-31. PMID- 23795130 TI - 1,3,5-Tris(4-bromo-phen-yl)-1,3,5-triazin-ane di-chloro-methane monosolvate. AB - In the main mol-ecule of the title compound, C21H18Br3N3.CH2Cl2, the triazinane ring adopts a chair conformation with three 4-brom-ophenyl substituents, two in diaxial positions and the third in an equatorial arrangement (eaa). The torsion angles around the N-C bonds in the triazinane ring are in the range 55.6 (5)-60.1 (5) degrees . The structure can be described as being built up of alternating layers along the b axis with the CH2Cl2 solvent mol-ecules sandwiched between these layers. No classical hydrogen-bonding inter-actions are observed in the crystal structure. PMID- 23795131 TI - Ethyl 7-oxo-7H-benzo[de]imidazo[5,1-a]iso-quinoline-11-carboxyl-ate-tri-fluoro acetic acid (1/1). AB - The structure of the title tri-fluoro-acetic acid adduct, C17H12N2O3.C2HF3O2, contains a tri-fluoro-acetic acid mol-ecule hydrogen bonded to the imine N atom of the imidazole ring of a nearly planar four-fused-ring system (r.m.s. deviatiation = 0.013 A). The carb-oxy-lic acid group of the triflouro-acetic acid mol-ecule is twisted with respect to the mean plane of the four-fused-ring sytem by 75.9 (2) degrees . A short intra-molecular C-H?O hydrogen bond occurs. In the crystal, the adduct mol-ecules are arranged into stacks along the b axis via pi pi inter-actions between imidazole rings and between imidazole and one of the benzene rings [centroid-centroid distances 3.352 (2) and 3.485 (2) A, respectively]. Molecules are linked via C-H?O hydrogen bonds, forming an alternating polymeric head-to-head/tail-to-tail stepped chain approximately along the a-axis direction and tilted on an axis bisecting the b and c axes. PMID- 23795132 TI - 5-Benz-yloxy-3-methyl-1-tosyl-1H-indole. AB - The title compound, C23H21NO3S, represents one of the few examples of a 5 substituted indole with a toluene-sulfonyl group bonded to the N atom. The benzyl group adopts a synclinal geometry with respect to the indole ring [dihedral angle = 59.95 (4) degrees ], while the tolyl ring is oriented close to perpendicular to the indole ring, making a dihedral angle of 81.85 (3) degrees . The indole N atom exhibits a slight pyramidalization. PMID- 23795133 TI - Rupatadine. AB - IN THE TITLE COMPOUND (SYSTEMATIC NAME: 8-chloro-11-{1-[(5-methyl-pyridin-3 yl)meth-yl]piperidin-4-yl-idene}-6,11-di-hydro-5H-benzo[5,6]cyclo-hepta-[1,2 b]pyridine), C26H26ClN3, the dihedral angle between the mean planes of the chloro phenyl and cyclo-hepta-[1,2-b]pyridinyl rings fused to the cyclo-heptane ring is 56.6 (1) degrees . The mean planes of the cyclo-hepta-[1,2-b]pyridinyl and 5 methyl-pyridin-3-yl rings are twisted by 64.9 (4) degrees . The central piperizene group is in a slightly distorted chair configuration. A weak intra molecular C-H?N inter-action is observed between the cyclo-hepta-[1,2-b]pyridinyl and piperidin-4-yl-idene moieties. PMID- 23795134 TI - 4-Cyano-1-methyl-pyridinium nitrate. AB - The title mol-ecular salt, C7H7N2 (+).NO3 (-), displays an inter-penetrating sheet structure parallel to a with each sheet containing nearly coplanar cations and anions, each ion being bis-ected by a crystallographic mirror plane. C-H?O hydrogen bonds involving both ring and methyl H atoms in addition to cation cation C-H?N hydrogen bonds (ring H to cyano N) serve to link the sheets together. In each set of parallel layers, the cations and anions stack with short distances of 3.094 (2) (between aligned nitrate N and pyridine N atoms) and 3.057 (2) A (between a nitrate O atom and the ring centroid). This motif is strikingly similar to the one that features in the isomeric salt 2-cyano-1-methyl-pyridinium nitrate. PMID- 23795135 TI - 2,2',5',6-Tetra-chloro-4-[(1S)-1-methyl-prop-oxy]biphen-yl. AB - In the title mol-ecule, C16H14Cl4O, the dihedral angle between the least-square planes of the benzene rings is 84.40 (7) degrees . No unusual intermolecular interactions are present. PMID- 23795136 TI - {2-[(1,3-Benzo-thia-zol-2-yl)meth-oxy]-5-bromo-phen-yl}(phen-yl)methanone. AB - In the title compound, C21H14BrNO2S, the dihedral angle between the planes of the benzo-thia-zole and phenyl-methanone groups is 63.4 (2) degrees . In the crystal, pairs of C-H?N hydrogen bonds link the mol-ecules to form inversion dimers, which are further linked by C-H?O inter-actions into chains along the c axis. C-H?pi and pi-pi inter-actions [centroid-centroid distance = 3.863 (1) A] further stabilize the mol-ecular assembly. PMID- 23795137 TI - (E)-9-(4-Fluoro-styr-yl)-3,3,6,6-tetra-methyl-3,4,5,6,7,9-hexa-hydro-2H-xanthene 1,8-dione. AB - In the title compound, C25H27FO3, each of the cyclo-hexenone rings adopts a half chair conformation, whereas the six-membered pyran ring adopts a flattened boat conformation, with the O and methine C atoms deviating by 0.0769 (15) and 0.196 (2) A, respectively, from the plane of the other four atoms (r.m.s. deviation = 0.004 A). The C=C double bond adopts an E conformation. The dihedral angle between the benzene and pyran (all atoms) rings is 89.94 (10) degrees . In the crystal, weak C-H?O hydrogen bonds link the mol-ecules into chains running parallel to the b axis. PMID- 23795138 TI - [6-(Furan-2-yl)-7-nitro-2,3,4,6,7,8-hexa-hydro-1H-pyrido[1,2-a]pyrimidin-9 yl](phen-yl)methanone. AB - The asymmetric unit of the title compound, C19H19N3O4, contains two mol-ecules with very few conformational differences; a C atom in the pyrimidine ring in one of the mol-ecules is disordered in a 0.688 (15):0.312 (15) ratio. In both mol ecules, the fused pyridine and pyrimidine rings adopt half-chair conformations. The dihedral angles between the furan and benzene rings are 81.00 (13) and 84.99 (10) degrees in the two mol-ecules. The mol-ecular structure is consolidated by intra-molecular N-H?O hydrogen bonding. In the crystal, C-H?O hydrogen bonds connect the molecules into a three-dimensional network. PMID- 23795139 TI - Ethyl 5-methyl-3-phenyl-isoxazole-4-carboxyl-ate. AB - In the title compound, C13H13NO3, the dihedral angle between the phenyl and isoxazole rings is 43.40 (13) degrees . The eth-oxy-carbonyl group is rotated out of the plane of the isoxazole ring by 16.2 (13) degrees . PMID- 23795140 TI - 2,4,5-Triphenyl-1-(prop-2-en-1-yl)-1H-imidazole. AB - In the title compound, C24H20N2, one of the ring C atoms and one of the ring N atoms are disordered over two sets of sites in a 0.615 (3):0.385 (3) ratio. The two parts of the disordered imidazole ring adopt an envelope conformation, with the undisordered ring N atom as the flap, displaced by -0.118 (6) and 0.226 (7) A, respectively, in the two disorder components from the plane through the other ring atoms. The crystal structure features C-H?N hydrogen bonds and C-H?pi inter actions, which lead to the formation of infinite chains along [010]. PMID- 23795141 TI - Methyl 2-[(2-chloro-quinolin-3-yl)(hy-droxy)meth-yl]acrylate. AB - There are two independent mol-ecules (A and B) in the asymmetric unit of the title compound, C14H12ClNO3. The mean planes of the methyl ester unit (Cmeth-yl-O C=O; r.m.s. deviation = 0.051 A for mol-ecule A and 0.016 A for mol-ecule B) and the chloro-quilonine ring system (r.m.s. deviation = 0.023 A for mol-ecule A and 0.014 A for mol-ecule B) form dihedral angles of 63.5 (1) degrees in mol-ecule A and 78.1 (1) degrees in mol-ecule B. The main difference between the two independent mol-ecules is reflected in the (H)O-C-C=C(H2) torsion angle which is 109.7 (2) degrees in mol-ecule A and 10.6 (2) degrees in mol-ecule B. An intra molecular O-H?O hydrogen bond is observed in mol-ecule A. In the crystal, mol ecules A and B are linked into pairs via bifurcated O-H?(N,Cl) hydrogen bonds and a weak C-H?O hydrogen bond links pairs of mol-ecules into chains along [100]. PMID- 23795142 TI - N,N'-Bis(4-hy-droxy-phen-yl)pyridine-2,6-dicarboxamide di-methyl-formamide monosolvate. AB - The mol-ecular structure of the pyridine derivative, C19H15N3O4.C3H7NO, shows almost planar geometry with dihedral angles of 6.9 (1) and 13.4 (1) degrees between the pyridine ring and the two benzene rings. This conformation is stabilized by two intra-molecular N-H?N(pyridine) bonds. In the crystal, strong O H?O(carboxamide) and N-H?O(hy-droxy-phen-yl) hydrogen bonds link the mol-ecules, forming a three-dimensional structure. The di-methyl-formamide solvent mol-ecules are not involved in the hydrogen bonding. The structure shows pseudosymmetry, but refinement in the space group Pbcn leads to significantly worse results and a disordered di-methyl-formamide mol-ecule. PMID- 23795143 TI - N'-Hy-droxy-pyridine-2-carboximidamide-succinic acid (2/1). AB - The asymmetric unit of the title co-crystal, C6H7N3O.0.5C4H6O4, comprises one N' hy-droxy-pyridine-2-carboximidamide mol-ecule and half a succinic acid mol-ecule (the whole molecule is generated by inversion symmetry). In the crystal, mol ecules are assembled into columns along [110], via strong N-H?O, O-H?O and O-H?N hydrogen bonds. PMID- 23795144 TI - 6a-Nitro-6-phenyl-6,6a,6b,7,8,9,10,12a-octa-hydro-spiro-[chromeno[3,4-a]indol izine-12,3'-indolin]-2'-one. AB - In the title compound, C28H25N3O4, the central pyrrolidine ring adopts adopts an envelope conformation with the N atom as the flap and the piperidine ring adopts a chair conformation. The pendant pyrrolidine ring is almost planar (r.m.s. deviation = 0.008 A). An intra-molecular C-H?O inter-action closes an S(6) ring. In the crystal, inversion dimers linked by pairs of N-H?O hydrogen bonds generate R 2 (2)(8) loops. PMID- 23795145 TI - 2-(4-Methyl-pyridin-2-yl)-4',4',6',6'-tetra-kis-(pyrrolidin-1-yl)-1H,2H-spiro [naphtho-[1,2-e][1,3,2]oxaza-phosphinine-3,2'-[1,3,5,2,4,6]tri-aza triphosphinine]. AB - In the title spiro-phosphazene derivative, C33H46N9OP3, the phosphazene and six membered N/O rings are in flattened chair and twisted-boat conformations, respectively. The naphthalene ring system and the pyridine ring are oriented at a dihedral angle of 41.82 (4) degrees . In the crystal, weak C-H?O hydrogen bonds link the mol-ecules related by translation along the a axis into chains. C-H?pi inter-actions aggregate these chains into layers parallel to the ab plane. PMID- 23795146 TI - 2-(4-Chloro-phen-yl)-N-(3,4-di-fluoro-phen-yl)acetamide. AB - In the title compound, C14H10ClF2NO, the dihedral angle between the mean planes of the 4-chloro-phenyl and 3,4-di-fluoro-phenyl rings is 65.2 (1) degrees . These two planes are twisted by 83.5 (5) and 38.9 (9) degrees , respectively, from that of the acetamide group. In the crystal, N-H?O hydrogen bonds form infinite chains along [100]. Weak C-H?O and C-H?F inter-actions are also observed and stack mol ecules along the b axis. PMID- 23795147 TI - 3-(2-Fluoro-phenyl-sulfin-yl)-2,4,6-tri-methyl-1-benzo-furan. AB - In the title compound, C17H15FO2S, the 2-fluoro-phenyl ring makes a dihedral angle of 87.53 (5) degrees with the mean plane [r.m.s. deviation = 0.013 (1) A] of the benzo-furan fragment. In the crystal, mol-ecules are linked by weak C-H?F, C-H?O and C-H?pi inter-actions, forming a three-dimensional network. PMID- 23795148 TI - 2-Benzoyl-4-chloro-phenyl benzoate. AB - In the title compound, C20H13ClO3, the dihedral angles between the benzoate and the chloro-benzene and benzoyl rings are 68.82 (5) and 53.76 (6) degrees , respectively, while the dihedral angle between the benzoyl and benzoate rings is 81.17 (5) degrees . The eight atoms of the benzoyl residue are essentially planar with the exception of the O atom which lies 0.1860 (5) A out of their mean plane (r.m.s. deviation = 0.97 A). The nine atoms of benzoate residue are also essentially planar (r.m.s. deviation = 0.20 A) with the ester O atom showing the greatest deviation [0.407 (12) A] from their mean plane. In the crystal, mol ecules are connected into centrosymmetric dimers by pairs of C-H?O hydrogen bonds. PMID- 23795149 TI - Drinking Patterns, Gender and Health III: Avoiding vs. Seeking Healthcare. AB - BACKGROUND: Inability to predict most health services use and costs using demographics and health status suggests that other factors affect use, including attitudes and practices that influence health and willingness to seek care. Alcohol consumption has generated interest because heavy, chronic consumption causes adverse health consequences, acute consumption increases injury, and moderate drinking is linked to better health while hazardous drinking and alcohol related problems are stigmatized and may affect willingness to seek care. METHODS: A stratified random sample of health-plan members completed a mail survey, yielding 7884 respondents (2995 male/4889 female). We linked survey data to 24 months of health-plan records to examine relationships between alcohol use, gender, health-related attitudes, practices, health, and service use. In-depth interviews with a stratified 150-respondent subsample explored individuals' reasons for seeking or avoiding care. RESULTS: Quantitative results suggest health-related practices and attitudes predict subsequent service use. Consistent predictors of care were having quit drinking, current at-risk consumption, cigarette smoking, higher BMI, disliking visiting doctors, and strong religious/spiritual beliefs. Qualitative analyses suggest embarrassment and shame are strong motivators for avoiding care. CONCLUSIONS: Although models included numerous health, functional status, attitudinal and behavioral predictors, variance explained was similar to previous reports, suggesting more complex relationships than expected. Qualitative analyses suggest several potential predictive factors not typically measured in service-use studies: embarrassment and shame, fear, faith that the body will heal, expectations about likelihood of becoming seriously ill, disliking the care process, the need to understand health problems, and the effects of self-assessments of health-related functional limitations. PMID- 23795150 TI - Visualization and measurement of capillary-driven blood flow using spectral domain optical coherence tomography. AB - Capillary-driven flow (CD-flow) in microchannels plays an important role in many microfluidic devices. These devices, the most popular being those based in lateral flow, are becoming increasingly used in health care and diagnostic applications. CD-flow can passively pump biological fluids as blood, serum or plasma, in microchannels and it can enhance the wall mass transfer by exploiting the convective effects of the flow behind the meniscus. The flow behind the meniscus has not been experimentally identified up to now because of the lack of high-resolution, non-invasive, cross-sectional imaging means. In this study, spectral-domain Doppler optical coherence tomography is used to visualize and measure the flow behind the meniscus in CD-flows of water and blood. Microchannels of polydimethylsiloxane and glass with different cross-sections are considered. The predictions of the flow behind the meniscus of numerical simulations using the power-law model for non-Newtonian fluids are in reasonable agreement with the measurements using blood as working fluid. The extension of the Lucas-Washburn equation to non-Newtonian power-law fluids predicts well the velocity of the meniscus of the experiments using blood. PMID- 23795152 TI - Catalytic Asymmetric Synthesis of Branched Chiral Allylic Phenyl Ethers from (E) Allylic Alcohols. AB - The first di-MU-amidate dipalladium complexes and a new di-MU-carboxylate dipalladium complex of the COP (cobalt oxazoline palladacycle) palladium(II) catalyst family are reported and characterized crystallographically. The di-MU amidate complex 3 or its enantiomer (ent-3) are the first asymmetric catalysts that allow commercially available, or readily accessible, (E)-2-alkene-1-ols to be transformed to enantioenriched branched allylic aryl ethers upon reaction of their trichloroacetimidate derivatives with phenols. The 3-aryloxy-1-alkene products are formed in high enantiomeric purity (typically 90-98% ee) and useful yields (61-88%). PMID- 23795151 TI - A Novel Bis-Thiourea Organocatalyst for the Asymmetric Aza-Henry Reaction. AB - A novel bis-thiourea BINAM-based catalyst for the asymmetric aza-Henry reaction has been developed. This catalyst promotes the reaction of N-Boc imines with nitroalkanes to afford beta-nitroamines with good yields and high enantioselectivities. This catalyst has the advantage that it can be prepared in a single step from commercially available materials. A model is proposed for the catalyst action where the both components of the reaction are activated simultaneously by hydrogen bonding. Regardless of the mechanism, the success of the present catalyst demonstrates the potential of bis-thioureas as an interesting class of relatively unexplored catalysts. PMID- 23795154 TI - A new beginning, plus more of the same / Un nouveau depart sur la voie que nous nous sommes tracee. PMID- 23795153 TI - Genetically engineered chimeric silk-silver binding proteins. PMID- 23795155 TI - Don't tamper with oxycodone. PMID- 23795157 TI - Ontario pharmacists concerned about the risks arising from approval of generic OxyContin. PMID- 23795156 TI - What's in a drug name? PMID- 23795158 TI - BC government reveals plans to lower generic drug prices to 20% of brand-name price by April 2014. PMID- 23795160 TI - PEI government signs new services agreement with PEI Pharmacists Association. PMID- 23795159 TI - Alberta College proposal to ban prescription-drug reward programs fosters public debate. PMID- 23795161 TI - Don't sacrifice generic drug industry for sake of Canada-European trade deal. PMID- 23795162 TI - Saskatchewan pharmacists pleased with demand for prescribing services, but seek to expand assessments for minor ailments. PMID- 23795164 TI - Building a welcoming community: The role of pharmacists in improving health outcomes for immigrants and refugees. PMID- 23795165 TI - SAFER-OPIOIDS: A structured approach to identifying key information and drug therapy problems in chronic noncancer pain patients using opioid therapy. PMID- 23795166 TI - Formulating medication adherence strategies using the PASSAction framework. PMID- 23795167 TI - Living MedsCheck: Learning how to deliver MedsCheck in community practice in Ontario. AB - OBJECTIVE: To share the experiences of graduating students as they learn to deliver a new medication review service in community pharmacies in Ontario, Canada. PRACTICE DESCRIPTION: Four graduating pharmacy students volunteered in different community pharmacies to learn how to navigate a new provincial program called MedsCheck, which pays pharmacists to do medication reviews. Each student selected his or her own practice site, including 2 independent community pharmacies, a grocery store chain pharmacy and a hospital outpatient pharmacy. PRACTICE INNOVATION: To help the students learn to deliver the new MedsCheck services, a faculty mentor met with them on a weekly basis. To reflect on doing MedsChecks in the "real world" and to elicit feedback from the online community, each student blogged about his or her experiences. RESULTS: All 4 students felt that peer mentoring improved their ability to deliver MedsCheck services. They also identified a number of barriers to delivering the MedsChecks and helped each other try to overcome the barriers. CONCLUSION: MedsCheck is a new service in Ontario and is not easily implemented in the current pharmacy model of practice. Peer mentoring is a helpful way to share successes and overcome barriers to delivery. Can Pharm J 2013;146:33-38. PMID- 23795168 TI - The geographic accessibility of pharmacies in Nova Scotia. AB - INTRODUCTION: Geographic proximity is an important component of access to primary care and the pharmaceutical services of community pharmacies. Variations in access to primary care have been found between rural and urban areas in Canadian and international jurisdictions. We studied access to community pharmacies in the province of Nova Scotia. METHODS: We used information on the locations of 297 community pharmacies operating in Nova Scotia in June 2011. Population estimates at the census block level and network analysis were used to study the number of Nova Scotia residents living within 800 m (walking) and 2 km and 5 km (driving) distances of a pharmacy. We then simulated the impact of pharmacy closures on geographic access in urban and rural areas. RESULTS: We found that 40.3% of Nova Scotia residents lived within walking distance of a pharmacy; 62.6% and 78.8% lived within 2 km and 5 km, respectively. Differences between urban and rural areas were pronounced: 99.2% of urban residents lived within 5 km of a pharmacy compared with 53.3% of rural residents. Simulated pharmacy closures had a greater impact on geographic access to community pharmacies in rural areas than urban areas. CONCLUSION: The majority of Nova Scotia residents lived within walking or short driving distance of at least 1 community pharmacy. While overall geographic access appears to be lower than in the province of Ontario, the difference appears to be largely driven by the higher proportion of rural dwellers in Nova Scotia. Further studies should examine how geographic proximity to pharmacies influences patients' access to traditional and specialized pharmacy services, as well as health outcomes and adherence to therapy. Can Pharm J 2013;146:39-46. PMID- 23795169 TI - The willingness of community pharmacists to participate in a practice-based research network. AB - BACKGROUND: Practice-based research networks (PBRNs) are groups of practitioners and researchers with an interest in designing, evaluating and disseminating solutions to the real-world problems of clinical practices. OBJECTIVE: To evaluate the level of interest of community pharmacists in participating in a PBRN and to document the services such a network should offer. METHOD: In a survey of community pharmacists in Montreal, Quebec, and surrounding areas, a questionnaire was mailed to a random sample of 1250 pharmacists. Two of the 28 questions were related to PBRNs: one assessed the pharmacists' interest in participating in a PBRN; the other sought their views on which services and activities this network should offer. RESULTS: In total, 571 (45.7%) pharmacists completed the questionnaire, but 6 did not answer the questions about the PBRN. Of the respondents, 58.9% indicated they were "very interested" or "interested" in joining a PBRN, while 41.1% reported little or no interest. The most popular potential services identified were access to clinical tools developed in research projects (77.0%), access to continuing education training programs developed in research projects (75.9%), information about conferences on pharmacy practice research (64.1%) and participation in the development of new pharmaceutical practices (56.1%). CONCLUSION: This study suggests that the level of interest that community pharmacists have in PBRNs is sufficient to further evaluate how such networks may optimize and facilitate pharmacy practice research. Can Pharm J 2013;146:47-54. PMID- 23795170 TI - The Council of the Federation, pharmacy and health care reform in Canada. PMID- 23795172 TI - Natural health products: Ask your pharmacist. PMID- 23795171 TI - Hypertension: Silent and/or ignored / L'hypertension silencieuse ou ignoree. PMID- 23795173 TI - Patient care and health compromised by drug shortages in Canada: Survey of physicians and pharmacists. PMID- 23795174 TI - Provincial/territorial governments join forces to make further cuts to generic drug prices. PMID- 23795176 TI - Canadian research finds automated calling system helps identify adverse drug reactions. PMID- 23795175 TI - Pharmacist prescribing for minor ailments could significantly relieve pressure on ERs, say New Brunswick pharmacists. PMID- 23795177 TI - Federal government unveils proposals to provide "red tape relief" to pharmacies. PMID- 23795178 TI - US court sentences Canadian Internet pharmacy pioneer to 4 years in prison. PMID- 23795179 TI - Public health watch. PMID- 23795181 TI - Cardiovascular risk: Are all NSAIDs alike? PMID- 23795182 TI - Antibiotic prophylaxis in vesicoureteral reflux: A practice revisited. PMID- 23795183 TI - Key pharmacy indicators: Capturing workload and measuring operational performance in a Canadian Forces clinic. PMID- 23795184 TI - Increased bruising with the combination of long-chain omega-3 fatty acids, flaxseed oil and clopidogrel. PMID- 23795185 TI - Putting cardiovascular risk into perspective: A view from a pharmacist patient. PMID- 23795186 TI - Pharmaceutical care and access to health information decisions involving minors: Characterizing the pharmacist's obligation to the patient. PMID- 23795188 TI - Charlottetown rocks! PMID- 23795187 TI - Women in pharmacy: A preliminary study of the attitudes and beliefs of pharmacy students. AB - BACKGROUND: Women have historically been attracted to pharmacy because it is widely perceived as a profession that offers them an opportunity to combine a professional career with a family. Women now make up the majority of practising pharmacists in Canada, yet the literature demonstrates disparities such as gender segregation and underrepresentation of women in senior positions. This study was intended to identify the attitudes and beliefs of pharmacy students about women's issues in pharmacy and raise awareness of these issues. METHODS: First- and fourth-year University of Saskatchewan pharmacy students were invited to share their overall impressions of the status of female pharmacists and the impact of women on the pharmacy profession through an online questionnaire. RESULTS: Of the 60 respondents, the majority disagreed that there is segregation of men and women in pharmacy. More fourth-year students than first-year students recognized the underrepresentation of women in pharmacy management. Many students believed the number of women in pharmacy would have no negative impact on the profession. Forty students (67.8%) agreed that it is important to maintain a significant proportion of men in pharmacy. CONCLUSION: Most pharmacy students in this study do not recognize gender disparities present in pharmacy or the impact the disproportionate number of women could have on the profession. Can Pharm J 2013;146:109-116. PMID- 23795189 TI - Pharmacists' duty of care / Obligation de diligence du pharmacien. PMID- 23795190 TI - Pharmacists can play a key role in implementing new national strategy to combat prescription drug abuse. PMID- 23795192 TI - BC pharmacists propose new clinical services to save millions in health care budget. PMID- 23795191 TI - Alberta government moves without warning to dramatically cut generic pricing to lowest level in the country. PMID- 23795193 TI - Pharmacy colleges in BC and Alberta still favour inducement bans, but not right away. PMID- 23795194 TI - Universite de Moncton develops partnership with the goal of educating pharmacists in New Brunswick. PMID- 23795195 TI - Public health watch. PMID- 23795196 TI - Home medication reviews by community pharmacists: Reaching out to homebound patients. PMID- 23795197 TI - Pharmacy Investment Club: Fostering financial management skills from beyond the classroom. PMID- 23795198 TI - The 2012-2013 Canadian Hypertension Education Program (CHEP) guidelines for pharmacists: An update. PMID- 23795199 TI - How the threat of antibiotic apocalypse helped a pharmacist find her voice. PMID- 23795200 TI - Responsibility and confidence: Identifying barriers to advanced pharmacy practice. AB - BACKGROUND: Despite the changing role of the pharmacist in patient-centred practice, pharmacists anecdotally reported little confidence in their clinical decision-making skills and do not feel responsible for their patients. Observational findings have suggested these trends within the profession, but there is a paucity of evidence to explain why. We conducted an exploratory study with an objective to identify reasons for the lack of responsibility and/or confidence in various pharmacy practice settings. METHODS: Pharmacist interviews were conducted via written response, face-to-face or telephone. Seven questions were asked on the topic of responsibility and confidence as it applies to pharmacy practice and how pharmacists think these themes differ in medicine. Interview transcripts were analyzed and divided by common theme. Quotations to support these themes are presented. RESULTS: Twenty-nine pharmacists were asked to participate, and 18 responded (62% response rate). From these interviews, 6 themes were identified as barriers to confidence and responsibility: hierarchy of the medical system, role definitions, evolution of responsibility, ownership of decisions for confidence building, quality and consequences of mentorship and personality traits upon admission. DISCUSSION: We identified 6 potential barriers to the development of pharmacists' self-confidence and responsibility. These findings have practical applicability for educational research, future curriculum changes, experiential learning structure and pharmacy practice. Due to bias and the limitations of this form of exploratory research and small sample size, evidence should be interpreted cautiously. CONCLUSION: Pharmacists feel neither responsible nor confident for their clinical decisions due to social, educational, experiential and personal reasons. Can Pharm J 2013;146:155-161. PMID- 23795201 TI - Enhanced medication management services in the community: A win-win proposal from an economic, clinical and humanistic perspective. AB - BACKGROUND: Pharmacists are now receiving reimbursement by the Ontario government to do medication reviews for patients on 3 or more medications. However, they are often too busy in the community setting to thoroughly review medications with patients. Having a designated pharmacist to provide medication reviews could increase the number of reviews performed. METHODS: Step 1 involved developing a business plan to determine the number of medication reviews that needed to be done to pay a pharmacist a full-time salary. Step 2 involved establishing the core elements of medication therapy management that included medication review, a medication-related action plan, documentation and follow-up. In step 3, eligible patients were called and invited to attend an appointment to review their medications with the pharmacist. Upon completion of the medication reviews, a random group of patients were requested to complete a satisfaction survey after the medication review. RESULTS: Three hundred thirty-six patients received billable medication reviews from April 4 to July 27, 2012. Twenty-seven additional visits were performed as follow-up visits. Eighty pharmaceutical opinions met the eligibility criteria for billing. Fifteen patients received counselling for smoking cessation. Medication reviews were completed for 19 patients from 8 other pharmacies. Extra revenue was generated through the sales of replacements of expired products. An average of 2.08 drug-related problems per patients was identified. One hundred percent of the patients were very satisfied with the service. CONCLUSION: A full-time pharmacist position providing enhanced medication management services generated enough income to pay for a full-time pharmacist's salary. The benefits to the patients were an increase in identification and resolution of drug-related problems, as well as an opportunity to receive disease state education and experience an improvement in disease states. Patients were extremely satisfied with the medication review process and the service provided to them. Can Pharm J 2013;146:162-168. PMID- 23795202 TI - An educator in a pharmacist's coat: Donna Woloschuk. PMID- 23795203 TI - CPhA and other health care professions: Working for a better health care system. PMID- 23795204 TI - Elementary school children's attentional biases in physical and numerical space. AB - Numbers are conceptualized spatially along a horizontal mental line. This view is supported by mounting evidence from healthy adults and patients with unilateral spatial neglect. Little is known about children's representation of numbers with respect to space. This study investigated elementary school children's directional biases in physical and numerical space to better understand the relation between space and number. We also examined the nature of spatial organization in numerical space. In two separate tasks, children (n=57) were asked to bisect a physical line and verbally estimate the midpoint of number pairs. In general, results indicated leftward biases in both tasks, but the degree of deviation did not correlate between the tasks. In the number bisection task, leftward bias (underestimating the midpoint) increased as a function of numerical magnitude and interval between number pairs. In contrast, a rightward deviation was found for smaller number pairs. These findings suggest that different underlying spatial attentional mechanisms might be directed in physical and numerical space in young school children, which would be integrated in adulthood. PMID- 23795205 TI - TARGETING THE GENOTOXIC EFFECTS OF ESTROGENS. AB - Our studies indicate that expression of antioxidative stress enzymes is upregulated by Selective Estrogen Receptor Modulators (SERMs) in breast epithelial cell lines, providing protection against the genotoxic effects of estrogens and against estrogen-induced mammary tumorigenesis. This upregulation of antioxidative stress enzymes requires Estrogen Receptor beta (ERbeta) and human homolog of Xenopus gene which Prevents Mitotic Catastrophe (hPMC2). Further studies indicate that hPMC2 has a functional exonuclease domain that is required for upregulation of antioxidative stress enzymes by SERMs and repair of estrogen induced abasic sites. PMID- 23795206 TI - Incorporating direct-to-consumer genomic information into patient care: attitudes and experiences of primary care physicians. AB - AIM: Despite predictions of increased clinical applications, little is known about primary care providers' (PCPs') readiness to apply genomics to patient care. The aim was to assess PCPs' current experience with genetic testing, their assessment of the understandability and clinical utility of information in sample direct-to-consumer reports for genomic assessment of disease risk and warfarin dosing and attitudes toward genomic medicine. MATERIALS & METHODS: A web-based survey of PCPs who are members of Knowledge Networks' Physician Consulting Network was conducted. RESULTS: Of the 502 respondents (23.3% response rate), most ordered genetic tests infrequently. When presented with the direct-to consumer genomic testing reports, most believed the reports were understandable, and would be willing to review results with a patient, and many believed the results would be helpful in patient management. CONCLUSION: Despite limited experience with genetic tests, PCPs are open to helping patients understand genomic information. However, additional physician education is needed. PMID- 23795207 TI - A cell-matrix model of anabolic and catabolic dynamics during cartilage biomolecule regulation. AB - Physiologic regulation of extracellular matrix (ECM) in articular cartilage tissue is controlled by cellular and molecular mechanisms which are not fully understood. It has been observed that the synthesis of the ECM structural molecules, glycosaminoglycan and collagen are promoted by growth factors such as IGF-1 and TGF-beta. Concomitant ECM degradation is promoted by a variety of cytokines such as IL-1. The clinical need for reparative therapies of articular cartilage is linked with its poor intrinsic healing capacity. The following modelling approach was applied to engineered cartilage as a platform for exploring cartilage biology and to introduce a predictive tool as a bioinformatic support system supporting regenerative therapies. Systems biology was adapted through a mathematical framework producing a computational intelligence paradigm to explore a controlled phasic regulatory influence of the inhibition and production of ECM biomolecules. Model outcomes describe a steady synthesis of ECM as a dependence on a cyclic influence of the catabolic action of proteases and anabolic action of growth factors. This relationship is shown quantitatively in a governing harmonic equation representing the simplified biological mechanisms of biomolecule homeostasis. PMID- 23795208 TI - Characterisation of polymer shelled microbubbles in wall less flow phantom using high frequency ultrasound and video microscopy. AB - A high frequency ultrasound pulse echo system and a video microscope were combined to investigate the relationship between backscatter from polymer shelled ultrasound contrast agents (UCAs) and their diameter. Individual UCAs (manufactured by Point Biomedical or Philips Research) were imaged while being sonicated with 40 MHz tone bursts. The backscatter magnitude produced by the Philips UCAs was proportional to UCA size, which is consistent with theoretically predicted behaviour of encapsulated microbubbles driven at frequencies above resonance. Despite being smaller, the Point UCAs produced a backscatter magnitude twice that of Philips UCAs, indicating that Point UCAs might behave quasi resonantly when excited at 40 MHz. PMID- 23795209 TI - The effect direction plot: visual display of non-standardised effects across multiple outcome domains. AB - Visual display of reported impacts is a valuable aid to both reviewers and readers of systematic reviews. Forest plots are routinely prepared to report standardised effect sizes, but where standardised effect sizes are not available for all included studies a forest plot may misrepresent the available evidence. Tabulated data summaries to accompany the narrative synthesis can be lengthy and inaccessible. Moreover, the link between the data and the synthesis conclusions may be opaque. This paper details the preparation of visual summaries of effect direction for multiple outcomes across 29 quantitative studies of the health impacts of housing improvement. A one page summary of reported health outcomes was prepared to accompany a 10 000-word narrative synthesis. The one page summary included details of study design, internal validity, sample size, time of follow up, as well as changes in intermediate outcomes, for example, housing condition. This approach to visually summarising complex data can aid the reviewer in cross study analysis and improve accessibility and transparency of the narrative synthesis where standardised effect sizes are not available. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 23795210 TI - Quantitation of dopamine, serotonin and adenosine content in a tissue punch from a brain slice using capillary electrophoresis with fast-scan cyclic voltammetry detection. AB - Methods to determine neurochemical concentrations in small samples of tissue are needed to map interactions among neurotransmitters. In particular, correlating physiological measurements of neurotransmitter release and the tissue content in a small region would be valuable. HPLC is the standard method for tissue content analysis but it requires microliter samples and the detector often varies by the class of compound being quantified; thus detecting molecules from different classes can be difficult. In this paper, we develop capillary electrophoresis with fast-scan cyclic voltammetry detection (CE-FSCV) for analysis of dopamine, serotonin, and adenosine content in tissue punches from rat brain slices. Using field-amplified sample stacking, the limit of detection was 5 nM for dopamine, 10 nM for serotonin, and 50 nM for adenosine. Neurotransmitters could be measured from a tissue punch as small as 7 ug (7 nL) of tissue, three orders of magnitude smaller than a typical HPLC sample. Tissue content analysis of punches in successive slices through the striatum revealed higher dopamine but lower adenosine content in the anterior striatum. Stimulated dopamine release was measured in a brain slice, then a tissue punch collected from the recording region. Dopamine content and release had a correlation coefficient of 0.71, which indicates much of the variance in stimulated release is due to variance in tissue content. CE-FSCV should facilitate measurements of tissue content in nanoliter samples, leading to a better understanding of how diseases or drugs affect dopamine, serotonin, and adenosine content. PMID- 23795212 TI - Benefits of hyperbaric oxygen therapy still doubtful. PMID- 23795211 TI - Descemet stripping endothelial keratoplasty--rapid recovery of visual acuity. AB - BACKGROUND: Technical innovations in corneal transplantation have now made it possible to replace only the diseased part of the cornea, rather than the entire cornea as in penetrating keratoplasty (PKP). Patients with endothelial insufficiency due to Fuchs endothelial dystrophy, bullous keratopathy, or endothelial failure after keratoplasty can be treated with the new methods of posterior lamellar corneal transplantation: Descemet stripping automated endothelial keratoplasty (DSAEK) and Descemet membrane endothelial keratoplasty (DMEK). It remains unclear which of these methods is better in the individual case. METHODS: We review the pertinent literature retrieved by a selective search in Medline and the Cochrane Library employing the terms "DMEK," "DSAEK," "DSEK," and "posterior lamellar keratoplasty." The publications considered in this article are those that contain important clinical information on the operative techniques. RESULTS: No randomized controlled trials of these techniques have been published to date. Numerous case series have shown that patients who undergo DSAEK (postoperative visual acuity >=0.5 in 38-100%), and especially those who undergo it in early or intermediate stages of endothelial insufficiency, achieve a better functional result more rapidly than patients treated with PKP (postoperative visual acuity >=0.5 in 47-61%). Only 23-47% of DSAEK patients achieve a visual acuity of 0.8 or more, compared to 36-79% of DMEK patients. Moreover, transplant rejection is seen in only 1-3% of cases of DMEK, compared to 0-8% after DSAEK and 1-23% after PKP. CONCLUSION: Numerous case series show clear advantages of DMEK over DSAEK, which, in turn, has better results than PKP. Nonetheless, randomized controlled trials are needed to determine which operative method is best in each stage of corneal disease. PMID- 23795213 TI - Hydrogel dressings are obsolete. PMID- 23795214 TI - Topical honey for diabetic foot ulcers. PMID- 23795215 TI - Wound care products are not completely expendable. PMID- 23795216 TI - Clear decision criteria are lacking. PMID- 23795217 TI - In reply. PMID- 23795219 TI - A Two-Step Penalized Regression Method with Networked Predictors. AB - Penalized regression incorporating prior dependency structure of predictors can be effective in high-dimensional data analysis (Li and Li 2008). Pan, Xie and Shen (2010) proposed a penalized regression method for better outcome prediction and variable selection by smoothing parameters over a given predictor network, which can be applied to analysis of microarray data with a given gene network. In this paper, we develop two modifications to their method for further performance enhancement. First, we employ convex programming and show its improved performance over an approximate optimization algorithm implemented in their original proposal. Second, we perform bias reduction after initial variable selection through a new penalty, leading to better parameter estimates and outcome prediction. Simulations have demonstrated substantial performance improvement of the proposed modifications over the original method. PMID- 23795218 TI - The diagnosis and treatment of giant cell arteritis. AB - BACKGROUND: Giant cell arteritis (GCA) is the most common systemic vasculitis in persons aged 50 and above (incidence, 3.5 per 100,000 per year). It affects cranial arteries, the aorta, and arteries elsewhere in the body, e.g., in the limbs. METHODS: We selectively review the pertinent literature, including guidelines and recommendations from Germany and abroad. RESULTS: The typical symptoms of new-onset GCA are bitemporal headaches, jaw claudiacation, scalp tenderness, visual disturbances, systemic symptoms such as fever and weight loss, and polymyalgia. The diagnostic assessment comprises laboratory testing (erythrocyte sedimentation rate, C-reactive protein), imaging studies (duplex sonography, high-resolution magnetic resonance imaging, positron-emission tomography), and temporal artery biopsy. The standard treatment is with corticosteroids (adverse effects: diabetes mellitus, osteoporosis, cataract, arterial hypertension). A meta-analysis of three randomized controlled trials led to a recommendation for treatment with methotrexate to lower the recurrence rate and spare steroids. Patients for whom methotrexate is contraindicated or who cannot tolerate the drug can be treated with azathioprine instead. CONCLUSION: Giant cell arteritis, if untreated, progresses to involve the aorta and its collateral branches, leading to various complications. Late diagnosis and treatment can have serious consequences, including irreversible loss of visual function. PMID- 23795220 TI - Priority-setting for evidence-based health outreach in community-based organizations: A mixed-methods study in three Massachusetts communities. PMID- 23795221 TI - Adolescents in Primary Care with Sub-Threshold Depressed Mood Screened for Participation in a Depression Prevention Study: Co-Morbidity and Factors Associated with Depressive Symptoms. AB - PURPOSE: Adolescents in primary care with sub-threshold depression symptoms may be candidates for early intervention to prevent onset of full major depressive disorder. Little is known about this population. METHOD: We screened consecutive adolescents (ages 14-21) in 13 primary care sites for presence of depression symptoms for "at least a few days" or "nearly every day" in the last two weeks for possible enrollment in a primary care/Internet-based depression prevention intervention (CATCH-IT). We report illness severity, prevalence of self-harm ideation, prevalence correlates (automatic negative thoughts, generalized self efficacy, perceived social support from family and friends) and co-occurring symptoms of other mental disorders with depressed mood. RESULTS: Twenty-one percent (N=293) of those screened reported a core symptom of depressive disorder of which 83 enrolled in the study and were analyzed. The sample was 40% ethnic minority with a mean zip code household income of $40,249 (SD=$14,500). Reporting at least one symptom of another mental disorder was common for anxiety (48%, N=40), substance abuse (31%, N=15), conduct disorder (71%, N=53), as were self harm ideation (16%, N=12) and reporting school impairment (100%, N=83). Prevalence correlates for current depressive symptoms included low self-efficacy, automatic negative thoughts, perceived low peer acceptance, and school impairment. CONCLUSIONS: Adolescents with sub-threshold depressed mood have frequent co-morbid symptoms that may need to be considered in developing prevention interventions. Early intervention targets to reduce depressed mood include pessimistic thinking, low self-efficacy, low peer acceptance, and school impairment. PMID- 23795223 TI - A novel approach to improve health status measurement in observational claims based studies of cancer treatment and outcomes. AB - OBJECTIVES: To develop and provide initial validation for amultivariate, claims based prediction model for disability status (DS), a proxymeasure of performance status (PS), among older adults. The model was designed to augment information on health status at the point of cancer diagnosis in studies using insurance claims to examine cancer treatment and outcomes. MATERIALS AND METHODS: We used data from the 2001-2005 Medicare Current Beneficiary Survey (MCBS), with observations randomly split into estimation and validation subsamples. We developed an algorithm linking self-reported functional status measures to a DS scale, a proxy for the Eastern Cooperative Oncology Group (ECOG) PS scale. The DS measure was dichotomized to focus on good [ECOG 0-2] versus poor [ECOG 3-4] PS. We identified potential claims-based predictors, and estimated multivariate logistic regression models, with poor DS as the dependent measure, using a stepwise approach to select the optimal model. Construct validity was tested by determining whether the predicted DS measure generated by the model was a significant predictor of survival within a validation sample from the MCBS. RESULTS AND CONCLUSION: One tenth of the beneficiaries met the definition for poor DS. The base model yielded high sensitivity (0.79) and specificity (0.92); positive predictive value=48.3% and negative predictive value=97.8%, c-statistic=0.92 and good model calibration. Adjusted poor claims-based DS was associated with an increased hazard of death (HR=3.53, 95% CI 3.18, 3.92). The ability to assess DS should improve covariate control and reduce indication bias in observational studies of cancer treatment and outcomes based on insurance claims. PMID- 23795225 TI - Self-perceptions of age among 292 chemotherapy-treated cancer patients: Exploring associations with symptoms and survival. AB - OBJECTIVE: A growing literature suggests that older individuals who report feeling younger than their actual chronological age enjoy better health and survival. The purpose of this study was to explore similar associations in patients with cancer. METHODS: Chemotherapy-treated cancer patients completed a previously-validated questionnaire item on their self-perception of age. Concurrent patient-reported number of symptoms and pain severity were recorded. In addition, baseline and longitudinal data captured demographics and vital status, respectively. RESULTS: Among 292 patients, 185 (63%) reported that they perceived themselves as younger than their actual age, 45 as older (15%), and 56 (19%) as the same age (unable to be determined in 6). The mean actual chronological age (standard deviation) among those who perceived themselves as younger, older, or the same age was 63 years (11), 54 (12), and 60 (10); (p < 0.0001). An inverse relationship was observed between self-perceived age and actual age (odds ratio 1.05 with 95% confidence interval of 1.02, 1.07; p = 0.0001) but, otherwise, no statistically significant relationships were observed with gender, cancer curability potential, number of symptoms, or pain severity. Improved survival was associated with fewer symptoms and the potential for curing the cancer, but not with patients' age perceptions. Qualitative themes such as positive thinking, staying engaged with life, the importance of family, and maintaining a sense of humor emerged among those who felt younger. CONCLUSION: A substantial percentage of patients with cancer - particularly older ones - report feeling younger than their actual age; this perception appears to have no relevance to symptoms or survival. PMID- 23795226 TI - A HIERARCHICAL MAX-STABLE SPATIAL MODEL FOR EXTREME PRECIPITATION. AB - Extreme environmental phenomena such as major precipitation events manifestly exhibit spatial dependence. Max-stable processes are a class of asymptotically justified models that are capable of representing spatial dependence among extreme values. While these models satisfy modeling requirements, they are limited in their utility because their corresponding joint likelihoods are unknown for more than a trivial number of spatial locations, preventing, in particular, Bayesian analyses. In this paper, we propose a new random effects model to account for spatial dependence. We show that our specification of the random effect distribution leads to a max-stable process that has the popular Gaussian extreme value process (GEVP) as a limiting case. The proposed model is used to analyze the yearly maximum precipitation from a regional climate model. PMID- 23795224 TI - Geriatric assessment is associated with completion of chemotherapy, toxicity, and survival in older adults with cancer. AB - OBJECTIVES: Our purpose was to determine whether geriatric assessments are associated with completion of a chemotherapy course, grade III/IV toxicity or survival in older adults with cancer. MATERIALS AND METHODS: In this prospective cohort study, patients aged 65 years and older with colorectal, lung, or breast cancer or lymphoma completed a brief geriatric assessment prior to chemotherapy. Endpoints included completion of the planned number of chemotherapy cycles, grade III/IV toxicity and survival. Multivariate logistic regression determined which factors were independently associated with completion of therapy, grade III/IV toxicity or death. RESULTS: Sixty-five patients were enrolled in the study. The median age was 73 years (range 65-89). Geriatric syndromes were common, including depression (21.5%), dependence on others to carry out instrumental activities of daily living (38.5%) and activities of daily living (10.8%), and comorbidities (mild 47.7%, moderate 20%, severe 15.4%). Of the 65 participants, 67.6%completed the planned number of chemotherapy cycles. Curative intent therapy [OR 4.97 (95% CI 1.21-18.81)], Eastern Cooperative Oncology Group (ECOG) performance status 2-3 [OR 0.089 (0.015-0.53)] and renal function [OR 1.03 (1.00-1.06) per ml/min] were significantly associated with therapy completion. Furthermore, 31.1% experienced grade III/IV nonhematologic toxicity. Moderate to severe comorbidities significantly increased the risk of grade III/IV non-hematologic toxicity [OR 6.13 (1.65-22.74)]. Patients who received chemotherapy with curative intent had lower mortality [HR 0.15 (0.06-0.42)], while patients who reported a fall in themonth prior to chemotherapy had an increased risk of death [HR 3.20 (1.13 9.11)]. CONCLUSIONS: Geriatric assessment is associatedwith completion of a planned number of cycles of chemotherapy, grade III/IV non-hematologic toxicity, and mortality. PMID- 23795227 TI - Organically Modified Silica Nanoparticles with Intraparticle Heavy-Atom Effect on the Encapsulated Photosensitizer for Enhanced Efficacy of Photodynamic Therapy. AB - We report a novel nanoassembly formulation for photodynamic therapy, which is composed of covalently iodine-concentrated organically modified silica (ORMOSIL) nanoparticles (diameter <30 nm) and a hydrophobic photosensitizer embedded therein. Comparative studies with iodinated and non-iodinated nanoparticles have demonstrated that the intraparticle external heavy-atom effect on the encapsulated photosensitizer molecules significantly enhances the efficiency of 1O2 generation, and thereby, the in vitro PDT efficacy. PMID- 23795222 TI - Advances in Integrative Nanomedicine for Improving Infectious Disease Treatment in Public Health. AB - INTRODUCTION: Infectious diseases present public health challenges worldwide. An emerging integrative approach to treating infectious diseases is using nanoparticle (NP) forms of traditional and alternative medicines. Advantages of nanomedicine delivery methods include better disease targeting, especially for intracellular pathogens, ability to cross membranes and enter cells, longer duration drug action, reduced side effects, and cost savings from lower doses. METHODS: We searched Pubmed articles in English with keywords related to nanoparticles and nanomedicine. Nanotechnology terms were also combined with keywords for drug delivery, infectious diseases, herbs, antioxidants, homeopathy, and adaptation. RESULTS: NPs are very small forms of material substances, measuring 1-100 nanometers along at least one dimension. Compared with bulk forms, NPs' large ratio of surface-area-to-volume confers increased reactivity and adsorptive capacity, with unique electromagnetic, chemical, biological, and quantum properties. Nanotechnology uses natural botanical agents for green manufacturing of less toxic NPs. DISCUSSION: Nanoparticle herbs and nutriceuticals can treat infections via improved bioavailability and antiinflammatory, antioxidant, and immunomodulatory effects. Recent studies demonstrate that homeopathic medicines may contain source and/or silica nanoparticles because of their traditional manufacturing processes. Homeopathy, as a form of nanomedicine, has a promising history of treating epidemic infectious diseases, including malaria, leptospirosis and HIV/AIDS, in addition to acute upper respiratory infections. Adaptive changes in the host's complex networks underlie effects. CONCLUSIONS: Nanomedicine is integrative, blending modern technology with natural products to reduce toxicity and support immune function. Nanomedicine using traditional agents from alternative systems of medicine can facilitate progress in integrative public health approaches to infectious diseases. PMID- 23795228 TI - Citrate-capped gold nanoparticle electrophoretic heat production in response to a time-varying radiofrequency electric-field. AB - The evaluation of heat production from gold nanoparticles (AuNPs) irradiated with radiofrequency (RF) energy has been problematic due to Joule heating of their background ionic buffer suspensions. Insights into the physical heating mechanism of nanomaterials under RF excitations must be obtained if they are to have applications in fields such as nanoparticle-targeted hyperthermia for cancer therapy. By developing a purification protocol which allows for highly-stable and concentrated solutions of citrate-capped AuNPs to be suspended in high resistivity water, we show herein, for the first time, that heat production is only evident for AuNPs of diameters <= 10 nm, indicating a unique size-dependent heating behavior not previously observed. Heat production has also shown to be linearly dependent on both AuNP concentration and total surface area, and severely attenuated upon AuNP aggregation. These relationships have been further validated using permittivity analysis across a frequency range of 10 MHz to 3 GHz, as well as static conductivity measurements. Theoretical evaluations suggest that the heating mechanism can be modeled by the electrophoretic oscillation of charged AuNPs across finite length scales in response to a time-varying electric field. It is anticipated these results will assist future development of nanoparticle-assisted heat production by RF fields for applications such as targeted cancer hyperthermia. PMID- 23795229 TI - Photoinduced Charge Transfer from Titania to Surface Doping Site. AB - We evaluate a theoretical model in which Ru is substituting for Ti at the (100) surface of anatase TiO2. Charge transfer from the photo-excited TiO2 substrate to the catalytic site triggers the photo-catalytic event (such as water oxidation or reduction half-reaction). We perform ab-initio computational modeling of the charge transfer dynamics on the interface of TiO2 nanorod and catalytic site. A slab of TiO2 represents a fragment of TiO2 nanorod in the anatase phase. Titanium to ruthenium replacement is performed in a way to match the symmetry of TiO2 substrate. One molecular layer of adsorbed water is taken into consideration to mimic the experimental conditions. It is found that these adsorbed water molecules saturate dangling surface bonds and drastically affect the electronic properties of systems investigated. The modeling is performed by reduced density matrix method in the basis of Kohn-Sham orbitals. A nano-catalyst modeled through replacement defect contributes energy levels near the bottom of the conduction band of TiO2 nano-structure. An exciton in the nano-rod is dissipating due to interaction with lattice vibrations, treated through non-adiabatic coupling. The electron relaxes to conduction band edge and then to the Ru cite with faster rate than hole relaxes to the Ru cite. These results are of the importance for an optimal design of nano-materials for photo-catalytic water splitting and solar energy harvesting. PMID- 23795231 TI - Assessment and instruction of oral reading fluency among adults with low literacy. AB - We statistically examined 295 low-literacy adults' oral reading fluency measured by total word and word error rates with connected prose. Based on four fluency ability groupings in relation to standardized assessments of reading-related skills (e.g., phonemic awareness, word recognition, vocabulary, comprehension, and general ability) the results suggest that adults that read at comparable correct word rates vary significantly in the number of total words and word errors. These differences were independent of assessed general ability level. Total word and word error rates, thus, offer a picture of learner reading ability that can help instructors emphasize instruction in deficit reading components. PMID- 23795230 TI - Folded Conformation, Cyclic Pentamer, Nano-Structure and PAD4 Binding Mode of YW3 56. AB - The physical and chemical mechanisms of small molecules with pharmacological activity forming nano-structures are developing into a new field of nano medicine. By using ROESY 2D NMR spectroscopy, trandem mass spectroscopy, transmission electron microscopy and computer-assisted molecular modeling, this paper demonstrated the contribution of the folded conformation, the intra- and intermolecular pi-pi stacking, the intra- and intermolecular hydrogen bonds, and the receptor binding free energy of 6-dimethylaminonaph-2-yl-{N-S-[1-benzylcarba moyl-4-(2-chloroacetamidobutyl)]-carboxamide (YW3-56) to the rapid formation of nano-rings and the slow formation of nano-capsules. Thus we have developed a strategy that makes it possible to elucidate the physical and chemical mechanisms of bioactive small molecules forming nano-structures. PMID- 23795232 TI - Efficient distribution estimation for data with unobserved sub-population identifiers. AB - We study efficient nonparametric estimation of distribution functions of several scientifically meaningful sub-populations from data consisting of mixed samples where the sub-population identifiers are missing. Only probabilities of each observation belonging to a sub-population are available. The problem arises from several biomedical studies such as quantitative trait locus (QTL) analysis and genetic studies with ungenotyped relatives where the scientific interest lies in estimating the cumulative distribution function of a trait given a specific genotype. However, in these studies subjects' genotypes may not be directly observed. The distribution of the trait outcome is therefore a mixture of several genotype-specific distributions. We characterize the complete class of consistent estimators which includes members such as one type of nonparametric maximum likelihood estimator (NPMLE) and least squares or weighted least squares estimators. We identify the efficient estimator in the class that reaches the semiparametric efficiency bound, and we implement it using a simple procedure that remains consistent even if several components of the estimator are mis specified. In addition, our close inspections on two commonly used NPMLEs in these problems show the surprising results that the NPMLE in one form is highly inefficient, while in the other form is inconsistent. We provide simulation procedures to illustrate the theoretical results and demonstrate the proposed methods through two real data examples. PMID- 23795233 TI - A Model-Based fMRI Analysis with Hierarchical Bayesian Parameter Estimation. AB - A recent trend in decision neuroscience is the use of model-based fMRI using mathematical models of cognitive processes. However, most previous model-based fMRI studies have ignored individual differences due to the challenge of obtaining reliable parameter estimates for individual participants. Meanwhile, previous cognitive science studies have demonstrated that hierarchical Bayesian analysis is useful for obtaining reliable parameter estimates in cognitive models while allowing for individual differences. Here we demonstrate the application of hierarchical Bayesian parameter estimation to model-based fMRI using the example of decision making in the Iowa Gambling Task. First we use a simulation study to demonstrate that hierarchical Bayesian analysis outperforms conventional (individual- or group-level) maximum likelihood estimation in recovering true parameters. Then we perform model-based fMRI analyses on experimental data to examine how the fMRI results depend upon the estimation method. PMID- 23795234 TI - Coronary Artery Calcium Testing in Symptomatic Patients: An Issue of Diagnostic Efficiency. AB - The detection and quantification of coronary artery calcification (CAC) significantly improves cardiovascular risk prediction in asymptomatic patients. Many have advocated for expanded CAC testing in symptomatic patients based on data demonstrating that the absence of quantifiable CAC in patients with possible angina makes obstructive coronary artery disease (CAD) and subsequent adverse events highly unlikely. However, the widespread use of CAC testing in symptomatic patients may be limited by the high background prevalence of CAC and its low specificity for obstructive CAD, necessitating additional testing ('test layering') in a large percentage of eligible patients. Further, adequately powered prospective studies validating the comparative effectiveness of a 'CAC first' approach with regards to cost, safety, accuracy and clinical outcomes are lacking. Due to marked reductions in patient radiation exposure and higher comparative accuracy and prognostic value make coronary computed tomographic angiography the preferred CT-based test for appropriately selected symptomatic patients. PMID- 23795236 TI - The rainbow and the worm: Establishing a new physics of life. AB - What is life? Many have asked this question, and no definitive answer is yet widely accepted. Is life something truly distinct from non-living stuff, as many dualists have suggested for millennia? Is there an elan vital that distinguishes living from dead stuff? Or is life about certain types of organization, metabolism, reproduction, goal-oriented behavior? None of these answers have yet won the debate. There is, however, an intriguing new set of ideas that have been developed by Mae-Wan Ho, a biophysicist and science activist (as she calls herself) based in London. Ho's basic assertion is that life exists on a spectrum and is at its root organized, quantum coherent energy. Ho's work attempts to bridge the gap between physics and biology by recognizing that there is no real gap at all-just a gap in current methods and habits of thinking. PMID- 23795235 TI - Chemical warfare: Leaf-cutting ants defend themselves and their gardens against parasite attack by deploying antibiotic secreting bacteria. AB - Leaf-cutting ants are well known for their highly complex social organization, which provides them with a strong defense against parasites invading their colonies. Besides this attribute, these insects have morphological, physiological and structural characteristics further reinforcing the defense of their colonies. With the discovery of symbiotic bacteria present on the integument of leaf cutting ants, a new line of defense was proposed and considered to be specific for the control of a specialized fungal parasite of the ants' fungus gardens (Escovopsis). However, recent studies have questioned the specificity of the integumental bacteria, as they were also found to inhibit a range of fungi, including entomopathogens. The microbiota associated with the leaf-cutting ant gardens has also been proposed as another level of chemical defense, protecting the garden from parasite invasion. Here we review the chemical defense weaponry deployed by leaf-cutting ants against parasites of their fungus gardens and of the ants themselves. PMID- 23795237 TI - Prior Sexual Trauma and Adjustment Following the Virginia Tech Campus Shootings: Examination of the Mediating Role of Schemas. AB - A sizable body of research supports trauma's cumulative nature. However, few studies have evaluated potential mechanisms through which the experience of multiple traumas leads to elevated distress. The current study sought to evaluate differences between sexual trauma victims and women who had not experienced sexual trauma in their adjustment following a mass trauma (college women exposed to the 2007 Virginia Tech campus shooting). In addition, the study examined whether maladaptive schema change (lower self-worth and less belief in benevolence) and social support mediated the relationship between experiencing multiple traumas (sexual trauma and the campus shooting) and distress. The sample consisted of 215 college women who were assessed preshooting as well as two months and one year following the campus shooting. Women who had experienced sexual trauma (either contact sexual abuse or sexual assault) were compared to those who had not on their one-year postshooting PTSD and depressive symptoms. Results supported that sexual trauma victims reported significantly more depressive symptoms and shooting-related PTSD as well as less belief in benevolence and lower family support. Family support and benevolence beliefs at the two month postshooting assessment were significant medi-ators of the association between sexual trauma history and depression and PTSD. Implications of the findings for future research evaluating the cumulative impact of multiple traumatic experiences are discussed. PMID- 23795238 TI - Synthesis of 4'-Ethynyl-2'-deoxy-4'-thioribonucleosides and Discovery of a Highly Potent and Less Toxic NRTI. AB - The synthesis of 4'-ethynyl-2'-deoxy-4'-thioribonucleosides was carried out utilizing an electrophilic glycosidation in which 4-ethynyl-4-thiofuranoid glycal 16 served as a glycosyl donor. Electrophilic glycosidation between 16 and the silylated nucleobases (N4-acetylcytosine, N6-benzoyladenine and N2-acetyl-O6 diphenylcarbamoylguanine) was carried out in the presence of N-iodosuccinimide (NIS) leading to the exclusive formation of the desired beta-anomers 29, 33 and 36. Anti-HIV studies demonstrated that these 4'-thio nucleosides were less cytotoxic to T-lymphocyte (i.e. MT-4 cells) than the corresponding 4'-ethynyl derivatives of 2'-deoxycytidine (44), 2'-deoxyadenosine (45) and 2' deoxyguanosine (46). Comparison of the selectivity indices (SI) was made between 4'-thionucleosides (32, 41 and 43) and the corresponding 4'-oxygen analogues 44 46 by using the reported CC50 and EC50 values. In the case of cytosine and adenine nucleosides, comparable SI values were obtained: 32 (545) and 45 (458); 41 (>230) and 45 (1,630). In contrast, 4'-ethynyl-2'-deoxy-4'-thioguanosine 43 was found to possess a SI value of >18,200, which is twenty times better than that of 46 (933). PMID- 23795239 TI - L-Aminoacyl-triazine derivatives are isoform-selective PI3Kbeta inhibitors that target non-conserved Asp862 of PI3Kbeta AB - A series of aminoacyl-triazine derivatives based upon the pan-PI3K inhibitor ZSTK474 were identified as potent and isoform selective inhibitors of PI3Kbeta. The compounds showed selectivity based upon stereochemistry with L-amino acyl derivatives preferring PI3Kbeta while their D-congeners favoured PI3Kdelta. The mechanistic basis of this inhibition was studied using site-directed mutants. One Asp residue, D862 was identified as a critical participant in binding to the PI3Kbeta-selective inhibitors distinguishing this class from other reported PI3Kbeta-selective inhibitors. The compounds show strong inhibition of cellular Akt phosphorylation and growth of PTEN-deficient MD-MBA-468 cells. PMID- 23795240 TI - Antimalarial and Structural Studies of Pyridine-containing Inhibitors of 1 Deoxyxylulose-5-phosphate Reductoisomerase. AB - 1-Deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) in the non-mevalonate isoprene biosynthesis pathway is a target for developing antimalarial drugs. Fosmidomycin, a potent DXR inhibitor, showed safety as well as efficacy against P. falciparum malaria in clinical trials. Based on our previous quantitative structure activity relationship (QSAR) and crystallographic studies, several novel pyridine-containing fosmidomycin derivatives were designed, synthesized and found to be highly potent inhibitors of P. falciparum DXR (PfDXR) having Ki values of 1.9 - 13 nM, with the best one being ~11* more active than fosmidomycin. These compounds also potently block the proliferation of multi-drug resistant P. falciparum with EC50 values as low as 170 nM. A 2.3 A crystal structure of PfDXR in complex with one of the inhibitors is reported, showing the flexible loop of the protein undergoes conformational changes upon ligand binding and a hydrogen bond and favorable hydrophobic interactions between the pyridine group and PfDXR account for the enhanced activity. PMID- 23795241 TI - Crystallographic Investigation and Selective Inhibition of Mutant Isocitrate Dehydrogenase. AB - Mutations in isocitrate dehydrogenase (IDH), a key enzyme in the tricarboxylic acid cycle, have recently been found in ~75% glioma and ~20% acute myeloid leukemia. Different from the wild-type enzyme, mutant IDH1 catalyzes the reduction of alpha-ketoglutaric acid to D-2-hydroxyglutaric acid. Strong evidence has shown mutant IDH1 represents a novel target for this type of cancer. We found two 1-hydroxypyridin-2-one compounds that are potent inhibitors of R132H and R132C IDH1 mutants with Ki values as low as 120 nM. These compounds exhibit >60 fold selectivity against wild-type IDH1 and can inhibit the production of D-2 hydroxyglutaric acid in IDH1 mutated cells, representing novel chemical probes for cancer biology studies. We also report the first inhibitor-bound crystal structures of IDH1(R132H), showing these inhibitors have H-bond, electrostatic and hydrophobic interactions with the mutant enzyme. Comparison with the substrate-bound IDH1 structures revealed the structural basis for the high enzyme selectivity of these compounds. PMID- 23795242 TI - Supramolecular Structures of Enzyme Clusters. AB - The structural characterization of subtilisin mesoscale clusters, which were previously shown to induce supramolecular order in biocatalytic self-assembly of Fmoc-dipeptides, was carried out by synchrotron small-angle X-ray, dynamic, and static light scattering measurements. Subtilisin molecules self-assemble to form supramolecular structures in phosphate buffer solutions. Structural arrangement of subtilisin clusters at 55 degrees C was found to vary systematically with increasing enzyme concentration. Static light scattering measurements showed the cluster structure to be consistent with a fractal-like arrangement, with fractal dimension varying from 1.8 to 2.6 with increasing concentration for low to moderate enzyme concentrations. This was followed by a structural transition around the enzyme concentration of 0.5 mg mL-1 to more compact structures with significantly slower relaxation dynamics, as evidenced by dynamic light scattering measurements. These concentration-dependent supramolecular enzyme clusters provide tunable templates for biocatalytic self-assembly. PMID- 23795243 TI - Virtual Screening for Dipeptide Aggregation: Toward Predictive Tools for Peptide Self-Assembly. AB - Several short peptide sequences are known to self-assemble into supramolecular nanostructures with interesting properties. In this study, coarse-grained molecular dynamics is employed to rapidly screen all 400 dipeptide combinations and predict their ability to aggregate as a potential precursor to their self assembly. The simulation protocol and scoring method proposed allows a rapid determination of whether a given peptide sequence is likely to aggregate (an indicator for the ability to self-assemble) under aqueous conditions. Systems that show strong aggregation tendencies in the initial screening are selected for longer simulations, which result in good agreement with the known self-assembly or aggregation of dipeptides reported in the literature. Our extended simulations of the diphenylalanine system show that the coarse-grain model is able to reproduce salient features of nanoscale systems and provide insight into the self assembly process for this system. PMID- 23795244 TI - Driven Metadynamics: Reconstructing Equilibrium Free Energies from Driven Adaptive-Bias Simulations. AB - We present a novel free-energy calculation method that constructively integrates two distinct classes of nonequilibrium sampling techniques, namely, driven (e.g., steered molecular dynamics) and adaptive-bias (e.g., metadynamics) methods. By employing nonequilibrium work relations, we design a biasing protocol with an explicitly time- and history-dependent bias that uses on-the-fly work measurements to gradually flatten the free-energy surface. The asymptotic convergence of the method is discussed, and several relations are derived for free-energy reconstruction and error estimation. Isomerization reaction of an atomistic polyproline peptide model is used to numerically illustrate the superior efficiency and faster convergence of the method compared with its adaptive-bias and driven components in isolation. PMID- 23795245 TI - Metabolic Tumor Volume on PET Reduced More than Gross Tumor Volume on CT during Radiotherapy in Patients with Non-Small Cell Lung Cancer Treated with 3DCRT or SBRT. AB - OBJECTIVE: We have previously demonstrated that tumor reduces in activity and size during the course of radiotherapy (RT) in a limited number of patients with non-small cell lung cancer (NSCLC). This study aimed to quantify the metabolic tumor volume (MTV) on PET and compare its changes with those of gross tumor volume (GTV) on CT during-RT for 3D conformal radiotherapy (3DCRT) and stereotactic body radiotherapy (SBRT). METHODS: Patients with stage I-III NSCLC treated with a definitive course of RT +/- chemotherapy were eligible for this prospective study. FDG-PET/CT scans were acquired within 2 weeks before RT (pre RT) and at about two thirds of total dose during-RT. PET-MTVs were delineated using a method combining the tumor/aorta ratio autosegmentation and CT anatomy based manual editing. Data is presented as mean (95% confident interval). RESULTS: The MTV delineation methodology was first confirmed to be highly reproducible by comparing volumes defined by different physicians and using different systems (coefficiency >0.98). Fifty patients with 88 primary and nodal lesions were evaluated. The mean ratios of MTV/GTV were 0.70(-0.07~1.47) and 0.33(-0.30~0.95) for pre-RT and during-RT, respectively. PET-MTV reduced by 70% (62-77%), while CT-GTV by 41% (33-49%) (p< 0.001) during-RT. MTV reduction was 72.9% and 15.4% for 3DCRT and SBRT, respectively (p< 0.001). CONCLUSION: PET-MTV reduced more than CT-GTV during-RT, while patients treated with 3DCRT reduced more than SBRT. RTOG1106 is using during-RT PET-MTV to adapt radiation therapy in 3DCRT. PMID- 23795246 TI - Pediatric flexible flatfoot; clinical aspects and algorithmic approach. AB - Flatfoot constitutes the major cause of clinic visits for pediatric foot problems. The reported prevalence of flatfoot varies widely due to numerous factors. It can be divided into flexible and rigid flatfoot. Diagnosis and management of pediatric flatfoot has long been the matter of controversy. Common assessment tools include visual inspection, anthropometric values, footprint parameters and radiographic evaluation. Most flexible flatfeet are physiologic, asymptomatic, and require no treatment. Otherwise, the physician should treat symptomatic flexible flatfeet. Initial treatment options include activity modification, proper shoe and orthoses, exercises and medication. Furthermore, comorbidities such as obesity and ligamenous laxity should be identified and managed, if applicable. When all nonsurgical treatment options faile, surgery can be considered. Our purpose in this article is to present a clinical algorithmic approach to pediatric flatfoot. PMID- 23795247 TI - Olfactory stimulation by vanillin prevents apnea in premature newborn infants. AB - OBJECTIVE: Apnea is one of the most common problems in premature newborns. The present study aimed to determine the effect of olfactory stimulation by vanillin on prevention of apnea in premature newborns. METHODS: In this randomized controlled trial, 36 premature newborns with the postnatal age of 2 days and weight under 2500 grams referred to the hospitals affiliated to Shiraz University of Medical Sciences, were selected through simple random sampling and allocated into control and experimental groups. The experimental group received olfactory stimulation by saturated vanillin solution, while the control group received no interventions. The newborns of both groups were continuously monitored for presence/absence of apnea and number of episodes of apnea as well as arterial blood oxygen saturation and heart rate for 5 days. The data were analyzed by independent Student t-test and repeat measure ANCOVA. FINDINGS: The presence of apnea revealed to be significantly different between the two groups in the first, second, and fourth day of the study (P<0.05). The number of episodes of apnea during five days was also significantly different between the study groups (t=8.32, P<0.05). Using olfactory stimulation by vanillin caused a 3.1-fold decrease in apnea and the effect size was 0.72. Moreover, the two groups were significantly different regarding the arterial blood oxygen and heart rate during the study period (P<0.05). CONCLUSION: This study indicated the beneficial effect of saturated vanillin solution on apnea; therefore, it may be used for prevention and treatment of apnea in premature infants. Further studies are needed to improve evidence-based practice in this regard. PMID- 23795248 TI - Cross-cultural adaptation, reliability, and validity of the autism treatment evaluation checklist in persian. AB - OBJECTIVE: The objectives of the current study were to translate and adapt Autism Treatment Evaluation Checklist (ATEC) into Persian language and to investigate its reliability and validity in an Iranian autistic sample. METHODS: A total sample of 134 children with autism spectrum disorders aged 6-15 years were assigned to the study. The process of cross-cultural adaptation was performed according to international methodological steps as following: translation, back translation, revision by an expert committee and pretest. A sample of 20 primary caregivers of autistic children were pretested. The content validity of the ATEC was reviewed by the expert committee all through the stages. The construct quality of the questionnaire was evaluated by comparison of the adapted version of the instrument with similar tests assessed similar factors. Moreover, the reliability of the questionnaire was evaluated through stability and homogeneity assessments. FINDINGS: The results showed good content validity and internal consistency (Cronbach's alpha: 0.86-0.93). In relation to construct validity, there was significant correlation between ATEC subscales and raw data obtained from Autism Diagnostic Interview-Revised (ADI-R) (r=0.38-0.79). The Intraclass Correlation Coefficient for the test-retest reliability was excellent for all the subscales and also for total scores (ICC: 0.79 - 0.93). CONCLUSION: Cross cultural adaptation of ATEC was successful. The psychometric properties were verified and indicated that the adapted questionnaire is valid and reliable to use in Iranian culture. PMID- 23795249 TI - Shifting epidemiology of hepatitis a infection and vaccination status of children aged 6 months-12 years: time for mass vaccination. AB - OBJECTIVE: This study was designed to determine the current age-related hepatitis A virus (HAV) seroprevalance, vaccination status of children and to evaluate the epidemiological shift in HAV serostatus living in Tekirdag, which is located in Thrace region, the European part of Turkey. METHODS: Children 6 months-12 years of age with simple health problems were included. Blood samples were studied for HAV IgM and IgG collectively. A questionnaire addressing several characteristics of subjects was administered to obtain basic descriptive data on HAV epidemiology. Vaccination status of the children was recorded according to the immunization cards. FINDINGS: The overall anti-HAV IgM and anti-HAV IgG prevalance in children aged 6 months - 12 years was 3.3% and 25.4% respectively. Maximum hepatitis A IgM positivity was in the 7-12 years age group 4.8% (n= 12; P<0.001) and maximum hepatitis A IgG positivity in the same age group was 34% (n = 85; P<0.001). HAV vaccination rate among patients aged more than 2 years was 11.03%. HAV IgG seroprevalance was higher in children of low monthly income families (36.1%, n = 78; P<0.001) than in the intermediate (17%, n = 31) and high income families (11.1%, n = 6). CONCLUSION: These results indicate a shift in Hepatitis A seroprevalance when compared with the previous studies. As HAV infection in childhood is decreasing, the pool of susceptible adolescents and young adults is increasing. Introduction of hepatitis A vaccination into the national immunization schedule of Turkey should be considered. PMID- 23795250 TI - Is There any Difference in Health Related Quality of Life, Self Care and Social Function in Children with Different Disabilities Living in Turkey? AB - OBJECTIVE: The aim of this study was to examine the differences in the health related quality of life and the self care and social function in daily life of children with different disabilities. METHODS: One hundred and two children with physical, emotional and cognitive disabilities (cerebral palsy, mental retardation, and hearing loss) and 28 children age matched as a control group were included in this study for the comparison. The Pediatric Evaluation of Disability Inventory (PEDI) was used to evaluate the independence and participation of children in daily life activities. The Turkish version of the Child Health Questionnaire-Parent form (CHQ - PF50) was used to evaluate the health related quality of life. FINDINGS: All 3 groups were different from the control group in terms of self-care and the social domains according to the PEDI results (P<0.05). Children with cerebral palsy (CP) were more dependent in the areas of self-care and mobility activities (P<0.05). The main difference was found in global general health (GGH), physical functioning (PF), the emotional impact on the parent (PE) subsections of the CHQ-PF50 between the CP and the hearing loss groups; the role of the physical (RP) and emotional behavior (BE) subsections between the mental retardation (MR) and the CP groups, and the BE and mental health (MH) subsections between the MR and the hearing loss (HL) groups (P<0.05). CONCLUSION: All the children with disabilities were different from the control group in their quality of life, self care and social function. However the status of the children with MR and HL were parallel between each other in their health related quality of life, self care and social function. On the other hand, the most affected and dependent group was children with CP. The results will provide guidelines for healthcare professionals in implementing effective rehabilitation programs, especially to those with cerebral palsy, to reduce the level of strain and increase the health related quality of life, self care and social function of children with different disabilities. PMID- 23795251 TI - Effects of tactile-kinesthetic stimulation on low birth weight neonates. AB - OBJECTIVE: Low Birth Weight [LBW] (1500gr <= Birth Weight <= 2499 gr) is one of the most serious health problems in neonates. These neonates need complementary interventions (e.g. tactile-kinesthetic stimulation) to promote development. This study was conducted to determine the effect of Tactile-Kinesthetic Stimulation (TKS) on physical and behavioral development of Low Birth Weight neonates. METHODS: This was a randomized controlled trial with equal randomization (1:1 for two groups) and parallel group design. Forty LBW neonates were randomly allocated into test (n = 20) and control (n = 20) groups. TKS was provided for three 15 minute periods per day for 10 consecutive days to the test group, with the massages consisting of moderate pressure strokes in supine and prone position and kinesthetic exercises consisting of flexion and extension of limbs. All measurements were taken before and after completion of the study with the same equipment (Philips electronic weighing scale with an accuracy of +/-5 grams and Brazelton Neonatal Behavioral Assessment) and by the same person. FINDINGS: There was a trend towards increased daily weight gain, but without statistical significance. On the Brazelton scale, the test group showed statistically significant improved scores on the 'motor' (P-value <0.001) and 'regulation of state' (P-value = 0.039) clusters after the 10 days TKS. CONCLUSION: TKS has no adverse effects on physiologic parameters and gives better adaptive behavior of LBW neonates compared to those without TKS. PMID- 23795252 TI - Adiponectin is a Good Marker for Metabolic State among Type 1 Diabetes Mellitus Patients. AB - OBJECTIVE: Adiponectin is secreted from adipose tissue. This hormone has a fundamental role in pathogenesis of insulin resistance, and has anti-inflammatory and anti-atherogenic effects. The objectives of this study were to compare serum adiponectin level between type 1 diabetics and healthy people and to assess its related factors, and also to determine the relationship between adiponectin and metabolic state. METHODS: This was a case control study involving 60 diabetics (25 good and 35 poor metabolic controlled) and 28 healthy persons (younger than 18 years old). The data about demographic (age and sex), clinical and paraclinical characteristics [body mass index (BMI), duration of disease, puberty state, and glycosylated hemoglobin (HbA1c) and adiponectin level in serum] were collected. Determinants of adiponectin were assessed using univariate and multiple linear regression analyses. FINDINGS: Mean (+/-SD) serum adiponectin level in healthy persons, good-controlled and poor-controlled type 1 diabetes mellitus patients were 9.16 (+/-4.2) ug/cc, 10.89 (+/-4.48)ug/cc, and 15.92 (+/ 8.26)ug/cc, respectively. Post hoc analysis revealed that differences of adiponectin between poor- and good-controlled type 1 diabetes mellitus patients (P=0.01) and between healthy persons and poor controlled type 1 diabetes mellitus (P<0.0001) were statistically significant. Adiponectin level was associated with puberty state and BMI in healthy persons. It was associated with puberty state and HbA1c in type 1 diabetic persons. CONCLUSION: Serum level of adiponectin was higher in type 1 diabetics than in healthy persons and it can be used as a good marker for metabolic control state among diabetics. PMID- 23795253 TI - Autoimmune hepatitis in children: experiences in a tertiary center. AB - OBJECTIVE: Autoimmune hepatitis (AIH) is a necroinflammatory liver disease of unknown etiology that occurs in the children of all ages. The present study aimed to evaluate the clinical and paraclinical presentations, including pattern of autoantibodies, response to treatment, mortality, and liver transplantation outcome in the Iranian children with AIH. METHODS: The medical records of 87 children (56 girls and 31 boy) diagnosed with AIH between 2001 and 2010 were retrospectively analyzed for clinical and paraclinical profiles and also treatment outcome. FINDINGS: The mean age of the patients was 10.1+/-4.5 years (64.4% females). The most common clinical findings were jaundice (70.1%), splenomegaly (67.8%), and hepatomegaly (51.7%). Antinuclear, anti-smooth muscle, and anti LKM antibodies were positive in 14/62, 22/53 and 6/40 patients, respectively (36 patients had type 1 AIH, 6 patients had type 2 AIH, 26 patients were seronegative, and autoantibodies were not available in 19 cases). The most common histological finding in the liver biopsies was chronic hepatitis with interface activity that was seen in 65 (74.7%) patients. The complete response was seen in 52 (59.8%) patients and 24 (27.6%) patients underwent liver transplantation. One-year and five-year survival rates were 87.5% and 80% in the transplanted patients. CONCLUSION: AIH should be kept in mind in the differential diagnosis of both acute and chronic liver diseases in the children and treatment with combination of corticosteroids and azathioprine is a good treatment option. In the patients with end stage liver cirrhosis that did not respond to medical therapy, liver transplantation is the treatment of choice. PMID- 23795254 TI - Comparing response inhibition and flexibility for two components of executive functioning in children with autism spectrum disorder and normal children. AB - OBJECTIVE: The aim of this study was investigating and comparing two components of executive functioning in children with high function autism with normal children. METHODS: This study was correlation descriptive (causal-comparative). There were two groups, one consisted of 15 participants of children with high function autism disorder (Intelligence quotient [IQ]>80) and the other consisted of 15 normal children, all age and education matched. They were compared with two neuro-cognitive tests, Color Word Stroop and Wisconsin Card Sorting, and one IQ test called Ravens Progressive Matrices test. FINDINGS: Analysis of data showed significant difference in both executive functionings, response inhibition (Stroop) and flexibility (Wisconsin Card Sorting) between normal children and children with autism disorder, but there was no significant relation between age and IQ and executive functioning in children with autism. CONCLUSION: The results showed that children with autism disorder have deficits in executive functions regardless of their IQ level and it can be attributed to the symptoms of autism spectrum disorders. PMID- 23795255 TI - Diagnostic value of provocative test by insulin combined with clonidine for growth hormone deficiency in children. AB - OBJECTIVE: To evaluate the diagnostic value of provocative test by insulin combined with clonidine for growth hormone deficiency (GHD) during childhood. METHODS: Eighty children underwent a provocative test with insulin(0.075U/Kg, intravenous) combined with clonidine (4MUg/kg, orally). Among them, 40 children underwent clonidine provocative test, 40 children underwent insulin tolerance test (ITT) in another day. FINDINGS: The specificity of ITT+clonidine test (74%, 88%) was remarkably higher than that of ITT (48%) or clonidine test (65%). ITT+clonidine test had a better accuracy (75%, 85%) than that of ITT (63%) or clonidine test (73%). CONCLUSION: We conclude that the combined clonidine+insulin test is a feasible, reliable, convenient, time saving, and safe tool for evaluation of the growth hormone (GH) axes than the clonidine test or ITT. PMID- 23795256 TI - Predictors of mortality in out born neonates with acute renal failure; an experience of a single center. AB - OBJECTIVE: To evaluate the incidence, etiology, outcome, and predictors of mortality in neonates with Acute Renal Failure (ARF) in an out born Neonatal Intensive Care Unit (NICU) of India. METHODS: A retrospective analysis of case records of out born neonates, who had ARF at admission or developed ARF during NICU stay, from January to December 2011 (one year) was done. FINDINGS: Out of the total 456 neonates admitted during the study period, 44 (9.6%) neonates with ARF (32 males, 12 females) were studied. Their mean gestational age, weight, and age at admission was 34.7+/-3.9 weeks, 2100+/-630 grams, and 2.1+/-6.3 respectively. Causes of ARF were pre-renal in 22 (50%), intrinsic renal failure in 16 (36.3%), and post-renal in six (13.6%). Oliguria was present in 29 neonates. Neonatal sepsis was the commonest cause of ARF, followed by perinatal asphyxia, respiratory distress syndrome, and genitourinary anomalies. ARF was present at admission in 37 neonates. The mortality rate was 15.9% (7/44). Thirty seven (84%) were discharged with complete recovery of renal functions and followed for six months. Shock, oliguria, need for mechanical ventilation, and presence of disseminated intravascular coagulopathy (DIC) emerged as predictors of mortality in neonates with ARF. CONCLUSION: The incidence and mortality rate of neonatal ARF were 9.6% and 15.9% respectively in our out born NICU. Neonatal sepsis was the commonest cause of ARF followed by perinatal asphyxia. Shock, oliguria, need for mechanical ventilation, and presence of DIC were associated with poor outcome. PMID- 23795257 TI - Reliability of pubertal self assessment method: an Iranian study. AB - OBJECTIVE: This investigation aims to evaluate the validity of a Persian Tanner Stages Self-Assessment Questionnaire. METHODS: In this cross sectional study, 190 male students aged 8-16 years selected from three layers of different regions of Tehran (North, Central and South) were enrolled. A Persian questionnaire illustrated with Tanner stages of puberty (genital development and pubic hair distribution) was prepared. Children were asked to select the illustration that best described their pubertal development. Tanner status of the children was also estimated by an independent physician using physical examination. The degree of agreement between subjects' judgments with assessments made by the rater was compared through the calculation of the weighted kappa statistic coefficient. FINDINGS: We found a substantial agreement between self-assessment of pubertal development made by the children and doctor's assessment of genital development (kappa=0.63, P<0.0001) and also the pubic hair distribution (kappa= 0.74, P<0.0001). Although a large proportion of subjects in G4 (89.2%) and G5 (85.7%) were capable of accurately or almost accurately identifying their own Tanner sexual stages, some degree of disagreement was observed in G3 Tanner stage (%46.9). CONCLUSION: Self-assessment of puberty should be used very cautiously and may not be a substitute method for routine evaluation of pubertal state especially for early and mid pubertal groups. PMID- 23795258 TI - Determining the correlation and accuracy of three methods of measuring neonatal bilirubin concentration. AB - OBJECTIVE: There are different methods for measuring bilirubin concentration; however, it is quite important for practitioners to know which method should be used in certain clinical situations. The present prospective study aimed to compare three different methods for measuring neonatal bilirubin concentrations. METHODS: All full term neonates who were either brought into emergency departments or admitted to the neonatal wards in Kerman city in 2011 were recruited (n = 428). The correlation coefficients were estimated for the routine ways of bilirubin concentrations including "Capillary", "Cutaneous" and "Laboratory" methods. FINDINGS: Of 428 recruited neonates, 178 were female. Mean age +/-SD was 178+/-71 hours. The correlation coefficient for "David Icterometer" vs "JM103" was 0.91, while the corresponding coefficient for "David Icterometer" vs "Capillary" was 0.96. It was also equivalent to 0.85 for correlation between "JM103" and "Capillary" methods. The David Icterometer measured an average of 2.36 mg/dl levels of bilirubin concentration compared to the JM103 method. The Capillary method showed a lower bilirubin level than the venous concentration (0.91 mg/dl on average). Compared with the "Capillary", the "JM103" measured a slightly higher level of bilirubin with an average 0.57 mg/dl. CONCLUSION: Due to low difference (less than 1 mg/dl) between "JM103" and the "Capillary methods" for measurement of neonatal bilirubin concentration, these two methods could alternatively be used instead of usual laboratory method. PMID- 23795259 TI - The effect of endotracheal tube suctioning education of nurses on decreasing pain in premature neonates. AB - OBJECTIVE: Endotracheal tube suctioning (ETS) is a painful and invasive procedure. Studies have shown that the performance of nurses in this procedure is weak, so we conducted a study to evaluate the effect of ETS education for nurses on neonates' pain in neonatal intensive care units (NICUs). METHODS: In a quasi experimental study, performance of 25 nurses working in NICU was assessed before and after ETS education by a checklist. In addition pain score of 50 neonates was measured using pain assessment tool (PIPP) one minute before, during and 5 minutes after ETS. The neonates had a gestational age of less than 37 weeks and were intubated (at least for 8 hours and up to 24 hours). A P. value of less than 0.05 was considered as statistically significant. FINDINGS: Mean scores of nurses' performance were significantly different before and after education (P<=0.001) by Wilcoxon test. Friedman test revealed that PIPPs before, during and after ETS were significantly different before and after education (P<=0.05). Mann Whitney test showed no significant differences between PIPPs before ETS, before and after education (P=0.2), but PIPPs during and after ETS were significantly different (P<=0.01). CONCLUSION: ETS causes moderate to severe pain in neonates. Education improved performance of nurses and decreased pain in neonates during and after ETS. Despite education, neonates will experience mild pain during ETS, so other interventions need to be considerate. PMID- 23795260 TI - Expression of T-cell Immunoglobulin- and Mucin-domain-containing Molecule-3 on Lymphocytes from Henoch-Schoenlein Purpura Patients. AB - OBJECTIVE: To investigate T-cell immunoglobulin domain and mucin domain containing molecule-3 (Tim-3) and its ligand galectin-9 mRNA expression in peripheral blood mononuclear cells (PBMCs) from Henoch-Schoenlein Purpura (HSP) patients. METHODS: Quantitative real-time reverse transcription-polymerase chain reaction (PCR) was used to examine the mRNA expression of Tim-3 and its ligand galectin-9 in PBMCs from HSP patients. ELISA methods were used to examine the levels of serum IFN-gamma and immunoglobulin A1 (IgA1). The Spearman rank test was used for correlation analysis between Tim-3, galectin-9 mRNA expression and serum IFN-gamma and IgA1 levels, respectively. FINDINGS: The results showed that Tim-3 and galectin-9 mRNA expression was obviously higher in patients, which was closely correlated with serum IFN-gamma and IgA1, respectively. CONCLUSION: The results suggested that Tim-3/Tim-3L may be related to the pathogenesis of HSP. PMID- 23795261 TI - Frequency of Hearing Impairment among Full-term Newborns in Yazd, Iran. AB - OBJECTIVE: Permanent congenital hearing loss, a common congenital anomaly, may affect speech and language acquisition, academic achievement and social development. Current standards emphasize early recognition of congenital hearing loss. This study was conducted to find the prevalence of hearing impairment in term newborns in Yazd, Iran. METHODS: This was a descriptive-analytic study conducted in Yazd on 7250 term newborns. Otoacoustic emissions (OAEs) test was performed in all newborns during the first 24 hours after birth. Those who failed to respond at the first step were retested 15 days later. Those who failed to respond at the second step too, were tested by acoustic brainstem responses (ABR) test. Chi square test was used for data analysis. FINDINGS: From 7250 newborns in the first step 598 (8.2%) and 682 (9.4%) ears (right and left, respectively) failed. In the second step 51 (0.7%) and 58 (0.8%) ears (right and left, respectively) failed. Consanguinity and route of delivery had significant effect on the frequency of hearing loss. CONCLUSION: The overall frequency of congenital hearing loss in this study was found high. PMID- 23795262 TI - Clinical findings of functional and secondary constipation in children. AB - OBJECTIVE: We aimed to evaluate clinical features and follow-up data of children with functional and secondary constipation. METHODS: Hospital records of 335 constipated children were evaluated. Children were divided into 2 groups as functional and secondary, and were compared with regard to clinical and anthropometric data. FINDINGS: Of 335 children (M/F 167/168, mean age 4.3+/-3.5 years) 91% had functional constipation (group 1). Family history of constipation was significantly higher in group 1. Malnutrition was found in 18% of group 1, 56% in group 2 (p < 0.001). CONCLUSION: If a constipated child has a family history of constipation but does not have failure to thrive and constipation begins at an older age, functional constipation is more probable. PMID- 23795263 TI - Successful treatment of congenital chyloperitoneum with platelet-rich fibrin glue. AB - BACKGROUND: Congenital chyloperitoneum is an uncommon clinical condition. A few cases of congenital chyloperitoneum in children have been described who were treated in a variety of methods. CASE PRESENTATION: Congenital chyloperito was diagnosed in a 5-day-old baby boy with a significant abdominal distension. Due to the failed conservative managements by medium-chain triglycerides (MCT) enriched milk and partial parenteral nutrition (PPN), the authors tried platelet rich fibrin glue (PRFG) as an alternative choice which was applied through an already inserted intra-abdominal catheter. PRFG successfully stopped the lymph leakage from all over the small intestinal mesentery; thereby PRFG may be considered as an effective alternative treatment before surgical intervention. CONCLUSION: Applying PRFG is an easy, safe, and effective alternative option that may be used to close the chylous ascites lymph leakage in children if conservative management with PPN fails. PMID- 23795264 TI - Spontaneous rupture of kidney due to posterior urethral valve-diagnostic difficulties. AB - BACKGROUND: Spontaneous kidney rupture could develop in the course of posterior urethral valve (PUV), the most common cause of outflow urinary tract obstruction in male infants. However, urinary extravasation is a rare complication among this group of children. CASE PRESENTATION: Our case report presents diagnostic difficulties connected with spontaneous kidney rupture due to PUV in a 6 week-old infant. Due to not equivocal images, thundery course of disease and rapid deterioration in the infant's condition, the patient required an urgent laparatomy. CONCLUSION: This case showed that the investigation of renal abnormalities during early neonatal period, is very important specifically in PUV that can lead to kidney rupture. PMID- 23795265 TI - Acanthosis nigricans, Abnormal Facial Appearance and Dentition in an Insulin Resistance Syndrome. AB - BACKGROUND: Insulin resistance syndromes are a heterogeneous group of disorders with variable clinical phenotypes, associated with increased blood glucose and insulin levels. CASE PRESENTATION: Herein, a 10-year old girl with abnormal face and dentition is presented. She has suffered from diabetes mellitus type I since she was 6 years old. Hyperglycemia did not respond to age appropriate insulin dosage; therefore, insulin dosage was increased, but did not lead to appropriate glycemic control. Twenty two exons of insulin receptor gene (INSR), on short arm of chromosome 19, were sequenced, but no identifiable disease causing mutation was detected. CONCLUSION: Although a rare mutation within the intronic or promoter region has not been excluded in this case, further molecular studies on patients with insulin resistance syndromes associated with certain features are needed. PMID- 23795266 TI - 'Watchful Waiting' May Be an Appropriate Treatment for ELBW Infant with Hepatic Mesenchymal Hamartoma. PMID- 23795267 TI - Accidental Intra-arterial Injection of Adenosine in a Child with Supraventricular Tachycardia. PMID- 23795268 TI - Pigmented epithelioid melanocytoma in a child: unusual clinical presentation. PMID- 23795269 TI - A neonate with kluyvera sepsis: a case report. PMID- 23795271 TI - Bone Marrow Abnormalities in HIV Disease. AB - INTRODUCTION: Hematological abnormalities are a common complication of HIV infection. Bone marrow abnormalities occur in all stages of HIV infection. Present work was carried out to study the bone marrow abnormalities in patients with HIV/AIDS. METHODS: 160 patients of HIV +ve were included in the study. A complete blood count, relevant biochemical investigations, CD4 counts were done, besides a thorough history and clinical examination. HIV positive patients were classified as those having AIDS and those without AIDS according to NACO criteria. Bone marrow examination was performed for indication of anemia, leucopenia, pancytopenia and thrombocytopenia. RESULTS: As per CDC criteria 59.81% patients had AIDS in 107 patients. The most common hematological abnormality was anemia, seen in 93.12% patients. Bone marrow was normocellular in 79.06% of non-AIDS and 79.68% of AIDS, hypocellular in 13.95% of non-AIDS and 12.5% of AIDS, hypercellular in 06.97% of non-AIDS and 07.81 % of AIDS patients. Dysplasia was statistically and significantly associated with anemia. For myelodysplasia in bone marrow in HIV patients we noted granulocytic dysplasia in 4.65% in Non - AIDS and 14.06% AIDS patients. Erythroid dysplasia was found in 9.30% in Non - AIDS, 12.5% in AIDS group. Thrombocytopenia was seen in 4 cases of ART (4.93%) and 3 cases (4.68%) of AIDS group. Abnormal cells like plasma cell, histiocyte and toxic granule were found in bone marrow. CONCLUSIONS: Myelodysplasia was more common in AIDS than in non AIDS patients. Granulocytic series is most commonly associated with evidence of dysplasia. Anemia in HIV patients can be a good clinical indicator to predict and access the underlying immune status. Thus bone marrow study is imperative to methodically observe and follow clinical and laboratory aberration in such patients in order to improve our diagnostic and therapeutic skills pertinent to HIV/AIDS. PMID- 23795270 TI - Treatment of acute myeloid leukemia with 20-30% bone marrow blasts. AB - The transition of patients with >=20% <30% bone marrow (BM) blast from the FAB category of myelodysplasia to the family of acute myeloid leukemia (AML) according to the recent WHO classification has not resolved the argument as to whether the natural history and responsiveness to therapy of these diseases is comparable to that of AML with > 30% BM blast. These controversies are even more manifest when it comes to elderly patients in whom concern for intensive chemotherapy (IC) related toxicity is the critical determinant for the therapeutic choice. In fact, due to concerns of treatment-related morbidity and mortality associated with delivery of IC, approximately only 30% of all patients >=65 years are considered eligible for this approach. Therefore, a great deal of attention has been dedicated to alternative agents such as hypomethylators (azacitidine and decitabine). Actually, these agents have shown efficacy with reduced toxicity when administered to elderly patients with 20-30% BM blasts and not eligible for IC. In the present review, we will discuss the clinical results achieved in the treatment of elderly patients with 20%-30% BM blasts AML using intensive chemotherapy (IC) or hypomethylating agents. Overall, our survey of the literature suggests that only controlled, randomized, clinical trials will answer the question as to whether hypomethylating agents has the potential to substitute for IC even in elderly patients with an optimal functional status. PMID- 23795272 TI - Assessment of diagnostic techniques of urinary tuberculosis. AB - Early diagnosis of active tuberculosis remains an elusive challenge. In addition, one third of the world's population is latently infected with Mycobacterium tuberculosis (Mtb) and up to 10% of infected individuals develop tuberculosis (TB) in their lifetime. In this investigation, the incidence of urinary tuberculosis among renal patients was studied. Three hundreds urine samples were processed for detection of Mtb by Ziehl-Neelsen (ZN) smear examination, Lowenstein Jensen (LJ) medium, radiometric BACTEC460 system as well as polymerase chain reaction (PCR) followed by DNA Enzyme Immunoassay (DEIA) test. Out of 300 urine samples, 2 were positive by both ZN smears and LJ medium with incidence rate of 0.66 %, 3 positive samples by BACTEC460 culture system with incidence of 1%. PCR assay gave more positive results than smear and culture examination (i.e. 8 positive samples with incidence rate of 2.6%). The specificities were 25% for both ZN smears and LJ medium, 37.5% for BACTEC460 culture system, and 100% for PCR test, while sensitivities of all assays were 100%. Thus PCR is a rapid and sensitive method for the early diagnosis of urinary tuberculosis. PMID- 23795273 TI - Tenofovir as rescue therapy following clinical failure to Lamivudine in severe acute hepatitis B. AB - Acute hepatitis B (AHB) is a self-limiting condition in more than 95% of cases. Treatment is however recommended in patients with severe AHB (<1% of cases), aiming to prevent liver failure and death. Various nucleos(t)ide analogues (NA) have been found to be effective in severe AHB, although NA-resistant strains causing AHB have been also recently reported. The use of tenofovir in severe AHB has only been described in 3 cases (1 adult and 1 infant with HBV mono-infection, 1 adult with HBV/HIV co-infection). We hereby report a 47-year-old treatment naive male, who developed severe AHB and was initially treated with lamivudine (LMV). Initial rapid biochemical response was followed by biochemical breakthrough after 9 days, suggesting LMV resistance. Rescue therapy with 'add on' tenofovir brought about a sustained improvement in biochemical, serological and virological markers until HBsAg was lost after 4 months. Thus, this is the second adult HBV mono-infected patient, who responded successfully to tenofovir in severe AHB. PMID- 23795274 TI - Endothelial Nitric Oxide Synthase (eNOS) Gene Polymorphism is Associated with Age Onset of Menarche in Sickle Cell Disease Females of India. AB - BACKGROUND AND OBJECTIVE: Females with sickle cell disease (SCD) often show late onset of menarche. In transgenic sickle cell mouse, deficiency of gene encoding endothelial nitric oxide synthase (eNOS) has been reported to be associated with late onset of menarche. Thus to explore the possible association of eNOS gene polymorphism with age of onset of menarche in SCD females, 3 important eNOS gene polymorphisms- eNOS 4a/b, eNOS 894G>T (rs1799983) and eNOS-786 T>C (rs2070744) and plasma nitrite levels were tested among three groups of females- SCD late menarche, SCD early menarche and control females. METHODOLOGY: About 39 SCD females comprising of 18 SCD early menarche and 21 SCD late menarche groups were studied along with 48 control females. Genotyping of eNOS gene polymorphisms were done by PCR-RFLP and quantification of plasma nitrite level was performed by ELISA based commercial kits. RESULTS: SCD late menarche females showed significantly higher prevalence and higher association of heterozygous genotypes, higher frequency of mutant alleles .4a., .T. and .C. as compared to that of control group and SCD early menarche group. The frequency of haplotype .4a-G-C. and haplotype .4b-G-C. (alleles in order of eNOS 4a/b, eNOS 894G>T and eNOS-786 T>C respectively) were found to be significantly high in SCD late menarche compared to combined groups of SCD early menarche and controls. SCD late menarche group had significantly low level of plasma nitrite concentration for all 3 eNOS gene polymorphisms as compared to controls and SCD early menarche females. CONCLUSION: eNOS gene polymorphism may influence age of onset of menarche in SCD females. PMID- 23795275 TI - Lenalidomide in combination with dexamethasone in elderly patients with advanced, relapsed or refractory multiple myeloma and renal failure. AB - Salvage therapy of elderly patients with advanced, relapsed and refractory multiple myeloma (MM) is often limited by poor marrow reserve and multi-organ impairment. In particular, renal failure occurs in up to 50% of such patients, and this can potentially limit the therapeutic options. Both thalidomide and bortezomib have proven effective in these patients, with an acceptable toxicity, while, in clinical practice, lenalidomide is generally not considered a first choice drug for MM patients with renal failure as early reports showed an increased hematological toxicity unless appropriate dose reduction is applied. Aim of this study was a retrospective evaluation of the efficacy of the combination Lenalidomide + Dexamethasone in a population of elderly MM patients treated in 5 Italian Centers. The study included 20 consecutive MM patients (9 M, 11 F, median age 76.5 years) with relapsed (N= 6) or refractory (N=13) MM and moderate to severe renal failure, defined as creatinine clearance (Cr Cl) < 50ml/min. Four patients were undergoing hemodyalisis at study entry. 85 % of the patients had been previously treated with bortezomib-containing regimens. Lenalidomide dose was adjusted according to renal function and patients clinical conditions Median treatment duration was 16 months (1-22), therapy was interrupted after 1 21-day cycle in 2 patients. Grade III-IV neutropenia was observed in 7 patients (35%); grade III-IV non hematological toxicity was recorded in 3 cases (28%). A > partial response was observed in 8 patients (40%), 1 of whom obtained a VGPR; 4 additional patients achieved a minor response. Median response duration was 16 months (range 2-19+ months). A complete and partial renal response was obtained in 4 and 3 patients, respectively, all of them were responsive to Lenalidomide-dexamethasone According to our data, LEN+DEX has shown efficacy and acceptable toxicity in this population of elderly patients with advanced MM and renal failure. PMID- 23795276 TI - The Challenge of AML in Older Patients. AB - There has been a gradual improvement in the outcome for younger patients with Acute Myeloid Leukaemia over the last two decades, but unfortunately this same progress is not apparent in older patients. "Old" has come to mean rather arbitrarily, patients over 60 years. This age cut off has been perpetuated by clinical trials whose eligibility is frequently at this cut point. Age is a continuous variable right through all age groups with AML and has independent prognostic significance. Chemo-resistance of the disease itself is part of the explanation, with a high frequency of adverse biology occurring at older age. Patient characteristics which compromise the delivery of treatment of adequate intensity are the other important influence. Medical co-morbidities are more frequent, and when combined with what is sometimes referred to as limited haematopoietic reserve, undoubtedly make successful delivery of intensive therapy less likely. The outstanding problem for older patients is that remission is usually not durable, and there has been little improvement in overall survival for the last three decades, then new approaches need. PMID- 23795277 TI - Diamond blackfan anemia: a tertiary care center experience. AB - Diamond Blackfan Anemia (DBA) is a rare hypoplastic anemia that presents in infancy with macrocytic anemia and reticulocytopenia. It is a ribosomopathy with autosomal dominant inheritance. In our series of 10 patients with DBA, congenital malformations were observed in 50% of the cases. Age at symptom onset ranged from 0-12 months. Age at diagnosis ranged from 4 months to 96 months. Male: female ratio was 9:1. Response to prednisolone was observed in 4 out of the 10 patients (either during initial treatment or during re-challenge). Response to cyclosporine was found to be poor. Bone marrow transplantation was successful in attaining remission in one patient. Malignancies were not reported in any patient possibly due to a short follow up period. PMID- 23795278 TI - Sphingomonas paucimobilis infections in children: 24 case reports. AB - Sphingomonas paucimobilis is a causative agent of infection in immunocompromised patients, and healthcare-associated infection. Although the infections associated with S.paucimobilis occurs rarely, it has been encountered with increasing frequency in clinical settings. In the current study we reported clinical features of the children with S.paucimobilis infection, and the antimicrobial susceptibilities of the isolated strains among the patients. This study was conducted in Dr. Behcet Uz Children's Hospital, Turkey, during the period of January 2005 and December 2012. The medical records of pediatric patients with positive cultures for S.paucimobilis were reviewed. Sphingomonas paucimobilis isolates were recovered from 24 pediatric patients. The median age was 4 years (ranging from 3 days infant to 15 years) and 58,3% were male. Eight (33,3%) of the patients were under 1 months of age. Among the patients; 13 (54,2%) infections were community related however 11(45.8%) infections were nosocomial infection. The median duration of hospital stay was 7 days (ranging from 4 to 22 days). The most effective antibiotics were fluoroquinolones, carbapenems, and trimethoprim/sulfamethoxazole. This is the first largest study in children to evaluate the clinical features of S. paucimobilis infections. Sphingomonas paucimobilis may cause infections in both previously healthy and immunocompromised children. Although variable antimicrobial regimens were achieved to the patients, there was no attributable fatality due to S.paucimobilis infections due to the low virulence of the bacteria. PMID- 23795279 TI - Congenital Thrombotic Thrombocytopenic Purpura: Atypical Presentation and New ADAMTS 13 Mutation in a Tunisian Child. AB - BACKGROUND: Congenital deficiency of ADAMTS13 is characterized by systemic platelet clumping, hemolytic anemia and multiorgan failure. Although, more than 100 mutations have been reported, atypical clinical presentation may be involved in diagnostic difficulties. CASE REPORT: A 2 year old Tunisian child presented with chronic thrombopenic purpura which failed to respond to corticosteroids. Hemolytic anemia with schistocytes, occurred ten months later, with no previous history of diarrhea or any neurological abnormality. Renal function and coagulation screening tests were normal. The count of platelet improved after fresh frozen infusion (FFP). Extensive investigations revealed a severe deficiency of ADAMTS 13 activity (level< 5%). Gene sequencing identified mutation in exon 18 of ADAMTS 13 gene. Prophylactic regimen with regular infusions of FFP was associated to favorable outcome. CONCLUSION: Early ADAMTS 13 activity testing and gene sequencing associated to precocious plasmatherapy are recommended to reduce morbidity and mortality of congenital TTP. PMID- 23795280 TI - Acute panmyelosis with myelofibrosis - a rare subtype of acute myeloid leukemia. AB - One case of acute panmyelosis with myelofibrosis (APMF) is here reported. A 45 year old male presented with abrupt onset of rapidly progressing low backache, weakness and pancytopenia. On examination there was no organomegaly. Peripheral blood examination revealed normocytic normochromic red blood cells with 10% circulating blasts. Flowcytometric examination of peripheral blood revealed blasts which were positive for CD34, HLA- DR and myeloid associated antigens (i.e. CD13 and CD33). Blasts were negative for anti MPO. Bone marrow aspirate resulted in a dry tap. Bone marrow biopsy revealed panmyeloid proliferation with scattered blasts which were CD34 positive on imunohistochemistry and negative for anti MPO. Reticulin stain showed grade III myelofibrosis (WHO). Differential diagnosis considered included AML-M7, MDS-RAEB II and AML with myelodysplasia. He was started on chemotherapy [idarubicin and cytarabine; 3+7 induction regimen followed by three cycles of HIDAC (High dose cytosine arabinoside)] after which patient was in complete morphological remission with markedly reduced bone marrow fibrosis. He is now being worked up for allogeneic stem cell transplantation. Patient is asymptomatic at eight months of diagnosis. In conclusion these patients should be managed aggressively with AML therapy and this case report reaffirms the fact that APMF is subtype of AML. PMID- 23795281 TI - Chronic granulomatous Aspergillus synovitis: a case report. AB - Aspergillus can cause invasive disease of various organs especially in patients with weakened immune systems. Aspergillus synovitis and arthritis are uncommon types of involvement due to this infection. Approaches to fungal osteoarticular infections are based on only case reports. This paper presents a rare case of chronic granulomatous Aspergillus synovitis in an immunocompromised 5-year old girl who was treated for acute lymphoblastic leukemia. PMID- 23795282 TI - Vascular endothelial growth factor in children with thalassemia major. AB - BACKGROUND: The beta-Thalassemia syndromes are the most common hereditary chronic hemolytic anemia due to impaired globin chain synthesis. Vascular endothelial growth factor (VEGF) plays several roles in angiogenesis which is a crucial process in the pathogenesis of several inflammatory, autoimmune and malignant diseases. Endothelial damage and inflammation make a significant contribution to the pathophysiology of beta-thalassemia. PURPOSE: : The aim of the study was to assess serum VEGF level in children with beta-thalassemia major as a marker of angiogenesis. METHODS: A total of 50 children entered the study, 40 patients with thalassemia major and 10 healthy controls. We used enzyme-linked immunosorbent assay for quantitative evaluation of VEGF. RESULTS: VEGF level was significantly higher in patients with beta-thalassemia major than healthy controls (p=0.001). VEGF level was also higher in splenectomised thalassemic patients than non splenectomised ones (p=0.001). There were a positive correlation between VEGF and chelation starting age (p=0.008), and a negative correlation between VEGF and frequency of blood transfusion (p=0.002). CONCLUSION: Thalassemia patients, especially splenectomized, have elevated serum levels of VEGF. Early chelation and regular blood transfusion help to decrease serum VEGF and the risk of angiogenesis. PMID- 23795283 TI - Synthesis, Activity and Metabolic Stability of Non-Ribose Containing Inhibitors of Histone Methyltransferase DOT1L. AB - Histone methyltransferase DOT1L is a drug target for MLL leukemia. We report an efficient synthesis of a cyclopentane-containing compound that potently and selectively inhibits DOT1L (Ki = 1.1 nM) as well as H3K79 methylation (IC50 ~ 200 nM). Importantly, this compound exhibits a high stability in plasma and liver microsomes, suggesting it is a better drug candidate. PMID- 23795284 TI - Network and satellite arrangements in liver disease. AB - Liver disease has evolved into a complex discipline with several tiers of service delivery. Patients' needs vary at different phases of their disease, with mobility between local hospitals and specialist centres being increasingly common. Liver transplantation requirements serve as a good illustration of this fluidity and the need for service providers to coordinate care delivery. This is facilitated by the development of networks and satellite relationships that can range in complexity and functionality. PMID- 23795285 TI - Endoscopic retrograde cholangiopancreatography: is the centre better? The case against centralisation of ERCP services. AB - More than 48 000 endoscopic retrograde cholangiopancreatographies (ERCP) are performed in the UK per annum; the majority within district general hospitals. The proposal for centralisation of ERCP services is based on evidence that technical success, length of stay and complication rates are related to the numbers of procedures performed. Local units wishing to continue their ERCP practice, must demonstrate that they are performing sufficient numbers of procedures in a safe, timely and competent fashion. PMID- 23795286 TI - Lifetime congenital isolated GH deficiency does not protect from the development of diabetes. AB - OBJECTIVES: Adult subjects with untreated, lifetime, isolated GH deficiency (IGHD) due to a homozygous GHRH receptor gene mutation (MUT/MUT) residing in Itabaianinha, Brazil, present with lower BMI, higher prevalence of impaired glucose tolerance (IGT), increased insulin sensitivity (IS), and reduced beta cell function (betaCF) when compared with non-BMI-matched homozygous normal controls. However, the prevalence of diabetes mellitus (DM) in this cohort is unknown. Comparing their IS and betaCF with BMI-matched individuals heterozygous for the same mutation (MUT/N) may be useful to elucidate the role of the GH-IGF1 axis in IS and betaCF. The purposes of this work were to verify the prevalence of IGT and DM in adult MUT/MUT subjects from this kindred and to compare IS and betaCF in MUT/MUT and MUT/N. DESIGN: Cross-sectional study. METHODS: We studied most (51) of the living IGHD adults of this kindred who are GH naive. The oral glucose tolerance test (OGTT) could be performed in 34 subjects, fasting glucose was measured in 15, while two had a previous diagnosis of DM. The OGTT results of 24 MUT/MUT subjects were compared with those of 25 BMI-matched MUT/N subjects. IS was assessed by homeostatic model assessment of insulin resistance (HOMA-IR), quantitative IS check index, and oral glucose IS index for 2 and 3 h. betaCF was assayed by HOMA-beta, insulinogenic index, and the area under the curve of insulin:glucose ratio. RESULTS: The prevalence of DM and IGT in IGHD was 15.68 and 38.23% respectively. IS was increased and betaCF was reduced in MUT/MUT in comparison with MUT/N. CONCLUSIONS: Lifetime, untreated IGHD increases IS, impairs betaCF, and does not provide protection from diabetes. PMID- 23795287 TI - Photoreceptor avascular privilege is shielded by soluble VEGF receptor-1. AB - Optimal phototransduction requires separation of the avascular photoreceptor layer from the adjacent vascularized inner retina and choroid. Breakdown of peri photoreceptor vascular demarcation leads to retinal angiomatous proliferation or choroidal neovascularization, two variants of vascular invasion of the photoreceptor layer in age-related macular degeneration (AMD), the leading cause of irreversible blindness in industrialized nations. Here we show that sFLT-1, an endogenous inhibitor of vascular endothelial growth factor A (VEGF-A), is synthesized by photoreceptors and retinal pigment epithelium (RPE), and is decreased in human AMD. Suppression of sFLT-1 by antibodies, adeno-associated virus-mediated RNA interference, or Cre/lox-mediated gene ablation either in the photoreceptor layer or RPE frees VEGF-A and abolishes photoreceptor avascularity. These findings help explain the vascular zoning of the retina, which is critical for vision, and advance two transgenic murine models of AMD with spontaneous vascular invasion early in life. DOI:http://dx.doi.org/10.7554/eLife.00324.001. PMID- 23795288 TI - The homologous recombination machinery modulates the formation of RNA-DNA hybrids and associated chromosome instability. AB - Genome instability in yeast and mammals is caused by RNA-DNA hybrids that form as a result of defects in different aspects of RNA biogenesis. We report that in yeast mutants defective for transcription repression and RNA degradation, hybrid formation requires Rad51p and Rad52p. These proteins normally promote DNA-DNA strand exchange in homologous recombination. We suggest they also directly promote the DNA-RNA strand exchange necessary for hybrid formation since we observed accumulation of Rad51p at a model hybrid-forming locus. Furthermore, we provide evidence that Rad51p mediates hybridization of transcripts to homologous chromosomal loci distinct from their site of synthesis. This hybrid formation in trans amplifies the genome-destabilizing potential of RNA and broadens the exclusive co-transcriptional models that pervade the field. The deleterious hybrid-forming activity of Rad51p is counteracted by Srs2p, a known Rad51p antagonist. Thus Srs2p serves as a novel anti-hybrid mechanism in vivo. DOI:http://dx.doi.org/10.7554/eLife.00505.001. PMID- 23795289 TI - Evolutionary principles of modular gene regulation in yeasts. AB - Divergence in gene regulation can play a major role in evolution. Here, we used a phylogenetic framework to measure mRNA profiles in 15 yeast species from the phylum Ascomycota and reconstruct the evolution of their modular regulatory programs along a time course of growth on glucose over 300 million years [corrected]. We found that modules have diverged proportionally to phylogenetic distance, with prominent changes in gene regulation accompanying changes in lifestyle and ploidy, especially in carbon metabolism. Paralogs have significantly contributed to regulatory divergence, typically within a very short window from their duplication. Paralogs from a whole genome duplication (WGD) event have a uniquely substantial contribution that extends over a longer span. Similar patterns occur when considering the evolution of the heat shock regulatory program measured in eight of the species, suggesting that these are general evolutionary principles. DOI:http://dx.doi.org/10.7554/eLife.00603.001. PMID- 23795290 TI - Viral genome structures are optimal for capsid assembly. AB - Understanding how virus capsids assemble around their nucleic acid (NA) genomes could promote efforts to block viral propagation or to reengineer capsids for gene therapy applications. We develop a coarse-grained model of capsid proteins and NAs with which we investigate assembly dynamics and thermodynamics. In contrast to recent theoretical models, we find that capsids spontaneously 'overcharge'; that is, the negative charge of the NA exceeds the positive charge on capsid. When applied to specific viruses, the optimal NA lengths closely correspond to the natural genome lengths. Calculations based on linear polyelectrolytes rather than base-paired NAs underpredict the optimal length, demonstrating the importance of NA structure to capsid assembly. These results suggest that electrostatics, excluded volume, and NA tertiary structure are sufficient to predict assembly thermodynamics and that the ability of viruses to selectively encapsidate their genomic NAs can be explained, at least in part, on a thermodynamic basis. DOI:http://dx.doi.org/10.7554/eLife.00632.001. PMID- 23795291 TI - Histone demethylase Lsd1 represses hematopoietic stem and progenitor cell signatures during blood cell maturation. AB - Here, we describe that lysine-specific demethylase 1 (Lsd1/KDM1a), which demethylates histone H3 on Lys4 or Lys9 (H3K4/K9), is an indispensible epigenetic governor of hematopoietic differentiation. Integrative genomic analysis, combining global occupancy of Lsd1, genome-wide analysis of its substrates H3K4 monomethylation and dimethylation, and gene expression profiling, reveals that Lsd1 represses hematopoietic stem and progenitor cell (HSPC) gene expression programs during hematopoietic differentiation. We found that Lsd1 acts at transcription start sites, as well as enhancer regions. Loss of Lsd1 was associated with increased H3K4me1 and H3K4me2 methylation on HSPC genes and gene derepression. Failure to fully silence HSPC genes compromised differentiation of hematopoietic stem cells as well as mature blood cell lineages. Collectively, our data indicate that Lsd1-mediated concurrent repression of enhancer and promoter activity of stem and progenitor cell genes is a pivotal epigenetic mechanism required for proper hematopoietic maturation. DOI:http://dx.doi.org/10.7554/eLife.00633.001. PMID- 23795292 TI - miR-124 controls male reproductive success in Drosophila. AB - Many aspects of social behavior are controlled by sex-specific pheromones. Gender appropriate production of the sexually dimorphic transcription factors doublesex and fruitless controls sexual differentiation and sexual behavior. miR-124 mutant males exhibited increased male-male courtship and reduced reproductive success with females. Females showed a strong preference for wild-type males over miR-124 mutant males when given a choice of mates. These effects were traced to aberrant pheromone production. We identified the sex-specific splicing factor transformer as a functionally significant target of miR-124 in this context, suggesting a role for miR-124 in the control of male sexual differentiation and behavior, by limiting inappropriate expression of the female form of transformer. miR-124 is required to ensure fidelity of gender-appropriate pheromone production in males. Use of a microRNA provides a secondary means of controlling the cascade of sex specific splicing events that controls sexual differentiation in Drosophila. DOI:http://dx.doi.org/10.7554/eLife.00640.001. PMID- 23795293 TI - The autoregulation of a eukaryotic DNA transposon. AB - How do DNA transposons live in harmony with their hosts? Bacteria provide the only documented mechanisms for autoregulation, but these are incompatible with eukaryotic cell biology. Here we show that autoregulation of Hsmar1 operates during assembly of the transpososome and arises from the multimeric state of the transposase, mediated by a competition for binding sites. We explore the dynamics of a genomic invasion using a computer model, supported by in vitro and in vivo experiments, and show that amplification accelerates at first but then achieves a constant rate. The rate is proportional to the genome size and inversely proportional to transposase expression and its affinity for the transposon ends. Mariner transposons may therefore resist post-transcriptional silencing. Because regulation is an emergent property of the reaction it is resistant to selfish exploitation. The behavior of distantly related eukaryotic transposons is consistent with the same mechanism, which may therefore be widely applicable. DOI:http://dx.doi.org/10.7554/eLife.00668.001. PMID- 23795294 TI - Temporal transcriptional response to ethylene gas drives growth hormone cross regulation in Arabidopsis. AB - The gaseous plant hormone ethylene regulates a multitude of growth and developmental processes. How the numerous growth control pathways are coordinated by the ethylene transcriptional response remains elusive. We characterized the dynamic ethylene transcriptional response by identifying targets of the master regulator of the ethylene signaling pathway, ETHYLENE INSENSITIVE3 (EIN3), using chromatin immunoprecipitation sequencing and transcript sequencing during a timecourse of ethylene treatment. Ethylene-induced transcription occurs in temporal waves regulated by EIN3, suggesting distinct layers of transcriptional control. EIN3 binding was found to modulate a multitude of downstream transcriptional cascades, including a major feedback regulatory circuitry of the ethylene signaling pathway, as well as integrating numerous connections between most of the hormone mediated growth response pathways. These findings provide direct evidence linking each of the major plant growth and development networks in novel ways. DOI:http://dx.doi.org/10.7554/eLife.00675.001. PMID- 23795295 TI - Intraflagellar transport drives flagellar surface motility. AB - The assembly and maintenance of all cilia and flagella require intraflagellar transport (IFT) along the axoneme. IFT has been implicated in sensory and motile ciliary functions, but the mechanisms of this relationship remain unclear. Here, we used Chlamydomonas flagellar surface motility (FSM) as a model to test whether IFT provides force for gliding of cells across solid surfaces. We show that IFT trains are coupled to flagellar membrane glycoproteins (FMGs) in a Ca(2+) dependent manner. IFT trains transiently pause through surface adhesion of their FMG cargos, and dynein-1b motors pull the cell towards the distal tip of the axoneme. Each train is transported by at least four motors, with only one type of motor active at a time. Our results demonstrate the mechanism of Chlamydomonas gliding motility and suggest that IFT plays a major role in adhesion-induced ciliary signaling pathways. DOI:http://dx.doi.org/10.7554/eLife.00744.001. PMID- 23795296 TI - Scaffold nucleoporins Nup188 and Nup192 share structural and functional properties with nuclear transport receptors. AB - Nucleocytoplasmic transport is mediated by nuclear pore complexes (NPCs) embedded in the nuclear envelope. About 30 different proteins (nucleoporins, nups) arrange around a central eightfold rotational axis to build the modular NPC. Nup188 and Nup192 are related and evolutionary conserved, large nucleoporins that are part of the NPC scaffold. Here we determine the structure of Nup188. The protein folds into an extended stack of helices where an N-terminal 130 kDa segment forms an intricate closed ring, while the C-terminal region is a more regular, superhelical structure. Overall, the structure has distant similarity with flexible S-shaped nuclear transport receptors (NTRs). Intriguingly, like NTRs, both Nup188 and Nup192 specifically bind FG-repeats and are able to translocate through NPCs by facilitated diffusion. This blurs the existing dogma of a clear distinction between stationary nups and soluble NTRs and suggests an evolutionary relationship between the NPC and the soluble nuclear transport machinery. DOI:http://dx.doi.org/10.7554/eLife.00745.001. PMID- 23795298 TI - Hopping rim to rim through the Golgi. AB - A novel approach based on tracking the fate of proteins that become 'stapled' to the walls of the Golgi yields insights into the long-sought mechanism of transport through this organelle. PMID- 23795297 TI - Condensin controls recruitment of RNA polymerase II to achieve nematode X chromosome dosage compensation. AB - The X-chromosome gene regulatory process called dosage compensation ensures that males (1X) and females (2X) express equal levels of X-chromosome transcripts. The mechanism in Caenorhabditis elegans has been elusive due to improperly annotated transcription start sites (TSSs). Here we define TSSs and the distribution of transcriptionally engaged RNA polymerase II (Pol II) genome-wide in wild-type and dosage-compensation-defective animals to dissect this regulatory mechanism. Our TSS-mapping strategy integrates GRO-seq, which tracks nascent transcription, with a new derivative of this method, called GRO-cap, which recovers nascent RNAs with 5' caps prior to their removal by co-transcriptional processing. Our analyses reveal that promoter-proximal pausing is rare, unlike in other metazoans, and promoters are unexpectedly far upstream from the 5' ends of mature mRNAs. We find that C. elegans equalizes X-chromosome expression between the sexes, to a level equivalent to autosomes, by reducing Pol II recruitment to promoters of hermaphrodite X-linked genes using a chromosome-restructuring condensin complex. DOI:http://dx.doi.org/10.7554/eLife.00808.001. PMID- 23795299 TI - Rad51, friend or foe? AB - A protein long recognized for its role in DNA repair has now paradoxically been implicated in DNA damage. PMID- 23795300 TI - Yeast rises to the occasion. AB - Genetic analyses of 15 species of yeast have shed new light on the divergence of gene regulation during evolution, with significant changes occurring after an event in which a whole genome was duplicated. PMID- 23795301 TI - Keeping blood vessels out of sight. AB - Researchers have identified a soluble receptor that prevents blood vessels forming in the outer retina-a process that can lead to blindness-by sequestering vascular endothelial growth factor. PMID- 23795302 TI - The early days of late blight. AB - Large-scale DNA sequencing of samples of foliage collected in the 19th century from plants infected with late blight has shown that the potato famines of the 1840s were triggered by a single clonal lineage of Phytophthora infestans, called HERB-1, which persisted for at least 50 years. PMID- 23795303 TI - The lasting influence of LSD1 in the blood. AB - An enzyme called LSD1 that controls the development of blood cells by manipulating gene expression in progenitor cells could be a therapeutic target for leukemia. PMID- 23795306 TI - The Genetics of Keratoconus: A Review. AB - Keratoconus is the most common ectatic disorder of the corneal. Genetic and environmental factors may contribute to its pathogenesis. The focus of this article is to summarize current research into the complex genetics of keratoconus. We discuss the evidence of genetic etiology including family-based linkage studies, twin studies, genetic mutations, and genome-wide association studies. The genes implicated potentially include VSX1, miR-184, DOCK9, SOD1, RAB3GAP1, and HGF. Besides the coding mutations, we also highlight the potential contribution of DNA copy number variants in the pathogenesis of keratoconus. Finally, we present future directions for genetic research in the understanding of the complex genetics of keratoconus and its clinical significance. As new functional, candidate genes for keratoconus are being discovered at a rapid pace, the molecular genetic mechanisms underlying keratoconus pathogenesis will advance our understanding of keratoconus and promote the development of a novel therapy. PMID- 23795308 TI - New Finite Difference Methods Based on IIM for Inextensible Interfaces in Incompressible Flows. AB - In this paper, new finite difference methods based on the augmented immersed interface method (IIM) are proposed for simulating an inextensible moving interface in an incompressible two-dimensional flow. The mathematical models arise from studying the deformation of red blood cells in mathematical biology. The governing equations are incompressible Stokes or Navier-Stokes equations with an unknown surface tension, which should be determined in such a way that the surface divergence of the velocity is zero along the interface. Thus, the area enclosed by the interface and the total length of the interface should be conserved during the evolution process. Because of the nonlinear and coupling nature of the problem, direct discretization by applying the immersed boundary or immersed interface method yields complex nonlinear systems to be solved. In our new methods, we treat the unknown surface tension as an augmented variable so that the augmented IIM can be applied. Since finding the unknown surface tension is essentially an inverse problem that is sensitive to perturbations, our regularization strategy is to introduce a controlled tangential force along the interface, which leads to a least squares problem. For Stokes equations, the forward solver at one time level involves solving three Poisson equations with an interface. For Navier-Stokes equations, we propose a modified projection method that can enforce the pressure jump condition corresponding directly to the unknown surface tension. Several numerical experiments show good agreement with other results in the literature and reveal some interesting phenomena. PMID- 23795307 TI - Neurotrophic Peptides: Potential Drugs for Treatment of Amyotrophic Lateral Sclerosis and Alzheimer's disease. AB - Neurodegenerative diseases are characterized by the progressive loss of neurons and glial cells in the central nervous system correlated to their symptoms. Among these neurodegenerative diseases are Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Neurodegeneration is mostly restricted to specific neuronal populations: cholinergic neurons in AD and motoneurons in ALS. The demonstration that the onset and progression of neurodegenerative diseases in models of transgenic mice, in particular, is delayed or improved by the application of neurotrophic factors and derived peptides from neurotrophic factors has emphasized their importance in neurorestoration. A range of neurotrophic factors and growth peptide factors derived from activity-dependent neurotrophic factor/activity-dependent neuroprotective protein has been suggested to restore neuronal function, improve behavioral deficits and prolong the survival in animal models. In this review article, we focus on the role of trophic peptides in the improvement of AD and ALS. An understanding of the molecular pathways involved with trophic peptides in these neurodegenerative diseases may shed light on potential therapies. PMID- 23795309 TI - Low glial angiotensinogen improves body habitus, diastolic function, and exercise tolerance in aging male rats. AB - OBJECTIVES: Long-term systemic blockade of the renin-angiotensin system (RAS) with either an angiotensin (Ang) II type 1 receptor antagonist or an angiotensin converting enzyme inhibitor attenuates age-related cardiac remodeling and oxidative damage, and improves myocardial relaxation. However, the role of the brain RAS in mediating the development of diastolic dysfunction during aging is not known. We hypothesized that low brain RAS protects against the development of age-related diastolic dysfunction and left ventricular remodeling. METHODS: Sixty week-old transgenic male ASrAOGEN rats (n =9), with normal circulating Ang II and functionally low brain Ang II, because of a GFAP promoter-linked angiotensinogen antisense targeted to glia, and age-matched and sex-matched Hannover Sprague Dawley (SD; n= 9) rats, with normal levels of both circulating and brain Ang II, underwent echocardiograms to evaluate cardiac structure and function. Postmortem hearts were further compared for histological, molecular, and biochemical changes consistent with cardiac aging. RESULTS: ASrAOGEN rats showed preserved systolic and diastolic function at mid-life and this was associated with a lower, more favorable ratio of the phospholamban-SERCA2 ratio, reduced incidence of histological changes in the left ventricle, and increased cardiac Ang-(1-7) when compared with the in-vivo functional, and ex-vivo structural and biochemical indices from age-matched SD rats. Moreover, ASrAOGEN rats had lower percent body fat and a superior exercise tolerance when compared with SD rats of the same age. CONCLUSION: Our data indicate that the central RAS plays a role in the maintenance of diastolic function and exercise tolerance in mid-life and this may be related to effects on body habitus. PMID- 23795310 TI - Saxagliptin Improves Glucose Tolerance but not Survival in a Murine Model of Dilated Cardiomyopathy. AB - Glucagon-like peptide 1 (GLP-1) agonists improve myocardial function and insulin sensitivity in the setting of chronic heart failure. Endogenously produced GLP-1 peptide (7-36) is rapidly cleaved by dipeptidyl peptidase 4 (DPP4) to the 9-36 peptide, which lacks anti-hyperglycemic activity. To elucidate the effect of increased endogenous GLP-1 during heart failure progression, the DPP4 inhibitor saxagliptin or vehicle was administered by daily oral gavage to female TG9 mice, a transgenic model of dilated cardiomyopathy, starting at day of life 42, just prior to the development of detectable contractile dysfunction. Saxagliptin treatment inhibited DPP4 activity >90% and increased GLP-1 levels 4-fold following a 2 gm/kg glucose load but did not affect fasting GLP-1 levels. There was no difference in food intake or body weight between groups. At 56 days of age, oral glucose tolerance was improved in saxagliptin-versus vehicle-treated animals (AUC0-120 1340 +/- 46 and 1501 +/- 43 min.mmol/L, respectively, p<0.015). In contrast to the effect of a GLP-1 agonist in TG9 mice, saxagliptin had no effect on survival (80.7 +/- 4.3 days) compared to vehicle-treated mice (79.6 +/- 3.6 days, p = 0.46). Taken together, these data indicate that improvement in glucose tolerance is not sufficient to improve survival. Future efforts to confirm these findings in additional models of heart failure are warranted. PMID- 23795311 TI - Helping cancer patients across the care continuum: the navigation program at the Queen's Medical Center. AB - Research suggests that cancer patient navigation improves care, but few reports describe the variety of patients managed by a hospital-based navigation program. Differences in navigated patients by the intensity (low, medium, or high) of navigation services they received were examined. The 835 clients seen by the navigators in a hospital-based cancer center were first stratified by quarter and by four ethnic groups. Randomized selection from each group assured there would be equal representation for analysis of Hawaiians, Filipinos, Japanese, and Whites and even numbers over all time intervals. Five professionals extracted data from these case records on demographics, type/stage of cancer, diagnosis and treatment dates, barriers, and navigator actions. Clients had breast (30.0%), lung (15.8%), esophageal (6.7%), colon (5.8%), ovarian (4.2%), prostate (3.3%), and other cancers (34.2%). The median number of actions taken on behalf of a client was 4 (range 1-83), and the median number of days a case was open was 14 (range 1-216). High intensity cases (those receiving more assistance over longer periods of time) were more likely than low-intensity cases to need help with education and reassurance, transportation, care coordination, and covering costs. Although there were no demographic differences across intensity groups, Neighbor Island patients from Hawai'i, Maui, Moloka'i, Lana'i and Kaua'i were more likely to need help with arranging travel, care coordination, and costs associated with getting treatment (all at P=.05), and patients on public insurance were more likely to have stage 4 cancer (P=.001) and to need help with costs (P=.006). Findings suggest that this hospital-based navigation program is filling a real need of patients across the cancer care continuum. A triage protocol and an integrated data capture system could help improve the targeting and documentation of cancer patient navigation services. PMID- 23795312 TI - The effects of extended release niacin on lipoprotein sub-particle concentrations in HIV-infected patients. AB - With the advent of highly active antiretroviral therapy (HAART), Cardiovascular Disease (CVD) has emerged as the leading cause of death in Human Immunodeficiency Virus (HIV) infected patients. An atherogenic lipoprotein phenotype has been described in HIV- infected patients with a predominance of small, low density lipoprotein (SLDL) particles with accompanying elevated triglycerides and reduced high density lipoprotein cholesterol. This randomized controlled pilot study was conducted to evaluate the efficacy of Extended Release Niacin (ERN) in improving the lipid profile in HIV patients. A total of 17 HIV positive subjects on HAART therapy with High Density Lipoprotein Cholesterol (HDL) levels below 40mg/dl and Low Density Lipoprotein Cholesterol (LDL) below 130mg/dl were enrolled. Nine were randomized to be treated with ERN titrated from a starting level of 500mg/night and titrated to a level of 1500mg/night. Eight patients were assigned to the control arm. No placebo was used. Lipoprotein profiles of the subjects were analyzed at baseline and at the end of 12 weeks using Nuclear Magnetic Resonance (NMR) spectroscopy. At the end of 12 weeks, NMR spectroscopic analysis revealed a significant increase in overall LDL size (1.2% in ERN treated subjects vs 2.0% decrease in control patients, P=.04) and a decrease in small LDL particle concentration (17.0% in ERN treated subjects vs 21.4% increase in control patients, P=.03) in subjects receiving ERN as compared to those in the control group. Only 1 subject receiving ERN developed serious flushing which was attributed to an accidental overdose of the drug. This pilot study demonstrates that ERN therapy in HIV-infected patients with low HDL is safe and effective in improving the lipoprotein profile in these patients. PMID- 23795313 TI - Favorable outcomes for Native Hawaiians and other Pacific Islanders with severe traumatic brain injury. AB - Traumatic brain injury (TBI) disproportionately impacts minority racial groups. However, limited information exists on TBI outcomes among Native Hawaiians and other Pacific Islanders (NHPI). All patients with severe TBI (Glasgow Coma Scale (GCS) <9) who were hospitalized at the state-designated trauma center in Hawai'i from March 2006 to February 2011 were studied. The primary outcome measure was discharge Glasgow Outcome Scale ([GOS]: 1, death; 2, vegetative state; 3, severe disability; 4, moderate disability; 5, good recovery), which was dichotomized to unfavorable (GOS 1-2) and favorable (GOS 3-5). Logistic regression analyses were performed to assess factors predictive of discharge functional outcome. A total of 181 patients with severe TBI (NHPI 27%, Asians 25%, Whites 30%, and others 17%) were studied. NHPI had a higher prevalence of assault-related TBI (25% vs 6.5%, P = .046), higher prevalence of chronic drug abuse (20% vs 4%, P = .02) and chronic alcohol abuse (22% vs 2%, P = .003), and longer intensive care unit length of stay (15+/-10 days vs 11+/-9 days, P < .05) compared to Asians. NHPI had lower prevalence of unfavorable functional outcomes compared to Asians (33% vs 61%, P = .006) and Whites (33% vs 56%, P = .02). Logistic regression analyses showed that Asian race (OR, 6.41; 95% CI, 1.68-24.50) and White race (OR, 4.32; 95% CI, 1.27-14.62) are independently associated with unfavorable outcome compared to NHPI. Contrary to the hypothesis, NHPI with severe TBI have better discharge functional outcomes compared to other major racial groups. PMID- 23795314 TI - Creutzfeldt-Jakob disease: a case report and differential diagnoses. AB - Sporadic Creutzfeldt-Jakob disease is a rare neurodegenerative disorder of unknown etiology that causes rapidly progressive dementia. This disease is uniformly fatal and most patients die within 12 months. Clinical findings include myoclonus, visual disturbances, and cerebellar and pyramidal/extrapyramidal signs in addition to rapidly progressive cognitive and functional impairment. These findings are all non-specific and it is often difficult and challenging to diagnose premortem because of low awareness and clinical suspicion. We present a 66-year-old woman with a 5-month history of rapidly progressive dementia. After a series of extensive diagnostic examinations and continuous follow-up, she was diagnosed with probable sporadic Creutzfeldt-Jakob disease based on Centers for Disease Control and Prevention (CDC) criteria, with key findings of rapidly progressive dementia, blurry vision, extrapyramidal signs (cogwheel rigidity), and abnormal hyperintensity signals on diffusion-weighted MRI. Her symptoms progressively worsened and she died 7 months after the onset. The postmortem brain autopsy demonstrated the presence of abnormal protease-resistant prion protein by Western Blot analysis. A literature review was performed on differential diagnoses that present with rapidly progressive dementia and thereby mimic sporadic Creutzfeldt-Jakob disease. These include Alzheimer's disease, dementia with Lewy Bodies, frontotemporal dementia, meningoencephalitis, corticobasal degeneration, progressive supranuclear palsy, CADASIL, and paraneoplastic encephalomyelitis. PMID- 23795315 TI - Teen Health Camp Hawai'i: inspiring Hawai'i's youth to be healthcare leaders of tomorrow. PMID- 23795316 TI - A new and innovative public health specialization founded on traditional knowledge and social justice: Native Hawaiian and Indigenous Health. PMID- 23795318 TI - A review of femtosecond laser assisted cataract surgery for Hawai'i. AB - Hawai'i has had the first US Food and Drug Administration approved femtosecond laser (LenSx as shown in figure) for cataract surgery since early 2012, a brand new laser technology for modern cataract surgery in Hawai'i. This article intends to evaluate the cost, safety, efficacy, advantages, and limitations of femtosecond laser-assisted cataract surgery through a review of the literature for the public of Hawai'i. A search was conducted using keywords to screen and select articles from PubMed. In addition, recent published peer reviewed articles pertinent to the femtosecond laser-assisted cataract surgery were selected and reviewed. Safety and efficacy of femtosecond laser-assisted cataract surgery were demonstrated in the literature, with improvements in anterior capsulotomy, phacofragmentation, and corneal incision. However, there were limitations within these studies which included small sample size and short-term follow-up. In addition, cost-benefit analysis has not yet been addressed. Long-term studies to compare the complication rate and visual outcome between the laser and conventional cataract surgery are warranted. PMID- 23795319 TI - Case of levodopa toxicity from ingestion of Mucuna gigantea. AB - Hawai'i is home to 1000 native species of flowering plants. Mucuna gigantea is one such Hawaiian species which has been studied as affordable sustenance and as a cover crop in developing countries. Mucuna gigantea and other Mucuna species (spp.) in general, are known to contain natural levodopa and its utility in the treatment of Parkinson's Disease has also been evaluated. Levodopa is converted in the periphery into dopamine which can then act on dopamine receptors to cause nausea, vomiting, arrhythmias, and hypotension. We describe a case in which a patient presents with abdominal pain, nausea, and vomiting after legume ingestion. The bean was ultimately identified as Mucuna gigantea and the patient was diagnosed with levodopa-induced gastrointestinal toxicity from consumption of the legume. A literature review was conducted using the database search engines, Biological Abstracts and PubMed, with a broad combination of keywords of which include "mucuna, "gigantean," "levodopa," "l-dopa," "toxicity," and the association between Mucuna gigantea ingestion and levodopa toxicity is discussed. These findings expand the differential diagnosis of abdominal pain associated with nausea and vomiting in the correct clinical context. PMID- 23795320 TI - Utilization of Children with Special Health Care Needs (CSHCN) Screener(c) by O'ahu's pediatricians. AB - O'ahu's primary care physicians are in the process of implementing the Patient Centered Medical Home (PCMH) model. The Medical Home Task Force recommends the implementation of the Children with Special Health Care Needs (CSHCN) Screener(c) as one of the two quality improvement programs that must be completed by each participating physician. This study sought to find how many pediatricians practice population health management and to determine barriers for incorporating population health management and care registries into practices. An online survey of 55 pediatricians in Hawai'i was conducted between January 10, 2012 and March 10, 2012. The survey contained questions regarding knowledge and use of population health management and investigated the utilization rate of the Screener(c). This survey provides baseline data on the implementation of this recommended screener, and informs the process that will be necessary to ensure maximal adoption of recommendations. Sixty percent of the survey participants have not incorporated population health management into their routine practice. Twenty three percent did not have knowledge of population health management and 85% did not use a chronic disease registry. As of August 2011, 95% had not screened their patients with the Screener(c). Reasons included not having heard of the Screener(c) and never having considered using a systematic process to ask patients to assess their health. Based on results, there are important educational goals that need to be accomplished in order for Hawai'i's physicians to transform their practices into effective PCMHs. Physicians will likely need instructional and monetary support to effectively change their practices into PCMHs. PMID- 23795321 TI - Liver disease among children in Hawai'i diagnosed with metabolic syndrome. AB - The purpose of this study was to evaluate the prevalence of and factors related to liver disease among children in Hawai'i with metabolic syndrome. The medical charts of children diagnosed with metabolic syndrome by an outpatient endocrinologist between January 2000 and December 2010 were reviewed. Liver disease prevalence was estimated based on serum alanine aminotransferase (ALT) levels, which were then assessed for associations with demographic (age, gender, ethnicity), anthropometric (body mass index), biochemical (fasting blood glucose, hemoglobin A1c, triglycerides, and total, LDL- and HDL-cholesterol), and clinical (blood pressure) characteristics of subjects. Serum ALT was available for 167 of the 195 subjects. The proportion of subjects with liver disease (105/167 [63%]) was greater than many traditional features of metabolic syndrome including hypertriglyceridemia (73/177 [41%]), hypertension (37/194 [19%]) and hyperglycemia (37/170 [22%]). Serum ALT values were positively associated with age (P=.030), and liver disease was more common among boys than girls (62/91 [68%] vs 43/76 [57%]), although this difference was not statistically significant (P=.123). There was a significant difference in liver disease across ethnicities (P=.029), and appeared to be more common in children with Pacific Islander surnames (14/16 [88%]), and less common in children with Hispanic surnames (7/20 [35%]). Diastolic blood pressure was the only obesity-related disease parameter associated with serum ALT after adjusting for age and gender (P=.018). In conclusion, liver disease was common among children diagnosed with metabolic syndrome in Hawai'i. Age, gender, and ethnicity may be important determinants of liver disease risk, and should be investigated further. PMID- 23795322 TI - Ultrasound education in obstetrics and gynecology: Hawai'i experience. PMID- 23795323 TI - Innovative Readiness Training & Tropic Care Kaua'i 2012. PMID- 23795325 TI - Editor's commentary. PMID- 23795326 TI - The importance of communication in the management of postoperative pain. AB - This study investigates the importance of communication in surgery and how delivering preoperative patient education can lead to better health outcomes postoperatively, via promoting tolerable pain scores and minimizing the use of narcotics after surgery. Patients who underwent outpatient surgery were randomly divided into groups to compare the pain scores of those who received preoperative patient education, the experimental group, and those who did not receive any form of patient education, the control group. Two weeks before surgery, the experimental group subjects received oral and written forms of patient education consisting of how the body responds to pain, and how endorphins cause natural analgesia. Moreover, patients were educated on the negative effects narcotics have on endorphin production and activity, as well as mechanisms of non-opioid analgesics. Of the 69 patients in the experimental group, 90% declined a prescription for hydrocodone after receiving preoperative education two weeks prior to surgery. The control group consisted of 66 patients who did not receive preoperative patient education and 100% filled their hydrocodone prescriptions. Patients in both groups were offered and received gabapentin and celecoxib preoperatively for prophylaxis of postoperative pain unless they declined. The control groups were found to have average pain scores significantly greater (P <.05) than the experimental groups and also a significantly longer (P <.005) duration of pain. This study illustrates the power of patient education via oral, written and visual communication, which can serve as an effective means to minimize narcotic analgesia after surgery. PMID- 23795327 TI - Retained pill camera at an entero-uracho-vesical fistula site in a patient with Crohn's disease. AB - An 18-year-old female patient with Crohn's disease had abdominal pain secondary to a retained pill camera. After several weeks of medical management, the camera spontaneously passed. However, the patient also had an intra-abdominal abscess that worsened, despite medical therapy. Surgical therapy was recommended and a 5cm infected urachal cyst with entero-urachal and vesico-urachal fistulas was discovered. An en-bloc resection of the entire area was performed to include the urachal cyst, the adherent portion of the dome of the bladder, and 15cm of associated ileum. The bladder was repaired, a suprapubic catheter was placed, and an ileo-ileal anastamosis was performed. Microscopic findings were consistent with active Crohn's disease and fistula formation. The entero-uracho-vesical fistula site was likely the site of the retained pill camera. The patient did well postoperatively and was discharged on postoperative day six without complications. PMID- 23795328 TI - Characteristics of patients with type 2 diabetes mellitus in two rural, medically underserved communities. AB - In the state of Hawai'i, Native Hawaiians and Filipinos suffer from increased disparities, compared to other groups, in diabetes prevalence and adverse health outcomes that are exacerbated by challenges to health care access among rural communities. To address the limited literature describing rural, underserved patients with diabetes in Hawai'i, this paper aims to characterize two rural communities that are located on Moloka'i and Lana'i in federally-designated medically underserved areas and that are served by a single Native Hawaiian health care system entitled Na Pu'uwai. Descriptive analyses examining associations between variables were performed using the baseline demographic information, clinical measures, and questionnaire responses collected from 40 adult study participants with diabetes. The data revealed that the study participants had a high prevalence of insulin use (60%); a HbA1c level greater than or equal to 9% (55%); a high-fat diet (73%); and comorbidities, including hyperlipidemia (85%), hypertension (83%), and obesity (70%). Furthermore, among the participants, the mean SF-12v2TM General Health Perceptions Score was significantly lower for participants with uncontrolled diabetes compared to those with controlled diabetes (P = .02); however, this association was not statistically significant in the multivariable regression model that adjusted for age and number of diabetes medications. Based on these results, the participants appear to belong to a high-risk group with a complicated manifestation of diabetes. This study adds to the growing body of literature demonstrating disparities in diabetes among rural, minority, and underserved communities, highlighting the need for further investigation, development, and implementation of strategies for reaching these vulnerable populations. PMID- 23795330 TI - Graduation Speech, May 12, 2013 convocation ceremony, John A. Burns School of Medicine, University of Hawai'i. PMID- 23795329 TI - Predictors of 25-hydroxyvitamin D levels in HIV-infected patients in Hawai'i. AB - HIV-infected individuals are at increased risk for several metabolic diseases, including low 25-hydroxyvitamin D [25(OH)D]. Data on the prevalence and risk factors for low 25(OH)D in HIV patients living in the tropics is scarce. Patients >= 40 years old on stable antiretroviral therapy were enrolled from March 2009 to July 2011 in Hawai'i (latitude 21 degrees North). Chemiluminescent immunoassay (DiaSorin) was used to determine plasma 25(OH)D levels. Patients were grouped by whether 25(OH)D was collected in summer (May 1 - September 30) or winter (October 1 - April 30). Of 158 patients enrolled, 88 (56%) and 70 (44%) were enrolled in winter and summer, respectively. There were 57.6% Caucasians and 88% men. Over all median (quartile1, quartile3) age was 51 (46, 57) years and median 25(OH)D was 32.4 (24.0, 41.0) ng/ml. Forty-three percent (n=68) had 25(OH)D<30.0 ng/ml. Median 25(OH)D levels were 29.6 (22.0, 38.0) ng/ml in winter and 36.9 (25.0, 44.5) ng/ml in summer (P = .01). Median body mass index (BMI) of winter patients was significantly higher (P = .03). By simple linear regression, log-transformed 25(OH)D was significantly associated with winter visit (beta = -.0737, P = .01), ethnicity (Caucasian versus non-Caucasian, beta = .1194, P < .01), BMI (beta = .0111, P < .01) and current use of zidovudine (beta = -.1233, P = .03). In multiple linear regression, only Caucasian ethnicity (beta = .1004, P < .01) and BMI (beta = -.0078, P = .02) retained statistical significance. Seasonal variation in 25(OH)D was observed but the significance of winter visit was not preserved in the final multivariate model. Ethnicity and BMI were better predictors of 25(OH)D levels than season in the tropics. PMID- 23795331 TI - Hawai'i's silent epidemic: children's caries (dental decay). PMID- 23795333 TI - Smoke-Free Policies in the Workplace and in the Home among American Indians. AB - OBJECTIVES: American Indians are more likely to smoke, less likely to have smoke free homes, and potentially less likely to have worksite smoke-free policies. We examined correlates of smoke-free policies at home and work among a community based sample of American Indians in the Midwest. METHODS: We examined correlates of smoke-free policies at home and work in a sample of American Indians in the Midwest using a community-based participatory research approach. RESULTS: 66.7% were nonsmokers, 15.6% smoked on some days, and 17.6% smoked every day. The majority (72.4%) had complete smoke-free home policies, 13.1% had partial restrictions, and 14.5% had no rules. Moreover, 62.7% had complete smoke-free worksite policies, 27.9% had partial policies, and 9.4% had no worksite smoke free policies. Factors associated with having a complete smoke-free home policy included being a college graduate (p=.005) and a nonsmoker versus a nondaily (p=.006) or a daily smoker (p<.001). Correlates of having a complete smoke-free worksite policy included being female (p=.005) and a nonsmoker versus a nondaily (p=.03) or a daily smoker (p<.001). Having complete worksite policies was associated with having smoke-free homes (p<.001). CONCLUSIONS: Having complete worksite policies was related to having smoke-free home policies; both were associated with being a nonsmoker. PMID- 23795334 TI - Airway Management & Assessment of Dyspnea in Emergency Department Patients with Acute Heart Failure. AB - Shortness of breath is the most common symptom in patients with acute heart failure (AHF). Ensuring adequate oxygenation and ventilation as well as symptomatic relief are key goals of early emergency department management. In this focused review, we describe how to assess dyspnea in clinical practice and how to treat AHF patients to relieve dyspnea, with initial discussion on Airway and Breathing management for patients who present in extremis. PMID- 23795335 TI - Abiraterone for the Treatment of Advanced Prostate Cancer. AB - Until recently, treatment options for castration-resistant prostate cancer (CRPC) were limited to only the chemotherapeutic agent docetaxel which demonstrated a survival advantage over palliative chemotherapy. Abiraterone acetate (AA) is an orally available, potent irreversible inhibitor of the adrenal microsomal enzyme cytochrome P450-17 (CYP17). In a large phase III study of AA in docetaxel pretreated patients, AA demonstrated excellent tolerance and a 4-month survival advantage over placebo, leading to the approval of AA for docetaxel-pretreated patients by the FDA in 2011. More recently, phase III data in docetaxel-naive patients have become available, showing clear clinical benefits in this population as well, and it is likely that the label for AA will soon be expanded to include men with CRPC who have not yet received chemotherapy. This article summarizes clinical studies of AA in CRPC patients and discusses the emerging treatment paradigm in this rapidly evolving area. PMID- 23795336 TI - The Mediator Complex and Lipid Metabolism. AB - The precise control of gene expression is essential for all biological processes. In addition to DNA-binding transcription factors, numerous transcription cofactors contribute another layer of regulation of gene transcription in eukaryotic cells. One of such transcription cofactors is the highly conserved Mediator complex, which has multiple subunits and is involved in various biological processes through directly interacting with relevant transcription factors. Although the current understanding on the biological functions of Mediator remains incomplete, research in the past decade has revealed an important role of Mediator in regulating lipid metabolism. Such function of Mediator is dependent on specific transcription factors, including peroxisome proliferator-activated receptor-gamma (PPARgamma) and sterol regulatory element binding proteins (SREBPs), which represent the master regulators of lipid metabolism. The medical significance of these findings is apparent, as aberrant lipid metabolism is intimately linked to major human diseases, such as type 2 diabetes and cardiovascular disease. Here, we briefly review the functions and molecular mechanisms of Mediator in regulation of lipid metabolism. PMID- 23795337 TI - COMPARATIVE PHARMACOKINETICS OF PAMAM-OH DENDRIMERS AND HPMA COPOLYMERS IN OVARIAN-TUMOR-BEARING MICE. AB - The purpose of this study was to model data from a head to head comparison of the in vivo fate of hyper-branched PAMAM dendrimers with linear HPMA copolymers in order to understand the influence of molecular weight (MW), hydrodynamic size (Rh) and polymer architecture on biodistribution in tumor-bearing mice using compartmental pharmacokinetic analysis. Plasma concentration data was modeled by two-compartment analysis using Winnonlin(r) to obtain elimination clearance (E.CL) and plasma exposure (AUCplasma). Renal clearance (CLR) was calculated from urine data collected over 1 week. A plasma-tumor link model was fitted to experimental plasma and tumor data by varying the tumor extravasation (K4, K6) and elimination (K5) rate constants using multivariable constrained optimization solver in Matlab(r). Tumor exposures (AUCtumor) were computed from area under the tumor concentration time profile curve by the linear trapezoidal method. Along with MW and Rh, polymer architecture was critical in affecting the blood and tumor pharmacokinetics of the PAMAM-OH dendrimers and HPMA copolymers. Elimination clearance decreased more rapidly with increase in hydrodynamic size for PAMAM-OH dendrimers as compared to HPMA copolymers. HPMA copolymers were eliminated renally to a higher extent than PAMAM-OH dendrimers. These results are suggestive of a difference in extravasation of polymers of varying architecture through the glomerular basement membrane. While the linear HPMA copolymers can potentially reptate through a pore smaller in size than their hydrodynamic radii in a random coil conformation, PAMAM dendrimers have to deform in order to permeate across the pores. With increase in molecular weight or generation, the deforming capacity of PAMAM-OH dendrimers is known to decrease, making it harder for higher generation PAMAM-OH dendrimers to sieve through the glomerulus as compared to HPMA copolymers of comparable molecular weights. PAMAM-OH dendrimer had greater tumor extravsation rate constants and higher tumor to plasma exposure ratios than HPMA copolymers of comparable molecular weights which indicated that in the size range studied, when in circulation, PAMAM-OH dendrimers had a higher affinity to accumulate in the tumor than the HPMA copolymers. PMID- 23795338 TI - Dioximate- and Bis(salicylaldiminate)-Bridged Titanium and Zirconium Alkoxides: Structure Elucidation by Mass Spectrometry. AB - The treatment of titanium alkoxides with 1,5-pentanedioxime or 2,5-hexanedioxime resulted in the formation of complexes [{TiL(OR)2}2] in which the dioximate ligands (L) bridge a dimeric Ti2(MU2-OR)2 unit. The structures of the complexes were determined by single-crystal structure analysis, ESI mass spectrometry, and 1D and 2D solution NMR spectroscopy. In contrast, the treatment of titanium alkoxides with dioximes bearing cyclic linkers, such as cyclohexyl or aryl groups, resulted in insoluble polymeric compounds. The treatment of various bis(salicylaldiminates) with titanium and zirconium alkoxides resulted in compounds with the same composition [{TiL(OR)2}2], in which, however, two monomeric Ti(OR)2 units are bridged by the ligands L. The two structural possibilities can be distinguished by low-energy collision-induced dissociation owing to their different fragmentation patterns. PMID- 23795339 TI - Efficacy of complete decongestive therapy (CDT) on edematous rat limb after lymphadenectomy demonstrated by real time lymphatic fluid tracing. AB - Although complete decongestive therapy (CDT) is considered to reduce the volume of lymphedema, there is no concrete evidence to sustain its efficacy. The purpose of the present study was to find new evidence of CDT based on visualizing the changes of lymph fluid accumulating in an edematous limb using indocyanine green (ICG) fluorescent lymphography in real time.Twelve lymphedema rats were divided randomly into two groups. On the first day, ICG was injected into an edematous limb of rats, and no-intervention and CDT was applied to groups 1 and 2, respectively, for two weeks. ICG lymphography and circumferential measurements were done every two days in each two-week observation. The results indicates that a fluorescent flow to the ipsilateral axillary fossa was identified in all rats. In addition, network-like and dermal backflow patterns were observed in the lower legs and thighs. While manual lymph drainage was applied in the CDT group, the flow moved more rapidly through this pathway than that in the no-intervention group. An area of high-intensity fluorescent signals concentrated around the injection sites diminished in the CDT group more than that in the no-intervention group after two weeks. Circumferential lengths of the edematous limbs were longer than the non-edematous limbs in both groups 1 and 2 on the day of ICG injection. The no-intervention group 1 showed no significance differences during 14 days, whereas the CDT group 2 exhibited very significant differences. These results suggest that CDT has beneficial effects in lymphedema treatment. PMID- 23795340 TI - Measuring quality in diabetes care: an expert-based statistical approach. AB - We present a methodology for using health insurance claims data to monitor quality of care. The method uses a statistical model trained on the quality ratings of a medical expert. In a pilot study, the expert rated the quality of care received over the course of two years by 101 diabetes patients. A logistic regression model accurately identified the quality of care for 86% of the patients. Because the model uses data derived from patients' health insurance claims it can be used to monitor the care being received by a large patient population. One important use of the model is to identify potential candidates for case management, especially patients with complicated medical histories. PMID- 23795341 TI - Establishing a trauma registry in Bhutan: needs and process. AB - BACKGROUND: Globally, trauma represents a growing and significant burden of disease. Many health systems have limited metrics with which to guide development and appropriately inform policy and management decisions with regard to trauma related health care delivery. FINDINGS: This paper outlines the establishment of need for improved trauma related metrics in the country of Bhutan and the process of development of a trauma registry at Jigme Dorji Wangchuck National Referral Hospital to meet that need. CONCLUSIONS: Trauma registries are important tools allowing health systems to respond to the shifting burden of disease; successful establishment of a trauma registry requires an understanding of the health system and broad institutional support. PMID- 23795342 TI - Relationship between male moths of Cryptoblabes gnidiella (Milliere) (Lepidoptera: Pyralidae) caught in sex pheromone traps and cumulative degree-days in vineyards in southern Uruguay. AB - Cryptoblabes gnidiella (Milliere) (Lepidoptera: Pyralidae) has been known in Uruguay for 30 years and only in vineyards, despite being polyphagous. In recent years, this pest has caused sporadic but serious damage on some grapevine cultivars. Understanding the insect's phenology and developing a monitoring program are essential aspects of integrated pest management. We monitored males using sexual pheromone traps on four cultivars of vine, Pinot noir, Tannat, Gewurztraminer, and Cabernet Sauvignon, in two vine-growing establishments in the Department of Canelones and compiled data on the accumulated effective temperatures for the southern area of Uruguay. We determined that this species undergoes three generations per year and overwinters without diapause as larvae on dried grapes remaining after harvest. Using the proportion of cumulative male moths caught from December to May from 2003-2007 on the four cultivars and the sum of effective temperatures above two previously-published lower-threshold temperatures for development, 12.26 degrees C and 13 degrees C, statistically significant logistic models were estimated. Predictions based on the resulting models suggested that they would be acceptable tools to improve the efficiency of integrated management of this pest in Uruguay. PMID- 23795343 TI - Design and Application of Magnetic-based Theranostic Nanoparticle Systems. AB - Recently, magnetic-based theranostic nanoparticle (MBTN) systems have been studied, researched, and applied extensively to detect and treat various diseases including cancer. Theranostic nanoparticles are advantageous in that the diagnosis and treatment of a disease can be performed in a single setting using combinational strategies of targeting, imaging, and/or therapy. Of these theranostic strategies, magnetic-based systems containing magnetic nanoparticles (MNPs) have gained popularity because of their unique ability to be used in magnetic resonance imaging, magnetic targeting, hyperthermia, and controlled drug release. To increase their effectiveness, MNPs have been decorated with a wide variety of materials to improve their biocompatibility, carry therapeutic payloads, encapsulate/bind imaging agents, and provide functional groups for conjugation of biomolecules that provide receptor-mediated targeting of the disease. This review summarizes recent patents involving various polymer coatings, imaging agents, therapeutic agents, targeting mechanisms, and applications along with the major requirements and challenges faced in using MBTN for disease management. PMID- 23795344 TI - Can experience-based household food security scales help improve food security governance? AB - Experience-based food security scales (EBFSSs) have been shown to be valid across world regions. EBFSSs are increasingly been included in national food and nutrition assessments and food hardship items have been added to regional and global public opinion polls. EBFSSs meet the SMART criteria for identifying useful indicators. And have the potential to help improve accountability, transparency, intersectoral coordination and a more effective and equitable distribution of resources. EBFSSs have increased awareness about food and nutrition insecurity in the court of public opinion. Thus, it's important to understand the potential that EBFSSs have for improving food and nutrition security governance within and across countries. The case of Brazil illustrates the strong likelihood that EBFSSs do have a strong potential to influence food and governance from the national to the municipal level. A recent Gallup World Poll data analysis on the influence of the '2008 food crisis' on food hardship illustrates how even a single item from EBFSSs can help examine if food security governance in different world regions modifies the impact of crises on household food insecurity. Systematic research that bridges across economics, political science, ethics, public health and program evaluation is needed to better understand if and how measurement in general and EBFSSs in particular affect food security governance. PMID- 23795345 TI - Redox Biology of Hydrogen Sulfide: Implications for Physiology, Pathophysiology, and Pharmacology. AB - Hydrogen sulfide (H2S) has emerged as a critical mediator of multiple physiological processes in mammalian systems. The pathways involved in the production, consumption, and mechanism of action of H2S appear to be sensitive to alterations in the cellular redox state and O2 tension. Indeed, the catabolism of H2S through a putative oxidation pathway, the sulfide quinone oxido-reductase system, is highly dependent on O2 tension. Dysregulation of H2S homeostasis has also been implicated in numerous pathological conditions and diseases. In this review, the chemistry and the main physiological actions of H2S are presented. Some examples highlighting the cytoprotective actions of H2S within the context of cardiovascular disease are also reported. Elucidation of the redox biology of H2S will enable the development of new pharmacological agents based on this intriguing new redox cellular signal. PMID- 23795347 TI - A Comparison of Logistic Regression, Logic Regression, Classification Tree, and Random Forests to Identify Effective Gene-Gene and Gene-Environmental Interactions. AB - Genome wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) that are associated with a variety of common human diseases. Due to the weak marginal effect of most disease-associated SNPs, attention has recently turned to evaluating the combined effect of multiple disease-associated SNPs on the risk of disease. Several recent multigenic studies show potential evidence of applying multigenic approaches in association studies of various diseases including lung cancer. But the question remains as to the best methodology to analyze single nucleotide polymorphisms in multiple genes. In this work, we consider four methods-logistic regression, logic regression, classification tree, and random forests-to compare results for identifying important genes or gene-gene and gene-environmental interactions. To evaluate the performance of four methods, the cross-validation misclassification error and areas under the curves are provided. We performed a simulation study and applied them to the data from a large-scale, population-based, case-control study. PMID- 23795348 TI - Reduced Expression of RNA Binding Protein CELF2, a Putative Tumor Suppressor Gene in Colon Cancer. AB - BACKGROUND & AIMS: Colon cancer is the third leading cause of cancer death in both men and women in the United States. Every year, 160000 cases of colorectal cancer are diagnosed, and 57000 patients die. CUGBP, Elav-like family member 2 (CELF2) is an RNA binding protein that modulates various posttranscriptional events including RNA splicing, shuttling, editing, stability and translation. Previous studies have demonstrated that CELF2 expression is low in colon cancer cells. Furthermore, ectopic overexpression of CELF2 induces cells to undergo death by mitotic catastrophe. Based on the above observations, we hypothesized that CELF2 expression might be reduced during neoplastic transformation of colon cells. METHODS: Forty human colon cancer tissues along with 10 uninvolved normal colon tissues from cancer patients were utilized for immunohistochemical analysis of CELF2 expression. RESULTS: We have observed that CELF2 levels are reduced in colon tumor tissues when compared to the normal intestinal tissues. The data set suggests that RNA binding protein CELF2 could be a potential tumor suppressor protein. CELF2 was predominantly nuclear in normal cells, while the cancer tissues had diffused cytoplasmic staining. CONCLUSION: CELF2 expression is consistently reduced during neoplastic transformation suggesting that it might play a crucial role in tumor initiation and progression. PMID- 23795346 TI - Sumoylation at the host-pathogen interface. AB - Many viral proteins have been shown to be sumoylated with corresponding regulatory effects on their protein function, indicating that this host cell modification process is widely exploited by viral pathogens to control viral activity. In addition to using sumoylation to regulate their own proteins, several viral pathogens have been shown to modulate overall host sumoylation levels. Given the large number of cellular targets for SUMO addition and the breadth of critical cellular processes that are regulated via sumoylation, viral modulation of overall sumoylation presumably alters the cellular environment to ensure that it is favorable for viral reproduction and/or persistence. Like some viruses, certain bacterial plant pathogens also target the sumoylation system, usually decreasing sumoylation to disrupt host anti-pathogen responses. The recent demonstration that Listeria monocytogenes also disrupts host sumoylation, and that this is required for efficient infection, extends the plant pathogen observations to a human pathogen and suggests that pathogen modulation of host sumoylation may be more widespread than previously appreciated. This review will focus on recent aspects of how pathogens modulate the host sumoylation system and how this benefits the pathogen. PMID- 23795349 TI - "I Might Be Ahead to Go to the Nursing Home": The Anticipated Relocation of an Older Rural Woman. PMID- 23795350 TI - [New TNM classification (AJCC 2009) and the pathological significance of sentinel lymph node biopsy in malignant melanoma]. AB - The novel TNM staging system (AJCC, 2009) has some new aspects on pathological microstaging of malignant melanoma. It highlights and reflects the importance of vertical growth phase of these tumors. Furthermore, the morphometrical evaluation of sentinel lymph nodes (SLNs) is more important than ever since, according to the new classification, even the presence of isolated tumor cells means more advanced stage. PMID- 23795351 TI - [Molecular classification and markers of malignant melanoma]. AB - Pathological classification of malignant melanoma did not change in the past decade, it was just completed with UV-induced skin alterations. A new feature, however, is the establishment of molecular classification of melanoma indicating that beside the most frequent genetic alterations (BRAF, NRAS, CKIT mutations) there is a wide variety of rare molecular subclasses. Unfortunately, none of these genetic alterations can be used to discriminate benign lesions from malignant ones. The frequently used "melanoma" markers are mostly melanosomal markers, therefore they are not helpful for this diagnostic purpose either. More recently, novel FISH kits have been developed analyzing characteristic copy number alterations specific for malignant melanoma. Though melanosomal markers are helpful in differencial diagnostics, the presence of normal melanocytes in various tissues (lymph nodes, intestine or brain) requires application of molecular techniques when melanoma metastasis is in question. PMID- 23795352 TI - [Prognostic and predictive markers of malignant melanoma]. AB - Malignant melanoma biologically can be divided into non-metastatic and metastatic forms which cannot be predicted precisely using classical clinicopathological parameters, therefore studies on novel genetic or protein markers are abundant in the literature. These studies did not result in clinically useful markers because mostly ignored the results of studies on the genetic basis of metastatic potential of malignant melanoma. Accordingly, the list of promising novel markers is short (BCL2, CDK2, MART-1, OPN). Similar to other solid malignancies, introduction of targeted therapy into clinical practice of melanoma turned the attention toward the genetic basis of resistance to chemo- and targeted therapies. These novel data could lead to the development of molecular diagnostics which can help in designing more effective therapeutic strategies of malignant melanoma. PMID- 23795353 TI - [Prognostic value of tumor-infiltrating immune cells in melanoma]. AB - Host cells representing an integral component of solid tumors, among them cells contributing to the development of native and adaptive immune responses, can exert both positive and negative effects on the outcome of the disease. Infiltration of T lymphocyte subsets and antigen presenting dendritic cells, crucial in mounting an efficient antitumor immune response, is generally associated with favorable prognosis. On the contrary, accumulation of tumor associated macrophages, mast cells and neutrophils, playing important roles in chronic inflammatory processes promoting tumor progression, predicts unfavorable disease outcome in most cases. In melanoma, studies on the prognostic impact of the lymphoid infiltrate in general, and that of T cells, yielded controversial results. In our studies, density of activated T lymphocytes correlated with patients' survival, and we obtained similar results in the case of B cells and mature dendritic cells. The amount of both B cells and dendritic cells showed correlation with that of activated T lymphocytes, and their combined analysis identified patient subgroups with different prognosis. According to data from the literature, intense infiltration by neutrophil granulocytes could be associated with shorter survival, while no unambiguous conclusions can be drawn from studies on the prognostic value of tumor-associated macrophages and other immune cell types. Our results indicate that a prominent infiltration of dendritic cells, B cells and activated T lymphocytes can be considered as a favorable prognostic factor in malignant melanoma. PMID- 23795354 TI - [Characterization of genetic alterations in primary human melanomas carrying BRAF or NRAS mutation]. AB - Human malignant melanoma is one of the most aggressive forms of skin cancer with an exceptionally bad prognosis. Melanoma often displays constitutively activated MAPK pathway through BRAF or NRAS mutations. It is also known that these mutations are almost never simultaneously present and that they appear at early stages and preserved throughout tumor progression, although it is proved that these alterations alone are insufficient to cause tumor progression. Therefore the first aim of our study was to evaluate those distinct genetic alterations which can properly differentiate the three important molecular subtypes of primary melanomas with a) BRAF, b) NRAS mutation and c) WT (wild type for both loci). High-resolution array comparative genomic hybridization (array CGH) was used to assess genome-wide analysis of DNA copy number alterations. Primary melanomas with BRAF mutation more frequently exhibited losses on 10q23-10q26 and gains on chromosome 7 and 1q23-1q25 compared to melanomas with NRAS mutation. Loss on the 11q23-11q25 sequence was found mainly in conjunction with NRAS mutation. Based on these results, we proved the existence of marked differences in the genetic pattern of the BRAF and NRAS mutated melanoma subgroups, which might suggest that these mutations contribute to the development of malignant melanoma in conjunction with distinct cooperating oncogenic events. In general, it is an interesting phenomenon suggesting that these mutations provide probably the "guiding force" for these tumors and it also suggests that there are alternative genetic pathways to melanoma. These additional oncogenic events which are associated with BRAF or NRAS mutations can provide rational additional targets for a combination therapy with kinase inhibitors. In this study we also investigated the specific dynamic activities among different signalling pathways highlighting the frequent alterations of genes involved in the signalling interactions between the MAPK-JAK pathways in BRAF mutated melanomas. Using a data mining algorithm we also found a gene alteration signature in the MAPK pathway that was commonly related to the presence of BRAF mutation in our melanoma cohorts. The second aim of this study was to develop an accurate Q-PCR method for determining the co-amplification pattern of six candidate genes that reside in the 11q13 amplicon core. We found that co-amplification of these candidate genes or the CCND1 amplification along with either BRAF or NRAS mutations might be more important for prognosis than the presence of these alterations alone. PMID- 23795355 TI - [Unblocking antitumor immune response: novel possibilities for the immunotherapy of melanoma]. AB - Recent advances in tumor immunology, a better understanding of mechanisms regulating the immune response has led to experimental and clinical testing of a novel type of immunotherapeutics: antibodies blocking negative regulatory mechanisms of T-cell activation [corrected]. The application of the CTLA-4 antagonist ipilimumab, the prototype of this new class of immune stimulating agents, represents the first treatment that resulted in significant prolongation of the survival of metastatic melanoma patients in randomized, controlled trial, leading to the approval of its use for the therapy of these patients in 2011. Together with the BRAF inhibitor vemurafenib, which was also approved in 2011, ipilimumab has changed the standard therapy of metastatic melanoma, and also paved the way for other agents aiming at influencing immune regulating molecules, of which antibodies blocking the PD-1 pathway also showed promising clinical activity. According to clinical experience collected so far, these agents induce objective tumor response in a relatively small proportion of patients, with a characteristic response kinetics frequently showing delayed activity, but resulting in durable remission in a considerable proportion of the responding patients. On the other hand, antitumor activity is frequently accompanied by significant toxicity. The spectrum of side effects is different from that of conventional therapies, and a large part of them is caused by the enhanced systemic immune activity. In order to spare non-responding patients of the severe side effects and to increase response rate, the search for biomarkers that could help in identifying patients likely to react to the treatment represents an important focus of studies. Furthermore, development of combinations with other immunotherapeutic modalities, chemo- or targeted therapies may further increase the efficiency of immunomodulatory antibodies. PMID- 23795357 TI - Meniscus tears. Avoiding knee pain. PMID- 23795356 TI - [Vemurafenib (Zelboraf) in the therapy of melanoma]. AB - The incidence of malignant melanoma is continuously rising, but the therapy of advanced melanoma remains insufficient. Advances in the understanding of the immunological and genetical background resulted in the development of a new target therapeutic agent, vemurafenib (Zelboraf) accepted by the FDA in 2011 and by the EMA in 2012. Vemurafenib improved the overall and progression-free survival of untreated melanoma with the mutation BRAF V600E. In a phase III study vemurafenib was associated with a 63% reduction in the risk of deaths compared with dacarbazine and of 74% in the risk of either death or disease progression. Objective response was 48% in the vemurafenib and 5% in the dacarbazine arm. Vemurafenib has special side effects, surprisingly even secondary skin tumors. Additional research is needed to understand the mechanism of drug resistance and to find new targeted therapeutic agents and combinations. PMID- 23795358 TI - Health tips. Vision for the future. PMID- 23795359 TI - High demand likely for prescription weight-control drugs. PMID- 23795360 TI - Cosmetic surgery. Common options for older adults. PMID- 23795361 TI - Denture care. A daily task. PMID- 23795362 TI - Osteoporosis drugs. Current and future options. PMID- 23795363 TI - I saw a celebrity on television running a marathon on a replaced knee joint. Is it OK to do things like that on a replaced knee or hip? PMID- 23795364 TI - I recently purchased a pedometer to see how many steps I take in a day. Where did the idea of walking 10,000 steps a day originate? PMID- 23795365 TI - [Endocrine disruptors--an unseen danger]. PMID- 23795366 TI - [The concept of spondyloarthritis]. PMID- 23795367 TI - [Malignant heart neoplasms]. PMID- 23795368 TI - Acute kidney injury: global health alert. AB - Acute kidney injury (AKI) is increasingly prevalent in developing and developed countries and is associated with severe morbidity and mortality. Most etiologies of AKI can be prevented by interventions at the individual, community, regional and in-hospital levels. Effective measures must include community-wide efforts to increase an awareness of the devastating effects of AKI and provide guidance on preventive strategies, as well as early recognition and management. Efforts should be focused on minimizing causes of AKI, increasing awareness of the importance of serial measurements of serum creatinine in high risk patients, and documenting urine volume in acutely ill people to achieve early diagnosis; there is as yet no definitive role for alternative biomarkers. Protocols need to be developed to systematically manage prerenal conditions and specific infections. More accurate data about the true incidence and clinical impact of AKI will help to raise the importance of the disease in the community, increase awareness of AKI by governments, the public, general and family physicians and other health care professionals to help prevent the disease. Prevention is the key to avoid the heavy burden of mortality and morbidity associated with AKI. PMID- 23795369 TI - Coronary stents attract like magnet inflammatory cells and induce stent thrombosis and Kounis syndrome. PMID- 23795370 TI - Author reply. PMID- 23795371 TI - Dental postcards LII. "It's my gum, chum!". PMID- 23795373 TI - HFMA's code of ethics. PMID- 23795372 TI - Dental trade cards XXXVIII. Victorian trade card bookmarks. PMID- 23795374 TI - Jeff Rich: Reducing costs to patients and the environment. PMID- 23795375 TI - Catch-22: when integrated care meets reduced payment. PMID- 23795376 TI - 5 ways to develop a path to pricing transparency. PMID- 23795377 TI - Buyer's brief: robotic surgery. PMID- 23795378 TI - Whatever it takes. PMID- 23795379 TI - Part A to part B rebilling: understanding the rules in a changing environment. AB - Under a recent CMS ruling, hospitals that have been denied payment for Medicare Part A services have the option to submit follow-up claims to Medicare Part B for some of these denied services. A CMS proposed rule threatens to remove that option by imposing barriers to the rebilling of claims denied under Part Afor payment under Part B. By commenting on the rule, hospitals may be able to persuade CMS to reject the proposed rule and, instead, adopt a policy similar to that in the ruling. Should CMS decide to finalize the rule, hospitals can use their comments in efforts either to convince Congress to enact statutory changes that would mandate expanded Part B rebilling or to challenge the final rule in litigation. PMID- 23795380 TI - Bringing the right players to the table. AB - Finance and clinical leaders should ensure that the appropriate stakeholders are part of planning the "how" of change. Clinicians should be included in strategy and decision making. Inclusion can help leaders make decisions that best serve patients. PMID- 23795381 TI - Boosting the bottom line of physician networks. AB - To improve the bottom line of owned physician practices, hospitals should: Identify disparities between physician pay and performance, and understand the factors that are creating these disparities. Review fees to make sure they are aligned with insurer and Medicare fee schedules. Analyze the work load and job resposibilities of office staff and modify staffng levels and job descriptions, if needed. PMID- 23795382 TI - A statewide partnership for reducing readmissions. AB - Three core programs have heped reduce reedrmissions in Illinois hospitals: Projct BOOST (better Outcomem by Optimizing Safe Transitions), whih focuses on redesigning hospital discharge processes and improving transitions of care. HP3: Hospitalist Program Peak Performance which provides ducational resources, motivation, and a process improvement structure for hospitalist programs. Communications and Palliative Care, which teaches physicians and dclinicians how to work with paients to define their goal of care and identify options to improve their quality of life. PMID- 23795383 TI - Michael McGinnis: on achieving best care at lower cost. PMID- 23795384 TI - Driving out waste: a framework to enhance value in clinical care. AB - Many healthcare providers today are seeking to improve the value of the care they deliver by implementing standardized clinical practice guidelines aimed at reducing variations in care, avoiding complications, and lowering costs. To succeed, such an initiative requires the full support and participation of the clinicians who will use the guidelines. Providers also should have a fully developed infrastructure consisting of a clinical content system, an analytics system, and a deployment system. PMID- 23795385 TI - Value 101: the basics of clinical transformation. AB - Health systems should take strong steps to ensure that their current and aspiring finance leaders are fully prepared to engage with clinicians in meeting the requirements of healthcare reform. In 2012, Bon Secours held a clinical transformation finance intensive to teach finance staff how to accelerate clinical transformation within their markets. The education and skills that Bon Secours' finance professionals gained from the intensive have strengthened the health system's ability to respond to the challenges of reform. PMID- 23795386 TI - Reducing pharmacy costs through improved utilization. AB - Strategies Trinity Regional Health System in Rock Island, III., used to reduce pharmacy expenses included: Leveraging benchmarking information to identify opportunities for cost savings. Implementing change management techniques, bolstered by well-presented and coherent data, to promote acceptance of change. Forming a multidisciplinary team of clinical and financial leaders to address quality, outcomes, and cost issues and collaborate on solutions. PMID- 23795387 TI - 4 strategies for achieving reform-ready IT. AB - Hospital leaders can take four strategic steps to ensure their IT systems are prepared to meet the requirements of healthcare reform: Examine the extent to which current IT system capacity is sufficient to meet future demands. Create a solid foundation for expanding IT capabilities or implementing a new IT system. Share ownership and accountability for IT development and implementation with end users. Reconsider the value of third-party solutions. PMID- 23795388 TI - Closing the ICD-l0 revenue gap. AB - Hospitals can improve clinical documentation under ICD-10 by implementing three strategies: Bring clinical documentation improvement (CDI) specialists and coders together for daily or weekly communications to improve documentation quality, processes, and outcomes. Encourage CDI specialists to engage in direct, one-on one conversations with physicians or generate queries, whether paper or EHR based, to clarify missing or unclear documentation to promote better overall clinical documentation outcomes. Assess ICD-10 hot spots for documentation gaps to mitigate risk of lost revenue under ICD-10. PMID- 23795389 TI - 5 strategies for improving performance of academic medical centers. AB - Academic medical centers should consider five strategies for becoming more cost efficient and profitable as reforms are implemented: Make faculty responsible for cost and quality. Explore opportunities to collaborate with community hospitals. Extend care and education beyond the walls of the organization, employing technology and innovative teaching practices. Maximize healthcare IT investment by sharing data-rich patient records with other medical centers and research institutes. Align research with business strategy. PMID- 23795390 TI - ACOs: a wolf in sheep's clothing? PMID- 23795391 TI - Communicating a value proposition. PMID- 23795392 TI - Hospitals are controlling major costs. PMID- 23795393 TI - Dentistry's role in sleep-disordered breathing. PMID- 23795394 TI - The periodontal probe and the millimeter scale. PMID- 23795396 TI - Dr. Charles Blum's comments on CRANIO's recent inclusion of sleep disorders. PMID- 23795395 TI - Dr. Spahl's open letter to the editor of the American journal of orthodontics and dentofacial orthopedics. PMID- 23795397 TI - The occlusal appliance effect on myofascial pain. AB - There are limited studies about the effects of occlusal appliance (OA) after three months of use. This study aimed to compare myofascial pain (MP) according to RDC/TMD, craniocervical relationships (CR) and masseter and temporalis bilateral electromyographic (EMG) activity, before and after three months of occlusal appliance use. Nineteen patients participated in this study. Cephalometric and RDC/TMD diagnostics were performed previously (baseline) and at the end of the study period (three months). EMG recordings at clinical mandibular rest position (MRP), during swallowing of saliva (SW) and during maximum voluntary clenching (MVC) were performed as follows: after one hour of use of an OA; after three months of using the OA for a minimum of 16 hours each day; and immediately after removal from the mouth. MP was relieved in all patients at the end of the study period. CR did not change significantly between baseline and after removal of the OA at the end of the study period. EMG activity during MRP, SW, and MVC decreased in both muscles after one hour using the OA and maintained the same level for the three-month period. When comparing baseline versus final EMG activity without OA, a significant decrease was only observed in the masseter muscle. The results observed in the present study are relevant to clinicians because they imply that the therapeutic effect of OA does not significantly affect the homeostasis of the craniocervical system. PMID- 23795398 TI - Gender differences in low and high pain palpation thresholds in the TMJ and neck areas. AB - The null hypothesis was that pain pressure thresholds are the same for young healthy males and females and do not differ between the temporomandibular joint (TMJ) and muscle sites. The aim of the current study was to compare pain pressure threshold levels using an algometer with a convex-formed contact piece and pressure increase rates similar to those in conventional finger palpation, making the conditions more like clinical examination of painful spots with commonly used physiotherapeutic methods. Healthy subjects, 12 male, mean age 22.5 +/- 1.62 (SD), and 12 female, 22.4 +/- 2.19 (SD), were enrolled. A transducer with a calibrated load range, 0 to 25 pounds, was used to measure pressure threshold levels for low (T1), VAS to approximately 2, and high (T2), VAS to approximately 8, pain levels bilaterally in the occipital (OC), sternocleidomastoid (SCM), upper trapezius (TU), transverse process of first vertebra (C1), and lateral temporomandibular joint (TMJ) areas. The null hypothesis was rejected. Levels T1 and T2 were significantly lower in the females in all tested areas. The range of the mean for T1 levels was 4.9-8.0 pounds for males and 3.2-5.1 pounds for females. For T2 levels, the range was 8.9-15.6 pounds for males and 6.2-10.3 pounds for females. Significant differences were found between muscle sites. These results support the use of different threshold levels: a) for males and females; and b) for different muscle areas. PMID- 23795399 TI - Effect of stabilization splint on occlusal force distribution during voluntary submaximal tooth clenching: a preliminary sleep simulation study. AB - The purpose of the study was to clarify the effect of a stabilization splint (SS) on the distribution of occlusal force around the dental arch during voluntary submaximal tooth clenching. Ten healthy volunteers participated in this study. For each subject, the maxillary SS was made of heat-cured hard acrylic resin with approximately one mm thickness at the molar regions. The subjects were asked to perform static clenching at either 40% or 80% maximum voluntary contraction (MVC) levels, with and without the SS in place, using visual feedback. The occlusal contact area and occlusal force were analyzed. When the SS was inserted, the mean tooth contact area and occlusal force significantly decreased at both 40% and 80% MVC levels (p < 0.01). The location of the occlusal balancing point changed towards the anterior after insertion of the SS. The results suggest that the SS has potential to reduce individual tooth-loading forces by evenly distributing the forces generated during sleep bruxism. PMID- 23795400 TI - Natural head position and growth of the facial part of the skull. AB - The aim of this study was to determine any correlation between natural head position and cranio-cervical growth direction and if natural head position influences facial growth direction. One hundred sixty (160) cephalometric radiographs were examined and cranio-cervical inclinations determined (angles: NS Ver, NS-OPT, NS-CVT). On the basis of the NS-ML angle, radiographs were divided into two groups: mandibular anteriorotation and posteriorotation. On the basis of the SGo/NMe index, two groups were formed: short-faced and long-faced subjects. The angles NS-Ver, NS-OPT, and NS-CVT describe cranio-cervical inclination. Subjects with anterior mandible growth do position their heads more vertically and have a shorter face, and those with posterior mandible growth tilt their heads more backwards and have a longer face. An adaptive head position can be a factor in altering the direction of facial growth. Determination of head position and mandible growth direction can be an important indicator in patients with TMD treatment. PMID- 23795401 TI - Relationship between chewing rate and masticatory performance. AB - The influence of mandibular movement timing on food breakdown remains unclear. The authors, therefore, sought to relate chewing rate with masticatory performance. Chewing rate, defined as the number of masticatory cycles habitually achieved per minute, was measured in 55 healthy dentulous subjects (age, 22.2 +/- 5.0 years). Subjects were grouped according to obtained values (cycles/minute): slower: < 70; middle: 70-90; and faster: > 90. Masticatory performance was determined through the sieve method, and the estimated comminuted median particle size (X50). Data was analyzed using the one-way ANOVA and chi-square tests (alpha = .05). Subjects with slower chewing rates showed higher (p < .05) masticatory performance (X50 = 3.05 +/- 0.77 mm). X50 was associated with chewing rate when subjects were categorized as better or poorer performers (chi-square = 11.25, p < .005). Thus, chewing rate was related to masticatory performance, with smaller food particles being achieved with a slower chewing rate. PMID- 23795402 TI - Morphological changes in the temporomandibular joint before and after sagittal splitting ramus osteotomy of the mandible for skeletal mandibular protrusion. AB - Changes of temporomandibular joint (TMJ) morphology were analyzed in 21 patients with mandibular protrusion corrected using bilateral sagittal split ramus osteotomy (SSRO) and mini-plate fixation with TMJ cephalometric laminographs. The condylar pass angle, eminence to the FH plane angle, and total height of fossa and lower height of fossa in both left and right sides, significantly decreased after surgery. The width of the condyle, in both left and right sides, significantly increased after treatment. However, in the joint spaces, there were no significant differences before and after treatment. The amount of change in the eminence to the FH plane angle, total height of fossa and lower height of fossa, before and after surgery, showed significant positive correlations with that of SNB, before and after surgery. These results suggest that adaptive bone remodeling of the TMJ might occur due to the correction of occlusion and craniofacial morphology by SSRO in patients with mandibular protrusion. PMID- 23795403 TI - Does low intensity laser therapy reduce pain and change orofacial myofunctional conditions? AB - Due to its multifactorial pain aspects, combined therapies are required for the the comprehensive management of temporomandibular joint disorders (TMD). Interdisciplinary forms of therapies, such as laser therapy, and health care or medical professionals, such as speech therapists, have been proposed for this comprehensive management. The aims of this study were the following: 1. verify whether low-intensity laser therapy would promote significant pain remission; 2. evaluate whether this changes orofacial myofunctional conditions in the sample, as tested, using the Orofacial Myofunctional Evaluation with Scores (OMES); and 3. evaluate whether or not the pain improvement would remain stable after a 30 day follow-up for pain conditions. The study included 12 female volunteers diagnosed with myofascial pain and ages ranging from 18 to 60 years old, with or without intra-articular TMD, according to axis I of the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). Participants were assessed for pain on palpation, using a visual analogue scale (VAS), before treatment (A1), immediately after 30 days of intervention, i.e, after eight sessions of Low Intensity Laser Therapy (LILT) (A2), and 30 days after the end of the treatment with LILT (A3) (follow-up). Comparing the three evaluation times, it was observed that there was a significant decrease in the values of subjective pain to palpation (p < 0.05). The initial pain (A1) differed significantly from the A2, but did not differ significantly from A3. PMID- 23795404 TI - A longitudinal study of the effect of experimental osteoporosis on bone trabecular structure in the rat mandibular condyle. AB - The authors performed a longitudinal study of the microstructural changes occurring in the mandibular condyle during osteoporosis using the findings obtained from micro-CT. The subjects used in this study were eight Sprague-Dawley rats. Among them, five were administered the immunosuppressant drug FK506 by injection for five weeks, while the other three were administered saline solution in the same manner. Micro-CT images were taken of the bilateral mandibular condyle, hip, and knee joints in all animals on days 1, 8, 15, 22, 29, and 36 following injection. Six indices of morphometric analysis were compared between the two groups. Significant differences were observed in BV/TV, Tb.Th, Tb.N, and Tb.Sp in the mandibular condyle, while trabecular bone density appeared to decrease in the immunosuppressant group on three-dimensional (3D) imaging. And, in comparison with the mandibular condyle and femur, they were similar. These results suggested that osteoporosis affects not only the femur, but also the mandibular condyle. PMID- 23795405 TI - Patient planning. PMID- 23795406 TI - Peace of mind. PMID- 23795407 TI - Star power. PMID- 23795408 TI - Defusing nerve damage. PMID- 23795409 TI - Oncology as a practice focus for NPs & PAs. PMID- 23795410 TI - Are you an advocate for your profession? PMID- 23795411 TI - Health policy: what's your role? PMID- 23795412 TI - Preventing colorectal cancer. PMID- 23795413 TI - Oral lichen planus. PMID- 23795414 TI - Chemotherapy-Induced mucositis. PMID- 23795415 TI - Resistant hypertension. PMID- 23795416 TI - Empowering physicians. PMID- 23795417 TI - Protecting patients. PMID- 23795419 TI - Financial overview. PMID- 23795418 TI - Recognizing excellence. PMID- 23795420 TI - Notable issues of the 2013 General Assembly. PMID- 23795422 TI - Judging from patients' and relatives' testimonials, healthcare professionals are excellent technical carers. PMID- 23795423 TI - Balanced scorecard: application in the General Panarcadian Hospital of Tripolis, Greece. AB - PURPOSE: The purpose of this paper is to discuss the application of the balanced scorecard (BSC) in the Greek public health sector. DESIGN/METHODOLOGY/APPROACH: The basic balanced scorecard theory has been adopted in the characteristics and individualities of the Greek public health system. The theoretical model developed was applied in the General Panarcadian Hospital of Tripolis (GPHT) in Greece. GPHT is a representative paradigm of a big regional Greek public hospital. It has about 300 beds and many clinics and specialties (internal medicine, cardiology, general surgery, intensive care unit, artificial kidney unit, etc.). Strategic management was performed for almost three years. The BSC model was formulated in an appropriate software program. The problems (both technical and managerial) faced during a three-year period along with the results of this management approach are presented in the current paper. The paper highlights some important gaps in the Greek public health system, while proposing actions to be taken. FINDINGS: The BSC theory can be very successful under certain conditions. ORIGINALITY/VALUE: Special attention is given to the peculiarities of the Greek public health situation. The paper presents for the first time a real life example of applying BSC in the Greek public health sector. PMID- 23795424 TI - Dimensions of hospital service quality: a critical review: perspective of patients from global studies. AB - PURPOSE: The purpose of this paper is to review the service quality dimensions established in various studies conducted across the world specifically applied to health care. DESIGN/METHODOLOGY/APPROACH: Studies conducted on quality of care selected from literature databases - Ebsco, Emerald Insight, ABI/Inform - was subjected to a comprehensive in-depth content analysis. FINDINGS: Service quality has been extensively studied with considerable efforts taken to develop survey instruments for measuring purposes. The number of dimensional structure varies across the studies. Self-administered questionnaire dominates in terms of mode of administration adopted in the studies, with respondents ranging from 18 to 85 years. Target sample size ranged from 84-2,000 respondents in self-administered questionnaires and for mail administration ranged from 300-2,600 respondents. Studies vary in terms of the scores used ranging from four to ten-point scale. A total of 27 of the studies have used EFA, 11 studies have used structural equation modelling and eight studies used gap scores. Cronbach's alpha is the most commonly used measure of scale reliability. There is variation in terms of measuring the content, criteria and construct validation among the studies. PRACTICAL IMPLICATIONS: The literature offers dimensions used in assessing patient perceived service quality. The review reveals diversity and a plethora of dimensions and methodology to develop the construct discussed. ORIGINALITY/VALUE: The reported study describes and contrasts a large number of service-quality measurement constructs and highlights the usage of dimensions. The findings are valuable to academics in terms of dimensions and methodology used, approach for analysis; whereas findings are of value to practitioners in terms of the dimensions found in the research and to identify the gap in their setting. PMID- 23795425 TI - Patients' preference on selecting a medical institution. AB - PURPOSE: The purpose of this paper is to evaluate the relative importance of attributes for patient selection of a medical institution and to quantitatively evaluate the impact of different types of organizational forms upon the patient's selection of a medical institution. DESIGN/METHODOLOGY/APPROACH: By using a conjoint analysis, evaluation criteria in patient selection of a medical institution were examined. The paper assumed the selection of a medical institution under the situation of "being given a diagnosis of suspected diabetes with a physical examination and then visiting a medical institution". The attributes included in the questionnaire were: quality of the medical institution, distance to the hospital, amount paid at the initial visit, amount paid at hospitalization for examinations, and organizational form of the hospital. Relative importance of the attributes and relative importance of organizational form were assessed. A total of 140 people were requested to respond to the questionnaire by way of researchers who have a connection with the authors. Completed responses were obtained from 111 subjects (79 per cent). FINDINGS: The results of the conjoint analysis revealed that the most important attribute was quality of the medical institution. Organizational form was the attribute with the lowest importance. The utility value of being a public hospital was the highest within the organizational form attribute for all respondents and being a private hospital was the lowest. The quality of the medical institution was considered the most important factor in selecting a medical institution and the type of organizational form was considered least important. Regarding organizational form, being a public hospital was most preferred and being a hospital managed by a company and a private hospital were least preferred respectively among healthcare professionals and other occupations. ORIGINALITY/VALUE: The paper provides a relative evaluation of the factors thought to be important for patients in Japan when selecting a medical institution. PMID- 23795426 TI - The distress thermometer: a rapid and effective tool for the oncology social worker. AB - PURPOSE: The psycho-oncology and social work services recognised that a cancer diagnosis and treatment can result in considerable emotional consequences for patients, yet the referral rate to both services was extremely low. Only very visibly distressed patients were being referred to the service. The "Distress Thermometer" (DT), a distress screening tool, was introduced as a pilot project with day care and inpatient oncology patients of St Vincent's University Hospital, Dublin, in an effort to improve the identification, management and treatment of psychological distress in oncology patients. The purpose of this paper is to evaluate the effectiveness of this new intervention. DESIGN/METHODOLOGY/APPROACH: The Psycho-oncology service in conjunction with the Medical Social Work Department and Nursing Management at St Vincent's University Hospital, Dublin, initiated a Distress Education Management and Training Programme (DEMP). The initiative involved providing a training programme for oncology nursing staff and the introduction of a distress-screening tool for patients. In 1998, the DT was developed and validated for evaluation of distress (and depression) in cancer. It was adopted into recommendations made by the US National Comprehensive Cancer Network. The DT is a simple, self-report, pencil and paper measure consisting of a line with a 0-10 scale anchored at the zero point with "No distress" and at scale point ten with "Extreme distress". Patients are given the instruction, "How distressed have you been during the past week on a scale of 0-10"? Patients indicated their level of distress with a mark on the scale. Patients scoring 4 or above were regarded as requiring intervention. The DT includes a problem checklist. The patient is asked to identify those problems from the checklist which are contributing to their score. The use of the DT was evaluated through interviews with patients and professionals. FINDINGS: Patients who scored four or above (38 per cent of patients), were seen by the Oncology Social Worker for psychosocial assessment and mental health triage. Patients who scored above a certain level (usually above 12/20) in the clinical range on the Hospital Anxiety and Depression scale (3 per cent) were referred to Psycho oncology. That 38 per cent of oncology patients required intervention from a specialist service accurately reflects international findings on the rate of distress among cancer patients. PRACTICAL IMPLICATIONS: Assessment of cancer patients' distress levels in a structured and planned manner with a Distress Thermometer, as recommended by best international practice, works very effectively and should be considered for all cancer out-patients This will have implications in terms of staff that will be required to manage such a service. ORIGINALITY/VALUE: This was the first time that this internationally recognised tool was used to such an extent and to positive effect in an Irish context. PMID- 23795427 TI - Factors influencing evidence-based practice by Iranian general practitioners. AB - PURPOSE: This study aims to fill the knowledge gap regarding general practitioners' (GPs) research utilization (RU) behavior in Iran. It also aims to find possible barriers to research use among GPs to inform organizational change processes. DESIGN/METHODOLOGY/APPROACH: The authors modified the research utilization questionnaire developed by Estabrooks et al, to address physicians' views. The questionnaire was piloted and its validity and reliability was assessed before being sent to GPs. A 77 percent response rate was eventually achieved. FINDINGS: Respondents were generally positive concerning research evidence use. Respondents' mean attitude score was 25.3 (SD = 5.6, min. 13, max. 37). However, less than 25 percent of the GPs practiced any form of RU in the last year. Absent facilities and resources, little authority to change practices, expected increases in patient visit durations and the poor access to research information were found to be the main RU barriers for GPs. PRACTICAL IMPLICATIONS: The borderline 77 percent response rate was reached despite sending questionnaires to non-responders two times. Considering the non-probability sampling used in this study, generalizing the results should be considered cautiously. ORIGINALITY/VALUE: Research utilization programs are new in Iran and there is little evidence to inform policies. This study focused attitudes concerning RU and GPs' knowledge concerning novel research and skills, and to some extent, GPs' behaviors toward RU. PMID- 23795428 TI - Managing healthcare waste in Ghana: a comparative study of public and private hospitals. AB - PURPOSE: The paper aims to examine the healthcare waste management practices of selected hospitals in Ghana. DESIGN/METHODOLOGY/APPROACH: The study adopted a multiple case approach, using two public and two private hospitals. FINDINGS: Findings indicate that both public hospitals and one private hospital have a waste management policy. Public and private hospitals have waste management plans and waste management teams. Public hospitals were found to generate more waste than the private hospitals. One private hospital and the public hospitals segregate their waste into different categories. This is done by first identifying the waste type and then separating non-infectious or general waste from infectious waste. Both public and private hospitals have internal storage facilities for temporarily storing the waste before they are finally disposed off site. On-site transportation in the public hospitals is done by using wheelbarrows, while covered bins with wheels are used to transport waste on-site in the private hospitals. In public and private hospitals, off-site transportation of the hospital waste is undertaken by Municipal Assemblies with the use of trucks. Both public and private hospitals employ standard methods for disposing of healthcare waste. ORIGINALITY/VALUE: The article provides insights into healthcare waste management from a Ghanaian perspective. PMID- 23795429 TI - Payment by results: are we missing something? AB - PURPOSE: Payment by results (PbR) was introduced to reward hospitals for productivity. In orthopaedic clinics there is a separate tariff for two procedures: removal of sutures (ROS) and attention to dressing (AD). The Trust claims a fee each time these have been performed. The purpose of this paper is to look at how many of these procedures were performed in an outpatient setting but were not claimed for because of poor documentation. DESIGN/METHODOLOGY/APPROACH: A retrospective study was performed analysing all orthopaedics clinics occurring in one month. After each consultation the clinician completes a coding pro forma and dictates a clinic letter. The pro forma contains a list of the orthopaedic procedures attracting a tariff and used for coding. A comparison was made between what was documented on the pro forma and the clinic letter to see how many times ROS and AD were done. FINDINGS: A total of 72 letters were extracted which contained ROS and AD. Only one of the ROS was documented on the pro forma and subsequently captured by the coders. In one month the Trust failed to claim 9,838 pounds. Annually this equates to a revenue loss totaling 118,056 pounds. Practical implications - Current coding practice is substandard. To maintain financial security Trusts must improve their coding policies as a matter of urgency. ORIGINALITY/VALUE: The paper demonstrates clearly that hospital trusts are losing out financially from this suboptimal practice. PMID- 23795430 TI - [Discussion of complication of spinal operation]. PMID- 23795431 TI - [Curative effect evaluation and complication analysis of Bryan artificial cervical disc replacement]. AB - OBJECTIVE: To observe the curative effects and complications of Bryan cervical disc replacement for cervical disc herniation. METHODS: From Jannary 2005 to December 2008,39 patients with cervical disc herniation were treated with Bryan cervical disc replacement. There were 20 males and 19 females,with an average age of 47 years old (ranged, 35 to 59). Spinal compression symptom (20 cases) and nerve root symptom (19 cases) were main clinical symptoms. Single level disc was replaced in 35 cases and two-level replaced in 4 cases. Offset and activity of prosthesis,cervical physiological curvature, heterotopic ossification, prosthetic fusion were observed by dynamic X-ray. According to Odom's standard and JOA score,nerve function were evaluated; and depending on NDI standard,clinical symptom and daily function status were recorded. RESULTS: All the patients were followed up from 16 to 36 months with an average of 24 months. Nerve function obviously improved and radiating pain of upper limb completely relieved. No patient with prosthetic anterior-posterior offset more than 2 mm was found. Prosthetic flexion and extention angle was (8.5+-1.8)degrees,left and right flexion range respectively were (3.5+/-1.2)degrees and (3.3+/-1.5)degrees. Cervical physiological curvature improved obviously or recovered normally. Three cases occurred in heterotopic ossification and 2 cases occurred in prosthetic fusion. According to Odom's standard,25 cases got an excellent results,9 good, 5 fair, the rate of excellent and good was 87.2%. JOA score increased from preoperative (8.26+/-1.32) to (15.71+/-1.89) at final follow-up and NDI decreased from preoperative (43.7+/-3.8) to (20.1+/-2.9) at final follow-up. CONCLUSION: Treatment of cervical disc herniation with Bryan cervical disc replacement can get the good curative effects,which can obtain good nerve functional recovery,cervical stability and activity. Nevertheless,the operation has typical complication such as heterotopic ossification and prosthetic fusion. Thus,it is important in chosing indication and operative procedure. PMID- 23795432 TI - [Analysis of reason and strategy for the failure of posterior pedicle screw short segment internal fixation on thoracolumbar fractures]. AB - OBJECTIVE: To analyze the reason and strategy for failure of posterior pedicle screw short-segment internal fixation on thoracolumbar fractures. METHODS: From March 2008 to December 2010,the clinical data of 18 patients with thoracolumbar fracture failed in posterior pedicle screw short-segment internal fixation were retrospectively analyzed. There were 11 males and 7 females with an average age of 37.2 years (ranged, 19 to 63). The time from the first operation to complication occurrence was from 6 to 44 months with an average of 14.3 months. Of them,fusion failure was in 7 cases (combined with screw breakage in 4 cases), the progressive neuro-dysfunction was in 5 cases,the progressive lumbodorsal pain was in 6 cases. All 18 patients with kyphosis were treated with anterior internal fixation remaining posterior fixation (9 cases) and anterior internal fixation after posterior fixation removal (9 cases). RESULTS: All the patients were followed up from 18 to 50 months with an average of 30.5 months. No intetnal fixation loosening and breakage were found, moreover, X-ray and lamellar CT showed bone healing well. Preoperative, postoperative at 3 months and at final follow-up, ODI score was respectively 31.6+/-5.1, 8.6+/-5.7, 8.3+/-3.2; VAS score was respectively 7.2+/-2.3, 2.3+/-0.7, 2.1+/-1.1; kyphosis angle was respectively (-21.2/-+7.8 degreeso, (-5.3+/-6.8 degrees ), (-5.8+/-7.8 )degrees. Compared with preoperative data ,above-listed items had obviously ameliorated(P<0.05). CONCLUSION: Treatment of thoracolumbar fracture with posterior pedicle screw short-segment internal fixation may result in the complications such as bone nonunion ,internal fixation breakage and progressive kyphosis. Anterior reconstruction may be a good strategy for the failure of posterior operation. PMID- 23795433 TI - [Analysis of correlative factors of non-surgical vertebral fractures after percutaneous vertebroplasty for osteoporotic vertebral compression fractures]. AB - OBJECTIVE: To investigate the correlative factors of non-surgical vertebral fractures after percutaneous vertebroplasty (PVP) for osteoporotic vertebral compression fractures(OVCFs). METHODS: From August 2009 to September 2011, 126 patients who underwent single-level PVP for OVCFs were included in this study. They were followed up with an average time of 13.6 months,divided into the refracture group and non-refracture group according to the onset of non-surgical vertebral fractures or not. In refracture group,there were 14 males and 18 females with an average age of (67.63+/-7.28) years(ranged, 54 to 82); and in non refracture group,there were 40 males and 54 females with an average age of (66.26+/-6.79) years (ranged, 55 to 76). The refracture group wps divided again into adjacent vertebral fracture (AVF) group (7 males and 13 females) and remote vertebral fracture(RVF) group (4 males and 8 females). The age, sex, bone mineral density(BMD), injecting bone cement volume, the recovery rate of vertebral body height,kyphosis corrected degree were recorded and the correlative factors of non surgical vertebral fractures were analyzed. RESULTS: There was no statistically significant differences in age, sex, BMD, injecting bone cement volume and kyphosis corrected degree between refracture group and non-refracture group (P>0.05), and there was statistically significant difference in the recovery rate of vertebral body height (P<0.05). There was no statistically significant difference in BMD, kyphosis corrected degree between adjacent vertebral fracture group and non-refracture group (P>0.05); and there was statistically significant difference in injecting bone cement volume,recovery rate of vertebral body height(P<0.05). There was no statistically significant difference in BMD,injecting bone cement volume,recovery rate of vertebral body height, kyphosis corrected degree between remote vertebral fracture group and non-refracture group (P>0.05). CONCLUSION: Recovery of vertebral body height may prefigure increasing risk of refracture in non-surgical vertebral body for the patient with OVCFs after PVP, and the adjacent vertebral fracture maybe concerned with injecting bone cement volume and recovery rate of vertebral body height. PMID- 23795434 TI - [Factor analysis of muscular paralysis due to nerve root injury after posterior lumbar interbody fusion (PLIF)]. AB - OBJECTIVE: To analyze the reasons of muscular paralysis due to nerve root injury after PLIF. METHODS: From January 2001 to January 2012, 1 250 cases underwent PLIF in our hospital, after operation, 29 cases occurred muscular paralysis due to nerve root injury. There were 10 males and 19 females with an average age of 61 years, 12 cases with one-segment, 14 cases with two-segment, 3 cases with three-segment. The clinical data of 29 patients were retrospectively analyzed including PODx (preoperative diagnosis), surgery procedure, postoperative symptoms and so on. RESULTS: The follow-up time was more than 1 year and the longest was 2.5 years with an average of 1 year and 7 months. Twenty-three patients obtained satisfactory results and muscle strength recovered to 4-5 levels,3 patients was poor and final muscle strength recovered to 0-2 levels. Recovering time after operation was directly proportional to the degree of injury,those muscle strength level was more than 2, usually could have significant improvement within 2 weeks. CONCLUSION: More complicated factors result in the reasons of nerve root injury after PLIF. Except those suffered severe grinding contusion and amputation, most of the patients can get satisfactory effect. PMID- 23795435 TI - [Analysis of epidural hematoma formative reason and its preventive measure after anterior cervical operation]. AB - OBJECTIVE: To explore the risk factors,preventive measure of epidural hematoma after anterior cervical operation. METHODS: From June 2005 and December 2012, 1,452 patients underwent anterior cervical operation in our hospital. Epidural hematoma occurred in 5 cases after operation and the incidence rate was 0.34%. There were 4 males and 1 female with an average age of 46.4 years (ranged, 33 to 55); 3 cases with cervical myelopathy, 1 case with cervical myelopathy and C5 vertebral angeioma, 1 case with ossification of cervical posterior longitudinal ligament. The occurred time,main clinical situation,duration of symptoms,operative management of epidural hematoma were analyzed. RESULTS: Five patients with epidural hematoma occurred within 24 h; the average interval between onset of symptoms and surgery was 4 h (ranged, 2 to 7). Operative treatment was accomplished in 5 cases by exploration and hematoma evacuation. There was significant improvement in all patients after reoperation. Epidural hematoma occurred again in one patient at 5 h after hematoma evacuation, and reoperation were performed to treat it. All patients were followed up from 6 to18 months with an average of 13.8 months. No recurrence was found. CONCLUSION: Intensive care in 24 h postoperatively is important because of epidural hematoma often occurs in this period,especialy in the period of 6-8 h postoperativey. Clinical findings and MRI can early diagnose epidural hematoma and help treatment. Once it is identified and surgical evacuation would be performed on time. PMID- 23795436 TI - [Analysis of postoperative complication and its preventive measure of cervical open-door expansive laminoplasty with lateral mass screw fixation]. AB - OBJECTIVE: To explore the postoperative complication and its preventive measure of cervical open-door expansive laminoplasty with lateral mass screw fixation in treating cervical canal stenosis. METHODS: From February 2008 to July 2011, 33 patients with cervical canal stenosis underwent cervical open-door expansive laminoplasty with lateral mass screw fixation. JOA score was used to evaluate clinical effects before and after operation. Of them, complications occurred in 6 cases, male in 2 cases and female in 4 cases. The reason of complications were analyzed. RESULTS: All the patients were followed up from 6 months to 2 years with an average of 10.3 months. The improvement rate of JOA was 78.8% and incidence rate of complication was 18.2% (6 cases). There were 2 cases of axiality symptoms, 1 case of lateral mass screw pulled-out, 2 cases of cerebrospinal fluid leakage with wound dehiscence, 1 case of nerve root parlysis. These complications correlated with operative design, manipulation,improved degree of cervical curvature,postoperative management and cooperation of patient. CONCLUSION: As an effective treatment, cervical open-door expansive laminoplasty with lateral mass screw fixation has lower incidence of axiality pain. Preoperative examination ,postoperative management ,meticulous surgical skill are very important to avoid complications. PMID- 23795437 TI - [Analysis of perioperative complications of percutaneous kyphoplasty for osteoporotic vertebral compression fracture]. AB - OBJECTIVE: To analyze the perioperative complications of percutaneous kyphoplasty (PKP) for osteoporotic vertebral compression fracture. METHODS: From June 2009 to December 2011, 63 patients with osteoporotic vertebral compression fracture underwent PKP, there were 18 males and 45 females with an average age of 75.3 years ( ranged, 62 to 91). All patients with severe back pain and without neurological symptoms and signs, which were confirmed by X-ray and MRI. Among them,there were 63 cases with severe osteoporosis, 37 cases with hypertension, 10 with coronary artery disease, 29 with anemia, 26 with diabetes, 11 with chronic obstructive pulmonary diseases and 8 with gastritis and peptic ulcer. The common perioperative complications were retropectively reviewed. RESULTS: Preoperative complications occured in 9 cases (14.3%), including hypostatic pneumonia (1 case), electrolyte disturbances (2 cases), urinary tract infection (2 cases), moderate anemia(2 cases),electrolyte disturbances combined with moderate anemia (1 case), hypostatic pneumonia combined with delirium (1 case). Intraoperative and postoperative. complications occurred in 17 cases (26.9%), there were bone cement correlated complications in 9 cases (14.3%), in which 2 cases of toxic reaction of bone cement and 7 cases of leakage (2 cases had clinical symptoms); there were non-bone cement correlated complications in 3 cases (4.8%), in which 1 case of focal hematoma caused by paracentesis, 1 case of transient nerve injury, 1 case of left intercostal neuralgia;there were transient hyperpathia in 5 cases after operation. All complications result in no severe consequence after treatment. CONCLUSION: Perioperative complications of percutaneous kyphoplasty are not uncommon,however,these complications may not cause serious consequence after active treatment,so prevention and treatment are important for it. PMID- 23795438 TI - [Analysis of clinical characteristics of elderly patients with spinal tuberculosis and its clinical effects with conservative treatment]. AB - OBJECTIVE: To analyze the clinical characteristics of elderly patients with spinal tuberculosis and explore its clinical effects with anti-TB drugs alone. METHODS: From January 2008 to July 2010, the data of 36 patients with spinal tuberculosis underwent conservative treatment of anti-TB drugs alone were analyzed. There were 19 males and 17 females with an average age of 73.5 years (ranged, 60 to 85). All patients were in the active phase with high ESR and CRP levels and were treated with 3HRZE/6-9HRE (course from 9 to 12 months). According to clinical symptoms, chemical examination, radiological image to adjust drug and depending on VAS score to evaluate pain. RESULTS: All the patients were followed up from 8 to 24 months with an average of 15 months. Tuberculose of 31 patients healed after chemotherapy from 9 to 12 months and ESR and CRP recovered normally. Levofloxacin and para-amino salicylic acid were used in 4 cases because of 4 cases occurred drug fast for RFP or INH, after 15 months, their obtained healing. Symptom of 1 case got worse during chemotherapy, and surgical treatment were performed, after 3 months, ESR and CRP recovered normally, X-ray and CT showed spinal osteosclerosis and fusion without significant kyphosis and internal fixation loosening. Cobb angle was respectively(17.6+/-2.3) degrees, (18.1+/-2.7) degrees before treatment and last follow-up (P>0.05). MRI showed abscess was absorbed and spinal inflammation subsidised. VAS score was respectively 6.5+/ 1.7, 1.4+/-0.5 before treatment and last follow-up (P<0.05). Seven patients had complications relating with drug adverse reaction,after discontinuation and treated with clinical symptom,the patients recovered normally. CONCLUSION: Anti TB drugs alone can obtain satisfactory effects in treating early senile spinal tuberculosis, but strict supervision and individual administration should not be disregardful. PMID- 23795439 TI - [Case-control study on needle-knife to cut off the medial branch of the lumbar posterior ramus under C-arm guiding for the treatment of low back pain caused by lumbar facet osteoarthritis]. AB - OBJECTIVE: To study the clinical efficacy of needle-knife to cut off the medial branch of the lumbar posterior ramus under C-arm guiding to treat low back pain caused by lumbar facet osteoarthritis. METHODS: From July 2009 to June 2011, 60 patients with low back pain caused by lumbar facet osteoarthritis were reviewed,including 34 males and 26 females, ranging in age from 39 to 73 years old,averaged 61.9 years old; the duration of the disease ranged from 6 to 120 months, with a mean of 18.9 months. All the patients were divided into two groups, 30 patients (18 males and 12 females, ranging in age from 39 to 71 years old, needle-knife group) were treated with needle-knife to cut off medial branch of the lumbar posterior ramus under C -arm guiding and the other 30 patients(16 males and 14 females, ranging in age from 41 to 73 years old, hormone injection group) were treated with hormone injection in lumbar facet joint under C-arm guiding. The preoperative JOA scores and the scores at the 1st, 12th and 26th weeks after treatment were analyzed. RESULTS: Before treatment,the JOA scores between the two groups had no significant difference (P= 0.479); after 1 week of treatment, the JOA scores between the two groups had significant difference (P= 0.040), the improvement rate of hormone injection group was superior than that of the needle-knife group,which were (58.73+/-18.20)% in needle-knife group and (71.10+/-22.19)% in hormone injection group; after 12 weeks of treatment, the JOA scores between the two groups had no significant difference(P=0.569), and the improvement rate between the two groups had no significant difference,which were (50.09+/-19.33)% in the needle-knife group and (48.70+/-18.36)%) in the hormone injection group; after 26 weeks of treatment,the JOA scores between the two groups had significant difference (P=0.000), the improvement rate of hormone injection group was superior than that of the needle-knife group,which were (48.56+/-28.24)% in needle-knife group and (15.62+/-11.23 )% in hormone injection group. CONCLUSION: Using needle-knife to cut off the medial branch of the lumbar posterior ramus could get longer efficacy than hormone injection in the treatment of lumbar facet osteoarthritis. PMID- 23795440 TI - [Analysis of intraoperative complications of microendoscopic disectomy and corresponding preventive measures]. AB - OBJECTIVE: To analyze the reasons of intraoperative complications of microendoscopic disectomy (MED) and corresponding preventive measures. METHODS: From October 2001 to January 2012, the data of 851 patients with lumbar disc herniation underwent MED were retrospectively analyzed. There were 469 males and 382 females with an average age of 42.5 years ranging 16 to 75. Course of disease was from 1 to 18 months with an average of 3 months. The segments of herniated disc including L3,4 of 24 cases, L4,5 of 418 cases and L5S1 of 409 cases . Main symptoms included low back pain with lower extremity radial pain and numbness. Of them,unilateral lower extremity symptom was in 729 cases and bilateral symptom was in 122 cases. There were at least 2 abnormal signs in the four signs which including feeling anormaly, muscle strength anormaly,dysreflexia and muscle atrophy. Distraction test of nerve was positive. CT or MRI findings must coincide with the clinical symptoms and signs. No lumbar instability,spinal stenosis,the upper lumbar disc herniation or combined with cauda equina nerve syndrome were found in 851 patients. The intraoperative complications were recorded and analyzed for the reasons of the intraoperative complication and related prevention measures. RESULTS: According to the Macnab standard,424 cases obstained excellent results, 321 good,106 fair,with excellent and good rate of 87.5%. The result was similar to the traditional open operation. One cases transferred to open operation due to equipment breakdown, case died for myocardial infarction at 11 days after the operation, 2 cases occurred acute epidural hematoma in 1 hour after operation. Injury of dura mate of spinal cord occurred in 28 cases and incidence rate was 3.29%(28/851); traction injury of nerve root occurred in 38 cases and incidence rate was 4.46% (38/851). One case occurred in retroperitoneal hematoma, 2 cases in incomplete cauda equina injury and 2 cases in incomplete nerve root breakage. CONCLUSION: Skilled endoscopic hemostasis techniques,careful and meticulous operation is very important for the prevention of intraoperative complications. Moreover,timely finding and treating the complications was effective measures to prevent the coniplications. PMID- 23795441 TI - [Prepatellar synovial hemangioma: a case report]. PMID- 23795442 TI - [Experimental study on vascular bundle implantation combined with cellular transplantation in treating rabbit femoral head necrosis]. AB - OBJECTIVE: To discuss the feasibility of vascular bundle implantation combined with allogeneic bone marrow stromal cells (BMSCs) transplantation in treating rabbit femoral head osteonecrosis and bone defect, in order to explore a new method for the treatment of femoral head necrosis. METHODS: Thirty-six New Zealand rabbits were randomly divided into three groups,with 12 rabbits in each group. Bilateral femoral heads of the rabbits were studied in the experiment. The models were made by liquid nitrogen frozen, and the femoral heads were drilled to cause bone defect. Group A was the control group,group B was stem cells transplantaion group of allograft marrow stromal,and group C was stem cells transplantation group of allograft marrow stromal combined with vascular bundle implantation. Three rabbits of each group were sacrificed respectively at 2, 4, 8, 12 weeks after operation. All specimens of the femoral heads were sliced for HE staining. Furthermore ,vascular density and the percentage of new bone trabecula of femoral head coronary section in defect area were measured and analyzed statistically. RESULTS: In group C,new bone trabecula and original micrangium formed at the 2nd week after operation; new bone trabecula was lamellar and interlaced with abundant micrangium at the 8th week;at the 12th week,the broadened,coarsened bone trabecula lined up regularly,and the mature bone trabecula and new marrow were visible. At the 2nd week after operation,there was no statistical significance in the percentage of new bone trabecula of femoral head coronary section in defect area between group B and C. While at 4, 8, 12 week after operation, vascular density and the percentage of new bone trabecula of femoral head coronary section in defect area of group C was higher than that of group B. CONCLUSION: Allogeneic bone marrow stromal cells cultured in vivo can form new bone trabecula, and can be applied to allotransplant. Vascular bundle implanted into the bone defect area of femoral head necrosis could improve blood supply, and promote the formation of bone trabecula. PMID- 23795443 TI - [Experimental study on the isolated culture of osteocytes and identification of osteoblasts in rats]. AB - OBJECTIVE: To establish a more stable method to isolate osteocytes in vitro, and then to find the differences with osteoblast biological characteristics. METHODS: Osteocytes and osteoblasts were isolated from the bone tissue of 3-day-old rats using sequential collagenase digestion. The cells were identified through cell morphology after 24 hours later. Alkaline phosphatase (ALP) kit was used to stain the first generation cells by Kaplow-way, the bone gla protein (BGP) of the cells were stained by immunocytochemitry. Measured ALP and computed its activity. RESULTS: Osteocytes and osteoblasts showed obviously differences in cell morphology. Osteocytes were star-shaped or dendrite-shaped within more dendrites, while osteoblasts were spindle-shaped with short dendrites. Osteocytes were negative for ALP, but osteoblasts were positive; Osteocytes were more positive for BGP, and osteoblasts were less positive. The secretion of ALP in osteocytes was lower than that of osteoblasts. CONCLUSION: Osteocytes can be isolated and cultured in vitro. These characteristics of osteocytes are apparently difference with those of osteoblasts. PMID- 23795444 TI - [Effects of geniposide on SNP-induced apoptosis of chondrocyte and cell cycle]. AB - OBJECTIVE: To study the effects of Geniposide on SNP(sodium nitroprusside) induced apoptosis of chondrocyte in vitro and cell cycle. METHODS: The chondrocyte of three-week-old SD rats were separated and cultivated. The second generation of chondrocyte cells were involved in experiment. Chondrocyte proliferation was measured by assay; flow cytometer were adopted to observe cell cycle and apoptosis rate; NO examination adopted nitrate reductase method. RESULTS: Geniposide could significantly decrease the percentage of SNP-induced chondrocytes in G0/G1 phase and increased percentage in S phase and G2/M phase. The apoptosis of chondrocyte and the concentration of NO in the culture supernatants was reduced significantly (r=0.917, P<0.01). CONCLUSION: Geniposide could impact SNP-induced apoptosis of chondrocyte by reducing the concentration of NO in the culture supernatants, promoting proliferation of chondrocytes, which is a probable and important mechanism of Geniposide preventing osteoarthritis. PMID- 23795445 TI - [Treatment of type C pelvic fracture with Stoppa approach and posterior percutaneous plate fixation]. AB - OBJECTIVE: To explore the clinical effects of Stoppa approach and posterior percutaneous plate in treating type C pelvic fracture. METHODS: From June 2009 to July 2011,16 patients with type C pelvic fracture were treated with reconstruction plate fixation in Stoppa approach for anterior lesions combined with posterior percutaneous plate fixation for posterior lesions.There were 11 males and 5 females,with an average age of 38.8 years (ranged, 22 to 59 years). According to the Tile classification,10 cases belonged to C1,4 belonged to C2,2 belonged to C3. Tometta and Majeed score standards were used to evaluate clinical results. RESULTS: Sixteen patients were followed up from 4 to 13 months with an average of 7.3 months. Operative time was from 80 to 140 min with an average of 100 min;blood loss volume was from 200 to 500 ml with an average of 280 ml; and the healing time of fracture was from 12 to 16 months with an average of 14 months. According to the Tometta score classification, 9 cases got excellent results, 6 good, 1 fair. According to the Majeed score classification, 9 cases obtained excellent results, 5 good, 2 fair. CONCLUSION: Reconstruction plate fixation in Stoppa approach for anterior lesions combined with posterior percutaneous plate fixation for posterior lesions is an ideal minimally invasive operation in treaing type C pelvic fracture. It can early exercise and has the advandages of small trauma, safe operaton,less complication, stable fixation. PMID- 23795446 TI - [Treatment of refractory lateral epicondylitis with modified Nirschl surgical technique]. AB - OBJECTIVE: To investigate the clinical effects of modified Nirschl surgical techniique in treating refractory lateral epicondylitis. METHODS: From March 2009 to January 2011,21 patients (21 elbows) with refractory lateral epicondylitis were treated in our hospital. There were 8 males and 13 females,ranged in age from 25 to 59 years with an average of (48.3+/-13.4) years and the duration time from 8 to 33 months with an average of (17.1+/-7.7) months;affected position in dominant sides of 16 cases and non-dominant sides of 5 cases. The patients had already received multiple non-operative treatments. Modified Nirschl surgical technique was performed,and operative origination from origin of musculus extensor carpi radialis brevis to discard process with small incision, the process place of extensor digitorum communis would be removed. The incisions were nursed by ice compress for 2 days after operation. Range of motion (ROM) and strengthening exercise of elbow joints started at the 1 week after plaster slab fixation; ROM and strengthening exercise of wrist joints also started at the 2 week after fixation. The pain, power of gripping and patient staisfaction were recorded after operation. Verhaar scaling were used to estimate the recovery. RESULTS: Seventeen patients were followed up from 13 to 22 months with an average of 16.3 months. According to Verhaar standard, 15 cases obtained excellent results and 2 good. No postoperative complication such as instability was found. CONCLUSION: Modified Nirschl surgical technique is an effective method in treating refractory lateral epicondylitis but correct to diagnosis and exclusion the coexisting diseases,accurate removal the process are important guarantee. PMID- 23795447 TI - [Investigation of operative process in treating lumbar intervertebral disc protrusion in aged patients]. AB - OBJECTIVE: To investigate the operative management and surgical techniques for lumber disc herniation (LDH) in aged patients (>or=65 years). METHODS: From 2005 to 2010,the data of 43 patients with LDH underwent surgical treatment were retrospectively analyzed. There were 25 males and 18 females,aged from 65 to 70 years old with an average of 67.6 years. The course of disease was from 6 weeks to 7 years with an average of 10.2 years. Fenestratiodn discectomy or extended fenestration discectomy and unilateral or bilateral fenestration were used according to the conditions of location,type of herniated macleos polposus and nerve root compression. Among the patients,the nerve root canal was enlarged,hyperplastic osteophyma and soft tissue were removed, bilateral articular process was reserved in order to maintain the stability of the lumbar segment. RESULTS: All the patients were followed up from 1.2 to 5.2 years. According to the criteria of HU you-gu, 25 cases got excellent results, 15 good, 2 fair and 1 poor. No infection or nerve injury was found. Nerve function of patients had a normal or near normal recovery. CONCLUSION: For the treatment of LDH in aged patents,it is key that reasonably choose the operative method, completely remove the hyperplasy of diseased region and enlarge the nerve root canal, thoroughly loose the nerve root. PMID- 23795448 TI - [Familial osteopoikilosis in the pelvic region combined with bilateral gluteal muscle contracture: a case report]. PMID- 23795449 TI - [Close reduction combined with minimally invasive percutaneous plate osteosynthesis for proximal and distal tibial fractures: a report of 56 patients]. AB - OBJECTIVE: To evaluate the clinical effects of close reduction combined with minimally invasive percutanous plate osteosynthesis (MIPPO) for proximal and distal tibial fractures. METHODS: From March 2007 to December 2010, 56 patients with proximal and distal tibial fractures were treated with close reduction combined with MIPPO technique. There were 39 males and 17 females,aged from 22 to 67 years with an average of 41.3 years. Left fracture was in 25 cases and right fracture was in 31 cases; proximal tibial fracture was in 15 cases and distal tibial fractures was in 41 cases; 34 cases caused by fall down and 22 cases caused by road accident. The mean time from injury to operation was 1.7 d. Clinical manifestation included pain, swelling of leg with limitation of activity. According to the standard of Johner-Wruhs, clinical effects were evaluated. RESULTS: The mean operative time was 46 min in 56 patients. All fractures obtained satisfactory reduction and the location of plate was good. Incisions healed with one-stage and no superficial or deep infection was found. All the patients were followed up from 8 to 23 months with an average of 14.2 months. Only one fracture complication with delayed union,and after auto grafting with ilium bone,the fracture got union. Other 55 cases obtained bone healing in 15 to 20 weeks after operation and no internal fixation failure was found. The time of walking was 4-6 months after operation,without limping at 7 months after operation. Both lower extremities were symmetrical and the function of knee and ankle got complete recovery. According to the criteria of Johner-Wruhs score,46 cases obtained excellent results,9 good and 2 fair. CONCLUSION: Treatment of proximal and distal tibial fractures with close reduction and MIPPO technique can not only preserve soft tissue,simplify operative procedure and decrease wound, but also can obtain rigid internal fixation and guarantee early function exercises of knee and ankle joints. The method has the advantages of less soft tissue injury, less blood loss, reliable fixation, which is effective method in treating proximal and distal tibial fractures and corresponds with the standpoint of biological fixation. PMID- 23795450 TI - [Centerpiece plating in the cervical single open-door laminoplasty]. AB - OBJECTIVE: To evaluate the value of the Centerpiece plate in the cervical single open-door laminoplasty and compared its advantages with conventional suture fixation methods. METHODS: From December 2009 to August 2011,32 patients with cervical spondylotic myelopathy were treated with operation. Of them, 15 cases underwent cervical single open-door laminoplasty and Centerpiece plate fixation (group A),there were 8 males and 7 females,aged from 51 to 65 years old with an average of 60.5 years and ranged in course of disease from 2 to 15 months; 17 cases underwent cervical single open-door laminoplasty and silk suture fixation (group B), there were 9 males and 8 females, aged from 49 to 66 years old with an average of 61.5 years and ranged in course of disease from 1 to 14 months. All the patients with unsteady gait symptom before operation and cervical MR imaging showed spinal cord compression and denaturation. According to standard of Japanese Orthopaedics Association (JOA) to evaluate the spinal nervers function before operation and at 6 months after operation;according to CT scan to determine the sagittal diameter (AP) of upper vertebral canal and cervical activity (ROM). RESULTS: All the patients were followed up from 8 to 20 months with an average of 13 months. All the incisions healed well and no complications such as internal fixation loosening and breakage,spinal cord injury, reclose-door were found. Postoperative symptoms relieved obviously and MRI and CT showed vertebral canal volume expanded significantly. Operative time and blood loss in group A were respectively (155.0+/-12.3) min, (407.0+/-11.8) ml and in group B were respectively (148.0+/-14.4) min, (398.0+/-15.4) ml. There was no significantly differenc, between two groups (P>0.05). JOA score in group A improved from preoperative 9.1+/-2.6 to postoperative 15.5+/-1.8 and in group B improved from preoperative 9.3 +/- 2.1 to postoperative 13.1 +/- 2.5 (P<0.05). CT sagittal diameter (AP) in group A increased from preoperative (10.7+/-2.4) mm to postoperative (17.6+/-3.2) mm and in group B increased from preoperative (11.6+/ 1.7) mm to postoperative (15.9+/-2.0) mm (P<0.05). Cervical activity (ROM) in group A be- fore and after operation were respectively (51.0+/-2.6) degrees, (45.0+/-3.5) degrees and in group B were respectively (52.0+/-1.8) and (42.0+/ 2.4). There was no significantly difference before operation between two groups (P>0.05) and there was significantly difference after operation between two groups (P<0.05). CONCLUSION: Treatment of cervical spondylotic myelopathy with posterior single open-door laminoplasty and Centerpiece plate fixation can enlarge spinal canal volume,keep original cervical activity, improve postoperative JOA score. The method has obviously advantages compared with traditional suture fixation methods. PMID- 23795451 TI - [Percutaneous vertebroplasty complications]. AB - Percutaneous vertebroplasty(PVP), among various other options,has become a mainstay in the management of osteoporotic compression vertebral fractures. The purpose of this article is to review complications arising from the procedure and describes methods to minimize them. Complications can be classified as mild,which may include a temporary increase in pain; transient hypotension and cement leakage in the intervertebral disc space or into paravertebral soft tissues, moderate, including infection; extravasation of cement into the foraminal or epidural space and severe such as cement leakage in the paravertebral veins, leading to pulmonary embolism, cardiac perforation, cerebral embolism or even death. PMID- 23795452 TI - [Application of biomarker CTX- II in osteoarthritis]. AB - Effective biomarkers for clinical usage of osteoarthritis are still limited. It was confirmed that C-terminal crosslinking telopeptide of type I collagen (CTX- II) was a specific marker reflecting degradation of articular cartilage. Detection of CTX- II could promptly reflect level of cartilage injury and degradation ,diagnose OA,predict its progress,monitor effects of drug treatment, thus, reflect the condition of osteoarthritis patient indirectly. Application of CTX- II focused mainly on in the early stage of OA and need together to detect with other biomarkers,in order to more accurately reflection of the pathological changes of OA,but the specific clinical significance of CTX- II results still need to improve further. PMID- 23795453 TI - [Research progress on proteomics in femur head necrosis]. AB - Appearance of proteomics technology can fleetly filt and reveal specificity biomarkers of disease, this will help to reveal the pathogenesis of femur head necrosis and help early diagnosis, find more effective methods and therapeutic targets. At present, they are hot spots that find out the occurred mechanism,related proteins of early diagnosis and early treatment and its functional identification; set up the early related database; optimize the protein extraction methods for research of femur head necrosis. This article reviews the application of study technology of related proteins of femur head necrosis on bone tissue, serum,related animal model,and in order to provide further research ideas. PMID- 23795454 TI - [Chromomeric organization of interphase chromosomes in Drosophila melanogaster]. AB - As a result of treatment of bioinformatic data on the genome localization of structural proteins, histone modifications, DNase-hypersensitive regions, replication origins (taken from modENCODE) and their cytological localization to polytene chromosome structures, it is shown here that two types of interphase chromosomes -polytene chromosomes from salivary glands and from mitotically dividing cells cultures - demonstrate identical pictures of interband/band, i. e. the same localization and length on physical map and the same sets of proteins. In the interbands of both chromosome types we find the proteins that control initiation of transcription (RNA-polymerase II, transcription factors), replication (ORC2) as well as proteins modifying nucleosome structure (WDS, NURF) and proteins of insulators (BEAF). The nucleosome density and H1 histone concentration in the interbands are depleted; localization of DNase hypersensitive regions corresponds strictly to the interbands. So, we conclude that both polytene and cell line interphase chromosomes are arranged according to general principle and polytene chromosomes represent precise model of interphase chromosomes. The interbands play a critical role in the initiation of transcription and replication. The interbands of interphase chromosomes are the sites of 5' parts of genes, while the 3' gene ends are located in the adjacent bands. The constancy of interbands decondensation results in the conclusion that the "interbands" genes are constantly active, i. e. they contain "house-keeping" genes. The large late replicating bands contain genes that do not have direct contact to the adjoining interbands are usually polygenic and contain tissue specific genes. PMID- 23795455 TI - [Contemporary approaches to B chromosome analysis]. AB - The most recent data on sequencing and analysis of non-coding genome parts have revealed surprising biological functions of sequences, which were previously thought to be junk. Here we review the progress of techniques for B chromosome analysis - from methods of classical cytogenetics to contemporary technologies of high throughout genome sequencing, - and discuss the perspectives of involving new species with additional chromosome to ongoing genomic projects. PMID- 23795456 TI - [Mechanism of transcription regulation by RNA polymerase II pausing]. AB - For many years, the recruitment of Pol II to promoter region was considered to be the key step in the regulation of transcription. However, Pol II complex was then detected at the promoters of transcriptionally inactive genes. On that kind of genes, transcription regulation is realized by stimulation of promoter bound complex transition into the elongation phase. The available data concerning phenomenon of the transcription regulation by RNA polymerase II pausing mechanism are summarized in the current review. Here we discuss both the detailed mechanism of this process, which was studied in the model of heat shock genes in Drosophila, and some new data obtained from genome-wide studies. Hypotheses concerning functional role of the genes transcriptional regulation by RNA polymerase pausing mechanism are suggested. PMID- 23795457 TI - [Microrna, evolution and cancer]. AB - MicroRNAs are known as a posttranscriptional negative regulators of gene expression by binding to the 3'UTP of target mRNAs in cytoplasm. More than 1600 microRNAs expressed in human cells, are involved in the regulation of embryogenesis, differentiation, cell cycle, apoptosis, senescence, thus determining cell fate. Up to 60 % of protein coding genes are under their control. Various sets of microRNAs found in different human tissues under normal and pathological conditions, including cancer, suggest that miRNAs are involved in most cellular pathways. To date, there is no doubt that regulatory potential of the genome is largely determined by miRNAs. In our study, we performed a comparative phylogenetic analysis of the origin and evolution of the total set of 1048 miRNAs in the human genome and investigated the role of certain miRNAs in carcinogenesis of thyroid and mammary glands, as potential diagnostic and prognostic biomarkers of malignancy. Analysis of phylogenetic distribution of miRNAs in the human genome has shown four peaks of appearance of new miRNA genes in the evolution from Methazoa to H. sapiens. The highest amount of new miRNA genes appeared after divergence of H. s. from common ancestor with P. t. Expansion of transposable elements in genome was accompanied by the origin of new miRNA genes on the basis of their sequences. More than 14 % from 1600 miRNAs of human genome originated from mobile elements and still remain. Profiles of expression of 5 miRNAs, pertaining to oncomicroRNAs - miR-21, -221, -222, -155 and -205 - allow distinguishing ductal invasive carcinoma of mammary gland and thyroid papillary carcinoma. The data obtained suggest different ways and roles of participation of the same miRNAs in carcinogenesis of thyroid and mammary glands. So, these miRNAs and profiles of their expression might be used in the diagnosis and prognosis of cancer. PMID- 23795458 TI - Small supernumerary marker chromosomes (sSMC) - what about the genotype-phenotype correlation? AB - Genotype-phenotype correlations in patients with small supernumerary marker chromosomes (sSMC) are still difficult to asses. Here we review the presently known influence of chromosomal imbalance induced by sSMC size and origin, mosaicism of sSMC in different cells of the body and uniparental disomy (UPD) of sSMC's sister chromosomes on the clinical outcome. PMID- 23795459 TI - Cytogenetic studies of small ape (Hylobatidae) chromosomes. AB - Each genus of small apes has a highly distinctive karyotype (karyomorph) at every level of cytogenetic analysis. Early workers using classical staining and banding had problems integrating the karyolocial data with that of other primates. Chromosome painting allowed syntenic homology maps to be constructed for each of the four karyomorphs (2n = 38, 44, 50 and 52). They revealed that the great apes and Old World monkeys had strongly conserved karyotypes while those of small apes were highly rearranged. However, they provided contradictory phylogenetic results to other bio-molecular tree of small ape evolution. More recently BAC-FISH investigations using a panel of about 900 BACs defined each breakpoint by spanning or flanking BAC clones The syntenic map was refined and now includes small segments of homology which had previously gone undected, marker order (synteny block orientation) and the location of ancestral and Evolutionarily New Centromeres. However, the BAC-FISH data similar to other biomolecular methods used up to now could not resolve the phylogenetic tree of hylobatids. These difficulties may be explained by the rapid divergence of crown hylobatids, reticulate evolution and incomplete lineage sorting. The lack of significant cytogenetic landmarks at the nodes of the gibbon tree could indicate that chromosomal rearrangements did not play a primary role in hylobatid speciation. PMID- 23795460 TI - [Novel complexes of gene expression and their role in the appearance and evolution of the genus Homo]. AB - Using genetic (yeast two-hybrid system) and biochemical (co-precipitation of proteins from cellular lysates) approaches, we have performed a whole-genome wide search for interacting partners of the previously described by us variants of hRPB11 subunit of human RNA polymerase II - hRPB1 1balpha, hRPB11calpha and hRPB1 1bbeta, hRPB 11cbeta - in fetal brain and Jurkat cell line libraries. In consequence, the main spectrum of the protein partners of these human specific isoforms of the RNA polymerase II subunit hRPB 11 (POLR2J) has been established. Functional characteristics of the uncovered protein partners of hRPB 11balpha and hRPB 11calpha isoforms clearly indicate that these isoforms, similarly to the main (major) subunit hRPB11a, are components of the distinct transcription complexes participating not only in the transcription of the specific DNA matrices, but involving also in the later stages of mRNA biogenesis. The RNA polymerase I-III common subunit hRPB6 (POLR2F) and basal component of the exon exon junction complex Y14 (RBM8A) have been found among the protein partners of the isoforms hRPB 11bbeta and hRPB 11cbeta together with a number of proteins involved in the biogenesis of microRNAs, including a novel, not previously described variant of the microRNA processing nuclease DROSHA, which indicates the existence of a special coordination between processes of transcription and RNA interference in the nuclei of human cells. PMID- 23795461 TI - [Late-replicating regions in salivary gland polytene chromosomes of Drosophila melanogaster]. AB - About 240 specific regions that are replicated at the very end of the S-phase have been identified in D. melanogaster polytene chromosomes. These regions have a repressive chromatine state, low gene density, long intergenic distances and are enriched in tissue specific genes. In polytene chromosomes, about a quarter of these regions have no enough time to complete replication. As a result, underreplication zones represented by fewer DNA copy number, appear. We studied 60 chromosome regions that demonstrated the most pronounced under-replication. By comparing the location of these regions on a molecular map with syntenic blocks found earlier for Drosophila species by von Grotthuss et al., 2010, we have shown that across the genus Drosophila, these regions tend to have conserved gene order. This forces us to assume the existence of evolutionary mechanisms aimed at maintaining the integrity of these regions. PMID- 23795462 TI - [P elements comprising mini-white marker gene suppression features in intergenic regions of Drosophila melanogaster genome]. AB - 12 492 intergenic regions were stratified into four classes according to protein coding genes mutual orientation flanking an intergenic region. It was revealed that transposon insertion sites number linearly correlates with number of promoters (none, one, or two) in an intergenic region. The vast majority oftransposons reside in intergenic regions with two promoters. Remarkably, the suppression manifestation, on the contrary, was most pronounced in ("promoterless" intergenic regions. Discussion of the phenomenon is based on the chromatin state analysis of various intergenic regions. PMID- 23795463 TI - [A genetic system for somatic and germinal lineage tracing in the Drosophila melanogaster gonads]. AB - Significant progress in the developmental biology of Drosophila is largely due to the improvement of methods of genetic manipulation and, in particular, development of ways to create mosaic organisms. The main characteristic of the mosaic organisms is the presence of genetically different populations of cells. For example, some tissues express a transgenic reporter gene that is absent in other cells of the body. This principle is used in a variety of the methods with the common name lineage tracing. The essence of these approaches is to perform the targeted changes in the genetic apparatus of progenitor cells that give rise to cell lines or organs and tissues. Genetic modification in progenitor cells, such as the ability to express a fluorescent protein, will be inherited by the next cell generations, and, as a result, the entire cell line or tissue will have a tag, which distinguishes it from the rest of the body. The lineage tracing methods allow tracking the cell generations, studying the cell proliferation process, tracing their origin and investigating the function of genes of interest in the development of a single tissue or organ. We have designed an approach to selectively label germ line or somatic cells in the gonads of Drosophila. PMID- 23795464 TI - [Domain regulation of gene expression in the intercalary heterochromatin of Drosophila melanogaster]. AB - A significant part of Drosophila genome is repressed in most cells. These areas, called intercalary heterochromatin regions, contain a significant amount of genes. Most of these genes work in well-defined cell types, that is, are tissue specific. The most numerous class of genes in the intercalary heterochromatin are testis-specific genes. These genes are activated only in maturing spermatocytes and their coordinated activation is necessary for the normal spermatogenesis. Our work aims to study the mechanism of activation of testis-specific genes. We have found that Comr, one of the factors required for their transcription, is associated with extensive regions of chromosomes, which are often coextensive with the repressed parts of the salivary glands chromosomes. However, Comr binding to the large chromatin domains leads to the selective activation of testis-specific genes only. Our results suggest that, at the initial stages, activation of the testis-specific genes involves the entire domains of intercalary heterochromatin. PMID- 23795465 TI - [Studies of Drosophila ATP-dependent chromatin assembly and remodeling factors]. AB - Chromatin assembly is a fundamentally important process that is essential for chromosome duplication subsequent to DNA replication. In addition, histone removal and incorporation take place constantly throughout the cell cycle in the course of DNA-utilizing processes, such as transcription, damage repair or recombination. In vitro, chromatin assembly requires the concerned action of histone chaperones and ATP-utilizing chromatin assembly factors. A novel, evolutionary conserved. ISWI-containing ATP-dependent chromatin assembly complex termed ToRC has been described. ToRC comprises ISWI, Toutatis and the transcriptional corepressor CtBP. In vivo studies have identified the Drosophila ATP-dependent chromatin-remodeling protein CHD1 as a key factor in the replication independent assembly of nucleosomes containing the variant histone H3.3. CHD1 functions within the network of partially redundant factors: mutations in individual chromatin assembly factors are viable, but combination of Chd1 mutations with mutations of other ATP-dependent chromatin assembly factors (acf1, dRsf1, tou) causes synthetic lethality. Thus, ATP-dependent molecular motor proteins, such as CHD1, function not only in remodeling of existing nucleosomes but also in de novo nucleosome assembly from DNA and histones. PMID- 23795466 TI - [Structural features of chromatin organization of 3C6/C7 interband in Drosophila melanogaster polytene chromosomes]. AB - This article presents an analysis of the causes of chromatin decompaction of interbands in Drosophila polytene chromosomes. On the example of interband 3C6/C7 of X chromosome, we investigate the ability of different DNA segments from the region to form an interband in a new genetic environment. Site-specific FLP recombination between two transposons with FRT-sites allows introducing the DNA fragments from the inter-band 3C6/C7 into plCon(dv) transposon located in cytologically well-characterized 84F region of chromosome 3 followed by electron microscopic analysis of changes in the region, caused by insertion of the DNA fragments into the transposon. Thus, it has shown that the insertion of DNA fragment 276 bp in length from 3C6/C7 region into the plCon(dv) transposon leads to the formation of a new interband between two thin bands which are represented by material of the transposon. To date, the DNA fragment is minimal known sequence that is necessary and sufficient for interband formation. In addition, the sequence containing three tandemly repeated copies of DNA fragment 0.9 kb including a fragment of 276 bp from the interband 3C6/C7 was integrated in the transposon. The presence of additional copies of the DNA fragment did not change the morphology of the resulting interband. It was shown that sites of hypersensitivity to DNase I persist in interbands formed in the new genetic environment. The data obtained allow us to start analysis of the specific factors (proteins, DNA motifs, etc.) that determine the formation of decompacted chromatin state in sertain interband region and, as a whole, chromometric organization of interphase chromosomes in Drosophila. PMID- 23795467 TI - Organization and maintenance of Drosophila telomeres: the roles of terminin and non-terminin proteins. AB - Drosophila telomeres are elongated by occasional transposition of specialized retroelements rather than telomerase activity, and are assembled independently of the sequence of the DNA termini. Drosophila telomeres are capped by terminin, a complex formed by the HOAP, Moi, Ver and HipHop proteins that localize exclusively at telomeres and protect them from fusion events. Other proteins required to prevent end-to-end fusion include HP 1 Eff/UbcD 1, ATM, the components of the Mrel 1-Rad50-Nbs (MRN) complex, and the Woc transcription factor. The terminin proteins are encoded by fast-evolving genes and are not evolutionarily conserved outside the Drosophila species. In contrast, the non terminin telomere capping proteins are not fast-evolving, do not localize only at telomeres and are conserved from yeasts to mammals. We propose that following telomerase loss, Drosophila rapidly evolved terminin to bind chromosome ends in a sequence-independent manner, and that non-terminin proteins did not evolve as rapidly as terminin because of the functional constraints imposed by their involvement in diverse cellular processes. This hypothesis suggests that the Drosophila non-terminin proteins might correspond to ancestral telomere associated proteins with homologues in other organisms including humans. PMID- 23795468 TI - [Fungal anthraquinones (review)]. AB - The review is devoted to the characteristics of anthraquinones--a group of pigments of quinoid nature often found in fungi. The distribution of anthraquinones in fungi, the routes of their biosynthesis, and their biological activity are considered. PMID- 23795469 TI - [Identification of the functional activity of synthetic polyamine analogues using a biotest system based on highly proliferating cultured human cells]. AB - A new biotest system was developed based on highly proliferating human cell cultures (lines LNCaP and PC-3). With the help of this system, two known synthetic polyamines--alpha-difluoromethylornithine (DFMO) and methylglioxalbis(guanylhydrason) (MGBG)--as well as four new synthetic analogues difenyl containing amines (DFCA-1-DFCA-4) with molecular weights of 725.5 (DFCA 1), 755.5 (DFCA-2), 655.5 (DFCA-3), and 681.5 Da (DFCA-4) were tested. In this biotest system, DFMO (0.1-400 microM) did not reveal functional activity, whereas for MGBG a cytotoxic effect was registered (100-200 microM). DFCA-1, DFCA-2, and DFCA-4 had a similar effect at concentrations of 10 microM and higher; DFCA-3, at a concentration of 50 microM and higher. Thus, DFCA-1 has a higher level of antiproliferating activity and may be considered as the most potent cytostatic agent. PMID- 23795470 TI - [Catalytic properties of enzymes from Erwinia carotovora involved in transamination of phenylpyruvate]. AB - Km for L-phenylalanine, L-glutamic acid, L-aspartic acid, and the corresponding keto acids were calculated, as well as Vmax, was measured for the following pairs of substrates: L-phenylalanine-2-ketoglutarate, L-phenylalanine-oxaloacetate, L glutamic acid-phenylpyruvate, and L-aspartic acid-phenylpyruvate for aminotransferases PATI, PAT2, and PAT3 from Erwinia carotovora catalyzing transamination of phenylpyruvate. The ping-pong bi-bi mechanism was shown for the studied aminotransferases. The substrate inhibition (Ks) of PAT3 with 2 ketoglutarate and oxaloacetate was 10.23 +/- 3.20 and 3.73 +/- 1.99 mM, respectively. PMID- 23795471 TI - [Recombinant Escherichia coli strains deficient in mixed acid fermentation pathways and capable of rapid aerobic growth on glucose with a reduced Crabtree effect]. AB - In this study, we constructed and characterized Escherichia coli strains deficient for mixed acid fermentation pathways, which are capable of rapid aerobic growth on glucose without pronounced bacterial Crabtree effect. The main pathways of production of acetic and lactic acids and ethanol in these strains were inactivated by a deletion of the ackA, pta, poxB, IdhA, and adhEgenes. The phosphoenolpyruvate-dependent phosphotransferase system of glucose transport and phosphorylation was inactivated in the strains by a deletion of the ptsG gene. The possibility of alternative transport and phosphorylation of the carbohydrate substrate was ensured in recombinants by constitutive expression of the galP and glk genes, which encode the low-affinity H+-symporter of D-galactose and glucokinase, respectively. SGMI.0DeltaptsG PtacgalP and SG M1.0DeltaptsG PIglk PtacgalP strains were capable of rapid aerobic growth in a minimal medium containing 2.0 and 10.0 g/l of glucose and secreted only small amounts of acetic acid and trace amounts of pyruvic acid. PMID- 23795472 TI - [Regulation of key enzymes of L-alanine biosynthesis by Brevibacterium flavum producer strains]. AB - The mechanisms of L-alanine overproduction by Brevibacterium flavum producer strains were studied. It was shown that beta-CI-L-alanine is an inhibitor of some key enzymes involved in the synthesis of L-alanine, including alanine transaminase and valine-pyruvate transaminase. Two highly active B. flavum GL1 and GL1 8 producer strains, which are resistant to the inhibitory effect of beta Cl-L-alanine, were obtained using a parental B. flavum AA5 producer strain, characterized by a reduced activity of alanine racemase (>or=98%). It was demonstrated that the increased L-alanine synthesis efficiency observed in the producer strains developed in this work is associated with the absence of inhibition of alanine transaminase by the end product of the biosynthesis reaction, as well as with the effect of derepression of both alanine transaminase and valine-pyruvate transaminase synthesis by the studied compound. PMID- 23795473 TI - [The directed modification of Escherichia coli MG1655 to obtain histidine producing mutants]. AB - Strain MG 1655+hisGr hisL'-Delta, purR, which produces histidine with a weight yield of approximately 12% from glucose, was constructed through directed chromosomal modifications of the laboratory Escherichia coli strain MG 1655+, which has a known genome sequence. A feedback-resistant ATP-phosphoribosyl transferase encoded by the mutant hisGr (E271 K) was the main determinant of histidine production. A further increase in histidine production was achieved by the expression enhance of a mutant his operon containing hisGr through the deleting attenuator region (hisL'-Delta). An increase in the expression of the wildtype his operon did not result in histidine accumulation. Deletion of the transcriptional regulator gene purR increased the biomass produced and maintained the level of histidine production per cell under the fermentation conditions used. PMID- 23795474 TI - [Novel NADPH-dependent L-aspartate dehydrogenases from the mesophilic nitrogen fixing bacteria Rhodopseudomonas palustris and Bradyrhizobium japonicum]. AB - The genes encoding putative L-aspartate dehydrogenases (EC 1.4.1.21, ADH) from the mesophilic nitrogen-fixing bacteria Rhodopseudomonas palustris and Bradyrhizobium japonicum were cloned and expressed in Escherichia coli. The respective enzymes in the form of hybrid proteins with N-terminal hexahistidine tags were purified to apparent homogeneity. Both enzymes catalyzed in vitro the reductive amination of oxaloacetate to L-aspartate by an order faster than the reverse reaction at a respective pH optimum of 8.0-9.0 and 9.8; also, the enzymes only catalyzed amination under physiological conditions (pH 7.0-8.0). Their specificity to NADPH was higher by 1-2 orders of magnitude than that to NADH. The apparent KM values of ADHs from R. palustris for oxaloacetate, ammonium, and NADPH at pH 9.0 were 9.2, 11.3, and 0.21 mM, respectively, and the corresponding KM values of ADH from B. japonicum were 21, 4.3, and 0.032 mM, respectively. The amination activity of novel ADHs may be important for the fixation of inorganic nitrogen in vivo and used for the construction of a bacterial strain-producer of L-aspartate by metabolic engineering methods. PMID- 23795475 TI - [Effect of cold plasma on the E. coli cell wall and plasma membrane]. AB - The effect of cold plasma on E. coli cells was studied. It was shown that the treatment of E. coli cells with cold plasma caused partial or total disruption of the plasma membrane integrity, which was accompanied by a release ofintracellular substances into the extracellular environment. A quantitative assessment of the extent of the damage to the cell membrane showed that a loss of no more than 23.6% of intracellular substances (calculated by the proportion of the intracellular nucleotide release) is sufficient to lead to cell death. The use of media with different ionic strength levels to create osmotic shock showed that the treatment of E. coli cells with cold plasma significantly decreased the cell wall strength. PMID- 23795476 TI - [Biosynthesis of polyhydroxybutyrate/valerate with different molecular weights during the growth of Methylobacterium extorquens G-10 on a methanol-pentanol mixture]. AB - The influence of the concentration and time of addition of cosubstrate (pentanol) on the molecular weight (MW) of the polyhydroxybutyrate/valerate (PHBV) copolymer synthesized by Methylobacterium extorquens G-10 during cultivation in a methanol containing medium has been studied. It was shown that an increase in the pentanol concentration to 20% in a mixture with methanol stimulated the biosynthesis of PHBV with a MW of approximately 1500 kDa and increased the content of valerate up to 50%, especially when pentanol was added to the log phase culture. High pentanol concentrations are toxic for the producer and reduce the total yield of PHBV. An MW increase to 1500 kDa lowers the melting temperature (from 172 to 162 degrees C) and the crystallinity degree (from 63 to 8%) of the biopolymer but increases its elasticity. The revealed variability of PHBV properties extends considerably the potential application areas of synthetic bioplastics. PMID- 23795477 TI - [Fungicidal activity of yeast isolated from chal (camel cultured milk product)]. AB - A Kluyveromyces strain secreting a fungicidal proteinaceous toxin has been isolated. Its maximal activity is observed at pH 5.0 and an increased osmotic pressure. This agent has been identified as a mycocin; it is active towards species belonging to the genus Kluyveromyces and some representatives of taxonomically related groups. PMID- 23795478 TI - Inhibitory effect of components from Streptomyces species on alpha-glucosidase and alpha-amilase of different origin. AB - The search for the effective and safe a-glucosidase and alpha-amylase inhibitors from Actinomycetaceae being antidiabetic agents is actual problem. Twenty one Streptomyces spp. of soil samples collected from different places of China were screened for the ability to produce this kind of inhibitory activities. Fermentation broth of isolated strains had absorbance between 350-190 nm. The Streptomyces strains PW003, ZG636, and ZG731 were characterized by special absorption at 280, 275, and 400 nm, respectively. Ten of the collected actinomycete strains had the ability to inhibit alpha-glucosidase or/and alpha amylase and the fermentation broth of the same strain had inhibitory activity varied greatly depending on the enzyme source. In the process to screen the leading compounds used as antidiabetic agents, human alpha-glucosidase and alpha amylase were revealed as the best used in trail compared with the same enzymes from other sources. Active alpha-glucosidase inhibitor was isolated from Streptomyces strain PW638 fermentation broth and identified as acarviostatin 103 by MS and N MR spectrometry. Its IC50 value was 1.25 and 12.23 microg/mL against human intestinal N-terminal maltase-glucoamylase and human pancreatic alpha amylase, respectively. PMID- 23795479 TI - Biochemical parameters of Saccharopolyspora erythraea during feeding ammonium sulphate in erythromycin biosynthesis phase. AB - The physiology of feeding ammonium sulphate in erythromycin biosynthesis phase of Saccharopolyspora erythraea on the regulation of erythromycin A (Er-A) biosynthesis was investigated in 50 L fermenter. At an optimal feeding ammonium sulphate rate of 0.03 g/L per h, the maximal Er-A production was 8281 U/mL at 174 h of growth, which was increased by 26.3% in comparison with the control (6557 U/mL at 173 h). Changes in cell metabolic response of actinomycete were observed, i.e. there was a drastic increase in the level of carbon dioxide evolution rate and oxygen consumption. Assays of the key enzyme activities and organic acids of S. erythraea and amino acids in culture broth revealed that cell metabolism was enhanced by ammonium assimilation, which might depend on the glutamate transamination pathway. The enhancement of cell metabolism induced an increase of the pool of TCA cycle and the metabolic flux of erythromycin biosynthesis. In general, ammonium assimilation in the erythromycin biosynthesis phase of S. erythraea exerted a significant impact on the carbon metabolism and formation of precursors of the process for dramatic regulation of secondary metabolites biosynthesis. PMID- 23795480 TI - [Water-soluble glucans from true cardamom (Elettaria cardamomum White at Maton) seeds]. AB - Water-soluble polysaccharides from seeds of true cardamom (Elettaria cardamomum White at Maton, family Zingiberaceae) have been studied. The study has shown the presence of neutral and acidic components in these polysaccharides. Three polysaccharides (380, 166, and 27 kDa) have been isolated from the neutral fraction. According to the structural analysis data, they represent alpha-glucans with different degrees of branching (7.1-46.1%); alpha-(1-->4)-D-glucopyranose residues of their backbone chains are substituted at the C6 position with single a-D-glucopyranose residues. Polysaccharides with such structures have a wide range of biological activity. The presence of branched alpha-glucans in E. cardamomum seeds has been demonstrated. PMID- 23795481 TI - [Aerobic methylobacteria as the basis for a biosensor for dichloromethane detection]. AB - Cells of dichloromethane (DChM) bacteria-destructors were immobilized by sorption on different types of membranes, which were fixed on the measuring surface of a pH-sensitive field transistor. The presence of DChM in the medium (0.6-8.8 mM) led to a change in the transistor's output signal, which was determined by the appearance of H+ ions in the medium due to DChM utilization by methylobateria. Among four strains of methylobacteria--Methylobacterium dichloromethanicum DM4, Methylobacterium extorquens DM 17, Methylopila helvetica DM6, and Ancylobacter dichloromethanicus DM 16--the highest and most stable activity toward DChM degradation was observed in the strain M. dichloromethanicum DM4. Among 11 types of membranes for cell immobilization, Millipore nitrocellulose membranes and chromatographic fiber paper GF/A, which allow one to obtain stable biosensor signals for 2 weeks without a bioreceptor change, were chosen as optimal carriers. PMID- 23795482 TI - [Potentiometric glucose determination in human serum samples with glucose oxidase biosensor based on iodide electrode]. AB - Glucose potentiometric biosensor was prepared by immobilizing glucose oxidase on iodide-selective electrode. The hydrogen peroxide formed after the oxidation of glucose catalysed by glucose oxidase (GOD) was oxidized by sodium molybdate (SMo) at iodide electrode in the presence ofdichlorometane. The glucose concentration was calculated from the decrease of iodide concentration determined by iodide selective sensor. The sensitivity of glucose biosensor towards iodide ions and glucose was in the concentration ranges of 1.0 x 10(-1) - 1.0 x 10(-6) M and 1.0 x 10(-2) - 1.0 x 10(-4) M, respectively. The characterization of proposed glucose biosensor and glucose assay in human serum were also investigated. PMID- 23795484 TI - Literature and medicine. Preface. PMID- 23795483 TI - [Antimicrobial activity of stable silver nanoparticles of a certain size]. AB - Conditions for obtaining stable silver nanoparticles smaller than 10 nm were developed using a binary stabilizer polyvinylpyrrolidone/sodium dodecylsulphate in optimal ratio. Optical spectra, morphology and dependence of size of the nanoparticles on the amount of reducing agent were studied. Colloidal solutions of nanosilver showed a high bactericidal activity against strains of Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa, and fungicidal activity against Candida albicans. The mechanism of action of nanosized silver on microbial cell was examined by laser scanning confocal microscope using fluorescent label. First step of antimicrobial effect on microorganisms was membrane damage and penetration of silver nanoparticles into the cell. Prolonged stability of nanoparticles and their antimicrobial activity over the past two years were showed. PMID- 23795485 TI - Malaria and the revision of Daisy Miller. PMID- 23795486 TI - Modernist autobiography, hysterical narrative, and the unnavigable river: the case of Freud and H.D. PMID- 23795487 TI - The end of sensibility: the nervous body in the early nineteenth century. PMID- 23795488 TI - Cancer experience and its narration: an accidental study. PMID- 23795489 TI - The cloister as therapeutic space: breast cancer narratives in the early modern world. PMID- 23795490 TI - Consulting physicians: the role of specialist medical advisers in Cormac McCarthy's contemporary fiction. PMID- 23795492 TI - Adsorption kinetics of non-ionic surfactants in micellar solutions: effects of added charge. AB - The kinetics of adsorption of micellar solutions of non-ionic surfactants have been studied in an overflowing cylinder. The addition of small amounts (< 10% of the total surfactant concentration) of ionic surfactants, CTAB and STS, to solutions of C16E8 causes a dramatic reduction in the rate of adsorption of the nonionic surfactant. The results are rationalised by a combination of monomer and micelle adsorption to the air-water interface. In the presence of trace ionic surfactants, only uncharged micelles adsorb. The adsorption kinetics are independent of the sign of the charge on the micelles, only on its magnitude. The influence of ionic surfactants on the adsorption rate is reversed by addition of millimolar concentrations of salt. Electrolyte screens the repulsions between micelles and the adsorbed monolayer and allows charged micelles to adsorb without first breaking down into monomers. PMID- 23795491 TI - Introductory lecture: interpreting and predicting Hofmeister salt ion and solute effects on biopolymer and model processes using the solute partitioning model. AB - Understanding how Hofmeister salt ions and other solutes interact with proteins, nucleic acids, other biopolymers and water and thereby affect protein and nucleic acid processes as well as model processes (e.g. solubility of model compounds) in aqueous solution is a longstanding goal of biophysical research. Empirical Hofmeister salt and solute "m-values" (derivatives of the observed standard free energy change for a model or biopolymer process with respect to solute or salt concentration m3) are equal to differences in chemical potential derivatives: m value = delta(dmu2/dm3) = delta mu23, which quantify the preferential interactions of the solute or salt with the surface of the biopolymer or model system (component 2) exposed or buried in the process. Using the solute partitioning model (SPM), we dissect mu23 values for interactions of a solute or Hofmeister salt with a set of model compounds displaying the key functional groups of biopolymers to obtain interaction potentials (called alpha-values) that quantify the interaction of the solute or salt per unit area of each functional group or type of surface. Interpreted using the SPM, these alpha-values provide quantitative information about both the hydration of functional groups and the competitive interaction of water and the solute or salt with functional groups. The analysis corroborates and quantifies previous proposals that the Hofmeister anion and cation series for biopolymer processes are determined by ion-specific, mostly unfavorable interactions with hydrocarbon surfaces; the balance between these unfavorable nonpolar interactions and often-favorable interactions of ions with polar functional groups determine the series null points. The placement of urea and glycine betaine (GB) at opposite ends of the corresponding series of nonelectrolytes results from the favorable interactions of urea, and unfavorable interactions of GB, with many (but not all) biopolymer functional groups. Interaction potentials and local-bulk partition coefficients quantifying the distribution of solutes (e.g. urea, glycine betaine) and Hofmeister salt ions in the vicinity of each functional group make good chemical sense when interpreted in terms of competitive noncovalent interactions. These interaction potentials allow solute and Hofmeister (noncoulombic) salt effects on protein and nucleic acid processes to be interpreted or predicted, and allow the use of solutes and salts as probes of PMID- 23795493 TI - Adsorption of solutes at liquid-vapor interfaces: insights from lattice gas models. AB - The adsorption behavior of ions at liquid-vapor interfaces exhibits several unexpected yet generic features. In particular, energy and entropy are both minimum when the solute resides near the surface, for a variety of ions in a range of polar solvents, contrary to predictions of classical theories. Motivated by this generality, and by the simple physical ingredients implicated by computational studies, we have examined interfacial solvation in highly schematic models, which resolve only coarse fluctuations in solvent density and cohesive energy. Here we show that even such lattice gas models recapitulate surprising thermodynamic trends observed in detailed simulations and experiments. Attention is focused on the case of two dimensions, for which approximate energy and entropy profiles can be calculated analytically. Simulations and theoretical analysis of the lattice gas highlight the role of capillary wave-like fluctuations in mediating adsorption. They further point to ranges of temperature and solute-solvent interaction strength where surface propensity is expected to be strongest. PMID- 23795494 TI - Surface and interfacial tensions of hofmeister electrolytes. AB - We present a theory that is able to account quantitatively for the surface and interfacial tensions of different electrolyte solutions. It is found that near the interface, ions can be separated into two classes: the kosmotropes and the chaotropes. While the kosmotropes remain hydrated near the interface and are repelled from it, the chaotropes loose their hydration sheath and become adsorbed to the surface. The anionic adsorption is strongly correlated with the Jones-Dole viscosity B-coefficient. Both hydration and polarizability must be taken into account to obtain a quantitative agreement with the experiments. To calculate the excess interfacial tension of the oil-electrolyte interface, the dispersion interactions must also be included. The theory can also be used to calculate the surface and the interfacial tensions of acid solutions, predicting a strong surface adsorption of hydronium ion. PMID- 23795495 TI - An ab initio approach to understanding the specific ion effect. AB - Although there is a consensus that large, polarizable anions will adsorb to the air-water interface, the precise interactions that give rise to surface enhancement are still being debated. Previously, we have demonstrated that there is a significant dependence on the choice of molecular interaction potential for I-adsorption at the air-water interface. Specifically, density functional theory (DFT) based interaction potentials lead to significantly less adsorption than empirical interaction potentials that include polarization. We have also demonstrated that DFT based interaction potentials can accurately capture the structure of the first solvation shell of both simple and polyatomic anions as compared to multi-edge X-ray absorption fine structure (XAFS) experiments. We utilize DFT to examine the local hydration structure of SCN- and IO3- that exhibit both chaotropic and kosmotropic characteristics. We compare and contrast the solvation structure of the polyatomic anions with the series of halide anions. A picture emerges where we can correlate local solvation structure to the ions' position in the Hofmeister series. PMID- 23795496 TI - How specific are ion specificities? A pilot NMR study. AB - NMR quadruple splitting measurements are a useful technique to investigate the adsorption behaviour of ions near to charged surfaces in liquid crystals made of surfactants of different headgroups. In the present paper we show the differences in lithium and sodium adsorption on dodecyl carboxylate and dodecyl sulphate bilayers as a function of surfactant concentration and for two temperatures. To this purpose we mixed the pure surfactants and also mixtures of the lithium and sodium surfactants with octanol as a cosurfactant in appropriate ratios and concentrations to obtain liquid crystals. It turned out that the measured specific ion effects are much more pronounced in the case of carboxylates than for sulphates. PMID- 23795497 TI - Simulation study of ion pairing in concentrated aqueous salt solutions with a polarizable force field. AB - The accuracy of empirical force fields is critical for meaningful molecular dynamics simulations of concentrated ionic solutions. Current models are typically developed on the basis of single ion properties such as the monohydrate energy in the gas phase, or the absolute hydration free energy at infinite dilution. However, the failure of these models to represent accurately the properties of concentrated solutions cannot be excluded. Here, these issues are illustrated for a polarizable potential based on classical Drude oscillators. To model accurately concentrated ionic solutions, the parameters of the potential functions are optimized to reproduce osmotic pressure data. The sodium-chloride potential of mean force in solution calculated from the empirically-adjusted model is consistent with the results from that calculated from ab initio CPMD simulations. PMID- 23795498 TI - Understanding ion-ion interactions in bulk and aqueous interfaces using molecular simulations. AB - In addition to its scientific significance, the distribution of ions in the bulk and at aqueous interfaces is also very important for practical reasons. Providing a quantitative description of the ionic distribution, and describing interactions between ions in different environments, remains a challenge, and is the subject of current debate. In this study, we found that interionic potentials of mean force (PMFs) and interfacial properties are very sensitive to the ion-ion interaction potential models. Our study predicted a Sr(2+)--CI- PMF with no contact ion-pair state and a shallow solvent-separated ion-pair state. In addition, we were able to quantitatively capture the experimental X-ray reflectivity results of the aqueous salt interface of the Sr(2+)--Cl- ion-pair, and provided a detailed physical description of the interfacial structure for this system. We also predicted the Xray reflectivity results for SrBr2 and SrI2 systems. PMID- 23795499 TI - A new structural technique for examining ion-neutral association in aqueous solution. AB - The method of intramolecular coordination number concentration invariance (ICNCI) is used on neutron diffraction with isotopic substitution (NDIS) measurements of aqueous solutions to separate the intra- and intermolecular contributions to the total intensities. Molecular dynamics simulations of corresponding systems are then used to interpret the ICNCI function. It is found that the ICNCI function (characterized by two concentration measurements) is sensitive specifically to intermolecular association and that the molecular dynamics can successfully replicate this function in the cases of the neutral species xylose and pyridine in aqueous solution. ICNCI functions can also be obtained by the addition of a cosolute (such as adding GdmCl or Gdm2SO4 to pyridine solutions). In that case it is found that molecular dynamics can replicate the ICNCI function for the addition of GdmCl to pyridine, but fails to successfully replicate the same function for the addition of Gdm2SO4. This result implies that the interaction of pyridine with guanidinium sulfate is over-estimated in these MD simulations, and is of significant importance to the use of molecular dynamics simulations to elucidate an atomic level understanding of the Hofmeister series. PMID- 23795501 TI - Ion cooperativity and the effect of salts on polypeptide structure--a molecular dynamics study of BBA5 in salt solutions. AB - Using molecular dynamics simulations, we investigated effects of inorganic salts on the structure and dynamics of a short alpha,beta-polypeptide, BBA5. The simulations showed that three model salts, NaI, NaF, and Na2SO3, have very different effects on the structure of the polypeptide. The addition of NaI to the aqueous solution caused denaturation and significantly weakened hydrogen bonds of the polypeptide. Na2SO3 strengthened the hydrophobic interactions and increased hydrogen bonding of the polypeptide. Preferred binding of Na+ to the backbone carbonyl groups of BBA5 occurred in the NaI solution, consistent with the weakened protein backbone hydrogen bonds, whereas Na+ is excluded more from the vicinity of the protein backbone in the Na2SO3 solution. This difference in Na+ binding correlates well with the different propensities of the counter ions approaching the protein surface: SO3(2-) is much more strongly expelled from the protein apolar surface than I-, and demonstrates the importance of cation-anion cooperativity in affecting protein structures. The binding of the two salts to and their effects on the hydration of the protein surface depends strongly on the polarity of the latter. However, both salts reduce the flexibility of the polypeptide and the fluctuation of its hydration layer. These simulations showed that the chaotropic NaI affects protein structure mainly through a direct binding of Na+ to the backbone and I- to the protein surface. The main effect of Na2SO3 manifests in strengthening the hydrophobic interaction and consequently the hydrogen bonding of the protein, more likely through an "indirect" mechanism. In addition, the simulations showed that NaF has a similar effect as Na2SO3 (but weaker than the latter, consistent with their positions in the Hofmeister series). PMID- 23795500 TI - Femtosecond study of the effects of ions and hydrophobes on the dynamics of water. AB - We study the effects of ions and hydrophobic molecular groups on the orientational dynamics of water using THz dielectric relaxation (THz-DR) and polarization-resolved femtosecond infrared (fs-IR) pump-probe spectroscopy. We measure the dynamics of water in solutions of NaI, NaCl, CsCl, guanidinium chloride (GndCl) and tetramethyl guanidinium chloride (TMGndCl) of different the static dipoles of their surrounding water molecules. With fs-IR we find that concentrations. With THz-DR we observe that strongly hydrated cations align the OD groups that form hydrogen bonds to halide anions reorient with two distinct time constants of 2 +/- 0.3 ps and 9 +/- 1 ps. The fast process is assigned to a wobbling motion of the OD group that keeps the hydrogen bond with the anion intact. The amplitude of this wobbling motion depends on the nature of both the anion and the counter cation. The replacement of four of the six hydrogen atoms of the weakly hydrated cation guanidinium by hydrophobic methyl groups leads to an exceptionally strong slowing down of the water dynamics. Hydrophobic groups thus appear to have a much stronger effect on the dynamics of water than ions. These findings give new insights in the mechanism of protein denaturation by GndCl and TMGndCl. PMID- 23795502 TI - Diversity in the mechanisms of cosolute action on biomolecular processes. AB - Numerous cellular cosolutes significantly impact the way that proteins and other biomacromolecules act and interact. We have followed the thermodynamic effect of several cosolute classes, including polymers, cellular osmolytes, and inorganic salts, on the stability of biomolecular folding and complexation. By comparing changes in free energy, enthalpy, and entropy upon cosolutes addition for these processes, we identify several thermodynamically distinct mechanisms. Surprisingly, even while many cosolutes display similar scaling of the change in stabilizing free energy with their concentration, a breakdown of this free energy into enthalpic and entropic contributions distinguishes different families of cosolutes. We discuss how these "thermodynamic fingerprints" can direct towards possible underlying mechanisms that govern the cosolute effect. PMID- 23795503 TI - Ion interactions with non-polar and amphiphilic solutes in water. AB - Despite its extensive use in, for example, the concentration and crystallization of proteins, the salting out phenomenon remains poorly understood, with many- sometimes contradictory--explanations found in the literature. Following our earlier work using isotope substitution neutron scattering on an aqueous tertiary butyl alcohol (TBA) with added NaCl that examined in detail the molecular-level interactions in the system, and suggested that attempts to understand salting out through ion perturbation of the non-polar hydration shell may not be appropriate, we report here on two further sets of high resolution structural experiments that detail the structural interactions between ion, solvent and amphiphile in a wider range of relevant systems. First, a set of X-ray absorption spectroscopy experiments probed the effects on the hydrophobic hydration shell of Kr of adding a range of different salts (specifically Na2SO4, NaClO4, NaCl, NaNO3 and Mg(ClO4)2). The bottom line from these experiments is that the hydration shell is essentially unaffected by the added ions, underlining further the stability of the shell to such perturbations. The second set of experiments was a further isotope substitution neutron scattering study of the molecular-level solution structures of aqueous TBA, this time for a range of different added ions (CsF, NaBr, and NaCl at three concentrations), for which we have in addition extracted equilibrium constants to quantify the relative strengths of the various interactions. From this second set of results, we can conclude again that the solvent structure is essentially unperturbed by both the various ions and the amphiphile, and also identify a number of ion-specific effects. Comparing our results with those obtained from simulations that are not constrained by the experimental data underlines how sensitive structural conclusions are to the assumed potential functions, and that drawing conclusions from simulations not constrained to fit experimental data can lead to seriously erroneous conclusions. PMID- 23795504 TI - Interactions between halide anions and a molecular hydrophobic interface. AB - Interactions between halide ions (fluoride and iodide) and t-butyl alcohol (TBA) dissolved in water are probed using a recently developed hydration-shell spectroscopic technique and theoretical cluster and liquid calculations. High ignal-to-noise Raman spectroscopic measurements are combined with multivariate curve resolution (Raman-MCR) to reveal that while there is little interaction between aqueous fluoride ions and TBA, iodide ions break down the tetrahedral hydration-shell structure of TBA and produce a red-shift in its CH stretch frequency, in good agreement with the theoretical effective fragment potential (EFP) molecular dynamics simulations and hybrid quantum/EFP frequency calculations. The results imply that there is a significantly larger probability of finding iodide than fluoride in the first hydration shell of TBA, although the local iodide concentration is apparently not as high as in the surrounding bulk aqueous NaI solution. PMID- 23795505 TI - Solution electrostatics beyond pH: a coarse grained approach to ion specific interactions between macromolecules. AB - Oblivious to ion specificity, pH has been a key parameter for macromolecular solutions for little more than a century. We here widen the concept by describing the ionization of macromolecules not only via pH, but also pX where X are other binding species. Using binding constants, measured by NMR, of chloride and thiocyanate to amino acid motifs on y-crystallin, we calculate i) titration curves as a function of pH and pX and ii) estimate second virial coefficients using both approximate theory and computer simulations. In agreement with experiment, a Hofmeister reversal for protein-protein interactions is observed when crossing iso-electric conditions. Thiocyanate binding further leads to large charge fluctuations that may trigger intermolecular charge regulation interactions. PMID- 23795506 TI - Ionic interactions in biological and physical systems: a variational treatment. AB - Chemistry is about chemical reactions. Chemistry is about electrons changing their configurations as atoms and molecules react. Chemistry has for more than a century studied reactions as if they occurred in ideal conditions of infinitely dilute solutions. But most reactions occur in salt solutions that are not ideal. In those solutions everything (charged) interacts with everything else (charged) through the electric field, which is short and long range extending to the boundaries of the system. Mathematics has recently been developed to deal with interacting systems of this sort. The variational theory of complex fluids has spawned the theory of liquid crystals (or vice versa). In my view, ionic solutions should be viewed as complex fluids, particularly in the biological and engineering context. In both biology and electrochemistry ionic solutions are mixtures highly concentrated (to approximately 10 M) where they are most important, near electrodes, nucleic ids, proteins, active sites of enzymes, and ionic channels. Ca2+ is always involved in biological solutions because the concentration (really free energy per mole) of Ca2+ in a particular location is the signal that controls many biological functions. Such interacting systems are not simple fluids, and it is no wonder that analysis of interactions, such as the Hofmeister series, rooted in that tradition has not succeeded as one would hope. Here, we present a variational treatment of ard spheres in a frictional dielectric with the hope that such a treatment of an lectrolyte as a complex fluid will be productive. The theory automatically extends to spatially nonuniform boundary conditions and the nonequilibrium systems and flows they produce. The theory is unavoidably self-consistent since differential equations are derived (not assumed) from models of (Helmholtz free) nergy and dissipation of the electrolyte. The origin of the Hofmeister series is (in my view) an inverse problem that becomes well posed when enough data from disjoint experimental traditions are interpreted with a self-consistent theory. PMID- 23795507 TI - Ionic specific effects on the structure, mechanics and interfacial softness of a polyelectrolyte brush. AB - Polymer brushes are assemblies of polymer chains grafted with one end group to a solid surface in a number high enough so that the chains are stretched away from the interface due to steric hindrance and/or electrostatic repulsion between neighbouring polymer units. Diblock copolymers have been used to build controlled switchable surfaces with a selective response to external stimuli specific o one of the blocks. Herein we study the structure, mechanical behaviour and interfacial softness of a diblock copolymer brush composed of N,N' dimethylmethylacrylamide (DMMAA) and methacrylic acid (MAA) considering different counterions and Hofmeister salts by means of atomistic molecular dynamics simulations. Li+, Na+, K+, Rb+ and Cs+ were used as counterions while NaF, NaCl, NaBr and NaI 1 molal aqueous salt solutions were used to study anion effects. Our results show that Li+ and Na+ cations form a strong salt bridge network with the carboxylic groups of MAA monomers belonging to neighbouring chains leading to a stretched monodisperse arrangement of the polymeric chains. On the other hand, the weaker salt bridge network upon addition of Rb+ and Cs+ cations promotes a partial collapse of the polyelectrolyte brushes. Addition of K+ cations leads to an intermediate arrangement. These esults have a direct impact on the mechanical behaviour of such soft surfaces and the packing of the polymer chains, i.e. the rigidity of the brush is ion specific and follows a Hofmeister series in the order Li+ > Na >> K+ > Rb+ > Cs+. We urthermore report that in those systems where a sodium halide salt is added, the ame swelling behaviour is observed independently of the nature of the added salt. However, the degree of ionic absorption within the brush is again ion specific n the order NaCl > NaBr > NaI > NaF at 1 m salt concentration. PMID- 23795508 TI - Measuring the interaction between ions, biopolymers and interfaces--one polymer at a time. AB - Atomic force microscopy (AFM) based single polymer force spectroscopy allows to detect the interaction (energy) between single polymers and interfaces in aqueous environment. We use this method to delineate the effect of ions, pH, co-solutes and temperature on the adhesion of biopolymers onto solid substrates. PMID- 23795509 TI - Interactions of monovalent salts with cationic lipid bilayers. AB - The influence of monovalent salts (NaF, NaCl, NaBr, NaClO4, KCl) on the properties of lipid bilayers composed of binary mixtures of zwitterionic DOPC (dioleoylphosphatidylcholine) and cationic DOTAP (dioleoyltrimethylammoniumpropane) is experimentally measured and numerically simulated. Both approaches report a specific adsorption of the studied anions at the cationic bilayer. The adsorption is enhanced for higher content of DOTAP in DOPC/DOTAP mixtures and for larger anions (Br and ClO4-). The nonmonotonic dependence of the lipid headgroup mobility, determined using time-dependent fluorescence shifts of Laurdan located at the bilayer carbonyl level, on the content of cationic lipid is preserved in all examined salt solutions. Its maximum, however, is shifted towards higher DOTAP concentrations in the row: NaF < NaCl < NaBr. The same ordering of salts is found for the simulated area per lipid and the measured rigidification of pure DOTAP bilayers. Simulations reveal that Br strongly binds to the cationic headgroups of DOTAP neutralising the bilayer, which induces lateral inhomogeneities in the form of hydrophilic and hydrophobic patches at the membrane-water interface for pure DOTAP. In the equimolar DOPC/DOTAP mixture the neutralising effect of Br results in bending of the PC headgroups to a bilayer-parallel orientation. F-, while attracted to the DOTAP bilayer, has an opposite effect to that of Br-, i.e. it increases local mobility at the lipid carbonyl level. We attribute this effect to the disruption of the hydrogen-bonded structure of the molecules of lipids and water caused by the presence of the adsorbed F-. PMID- 23795510 TI - Ion specific effects of alkali cations on the catalytic activity of HIV-1 protease. AB - Human immunodeficiency virus 1 protease (HIV-1 PR), an important therapeutic target for the treatment of AIDS, is one of the most well-studied enzymes. However, there is still much to learn about the regulation of the activity and inhibition of this key viral enzyme. Specifically, the mechanism of activation of HIV-1 PR from the viral polyprotein upon HIV maturation is still not understood. It has been suggested that external factors like pH or salt concentration might contribute to regulation of this crucial step in the viral life cycle. Recently, we analyzed the activity of HIV-1 PR in aqueous solutions of sodium and potassium chloride by experimental determination of enzyme kinetics and molecular dynamics simulations. We showed that the effect of salt concentration is cation-specific [Heyda et al., Phys. Chem. Chem. Phys., 2009 (11), 7599]. In this study, we extended this analysis for other alkali cations and found that the dependence of the initial velocity of peptide substrate hydrolysis on the nature of the cation follows the Hofmeister series, with the exception of caesium. Significantly higher catalytic efficiencies both in terms of substrate binding (K(M)) and turnover number (kcat) are observed in the presence of K+ compared to Na+ or Li+ at corresponding salt concentrations. Molecular dynamics simulations suggest that both lithium and sodium are attracted more strongly than potassium and caesium to the protein surface, mostly due to stronger interactions with carboxylate side chain groups of aspartates and glutamates. Furthermore, we observed a surprising decrease in the K(M) value for a specific substrate at very low salt concentration. The molecular mechanism of this phenomenon will be further analyzed. PMID- 23795512 TI - Concluding remarks: Cum grano salis. AB - Hofmeister effects are part of a larger story--one in which the devil is perhaps in the details, but which promises to give us a much deeper understanding of how the solvent is a part of cell and molecular biology. PMID- 23795513 TI - Unnecessary for gentlemen. PMID- 23795511 TI - Dramatically stabilizing multiprotein complex structure in the absence of bulk water using tuned Hofmeister salts. AB - The role that water plays in the salt-based stabilization of proteins is central to our understanding of protein biophysics. Ion hydration and the ability of ions to alter water surface tension are typically invoked, along with direct ion protein binding, to describe Hofmeister stabilization phenomena observed for proteins experimentally, but the relative influence of these forces has been extraordinarily difficult to measure directly. Recently, we have used gas-phase measurements of proteins and large multiprotein complexes, using a combination of innovative ion mobility (IM) and mass spectrometry (MS) techniques, to assess the ability of bound cations and anions to stabilize protein ions in the absence of the solvation forces described above. Our previous work has studied a broad set of 12 anions bound to a range of proteins and protein complexes, and while primarily motivated by the analytical challenges surrounding the gas-phase measurement of solution-phase relevant protein structures, our work has also lead to a detailed physical mechanism of anion-protein complex stabilization in the absence of bulk solvent. Our more-recent work has screened a similarly-broad set of cations for their ability to stabilize gas-phase protein structure, and we have discovered surprising differences between the operative mechanisms for cations and anions in gas-phase protein stabilization. In both cases, cations and anions affect protein stabilization in the absence of solvent in a manner that is generally reversed relative to their ability to stabilize the same proteins in solution. In addition, our evidence suggests that the relative solution-phase binding affinity of the anions and cations studied here is preserved in our gas phase measurements, allowing us to study the influence of such interactions in detail. In this report, we collect and summarize such gas-phase measurements to distill a generalized picture of salt-based protein stabilization in the absence of bulk water. Further, we communicate our most recent efforts to study the combined effects of stabilizing cations and anions on gas-phase proteins, and identify those salts that bear anion/cation pairs having the strongest stabilizing influence on protein structures PMID- 23795515 TI - Prevention is key. PMID- 23795514 TI - ARTiculating concerns about interim therapeutic restorations. PMID- 23795516 TI - Cheating one and all. PMID- 23795517 TI - Oral medicine update: oral cancer--screening, lesions and related infections. PMID- 23795518 TI - Standard examination and adjunctive techniques for detection of oral premalignant and malignant lesions. AB - This article outlines how to perform a standard comprehensive extraoral and intraoral examination and the existing commercially available adjunctive techniques for the early detection of oral cancer and premalignant lesions. Visualization-based techniques (e.g., autofluorescence and chemiluminescence), toluidine blue vital staining, cytopathologic tests and high-risk human papillomavirus testing are discussed in detail, including the indications and protocols for use, their advantages and disadvantages and clinical cases. PMID- 23795519 TI - Diagnosis and management of mucosal lesions with the potential for malignant transformation. AB - Squamous cell carcinoma is the most common oral cancer of the head and neck region. Up to 50 percent of these cancers have spread by the time of diagnosis; therefore, early diagnosis is vital. Oral lichen planus and epithelial dysplasia are two of the most common types of oral lesions with the potential for malignant transformation. The epidemiology and management of these conditions are discussed in this review. PMID- 23795520 TI - Human papillomavirus: the fundamentals of HPV for oral health care providers. AB - Human papillomavirus (HPV) has become widely known as the causative agent of cervical cancer and some oropharyngeal cancers. The development of HPV vaccines has further piqued public interest. As a result, dentists will have increasing numbers of patients who will inquire about oral HPV infection and its prevention by means of vaccination. Dental professionals must be informed.This review provides an overview of HPV, its association with HIV and oropharyngeal cancer and information on HPVvaccinations. PMID- 23795521 TI - Savoring the service agreement. PMID- 23795522 TI - Economic lessons in the land of plenty. PMID- 23795523 TI - In adults (ages 20 - 50) with gastroesophageal reflux disease taking a proton pump inhibitor daily who present with new onset headache, are there common co morbid conditions? PMID- 23795524 TI - Screening for substance abuse in pregnancy. AB - Several states have proposed laws that urine drug screening be performed as a part of qualifying for public assistance. At least one state (Florida) has passed such a law, and several other states are considering similar laws. The Oklahoma Commission on Children and Youth created a committee to study laws and policies regarding the use of illegal drugs while pregnant. To get a better understanding of drug screening and pregnancy, 151 consecutive obstetrical patients receiving Medicaid were screened at their initial obstetrical visit by verbal and written questionnaire's concerning the use of alcohol, nicotine, and other illicit?dangerous drugs; in addition a urine drug screen for the use of illicit or dangerous drugs was performed. The patient histories regarding the use of dangerous or illicit substances was reviewed and compared with the urine drug screens performed at the same visit. The authors note that when studied the incidence of substance abuse has been similar in patient population receiving public assistance and patient populations with traditional insurance. Oklahoma is one of 13 states with laws requiring mandatory reporting of substance abuse in pregnancy or the exposure of the newborn to illicit substances. PMID- 23795525 TI - SoonerCare reflections. PMID- 23795526 TI - Dr. D. Robert McCaffree. PMID- 23795527 TI - Five things physicians and patients should question. PMID- 23795528 TI - Ethics and respect for each other. PMID- 23795529 TI - Clinical scholar: 2013. PMID- 23795530 TI - Decreasing infections, reducing falls, maximizing prevention, improving care: a formula for success for 6 hospitals earning ANA's award for nursing quality. PMID- 23795531 TI - Position statement--title: Medicaid expansion in Colorado. PMID- 23795532 TI - Dealing with domestic violence. PMID- 23795533 TI - RCN congress highlights emergency care pressures. PMID- 23795534 TI - Premature deaths of vulnerable people due to poor quality care. PMID- 23795535 TI - Staff should take opportunities to identify and help trafficking victims. PMID- 23795536 TI - Right place, right time. PMID- 23795537 TI - Caring for people who experience domestic abuse. AB - Domestic abuse can affect anyone and is recognised as a global problem that results in physical, psychological and economic harm. People who experience domestic violence often attend emergency departments after an incident, but many victims go unnoticed by healthcare professionals. This article identifies and discusses some of the challenges faced by emergency nurses in recognising and managing patients affected by domestic violence. It also discusses how addressing these challenges can improve identification of, and support for, those who have been affected. PMID- 23795538 TI - Development of a short-stay unit in an emergency department. AB - In 2009, the Royal Victoria Hospital, Belfast, established a nine-bed, short-stay unit in its emergency department. This article explains the rationale for the model of care delivery adopted, and the importance of developing and working with integrated care pathways. It also discusses four areas essential to the effective running of the unit: interdisciplinary collaboration, training for clinical nurse leaders, management of change and leadership. PMID- 23795539 TI - Diagnosing and managing invasive meningococcal disease in children. AB - In developed countries, invasive meningococcal disease (IMD) is a leading infectious cause of death among children. In the UK, Neisseria meningitidis serogroup B is the most frequently identified cause of IMD. This article describes a clinical audit in which early management of IMD is compared with recommendations in the relevant guidelines. It confirms the importance of early recognition of IMD and the need to review previous, less serious diagnoses in ill children. Emergency department nurses play a vital role in the early recognition and management of IMD. Introduction of a meningococcal B vaccine is likely to benefit children in the UK. PMID- 23795540 TI - Expert advice. PMID- 23795541 TI - Our duty is to promote health. PMID- 23795542 TI - Marathon MMR vaccination takes place across the UK. PMID- 23795543 TI - Children seen but not heard in healthcare development. PMID- 23795544 TI - Fewer young people using or being offered drugs and alcohol. PMID- 23795545 TI - Support of a child after brain tumour diagnosis. AB - 'Sam' was a six-year-old boy with medulloblastoma causing obstructive hydrocephalus and ataxia. Surgery, rehabilitation and possible long-term disability or neurological deficit were prepared for thoroughly by Sam and his family with the help of a multidisciplinary team. Full resection was successful but was followed by posterior fossa syndrome. His parents, who were under great stress throughout, were encouraged to communicate their concerns in a designated environment and to assist in their child's rehabilitation. A care plan ensured that they were involved with, but not overwhelmed by, his needs and the long-term prognosis. PMID- 23795546 TI - Needs and priorities of young people with human immunodeficiency virus. AB - AIMS: To ascertain the views of young people in the UK with human immunodeficiency virus (HIV) about their health care, and to compare these views with the perceptions of nurses involved in this sector and the current social policy response. METHODS: Young people, aged 16 to 24 years, who have HIV and attend a specialist voluntary organisation and pre- and post-registration nurses attending an HIV care course were selected by convenience sampling. A cross sectional survey was conducted by questionnaire. RESULTS: Hospital-based HIV clinics and services were the favoured source of care. There was consensus among the young people that care providers should be informative and approachable, and that care provision should include help to understand issues, such as pregnancy and contraception. CONCLUSIONS: Professionals involved in creating future social policy and commissioning services need to respond to young people's priorities and adapt to the patient's developing sexuality and the changing demographics of young people with HIV. PMID- 23795547 TI - An overview of surgical stoma construction and its effects on the child and their family. AB - Having a stoma can be a difficult adjustment for the child or young person and his or her family. Children's stoma nurses provide support and education to the family at this time to help them come to terms with the changes this requires. This article discusses the different types of stoma, why a stoma might be needed, how the children's stoma nurse can help prepare the child or young person and his or her family for having a stoma, the practical aspects of stoma care and possible complications that might be experienced and how to manage them. PMID- 23795548 TI - Always move forward. PMID- 23795549 TI - Room temperature magnetism in layered double hydroxides due to magnetic nanoparticles. AB - Some recent reports claiming room temperature spontaneous magnetization in layered double hydroxides (LDHs) have been published; however, the reported materials cause serious concern as to whether this cooperative magnetic behavior comes from extrinsic sources, such as spinel iron oxide nanoparticles. The syntheses of crystalline Fe(3+)-based LDHs with and without impurities have been developed, highlighting the care that must be taken during the synthetic process in order to avoid misidentification of magnetic LDHs. PMID- 23795550 TI - DNA computation in mammalian cells: microRNA logic operations. AB - DNA computation can utilize logic gates as modules to create molecular computers with biological inputs. Modular circuits that recognize nucleic acid inputs through strand hybridization activate computation cascades to produce controlled outputs. This allows for the construction of synthetic circuits that can be interfaced with cellular environments. We have engineered oligonucleotide AND gates to respond to specific microRNA (miRNA) inputs in live mammalian cells. Both single and dual-sensing miRNA-based computation devices were synthesized for the cell-specific identification of endogenous miR-21 and miR-122. A logic gate response was observed with miRNA expression regulators, exhibiting molecular recognition of miRNA profile changes. Nucleic acid logic gates that are functional in a cellular environment and recognize endogenous inputs significantly expand the potential of DNA computation to monitor, image, and respond to cell-specific markers. PMID- 23795551 TI - Deep architectures and deep learning in chemoinformatics: the prediction of aqueous solubility for drug-like molecules. AB - Shallow machine learning methods have been applied to chemoinformatics problems with some success. As more data becomes available and more complex problems are tackled, deep machine learning methods may also become useful. Here, we present a brief overview of deep learning methods and show in particular how recursive neural network approaches can be applied to the problem of predicting molecular properties. However, molecules are typically described by undirected cyclic graphs, while recursive approaches typically use directed acyclic graphs. Thus, we develop methods to address this discrepancy, essentially by considering an ensemble of recursive neural networks associated with all possible vertex centered acyclic orientations of the molecular graph. One advantage of this approach is that it relies only minimally on the identification of suitable molecular descriptors because suitable representations are learned automatically from the data. Several variants of this approach are applied to the problem of predicting aqueous solubility and tested on four benchmark data sets. Experimental results show that the performance of the deep learning methods matches or exceeds the performance of other state-of-the-art methods according to several evaluation metrics and expose the fundamental limitations arising from training sets that are too small or too noisy. A Web-based predictor, AquaSol, is available online through the ChemDB portal ( cdb.ics.uci.edu ) together with additional material. PMID- 23795552 TI - Intersensory redundancy hinders face discrimination in preschool children: evidence for visual facilitation. AB - Although infants and children show impressive face-processing skills, little research has focused on the conditions that facilitate versus impair face perception. According to the intersensory redundancy hypothesis (IRH), face discrimination, which relies on detection of visual featural information, should be impaired in the context of intersensory redundancy provided by audiovisual speech and enhanced when intersensory redundancy is absent. Evidence of this visual facilitation and intersensory interference was found in a recent study of 2-month-old infants (Bahrick, Lickliter, & Castellanos, in press). The present study is the first to extend tests of this principle of the IRH to children. Using a more difficult face recognition task in the context of a story, results from 4-year-old children paralleled those of infants and demonstrate that face discrimination in children is also facilitated by dynamic, visual-only exposure, in the absence of intersensory redundancy. PMID- 23795553 TI - Strategy repetition in young and older adults: a study in arithmetic. AB - We investigated a new phenomenon that sheds light on age-related differences in strategy selection: the strategy repetition phenomenon (i.e., tendency to repeat the same strategy over consecutive items). Young and older adults had to provide the best estimates of multiplication problems like 47 * 86. They had to select the best of 2 rounding strategies on each problem, the rounding-down strategy (i.e., doing 40 * 80 = 3,200) or the rounding-up strategy (i.e., doing 50 * 90 = 4,500). Data showed that both young and older adults repeated the same strategy over consecutive problems more often than chance and repeated strategies more often in the 2-prime condition (i.e., after executing one strategy to solve the 2 immediately preceding problems) than in the 1-prime condition (i.e., after executing a strategy on one immediately preceding problem). Moreover, this strategy repetition phenomenon increased with age, especially in the most difficult condition (e.g., when participants solved rounding-up problems in the 2 prime condition). Our findings have important theoretical and empirical implications for computational models of strategy selection and for furthering our understanding of strategic development during adulthood. PMID- 23795554 TI - The construction of moral agency in mother-child conversations about helping and hurting across childhood and adolescence. AB - This study examined mother-child conversations about children's and adolescents' past harmful and helpful actions. The sample included 100 mothers and their 7-, 11-, or 16-year-old children; each dyad discussed events when the child (a) helped a friend and (b) hurt a friend. Analyses suggested that conversations about help may serve to facilitate children's sense of themselves as prosocial moral agents; mothers focused on children's feelings of pride, positive judgments of the child's behavior, and positive insights about the child's characteristics that could be drawn from the event. In turn, conversations about harm were more elaborated and contentious than those about help, and reflected more complex maternal goals; although mothers highlighted children's wrongdoing (e.g., by noting negative consequences of the child's actions for others), they also engaged in a variety of strategies that may support children's ability to reconcile their harmful actions with a positive self-view (e.g., by noting what children did do well or their capacity for repair). With respect to age effects, results revealed that older children played an increasingly active and spontaneous role in discussions. Furthermore, as compared with 7-year-olds, conversations with 11- and 16-year-olds focused more on psychological insights that could be drawn from experiences and less on children's concrete harmful and helpful actions. Overall, results illuminate the processes whereby conversations with mothers may further children's developing understandings of their own and others' moral agency, and how discussions of prosocial and transgressive moral experiences may provide distinct but complementary opportunities for moral socialization. PMID- 23795556 TI - Colorimetric detection of Co2+ ion using silver nanoparticles with spherical, plate, and rod shapes. AB - A highly sensitive colorimetric sensing platform for the selective trace analysis for Co(2+) ions is reported, based on glutathione (GSH)-modified silver nanoparticles (AgNP). The shape of metallic nanoparticles used in colorimetric detection, using the unique optical properties of plasmonic nanoparticles, is almost spherical. Therefore, in this work we attempted to investigate the selective detection of heavy metal ion (Co(2+)), with the shape of AgNPs (nanosphere, nanoplate, and nanorod). GSH-AgNP with spherical shape shows a high sensitivity for all of the metal ions (Ni(2+), Co(2+), Cd(2+), Pb(2+), and As(3+)) but poor selective recognition for target metal ions. Whereas, AgNPs solution containing rod-type GSH-AgNP has a special response to Co(2+), and its selective detection might be based on the cooperative effect of CTAB and GSH. Therefore, Co(2+) ion could be selectively recognized using rod-type GSH-AgNPs. PMID- 23795555 TI - The indirect effects of maternal emotion socialization on friendship quality in middle childhood. AB - Emotion development processes have long been linked to social competence in early childhood but rarely have these associations been examined in middle childhood or with relational outcomes. Guided by theories of interpersonal relationships and emotion socialization, the current study was designed to fill these gaps by examining a longitudinal process model indirectly linking emotion development to friendship quality. Data were drawn from 336 children (179 girls, 65% White), their mothers, and their teachers across 3 time points spanning the ages of 5-10 years. A path analysis model was utilized to examine the way in which maternal emotion socialization indirectly affects children's friendship quality. Results supported the hypothesized model in which maternal emotion socialization strategies used when children were age 5 were associated with changes in friendship quality from ages 7 to 10 via changes in children's emotion regulation. Findings highlight the importance of emotional processes for relational outcomes in middle childhood. PMID- 23795557 TI - Kinetic manipulation of silicide phase formation in Si nanowire templates. AB - The phase formation sequence of silicides in two-dimensional (2-D) structures has been well-investigated due to their significance in microelectronics. Applying high-quality silicides as contacts in nanoscale silicon (Si) devices has caught considerable attention recently for their potential in improving and introducing new functions in nanodevices. However, nucleation and diffusion mechanisms are found to be very different in one-dimensional (1-D) nanostructures, and thus the phase manipulation of silicides is yet to be achieved there. In this work, we report kinetic phase modulations to selectively enhance or hinder the growth rates of targeted nickel (Ni) silicides in a Si nanowire (NW) and demonstrate that Ni31Si12, delta-Ni2Si, theta-Ni2Si, NiSi, and NiSi2 can emerge as the first contacting phase at the silicide/Si interface through these modulations. First, the growth rates of silicides are selectively tuned through template structure modifications. It is demonstrated that the growth rate of diffusion limited phases can be enhanced in a porous Si NW due to a short diffusion path, which suppresses the formation of interface limited NiSi2. In addition, we show that a confining thick shell can be applied around the Si NW to hinder the growth of the silicides with large volume expansion during silicidation, including Ni31Si12, delta-Ni2Si, and theta-Ni2Si. Second, a platinum (Pt) interlayer between the Ni source and the Si NW is shown to effectively suppress the formation of the phases with low Pt solubility, including the dominating NiSi2. Lastly, we show that with the combined applications of the above-mentioned approaches, the lowest resistive NiSi phase can form as the first phase in a solid NW with a Pt interlayer to suppress NiSi2 and a thick shell to hinder Ni31Si12, delta-Ni2Si, and theta-Ni2Si simultaneously. The resistivity and maximum current density of NiSi agree reasonably to reported values. PMID- 23795558 TI - Preparation of anti-vicinal amino alcohols: asymmetric synthesis of D-erythro sphinganine, (+)-spisulosine, and D-ribo-phytosphingosine. AB - Two variations of the Overman rearrangement have been developed for the highly selective synthesis of anti-vicinal amino alcohol natural products. A MOM ether directed palladium(II)-catalyzed rearrangement of an allylic trichloroacetimidate was used as the key step for the preparation of the protein kinase C inhibitor D erythro-sphinganine and the antitumor agent (+)-spisulosine, whereas the Overman rearrangement of chiral allylic trichloroacetimidates generated by the asymmetric reduction of an alpha,beta-unsaturated methyl ketone allowed rapid access both to D-ribo-phytosphingosine and L-arabino-phytosphingosine. PMID- 23795560 TI - Caveats for causal interpretations of linear regression coefficients for fine particulate (PM2.5) air pollution health effects. AB - Recent linear regression analyses have concluded that decreasing levels of fine particulate matter (PM2.5) air pollution have increased life expectancy in the United States. These findings have left unresolved questions about the causal relation between reductions in PM2.5 levels and changes in cause-specific (especially, cardiovascular disease, CVD) mortality risks. Their robustness (e.g., sensitivity to deletion of a single data point) has also been questioned. We investigate these issues in the National Mortality and Morbidity Air Pollution Study database. Comparing changes in PM2.5 levels and cause-specific mortality rates for elderly people in 24 cities between two periods separated by a decade (1987-1989 and 1999-2000) shows that reductions in PM2.5 were significantly associated with increases in respiratory mortality rates and with decreases in CVD mortality rates. CVD and all-cause mortality risks fell equally for all months of the year over this period, but average PM2.5 levels increased significantly for winter months. This casts doubts on the causal interpretation that declines in PM2.5 over the decade caused reduced short-term mortality risks. Nonlinear regression suggests that reduced or negative marginal health benefits are associated with reductions of PM2.5 below 1999-2000 levels (about 15 MUg/m(3)). Such nonlinear relations imply that risk communication statements that project a constant incremental reduction in mortality risks per unit reduction in PM2.5 do not adequately reflect the realistic possibility of nonlinear exposure response relations and diminishing returns to further exposure reductions. PMID- 23795559 TI - Active-site inhibitors modulate the dynamic properties of human monoacylglycerol lipase: a hydrogen exchange mass spectrometry study. AB - Human monoacylglycerol lipase (hMGL) regulates endocannabinoid signaling primarily by deactivating the lipid messenger 2-arachidonoylglycerol. Agents that carbamylate hMGLs catalytic Ser(122) constitute a leading class of therapeutically promising hMGL inhibitors. We have applied peptide-level hydrogen/deuterium exchange mass spectrometry to characterize hMGL's conformational responses to two potent carbamylating inhibitors, AM6580 (irreversible) and AM6701 (slowly reversible). A dynamic, solvent-exposed lid domain is characteristic of hMGL's solution conformation. Both hMGL inhibitors restricted backbone enzyme motility in the active-site region and increased substrate binding-pocket solvent exposure. Covalent reaction of AM6580 with hMGL generates a bulkier carbamylated Ser(122) residue as compared to the more discrete Ser(122) modification by AM6701, a difference reflected in AM6580's more pronounced effect upon hMGL conformation. We demonstrate that structurally distinct carbamylating hMGL inhibitors generate particular conformational ensembles characterized by region-specific hMGL dynamics. By demonstrating the distinctive influences of two hMGL inhibitors on enzyme conformation, this study furthers our understanding at the molecular level of the dynamic features of hMGL interaction with small-molecule ligands. PMID- 23795561 TI - The formulation of a nasal nanoemulsion zaleplon in situ gel for the treatment of insomnia. AB - BACKGROUND: Zaleplon is a drug used for the treatment of insomnia and is available in tablet form; however, it has two major problems. First, the drug undergoes extensive first pass metabolism, resulting in only 30% bioavailability, and second, the drug has a poor aqueous solubility, which delays the onset of action. OBJECTIVE: The objective of this study is to utilise nanotechnology to formulate zaleplon into a nasal in situ nanoemulsion gel (NEG) to provide a solution for the previously mentioned problems. METHODS: The solubility of zaleplon in various oils, surfactants and co-surfactants was estimated. Pseudo ternary phase diagrams were developed and various nanoemulsion (NE) formulations were prepared; these formulations were subjected to visual characterisation, thermodynamic stability study and droplet size and conductivity measurements. Carbopol 934 was used as an in situ gelling agent. The gel strength, pH, gelation time, in vitro release and ex vivo nasal permeation were determined. The pharmacokinetic study of the NEG was carried out in rabbits. RESULTS: Stable NEs were successfully developed with a droplet size range of 35 to 73 nm. A NEG composed of 15% Miglyol, 30% Labrasol and 10% PEG 200 successfully provided the maximum in vitro and ex vivo permeation and enhanced the bioavailability in the rabbits by eightfold, when compared with the marketed tablets. CONCLUSION: The nasal NEG is a promising novel formula for zaleplon that has higher nasal tissue permeability and enhanced systemic bioavailability. PMID- 23795562 TI - Towards universal salt iodisation in India: achievements, challenges and future actions. AB - India is one of the first countries to introduce salt iodisation, but the national programme has experienced major setbacks. The purpose of this paper is to review the national efforts towards universal salt iodisation (USI) in India and highlight key challenges in programme implementation. A brief historical overview of the salt iodisation programme is provided and the current status of the household usage of iodised salt and population iodine status is described. The present status of the USI programme together with the challenges being faced towards achieving USI are classified in five categories, which represent the five guiding principles crucial to sustained USI programme success: ensuring political commitment, forming partnerships and coalition, ensuring availability of adequately iodised salt, strengthening the monitoring system and maintaining continuous advocacy, education and communication. A future agenda towards the achievement of USI is also proposed. PMID- 23795563 TI - Clinical outcomes following percutaneous coronary intervention with drug-eluting stents versus bare metal stents in patients on chronic hemodialysis. AB - BACKGROUND: Patients on chronic hemodialysis (HD) are recognized as a high-risk group for adverse events after percutaneous coronary intervention, and whether drug-eluting stents (DES) are associated with improved outcomes over bare metal stents (BMS) is still uncertain. The purpose of this study was to assess the efficacy of DES compared with BMS at short- and long-term follow-up (FU) in an unselected sample of HD patients. METHODS AND RESULTS: In the time period 2005 2010, consecutive patients on chronic HD treated with percutaneous coronary intervention (PCI) and stent implantation were retrospectively selected and analyzed. A total of 169 patients were selected, 77 treated exclusively with BMS and 92 exclusively with DES. Baseline clinical characteristics were similar in the 2 groups as well as the number of treated vessels, treated lesions, and the stent per patient ratio. At longest available FU, no difference between the 2 study groups was found in terms of cardiac death (18.2% vs 16.3%, P=0.83), myocardial infarction (2.5% vs 8.6%, P=0.09), cerebrovascular accidents (0% vs 1.1%, P=0.98), and target vessel revascularization (TVR) (9.1% vs 16.3%, P=0.17). Major adverse cardiac and cerebrovascular events-free survival at 1,500 days in the BMS and DES groups was 57.6% and 50.9% (P=0.11), respectively. CONCLUSIONS: PCI in patients on chronic HD treatment is associated with a high incidence of adverse events at FU, mainly represented by death. In our study, the use of DES was not associated with a reduction of target lesion revascularization (TLR) and TVR. PMID- 23795564 TI - MicroRNAs and bacterial infection. AB - MicroRNAs, small non-coding RNAs expressed by eukaryotic cells, play pivotal roles in shaping cell differentiation and organism development. Deregulated microRNA expression is associated with several types of diseases including cancers, immune disorders and infection. Acting at the post-transcriptional level, miRNAs have expanded our understanding of the control of gene expression in regulatory networks involved in the adaptation to environmental situations such as biotic stress. It is increasingly clear that miRNAs are an important part of the host response to microbes. This review presents the current state of knowledge about the role of miRNAs in the response to both bacterial pathogens and commensal bacteria in human cells or animal experimental models. Some microRNAs, including miR-146, miR-155, miR-125, let-7 and miR-21, are commonly affected during bacterial infection and contribute to immune responses protecting the organism against overwhelmed inflammation. Cell-specific relationships between miRNAs and their targets are also engaged in the alterations induced by virulent bacteria in the proliferation/differentiation/apoptosis pathways of their host cells. In a separate role, miRNA modulation also represents a mechanism through which commensal bacteria impact the regulation of the barrier function and intestinal homeostasis. PMID- 23795565 TI - Four new sesquiterpenoids from cultures of the fungus Funalia trogii. AB - Four new drimane sesquiterpenoids, named as funatrols A-D, together with isodrimenediol, were isolated from cultures of the fungus Funalia trogii. The new structures were elucidated by means of spectroscopic methods. All compounds were tested for their cytotoxicities against five human cancer cell lines. PMID- 23795566 TI - Elevated mean neutrophil volume+CRP is a highly sensitive and specific predictor of neonatal sepsis. PMID- 23795567 TI - Modeling spatial correlation of DNA deformation: DNA allostery in protein binding. AB - We report a study of DNA deformations using a coarse-grained mechanical model and quantitatively interpret the allosteric effects in protein-DNA binding affinity. A recent single-molecule study (Kim et al. Science 2013, 339, 816) showed that when a DNA molecule is deformed by specific binding of a protein, the binding affinity of a second protein separated from the first protein is altered. Experimental observations together with molecular dynamics simulations suggested that the origin of the DNA allostery is related to the observed deformation of DNA's structure, in particular, the major groove width. To unveil and quantify the underlying mechanism for the observed major groove deformation behavior related to the DNA allostery, here we provide a simple but effective analytical model where DNA deformations upon protein binding are analyzed and spatial correlations of local deformations along the DNA are examined. The deformation of the DNA base orientations, which directly affect the major groove width, is found in both an analytical derivation and coarse-grained Monte Carlo simulations. This deformation oscillates with a period of 10 base pairs with an amplitude decaying exponentially from the binding site with a decay length lD ~10 base pairs as a result of the balance between two competing terms in DNA base-stacking energy. This length scale is in agreement with that reported from the single-molecule experiment. Our model can be reduced to the worm-like chain form at length scales larger than lP but is able to explain DNA's mechanical properties on shorter length scales, in particular, the DNA allostery of protein-DNA interactions. PMID- 23795568 TI - Epidemiology of basal cell carcinoma in Lithuania, 1996-2010. AB - BACKGROUND: Nonmelanoma skin cancer is the most common cancer among the white population. OBJECTIVES: To describe the epidemiology of basal cell carcinoma (BCC) in Lithuania by analysing population-based incidence, with special emphasis on sex- and subsite-specific changes over time. METHODS: Data from the Lithuanian Cancer Registry for the period 1996-2010 were used to analyse trends in the incidence rates for BCC. Only the first case of BCC per patient was included in this analysis. Age-standardized rates were calculated for both sexes. Standardization was performed using the direct method (European standard population). RESULTS: Since 1996, overall BCC incidence rates have increased from 27.4 to 46.0 cases per 100,000 in Lithuania. In 1996, the incidence of BCC was higher among women than men (28.2 vs. 27.6 per 100,000, respectively). Incidence of BCC during the study period increased faster among men than among women (by 3.3% and 2.6% per year, respectively), while the incidence among both sexes in 2010 became almost equal -46.4 among men and 47.4 among women per 100,000. The head and neck was the most common site of BCCs for both sexes (31.0 and 32.9 per 100,000 among men and women, respectively). CONCLUSIONS: The incidence of BCC in Lithuania is lower than that reported in Northern and Western Europe. The population-based data for BCC from Lithuania are closely comparable, with regard to age, tumour localization and place of residence, with the existing literature from other European cancer registries. PMID- 23795569 TI - Signal detection theory approach to gastroesophageal reflux disease: a new method for symptom analysis of impedance-pH data. AB - An accurate reflux-symptom relationship analysis method is an unmet need in gastroesophageal reflux disease (GERD) diagnosis. The aim of this study was to adapt signal detection theory (SDT) approach to reflux-symptom relationship analysis to develop a new diagnosis method. Patients with predominant symptoms of heartburn and regurgitation were enrolled. Proton pump inhibitor (PPI)-responsive and PPI-unresponsive groups were created via interview and PPI trial. Patients then underwent stationary esophageal manometry and 24-hour multichannel intraluminal impedance-pH monitoring. SDT measurement parameters (discriminability: d' and criterion: c) were calculated using empirically selected time windows (0.5, 1, 2, 3, 4 and 5 minutes). The time window that provided the highest d' value was selected as the optimal time window. A cut-off d' value that optimally separates two groups was found using receiver operating characteristics analysis. Sixty-three patients completed the study (45 PPI responsive). Optimal time window and cut-off d' value were found as 1 and 0.767 minute, respectively. Symptom association probability (SAP) index values showed good correlation (rS = 0.7182, P < 0.0001) with d' values. SDT approach to reflux symptom relationship analysis showed sensitivity (89% vs. 78%) and negative predictive values (75% vs. 60%) favorable over SAP index analysis. SDT approach using 1-minute time window and 0.767 cut-off d' value provides us a new and more accurate measure of reflux-symptom relationship than SAP index analysis. PMID- 23795570 TI - Role of Etv2-positive cells in the remodeling morphogenesis during vascular development. AB - Etv2 is a critical determinant for the commitment of endothelial (EC) and hematopoietic (HPC) cells from mesoderm. Etv2 is assumed to be transiently required for EC commitment but dispensable after most ECs differentiate around E9.5. To confirm the time window of Etv2 requirement, Etv2 was ablated at different time points using ROSA26CreER mice. Unexpectedly, Etv2 ablation at E9.5 caused vascular remodeling defects in cranial and yolk sac vasculature. Immunostaining showed that Etv2+/VE-cadherin (VECAD)- cells were present around forming vasculature, mostly co-expressing Flk-1 with a small number of Etv2+/VECAD+ cells, indicating that Etv2+/Flk-1+/VECAD- cells are the major Etv2+ population promoting vascular remodeling around E9.5. Gene expression analysis showed up-regulation of Fgf proteins, Il-6, Glypican-3 and matrix metalloproteases in Etv2+/VEDAC- cells over Etv2-/VECAD+ mature ECs. Blockade of those factors caused reduced EC sprouting in ex vivo explant culture from E9.5 embryos, suggesting the functional significance of environmental factors derived from Etv2+ cells. Altogether, we propose that Etv2+/VEDAC- cells around E9.5 E10.5 provide extracellular factors to complete vascular morphogenesis in addition to becoming differentiated ECs incorporated into vessels. This insight for the new role of Ets protein in perivascular Flk-1+/VECAD-/(Etv2+) cells to induce expression of angiogenic factors may provide another strategy to control angiogenesis. PMID- 23795571 TI - Antimicrobial stewardship. PMID- 23795572 TI - Antimicrobial stewardship: impact and challenges. PMID- 23795573 TI - A nationwide survey of antimicrobial stewardship practices. AB - OBJECTIVE: The goal of this study was to characterize hospital antimicrobial stewardship practices nationwide and to identify factors associated with the presence of these programs. METHODS: The first web-based survey was sent in 2009 to members of the Yankee Alliance and the Premier Healthcare Alliance, nationwide organizations of health-care providers. The second survey, a slightly modified version of the first, was sent in 2010 to a commercially purchased list of hospital pharmacy director e-mail addresses. RESULTS: A total of 406 responses were received from ~5890 providers targeted, for an overall response rate of ~7%. More than one half (206 of 406) of the respondents reported having what they considered to be a formal antimicrobial stewardship program (ASP). Among all respondents regardless of presence or absence of an ASP, 96.4% (351 of 364) were using some form of antimicrobial stewardship technique. Of those respondents working in hospitals without an ASP, 63.3% (114 of 180) had considered implementing one. After controlling for all significant variables, those that remained which were significantly associated with having an ASP were survey (Premier vs commercial), having an infectious disease consultation service, and having an infectious disease pharmacist. CONCLUSIONS: In this survey of 406 respondents from across the country, we found that just more than one half of hospitals had what they considered to be formal ASPs; however, the vast majority were using stewardship techniques to optimize the use of antibiotics. Common barriers to implementation of ASPs included staffing constraints and insufficient funding. PMID- 23795574 TI - When pharmacodynamics trump costs: an antimicrobial stewardship program's approach to selecting optimal antimicrobial agents. AB - BACKGROUND: Treatment of Pseudomonas aeruginosa infections is increasingly challenging because of escalating resistance. Antimicrobial stewardship programs provide guidance for clinicians regarding use of the most appropriate antimicrobial at the right dose, duration, and route in addition to being cost effective. Optimizing antimicrobial therapy by using pharmacokinetic/pharmacodynamic principles such as extending time above the MIC is 1 stewardship strategy to reduce antimicrobial resistance. OBJECTIVE: The goal of this study was to evaluate our current dosing strategy for cefepime and the formulary carbapenem (imipenem) compared with meropenem and doripenem to determine the best dosing strategy for achieving maximal pharmacodynamic activity against an institution-specific population of P aeruginosa isolates. METHODS: Consecutive, nonduplicate, blood (n = 39) or bronchial alveolar lavage (n = 25) isolates of P aeruginosa from adult, hospitalized (2009-2010) critically ill patients underwent MIC testing by using broth microdilution. A pharmacokinetic model was developed and used with Monte Carlo simulation to evaluate the ability of imipenem, meropenem, doripenem, and cefepime to achieve optimal bactericidal activity as varying doses infused over standard infusions (SIs; 0.5-1 hour) or prolonged infusions (PIs; 3-4 hours). A regimen was defined as optimal if the cumulative fraction response (CFR) was >=90%. RESULTS: None of the imipenem regimens modeled as SI or PI achieved a CFR >=90%. Meropenem at 1 to 2 g q8h PI achieved a CFR >=90%. Doripenem 0.5, 1, or 2 g q8h PI achieved a CFR >=90%. The only cefepime regimen that achieved a CFR >=90% was 2 g q8h PI. Overall susceptibility rates to P aeruginosa were highest with cefepime (91%), followed by meropenem (83%), doripenem (78%), and imipenem (72%). Our antimicrobial stewardship programs recommended switching from imipenem to doripenem 0.5g q8h PI, which was 36% more costly in drug acquisition costs. Cefepime dosing was increased from 2 g q12h SI to 2 g q8h PI, a 52% increase in drug acquisition cost. CONCLUSIONS: Antimicrobial stewardship programs should consider pharmacodynamic modeling to select the optimal dosing strategies to guide therapy in an era of escalating antimicrobial resistance. Using the percent susceptibility alone can be misleading and ultimately the most expensive if the patient fails to respond. PMID- 23795575 TI - A stewardship program's retrospective evaluation of vancomycin AUC24/MIC and time to microbiological clearance in patients with methicillin-resistant Staphylococcus aureus bacteremia and osteomyelitis. AB - BACKGROUND: Current guidelines for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia recommend targeting a vancomycin AUC24/MIC >=400. Data on the association between AUC24/MIC and microbiological clearance in patients with concomitant MRSA bacteremia and MRSA osteomyelitis are limited. OBJECTIVE: The objective of this study is to evaluate the association between the vancomycin AUC24/MIC and time to microbiological clearance in patients with concomitant MRSA bacteremia and MRSA osteomyelitis. METHODS: Adult inpatients with concomitant MRSA bacteremia and MRSA osteomyelitis treated with vancomycin from January 1, 2007, through December 31, 2011, were evaluated. Classification and regression tree analysis was used to identify the AUC24/MIC associated with time to microbiological clearance. RESULTS: Fifty-nine patients had complete data available for review and were included in the analysis. Classification and regression tree analysis identified an AUC/MIC of 293 as the breakpoint that provides the greatest difference in time to microbiological clearance. On univariate analysis, mean (SD) time to clearance was 2 days shorter when the AUC/MIC was >293 (4 [2] days vs 6 [3] days, P = 0.01). Mean (SD) infection-related length of stay was 13 (6) versus 18 (14) days in patients with an AUC24/MIC ratio >293 or <=293, respectively (P = 0.25). In patients with an AUC24/MIC <=293, 39% versus 17% (P = 0.09) had recurrent bacteremia and were readmitted compared with patients with an AUC/MIC >293. Only 9% were able to achieve an AUC24/MIC >293 when the vancomycin MIC was >1 MUg/mL. CONCLUSIONS: We observed a >2.5-fold increase in time to microbiological clearance in patients with concomitant MRSA bacteremia and MRSA osteomyelitis unable to achieve a vancomycin AUC24/MIC >293. A 5-day increase in hospital and infection-related length of stay was observed when this target was not achieved. Recurrence of bacteremia and hospital readmissions were higher in the cohort who did not achieve an AUC24/MIC >293. Only 9% of patients were able to achieve an AUC24/MIC >293 if the isolate MIC was >1 MUg/mL. Trough concentration did not correlate with AUC24/MIC. In patients with concomitant MRSA bacteremia and MRSA osteomyelitis treated with vancomycin, stewardship programs should optimize pharmacodynamic parameters, specifically AUC24/MIC, or alternative therapies should be considered. PMID- 23795576 TI - Pharmacokinetic interactions of valsartan and hydrochlorothiazide: an open-label, randomized, 4-period crossover study in healthy Egyptian male volunteers. AB - BACKGROUND: Co-administration of valsartan (VAL) and hydrochlorothiazide (HCT) has been used to regulate blood pressure. Compliance with a multiple medication regimen can be difficult for some patients; therefore, a combination of VAL + HCT tablets may be a suitable alternative. OBJECTIVE: This study was conducted to compare the rate and extent of absorption of VAL and HCT after oral administration as a fixed-dose combination (FDC) tablet and concomitant administration of the individual drugs under fasting conditions in healthy Egyptian subjects. The study was extended to investigate any potential interaction between VAL and HCT. METHODS: This study was conducted as an open label, randomized study with 2 parts (parts I and II), with each part consisting of 4 single-dose treatment periods with a crossover design and 2-week washout periods. Blood samples were collected up to 48 hours postdose, and plasma was analyzed for VAL and HCT concentrations by using HPLC. The pharmacokinetic properties of each drug after co-administration of VAL and HCT were compared with those of each drug administered alone. Tolerability was assessed by physical examination and verbally questioning subjects regarding their well-being and any feelings of discomfort. All events reported by the subjects were recorded in adverse-event forms. RESULTS: Forty-eight healthy subjects were enrolled (24 in each part), and all subjects completed the study. None of the participants showed any sign of adverse drug reactions during or after the completion of the study. Statistical analysis confirmed that the 90% CIs for AUC and Cmax of VAL/HCT FDC and VAL + HCT were within the commonly accepted bioequivalence range of 0.8 to 1.25. As a result, from an in vivo pharmacokinetic perspective, 1 FDC tablet could be considered interchangeable in medical practice with the 2 individual reference tablets. However, the 90% CIs between VAL alone and when administered with HCT, either as FDC or concomitantly, indicated the presence of an interaction between VAL and HCT, which would significantly decrease the systemic exposure and intensity of VAL absorption. The co-administration of HCT with VAL decreased the AUC and Cmax of HCT nonsignificantly compared with administration of HCT alone. CONCLUSIONS: Both VAL/HCT FDC and VAL + HCT were well tolerated. The safety/efficacy profile of VAL + HCT co-administration therapy could be extended to the VAL/HCT FDC tablet. The interaction of HCT with other angiotensin receptor blockers should be investigated to determine whether this interaction is limited to VAL or if other angiotensin-receptor blockers have the same pharmacokinetic interactions. Further studies are necessary to determine the role of efflux and influx transporters on VAL and HCT disposition and pharmacokinetics. PMID- 23795577 TI - Pharmacokinetic properties of once-daily oral low-dose mesylate salt of paroxetine (LDMP 7.5 mg) following single and multiple doses in healthy postmenopausal women. AB - BACKGROUND: Low-dose mesylate salt of paroxetine (LDMP 7.5 mg) is being investigated for the treatment of vasomotor symptoms associated with menopause. OBJECTIVE: This Phase I, open-label, single- and multiple-dose study evaluated the pharmacokinetic properties, safety and tolerability of LDMP in postmenopausal, nonsmoking women aged >=40 years. METHODS: After a 3-week screening period, subjects received LDMP 7.5-mg capsules as a single dose on day 1 and then as multiple doses (once daily for 14 days) on Days 6-19. Blood samples were collected predose and up to 120 hours postdose on day 1 (single-dose pharmacokinetic profile), at predose (after 12 doses) on day 18, and at predose and up to 24 hours postdose on day 19 (multiple-dose pharmacokinetic profile). Capsules were taken with 240 mL of water while subjects were fasted. Safety was evaluated throughout the study. RESULTS: Twenty-four women (mean age, 56 years) completed the study. On day 1, median Tmax was ~6 hours, and mean t1/2 was 17.30 hours. Mean plasma concentrations attained predose on days 18 and 19 (days 13 and 14 of multiple dosing) and at 24 hours postdose (day 20) were similar, suggesting that steady state was achieved by day 13 of multiple dosing after 12 daily doses. Mean AUC0-24 h at steady state (day 14 of multiple dosing) was ~3-fold greater than AUC0-infinity on day 1, indicating nonlinear pharmacokinetics. Mean Cmax on day 14 of multiple dosing was ~5-fold greater than that attained on day 1, and the accumulation index (AUCday 19/AUCday 1) at steady state was 9.71. Fluctuation index (calculated as [(Cmax - Cmin)/Cavg ss] * 100) was 75.8%. Most subjects (23/24 [95.8%]) experienced at least 1 treatment-emergent adverse event (AE); however, most AEs (67 events in 22/24 subjects [91.7%]) were mild, and the remainder were moderate. Seventeen subjects experienced 33 AEs that were deemed possibly or probably related to LDMP. No serious AEs were reported, and no clinically meaningful changes in laboratory values, vital signs, or ECGs were observed. CONCLUSIONS: On multiple dosing, LDMP exhibited nonlinear pharmacokinetics and was well tolerated in these healthy postmenopausal women; the extent of accumulation was consistent with data from the published literature. PMID- 23795578 TI - Association between smoking cessation and short-term health-care use: results from an international prospective cohort study (ATTEMPT). AB - BACKGROUND AND AIMS: Previous studies have found that smoking cessation is associated with a short-term increase in health-care use. This may be because 'sicker' smokers are more likely to stop smoking. The current study assessed the association between smoking cessation and health-care use, adjusting for pre cessation physical and mental health conditions. DESIGN/SETTING: Data came from the ATTEMPT cohort, a multi-national prospective survey of smokers in the United States, Canada, United Kingdom, France and Spain, that lasted 18 months (with follow-ups every 3 months). PARTICIPANTS: A total of 3645 smokers completed the baseline questionnaire. All participants smoked at least five cigarettes per day, intended to quit smoking within the next 3 months and were between 35 and 65 years of age. MEASUREMENTS: Participants were asked questions about their socio demographic and smoking characteristics, as well previous smoking-related morbidities. Participants were also asked to report their health-care use in the previous 3 months i.e. emergency room (ER) visits, hospitalization, whether hospitalization required surgery, and health-care appointments. FINDINGS: A total of 8252, 4779 and 1954 baseline episodes of smoking were available for 3, 6 and 12 months, respectively. Of these, 2.8% (n = 230), 0.9% (n = 40) and 0.7% (n = 14) were followed by 3, 6 and 12 months of abstinence. No significant differences were found among 3, 6 or 12 months of abstinence and ER visits, hospitalization and whether hospitalization required surgery or health-care visits. However, 6 month smoking cessation episodes were associated with higher odds of reporting an appointment with a dietician. CONCLUSION: Smoking cessation does not appear to be associated with a substantial short-term increase or decrease in health-care use after adjusting for pre-cessation morbidities. PMID- 23795579 TI - More than 50% reduction of wear in polyethylene liners with alumina heads compared to cobalt-chrome heads in hip replacements: a 10-year follow-up with radiostereometry in 43 hips. AB - BACKGROUND AND PURPOSE: Excessive wear of acetabular liners in hip replacements may lead to osteolysis and cup loosening. Different head materials are currently used. We measured differences in wear between alumina and cobalt-chrome heads with the same polyethylene liner. PATIENTS AND METHODS: 39 patients (43 hips) with osteoarthritis were included in a study with 10-year follow-up. Wear was measured as proximal and 3D penetration of the head in the liner with radiostereometry (RSA). All the patients were followed clinically with Harris hip score (HHS) for up to 10 years. Radiolucent lines and osteolytic lesions were assessed on plain radiographs. RESULTS: With alumina heads, proximal wear (95% CI) after 10 years was 0.62 (0.44-0.80) mm as compared to 1.40 (1.00-1.80) mm in the cobalt-chrome group. For 3D wear, the results were 0.87 (0.69-1.04) mm for alumina heads and 1.78 (1.35-2.21) mm for cobalt-chrome heads. Median (range) HHS was 98 (77-100) in the alumina group and it was 93 (50-100) in the cobalt-chrome group (p = 0.01). We found no difference in osteolysis between the groups. INTERPRETATION: We found better wear properties with alumina heads than with cobalt-chrome heads. We recommend the use of alumina heads in patients in whom a high wear rate might be anticipated. PMID- 23795580 TI - Radiolabeling and in vitro /in vivo evaluation of N-(1-adamantyl)-8-methoxy-4-oxo 1-phenyl-1,4-dihydroquinoline-3-carboxamide as a PET probe for imaging cannabinoid type 2 receptor. AB - The cannabinoid type 2 (CB2) receptor plays an important role in neuroinflammatory and neurodegenerative diseases such as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease and is therefore a very promising target for therapeutic approaches as well as for imaging. Based on the literature, we identified one 4-oxoquinoline derivative(designated KD2) as the lead structure. It was synthesized, radiolabeled and evaluated as a potential imaging tracer for CB2. [11C]KD2 was obtained in 99% radiochemical purity.Moderate blood-brain barrier (BBB) passage was predicted for KD2 from an in vitro transport assay with P-glycoprotein-transfected Madin Darby canine kidney cells. No efflux of KD2 by P-glycoprotein was detected. In vitro autoradiography of rat and mouse spleen slices demonstrated that [11C]KD2 exhibits high specific binding towards CB2. High spleen uptake of [11C]KD2 was observed in dynamic positron emission tomography(PET) studies with Wistar rats and its specificity was confirmed by displacement study with a selective CB2 agonist, GW405833. A pilot autoradiography study with post-mortem spinal cord slices from amyotrophic lateral sclerosis (ALS)patients with [11C]KD2 suggested the presence of CB2 receptors under disease conditions. Specificity of [11C]KD2 binding could also be demonstrated on these human tissues. In conclusion, [11C]KD2 shows good in vitro and in vivo properties as a potential PET tracer for CB2. PMID- 23795581 TI - Model of magnetically guided fetal cardiac intervention: potential to avoid direct cardiac puncture. AB - OBJECTIVE: Fetal cardiac interventions are performed via direct cardiac puncture and are associated with significant fetal morbidity. The feasibility of utilizing magnetic navigation to maneuver a guide wire and balloon across a fetal aortic valve without direct cardiac puncture is tested. METHODS: A fetal heart model was manufactured and placed in a catheterization laboratory equipped with magnetic navigation. Magnetically steerable guide wires along with commercially available coronary balloons were inserted into the model at a site mimicking a hepatic vein. RESULTS: Passage of the wire and balloon was achieved on every attempt. The model was suitable for testing although the structural characteristics of the model made wire passage from the right to the left atrium the most challenging aspect. Once the wire was positioned in the left ventricle, it was easily maneuvered 180 degrees towards the left ventricular outflow tract and then the descending aorta. Advancement of a coronary balloon over this wire was uncomplicated. CONCLUSION: In a fetal heart model, it is feasible to deliver a wire and balloon from abdominal venous access antegrade across the aortic valve. Progression to fetal lamb models is planned and may advance fetal cardiac interventions by reduction of fetal morbidity. PMID- 23795582 TI - Early regular versus late selective poractant treatment in preterm infants born between 25 and 30 gestational weeks: a prospective randomized multicenter study. AB - OBJECTIVE: Surfactant treatment in the early hours of life significantly decreases the rates of death and air leak, and increases survival without bronchopulmonary dysplasia (BPD) in preterm infants. We aimed to compare the impact of early surfactant (ES) administration to late selective (LS) treatment on neonatal outcomes in preterm infants. METHODS: All preterm infants between 25 and 30 wks gestational age and who were not entubated in the delivery room and did not have any major congenital malformation or perinatal asphyxia were randomized to ES treatment (200 mg/kg Curosurf(r) administration in 1 hour after birth) or LS treatment (200 mg/kg Curosurf(r)administration in the first 6 h of life if needed). The patients were treated by nasal continuous positive airway pressure (nCPAP) treatment regardless of the surfactant requirement. Outcomes were the necessity of mechanical ventilation, nCPAP duration, the oxygen requirement duration, the rates of BPD, retinopathy of prematurity (ROP) and mortality, and the assessment of the following situations; (pneumothorax, patent ductus arteriosus (PDA), necrotizing enterocolitis (NEC), and intraventricular hemorrhage (IVH) >= grade III). RESULTS: Among 159 infants enrolled in the study, 79 were randomized to ES and 80 to LS treatment groups. Thirty-five patients (44%) in the LS treatment group needed surfactant administration. Necessity of second dose surfactant administration was 8.9% in the ES treatment group. Although necessity of mechanical ventilation, nCPAP duration, oxygen need duration, rates of PDA, NEC, BPD, ROP stage >3 and mortality did not show a significant difference between groups, the ES treatment group had lower rates of pneumothorax and IVH >= grade III when compared to the LS treatment group. CONCLUSIONS: ES treatment decreases IVH (>= grade III) and pneumothorax rates but does not have any effect on BPD when compared to LS. PMID- 23795584 TI - The endothelin A receptor mediates fibrocyte differentiation in chronic obstructive asthma. The involvement of connective tissue growth factor. AB - RATIONALE: Fibrocytes possess increased differentiability into alpha-smooth muscle actin (alpha-SMA)(+) myofibroblasts in chronic obstructive asthma (COA) and contribute to pulmonary fibrosis. Endothelin-1 (ET-1) induces matrix associated gene expression through the ETA receptor (ETAR) and promotes fibroblast differentiation. However, the mechanism of fibrocyte differentiation remains unclear. OBJECTIVES: To define the roles of the ETAR and connective tissue growth factor (CTGF) expression in fibrocytes in the development of fibrosis in COA. METHODS: Blood nonadherent non-T (NANT) cells were isolated, and fibrocytes expressing CD45, collagen I, CTGF, ETAR, or alpha-SMA were identified by flow cytometry. MEASUREMENTS AND MAIN RESULTS: We showed the accumulation of fibrocytes in bronchial walls and overexpression of CTGF in fibrocytes from patients with COA. After being cultured, CTGF was increased in fibrocytes from patients with COA, but not from those of normal participants or patients with asthma without obstruction. Serum levels of ET-1 and the expression of the ETAR in fibrocytes were significantly higher in patients with COA compared with normal participants and patients with asthma without obstruction. Treatment with the ETAR antagonist (BQ123), but not ETBR antagonist (BQ788), reduced the expression of CTGF and alpha-SMA in fibrocytes and fibrocyte differentiation in patients with COA. Furthermore, treatment with BQ123 or an anti-CTGF antibody attenuated alpha-SMA expression induced by ET-1 in fibrocytes from normal participants. CONCLUSIONS: Our findings demonstrate for the first time that the ETAR pathway is vital for CTGF expression, which results in fibrocyte differentiation in COA, and suggests that an ETAR antagonist may be a potential antifibrotic agent in preventing the development of fibrosis in patients with COA. PMID- 23795586 TI - That "poker face" just might lose you the game! The impact of expressive suppression and mimicry on sensitivity to facial expressions of emotion. AB - Successful interpersonal functioning often requires both the ability to mask inner feelings and the ability to accurately recognize others' expressions--but what if effortful control of emotional expressions impacts the ability to accurately read others? In this study, we examined the influence of self controlled expressive suppression and mimicry on facial affect sensitivity--the speed with which one can accurately identify gradually intensifying facial expressions of emotion. Muscle activity of the brow (corrugator, related to anger), upper lip (levator, related to disgust), and cheek (zygomaticus, related to happiness) were recorded using facial electromyography while participants randomized to one of three conditions (Suppress, Mimic, and No-Instruction) viewed a series of six distinct emotional expressions (happiness, sadness, fear, anger, surprise, and disgust) as they morphed from neutral to full expression. As hypothesized, individuals instructed to suppress their own facial expressions showed impairment in facial affect sensitivity. Conversely, mimicry of emotion expressions appeared to facilitate facial affect sensitivity. Results suggest that it is difficult for a person to be able to simultaneously mask inner feelings and accurately "read" the facial expressions of others, at least when these expressions are at low intensity. The combined behavioral and physiological data suggest that the strategies an individual selects to control his or her own expression of emotion have important implications for interpersonal functioning. PMID- 23795585 TI - Synthesis and inhibitory effects of some novel 1,3-diarylprop-2-en-1-one analogues in Foxp3 expression: a novel class of anti-cancer candidates. AB - A series of novel analogues of 1,3-diarylprop-2-en-1-one (3a-m) were synthesized and evaluated for their inhibitory activity of FOX P3 gene expression and apoptosis in CD4(+)T cells that had been isolated from the spleen of 8 to 10 weeks old mice. The structure-activity relationship (SAR) of the R1 and R2 modification was studied to identify a candidate with the maximum potency. Of these compounds, 3d showed the highest inhibitory activity of FOX P3 gene expression and apoptosis (66.5 % inhibition at 10 MUM). To the best of the authors' knowledge this is the first report of 1,3- diarylprop-2-en-1-ones as regulators of FOX P3 gene expression. PMID- 23795587 TI - Americans and Palestinians judge spontaneous facial expressions of emotion. AB - The claim that certain emotions are universally recognized from facial expressions is based primarily on the study of expressions that were posed. The current study was of spontaneous facial expressions shown by aborigines in Papua New Guinea (Ekman, 1980); 17 faces claimed to convey one (or, in the case of blends, two) basic emotions and five faces claimed to show other universal feelings. For each face, participants rated the degree to which each of the 12 predicted emotions or feelings was conveyed. The modal choice for English speaking Americans (n = 60), English-speaking Palestinians (n = 60), and Arabic speaking Palestinians (n = 44) was the predicted label for only 4, 5, and 4, respectively, of the 17 faces for basic emotions, and for only 2, 2, and 2, respectively, of the 5 faces for other feelings. Observers endorsed the predicted emotion or feeling moderately often (65%, 55%, and 44%), but also denied it moderately often (35%, 45%, and 56%). They also endorsed more than one (or, for blends, two) label(s) in each face-on average, 2.3, 2.3, and 1.5 of basic emotions and 2.6, 2.2, and 1.5 of other feelings. There were both similarities and differences across culture and language, but the emotional meaning of a facial expression is not well captured by the predicted label(s) or, indeed, by any single label. PMID- 23795583 TI - Nuclear receptor coactivators: regulators of steroid action in brain and behaviour. AB - Steroid hormones act in specific regions of the brain to alter behaviour and physiology. Although it has been well established that the bioavailability of the steroid and the expression of its receptor is critical for understanding steroid action in the brain, the importance of nuclear receptor coactivators in the brain is becoming more apparent. The present review focuses on the function of the p160 family of coactivators, which includes steroid receptor coactivator-1 (SRC-1), SRC-2 and SRC-3, in steroid receptor action in the brain. The expression, regulation and function of these coactivators in steroid-dependent gene expression in both brain and behaviour are discussed. PMID- 23795588 TI - Explicit and spontaneous retrieval of emotional scenes: electrophysiological correlates. AB - When event-related potentials (ERP) are measured during a recognition task, items that have previously been presented typically elicit a larger late (400-800 ms) positive potential than new items. Recent data, however, suggest that emotional, but not neutral, pictures show ERP evidence of spontaneous retrieval when presented in a free-viewing task (Ferrari, Bradley, Codispoti, Karlsson, & Lang, 2012). In two experiments, we further investigated the brain dynamics of implicit and explicit retrieval. In Experiment 1, brain potentials were measured during a semantic categorization task, which did not explicitly probe episodic memory, but which, like a recognition task, required an active decision and a button press, and were compared to those elicited during recognition and free viewing. Explicit recognition prompted a late enhanced positivity for previously presented, compared with new, pictures regardless of hedonic content. In contrast, only emotional pictures showed an old-new difference when the task did not explicitly probe episodic memory, either when making an active categorization decision regarding picture content, or when simply viewing pictures. In Experiment 2, however, neutral pictures did prompt a significant old-new ERP difference during subsequent free viewing when emotionally arousing pictures were not included in the encoding set. These data suggest that spontaneous retrieval is heightened for salient cues, perhaps reflecting heightened attention and elaborative processing at encoding. PMID- 23795589 TI - Reappraisal as a mediator in the link between 5-HTTLPR and social anxiety symptoms. AB - Social anxiety symptoms have been related to (a) polymorphisms in the serotonin transporter gene-promoter region (also, serotonin-transporter-linked polymorphic region; 5-HTTLPR) and (b) reduced use of adaptive forms of emotion regulation such as reappraisal. It is not known, however, whether reappraisal functions as a mediator in the link between 5-HTTLPR and social anxiety. To address this issue, 182 unselected community volunteers were tested for 5-HTTLPR status, and self report measures of social anxiety symptoms and reappraisal use were obtained. Relative to other participants, those with two low-expressing alleles displayed increased social anxiety and decreased reappraisal. As predicted, the influence of 5-HTTLPR on social anxiety symptoms was transmitted via reappraisal, and this effect of 5-HTTLPR was observed using two different measures of reappraisal. These findings suggest that cognitive reappraisal may be an intermediate phenotype of the social anxiety spectrum, and that individuals with low expressing 5-HTTLPR genotypes may benefit the most from cognitive-behavioral psychotherapy because they do not appear to engage as frequently as others in reappraisal. PMID- 23795590 TI - Erroneous and correct actions have a different affective valence: evidence from ERPs. AB - The accuracy of actions is swiftly determined through specific monitoring brain systems. Event-related potential (ERP) studies have shown that error commission is associated with the generation of the error-related negativity (ERN/Ne), whereas correct actions are associated with the correct-related negativity (CRN). Although the exact functional meaning of the ERN/Ne (and CRN) component remains debated, some authors have suggested that it reflects the processing of the emotional significance of actions. However, no study to date has directly linked amplitude changes at the level of the ERN/Ne-CRN to the affective processing of actions. To decode the emotional valence of actions performed during a go/no-go task, the authors used an evaluative priming method in this study. After each action following the go/no-go stimulus, participants had to categorize an evaluative word as either positive or negative. Behavioral results showed that response errors (i.e., false alarms, FAs) performed during the go/no-go task led to a faster categorization of negative than positive words. Remarkably, this evaluative priming effect was related to the magnitude of the ERN/Ne component generated during the go/no-go task. Moreover, ERP results showed that the processing of evaluative words following FAs was influenced early on after word onset (early posterior negativity-EPN effect), while it was influenced later following correct as well as incorrect actions (late positive potential-LPP effect). Altogether, these ERP results suggest that the action-related ERN-CRN component encodes the perceived emotional significance of actions, such that early stages of evaluative word processing following these actions are influenced by this automatic process. PMID- 23795591 TI - Vicarious learning and unlearning of fear in childhood via mother and stranger models. AB - Evidence shows that anxiety runs in families. One reason may be that children are particularly susceptible to learning fear from their parents. The current study compared children's fear beliefs and avoidance preferences for animals following positive or fearful modeling by mothers and strangers in vicarious learning and unlearning procedures. Children aged 6 to 10 years (N = 60) were exposed to pictures of novel animals either alone (control) or together with pictures of their mother or a stranger expressing fear or happiness. During unlearning (counterconditioning), children saw each animal again with their mother or a stranger expressing the opposite facial expression. Following vicarious learning, children's fear beliefs increased for animals seen with scared faces and this effect was the same whether fear was modeled by mothers or strangers. Fear beliefs and avoidance preferences decreased following positive counterconditioning and increased following fear counterconditioning. Again, learning was the same whether the model was the child's mother or a stranger. These findings indicate that children in this age group can vicariously learn and unlearn fear-related cognitions from both strangers and mothers. This has implications for our understanding of fear acquisition and the development of early interventions to prevent and reverse childhood fears and phobias. PMID- 23795592 TI - Commitment to a purpose in life: an antidote to the suffering by individuals with social anxiety disorder. AB - Recent acceptance- and mindfulness-based cognitive-behavioral interventions explicitly target the clarification and commitment to a purpose in life. Yet, scant empirical evidence exists on the value of purpose as a mechanism relevant to psychopathology or well-being. The present research explored daily (within person) fluctuations in purposeful pursuits and well-being in a community sample of 84 adults with (n = 41) and without (n = 43) the generalized subtype of social anxiety disorder (SAD). After completing an idiographic measure of purpose in life, participants monitored their effort and progress toward this purpose, along with their well-being each day. Across 2 weeks of daily reports, we found that healthy controls reported increased self-esteem, meaning in life, positive emotions, and decreased negative emotions. People with SAD experienced substantial boosts in well-being indicators on days characterized by significant effort or progress toward their life purpose. We found no evidence for the reverse direction (with well-being boosting the amount of effort or progress that people with SAD devote to their purpose), and effects could not be attributed to comorbid mood or anxiety disorders. Results provide evidence for how commitment to a purpose in life enriches the daily existence of people with SAD. The current study supports principles that underlie what many clinicians are already doing with clients for SAD. PMID- 23795593 TI - Approach behavior can mitigate predominately univalent negative attitudes: evidence regarding insects and spiders. AB - Three experiments tested whether disliking of predominately univalently negative attitude objects could be reduced by a procedure pairing approach behaviors with subliminally presented images of the objects. Experiment 1 demonstrated that participants who approached images of insects rated insects less negatively than participants who did not approach insect pictures. Experiment 2 extended this effect to spiders and used an implicit measure of spider attitudes. Experiment 3 examined the consequences of an approach induction for affect during actual approach behavior in a sample of individuals with elevated levels of spider fear by using a Behavioral Approach Task. Fearful individuals who approached spider pictures reported less anxiety when encountering live spiders than participants who did not approach spider pictures. As such, the results provided evidence on explicit, implicit, and behavioral measures that negative and predominately univalent attitudes can be influenced by approach behaviors. Implications for attitude change interventions and potential contribution to the efficacy of exposure therapy are discussed. PMID- 23795594 TI - Adolescent friendships in the context of dual risk: the roles of low adolescent distress tolerance and harsh parental response to adolescent distress. AB - Given extensive evidence about the importance of relationships with friends during development, a large body of research has examined the correlates of these significant social experiences. Most of this research, however, has examined either individual characteristics (e.g., behavior, personality) or contextual factors (e.g., family), and most of the work has studied relationships during childhood. The present study extended previous research by examining how both an individual factor (adolescent distress tolerance) and a contextual factor (parental response to adolescent distress) are linked to adolescents' friendships. Adolescents (N = 161) completed two behavioral measures of distress tolerance, and parents reported about their responses to adolescent distress. Although distress tolerance and parental responses to distress were not directly associated with adolescents' positive or negative friendship experiences, for adolescents with low distress tolerance, harsh parental responses were negatively associated with adolescents' positive friendship quality. Further, for adolescents whose parents used harsh responses to distress, distress tolerance was negatively associated with adolescents' positive friendship quality. Results highlight the importance of studying both individual and familial factors related to adolescents' social functioning. PMID- 23795595 TI - Computational repositioning and experimental validation of approved drugs for HIF prolyl hydroxylase inhibition. AB - HIF stability and activation are governed by a family of dioxygenases called HIF prolyl-4-hydroxylases (PHDs). It has been identified as a new target to augment the adaptive machinery that governs cytoprotection in disorders associated with ischemia/reperfusion, inflammation, and oxidative stress. In this sense, PHD inhibition has been proposed to mimic, at least in part, the protective effects of exposure to hypoxia. Exploiting drug polypharmacology to identify novel modes of actions for drug repurposing has gained significant attention in the current era of weak drug pipelines. The present work plan aims at giving new purpose to some well-established FDA-approved drugs. Here, we propose that by combining the literature survey, docking, and manual interpretation altogether, we were able to perform virtual screening on FDA-approved drugs to identify potential PHD inhibitors. Upon screening of 1537 marketed drugs, a final set of six hits were selected for experimental testing. All six drugs were divers, and immuno blotting was carried out to evaluate their ability to upregulate HIF in order to validate our hypothesis. Out of the six, three drugs showed significant upregulation of HIF possibly by inhibiting the PHD. It is believed that the appropriate use of the literature survey, docking, manual interpretation, and experimental validation strategy in the drug design process should improve the ability to identify hits and confirm their potential to serve as basis for drug repurposing. PMID- 23795596 TI - Nanoscale imaging of InN segregation and polymorphism in single vertically aligned InGaN/GaN multi quantum well nanorods by tip-enhanced Raman scattering. AB - Vertically aligned GaN nanorod arrays with nonpolar InGaN/GaN multi quantum wells (MQW) were grown by MOVPE on c-plane GaN-on-sapphire templates. The chemical and structural properties of single nanorods are optically investigated with a spatial resolution beyond the diffraction limit using tip-enhanced Raman spectroscopy (TERS). This enables the local mapping of variations in the chemical composition, charge distribution, and strain in the MQW region of the nanorods. Nanoscale fluctuations of the In content in the InGaN layer of a few percent can be identified and visualized with a lateral resolution below 35 nm. We obtain evidence for the presence of indium clustering and the formation of cubic inclusions in the wurtzite matrix near the QW layers. These results are directly confirmed by high-resolution TEM images, revealing the presence of stacking faults and different polymorphs close to the surface near the MQW region. The combination of TERS and HRTEM demonstrates the potential of this nanoscale near field imaging technique, establishing TERS as a very potent, comprehensive, and nondestructive tool for the characterization and optimization of technologically relevant semiconductor nanostructures. PMID- 23795597 TI - Highly cross-linked and biocompatible polyphosphazene-coated superparamagnetic Fe3O4 nanoparticles for magnetic resonance imaging. AB - Highly cross-linked and biocompatible poly(cyclotriphosphazene-co-4,4' sulfonyldiphenol) (PZS) were used to directly coat hydrophilic superparamagnetic Fe3O4 nanoparticles by a facile but effective one-pot polycondensation. The obtained core-shell Fe3O4@PZS nanohybrids were characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), Fourier-transform infrared (FTIR) and X-ray diffraction spectra. Interesting, the size and T2 relaxivity of Fe3O4@PZS increased with increasing the mass ratio of Fe3O4 to PZS. All these nanohybrids could be internalized by HeLa cells but show negligible cytotoxicity. The PZS layer slowly degraded into less dangerous forms such as 4,4'-sulfonyldiphenol, phosphate and ammonia at neutral or acid atmosphere. Considering their excellent water dispersibility, colloidal and chemical stability, magnetic manipulation, and magnetic resonance imaging (MRI) properties, Fe3O4@PZS nanohybrids have great potential in MRI diagnosis of cancer. PMID- 23795598 TI - Complexes with redox-active ligands: synthesis, structure, and electrochemical and photophysical behavior of the Ru(II) complex with TTF-annulated phenanthroline. AB - Ru(II) complexes with chelating ligands, 4',5' ethylenedithiotetrathiafulvenyl[4,5-f][1,10]phenanthroline (L1), 1,3-dithiole-2 thiono[4,5-f][1,10]phenanthroline (L2), and 1,3-dithiole-2-ono[4,5 f][1,10]phenanthroline (L3), have been prepared and their structural, electrochemical, and photophysical properties investigated. Density functional theory (DFT) calculations indicate that the highest occupied molecular orbital of [Ru(bpy)2(L1)](PF6)2 (1) is located on the tetrathiafulvalene (TTF) subunit and appears ~0.6 eV above the three Ru-centered d orbitals. In agreement with this finding, 1 exhibits three reversible oxidations: the two at lower potentials take place on the TTF subunit, and the one at higher potential is due to the Ru(3+)/Ru(2+) redox couple. Complexes [Ru(bpy)2(L2)](PF6)2 (2) and [Ru(bpy)2(L3)](PF6)2 (3) exhibit only the Ru(3+)/Ru(2+)-related oxidation. The optical absorption spectra of all complexes reveal a characteristic metal-to ligand charge transfer (MLCT) band centered around 450 nm. In addition, in the spectrum of 1 the MLCT band is augmented by a low-energy tail that extends beyond 500 nm and is attributed to the intraligand charge transfer (ILCT) transition of L1, according to time-dependent DFT calculations. The substantial decrease in the luminescence quantum yield of 1 compared to those of 2 and 3 is attributed to the reductive quenching of the emissive state via electron transfer from the TTF subunit to the Ru(3+) center, thus allowing nonradiative relaxation to the ground state through the lower-lying ILCT state. In the presence of O2, complex 1 undergoes a photoinduced oxidative cleavage of the central C?C bond of the TTF fragment, resulting in complete transformation to 3. This photodegradation process was studied with (13)C NMR and optical absorption spectroscopy. PMID- 23795599 TI - Electronic origin for the phase transition from amorphous Li(x)Si to crystalline Li15Si4. AB - Silicon has been widely explored as an anode material for lithium ion battery. Upon lithiation, silicon transforms to amorphous LixSi (a-LixSi) via electrochemical-driven solid-state amorphization. With increasing lithium concentration, a-LixSi transforms to crystalline Li15Si4 (c-Li15Si4). The mechanism of this crystallization process is not known. In this paper, we report the fundamental characteristics of the phase transition of a-LixSi to c-Li15Si4 using in situ scanning transmission electron microscopy, electron energy loss spectroscopy, and density function theory (DFT) calculation. We find that when the lithium concentration in a-LixSi reaches a critical value of x = 3.75, the a Li3.75Si spontaneously and congruently transforms to c-Li15Si4 by a process that is solely controlled by the lithium concentration in the a-LixSi, involving neither large-scale atomic migration nor phase separation. DFT calculations indicate that c-Li15Si4 formation is favored over other possible crystalline phases due to the similarity in electronic structure with a-Li3.75Si. PMID- 23795600 TI - Structure and thermotropic phase behavior of a homologous series of bioactive N acyldopamines. AB - N-Acyldopamines (NADAs), which are present in mammalian nervous tissues, exhibit interesting biological and pharmacological properties. In the present study, a homologous series of NADAs with varying acyl chains (n = 12-20) have been synthesized and characterized. Differential scanning calorimetric studies show that in the dry state the transition temperatures, enthalpies, and entropies of NADAs exhibit odd-even alternation with the values corresponding to the even chain length series being slightly higher. Both even and odd chain length NADAs display a linear dependence of the transition enthalpies and entropies on the chain length. However, odd-even alternation was not observed in the calorimetric properties upon hydration, although the transition enthalpies and entropies exhibit linear dependence. Linear least-squares analyses yielded incremental values contributed by each methylene group to the transition enthalpy and entropy and the corresponding end contributions. N-Lauroyldopamine (NLDA) crystallized in the monoclinic space group C2/c with eight symmetry-related molecules in the unit cell. Single-crystal X-ray diffraction studies show that NLDA molecules are organized in the bilayer form, with a head-to-head (and tail-to-tail) arrangement of the molecules. Water-mediated hydrogen bonds between the hydroxyl groups of the dopamine moieties of opposing layers and N-H...O hydrogen bonds between the amide groups of adjacent molecules in the same layer stabilize the crystal packing. These results provide a thermodynamic and structural basis for investigating the interaction of NADAs with other membrane lipids, which are expected to provide clues to understand how they function in vivo, e.g., as signaling molecules in the modulation of pain. PMID- 23795601 TI - Mechanistic diversity in thermal fragmentation reactions: a computational exploration of CO and CO2 extrusions from five-membered rings. AB - The mechanisms of a variety of thermal pericyclic fragmentation reactions of five membered heterocyclic rings are subjected to scrutiny at a density functional level by computation of transition state free energy barriers and intrinsic reaction coordinates (IRCs). The preferred computed products generally match those observed in flash vacuum thermolysis experiments. For certain reactions, which also have the highest reaction temperatures and computed barriers, a degree of multireference character to the wave function manifests in an overestimation of the DFT-computed barrier, with a more reasonable barrier obtained by a CASSCF single point energy calculation. Many of the IRCs exhibit "hidden intermediates" along the reaction pathway, but conversely reactions that could be considered to involve the formation of an intermediate nitrene prior to alkyl or aryl migration show no evidence of such an intermediate. Such exploration of the diversity of behavior in a class of compounds using computational methods with interactive presentation of the results within the body of a journal article is suggested as being almost a sine qua non for laboratory-based research on reactive intermediates. PMID- 23795602 TI - Aryl nitrene rearrangements: spectroscopic observation of a benzazirine and its ring expansion to a ketenimine by heavy-atom tunneling. AB - In the photodecompositions of 4-methoxyphenyl azide (1) and 4-methylthiophenyl azide (5) in argon matrixes at cryogenic temperatures, benzazirine intermediates were identified on the basis of IR spectra. As expected, the benzazirines photochemically rearranged to the corresponding ketenimines and triplet nitrenes. Interestingly, with the methylthio substituent, the rearrangement of benzazirine 8 to ketenimine 7 occurred at 1.49 * 10(-5) s(-1) even in the dark at 10 K, despite a computed activation barrier of 3.4 kcal mol(-1). Because this rate is 10(57) times higher than that calculated for passing over the barrier and because it shows no temperature dependence, the rearrangement mechanism is interpreted in terms of heavy-atom tunneling. PMID- 23795603 TI - Ethnicity as a predictor of detention under the Mental Health Act. AB - BACKGROUND: There has been major concern about the 'over-representation' of Black and ethnic minority groups amongst people detained under the Mental Health Act (MHA). We explored the effect of patient ethnicity on detention following an MHA assessment, once confounding variables were controlled for. METHOD: Prospective data were collected for all MHA assessments over 4-month periods in the years 2008, 2009, 2010 and 2011 each in three regions in England: Birmingham, West London and Oxfordshire. Logistic regression modelling was conducted to predict the outcome of MHA assessments - either resulting in 'detention' or 'no detention'. RESULTS: Of the 4423 MHA assessments, 2841 (66%) resulted in a detention. A diagnosis of psychosis, the presence of risk, female gender, level of social support and London as the site of assessment predicted detention under the MHA. Ethnicity was not an independent predictor of detention. CONCLUSIONS: There is no evidence for that amongst those assessed under the MHA, ethnicity has an independent effect on the odds of being detained. PMID- 23795604 TI - Stress and social support in gay, lesbian, and heterosexual couples: direct effects and buffering models. AB - The beneficial effect of social support on the well-being of individuals and romantic relationships has been extensively studied in married heterosexual relationships. The direct effects model suggests that social support is directly associated with well-being, while the social buffering model describes how social support can protect individual well-being from the negative impact of stress. In the present study, we seek to test the extent to which these processes apply to gay and lesbian couples. We use a sample of 111 gay, lesbian, and married heterosexual couples to test the predictions of the social buffering models across relationship types. Irrespective of sexual orientation, the results suggest that social support from family and friends is directly related to well being, while support provided by one's romantic partner buffered individual well being from the negative impact of stress. The direct and buffering effects of partner support on romantic relationship quality were likewise consistent across couple types. While the amount of social support received from family members had a beneficial effect on the relationship quality of heterosexual couples, family support was unrelated to relationship quality in same-sex couples. Furthermore, the relation between friend support and relationship quality differed across couple types. We discuss the results in the context of the unique challenges faced by same-sex couples. PMID- 23795605 TI - Maternal parenting behaviors and child coping in African American families. AB - The purpose of the current study was to examine the impact of three parental influences (i.e., socialization of coping, modeling of coping, and the parent child relationship) on coping strategies of African American children, as well as child gender as a moderator of these associations. Participants were 83 African American children (mean age = 11.2, SD = 1.44) and their maternal caregivers (mean age = 40.45, SD = 9.55). Both children and parents completed measures of coping behaviors, parental socialization of coping, and maternal support. Regression analyses demonstrated that child reports of their mothers' behavior were better predictors of child coping than mothers' self-reports, with child reports of maternal support and socialization of coping predicting child coping. Results also revealed that child gender moderated the association between maternal parenting behavior and child coping. Specifically, maternal parenting behaviors were more important for girls' coping strategies than for boys' coping strategies. Our results add to the literature on the effects of parent-child relationships on children's responses to stress. PMID- 23795606 TI - Parenting and attachment among low-income African American and Caucasian preschoolers. AB - Despite a plethora of research on parenting and infant attachment, much less is known about the contributions of parenting to preschool attachment, particularly within different racial groups. This study seeks to build on the extant literature by evaluating whether similar associations between parenting and attachment can be observed in African American and Caucasian families, and whether race moderates them. Seventy-four primary caregivers and their preschool children (51% African American, 49% Caucasian, 46% male) from similar urban, low income backgrounds participated in two visits 4 weeks apart when children were between 4 and 5 years of age. Attachment was scored from videotapes of the Strange Situation paradigm using the preschool classification system developed by Cassidy, Marvin, and the MacArthur Working Group. Parenting was assessed using a multimethod, multicontext approach: in the child's home, in the laboratory, and via parent-report. Seventy-three percent of the children were classified as securely attached. Warm, responsive parenting behavior (but not race) predicted attachment. Although parents of African American and Caucasian children demonstrated some significant differences in parenting behaviors, race did not moderate the relationship between parenting and child attachment. These findings highlight the direct role that parenting plays over and above race in determining attachment security during the preschool period. PMID- 23795608 TI - Characterization of heterocyclic rings through quantum chemical topology. AB - Five-membered rings are found in a myriad of molecules important in a wide range of areas such as catalysis, nutrition, and drug and agrochemical design. Systematic insight into their largely unexplored chemical space benefits from first principle calculations presented here. This study comprehensively investigates a grand total of 764 different rings, all geometry optimized at the B3LYP/6-311+G(2d,p) level, from the perspective of Quantum Chemical Topology (QCT). For the first time, a 3D space of local topological properties was introduced, in order to characterize rings compactly. This space is called RCP space, after the so-called ring critical point. This space is analogous to BCP space, named after the bond critical point, which compactly and successfully characterizes a chemical bond. The relative positions of the rings in RCP space are determined by the nature of the ring scaffold, such as the heteroatoms within the ring or the number of pi-bonds. The summed atomic QCT charges of the five ring atoms revealed five features (number and type of heteroatom, number of pi bonds, substituent and substitution site) that dictate a ring's net charge. Each feature independently contributes toward a ring's net charge. Each substituent has its own distinct and systematic effect on the ring's net charge, irrespective of the ring scaffold. Therefore, this work proves the possibility of designing a ring with specific properties by fine-tuning it through manipulation of these five features. PMID- 23795607 TI - Newlyweds' optimistic forecasts of their marriage: for better or for worse? AB - Newlywed spouses routinely hope and believe that their relationships will thrive, but theoretical accounts differ on whether optimistic projections such as believing that one's marriage will improve are sources of strength, random forecasting errors, or self-protective mechanisms. To test these opposing perspectives, we asked 502 newlywed spouses in 251 marriages to predict how their overall feelings about their relationships would change over the following four years, and we then compared these reports to their prospective marital satisfaction trajectories. Nearly all spouses predicted their marital satisfaction would remain stable or improve over the following four years. Marital satisfaction declined on average despite this high overall level of optimism. Wives with the most optimistic forecasts showed the steepest declines in marital satisfaction. These wives also had lower self-esteem and higher levels of stress and physical aggression toward their partners initially. Thus, believing that one's marriage will improve does not make it so and instead may paradoxically mask risky relationships among women. These findings may be important in helping to understand low rates of premarital counseling utilization by showing that nearly all couples overestimate the durability of their existing satisfied feelings at the start of their marriage. Future research is needed to understand the psychological processes allowing couples to commit to and stay in risky relationships. PMID- 23795609 TI - Hybrid III-nitride/organic semiconductor nanostructure with high efficiency nonradiative energy transfer for white light emitters. AB - A novel hybrid inorganic/organic semiconductor nanostructure has been developed, leading to very efficient nonradiative resonant-energy-transfer (RET) between blue emitting InGaN/GaN multiple quantum wells (MQWs) and a yellow light emitting polymer. The utilization of InGaN/GaN nanorod arrays allows for both higher optical performance of InGaN blue emission and a minimized separation between the InGaN/GaN MQWs and the emitting polymer as a color conversion medium. A significant reduction in decay lifetime of the excitons in the InGaN/GaN MQWs of the hybrid structure has been observed as a result of the nonradiative RET from the nitride emitter to the yellow polymer. A detailed calculation has demonstrated that the efficiency of the nonradiative RET is as high as 73%. The hybrid structure exhibits an extremely fast nonradiative RET with a rate of 0.76 ns(-1), approximately three times higher than the InGaN/GaN MQW nonradiative decay rate of 0.26 ns(-1). It means that the RET dominates the nonradiative processes in the nitride quantum well structure, which can further enhance the overall device performance. PMID- 23795610 TI - Decatantalate--the last member of the group 5 decametalate family. AB - A tetra-n-butylammonium (TBA) salt of [Ta10O28](6-) was synthesized by heating TBA6[H2Ta6O19] in toluene for a prolonged period. X-ray structural analysis of TBA6[Ta10O28].6H2O revealed that the anion has the decametalate structure and is isostructural with the decavanadate and decaniobate anions [a = 15.8517(8) A, b = 19.364(1) A, c = 21.935(1) A, beta = 93.638(1) degrees , V = 6719.4(6) A(3), Z = 2, and space group P2(1)/n at 292(2) K]. PMID- 23795611 TI - In utero LPS exposure impairs preterm diaphragm contractility. AB - Preterm birth is associated with inflammation of the fetal membranes (chorioamnionitis). We aimed to establish how chorioamnionitis affects the contractile function and phenotype of the preterm diaphragm. Pregnant ewes received intra-amniotic injections of saline or 10 mg LPS, 2 days or 7 days before delivery at 121 days of gestation (term = 150 d). Diaphragm strips were dissected for the assessment of contractile function after terminal anesthesia. The inflammatory cytokine response, myosin heavy chain (MHC) fibers, proteolytic pathways, and intracellular molecular signaling were analyzed using quantitative PCR, ELISA, immunofluorescence staining, biochemical assays, and Western blotting. Diaphragm peak twitch force and maximal tetanic force were approximately 30% lower than control values in the 2-day and 7-day LPS groups. Activation of the NF-kappaB pathway, an inflammatory response, and increased proteasome activity were observed in the 2-day LPS group relative to the control or 7-day LPS group. No inflammatory response was evident after a 7-day LPS exposure. Seven-day LPS exposure markedly decreased p70S6K phosphorylation, but no effect on other signaling pathways was evident. The proportion of MHC IIa fibers was lower than that for control samples in the 7-day LPS group. MHC I fiber proportions did not differ between groups. These results demonstrate that intrauterine LPS impairs preterm diaphragmatic contractility after 2-day and 7 day exposures. Diaphragm dysfunction, resulting from 2-day LPS exposure, was associated with a transient activation of proinflammatory signaling, with subsequent increased atrophic gene expression and enhanced proteasome activity. Persistently impaired contractility for the 7-day LPS exposure was associated with the down-regulation of a key component of the protein synthetic signaling pathway and a reduction in the proportions of MHC IIa fibers. PMID- 23795612 TI - The total synthesis of hypodematine. AB - Hypodematine, isolated from Hypodematium sinense Iwatsuki as an alkaloid with a new skeleton, was synthesized via nine reaction steps, in which the synthesis of 2-aryl-1-benzazocines via Beckmann rearrangement of 5H-benzocyclohepten-5-one oxime mesylate in dry toluene is discussed. PMID- 23795613 TI - Ionic liquids in drug delivery. AB - INTRODUCTION: To overcome potential problems with solid-state APIs, such as polymorphism, solubility and bioavailability, pure liquid salt (ionic liquid) forms of active pharmaceutical ingredients (API-ILs) are considered here as a design strategy. AREAS COVERED: After a critical review of the current literature, the recent development of the API-ILs strategy is presented, with a particular focus on the liquefaction of drugs. A variety of IL tools for control over the liquid salt state of matter are discussed including choice of counterion to produce an IL from a given API; the concept of oligomeric ions that enables liquefaction of solid ILs by changing the stoichiometry or complexity of the ions; formation of 'liquid co-crystals' where hydrogen bonding is the driving force in the liquefaction of a neutral acid-base complex; combining an IL strategy with the prodrug strategy to improve the delivery of solid APIs; using ILs as delivery agents via trapping a drug in a micelle and finally ILs designed with tunable hydrophilic-lipophilic balance that matches the structural requirements needed to solubilize poorly water-soluble APIs. EXPERT OPINION: The authors believe that API-IL approaches may save failed lead candidates, extend the patent life of current APIs, lead to new delivery options or even new pharmaceutical action. They encourage the pharmaceutical industry to invest more research into the API-IL platform as it could lead to fast-tracked approval based on similarities to the APIs already approved. PMID- 23795614 TI - Cochlear implantation through the middle fossa: an anatomic study for a novel technique. AB - CONCLUSION: The technique proposed is simple, reliable, and provides sufficient exposure of the basal portion of the cochlea while avoiding disabling complications. It enables visualization of the cochlear basal turn and the osseous spiral lamina, facilitating the insertion of the cochlear implant array through the scala tympani. OBJECTIVES: To describe a novel approach for exposing the cochlear basal turn for cochlear implantation through the middle cranial fossa. METHODS: Fifty temporal bones were dissected and a cochleostomy was performed via a middle fossa approach on the most superficial part of the cochlear basal turn, using the superior petrosal sinus, the skeletonized petrous apex, the lateral surface of the meatal plane trailed on the petrous apex from its most proximal portion, and the great superficial petrosal nerve as landmarks. The distance between the landmarks and the distance between the cochleostomy and the round window were measured. RESULTS: In all temporal bones, only the top portion of the cochlear basal turn was uncovered. The cochleostomy allowed both the scala tympani and the vestibule to be exposed. A computed tomography scan of the temporal bones was performed to document the electrode insertion from the cochlear basal turn until its apex. The mean +/- SD minor and major distances between the cochleostomy and the meatal plane were estimated to be 2.48 +/- 0.88 mm and 3.11 +/- 0.86 mm, respectively. The mean distance from the cochleostomy to the round window was 8.38 +/- 1.96 mm, and that to the superior petrosal sinus was 9.19 +/- 1.59 mm. The mean minor and major distances between the cochleostomy and the long axis of the meatal plane from its most proximal portion were estimated to be 6.63 +/- 1.38 mm and 8.29 +/- 1.43 mm, respectively. PMID- 23795615 TI - Site-selective deposition of twinned platinum nanoparticles on TiSi2 nanonets by atomic layer deposition and their oxygen reduction activities. AB - For many electrochemical reactions such as oxygen reduction, catalysts are of critical importance, as they are often necessary to reduce reaction overpotentials. To fulfill the promises held by catalysts, a well-defined charge transport pathway is indispensable. Presently, porous carbon is most commonly used for this purpose, the application of which has been recently recognized to be a potential source of concern. To meet this challenge, here we present the development of a catalyst system without the need for carbon. Instead, we focused on a conductive, two-dimensional material of a TiSi2 nanonet, which is also of high surface area. As a proof-of-concept, we grew Pt nanoparticles onto TiSi2 by atomic layer deposition. Surprisingly, the growth exhibited a unique selectivity, with Pt deposited only on the top/bottom surfaces of the nanonets at the nanoscale without mask or patterning. Pt {111} surfaces are preferably exposed as a result of a multiple-twinning effect. The materials showed great promise in catalyzing oxygen reduction reactions, which is one of the key challenges in both fuel cells and metal air batteries. PMID- 23795616 TI - Effect of induced hypothermia on lipopolysaccharide-induced lung injury in neonatal rats. AB - OBJECTIVES: Recent data suggest that induced hypothermia has some protective effects on experimental lung injury. We aimed to evaluate the protective effect of mild hypothermia in a rat model of lipopolysaccharide (LPS) induced neonatal lung injury. METHODS: Wistar rat pups were divided into four groups, specifically: (i) A control group, with no LPS administration and maintained in room air; (ii) A LPS group, with antenatal LPS administrated and maintained in room air; (iii) A LPS + hypothermia group, with antenatal LPS administrated and exposed to hypothermia; (iv) A hypothermia group, with no LPS administration and exposed to hypothermia. Intraperitoneal LPS was injected into maternal rats at the 19th and 20th gestational days to establish a neonatal lung injury model. Mild hypothermia was started at the postnatal 24th hour and continued during 24 h. At the postnatal 7th day, the rats were sacrificed and lung samples were evaluated for immunohistochemical tests and proinflammatory gene expression levels. RESULTS: Hypothermia therapy attenuated the damaging effects of antenatal LPS administration. Furthermore, hypothermia therapy reduced gene expression of pro-inflammatory cytokines (IL-6, IL-1alpha, IL-1beta, TNF-alpha) and induced the expression of a potent anti-inflammatory cytokine (IL-10). CONCLUSION: The results of this study indicated that mild hypothermia therapy is effective in an LPS induced neonatal lung injury model. If these results are supported by further studies, hypothermia may also be a new therapy option for preventing bronchopulmonary dysplasia. PMID- 23795617 TI - Effect of phenotypic selection on stochastic gene expression. AB - Genetically identical cells in the same population can take on phenotypically variable states, leading to differentiated responses to external signals, such as nutrients and drug-induced stress. Many models and experiments have focused on a description based on discrete phenotypic states. Here, we consider the effects of selection acting on a single trait, which we explicitly link to the variable number of proteins expressed by a gene. Considering different regulatory models for the gene under selection, we calculate the steady-state distribution of expression levels and show how the population adapts its expression to enhance its fitness. We quantitatively relate the overall fitness of the population to the heritability of expression levels and their diversity within the population. We show how selection can increase or decrease the variability in the population, alter the stability of bimodal states, and impact the switching rates between metastable attractors. PMID- 23795618 TI - The impact of inherited thrombophilia on first trimester combined aneuploidy screening test parameters. AB - OBJECTIVE: To determine whether inherited thrombophilia affects components of first trimester combined aneuploidy screening test. METHOD: A case-control study was performed between January 1st and December 31st 2011, at a tertiary referral hospital. Singleton pregnancies with inherited thrombophilia that underwent first trimester (11-13(+6) week) combined aneuploidy screening test were included in the study. Pregnancy associated plasma protein-A (PAPP-A), free beta-human chorionic gonadotropin (fbHCG) and fetal nuchal translucency (NT) were compared between the study group and controls. RESULTS: Within the study period, 15,881 women with singleton pregnancies had a combined first trimester aneuploidy screening test at our institution. Among these, 207 women met the inclusion criteria. A control group that comprised 625 women with similar gestational age was generated, using a 1:3 ratio. PAPP-A levels were significantly higher, whereas fbHCG levels and fetal NT measurements were lower in women with inherited thrombophilia (p < 0.001). CONCLUSION: Our study suggested that PAPP-A, free b HCG and NT MoM levels display alterations in women with inherited thrombophilia. Future trials are needed to assess the need for readjustment of risk in these patients. PMID- 23795619 TI - Electroreductive transformation of [60]fullerosultones into fullerosulfonic acids. AB - Novel C60 derivatives of a singly bonded dimer and a 1,4-adduct bearing a sulfonic acid functionality have been prepared via the electroreductive transformation of a [60]fullerosultone. It has been shown that the reaction of the in situ formed dianion with benzyl bromide is initiated by a ring-opening of the [60]fullerosultone via the C60-O bond cleavage upon receiving one electron. The [60]fullerosultone dianion is electrooxidized at 0.40 V to afford the singly bonded dimer species, which can be further electrooxidized at 1.30 V to restore the starting material [60]fullerosultone. The reaction mechanism is studied with the cyclic voltammetry and vis-NIR spectroscopy. PMID- 23795620 TI - Isoform characterisation, heterologous expression and functional analysis of two lectins from Vatairea macrocarpa. AB - VML is a lectin from Vatairea macrocarpa seeds that has various biological activities. Here, we describe three new lectin isoforms from V. macrocarpa identified through genomic DNA analysis. One of these isoforms has high similarity to VML, while another that has noteworthy differences. We have denoted the new isoforms as VML-2, VML-3 and VML-4. Recombinant VML (rVML) and VML-2 (rVML-2) were expressed in Escherichia coli and were anticipated to have similar biological activity compared to native VML. Recombinant lectins were produced using a synthetic gene strategy to improve the expression levels. We obtained two active recombinant lectin isoforms from V. macrocarpa, and there was no significant difference between their biological activities. The conservation between carbohydrate-binding sites of recombinant and native proteins was demonstrated by specific inhibition of hemagglutin activity by D-galactose and lactose. However, no inhibition was observed in the presence of glucose and mannose. Our data show that the recombinant lectins VML and VML-2 are active and capable of recognising D-galactose and lactose. Moreover, the absence of glycosylation does not interfere with their biological activity. PMID- 23795622 TI - Detection of isomeric microscopic host-guest complexes. A time-evolving cucurbit[7]uril complex. AB - The formation of inclusion complexes between the cucurbit[7]uril host and a cationic guest containing ferrocenylmethyl and adamantyl residues connected to an ammonium nitrogen initially leads to an ~1:1 mixture of two isomeric microscopic complexes, which evolves as a function of time toward the thermodynamically stable mixture, dominated by the adamantyl-included complex. PMID- 23795621 TI - Randomized controlled trial of computerized cognitive behavioural therapy for depressive symptoms: effectiveness and costs of a workplace intervention. AB - BACKGROUND: Depression and anxiety are major causes of absence from work and underperformance in the workplace. Cognitive behavioural therapy (CBT) can be effective in treating such problems and online versions offer many practical advantages. The aim of the study was to investigate the effectiveness of a computerized CBT intervention (MoodGYM) in a workplace context. METHOD: The study was a phase III two-arm, parallel randomized controlled trial whose main outcome was total score on the Work and Social Adjustment Scale (WSAS). Depression, anxiety, psychological functioning, costs and acceptability of the online process were also measured. Most data were collected online for 637 participants at baseline, 359 at 6 weeks marking the end of the intervention and 251 participants at 12 weeks post-baseline. RESULTS: In both experimental and control groups depression scores improved over 6 weeks but attrition was high. There was no evidence for a difference in the average treatment effect of MoodGYM on the WSAS, nor for a difference in any of the secondary outcomes. CONCLUSIONS: This study found no evidence that MoodGYM was superior to informational websites in terms of psychological outcomes or service use, although improvement to subthreshold levels of depression was seen in nearly half the patients in both groups. PMID- 23795623 TI - Getting mental health care where it is needed. AB - There has been a powerful call for better funding for mental health services in the United States. The effort to build capacity in mental health centers is much needed. We need more and better-trained staff, funding that can reduce barriers, and shorten waiting times. The movement to integrate mental health clinicians as part of the care team in primary care will be much more likely to find and engage people who are very troubled but are not seeking mental health care. To increase the likelihood of getting care to troubled people earlier and engaging them in care more effectively, any effort to improve funding for mental health should include a clear focus on improving the integration of mental health into primary care. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 23795624 TI - Current and potential support for chronic disease management in the United States: the perspective of family and friends of chronically ill adults. AB - Family members and friends can be an important source of self-management support for older adults with chronic diseases. We characterized the U.S. population of potential and current "disease management supporters" for people with chronic illness who are independent in activities of daily living, the help that supporters could provide, and barriers to increasing support. We used a nationally representative survey of U.S. adults (N = 1,722). Forty-four percent of respondents (representing 100 million US adults) help a family member or friend with chronic disease management; another 9% (representing 21 million U.S. adults) are willing to start. Most are willing to assist with key tasks such as medication use and communicating with providers, although they feel constrained by privacy concerns and a lack of patient health information. The majority of U.S. adults already helps, or would be willing to help, one of their family members or friends with chronic illness care. Supporters' specific concerns could be addressed through innovative programs. PMID- 23795625 TI - Parent-reported outcomes of comprehensive care for children with medical complexity. AB - The Medical Home Clinic for Special Needs Children (MHCL) at Arkansas Children's Hospital provides comprehensive care oversight for children with medical complexity (CMC). The objective of this study is to evaluate parent perceptions of health care delivery outcomes after 12 months of enrollment in the MHCL. This is a prospective cohort study of parents of MHCL patients, who completed surveys at initial and 12-month visits. Surveys assessed parent health, child health and function, family stress, and overall satisfaction, using previously validated measures and scales. Paired analyses examined differences in measures between baseline and 12 months. One-hundred and twenty of 174 eligible parents completed the follow-up survey at 12 months. Respondents were 63% White/Caucasian, 90% biological parent, and 48% with an annual family income < $20,000. From baseline to 12 months, a greater number of respondents reported having a care plan (53% vs. 85%, p < .001); fewer respondents needed help with care coordination (78% vs. 31%, p < .001). No changes were seen in reports of having emotional needs met. Parents reported a decline in the physical subscale of the SF-12 Health-Related Quality of Life measure (49.1 vs. 46.4, p < .01), with those parents with >= 1 additional child with special needs reporting a marked decline (49.2 vs. 42.5, p < .001). No other changes in family impact were found. We conclude that comprehensive care oversight may improve care coordination for parents of CMC, but no association with improved parent health was found. Future studies should identify the factors that influence parental burden and tailor clinical interventions to address such factors. PMID- 23795626 TI - Individual and family predictors of psychological control in parents raising children with type 1 diabetes. AB - The purpose of this research is to examine how metabolic control, parents' marital conflict, and parental caregiver burden are related to parents' use of psychological control in families raising a child with Type 1 diabetes (T1D). Differences between mothers and fathers are also considered. In this cross sectional study, parents of 85 children with T1D independently completed self report questionnaires; metabolic control levels were obtained through patient medical records. Structural equation modeling showed that better metabolic control is related to lower levels of fathers' caregiver burden, and marital conflict is positively related to both mothers' and fathers' ratings of caregiver burden. Mothers' caregiver burden is positively related to their psychological control (a type of parental behavior that threatens children's autonomous thoughts and feelings) and, similarly, fathers' caregiver burden is positively related to their psychological control. Paths in the model differed by parent gender, but there were no crossover effects. Future research is needed to develop new, effective interventions for children with diabetes and their parents, focusing not only on the child but on multiple family systems. PMID- 23795628 TI - Factors related to caregiver state anxiety and coping with a child's chronic illness. AB - The resiliency of families, based on family functioning and family hardiness, may influence caregivers' anxiety while their child is in the hospital undergoing treatment for his or her chronic illness. The current study assessed the relationship among these factors for caregivers of children with various chronic illnesses who were residing at a local Ronald McDonald House (RMH). Caregivers completed paper-based questionnaires to assess family hardiness, functioning, and parent state anxiety and interviews to identify positive and negative strategies and behaviors affecting how they were coping with their child's illness. Findings indicated that family functioning mediated the relationship between family hardiness and caregiver anxiety as a resilience factor that further reduced caregiver anxiety. During interviews, caregivers suggested that support from family members strengthened their coping abilities. Negative interactions with their child's medical team and not knowing how or being equipped to help their child live with his or her illness heightened caregiver stress. Future research should focus on developing, implementing, and measuring the effectiveness of interventions to improve caregiver support, such as by holding caregiver support groups at local RMHs, especially during a child's hospitalization. PMID- 23795627 TI - The home environment and family asthma management among ethnically diverse urban youth with asthma. AB - Although the pediatric psychology literature underscores the importance of illness-related aspects of the home environment for optimal family asthma management, little is known about the contribution of more global aspects of the home environment (e.g., family routines/schedule, quality of stimulation provided to child) to asthma management in ethnic minority and urban families. The goals of this study were to (a) explore ethnic/racial group differences in global and specific dimensions of home environment quality among Latino, non-Latino White (NLW), and African American urban children with asthma; and (b) examine associations between the quality and quantity of support and stimulation within the home environment, as measured by the HOME Inventory, and family asthma management. Urban, low-income children (N = 131) between the ages of 6 and 13 with asthma and a primary caregiver participated in a multimodal assessment, including an in-home observation and semistructured interviews to assess aspects of home environment quality and family asthma management practices. While controlling for poverty, no ethnic group differences were found in the global home environment; however, there were significant differences in specific dimensions (e.g., Family Participation in Developmentally Stimulating Experiences, and Aspects of the Physical Environment) of home environment quality. Across the whole sample, home environment quality predicted family asthma management. When examining this association for specific ethnic groups, this finding did not hold for the Latino subsample. The results highlight the need to consider ethnic group differences in non-illness-specific aspects of the home environment when addressing families' asthma management strategies. PMID- 23795629 TI - "There is still so much ahead of us"-family functioning in families of palliative cancer patients. AB - Adopting a systems approach, parental cancer has its impact on patients, spouses, and dependent children. The purpose of the current study was to examine family functioning dependent on parental disease stage and on family member perspective in families of cancer patients with adolescent children. The cross-sectional study was conducted within a German multisite research project of families before their first child-centered counseling encounter. The sample comprised individuals nested within N = 169 families. Analyses performed included analysis of covariance (ANCOVA) and intraclass correlation. Open answers were analyzed following quantitative content analysis procedures. Between 15% and 36% of family members reported dysfunctional general functioning scores. Parents indicated more dysfunctional scores on the Family Assessment Device scale Roles, and adolescents more dysfunctional Communication scores. Regarding assessment of family functioning, there was higher agreement in families with parents in a palliative situation. For adolescents with parents in palliation, incidents because of the disease tend to become more dominant, and spending time with the family tends to become even more important. As our study pointed out, parental cancer, and especially parental palliative disease, is associated with both perceived critical and positive aspects in family functioning. Supporting families in these concerns as well as encouraging perceptions of positive aspects are important components of psycho-oncological interventions for families with dependent children. PMID- 23795630 TI - Family system dynamics and type 1 diabetic glycemic variability: a vector-auto regressive model. AB - Statistical approaches rooted in econometric methodology, so far foreign to the psychiatric and psychological realms have provided exciting and substantial new insights into complex mind-body interactions over time and individuals. Over 120 days, this structured diary study explored the mutual interactions of emotions within a classic 3-person family system with its Type 1 diabetic adolescent's daily blood glucose variability. Glycemic variability was measured through daily standard deviations of blood glucose determinations (at least 3 per day). Emotions were captured individually utilizing the self-assessment manikin on affective valence (negative-positive), activation (calm-excited), and control (dominated-dominant). Auto- and cross-correlating the stationary absolute (level) values of the mutually interacting parallel time series data sets through vector autoregression (VAR, grounded in econometric theory) allowed for the formulation of 2 concordant models. Applying Cholesky Impulse Response Analysis at a 95% confidence interval, we provided evidence for an adolescent being happy, calm, and in control to exhibit less glycemic variability and hence diabetic derailment. A nondominating mother and a happy father seemed to also reduce glycemic variability. Random shocks increasing glycemic variability affected only the adolescent and her father: In 1 model, the male parent felt in charge; in the other, he calmed down while his daughter turned sad. All reactions to external shocks lasted for less than 4 full days. Extant literature on affect and glycemic variability in Type 1 diabetic adolescents as well as challenges arising from introducing econometric theory to the field were discussed. PMID- 23795635 TI - Oral health of vulnerable older adults and persons with -disabilities: a National Coalition Consensus Conference. PMID- 23795631 TI - Cancer-related traumatic stress reactions in siblings of children with cancer. AB - The purpose of this study was to explore cancer-related posttraumatic stress (PTS) reactions in siblings of children with cancer including prevalence, common symptoms, comorbidity with anxiety and depression, and gender- and age-related patterns. A total of 125 children (63 girls) between the ages of 8 and 17 (M = 12.4; SD = 2.9 years) with a brother or sister with cancer, diagnosed 4 to 38 months prior to the study (M = 1.3 years; SD = 6.7 months), completed the Child PTSD Symptom Scale (CPSS), Revised Children's Manifest Anxiety Scale, and Child Depression Inventory-Short Form. Over half of the sample (60%) scored in the moderate to severe range for PTS and 22% fulfilled full criteria for PTSD based upon CPSS responses. Nearly 75% reported "Feeling upset when you think about or hear about the cancer," and "Trying not to think about, talk about, or have feelings about the cancer." Over 60% reported arousal symptoms. PTS symptoms reportedly interfered with functioning for 75% of the sample and co-occurred with anxiety and depressive symptoms. Gender and age-related patterns were not found. Siblings of children with cancer experience cancer-related PTS reactions and greater attention should be paid to ameliorating their cancer-related distress with empirically based treatments. PMID- 23795636 TI - The oral health of vulnerable older adults and persons with disabilities. AB - Demographic trends in the United States show that the number of people with one or more disabilities is going to increase dramatically over the coming decades. This paper describes the types of disabilities that make up this increase and documents growth of this population over the next 40 years. Dental care market forces are defined and analyzed as they will influence the ability of vulnerable elders and people with disabilities to purchase dental care. The capacity of the dental profession to deliver appropriate high quality dental services to vulnerable elders and people with disabilities is also discussed. Dental disease trends are presented along with a description of the changing living arrangements characterized by the newly termed "senior industry." The paper concludes with the disquieting conclusion that the need for dental care among vulnerable elders and people with disabilities will dramatically increase while the capacity of the dental profession will not keep up with the expanding need and demand for dental case across the entire U.S. population. Thus, disparities in oral health and access to dental care are likely to occur for vulnerable able older adults and persons with disabilities. PMID- 23795637 TI - Medical considerations relating to the oral health of older adults. AB - This review paper was written in conjunction with the 2010 National Coalition Consensus Conference: Oral Health of Vulnerable Older Adults and Persons with Disabilities. It provides an overview of specific medical considerations involved with dental diagnosis and treatment of this "at risk population." The role of oral inflammation is referenced within the context of the oral/systemic paradigm (e.g., diabetes, cardiovascular disease/stroke, respiratory diseases, and cognition). Oral manifestations associated with multi-organ diseases, tobacco/alcohol use, and medications are additionally discussed. Finally, the paper encourages development of interdisciplinary approaches to positively influence health outcomes. PMID- 23795638 TI - Oral health delivery systems for older adults and people with disabilities. AB - This article describes new oral health care system models designed to meet the needs of a rapidly growing population of older adults and people with disabilities. These populations are not currently able to access traditional dental offices and clinics to the same degree that younger and much healthier population groups do. So new models proactively target specific community organizations where these high-risk underserved population groups live, work, go to school, or obtain other health or social services. Collaborative on-site and clinic-based teams establish "Virtual Dental Homes" that provide ongoing, year round access to oral health services designed to prevent mouth infections, deliver evidence-based preventive care, and restore infected individuals to stable and sustainable oral health. These new delivery models are beginning to demonstrate better health care delivery, better health outcomes, and the potential to drive down total health care costs for older adults and people with disabilities. PMID- 23795639 TI - Professional education to meet the oral health needs of older adults and persons with disabilities. AB - A well-prepared dental workforce is critical to improving the oral health of special needs patients. This paper, originally presented at the National Coalition Consensus Conference: Oral Health of Vulnerable Older Adults and Persons with Disabilities, reviews and suggests opportunities to enhance the professional education of the dental workforce, including enhanced faculty training in gerontology, geriatrics and special patient care, and opportunities for improved curricula and team training both within the dental team and among the diverse group of health professional that often collaborate in the care of special needs patients. Other considerations include the creation of a specialty of Special Care Dentistry, and the effective use of dental team members in the care of special needs patients. PMID- 23795640 TI - Engaging the U.S. Congress in the oral health of special-needs adults: lessons from pediatric oral health policy. AB - The U.S. Congress has a long history of attending to insurance coverage for children's oral health services while being relatively silent about adult dental care. Yet many adults, made vulnerable by their disabilities and illnesses, are dependent upon governmental programs. This paper contrasts the robust history of federal legislative action in support of children's oral health with the lack of attention to adults' oral health to identify approaches that advocates may consider when engaging Congress in improving oral health for disabled and older adults. It provides a historical context of Congressional action on dental coverage from Medicaid and Medicare in the 1960s through passage of the Affordable Care Act in 2010 and explicates the misconception that Congress has demonstrated about the importance of oral health for adults' well-being and general health. Drivers and strategies for policy change are described and recommendations are made to expand coverage for vulnerable adults. PMID- 23795641 TI - Proceedings of the National Coalition Consensus Conference on Oral Health of Vulnerable Older Adults and Persons with Disabilities. PMID- 23795643 TI - Serving the new masters - dendritic cells as hosts for stealth intracellular bacteria. AB - Dendritic cells (DCs) serve as the primers of adaptive immunity, which is indispensable for the control of the majority of infections. Interestingly, some pathogenic intracellular bacteria can subvert DC function and gain the advantage of an ineffective host immune reaction. This scenario appears to be the case particularly with so-called stealth pathogens, which are the causative agents of several under-diagnosed chronic diseases. However, there is no consensus how less explored stealth bacteria like Coxiella, Brucella and Francisella cross-talk with DCs. Therefore, the aim of this review was to explore the issue and to summarize the current knowledge regarding the interaction of above mentioned pathogens with DCs as crucial hosts from an infection strategy view. Evidence indicates that infected DCs are not sufficiently activated, do not undergo maturation and do not produce expected proinflammatory cytokines. In some cases, the infected DCs even display immunosuppressive behaviour that may be directly linked to the induction of tolerogenicity favouring pathogen survival and persistence. PMID- 23795642 TI - Nesfatin-1 activates cardiac vagal neurons of nucleus ambiguus and elicits bradycardia in conscious rats. AB - Nesfatin-1, a peptide whose receptor is yet to be identified, has been involved in the modulation of feeding, stress, and metabolic responses. More recently, increasing evidence supports a modulatory role for nesfatin-1 in autonomic and cardiovascular activity. This study was undertaken to test if the expression of nesfatin-1 in the nucleus ambiguus, a key site for parasympathetic cardiac control, may be correlated with a functional role. As we have previously demonstrated that nesfatin-1 elicits Ca2+ signaling in hypothalamic neurons, we first assessed the effect of this peptide on cytosolic Ca2+ in cardiac pre ganglionic neurons of nucleus ambiguus. We provide evidence that nesfatin-1 increases cytosolic Ca2+ concentration via a Gi/o-coupled mechanism. The nesfatin 1-induced Ca2+ rise is critically dependent on Ca2+ influx via P/Q-type voltage activated Ca2+ channels. Repeated administration of nesfatin-1 leads to tachyphylaxis. Furthermore, nesfatin-1 produces a dose-dependent depolarization of cardiac vagal neurons via a Gi/o-coupled mechanism. In vivo studies, using telemetric and tail-cuff monitoring of heart rate and blood pressure, indicate that microinjection of nesfatin-1 into the nucleus ambiguus produces bradycardia not accompanied by a change in blood pressure in conscious rats. Taken together, our results identify for the first time that nesfatin-1 decreases heart rate by activating cardiac vagal neurons of nucleus ambiguus. Our results indicate that nesfatin-1, one of the most potent feeding peptides, increases cytosolic Ca2+ by promoting Ca2+ influx via P/Q channels and depolarizes nucleus ambiguus neurons; both effects are Gi/o-mediated. In vivo studies indicate that microinjection of nesfatin-1 into nucleus ambiguus produces bradycardia in conscious rats. This is the first report that nesfatin-1 increases the parasympathetic cardiac tone. PMID- 23795644 TI - A focused ethnographic assessment of Middle Eastern mothers' infant feeding practices in Canada. AB - The aim of this study was to examine the barriers to following complementary feeding guidelines among Middle Eastern mothers and the cultural considerations of practitioners from an emic perspective. This is a two-phase focused ethnographic assessment of infant feeding among 22 Middle Eastern mothers in Western Canada who had healthy infants aged <1 year. Data were collected through four focus groups conducted in Arabic/Farsi, and were further complemented by comprehensive survey data collected in the second phase of study. Mothers' main criterion for choosing infant foods was whether or not foods were Halal, while food allergens were not causes for concern. Vitamin D supplements were not fed to 18/22 of infants, and mashed dates (Halawi), rice pudding (Muhallabia/Ferni) and sugared water/tea were the first complementary foods commonly consumed. Through constant comparison of qualitative data, three layers of influence emerged, which described mothers' process of infant feeding: socio-cultural, health care system and personal factors. Culture was an umbrella theme influencing all aspects of infant feeding decisions. Mothers cited health care professionals' lack of cultural considerations and lack of relevance and practicality of infant feeding guidelines as the main reasons for ignoring infant feeding recommendations. Early introduction of pre-lacteal feeds and inappropriate types of foods fed to infants among immigrant/refugee Middle Eastern mothers in Canada is cause of concern. Involving trained language interpreters in health teams and educating health care staff on cultural competency may potentially increase maternal trust in the health care system and eventually lead to increased awareness of and adherence to best practices with infant feeding recommendations. PMID- 23795645 TI - Third-generation autofluorescence endoscopy for the detection of early neoplasia in Barrett's esophagus: a pilot study. AB - In Barrett's esophagus (BE), second-generation autofluorescence imaging (AFI-II) improves targeted detection of high-grade intra-epithelial neoplasia (HGIN) and early cancer (EC), yet suffers from high false-positive (FP) rates. The newest generation AFI (AFI-III) specifically targets fluorescence in malignant cells and may therefore improve detection of early neoplasia and reduce FP rate. The aim was to compare AFI-III with AFI-II for endoscopic detection of early neoplasia in BE. BE patients with endoscopically inconspicuous neoplasia underwent two diagnostic endoscopies (AFI-II/AFI-III) in a single session. End-points: number of patients and lesions with HGIN/EC detected with AFI-II and AFI-III after white light endoscopy (WLE) and the value of reinspection of AFI-positive areas with WLE and narrow-band imaging. Forty-five patients were included (38 males, age 65 years). Nineteen patients showed HGIN/EC. AFI-II inspection after WLE increased detection of HGIN/EC from 9 to 15 patients (47 to 79%); AFI-III increased detection from 9 to 17 patients (47 to 89%). WLE plus random biopsies diagnosed 13/19 (68%) HGIN/EC patients. One hundred and four abnormal AFI areas were inspected; 23 (22%) showed HGIN/EC. AFI-II increased detection of HGIN/EC from 10 to 18 lesions (43 to 78%). AFI-III increased detection from 10 to 20 lesions (43 87%). FP rate was 86% for AFI-II and AFI-III. Reinspection with WLE or narrow band imaging reduced FP rate to 21% and 22%, respectively, but misclassified HGIN/EC lesions as unsuspicious in 54% and 31%, respectively. This first feasibility study on third-generation AFI again showed improved targeted detection of HGIN/EC in BE. However, the results do not suggest AFI-III performs significantly better than conventional AFI-II. PMID- 23795646 TI - Multiple behavioural impulsivity tasks predict prospective alcohol involvement in adolescents. AB - AIMS: We investigated reciprocal prospective relationships between multiple behavioural impulsivity tasks (assessing delay discounting, risk-taking and disinhibition) and alcohol involvement (consumption, drunkenness and problems) among adolescents. We hypothesized that performance on the tasks would predict subsequent alcohol involvement, and that alcohol involvement would lead to increases in behavioural impulsivity over time. DESIGN: Cross-lagged prospective design in which impulsivity and alcohol involvement were assessed five times over 2 years (once every 6 months, on average). SETTING: Classrooms in secondary schools in North West England. PARTICIPANTS: Two hundred and eighty-seven adolescents (51.2% male) who were aged 12 or 13 years at study enrolment. MEASUREMENTS: Participants reported their alcohol involvement and completed computerized tasks of disinhibition, delay discounting and risk-taking at each assessment. Cross-sectional and prospective relationships between the variables of interest were investigated using cross-lagged analyses. FINDINGS: All behavioural impulsivity tasks predicted a composite index of alcohol involvement 6 months later (all Ps < 0.01), and these prospective relationships were reliable across the majority of time-points. Importantly, we did not observe the converse relationship across time: alcohol involvement did not predict performance on behavioural impulsivity tasks at any subsequent time point. CONCLUSIONS: Several measures of impulsivity predict escalation in alcohol involvement in young adolescents, but alcohol use does not appear to alter impulsivity. PMID- 23795647 TI - Analysis of distribution patterns of Propionibacterium acnes phylotypes and Peptostreptococcus species from acne lesions. AB - BACKGROUND: The precise roles of Propionibacterium acnes and other anaerobic bacteria in the pathogenesis of acne are still unclear. Recent studies have shown that P. acnes can be further classified into several phylotypes with distinct phenotypes and virulence. Their distribution patterns in acne lesions have rarely been demonstrated. OBJECTIVES: To analyse distribution patterns of P. acnes phylotypes and Peptostreptococcus species on the skin surface of patients with acne and healthy controls, and in comedones, papules and pustules from patients. METHODS: A total of 370 samples from 95 patients with acne and 65 samples from 65 healthy controls were investigated. Three P. acnes phylotypes and three Peptostreptococcus species were identified by polymerase chain reaction primarily using type-specific primers. RESULTS: There was no significant difference in the microflora of the skin surface samples between patients with acne and healthy controls. In acne lesions, distribution patterns between skin surface and comedonal lesions were similar, but they were significantly different from those of both papules and pustules. In the inflammatory acne lesions, the proportion of type IA P. acnes was increased, while those of type IB and II were decreased. The proportion of Peptostreptococcus species was also increased significantly in the inflammatory lesions. CONCLUSIONS: At the precision of this qualitative study, our results do not provide any evidence that different phylotypes in the surface microflora might be important in triggering acne. However, type IA P. acnes and Peptostreptococcus species might be more closely associated with inflammatory acne lesions. PMID- 23795649 TI - Prognostic markers for acute heart failure. AB - INTRODUCTION: Acute heart failure (AHF) is the leading cause of hospitalization in patients over 65 years, representing a heterogenic syndrome and a major burden, as it is associated with elevated health expenditures and high rates of mortality and readmission. AREAS COVERED: This article provides a review of individual markers for risk stratification, including clinical, cardiorenal, hemodynamic, neurohormonal and cardiac biomarkers. In addition, aspects as complementary value, monitoring, risk models and events prediction are analyzed. EXPERT OPINION: In clinical practice, risk stratification of AHF is complex and relies on the integration of bedside evaluation and laboratory biomarkers. Measures of congestion and perfusion, renal function, natriuretic peptides and cardiac troponins have become standard risk markers of death and/or readmission. However, there are numerous research findings that do not translate into an improved clinical management of individuals and a reduction of health costs. Research on this field needs to be redirected in a prospective manner in order to evaluate risk models in the emergency department. This would allow safe identification of patients at lower risk - who could be transferred and managed in out-patient facilities - as well as those biomarkers that, by reflecting pathophysiological routes, could be used as a guide to related therapeutics for improving outcomes. In addition, the identification of specific markers and models closely related with the risk of recurrent AHF is mandatory. Consequently, it is the time for clinicians working in networks to assume a leading role in translating risk assessment in AHF into clinical practice. PMID- 23795648 TI - Persistence of LPS-induced lung inflammation in surfactant protein-C-deficient mice. AB - Pulmonary surfactant protein-C (SP-C) gene-targeted mice (Sftpc(-/-)) develop progressive lung inflammation and remodeling. We hypothesized that SP-C deficiency reduces the ability to suppress repetitive inflammatory injury. Sftpc(+/+) and Sftpc(-/-) mice given three doses of bacterial LPS developed airway and airspace inflammation, which was more intense in the Sftpc(-/-) mice at 3 and 5 days after the final dose. Compared with Sftpc(+/+)mice, inflammatory injury persisted in the lungs of Sftpc(-/-) mice 30 days after the final LPS challenge. Sftpc(-/-) mice showed LPS-induced airway goblet cell hyperplasia with increased detection of Sam pointed Ets domain and FoxA3 transcription factors. Sftpc(-/-) type II alveolar epithelial cells had increased cytokine expression after LPS exposure relative to Sftpc(+/+) cells, indicating that type II cell dysfunction contributes to inflammatory sensitivity. Microarray analyses of isolated type II cells identified a pattern of enhanced expression of inflammatory genes consistent with an intrinsic low-level inflammation resulting from SP-C deficiency. SP-C-containing clinical surfactant extract (Survanta) or SP-C/phospholipid vesicles blocked LPS signaling through the LPS receptor (Toll like receptor [TLR] 4/CD14/MD2) in human embryonic kidney 293T cells, indicating that SP-C blocks LPS-induced cytokine production by a TLR4-dependent mechanism. Phospholipid vesicles alone did not modify the TLR4 response. In vivo deficiency of SP-C leads to inflammation, increased cytokine production by type II cells, and persistent inflammation after repetitive LPS stimulation. PMID- 23795651 TI - Concerted interaction between origin recognition complex (ORC), nucleosomes and replication origin DNA ensures stable ORC-origin binding. AB - Chromosomal replication origins, where DNA replication is initiated, are determined in eukaryotic cells by specific binding of a six-subunit origin recognition complex (ORC). Many biochemical analyses have showed the detailed properties of the ORC-DNA interaction. However, because of the lack of in vitro analysis, the molecular architecture of the ORC-chromatin interaction is unclear. Recently, mainly from in vivo analyses, a role of chromatin in the ORC-origin interaction has been reported, including the existence of a specific pattern of nucleosome positioning around origins and of a specific interaction between chromatin-or core histones-and Orc1, a subunit of ORC. Therefore, to understand how ORC establishes its interaction with origin in vivo, it is essential to know the molecular mechanisms of the ORC-chromatin interaction. Here, we show that ORC purified from yeast binds more stably to origin-containing reconstituted chromatin than to naked DNA and forms a nucleosome-free region at origins. Molecular imaging using atomic force microscopy (AFM) shows that ORC associates with the adjacent nucleosomes and forms a larger complex. Moreover, stable binding of ORC to chromatin requires linker DNA. Thus, ORC establishes its interaction with origin by binding to both nucleosome-free origin DNA and neighboring nucleosomes. PMID- 23795652 TI - Luminescent P-chirogenic copper clusters. AB - P-chirogenic clusters of the cubanes [Cu4I4L4] (L = chiral phosphine) were prepared from (+)- and (-)-ephedrine with L = (S)- or (R)-(R)(Ph)(i-Pr)P (with R = CH3 (seven steps) or C17H35 (10 steps)) with e.e. up to 96%. The X-ray structure of [Cu4I4((R)-(CH3)(Ph)(i-Pr)P)4] confirmed the cubane structure with average Cu...Cu and Cu...I distances of 2.954 and 2.696 A, respectively. The cubane structure of the corresponding [Cu4I4((S)-(CH3)(Ph)(i-Pr)P)4] was established by the comparison of the X-ray powder diffraction patterns, and the opposite optical activity of the (S)- and (R)-ligand-containing clusters was confirmed by circular dichroism spectroscopy. Small-angle X-ray scattering patterns of one cluster bearing a C17H35 chain exhibit a weak signal at 2theta ~ 2.8 degrees (d ~ 31.6 A), indicating some molecular ordering in the liquid state. The emission spectra exhibit two emission bands, both associated with triplet excited states. These two bands are assigned as follows: the high energy emission is due to a halide-to-ligand charge transfer, XLCT, state mixed with LXCT (ligand-to-halide-charge-transfer). The low energy band is assigned to a cluster-centered excited state. Both emissions are found to be thermochromic with the relative intensity changing between 77 and 298 K for the clusters in methylcyclohexane solution. Several differences are observed in the photophysical parameters, emission quantum yields and lifetimes for R = CH3 and C17H35. The measurements of the polarization along the emission indicate that the emission is depolarized, consistent with an approximate tetrahedral geometry of the chromophores. PMID- 23795654 TI - DSM-IV defined conduct disorder and oppositional defiant disorder: an investigation of shared liability in female twins. AB - BACKGROUND: DSM-IV specifies a hierarchal diagnostic structure such that an oppositional defiant disorder (ODD) diagnosis is applied only if criteria are not met for conduct disorder (CD). Genetic studies of ODD and CD support a combination of shared genetic and environmental influences but largely ignore the imposed diagnostic structure. METHOD: We examined whether ODD and CD share an underlying etiology while accounting for DSM-IV diagnostic specifications. Data from 1446 female twin pairs, aged 11-19 years, were fitted to two-stage models adhering to the DSM-IV diagnostic hierarchy. RESULTS: The models suggested that DSM-IV ODD-CD covariation is attributed largely to shared genetic influences. CONCLUSIONS: This is the first study, to our knowledge, to examine genetic and environmental overlap among these disorders while maintaining a DSM-IV hierarchical structure. The findings reflect primarily shared genetic influences and specific (i.e. uncorrelated) shared/familial environmental effects on these DSM-IV-defined behaviors. These results have implications for how best to define CD and ODD for future genetically informed analyses. PMID- 23795656 TI - Impact of scheduled angiographic follow-up in patients treated with primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. AB - Routine scheduled angiographic follow-up (SAF) after percutaneous coronary intervention (PCI) has been associated with a higher rate of target vessel revascularization (TVR). Its benefits are not known. SAF at 13 months after ST segment elevation myocardial infarction (STEMI) was planned in the first 1,800 successfully stented patients enrolled in the Harmonizing Outcomes with RevascularIZatiON and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial. We compared the outcomes of patients with and without SAF at 1 year (before SAF) and at 3 years (after SAF). There were 1,197 patients (66.5% of expected) with and 2,207 patients without SAF. Prior to SAF, the 1-year composite rate of death or myocardial infarction (MI) was not significantly different between the 2 groups (2.7% vs. 3.9%, respectively, P=0.06), although the rate of death was lower (0.1% vs. 2.2%, P<0.0001), nor were there differences in the 1-year rates of TVR, stent thrombosis or major adverse cardiac and cerebral events). At 3 years, death or MI rates were again similar between the groups (8.3% vs. 9.5%, P=0.22), but TVR was more common in the SAF group (17.0% vs. 8.6%, P<0.0001), due to an increase in TVR at time of SAF. In the SAF group, patients in whom TVR was performed before or after the 13-month SAF window had markedly higher 3-year rates of MI and stent thrombosis than patients in whom TVR was performed during SAF or not at all. In conclusion, SAF after primary PCI in STEMI is associated with doubling of the rate of revascularization without an improvement in death or MI, and therefore cannot be recommended. PMID- 23795655 TI - Hemoglobin variants in Muslim community in South Gujarat, Western India. PMID- 23795653 TI - The implication of neuroactive steroids in Tourette's syndrome pathogenesis: A role for 5alpha-reductase? AB - Tourette's syndrome (TS) is a neurodevelopmental disorder characterised by recurring motor and phonic tics. The pathogenesis of TS is considered to reflect dysregulations in the signalling of dopamine (DA) and other neurotransmitters, which lead to excitation/inhibition imbalances in cortico-striato-thalamocortical circuits. The causes of these deficits may reflect complex gene * environment * sex (G * E * S) interactions; indeed, the disorder is markedly predominant in males, with a male-to-female prevalence ratio of approximately 4 : 1. Converging lines of evidence point to neuroactive steroids as being likely molecular candidates to account for G * E * S interactions in TS. Building on these premises, our group has begun examining the possibility that alterations in the steroid biosynthetic process may be directly implicated in TS pathophysiology; in particular, our research has focused on 5alpha-reductase (5alphaR), the enzyme catalysing the key rate-limiting step in the synthesis of pregnane and androstane neurosteroids. In clinical and preclinical studies, we found that 5alphaR inhibitors exerted marked anti-DAergic and tic-suppressing properties, suggesting a central role for this enzyme in TS pathogenesis. Based on these data, we hypothesise that enhancements in 5alphaR activity in early developmental stages may lead to an inappropriate activation of the 'backdoor' pathway for androgen synthesis from adrenarche until the end of puberty. We predict that the ensuing imbalances in steroid homeostasis may impair the signalling of DA and other neurotransmitters, ultimately resulting in the facilitation of tics and other behavioural abnormalities in TS. PMID- 23795658 TI - The role of baseline impedance as a marker of mucosal integrity in children with gastro esophageal reflux disease. AB - OBJECTIVES: Diagnosis of gastro esophageal reflux disease (GERD) in children is challenging. 24-h-pH-multichannel-intraluminal-impedance measurement (pH-MII) is the best diagnostic tool to display gastro esophageal reflux whereas esophageal endoscopy indicates mucosal lesions. The aim of this study was to compare esophageal endoscopy results with reflux parameters such as acid exposure time (reflux index RI), bolus exposure time (bolus index BI), baseline impedance level (BIL) detected by pH-MII in children with suspected GERD. METHODS: Analysis of data from 285 children (38 infants) referred to our hospital with suspected GERD. Division into three 'reflux esophagitis' (RE)-stages depending on the severity of endoscopic and histological findings and comparison with reflux parameters in these stages. Further categorization into four groups based on the pH-MII results. RESULTS: Children with high-grade esophagitis had a significantly lower BIL; otherwise there was no significant association between elevated reflux parameters and esophagitis. Pathological pH-MII results (RI and BI) were associated with lower BIL in the distal impedance channel. The BIL was significantly lower in infants compared to children >1 year regardless of the RI or BI. The main difference between these groups regarding reflux parameters was a longer BI and a higher number of retrograde bolus movements. CONCLUSION: Pathologic pH-MII results are not predictive for an erosive esophagitis and vice versa. Therefore, these two procedures cannot replace each other. A lower BIL is associated with esophagitis >= LA-grade B and may be caused by longer acid but also by longer bolus exposure and thus may be another useful parameter in GERD monitoring. PMID- 23795657 TI - Effects of maternal exposure to phthalates and bisphenol A during pregnancy on gestational age. AB - OBJECTIVE: Phthalates and bisphenol A (BPA) are ubiquitous environmental toxicants, present in high concentrations in numerous consumer products. We hypothesized that maternal exposure to phthalates and BPA in pregnancy is associated with shortened gestation. METHODS: Urinary phthalate and BPA metabolites from 72 pregnant women were measured at the last obstetric clinic visit prior to delivery. Using linear regression models, we estimated the change in gestational age associated with each interquartile range (IQR) increase in phthalate and BPA metabolite concentration. RESULTS: IQR increases in urinary mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and BPA concentrations were associated with 4.2 and 1.1 d decreases in gestation, respectively. When stratified by gender, these alterations were found only in male infants. CONCLUSIONS: We conclude that MEHHP and BPA (free + glucuronide) are associated with reductions in gestation, with effects observed only in males. Our findings are consistent with the idea that these agents induce gender-specific alterations in signaling via PPAR-gamma transcription factor, androgen precursors and/or inflammatory mediators during the initiation of labor. PMID- 23795659 TI - The prevalence of Helicobacter pylori infection in the Netherlands. AB - BACKGROUNDS: The prevalence of Helicobacter pylori has been declining in the developed countries, as it has the incidence of distal gastric carcinoma. Monitoring this decline and identifying populations not benefiting from this decline is a fit task for public health authorities, with blood donors an obvious source of sera. MATERIALS AND METHODS: We tested 1550 randomly selected blood donors, spread over 5-10 year age cohorts, from four regions in the southern half of The Netherlands, for the presence of antibodies against H. pylori and the CagA antigen. These donors were drawn from an area comprising 46% of the native Dutch population, but did not include non-European immigrants. RESULTS: We observed an age specific decline in the mean seroprevalence of H. pylori from 48% for donors born between 1946 and 1935 to 16% for those born between 1987 and 1977. In H. pylori positive donors, the CagA seroprevalence declined from 38% to 14% in the same age cohorts. There were no significant differences between regions in either prevalence. CONCLUSIONS: Our results are compatible with a persistent age-cohort phenomenon for H. pylori prevalence, with the most pronounced decline of CagA+ strains. Nevertheless, almost one in six of the young native Dutch population remains H. pylori positive, implying that, without specific intervention, this bacterium will remain common over the coming decades. PMID- 23795660 TI - Role of miR-19a targeting TNF-alpha in mediating ulcerative colitis. AB - OBJECTIVE: Ulcerative colitis (UC) is a widely studied inflammatory disease associated with differential expression of genes involved in immune function, wound healing, and tissue remodeling. MicroRNAs have been reported to play a role in various cancer types. However, the mechanism of how microRNAs regulate UC remains unclear. METHODS: In the present study, we investigated the role of miR 19a and tumor necrosis factor (TNF)-alpha in human colon tissues with UC and dextran sodium sulfate (DSS)-induced experimental colitis. RESULTS: We identified that the expression of miR-19a was significantly reduced and TNF-alpha was remarkably increased in human colon tissue with UC. Moreover, this observation of miR-19a and TNF-alpha was also occurred in DSS-treated mice colitis. Further, we observed that miR-19a directly regulated TNF-alpha expression because miR-19a can suppress the expression of wild-type TNF-alpha reporter, but not the mutant form. The expression of inflammatory factors TNF-alpha, IL-8, and GM-GSF were significantly elevated upon application of miR-19a inhibitor. CONCLUSION: Taken together, this study determines the levels of miR-19a and TNF-alpha in both DSS induced experimental murine colitis and human UC and further demonstrates that miR-19a might directly regulate TNF-alpha. The findings may provide a new insight in the clinical treatment of UC. PMID- 23795661 TI - Retreatment with peg-interferon and ribavirin in patients with chronic hepatitis C virus genotype 2 or 3 infection with prior relapse. AB - OBJECTIVES: Uncertainty remains regarding the efficacy of retreatment with current standard-of-care peg-interferon (peg-IFN) and ribavirin among patients infected with hepatitis C virus (HCV) genotypes 2 or 3 with relapse after prior therapy. MATERIALS AND METHODS: Seventy-one patients with chronic HCV genotype 2/3 with prior relapse were enrolled in a phase III multicenter study. Patients were retreated with peg-IFNalpha-2a 180 MUg per week and ribavirin 1000/1200 mg daily. Patients having received previous therapy for 24 weeks were retreated for 48 weeks (Group A), whereas patients having received at least 12 weeks but less than 24 weeks of treatment were allocated to either 48 (Group B) or 24 weeks (Group C) on the basis of whether they had achieved rapid virological response (RVR). RESULTS: Sustained virological response (SVR) rates of 53%, 81% and 75% were achieved in groups A, B and C, respectively. Patients with favorable baseline characteristics, e.g., less advanced liver fibrosis, age <40 years, duration of infection <20 years, or BMI < 25 kg/m(2), tended to have more favorable outcomes. All patients achieving HCV RNA below 1000 IU/mL day 6 achieved SVR in contrast to none of the patients with detectable HCV RNA at week 12. CONCLUSIONS: Retreatment with peg-IFN and ribavirin for 24-48 weeks entails SVR among the majority of HCV genotype 2/3 infected patients with prior relapse. However, in light of the prolonged treatment duration, moderate effect and considerable side effects, deterring therapy until new options are available may be preferential, particularly in patients previously treated for 24 weeks. PMID- 23795662 TI - Embryological aspects in autoimmune pancreatitis, proposal of autoimmune dorsal pancreatitis. AB - OBJECTIVE: We examined the anatomy of the pancreatic duct system in patients with autoimmune pancreatitis (AIP) from the standpoint of embryological pancreatic primordial. MATERIAL AND METHODS: The pancreatic duct system involved in 83 AIP patients was embryologically divided into both ventral and dorsal pancreatic ducts (VD type), only the dorsal pancreatic duct (D type), or only the ventral pancreatic duct (V type). RESULTS: The 83 AIP patients were divided into 62 VD type, 20 D type, and 1 V type. Obstructive jaundice was significantly more frequent in VD type (87%) than in D type (0%; p < 0.01), and abdominal pain was more frequent in D type (24%) than in VD type (2%; p < 0.01). Stenosis of the lower bile duct was detected in 98% of VD type and 15% of D type (p < 0.01). In the 67 patients with involvement of the pancreatic head, only the dorsal pancreatic duct was involved with a normal ventral pancreatic duct in four patients (D type). In the four D-type patients, the pancreatic duct system showed complete pancreas divisum (n = 1), incomplete pancreas divisum (n = 2), or normal pancreatic duct system (n = 1). Stenosis of the lower bile duct was seen in three patients, but was mild, resulting in no obstructive jaundice. Three patients reported abdominal pain and one patient developed acute pancreatitis. CONCLUSIONS: We propose a new entity of "autoimmune dorsal pancreatitis" in which only the dorsal pancreas is involved, and involvement of the lower bile duct and obstructive jaundice is rare. PMID- 23795664 TI - Electrostatic modulation of aromatic rings via explicit solvation of substituents. AB - Solvent effects are implicated as playing a major role in modulating electrostatic interactions via through-space and polarization effects, but these phenomena are often hard to dissect. By using synthetic molecular torsion balances and a simple explicit solvation model, we demonstrate that the solvation of substituents substantially affects the electrostatic potential of aromatic rings. Although polarization effects are important, we show that a simple additive through-space model also provides a reasonable account of the experimental data. The results deliver insights into solvent structure and might contribute to the development of computationally inexpensive solvent models. PMID- 23795663 TI - Multicenter randomized controlled trial comparing the performance of 22 gauge versus 25 gauge EUS-FNA needles in solid masses. AB - BACKGROUND AND AIMS: Few randomized studies have assessed the clinical performance of 25-gauge (25G) needles compared with 22-gauge (22G) needles during endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) biopsy of intra abdominal lesions. We aimed to compare the diagnostic yield, as well as performance characteristics of 22G versus 25G EUS biopsy needles by determining their diagnostic capabilities, the number of needle passes as well as cellularity of aspirated tissue specimen. METHODS: The study is a prospective, randomized, multicenter study. Patients were referred between January 2009 and January 2010 for diagnostic EUS including EUS-guided FNA of different lesions adjacent to the upper GI tract. All patients were randomized to EUS-FNA performed with either a 22G or 25G aspiration needle. RESULTS: EUS-FNA was performed in 135 patients (62 patients with a 22G needle). Sensitivity and specificity of the 22G needle was 94.1% and 95.8%, respectively, and for the 25G needle 94.1% and 100%, respectively. Investigators reported better visualization and performance for the 22G needle compared to the 25G (p < 0.0001). The number of tissue slides obtained was higher for the 22G needle during the second and third needle passes (p < 0.05). We did not observe significant differences between the number and preservation status of obtained cells (p > 0.05). CONCLUSIONS: A significant difference was found between the two types of needles in terms of reduced visualization of the 25G needle and suboptimal performance rating. However, this did not impact on overall results since both needles were equally successful in terms of a high diagnostic yield and overall accuracy. PMID- 23795665 TI - Optical properties of graphene nanoribbons encapsulated in single-walled carbon nanotubes. AB - We report the photoluminescence (PL) from graphene nanoribbons (GNRs) encapsulated in single-walled carbon nanotubes (SWCNTs). New PL spectral features originating from GNRs have been detected in the visible spectral range. PL peaks from GNRs have resonant character, and their positions depend on the ribbon geometrical structure in accordance with the theoretical predictions. GNRs were synthesized using confined polymerization and fusion of coronene molecules. GNR@SWCNTs material demonstrates a bright photoluminescence both in infrared (IR) and visible regions. The photoluminescence excitation mapping in the near-IR spectral range has revealed the geometry-dependent shifts of the SWCNT peaks (up to 11 meV in excitation and emission) after the process of polymerization of coronene molecules inside the nanotubes. This behavior has been attributed to the strain of SWCNTs induced by insertion of the coronene molecules. PMID- 23795666 TI - Direct measurement of current-phase relations in superconductor/topological insulator/superconductor junctions. AB - Proximity to a superconductor is predicted to induce exotic quantum phases in topological insulators. Here, scanning superconducting quantum interference device (SQUID) microscopy reveals that aluminum superconducting rings with topologically insulating Bi2Se3 junctions exhibit a conventional, nearly sinusoidal 2pi-periodic current-phase relations. Pearl vortices occur in longer junctions, indicating suppressed superconductivity in aluminum, probably due to a proximity effect. Our observations establish scanning SQUID as a general tool for characterizing proximity effects and for measuring current-phase relations in new materials systems. PMID- 23795667 TI - Segmental relaxations and crystallization-induced phase separation in PVDF/PMMA blends in the presence of surface-functionalized multiwall carbon nanotubes. AB - Crystallization-induced phase separation and segmental relaxations in poly(vinylidene fluoride)/poly(methyl methacrylate) (PVDF/PMMA) blends was systematically investigated by melt-rheology and broadband dielectric spectroscopy in the presence of multiwall carbon nanotubes (MWNTs). Different functionalized MWNTs (amine, -NH2; acid, -COOH) were incorporated in the blends by melt-mixing above the melting temperature of PVDF, where the blends are miscible, and the crystallization induced phase separation was probed in situ by shear rheology. Interestingly, only -NH2 functionalized MWNTs (a-MWNTs) aided in the formation of beta-phase (trans-trans) crystals in PVDF, whereas both the neat blends and the blends with -COOH functionalized MWNTs (c-MWNTs) showed only alpha phase (trans-gauche-trans-gauche') crystals as inferred from wide-angle X-ray diffraction (WXRD) and Fourier transform infrared (FTIR). Furthermore, blends with only a-MWNTs facilitated in heterogeneous nucleation in the blends manifesting in an increase in the calorimetric crystallization temperature and hence, augmented the rheologically determined crystallization induced phase separation temperature. The dielectric relaxations associated with the crystalline phase of PVDF (alphac) was completely absent in the blends with a MWNTs in contrast to neat blends and the blends with c-MWNTs in the dielectric loss spectra. The relaxations in the blends investigated here appeared to follow Havriliak-Negami (HN) empirical equations, and, more interestingly, the dynamic heterogeneity in the system could be mapped by an extra relaxation at higher frequency at the crystallization-induced phase separation temperature. The mean relaxation time (tauHN) was evaluated and observed to be delayed in the presence of MWNTs in the blends, more prominently in the case of blends with a-MWNTs. The latter also showed a significant increase in the dielectric relaxation strength (Deltaepsilon). Electron microscopy and selective etching was used to confirm the localization of MWNTs in the amorphous phases of the interspherulitic regions as observed from scanning electron microscopy (SEM). The evolved crystalline morphology, during crystallization-induced phase separation, was observed to have a strong influence on the charge transport processes in the blends. These observations were further supported by the specific interactions (like dipole induced dipole interaction) between a-MWNTs and PVDF, as inferred from FTIR, and the differences in the crystalline morphology as observed from WXRD and polarized optical microscopy (POM). PMID- 23795668 TI - Theoretical study on the acidities of chiral phosphoric acids in dimethyl sulfoxide: hints for organocatalysis. AB - The pKa values of 41 chiral phosphoric acid-family catalysts in DMSO were predicted using the SMD/M06-2x/6-311++G(2df,2p)//B3LYP/6-31+G(d) method for the first time. The study showed that the calculated pKa's range from -4.23 to 6.16 for absolute pKa values and from -4.21 to 6.38 for relative pKa values. Excellent agreement between the calculated and experimental pKa's was achieved for the few available cases (to a precision of around 0.4 pKa unit), indicating that this strategy may be suitable for calculating highly accurate pKa's. A good linear correlation between the pKa's for 3 and 3' disubstituted phenyl BINOL phosphoric acids and the Hammett constants was obtained. The relationship between the acidities of phosphoric acid catalysts and their reaction activity and selectivity was also discussed. Knowledge of the pKa values of phosphoric acids should be of great value for the understanding of chiral Bronsted acid-catalyzed reactions and may aid in future catalyst design. PMID- 23795669 TI - A new species of Spirura Blanchard, 1849 (Nematoda: Spiruridae) parasite of Heliosciurus gambianus and Xerus erythropus (Rodentia: Sciuridae) in Senegal. AB - A new species of Spirura is described from the stomach of Heliosciurus gambianus and Xerus erythropus (Sciuridae). Considering the number of preanal papillae of males, Babero (1973 ) and Giannetto and Canestri Trotti (1995) proposed the subdivision of the genus into 2 groups; those with 4 pairs of preanal papillae (25 species) and with more than 4 pairs of preanal papillae (4 species). Spirura mounporti n. sp. belongs to the second, with 5 pairs of preanal papillae, and differs from Spirura infundibuliformis (McLeod, 1933) Anderson et al., 1993 , Spirura zapi ( Erickson, 1938 ) Chabaud et al., 1965 , Spirura leiperi Gupta and Trivedi, 1985, and Spirura michiganensis Sandground, 1935 in the number of pairs of pre-cloacal papillae. The new species further differs from other species of the genus in having 21 caudal papillae, in the ratio of spicules:body length, and in its morpho-anatomical characters. PMID- 23795670 TI - Microprecision delivery of oligonucleotides in a 3D tissue model and its characterization using optical imaging. AB - Despite significant potential of oligonucleotides (ONs) for therapeutic and diagnostic applications, rapid and widespread intracellular delivery of ONs in cells situated in tissues such as skin, head and neck cavity, and eye has not been achieved. This study was aimed at evaluating the synergistic combination of microneedle (MN) arrays and biochemical approaches for localized intratissue delivery of oligonucleotides in living cells in 3D tissue models. This synergistic combination was based on the ability of MNs to precisely deliver ONs into tissues to achieve widespread distribution, and the ability of biochemical agents (streptolysin O (SLO) and cholesterol conjugation to ONs) to enhance intracellular ON delivery. The results of this study demonstrate that ON probes were uniformly coated on microneedle arrays and were efficiently released from the microneedle surface upon insertion in tissue phantoms. Co-insertion of microneedles coated with ONs and SLO into 3D tissue models resulted in delivery of ONs into both the cytoplasm and nucleus of cells. Within a short incubation time (35 min), ONs were observed both laterally and along the depth of a 3D tissue up to a distance of 500 MUm from the microneedle insertion point. Similar widespread intratissue distribution of ONs was achieved upon delivery of ON cholesterol conjugates. Uniformity of ON delivery in tissues improved with longer incubation times (24 h) postinsertion. Using cholesterol-conjugated ONs, delivery of ON probes was limited to the cytoplasm of cells within a tissue. Finally, delivery of cholesterol-conjugated anti-GFP ON resulted in reduction of GFP expression in HeLa cells. In summary, the results of this study provide a novel approach for efficient intracellular delivery of ONs in tissues. PMID- 23795671 TI - Maternal serum soluble HLA-G in complicated pregnancies. AB - Preeclampsia, intrauterine growth retardation (IUGR), oligohydramnios, abortus, preterm birth and premature rupture of the membranes (PROM) are significant complications of pregnancy. Insufficient trophoblastic invasion plays an important role in the pathophysiology of pregnancy complications. Soluble human leukocyte antigen-gestation (HLA-G)1/G5 is a molecule associated with trophoblast invasion. When pregnancy complications are predicted early, strategies to prevent these complications can be implemented. The aim of this study was to investigate the relationship between first trimester maternal serum soluble HLA-G1/G5 levels and high-risk pregnancies. A total of 232 pregnant women were followed prospectively. Maternal blood samples were collected for determination of soluble HLA-G1/G5 levels at 11-14 weeks, during which routine serum free beta human chorionic gonadotropin (betahCG) and pregnancy associated plasma protein-A (PAPP A) level determinations in addition to nuchal translucency (NT) measurements for Down's syndrome screening were done during 20-22 weeks gestation. The subjects were classified into normal pregnancy, preeclampsia, oligohydramnios, IUGR, preterm birth and PROM groups. First trimester maternal serum soluble HLA-G1/G5 levels were not significantly different between the groups. First trimester soluble HLA-G1/G5 did not predict high-risk pregnancies. Studies with larger number of cases are need to confirm our findings. PMID- 23795672 TI - X chromosome-wide association study of follicular lymphoma. PMID- 23795673 TI - Synthesis and antiprotozoal activity of dicationic m-terphenyl and 1,3 dipyridylbenzene derivatives. AB - 4,4"-Diamidino-m-terphenyl (1) and 36 analogues were prepared and assayed in vitro against T rypanosoma brucei rhodesiense , Trypanosoma cruzi , Plasmodium falciparum , and Leishmania amazonensis . Twenty-three compounds were highly active against T. b. rhodesiense or P. falciparum. Most noteworthy were amidines 1, 10, and 11 with IC50 of 4 nM against T. b. rhodesiense, and dimethyltetrahydropyrimidinyl analogues 4 and 9 with IC50 values of <= 3 nM against P. falciparum. Bis-pyridylimidamide derivative 31 was 25 times more potent than benznidazole against T. cruzi and slightly more potent than amphotericin B against L. amazonensis. Terphenyldiamidine 1 and dipyridylbenzene analogues 23 and 25 each cured 4/4 mice infected with T. b. rhodesiense STIB900 with four daily 5 mg/kg intraperitoneal doses, as well as with single doses of <= 10 mg/kg. Derivatives 5 and 28 (prodrugs of 1 and 25) each cured 3/4 mice with four daily 25 mg/kg oral doses. PMID- 23795675 TI - Nitrogen deprivation promotes Populus root growth through global transcriptome reprogramming and activation of hierarchical genetic networks. AB - We show a distinct and previously poorly characterized response of poplar (Populus tremula * Populus alba) roots to low nitrogen (LN), which involves activation of root growth and significant transcriptome reprogramming. Analysis of the temporal patterns of enriched ontologies among the differentially expressed genes revealed an ordered assembly of functionally cohesive biological events that aligned well with growth and morphological responses. A core set of 28 biological processes was significantly enriched across the whole studied period and 21 of these were also enriched in the roots of Arabidopsis thaliana during the LN response. More than half (15) of the 28 processes belong to gene ontology (GO) terms associated with signaling and signal transduction pathways, suggesting the presence of conserved signaling mechanisms triggered by LN. A reconstruction of genetic regulatory network analysis revealed a sub-network centered on a PtaNAC1 (P. tremula * alba NAM, ATAF, CUC 1) transcription factor. PtaNAC1 root-specific up-regulation increased root biomass and significantly changed the expression of the connected hub genes specifically under LN. Our results provide evidence that the root response to LN involves hierarchically structured genetic networks centered on key regulatory factors. Targeting these factors via genetic engineering or breeding approaches can allow dynamic adjustment of root architecture in response to variable nitrogen availabilities in the soil. PMID- 23795674 TI - Influence of affective manipulations on cigarette craving: a meta-analysis. AB - BACKGROUND AND AIMS: Retrospective self-report and observational studies have yielded inconsistent findings regarding the capacity of negative affect (NA) to increase smoking motivation among dependent samples. Controlled laboratory studies offer an alternative paradigm for testing the role of affective state upon smoking motivation. The aim of the current study was to quantify cue provoked cravings produced by affective manipulations in the published literature, and to identify theoretical and methodological moderators. METHODS: We conducted a systematic literature search to identify experimental studies that manipulated NA or positive affect (PA), and assessed post-manipulation craving. Separate random-effects meta-analyses examined NA and PA cues as predictors of self-reported craving. Self-reported affect (NA and PA), nicotine deprivation, gender, nicotine dependence, order of cue presentation, single versus multi-item craving assessment and affect induction method were tested as moderators of affective cue-induced craving. RESULTS: NA manipulations produced a medium effect [g = 0.47; confidence interval (CI) = 0.31-0.63] on craving, but no main effects were found for PA manipulations (g = 0.05; CI = -0.09 to 0.20) on craving. Self reported NA moderated the extent to which NA and PA manipulations elicited craving (P < 0.02 for each). That is, more effective NA manipulations produced greater cravings, and PA manipulations reduced cravings when they reduced NA. CONCLUSIONS: Laboratory studies indicate that negative, but not positive, affect is a situational determinant of cravings to smoke among dependent smokers. Adverse emotional states increase craving to smoke among dependent smokers, but positive emotional states do not consistently reduce craving to smoke. PMID- 23795676 TI - Response to 'Determining the utility of the 60-min cortisol measurement in the short Synacthen test'. PMID- 23795677 TI - Rutin : therapeutic potential and recent advances in drug delivery. AB - INTRODUCTION: Natural compounds such as bioflavonoids have found application in health care system due to their wide biological activities, high safety margins and lower cost. Rutin , a polyphenolic bioflavonoid has shown wide range of pharmacological applications due to its significant antioxidant properties. Conventionally, it is used as antimicrobial, antifungal, and antiallergic agent. However, current research has shown its multispectrum pharmacological benefits for the treatment of various chronic diseases such as cancer, diabetes, hypertension and hypercholesterolemia. Its use is advantageous over other flavonoids as it is a nontoxic and nonoxidizable molecule. AREAS COVERED: This review focus on various studies done on rutin explaining its broad spectrum pharmacological activities. In addition, this review will also focus on the challenges associated with the drug and various approaches to improve the oral bioavailability of rutin. EXPERT OPINION: Rutin is a highly potent molecule due to its strong antioxidant properties. In the near future, enhancing its bioavailability using novel drug delivery methods having minimum side effects will bring this promising natural molecule to the forefront of therapy for the treatment of various chronic human diseases. PMID- 23795678 TI - Using grounded theory methodology to conceptualize the mother-infant communication dynamic: potential application to compliance with infant feeding recommendations. AB - Excessive, rapid weight gain in early infancy has been linked to risk of later overweight and obesity. Inappropriate infant feeding practices associated with this rapid weight gain are currently of great interest. Understanding the origin of these practices may increase the effectiveness of interventions. Low-income populations in the Southeastern United States are at increased risk for development of inappropriate infant feeding practices, secondary to the relatively low rates of breastfeeding reported from this region. The objective was to use grounded theory methodology (GTM) to explore interactions between mothers and infants that may influence development of feeding practices, and to do so among low-income, primiparous, Southeastern United States mothers. Analysis of 15 in-depth phone interviews resulted in development of a theoretical model in which Mother-Infant Communication Dynamic emerged as the central concept. The central concept suggests a communication pattern developed over the first year of life, based on a positive feedback loop, which is harmonious and results in the maternal perception of mother and infant now speaking the same language. Importantly, though harmonious, this dynamic may result from inaccurate maternal interpretation of infant cues and behaviours, subsequently leading to inappropriate infant feeding practices. Future research should test this theoretical model using direct observation of mother-infant communication, to increase the understanding of maternal interpretation of infant cues. Subsequently, interventions targeting accurate maternal interpretation of and response to infant cues, and impact on rate of infant weight gain could be tested. If effective, health care providers could potentially use these concepts to attenuate excess rapid infant weight gain. PMID- 23795679 TI - Common variation in NCAN, a risk factor for bipolar disorder and schizophrenia, influences local cortical folding in schizophrenia. AB - BACKGROUND: Recent studies have provided strong evidence that variation in the gene neurocan (NCAN, rs1064395) is a common risk factor for bipolar disorder (BD) and schizophrenia. However, the possible relevance of NCAN variation to disease mechanisms in the human brain has not yet been explored. Thus, to identify a putative pathomechanism, we tested whether the risk allele has an influence on cortical thickness and folding in a well-characterized sample of patients with schizophrenia and healthy controls. METHOD: Sixty-three patients and 65 controls underwent T1-weighted magnetic resonance imaging (MRI) and were genotyped for the single nucleotide polymorphism (SNP) rs1064395. Folding and thickness were analysed on a node-by-node basis using a surface-based approach (FreeSurfer). RESULTS: In patients, NCAN risk status (defined by AA and AG carriers) was found to be associated with higher folding in the right lateral occipital region and at a trend level for the left dorsolateral prefrontal cortex. Controls did not show any association (p > 0.05). For cortical thickness, there was no significant effect in either patients or controls. CONCLUSIONS: This study is the first to describe an effect of the NCAN risk variant on brain structure. Our data show that the NCAN risk allele influences cortical folding in the occipital and prefrontal cortex, which may establish disease susceptibility during neurodevelopment. The findings suggest that NCAN is involved in visual processing and top-down cognitive functioning. Both major cognitive processes are known to be disturbed in schizophrenia. Moreover, our study reveals new evidence for a specific genetic influence on local cortical folding in schizophrenia. PMID- 23795680 TI - Translational research on esophageal adenocarcinoma: from cell line to clinic. AB - Human esophageal adenocarcinoma (EAC) cell lines have made a substantial contribution to elucidating mechanisms of carcinogenesis and drug discovery. Model research on EAC relies almost entirely on a relatively small set of established tumor cell lines because appropriate animal models are lacking. Nowadays, more than 20% of all fundamental translational research studies regarding EAC are partially or entirely based on these cell lines. The ready availability of these cell lines to investigators worldwide have resulted in more than 250 publications, including many examples of important biomedical discoveries. The high genomic similarities (but certainly not completely identical) between the EAC cell lines and their original tumors provide rational for their use. Recently, in a collaborative effort all available EAC cell lines have been verified resulting in the establishment of a reliable panel of 10 EAC cell lines. It could be expected that the value of these cell lines increases as unlimited source of tumor material because new biomedical techniques require more tumor cells and the supply of viable tumor cells is diminishing because of neoadjuvant chemo(radio)therapy of patients with EAC. Here, we review the history of the EAC cell lines and their utility in translational research and biomedical discovery. PMID- 23795681 TI - Cascading "Triclick" functionalization of poly(caprolactone) thin films quantified via a quartz crystal microbalance. AB - A series of mono- and multifunctionalized degradable polyesters bearing various "clickable" groups, including ketone, alkyne, azide, and methyl acrylate (MA) are reported. Using this approach, we demonstrate a cascade approach to immobilize and quantitate three separate bioactive groups onto poly(caprolactone) (PCL) thin films. The materials are based on tunable copolymer compositions of epsilon caprolactone and 2-oxepane-1,5-dione. A quartz crystal microbalance (QCM) was used to quantify the rate and extent of surface conjugation between RGD peptide and polymer thin films using "click" chemistry methods. The results show that alkyne-functionalized polymers have the highest conversion efficiency, followed by MA and azide polymers, while polymer films possessing keto groups are less amenable to surface functionalization. The successful conjugation was further confirmed by static contact angle measurements, with a smaller contact angle correlating directly with lower levels of surface peptide conjugation. QCM results quantify the sequential immobilization of peptides on the PCL thin films and indicate that Michael addition must occur first, followed by azide-alkyne Huisgen cycloadditions. PMID- 23795682 TI - Molecular imaging: an innovative force in musculoskeletal radiology. AB - OBJECTIVE: A review of the innovative role molecular imaging plays in musculoskeletal radiology is provided. Musculoskeletal molecular imaging is under development in four key areas: imaging the activity of osteoblasts and osteoclasts, imaging of molecular and cellular biomarkers of arthritic joint destruction, cellular imaging of osteomyelitis, and imaging generators of musculoskeletal pain. CONCLUSION: Together, these applications suggest that next generation musculoskeletal radiology will facilitate quantitative visualization of molecular and cellular biomarkers, an advancement that appeared futuristic just a decade ago. PMID- 23795683 TI - Receptor-mediated recognition of mycobacterial pathogens. AB - Mycobacteria are a genus of bacteria that range from the non-pathogenic Mycobacterium smegmatis to Mycobacterium tuberculosis, the causative agent of tuberculosis in humans. Mycobacteria primarily infect host tissues through inhalation or ingestion. They are phagocytosed by host macrophages and dendritic cells. Here, conserved pathogen-associated molecular patterns (PAMPs) on the surface of mycobacteria are recognized by phagocytic pattern recognition receptors (PRRs). Several families of PRRs have been shown to non-opsonically recognize mycobacterial PAMPs, including membrane-bound C-type lectin receptors, membrane-bound and cytosolic Toll-like receptors and cytosolic NOD-like receptors. Recently, a possible role for intracellular cytosolic PRRs in the recognition of mycobacterial pathogens has been proposed. Here, we discuss currentideas on receptor-mediated recognition of mycobacterial pathogens by macrophages and dendritic cells. PMID- 23795684 TI - Optimal revascularization strategies for percutaneous coronary intervention of distal anastomotic lesions after coronary artery bypass surgery. AB - OBJECTIVE: To determine the best revascularization strategy when treating distal anastomotic lesions. BACKGROUND: Distal anastomotic lesions are the most common reason for venous graft failure especially early after bypass surgery. However, the best percutaneous method for treating these lesions is still controversial. METHODS: All patients from 2/2000 to 1/2011 who underwent percutaneous coronary intervention of bypass graft distal anastomotic lesions were retrospectively enrolled. Among the 139 patients included, 26 (18.7%) were treated with plain old balloon angioplasty (POBA), 68 (48.9%) with bare metal stents (BMS), and 45 (32.4%) with drug-eluting stents (DES). RESULTS: Baseline characteristics were generally comparable among the 3 groups. At 6 months' follow-up, the highest rate of target lesion revascularization-major adverse cardiac events (TLR-MACE) was seen in the BMS group compared to the DES and POBA groups (16.2 vs. 2.2 vs. 3.8%, respectively, P=0.03), which was driven mainly by the highest rates of death and TLR in the BMS group (11.8 and 4.7%, respectively). At 1-year follow-up, a higher rate of TLR-MACE was seen in the BMS group compared to the DES and POBA groups (20.6 vs. 11.1 vs. 7.7%, respectively, P=0.19). After adjustment, on Cox regression analysis for hazard ratios, no significant differences were found among the 3 groups at 1-year follow-up of TLR-MACE. CONCLUSIONS: When selecting the treatment modality for saphenous vein graft distal anastomotic lesions, BMS implantation should be discouraged while POBA and DES implantation can be performed with favorable long-term outcomes. The optimal treatment approach should be evaluated in large, randomized clinical trials. PMID- 23795685 TI - A comparison of positive reinforcement training techniques in owl and squirrel monkeys: time required to train to reliability. AB - Positive reinforcement training (PRT) techniques enhance the psychological well being of nonhuman primates by increasing the animal's control over his or her environment and desensitizing the animal to stressful stimuli. However, the literature on PRT in neotropical primates is limited. Here PRT data from owl monkeys and squirrel monkeys are presented, including the length of time to train subjects to target, present hand, and present foot, important responses that can be used to aid in health inspection and treatment. A high percentage of the squirrel and owl monkeys were successfully trained on target and present hand. Present foot, a less natural response, was harder to train and maintain. Although squirrel monkeys did learn to target significantly faster than owl monkeys, the 2 genera did not differ on time to train on subsequent behavior. These data demonstrate that although owl monkeys may require slightly more time to acclimate to a PRT program, it is still possible to establish a PRT program with neotropical primates, and once animals have been introduced to the program, they can learn new responses in a relatively few short sessions. PMID- 23795686 TI - Community partnering as a tool for improving live release rate in animal shelters in the United States. AB - Collaboration among all shelters and nonhuman animal welfare groups within a community along with the transparent, shared reporting of uniform data have been promoted as effective ways to increase the number of animals' lives saved. This article summarizes the shelter intakes, outcomes, and live release rate (LRR) from 6 geographically diverse communities participating in the American Society for the Prevention of Cruelty to Animals Partnership program for 5 years (2007 2011). This program is both a grant program and a coaching program that works to focus the community partners on a data-driven goal using standardized definitions and metrics. There was improvement in LRR in all communities over time regardless of intake numbers, human population, or mix of dogs/puppies and cats/kittens entering shelters. Averaged across all communities over the 5-year period, there was an overall improvement in LRR of 62%. Within individual communities, the degree of improvement ranged from 18% to 96%. This improvement in LRR was accomplished through a wide variety of programs in each community based on resources and interests during the time period. PMID- 23795687 TI - The use of positive reinforcement in training zebra sharks (Stegostoma fasciatum). AB - Positive reinforcement training (PRT) was used on 4 adult zebra sharks, Stegostoma fasciatum, housed at the Downtown Aquarium, Denver, to determine the ability of zebra sharks to become desensitized to various stimuli associated with veterinary procedures. One male and 3 female sharks were trained for 12 weeks. As a result of PRT, all 4 zebra sharks were desensitized to staying within a closed holding tank off of the main exhibit, the presence of multiple trainers in the closed holding tank, and tactile stimulation. One of the 4 zebra sharks was also successfully desensitized to the presence of a stretcher being brought into the holding tank. All of these procedures are common in veterinary examinations, and it is hoped that desensitization to these stimuli will reduce the stress associated with examinations. The training accomplished has allowed for easier maintenance of the zebra sharks by the aquarium staff and an improvement in the care of the sharks. PMID- 23795688 TI - Individualism and nonindividualism in the application of nonhuman animal welfare to policy. AB - Science-based policy making and assessments are individualistic insofar as they are sensitive to interindividual differences, intraindividual connectivity, or both. Several scientists and policymakers have argued that nonhuman animal welfare should relate to individual animals, but there are reasons for both individualistic and nonindividualistic approaches. Opportunities to develop more individualistic approaches include employing concepts such as "quality-of-life," "welfare opportunities," and greater stockperson flexibility. PMID- 23795689 TI - Improved nonhuman animal welfare is related more to income equality than it is to income. AB - The link between nonhuman animal welfare, income, and income inequality (Gini coefficient) was tested using consumption of animal products, laws protecting animals on the farm from the worst abuses, and animals used in experimentation as indicators. Experimentation on all animals and on rodents significantly increased in high-income European countries, although there was some evidence that the increase in experimentation on cats and dogs started to flatten out for the highest income countries. Consumption of all flesh products in high-income countries declined in more equal societies. More equal high-income countries also had stricter regulations protecting animals, although the same correlation was not seen between U.S. states. In New Zealand, there was some evidence that testing on cats and dogs declined during years when equality was improving. The results provide little evidence for a Kuznets effect of income on animal welfare, with the possible exception of companion animal treatment. They do, however, suggest that greater equality can be a predictor for better treatment of animals. Previous research has strongly suggested that social conditions for humans improve with greater equality. The same may be true for nonhuman animals. Alternatively, conditions conducive to improving human income equality may also lead to better animal welfare outcomes. PMID- 23795690 TI - In search of the internal structure of the processes underlying interval timing in the sub-second and the second range: a confirmatory factor analysis approach. AB - One of the earliest accounts of duration perception by Karl von Vierordt implied a common process underlying the timing of intervals in the sub-second and the second range. To date, there are two major explanatory approaches for the timing of brief intervals: the Common Timing Hypothesis and the Distinct Timing Hypothesis. While the common timing hypothesis also proceeds from a unitary timing process, the distinct timing hypothesis suggests two dissociable, independent mechanisms for the timing of intervals in the sub-second and the second range, respectively. In the present paper, we introduce confirmatory factor analysis (CFA) to elucidate the internal structure of interval timing in the sub-second and the second range. Our results indicate that the assumption of two mechanisms underlying the processing of intervals in the second and the sub second range might be more appropriate than the assumption of a unitary timing mechanism. In contrast to the basic assumption of the distinct timing hypothesis, however, these two timing mechanisms are closely associated with each other and share 77% of common variance. This finding suggests either a strong functional relationship between the two timing mechanisms or a hierarchically organized internal structure. Findings are discussed in the light of existing psychophysical and neurophysiological data. PMID- 23795691 TI - Novel uses of imaging in AF ablation. AB - AF represents a significant burden for patients, clinicians and health policy makers alike. Catheter based AF ablation is gaining an increasing role as an effective treatment for AF, capable of reducing or even eliminating the disease. AF ablation relies on isolation of arrhthymogenic triggers and alteration of the atrial substrate by carefully targeted atrial ablation, using a minimally invasive approach. Pre-procedural CT, MRI and echocardiography are crucial in evaluating the degree of atrial remodelling which may impact of procedural success, as well as identification of crucial cardiac and non-cardiac adjacent structures, and LAA thrombus. Electro-anatomical mapping is the cornerstone of intra-procedural imaging, which can be optimised by integration with pre procedural imaging. Other technologies such as 3D rotational angiograpy, intracardiac echocardiography and real-time MRI are improving the safety and efficacy of the procedure. Post-procedural MRI and CT can effectively monitor and evaluate procedural complications and atrial structure and remodelling. Recent patents demonstrate the wealth of technological advancements in AF ablation and are evident in multiple aspects of the procedure. PMID- 23795692 TI - Recent advances in antiarrhythmic drug treatment of atrial fibrillation. AB - Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia in clinical practice associated with significant morbidity and mortality. With the growing number of the affected individuals, the development of safe and effective treatment options for AF has become a worldwide priority. Currently available antiarrhythmic medications for the restoration and maintenance of sinus rhythm have limitations due to the modest efficacy and a potential for adverseeffects. Although substantial progress has been made in AF-ablation techniques, broad application of these nonpharmacological treatment modalities is limited and antiarrhythmic drug treatment is still the cornerstone and the first-line therapy for the majority of AF patients. Improvements in the understanding of the principal pathophysiological mechanisms of AF obtained in the last several years have provided promising treatment opportunities. New therapeutic options are based on the more selective targeting of ion channels and intercellular connection proteins predominantly expressed in the atria, the restoration of intracellular Ca(2+) homeostasis and the prevention of AF-associated electrical and structural remodeling. In this review, we provide a highlight of the most important pathophysiological mechanisms in AF with a relation to the potential therapeutic interventions, and discuss novel findings regarding the current and future pharmacological AF management and recent patents. PMID- 23795693 TI - Induced synthesis of oestrogens by glia in the songbird brain. AB - Studies on birds have long provided landmarks and touchstones in the fields of neuroendocrinology, immunology and neuroplasticity. The passerine brain is an excellent model for studying the actions of hormones, including steroids, on a diversity of behavioural endpoints. Oestrogens, for example, have profound effects on avian neuroanatomy and neurophysiology throughout life and, importantly, are synthesised at high levels within neurones of the songbird brain. More recently, aromatisation in another set of neural cells has been identified. Specifically, aromatase expression is induced in astrocytes and radial glia following disruption of the neuropil by multiple forms of perturbation. The avian brain, therefore, can be provided with high levels of oestrogens constitutively or via induction, by aromatisation in neurones and glia, respectively. In this review, we begin with the initial discovery of aromatisation by non-neuronal cells and discuss the mechanisms underlying the induction of aromatase expression in glial cells. We then focus on the emerging interactions between the neuroendocrine and neuroimmune systems with respect to brain injury. Next, we briefly review the extensive literature on the influence of glial aromatisation on neuroplasticity, and end with some recent data on sex differences in the induction of glial aromatase in the zebra finch. Throughout this review, we consider the unanswered questions and future studies that may emerge from these findings. PMID- 23795694 TI - Self-assembled containers based on extended tetrathiafulvalene. AB - Two original self-assembled containers constituted each by six electroactive subunits are described. They are synthesized from a concave tetratopic pi extended tetrathiafulvalene ligand bearing four pyridyl units and cis M(dppf)(OTf)2 (M = Pd or Pt; dppf = 1,1'-bis(diphenylphosphino)ferrocene; OTf = trifluoromethane-sulfonate) complexes. Both fully characterized assemblies present an oblate spheroidal cavity that can incorporate one perylene molecule. PMID- 23795695 TI - Correlation approach for the detection of the heartbeat intervals using force sensors placed under the bed posts. AB - This study proposes a method for detecting the heartbeat intervals of a person lying on a bed from ballistocardiographic signals recorded unobtrusively with four dynamic force sensors located under the bed posts. The method does not recognize individual heartbeats, but the intervals where the correlation between two consecutive signal segments maximizes. This study evaluated the performance of the method with nine subjects in 1-h long recordings and achieved 91% beat-to beat interval (BBI) recognition coverage; 98.6% of the detected BBIs differed less than 50 ms from the values calculated from a reference electrocardiogram signal. This study also evaluated the reliability of two parameters of heart rate variability that have been used in sleep quality assessment in several studies and are usually calculated for 30 s epochs. The results suggest that the method is able to provide sufficient reliability for using the data in evaluation of sleep quality. PMID- 23795696 TI - Experimental research on anchoring force in intestine for the motion of capsule robot. AB - Multiple research groups are currently attempting to develop less-invasive robotic capsule endoscopes (RCEs) with better outcomes for enteroscopic procedures. Understanding the biomechanical response of the bowel to RCE is crucial for optimizing the design of these devices. For this reason, this study aims to develop an analytical model to predict the anchoring force of the model when travelling through the intestine. Previous work has developed, characterized and tested the frictional characteristics of the intestine with microgroove structures that had different surface contours. This work tested basic anchoring force characteristics with custom-built testers and clamping mechanism dummies to analyse the robot clamping movement (which is vital to improving movement efficiency). Balloon-shaped and leg-based clamping mechanisms were developed, which were found to have variable anchoring forces from 0.01 N to 1.2 N. After analysing the experimental results it was found that: (a) robot weight does not play a major role in anchoring force; (b) an increase in anchoring force corresponded to an increase in diameter of the clamping mechanism; and (c) textured contact surfaces effectively increased friction. These results could be explained by the biomechanical response of the intestine, friction and mucoadhesion characteristics of the small intestine material. With these factors considered, a model was developed for determining anchoring force in the small intestine. PMID- 23795697 TI - The effect of foot arch on plantar pressure distribution during standing. AB - The aim of this study was to explore how foot type affects plantar pressure distribution during standing. In this study, 32 healthy subjects voluntarily participated and the subject feet were classified as: normal feet (n = 23), flat feet (n = 14) and high arch feet (n = 27) according to arch index (AI) values obtained from foot pressure intensity image analysis. Foot pressure intensity images were acquired by a pedopowergraph system to obtain a foot pressure distribution parameter-power ratio (PR) during standing in eight different regions of the foot. Contact area and mean PR were analysed in hind foot, mid foot and fore foot regions. One-way analysis of variance was used to determine statistical differences between groups. The contact area and mean PR value beneath the mid-foot was significantly increased in the low arch foot when compared to the normal arch foot and high arch foot (p < 0.001) in both feet. However, subjects with low-arch feet had significantly higher body mass index (BMI) compared to subjects with high-arch feet (p < 0.05) and subjects with normal arch feet (p < 0.05) in both feet. In addition, subjects with low-arch feet had significant differences in arch index (AI) value as compared to subjects with high-arch feet (p < 0.001) and subjects with normal arch feet (p < 0.05) in both feet. Mean mid-foot PR value were positively (r = 0.54) correlated with increased arch index (AI) value. A significant (p < 0.05) change was obtained in PR value beneath the mid-foot of low arch feet when compared with other groups in both feet. The findings suggest that there is an increased mid-foot PR value in the low arch foot as compared to the normal arch foot and high arch foot during standing. Therefore, individuals with low arch feet could be at high risk for mid foot collapse and Charcot foot problems, indicating that foot type should be assessed when determining an individual's risk for foot injury. PMID- 23795701 TI - Formation of a stable p-n junction in a liquid-gated MoS2 ambipolar transistor. AB - Molybdenum disulfide (MoS2) has gained attention because of its high mobility and circular dichroism. As a crucial step to merge these advantages into a single device, we present a method that electronically controls and locates p-n junctions in liquid-gated ambipolar MoS2 transistors. A bias-independent p-n junction was formed, and it displayed rectifying I-V characteristics. This p-n diode could perform a crucial role in the development of optoelectronic valleytronic devices. PMID- 23795702 TI - Dynamics and mechanism of flame retardants in polymer matrixes: experiment and simulation. AB - We investigate the dynamics and the mechanism of flame retardants in polycarbonate matrixes to explore for a way of designing efficient and environment-friendly flame retardants. The high phosphorus content of organic phosphates has been considered as a requirement for efficient flame retardants. We show, however, that one can enhance the efficiency of flame retardants even with a relatively low phosphorus content by tuning the dynamics and the intermolecular interactions of flame retardants. This would enable one to design bulkier flame retardants that should be less volatile and less harmful in indoor environments. UL94 flammability tests indicate that even though the phosphorus content of 2,4-di-tert-butylphenyl diphenyl phosphate (DDP) is much smaller with two bulky tertiary butyl groups than that of triphenyl phosphate (TPP), DDP should be as efficient of a flame retardant as TPP, which is a widely used flame retardant. On the other hand, the 2-tert-butylphenyl diphenyl phosphate (2 tBuDP), with a lower phosphorus content than TPP but with a greater phosphorus content than DDP, is less efficient as a flame retardant than both DDP and TPP. Dynamic secondary ion mass spectrometry and molecular dynamics simulations reveal that the diffusion of DDP is slower by an order of magnitude at low temperature than that of TPP but becomes comparable to that of TPP at the ignition temperature. This implies that DDP should be much less volatile than TPP at low temperature, which is confirmed by thermogravimetric analysis. We also find from Fourier transform infrared spectroscopy that Fries rearrangement and char formation are suppressed more by DDP than by TPP. The low volatility and the suppressed char formation of DDP suggest that the enhanced flame retardancy of DDP should be attributed to its slow diffusivity at room temperature and yet sufficiently high diffusivity at high temperature. PMID- 23795703 TI - Synthesis of 1-vinylidene-naphthofurans: a thermally reversible photochromic system that colors only when adsorbed on silica gel. AB - A set of new 1-vinylidene-1,2-dihydro-naphtho[2,1-b]furans were unexpectedly obtained in the reaction of 2-naphthol with readily available 1,1,4,4 tetraarylbut-2-yne-1,4-diols. Surprisingly, when adsorbed in silica gel, these compounds exhibit photochromism at room temperature, whereas not in solution and in the solid state. UV or sunlight irradiation leads, in a few seconds, to the formation of intense pink/violet to green colors that bleach completely in a few minutes in the dark. These new compounds also exhibit reversible acidochromic properties in solution: addition of TFA leads to the opening of the furan ring and addition of a proton to the allene function, leading to a conjugated and violet tertiary carbocation that returned immediately to the uncolored allenic structure upon addition of a weak base. PMID- 23795704 TI - Monogenoid infection of neonatal and older juvenile lemon sharks, Negaprion brevirostris (Carcharhinidae), in a shark nursery. AB - Fifty lemon sharks, Negaprion brevirostris , were captured in a shallow, mangrove fringed shark nursery at Bimini, Bahamas and examined for the presence of skin dwelling ectoparasitic monogenoids (Monogenoidea). Sixteen sharks were infected by Dermophthirius nigrellii (Microbothriidae); the youngest host was estimated to be 3- to 4-wk-old. Infection prevalence, mean intensity, and median intensity (0.32, 2.63, and 2.0, respectively, for all sharks) were not significantly different between neonates (estimated ages 3- to 10-wk-old) and non-neonatal juveniles (estimated ages 1- to 4-yr-old), suggesting that soon after parturition lemon sharks acquire infection levels of D. nigrellii matching those of juvenile conspecifics. Monogenoids were only found on the trailing portion of the first and second dorsal fins and upper lobe of the caudal fin. The prevalence of D. nigrellii was highest on the first dorsal fin; however, the mean and median intensities of D. nigrellii were similar between fins in all but 1 case. These results raise important husbandry implications regarding the practice of preferentially seeking neonatal and other small lemon sharks for captivity. PMID- 23795705 TI - Subjective social status predicts wintertime febrile acute respiratory illness among women healthcare personnel. AB - OBJECTIVE: We ask whether subjective social status (SSS) predicts rates of wintertime febrile acute respiratory illness (ARI). METHODS: 1,373 women and 346 men were enrolled from September 1 through November 30, 2010 as part of a prospective cohort study of health care personnel (HCP) at two medical centers. A questionnaire was completed at enrollment followed by 20 weeks of surveillance. ARI was an illness with fever and cough self-reported via weekly telephone or Internet-based surveillance. RESULTS: For both sexes, lower SSS was associated with younger age, less education, lower neighborhood household income, being unmarried, lower occupational status, working in outpatient settings, and poorer self-rated health status. Demographic and occupational covariates explained 23% and 42% of the variance (R2) in SSS among women and men, respectively. Smoking, exercise frequency, and sleep quality were also associated with SSS, but these factors explained little additional variance (3-4%). Among women HCP, lower SSS at enrollment was associated with higher rates of subsequent ARI (unadjusted beta = -.21 [+/-.05], p < .001 for ordinal data). Adjusting for all covariates reduced the effect size of the SSS minimally (adjusted beta = -.19 [+/-.06], p < .001). Among men HCP, there was no univariate SSS-ARI association and after adjusting for all covariates the effect was opposite of our hypothesis (adjusted beta = .33 [+/-.17], p < .05). CONCLUSIONS: Women (but not men) with lower SSS were more likely to report an ARI during surveillance, and the SSS-ARI association was independent of demographics, occupational status, health, and health behaviors. PMID- 23795706 TI - Behavioral intentions to HIV test and subsequent testing: the moderating role of sociodemographic characteristics. AB - OBJECTIVE: Health behavior theorists have proposed that cognitive variables (e.g., intentions to change, self-efficacy) drive individual health behaviors, and most HIV/AIDS prevention interventions are grounded in this notion. However, some scholars have suggested that marginalized groups experience structural barriers to enacting their healthy intentions, and thus, cognitive variables might be a poorer predictor of health behaviors in these populations. The purpose of the present study was to test the possibility that intentions are a poorer predictor of behavior among younger, lower SES, and ethnic minority individuals. METHOD: Using longitudinal data from a sample of men who have sex with men (N = 487), we examined whether baseline behavioral intentions to obtain an HIV test differed by socioeconomic status (SES), age, and race/ethnicity and whether the prospective association between intentions to test and subsequent testing differed by these sociodemographic variables. RESULTS: Lower-status individuals expressed equal or greater intentions to obtain an HIV test at baseline. However, intentions to obtain an HIV test did not predict subsequent testing behavior among low-SES men and younger men. Race/ethnicity did not moderate the intentions behavior relation. CONCLUSIONS: Although lower-status individuals express equal or greater intentions to obtain HIV testing, they appear to be less likely to act on these intentions. HIV prevention strategies that target cognitive variables, such as intentions, must recognize that they may be less reliable predictors of health behavior among vulnerable populations. Future research and interventions must explore and address the barriers that marginalized and lower-status individuals experience in enacting their healthy intentions. PMID- 23795700 TI - A new set of primers for COI amplification from freshwater microcrustaceans. AB - Despite the contribution of DNA barcoding towards understanding the biodiversity and distribution of species, the success of COI amplification has been quite variable when it comes to freshwater zooplankton (Elias-Gutierrez & Valdez-Moreno 2008; Jeffery et al. 2011). Some genera of microcrustaceans seem to be more difficult to amplify than others. For example, Macrothrix, Scapholeberis, Diaphanosoma and cyclopoids have yielded limited results. Among several possible reasons for the inability to barcode freshwater microcrustaceans is that there does not exist a specific set of primers for COI amplification. To this end, we developed a zooplankton - specific set of primers, which significantly increased average amplification success (20% increase). With these primers, we observed an overall success of over 70% for Sididae and Chydoridae, and more than 80% for Daphniidae, Moinidae, Bosminidae, Macrothricidae, Ilyocryptidae and Diaptomidae. We also demonstrate a simple alteration to a common specimen fixation method that increases the overall recovery of barcodes from freshwater zooplankton. Collectively, we believe our results will greatly aid the recovery of barcodes from these difficult groups. PMID- 23795707 TI - Distress and the parenting dynamic among BRCA1/2 tested mothers and their partners. AB - OBJECTIVE: To investigate the influence of dyadic parenting relationships on psychological distress among mothers tested for BRCA1/2 genetic mutations and their untested partners. METHODS: Data were from a prospective study of mothers suspected to be at risk for hereditary breast/ovarian cancer who underwent genetic counseling and BRCA1/2 testing and their untested parenting partners (n = 109 parenting dyads). Participants completed assessments before and 1 month after genetic testing. Structural equation modeling was used to examine relationships among mothers' and partners' psychological distress, decisional conflict surrounding communication of test results to their offspring, and the parent child communication relationship. Psychological distress was measured using items modified from the Brief Symptom Inventory. RESULTS: Among mothers, greater psychological distress (B = 0.29, p < .001) and poorer parent-child communication (B = -0.12, p < .01) at baseline predicted greater distress at follow-up. Among partners, greater distress at baseline predicted greater distress at follow-up (B = 0.67, p < .001). Mother and partner decisional conflict at baseline were equally associated with the other dyad member's distress at follow-up (B = 1.17, p < .01), but not their own distress. CONCLUSIONS: Our findings indicate that conflicted decision-making over family communication of hereditary breast/ovarian cancer genetic test results for one member of a parenting dyad adversely affects the other dyad member's psychological well-being. Interventions to improve outcomes for mothers who may be at-risk for hereditary breast and ovarian cancer and undergoing BRCA1/2 genetic testing should attend to mothers' and their partners' preferences regarding family communication about hereditary cancer risk. PMID- 23795708 TI - Enrollment in prescription drug insurance: the interaction of numeracy and choice set size. AB - OBJECTIVE: To determine how choice set size affects decision quality among individuals of different levels of numeracy choosing prescription drug plans. METHOD: Members of an Internet-enabled panel age 65 and over were randomly assigned to sets of prescription drug plans varying in size from 2 to 16 plans from which they made a hypothetical choice. They answered questions about enrollment likelihood and the costs and benefits of their choice. The measure of decision quality was enrollment likelihood among those for whom enrollment was beneficial. Enrollment likelihood by numeracy and choice set size was calculated. A model of moderated mediation was analyzed to understand the role of numeracy as a moderator of the relationship between the number of plans and the quality of the enrollment decision and the roles of the costs and benefits in mediating that relationship. RESULTS: More numerate adults made better decisions than less numerate adults when choosing among a small number of alternatives but not when choice sets were larger. Choice set size had little effect on decision making of less numerate adults. Differences in decision making costs between more and less numerate adults helped explain the effect of choice set size on decision quality. CONCLUSIONS: Interventions to improve decision making in the context of Medicare Part D may differentially affect lower and higher numeracy adults. The conflicting results on choice overload in the psychology literature may be explained in part by differences amongst individuals in how they respond to choice set size. PMID- 23795709 TI - Longitudinal trajectories of parental involvement in Type 1 diabetes and adolescents' adherence. AB - OBJECTIVE: The purpose of this study was to examine longitudinal trajectories of parental involvement and adolescent adherence to the Type 1 diabetes regimen, to determine whether changes in multiple facets of parental involvement over time predicted subsequent changes in adolescents' adherence, and to examine whether adolescent self-efficacy mediated the effect of parental involvement on adherence. METHOD: Two hundred fifty-two adolescents (M age = 12.49 years, SD = 1.53; 53.6% females) diagnosed with Type 1 diabetes mellitus, their mothers, and 188 fathers were enrolled in a 2.5-year longitudinal study. Across 5 time points, up to 252 adolescents and their parents completed measures of adherence, parental involvement (diabetes monitoring, behavioral involvement in diabetes management, and acceptance), and adolescent diabetes self-efficacy. RESULTS: Using multilevel modeling, analyses indicated significant average declines over time in adherence and most indicators of parental involvement. Lagged multilevel models indicated that declines in mothers' and fathers' acceptance and diabetes monitoring predicted subsequent declines in adolescents' adherence. Additional analyses revealed that longitudinal associations between both maternal acceptance and diabetes monitoring and subsequent adolescent adherence were mediated by adolescents' self-efficacy. CONCLUSIONS: Results of this study, which were largely consistent across reporters, highlight the importance of maintaining parental involvement in diabetes across adolescence and suggest that parental involvement is beneficial for adolescents' adherence, in part, because it contributes to higher self-efficacy for diabetes management among adolescents. PMID- 23795710 TI - Cystic hygroma detected in the first trimester scan in Hong Kong. AB - OBJECTIVE: To investigate the outcome of fetuses with cystic hygroma (CH) diagnosed at the first trimester from a general population in Hong Kong. METHOD: This was a prospective study of 30 fetal cystic hygroma detected at 11 to 13 + 6 weeks' gestation in 8835 sequential unselected pregnancies. Fetal cystic hygroma was categorized as isolated cystic hygroma (ICH) or associated cystic hygroma (ACH) according to the presence of associated multiple congenital structural abnormalities (MCA). RESULTS: There were 10 cases of ICH and 20 cases of ACH. The karyotypes were obtained in 29 cases. In the ICH, 30% (3/10) were associated with chromosomal abnormalities. In the ACH, 65% (13/20) were associated with major chromosomal abnormalities. CONCLUSION: This study suggests that the prognosis of cystic hygroma detected in the first trimester is guarded, with high incidence of MCA (66.7%, 20/30) and chromosomal abnormalities (53.3%, 16/30). The findings support detailed ultrasound examination and invasive prenatal diagnosis for cystic hygroma. PMID- 23795711 TI - Detection of circulating tumour DNA in patients with aggressive B-cell non Hodgkin lymphoma. PMID- 23795712 TI - The prevalence, predictors and associated health outcomes of high nicotine dependence using three measures among US smokers. AB - AIMS: Using the Fagerstrom Test of Nicotine Dependence (FTND), the Heaviness of Smoking Index (HSI) and the time-to-first-cigarette (TTFC), this study estimated prevalence, evaluated optimal scale cut-offs, identified predictors and assessed potential impact on health, productivity and health-care use of high nicotine dependence among US smokers. DESIGN, SETTING AND PARTICIPANTS: This cross sectional study used 2011 National Health and Wellness Survey data (n = 50 000). MEASUREMENTS: Nicotine dependence, demographic data, measures of health, productivity and health-care use and health attitudes were assessed. FINDINGS: The prevalence of high nicotine dependence ranged from 23% (TTFC < 5 minutes) to 63.6% (TTFC < 30 minutes). Based on diagnostic accuracy, the cut-offs for high nicotine dependence using HSI and TTFC varied according to FTND cut-off: if FTND > 4, then HSI > 3 and TTFC < 30 minutes represented optimal cut-offs; if FTND > 5, HSI > 4 and TTFC < 5 minutes represented optimal cut-offs. Across all measures, high nicotine dependence was related significantly to being male, single, age 45-64 years and Caucasian; lower education; lack of health insurance; under/unemployment; comorbid respiratory or cardiovascular disease, diabetes or psychiatric illness; and lower rates of exercise and concern for weight control. Controlling for demographic variables and comorbid physical and psychiatric illness, high nicotine dependence, measured by FTND, HSI or TTFC, was associated significantly with reduced mental and physical quality of life, reduced work place productivity and more health-care use. CONCLUSIONS: High nicotine dependence is associated with lower quality of life, lower work productivity and higher health-care use. The Heaviness of Smoking Index and the time-to-first cigarette can provide useful screening measures of nicotine dependence in clinical and research settings. PMID- 23795713 TI - Thiazolylaminomannosides as potent antiadhesives of type 1 piliated Escherichia coli isolated from Crohn's disease patients. AB - Adherent-invasive Escherichia coli (AIEC) have previously been shown to induce gut inflammation in patients with Crohn's disease (CD). We developed a set of mannosides to prevent AIEC attachment to the gut by blocking the FimH bacterial adhesin. The crystal structure of the FimH lectin domain in complex with a lead thiazolylaminomannoside highlighted the preferential position for pharmacomodulations. A small library of analogues showing nanomolar affinity for FimH was then developed. Notably, AIEC attachment to intestinal cells was efficiently prevented by the most active compound and at around 10000-fold and 100-fold lower concentrations than mannose and the potent FimH inhibitor heptylmannoside, respectively. An ex vivo assay performed on the colonic tissue of a transgenic mouse model of CD confirmed this antiadhesive potential. Given the key role of AIEC in the chronic intestinal inflammation of CD patients, these results suggest a potential antiadhesive treatment with the FimH inhibitors developed. PMID- 23795714 TI - Indole-3-butyric acid induces lateral root formation via peroxisome-derived indole-3-acetic acid and nitric oxide. AB - Controlled plant growth requires regulation through a variety of signaling molecules, including steroids, peptides, radicals of oxygen and nitrogen, as well as the 'classical' phytohormone groups. Auxin is critical for the control of plant growth and also orchestrates many developmental processes, such as the formation of new roots. It modulates root architecture both slowly, through actions at the transcriptional level and, more rapidly, by mechanisms targeting primarily plasma membrane sensory systems and intracellular signaling pathways. The latter reactions use several second messengers, including Ca(2+) , nitric oxide (NO) and reactive oxygen species (ROS). Here, we investigated the different roles of two auxins, the major auxin indole-3-acetic acid (IAA) and another endogenous auxin indole-3-butyric acid (IBA), in the lateral root formation process of Arabidopsis and maize. This was mainly analyzed by different types of fluorescence microscopy and inhibitors of NO production. This study revealed that peroxisomal IBA to IAA conversion is followed by peroxisomal NO, which is important for IBA-induced lateral root formation. We conclude that peroxisomal NO emerges as a new player in auxin-induced root organogenesis. In particular, the spatially and temporally coordinated release of NO and IAA from peroxisomes is behind the strong promotion of lateral root formation via IBA. PMID- 23795715 TI - Intimate partner violence and infant feeding practices in India: a cross sectional study. AB - Intimate partner violence (IPV) is widespread; yet research is thin and equivocal regarding its potential adverse effects on infant feeding practices. With a national sample of 3552 mothers and infants aged 180 days or younger from the 2005-2006 National Family Health Survey for India, we used logistic regression to estimate the unadjusted and adjusted associations of maternal reported lifetime exposure to any IPV and to physical or sexual IPV with feeding practices at birth and in the prior 24 h. Compared with their unexposed counterparts, mothers exposed to any IPV and to any physical or sexual IPV had higher adjusted odds of giving their infant liquids [aOR 1.32, 95% confidence interval (CI) 1.04-1.66; aOR 1.37, 95% CI 1.08-1.75, respectively], and thus lower adjusted odds of exclusively breastfeeding their infant in the prior 24 h (aOR 0.78, 95% CI 0.62 0.98; aOR 0.74, 95% CI 0.58-0.95). Mothers exposed to physical or sexual IPV also had higher adjusted odds of feeding their infant solids in the prior 24 h (aOR 1.50, 95% CI 1.01-2.23). Exposure to IPV was not significantly associated with breastfeeding immediately after birth or with bottle feeding in the prior 24 h. Perinatal screening for IPV, and addressing IPV and feeding practices in exposed mothers, may improve maternal health and infant nutrition in similar settings. PMID- 23795716 TI - The pharmacokinetics of glatiramer acetate for multiple sclerosis treatment. AB - INTRODUCTION: Multiple sclerosis (MS) is a T-cell-mediated disease affecting the central nervous system (CNS), characterized by demyelination and axonal degeneration. INF-beta1b was the first drug approved for MS patients in 1993. In 1996, glatiramer acetate (GA), a synthetic copolymer, was approved in the USA for the treatment of relapsing-remitting MS (RRMS) and clinically isolated syndrome (CIS). Although the immunological action of GA has been fully investigated, the exact mechanisms of action of GA are still not completely elucidated. Several in vitro studies on mice and human antigen-presenting cells (APCs) have shown that GA is able to bind to the major histocompatibility complex (MHC), on the surface of APCs, recognizing myelin basic protein (MBP). AREAS COVERED: This review explores the pharmacological characteristics of GA, its mechanism of action and its pharmacokinetics properties. The article also provides information on the efficacy, tolerability and an overview of the most important clinical data on GA. EXPERT OPINION: Despite the development of novel compounds, it is not surprising that GA is, to date, one of the most prescribed drugs for RRMS patients and CIS patients. The proven efficacy and the mild adverse events, makes GA a good therapeutic option in the early stage of the disease. This is particularly useful for patients who suffer flu-like symptoms from other RRMS therapies as an alternative. PMID- 23795718 TI - Developing a real-time quantitative loop-mediated isothermal amplification assay as a rapid and accurate method for detection of Brucellosis. AB - AIM: The aim of this study was designing a LAMP method for the rapid detection of Brucella and development of a sensitive quantitative-LAMP (Q-LAMP) assay for quantification of brucellosis. METHODS AND RESULTS: In this study for the LAMP detection of the causative agent of brucellosis, we used specifically designed primers to target the omp25 conserved gene of Brucella spp. The sensitivity of the LAMP method was evaluated by preparing serial tenfold dilution of omp25 gene containing plasmid followed by performing the LAMP reaction. To improve the assay as a quantitative test, LAMP products in the serial dilution were evaluated by Loopamp real-time turbidimeter system and then standard curve was generated by plotting time threshold values against log of copy number. The assay specificity was evaluated using Brucella genomic DNA and a panel containing genomes of 11 gram-positive and gram-negative organisms. The LAMP assay was highly specific and no amplification products were observed from the non-Brucella organisms. The test sensitivity for visual detection of turbidity or fluorescent colour change and also agarose gel electrophoresis was 560 ng and 5.6 ng, respectively. The lower limit of detection was 17 copies of the gene that could be detected in 50 min. CONCLUSIONS: The results of this study indicated that the LAMP assay is a simple, rapid, sensitive and specific technique for detection of Brucella spp. that may improve diagnostic potential in clinical laboratories. SIGNIFICANCE AND IMPACT OF THE STUDY: The LAMP assay because of the simplicity and low cost can be preferred to other molecular methods in the diagnosis of infectious diseases. PMID- 23795717 TI - Advanced paternal age at birth: phenotypic and etiologic associations with eating pathology in offspring. AB - BACKGROUND: Advanced paternal age at birth has been linked to several psychiatric disorders in offspring (e.g. schizophrenia) and genetic mechanisms are thought to underlie these associations. This study is the first to investigate whether advanced paternal age at birth is associated with eating disorder risk using a twin study design capable of examining both phenotypic and genetic associations. METHOD: In a large, population-based sample of female twins aged 8-17 years in mid-puberty or beyond (n = 1722), we investigated whether advanced paternal age was positively associated with disordered eating symptoms and an eating disorder history [i.e. anorexia nervosa (AN), bulimia nervosa (BN) or binge eating disorder (BED)] in offspring. Biometric twin models examined whether genetic and/or environmental factors underlie paternal age effects for disordered eating symptoms. RESULTS: Advanced paternal age was positively associated with disordered eating symptoms and an eating disorder history, where the highest level of pathology was observed in offspring born to fathers ?40 years old. The results were not accounted for by maternal age at birth, body mass index (BMI), socio-economic status (SES), fertility treatment or parental psychiatric history. Twin models indicated decreased genetic, and increased environmental, effects on disordered eating with advanced paternal age. CONCLUSIONS: Advanced paternal age increased risk for the full spectrum of eating pathology, independent of several important covariates. However, contrary to leading hypotheses, environmental rather than genetic factors accounted for paternal age-disordered eating associations. These data highlight the need to explore novel (potentially environmental) mechanisms underlying the effects of advanced paternal age on offspring eating disorder risk. PMID- 23795719 TI - A simple novel technique to induce short-lasting local brain ischaemia in the rat. AB - AIMS: Brain ischaemia models are essential to study the pathomechanisms of stroke. Our aim was to investigate the reliability and reproducibility of our novel focal ischaemia-reperfusion model. METHODS: To induce a cortical transient ischaemic attack, we lifted the distal middle cerebral artery (MCA) with a special hook. The early changes after 2 * 15-min occlusion were observed in the somatosensory evoked responses (SERs). The histological responses to 2 * 15-min MCA occlusion and to 30-, 45- or 60-min ischaemia were examined after a 1-day survival period by 2,3,5-triphenyltetrazolium chloride (TTC) and Fluoro Jade C (FJC) staining. Another group, with 30-min ischaemia, was analysed histologically by FJC, S100 and CD11b labelling after a 5-day survival period. RESULTS: The amplitudes of the SERs decreased immediately at the beginning of the ischaemic period, and remained at a reduced level during the ischaemia. Reperfusion resulted in increasing SER amplitudes, but they never regained the control level. The short-lasting ischaemia did not lead to brain infarction when evaluated with TTC, but intense labelling was found with FJC. The 30-min ischaemia did not result in FJC labelling after 1 day, but marked labelling was observed after 5 days with FJC, S100 and CD11b in the cortical area supplied by the MCA. CONCLUSIONS: We present here a novel, readily reproducible method to induce focal brain ischaemia. The ischaemia-reperfusion results in noteworthy changes in the SERs and the appearance of conventional tissue damage markers. This method involves possibilities for precise blood flow regulation, and the setting of the required level of perfusion. PMID- 23795720 TI - Esophagectomy for failed endoscopic therapy in patients with high-grade dysplasia or intramucosal carcinoma. AB - Endoscopic therapy (ablation +/- endoscopic resection) for high-grade dysplasia and/or intramucosal carcinoma (IMC) of the esophagus has demonstrated promising results. However, there is a concern that a curable, local disease may progress to systemic disease with repeated endotherapy. We performed a retrospective review of patients who underwent esophagectomy after endotherapy at three tertiary care esophageal centers from 2006 to 2012. Our objective was to document the clinical and pathologic outcomes of patients who undergo esophagectomy after failed endotherapy. Fifteen patients underwent esophagectomy after a mean of 13 months and 4.1 sessions of endotherapy for progression of disease (53%), failure to clear disease (33%), or recurrence (13%). Initially, all had Barrett's, 73% had >=3-cm segments, 93% had a nodule or ulcer, and 91% had multifocal disease upon presentation. High-grade dysplasia was present at index endoscopy in 80% and IMC in 33%, and some patients had both. Final pathology at esophagectomy was T0 (13%), T1a (60%), T1b (20%), and T2 (7%). Positive lymph nodes were found in 20%: one patient was T2N1 and two were T1bN1. Patients with T1b, T2, or N1 disease had more IMC on index endoscopy (75% vs. 18%) and more endotherapy sessions (median 6.5 vs. 3). There have been no recurrences a mean of 20 months after esophagectomy. Clinical outcomes were comparable to other series, but submucosal invasion (27%) and node-positive disease (20%) were encountered in some patients who initially presented with a locally curable disease and eventually required esophagectomy after failed endotherapy. An initial pathology of IMC or failure to clear disease after three treatments should raise concern for loco-regional progression and prompt earlier consideration of esophagectomy. PMID- 23795721 TI - Synthesis, characterization and self-assembly of biosurfactants based on hydrophobically modified inulins. AB - Biosurfactants have been synthesized using a low energy, environmentally friendly process by the derivatization of inulin with octenyl (OSA) and dodecenyl (DDSA) succinic anhydrides in aqueous solution. The inulin and its derivatives have been characterized using gel permeation chromatography/multi angle light scattering (GPC/MALLS), high-performance anion exchange chromatography with pulsed amperometric detection (HPAEC-PAD), Fourier transform infrared spectroscopy (FTIR), and NMR, and the reaction efficiency was found to be between 59 and 95%. The efficiency was generally higher for OSA derivatives compared to DDSA derivatives. The hydrophobic derivatives were found to aggregate in solution and the critical aggregation concentration (CAC) was determined using dye solubilization, surface tension, dynamic light scattering (DLS), and conductivity. There was reasonable agreement in the CAC values obtained by the different techniques except for conductivity. It was found that the CAC decreased with increasing alkenyl chain length and degree of modification, and the values were significantly lower for the DDSA derivatives compared to the OSA derivatives. GPC elution profiles for the DDSA-inulin using 12 mol % reagent confirmed the presence of aggregates with a molecular mass of ~2.5 * 10(6) g/mol and a radius of gyration of ~25 nm corresponding to ~550 inulin molecules. DLS study was undertaken to determine the hydrodynamic radius, and values obtained for the DDSA (12%) derivative were 30 nm in both water and 0.1 M sodium nitrate, while for the OSA (12%) derivative values of 13 and 7 nm were obtained. The derivatives have potential application in the stabilization of particulate dispersions and emulsions and also in the encapsulation and delivery of drugs. PMID- 23795722 TI - Electrochemical glucose biosensor based on nickel oxide nanoparticle-modified carbon paste electrode. AB - In the present work, we designed an amperometric glucose biosensor based on nickel oxide nanoparticles (NiONPs)-modified carbon paste electrode. The biosensor was prepared by incorporation of glucose oxidase and NiONPs into a carbon paste matrix. It showed good analytical performances such as high sensitivity (367 MUA mmolL(-1)) and a wide linear response from 1.9*10(-3) mmolL( 1) to 15.0 mmolL(-1) with a limit of detection (0.11 MUmolL(-1)). The biosensor was used for the determination of glucose in human serum samples. The results illustrate that NiONPs have enormous potential in the construction of biosensor for determination of glucose. PMID- 23795723 TI - Comparison of some biochemical properties of artichoke polyphenol oxidase entrapped in alginate-carrageenan and alginate gels. AB - Polyphenol oxidase (PPO, EC.1.14.18.1) isolated from artichoke (Cynara scolymus) was entrapped within alginate and alginate+ carrageenan beads, and the catecholase and cresolase activities of both entrapped enzymes were determined. Some properties of these immobilized enzymes such as optimum pH and temperature, kinetic parameters (Km and Vmax), thermal, and storage stability were determined and compared to each other. The highest catecholase activity was observed in alginate gel (370 U/g bead) while the highest cresolase activity was in alginate+ carrageenan gel (90 U/g bead). For catecholase and cresolase activities, optimum pHs of alginate and alginate+ carrageenan beads were determined to be 7.0 and 4.0, respectively. Optimum temperatures for catecholase activity were determined to be 40 degrees C for both entrapped enzymes. These values for cresolase activity were 30 degrees C and 20 degrees C, respectively. Immobilized artichoke PPOs greatly preserved their thermal stability which exists anyway. The catalytic efficiency value (Vmax/Km) of the alginate beads is approximately high as two-and a-half folds of that of alginate+kappa-carrageenan beads for cresolase activity. These values were very close for catecholase activity. Immobilized beads saved their both activities after 30 days of storage at 4 degrees C. PMID- 23795725 TI - Pulmonary hypertension at high altitude. PMID- 23795724 TI - Enhancement of cisplatin-based TACE by a hemoglobin-based oxygen carrier in an orthotopic rat HCC model. AB - OBJECTIVE: Hypoxic tumor cells are more resistant to standard chemotherapies. A number of studies indicated that improving oxygenation inside the tumor could serve as a potential strategy to target hypoxia-induced chemoresistance. In this study, we examined whether a hemoglobin-based oxygen carrier (OC89) could increase tumor oxygenation and thus enhance the efficiency of transarterial chemoembolization (TACE) in an orthotopic rat HCC model. METHODS: Efficiency of the hemoglobin-based oxygen carrier (OC89) in improving tumor oxygenation was examined by OxyLab pO2. Sensitization of chemotherapy (cisplatin) in TACE by OC89 was evaluated in four different therapeutic regimens including cisplatin (1 mg/kg)+OC89 (0.2 g/kg), cisplatin (1 mg/kg)+OC89 (0.4 g/kg), cisplatin (3 mg/kg)+OC89 (0.2 g/kg), cisplatin (3 mg/kg)+OC89 (0.4 g/kg). For all the therapeutic regimens, a single delivery of OC89 via the tail vein was performed 1 h before TACE. RESULTS: Compared with Ringer's buffer, systemic delivery of OC89 (0.4 g/kg) attenuated tumor hypoxia (p<0.05). Additionally, partial pressure of oxygen (pO2) fraction of low readings (0-10 mmHg) inside the tumor decreased from 74.1% to 24.6% after OC89 delivery, while pO2 fraction of high readings (15-25 mmHg) increased from 22.2% to 41.5%. When cisplatin was combined with OC89, regimen cisplatin (3 mg/kg)+OC89 (0.4 g/kg) resulted in a significant inhibition of tumor growth at Day 21 after therapy (p<0.05). Further investigation indicated that OC89 delivery influenced anti-apoptotic and pro-apoptotic balance of the UPR pathway in the tumor. CONCLUSIONS: Our data suggest that targeting tumor hypoxia with the hemoglobin-based O2 carrier serves as a promising approach to enhance the efficacy of cisplatin-based chemotherapy in HCC. PMID- 23795728 TI - Considerations on safety and treatment of patients with chronic heart failure at high altitude. AB - Prognosis and quality of life of chronic heart failure (HF) patients have greatly improved over the last decade. Consequently, many patients are willing to spend leisure time at altitude, usually <3500 m, but their safety in doing so is undefined. HF is a syndrome that often has relevant co-morbidities, such as pulmonary hypertension, COPD, unstable cardiac ischemia, and anemia. HF co morbidities may per se impede a safe stay at altitude. Exercise at simulated altitude is associated with a reduction in performance, which is greater in HF patients than in normal subjects and greater in patients with most severe HF. In normal subjects, the reduction in performance is ~2% every 1000 m altitude increase, whereas it is 4% and 10% in HF patients with normal or slightly diminished exercise capacity and in HF patients with markedly diminished exercise capacity. On-field experience with HF patients at altitude is limited to subjects driven to altitude (3454 m) for a few hours. The data showed a reduction in exercise capacity similar to that reported at simulated altitude. "Optimal" HF treatment in patients spending time at altitude is likely different from optimal treatment at sea level, particularly as regards beta-blockers. Carvedilol, a beta1-beta2-alpha-blocker, reduces the hypoxic ventilatory response through a reduction of the chemoreflex response, and it reduces alveolar-capillary gas diffusion, which is under control by beta2-receptors. These actions are not shared by selective beta1-blockers such as bisoprolol and nebivolol, which should be preferred for treatment of HF patients willing to spend time at altitude. In conclusion, spending time at altitude (<3500 m) is safe for HF patients, provided that subjects are free of co-morbidities that may directly interfere with the adaptation to altitude. However, HF patients experience a reduction of exercise capacity in proportion to HF severity and altitude. Finally, HF patients should undergo a specific "altitude-tailored treatment" to avoid pharmacological interference with altitude adaptation mechanisms. PMID- 23795729 TI - Hypoxic pulmonary vasoconstriction. AB - Hypoxic pulmonary vasoconstriction (HPV) continues to fascinate cardiopulmonary physiologists and clinicians since its definitive description in 1946. Hypoxic vasoconstriction exists in all vertebrate gas exchanging organs. This fundamental response of the pulmonary vasculature in air breathing animals has relevance to successful fetal transition to air breathing at birth and as a mechanism of ventilation-perfusion matching in health and disease. It is a complex process intrinsic to the vascular smooth muscle, but with in vivo modulation by a host of factors including the vascular endothelium, erythrocytes, pulmonary innervation, circulating hormones and acid-base status to name only a few. This review will provide a broad overview of HPV and its mechansms and discuss the advantages and disadvantages of HPV in normal physiology, disease and high altitude. PMID- 23795730 TI - Cellular responses to hypoxia in the pulmonary circulation. AB - Hypoxia can be defined as a reduction in available oxygen, whether in a whole organism or in a tissue or cell. It is a real life cause of pulmonary hypertension in humans both in terms of patients with chronic hypoxic lung disease and people living at high altitude. The effect of hypoxia on the pulmonary vasculature can be described in two ways; Hypoxic pulmonary vasoconstriction (HPV) (resulting from smooth muscle cell contraction) and pulmonary vascular remodelling (PVR) (resulting from pulmonary vascular cell proliferation). The pulmonary artery is made up of three resident cell types, the endothelial (intima), smooth muscle (media) and fibroblast (adventitia) cells. This review will examine the effects of hypoxia on the cells of the pulmonary vasculature and give an insight into the possible underlying mechanisms. PMID- 23795731 TI - Pulmonary hypertension and chronic mountain sickness. AB - Chronic mountain sickness is a syndrome of severe symptomatic polycythemia and hypoxemia occurring in natives or long-term high altitude sojourners. The condition may be complicated by pulmonary hypertension in proportion to decreased oxygenation, indicating hypoxic vasoconstriction and remodeling. Exercise in these patients is associated with a steep slope of pulmonary artery pressure-flow relationships and decreased vascular distensibility. Correction of pulmonary vascular resistance for increased hematocrit decreases the severity of pulmonary hypertension. Exercise-induced pulmonary hypertension in chronic mountain sickness does not affect exercise capacity, in relation to high oxygen content of the blood and increased lung diffusing capacity. Right ventricular failure seems to be an uncommon complication of chronic mountain sickness, but the exact prevalence of the condition is not known. Acetazolamide given for 6 months to patients with chronic mountain sickness improves oxygenation, polycythemia, and pulmonary artery pressure. PMID- 23795732 TI - Mechanisms and drug therapy of pulmonary hypertension at high altitude. AB - Pulmonary vasoconstriction represents a physiological adaptive mechanism to high altitude. If exaggerated, however, it is associated with important morbidity and mortality. Recent mechanistic studies using short-term acute high altitude exposure have provided insight into the importance of defective vascular endothelial and respiratory epithelial nitric oxide (NO) synthesis, increased endothelin-1 bioavailability, and overactivation of the sympathetic nervous system in causing exaggerated hypoxic pulmonary hypertension in humans. Based on these studies, drugs that increase NO bioavailability, attenuate endothelin-1 induced pulmonary vasoconstriction, or prevent exaggerated sympathetic activation have been shown to be useful for the treatment/prevention of exaggerated pulmonary hypertension during acute short-term high altitude exposure. The mechanisms underpinning chronic pulmonary hypertension in high altitude dwellers are less well understood, but recent evidence suggests that they differ in some aspects from those involved in short-term adaptation to high altitude. These differences have consequences for the choice of the treatment for chronic pulmonary hypertension at high altitude. Finally, recent data indicate that fetal programming of pulmonary vascular dysfunction in offspring of preeclampsia and children generated by assisted reproductive technologies represents a novel and frequent cause of pulmonary hypertension at high altitude. In animal models of fetal programming of hypoxic pulmonary hypertension, epigenetic mechanisms play a role, and targeting of these mechanisms with drugs lowers pulmonary artery pressure. If epigenetic mechanisms also are operational in the fetal programming of pulmonary vascular dysfunction in humans, such drugs may become novel tools for the treatment of hypoxic pulmonary hypertension. PMID- 23795733 TI - Current and future therapeutic targets for pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) remains a poorly understood disorder with dire consequences. Progression of disease often leads to right heart failure and death without lung transplantation. Limited therapeutic strategies exist for the treatment of PAH and current medical treatment consists of two major categories, supportive care therapeutics and pulmonary vasculature targeted therapy. Supportive care includes anticoagulants and inotropic agents, while pulmonary vasculature targets currently available include endothelin antagonists, phosphodiesterase inhibitors and prostacyclin analogs. While these therapies have shown efficacy in hemodynamic and functional outcomes; halting the progression of disease, reversal, and clinical cure has been elusive. Combination therapy and newer agents may provide innovative insight into the disease process and ultimately change the prognosis of this fatal disease. By utilizing specific targets on the cell membrane, second messengers systems or signaling peptides, novel therapeutic strategies will hopefully emerge. In this review we discuss the currently available therapeutic options and their pulmonary vasculature targets as well as some future therapeutic targets that have promising results in human trials. PMID- 23795734 TI - High altitude impairs in vivo immunity in humans. AB - The aim was to assess the effect of high altitude on the development of new immune memory (induction) using a contact sensitization model of in vivo immunity. We hypothesized that high-altitude exposure would impair induction of the in vivo immune response to a novel antigen, diphenylcyclopropenone (DPCP). DPCP was applied (sensitization) to the lower back of 27 rested controls at sea level and to ten rested mountaineers 28 hours after passive ascent to 3777 m. After sensitization, mountaineers avoided strenuous exercise for a further 24 hours, after which they completed alpine activities for 11-18 days. Exactly 4 weeks after sensitization, the strength of immune memory induction was quantified in rested mountaineers and controls at sea level, by measuring the response to a low, dose-series DPCP challenge, read at 48 hours as skin measures of edema (skinfold thickness) and redness (erythema). Compared with control responses, skinfold thickness and erythema were reduced in the mountaineers (skinfold thickness,-52%, p=0.01, d=0.86; erythema, -36%, p=0.02, d=0.77). These changes in skinfold thickness and erythema were related to arterial oxygen saturation (r=0.7, p=0.04), but not cortisol (r<0.1, p>0.79), at sensitization. In conclusion, this is the first study to show, using a contact sensitization model of in vivo immunity, that high altitude exposure impairs the development of new immunity in humans. PMID- 23795735 TI - Determination of bone mass using multisite quantitative ultrasound and biochemical markers of bone turnover during residency at extreme altitude: a longitudinal study. AB - A group of 221 male healthy volunteers of Indian Army were the subjects of the study. The baseline parameters of skeletal health were measured during their residency at an altitude of 3542 m. These subjects were then taken to an extreme altitude (EA, 5400-6700 m) where they stayed for about 4 months. The study parameters were repeated following their de-induction (DI) to 3542 m. On random selection, a subgroup was constituted from the above mentioned volunteers for detailed investigations on various bone turnover markers. Results of this study indicate a loss of body weight after DI from EA. The bone impairment was detected at the proximal phalanx, which is known to undergo early morpho-structural changes associated with bone resorption. The intact parathyroid hormone (i-PTH) levels showed a significant increase, while alkaline phosphatase (ALP) and bone specific alkaline phosphatase (BAP) activities declined significantly after DI from EA. This elevation in i-PTH might be required for maintenance of blood Ca level. 25 (OH) Vitamin D3 (25VitD) and calcitonin (CT) also showed a significant decline, which may suggest a negative impact on bone formation during sojourn at EA. The causes of deterioration of skeletal health at EA although are poorly understood but may be due to acute hypoxemia arising from extreme hypobaric hypoxia prevalent at extreme altitude. PMID- 23795736 TI - Brainstem auditory evoked responses in children living at high altitude in the andes mountains. AB - OBJECTIVES: This neurophysiological study compared brainstem auditory evoked responses (BAER) in children living at high elevations (2800 to 3000 meters) in the Andes Mountains of Ecuador with a reference group of children living at sea level in the U.S. METHODS: BAER absolute latencies of waves I through V; interpeak latencies I-III, III-V, and I-V; amplitudes of waves I and V; and the V/I amplitude ratio were measured by scalp electrodes at acoustic click stimulus rates of 10 and 50 pulses per second (pps). RESULTS: Statistical analysis showed that the high-altitude group had significantly longer absolute and interpeak BAER latencies than the sea-level reference group at both the 10 and 50 pps stimulus rates for most wave peaks. The amplitudes of waves I and V were significantly reduced for the high-altitude group at 10 and 50 pps, suggesting blood O2 saturation effects. CONCLUSIONS: The BAER of children in the high-altitude group suggested physiological anomalies in auditory neural conduction and summation compared with the sea-level group. The results further suggest that small physiological effects of altitude on BAER, especially at elevations near 3000 meters and higher, should be taken into consideration in the evaluation of brainstem auditory function. PMID- 23795738 TI - Dead space mask eliminates central apnea at altitude. AB - Travelers to high altitude may have disturbed sleep due to periodic breathing with frequent central apneas. We tested whether a mask with added dead space could reduce the central apneas of altitude. 16 subjects were recruited, age 18 35, residing at 4600 ft (1400 m). They each slept one night with full polysomnographic monitoring, including end tidal CO2, in a normobaric hypoxia tent simulating 12,000 ft. (3658 m) altitude. Those who had a central apnea index (CAI) >20/h returned for a night in the tent for dead space titration, during which they slept with increasing amounts of dead space, aiming for a CAI <5/h or <10% of baseline. Then each subject slept another night with the titrated amount of dead space. Of the 16 subjects, 5 had a central apnea index >20/h mean 49.1, range 21.4-131.5/hr. In each of the 5, the dead space mask reduced the CAI by at least 88% to a mean of 3.1, range 0.9-7.1/h, (p=0.04). Hypopnea index was unchanged. Three subjects required 500 cc of dead space or less. One subject required 860 cc, and one required 2.1 L. Morning symptoms and arousal index were not significantly affected by the dead space mask. Dead space did not appear to increase the CO2 reserve. At 12,000 ft., central apneas can be effectively reduced with a dead space mask, but clinical utility will require further evaluation. PMID- 23795737 TI - Effect of acetazolamide and gingko biloba on the human pulmonary vascular response to an acute altitude ascent. AB - Acetazolamide and gingko biloba are the two most investigated drugs for the prevention of acute mountain sickness (AMS). Evidence suggests that they may also reduce pulmonary artery systolic pressure (PASP). To investigate whether these two drugs for AMS prevention also reduce PASP with rapid airlift ascent to high altitude, a randomized controlled trial was conducted on 28 healthy young men with acetazolamide (125 mg bid), gingko biloba (120 mg bid), or placebo for 3 days prior to airlift ascent (397 m) and for the first 3 days at high altitude (3658 m). PASP, AMS, arterial oxygen saturation (Sao2), mean arterial pressure (MAP), heart rate (HR), forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), and peak expiratory flow (PEF) were assessed both at 397 m and 3658 m. HR, PEF, and PASP increased with altitude exposure (p<0.05), and SaO2 decreased (p<0.05). PASP with acetazolamide (mean at 3658 m, 26.2 mm Hg; incremental change, 4.7 mm Hg, 95% CI., 2.6-6.9 mm Hg) was lower than that with ginkgo biloba (mean at 3658 m, 33.7 mm Hg, p=0.001; incremental change, 13.1 mm Hg, 95%CI., 9.6-16.5 mm Hg, p=0.002), and with placebo (mean at 3658 m, 34.7 mm Hg, p<0.001; 14.4 mm Hg, 95% CI., 8.8-20.0 mm Hg, p=0.001). The data show that a low prophylactic dosage of acetazolamide, but not gingko biloba, mitigates the early increase of PASP in a quick ascent profile. PMID- 23795739 TI - Intermittent hypobaric hypoxia promotes atherosclerotic plaque instability in ApoE-deficient mice. AB - AIM: Sudden cardiac death is one of the most frequent causes of death at high altitude. It has been reported that the intermittent normobaric hypoxia experienced by patients with obstructive sleep apnea may enhance the development of atherosclerosis. However, the effect of hypobaric hypoxia, which mimics the ambient air at high altitude, in the development of atherosclerosis has not been investigated. METHODS: Twenty male ApoE-deficient mice, 8 weeks of age, were subjected to either control conditions or intermittent hypobaric hypoxia (IHH) for 8 weeks. Mice in the IHH group were exposed to a hypobaric chamber that replicated the hypobaric hypoxia conditions found at 4000 m altitude for 8 hours a day. RESULTS: IHH-exposed mice did not significantly differ from control mice in plasma lipid levels, including triglyceride, total cholesterol, low-density lipoprotein, and high-density lipoprotein. The hematoxylin and eosin-stained sections of the aortic root showed similar plaque size between the groups. However, IHH-treated mice exhibited significantly decreased plaque collagen content, a feature of atherosclerotic plaque stability. Additionally, matrix metalloproteinase (MMP)-9 protein expression was significantly increased, whereas tissue inhibitor of MMP (TIMP)-2 expression was decreased after exposure to IHH. CONCLUSION: IHH may promote atherosclerotic plaque instability in ApoE-deficient mice by changing the balance of MMPs and TIMPs. PMID- 23795740 TI - Medical continuing education: reform of teaching methods about high altitude disease in China. AB - The purpose of high altitude continuing medical education is to adapt knowledge and skills for practical application on the plateau. Most trainees have experience with academic education and grassroots work experience on the plateau, so they want knowledge about new advances in the pathogenesis, diagnosis, and treatment of high altitude disease. As such, traditional classroom teaching methods are not useful to them. Training objects, content, and methods should attempt to conduct a variety of teaching practices. Through continuing medical education on high altitude disease, the authors seek to change the traditional teaching model away from a single classroom and traditional written examinations to expand trainees' abilities. These innovative methods of training can improve both the quality of teaching and students' abilities to prevent and treat acute mountain sickness, high altitude pulmonary edema, high altitude cerebral edema, and chronic mountain sickness to increase the quality of high altitude medical care. PMID- 23795741 TI - Acute kidney injury at high altitude. AB - Acute ascent to high altitudes beyond 2400 m (300 feet) can cause acute mountain sickness (AMS) and may develop into life-threatening complications such as high altitude cerebral (HACE) and pulmonary edema (HAPE). We report a case of acute kidney injury (AKI) without other organ involvement in a previously healthy young man after sudden high altitude exposure of up to 5200 m. Acute systemic hypoxia as well as prolonged renal hypoperfusion may be responsible for his kidney injury. PMID- 23795742 TI - High altitude, continuous positive airway pressure, and obstructive sleep apnea: subjective observations and objective data. AB - We report observations made by one of the authors who ascended to the Thorang La pass (5416 m) in the Nepal Himalaya in October 2010, despite moderate-severe obstructive sleep apnea. We report the first recorded use of nasal CPAP to treat high altitude pulmonary edema (progressively severe dyspnea at rest and severe orthopnea, with tachycardia and tachypnea) that occurred at 4400 meters, when snow and darkness made safe evacuation difficult. We also present objective longitudinal data of the effects of altitude on auto-adjusting CPAP delivered via a portable nasal CPAP device, and on the apnea hypopnea index measured during sleep while using the device. OSA may be a risk factor for the development of high altitude pulmonary edema and we suggest that a nasal CPAP device located in high altitude trekking stations may provide an additional or alternative treatment option for managing high altitude pulmonary edema until evacuation is possible. PMID- 23795744 TI - Oestrogens as modulators of neuronal signalosomes and brain lipid homeostasis related to protection against neurodegeneration. AB - Oestrogens trigger several pathways at the plasma membrane that exert beneficial actions against neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Part of these actions takes place in lipid rafts, which are membrane domains with a singular protein and lipid composition. These microdomains also represent a preferential site for signalling protein complexes, or signalosomes. A plausible hypothesis is that the dynamic interaction of signalosomes with different extracellular ligands may be at the basis of neuronal maintenance against different neuropathologies. Oestrogen receptors are localised in neuronal lipid rafts, taking part of macromolecular complexes together with a voltage-dependent anion channel (VDAC), and other molecules. Oestradiol binding to its receptor at this level enhances neuroprotection against amyloid-beta degeneration through the activation of different signal transduction pathways, including VDAC gating modulation. Moreover, part of the stability and functionality of signalling platforms lays on the distribution of lipid hallmarks in these microstructures, which modulate membrane physicochemical properties, thus favouring molecular interactions. Interestingly, recent findings indicate a potential role of oestrogens in the preservation of neuronal membrane physiology related to lipid homeostasis. Thus, oestrogens and docosahexaenoic acid may act synergistically to stabilise brain lipid structure by regulating neuronal lipid biosynthetic pathways, suggesting that part of the neuroprotective effects elicited by oestrogens occur through mechanisms aimed at preserving lipid homeostasis. Overall, oestrogen mechanisms of neuroprotection may occur not only by its interaction with neuronal protein targets through nongenomic and genomic mechanisms, but also through its participation in membrane architecture stabilisation via 'lipostatic' mechanisms. PMID- 23795745 TI - Low-pressure pneumoperitoneum during laparoscopic donor nephrectomy to optimize live donors' comfort. AB - Nowadays, laparoscopic donor nephrectomy (LDN) has become the gold standard to procure live donor kidneys. As the relationship between donor and recipient loosens, it becomes of even greater importance to optimize safety and comfort of the surgical procedure. Low-pressure pneumoperitoneum has been shown to reduce pain scores after laparoscopic cholecystectomy. Live kidney donors may also benefit from the use of low pressure during LDN. To evaluate feasibility and efficacy to reduce post-operative pain, we performed a randomized blinded study. Twenty donors were randomly assigned to standard (14 mmHg) or low (7 mmHg) pressure during LDN. One conversion from low to standard pressure was indicated by protocol due to lack of progression. Intention-to-treat analysis showed that low pressure resulted in a significantly longer skin-to-skin time (149 +/- 86 vs. 111 +/- 19 min), higher urine output during pneumoperitoneum (23 +/- 35 vs. 11 +/ 20 mL/h), lower cumulative overall pain score after 72 h (9.4 +/- 3.2 vs. 13.5 +/- 4.5), lower deep intra-abdominal pain score (11 +/- 3.3 vs. 7.5 +/- 3.1), and a lower cumulative overall referred pain score (1.8 +/- 1.9 vs. 4.2 +/- 3). Donor serum creatinine levels, complications, and quality of life dimensions were not significantly different. Our data show that low-pressure pneumoperitoneum during LDN is feasible and may contribute to increase live donors' comfort during the early post-operative phase. PMID- 23795746 TI - Emergency major abdominal surgery--'the times they are a-changing'. PMID- 23795747 TI - Laparoscopic ventral rectopexy. PMID- 23795751 TI - A sugar-functionalized amphiphilic pillar[5]arene: synthesis, self-assembly in water, and application in bacterial cell agglutination. AB - A novel sugar-functionalized amphiphilic pillar[5]arene containing galactose groups as the hydrophlic part and alkyl chains as the hydrophobic part was designed and synthesized. It self-assembles in water to produce nanotubes as confirmed by TEM, SEM, and fluorescence microscopy. These nanotubes, showing low toxicity to both cancer and normal cells, can be utilized as excellent cell glues to agglutinate E. coli. The existence of galactoses on these nanotubes provides multivalent ligands that have high affinity for carbohydrate receptors on E. coli. PMID- 23795752 TI - Single defect center scanning near-field optical microscopy on graphene. AB - We present a scanning-probe microscope based on an atomic-size emitter, a single nitrogen-vacancy center in a nanodiamond. We employ this tool to quantitatively map the near-field coupling between the NV center and a flake of graphene in three dimensions with nanoscale resolution. Further we demonstrate universal energy transfer distance scaling between a point-like atomic emitter and a two dimensional acceptor. Our study paves the way toward a versatile single emitter scanning microscope, which could image and excite molecular-scale light fields in photonic nanostructures or single fluorescent molecules. PMID- 23795753 TI - Transposable elements and microevolutionary changes in natural populations. AB - Transposable elements (TEs) usually represent the most abundant and dynamic fraction of genomes in almost all living organisms. The overall capacity of such 'junk DNA' to induce mutations and foster the reorganization of functional genomes suggests that TE may be of central evolutionary significance. However, to what extent TE dynamics drive and is driven by the evolutionary trajectory of host taxa remains poorly known. Further work addressing the fate of TE insertions in natural populations is necessary to shed light on their impact on microevolutionary processes. Here, we highlight methodological approaches (i.e. transposon displays and high-throughput sequencing), tracking TE insertions across large numbers of individuals and discuss their pitfalls and benefits for molecular ecology surveys. PMID- 23795754 TI - Real-time PCR-assay in the delivery suite for determination of group B streptococcal colonization in a setting with risk-based antibiotic prophylaxis. AB - OBJECTIVE: Intrapartum antibiotic prophylaxis (IAP) reduces the incidence of neonatal early onset group B streptococcal infections. The present study investigated if an automated PCR-assay, used bedside by the labor ward personnel was manageable and could decrease the use of IAP in a setting with a risk-based IAP strategy. METHODS: The study comprises two phases. Phase 1 was a multicenter, randomized, controlled trial. Women with selected risk-factors were allocated either to PCR-IAP (prophylaxis given if positive or indeterminate) or IAP. A vaginal/rectal swab and superficial swabs from the neonate for conventional culture were also obtained. Phase 2 was non-randomized, assessing an improved version of the assay. RESULTS: Phase 1 included 112 women in the PCR-IAP group and 117 in the IAP group. Excluding indeterminate results, the assay showed a sensitivity of 89% and a specificity of 90%. In 44 % of the PCR assays the result was indeterminate. The use of IAP was lower in the PCR group (53 versus 92%). Phase 2 included 94 women. The proportion of indeterminate results was reduced (15%). The GBS colonization rate was 31%. CONCLUSION: The PCR assay, in the hands of labor ward personnel, can be useful for selection of women to which IAP should be offered. PMID- 23795755 TI - Personality disorder and self-rated health: a population-based cross-sectional survey. AB - Little is known about the impact of personality disorder (PD) on the health of people living in the community. The authors set out to examine the association between PD and general health, using a cross-sectional survey of a representative community sample in London, UK. A total of 1,698 adults aged 16 years or over from 1,075 randomly selected households were recruited and interviewed face-to face by trained interviewers. Using multivariable logistic regression, the authors examined the cross-sectional association between PD screen status, as assessed by the Standardised Assessment of Personality-Abbreviated Scale (SAPAS), and self-rated health, adjusting for demographic and health covariates. Of the participants, 14.5% screened positively for PD. A greater proportion of those scoring positively for PD reported poor self-rated health, compared to screen negative participants (41.3% versus 15.0%). This association was reduced, but remained significant, after adjustment for potential confounders (unadjusted odds ratio (OR) = 3.99, 95% CI [2.93, 5.42]; fully adjusted OR = 1.53, 95% CI [1.02, 2.29]. Of note, subthreshold symptoms of PD were significantly associated with poor self-rated health (unadjusted OR per unit SAPAS score increment = 1.53, 95% CI [1.40, 1.67]; fully adjusted OR = 1.19, 95% CI [1.07, 1.33]. Furthermore, people screening positive for PD were more likely to report multiple (three or more) long-standing illnesses. The authors conclude that in the general population, individuals who are at high risk for PD are independently at increased risk of poor general health. PMID- 23795756 TI - Reasons for self-mutilation reported by borderline patients over 16 years of prospective follow-up. AB - The main objective of this study was to assess the reasons for episodes of self mutilation engaged in by patients with borderline personality disorder (BPD) over 16 years of prospective follow-up. Two hundred and ninety patients meeting both DIB-R and DSM-III-R criteria for BPD were interviewed every 2 years. The authors divided the borderline patients into two groups: those with a more extensive and those with a less extensive lifetime history of self-mutilation at study entry. These groups were not significantly different than one another on either of the interpersonally directed reasons for self-mutilation studied. However, those in the more extensive group were significantly more likely to report each of the five internally directed reasons studied. The results of this study suggest that borderline patients with a more extensive history of self-mutilation are best distinguished from those with a less extensive history by episodes of self-harm that are motivated, at least in part, by dysphoric inner states. PMID- 23795757 TI - The effect of personality disorders on treatment outcomes in patients with obsessive-compulsive disorders. AB - The effect of comorbid personality disorders (PD) on treatment outcomes in obsessive-compulsive disorder (OCD) is unclear. The authors systematically review results from investigations of therapy outcomes in adult patients with OCD and a comorbid PD. PsycINFO and MEDLINE were searched for original articles. Twenty three studies assessing PDs through interviews were selected. Cluster A PDs, particularly schizotypal PD, narcissistic PD, and the presence of two or more comorbid PDs, were associated with poorer treatment outcomes in patients with OCD. With regard to other PDs and clusters, the results are inconsistent or the sample sizes are too small to reach a conclusion. OCD patients with different comorbid PDs differ in their therapeutic response to treatment. To optimize the treatment of OCD, the predictive value of PDs on the treatment outcome should be further investigated, and treatment of Axis I and II comorbidity requires more attention. PMID- 23795758 TI - Impact of treatment intensity on suicidal behavior and depression in borderline personality disorder: a critical review. AB - The effectiveness of less versus more intensive psychological therapies in reducing suicidal behavior and depression in suicidal patients with borderline personality disorder (BPD) was examined. Electronic databases were searched. Trials were separated into less versus more intensive therapies. Suicidal acts and depression outcome data were assessed. Six trials met search criteria (cognitive-behavioral therapy for personality disorder, mentalization-based therapy, dialectical behavior therapy). Seven measures of suicidal acts and two measures of depression were used in studies. Both less and more intensive therapies report significant decreases in suicidal behaviors. Apart from one small trial, both less and more intensive therapies report decreases in depression with no differences between therapies and control conditions. Two follow-up studies showed that reductions in suicidal behavior and depression are maintained over time. The authors conclude that both less and more intensive therapies are effective in treating depression and suicidal behaviors in patients with BPD. Clinicians should deliver the least intensive interventions that will provide these significant health gains. PMID- 23795759 TI - Developmental trajectories to male borderline personality disorder. AB - Due to the higher diagnostic prevalence of borderline personality disorder (BPD) in females, there exists a dearth of literature on the manifestations of BPD in men and minimal information on male developmental trajectories to the disorder. To identify precursors of BPD in males, surveys were administered to parents about their BPD male offspring and non-BPD male siblings. Questions covered aspects of probands' lives from infancy to late adolescence. BPD offspring were identified through self-reported clinical diagnoses and standardized diagnostic criteria embedded within the survey. A total of 263 male offspring (97 meeting strict criteria for BPD and 166 non-BPD siblings) were studied. The authors found that parents describe the early emergence of a constellation of symptoms in their BPD sons that include separation anxiety starting in infancy, body image concerns in childhood, and impulsivity, emptiness, and odd thinking in adolescence. This trajectory differs from the developmental course found in females diagnosed with BPD. PMID- 23795760 TI - Ureteroscopy with and without safety guide wire: should the safety wire still be mandatory? AB - BACKGROUND AND PURPOSE: Although the evidence is sparse, most urologists advise the insertion of a safety guide wire (SGW) alongside the ureteroscope whenever performing ureteroscopy (URS). The aim of the study was to compare the results of ureteroscopic treatment for ureteral stones at the Oslo University Hospital (OUH), where the SGW is routinely used, with the results at the Haukeland University Hospital (HUH), where the SGW is routinely omitted. The primary goal was to evaluate the success rates of passing the ureteroscope through the orifice, the ability to access the ureteral stone, and the ability to place a ureteral stent when needed after the endoscopy. The secondary goals were to compare the perioperative complication rates and stone-free rates at the two hospitals. MATERIALS AND METHODS: A retrospective review of 500 URS for ureteral calculi at each of the two hospitals, during 2004-2010, was performed. Relevant data were extracted from the medical records. The exact chi-squared, Mann-Whitney U, and independent-samples t-tests were used comparing the results at the two hospitals. RESULTS: An SGW was used in 480 (96.2%) of the URS procedures at OUH and in 7 (1.4%) at HUH. No significant differences were found between the two hospitals in the success rates of passing the ureteroscope through the orifice, in the ability to access the ureteral calculus, or in the ability to place a ureteral stent when needed after the endoscopy. There were no significant differences in the number of intraoperative complications, but postendoscopic ureteral stenosis occurred more often at OUH (3.4%) than at HUH (1.2%), p=0.039. The overall stone-free rate was higher at HUH (85.9%) compared to OUH (77.1%), p=0.001. CONCLUSION: No superior results were found at the hospital with the routine use of an SGW. It may be questioned if the SGW still should be considered mandatory. PMID- 23795762 TI - The association between cannabis use and depression: a systematic review and meta analysis of longitudinal studies. AB - BACKGROUND: Longitudinal studies reporting the association between cannabis use and developing depression provide mixed results. The objective of this study was to establish the extent to which different patterns of use of cannabis are associated with the development of depression using meta-analysis of longitudinal studies. METHOD: Peer-reviewed publications reporting the risk of developing depression in cannabis users were located using searches of EMBASE, Medline, PsychINFO and ISI Web of Science. Only longitudinal studies that controlled for depression at baseline were included. Data on several study characteristics, including measures of cannabis use, measures of depression and control variables, were extracted. Odds ratios (ORs) were extracted by age and length of follow-up. RESULTS: After screening for 4764 articles, 57 articles were selected for full text review, of which 14 were included in the quantitative analysis (total number of subjects = 76058). The OR for cannabis users developing depression compared with controls was 1.17 [95% confidence interval (CI) 1.05-1.30]. The OR for heavy cannabis users developing depression was 1.62 (95% CI 1.21-2.16), compared with non-users or light users. Meta-regression revealed no significant differences in effect based on age of subjects and marginal difference in effect based on length of follow-up in the individual studies. There was large heterogeneity in the number and type of control variables in the different studies. CONCLUSIONS: Cannabis use, and particularly heavy cannabis use, may be associated with an increased risk for developing depressive disorders. There is need for further longitudinal exploration of the association between cannabis use and developing depression, particularly taking into account cumulative exposure to cannabis and potentially significant confounding factors. PMID- 23795761 TI - LITAF, a BCL6 target gene, regulates autophagy in mature B-cell lymphomas. AB - We have previously reported that LITAF is silenced by promoter hypermethylation in germinal centre-derived B-cell lymphomas, but beyond these data the regulation and function of lipopolysaccharide-induced tumour necrosis factor (TNF) factor (LITAF) in B cells are unknown. Gene expression and immunohistochemical studies revealed that LITAF and BCL6 show opposite expression in tonsil B-cell subpopulations and B-cell lymphomas, suggesting that BCL6 may regulate LITAF expression. Accordingly, BCL6 silencing increased LITAF expression, and chromatin immunoprecipitation and luciferase reporter assays demonstrated a direct transcriptional repression of LITAF by BCL6. Gain- and loss-of-function experiments in different B-cell lymphoma cell lines revealed that, in contrast to its function in monocytes, LITAF does not induce lipopolysaccharide-mediated TNF secretion in B cells. However, gene expression microarrays defined a LITAF related transcriptional signature containing genes regulating autophagy, including MAP1LC3B (LC3B). In addition, immunofluorescence analysis co-localized LITAF with autophagosomes, further suggesting a possible role in autophagy modulation. Accordingly, ectopic LITAF expression in B-cell lymphoma cells enhanced autophagy responses to starvation, which were impaired upon LITAF silencing. Our results indicate that the BCL6-mediated transcriptional repression of LITAF may inhibit autophagy in B cells during the germinal centre reaction, and suggest that the constitutive repression of autophagy responses in BCL6 driven lymphomas may contribute to lymphomagenesis. PMID- 23795763 TI - Relationship between theory of mind and functional independence is mediated by executive function. AB - Theory of mind (ToM) is the ability to comprehend another person's perspective. Although there is much literature of ToM in children, there is a limited and somewhat inconclusive amount of studies examining ToM in a geriatric population. This study examined ToM's relationship to functional independence. Two tests of ToM, tests of executive function, and a measure of functional ability were administered to cognitively intact older adults. Results showed that 1 test of ToM (Strange Stories test) significantly accounted for variance in functional ability, whereas the other did not (Faux Pas test). In addition, Strange Stories test performance was partially driven by a verbal abstraction-based executive function: proverb interpretation. A multiple mediation model was employed to examine whether executive functions explained the relationship between the Strange Stories test and functional ability. Results showed that both the combined and individual indirect effects of the executive function measures mediated the relationship. We argue that, although components of ToM are associated with functional independence, ToM does not appear to account for additional variance in functional independence beyond executive function measures. PMID- 23795764 TI - Impaired retrieval monitoring for past and future autobiographical events in older adults. AB - Older adults are more likely than younger adults to confuse real and imagined events in episodic memory. This deficit may be attributed to a reduction in the specific features available for recollection (i.e., retrieval success) or to a deficit in the search and decision processes operating during recollection attempts (i.e., retrieval monitoring). The present experiments used a two-phase event-generation task to manipulate retrieval success and test for age-related deficits in retrieval monitoring. In the first phase, participants generated real autobiographical events from their past and imagined plausible future events in response to cue words. We used elaboration instructions to experimentally manipulate the amount of features associated with these generated events. In the second phase administered 24 hours later, we gave recollection tests that required participants to discriminate between these previously generated past and future events in memory. As predicted, the elaboration manipulation increased the amount of features that could be recollected in association with the generated events in both age groups (including cognitive operations in Experiment 1 and perceptual details in Experiment 2). However, older adults were more likely than younger adults to confuse past and future events in memory, and critically, elaboration did not minimize these age-related confusions. These findings imply that aging impairs the ability to accurately monitor retrieval for features that are characteristic of autobiographical events, above and beyond age-related impairments in the retrieval of the recollected information itself. PMID- 23795766 TI - Longitudinal change in spousal similarities in mental health: between-couple and within-couple perspectives. AB - Research based on between-couple perspectives indicate that spouses share similarities in a range of psychosocial characteristics. In this study, the authors add to existing research by examining spousal similarities in mental health and its time-related change from both between-couple and within-couple perspectives. The authors apply latent growth models to 9-wave annual longitudinal data obtained from 3,410 adult couples in the Household, Income and Labor Dynamics in Australia Survey (HILDA; Mage wives = 48 years, Mage husbands = 50 years). In a first step, the authors corroborate extant findings from a between-couple perspective that spouses show considerable similarities in levels of and changes in mental health. In a second step, they calculate a within-couple similarity index (i.e., using absolute difference scores calculated based on the 2 partners' mental health). The authors show that mental health ratings between partners within a given spousal unit differed considerably (0.88 SD) and that these differences remained relatively stable over time. Examining between-couple differences in within-couple similarity revealed that larger discrepancies were associated with lower mental health (of individual partners), chronic health conditions, less marital satisfaction, and elevated risks for dissolution of the partnership. The authors discuss ways to integrate this counterintuitive set of findings with research originating from between-couple and within-couple perspectives, argue that a certain degree of spousal differences-if kept within certain bounds-can be adaptive serving developmental and relationship functions, and suggest routes for future inquiry on spousal similarities. PMID- 23795765 TI - Scaffolding across the lifespan in history-dependent decision-making. AB - We examined the relationship between pressure and age-related changes in decision making using a task for which currently available rewards depend on the participant's previous history of choices. Optimal responding in this task requires the participant to learn how his or her current choices affect changes in the future rewards given for each option. Building on the scaffolding theory of aging and cognition, we predicted that when additional frontal resources are available, compensatory recruitment leads to increased monitoring and increased use of heuristic-based strategies, ultimately leading to better performance. Specifically, we predicted that scaffolding would result in an age-related performance advantage under no pressure conditions. We also predicted that, although younger adults would engage in scaffolding under pressure, older adults would not have additional resources available for increased scaffolding under pressure-packed conditions, leading to an age-related performance deficit. Both predictions were supported by the data. In addition, computational models were used to evaluate decision-making strategies employed by each participant group. As expected, older adults under no pressure conditions and younger adults under pressure conditions showed increased use of heuristic-based strategies relative to older adults under pressure and younger adults under no pressure, respectively. These results are consistent with the notion that scaffolding can occur across the life span in the face of an environmental challenge. PMID- 23795767 TI - Dyadic analysis of self-efficacy and perceived support: the relationship of individual and spousal characteristics with physical activity among middle-aged and young-older adults. AB - The purpose of this study was to examine the associations among self-efficacy, perceived support, and physical activity in middle-aged and older married couples. A total of 116 middle-aged and older couples (M = 58.86 years, SD = 7.16, range 50-74) participated in the study. A dyadic approach to path modeling was taken. The final model indicated that for both husbands and wives, one's own self-efficacy was directly related to physical activity. In addition, husband self-efficacy was positively related to wive physical activity and indirectly related to wife physical activity through wife self-efficacy. Wife self-efficacy was indirectly related to husband physical activity via the level of husband perceived support. These results provide evidence for the importance of incorporating spousal characteristics in addition to individual characteristics when investigating physical activity during middle and later married life. PMID- 23795768 TI - A prospective study of volunteerism and hypertension risk in older adults. AB - The purpose of the current study was to determine whether volunteerism is prospectively associated with hypertension risk among older adults. Participants provided data during the 2006 and 2010 waves of the Health and Retirement Study, a longitudinal panel survey using a nationally representative sample of community dwelling older adults (age > 50 years). Volunteerism and blood pressure were measured at baseline and again 4 years later. Analyses excluded individuals hypertensive at baseline and controlled for age, race, sex, education, baseline systolic/diastolic blood pressure, and major chronic illnesses. Those who had volunteered at least 200 hr in the 12 months prior to baseline were less likely to develop hypertension (OR = 0.60; 95% CI [0.40, 0.90]) than nonvolunteers. There was no association between volunteerism and hypertension risk at lower levels of volunteer participation. Volunteering at least 200 hr was also associated with greater increases in psychological well-being (B = 0.99, beta = .05, p = .006) and physical activity (B = 0.21, beta = .05, p = .04) compared with nonvolunteers; however, these factors did not explain the association of volunteerism with hypertension risk. PMID- 23795769 TI - Exercise holds immediate benefits for affect and cognition in younger and older adults. AB - Physical activity is associated with improved affective experience and enhanced cognitive processing. Potential age differences in the degree of benefit, however, are poorly understood because most studies examine either younger or older adults. The present study examined age differences in cognitive performance and affective experience immediately following a single bout of moderate exercise. Participants (144 community members aged 19 to 93) were randomly assigned to one of two experimental conditions: (a) exercise (15 min of moderate intensity stationary cycling) or (b) control (15 min completing ratings of neutral IAPS images). Before and after the manipulation, participants completed tests of working memory and momentary affect experience was measured. Results suggest that exercise is associated with increased levels of high-arousal positive affect (HAP) and decreased levels of low-arousal positive affect (LAP) relative to control condition. Age moderated the effects of exercise on LAP, such that younger age was associated with a drop in reported LAP postexercise, whereas the effects of exercise on HAP were consistent across age. Exercise also led to faster RTs on a working memory task than the control condition across age. Self reported negative affect was unchanged. Overall, findings suggest that exercise may hold important benefits for both affective experience and cognitive performance regardless of age. PMID- 23795770 TI - Audit of a clinical guideline for neonatal hypoglycaemia screening. AB - AIM: This study aims to evaluate adherence to a clinical guideline for screening and prevention of neonatal hypoglycaemia on the post-natal wards. METHODS: Retrospective chart review of 581 healthy term neonates born at a tertiary maternity hospital. Indications for hypoglycaemia screening included small for gestational age (SGA), infants of diabetic mothers (IDM; gestational, Type 1 or 2), symptomatic hypoglycaemia, macrosomia and wasted (undernourished) appearance. Outcomes were protocol entry and adherence with hypoglycaemia prevention strategies including early and frequent feeding and timely blood glucose measurement. RESULTS: Of 115 neonates screened for hypoglycaemia, 67 were IDM, 19 were SGA (including two both IDM and SGA), and two were macrosomic. One IDM and one SGA were not screened. Twenty-two neonates were screened for a reason not identifiable from the medical record, and 13 neonates were SGA by a definition different to the guideline definition, including five who were also IDM. Guideline adherence was variable. Few neonates (41 of 106, 39%) were fed in the first post-natal hour, and blood glucose measurement occurred later than recommended for 41 of 106 (39%) of neonates. CONCLUSIONS: Most IDM and SGA neonates were screened. While guideline adherence overall was comparable with other studies, neonates were fed late. We recommend staff education about benefits of early (within the first hour) frequent breastfeeding for neonates at risk. PMID- 23795771 TI - Selective cannabinoid receptor type 2 (CB2) agonists: optimization of a series of purines leading to the identification of a clinical candidate for the treatment of osteoarthritic pain. AB - A focused screening strategy identified thienopyrimidine 12 as a cannabinoid receptor type 2 agonist (hCB2) with moderate selectivity over the hCB1 receptor. This initial hit suffered from poor in vitro metabolic stability and high in vivo clearance. Structure-activity relationships describe the optimization and modification to a new more polar series of purine CB2 agonists. Examples from this novel scaffold were found to be highly potent and fully efficacious agonists of the human CB2 receptor with excellent selectivity against CB1, often having no CB1 agonist activity at the highest concentration measured (>100 MUM). Compound 26 is a centrally penetrant molecule which possesses good biopharmaceutical properties, is highly water-soluble, and demonstrates robust oral activity in rodent models of joint pain. In addition, the peripherally restricted molecule 22 also demonstrated significant efficacy in the same analgesic model of rodent inflammatory pain. PMID- 23795772 TI - Maternal milk DHA content predicts cognitive performance in a sample of 28 nations. AB - Convergent evidence from neuronal biology and hominin brain hypertrophy suggests that omega-3 fatty acids are a limiting resource for neural and cognitive development in Homo sapiens, and therefore that children from populations with higher omega-3 availability should display superior cognitive performance. Using multiple regression, we tested this prediction in a sample of 28 countries, with Programme for International Student Assessment (PISA) math scores in 2009 as an index of cognitive performance, and country-specific breast milk levels of omega 3 docosahexaenoic acid (DHA) as an index of omega-3 availability. Breast milk DHA makes a highly significant contribution to math scores (beta = 0.462, P = 0.006), greater in magnitude than the control variables of per capita Gross Domestic Product (PCGDP) and educational expenditures per pupil. Together, dietary fish (positively) and total fat (negatively) explain 61% of the variance in maternal milk DHA in a larger sample of 39 countries. PMID- 23795773 TI - Pioglitazone alleviates the mitochondrial apoptotic pathway and mito-oxidative damage in the d-galactose-induced mouse model. AB - Chronic injection of d-galactose can cause gradual deterioration in learning and memory capacity, and activates oxidative stress, mitochondrial dysfunction and apoptotic cell death in the brain of mice. Thus, it serves as an animal model of ageing. Recent evidence has shown that mild cognitive impairment in humans might be alleviated by treatment with piogliatzone (peroxisome proliferator-activated receptor gamma (PPARgamma) agonists). To continue exploring the effects of piogliatzone in this model, we focused on behavioural alteration, oxidative damage, mitochondrial dysfunction and apoptosis in d-galactose-induced mice. The ageing model was established by administration of d-galactose (100 mg/kg) for 6 weeks. Pioglitazone (10 and 30 mg/kg) and bisphenol A diglycidyl ether (15 mg/kg) were given daily to d-galactose-induced senescent mice. The cognitive behaviour of mice was monitored using the Morris water maze. The anti-oxidant status and apoptotic activity in the ageing mice was measured by determining mito-oxidative parameters and caspase-3 activity in brain tissue. Systemic administration of d galactose significantly increased behavioural alterations, biochemical parameters, mitochondrial enzymes, and activations of caspase-3 and acetylcholinesterase enzyme activity as compared with the control group. Piogliatzone treatment significantly improved behavioural abnormalities, biochemical, cellular alterations, and attenuated the caspase-3 and acetylcholinesterase enzyme activity as compared with the control. Furthermore, pretreatment of BADGE (PPARgamma antagonist) with pioglitazone reversed the protective effect of pioglitazone in d-galactose-induced mice. The present study highlights the protective effects of pioglitzone against d-galactose-induced memory dysfunction, mito-oxidative damage and apoptosis through activation of PPARgamma receptors. These findings suggest that pioglitazone might be helpful for the prevention or alleviation of ageing. PMID- 23795774 TI - Proteomic profiling of developing cotton fibers from wild and domesticated Gossypium barbadense. AB - Pima cotton (Gossypium barbadense) is widely cultivated because of its long, strong seed trichomes ('fibers') used for premium textiles. These agronomically advanced fibers were derived following domestication and thousands of years of human-mediated crop improvement. To gain an insight into fiber development and evolution, we conducted comparative proteomic and transcriptomic profiling of developing fiber from an elite cultivar and a wild accession. Analyses using isobaric tag for relative and absolute quantification (iTRAQ) LC-MS/MS technology identified 1317 proteins in fiber. Of these, 205 were differentially expressed across developmental stages, and 190 showed differential expression between wild and cultivated forms, 14.4% of the proteome sampled. Human selection may have shifted the timing of developmental modules, such that some occur earlier in domesticated than in wild cotton. A novel approach was used to detect possible biased expression of homoeologous copies of proteins. Results indicate a significant partitioning of duplicate gene expression at the protein level, but an approximately equal degree of bias for each of the two constituent genomes of allopolyploid cotton. Our results demonstrate the power of complementary transcriptomic and proteomic approaches for the study of the domestication process. They also provide a rich database for mining for functional analyses of cotton improvement or evolution. PMID- 23795775 TI - Glycerol and environmental factors: effects on 1,3-propanediol production and NAD(+) regeneration in Lactobacillus panis PM1. AB - AIMS: This study was conducted to understand the influences of fermentation factors in NADH recycling and mechanisms of 1,3-propanediol (1,3-PDO) production in Lactobacillus panis PM1. METHODS AND RESULTS: We conducted metabolite analyses, qRT-PCR of the glycerol reductive pathway [glycerol dehydratase (DhaB) and 1,3-PDO dehydrogenase (DhaT)] and DhaT activity assays at different pH, temperature and initial glycerol concentrations. The supplementation of 150 mmol l(-1) glycerol caused a shift in NADH flux from ethanol to 1,3-PDO production, whereas 300 mol l(-1) glycerol negatively affected the regeneration of NAD(+) via 1,3-PDO production. This retardation decreased transcription levels and specific activities of DhaT. The decreased DhaT activity eventually caused the shutdown of 1,3-PDO production. Temperature and pH did not significantly affect the specific activity of DhaT, whereas expression of genes for DhaB and DhaT was activated under acidic conditions. Moreover, fresh glucose addition after its depletion could not restart the glycerol reduction, but increased ethanol production. CONCLUSIONS: Those environmental factors affect 1,3-PDO production in different ways through changing the expression level of enzymes and shifting the NAD(+) regeneration pathways. SIGNIFICANCE AND IMPACT OF THE STUDY: Our findings elucidated a key element to optimize 1,3-PDO production by Lact. panis PM1, which potentially improves 1,3-PDO manufacturing efficiencies. PMID- 23795776 TI - Aggressive behavior and its associations with posttraumatic stress and academic achievement following a natural disaster. AB - Despite an abundance of evidence linking maltreatment and violence-related trauma exposure to externalizing problems in youth, there is surprisingly little evidence to support a direct link between disaster exposure and youth aggressive behavior. This study tested the theory that there is primarily an indirect association between disaster exposure and aggression via posttraumatic stress disorder (PTSD) symptoms. The current study also examined the association between aggression and academic achievement. A sample of 191 4th- to 8th-grade minority youth who experienced Hurricane Katrina were assessed for aggressive behavior using the Peer Conflict Scale (PCS), disaster exposure, PTSD symptoms, and academic achievement. Structural equation modeling of the set of associations was consistent with the theory suggesting that there is an indirect link between disaster exposure and aggression through PTSD symptoms. Aggression was negatively associated with academic achievement, and modeling indicated that the set of associations was age and gender invariant. Findings advance the theoretical understanding of the linkage between aggression and disaster exposure. Findings also support the utility of the PCS in disaster research and the link between PCS scores and academic achievement. PMID- 23795777 TI - Nanoscale amphiphilic macromolecules with variable lipophilicity and stereochemistry modulate inhibition of oxidized low-density lipoprotein uptake. AB - Amphiphilic macromolecules (AMs) based on carbohydrate domains functionalized with poly(ethylene glycol) can inhibit the uptake of oxidized low density lipoprotein (oxLDL) and counteract foam cell formation, a key characteristic of early atherogenesis. To investigate the influence of lipophilicity and stereochemistry on the AMs' physicochemical and biological properties, mucic acid based AMs bearing four aliphatic chains (2a) and tartaric acid-based AMs bearing two (2b and 2l) and four aliphatic chains (2g and 2k) were synthesized and evaluated. Solution aggregation studies suggested that both the number of hydrophobic arms and the length of the hydrophobic domain impact AM micelle sizes, whereas stereochemistry impacts micelle stability. 2l, the meso analogue of 2b, elicited the highest reported oxLDL uptake inhibition values (89%), highlighting the crucial effect of stereochemistry on biological properties. This study suggests that stereochemistry plays a critical role in modulating oxLDL uptake and must be considered when designing biomaterials for potential cardiovascular therapies. PMID- 23795778 TI - Dietary habits and esophageal cancer. AB - Cancer of the esophagus is an underestimated, poorly understood, and changing disease. Its overall 5-year survival is less than 20%, even in the United States, which is largely a function of a delay in diagnosis until its more advanced stages. Additionally, the epidemiologic complexities of esophageal cancer are vast, rendering screening and prevention limited at best. First, the prevalence of esophageal cancer is unevenly distributed throughout the world. Second, the two histological forms (squamous cell and adenocarcinoma) vary in terms of their geographic prevalence and associated risk factors. Third, some populations appear at particular risk for esophageal cancer. And fourth, the incidence of esophageal cancer is in continuous flux among groups. Despite the varied prevalence and risks among populations, some factors have emerged as consistent associations while others are only now becoming more fully recognized. The most prominent, scientifically supported, and long-regarded risk factors for esophageal cancer are tobacco, alcohol, and reflux esophagitis. Inasmuch as the above are regarded as important risk factors for esophageal cancer, they are not the sole contributors. Dietary habits, nutrition, local customs, and the environment may be contributory. Along these lines, vitamins, minerals, fruits, vegetables, meats, fats, salted foods, nitrogen compounds, carcinogens, mycotoxins, and even the temperature of what we consume are increasingly regarded as potential etiologies for this deadly although potentially preventable disease. The goal of this review is to shed light on the less known role of nutrition and dietary habits in esophageal cancer. PMID- 23795779 TI - Luminous efficiency of axial In(x)Ga(1-x)N/GaN nanowire heterostructures: interplay of polarization and surface potentials. AB - Using continuum elasticity theory and an eight-band k.p formalism, we study the electronic properties of GaN nanowires with axial InxGa1-xN insertions. The three dimensional strain distribution in these insertions and the resulting distribution of the polarization fields are fully taken into account. In addition, we consider the presence of a surface potential originating from Fermi level pinning at the sidewall surfaces of the nanowires. Our simulations reveal an in-plane spatial separation of electrons and holes in the case of weak piezoelectric potentials, which correspond to an In content and layer thickness required for emission in the blue and violet spectral range. These results explain the quenching of the photoluminescence intensity experimentally observed for short emission wavelengths. We devise and discuss strategies to overcome this problem. PMID- 23795781 TI - Understanding the way we think. PMID- 23795782 TI - Laparoscopic radical prostatectomy is also oncologically safe and effective! PMID- 23795780 TI - Glutathione peroxidase mimic ebselen improves glucose-stimulated insulin secretion in murine islets. AB - AIMS: Glutathione peroxidase (GPX) mimic ebselen and superoxide dismutase (SOD) mimic copper diisopropylsalicylate (CuDIPs) were used to rescue impaired glucose stimulated insulin secretion (GSIS) in islets of GPX1 and(or) SOD1-knockout mice. RESULTS: Ebselen improved GSIS in islets of all four tested genotypes. The rescue in the GPX1 knockout resulted from a coordinated transcriptional regulation of four key GSIS regulators and was mediated by the peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC-1alpha)-mediated signaling pathways. In contrast, CuDIPs improved GSIS only in the SOD1 knockout and suppressed gene expression of the PGC-1alpha pathway. INNOVATION: Islets from the GPX1 and(or) SOD1 knockout mice provided metabolically controlled intracellular hydrogen peroxide (H2O2) and superoxide conditions for the present study to avoid confounding effects. Bioinformatics analyses of gene promoters and expression profiles guided the search for upstream signaling pathways to link the ebselen initiated H2O2 scavenging to downstream key events of GSIS. The RNA interference was applied to prove PGC-1alpha as the main mediator for that link. CONCLUSION: Our study revealed a novel metabolic use and clinical potential of ebselen in rescuing GSIS in the GPX1-deficient islets and mice, along with distinct differences between the GPX and SOD mimics in this regard. These findings highlight the necessities and opportunities of discretional applications of various antioxidant enzyme mimics in treating insulin secretion disorders. REBOUND TRACK: This work was rejected during standard peer review and rescued by Rebound Peer Review (Antioxid Redox Signal 16: 293-296, 2012) with the following serving as open reviewers: Regina Brigelius-Flohe, Vadim Gladyshev, Dexing Hou, and Holger Steinbrenner. PMID- 23795783 TI - Quantitative measurement of the androgen receptor in prepuces of boys with and without hypospadias. PMID- 23795784 TI - Comparison of prostate cancer diagnosis in patients receiving unrelated urological and non-urological cancer care. AB - OBJECTIVE: To evaluate prostate cancer diagnosis rates and survival outcomes in patients receiving unrelated (non-prostate) urological care with those in patients receiving non-urological care. MATERIALS AND METHODS: We conducted a population-based study using the Surveillance Epidemiology and End Results (SEER) database to identify men who underwent surgical treatment of renal cell carcinoma (RCC; n = 18,188) and colorectal carcinoma (CRC; n = 45,093) between 1992 and 2008. Using SEER*stat software to estimate standardized incidence ratios (SIRs), we investigated rates of prostate cancer diagnosis in patients with RCC and patients with CRC. Adjusting for patient age, race and year of diagnosis on multivariate analysis, we used Cox and Fine and Gray proportional hazards regressions to evaluate overall and disease-specific survival endpoints. RESULTS: The observed incidence of prostate cancer was higher in both the patients with RCC and those with CRC: SIR = 1.36 (95% confidence interval [CI] 1.27-1.46) vs 1.06 (95% CI 1.02-1.11). Adjusted prostate cancer SIRs were 30% higher (P < 0.001) in patients with RCC. Overall (hazard ratio = 1.13, P < 0.001) and primary cancer-adjusted mortalities (sub-distribution Hazard Ratio (sHR) = 1.17, P < 0.001) were higher in patients with RCC with no significant difference in prostate cancer-specific mortality (sHR = 0.827, P = 0.391). CONCLUSION: Rates of prostate cancer diagnosis were higher in patients with RCC (a cohort with unrelated urological cancer care) than in those with CRC. Despite higher overall mortality in patients with RCC, prostate cancer-specific survival was similar in both groups. Opportunities may exist to better target prostate cancer screening in patients who receive non-prostate-related urological care. Furthermore, urologists should not feel obligated to perform prostate-specific antigen screening for all patients receiving non-prostate-related urological care. PMID- 23795785 TI - Bone metastases in germ cell tumours: lessons learnt from a large retrospective study. AB - OBJECTIVE: To determine the characteristics of patients with germ cell cancer and bone metastases. PATIENTS AND METHODS: The case records of patients with known germ cell tumours (GCTs) within the Anglian Germ Cell Cancer Group database between January 2005 and March 2011 were reviewed retrospectively. Data were collected for histopathology, presence of bone metastases at diagnosis or relapse, site of bone metastases and imaging method used to confirm bone metastases, treatment received, response to treatment and overall survival. We present here the largest unselected cohort of bone metastases in patients with GCTs. RESULTS: In all, 2550 cases of GCTs were reviewed and there was bone involvement in 19 cases. The primary site was either testicular (13/19), mediastinal (1/19) or unknown (5/19). Most cases were non-seminomatous GCTs (11/19, 58%) and only three cases of seminomatous GCTs (3/19, 16%) with five cases in which diagnosis was based on clinical history and significantly raised GCT markers (5/19, 26%). In all of these five cases beta-human chorionic gonadotrophin was raised and in three alpha-fetoprotein was raised, consistent with non-seminomatous GCT. There were bone metastases at diagnosis (0.51%, 13/2550) or at relapse (0.24%, 6/2550). The sites of bone metastases were the vertebrae (15/19, 79%), pelvis (3/19, 16%), ribs (3/19, 16%) and femur (2/19, 11%). Ten patients (53%) had solitary, and nine patients (47%) had multiple, sites of bone metastases. In patients presenting with bone metastases at diagnosis compared with relapse, the mortality rate was 23% (3/13) and 50% (3/6), respectively. After receiving one line of chemotherapy, nine patients (47%) remained in remission not requiring further treatment, six (32%) required further chemotherapy due to subsequent relapse, three (16%) died after first-line chemotherapy and one was lost to follow-up. At the time of data collection and based on the last clinic follow-up, six patients (32%) had died with a median (interquartile range, IQR) follow-up of 11.5 (4.3, 24.8) months and 10 (53%) remained alive with a median (IQR) follow-up of 26 (13.5, 48) months Three patients were lost to follow-up. Of the known patients alive, eight (42%) remained in remission and two (11%) had recurrent disease requiring further treatment. CONCLUSION: Although bone disease in germ cell cancer is rare, awareness of this condition is important and there is a need for prospective evaluation of patient characteristics, treatment approaches and survival outcome in this group of patients. PMID- 23795786 TI - Causes of death in men with prostate cancer: an analysis of 50,000 men from the Thames Cancer Registry. AB - OBJECTIVE: To investigate causes of death in a UK cohort of patients with prostate cancer. PATIENTS AND METHODS: We examined causes of death in a UK cohort of 50,066 men with prostate cancer diagnosed between 1997 and 2006 reported to the Thames Cancer Registry (TCR) and followed-up to the end of 2007. The underlying cause of death was taken from the death certificate. Uptake of PSA screening was low in the UK during the period studied. We examined the relationship between cause of death and patient characteristics at diagnosis including age, cancer stage, and treatment (<=6 months of diagnosis). RESULTS: In all, 20,181 deaths occurred during the period; 49.8% recorded as being due to prostate cancer, 17.8% to cardiovascular disease, 11.6% to other cancers, and 20.7% to other causes. Irrespective of age, cancer stage, or treatment <=6 months of diagnosis, prostate cancer was an important cause of death ranging from 31.6% to 74.3% of all deaths in different subgroups. CONCLUSION: For men with prostate cancer diagnosed in a setting where uptake of PSA screening is low, our findings challenge the belief that prostate cancer is not an important cause of death. PMID- 23795787 TI - Does experience in creating a robot-assisted partial nephrectomy (RAPN) programme in an academic centre impact outcomes or complication rate? AB - OBJECTIVE: To evaluate the impact of increased experience in robot-assisted partial nephrectomy (RAPN) on perioperative and oncological outcomes To detail the complications encountered in establishing a RAPN programme at a tertiary referral centre and the factors associated with these complications. PATIENTS AND METHODS: The initial consecutive 233 patients undergoing RAPN between March 2008 and May 2012 at our institution were identified. Patients were divided into quartiles to evaluate outcomes, and uni- and multivariate predictors of complications were calculated. RESULTS: In progressive quartiles, patients tended to have more complex renal tumours as evaluated by R.E.N.A.L. nephrometry (P < 0.01) or preoperative aspects and dimensions used for an anatomical classification (PADUA) scores (P = 0.003), and percentage endophytic (P = 0.01). Developing technique increased the patients undergoing unclamped PN (P < 0.01). The mean time in the operating room (from skin incision to closure) decreased significantly from 225 to 183 min (P < 0.01) and warm ischaemia time decreased from 28 to 15 min, when clamping (P < 0.01). Clavien graded complication rate (P = 0.26) and positive margin rate (P = 0.32) was unchanged by quartile. CONCLUSION: We show that increasing experience allows more complex tumours to be removed with similar outcomes in patients undergoing RAPN. The complication rates and perioperative outcomes were similar in four successive quartiles of an initial experience of RAPN. PMID- 23795788 TI - Transurethral enucleation and resection of the prostate vs transvesical prostatectomy for prostate volumes >80 mL: a prospective randomized study. AB - OBJECTIVES: To compare the efficacy and safety of transurethral enucleation and resection of the prostate (TUERP) and transvesical prostatectomy (TVP) for patients with benign prostatic hyperplasia (BPH) and prostate volumes >80 mL. PATIENTS AND METHODS: A total of 100 patients with urodynamic obstruction and prostate volume >80 mL were prospectively randomized and enrolled in the study at a tertiary hospital. Patients underwent TVP or TUERP performed by one of two surgeons with experience of a large number of cases. All patients were preoperatively evaluated using patient age, prostate volume measurement, clinical characteristics of digital rectal examination, self-assessment using the International Prostate Symptom Scores (IPSS) questionnaire, a quality-of-life (QoL) questionnaire, maximum urinary flow rate (Qmax ), post-void residual urine volume (PVR), urine analysis, blood sample analysis, including determination of prostate-specific antigen (PSA) and haemoglobin concentration. All patients were assessed peri-operatively and postoperatively at 3 and 12 months. All complications were documented. RESULTS: Of 100 patients eligible to participate, 92 patients completed 12 months of follow-up. Patients who underwent TUERP had shorter catheterization times and hospital stays. Operation duration was not significantly different between the two surgical groups (P = 0.107). The resected adenoma weight in the TVP group was more than that in the TUERP group, but the difference was not significant (P = 0.062). There were no significant differences in IPSS, PVR, Qmax or QoL scores between the groups at 3 and 12 months. The patients in the TVP group appeared to have a better Qmax at 3 months, however, the difference was not significant (P = 0.081). Adverse events were similar in the two groups. CONCLUSION: We found that TUERP had efficacy and safety equivalent to that of TVP for patients with BPH and prostate volume >80 mL. PMID- 23795789 TI - Emergent ureteric stent vs percutaneous nephrostomy for obstructive urolithiasis with sepsis: patterns of use and outcomes from a 15-year experience. AB - OBJECTIVES: To characterize the use of emergent JJ ureteric stent placement and percutaneous nephrostomy (PCN) for patients with obstructive urolithiasis with sepsis, and to determine whether outcomes differ between the two treatment methods. PATIENTS AND METHODS: A total of 130 patients with obstructive urolithiasis and systemic inflammatory response syndrome criteria were identified retrospectively from a single health system database from 1995 to 2011. Primary outcomes included stone-related and clinical variables which predicted the use of each treatment method. Secondary outcomes included the length of hospital stay, risk of intensive care unit (ICU) admission, and surgical approach used for definitive stone management. RESULTS: The overall rate of failed procedures was 2.3% (3/130), with one in-hospital death (0.8%). Patients treated with PCN had larger stones (10 vs 7 mm, P = 0.031), and were more acutely ill (acute physiology, age, chronic health evaluation [APACHE] II scores of 15 vs 11, P = 0.036) than those treated with JJ stent placement. Patients treated with PCN were more likely to require ICU admission (odds ratio: 3.23, 95% confidence interval [CI]: 1.24-8.41, P = 0.016), and demonstrated longer length of hospital stay (beta: 0.47, 95% CI: 0.20-0.74, P = 0.001), even when adjusting for age, APACHE II score, and Charlson Comorbidity Index score. After resolution of sepsis, patients treated with PCN were more likely to be treated definitively with a percutaneous approach, while patients treated with JJ stent placement were more likely to be treated ureteroscopically. CONCLUSIONS: Both JJ stent placement and PCN drainage appear effective. Patients with larger stones and who are more acutely ill are more likely to be treated with PCN. Additional randomized clinical trials of adequate power are warranted to define the optimum management of these often complex cases. PMID- 23795790 TI - Impaired cardiopulmonary reserve in an elderly population is related to postoperative morbidity and length of hospital stay after radical cystectomy. AB - OBJECTIVE: To determine the relationship of preoperatively measured cardiorespiratory function, to the development of postoperative complications and length of hospital stay (LOS) in a cohort of patients undergoing radical cystectomy (RC), as RC and conduit formation is curative but is associated with significant postoperative morbidity and mortality. PATIENTS AND METHODS: Consecutive patients planned to have RC underwent cardiopulmonary exercise testing (CPET) to a standardised protocol. The results of the CPET were 'blinded' from the clinicians involved in the care of the patients. Patients were prospectively monitored for the primary outcome of postoperative complications, as defined by a validated classification (Clavien-Dindo). Secondary outcome included LOS and mortality. RESULTS: In all, 82 patients underwent CPET before RC. Eight patients did not subsequently undergo RC and a further five did not exercise sufficiently to allow for appropriate determination of the cardiopulmonary variables of interest. There was a significant difference in LOS between those patients who had a major perioperative complication (Clavien score > 3) and those that did not (16 vs 30 days; P < 0.001; hazard ratio [HR] 3.6, 95% confidence interval [CI] 2.1-6.3). The anaerobic threshold (AT) remained as the only significant independent predictor variable for the presence or absence of major postoperative complications (odds ratio 0.74, 95% CI 0.57-0.97; P = 0.03). When the optimal predictive value of AT of 12 mL/min/kg was used as a fitness marker, there was a significant relationship between fitness and LOS (median LOS: 'unfit' 22 days vs 'fit' 16 days; HR 0.47, 95% CI 0.28-0.80; P = 0.006) CONCLUSION: Impaired preoperative cardiopulmonary reserve was related to major morbidity, prolonged LOS and increased use of critical care resource after RC. This has important health and economic implications for risk assessment, rationalisation of postoperative resource and the potential for therapeutic preoperative intervention with exercise therapy. PMID- 23795791 TI - Renal function and cardiovascular outcomes after living donor nephrectomy in the UK: quality and safety revisited. AB - OBJECTIVE: To determine renal function and cardiovascular outcomes after living donor nephrectomy (LDN). Living donor kidney transplantation has become established as the treatment of choice for end-stage renal failure. Benefits to the recipient have to be balanced against perioperative and long-term health risks to the donor. SUBJECTS/PATIENTS AND METHODS: The UK Transplant Registry (UKTR) was used to identify 4586 living donors who had donated a kidney for transplantation in the UK between 2001 and 2008. This study was conducted with the consent and support of the NHS Blood and Transplant (NHSBT) Kidney and Pancreas Research Group. RESULTS: The mean glomerular filtration rate (GFR) fell from 103 mL/min/1.73 m(2) before LDN to 58 mL/min/1.73 m(2) 1 year after LDN. At 1 year after LDN 60% of donors had a GFR of <60 mL/min/1.73 m(2). A GFR of <60 mL/min/1.73 m(2) after LDN was associated with older age, females, lower GFR before LDN, White ethnicity, earlier LDN period, unrelated donor type and body mass index of >25 kg/m(2). Over a 2-year period after LDN there was an overall mortality rate of 0.39%, cardiovascular death in one patient (mortality rate of 0.02%) and a major cardiovascular event rate of 0.44%. CONCLUSION: In this study we show that mild renal dysfunction is common after LDN; however, due to the short duration of follow-up we are unable to comment on whether this subsequently leads to an increased risk of developing of cardiovascular disease. PMID- 23795792 TI - Cannabinoid receptors 1 and 2 are associated with bladder dysfunction in an experimental diabetic rat model. AB - OBJECTIVE: To investigate diabetes-associated changes in urinary bladder expression of cannabinoid receptors 1 and 2 (CB1 and CB2) and the functional role of CB agonists and antagonists in mediating phasic contractions of isolated bladder strips using a streptozotocin-induced diabetic rat model. MATERIALS AND METHODS: The bladder and dorsal root ganglion (DRG) were removed from diabetic rats and age-matched controls 8-10 weeks after diabetes induction. Expression of CB1 and CB2 mRNA was studied using quantitative real-time PCR and protein levels were determined by Western blot analysis. The effect of increasing concentrations (0.1-100 MUM) of the mixed CB1/CB2 agonist R(+)-WIN 55,212-2 (WIN), selective CB1 antagonist (AM251) and selective CB2 antagonist (AM630) on carbachol-evoked contraction of bladder strips from control and diabetic rats was investigated. WIN-induced alterations of bladder strip contraction were then studied after pre incubation with AM251 and AM630. RESULTS: Diabetes induced decreased CB1 protein and mRNA expression in both the bladder and DRG (P < 0.05), while decreased CB2 expression was observed in the bladder (P < 0.05). WIN decreased the amplitude, but not frequency, of carbachol-induced phasic contractions of bladder strips in a concentration-dependent manner and this effect was diminished in the diabetic state. AM630 and AM251 had no effect on isolated detrusor muscle function. Moreover, pre-incubation with AM251 partially counteracted the effect of WIN on detrusor muscle contraction. CONCLUSION: The results indicate that CB1 and CB2 are responsible for the pathogenesis of bladder dysfunction in diabetes mellitus and represent a viable target for pharmacological treatment of bladder cystopathy. PMID- 23795793 TI - Validation of voiding diary for stratification of bladder pain syndrome according to the presence/absence of cystoscopic abnormalities: a two-centre prospective study. AB - OBJECTIVE: To assess the value of the voiding diary in the management of patients with bladder pain syndrome for predicting the presence or absence of cystoscopic abnormalities. PATIENTS AND METHODS: From November 2009 to March 2011, 54 consecutive patients (39 women and 15 men) with bladder pain syndrome, as defined by the European Society for the Study of Interstitial Cystitis/Bladder Pain Syndrome (ESSIC) criteria, were prospectively enrolled in this two-centre study. All patients completed a home voiding diary on 3 consecutive days, which included analysis of voiding frequency, voided volume and severity of pre- and post voiding pain. The variables were evaluated on a numeric pain scale (NPS). All patients then underwent standardized cystoscopy under anaesthesia. Patients were stratified into two groups: a group with or a group without cystoscopic abnormalities. Voiding diary variables were compared using Student's t-test. RESULTS: Cystoscopic abnormalities were found in 33 patients. The group of patients with cystoscopic abnormalities had significantly more severe frequency (P = 0.034), especially nocturnal frequency (P = 0.009), a significantly lower mean voiding volume and lower sd from the mean (P = 0.011 and P = 0.014), and a significantly lower mean post-voiding NPS score (P = 0.039). CONCLUSION: On analysis of the voiding diaries, we found that different patient profiles were associated with the cystoscopic appearance of the bladder. A clinical voiding score was proposed to predict the cystoscopic appearance of the bladder on the basis of the voiding diary in bladder pain syndrome but needs to be validated on an independent population. PMID- 23795794 TI - In-hospital mortality and failure-to-rescue rates after radical cystectomy. AB - OBJECTIVE: To show the underlying variability in peri-operative mortality after radical cystectomy (RC) by analysing failure-to-rescue (FTR) rates, i.e. deaths after complications. MATERIALS AND METHODS: Patients undergoing RC for non metastatic bladder cancer (BCa) were identified from the Nationwide Inpatient Sample, 1999-2009, resulting in a weighted estimate of 79,972 patients. The FTR rates were assessed according to patient and hospital characteristics, as well as complication type. Generalized linear regression analyses were performed. RESULTS: Overall, 26,740 patients had a complication, corresponding to a FTR rate of 5.5%. Septicaemia (odds ratio [OR]: 13.41, P < 0.001) and cardiac (OR: 3.97, P < 0.001), wound-related (OR: 2.12, P < 0.001), genitourinary (OR: 1.62, P = 0.045) and haematological (OR: 1.78, P = 0.008) complications were associated with FTR. Older age (OR: 1.05, P < 0.001), increasing comorbidities (OR: 1.33, P < 0.001), Medicare (OR: 1.52, P = 0.016), and Medicaid insurance status (OR: 2.10, P = 0.029) were associated with higher odds of FTR. Conversely, increasing hospital volume (OR: 0.992, P = 0.014) reduced the odds of FTR. CONCLUSIONS: Whereas both patient and hospital characteristics were associated with increased odds of FTR, the occurrence of septicaemia and cardiac complications were the most strongly associated with a higher risk of in-hospital mortality. PMID- 23795795 TI - Patient characteristics and outcomes in metastatic upper tract urothelial carcinoma after radical nephroureterectomy: the experience of Japanese multi institutions. AB - OBJECTIVES: To investigate oncological outcomes and prognostic factors in patients with upper tract urothelial carcinoma (UTUC) who experienced disease recurrence after radical nephroureterectomy (RNU). Few studies have focused on the clinical courses of patients who experienced disease recurrence after RNU. PATIENTS AND METHODS: A total of 204 UTUC patients who experienced disease recurrence from a retrospective multi-institutional cohort were included in the present study. Associated patient outcomes were analyzed using multivariate analysis. RESULTS: The mean time from RNU to first disease recurrence was 15.0 months and ~90% of patients experienced disease recurrence within the first 3 years after RNU. During a median follow-up of 8.1 month after disease recurrence, 165 patients died from UTUC and five patients died from other causes. In the 204 cohorts, 1- and 3-year cancer-specific survival rates were 40.2% and 9.7%, respectively, and 1- and 3-year overall survival rates were 39.5% and 9.4%, respectively. After disease recurrence, 132 patients underwent systemic chemotherapy, and a subgroup analysis of patients who underwent systemic chemotherapy multivariate analysis showed that performance status, the presence of liver metastasis and the number of recurrence sites were independently prognostic of cancer-specific and overall survival after relapsing. According to three significant variables, 1- and 3-year cancer-specific survival rates were 72.7% and 20.8% in patients with no risk factors, 46.5% and 7.5% in patients with one risk factor, and 26.4% and 4.4% in patients with two or three risk factors, respectively (P < 0.001). CONCLUSIONS: Most patients died from UTUC within 3 years, even though systemic chemotherapies were administered after relapsing. Multivariate analysis showed that performance status, the presence of liver metastasis and the number of recurrence sites were independently related to poor survival after systemic chemotherapy. PMID- 23795796 TI - Patterns of management and surveillance imaging amongst medical oncologists in Australia for stage I testicular cancer. AB - OBJECTIVE: To determine the patterns of management and surveillance imaging amongst medical oncologists in Australia for stage I testicular cancer during 2010. METHODS: We conducted a survey comprising 14 questions about the management strategy and surveillance imaging for all patients with stage I testicular cancer treated over the previous 12 months. RESULTS: A total of 52 medical oncologists documented the management for an estimated 470 patients. For seminoma, management was in the form of surveillance in 33%, radiotherapy in 5% and adjuvant carboplatin in 62% of patients. For non-seminoma, management was surveillance in 73%, adjuvant chemotherapy in 23% and retroperitoneal lymph node dissection in 4% of patients. The frequency of surveillance imaging was highly variable, and >=10 computed tomography (CT) scans were used by 38% of clinicians for seminoma and 46% of clinicians for non-seminoma. CONCLUSION: We found considerable variation in management patterns. The infrequent use of surveillance and frequent use of carboplatin for seminoma differs from international guidelines. Radiation exposure from CT imaging should be reduced through standardized follow-up protocols, and possibly by alternate imaging methods if validated in appropriate studies. PMID- 23795797 TI - Effect of statin use on outcomes of non-muscle-invasive bladder cancer. AB - OBJECTIVES: To assess the impact of statin use on outcomes of patients with non muscle-invasive bladder cancer (NMIBC). To measure the effect of statin use on the efficacy of intravesical bacillus Calmette-Guerin (BCG) therapy. PATIENTS AND METHODS: A retrospective analysis was performed on 1117 patients treated with transurethral resection of the bladder (TURB) for NMIBC at three institutions between 1996 and 2007. Statin use at the time of diagnosis was recorded for each patient. Univariable Cox regression models addressed the association of statin use with disease recurrence, disease progression, cancer-specific mortality and overall mortality in all patients, patients with primary NMIBC, patients not treated with BCG, and patients treated with BCG. RESULTS: Overall, 341 patients (30.5%) used statins and 776 (69.5%) did not. Within a median (interquartile range) follow-up of 62.7 (25.0-110.7) months, 469 patients (42.0%) experienced disease recurrence, 103 (9.2%) progression, 50 (4.5%) cancer-specific mortality, and 299 (26.8%) any-cause mortality. In univariable Cox regression analyses, statin use was not associated with any of these four endpoints (P > 0.05 for all). In subgroup analyses, statin use was also not associated with prognosis in patients with primary NMIBC or patients not receiving BCG (P > 0.05 for all four endpoints). Statin use was not associated with response to BCG (P > 0.05 for all four endpoints). CONCLUSION: Statin users did not experience different outcomes compared with non-users and statin use did not affect the efficacy of BCG immunotherapy; these data do not support modification or discontinuation of statin therapy for patients with NMIBC. PMID- 23795798 TI - Unaltered oncological outcomes of radical cystectomy with extended lymphadenectomy over three decades. AB - OBJECTIVE: To evaluate oncological outcome trends over the last three decades in patients after radical cystectomy (RC) and extended pelvic lymph node (LN) dissection. PATIENTS AND METHODS: Retrospective analysis of the University of Southern California (USC) RC cohort of patients (1488 patients) operated with intent to cure from 1980 to 2005 for biopsy confirmed muscle-invasive urothelial bladder cancer. To focus on outcomes of unexpected (cN0M0) LN-positive patients, the USC subset was extended with unexpected LN-positive patients from the University of Berne (UB) (combined subgroup 521 patients). Patients were grouped and compared according to decade of surgery (1980-1989/1990-1999/>=2000). Survival probabilities were calculated with Kaplan-Meier plots, log-rank tests compared outcomes according to decade of surgery, followed by multivariable verification. RESULTS: The 10-year recurrence-free survival was 78-80% in patients with organ-confined, LN-negative disease, 53-60% in patients with extravesical, yet LN-negative disease and ~30% in LN-positive patients. Although the number of patients receiving systemic chemotherapy increased, no survival improvement was noted in either the entire USC cohort, or in the combined LN positive USC-UB cohort. In contrast, patient age at surgery increased progressively, suggesting a relative survival benefit. CONCLUSIONS: Radical surgery remains the mainstay of therapy for muscle-invasive bladder cancer. Yet, our study reveals predictable outcomes but no survival improvement in patients undergoing RC over the last three decades. Any future survival improvements are likely to result from more effective systemic treatments and/or earlier detection of the disease. PMID- 23795799 TI - When to perform lymph node dissection in patients with renal cell carcinoma: a novel approach to the preoperative assessment of risk of lymph node invasion at surgery and of lymph node progression during follow-up. AB - OBJECTIVE: To identify preoperatively patients who might benefit from lymph node dissection (LND). PATIENTS AND METHODS: We assessed lymph node invasion (LNI) at final pathology and lymph node (LN) progression during the follow-up for 1983 patients with RCC, treated with either partial or radical nephrectomy. LN progression was defined as the onset of a new clinically detected lymphadenopathy (>10 mm) in the retroperitoneal lymphatic area. Logistic regression analyses were used to assess the effect of each potential clinical predictor (age, body mass index, tumour side, symptoms, performance status, clinical tumour size, clinical tumour-node-metastasis stage, and albumin, calcium, creatinine, haemoglobin and platelet levels) on the outcome of interest. The most parsimonious multivariable predictive model was developed, and discrimination, calibration and net benefit were calculated. RESULTS: The prevalence of LNI was 6.1% (120/1983 patients) and during the follow-up period, 82 patients (4.1%) experienced LN progression. On multivariable analyses, the most informative independent predictors were tumour stage (cT3-4 vs cT1-2, odds ratio [OR] 1.52, P = 0.05), clinical nodal status [cN1 vs cN0, OR 7.09, P < 0.001], metastases at diagnosis (OR 3.04, P < 0.001) and clinical tumour size (OR 1.14, P < 0.001). The accuracy of the multivariable model was found to be 86.9%, with excellent calibration and net benefit at decision-curve analyses. CONCLUSIONS: By relying on a unique approach, combining the risk of harbouring LNI and/or LN progression during the follow-up period, we have provided the first clinical presurgery model predicting the need for LND. PMID- 23795800 TI - A longitudinal study of anxiety, depression and distress as predictors of sexual and urinary quality of life in men with prostate cancer. AB - OBJECTIVE: To evaluate the prevalence of depression, anxiety and distress among active surveillance (AS) and radical prostatectomy (RP) patients. To evaluate the impact of these symptoms at baseline on urinary and sexual quality of life at follow-up. PATIENTS AND METHODS: Patients managed with AS or RP who completed validated questionnaires assessing levels of depression, anxiety, distress and urinary (UF) and sexual function (SF) and bother comprised the final analytic cohort. These measures were completed at baseline, within 1 year, and between 1 and 3 years from baseline. Mixed model repeated measures analysis was used to examine associations between mental health at baseline and sexual and urinary outcomes in a subset of RP patients with complete follow-up. RESULTS: Among 679 men who comprised the study cohort, baseline prevalence of moderate or higher levels of depression or anxiety were low (<5%), while levels of mild depression or anxiety ranged from 3-16% over time. Baseline levels of elevated distress ranged from 8-20%. Among men who provided data at baseline and follow-up, there were no significant differences between AS and RP patients in the proportion of men with elevated levels of depression, anxiety, or distress. Among 177 men who underwent RP and had complete follow-up moderate or higher levels of depression or anxiety appeared to be associated with post-treatment SF and bother, while elevated levels of distress were associated with post-treatment UF. CONCLUSION: Moderate or higher levels of depression or anxiety were low in men with localised prostate cancer but were associated with sexual outcomes, while elevated distress was associated with urinary outcomes. Greater attention should be paid to mental health symptoms among men with prostate cancer, as these symptoms may be associated with quality of life outcomes. PMID- 23795801 TI - Is mechanical bowel preparation in laparoscopic radical prostatectomy beneficial? An analysis of a Japanese national database. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Recently, the ineffectiveness of bowel mechanical preparation prior to colorectal surgery was focused on. Although its effectiveness was widely accepted in laparoscopic prostatectomy, the data were limited. This retrospective multicentre study compared laparoscopic prostatectomy cases with and without bowel preparation and did not demonstrate the preparation's preferable effect in operation time and complication incidence, which suggested justification of the omission of bowel preparation. OBJECTIVE: To evaluate the effect of mechanical bowel preparation (MBP) prior to laparoscopic radical prostatectomy on peri-operative outcomes. PATIENTS AND METHODS: Patients undergoing laparoscopic radical prostatectomy for T1-T2 tumours between 2008 and 2010 were identified in the Japanese Diagnosis Procedure Combination database. Patients were classified into a preoperative MBP group and a non-MBP group. The effects of MBP were evaluated by multivariate regression analysis of overall complication rate, operation time, postoperative length of stay (PLOS) and total costs with generalized estimating equations adjustment involving age, body mass index, Charlson score, hospital academic status and hospital volume. RESULTS: Comparing the 154 non-MBP and 580 MBP patients, overall complication rate, operation time, PLOS and total costs were 6.5% vs 6.9% (P = 0.860), 222 vs 250 min (P = 0.001), 11 vs 10 days (P < 0.001) and 18,941 vs 19,015 US dollars (P = 0.032), respectively. In the multivariate analyses, no significant differences were observed for the four outcomes (P = 0.961, 0.194, 0.383 and 0.993, respectively). Complications were more frequently observed in older patients, and operation time tended to be longer in patients with higher body mass index and in hospitals with lower volumes. Longer PLOS and higher total costs were associated with older age, higher Charlson score and lower hospital volume. CONCLUSIONS: We could not find any superiority of MBP on overall complications, operation time, PLOS and total costs in laparoscopic radical prostatectomy. The results support that MBP can be omitted prior to laparoscopic radical prostatectomy for T1-T2 prostate cancer. PMID- 23795802 TI - Laparoscopic partial nephrectomy (LPN) for totally intrarenal tumours. AB - OBJECTIVE: To evaluate the feasibility and outcomes of laparoscopic partial nephrectomy (LPN) for totally intrarenal tumours (TIT). PATIENTS AND METHODS: TIT were defined as completely intraparenchymatic masses, without any exophytic element. Identification of such a tumour necessitates guidance of intraoperative laparoscopic ultrasonography. Data of patients with TIT who underwent LPN was collected from our Ethical Committee-approved database. Their data was compared with that of patients who underwent LPN for tumours with any degree of exophytic element. The two groups were compared for preoperative data (age, gender, tumour size and location), intraoperative variables (warm ischemia time [WIT], open conversions rate, radical nephrectomy [RN] rate, blood loss and other complications), and postoperative data (renal function, reoperation rates, pathological results, and incidence of positive surgical margins). RESULTS: Among 458 patients who underwent LPN, 41 had TIT. The mean (sd) tumour size was 2.6 (0.8) cm, mean WIT was 22.6 (13.8) min and blood loss was 279 (210) mL. The RN rate was significantly higher in the TIT group compared with the remaining cohort of LPNs (9.7% vs 5.3%). The intra- and postoperative complications, open conversion and positive margin rates were similar between the two groups. Malignant tumours were found in 84.2% and 78.2%, respectively. CONCLUSIONS: LPN for a TIT is technically feasible. TIT carry a significantly higher RN rate due to tumour involvement of vital kidney structures. This aspect should be discussed with the patient preoperatively but TIT should not be considered a definitive indication for RN. PMID- 23795803 TI - Suprapubic-assisted laparoendoscopic single-site surgery (LESS) in urology: our experience. AB - OBJECTIVE: To report our experience with suprapubic-assisted laparoendoscopic single-site surgery (SA-LESS) in urology. PATIENTS AND METHODS: In all, 236 patients underwent SA-LESS A 5- and 10-mm (or two 5-mm) trocars were inserted at the medial margin of the umbilicus. A 10- or 5-mm trocar was inserted into the abdominal cavity below the ipsilateral pubic hairline. The technique for the SA LESS is similar to that of the standard laparoscopy, with conventional instruments placed in the abdominal trocars, under direct vision achieved by a 10 mm conventional 30 degrees or 5-mm flexible-tip 0 degrees laparoscope placed through the trocar below the pubic hairline. RESULTS: SA-LESS was successfully completed in 229 patients, without the need for ancillary trocars or additional instruments. Six patients required conversion to standard laparoscopy because of intraoperative bleeding (five) and failure to progress (one). One patient underwent open conversion because of gradual bleeding during the dissection of a dense adhesive renal pedicle due to infection and fibrosis The various SA-LESS procedures performed included adrenalectomy (15), renal cyst excision (19), nephrectomy (78; simple 63, radical 15), nephroureterectomy (three), nephron sparing surgery (three), heminephroureterectomy (five), pyeloplasty (nine), pyelolithotomy (six), and ureterolithotomy (98). The median operative time was 81, 106, 92, 140, and 85 min, and the estimated blood loss was 60, 205, 115, 75, and 55 mL for adrenalectomy, simple nephrectomy, radical nephrectomy, pyeloplasty, and ureterolithotomy, respectively. At a mean (range) follow-up of 14.8 (2-27) months there was a hidden umbilicus scar. The scar below the pubic hairline was not detectable because of pubic hair covering. CONCLUSIONS: SA-LESS appears to be feasible, safe and effective. Compared with umbilical LESS, the placement of a trocar at the umbilicus and below the pubic hairline not only decreases the difficulty of surgery but also leads to little postoperative pain and good cosmetic results. PMID- 23795804 TI - Substituent effects on the cooperativity of halogen bonding. AB - DFT calculations (B97-1) with the 6-31+G(d,p)-LanL2DZdp basis set were used to analyze the intermolecular interactions in 4-Z-Py...XCN...XCN triads (Z = H, F, OH, OCH3, CH3, NH2, NO2, and CN; Py = pyridine; and X = Cl and Br) that are connected by halogen-bond interactions. To understand the properties of the systems better, the corresponding dyads are also studied. Particular attention is given to parameters such as cooperative energy. All complexes show cooperative energy ranging from -1.39 to -3.46 kJ mol(-1) and -2.61 to -5.84 kJ mol(-1) for X = Cl and Br, respectively. We show that the effect of the substituents on the title interactions strongly depends on the nature of the substituents (Z). Thus, the electron-donor and electron-acceptor substituents increase and decrease the stability of complexes, respectively. The electronic properties of the complexes have been analyzed using molecular electrostatic potential (MEP) and minimum average local ionization energy, and the parameters were derived from the atoms in molecules (AIM) and natural bond orbital (NBO) methodologies. PMID- 23795805 TI - Cyclosporine versus everolimus: effects on the glomerulus. AB - Inhibitors of the mammalian target of rapamycin (mTOR) have been associated with proteinuria. We studied the development of proteinuria in renal transplant recipients (RTR) treated with the mTOR inhibitor everolimus in comparison with a calcineurin inhibitor. We related the presence of proteinuria to histopathological glomerular findings in two-yr protocol biopsies. In a single center study, nested in a multicenter randomized controlled trial, we determined eGFR, proteinuria, and renal biopsy data (light- and electron microscopy) of RTR receiving prednisolone/everolimus (P/EVL) (n = 16) in comparison with patients treated with prednisolone/cyclosporine A (P/CsA) (n = 7). All patients had been on the above-described maintenance immunosuppression for 18 months. Renal function at two yr after transplantation did not differ between patients receiving P/EVL or P/CsA (eGFR 45.5 vs. 45.7 mL/min/1.73 m(2)). Proteinuria was slightly increased in P/EVL vs. P/CsA group (0.29 vs. 0.14 g/24 h, p = 0.06). There were no differences in light- or electron microscopic findings. We could not demonstrate increased podocyte effacement or changes in glomerular basement membrane (GBM) thickness in P/EVL-treated patients. In conclusion, long-term treatment with everolimus leaves the GBM and podocytes unaffected. PMID- 23795806 TI - Vascular endothelial growth factor: the salt in the Hodgkin cytokine stew? PMID- 23795807 TI - Changes in metabolic markers in insulin-producing beta-cells during hypoxia induced cell death as studied by NMR metabolomics. AB - This study was designed to investigate changes in the metabolites in the intracellular fluid of the pancreatic beta-cell line INS-1 to identify potential early and late biomarkers for predicting hypoxia-induced cell death. INS-1 cells were incubated under normoxic conditions (95% air, 5% CO2) or hypoxic conditions (1% O2, 5% CO2, 95% N2) for 2, 4, 6, 12, or 24 h. The biological changes indicating the process of cell death were analyzed using the MTT assay, flow cytometry, Western blotting, and immunostaining. Changes in the metabolic profiles from cell lysates were identified using 1H nuclear magnetic resonance (1H NMR) spectroscopy, and the spectra were analyzed by the multivariate model Orthogonal Projections to Latent Structure-Discriminant Analysis. Cell viability decreased approximately 40% after 12-24 h of hypoxia, coincident with a high level of cleaved caspase-3. A high level of HIF-1alpha was detected in the 12-24 h hypoxic conditions. The metabolite profiles were altered according to the degree of exposure to hypoxia. A spectral analysis showed significant differences in creatine-containing compounds at the early stage (2-6 h) and taurine containing compounds at the late stage (12-24 h), with the detection of HIF 1alpha and cleaved caspase-3 in cells exposed to hypoxia compared to normoxia. Glycerophosphocholine decreased during the early stage hypoxia. The change in taurine- and creatine-containing compounds and choline species could be involved in the beta-cell death process as inhibitors or activators of cell death. Our results imply that assessment by 1H NMR spectroscopy would be a useful tool to predict the cell death process and to identify molecules regulating hypoxia induced cell death mechanisms. PMID- 23795808 TI - Paradoxical oncogenesis: are all BRAF inhibitors equal? AB - Cutaneous squamous cell carcinoma (cSCC) is a concerning toxicity with BRAF inhibitors in the treatment for melanoma. While the two drugs shown to improve survival, vemurafenib, and dabrafenib, have similar efficacy, the reported rates of cSCC are quite different. Drawing upon preclinical and clinical trial data, this article discusses the potential factors behind the different cSCC incidences reported with the two BRAF inhibitors and provides a strategic approach to understand this issue further. PMID- 23795809 TI - Loop diuretics and ultrafiltration in heart failure. AB - INTRODUCTION: Despite widespread use of loop diuretics in congestive heart failure (HF) to achieve decongestion and relief of symptoms, as recommended by the current guidelines, there is uncertainty as to their long-term therapeutic efficacy and safety. Their efficacy and safety compared to venous ultrafiltration are currently under investigation in acute decompensated HF patients. AREAS COVERED: In this article, the authors review current available data related to efficacy and safety of loop diuretics and ultrafiltration in HF. EXPERT OPINION: The literature review highlights an unmet clinical need for evidence-based algorithms, potentially using not only the classical clinical signs and symptoms of congestion as well as the estimated glomerular filtration rate and serum electrolytes, but also biomarkers of congestion/decongestion, neurohumoural activation or urinary kidney injury molecules, in order to optimize both loop diuretics and renin-angiotensin-aldosterone system blocker use in HF patients. PMID- 23795810 TI - Citronellal, a monoterpene present in Java citronella oil, attenuates mechanical nociception response in mice. AB - CONTEXT: Citronellal is a monoterpene present in the oil of many species, including Cymbopogon winterianus Jowitt (Poaceae). OBJECTIVE: The present study investigated the effect of citronellal on inflammatory nociception induced by different stimuli and examined the involvement of the NO-cGMP-ATP-sensitive K+ channel pathway. MATERIALS AND METHODS: We used male Swiss mice (n = 6 per group) that were treated intraperitoneally with citronellal (25, 50 or 100 mg/kg) 0.5 h after the subplantar injection of 20 MUl of carrageenan (CG; 300 ug/paw), tumor necrosis factor-alpha (TNF-alpha; 100 pg/paw), prostaglandin E2 (PGE2; 100 ng/paw) or dopamine (DA; 30 MUg/paw). The mechanical nociception was evaluated at 0.5, 1, 2 and 3 h after the injection of the agents, using a digital analgesimeter (von Frey). The effects of citronellal were also evaluated in the presence of L-NAME (30 mg/kg) or glibenclamide (5 mg/kg). RESULTS: At all times, citronellal in all doses inhibited the development of mechanical nociception induced by CG (p < 0.001 and p < 0.01) and TNF-alpha (p < 0.001, p < 0.01, and p < 0.05). The citronellal was able to increase the pain threshold in the DA test (p < 0.001, p < 0.01, and p < 0.05) and in the PGE2 test at all times (p < 0.001 and p < 0.05). L-NAME and glibenclamide reversed the antinociceptive effects of the citronellal at higher doses in the PGE2 test. DISCUSSION AND CONCLUSION: These data suggest that citronellal attenuated mechanical nociception, mediated in part by the NO-cGMP-ATP-sensitive K+ channel pathway. PMID- 23795811 TI - An aromatic amino acid in the coiled-coil 1 domain plays a crucial role in the auto-inhibitory mechanism of STIM1. AB - STIM1 (stromal interaction molecule 1) is one of the key elements that mediate store-operated Ca2+ entry via CRAC (Ca2+- release-activated Ca2+) channels in immune and non-excitable cells. Under physiological conditions, the intramolecular auto-inhibitions in STIM1 C- and STIM1 N-termini play essential roles in keeping STIM1 in an inactive state. However, the auto-inhibitory mechanism of the STIM1 C-terminus is still unclear. In the present study, we first predicted a short inhibitory domain (residues 310-317) in human STIM1 that might determine the different localizations of human STIM1 from Caenorhabditis elegans STIM1 in resting cells. Next, we confirmed the prediction and further identified an aromatic amino acid residue, Tyr316, that played a crucial role in maintaining STIM1 in a closed conformation in quiescent cells. Full-length STIM1 Y316A formed constitutive clusters near the plasma membrane and activated the CRAC channel in the resting state when co-expressed with Orai1. The introduction of a Y316A mutation caused the higher-order oligomerization of the in vitro purified STIM1 fragment containing both the auto-inhibitory domain and CAD(CRAC activating domain).We propose that the Tyr316 residue may be involved in the auto inhibitory mechanism of the STIM1 C-terminus in the quiescent state. This inhibition could be achieved either by interacting with the CAD using hydrogen and/or hydrophobic bonds, or by an intermolecular interaction using repulsive forces, which maintained a dimeric STIM1. PMID- 23795812 TI - Relation between fetuin-A levels and fibroblast growth factor 23 with the severity of coronary artery disease measured by SYNTAX scores. AB - Diagnosis of coronary artery disease requires invasive procedures that are typically not implemented until clinical warning signs are apparent. The goal of this study was to determine the relation between the severity of coronary artery disease, as measured by the SYNTAX scoring system, with serum levels of fetuin-A and fibroblast growth factor 23 (FGF23) in the general population. We enrolled 165 patients who had stable angina and positive results on treadmill testing or abnormal results on thallium myocardial perfusion scanning showing perfusion defects or who had acute coronary syndromes. Patients were hospitalized for evaluation with angiography, with or without simultaneous percutaneous coronary intervention. SYNTAX Scores were calculated on the basis of the results of coronary angiography using a computer-based questionnaire of sequential and interactive self-guided questions. Univariate analysis was used to assess the significance of fetuin-A and FGF23, as well as gender, age, body mass index, waist circumference, diabetes, hypertension, creatinine, total cholesterol, cholesterol, triglycerides, and high-sensitivity C-reactive protein in relation to cardiovascular disease severity. Multivariate analysis with stepwise regression was used to assess the utility of fetuin-A and FGF23 as predictors of SYNTAX Score. Multivariate analysis showed log fetuin-A to be a significant predictor of SYNTAX Score (p <0.0001) after controlling for the significant factors gender, cholesterol levels, and log high-sensitivity C-reactive protein. Log FGF23 values were also shown by multivariate regression to significantly predict SYNTAX Score (p = 0.0137) after controlling for gender, creatinine, cholesterol, and log high-sensitivity C-reactive protein. In conclusion, fetuin-A and FGF23 can be considered in combination with noninvasive test results as patient selection criteria for performing angiography. PMID- 23795813 TI - Relation between serum PAPP-A level and umbilical cord thickness during first trimester of pregnancy. AB - PURPOSE: To evaluate the relation between umbilical cord diameter versus pregnancy associated plasma protein-A (PAPP-A) level in first trimester women. METHOD: Cord diameter were measured and patients were divided into two groups according to frequency distribution analysis as below or above 3.7 mm for free loop diameter (FCD) and below or above 3.4 mm for cord measurement at umbilicus (ACD). Groups were compared with each other. RESULTS: Strong correlations were found between ACD versus PAPP-A. CONCLUSION: By using strong correlation between ACD versus PAPP-A, it may be possible to reduce unnecessary amniocentesis due to false positive screening results. PMID- 23795814 TI - Mutational analysis of 48G7 reveals that somatic hypermutation affects both antibody stability and binding affinity. AB - The monoclonal antibody 48G7 differs from its germline precursor by 10 somatic mutations, a number of which appear to be functionally silent. We analyzed the effects of individual somatic mutations and combinations thereof on both antibody binding affinity and thermal stability. Individual somatic mutations that enhance binding affinity to hapten decrease the stability of the germline antibody; combining these binding mutations produced a mutant with high affinity for hapten but exceptionally low stability. Adding back each of the remaining somatic mutations restored thermal stability. These results, in conjunction with recently published studies, suggest an expanded role for somatic hypermutation in which both binding affinity and stability are optimized during clonal selection. PMID- 23795816 TI - Maternal factor V Leiden and prothrombin mutations do not seem to contribute to the occurrence of two or more than two consecutive miscarriages in Caucasian patients. AB - BACKGROUND: We analysed the prevalence of the most common hereditary thrombophilia (hTP) - factor V Leiden (FVL) mutation, prothrombin 20210 G>A substitution (PT) - and the 677 C>T replacement in the 5,10 methylenetetrahydrofolate reductase (MTHFR) gene in Caucasian patients with a history of two and more consecutive recurrent miscarriages (RMs) as compared to healthy controls with an identical ethnic background and at least one live birth. METHODS: A multicenter analysis of three hTP was performed in 641 RM patients identically screened at specialized university centres. RESULTS: The study groups consisted of 240 patients with 2 (1) and 401 patients with >2 miscarriages (2) and were compared with 157 controls. There was no significant difference in the prevalence of the hTP between RM patients and controls nor within the two study groups. Subgroup analysis showed that the homozygous MTHFR polymorphism was significantly more prevalent in the study group 2 as compared to study group 1 (13.9 versus 7.9%, P = 0.02). CONCLUSION: In Caucasians, maternal FVL or PT mutations do not seem to contribute to the pathophysiology of RM, irrespective of the number of miscarriages. However, the role of the homozygous MTHFR polymorphism merits further investigation. PMID- 23795817 TI - Medical management of critical limb ischaemia: where do we stand today? AB - Critical limb ischaemia (CLI) is a severe form of peripheral arterial disease (PAD). CLI often causes disabling symptoms of pain and can lead to loss of the affected limb. It is also associated with increased risk of myocardial infarction, stroke and death from cardiovascular disease. The aims of management in patients with CLI are to relieve ischaemic pain, heal ulcers, prevent limb loss, improve function and quality of life and prolong survival. Here, current evidence regarding the medical management of CLI is reviewed. Cardiovascular risk factors should be assessed in all patients with CLI; smoking cessation and treatment of hypertension, hyperlipidaemia and diabetes all reduce the mortality rate in those with PAD. Antiplatelet agents (either aspirin or clopidogrel) are recommended to reduce both the incidence of cardiovascular events and risk of arterial occlusion. By contrast, routine use of anticoagulation (either warfarin or heparin) is not recommended. Treatment of the limbs themselves is often more challenging. Prostanoids may have some efficacy for treating rest pain and for ulcer healing, and iloprost shows favourable results in reducing the risk of major amputations, but long-term follow-up data regarding disease progression are lacking. There is insufficient evidence to support the use of naftidrofuryl or cilostazol, and pentoxifylline is not beneficial. Furthermore, there is no evidence of proven benefit of hyperbaric oxygen. A number of angiogenic growth factors have been studied in Phase I studies and randomized controlled trials (RCTs). They appear to be safe, but efficacy results have been mixed. Treatment with stem cells also shows some potential from early trials, but further larger RCTs are needed to demonstrate clear benefit. Thrombolysis may be an alternative for patients who develop acute limb ischaemia and are unsuitable for surgical intervention. However, newer endovascular techniques are likely to have a greater role in the future. PMID- 23795819 TI - A brush with danger: historical review of topical immunotherapy for alopecia areata. PMID- 23795820 TI - Woody clockworks: circadian regulation of night-time water use in Eucalyptus globulus. AB - The role of the circadian clock in controlling the metabolism of entire trees has seldom been considered. We tested whether the clock influences nocturnal whole tree water use. Whole-tree chambers allowed the control of environmental variables (temperature, relative humidity). Night-time stomatal conductance (gs ) and sap flow (Q) were monitored in 6- to 8-m-tall Eucalyptus globulus trees during nights when environmental variables were kept constant, and also when conditions varied with time. Artificial neural networks were used to quantify the relative importance of circadian regulation of gs and Q. Under a constant environment, gs and Q declined from 0 to 6 h after dusk, but increased from 6 to 12 h after dusk. While the initial decline could be attributed to multiple processes, the subsequent increase is most consistent with circadian regulation of gs and Q. We conclude that endogenous regulation of gs is an important driver of night-time Q under natural environmental variability. The proportion of nocturnal Q variation associated with circadian regulation (23-56%) was comparable to that attributed to vapor pressure deficit variation (25-58%). This study contributes to our understanding of the linkages between molecular and cellular processes related to circadian regulation, and whole-tree processes related to ecosystem gas exchange in the field. PMID- 23795818 TI - Design and development of stable, water-soluble, human Toll-like receptor 2 specific monoacyl lipopeptides as candidate vaccine adjuvants. AB - Antigens in modern subunit vaccines are largely soluble and poorly immunogenic proteins inducing relatively short-lived immune responses. Appropriate adjuvants initiate early innate immune responses, amplifying subsequent adaptive immune responses. Agonists of Toll-like receptor 2 (TLR2) are devoid of significant proinflammatory activity in ex vivo human blood models and yet are potently adjuvantic, suggesting that this chemotype may be a safe and effective adjuvant. Our earlier work on the monoacyl lipopeptide class of TLR2 agonists led to the design of a highly potent lead but with negligible aqueous solubility, necessitating the reintroduction of aqueous solubility. We explored several strategies of introducing ionizable groups on the lipopeptide, as well as the systematic evaluation of chemically stable bioisosteres of the ester-linked palmitoyl group. These studies have led to a fully optimized, chemically stable, and highly water-soluble human TLR2-specific agonist, which was found to have an excellent safety profile and displayed prominent adjuvantic activities in rabbit models. PMID- 23795821 TI - Asymmetric synthesis of both enantiomers of arteludovicinolide A. AB - The first total synthesis of either enantiomer of Arteludovicinolide A and their biological evaluation is reported, featuring a new strategy for the asymmetric construction of gamma-butyrolactones with stereogenic side chains in the 4 position. Starting from the renewable resource methyl 2-furoate, the sesquiterpene lactone was synthesized in 9 steps and 4.8% overall yield via an asymmetric cyclopropanation and two diastereoselective nucleophile additions making use of a donor-acceptor-cyclopropane-lactonization cascade. At noncytotoxic concentrations (<=10 MUM) (+)-1 was found to have a 15 times higher anti-inflammatory activity (4.87 +/- 1.1 MUM) than previously reported for concentrations of >=45 MUM. PMID- 23795822 TI - Regulation of CuZnSOD and its redox signaling potential: implications for amyotrophic lateral sclerosis. AB - SIGNIFICANCE: Molecular oxygen is a Janus-faced electron acceptor for biological systems, serving as a reductant for respiration, or as the genesis for oxygen derived free radicals that damage macromolecules. Superoxide is well known to perturb nonheme iron proteins, including Fe/S proteins such as aconitase and succinate dehydrogenase, as well as other enzymes containing labile iron such as the prolyl hydroxylase domain-containing family of enzymes; whereas hydrogen peroxide is more specific for two-electron reactions with thiols on glutathione, glutaredoxin, thioredoxin, and the peroxiredoxins. RECENT ADVANCES: Over the past two decades, familial cases of amyotrophic lateral sclerosis (ALS) have been shown to have an association with commonly altered superoxide dismutase 1 (SOD1) activity, expression, and protein structure. This has led to speculation that an altered redox balance may have a role in creating the ALS phenotype. CRITICAL ISSUES: While SOD1 alterations in familial ALS are manifold, they generally create perturbations in the flux of electrons. The nexus of SOD1 between one- and two-electron signaling processes places it at a key signaling regulatory checkpoint for governing cellular responses to physiological and environmental cues. FUTURE DIRECTIONS: The manner in which ALS-associated mutations adjust SOD1's role in controlling the flow of electrons between one- and two-electron signaling processes remains obscure. Here, we discuss the ways in which SOD1 mutations influence the form and function of copper zinc SOD, the consequences of these alterations on free radical biology, and how these alterations might influence cell signaling during the onset of ALS. PMID- 23795823 TI - Predictors and moderators in the randomized trial of multifamily psychoeducational psychotherapy for childhood mood disorders. AB - This study investigated predictors and moderators of mood symptoms in the randomized controlled trial (RCT) of Multi-Family Psychoeducational Psychotherapy (MF-PEP) for childhood mood disorders. Based on predictors and moderators in RCTs of psychosocial interventions for adolescent mood disorders, we hypothesized that children's greater functional impairment would predict worse outcome, whereas children's stress/trauma history and parental expressed emotion and psychopathology would moderate outcome. Exploratory analyses examined other demographic, functioning, and diagnostic variables. Logistic regression and linear mixed effects modeling were used in this secondary analysis of the MF-PEP RCT of 165 children, ages 8 to 12, with mood disorders, a majority of whom were male (73%) and White, non-Hispanic (90%). Treatment nonresponse was significantly associated with higher baseline levels of global functioning (i.e., less impairment; Cohen's d = 0.51) and lower levels of stress/trauma history (d = 0.56) in children and Cluster B personality disorder symptoms in parents (d = 0.49). Regarding moderators, children with moderately impaired functioning who received MF-PEP had significantly decreased mood symptoms (t = 2.10, d = 0.33) compared with waitlist control. MF-PEP had the strongest effect on severely impaired children (t = 3.03, d = 0.47). Comprehensive assessment of demographic, youth, parent, and familial variables should precede intervention. Treatment of mood disorders in high-functioning youth without stress/trauma histories and with parents with elevated Cluster B symptoms may require extra therapeutic effort, whereas severely impaired children may benefit most from MF-PEP. PMID- 23795824 TI - Comparison of idiopathic achalasia and Chagas' disease esophagopathy at the light of high-resolution manometry. AB - The comparison between idiopathic achalasia (IA) and Chagas' disease esophagopathy (CDE) may evaluate if treatment options and their outcomes can be accepted universally. This study aims to compare IA and CDE at the light of high resolution manometry. We studied 86 patients with achalasia: 45 patients with CDE (54% females, mean age 55 years) and 41 patients with IA (58% females, mean age 49 years). All patients underwent high-resolution manometry. Upper esophageal sphincter parameters were similar (basal pressure CDE = 72 +/- 45 mmHg, IA = 82 +/- 57 mmHg; residual pressure CDE = 9.9 +/- 9.9 mmHg, IA = 9.8 +/- 7.5 mmHg). In the body of the esophagus, the amplitude was higher in the IA group than the CDE group at 3 cm (CDE = 15 +/- 14 mm Hg, IA = 42 +/- 52 mmHg, P = 0.003) and 7 cm (CDE = 16 +/- 15 mmHg, IA = 36 +/- 57 mmHg, P = 0.04) above the lower esophageal sphincter (LES). The LES basal pressure (CDE = 17 +/- 16 mmHg, IA = 40 +/- 22 mmHg, P < 0.001) and residual pressure (CDE = 12 +/- 11 mmHg, IA = 27 +/- 13 mmHg, P < 0.001) were also higher in the IA group. Our results show that: (i) there is no difference in regards to the upper esophageal sphincter; (ii) higher pressures of the esophageal body are noticed in patients with IA; and (iii) basal and residual pressures of the LES are lower in patients with CDE. Our results did not show expressive manometric differences between IA and CDE. Some differences may be attributed to a more pronounced esophageal dilatation in patients with CDE. PMID- 23795825 TI - Direct spray drying and microencapsulation of probiotic Lactobacillus reuteri from slurry fermentation with whey. AB - AIMS: Formulations of dietary probiotics have to be robust against process conditions and have to maintain a sufficient survival rate during gastric transit. To increase efficiency of the encapsulation process and the viability of applied bacteria, this study aimed at developing spray drying and encapsulation of Lactobacillus reuteri with whey directly from slurry fermentation. METHODS AND RESULTS: Lactobacillus reuteri was cultivated in watery 20% (w/v) whey solution with or without 0.5% (w/v) yeast extract supplementation in a submerged slurry fermentation. Growth enhancement with supplement was observed. Whey slurry containing c. 10(9) CFU g(-1) bacteria was directly spray-dried. Cell counts in achieved products decreased by 2 log cycles after drying and 1 log cycle during 4 weeks of storage. Encapsulated bacteria were distinctively released in intestinal milieu. Survival rate of encapsulated bacteria was 32% higher compared with nonencapsulated ones exposed to artificial digestive juice. CONCLUSIONS: Probiotic L. reuteri proliferate in slurry fermentation with yeast-supplemented whey and enable a direct spray drying in whey. The resulting microcapsules remain stable during storage and reveal adequate survival in simulated gastric juices and a distinct release in intestinal juices. SIGNIFICANCE AND IMPACT OF THE STUDY: Exploiting whey as a bacterial substrate and encapsulation matrix within a coupled fermentation and spray-drying process offers an efficient option for industrial production of vital probiotics. PMID- 23795826 TI - The complete mitochondrial genome of Liobagrus marginatus (Teleostei, Siluriformes: Amblycipitidae). AB - The Liobagrus marginatus is an economic fish which distribute in the upstream of Yangtze river and its distributary. For its taste fresh, environmental pollution and overfishing, its population declined drastically and body miniaturization in recent decades, so it is essential to protect its resource. In this study, the complete mitochondrial genome sequence of Liobagrus marginatus was sequenced, which contains 22 tRNA genes, 13 protein-coding genes, 2 rRNA genes, and a non coding control region with the total length of 16,497 bp. The gene arrangement and composition are similar to most of other fish. Most of the genes are encoded on heavy-strand, except for eight tRNA and ND6 genes. Just like most other vertebrates, the bias of G and C has been found in statistics results of different genes/regions. The complete mitochondrial genome sequence of Liobagrus marginatus would contribute to better understand population genetics, evolution of this lineage, and will help administrative departments to make rules and laws to protect it. PMID- 23795827 TI - Complete mitochondrial genome of the furry lobster Palinurellus wieneckii (De Man, 1881) (Decapoda, Achelata, Palinuridae). AB - Complete sequence of the mitochondrial genome (mitogenome) for the rare lobster genus Palinurellus (species P. wieneckii) is reported for the first time. The genus Palinurellus is peculiar looking and was previously considered to belong to a distinct family Synaxidae. However, recent molecular phylogenetic analyses based on partial sequences of various genes showed that Synaxidae is an invalid family and Palinurellus should be placed inside Palinuridae. The complete mitogenome of P. wieneckii is compared to the genetic structures with six other Achelata species with mitogenome sequence reported. The gene order of P. wieneckii is identical to the other Achelata lobsters, but with lower A + T content (63.6% versus 64.5-67.5%). Sequence nucleotide dissimilarity of P. wieneckii is considerably higher (37.7-40.3%) than amongst the five Palinuridae s.s. species (17.1-32.9%), and approximate to the range between Palinuridae s.s. and Scyllaridae (39.1-40.4%). PMID- 23795828 TI - Population divergence and structure of Cirrhinus mrigala from peninsular rivers of India, revealed by mitochondrial cytochrome b gene and truss morphometric analysis. AB - Genetic diversity and population structure of Cirrhinus mrigala from peninsular riverine systems of India was studied using mitochondrial DNA gene, cytochrome b and truss morphometric analysis. Analysis of 982 bp of the cytochrome b gene from 182 samples collected from six rivers revealed the presence of 28 haplotypes with overall high haplotype diversity value of 0.78981 and nucleotide diversity value of 0.00215. Analysis of molecular variance (AMOVA) showed that genetic variation is mainly harbored within populations rather than among populations. The pairwise Fst values (-0.009 to 0.084) was indicative of a low genetic structure among mrigal populations. Morphometric examination of 243 samples using 10 truss landmarks and principal component analysis showed a similar trend when compared with genetic data. Overall, low genetic and morphometric differences were observed despite those populations from different geographic locations. The results of this study would provide essential information to resource recovery and help in delineating populations for fishery management. Besides, the data will provide a valuable baseline for further investigations on the geographic distribution of this commercially important fish species. PMID- 23795829 TI - Complete mitochondrial genome of the endangered Sakhalin taimen Parahucho perryi (Salmoniformes, Salmonidae). AB - The complete mitochondrial genome sequence of Parahucho perryi has been obtained by the next generation sequencing, which contained 22 tRNA genes, 13 protein coding genes, 2 rRNA genes and non-coding control region with the total length of 16,651 bp. The gene content, arrangement, codon usage and base composition of P. perryi mitogenome are identical to those observed in salmonids and most other teleost fishes. The sequence data could provide useful information for the studies on molecular systematics and conservation genetics. PMID- 23795830 TI - The complete mitogenome of the lined shore crab Pachygrapsus crassipes Randall 1840 (Crustacea: Decapoda: Grapsidae). AB - In this study we sequenced and analyzed the complete mitochondrial genome (mitogenome) of the lined shore crab Pachygrapsus crassipes Randall, 1840 (Crustacea: Grapsidae). The full-length P. crassipes mitogenome is 15,652 bp in size, which encodes the same 37 genes as all metazoan mitogenomes. Both AT contents of the entire molecule as well as putative control region display lowest values among all mitogenomes of the brachyuran crabs determined to date. The mitochondrial gene order follows a classic crab-type arrangement that underwent a unique tRNA translocation from the pancrustacean ancestral pattern. Our results will provide important data for phylogenetic as well as biogeographic studies. PMID- 23795831 TI - Complete mitochondrial genome of Amur sturgeon (Acipenser schrenckii). AB - The complete mitochondrial genome of Amur sturgeon (Acipenser schrenckii) was determined in this study. The mitogenome is 16,684 bp in length and contains 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes and 2 non coding regions (the control region and the putative origin of the light strand replication) with a typical vertebrate mitochondrial gene arrangement. The overall base composition of the heavy strand is 30.07% for A, 29.36% for C, 16.44% for G and 24.13% for T, with a slight AT bias of 54.20%. PMID- 23795832 TI - Mitochondrial DNA sequence of Mongolian redfin (Chanodichthys mongolicus). AB - Monglian redfin is a kind of freshwater aquaculture species which has an important economic value in China. In this study, we report the complete sequence of mitochondrial genome of Monglian redfin. The complete mitochondrial genome sequence is determined to be 16,621 base pairs (bp) in length and contain 13 protein-coding gene (PCGs), 22 transfer RNA genes, large (rrnL) and small (rrnS) ribosomal RNA, and the non-coding control region. Its total A+T content is 55.98%. We also analyzed the structure of control region, six conserved sequence blocks (CSBs) (CSB-1, CSB-2, CSB-3, CSB-D, CSB-E and CSB-F) and one potential termination-associated sequence were detected and the control region also included a 2-bp tandem repeat with eight repeat times. PMID- 23795833 TI - Genetic variability in the three mitochondrial genes among Oesophagostomum asperum isolates from different regions in Shaanxi and Hunan Provinces, China. AB - The present study examined sequence variations in three mitochondrial DNA (mtDNA) regions, namely, NADH dehydrogenase subunit 5 (nad5), adenosine triphosphate subunit 6 (atp6) and cytochrome c oxidase subunit 3 (cox3), among Oesophagostomum asperum isolates from different regions in Shaanxi and Hunan provinces, China. The lengths for partial sequences of nad5 (pnad5), atp6 (patp6) and cox3 (pcox3) were 427 bp, 381 bp and 337 bp, respectively. The intra-specific sequence variations among all O. asperum samples were 0-2.11%, 0-1.84% and 0-1.48% for pnad5, patp6 and pcox3, respectively, while the inter-specific sequence differences among Oesophagostomum species in pig and small ruminants were 18 21.3% for pnad5, 18.3-24.5% for patp6 and 10.6-13.7% for pcox3. A phylogenetic analysis based on combined sequences of three mtDNA fragments indicated that all O. asperum isolates were grouped in one solid clade, and the Oesophagostomum spp. from pig were located in another clade. However, these mtDNA fragments could not reveal genetic relationships of geographical isolates of O. asperum in China. These results provided valuable information for studying population genetics of Oesophagostomum spp., and for controlling Oesophagostomum infection in animals as well as humans. PMID- 23795834 TI - Complete mitochondrial genome organization of Tor putitora. AB - The complete mitochondrial genome of Tor putitora, an endemic coldwater fish of Himalayas was determined for the first time. The genome is 16,576 bp in length and consists of 13 protein coding genes, 22 tRNAs, 2 rRNA genes and 1 putative control region. The gene organization and its order were similar to other vertebrates. The overall base composition was; A: 31.9%, G: 15.6%, C: 27.5%, T: 25%, A + T content 56.9% and the G + C content 43.1%. The control region was also consisted of a microsatellite locus (TA) 13 between 16,456 to 16,481 bp. The present study will provide the rationale for the management and conservation of T. putitora. PMID- 23795835 TI - The complete mitochondrial genome of the endangered butterfly Luehdorfia taibai Chou (Lepidoptera: Papilionidae). AB - We have determined the complete mitochondrial genome of the endangered butterfly, Luehdorfia taibai. The total lenth of the L. taibai mitogenome is 15,553 bp with 81% A + T content. It consists of 13 protein-coding, 22 tRNA, 2 rRNA genes and an A + T-rich region. All the protein-coding genes used ATN as start codon and TAA as stop codon, except for COI gene, which used CGA as start codon. The A + T-rich region was 939 bp in lenth with 95% A + T content. L. taibai mitogenome contained an extra tRNA(Leu), located from 191 bp to 259 bp, of which function was not clear. PMID- 23795836 TI - Second generation DNA sequencing of the mitogenome of the Chinstrap penguin and comparative genomics of Antarctic penguins. AB - The complete mitochondrial genome of the Chinstrap penguin (Pygoscelis antarcticus) was sequenced and compared with other penguin mitogenomes. The genome is 15,972 bp in length with the number and order of protein coding genes and RNAs being very similar to that of other known penguin mitogenomes. Comparative nucleotide analysis showed the Chinstrap mitogenome shares 94% homology with the mitogenome of its sister species, Pygoscelis adelie (Adelie penguin). Divergence at nonsynonymous nucleotide positions was found to be up to 23 times less than that observed in synonymous positions of protein coding genes, suggesting high selection constraints. The complete mitogenome data will be useful for genetic and evolutionary studies of penguins. PMID- 23795837 TI - Complete mitochondrial genome of the humpback grouper Cromileptes altivelis. AB - The complete mitochondrial genome (16,497 bp) of the humpback grouper Cromileptes altivelis is first presented in this study. The gene arrangement and translate orientation of C. altivelis is identical to most vertebrates, including 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes and a putative control region. The overall nucleotide composition of the H-strand is 29.80% A, 26.23% T, 15.67% G and 29.02% C. The origin of the light-strand replication was identified between the tRNA-Asn and tRNA-Cys genes, while the termination associated sequence (TAS) and conserved sequence blocks (CSB1-3) were identified in the control region. PMID- 23795838 TI - Complete mitochondrial genome of an aquatic moth, Elophila interruptalis (Lepidoptera: Crambidae). AB - The aquatic moth, Elophila interruptalis (Lepidoptera: Crambidae) belongs to the subfamily Nymphulinae, nearly all of which are aquatic in their entire larval and pupal stages. The 15,351-bp long complete mitogenome consisted of a typical set of genes (13 protein-coding genes, two rRNA genes and 22 tRNA genes) and one major non-coding A+T-rich region, with the typical arrangement found in the majority of Lepidoptera. One of the unusual features of the E. interruptalis mitogenome is the presence of a tRNA(Phe)-like sequence beyond the A+T-rich region. The sequence is encoded in the minor strand of the genome overlapping with the reversely encoded regular tRNA(Glu) by 65 bp. The sequence divergence of the tRNA(Phe)-like sequence to that of regular E. interruptalis tRNA(Phe) and other within-familial species was as low as 59% ~ 71%, but has a proper folding structure with well-matched stems and identical anticodon sequences to the regular copy. PMID- 23795839 TI - The complete mitochondrial genomes of natural diploid and tetraploid loaches Misgurnus anguillicaudatus (Cypriniformes: Cobitidae). AB - Dojo loach Misgurnus anguillicaudatus, a small-sized freshwater fish species, is not only one of the most important cultured fish in East Asia, but also a promising model animal to study evolutionary biology for polyploidy. We sequenced the complete mitochondrial genomes from the natural diploid and tetraploid individuals of this species. The two different cytotypes loaches share the same length (16,646 bp) and structural organization of mitochondrial genome. The two genomes have 98.3% nucleotide sequence similarity, and the biggest nucleotide sequence divergence between homologous genes is observed in CYTB gene. PMID- 23795840 TI - Complete mitochondrial genome of the San Lucan gecko, Phyllodactylus unctus (Sauria, Gekkota, Phyllodactylidae), in comparison with Tarentola mauritanica. AB - We sequenced the complete mitochondrial genome of the San Lucan gecko, Phyllodactylus unctus, which is endemic to Mexico. The complete mitochondrial genome was 16,881 bp in size, consisting of 37 genes coding for 13 proteins, 2 rRNAs, 22 tRNAs and 1 control region. Its gene arrangement pattern was identical with most vertebrates. We compared the mitochondrial genome of P. unctus with that of the Moorish gecko, Tarentola mauritanica, which is the only other sequenced species from Phyllodactylidae. Nucleotide sequence divergence (p distance) between two mitochondrial genomes was 31.32%. The detailed comparison between the mitochondrial genomes of two species was done. PMID- 23795841 TI - The complete mitogenome of the Chinese swamp shrimp Neocaridina denticulata sinensis Kemp 1918 (Crustacea: Decapoda: Atyidae). AB - In this study we determined the complete mitochondrial genome (mitogenome) of the Chinese swamp shrimp Neocaridina denticulata sinensis Kemp, 1918 (Decapoda, Atyidae). The mitogenome consists of 15,561 bp encoding 37 genes that are involved in mitochondrial protein synthesis as well as respiration chain/oxidative phosphorylation. Besides, a 672-bp putative control region was identified between the small subunit ribosomal RNA and tRNA-Ile genes, the size and AT content of which is moderate within the Decapoda. The gene arrangement of the mitogenome follows the pancrustacean ancestral pattern shared by the decapod subfamily Dendrobranchiata, pleocyematan infrafamilies Caridea and Palinura. Our results will provide important data for various levels of phylogeny and further evolution. PMID- 23795842 TI - The complete mitogenome of the turnip moth Agrotis segetum (Lepidoptera: Noctuidae). AB - Abstract The complete mitochondrial genome (mitogenome) of the turnip moth Agrotis segetum (Lepidoptera: Noctuidae) was determined (GenBank accession No. KC894725). This is the first sequenced mitogenome from the subfamily Noctuinae of Noctuidae. The length of this mitogenome is 15,378 bp with a A+T content of 80.7%. There are 37 typical animal mitochondrial genes and a A+T-rich region. The tRNA gene trnM was the only rearranged gene compared with the pupative ancestral arrangement of insects. All protein-coding genes start with ATN start codon except for the gene cox1, which uses CGA as in other lepidopteran species. Ten protein-coding genes stop with termination codon TAA, whereas three protein coding gene use incomplete stop codon T. The A+T-region is located between rrnS and trnM with a length of 332 bp and A+T content of 93.5%. PMID- 23795843 TI - Large scale deletions of the mitochondrial DNA in astheno, asthenoterato and oligoasthenoterato-spermic men. AB - The purpose of this study was to investigate the association of large-scale deletions of mtDNA between idiopathic astheno, asthenoterato and oligoasthenoterato-spermic as patient group and normospermic as control group. Forty semen samples including: 10 asthenospermic (A), 10 asthenoteratospermic (AT), 10 oligoasthenoteratospermic (OAT) and 10 normospermic samples as control group, were collected from IVF center. Our analysis of long-range polymerase chain reaction were shown multiple deletions; 4977-bp, 7599-bp and 7491-bp of mtDNA in spermatozoa of patients (A, AT and OAT) and control groups. However, the frequency of multiple mtDNA deletions in astheno (60%), asthenoterato (60%), oligoasthenoterato (70%) spermic groups were significantly higher than normal (40%) group. These results suggest that mtDNA mutations cause infertility through an effect on sperm motility. Therefore, identification of mtDNA mutations and large scale deletions in the pathophysiology of human spermatozoa dysfunction is considered to be important to better understanding of the etiology of idiopathic infertility. PMID- 23795844 TI - Complete mitochondrial genome of Hainan partridge, Arborophila ardens (Galliformes: Phasianidae). AB - The Hainan partridge, Arborophila ardens belongs to family Phasianidae, and distributes only in Hainan, China. In this study, the complete mitochondrial genome of A. ardens was first sequenced and characterized. The genome is 16,727 bases in length. Bayesian inference, maximum likelihood and maximum parsimony methods were used to construct phylogenetic trees based on 12 concatenated protein-coding genes located on the heavy strand. Phylogenetic analyses further confirm the Arborophila placed at the root of Phasianidae. Arborophila ardens show closer relationship with A. rufipectus than A. rufogularis and A. gingica which cluster as sister group to A. ardens and A. rufipectus. PMID- 23795845 TI - Phylogenetic analysis of the Mustela altaica (Carnivora: Mustelidae) based on complete mitochondrial genome. AB - The mountain weasel (Mustela altaica) belongs to family Mustelidae, which is the near threatened species in the IUCN Red List. In this study, the complete mitochondrial genome of M. altaica was sequenced and characterized. The genome is 16,521 bases in length (GenBank accession no. KC815122). The nucleotide sequence data of 12 heavy-strand protein-coding genes of M. altaica and other 20 Mustelidae species were used for phylogenetic analyses. Trees constructed by using Bayesian inference, maximum parsimony and maximum likelihood demonstrated that M. altaica was close to Mustela nivalis and they were sister to Mustela putorius and Mustela sibirica. PMID- 23795846 TI - Next generation sequencing yields the complete mitochondrial genome of the scarce blue-tailed damselfly, Ischnura pumilio. AB - We report the entire mitochondrial genome of the scarce blue-tailed damselfly, Ischnura pumilio (Odonata, Coenagrionidae), using next-generation sequencing on genomic DNA. A de novo assembly provided a single contiguous sequence of 15,250 bp that contained the A + T-rich region and all standard coding regions; gene configuration is similar to other odonates and comprises 13 protein-coding genes, two rRNA genes (12 S and 16 S rRNA) and 22 tRNA genes. We found a unique intergenic spacer in I. pumilio and confirm that the intergenic spacer s5 likely represents a synapomorphy between Anisoptera and Zygoptera. This is the first mitogenome sequence obtained for a member of the Coenagrionidae and demonstrates how next-generation sequencing technology can obtain mtDNA genome sequences without prior sample processing or primer design. PMID- 23795847 TI - The mitogenome of Pangasius sutchi (Teleostei, Siluriformes: Pangasiidae). AB - The Pangasius sutchi is an important ornamental and economic fish in Southeast Asia e.g. Thailand, Malaysia and China. The complete mitochondrial genome sequence of P. sutchi has been sequenced, which contains 22 tRNA genes, 13 protein-coding genes, 2 rRNA genes and a non-coding control region with the total length of 16,522 bp. The gene order and composition are similar to most of other vertebrates. Just like most other vertebrates, the bias of G and C was found in different region/genes statistics results. Most of the genes are encoded on heavy strand, except for eight tRNA and ND6 genes. The mitogenome sequence of P. sutchi would contribute to better understand population genetics, evolution of this lineage. PMID- 23795848 TI - Mitochondrial genome of the Emberiza rustica (Emberizidae: Emberiza). AB - Emberiza rustica, least concern species (IUCN), is a passerine bird in the bunting family with wide geographical range. The complete mitochondrial genome of E. rustica (16,798 bp in length) had been analyzed for building the database. Similar to the typical mtDNA of vertebrates, it contained 37 genes (13 protein coding genes, 2 rRNA genes and 22 tRNA genes) and a non-coding region (D-loop). All the protein-coding genes in E. rustica were distributed on the H-strand, except for the ND6 subunit gene and 10 tRNA genes which were encoded on the L strand. PMID- 23795849 TI - Complete mitochondrial genome of the threespot grouper Epinephelus trimaculatus. AB - We present the complete mitochondrial genome of the three-spot grouper Epinephelus trimaculatus (16,761 bp) in this study. The gene order and orientation in E. trimaculatus were the same as the typical vertebrates. The COI and ND4 genes started with the GTG codon and the ATP6 gene started with the CTG codon, the remaining protein-coding genes started with the ATG codon. All protein coding genes used the TAA or incomplete T as the stop codon. A 41 bp sequence was identified as the origin of L-strand replication (OL) between tRNA-Asn and tRNA Cys genes. The tRNA-Ser2 lost the dihydrouridine (DHU) arm and formed one loop. A tandem repeat motif (5'-AAATACATAATATGCTTT-3') and three conserved sequence blocks (CSB1-3) were found in the control region. PMID- 23795850 TI - The complete mitochondrial genome of Hyattella sinuosa (Dictyoceratida: Spongiidae). AB - The mitochondrial genome of Hyattella sinuosa (Dictyoceratida: Spongiidae) is a circular molecule of 16,422 bp in length, containing 14 protein-coding genes, 2 ribosomal RNA genes, 2 transfer RNA genes(trnW and trnM) and 13 non-coding segments. All genes are distributed in the same strand (H-strand). The overall base composition of the H-strand is as follows: T (37.72%), C (11.27%), A (25.14%), G (25.86%), with GC- and AT-skew of 0.393 and -0.2, respectively, reflecting unbalanced base composition between the two strands. The non-coding regions are 1240 bp in total length, with high-AT content (73.72%). The current mitochondrial genome is identical to that of Hippospongia Lachne (Family Spongiidae) in gene order and contents, except for the absence of the repeat hairpin-forming element (RHE) in the non-coding regions. PMID- 23795851 TI - Identification of sequence polymorphisms in the D-loop region of mitochondrial DNA as a risk factor for non-Hodgkin lymphoma. AB - Accumulation of single nucleotide polymorphisms (SNPs) in the displacement loop (D-loop) of mitochondrial DNA (mtDNA) may be associated with an increased cancer risk. We investigated the non-Hodgkin lymphoma (NHL) risk profile of D-loop SNPs in a case-control study. The minor alleles of nucleotides 73A/G, 263A/G, 315C/C insert were associated with a decreased risk for NHL. The minor alleles of the nucleotides 200G/A were specifically associated with the risk of diffuse large B cell lymphoma, whereas the minor allele of nucleotides 16362C/T and 249Del/A was specifically associated with the decreased risk of T-cell lymphoma. In conclusion, SNPs in mtDNA are potential modifiers of NHL risk. The analysis of genetic polymorphisms in the mitochondrial D-loop can help identify subgroups of patients who are at a high risk of developing NHL. PMID- 23795852 TI - The complete mitochondrial genome sequence of Acrossocheilus monticolus (Teleostei, Cypriniformes, Cyprinidae). AB - The complete mitogenome sequence of Acrossocheilus monticolus, which is endemic to China, was determined using long PCR reactions. The genome is 16,599 bp in length, including 13 typical vertebrate protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes and a control region. Except for eight tRNA and ND6 genes, all other mitochondrial genes are encoded on the heavy strand. The gene order and composition of A. monticolus was similar to that of most other vertebrates. The descending order of the base composition on heavy strand was 31.4% A, 28.2% C, 24.5% T, 15.8% G, with a relatively lower level of G and a slight AT bias of 55.9%. The codon usage followed the typical vertebrate mitochondrial pattern (ATG or GTG for start codon and TAA or TAG for stop codon). There are 7 regions of gene overlap totaling 23 bp and 13 intergenic spacer regions totaling 69 bp. PMID- 23795853 TI - Complete mitochondrial genome sequence of Nectogale elegans. AB - The elegant water shrew (Nectogale elegans) belongs to the family Soricidae, and distributes in northern South Asia, central and southern China and northern Southeast Asia. In this study, the complete mitochondrial genome of N. elegans was sequenced. It was determined to be 17,460 bases, and included 13 protein coding genes (PCGs), 22 tRNA genes, 2 ribosomal RNA genes and one non-coding region, which is similar to other mammalian mitochondrial genomes. Bayesian inference and maximum likelihood methods were used to construct phylogenetic trees based on 12 heavy-strand concatenated PCGs. Phylogenetic analyses further confirmed that Crocidurinae diverged prior to Soricinae, and Sorex unguiculatus differentiated earlier than N. elegans. PMID- 23795854 TI - Mitochondrial genome of the hydrothermal vent crab Austinograea alayseae (Crustacea: Bythograeidae): genetic differences between individuals from Tofua Arc and Manus Basin. AB - The brachyuran crab Austinograea alayseae is one of the most common species found in hydrothermal vent fields of the southwestern Pacific Ocean. In this study, we found that the mitochondrial genome (mitogenome) of A. alayseae from Tofua Arc is 15,611 bp in length and has the typical gene arrangement of a brachyuran. We also compared the mitogenomes of A. alayseae from two different regions, Tofua Arc and Manus Basin. Their genomes were identical, except for the control region, which showed 82.29% nucleotide similarity. These results will be helpful in developing stable markers for the identification of A. alayseae at the sub-species level. PMID- 23795855 TI - Mitochondrial genome of the Chung-an ground lizard Takydromus sylvaticus (Reptilia: Lacertidae). AB - The Chung-an ground lizard Takydromus sylvaticus is an endemic and long-lost reptile species in China. In this study, its mitochondrial genome (mitogenome) sequence was firstly determined by long PCR and primer walking methods. The genome is 17,838 bp long and contains 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes and 2 main noncoding regions (the control region and the putative L-strand replication origin). The gene order and contents in the T. sylvaticus mitogenome is identical to that found in typical vertebrates, suggesting that it represents an ancestral arrangement. Within the control region, typical conserved domains and distinct repeat regions were identified. PMID- 23795856 TI - High frequency of CD29high intermediate monocytes correlates with the activity of chronic graft-versus-host disease. PMID- 23795857 TI - Methodological development of an exploratory randomised controlled trial of an early years' nutrition intervention: the CHERRY programme (Choosing Healthy Eating when Really Young). AB - Good nutrition in the early years of life is vitally important for a child's development, growth and health. Children's diets in the United Kingdom are known to be poor, particularly among socially disadvantaged groups, and there is a need for timely and appropriate interventions that support parents to improve the diets of young children. The Medical Research Council has highlighted the importance of conducting developmental and exploratory research prior to undertaking full-scale trials to evaluate complex interventions, but have provided very limited detailed guidance on the conduct of these initial phases of research. This paper describes the initial developmental stage and the conduct of an exploratory randomised controlled trial undertaken to determine the feasibility and acceptability of a family-centred early years' nutrition intervention. Choosing Healthy Eating when Really Young (CHERRY) is a programme for families with children aged 18 months to 5 years, delivered in children's centres in one urban (Islington) and one rural (Cornwall) location in the United Kingdom. In the development stage, a mixed-methods approach was used to investigate the nature of the problem and options for support. A detailed review of the evidence informed the theoretical basis of the study and the creation of a logic model. In the feasibility and pilot testing stage of the exploratory trial, 16 children's centres, with a sample of 394 families were recruited onto the study. We hope that the methodology, which we present in this paper, will inform and assist other researchers in conducting community-based, exploratory nutrition research in early years settings. PMID- 23795858 TI - Psychotic disorder is an independent risk factor for increased fasting glucose and waist circumference. AB - BACKGROUND: Psychosis is associated with excess cardiovascular morbidity and mortality. AIMS: To determine the prevalence of cardiovascular risk factors in patients with psychotic disorders compared with the population. METHODS: 731 consecutive patients with psychosis recruited from psychiatric outpatient clinics in Stockholm County, Sweden, were compared with 5580 individuals from a population study performed in the same area. The main outcome measures were waist circumference, body mass index (BMI) and fasting glucose. RESULTS: Mean waist circumference in patients vs. controls was for males 106 and 94 cm, respectively, and for females 97 and 85 cm, respectively (P < 0.001); mean fasting glucose in patients vs. controls was for males 5.8 and 5.2 mmol/l, respectively, and for females 5.6 and 4.8 mmol/l, respectively (P < 0.001). Comparisons were controlled for differences in age and family history of diabetes. Increased waist circumference was more common in psychotic patients compared with controls (OR = 3.99; 95% CI 3.09-5.15), controlling for fasting insulin, differences in gender, blood pressure, fasting glucose, family history of diabetes, age and tobacco use. Increased fasting blood glucose was also more common in psychotic patients (OR = 2.41; 95% CI 1.84-3.14) controlling for the same factors with the exception of fasting glucose and with the addition of increased waist circumference. CONCLUSION: Our study shows that the psychosis illness per se can be considered as a cardiovascular risk factor, independent of the traditional risk factors such as age and smoking. PMID- 23795859 TI - What is the evidence for the use of second-generation antipsychotic long-acting injectables as maintenance treatment in bipolar disorder? AB - BACKGROUND: In recent years, the use of second-generation antipsychotics long acting injectable in the maintenance treatment of bipolar disorder has sparked interest in improving adherence and reducing the risk of relapse. AIMS: This report aims to review the available evidence concerning the use of second generation antipsychotics depot in bipolar disorder and specify the typology of patients that could be eligible for this formulation. METHODS: A systematic review of the literature was conducted using Pubmed and EMBASE. RESULTS: Data available for the clinician assessing the interests of second-generation antipsychotics depot in long-term treatment of bipolar disorder are limited to risperidone. It seems particularly relevant for bipolar patients with poor adherence or early in the course of illness and can be used as monotherapy with manic polarity. It should always be considered for use in combination with at least one other mood stabilizer in patients with depressive polarity. As for other medications, the benefit/risk ratio for a long-acting should be evaluated individually. CONCLUSIONS: If using a depot formulation could be considered for all patients in order to approach a perfect compliance, patients with certain clinical profiles could be an argument for prioritizing the use of long-acting injectable as maintenance treatment. Additional studies are needed with other second-generation antipsychotics depot in bipolar patients to generalize their use in the maintenance treatment of bipolar disorder but the future golden standard of studies with long-acting formulations remains to be defined. PMID- 23795860 TI - Trait-aggressiveness and impulsivity: role of psychological resilience and childhood trauma in a sample of male prisoners. AB - BACKGROUND: One of the major challenges for research in the field of human aggression is the need to define the role of personality and trait-like dimensions, such as impulsivity and aggressiveness, in predisposing to violent behavior. AIMS: 1) To determine whether trait- aggressiveness and impulsivity may be associated with socio-demographic, clinical and crime history variables in a sample of male prisoners; 2) to detect any association of those traits with measures of early traumatic experiences and current resilience traits. METHODS: A sample of male prisoners (n = 1356) underwent the Brown-Goodwin Assessment for Lifetime History of Aggression (BGLHA) and the Barratt Impulsivity Scale (BIS). Axis I psychiatric disorders were also assessed. Early traumatic experiences and psychological resilience were detected respectively by the Childhood Trauma Questionnaire (CTQ) and the Connor-Davidson Resilience Scale (CD-RISC). Two non linear logistic regression models were performed to test for the best predictors of trait-aggressiveness and impulsivity. RESULTS: Subjects with a history of substance use disorders and self-mutilation reported both higher BGLHA and BIS scores. Axis I disorders and suicide attempts were associated with aggressiveness, but not to impulsivity. A consistent correlation was found between BGLHA scores and early traumatic experiences. Resilience was positively correlated to impulsivity but not to aggressiveness scores. CONCLUSIONS: Our results support the view that aggressiveness and impulsivity are two different, albeit related trait-like dimensions of personality, having a different relationship with resilience, and, inferentially, a different impact over the development of psychiatric disorders. PMID- 23795861 TI - Gaba transporter SLC6A11 gene polymorphism associated with tardive dyskinesia. AB - BACKGROUND: Gamma-aminobutyric acid (GABA) insufficiency has been reported to be related to the tardive dyskinesia (TD) susceptibility. Inada et al. (Pharmacogenet Genomics 2008;18:317-23) identified eight genes belonging to GABA receptor signaling pathway that may be involved in TD susceptibility by genome wide screening and they replicated associations in an independent sample for polymorphisms in SLC6A11 (GABA transporter 3), GABRG3 (c-3 subunit of GABA-A receptor) and GABRB2 (beta-2 subunit of GABA-A receptor). In this study, we tried to replicate their finding in a larger Korean sample and find if any of the genes was associated with the susceptibility to TD. METHODS: We selected three polymorphisms in SLC6A11 (rs4684742), GABRG3 (rs2061051) and GABRB2 (rs918528) from the previous study. We carried out a case-control study (105 TD and 175 non TD schizophrenic patients) to identify the association between the three candidate polymorphisms and susceptibility to TD and their epistatic interactions by using the multifactor dimensionality reduction (MDR) algorithm. RESULTS: Among the three variants, SCL6A11 genotypes distribution showed a significant difference between the TD and non-TD patients (P = 0.049). However, GABRG3 and GABRB2 genotype distributions were not associated with TD (P = 0.268 and P = 0.976, respectively). Further, our analyses provided significant evidence for gene-gene interactions (SCL6A11, GABRG3 and GABRB2) in the development of TD. The odds ratio increased to 2.53 (CI = 1.515-4.217, P = 0.0003) when the genetic susceptibility to TD was analyzed with the three genes considered altogether through MDR approach. CONCLUSION: These results suggest that GABA receptor signaling pathway was associated with the increased susceptibility to TD in Korean schizophrenic patients. PMID- 23795862 TI - Neurocognitive effects of aripiprazole in adolescents and young adults with schizophrenia. AB - BACKGROUND: The use of aripiprazole has been associated with a positive influence on mood and improved cognitive skills and social interactions; however, studies of its effects on young schizophrenic patients have been limited to active symptoms. AIMS: This prospective, open-label study investigated the neurocognitive effects of aripiprazole in adolescents and young adults with first and repeated episodes of schizophrenia. METHODS: Twenty-three of 42 schizophrenic outpatients aged 12-26 completed a trial of aripiprazole, and its efficacy was determined using the Brief Psychiatric Rating Scale (BPRS), Clinical Global Impressions Severity (CGI-S) and WHO Quality of Life (WHOQOL) scales. Cognitive function was measured with the Cognitive Performance Test (CPT) and Wisconsin Card Sorting Test (WCST) at 4, 12 and 24 weeks of treatment. RESULTS: Results showed statistically significant improvements in BPRS, CGI-S and WHOQOL scores in certain (but not all) subcategories of cognitive measures including CPT detectability and total errors and perseverative errors on the WCST. There were few adverse side-effects. CONCLUSIONS: Psychotic symptoms and cognitive skills improved during treatment with aripiprazole in adolescents and young adults with schizophrenia. Patients with first psychotic episodes did better than did those with repeat episodes. PMID- 23795864 TI - pH-responsive supramolecular vesicles based on water-soluble pillar[6]arene and ferrocene derivative for drug delivery. AB - The drug delivery system based on supramolecular vesicles that were self assembled by a novel host-guest inclusion complex between a water-soluble pillar[6]arene (WP6) and hydrophobic ferrocene derivative in water has been developed. The inclusion complexation between WP6 and ferrocene derivative in water was studied by (1)H NMR, UV-vis, and fluorescence spectroscopy, which showed a high binding constant of (1.27 +/- 0.42) * 10(5) M(-1) with 1:1 binding stoichiometry. This resulting inclusion complex could self-assemble into supramolecular vesicles that displayed a significant pH-responsive behavior in aqueous solution, which were investigated by fluorescent probe technique, dynamic laser scattering, and transmission electron microscopy. Furthermore, the drug loading and in vitro drug release studies demonstrated that these supramolecular vesicles were able to encapsulate mitoxantrone (MTZ) to achieve MTZ-loaded vesicles, which particularly showed rapid MTZ release at low-pH environment. More importantly, the cellular uptake of these pH-responsive MTZ-loaded vesicles by cancer cells was observed by living cell imaging techniques, and their cytotoxicity assay indicated that unloaded vesicles had low toxicity to normal cells, which could dramatically reduce the toxicity of MTZ upon loading of MTZ. Meanwhile, MTZ-loaded vesicles exhibited comparable anticancer activity in vitro as free MTZ to cancer cells under examined conditions. This study suggests that such supramolecular vesicles have great potential as controlled drug delivery systems. PMID- 23795866 TI - Protein kinase C inhibitors: a patent review (2010 - present). AB - INTRODUCTION: Protein kinase C (PKC) comprises at least 10 isoforms, pivotal in various cellular differentiation processes and in other specific cellular functions. Catalytic subunits of all PKCs are highly conserved which play a central role in the development of kinase-specific inhibitors for the treatment of a number of diseases and also in the drug resistance and immunological disorders. The authors' previous work of reviewing patents of PKC inhibitors is continued in this report. AREA COVERED: Thorough survey on the physiological roles of PKC isoforms and patents filed for PKC inhibitors from 2010 to present representing new and potential strategy for the cure and prevention of disorders due to elevation in various PKC levels is reported. EXPERT OPINION: The PKC isoforms are unique in terms of tissue distribution and an elevation in any isoform level results in different diseased conditions. Different PKC isoforms have high sequence identity but they are involved in different diseases. Crystal structure of few PKC isoforms viz. C1 domain of PKCdelta, the C2 domains of PKCalpha and beta, kinase domain and full structure of PKCbetaII are known. Identification of more crystal structures and thorough analysis of available structures and information on the PKC ligands will be helpful in the drug designing and development processes. PMID- 23795863 TI - Viral-host interactions that control HIV-1 transcriptional elongation. PMID- 23795868 TI - Timing of planned repeat cesarean delivery after two or more previous cesarean sections--risk for unplanned cesarean delivery and pregnancy outcome. AB - objective: To assess the effect of the scheduled gestational age for a repeat planned cesarean section (CS) on the risk for adverse pregnancy outcome in women with two or more previous CS. METHODS: A retrospective cohort study of all women after >=2 previous CS who were scheduled for a repeat planned CS. Women were divided into two groups at which the planned CS was scheduled: 38-week group or 39-week group. RESULTS: Overall, 377 were enrolled, 264 (70.0%) and 113 (30.0%) in the 38-week and the 39-week groups, respectively. The rate of an unplanned CS was significantly higher in the 39-week versus the 38-week group (23.0% versus 13.3%, p = 0.02). A repeat planned CS scheduled to week 39 was associated with an increased risk of maternal adverse outcome (31.9% versus 21.6%, p = 0.03). There was no significant difference in the rate of adverse neonatal outcome between the two groups (20.8% versus 23.0%, p = 0.5). The lowest rate of any adverse outcome (maternal and/or neonatal) was observed when CS was scheduled to 38 + 1 weeks of gestation. CONCLUSIONS: In women after two cesarean sections, scheduling a planned CS at around 39 weeks compared with at around 38 weeks is associated with an increased risk for maternal adverse outcome with no apparent advantage in terms of neonatal outcome. PMID- 23795867 TI - Sustained release of matrix metalloproteinase-3 to trabecular meshwork cells using biodegradable PLGA microparticles. AB - Accumulation of extracellular matrix (ECM) materials in the trabecular meshwork (TM) is believed to be a contributing factor to intraocular pressure (IOP) elevation, a risk factor/cause of primary open angle glaucoma, a major blinding disease. Matrix metalloproteinase-3 (MMP-3) is one of the proteinases that can effectively degrade ECM elements such as fibronectin, and MMP-3 delivery to the TM represents a promising approach for IOP reduction and treatment of glaucoma. In this study, we tested the feasibility of using polymeric microparticles to achieve a slow and sustained release of active MMP-3 to cultured human TM cells. beta-Casein, with molecular weight (24 kDa) and hydrophobicity similar to those of the active MMP-3 fragment (19.2 kDa), was first employed as a model for initial testing. beta-casein was encapsulated into poly(lactic-co-glycolic acid) (PLGA) microparticles using a double emulsion procedure at an encapsulation efficiency of approximately 45%. The PLGA microparticles were chosen given their biocompatibility and the proven capacity of sustained release of encapsulated molecules. The release test conducted in the culture medium showed a slow and sustained release of the protein over 20 days without a significant initial burst release. Active MMP-3 was subsequently encapsulated into PLGA microparticles with an encapsulation efficiency of approximately 50%. A biofunctional assay utilizing human TM cells was set up in which the reduction of fibronectin was used as an indicator of enzyme activity. It was observed that fibronectin staining was markedly reduced by the medium collected from MMP-3-microparticle-treated cultures compared to that from blank- and beta-casein-microparticle controls, which was validated using a direct MMP-3 activity assay. The controlled release of MMP-3 from the microparticles resulted in sustained degradation of fibronectin up to 10 days. This proof-of-concept undertaking represents the first study on the controlled and sustained release of active MMP-3 to TM cells via encapsulation into PLGA microparticles as a potential treatment of glaucoma. PMID- 23795869 TI - Comparison of clinical features in patients with persistent and nonpersistent cryptococcal meningitis: twelve years of clinical experience in four centers in China. AB - BACKGROUND AND AIMS: Cryptococcal meningitis (CM) has gradually increased in the recent 20 years in the whole world. Although the mortality decreased significantly in recent years, it was still high, especially in patients with persistent infection. Therefore, we compare differences of clinical features between persistent and nonpersistent CM patients. METHODS: We conducted a retrospective review of medical records of patients diagnosed with CM from January 2000 to December 2011 in four centers in China, including demographic features, underlying diseases, clinical presentations, laboratory data, and so on. RESULTS: Of 106 CM patients enrolled, 16 were identified as persistent cases. Among all variables, persistent CM patients were more like to be human immunodeficiency viruses (HIV) infection (P < 0.05), stiff neck (P < 0.01), a serum hemoglobin < 90 g/L (P < 0.01), a serum potassium concentration <2.7 mg/L (P < 0.01), an intracranial pressure (ICP) >400 mmH2 O (P < 0.01), and a latex agglutination cryptococcal antigen titer of cerebrospinal fluid (CSF LACT) >1:1024 (P < 0.01) than nonpersistent ones. A multivariate analysis showed that HIV infection (OR 7.49), stiff neck (OR 11.7), a serum potassium <2.7 mmol/L (OR 9.45), and an ICP >400 mmH2 O (OR 6.83) were closely correlated with persistent CM. CONCLUSIONS: Although it is difficult to deal with persistent CM nowadays, some cases could be predicted early enough in the future, so as to be treated appropriately and have relatively good outcomes. PMID- 23795865 TI - Use of vitamin D supplements during infancy in an international feeding trial. AB - OBJECTIVE: To examine the use of vitamin D supplements during infancy among the participants in an international infant feeding trial. DESIGN: Longitudinal study. SETTING: Information about vitamin D supplementation was collected through a validated FFQ at the age of 2 weeks and monthly between the ages of 1 month and 6 months. SUBJECTS: Infants (n 2159) with a biological family member affected by type 1 diabetes and with increased human leucocyte antigen-conferred susceptibility to type 1 diabetes from twelve European countries, the USA, Canada and Australia. RESULTS: Daily use of vitamin D supplements was common during the first 6 months of life in Northern and Central Europe (>80% of the infants), with somewhat lower rates observed in Southern Europe (> 60%). In Canada, vitamin D supplementation was more common among exclusively breast-fed than other infants (e.g., 71% v. 44% at 6 months of age). Less than 2% of infants in the U.S.A. and Australia received any vitamin D supplementation. Higher gestational age, older maternal age and longer maternal education were study-wide associated with greater use of vitamin D supplements. CONCLUSIONS: Most of the infants received vitamin D supplements during the first 6 months of life in the European countries, whereas in Canada only half and in the U.S.A. and Australia very few were given supplementation. PMID- 23795870 TI - Physicians in long-term recovery who are members of alcoholics anonymous. AB - BACKGROUND: There is little empirical literature on the experience in sobriety of long-term, committed members of Alcoholics Anonymous (AA). OBJECTIVE: Studies on the experience of long-term members, however, can yield a better understanding of the role of spirituality in AA membership, and how the program helps stabilize abstinence. METHODS: We studied 144 physicians at a conference of doctors in AA. RESULTS: Respondents had a mean period of sobriety of 140 months. Compared to normative populations, they scored higher on scales for depression and anxiety, and were more adherent to the spiritual character of AA, rather than a formally religious orientation. Those who reported "having a spiritual awakening" were more likely to "experience God's presence" on most days (81% vs. 19%) and were less likely to report craving for alcohol (21% vs. 41%) than those who did not. Respondents who had a history of being enrolled in State Physicians' Health Programs did not differ significantly on any of the aforesaid subjective variables from those who were not enrolled. CONCLUSION: The experience of long term AA members can be characterized in terms of abstinence, spirituality, and alcohol craving. SCIENTIFIC SIGNIFICANCE: The study of long-term AA members can shed light on mechanisms of achieving abstinence in this fellowship. PMID- 23795871 TI - Reductions in anxiety and depression symptoms in youth receiving substance use treatment. AB - BACKGROUND AND OBJECTIVES: Research shows that interventions for substance use disorders may be helpful in reducing internalizing disorders in adolescents. This paper examines the prevalence and reductions of anxiety and depression symptoms among youth receiving substance use treatment. METHODS: Four hundred eighty adolescents ages 12-17 who received treatment for substance abuse as part of the Brief Strategic Family Therapy effectiveness trial were screened for anxiety and depression using the Diagnostic Interview Schedule for Children-Predictive Scales (DISC-PS). Twelve-month post-randomization assessments were completed by 327 parents and 315 youth. Sixty-five percent of the sample was found to have probability of at least one anxiety disorder or depression diagnosis. RESULTS: Significant reduction of anxiety and depressive symptoms and significant reductions in probable anxiety and depression diagnoses were observed at follow up. Few differences by treatment type and by ethnic group were noticed. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Findings indicate that substance use interventions might help reduce the prevalence of anxiety and depressive symptoms and the probability of these disorders. PMID- 23795872 TI - Mania precipitated by opioid withdrawal: a retrospective study. AB - OBJECTIVE: Little evidence is available on the occurrence of mania following opioid withdrawal. This is the first report on clinical and demographic characteristics of mania precipitated by opioid withdrawal in a relatively large sample. METHOD: In this study, we assessed the files of the patients admitted to a large referral psychiatric hospital during a 3-year period with a presentation of manic episode shortly after opioid withdrawal. Forty-five relevant cases (one woman) were found, including 28 patients with their first manic episode, and 17 patients with a previous history of bipolar disorder. RESULTS: Most of the identified cases had a long history (mean = 11.8 years) of opium dependence (24 cases used only opium and 16 cases opium and other opioids) and had recently experienced an intense withdrawal (25 cases). These associations were present in both first-episode patients and those with recurrent episodes. CONCLUSION: Emergence of mania following opioid withdrawal could be partly explained by mood stabilizing effects of opioids. Other than the type of opioid, it seems that the duration of use and withdrawal method might play a role. Caution should be used while detoxifying patients with a long history of opioid use. PMID- 23795873 TI - Impact of cannabis use during stabilization on methadone maintenance treatment. AB - BACKGROUND AND OBJECTIVES: Illicit drug use, particularly of cannabis, is common among opiate-dependent individuals and has the potential to impact treatment in a negative manner. METHODS: To examine this, patterns of cannabis use prior to and during methadone maintenance treatment (MMT) were examined to assess possible cannabis-related effects on MMT, particularly during methadone stabilization. Retrospective chart analysis was used to examine outpatient records of patients undergoing MMT (n = 91), focusing specifically on past and present cannabis use and its association with opiate abstinence, methadone dose stabilization, and treatment compliance. RESULTS: Objective rates of cannabis use were high during methadone induction, dropping significantly following dose stabilization. History of cannabis use correlated with cannabis use during MMT but did not negatively impact the methadone induction process. Pilot data also suggested that objective ratings of opiate withdrawal decrease in MMT patients using cannabis during stabilization. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: The present findings may point to novel interventions to be employed during treatment for opiate dependence that specifically target cannabinoid-opioid system interactions. PMID- 23795875 TI - Predictors of substance abuse treatment outcome in hospitalized veterans. AB - BACKGROUND AND OBJECTIVES: Historically patients consulted for the substance abuse treatment from the medical surgical floors have a very low show rate for the substance abuse treatment. The authors performed retrospective chart review to find predictors of substance abuse treatment outcome in hospitalized veterans at Atlanta VA Medical Center. METHODS: The medical records from all the patients who were admitted to the medical/surgical floor with substance abuse consults from January-December 2009 were reviewed. A total of 235 consults were received. Those records were examined to find the predictors for substance abuse treatment. RESULTS: Multiple variables were tested for significance - patient demographics, housing status, employment, reason for hospitalization, toxicology screens, co morbid psychiatric and medical conditions, physician visits, and patients on waiting list. All variables were given cut-off point for the p-value of .10. These variables were then included in the logistic regression model. It was found that homelessness (chi2 = 16.14 and p < .0001) was the only individual variable that showed a statistically significant correlation with starting the program. It was found that homelessness (chi2 = 19.21 and p < .0001) was the only individual variable that showed statistically significant correlation with completing the program. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Our study supports that for veterans with substance abuse, housing was the only consistent predictor to enter intensive outpatient program (IOP), complete IOP, and start aftercare. Our study demonstrates the need for and potential benefit of providing stable housing for the homeless veterans. PMID- 23795874 TI - Buprenorphine treatment outcomes among opioid-dependent cocaine users and non users. AB - BACKGROUND AND OBJECTIVES: National treatment guidelines state that polysubstance users, including cocaine users, may not be appropriate candidates for office based buprenorphine treatment. However, data to support this recommendation are sparse and conflicting, and the implications of this recommendation may include limiting the usefulness of buprenorphine treatment, as cocaine use is common among opioid-dependent individuals seeking buprenorphine treatment. We compared buprenorphine treatment outcomes (6-month treatment retention and self-reported opioid use over 6 months) in opioid-dependent cocaine users versus non-users who initiated buprenorphine treatment at an urban community health center. METHODS: We followed 87 participants over 6 months, collecting interview and medical record data. We used logistic regression models to test whether baseline cocaine use was associated with treatment retention and mixed effects nonlinear models to test whether baseline cocaine use was associated with self-reported opioid use. RESULTS: At baseline, 39.1% reported cocaine use. In all participants, self reported opioid use decreased from 89.7% to 27.4% over 6 months, and 6-month treatment retention was 54.5%. We found no significant difference in 6-month treatment retention (AOR = 1.56, 95% CI: .58-4.17, p = .38) or self-reported opioid use (AOR = .89, 95% CI: .26-3.07, p = .85) between cocaine users and non users. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: This study demonstrates that buprenorphine treatment retention is not worse in cocaine users than non-users, with clinically meaningful improvements in self-reported opioid use. These findings suggest that opioid-dependent cocaine users attain considerable benefits from office-based buprenorphine treatment and argue for the inclusion of these patients in office-based buprenorphine treatment programs. PMID- 23795876 TI - Biopsychosocial pathways to alcohol-related problems. AB - BACKGROUND: Drinking to cope has been associated with negative consequences among college students. Less is known about the biopsychosocial pathways that increase the susceptibility to these drinking problems. This study aims to assess the relationship between biopsychosocial variables that have been shown to impact substance-based coping (ie, alexithymia, childhood/adolescent abuse, and genetics). METHODS: Self-report and genetic [DRD2 genotype (A1- or A1+)] information were collected from 297 participants. RESULTS: Using structural equation models, results found that greater amounts of emotional abuse predicted alexithymia, and substance-based coping predicted drinking problems among both groups. However, among persons with the A1+ allele, greater levels of alexithymia were associated with greater levels of substance-based coping. CONCLUSIONS: These results indicate that the A1+ allele may link alexithymia and prior emotional abuse to a higher risk for substance-based coping and subsequent alcohol problems. PMID- 23795878 TI - Assistant District Attorney decision making when referring to drug treatment court. AB - BACKGROUND: Contact with the criminal justice system represents a critical point for drug involved offenders to access treatment and prevention services. Treatment and service provision under community supervision are known to be more likely than incarceration to affect positive change in terms of reduced substance use, reduced HIV risk behaviors, and increments in community reintegration. The decision-making process by Assistant District Attorneys (ADAs), frequent primary gate-keepers of jail diversion programming, when referring to diversion programs (as opposed to traditional adjudication) is poorly understood. OBJECTIVE: To contribute to literature regarding the optimization of jail diversion referral practice, the current study sought to investigate what influences such decisions by Dane County ADAs. METHODS: We surveyed 24 ADAs and received 19 completed questionnaires. RESULTS: ADA decision making was in agreement with existing literature regarding offender factors associated with drug court completion, including social factors, criminal history, and primary substance used. ADA beliefs conflicted with current literature regarding drug treatment facilitating reductions in criminal behavior. CONCLUSION: Additional research is needed to further assess the decision-making process by primary diversion program gatekeepers. SCIENTFIC SIGNIFICANCE: Dissemination of relevant findings to prosecutors will facilitate optimization of referral to therapeutic jurisprudence programming and the matching of offenders to services. PMID- 23795877 TI - Self-efficacy and motivation to quit marijuana use among young women. AB - BACKGROUND AND OBJECTIVES: Assessing motivation to quit substance use is recommended as part of brief interventions. The purpose of this study was to determine correlates of desire to quit marijuana use among young adult women enrolled in a brief motivational intervention trial. METHODS: Participants were 332 female marijuana users, aged 18-24, who rated their current desire to quit using a single item change ladder. We hypothesized self-efficacy and prior quit attempts will interact in this population to increase motivation to quit. RESULTS: Participants had a mean age of 20.5 years, 67.7% were non-Hispanic Caucasian, and 60% had some desire to quit marijuana use. Using multivariate linear regression, quit desire was significantly lower among Caucasians (b = .256; 95% CI -.489; -.037) and more frequent marijuana users (b = -.268; 95% CI .372; -.166), and higher among those with previous quit attempts (b = .454; 95% CI .235; .671), and greater marijuana problem severity (b = .408; 95% CI .302; .514). Greater refusal self-efficacy was associated with greater quit desire among participants with previous quit attempts, but not among those without prior quit attempts (b = .241; 95% CI .050; .440). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Understanding the factors relating to quit desire among marijuana users may allow clinicians to tailor counseling so as to increase readiness to quit and decrease use and its associated consequences. PMID- 23795879 TI - Changes in smoking level after viewing graphic cigarette warnings: preliminary findings. AB - BACKGROUND AND OBJECTIVES: Some countries require graphic warnings on cigarette packages, and other countries, including the United States, may follow that lead. A few studies have produced findings suggesting that graphic warnings may have effects on smoking-related attitudes and behaviors. The objective of the present study was to gather evidence on the effects of graphic warnings on smoking level and related behavior. METHODS: This study was conducted with 89 adult smokers in the United States to examine the effects of warnings that included graphic images of cosmetically important physical harm caused by smoking. Participants completed measures of smoking level and cessation-related behavior before and after viewing 4 weekly health warnings about smoking, each with a graphic image showing cosmetically important health harm caused by smoking. RESULTS: The study results showed significant improvement on all measures, providing pre-post evidence of a significant decrease in smoking level after viewing graphic and written warnings. The more participants perceived the warnings as distressing and useful, the more their smoking decreased. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: The study findings provide preliminary evidence that graphic warnings can lead to increases in cessation-related behavior and decreases in level of smoking. PMID- 23795880 TI - A spatial analysis of student binge drinking, alcohol-outlet density, and social disadvantages. AB - BACKGROUND AND OBJECTIVES: This paper examined whether and how student binge drinking at the individual level was influenced by population disadvantages, community instability, alcohol-outlet density, and protective factors generated by community and school. METHODS: We used a dataset collected in 2002 by the Alabama Department of Mental Health, with additional materials generated by the 2000 Census and from the Alabama State Department of Education. School-catchments were employed as geographic units of analysis. The final sample comprised 78,138 public-school students in grades 6-12 who attended schools located in the 566 school-catchments. RESULTS: We hypothesized the presence of spatial processes that, once identified, would enhance understanding of student binge drinking. Our results confirmed that student binge drinking in a focal area was affected by that area's structural factors and also by individual-level risk and protective factors. The results did not support the hypothesized impact of surrounding areas' characteristics on student binge drinking in the focal area. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: The results of our study clearly indicate that both environment-based factors and individual-level risk and protective factors are important in explaining student binge drinking in Alabama. PMID- 23795881 TI - Alcohol use disorders among substance dependent women on Temporary Assistance with Needy Families: more information for diagnostic modifications for DSM-5. AB - PURPOSE: While modifications to alcohol use disorder (AUD) criteria are proposed for DSM-5, examination of the criteria's performance among highly vulnerable populations is lacking. This study determined the dimensionality and rank order severity of the DSM-IV AUD criteria among Temporary Assistance for Needy Families (TANF) recipients with high rates of chemical dependency and co-morbid mental health disorders. METHOD: Secondary analysis was performed on data from 461 TANF eligible women screened for AUD criteria using the Structured Clinical Interview for DSM-IV-TR. Exploratory (EFA) and confirmatory factor analyses (CFA) were performed on the AUD criteria. Two-parameter Item Response Theory (IRT) analysis was performed to determine item location and discrimination of criteria for both abuse and dependence. Differential item functioning for those with an additional substance use disorder or with high levels of depressive symptoms was explored. RESULTS: 41.2% met criteria for dependence, and 4.4% for abuse. EFA and CFA revealed a two-factor model provided adequate fit to criteria, and IRT indicated a potential hierarchical order between the criteria-abuse being more severe but dependence having greater reliability. CONCLUSION: Contrary to existing literature, findings suggest that a two-factor solution may be appropriate. Implications are discussed. PMID- 23795882 TI - Predictors of diabetes mellitus and abnormal blood glucose in patients receiving opioid maintenance treatment. AB - BACKGROUND: Buprenorphine is a partial opioid agonist and may have less impact on the risk of developing diabetes mellitus (DM) compared to full opioid agonists like methadone. METHODS: We conducted an observational retrospective study to investigate the predictable factors for impaired glucose tolerance and predisposition to DM in two groups of opiate addicts receiving long-term methadone maintenance treatment (MMT) [n = 58] or buprenorphine maintenance treatment (BMT) [n = 61]. RESULTS: In our cohort, being African American, hepatitis C positive status, elevated AST, and ALT, and being on methadone were significantly correlated to being diagnosed with DM. Among all those factors, being on methadone was most significantly related to being diagnosed with DM (chi2 = 3.9888, p-value = .0458). The BMI was the only factor that was significantly correlated to having abnormal A1c level (chi2 = 6.4229, p-value = .0113). CONCLUSIONS: Buprenorphine may be less likely to contribute to the development of DM than methadone. More research is needed to understand the link between opioids and DM. PMID- 23795883 TI - Does adolescent gambling co-occur with young fatherhood? AB - BACKGROUND: Young fatherhood is associated with various adverse outcomes. This study aims to describe the relationship of adolescent gambling with young fatherhood (by age 20) while adjusting for several young fatherhood antecedents. METHODS: Data were from 294 males who have been followed for 16 years since entering first grade in nine inner city public schools (86% African Americans, 81% of the original male cohort). Self-reports of impregnation (including age) and gambling were collected during late adolescence. Nelson-Aalen curves and Cox regression models assessed the hazard of young fatherhood among adolescent nongamblers, social gamblers, and problem gamblers. RESULTS: More young fathers than nonfathers reported adolescent social (49.2% vs. 42.5%) and problem gambling (28.3% vs. 13.2%, p < .001). Problem gamblers were the most likely to impregnate someone by age 20, followed by social gamblers, then nongamblers. Problem gambling (aHR = 3.16, 95% CI = 1.75, 5.72, p < .001) had the highest increased hazards of young fatherhood, followed by social gambling (aHR = 1.95, 95% CI = 1.30, 2.94, p = .001), high school dropout (aHR = 1.75, 95% CI = 1.14, 2.70, p = .01), and subsidized lunch status (aHR = 1.69, 95% CI = 1.01, 2.38, p = .04). CONCLUSION: Adolescent male gamblers, particularly problem gamblers, were more likely than their nongambling peers to become fathers by the age of 20. Such a result shows that there is a subpopulation of males who are at high risk for adverse outcomes such as young parenthood and problem behaviors. Only through further studies could the needs of this subpopulation be better assessed so that appropriate assistance could be delivered to better the lives of such individuals. PMID- 23795885 TI - Mediators of cognitive behavioral therapy for anxiety-disordered children and adolescents: cognition, perceived control, and coping. AB - The purpose is to investigate whether a change in putative mediators (negative and positive thoughts, coping strategies, and perceived control over anxious situations) precedes a change in anxiety symptoms in anxiety-disordered children and adolescents receiving cognitive behavioral therapy (CBT). Participants were 145 Dutch children (8-18 years old, M = 12.5 years, 57% girls) with a primary anxiety disorder. Assessments were completed pretreatment, in-treatment, posttreatment, and at 3-month follow-up. Sequential temporal dependencies between putative mediators and parent- and child-reported anxiety symptoms were investigated in AMOS using longitudinal Latent Difference Score Modeling. During treatment an increase of positive thoughts preceded a decrease in child-reported anxiety symptoms. An increase in three coping strategies (direct problem solving, positive cognitive restructuring, and seeking distraction) preceded a decrease in parent-reported anxiety symptoms. A reciprocal effect was found for perceived control: A decrease in parent-reported anxiety symptoms both preceded and followed an increase in perceived control. Using a longitudinal design, a temporal relationship between several putative mediators and CBT-outcome for anxious children was explored. The results suggest that a change in positive thoughts, but not negative thoughts, and several coping strategies precedes a change in symptom reduction and, therefore, at least partly support theoretical models of anxiety upon which the anxiety intervention is based. PMID- 23795884 TI - Picking sides: distinct roles for CYP76M6 and CYP76M8 in rice oryzalexin biosynthesis. AB - Natural products biosynthesis often requires the action of multiple CYPs (cytochromes P450), whose ability to introduce oxygen, increasing solubility, is critical for imparting biological activity. In previous investigations of rice diterpenoid biosynthesis, we characterized CYPs that catalyse alternative hydroxylation of ent-sandaracopimaradiene, the precursor to the rice oryzalexin antibiotic phytoalexins. In particular, CYP76M5, CYP76M6 and CYP76M8 were all shown to carry out C-7beta hydroxylation, whereas CYP701A8 catalyses C-3alpha hydroxylation, with oxy groups found at both positions in oryzalexins A-D, suggesting that these may act consecutively in oryzalexin biosynthesis. In the present paper, we report that, although CYP701A8 only poorly reacts with 7beta hydroxy-ent-sandaracopimaradiene, CYP76M6 and CYP76M8 readily react with 3alpha hydroxy-ent-sandaracopimaradiene. Notably, their activity yields distinct products, resulting from hydroxylation at C-9beta by CYP76M6 or C-7beta by CYP76M8, on different sides of the core tricyclic ring structure. Thus CYP76M6 and CYP76M8 have distinct non-redundant roles in orzyalexin biosynthesis. Moreover, the resulting 3alpha,7beta- and 3alpha,9beta-diols correspond to oryzalexins D and E respectively. Accordingly, the results of the present study complete the functional identification of the biosynthetic pathway underlying the production of these bioactive phytoalexins. In addition, the altered regiochemistry catalysed by CYP76M6 following C-3alpha hydroxylation has some implications for its active-site configuration, offering further molecular insight. PMID- 23795886 TI - The value of suppressor effects in explicating the construct validity of symptom measures. AB - Suppressor effects are operating when the addition of a predictor increases the predictive power of another variable. We argue that suppressor effects can play a valuable role in explicating the construct validity of symptom measures by bringing into clearer focus opposing elements that are inherent--but largely hidden--in the measure's overall score. We illustrate this point using theoretically grounded, replicated suppressor effects that have emerged in analyses of the original Inventory of Depression and Anxiety Symptoms (IDAS; Watson et al., 2007) and its expanded 2nd version (IDAS-II; Watson et al., 2012). In Study 1, we demonstrate that the IDAS-II Appetite Gain and Appetite Loss scales contain both (a) a shared distress component that creates a positive correlation between them and (b) a specific symptom component that produces a natural negative association between them (i.e., people who recently have experienced decreased interest in food/loss of appetite are less likely to report a concomitant increase in appetite/weight). In Study 2, we establish that mania scales also contain 2 distinct elements-namely, high energy/positive emotionality and general distress/dysfunction-that oppose each another in many instances. In both studies, we obtained evidence of suppression effects that were highly robust across different types of respondents (e.g., clinical outpatients, community adults, college students) and using both self-report and interview-based measures. These replicable suppressor effects establish that many homogeneous, unidimensional symptom scales actually contain distinguishable components with distinct--at times, even antagonistic--properties. PMID- 23795887 TI - Novel psychoactive drug use among younger adults involved in US nightlife scenes. AB - INTRODUCTION AND AIMS: The emergence of novel psychoactive substances has been reported in clinical studies and recent studies of users. The use of these substances in European nightlife scenes is well documented. Little research has been done to identify the prevalence of these drugs among young adults active in other regions. We focus our sample on socially active young adults to gain an indication of the prevalence and understanding of demographic factors associated with past year mephedrone ('meph', 'bath salts') and synthetic cannabinoid ('spice', 'K2') use. DESIGN AND METHODS: This study reports on the results of a field-based survey of 1740 patrons at nightlife venues in New York City. RESULTS: Within the sample, 8.2% reported use of synthetic cannabinoids and 1.1% reported the use of mephedrone. Gay and bisexual men reported higher prevalence of mephedrone use. Latinos reported higher prevalence of synthetic cannabinoid use. Multivariate analyses indicate that sexual minority identity is associated with mephedrone use and younger age and Latino ethnicity are associated with synthetic cannabinoid use. DISCUSSION AND CONCLUSION: The findings suggest that the use of synthetic cannabinoids and mephedrone among adults in US nightlife scenes remains relatively low in comparison with European nightlife scenes, and is low relative to other drug use among young people within these scenes. PMID- 23795890 TI - Dearomatization strategy of beta-enamino ester: construction of indenoazepines via tandem Michael addition/polycyclization. AB - A dearomatization strategy of beta-enamino esters was developed to construct indenoazepine derivatives. The oxidative dearomatization was combined with a base promoted tandem Michael addition/polycyclization and an acid-catalyzed aromatization. The nonaromatic structure of the Michael adducts might be essential to the realization of the 7-endo-dig cyclization. PMID- 23795891 TI - Antiplasmodial and cytotoxic flavans and diarylpropanes from the stems of Combretum griffithii. AB - Four new flavans, griffinoids A-D (1-4), and two new diarylpropanes, griffithanes E and F (7 and 8), together with two known flavans (5 and 6), four known diarylpropanes, and beta-sitosterol, were isolated from the EtOAc extract of the stems of Combretum griffithii. Compounds 3, 4, 5, and 9 exhibited weak antiplasmodial activity, with IC50 values of 15.74, 13.04, 9.66, and 14.45 MUM, respectively. In addition, compounds 4, 5, and 8 also exhibited weak cytotoxicity toward one or more cancer cell lines including human epidermoid carcinoma, human breast cancer, and human small cell lung cancer cell lines. PMID- 23795888 TI - A Golgi and tonoplast localized S-acyl transferase is involved in cell expansion, cell division, vascular patterning and fertility in Arabidopsis. AB - S-acylation of eukaryotic proteins is the reversible attachment of palmitic or stearic acid to cysteine residues, catalysed by protein S-acyl transferases that share an Asp-His-His-Cys (DHHC) motif. Previous evidence suggests that in Arabidopsis S-acylation is involved in the control of cell size, polarity and the growth of pollen tubes and root hairs. Using a combination of yeast genetics, biochemistry, cell biology and loss of function genetics the roles of a member of the protein S-acyl transferase PAT family, AtPAT10 (At3g51390), have been explored. In keeping with its role as a PAT, AtPAT10 auto-S-acylates, and partially complements the yeast akr1 PAT mutant, and this requires Cys(192) of the DHHC motif. In Arabidopsis AtPAT10 is localized in the Golgi stack, trans Golgi network/early endosome and tonoplast. Loss-of-function mutants have a pleiotropic phenotype involving cell expansion and division, vascular patterning, and fertility that is rescued by wild-type AtPAT10 but not by catalytically inactive AtPAT10C(192) A. This supports the hypothesis that AtPAT10 is functionally independent of the other Arabidopsis PATs. Our findings demonstrate a growing importance of protein S-acylation in plants, and reveal a Golgi and tonoplast located S-acylation mechanism that affects a range of events during growth and development in Arabidopsis. PMID- 23795892 TI - Moving away from the reference genome: evaluating a peptide sequencing tagging approach for single amino acid polymorphism identifications in the genus Populus. AB - The genetic diversity across natural populations of the model organism, Populus, is extensive, containing a single nucleotide polymorphism roughly every 200 base pairs. When deviations from the reference genome occur in coding regions, they can impact protein sequences. Rather than relying on a static reference database to profile protein expression, we employed a peptide sequence tagging (PST) approach capable of decoding the plasticity of the Populus proteome. Using shotgun proteomics data from two genotypes of P. trichocarpa, a tag-based approach enabled the detection of 6653 unexpected sequence variants. Through manual validation, our study investigated how the most abundant chemical modification (methionine oxidation) could masquerade as a sequence variant (Ala >Ser) when few site-determining ions existed. In fact, precise localization of an oxidation site for peptides with more than one potential placement was indeterminate for 70% of the MS/MS spectra. We demonstrate that additional fragment ions made available by high energy collisional dissociation enhances the robustness of the peptide sequence tagging approach (81% of oxidation events could be exclusively localized to a methionine). We are confident that augmenting fragmentation processes for a PST approach will further improve the identification of single amino acid polymorphism in Populus and potentially other species as well. PMID- 23795893 TI - B6.g7 mice reconstituted with BDC2.5 non-obese diabetic (BDC2.5NOD) stem cells do not develop autoimmune diabetes. AB - In BDC2.5 non-obese diabetic (BDC2.5NOD) mice, a spontaneous model of type 1 diabetes, CD4(+) T cells express a transgene-encoded T cell receptor (TCR) with reactivity against a pancreatic antigen, chromogranin. This leads to massive infiltration and destruction of the pancreatic islets and subsequent diabetes. When we reconstituted lethally irradiated, lymphocyte-deficient B6.g7 (I-A(g7+)) Rag(-/-) mice with BDC2.5NOD haematopoietic stem and progenitor cells (HSPC; ckit(+)Lin(-)Sca-1(hi)), the recipients exhibited hyperglycaemia and succumbed to diabetes. Surprisingly, lymphocyte-sufficient B6.g7 mice reconstituted with BDC2.5NOD HSPCs were protected from diabetes. In this study, we investigated the factors responsible for attenuation of diabetes in the B6.g7 recipients. Analysis of chimerism in the B6.g7 recipients showed that, although B cells and myeloid cells were 98% donor-derived, the CD4(+) T cell compartment contained ~50% host derived cells. These host-derived CD4(+) T cells were enriched for conventional regulatory T cells (Tregs ) (CD25(+) forkhead box protein 3 (FoxP3)(+)] and also for host- derived CD4(+)CD25(-)FoxP3(-) T cells that express markers of suppressive function, CD73, FR4 and CD39. Although negative selection did not eliminate donor-derived CD4(+) T cells in the B6.g7 recipients, these cells were functionally suppressed. Thus, host-derived CD4(+) T cells that emerge in mice following myeloablation exhibit a regulatory phenoytpe and probably attenuate autoimmune diabetes. These cells may provide new therapeutic strategies to suppress autoimmunity. PMID- 23795894 TI - Immunological evaluation of a synthetic Clostridium difficile oligosaccharide conjugate vaccine candidate and identification of a minimal epitope. AB - Clostridium difficile is the cause of emerging nosocomial infections that result in abundant morbidity and mortality worldwide. Thus, the development of a vaccine to kill the bacteria to prevent this disease is highly desirable. Several recently identified bacterial surface glycans, such as PS-I and PS-II, are promising vaccine candidates to preclude C. difficile infection. To circumvent difficulties with the generation of natural PS-I due to its low expression levels in bacterial cultures, improved chemical synthesis protocols for the pentasaccharide repeating unit of PS-I and oligosaccharide substructures were utilized to produce large quantities of well-defined PS-I related glycans. The analysis of stool and serum samples obtained from C. difficile patients using glycan microarrays of synthetic oligosaccharide epitopes revealed humoral immune responses to the PS-I related glycan epitopes. Two different vaccine candidates were evaluated in the mouse model. A synthetic PS-I repeating unit CRM197 conjugate was immunogenic in mice and induced immunoglobulin class switching as well as affinity maturation. Microarray screening employing PS-I repeating unit substructures revealed the disaccharide Rha-(1->3)-Glc as a minimal epitope. A CRM197-Rha-(1->3)-Glc disaccharide conjugate was able to elicit antibodies recognizing the C. difficile PS-I pentasaccharide. We herein demonstrate that glycan microarrays exposing defined oligosaccharide epitopes help to determine the minimal immunogenic epitopes of complex oligosaccharide antigens. The synthetic PS-I pentasaccharide repeating unit as well as the Rha-(1->3)-Glc disaccharide are promising novel vaccine candidates against C. difficile that are currently in preclinical evaluation. PMID- 23795895 TI - Eagle's syndrome. PMID- 23795896 TI - Thyrotoxicosis and neck pain: getting the right test at the right time. PMID- 23795897 TI - Quantitative ST-depression in acute coronary syndromes: the PLATO electrocardiographic substudy. AB - BACKGROUND: We evaluated whether electrocardiogram (ECG) characteristics were aligned with clinical outcomes and the effect of ticagrelor within the diverse spectrum of non-ST-elevation acute coronary syndrome patients enrolled in the PLATelet inhibition and patient Outcomes (PLATO) trial. METHODS: There were 8884 PLATO patients who had baseline ECGs assessed by a core laboratory; of these, 4935 had an ECG at hospital discharge that also was assessed. Associations with study treatment on vascular death or myocardial infarction within 1 year were examined. RESULTS: At baseline, most patients had either no or <=0.5 mm of ST segment depression (57%); 26% had 1.0 mm, and 17% had more extensive depression (>1.0 mm). Across the baseline ST-segment depression strata, there was a consistent treatment benefit with ticagrelor versus clopidogrel on vascular death/myocardial infarction. The extent of residual ST-segment depression at discharge was similar in the treatment groups, and the treatment effect did not differ by the extent of discharge ST-segment depression. There was a progressive increase in vascular death/myocardial infarction with increasing extent of baseline ST-segment depression (1.0 mm [vs no/0.5 mm]: hazard ratio [HR] 1.22; 95% confidence interval [CI], 1.03-1.45; >1.0 mm: HR 1.49; 95% CI, 1.24-1.78; P <.001) and at discharge (HR 1.28; 95% CI, 1.02-1.61; HR 2.13; 95% CI, 1.54-2.95; P <.001). CONCLUSION: The treatment effect of ticagrelor among non-ST-segment elevation acute coronary syndrome patients was consistently expressed across all baseline ST-segment depression strata. There was no indication of an anti ischemic benefit of ticagrelor as reflected on the discharge ECG. Our data affirm the independent prognostic relationship of both baseline and hospital discharge ST-segment depression on outcomes within 1 year in non-ST-segment-elevation acute coronary syndrome patients. PMID- 23795898 TI - Association between coffee intake and gastroesophageal reflux disease: a meta analysis. AB - Gastroesophageal reflux disease (GERD) is one of the most common diseases affecting patients worldwide, but its risk factors and causes are not clearly known. The aim of this study was to investigate the effect of coffee intake on GERD by a meta-analysis. We searched online published research databases such as PubMed, EMBASE, and Cochrane Library for studies that were published up to December 2012. These publications were reviewed by two independent authors, and studies that fulfilled the criteria were selected. Whenever there was a disagreement between the authors, a consensus was reached by discussion. Fifteen case-control studies were included in the final analysis. A meta-analysis showed that there was no significant association between coffee intake and GERD. The odds ratio was 1.06 (95% confidence interval, 0.94-1.19). In subgroup analyses in which the groups were subdivided based on the definition of GERD (diagnosed by endoscopy or by symptoms alone), only the endoscopy group showed a significantly higher odds ratio. In subgroup analyses in which the groups were subdivided based on the amount of coffee intake, quality of study, and assessment of exposure, there was no significant association between coffee intake and GERD. PMID- 23795899 TI - Pitfalls in the diagnosis of intravascular large B-cell lymphoma. PMID- 23795900 TI - Combined handling of prostate base/bladder neck and seminal vesicles in radical prostatectomy specimens: our approach with the whole mount technique. PMID- 23795902 TI - Appendectomy during pregnancy--is pregnancy outcome depending by operation technique? AB - OBJECTIVE: To compare perioperative and pregnancy outcome between women undergoing laparoscopic appendectomy and those undergoing open appendectomy during pregnancy for presumed acute appendicitis. METHODS: A retrospective cohort study of all women undergoing appendectomy during pregnancy in a tertiary referral medical center from 2000 to 2009. Outcome was compared between those undergoing laparoscopic appendectomy and those undergoing open appendectomy. RESULTS: Overall, 83,510 deliveries occurred during the study period, 85 (0.10%) were eligible for the study group. Of these, 26 (31%) had a laparoscopic appendectomy and 59 (69%) had an open appendectomy. No significant difference was found in the general, delivery and neonatal outcome characteristics between the two groups. There was a significant difference in the mean gestational age at surgery between laparoscopic appendectomy and the open appendectomy groups (14.6 versus 19.3 weeks respectively, p = 0.009). Post-operative complications (fever >38.0 degrees C or the presence of uterine contractions) rate was higher in the open appendectomy compared to the laparoscopic appendectomy group (25.5% versus 3.8%, respectively, p = 0.009). CONCLUSION: Laparoscopic appendectomy appears to be a safe procedure for presumed acute appendicitis during pregnancy with less post-operative complications as compared to open appendectomy. PMID- 23795901 TI - Life spanning murine gene expression profiles in relation to chronological and pathological aging in multiple organs. AB - Aging and age-related pathology is a result of a still incompletely understood intricate web of molecular and cellular processes. We present a C57BL/6J female mice in vivo aging study of five organs (liver, kidney, spleen, lung, and brain), in which we compare genome-wide gene expression profiles during chronological aging with pathological changes throughout the entire murine life span (13, 26, 52, 78, 104, and 130 weeks). Relating gene expression changes to chronological aging revealed many differentially expressed genes (DEGs), and altered gene sets (AGSs) were found in most organs, indicative of intraorgan generic aging processes. However, only <= 1% of these DEGs are found in all organs. For each organ, at least one of 18 tested pathological parameters showed a good age predictive value, albeit with much inter- and intraindividual (organ) variation. Relating gene expression changes to pathology-related aging revealed correlated genes and gene sets, which made it possible to characterize the difference between biological and chronological aging. In liver, kidney, and brain, a limited number of overlapping pathology-related AGSs were found. Immune responses appeared to be common, yet the changes were specific in most organs. Furthermore, changes were observed in energy homeostasis, reactive oxygen species, cell cycle, cell motility, and DNA damage. Comparison of chronological and pathology-related AGSs revealed substantial overlap and interesting differences. For example, the presence of immune processes in liver pathology-related AGSs that were not detected in chronological aging. The many cellular processes that are only found employing aging-related pathology could provide important new insights into the progress of aging. PMID- 23795903 TI - Characteristics of major Escherichia coli reductases involved in aerobic nitro and azo reduction. AB - AIMS: Escherichia coli is able to reduce azo compounds such as methyl red (MR) and nitro compounds such as 7-nitrocoumarin-3-carboxylic acid (7NCCA). The aim of this study was to clarify the specificity of the major E. coli reductases. METHODS AND RESULTS: Enzymatic assays with pure enzymes obtained after cloning, overproduction and purification under native or denaturing conditions were performed on three enzymes: AzoR, NfsA and NfsB. Their dependence on putative cofactors such as flavin mononucleotide (FMN), NADH and NADPH was studied as well as the reductase capacity of E. coli mutants depleted for one, two or three of the corresponding genes. CONCLUSIONS: AzoR was able to reduce both MR and 7NCCA, whereas NfsA and NfsB could only reduce the nitro compound. AzoR and NfsB were strictly FMN dependent in contrast to NfsA. At a low oxygen concentration, the three proteins were not mandatory for azo reduction and nitro reduction, but in optimal aerobic conditions, azoR was essential for MR reduction, and an nfsA/nfsB combination was important for 7NCCA reduction. Overexpression of azoR gene was able to compensate for the loss of nfsA and nfsB under aerobic conditions. SIGNIFICANCE AND IMPACT OF STUDY: These data provide new insights into the substrate specificity of major E. coli nitroreductases and demonstrate that oxygen is an important parameter to take into account in studies of nitroreductase activity. PMID- 23795904 TI - Processing/formulation parameters determining dispersity of chitosan particles: an ANNs study. AB - Although a great number of studies may be found in literature about the parameters affecting the size of chitosan nanoparticles, no systematic work so far has detailed the factors affecting the polydispersity of chitosan as an important factor determining the quality of many preparations. Herein, using artificial neural networks (ANNs), four independent variables, namely, pH and concentration of chitosan solution as well as time and amplitude of sonication of the solution were studied to determine their influence on the polydispersity of solution. We found that in an ultrasound prepared nanodispersion of chitosan, all the four input parameters have reverse but non-linear relation with the polydispersity of the nanoparticles. PMID- 23795905 TI - Repeated dose toxicity study of Vibrio cholerae-loaded gastro-resistant microparticles. AB - CONTEXT: Microencapsulation of antigens has been extensively studied over the last decades aiming at improving the immunogenicity of vaccine candidates. OBJECTIVE: Addressing microparticles (MPs) toxicity in rats. MATERIAL AND METHODS: Spray-dried Eudragit(r) L 30 D-55 MPs and Eudragit(r) L 30 D-55 alginate MPs were elaborated and characterized. MPs obtained were administered to rats, three groups were defined: G1, control group; G2, administered with Vibrio cholerae (VC)-loaded MPs; G3, receiving VC-loaded alginate MPs. Animals received three vaccine doses. Body weight, food and water intake were controlled during the study. Haematological parameters, vibriocidal titres, organ weight and histology in necropsy were also analyzed. RESULTS: All animals grew healthy. Body weight gain, food and water intake and haematological parameters remained within physiological values, showing no treatment-related differences. Moreover, organ weight changes were not detected and animals developed protective vibriocidal titres. CONCLUSION: VC-loaded MPs and VC-loaded alginate MPs have proved to be safe and effective in the assessed conditions. PMID- 23795906 TI - Preparation and characterisation of gastroretentive alginate beads for targeting H. pylori. AB - There are various obstacles in the eradication of Helicobacter pylori (H. pylori) infections including low drug levels due to short gastric residence times and poor accessibility of the drug at the site of the infection. In this study, calcium alginate beads containing metronidazole were prepared by ionotropic gelation with diameters ranging from 2 to 3 mm and bulk densities ranging from 0.11 to 0.23 g/cm(3). These beads failed buoyancy tests and released the drug rapidly. The formulation was modified in order to improve floating and modify their drug release profile through addition of oil and coating with chitosan. Upon modification, buoyancy improved and drug release was sustained. This novel formulation will ensure retention for a longer period in the stomach and control the release of drug, ensuring high local drug concentrations, leading to improved eradication of the bacteria. PMID- 23795907 TI - [Presentation]. PMID- 23795908 TI - The Self- and Other-Interest Inventory. AB - Five studies develop and validate the Self- and Other-Interest Inventory, an individual-difference measure of the motivation to act in one's own interest and the motivation to act in another's interest that measures these motivations at the level of self-beliefs. Study 1 demonstrates that self- and other-interest can be measured reliably and validly, as independent constructs, with a self-report measure. Study 2 develops a version of the Self- and Other-Interest Inventory for use with a general population and demonstrates systematic changes in the relation between self- and other-interest scores with age. Study 3 shows that self- and other-interest scores vary independently, as a function of the accessibility of related values. Study 4 provides evidence that self-interest scores predict behaviors that benefit the self and that other-interest scores predict behaviors that benefit another person. Finally, Study 5 demonstrates that in situations that involve a trade-off between the pursuit of self-interest and the pursuit of other-interest, such as the prisoner's dilemma, self- and other-interest scores contribute independently to behavioral prediction. PMID- 23795909 TI - Great expectations: different high-risk activities satisfy different motives. AB - Research on people's motives for engaging in high-risk activities has typically been viewed through the single-focused lens of sensation seeking. We provide evidence that comprehensively challenges that view. First, we develop and confirm the structure of a 3-factor measure of motives: the Sensation Seeking, Emotion Regulation, and Agency Scale (SEAS; Study 1). We then use the SEAS to provide evidence of differential motives for 2 high-risk activities: skydiving and mountaineering. The motive for skydiving is strongly associated with sensation seeking; the motive for mountaineering is strongly associated with emotion regulation and agency but not with sensation seeking (Study 2). We also show that these conclusions cannot be drawn from existing measures of personality and sensation seeking (Study 3). Finally, individuals who are motivated by emotion regulation and agency needs also have greater expectations regarding their emotion regulation and agency. It is these greater expectations that most successfully discriminate mountaineers from skydivers and control participants (Study 4). It is concluded that researchers should no longer consider risk takers as a homogenous sensation-seeking group and that they should consider risk taking as a potential model of human endeavor. The SEAS can be used as a measure of motives for behavior whenever sensation seeking, agency, or emotion regulation is thought to be at the core of such motives, and the results are discussed in the context of encouraging personality researchers to consider the specific spontaneous behaviors that motivate different people. PMID- 23795910 TI - Ex-vivo ocular surface stem cell therapies: current techniques, applications, hurdles and future directions. AB - Engineered tissue derived from ocular surface stem cells (SCs) are a cutting edge biotechnology for repair and restoration of severely damaged eyes as a result of ocular surface dysfunction because of SC failure. Ex-vivo SC expansion techniques have advanced significantly since the first patients were treated in the late 1990s. The techniques and clinical reports reviewed here highlight the evolution and successes of these techniques, while also revealing gaps in our understanding of ocular surface and SC biology that drives further research and development in this field. Although hurdles still remain before stem-cell-based therapies are more widely available for patients with devastating ocular surface disease, recent discoveries in the field of mesenchymal SCs and the potential of induced pluripotent SCs heralds a promising future for clinicians and our patients. PMID- 23795911 TI - Self-sufficient and exclusive oxygenation of methane and its source materials with oxygen to methanol via metgas using oxidative bi-reforming. AB - A combination of complete methane combustion with oxygen of the air coupled with bi-reforming leads to the production of metgas (H2/CO in 2:1 mole ratio) for exclusive methanol synthesis. The newly developed oxidative bi-reforming allows direct oxygenation of methane to methanol in an overall economic and energetically efficient process, leaving very little, if any, carbon footprint or byproducts. PMID- 23795912 TI - Getting old is not for sissies! PMID- 23795914 TI - Protein kinase C inhibitors: a patent review (2008 - 2009). AB - INTRODUCTION: The protein kinase C (PKC) is a family of multifunctional isoenzymes involved in apoptosis, migration, adhesion, tumorgenesis, cardiac hypertrophy, angiogenesis, platelet function and inflammation. It also plays a vital role in the regulation of signal transduction, cell proliferation and differentiation through positive and negative regulation of the cell cycle. In this work, we reviewed the existing PKC inhibitors and several patents linked to PKC inhibitors. AREAS COVERED: Thorough survey on the PKC inhibitors having clinical importance and patents filed for these inhibitors from 2008 - 2009 is reported. EXPERT OPINION: PKCs are highly potential therapeutic targets for treating diabetic complications, oncological, inflammatory, immunological and dermatological disorders. The clinical trial candidates of PKCs mainly target the catalytic domain, which is highly conserved throughout the PKC family making it difficult to target a particular isoform selectively. Relatively less chemical space and fewer bisubstrate inhibitors targeting both ATP and regulatory domain are explored for PKCs, more research in these areas will be helpful in overcoming existing problems. PMID- 23795915 TI - Remote aryl cyanation via isocyanide-cyanide rearrangement on tosylmethyl isocyanide derivatives. AB - The reaction of alkyl tosylmethyl isocyanides and 2-bromobenzyl bromides in the presence of t-BuLi gives rise to a cascade reaction to give unexpected 2 substituted 2,3-dihydro-1H-indenimines which, upon treatment with t-BuOK, rearrange to 2-vinylbenzonitriles in high overall yields. This simple procedure represents a new approach to the synthesis of aromatic nitriles via isocyanide cyanide interconversion. PMID- 23795916 TI - Boreal feather mosses secrete chemical signals to gain nitrogen. AB - The mechanistic basis of feather moss-cyanobacteria associations, a main driver of nitrogen (N) input into boreal forests, remains unknown. Here, we studied colonization by Nostoc sp. on two feather mosses that form these associations (Pleurozium schreberi and Hylocomium splendens) and two acrocarpous mosses that do not (Dicranum polysetum and Polytrichum commune). We also determined how N availability and moss reproductive stage affects colonization, and measured N transfer from cyanobacteria to mosses. The ability of mosses to induce differentiation of cyanobacterial hormogonia, and of hormogonia to then colonize mosses and re-establish a functional symbiosis was determined through microcosm experiments, microscopy and acetylene reduction assays. Nitrogen transfer between cyanobacteria and Pleurozium schreberi was monitored by secondary ion mass spectrometry (SIMS). All mosses induced hormogonia differentiation but only feather mosses were subsequently colonized. Colonization on Pleurozium schreberi was enhanced during the moss reproductive phase but impaired by elevated N. Transfer of N from cyanobacteria to their host moss was observed. Our results reveal that feather mosses likely secrete species-specific chemo-attractants when N-limited, which guide cyanobacteria towards them and from which they gain N. We conclude that this signalling is regulated by N demands of mosses, and serves as a control of N input into boreal forests. PMID- 23795917 TI - Impaired hippocampal theta oscillations in the mice null alpha7 nicotinic acetylcholine receptors. PMID- 23795918 TI - Openness to experience, intellect, and cognitive ability. AB - An instrument designed to separate 2 midlevel traits within each of the Big Five (the Big Five Aspect Scales [BFAS]) was used to clarify the relation of personality to cognitive ability. The BFAS measures Openness to Experience and Intellect as separate (although related) traits, and refers to the broader Big Five trait as Openness/Intellect. In 2 samples (N = 125 and 189), Intellect was independently associated with general intelligence (g) and with verbal and nonverbal intelligence about equally. Openness was independently associated only with verbal intelligence. Implications of these findings are discussed for the empirical and conceptual relations of intelligence to personality and for the mechanisms potentially underlying both Openness/Intellect and cognitive ability. PMID- 23795919 TI - Characterization of a chemical affinity probe targeting Akt kinases. AB - Protein kinases are key regulators of cellular processes, and aberrant function is often associated with human disease. Consequently, kinases represent an important class of therapeutic targets and about 20 kinase inhibitors (KIs) are in clinical use today. Detailed knowledge about the selectivity of KIs is important for the correct interpretation of their pharmacological and systems biological effects. Chemical proteomic approaches for systematic kinase inhibitor selectivity profiling have emerged as important molecular tools in this regard, but the coverage of the human kinome is still incomplete. Here, we describe a new affinity probe targeting Akt and many other members of the AGC kinase family that considerably extends the scope of KI profiling by chemical proteomics. In combination with the previously published kinobeads, the synthesized probe was applied to selectivity profiling of the Akt inhibitors GSK690693 and GSK2141795 in human cancer cells. The results confirmed the inhibition of all Akt isoforms and of a number of known as well as CDC42BPB as a novel putative target for GSK690693. This work also established, for the first time, the kinase selectivity profile of the clinical phase I drug GSK2141795 and identified PRKG1 as a low nanomolar kinase target as well as the ATP-dependent 5'-3' DNA helicase ERCC2 as a potential new non-kinase off-target. PMID- 23795920 TI - A prospective study of maternal fatty acids, micronutrients and homocysteine and their association with birth outcome. AB - Our earlier studies both in animals and in humans have indicated that micronutrients (folic acid, vitamin B12) and long-chain polyunsaturated fatty acids, especially docosahexaenoic acid (DHA), are interlinked in the one-carbon cycle, which plays an important role in fetal 'programming' of adult diseases. The present study examines the levels of maternal and cord plasma fatty acids, maternal folate, vitamin B12 and homocysteine in healthy mothers at various time points during pregnancy and also examine an association between them. A longitudinal study of 106 normal pregnant women was carried out, and maternal blood was collected at three time points, viz., T1 = 16-20th week, T2 = 26-30th week and T3 = at delivery. Cord blood was collected at delivery. Fatty acids were estimated using a gas chromatograph. Levels of folate, vitamin B12 and homocysteine were estimated by the chemiluminescent microparticle immunoassay (CMIA) technology. Maternal plasma folate (P < 0.05), vitamin B12 (P < 0.01) and DHA (P < 0.05) levels were lowest, while maternal homocysteine levels were highest (P < 0.01) at T3. There was a negative association between maternal DHA and homocysteine at T2 (P < 0.05) and T3 (P < 0.01). There was a positive association between plasma DHA in maternal blood at T3 and cord blood. Furthermore, there was a positive association between maternal folate and vitamin B12 at T3 and baby weight, whereas maternal homocysteine at T1 were inversely associated with baby weight at delivery. Our study provides evidence for the associations of folic acid, vitamin B12, homocysteine with DHA and baby weight, suggesting that a balanced dietary supplementation of folate-vitamin B12-DHA during pregnancy may be beneficial. PMID- 23795921 TI - Discovery fit-for-purpose ligand-binding PK assays: what's really important? PMID- 23795922 TI - Antibody-drug conjugate drug development: where are the challenges? PMID- 23795923 TI - Acquisition of diagnostic tracers to enhance understanding of tau protein in Alzheimer's disease. PMID- 23795924 TI - Interview with Leroy Hood. AB - Leroy Hood has an MD from Johns Hopkins and a PhD from Caltech. He was a professor at Caltech for 22 years, at the University of Washington for 8 years, and has been President and co-founder of the Institute for Systems Biology for the past 13 years. His interests include technology development, molecular immunology, genomics, systems biology, cancer and neurodegeneration. He has published more than 700 papers, has 36 patents and has been involved in the start up of 13 different companies. He has won numerous awards including the Lasker Award (1987), the Kyoto Prize (2002), the Russ Prize (2011) and, most recently, the Medal of Science (2011). He is a member of the National Academy of Sciences, the National Academy of Engineer and the Institute of Medicine. He is currently focused on taking a systems approach to disease. Here he talks to Lisa Parks, Assistant Commissioning Editor of Bioanalysis. PMID- 23795925 TI - Bioanalysis Young Investigator Award 2013. PMID- 23795926 TI - Bioanalytical implementation of plasma capillary microsampling: small hurdles, large gains. PMID- 23795927 TI - Severe impact of hemolysis on stability of phenolic compounds. AB - Eugenie-Raphaelle Berube has obtained a Bachelor of Science in Biochemistry from Universite du Quebec a Montreal. She previously worked at the St-Lawrence Center of Environment, Canada, conducting biomarker analysis to measure the impact of contaminants on aquatic species. She has been working in the bioanalysis industry for the past 8 years at Algorithme Pharma, a CRO located in Laval, Canada, becoming a scientist in bioanalytical method development for the quantitation of pharmaceuticals in biological fluids. The presence of hemolyzed plasma samples can negatively impact preclinical and clinical sample analysis. During the method development of morphine, post-extracted instability issues were encountered in human hemolyzed plasma when compared with nonhemolyzed plasma (called normal plasma for simplicity). Investigation revealed that the presence of methemoglobin using a high pH reconstitution solution led to degradation of morphine over time. The degradation probably results from radical oxidation of the ionized phenolic group promoted by the presence of methemoglobin. Pseudomorphine, the product of oxidative dimerization of morphine, was observed as one of the degradation products in hemolyzed plasma. This hypothesis was extended to raloxifene, another phenol-containing compound. On the other hand, no instability was detected for drug products bearing a masked phenol group or carboxylic acid functionality. The issue of morphine instability was resolved by using a reconstitution solution at a pH below the pKa of the phenol moiety. PMID- 23795928 TI - Determination of artemether and dihydroartemisinin in human plasma with a new hydrogen peroxide stabilization method. AB - BACKGROUND: Numerous methods have been reported for the determination of artemether (ARM) and its metabolite dihydroartemisinin (DHA) in plasma. However, stability issues in patient plasma have not received enough attention. RESULTS: An LC-MS/MS method for simultaneous determination of ARM and DHA in human plasma (K3EDTA) turned out to be problematic: ARM and DHA were degraded partially or completely in some patient plasma samples as indicated by the stable isotope labeled internal standards. We postulated iron II (Fe(2+)) in hemoglobin or its derived products from malaria patients causes degradation of the drugs, and found that hydrogen peroxide (H2O2) protected the drugs from degradation. Acidifying plasma increased recovery of ARM significantly. Using only 50 ul of plasma sample, the method has a LLOQ at 0.5 ng/ml for both ARM and DHA. CONCLUSION: H2O2 is a stabilizing agent for artemisinin derivatives. The modified method is reliable and sensitive. PMID- 23795929 TI - Stability of metabolites in dried blood spots stored at different temperatures over a 2-year period. AB - BACKGROUND: Quantitative LC-ESI-MS/MS, developed from newborn screening, is increasingly used for targeted metabolite profiling. Dried blood spots (DBS) provide easily obtainable biological samples but long-term stability data are sparse. DBS were stored at ambient temperature (room temperature [RT]; 21 degrees C), -20 and -80 degrees C. Metabolites were analyzed at 12 time points (0-104 weeks) by LC-ESI-MS/MS, using fully quantitative stable isotope dilution. RESULTS: Principal component analysis showed alterations in metabolite stability at different temperatures, with major changes only at RT. Univariate analysis for individual analytes demonstrated increases or reductions in concentration. CONCLUSION: Significant changes are observed in certain DBS metabolites at RT, which are attenuated or not present when frozen. These data will help to inform the design, analysis and interpretation of future DBS studies. PMID- 23795930 TI - Online spectral library for GC-atmospheric pressure chemical ionization-ToF MS. AB - BACKGROUND: Invented more than three decades ago by Horning, GC-MS under atmospheric pressure chemical ionization (GC-APCI-MS) has only recently emerged from years of obscurity. However, the general acceptance of GC-APCI-MS is certainly constrained by the lack of spectral libraries, which make the traditional GC-MS approaches so powerful. RESULTS: Here we present a concept of a GC-APCI-QqToF spectral library. The library is web-based, fully searchable and at moment includes spectra of 150 compounds from the most common chemical families. The fragmentation pattern of some chemical families is explained and a protocol for de novo identification has been provided in order to facilitate the identification of unknown compounds. CONCLUSION: A library for GC-APCI-QqToF is now publicly available online. PMID- 23795931 TI - Determination of fatty acid methyl esters by GC-triple quadrupole MS using electron and chemical ionization. AB - BACKGROUND: The main objective of this study was to explore the potential use of electron ionization (EI) and chemical ionization (CI) techniques in fatty acid measurement. MS/MS, together with main fragment ions in EI and positive CI of 37 fatty acid methyl esters (FAMEs), were investigated using a triple quadrupole mass spectrometer. RESULTS: Our results demonstrated that several diagnostic ions of FAMEs could be confirmed using EI. On the other hand, the characteristic fragmentation patterns and probable pathway of FAMEs could be deduced from the collision-induced dissociation mass spectra when using positive CI. Owing to its capability in using the specific ions of fatty acids for selected ion monitoring and SRM, CI is considered to be more suitable for fatty acid quantitative analysis. Based on these features, a systematic strategy was then developed to integrate these fragments for GC-MS/MS for the determination of fatty acids. CONCLUSION: This approach offers a rapid and accurate method for measuring a wide spectrum of fatty acids. PMID- 23795932 TI - A method for sensitive staining of DNA in polyacrylamide gels using basic fuchsin. AB - BACKGROUND: PAGE is a widely used analytical method to resolve components of a DNA mixture based on their size. Various DNA visualization methods including fluorescence, visible dye and silver have been used for the detection of gel separated DNA, with each having different advantages and disadvantages in terms of sensitivity, safety and simplicity. RESULTS: A fast and sensitive visible dye based staining method for DNA in polyacrylamide gels using basic fuchsin (BF) is described. As low as 10-20 pg of DNA can be visualized within 10 min; the sensitivity is fourfold more sensitive than that of SYBR(r) Gold stain, the most sensitive commercial fluorescent probe, but similar to silver staining kit from GE Healthcare. In addition, the mechanism studies suggest that the interaction of BF with DNA is mainly contributed by non-intercalative binding mode. CONCLUSION: By comprehensive studies of this visible dye-based protocol, we concluded that BF stain is a fast and sensitive method currently available for detecting DNA in polyacrylamide gels. PMID- 23795933 TI - Oral fluid for the detection of drugs of abuse using immunoassay and LC-MS/MS. AB - The utility of oral fluid as a sample matrix for the analysis of drugs has been increasing in popularity over the last few years. This is largely because of collection advantages over other matrices, but also due to the rapid improvements in analytical assays including highly sensitive liquid reagent format enzyme immunoassays and LC-MS/MS. This review will highlight improvements in assay formats, sensitivity, laboratory equipment and sample processing using low sample volumes to expand drug test profiles. PMID- 23795934 TI - Controlling sources of preanalytical variability in doping samples: challenges and solutions. AB - The use of illicit substances and methods contravenes the ethics of sports and may be associated with side effects. Antidoping testing is an essential tool for preventing or limiting the consequences of cheating in sports. As for conventional laboratory testing, major emphasis has been placed on analytical quality, overlooking the inherent risks that may arise from analysis of unsuitable doping samples. The adherence to scrupulous criteria for collection, handling, transportation and storage of samples, especially blood and urine samples, is essential. The leading preanalytical variables that influence doping sample quality include biological variability, sample collection, venous stasis, spurious hemolysis and presence of other interfering substances, sample manipulation and degradation, and inappropriate conditions for transportation and storage. This article provides a personal overview about the current challenges in preanalytical management of doping samples, as well as potential solutions for preventing the negative impact of preanalytical variables on sample quality and test results. PMID- 23795935 TI - Salting-out assisted liquid-liquid extraction for bioanalysis. AB - Salting-out assisted liquid-liquid extraction (SALLE) applies the salting-out effect to separate water-miscible organic solvent such as acetonitrile from plasma or other aqueous biofluids, and can extract a wide range of drug and metabolites, including many hydrophilic compounds. In most cases, the separated organic phase can be directly injected for bioanalysis, or with a simple dilution. SALLE provides similar simplicity to protein precipitation, but cleaner extracts due to a true phase separation. SALLE is also faster, more environmentally friendly and more cost-efficient than conventional liquid-liquid extraction and SPE. Through 96-well automation, SALLE can be easily integrated into the overall high-throughput LC-MS/MS bioanalysis strategy to increase productivity. This article provides a critical overview of the literatures on SALLE and perspectives of the future bioanalytical application of this often overlooked extraction technique. Important parameters impacting SALLE-LC-MS/MS assays are also discussed. PMID- 23795938 TI - Season is associated with Pseudomonas aeruginosa acquisition in young children with cystic fibrosis. AB - Pseudomonas aeruginosa, the principal respiratory pathogen in cystic fibrosis (CF) patients, is ubiquitous in the environment. Initial P. aeruginosa isolates in CF patients are generally environmental in nature. However, little information regarding seasonality of P. aeruginosa acquisition is available. We conducted a retrospective study to evaluate the seasonality of initial P. aeruginosa acquisition in young children with CF in the USA using the Cystic Fibrosis Foundation National Patient Registry from 2003 to 2009. Additionally, we assessed whether seasonal acquisition varied by climate zone. A total of 4123 children met inclusion criteria and 45% (n = 1866) acquired P. aeruginosa during a mean 2.0 years (SD 0.2 years) of follow up. Compared with winter, increased P. aeruginosa acquisition was observed in summer (incidence rate ratio (IRR): 1.22; 95% CI: 1.07-1.40) and autumn (IRR: 1.34; 95% CI: 1.18-1.52), with lower acquisition observed in spring (IRR: 0.81; 95% CI: 0.70-0.94). Seasonal variations in P. aeruginosa acquisition rates in the temperate and continental climate zones were similar to those in the overall cohort. In contrast, no significant seasonal effect was observed in the dry climate zone. In a corresponding analysis, no seasonal difference was observed in the rate of acquisition of Staphylococcus aureus, another common CF respiratory pathogen. These results provide preliminary support that climatic factors may be associated with initial P. aeruginosa acquisition in CF patients. Investigation and identification of specific risk factors, as well as awareness of seasonal variation, could potentially inform clinical recommendations including increased awareness of infection control and prevention strategies. PMID- 23795939 TI - 11beta-HSD1 inhibitors from Walsura cochinchinensis. AB - A search for inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta HSD1) from Walsura cochinchinensis yielded 10 new limonoids, cochinchinoids A-J (1-10), and two new triterpenoids, 3-epimesendanin S (11) and cochinchinoid K (12). Their structures were assigned on the basis of spectroscopic data, with the absolute configurations of 1 and 12 being established by X-ray diffraction analysis. Of these compounds, cochinchinoid K (12) displayed inhibitory activity against mouse 11beta-HSD1 with an IC50 value of 0.82 MUM. PMID- 23795940 TI - Long-term stimulation of areca nut components results in increased chemoresistance through elevated autophagic activity. AB - BACKGROUND: We previously demonstrated the autophagy-inducing activity in the crude extract of areca nut (ANE) and its 30-100 kDa fraction (ANE 30-100 K). This study aimed to analyze whether chronic ANE and ANE 30-100 K stimulations lead to higher stress resistance and autophagic activity in oral cells, and whether the resulting autophagic status in stimulated cells correlates with stress resistance. MATERIALS AND METHODS: Malignant cells from the mouth oral epidermoid carcinoma Meng-1 (OECM-1) and blood (Jurkat T) origins were stimulated with non cytotoxic ANE and ANE 30-100 K for 3 months. Sensitivity to anticancer drugs of and autophagy status in stimulated cells, analyzed respectively by XTT assay and calculating microtubule-associated protein 1 light chain 3-II LC3-II/beta-actin ratios from Western blot, were compared to non-treated cells. Autophagy inhibitors, 3-methyladenine (3-MA) and chloroquine (CQ), were used to assess whether autophagy inhibition interferes the altered chemoresistance. RESULTS: Areca nut extract-stimulated (ANE-s) and ANE 30-100 K-stimulated (30-100 K-s) OECM-1 and Jurkat T cells generally exhibited higher cisplatin and 5-fluorouracil (5-FU) resistances, compared to non-stimulated cells. Most stimulated cells expressed significantly higher levels of LC3-II and Atg4B proteins. Interestingly, these cells also showed stronger tolerances against hypoxia environment and expressed higher LC3-II levels under glucose-deprived and hypoxia conditions. Finally, both 3-MA and CQ alleviated, albeit to different degrees, the increased chemoresistance in ANE-s and/or 30-100 K-s cells. CONCLUSIONS: Chronic stimulations of ANE or ANE 30-100 K may increase tolerance of oral cancer and leukemia T cells to anticancer drugs, as well as to glucose deprivation and hypoxia conditions, and cause an elevation of autophagy activity responsible for increased drug resistance. PMID- 23795942 TI - Identification and characterization of functional centromeres of the common bean. AB - In higher eukaryotes, centromeres are typically composed of megabase-sized arrays of satellite repeats that evolve rapidly and homogenize within a species' genome. Despite the importance of centromeres, our knowledge is limited to a few model species. We conducted a comprehensive analysis of common bean (Phaseolus vulgaris) centromeric satellite DNA using genomic data, fluorescence in situ hybridization (FISH), immunofluorescence and chromatin immunoprecipitation (ChIP). Two unrelated centromere-specific satellite repeats, CentPv1 and CentPv2, and the common bean centromere-specific histone H3 (PvCENH3) were identified. FISH showed that CentPv1 and CentPv2 are predominantly located at subsets of eight and three centromeres, respectively. Immunofluorescence- and ChIP-based assays demonstrated the functional significance of CentPv1 and CentPv2 at centromeres. Genomic analysis revealed several interesting features of CentPv1 and CentPv2: (i) CentPv1 is organized into an higher-order repeat structure, named Nazca, of 528 bp, whereas CentPv2 is composed of tandemly organized monomers; (ii) CentPv1 and CentPv2 have undergone chromosome-specific homogenization; and (iii) CentPv1 and CentPv2 are not likely to be commingled in the genome. These findings suggest that two distinct sets of centromere sequences have evolved independently within the common bean genome, and provide insight into centromere satellite evolution. PMID- 23795941 TI - IFN-gamma stimulated human umbilical-tissue-derived cells potently suppress NK activation and resist NK-mediated cytotoxicity in vitro. AB - Umbilical cord tissue represents a unique source of cells with potential for cell therapy applications for multiple diseases. Human umbilical tissue-derived cells (hUTC) are a developmentally early stage, homogenous population of cells that are HLA-ABC dim, HLA-DR negative, and lack expression of co-stimulatory molecules in the unactivated state. The lack of HLA-DR and co-stimulatory molecule expression on unactivated hUTC may account for their reduced immunogenicity, facilitating their use in allogeneic settings. However, such approaches could be confounded by host innate cells such as natural killer (NK) cells. Here, we evaluate in vitro NK cell interactions with hUTC and compare them with human mesenchymal stem cells (MSC). Our investigations show that hUTC suppress NK activation, through prostaglandin-E2 secretion in a contact-independent manner. Prestimulation of hUTC or human MSC with interferon gamma (IFN-gamma) induced expression of the tryptophan degrading enzyme indoleamine 2, 3 dioxygenase, facilitating enhanced suppression. However, resting NK cells of different killer immunoglobulin-like receptor haplotypes did not kill hUTC or MSC; only activated NK cells had the ability to kill nonstimulated hUTC and, to a lesser extent, MSC. The cell killing process involved signaling through the NKG2D receptor and the perforin/granzyme pathway; this was supported by CD54 (ICAM-1) expression by hUTC. IFN-gamma stimulated hUTC or hMSC were less susceptible to NK killing; in this case, protection was associated with elevated HLA-ABC expression. These data delineate the different mechanisms in a two-way interaction between NK cells and two distinct cell therapies, hUTC or hMSC, and how these interactions may influence their clinical applications. PMID- 23795943 TI - Do differentials in the support and advice available at UK schools and colleges influence candidate performance in the medical school admissions interview? A survey of direct school leaver applicants to a UK medical school. AB - BACKGROUND: To our knowledge, nothing is known about whether differentials in support and advice during preparation for the interview influence candidate performance and thereby contribute to bias in selection for medical school. AIM: To assess if differences in advice and support with preparation for the medical school admissions interview given type of school last attended influence interview score achieved by direct school leaver applicants to study on an undergraduate UK medical degree course. METHODS: Confidential self-completed on line questionnaire survey. RESULTS: Interview performance was positively related to whether a teacher, tutor or career advisors at the School or College last attended had advised a respondent to prepare for the interview, had advised about the various styles of medical interview used and the types of questions asked, and what resources were available to help in preparation. Respondents from Private/Independent schools were more likely than those from State schools to have received such advice and support. CONCLUSIONS: Differentials in access to advice on and support with preparation for the medical school interview may advantage some candidates over others. This inequity would likely be ameliorated by the provision of an authoritative and comprehensive guide to applying to medical school outlining admission requirements and the preparation strategy applicants should use in order to best meet those requirements. The guide could be disseminated to the Principals of all UK schools and colleges and freely available electronic versions signposted in medical school prospectuses and the course descriptor on the Universities and Colleges Admissions Service. PMID- 23795944 TI - An immunofluorescence assay for the detection of wheat rust species using monoclonal antibody against urediniospores of Puccinia triticina. AB - AIMS: Wheat (Triticum aestivum) is one of the most important crop species, but yields are often drastically reduced by rust epidemics. In this report, we describe a rapid and sensitive immunofluorescence method for the detection of urediniospores of the fungi Puccinia striiformis f. sp. tritici, Puccinia triticina and Puccinia graminis f. sp. tritici, which are causal agents of wheat rust. METHODS AND RESULTS: The method uses monoclonal antibody LPT-2 against the urediniospores of P. triticina and PE-cy3 goat anti-mouse. Urediniospores of P. triticina or those of two species that are difficult to distinguish from P. triticina, P. striiformis f. sp. tritici or P. graminis f. sp. tritici were immobilized on a glass slide, and the sample was then treated with LPT-2. Thereafter, a second antibody, goat anti-mouse conjugated PE-cy3, was added, and the slide was observed in a fluoroscope. The fluorescent signal was strong with P. triticina urediniospores, weak with P. striiformis f. sp. tritici urediniospores and weak-to-intermediate with P. graminis f. sp. tritici urediniospores. The detection limit of this method was 2 ng ml(-1) of the monoclonal antibody LPT-2. CONCLUSIONS: In this article, we describe the production and diagnostic application of a novel mouse monoclonal antibody specific to urediniospores of P. triticina. SIGNIFICANCE AND IMPACT OF THE STUDY: After further technical development, this method may become a tool for on-site identification of P. triticina urediniospores and will therefore help in the selection and timing of fungicide applications for control of wheat rust outbreaks. PMID- 23795945 TI - HIV protease inhibitors induce senescence and alter osteoblastic potential of human bone marrow mesenchymal stem cells: beneficial effect of pravastatin. AB - HIV-infected patients receiving antiretroviral therapy present an increased prevalence of age-related comorbidities, including osteoporosis. HIV protease inhibitors (PIs) have been suspected to participate to bone loss, but the mechanisms involved are unknown. In endothelial cells, some PIs have been shown to induce the accumulation of farnesylated prelamin-A, a biomarker of cell aging leading to cell senescence. Herein, we hypothesized that these PIs could induce premature aging of osteoblast precursors, human bone marrow mesenchymal stem cells (MSCs), and affect their capacity to differentiate into osteoblasts. Senescence was studied in proliferating human MSCs after a 30-day exposure to atazanavir and lopinavir with or without ritonavir. When compared to untreated cells, PI-treated MSCs had a reduced proliferative capacity that worsened with increasing passages. PI treatment led to increased oxidative stress and expression of senescence markers, including prelamin-A. Pravastatin, which blocks prelamin-A farnesylation, prevented PI-induced senescence and oxidative stress, while treatment with antioxidants partly reversed these effects. Moreover, senescent MSCs presented a decreased osteoblastic potential, which was restored by pravastatin treatment. Because age-related bone loss is associated with increased bone marrow fat, we also evaluated the capacity of PI-treated MSCs to differentiate into adipocyte. We observed an altered adipocyte differentiation in PI-treated MSCs that was reverted by pravastatin. We have shown that some PIs alter osteoblast formation by affecting their differentiation potential in association with altered senescence in MSCs, with a beneficial effect of statin. These data corroborate the clinical observations and allow new insight into pathophysiological mechanisms of PI-induced bone loss in HIV-infected patients. PMID- 23795946 TI - MYC status determination in aggressive B-cell lymphoma: the impact of FISH probe selection. AB - AIMS: To assess how hybridization probe design may affect MYC status determination in Burkitt lymphoma and diffuse large B-cell lymphoma. METHODS AND RESULTS: We compared the results obtained with one dual-fusion and two break apart commercial probes in a retrospective series of 91 aggressive B-cell lymphomas. All three probes were able to detect the IGH-MYC translocation in every case bearing it (13/13). However, seven of 13 (54%) non-IGH-MYC (light chain immunoglobulin or non-immunoglobulin-MYC) rearrangements were unambiguously detected by just one of the probes tested. On the other hand, when the IGH-MYC dual-fusion probe was used, nine of 15 (60%) cases with a hybridization pattern suggestive of a non-IGH-MYC translocation were attributable to MYC copy gain rather than MYC rearrangement, as demonstrated by both break-apart probes. CONCLUSIONS: Taking into account the prognostic and therapeutic implications of the MYC translocation, probe design and limitations should be particularly kept in mind when MYC hybridization patterns are interpreted. In our experience, detection of 8q24 abnormalities could be optimized by a two-probe approach involving the application of both IGH-MYC dual-fusion and MYC break-apart selected kits. PMID- 23795947 TI - Demographic and work-related correlates of job burnout in professional eating disorder treatment providers. AB - Patients with eating disorders present unique challenges to treatment providers that may contribute to job burnout. This study examined demographic and work related correlates of three primary components of burnout (i.e., emotional exhaustion, cynicism, and lack of personal accomplishment) in a sample of 296 professional eating disorder treatment providers. Participants completed the Maslach Burnout Inventory-Human Services Survey (MBI-HSS; Maslach, Jackson, & Leiter, 1996), demographics, and a questionnaire developed by the authors measuring eating disorder-specific factors theorized to be relevant to burnout. Overall, participants reported comparable levels of emotional exhaustion but significantly less cynicism and lack of personal accomplishment relative to established norms for mental health care providers on the MBI-HSS. Analyses of variance and backward regression analyses suggested that higher levels of burnout were associated with being younger, female, and overweight; working longer hours; having less experience; and experiencing a patient's death. Conversely, working in a private practice setting, having children, and having a personal history of an eating disorder were associated with lower burnout levels. Furthermore, over 45% of participants reported that treatment resistance, ego-syntonicity, high relapse rates, worry about patient survival, emotional drain, lack of appropriate financial reimbursement, and extra hours spent working contributed to feelings burned out somewhat to very much. Overall, these data suggest that emotional exhaustion is the most common aspect of burnout experienced by eating disorder treatment providers and highlight some of the key correlates of burnout for this population, which can be used to inform prevention and intervention efforts. PMID- 23795949 TI - Carer and staff perspectives on supplementary suckling for treating infant malnutrition: qualitative findings from Malawi. AB - Severe acute malnutrition (SAM) in infants aged <6 months is a major global health problem. Supplementary suckling (SS) is widely recommended as an inpatient treatment technique for infant <6 months SAM. Its aim is to re-establish effective exclusive breastfeeding. Despite widespread support in guidelines, research suggests that field use of SS is limited in many settings. In this study, we aimed therefore to describe and understand the barriers and facilitating factors to SS as a treatment technique for infant SAM. We conducted qualitative interviews and focus group discussions in a hospital setting in Blantyre, Malawi, with ward staff and caregivers of infants <2 years. We created a conceptual framework based on five major themes identified from the data: (1) motivation; (2) breastfeeding views; (3) practicalities; (4) understanding; and (5) perceptions of hospital-based medicine. Within each major theme, more setting specific subthemes can also be developed. Other health facilities considering SS roll-out could consider their own barriers and facilitators using our framework; this will facilitate the implementation of SS, improve staff confidence and therefore give SS a better chance of success. Used to shape and guide discussions and inform action plans for implementing SS, the framework has the potential to facilitate SS roll-out in settings other than Malawi, where this study was conducted. We hope that it will help pave the way to more widespread SS, more research into its use and effectiveness, and a stronger evidence-base on malnutrition in infants aged <6 months. PMID- 23795948 TI - Fabrication, characterization, and functionalization of dual carbon electrodes as probes for scanning electrochemical microscopy (SECM). AB - Dual carbon electrodes (DCEs) are quickly, easily, and cheaply fabricated by depositing pyrolytic carbon into a quartz theta nanopipet. The size of DCEs can be controlled by adjusting the pulling parameters used to make the nanopipet. When operated in generation/collection (G/C) mode, the small separation between the electrodes leads to reasonable collection efficiencies of ca. 30%. A three dimensional finite element method (FEM) simulation is developed to predict the current response of these electrodes as a means of estimating the probe geometry. Voltammetric measurements at individual electrodes combined with generation/collection measurements provide a reasonable guide to the electrode size. DCEs are employed in a scanning electrochemical microscopy (SECM) configuration, and their use for both approach curves and imaging is considered. G/C approach curve measurements are shown to be particularly sensitive to the nature of the substrate, with insulating surfaces leading to enhanced collection efficiencies, whereas conducting surfaces lead to a decrease of collection efficiency. As a proof-of-concept, DCEs are further used to locally generate an artificial electron acceptor and to follow the flux of this species and its reduced form during photosynthesis at isolated thylakoid membranes. In addition, 2-dimensional images of a single thylakoid membrane are reported and analyzed to demonstrate the high sensitivity of G/C measurements to localized surface processes. It is finally shown that individual nanometer-size electrodes can be functionalized through the selective deposition of platinum on one of the two electrodes in a DCE while leaving the other one unmodified. This provides an indication of the future versatility of this type of probe for nanoscale measurements and imaging. PMID- 23795950 TI - Openness to Experience: its lower level structure, measurement, and cross cultural equivalence. AB - Openness to Experience is an important but relatively poorly understood personality construct. Advances in openness research require further construct clarification as well as establishment of a common framework for conceptualizing and measuring the lower level structure of the construct. In this article, we present data from 3 studies to address this research need. In Study 1, we identify 6 facets of Openness to Experience--intellectual efficiency, ingenuity, curiosity, aesthetics, tolerance, and depth--based on a factor analysis of 36 existing Openness-related scales. In Study 2, we present further validity evidence for the 6-facet structure based on a newly developed measure of Openness. Data from this study also suggest the presence of 2 intermediate-level factors (i.e., aspects) of Openness: intellect and culture. In Study 3, we present a short form of the newly developed measure, retaining items that showed the highest internal consistency and measurement invariance across 3 samples: U.S. undergraduates, Chinese MBA students, and Chinese undergraduates. Together these 3 studies offer a more nuanced understanding of the multifaceted nature of the Openness construct. PMID- 23795951 TI - Necrotizing soft tissue infections caused by Streptococcus pyogenes and Streptococcus dysgalactiae subsp. equisimilis of groups C and G in western Norway. AB - Streptococcus pyogenes (group A streptococcus, GAS) is a major cause of necrotizing soft tissue infection (NSTI). On rare occasions, other beta haemolytic streptococci may also cause NSTI, but the significance and nature of these infections has not been thoroughly investigated. In this study, clinical and molecular characteristics of NSTI caused by GAS and beta-haemolytic Streptococcus dysgalactiae subsp. equisimilis of groups C and G (GCS/GGS) in western Norway during 2000-09 are presented. Clinical data were included retrospectively. The bacterial isolates were subsequently emm typed and screened for the presence of genes encoding streptococcal superantigens. Seventy cases were identified, corresponding to a mean annual incidence rate of 1.4 per 100 000. Sixty-one of the cases were associated with GAS, whereas GCS/GGS accounted for the remaining nine cases. The in-hospital case fatality rates of GAS and GCS/GGS disease were 11% and 33%, respectively. The GCS/GGS patients were older, had comorbidities more often and had anatomically more superficial disease than the GAS patients. High age and toxic shock syndrome were associated with mortality. The Laboratory Risk Indicator for Necrotizing Fasciitis laboratory score showed high values (>=6) in only 31 of 67 cases. Among the available 42 GAS isolates, the most predominant emm types were emm1, emm3 and emm4. The virulence gene profiles were strongly correlated to emm type. The number of superantigen genes was low in the four available GCS/GGS isolates. Our findings indicate a high frequency of streptococcal necrotizing fasciitis in our community. GCS/GGS infections contribute to the disease burden, but differ from GAS cases in frequency and predisposing factors. PMID- 23795952 TI - Malignant melanoma in pigmented skin: does the current interventional model fit a different clinical, histologic, and molecular entity? AB - BACKGROUND: Although the incidence of malignant melanoma in African Americans is considerably lower than in Caucasians, African Americans have a less-favorable prognosis related to later presentation and more deeply invasive lesions at diagnosis. OBJECTIVE: To review the current literature addressing the specific clinical, histopathologic, and molecular features of melanoma in darkly pigmented individuals. METHODS: We reviewed the most up-to-date literature pertaining to melanoma in this patient population, including data from clinical studies, epidemiologic analyses, and molecular and genetic studies. RESULTS: Several studies have suggested differences between lightly and darkly pigmented populations with regard to clinicopathologic character and the underlying genetic processes affecting its pathogenesis. CONCLUSION: Further investigation is warranted to better elucidate the clinical and underlying biological differences in melanoma between Caucasians and African Americans. Such research may help to ameliorate the disparities in melanoma outcomes through improved screening, public health measures aimed at prevention, and potentially novel targeted therapeutic approaches. PMID- 23795954 TI - Gender differences in HIV-related stigma in Kenya. AB - Stigma associated with HIV/AIDS directly and indirectly drives HIV transmission. We examined how factors associated with HIV-related stigma differed by gender, using data from the 2008-2009 Kenya Demographic and Health Survey (KDHS). Descriptive, bivariate and multinomial logistic regression analyses were conducted on selected HIV-related stigma indicators for men and women. Bivariate analyses showed significant gender differences in the overall HIV Stigma index with a higher proportion of women than men presented at the highest stigma level (4.9% vs 2.7%, p < 0.01). Women were more likely to express higher stigmatic attitudes for all components of stigma measured than men. Multivariate analyses showed that HIV-related knowledge had significant inverse dose-response for both men and women. For instance, compared to women in the first HIV-related knowledge quartile, a 1 unit increase in HIV-related knowledge among women at the third HIV related knowledge quartile was expected to lead to a 63.8% decrease in HIV related stigma (95% CI [0.21, 0.63]) for women with high stigma, 57.8% decrease for similar women with medium stigma (95% CI [0.33, 0.55]) and 28.4% decrease for those with low stigma (95% CI [0.57, 0.90]). Acceptance with the statement "a husband is justified to hit or beat his wife if she refuses to have sex with him" was a significant risk factor for expression of stigmatising attitudes at all levels for women (High: OR = 1.49, 95% CI [1.02, 2.17]), Medium: OR = 1.47, 95% CI [1.18, 1.82], Low: OR = 1.38, 95% CI [1.10, 1.73]) and men at medium stigma (OR = 2.02, 95% CI [1.38, 2.95]). Other notable gender differences were found in employment, marital status, ethnicity, region of residence, wealth and media exposure. Our results showed that women in the general Kenyan population had higher stigmatic attitudes than men. This was associated with differences in risk factor profile and confirmed previous literature on complexity of social-cultural factors associated with HIV-related stigma. PMID- 23795953 TI - Multiplex biomarkers in blood. AB - Advances in the field of blood biomarker discovery will help in identifying Alzheimer's disease in its preclinical stage, allowing treatment to be initiated before irreversible damage occurs. This review discusses some recent past and current approaches being taken by researchers in the field. Individual blood biomarkers have been unsuccessful in defining the disease pathology, progression and thus diagnosis. This directs to the need for discovering a multiplex panel of blood biomarkers as a promising approach with high sensitivity and specificity for early diagnosis. However, it is a great challenge to standardize a worldwide blood biomarker panel due to the innate differences in the population tested, nature of the samples and methods utilised in different studies across the globe. We highlight several issues that result in the lack of reproducibility in this field of research currently faced by researchers. Several important measures are summarized towards the end of the review that can be taken to minimize the variability among various centres. PMID- 23795955 TI - Surface zwitterionization of expanded poly(tetrafluoroethylene) membranes via atmospheric plasma-induced polymerization for enhanced skin wound healing. AB - Development of bioinert membranes to prevent blood clotting, tissue adhesion, and bacterial attachment is important for the wound healing process. In this work, two wound-contacting membranes of expanded poly(tetrafluoroethylene) (ePTFE) grafted with zwitterionic poly(sulfobetaine methacrylate) (PSBMA) and hydrophilic poly(ethylene glycol) methacrylate (PEGMA) via atmospheric plasma-induced surface copolymerization were studied. The surface grafting chemical structure, hydrophilicity, and hydration capability of the membranes were determined to illustrate the correlations between bioadhesive properties and wound recovery of PEGylated and zwitterionic ePTFE membranes. Bioadhesive properties of the membranes were evaluated by the plasma protein adsorption, platelet activation, blood cell hemolysis, tissue cell adhesion, and bacterial attachment. It was found that the zwitterionic PSBMA-grafted ePTFE membrane presented high hydration capability and exhibited the best nonbioadhesive character in contact with protein solution, human blood, tissue cells, and bacterial medium. This work shows that zwitterionic membrane dressing provides a moist environment, essential for "deep" skin wound healing observed from the animal rat model in vivo and permits a complete recovery after 14 days, with histology of repaired skin similar to that of normal skin tissue. This work suggests that the bioinert nature of grafted PSBMA polymers obtained by controlling grafting structures gives them great potential in the molecular design of antibioadhesive membranes for use in skin tissue regeneration. PMID- 23795956 TI - The Undergraduate Medical and Health Sciences Admissions Test: what is it measuring? AB - BACKGROUND: The Undergraduate Medical and Health Sciences Admissions Test (UMAT) is used to select medical students in Australia and New Zealand but empirical evidence of its construct validity has never been reported. AIMS: To identify the underlying constructs assessed in each of the three sections of the UMAT. Based on conclusions from an early qualitative study (Mercer & Chiavaroli 2006), it was expected that Section 1 scores would correlate with scores obtained from standard measures of cognitive ability (verbal and numeric reasoning), Section 2 scores would correlate with emotional intelligence, and Section 3 scores would be most strongly related to abstract or non-verbal reasoning ability. METHOD: Final year high school students (n = 432) completed tests of numerical, verbal, and non verbal cognitive ability, and emotional intelligence. Correlations and multiple regressions assessed the relationship of these tests with scores on each section of the UMAT. RESULTS: UMAT Section 1 was significantly related to verbal, non verbal, and numerical reasoning tests. Section 2 was significantly related to emotional intelligence and verbal reasoning, but the majority of variance in this section's scores remained unexplained. Section 3 scores significantly correlated with non-verbal and numerical reasoning. CONCLUSIONS: The UMAT Sections 1 and 3 appear to be tests of cognitive abilities. Further research is required to identify the constructs being measured by Section 2. PMID- 23795957 TI - Statistical regression model of standard and new laboratory markers and its usefulness in prediction of preeclampsia. AB - OBJECTIVE: This study was undertaken to investigate the usefulness of angiogenic markers and standard laboratory parameters measurement after 20th week of pregnancy for the individual prediction of preeclampsia (PE). METHODS: A prospective designed study included 34 patients with PE and a control group of 35 uncomplicated pregnancies. Patients were recruited from 20th until 41st week of pregnancy at the Department of Obstetrics and Gynecology, General Hospital Celje, Slovenia. PlGF (placental growth factor), sFlt-1 (soluble fms-like tyrosine kinase 1), erythrocytes, leukocytes, platelets, hemoglobin, hematocrit, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, alkaline phosphatase, total bilirubin, urea, creatinine, urate, body mass index, body surface area, parity, and age were evaluated to predict the occurrence of PE based on multivariate logistic regression model. RESULTS: When parameters such as PlGF, sFlt-1, and urates were included into logistic regression model, we correctly classified 85% patients. With additional two models which also contained anthropometric parameters, we correctly classified 88% and 91% patients, respectively. CONCLUSION: Our results demonstrated that angiogenic markers and urates individually and particularly when used as laboratory test panel have significant prognostic value in the prediction of PE. PMID- 23795958 TI - Exomethylene-3,4-ethylenedioxythiophene (emEDOT): a new versatile building block for functionalized electropolymerized poly(3,4-ethylenedioxythiophenes) (PEDOTs). AB - A new versatile thiophene derivative exomethylene-3,4-ethylenedioxythiophene (emEDOT) is introduced. The molecule can be straightforwardly prepared in two steps from commercially available derivatives and enables facile further derivatization through both acid catalyzed additions of alcohols and standard thiol-ene click chemistry. The preparation of electrochromic materials and of an electrochemical avidine sensor is shown by the oxidative polymerizations of several functionalized EDOT monomers straightforwardly prepared from emEDOT. PMID- 23795959 TI - Understanding the efficiency of autonomous nano- and microscale motors. AB - We analyze the power conversion efficiency of different classes of autonomous nano- and micromotors. For bimetallic catalytic motors that operate by a self electrophoretic mechanism, there are four stages of energy loss, and together they result in a power conversion efficiency on the order of 10(-9). The results of finite element modeling agree well with experimental measurements of the efficiency of catalytic Pt-Au nanorod motors. Modifications of the composition and shape of bimetallic catalytic motors were predicted computationally and found experimentally to lead to higher efficiency. The efficiencies of bubble-propelled catalytic micromotors, magnetically driven flagellar motors, Janus micromotors driven by self-generated thermal gradients, and ultrasonically driven metallic micromotors are also analyzed and discussed. PMID- 23795960 TI - Analysis of clinical characteristics of 516 patients with non-Hodgkin's lymphoma in Shanghai area. AB - The aim was to determine the clinical and cytogenetic characteristics of non Hodgkin's lymphoma (NHL) in Shanghai. A retrospective analysis was conducted in 516 patients with NHL. Patient clinical data, including age, sex, diagnosis, immunophenotypes, and karyotypes, were collected. The median age was 58 years. There was a male predominance in all NHL, except extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. Patients with B cell NHL (1.5%) expressed CD3. T cell NHL patients (11.5%) expressed CD20. Epstein-Barr virus latent integral membrane protein 1, BCL6, CD10, Bcl-2, CD68, myeloperoxidase, CD99, CD30, CD15, and CD43 were present in various types of NHL. Complex karyotypes accounted for 92.3% of the 73.7% patients with abnormal karyotypes. Immunoglobin heavy chain gene translocation was present in 60.3% of B cell and 23.7% of T/NK cell neoplasms. Understanding the complex clinicopathological and molecular features of NHL may help with prognosis and serve as targets for treatments. PMID- 23795961 TI - Photodissociation of ozone from 321 to 329 nm: the relative yields of O(3P2) with O2(X 3Sigmag(-)), O2(a 1Deltag) and O2(b 1Sigmag(+)). AB - Product imaging of O((3)P2) following dissociation of ozone has been used to determine the relative yields of the product channels O((3)P2) + O2(X (3)Sigmag( )) of ozone. All three channels are prominent at all wavelengths investigated. O2 vibrational distributions for each channel and each wavelength are also estimated assuming Boltzmann rotational distributions. Averaged over wavelength in the measured range, the yields of the O((3)P2) + O2(X (3)Sigmag(-)), O((3)P2) + O2(a (1)Deltag), and O((3)P2) + O2(b (1)Sigmag(+)) channels are 0.36, 0.31,and 0.34, respectively. Photofragment distributions in the spin-allowed channel O((3)P) + O2(X (3)Sigmag(-)) are compared with the results of quantum mechanical calculations on the vibronically coupled PESs of the singlet states B (optically bright) and R (repulsive). The experiments suggest that considerably more vibrational excitation and less rotational excitation occur than predicted by the quantum calculations. The rotational distributions, adjusted to fit the experimental images, suggest that the dissociation takes place from a more linear configuration than the Franck-Condon bending angle of 117 degrees . The dissociation at most wavelengths results in a positive value of the anisotropy parameter, beta, both in the experiment and in the calculations. Calculations indicate that both nonadiabatic transitions and intersystem crossings substantially reduce beta below the nominal value of 2. PMID- 23795963 TI - Conditioned medium from horse amniotic membrane-derived multipotent progenitor cells: immunomodulatory activity in vitro and first clinical application in tendon and ligament injuries in vivo. AB - We have recently demonstrated that heterologous transplantation of horse amniotic membrane-derived mesenchymal cells (AMCs) can be useful for cell therapy applications in tendon diseases, and hypothesized that these cells may promote tendon repair via paracrine-acting molecules targeting inflammatory processes. To test this hypothesis, here we examined the immunomodulatory characteristics of AMCs and of their conditioned medium (AMC-CM) in vitro, and studied the potential therapeutic effect of AMC-CM in thirteen different spontaneous horse tendon and ligament injuries in vivo. Our results demonstrate that AMCs are capable of inhibiting peripheral blood mononuclear cell (PBMC) proliferation after allogenic stimulation either when cocultured in cell-to-cell contact, or when the two cell types are physically separated by a transwell membrane, suggesting that soluble factors are implicated in this phenomenon. Our hypothesis is further supported by the demonstration that PBMC proliferation is inhibited by AMC-CM. In our in vivo studies, no significant adverse effects were observed in treated tendons, and clinical and ultrasonographical evaluation did not reveal evidence of inappropriate tissue or tumor formation. Clinical outcomes were favorable and the significantly lower rate (15.38%) of reinjuries observed compared to untreated animals, suggests that treatment with AMC-CM is very efficacious. In conclusion, this study identifies AMC-CM as a novel therapeutic biological cell-free product for treating horse tendon and ligament diseases. PMID- 23795962 TI - Reduced mammalian target of rapamycin activity facilitates mitochondrial retrograde signaling and increases life span in normal human fibroblasts. AB - Coordinated expression of mitochondrial and nuclear genes is required to maintain proper mitochondrial function. However, the precise mechanisms that ensure this coordination are not well defined. We find that signaling from mitochondria to the nucleus is influenced by mammalian target of rapamycin (mTOR) activity via changes in autophagy and p62/SQSTM1 turnover. Reducing mTOR activity increases autophagic flux, enhances mitochondrial membrane potential, reduces reactive oxygen species within the cell, and increases replicative life span. These effects appear to be mediated in part by an interaction between p62/SQSTM1 and Keap1. This interaction allows nuclear accumulation of the nuclear factor erythroid 2-like 2 (NFE2L2, also known as nuclear factor related factor 2 or NRF2), increased expression of the nuclear respiratory factor 1 (NRF1), and increased expression of nuclear-encoded mitochondrial genes, such as the mitochondrial transcription factor A, and mitochondrial-encoded genes involved in oxidative phosphorylation. These findings reveal a portion of the intracellular signaling network that couples mitochondrial turnover with mitochondrial renewal to maintain homeostasis within the cell and suggest mechanisms whereby a reduction in mTOR activity may enhance longevity. PMID- 23795964 TI - Chelation therapy: overlooked in the treatment and prevention of diabetes complications? PMID- 23795965 TI - Anticancer drugs deliver themselves to cancer cells. PMID- 23795966 TI - Interview with Frank Ivy Carroll. AB - Frank Ivy Carroll received his BS degree in chemistry from Auburn University (AL, USA) in 1957 and was awarded the PhD in chemistry by the University of North Carolina at Chapel Hill (NC, USA) in 1961. He joined the research staff of the Research Triangle Institute (NC, USA) as a Research Chemist and rose steadily to the position of Vice President of the Chemistry and Life Sciences Group, a position he held from 1996-2001. Dr Carroll also served as Director of the Center for Organic and Medicinal Chemistry from 1975-2007. He is presently Distinguished Fellow for Medicinal Chemistry. Dr Carroll has varied research interests, but since 1990, a major thrust of his research efforts has involved development of pharmacotherapies for substance abuse (cocaine, nicotine, methamphetamine, opioids and ethanol) and other CNS disorders. Dr Carroll has published 468 peer reviewed articles, 33 book chapters and 46 patents and has received numerous awards for his research accomplishments; the most recent are: the 2010 North Carolina Award for Science; the 2010 National Institute on Drug Abuse Public Service Award for Significant Achievement; and the 2012 Alfred Burger Award in Medicinal Chemistry from the American Chemical Society. In 2007, he was inducted into the American Chemical Society Medicinal Chemistry Hall of Fame. Interview conducted by Hannah Coaker, Assistant Commissioning Editor. PMID- 23795968 TI - Androgen receptor modulators: a marriage of chemistry and biology. AB - Androgenic steroids are important for male development in utero and secondary sexual characteristics at puberty. In addition, androgens play a role in non reproductive tissues, such as bone and muscle in both sexes. The actions of the androgens testosterone and dihydrotestosterone are mediated by a single receptor protein, the androgen receptor. Over the last 60-70 years there has been considerable research interest in the development of inhibitors of androgen receptor for the management of diseases such as prostate cancer. However, more recently, there is also a growing appreciation of the need for selective androgen modulators that would demonstrate tissue-selective agonist or antagonist activity. The chemistry and biology of selective agonists, antagonists and selective androgen receptor modulators will be discussed in this review. PMID- 23795969 TI - Protein crystallography and fragment-based drug design. AB - Crystallography is a major tool for structure-driven drug design, as it allows knowledge of the 3D structure of protein targets and protein-ligand complexes. However, the route for crystal structure determination involves many steps, some of which may hamper its high-throughput use. Recent efforts have produced significant advances in experimental and computational tools and protocols. They include automatic crystallization tools, faster data collection devices, more efficient phasing methods and improved ligand-fitting procedures. The timescales of drug-discovery processes have been also reduced by using a fragment-based screening approach. Herein, the achievements in protein crystallography over the last 5 years are reviewed, and advantages and disadvantages of the fragment-based approaches to drug discovery that make use of x-ray crystallography as a primary screening method are examined. In particular, in some detail, five recent case studies pertaining to the development of new hits or leads in relevant therapeutic areas, such as cancer, immune response, inflammation, metabolic syndrome and neurology are described. PMID- 23795970 TI - Potential therapeutic applications of RNA cap analogs. AB - Cap analogs are chemically modified derivatives of the unique cap structure present at the 5' end of all eukaryotic mRNAs and several non-coding RNAs. Until recently, cap analogs have served primarily as tools in the study of RNA metabolism. Continuing advances in our understanding of cap biological functions (including RNA stabilization, pre-mRNA splicing, initiation of mRNA translation, as well as cellular transport of mRNAs and snRNAs) and the consequences of the disruption of these processes - resulting in serious medical disorders - have opened new possibilities for pharmaceutical applications of these compounds. In this review, the medicinal potential of cap analogs in areas, such as cancer treatment (including eIF4E targeting and mRNA-based immunotherapy), spinal muscular atrophy treatment, antiviral therapy and the improvement of the localization of nucleus-targeting drugs, are highlighted. Advances achieved to date, challenges, plausible solutions and prospects for the future development of cap analog-based drug design are described. PMID- 23795967 TI - IL-1beta, RAGE and FABP4: targeting the dynamic trio in metabolic inflammation and related pathologies. AB - Within the past decade, inflammatory and lipid mediators, such as IL-1beta, FABP4 and RAGE, have emerged as important contributors to metabolic dysfunction. As growing experimental and clinical evidence continues to tie obesity-induced chronic inflammation with dysregulated lipid, insulin signaling and related pathologies, IL-1beta, FABP4 and RAGE each are being independently implicated as culprits in these events. There are also convincing data that molecular pathways driven by these molecules are interconnected in exacerbating metabolic consequences of obesity. This article highlights the roles of IL-1beta, FABP4 and RAGE in normal physiology as well as focusing specifically on their contribution to inflammation, insulin resistance, atherosclerosis, Type 2 diabetes and cancer. Studies implicating the interconnection between these pathways, current and emerging therapeutics, and their use as potential biomarkers are also discussed. Evidence of impact of IL-1beta, FABP4 and RAGE pathways on severity of metabolic dysfunction underlines the strong links between inflammatory events, lipid metabolism and insulin regulation, and offers new intriguing approaches for future therapies of obesity-driven pathologies. PMID- 23795972 TI - Ustilago maydis reprograms cell proliferation in maize anthers. AB - The basidiomycete Ustilago maydis is a ubiquitous pathogen of maize (Zea mays), one of the world's most important cereal crops. Infection by this smut fungus triggers tumor formation in aerial plant parts within which the fungus sporulates. Using confocal microscopy to track U. maydis infection on corn anthers for 7 days post-injection, we found that U. maydis is located on the epidermis during the first 2 days, and has reached all anther lobe cell types by 3 days post-injection. Fungal infection alters cell-fate specification events, cell division patterns, host cell expansion and host cell senescence, depending on the developmental stage and cell type. Fungal effects on tassel and plant growth were also quantified. Transcriptome profiling using a dual organism microarray identified thousands of anther genes affected by fungal infection at 3 days post-injection during the cell-fate specification and rapid cell proliferation phases of anther development. In total, 4147 (17%) of anther expressed genes were altered by infection, 2018 fungal genes were expressed in anthers, and 206 fungal secretome genes may be anther-specific. The results confirm that U. maydis deploys distinct genes to cause disease in specific maize organs, and suggest mechanisms by which the host plant is manipulated to generate a tumor. PMID- 23795973 TI - Impact of immediate loading on early soft tissue healing at two-piece implants placed in fresh extraction sockets: an experimental study in the beagle dog. AB - OBJECTIVES: To study early soft tissue healing of immediately placed implants with or without immediate loading in the dog. MATERIAL AND METHODS: Forty-eight implants were placed in the distal sockets of Pm3 and Pm4 in the lower jaw of 12 beagle dogs immediately after tooth extraction. In the control group, no loading was applied. In the test group, an immediate loading restoration with occlusal contacts was performed. Dogs were sacrificed at 2, 4, and 8 weeks for histological analysis. RESULTS: At the end of the study, there was a 100% implant and prosthesis survival. The biological width dimension was similar in both groups at all the studied healing periods. This dimension tended to decrease from week 2 to 8 in both groups, on both the buccal and lingual side. The barrier epithelium tended to stop at the implant-abutment interface in both groups and also decreased in length from week 2 to 8, on the buccal and the lingual side. Soft tissue recession remained low and occurred mainly in the test group. CONCLUSIONS: The characteristics, dimension, and healing pattern of the peri implant soft tissues were similar around immediate implants with or without immediate loading. PMID- 23795974 TI - Enhanced pathogenicity of biofilm-negative Staphylococcus epidermidis isolated from platelet preparations. AB - BACKGROUND: The platelet (PLT) storage environment triggers the formation of surface-attached aggregates known as biofilms by the common PLT contaminant Staphylococcus epidermidis. The biofilm matrix is largely composed of polysaccharide intercellular adhesin (PIA) mediated by the icaADBC operon. However, PIA-negative S. epidermidis has been reported to form biofilms in PLT concentrates (PCs). Since biofilm formation is associated with increased virulence, this study was aimed at determining if PIA-negative S. epidermidis grown in PCs presents enhanced virulence using the nematode Caenorhabditis elegans as a host model for bacterial pathogenesis. STUDY DESIGN AND METHODS: Biofilm-positive S. epidermidis ATCC 35984 and 9142, which carry the icaADBC operon, and biofilm-negative S. epidermidis ATCC 12228 and 9142 DeltaicaA were grown in regular media and in PCs and biofilm formation was quantified using a crystal violet assay. The virulence of these strains after passage through PCs was tested using nematode killing assays. Nematode survival was calculated using the Kaplan-Meier method and statistical differences were determined by log-rank analysis. RESULTS: All S. epidermidis strains were able to form biofilms in PCs. Although persistence of a biofilm-positive phenotype in the biofilm-negative strains grown in PCs was not observed after passage in regular medium, the virulence of all strains was significantly increased as demonstrated by shortened life spans of the nematodes in C. elegans killing assays. CONCLUSION: Our findings highlight the potential of an increased risk of nosocomial infections caused by S. epidermidis in transfusion recipients since PC storage conditions promote biofilm formation, and possibly pathogenicity, of strains traditionally known to be attenuated for virulence. PMID- 23795976 TI - Effect of complementary feeding with lipid-based nutrient supplements and corn soy blend on the incidence of stunting and linear growth among 6- to 18-month-old infants and children in rural Malawi. AB - Low nutritional value of complementary foods is associated with high incidence of childhood growth stunting in low-income countries. This study was done to test a hypothesis that dietary complementation with lipid-based nutrient supplements (LNS) promotes linear growth and reduces the incidence of severe stunting among at-risk infants. A total of 840 6-month-old healthy infants in rural Malawi were enrolled to a randomised assessor-blinded trial. The participants received 12 month supplementation with nothing, milk-LNS, soy-LNS, or corn-soy blend (CSB). Supplements provided micronutrients and approximately 280 kcal energy per day. Outcomes were incidence of severe and very severe stunting [length-for-age z score, (LAZ) < -3.00 and <-3.50, respectively], and change in LAZ. The incidence of severe stunting was 11.8%, 8.2%, 9.1% and 15.5% (P = 0.098) and that of very severe stunting 7.4%, 2.9%, 8.0% and 6.4% (P = 0.138) in control, milk-LNS, soy LNS and CSB groups, respectively. Between 9 and 12 months of age, the mean change in LAZ was -0.15, -0.02, -0.12 and -0.18 (P = 0.045) for control, milk-LNS, soy LNS and CSB groups, respectively. There was no significant between-group difference in linear growth during other age-intervals. Although participants who received milk-LNS had the lowest incidence of severe and very severe stunting, the differences between the groups were smaller than expected. Thus, the results do not provide conclusive evidence on a causal association between the LNS supplementation and the lower incidence of stunting. Exploratory analyses suggest that provision of milk-LNS, but not soy-LNS promotes linear growth among at-risk infants mainly between 9 and 12 months of age. PMID- 23795975 TI - Clinically relevant reductions in HbA1c without hypoglycaemia: results across four studies of saxagliptin. AB - BACKGROUND: In four 24-week controlled studies, the antihyperglycaemic efficacy of saxagliptin was demonstrated in patients with type 2 diabetes mellitus as add on therapy to glyburide, a thiazolidinedione, or metformin, and when used in initial combination with metformin vs. metformin monotherapy in drug-naive patients. METHODS: Data from these studies were analysed to compare the proportions of patients who achieved specific reductions from baseline in glycated haemoglobin [HbA(1c); reductions of >= 0.5% and >= 0.7% in all studies (prespecified); reductions >= 1.0% in the add-on studies and >= 1.0% to >= 2.5% in the initial combination study (post hoc)] for saxagliptin vs. comparator at week 24. We report overall rates of glycaemic response defined by these reductions in HbA(1c) and rates of response without experiencing hypoglycaemia. RESULTS: Large glycaemic response rates were higher with saxagliptin 2.5 and 5 mg/day than with comparator (HbA(1c) >= 1.0%, 31.7-50.3% vs. 10.3-20.0%) as add on therapy and higher with saxagliptin 5 mg/day as initial combination with metformin than with metformin monotherapy (HbA(1c) >= 2.0%, 68.3% vs. 49.8%) in drug-naive patients. Addition of saxagliptin was associated with a low incidence of hypoglycaemia; overall response rates and response rates excluding patients who experienced hypoglycaemia were similar. Analysis of several demographic and baseline clinical variables revealed no consistent correlations with response to saxagliptin. CONCLUSIONS: Whether receiving saxagliptin as an add-on therapy to glyburide, a thiazolidinedione, or metformin or in initial combination with metformin, a greater percentage of patients achieve clinically relevant large reductions in HbA(1c) vs. comparator, with a low incidence of hypoglycaemia. PMID- 23795977 TI - Dual-functionalized porous Si/hydrogel hybrid for label-free biosensing of organophosphorus compounds. AB - A multifunctional porous Si (PSi) nanostructure is designed to combine a responsive PSi/hydrogel hybrid interfaced with a biorecognition element to selectively recognize small model molecules, organophosphorus compounds (OPCs), of high biological importance. A pH-responsive poly(2-dimethylaminoethyl methacrylate) [poly(DMAEMA)] hydrogel is synthesized and patterned in situ within an oxidized PSi Fabry-Perot thin film. The resulting new hybrid displays a well defined, rapid, and reversible optical response to pH changes. We employ this hybrid as an optical transducer element in a biosensing scheme by integrating it with organophosphorus hydrolase (OPH), capable of selective OPC hydrolysis. The enzyme is immobilized onto the pore walls of the oxidized PSi scaffold, resulting in an array of catalytic nanoscale chambers for the degradation of OPCs. Thus, the biosensor function relies on diffusion of the OPCs hydrolysis products from the catalytic chambers, through the interconnected pores network, to the hybrid region triggering its optical response. Exposure to the model target analyte results in a rapid and reproducible change in the optical reflectivity spectrum of the hybrid, allowing for label-free detection and quantification of OPCs in a simple and reliable manner. PMID- 23795978 TI - Recovering from an interruption: investigating speed-accuracy trade-offs in task resumption behavior. AB - Interruptions are disruptive because they take time to recover from, in the form of a resumption lag, and lead to an increase in the likelihood of errors being made. Despite an abundance of work investigating the effect of interruptions on routine task performance, little is known about whether there is a link between how quickly a task is resumed following an interruption (i.e., the duration of the postinterruption resumption lag) and the likelihood that an error is made. Two experiments are reported in which participants were interrupted by a cognitively demanding secondary mental arithmetic task while working on a routine sequential data-entry task. In Experiment 1 the time-cost of making an error on the primary task was varied between conditions. When errors were associated with a high time-cost penalty, participants made fewer errors and resumed the primary task more slowly than when errors were associated with a low time-cost penalty. In Experiment 2 participants were prohibited from resuming the primary task quickly by a 10-s system lockout period following the completion of the interrupting task. This lockout period led to a significant reduction in resumption errors because the lockout prohibited fast, inaccurate task resumptions. Taken together, our results suggest that longer resumption lags following an interruption are beneficial in terms of reducing the likelihood of errors being made. We discuss the practical implications of how systems might be designed to encourage more reflective task resumption behavior in situations where interruptions are commonplace. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 23795979 TI - Fuzzy risk perception: correlates of "fuzzy" and specific measures of outcome likelihood in young drinkers. AB - Promoting informed choices about alcohol use requires understanding the nature of drinkers' risk perceptions and how these influence decision-making. Fuzzy trace theory states that people use imprecise "fuzzy" risk representations, which are based on the broad cognitive and affective meanings of risk-related experiences, whereas traditionally used measures request precise unitary estimations. Fuzzy representations may be less affected by defensive self-enhancement biases inherent in unitary estimates and better predictors of decision outcomes because they better reflect risk-related affect. Conversely, unitary estimates are based in specific experience and should be better associated with objective risk. Fuzziness was operationalized as a bounded range of undergraduate drinkers' lowest and highest "possibly true" estimates of likelihood for eight alcohol related outcomes on an unmarked scale anchored by the terms "no chance" and "certain." This allowed comparison to unitary estimates and objective alcohol related risk (Alcohol Use Disorders Identification Test [AUDIT] scores). Consistent with self-enhancement, unitary estimates were lower than bounded estimate midpoints. An accountability manipulation, which reduces self enhancement, increased unitary but not bounded estimates. These effects were stronger in participants scoring highly on defensive coping. Bounded estimates were better predicted by risk-related affect and they more strongly predicted intention to reduce drinking. Unitary measures were better predicted by AUDIT scores. Accountability manipulations suppress heuristic thought, reduced correlations between bounded estimates and affect and intention, and eliminated unitary and bounded differences in prediction of AUDIT scores. Drinkers prefer fuzzy representations that reflect affective information when making decisions, but improving risk-based decisions may involve combining the best elements of bounded and unitary representations. PMID- 23795980 TI - Intentionally forgetting other-race faces: costs and benefits? AB - Eyewitnesses to events with multiple actors might be aware that during a subsequent investigation some actors will need to be remembered and others can be forgotten. Research on the directed-forgetting procedure suggests that when some information is cued to be forgotten, retention of other information is enhanced. In three experiments, directed-forgetting conditions were compared with control conditions to assess potential costs and benefits of forgetting other-race faces. In Experiment 1, undergraduate students (N = 148; mostly Caucasian) viewed all Black faces or all Asian faces followed by overt remember or forget cues. Participants in the directed-forgetting conditions of Experiments 2 and 3 received more covert cues instructing them to remember the faces of one race and to forget the faces of another race. In Experiment 2, undergraduate students (N = 116; all Caucasian) viewed Black and Asian faces within the context of a criminal storyline. In Experiment 3, undergraduate students (N = 94; all Caucasian) again viewed Black and Asian faces; however, the remember and forget cues were embedded in a noncriminal narrative. Although faces generally were forgotten on cue, forgetting some faces did not enhance memory for other faces. Furthermore, recognition of remember-cued faces was impaired by exposure to forget-cued faces. These findings indicate that faces can be forgotten on cue, but that doing so confers no benefit for remembering other faces. Eyewitnesses are advised that exposure to irrelevant faces reduces the likelihood that relevant faces will be remembered, even when effort is allocated to forgetting the irrelevant faces. PMID- 23795981 TI - Verbal and numerical consumer recommendations: switching between recommendation formats leads to preference inconsistencies. AB - Many Web sites provide consumers with product recommendations, which are typically presented by a sequence of verbal reviews and numerical ratings. In three experiments, we demonstrate that when participants switch between formats (e.g., from verbal to numerical), they are more prone to preference inconsistencies than when they aggregate the recommendations within the same format (e.g., verbal). When evaluating recommendations, participants rely primarily on central-location measures (e.g., mean) and less on other distribution characteristics (e.g., variance). We explain our findings within the theoretical framework of stimulus-response compatibility and we make practical recommendations for the design of recommendation systems and Web portals. PMID- 23795982 TI - The effect of transparency on recognition of overlapping objects. AB - Are overlapping objects easier to recognize when the objects are transparent or opaque? It is important to know whether the transparency of X-ray images of luggage contributes to the difficulty in searching those images for targets. Transparency provides extra information about objects that would normally be occluded but creates potentially ambiguous depth relations at the region of overlap. Two experiments investigated the threshold durations at which adult participants could accurately name pairs of overlapping objects that were opaque or transparent. In Experiment 1, the transparent displays included monocular cues to relative depth. Recognition of the back object was possible at shorter durations for transparent displays than for opaque displays. In Experiment 2, the transparent displays had no monocular depth cues. There was no difference in the duration at which the back object was recognized across transparent and opaque displays. The results of the two experiments suggest that transparent displays, even though less familiar than opaque displays, do not make object recognition more difficult, and possibly show a benefit. These findings call into question the importance of edge junctions in object recognition. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 23795983 TI - Detection of vehicle approach in the presence of additional motion and simulated observer motion at road junctions. AB - One of the key contributory factors for accident involvement is the misjudgment of vehicle approach. Past research has indicated that individuals can use the rate of visual "looming" in order to judge the time to arrival (TTA) of approaching vehicles. Although a large number of road traffic collisions occur at roadside junctions, very little research has focused on individuals' abilities to detect the onset of visual looming within a complex road scene at junction scenarios. In this research, computer generated scenes with photorealistic vehicle images, and a psychophysical staircase methodology, were used to explore drivers' ability to detect the approach of both motorcycles and cars within a contextually rich city scene. Across three experiments the effect of additional vehicular and observer motion on driver detection of vehicle approach was assessed. Results showed that individuals were significantly poorer at detecting the approach of the motorcycle stimulus compared with the car stimulus. Results also showed that additional vehicular motion within the scene had a negative effect on detection thresholds for the car stimulus. Finally, the results showed that introducing lateral global motion of the scene, such as might occur if the observer was moving steadily forward from a junction, negatively affected detection thresholds. The theoretical implications of the findings are discussed, including how vehicles traveling at high speed are often below the threshold for detecting visual looming. Practical implications for road design and layout are discussed that address the perceptual errors noted. PMID- 23795986 TI - Annexin A1 expression in a splenic diffuse red pulp small B-cell lymphoma: report of the first case. PMID- 23795984 TI - Risk of choroidal neovascularization among the uveitides. AB - PURPOSE: To evaluate the risk, risk factors, and visual impact of choroidal neovascularization (CNV) in uveitis cases. DESIGN: Retrospective cohort study. METHODS: Standardized medical record review at 5 tertiary centers. RESULTS: Among 15,137 uveitic eyes (8868 patients), CNV was rare in the cases of anterior or intermediate uveitis. Among the 4041 eyes (2307 patients) with posterior uveitis or panuveitis, 81 (2.0%) had CNV at presentation. Risk factors included posterior uveitis in general and specific uveitis syndromes affecting the outer retina retinal pigment epithelium-choroid interface. Among the 2364 eyes (1357 patients) with posterior uveitis or panuveitis and free of CNV at the time of cohort entry, the cumulative 2-year incidence of CNV was 2.7% (95% confidence interval [CI], 1.8% to 3.5%). Risk factors for incident CNV included currently active inflammation (adjusted hazard ratio [aHR], 2.13; 95% CI, 1.26 to 3.60), preretinal neovascularization (aHR, 3.19; 95% CI, 1.30 to 7.80), and prior diagnosis of CNV in the contralateral eye (aHR, 5.79; 95% CI, 2.77 to 12.09). Among specific syndromes, the incidence was greater in Vogt-Koyanagi-Harada syndrome (aHR, 3.37; 95% CI, 1.52 to 7.46) and punctate inner choroiditis (aHR, 8.67; 95% CI, 2.83 to 26.54). Incident CNV was associated with a 2-line loss of visual acuity (+0.19 logarithm of the minimal angle of resolution units; 95% CI, 0.079 to 0.29) from the preceding visit. CONCLUSIONS: CNV is an uncommon complication of uveitis associated with visual impairment that occurs more commonly in forms affecting the outer retina-retinal pigment epithelium-choroid interface, during periods of inflammatory activity, in association with preretinal neovascularization, and in second eyes of patients with unilateral CNV. Because CNV is treatable, a systematic approach to early detection in high risk patients may be appropriate. PMID- 23795985 TI - A prospective randomized trial of intravitreal bevacizumab versus ranibizumab for the management of diabetic macular edema. AB - PURPOSE: To compare visual acuity and spectral-domain optical coherence tomography (SDOCT) outcomes associated with intravitreal (IV) bevacizumab vs IV ranibizumab for the management of diabetic macular edema (DME). DESIGN: Prospective randomized trial. METHODS: Forty-eight patients (63 eyes) with center involved DME were randomly assigned to receive 1.5 mg (0.06 cc) IV bevacizumab or 0.5 mg (0.05 cc) IV ranibizumab at baseline and monthly if central subfield thickness was greater than 275 MUm. RESULTS: Forty-five patients (60 eyes) completed 48 weeks of follow-up. At baseline, mean +/- standard error best corrected visual acuity (BCVA) (logMAR) was 0.60 (20/80) +/- 0.05 in the IV bevacizumab group and 0.63 (20/85) +/- 0.05 in the IV ranibizumab group. A significant improvement in mean BCVA was observed in both groups at all study visits (P < .05); this improvement was significantly greater in the IV ranibizumab group compared with the IV bevacizumab group at weeks 8 (P = .032) and 32 (P = .042). A significant reduction in mean central subfield thickness was observed in both groups at all study visits compared with baseline (P < .05), with no significant difference in the magnitude of macular thickness reduction between groups. The mean number of injections was significantly higher (P = .005) in the IV bevacizumab group (9.84) than in the IV ranibizumab group (7.67). CONCLUSIONS: IV bevacizumab and IV ranibizumab are associated with similar effects on central subfield thickness in patients with DME through 1 year of follow-up. IV ranibizumab is associated with greater improvement in BCVA at some study visits, and the mean number of injections is higher in the IV bevacizumab group. PMID- 23795987 TI - American Society for Dermatologic Surgery dermatologic surgery drug and device nomenclature recommendations. AB - BACKGROUND: There is a lack of consensus regarding appropriate nomenclature for drugs and devices used in surgical and cosmetic dermatology. OBJECTIVE: To develop a rules-based system for naming drugs and devices commonly used in dermatologic surgery that generates identifiers and modifiers that are clear, complete, and brief. METHODS: Using an iterative modified consensus process, five subject-area work groups of the ASDS Lexicon Task Force were charged with developing standard terminology for the drugs and devices subsumed under their topic. A subcommittee comprising the chairs of the workgroups initially developed the general rules that guided the consensus process; subsequently, this subcommittee merged the 5 resulting documents into a single work product. Two external reviewers with expertise in dermatologic drugs and devices reviewed the final document for errors and omissions. RESULTS: General characteristics sought in systematic names included: brevity, clarity, non-overlapping (mutually exclusive) nature, within-class similarity, preservation of current usage when possible, and potential for inclusion of future refinements. CONCLUSION: Naming of drugs and devices in dermatologic surgery can be improved to increase comprehensibility and utility in both clinical and research contexts. Particularly for devices, the use of systematic names can reduce repeated mention of proprietary names in scientific discourse. Any naming system should be amenable to modification, correction, and the continual incorporation of novel agents. PMID- 23795988 TI - Building a professionalism framework for healthcare providers in China: a nominal group technique study. AB - BACKGROUND: Medical professionalism is valued globally. However, Western frameworks of medical professionalism may not resonate with the cultural values of non-Western countries. AIMS: This study aims to formulate a professionalism framework for healthcare providers at Peking Union Medical College (PUMC) in China. METHODS: This study was conducted using nominal group technique (NGT) in a convenient sample of 97 participants at PUMC in November and December, 2011. Participants were sorted into 13 occupational groups, each discussing and ranking categories of medical professionalism. The authors compared the results of each group's ranked categories and analyzed meeting transcripts. RESULTS: A pre existing framework provided eight categories: clinical competence, communication, ethics, humanism, excellence, accountability, altruism, and integrity. Participants created four categories: teamwork, self-management, health promotion, and economic considerations. Clinical competence and communication ranked highly among most groups. Only hospital volunteers and resident physicians included self-management in their top-ranked items. Only public health experts prioritized health promotion. Standardized patients were unique in mentioning "economic considerations." Medical students and attending physicians both referenced Chinese traditional values. CONCLUSIONS: Our study was able to document effects of East Asian cultural influences and conflicts between Western ideologies and Asian traditions that led to divergent interpretations of medical professionalism. PMID- 23795989 TI - Assessment of fullerene derivatives as rolling journals in a finite carbon nanotube bearing. AB - Conformance assessment of rolling journals in a molecular bearing has been carried out with a combination of fullerenes and finite single-wall carbon nanotube molecules through quantitative analysis of the binding affinities. Endohedral fullerenes were applicable to three-body molecular bearings with slightly weaker binding affinities. Exohedral shaft moieties on C60 journals affected the binding affinities to reduce the binding constants to a considerable extent, and oval-spherical C70 journals were superior in tolerating bulky shaft attachments. PMID- 23795990 TI - Clinical significance of serum hyaluronan in chronic fibrotic interstitial pneumonia. AB - BACKGROUND AND OBJECTIVE: Hyaluronan is an important constituent of the extracellular matrix in lungs, and growing evidence demonstrates its important biological properties in the lung. However, its role in interstitial pneumonia remains to be fully clarified. The goal of this study was to clarify the role of hyaluronan in interstitial pneumonia. METHODS: Hyaluronan in serum and bronchoalveolar lavage (BAL) fluid of chronic interstitial pneumonia (CIP) patients was measured, and the correlation with clinical parameters was determined. In addition, the correlation between hyaluronan in serum and clinical parameters was analysed in patients with acute exacerbation of interstitial pneumonia (IP-AE). RESULTS: When compared with healthy controls, serum hyaluronan was significantly greater in patients with CIP and was positively correlated with serum biomarkers of inflammation and fibrosis, such as C-reactive protein and surfactant protein-D. In BAL fluid, the amount of hyaluronan was positively correlated with the percentage of inflammatory cells and the amount of CXCL8. When compared with CIP patients, patients with IP-AE had significantly greater amounts of serum hyaluronan, and patients with the highest serum hyaluronan had the worst 60-day outcomes. CONCLUSIONS: This work suggests that serum hyaluronan may be a clinically useful biomarker of interstitial pneumonia and suggests the possibility that hyaluronan is involved in the pathogenesis of interstitial pneumonia by recruiting inflammatory cells into the lungs. PMID- 23795991 TI - Spectrum of imaging manifestations in non-neoplastic gastric pathologies. AB - This article illustrates a wide spectrum of non-neoplastic gastric pathologies on cross-sectional imaging. Salient features of inflammatory, infectious, vascular, traumatic, and miscellaneous conditions of the stomach have been discussed and imaging clues to reach an accurate diagnosis are stressed upon. PMID- 23795992 TI - Pelvic congestion syndrome. AB - Pelvic congestion syndrome (PCS) is an important cause of chronic pelvic pain in female patients. Chronic pelvic pain, defined as lower abdominal or pelvic pain for a duration of 6 months or more, causes significant morbidity and results in a large number of diagnostic laparoscopies. It is of utmost importance to identify treatable causes of chronic pelvic pain, one of which is PCS. The etiology, clinical features, investigations, and treatment options in PCS have been discussed in this paper. PMID- 23795993 TI - Postcardiac injury syndrome following transvenous pacer or defibrillator insertion: CT imaging and review of the literature. AB - Postcardiac injury syndrome (PCIS) is a frequent clinical entity developing as a complication of cardiac procedures. Some of these may be only minor procedures, such as the insertion of permanent pacer or defibrillator devices. The purpose of this article is to review and illustrate its common imaging findings. PCIS is expected to occur in approximately 1%-2% of patients after pacer or defibrillator device placement. The mechanism of pericarditis following implantation is unclear, but it may involve a direct irritation of the pericardium by minimally protruding electrodes, low-grade bleeding with hemorrhagic pericarditis, and a late autoimmune or inflammatory response to those insults. Radiologists may detect findings that in the appropriate clinical setting should raise the possibility of PCIS. On chest x-ray, the findings include the presence of a pericardial or pleural effusion or both. Computed tomography, in addition to having better characterization capabilities of the pericardial or pleural effusion or both, may also accomplish the diagnosis of lead perforation. Although typically rather benign, PCIS may result in significant morbidity and potential mortality due to arrhythmias, noncardiac pulmonary edema, and cardiac tamponade. Therefore, its early detection is of clinical importance. PMID- 23795994 TI - Controversies in breast MRI. AB - When used for appropriate indications, breast magnetic resonance imaging (MRI) is a powerful diagnostic tool. However, breast MRI has its share of controversies. These controversies can be a source of confusion for the radiologist or referring physician. This paper addresses 4 breast MRI controversies that we frequently encounter at our university hospital practice: (1) what are the appropriate indications for screening breast MRI? (2) what are the appropriate indications for the use of breast MRI as a problems-solving modality? (3) how does one interpret MRI imaging features that have substantial overlap between benign and malignant conditions? and (4) what are the appropriate indications for preoperative breast MRI? Illustrative case examples are provided. PMID- 23795995 TI - Imaging of the inguinal canal in children. AB - The inguinal canal is often seen at the edge of the field of view on plain radiography, computed tomography, or magnetic resonance imaging and may often not be scanned when performing sonography of the scrotum or abdomen. As a result, pathology in this anatomical region may be easily overlooked. The peculiar embryology of the inguinal canal makes the identification of pathology in the inguinal region significant, as some of the processes that take place within the scrotum may originate in the abdomen, and vice versa. This article reviews the relevant embryology of the inguinal canal, discusses abdominal and scrotal conditions that involve the inguinal region, and illustrates associated pathology. PMID- 23795996 TI - Design and preparation of a core-shell metal-organic framework for selective CO2 capture. AB - The design of a core-shell metal-organic framework comprising a porous bio-MOF 11/14 mixed core and a less porous bio-MOF-14 shell is reported. The growth of the MOF shell was directly observed and supported by SEM and PXRD. The resulting core-shell material exhibits 30% higher CO2 uptake than bio-MOF-14 and low N2 uptake in comparison to the core. When the core-shell architecture is destroyed by fracturing the crystallites via grinding, the amount of N2 adsorbed doubles but the CO2 adsorption capacity remains the same. Finally, the more water stable bio-MOF-14 shell serves to prevent degradation of the water-sensitive core in aqueous environments, as evidenced by SEM and PXRD. PMID- 23795997 TI - Validity of six openness facets in predicting work behaviors: a meta-analysis. AB - To illustrate the importance of facet-level investigations in predicting organizational outcomes and the need for more primary studies on this topic, we conducted a meta-analysis that took an exploratory look at differential relationships among 7 organizational criteria and Openness traits varying in breadth. Nine Openness predictors--the global dimension, 2 aspects (intellect and culture), and 6 facets (intellectual efficiency, ingenuity, curiosity, aesthetics, tolerance, and depth)--were examined in relations with various organizational criteria such as traditional performance outcomes (task performance, contextual performance, counterproductive work behavior), turnover, leadership effectiveness, training performance, and adaptive performance. Our results support the idea that Openness facets could exhibit differential validity for many organizational outcomes. PMID- 23795998 TI - Analysing variation in Drosophila aging across independent experimental studies: a meta-analysis of survival data. AB - Survival records of longevity experiments are a key component in research on aging. However, surprisingly there have been very few cross-study analyses, besides comparisons of median lifespans or similar summary information. Here, we use a large set of full survival data from various studies to address questions in aging, which are beyond the scope of individual studies. We characterize survival differences between female and male flies of different genetic Drosophila strains, showing significant differences between strains. We further analyse the variation in survival of control cohorts recorded under highly similar conditions within different Drosophila strains. We found that overall transgenic constructs of the UAS/GAL4 expression system which should have no effect (e.g. a GAL4 construct alone) extend lifespan significantly in the w1118 strain. Using a large data set comprised of various studies, we found no evidence for larger lifespan extensions being associated with shorter lifespans of the control in Drosophila. This demonstrates that lifespan extending treatments are not purely rescuing weak backgrounds. PMID- 23795999 TI - Rene P. Schwarzenbach: four decades of stimulating cooperation and friendship. PMID- 23796000 TI - Co-infection with vaginal Ureaplasma urealyticum and Mycoplasma hominis increases adverse pregnancy outcomes in patients with preterm labor or preterm premature rupture of membranes. AB - OBJECTIVE: The purpose of this study was to determine the prevalence of Ureaplasma urealyticum (UU) and Mycoplasma hominis (MH) in patients with preterm labor or preterm premature rupture of membranes (PPROM) and to determine the effect of these organisms on pregnancy outcomes based on the density of colonization. METHODS: The study group consisted of 184 women with preterm labor or PPROM. Vaginal cultures for UU and MH were performed for all patients at admission, and the placentas were histologically evaluated after delivery. RESULTS: The prevalence of positive vaginal fluid cultures for genital mycoplasma was 62.5% (112/179). This group included 99 patients carrying only UU and 13 carrying both organisms. No patients were found to carry only MH. Compared to patients only positive for UU, patients with both organisms showed significantly decreased gestational age at birth and birth weight, and significant increases in the incidences of preterm birth, NICU admissions and histologic chorioamnionitis. CONCLUSION: Vaginal MH tends to be detected with UU, and patients carrying both organisms simultaneously had more severe adverse pregnancy outcomes compared to patients in preterm labor or PPROM who were only positive for UU. PMID- 23796001 TI - Geriatric patient care by U.S. pharmacists in healthcare teams: systematic review and meta-analyses. AB - OBJECTIVES: To conduct a systematic review and meta-analyses to examine the effects of pharmacists' care on geriatric patient-oriented health outcomes in the United States (U.S.). DESIGN: Studies examining U.S. pharmacists' patient care services from inception of the databases through July 2012 were searched. The databases searched include PubMed/MEDLINE, Ovid/MEDLINE, ABI/INFORM, Health Business Fulltext Elite, Academic Search Complete, International Pharmaceutical Abstracts, PsycINFO, Cochrane Database, and Clinical Trials.gov. Studies reporting pharmacists' intervention for geriatric patients, comparison groups, and patient-oriented outcomes were assessed. Dual review for inclusion and data extraction were performed. SETTING: University of Arizona College of Pharmacy. MEASUREMENTS: Study and participant characteristics, pharmacist intervention, and outcomes with data for meta-analyses were collected. A forest plot was constructed to obtain a pooled standardized mean difference using a random effects model. RESULTS: One hundred fifty-two articles were reviewed, with 20 resulting studies included in the final meta-analyses. Study sample size ranged from 36 to 4,218, with mean age of subjects being 65 and older. The studies were most frequently conducted in ambulatory care clinics, followed by inpatient settings; the majority focused on multiple diseases and conditions. Pharmacist activities varied widely, with technical interventions used most often. Favorable results were found in all outcome categories, and meta-analyses conducted for therapeutic, safety, hospitalization, and adherence were significant (P < .001), favoring pharmacist care over comparison. Some identifiable variability existed between included studies. CONCLUSION: Pharmacist intervention has favorable effects on therapeutic, safety, hospitalization, and adherence outcomes in older adults. Pharmacists should be involved in team-based care of older adults. PMID- 23796002 TI - Is uracil aromatic? The enthalpies of hydrogenation in the gaseous and crystalline phases, and in aqueous solution, as tools to obtain an answer. AB - The enthalpy of hydrogenation of uracil was derived from the experimental enthalpies of formation, in the gaseous phase, of uracil and 5,6-dihydrouracil, in order to analyze its aromaticity. The enthalpy of formation of 5,6 dihydrouracil was obtained from combustion calorimetry, Knudsen effusion technique and Calvet microcalorimetry results. High-level computational methods were tested for the enthalpy of hydrogenation of uracil, but only with G3 was possible to obtain results in agreement with the experimental ones. It was found that uracil possesses 30.0% of aromatic character in the gaseous phase. Using both implicit, explicit, and hybrid solvation methods, it was possible to obtain a reference value for the enthalpy of hydrogenation of uracil in the aqueous solution and the effect of polarity and hydrogen bonds on the aromaticity of uracil was analyzed. The value of the hydrogenation enthalpy of uracil in aqueous solution was compared with the experimental value in the crystal phase, also dominated by polarity and hydrogen bonds, derived from combustion calorimetry results. The supramolecular effects on the crystal lattice were explored by the computational simulation of pi-pi staking dimers and hydrogen bonded dimers. PMID- 23796003 TI - Microradiography and microcomputed tomography comparative analysis in human bone cores harvested after maxillary sinus augmentation: a pilot study. AB - OBJECTIVES: The aim of this study was to compare microradiography (MR) and microcomputed tomography (MUCT) analysis of bone samples following maxillary sinus augmentation at different time periods and determine the relationships between measured area and volume fractions. MATERIALS AND METHODS: Lateral window sinus grafts were performed on 10 patients using a mineralized human bone allograft (MHBA). At implant placement, 5-13 months after surgery, 10 bone core biopsies were harvested. Prior to histologic sectioning, bone samples were evaluated with MUCT. The morphometric parameters computed by MR and MUCT were compared using Pearson's correlation and Bland and Altman analysis and included hard tissue fraction (HV/TV:%), soft tissue fraction (SV/TV:%), vital bone fraction (BV/TV:%) and residual graft fraction (GV/TV:%). RESULTS: Strong positive correlation between MR and MUCT was found for HV/TV and SV/TV and BV/TV [r = 0.84, 0.84 and 0.69, respectively] but weak for GV/TV [r = 0.10]. CONCLUSION: MUCT technology shows promising potential as an indicator of bone morphology changes; however, caution should be used in interpreting morphometric parameters, as the different methods reveal important biases. PMID- 23796004 TI - Comparative molecular dynamics simulation studies for determining factors contributing to the thermostability of chemotaxis protein "CheY". AB - Comparative molecular dynamics simulations of chemotaxis protein "CheY" from thermophilic origin Thermotoga maritima and its mesophilic counterpart Salmonella enterica have been performed for 10 ns each at 300 and 350 K, and 20 ns each at 400 and 450 K. The trajectories were analyzed in terms of different factors like root-mean-square deviation, root-mean-square fluctuation, radius of gyration, solvent accessible surface area, H-bonds, salt bridge content, and protein solvent interactions which indicate distinct differences between the two of them. The two proteins also follow dissimilar unfolding pathways. The overall flexibility calculated by the trace of the diagonalized covariance matrix displays similar flexibility of both the proteins near their optimum growth temperatures. However, at higher temperatures mesophilic protein shows increased overall flexibility than its thermophilic counterpart. Principal component analysis also indicates that the essential subspaces explored by the simulations of two proteins at different temperatures are nonoverlapping and they show significantly different directions of motion. However, there are significant overlaps within the trajectories and similar direction of motions are observed for both proteins at 300 K. Overall, the mesophilic protein leads to increased conformational sampling of the phase space than its thermophilic counterpart. This is the first ever study of thermostability of CheY protein homologs by using protein dynamism as a main impact. Our study might be used as a model for studying the molecular basis of thermostability of two homologous proteins from two organisms living at different temperatures with less visible differences. PMID- 23796005 TI - 4-Dimethylaminopyridine promoted interfacial polymerization between hyperbranched polyesteramide and trimesoyl chloride for preparing ultralow-pressure reverse osmosis composite membrane. AB - We have presented a concept of ultralow-pressure reverse osmosis membrane based on hyperbranched polyesteramide through interfacial reaction promoted by pyridine derivate. In this strategy, a key catalyst of 4-dimethylaminopyridine, which can both eliminate the steric hindrance of acyl transfer reaction and facilitate the phase transfer in interfacial polymerization, is adopted to drive the formation of a thin film composite membrane from the hyperbranched polyesteramide and trimesoyl chloride. The results of the characterization demonstrate that a dense, rough, and hydrophilic active layer with a thickness of about 100 nm is formed when the 4-dimethylaminopyridine catalyst is used. The salt rejections for Na2SO4, NaCl, and MgSO4 of the as-prepared composite membrane are higher than 92%, especially for Na2SO4 with 98% rejection. The water fluxes reach about 30-40 L.m(-2).h(-1) even at an operation pressure of 0.6 MPa. The membrane exhibits good chlorine-resistance ability but poor resistance abilities to acidic and alkaline solutions in the physical-chemical stability experiment. It is also found that the resultant membrane possesses excellent separation performance for PEG-200, showing a promising way to separate small organic molecules from water. PMID- 23796007 TI - Morphologic radiographic study of the proximal sesamoid bones of the forelimb in thoroughbred racehorses in training. AB - The aim of this study was to identify differences in bone shape (height and width) of proximal sesamoid bones (PSB) in 2-year-old Thoroughbred racehorses in training. Dorsal 15 degrees proximal-palmarodistal oblique images of each metacarpophalangeal joint were acquired before the horses started training and at 1 year after the start of exercise and racing. There were no changes in height and width of PSBs induced by training. There was a significant difference of height and width between medial and lateral PSBs. In both forelimbs, the medial PSB was significantly wider and shorter than the lateral PSB. The medial PSB of the right forelimb was significantly wider than that of the left forelimb. These results might explain some limb predilection for fracture of PSBs. The difference in strain pattern between medial and lateral PSBs in different loading conditions needs to be investigated. PMID- 23796006 TI - Incidence of internal tandem duplications and D835 mutations of FLT3 gene in chronic myeloid leukemia patients from Southern India. AB - OBJECTIVE: To screen two important FLT3 mutations (internal tandem duplication (ITD) and D835 point mutations) in chronic myeloid leukemia (CML) patients from Southern India and report their incidence. METHODS: Screened 350 CML patients and 350 controls for the two FLT3/mutations through polymerase chain reaction and restriction fragment length polymorphism methods. RESULTS: ITDs were detected in 12 of the 350 CML patients (3.4%) and D835 mutations in only four cases (1.14%), relatively low in frequency as compared to those reported earlier from non-Indian populations. None of the cases showed simultaneous occurence of both ITD and D835 mutations. DISCUSSION: These FLT3 mutations seem to be very rare in CML, and it is possible that these could be found only in a subset of patients who are in the progressive stage and/or with varied drug response. Prospective studies are needed to confirm the role of FLT3 mutations in CML pathogenesis, which may help devising therapeutic interventions. PMID- 23796008 TI - False-positive iodine-131 whole-body scan findings in patients with differentiated thyroid carcinoma: report of 11 cases and review of the literature. AB - BACKGROUND: Iodine-131 (I-131) whole-body scan (WBS) plays an important role in the management of patients with differentiated thyroid carcinoma (DTC), to detect normal thyroid remnants and recurrent or metastatic disease. A focus of I-131 accumulation outside the thyroid bed and the areas of physiological uptake is strongly suggestive of a distant functioning metastasis. However, many false positive I-131 WBS findings have been reported in the literature. PATIENT FINDINGS: We describe a series of 11 personal cases of patients with DTC, collected from 1992 to 2011, in whom diagnostic or post-treatment WBS showed false-positive retention of I-131 in various locations. SUMMARY: False-positive accumulations of I-131 on WBS may be classified according to the underlying pathophysiological mechanisms: external and internal contaminations by body secretions, ectopic normal thyroid and gastric tissues, inflammatory and infectious diseases, benign and malignant tumors, cysts and effusions of serous cavities, thymic uptake, and other non classified causes. CONCLUSIONS: Clinicians must be aware of possible false-positive findings to avoid misinterpretations of the I-131 WBS, which could lead to inappropriate treatments. PMID- 23796009 TI - Topographic diagnosis: respective roles of morphological and functional imaging. PMID- 23796010 TI - Bisphenol A: an endocrine and metabolic disruptor. AB - Bisphenol A (BPA), initially designed, like diethylstilbestrol, as a synthetic estrogen, has been rapidly and widely used for its cross-linking properties in the manufacture of polycarbonate plastics and epoxy resins. Because of incomplete polymerization and degradation of the polymers by exposure to higher than usual temperatures, BPA leaches out from food and beverage containers, as well as from dental sealants. In humans, free active unconjugated BPA is metabolized by rapid glucurono- or sulfo-conjugation and eliminated via renal clearance. However, exposure to environmental nanomolar concentrations of BPA is ubiquitous and continuous via different routes: oral, air, skin. In rodents, fetal and perinatal exposure to such environmentally relevant doses of BPA has been shown to affect the brain, liver, gut, adipose tissue, endocrine pancreas, mammary gland and reproductive tract and function. Similar concentrations are also able in vitro to impact human malignant breast, prostate, male germ or adipocyte cell lines (with a promoting effect and by interfering with chemotherapy drugs), or to stimulate pancreatic beta cell insulin secretion. High levels of BPA have recently been correlated with obesity, diabetes, cardiovascular diseases, polycystic ovarian disease or low sperm count. However, before the real impact of BPA on human health can be clearly assessed, prospective longitudinal epidemiological studies are needed as well as characterization of selective biomarkers to verify long term exposure and selective imprinting. PMID- 23796011 TI - The plastic occluder: a protective instrument during cryosurgery. PMID- 23796013 TI - Prenatal and postnatal factors increase risk of severe ROP. AB - To determine that slower weight premature twins have more risk to develop severe retinopathy of prematurity (ROP) than the higher weight twins. We know that the lower weight twins had less optimal intra-uterine environments than their higher weight twins. We screened 94 consecutive premature twins for ROP. We compared the lower weight twins (n = 47) against their higher weight twins (n = 47). The risk of severe ROP (ROP stage 3 or greater) was significantly higher in the lower weight twin group (p < 0.006). In the same way, in the lower weight twin group the non-perfused area of the temporal retinal artery was higher than that of the other group (an average of 1.2 diameters of the optic nerve head), in the 4-6 postnatal weeks (p < 0.004). The lower weight twin group have an increased risk of severe ROP associated with bacteremia (p = 0.045), or a weight gain less than 7 g per day in the 4-6 postnatal weeks (p = 0.013) or a supplementary postnatal oxygen >4 days (p = 0.007) compared to the higher weight twin group. We confirm Dr. Lee's work that less optimal prenatal factors, in preterm twins, increase the risk of severe ROP. PMID- 23796012 TI - What aspects of rehabilitation provision contribute to self-reported met needs for rehabilitation one year after stroke--amount, place, operator or timing? AB - BACKGROUND AND OBJECTIVE: To a large extent, people who have suffered a stroke report unmet needs for rehabilitation. The purpose of this study was to explore aspects of rehabilitation provision that potentially contribute to self-reported met needs for rehabilitation 12 months after stroke with consideration also to severity of stroke. METHODS: The participants (n = 173) received care at the stroke units at the Karolinska University Hospital, Sweden. Using a questionnaire, the dependent variable, self-reported met needs for rehabilitation, was collected at 12 months after stroke. The independent variables were four aspects of rehabilitation provision based on data retrieved from registers and structured according to four aspects: amount of rehabilitation, service level (day care rehabilitation, primary care rehabilitation and home-based rehabilitation), operator level (physiotherapist, occupational therapist, speech therapist) and time after stroke onset. Multivariate logistic regression analyses regarding the aspects of rehabilitation were performed for the participants who were divided into three groups based on stroke severity at onset. RESULTS: Participants with moderate/severe stroke who had seen a physiotherapist at least once during each of the 1st, 2nd and 3rd-4th quarters of the first year (OR 8.36, CI 1.40-49.88 P = 0.020) were more likely to report met rehabilitation needs. CONCLUSION: For people with moderate/severe stroke, continuity in rehabilitation (preferably physiotherapy) during the first year after stroke seems to be associated with self-reported met needs for rehabilitation. PMID- 23796014 TI - Get real: putting models of climate change and species interactions in practice. AB - Forecasts of the ecological impacts of climate change are generally focused on direct impacts to individual species. Theory and case studies suggest that indirect effects associated with species interactions may alter these direct responses. How can we tractably predict in which cases indirect effects are likely to be important and appropriately model the interaction of abiotic and biotic drivers? One viable strategy is to characterize partitioning between species along thermal, temporal, and spatial niche axes. The partitioning can be informed by assessing functional traits. Mechanistic models can then be applied to predict how climate change will alter niche partitioning. I illustrate this approach by asking whether competition has altered the responses of Caribbean Anolis lizards to recent warming and find that forested habitat has become more suitable for a warm-adapted, open species, and less suitable for a cool-adapted forest inhabitant. Competition may result in competitive displacement of the cool adapted species as the warm-adapted species moves into the forest. Species interactions may accentuate abundance and distribution shifts predicted in response to climate change along the elevation gradient. PMID- 23796015 TI - Computer-automated silica aerosol generator and animal inhalation exposure system. AB - Inhalation exposure systems are necessary tools for determining the dose response relationship of inhaled toxicants under a variety of exposure conditions. The objective of this study was to develop an automated computer controlled system to expose small laboratory animals to precise concentrations of uniformly dispersed airborne silica particles. An acoustical aerosol generator was developed which was capable of re-suspending particles from bulk powder. The aerosolized silica output from the generator was introduced into the throat of a venturi tube. The turbulent high-velocity air stream within the venturi tube increased the dispersion of the re-suspended powder. That aerosol was then used to expose small laboratory animals to constant aerosol concentrations, up to 20 mg/m(3), for durations lasting up to 8 h. Particle distribution and morphology of the silica aerosol delivered to the exposure chamber were characterized to verify that a fully dispersed and respirable aerosol was being produced. The inhalation exposure system utilized a combination of airflow controllers, particle monitors, data acquisition devices and custom software with automatic feedback control to achieve constant and repeatable exposure environments. The automatic control algorithm was capable of maintaining median aerosol concentrations to within +/ 0.2 mg/m(3) of a user selected target concentration during exposures lasting from 2 to 8 h. The system was able to reach 95% of the desired target value in <10 min during the beginning phase of an exposure. This exposure system provided a highly automated tool for conducting inhalation toxicology studies involving silica particles. PMID- 23796016 TI - Urinary S-PMA related to indoor benzene and asthma in children. AB - INTRODUCTION: Benzene is a ubiquitous pollutant of both indoor and outdoor environments which impacts on respiratory health. Our aim was to relate urinary S phenylmercapturic acid (S-PMA), a biomarker of benzene exposure, to benzene concentrations and related sources at home and asthma in a population-based sample of children. METHODS: Exposure to benzene was assessed in the dwellings of 63 children (32 asthmatics and 31 controls) through the identification of sources of benzene and in situ assessments with passive samplers. The determination of urinary S-PMA was obtained by liquid chromatography-mass spectrometry. RESULTS: At home, asthmatics were significantly more polluted by benzene levels from ambient sampling than controls (p <= 0.05). Benzene exposure significantly aggravated asthma symptoms overall in non-atopic children (OR = 10.10; 95% confidence interval: 10.10). Urinary S-PMA was significantly associated with benzene concentrations in the entire population (regression coefficient = 0.28, 95% CI: 0.07-0.49; p < 0.05) and asthma (OR = 7.69; 95% CI: 1.37-42.52 for an increase of 1 ug/g creatinine of urinary S-PMA). However, after adjustment for environmental tobacco smoking exposure, familial allergy, age and sex, the latter relationship was no more significant (OR = 4.95; 95% CI: 0.91-27.4, p < 0.10). Both benzene concentrations and urinary S-PMA concentrations were higher in dwelling built after 1948 and in flats. CONCLUSIONS: Our study suggests a relationship between childhood asthma and benzene concentrations at home, even at low levels of this pollutant. This was confirmed when considering urinary S-PMA, which was related to both benzene concentrations and asthma. Further epidemiological and toxicological studies are needed to confirm our results. PMID- 23796017 TI - Assessment of geographical variation in the respiratory toxicity of desert dust particles. AB - The health consequences of sand particle inhalation are incompletely understood. This project evaluated the respiratory toxicity of sand particles collected at military bases near Fort Irwin USA, in Iraq (Camp Victory, Taji and Talil), and Khost Afghanistan. Our primary focus was on assessing the role of soluble metals in the respiratory toxicity of the sand particles using in vitro and in vivo methods. Replicating rat type II alveolar cell cultures (RLE-6TN) were exposed to sand extracts or vehicle control in serum-free media for <=24 h. Cytotoxicity was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and assessment of lactate dehydrogenase leakage. The relative in vitro cytotoxicity of the sand extracts was Taji ~ Talil > Afghanistan > Camp Victory ~ Fort Irwin. We also assessed extracts of Camp Victory, Afghanistan, and Taji sand for acute and delayed pulmonary toxicity in rats following intratracheal administration. Assessments included biochemical analysis of bronchoalveolar lavage fluid (BALF) and lung histopathology. The in vitro cytotoxicity assay results were partially predictive of in vivo responses. The more cytotoxic Taji sand extract induced an acute irritant response in rats following intratracheal administration. Rats given the less cytotoxic Camp Victory sand extract had minimal biochemical or cytological BALF changes whereas rats given either the Afghanistan or Taji sand extracts demonstrated BALF changes that were suggestive of mild lung inflammation. Unexpectedly, we observed similar lung pathology in all extract-exposed rats. The results of our study can be used to prioritize future particle inhalation studies or guide epidemiological study design. PMID- 23796018 TI - Carbon nanodots as a matrix for the analysis of low-molecular-weight molecules in both positive- and negative-ion matrix-assisted laser desorption/ionization time of-flight mass spectrometry and quantification of glucose and uric acid in real samples. AB - Carbon nanodots were applied for the first time as a new matrix for the analysis of low-molecular-weight compounds by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) in both positive- and negative ion modes. A wide range of small molecules including amino acids, peptides, fatty acids, as well as beta-agonists and neutral oligosaccharides were analyzed by MALDI MS with carbon nanodots as the matrix, and the lowest 0.2 fmol limits-of detection were obtained for octadecanoic acid. Clear sodium and potassium adducts and deprotonated signals were produced in positive- and negative-ion modes. Furthermore, the glucose and uric acid in real samples were quantitatively determined by the internal standard method with the linear range of 0.5-9 mM and 0.1-1.8 mM (R(2) > 0.999), respectively. This work gives new insight into the application of carbon nanodots and provides a general approach for rapid analysis of low-molecular-weight compounds. PMID- 23796019 TI - Evaluation of a point-of-care coagulation analyzer (Abaxis VSPro) for identification of coagulopathies in dogs. AB - OBJECTIVE: To evaluate the ability of the Abaxis VSPro, a point-of-care analyzer that measures prothrombin time (PT) and activated partial thromboplastin time (aPTT), to identify dogs with coagulopathies caused by administration of anticoagulants. SETTING: Veterinary teaching hospital. ANIMALS: Six healthy adult dogs that are part of a preexisting research colony. One dog was not included in the warfarin portion of the study. MEASUREMENTS AND MAIN RESULTS: Unfractionated heparin (UFH, 50 U/kg i.v. once then 300 U/kg s.q. q 8 h) was administered to prolong aPTT. Citrated whole blood was used for PT and aPTT analyses with the VSPro and were run in duplicate. The VSPro results were compared to PT and aPTT measured in plasma with a standard benchtop coagulometer (AMAX Destiny). A washout period of at least 24 hours followed. Once dogs had normal PT and aPTT values, warfarin was administered (0.25-0.30 mg/kg p.o.) once then (0.15 mg/kg p.o.) as needed up to every 12 hours to prolong PT values. Seventy separate samples were evaluated for PT and 73 samples for aPTT. Pearson correlation coefficients (PCC) for replicate VSPro measures of PT and aPTT were 0.941 and 0.891, respectively (P < 0.001). The PCC between VSPro and AMAX was 0.578 for PT and of 0.865 for PTT (P < 0.001). Receiver operating characteristic (ROC) analysis indicated a maximum sensitivity and specificity for diagnosis of coagulopathy (by AMAX) at VSPro PT value of 21.6 seconds (sensitivity 72%, specificity 86%) and a maximum sensitivity and specificity at VSPro aPTT of 105.3 seconds (sensitivity 93%, specificity 89%). The positive predictive value for PT and aPTT were 84% and 89%, respectively. CONCLUSIONS: The Abaxis VSPro showed acceptable correlation with clinical laboratory tests, and is a useful POC device for identification of animals with abnormalities in PT or aPTT. PMID- 23796020 TI - Scleroderma pathogenesis: a pivotal role for fibroblasts as effector cells. AB - Scleroderma (systemic sclerosis; SSc) is characterised by fibrosis of the skin and internal organs in the context of autoimmunity and vascular perturbation. Overproduction of extracellular matrix components and loss of specialised epithelial structures are analogous to the process of scar formation after tissue injury. Fibroblasts are the resident cells of connective tissue that become activated at sites of damage and are likely to be important effector cells in SSc. Differentiation into myofibroblasts is a hallmark process, although the mechanisms and cellular origins of this important fibroblastic cell are still unclear. This article reviews fibroblast biology in the context of SSc and highlights the potentially important place of fibroblast effector cells in fibrosis. Moreover, the heterogeneity of fibroblast properties, multiplicity of regulatory pathways and diversity of origin for myofibroblasts may underpin clinical diversity in SSc, and provide novel avenues for targeted therapy. PMID- 23796021 TI - Ethnic differences in quality of life in insured older adults with diabetes mellitus in an integrated delivery system. AB - OBJECTIVES: To explore racial and ethnic (ethnic hereafter) differences in health related quality of life (HRQL) in older adults with diabetes mellitus in an integrated delivery system. DESIGN: Observational cross-sectional study. SETTING: Kaiser Permanente Northern California. PARTICIPANTS: Ethnic-stratified, random sample of 6,096 adults with diabetes mellitus aged 60 to 75 who completed a HRQL questionnaire. MEASUREMENTS: Physical and mental HRQL were measured based on the Medical Outcomes Study 8-item Short Form Survey (range 0-100, mean 50). Age- and sex-adjusted weighted linear regression models estimated associations between ethnicity and HRQL and evaluated potential mediators (socioeconomic status, acculturation, health behaviors, diabetes mellitus-related conditions). Differences in ethnic-specific, adjusted mean HRQL scores were tested (reference whites). RESULTS: Physical HRQL was better for Filipinos (48.3, 95% confidence interval (CI) = 47.0-49.6, P < .001), Asians (48.1, 95% CI = 46.8-49.3, P < .001), Hispanics (45.1, 95% CI = 44.2-46.0, P < .001), and blacks (44.2, 95% CI = 43.3-45.1, P = .04) than whites (42.9, 95% CI = 42.6-43.2). Adjusting for potential mediators did not change these relationships. Mental HRQL was better only for Asians (52.7, 95% CI = 51.6-53.7, P = .01) than for whites (51.0, 95% CI = 50.7-51.3), but this difference was small and became nonsignificant after adjustment for socioeconomic status, acculturation, health behaviors, and diabetes mellitus-related conditions. CONCLUSION: In older adults with diabetes mellitus in a well-established integrated healthcare delivery system, ethnic minorities had better physical HRQL than whites. Equal access to care in an integrated delivery system may hold promise for reducing health disparities in diabetes mellitus-related patient-reported outcomes. PMID- 23796022 TI - Insertion of arynes into N-halo bonds: a direct approach to o-haloaminoarenes. AB - A new approach to access o-haloaminoarenes has been achieved by insertion of arynes into a nitrogen-halide bond (N-X). This transition-metal-free transformation displays a broad substrate scope of arynes, good compatibility with functional groups, and high regioselectivity. Representative transformations of the o-haloaminoarenes are described to highlight their utility for rapid access to diversely functionalized aminoarene derivatives. PMID- 23796023 TI - The gompertz function can coherently describe microbial mineralization of growth sustaining pesticides. AB - Mineralization of (14)C-labeled tracers is a common way of studying the environmental fate of xenobiotics, but it can be difficult to extract relevant kinetic parameters from such experiments since complex kinetic functions or several kinetic functions may be needed to adequately describe large data sets. In this study, we suggest using a two-parameter, sigmoid Gompertz function for parametrizing mineralization curves. The function was applied to a data set of 252 normalized mineralization curves that represented the potential for degradation of the herbicide MCPA in three horizons of an agricultural soil. The Gompertz function fitted most of the normalized curves, and trends in the data set could be visualized by a scatter plot of the two Gompertz parameters (rate constant and time delay). For agricultural topsoil, we also tested the effect of the MCPA concentration on the mineralization kinetics. Reduced initial concentrations lead to shortened lag-phases, probably due to reduced need for bacterial growth. The effect of substrate concentration could be predicted by simply changing the time delay of the Gompertz curves. This delay could to some extent also simulate concentration effects for 2,4-D mineralization in agricultural soil and aquifer sediment and 2,6-dichlorobenzamide mineralization in single-species, mineral medium. PMID- 23796024 TI - Bias-motivated bullying and psychosocial problems: implications for HIV risk behaviors among young men who have sex with men. AB - The present study aimed to determine whether the experience of bias-motivated bullying was associated with behaviors known to increase the risk of HIV infection among young men who have sex with men (YMSM) aged 18-29, and to assess whether the psychosocial problems moderated this relationship. Using an Internet based direct marketing approach in sampling, we recruited 545 YMSM residing in the USA to complete an online questionnaire. Multiple linear regression analyses tested three regression models where we controlled for sociodemographics. The first model indicated that bullying during high school was associated with unprotected receptive anal intercourse within the past 12 months, while the second model indicated that bullying after high school was associated with engaging in anal intercourse while under the influence of drugs or alcohol in the past 12 months. In the final regression model, our composite measure of HIV risk behavior was found to be associated with lifetime verbal harassment. None of the psychosocial problems measured in this study - depression, low self-esteem, and internalized homonegativity - moderated any of the associations between bias motivated bullying victimization and HIV risk behaviors in our regression models. Still, these findings provide novel evidence that bullying prevention programs in schools and communities should be included in comprehensive approaches to HIV prevention among YMSM. PMID- 23796025 TI - Cutaneous manifestations of systemic non-Hodgkin lymphomas (NHL): study and review of literature. AB - Systemic non-Hodgkin lymphomas are often accompanied by cutaneous manifestations, which are not always looked out for. Nevertheless, these alterations can be very important because their presence is lied to the clinical behaviour of the underlying malignancy, with an early recognition being fundamental. The aim of this study was to make order in this topic and propose a preliminary classification of the cutaneous manifestations associated with non-Hodgkin lymphomas. We performed a retrospective chart review of 62 haematological patients affected by non-Hodgkin systemic lymphomas with dermatological manifestations, who were evaluated from January 2007 to December 2011, and combined these results with a systematic review of Pub medical literature from 1937 to 2011 on this topic. A preliminary classification of these manifestations has been proposed, dividing them in specific and non-specific ones, along with a description of the clinical features and those cases observed in our department. A preliminary approach has been proposed for the study of these manifestations that could be helpful in understanding the biological behaviour and aid early recognition of a flare up in systemic non-Hodgkin lymphomas. PMID- 23796026 TI - On the importance of unprecedented lone pair-salt bridge interactions in Cu(II) malonate-2-amino-5-chloropyridine-perchlorate ternary system. AB - A Cu(II)-malonate complex with formula {(C5H6N2Cl)12[Cu(1)(C3H2O4)2][Cu(2)(C3H2O4)2(H2O)2][Cu(4)(C3H2O4)2][Cu(3)(C3H2O4) (H2O)2](ClO4)4}n (1) [C5H6N2Cl = protonated 2-amino-5-chloropyridine, C3H4O4 = malonic acid, ClO4(-) = perchlorate] has been synthesized from purely aqueous media simple by mixing the reactants in their stoichiometric ratio, and its crystal structure has been determined by single-crystal X-ray diffraction. In 1, copper(II) malonate units form infinite 1D polymeric chains, which are interlinked by hydrogen bonds to generate 2D sheets. These 2D sheets are joined side by side primarily by various hydrogen bonds to form a 3D structure. A multitude of salt bridges are formed in this structure, connecting the protonated 2-amino-5-chloropyridines and the malonate ligands of the polymeric polyanion. Examining this characteristic of the solid-state architecture, we noticed several salt-bridge (sb)...pi interactions and an unexplored interaction between the lone pair (lp) of one malonate oxygen atom and a planar salt bridge. The combination of this interaction with various other weak intermolecular forces results in a remarkably extended supramolecular network combining a wide variety of interactions involving pi-systems (Cl...pi, pi...pi) and salt bridges (sb...pi and lp...sb). We describe the energetic and geometric features of this lone pair salt-bridge interaction and explore its impact on the resultant supramolecular organization using theoretical DFT-D3 calculations. PMID- 23796027 TI - Advocacy of home telehealth care among consumers with chronic conditions. AB - AIMS AND OBJECTIVES: To describe use of home telehealth care as an alternative for chronic disease management from users' perspective. BACKGROUND: As the population ages, telehealth is increasingly being used to tackle problems related to the fast growing ageing population. Home telehealth care therefore poses challenges and offers opportunities for patients and healthcare providers. DESIGN: A qualitative approach was adopted with a purposeful sample of 20 patients residing in Taiwan. METHOD: Patients who had received the service for three months and were willing to share their experiences were recruited. Data were collected by face-to-face interviews with semi-structured interview guideline (n = 8) and a focus group discussion (n = 12) in 2010. A qualitative content analysis was used. RESULTS: Four key themes were identified: perceived support and security, enhanced disease self-management, concerned with using the devices and worries about the cost by patients. Most users favoured using the service to control their chronic conditions because of its convenience and accessibility, and their condition could be measured daily to enhance their sense of security. Users could determine and understand changes in their condition and improve medical regimen compliance, and they were empowered to revise their lifestyles for better disease self-management. However, users were concerned about the utility of the service, because they were unfamiliar with the operating procedures and doubted its quality. As the service is still in stage of pilot testing, users worried about possible cost and reimbursement policy changes in the future. CONCLUSION: Most users perceived telehealth care was a convenient and useful model for healthcare-delivery. It increased the availability of health care and improved the self-care ability of patients. RELEVANCE TO CLINICAL PRACTICE: To advocate for home telehealth care, nurses must play an active role in providing consumers with proper training and support for any problems when adopting the system to foster patients' willingness to use this service. PMID- 23796028 TI - Inhibition of interleukin-13 gene expression by triptolide in activated T lymphocytes. AB - BACKGROUND AND OBJECTIVE: Triptolide, a type of diterpenoid, is the active compound of Tripterygium wilfordii; it plays roles in anti-inflammatory and immune response regulation. Our objective was to investigate the mechanism of the inhibitory effect of triptolide on interleukin-13 (IL-13) gene expression in activated T lymphocytes. Understanding the molecular mechanism by which triptolide exerts a therapeutic function may be useful in developing a pharmaceutical treatment for asthma. METHODS: Peripheral blood mononuclear cells (PBMC) and Hut-78 cells were stimulated with anti-CD3/CD28 with or without co incubation with triptolide. The alteration of IL-13 messenger RNA (mRNA), expression and protein level were analysed using real-time reverse transcription polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay, respectively. The intracellular distribution profile of transcription factor GATA3 and nuclear factor of activated T cells (NFAT1) were analysed by Western blotting. The binding rates of GATA3 and NFAT1 to the promoter sequence of IL-13 were analysed by chromatin immunoprecipitation (ChIP) PCR. RESULTS: In PBMC, the release of IL-13 was dependent on anti-CD3/CD28 stimulation. Its release could be inhibited by triptolide at the concentration of 500 nmol. In Hut-78 cells, IL-13 mRNA and protein expression were increased with anti-CD3/CD28 stimulation and significantly inhibited by incubation with 28 nmol triptolide. This concentration of triptolide also significantly inhibited the nuclear translocation of GATA3 and NFAT1 reducing the binding rate to the IL-13 gene promoter. CONCLUSIONS: Triptolide inhibits IL-13 gene transcription and protein expression by inhibiting GATA3 and NFAT1 nuclear translocation and their binding rates to the IL-13 gene promoter region. PMID- 23796029 TI - Quality improvement in clinical teaching through student evaluations of rotations and feedback to departments. AB - BACKGROUND: Clinical teaching at medical schools needs continual improvement. We used a new evaluation instrument to gather student ratings on a departmental level across all clinical rotations. The ratings were used to enable cross comparison of departmental clinical teaching quality, official ranking and feedback as a method to improve teaching quality. This study was designed to evaluate whether these interventions increased the quality of clinical teaching. METHODS: A web-based questionnaire consisting of 10 questions (Likert scale 1-6) was introduced into all hospital departments at Uppsala University Hospital, Sweden. Specific feedback was given to participating departments based on the assessments collected. Action plans were created in order to address areas for departmental improvement. Questionnaire scores were used as a measure of clinical teaching quality. RESULTS: Mean follow-up time was 2.5 semesters. The student response rate was 70% (n = 1981). The departments' median ratings (25th-75th percentile) for the baseline were 4.05 (3.80-4.30). At follow-up, the median rating had increased to 4.56 (4.29-4.72) (p < 0.001). CONCLUSION: The introduction of a uniform clinical teaching evaluation instrument enabled cross comparison between clinical departments. Specific feedback enabled the development of action plans in the departments. This caused a rapid and substantial increase in the quality of clinical teaching. PMID- 23796030 TI - AGEs, contributors to placental bed vascular changes leading to preeclampsia. AB - Glycation of proteins or other biomolecules and their further long-term degradation result in the formation of advanced glycation end products, AGEs. AGEs and other ligands interact with their receptors, RAGEs, localized to a variety of tissues, but mainly in endothelium and vascular wall cells. This interaction triggers diverse signaling pathways that converge on the activation of NF-kappaB and the initiation of a local inflammatory reaction that, when prolonged, results in dysfunctional features. Preeclampsia is a serious vascular disorder centred at the placenta-uterine interface, the placental bed, but the condition extends to the mother's circulation. RAGEs have notorious expression in the placental bed tissues along pregnancy but, in addition, RAGEs and their ligands are expressed in the fetal membranes and are found in the amniotic fluid and the mother's serum. Disorders complicating pregnancies and having an important vascular involvement, as preeclampsia and diabetes mellitus, have additional enhanced AGE/RAGE expression variation. This indicates that for their assessment, the assay of RAGEs or their ligands may become useful diagnostic or prognostic procedures. PMID- 23796031 TI - Structural effects in photopolymerized sodium AMPS hydrogels crosslinked with poly(ethylene glycol) diacrylate for use as burn dressings. AB - Synthetic hydrogel polymers were prepared by free radical photopolymerization in aqueous solution of the sodium salt of 2-acrylamido-2-methylpropane sulfonic acid (Na-AMPS). Poly(ethylene glycol) diacrylate (PEGDA) and 4,4'-azo-bis(4 cyanopentanoic acid) were used as the crosslinker and UV-photoinitiator, respectively. The effects of varying the Na-AMPS monomer concentration within the range of 30-50% w/v and the crosslinker concentration within the range of 0.1 1.0% mol (relative to monomer) were studied in terms of their influence on water absorption properties. The hydrogel sheets exhibited extremely high swelling capacities in aqueous media which were dependent on monomer concentration, crosslink density, and the ionic strength and composition of the immersion medium. The effects of varying the number-average molecular weight of the PEGDA crosslinker from [Formula: see text] = 250 to 700 were also investigated. Interestingly, it was found that increasing the molecular weight and therefore the crosslink length at constant crosslink density decreased both the rate of water absorption and the equilibrium water content. Cytotoxicity testing by the direct contact method with mouse fibroblast L929 cells indicated that the synthesized hydrogels were nontoxic. On the basis of these results, it is considered that photopolymerized Na-AMPS hydrogels crosslinked with PEGDA show considerable potential for biomedical use as dressings for partial thickness burns. This paper describes some structural effects which are relevant to their design as biomaterials for this particular application. PMID- 23796032 TI - Endogenously triggered electrospun fibres for tailored and controlled antibiotic release. AB - The study was aimed at assessing the potential of enzyme-embedded antibiotic releasing polycaprolactone (PCL)-based electrospun fibres for tunable drug delivery. This was attempted by incorporation of gentamicin sulphate (GS) in the biocompatible polymer (PCL) matrix, with the degradation of the matrix being ensured by co-impregnating a polymer-degrading enzyme (lipase). Single phase solutions were obtained by hydrophobic ion pairing of GS and surfactant coating of lipase with an anionic surfactant, docusate sodium salt Aerosol OT (AOT). By electrospinning the solution, we could produce PCL fibres containing 11% (w/w) GS AOT and 28 U (w/w) lipase-AOT. However, sustained release of GS was not obtained. FESEM analysis showed that the fibres did not undergo the expected degradation. Subsequent experiments with unmodified lipase gave satisfactory results; the polymer underwent degradation displaying characteristic perforations in the fibres, suggestive of 'endo-attack'. By modulating the concentrations of lipase (1 to 28 U, w/w), we could obtain GS release rates that varied from 0.53 to 32 mg/ml/d. Accordingly, the lifetime of the fibres could be tuned (10 h to 25 days). The fibres showed excellent antibacterial activity against Staphylococcus aureus throughout their lifetime. PMID- 23796033 TI - A large mobility of hydrophilic molecules at the outmost layer controls the protein adsorption and adhering behavior with the actin fiber orientation of human umbilical vein endothelial cells (HUVEC). AB - Adhesion behaviors of human umbilical vein endothelial cells (HUVECs) are interestingly affected by the mobility of hydrophilic chains on the material surfaces. Surfaces with different molecular mobilities were prepared using ABA type block copolymers consisting polyrotaxane (PRX) or poly(ethylene glycol) (PEG) central block (A block), and amphiphilic anchoring B blocks of poly(2 methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate) (PMB). Two different molecular mobilities of the PRX chains were designed by using normal alpha-cyclodextrin (alpha-CD) or alpha-CD whose hydroxyl groups were converted to methoxy groups in a given ratio to improve its molecular mobility (PRX-PMB and OMe-PRX-PMB). The surface mobility of these materials was assessed as the mobility factor (Mf), which is measured by quartz crystal microbalance with dissipation monitoring system. HUVECs adhered on OMe-PRX-PMB surface much more than PRX-PMB and PMB-block-PEG-block-PMB (PEG-PMB) surfaces. These different HUVEC adhesions were correlated with the density of cell-binding site of adsorbed fibronectin. In addition, the alignment of the actin cytoskeleton of adhered HUVECs was strongly suppressed on the PEG-PMB, PRX-PMB, and OMe-PRX-PMB in response to the increased Mf value. Remarkably, the HUVECs adhered on the OMe-PRX PMB surface with much less actin organization. We concluded that not only the cell adhesion but also the cellular function are regulated by the molecular mobility of the outmost material surfaces. PMID- 23796034 TI - Injectable and biodegradable sugar beet pectin/gelatin hydrogels for biomedical applications. AB - Injectable hydrogels have advantages over pre-formed hydrogels in biomedical applications. In our previous study, we showed usefulness of sugar beet pectin (SBP) as an injectable gel material. However, the in vivo biodegradability of the gels was low because animals lack suitable hydrolytic enzymes of SBP. In this study we developed SBP-based injectable gels with higher in vivo biodegradability than the previous SBP gels by incorporating biodegradable gelatin into the latter. An aqueous solution with dissolved SBP and gelatin rapidly (< 1 min) formed gels through a horseradish peroxidase-catalyzed oxidative coupling reaction between feruloyl moieties on the SBP molecules and phenolic moieties on the gelatin molecules. Gelation time and mechanical properties of the gels were tunable by adjusting the polymer concentrations. The gels containing doxorubicin, an anti-cancer drug, successfully suppressed the growth of a solid tumor created by subcutaneous injection of mouse melanoma B16F1 cells into nude mice. These results indicate that injectable and biodegradable SBP/gelatin gels are useful in biomedical applications. PMID- 23796035 TI - Engineering three-dimensional macroporous hydroxyethyl methacrylate-alginate gelatin cryogel for growth and proliferation of lung epithelial cells. AB - Three-dimensional (3D) growth of cell is of particular interest in the field of tissue engineering and regenerative medicine. Scaffolds used for this purpose are often tailor-made to mimic the microenvironment and the extracellular matrix of the tissue with defined role such as to provide appropriate structural, chemical, and mechanical support. The aim of the study was to design the macroporous matrix with potential in the field of tissue engineering especially for lung muscle regeneration. Blend of hydroxyethyl methacrylate-alginate-gelatin (HAG) cryogel scaffold was synthesized using cryogelation technique and this polymer material combination is being reported first time. The rheology study showed the elastic property of the material in wet state with no variation in storage modulus (G'), loss modulus (G"), and phase angle upon temperature variation. The microcomputer tomography (micro-CT) analysis confirmed the homogenous polymer structure with average pore diameter of 84 MUm. Scaffold synthesized using polymer combinations which is mixture of polysaccharide (alginate) and protein (gelatin) provides supportive environment for human lung epithelial cell proliferation confirmed by cytoskeletal stain phalloidin and nuclei staining 4',6-diamidino-2-phenylindole checked for over three weeks. The in vivo biocompatibility was further performed which showed integration of scaffold to the surrounding tissue with ability to recruit cells. However, at first week, small amount of infiltrating mast cells were found which subsequently diminished in following weeks. Immunohistochemistry for dendritic cells confirmed in vivo biocompatible nature of the HAG scaffold. The mechanical strength, stiffness, elastic measurements, in vivo compatibility, and in vitro lung cell proliferation show the potentiality of HAG materials for lung tissue engineering. PMID- 23796036 TI - Synthesis of low-molecular weight protein (LMWP) lysozyme-curcumin conjugates for kidney drug targeting. AB - The low-molecular weight protein (LMWP) lysozyme is a suitable drug carrier for renal drug targeting. Presented herein is a lysozyme-curcumin renal drug delivery system that possesses the potential to achieve a highly effective yet less toxic therapy. Briefly, the approach involves synthesis of the lysozyme-drug (curcumin) conjugates by coupling the drug to the activated functional groups on lysozyme via hydrolyzable ester linkages. The successful synthesis of LMWP lysozyme curcumin (LZMC) conjugates was determined by Fourier transform infrared spectroscopy and (1)H NMR. The cellular uptake of LZMC conjugates was tested against proximal tubular (HK-2) cells. Compared to free curcumin, the LZMC conjugates exhibited high-cellular uptake efficiency in HK-2 cells. Fluorescence image of mouse kidneys at different time points after free curcumin and LZMC conjugates tail vein injection shows that the kidney of mice injected with LZMC conjugates showed the strongest fluorescence signals, and the specific signals last for at least 26 h. PMID- 23796037 TI - Neuronal cells' behavior on polypyrrole coated bacterial nanocellulose three dimensional (3D) scaffolds. AB - In this work, polypyrrole (PPy) was in situ polymerized onto the surface of bacterial nanocellulose (BNC) produced by Gluconacetobacter xylinus, by chemical oxidation in aqueous medium using ammonium persulfate. Composites (BNC/PPy) were produced with varying concentrations of pyrrole (Py). The produced BNC/PPy membranes were used as a template for the seeding of PC12 rat neuronal cells. Cell suspensions were directly seeded onto the surfaces of the BNC/PPy membranes. The Py concentration affected the behavior of neuronal cells that adhered and grew significantly more on BNC/PPy comparatively to BNC. Scanning electron microscopy (SEM) micrographs revealed that PC12 cells adhered on the surface of the BNC and BNC/PPy membranes. Conductive PPy coatings on nanofibers acting as an active interface for tissue engineering may be used to regulate cell activity through electrical stimulations. PMID- 23796038 TI - Biomechanical characterization of a low density silicone elastomer filled with hollow microspheres for maxillofacial prostheses. AB - An ideal material for maxillofacial prostheses has not been found. We created a novel material: silicone elastomer filled with hollow microspheres and characterized its biomechanical properties. Expancel hollow microspheres were mixed with MDX4-4210 silicone elastomer using Q7-9180 silicone fluid as diluent. The volume fractions of microspheres were 0, 5, 15, and 30% v/v (volume ratio to the total volume of MDX4-4210 and microspheres). The microspheres dispersed well in the matrix. The physical properties and biocompatibility of the composites were examined. Shock absorption was the greatest by the 5% v/v composite, and decreased with increasing concentrations of microspheres. The density, thermal conductivity, Shore A hardness, tear and tensile strength decreased with increasing concentrations of microspheres, while elongation at break increased. Importantly, the tear strength of all composites was markedly lower than that of pure silicone elastomer. Cell viability assays indicated that the composite was of good biocompatibility. The composite with a volume fraction of 5% exhibited the optimal properties for use as a maxillofacial prosthesis, though its tear strength was markedly lower than that of silicone elastomer. In conclusion, we developed a novel light and soft material with good flexibility and biocompatibility, which holds a promising prospect for clinical application as maxillofacial prosthesis. PMID- 23796039 TI - First fabrication of electrowetting display by using pigment-in-oil driving pixels. AB - We report the first fabrication of pigment particle-based electrowetting display (EWD) by using the requisite poly(isobutylene)-imide (PIB-imide) for effectively dispersing insoluble colorant in decane/water system. The series of PIB-imide dispersants were prepared from the amidation/imidation of PIB-succinic anhydride with different hydrophobic lengths and a suitable amine. The structurally tailored dispersants by adopting the highly hydrophobic PIB tails allows the formation of homogeneous dispersion of nanosized pigment particles in decane and clearly separated from water. The pigment dispersion at particle size of ca. 100 nm and a low viscosity of 2-3 cps was obtained and fabricated into an EWD device which was operated at a driving voltage of 15-20 V in achieving a maximum aperture ratio of 80%. With the advantage of both fast response time and vivid color, the pigment-based EWD, as shown in the video, stands out as a promising new option for future transparent display and serves as a critical foundation for the next-generation advanced display applications. PMID- 23796041 TI - Oxazinoindolines as fluorescent H+ turn-on chromoionophores for optical and electrochemical ion sensors. AB - We propose here a new class of fluorescent H(+) turn-on oxazinoindoline (Ox) dyes as chromoionophores suitable for the development of polymeric ion-selective membranes. Through rational design, oxazinoindolines with varying basicities and tunable absorption bands that extend to the near-infrared region were prepared. The basicities of the compounds were evaluated by potentiometry and fluorescence spectroscopy. By comparing the potentiometric lower detection limit with chromoionophore I (pKa = 14.80 +/- 0.03 in PVC-NPOE), pKa values were determined for Ox Y, Ox R, and Ox B to be 9.80 +/- 0.03, 12.85 +/- 0.03, and 12.95 +/- 0.03, respectively. Unlike conventional pH indicators that involve only a protonated and deprotonated form, a third species, arising from the thermal isomerization of the Ox compounds in polar solvents, may influence the overall protonation equilibrium. Interestingly, this results in an apparent pKa increase in the fluorescence mode when more polar PVC-NPOE membranes were utilized. The isomerization is suppressed in nonpolar PVC-DOS membranes. Na(+)-selective optical sensors were successfully prepared using the Ox dyes as an early application of the compounds in ion-selective optical sensors. The compounds were also successfully evaluated in a dynamic electrochemistry (chronopotentiometry) sensing mode for the detection of total alkalinity. PMID- 23796040 TI - The evolving course of HNF4A hyperinsulinaemic hypoglycaemia--a case series. AB - BACKGROUND: Hepatocyte nuclear factor 4 alpha (HNF4A) gene mutations have a well recognized role in maturity-onset diabetes of the young and have recently been described in congenital hyperinsulinism. A biphasic phenotype has been postulated, with macrosomia and congenital hyperinsulinism in infancy, and diabetes in young adulthood. In this case series, we report three children with HNF4A mutations (two de novo) and diazoxide-responsive congenital hyperinsulinism, highlighting the potential for ongoing diazoxide requirement and the importance of screening for these mutations even in the absence of family history. CASE REPORTS: All patients presented with macrosomia (mean birthweight 4.26 kg) and hyperinsulinaemic hypoglycaemia soon after birth (median age 1 day). All three (age range 7 months to 11 years 10 months) remain on diazoxide therapy, with dose requirements increasing in one patient. There was no prior family history of diabetes, neonatal hypoglycaemia or macrosomia. Parents were screened for HNF4A mutations post-diagnosis and one father was subsequently found to have maturity-onset diabetes of the young. CONCLUSIONS: This case series follows the evolving course of three patients with confirmed HNF4A-mediated congenital hyperinsulinism, highlighting (1) the variable natural history of these mutations, (2) the potential for prolonged diazoxide requirement, even into adolescence, and (3) the need for screening, regardless of family history. PMID- 23796042 TI - The cost of keeping it hidden: decomposing concealment reveals what makes it depleting. AB - People possess information or identities that it sometimes behooves them to conceal, but at what cost? Participants who were instructed to conceal information during a short interview--either their sexual orientation (Studies 1 3) or specified words (Study 4)--showed evidence of self-regulatory depletion. Concealment led to deficits in intellectual acuity, interpersonal restraint, physical stamina, and executive function. We decomposed depletion into 2 component processes that, together or separately, might contribute to the observed depletion. When actively concealing information, one must monitor for specific content to inhibit. If taboo content is detected, one must modify or alter one's speech from what one would have said otherwise. Concealment produced depletion even when there was no need to actually alter one's speech (Studies 2 and 4), demonstrating that monitoring one's speech for content to conceal was sufficient to cause depletion. In contrast, having to alter one's speech without having to monitor for specific content to inhibit--either by adding false content (Study 3) or inserting specific words into one's speech stream (Study 4)--did not lead to measurable depletion. In this way, the studies are the first to assess which part of an act of self-regulation--monitoring for specific behavior to override or the actual altering of that behavior--is responsible for observed depletion. Furthermore, the research suggests that social environments that explicitly or implicitly encourage identity concealment may prevent people from performing optimally. PMID- 23796043 TI - What is learned from repeated pairings? On the scope and generalizability of evaluative conditioning. AB - The investigation of evaluative conditioning (EC) has been mainly concerned with the conditioning of individual stimuli. Namely, a specific conditioned stimulus (CS) is paired with a positive or negative unconditioned stimulus and consequently acquires the valence of the unconditioned stimulus. In the present article, we expand the notion of EC to CS cues (e.g., gender) as distinguished from CS objects (e.g., an individual). We developed a conditioning paradigm that allows for the simultaneous investigation of both types of EC effects, evaluative identity conditioning and evaluative cue conditioning. The experiments demonstrate that EC has the potential to change attitudes not only toward CS individuals but also toward CS cues. We applied this twofold approach to both impoverished and more complex learning environments, demonstrating that evaluative identity conditioning is dependent on stimulus complexity while evaluative cue conditioning depends on the complexity of the stimulus context. The findings have distinct implications for the generalization of EC effects as well as for the investigation of EC. PMID- 23796044 TI - Differential iron-bioavailability with relation to nutrient compositions in polished rice among selected Chinese genotypes using Caco-2 cell culture model. AB - Genotypic variation of iron bioavailability and the relationship between iron bioavailability and nutrient composition in polished rice among 11 rice genotypes were assessed using an in vitro digestion/Caco-2 cell model. The results indicated that significant differences in iron bioavailability were detected among tested rice genotypes, with a 3-fold range, suggesting a possibility of selecting high bioavailable iron by plant breeding. Although iron bioavailability was not significantly correlated with Fe concentration in polished rice among tested rice genotypes, the results also indicated that most of the iron dense genotypes showed relatively high ferritin formation in Caco-2 cell and transported iron. Additionally, iron bioavailability in polished rice was enhanced by addition of ascorbic acid, with a much wider range of Fe bioavailability variation in polished rice with addition of ascorbic acid than that without addition of ascorbic acid. The positive relationship between iron bioavailability in polished rice and cysteine concentration (R = 0.669) or sulfur (S) concentration (R = 0.744) among tested rice genotypes, suggests that cysteine and sulfur concentration in polished rice could be used as an indicator for high iron bioavailability. PMID- 23796045 TI - The effect of sildenafil on evolving bronchopulmonary dysplasia in extremely preterm infants: a randomised controlled pilot study. AB - OBJECTIVE: Sildenafil has been shown to preserve alveolar growth and lung angiogenesis in a rat model of bronchopulmonary dysplasia. We conducted a proof of-concept randomised controlled pilot study to assess the feasibility of oral sildenafil treatment in extremely preterm infants with evolving bronchopulmonary dysplasia. METHODS: Preterm infants <28 weeks gestational age were eligible if they were mechanically ventilated on day 7 of life. Infants were randomised to a 4-weeks course of either oral sildenafil (3 mg/kg/day) or placebo solution. Pre discharge cardiorespiratory outcomes and medication side effects were collected. RESULTS: Twenty infants were randomised, 10 received sildenafil (mean gestational age 24 + 5 weeks (SD 4.9 days), mean weight 692 g (SD 98)) and 10 received placebo (mean gestational age 24 + 5 weeks (SD 6.5 days), mean weight 668 g (SD 147)). One infant in the sildenafil group did not receive treatment because of an early pneumoperitoneum. Two infants did not complete the study (transferred out). Of the remaining seven treated infants, three died (two from respiratory-related causes). One infant in the control group died from a non-respiratory cause. Sildenafil did not reduce length of invasive (median 688 versus 227 h) or non invasive ventilation (median 1609 versus 1416 h). More infants in the sildenafil group required postnatal steroid treatment. One infant developed hypotension following sildenafil administration and was excluded after three doses. CONCLUSIONS: In this pilot study, oral sildenafil treatment did not improve any short-term respiratory outcomes in extremely preterm infants. PMID- 23796046 TI - Use of evidence in clinical guidelines and everyday practice for mechanical ventilation in Swedish intensive care units. AB - BACKGROUND AND AIM: One way to support evidence-based decisions in health care is by clinical guidelines, in particular, in highly specialized care such as intensive care units (ICUs). The aim of this study was to explore the development and dissemination of guidelines regarding mechanical ventilation (MV) in Swedish ICUs, and the use of evidence on MV in guidelines and everyday practice. METHODS: Inviting all general ICUs in Sweden (N = 65), a national survey was performed on occurrence of MV guidelines, and a review of submitted ICU guidelines by four evidence items from the AGREE instrument. In addition, ICU head nurses and senior physicians were interviewed using semistructured and open-ended questions to explore development and dissemination of MV guidelines, staff adherence or nonadherence to guidelines, and everyday practice of MV management bedside. FINDINGS: Fifty-five ICUs (85%) participated in the study; 51 ICUs submitted a total of 245 guidelines, including recommendations for medical or nursing MV actions. None of the documents included how evidence had been sought or assessed, while 22% included a list of references (n = 54). No guidelines included patients' experiences of MV. According to the managers, the guidelines were most often compiled by a multiprofessional team sharing the information through the ICU's website. The guidelines were mainly used as a basis for MV management bedside, but variation occurred as a result of personal preferences, lack of awareness, and adjustment to patients' needs. CONCLUSIONS: Local MV guidelines seem to constitute a basis for healthcare practice in Swedish ICUs, even though the evidence proposed was limited with respect to how it was attained and lacked patient perspectives. In addition, the strategies used for dissemination were limited, suggesting that further initiatives are needed to support knowledge translation in advanced healthcare environments such as ICUs. PMID- 23796047 TI - What do people appreciate in physicians' communication? An international study with focus groups using videotaped medical consultations. AB - BACKGROUND: The literature shows that the quality of communication is usually determined from a professional perspective. Patients or lay people are seldom involved in the development of quality indicators or communication. OBJECTIVE: To give voice to the lay people perspective on what constitutes 'good communication' by evoking their reactions to variations in physician communication. DESIGN: Lay people from four different countries watched the same videotaped standardized medical encounters and discussed their preferences in gender-specific focus groups who were balanced in age groups. SETTING AND PARTICIPANTS: Two hundred and fifty-nine lay people (64 NL, 72 IT, 75 UK and 48 BE) distributed over 35 focus groups of 6-8 persons each. MAIN VARIABLES STUDIED: Comments on doctors' behaviours were classified by the GULiVer framework in terms of contents and preferences. RESULTS: Participants prevalently discussed 'task-oriented expressions' (39%: competency, self-confident, providing solutions), 'affective oriented/emotional expressions' (25%: empathy, listening, reassuring) and 'process-oriented expressions' (23%: flexibility, summarizing, verifying). 'Showing an affective attitude' was most appreciated (positive percentage within category: 93%, particularly facilitations and inviting attitude), followed by 'providing solution' (85%). Among disfavoured behaviour, repetitions (88%), 'writing and reading' (54%) and asking permission (42%) were found. CONCLUSIONS: Although an affective attitude is appreciated by nearly everybody, people may vary widely in their communication needs and preferences: what is 'good communication' for one person may be disliked or even a source of irritation for another. A physician should be flexible and capable of adapting the consultation to the different needs of different patients. This challenges the idea of general communication guidelines. PMID- 23796048 TI - Hemorrhagic complications of direct thrombin inhibitors-subarachnoid hemorrhage during dermabrasion for scar revision. PMID- 23796050 TI - Pattern-based sensing of peptides and aminoglycosides with a single molecular probe. AB - A coumarin-based molecular probe can be used for the sensing of peptides and aminoglycoside antibiotics. The probe reacts with the primary amine group(s) of the analytes to give a mixture of covalent adducts with distinct colors. Each analyte gives rise to a characteristic UV-vis spectrum. A pattern-based analysis of the spectra allows identifying structurally related analytes. Furthermore, it is possible to obtain information about the quantity and the purity of the analytes. PMID- 23796049 TI - Open access to tree genomes: the path to a better forest. AB - An open-access culture and a well-developed comparative-genomics infrastructure must be developed in forest trees to derive the full potential of genome sequencing in this diverse group of plants that are the dominant species in much of the earth's terrestrial ecosystems. PMID- 23796051 TI - Theoretical studies of potential energy surface and bound states of the strongly bound He(1S)-BeO (1Sigma+) complex. AB - We perform electronic structure calculations of the potential energy surface of the He...BeO((1)Sigma(+)) complex. We use several different methods to characterize this unusual interaction. We apply coupled cluster singles, doubles, and noniterative triples [CCSD(T)] and the multireference configuration interaction [MRCI] levels of theory. The nature of the interaction is studied with symmetry-adapted perturbation theory (SAPT) based on DFT and CCSD description of the intramonomer electron densities. Our best estimate of the well depth is 1876.5 cm(-1) at the CCSD(T) level, while the dissociation energy, corrected for the zero-point energy, is equal to 1446.7 cm(-1). The global minimum is located for the collinear He...Be-O geometry at Re = 4.45a0. The rotational constant of the He-BeO complex in its ground state is 0.863 cm(-1). We also calculate bound states of the He...BeO complex for J = 0 and J = 1 (total angular momentum). PMID- 23796052 TI - Fluticasone uptake across Calu-3 cells is mediated by salmeterol when deposited as a combination powder inhaler. AB - BACKGROUND AND OBJECTIVE: We assessed whether co-deposition of a long-acting beta2 -agonist and a corticosteroid affects their respective transport rates across epithelial cells. METHODS: Drug particles were deposited on the air interface culture of Calu-3 cells using a twin-stage impinger. We compared the transport rate of salmeterol and fluticasone across the epithelial cells using commercially available formulations (Serevent, Flixotide and Seretide). The transepithelial resistance of Calu-3 cells was measured before and after each deposition to monitor epithelial resistance. RESULTS: The codeposition of salmeterol and fluticasone had no significant effect on transport of salmeterol through the cell layer. In contrast, the rate of fluticasone propionate transport in presence of salmeterol xinofoate was significantly lower (0.53 +/- 0.20%) compared with the single fluticasone formulation (2.36 +/- 0.97%). Furthermore, the resistance of the epithelial cells was significantly increased after salmeterol deposition from both single and combination products. CONCLUSIONS: Our data demonstrate that salmeterol may decrease the permeability of epithelial cells, resulting in slower fluticasone transport across Calu-3 epithelial monolayers. The subsequent increased residence time of fluticasone in the airways could prolong its anti-inflammatory effects. PMID- 23796053 TI - Antioxidant phenolic glycoside and flavonoids from Pieris japonica. AB - A new phenolic glycoside, benzyl 2-hydroxy-4-O-beta-D-glucopyranosyl-benzoate (1), along with nine known flavonoids, epicatechin-(2 -> O -> 7,4 -> 8)-ent epicatechin (2), bis-8,8'-catechinylmethane (3), quercetin (4), quercetin-3-O alpha-L-arabinfuranoside (5), quercetin-3-O-alpha-L-rhamnopyranoside (6), astilbin (7), engeletin (8), (2S,3R)-ent-catechin (9), and 2',4-dihydroxy-4' methoxy-6'-O-beta-D-glucopyranosyl dihydrochalcone (10), was isolated from the flowers of Pieris japonica. Their structures were elucidated on the basis of MS, 1D NMR, and 2D NMR techniques. This paper describes the isolation, structural elucidation as well as in vitro antioxidant activity of these compounds. PMID- 23796054 TI - Monitoring trehalose uptake and conversion by single bacteria using laser tweezers Raman spectroscopy. AB - Having the ability to monitor metabolic activity at the scale of single bacterial cells noninvasively would enable us to follow changes in the distribution of activity in bacterial systems which is of major importance for topics such as integration of metabolism and development, metabolic engineering, microbial activity and drug resistance, cell-cell interactions, and quorum sensing. Here, we used laser tweezers Raman spectroscopy to monitor the in vivo real-time uptake and conversion of trehalose by single bacterial cells. This approach can be used for the quantitative determination of sugar uptake by a single bacterium and its metabolic response to the sugar application with time. We show that uptake of trehalose can be quantified in single living bacterial cells held in place by an optical trap while simultaneously collecting Raman spectra upon application of sugar to the medium. This technique yields real-time chemical information in a label-free manner, thus eliminating the limitations of toxicity of the isotopic probes common in studying transport processes. It can substitute the laborious and time-consuming analytical evaluation. Although the single-cell Raman spectroscopy method demonstrated here is focused on the study of trehalose uptake by Sinorhizobium meliloti, the demonstrated approach is applicable to many different organisms and carbohydrates in general. PMID- 23796055 TI - Brain structural change and gait decline: a longitudinal population-based study. AB - OBJECTIVES: To investigate longitudinal associations between changes in brain structure and gait decline. DESIGN: Longitudinal. SETTING: Population-based Tasmanian Study of Cognition and Gait. PARTICIPANTS: Two hundred twenty-five individuals aged 60 to 86 (mean age 71.4 +/- 6.8) randomly selected from the electoral roll with baseline and follow-up data. MEASUREMENTS: Volumes of gray matter, white matter, hippocampi, and white matter lesions (WML) were estimated using automated segmentation from magnetic resonance imaging (MRI). Gait variables were measured using a computerized walkway. Linear regression was used to estimate the association between change in brain MRI measures and change in gait. Time between measurements, age, sex, BMI, education level, total intracranial volume, baseline infarcts, and medical history were used as baseline covariates. RESULTS: Mean follow-up was 30.6 months. White matter atrophy was associated with a decline in gait speed (P = .001), step length (P = .005), and cadence (P = .001). WML progression was associated with a decline in gait speed (P = .04), and its association with decline in step length was stronger with greater baseline age (P for interaction = .04). Hippocampal atrophy was associated with a decline in gait speed (P = .006) and step length (P = .001). Total gray matter atrophy was associated with decline in cadence in those with cerebral infarcts (P for interaction = .02). CONCLUSION: These are the first longitudinal data demonstrating the relative contributions of brain atrophy and WML progression to gait decline in older people. Effect modification according to age and infarcts suggests a contribution of reduced physiological and brain reserve. Interventions targeting brain health may be important in preventing mobility decline in older people. PMID- 23796056 TI - Integrating continuing medical education and faculty development into a single course: effects on participants' behaviour. AB - BACKGROUND: Integrating continuing medical education (CME) and faculty development (FD) into a single course can save time for physicians with teaching responsibilities. However, little is known about the effectiveness of integrated courses. AIM: To determine if there are differences in effectiveness between the CME and FD items as they were integrated in one course. METHODS: Using the commitment-to-change model to assess plans for change from all participants and reported implementation of plans three month after courses. This model is suitable for stimulating and assessing effectiveness of CME. Unplanned changes were also recorded. RESULTS: One hundred and twenty-seven respondents (of 182 participants) referred to 266 planned changes (out of 384), of which 168 (63%) were reported as implemented. Furthermore, 83 non-planned changes were indicated. In total 251 changes were reported and demonstrated that CME as well as FD items were effective. CONCLUSIONS: This study reveals that integrating CME and FD into a single course is highly effective in changing physicians' medical practice as well as teaching practice. Although all course items were effective, participants choose more FD items than CME, so future research has to focus on which variables determine those choices. PMID- 23796057 TI - Characterization of insertion sites and development of locus-specific assays for three broiler-derived subgroup E avian leukosis virus proviruses. AB - This report deals with the identification of novel elements belonging to a family of endogenous retroviruses, designated endogenous avian leukosis virus-type proviral elements (ALVE), that reside in the genome of the chicken and are closely related to exogenous avian leukosis viruses. The study of ALVE elements in the chicken genome serves as a model system for understanding the interplay between endogenous viruses and their vertebrate hosts in general, including humans. In this report, we characterize the insertion sites and describe locus specific, diagnostic polymerase chain reaction-based assays for three previously discovered, but as yet not localized, ALVE elements. In addition, we assess the proviral integrity, provide the complete element sequence and examine the genomic environs of the three broiler-derived elements. PMID- 23796059 TI - Motor inhibition in aging: impacts of response type and auditory stimulus. AB - The authors examined the effects of response types and the presentation of auditory stimulus on motor inhibition. Continuous responding tasks were conducted with 27 younger adults and 39 older adults. The results indicated the following: (a) response type significantly affected error rates in older adults, (b) the presentation of an auditory stimulus facilitated responses and decreased reaction times in both younger and older adults, (c) the presentation of an auditory stimulus also increased error rates in older adults, and (d) the effect of response type on error rate remained in experiments conducted under different conditions in older adults. This suggests that in older adults, movement and the associated nervous excitation have significant effects on motor inhibition. PMID- 23796060 TI - Sewage sludge biochar influence upon rice (Oryza sativa L) yield, metal bioaccumulation and greenhouse gas emissions from acidic paddy soil. AB - Biochar addition to soil has been proposed to improve plant growth by increasing soil fertility, minimizing bioaccumulation of toxic metal(liod)s and mitigating climate change. Sewage sludge (SS) is an attractive, though potentially problematic, feedstock of biochar. It is attractive because of its large abundance; however, it contains elevated concentrations of metal(loid)s and other contaminants. The pyrolysis of SS to biochar (SSBC) may be a way to reduce the availability of these contaminants to the soil and plants. Using rice plant pot experiments, we investigated the influence of SSBC upon biomass yield, bioaccumulation of nutrients, and metal(loid)s, and green housegas (GHG) emissions. SSBC amendments increased soil pH, total nitrogen, soil organic carbon and available nutrients and decreased bioavailable As, Cr, Co, Ni, and Pb (but not Cd, Cu, and Zn). Regarding rice plant properties, SSBC amendments significantly (P <= 0.01) increased shoot biomass (71.3-92.2%), grain yield (148.8-175.1%), and the bioaccumulation of phosphorus and sodium, though decreased the bioaccumulation of nitrogen (except in grain) and potassium. Amendments of SSBC significantly (P <= 0.05) reduced the bioaccumulation of As, Cr, Co, Cu, Ni, and Pb, but increased that of Cd and Zn, though not above limits set by Chinese regulations. Finally regarding GHG emissions, SSBC significantly (P < 0.01) reduced N2O emissions and stimulated the uptake/oxidation of CH4 enough to make both the cultivated and uncultivated paddy soil a CH4 sink. SSBC can be beneficial in rice paddy soil but the actual associated benefits will depend on site-specific conditions and source of SS; long-term effects remain a further unknown. PMID- 23796061 TI - Person-centred reviews as a mechanism for planning the post-school transition of young people with intellectual disability. AB - BACKGROUND: Person-centred planning has played a key role in the transformation of intellectual disabilities services for more than a decade. The literature has identified clear advantages for service users when service delivery is planned around the individual rather than the user is made to fit into service structures. Researchers however have pointed out that there is a lack of evidence that person-centred planning positively influences outcomes for users. METHOD: Our study examined the application of person-centred planning during transition for young people with intellectual disabilities. We investigated the nature and content of 44 person-centred reviews of transition planning for this population in a local authority in the UK. We carried out a documentary analysis of all person-centred plans and conducted telephone interviews with all families participating in the programme. We focused on the issue of attendance at review meetings and what was discussed during the meetings. RESULTS: Analysis of the data shows an increase in the participation of young people and carers at review meetings and a significant shift in topics discussed during the transition planning process compared with previous programmes. However, some of these effects may dissipate once young people are actually leaving school as planning well is not synonymous with having an improved range of placement options. CONCLUSIONS: The findings suggest that person-centred planning can impact positively on some aspects of transition planning, while it may be too optimistic to expect radical improvement in other area. Key to further improvements is to complement person-centred planning with consistent involvement of all relevant stakeholders in planning for individuals. PMID- 23796062 TI - The roles of miR-146a in the differentiation of Jurkat T-lymphoblasts. AB - INTRODUCTION: T-cell acute lymphoblastic leukemia (T-ALL) is caused by a defect in T-cell maturation to the mature T cell. T-ALL is a poor prognostic hematopoietic malignancy. In order to establish a successful therapeutic treatment plan, it is essential to understand the biology of T-cell development and molecules that contribute to this process. This study uses Jurkat T cells, as a well-established model for in vitro study of T-ALL to investigate the role of the microRNA (miRNA), miR-146a, on gene expressions involved in T-cell differentiation. MATERIALS AND METHODS: The permanent over-expression of miR-146a was established using a lentivector that expressed GFP hsa-mir-146a miRNA. We used quantitative real-time polymerase chain reaction and flow cytometry for T cell differentiation to monitor induction of the differentiation process by assessing changes in expression of some distinct transcription factors and cell surface markers. RESULTS: Ectopic expression of miR-146a resulted in significant up-regulation of PU.1, c-Fos, CCAAT/enhancer-binding protein alpha (C/EBPalpha) and GATA3, and slight up-regulation of Foxp3 and Runx1. There was a significant, moderate down-regulation in the expressions of Notch1, LIM-domain only (Lmo2), son of sevenless 1 (SOS1), Ikaros, and signal transducer and activator of transcription 3 (STAT3). CONCLUSION: Our results indicated that ectopic expression of miR-146a could not independently induce differentiation in lymphoblastic cells. However, the expression of multiple genes involved in T-cell differentiation and T-cell CD markers were found to be affected. These results have suggested a potential tumor suppressive, immunomodulatory and cell activator role for miR146-a. PMID- 23796063 TI - Forage and sugar in dairy calves' starter diet and their interaction on performance, weaning age and rumen fermentation. AB - The effects of sugar and forage inclusion in calves' starter and their interaction on animal performance and rumen fermentation parameters were investigated. Twenty-eight neonatal Holstein male calves 3 days of age with average body weights of 42 +/- 4 kg were allocated to four different treatments. All calves were fed a similar basal diet consisting of milk and concentrate. The experimental treatments were: (i) basal diet with no supplementation (Control, hereafter designated by C), (ii) basal diet plus 5% granular sugar cane (Sugar, designated by S), (iii) basal diet plus 5% forage (Forage, designated by F) and (iv) basal diet plus 5% forage with 5% granular sugar cane (F * S). Supplement ingredients were used on a dry matter (DM) basis. Rumen fluid parameters were measured twice on days 35 and 70 of the study period. The calves were weaned when they could consume 1 kg of starter for three consecutive days. The results show that starter intake was not affected by treatment; however, the lowest ADG was observed with calves in the sugar treatment. Weaning age was affected by treatments, and forage showed to reduce milk consumption period down to its shortest. Forage-sugar interaction was found to have no effects on animal performance. The structural body indices as well as the health status of the calves were similar in different treatments. Rumen pH did not differ among the treatment groups. Among the rumen parameters, total VFA concentration and molar proportions of butyrate and propionate did not exhibit any significant differences among the treatments. However, ruminal acetate concentration decreased in calves that fed sugar cane during the early weeks of the study period. Comparison of forage and sugar included in the starter diets revealed that forage reduced weaning age, while sugar cane had a negative effect on calves' performance. PMID- 23796064 TI - Risk of pneumonia and pneumococcal disease in people hospitalized with diabetes mellitus: English record-linkage studies. AB - BACKGROUND: The risk of invasive pneumococcal disease is higher in people with diabetes mellitus than those without. People with diabetes should be considered for routine pneumococcal immunization. This policy has been in place in England for more than a decade. We aimed to estimate, at the population level, the current scale of excess risk of pneumococcal disease in patients with diabetes, and whether the risks have decreased in recent years with the introduction of a pneumococcal vaccine. METHODS: We used two data sets of linked hospital admission and death records-the Oxford Record Linkage Study (1963-1998) and all-England linked hospital episode statistics (1999-2011). As a measure of relative risk, we calculated the rate ratio of pneumococcal disease in cohorts of people hospitalized with diabetes compared with cohorts without a record of diabetes. RESULTS: The risk of pneumococcal disease in patients hospitalized with diabetes mellitus has declined a little, but it is still high. The all-ages rate ratio in England declined from 1.92 (95% CI 1.89-1.94) in 1999-2002 to 1.68 (95% CI 1.65 1.71) in 2007-2011. In people aged under 60 years, rate ratios were higher and their decline was more substantial: rate ratios declined from 3.37 (95% CI 3.28 3.46) in 1999-2002 to 2.33 (95% CI 2.21-2.45) in 2007-2011. CONCLUSIONS: Patients admitted to hospital with diabetes mellitus remain at increased risk of pneumococcal infection despite a national immunization policy. Possible explanations for the elevated risk include low vaccine uptake or low effectiveness of available vaccine. Clinicians should be aware of the risk of pneumococcal infection in people with diabetes. PMID- 23796065 TI - Rapid guidance of visual search by object categories. AB - Visual search is often controlled by attentional templates that represent specific target items or target features, but can also be directed toward object categories. We studied the relationship between item-based and category-guided attentional control during visual search for one specific item (e.g., the letter C), two or three items (e.g., the letters C, F, and X), or categorically defined targets (e.g., any letter). To assess the efficiency of visual search for single, multiple, or category-defined targets, we measured the N2pc component as an electrophysiological marker of attentional target selection. In Experiment 1, where targets were presented among distractors from a different category (e.g., letters among digits), a category-based selection strategy was available. Category-based attentional control triggered spatially selective modulations of visual-perceptual processing that emerged within less than 200 ms after stimulus onset and preceded the effects of item-specific attentional templates. In Experiment 2, where letter targets appeared among letter distractors, target detection could no longer be guided by categorical top-down task sets. Search efficiency decreased as the target set size increased, in line with capacity limitations for item-specific attentional templates. Results demonstrate that category-based attentional guidance can be used rapidly and efficiently during visual search for alphanumeric targets. PMID- 23796066 TI - Turning knowledge into action at the point-of-care: the collective experience of nurses facilitating the implementation of evidence-based practice. AB - BACKGROUND: Facilitation is considered a way of enabling clinicians to implement evidence into practice by problem solving and providing support. Practice development is a well-established movement in the United Kingdom that incorporates the use of facilitators, but in Canada, the role is more obtuse. Few investigations have observed the process of facilitation as described by individuals experienced in guideline implementation in North America. AIM: To describe the tacit knowledge regarding facilitation embedded in the experiences of nurses implementing evidence into practice. METHODS: Twenty nurses from across Canada were purposively selected to attend an interactive knowledge translation symposium to examine what has worked and what has not in implementing evidence in practice. This study is an additional in-depth analysis of data collected at the symposium that focuses on facilitation as an intervention to enhance evidence uptake. Critical incident technique was used to elicit examples to examine the nurses' facilitation experiences. Participants shared their experiences with one another and completed initial data analysis and coding collaboratively. The data were further thematically analyzed using the qualitative inductive approach of constant comparison. RESULTS: A number of factors emerged at various levels associated with the successes and failures of participants' efforts to facilitate evidence-based practice. Successful implementation related to: (a) focus on a priority issue, (b) relevant evidence, (c) development of strategic partnerships, (d) the use of multiple strategies to effect change, and (e) facilitator characteristics and approach. Negative factors influencing the process were: (a) poor engagement or ownership, (b) resource deficits, (c) conflict, (d) contextual issues, and (e) lack of evaluation and sustainability. CONCLUSIONS: Factors at the individual, environmental, organizational, and cultural level influence facilitation of evidence-based practice in real situations at the point-of-care. With a greater understanding of factors contributing to successful or unsuccessful facilitation, future research should focus on analyzing facilitation interventions tailored to address barriers and enhance facilitators of evidence uptake. PMID- 23796067 TI - Pharmacokinetics of caspofungin increased dosage in a patient on rifampin containing anti-tubercular treatment. AB - We describe a patient treated with caspofungin and rifampin; after increasing the dosage of the former (70 mg/day) we observed an unexpectedly lower plasma exposure (AUC0-24 79.5 MUg/ml*h vs. 108.8 MUg/ml*h). Although rifampin-mediated complete enzyme induction may take longer than 2 weeks, the clinical advantage of an increased caspofungin dose deserves clinical investigation. PMID- 23796068 TI - Maternal race and neonatal outcomes after elective repeat cesarean delivery. AB - OBJECTIVE: To determine the effect of race in the risks of prematurity-related complications (PRC) after elective repeat cesarean delivery (ERCD). METHODS: The NCHS-CDC Database for the U.S. (2004-2008) was used. ERCD cases were included. Exclusion criteria were multiple gestation, trial of labor, fetal anomalies, history of diabetes and/or hypertension. PRC analyzed were: Apgar score, assisted ventilation, intensive care admission, surfactant use, antibiotic use, seizures. Regression analysis was performed to calculate the odds ratio (OR) of these variables. Deliveries at 36-40 weeks were studied with 40 weeks as reference. RESULTS: Totally, 785,340 ERCDs were performed between 36 and 40 weeks. For the overall population, there was not difference in adverse outcomes between 39 and 40 weeks. The rates of PRC were significantly higher in newborns at 38 compared to 39 weeks, with similar findings in sub-analysis of whites. For African Americans, the rate of PRC was not significantly different at 38 compared to 39 weeks. CONCLUSIONS: We report increased rates of PRC after ERCD before 39 weeks, similar findings from smaller hospital-based studies. For African-American newborns, there was no further decrease in PRC after 38 weeks suggesting earlier maturation of these fetuses. The study does not propose changing the current 39 weeks threshold for ERCD. PMID- 23796069 TI - Physically adsorbed fullerene layer on positively charged sites on zinc oxide cathode affords efficiency enhancement in inverted polymer solar cell. AB - We present a novel idea for overcoming the drawback of poor contact between the ZnO cathode and active layer interface in an inverted polymer solar cell (i-PSC), simply by incorporating an electron-acceptor self-assembled monolayer (SAM)- tetrafluoroterephthalic acid (TFTPA)--on the ZnO cathode surface to create an electron-poor surface of TFTPA on ZnO. The TFTPA molecules on ZnO are anchored on the ZnO surface by reacting its carboxyl groups with hydroxyl groups on the ZnO surface, such that the tetrafluoroterephthalate moieties lay on the surface with plane-on electron-poor benzene rings acting as positive charge centers. Upon coating a layer of fullerenes on top of it, the fullerene molecules can be physically adsorbed by Coulombic interaction and facilitate a promoted electron collection from the bulk. The active layer is composed of the mid bandgap polymer poly(3-hexylthiophene) (P3HT) or low bandgap polymer, poly[[4,8-bis[(2 ethylhexyl)oxy]benzo[1,2-b:4,5-b']dithiophene-2,6-diyl][3-fluoro-2-[(2 ethylhexyl) carbonyl]thieno[3,4-b]thiophenediyl]] (PTB7), as the donor and [6,6] phenyl-C61-butyric acid methyl ester (PC61BM) or [6,6]-phenyl-C71-butyric acid methyl ester (PC71BM) as the acceptor. Significant enhancement in power conversion efficiency (PCE) was observed for the devices with the active layer P3HT:PC61BM (or PC71BM) by promoting from 3.20 to 4.03% (or from 3.27 to 4.04%) and with the active layer PTB7:PC71BM from 6.03 to 6.90%. This method should be also applicable to other types of active layer. PMID- 23796070 TI - Outcomes of induction chemotherapy followed by chemoradiation using intensity modulated radiation therapy for esophageal adenocarcinoma. AB - This study looks at toxicity and survival data when chemoradiation (CRT) is delivered using intensity-modulated radiation therapy (IMRT) after induction chemotherapy. Forty-one patients with esophageal adenocarcinoma treated with IMRT from March 2007 to May 2009 at Memorial Sloan-Kettering Cancer Center were analyzed. All patients received induction chemotherapy prior to CRT. Thirty-nine percent (n = 16) of patients underwent surgical resection less than 4 months after completing CRT. Patients were predominantly male (78%), with a median age of 68 years (range 32-85 years). The majority of acute treatment-related toxicity was hematologic or gastrointestinal, with 17% of patients having grade 3+ hematologic toxicity and 12% of patients having grade 3+ gastrointestinal toxicity. Only two patients developed grade 2-3 pneumonitis (5%) and 5 patients experienced post-operative pulmonary complications (29%). Eight patients (20%) required a treatment break. With a median follow up of 41 months for surviving patients, 2-year overall survival was 61%, and the cumulative incidences of local failure (LF) and distant metastases were 40% and 51%, respectively. This rate of LF was reduced to 13% in patients who underwent surgical resection. Surgery and younger age were significant predictors of decreased time to LF on univariate analysis. Induction chemotherapy followed by CRT using IMRT in the treatment of esophageal cancer is well tolerated and is not associated with an elevated risk of postoperative pulmonary complications. The use of IMRT may allow for integration of more intensified systemic therapy or radiation dose escalation for esophageal adenocarcinoma, ultimately improving outcomes for patients with this aggressive disease. PMID- 23796071 TI - Parents' decision making and access to preventive healthcare for young children: applying Andersen's Model. AB - BACKGROUND AND OBJECTIVE: Implementing preventive health care for young children provides the best chance of improving health and changing a child's life course. In Australia, despite government support for preventive health care, uptake of preventive services for young children is low. Using Andersen's behavioural model of health-care utilization, we aimed to understand how parents conceptualized their children's preventive health care and how this impacted on access to preventive health-care services. DESIGN: Semi-structured telephone interviews conducted between May and July 2011. SETTING AND PARTICIPANTS: Twenty-eight parents of children aged 3-5 years from three diverse socio-economic areas of Melbourne, Australia. RESULTS: Thematic analysis showed parents' access to child preventive health care was determined by birth order of their child, cultural health beliefs, personal health practices, relationship with the health provider and the costs associated with health services. Parents with more than one child placed their own experience ahead of professional expertise, and their younger children were less likely to complete routine preventive health checks. Concerns around developmental delays required validation through family, friends and childcare organizations before presentation to health services. CONCLUSIONS: To improve child preventive health requires increased flexibility of services, strengthening of inter-professional relationships and enhancement of parents' knowledge about the importance of preventive health in early childhood. Policies that encourage continuity of care and remove point of service costs will further reduce barriers to preventive care for young children. Recent reforms in Australia's primary health care and the expansion of child preventive health checks into general practice present a timely opportunity for this to occur. PMID- 23796073 TI - Silver-mediated methoxycarbonyltetrafluoroethylation of arenes. AB - In the presence of silver(I) fluoride, highly fluorinated olefins react readily under solvent-free conditions with arenes via CH-substitution. This transformation could be used to synthesize various methoxycarbonyltetrafluoroethylated aromatic triazenes and anisoles under high functional group tolerance. The method could be applied to the synthesis of a formal fluorinated bioisostere of the NSAID flurbiprofen. To the best of our knowledge, this is the first example which uses highly fluorinated olefins for the perfluoroalkylation of aromatic substrates. PMID- 23796072 TI - Interactions of beneficial and detrimental root-colonizing filamentous microbes with plant hosts. AB - Understanding commonalities and differences of how symbiotic and parasitic microbes interact with plants will improve advantageous interactions and allow pathogen control strategies in crops. Recently established systems enable studies of root pathogenic and symbiotic interactions in the same plant species. PMID- 23796074 TI - Risk factors for respiratory symptoms in adults: the Busselton Health Study. AB - BACKGROUND AND OBJECTIVE: The prevalence of reported doctor-diagnosed 'asthma' increased between 1990 and 2005-2007 in Busselton, Western Australia, accompanied by increased reported cough and phlegm but not recent wheeze. Possible reasons for the increase in diagnosed asthma include environmental exposures and diagnostic transfer. The aim of this study was to relate subject characteristics and exposures to the presence of wheeze and/or current cough/phlegm in the 2005 2007 survey. METHODS: A gender- and age-stratified random sample of 2862 adults from the Busselton shire completed questionnaires regarding doctor-diagnosed asthma, respiratory symptoms and environmental exposures; and measures of anthropometry, spirometry, exhaled nitric oxide (eNO), airway hyperresponsiveness (AHR) and atopy. Associations between respiratory symptoms and subject characteristics were assessed in 2656 subjects. RESULTS: Wheeze was reported by 23% of subjects, cough/phlegm by 22% and both by 9%. The significant and independent correlates of wheeze were reflux symptoms, lung function, AHR, eNO, atopy, body mass index and smoking. The significant and independent correlates of cough/phlegm were reflux symptoms, lung function, smoking and dusty job. Subjects more likely to report only wheeze than only cough/phlegm were female, aged <40 years, atopic, had lower percentage predicted forced expiratory volume in one second (FEV1) or higher percentage predicted force vital capacity. CONCLUSIONS: A variety of risk factors was associated with wheeze or cough/phlegm or both. Increased non-allergic exposures may account for increased prevalence of reported cough and phlegm and may contribute to increased reported asthma in adults. PMID- 23796075 TI - Consequences of proline-to-alanine substitutions for the stability and refolding of onconase. AB - Peptidyl-prolyl isomerization reactions can make for rate-limiting steps in protein folding due to their high activation energy. Onconase, an unusually stable ribonuclease A homologue from the Northern leopard frog, contains four trans proline residues in its native state. During the refolding from its guanidine hydrochloride unfolded state, which includes the formation of a folding intermediate, the slowest of the three phases has earlier been attributed to a cis-to-trans peptidyl-prolyl isomerization reaction. We thus substituted all four proline residues individually by alanine and investigated the effect of the amino acid substitutions on the folding and stability of the onconase variants. All onconase variants proved to adopt a tertiary structure comparable with that of the wild-type protein. Although the slow phase was not eliminated for any of the variants, the P43A substitution resulted in an increase in the rate constant of the fast folding phase, i.e. a faster formation of the folding intermediate. This variant also exhibits a significant increase in thermodynamic stability. As residue 43 belongs to those residues that are protected from hydrogen exchange with the solvent in the folding intermediate, the increase in the rate constant and stability of the P43A variant emphasizes the importance of the intermediate for the folding of onconase. PMID- 23796076 TI - A near-infrared, surface-enhanced, fluorophore-linked immunosorbent assay. AB - The enzyme-linked immunosorbent assay is commonly used for research and clinical applications but typically suffers from a limited linear range and is difficult to multiplex. The fluorophore-linked immunosorbent assay is a closely related technique with good linear range and the ability to detect multiple antigens simultaneously but is typically less sensitive. Here, we demonstrate a near infrared, surface-enhanced fluorophore-linked immunosorbent assay with sensitivity comparable to its enzyme-linked counterpart. A 59-fold enhancement to sensitivity (slope of linear fit) and an 8-fold improvement in LOD are demonstrated on a direct assay with rabbit immunoglobulin-G as a model system. The technique is also tested on a clinically relevant assay to detect alpha fetoprotein, in which a 42-fold enhancement to sensitivity is demonstrated along with a 16-fold improvement in LOD. The technique enables these accomplishments while maintaining the entire traditional assay protocol and simply adding two steps at the end. This technique may prove superior to current protocols for biomarker research and clinical diagnoses, which require high sensitivity along with quantitation over an extended range. PMID- 23796077 TI - Two new acridone alkaloids from the branch of Atalantia buxifolia and their biological activity. AB - Two new acridone alkaloids, 3-methoxy-1,4,5-trihydroxy-10-methylacridone (1) and 2,3-dimethoxy-1,4,5-trihydroxy-10-methylacridone (2), were isolated from the ethanol extract of the branch of Atalantia buxifolia. Their structures were elucidated by spectroscopic methods including 1D and 2D NMR. Compounds 1 and 2 exhibited significant antibacterial activity against Staphylococcus aureus and weak inhibitory effect on acetylcholinesterase. PMID- 23796078 TI - A biomechanical evaluation of three drop wire configurations. AB - OBJECTIVE: Evaluate effect of adding drop wires to single-ring constructs. STUDY DESIGN: Biomechanical study SAMPLE POPULATION: Single ring circular external skeletal fixator constructs stabilizing a Delrin segment bone model. METHODS: Eight replicates of 5 constructs made with 66 mm complete rings, 1.6 mm olive wires, and a 15.9-mm diameter Delrin rod were loaded in axial compression, craniocaudal and mediolateral bending, and torsion. Constructs tested were: (1) base single-ring construct; (2) single-ring construct with a drop wire mounted on fixation bolts; (3) single-ring construct with a drop wire mounted on 1-hole posts; (4) single-ring construct with a drop wire mounted on 2-hole posts; and (5) 2-ring construct. Construct stiffness for each mode of loading was compared using repeated measures ANOVAs (P <= .05). RESULTS: Axial compression and torsion: the 2-ring construct was stiffer than all others. Drop wire constructs were stiffer than the single-ring construct, but not significantly different from each other. Craniocaudal bending: the 2-ring construct was stiffest with the 2 hole post construct being stiffer than all except the 2-ring construct. Mediolateral bending: the 2-hole post construct was stiffer than the 2-ring construct, which was stiffer than the 1-hole post construct, which was stiffer than the fixation-bolt construct, which was stiffer than the single-ring construct. CONCLUSIONS: Drop wires improved stiffness of single-ring constructs in all loading modalities. Positioning the drop wire farther from the ring surface significantly improved craniocaudal and mediolateral bending stiffness, but did not affect axial compression and torsional stiffness. PMID- 23796079 TI - JVIR clouds, maps, and data visualization: what we write and build upon--and a plea for better views. PMID- 23796080 TI - A study of inventiveness among Society of Interventional Radiology members and the impact of their social networks. AB - PURPOSE: To investigate the nature of inventiveness among members of the Society of Interventional Radiology (SIR) and learn what influenced the inventors and assisted their creativity. MATERIALS AND METHODS: The membership directory of the SIR was cross-referenced with filings at the United States Patent and Trademark Organization (USPTO) and the Patent Cooperation Treaty (PCT). The inventors were queried with an online survey to illuminate their institutions of training and practice as well as enabling or inhibiting factors to their inventiveness. Responses were analyzed through the construction of social network maps and thematic and graphical analysis. RESULTS: It was found that 457 members of the SIR held 2,492 patents or patent filings. After 1986, there was a marked and sustained increase in patent filings. The online survey was completed by 73 inventors holding 470 patents and patent filings. The social network maps show the key role of large academic interventional radiology departments and individual inventors in the formation of interconnectivity among inventors and the creation of the intellectual property (IP). Key inhibitors of the inventive process include lack of mentorship, of industry contacts, and of legal advice. Key enablers include mentorship, motivation, and industry contacts. CONCLUSIONS: Creativity and inventiveness in SIR members stem from institutions that are hubs of innovation and networks of key innovators; inventors are facilitated by personal motivation, mentorship, and strong industry contacts. PMID- 23796081 TI - Society of Interventional Radiology position statement on recent change to the ASA's moderate sedation standards: capnography. PMID- 23796082 TI - Planning US for percutaneous radiofrequency ablation of small hepatocellular carcinomas (1-3 cm): value of fusion imaging with conventional US and CT/MR images. AB - PURPOSE: To assess whether fusion of conventional ultrasonography (US) with liver computed tomography/magnetic resonance images for planning US for percutaneous radiofrequency (RF) ablation can reduce false-positive detection and enhance lesion detectability of small hepatocellular carcinomas (HCCs) on conventional US. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board, and informed consent was waived. A total of 137 patients with single HCCs (mean +/- standard deviation, 1.7 +/- 0.6 cm; range, 1.1-3.0 cm) were included. Planning US was performed by two radiologists by using conventional US first and fusion imaging later in the same session. The false positive detection rate of conventional US was assessed with the results of fusion imaging used as a reference standard. True-positive detection rates on conventional US and fusion imaging were compared by McNemar test. Initially undetectable HCCs on conventional US that became detectable after image fusion were also assessed. RESULTS: The false-positive detection rate of conventional US was 7.7% (nine of 117). Overall true-positive detection rates on conventional US and fusion imaging were 78.8% (108 of 137) and 90.5% (124 of 137), respectively (P = .0002); the rates were significantly different between conventional US and fusion imaging for HCCs smaller than 2.0 cm, but not for HCCs 2.0 cm or larger. Of 20 initially undetectable HCCs on conventional US, nine (45.0%) became detectable after image fusion. CONCLUSIONS: Fusion imaging for planning US for percutaneous RF ablation can reduce false-positive detection and enhance lesion detectability of small HCCs on conventional US. PMID- 23796083 TI - Pulseless angiography. PMID- 23796084 TI - Trends in epistaxis embolization in the United States: a study of the nationwide inpatient sample 2003-2010--caveat emptor. PMID- 23796085 TI - Carbon dioxide contrast enhancement for C-arm CT utility for treatment planning during hepatic embolization procedures. AB - A pilot study was performed to evaluate the use of carbon dioxide (CO2) as a contrast medium for C-arm computed tomography (CT). C-arm CT using CO2 was performed during embolization procedures in12 patients with hepatic malignancies and severe iodine allergy or high risk for nephrotoxicity. C-arm CT using gadolinium or iodinated contrast medium was performed for comparison. Of segmental arteries identified by conventional contrast enhancement, 96% were also seen with CO2 enhancement, but subsegmental arteries were not reliably depicted. CO2 enhancement identified 60% of tumors. Small, hypovascular, and infiltrative tumors were difficult to detect. CO2 is a promising alternative intraarterial contrast agent for C-arm CT. PMID- 23796086 TI - Cone-beam CT: an additional imaging tool in the interventional treatment and management of low-flow vascular malformations. AB - PURPOSE: To evaluate the impact of cone-beam computed tomography (CT) during sclerotherapy of low-flow vascular malformations. MATERIALS AND METHODS: Eighty seven cone-beam CT examinations were acquired during 81 sclerotherapy treatments of low-flow malformations in 48 patients: 81 were performed to evaluate sclerosing agent diffusion and six were performed to evaluate needle or catheter positioning before injection of therapeutic agent. Image quality was rated by two observers. Clinical impact of cone-beam CT in the assessment of therapeutic agent diffusion, needle or catheter positioning, subsequent treatment planning, and complication detection was evaluated. The kappa-statistic was used to assess interobserver reliability and proportions, with associated 95% confidence intervals (CIs). RESULTS: All cone-beam CT images were successfully acquired. Image quality was rated as excellent or good for the majority of studies, with substantial interobserver reliability (kappa = 0.648). Cone-beam CT studies improved assessment of therapeutic agent diffusion in 83% of cases (67 of 81; 95% CI, 75%-91%) for observer 1, who had access to ultrasound, fluoroscopic, and digital subtraction angiographic (DSA) imaging, and in 95% of cases (77 of 81; 95% CI, 90%-100%) for observer 2, who had access to only stored fluoroscopic spot radiographs and DSA images. Cone-beam CT impacted planning of the next treatment session in 49% of cases (40 of 81; 95% CI, 38%-60%). In 7% of cases (six of 81; 95% CI, 1%-13%), complications such as migration of therapeutic agent or compression of upper airways were detected that were not seen with other imaging. CONCLUSIONS: Cone-beam CT can be a useful adjunctive imaging tool, providing information to help decision-making during percutaneous sclerotherapy and ongoing management of low-flow vascular malformations. PMID- 23796087 TI - Outcomes of metallic biliary stent insertion in patients with malignant bilobar obstruction. AB - PURPOSE: To assess clinical outcomes of metal stent insertion in patients with bilobar bile duct obstruction by malignant tumors. MATERIALS AND METHODS: Records of 120 consecutive patients who underwent placement of metallic stents for palliation of malignant bilobar biliary obstruction between 1995 and 2010 were retrospectively reviewed. Single-duct stent insertion was performed in 44 patients with one liver lobe that accounted for more than 70% of total liver volume or only one patent lobar portal vein (group 1). Bilobar stent insertion was performed in 60 patients with approximately equal lobe sizes, patent lobar portal veins, or cholangitis at presentation (group 2). In 16 patients with discontiguous right anterior and posterior segmental ducts (group 3), three stents were deployed in the left lobar and right anterior and posterior segmental ducts. Overall survival, primary patency, and patient morbidity rates following stent insertion were assessed. RESULTS: No significant differences in mean overall survival (group 1, 7.3 mo; group 2, 10.3 mo; group 3, 6.5 mo; P = .21) or mean primary stent patency (group 1, 4.2 mo; group 2, 5.9 mo; group 3, 3.5 mo; P = .17) were demonstrated. However, patients in group 3 were significantly more likely to require hospitalizations for cholangitis and additional invasive procedures for recurrent biliary obstruction than patients in groups 1 and 2. CONCLUSIONS: Unilobar and bilobar metal stent insertion led to similar outcomes when treatment decision was based on relative liver lobe volumes, lobar portal vein patency, and presence of cholangitis on presentation. PMID- 23796088 TI - Phase II study of percutaneous transesophageal gastrotubing for patients with malignant gastrointestinal obstruction; JIVROSG-0205. AB - PURPOSE: This multicenter, prospective study was conducted to evaluate the efficacy of percutaneous transesophageal gastrotubing (PTEG) as an esophagostomy procedure for bowel decompression in patients with malignant bowel obstruction. MATERIALS AND METHODS: The study subjects were patients with malignant bowel obstruction treated with a nasogastric tube (NGT). After receiving PTEG, efficacy evaluations were conducted, with NGT designated as the control state. The procedure was considered effective only when discomfort in the nasopharynx was improved for at least 2 weeks. Safety was evaluated by using National Cancer Institute Common Toxicity Criteria, version 2.0. PTEG was performed by using a PTEG kit. RESULTS: From February 2003 to December 2005, 33 patients were enrolled. The technical success rate was 100%, and the procedure was considered effective in 30 of 33 cases. The three cases in which the procedure was ineffective could not be evaluated as a result of deterioration of general status or early death. The one recorded complication was a tracheoesophageal fistula that caused grade 2 aspiration pneumonia. CONCLUSIONS: PTEG is an effective technique to relieve discomfort in the nasopharynx caused by NGT in patients with terminal malignant tumors. PTEG should be considered an efficacious method for bowel decompression in patients who are ineligible for surgical procedures, percutaneous gastrostomy, or percutaneous enterostomy. PMID- 23796089 TI - Clogged gastrostomy catheter. PMID- 23796090 TI - Respiration-induced deformations of the superior mesenteric and renal arteries in patients with abdominal aortic aneurysms. AB - PURPOSE: To quantify respiration-induced deformations of the superior mesenteric artery (SMA), left renal artery (LRA), and right renal artery (RRA) in patients with small abdominal aortic aneurysms (AAAs). MATERIALS AND METHODS: Sixteen men with AAAs (age 73 y +/- 7) were imaged with contrast-enhanced magnetic resonance angiography during inspiratory and expiratory breath-holds. Centerline paths of the aorta and visceral arteries were acquired by geometric modeling and segmentation techniques. Vessel translations and changes in branching angle and curvature resulting from respiration were computed from centerline paths. RESULTS: With expiration, the SMA, LRA, and RRA bifurcation points translated superiorly by 12.4 mm +/- 9.5, 14.5 mm +/- 8.8, and 12.7 mm +/- 6.4 (P < .001), and posteriorly by 2.2 mm +/- 2.7, 4.9 mm +/- 4.2, and 5.6 mm +/- 3.9 (P < .05), respectively, and the SMA translated rightward by 3.9 mm +/- 4.9 (P < .01). With expiration, the SMA, LRA, and RRA angled upward by 9.7 degrees +/- 6.4, 7.5 degrees +/- 7.8, and 4.9 degrees +/- 5.3, respectively (P < .005). With expiration, mean curvature increased by 0.02 mm(-1) +/- 0.01, 0.01 mm(-1) +/- 0.01, and 0.01 mm(-1) +/- 0.01 in the SMA, LRA, and RRA, respectively (P < .05). For inspiration and expiration, RRA curvature was greater than in other vessels (P < .025). CONCLUSIONS: With expiration, the SMA, LRA, and RRA translated superiorly and posteriorly as a result of diaphragmatic motion, inducing upward angling of vessel branches and increased curvature. In addition, the SMA exhibited rightward translation with expiration. The RRA was significantly more tortuous, but deformed less than the other vessels during respiration. PMID- 23796091 TI - Chronic total occlusion of the iliac artery: endoluminal reentry using a metal stiffening cannula. AB - When chronic total occlusion of the iliac artery cannot be crossed with traditional guide wires and catheters, the metal stiffener from a universal drainage catheter kit can be shaped and used to direct a guide wire from a subintimal tract into the true lumen. In the present report, reentry was achieved in 12 of 12 patients with the use of the cannula. This technique provides a useful alternative for treatment of chronic total iliac occlusions. PMID- 23796092 TI - Distribution of reported StarClose SE vascular closure device complications in the manufacturer and user facility device experience database. AB - PURPOSE: To evaluate the type and frequency of complications associated with the StarClose SE vascular closure device reported to the U.S. Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database for comparison with complications reported in clinical trials. MATERIALS AND METHODS: Complications reported in the MAUDE database related to use of the StarClose SE vascular closure device were reviewed. Keyword searches by device and manufacturer were performed for a 16-month period from July 2009-October 2010. Reports were analyzed according to complication type, frequency, and resolution, if specified. These data were compared with data on StarClose SE device complications, which included three prospective randomized trials and five prospective nonrandomized trials. RESULTS: Keyword searches returned 1,107 total records and 1,118 categorizable StarClose SE device complications from the 16 month MAUDE database-reporting period. Complications in order of frequency (absolute number and relative frequency, respectively) included failure to achieve hemostasis (409, 36.6%), inability to complete the deployment sequence (268, 24.0%), entrapped deployment device (224, 20%), clip not deployed (151,13.5%), late bleeding or oozing from dermatotomy site (25, 2.2%), vessel occlusion (19, 1.7%), retroperitoneal hematoma (12, 1.1%), pseudoaneurysm formation (6, 0.5%) and death (4, 0.4%). The distribution of complications differed appreciably from the combined adverse events compiled from the published trials evaluating the StarClose SE device. There were no records describing inability to remove the deployment device in the published trials, whereas this represented the third most common complication reported to the MAUDE database. Bleeding or oozing from the dermatotomy site, the most frequent relative complication reported in the published literature (53.4%), represented 2.2% of the total complications reported to the MAUDE database. CONCLUSIONS: The type and frequency of complications reported in the MAUDE database on the StarClose SE vascular closure device differ from those published in clinical trials both in relative distribution and in type. Although these differences may reflect in part reporting biases, the distribution of complications reported to the MAUDE database may represent useful information in the use of this device. PMID- 23796093 TI - Percutaneous closure devices do not reduce the risk of major access site complications in patients undergoing elective carotid stent placement. AB - PURPOSE: To examine the risk of femoral access site complications in patients undergoing carotid stent placement who were treated with a closure device compared with patients who were not treated with a closure device. MATERIALS AND METHODS: A national, multihospital patient database, the Premier Perspective database, was used to identify patients hospitalized for carotid stent placement from 2006-2011. To reduce potential selection bias, a propensity score was generated for each patient using relevant clinical variables. Propensity score adjustment via 1:1 matching was performed on patients who did and did not receive a closure device. Primary outcomes were minor femoral access site complications and major complications requiring procedural intervention. Secondary outcomes included in-hospital mortality, stroke, and blood transfusion. RESULTS: Among 12,287 patients who underwent carotid stent placement at 217 hospitals, 6,398 (52%) received a closure device on the day of the procedure. After propensity score matching, patients who received a closure device had a lower likelihood of minor access site complications (4.2% vs 5.4%; odds ratio = 0.77; 95% confidence interval, 0.55-0.93; P = .0071) compared with patients who did not receive a closure device; however, this difference was small and likely not clinically relevant. Both groups had a similar risk of major access site complications (P = .32), in-hospital mortality (P = .0520), and stroke (P = .31). CONCLUSIONS: Use of a closure device was not associated with a substantially reduced risk of major adverse events after carotid stent placement and was associated with only a small improvement in minor access site complications. PMID- 23796094 TI - Hybrid treatment option for aortic arch anomalies and descending thoracic aortic aneurysm. PMID- 23796095 TI - Failure of filter reexpansion during unsuccessful retrieval of Option inferior vena cava filter. PMID- 23796096 TI - Durable plug and Onyx occlusion of a refractory bile leak. PMID- 23796097 TI - Bleeding into a pulmonary cyst caused by pulmonary radiofrequency ablation. PMID- 23796098 TI - Direct percutaneous sac injection for treatment of a thoracic type II endoleak. PMID- 23796099 TI - Interventional radiologic placement of Denver pleuroperitoneal shunt for refractory chylothorax. PMID- 23796100 TI - Re: Hepatotoxicity after transarterial chemoembolization and transjugular intrahepatic portosystemic shunt: do two rights make a wrong? PMID- 23796101 TI - Reply to Re: Hepatotoxicity after transarterial chemoembolization and transjugular intrahepatic portosystemic shunt: do two rights make a wrong? PMID- 23796102 TI - Bihemispheric anodal corticomotor stimulation using transcranial direct current stimulation improves bimanual typing task performance. AB - Transcranial direct current stimulation (tDCS) is associated with improved unimanual skilled hand use. The authors assessed effects of bihemispheric anodal corticomotor tDCS (BAC-tDCS) on bimanual skilled hand use. Twenty-eight nondisabled subjects were randomized to either BAC-tDCS or sham-tDCS, 20 min daily for 5 consecutive days. Performance on a bimanual typing (BT) task and a short-term memory (STM) task was assessed daily and at 1-week follow-up. Mean change between Day 1 and Day 5 in BT score with BAC-tDCS (19.4 points; 95% CI [12.82, 25.99]) was significantly greater (p =.04) than change with sham-tDCS (12.5 points; 95% CI [7.6, 17.3]). Neither group retained improvements in BT score at follow-up. BAC-tDCS had no effect on STM. These results may have implications for interventions to improve hand function in persons with bilateral hand dysfunction. PMID- 23796103 TI - Presidential Address: XXVI International Biometric Conference, Kobe, Japan, August 2012 education in developing countries--the role of IBS. AB - Here we discuss the building of statistical knowledge, mainly in developing countries. We highlight some words from Past IBS Presidents and IBS actions that show the role of IBS in education with an emphasis on developing countries. Some examples show that international exchanges are a well-known way of improving the quality of teaching, learning and research and stress the point that individual initiatives are very important (and fruitful) for education, but we should encourage some more general actions. PMID- 23796104 TI - IBS: transformation of our governance. AB - In my Presidential Address at the 2010 International Biometric Conference in Florianopolis, I outlined the revised governance structure for the International Biometric Society (IBS). That structure was subsequently modified, with the final version being approved by the society membership in June 2012. The membership also approved the merger of the constitution with the bylaws, effectively dissolving the constitution (as it was no longer consistent with practice). From January 1, 2013, responsibility for the governance and leadership of the IBS rests with a 15-member Executive Board which will be supported by a larger Representative Council whose members are selected by and from each of the society's regions. The Representative Council is responsible for overseeing the determination of the Executive Board, providing advice on strategic and policy issues, and contributing to the operation of the IBS. This Council will be an effective conduit between the regions and the Executive Board, aided by the Chair attending all Board meetings. PMID- 23796105 TI - Partially linear structure selection in Cox models with varying coefficients. AB - To explore the nonlinear interactions between covariates and an index variable, partially linear proportional hazards models have been proposed for censored survival data. However, specification of the partially linear structure was usually carried out in an ad-hoc manner by first fitting a full varying coefficient model and visually examining the resulting fit to identify the linear part. In this article, we consider the problem of coefficient estimation and constant coefficient identification based on a double shrinkage approach. Variable selection is also considered in a coherent estimation framework, resulting in a double-penalization procedure. Under the mild assumptions, we establish asymptotic properties for the procedure such as consistency, sparesistency, constansistency, and asymptotic normality. We evaluate the performance of the proposed method by numerical simulations and demonstrate its application using a breast cancer data set. PMID- 23796109 TI - Effect of dietary potassium and anionic salts on acid-base and mineral status in periparturient cows. AB - Dry cow diets based on grassland forage from intensive production contain high amounts of K and could be responsible for a reduced ability to maintain Ca homoeostasis. The aim of this study was to determine whether a moderate anionic salt supplementation to a forage-based pre-calving diet with varying native K content affects the mineral and acid-base status in transition cows. Twenty-four dry and pregnant Holstein cows, without antecedent episodes of clinical hypocalcemia, were assigned to two diets during the last 4 weeks before estimated calving date. Twelve cows were fed a hay-based diet low in K (18 g K/kg DM), and 12, a hay-based diet high in K (35 g K/kg DM). Within each diet, six cows received anionic salts during the last 2 weeks before the estimated calving day. After calving, all cows received the high K diet ad libitum. Blood samples were taken daily from day 11 pre-partum to day 5 post-partum. Urine samples were taken on days 7 and 2 pre-partum and on day 2 post-partum. The anionic salt did not alter feed intake during the pre-partum period. Serum Ca was not influenced by the dietary treatments. Feeding pre-partum diets with low K concentrations induced a reduced metabolic alkalotic charge, as indicated by reduced pre-partum urinary base-acid quotient. Transition cows fed the low K diet including anionic salts induced a mild metabolic acidosis before calving, as indicated by higher urinary Ca, lower urinary pH and net acid-base excretion. Although serum Ca during the post-partum period was not affected by dietary treatment, feeding a low K diet moderately supplemented with anionic salts to reach a dietary cation anion difference close to zero permitted to obtain a metabolic response in periparturient cows without altering the dry matter intake. PMID- 23796110 TI - Copper sludge from printed circuit board production/recycling for ceramic materials: a quantitative analysis of copper transformation and immobilization. AB - The fast development of electronic industries and stringent requirement of recycling waste electronics have produced a large amount of metal-containing waste sludge. This study developed a waste-to-resource strategy to beneficially use such metal-containing sludge from the production and recycling processes of printed circuit board (PCBs). To observe the metal incorporation mechanisms and phase transformation processes, mixtures of copper industrial waste sludge and kaolinite-based materials (kaolinite and mullite) were fired between 650 and 1250 degrees C for 3 h. The different copper-hosting phases were identified by powder X-ray diffraction (XRD) in the sintered products, and CuAl2O4 was found to be the predominant hosting phase throughout the reactions, regardless of the strong reduction potential of copper expected at high temperatures. The experimental results indicated that CuAl2O4 was generated more easily and in larger quantities at low-temperature processing when using the kaolinite precursor. Maximum copper transformations reached 86% and 97% for kaolinite and mullite systems, respectively, when sintering at 1000 degrees C. To monitor the stabilization effect after thermal process, prolonged leaching tests were carried out using acetic acid with an initial pH value of 2.9 to leach the sintered products for 20 days. The results demonstrated the decrease of copper leachability with the formation of CuAl2O4, despite different sintering behavior in kaolinite and mullite systems. This study clearly indicates spinel formation as the most crucial metal stabilization mechanism when sintering copper sludge with aluminosilicate materials, and suggests a promising and reliable technique for reusing metal-containing sludge as ceramic materials. PMID- 23796111 TI - The individual supported living (ISL) manual: a planning and review instrument for individual supported living arrangements for adults with intellectual and developmental disabilities. AB - BACKGROUND: Following the closure of large residential facilities over the past several decades, emphasis on community living for adults with developmental disabilities has strengthened. However, the concept of community living is ambiguous. The term is often associated with congregation of people with disabilities in ordinary houses 'in' the community. Group homes, the most common contemporary formal expression of 'community living', may use ordinary houses and accommodate a small number of residents comparable to a large family. Individual supported living (ISL) arrangements around a single person with a disability using person-centred principles are occurring with increasing frequency. The ISL manual was developed over 4 years in two sequential research projects to produce a quality framework articulating ISL and operationalising the framework into a review and planning instrument for ISL arrangements. METHOD: The ISL manual was developed in three stages and overseen by a reference group of key stakeholders purposively recruited as well-versed in ISL. The first stage operationalised the quality framework over two half-day workshops with a group of key informants. Participants identified indicators and sources of evidence for each attribute of the quality framework. The quality framework, indicators, and sources of evidence were compiled into an initial evaluation instrument of nine themes consisting of 27 attributes. This was piloted in two rounds to enhance the utility of the instrument and develop the final manual which contained eight themes and 21 attributes. A comprehensive literature search was carried out to identify relevant empirical ISL studies. RESULTS: The literature search identified four empirical studies that incorporated ISL over the preceding 3 years. A previous literature search from the first research project that produced the quality framework spanned 27 years and identified five empirical studies. We concluded that the empirical base for developing evidence for the nature and outcomes of ISL arrangements was sparse. The ISL manual and scoring booklet developed in the current research project includes six illustrative case studies of ISL, instructions for potential users to review living arrangements or set up a new arrangement, and the review framework consisting of descriptions of themes and attributes, indicators, and sources of evidence. CONCLUSIONS: The dearth of empirical studies of ISL arrangements for people with developmental disabilities, despite increased policy emphasis on individualised options, underscores the importance of planning and review tools to promote quality outcomes. The ISL manual can assist adults with developmental disabilities, families, carers, and service providers to plan and review ISL arrangements. Further research will enhance the properties of this instrument and establish the relationship between quality of ISL arrangements and outcomes such as quality of life, and participation and inclusion. PMID- 23796112 TI - A comparison of pubertal maturity and growth. AB - BACKGROUND: Growth and pubertal development have each been studied in detail, but rarely in conjunction. AIM: The study aim was to determine what somatic and pubertal development have in common and how they differ and to quantify the association between milestones for growth and for pubertal development (in terms of pubic hair and genitalia/breast, Age of Peak Testes Velocity, APTV and menarche) in relation both to chronological (CA) and bone age (RUS). SUBJECTS AND METHODS: The data analysed are from the 1st Zurich Longitudinal Growth Study, with 120 boys and 112 girls with almost complete data from birth to adulthood. RESULTS: Variability of pubertal milestones was somewhat reduced in terms of RUS, in particular in later phases. Pubic hair phase PH2 appeared ~1 year after the onset of the pubertal spurt. Around the age of maximal deceleration (T9) an adult like appearance of pubic hair, genitalia and breasts was reached in most cases. APTV occurred close to T8. Correlations were large between milestones for growth and PH stages and also with menarche or APTV. CONCLUSIONS: A successful modelling of testis growth led to a new pubertal milestone, APTV. The high correlations between the phenomenologically different domains "linear growth" and "pubertal development", and the high correlations between RUS and linear growth previously established allow the conclusion that these different domains develop along similar biological mechanisms, which are steered mainly by genetic factors. PMID- 23796113 TI - Self-reported non-severe hypoglycaemic events in Europe. AB - AIMS: Hypoglycaemia presents a barrier to optimum diabetes management but data are limited on the frequency of hypoglycaemia incidents outside of clinical trials. The present study investigated the rates of self-reported non-severe hypoglycaemic events, hypoglycaemia awareness and physician discussion of events in people with Type 1 diabetes mellitus or insulin-treated Type 2 diabetes mellitus. METHODS: People in seven European countries aged >15 years with Type 1 diabetes or insulin-treated Type 2 diabetes (basal-only, basal-bolus and other insulin regimens) were recruited via consumer panels, nurses, telephone recruitment and family referrals. Respondents completed four online questionnaires. The first questionnaire collected background information on demographics and hypoglycaemia-related behaviour, whilst all four questionnaires collected data on non-severe hypoglycaemic events in the preceding 7 days. RESULTS: Analysis was based on 11 440 respondent-weeks from 3827 respondents. All participants completed the first questionnaire and 57% completed all four. The mean number of events/respondent-week was 1.8 (Type 1 diabetes) and 0.4-0.7 (Type 2 diabetes, with different insulin treatments) corresponding to annual event rates of 94 and 21-36, respectively. A total of 63% of respondents with Type 1 diabetes and 49-64% of respondents with Type 2 diabetes, treated with different insulin regimens, who experienced hypoglycaemic events, reported impaired hypoglycaemia awareness or unawareness. A high proportion of respondents rarely or never informed their general practitioner/specialist about hypoglycaemia: 65% (Type 1 diabetes) and 50-59% (Type 2 diabetes). Overall, 16% of respondents with Type 1 diabetes and 26% of respondents with Type 2 diabetes reported not being asked about hypoglycaemia during routine appointments. CONCLUSION: Non-severe hypoglycaemic events are common amongst people with Type 1 diabetes and insulin treated Type 2 diabetes in real-world settings. Many rarely or never inform their general practitioner/specialist about their hypoglycaemia and the real burden of hypoglycaemia may be underestimated. PMID- 23796114 TI - Postasphyxial renal injury in newborns as a prognostic factor of neurological outcome. AB - OBJECTIVE: To estimate if an acute postasphyxial renal injury in newborns could indicate a neurological outcome. METHODS: We conducted a prospective clinical trial on 50 full-term newborns with 5-minute Apgar score <7 (asphyxiated group) and a control group of 50 full-term newborns with 5-min Apgar score >= 7 (non asphyxiated group). Renal function was assessed on the third day of life by serum values of creatinine, cystatin C and beta2-microglobulin (beta2M) and glomerular filtration rate (GFR). All newborns had brain and renal ultrasonography at early stages and were followed by Amiel-Tison Neurological Assassment (ATNA) throughout the first year of life. RESULTS: Mean GFR was significantly lower in asphyxiated than in non-asphyxiated group (22.08 +/- 6.66 ml/min/1, 73 m(2) versus 35.42 +/- 2.26 ml/min/1, 73 m(2); p < 0.001) and serum values of creatinine, cystatin C and beta2M were significantly higher (1.13 versus 0.66 mg/dl; 3.92 versus 1.52 mg/l; 1.53 versus 0.99 mg/l; p < 0.001). In asphyxiated group ATNA results throughout the first year of life significantly correlated with renal function (p < 0.01). A correlation of ATNA with Apgar score at 5 min, Sarnat and Sarnat staging of hypoxic ischemic encephalopathy and brain and renal ultrasonography has also been significant (p < 0.01). CONCLUSIONS: Our study showed a significant correlation between early impairment of renal function due to neonatal asphyxia with neurological outcome at the end of the first year of life. PMID- 23796115 TI - A single-nucleotide polymorphism in the 3' untranslated region of the LPIN1 gene and association analysis with performance traits in chicken. AB - 1. A single nucleotide polymorphism (SNP), c.*77C>G, was found in the 3' UTR of the chicken LPIN1 gene by DNA sequencing. In total, 860 chickens were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in a F2 resource population obtained by crossing F0 Gushi chickens and Anka broilers, and the associations of this polymorphism with chicken growth, carcass, muscle fibre traits and serum biochemistry parameters were analysed. 2. Significant associations were found between the polymorphism and breast muscle fibre diameter (FDB). Comparison of the different genotypes of c.*77C>G in the F2 resource population showed that the GG genotype had significantly higher values than that of CG genotype in FDB. c.*77C>G was predicted to cause changes to multiple microRNA (miRNA) binding sites. But the total mRNA level of chicken LPIN1, LPIN1-;alpha and LPIN1-beta in liver and muscle tissues did not show significant difference among GG, CG and CC genotypes, respectively. 3. The results suggested that chicken LPIN1 has a potential effect on muscle fibre development, but no effect on other studied traits. PMID- 23796116 TI - Potential of a commercially available water acidification product for reducing Campylobacter in broilers prior to slaughter. AB - 1. This study investigated the potential of a commercially available acidified water treatment (PWT) for reducing the number of Campylobacter in vitro and other bacteria in the gut of live broilers. 2. In vitro tests indicated that PWT was highly effective for reducing Campylobacter jejuni and Campylobacter coli at the recommended concentration in water, reducing populations by greater than 7 log10 CFU/ml after 24 h exposure. The decrease in the number of Salmonella serovar Enteritidis and Escherichia coli was not significant. 3. Addition of PWT to the broiler drinking water for the first 7 d, 2 d before and 2 d after each feed change and at feed withdrawal prior to slaughter or only after feed withdrawal had no effect on the number of Campylobacter in caecal samples on farm before thinning and depopulation compared to untreated controls. 4. Although PWT was effective for reducing Campylobacter in water, the results suggest that it does not reduce the number of Campylobacter in the caeca of broilers prior to slaughter under the conditions used in the study. PMID- 23796117 TI - Identification of antibodies against hydropericardium syndrome in wild birds. AB - 1. Domestic fowl and free-living birds were examined for the presence or absence of antibodies against hydropericardium syndrome (HPS) using an indirect haemagglutination assay. 2. Two-hundred and eighty serum samples of commercial (45 broilers, 20 adult layers and 15 Fayoumi fowl) and wild birds, including 65 peafowl, 45 pigeons, 10 crows, 30 house sparrows, 10 doves, 15 ducks, 10 parrots and 15 guinea fowl, were collected and examined. 3. The percentage of HPS positive serum samples was 80% in house crows, 78% in pigeons, 7% in house sparrows and 6% in peafowl. 4. The sera obtained from parrots, doves, ducks and guinea fowl were all negative. 5. This study suggests that crows and pigeons could be carriers of the HPS agent. PMID- 23796118 TI - Apilarnil reduces fear and advances sexual development in male broilers but has no effect on growth. AB - 1. An experiment was conducted to determine the possibility of stimulating sexual development at an early age in male and female broiler chickens by administration of apilarnil, a natural bee product, in the pre-pubertal period. 2. From 28 to 55 d of age, birds were given apilarnil orally. The effects of low (2.5 g/bird) and high (7.5 g/bird) doses of apilarnil on growth performance, testicular weight, secondary sexual characteristics, blood lipids, testosterone and fearful behaviour were evaluated. 3. Apilarnil administration did not cause a positive effect on growth performance of male and female broilers suggesting that apilarnil did not have an anabolic effect. 4. Apilarnil administration suppressed blood glucose and cholesterol. 5. Birds receiving apilarnil remained immobile for a shorter period in a tonic imobiliy test and showed less home-cage avoidance responses suggesting a lower level of fearfulness. 6. Increases in testicular weight, testosterone concentration and comb growth in males receiving apilarnil implied that it stimulates the sexual maturation at an early age. However, a similar stimulation of secondary sexual characteristics was not observed in females. PMID- 23796119 TI - The influence of diet composition on egg and chick traits in captive Greater Rhea females. AB - 1. This study was conducted to evaluate the influence of diet composition on egg number, physical and chemical characteristics of eggs and weight and survival of chicks throughout a breeding season in a captive-bred population of greater rheas (Rhea americana). 2. From August to December, individuals were offered two diets: processed feed for rheas and processed feed for chicken (which is the feed most commonly offered to farmed rheas in Argentina). Reproductive performance of 15 females was monitored and female body weight was recorded before egg-laying onset. Within each experimental group, the following variables were determined: egg morphometric variables and percentage of components, fatty acid composition, hatching success and initial weight of chicks and mortality during the first week of life. 3. Females that were fed on processed feed for rheas delayed onset of laying and reduced laying period and number of eggs produced. However, females of this group laid larger eggs, with higher percentages of yolk and yolk lipids, and exhibited higher hatching success and chick weight compared with those that received chicken diet. Survivorship of chicks in their first week of life was not affected by composition of the diet offered to parental female. 4. Some reproductive parameters of captive greater rhea females fed on processed feed for rheas were higher than those of individuals receiving processed feed for chicken. PMID- 23796120 TI - Pharmacokinetics of enrofloxacin after multiple subcutaneous and intramuscular administrations in adult ostriches. AB - 1. The objective of the study was to evaluate the comparative pharmacokinetic behaviour of enrofloxacin in adult ostriches after single and multiple intramuscular (IM) and subcutaneous (SC) administrations. In addition, tissue tolerance was evaluated. 2. Enrofloxacin was well absorbed, but showed a short permanence after both administration routes. After multiple dose administrations the maximum and minimum peak plasma concentrations were very similar for both routes, obtaining a steady state phase from the second dose that extended until the last evaluated administration. 3. There was no significant accumulation after multiple IM or SC doses; however, there were differences in a fluctuation index after multiple intramuscular administrations that could be related to muscle damage. 4. The different microbiological efficacy indicators (PK/PD indices) obtained, the pharmacokinetic behaviour and CK serum concentrations suggest that subcutaneous enrofloxacin administration of 15 mg/kg every 12 h produce and maintain an efficient concentration of antibiotic that is a safer and more effective therapeutic option than intramuscular administration. PMID- 23796121 TI - Expression of TRPV6 and CaBP-D28k in the egg shell gland (uterus) during the oviposition cycle of the laying hen. AB - 1. The aim of this study was to investigate the localisation of the transient receptor potential vanilloid channel type 6 (TRPV6) in egg shell gland (ESG) and examine the dynamic expression of TRPV6 and Calbindin-d28k (CaBP-D28k), as well as the changes in concentration of total calcium (Ca), total inorganic phosphorus (P), alkaline phosphatase (ALP), parathyroid hormone (PTH) and calcitonin (CT) in plasma during the oviposition cycle. 2. The plasma ALP activity was notably increased at 8 h. In addition, plasma CT was highest at 0 h and significantly lower at 8 h. The change of plasma PTH concentration increased slightly post oviposition and reached a maximum at 16 h. 3. Immunohistochemical analysis indicated that TRPV6 was strongly localised to the apical luminal epithelium of the mucosa. The mRNA levels of TRPV6 and CaBP-D28k in the ESG remained very low from 0 to 4.5 h, but were significantly increased at 16 h. Furthermore, Western blotting analysis showed that the expression of TRPV6 and CaBP-D28k also reached a maximum at 16 h and was different from the concentration of CaBP-D28k. 4. In conclusion, the epithelial Ca(2+) channel TRPV6 is strongly expressed in the epithelial cells of the eggshell gland, and the increase of TRPV6 and CaBP-D28k mRNA and protein expression during eggshell formation suggests that active Ca(2+) transcellular transport exerts significant effects in delivering active calcium in the ESG. PMID- 23796122 TI - Acute physiological responses to physiotherapy applications pre and post autologous stem cell transplantation: an experimental study. AB - OBJECTIVE: We aimed to investigate the acute physiological responses (APR) to physiotherapy applications in patients undergoing autologous stem cell transplantation (ASCT), the difference between pre- and post-ASCT according to APR. METHODS: Twenty-six patients who were hospitalized for ASCT attended regular physiotherapy program. APR was recorded in the beginning and at the end of each exercise session. The differences in APR were calculated for each session. The mean values of the differences in APR were computed in pre-conditioning, pre-, and post-ASCT. Daily complete blood counts were also recorded during ASCT. RESULTS: Hemoglobin and platelet counts were significantly lower pre- and post ASCT. Neutrophil counts were significantly lower post-ASCT. The difference in systolic blood pressure (SBP) in the beginning and at the end of the exercise sessions was significantly higher post-ASCT in comparison to pre-ASCT. CONCLUSION: There was no significant change in APR except the SBP which suggests that similar level of exercise intensity could be tolerated in pre- and post-ASCT periods as well as preconditioning. PMID- 23796124 TI - MAPping out distribution routes for kinesin couriers. AB - In the crowded environment of eukaryotic cells, diffusion is an inefficient distribution mechanism for cellular components. Long-distance active transport is required and is performed by molecular motors including kinesins. Furthermore, in highly polarised, compartmentalised and plastic cells such as neurons, regulatory mechanisms are required to ensure appropriate spatio-temporal delivery of neuronal components. The kinesin machinery has diversified into a large number of kinesin motor proteins as well as adaptor proteins that are associated with subsets of cargo. However, many mechanisms contribute to the correct delivery of these cargos to their target domains. One mechanism is through motor recognition of sub-domain-specific microtubule (MT) tracks, sign-posted by different tubulin isoforms, tubulin post-translational modifications, tubulin GTPase activity and MT-associated proteins (MAPs). With neurons as a model system, a critical review of these regulatory mechanisms is presented here, with a particular focus on the emerging contribution of compartmentalised MAPs. Overall, we conclude that - especially for axonal cargo - alterations to the MT track can influence transport, although in vivo, it is likely that multiple track-based effects act synergistically to ensure accurate cargo distribution. PMID- 23796123 TI - Overlapping and distinct gray and white matter abnormalities in schizophrenia and bipolar I disorder. AB - OBJECTIVES: Schizophrenia and bipolar disorder may share common neurobiological mechanisms, but few studies have directly compared gray and white matter structure in these disorders. We used diffusion-weighted magnetic resonance imaging and a region of interest based analysis to identify overlapping and distinct gray and white matter abnormalities in 35 patients with schizophrenia and 20 patients with bipolar I disorder in comparison to 56 healthy volunteers. METHODS: We examined fractional anisotropy within the white matter and mean diffusivity within the gray matter in 42 regions of interest defined on a probabilistic atlas following non-linear registration of the images to atlas space. RESULTS: Patients with schizophrenia had significantly lower fractional anisotropy in temporal (superior temporal and parahippocampal) and occipital (superior and middle occipital) white matter compared to patients with bipolar disorder and healthy volunteers. By contrast, both patient groups demonstrated significantly higher mean diffusivity in frontal (inferior frontal and lateral orbitofrontal) and temporal (superior temporal and parahippocampal) gray matter compared to healthy volunteers, but did not differ from each other. CONCLUSIONS: Our study implicates overlapping gray matter frontal and temporal lobe structural alterations in the neurobiology of schizophrenia and bipolar I disorder, but suggests that temporal and occipital lobe white matter deficits may be an additional risk factor for schizophrenia. Our findings may have relevance for future diagnostic classification systems and the identification of susceptibility genes for these disorders. PMID- 23796125 TI - Highly hydrophilic polyvinylidene fluoride (PVDF) ultrafiltration membranes via postfabrication grafting of surface-tailored silica nanoparticles. AB - Polyvinylidene fluoride (PVDF) has drawn much attention as a predominant ultrafiltration (UF) membrane material due to its outstanding mechanical and physicochemical properties. However, current applications suffer from the low fouling resistance of the PVDF membrane due to the intrinsic hydrophobic property of the membrane. The present study demonstrates a novel approach for the fabrication of a highly hydrophilic PVDF UF membrane via postfabrication tethering of superhydrophilic silica nanoparticles (NPs) to the membrane surface. The pristine PVDF membrane was grafted with poly(methacrylic acid) (PMAA) by plasma induced graft copolymerization, providing sufficient carboxyl groups as anchor sites for the binding of silica NPs, which were surface-tailored with amine-terminated cationic ligands. The NP binding was achieved through a remarkably simple and effective dip-coating technique in the presence or absence of the N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC)/N hydroxysuccinimide (NHS) cross-linking process. The properties of the membrane prepared from the modification without EDC/NHS cross-linking were comparable to those for the membrane prepared with the EDC/NHS cross-linking. Both modifications almost doubled the surface energy of the functionalized membranes, which significantly improved the wettability of the membrane and converted the membrane surface from hydrophobic to highly hydrophilic. The irreversibly bound layer of superhydrophilic silica NPs endowed the membranes with strong antifouling performance as demonstrated by three sequential fouling filtration runs using bovine serum albumin (BSA) as a model organic foulant. The results suggest promising applications of the postfabrication surface modification technique in various membrane separation areas. PMID- 23796126 TI - Genomics reveals new landscapes for crop improvement. AB - The sequencing of large and complex genomes of crop species, facilitated by new sequencing technologies and bioinformatic approaches, has provided new opportunities for crop improvement. Current challenges include understanding how genetic variation translates into phenotypic performance in the field. PMID- 23796127 TI - Clinical remission following endoscopic placement of retrievable, fully covered metal stents in patients with esophageal achalasia. AB - Metal stents may represent an alternative therapy in the treatment of achalasia. We therefore evaluated the effectiveness of retrievable, fully covered metal stents in patients with achalasia. Fifty-nine patients with achalasia were treated with retrievable, fully covered metal stents. Symptoms using a global symptom score (0-10), lower esophageal sphincter (LES) resting pressure, LES relaxation, and simultaneous contraction of the esophagus were analyzed before and 1 week and 1 month after intervention. Complications and treatment outcomes were followed up at 6, 12, 18, and 24 months postoperatively. Stent placement was successful, and clinical symptoms resolved (P < 0.01) in all patients. Regurgitation, dysphagia and chest pain improved significantly (all P < 0.01). Therapy improved LES resting pressure (51.4 +/- 9.7 mmHg pretherapy vs. 20.9 +/- 8.1 mmHg post-therapy), LES relaxation (58.1 +/- 17.1% pretherapy vs. 84.5 +/- 18.9% post-therapy), and simultaneous contraction of the esophagus (36.1 +/- 8.6% pretherapy vs. 69.4 +/- 23.1% post-therapy) 1 month after stent placement (all P < 0.01). The cumulative clinical remission rates 6, 12, 18, 24, 30, and 36 months after stent removal were 90.9%, 81.8%, 76.4%, 69.1%, 65.5%, and 49.1%, respectively. All patients tolerated stent placement. Twelve patients (25.5%) complained of substernal pain and five (10.6%) had substernal burning. Stents migrated in four patients (8.5%). Insertion of retrievable, fully covered metal stents is an effective and safe treatment in patients with achalasia. PMID- 23796128 TI - Flexible C2-symmetric bis-sulfoxides as ligands in enantioselective 1,4-addition of boronic acids to electron-deficient alkenes. AB - The application of acyclic C2-symmetric chelating bis-sulfoxide ligands in the Rh(I)-catalyzed enantioselective 1,4-addition of boronic acids to electron deficient alkenes is reported. Among the acyclic ethane-bridged bis-sulfoxides tested, the ligand Ferbisox (11), bearing ferrocenyl moieties as substituents at the sulfinyl sulfurs, has exhibited the best results in terms of chemical yield (up to 96%) and enantioselectivity (up to 97% ee). The conjugate addition takes place smoothly in toluene at room temperature in short reaction times (typically 2 h). The reaction scope, including the use of different boronic acids, five-, six-, and seven-membered cyclic enones, an unsaturated lactone, and the most challenging acyclic ketones, is reported. An X-ray diffraction study of the [Ferbisox.RhCl]2 precatalyst clearly exhibits a dimeric structure with an S coordination of the sulfoxide to rhodium. On the basis of the X-ray data and on structural studies conducted in solution by (1)H NMR, a model explaining the high enantioselection observed is proposed. PMID- 23796129 TI - Aptamer-based plasmonic sensor array for discrimination of proteins and cells with the naked eye. AB - We developed a colorimetric sensor array with reported protein aptamers as nonspecific receptors. We found that different target proteins could make the aptamer-protected gold nanoparticles (AuNPs) exhibit different aggregation behaviors in the presence of a high concentration salt and cause various color change. On the basis of this phenomenon, we applied a series of reported protein aptamers as a receptor array obtaining a distinct response pattern to each target protein. Seven proteins have been well distinguished with the naked eye at the 50 nM level. Cancerous human cells have also been discriminated from noncancerous cells. This method is simple, label-free, and sensitive. It will broaden the application filed of plasmonic nanoparticle-based sensors and give a new direction of developing sensitive array sensing systems. PMID- 23796130 TI - The discovery of novel actions is affected by very brief reinforcement delays and reinforcement modality. AB - ABSTRACT The authors investigated the ability of human participants to discover novel actions under conditions of delayed reinforcement. Participants used a joystick to search for a target indicated by visual or auditory reinforcement. Reinforcement delays of 75-150 ms were found to significantly impair action acquisition. They also found an effect of modality, with acquisition superior with auditory feedback. The duration at which delay was found to impede action discovery is, to the authors' knowledge, shorter than that previously reported from work with operant and causal learning paradigms. The sensitivity to delay reported, and the difference between modalities, is consistent with accounts of action discovery that emphasize the importance of a time stamp in the motor record for solving the credit assignment problem. PMID- 23796132 TI - Do lifestyle changes reduce serious outcomes in diabetes? PMID- 23796133 TI - Topical treatments for chronic plaque psoriasis of the scalp: a systematic review. AB - BACKGROUND: Chronic plaque psoriasis is the most common type of psoriasis and is characterized by redness, thickness and scaling. First-line management is with topical treatments. OBJECTIVES: Our objective was to establish the effectiveness, tolerability and safety of topical treatments for people with chronic plaque psoriasis of the scalp, assessing placebo-controlled trials of all treatments and head-to-head trials that assessed vitamin D analogues. METHODS: As part of a Cochrane review of topical treatments for psoriasis, we systematically searched electronic databases for randomized controlled trials. The review included 26 randomized controlled trials of treatments for psoriasis of the scalp with 8020 participants. Trials used several measures to assess changes in psoriasis severity: these were combined using the standardized mean difference metric and interpreted by reporting as a six-point global improvement score. RESULTS: On effectiveness grounds, very potent or potent steroid treatments should be preferred to vitamin D3 analogue with approximately an average 10% additional improvement on a six-point scale. Vitamin D3 analogue combined with potent steroid appears slightly more effective than potent steroid monotherapy (3% additional improvement on a six-point scale). Rates of withdrawal from treatment and adverse events in trials were generally low and similar to those for placebo. There remains uncertainty about the atrophic potential of corticosteroid treatments for scalp psoriasis. CONCLUSIONS: Corticosteroids are more effective than vitamin D analogues and similarly tolerated. However, further research is needed to inform long-term maintenance treatment and provide appropriate safety data. PMID- 23796134 TI - Single-molecule atomic force microscopy unravels the binding mechanism of a Burkholderia cenocepacia trimeric autotransporter adhesin. AB - Trimeric autotransporter adhesins (TAAs) are bacterial surface proteins that fulfil important functions in pathogenic Gram-negative bacteria. Prominent examples of TAAs are found in Burkholderia cepacia complex, a group of bacterial species causing severe infections in patients with cystic fibrosis. While there is strong evidence that Burkholderia cenocepacia TAAs mediate adhesion, aggregation and colonization of the respiratory epithelium, we still know very little about the molecular mechanisms behind these interactions. Here, we use single-molecule atomic force microscopy to unravel the binding mechanism of BCAM0224, a prototype TAA from B. cenocepacia K56-2. We show that the adhesin forms homophilic trans-interactions engaged in bacterial aggregation, and that it behaves as a spring capable to withstand high forces. We also find that BCAM0224 binds collagen, a major extracellular component of host epithelia. Both homophilic and heterophilic interactions display low binding affinity, which could be important for epithelium colonization. We then demonstrate that BCAM0224 recognizes receptors on living pneumocytes, and leads to the formation of membrane tethers that may play a role in promoting adhesion. Collectively, our results show that BCAM0224 is a multifunctional adhesin endowed with remarkable binding properties, which may represent a general mechanism among TAAs for strengthening bacterial adhesion. PMID- 23796135 TI - A quantitative assessment of educational integration of students with Down syndrome in the Netherlands. AB - BACKGROUND: In the Netherlands, as in many other countries, there are indications of an inclusive school policy for children with Down syndrome. However, there is a lack of studies that evaluate to what extent this policy has actually succeeded in supporting the mainstreaming of these students. METHOD: For the period 1984 2011, the number of children with Down syndrome entering regular education and the percentage of children still in regular education after 1-7 years were estimated on basis of samples from the database of the Dutch Down Syndrome Foundation. These estimations were combined with historical demographic data on the total number of children with Down syndrome in primary school age. Validity of the model was examined by comparison of the model-based estimations of numbers and percentages in regular education with relevant available empirical data from the Dutch Ministry of Education and from Dutch special schools. RESULTS: The percentage of all children with Down syndrome in the age range 4-13 in regular primary education has risen from 1% or 2% (at the very most about 20 children) in 1986-1987, to 10% (about 140 children) in 1991-1992, to 25% (about 400) in 1996 1997, to 35% (about 650) in 2001-2002 and to 37% (about 800) since 2005-2006. The proportional increase stopped in recent years. CONCLUSION: During the 1980s and 1990s, clearly more and more children with Down syndrome were in regular education, being supported by the then existing ad hoc regulations aimed at providing extra support in regular education. In the Netherlands, in 2003, these temporary regulations were transformed into structural legislation for children with disabilities. With regard to the mainstreaming of students with Down syndrome, the 2003 legislation has consolidated the situation. However, as percentages in regular education stayed fairly constant after 2000, it has failed to boost the mainstreaming of children with Down syndrome. The results of this study are discussed in the context of national and international legislation and educational policy. PMID- 23796136 TI - Prevalence and risk factors of Helicobacter pylori infection in Chinese maritime workers. AB - BACKGROUND: Helicobacter pylori infection is very common worldwide. AIM: To evaluate the prevalence and identify the risk factors for Helicobacter pylori infection in Chinese maritime workers. SUBJECTS AND METHODS: Between March 2010 and October 2010, 3995 subjects were selected in the Hospital of Dalian Port. The presence of Helicobacter pylori infection was confirmed using laboratory tests (serum IgG anti-Helicobacter pylori antibodies) and background information, family history, lifestyle and eating habits were collected using questionnaires. RESULTS: The prevalence of Helicobacter pylori infection was 44.9% in these Chinese maritime workers. Prevalence of Helicobacter pylori infection was associated with family income, living space, family history of gastrointestinal diseases, smoking, drinking tea, raw vegetables consumption, spicy food, pickle food, dining outside, no regular meal and dish sharing. Further analysis with multivariate logistic regression analysis indicated that raw vegetables consumption, pickle food consumption, family income and family history of gastrointestinal diseases were independent predictors for Helicobacter pylori infection. No association was found between infection and gender, marital status, education, alcohol consumption and tap water consumption. CONCLUSION: Helicobacter pylori infection is associated with raw vegetables consumption, pickle food consumption, family income and family history of gastrointestinal disease among Chinese maritime workers. PMID- 23796137 TI - Glycogen synthase kinase 3 substrates in mood disorders and schizophrenia. AB - The dominant genetic and environmental causes of mood disorders and schizophrenia have not been forthcoming, so alternative approaches are required to elucidate the mechanisms underlying these diseases and to develop improved treatments for use in the clinic. Pharmacological evidence implicates glycogen synthase kinase 3 (GSK3) as a key target of current therapeutics, and this is well supported by genetic studies in animal models. Several upstream regulators of GSK3 are also genetically associated with mood disorders and schizophrenia, further suggesting convergence on GSK3 signalling. Whereas pathways upstream of GSK3 are being elucidated, relatively little progress has been made in identifying targets downstream of GSK3 that mediate its functional effects. This is important, because these substrates themselves could become next-generation therapeutic targets that are more potent and specific than current therapeutics targeting GSK3. Here, a few likely candidates and their connection to mood disorders and schizophrenia are discussed. PMID- 23796138 TI - Formation of 4(5)-methylimidazole and its precursors, alpha-dicarbonyl compounds, in Maillard model systems. AB - Glyoxal, methylglyoxal, and diacetyl formed from sucrose alone and from a D glucose/ammonia Maillard model system were analyzed by gas chromatography. They are known as precursors of 4(5)-methylimidazole (MI). Glyoxal and methylglyoxal formed more in acidic conditions than in basic conditions, whereas diacetyl formed the most at the highest basic condition of pH 12. Glyoxal formation from sucrose ranged from 0.33 to 32.90 MUg/g under four different time and temperature conditions. Amounts of glyoxal, methylglyoxal, and diacetyl formed in Maillard model systems ranged from 2.98 to 46.12 MUg/mL, from 8.27 to 156.61 MUg/mL, and from 14.94 to 1588.45 MUg/mL, respectively. 4(5)-MI formation in the same model systems ranged from 28.56 to 1269.71 MUg/mL. Addition of sodium sulfite reduced formation of these chemicals significantly. Total alpha-dicarbonyl compounds in 12 commercial soft drinks ranged from 5.75 to 50.72 MUg/mL. 4(5)-MI was found in levels ranging from 1.76 to 28.11 ng/mL in 10 commercial soft drinks. PMID- 23796139 TI - Development and performance characterization of a polyamide nanofiltration membrane modified with covalently bonded aramide dendrimers. AB - A first generation of amine terminated aramide dendrimers (G1-NH2) was covalently attached to the polyamide (PA) active layer of a commercially available nanofiltration (NF) membrane. Amide bonds between G1-NH2 and PA free carboxylic groups were formed by activation of the carboxylic groups with 1-ethyl-3-(3 dimethylaminopropyl) carbodiimide (EDC) or 2-chloro-1-methylpyridinium iodide (CMPI), followed by aminolysis. Dendrimer attachment was assessed by indirectly measuring the concentration of carboxylic groups and amine groups before and after membrane modification with RBS using yttrium and tungstate ions (Y(3+) and WO4(2-)) as ion probes. RBS analyses showed a decrease in the concentration of carboxylic groups and an increase in amine groups on the membrane active layer, consistent with dendrimers attaching covalently to the active layer. Permeation experiments with Rhodamine WT (R-WT) revealed that the water and solutes permeability decreased after modification with dendrimer G1-NH2. Water permeability of G1-NH2 modified membrane decreased by 16-19% using EDC combined with sulfo-N-hydroxysuccinimide (s-NHS), and by 17-33% using CMPI. The permeability of the electrolyte BaCl2 decreased by 54% after G1-NH2 modification using EDC/s-NHS and only by 20% using CMPI, the latter consistent with a weaker Donnan exclusion effect. The permeability of the larger solute R-WT decreased by 82% in modified G1-NH2 membranes when using EDC/s-NHS, and 64% for cross-linking reagent CMPI. Thus, the use of EDC/s-NHS was more favorable because it resulted in higher gains in solute rejection with lower losses in water permeability. PMID- 23796140 TI - Total synthesis of 3,7-dimethyl-7-hydroxy-2-octen-1,6-olide and 3,7-dimethyl-2,6 octadien-1,6-olide. AB - 3,7-Dimethyl-7-hydroxy-2-octen-1,6-olide and 3,7-dimethyl-2,6-octadien-1,6-olide, the natural bioactive compounds isolated from the fruit of Litsea cubeba and the liverwort Plagiochila rutilans, were totally synthesized using easily available cis-geraniol as raw material in short, convenient, and low-cost, five-step reactions including three steps of oxidation, cyclization, and dehydration, with an overall yield of 47.5% and 37.3%. PMID- 23796141 TI - Protease concentration in amniotic fluid at term and early childhood respiratory symptoms. AB - OBJECTIVE: Asthma is a common chronic disease associated with altered proteolytic activity. The present study tested the hypothesis that altered protease concentration in amniotic fluid (AF), an index of airway fluid at birth, precedes early cough and wheeze. METHODS: AF was collected and analysed for the following: matrix metalloproteinases (MMP) -2, -8 and -9, tissue inhibitor of metalloproteinases (TIMP) -1 and 2, plasminogen activator inhibitor (PAI)-1. Infant were followed up at ages 1, 2 and 3 years. RESULTS: Samples of AF were obtained in 92 infants. There were inconsistent and relatively small differences in some analytes between those individuals with and without symptoms at ages one and two years. PAI-1 concentrations were reduced in association with cough at age 1 year (p = 0.035). Reduced MMP-8:TIMP-2 ratio was associated with wheeze at age 2 years (p = 0.038). There were no associations between AF analytes and symptoms at 3 years of age. CONCLUSION: There is heterogeneity in concentrations of proteases and their inhibitors in airways at birth but in this exploratory study, there was no consistent evidence that protease concentration at birth was important to later respiratory symptoms. PMID- 23796142 TI - Unexpected regioselectivity switch: organophosphine-triggered reactions of cyclopropene-1,1-dicarboxylates with aldehydes. AB - With tris(4-methoxyphenyl)phosphine as the nucleophilic reagent, the readily available cyclopropene-1,1-dicarboxylates undergo a ring-opening reaction to generate a Wittig-type intermediate, which would react with aromatic aldehydes to yield (E)-5-aryl-2-(methoxycarbonyl)-2,4-pentadienoates. It is interesting to observe that the regioselectivity of the ring-opening reaction is switched. PMID- 23796143 TI - Molecular diagnostic algorithm for epidermal growth factor receptor mutation detection in Asian lung adenocarcinomas: comprehensive analyses of 445 Taiwanese patients with immunohistochemistry, PCR-direct sequencing and Scorpion/ARMS methods. AB - BACKGROUND AND OBJECTIVE: Therapeutic responses of lung adenocarcinoma patients to tyrosine kinase inhibitors (TKIs) of epidermal growth factor receptor (EGFR) are closely associated with activating mutations within the EGFR tyrosine kinase domain. Screening activating EGFR mutations prior to selection for therapeutic strategy has been considered extremely valuable for clinical management of lung adenocarcinoma patients in Asian countries including Taiwan, where the EGFR mutation rate is higher than in the rest of the world. Currently there is no consensus on the method of choice to assess EGFR mutations in tumour tissue. METHODS: We enrolled 445 lung adenocarcinoma patients for analysis of tumour EGFR mutations using polymerase chain reaction (PCR)-direct sequencing, scorpion/amplified refractory mutation system (ARMS) technology and immunohistochemistry with mutation-specific antibodies. RESULTS: Two hundred forty-five patients (245/445; 55%) were found to harbour activating EGFR mutations using PCR-direct sequencing method, with a majority of patients (233/245; 95%) carrying exon 19 deletion or p.L858R point mutations. One hundred three of 200 patients were negative for EGFR mutations from PCR-direct sequencing were further analysed using Scorpion/ARMS technology. Up to 30% of the PCR-direct sequencing negative patients turned out to be positive in the Scorpion/ARMS EGFR mutation tests. For immunohistochemistry analysis of EGFR mutations, the p.E746_A750del specific antibody showed a sensitivity of 57% and a specificity of 100% for exon 19 deletions while the p.L858R point mutation specific antibody showed a sensitivity of 68% and a specificity of 95%. CONCLUSIONS: Based on this study, we proposed an algorithm for comprehensive and efficient testing of EGFR mutations on lung adenocarcinoma patients in Asia. PMID- 23796144 TI - Does allergic rhinitis make a difference to the respiratory resistance and reactance of asthma? AB - BACKGROUND: Concomitant allergic rhinitis (AR) in asthmatic patients can contribute to increased asthma exacerbations and poorer symptom control. A recent study indicated that impulse oscillometry is a more sensitive measure of change in airway function than spirometry, but this has not been used to compare asthmatic patients with or without AR. OBJECTIVE: We used impulse oscillometry (Mostgraph-01) to examine the impact of AR on asthma. METHODS: Impulse oscillometry and spirometry were assessed in 50 patients with asthma only and 95 patients with asthma and AR. RESULTS: Mean age in the asthma only group was significantly higher than in the asthma with AR group. Therefore, analysis of covariance adjusted for age was used to compare between these two groups. Percentage of mean forced expiratory volume in 1 s (FEV1), respiratory resistance at 5 Hz (R5) minus respiratory resistance at 20 Hz (R20), and resonant frequency (Fres) in the asthma with AR group were significantly less severe than in the asthma only group. Parameters of resistance and reactance were correlated with age and body mass index only in the asthma with AR group but not in the asthma only group. Correlations were observed between rate of change of maximum mid expiratory flow and impulse oscillometry values of R5 and Fres in the asthma only group, but not between the rate of change of FEV1 and impulse oscillometry values. CONCLUSION: Asthma with AR was associated with higher lung function and better values of resistance and reactance than asthma only. PMID- 23796146 TI - Exciton dynamics of CdS thin films produced by chemical bath deposition and DC pulse sputtering. AB - Exciton dynamics of CdS films have been investigated using ultrafast laser spectroscopy with an emphasis on understanding defect-related recombination. Two types of CdS films were deposited on glass substrates via direct current pulse sputtering (DCPS) and chemical bath deposition (CBD) techniques. The films displayed distinct morphological, optical, and structural properties. Their exciton and charge carrier dynamics within the first 1 ns following photoexcitation were characterized by femotosecond pump probe spectroscopy. A singular value decomposition (SVD) global fitting technique was employed to extract the lifetime and wavelength dependence of transient species. The excited electrons of the DCPS sample decays through 1.8, 8, 65, and 450 ps time constants which were attributed to donor level electron trapping, valence band (VB) -> conduction band (CB) recombination, shallow donor recombination, and deep donor recombination, respectively. The CBD sample shows time constants of 6, 65, and 450 ps which were attributed to CB -> VB recombination, sulfur vacancy (VS) recombination, and VS -> oxygen interstitial (Oi) donor-acceptor pair (DAP) recombination, respectively. It was found that the DCPS deposition technique produces films with lower defect density and improved carrier dynamics, which are important for high performance solar cell applications. PMID- 23796145 TI - Overweight and television and computer habits in Swedish school-age children and adolescents: a cross-sectional study. AB - The aim of this cross-sectional study was to investigate the prevalence of overweight and obesity in children and adolescents (6-16 years), and relationships between being overweight and sleep, experiencing of fatigue, enjoyment of school, and time spent in watching television and in sitting at the computer. Trained school nurses measured the weight and height of 2891 children aged 6, 7, 10, 14, and 16, and distributed a questionnaire to them regarding television and computer habits, sleep, and enjoyment of school. Overweight, obesity included, was present in 16.1% of the study population. Relationships between lifestyle factors and overweight were studied using multivariate logistic regression analysis. Having a bedroom television and spending more than 2 h a day watching television were found to be associated with overweight (OR 1.26 and 1.55 respectively). No association was found between overweight and time spent at the computer, short sleep duration, enjoyment of school, tiredness at school, or difficulties in sleeping and waking up. It is recommended that the school health service discuss with pupils their media habits so as to promote their maintaining a healthy lifestyle. PMID- 23796147 TI - AgNa(VO2F2)2: a trioxovanadium fluoride with unconventional electrochemical properties. AB - We present structural and electrochemical analyses of a new double-wolframite compound: AgNa(VO2F2)2 or SSVOF. SSVOF is fully ordered and displays electrochemical characteristics that give insight into electrode design for energy storage beyond lithium-ion chemistries. The compound contains trioxovanadium fluoride octahedra that combine to form one-dimensional chain-like basic building units, characteristic of wolframite (NaWO4). The 1D chains are stacked to create 2D layers; the cations Ag(+) and Na(+) lie between these layers. The vanadium oxide-fluoride octahedra are ordered by the use of cations (Ag(+), Na(+)) that differ in polarizability. In the case of sodium-ion batteries, thermodynamically, the use of a sodium anode introduces a 300 mV loss in overall cell voltage as compared to a lithium anode; however, this can be counter-balanced by introduction of fluoride into the framework to raise the reduction potentials via an inductive effect. This allows sodium-ion batteries to have comparable voltages to lithium systems. With SSVOF as a baseline compound, we have identified new materials design rules for emerging sodium-ion systems that do not apply to lithium-ion systems. These strategies can be applied broadly to provide materials of interest for fundamental structural chemistry and appreciable voltages for sodium-ion electrochemistry. PMID- 23796131 TI - Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. AB - BACKGROUND: Weight loss is recommended for overweight or obese patients with type 2 diabetes on the basis of short-term studies, but long-term effects on cardiovascular disease remain unknown. We examined whether an intensive lifestyle intervention for weight loss would decrease cardiovascular morbidity and mortality among such patients. METHODS: In 16 study centers in the United States, we randomly assigned 5145 overweight or obese patients with type 2 diabetes to participate in an intensive lifestyle intervention that promoted weight loss through decreased caloric intake and increased physical activity (intervention group) or to receive diabetes support and education (control group). The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina during a maximum follow-up of 13.5 years. RESULTS: The trial was stopped early on the basis of a futility analysis when the median follow-up was 9.6 years. Weight loss was greater in the intervention group than in the control group throughout the study (8.6% vs. 0.7% at 1 year; 6.0% vs. 3.5% at study end). The intensive lifestyle intervention also produced greater reductions in glycated hemoglobin and greater initial improvements in fitness and all cardiovascular risk factors, except for low-density-lipoprotein cholesterol levels. The primary outcome occurred in 403 patients in the intervention group and in 418 in the control group (1.83 and 1.92 events per 100 person-years, respectively; hazard ratio in the intervention group, 0.95; 95% confidence interval, 0.83 to 1.09; P=0.51). CONCLUSIONS: An intensive lifestyle intervention focusing on weight loss did not reduce the rate of cardiovascular events in overweight or obese adults with type 2 diabetes. (Funded by the National Institutes of Health and others; Look AHEAD ClinicalTrials.gov number, NCT00017953.). PMID- 23796148 TI - Markers suggest reduced malignant potential of subsquamous intestinal metaplasia compared with Barrett's esophagus. AB - Esophageal subsquamous intestinal metaplasia (SSIM) is frequently observed in patients with Barrett's esophagus (BE) and can also be found in patients after endoscopic ablative treatments for dysplastic BE. While these 'buried glands' appear identical to BE glands, features of SSIM and its malignant potency have yet to be fully elucidated. To determine differences in malignant potential between nondysplastic BE and SSIM, the Automated Cellular Imaging System was used to assess and compare changes in DNA content between SSIM and BE. Samples were further immunostained for Ki67 and Lgr5 to gauge general proliferative and possible stem cell features, respectively, in SSIM cells compared with BE glands. No significant differences were found between SSIM and BE with regards to DNA ploidy aberrance. However, significant differences were noted between SSIM and BE upon immunohistochemical analysis. SSIM was found to be negative for both Ki67 and Lgr5 while BE was positive for both markers. SSIM cells appear to be relatively quiescent and behave differently from BE, suggesting a reduced proclivity toward cancer progression. PMID- 23796149 TI - Unusual compensatory neural connections following disruption of corpus callosum fibers in a patient with corpus callosum hemorrhage. AB - OBJECTIVE: We report on a patient with hemorrhage of the corpus callosum (CC) in whom unusual compensatory neural connections were observed following disruption of CC fibers. METHODS: A 42-year-old female patient presented with callosal alien hand syndrome (AHS) after the onset of the hemorrhage. She showed a rapid recovery and the symptoms of her AHS had almost disappeared at 7 weeks after onset. We performed diffusion tensor tractography (DTT) for the evaluation of CC fibers and performed a comparison with DTT findings acquired from a normal subject (a 47-year-old female). RESULTS: Findings on DTT of the patient revealed extensive disruption of CC fibers passing through the anterior portion of the genu and most of the CC body. We observed that CC fibers in the right and left temporal lobes joined with the right and left inferior fronto-occipital fasciculus, respectively, and these neural fibers were connected to each other through the anterior commissure. These changes of neural connections were not observed in the normal subject. CONCLUSION: We think that the unusual neural connections in this patient were compensatory phenomena for disruption of CC fibers. In addition, the good recovery from symptoms of AHS in this patient appears to be correlated with these unusual compensatory neural connections. We believe that the results of this study suggest a mechanism for neural recovery following injury of the CC fibers. PMID- 23796150 TI - Algorithm for the diagnosis and management of suspected pump thrombus. AB - Pump thrombosis is a dreaded complication of long-term implantable ventricular assist devices. No guidance exists regarding the diagnosis and management of this entity despite its significant morbidity. After considerable thought and deliberation, a group of leading investigators in the field of mechanical support propose an algorithm for the diagnosis and management of this vexing entity based on clinical symptoms and serologic and imaging studies. PMID- 23796151 TI - Disparities in lung transplantation. PMID- 23796152 TI - HeartWare ventricular assist system for bridge to transplant: combined results of the bridge to transplant and continued access protocol trial. AB - BACKGROUND: The HeartWare Ventricular Assist System (HeartWare Inc, Framingmam, MA) is a miniaturized implantable, centrifugal design, continuous-flow blood pump. The pivotal bridge to transplant and continued access protocols trials have enrolled patients with advanced heart failure in a bridge-to-transplant indication. METHODS: The primary outcome, success, was defined as survival on the originally implanted device, transplant, or explant for ventricular recovery at 180 days. Secondary outcomes included an evaluation of survival, functional and quality of life outcomes, and adverse events. RESULTS: A total of 332 patients in the pivotal bridge to transplant and continued access protocols trial have completed their 180-day primary end-point assessment. Survival in patients receiving the HeartWare pump was 91% at 180 days and 84% at 360 days. Quality of life scores improved significantly, and adverse event rates remain low. CONCLUSIONS: The use of the HeartWare pump as a bridge to transplant continues to demonstrate a high 180-day survival rate despite a low rate of transplant. Adverse event rates are similar or better than those observed in historical bridge-to-transplant trials, despite longer exposure times due to longer survival and lower transplant rates. PMID- 23796153 TI - Use of a multiplex polymerase chain reaction system for enhanced bloodstream pathogen detection in thoracic transplantation. AB - BACKGROUND: Bloodstream infections (BSIs) constitute a frequent post-transplant complication in thoracic allograft recipients, especially during the early post surgical period when patients are under intense immunosuppression. Thus, early and accurate identification of the responsible pathogens is of critical importance for patient survival. In this study we investigated the potential clinical utility of a multiplex real-time polymerase chain reaction (PCR) technology (SeptiFast; Roche Diagnostics) for the detection of BSIs in a cohort of thoracic allograft recipients. METHODS: Our observational study included analysis of 130 blood samples from 30 thoracic allograft recipients (23 heart and 7 lung) using SeptiFast in parallel with blood culture. Samples were drawn when there were clinical and laboratory signs of BSI. The applied molecular assay has been designed to allow direct detection of a wide panel of Gram-positive and Gram negative bacteria and fungi in blood samples. RESULTS: Real-time PCR yielded concurrent negative and positive results with blood culture methodology in 113 (86.9%) and 5 (3.9%) samples, respectively, with 100% concordance in species identification. SeptiFast identified microorganisms in 9 (6.9%) additional samples that were negative by blood culture. The combined use of SeptiFast and blood culture during the early post-transplant period (<2 months) significantly increased the number of positive samples detected to 17.9% (14 of 78) from 7.7% (6 of 78) detected by blood culture alone (p < 0.05). SeptiFast results were available, on average, within 6 hours from sample collection. CONCLUSIONS: The PCR-based SeptiFast test is a valuable addition to the traditional blood culture method for rapid etiologic diagnosis of BSIs in thoracic transplant recipients, especially during the early post-transplant period. PMID- 23796154 TI - Plasma protein biosignatures for detection of cardiac allograft vasculopathy. AB - BACKGROUND: Coronary angiography remains the most widely used tool for routine screening and diagnosis of cardiac allograft vasculopathy (CAV), a major pathologic process that develops in 50% of cardiac transplant recipients beyond the first year after transplant. Given the invasiveness, expense, discomfort, and risk of complications associated with angiography, a minimally invasive alternative that is sensitive and specific would be highly desirable for monitoring CAV in patients. METHODS: Plasma proteomic analysis using isobaric tags for relative and absolute quantitation-matrix-assisted laser desorption ionization double time-of-flight mass spectrometry was carried out on samples from 40 cardiac transplant patients (10 CAV, 9 non-significant CAV, 21 possible CAV). Presence of CAV was defined as left anterior descending artery diameter stenosis >= 40% by digital angiography and quantitatively measured by blinded expert appraisal. Moderated t-test robust-linear models for microarray data were used to identify biomarkers that are significantly differentially expressed between patient samples with CAV and with non-significant CAV. A proteomic panel for diagnosis of CAV was generated using the Elastic Net classification method. RESULTS: We identified an 18-plasma protein biomarker classifier panel that was able to classify and differentiate patients with angiographically significant CAV from those without significant CAV, with an 80% sensitivity and 89% specificity, while providing insight into the possible underlying immune and non-alloimmune contributory mechanisms of CAV. CONCLUSION: Our results support of the potential utility of proteomic biomarker panels as a minimally invasive means to identify patients with significant, angiographically detectable coronary artery stenosis in the cardiac allograft, in the context of post-cardiac transplantation monitoring and screening for CAV. The potential biologic significance of the biomarkers identified may also help improve our understanding of CAV pathophysiology. PMID- 23796155 TI - A cardioprotective preservation strategy employing ex vivo heart perfusion facilitates successful transplant of donor hearts after cardiocirculatory death. AB - BACKGROUND: Ex vivo heart perfusion (EVHP) has been proposed as a means to facilitate the resuscitation of donor hearts after cardiocirculatory death (DCD) and increase the donor pool. However, the current approach to clinical EVHP may exacerbate myocardial injury and impair function after transplant. Therefore, we sought to determine if a cardioprotective EVHP strategy that eliminates myocardial exposure to hypothermic hyperkalemia cardioplegia and minimizes cold ischemia could facilitate successful DCD heart transplantation. METHODS: Anesthetized pigs sustained a hypoxic cardiac arrest and a 15-minute warm ischemic standoff period. Strategy 1 hearts (S1, n = 9) underwent initial reperfusion with a cold hyperkalemic cardioplegia, normothermic EVHP, and transplantation after a cold hyperkalemic cardioplegic arrest (current EVHP strategy). Strategy 2 hearts (S2, n = 8) underwent initial reperfusion with a tepid adenosine-lidocaine cardioplegia, normothermic EVHP, and transplantation with continuous myocardial perfusion (cardioprotective EVHP strategy). RESULTS: At completion of EVHP, S2 hearts exhibited less weight gain (9.7 +/- 6.7 [S2] vs 21.2 +/- 6.7 [S1] g/hour, p = 0.008) and less troponin-I release into the coronary sinus effluent (4.2 +/- 1.3 [S2] vs 6.3 +/- 1.5 [S1] ng/ml; p = 0.014). Mass spectrometry analysis of oxidized pleural in post-transplant myocardium revealed less oxidative stress in S2 hearts. At 30 minutes after wean from cardiopulmonary bypass, post-transplant systolic (pre-load recruitable stroke work: 33.5 +/- 1.3 [S2] vs 19.7 +/- 10.9 [S1], p = 0.043) and diastolic (isovolumic relaxation constant: 42.9 +/- 6.7 [S2] vs 65.2 +/- 21.1 [S1], p = 0.020) function were superior in S2 hearts. CONCLUSION: In this experimental model of DCD, an EVHP strategy using initial reperfusion with a tepid adenosine lidocaine cardioplegia and continuous myocardial perfusion minimizes myocardial injury and improves short-term post-transplant function compared with the current EVHP strategy using cold hyperkalemic cardioplegia before organ procurement and transplantation. PMID- 23796156 TI - Remembering Robyn Barst. PMID- 23796157 TI - Percutaneous mechanical circulatory support for systemic ventricular failure after the Mustard procedure. PMID- 23796158 TI - Spatiotemporal regulation of Rho1 and Cdc42 activity during Candida albicans filamentous growth. AB - Rho G-proteins are critical for polarized growth, yet little is known about the dynamics of their activation during fungal filamentous growth. We first investigated the roles of Rho1 and Rho2 during Candida albicans filamentous growth. Our results show that Rho1 is required for invasive filamentous growth and that Rho2 is not functionally redundant with Rho1. Using fluorescent reporters, we examined the dynamics of the active form of Rho1 and Cdc42 during initiation and maintenance of hyphal growth. Quantitative analyses indicated that the distribution, but not the level, of these active G-proteins is altered during initial polarization upon germ tube emergence. A comparison of the dynamics of these active G-proteins during budding and hyphal growth indicates that a higher concentration of active Cdc42 was recruited to the germ tube tip than to the bud tip. During hyphal elongation, active Cdc42 remained tightly restricted to the hyphal tip, whereas active Rho1 was broadly associated with the apex and subsequently recruited to the cell division site. Furthermore, our data suggest that phosphoinositide-bis-phosphates are critical to stabilize active Rho1 at the growth site. Together, our results point towards different regulation of Cdc42 and Rho1 activity during initiation and maintenance of filamentous growth. PMID- 23796159 TI - Red cell distribution width and hypertensive response to exercise in patients with type 2 diabetes mellitus. AB - OBJECTIVE: There is no study about hypertensive response to exercise (HRE), which is a marker of unborn hypertension (HT), and red cell distribution width (RDW) association, in diabetic normotensive patients. So, we aimed to investigate any correlation among RDW and HRE in normotensive type 2 diabetic patients. METHODS: Consecutive type 2 diabetic patients without history of HT and with normal blood pressure (BP) on ambulatory BP monitoring were included to the study. We divided the patients into two groups depending on their peak systolic BP on exercise; HRE (Group 1) or normal response to exercise (Group 2). RESULTS: Data of 75 diabetic patients (51.9 +/- 9.7) were analyzed (31 male (48%)). Their mean RDW was 13.11 +/- 0.46. Patients with HRE were significantly older than patients without HRE. Smoking was more frequent in Group 2. Gender distribution and body mass index were similar between the groups. Else hemoglobin, hematocrit, red blood cell count and RDW values were not significantly different. Office systolic BP and diastolic BP, daytime and 24-h systolic BP were significantly higher in Group 1 but heart rate was similar between the groups. CONCLUSIONS: This study revealed that RDW do not differ between diabetic normotensive patients with HRE or not. PMID- 23796160 TI - Hepcidin levels in diabetes mellitus and polycystic ovary syndrome. AB - AIM: Increased body iron is associated with insulin resistance. Hepcidin is the key hormone that negatively regulates iron homeostasis. We hypothesized that individuals with insulin resistance have inadequate hepcidin levels for their iron load. METHODS: Serum concentrations of the active form of hepcidin (hepcidin 25) and hepcidin:ferritin ratio were evaluated in participants with Type 2 diabetes (n = 33, control subjects matched for age, gender and BMI, n = 33) and participants with polycystic ovary syndrome (n = 27, control subjects matched for age and BMI, n = 16). To investigate whether any changes observed were associated with insulin resistance rather than insulin deficiency or hyperglycaemia per se, the same measurements were made in participants with Type 1 diabetes (n = 28, control subjects matched for age, gender and BMI, n = 30). Finally, the relationship between homeostasis model assessment of insulin resistance and serum hepcidin:ferritin ratio was explored in overweight or obese participants without diabetes (n = 16). RESULTS: Participants with Type 2 diabetes had significantly lower hepcidin and hepcidin:ferritin ratio than control subjects (P < 0.05 and P < 0.01, respectively). Participants with polycystic ovary syndrome had a significantly lower hepcidin:ferritin ratio than control subjects (P < 0.05). There was no significant difference in hepcidin or hepcidin:ferritin ratio between participants with Type 1 diabetes and control subjects (P = 0.88 and P = 0.94). Serum hepcidin:ferritin ratio inversely correlated with homeostasis model assessment of insulin resistance (r = -0.59, P < 0.05). CONCLUSION: Insulin resistance, but not insulin deficiency or hyperglycaemia per se, is associated with inadequate hepcidin levels. Reduced hepcidin concentrations may cause increased body iron stores in insulin-resistant states. PMID- 23796161 TI - Precapillary oxygenation contributes relevantly to gas exchange in the intact lung. AB - RATIONALE: Oxygen uptake is the elemental function of the lung. However, current understanding of this process has largely been derived from theoretical considerations and measurements of global pulmonary gas exchange. OBJECTIVES: To report the direct visualization of pulmonary oxygen uptake in vivo and its use for the analysis of temporal and spatial oxygenation profiles along individual arteriovenous pathways in lungs of healthy and chronic hypoxic mice. METHODS: A murine model for intravital microscopy of the breathing lung under sealed thorax conditions was combined with multispectral oximetry for two-dimensional oxygen saturation mapping. This combination allowed for visualization of the blood oxygenation process from pulmonary arterioles to capillaries and venules in two dimensional oxygen saturation maps. MEASUREMENTS AND MAIN RESULTS: Temporal and spatial oxygenation profiles revealed that oxygenation occurs within 100 milliseconds over a distance of approximately 130 MUm in the pulmonary microvasculature of the anesthetized mouse. About 50% of total oxygen uptake takes place in precapillary arterioles of less than 30 MUm in diameter before the blood enters the alveolar capillary bed. In chronic hypoxic mice, precapillary oxygenation was significantly attenuated as a result of the widened transarteriolar diffusion distance. CONCLUSIONS: Oxygen saturation mapping in the intact lung yields unique insights into the temporal and spatial characteristics of pulmonary gas exchange in intact and diseased lungs. Precapillary gas exchange contributes importantly to blood oxygenation at rest, but is attenuated in remodeled lung arterioles, which may be of relevance in pulmonary hypertension. PMID- 23796162 TI - Test of an intervention to improve knowledge of women with intellectual disabilities about cervical and breast cancer screening. AB - BACKGROUND: There is a critical need for evidence-based health education interventions for women with intellectual disabilities (IDs) to promote receipt of preventive health screenings. Previous research has established Women Be Healthy, an 8-week classroom-style intervention designed to teach women with IDs about breast and cervical cancer screenings, as a promising practice. However, additional research is needed to determine how to further improve screening related knowledge gains. This study aimed to test a modified version of Women Be Healthy, Women Be Healthy 2, and compare its effectiveness in increasing knowledge gains to the original intervention. METHOD: Women living in the community across one state in the United States were randomly assigned to a treatment (n = 98), delayed treatment, (n = 35), or no intervention group (n = 65). Women in the treatment group received Women Be Healthy, and women in the delayed treatment group received the modified Women Be Healthy 2. Baseline and post-intervention interviews were conducted to measure knowledge of cervical and breast cancer screening. Knowledge scores were compared across groups. RESULTS: Among the nine knowledge items measured, one breast knowledge measure and one cervical knowledge measure showed statistically significant group differences; marginally significant differences were observed for two other knowledge measures. After adjusting for covariates, women who received Women Be Healthy 2 had increased knowledge overall compared with the women receiving no intervention. CONCLUSION: Women Be Healthy 2 is promising, but additional efforts appear necessary to increase the knowledge women with IDs have about cervical and breast cancer screening. PMID- 23796163 TI - Vacuum-assisted closure therapy for vascular graft infection (Szilagyi grade III) in the groin-a 10-year multi-center experience. AB - The aim of the study was to evaluate the benefit of vacuum-assisted closure (VAC) therapy in the management of deep, alloplastic graft infections (Szilagyi grade III) in the groin. From 2000 to 2009, we identified and included in our study 72 deep inguinal infections in 68 patients, involving native as well as synthetic graft or patch material. There were 29 early graft infections (<30 days after implantation) and 43 late infections (>=30 days after implantation). Among these, 17 cases involved native grafts/patches (12 grafts and 5 patches), while 55 cases involved non-native grafts/patches [26 polytetrafluorethylene (PTFE) grafts and 24 Dacron grafts (Haemashield, Meadox Medical, Boston Scientific Corporation, Natick, NY; Gelsoft graft, Vascutek, Inchinnan, Renfrewshire, Scotland, UK; Intervascular, Mahwah, NJ); INVISTA, and 5 Vascu-Guard(TM) bovine pericardial patches; Synovis Surgical Innovation]. All patients were treated with multiple wound debridements, graft salvage, sartorius myoplasty, intravenous antibiotics and VAC therapy until thorough surface healing was achieved. Exclusion criteria were an alloplastic graft infection with proximal expansion above the inguinal ligament, blood culture positive for septicaemia or septic anastomotic herald or overt bleeding. Nine months after initiation of therapy, overall, graft/patch salvage was achieved in 61 of 72 (84.7%) cases. Of the native graft/patch group, infected graft material was replaced with an autogenous great saphenous vein graft or patch in four patients (23.5%). In the non-native group, vein or synthetic graft preservation without revision was achieved in 48 of 55 (87.3%) patients. The mean duration of VAC therapy was 16 +/- 7.7 days, and postoperative mean hospital stay was 25.3 +/- 8.5 days. In 23 of 72 (31.9%) cases, a secondary closure of the wound was achieved; in the other 49 cases, wound healing was achieved by meshed split-thickness skin grafting. Mean wound healing time for all wounds was 24.3 +/- 12.5 days. Specific complications during VAC therapy were wound fluid retention in 2 cases and an increased need for analgesics in 12 cases (16.66%). Negative pressure wound therapy (NPWT) has been reported to be useful in the treatment of severe wound infections. Even in the presence of synthetic vascular graft material, NPWT can greatly simplify challenging wound-healing problems leading to wound dehiscence and its sequelae. Our long-term experience demonstrates the safety and effectiveness of VAC therapy in the management of deep graft infections. PMID- 23796164 TI - Effect of heating on chain conformation of branched beta-glucan in water. AB - The thermal stability of polysaccharides under heat treatment is an important factor to their functionality in food and pharmaceutical fields. The stiff branched beta-glucan coded as AF1-1 isolated from Auricularia auricula-judae was investigated with viscometry, dynamic light scattering (DLS), and size-exclusion chromatography combined with multiangle laser light scattering (SEC-MALLS) in water at 25 to 170 degrees C. The chain conformation of AF1-1 in the aqueous solution exhibited a sharp decrease in viscosity, hydrodynamic radius (Rh), and weight-average molecular weight (Mw) at elevated temperature in a narrow range of 140 to 160 degrees C. It was confirmed that the conformation transitions of the AF1-1 chains from rod-like chains to the flexible occurred during heating to 140 160 degrees C for 30 min, leading to the coexistence of the flexible chains and stiff chains at 155 degrees C as a result of the breaking of the intra- and intermolecular hydrogen bonds of the AF1-1 macromolecules. The results from scanning electron microscopy and atomic force microscopy further directly proved that the AF1-1 nanofibers in water were destructed into flexible coils consisting of individual chain at the elevated temperature higher than 155 degrees C, supporting the conformation transition. The conformational transition from stiff to flexible chains at 140-160 degrees C was irreversible. However, the chain shape and stiffness of AF1-1 was stable below 140 degrees C and hardly changed with an increase in the temperature. This was important for the application in the fields of food and pharmaceutical. PMID- 23796165 TI - Influence of conjugation axis on the optical and electronic properties of aryl substituted benzobisoxazoles. AB - Six different 2,6-diethyl-4,8-diarylbenzo[1,2-d:4,5-d']bis(oxazoles) and four different 2,4,6,8-tetraarylbenzobisoxazoles were synthesized in two steps: a Lewis acid catalyzed orthoester cyclization followed by a Suzuki or Stille cross coupling with various arenes. The influence of aryl group substitution and/or conjugation axis variation on the optical and electronic properties of these benzobis(oxazole) (BBO) compounds was evaluated. Structural modifications could be used to alter the HOMO, LUMO, and band gap over a range of 1.0, 0.5, and 0.5 eV, respectively. However, depending on the location and identity of the substituent, the HOMO level can be altered without significantly impacting the LUMO level. This is supported by the calculated frontier molecular orbitals. Our results indicate that the FMOs and band gaps of benzobisoxazoles can be readily modified either jointly or individually. PMID- 23796167 TI - Effect of intense pulsed light treatment on human skin in vitro: analysis of immediate effects on dermal papillae and hair follicle stem cells. AB - BACKGROUND: Hair follicles house a permanent pool of epithelial stem cells. Intense pulsed light (IPL) sources have been successfully used for hair removal, but long-term hair reduction may require several treatments. Many questions remain regarding the impact of IPL treatment on the structure of the hair follicle, more specifically on hair follicular stem cells and dermal papilla cells, a group of specialized cells that orchestrate hair growth. OBJECTIVES: To characterize the destruction of human hair follicles and surrounding tissues following IPL treatment, with more attention paid to the bulge and the bulb regions. METHODS: Human scalp specimens of Fitzpatrick skin phototype II were exposed ex vivo to IPL pulses and were then processed for histological analysis, immunodetection of stem cell-associated keratin 19, and revelation of the endogenous alkaline phosphatase activity expressed in dermal papilla cells. RESULTS: Histological analysis confirmed that pigmented structures, such as the melanin-rich matrix cells of the bulb in anagen follicles and the hair shaft, are principally targeted by IPL treatment, while white hairs and epidermis remained unaffected. Damage caused by heat sometimes extended over the dermal papilla cells, while stem cells were mostly spared. CONCLUSIONS: IPL epilation principally targets pigmented structures. Our results suggest that, under the tested conditions, collateral damage does not deplete stem cells. Damage at the dermal papilla was observed only with high-energy treatment modalities. Extrapolated to frequently treated hairs, these observations explain why some hairs grow back after a single IPL treatment. PMID- 23796166 TI - The promise of genomics in the study of plant-pollinator interactions. AB - Flowers exist in exceedingly complex fitness landscapes, in which subtle variation in each trait can affect the pollinators, herbivores and pleiotropically linked traits in other plant tissues. A whole-genome approach to flower evolution will help our understanding of plant-pollinator interactions. PMID- 23796168 TI - Obesity and adverse pregnancy outcomes in twin pregnancies. AB - OBJECTIVE: To compare pregnancy outcomes in twin pregnancies based on maternal pre-pregnancy body mass index (BMI). METHODS: Historical cohort study of all twin pregnancies >24 weeks managed by one maternal-fetal medicine practice from 2005 to 2012. We compared pregnancy outcomes between pre-pregnancy obese (BMI >= 30 kg/m(2)) and normal weight women (BMI 18.5-24.99 kg/m(2)). We also compared pre pregnancy normal weight women to overweight women (BMI 25-29.99 kg/m(2)) and underweight women (BMI <18.5 kg/m(2)). Chi square, Fisher's exact test, Student's t-test, and one-way ANOVA were used as appropriate. A p value of <0.05 was considered significant. RESULTS: Five hundred fourteen patients with twin pregnancies were included. Pre-pregnancy obesity was associated with gestational hypertension (34.1% versus 17.9%, p = 0.011), preeclampsia (27.3% versus 14.4%, p = 0.028), and gestational diabetes (22.2% versus 4.7%, p < 0.001). Pre-pregnancy overweight was associated with gestational diabetes (13.7% versus 4.7%, p = 0.002). Pre-pregnancy underweight was not associated with any adverse pregnancy outcomes. Comparing outcomes across normal weight, overweight, and obese women, the rates of gestational diabetes and gestational hypertension increased significantly across the three groups. CONCLUSION: In patients with twin pregnancy, pre-pregnancy obesity is associated with adverse pregnancy outcomes, including gestational diabetes, gestational hypertension, and preeclampsia. PMID- 23796169 TI - Treating attachment trauma with plain old therapy. PMID- 23796170 TI - For better or worse: the role of revictimization and stress in the course of treatment for dissociative disorders. AB - Revictimization and life stressors are common among dissociative disorder (DD) patients, yet no studies have examined the prevalence rates for these experiences or their relationships with treatment outcome. This study aimed to examine the rates of revictimization and victimization of others using therapist-DD patient pairs from the naturalistic Treatment of Patients with Dissociative Disorders (TOP DD) study while also considering the role of revictimization and life stressors among 49 patients who greatly improved or worsened during 30 months of treatment. Therapists reported that sexual and physical revictimization in the previous 6 months was high among the patients (3.5%-7.0% and 4.1%-7.1% in the overall TOP DD sample, respectively), and emotional revictimization was quite high (29%-36%). Revictimization showed a decreasing trend over the 30 months of the study. Therapists reported that more than a quarter of the patients who were revictimized were also occasionally emotionally or physically abusive to others. More patients showed sudden improvement versus sudden worsening in patient reported symptoms at 1 or more time point(s). Patients who improved had significantly fewer revictimizations and stressors overall than patients who worsened, suggesting that revictimization and/or stressors may contribute to worsening in treatment. Further research is needed to learn more about the roles of revictimization, victimization of others, and stressors in DD treatment. [Supplementary material is available for this article. Go to the publisher's online edition of Journal of Trauma & Dissociation for the following supplemental resource: Baseline Demographic Information of TOP DD Improving and Worsening Subgroups]. PMID- 23796171 TI - The intergenerational transmission of trauma as a disruption of the dialogical self. AB - This article is framed as a statement of conclusions derived from a doctoral research process I conducted. The research involved an exploration of the intergenerational transmission of trauma in the lives of mothers and their adult children. The impact of trauma on families can be seen in the various ways in which disruptions in the mother's emotional experience, and in her capacity to contain her child, influence the child's internal world (K. Lyons-Ruth & D. Jacobvitz, 1999 ; M. Main & E. Hesse, 1990). Working from a relational psychoanalytic and attachment theoretic conceptual framework, I consider the intergenerational transmission of trauma in terms of dissociation as the primary psychic defense that manifests in the inner and relational lives of survivors of trauma and their children. Dissociation is framed as a simultaneously intrapsychic and intersubjective process and is defined as a disruption of internal dialogue between conflicting self-states. I explore the disruption of dialogue with reference to G. Dimaggio's (2006) dominant and impoverished narrative trends, identifying these as primary indicators of an intergenerationally manifested dissociative and avoidant process. PMID- 23796172 TI - The primary prevention of PTSD: a systematic review. AB - There has been abundant research targeting the secondary and tertiary prevention and treatment of posttraumatic stress disorder (PTSD), including different forms of debriefing, treatments for acute stress disorder, and targeted intervention strategies (M. T. Feldner, C. M. Monson, & M. J. Friedman, 2007). However, there remains a scarcity of research pertaining to the primary, pretrauma prevention of PTSD. A systematic review was conducted in order to identify and synthesize all programs aimed at the primary prevention of PTSD to date. A broad search strategy was used, yielding 15,014 studies in 4 languages published between 1915 and 2012. Studies in which a resilience-building intervention was delivered prior to a potentially traumatic event, with data collected regarding psychological well being, were eligible. A total of 7 studies were identified as meeting these criteria. Currently, there is no solid body of research on the primary prevention of PTSD to justify or guide interventions. The limitations and future directions of research in this domain are discussed. PMID- 23796173 TI - Dissociative depression among women in the community. AB - This study screened the prevalence and correlates of dissociative disorders among depressive women in the general population. The Dissociative Disorders Interview Schedule and the posttraumatic stress disorder (PTSD) and borderline personality disorder sections of the Structured Clinical Interview for DSM-IV were administered to 628 women in 500 homes. The prevalence of current major depressive episode was 10.0%. Of the women, 26 (40.6%) had the lifetime diagnosis of a DSM-IV, dissociative disorder, yielding a prevalence of 4.1% for dissociative depression. This group was younger (mean age = 30.7 years) than the nondissociative depression women (mean age = 39.6 years). There was no difference between the 2 groups on comorbid somatization disorder, PTSD, or borderline personality disorder. Besides suicide attempts, the dissociative group was characterized by secondary features of dissociative identity disorder; Schneiderian symptoms; borderline personality disorder criteria; and extrasensory perceptions, including possession experiences. They reported suicidality, thoughts of guilt and worthlessness, diminished concentration and indecisiveness, and appetite and weight changes more frequently than the nondissociative group. Early cessation of school education and childhood sexual abuse were frequently reported by the dissociative depression group. With its distinct features, the concept of dissociative depression may facilitate understanding of treatment resistance in, development of better psychotherapy strategies for, and new thinking on the neurobiology and pharmacotherapy of depressive disorders. PMID- 23796174 TI - Exposing shame in dancers and athletes: shame, trauma, and dissociation in a nonclinical population. AB - The relationship between shame, past traumatic events, and dissociation in a nonclinical university and community sample of pre-professional/professional dancers (n = 140) and recreational/competitive athletes (n = 99) was investigated in this cross-sectional study, which was approved by an institutional review board. Participants completed 3 self-report measures (i.e., the Dissociative Experiences Scale, Internalized Shame Scale, Traumatic Events Questionnaire), and the analyses included correlation, multivariate analysis of variance, and a series of regression analyses. The investigation indicated that dancers had increased shame and dissociation in comparison to athletes, and males had more traumatic experiences and increased dissociation relative to females. In the regression analyses, being a dancer, traumatic experiences, and shame predicted dissociation. Clinical recommendations include integrating shame treatment with dissociative-disordered patients and noting that dancers may need more psychological skill training to manage shame and dissociation. PMID- 23796175 TI - Dissociative symptoms over a year in a sample of sexually abused children. AB - This study aims to document the evolution of dissociative symptoms over time in preschoolers who disclose sexual abuse. Specifically, this study explores the frequency of dissociative symptoms as a function of child gender. A follow-up evaluation was conducted 1 year after initial disclosure among a sample of 48 sexually abused children, and their results were contrasted with those of a control group composed of 71 non abused children. Children's dissociative symptoms were evaluated by non-offending parents. Data showed that children reporting sexual abuse displayed a greater frequency of dissociative symptoms than non-sexually abused children at both evaluation times. Further analysis indicated that the evolution of dissociative symptoms in sexually abused children may be gender related. Although a decline in dissociation symptoms over time was evident for sexually abused girls at follow-up, sexually abused boys displayed greater dissociative symptoms. Results are discussed in terms of their implications for interventions for sexually abused children. PMID- 23796176 TI - Dissociative mental states are canonically associated with decreased temporal theta activity on spectral analysis of EEG. AB - Quantitative electroencephalographic (QEEG) changes relating to dissociative experiences have only rarely been demonstrated, and dissociative states were not quantified in those studies. The aim of this study was to explore concurrent associations between quantified dissociative states and QEEG spectral parameters, in particular theta activity, in psychiatric patients. Fifty psychiatric patients completed the State Scale of Dissociation (SSD) immediately after a 15-min EEG recording. The EEG was assessed by conventional clinical visual analysis as well as by quantitative (QEEG) spectral analysis. Canonical analysis was performed between the set of SSD subscale scores and the following QEEG parameters: alpha theta magnitude ratios, and relative as well as absolute theta magnitude obtained from right and left mid- to posterior-temporal and parieto-occipital derivations. The SSD transferred well to the present data in terms of reliability and internal criterion-related validity. The SSD and Dissociative Experiences Scale (DES) correlated significantly (r = .73, p < .001). Conventional EEG analysis identified 29 EEGs (58%) as abnormal. The main abnormality in 23 EEGs was slowing, maximal temporally in half of these cases. Canonical analyses confirmed a statistically significant relationship between the dissociation variables (especially conversion and depersonalization symptoms) and the QEEG variables (especially relative theta magnitude in the temporal regions; R = .72, p = .03, for SSD-QEEG; and R = .66, p = .04, for DES-QEEG). Quantified dissociative mental states are positively canonically associated with decreased temporal theta activity and increased alpha-theta ratios on QEEG in psychiatric patients with a high tendency to dissociate. The potential implications of the dissociation-theta alpha relationship for understanding normal attentional processes need to be studied further. PMID- 23796178 TI - Evolving connectivity between genetic oscillators and switches using evolutionary algorithms. AB - Although hypothesised there has been little investigation into how complex gene regulatory networks can evolve from simple regulatory motifs through modularisation, duplication and specialisation processes. In order to simulate natural evolution in a computational environment we evolve the connection between a genetic oscillator and a toggle switch motif using an evolutionary algorithm. We observe a connectivity preference between the motifs that is dependent on the coupling arrangement rather than on objective set-up. In addition, our results indicate the existence of a threshold in the connection parameters for the resulting dynamics for a specific coupling arrangement and objective set-up. We demonstrate that simple motifs can successfully be coupled through artificial evolution to form more complex, modular regulatory networks. These findings support, in principle, the above-mentioned hypothesis on evolutionary mechanisms in biological systems. PMID- 23796179 TI - Identification of essential proteins from weighted protein-protein interaction networks. AB - Identifying essential proteins is very important for understanding the minimal requirements of cellular survival and development. Fast growth in the amount of available protein-protein interactions has produced unprecedented opportunities for detecting protein essentiality on network level. A series of centrality measures have been proposed to discover essential proteins based on network topology. Unfortunately, the protein-protein interactions produced by high throughput experiments generally have high false positives. Moreover, most of centrality measures based on network topology are sensitive to false positives. We therefore propose a new method for evaluating the confidence of each interaction based on the combination of logistic regression-based model and function similarity. Nine standard centrality measures in weighted network were redefined in this paper. The experimental results on a yeast protein interaction network shows that the weighting method improved the performance of centrality measures considerably. More essential proteins were discovered by the weighted centrality measures than by the original centrality measures used in the unweighted network. Even about 20% improvements were obtained from closeness centrality and subgraph centrality. PMID- 23796180 TI - Genome-wide analysis and modeling of DNA methylation susceptibility in 30 breast cancer cell lines by using CpG flanking sequences. AB - DNA methylation is an epigenetic modification of DNA that adds a methyl group to cytosine. Aberrant DNA methylation in the CpG context is frequently observed in cancer cells and it is known that aberrant DNA methylation silences tumor repressor genes. However, the mechanism of DNA methylation is not well understood. A widely accepted hypothesis is that DNA methylation does not randomly occur and may be controlled by some instructive mechanisms. In this paper, we conducted an extensive study on this important question by using proprietary sequencing data from methyl-binding domain protein (MBD)-Cap ChIP sequencing experiments for 30 breast cancer cell lines. The goal of our study is to investigate difference in nucleotide composition around CpG sites, where high levels of methylation are observed, and use the information for modeling DNA methylation susceptibility. First, we observed that DNA methylation is not uniform in the whole-genome region and also that the character composition of CpG flanking sequences are significantly different between hyper- and hypo-methylated groups. In an in-depth study, we used information theoretic approaches such as entropy and relative entropy to delineate character composition features and found enrichment of A (Adenine) and T (Thymine) in specific positions around hyper-methylated sites. As the methylation level is increased, A, T proportions in specific positions around hypermethylated sites are increased while A, T proportions in other positions around hypermethylated sites are decreased. Second, we built predictive models for methylation susceptibility by using characters flanking CpG sites as features and hyper-/hypo-methylation status as class. Third, we constructed predictive models using a log odds score of two profiles from DNA sequences surrounding CpG sites of hyper- and hypo-methylated groups. This analysis showed that distribution of profile scores of hyper-/hypo methylated sites sequences is quite distinct. Our genome-wide CpG methylation study shows that nucleotides around CpG sites caries information for cytosine methylation. This is consistent with the seminal work on the instructive evidence of DNA methylation by Keshet et al. (Nature Genetics, 38(2), 149-153 2006). Our study is on the full genome scale and used the sequencing data, thus our study is significantly different in terms of resolution of data and analysis methods used for the study by Keshet et al. PMID- 23796181 TI - Influence of mRNA features on siRNA interference efficacy. AB - Design of small interference RNA (siRNA) is one of the most important steps in effectively applying the RNA interference (RNAi) technology. The current siRNA design often produces inconsistent design results, which often fail to reliably select siRNA with clear silencing effects. We propose that when designing siRNA, one should consider mRNA global features and near siRNA-binding site local features. By a linear regression study, we discovered strong correlations between inhibitory efficacy and both mRNA global features and neighboring local features. This paper shows that, on average, less GC content, fewer stem secondary structures, and more loop secondary structures of mRNA at both global and local flanking regions of the siRNA binding sites lead to stronger inhibitory efficacy. Thus, the use of mRNA global features and near siRNA-binding site local features are essential to successful gene silencing and hence, a better siRNA design. We use a random forest model to predict siRNA efficacy using siRNA features, mRNA features, and near siRNA binding site features. Our prediction method achieved a correlation coefficient of 0.7 in 10-fold cross validation in contrast to 0.63 when using siRNA features only. Our study demonstrates that considering mRNA and near siRNA binding site features helps improve siRNA design accuracy. The findings may also be helpful in understanding binding efficacy between microRNA and mRNA. PMID- 23796182 TI - Enhancing genomics information retrieval through dimensional analysis. AB - We propose a novel dimensional analysis approach to employing meta information in order to find the relationships within the unstructured or semi-structured document/passages for improving genomics information retrieval performance. First, we make use of the auxiliary information as three basic dimensions, namely "temporal", "journal", and "author". The reference section is treated as a commensurable quantity of the three basic dimensions. Then, the sample space and subspaces are built up and a set of events are defined to meet the basic requirement of dimensional homogeneity to be commensurable quantities. After that, the classic graph analysis algorithm in the Web environments is applied on each dimension respectively to calculate the importance of each dimension. Finally, we integrate all the dimension networks and re-rank the outputs for evaluation. Our experimental results show the proposed approach is superior and promising. PMID- 23796183 TI - Classifying temporal microarray data by selecting informative genes. AB - In order to more accurately predict an individual's health status, in clinical applications it is often important to perform analysis of high-dimensional gene expression data that varies with time. A major challenge in predicting from such temporal microarray data is that the number of biomarkers used as features is typically much larger than the number of labeled subjects. One way to address this challenge is to perform feature selection as a preprocessing step and then apply a classification method on selected features. However, traditional feature selection methods cannot handle multivariate temporal data without applying techniques that flatten temporal data into a single matrix in advance. In this study, a feature selection filter that can directly select informative features from temporal gene expression data is proposed. In our approach, we measure the distance between multivariate temporal data from two subjects. Based on this distance, we define the objective function of temporal margin based feature selection to maximize each subject's temporal margin in its own relevant subspace. The experimental results on synthetic and two real flu data sets provide evidence that our method outperforms the alternatives, which flatten the temporal data in advance. PMID- 23796184 TI - Model-based clustering with gene ranking using penalized mixtures of heavy-tailed distributions. AB - Cluster analysis of biological samples using gene expression measurements is a common task which aids the discovery of heterogeneous biological sub-populations having distinct mRNA profiles. Several model-based clustering algorithms have been proposed in which the distribution of gene expression values within each sub group is assumed to be Gaussian. In the presence of noise and extreme observations, a mixture of Gaussian densities may over-fit and overestimate the true number of clusters. Moreover, commonly used model-based clustering algorithms do not generally provide a mechanism to quantify the relative contribution of each gene to the final partitioning of the data. We propose a penalized mixture of Student's t distributions for model-based clustering and gene ranking. Together with a resampling procedure, the proposed approach provides a means for ranking genes according to their contributions to the clustering process. Experimental results show that the algorithm performs well comparably to traditional Gaussian mixtures in the presence of outliers and longer tailed distributions. The algorithm also identifies the true informative genes with high sensitivity, and achieves improved model selection. An illustrative application to breast cancer data is also presented which confirms established tumor sub-classes. PMID- 23796185 TI - Disruption of protein complexes. AB - Protein complexes are a cornerstone of many biological processes and, together, they form various types of molecular machinery that perform a vast array of biological functions. Different complexes perform different functions and, the same complex can perform very different functions that depend on a variety of factors. Thus disruption of protein complexes can be lethal to an organism. It is interesting to identify a minimal set of proteins whose removal would lead to a massive disruption of protein complexes and, to understand the biological properties of these proteins. A method is presented for identifying a minimum number of proteins from a given set of complexes so that a maximum number of these complexes are disrupted when these proteins are removed. The method is based on spectral bipartitioning. This method is applied to yeast protein complexes. The identified proteins participate in a large number of biological processes and functional modules. A large proportion of them are essential proteins. Moreover, removing these identified proteins causes a large number of the yeast protein complexes to break into two fragments of nearly equal size, which minimizes the chance of either fragment being functional. The method is also superior in these aspects to alternative methods based on proteins with high connection degree, proteins whose neighbors have high average degree, and proteins that connect to lots of proteins of high connection degree. Our spectral bipartitioning method is able to efficiently identify a biologically meaningful minimal set of proteins whose removal causes a massive disruption of protein complexes in an organism. PMID- 23796186 TI - Biotransformation of mogrosides from Siraitia grosvenorii Swingle by Saccharomyces cerevisiae. AB - Mogrosides are a group of triterpenoidal saponins from the fruit of Siraitia grosvenorii Swingle; they are intensely sweet and have consequently been used as a substitute for sugar by the food industry. The lack of efficient methods to produce specific mogrosides has hindered investigation of the relationship between their structure and bioactivity, e.g., down-regulation of blood glucose levels, anti-inflammation, and antiviral infection. Here, we attempt to selectively convert the major saponin mogroside V, a mogrol pentaglucoside, into mogroside III E, a triglucoside, via the beta-glucosidases of the budding yeast Saccharomyces cerevisiae. We report that the beta-glucopyranosyl and beta glucopyranosyl-(1->2)-beta-d-glucopyranosyl attached on C-3 and -24 of mogrol, respectively, were resistant to hydrolysis by yeast beta-d-glucosidases. We further screened 16 mutants bearing single defective glucanase or glucosidase genes, thereby demonstrating that Exg1 is a major enzyme of the initiation of mogroside V conversion. Deletion of the KRE6 gene unexpectedly facilitated the production of mogroside III E in yeast culture. This paper demonstrates that yeast knockout mutants are a valuable tool for saponin modification and for studying the specificity of glucosidase function. PMID- 23796187 TI - S100B and NSE as useful postmortem biochemical markers of traumatic brain injury in autopsy cases. AB - Postmortem analysis of relevant biomarkers might aid in characterizing causes of death and survival times in legal medicine. However, there are still no sufficiently established results of practical postmortem biochemical investigations in cases of traumatic brain injury (TBI). The two biomarkers--S100 protein subunit B (S100B) and neuronal specific enolase (NSE)--could be of special interest. Therefore, the aim of the present study was to investigate changes in their postmortem levels for further determination of brain damage in TBI. In 17 cases of TBI (average age, 58 years) and in 23 controls with different causes of death (average age, 59 years), serum and cerebrospinal fluid (CSF) samples were analyzed with a chemiluminescence immunoassay for marker expression. An increase in serum S100B, as well as a subsequent decrease after survival times>4 days, were detected in TBI cases (p<0.01). CSF NSE values >6,000 ng/mL and CSF S100B levels >10,000 ng/mL seem to indicate a TBI survival time of at least 15 min (p<0.01). It is of particular interest that CSF S100B levels (p<0.01) and serum S100B levels (p<0.05) as well as CSF NSE values (p<0.01) were significantly higher in TBI cases in comparison to the controls, especially when compared with fatal non-head injuries. In conclusion, the present findings emphasize that S100B and NSE are useful markers in postmortem biochemistry in cases of suspected TBI. Further, S100B may be helpful to estimate the survival time of fatal injuries in legal medicine. PMID- 23796188 TI - Two new triterpenoid saponins from the leaves of Aralia elata. AB - Phytochemical investigation of the leaves of Aralia elata has led to the isolation of two new compounds 3-O-beta-D-glucopyranosyl-(1 -> 3)-beta-D glucopyranosyl-(1 -> 3)-beta-D-glucopyranosyl echinocystic acid (1) and 3-O-beta D-glucopyranosyl-(1 -> 3)-beta-D-glucopyranosyl-(1 -> 3)-beta-D-glucopyranosyl oleanolic acid 28-O-beta-D-glucopyranoside (2), together with four known compounds 3-6, which were isolated for the first time from this genus. Structural determination was accomplished by spectroscopic analysis, particularly by 13C NMR, 2D NMR, and HR-ESI-MS techniques. PMID- 23796189 TI - Early experience of reinforcing the ligation of the intersphincteric fistula tract procedure with a bioprosthetic graft (BioLIFT) for anal fistula. AB - BACKGROUND: The BioLIFT procedure involves placing a bioprosthetic graft in the intersphincteric space during the ligation of the intersphincteric fistula tract (LIFT) procedure. Our study was aimed to describe our experience in the BioLIFT procedure. METHODS: A review of all patients who underwent the BioLIFT procedure for anal fistula from September 2011 to August 2012 was performed. Endoanal ultrasonography and manometry tests were performed in all patients. RESULTS: Thirteen patients with 16 fistulas underwent the BioLIFT procedure. All of them had at least a seton inserted previously and the median interval to the BioLIFT procedure was 20 (range, 10-41) weeks. Four patients failed a prior LIFT procedure. More than half of the fistulas (56.3%) had anterior internal openings and there was a female preponderance (n = 7, 53.8%). Over a median follow up of 26 (12-51) weeks, 11 (68.8%) fistulas had healed. The median interval between the BioLIFT procedure to the diagnosis of failure was 3 (2-7) weeks. All five failures had only isolated discharges at the intersphincteric wounds. Two had already undergone successful lay-open fistulotomy, giving a secondary success rate of 81.3%. The remaining three patients are on review. No patient developed incontinent symptoms following the BioLIFT procedure and there were no significant differences between the pre-procedural or post-procedural maximal resting and squeeze anal manometric pressures. CONCLUSION: The BioLIFT procedure can achieve a primary success rate of 68.8%. When coupled with a simple lay-open fistulotomy for the subsequent intersphincteric fistula, the success rate in eradicating the fistula rose to 81.3%. PMID- 23796190 TI - Copper-catalyzed hydroquinone oxidation and associated redox cycling of copper under conditions typical of natural saline waters. AB - A detailed kinetic model has been developed to describe the oxidation of Cu(I) by O2 and the reduction of Cu(II) by 1,4-hydroquinone (H2Q) in the presence of O2 in 0.7 M NaCl solution over a pH range of 6.5-8.0. The reaction between Cu(I) and O2 is shown to be the most important pathway in the overall oxidation of Cu(I), with the rate constant for this oxidation process increasing with an increasing pH. In 0.7 M NaCl solutions, Cu(II) is capable of catalyzing the oxidation of H2Q in the presence of O2 with the monoanion, HQ(-), the kinetically active hydroquinone form, reducing Cu(II) with an intrinsic rate constant of (5.0 +/- 0.4) * 10(7) M( 1) s(-1). Acting as a chain-propagating species, the deprotonated semiquinone radical (SQ(*) (-)) generated from both the one-electron oxidation of H2Q and the one-electron reduction of 1,4-benzoquinone (BQ) also reacts rapidly with Cu(II) and Cu(I), with the same rate constant of (2.0 +/- 0.5) * 10(7) M(-1) s(-1). In addition to its role in reformation of Cu(II) via continuous oxidation of Cu(I), O2 rapidly removes SQ(*) (-), resulting in the generation of O2(*) (-). Agreement between half-cell reduction potentials of different redox couples provides confirmation of the veracity of the proposed model describing the interactions of copper and quinone species in circumneutral pH saline solutions. PMID- 23796191 TI - AESOPS: a randomised controlled trial of the clinical effectiveness and cost effectiveness of opportunistic screening and stepped care interventions for older hazardous alcohol users in primary care. AB - BACKGROUND: There is clear evidence of the detrimental impact of hazardous alcohol consumption on the physical and mental health of the population. Estimates suggest that hazardous alcohol consumption annually accounts for 150,000 hospital admissions and between 15,000 and 22,000 deaths in the UK. In the older population, hazardous alcohol consumption is associated with a wide range of physical, psychological and social problems. There is evidence of an association between increased alcohol consumption and increased risk of coronary heart disease, hypertension and haemorrhagic and ischaemic stroke, increased rates of alcohol-related liver disease and increased risk of a range of cancers. Alcohol is identified as one of the three main risk factors for falls. Excessive alcohol consumption in older age can also contribute to the onset of dementia and other age-related cognitive deficits and is implicated in one-third of all suicides in the older population. OBJECTIVE: To compare the clinical effectiveness and cost-effectiveness of a stepped care intervention against a minimal intervention in the treatment of older hazardous alcohol users in primary care. DESIGN: A multicentre, pragmatic, two-armed randomised controlled trial with an economic evaluation. SETTING: General practices in primary care in England and Scotland between April 2008 and October 2010. PARTICIPANTS: Adults aged >= 55 years scoring >= 8 on the Alcohol Use Disorders Identification Test (10-item) (AUDIT) were eligible. In total, 529 patients were randomised in the study. INTERVENTIONS: The minimal intervention group received a 5-minute brief advice intervention with the practice or research nurse involving feedback of the screening results and discussion regarding the health consequences of continued hazardous alcohol consumption. Those in the stepped care arm initially received a 20-minute session of behavioural change counselling, with referral to step 2 (motivational enhancement therapy) and step 3 (local specialist alcohol services) if indicated. Sessions were recorded and rated to ensure treatment fidelity. MAIN OUTCOME MEASURES: The primary outcome was average drinks per day (ADD) derived from extended AUDIT--Consumption (3-item) (AUDIT-C) at 12 months. Secondary outcomes were AUDIT-C score at 6 and 12 months; alcohol-related problems assessed using the Drinking Problems Index (DPI) at 6 and 12 months; health-related quality of life assessed using the Short Form Questionnaire-12 items (SF-12) at 6 and 12 months; ADD at 6 months; quality-adjusted life-years (QALYs) (for cost utility analysis derived from European Quality of Life-5 Dimensions); and health and social care resource use associated with the two groups. RESULTS: Both groups reduced alcohol consumption between baseline and 12 months. The difference between groups in log-transformed ADD at 12 months was very small, at 0.025 [95% confidence interval (CI)--0.060 to 0.119], and not statistically significant. At month 6 the stepped care group had a lower ADD, but again the difference was not statistically significant. At months 6 and 12, the stepped care group had a lower DPI score, but this difference was not statistically significant at the 5% level. The stepped care group had a lower SF-12 mental component score and lower physical component score at month 6 and month 12, but these differences were not statistically significant at the 5% level. The overall average cost per patient, taking into account health and social care resource use, was L488 [standard deviation (SD) L826] in the stepped care group and L482 (SD L826) in the minimal intervention group at month 6. The mean QALY gains were slightly greater in the stepped care group than in the minimal intervention group, with a mean difference of 0.0058 (95% CI -0.0018 to 0.0133), generating an incremental cost effectiveness ratio (ICER) of L1100 per QALY gained. At month 12, participants in the stepped care group incurred fewer costs, with a mean difference of -L194 (95% CI -L585 to L198), and had gained 0.0117 more QALYs (95% CI -0.0084 to 0.0318) than the control group. Therefore, from an economic perspective the minimal intervention was dominated by stepped care but, as would be expected given the effectiveness results, the difference was small and not statistically significant. CONCLUSIONS: Stepped care does not confer an advantage over minimal intervention in terms of reduction in alcohol consumption at 12 months post intervention when compared with a 5-minute brief (minimal) intervention. TRIAL REGISTRATION: This trial is registered as ISRCTN52557360. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 17, No. 25. See the HTA programme website for further project information. PMID- 23796192 TI - Esophageal squamous cell carcinoma (ESCC): advance in genomics and molecular genetics. AB - Esophageal cancer is aggressive and has poor prognosis. Esophageal squamous cell carcinoma (ESCC) is histologically the most prevalent type of esophageal cancer and ranked as the sixth leading cause of cancer death worldwide. In recent years, cancer has been widely regarded as genetic disease, as well as epigenetic abnormalities including DNA methylation, histone deacetylation, chromatin remodeling, gene imprinting and noncoding RNA regulation. In this review, we will provide a general overview of genes, proteins and microRNAs that are involved in the development of ESCC, which aims to enhance our understanding of molecular mechanisms implicated in ESCC development and progression. PMID- 23796193 TI - Application of randomized clinical trial data to actual practice: apixaban therapy for reduction of stroke risk in non-valvular atrial fibrillation patients. AB - BACKGROUND: Clinical event rates may differ among patients treated in the real world (RW) compared to randomized controlled trials (RCTs). When translating the efficacy of new treatments to RW, the relative risk reductions (RRRs) from RCTs may produce different absolute risk reductions in RW. OBJECTIVE: To estimate the absolute effect of apixaban on stroke and major bleeding (MB) rates in a RW non valvular atrial fibrillation (NVAF) population. METHODS: NVAF patients were selected during 2007-2010 from a population of U.S. commercial and Medicare health plans using the Medco claims database. Pharmacy claims were used to define warfarin exposure periods. Stroke and MB were identified using diagnosis codes. RW event rates were calculated during periods of warfarin exposure. The numbers of stroke and MB events estimated to be avoided in RW with apixaban versus warfarin were calculated by applying RRRs from the ARISTOTLE trial to RW rates from the Medco database. The Medco data did not contain information for patients receiving apixaban as it was not on the market at the time of analysis. RESULTS: Stroke and MB rates among RW NVAF patients during warfarin exposure were higher compared with event rates in patients treated with warfarin in ARISTOTLE (stroke: 5.29 vs. 1.51 per 100 person years (PYs); MB: 10.78 vs. 3.09 per 100 PYs). If RRRs from trials persist in RW, apixaban vs. warfarin would result in greater absolute risk reductions (ARRs) and a lower number needed to treat (NNT) in RW vs. ARISTOTLE (stroke: 91 vs. 313; MB: 30 vs. 105). CONCLUSION: The impact of apixaban, as an alternative to warfarin in RW may be greater than in RCTs. The NNT with apixaban versus warfarin in RW may be lower versus ARISTOTLE if RRRs from the trial persists in RW and if baseline stroke and MB rates among RW patients are higher compared to trial participants. PMID- 23796194 TI - Interaction of cyclic mechanical stretch and toll-like receptor 4-mediated innate immunity in rat alveolar type II cells. AB - BACKGROUND AND OBJECTIVE: In cases of infection-induced acute lung injury, mechanical ventilation might be necessary to maintain oxygenation. Although low tidal volume ventilation is applied, alveolar over-distension may occur and result in ventilator-induced lung injury. In this study, we investigate (i) the influence of lipopolysaccharide (LPS) stimulation on high-amplitude stretching; and (ii) the effect of stretching on LPS-mediated immune response in isolated rat alveolar type II cells. METHODS: Type II cells were incubated with LPS and stretched for 24 h on elastic membranes. Initially we examined apoptosis and lactic acid dehydrogenase release in LPS-treated stretched cells. Furthermore we determined toll-like receptor (TLR) 4 expression, TLR4 signalling by analysis of nuclear factor kappaB (NF-kappaB) activation and the secretion of inflammatory cytokines (monocyte chemoattractant protein-1, macrophage inflammatory protein-2, interleukin-1 beta, tumour necrosis factor alpha). RESULTS: Our results show that LPS increases apoptosis and cytotoxicity in high amplitude stretched cells. Stretching and LPS activate NF-kappaB. The LPS influence is the prevailing one while no synergistic effects were observed by additional stretching. LPS stimulates an increased secretion of the inflammatory mediators only. Stretching had no influence on cytokines secretion. CONCLUSIONS: We conclude that activation of TLR4 mediated immunity intensifies cell damage caused by stretching whereas in return stretching had no influence on TLR4 mediated innate immunity. PMID- 23796195 TI - Adverse events of surgical extrusion in treatment for crown-root and cervical root fractures: a systematic review of case series/reports. AB - BACKGROUND: Crown-root and cervical root fractures constitute a restorative challenge due to sub-gingival position of the fracture margin. Surgical tooth extrusion is one of the treatment options. There is uncertainty regarding the prognosis of such treatment modality. OBJECTIVE: To assess adverse events of surgical tooth extrusion in the treatment for crown-root and cervical root fractures in permanent teeth. METHODS: PubMed, Embase, and Google Scholar were searched through 15th of June 2012. Search was limited to English and Arabic languages. Reference list of relevant studies were hand-searched. Grey literature was searched using Open Grey. Two review authors independently extracted data, while only one assessed trial quality using 8-point methodological index for non randomized studies (MINORS) scale. A sensitivity analysis was performed to exclude studies with suspected patients' duplicates. RESULTS: Eleven case reports and eight case series involving 226 patients with 243 teeth were identified. No randomized controlled trials were found. The mean quality score for all case series was 9 suggesting a fair quality, while that of all case reports was 5 suggesting poor quality. Non-progressive root resorption is the most common finding following surgical extrusion with an event rate of 30% (95% CI 24.6 36.7%). This is followed by low event rates of tooth loss (5%), slight mobility (4.6%), marginal bone loss (3.7%), and progressive root resorption (3.3%). No ankylosis occurred to any extruded tooth, while severe tooth mobility showed negligible overall event rate of 0.4%. CONCLUSION: The available evidence suggests that surgical tooth extrusion is a valid technique in management of crown-root and cervical root fracture of permanent teeth. Minimal adverse events and good prognosis are expected. Further, surgical extrusion can be considered as a treatment option in teeth suffering sub-gingival decay. PMID- 23796197 TI - Commentary on "A phase II study of oportuzumab monatox: an immunotoxin therapy for patients with noninvasive urothelial carcinoma in situ previously treated with bacillus Calmette-Guerin." Kowalski M, Guindon J, Brazas L, Moore C, Entwistle J, Cizeau J, Jewett MA, MacDonald GC: J Urol 2012;188(5):1712-8 [Epub 2012 Sep 19]. AB - PURPOSE: A phase II study was performed to assess the efficacy and tolerability of intravesical oportuzumab monatox in patients with urothelial carcinoma in situ of the bladder. Bacillus Calmette-Guerin treatment had previously failed in all patients. MATERIALS AND METHODS: A total of 46 patients received 1 induction cycle of 6 (cohort 1) or 12 (cohort 2) weekly intravesical oportuzumab monatox (VB4-845) instillations of 30 mg, followed by up to 3 maintenance cycles of 3 weekly administrations every 3 months. RESULTS: A complete response to oportuzumab monatox was seen in 9 of 22 patients (41%) in cohort 1 and 9 of 23 (39%) in cohort 2 at the 3-month evaluation. A total of 20 patients (44%) achieved a complete response. Two other patients without carcinoma in situ who achieved a complete response were not included in the study due to the development of noninvasive papillary (Ta) disease. Median time to recurrence in patients who achieved a complete response was 274 and 408 days in cohorts 1 and 2, respectively. Overall 7 patients (16%) remained disease-free. Post-study assessment demonstrated that these patients were still disease-free at last followup (18 to 25 months). The most common adverse events were mild to moderate reversible bladder symptoms. CONCLUSIONS: Oportuzumab monatox was effective and well tolerated in patients with bacillus Calmette-Guerin refractory carcinoma in situ of the bladder. These results demonstrate the clinical benefit of oportuzumab monatox and support its continued development for the second line treatment of nonmuscle invasive bladder cancer. PMID- 23796196 TI - Primary ciliary dyskinesia. Recent advances in diagnostics, genetics, and characterization of clinical disease. AB - Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder of motile cilia that leads to oto-sino-pulmonary diseases and organ laterality defects in approximately 50% of cases. The estimated incidence of PCD is approximately 1 per 15,000 births, but the prevalence of PCD is difficult to determine, primarily because of limitations in diagnostic methods that focus on testing ciliary ultrastructure and function. Diagnostic capabilities have recently benefitted from (1) documentation of low nasal nitric oxide production in PCD and (2) discovery of biallelic mutations in multiple PCD-causing genes. The use of these complementary diagnostic approaches shows that at least 30% of patients with PCD have normal ciliary ultrastructure. More accurate identification of patients with PCD has also allowed definition of a strong clinical phenotype, which includes neonatal respiratory distress in >80% of cases, daily nasal congestion and wet cough starting soon after birth, and early development of recurrent/chronic middle-ear and sinus disease. Recent studies, using advanced imaging and pulmonary physiologic assessments, clearly demonstrate early onset of lung disease in PCD, with abnormal air flow mechanics by age 6-8 years that is similar to cystic fibrosis, and age-dependent onset of bronchiectasis. The treatment of PCD is not standardized, and there are no validated PCD-specific therapies. Most patients with PCD receive suboptimal management, which should include airway clearance, regular surveillance of pulmonary function and respiratory microbiology, and use of antibiotics targeted to pathogens. The PCD Foundation is developing a network of clinical centers, which should improve diagnosis and management of PCD. PMID- 23796198 TI - Commentary on "Plasma carotenoids and vitamin C concentrations and risk of urothelial cell carcinoma in the European Prospective Investigation into Cancer and Nutrition." Ros MM, Bueno de Mesquita HB, Kampman E, Aben KK, Buchner FL, Jansen EH, van Gils CH, Egevad L, Overvad K, Tjonneland A, Roswall N, Boutron Ruault MC, Kvaskoff M, Perquier F, Kaaks R, Chang Claude J, Weikert S, Boeing H, Trichopoulou A, Lagiou P, Dilis V, Palli D, Pala V, Sacerdote C, Tumino R, Panico S, Peeters PH, Gram IT, Skeie G, Huerta JM, Barricarte A, Quiros JR, Sanchez MJ, Buckland G, Larranaga N, Ehrnstrom R, Wallstrom P, Ljungberg B, Hallmans G, Key TJ, Allen NE, Khaw KT, Wareham N, Brennan P, Riboli E, Kiemeney LA, National Institute for Public Health and the Environment, Bilthoven, Netherlands: Am J Clin Nutr 2012;96(4):902-10 [Epub 2012 Sep 5]. AB - BACKGROUND: Published associations between dietary carotenoids and vitamin C and bladder cancer risk are inconsistent. Biomarkers may provide more accurate measures of nutrient status. OBJECTIVE: We investigated the association between plasma carotenoids and vitamin C and risk of urothelial cell carcinoma (UCC) in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition. DESIGN: A total of 856 patients with newly diagnosed UCC were matched with 856 cohort members by sex, age at baseline, study center, date and time of blood collection, and fasting status. Plasma carotenoids (alpha- and beta-carotene, beta-cryptoxanthin, lycopene, lutein, and zeaxanthin) were measured by using reverse-phase HPLC, and plasma vitamin C was measured by using a colorimetric assay. Incidence rate ratios (IRRs) were estimated by using conditional logistic regression with adjustment for smoking status, duration, and intensity. RESULTS: UCC risk decreased with higher concentrations of the sum of plasma carotenoids (IRR for the highest compared with the lowest quartile: 0.64; 95% CI: 0.44, 0.93; P-trend = 0.04). Plasma beta-carotene was inversely associated with aggressive UCC (IRR: 0.51; 95% CI: 0.30, 0.88; P-trend = 0.02). Plasma lutein was inversely associated with risk of nonaggressive UCC (IRR: 0.56; 95% CI: 0.32, 0.98; P-trend = 0.05). No association was observed between plasma vitamin C and risk of UCC. CONCLUSIONS: Although residual confounding by smoking or other factors cannot be excluded, higher concentrations of plasma carotenoids may reduce risk of UCC, in particular aggressive UCC. Plasma lutein may reduce risk of nonaggressive UCC. PMID- 23796199 TI - Commentary on "The value of transurethral bladder biopsy after intravesical bacillus Calmette-Guerin instillation therapy for nonmuscle invasive bladder cancer: a retrospective, single center study and cumulative analysis of the literature." Swietek N, Waldert M, Rom M, Schatzl G, Wiener HG, Susani M, Klatte T. Department of Urology, Medical University of Vienna, Vienna, Austria: J Urol 2012;188(3):748-53 [Epub 2012 Jul 20]. AB - PURPOSE: We evaluated the need of routine transurethral biopsies after an induction course of intravesical bacillus Calmette-Guerin for high grade nonmuscle invasive bladder cancer. MATERIALS AND METHODS: This retrospective study included 180 patients with high grade nonmuscle invasive bladder cancer who underwent a 6-week induction course of bacillus Calmette-Guerin. Cystoscopic findings, urinary cytology and pathological results of transurethral biopsy were evaluated. For cumulative meta-analysis we systematically reviewed studies indexed in MEDLINE((r)), EMBASE((r)) and Web of Science((r)). The records of 740 patients from a total of 7 studies were finally analyzed. RESULTS: Biopsy was positive in 58 patients (32%). Cystoscopy appeared normal in 75 patients (42%) and showed only erythema in 51 (28%) and tumor in 54 (30%), of whom 6 (8%), 11 (22%) and 41 (76%), respectively, showed positive findings at biopsy. The positive predictive value of erythema was 15% with negative cytology and 56% with positive cytology. The positive predictive value of a tumor with negative and positive cytology was 63% and 89%, respectively. A combination of negative cytology and normal cystoscopy was associated with a negative biopsy in 94% of cases. A total of 970 bladder biopsies were taken, of which 137 (14%) were positive, including 20 of 125 erythematous lesions (16%), 73 of 107 tumors (68%) and 44 of 738 normal-appearing areas (6%). Cumulative analysis findings were comparable. CONCLUSIONS: Routine transurethral bladder biopsies after a bacillus Calmette-Guerin induction course are not necessary. An individually approach is recommended, tailored from cystoscopic findings and cytology. PMID- 23796200 TI - Commentary on "Carboplatin based induction chemotherapy for nonorgan confined bladder cancer--a reasonable alternative for cisplatin unfit patients?" Mertens LS, Meijer RP, Kerst JM, Bergman AM, van Tinteren H, van Rhijn BW, Horenblas S, Department of Urology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands: J Urol 2012;188(4):1108-13 [Epub 2012 Aug 15]. AB - PURPOSE: We investigated induction carboplatin based chemotherapy in patients with nonorgan confined urothelial carcinoma who were considered unfit for cisplatin. A comparison was made with patients who received induction cisplatin based combination chemotherapy. MATERIALS AND METHODS: We identified 167 patients with nonorgan confined urothelial carcinoma who received induction cisplatin based combination chemotherapy (126) or gemcitabine and carboplatin (41) at our hospital between 1990 and 2010. Of the patients 124 completed 4 cycles of cisplatin based combination chemotherapy or gemcitabine and carboplatin. Clinical response (ycTNM) was evaluated according to RECIST (Response Evaluation Criteria in Solid Tumors) 1.1. Radical cystectomy and bilateral extended pelvic lymph node dissection were performed in 106 patients. A pathological complete response was defined as no evidence of disease (ypT0N0). Disease specific survival was analyzed using the Kaplan-Meier method. Multivariate analysis was performed. RESULTS: Complete clinical response rates did not differ significantly among the treatment groups. A pathological complete response was seen in 33.7% of specimens in the cisplatin based combination chemotherapy group vs 30.3% in the gemcitabine and carboplatin group (p = 0.808). We found no significant difference in disease specific survival between patients who started cisplatin based combination chemotherapy and those who started gemcitabine and carboplatin. For patients who completed 4 cycles and underwent radical cystectomy there was also no significant difference in disease specific survival between the groups. On multivariate analysis a pathological complete response was the only variable significantly associated with disease specific survival (p<0.045). CONCLUSIONS: Induction gemcitabine and carboplatin for nonorgan confined urothelial carcinoma achieves clinical and pathological response rates, and survival outcomes comparable to those of the cisplatin based combination chemotherapy schemes. Our data suggest that a carboplatin based regimen can be considered a reasonable alternative for cisplatin unfit patients in the preoperative setting. PMID- 23796201 TI - Commentary on "Risks of primary extracolonic cancers following colorectal cancer in Lynch syndrome." Win AK, Lindor NM, Young JP, Macrae FA, Young GP, Williamson E, Parry S, Goldblatt J, Lipton L, Winship I, Leggett B, Tucker KM, Giles GG, Buchanan DD, Clendenning M, Rosty C, Arnold J, Levine AJ, Haile RW, Gallinger S, Le Marchand L, Newcomb PA, Hopper JL, Jenkins MA, Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, Melbourne School of Population Health, The University of Melbourne, Victoria, Australia: J Natl Cancer Inst 2012;104(18):1363-72 [Epub 2012 Aug 28]. AB - BACKGROUND: Lynch syndrome is a highly penetrant cancer predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes. We estimated the risks of primary cancers other than colorectal cancer following a diagnosis of colorectal cancer in mutation carriers. METHODS: We obtained data from the Colon Cancer Family Registry for 764 carriers of an MMR gene mutation (316 MLH1, 357 MSH2, 49 MSH6, and 42 PMS2), who had a previous diagnosis of colorectal cancer. The Kaplan-Meier method was used to estimate their cumulative risk of cancers 10 and 20 years after colorectal cancer. We estimated the age-, sex-, country- and calendar period-specific standardized incidence ratios (SIRs) of cancers following colorectal cancer, compared with the general population. RESULTS: Following colorectal cancer, carriers of MMR gene mutations had the following 10 year risk of cancers in other organs: kidney, renal pelvis, ureter, and bladder (2%, 95% confidence interval [CI] = 1% to 3%); small intestine, stomach, and hepatobiliary tract (1%, 95% CI = 0.2% to 2%); prostate (3%, 95% CI = 1% to 5%); endometrium (12%, 95% CI = 8% to 17%); breast (2%, 95% CI = 1% to 4%); and ovary (1%, 95% CI = 0% to 2%). They were at elevated risk compared with the general population: cancers of the kidney, renal pelvis, and ureter (SIR = 12.54, 95% CI = 7.97 to 17.94), urinary bladder (SIR = 7.22, 95% CI = 4.08 to 10.99), small intestine (SIR = 72.68, 95% CI = 39.95 to 111.29), stomach (SIR = 5.65, 95% CI = 2.32 to 9.69), and hepatobiliary tract (SIR = 5.94, 95% CI = 1.81 to 10.94) for both sexes; cancer of the prostate (SIR = 2.05, 95% CI = 1.23 to 3.01), endometrium (SIR = 40.23, 95% CI = 27.91 to 56.06), breast (SIR = 1.76, 95% CI = 1.07 to 2.59), and ovary (SIR = 4.19, 95% CI = 1.28 to 7.97). CONCLUSION: Carriers of MMR gene mutations who have already had a colorectal cancer are at increased risk of a greater range of cancers than the recognized spectrum of Lynch syndrome cancers, including breast and prostate cancers. PMID- 23796202 TI - Commentary on "Surveillance guidelines based on recurrence patterns after radical cystectomy for bladder cancer: the Canadian Bladder Cancer Network experience." Yafi FA, Aprikian AG, Fradet Y, Chin JL, Izawa J, Rendon R, Estey E, Fairey A, Cagiannos I, Lacombe L, Lattouf JB, Bell D, Saad F, Drachenberg D, Kassouf W. Department of Surgery (Urology), McGill University, Quebec, Canada: BJU Int 2012;110(9):1317-23 [Epub 2012 Apr 13]. AB - Study Type-Prognosis (cohort) Level of Evidence 2a. What's known on the subject? and What does the study add? Radical cystectomy with pelvic lymph node dissection is recognized as the standard of care for carcinoma invading bladder muscle and for refractory non-muscle-invasive bladder cancer. Owing to high recurrence and progression rates, a two-pronged strict surveillance regimen, consisting of both functional and oncological follow-up, has been advocated. It is also well recognized that more aggressive tumours with extravesical disease and node positive disease recur more frequently and have worse outcomes. This study adds to the scant body of literature available regarding surveillance strategies after radical cystectomy for bladder cancer. In the absence of any solid evidence supporting the role of strict surveillance regimens, this extensive examination of recurrence patterns in a large multi-institutional project lends further support to the continued use of risk-stratified follow-up and emphasizes the need for earlier strict surveillance in patients with extravesical and node-positive disease. OBJECTIVES: To review our data on recurrence patterns after radical cystectomy (RC) for bladder cancer (BC). To establish appropriate surveillance protocols. PATIENTS AND METHODS: We collected and pooled data from a database of 2287 patients who had undergone RC for BC between 1998 and 2008 in eight different Canadian academic centres. Of the 2287 patients, 1890 had complete recurrence information and form the basis of the present study. RESULTS: A total of 825 patients (43.6%) developed recurrence. According to location, 48.6% of recurrent tumours were distant, 25.2% pelvic, 14.5% retroperitoneal and 11.8% to multiple regions such as pelvic and retroperitoneal or pelvic and distant. The median (range) time to recurrence for the entire population was 10.1 (1-192) months with 90 and 97% of all recurrences within 2 and 5 years of RC, respectively. According to stage, pTxN+ tumours were more likely to recur than p >= T3N0 tumours and p <= T2N0 tumours (5-yr RFS 25% vs. 44% vs. 66% respectively, P < 0.001). Similarly, pTxN+ tumours had a shorter median time to recurrence (9 months, range 1-72 months) than p >= T3N0 tumours (10 months, range 1-70 months) or p <= T2N0 tumours (14 months, range 1-192 months, P < 0.001). CONCLUSIONS: Differences in recurrence patterns after RC suggest the need for varied follow-up protocols for each group. We propose a stage-based protocol for surveillance of patients with BC treated with RC that captures most recurrences while limiting over-investigation. PMID- 23796203 TI - Commentary on "Predictive capacity of four comorbidity indices estimating perioperative mortality after radical cystectomy for urothelial carcinoma of the bladder." Mayr R, May M, Martini T, Lodde M, Pycha A, Comploj E, Wieland WF, Denzinger S, Otto W, Burger M, Fritsche HM. Department of Urology, Central Hospital of Bolzano, Bolzano, Italy: BJU Int 2012;110(6 Pt B):E222-7 [Epub 2012 Feb 7]. AB - What's known on the subject? and What does the study add? The degree of comorbidity significantly affects the course of patients with bladder cancer undergoing radical cystectomy (RC). To our knowledge this is the first study comparing four different comorbidity indices in patients undergoing RC for urothelial carcinoma to assess the best clinical predictors for 90-day perioperative mortality. We concluded that the ASA score should be the method of choice, as it showed a predictive ability superior to that of ECOG and CCI, and is much easier to generate than the ACE-27. OBJECTIVE: To evaluate which of the following among the Adult Comorbidity Evaluation-27 (ACE-27), the Charlson Comorbidity Index (CCI), the Eastern Cooperative Oncology Group performance status (ECOG) and the American Society of Anesthesiologists (ASA) comorbidity scores correlate best with perioperative mortality after radical cystectomy (RC) for urothelial carcinoma (UC) of the bladder. PATIENTS AND METHODS: A study was carried out on 555 unselected consecutive patients without neoadjuvant chemotherapy who underwent RC for UC of the bladder from 2000 to 2010 at one of two institutions. Patients' medical records were reviewed retrospectively. We established a defined binary linear progression model based on clinical variables to predict perioperative mortality<90 days after RC (90PM). To this model we added, individually, the comorbidity indices ACE-27, CCI, ECOG, and ASA to assess their predictive capacity regarding 90PM. RESULTS: The overall 90PM was 7.9%. Age (P = 0.01) and clinical distant metastatic tumour stage (P = 0.002) were independent predictors for 90PM in the multivariate analysis. Each of the four investigated comorbidity indices was able to significantly increase the predictive capacity of the basic model: ECOG +13.5%, (odds ratio [OR]: 1.61, P = 0.036; area under the curve [AUC] 74.7), ASA Score +28.3% (OR: 2.19, P = 0.004; AUC 76.1), Charlson Index +12.3% (OR: 1.31, P = 0.047; AUC 73.8) and ACE-27 + 29.8% (OR: 1.72, P = 0.004; AUC 76.1). CONCLUSIONS: ASA and ACE-27 show a nearly identical clinical predictive value for perioperative mortality. Both scores could be considered for clinical practice. With regard to ease of generation and availability, the ASA score can be regarded as the best instrument. PMID- 23796204 TI - Commentary on "Phase II trial of cetuximab with or without paclitaxel in patients with advanced urothelial tract carcinoma." Wong YN, Litwin S, Vaughn D, Cohen S, Plimack ER, Lee J, Song W, Dabrow M, Brody M, Tuttle H, Hudes G, University of Pennsylvania, Philadelphia, PA: J Clin Oncol 2012;30(28):3545-51 [Epub 2012 Aug 27]. AB - PURPOSE: The benefit of salvage chemotherapy is modest in metastatic urothelial cancer. We conducted a randomized, noncomparative phase II study to measure the efficacy of cetuximab with or without paclitaxel in patients with previously treated urothelial cancer. PATIENTS AND METHODS: Patients with metastatic urothelial cancer who received one line of chemotherapy in the perioperative or metastatic setting were randomly assigned to 4-week cycles of cetuximab 250 mg/m(2) with or without paclitaxel 80 mg/m(2) per week. We used early progression as an indicator of futility. Either arm would close if seven of the initial 15 patients in that arm progressed at the first disease evaluation at 8 weeks. RESULTS: We enrolled 39 evaluable patients. The single-agent cetuximab arm closed after nine of the first 11 patients progressed by 8 weeks. The combination arm completed the full accrual of 28 patients, of whom 22 patients (78.5%) had visceral disease. Twelve of 28 patients had progression-free survival greater than 16 weeks. The overall response rate was 25% (95% CI, 11% to 45%; three complete responses and four partial responses). The median progression-free survival was 16.4 weeks (95% CI, 12 to 25.1 weeks), and the median overall survival was 42 weeks (95% CI, 30.4 to 78 weeks). Treatment-related grade 3 and 4 adverse events that occurred in at least two patients were rash (six cases), fatigue (five cases), and low magnesium (three cases). CONCLUSION: Although it had limited activity as a single agent, cetuximab appears to augment the antitumor activity of paclitaxel in previously treated urothelial cancers. The cetuximab and paclitaxel combination merits additional study to establish its role in the treatment of urothelial cancers. PMID- 23796205 TI - Commentary on "The clinical epidemiology of urachal carcinoma: results of a large, population based study." Bruins HM, Visser O, Ploeg M, Hulsbergen-van de Kaa CA, Kiemeney LA, Witjes JA, Department of Urology, Radboud University Medical Centre, Utrecht, The Netherlands: J Urol 2012;188(4):1102-7 [Epub 2012 Aug 15]. AB - PURPOSE: Survival data on urachal carcinoma are sparse due to the low prevalence of this cancer. We report urachal carcinoma clinical outcomes and prognostic factors in a large, population based cohort of patients with long-term followup. MATERIALS AND METHODS: Data were collected from the nationwide Netherlands Cancer Registry. Urachal carcinoma cases were also cross-referenced using the PALGA (Nationwide Network and Registry of Histology and Cytopathology) database. Pathology report summaries were reviewed. A total of 152 patients diagnosed with urachal carcinoma between 1989 and 2009 were included in analysis. The Sheldon staging system was used to classify urachal carcinoma. Median followup was 9.2 years. Primary outcomes were overall and relative survival. Prognostic factors were calculated using univariate and multivariate hazard regression models. RESULTS: The incidence of urachal carcinoma was 0.2% of all bladder cancers. A total of 45 patients (30%) presented with lymph node or distant metastasis. Five year overall and relative survival was 45% and 48%, respectively. On multivariate analysis prognostic factors for impaired survival were lymph node metastasis (HR 1.7, 95% CI 1.2-2.6), tumor growth in the abdominal wall, peritoneum and/or adjacent organs (HR 5.2, 95% CI 2.6-10.3), distant metastasis (HR 5.3, 95% CI 2.8 9.9) and macroscopic residual tumor (HR 5.2, 95% CI 1.2-21.8). CONCLUSIONS: Urachal carcinoma is rare, accounting for 0.2% of all bladder cancers. Many patients present with advanced disease. The prognosis of urachal carcinoma depends mostly on tumor stage, particularly the presence or absence of metastatic disease. PMID- 23796206 TI - An unusual case of multiple melanoma and non-melanoma skin cancers of the leg. PMID- 23796207 TI - Telescoped synthesis of stereodefined pyrrolidines. AB - Telescoped and one-pot olefination/asymmetric functionalization approaches to disubstituted pyrrolidines (dr up to 99:1, up to 99% ee) have been developed using commercially available tetramisole (0.1 to 5 mol %). Using OTMS-quinidine as the Lewis base gives preferential access to an anti-configured pyrrolidine in high enantioselectivity. PMID- 23796208 TI - Intervention for promoting breast milk use in neonatal intensive care unit: a pilot study. AB - OBJECTIVE: The health benefits provided by breast milk are significant in preterm infants. Despite recommendations, rates of breastfeeding in preterm infants are lower than in term infants. The aim of this study was to evaluate the efficacy of a multidisciplinary intervention in promoting any breastfeeding in preterm infants at discharge. METHODS: A prospective non-randomized interventional cohort study was conducted. One hundred and twenty-two preterm infants constituted the historical group. A multidisciplinary intervention was performed including staff training and setting up and implementation of a written breastfeeding procedure. RESULTS: One hundred and ten preterm infants were enrolled in the intervention group. The percentage of infants fed human milk at discharge was 69 and 62 in the intervention group and in the historical group, respectively. The percentage change from any breastfeeding at full enteral feeding attainment to formula feeding at discharge was lower in the intervention group than in the historical group (-9 versus -23). Belonging to the intervention group and having at least one stress factor during pregnancy were independently associated with any breast milk feeding at discharge. CONCLUSIONS: The multidisciplinary intervention performed appears to be effective in promoting any breastfeeding in preterm infants at discharge. PMID- 23796210 TI - Low-dose abdominal CT: comparison of low tube voltage with moderate-level iterative reconstruction and standard tube voltage, low tube current with high level iterative reconstruction. AB - AIM: To evaluate the quality of 100 kVp images with a hybrid iterative reconstruction algorithm level of 40% and 120 kVp (low-tube-current) images with a hybrid iterative reconstruction algorithm level of 60% in low-dose abdominal computed tomography (CT) using almost the same radiation dose. MATERIALS AND METHODS: This prospective study received institutional review board approval and written informed consent was obtained. One hundred and ten patients undergoing abdominal dynamic CT were randomly assigned to one of two protocols (100 and 120 kVp protocols). Radiation doses of the two protocols were almost identical. The 120 kVp images were post-processed with a hybrid iterative reconstruction algorithm level of 60% (i-120 kVp). The 100 kVp images were post-processed with a hybrid iterative reconstruction algorithm level of 40% (i-100 kVp). The effective dose (ED), image noise, CT attenuation, and signal-to-noise ratio (SNR) of the subcutaneous fat, muscle, liver, pancreas, and kidneys were compared between the protocols using Student's t-test. Qualitative analysis was also performed between the protocols. RESULTS: There were no significant differences in ED and SNR of any of the regions of interest (ROIs) between the protocols (p > 0.05). However, in the qualitative analysis, unnatural texture was significantly greater in the i 120 kVp than in the i-100 kVp protocol (p < 0.01). There were no other significant differences in the image quality between the protocols (p > 0.05). CONCLUSION: The combined use of low tube voltage and moderate-level iterative reconstruction techniques can be a more effective strategy for reducing patient radiation dose while attaining acceptable image quality than the use of standard tube voltage, low tube current with high-level iterative reconstruction. PMID- 23796209 TI - Extensive lysine acetylation occurs in evolutionarily conserved metabolic pathways and parasite-specific functions during Plasmodium falciparum intraerythrocytic development. AB - Lysine acetylation has emerged as a major post-translational modification involved in diverse cellular functions. Using a combination of immunoisolation and liquid chromatography coupled to accurate mass spectrometry, we determined the first acetylome of the human malaria parasite Plasmodium falciparum during its active proliferation in erythrocytes with 421 acetylation sites identified in 230 proteins. Lysine-acetylated proteins are distributed in the nucleus, cytoplasm, mitochondrion and apicoplast. Whereas occurrence of lysine acetylation in a similarly wide range of cellular functions suggests conservation of lysine acetylation through evolution, the Plasmodium acetylome also revealed significant divergence from those of other eukaryotes and even the closely related parasite Toxoplasma. This divergence is reflected in the acetylation of a large number of Plasmodium-specific proteins and different acetylation sites in evolutionarily conserved acetylated proteins. A prominent example is the abundant acetylation of proteins in the glycolysis pathway but relatively deficient acetylation of enzymes in the citrate cycle. Using specific transgenic lines and inhibitors, we determined that the acetyltransferase PfMYST and lysine deacetylases play important roles in regulating the dynamics of cytoplasmic protein acetylation. The Plasmodium acetylome provides an exciting start point for further exploration of functions of acetylation in the biology of malaria parasites. PMID- 23796211 TI - Contrast-enhanced MR enterography as a stand-alone tool to evaluate Crohn's disease in a paediatric population. AB - AIM: To assess the performance of contrast-enhanced T1-weighted magnetic resonance imaging (MRI) alone in the evaluation of Crohn's disease in comparison to all magnetic resonance enterography (MRE) imaging sequences together in an attempt to suggest limitation of the number of overall unenhanced sequences need for the follow-up evaluation. MATERIALS AND METHODS: Twenty-five paediatric patients (mean age 14.1 +/- 3.7 years, male = 12, female = 13) underwent MRE at 1.5 T for evaluation of Crohn's disease. Two radiologists reviewed only contrast enhanced T1-weighted images in consensus on the first session. Whole images including unenhanced (steady-state free precession, single-shot fast spin-echo (HASTE), fat-suppressed T2-weighted) and contrast-enhanced T1-weighted sequences were reviewed in consensus during the second session with a 1 month interval, which was used as a reference standard. The readers evaluated the presence or absence of disease in 10 bowel segments in each patient. For the abnormal bowel segments, the readers then evaluated for active versus inactive disease and for the presence or absence of abscess. Sensitivity, specificity, and overall accuracy were calculated for detecting active inflammation. RESULTS: There were 53/250 bowel segments with active inflammation using the reference standard imaging method. The sensitivity, specificity, and accuracy for diagnosing active inflammation using contrast-enhanced images alone were 83.3%, 86.9%, and 84.9%. In five of the false-positive cases of detecting abscess from contrast-enhanced imaging alone, absence of abscesses was confirmed on the non-fat-suppressed HASTE images. CONCLUSION: The number of MRE sequences in paediatric Crohn's patients can be decreased while maintaining diagnostic accuracy using contrast-enhanced T1 and non-fat-suppressed HASTE images. PMID- 23796212 TI - Adherence to the Sydney System guidelines increases the detection of Helicobacter gastritis and intestinal metaplasia in 400738 sets of gastric biopsies. AB - BACKGROUND: The diagnostic yield of individual gastric biopsies and the adherence to the Sydney System guidelines in the United States are unknown. AIMS: To evaluate the yield of different gastric sampling strategies and determine the adherence to the Sydney System guidelines in a nationwide sample of endoscopists. METHODS: Using a database of biopsy records diagnosed at a single pathology laboratory, we analysed the results of gastric biopsies taken to evaluate gastric inflammatory conditions in patients with no endoscopic lesions. We then stratified the specimens by site of origin and number of mucosal fragments and calculated the relationship between number and origin of biopsy specimens and detection of Helicobacter pylori and intestinal metaplasia. RESULTS: Of 400 738 biopsy sets, 66.0% were submitted as antrum; 17.4% as corpus; 2.6% as cardia; and 24.7% without topographic identifiers. Separate containers with at least two antral and two corpus specimens (Sydney System compliant) were available in 15 645 cases (3.9%). For antrum, corpus, and unspecified sites, each additional tissue fragment was associated with an incremental increase in the yield for both H. pylori and intestinal metaplasia. Sydney System-compliant sets had significantly greater yield than most of the unspecified or single-site sets (14.8% and 6.0% respectively). The incisura angularis, rarely sampled, yielded minimal additional diagnostic information. CONCLUSIONS: In the absence of lesions, the acquisition of at least two biopsy specimens from antrum and corpus, essentially following the Sydney System recommendations, is a sensible strategy that guarantees the maximum diagnostic yield for the most common gastric inflammatory conditions. PMID- 23796213 TI - Direct observation of individual particle armored bubble interaction, stability, and coalescence dynamics. AB - The interactions between two individual particle-stabilized bubbles were investigated, in the absence of surfactant, using a combination of coalescence rig and high-speed video camera. This combination allows the visualization of bubble coalescence dynamics which provide information on bubble stability. Experimental data suggested that bubble stability is enhanced by both the adsorption of particles at the interface as indicated by the long induction time and the increase in damping coefficient at high surface coverage. The interaction between an armored bubble and a bare bubble (asymmetric interaction) can be destabilized through the addition of a small amount of salt, which suggested that electrostatic interactions play a significant role in bubble stability. Interestingly, the DLVO theory cannot be used to describe the bubble stability in the case of a symmetric interaction as coalescence was inhibited at 0.1 M KCl in both the absence and presence of particles at the interfaces. Furthermore, bubbles can also be destabilized by increasing the particle hydrophobicity. This behavior is due to thinner liquid films between bubbles and an increase in film drainage rate. The fraction of particles detached from the bubble surface after film rupture was found to be very similar within the range of solution ionic strength, surface coverage, and particle hydrophobicity studied. This lack of dependence implies that the kinetic energy generated by the coalescing bubbles is larger than the attachment energy of the particles and dominates the detachment process. This study illuminates the stability behavior of individual particle stabilized bubbles and has potential impact on processes which involve their interaction. PMID- 23796214 TI - Does psychosocial stress play a role in the exacerbation of psoriasis? AB - It is widely accepted that psychosocial stress can result from the daily strains of living with a diagnosis of psoriasis. There is now an evolving body of work to suggest that psychosocial stress may also play a role in the exacerbation of psoriasis. We discuss the historical evidence supporting a temporal relationship between psychosocial stress and the exacerbation of psoriasis. The underlying pathophysiological mechanisms by which this occurs are largely unknown, but current evidence points towards a role for nerve-related factors, namely their interaction with mast cells and the potentiation of neurogenic inflammation in this regard. It is also likely that the physiological stress response in patients with psoriasis differs from that in healthy individuals, as evidenced by alterations in the hypothalamic-pituitary-adrenal axis and sympathetic-adrenal medullary system function. Psychological stress results in a redistribution of leucocytes with increased trafficking of inflammatory cells into the skin, which may exacerbate psoriasis. Langerhans cells play a role in the stress response of normal skin; their function in the stress response of patients with psoriasis is open to speculation. We discuss the influence of stress reactivity in patients with psoriasis and the impact of stress reduction strategies in the management of psoriasis. Finally, we suggest potentially fruitful areas for future research. PMID- 23796215 TI - Royal sun medicinal mushroom, Agaricus brasiliensis Ka21 (higher Basidiomycetes), as a functional food in humans. AB - The Royal Sun medicinal mushroom, Agaricus brasiliensis, is used as a natural health product. In Japan, however, the quality control of some of these mushroom products has been viewed as a safety problem. Focusing on the quality control of A. brasiliensis KA21, we have performed several safety studies. To date, we have established evidence that this mushroom can be used safely as an immunostimulant and to mediate biochemical parameters associated with obesity or diabetes. Furthermore, to improve the manufacturing process of this mushroom, we have studied the relationship between its pharmaceutical actions and the conditions of its cultivation and thermal management. The purpose of this review is to report the findings of basic and clinical studies of the fruit body of A. brasiliensis KA21. PMID- 23796216 TI - Royal sun medicinal mushroom Agaricus brasiliensis (higher Basidiomycetes) and the attenuation of pulmonary inflammation induced by 4-(methylnitrosamino)-1-(3 pyridyl)-1-butanone (NNK). AB - Agaricus brasiliensis currently is one of the most studied fungi because of its nutritional and therapeutic properties as an anti-inflammatory agent and an adjuvant in cancer chemotherapy. The effects of orally administered aqueous A. brasiliensis extract (14.3- and 42.9-mg doses) on parenchymal lung damage induced by carcinogenic 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were observed in Wistar rats. NNK treatment induced pulmonary inflammation, but not lung cancer, in the rats. The lungs of animals treated with NNK showed a higher level of inflammation than those of the control group according to histopathologic examinations (P < 0.01) and kurtosis analysis (P < 0.001) of a global histogram generated from thoracic computed tomography scans. There was no significant difference in the alveolar and bronchial exudates between animals treated with a 14.3-mg dose of A. brasiliensis extract and the control without NNK. However, a significant difference was found between animals treated with NNK, received a 42.9-mg dose of A. brasiliensis (P < 0.05), and the controls not treated with NNK. We did not observe a significant difference between the kurtoses of the A. brasiliensis (14.3 mg) and control groups. However, a 42.9-mg dose of A. brasiliensis resulted in lower kurtosis values than those observed in the control group (P < 0.001). In conclusion, a low dose of A. brasiliensis was more effective in attenuating pulmonary inflammation. Similar to the histopathological results, the computed tomography scans also showed a protective effect of A. brasiliensis at the lower dose, which prevented gross pulmonary consolidation. PMID- 23796217 TI - The agaricoglyceride of royal sun medicinal mushroom, Agaricus brasiliensis (higher basidiomycetes) is anti-inflammatory and reverses diabetic glycemia in the liver of mice. AB - The agaricoglyceride is a new fungal secondary metabolite that constitutes esters of chlorinated 4-hydroxy benzoic acid and glycerol. The objective of this study was to explore whether the administration of agaricoglyceride could correct hepatic glycemic metabolism dysfunction by attenuating inflammation in the liver. The effects of agaricoglycerides on tumor necrosis factor-alpha, interleukin 1beta, vascular endothelial growth factor-alpha, interleukin-17, insulin secretion, adiponectin, leptin, hepatic glycogen, nuclear factor-kappaB activation, and total antioxidant activity were studied respectively. We demonstrated that administration of agaricoglycerides alleviated glycemic metabolism dysfunction, inflammation, and oxidative stress in mice. These data indicate that agaricoglyceride supplementation could restrain metabolic dysfunction through suppressing the nuclear factor-kappaB pathway as well as decreasing the levels of inflammatory cytokines and total antioxidant activities. PMID- 23796218 TI - Macrophage activation-mediated hydrogen peroxide generation by the royal sun medicinal mushroom Agaricus brasiliensis (Higher Basidiomycetes). AB - Agaricus brasiliensis has been demonstrated to have potent antitumor activity. The activity is postulated to act through mediation of the host immune system. We have reported that A. brasiliensis extract (ABE) inhibited compound 48/80 induced a systemic anaphylaxis-like reaction, ear swelling response, and passive cutaneous anaphylaxis-like reaction in mice. There is some recent information available on the mechanism of antiallergic effects resulting from oral administration of ABE. However, information regarding how ABE may activate macrophages through intestinal epithelial cells is still limited. To clarify the mechanism of macrophages activation by ABE, a gut in vitro model constructed of Caco-2 and RAW264.7 cells was applied. Treatment of ABE to the apical compartment resulted in significant increases in tumor necrosis factor (TNF)-alpha production in the basolateral compartment. Moreover, addition of catalase to the basolateral compartment before ABE treatment suppressed TNF-alpha production completely, but the addition of superoxide dismutase did not suppress this at all. These data suggest that ABE could potentiate hydrogen peroxide emissions from Caco-2 cells into the basolateral side and activate macrophages, which is important in the immune system. PMID- 23796219 TI - MT-alpha-glucan from the fruit body of the maitake medicinal mushroom Grifola frondosa (higher Basidiomyetes) shows protective effects for hypoglycemic pancreatic beta-cells. AB - The hypoglycemic effect of an alpha-glucan (designated here as MT-alpha-glucan) from the fruit body of the Maitake medicinal mushroom, Grifola frondosa, on a murine type 2 diabetes mellitus (T2DM) model was evaluated. Body weight and levels of fasting plasma glucose, glycosylated hemoglobin, triglycerides, cholesterol, free fatty acid, nitric oxide (NO), NO synthase, inducible NO synthase, and hepatic malondialdehyde content decreased significantly when MT alpha-glucan was administered to T2DM mice. The content of serum insulin, hepatic glycogen, and reduced glutathione and the activity of superoxide dismutase and glutathione peroxidase increased significantly when MT-alpha-glucan was administered to T2DM mice. Histopathological changes of the pancreas were ameliorated in the treatment group. These data suggest that MT-alpha-glucan has a hypoglycemic effect on T2DM mice, which might be related to its protective effect of pancreatic beta-cells exerted by decreasing levels of factors that destroy beta-cells, such as oxidative stress and NO synthesis. PMID- 23796220 TI - Hepatoprotective effects of aqueous extract from Lingzhi or Reishi medicinal mushroom Ganoderma lucidum (higher basidiomycetes) on alpha-amanitin-induced liver injury in mice. AB - The Lingzhi or Reishi mushroom Ganoderma lucidum is a well-known traditional medicinal mushroom that has been shown to have obvious hepatoprotective effects. The aim of this study was to evaluate the hepatoprotective effects of G. lucidum aqueous extracts (GLEs) on liver injury induced by alpha-amanitin (alpha-AMA) in mice and to analyze the possible hepatoprotective mechanisms related to radical scavenging activity. Mice were treated with alpha-AMA prepared from Amanita exitialis and then administrated with GLE after the alpha-AMA injection. The hepatoprotective activity of the GLE was compared with the reference drug silibinin (SIL). alpha-AMA induced a significant elevation in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and provoked a significant reduction of superoxide dismutase (SOD) and catalase (CAT) activities and a significant increment of malondialdehyde (MDA) content in liver homogenate. Treatment with GLE or SIL significantly decreased serum ALT and AST levels, significantly increased SOD and CAT activities, and decreased MDA content in liver compared with the alpha-AMA control group. The histopathological examination of liver sections was consistent with that of biochemical parameters. The results demonstrated that GLE induces hepatoprotective effects on acute liver injury induced by alpha-AMA; these protective effects may be related in part to the antioxidant properties of GLE. PMID- 23796221 TI - Cultivation of medicinal caterpillar fungus, Cordyceps militaris (Ascomycetes), and production of cordycepin using the spent medium from levan fermentation. AB - A process of tandem cultivation for the production of green and invaluable bioproducts (levan and Cordycepes militaris) useful for medical applications has been successfully developed. The process involves first cultivating Bacillus subtilis strain natto in sucrose medium to produce levan, followed by the subsequent cultivation of C. militaris in liquid- and solid-state cultures using the spent medium from levan fermentation as substrates. The factors affecting the cell growth and production of metabolites of C. militaris were investigated, and the various metabolites produced in the culture filtrate, mycelia, and fruiting body were analyzed. In addition, cordycepin was prepared from the solid waste medium of C. militaris. This is an excellent example in the development of cost effective biorefineries that maximize useful product formation from the available biomass. The preparation of cordycepin from solid waste medium of C. militaris using a method with high extraction efficiency and minimum solvent usage is also environmentally friendly. PMID- 23796222 TI - Isolation, purification, and immunological activities of a low-molecular-weight polysaccharide from the Lingzhi or Reishi medicinal mushroom Ganoderma lucidum (higher Basidiomycetes). AB - To obtain a low-molecular-weight polysaccharide with immuno-enhancing activity, hot water extract of Ganoderma lucidum fruit bodies was separated by membrane ultrafiltration, anion exchange, and gel filtration chromatography, and the immunological activities of fractions were assessed on the basis of nitric oxide production by RAW 264.7 macrophages. A novel polysaccharide (TB3-2-2) was successfully isolated and purified. TB3-2-2 is a homogeneous polysaccharide, with a relative molecular weight of 5.11 * 103 Da, identified by high-performance liquid chromatography and was composed of galactose and glucose in a molar ratio of 2:3 determined by high-performance anion exchange chromatography. TB3-2-2 had a carbohydrate content of 99%, as measured using the phenol-sulfuric acid method. Proliferation of mouse spleen lymphocytes and the expression level of interleukin 6 was significantly increased by TB3-2-2. Results indicate that the low-molecular weight polysaccharide with immunological activity in G. lucidum is worthy of further research and development. PMID- 23796223 TI - Preliminary results on antigenotoxic effects of dried mycelia of two medicinal mushrooms in Drosophila melanogaster somatic mutation and recombination test. AB - In this study, the antigenotoxic effects of dried mycelia from Trametes versicolor and Pleurotus ostreatus were investigated using a Drosophila melanogaster somatic mutation and recombination test (SMART), which is based on the principle that the loss of heterozygosity of suitable recessive marker hairs, such as multiple wing (mwh) and flare-3 (flr3), can lead to the formation of mutant clones of larval cells, which then are expressed as spots on the wings of the adult flies. In this study, dried mycelia from T. versicolor and P. ostreatus alone (7.5, 15, and 30 mg) were examined for genotoxicity and combined with mitomycin C (MMC; 0.05 mM) for antigenotoxicity. Commonly known mutagen which is mitomycin C (MMC) was used as positive control. The results showed that the dried mycelia of mushrooms were not genotoxic themselves. Nevertheless, the mushrooms have antigenotoxic activity by reducing the frequency of MMC-induced spots in varying proportions. Thus, powders of these 2 fungi were able to suppress somatic cell mutation induced by MMC. These results suggest that T. versicolor and P. ostreatus have antigenotoxic activity, including antirecombinogenic activity. PMID- 23796224 TI - Patient time costs attributable to healthcare use in diabetes: results from the population-based KORA survey in Germany. AB - AIMS: Patient time costs have been described to be substantial; however, data are highly limited. We estimated patient time costs attributable to outpatient and inpatient care in study participants with diagnosed diabetes, previously undetected diabetes, impaired glucose regulation and normal glucose tolerance. METHODS: Using data of the population-based KORA S4 study (55-74 years, random sample of n = 350), we identified participants' stage of glucose tolerance by oral glucose tolerance test. To estimate mean patient time costs per year (crude and standardized with respect to age and sex), we used data regarding time spent with ambulatory visits including travel and waiting time and with hospital stays (time valued at a 2011 net wage rate of ?20.63/h). The observation period was 24 weeks and data were extrapolated to 1 year. RESULTS: Eighty-nine to 97% of participants in the four groups (diagnosed diabetes, undetected diabetes, impaired glucose regulation and normal glucose tolerance.) had at least one physician contact and 4-14% at least one hospital admission during the observation period. Patient time [h/year (95% CI)] was 102.0 (33.7-254.8), 53.8 (15.0-236.7), 59.3 (25.1-146.8) and 28.6 (21.1-43.7), respectively. Age-sex standardized patient time costs per year (95% CI) were ?2447.1 (804.5-6143.6), ?880.4 (259.1-3606.7), ?1151.6 (454.6-2957.6) and ?589.2 (435.8-904.8). CONCLUSIONS: Patient time costs were substantial--even higher than medication costs in the same study population. They are higher in participants with diagnosed diabetes, but also in those with undetected diabetes and impaired glucose regulation compared with those with normal glucose tolerance. Research is needed in larger populations to receive more precise and certain estimates that can be used in health economic evaluation. PMID- 23796225 TI - Molecular docking and QSAR studies: noncovalent interaction between acephate analogous and the receptor site of human acetylcholinesterase. AB - Twelve new compounds of acephate (Ace) analogues were synthesized and characterized by (31)P, (13)C, and (1)H NMR and IR spectroscopy. The probable insecticide potential of these compounds as well as 23 previously prepared molecules with a general skeleton of RC(O)-NH-P(O)X1X2 was predicted by PASS software. Docking analysis showed that hydrophobic interaction and hydrogen bonding were created between the functional groups of Ace derivatives and the receptor sites of acetylcholinesterase. PCA-QSAR indicated that the electronic descriptors are dominated in comparison with the structural descriptors. The experimental-QSAR (R(2) = 0.903 and VIF < 2.997) and DFT-QSAR (R(2) = 0.990 and VIF <= 10) models clarified that the net charge of functional groups contributes an important function in an inhibition mechanism. Validity and integrity of this model were confirmed by the LOO cross-validation method with q(2) = 0.940 and low residuals between the training and testing sets. The correlation matrix of DFT QSAR model confirmed the molecular docking results. PMID- 23796226 TI - Colonic diverticulitis in young Asians: a predominantly mild and right-sided disease. AB - BACKGROUND: The management of diverticulitis in young Asian patients remains challenging. This study aimed to highlight the issues of managing diverticulitis in young Asians. METHODS: A retrospective review of all patients who were admitted for acute colonic diverticulitis from October 2003 to December 2008 was performed. Patients who were <=50 year old were considered 'young' and formed the study group. RESULTS: The study group consisted of 142 patients. The majority (n = 126, 88.7%) had right-sided diverticulitis and most (n = 117, 82.4%) were mild in severity. Most of the patients who underwent emergency surgery were for suspected appendicitis (39/56, 69.6%). When we compared between those aged <=50 and >50 years, the older group had worse diverticulitis (odds ratio (OR), 4.90, 95% confidence interval (CI), 2.00-11.99), been operated for indications other than suspected appendicitis (OR, 13.08, 95% CI, 5.42-31.56) and undergone a colectomy (OR, 9.96, 95% CI, 4.12-24.10). The younger group had a much higher incidence of right-sided disease (OR: 7.80, 95% CI: 4.32-14.07). Over a median follow-up of 40 (6-90) months, 7 (4.9%) patients were readmitted for a total of eight times for recurrent attacks of diverticulitis and all were successfully treated conservatively. Five other patients underwent elective surgery for persistent symptoms. CONCLUSION: Diverticulitis in young Asians is often right sided and mild in severity. A significant proportion is only diagnosed when operated for presumed appendicitis. Recurrent attacks are uncommon and can often be treated non-surgically. PMID- 23796227 TI - Three unusual sesquineolignans from Alpinia conchigera. AB - Three unusual sesquineolignans conchignans A, B, and C, together with two known compounds vanillin and phloroglucinol, were isolated from the whole plants of Alpinia conchigera. Their structures were established by spectroscopic analysis, including 2D NMR spectroscopic techniques. PMID- 23796228 TI - Therapeutic targeting of the axonal and microvascular change associated with repetitive mild traumatic brain injury. AB - Recent interest in mild traumatic brain injury (mTBI) has increased the recognition that repetitive mTBI occurring within the sports and military settings can exacerbate the adverse consequences of the initial injury. While multiple studies have recently reported the pathological, metabolic, and functional changes associated with repetitive mTBI, no consideration has been given to the development of therapeutic approaches to attenuate these abnormalities. In this study, we used the model of repetitive impact acceleration insult previously reported by our laboratory to cause no initial structural and functional changes, yet evoke dramatic change following second insult of the same intensity. Using this model, we employed established neuroprotective agents including FK506 and hypothermia that were administered 1 h after the second insult. Following either therapeutic intervention, changes of cerebral vascular reactivity to acetylcholine were assessed through a cranial window. Following the completion of the vascular studies, the animals were prepared to access the numbers of amyloid precursor protein (APP) positive axons, a marker of axonal damage. Following repetitive injury, cerebral vascular reactivity was dramatically preserved by either therapeutic intervention or the combination thereof compared to control group in which no intervention was employed. Similarly, APP density was significantly lower in the therapeutic intervention group compared in controls. Although the individual use of FK506 or hypothermia exerted significant protection, no additive benefit was found when both therapies were combined. In sum, the current study demonstrates that the exacerbated pathophysiological changes associated with repetitive mTBI can be therapeutically targeted. PMID- 23796229 TI - Enhanced chlorine dioxide decay in the presence of metal oxides: relevance to drinking water distribution systems. AB - Chlorine dioxide (ClO2) decay in the presence of typical metal oxides occurring in distribution systems was investigated. Metal oxides generally enhanced ClO2 decay in a second-order process via three pathways: (1) catalytic disproportionation with equimolar formation of chlorite and chlorate, (2) reaction to chlorite and oxygen, and (3) oxidation of a metal in a reduced form (e.g., cuprous oxide) to a higher oxidation state. Cupric oxide (CuO) and nickel oxide (NiO) showed significantly stronger abilities than goethite (alpha-FeOOH) to catalyze the ClO2 disproportionation (pathway 1), which predominated at higher initial ClO2 concentrations (56-81 MUM). At lower initial ClO2 concentrations (13 31 MUM), pathway 2 also contributed. The CuO-enhanced ClO2 decay is a base assisted reaction with a third-order rate constant of 1.5 * 10(6) M(-2) s(-1) in the presence of 0.1 g L(-1) CuO at 21 +/- 1 degrees C, which is 4-5 orders of magnitude higher than in the absence of CuO. The presence of natural organic matter (NOM) significantly enhanced the formation of chlorite and decreased the ClO2 disproportionation in the CuO-ClO2 system, probably because of a higher reactivity of CuO-activated ClO2 with NOM. Furthermore, a kinetic model was developed to simulate CuO-enhanced ClO2 decay at various pH values. Model simulations that agree well with the experimental data include a pre-equilibrium step with the rapid formation of a complex, namely, CuO-activated Cl2O4. The reaction of this complex with OH(-) is the rate-limiting and pH-dependent step for the overall reaction, producing chlorite and an intermediate that further forms chlorate and oxygen in parallel. These novel findings suggest that the possible ClO2 loss and the formation of chlorite/chlorate should be carefully considered in drinking water distribution systems containing copper pipes. PMID- 23796231 TI - Feasibility study of a self-guided cognitive behaviour therapy internet intervention for cancer carers. AB - Despite the evidence base for Internet-delivered self-help programmes, their application to cancer carers has not been reported. This feasibility study evaluated a 6-week internet cognitive behaviour therapy (CBT) programme for early stage cancer carers. The study participants comprised 13 carers who were recruited over a 17-month period. Measures included distress, quality of life and programme engagement. Changes over time were measured using effect sizes (Cohen's d), whereas acceptibility was assessed using qualitative feedback. Low enrolment and high attrition rates resulted in a failure to demonstrate feasibility. Large improvements in negative affect (d=0.88) and emotional functioning (d=0.62) were found. For treatment completers, the intervention holds promise in reducing distress. However, in light of the serious challenges with recruitment and retention, further research is needed to resolve participation barriers. PMID- 23796230 TI - The circadian clock goes genomic. AB - Large-scale biology among plant species, as well as comparative genomics of circadian clock architecture and clock-regulated output processes, have greatly advanced our understanding of the endogenous timing system in plants. PMID- 23796232 TI - A new parameter estimation method for solute transport in a column. AB - To study contaminant transport in groundwater, an essential requirement is robust and accurate estimation of the transport parameters such as dispersion coefficient. The commonly used inverse error function method (IEFM) may cause unacceptable errors in dispersion coefficient estimation using the breakthrough curves (BTCs) data. We prove that the random error in the measured concentrations, which might be described by a normal distribution, would no longer follow the normal distribution after the IEFM transformation. In this study, we proposed a new method using the weighted least squares method (WLSM) to estimate the dispersion coefficient and velocity of groundwater. The weights were calculated based on the slope of the observed BTCs. We tested the new method against other methods such as genetic algorithm and CXTFIT program and found great agreement. This new method acknowledged different characteristics of solute transport at early, intermediate, and late time stages and divided BTCs into three sections for analysis. The developed method was applied to interpret three column tracer experiments by introducing continuous, constant-concentration of sodium chloride (NaCl) into columns filled with sand, gravel, and sand-gravel media. This study showed that IEFM performed well only when the observed data points were located in the linear (intermediate time) section of BTCs; it performed poorly when data points were in the early and late time stages. The new WLSM method, however, performed well for data points scattering over the entire BTCs and appeared promising in parameter estimation for solute transport in a column. PMID- 23796233 TI - Children's exercise behavior: the moderating role of habit processes within the theory of planned behavior. AB - PURPOSE: The moderating effect of exercise habit strength and specific habit processes within the theory of planned behavior (TPB) was tested in children. METHODS: Participants were primary school students (N = 380, mean age = 10.46 +/- .52). The data were collected using self-report measures followed by one-mile run test performance. Data were analyzed using structural equation modeling. RESULTS: The findings revealed that 34, 57, and 9% of students could be classified as low, moderate, and high in PA, respectively. Path analysis for the overall model revealed significant path loadings (p = < .05), except for the attitude-intention path. Moderating effects results revealed that strong habit strength extinguished the effects of intention on PA. CONCLUSION: Habit strength has the potential to minimize the deliberate processes associated with intention to exercise, thereby increasing the probability of intention-behavior translation. For specific habit processes, only negative affect appears to moderate the relationships between the TPB variables. PMID- 23796234 TI - Comparison of patient-specific internal gross tumor volume for radiation treatment of primary esophageal cancer based separately on three-dimensional and four-dimensional computed tomography images. AB - To compare the target volume, position and matching index of the patient-specific internal gross tumor volume (IGTV) based on three-dimensional (3D) and four dimensional (4D) computed tomography (CT) images for primary esophageal cancer. Twenty-nine patients with primary thoracic esophageal cancer underwent 3DCT and 4DCT scans during free breathing. IGTVs were constructed using three approaches: combining the gross target volumes from the 10 respiratory phases of the 4DCT dataset to produce IGTV10 ; IGTV2 was acquired by combining the two extreme phases; and IGTV3D was created from the 3DCT-based gross target volume by enlarging the 95th percentile of motion in each direction measured by the 4DCT. 0.16 cm lateral (LR), 0.14 cm anteroposterior (AP) and 0.29 cm superoinferior (SI) in the upper; 0.18 cm LR, 0.10 cm AP and 0.63 cm SI in the middle; and 0.40 cm LR, 0.58 cm AP and 0.82 cm in the lower thoracic esophagus could account for 95% of respiratory-induced tumor motion. The centroid position shift between IGTV10 and IGTV2 was all below 0.10 cm, and less than 0.20 cm between IGTV10 and IGTV3D . IGTV10 was bigger than IGTV2 ; the mean value of matching index for IGTV2 to IGTV10 was 0.87 +/- 0.05, 0.85 +/- 0.06 and 0.83 +/- 0.05 for upper, middle and distal thoracic esophageal tumors, respectively, and just 0.57 +/- 0.11, 0.56 +/- 0.13 and 0.40 +/- 0.03 between IGTV3D and IGTV10 . 4DCT-based IGTV10 is a reasonable patient-specific IGTV for primary thoracic esophageal cancer, and IGTV2 is considered as an acceptable alternative to IGTV10 . However, it seems unreasonable to use IGTV3D substitute IGTV10 . PMID- 23796235 TI - Vasopressin compared with norepinephrine augments the decline of plasma cytokine levels in septic shock. AB - RATIONALE: Changes in plasma cytokine levels may predict mortality, and therapies (vasopressin versus norepinephrine) could change plasma cytokine levels in early septic shock. OBJECTIVES: Our hypotheses were that changes in plasma cytokine levels over 24 hours differ between survivors and nonsurvivors, and that there are different effects of vasopressin and norepinephrine on plasma cytokine levels in septic shock. METHODS: We studied 394 patients in a randomized, controlled trial of vasopressin versus norepinephrine in septic shock. We used hierarchical clustering and principal components analysis of the baseline cytokine concentrations to subgroup cytokines; we then compared survivors to nonsurvivors (28 d) and compared vasopressin- versus norepinephrine-induced changes in cytokine levels over 24 hours. MEASUREMENTS AND MAIN RESULTS: A total of 39 plasma cytokines were measured at baseline and at 24 hours. Hierarchical clustering and principal components analysis grouped cytokines similarly. Survivors (versus nonsurvivors) had greater decreases of overall cytokine levels (P < 0.001). Vasopressin decreased overall 24-hour cytokine concentration compared with norepinephrine (P = 0.037). In less severe septic shock, the difference in plasma cytokine reduction over 24 hours between survivors and nonsurvivors was less pronounced than that seen in more severe septic shock. Furthermore, vasopressin decreased interferon-inducible protein 10 and granulocyte colony-stimulating factor more than did norepinephrine in less severe septic shock, whereas vasopressin decreased granulocyte-macrophage colony stimulating factor in patients who had more severe shock. CONCLUSIONS: Survivors of septic shock had greater decreases of cytokines, chemokines and growth factors in early septic shock. Vasopressin decreased 24-hour plasma cytokine levels more than did norepinephrine. The vasopressin-associated decrease of cytokines differed according to severity of shock. Clinical trial registered with www.controlled-trials.com (ISRCTN94845869). PMID- 23796236 TI - Variability and consistency in lung inflammatory responses to particles with a geogenic origin. AB - BACKGROUND AND OBJECTIVE: Particulate matter <10 MUm (PM10 ) is well recognized as being an important driver of respiratory health; however, the impact of PM10 of geogenic origin on inflammatory responses in the lung is poorly understood. This study aimed to assess the lung inflammatory response to community sampled geogenic PM10 . METHODS: This was achieved by collecting earth material from two regional communities in Western Australia (Kalgoorlie-Boulder and Newman), extracting the PM10 fraction and exposing mice by intranasal instillation to these particles. The physicochemical characteristics of the particles were assessed and lung inflammatory responses were compared to control particles. The primary outcomes were cellular influx and cytokine production in the lungs of the exposed mice. RESULTS: The physical and chemical characteristics of the PM10 from Kalgoorlie and Newman differed with the latter having a higher concentration of Fe and a larger median diameter. Control particles (2.5 MUm polystyrene) caused a significant influx of inflammatory cells (neutrophils) with little production of proinflammatory cytokines. In contrast, the geogenic particles induced the production of MIP-2, IL-6 and a significant influx of neutrophils. Qualitatively, the response following exposure to particles from Kalgoorlie and Newman were consistent; however, the magnitude of the response was substantially higher in the mice exposed to particles from Newman. CONCLUSIONS: The unique physicochemical characteristics of geogenic particles induced a proinflammatory response in the lung. These data suggest that particle composition should be considered when setting community standards for PM exposure, particularly in areas exposed to high geogenic particulate loads. PMID- 23796238 TI - Morphine-induced cognitive impairment is attenuated by induced pain in rats. AB - Opioid medications are frequently used in the effective treatment of intractable pain, but prolonged use of such medications can be complicated by a host of adverse effects. Among these adverse effects, tolerance and mental clouding can be especially disabling and can lead to both a reduced effectiveness of treatment and a reduced quality of life for many requiring treatment with these medications. Here we examined the relative contributions of complete Freund's adjuvant (CFA)-induced inflammatory pain and opioid medication on spatial memory for a well-learned task in male Sprague-Dawley rats. Although CFA, by itself, had little effect on spatial memory, morphine administered to pain-free animals produced profound detrimental effects on spatial memory that persisted longer than the analgesic effectiveness of the drug. However, no significant cognitive deficits were observed in animals receiving morphine in the presence of CFA induced pain. Taken together, these results are evidence that the pain state of the organism can alter some of the negative effects of morphine. PMID- 23796239 TI - Effect of Kangaroo mother care in reducing pain due to heel prick among preterm neonates: a crossover trial. AB - BACKGROUND: Preterm neonates undergo several painful procedures in NICU including heel prick for blood sugar monitoring. Nonpharmacological interventions have been tried to decrease this procedural pain. There are only few studies on Kangaroo mother care (KMC) in reducing pain among preterm neonates. METHOD: This crossover trial was conducted at a tertiary care teaching hospital in south India. Premature Infant Pain Profile (PIPP) related to heel prick was assessed in 50 preterm neonates undergoing KMC and compared with 50 preterm babies without KMC. RESULTS: PIPP scores at 15 minutes and 30 minutes after heel prick were significantly less in KMC group compared to control group. Mean PIPP difference between baseline and 30 minutes after heel prick was also significantly low in KMC group compared to control group. CONCLUSION: KMC is effective in reducing pain due to heel prick among preterm babies. PMID- 23796237 TI - Noradrenergic alpha-2 receptor modulators in the ventral bed nucleus of the stria terminalis: effects on anxiety behavior in postpartum and virgin female rats. AB - Emotional hyperreactivity can inhibit maternal responsiveness in female rats and other animals. Maternal behavior in postpartum rats is disrupted by increasing norepinephrine release in the ventral bed nucleus of the stria terminalis (BSTv) with the alpha2-autoreceptor antagonist, yohimbine, or the more selective alpha2 autoreceptor antagonist, idazoxan (Smith et al., 2012). Because high noradrenergic activity in the BSTv can also increase anxiety-related behaviors, increased anxiety may underlie the disrupted mothering of dams given yohimbine or idazoxan. To assess this possibility, anxiety-related behaviors in an elevated plus maze were assessed in postpartum rats after administration of yohimbine or idazoxan. It was further assessed if the alpha2-autoreceptor agonist clonidine (which decreases norepinephrine release) would, conversely, reduce dams' anxiety. Groups of diestrous virgins were also examined. It was found that peripheral or intra-BSTv yohimbine did increase anxiety-related behavior in postpartum females. However, BSTv infusion of idazoxan did not reproduce yohimbine's anxiogenic effects and anxiety was not reduced by peripheral or intra-BSTv clonidine. Because yohimbine is a weak 5HT1A receptor agonist, other groups of females received BSTv infusion of the 5HT1A receptor agonist 8OH-DPAT, but it did not alter their anxiety-related behavior. Lastly, levels of norepinephrine and serotonin in tissue punches from the BSTv did not differ between postpartum and diestrous rats, but serotonin turnover was lower in mothers. These results suggest that the impaired maternal behavior after BSTv infusion of yohimbine or idazoxan cannot both be readily explained by an increase in dams' anxiety, and that BSTv alpha2-autoreceptor modulation alone has little influence on anxiety related behaviors in postpartum or diestrous rats. PMID- 23796241 TI - Exposure ethics: does HIV pre-exposure prophylaxis raise ethical problems for the health care provider and policy maker? AB - The last few years have seen dramatic progress in the development of HIV pre exposure prophylaxis (PrEP). These developments have been met by ethical concerns. HIV interventions are often thought to be ethically difficult. In a context which includes disagreements over human rights, controversies over testing policies, and questions about sexual morality and individual responsibility, PrEP has been seen as an ethically complex intervention. We argue that this is mistaken, and that in fact, PrEP does not raise new ethical concerns. Some of the questions posed by PrEP are not specific to HIV prophylaxis, but simply standard public health considerations about resource allocation and striking a balance between individual benefit and public good. We consider sexual disinhibition in the context of private prescriptions, and conclude that only unjustified AIDS-exceptionalism or inappropriate moralism about sex supports thinking that PrEP raises new ethical problems. This negative conclusion is significant in a context where supposed ethical concerns about PrEP have been raised, and in the context of HIV exceptionalism. PMID- 23796240 TI - Structure-function analysis of the LytM domain of EnvC, an activator of cell wall remodelling at the Escherichia coli division site. AB - Proteins with LytM (Peptidase_M23) domains are broadly distributed in bacteria and have been implicated in a variety of important processes, including cell division and cell-shape determination. Most LytM-like proteins that have been structurally and/or biochemically characterized are metallo-endopeptidases that cleave cross-links in the peptidoglycan (PG) cell wall matrix. Notable exceptions are the Escherichia coli cell division proteins EnvC and NlpD. These LytM factors are not hydrolases themselves, but instead serve as activators that stimulate PG cleavage by target enzymes called amidases to promote cell separation. Here we report the structure of the LytM domain from EnvC, the first structure of a LytM factor implicated in the regulation of PG hydrolysis. As expected, the fold is highly similar to that of other LytM proteins. However, consistent with its role as a regulator, the active-site region is degenerate and lacks a catalytic metal ion. Importantly, genetic analysis indicates that residues in and around this degenerate active site are critical for amidase activation in vivo and in vitro. Thus, in the regulatory LytM factors, the apparent substrate binding pocket conserved in active metallo-endopeptidases has been adapted to control PG hydrolysis by another set of enzymes. PMID- 23796242 TI - Laboratory diagnosis of paraneoplastic pemphigus. AB - BACKGROUND: Paraneoplastic pemphigus (PNP) is a multiorgan disease characterized by antibodies against plakins, desmogleins and the alpha2-macroglobulin-like-1 (A2ML1) protein, in association with an underlying neoplasm. Accurate diagnosis relies on the demonstration of these autoantibodies in serum. OBJECTIVES: To evaluate the value of different laboratory techniques in the serological diagnosis of PNP. METHODS: We performed immunoblotting, envoplakin (EP) enzyme linked immunosorbent assay (ELISA), indirect immunofluorescence (IIF) on rat bladder, radioactive immunoprecipitation and a nonradioactive combined immunoprecipitation-immunoblot assay. Additional assays included BP180 ELISA and BP230 ELISA. We included the sera of 19 patients with PNP and 40 control subjects. RESULTS: The sensitivities were 63% for anti-EP ELISA, 74% for rat bladder IIF, 89% for immunoblotting, 95% for radioactive immunoprecipitation and 100% for nonradioactive immunoprecipitation. Specificities ranged from 86% to 100%. The BP180 and BP230 ELISAs had low sensitivity and specificity for PNP. The combination of rat bladder IIF and immunoblot showed 100% sensitivity and specificity. The analysis of sequential PNP sera showed that antibody titres may decrease over time, possibly resulting in negative outcomes for EP ELISA and rat bladder IIF studies. CONCLUSIONS: The detection of autoantibodies against EP and periplakin, or A2ML1 by immunoprecipitation is most sensitive for PNP. The combination of rat bladder IIF and immunoblotting is equally sensitive and highly specific, and represents an alternative valuable and relatively easy approach for the serological diagnosis of PNP. PMID- 23796243 TI - DNA and RNA "traffic lights": synthetic wavelength-shifting fluorescent probes based on nucleic acid base substitutes for molecular imaging. AB - The DNA base substitute approach by the (S)-3-amino-1,2-propanediol linker allows placing two fluorophores in a precise way inside a given DNA framework. The double helical architecture around the fluorophores, especially the DNA-induced twist, is crucial for the desired photophysical interactions. Excitonic, excimer, and energy transfer interactions yield fluorescent DNA and RNA probes with dual emission color readout. Especially, our DNA and RNA "traffic light" that combines the green emission of TO with the red emission of TR represents an important tool for molecular imaging and can be applied as aptasensors and as probes to monitor the siRNA delivery into cells. The concept can be extended to the synthetically easier to access postsynthetic 2'-modifications and the NIR range. Thereby, the pool of tailor-made fluorescent nucleic acid conjugates can be extended. PMID- 23796244 TI - Gradual disordering of the native state on a slow two-state folding protein monitored by single-molecule fluorescence spectroscopy and NMR. AB - Theory predicts that folding free energy landscapes are intrinsically malleable and as such are expected to respond to perturbations in topographically complex ways. Structural changes upon perturbation have been observed experimentally for unfolded ensembles, folding transition states, and fast downhill folding proteins. However, the native state of proteins that fold in a two-state fashion is conventionally assumed to be structurally invariant during unfolding. Here we investigate how the native and unfolded states of the chicken alpha-spectrin SH3 domain (a well characterized slow two-state folder) change in response to chemical denaturants and/or temperature. We can resolve the individual properties of the two end-states across the chemical unfolding transition employing single molecule fluorescence spectroscopy (SM-FRET) and across the thermal unfolding transition by NMR because SH3 folds-unfolds in the slow chemical exchange regime. Our results demonstrate that alpha-spectrin SH3 unfolds in a canonical way in the sense that it converts between the native state and an unfolded ensemble that expands in response to chemical denaturants. However, as conditions become increasingly destabilizing, the native state also expands gradually, and a large fraction of its native intramolecular hydrogen bonds break up. This gradual disordering of the native state takes place in times shorter than the 100 MUs resolution of our SM-FRET experiments. alpha-Spectrin SH3 thus showcases the extreme plasticity of folding landscapes, which extends to the native state of slow two-state proteins. Our results point to the idea that folding mechanisms under physiological conditions might be quite different from those obtained by linear extrapolation from denaturing conditions. Furthermore, they highlight a pressing need for re-evaluating the conventional procedures for analyzing and interpreting folding experiments, which may be based on too-simplistic assumptions. PMID- 23796245 TI - Glaucocalyxin A and B-induced cell death is related to GSH perturbation in human leukemia HL-60 cells. AB - Glaucocalyxin (Gla) A-C are major ent-kauranoid diterpenoids isolated from Rabdosia japonica var. glaucocalyx, a plant used in Chinese traditional medicine as an antitumor and anti-inflammatory agent. The present investigation was carried out to observe whether cellular reduced glutathione (GSH) plays important roles in Gla -induced cytotoxicity. Among major ent-kauranoid diterpenoids isolated, Gla A and B dose-dependently decreased the growth of HL-60 cells with an IC50 of approximately 6.15 and 5.86 uM at 24 h, respectively. Both Gla A and B could induce apoptosis, G2/M-phase cycle arrest, DNA damage and the accumulation of reactive oxygen species (ROS) in HL-60 cells. Moreover, Gla A, B caused rapid decrease of the intracellular GSH content, while inhibition of cellular GSH synthesis by buthionine sulfoximine (BSO) augmented the induced cytotoxicity and apoptosis in HL-60 cells. On the other hand, the administration of GSH or GSH precursor N-acetyl-cysteine (NAC) could rescue Gla A, B-depleted cellular GSH, and abrogate the induced cytotoxicity, G2/M-phase cycle arrest, DNA damage and ROS accumulation in HL-60 cells. Furthermore, Gla A, B decreased the activity of the GSH-related enzymes including glutathione reductase (GR) and glutathione peroxidase (GPX). These data suggest that the intracellular GSH redox system plays important roles in regulating the Gla A, B-induced cytotoxicity on HL-60 cells. PMID- 23796246 TI - Naturally-occurring dimers of flavonoids as anticarcinogens. AB - Biflavonoids are dimers of flavonoid moieties linked by a C-C or C-O-C bond. Simple, complex, rearranged, natural and ketalized Diels-Alder adducts, benzofuran derivatives, and spirobiflavonoids are some of the structural groups of biflavonoids. These compounds are mainly distributed in the Gymnosperms, Angiosperms (monocots and dicots), ferns (Pteridophyta), and mosses (Bryophyta). Biflavonoids have shown a variety of biological activities, including anticancer, antibacterial, antifungal, antiviral, antiinflammatory, analgesic, antioxidant, vasorelaxant, anticlotting, among others. This work is focused on probably the most potentially relevant biological activity of biflavonoids, the anticancer activity and the involved mechanisms of action, such as induction of apoptosis [inhibition of cyclic nucleotide phosphodiesterases; effects on NF-kappaB family of transcription factors; activation of caspase(s); inhibition effects on bcl-2 expression, and upregulation of p53 and caspase-3 gene expression]; inhibition of angiogenesis [anti-proliferative effects; activation of Rho-GTPases and ERK signaling pathways; inhibition of FASN activity]; inhibition of pre-mRNA splicing; inhibition of human DNA topoisomerases I and II-alpha; anti inflammatory/ immunoregulatory effects [inhibition of XO; inhibition of proinflammatory enzymes, such as PLA2 and COX; effects on cytokines mediated COX 2 and iNOS expression]; modulation of immune response; inhibition of protein tyrosine phosphorylation; antioxidant and analgesic activities in relation to the anticarcinogen behavior. For that reason the structures and anticarcinogenic activities of 83 biflavonoids are thoroughly discussed. The results of this work indicate that biflavonoids strongly affect the cancer cells with little effect on normal cell proliferation, suggesting a therapeutic potential against cancer. PMID- 23796247 TI - In silico study of desmosdumotin as an anticancer agent: homology modeling, docking and molecular dynamics simulation approach. AB - P-glycoprotein (P-gp) is responsible for the multidrug resistance (MDR) and involved in the expulsion of xenobiotics out of cell. In this paper, homology modeling, docking and molecular dynamics simulation (MDS) was performed for the human P-gp desmosdumotin inhibitor. Docking study was carried out in the P-gp nucleotide binding domain 2 (NBD2). The desmosdumotin binding region occupied the ATP binding region (flavonoid binding region) with hydrophobic and hydrophilic interactions. Analysis of root mean square deviations (RMSDs) of active site residues indicated the binding site residues were stable throughout the simulation period. As shown in previous results with structurally similar flavonoid compounds, van der Waals and electrostatic interactions were found to be important factors for the desmosdumotin-NBD2 inhibition. Docking results suggest that desmosdumotin interacts with the NBD2 through both hydrogen bonds (Lys1076, Ser1077 and Thr1078) and hydrophobic interactions (Tyr1044, Val1052, Gly1073 and Cys1074). In addition, the involvement of other amino-acids was identified via MDS (Lys1076 and Ser1077 for hydrogen bonds and Tyr1044, Val1052, Gly1073, Cys1074 and Gly1075 for hydrophobic interactions). Thus, current preliminary model of interactions between desmosdumotin-NBD2 could be helpful to understand the in-depth inhibition mechanism of P-gp at NBD2 level and to design more potent inhibitors which could effectively overcome MDR of anticancer agents. PMID- 23796249 TI - The role of phenolic compounds in the fight against cancer--a review. AB - Cancer is a worldwide scourge; it's the leading cause of death in developed countries and is increasing in developing countries. Mankind has been trying with effort to find better and cheaper treatments with fewer side effects, to reduce the incidence of the disease and its consequent mortality. For many years, phenolic compounds have been intensely studied for their antitumor, proapoptotic and antiangiogenic effects. In recent years, the usage of these compounds has increased considerably. This manuscript intends to structurally characterize the different phenolic compounds (flavonoids, hydroxycinnamates, hydroxybenzoates, coumarins, xanthones, chalcones, stilbenes, lignins and lignans) and their metabolic pathways as well as review the most important results regarding these compounds and their derivatives in cancer treatment and prevention both in tumor cell lines in vitro, in murine models in vivo and finally some results regarding human trials. PMID- 23796248 TI - Differential effects of polyphenols on proliferation and apoptosis in human myeloid and lymphoid leukemia cell lines. AB - BACKGROUND: Mortality rates for leukemia are high despite considerable improvements in treatment. Since polyphenols exert pro-apoptotic effects in solid tumors, our study investigated the effects of polyphenols in haematological malignancies. The effect of eight polyphenols (quercetin, chrysin, apigenin, emodin, aloe-emodin, rhein, cis-stilbene and trans-stilbene) were studied on cell proliferation, cell cycle and apoptosis in four lymphoid and four myeloid leukemic cells lines, together with normal haematopoietic control cells. METHODS: Cellular proliferation was measured by CellTiter-Glo((r)) luminescent assay; and cell cycle arrest was assessed using flow cytometry of propidium iodide stained cells. Apoptosis was investigated by caspase-3 activity assay using flow cytometry and apoptotic morphology was confirmed by Hoescht 33342 staining. RESULTS: Emodin, quercetin, and cis-stilbene were the most effective polyphenols at decreasing cell viability (IC50 values of 5-22 MUM, 8-33 MUM, and 25-85 MUM respectively) and inducing apoptosis (AP50 values (the concentration which 50% of cells undergo apoptosis) of 2-27 MUM, 19-50 MUM, and 8-50 MUM respectively). Generally, lymphoid cell lines were more sensitive to polyphenol treatment compared to myeloid cell lines, however the most resistant myeloid (KG-1a and K562) cell lines were still found to respond to emodin and quercetin treatment at low micromolar levels. Non-tumor cells were less sensitive to all polyphenols compared to the leukemia cells. CONCLUSIONS: These findings suggest that polyphenols have anti-tumor activity against leukemia cells with differential effects. Importantly, the differential sensitivity of emodin, quercetin, and cis stilbene between leukemia and normal cells suggests that polyphenols are potential therapeutic agents for leukemia. PMID- 23796250 TI - Inversion of the stereochemistry around the sulfur atom of the axial methionine side chain through alteration of amino acid side chain packing in Hydrogenobacter thermophilus cytochrome C552 and its functional consequences. AB - In cytochrome c, the coordination of the axial Met Sdelta atom to the heme Fe atom occurs in one of two distinctly different stereochemical manners, i.e., R and S configurations, depending upon which of the two lone pairs of the Sdelta atom is involved in the bond; hence, the Fe-coordinated Sdelta atom becomes a chiral center. In this study, we demonstrated that an alteration of amino acid side chain packing induced by the mutation of a single amino acid residue, i.e., the A73V mutation, in Hydrogenobacter thermophilus cytochrome c552 (HT) forces the inversion of the stereochemistry around the Sdelta atom from the R configuration [Travaglini-Allocatelli, C., et al. (2005) J. Biol. Chem. 280, 25729-25734] to the S configuration. Functional comparison between the wild-type HT and the A73V mutant possessing the R and S configurations as to the stereochemistry around the Sdelta atom, respectively, demonstrated that the redox potential (Em) of the mutant at pH 6.00 and 25 degrees C exhibited a positive shift of ~20 mV relative to that of the wild-type HT, i.e., 245 mV, in an entropic manner. Because these two proteins have similar enthalpically stabilizing interactions, the difference in the entropic contribution to the Em value between them is likely to be due to the effect of the conformational alteration of the axial Met side chain associated with the inversion of the stereochemistry around the Sdelta atom due to the effect of mutation on the internal mobility of the loop bearing the axial Met. Thus, the present study demonstrated that the internal mobility of the loop bearing the axial Met, relevant to entropic control of the redox function of the protein, is affected quite sensitively by the contextual stereochemical packing of amino acid side chains in the proximity of the axial Met. PMID- 23796251 TI - Peroxisome proliferator-activated receptor-gamma activators monascin and rosiglitazone attenuate carboxymethyllysine-induced fibrosis in hepatic stellate cells through regulating the oxidative stress pathway but independent of the receptor for advanced glycation end products signaling. AB - Advanced glycation end products (AGEs) signaling through its receptors (RAGE) results in an increase in reactive oxygen species (ROS) and is thought to contribute to hepatic fibrosis via hyperglycemia. Carboxymethyllysine (CML) is a key AGE, with highly reactive dicarbonyl metabolites. We investigated the inhibitory effect of Monascus -fermented metabolite monascin and rosiglitazone on CML-induced RAGE signaling in hepatic stellate cells (HSCs) and its resulting antihepatic fibrosis activity. We found that monascin and rosiglitazone upregulated peroxisome proliferator-activated receptor-gamma (PPAR-gamma) to attenuate alpha-smooth muscle actin (SMA) and ROS generation in CML-treated HSCs in a RAGE activation-independent pathway. Therefore, monascin may delay or inhibit the progression of liver fibrosis through the activation of PPAR-gamma and might prove to be a major antifibrotic mechanism to prevent liver disease. PMID- 23796253 TI - Reasonability and conscientious objection in medicine: a reply to Marsh and an elaboration of the reason-giving requirement. AB - In this paper I defend the Reasonability View: the position that medical professionals seeking a conscientious exemption must state reasons in support of their objection and allow those reasons to be subject to evaluation. Recently, this view has been criticized by Jason Marsh as proposing a standard that is either too difficult to meet or too easy to satisfy. First, I defend the Reasonability View from this proposed dilemma. Then, I develop this view by presenting and explaining some of the central criteria it uses to assess whether a conscientious objection is proper grounds for extending an exemption to a medical practitioner. PMID- 23796252 TI - Association of pain with HbA1c in a predominantly black population of community dwelling adults with diabetes: a cross-sectional analysis. AB - AIMS: To assess the relationship between pain and HbA(1c) levels in a predominantly black population with diabetes, and to determine whether self management behaviours (exercise and diet) and symptoms of depression mediate this relationship. METHODS: We analysed cross-sectional data from 417 community dwelling individuals with diabetes in rural Alabama, USA. Binary logistic regression was used to analyse the relationship between pain and HbA(1c) levels, defined as relatively good [<= 64 mmol/mol (<= 8.0%)] and relatively poor [> 64 mmol/mol (> 8.0%)], after adjusting for sociodemographics, insulin use, medication count, cigarette smoking history and body mass index (BMI). We examined the mediating roles of exercise, diet, and symptoms of depression using bootstrapping. RESULTS: Participants were primarily black (86.6%), female (76.1%) and reported an annual income of <=$20,000 (52.7%). Their mean (sd) age was 59.6 (12.8) years. The majority of the participants reported moderate to extreme pain (71.5%). Participants reporting pain were more than twice as likely to have HbA(1c) levels > 64 mmol/mol (8.0%) in the fully adjusted model (odds ratio 2.33 [95% CI 1.28-4.24]; P < 0.05). Diet significantly mediated the relationship between pain and HbA(1c) control (beta = 0.06; 95% CI: 0.01-0.17), but only in the unadjusted model. Exercise and symptoms of depression were not significant mediators. CONCLUSIONS: A significant independent relationship between pain and HbA(1c) control was found in this mainly black population, which was not explained by self-management behaviours or symptoms of depression. Future research is needed to delineate the mechanism by which pain influences HbA(1c) control, especially among black people with diabetes on low incomes. PMID- 23796254 TI - Template-free synthesis of hierarchical porous metal-organic frameworks. AB - A template-free synthesis of a hierarchical microporous-mesoporous metal-organic framework (MOF) of zinc(II) 2,5-dihydroxy-1,4-benzenedicarboxylate (Zn-MOF-74) is reported. The surface morphology and porosity of the bimodal materials can be modified by etching the pore walls with various synthesis solvents for different reaction times. This template-free strategy enables the preparation of stable frameworks with mesopores exceeding 15 nm, which was previously unattained in the synthesis of MOFs by the ligand-extension method. PMID- 23796255 TI - Risk factors and perinatal outcomes associated with idiopathic small for gestational age Taiwanese newborns. AB - OBJECTIVE: To determine risk factors and perinatal outcomes associated with small for gestational age (SGA) neonates among healthy pregnant women. METHODS: A retrospective cohort study was conducted of 49 945 women who gave birth at Chang Gung Memorial Hospital, Taipei, Taiwan, after 24weeks of pregnancy. Idiopathic SGA newborns (n=3398) were characterized by a birth weight below the 10th percentile for mean weight corrected for GA and fetal sex. RESULTS: Risk factors for idiopathic SGA newborns included hypercoiling of the umbilical cord (adjusted odds ratio [aOR], 3.3; 95% confidence interval [CI], 1.6-7.0); prior fetal death (aOR, 2.8; 95% CI, 2.0-3.9); primiparity (aOR, 1.5; 95% CI, 1.4-1.7); adolescent pregnancy (aOR, 1.5; 95% CI, 1.2-2.0), low prepregnancy weight (aOR, 1.6; 95% CI, 1.5-1.8), low prepregnancy body mass index (aOR, 1.1; 95% CI, 1.0-1.3); short stature (aOR, 1.3; 95% CI, 1.1-1.4); and entangled umbilical cord (aOR, 1.1; 95% CI, 1.0-1.3). Idiopathic SGA newborns correlated with increased risk of adverse perinatal outcomes, including fetal death, low Apgar scores, oligohydramnios, placental abruption, and admission to the neonatal intensive care unit. CONCLUSION: Some risk factors for idiopathic SGA newborns were modifiable, suggesting potential implications for public health. PMID- 23796256 TI - A systematic review of the evidence for complementary and alternative medicine in infertility. AB - BACKGROUND: The use of complementary and alternative medicine (CAM) by patients and physicians has increased markedly in recent years. Many case reports, case series, and uncontrolled trials of varying quality have been completed; however, there is now a slowly increasing number of randomized controlled trials (RCTs) examining the use of CAM. OBJECTIVES: To identify, survey, and review RCTs investigating the use of CAM for infertility treatment. SEARCH STRATEGY: The MEDLINE and Cochrane databases were electronically searched. SELECTION CRITERIA: RCTs examining modalities for treatment or improvement of health status were reviewed. DATA COLLECTION AND ANALYSIS: RCTs were included based on use of objective measures, articles written in English, availability through the University of Michigan database, and clear published clinical outcomes. MAIN RESULTS: Thirty-seven articles assessing a variety of CAM modalities met inclusion criteria. Acupuncture, selenium supplementation, weight loss, and psychotherapeutic intervention had 3 or more studies demonstrating beneficial effect. Other interventions had been studied less and evidence for them was limited. CONCLUSIONS: Although there is preliminary evidence of the effectiveness of some CAM interventions among infertile patients, many of these interventions require further investigation before they can be considered for routine clinical use. PMID- 23796257 TI - Reproductive health concerns of women contending with spousal violence and husband's alcohol use in a Mumbai slum community. PMID- 23796258 TI - Velamentous insertion of the umbilical cord of twin B as a cause of vasa previa in monochorionic diamniotic twins. PMID- 23796259 TI - A multi-country study of the "intrapartum stillbirth and early neonatal death indicator" in hospitals in low-resource settings. AB - OBJECTIVE: To determine the feasibility of introducing a simple indicator of quality of obstetric and neonatal care and to determine the proportion of potentially avoidable perinatal deaths in hospitals in low-income countries. METHODS: Between September 1, 2011, and February 29, 2012, data were collected from consecutive women who were admitted to the labor ward of 1 of 6 hospitals in 4 low-income countries. Fetal heart tones on admission were monitored, and demographic and birth data were recorded. RESULTS: Data were obtained for 3555 women and 3593 neonates (including twins). The doptone was used on 97% of women admitted. The overall perinatal mortality rate was 34 deaths per 1000 deliveries. Of the perinatal deaths, 40%-45% occurred in the hospital and were potentially preventable by better hospital care. CONCLUSION: The results demonstrated that it is possible to accurately determine fetal viability on admission via a doptone. Implementation of doptone use, coupled with a concise data record, might form the basis of a low-cost and sustainable program to monitor and evaluate efforts to improve quality of care and ultimately might help to reduce the in-hospital component of perinatal mortality in low-income countries. PMID- 23796260 TI - New global guidance supports community and lay health workers in postpartum hemorrhage prevention. AB - New global guidance has emerged to support countries as they consider introducing or scaling-up misoprostol for postpartum hemorrhage (PPH). The World Health Organization (WHO) and the International Federation of Gynecology and Obstetrics (FIGO) recognize the critical role that community and lay health workers play in preventing PPH and increasing access to misoprostol where skilled birth attendants are not available. As case examples from Nigeria and Nepal illustrate, community engagement and empowerment are critical strategies in successful misoprostol for PPH programs, and must increasingly be viewed as part of efforts to improve maternal health and achieve Millennium Development Goal 5. PMID- 23796261 TI - Clinicopathological features of narrow-band imaging endoscopy and immunohistochemistry in ultraminute esophageal squamous neoplasms. AB - To reveal clinicopathological features of narrow-band imaging (NBI) endoscopy and immunohistochemistry in ultraminute esophageal squamous neoplasms. If a lesion diameter was smaller or same compared with a width of closed biopsy forceps, a lesion was defined to be an ultraminute lesion. Twenty-five consecutive patients with 33 ultraminute esophageal lesions that were removed by endoscopic mucosal resection were included in the present study. We conducted two questionnaire surveys of six endoscopists by their retrospective review of endoscopic still images. The six endoscopists evaluated the endoscopic findings of the ultraminute lesions on still images taken by conventional white-light imaging endoscopy and non-magnified NBI endoscopy in the first questionnaire, and taken by magnified NBI endoscopy in the second questionnaire. An experienced pathologist who was unaware of any endoscopic findings made histological diagnosis and evaluated immunoexpression of p53 and Ki67. The 33 ultraminute lesions were all determined to be either 11 high-grade intraepithelial neoplasias (HGIENs) or 22 low-grade intraepithelial neoplasias (LGIENs). The tumor diameters were histologically confirmed to be <3 mm. All of the ultraminute tumors were visualized as unstained areas and brownish areas by real-time endoscopy with Lugol dye staining and non magnified NBI endoscopy, respectively. All of the ultraminute IENs were visualized as brownish areas by real-time non-magnified NBI endoscopy. Three of the 25 patients with the ultraminute IENs (12%) had multiple brownish areas (more than several areas) in the esophagus on real-time non-magnified NBI endoscopy. All of the ultraminute IENs were visualized as unstained areas by real-time Lugol chromoendoscopy. Twenty of the 25 patients (80%) had multiple unstained areas (more than several areas) in the esophagus on real-time Lugol chromoendoscopy. The first questionnaire survey revealed that a significantly higher detection rate of the ultraminute IENs on non-magnified NBI endoscopy images compared with conventional white-light imaging endoscopy ones (100% vs. 72%, respectively: P < 0.0001). The second questionnaire survey revealed that presence rates of any magnified NBI endoscopy findings were not significantly different between HGIENs and LGIENs. Proliferation, dilation, and various shapes of intrapapillary capillary loops indicated remarkably high presence rates of more than 90% in both HGIENs and LGIENs. Six of 22 LGIENs (27%) and 3 of 11 HGIENs (27%) show a positive expression for p53. None of peri-IEN epithelia was positive for p53. A mean of Ki67 labeling index of LGIENs was 33% and that of HGIENs 36%. Ki67 labeling index was significantly greater in the LGIENs and HGIENs compared with that in the peri-IEN epithelia. There were no significant differences in p53 expression and Ki67 labeling index between the HGIENs and LGIENs. Non magnified/magnified NBI endoscopy could facilitate visualization and characterization of ultraminute esophageal squamous IENs. The ultraminute HGIENs and LGIENs might have comparable features of magnified NBI endoscopy and immunohistochemistry. PMID- 23796262 TI - Steroidal saponins from Anemarrhena asphodeloides. AB - Two new steroidal saponins, named anemarnoside A and anemarnoside B, along with three known compounds, timosaponin J, timosaponin B II, and timosaponin B, have been isolated from Anemarrhena asphodeloides. Their structures were established by spectroscopic techniques (IR, MS, 1D NMR, and 2D NMR) and by comparison with published data. PMID- 23796263 TI - Role of antifeeding prophage (Afp) protein Afp16 in terminating the length of the Afp tailocin and stabilizing its sheath. AB - The Serratia entomophila antifeeding prophage Afp, forms a phage-tail-like particle that acts on the New Zealand grass grub, Costelytra zealandica with a 3 day LD50 of approximately 500 Afp particles per larva. Genes (afp1-18) encoding components of Afp were expressed and their products purified allowing morphological assessment of the products by transmission electron microscopy (TEM). Expression of afp1-15 resulted in the formation of a non-sheathed structure termed the tube-baseplate complex or TBC, composed of an irregular length tube attached to a baseplate with associated tail fibres. Expression of afp1-16 produced mature, normal-length Afp particles, whereas coexpression of afp16 with afp1-15 in trans resulted in the formation of aberrant Afp particles of variable lengths. A C-terminally truncated Afp16 mutant resulted in a phenotype intermediate between mature Afp and TBC. The addition of purified Afp16 to Afp unravelled by acidic treatment resulted in the formation of shorter tubes when specimen pH was adjusted to 7 than those formed in the absence of Afp16. Analysis of TEM images of purified Afp16 revealed a hexameric ring-like structure similar to that formed by gp3 of phage T4 and gpU of phage lambda. Our results suggest that Afp16 terminates tube elongation and is involved in sheath formation. PMID- 23796264 TI - Fetal thrombotic vasculopathy accompanied by fetal growth restriction. AB - Fetal thrombotic vasculopathy, a rare condition, is defined as thrombosis in the fetal circulation of placenta causing fibrotic villi and its detection before delivery is difficult. Thrombosis in fetal placenta involves various problems such as uteroplacental insufficiency, central nervous system injury and even perinatal death. Here, we report a case of fetal arterial thrombosis predisposed to neonatal neurologic impairment. This case emphasizes an importance of placental biopsy, especially when the neonate seems to have problems. We recommend that pathological examination of placenta be performed not only when abnormal gross findings of placenta, but also when fetal abnormalities are observed. PMID- 23796265 TI - Nudge, nudge, wink, wink: love, sex and gay men with intellectual disabilities - a helping hand or a human right? AB - BACKGROUND: How do human rights help us with the experiences of people with intellectual disabilities (ID) who face discrimination and barriers in their sexual lives? Men with ID who are gay face a whole range of rights violations when it comes to exercising their sexual identity. How can such a seemingly marginalised group draw on rights based claims for better and equal treatment? This paper explores how the power of men's own stories may usefully challenge prevailing social norms and in turn strengthen human rights claims in this area. It also reflects on the challenges posed to such an agenda by current economic difficulties and changes in the organisation of adult social care in the UK. METHOD: The paper draws on empirical research with gay men with ID completed in the UK in 2005 and briefly revisits some key messages from the data. It also considers the wider literature on the power and possibilities of human rights, 'intimate stories' and translating human rights into everyday change. CONCLUSIONS: Gay men with ID tell powerful stories of love, longing and exclusion. Such stories have the capacity to transform wider social attitudes and in turn strengthen the rights claims of this marginalised groups. There are question marks about the possibility of such change in a time of austerity and the broader move in the UK's welfare state from the collective to the individual consumer of services. However, the telling of men's 'intimate stories' creates an almost unassailable challenge to current discriminatory practices and norms. PMID- 23796266 TI - Burnout in orthopaedic surgeons: a review. AB - BACKGROUND: Training and practice of orthopaedic surgery are stressful endeavours, placing orthopaedic surgeons at risk of burnout. Burnout syndrome is associated with negative outcomes for patients, institutions and, especially, the surgeon. The aim of this review is to summarize available literature on burnout among orthopaedic surgeons and provide recommendations for future work in this field. METHODS: A search of MEDLINE (1946-present) and EMBASE (search terms: 'Burnout, Professional' AND 'Orthopaedics'; 'Stress, Psychological' AND 'Orthopaedic Surgery'; 'Fatigue, Mental' AND 'Orthopaedic Surgery') was performed. The authors focused on articles that assessed burnout among orthopaedic surgeons. All studies used the Maslach Burnout Inventory allowing for cross-study (and cross-country) comparisons. RESULTS: Burnout rates among orthopaedic surgeons are in the range of 50-60%, higher than surgeons in general (range: 30-40% for surgeons in general), with the highest rate (emotional exhaustion and depersonalization scores) among orthopaedic residents, followed by department chairs, followed by faculty members. Both objective factors (caseload, practice setting, etc.) and subjective factors (perception that career was unrewarding, perception of lack of autonomy, etc.) contribute to burnout; however, subjective factors show a stronger correlation. CONCLUSION: Despite the heavy burnout rates among orthopaedic surgeons, little work has been performed in this field. Factors responsible for burnout among various orthopaedic populations should be determined, and appropriate interventions designed to reduce burnout. PMID- 23796267 TI - Direct photodegradation of androstenedione and testosterone in natural sunlight: inhibition by dissolved organic matter and reduction of endocrine disrupting potential. AB - In surface waters, two of the most commonly observed androgenic steroid hormones are androstenedione (AD) and testosterone (T). This study compares the photodegradation of dilute (<10 MUg L(-1)) aqueous solutions of AD and T in natural sunlight, and evaluates the endocrine-disrupting potential of the resulting solutions. This study also examines the effect of dissolved organic matter (DOM) on AD photodegradation. During spring and summer at Henderson, NV, USA (latitude 36.04 degrees N), AD and T underwent direct photodegradation, with half-lives ranging from 3.7 to 10.8 h. In three model DOM solutions, AD's half life increased by 11% to 35%. Using screening factors to eliminate DOM's inner filter effect, quantum yield calculations suggested that light screening was primarily responsible for AD's increased half-life, and that physical quenching further inhibited AD's photodegradation in two out of three DOM solutions. In vitro androgenic activity of the AD and T solutions decreased approximately as fast as AD and T were removed, suggesting that solar photodegradation reduces the risk of endocrine disruption in surface waters impacted by AD or T, subject to continuing inputs. Reduced in vitro androgenic activity appears to be related to steroid ring cleavage and the formation of highly oxidized photoproducts. PMID- 23796268 TI - The flash-lag effect and related mislocalizations: findings, properties, and theories. AB - If an observer sees a flashed (briefly presented) object that is aligned with a moving target, the perceived position of the flashed object usually lags the perceived position of the moving target. This has been referred to as the flash lag effect, and the flash-lag effect has been suggested to reflect how an observer compensates for delays in perception that are due to neural processing times and is thus able to interact with dynamic stimuli in real time. Characteristics of the stimulus and of the observer that influence the flash-lag effect are reviewed, and the sensitivity or robustness of the flash-lag effect to numerous variables is discussed. Properties of the flash-lag effect and how the flash-lag effect might be related to several other perceptual and cognitive processes and phenomena are considered. Unresolved empirical issues are noted. Theories of the flash-lag effect are reviewed, and evidence inconsistent with each theory is noted. The flash-lag effect appears to involve low-level perceptual processes and high-level cognitive processes, reflects the operation of multiple mechanisms, occurs in numerous stimulus dimensions, and occurs within and across multiple modalities. It is suggested that the flash-lag effect derives from more basic mislocalizations of the moving target or flashed object and that understanding and analysis of the flash-lag effect should focus on these more basic mislocalizations rather than on the relationship between the moving target and the flashed object. PMID- 23796269 TI - Can callous-unemotional traits enhance the understanding, diagnosis, and treatment of serious conduct problems in children and adolescents? A comprehensive review. AB - This article provides a comprehensive review of the research on the use of callous and unemotional (CU) traits for designating an important subgroup of children and adolescents with severe conduct problems. It focuses on the etiological significance of recognizing this subgroup of youths with severe conduct problems, its implications for diagnostic classification, and the treatment implications of this research. The review highlights limitations in existing research and provides directions for future research. The available research suggests that children and adolescents with severe conduct problems and elevated CU traits show distinct genetic, cognitive, emotional, biological, environmental, and personality characteristics that seem to implicate different etiological factors underlying their behavior problems relative to other youths with severe conduct problems. Recognizing these subgroups could be critical for guiding future research on the causes of severe conduct problems in children and adolescents. Further, children and adolescents with both severe conduct problems and elevated CU traits appear to be at risk for more severe and persistent antisocial outcomes, even controlling for the severity of their conduct problems, the age of onset of their conduct problems, and common comorbid problems, which supports the clinical importance of designating this group in diagnostic classification systems. Finally, although children and adolescents with both severe conduct problems and elevated CU traits tend to respond less positively to typical interventions provided in mental health and juvenile justice settings, they show positive responses to certain intensive interventions tailored to their unique emotional and cognitive characteristics. PMID- 23796270 TI - Two cases of clear cell sarcoma with different clinical and genetic features: cutaneous type with BRAF mutation and subcutaneous type with KIT mutation. AB - Clear cell sarcoma (CCS), also known as malignant melanoma of soft parts, is a rare malignancy constituting approximately 1% of all soft-tissue sarcomas. It occurs predominantly in the lower extremities of young adults, manifesting as a deep, painless, slow-growing mass. CCS is sometimes confused with other types of melanoma because of its melanocytic differentiation. Although BRAF and KIT mutations are well-known melanocytic tumour-promoting mutations frequently found in cutaneous melanoma, they are rare or absent in CCS. We present two cases of CCS with different clinical and genetic features. Both female patients, aged 25 and 20 years, presented with a palpable nodule on a lower extremity. Biopsies of both tumours revealed features diagnostic of CCS. Each tumour cell was positive for S100 protein and HMB-45. However, one patient's tumour was localized to the dermis, with many multinucleated giant cells, whereas the other was located in the deep subcutaneous fat layer near bone. Fluorescence in situ hybridization demonstrated the presence of a characteristic Ewing sarcoma RNA-binding protein (EWSR)1 gene rearrangement in both cases. Reverse-transcription polymerase chain reaction (PCR) and sequencing of the PCR product revealed an EWSR1-activating transcription factor 1 type 1 fusion transcript in both cases. In addition, we detected BRAF mutation in the dermal type and KIT mutation in the subcutaneous type. It is of interest that the BRAF and KIT mutations are known to be very rare in CCS. On the basis of our observations, we suggest that mutation inhibitors may be useful in selected patients with mutated CCS lineages. PMID- 23796271 TI - DNA structure matters. PMID- 23796272 TI - Lewis acid catalyzed S(N)2-type ring opening of N-activated aziridines with electron-rich arenes/heteroarenes. AB - An efficient Lewis acid catalyzed S(N)2-type ring opening of substituted aziridines with electron-rich arenes/heteroarenes to provide substituted 2,2 diaryl/heteroarylethylamines in excellent yields and stereoselectivity (er, dr >99:1) is described. PMID- 23796273 TI - Planned conservative management of placenta accreta - experience of a regional general hospital. AB - OBJECTIVE: There are only a few series treating >=10 cases of accreta conservatively, all from university teaching hospitals, with reported success rate of 60-85%. We reported the first series of accreta managed by planned uterine conservation in the setting of non-university district general hospital. METHODS: Women with placenta previa overlying previous cesarean scar who desired uterine conservation were included. For cases with accreta confirmed during cesarean delivery, placenta was purposefully left behind, followed immediately by uterine artery embolization. Cases were followed in our special postnatal clinic. Charts were reviewed to retrieve clinical details. RESULTS: Among 15 cases of placenta previa overlying cesarean scar opting for conservative management, 12 (80%) were confirmed to be accreta intra-operatively. They had 20-100% of the adherent placentae retained (median 90%) and their uterus preserved. Postpartum, abnormal vaginal bleeding and/or infection led to unscheduled readmission in 67% (8/12), all managed conservatively. Sonographic resolution of placenta took 2-13 months (median 6.6), and was later than menstrual return in 11 cases. CONCLUSIONS: Successful planned conservative management of placenta accreta is feasible in the setting of district general hospital with facilities for interventional radiology. PMID- 23796274 TI - A rat model for orthodontic translational expansive tooth movement. AB - OBJECTIVES: To present the development of an experimental model in rats for translational expansive tooth movement. SETTING AND SAMPLE: Section of Periodontology at Department of Dentistry Aarhus University. Twenty male Wistar rats in two pilot experimental settings plus seven animals without any intervention serving as controls. MATERIAL AND METHODS: The second molar (group P1) or the second and third molar (group P2) in the maxillae of the animals were moved buccally using transpalatal beta-titanium springs. In the group P2, two spring types (high force and low force) and two preangulations (0 degrees passive or 30 degrees torsion moment) were tested. The amount and type of tooth movement achieved and the resulting skeletal effect were assessed on microCT images, histological analysis was performed on few selected specimens. RESULTS: Expansive translational root movement amounting half a tooth width was achieved. Comparison of the amount of tooth movement at the right and left side of the maxilla showed that the expansion was rather symmetrical in the P2 group. Skeletal widening of the maxilla contributed in the P2 group to approximately one third of the total root movement, whereas two-thirds were dental movement. CONCLUSION: With the model used in the P2 group, further research on translational expansive tooth movement and its effect on the periodontium can be pursued. In models for orthodontic expansion, it is strongly recommended to separately evaluate skeletal and dental effects. PMID- 23796275 TI - Bioethics methods in the ethical, legal, and social implications of the human genome project literature. AB - While bioethics as a field has concerned itself with methodological issues since the early years, there has been no systematic examination of how ethics is incorporated into research on the Ethical, Legal and Social Implications (ELSI) of the Human Genome Project. Yet ELSI research may bear a particular burden of investigating and substantiating its methods given public funding, an explicitly cross-disciplinary approach, and the perceived significance of adequate responsiveness to advances in genomics. We undertook a qualitative content analysis of a sample of ELSI publications appearing between 2003 and 2008 with the aim of better understanding the methods, aims, and approaches to ethics that ELSI researchers employ. We found that the aims of ethics within ELSI are largely prescriptive and address multiple groups. We also found that the bioethics methods used in the ELSI literature are both diverse between publications and multiple within publications, but are usually not themselves discussed or employed as suggested by bioethics method proponents. Ethics in ELSI is also sometimes undistinguished from related inquiries (such as social, legal, or political investigations). PMID- 23796276 TI - Computer modeling of diabetes and its complications: a report on the fifth mount hood challenge meeting. PMID- 23796277 TI - Reporting of patient-reported outcomes in randomized trials: the CONSORT PRO extension. PMID- 23796278 TI - ePRO systems validation: clearly defining the roles of clinical trial teams and ePRO system providers. PMID- 23796279 TI - Digitization of patient-reported outcomes. PMID- 23796280 TI - Pediatric patient-reported outcome instruments for research to support medical product labeling: report of the ISPOR PRO good research practices for the assessment of children and adolescents task force. AB - BACKGROUND: Patient-reported outcome (PRO) instruments for children and adolescents are often included in clinical trials with the intention of collecting data to support claims in a medical product label. OBJECTIVE: The purpose of the current task force report is to recommend good practices for pediatric PRO research that is conducted to inform regulatory decision making and support claims made in medical product labeling. The recommendations are based on the consensus of an interdisciplinary group of researchers who were assembled for a task force associated with the International Society for Pharmacoeconomics and Outcomes Research (ISPOR). In those areas in which supporting evidence is limited or in which general principles may not apply to every situation, this task force report identifies factors to consider when making decisions about the design and use of pediatric PRO instruments, while highlighting issues that require further research. GOOD RESEARCH PRACTICES: Five good research practices are discussed: 1) Consider developmental differences and determine age-based criteria for PRO administration: Four age groups are discussed on the basis of previous research (<5 years old, 5-7 years, 8-11 years, and 12-18 years). These age groups are recommended as a starting point when making decisions, but they will not fit all PRO instruments or the developmental stage of every child. Specific age ranges should be determined individually for each population and PRO instrument. 2) Establish content validity of pediatric PRO instruments: This section discusses the advantages of using children as content experts, as well as strategies for concept elicitation and cognitive interviews with children. 3) Determine whether an informant-reported outcome instrument is necessary: The distinction between two types of informant-reported measures (proxy vs. observational) is discussed, and recommendations are provided. 4) Ensure that the instrument is designed and formatted appropriately for the target age group. Factors to consider include health-related vocabulary, reading level, response scales, recall period, length of instrument, pictorial representations, formatting details, administration approaches, and electronic data collection (ePRO). 5) Consider cross-cultural issues. CONCLUSIONS: Additional research is needed to provide methodological guidance for future studies, especially for studies involving young children and parents' observational reports. As PRO data are increasingly used to support pediatric labeling claims, there will be more information regarding the standards by which these instruments will be judged. The use of PRO instruments in clinical trials and regulatory submissions will help ensure that children's experience of disease and treatment are accurately represented and considered in regulatory decisions. PMID- 23796281 TI - Validation of electronic systems to collect patient-reported outcome (PRO) data recommendations for clinical trial teams: report of the ISPOR ePRO systems validation good research practices task force. AB - Outcomes research literature has many examples of high-quality, reliable patient reported outcome (PRO) data entered directly by electronic means, ePRO, compared to data entered from original results on paper. Clinical trial managers are increasingly using ePRO data collection for PRO-based end points. Regulatory review dictates the rules to follow with ePRO data collection for medical label claims. A critical component for regulatory compliance is evidence of the validation of these electronic data collection systems. Validation of electronic systems is a process versus a focused activity that finishes at a single point in time. Eight steps need to be described and undertaken to qualify the validation of the data collection software in its target environment: requirements definition, design, coding, testing, tracing, user acceptance testing, installation and configuration, and decommissioning. These elements are consistent with recent regulatory guidance for systems validation. This report was written to explain how the validation process works for sponsors, trial teams, and other users of electronic data collection devices responsible for verifying the quality of the data entered into relational databases from such devices. It is a guide on the requirements and documentation needed from a data collection systems provider to demonstrate systems validation. It is a practical source of information for study teams to ensure that ePRO providers are using system validation and implementation processes that will ensure the systems and services: operate reliably when in practical use; produce accurate and complete data and data files; support management control and comply with any existing regulations. Furthermore, this short report will increase user understanding of the requirements for a technology review leading to more informed and balanced recommendations or decisions on electronic data collection methods. PMID- 23796282 TI - Value of information analysis from a societal perspective: a case study in prevention of major depression. AB - OBJECTIVES: Productivity losses usually have a considerable impact on cost effectiveness estimates while their estimated values are often relatively uncertain. Therefore, parameters related to these indirect costs play a role in setting priorities for future research from a societal perspective. Until now, however, value of information analyses have usually applied a health care perspective for economic evaluations. Hence, the effect of productivity losses has rarely been investigated in such analyses. The aim of the current study therefore was to investigate the effects of including or excluding productivity costs in value of information analyses. METHODS: Expected value of information analysis (EVPI) was performed in cost-effectiveness evaluation of prevention from both societal and health care perspectives, to give us the opportunity to compare different perspectives. Priorities for future research were determined by partial EVPI. The program to prevent major depression in patients with subthreshold depression was opportunistic screening followed by minimal contact psychotherapy. RESULTS: The EVPI indicated that regardless of perspective, further research is potentially worthwhile. Partial EVPI results underlined the importance of productivity losses when a societal perspective was considered. Furthermore, priority setting for future research differed according to perspective. CONCLUSIONS: The results illustrated that advise for future research will differ for a health care versus a societal perspective and hence the value of information analysis should be adjusted to the perspective that is relevant for the decision makers involved. The outcomes underlined the need for carefully choosing the suitable perspective for the decision problem at hand. PMID- 23796283 TI - Cost-effectiveness of new oral anticoagulants compared with warfarin in preventing stroke and other cardiovascular events in patients with atrial fibrillation. AB - OBJECTIVES: The primary objective was to assess the cost-effectiveness of new oral anticoagulants compared with warfarin in patients with nonvalvular atrial fibrillation. Secondary objectives related to assessing the cost-effectiveness of new oral anticoagulants stratified by center-specific time in therapeutic range, age, and CHADS2 score. METHODS: Cost-effectiveness was assessed by the incremental cost per quality-adjusted life-year (QALY) gained. Analysis used a Markov cohort model that followed patients from initiation of pharmacotherapy to death. Transition probabilities were obtained from a concurrent network meta analysis. Utility values and costs were obtained from published data. Numerous deterministic sensitivity analyses and probabilistic analysis were conducted. RESULTS: The incremental cost per QALY gained for dabigatran 150 mg versus warfarin was $20,797. Apixaban produced equal QALYs at a higher cost. Dabigatran 110 mg and rivaroxaban were dominated by dabigatran 150 mg and apixaban. Results were sensitive to the drug costs of apixaban, the time horizon adopted, and the consequences from major and minor bleeds with dabigatran. Results varied by a center's average time in therapeutic range, a patient's CHADS2 score, and patient age, with either dabigatran 150 mg or apixaban being optimal. CONCLUSIONS: Results were highly sensitive to patient characteristics. Rivaroxaban and dabigatran 110 mg were unlikely to be cost-effective. For different characteristics, apixaban or dabigatran 150 mg were optimal. Thus, the choice between these two options may come down to the price of apixaban and further evidence on the impact of major and minor bleeds with dabigatran. PMID- 23796284 TI - Cost-effectiveness of trabectedin plus pegylated liposomal doxorubicin for the treatment of women with relapsed platinum-sensitive ovarian cancer in the UK: analysis based on the final survival data of the OVA-301 trial. AB - OBJECTIVES: To estimate the cost-effectiveness of trabectedin plus pegylated liposomal doxorubicin (PLD) compared with PLD alone for the treatment of patients with relapsed platinum-sensitive ovarian cancer who are not expected to benefit from retreatment with platinum-based therapies based on the final survival data published in October 2012. METHODS: A decision-analytic model estimated the cost per quality-adjusted life-year (QALY) gained for trabectedin plus PLD compared with PLD alone from the UK National Health Service and Personal Social Services perspective over a lifetime horizon. Mean progression-free survival and overall survival were calculated by using parametric survival distributions adjusted for imbalances discovered in the final survival data. Between-arm imbalances included the platinum-free interval, cancer antigen 125 (CA-125), and Eastern Cooperative Oncology Group performance score. Cost categories included drug, administration, medical management, and treatment of adverse events. Quality of life was measured by using the EuroQol five-dimensional questionnaire. Uncertainty was addressed by deterministic and probabilistic sensitivity analysis. RESULTS: Over a lifetime horizon, trabectedin plus PLD increased mean progression-free survival by 3.0 months and overall survival by 9.7 months compared with PLD alone. The additional cost and QALYs of trabectedin plus PLD were L18,476 and 0.49, resulting in an incremental cost-effectiveness ratio of L38,026 per QALY. Sensitivity analyses showed that results were sensitive to platinum-free interval adjustment and the choice of survival distributions. CONCLUSIONS: The analysis estimated a significant improvement in mean overall survival and incremental cost per QALY compared with that calculated in the original National Institute for Health and Clinical Excellence assessment, which was based on immature survival data. PMID- 23796285 TI - Cost-effectiveness of early assisted discharge for COPD exacerbations in The Netherlands. AB - OBJECTIVES: Hospital admissions for exacerbations of chronic obstructive pulmonary disease are the main cost drivers of the disease. An alternative is to treat suitable patients at home instead of in the hospital. This article reports on the cost-effectiveness and cost-utility of early assisted discharge in The Netherlands. METHODS: In the multicenter randomized controlled Assessment of GOing Home under Early Assisted Discharge trial (n = 139), one group received 7 days of inpatient hospital treatment (HOSP) and one group was discharged after 3 days and treated at home by community nurses for 4 days. Health care resource use, productivity losses, and informal care were recorded in cost questionnaires. Microcosting was performed for inpatient day costs. RESULTS: Seven days after admission, mean change from baseline Clinical Chronic Obstructive Pulmonary Disease Questionnaire score was better for HOSP, but not statistically significantly: 0.29 (95% confidence interval [CI]-0.04 to 0.61). The difference in the probability of having a clinically relevant improvement was significant in favor of HOSP: 19.0%-point (95% CI 0.5%-36.3%). After 3 months of follow-up, differences in effectiveness had almost disappeared. The difference in quality adjusted life-years was 0.0054 (95% CI-0.021 to 0.0095). From a health care perspective, early assisted discharge was cost saving:-?244 (treatment phase, 95% CI-?315 to-?168) and-?168 (3 months, 95% CI-?1253 to ?922). Societal perspective: ?65 (treatment phase, 95% CI-?152 to ?25) and ?908 (3 months, 95% CI-?553 to ?2296). The savings per quality-adjusted life-year lost were ?31,111 from a health care perspective. From a societal perspective, HOSP was dominant. CONCLUSIONS: No clear evidence was found to conclude that either treatment was more effective or less costly. PMID- 23796286 TI - Probability elicitation to inform early health economic evaluations of new medical technologies: a case study in heart failure disease management. AB - OBJECTIVES: Early estimates of the commercial headroom available to a new medical device can assist producers of health technology in making appropriate product investment decisions. The purpose of this study was to illustrate how this quantity can be captured probabilistically by combining probability elicitation with early health economic modeling. The technology considered was a novel point of-care testing device in heart failure disease management. METHODS: First, we developed a continuous-time Markov model to represent the patients' disease progression under the current care setting. Next, we identified the model parameters that are likely to change after the introduction of the new device and interviewed three cardiologists to capture the probability distributions of these parameters. Finally, we obtained the probability distribution of the commercial headroom available per measurement by propagating the uncertainty in the model inputs to uncertainty in modeled outcomes. RESULTS: For a willingness-to-pay value of ?10,000 per life-year, the median headroom available per measurement was ?1.64 (interquartile range ?0.05-?3.16) when the measurement frequency was assumed to be daily. In the subsequently conducted sensitivity analysis, this median value increased to a maximum of ?57.70 for different combinations of the willingness-to-pay threshold and the measurement frequency. CONCLUSIONS: Probability elicitation can successfully be combined with early health economic modeling to obtain the probability distribution of the headroom available to a new medical technology. Subsequently feeding this distribution into a product investment evaluation method enables stakeholders to make more informed decisions regarding to which markets a currently available product prototype should be targeted. PMID- 23796287 TI - Evaluating the cost-effectiveness of diagnostic tests in combination: is it important to allow for performance dependency? AB - OBJECTIVES: To investigate the importance of accounting for potential performance dependency when evaluating the cost-effectiveness of two diagnostic tests used in combination. METHODS: Two meta-analysis models were fitted to estimate the diagnostic accuracy of Wells score and Ddimer in combination. The first model assumes that the two tests perform independently of one another; thus, two separate meta-analyses were fitted to the Ddimer and Wells score data and then combined. The second model allows for any performance dependency of the two tests by incorporating published data on the accuracy of Ddimer stratified by Wells score, as well as studies of Ddimer alone and Wells score alone. The results from the two meta-analysis models were input into a decision model to assess the impact that assumptions regarding performance dependency have on the overall cost effectiveness of the tests. RESULTS: The results highlight the importance of accounting for potential performance dependency when evaluating the cost effectiveness of diagnostic tests used in combination. In our example, assuming the diagnostic performance of the two tests to be independent resulted in the strategy "Wells score moderate/high risk treated for DVT and Wells score low risk tested further with Ddimer" being identified as the most cost-effective at the L20,000 willingness-to-pay threshold (probability cost-effective 0.8). However, when performance dependency is modeled, the most cost-effective strategies were "Ddimer alone" and "Wells score low/moderate risk discharged and Wells score high risk further tested with Ddimer" (probability cost-effective 0.4). CONCLUSIONS: When evaluating the effectiveness and cost-effectiveness of diagnostic tests used in combination, failure to account for diagnostic performance dependency may lead to erroneous results and nonoptimal decision making. PMID- 23796288 TI - Using whole disease modeling to inform resource allocation decisions: economic evaluation of a clinical guideline for colorectal cancer using a single model. AB - OBJECTIVE: To assess the feasibility and value of simulating whole disease and treatment pathways within a single model to provide a common economic basis for informing resource allocation decisions. METHODS: A patient-level simulation model was developed with the intention of being capable of evaluating multiple topics within National Institute for Health and Clinical Excellence's colorectal cancer clinical guideline. The model simulates disease and treatment pathways from preclinical disease through to detection, diagnosis, adjuvant/neoadjuvant treatments, follow-up, curative/palliative treatments for metastases, supportive care, and eventual death. The model parameters were informed by meta-analyses, randomized trials, observational studies, health utility studies, audit data, costing sources, and expert opinion. Unobservable natural history parameters were calibrated against external data using Bayesian Markov chain Monte Carlo methods. Economic analysis was undertaken using conventional cost-utility decision rules within each guideline topic and constrained maximization rules across multiple topics. RESULTS: Under usual processes for guideline development, piecewise economic modeling would have been used to evaluate between one and three topics. The Whole Disease Model was capable of evaluating 11 of 15 guideline topics, ranging from alternative diagnostic technologies through to treatments for metastatic disease. The constrained maximization analysis identified a configuration of colorectal services that is expected to maximize quality adjusted life-year gains without exceeding current expenditure levels. CONCLUSIONS: This study indicates that Whole Disease Model development is feasible and can allow for the economic analysis of most interventions across a disease service within a consistent conceptual and mathematical infrastructure. This disease-level modeling approach may be of particular value in providing an economic basis to support other clinical guidelines. PMID- 23796289 TI - Examining item content and structure in health status and health outcomes instruments: toward the development of a grammar for better understanding of the concepts being measured. AB - OBJECTIVES: Health outcomes instruments assess diverse health concepts. Although item-level concepts are considered fundamental elements, the field lacks structures for evaluating and organizing them for decision making. This article proposes a grammar using item stems, response options, and recall periods to systematically identify item-level concepts. The grammar uses "core concept," "evaluative component," and "recall period" as intuitive terms for communicating with stakeholders. Better characterization of concepts is necessary for classifying instrument content and linking it to treatment benefit. METHODS: Items in 2 generic and 21 disease-specific instruments were evaluated to develop and illustrate the use of the grammar. Concepts were assigned International Classification of Functioning, Disability and Health codes for exploring the value that the grammar and a classification system add to the understanding of content across instruments. RESULTS: The 23 instruments include many core concepts; emotional function is the only concept assessed in all instruments. Concepts in disease-specific instruments show obvious patterns; for example, arthritis instruments focus on physical function. The majority of instruments used the same response options across all items, with five-point scales being the most common. Most instruments used one recall period for all items. Shorter recall periods were used for conditions associated with "flares," such as chronic obstructive pulmonary disease and "skin disease." Every diagnosis, however, showed variation across instruments in the recall period used. CONCLUSIONS: This analysis indicates the proposed grammar's potential for discerning the conceptual content within and between health outcomes instruments and illustrates its value for improving communication between stakeholders and for making decisions related to treatment benefit. PMID- 23796290 TI - The mental component of the short-form 12 health survey (SF-12) as a measure of depressive disorders in the general population: results with three alternative scoring methods. AB - OBJECTIVES: To evaluate the performance of the Mental Component of the Short-Form 12 Health Survey, Version 1(SF-12v1), as a screening measure of depressive disorders. METHODS: Data come from the European Study of the Epidemiology of Mental Disorders (ESEMeD), a cross-sectional survey carried out on representative samples of 21,425 individuals from the noninstitutionalized adult general population of six European countries (response rate = 61.2%). The SF-12 was administered and scored according to three algorithms: the "original" method (mental component summary of SF-12 [MCS-12]), the RAND-12 (RAND-12 Mental Health Composite [RAND-12 MHC]), and the Bidemensional Response Process Model 12 mental health score (BRP-12 MHS), based on a two-factor Item Response Theory graded response model. Thirty-day and 12-month depressive disorders (major depressive episode or dysthymia) were assessed with the Composite International Diagnostic Interview, Version 3.0, by using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria. Receiver operating characteristic curves analysis was carried out, and optimal cutoff points maximizing balance between sensitivity (SN) and specificity (SP) were chosen for the three methods. RESULTS: Prevalence of 30-day and 12-month depressive disorders in the overall sample was 1.5% and 4.4%, respectively. The area under the curve for 30-day depressive disorders was 0.92, and it decreased to 0.85 for 12-month disorders, regardless of the scoring method. Optimal cutoff for 30-day depressive disorders was 45.6 (SN = 0.86; SP = 0.88) for the MCS-12, 44.5 for the RAND-12 MHC (SN = 0.87, SP = 0.86), and 40.2 for the BRP-12 MHS (SN = 0.87, SP = 0.87). The selected 12-month cutoffs for MCS-12 and RAND-12 MHC were between 4.2 and 5.8 points below the general population means of each country, with SN range 0.67 to 0.78 and SP range 0.77 to 0.87. CONCLUSIONS: The SF-12 yielded acceptable results for detecting both active and recent depressive disorders in general population samples, suggesting that the questionnaire could be used as a useful screening tool for monitoring the prevalence of affective disorders and for targeting treatment and prevention. PMID- 23796291 TI - Health-related quality of life of ticagrelor versus clopidogrel in patients with acute coronary syndromes-results from the PLATO trial. AB - OBJECTIVES: The purpose of this study was to compare the effects of ticagrelor versus clopidogrel on health-related quality of life in the PLATelet inhibition and patient Outcomes (PLATO) trial. BACKGROUND: The PLATO trial showed that ticagrelor was superior to clopidogrel for the prevention of cardiovascular death, myocardial infarction, or stroke in a broad population of patients with acute coronary syndromes. METHODS: HRQOL in the PLATO study was measured at hospital discharge, 6-month visit, and end of treatment (anticipated at 12 months) by using the EuroQol five-dimensional (EQ-5D) questionnaire. All patients who had an EQ-5D questionnaire assessment at discharge from the index hospitalization (n = 15,212) were included in the study. Patients who died prior to the end-of-treatment visit were assigned an EQ-5D questionnaire value of 0. RESULTS: The EQ-5D questionnaire value at discharge among 7631 patients assigned to ticagrelor was 0.847 and among 7581 patients assigned to clopidogrel was 0.846 (P = 0.71). At 12 months, the mean EQ-5D questionnaire value was 0.840 for ticagrelor and 0.832 for clopidogrel (P = 0.046). Excluding patients who died resulted in mean EQ-5D questionnaire values of 0.864 among ticagrelor patients and 0.863 among clopidogrel patients (P = 0.69). CONCLUSIONS: In patients hospitalized with acute coronary syndromes with or without ST-segment elevation, treatment with ticagrelor was associated with a lower mortality but otherwise no difference in quality of life relative to treatment with clopidogrel. The improved survival and reduction in cardiovascular events with ticagrelor are therefore obtained with no loss in quality of life. PMID- 23796292 TI - QALY and productivity loss: empirical evidence for "double counting". AB - OBJECTIVES: When quality-adjusted life-years are used for economic evaluation, the controversial issue of "double counting" of productivity loss emerges, particularly given the lack of empirical data. METHODS: In this study, we performed a Web-based, large-sample survey to address the issue of double counting. To determine the influence of income reduction on utility scores, we obtained utility scores of eight health states with three instruction types: a) no instruction, b) instructed to consider income reduction, and c) instructed not to consider income reduction (compensated). Respondents were randomly sampled from the online panel and asked to evaluate 1 of 24 patterns by both standard gamble and time trade-off methods. RESULTS: A total of 6551 respondents completed the questionnaire. First, despite the lack of instruction on income reduction, many respondents spontaneously assumed lost income. The proportion tended to be higher when considering more severe health states. Second, the degree of assumed income reduction was related to utility scores. For a 10% income reduction, respondents assumed a 0.02- to 0.04-decrease in utility score (both standard gamble and time trade-off methods). Third, utility scores did not change significantly when instruction was given not to consider income reduction (compensated) compared with when no instruction was given. CONCLUSIONS: An assumed income reduction clearly influenced utility scores; however, compensation for lost income failed to sufficiently improve utility scores. In our view, the effect of income on utility scores does not only reflect wage loss. Our results suggest that the impact of double counting is negligible. PMID- 23796293 TI - Assessing the value of symptom relief for patients with gastroesophageal reflux disease treatment: willingness to pay using a discrete choice experiment. AB - OBJECTIVES: To assess patients' preferences and estimate willingness to pay (WTP) for gastroesophageal reflux disease (GERD) treatments. METHOD: Patients were randomly selected from a multicenter clinical study to participate in the discrete choice experiment (DCE) survey. Relevant treatment attributes were identified through literature review, clinical expert consultation, and focus groups. The DCE included 14 choice tasks composed of six attributes, three treatment profiles, and a "none"option considering orthogonality, D-efficiency, and level balance, while keeping patient response burden reasonable. Individual level preferences and WTP were estimated by aggregate-level conditional logit and hierarchical Bayes analyses. RESULTS: Our sample of 361, drawn from a clinical trial, had a mean age of 57 years, were primarily women (53%), and rated their GERD symptoms as mild/moderate (31%) and moderately severe/severe (7%). Most important attributes of GERD treatment were (in order) as follows: avoiding side effects, sleeping discomfort, daytime discomfort, dietary changes, medication cost, and treatment frequency. Simulations found that patients are willing to pay an additional US $36 to reduce susceptibility to side effects from moderate to mild or to decrease the frequency of sleeping discomfort. Patients 65 years or older were willing to pay less for daytime discomfort relief, while women would pay more to avoid sleeping discomfort. CONCLUSIONS: Key factors concerning patients with GERD and their preference for treatment features to control GERD symptoms were confirmed. A DCE estimated WTP by GERD sufferers for relief from symptoms and avoidance of side effects using relevant treatment costs. These findings may help guide clinical treatment decisions for individual patients to improve GERD symptom control. PMID- 23796294 TI - Using a survey to estimate health expectancy and quality-adjusted life expectancy to assess inequalities in health and quality of life. AB - BACKGROUND: There has been a policy debate in the United Kingdom about moving beyond traditional measures of life expectancy and economic output to developing more meaningful ways of measuring national well-being. OBJECTIVE: To test whether quality adjusted life expectancy (QALE) was a useful indicator of health inequalities. METHODS: EuroQol five-dimensional questionnaire data from a well being survey was combined with actuarial life expectancy (LE) data to estimate healthy LE (HLE), that is, years of life lived in good health, and QALE, that is, quality-adjusted life-years (QALYs) lived for Wirral, a borough in the north west of England. RESULTS: The gap between Wirral and the most deprived areas was 4.45 years for LE, 5.34 for QALE, and 7.55 for HLE. The gap in QALE was 20% greater than the gap in LE, while the gap in HLE was 70% greater. CONCLUSIONS: The fact that the QALE gap value lies between the HLE value and the LE value suggests that QALE is a more sensitive indicator than HLE, as in this study QALE is derived from 243 possible EuroQol five-dimensional questionnaire profiles whereas HLE is based only on whether or not an individual rates his or her health as good, a binary variable. This study discusses how QALE could be a useful indicator for measuring health inequalities in future, especially as cost utility and QALYs are seen as the gold standard used by the National Institute for Health and Clinical Excellence in the United Kingdom to measure outcomes for health interventions in England, and discusses how a monetary valuation of QALYs could be used to put a societal cost on health inequalities. PMID- 23796295 TI - Estimating the effectiveness of HPV vaccination in the open population: a Bayesian approach. AB - OBJECTIVES: Estimation of the effectiveness of human papillomavirus (HPV) vaccination in the open population on the basis of published data from various sources. METHODS: A Bayesian approach was used to reanalyze the data underlying a guidance by the Dutch National Health Insurance Board about the quadrivalent HPV vaccine Gardasil. Several studies document the vaccine's effectiveness in preventing cases in different subpopulations. None of these (sub)populations, however, is representative of the actual target population that the vaccination program will be applied to. We used a Bayesian approach for restructuring the data by means of reweighting the subpopulations by using HPV prevalence data, to estimate the effectiveness that can be expected in the actual target population. RESULTS: The original data show an effectiveness of 44% in the entire population and an effectiveness of 98% for women who were compliant and were HPV-free at the start of the study. In the study population, the HPV prevalence was below 4%. In the relevant target population, however, the actual prevalence could be very different. In fact, some publications find an HPV prevalence of around 10%. We used Bayesian techniques to estimate the effectiveness in the actual target population. We found a mean effectiveness of 25%, and the probability that the effectiveness in the target population exceeds 50% is virtually zero. The results are very sensitive to the HPV prevalence that is used. CONCLUSIONS: A supplementary analysis can put together the bits and pieces of information to arrive at more relevant answers. A Bayesian approach allows for integrating all the evidence into one model in a straightforward way and results in very intuitive probability statements. PMID- 23796297 TI - Meta-analysis of the accuracy of two diagnostic tests used in combination: application to the ddimer test and the wells score for the diagnosis of deep vein thrombosis. AB - OBJECTIVES: It is standard practice for diagnostic tests to be evaluated against gold standards in isolation. In routine clinical practice, however, it is commonplace for multiple tests to be used before making definitive diagnoses. This article describes a meta-analytic modeling framework developed to estimate the accuracy of the combination of two diagnostic tests, accounting for the likely nonindependence of the tests. METHODS: A novel multicomponent framework was developed to synthesize information available on different parameters in the model. This allows data to be included from studies evaluating single tests or both tests. Different likelihoods were specified for the different sources of data and linked by means of common parameters. The framework was applied to evaluate the diagnostic accuracy of the Ddimer test and the Wells score for deep vein thrombosis, and the results were compared with those of a model in which independence of tests was assumed. All models were evaluated by using Bayesian Markov chain Monte Carlo simulation methods. RESULTS: The results showed the importance of allowing for the (likely) nonindependence of tests in the meta analysis model when evaluating a combination of diagnostic tests. The analysis also highlighted the relatively limited impact of those studies that evaluated only one of the two tests of interest. CONCLUSIONS: The models developed allowed the assumption of independence between diagnostic tests to be relaxed while combining a broad array of relevant information from disparate studies. The framework also raises questions regarding the utility of studies limited to the evaluation of single diagnostic tests. PMID- 23796296 TI - Radical cystectomy versus bladder-preserving therapy for muscle-invasive urothelial carcinoma: examining confounding and misclassification biasin cancer observational comparative effectiveness research. AB - OBJECTIVES: Radical cystectomy (RC) is the standard treatment for muscle-invasive urothelial carcinoma of the bladder. Trimodality bladder-preserving therapy (BPT) is an alternative to RC, but randomized comparisons of RC versus BPT have proven infeasible. To compare RC versus BPT, we undertook an observational cohort study using registry and administrative claims data from the Surveillance, Epidemiology and End Results-Medicare database. METHODS: We identified patients age 65 years or older diagnosed between 1995 and 2005 who received RC (n = 1426) or BPT (n = 417). We examined confounding and stage misclassification in the comparison of RC and BPT by using multivariable adjustment, propensity score-based adjustment, instrumental variable (IV) analysis, and simulations. RESULTS: Patients who received BPT were older and more likely to have comorbid disease. After propensity score adjustment, BPT was associated with an increased hazard of death from any cause (hazard ratio [HR] 1.26; 95% confidence interval [CI] 1.05-1.53) and from bladder cancer (HR 1.31; 95% CI 0.97-1.77). Using the local area cystectomy rate as an instrument, IV analysis demonstrated no differences in survival between BPT and RC (death from any cause HR 1.06; 95% CI 0.78-1.31; death from bladder cancer HR 0.94; 95% CI 0.55-1.18). Simulation studies for stage misclassification yielded results consistent with the IV analysis. CONCLUSIONS: Survival estimates in an observational cohort of patients who underwent RC versus BPT differ by analytic method. Multivariable and propensity score adjustment revealed greater mortality associated with BPT relative to RC, while IV analysis and simulation studies suggest that the two treatments are associated with similar survival outcomes. PMID- 23796298 TI - Illustrating potential efficiency gains from using cost-effectiveness evidence to reallocate Medicare expenditures. AB - OBJECTIVES: The Centers for Medicare & Medicaid Services does not explicitly use cost-effectiveness information in national coverage determinations. The objective of this study was to illustrate potential efficiency gains from reallocating Medicare expenditures by using cost-effectiveness information, and the consequences for health gains among Medicare beneficiaries. METHODS: We included national coverage determinations from 1999 through 2007. Estimates of cost effectiveness were identified through a literature review. For coverage decisions with an associated cost-effectiveness estimate, we estimated utilization and size of the "unserved" eligible population by using a Medicare claims database (2007) and diagnostic and reimbursement codes. Technology costs originated from the cost effectiveness literature or were estimated by using reimbursement codes. We illustrated potential aggregate health gains from increasing utilization of dominant interventions (i.e., cost saving and health increasing) and from reallocating expenditures by decreasing investment in cost-ineffective interventions and increasing investment in relatively cost-effective interventions. RESULTS: Complete information was available for 36 interventions. Increasing investment in dominant interventions alone led to an increase of 270,000 quality-adjusted life-years (QALYs) and savings of $12.9 billion. Reallocation of a broader array of interventions yielded an additional 1.8 million QALYs, approximately 0.17 QALYs per affected Medicare beneficiary. Compared with the distribution of resources prior to reallocation, following reallocation a greater proportion was directed to oncology, diagnostic imaging/tests, and the most prevalent diseases. A smaller proportion of resources went to cardiology, treatments (including drugs, surgeries, and medical devices, as opposed to nontreatments such as preventive services), and the least prevalent diseases. CONCLUSIONS: Using cost-effectiveness information has the potential to increase the aggregate health of Medicare beneficiaries while maintaining existing spending levels. PMID- 23796299 TI - Measuring the quality of a childhood cancer care delivery system: assessing stakeholder agreement. AB - OBJECTIVES: We described previously the development of a set of quality indicators (QIs) of a childhood cancer system in Ontario, Canada. The purpose of this study was to determine the acceptability of the proposed set of QIs among stakeholders of the childhood cancer system. METHODS: A modified Delphi method was used to assess stakeholder agreement on the value of the proposed QIs. A QI evaluation survey was mailed to a stakeholder group of 23 multidisciplinary health care providers, survivors, parents, and policymakers who rated each QI on specific criteria. Prior to an in-person consensus meeting, the distribution of scores was provided to panel members. At the meeting, QIs were reevaluated and discussed in three successive rounds. QIs with 80% or more of panel agreement were considered endorsed. RESULTS: Overall, 20 QIs were endorsed by the panel, measuring all seven quality dimensions of Ontario's Cancer System Quality Index framework. Five QIs were endorsed by 100% of the panel as follows: Five-year event-free survival, chemotherapy admission delay, drug availability, sufficient multidisciplinary staff, and parent satisfaction. Although none of the QIs relating to end-of-life or Satellite care were endorsed, panel members emphasized the need to measure these components of the system. CONCLUSIONS: Standardized implementation of the 20 pediatric cancer QIs endorsed by the multidisciplinary stakeholder panel will provide ongoing monitoring of various dimensions of system quality and the development of benchmarks over time, greatly augmenting the ability to identify needed system improvements across populations and jurisdictions. PMID- 23796300 TI - Measuring the quality of a childhood cancer care delivery system: quality indicator development. AB - OBJECTIVES: A set of indicators to assess the quality of a childhood cancer system has not been identified in any jurisdiction internationally, despite the movement toward increased accountability and provision of high-quality care with limited health care resources. This study was conducted to develop a set of quality indicators (QIs) of a childhood cancer control and health care delivery system in Ontario, Canada. METHODS: A systematic review and targeted gray literature search were conducted to identify potential childhood cancer QIs. A series of investigator focus group sessions followed to review all QIs identified in the literature, and to generate a provisional QI set for a childhood cancer system. QIs were evaluated by three content experts in a sequential selection process on the basis of a series of criteria to select a subset for presentation to stakeholders. Following an appraisal of the relevance of quality assessment frameworks, remaining QIs were mapped onto the Cancer System Quality Index framework. RESULTS: The systematic review yielded few relevant childhood cancer system QIs. Overall, 120 provisional QIs were developed by the investigator group. Based on median QI rating scores, representation across the childhood cancer continuum, and feasibility of data collection, a subset of 33 QIs was selected for stakeholder consideration. CONCLUSIONS: The subset of 33 QIs developed on the basis of a systematic literature review and consensus provides the basis for the selection of a set of QIs for ongoing, standardized monitoring of various dimensions of quality in a childhood cancer system. PMID- 23796301 TI - A checklist for ascertaining study cohorts in oncology health services research using secondary data: report of the ISPOR oncology good outcomes research practices working group. AB - OBJECTIVES: The ISPOR Oncology Special Interest Group formed a working group at the end of 2010 to develop standards for conducting oncology health services research using secondary data. The first mission of the group was to develop a checklist focused on issues specific to selection of a sample of oncology patients using a secondary data source. METHODS: A systematic review of the published literature from 2006 to 2010 was conducted to characterize the use of secondary data sources in oncology and inform the leadership of the working group prior to the construction of the checklist. A draft checklist was subsequently presented to the ISPOR membership in 2011 with subsequent feedback from the larger Oncology Special Interest Group also incorporated into the final checklist. RESULTS: The checklist includes six elements: identification of the cancer to be studied, selection of an appropriate data source, evaluation of the applicability of published algorithms, development of custom algorithms (if needed), validation of the custom algorithm, and reporting and discussions of the ascertainment criteria. The checklist was intended to be applicable to various types of secondary data sources, including cancer registries, claims databases, electronic medical records, and others. CONCLUSIONS: This checklist makes two important contributions to oncology health services research. First, it can assist decision makers and reviewers in evaluating the quality of studies using secondary data. Second, it highlights methodological issues to be considered when researchers are constructing a study cohort from a secondary data source. PMID- 23796302 TI - Computer modeling of diabetes and its complications: a report on the Fifth Mount Hood challenge meeting. AB - OBJECTIVES: The Mount Hood Challenge meetings provide a forum for computer modelers of diabetes to discuss and compare models, to assess predictions against data from clinical trials and other studies, and to identify key future developments in the field. This article reports the proceedings of the Fifth Mount Hood Challenge in 2010. METHODS: Eight modeling groups participated. Each group was given four modeling challenges to perform (in type 2 diabetes): to simulate a trial of a lipid-lowering intervention (The Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus [ASPEN]), to simulate a trial of a blood glucose-lowering intervention (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation [ADVANCE]), to simulate a trial of a blood pressure lowering intervention (Cardiovascular Risk in Diabetes [ACCORD]), and (optional) to simulate a second trial of blood glucose-lowering therapy (ACCORD). Model outcomes for each challenge were compared with the published findings of the respective trials. RESULTS: The results of the models varied from each other and, in some cases, from the published trial data in important ways. In general, the models performed well in terms of predicting the relative benefit of interventions, but performed less well in terms of quantifying the absolute risk of complications in patients with type 2 diabetes. Methodological challenges were highlighted including matching trial end-point definitions, the importance of assumptions concerning the progression of risk factors over time, and accurately matching the patient characteristics from each trial. CONCLUSIONS: The Fifth Mount Hood Challenge allowed modelers, through systematic comparison and validation exercises, to identify important differences between models, address key methodological challenges, and discuss avenues of research to improve future diabetes models. PMID- 23796303 TI - Systematic searching and selection of health state utility values from the literature. AB - Health state utility values (HSUVs) are important parameters in decision models in health technology assessment submissions. Reimbursement agencies, such as the National Institute for Health and Clinical Excellence, recognize that such values are obtainable from the published literature. However, to use published values in health technology assessment submissions, it should be demonstrated that HSUVs have been identified and selected systematically to avoid using biased HSUVs resulting in cost-effectiveness analyses. This article presents guidance on how to conduct a systematic literature review to identify and select HSUVs from the published literature based on the authors' experience. A case study is used to demonstrate some of the features of a systematic HSUV review. Methods are discussed in relation to identifying and selecting the evidence, performing quality and relevance assessment, and undertaking data extraction. It has been developed from a Technical Support Document produced for the National Institute for Health and Clinical Excellence by the Decision Support Unit at the School of Health and Related Research, University of Sheffield. PMID- 23796304 TI - Comparative effectiveness in personalized medicine-clearly defining the intended use population. PMID- 23796305 TI - Authors' response to "comparative effectiveness and personalized medicine" by Dr. J.C. Hornberger. PMID- 23796306 TI - A possible simplification of the Goss-modified Abraham solvation equation. AB - Abraham solvation equations find widespread use in environmental chemistry and pharmaco-chemistry. Recently Goss proposed a modified Abraham solvation equation. For various partitioning processes, the present study investigates the consequences for the fit when the Abraham solvation parameter V is left out of this modified solvation equation. For air-organic solvent partition, the Abraham solvation parameter V can be omitted from the Goss-modified Abraham solvation equation without any loss of statistical quality. For air-water partitioning, organic biphasic system partitioning, as well as water-organic solvent partitioning, omitting the V parameter from the Goss-modified Abraham solvation equation leads to only a small deterioration of statistic quality. PMID- 23796307 TI - Effects of dissolved organic matter on adsorbed Fe(II) reactivity for the reduction of 2-nitrophenol in TiO2 suspensions. AB - Dissolved organic matter (DOM) is widespread in aquatic and terrestrial environments. Iron is the most abundant transition metal in the Earth's crust. The biogeochemistry of iron and the strength of Fe(II) as a reducing agent while adsorbed on minerals are affected by DOM. This study investigated the effects of Fe(II)/DOM interactions on the reduction of 2-nitrophenol (2-NP) in TiO2 suspensions. Kinetic measurements demonstrated that rates (k) of 2-NP reduction by adsorbed Fe(II) species are affected by adding DOM (denoted O-DOM), and the obtained k values under the impact of the Fe(II)/DOM interaction with different molecular weight DOM fractions [including MW<3500Da (L-DOM), 350014000Da (H-DOM)] showed significant differences. The enhanced rates of 2-NP reduction contributed to increases in the amount of adsorbed Fe(II) species and negative shifts in peak oxidation potential values (EP) in CV tests. For different molecular weight DOM fractions, increases in k (O-DOM= 7.8 mmol/L. The newborns of mothers with a GCT >= 7.8 mmol/L had significantly higher level of FNSI ([kg/m(2)], boys: 1.336 versus 1.296, p < 0.001; girls: 1.312 versus 1.268, p < 0.0001). Logistic regression results, after adjustment for maternal age, residence, education, nationality, history of disease and reproduction, insurance and gestational age, indicated that every unit increase in FNSI was associated with approximately threefold higher odds (OR [95% CI]: 3.6 [1.5, 8.9]) of being in GCT >= 7.8 mmol/L for women giving birth as boys and fivefold higher odds (5.9 [2.5, 14.1]) for giving birth as girls. CONCLUSIONS: Women with a GCT >= 7.8 mmol/L have babies with a higher FNSI, suggesting that these infants may be overnourished before birth and may increase cardiovascular risk in their future. PMID- 23796320 TI - Identification of a serine protease inhibitor which causes inclusion vacuole reduction and is lethal to Chlamydia trachomatis. AB - The mechanistic details of the pathogenesis of Chlamydia, an obligate intracellular pathogen of global importance, have eluded scientists due to the scarcity of traditional molecular genetic tools to investigate this organism. Here we report a chemical biology strategy that has uncovered the first essential protease for this organism. Identification and application of a unique CtHtrA inhibitor (JO146) to cultures of Chlamydia resulted in a complete loss of viable elementary body formation. JO146 treatment during the replicative phase of development resulted in a loss of Chlamydia cell morphology, diminishing inclusion size, and ultimate loss of inclusions from the host cells. This completely prevented the formation of viable Chlamydia elementary bodies. In addition to its effect on the human Chlamydia trachomatis strain, JO146 inhibited the viability of the mouse strain, Chlamydia muridarum, both in vitro and in vivo. Thus, we report a chemical biology approach to establish an essential role for Chlamydia CtHtrA. The function of CtHtrA for Chlamydia appears to be essential for maintenance of cell morphology during replicative the phase and these findings provide proof of concept that proteases can be targeted for antimicrobial therapy for intracellular pathogens. PMID- 23796321 TI - Brain perfusion SPECT provides new insight on neurobiological effects of hyperbaric hyperoxia. PMID- 23796322 TI - Homoleptic "star" Ru(II) polypyridyl complexes: shielded chromophores to study charge-transfer at the sensitizer-TiO2 interface. AB - Three homoleptic star-shaped ruthenium polypyridyl complexes, termed Star YZ1, Star YZ2, and Star YZ3, where the Ru(II) center is coordinated to three bipyridine ligands each carrying two oligo(phenylene ethynylene) (OPE) rigid linker units terminating with isophthalic ester (Ipa) groups for binding to metal oxide surfaces were synthesized. In Star YZ3, each OPE linker was substituted with two n-butoxy (n-BuO) solubilizing groups. Star complex YZ4, which is homoleptic but lacks the octahedral symmetry, was synthesized as a reference compound. The Star complexes were synthesized using two approaches: in the first, Ru(4,4'-(Br)2-2,2'-bpy)3 was reacted in a Sonogashira cross coupling reaction with the ethynyl-OPE-Ipa linkers; in the second, the 2,2'-bpy-OPE-Ipa ligands were reacted with Ru(DMSO)4(PF6)2. The photophysical behavior of the Star complexes were studied in fluid solution and anchored to the surface of mesoporous nanocrystalline TiO2 thin films (Star/TiO2). To a first approximation the excited state behavior in CH3CN was unchanged when the compounds were anchored to a TiO2 thin film, indicating that the highly symmetrical (octahedral) and rigid molecular structure of the ligands shielded the chromophoric core from the TiO2 semiconductor. Inefficient excited state injection, phi(inj) < 0.05, was observed to occur on a nanosecond time scale with slow recombination. In addition, the presence of n-BuO groups on the linker unit gave a large increase in the extinction coefficient of YZ3, which allows for enhanced harvesting of sunlight. The results indicate that molecular design on the nanometer length scale can be utilized to control excited state relaxation pathways at semiconductor surfaces. PMID- 23796323 TI - A concise synthesis of xestospongic acid methyl ester with pancreatic lipase inhibitory activity. AB - Xestospongic acid methyl ester, a naturally brominated fatty acid with potent pancreatic lipase inhibitory activity in vitro, was synthesized from 5-hexynol in 30% total yield. PMID- 23796324 TI - Clinical and dermoscopic characteristics of new naevi in adults: results from a cohort study. AB - BACKGROUND: Naevogenesis is a process known to occur throughout life. To date, investigators have made conclusions about new naevi in adults based on results of cross-sectional studies. OBJECTIVES: To determine the incidence of new naevus development in adults and to describe the dermoscopic morphology of new naevi. METHODS: A cohort of 182 patients seen at the outpatient dermatology clinic at Memorial Sloan-Kettering Cancer Center between 2000 and 2009 was evaluated with baseline total body photographs. The patients were aged 17 years or older and had presented for routine follow-up surveillance examination at least 3 months after baseline total body photographs. The number of new naevi and the dermoscopic morphology of these naevi were recorded. RESULTS: Of the 182 patients evaluated, 50 (27%) developed at least one new naevus during follow-up. The incidence of new naevi was 202 per 1000 person-years of follow-up. The most common types of naevi were reticular (47.1%), followed by the homogeneous (22.1%) and complex (reticuloglobular) patterns (15.4%). CONCLUSIONS: Our results provide support for the theory that there are two distinct pathways of naevogenesis, a dynamic process occurring throughout life. This study demonstrates that the predominant dermoscopic morphology of newly acquired naevi in adults is reticular. PMID- 23796325 TI - Systematic review of genuine versus spurious side-effects of beta-blockers in heart failure using placebo control: recommendations for patient information. AB - BACKGROUND: Patients trying life-preserving agents such as beta-blockers may be discouraged by listings of harmful effects provided in good faith by doctors, drug information sheets, and media. We systematically review the world experience of side-effect information in blinded, placebo-controlled beta-blockade in heart failure. We present information for a physician advising a patient experiencing an unwanted symptom and suspecting the drug. METHODS: We searched Medline for double-blinded randomized trials of beta-blocker versus placebo in heart failure reporting side-effects. We calculated, per 100 patients reporting the symptom on beta-blockade, how many would have experienced it on placebo: the "proportion of symptoms non-pharmacological". RESULTS: 28 of the 33 classically-described side effects are not significantly more common on beta-blockers than placebo. Of the 100 patients developing dizziness on beta-blockers, 81 (95% CI 73-89) would have developed it on placebo. For diarrhoea this proportion is 82/100 (70-95), and hyperglycaemia 83/100 (68-98). For only two side-effects is this under half (i.e. predominantly due to beta-blocker): bradycardia (33/100, CI 21-44) and intermittent claudication (41/100, 2-81). At least 6 so-called side-effects are less common on beta-blocker than placebo, including depression (reduced by 35%, p<0.01) and insomnia (by 27%, p=0.01). CONCLUSIONS: Clinicians might reconsider whether it is scientifically and ethically correct to warn a patient that a drug might cause them a certain side-effect, when randomized controlled trials show no significant increase, or indeed a significant reduction. A better informed consultation could, in patients taking beta-blockers, alleviate suffering. In patients who might otherwise not take the drug, it might prevent deaths. PMID- 23796326 TI - Amphidynamic crystals of a steroidal bicyclo[2.2.2]octane rotor: a high symmetry group that rotates faster than smaller methyl and methoxy groups. AB - The synthesis, crystallization, single crystal X-ray structure, and solid state dynamics of molecular rotor 3 provided with a high symmetry order and relatively cylindrical bicyclo[2.2.2]octane (BCO) rotator linked to mestranol fragments were investigated in this work. By use of solid state (13)C NMR, three rotating fragments were identified within the molecule: the BCO, the C19 methoxy and the C18 methyl groups. To determine the dynamics of the BCO group in crystals of 3 by variable temperature (1)H spin-lattice relaxation (VT (1)H T1), we determined the (1)H T1 contributions from the methoxy group C19 by carrying out measurements with the methoxy-deuterated isotopologue rotor 3-d6. The contributions from the quaternary methyl group C18 were estimated by considering the differences between the VT (1)H T1 of mestranol 8 and methoxy-deuterated mestranol 8-d3. From these studies it was determined that the BCO rotator in 3 has an activation energy of only 1.15 kcal mol(-1), with a barrier for site exchange that is smaller than those of methyl (E(a) = 1.35 kcal mol(-1)) and methoxy groups (E(a) = 1.92 kcal mol(-1)), despite their smaller moments of inertia and surface areas. PMID- 23796327 TI - Radical lymphadenectomy in esophageal cancer: from the past to the present. AB - Lymphadenectomy as an essential part of the surgical treatment has been one of the most controversial aspects in the management of esophageal cancers. The purpose of this article was to review the evolution, the current role, and the optimal extent of lymphadenectomy for the treatment of esophageal cancers. Studies discussing the outcome of esophagectomy with lymph nodes dissection and comparing among different extent of lymphadenectomy were used in the analysis. Several studies including recently published articles reveal that additional radical lymphadenectomy may be beneficial in some patients with non-extreme esophageal cancer undergoing esophagectomy, whereas two-field lymph node dissection is suitable for distal esophageal cancers regardless of the histology of the tumor. Minimally invasive surgery and neoadjuvant therapy combined with radical surgery seem to show more benefit in selected cases, but further studies should be required to clearly demonstrate their efficacy and safety. The expertise and experience of the surgeons should also be taken into account in determining the success of these radical procedures. PMID- 23796336 TI - From triple threat to octopus: reflections on the roles of pediatric division chiefs in the current era. PMID- 23796337 TI - 50 Years ago in The Journal of Pediatrics: The changing picture of cerebral dysfunction in early childhood. PMID- 23796338 TI - 50 Years ago in The Journal of Pediatrics: Severe aortic stenosis in infancy. PMID- 23796339 TI - 50 Years ago in The Journal of Pediatrics: congenital abnormalities of the urinary system, IV: valvular obstruction of the posterior urethra. PMID- 23796340 TI - 50 Years ago in The Journal of Pediatrics: jaundice associated with severe bacterial infection in young infants. PMID- 23796341 TI - Consensus-derived practice standards plan for complicated Kaposiform hemangioendothelioma. PMID- 23796342 TI - Point-of-care ultrasound in diagnosing pneumonia in children. PMID- 23796343 TI - Maternal prenatal folic acid supplementation is associated with a reduction in development of autistic disorder. PMID- 23796344 TI - Improvement of child behavior is associated with resolution of intimate partner violence. PMID- 23796345 TI - School-based asthma controller medication administration is associated with cost savings. PMID- 23796346 TI - Significant variability in 30-day unplanned readmission rates among children's hospitals. PMID- 23796347 TI - Association of TLR2, TLR3, TLR4 and CD14 genes polymorphisms with oral cancer risk and survival. AB - OBJECTIVES: The aim of this study is to investigate association between polymorphisms in TLR2, TLR3, TLR4 and CD14 genes or their haplotypes with oral squamous cell carcinomas (OSCC) risk and survival. METHODS: The study was conducted on 93 OSCC patients and 104 cancer-free controls. Polymorphisms were genotyped by real-time PCR or PCR-RFLP method. RESULTS: Significant increase in oral cancer risk was observed in individuals with mutated genotype of TLR3 rs3775291 polymorphism (OR = 1.096, P = 0.036) compared to wild-type. The heterozygous and mutated genotype of TLR3 rs5743312 polymorphism had worse survival in group of patients with stage III tumours (P = 0.043). Multivariate Cox regression analysis revealed that TLR3 rs5743312 polymorphism could be considered as prognostic marker in advanced III stage OSCC (HR = 2.456, P = 0.007), but not independently of nodal status. TLR3 rs3775291 and rs5743312 polymorphisms were in strong linkage disequilibrium. Haplotype TG was associated with worse prognosis in OSCC patients in comparison with common CG haplotype (HR = 1.717, P = 0.042). Interaction among polymorphisms in TLR2, TLR3 and CD14 genes was observed (P = 0.010). CONCLUSIONS: TLR3 rs5743312 polymorphism could be considered as potential predictor of worse overall survival in advanced oral cancer, but not independently of nodal status. Haplotypes in TLR3 gene might be associated with poor prognosis in OSCC patients. PMID- 23796348 TI - Synthesis of enantiopure fluorohydrins using alcohol dehydrogenases at high substrate concentrations. AB - The use of purified and overexpressed alcohol dehydrogenases to synthesize enantiopure fluorinated alcohols is shown. When the bioreductions were performed with ADH-A from Rhodococcus ruber overexpressed in E. coli, no external cofactor was necessary to obtain the enantiopure (R)-derivatives. Employing Lactobacillus brevis ADH, it was possible to achieve the synthesis of enantiopure (S) fluorohydrins at a 0.5 M substrate concentration. Furthermore, due to the activated character of these substrates, a huge excess of the hydrogen donor was not necessary. PMID- 23796349 TI - Reducing intoxication among bar patrons: some lessons from prevention of drinking and driving. AB - Intoxication in and around licensed premises continues to be common, despite widespread training in the responsible service of alcohol and laws prohibiting service to intoxicated individuals. However, research suggests that training and the existence of laws are unlikely to have an impact on intoxication without enforcement, and evidence from a number of countries indicates that laws prohibiting service to intoxicated individuals are rarely enforced. Enforcement is currently hampered by the lack of a standardized validated measure for defining intoxication clearly, a systematic approach to enforcement and the political will to address intoxication. We argue that adoption of key principles from successful interventions to prevent driving while intoxicated could be used to develop a model of consistent and sustainable enforcement. These principles include: applying validated and widely accepted criteria for defining when a person is 'intoxicated'; adopting a structure of enforceable consequences for violations; implementing procedures of unbiased enforcement; using publicity to ensure that there is a perceived high risk of being caught and punished; and developing the political will to support ongoing enforcement. Research can play a critical role in this process by: developing and validating criteria for defining intoxication based on observable behaviour; documenting the harms arising from intoxication, including risk curves associated with different levels of intoxication; estimating the policing, medical and social costs from intoxicated bar patrons; and conducting studies of the cost-effectiveness of different interventions to reduce intoxication. PMID- 23796350 TI - JAK2/STAT3 activation by melatonin attenuates the mitochondrial oxidative damage induced by myocardial ischemia/reperfusion injury. AB - Ischemia/reperfusion injury (IRI) is harmful to the cardiovascular system and causes mitochondrial oxidative stress. Numerous data indicate that the JAK2/STAT3 signaling pathway is specifically involved in preventing myocardial IRI. Melatonin has potent activity against IRI and may regulate JAK2/STAT3 signaling. This study investigated the protective effect of melatonin pretreatment on myocardial IRI and elucidated its potential mechanism. Perfused isolated rat hearts and cultured neonatal rat cardiomyocytes were exposed to melatonin in the absence or presence of the JAK2/STAT3 inhibitor AG490 or JAK2 siRNA and then subjected to IR. Melatonin conferred a cardio-protective effect, as shown by improved postischemic cardiac function, decreased infarct size, reduced apoptotic index, diminished lactate dehydrogenase release, up-regulation of the anti apoptotic protein Bcl2, and down-regulation of the pro-apoptotic protein Bax. AG490 or JAK2 siRNA blocked melatonin-mediated cardio-protection by inhibiting JAK2/STAT3 signaling. Melatonin exposure also resulted in a well-preserved mitochondrial redox potential, significantly elevated mitochondrial superoxide dismutase (SOD) activity, and decreased formation of mitochondrial hydrogen peroxide (H2 O2 ) and malondialdehyde (MDA), which indicates that the IR-induced mitochondrial oxidative damage was significantly attenuated. However, this melatonin-induced effect on mitochondrial function was reversed by AG490 or JAK2 siRNA treatment. In summary, our results demonstrate that melatonin pretreatment can attenuate IRI by reducing IR-induced mitochondrial oxidative damage via the activation of the JAK2/STAT3 signaling pathway. PMID- 23796357 TI - Can POSSUM accurately predict post-operative complications risk in patients with abdominal Crohn's disease? AB - BACKGROUND: Although the majority of patients with Crohn's disease (CD) are young, they are often seriously ill when surgery is required. The Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (POSSUM) is a risk prediction scoring system estimating 30-day complications. The primary endpoint was to evaluate POSSUM efficacy in this subgroup. The secondary endpoint was to determine any potential correlation between POSSUM, Harvey Bradshaw Index (HBI), length of stay (LOS) and anastomotic leak. METHODS: All patients affected by abdominal CD who underwent elective and emergency surgery from 2006 to 2011 were prospectively enrolled in the study. POSSUM expected morbidity and mortality were compared to the observed outcomes (O/E ratio). Logistic regression analysis was performed to evaluate POSSUM and HBI adequacy. Correlation between POSSUM, HBI, LOS and anastomotic leak was investigated with linear regression analysis. RESULTS: One hundred twenty-three patients underwent abdominal surgery. The overall 30-day mortality rate estimated by the Portsmouth POSSUM was 1.22% (95% confidence interval (CI) 0.4-3.6) while no deaths were observed (O/E = 0). The prediction regarding the post-operative complication rate was 22.04% (95% CI 11.1-51.2) and the observed overall morbidity rate was 21.95% (O/E = 0.99). The mean HBI score was 6.85 while LOS was 9.4 days. POSSUM and HBI were found to be significant predictors of post-operative complications at the univariate logistic regression analysis (OR 1.17 95% CI 1.06-1.30 and OR 1.25 95% CI 1.04-1.49, respectively). Linear regression analysis showed a significant correlation between POSSUM, HBI and LOS. CONCLUSION: POSSUM is precise in predicting post-operative complications in patients with abdominal CD. POSSUM correlates with HBI. PMID- 23796358 TI - Oxidative and antioxidative status of children with acute bronchiolitis. AB - OBJECTIVE: Oxidative stress has been shown to contribute to the pathogenesis of acute and chronic lung inflammatory diseases. This article aimed to evaluate the oxidant/antioxidant status of children with acute bronchiolitis through the measurement of plasma total antioxidant capacity, total oxidant status, and oxidative stress index. METHODS: Children with acute bronchiolitis admitted to the pediatric emergency department of a university hospital between January and April of 2012 were compared with age-matched healthy controls. Patients with acute bronchiolitis were classified as mild and moderate bronchiolitis. Oxidative and antioxidative status were assessed by measurement of plasma total antioxidant capacity, total oxidant status, and oxidative stress index. RESULTS: Thirty-one children with acute bronchiolitis aged between 3 months and 2 years, and 39 healthy children were included. Total oxidative status (TOS) was higher in patients with acute bronchiolitis than the control group (5.16+/-1.99 MUmol H2O2 versus 3.78+/-1.78 MUmol H2O2 [p=0.004]). Total antioxidant capacity (TAC) was lower in children with bronchiolitis than the control group (2.51+/-0.37 MUmol Trolox eqv/L versus 2.75+/-0.39 MUmol Trolox eqv/L [p=0.013]). Patients with moderate bronchiolitis presented higher TOS levels than those with mild bronchiolitis and the control group (p=0.03, p<0.001, respectively). Patients with moderate bronchiolitis had higher oxidative stress index levels than the control group (p=0.015). Oxygen saturation level of bronchiolitis patients was inversely correlated with TOS (r=-0.476, p<0.05). CONCLUSION: The balance between oxidant and antioxidant systems is disrupted in children with moderate bronchiolitis, which indicates that this stress factor may have a role in the pathogenesis of the disease. PMID- 23796359 TI - A double-blind placebo-controlled randomized trial on probiotics in small bowel bacterial overgrowth in children treated with omeprazole. AB - OBJECTIVE: To evaluate the incidence of small bowel bacterial overgrowth (SBBO) in children treated with omeprazole, and to test whether probiotics influence the incidence. METHODS: A double-blinded, placebo-controlled trial was performed in 70 children treated orally during four weeks with 20mg omeprazole per day. Lactobacillus rhamnosus R0011 (1.9*10(9) cfu) and Lactobacillus acidophilus R0052 (0.1*10(9) cfu) were simultaneously given daily to 36 subjects (probiotic group), while 34 subjects received placebo (placebo group). The diagnosis of SBBO was based on the development of suggestive symptoms, in combination with a positive glucose breath test. RESULTS: After one month of proton pump inhibitor (PPI) treatment, 30% (21/70) had a positive breath test suggesting SBBO; of these 62% were symptomatic. Five children developed SBBO-like symptoms, but had a negative breath test; and 44 (63%) were symptom free and had a negative breath test. There was no difference in the incidence of positive breath tests in the probiotic versus the placebo group (33% vs 26.5%; p=0.13). CONCLUSIONS: Since symptoms suggesting SBBO developed in 26% of PPI-treated children, and since the glucose breath test was abnormal in 72% of these, this side-effect should be more frequently considered. The probiotic tested did not decrease the risk to develop SBBO. PMID- 23796360 TI - Several platelet receptors and their ligands are involved in platelet- dependent thrombus formation. PMID- 23796361 TI - Preventing diabetes blindness: cost effectiveness of a screening programme using digital non-mydriatic fundus photography for diabetic retinopathy in a primary health care setting in South Africa. AB - BACKGROUND: South Africa like many other developing countries is experiencing an epidemiologic transition with a marked increase in the non-communicable disease (NCD) burden. Diabetic retinopathy is the most common cause of incidental blindness in adults. A screening programme using a mobile fundal camera in a primary care setting has been shown to be effective in the country. Information on affordability and cost is essential for policymakers to consider its adoption. METHODS: Economic evaluation is the comparative analysis of competing alternative interventions in terms of costs and consequences. A cost effectiveness analysis was done using actual costs from the primary care screening programme. RESULTS: A total of 14,541 patients were screened in three primary healthcare facilities in the Western Cape. Photographs were taken by a trained technician with supervision by an ophthalmic nurse. The photographs were then read by a medical officer with ophthalmic experience. A cost effective ratio of $1206 per blindness case averted was obtained. This included costs for screening and treating an individual. The cost just to screen a patient for retinopathy was $22. The costs of screening and treating all incident cases of blindness due to diabetes in South Africa would be 168,000,000 ZAR ($19,310,344) per annum. CONCLUSION: Non mydriatic digital fundoscopy is a cost effective measure in the screening and diagnosis of diabetic retinopathy in a primary care setting in South Africa. The major savings in the long term are a result of avoiding government disability grant for people who suffer loss of vision. PMID- 23796362 TI - Molecular characterization and expression profile of ghrelin gene during different reproductive phases in buffalo (Bubalus bubalis). AB - Ghrelin, a novel motilin-related endogenous ligand for growth hormone secretagouge receptor, is implicated in various biological functions, including regulation of female reproduction. But the presence of ghrelin and its role in reproductive functions in buffalo, a species with poor reproductive efficiency, is not known. In the present study full-length ghrelin cDNA was isolated from bubaline abomasum, which encodes the entire prepropeptide of 116 amino acids. The deduced amino acid sequence of ghrelin of buffalo showed >95% and 31% identity with that of ruminants (cattle, sheep, and goat) and humans, respectively. Analysis of synonymous and nonsynonymous nucleotide substitutions in the coding region of ghrelin indicated that these sequences of different species have been under purifying selection. The 3995-bp amplicon of ghrelin gene consisting of 4 exons and 3 introns was cloned with genomic DNA from buffalo. Further, ghrelin expression was determined by quantitative real-time PCR, in situ hybridization, and immunohistochemistry in bubaline endometrial tissues at different stages of the estrous cycle and early pregnancy. Our results indicated the persistent expression of ghrelin mRNA and protein in the endometrium during stage I (day 3 5), stage II (day 6-15), and stage III (day 16-21) of the estrous cycle and also during early (~day 30-40) pregnancy. Immunohistochemistry and quantitative real time PCR experiments indicated the relatively higher expression of ghrelin in the endometrium during stage II (day 6-15) of the estrous cycle and early pregnancy than during stage I (day 3-5) and stage III (day 16-21) of the estrous cycle, but no statistically significant difference in ghrelin expression was observed among stages. To conclude, the results of the present study indicate the persistent expression of ghrelin in the uterine endometrium throughout the estrous cycle and in early pregnancy which might be helpful in determining its role in buffalo reproduction. PMID- 23796363 TI - General modal properties of optical resonances in subwavelength nonspherical dielectric structures. AB - Subwavelength dielectric structures offer an attractive low-loss alternative to plasmonic materials for the development of resonant optics functionalities such as metamaterials and optical antennas. Nonspherical-like rectangular dielectric structures are of the most interest from the standpoint of device development due to fabrication convenience. However, no intuitive fundamental understanding of the optical resonance in nonspherical dielectric structures is available, which has substantially delayed the development of dielectric resonant optics devices. Here, we elucidate the general fundamentals of the optical resonance in nonspherical subwavelength dielectric structures with different shapes (rectangular or triangular) and dimensionalities (1D nanowires or 0D nanoparticles). We demonstrate that the optical properties of nonspherical dielectric structures are dictated by the eigenvalue of the structure's leaky modes. Leaky modes are defined as optical modes with propagating waves outside the structure. We also elucidate the dependence of the modal eigenvalue on physical features of the structure. The eigenvalue shows scale invariance with respect to the size of the structure, weak dependence on the refractive index, but linear dependence on the size ratio of different sides of the structure. We propose a modified Fabry-Perot model to account for the linear dependence. The knowledge of leaky modes, including the role in optical responses and the dependence on physical features, can serve as a powerful guide for the rational design of devices with desired optical resonances. It may open up a pathway to design devices with functionality that has not been explored due to the lack of intuitive understanding, for instance, imaging devices able to sense incident angle or superabsorbing photodetectors. PMID- 23796365 TI - Polar body biopsy. AB - Polar body biopsy combined with array comparative genomic hybridization allows detection of maternal chromosomal aberrations. Although it has limitations, it can be seen as an alternative to blastomere and trophectoderm biopsy. PMID- 23796364 TI - A cyclic peptide inhibitor of HIF-1 heterodimerization that inhibits hypoxia signaling in cancer cells. AB - Hypoxia inducible factor-1 (HIF-1) is a heterodimeric transcription factor that acts as the master regulator of cellular response to reduced oxygen levels, thus playing a key role in the adaptation, survival, and progression of tumors. Here we report cyclo-CLLFVY, identified from a library of 3.2 million cyclic hexapeptides using a genetically encoded high-throughput screening platform, as an inhibitor of the HIF-1alpha/HIF-1beta protein-protein interaction in vitro and in cells. The identified compound inhibits HIF-1 dimerization and transcription activity by binding to the PAS-B domain of HIF-1alpha, reducing HIF-1-mediated hypoxia response signaling in a variety of cell lines, without affecting the function of the closely related HIF-2 isoform. The reported cyclic peptide demonstrates the utility of our high-throughput screening platform for the identification of protein-protein interaction inhibitors, and forms the starting point for the development of HIF-1 targeted cancer therapeutics. PMID- 23796366 TI - In women, the reproductive harm of toxins such as tobacco smoke is reversible in 6 months: basis for the "olive tree" hypothesis. PMID- 23796367 TI - Mitomycin-C: 'a ray of hope' in refractory corrosive esophageal strictures. AB - Increasingly frequent dilation may become a self-defeating cycle in refractory stricture as recurrent trauma enhance, scar formation, and ultimately recurrence and potential worsening of the stricture. In 12 patients of caustic induced esophageal stricture, who failed to respond despite rigorous dilatation regimen for more than one year, a trial of topical mitomycin-C application to improve dilatation results was undertaken, considering the recently reported efficacy and safety of this agent. Mitomycin-C was applied for 2-3 minutes at the strictured esophageal segment after dilation with wire-guided Savary-Gilliard dilator. Patient was kept nil by mouth for 2-3 hours. After 4-6 sessions of mitomycin-C treatment, resolution of symptoms and significant improvement in dysphagia score and periodic dilatation index was seen in all 12 patients. Mitomycin-C topical application may be a useful strategy in refractory corrosive esophageal strictures and salvage patients from surgery. PMID- 23796368 TI - Letter from the guest editor: abdominal imaging update. PMID- 23796369 TI - Case of the season: ectopic pancreas. PMID- 23796370 TI - Emerging technologies in CT- radiation dose reduction and dual-energy CT. PMID- 23796371 TI - Contemporary and emerging technologies in abdominal magnetic resonance imaging. PMID- 23796372 TI - New technologies in clinical ultrasound. PMID- 23796373 TI - The role of ultrasound in the evaluation of inflammatory bowel disease. PMID- 23796374 TI - Current status of CT, magnetic resonance, and barium in inflammatory bowel disease. PMID- 23796375 TI - Staging of pancreatic cancer: role of imaging. PMID- 23796376 TI - Cystic pancreatic neoplasms: imaging features and management strategy. PMID- 23796377 TI - Computed tomographic colonography: evidence and techniques for screening. PMID- 23796378 TI - Imaging after local tumor therapies: kidney and liver. PMID- 23796379 TI - Brachioradial pruritus: Mayo Clinic experience over the past decade. AB - BACKGROUND: Brachioradial pruritus (BRP) is a fascinating condition that is seen increasingly often, but any additional data from retrospective observational studies can still enhance our understanding. OBJECTIVES: To review our experience at the Mayo Clinic with patients presenting with BRP. METHODS: We retrospectively reviewed the clinical records of patients diagnosed with BRP between 1999 and 2011. RESULTS: In total, 111 patients (80 female, 72%) had been diagnosed with BRP. Their mean age was 59 years, range 12-84 years. Symptoms were bilateral in 84 (75.7%). Fifty-four patients (48.6%) reported prolonged exposure to the sun, and 16 had a history of neck concerns. Forty-five (40.5%) had undergone imaging studies of the neck; of these, eight had foraminal stenosis, six had protrusion of the intervertebral disk and six had stenosis of the spinal canal; 10 had more than one cervical abnormality. Thirty-one patients had been referred to neurology; eight of these had BRP attributed to a radiculopathy or peripheral neuropathy. Several topical and oral medications were prescribed. Seventy-five patients had a follow-up; of these, nine (12%) had complete resolution, 13 (17%) had improvement, four (5%) showed no change and 49 (65%) had no mention of BRP. CONCLUSIONS: Brachioradial pruritus presented most commonly in female patients and was observed over a wide age range. Although a third of patients with imaging studies had cervical abnormalities, the significance of these findings is unclear, as no structural causes of BRP were found in most cases. Some treatments were more successful than others. PMID- 23796380 TI - Fe3O4 nanocrystals tune the magnetic regime of the Fe/Ni molecular magnet: a new class of magnetic superstructures. AB - A new class of organometallic-inorganic magnetic material was engineered by a sonochemically assisted self-assembly process between magnetite nanoparticles (biogenic Fe3O4, hard constituent) functionalized with isonicotinic acid and a metamagnetic organometallic complex ([Ni(en)2]3[Fe(CN)6]2.3H2O, soft constituent). In such bottom-up methodology, hard and soft counterparts form well organized microdimensional clusters that showed morphological fingerprints and magnetic behavior clearly distinct from those of the initial building units. In the engineered soft-hard material, the magnetite nanocrystals induced ferromagnetic ordering at room temperature of closer contact layers of [Ni(en)2]3[Fe(CN)6]2.3H2O, thus demonstrating the ability to sensibly modify the [Ni(en)2]3[Fe(CN)6]2.3H2O paramagnetic regime. The magnetic ordering of [Ni(en)2]3[Fe(CN)6]2.3H2O was triggered by the intrinsic local field of the hard magnetic nanocrystals, which resembled, to some extent, the effects promoted by large, external magnetic fields. PMID- 23796381 TI - Surgical treatment of elbow stiffness caused by post-traumatic heterotopic ossification. AB - BACKGROUND: Heterotopic ossification (HO) is considered as a common extrinsic cause of elbow stiffness. The purpose of this study was to show the results of surgical treatment for post-traumatic elbow stiffness caused by HO in a large, consecutive series of patients in a single unit. METHODS: We retrospectively reviewed 77 surgically treated patients with post-traumatic elbow stiffness caused by HO. Final motion arc and Mayo Elbow Performance Index (MEPI) were assessed as final results. Univariable and multivariable analyses were done to determine which factors had an effect on the final motion arc. RESULTS: The average arc of elbow motion increased from 45 degrees preoperatively to 112 degrees , with an improvement of 67 degrees at the final follow-up evaluation. The mean MEPI score was 91.9. At the final evaluation, 65 patients (84.4%) obtained a total motion arc of >=100 degrees . Recurrent HO was observed in 16 patients postoperatively, and 6 underwent repeated surgical release. The time from the initial injury to surgical release with a cutoff value of 19 months was the only independent factor affecting the final range of motion (ROM) in multivariable median regression analysis. With the numbers studied, no significant association was found between the final ROM and other clinical variables except for the recurrence of HO (93 degrees vs 117 degrees ). CONCLUSIONS: From the results of our study, we can support the surgical treatment of elbow stiffness caused by post-traumatic HO regardless of preoperative ROM. However, recurrence of heterotopic bone and delay in surgery of more than 19 months are associated with less favorable results. PMID- 23796382 TI - Comments regarding measurement of posterior capsular thickness after rotator cuff repair. PMID- 23796383 TI - Effectiveness of bracing in the treatment of nonosseous restriction of elbow mobility: a systematic review and meta-analysis of 13 studies. AB - BACKGROUND: Restriction of elbow mobility is a very frequent complaint after trauma or surgery. The objective of this study was to assess and compare the effectiveness of dynamic, static, or static-progressive bracing in patients with elbow stiffness of traumatic or postoperative origin and without evidence of ossification. For the purpose of this study, effectiveness was measured as the increase in total range of motion, as well as extension and flexion. MATERIALS AND METHODS: We performed a systematic search of the keywords "elbow AND (stiffness OR stiff) AND (brace OR splint OR conservative)" in the online databases PubMed, EMBASE, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and the Cochrane Library. We included all clinical studies using dynamic or static bracing in patients with elbow stiffness. Eligible outcomes were changes in total range of motion, flexion, and extension; sustainability of results; and complications. RESULTS: We included 13 eligible studies, providing data on 14 treated groups in 247 patients. The mean age of these patients was 34.5 +/- 10.4 years, and female patients comprised 46% +/- 12%. The mean duration from the incident to the start of brace treatment was 6.9 +/- 5.1 months. The mean improvement in range of motion during the course of treatment was 38.4 degrees +/- 8.9 degrees (95% confidence interval, 39.5 degrees -41.8 degrees ). CONCLUSIONS: The current evidence strongly supports the use of static-progressive stretching 3 times 30 minutes per day in each direction as a first line of treatment in patients with post-traumatic and postsurgical elbow stiffness. If this treatment fails or if reasons for stiffness other than soft-tissue incompliance are identified, further surgical interventions should be considered. PMID- 23796384 TI - Addressing glenoid bone deficiency and asymmetric posterior erosion in shoulder arthroplasty. AB - Glenoid bone deficiency and eccentric posterior wear are difficult problems faced by shoulder arthroplasty surgeons. Numerous options and techniques exist for addressing these issues. Hemiarthroplasty with concentric glenoid reaming may be a viable alternative in motivated patients in whom glenoid component failure is a concern. Total shoulder arthroplasty has been shown to provide durable pain relief and excellent function in patients, and numerous methods and techniques can assist in addressing bone loss and eccentric wear. However, the ideal amount of version correction in cases of severe retroversion has not yet been established. Asymmetric reaming is a commonly used technique to address glenoid version, but correction of severe retroversion may compromise bone stock and component fixation. Bone grafting is a technically demanding alternative for uncontained defects and has mixed clinical results. Specialized glenoid implants with posterior augmentation have been created to assist the surgeon in correcting glenoid version without compromising bone stock, but clinical data on these implants are still pending. Custom implants or instruments based on each patient's unique glenoid anatomy may hold promise. In elderly, sedentary patients in whom bone stock and soft-tissue balance are concerns, reverse total shoulder arthroplasty may be less technically demanding while still providing satisfactory pain relief and functional improvements. PMID- 23796385 TI - Clinical outcomes of hemiarthroplasty and biological resurfacing in patients aged younger than 50 years. AB - BACKGROUND: Total shoulder arthroplasty as a treatment for glenohumeral degenerative joint disease is well accepted but has been less predictable with regard to outcomes and durability in a younger aged population, typically aged younger than 50 years. This younger population has a greater potential for glenoid component loosening. This has led surgeons to perform hemiarthroplasty or hemiarthroplasty with biological resurfacing of the glenoid in an effort to avoid the potential problems with a polyethylene glenoid and obtain durable and acceptable results for these patients. METHODS: The study included 44 patients, with 23 undergoing hemiarthroplasty alone and 21 undergoing hemiarthroplasty with biological resurfacing of the glenoid. All patients were aged younger than 50 years. Preoperative diagnoses, comorbidities, demographics, and range of motion were collected. Preoperative and postoperative radiographs were obtained. Preoperative and postoperative objective scoring measures (Single Assessment Numeric Evaluation, American Shoulder and Elbow Surgeons score, visual analog scale, Simple Shoulder Test, Constant-Murley) were used. RESULTS: Mean follow-up was 3.8 years for the hemiarthroplasty group and 3.6 years for the biological resurfacing group. Six patients in the hemiarthroplasty and 12 patients in the biological resurfacing group were considered failures due to revision surgery or an American Shoulder and Elbow Surgeons score <50. The hemiarthroplasty group had significantly better visual analog scale and Single Assessment Numeric Evaluation scores. CONCLUSIONS: There was a significant failure rate in the hemiarthroplasty and the biologic resurfacing groups compared with results in the literature. Improved outcomes and lower failure rates were observed in the hemiarthroplasty group compared with the biological resurfacing group in this study. PMID- 23796386 TI - Small head circumference at birth and early age at adiposity rebound. AB - AIMS: The adiposity rebound is the age in childhood when body mass index is at a minimum before increasing again. The age at rebound is highly variable. An early age is associated with increased obesity in later childhood and adult life. We have reported that an early rebound is predicted by low weight gain between birth and 1 year of age and resulting low body mass index at 1 year. Here, we examine whether age at adiposity rebound is determined by influences during infancy or is a consequence of foetal growth. Our hypothesis was that measurements of body size at birth are related to age at adiposity rebound. METHODS: Longitudinal study of 2877 children born in Helsinki, Finland, during 1934-1944. RESULTS: Early age at adiposity rebound was associated with small head circumference and biparietal diameter at birth, but not with other measurements of body size at birth. The mean age at adiposity rebound rose from 5.8 years in babies with a head circumference of <=33 cm to 6.2 in babies with a head circumference of >36 cm (P for trend = 0.007). The association between thinness in infancy and early rebound became apparent at 6 months of age. It was not associated with adverse living conditions. In a simultaneous regression, small head circumference at birth, high mother's body mass index and tall maternal stature each had statistically significant trends with early adiposity rebound (P = 0.002, <0.001, 0.004). CONCLUSION: We hypothesize that the small head size at birth that preceded an early adiposity rebound was the result of inability to sustain a rapid intra uterine growth trajectory initiated in association with large maternal body size. This was followed by catch-up growth in infancy, and we hypothesize that this depleted the infant's fat stores. PMID- 23796389 TI - Use of high-pressure balloon dilatation of the ureterovesical junction instead of ureteral reimplantation to treat primary obstructive megaureter: is it justified? AB - OBJECTIVE: To compare outcomes between high-pressure balloon dilatation of the ureterovesical junction (UVJ) and ureteral reimplantation with ureteral tapering to treat primary obstructive megaureter (POM). PATIENTS AND METHODS: Retrospective review of clinical data from patients who underwent surgical treatment of POM from 2005 to 2010. Patients were divided into two groups: endoscopic treatment (ET) with UVJ dilatation and ureteral reimplantation (UR) with Cohen's or Leadbetter-Politano neoureterocystostomy and Hendren's tapering. Preoperative studies included ultrasound scan (US), voiding cystourethrography, and diuretic isotopic renogram. Outcome parameters were US, differential renal function (DRF), presence of postoperative vesicoureteral reflux, need for secondary reimplantation and complications. RESULTS ET: 13 patients with a median age of 7 (4-24) months; UR: 12 patients with a median age of 14 (7-84) months, with no statistical differences in age and gender between groups. Preoperative US parameters were similar. ET: mean diameter of renal pelvis, calices and ureter was 23.5 mm, 13.46 mm and 15.77 mm respectively. UR: mean diameter of renal pelvis, calices and ureter was 22.25 mm, 11.75 mm, and 19.08 mm, respectively. Preoperative DRF was 45.62% and 39.33% for ET and UR, respectively (p > 0.05). Significant improvement of hydroureteronephrosis was observed in 11/13 patients of ET and 11/12 patients of UR (p > 0.05). Postoperative DRF was 42% and 48% for ET and UR, respectively (p > 0.05). Postoperative vesicoureteral reflux was observed in 2 patients of ET and 1 of UR (p > 0.05). Secondary ureteral reimplantation was needed in 3 patients of ET and 2 of UR (p > 0.05). CONCLUSION: Endoscopic treatment of POM is as effective as ureteral reimplantation but further randomized clinical trials are needed to support these results. PMID- 23796390 TI - Strategies for triggered drug release from tumor targeted liposomes. AB - INTRODUCTION: Long circulating liposomal drug carriers are widely used in experimental cancer therapy because they avoid excretion and benefit from the enhanced permeability and retention-effect to accumulate at the tumor site while simultaneously limiting systemic exposure to the cytotoxic drug due to their high stability. A drawback of the stability of the formulation is that the unloading of the drug at the target site is very poor. This opens up a new challenge to trigger drug release at the target site, while still retaining most of the drug inside the carrier while it resides in the bloodstream. AREAS COVERED: A short introduction is given about lipid polymorphism and phase behavior. To illustrate how this can be used to design triggered release systems, the development of delivery systems that are activated by tumor environment, UV or visible light and mild heat are discussed. The most recent triggered release systems have evolved even further, creating a need for more sophisticated triggers, which are as non invasive and patient friendly as possible. EXPERT OPINION: Currently the most promising triggered release systems that have advanced furthest are thermosensitive liposomal delivery systems. As mild hyperthermia also increases tissue permeability it appears a suitable trigger for drug release while it also assists in drug accumulation. Combined with an advanced imaging system in the MR high intensity focused ultrasound, this could be the combination of delivery system and trigger that can achieve clinical success. PMID- 23796387 TI - Causes and consequences of age-related steroid hormone changes: insights gained from nonhuman primates. AB - Similar to humans, rhesus macaques (Macaca mulatta) are large, long-lived diurnal primates, and show similar age-related changes in the secretion of many steroid hormones, including oestradiol, testosterone, cortisol and dehydroepiandrosterone (DHEA). Consequently, they represent a pragmatic animal model in which to examine the mechanisms by which these steroidal changes contribute to perturbed sleep wake cycles and cognitive decline in the elderly. Using remote serial blood sampling, we have found the circulating levels of DHEA sulphate, as well as oestradiol and testosterone, decline markedly in old monkeys. Furthermore, using the real-time polymerase chain reaction, we have shown that the genes for the enzymes associated with the conversion of DHEA to oestradiol and testosterone (3beta-hydroxysteroid dehydrogenase, 17beta-hydroxysteroid dehydrogenase, and aromatase) are highly expressed in brain areas associated with cognition and behaviour, including the hippocampus, prefrontal cortex and amygdala. Taken together, these findings suggest that the administration of supplementary DHEA in the elderly may have therapeutic potential for cognitive and behavioural disorders, although with fewer negative side effects outside of the central nervous system. To test this, we have developed a novel steroid supplementation paradigm for use in old animals; this involves the oral administration of DHEA and testosterone at physiologically relevant times of the day to mimic the circadian hormone patterns observed in young adults. We are currently evaluating the efficacy of this steroid supplementation paradigm with respect to reversing age-associated disorders, including perturbed sleep-wake cycles and cognitive decline, as well as an impaired immune response. PMID- 23796391 TI - Synthesis and antitumor activity evaluation of a novel series of camptothecin analogs. AB - A series of novel 10-substituted camptothecin analogs (3-10) with a carbamate linker were synthesized, and their biological activities were evaluated. The amino acid-linked carbamate derivatives (8-10) of the camptothecin-type natural product not only possessed good to excellent inhibitory activity against three human tumor cell lines K562, HepG2, and HT-29, but also showed significantly less cytotoxicity against normal human cell HEK293 (half maximal inhibiting concentration >10 MUM). The selectivity of compound 9 toward tumor cells relative to normal cells is at least 250 times better than that of camptothecin. The preliminary testing result indicated that the solubility of these compounds was also improved compared to that of 10-hydroxy camptothecin. PMID- 23796392 TI - Long-lifetime and asymmetric singlet oxygen photoluminescence from aqueous fullerene suspensions. AB - The photoexcited aqueous fullerene (C60) suspension was shown to exhibit an asymmetric photoluminescence (PL) spectrum, which, different from the symmetric spectrum observed previously in C60 solutions or suspensions, still stems from the characteristic phosphorescence of singlet oxygen (O2(a(1)Delta)) owing to its dependence on oxygen concentration. In contrast to the microsecond-level lifetime of O2(a(1)Delta) in water solutions, that in our C60 suspensions was measured at room temperature to be relatively long, about 2-3 ms, which is ~1000 times longer than the value reported by Bilski et al. The physical mechanism for the asymmetric O2(a(1)Delta) PL from C60 suspensions was studied in depth, indicating that it in fact originates from O2 molecules trapped in the C60 lattice within the suspended C60 aggregates (nC60). This mechanism, which can explain well our above results, was further validated by the nC60's high-resolution transmission electron microscopy (HRTEM) images with lattice fringes and the experimental temperature dependence of O2(a(1)Delta) lifetimes in nC60 suspensions. Our findings suggest that the bulk-phase O2(a(1)Delta) in aqueous nC60 suspensions results from the diffusion of the O2(a(1)Delta) generated within the interior of nC60 aggregates. PMID- 23796393 TI - Sensorial differences according to sex and ages. AB - OBJECTIVE: To investigate age and sex differences in orofacial sensory detection. METHODS: One hundred and twenty-six (126) healthy subjects were divided into five groups according to their ages. They were assessed with a quantitative sensory testing protocol for gustative, olfactory, thermal (cold/warm), mechanical (tactile/vibration/electric), and pain (deep/superficial) detection thresholds. The corneal reflex was also evaluated. Data were analyzed with the one-way ANOVA, chi-squared, Fisher's exact, Mann-Whitney, and Kruskal-Wallis tests. RESULTS: The groups of subjects over 61 years old had higher olfactory (P < 0.001), gustative (sweet P = 0.004, salty P = 0.007, sour P = 0.006), thermal (warm P < 0.001, cold P < 0.001), and tactile (P < 0.001) detection thresholds than the others. The vibration detection threshold was high only for subjects over 75 years old (P < 0.001). The electric and deep pain detection thresholds were different for the 61 75 years old group (P <= 0.001). Women in all age groups had lower gustative (sweet P = 0.020, salty P = 0.002, sour P < 0.001, and bitter P = 0.002), olfactory (P = 0.010), warm (P < 0.001) and deep (P < 0.001), and superficial pain (P = 0.008) detection thresholds than men, and men from all age groups had lower vibratory detection thresholds (P = 0.006) than women. CONCLUSION: High sensory detection thresholds were observed in subjects over the 6th decade of life, and women had a more accurate sensory perception than men. PMID- 23796394 TI - New guidelines are needed to improve the reporting of trials in addiction sciences. PMID- 23796395 TI - Hepatic haemangioma: common and uncommon imaging features. AB - The haemangioma, the most common non-cystic hepatic lesion, most often discovered by chance, may in certain situations raise diagnostic problems in imaging. In this article, the authors first demonstrate that the radiological appearance of the hepatic haemangioma, in its typical form, is closely related to three known histological sub-types. They then show that certain atypical features should be known in order to establish a diagnosis. They also observe the potential interactions between the haemangioma, an active vascular lesion, and the adjacent hepatic parenchyma. Finally, they discuss the specific paediatric features of hepatic haemangiomas and illustrate the case of a hepatic angiosarcoma. PMID- 23796396 TI - Which dose for what image? Iterative reconstruction for CT scan. AB - PURPOSE: To evaluate the potential of iterative reconstruction for reducing the dose given to the patient during abdominal CT scanning. MATERIALS AND METHODS: A double abdominal CT scan acquisition (Somatom Definition AS+ Siemens) performed without contrast administration at -30% and at -70% of the doses (mAs) was compared to the standard acquisition in 10 patients. The raw data were reconstructed by filtered back projection (FBP) and using the SAFIRE iterative reconstruction method (five levels of iteration). The signal, noise, signal-to noise ratio (SNR) and the contrast-to-noise ratio (CNR) were compared for three regions of interest, including the kidney, psoas and abdominal fat. RESULTS: The signal in each region of interest was not modified based on the type of reconstruction. The noise level decreased significantly during the passage from the FBP to SAFIRE, as well as with the increase in the SAFIRE level. The SNR and CNR therefore increased with the use of iterative reconstructions. The increase in noise observed between the acquisition at -30% and that at -70% was compensated by the use of higher SAFIRE levels. CONCLUSION: Iterative reconstructions can be used to improve the SNR and CNR at a constant dose or to reduce the dose by keeping the same SNR and CNR on abdominal CT images. PMID- 23796397 TI - Editorial comment. PMID- 23796398 TI - Preventive effect of specific antioxidant on oxidative renal cell injury associated with renal crystal formation. AB - OBJECTIVE: To investigate whether calcium oxalate monohydrate (COM), a key element of hyperoxaluria, would induce renal cell injury through oxidative stress and also whether certain antioxidants could prevent chemically induced renal crystal formation in rats. MATERIALS AND METHODS: COM-exerted oxidative stress on the kidney epithelial Madin-Darby canine kidney cells was assessed using the lipid peroxidation assay. Glyoxalase I (Gly-I) activity was also determined. Two antioxidants, vitamin C and N-acetylcysteine (NAC), were then tested to determine whether they could abolish such oxidative stress in Madin-Darby canine kidney cells. Both antioxidants were also tested to determine whether they might prevent or reduce renal crystal formation induced with ethylene glycol (EG) and vitamin D3 (VD3) in Wistar rats. RESULTS: COM (200 MUg/mL) demonstrated ~1.3-fold greater oxidative stress with a significant reduction in cell viability and Gly-I activity compared with controls. However, such adverse events were almost completely prevented with NAC but not with vitamin C. In the animal study, no renal crystals were seen in the sham group. However, numerous crystals, with reduced Gly-I activity and elevated oxidative stress, were found in the EG-VD3 group. However, markedly (>70%) fewer crystals, with full Gly-I activity and diminished oxidative stress, were detected in the EG-VD3+NAC group. CONCLUSION: COM exerted oxidative stress on Madin-Darby canine kidney cells, leading to cell viability reduction and Gly-I inactivation, with NAC fully preventing such adverse consequences. Similarly, numerous crystals with Gly-I inactivation and elevated oxidative stress seen in the rats (EG-VD3) were also significantly prevented with NAC supplement. Thus, NAC might have clinical implications in preventing oxidative renal cell injury and, ultimately, kidney stone formation. PMID- 23796400 TI - Using regression models to determine the poroelastic properties of cartilage. AB - The feasibility of determining biphasic material properties using regression models was investigated. A transversely isotropic poroelastic finite element model of stress relaxation was developed and validated against known results. This model was then used to simulate load intensity for a wide range of material properties. Linear regression equations for load intensity as a function of the five independent material properties were then developed for nine time points (131, 205, 304, 390, 500, 619, 700, 800, and 1000s) during relaxation. These equations illustrate the effect of individual material property on the stress in the time history. The equations at the first four time points, as well as one at a later time (five equations) could be solved for the five unknown material properties given computed values of the load intensity. Results showed that four of the five material properties could be estimated from the regression equations to within 9% of the values used in simulation if time points up to 1000s are included in the set of equations. However, reasonable estimates of the out of plane Poisson's ratio could not be found. Although all regression equations depended on permeability, suggesting that true equilibrium was not realized at 1000s of simulation, it was possible to estimate material properties to within 10% of the expected values using equations that included data up to 800s. This suggests that credible estimates of most material properties can be obtained from tests that are not run to equilibrium, which is typically several thousand seconds. PMID- 23796401 TI - Modelling creep behaviour of the human intervertebral disc. AB - The mechanical behaviour of an intervertebral disc is time dependent. In literature different constitutive equations have been used to describe creep. It is unsure whether these different approaches yield valid predictions. In this study, we compared the validity of different equations for the prediction of creep behaviour. To this end, human thoracic discs were preloaded at 0.1 MPa for 12h, compressed (0.8 MPa) for 24h and finally unloaded (0.1 MPa) for 24h. A Kohlrausch-Williams-Watts (KWW) model and a Double-Voight (DV) model were fitted to the creep data. Model parameters were calculated for test durations of 4, 8, 12, 16, 20 and 24h. Both models described the measured data well, but parameters were highly sensitive to test duration. The estimated time constant varied with test duration from 3.6 to 17h. When extrapolating beyond test duration, the DV model under-estimated and the KWW model over-estimated creep. The 24h experiment was still too short for an accurate determination of the parameters. Therefore, parameters obtained in this paper can be used to describe normal behaviour, but are not suitable for extrapolation beyond the test duration. PMID- 23796402 TI - Breast cancer surgery volume-cost associations: hierarchical linear regression and propensity score matching analysis in a nationwide Taiwan population. AB - BACKGROUND: No outcome studies have longitudinally and systematically compared the effects of hospital and surgeon volume on breast cancer surgery costs in an Asian population. This study purposed to evaluate the use of hospital and surgeon volume for predicting breast cancer surgery costs. METHODS: This cohort study retrospectively analyzed 97,215 breast cancer surgeries performed from 1996 to 2010. Relationships between volumes and costs were analyzed by propensity score matching and by hierarchical linear regression. RESULTS: The mean breast cancer surgery costs for all breast cancer surgeries performed during the study period was $1485.3 dollars. The average breast cancer surgery costs for high-volume hospitals and surgeons were 12% and 26% lower, respectively, than those for low volume hospitals and surgeons. Propensity score matching analysis showed that the average breast cancer surgery costs for breast cancer surgery procedures performed by high-volume hospitals ($1428.6 dollars) significantly differed from the average breast cancer surgery costs of those performed by low-/medium-volume hospitals ($1514.0 dollars) and that the average breast cancer surgery costs of procedures performed by high-volume surgeons ($1359.0 dollars) significantly differed from the average breast cancer surgery costs of those performed by low /medium-volume surgeons ($1550.3 dollars) (P < 0.001). CONCLUSIONS: The factors significantly associated with hospital resource utilization for this procedure included age, surgical type, Charlson co-morbidity index score, hospital type, hospital volume, and surgeon volume. The data indicate that analyzing and emulating the treatment strategies used by high-volume hospitals and by high volume surgeons may reduce overall breast cancer surgery costs. PMID- 23796403 TI - Catalytic ketyl-olefin cyclizations enabled by proton-coupled electron transfer. AB - Concerted proton-coupled electron transfer is a key mechanism of substrate activation in biological redox catalysis. However, its applications in organic synthesis remain largely unexplored. Herein, we report the development of a new catalytic protocol for ketyl-olefin coupling and present evidence to support concerted proton-coupled electron transfer being the operative mechanism of ketyl formation. Notably, reaction outcomes were correctly predicted by a simple thermodynamic formalism relating the oxidation potentials and pKa values of specific Bronsted acid/reductant combinations to their capacity to act jointly as a formal hydrogen atom donor. PMID- 23796404 TI - The Gac/Rsm and cyclic-di-GMP signalling networks coordinately regulate iron uptake in Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is a versatile bacterial pathogen capable of occupying diverse ecological niches. To cope with iron limitation, P. aeruginosa secretes two siderophores, pyoverdine and pyochelin, whose ability to deliver iron to the cell is crucial for biofilm formation and pathogenicity. In this study, we describe a link between iron uptake and the Gac/Rsm system, a conserved signal transducing pathway of P. aeruginosa that controls the production of extracellular products and virulence factors, as well as the switch from planktonic to biofilm lifestyle. We have observed that pyoverdine and pyochelin production in P. aeruginosa is strongly dependent on the activation state of the Gac/Rsm pathway, which controls siderophore regulatory and biosynthetic genes at the transcriptional level, in a manner that does not involve regulation of ferric uptake regulator (Fur) expression. Gac/Rsm-mediated regulation of iron uptake genes appears to be conserved in different P. aeruginosa strains. Further experiments led to propose that the Gac/Rsm system regulates siderophore production through modulation of the intracellular levels of the second messenger c-di-GMP, indicating that the c-di-GMP and the Gac/Rsm regulatory networks essential for biofilm formation can also coordinately control iron uptake in P. aeruginosa. PMID- 23796406 TI - Amphiphilic peptide-loaded nanofibrous calcium phosphate microspheres promote hemostasis in vivo. AB - Most fatalities from trauma occur due to severe blood loss. There is a need for improved hemostatic biomaterials that can address this problem. The aim of this study was to determine the in vivo efficacy of nanofibrous microspheres (NFM) loaded with hemostatic peptides, specifically ideal amphipathic peptides (IAP) that have been demonstrated to possess both procoagulant and antifibrinolyic activities. We demonstrate that IAP can be coupled to NFM (IAP-NFM) to form matrices that exhibit substantial hemostatic activity. IAP-NFM matrices were compared to a commercial zeolitic hemostatic biomaterial (QuikClot) and have superior efficacy in reducing bleeding in vivo. In both a murine tail transection and a murine hepatic injury model, bleeding times were significantly reduced (P<0.05) with the use of IAP-NFM as compared with equal masses of either QuikClot or NFM alone, or no treatment. Importantly, histological examination revealed no tissue injury when IAP-NFM or NFM were applied to hepatic lacerations. In contrast, QuikClot caused widespread hepatocyte degeneration and necrosis, with higher average injury zone thickness as determined by semiquantitative analysis. In summary, NFM was able to maintain the pro-coagulant properties of IAP in our preclinical model, caused no observable tissue damage at the site of application and had better performance than QuikClot controls. PMID- 23796405 TI - Hematopoietic cell differentiation from embryonic and induced pluripotent stem cells. AB - Pluripotent stem cells, both embryonic stem cells and induced pluripotent stem cells, are undifferentiated cells that can self-renew and potentially differentiate into all hematopoietic lineages, such as hematopoietic stem cells (HSCs), hematopoietic progenitor cells and mature hematopoietic cells in the presence of a suitable culture system. Establishment of pluripotent stem cells provides a comprehensive model to study early hematopoietic development and has emerged as a powerful research tool to explore regenerative medicine. Nowadays, HSC transplantation and hematopoietic cell transfusion have successfully cured some patients, especially in malignant hematological diseases. Owing to a shortage of donors and a limited number of the cells, hematopoietic cell induction from pluripotent stem cells has been regarded as an alternative source of HSCs and mature hematopoietic cells for intended therapeutic purposes. Pluripotent stem cells are therefore extensively utilized to facilitate better understanding in hematopoietic development by recapitulating embryonic development in vivo, in which efficient strategies can be easily designed and deployed for the generation of hematopoietic lineages in vitro. We hereby review the current progress of hematopoietic cell induction from embryonic stem/induced pluripotent stem cells. PMID- 23796407 TI - The calcium silicate/alginate composite: preparation and evaluation of its behavior as bioactive injectable hydrogels. AB - In this study, an injectable calcium silicate (CS)/sodium alginate (SA) hybrid hydrogel was prepared using a novel material composition design. CS was incorporated into an alginate solution and internal in situ gelling was induced by the calcium ions directly released from CS with the addition of d-gluconic acid delta-lactone (GDL). The gelling time could be controlled, from about 30s to 10 min, by varying the amounts of CS and GDL added. The mechanical properties of the hydrogels with different amounts of CS and GDL were systematically analyzed. The compressive strength of 5% CS/SA hydrogels was higher than that of 10% CS/SA for the same amount of GDL. The swelling behaviors of 5% CS/SA hydrogels with different contents of GDL were therefore investigated. The swelling ratios of the hydrogels decreased with increasing GDL, and 5% CS/SA hydrogel with 1% GDL swelled by only less than 5%. Scanning electron microscopy (SEM) observation of the scaffolds showed an optimal interconnected porous structure, with the pore size ranging between 50 and 200 MUm. Fourier transform infrared spectroscopy and SEM showed that the CS/SA composite hydrogel induced the formation of hydroxyapatite on the surface of the materials in simulated body fluid. In addition, rat bone mesenchymal stem cells (rtBMSCs) cultured in the presence of hydrogels and their ionic extracts were able to maintain the viability and proliferation. Furthermore, the CS/SA composite hydrogel and its ionic extracts stimulated rtBMSCs to produce alkaline phosphatase, and its ionic extracts could also promote angiogenesis of human umbilical vein endothelial cells. Overall, all these results indicate that the CS/SA composite hydrogel efficiently supported the adhesion, proliferation and differentiation of osteogenic and angiogenic cells. Together with its porous three-dimensional structure and injectable properties, CS/SA composite hydrogel possesses great potential for bone regeneration and tissue engineering applications. PMID- 23796408 TI - Functionalization of polyanhydride microparticles with di-mannose influences uptake by and intracellular fate within dendritic cells. AB - Innovative vaccine delivery platforms can facilitate the development of effective single-dose treatment regimens to control emerging and re-emerging infectious diseases. Polyanhydride microparticles are promising vaccine delivery vehicles due to their ability to stably maintain antigens, provide tailored release kinetics and function as adjuvants. A major obstacle for the use of microparticle based vaccines, however, is their limited uptake by dendritic cells (DCs). In this study, we functionalized the microparticle surface with di-mannose in order to target C-type lectin receptors (CLRs) on DCs. Polyanhydride particles based on sebacic acid (SA), 1,6-bis(p-carboxyphenoxy)hexane (CPH) and 1,8-bis(p carboxyphenoxy)-3,6-dioxaoctane (CPTEG) were evaluated. Co-incubation of di mannose-functionalized microparticles up-regulated the expression of CLRs on DCs. More importantly, di-mannose functionalization increased the uptake, as measured by the percentage of cells internalizing particles. The uptake of CPH:SA microparticles increased ~20-fold, from 0.82% (non-functionalized) to 20.2%, and internalization of CPTEG:CPH microparticles increased ~7-fold from 1.35% (non functionalized) to 9.3% upon di-mannose functionalization. Both di-mannose functionalized and non-functionalized particles trafficked to lysosomes. Together, these studies demonstrate that employing rational vaccine design principles, such as the targeting of CLRs on antigen-presenting cells, can enhance delivery of encapsulated antigens and potentially induce a more robust adaptive immune response. PMID- 23796409 TI - Profiling of steroid metabolites after transdermal and oral administration of testosterone by ultra-high pressure liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. AB - The screening of testosterone (T) misuse for doping control is based on the urinary steroid profile, including T, its precursors and metabolites. Modifications of individual levels and ratio between those metabolites are indicators of T misuse. In the context of screening analysis, the most discriminant criterion known to date is based on the T glucuronide (TG) to epitestosterone glucuronide (EG) ratio (TG/EG). Following the World Anti-Doping Agency (WADA) recommendations, there is suspicion of T misuse when the ratio reaches 4 or beyond. While this marker remains very sensitive and specific, it suffers from large inter-individual variability, with important influence of enzyme polymorphisms. Moreover, use of low dose or topical administration forms makes the screening of endogenous steroids difficult while the detection window no longer suits the doping habit. As reference limits are estimated on the basis of population studies, which encompass inter-individual and inter-ethnic variability, new strategies including individual threshold monitoring and alternative biomarkers were proposed to detect T misuse. The purpose of this study was to evaluate the potential of ultra-high pressure liquid chromatography (UHPLC) coupled with a new generation high resolution quadrupole time-of-flight mass spectrometer (QTOF-MS) to investigate the steroid metabolism after transdermal and oral T administration. An approach was developed to quantify 12 targeted urinary steroids as direct glucuro- and sulfo-conjugated metabolites, allowing the conservation of the phase II metabolism information, reflecting genetic and environmental influences. The UHPLC-QTOF-MS(E) platform was applied to clinical study samples from 19 healthy male volunteers, having different genotypes for the UGT2B17 enzyme responsible for the glucuroconjugation of T. Based on reference population ranges, none of the traditional markers of T misuse could detect doping after topical administration of T, while the detection window was short after oral TU ingestion. The detection ability of the 12 targeted steroids was thus evaluated by using individual thresholds following both transdermal and oral administration. Other relevant biomarkers and minor metabolites were studied for complementary information to the steroid profile, including sulfoconjugated analytes and hydroxy forms of glucuroconjugated metabolites. While sulfoconjugated steroids may provide helpful screening information for individuals with homozygotous UGT2B17 deletion, hydroxy glucuroconjugated analytes could enhance the detection window of oral T undecanoate (TU) doping. PMID- 23796411 TI - Identification of mutations in the genome of rotavirus SA11 temperature-sensitive mutants D, H, I and J by whole genome sequences analysis and assignment of tsI to gene 7 encoding NSP3. AB - The complete coding sequences of the four unassigned temperature-sensitive (ts) Baylor prototype rotavirus mutants (SA11ts D, H, I and J) were sequenced by deep sequencing double-stranded RNA using RNA-seq. Non-silent mutations were assigned to a specific mutant by Sanger sequencing RT-PCR products from each mutant. Mutations that led to amino acid changes were found in all genes except for genes 1 (VP1), 10 (NSP4) and 11 (NSP5/6). Based on these sequence analyses and earlier genetic analyses, the ts mutations in gene 7, which encodes the protein NSP3, were assigned to ts mutant groups I and H, and confirmed by an in vitro RNA binding assay with recombinant proteins. In addition, ts mutations in gene 6 were assigned to tsJ. The presence of non-conservative mutations in two genes of two mutants (genes 4 and 2 in tsD and genes 3 and 7 in tsH) underscores the necessity of sequencing the whole genome of each rotavirus ts mutant prototype. PMID- 23796412 TI - On the experience of stigma by persons with epilepsy in Sweden and Iran--a comparative study. AB - PURPOSE: The aim of this paper is to compare the experience of stigma by persons with epilepsy in Sweden and Iran. METHOD: An adapted version of the Internalized Stigma of Mental Illness Scale was completed by 130 persons with epilepsy in Tehran and 93 patients at a neurology clinic in Sweden. RESULTS: The Swedish subjects reported a significantly lower level of experienced stigmatization than the Iranian patients, which we think is an effect of a more individualized medical treatment and a longer experience of health education in the Swedish society. CONCLUSION: Improved seizure control, legislative measures and health education are major contributory factors for stigma reduction in a society as regards epilepsy and probably also other medical conditions. PMID- 23796413 TI - Further experience with distal aortic perfusion and motor-evoked potential monitoring in the management of extent I-III thoracoabdominal aortic anuerysms. AB - BACKGROUND: Prior studies indicated improved early mortality and paraplegia rates in a small cohort of patients with type I-III thoracoabdominal aortic aneurysms (TAAs) treated with atriofemoral bypass (AFB) and motor-evoked potentials (MEVPs) when compared with a propensity-matched cohort of patients treated with the clamp and sew (CS) method, wherein epidural cooling was the principal spinal cord protective adjunct. The use of AFB/MEVP increases the complexity of TAA repair and in this study, we address whether the early benefits will be sustained when this is applied to a general population with type I-III TAAs. METHODS: Consecutive patients undergoing repair of nonruptured Crawford extent I-III TAAs from 1/1987 to 12/2011 were identified. Patients were stratified according to operative approach (AFB/MEVP vs CS). Endpoints included long-term survival, and the composite outcome of perioperative death and paraplegia. A multivariate, risk adjusted model was then created to determine if operative approach independently influenced outcome. RESULTS: There were 485 patients (CS = 385 [79%]; AFB/MEVP = 100 [21%]). The cohorts differed in that the AFB/MEVP group was younger (65.8 +/- 12.5 years vs 70.9 +/- 9.7 years; P < .001), had more extent I/II aneurysms (66% vs 50.1%; P = .005), and had more chronic dissections (30.3% vs 18.9%; P = .018). Operative variables differed in that the AFB/MEVP cohort had longer operative times (434 +/- 112 minutes vs 324 +/- 98 minutes; P < .001) and higher blood turnover (6028 +/- 3473 mL vs 3581 +/- 3111 mL; P < .0001). There was no difference in the rate of intraoperative death (AFB/MEVP = 1.0% vs CS = 0.5%; P = .50), length of intensive care unit stay (AFB/MEVP = 9.6 +/- 8.6 days vs CS = 9.5 +/- 12.3 days; P = .95) or hospital length of stay (AFB/MEVP = 19.9 +/- 12.6 days vs CS = 21.6 +/- 23.5 days; P = .49). The composite perioperative death and paraplegia rate was lower in the AFB/MEVP cohort (7% vs 19%; P = .004). The multivariate model for predictors of the composite outcome showed that AFB/MEVP was protective (odds ratio, 0.39; 95% confidence interval, 0.17-0.9; P = .028). Long-term (4-year) survival was improved in the AFB/MEVP group as well (73 +/- 6% vs 60 +/- 3%; P = .004). CONCLUSIONS: AFB/MEVP is an independent predictor of improved perioperative death and paraplegia rates as well as long-term survival in patients undergoing repair of type I-III TAAs and is the preferred operative strategy. PMID- 23796414 TI - Blood flow dynamics in patients with hemodialysis access-induced hand ischemia. AB - OBJECTIVE: Hand ischemia may occur in the presence of a hemodialysis arteriovenous fistula (AVF), but its pathophysiology is partly unclear. The aim of this observational study was to investigate flow characteristics of forearm arteries in patients with a brachial artery-based AVF suffering from hemodialysis access-induced distal ischemia (HAIDI). METHODS: A questionnaire scored hand ischemia in patients with HAIDI scheduled for revisional surgery (no symptoms of ischemia, 0 points; maximal ischemia, 500 points). Systolic index finger pressures (Pdig) and digital brachial index (DBI) were determined with open and compressed AVF. Blood flow direction and peak systolic velocity (PSV) were measured in radial and ulnar arteries using Doppler ultrasonography. Age- and sex matched hemodialysis patients without HAIDI served as controls (CONT). RESULTS: Questionnaire scores were 258 +/- 30 in patients with HAIDI (n = 10) compared with 31 +/- 16 in CONT (n = 10; P < .01). Pdig and DBI with open AVF were lower in the HAIDI group than the CONT group (Pdig 22 +/- 10 vs 102 +/- 10 mm Hg; DBI 0.18 +/- 0.08 vs 0.70 +/- 0.04; both P < .01). Ulnar artery PSV was lower in HAIDI compared with CONT patients (38 +/- 4 vs 56 +/- 3 cm/s; P < .01). Mean ulnar artery PSV was significantly correlated to Pdig (r = 0.87; P < .01) in contrast to mean radial artery PSV (r = 0.06; P = .81). Ulnar artery blood flow direction was always toward the ischemic hand (n = 20). However, blood flow was reversed in just a short segment of the proximal radial artery in one HAIDI patient but also in two CONT patients. CONCLUSIONS: Hand ischemia in hemodialysis patients with a brachial artery-based AVF is not caused by a reversed blood flow direction in forearm arteries. However, forearm blood flow is diminished in these patients leading to critically reduced arterial pressures in the hand. PMID- 23796415 TI - Development of a practical metabolite identification technique for non-targeted metabolomics. AB - Metabolite identification is one of the major challenges of non-targeted metabolomics involving liquid chromatography coupled with mass spectrometry (LC MS). Compound databases contain enormous numbers of records, which makes compound identification difficult in practice because each search will return a large number of candidates. We therefore developed a practical compound identification system using LC-MS with high mass accuracy and MS(n) capability, combined with a compound database. A large number of candidates were evaluated by score calculation based on a combination of formulae and spectral assignments. Here, we demonstrate this method using green tea extract as a model sample. We applied our approach to predict the structures of compounds of interest, and the correct identification of several candidates was confirmed by comparisons to analysis of chemical standards. PMID- 23796416 TI - A facile and efficient strategy to enhance hydrophilicity of zwitterionic sulfoalkylbetaine type monoliths. AB - In order to prepare zwitterionic HILIC monolithic columns with high polarity, the highly hydrophilic monomer N,N-dimethyl-N-acryloyloxyethyl-N-(3 sulfopropyl)ammonium betaine (SPDA) and crosslinker N,N'-methylenebisacrylamide (MBA) were employed for developing a novel sulfoalkylbetaine type stationary phase. The polymerization parameters were systematically optimized in order to obtain a satisfactory performance for column permeability, mechanical stability, hydrophilicity, efficiency and selectivity. Compared to the previously reported poly(N,N-dimethyl-N-methacryloxyethyl-N-(3-sulfopropyl)ammonium betaine-co ethylene dimethacrylate) (poly(SPE-co-EDMA)) monolith and the poly(SPDA-co-EDMA) monolith that we developed, a significantly enhanced hydrophilicity was obtained on the poly(SPDA-co-MBA) monolithic column, illustrated by the lowered critical composition of the mobile phase corresponding to the transition from the HILIC to the RP mode. Excellent permeability, reproducibility and stability were achieved on this optimized poly(SPDA-co-MBA) monolith. A column efficiency of 70,000plates/m was obtained for the analysis of bases at a linear velocity of 1.95mm/s. As expected, by studying the influence of mobile phase pH and salt concentration on their retention, a weak electrostatic repulsion interaction for negatively charged analytes was also observed at low organic solvent content on the poly(SPDA-co-MBA) monolithic column. The final optimized poly(SPDA-co-MBA) monolith exhibited good selectivity for a series of polar compounds, such as phenols, bases, benzoic acid derivatives, small peptides, urea and allantoin. PMID- 23796410 TI - Understanding and altering cell tropism of vesicular stomatitis virus. AB - Vesicular stomatitis virus (VSV) is a prototypic nonsegmented negative-strand RNA virus. VSV's broad cell tropism makes it a popular model virus for many basic research applications. In addition, a lack of preexisting human immunity against VSV, inherent oncotropism and other features make VSV a widely used platform for vaccine and oncolytic vectors. However, VSV's neurotropism that can result in viral encephalitis in experimental animals needs to be addressed for the use of the virus as a safe vector. Therefore, it is very important to understand the determinants of VSV tropism and develop strategies to alter it. VSV glycoprotein (G) and matrix (M) protein play major roles in its cell tropism. VSV G protein is responsible for VSV broad cell tropism and is often used for pseudotyping other viruses. VSV M affects cell tropism via evasion of antiviral responses, and M mutants can be used to limit cell tropism to cell types defective in interferon signaling. In addition, other VSV proteins and host proteins may function as determinants of VSV cell tropism. Various approaches have been successfully used to alter VSV tropism to benefit basic research and clinically relevant applications. PMID- 23796417 TI - Separation of closely eluting chloronaphthalene congeners by two-dimensional gas chromatography/quadrupole mass spectrometry: an advanced tool in the study and risk analysis of dioxin-like chloronaphthalenes. AB - Two capillary columns of different polarity were applied in a two-dimensional gas chromatography system coupled to a quadrupole mass spectrometric detection (GCxGC/qMS) in order to separate and identify all of the possible 22 isomers of tetra-, 14 of penta- and 10 of hexachloronaphthalene that may occur in selected industrial chemicals. The two-dimensional GCxGC separation was achieved using Rt beta DEXcst and DB-WAX phases, and data imaging was done by 2D and 3D mapping. This combination allows for the analysis of all tetra- to hexachloronaphthalene congeners in a single instrumental run without any pre-separation or fractionation of the analytes. The novel methodology described here can assist in the accurate determination and expression of dioxin-like toxicity of tetrachloronaphthalenes to octachloronaphthalene that are usually present as mixtures at least in abiotic materials such as technical chloronaphthalene formulations (e.g. Halowax mixtures), and wastes containing Halowaxes and other CN formulations. PMID- 23796418 TI - Dietary standards for school catering in France: serving moderate quantities to improve dietary quality without increasing the food-related cost of meals. AB - OBJECTIVE: To assess the impact on food-related cost of meals to fulfill the new compulsory dietary standards for primary schools in France. DESIGN: A descriptive study assessed the relationship between the level of compliance with the standards of observed school meals and their food-related cost. An analytical study assessed the cost of series of meals published in professional journals, and complying or not with new dietary standards. The costs were based on prices actually paid for food used to prepare school meals. MAIN OUTCOME MEASURE: Food related cost of meals. ANALYSIS: Parametric and nonparametric tests from a total of 42 and 120 series of 20 meals in the analytical and descriptive studies, respectively. RESULTS: The descriptive study indicated that meeting the standards was not related to cost. The analytical study showed that fulfilling the frequency guidelines increased the cost, whereas fulfilling the portion sizes criteria decreased it. Series of meals fully respecting the standards (ie, frequency and portion sizes) cost significantly less (-0.10 ?/meal) than series not fulfilling them, because the standards recommend smaller portion sizes. CONCLUSIONS AND IMPLICATIONS: Introducing portion sizes rules in dietary standards for school catering may help increase dietary quality without increasing the food cost of meals. PMID- 23796420 TI - miR-26a inhibits proliferation and motility in bladder cancer by targeting HMGA1. AB - It is increasingly clear that microRNAs play a crucial role in tumorigenesis. Recently, emerging evidence suggested that miR-26a is aberrantly expressed in tumor tissues. In our study, frequent down-regulation of miR-26a was observed in 10 human bladder cancer tissues. Forced expression of miR-26a in the bladder cancer cell line T24 inhibited cell proliferation and impaired cell motility. High mobility group AT-hook 1 (HMGA1), a gene that modulates cell cycle transition and cell motility, was verified as a novel target of miR-26a in bladder cancer. These findings indicate an important role for miR-26a in the molecular etiology of bladder cancer and implicate the potential application of miR-26a in bladder cancer therapy. PMID- 23796419 TI - Respiratory virus infections in hospitalized children and adults in Lao PDR. AB - BACKGROUND: Acute respiratory infections are an important cause of morbidity and mortality worldwide, with a major burden of disease in developing countries. The relative contribution of viruses in acute lower respiratory infections (ALRI) is, however, poorly documented in Lao PDR. OBJECTIVE: The objective of this study is to investigate the etiology of ALRI in patients of all ages in two hospitals of Laos. METHODS: Multiplex PCR/RT-PCR methods were used to target 18 major common respiratory viruses. Between August 2009 and October 2010, samples from 292 patients presenting with ALRI were collected. RESULTS AND CONCLUSION: Viruses were detected in 162 (55%) samples. In 48% (140/292) of the total ALRI cases, a single virus was detected while coinfections were observed in 8% (22/292) of the samples. The most frequent viruses were rhinovirus/enterovirus (35%), human respiratory syncytial virus (26%), and influenza viruses (13%). Parainfluenza viruses were detected in 9%, adenovirus in 6%, human metapneumovirus in 4%, coronaviruses (229E, NL63, OC43, HKU1) in 4%, and bocavirus in 3% of ALRI specimens. Most viral infections occurred in patients below 5 years of age. The distribution of viruses varied according to age-groups. No significant correlation was observed between the severity of the disease and the age of patients or the virus species. This study provides the description of viral etiology among patients presenting with ALRI in Lao PDR. Additional investigations are required to better understand the clinical role of the different viruses and their seasonality in Laos. PMID- 23796421 TI - RNA self-processing: formation of cyclic species and concatemers from a small engineered RNA. AB - We have engineered a self-processing RNA, derived from the hairpin ribozyme that runs through a cascade of cleavage and ligation reactions thereby changing its topology. The first two cleavage events leave the resulting RNA with a 5'-OH group and a 2',3'-cyclic phosphate. Thus, upon refolding, intramolecular ligation delivers a cyclic species. In addition, we demonstrate formation of concatemers resulting from multiple intermolecular ligations. Our results demonstrate the potential of RNA for self-supported topology changes and support the suggestion of 2',3'-cyclic phosphates being suitable activated building blocks for reversible phosphodiester bond formation in the RNA world. PMID- 23796422 TI - Long-term outcome of intravenous therapy with rituximab in patients with primary cutaneous B-cell lymphomas. AB - BACKGROUND: The monoclonal antibody rituximab directed against the B-cell antigen CD20 was approved for the treatment of B-cell lymphomas and maintenance therapy in follicular lymphomas more than a decade ago. However, median follow-up in case series of intravenous rituximab therapy in primary cutaneous B-cell lymphomas (CBCL) lasts only up to 3 years. We retrospectively analysed a cohort of CBCL patients treated with rituximab to gain more long term information. PATIENTS AND METHODS: Eighteen patients, treated intravenously with rituximab for a primary cutaneous B-cell lymphoma [follicle centre lymphoma (PCFCL), n = 11; diffuse large B-cell lymphoma, leg type (PCLBCL, leg type), n = 5; marginal zone B-cell lymphoma (PCMZL), n = 2] were included. The response rate (RR), time to relapse (TTR), and course of the disease after treatment were analysed. RESULTS: The overall RR was 89% (16 of 18 patients). Within the median follow-up time of 52 months, 81% (13 of 16) of patients experienced a relapse; the median TTR was 25 months. The duration of remission was significantly shorter in patients presenting with generalized skin lesions at start of therapy. Both nonresponding patients suffered from PCLBCL, leg type, with extracutaneous manifestations. In responders severe adverse events, the occurrence of extracutaneous dissemination or nodal lymphomas were not observed during follow-up. CONCLUSIONS: Therapy with rituximab is effective and safe for the treatment of PCFCL, but relapses, in particular in patients with generalized skin involvement, are commonly observed. However, all patients with relapses responded well to treatment and therefore maintenance therapy does not seem to be indicated. Patients with PCLBCL, leg type, should receive chemotherapy in addition to rituximab. PMID- 23796423 TI - David Frank, the editor in chief, tasked us with the preparation of this August issue. Introduction. PMID- 23796424 TI - Simultaneous production of high quality biodiesel and glycerin from Jatropha oil using ion-exchange resins as catalysts and adsorbent. AB - The simultaneous production of high quality biodiesel and glycerin was realized by a bench-scale process using expanded-bed reactors packed with cation- and anion-exchange resins. The mixed-solution of crude Jatropha oil and methanol at a stoichiometric molar ratio was supplied to the process. The free fatty acid as well as triglyceride was completely converted to biodiesel. All by-products were adsorbed on the resin and the effluent from the process was free from them. The effluent fully met the international biodiesel standard specifications without any downstream purification processes except for removing methanol. The glycerin adsorbed on the resin was completely recovered as a transparent methanol solution during regeneration of the resin. PMID- 23796425 TI - West Africa's drug trade: reasons for concern and hope. PMID- 23796426 TI - Incidental detection of Hurthle cell adenoma by 18F-choline PET/CT scan in a patient with prostate cancer. PMID- 23796427 TI - Personalized medicine: predicting the risk of complications of cancer therapy. PMID- 23796428 TI - Capillary electrophoresis-mass spectrometry reveals the distribution of carbon metabolites during nitrogen starvation in Synechocystis sp. PCC 6803. AB - Nitrogen availability is one of the most important factors for the survival of cyanobacteria. Previous studies on Synechocystis revealed a contradictory situation with regard to metabolism during nitrogen starvation; that is, glycogen accumulated even though the expressions of sugar catabolic genes were widely upregulated. Here, we conducted transcript and metabolomic analyses using capillary electrophoresis-mass spectrometry on Synechocystis sp. PCC 6803 under nitrogen starvation. The levels of some tricarboxylic acid cycle intermediates (succinate, malate and fumarate) were greatly increased by nitrogen deprivation. Purine and pyrimidine nucleotides were markedly downregulated under nitrogen depletion. The levels of 19 amino acids changed under nitrogen deprivation, especially those of amino acids synthesized from pyruvate and phosphoenolpyruvate, which showed marked increases. Liquid chromatography-mass spectrometry analysis demonstrated that the amount of NADPH and the NADPH/NADH ratio decreased under nitrogen depletion. These data demonstrate that there are increases in not only glycogen but also in metabolites downstream of sugar catabolism in Synechocystis sp. PCC 6803 under nitrogen starvation, resolving the contradiction between glycogen accumulation and induction of sugar catabolic gene expression in this unicellular cyanobacterium. PMID- 23796429 TI - Antimicrobial activity of Willowherb (Epilobium angustifolium L.) leaves and flowers. AB - Since the aetiology of benign prostatic hyperplasia (BHP) is still unknown, the use of medicinal herb extracts and products prepared thereof are recommended due to their antimicrobial activity, especially during early stages of BHP. A comparison was performed of the in vitro antimicrobial activity (using broth microdilution assay) of flowers and leaves of willowherb (Epilobium angustifolium L., Onagraceae) from Mt. Velebit (Croatia). The strains (standard ATCC and clinical isolates) of Staphylococcus aureus (including MRSA), Bacillus subtilis, Escherichia coli (including p-fimbriae positive strain), Pseudomonas aeruginosa, Proteus mirabilis, Candida albicans, C. tropicalis, C. dubliniensis and Saccharomyces cerevisiae were susceptible with MIC values between 4.6+/-0.2 and 18.2+/-0.8 mg/mL. The results of in vitro studies showed that no differences were found in the antimicrobial activity between the ethanol extracts of leaves and flowers of E. angustifolium. Using the quantitative fluorescent assay with ethidium bromide and acridine orange, the viability of C. albicans ATCC 10231 was assessed after in vitro exposure to E. angustifolium leaf and flower ethanol extracts. Apoptosis of C. albicans blastospores dominated over necrosis in all treated samples after short-term exposure with 6 to 12 mg/mL of extracts. In addition to the valuable biological activity of E. angustifolium extracts, the data obtained from the in vitro diffusion, the dilution assay and antifungal viability fluorescent assay suggest that leaf and flower ethanol extracts of E. angustifolium L. are a promising complementary herbal therapy of conditions such as BHP. PMID- 23796430 TI - Material property discontinuities in intervertebral disc porohyperelastic finite element models generate numerical instabilities due to volumetric strain variations. AB - Numerical studies of the intervertebral disc (IVD) are important to better understand the load transfer and the mechanobiological processes within the disc. Among the relevant calculations, fluid-related outputs are critical to describe and explore accurately the tissue properties. Porohyperelastic finite element models of IVD can describe accurately the disc behaviour at the organ level and allow the inclusion of fluid effects. However, results may be affected by numerical instabilities when fast load rates are applied. We hypothesized that such instabilities would appear preferentially at material discontinuities such as the annulus-nucleus boundary and should be considered when testing mesh convergence. A L4-L5 IVD model including the nucleus, annulus and cartilage endplates were tested under pure rotational loads, with different levels of mesh refinement. The effect of load relaxation and swelling were also studied. Simulations indicated that fluid velocity oscillations appeared due to numerical instability of the pore pressure spatial derivative at material discontinuities. Applying local refinement only was not enough to eliminate these oscillations. In fact, mesh refinements had to be local, material-dependent, and supplemented by the creation of a material transition zone, including interpolated material properties. Results also indicated that oscillations vanished along load relaxation, and faster attenuation occurred with the incorporation of the osmotic pressure. We concluded that material discontinuities are a major cause of instability for poromechanical calculations in multi-tissue models when load velocities are simulated. A strategy was presented to address these instabilities and recommendations on the use of IVD porohyperelastic models were given. PMID- 23796432 TI - Can bioadhesive nanoparticles allow for more effective particle uptake from the small intestine? AB - There has been increasing interest in developing bioadhesive nanoparticles due to their great potential as carriers for therapeutics in oral drug delivery systems. Despite decades of research, such a system still has not been successfully implemented. This paper demonstrates the enormous potential of such engineered systems: the incorporation of a bioadhesive coating, poly(butadiene-maleic anhydride-co-L-DOPA) (PBMAD), to non-bioadhesive nanospheres resulted in an enhancement of particle uptake in the small intestine from 5.8+/-1.9% to 66.9+/ 12.9%. Direct correlation was obtained between bulk tensile strength, in vitro binding to everted intestinal sacs and quantitative in vivo uptake; this data suggests that bulk properties of polymers can be used to predict bioadhesive properties of nano- and microparticles. The differential distribution of the nanospheres to various tissues following uptake suggests surface chemistry plays a significant role in their localization within the body. The results of these studies provide strong support for the use of bioadhesive polymers to enhance nano- and micro-particle uptake from the small intestine for oral drug delivery. PMID- 23796431 TI - Design and evaluation of new pH-sensitive amphiphilic cationic lipids for siRNA delivery. AB - Synthetic small interfering RNA (siRNA) has become the basis of a new generation of gene-silencing cancer therapeutics. However, successful implementation of this novel therapy relies on the ability to effectively deliver siRNA into target cells and to prevent degradation of siRNA in lysosomes after endocytosis. In this study, our goal was to design and optimize new amphiphilic cationic lipid carriers that exhibit selective pH-sensitive endosomal membrane disruptive capabilities to allow for the efficient release of their siRNA payload into the cytosol. The pH sensitive siRNA carriers consist of three domains (cationic head, hydrophobic tail, amino acid-based linker). A library of eight lipid carriers were synthesized using solid phase chemistry, and then studied to determine the role of (1) the number of protonable amines and overall pKa of the cationic head group, (2) the degree of unsaturation of the hydrophobic tail, and (3) the presence of histidine residues in the amino acid linker for transfection and silencing efficacy. In vitro screening evaluation of the new carriers demonstrated at least 80% knockdown of a GFP reporter in CHO cells after 72h. The carriers ECO and ECLn performed the best in a luciferase knockdown study in HT29 human colon cancer cells, which were found to be more difficult to transfect. They significantly reduced expression of this reporter to 22.7+/-3.31% and 23.5+/ 5.11% after 72h post-transfection, better than Lipofectamine RNAiMax. Both ECO and ECLn carriers caused minimal cytotoxicity, preserving relative cell viabilities at 87.3+/-2.72% and 88.9+/-6.84%, respectively. A series of hemolysis assays at various pHs revealed that increasing the number of amines in the protonable head group, and removing the histidine residue from the linker, both resulted in improved membrane disruptive activity at the endosomal pH of 6.5. Meanwhile, the cellular uptake into HT29 cancer cells was improved, not only by increasing the amines of the head group, but also by increasing the degree of unsaturation in the lipid tails. Due to flexibility of the synthetic procedure, the delivery system could be modified further for different applications. The success of ECO and ECLn for in vitro siRNA delivery potentially makes them promising candidates for future in vivo studies. PMID- 23796433 TI - Genetic diversity and substantial population differentiation in Crassostrea hongkongensis revealed by mitochondrial DNA. AB - The Hong Kong oyster, Crassostrea hongkongensis, is an important fisheries resource that is cultivated in the coastal waters of the South China Sea. Despite significant advances in understanding biological and taxonomic aspects of this species, no detailed study of its population genetic diversity in regions of extensive cultivation are available. Direct sequencing of the mtDNA cox1 gene region was used to investigate genetic variation within and between eleven C. hongkongensis populations collected from typical habitats. Sixty-two haplotypes were identified; only haplotype 2 (21.74% of total haplotypes) was shared among all the eleven populations, and most of the observed haplotypes were restricted to individual populations. Both AMOVA and FST analyses revealed significant population structure, and the isolation by distance (IBD) was confirmed. The highest local differentiation was observed between the sample pools from Guangxi versus Guangdong and Fujian, which are separated by a geographic barrier, the Leizhou Peninsula. Current knowledge from seed management suggests that seed transfer from Guangxi province has likely reduced the divergence that somewhat naturally exists between these pools. The findings from the present study could be useful for genetic management and may serve as a baseline by which to monitor future changes in genetic diversity, either due to natural or anthropogenic impacts. PMID- 23796434 TI - Conserved microRNAs miR-8-5p and miR-2a-3p modulate chitin biosynthesis in response to 20-hydroxyecdysone signaling in the brown planthopper, Nilaparvata lugens. AB - Molting is an important developmental process in insects, usually along with synthesis and degradation of chitin. 20-hydroxyecdysone (20E), an insect hormone, has been reported to contribute to many processes including molting. However, little is known about the link between the chitin biosynthesis pathway and 20E signaling. Here, we report that conserved miR-8-5p (miR-8-5p) and miR-2a-3p and their new target genes are critical for ecdysone-induced chitin biosynthesis in a hemipteran insect Nilaparvata lugens. We found that membrane-bound trehalase (Tre 2) and phosphoacetylglucosamine mutase (PAGM) in the chitin biosynthesis pathway were targets of miR-8-5p and miR-2a-3p, respectively, through bioinformatic analysis and experimental verification. The levels of miR-8-5p and miR-2a-3p were reduced, whereas the levels of Tre-2 and PAGM were up-regulated in response to 20E. In addition, miR-8-5p and miR-2a-3p were transcriptionally repressed by an early-response gene, the Broad-Complex (BR-C), in the 20E signaling pathway. Moreover, the overexpression of miR-8-5p and miR-2a-3p led to a significant reduction in the survival rate along with a molting obstacles defect phenotype caused by miR-2a-3p mimics feeding, and the chitin content of N. lugens was simultaneously reduced. Thus, miR-8-5p and miR-2a-3p act as molecular link that tune the chitin biosynthesis pathway in response to 20E signaling. PMID- 23796435 TI - De novo characterization of transcriptome and gene expression dynamics in epidermis during the larval-pupal metamorphosis of common cutworm. AB - Larval cuticle is degraded and replaced by the pupal counterpart during larval pupal metamorphosis in the holometabolous insects. In addition to the extrinsic transformation, the epidermis goes through significant changes at molecular levels. To elucidate the intrinsic mechanism of epidermal metamorphosis, the dynamics of chitin content in the cuticle was examined in an important agricultural lepidopteran, the common cutworm, and the transcriptome was analyzed using Illumina sequencing technology. Gene expression profiles during the metamorphosis were further studied by both the digital gene expression (DGE) system and real-time quantitative PCR. The results showed that the chitin content decreased in prepupae and then increased in pupae. A total of 58 million sequencing reads were obtained and assembled into 70,346 unigenes. Over 9000 unigenes were identified to express differentially during the transformation process. As compared with the 6th instar feeding larvae, the most significant changes took place in the proteasome and metabolic pathways in prepupae and pupae, respectively. The cytochrome P450s, VHDLs, chitinase, serine protease and genes involved in sex pheromone biosynthesis changed their mRNA levels remarkably. Three chitinolytic enzymes (chitinase, beta-N-acetylglucosaminidase and chitin deacetylase) showed distinct mRNA expression patterns, the former two enzymes revealed the highest expression in prepupae, however the latter one showed its climax mRNA level in pupae. The gene expression patterns suggest that chitinase and beta-N-acetylglucosaminidase may be responsible for the degradation of larval cuticles, whereas chitin deacetylase may help to degrade the pupal counterparts. Gene expression dynamics also implied that the chitin of pupal cuticle might be formed by recycling of the degraded chitin of larval cuticle rather than through de novo synthesis. The 20E-induced nuclear receptors seem to be important factors regulating chitin metabolic enzymes during the cuticle remodeling. Our data provide a comprehensive resource for exploring the molecular mechanism of epidermal metamorphosis in insects. PMID- 23796436 TI - Regulation of sleep by the short neuropeptide F (sNPF) in Drosophila melanogaster. AB - The short neuropeptide F (sNPF), a neuropeptide in the central nervous system (CNS) of Drosophila melanogaster, is expressed in a large population of diverse neurons of brain. Most of these neurons are intrinsic interneurons of the mushroom bodies, which are the most prominent insect bilateral CNS structures that regulate memory and sleep. However, its role in sleep regulation still remains elusive. Here, we showed that sNPF-deficient female and male flies exhibit sleep enhancement with an increase of sleep bout duration. Loss of function of sNPF and sNPFR1 also elevated sleep. Moreover, the homeostatic regulation of flies after sleep deprivation was disrupted by aberrant sNPF signaling, since sleep deprivation increased transcription of sNPF and wakefulness at night in control flies but not in the sNPF mutant flies, suggesting that sNPF autoregulation plays an important role in sleep homeostasis. We further verified that sNPF signal elevated cAMP levels, and subsequently activated the downstream CREB transcription factor. The duration of sleep was found to be inversely related to cAMP signaling and CREB activity in the mushroom bodies. Thus, we concluded that sleep might be regulated by sNPF through modulating the cAMP-PKA-CREB signal pathway in vivo. PMID- 23796437 TI - Differential effects of genetic susceptibility factors in males and females with multiple sclerosis. AB - Multiple sclerosis (MS), a putative autoimmune disease, has a well documented female preponderance among patients. However, this is not the only sex effect observed in the disease. Unaffected mothers appear to be at a higher risk to transmit susceptibility (genetic, environmental or interactions thereof) compared to unaffected fathers. This maternal effect can range from intrauterine exposures to transmission of genotypes and epigenetics. PMID- 23796438 TI - Outcome of angiographic embolisation for unstable pelvic ring injuries: Factors predicting success. AB - INTRODUCTION: Angiographic embolisation (AE) is a successful treatment for haemodynamically unstable pelvic ring injuries. However, recent evidence has shown a significant complication rate following AE together with a lower success rate than previously reported. The aim of the current study was to review and indentify the factors predicting success or failure of AE. PATIENTS AND METHODS: 651 patients with high energy (ISS>16) pelvic ring injuries were treated in our institution between the years 1997 and 2009. Mean patient age was 37 (range 5-89) years, and the average ISS 33.4 (range 16-66). Patients' information was collected from the institution's trauma registry as well as from the patient's medical chart and radiographs. Data included age, ISS, length of stay, ICU stay, initial blood pressure and pulse, blood products consumption, blood creatinine levels, fracture type and treatment, embolisation details, complications and mortality. 61 patients (9.3%) underwent urgent angiography due to haemodynamic instability. Angiography was positive (PA) in 38 patients (62.3%) and was negative for haemorrhage (NA) in the remaining 23 (37.7%). RESULTS: Ten patients required a branch vessel embolisation while 17 patients required major vessel embolisation, 11 required bilateral internal iliac embolisation and three patients underwent multiple vessel embolisation. Overall mortality rate was 26%. 32 patients required surgical intervention for pelvic ring stabilisation. Significant reduction in blood transfusion was seen in patients with an APC fracture type following AE. No significant correlation was found between fracture type and mortality. Multiple vessel embolisations were associated with increased surgical complications and mortality. DISCUSSION: Angiographic embolisation provides a reasonable option for haemodynamically unstable pelvic ring injured patients with an acceptable outcome, supporting previously reported literature. Patients with unstable APC type pelvic fracture may benefit the most from early angiographic embolisation. Patients requiring multiple vessel embolisation have a guarded outcome. PMID- 23796439 TI - Collection and visualization of dietary behavior and reasons for eating using Twitter. AB - BACKGROUND: Increasing an individual's awareness and understanding of their dietary habits and reasons for eating may help facilitate positive dietary changes. Mobile technologies allow individuals to record diet-related behavior in real time from any location; however, the most popular software applications lack empirical evidence supporting their efficacy as health promotion tools. OBJECTIVE: The purpose of this study was to test the feasibility and acceptability of a popular social media software application (Twitter) to capture young adults' dietary behavior and reasons for eating. A secondary aim was to visualize data from Twitter using a novel analytic tool designed to help identify relationships among dietary behaviors, reasons for eating, and contextual factors. METHODS: Participants were trained to record all food and beverages consumed over 3 consecutive days (2 weekdays and 1 weekend day) using their mobile device's native Twitter application. A list of 24 hashtags (#) representing food groups and reasons for eating were provided to participants to guide reporting (eg, #protein, #mood). Participants were encouraged to annotate hashtags with contextual information using photos, text, and links. User experience was assessed through a combination of email reports of technical challenges and a 9-item exit survey. Participant data were captured from the public Twitter stream, and frequency of hashtag occurrence and co-occurrence were determined. Contextual data were further parsed and qualitatively analyzed. A frequency matrix was constructed to identify food and behavior hashtags that co occurred. These relationships were visualized using GMap algorithmic mapping software. RESULTS: A total of 50 adults completed the study. In all, 773 tweets including 2862 hashtags (1756 foods and 1106 reasons for eating) were reported. Frequently reported food groups were #grains (n=365 tweets), #dairy (n=221), and #protein (n=307). The most frequently cited reasons for eating were #social (activity) (n=122), #taste (n=146), and #convenience (n=173). Participants used a combination of study-provided hash tags and their own hash tags to describe behavior. Most rated Twitter as easy to use for the purpose of reporting diet related behavior. "Maps" of hash tag occurrences and co-occurrences were developed that suggested time-varying diet and behavior patterns. CONCLUSIONS: Twitter combined with an analytical software tool provides a method for capturing real-time food consumption and diet-related behavior. Data visualization may provide a method to identify relationships between dietary and behavioral factors. These findings will inform the design of a study exploring the use of social media and data visualization to identify relationships between food consumption, reasons for engaging in specific food-related behaviors, relevant contextual factors, and weight and health statuses in diverse populations. PMID- 23796440 TI - Breast cancer surgery and suction drains: to do or not to do! PMID- 23796441 TI - Competition of zinc(II) with cadmium(II) or mercury(II) in binding to a 12-mer peptide. AB - Speciation of the complexes of zinc(II) with a dodecapeptide (Ac-SCPGDQGSDCSI NH2), inspired by the metal binding domain of MerR metalloregulatory proteins, have been studied by pH-potentiometric titrations, UV, SRCD (synchrotron radiation circular dichroism) and (1)H NMR experiments. (MerR is a family of transcriptional regulators the archetype of which is the Hg(2+)-responsive transcriptional repressor-activator MerR protein.) The aim of the ligand-design was to retain the advantageous metal binding features of MerR proteins in a model peptide for the efficient capture of toxic metal ions. The peptide binds zinc(II) via two deprotonated Cys-thiol groups and one of the Asp-carboxylates in the ZnL parent complex, possessing a remarkably high stability (logK=9.93). In spite of the relatively long peptide loop, bis-complexes are also formed with the metal ion under basic conditions. In a competition with cadmium(II) or mercury(II), zinc(II) cannot prevent the binding of toxic metal ions by the thiolate donor groups of the ligand. Around neutral pH one equivalent of mercury(II) was shown to fully replace zinc(II) from the ZnL species. Partial replacement of zinc(II) from the peptide by one equivalent of cadmium(II), relative to zinc(II) and the ligand, is also presumable, nevertheless, spectroscopic data may suggest the formation of mixed metal ion complexes, as well. Based on the obtained results the investigated dodecapeptide can be a promising candidate for capturing toxic metal ions in practical applications. PMID- 23796442 TI - Insertion of beta-alanine in model peptides for copper binding to His96 and His111 of the human prion protein. AB - The prion protein coordinates copper with high affinity in the regions encompassing residues 92-99 (GGGTHSQW) and 106-115 (KTNMKHMAGA). Cu(II) binding to these sites involves the coordination of the His96/His111 imidazole ring and backbone deprotonated amides that precede the His residue. Such a coordination arrangement involves the formation of hexa- and penta-membered cycles that provide further stabilization of the metal-peptide complex. The purpose of the present study is to introduce a methylene group in the peptide backbone, to evaluate the impact of increasing the size of these cycles in Cu(II) binding. Thus, a beta-alanine residue was inserted at different positions preceding the His residue in these prion fragments, and their Cu(II) coordination properties were assessed by UV-Visible absorption, circular dichroism, and electron paramagnetic resonance. Spectroscopic data show that the insertion of a methylene group leads to a completely different Cu(II) coordination that involves the His96/His111 imidazole ring and nitrogen or oxygen atoms provided by the peptide backbone towards the C-terminal. This study clearly shows that two main factors determine the nature of Cu(II)-peptide complexes involving an anchoring His residue and deprotonated amides from the backbone chain: i) the stabilization of Cu(II)-peptide complexes due to the formation of cyclic structures (i.e. chelate effect) and ii) the nature of the residues associated to the deprotonated amide groups that participate in metal ion coordination. PMID- 23796443 TI - TGF-beta1 promotes transition of mesothelial cells into fibroblast phenotype in response to peritoneal injury in a cell culture model. AB - BACKGROUND: Peritoneal adhesions are a clinical problem. A key to the understanding of peritoneal adhesions is to study the healing of mesothelial cells within the peritoneal cavity following surgery. Transforming growth factor beta (TGF-betas) affects this healing process. The aim of this study was to investigate the effects of different concentrations of TGF-beta1 on the healing rate and healing properties of mesothelial cells. MATERIALS AND METHODS: Human mesothelial cells from peritoneal fluid were collected, cultured and a mechanical wound was created. The restoration of the mesothelial surface with and without increasing concentrations of TGF-beta1 was monitored. RESULTS: The denuded area was restored within 24 h. The healing rate was most extensive between the first and second hour after the damage (61.9 +/- 22.8 MUm/h). No significant difference in healing rate were observed when increasing levels of TGF-beta1 were used. However, higher concentrations of TGF-beta1 increased cell size and the cells presented more fibroblast specific properties. Lower TGF-beta1 concentrations increased the number of proliferating cells. CONCLUSIONS: This study indicates the importance of high levels TGF-beta1 in mesothelial cell healing, mainly by changing the actual healing properties of the cells. Elevated levels of TGF-beta1 might promote mesothelial cell transition towards a more fibroblast-like appearance. PMID- 23796444 TI - The introduction of an acute physiological support service for surgical patients is an effective error reduction strategy. AB - INTRODUCTION: Acute surgical patients are particularly vulnerable to human error. The Acute Physiological Support Team (APST) was created with the twin objectives of identifying high-risk acute surgical patients in the general wards and reducing both the incidence of error and impact of error on these patients. A number of error taxonomies were used to understand the causes of human error and a simple risk stratification system was adopted to identify patients who are particularly at risk of error. RESULTS: During the period November 2012-January 2013 a total of 101 surgical patients were cared for by the APST at Edendale Hospital. The average age was forty years. There were 36 females and 65 males. There were 66 general surgical patients and 35 trauma patients. Fifty-six patients were referred on the day of their admission. The average length of stay in the APST was four days. Eleven patients were haemo-dynamically unstable on presentation and twelve were clinically septic. The reasons for referral were sepsis,(4) respiratory distress,(3) acute kidney injury AKI (38), post-operative monitoring (39), pancreatitis,(3) ICU down-referral,(7) hypoxia,(5) low GCS,(1) coagulopathy.(1) The mortality rate was 13%. A total of thirty-six patients experienced 56 errors. A total of 143 interventions were initiated by the APST. These included institution or adjustment of intravenous fluids (101), blood transfusion,(12) antibiotics,(9) the management of neutropenic sepsis,(1) central line insertion,(3) optimization of oxygen therapy,(7) correction of electrolyte abnormality,(8) correction of coagulopathy.(2) CONCLUSION: Our intervention combined current taxonomies of error with a simple risk stratification system and is a variant of the defence in depth strategy of error reduction. We effectively identified and corrected a significant number of human errors in high-risk acute surgical patients. This audit has helped understand the common sources of error in the general surgical wards and will inform on-going error reduction initiatives. PMID- 23796445 TI - The short-term outcome in esophagogastric junctional adenocarcinoma patients receiving total gastrectomy: laparoscopic versus open gastrectomy--a retrospective cohort study. AB - OBJECTIVE: This study aimed to compare the quality of life in Siewert type II esophagogastric junctional adenocarcinoma patients receiving either laparoscopic total gastrectomy or open total gastrectomy. METHODS: From Sep 1, 2008 to May 1, 2012, totally 204 consecutive patients with Siewert type II esophagogastric junctional adenocarcinoma were involved in this retrospective study. Patients were assigned to receive either laparoscopic total gastrectomy or open total gastrectomy. Details concerning the postoperative outcomes and the quality of life questionnaire were collected and compared. RESULTS: Totally 104 patients were involved in the open gastrectomy group and 100 in the laparoscopic gastrectomy group. No differences were noted between the groups in demographics, blood loss, anastomotic leak, anastomotic stricture, hospital stay, reoperation and in-hospital mortality. Totally 188 cases of patients (92.16%) responded to the questionnaire measures during the entire follow-up period, including 93 (93%) in the laparoscopic group and 95 (91.35%) in the open group. The score of every scale and item in laparoscopic group improved much more quickly comparing with the open group, suggesting that patients in laparoscopic group recovered much more quickly than those in open group. CONCLUSIONS: Laparoscopic total gastrectomy could lead to a significant improvement of the short-term benefits for patients with esophagogastric junctional adenocarcinoma as compared with open group. PMID- 23796446 TI - Establishing a regional enterocutaneous fistula service: the Royal London hospital experience. AB - BACKGROUND: The development of enterocutaneous fistula (ECF) is one of the most challenging complications encountered in colorectal surgery. Currently, only two supra-regional centres are nationally designated in the United Kingdom to treat ECF patients. The aim of this study was to assess clinical outcome measures following the implementation of an ECF service at The Royal London Hospital. METHODS: All patients diagnosed with enterocutaneous fistula between December 2005 and November 2011 were recruited to the study. Clinical outcomes analysed included successful ECF closure, number of surgical procedures required for successful ECF closure, re-fistulation rates and morbidity/mortality data. RESULTS: 41 patients (20 M:21 F) of median age 54 years (range, 16-81) were studied. Patients had undergone a median of 4 (range, 1-18) operations prior to referral. Eleven fistulas (27%) healed spontaneously. Of the remaining 30 patients, 5 (17%) died before surgery due to uncontrollable sepsis and 6 (20%) refused surgical intervention and were managed conservatively. Nineteen patients (63%) underwent definitive surgical repair requiring a median of 1 (range, 1-2) operations, with recurrent fistulation reported in 4 patients (21%). No intra operative mortality was encountered. Two (11%) patients died postoperatively due to cardio-respiratory complications. CONCLUSIONS: These data compare favourably with outcome measures reported by designated national centres, suggesting ECF patients can be safely managed closer to home in regional units that have the appropriate expertise. Nevertheless, management of this condition remains critically dependent upon a dedicated multidisciplinary team approach. PMID- 23796447 TI - The protective effect of curcumin on ischemia-reperfusion injury in rat ovary. AB - BACKGROUND: To evaluate the protective effects of curcumin in experimental ischemia and ischemia/reperfusion (I/R) injury of rat ovaries. METHODS: Forty eight female adult Wistar Albino rats were used. Rats divided into six groups and designed: Sham, Torsion, Detorsion, Sham + Curcumin, Torsion + Curcumin, and Detorsion + Curcumin. Except for the Sham and Sham + Curcumin group, all groups were performed to bilateral adnexal torsion for 3 h. Bilateral adnexal detorsion was implemented in the Detorsion and Detorsion + Curcumin groups. The injection of curcumin was intraperitoneally achieved 30 min before the sham, torsion and detorsion. RESULTS: Total oxidant status levels (TOS), oxidative stress index (OSI) and histologic scores values of ovarian tissue were higher in the torsion and detorsion groups than the sham group (p < 0.05). There was a strong correlation between the total histologic scores of I/R injury and the OSI (r = 0.809, p < 0.001). By the use of curcumin, a significant decrease was established in the mean levels of oxidant markers and histopathologic scores of the ovarian tissues. CONCLUSIONS: Administration of curcumin is effective in reversing tissue damage induced by ischemia-reperfusion injury in ovarian torsion. PMID- 23796448 TI - How to train an aspiring surgeon--experiences from Operation Hernia. PMID- 23796449 TI - Pinda: a web service for detection and analysis of intraspecies gene duplication events. AB - We present Pinda, a Web service for the detection and analysis of possible duplications of a given protein or DNA sequence within a source species. Pinda fully automates the whole gene duplication detection procedure, from performing the initial similarity searches, to generating the multiple sequence alignments and the corresponding phylogenetic trees, to bootstrapping the trees and producing a Z-score-based list of duplication candidates for the input sequence. Pinda has been cross-validated using an extensive set of known and bibliographically characterized duplication events. The service facilitates the automatic and dependable identification of gene duplication events, using some of the most successful bioinformatics software to perform an extensive analysis protocol. Pinda will prove of use for the analysis of newly discovered genes and proteins, thus also assisting the study of recently sequenced genomes. The service's location is http://orion.mbg.duth.gr/Pinda. The source code is freely available via https://github.com/dgkontopoulos/Pinda/. PMID- 23796450 TI - OLYMPUS: an automated hybrid clustering method in time series gene expression. Case study: host response after Influenza A (H1N1) infection. AB - The increasing flow of short time series microarray experiments for the study of dynamic cellular processes poses the need for efficient clustering tools. These tools must deal with three primary issues: first, to consider the multi functionality of genes; second, to evaluate the similarity of the relative change of amplitude in the time domain rather than the absolute values; third, to cope with the constraints of conventional clustering algorithms such as the assignment of the appropriate cluster number. To address these, we propose OLYMPUS, a novel unsupervised clustering algorithm that integrates Differential Evolution (DE) method into Fuzzy Short Time Series (FSTS) algorithm with the scope to utilize efficiently the information of population of the first and enhance the performance of the latter. Our hybrid approach provides sets of genes that enable the deciphering of distinct phases in dynamic cellular processes. We proved the efficiency of OLYMPUS on synthetic as well as on experimental data. The discriminative power of OLYMPUS provided clusters, which refined the so far perspective of the dynamics of host response mechanisms to Influenza A (H1N1). Our kinetic model sets a timeline for several pathways and cell populations, implicated to participate in host response; yet no timeline was assigned to them (e.g. cell cycle, homeostasis). Regarding the activity of B cells, our approach revealed that some antibody-related mechanisms remain activated until day 60 post infection. The Matlab codes for implementing OLYMPUS, as well as example datasets, are freely accessible via the Web (http://biosignal.med.upatras.gr/wordpress/biosignal/). PMID- 23796451 TI - Dip-pen-based direct writing of conducting silver dots. AB - Direct fabrication of micro- and nanoscale metallic structures is advantageous for many applications. Here, we use dip-pen lithography with silver(I) carboxylate [AgO2C(CH2OCH2)3H] in diethylene glycol as precursor ink for the generation of conducting metal structures. After annealing the written dots, solid silver structures are generated. We investigate the influence of several parameters such as substrate functionalization and ink composition on the pattern formation. We found that a substrate coating with perfluorinated silane is necessary, if diethylene glycol will be used as ink carrier. By variation in ink concentration and ink carrier composition, structures with diameters ranging from ~20 MUm to ~2 MUm and with metal fractions ranging from ~5% to ~80% were fabricated. After gold enhancement of the written patterns, resistivities in the range of 4*10(-5) Omegam on the structures were determined. The ink system introduced here appears promising for the direct fabrication of various metal or metal oxide patterns. PMID- 23796453 TI - Pin1 inhibitors: Pitfalls, progress and cellular pharmacology. AB - Compelling data supports the hypothesis that Pin1 inhibitors will be useful for the therapy of cancer: Pin1 deficient mice resist the induction of breast cancers normally evoked by expression of MMTV-driven Ras or Erb2 alleles. While Pin1 poses challenges for drug discovery, several groups have identified potent antagonists by structure based drug design, significant progress has been made designing peptidic inhibitors and a number of natural products have been found that blockade Pin1, notably epigallocatchechin gallate (EGCG), a major flavonoid in green tea. Here we critically discuss the modes of action and likely specificity of these compounds, concluding that a suitable chemical biology tool for probing the function of Pin1 has yet to be found. We conclude by outlining some open questions regarding the target validation of Pin1 and the prospects for identification of improved inhibitors in the future. PMID- 23796454 TI - Sandmeyer reaction repurposed for the site-selective, non-oxidizing radioiodination of fully-deprotected peptides: studies on the endogenous opioid peptide alpha-neoendorphin. AB - Standard radioiodination methods lack site-selectivity and either mask charges (Bolton-Hunter) or involve oxidative reaction conditions (chloramine-T). Opioid peptides are very sensitive to certain structural modifications, making these labeling methods untenable. In our model opioid peptide, alpha-neoendorphin, we replaced a tyrosyl hydroxyl with an iodine, and in cell lines stably expressing mu, delta, or kappa opioid receptors, we saw no negative effects on binding. We then optimized a repurposed Sandmeyer reaction using copper(I) catalysts with non redoxing/non-nucleophilic ligands, bringing the radiochemical yield up to around 30%, and site-selectively incorporated radioactive iodine into this position under non-oxidizing reaction conditions, which should be broadly compatible with most peptides. The (125)I- and (131)I-labeled versions of the compound bound with high affinity to opioid receptors in mouse brain homogenates, thus demonstrating the general utility of the labeling strategy and of the peptide for exploring opioid binding sites. PMID- 23796455 TI - Central obesity in asymptomatic volunteers is associated with increased intrasphincteric acid reflux and lengthening of the cardiac mucosa. AB - BACKGROUND & AIMS: In the West, a substantial proportion of subjects with adenocarcinoma of the gastric cardia and gastroesophageal junction have no history of reflux. We studied the gastroesophageal junction in asymptomatic volunteers with normal and large waist circumferences (WCs) to determine if central obesity is associated with abnormalities that might predispose individuals to adenocarcinoma. METHODS: We performed a study of 24 healthy, Helicobacter pylori-negative volunteers with a small WC and 27 with a large WC. Abdominal fat was quantified by magnetic resonance imaging. Jumbo biopsy specimens were taken across the squamocolumnar junction (SCJ). High-resolution pH metry (12 sensors) and manometry (36 sensors) were performed in upright and supine subjects before and after a meal; the SCJ was visualized fluoroscopically. RESULTS: The cardiac mucosa was significantly longer in the large WC group (2.5 vs 1.75 mm; P = .008); its length correlated with intra-abdominal (R = 0.35; P = .045) and total abdominal (R = 0.37; P = .034) fat. The SCJ was closer to the upper border of the lower esophageal sphincter (LES) in subjects with a large WC (2.77 vs 3.54 cm; P = .02). There was no evidence of excessive reflux 5 cm above the LES in either group. Gastric acidity extended more proximally within the LES in the large WC group, compared with the upper border (2.65 vs 4.1 cm; P = .027) and peak LES pressure (0.1 cm proximal vs 2.1 cm distal; P = .007). The large WC group had shortening of the LES, attributable to loss of the distal component (total LES length, 3 vs 4.5 cm; P = .043). CONCLUSIONS: Central obesity is associated with intrasphincteric extension of gastric acid and cardiac mucosal lengthening. The latter might arise through metaplasia of the most distal esophageal squamous epithelium and this process might predispose individuals to adenocarcinoma. PMID- 23796456 TI - Activation of the MAS receptor by angiotensin-(1-7) in the renin-angiotensin system mediates mesenteric vasodilatation in cirrhosis. AB - BACKGROUND & AIMS: Splanchnic vascular hypocontractility with subsequent increased portal venous inflow leads to portal hypertension. Although the renin angiotensin system contributes to fibrogenesis and increased hepatic resistance in patients with cirrhosis, little is known about its effects in the splanchnic vasculature, particularly those of the alternate system in which angiotensin (Ang) II is cleaved by the Ang-converting enzyme-2 (ACE2) to Ang-(1-7), which activates the G-protein-coupled Mas receptor (MasR). We investigated whether this system contributes to splanchnic vasodilatation and portal hypertension in cirrhosis. METHODS: We measured levels of renin-angiotensin system messenger RNA and proteins in splanchnic vessels from patients and rats with cirrhosis. Production of Ang-(1-7) and splanchnic vascular reactivity to Ang-(1-7) was measured in perfused mesenteric vascular beds from rats after bile-duct ligation. Ang-(1-7) and MasR were blocked in rats with cirrhosis to examine splanchnic vascular hemodynamics and portal pressure response. RESULTS: Levels of ACE2 and MasR were increased in splanchnic vessels from cirrhotic patients and rats compared with healthy controls. We also observed an ACE2-dependent increase in Ang-(1-7) production. Ang-(1-7) mediated splanchnic vascular hypocontractility in ex vivo splanchnic vessels from rats with cirrhosis (but not control rats) via MasR stimulation. Identical effects were observed in the splanchnic circulation in vivo. MasR blockade reduced portal pressure, indicating that activation of this receptor in splanchnic vasculature promotes portal inflow to contribute to development of portal hypertension. In addition, the splanchnic effects of MasR required nitric oxide. Interestingly, Ang-(1-7) also decreased hepatic resistance. CONCLUSIONS: In the splanchnic vessels of patients and rats with cirrhosis, increased levels of ACE2 appear to increase production of Ang-(1-7), which leads to activation of MasR and splanchnic vasodilatation in rats. This mechanism could cause vascular hypocontractility in patients with cirrhosis, and might be a therapeutic target for portal hypertension. PMID- 23796458 TI - Aggressive interactions during free-play at preschool of children with and without developmental coordination disorder. AB - This aim of this study was to investigate an unexpected finding from a larger study examining the play of preschool children with and without developmental coordination disorder (DCD). We found that children with DCD were more frequently involved in aggressive incidents during free-play than their peers. Children with (n=32) and without DCD (n=31) were videotaped during free-play at preschool and their play was assessed using the Play Observation Scale. A post hoc analysis was conducted using a specifically developed rating instrument to examine the aggressive incidents captured on video. Videos from 18 children with DCD and 8 typically developing children without DCD were found to contain aggressive incidents. Children with DCD were significantly more often involved as both aggressor (p=.016) and victim (p=.008) than children without DCD (p=.031). This is the first study to identify victimization and aggression as being problematic for children with DCD as young as 4 years of age and needs replication. Given the negative consequences of involvement in aggression and victimization, play-based early intervention focusing on prevention needs to be developed and implemented. PMID- 23796457 TI - Racial and ethnic variations in the effects of family history of colorectal cancer on screening compliance. AB - BACKGROUND & AIMS: Individuals with a family history of colorectal cancer (CRC) have a higher risk of developing CRC than the general population, and studies have shown that they are more likely to undergo CRC screening. We assessed the overall and race- and ethnicity-specific effects of a family history of CRC on screening. METHODS: We analyzed data from the 2009 California Health Interview Survey to estimate overall and race- and ethnicity-specific odds ratios (ORs) for the association between family history of CRC and CRC screening. RESULTS: The unweighted and weighted sample sizes were 23,837 and 8,851,003, respectively. Individuals with a family history of CRC were more likely to participate in any form of screening (OR, 2.3; 95% confidence limit [CL], 1.7, 3.1) and in colonoscopy screening (OR, 2.7; 95% CL, 2.2, 3.4) than those without a family history, but this association varied among racial and ethnic groups. The magnitude of the association between family history and colonoscopy screening was highest among Asians (OR, 6.1; 95% CL, 3.1, 11.9), lowest among Hispanics (OR, 1.4; 95% CL, 0.67, 2.8), and comparable between non-Hispanic whites (OR, 3.1; 95% CL, 2.6, 3.8) and non-Hispanic blacks (OR 2.6; 95% CL, 1.2, 5.7) (P for interaction < .001). CONCLUSIONS: The effects of family history of CRC on participation in screening vary among racial and ethnic groups, and have the lowest effects on Hispanics, compared with other groups. Consequently, interventions to promote CRC screening among Hispanics with a family history should be considered. PMID- 23796459 TI - Three non-ambulatory adults with multiple disabilities exercise foot-leg movements through microswitch-aided programs. AB - This study assessed the use of microswitch-aided programs to help three non ambulatory adults with multiple disabilities exercise foot-leg responses. Those responses served to activate a largely neglected part of the participants' body, with possibly positive physical implications (e.g., for blood circulation, swelling, and muscle strength). Intervention focused on the left and right foot leg response, separately. Eventually, sessions with one response were alternated with sessions with the other response. Responses were monitored via microswitches and followed by 8s of preferred stimulation (e.g., music and vibrotactile stimulation), which was automatically delivered. The results showed that all three participants had high levels of foot-leg responses during the intervention phases and a 3-week post-intervention check. The participants also displayed expressions of positive involvement during those study periods (i.e., engaged in behaviors, such as music-related head movements, smiles, or touching the vibratory devices) that could be interpreted as forms of interest/pleasure and happiness. These results are in line with previous findings in this area and can be taken as an important confirmation of the strength and dependability of the approach in motivating non-ambulatory persons with multiple disabilities to engage in foot-leg movements. The practical implications of these findings are discussed. PMID- 23796461 TI - Oncogenic isocitrate dehydrogenase mutations: mechanisms, models, and clinical opportunities. AB - Heterozygous mutations in catalytic arginine residues of isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) are common in glioma, acute myeloid leukemia, chondrosarcoma, cholangiocarcinoma, and angioimmunoblastic T-cell lymphoma. The mutant enzymes acquire a neomorphic activity that converts alpha ketoglutarate (alpha-KG) to D-2-hydroxyglutarate (D2HG), a rare metabolite. In cells and tissues expressing mutant IDH, D2HG concentrations are highly elevated. D2HG may act as an "oncometabolite" by inhibiting a class of alpha-KG-dependent enzymes involved in epigenetic regulation, collagen synthesis, and cell signaling. Knock-in mouse models of IDH1 mutations have shed light on these mechanisms and will provide valuable animal models for further investigation. PMID- 23796460 TI - Transcriptional signature of progesterone in the fathead minnow ovary (Pimephales promelas). AB - A growing number of studies have examined transcriptional responses to sex steroids along the hypothalamic-pituitary-gonadal axis in teleost fishes. However, data are lacking on the molecular cascades that underlie progesterone signaling. The objective of this study was to characterize the transcriptional response in the ovary of fathead minnows (Pimephales promelas) in response to progesterone (P4). Fathead minnow ovaries were exposed in vitro to 500 ng P4/L. Germinal vesicle migration and breakdown (GVBD) was observed and microarrays were used to identify gene cascades affected by P4. Microarray analysis identified 1702 differentially expressed transcripts after P4 treatment. Functional enrichment analysis revealed that transcripts involved in the molecular functions of protein serine/threonine kinase activity, ATP binding, and activity of calcium channels were increased after P4 treatment. There was an overwhelming decrease in levels of transcripts of genes that are structural constituents of ribosomes with P4 treatment. There was also evidence for gene expression changes in steroid and maturation-related transcripts. Pathway analyses identified cell cycle regulation, insulin action, hedgehog, and B cell activation as pathways containing an over-representation of highly regulated transcripts. Significant regulatory sub-networks of P4-mediated transcripts included genes regulated by tumor protein p53 and E2F transcription factor 1. These data provide novel insight into the molecular signaling cascades that underlie P4-signaling in the ovary and identify genes and processes that may indicate premature GVBD due to environmental pollutants that mimic progestins. PMID- 23796462 TI - Commentary regarding uptake of carotid artery stenting in England and subsequent vascular admissions: an appropriate response to emerging evidence? PMID- 23796463 TI - Adaptation and learning of molecular networks as a description of cancer development at the systems-level: potential use in anti-cancer therapies. AB - There is a widening recognition that cancer cells are products of complex developmental processes. Carcinogenesis and metastasis formation are increasingly described as systems-level, network phenomena. Here we propose that malignant transformation is a two-phase process, where an initial increase of system plasticity is followed by a decrease of plasticity at late stages of carcinogenesis as a model of cellular learning. We describe the hallmarks of increased system plasticity of early, tumor initiating cells, such as increased noise, entropy, conformational and phenotypic plasticity, physical deformability, cell heterogeneity and network rearrangements. Finally, we argue that the large structural changes of molecular networks during cancer development necessitate a rather different targeting strategy in early and late phase of carcinogenesis. Plastic networks of early phase cancer development need a central hit, while rigid networks of late stage primary tumors or established metastases should be attacked by the network influence strategy, such as by edgetic, multi-target, or allo-network drugs. Cancer stem cells need special diagnosis and targeting, since their dormant and rapidly proliferating forms may have more rigid, or more plastic networks, respectively. The extremely high ability of cancer stem cells to change the rigidity/plasticity of their networks may be their key hallmark. The application of early stage-optimized anti-cancer drugs to late-stage patients may be a reason of many failures in anti-cancer therapies. Our hypotheses presented here underlie the need for patient-specific multi-target therapies applying the correct ratio of central hits and network influences - in an optimized sequence. PMID- 23796464 TI - Portal vein thrombosis with renal cell carcinoma: a case report. AB - Portal vein thrombosis refers to an obstruction of blood flow in the portal vein; this rare disease can be both local and systemic. Local risk factors, accounting for about 70% of cases, can be abdominal cancers, inflammatory of infective diseases, surgical procedures or cirrhosis. A 62-year-old man, affected by hypertension and taking acetylsalicylic acid after a myocardial infarction in 1994, developed deep venous thrombosis on the right leg. Six months later the patient was admitted to the emergency unit due to abdominal pain. A CT scan revealed the presence of a complete splanchnic vein thrombosis and a primary tumor on the right kidney. The patient was treated with total parenteral nutrition and intravenous solution of heparin sodium first and then, because of occurrence of allergy, fondaparinux, with improvement of the abdominal pain. Subsequently he underwent right radical nephrectomy. PMID- 23796465 TI - Medication administration errors among paediatric nurses in Lagos public hospitals: an opinion survey. AB - OBJECTIVE: There is paucity of data on paediatric medicine administration error (MAE) in developing countries. This study aimed to investigate the experience of MAEs among paediatric nurses working in public hospitals in Lagos, Nigeria. DESIGN: A confidential, self-reporting questionnaire was the instrument for the study. SETTING: Public hospitals in Lagos, Nigeria with established paediatric services and departments. PARTICIPANTS: Paediatric nurses. METHODS: The questionnaire was administered to 75 nurses working in public hospitals in Lagos to obtain information on the experience of medication errors during their entire career, as well as to know their views on the nature of MAEs and the contributing factors. RESULTS: Fifty nurses responded to give a response rate of 66.7%. All the participants were females with a mean +/- s.d age of 35.3 +/- 10.7 years. Thirty two (64%) had committed at least one medication error over the course of their career. Wrong dose error (24; 48%) and wrong timing of medicine administration (20; 40%) were the MAEs frequently committed by the participants. The consequences of the errors included shock (23; 46%), restlessness (21; 42%), disorientation (11; 22%), and respiratory depression (10; 20%). Increased workload (26; 52%) and not double checking medicine doses (12; 24%) were the major factors the nurses perceived to be contributing to MAEs. Only 15(30%) nurses had reported MAEs to their superiors. Fear of intimidation, retribution or being punished (11; 22%) and lack of policies in place to report errors (13; 26%) were the two major barriers to reporting MAEs. Half (50%) of the nurses indicated that policies were available in their work places to prevent medication errors. CONCLUSIONS: Medication administration errors were frequently committed by the participants and resulted in some inconsequential effects, morbidity and deaths. Appropriate measures should be implemented to prevent future occurrences of MAEs. PMID- 23796466 TI - Sharps injuries among health care workers in Cairo University Hospitals. AB - BACKGROUND: Health care workers (HCWs) are exposed to blood borne pathogens, through job-related risk factors like sharps injuries (SIs). Sharps injuries can be prevented by safer devices and through education and training of universal precautions and safe work practices. OBJECTIVES: The present study aims to examine the current situation of infection control at Cairo University Hospitals in Egypt, through studying SIs among health care workers and evaluating the preventive measures. SUBJECTS AND METHODS: The first part of this study was cross sectional in design. A self-administered Arabic questionnaire was designed for this study based on EPINet (Exposure Prevention Information Network) Needle Stick and Sharps injuries reporting Sheet. The second part of the study was an interventional design to evaluate the effectiveness of preventive measures which were introduced since the beginning of 2011. RESULTS: Forty percent of the participants (416/1036) reported at least one sharps injury in the preceding year (2010), of which more than 70% (293/416) experienced more than one injury. 88.9% (370/416, p < 0.001) of HCWs did not report their injury. Following intervention measures injury rates were significantly reduced from 36.9/100 person in 2010 in the intensive care units, to 12.4/100 person during 2011, (X2 = 21.419 and P value < 0.001). CONCLUSION: There is a high occurrence of sharps injuries in Cairo University Hospitals. Implementation of safety devices and adequate training will lead to reduction of SIs among HCWs. PMID- 23796467 TI - Anonymous, internal online reporting of poor handwriting in clinical notes. PMID- 23796468 TI - Predicting and managing adverse reactions of psychotropic drugs. AB - BACKGROUND: Neuroleptic induced extrapyramidal disorders are often presented in a form of orofacial hyperkinesias and dystonia. Rational use of neuroleptic drugs requires individualised approach to a patient, however simple criteria for determining individual, "personalised" dosage regimen have not been fully developed for routine practice in resource-limited hospital settings. OBJECTIVE: To study the tonus of tongue muscles as a measure of orofacial dystonia and the total hepatic oxidative capacity as a potential predictor of excessive vulnerability to neuroleptic-induced dystonia in psychiatric patients. METHODS: We measured the maximal force of the tongue manoeuvre (F, g/cm2), the total (integral) hepatic oxidative capacity by the antipyrine-test and used chlorpromazine equivalent to calculate the total daily neuroleptic load in 283 psychiatric patients and 30 healthy volunteers. RESULTS: The tonus of tongue muscles depends on the total daily neuroleptic dose and the length of antipsychotic treatment. The higher the total daily neuroleptic dose and the longer the treatment history, the greater the tongue muscles' tonus is. The tongue muscles' tonus was greater in patients with low rate of oxidative antipyrine metabolism. Antidepressants contributed to the increased tonus of the tongue muscles in "slow metabolisers" of antipyrine. CONCLUSIONS: The simple and cheap measurements of total hepatic oxidative capacity and of muscle tonus of the tongue could be used to predict and manage neuroleptic-induced adverse reactions. PMID- 23796469 TI - New onset alcohol dependence linked to treatment with selective serotonin reuptake inhibitors. AB - BACKGROUND: Genetic and environmental factors influence the development of alcohol dependence and alcohol dependence increases the risk of developing Major Depressive Disorder-MDD (vice versa). Amongst antidepressants, the selective serotonin reuptake inhibitors (SSRIs) are likely the most frequently prescribed for MDD. However, findings on the role of SSRIs in alleviating alcoholism are conflicting. CASE DESCRIPTION: A review of the literature is highlighted with a case of middle-aged lady with new onset alcohol dependence syndrome after commencement of SSRI, which resolved following discontinuation of the SSRIs and the introduction of Mirtazapine. DISCUSSION: The serotonin transporter gene has been linked to excessive drinking, early-onset problem drinking, alcohol dependence, anxiety and impulsiveness. While the evidence for antidepressant use appears consistent in alleviating depressive symptoms in patients with comorbid alcohol dependence and depression, some groups of patients may show an increase in alcohol consumption. Alternatively, there are a series of studies suggesting that antagonism of S-3 receptors can lead to diminished cravings for alcohol. This case highlights the need for further research into the effects of SSRIs on alcohol consumption in those with and without previous alcohol dependence syndromes. It also indicates a need to monitor changes in alcohol consumption and behaviour while on SSRIs. PMID- 23796470 TI - Data based medicine and clinical judgement. AB - Randomized controlled trials (RCTs) are a useful tool to check the effectiveness of drugs but have come to shape the culture of medicine in a manner that increasingly compromises medical care. Dependence on RCT evidence is compromised by the well-known problems stemming non-publication of trials, lack of access to trial data, ghostwriting of those trials that are published and a variety of coding and other strategies to hide harms. But what is less appreciated is that whenever a drug and an illness can produce the same benefit or harm that the outcomes of RCTs can be profoundly misleading. This article gives examples of how RCTs can produce the wrong answer. PMID- 23796471 TI - Data and evidence: there is a difference! (a commentary and debate on Healy et al.). PMID- 23796472 TI - Recommendations from the thirty-fifth annual meeting of national pharmacovigilance centres. PMID- 23796473 TI - The systematic removal of participants post-randomization can lead to alternate explanations of the results. PMID- 23796474 TI - Re: "Appropriate responsibilities and actions of radiologists in radiologic accidents and crises". PMID- 23796476 TI - Reply to: "Flow cytometry makes all the difference". PMID- 23796475 TI - Regulation of accumulation and function of myeloid derived suppressor cells in different murine models of hepatocellular carcinoma. AB - BACKGROUND & AIMS: Myeloid derived suppressor cells (MDSC) are immature myeloid cells with immunosuppressive activity. They accumulate in tumor-bearing mice and humans with different types of cancer, including hepatocellular carcinoma (HCC). The aim of this study was to examine the biology of MDSC in murine HCC models and to identify a model, which mimics the human disease. METHODS: The comparative analysis of MDSC was performed in mice, bearing transplantable, diethylnitrosoamine (DEN)-induced and MYC-expressing HCC at different ages. RESULTS: An accumulation of MDSC was found in mice with HCC irrespective of the model tested. Transplantable tumors rapidly induced systemic recruitment of MDSC, in contrast to slow-growing DEN-induced or MYC-expressing HCC, where MDSC numbers only increased intra-hepatically in mice with advanced tumors. MDSC derived from mice with subcutaneous tumors were more suppressive than those from mice with DEN induced HCC. Enhanced expression of genes associated with MDSC generation (GM CSF, VEGF, IL6, IL1beta) and migration (MCP-1, KC, S100A8, S100A9) was observed in mice with subcutaneous tumors. In contrast, only KC levels increased in mice with DEN-induced HCC. Both KC and GM-CSF overexpression or anti-KC and anti-GM CSF treatment controlled MDSC frequency in mice with HCC. Finally, the frequency of MDSC decreased upon successful anti-tumor treatment with sorafenib. CONCLUSIONS: Our data indicate that MDSC accumulation is a late event during hepatocarcinogenesis and differs significantly depending on the tumor model studied. PMID- 23796478 TI - Novel multidrug therapy for disseminated rhinosporidiosis, refractory to dapsone case report. AB - Rhinosporidiosis is a chronic granulomatous disorder, caused by Rhinosporidium seeberi endemic in India and Sri Lanka. The most common sites are the nasal mucosa and the nasopharynx and cutaneous lesions usually occur as a part of disseminated rhinosporidiosis. Dapsone has been frequently used in treating disseminated disease in immunocompetent individuals. Here we report a case of disseminated rhinosporidiosis in an immunocompromised individual on antiretroviral drugs, non-responsive to Dapsone and therefore treated with a multidrug therapy of Cycloserine, Dapsone and Ketoconazole with good response. PMID- 23796477 TI - Development of a field-friendly automated dietary assessment tool and nutrient database for India. AB - Studies of diet and disease risk in India and among other Asian-Indian populations are hindered by the need for a comprehensive dietary assessment tool to capture data on the wide variety of food and nutrient intakes across different regions and ethnic groups. The nutritional component of the India Health Study, a multicentre pilot cohort study, included 3908 men and women, aged 35-69 years, residing in three regions of India (New Delhi in the north, Mumbai in the west and Trivandrum in the south). We developed a computer-based, interviewer administered dietary assessment software known as the 'NINA-DISH (New Interactive Nutrition Assistant - Diet in India Study of Health)', which consisted of four sections: (1) a diet history questionnaire with defined questions on frequency and portion size; (2) an open-ended section for each mealtime; (3) a food preparer questionnaire; (4) a 24 h dietary recall. Using the preferred meal-based approach, frequency of intake and portion size were recorded and linked to a nutrient database that we developed and modified from a set of existing international databases containing data on Indian foods and recipes. The NINA DISH software was designed to be easily adaptable and was well accepted by the interviewers and participants in the field. A predominant three-meal eating pattern emerged; however, patterns in the number of foods reported and the primary contributors to macro- and micronutrient intakes differed by region and demographic factors. The newly developed NINA-DISH software provides a much needed tool for measuring diet and nutrient profiles across the diverse populations of India with the potential for application in other South Asian populations living throughout the world. PMID- 23796479 TI - Topics in Companion Animal Medicine. Foreword. PMID- 23796480 TI - Adderall(r) (amphetamine-dextroamphetamine) toxicity. AB - The American Psychiatric Association estimates that 3-7% of US school-aged children exhibit attention-deficit/hyperactivity disorder (ADHD). Adderall((r)) (amphetamine dextroamphetamine) and a variety of brand names and generic versions of this combination are available by prescription to treat ADHD and narcolepsy. Both immediate and sustained release products are used as are single agent amphetamine medication. Knowing the exact agent ingested can provide information of dose labeled and length of clinical effects. These drugs are used off label by college students for memory enhancement, test taking ability, and for study marathons. These agents are DEA Schedule II controlled substances with high potential for abuse. For humans with ADHD or narcolepsy, standard recommended dosage is 5-60 mg daily. Amphetamine and its analogues stimulate the release of norepinephrine affecting both alpha- and beta-adrenergic receptor sites. alpha Adrenergic stimulation causes vasoconstriction and an increase in total peripheral resistance. beta-Adrenergic receptor stimulation leads to an increase in heart rate, stroke volume, and skeletal muscle blood flow. Clinical signs of Adderall((r)) overdose in humans and dogs include hyperactivity, hyperthermia, tachycardia, tachypnea, mydriasis, tremors, and seizures. In addition, Adderall intoxication in dogs has been reported to cause hyperthermia, hypoglycemia, hypersegmentation of neutrophils, and mild thrombocytopenia. Diagnosis can be confirmed by detecting amphetamine in stomach contents or vomitus, or by positive results obtained in urine tests for illicit drugs. Treatment is directed at controlling life-threatening central nervous system and cardiovascular signs. Seizures can be controlled with benzodiazepines, phenothiazines, pentobarbital, and propofol. Cardiac tachyarrhythmias can be managed with a beta-blocker such as propranolol. Intravenous fluids counter the hyperthermia, assist in maintenance of renal function, and help promote the elimination of amphetamine and its analogues. Prognosis after poisoning with Adderall((r)) depends upon the severity and duration of clinical signs at presentation. Differential diagnoses that should be considered in cases of suspected amphetamine overdose are any other agents that can cause central nervous system stimulation, tremors, and seizures. This article discusses our present understanding of Adderall((r)) intoxication and examines 3 dogs presented to our practice after ingestion of large amounts of the drug. PMID- 23796481 TI - Marijuana poisoning. AB - The plant Cannabis sativa has been used for centuries for the effects of its psychoactive resins. The term "marijuana" typically refers to tobacco-like preparations of the leaves and flowers. The plant contains more than 400 chemicals but the cannabinoid delta-9-tetrahydrocannabinol (THC) is the major psychoactive constituent. "Hashish" is the resin extracted from the tops of flowering plants and generally has a much higher THC concentration. Marijuana is the most commonly used illicit drug in the United States. Currently, several states have passed legislation to decriminalize possession of small amounts of marijuana for both medical and personal use and several other states have similar legislation under consideration. The most common form of marijuana use in humans is inhalation of the smoke of marijuana cigarettes, followed by ingestion. In animals, although secondhand smoke inhalation is possible, the most common source of exposure is through ingestion of the owner's marijuana supply. The minimum lethal oral dose for dogs for THC is more than 3 g/kg. Although the drug has a high margin of safety, deaths have been seen after ingestion of food products containing the more concentrated medical-grade THC butter. There are two specific cannabinoid receptors in humans and dogs, CB1 (primarily in central nervous system) and CB2 (peripheral tissues). In animals, following oral ingestion, clinical effects begin within 60 minutes. All of the neuropharmacologic mechanisms by which cannabinoids produce psychoactive effects have not been identified. However, CB1 activity is believed to be responsible for the majority of cannabinoid clinical effects. Highly lipid soluble, THC is distributed in fat, liver, brain, and renal tissue. Fifteen percent of THC is excreted into the urine and the rest is eliminated in the feces through biliary excretion. Clinical signs of canine intoxication include depression, hypersalivation, mydriasis, hypermetria, vomiting, urinary incontinence, tremors, hypothermia, and bradycardia. Higher dosages may additionally cause nystagmus, agitation, tachypnea, tachycardia, ataxia, hyperexcitability, and seizures. Treatment of marijuana ingestion in animals is largely supportive. Vital signs including temperature and heart rate and rhythm must be continually monitored. Stomach content and urine can be tested for cannabinoids. Gas chromatography and mass spectrometry can be utilized for THC detection but usually may take several days and are not practical for initiation of therapy. Human urine drug-screening tests can be unreliable for confirmation of marijuana toxicosis in dogs owing to the interference of a large number of the metabolites in canine urine. False negatives may also arise if testing occurs too recently following THC ingestion. Thus, the use of human urine drug-screening tests in dogs remains controversial. No specific antidote presently exists for THC poisoning. Sedation with benzodiazepines may be necessary if dogs are severely agitated. Intravenous fluids may be employed to counter prolonged vomiting and to help control body temperature. Recently, the use of intralipid therapy to bind the highly lipophilic THC has been utilized to help reduce clinical signs. The majority of dogs experiencing intoxication after marijuana ingestion recover completely without sequellae. Differential diagnoses of canine THC toxicosis include human pharmaceuticals with central nervous system stimulatory effects, drugs with central nervous system depressant effects, macrolide parasiticides, xylitol, and hallucinogenic mushrooms. PMID- 23796482 TI - Selective serotonin reuptake inhibitor exposure. AB - Many antidepressants inhibit serotonin or norepinephrine reuptake or both to achieve their clinical effect. The selective serotonin reuptake inhibitor class of antidepressants (SSRIs) includes citalopram, escitalopram (active enantiomer of citalopram), fluoxetine, fluvoxamine, paroxetine, and sertraline. The SSRIs are as effective as tricyclic antidepressants in treatment of major depression with less significant side effects. As a result, they have become the largest class of medications prescribed to humans for depression. They are also used to treat obsessive-compulsive disorder, panic disorders, alcoholism, obesity, migraines, and chronic pain. An SSRI (fluoxetine) has been approved for veterinary use in treatment of canine separation anxiety. SSRIs act specifically on synaptic serotonin concentrations by blocking its reuptake in the presynapse and increasing levels in the presynaptic membrane. Clinical signs of SSRI overdose result from excessive amounts of serotonin in the central nervous system. These signs include nausea, vomiting, mydriasis, hypersalivation, and hyperthermia. Clinical signs are dose dependent and higher dosages may result in the serotonin syndrome that manifests itself as ataxia, tremors, muscle rigidity, hyperthermia, diarrhea, and seizures. Current studies reveal no increase in appearance of any specific clinical signs of serotonin toxicity with regard to any SSRI medication. In people, citalopram has been reported to have an increased risk of electrocardiographic abnormalities. Diagnosis of SSRI poisoning is based on history, clinical signs, and response to therapy. No single clinical test is currently available to confirm SSRI toxicosis. The goals of treatment in this intoxication are to support the animal, prevent further absorption of the drug, support the central nervous system, control hyperthermia, and halt any seizure activity. The relative safety of the SSRIs in overdose despite the occurrence of serotonin syndrome makes them more desirable than other antidepressants. The prognosis in animals that receive treatment is excellent. In one retrospective study, there were no deaths in 313 SSRI-poisoned dogs. No characteristic or classic histopathologic lesions result from SSRI toxicosis. Differential diagnoses for SSRI overdose must include ingestions of other serotonergic medications such as phenylpiperidine opioids (fentanyl and tramadol), mirtazapine, buspirone, amitraz, and chlorpheniramine. PMID- 23796483 TI - Xylitol. AB - Xylitol is a prevalent sugar substitute found in a wide variety of foods, particularly those labeled as "low carb." It is found in many medicines and dental products both for its antibacterial activity and to increase palatability. Originally, this toxin was recognized as a problem in dogs following sugarless gum ingestions. Xylitol is generally nontoxic to mammals except for dogs. In the dog, xylitol induces marked increases in insulin production and occasionally hepatopathy. The clinical syndrome is manifested with signs consistent with profound hypoglycemia, hypokalemia, hypophosphatemia, and acute hepatic failure. Treatment relies upon administration of intravenous glucose, hepatic support, and general supportive care. PMID- 23796484 TI - Bromethalin. AB - Bromethalin is a potent neurotoxin capable of inducing fatal cerebral edema in companion animals. Bromethalin decreases adenosine triphosphate production resulting in cerebral edema. Toxicosis can be seen in cats and dogs with oral exposures as low as 0.3 and 2.5mg/kg, respectively. High doses produce severe muscle tremors, hyperthermia, seizures, and death within a couple hours postingestion. The usual presentation after moderate to low exposure develops over 12-24 hours with progressive ataxia, paresis, and hindlimb paralysis. Central nervous system depression continues to semicoma or coma. Diagnosis is based upon history of exposure, development of progressive appropriate clinical signs and chemical confirmation in tissues. Treatment relies heavily upon early emesis induction and prolonged decontamination with pulse dosing of activated charcoal. There is no specific antidote; attempts to control cerebral edema with diuretics and corticosteroids have met with limited success. Significant supportive care is usually required, often including seizure management, nutritional support, and defense against decubital ulceration. Prognosis is guarded to poor. PMID- 23796485 TI - Cholecalciferol. AB - The primary source of exposure to cholecalciferol in dogs and cats is ingestion of rodenticide baits with vitamin D3 as the active ingredient. Other sources of this toxin are human medications and rarely, contaminated pet food. Although the reported lethal dose 50% for cholecalciferol is 88 mg/kg, deaths have been seen with an individual exposure of 2 mc g/kg in dogs. Clinical signs are induced by profound hypercalcemia affecting multiple body systems. Clinical presentations may include anorexia, depression, muscle weakness, vomiting, polyuria, polydipsia, dehydration, abdominal pain, hematemesis, melena, and bradycardia. Tissue mineralization may develop if calcium * phosphorous product is greater than 60. Serum testing for hypercalcemia, hyperphosphatemia, and decreased serum parathyroid hormone are confirmatory. Initial treatment relies upon decontamination with emesis induction followed by administration of pulse-dose activated charcoal designed to interfere with the extensive enterohepatic recirculation of toxin. Medical management is designed to decrease serum calcium levels by use of intravenous fluid diuresis with administration of furosemide and prednisolone. Biphosphate pamidronate is used to inhibit calcium release from the bone. Phosphate binders aid in decreasing phosphate availability to interact with calcium. The prognosis is better if treatment is instituted early before development of hypercalcemia and hyperphosphatemia enables tissue mineralization to progress. PMID- 23796486 TI - Polyurethane adhesive ingestion. AB - Polyurethane adhesives are found in a large number of household products in the United States and are used for a variety of purposes. Several brands of these expanding wood glues (those containing diphenylmethane diisocyanate [MDI]) have the potential to form gastrointestinal (GI) foreign bodies if ingested. The ingested adhesive forms an expanding ball of glue in the esophagus and gastric lumen. This expansion is caused by a polymerization reaction using the heat, water, and gastric acids of the stomach. A firm mass is created that can be 4-8 times its original volume. As little as 2 oz of glue have been reported to develop gastric foreign bodies. The obstructive mass is reported to form within minutes of ingestion of the adhesive. The foreign body can lead to esophageal impaction and obstruction, airway obstruction, gastric outflow obstruction, mucosal hemorrhage, ulceration, laceration, perforation of the esophageal and gastric linings, and death. Clinical signs following ingestion include anorexia, lethargy, vomiting, tachypnea, and abdominal distention and pain, and typically develop within 12 hours. Clinical signs may depend upon the size of the mass. If left untreated, perforation and rupture of the esophagus or stomach can occur. The glue mass does not stick to the GI mucosa and is not always detectable on abdominal palpation. Radiographs are recommended to confirm the presence of the "glue-ball" foreign body, and radiographic evidence of the obstruction may be seen as early as 4-6 hours following ingestion. Emesis is contraindicated owing to the risk of aspiration of the glue into the respiratory tree or the subsequent lodging of the expanding glue mass in the esophagus. Likewise, efforts to dilute the glue and prevent the formation of the foreign body through administration of liquids, activated charcoal, or bulk-forming products to push the foreign body through the GI tract have proven ineffective. Even endoscopy performed to remove the foreign body has been shown to be unreliable. The safest, most effective, and successful therapy is surgical intervention to remove the GI foreign body. If performed early enough, complete recovery of the animal can be expected. Differential diagnoses for polyurethane adhesive ingestion include any potential cause of GI obstruction. The public is largely unaware of the hazards that ingestion of this product may produce. Public education efforts are needed to inform pet owners about the hazards of these glues and the overall importance of providing our companion animals with safe, poison-free environments. PMID- 23796487 TI - A novel Lys141Thr mutation in small heat shock protein 22 (HSPB8) gene in Charcot Marie-Tooth disease type 2L. AB - Charcot-Marie-Tooth disease (CMT) is a group of clinically and genetically heterogeneous peripheral neuropathies. HSPB8 gene encodes heat shock protein 22 (HSP22) which belongs to the superfamily of small stress induced proteins. Mutations in HSPB8 are implicated to CMT2L and distal hereditary motor neuropathy 2A (dHMN2A). All three reported HSPB8 mutations are interestingly located in the Lys141 residue. In the present study, we examined a Korean axonal CMT patient who presented distal limb atrophy, sensory loss, areflexia, and axonal loss of large myelinated fibers. Whole exome sequencing identified a novel missense mutation c.422A>C (p.Lys141Thr) in HSPB8 as the underlying cause of the CMT2 patient. The mutation was regarded as a de novo case because both unaffected parents have no such mutation. The patient with HSPB8 mutation is the first case in Koreans. Clinical heterogeneities have been revealed in patients with Lys141 mutation; the present patient revealed similar phenotype of CMT2L. In addition, the lower limb MRI revealed a similarity between our HSPB8 and HSPB1 patients. It seems that the Lys141 site in the alpha-crystallin domain of HSPB8 is regarded as a mutational hot spot for peripheral neuropathy development, and mutations even in the same codon can exhibit different CMT phenotypes. PMID- 23796488 TI - Stabilising cysteinyl thiol oxidation and nitrosation for proteomic analysis. AB - Oxidation and S-nitrosylation of cysteinyl thiols (Cys-SH) to sulfenic (Cys-SOH), sulfinic (Cys-SO2H), sulfonic acids (Cys-SO3H), disulphides and S-nitrosothiols are suggested as important post-translational modifications that can activate or deactivate the function of many proteins. Non-enzymatic post-translational modifications to cysteinyl thiols have been implicated in a wide variety of physiological and pathophysiological states but have been difficult to monitor in a physiological setting because of a lack of experimental tools. The purpose of this review is to bring together the approaches that have been developed for stably trapping cysteine either in its reduced or oxidised forms for enrichment and or subsequent mass spectrometric analysis. These tools are providing insight into potential targets for post-translational modifications to cysteine modification in vivo. This article is part of a Special Issue entitled: Special Issue: Posttranslational Protein modifications in biology and Medicine. PMID- 23796489 TI - Functional proteomic approach to discover geographic variations of king cobra venoms from Southeast Asia and China. AB - This study deciphers the geographic variations of king cobra (Ophiophagus hannah) venom using functional proteomics. Pooled samples of king cobra venom (abbreviated as Ohv) were obtained from Indonesia, Malaysia, Thailand, and two provinces of China, namely Guangxi and Hainan. Using two animal models to test and compare the lethal effects, we found that the Chinese Ohvs were more fatal to mice, while the Southeast Asian Ohvs were more fatal to lizards (Eutropis multifasciata). Various phospholipases A2 (PLA2s), three-finger toxins (3FTxs) and Kunitz-type inhibitors were purified from these Ohvs and compared. Besides the two Chinese Ohv PLA2s with known sequences, eight novel PLA2s were identified from the five Ohv samples and their antiplatelet activities were compared. While two 3FTxs (namely oh-55 and oh-27) were common in all the Ohvs, different sets of 3FTx markers were present in the Chinese and Southeast Asian Ohvs. All the Ohvs contain the Kunitz inhibitor, OH-TCI, while only the Chinese Ohvs contain the inhibitor variant, Oh11-1. Relative to the Chinese Ohvs which contained more phospholipases, the Southeast Asian Ohvs had higher metalloproteinase, acetylcholine esterase, and alkaline phosphatase activities. BIOLOGICAL SIGNIFICANCE: Remarkable variations in five king cobra geographic samples reveal fast evolution and dynamic translational regulation of the venom which probably adapted to different prey ecology as testified by the lethal tests on mice and lizards. Our results predict possible variations of the king cobra envenoming to human and the importance of using local antivenin for snakebite treatment. PMID- 23796490 TI - Insights into enzyme secretion by filamentous fungi: comparative proteome analysis of Trichoderma reesei grown on different carbon sources. AB - Trichoderma reesei is the main industrial producer of lignocellulolytic enzymes, and the secretory behavior of this fungus strongly depends on the carbon sources. To gain insights into how the T. reesei adapts to various carbons and regulates enzyme production, the extra- and intracellular proteomes of T. reesei grown in defined medium with lactose or xylose as the carbon source were investigated. Results indicated that the composition of extracellular proteome differed considerably depending on the carbons. The main cellobiohydrolases, i.e. Cel7a/Cel6 were the most abundant cellulolytic enzymes identified in both media, and found to be more abundant in lactose-grown culture. As compared to lactose, xylose can serve as a potent inducer of xylanolytic enzymes. Interestingly, most identified intracellular proteins are involved in carbon metabolism. Enzymes involved in utilization of xylose, such as d-xylose reductase (Xyl1p) and d xylose dehydrogenase (Xyl2p), were present at elevated levels in the culture growing on xylose but only in minor amounts in the lactose culture. However, lactose induction significantly activated the expression of key enzymes involved in glycolysis pathway and citrate cycle. Importantly, the protein Xyl1p which participates both in the lactose and the xylose catabolism was verified as a potential regulator for cellulase formation in T. reesei. BIOLOGICAL SIGNIFICANCE: This study not only gives an overview of the ubiquitous cellular changes induced by the two conventional carbon substrates, but offers the framework for understanding the mechanisms behind the carbon-dependent induction of extracellular enzymes in T. reesei. Moreover, this study provides a potential target (Xyl1p) that could be tentatively used for metabolic engineering of T. reesei for cost-effective cellulase production. PMID- 23796491 TI - Comparative studies focusing on transgenic through cp4EPSPS gene and non transgenic soybean plants: an analysis of protein species and enzymes. AB - This work evaluates the activity of a few key enzymes involved in combating reactive oxygen species (ROS), such as ascorbate peroxidase (EC 1.11.1.11), catalase (EC 1.11.1.6), glutathione reductase (EC 1.6.4.2), and superoxide dismutase (EC 1.15.1.1), as well as the concentration of malondialdehyde and hydrogen peroxide in transgenic and non-transgenic soybean leaves. Additionally, differential protein species from leaves of both genotypes were evaluated by applying a regulation factor of >=1.8 to further corroborate the hypothesis that genetic modification itself can be a stress factor for these plants. For this task, transgenic soybean plants were obtained from seeds modified with the cp4EPSPS gene. The results revealed higher activities of all evaluated enzymes in transgenic than in non-transgenic soybean leaves (ranging from 13.8 to 70.1%), as well as higher concentrations of malondialdehyde and hydrogen peroxide in transgenic soybean leaves, clearly indicating a condition of oxidative stress established in the transgenic genotype. Additionally, 47 proteins were differentially abundant when comparing the leaves of both plants, with 26 species accurately identified, including the protein involved in the genetic modification (CP4EPSPS). From these results, it is possible to conclude that the plant is searching for a new equilibrium to maintain its metabolism because the stress condition is being maintained within levels that can be tolerated by the plant. BIOLOGICAL SIGNIFICANCE: The present paper is the first one in the literature where are shown translational aspects involving plant stress and the genetic modification for soybean involving the cp4 EPSPS gene. The main biological importance of this work is to make possible the demystification of the genetic modification, allowing answers for some questions that still remain unknown, and enlarge our knowledge about genetically modified organisms. This article is part of a Special Issue entitled: Translational Plant Proteomics. PMID- 23796492 TI - The transcriptome of Echinostoma caproni adults: further characterization of the secretome and identification of new potential drug targets. AB - Echinostomes are cosmopolitan parasites that infect a large number of different warm-blooded hosts, both in nature and in the laboratory. They also constitute an important group of food-borne trematodes of public health importance mainly in Southeast Asia and the Far East. In addition, echinostomes are an ideal model to study several aspects of intestinal helminth biology, since they present a number of advantages. For example, echinostomes are large worms whose life cycle is relatively easy to maintain in the laboratory. Recently, several studies documented their great value in the study of intestinal helminth-vertebrate host relationship. Detailed knowledge of their genome, transcriptome and proteome is likely to have an important impact on the development of control strategies for intestinal helminths. We present the first transcriptome of the adult stage of Echinostoma caproni using 454 sequencing coupled to a semi-automated bioinformatic analyses. 557,236 raw sequence reads were assembled into 28,577 contiguous sequences using iAssembler. 23,296 putative proteins were characterized based on homology, gene ontology and/or biochemical pathways. Comparisons of the transcriptome of E. caproni with those of other trematodes revealed similarities in the transcription pattern of molecules inferred to have key roles in parasite-host interactions. Enzymatic proteins like kinases and peptidases were abundant. Of the 3415 predicted excretory/secretory proteins compiled (including non-classical secretory proteins), 180 different proteins were confirmed by proteomic analysis. Potential drug targets were also identified. BIOLOGICAL SIGNIFICANCE: In this study the first transcriptome of the adult stage of E. caproni is presented and compared to those of other trematodes revealing similarities in transcription for molecules inferred to have key roles in parasite-host interactions. 3415 predicted excretory/secretory proteins were compiled, being 180 different proteins confirmed by proteomic analysis. The current transcriptome data increased by nine times the number of previous protein identifications. In addition, potential drug targets for this parasite were identified. The present dataset should provide a solid foundation for future fundamental genomic, proteomic, and metabolomic explorations of E. caproni, as well as a basis for applied outcomes, such as the development of novel methods of intervention against this model organism and related parasites. PMID- 23796493 TI - Pinpointing differentially expressed domains in complex protein mixtures with the cloud service of PatternLab for Proteomics. AB - Mass-spectrometry-based shotgun proteomics has become a widespread technology for analyzing complex protein mixtures. Here we describe a new module integrated into PatternLab for Proteomics that allows the pinpointing of differentially expressed domains. This is accomplished by inferring functional domains through our cloud service, using HMMER3 and Pfam remotely, and then mapping the quantitation values into domains for downstream analysis. In all, spotting which functional domains are changing when comparing biological states serves as a complementary approach to facilitate the understanding of a system's biology. We exemplify the new module's use by reanalyzing a previously published MudPIT dataset of Cryptococcus gattii cultivated under iron-depleted and replete conditions. We show how the differential analysis of functional domains can facilitate the interpretation of proteomic data by providing further valuable insight. PMID- 23796494 TI - Identification of differentially expressed proteins in atherosclerotic aorta and effect of vitamin E. AB - Atherosclerosis is a chronic inflammatory disorder that occurs as a result of mononuclear lymphocyte infiltration to the arterial wall, smooth muscle cell proliferation and damage in the arterial wall caused by extracellular matrix accumulation. Besides several genetic and environmental factors, increased serum cholesterol and oxidized low density lipoproteins are considered to be major inducing factors of atherosclerosis. Several protective agents have been used to prevent the progression of atherosclerosis and recently vitamin E has been focused because of its significant role in signaling mechanisms. Since many different cell types are involved in the development of hypercholesterolemia induced atherosclerosis, it is important to investigate wide range of proteins to highlight the pathologic and diagnostic mechanisms. In this study, by using proteomic technique, we identified differentially expressed proteins following cholesterol and also vitamin E treatments. The expressions of apolipoprotein A I and apolipoprotein E involved in lipid metabolism, peroxiredoxin 1, peroxiredoxin 2 and thioredoxin involved in antioxidant system, 14-3-3 protein zeta delta and 14-3-3 protein beta alpha in cell signaling, biglycan, vimentin, tropomyosin and smooth muscle alpha-actin as structural and contractile proteins have been discussed. BIOLOGICAL SIGNIFICANCE: We observed several protein alterations in aorta of cholesterol fed and vitamin E treated rabbits.These differentially expressed proteins associated with key mechanisms involved in atherosclerosis and signaling mechanisms related with vitamin E. These findings for different proteins might be helpful for deciphering the pathogenesis in atherosclerosis. In addition it provides a new perspective to understand mechanisms of beneficial effect of vitamin E on the signaling pathways in atherogenesis. This article is part of a Special Issue entitled: Posttranslational Protein modifications in biology and Medicine. PMID- 23796495 TI - The influence of the duration of the expulsive stage of parturition on the occurrence of postpartum oxidative stress in sows with uncomplicated, spontaneous farrowings. AB - The aim of the study was to determine the influence of the duration of the expulsive stage of parturition on the occurrence of postpartum oxidative stress in sows with uncomplicated, spontaneous farrowings. Twenty-five pregnant gilts were divided into three groups on the basis of duration of the expulsive stage of farrowing: (I) duration of the expulsive stage was below 3 hours; (II) duration of the expulsive stage ranged from 3 to 6 hours; (III) duration of the expulsive stage was longer than 6 hours. Blood samples were collected at 24 to 48 hours before and 24 hours after parturition. As indicators of alterations in the redox state, we quantified the enzymatic activity of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and catalase (CAT), as well as the blood levels of glutathione (GSH), thiobarbituric acid reactive substances (TBARS), and sulfhydryl groups (SH groups). In group III, it was found that erythrocyte activity of CAT (63.89 +/- 6.70 vs. 53.18 +/- 2.32 U/g Hb), as well as plasma GSH concentration (0.088 +/- 0.020 vs. 0.045 +/- 0.024 mmol/g protein) and SH groups content (5.045 +/- 1.256 vs. 3.383 +/- 0.430 MUmol/g protein) decreased significantly (P < 0.05) at 24 hours after parturition, compared with their values during the last 48 hours before parturition. The concentration of TBARS increased not significantly, although markedly at 24 hours postpartum in group III (0.124 +/- 0.014 vs. 0.153 +/- 0.031 MUmol/g protein). The results indicate that uncomplicated, spontaneous parturition can lead to the occurrence of oxidative stress during the early postparturient period in sows, the intensity of which is related to the duration of the expulsive stage. PMID- 23796496 TI - Infection of juvenile edible crabs, Cancer pagurus by a haplosporidian-like parasite. AB - This study aimed to examine the pathobiology of a haplosporidian-like infection in juvenile (pre-recruit) edible crabs (Cancer pagurus) from two locations in South West Wales, UK. Infected crabs showed no external symptoms of the disease but dissection revealed an infected and hypertrophic antennal gland. Histological examination showed extensive parasitisation of the antennal gland overlying the hepatopancreas. Heavily infected crabs also showed the presence of parasites with morphological similarities to Haplosporidia in the labyrinth of the antennal gland and in the gills. The spread of the infection from the antennal gland to the gills suggests that these parasites are released into the haemolymph. Attempts to characterise the haplosporidian-like organism using several primers previously shown to amplify members of the phylum Haplosporidia failed. The prevalence of infection in juvenile edible crabs varied throughout the sampling period of November 2011 to July 2012 with the lowest level of ca. 15% in November peaking at 70% in March. This parasite may represent a threat to the sustainability of edible crab fisheries in this region if the damage observed in the antennal gland and gills results in host mortality. The identification of these parasites as members of the phylum Haplosporidia based on morphology alone must be seen as tentative in the absence of sequence data. PMID- 23796497 TI - Spore loads of Paranosema locustae (Microsporidia) in heavily infected grasshoppers (Orthoptera: Acridoidea) of the Argentine Pampas and Patagonia. AB - Paranosema locustae, an entomopathogen of grasshoppers and locusts, remains the only microsporidium registered as a biocontrol agent. After introductions from North America, it became established in grasshopper communities of Argentina. We measured the infection intensity of field collected, heavily infected male and female adults of individuals belonging to six grasshopper species, five melanoplines (Melanoplinae) (Baeacris pseudopunctulatus, Dichroplus maculipennis, Dichroplus vittatus, Neopedies brunneri, Scotussa lemniscata), and one gomphocerine (Gomphocerinae) (Staurorhectus longicornis). Average spore load among heavily infected grasshoppers ranged from 8.7+/-0.5*10(7) to 1.1+/ 0.7*10(9). Only females of B. pseudopunctulatus and S. longicornis showed significantly higher spore loads than the males. PMID- 23796498 TI - [Malignant pleural mesothelioma after radiation treatment for Hodgkin lymphoma]. AB - Malignant mesothelioma is a relatively uncommon malignancy. Although the pathogenesis is primarily related to asbestos, the role of ionizing radiation is more controversial. We report the case of a 41-year-old male who developed pleural mesothelioma. He had both, a prior short asbestos exposure and a thoracic radiotherapy for Hodgkin's disease 26years before. The evidence for radiotherapy as cause for mesothelioma is expanding and the diagnosis of mesothelioma in patients who had previous irradiation should be kept in mind. PMID- 23796499 TI - [How practical guidelines can be applied in poor countries? Example of the introduction of a bronchoscopy unit in Cambodia]. AB - According to UN, Cambodia is one of the poorest countries in the World. Respiratory diseases are current public health priorities. In this context, a new bronchoscopy unit (BSU) was created in the respiratory medicine department of Preah Kossamak hospital (PKH) thanks to a tight cooperation between a French and a Cambodian team. Aim of this study was to describe conditions of introduction of this equipment. Two guidelines for practice are available. They are respectively edited by the French and British societies of pulmonology. These guidelines were reviewed and compared to the conditions in which BS was introduced in PKH. Each item from guidelines was combined to a categorical value: "applied", "adapted" or "not applied". In 2009, 54 bronchoscopies were performed in PKH, mainly for suspicion of infectious or tumour disease. In total, 52% and 46% of the French and British guideline items respectively were followed in this Cambodian unit. Patient safety items are those highly followed. By contrast "staff safety" items were those weakly applied. Implementation of EBS in developing countries seems feasible in good conditions of quality and safety for patients. However, some recommendations cannot be applied due to local conditions. PMID- 23796500 TI - Comorbidity status does not independently predict survival outcomes after radical nephroureterectomy for upper tract urothelial carcinoma. PMID- 23796501 TI - Alpha-synuclein overexpression increases phospho-protein phosphatase 2A levels via formation of calmodulin/Src complex. AB - Alpha-synuclein (alpha-Syn) is the principal protein component of Lewy bodies, a pathological hallmark of Parkinson's disease (PD). This protein may regulate protein phosphatase 2A (PP2A) activity, although the molecular mechanisms for alpha-Syn-mediated regulation of PP2A and the potential neuroprotective actions of PP2A against PD-associated pathology remain largely unexplored. We found that alpha-Syn gene overexpression in SK-N-SH cells and primary neurons led to PP2A/C phosphorylation at Y307, a known target of Src kinase, and consequent phosphatase inhibition. In addition, phospho-activated Src (p-Y416 Src, pSrc) was higher in SK-N-SH cells and primary neurons overexpressing alpha-Syn. Thus, alpha-Syn may promote Src activation and PP2A inactivation, leading to hyperphosphorylation of proteins. Immunoprecipitation revealed higher calmodulin/Src complex formation in alpha-Syn-overexpressing cells and alpha-Syn transgenic mice. A TUNEL apoptosis assay and an MTT cell viability assay demonstrated that the PP2A activator C2 ceramide protected neurons against alpha-Syn-induced cell injury. Buffering the Ca(2+) elevations induced by alpha-Syn overexpression ameliorated the cytotoxicity of alpha-Syn. Our findings define a potential molecular mechanism for alpha-Syn-mediated regulation of PP2A through formation of the calmodulin/Src complex, activation of Src, and Src-mediated phospho-inhibition of PP2A. Overexpression of alpha-Syn may lead to neurodegeneration in PD in part by suppressing the endogenous neuroprotective activity of PP2A. PMID- 23796502 TI - Angiotensin II regulates collagen metabolism through modulating tissue inhibitor of metalloproteinase-1 in diabetic skin tissues. AB - We investigated the effect of angiotensin II (Ang II) on matrix metalloproteinase 1 (MMP-1)/tissue inhibitor of metalloproteinase-1 (TIMP-1) balance in regulating collagen metabolism of diabetic skin. Skin tissues from diabetic model were collected, and the primary cultured fibroblasts were treated with Ang II receptor inhibitors before Ang II treatment. The collagen type I (Coll I) and collagen type III (Coll III) were measured by histochemistry. The expressions of transforming growth factor-beta (TGF-beta), MMP-1, TIMP-1 and propeptides of types I and III procollagens in skin tissues and fibroblasts were quantified using polymerase chain reaction (PCR), Western blot or enzyme-linked immunosorbent assay (ELISA). Collagen dysfunction was documented by changed collagen I/III ratio in streptozotocin (STZ)-injected mice compared with controls. This was accompanied by increased expression of TGF-beta, TIMP-1 and propeptides of types I and III procollagens in diabetic skin tissues. In primary cultured fibroblasts, Ang II prompted collagen synthesis accompanied by increases in the expressions of TGF-beta, TIMP-1 and types I and III procollagens, and these increases were inhibited by losartan, an Ang II type 1 (AT1) receptor blocker, but not affected by PD123319, an Ang II type 2 (AT2) receptor antagonist. These findings present evidence that Ang-II-mediated changes in the productions of MMP-1 and TIMP-1 occur via AT1 receptors and a TGF-beta-dependent mechanism. PMID- 23796503 TI - Roles of larval sea urchin spicule SM50 domains in organic matrix self-assembly and calcium carbonate mineralization. AB - The larval spicule matrix protein SM50 is the most abundant occluded matrix protein present in the mineralized larval sea urchin spicule. Recent evidence implicates SM50 in the stabilization of amorphous calcium carbonate (ACC). Here, we investigate the molecular interactions of SM50 and CaCO3 by investigating the function of three major domains of SM50 as small ubiquitin-like modifier (SUMO) fusion proteins - a C-type lectin domain (CTL), a glycine rich region (GRR) and a proline rich region (PRR). Under various mineralization conditions, we find that SUMO-CTL is monomeric and influences CaCO3 mineralization, SUMO-GRR aggregates into large protein superstructures and SUMO-PRR modifies the early CaCO3 mineralization stages as well as growth. The combination of these mineralization and self-assembly properties of the major domains synergistically enable the full length SM50 to fulfill functions of constructing the organic spicule matrix as well as performing necessary mineralization activities such as Ca(2+) ion recruitment and organization to allow for proper growth and development of the mineralized larval sea urchin spicule. PMID- 23796505 TI - Role of Slit and Robo proteins in the development of dopaminergic neurons. AB - Dopamine plays a number of important roles in the nervous system and the dopaminergic system is affected in several brain disorders. It is therefore of great interest to study the axonal guidance systems that specifically participate in the correct establishment of dopaminergic projections during development and possibly during regenerative processes. In recent years, several reports have shown that Slits and their Robo receptors control the growth of longitudinal (both ascending and descending) mesodiencephalic dopaminergic axons to their appropriate target areas. In vitro studies have shown that Slit1, 2 and 3 are potent repellents of dopamine neurite extension. In vivo studies using both mice and zebrafish mutants for Slits and Robos have shown that Slits and Robos control the lateral and dorsoventral positioning of dopaminergic longitudinal projections during early development. In the present review, we aimed to compile the existing knowledge from both in vitro and in vivo studies on the role of Slit and Robo proteins in the development of dopaminergic neurons as a basis for future studies. PMID- 23796504 TI - Computational methods for constructing protein structure models from 3D electron microscopy maps. AB - Protein structure determination by cryo-electron microscopy (EM) has made significant progress in the past decades. Resolutions of EM maps have been improving as evidenced by recently reported structures that are solved at high resolutions close to 3A. Computational methods play a key role in interpreting EM data. Among many computational procedures applied to an EM map to obtain protein structure information, in this article we focus on reviewing computational methods that model protein three-dimensional (3D) structures from a 3D EM density map that is constructed from two-dimensional (2D) maps. The computational methods we discuss range from de novo methods, which identify structural elements in an EM map, to structure fitting methods, where known high resolution structures are fit into a low-resolution EM map. A list of available computational tools is also provided. PMID- 23796506 TI - Look before you (s)leep: evaluating the use of fatigue detection technologies within a fatigue risk management system for the road transport industry. AB - Fatigue is a significant risk factor in workplace accidents and fatalities. Several technologies have been developed for organisations seeking to identify and reduce fatigue-related risk. These devices purportedly monitor behavioural correlates of fatigue and/or task performance and are understandably appealing as a visible risk control. This paper critically reviews evidence supporting fatigue detection technologies and identifies criteria for assessing evidence supporting these technologies. Fatigue detection devices, and relevant reliability and validation data, were identified by systematically searching the scientific, grey and marketing literature. Identified devices typically assessed correlates of fatigue using either psychophysiological measures or embedded performance measures drawn from the equipment being operated. Critically, the majority of the 'validation' data were not found within the scientific peer-reviewed literature, but within the quasi-scientific, grey or marketing literature. Based on the validation evidence available, none of the current technologies met all the proposed regulatory criteria for a legally and scientifically defensible device. Further, none were sufficiently well validated to provide a comprehensive solution to managing fatigue-related risk at the individual level in real time. Nevertheless, several of the technologies may be considered a potentially useful element of a broader fatigue risk management system. To aid organisations and regulators contemplating their use, we propose a set of evaluative and operational criteria that would likely meet the legal requirements for exercising due diligence in the selection and use of these technologies in workplace settings. PMID- 23796507 TI - Short- and long-term phasing of intraocular pressure in stable and progressive glaucoma. AB - AIMS: To evaluate short- (ST) and long-term (LT) intraocular pressure (IOP) in patients with stable (SG) and progressive glaucoma (PG). MATERIALS AND METHODS: Fifty-two patients with treated glaucoma received a baseline 24-hour IOP curve and, every 6 months for 2 years, office-hour curve plus visual field test. Based on field changes, they were divided into 24 SG and 28 PG. ST and LT IOP mean, peak and fluctuation (standard deviation of measurements) were calculated. Parameters determining progression were evaluated by logistic regression. RESULTS: At ST, SG and PG, respectively, had mean IOP of 16.8 +/- 2.2 and 15.3 +/ 1.8 mm Hg; peak of 19.7 +/- 3.3, 17.4 +/- 2.3 mm Hg; fluctuation of 2.3 +/- 1.2, and 1.6 +/- 0.6 mm Hg. LT parameters did not change in SG, whereas a significant increase of mean (+1.0 +/- 1.5 mm Hg, p = 0.05), peak (2.0 +/- 2.4 mm Hg, p = 0.0002), and fluctuation (0.5 +/- 1.1 mm Hg, p = 0.008) occurred in PG. Mean, peak, and fluctuation were correlated, except mean and fluctuation in the long term. Association with progression was shown for change in mean IOP between ST and LT, and ST peak. CONCLUSIONS: SG and PG may show different IOP parameters when intensively measured at baseline and follow-up. Mean IOP change between ST and LT periods and ST peak were the parameters associated with progression. PMID- 23796508 TI - Designing eHealth that Matters via a Multidisciplinary Requirements Development Approach. AB - BACKGROUND: Requirements development is a crucial part of eHealth design. It entails all the activities devoted to requirements identification, the communication of requirements to other developers, and their evaluation. Currently, a requirements development approach geared towards the specifics of the eHealth domain is lacking. This is likely to result in a mismatch between the developed technology and end user characteristics, physical surroundings, and the organizational context of use. It also makes it hard to judge the quality of eHealth design, since it makes it difficult to gear evaluations of eHealth to the main goals it is supposed to serve. OBJECTIVE: In order to facilitate the creation of eHealth that matters, we present a practical, multidisciplinary requirements development approach which is embedded in a holistic design approach for eHealth (the Center for eHealth Research roadmap) that incorporates both human-centered design and business modeling. METHODS: Our requirements development approach consists of five phases. In the first, preparatory, phase the project team is composed and the overall goal(s) of the eHealth intervention are decided upon. Second, primary end users and other stakeholders are identified by means of audience segmentation techniques and our stakeholder identification method. Third, the designated context of use is mapped and end users are profiled by means of requirements elicitation methods (eg, interviews, focus groups, or observations). Fourth, stakeholder values and eHealth intervention requirements are distilled from data transcripts, which leads to phase five, in which requirements are communicated to other developers using a requirements notation template we developed specifically for the context of eHealth technologies. RESULTS: The end result of our requirements development approach for eHealth interventions is a design document which includes functional and non-functional requirements, a list of stakeholder values, and end user profiles in the form of personas (fictitious end users, representative of a primary end user group). CONCLUSIONS: The requirements development approach presented in this article enables eHealth developers to apply a systematic and multi-disciplinary approach towards the creation of requirements. The cooperation between health, engineering, and social sciences creates a situation in which a mismatch between design, end users, and the organizational context can be avoided. Furthermore, we suggest to evaluate eHealth on a feature-specific level in order to learn exactly why such a technology does or does not live up to its expectations. PMID- 23796509 TI - Calcineurin inhibitor nephrotoxicity: a review and perspective of the evidence. AB - BACKGROUND: There is no doubt that acute calcineurin inhibitor (CNI) nephrotoxicity exists; however, chronic CNI nephrotoxicity is questionable at best. METHODS: We reviewed the literature to identify original articles related to the use of CNIs in renal and nonrenal solid organ transplantation in order to examine the available evidence about their chronic nephrotoxicity and contribution to graft failure. RESULTS: Early clinical experience and animal studies support the evidence of CNI nephrotoxicity. These findings evolved into the dogma that CNI nephrotoxicity is the major cause of late renal allograft failure. However, in transplanted kidneys the specific role of chronic CNI nephrotoxicity has been questioned. The emerging literature clearly highlights the lack of solid evidence for the role of CNIs as the sole and major injurious agents that cause chronic renal dysfunction and subsequent graft failure. Most of the evidence available to date is against complete CNI avoidance, and minimization appears to be a more viable strategy. It is becoming increasingly clear that the typical pathological lesions linked to chronic CNI use are highly nonspecific, and most of the chronic changes that have been attributed to chronic CNI nephrotoxicity are the consequences of previously unrecognized immunologic injuries. One needs to keep in mind that the potential risk of side effects of CNI use should be balanced against the risk of rejection. CONCLUSIONS: More research should focus on addressing the true causes of chronic graft dysfunction rather than focusing on the overexaggerated contribution of CNIs to late graft loss. PMID- 23796510 TI - Screening for GNAS genetic and epigenetic alterations in progressive osseous heteroplasia: first Italian series. AB - Progressive osseous heteroplasia (POH) is a rare autosomal dominant disorder of mesenchymal differentiation characterized by progressive heterotopic ossification (HO) of dermis, deep connective tissues and skeletal muscle. Usually, initial bone formation occurs during infancy as primary osteoma cutis (OC) then progressively extending into deep connective tissues and skeletal muscle over childhood. Most cases of POH are caused by paternally inherited inactivating mutations of GNAS gene. Maternally inherited mutations as well as epigenetic defects of the same gene lead to pseudohypoparathyroidism (PHP) and Albright's hereditary osteodystrophy (AHO). During the last decade, some reports documented the existence of patients with POH showing additional features characteristic of AHO such as short stature and brachydactyly, previously thought to occur only in other GNAS-associated disorders. Thus, POH can now be considered as part of a wide spectrum of ectopic bone formation disorders caused by inactivating GNAS mutations. Here, we report genetic and epigenetic analyses of GNAS locus in 10 patients affected with POH or primary OC, further expanding the spectrum of mutations associated with this rare disease and indicating that, unlike PHP, methylation alterations at the same locus are absent or uncommon in this disorder. PMID- 23796511 TI - Uterine adenomyoma with exophytic subserosal growth: case report of rare manifestation with image diagnosis and laparoscopic-assisted excision. AB - Uterine adenomyoma is a nodular aggregated form of adenomyosis composed of heterotopic endometrial or endometrium-like structures in the myometrium, with adjacent myometrial hyperplasia. Although adenomyoma is not extremely rare, reports of adenomyoma showing exophytic subserosal growth are limited. A 32-year old nulligravida woman had sudden onset of lower abdominal pain. In addition to a left endometriotic cyst, a heterogeneous mass lesion showing mural and exophytic subserosal growth was noted in the posterior wall of the uterus. In a two-port laparoscopic-assisted procedure, the subserosal nodule was excised using ultrasonic coagulating shears, followed by excision of the mural lesion using a round loop electrode and a high-frequency electrosurgical unit. The histopathologic diagnosis was adenomyoma. PMID- 23796512 TI - Musculoskeletal pain in gynecologic surgeons. AB - OBJECTIVE: To describe the prevalence of musculoskeletal pain and symptoms in gynecologic surgeons. DESIGN: Prospective cross-sectional survey study (Canadian Task Force classification II-2). SETTING: Virtual. All study participants were contacted and participated via electronic means. PARTICIPANTS: Gynecologic surgeons. INTERVENTIONS: An anonymous, web-based survey was distributed to gynecologic surgeons via electronic newsletters and direct E-mail. MEASUREMENTS AND MAIN RESULTS: There were 495 respondents with complete data. When respondents were queried about their musculoskeletal symptoms in the past 12 months, they reported a high prevalence of lower back (75.6%) and neck (72.9%) pain and a slightly lower prevalence of shoulder (66.6%), upper back (61.6%), and wrist/hand (60.9%) pain. Many respondents believed that performing surgery caused or worsened the pain, ranging from 76.3% to 82.7% in these five anatomic regions. Women are at an approximately twofold risk of pain, with adjusted odds ratios (OR) of 1.88 (95% confidence interval [CI], 1.1-3.2; p = .02) in the lower back region, OR 2.6 (95% CI, 1.4-4.8; p = .002) in the upper back, and OR 2.9 (95% CI, 1.8-4.6; p = .001) in the wrist/hand region. CONCLUSION: Musculoskeletal symptoms are highly prevalent among gynecologic surgeons. Female sex is associated with approximately twofold risk of reported pain in commonly assessed anatomic regions. PMID- 23796513 TI - Does excessive flatfoot deformity affect function? A comparison between symptomatic and asymptomatic flatfeet using the Oxford Foot Model. AB - Treatment of asymptomatic flexible flatfeet is a subject of great controversy. The purpose of this study was to examine foot function during walking in symptomatic (SFF) and asymptomatic (ASFF) flexible flatfeet. Thirty-five paediatric and juvenile patients with idiopathic flexible flatfeet were recruited from an orthopaedic outpatient department (14 SFF and 21 ASFF). Eleven age matched participants with typically developing feet served as controls (TDF). To study foot function, 3D multi-segment foot kinematics and ankle joint kinetics were captured during barefoot gait analysis. Overall, alterations in foot kinematics in flatfeet were pronounced but differences between SFF and ASFF were not observed. Largest discriminatory effects between flatfeet and TDF were noticed in reduced hindfoot dorsiflexion as well as in increased forefoot supination and abduction. Upon clinical examination, restrictions in passive dorsiflexion in ASFF and SFF were significant. During gait, the hindfoot in flatfeet (both ASFF and SFF) was more everted, but less flexible. In sagittal plane, limited hindfoot dorsiflexion of ASFF and SFF was compensated for by increased forefoot mobility and a hypermobile hallux. Concerning ankle kinetics, SFF lacked positive joint energy for propulsion while ASFF needed to absorb more negative ankle joint energy during loading response. This may risk fatigue and overuse syndrome of anterior shank muscles in ASFF. Hence, despite a lack of symptoms flatfoot deformity in ASFF affected function. Yet, contrary to what was expected, SFF did not show greater deviations in 3D foot kinematics than ASFF. Symptoms may rather depend on tissue wear and subjective pain thresholds. PMID- 23796514 TI - S100A6 competes with the TAZ2 domain of p300 for binding to p53 and attenuates p53 acetylation. AB - S100A6 is a calcium binding protein that, like some other members of the S100 protein family, is able to bind p53. This interaction may be physiologically relevant considering the numerous connotations of S100 proteins and of S100A6, in particular, with cancer and metastasis. In this work, we show that the interaction with S100A6 is limited to unmodified or phosphorylated p53 and is inhibited by p53 acetylation. Using in vitro acetylation assay, we show that the presence of S100A6 attenuates p53 acetylation by p300. Furthermore, using ELISA, we show that S100A6 and the TAZ2 domain of p300 bind p53 with similar affinities and that S100A6 effectively competes with TAZ2 for binding to p53. Our results add another element to the complicated scheme of p53 activation. PMID- 23796515 TI - FERM domain of moesin desorbs the basic-rich cytoplasmic domain of l-selectin from the anionic membrane surface. AB - Moesin and calmodulin (CaM) jointly associate with the cytoplasmic domain of l selectin in the cell to modulate the function and ectodomain shedding of l selectin. Using fluorescence spectroscopy, we have examined the association of moesin FERM domain with the recombinant transmembrane and cytoplasmic domains of l-selectin (CLS) reconstituted in model phospholipid liposomes. The dissociation constant of moesin FERM domain to CLS in the phosphatidylcholine liposome is about 300nM. In contrast to disrupting the CaM association with CLS, inclusion of anionic phosphatidylserine lipids in the phosphatidylcholine liposome increased the apparent binding affinity of moesin FERM domain for CLS. Using the environmentally sensitive fluorescent probe attached to the cytoplasmic domain of CLS and the nitroxide quencher attached to the lipid bilayer, we showed that the association of moesin FERM domain induced the desorption of the basic-rich cytoplasmic domain of CLS from the anionic membrane surface, which enabled subsequent association of CaM to the cytoplasmic domain of CLS. These results have elucidated the molecular basis for the moesin/l-selectin/CaM ternary complex and suggested an important role of phospholipids in modulating l-selectin function and shedding. PMID- 23796516 TI - CryoEM and molecular dynamics of the circadian KaiB-KaiC complex indicates that KaiB monomers interact with KaiC and block ATP binding clefts. AB - The circadian control of cellular processes in cyanobacteria is regulated by a posttranslational oscillator formed by three Kai proteins. During the oscillator cycle, KaiA serves to promote autophosphorylation of KaiC while KaiB counteracts this effect. Here, we present a crystallographic structure of the wild-type Synechococcus elongatus KaiB and a cryo-electron microscopy (cryoEM) structure of a KaiBC complex. The crystal structure shows the expected dimer core structure and significant conformational variations of the KaiB C-terminal region, which is functionally important in maintaining rhythmicity. The KaiBC sample was formed with a C-terminally truncated form of KaiC, KaiC-Delta489, which is persistently phosphorylated. The KaiB-KaiC-Delta489 structure reveals that the KaiC hexamer can bind six monomers of KaiB, which form a continuous ring of density in the KaiBC complex. We performed cryoEM-guided molecular dynamics flexible fitting simulations with crystal structures of KaiB and KaiC to probe the KaiBC protein protein interface. This analysis indicated a favorable binding mode for the KaiB monomer on the CII end of KaiC, involving two adjacent KaiC subunits and spanning an ATP binding cleft. A KaiC mutation, R468C, which has been shown to affect the affinity of KaiB for KaiC and lengthen the period in a bioluminescence rhythm assay, is found within the middle of the predicted KaiBC interface. The proposed KaiB binding mode blocks access to the ATP binding cleft in the CII ring of KaiC, which provides insight into how KaiB might influence the phosphorylation status of KaiC. PMID- 23796517 TI - Thermodynamic and structural determinants of differential Pdx1 binding to elements from the insulin and IAPP promoters. AB - In adult mammals, the production of insulin and other peptide hormones, such as the islet amyloid polypeptide (IAPP), is limited to beta-cells due to tissue specific expression of a set of transcription factors, the best known of which is pancreatic duodenal homeobox protein 1 (Pdx1). Like many homeodomain transcription factors, Pdx1 binds to a core DNA recognition sequence containing the tetranucleotide 5'-TAAT-3'; its consensus recognition element is 5' CTCTAAT(T/G)AG-3'. Currently, a complete thermodynamic profile of Pdx1 binding to near-consensus and native promoter sequences has not been established, obscuring the mechanism of target site selection by this critical transcription factor. Strikingly, while Pdx1 responsive elements in the human insulin promoter conform to the pentanucleotide 5'-CTAAT-3' sequence, the Pdx1 responsive elements in the human iapp promoter all contain a substitution to 5'-TTAAT-3'. The crystal structure of Pdx1 bound to the consensus nucleotide sequence does not explain how Pdx1 identifies this natural variation, if it does at all. Here we report a combination of isothermal calorimetric titrations, NMR spectroscopy, and extensive multi-microsecond molecular dynamics calculations of Pdx1 that define its interactions with a panel of natural promoter elements and consensus-derived sequences. Our results show a small preference of Pdx1 for a C base 5' relative to the core TAAT promoter element. Molecular mechanics calculations, corroborated by experimental NMR data, lead to a rational explanation for sequence discrimination at this position. Taken together, our results suggest a molecular mechanism for differential Pdx1 affinity to elements from the insulin and iapp promoter sequences. PMID- 23796518 TI - Resurrection of an Urbilaterian U1A/U2B"/SNF protein. AB - The U1A/U2B"/SNF family of proteins found in the U1 and U2 spliceosomal small nuclear ribonucleoproteins is highly conserved. In spite of the high degree of sequence and structural conservation, modern members of this protein family have unique RNA binding properties. These differences have necessarily resulted from evolutionary processes, and therefore, we reconstructed the protein phylogeny in order to understand how and when divergence occurred and how protein function has been modulated. Contrary to the conventional understanding of an ancient human U1A/U2B" gene duplication, we show that the last common ancestor of bilaterians contained a single ancestral protein (URB). The gene for URB was synthesized, the protein was overexpressed and purified, and we assessed RNA binding to modern snRNA sequences. We find that URB binds human and Drosophila U1 snRNA SLII and U2 snRNA SLIV with higher affinity than do modern homologs, suggesting that both Drosophila SNF and human U1A/U2B" have evolved into weaker binders of one RNA or both RNAs. PMID- 23796520 TI - Functional characterization of two microsomal fatty acid desaturases from Jatropha curcas L. AB - Linoleic acid (LA, C18:2) and alpha-linolenic acid (ALA, C18:3) are polyunsaturated fatty acids (PUFAs) and major storage compounds in plant seed oils. Microsomal omega-6 and omega-3 fatty acid (FA) desaturases catalyze the synthesis of seed oil LA and ALA, respectively. Jatropha curcas L. seed oils contain large proportions of LA, but very little ALA. In this study, two microsomal desaturase genes, named JcFAD2 and JcFAD3, were isolated from J. curcas. Both deduced amino acid sequences possessed eight histidines shown to be essential for desaturases activity, and contained motif in the C-terminal for endoplasmic reticulum localization. Heterologous expression in Saccharomyces cerevisiae and Arabidopsis thaliana confirmed that the isolated JcFAD2 and JcFAD3 proteins could catalyze LA and ALA synthesis, respectively. The results indicate that JcFAD2 and JcFAD3 are functional in controlling PUFA contents of seed oils and could be exploited in the genetic engineering of J. curcas, and potentially other plants. PMID- 23796519 TI - Dissecting the effects of periplasmic chaperones on the in vitro folding of the outer membrane protein PagP. AB - Although many periplasmic folding factors have been identified, the mechanisms by which they interact with unfolded outer membrane proteins (OMPs) to promote correct folding and membrane insertion remain poorly understood. Here, we have investigated the effect of two chaperones, Skp and SurA, on the folding kinetics of the OMP, PagP. Folding kinetics of PagP into both zwitterionic diC12:0PC (1,2 dilauroyl-sn-glycero-3-phosphocholine) liposomes and negatively charged 80:20 diC12:0PC:diC12:0PG [1,2-dilauroyl-sn-glycero-3-phospho-(1'-rac-glycerol)] liposomes were investigated using a combination of spectroscopic and SDS-PAGE assays. The results indicate that Skp modulates the observed rate of PagP folding in a manner that is dependent on the composition of the membrane and the ionic strength of the buffer used. These data suggest that electrostatic interactions play an important role in Skp-assisted substrate delivery to the membrane. In contrast, SurA showed no effect on the observed folding rates of PagP, consistent with the view that these chaperones act by distinct mechanisms in partially redundant parallel chaperone pathways that facilitate OMP assembly. In addition to delivery of the substrate protein to the membrane, the ability of Skp to prevent OMP aggregation was investigated. The results show that folding and membrane insertion of PagP can be restored, in part, by Skp in conditions that strongly favour PagP aggregation. These results illustrate the utility of in vitro systems for dissecting the complex folding environment encountered by OMPs in the periplasm and demonstrate the key role of Skp in holding aggregation-prone OMPs prior to their direct or indirect delivery to the membrane. PMID- 23796521 TI - Sepal phenolic profile during Helleborus niger flower development. AB - Morphological changes and phenolic patterns of developing hellebore sepals and the effects of pistil removal on these parameters were studied by comparing six flower stages of Helleborus niger. Color changes were evaluated colorimetrically, chlorophyll content was measured spectrophotometrically, and anthocyanins and flavonols were identified and quantified with HPLC-MS. Pistil removal not only altered the morphological development of hellebore flower resulting in smaller flower and significant color changes but also lead to several biochemical modifications. Five cyanidin glycosides have been identified from the group of anthocyanins in hellebore. Individual and total anthocyanin content increased from bud to subsequent developmental stages. Moreover, significantly higher content levels of individual and total anthocyanins have been measured in non pollinated flower sepals compared to sepals of pollinated flowers. From the group of flavonols eight quercetin and kaempferol compounds have been quantified in hellebore sepals. Flavonol content significantly decreased during flower development with lowest levels recorded in sepals of non-pollinated and senescent pollinated hellebore flowers. Sepals of pollinated flowers contained highest levels of chlorophyll and significantly lower amounts of chlorophyll were measured in non-pollinated flowers and in sepals of senescent stage. PMID- 23796522 TI - Flowering is delayed by mutations in homologous genes CAPRICE and TRYPTICHON in the early flowering Arabidopsis cpl3 mutant. AB - CAPRICE (CPC) and CAPRICE-like (CPL) myeloblastosis (MYB) family members [including TRYPTICHON (TRY) and ENHANCER OF TRYPTICHON AND CAPRICE (ETC)] of Arabidopsis thaliana encode R3-type MYB transcription factors that promote root hair differentiation and inhibit trichome formation in a redundant manner. Previously, we reported that the CPL3 gene affects flowering. The cpl3 mutant plants flower earlier and with fewer leaves than the wild type. In this study, we show that mutations in CPC or TRY delay flowering of cpl3 plants. A mutation in ETC1 did not further delay flowering but reduced plant size. Our study provides insight into the regulation of flowering time by the CPC-like MYB gene family. PMID- 23796523 TI - Structural and expression studies of interferon regulatory factor 8 in Japanese flounder, Paralichthys olivaceus. AB - Interferon regulatory factor 8 (IRF8) plays a role in both innate and adaptive systems in mammals. In this study, the gene and promoter sequences of Japanese flounder, Paralichthys olivaceus, (Po) IRF8 were cloned, and its expression in response to polyinosinic:polycytidylic acid (poly I:C) and lymphocystis disease virus (LCDV) challenges was studied in vivo. The PoIRF8 gene spans over 3.3 kb with a structure of 9 exon-8 intron and encodes 420 amino acids. The putative protein shows the highest sequence identity (69.5-89.0%) to fish IRF8 and possesses a DNA-binding domain (DBD), an IRF-association domain (IAD) and a nuclear localization signal (NLS) of vertebrate IRF8. Phylogenetic analysis classified PoIRF8 into the cluster of fish IRF8 within vertebrate IRF8 group of IRF4 subfamily. A number of transcription factor binding sites were identified in the 2348-bp 5' flanking region of PoIRF8 gene, including those of transcription factors for type I and type II interferon (IFN) inducible genes and genes regulating the development and function of lymphomyeloid cells in mammals. The PoIRF8 transcripts were expressed in all examined tissues of healthy flounders, with higher levels observed in the immune relevant tissues. They were up regulated by both poly I:C and LCDV treatments in the spleen, head kidney, gills and muscle in an early phase of immune responses, with initiation and peak time points of induction prior to type I IFN and Mx. Relative to LCDV, the induction by poly I:C was quicker in all four tissues. These results indicate an involvement of PoIRF8 in the host's antiviral responses and a functional conservation of IRF8 between fish and mammals. PMID- 23796524 TI - Neuropsychological functioning in young subjects with generalized anxiety disorder with and without pharmacotherapy. AB - The purpose of this study was to investigate the neuropsychological functioning and the effect of antidepressant drug intake on cognitive performance in a group of relatively young generalized anxiety disorder (GAD) patients. Forty patients with a DSM-IV diagnosis of GAD and 31 healthy subjects participated in the study (Control group, CON). None of the selected subjects had comorbid depression. GAD subjects were divided into two different subgroups: 18 were taking antidepressants [GAD-pharmacotherapy (GAD-p group)] and 22 were treatment-naive (GAD group). Each group was administered with a comprehensive neuropsychological battery to assess attention, memory and executive functions. Performance on executive and non-verbal memory tasks of both GAD groups was largely worse than the CON group. However, these deficits seem to be more marked in patients taking antidepressants, especially in the domains of attention, non-verbal memory and executive functions. The present study indicates that GAD is associated with cognitive impairments among young adults. However, the observed association of neuropsychological deficits and the use of pharmacotherapy suggest a possible effect of antidepressant treatment on attention, executive functioning and non verbal memory. PMID- 23796526 TI - A novel approach to cardiovascular health by optimizing risk management (ANCHOR): behavioural modification in primary care effectively reduces global risk. AB - BACKGROUND: Primary care is well positioned to facilitate cardiovascular risk improvement and reduce future cardiovascular disease (CVD) burden. METHODS: The efficacy of risk factor screening, behavioural counselling, and pharmacological treatment to lower CVD risk was assessed via a prospective pre- and postintervention health risk assessment, individualized intervention with behaviour modification, risk factor treatment, and linkage to community programs, with 1-year follow-up and final health risk assessment. Primary outcome was the proportion of subjects with moderate and high baseline Framingham Risk Score (FRS) reducing their risk by 10% and 25%, respectively; the secondary end point was the proportion dropping >= 1 risk category. RESULTS: Patients were enrolled (N = 1509) from March 2006 through October 2008 and 72% completed the study. This analysis focuses on 563 subjects with moderate or high baseline FRS, and excluded 325 low-risk patients and 205 with established CVD or diabetes mellitus. Median age was 56 years, 57.7% were female. The primary outcome was achieved in 31.8% (N = 112; 95% confidence interval [CI], 26.9%-36.6%) of moderate risk FRS participants and 47.9% (N = 101; 95% CI, 41.2%-54.6%) of high-risk participants. The secondary outcome was achieved by 37.2% (N = 210; 95% CI, 33.2%-41.2%). Prevalence of metabolic syndrome fell from 79.2% (N = 446; 95% CI, 75.9%-82.6%) at entry to 52.8% (N = 303; 95% CI, 48.7%-56.9%) at study end. Significant improvements in all modifiable risk factors occurred through lifestyle modification. CONCLUSIONS: Global cardiovascular risk can be effectively decreased via lifestyle changes informed by readiness to change assessment and individualized counselling targeting specific behaviours. TRIAL REGISTRATION: ClinicalTrials.gov number NCT01620996. PMID- 23796525 TI - The impact of self-reported life stress on current impulsivity in cocaine dependent adults. AB - Current cocaine treatments may be enhanced with a better understanding of the underlying mechanisms that contribute to the onset and maintenance of the disease, such as life stress and impulsivity. Life stress and impulsivity have previously been studied independently as contributors to drug use, and the current study expands upon past research by examining how these factors interact with one another. The aim of the current study was to evaluate the role of life stress in predicting impulsivity in a non-treatment seeking cocaine-dependent sample (N=112). Analyses revealed that trait impulsivity (as measured by the Barratt Impulsiveness Scale) was associated with education (r=-3.09, p<0.01), as those who had higher educational attainment also reported lower rates of trait impulsivity. In addition, those over the age of 30 demonstrated lower impulsivity in decision-making (as measured by delay discounting) than those under 30 (t=2.21, p=0.03). Overall exposure to life stress was not significantly correlated to either aspect of impulsivity. However several specific life stressors were significantly related to greater impulsivity including having been put up for adoption or in foster care (t=-2.96, p<0.01), and having a child taken away against their will (t=-2.68, p=0.01). These findings suggest that age and education relate to impulsivity; and that while an overall compilation of life stress scores was not related to impulsivity, specific types of stress related to either being taken away from a parent or having a child taken away were. Future studies should assess these constructs longitudinally to restrict response bias. PMID- 23796527 TI - Longitudinal changes in brains of patients with fluent primary progressive aphasia. AB - Primary progressive aphasia (PPA) is a rare clinical dementia syndrome with predominant, progressive language impairment. Clinical symptoms, linguistic impairment and the course of the disease may vary considerably between patients. In order to capture these aspects, longitudinal assessments of neurofunctional changes in PPA including their relationship to behaviour and clinical symptoms are mandatory, ideally at intervals shorter than 1 year. Here, we report a longitudinal fMRI study investigating the development of lexical processing and their neural basis in PPA patients over 1year. Four logopenic PPA patients and four matched controls were scanned 3 times (T1, T2, T3, at 6months intervals) while performing a visual lexical decision task on German words and pseudowords. Group differences for the lexicality effect (pseudowords>words) were assessed at time point T1 and its longitudinal changes in the BOLD signal associated with the lexicality effect were analysed. Brain atrophy was assessed with a high resolution MPRAGE sequence and analysed using deformation based morphometry (DBM). From the very beginning of the study, PPA patients showed reduced left hemispheric and increased right-hemispheric activations compared to controls. During the progression of the disease, activation increased predominantly in left posterior middle temporal gyrus (pMTG) and inferior frontal junction area, whereas the same regions decreased in activity in control brains. Interestingly, DBM data showed that this increase in activation in PPA patients was accompanied by progressing atrophy in the same regions. At a behavioural level, the accuracy in the lexical decision task was comparably high for both groups during the whole period of examination, despite some large variability between patients. To conclude, the dissociation between (i) maintained high performance, (ii) increased activity in regions involved in lexical access such as pMTG, and (iii) progressive atrophy of the very same regions supports the notion of a compensatory mechanism in brains of PPA patients for maintaining language while brain atrophy is progressing. The activity increase within a left-lateralised fronto-temporal network seems vital for high-level performance, whereas initial right-hemispheric recruitment of homologue language regions, which is reminiscent of that in vascular aphasics, has no continuous impact on lexical performance. PMID- 23796528 TI - Assessing the assessors of quality of life. PMID- 23796529 TI - Lipoatrophy is associated with an increased risk of Hashimoto's thyroiditis and coeliac disease in female patients with type 1 diabetes. AB - BACKGROUND/AIMS: Lipoatrophy (LA) is a rare, possibly under-recognised side effect of insulin treatment of unclear aetiology. The aim of this study was to describe the characteristics of patients with type 1 diabetes (T1D) who have LA and to explore the relationship between LA and other autoimmune diseases based on the hypothesis that additional autoimmune phenomena are more prevalent in T1D patients with LA. METHODS: This was a cross-sectional observational study of T1D patients with LA in comparison to T1D patients without LA who are registered with the Diabetes Patienten-Verlaufsdokumentationssystem database of 241,650 patients in Germany and Austria. RESULTS: Hashimoto's thyroiditis and coeliac disease were more prevalent in patients with LA (p < 0.001 for both). LA was associated with an increased risk of Hashimoto's thyroiditis and coeliac disease in female patients [odds ratio (OR) 2.5, p = 0.003, and OR 3.1, p = 0.02, respectively]. This relationship persisted after adjustment for current age, duration of diabetes and calendar year of treatment (OR 2.7, p = 0.002, and OR 3.5, p = 0.01, respectively). CONCLUSION: These findings support the hypothesis that an immune complex-mediated inflammatory process may be important in the development of LA. PMID- 23796530 TI - Dynamic landscapes: a model of context and contingency in evolution. AB - Although the basic mechanics of evolution have been understood since Darwin, debate continues over whether macroevolutionary phenomena are driven by the fitness structure of genotype space or by ecological interaction. In this paper we propose a simple model capturing key features of fitness-landscape and ecological models of evolution. Our model describes evolutionary dynamics in a high-dimensional, structured genotype space with interspecies interaction. We find promising qualitative similarity with the empirical facts about macroevolution, including broadly distributed extinction sizes and realistic exploration of the genotype space. The abstraction of our model permits numerous applications beyond macroevolution, including protein and RNA evolution. PMID- 23796531 TI - A new electrochemical method for the detection of cancer cells based on small molecule-linked DNA. AB - Sensitive and accurate detection of cancer cells plays a crucial role in clinical diagnosis, treatment and prognosis of tumors. In this paper, we report a new electrochemical method for highly selective and sensitive detection of cancer cells by using small molecule-linked DNA as probes. The methodology is based on the fact that exonuclease I can catalyze the digestion of folate-linked DNA probes that are immobilized on an electrode surface; however, in the presence of the target cells, such as human breast cancer MCF-7 cells, the probes can be protected from digestion upon the binding with folate receptor that is over expressed on the cell surface. Consequently, cancer cells can be efficiently detected by monitoring the status of the probe DNA with electrochemical techniques. In this study, the protection to exonuclease I-catalyzed digestion has also been proven by electrochemical studies. Moreover, the proposed method has been proven to linearly detect MCF-7 cells in a wide range from 10(2)-10(6) cell mL(-1) with a low detection limit of 67 cell mL(-1), which can also easily distinguish the folate receptor-negative normal cells, for instance, islet beta cells. The reproduction of the detection is also satisfactory, since the relative standard deviations for three independent measurements of different concentration of MCF-7 cells are all within 10%. By replacing the small molecules linked on the DNA probe, other cancer cells can also be detected by making use of this proposed method. Therefore, our cytosensor may have great potential in clinical applications. PMID- 23796532 TI - The differential detection of methicillin-resistant, methicillin-susceptible and borderline oxacillin-resistant Staphylococcus aureus by surface plasmon resonance. AB - Two hundred fifty Staphylococcus aureus clinical isolates were studied to determine their susceptibilities to beta-lactam antibiotics. Among these isolates, 16 were methicillin-sensitive S. aureus (MSSA), 207 were methicillin resistant S. aureus (MRSA) and 27 were borderline oxacillin-resistant S. aureus (BORSA). Currently, the reported mechanism of methicillin resistance in S. aureus is the production of a distinctive penicillin binding protein 2a (PBP2a), which exhibits low affinity toward beta-lactams. A surface plasmon resonance biosensor was evaluated for its ability to identify MRSA and to distinguish these strains from MSSA and BORSA, by specifically detecting PBP2a. We found that the system permits label-free, real-time, specific detection of pathogens for concentrations as low as 10 colony forming units/milliliter (CFU/ml), in less than 20 min. This system promises to become a diagnostic tool for bacteria that cause major public concern in clinical settings. PMID- 23796533 TI - Fast nonlinear region localisation for nonlinear dielectric spectroscopy of biological suspensions. AB - The nonlinear properties of biological suspensions have been previously presented as a bulk phenomenon without the influences of the electrodes. However, some authors have showed that the behaviour of a biological suspension is due to the nonlinear characteristics of the electrode-electrolyte interface (EEI), which is modulated by the presence of yeast cells. We have developed a method, complementary to the nonlinear dielectric spectroscopy (NLDS) which is used for the study of the behaviour of EEI with resting cell suspensions of Saccharomyces cerevisiae. The method allows researchers to detect simply and quickly the voltage and frequency ranges where the metabolic activity of yeasts is detectable. This method does not replace NLDS, and aims to reduce the time during which the electrodes are exposed to corrosion by high voltages. In this paper we applied AC overpotentials (10-630 mV) with frequencies in the range from 1 to 1000 Hz. Also, we measured current harmonic distortion produced by the nonlinearity of the interface. Changes in the transfer function were observed when yeast suspension was used. Apart from the nonlinear response typical of the EEI, we also observed the biological nonlinear behaviour. The changes in the transfer functions were assessed using the overlapping index which was defined in terms of the conditional probability. The methodology was contrasted favourably with Fourier analysis. This novel strategy has the advantages of simplicity, sensitivity, reproducibility and involves basic tools such as the usual measurement of current. PMID- 23796534 TI - Dielectric spectroscopy as a viable biosensing tool for cell and tissue characterization and analysis. AB - The use of dielectric spectroscopy to carry out real time observations of cells and to extract a wealth of information about their physiological properties has expanded in recent years. This popularity is due to the simple, easy to use, non invasive and real time nature of dielectric spectroscopy. The ease of integrating dielectric spectroscopy with microfluidic devices has allowed the technology to further expand into biomedical research. Dielectric spectra are obtained by applying an electrical signal to cells, which is swept over a frequency range. This review covers the different methods of interpreting dielectric spectra and progress made in applications of impedance spectroscopy for cell observations. First, methods of obtaining specific electrical properties of cells (cell membrane capacitance and cytoplasm conductivity) are discussed. These electrical properties are obtained by fitting the dielectric spectra to different models and equations. Integrating models to reduce the effects of the electrical double layer are subsequently covered. Impedance platforms are then discussed including electrical cell substrate impedance sensing (ECIS). Categories of ECIS systems are divided into microelectrode arrays, interdigitated electrodes and those that allow differential ECIS measurements. Platforms that allow single cell and sub single cell measurements are then discussed. Finally, applications of impedance spectroscopy in a range of cell observations are elaborated. These applications include observing cell differentiation, mitosis and the cell cycle and cytotoxicity/cell death. Future applications such as drug screening and in point of care applications are then covered. PMID- 23796535 TI - Development and primary application of a fluorescent liquid bead array for the simultaneous identification of multiple genetically modified maize. AB - An integration event-specific fluorescent liquid bead array was developed for the simultaneous identification of 10 genetically modified (GM) maize, including Bt176, Bt11, MON810, NK603, GA21, MON88017, MON89034, MIR604, T25 and MIR162, as well as one non-GM maize. The system comprised 11 specific oligonucleotide probes labeled with an amino group and coupled to fluorescence-encoded microspheres. To enable fluorescence detection, 11 pairs of primers labeled with biotin at the 5' ends were used. The hybridization signal of biotinylated PCR product to the probe coupled microspheres was then detected. The limit of detection of this assay was 0.1% for GM maize, which is lower than the current labeling threshold levels enforced in the EU (0.9%). The results of the positive and negative controls were consistent with their expected situation, which showed that the method was highly specific. We detected GM maize in 20 of the 1370 commercial food samples tested, which were labeled as containing maize. The overall sensitivity, specificity, rapidity and high throughput capacity of this liquid chip system suggest that it could provide a significant improvement over current methods, and potentially offer an improved platform for further research into the detection of other GM plants. PMID- 23796536 TI - A sensitive and selective molecularly imprinted sensor combined with magnetic molecularly imprinted solid phase extraction for determination of dibutyl phthalate. AB - A highly sensitive and selective molecularly imprinted (MIP) sensor combined with magnetic molecularly imprinted solid phase extraction (MMISPE) was developed for the determination of dibutyl phthalate (DBP) in complex matrixes. The magnetic molecularly imprinted polymer (MMIP) was synthesized as solid phase extraction (SPE) sorbet to extract DBP from complex matrixes and as sensing element to improve the selectivity of the imprinted sensor. The morphologies of MMIP and MIP sensor were characterized by using scanning electron microscope (SEM) and transmission electron microscopy (TEM). The electrochemical performances of MIP sensor were investigated by cyclic voltammetry (CV) and differential pulse voltammetry (DPV). The conditions of preconcentration, elution and electrochemical determination were studied in detail. Under the optimized experimental conditions, the response currents of the MIP-sensor exhibited a linear relationship towards DBP concentrations ranging from 1.0 * 10(-8)g/L to 1.0 * 10(-3)g/L. The limit of detection of the MMIP-sensor coupled with the MMISPE was calculated as 0.052 ng/L. The MMIP-sensor coupled with the MMISPE was applied to detect DBP in complex samples successfully. PMID- 23796537 TI - Short-term acute hypercapnia affects cellular responses to trace metals in the hard clams Mercenaria mercenaria. AB - Estuarine and coastal habitats experience large fluctuations of environmental factors such as temperature, salinity, partial pressure of CO2 ( [Formula: see text] ) and pH; they also serve as the natural sinks for trace metals. Benthic filter-feeding organisms such as bivalves are exposed to the elevated concentrations of metals in estuarine water and sediments that can strongly affect their physiology. The effects of metals on estuarine organisms may be exacerbated by other environmental factors. Thus, a decrease in pH caused by high [Formula: see text] (hypercapnia) can modulate the effects of trace metals by affecting metal bioavailability, accumulation or binding. To better understand the cellular mechanisms of interactions between [Formula: see text] and trace metals in marine bivalves, we exposed isolated mantle cells of the hard clams (Mercenaria mercenaria) to different levels of [Formula: see text] (0.05, 1.52 and 3.01 kPa) and two major trace metal pollutants - cadmium (Cd) and copper (Cu). Elevated [Formula: see text] resulted in a decrease in intracellular pH (pHi) of the isolated mantle cells from 7.8 to 7.4. Elevated [Formula: see text] significantly but differently affected the trace metal accumulation by the cells. Cd uptake was suppressed at elevated [Formula: see text] levels while Cu accumulation has greatly accelerated under hypercapnic conditions. Interestingly, at higher extracellular Cd levels, labile intracellular Cd(2+) concentration remained the same, while intracellular levels of free Zn(2+) increased suggesting that Cd(2+) substitutes bound Zn(2+) in these cells. In contrast, Cu exposure did not affect intracellular Zn(2+) but led to a profound increase in the intracellular levels of labile Cu(2+) and Fe(2+). An increase in the extracellular concentrations of Cd and Cu led to the elevated production of reactive oxygen species under the normocapnic conditions (0.05 kPa [Formula: see text] ); surprisingly, this effect was mitigated in hypercapnia (1.52 and 3.01 kPa). Overall, our data reveal complex and metal-specific interactions between the cellular effects of trace metals and [Formula: see text] in clams and indicate that variations in environmental [Formula: see text] may modulate the biological effects of trace metals in marine organisms. PMID- 23796538 TI - Genomic and phenotypic response of hornyhead turbot exposed to municipal wastewater effluents. AB - Laboratory tests with marine flatfish were conducted to investigate associations among gene expression, higher biological responses and wastewater effluent exposure. In the present study, male hornyhead turbot (Pleuronichthys verticalis) were exposed to environmentally realistic (0.5%) and higher (5%) concentrations of chemically enhanced advanced-primary (PL) and full-secondary treated (HTP) effluents from two southern California wastewater treatment plants (WWTP). Hepatic gene expression was examined using a custom low-density microarray. Alterations in gene expression (vs. controls) were observed in fish exposed to both effluent types. Fish exposed to 0.5% PL effluent showed changes in genes involved in the metabolism of xenobiotics, steroids, and lipids, among other processes. Fish exposed to 5% PL effluent showed expression changes in genes involved in carbohydrate metabolism, stress responses, xenobiotic metabolism, and steroid synthesis, among others. Exposure to 5% HTP effluent changed the expression of genes involved in lipid, glutathione and xenobiotic metabolism, as well as immune responses. Although no concentration-dependent patterns of response to effluent exposure were found, significant Spearman correlations were observed between the expression of 22 genes and molecular and/or higher biological responses. These results indicate that microarray gene expression data correspond to higher biological responses and should be incorporated in studies assessing fish health after exposure to complex environmental mixtures. PMID- 23796539 TI - Mussel oligopeptides ameliorate cognition deficit and attenuate brain senescence in D-galactose-induced aging mice. AB - Dietary supplementation exerts beneficial effects in reducing incidence of chronic neurodegenerative diseases. The purpose of this study was to examine protective effects of mussel (Mytilus edulis) oligopeptides supplementation on brain function in D-galactose induced aging mice. Sixty female 8-month-old mice were randomly divided into five groups: vehicle control, D-galactose, and D galactose combined with 200, 500, 1000 mg/kg mussel oligopeptides. The results showed that mussel oligopeptides could improve cognitive learning and memory ability and protect the hippocampal neurons. In addition, GSH, SOD and GSH-pX activities were increased and MDA level was significantly decreased in mice fed with mussel oligopeptides. It was also found that mussel oligopeptides supplementation prevented D-galactose-induced elevations of iNOS activity and NO production and lactate acid levels in brain. Moreover, PI3K and Akt genes were up regulated by mussel oligopeptides supplementation. These findings suggest that mussel oligopeptides are able to enhance exercise capacity and protect against oxidative damage caused by D-galactose in aging model mice through regulating oxidation metabolism and PI3K/Akt/NOS signal pathway. Therefore, mussel oligopeptides are good materials for future development of healthcare products to combat age-related brain dysfunction and to improve healthy life span. PMID- 23796540 TI - A novel anticonvulsant modulates voltage-gated sodium channel inactivation and prevents kindling-induced seizures. AB - Here, we explore the mechanism of action of isoxylitone (ISOX), a molecule discovered in the plant Delphinium denudatum, which has been shown to have anticonvulsant properties. Patch-clamp electrophysiology assayed the activity of ISOX on voltage-gated sodium channels (VGSCs) in both cultured neurons and brain slices isolated from controls and rats with experimental epilepsy(kindling model). Quantitative transcription polymerase chain reaction (qRT-PCR) (QPCR) assessed brain-derived neurotrophic factor (BDNF) mRNA expression in kindled rats, and kindled rats treated with ISOX. ISOX suppressed sodium current (I(Na)) showing an IC50 value of 185 nM in cultured neurons. ISOX significantly slowed the recovery from inactivation (ISOX tau = 18.7 ms; Control tau = 9.4 ms; p < 0.001). ISOX also enhanced the development of inactivation by shifting the Boltzmann curve to more hyperpolarized potentials by -11.2 mV (p < 0.05). In naive and electrically kindled cortical neurons, the IC50 for sodium current block was identical to that found in cultured neurons. ISOX prevented kindled stage 5 seizures and decreased the enhanced BDNF mRNA expression that is normally associated with kindling (p < 0.05). Overall, our data show that ISOX is a potent inhibitor of VGSCs that stabilizes steady-state inactivation while slowing recovery and enhancing inactivation development. Like many other sodium channel blocker anti-epileptic drugs, the suppression of BDNF mRNA expression that usually occurs with kindling is likely a secondary outcome that nevertheless would suppress epileptogenesis. These data show a new class of anti-seizure compound that inhibits sodium channel function and prevents the development of epileptic seizures. PMID- 23796541 TI - Cyclosporine attenuates arginine transport, in human endothelial cells, through modulation of cationic amino acid transporter-1. AB - BACKGROUND: The spectrum of cardiovascular toxicity by cyclosporine (CsA) includes hypertension, accelerated atherosclerosis, and thrombotic microangiopathy, all of which are the result of endothelial cell dysfunction. Endothelial cell dysfunction is characterized by decreased endothelial nitric oxide synthase (eNOS) activity. Cationic amino acid transporter-1 (CAT-1) is the specific arginine transporter for eNOS. CsA has been shown to attenuate nitric oxide (NO) generation. However, the mechanism remains elusive. We hypothesize that CsA inhibits eNOS activity through modulation of its selective arginine supplier CAT-1. METHODS: We studied the effect of CsA on arginine uptake, NO2/NO3 generation, and CAT-1, protein kinase Calpha (PKCalpha), and phosphorylated PKCalpha protein expression in human umbilical vein endothelial cell cultures (HUVEC) in the absence and presence of L-arginine. RESULTS: CsA (0.5-2 MUg/ml) significantly attenuated arginine transport in a dose- and time-dependent manner, a phenomenon which was prevented by co-incubation with L-arginine (1 mM). The aforementioned findings were accompanied by increased protein nitration, a measure for peroxynitrite accumulation. In contrast, no changes were observed in NO2/NO3 generation. CsA significantly decreased the abundance of CAT-1 protein, an effect that was attenuated by L-arginine. PKCalpha and phosphorylated PKCalpha (CAT-1 inhibitors) protein contents were not affected by CsA. CONCLUSION: CsA inhibits arginine transport and induces protein nitration in HUVEC through modulation of CAT-1. PMID- 23796542 TI - Fish assemblages on shipwrecks and natural rocky reefs strongly differ in trophic structure. AB - In the present work fish assemblages over two metallic vessels, five and 105 years old, and two natural rocky reefs were compared. The hypothesis that shipwrecks support assemblages with trophic structure similar to that encountered on natural reefs was rejected. Artificial and natural reefs strongly differ in their trophic structure, both in their multivariate composition and in biomass of most guilds. Substrate characteristics such as rugosity and benthic cover were found to influence the trophic organisation of the communities. Moreover, slow paced structural changes over time in both biotic and abiotic aspects of wrecks appear responsible for younger and older artificial reefs be dissimilar in respect to biomass density of most feeding guilds. However, the older artificial reef did not present any strikingly "intermediate" feature between the younger artificial reef and the natural reefs, evidencing that distinct trophic assemblages exist over wrecks. Finally, the results found indicate that the use of shipwrecks as mitigation tool for losses of natural reefs may not be fully appropriate as they greatly differ in trophic structure, and consequently in energy flow, from natural reefs. Also, setting shipwrecks near natural reefs should be avoided as they differ in resources availability for many species, which may alter the community structure of natural habitats. PMID- 23796543 TI - The contribution of fronto-parietal regions to sentence comprehension: insights from the Moses illusion. AB - To interpret a sentence, the reader must not only process the linguistic input, but many times has also to draw inferences about what is implicitly stated. In some cases, the generation and integration of inferred information may lead to semantic illusions. In these sentences, subjects fail to detect errors such as in "It was two animals of each kind that Moses took on the ark" despite knowing that the correct answer is Noah, not Moses. The relative inability to notice these errors raises questions about how people establish and integrate inferences and which conditions improve error detection. To unravel the neural processes underlying inference and error detection in language comprehension, we carried out an fMRI study in which participants read sentences containing true or false statements. The false statements either took the form of more obvious (i.e., clearly false) or subtle (i.e., semantic illusions) inconsistent relations. Participants had to decide if each statement was true or false. Processing semantic illusions relative to true and clearly false sentences significantly engaged the right inferior parietal lobule, suggesting higher demands in establishing coherence. Successful versus unsuccessful error detection revealed a network of regions, including right dorsolateral prefrontal cortex, orbitofrontal, insula/putamen and anterior cingulate cortex. Such activation was significantly correlated with overall response accuracy to the illusions. These results suggest that to detect the semantic conflict, people must inhibit the tendency to draw pragmatic inferences. These findings demonstrate that fronto parietal areas are involved in inference and inhibition processes necessary for establishing semantic coherence. PMID- 23796544 TI - Simultaneous EEG-fMRI acquisition at low, high and ultra-high magnetic fields up to 9.4 T: perspectives and challenges. AB - In this perspectives article we highlight the advantages of simultaneous acquisition of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). As MRI moves towards using ultra-high magnetic fields in the quest for increased signal-to-noise, the question arises whether combined EEG fMRI measurements are feasible at magnetic fields of 7 T and higher. We describe the challenges of MRI-EEG at 1.5, 3, 7 and 9.4 T and review the proposed solutions. In an outlook, we discuss further developments such as simultaneous trimodal imaging using MR, positron emission tomography (PET) and EEG under the same physiological conditions in the same subject. PMID- 23796545 TI - Direct visualization of short transverse relaxation time component (ViSTa). AB - White matter of the brain has been demonstrated to have multiple relaxation components. Among them, the short transverse relaxation time component (T2<40 ms; T2*<25 ms at 3 T) has been suggested to originate from myelin water whereas long transverse relaxation time components have been associated with axonal and/or interstitial water. In myelin water imaging, T2 or T2* signal decay is measured to estimate myelin water fraction based on T2 or T2* differences among the water components. This method has been demonstrated to be sensitive to demyelination in the brain but suffers from low SNR and image artifacts originating from ill conditioned multi-exponential fitting. In this study, a novel approach that selectively acquires short transverse relaxation time signal is proposed. The method utilizes a double inversion RF pair to suppress a range of long T1 signal. This suppression leaves short T2* signal, which has been suggested to have short T1, as the primary source of the image. The experimental results confirm that after suppression of long T1 signals, the image is dominated by short T2* in the range of myelin water, allowing us to directly visualize the short transverse relaxation time component in the brain. Compared to conventional myelin water imaging, this new method of direct visualization of short relaxation time component (ViSTa) provides high quality images. When applied to multiple sclerosis patients, chronic lesions show significantly reduced signal intensity in ViSTa images suggesting sensitivity to demyelination. PMID- 23796547 TI - Relationships between years of education and gray matter volume, metabolism and functional connectivity in healthy elders. AB - More educated elders are less susceptible to age-related or pathological cognitive changes. We aimed at providing a comprehensive contribution to the neural mechanism underlying this effect thanks to a multimodal approach. Thirty six healthy elders were selected based on neuropsychological assessments and cerebral amyloid imaging, i.e. as presenting normal cognition and a negative florbetapir-PET scan. All subjects underwent structural MRI, FDG-PET and resting state functional MRI scans. We assessed the relationships between years of education and i) gray matter volume, ii) gray matter metabolism and iii) functional connectivity in the brain areas showing associations with both volume and metabolism. Higher years of education were related to greater volume in the superior temporal gyrus, insula and anterior cingulate cortex and to greater metabolism in the anterior cingulate cortex. The latter thus showed both volume and metabolism increases with education. Seed connectivity analyses based on this region showed that education was positively related to the functional connectivity between the anterior cingulate cortex and the hippocampus as well as the inferior frontal lobe, posterior cingulate cortex and angular gyrus. Increased connectivity was in turn related with improved cognitive performances. Reinforcement of the connectivity of the anterior cingulate cortex with distant cortical areas of the frontal, temporal and parietal lobes appears as one of the mechanisms underlying education-related reserve in healthy elders. PMID- 23796546 TI - Reducing motion artifacts for long-term clinical NIRS monitoring using collodion fixed prism-based optical fibers. AB - As the applications of near-infrared spectroscopy (NIRS) continue to broaden and long-term clinical monitoring becomes more common, minimizing signal artifacts due to patient movement becomes more pressing. This is particularly true in applications where clinically and physiologically interesting events are intrinsically linked to patient movement, as is the case in the study of epileptic seizures. In this study, we apply an approach common in the application of EEG electrodes to the application of specialized NIRS optical fibers. The method provides improved optode-scalp coupling through the use of miniaturized optical fiber tips fixed to the scalp using collodion, a clinical adhesive. We investigate and quantify the performance of this new method in minimizing motion artifacts in healthy subjects, and apply the technique to allow continuous NIRS monitoring throughout epileptic seizures in two epileptic in-patients. Using collodion-fixed fibers reduces the percent signal change of motion artifacts by 90% and increases the SNR by 6 and 3 fold at 690 and 830 nm wavelengths respectively when compared to a standard Velcro-based array of optical fibers. The SNR has also increased by 2 fold during rest conditions without motion with the new probe design because of better light coupling between the fiber and scalp. The change in both HbO and HbR during motion artifacts is found to be statistically lower for the collodion-fixed fiber probe. The collodion-fixed optical fiber approach has also allowed us to obtain good quality NIRS recording of three epileptic seizures in two patients despite excessive motion in each case. PMID- 23796548 TI - Oscillatory dynamics of response competition in human sensorimotor cortex. AB - Neurophysiological studies in non-human primates have provided evidence for simultaneous activation of competing responses in the (pre)motor cortex. Human evidence, however, is limited, partly because experimental approaches have often mapped competing responses to paired effectors represented in opposite hemispheres, which restricts the analysis to between-hemisphere comparisons and allows simultaneous execution. A demonstration of competition between different movement plans in the motor cortex is more compelling when simultaneous execution of the alternative responses is ruled out and they are represented in one motor cortex. Therefore, in the current MEG study we have used a unimanual Eriksen flanker paradigm with alternative responses assigned to flexion and extension of the right index finger, activating different direction-sensitive neurons within the finger representation area of the same motor cortex. Results showed that for stimuli eliciting response competition the pre-response motor cortex beta-band (17-29 Hz) power decreased stronger than for stimuli that did not induce response competition. Furthermore, response competition elicited an additional pre response mid-frontal high-gamma band (60-90 Hz) power increase. Finally, larger gamma-band effect sizes correlated with greater behavioral response delay induced by response competition. Taken together, our results provide evidence for co activation of competing responses in the human brain, consistent with evidence from non-human primates. PMID- 23796549 TI - Primary cutaneous marginal zone B-cell lymphoma: response to treatment and disease-free survival in a series of 137 patients. AB - BACKGROUND: Primary cutaneous marginal zone B-cell lymphomas are low-grade lymphomas running an indolent course. Skin relapses have been frequently reported but little information about disease-free survival (DFS) is available. OBJECTIVE: We sought to evaluate relapse rate and DFS in patients with primary cutaneous marginal zone B-cell lymphomas. METHODS: Clinical features, European Organization for Research and Treatment of Cancer/International Society for Cutaneous Lymphomas stage, light chain restriction, clonality, treatments, skin relapses, DFS, stage progression, extracutaneous disease, and outcome are analyzed in a series of 137 patients. RESULTS: Patients were classified as solitary lesion (T1) (n = 70; 51%), regional skin involvement (T2) (n = 40; 29%), and generalized skin lesions (T3) (n = 27; 20%). Surgical excision, local radiotherapy, or a combination were the initial treatment in 118 patients (86%). In 121 of 137 patients (88%) a complete remission was observed after initial treatment, including 99 of 106 patients (93%) with solitary or localized disease and 22 of 31 patients (71%) with multifocal lesions. Cutaneous relapses were observed in 53 patients (44%). Median DFS was 47 months. Patients with multifocal lesions or T3 disease showed higher relapse rate and shorter DFS. No significant differences were observed between surgery and radiotherapy, but surgery alone was associated with more recurrences at initial site. Overall survival at 5 and 10 years was 93%. Six patients (4%) developed extracutaneous disease during follow-up. LIMITATIONS: This was a case series retrospective study. CONCLUSION: Our results support long-term follow-up in patients with primary cutaneous marginal zone B cell lymphomas. Disseminated skin lesions have higher relapse rate and shorter DFS suggesting further investigation on systemic therapies in such a group of patients. PMID- 23796550 TI - Portal hypertension and ascites secondary to Erdheim Chester Disease without intrinsic liver involvement on liver biopsy. PMID- 23796551 TI - Radiculoneuropathy associated with acute hepatitis E. PMID- 23796552 TI - Small bowel adenocarcinoma: epidemiology, risk factors, diagnosis and treatment. AB - Small bowel adenocarcinomas are rare tumours, but their incidence is increasing. Their most common primary location is the duodenum. The few studies that have collected data regarding small bowel adenocarcinoma are not homogeneous and are widely spread over time. Even though these tumours are most often sporadic, some predisposing diseases have been identified, among which Crohn's disease and genetic syndromes. Early diagnosis of small bowel adenocarcinoma remains difficult despite significant radiological and endoscopic progress. After surgical resection the main prognostic factor is node invasion; in this case, adjuvant chemotherapy can be expected to be beneficial, although this has not been established by randomised trials. For metastatic disease, platinum-based chemotherapy seems to be the most effective treatment. Targeted therapies have not yet been evaluated in this type of cancer. PMID- 23796553 TI - Synaptogenesis in the foetal and neonatal cerebellar system. 2. Pontine nuclei and cerebellar cortex. AB - Precise temporal and spatial sequences of synaptogenesis were demonstrated in 172 human foetuses and neonates post-mortem in transverse paraffin sections of pons and cerebellar vermis and hemispheres, using synaptophysin immunoreactivity of this protein of synaptic vesicular walls. The pontine nuclei exhibit a transitory patchy pattern not predicted from the uniform histology and reminiscent of the corpus striatum; synaptic vesicle reactivity appears at 20 weeks and is uniform by 34 weeks. In the cerebellar cortex, the vermis matures sooner than the cerebellar hemispheres and the paravermal portions earlier than the lateral folia. The earliest synapses occur around the somata of Purkinje neurons and later in the internal granular layer, but synaptic glomeruli are not well formed until after 26 weeks. The normal patterns here shown, together with earlier data of the Guillain-Mollaret triangle, provide controls for the interpretation of synaptic delay or precociousness and other pathological patterns in malformations, genetic/metabolic conditions and prenatal acquired insults affecting the human foetus. PMID- 23796554 TI - Plural provision of primary medical care in England, 2002-2012. AB - OBJECTIVES: Health care reforms often include provider diversification, including privatization, to increase competition and thereby health care quality and efficiency. Donabedian's organizational theory implies that the consequences will vary according to the providers' ownership. The aim was to examine how far that theory applies to changes in English NHS primary medical care (general practice) since 1998, and the consequences for patterns of service provision. METHODS: Framework analysis whose categories and structure reflected Donabedian's theory and its implications, populated with data from a systematic review, administrative sources and press rapportage. RESULTS: Two patterns of provider diversification occurred: 'native' diversification among existing providers and plural provision as providers with different types of ownership were introduced. Native diversification occurred through: extensive recruitment of salaried GPs; extending the range of services provided by general practices; introducing limited liability partnerships; establishing GPs with special clinical interests; and introducing a wider range of services for GPs to refer to. All of these had little apparent effect on competition between general practices. Plural provision involved: increased primary care provision by corporations; introducing GP-owned firms; establishing social enterprises (initially mostly out-of-hours cooperatives); and Primary Care Trusts taking over general practices. Plural provision was on a smaller scale than native diversification and appeared to go into reverse in 2011. CONCLUSIONS: Although the available data confirm the implications of Donabedian's theory, there are exceptions. Native diversification and plural provision policies differ in their implications for service development. PMID- 23796555 TI - Physical therapy mandates by Medicare administrative contractors: effective or wasteful? AB - Documentation of medical necessity for arthroplasty has come under scrutiny by Medicare. In some jurisdictions three months of physical therapy prior to arthroplasty has been mandated. The purpose of this study was to determine the efficacy and cost of this policy to treat advanced osteoarthritis. A systematic review was performed to assimilate efficacy data for physical therapy in patients with advanced osteoarthritis. The number of arthroplasties performed annually was obtained to calculate cost. Evidence-based studies documenting the efficacy of physical therapy in treating advanced arthritis are lacking with a potential cost of 36-68 million dollars. Physical therapy mandates by administrative contractors are not only ineffective but are costly without patient benefit. Medical necessity documentation should be driven by orthopedists not retroactively by Medicare contractors. PMID- 23796556 TI - Up to 10-year follow-up of the Oxford medial partial knee arthroplasty--695 cases from a single institution. AB - Partial knee arthroplasty (PKA) has shown obvious advantages compared to total knee arthroplasty, but survival of PKA from different institutions and registries has differed. In our institution, 695 consecutive Oxford medial PKAs were performed from 2002 to 2011 with mean follow-up of 4.6 years. The overall 10.7 year survival rate was 85.3% (95% CI: 78.7%-90.0%), and no difference in survival for gender and age younger or older than 60 years was found. One year after PKA, 94.3% were very satisfied or satisfied, as were 93.6% six years postoperatively. The revision rate was 7.3% (n=51), and the most common causes for revision were progression of osteoarthritis (n=16), aseptic loosening (n=11), and pain without loosening (n=10). Only 50% of patients revised for pain without loosening had a satisfactory outcome. PMID- 23796557 TI - Comment on article "cement-in-cement revision for selected Vancouver type B1 femoral periprosthetic fractures: a biomechanical analysis". PMID- 23796558 TI - DVT prophylaxis after TKA: routine anticoagulation vs risk screening approach - a randomized study. AB - The American College of Chest Physicians (ACCP) recommended routine anticoagulation for thromboprophylaxis in patients undergoing lower limb arthroplasty. We compared results of routine anticoagulation Vs risk stratified approach for Deep Venous Thrombosis (DVT) prophylaxis after TKA in terms of symptomatic DVT and wound complications. Nine hundred TKAs done in 673 patients were randomized after DVT risk screening to routine anticoagulation (n = 450) or to risk stratification (n = 450) and selective anticoagulation. 194 patients in the risk screening group received only Aspirin. Primary outcome was symptomatic DVT and wound complication. This randomized study showed that the symptomatic DVT rates after TKA were similar whether patients were routinely anticoagulated or selectively anticoagulated after risk screening. However there was a significantly higher incidence of wound complications (P < 0.014) after routine anticoagulation. PMID- 23796559 TI - Radiofrequency identification specimen tracking in anatomical pathology: pilot study of 1067 consecutive prostate biopsies. AB - Improved methods such as radiofrequency identification (RFID) are needed to optimize specimen tracking in anatomical pathology. We undertook a study of RFID in an effort to optimize specimen tracking and patient identification, including the following: (1) creation of workflow process maps, (2) evaluation of existing RFID hardware technologies, (3) creation of Web-based software to support the RFID-enabled workflow, and (4) assessment of the impact with a series of prostate biopsies. We identified multiple steps in the workflow process in which RFID enhanced specimen tracking. Multiple product choices were found that could withstand the harsh heat and chemical environments encountered in pathology processing, and software that was compatible with our laboratory information system was designed in-house. A total of 1067 prostate biopsies were received, and 78.3% were successfully processed with the RFID system. Radiofrequency identification allowed dynamic specimen tracking throughout the workflow process in anatomical pathology. PMID- 23796560 TI - Aptamer identification of brain tumor-initiating cells. AB - Glioblastomas display cellular hierarchies with self-renewing tumor-initiating cells (TIC), also known as cancer stem cells, at the apex. Although the TIC hypothesis remains controversial and the functional assays to define the TIC phenotype are evolving, we and others have shown that TICs may contribute to therapeutic resistance, tumor spread, and angiogenesis. The identification of TICs has been informed by the use of markers characterized in normal stem cells, but this approach has an inherent limitation to selectively identify TICs. To develop reagents that enrich TICs but not matched non-TICs or tissue-specific stem cells, we adopted Cell-Systematic Evolution of Ligands by Exponential Enrichment (Cell-SELEX) to identify glioblastoma TIC-specific nucleic acid probes aptamers-that specifically bind TICs. In this study, using Cell-SELEX with positive selection for TICs and negative selection for non-TICs and human neural progenitor cells, we identified TIC aptamers that specifically bind to TICs with excellent dissociation constants (Kd). These aptamers select and internalize into glioblastoma cells that self-renew, proliferate, and initiate tumors. As aptamers can be modified to deliver payloads, aptamers may represent novel agents that could selectively target or facilitate imaging of TICs. PMID- 23796561 TI - Intratumoral modeling of gefitinib pharmacokinetics and pharmacodynamics in an orthotopic mouse model of glioblastoma. AB - Like many solid tumors, glioblastomas are characterized by intratumoral biologic heterogeneity that may contribute to a variable distribution of drugs and their associated pharmacodynamic responses, such that the standard pharmacokinetic approaches based on analysis of whole-tumor homogenates may be inaccurate. To address this aspect of tumor pharmacology, we analyzed intratumoral pharmacokinetic/pharmacodynamic characteristics of the EGFR inhibitor gefitinib in mice with intracerebral tumors and developed corresponding mathematical models. Following a single oral dose of gefitinib (50 or 150 mg/kg), tumors were processed at selected times according to a novel brain tumor sectioning protocol that generated serial samples to measure gefitinib concentrations, phosphorylated extracellular signal-regulated kinase (pERK), and immunohistochemistry in 4 different regions of tumors. Notably, we observed up to 3-fold variations in intratumoral concentrations of gefitinib, but only up to half this variability in pERK levels. As we observed a similar degree of variation in the immunohistochemical index termed the microvessel pericyte index (MPI), a measure of permeability in the blood-brain barrier, we used MPI in a hybrid physiologically-based pharmacokinetic (PBPK) model to account for regional changes in drug distribution that were observed. Subsequently, the PBPK models were linked to a pharmacodynamic model that could account for the variability observed in pERK levels. Together, our tumor sectioning protocol enabled integration of the intratumoral pharmacokinetic/pharmacodynamic variability of gefitinib and immunohistochemical indices followed by the construction of a predictive PBPK/pharmacodynamic model. These types of models offer a mechanistic basis to understand tumor heterogeneity as it impacts the activity of anticancer drugs. PMID- 23796562 TI - A sequence polymorphism in miR-608 predicts recurrence after radiotherapy for nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma is treated with radiotherapy and other modalities, but there is little information on individual genetic factors to help predict and improve patient outcomes. Single-nucleotide polymorphisms (SNP) in mature microRNA (miRNA) sequences have the potential to exert broad impact as miRNAs target many mRNAs. The aim of this study was to evaluate the effects of SNPs in mature miRNA sequences on clinical outcome in patients with nasopharyngeal carcinoma receiving radiotherapy. In particular, we analyzed associations between seven SNPs and nasopharyngeal carcinoma locoregional recurrence (LRR) in 837 patients from eastern China, validating the findings in an additional 828 patients from southern China. We found that miR-608 rs4919510C > G exhibited a consistent association with LRR in the discovery set [HR, 2.05; 95% confidence interval (CI), 1.35-3.21], the validation set (HR, 2.24; 95% CI, 1.45-3.38), and the combined dataset (HR, 2.08; 95% CI, 1.41-3.26). Biochemical investigations showed that rs4919510C > G affects expression of miR-608 target genes along with nasopharyngeal carcinoma cell growth after irradiation in vivo and in vitro. Notably, X-ray radiation induced more chromatid breaks in lymphocyte cells from rs4919510CC carriers than in those from subjects with other genotypes (P = 0.0024). Our findings reveal rs4919510C > G in miR-608 as a simple marker to predict LRR in patients with radiotherapy-treated nasopharyngeal carcinoma. PMID- 23796564 TI - The relationship between glucose metabolism, metabolic syndrome, and bone specific alkaline phosphatase: a structural equation modeling approach. AB - CONTEXT: Serum alkaline phosphatase plays a role in vascular calcification. It is found in various tissues, whereas bone-specific alkaline phosphatase (BAP) more specifically reflects mineral metabolism. The relationship of serum alkaline phosphatase (total and bone-specific) with diabetes and metabolic syndrome (MetS), 2 major risk factors of vascular calcification, is largely unknown. OBJECTIVE: We aimed to investigate the relationships between glucose metabolism, components of the MetS, and alkaline phosphatase. DESIGN AND SETTING: This was a cross-sectional study of a nationally representative sample of the U.S. population in 1999 through 2004. PARTICIPANTS: Participants were 3773 nondiabetic participants of the National Health and Nutrition Examination Survey 1999-2004. MAIN OUTCOME MEASURES: We measured serum BAP and total alkaline phosphatase. RESULTS: In multivariable linear regression, updated homeostasis model assessment (HOMA2) for insulin resistance (beta = 0.068), HOMA2 for beta-cell function (beta = 0.081), insulin (beta = 0.065), mean arterial pressure (beta = 0.15), and high density lipoprotein (HDL)-cholesterol (beta = 0.209) were positively associated with BAP, whereas HOMA2 for insulin sensitivity (beta = -0.065) was negatively associated with BAP. On the other hand, only mean arterial pressure and HDL cholesterol were significantly associated with total alkaline phosphatase. Moreover, a structural equation model revealed that hypertension, low HDL, and insulin resistance had significant direct effects on serum BAP levels, whereas obesity and inflammation might have indirect effects on serum BAP levels. The overall model showed very good fit to the data (comparative fit index = 0.995, root mean square error of approximation = 0.037, and standardized root mean square residual = 0.006). CONCLUSION: Glucose metabolism and MetS are significantly related to serum BAP levels. How BAP mediates vascular calcification in diabetes and MetS warrants further studies. PMID- 23796563 TI - Inhibition of AMPK and Krebs cycle gene expression drives metabolic remodeling of Pten-deficient preneoplastic thyroid cells. AB - Rapidly proliferating and neoplastically transformed cells generate the energy required to support rapid cell division by increasing glycolysis and decreasing flux through the oxidative phosphorylation (OXPHOS) pathway, usually without alterations in mitochondrial function. In contrast, little is known of the metabolic alterations, if any, which occur in cells harboring mutations that prime their neoplastic transformation. To address this question, we used a Pten deficient mouse model to examine thyroid cells where a mild hyperplasia progresses slowly to follicular thyroid carcinoma. Using this model, we report that constitutive phosphoinositide 3-kinase (PI3K) activation caused by PTEN deficiency in nontransformed thyrocytes results in a global downregulation of Krebs cycle and OXPHOS gene expression, defective mitochondria, reduced respiration, and an enhancement in compensatory glycolysis. We found that this process does not involve any of the pathways classically associated with the Warburg effect. Moreover, this process was independent of proliferation but contributed directly to thyroid hyperplasia. Our findings define a novel metabolic switch to glycolysis driven by PI3K-dependent AMPK inactivation with a consequent repression in the expression of key metabolic transcription regulators. PMID- 23796566 TI - Upregulated miR-155 in papillary thyroid carcinoma promotes tumor growth by targeting APC and activating Wnt/beta-catenin signaling. AB - CONTEXT: MicroRNAs (miRNAs) are strongly implicated in many cancers, including papillary thyroid carcinoma (PTC), which is the most common malignancy in thyroid tissue. Recently, miRNA-155 (miR-155) has been proved to play a substantial role in liposarcoma and breast cancer, but its functions in the context of PTC remain unknown. OBJECTIVES: The objective was to investigate the potential involvement of miR-155 in PTC. DESIGN: Expression levels of miR-155 were assessed via quantitative real-time PCR in 20 pairs of human PTC and adjacent normal tissues and in 4 human PTC cell lines. Lentiviral miR-155 overexpression models were performed in TPC-1 and CGTH-W3 cells, and the effects on cell growth were evaluated. We have searched for miR-155 targets and identified the hypothesis that miR-155 could promote tumor growth of PTC by targeted regulation of adenomatous polyposis coli (APC) expression and activating the Wnt/beta-catenin signaling. RESULTS: MiR-155 levels were markedly increased in PTC specimens and PTC cell lines. Overexpression of miR-155 dramatically promoted PTC cell viability and colony formation in vitro, whereas miR-155 depletion reduced these parameters. Further studies revealed that APC is a novel miR-155 target, because miR-155 bound directly to its 3'-untranslated region and reduced both the mRNA and protein levels of APC. Similar to the miR-155 over-expression, APC downregulation promoted cell growth, whereas rescued APC expression reversed the promotive effect of miR-155. Furthermore, miR-155 overexpression resulted in activation of beta-catenin and induction of several downstream genes including c Myc, cyclin D1, TCF-1. and LEF-1. Depletion of beta-catenin partially prevented miR-155-induced tumor cell viability and colony formation. In xenograft animal experiments, we found overexpressed miR-155 effectively promoted tumor growth of PTC cells. CONCLUSIONS: Our results indicate that miR-155 functions as an oncogene in PTC. By targeting APC, miR-155 efficiently regulates the Wnt/beta catenin signaling. And miR-155 may be a potential therapeutic or diagnostic/prognostic target for treating PTC. PMID- 23796565 TI - Increased brain transport and metabolism of acetate in hypoglycemia unawareness. AB - CONTEXT: Intensive insulin therapy reduces the risk for long-term complications in patients with type 1 diabetes mellitus (T1DM) but increases the risk for hypoglycemia-associated autonomic failure (HAAF), a syndrome that includes hypoglycemia unawareness and defective glucose counterregulation (reduced epinephrine and glucagon responses to hypoglycemia). OBJECTIVE: The objective of the study was to address mechanisms underlying HAAF, we investigated whether nonglucose fuels such as acetate, a monocarboxylic acid (MCA), can support cerebral energetics during hypoglycemia in T1DM individuals with hypoglycemia unawareness. DESIGN: Magnetic resonance spectroscopy was used to measure brain transport and metabolism of [2-(13)C]acetate under hypoglycemic conditions. SETTING: The study was conducted at the Yale Center for Clinical Investigation Hospital Research Unit, Yale Magnetic Resonance Research Center. PATIENTS AND OTHER PARTICIPANTS: T1DM participants with moderate to severe hypoglycemia unawareness (n = 7), T1DM controls without hypoglycemia unawareness (n = 5), and healthy nondiabetic controls (n = 10) participated in the study. MAIN OUTCOME MEASURE(S): Brain acetate concentrations, (13)C percent enrichment of glutamine and glutamate, and absolute rates of acetate metabolism were measured. RESULTS: Absolute rates of acetate metabolism in the cerebral cortex were 1.5-fold higher among T1DM/unaware participants compared with both control groups during hypoglycemia (P = .001). Epinephrine levels of T1DM/unaware subjects were significantly lower than both control groups (P < .05). Epinephrine levels were inversely correlated with levels of cerebral acetate use across the entire study population (P < .01), suggesting a relationship between up-regulated brain MCA use and HAAF. CONCLUSION: Increased MCA transport and metabolism among T1DM individuals with hypoglycemia unawareness may be a mechanism to supply the brain with nonglucose fuels during episodes of acute hypoglycemia and may contribute to the syndrome of hypoglycemia unawareness, independent of diabetes. PMID- 23796567 TI - 25-Hydroxyvitamin D, calcium intake, and bone mineral content in adolescents and young adults: analysis of the fourth and fifth Korea National Health and Nutrition Examination Survey (KNHANES IV-2, 3, 2008-2009 and V-1, 2010). AB - CONTEXT: The amount of calcium and vitamin D needed to support bone development is still uncertain. OBJECTIVE: We examined the association of 25-hydroxyvitamin D [25(OH)D] and calcium intake with bone mineral content (BMC). DESIGN: A total of 2918 subjects (1345 males and 1573 females) aged 10 to 29 years from the 2008 2010 Korea National Health and Nutrition Examination Survey were stratified into 3 age groups: early adolescents, late adolescents, and young adults. OUTCOME MEASURES: BMC of femoral neck, total hip, and lumbar spine were evaluated in each group according to quartiles of serum 25(OH)D concentration and calcium intake. RESULTS: Mean serum 25(OH)D for all males and females were 43.4 and 39.2 nmol/L, and calcium intakes were 524.4 and 437.2 mg/d, respectively. Early adolescent and young adult males had strong and significant associations of serum 25(OH)D with BMC at each skeletal site. The association was not linear, and a step up was observed at a 25(OH)D concentration of 53.0 nmol/L. Although the impact of calcium intake on BMC was not evident, the top quartile of both serum 25(OH)D and calcium intake had a higher BMC than those in the top quartile of either nutrient alone in these subjects. In late adolescent males and in females, 25(OH)D and BMC associations were inconsistent. CONCLUSIONS: This cross-sectional study indicates a significant association of serum 25(OH)D concentration with BMC and a supportive role of calcium on bone mass for early adolescents and young adult males. We believe that a large proportion of young Koreans would attain greater BMC if they increased their 25(OH)D concentrations and calcium intake. PMID- 23796568 TI - Insulin resistance and impaired pancreatic beta-cell function in adult offspring of women with diabetes in pregnancy. AB - CONTEXT: Offspring of women with diabetes during pregnancy have an increased risk of glucose intolerance in adulthood, but the underlying mechanisms are unknown. OBJECTIVE: We aimed to investigate the effects of intrauterine hyperglycemia on insulin secretion and action in adult offspring of mothers with diabetes. DESIGN, SETTING, AND PARTICIPANTS: A cohort of 587 Caucasian offspring, without known diabetes, was followed up at the age of 18-27 years. We included 2 groups exposed to maternal diabetes in utero: offspring of women with gestational diabetes mellitus (n = 167) or type 1 diabetes (n = 153). Two reference groups were included: offspring of women with risk factors for gestational diabetes mellitus but normoglycemia during pregnancy (n = 139) and offspring from the background population (n = 128). MAIN OUTCOME MEASURES: Indices of insulin sensitivity and insulin release were calculated using insulin and glucose values from a standard oral glucose tolerance test (120 minutes, 75 g glucose). Pancreatic beta-cell function taking the prevailing insulin sensitivity into account was estimated by disposition indices. RESULTS: Both groups of offspring exposed during pregnancy to either maternal gestational diabetes or type 1 diabetes had reduced insulin sensitivity compared with offspring from the background population (both P < .005). We did not find any significant difference in absolute measures of insulin release. However, the disposition index was significantly reduced in both the diabetes-exposed groups (both P < .005). CONCLUSION: Reduced insulin sensitivity as well as impaired pancreatic beta-cell function may contribute to the increased risk of glucose intolerance among adult offspring born to women with diabetes during pregnancy. PMID- 23796569 TI - Central hypothyroidism and its replacement have a significant influence on cardiovascular risk factors in adult hypopituitary patients. AB - CONTEXT: Thyroid dysfunction may have detrimental effects on patient outcomes. Few studies have assessed this issue in patients with secondary hypothyroidism. OBJECTIVE: Our objective was to test the hypothesis that thyroid hormone status has an impact on cardiovascular risk factors in adult patients with hypopituitarism. DESIGN AND SETTING: This was a retrospective observational study (1993-2012) at a tertiary referral university hospital. PATIENTS: All GH deficient patients starting GH replacement (1993-2009) with measured free T4 (fT4) (n = 208). Baseline fT4 defined patients as TSH-sufficient and TSH deficient (further divided into tertiles according to baseline fT4; first tertile had lowest fT4). MAIN OUTCOME MEASURES: Anthropometric (body mass index [BMI], waist circumference, total fat (fat mass) and lean body mass [LBM]) and biochemical (lipids and fasting plasma glucose) data were collected at baseline and a median 4.1 years after commencement of GH. RESULTS: At baseline, fT4 was negatively associated with BMI and waist circumference, but positively with high density lipoprotein, independent of age, gender, and IGF-I (SD score). Only first tertile TSH-deficient patients had higher BMI (P = .02), fat mass (P = .03), total cholesterol (P = .05), triglycerides (P < .01), and waist circumference (P = .01), and lower high-density lipoprotein cholesterol (P = .03) as compared with TSH-sufficient patients. At follow-up, IGF-I, LBM, and plasma glucose had increased in all subgroups (P < .01). The change in fT4 (DeltafT4) (follow-up - baseline) was negatively correlated to DeltaBMI, DeltaLBM, Deltatotal cholesterol, and Deltalow-density lipoprotein cholesterol (all P < .05, adjusted for DeltaIGF-I and DeltaGH and hydrocortisone dose). The negative correlation to Deltatotal cholesterol and Deltalow-density lipoprotein cholesterol persisted only in first-tertile TSH-deficient patients. CONCLUSION: This single-center study over a 20-year period has strengthened the importance of improved awareness of thyroid status and optimal thyroid replacement of hypopituitary patients to reduce cardiovascular risks in hypopituitary patients. PMID- 23796570 TI - A randomized, controlled clinical trial of a novel intravesical pressure attenuation device for the treatment of stress urinary incontinence. AB - PURPOSE: In this clinical trial we evaluated the efficacy, safety and tolerability of a novel pressure attenuation device for the reduction or elimination of female stress urinary incontinence using a prospective, randomized, single-blind, multicenter design. MATERIALS AND METHODS: A total of 166 female patients with stress urinary incontinence were randomized 2:1 to treatment with an intravesical pressure attenuation device (112) or sham procedure (54). In the treatment arm the device was replaced every 90 days and in the sham arm device replacement was simulated every 90 days. The primary outcome measure was Stamey score improvement of 1 or more at 6 months. An additional outcome measure evaluated at 6 months was a composite score combining data from a provocative pad test and patient impression of symptom improvement. RESULTS: In the treatment arm 40.9% of women achieved the primary end point, compared to only 22.4% in the sham arm (p=0.046 in per protocol analysis). In an intent to treat analysis, 28.6% of women in the treatment arm reached the primary end point vs 22.2% of women in the sham arm (p=0.455). 50.8% of women in the treatment arm reached the composite end point compared to 16.3% of women in the control arm (p<0.001, intent to treat analysis). Three-day voiding diaries revealed a mean reduction in total daily leakage events after 6 months from 4.4 per day to 2.5 per day (43.2%) in the treatment group vs 5.4 per day to 4.1 per day (24.1% reduction) in the control group (p<0.001). CONCLUSIONS: Minimally invasive treatment for female stress urinary incontinence with a first-generation intravesical pressure attenuation device was safe and effective when evaluated by a composite end point. For those patients that can tolerate the device, the concept of pressure attenuation as a therapy for stress urinary incontinence is valid and feasible. Further modifications are anticipated for this device potentially resulting in improved outcomes. PMID- 23796572 TI - Comparative diagnostic and analytical performance of PCR and LAMP-based trypanosome detection methods estimated using pooled whole tsetse flies and midguts. AB - Detection of trypanosomes that cause disease in human beings and livestock within their tsetse fly hosts is an essential component of vector and disease control programmes. Several molecular-based diagnostic tests have been developed for this purpose. Many of these tests, while sensitive, require analysis of trypanosome DNA extracted from single flies, or from pooled tsetse fly heads and amplified trypanosome DNA. In this study, we evaluated the relative analytical and diagnostic sensitivities of two PCR-based tests (ITS and TBR) and a Trypanozoon specific LAMP assay using pooled whole tsetse flies and midguts spiked with serially diluted procyclics of a laboratory strain of Trypanosoma brucei brucei (KETRI 3386). Test sensitivity was also evaluated using experimentally infected tsetse flies. The aim was to determine the most appropriate pooling strategy for whole tsetse and midguts. RIME-LAMP had the highest diagnostic sensitivity (100%) followed by TBR-PCR (95%) and ITS-PCR (50%) in detecting trypanosome DNA from pooled tsetse midguts. RIME-LAMP also had the best diagnostic specificity (75%) followed by ITS-PCR (68%) and TBR-PCR (50%). The relative detection limit determined by serial dilution of procyclics was below 10(-6) (equivalent to 1parasite/ml). Using TBR-PCR, ITS-PCR and RIME-LAMP, it was possible to detect trypanosome DNA in single flies or in pools of 2, 3, 4, 5, 10, or 15 flies/midguts. The proportion of positive pools declined by up to 60% when testing pools of 15 whole flies as opposed to testing pools of 5-10 flies. Additionally, it was possible to detect DNA in a single infected tsetse fly in the background of 4, 9, or 14 uninfected tsetse flies. Averaged across pool sizes and tsetse species, RIME-LAMP detected the highest proportion of positive pools in spiked whole tsetse and midguts (86.6% and 87.2%) followed by TBR-PCR (78. 6% and 79.2%) and ITS-PCR (34.3% and 40.2%). There were no significant differences between the proportions of positive pools detected in whole flies and midguts. We conclude that pooling of whole tsetse/midguts is an effective strategy to reduce hands-on-time and hence has potential application in large scale xenomonitoring to generate epidemiological data for decision making. RIME-LAMP offers the best diagnostic sensitivity and specificity on pooled tsetse midguts, thus demonstrating its superior diagnostic performance when compared with TBR-PCR and ITS-PCR. Using pools of whole tsetse or midguts as source of DNA does not have any significant effect on test results and is more representative of the field conditions where the proportion of flies with infected midguts tends to be higher than flies with infected salivary glands. Therefore to save time and minimize costs, pooling of whole tsetse flies is recommended. PMID- 23796573 TI - Painful ophthalmoplegia: the role of imaging and steroid response in the acute and subacute setting. AB - BACKGROUND AND PURPOSE: Although reports of single cases of painful ophthalmoplegia (PO) are common, studies considering larger case series are lacking. Here, we aimed to determine the relative frequencies of ocular neuropathies, the causes, the usefulness of diagnostic procedures and the role of steroid treatment in PO. METHODS: Between January 2006 and September 2012, 149 patients' charts who presented with diplopia in our emergency department were studied retrospectively. 34 of them met the inclusion criteria that included recent (<=3 days) symptom onset and a minimum of diagnostic work. RESULTS: 32% of single or combined ocular motor nerve palsies were of diabetic microvascular etiology and most of them were IIIrd or VIth nerve neuropathies. The most useful, in terms of sensitivity and specificity of diagnostic test in the acute setting was ESR, whereas MR-angiography and focused cavernous sinus imaging led to diagnosis in the post-acute phase. Pain response to steroids was non-specific, in contrast to palsy improvement after steroid administration which was indicative of Tolosa-Hunt syndrome or temporal arteritis. CONCLUSIONS: Although acute and subacute PO might be intuitively associated with Tolosa-Hunt syndrome or sinister pathology such as aneurysmal hemorrhage, our data show that these causes are far less common than diabetic microvascular palsies. Brain CT, MR-imaging of brainstem, cerebellum or hemispheres, CSF analysis and pain response to steroids are nonspecific and hence less helpful in order to arrive at a diagnosis. Instead, improved ocular motility after steroid treatment, as well as MR angiography and cavernous sinus imaging appear more useful for this purpose. PMID- 23796571 TI - Evolutionary consequences, constraints and potential of polyploidy in plants. AB - Polyploidy, the possession of more than 2 complete genomes, is a major force in plant evolution known to affect the genetic and genomic constitution and the phenotype of an organism, which will have consequences for its ecology and geography as well as for lineage diversification and speciation. In this review, we discuss phylogenetic patterns in the incidence of polyploidy including possible underlying causes, the role of polyploidy for diversification, the effects of polyploidy on geographical and ecological patterns, and putative underlying mechanisms as well as chromosome evolution and evolution of repetitive DNA following polyploidization. Spurred by technological advances, a lot has been learned about these aspects both in model and increasingly also in nonmodel species. Despite this enormous progress, long-standing questions about polyploidy still cannot be unambiguously answered, due to frequently idiosyncratic outcomes and insufficient integration of different organizational levels (from genes to ecology), but likely this will change in the near future. See also the sister article focusing on animals by Choleva and Janko in this themed issue. PMID- 23796574 TI - Improving the glycosyltransferase activity of Agrobacterium tumefaciens glycogen synthase by fusion of N-terminal starch binding domains (SBDs). AB - Glycogen and starch, the major storage carbohydrate in most living organisms, result mainly from the action of starch or glycogen synthases (SS or GS, respectively, EC 2.4.1.21). SSIII from Arabidopsis thaliana is an SS isoform with a particular modular organization: the C-terminal highly conserved glycosyltransferase domain is preceded by a unique specific region (SSIII-SD) which contains three in tandem starch binding domains (SBDs, named D1, D2 and D3) characteristic of polysaccharide degrading enzymes. N-terminal SBDs have a probed regulatory role in SSIII activity, showing starch binding ability and modulating the catalytic properties of the enzyme. On the other hand, GS from Agrobacterium tumefaciens has a simple primary structure organization, characterized only by the highly conserved glycosyltransferase domain and lacking SBDs. To further investigate the functional role of A. thaliana SSIII-SD, three chimeric proteins were constructed combining the SBDs from A. thaliana with the GS from A. tumefaciens. Recombinant proteins were expressed in and purified to homogeneity from Escherichia coli cells in order to be kinetically characterized. Furthermore, we tested the ability to restore in vivo glycogen biosynthesis in transformed E. coli glgA(-) cells, deficient in GS. Results show that the D3-GS chimeric enzyme showed increased capacity of glycogen synthesis in vivo with minor changes in its kinetics parameters compared to GS. PMID- 23796575 TI - Characterization of the first eukaryotic cold-adapted patatin-like phospholipase from the psychrophilic Euplotes focardii: Identification of putative determinants of thermal-adaptation by comparison with the homologous protein from the mesophilic Euplotes crassus. AB - The ciliated protozoon Euplotes focardii, originally isolated from the coastal seawaters of Terra Nova Bay in Antarctica, shows a strictly psychrophilic phenotype, including optimal survival and multiplication rates at 4-5 degrees C. This characteristic makes E. focardii an ideal model species for identifying the molecular bases of cold adaptation in psychrophilic organisms, as well as a suitable source of novel cold-active enzymes for industrial applications. In the current study, we characterized the patatin-like phospholipase from E. focardii (EfPLP), and its enzymatic activity was compared to that of the homologous protein from the mesophilic congeneric species Euplotes crassus (EcPLP). Both EfPLP and EcPLP have consensus motifs conserved in other patatin-like phospholipases. By analyzing both esterase and phospholipase A2 activity, we determined the thermostability and the optimal pH, temperature dependence and substrates of these enzymes. We demonstrated that EfPLP shows the characteristics of a psychrophilic phospholipase. Furthermore, we analyzed the enzymatic activity of three engineered versions of the EfPLP, in which unique residues of EfPLP, Gly80, Ala201 and Val204, were substituted through site-directed mutagenesis with residues found in the E. crassus homolog (Glu, Pro and Ile, respectively). Additionally, three corresponding mutants of EcPLP were also generated and characterized. These analyses showed that the substitution of amino acids with rigid and bulky charged/hydrophobic side chain in the psychrophilic EfPLP confers enzymatic properties similar to those of the mesophilic patatin-like phospholipase, and vice versa. This is the first report on the isolation and characterization of a cold-adapted patatin-like phospholipase from eukaryotes. The results reported in this paper support the idea that enzyme thermal adaptation is based mainly on some amino acid residues that influence the structural flexibility of polypeptides and that EfPLP is an attractive biocatalyst for industrial processes at low temperatures. PMID- 23796576 TI - Psychrophilic anaerobic digestion of lignocellulosic biomass: a characterization study. AB - Psychrophilic (20 degrees C) specific methane (CH4) yield from cellulose (C), xylan (X), cellulose/xylan mixture (CX), cow feces (CF), and wheat straw (WS) achieved (Nl CH4 kg(-1)VS) of 338.5 +/- 14.3 (C), 310.5 +/- 3.4 (X), 305.5 +/- 29.6 (CX mixture), and 235.3 +/- 22.7 (WS) during 56 days, and 237.6 +/- 17.7 (CF) during 70 days. These yields corresponded to COD recovery of 73.3 +/- 3.1% (C)=69.1 +/- 0.76% (X)=67.3 +/- 5.8% (CX mixture)>52.9 +/- 2.6% (CF)>46.5 +/- 2.7% (WS). Cellulose-fed culture had a lower and statistically different initial CH4 production rate from those calculated for cultures fed X, CX mixture, CF and WS. It seemed that the presence of hemicellulose in complex substrate such as wheat straw and cow feces supported the higher initial CH4 rate compared to cellulose. Biomethanation of the pure and complex lignocellulosic substrates tested is feasible at psychrophilic conditions given that a well-adapted inoculum is used; however, hydrolysis was the rate limiting step. PMID- 23796577 TI - Follicular dermal papilla structures by organization of epithelial and mesenchymal cells in interfacial polyelectrolyte complex fibers. AB - The hair follicle is a regenerating organ that produces a new hair shaft during each growth cycle. Development and cycling of the hair follicle is governed by interactions between the epithelial and mesenchymal components. Therefore, development of an engineered 3D hair follicle would be useful for studying these interactions to identify strategies for treatment of hair loss. We have developed a technique suitable for assembly of different cell types in close proximity in fibrous hydrogel scaffolds with resolutions of ~50 MUm. By assembly of dermal papilla (DP) and keratinocytes, structures similar to the native hair bulb arrangement are formed. Gene expression of these constructs showed up-regulation of molecules involved in epithelial-mesenchymal interactions of the hair follicle. Implantation of the follicular structures in SCID mice led to the formation of hair follicle-like structures, thus demonstrating their hair inductive ability. The transparency of the fiber matrix and the small dimensions of the follicular structures allowed the direct quantitation of DP cell proliferation by confocal microscopy, clearly illustrating the promoting or inhibitory effects of hair growth regulating agents. Collectively, our results suggested a promising application of these 3D engineered follicular structures for in vitro screening and testing of drugs for hair growth therapy. PMID- 23796579 TI - Biodistribution of sub-10 nm PEG-modified radioactive/upconversion nanoparticles. AB - The biodistribution of lanthanide-based upconversion nanophosphors (UCNPs) has attracted increasing attention, and all of the reported UCNPs display metabolism in the liver and spleen mainly. Herein, ~8 nm poly(ethylene glycol) (PEG)-coated NaYF4 nanoparticles codoped with Yb(3+), Er(3+), and (or) radioactive (153)Sm(3+) ions were synthesized, through a hydrothermal synthetic system assisted by binary cooperative ligands with oleic acid and PEG dicarboxylic acids. The as-prepared PEG-coating NaYF4:Yb,Er and NaYF4:Yb,Er,(153)Sm are denoted as PEG-UCNPs and PEG UCNPs((153)Sm), respectively. PEG-UCNPs were characterized by transmission electron microscope (TEM), X-ray diffraction (XRD) analysis, and Fourier transform infrared (FTIR) spectroscopy. The PEG-UCNPs showed excellent water solubility with a hydrodynamic diameter of ~10 nm and displayed upconversion luminescence (UCL) under continuous-wave excitation at 980 nm. At the same time, the (153)Sm-doped nanoparticles PEG-UCNPs((153)Sm) displayed radioactivity, and time-dependent biodistribution of PEG-UCNPs((153)Sm) was investigated, through single-photon emission computed tomography (SPECT) imaging and gamma-counter analysis. Interestingly, PEG-UCNPs((153)Sm) had a long blood retention time and were partly eliminated through urinary pathways in vivo. Therefore, the concept of fabricating PEG-coated, small nanosize (sub-10 nm) nanoparticles with radioactive property is a useful strategy for providing a potential method to monitor lanthanide nanoparticles renal clearable. PMID- 23796580 TI - Substrate conductivity dependent modulation of cell proliferation and differentiation in vitro. AB - In designing and developing various biomaterials, the influence of substrate properties, like surface topography, stiffness and wettability on the cell functionality has been investigated widely. However, such study to probe into the influence of the substrate conductivity on cell fate processes is rather limited. In order to address this issue, spark plasma sintered HA-CaTiO3 (Hydroxyapatite Calcium titanate) has been used as a model material system to showcase the effect of varying conductivity on cell functionality. Being electroactive in nature, mouse myoblast cells (C2C12) were selected as a model cell line in this study. It was inferred that myoblast adhesion/growth systematically increases with substrate conductivity due to CaTiO3 addition to HA. Importantly, parallel arrangement of myoblast cells on higher CaTiO3 containing substrates indicate that self-adjustable cell patterning can be achieved on conductive biomaterials. Furthermore, enhanced myoblast assembly and myotube formation were recorded after 5 days of serum starvation. Overall, the present study conclusively establishes the positive impact of the substrate conductivity towards cell proliferation and differentiation as well as confirms the efficacy of HA-CaTiO3 biocomposites as conductive platforms to facilitate the growth, orientation and fusion of myoblasts, even when cultured in the absence of external electric field. PMID- 23796578 TI - A review of therapeutic prospects of non-viral gene therapy in the retinal pigment epithelium. AB - Ocular gene therapy has been extensively explored in recent years as a therapeutic avenue to target diseases of the cornea, retina and retinal pigment epithelium (RPE). Adeno-associated virus (AAV)-mediated gene therapy has shown promise in several RPE clinical trials but AAVs have limited payload capacity and potential immunogenicity. Traditionally however, non-viral alternatives have been plagued by low transfection efficiency, short-term expression and low expression levels. Recently, these drawbacks have begun to be overcome by the use of specialty carriers such as polylysine, liposomes, or polyethyleneimines, and by inclusion of suitable DNA elements to enhance gene expression and longevity. Recent advancements in the field have yielded non-viral vectors that have favorable safety profiles, lack immunogenicity, exhibit long-term elevated gene expression, and show efficient transfection in the retina and RPE, making them poised to transition to clinical applications. Here we discuss the advancements in nanotechnology and vector engineering that have improved the prospects for clinical application of non-viral gene therapy in the RPE. PMID- 23796581 TI - Retinitis Pigmentosa: over-expression of anti-ageing protein Klotho in degenerating photoreceptors. AB - Retinitis Pigmentosa involves a hereditary degeneration of photoreceptors by as yet unresolved mechanisms. The secretable protein alpha-Klotho has a function related to ageing processes, and alpha-Klotho-deficient mice have reduced lifespan and declining functions in several tissues. Here, we studied Klotho in connection with inherited photoreceptor degeneration. Increased nuclear immunostaining for alpha-Klotho protein was seen in degenerating photoreceptors in four different Retinitis Pigmentosa models (rd1, rd2 mice; P23H, S334ter rhodopsin mutant rats). Correspondingly, in rd1 retina alpha-Klotho mRNA expression was significantly up-regulated. Moreover, immunostaining for another Klotho family protein, beta-Klotho, also co-localized with degenerating rd1 photoreceptors. The rd1 retina displayed reduced levels of fibroblast growth factor 15, a member of the fibroblast growth factor subfamily for which Klotho acts as a co-receptor. Exogenous alpha-Klotho protein added to retinal explant cultures did not affect cell death in rd1 retinae, but caused a severe layer disordering in wild-type retinae. Our study suggests Klotho as a novel player in the retina, with a clear connection to photoreceptor cell death as well as with an influence on retinal organization. PMID- 23796582 TI - Renal impairment and clinical outcomes of Clostridium difficile infection in two randomized trials. AB - BACKGROUND/AIMS: Patients with chronic kidney disease (CKD) have increased risk for Clostridium difficile infection (CDI) and for subsequent mortality. We determined the effect of CKD on response to treatment for CDI. METHODS: This is a post hoc analysis of two randomized controlled phase 3 trials that enrolled patients with CDI. Patients received either fidaxomicin 200 mg b.i.d. or vancomycin 125 mg q.i.d. for 10 days. Univariate and multivariate analyses compared end points by treatment received and CKD stage. RESULTS: At baseline, 27, 21, and 9% of the patients had stage 2 (60-89 ml/min/1.73 m(2)), stage 3 (30 59), and stage 4 or higher (<30) CKD. Cure rates were similar for normal (91%) and stage 2 CKD (92%), but declined to 80% for stage 3 and to 75% for stage 4 CKD (p < 0.001 for trend). Time to resolution of diarrhea (TTROD) increased with stage 3 and stage 4 CKD. CDI recurrence rates 4 weeks after treatment were 16, 20, 27, and 24% for normal, stage 2, stage 3, and stage 4 or higher CKD, respectively. Mortality increased with CKD stage. In multivariate analyses, stage 3 or higher CKD correlated with lower odds of cure, greater chance of recurrence, and lower odds of sustained response 28 days after treatment. Initial cure rates were similar in the vancomycin or fidaxomicin groups; however, the rate of recurrence was higher following vancomycin treatment independent of renal function. The presence of immunosuppression did not alter this effect. CONCLUSION: Progressive CKD is associated with increased TTROD, lower cure rates, and higher recurrence rates with treatment of CDI. PMID- 23796583 TI - First Spanish version of the Memorial Delirium Assessment Scale: psychometric properties, responsiveness, and factor loadings. AB - CONTEXT: The Memorial Delirium Assessment Scale (MDAS) is a reliable and validated instrument with which to assess delirium. However, MDAS responsiveness has only been investigated in an indirect way. Also, neurobehavioral and global cognitive factors seem to be the MDAS main factor loads. OBJECTIVES: The primary objective of this study was to evaluate MDAS responsiveness and analyze individual factors on this scale. The secondary objective was to confirm concurrent validity and reliability of the Spanish version of the MDAS. METHODS: The translation-back translation method was used to obtain the Spanish version of the MDAS. Delirium diagnosis was determined by the clinical Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria and with the Confusion Assessment Method. Responsiveness and factor loadings were determined with the Delirium Rating Scale-Revised-98, the Mini-Mental State Examination (MMSE), and the MDAS at baseline (0 hours) and at 72 hours. RESULTS: Variation in the scores of the Delirium Rating Scale-Revised-98 shows a correlation of r = 0.93, with variation in MDAS scores at P < 0.001. Variation in MMSE scores shows a correlation of r = -0.84, with variation in MDAS scores at P = 0.015. Factor I, neurobehavioral (reduced awareness, reduced attention, perceptual disturbance, delusions, altered psychomotor activity, and sleep-wake cycle disturbance), correlated moderately with the MMSE at -0.56. Factor II, global cognitive (disorientation, short-term memory impairment, impaired digit span, and disorganized thinking), correlated strongly with the MMSE at -0.81. Factor II was significantly more reliable than Factor I, rho = 0.7, P = 0.01. CONCLUSION: The high responsiveness confirms the value of the MDAS for ongoing delirium assessment. Two differentiated factor loadings point to a potential future need for MDAS subscales. PMID- 23796584 TI - Prevalence of breakthrough cancer pain: a systematic review and a pooled analysis of published literature. AB - CONTEXT: Despite the large body of literature on breakthrough cancer pain (BTcP), an accurate estimate of BTcP prevalence is still not available. OBJECTIVES: To provide an estimate of BTcP prevalence and investigate the association between different prevalence rates and possible determinants. METHODS: We conducted MEDLINE and EMBASE searches for studies published from 1990 to 2012 reporting data on BTcP prevalence in adult cancer populations. Pooled prevalence rates from observational studies with an acceptable methodological quality were computed. The association between BTcP prevalence and possible predictors was investigated using subgroup analyses and meta-regression. RESULTS: Twenty-seven observational studies were identified. When quality criteria were applied, only 19 studies were included in the pooled analysis. The overall pooled prevalence was 59.2%, with high heterogeneity. The lowest prevalence rates were detected in studies conducted in outpatient clinics (39.9%), and the highest prevalence was reported in studies conducted in hospice (80.5%). The association between BTcP prevalence and other determinants such as publication year, age, gender, metastatic disease prevalence, or baseline pain intensity did not reach statistical significance. CONCLUSION: In the context of a large between-studies heterogeneity, more than one in two patients with cancer pain also experiences BTcP, with some variability according to clinical and organizational variables. PMID- 23796585 TI - Half-body irradiation with tomotherapy for pain palliation in metastatic breast cancer. AB - CONTEXT: Half-body irradiation (HBI) is the fastest and most effective tool against uncontrolled pain from widespread bone metastases but is somewhat toxic. OBJECTIVES: To assess the feasibility of lower HBI with helical tomotherapy in patients with metastatic breast cancer in terms of acute toxicity and delay in chemotherapy administration. METHODS: Thirteen breast cancer patients with multiple painful bone metastases to the lower half of the body were enrolled in this prospective trial. Eight patients were receiving chemotherapy. Target volume included all bones from the L3-L4 interface to the femoral shafts. Radiation consisted of 8 Gy in one fraction, delivered with helical tomotherapy. Patients were premedicated only with oral steroids. Pain intensity was scored using the Numeric Rating Scale from 0 to 10. Toxicity was scored using the Common Terminology Criteria for Adverse Events, version 3.0. Quality of life was scored with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, before and 21 days after the radiation course. This trial was approved by the local review board. RESULTS: Median follow-up was at seven months (range 2-12 months). All but two patients had pain relief in the radiated field. Six patients stopped their analgesic drug consumption. Toxicity was acceptable: two Grade 3 hematologic toxicities were registered (anemia and leukopenia). Grade 1-2 toxicities were hematologic = 13, fever = 3, nausea = 2, and diarrhea = 1. Three of the eight patients had a delay in chemotherapy administration because of leukopenia or anemia. Twelve patients answered to European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, and an improved quality of life was documented in eight cases. CONCLUSION: Lower HBI delivered with helical tomotherapy resulted in a well-tolerated regimen, without significant delay in chemotherapy schedule. PMID- 23796586 TI - Concepts and definitions for "actively dying," "end of life," "terminally ill," "terminal care," and "transition of care": a systematic review. AB - CONTEXT: The terms "actively dying," "end of life," "terminally ill," "terminal care," and "transition of care" are commonly used but rarely and inconsistently defined. OBJECTIVES: We conducted a systematic review to examine the concepts and definitions for these terms. METHODS: We searched MEDLINE, PsycINFO, Embase, and CINAHL for published peer-reviewed articles from 1948 to 2012 that conceptualized, defined, or examined these terms. Two researchers independently reviewed each citation for inclusion and then extracted the concepts/definitions when available. We also searched 10 dictionaries, four palliative care textbooks, and 13 organization Web sites, including the U.S. Federal Code. RESULTS: One of 16, three of 134, three of 44, two of 93, and four of 17 articles defined or conceptualized actively dying, end of life, terminally ill, terminal care, and transition of care, respectively. Actively dying was defined as "hours or days of survival." We identified two key defining features for end of life, terminally ill, and terminal care: life-limiting disease with irreversible decline and expected survival in terms of months or less. Transition of care was discussed in relation to changes in 1) place of care (e.g., hospital to home), 2) level of professions providing the care (e.g., acute care to hospice), and 3) goals of care (e.g., curative to palliative). Definitions for these five terms were rarely found in dictionaries, textbooks, and organizational Web sites. However, when available, the definitions were generally consistent with the concepts discussed previously. CONCLUSION: We identified unifying concepts for five commonly used terms in palliative care and developed a preliminary conceptual framework toward building standardized definitions. PMID- 23796587 TI - Advance care planning and physician orders in nursing home residents with dementia: a nationwide retrospective study among professional caregivers and relatives. AB - CONTEXT: Advance care planning (ACP) is key to good palliative care for nursing home (NH) residents with dementia. OBJECTIVES: We examined the extent to which the family physicians (FPs), nurses, and the relative most involved in the resident's care are informed about ACP, written advance directives, and FP treatment orders (FP-orders) for NH residents dying with dementia. We also examined the congruence among FP, nurse, and relative regarding the content of ACP. METHODS: This was a representative nationwide post-mortem study (2010) in Flanders, Belgium, using random cluster sampling. In selected NHs, all deaths of residents with dementia in a three month period were reported. A structured questionnaire was completed by the FP, the nurse, and the patient's relative. RESULTS: We identified 205 deceased residents with dementia in 69 NHs. Residents expressed their wishes regarding end-of-life care in 11.8% of cases according to the FP. The FP and nurse spoke with the resident in 22.0% and 9.7% of cases, respectively, and with the relative in 70.6% and 59.5%, respectively. An advance directive was present in 9.0%, 13.6%, and 18.4% of the cases according to the FP, nurse, and the relative, respectively. The FP-orders were present in 77.3% according to the FP, and discussed with the resident in 13.0% and with the relative in 79.3%. Congruence was fair (FP-nurse) on the documentation of FP orders (k=0.26), and poor to slight on the presence of an advance directive (FP relative, k=0.03; nurse-relative, k=-0.05; FP-nurse k=0.12). CONCLUSION: Communication regarding care is rarely patient driven and more often professional caregiver or family driven. The level of congruence between professional caregivers and relatives is low. PMID- 23796588 TI - Gut microbes influence fitness and malaria transmission potential of Asian malaria vector Anopheles stephensi. AB - The midgut of parasite transmitting vector, Anopheles stephensi is a physiologically dynamic ecological niche of resident microbes. The gut resident microbes of anisomorphic and physiologically variable male and female A. stephensi mosquitoes were different (Rani et al., 2009). To understand the possible interaction of gut microbes and mosquito host, we examined the contribution of the microbe community on the fitness of the adult mosquitoes and their ability to permit development of the malaria parasite. A. stephensi mosquitoes were fed with antibiotic to sterilize their gut to study longevity, blood meal digestion, egg laying and maturation capacity, and consequently ability to support malaria parasite development. The sterilization of gut imparted reduction in longevity by a median of 5 days in male and 2 days in female mosquitoes. Similarly, the sterilization also diminished the reproductive potential probably due to increased rate of the resorption of follicles in ovaries coupled with abated blood meal digestion in gut-sterilized females. Additionally, gut sterilization also led to increased susceptibility to oocyst development upon feeding on malaria infected blood. The susceptibility to malaria parasite introduced upon gut sterilization of A. stephensi was restored completely upon re-colonization of gut by native microbes. The information provided in the study provides insights into the role of the gut-resident microbial community in various life events of the mosquito that may be used to develop alternate malaria control strategies, such as paratransgenesis. PMID- 23796590 TI - A phylogenetic hypothesis for the recently diversified Ruschieae (Aizoaceae) in southern Africa. AB - The Ruschieae is a large tribe of about 1600 species of succulent perennials. They form a major component of the arid parts of the Greater Cape Floristic Region, both in numbers of species and in their density of coverage. So far phylogenetic relationships within the tribe have been unresolved, largely through the paucity of variable molecular characters and this is ascribed to the tribe's recent and rapid radiation. Our phylogeny is based on 10 chloroplast gene regions and represents a nearly complete sampling of the 100 currently recognised genera of the Ruschieae. These chloroplast regions yielded relatively few phylogenetically informative characters, consequently providing only limited resolution in and poor support for many parts of the phylogeny. Nevertheless, for the first time, we provide well-supported evidence that taxa with mostly mesomorphic, often ephemeral leaves and weakly persistent fruits form a basal grade of lineages in the Ruschieae. These lineages subtend a large polytomy of taxa with almost exclusively xeromorphic, persistent leaves and strongly persisting fruits. Among the basal grade of lineages, those occurring within the winter-rainfall region typically shed their leaves or form (at least partly) a protective, dry sheath around the apical bud during the dry summer months, as a means of escaping the summer drought. This contrasts with taxa of the basal grade from outside the winter-rainfall region, in which the leaves persist. Our results show that, in both strongly and weakly persistent fruits, specialised characteristics of the fruit evolved repeatedly and so these structures are highly homoplasious. Perhaps as a consequence of repeated changes towards increased persistence and specialisation of leaves and fruits, several clades show little morphological cohesion. However, as in other groups in the Cape Flora, most clades in the Ruschieae represent regional groupings. Our analysis of sequences of the nuclear gene 'chloroplast-expressed glutamine synthetase' (ncpGS) revealed extensive paralogy within the Ruschieae, but found an intact reading frame in all its members. More data on the cytology of the Ruschieae is needed to evaluate whether the paralogy observed is due to gene duplication or polyploidy. PMID- 23796589 TI - Can host receptors for fungi be targeted for treatment of fungal infections? AB - The invasion and stimulation of normally non-phagocytic host cells, such as epithelial and endothelial cells, is a key step in the pathogenesis of many fungal infections. In most cases, host cell invasion and/or stimulation of a proinflammatory response is induced when proteins or carbohydrates on the fungal cell surface bind to receptors on the host cell. Although many of these fungal host cell interactions have only been investigated in vitro, the therapeutic efficacy of blocking the host cell receptors for Candida albicans and Rhizopus oryzae has been demonstrated in experimental animal models of infection. We summarize recent studies of the fungal receptors on normally non-phagocytic host cells and the therapeutic implications of blocking these receptors. PMID- 23796591 TI - Inexperienced sonographers can successfully visualize and assess a three dimensional image of the fetal face using a standardized ultrasound protocol. AB - INTRODUCTION: A standardized three-dimensional ultrasonographic (3DUS) protocol is described that allows fetal face reconstruction. Ability to identify cleft lip with 3DUS using this protocol was assessed by operators with minimal 3DUS experience. MATERIAL AND METHODS: 260 stored volumes of fetal face were analyzed using a standardized protocol by operators with different levels of competence in 3DUS. The outcomes studied were: (1) the performance of post-processing 3D face volumes for the detection of facial clefts; (2) the ability of a resident with minimal 3DUS experience to reconstruct the acquired facial volumes, and (3) the time needed to reconstruct each plane to allow proper diagnosis of a cleft. RESULTS: The three orthogonal planes of the fetal face (axial, sagittal and coronal) were adequately reconstructed with similar performance when acquired by a maternal-fetal medicine specialist or by residents with minimal experience (72 vs. 76%, p = 0.629). The learning curve for manipulation of 3DUS volumes of the fetal face corresponds to 30 cases and is independent of the operator's level of experience. DISCUSSION: The learning curve for the standardized protocol we describe is short, even for inexperienced sonographers. This technique might decrease the length of anatomy ultrasounds and improve the ability to visualize fetal face anomalies. PMID- 23796592 TI - Cerebral air embolism during an aircraft flight in a passenger with an air-filled lung cavity associated with remote lung surgery. PMID- 23796593 TI - A new paradigm for obtaining marketing approval for pediatric-sized prosthetic heart valves. AB - OBJECTIVE: Congenital heart valve disease is one of the most common abnormalities in children. There are limited technological solutions available for treating children with congenital heart valve diseases. The aim of this study is to provide the details of the consensus reached in terms of pediatric definitions, design approach, in vitro testing, and clinical trials, which may be used as guidance for developing prosthetic heart valves for the pediatric indication. METHODS: In stark contrast to the various designs of adult-sized replacement valves available in the market, there are no Food and Drug Administration (FDA) approved prosthetic heart valves available for use in the pediatric population. There is a pressing need for FDA-approved pediatric valve devices in the United States. The pediatric patient population has been typically excluded from replacement heart valve trials for several reasons. In January 2010, heart valve manufacturers and pediatric clinicians collaborated with academicians and FDA staff in a workshop to suggest ways to successfully evaluate pediatric prosthetic valves and conduct pediatric clinical trials to provide acceptable heart valve replacement options for this patient population. RESULTS: Recommendations, derived from ISO 5840:2005 and the 2010 FDA Draft Replacement Heart Valve Guidance, are provided for hydrodynamic, durability, and fatigue testing. CONCLUSIONS: The article specifically addresses in vitro and premarket and postmarket approval clinical studies that should be considered by a heart valve manufacturer for obtaining regulatory approval of pediatric sizes of prosthetic heart valve designs that are already approved for adult clinical use. PMID- 23796594 TI - Change in lung function over time in male metropolitan firefighters and general population controls: a 3-year follow-up study. AB - OBJECTIVES: Previous studies in firefighters have been contradictory regarding their course of lung function over time. The aim of this ongoing study is to investigate how changes in lung function over time in male metropolitan firefighters compare with those in population controls, and to explore associations between firefighters' use of personal respiratory protection devices during occupational exposures and their risk of accelerated lung function decline. METHODS: A prospective comparison of FEV1 (forced expiratory volume in 1 second) and FVC (forced vital capacity) was performed between 281 firefighters and 933 population controls. Logistic regression models were used to compare changes from baseline of FEV1 and FVC after 3 years and risk of accelerated decline between the cohorts. Within the firefighter cohort, risk of accelerated decline was compared between subgroups based on use of respiratory protection devices. RESULTS: Controls showed similar mean annual declines for FEV1 and FVC across age categories, whereas firefighters aged <45 years showed increasing values over time (p=0.040). Firefighters had a lower odds of accelerated FEV1 decline compared with controls (OR=0.60, 95%CI 110.44; 0.83), but firefighters who never or rarely used respiratory protection during fire knockdown had a higher odds of accelerated FEV1 decline compared with those who used it often or frequently (OR=2.20, 95%CI 1.02; 4.74). CONCLUSIONS: Younger generations of firefighters showed an increase in lung function relative to older colleagues, while population controls consistently showed decline of lung function across all ages. Firefighters who reported to be incompliant in using respiratory protection showed an increased risk of accelerated FEV1 decline. PMID- 23796595 TI - Occupational exposure and thoracic malignancies, is there a relationship? AB - OBJECTIVES: The aim of this study was to evaluate the effect of occupational exposure in the occurrence of lung cancer. METHOD: Three-hundred lung cancer cases diagnosed between September 1, 1999, and September 31, 2007, and 300 healthy controls were enrolled in this case-control study. Life-long occupational history, gender, age, exposure to asbestos, comorbidities, and smoking status were collected. RESULTS: The mean age of the 300 lung cancer cases was 60.3 +/- 9.9 year (91.7% male and 8.3% female), and the mean age of healthy control group was 60.4 +/- 10.5 year (95.0% male and 5.0% female). The most frequent histological types were squamous (172, 57.3%), adeno (69, 23.1%), and small cell (37, 12.3%). There was an increased risk of lung cancer occurrence among agriculture workers (OR=1.89, 95% Cl=1.17-2.98) (p=0.009). Inorganic dust exposure (OR=1.81, 95% Cl=1.0-3.25) (p=0.049) and organic dust exposure (OR=1.89, 95% Cl=1.0-3.59) (p=0.05) were found to be related with high frequency of having lung cancer. CONCLUSION: Workers who had occupational exposure to organic and inorganic dust, especially in the agricultural field, had higher risk of lung cancer occurrence when compared with office workers. PMID- 23796596 TI - Scapular kinematics and muscle activities during pushing tasks. AB - OBJECTIVES: Pushing tasks are functional activities of daily living. However, shoulder complaints exist among workers exposed to regular pushing conditions. It is crucial to investigate the control of shoulder girdles during pushing tasks. The objective of the study was to demonstrate scapular muscle activities and motions on the dominant side during pushing tasks and the relationship between scapular kinematics and muscle activities in different pushing conditions. METHODS: Thirty healthy adults were recruited to push a four-wheel cart in six pushing conditions. The electromyographic signals of the upper trapezius (UT) and serratus anterior (SA) muscles were recorded. A video-based system was used for measuring the movement of the shoulder girdle and scapular kinematics. Differences in scapular kinematics and muscle activities due to the effects of handle heights and weights of the cart were analyzed using two-way ANOVA with repeated measures. The relationships between scapular kinematics and muscle activities were examined by Pearson's correlation coefficients. RESULTS: The changes in upper trapezius and serratus anterior muscle activities increased significantly with increased pushing weights in the one-step pushing phase. The UT/SA ratio on the dominant side decreases significantly with increased handle heights in the one-step pushing phase. The changes in upward rotation, lateral slide and elevation of the scapula decreased with increased pushing loads in the trunk-forward pushing phase. CONCLUSIONS: This study indicated that increased pushing loads result in decreased motions of upward rotation, lateral slide and elevation of the scapula; decreased handle heights result in relatively increased activities of the serratus anterior muscles during pushing tasks. PMID- 23796597 TI - Low back pain and associated presenteeism among hospital nursing staff. AB - OBJECTIVES: In spite of the high prevalence of low back pain (LBP) and presenteeism previously observed among nurses, no study has assessed the risk of presenteeism specifically due to LBP in nursing staff. Therefore, aim of the present study was to assess prevalence and risk factors of presenteeism due to LBP among hospital nursing personnel. METHODS: 174 female nurses underwent a clinical interview and filled in a questionnaire on sociodemographics, LBP symptoms and associated sickness absence, mental symptoms, burnout and on exposure to workplace organizational, psychosocial and ergonomic factors; 111 subjects affected by LBP were included in the analysis. The effect of sociodemographic and workplace characteristics on presenteeism was examined through multivariate Poisson robust regression models. RESULTS: Prevalence of presenteeism due to LBP was 58%, with wide differences between registered nurses and nursing aides (p=0.001). Only a few workplace factors were significantly associated with presenteeism, including frequent stooping, which decreased the risk of presenteeism, and good working climate and procedural justice, which increased it. CONCLUSIONS: Presenteeism due to LBP was very high among registered nurses and was influenced only by workplace, but not by sociodemographic characteristics. Presenteeism due to LBP among registered nurses should be closely monitored, and effort should be made to reduce it to prevent future work disability associated with LBP. PMID- 23796598 TI - Natural pathways towards polyploidy in animals: the Squalius alburnoides fish complex as a model system to study genome size and genome reorganization in polyploids. AB - When comparing the known picture of polyploidy in animals and in plants, it is possible to recognize some similarities, namely: (i) multiple and recurrent origins in several well-established taxonomic groups; (ii) a strong and regular association with hybridization events; (iii) the production of genotypic diversity; (iv) a rapid genomic reshuffling; (v) a very active role of transposable elements in allopolyploids; (vi) a comparatively privileged occurrence in harsher environments when compared with their diploid relatives, and (vii) gene silencing and divergence of duplicated genes without disruption of duplicated loci. Research on polyploidy was highly biased towards plants during the last century because polyploidy in animals was for long time considered rare, occasional and irrelevant from an evolutionary perspective. However, as empirically observed in plants, genome rediploidization starts in polyploid organisms immediately after the polyploid shock. Given the speed and dynamicity of this process, evidence of genome multiplication is completely erased over time, and hence, only the most recent events are likely to be acknowledged. Although varying in expression between and within taxonomic groups, polyploidy and hybridization are ubiquitous in animals and may be recurrent, fostering evolution. Since evolutionary allopolyploid genomes behave as biologically diploid, zoologists have to challenge the old paradigm of an irrelevant evolutionary role in animals using current genomic and cytogenomic tools. These methods are most likely to reveal the role of polyploid mechanisms in producing evolutionary novelties. Nonsexual complexes are the perfect models to bridge the gap between empirical and theoretical research, while the evolutionary process is in action. Such animal complexes represent a transient stage that, in general, moves towards a polyploid stage, where bisexuality might be recovered, ultimately giving rise to a new gonochoric species. These pathways are herein illustrated by the Iberian allopolyploid Squalius alburnoides. Some general aspects on this fish's complex are updated and reviewed, namely the reproductive modes of the distinct genomotypes, since variable ploidies and genomic combinations occur in natural populations. Most recent data on the mechanisms of gene expression regulation and the importance of the genomic context in driving allelic expression are also included. It was first demonstrated that a regulatory mechanism involving dosage compensation by gene-copy silencing exists in allotriploid females and that allelic expression patterns differed either between genomically equivalent individuals or within the same individual (between tissues and genes). Thus, instead of a whole haplome inactivation, a biased silencing towards repression of a specific allele was observed as well as a reduction of the transcript levels to the diploid state. See also sister article focusing on plants by Tayale and Parisod in this themed issue. PMID- 23796599 TI - Semi-stochastic models for Salmonella infection within finishing pig units in the UK. AB - A multi-group semi-stochastic model is formulated to describe Salmonella dynamics on a pig herd within the UK and assess whether farm structure has any effect on the dynamics. The models include both direct transmission and indirect (via free living infectious units in the environment and airborne infection). The basic reproduction number R0 is also investigated. The models estimate approximately 24.6% and 25.4% of pigs at slaughter weight will be infected with Salmonella within a slatted-floored and solid-floored unit respectively, which corresponds to values found in previous abattoir and farm studies, suggesting that the model has reasonable validity. Analysis of the models identified the shedding rate to be of particular importance in the control of Salmonella spread, a finding also evident in an increase in the R0 value. PMID- 23796600 TI - Listening to victims: use of a Critical Incident Reporting System to enable adult victims of childhood sexual abuse to participate in a political reappraisal process in Germany. AB - Recent revelations about the scope and severity of past child sexual abuse in German institutions set off a broad public debate on this issue, and led to the establishment of a politically appointed Round Table committee and an Independent Commissioner whose mandates were to reappraise the issue and develop recommendations for future policies. A media campaign was launched to publicize the establishment of a Critical Incident Reporting System (CIRS) whereby now adult victims of past abuse could anonymously provide testimonials and let policy makers know what issues were important to them. Respondents could either call a hotline number or communicate by mail or email. The information collected was documented and analyzed by a research team, and the results of interim reports were included in the recommendations of the Independent Commissioner and the Round Table committee. Most of the respondents described severe and repeated occurrences of childhood sexual abuse. For many, priorities were improvements in therapy and counseling services, the abolishment of the statute of limitations on prosecuting offenders, and financial compensation. Based on the recommendations of the Round Table and the Independent Commissioner, two new laws were adopted as well as an action plan and some guidelines. In addition to rules for recompensation of victims in an institutional context a fund for victims of sexual abuse in intrafamilial context was established by the Federal Government. Another effect of this process was raising societal sensitivity to the problem of child sexual abuse. The use of a CIRS enabled those directly affected by childhood sexual abuse to have some input into a political process designed to address this issue. Such an approach could have applicability in other countries or in other domains of public health and other forms of societal conflict as well. PMID- 23796601 TI - Should we use postresuscitation ECG to decide for immediate invasive coronary strategy after resuscitated cardiac arrest? PMID- 23796603 TI - Why we should care about changes in cardiac rhythms during in-hospital ALS? PMID- 23796602 TI - Continuous neuromuscular blockade is associated with decreased mortality in post cardiac arrest patients. AB - AIM: Neuromuscular blockade may improve outcomes in patients with acute respiratory distress syndrome. In post-cardiac arrest patients receiving therapeutic hypothermia, neuromuscular blockade is often used to prevent shivering. Our objective was to determine whether neuromuscular blockade is associated with improved outcomes after out-of-hospital cardiac arrest. METHODS: A post hoc analysis of a prospective observational study of comatose adult (>18 years) out-of-hospital cardiac arrest at 4 tertiary cardiac arrest centers. The primary exposure of interest was neuromuscular blockade for 24h following return of spontaneous circulation and primary outcomes were in-hospital survival and functional status at hospital discharge. Secondary outcomes were evolution of oxygenation (PaO2:FiO2), and change in lactate. We tested the primary outcomes of in-hospital survival and neurologically intact survival with multivariable logistic regression. Secondary outcomes were tested with multivariable linear mixed-models. RESULTS: A total of 111 patients were analyzed. In patients with 24h of sustained neuromuscular blockade, the crude survival rate was 14/18 (78%) compared to 38/93 (41%) in patients without sustained neuromuscular blockade (p=0.004). After multivariable adjustment, neuromuscular blockade was associated with survival (adjusted OR: 7.23, 95% CI: 1.56-33.38). There was a trend toward improved functional outcome with neuromuscular blockade (50% versus 28%; p=0.07). Sustained neuromuscular blockade was associated with improved lactate clearance (adjusted p=0.01). CONCLUSIONS: We found that early neuromuscular blockade for a 24-h period is associated with an increased probability of survival. Secondarily, we found that early, sustained neuromuscular blockade is associated with improved lactate clearance. PMID- 23796604 TI - The role of carbohydrate binding module (CBM) at high substrate consistency: comparison of Trichoderma reesei and Thermoascus aurantiacus Cel7A (CBHI) and Cel5A (EGII). AB - The role of CBM in two fungal model cellulase systems, consisting of Cel7A and Cel5A, from Trichoderma reesei and Thermoascus aurantiacus, were compared in the hydrolysis of various substrates. For comparison, family-1 CBM's were introduced to the T. aurantiacus and removed from the T. reesei enzymes. Especially at high dry matter consistencies of lignocellulosic substrates, pretreated wheat straw and spruce, the T. aurantiacus enzymes lacking CBM outperformed the enzymes carrying the CBM. In these conditions, the CBM-less enzymes from both organisms obviously recognized and bound to the substrate at higher probability than in dilute systems. Avoiding the unproductive binding to lignin caused by the CBMs obviously enhanced the hydrolytic performance. The lignin binding effect was, however, not entirely caused by the CBM, but also by the different structures and affinities of the core enzymes to lignin. Due to decreased binding, the CBM-less enzymes would allow reuse, potentially decreasing hydrolysis costs. PMID- 23796605 TI - Enhanced biological nutrient removal in sequencing batch reactors operated as static/oxic/anoxic (SOA) process. AB - An innovative static/oxic/anoxic (SOA) activated sludge process characterized by static phase as a substitute for conventional anaerobic stage was developed to enhance biological nutrient removal (BNR) with influent ammonia of 20 and 40 mg/L in R1 and R2 reactors, respectively. The results demonstrated that static phase could function as conventional anaerobic stage. In R1 lower influent ammonia concentration facilitated more polyphosphate accumulating organisms (PAOs) growth, but secondary phosphorus release occurred due to NOx(-) depletion during post-anoxic period. In R2, however, denitrifying phosphorus removal proceeded with sufficient NOx(-). Both R1 and R2 saw simultaneous nitrification denitrification. Glycogen was utilized to drive post-denitrification with denitrification rates in excess of typical endogenous decay rates. The anoxic stirring duration could be shortened from 3 to 1.5h to avoid secondary phosphorus release in R1 and little adverse impact was found on nutrients removal in R2. PMID- 23796606 TI - Effect of algogenic organic matter (AOM) and sodium chloride on Nannochloropsis salina flocculation efficiency. AB - This study evaluates the effect of polymer molecular weight and charge density, algogenic organic matter (AOM), and salt concentration on harvesting efficiency of marine microalgae. Aluminum chloride (AlCl3), chitosan, and five synthetic cationic polymers of different molecular weights and charge density levels were used as flocculation agents. Polymer flocculation of marine microalgae was most efficient when using the highest charge density polymer (FO4990). The flocculant dosage irrespectively of the agent chemistry and charge density was affected by the amount of AOM secreted into the culture media. The presence of AOM increased the amount of required flocculant 7-fold when using synthetic cationic polymers; 10-fold with chitosan; and ~3-fold with AlCl3. Salt concentration of 5 or 35 g/L NaCl alone did not significantly affect removal efficiency, indicating that AOM were the main cause for the increased flocculant dosage requirement. The synthetic cationic polymer (FO4990) was the least expensive flocculation agent. PMID- 23796607 TI - Heterologous expression of Lactobacillus casei RecO improved the multiple-stress tolerance and lactic acid production in Lactococcus lactis NZ9000 during salt stress. AB - The aim of this study was to investigate the effect of nisin-inducible RecO expression on the stress tolerance of Lactococcus lactis NZ9000. RecO protein from Lactobacillus casei Zhang was introduced into Lactococcus lactis NZ9000 by using a nisin-inducible expression system. The recombinant strain (NZ-RecO) exhibited higher growth performances and survival rate compared with the control strain (NZ-Vector) under stress conditions. In addition, the NZ-RecO strain exhibited 1.37-, 1.41-, and 1.42-fold higher biomass, lactate production, lactate productivity, compared with the corresponding values for NZ-Vector during NaCl stressed condition. Analysis of lactate dehydrogenase (LDH) activity showed that the production of RecO maintained the stability of LDH during salt stress. These results suggest that overproduction of RecO improved the multiple-stress tolerance and lactic acid production in Lactococcus lactis NZ9000 during salt stress. Results presented in this study may help to enhance the industrial utility of lactic acid bacteria. PMID- 23796608 TI - Immobilized acclimated biomass-powdered activated carbon for the bioregeneration of granular activated carbon loaded with phenol and o-cresol. AB - The objectives of the study are to use immobilized acclimated biomass and immobilized biomass-powdered activated carbon (PAC) as a novel approach in the bioregeneration of granular activated carbon (GAC) loaded with phenol and o cresol, respectively, and to compare the efficiency and rate of the bioregeneration of the phenolic compound-loaded GAC using immobilized and suspended biomasses under varying GAC dosages. Bioregeneration of GAC loaded with phenol and o-cresol, respectively, was conducted in batch system using the sequential adsorption and biodegradation approach. The results showed that the bioregeneration efficiency of GAC loaded with phenol or o-cresol was basically the same irrespective of whether the immobilized or suspended biomass was used. Nonetheless, the duration for bioregeneration was longer under immobilized biomass. The beneficial effect of immobilized PAC-biomass for bioregeneration is the enhancement of the removal rate of the phenolic compounds via adsorption and the shortening of the bioregeneration duration. PMID- 23796609 TI - [Cephalosporin use in hospitalized patients with pneumonia]. PMID- 23796610 TI - [Withdrawal of assisted ventilation in the home: making decisions in paediatric palliative care]. AB - End-of-life care is of growing interest in Paediatrics. The number of children with diseases being treated using high-technology as palliative treatment has also increased. The creation of multidisciplinary care teams with 24/7 hours home care may prevent prolonged hospital stays in these patients. To adapt the treatment in order to avoid new hospital admissions and to obtain a better quality of life is a desirable objective. The taking of decisions and subsequent withdrawal of mechanical ventilation in the home is presented, along with the underlying disease and the acute event that led to the worsening of the patient. The decision-making and clinical management until the death of the patient is then discussed and reviewed. PMID- 23796611 TI - [Emergence of invasive pneumococcal disease caused by non-vaccine serotypes in the era of the 7-valent conjugate vaccine]. AB - INTRODUCTION: There has been an increased incidence in invasive pneumococcal disease (IPD) produced by non-vaccine serotype (NVS) of Streptococcus pneumoniae after the introduction of PCV7. Our objective was to describe the epidemiological, clinical and microbiological characteristics of IPD caused by NVS in a tertiary hospital in Madrid. PATIENTS AND METHODS: Retrospective (1998 2004) and prospective (2005-2009) study evaluating IPD caused by NVS in children. The study was divided into three periods: P1 (1998-2001) when PCV7 was not commercialized; P2 (2002-2005) with 40% vaccine coverage among children; and P3 (2006-2009) when the vaccine was added to the Childhood Immunization Schedule in Madrid. RESULTS: We analyzed 155 cases of IPD. One hundred and fifty of these isolates were serotyped (100 were NVS). There was an increase in the prevalence of IPD from P1 (31%) to P2 (54%) and P3 (91%). The most relevant emerging serotypes were 19A, 7F, 1, 5, 3 and 15C. The most significant clinical syndromes produced by some specific serotypes were as follows: lower respiratory tract infection (LRTI) by serotypes 1, 3, 5 and 15C; LRTI, primary bacteremia and meningitis by serotype 19A; and primary bacteremia by serotype 7F (66%). The large majority (83.8%) of NVS were sensitive to penicillin. CONCLUSIONS: There has been an increased prevalence of IPD caused by NVS since the introduction of PCV7. These changes should prompt the introduction of new pneumococcal vaccines, which include most of the NVS, in the childhood immunization calendar to prevent IPD in children. PMID- 23796612 TI - [Infant with vomiting, elevated transaminases and fever: an unsuspected diagnosis]. PMID- 23796613 TI - [Efficacy of treatment with I(131) in paediatric Graves disease]. AB - INTRODUCTION: Radioiodine is an important therapeutic option in young patients with Grave's disease (GD). In the United States it is a widespread therapy, but in Europe its use in paediatrics is still controversial. AIM: To report our experience in radioiodine therapy of paediatric GD patients and analyse its effectiveness and safety. PATIENTS AND METHODS: We retrospectively studied our paediatric population (<18 years of age) with GD, diagnosed from 1982 to 2012. A curative option was offered to patients who did not respond to anti-thyroid drug (AT) at puberty. We analysed, the patient characteristics, TSH, T4, T3 and thyroid antibodies levels, AT response, remission post I(131), side effects, and hypothyroidism rates. RESULTS: A total of 50 patients were diagnosed with GD from 1982 to 2012. All patients received AT as initial treatment (mean duration: 35.3+/-25.9 months). Permanent remission was achieved in 46%. Thyroidectomy was performed in 5 patients, and 14 patients received I(131) (mean dose: 10.9+/-1.09 mCi). Remission with I(131) was obtained in 100%. The rate of permanent hypothyroidism was 90%. There was no progression of ophthalmopathy or side effects in any patients treated with I(131.) CONCLUSION: Radioiodine treatment of paediatric GD patients is safe, leads to complete remission at the expense of hypothyroidism, and does not exacerbate ophthalmopathy. It can be considered in patients older than 5 years, who do no not respond to AT or with significant side effects with this medication. PMID- 23796614 TI - [Adrenal tumours in childhood]. AB - This special article aims to summarise the current knowledge regarding the two groups of tumours with their origin in the adrenal gland: 1) adrenocortical tumours, derived from the cortex of the adrenal gland and 2) phaeochromocytomas and paragangliomas, neuroendocrine tumours derived from nodes of neural crest derived cells symmetrically distributed at both sides of the entire spine (paragangliomas [PG]). These PGs can be functioning tumors that secrete catecholamines, which confers their typical dark colour after staining with chromium salts (chromaffin tumors). Among these, the term phaeochromocytoma (PC) is restricted to those PGs derived from the chromaffin cells in the adrenal medulla (intra-adrenal PGs), whereas the term PG is used for those sympathetic or parasympathetic ones in an extra-adrenal location. We analyse the state of the art of their pathogenic and genetic bases, as well as their clinical signs and symptoms, the tests currently available for performing their diagnosis (biochemical, hormonal, imaging and molecular studies) and management (surgery, pre- and post-surgical medical treatment), considering the current and developing strategies in chemo- and radiotherapy. PMID- 23796615 TI - Fatigue in drug-naive Parkinson's disease. AB - OBJECTIVES: Fatigue is common in Parkinson's disease (PD), causing serious negative effects on quality of life. Despite its clinical importance, the nature of fatigue in PD is poorly understood because its underlying neurobiology is unknown. Fatigue can be more complicated in advanced PD because of its chronicity. In order to find features that are innate to fatigue in PD, it would be useful to conduct a study looking at de novo PD. Assessing fatigue in de novo patients allows excluding at least one confounding factor. METHODS: We prospectively investigated 87 drug-naive PD patients. Thirty-nine patients (44.8%) were found to have fatigue around the time of diagnosis of PD. RESULTS: We found that depression and difficulties with activities of daily living were independent risk factors for fatigue; however, motor dysfunction was not related. Clinically meaningful responses to dopaminergic medication were observed. DISCUSSION: Our study determined that fatigue occurs in the early stages of PD. It can inform clinical decision-making to significantly benefit PD patients with fatigue. PMID- 23796616 TI - Too ill for an implantable cardioverter defibrillator? PMID- 23796617 TI - Ten-year trends in the use of catheter ablation for treatment of atrial fibrillation vs. the use of coronary intervention for the treatment of ischaemic heart disease in Australia. AB - AIMS: Percutaneous coronary intervention (PCI) and catheter ablation are well accepted therapeutic interventions for treatment of coronary artery disease and atrial fibrillation (AF), respectively. We sought to examine temporal trends in the provision of these services over the past decade in Australia. METHODS AND RESULTS: A retrospective review of the numbers of PCIs and AF ablations from 2000/01 to 2009/10 was performed on data from three sources: the Australian Institute of Health, Welfare and Aging (AIHW), Medicare Australia database (MA), and local records at a high volume tertiary referral centre (RMH) for AF ablation. Linear regression models were fitted comparing trends in population adjusted procedural numbers over the 10-year period. There was a 5% per year population-adjusted increment in PCIs over 10 years from both the AIHW and MA sources, respectively (P < 0.001). This was similar to the growth rate of all cardiovascular procedures (AIHW: 5.1 vs. 3.8%/year, P = 0.27). Atrial fibrillation ablations showed a 30.9, 23.2, and 39.8% per year population adjusted increment over 10 years from the AIHW, MA, and RMH sources respectively (P < 0.001 for all). Growth of AF ablations was significantly higher than PCIs (P < 0.001 for AIHW and MA sources) and all cardiovascular procedures (AIHW: 30.9 vs. 3.8%/year, P < 0.001). CONCLUSION: The provision of catheter-based AF ablation services in Australia has increased exponentially over the past decade. Its annual growth rate exceeded that of PCIs and all cardiovascular procedures. Given the increasing epidemic of AF, these data have critical implications for public health policy assessing the adequacy of infrastructure, training, and funding for AF ablation services. PMID- 23796618 TI - Surgical vs. transcatheter pulmonary vein isolation as first invasive treatment in patients with atrial fibrillation: a matched group comparison. AB - AIMS: Pulmonary vein isolation (PVI) can be considered for treatment of symptomatic atrial fibrillation (AF). Nowadays, in addition to transcatheter ablation, thoracoscopic surgical PVI is available. The aim of this study is to compare clinical outcome of surgical with transcatheter PVI as first invasive treatment strategy of AF. METHODS AND RESULTS: From June 2009 to November 2011, 33 patients underwent minimally invasive surgical PVI, and were matched (1:2 fashion) retrospectively according to age, sex, and AF type, with 66 patients who underwent transcatheter PVI. Success was defined as freedom from atrial arrhythmias on 24 h Holter monitoring without use of anti-arrhythmic drugs (AADs) at 1 year. Mean age was 52 +/- 10 years, 82% were male. Paroxysmal AF was present in 76 patients (77%), persistent AF in 23 (23%) patients. None underwent prior ablations, and failed on 1.2 +/- 0.6 AADs. At 12 months, complete freedom from atrial arrhythmias without AADs in the surgical PVI group was 88% compared with 41% in the transcatheter PVI group (P < 0.001). Freedom from atrial arrhythmias with AADs was 91 vs. 62%, in the surgical vs. transcatheter PVI group, respectively (P = 0.002). Complications occurred in seven (21%) surgical PVI patients, and three (5%) transcatheter PVI patients (P = 0.015). CONCLUSION: In present matched study comparing a surgical with transcatheter PVI treatment strategy in symptomatic AF patients failed on AADs, but without prior ablations, a surgical PVI strategy was more effective to prevent recurrence of atrial arrhythmias, than a transcatheter PVI treatment strategy. However, complications were more frequent with surgical PVI. PMID- 23796619 TI - Lateral parapatellar approach with tibial tubercle osteotomy for the treatment of non-correctable valgus knee osteoarthritis: a retrospective clinical study. AB - BACKGROUND: The aim of this retrospective study was to evaluate the efficacy of a lateral parapatellar approach combined with a tibial tubercle osteotomy (TTO) in patients undergoing total knee arthroplasty (TKA) with non-correctable valgus knee osteoarthritis. METHODS: We studied 53 consecutive patients (57 knees) who had a primary TKA via lateral parapatellar approach with a global step-cut "coffin" type TTO over a 10-year period. All patients had non-correctable grade II valgus deformity according to the Ranawat classification. The average age of patients was 71 years (45 to 77) and the mean follow-up was 39 months (20 to 98). RESULTS: Post-surgery, there was a significant improvement in knee extension (p=0.002), flexion (p=0.006), Knee Society Pain and Function Scores (p<0.001) and WOMAC Osteoarthritis Index (p<0.001). The tibiofemoral angle changed from a preoperative median value of 11 deg (10 to 17) to a postoperative value of 3.75 deg (0 to 9). Congruent patellar tracking was observed in all cases. All but one osteotomy united in a median period of 16.7 weeks (9 to 28) and no hardware removal was required. One knee developed infection treated with two-stage reconstruction. A proximal tibial stress fracture also occurred in a patient on long-term bisphosphonate therapy. CONCLUSION: Lateral parapatellar approach along with TTO is an effective technique for addressing non-correctable valgus knee deformity during TKA. PMID- 23796620 TI - Epithelial-disruption collagen crosslinking for keratoconus: one-year results. AB - PURPOSE: To evaluate the efficacy of epithelial-disruption collagen crosslinking (CXL) for progressive keratoconus using a corneal disruptor device and a riboflavin solution designed for a transepithelial technique. SETTING: Magna Graecia University Eye Clinic, Catanzaro, Italy. DESIGN: Prospective comparative case series. METHODS: The most severely affected eye of patients with bilateral progressive keratoconus was treated. The fellow eye served as a control. Follow up was 12 months. A corneal disruptor device was used to create pockmarks in the epithelium. Riboflavin solution was applied for 30 minutes and irradiation for 30 minutes. Three days postoperatively, patients were asked to assess the level of pain. RESULTS: The study comprised 28 patients (mean age 28 years). The mean postoperative pain score was 4.3, 2.6, and 2.1 at 1 day, 2 days, and 3 days. The mean preoperative uncorrected (UDVA) and corrected (CDVA) distance visual acuities improved from 0.73 logMAR +/- 0.21 (SD) and 0.30 +/- 0.11 logMAR to 0.48 +/- 0.15 logMAR and 0.25 +/- 0.1 logMAR, respectively, at 12 months (P=.02). The mean spherical equivalent refraction decreased 0.96 diopter (D). The mean baseline apical keratometry, apical gradient curvature, average pupillary power, inferior-superior index, and cone area were 59.21 D, 8.91 D, 47.9 D, 11.49 mm(2), and 10.32 mm(2), respectively. At 12 months, these values were 56.18 D, 7.32 D, 41.34 D, 9.65 mm(2), and 7.75 mm(2), respectively. No adverse effects were observed. CONCLUSIONS: Corneal epithelial-disruption CXL was safe and effective in medium-term stabilization of keratoconus with an improvement in topographic and refractive parameters and less patient discomfort. PMID- 23796621 TI - Pachymetry changes during corneal crosslinking: effect of closed eyelids and hypotonic riboflavin solution. AB - PURPOSE: To evaluate pachymetry changes during standard corneal crosslinking (CXL) and the effect of closed eyelids and hypotonic riboflavin in thin corneas. SETTING: Department of Ophthalmology, Medical University of Vienna, Vienna, Austria. DESIGN: Comparative case series. METHODS: Eyes with progressive keratoconus had standard epithelium-off CXL. In Group 1, a lid speculum was used during the procedure. In Group 2, the lids were closed during saturation with riboflavin. In Group 3, hypotonic riboflavin was used. In Groups 1 and 2, swelling was performed with hypotonic riboflavin if pachymetry was less than 400 MUm. The thinnest corneal pachymetry (TCP) was measured preoperatively, after epithelium removal, and every 10 minutes thereafter. RESULTS: Thirty-five eyes were evaluated. After epithelium removal, the mean TCP was 401 MUm +/- 15 (SD), 411 +/- 35 MUm, and 400 +/- 24 in Groups 1, 2, and 3, respectively. In Group 1, the TCP decreased to 355 +/- 23 MUm after the first 30 minutes. In Group 2, the TCP remained stable throughout the saturation phase. In Group 3, the TCP increased. During the irradiation phase, a reduction in pachymetry occurred in all groups. Thinnest corneal pachymetry readings less than 400 MUm were found in all eyes irrespective of the protocol. CONCLUSIONS: Corneal desiccation with riboflavin with 20% dextran can be avoided when removing the lid speculum during saturation with riboflavin. The use of hypotonic riboflavin solution increased corneal pachymetry, although the final TCP remained unchanged. To increase endothelial safety, new isooncotic solutions are needed. PMID- 23796622 TI - Interface fluid syndrome after laser in situ keratomileusis following herpetic keratouveitis. AB - We report an unusual case of a 28-year-old man who developed interface fluid with herpetic keratouveitis and elevated intraocular pressure (IOP) after laser in situ keratomileusis (LASIK) in the left eye. The IOP was unmeasurable with the Goldmann applanation tonometer; rebound tonometry showed an IOP of 30 mm Hg in the central cornea and 58 mm Hg in the superior cornea. Medical treatment of the elevated IOP resulted in resolution of the accumulated interface fluid. This case highlights the inaccuracy of IOP measurements in the central cornea with interface fluid or central corneal edema caused by elevated IOP after LASIK and shows the efficacy of IOP measurements at the peripheral cornea using rebound tonometry. It also shows that uveitis can be a risk factor for interface fluid syndrome after LASIK. PMID- 23796623 TI - Effect of irradiation time on riboflavin-ultraviolet-A collagen crosslinking in rabbit sclera. AB - PURPOSE: To determine the effect of the duration of irradiation on the biomechanical parameters of combined riboflavin-ultraviolet-A (UVA) collagen crosslinking (CXL) in rabbit sclera. SETTING: Department of Ophthalmology, Provincial Hospital affiliated with Shandong University, Shandong, China. DESIGN: Experimental study. METHODS: Thirty-six New Zealand rabbits were divided into 6 groups based on the duration of irradiation (10, 20, 30, 40, 50, or 60 minutes). After the application of riboflavin 0.1% drops (without dextran) as a photosensitizer, the animals were irradiated with 3 mW/cm(2) UVA at 365 nm. Only the left eye of each rabbit was treated. All the animals were humanely killed 24 hours postoperatively. One eye in each treated group was used for light microscopy. The other treated eye and all control eyes were prepared for biomechanical testing. The biomechanical parameters were ultimate stress, Young modulus, and the physiological modulus. RESULTS: The eyes irradiated for 10 or 20 minutes did not differ significantly from the control eyes. Stress-strain measurement of scleral strips irradiated for 40 minutes or longer showed a significant increase in the ultimate stress, Young modulus, and the physiological modulus. There was a significant increase in the physiological modulus of scleral strips irradiated for 30 minutes or longer. Eyes that were irradiated for 50 minutes and 60 minutes had retinal damage. CONCLUSIONS: Riboflavin-UVA CXL can lead to a noticeable increase in the biomechanical stiffness of the sclera. The physiological modulus is the most sensitive tool to measure stiffness. In this study, the optimum duration of irradiation was 40 minutes. PMID- 23796624 TI - The ankyrin-3 gene is associated with posttraumatic stress disorder and externalizing comorbidity. AB - BACKGROUND: The ankyrin 3 gene (ANK3) produces the ankyrin G protein that plays an integral role in regulating neuronal activity. Previous studies have linked ANK3 to bipolar disorder and schizophrenia. A recent mouse study suggests that ANK3 may regulate behavioral disinhibition and stress reactivity. This led us to hypothesize that ANK3 might also be associated with stress-related psychopathology such as posttraumatic stress disorder (PTSD), as well as disorders of the externalizing spectrum such as antisocial personality disorder and substance-related disorders that are etiologically linked to impulsivity and temperamental disinhibition. METHODS: We examined the possibility of association between ANK3 SNPs and both PTSD and externalizing (defined by a factor score representing a composite of adult antisociality and substance abuse) in a cohort of white non-Hispanic combat veterans and their intimate partners (n=554). Initially, we focused on rs9804190-a SNP previously reported to be associated with bipolar disorder, schizophrenia, and ankyrin G expression in brain. Then we examined 358 additional ANK3 SNPs utilizing a multiple-testing correction. RESULTS: rs9804190 was associated with both externalizing and PTSD (p=0.028 and p=0.042 respectively). Analysis of other ANK3 SNPs identified several that were more strongly associated with either trait. The most significant association with externalizing was observed at rs1049862 (p=0.00040, pcorrected=0.60). The most significant association with PTSD (p=0.00060, pcorrected=0.045) was found with three SNPs in complete linkage disequilibrium (LD)-rs28932171, rs11599164, and rs17208576. CONCLUSIONS: These findings support a role of ANK3 in risk of stress related and externalizing disorders, beyond its previous associations with bipolar disorder and schizophrenia. PMID- 23796625 TI - NUCB2/nesfatin-1 is associated with elevated scores of anxiety in female obese patients. AB - Nesfatin-1 is derived from nucleobindin2 (NUCB2) and implicated in the regulation of food intake and body weight. Plasma levels are altered under conditions of chronically altered body weight such as obesity. Nesfatin-1 was also shown to be involved in the modulation of emotion. Since obesity is often associated with anxiety and depression we investigated plasma NUCB2/nesfatin-1 levels in obese women (n=77) over a broad range of body mass index (BMI, 32-67 kg/m(2)) with different levels of anxiety assessed by the generalized anxiety disorder questionnaire (GAD-7). Stress was assessed using the perceived stress questionnaire (PSQ-20) and depression using the patient health questionnaire (PHQ 9). The study population was divided in patients with low anxiety (n=40, GAD scores, mean +/- SD, 5.0 +/- 2.7) and high anxiety (n=37, 14.2 +/- 3.3, p<0.001). Patients with high anxiety showed higher levels of NUCB2/nesfatin-1 (+33%), perceived stress (+60%) and depression (+98%) compared to the low anxiety group (p<0.001). NUCB2/nesfatin-1 levels positively correlated with GAD-7 (r=0.68, p<0.001), total PSQ-20 (r=0.57, p<0.001) and PHQ-9 scores (r=0.45, p<0.001), while no significant correlation was observed with BMI (r=-0.21, p=0.09). Also the subscales of the PSQ-20, "worries", "tension" and "demands" were higher in the high anxiety group and correlated positively with NUCB2/nesfatin-1 (p<0.001), whereas "joy" was lower and correlated negatively with NUCB2/nesfatin-1 (p=0.015). Summarized, plasma NUCB2/nesfatin-1 levels were altered under conditions of perceived anxiety, stress and depression in obese women. No correlation was observed with BMI. These data point toward an involvement of NUCB2/nesfatin-1 in the regulation of emotion in addition to its impact on body weight. PMID- 23796626 TI - Can bedside emergency ultrasonography enhance clinical decisionmaking in emergency department patients presenting with symptoms of biliary colic? PMID- 23796627 TI - Quality and safety implications of emergency department information systems. AB - The Health Information Technology for Economic and Clinical Health Act of 2009 and the Centers for Medicare & Medicaid Services "meaningful use" incentive programs, in tandem with the boundless additional requirements for detailed reporting of quality metrics, have galvanized hospital efforts to implement hospital-based electronic health records. As such, emergency department information systems (EDISs) are an important and unique component of most hospitals' electronic health records. System functionality varies greatly and affects physician decisionmaking, clinician workflow, communication, and, ultimately, the overall quality of care and patient safety. This article is a joint effort by members of the Quality Improvement and Patient Safety Section and the Informatics Section of the American College of Emergency Physicians. The aim of this effort is to examine the benefits and potential threats to quality and patient safety that could result from the choice of a particular EDIS, its implementation and optimization, and the hospital's or physician group's approach to continuous improvement of the EDIS. Specifically, we explored the following areas of potential EDIS safety concerns: communication failure, wrong order-wrong patient errors, poor data display, and alert fatigue. Case studies are presented that illustrate the potential harm that could befall patients from an inferior EDIS product or suboptimal execution of such a product in the clinical environment. The authors have developed 7 recommendations to improve patient safety with respect to the deployment of EDISs. These include ensuring that emergency providers actively participate in selection of the EDIS product, in the design of processes related to EDIS implementation and optimization, and in the monitoring of the system's ongoing success or failure. Our recommendations apply to emergency departments using any type of EDIS: custom-developed systems, best of-breed vendor systems, or enterprise systems. PMID- 23796628 TI - Circulatory death determination in uncontrolled organ donors: a panel viewpoint. AB - One barrier for implementing programs of uncontrolled organ donation after the circulatory determination of death is the lack of consensus on the precise moment of death. Our panel was convened to study this question after we performed a similar analysis on the moment of death in controlled organ donation after the circulatory determination of death. We concluded that death could be determined by showing the permanent or irreversible cessation of circulation and respiration. Circulatory irreversibility may be presumed when optimal cardiopulmonary resuscitation efforts have failed to restore circulation and at least a 7-minute period has elapsed thereafter during which autoresuscitation to restored circulation could occur. We advise against the use of postmortem organ support technologies that reestablish circulation of warm oxygenated blood because of their risk of retroactively invalidating the required conditions on which death was declared. PMID- 23796629 TI - In vitro human adipose-derived stromal/stem cells osteogenesis in akermanite:poly epsilon-caprolactone scaffolds. AB - This study compared the metabolic activity, cell proliferation and osteogenic differentiation of human adipose-derived stromal/stem cells cultured on four different scaffolds (poly-epsilon-caprolactone, akermanite:poly-epsilon caprolactone composites, akermanite and beta-tricalcium phosophate) with or without osteogenic media supplementation for up to 21 days. The hypothesis was that human adipose-derived stromal/stem cells osteogenesis in akermanite containing scaffolds would be greater than the other scaffold types independent of the media supplementation. According to the results, human adipose-derived stromal/stem cells loaded on different scaffolds and cultured in both media conditions displayed significant changes in the metabolic activity and cell proliferation. After 21 days of culture in osteogenic medium, the human adipose derived stromal/stem cells loaded onto akermanite-based scaffolds had greater calcium deposition and osteocalcin expression relative to human adipose-derived stromal/stem cells loaded onto beta-tricalcium phosophate and poly-epsilon caprolactone. In vivo investigations are needed to further assess the bone tissue engineering potential of human adipose-derived stromal/stem cells loaded to akermanite:poly-epsilon-caprolactone composites. PMID- 23796630 TI - RGD-conjugated iron oxide magnetic nanoparticles for magnetic resonance imaging contrast enhancement and hyperthermia. AB - The purpose of this study was to develop a specific targeting magnetic nanoparticle probe for magnetic resonance imaging and therapy in the form of local hyperthermia. Carboxymethyl dextran-coated ultrasmall superparamagnetic iron oxide nanoparticles with carboxyl groups were coupled to cyclic arginine glycine-aspartic peptides for integrin alpha(v)beta3 targeting. The particle size, magnetic properties, heating effect, and stability of the arginine-glycine aspartic-ultrasmall superparamagnetic iron oxide were measured. The arginine glycine-aspartic-ultrasmall superparamagnetic iron oxide demonstrates excellent stability and fast magneto-temperature response. Magnetic resonance imaging signal intensity of Bcap37 cells incubated with arginine-glycine-aspartic ultrasmall superparamagnetic iron oxide was significantly decreased compared with that incubated with plain ultrasmall superparamagnetic iron oxide. The preferential uptake of arginine-glycine-aspartic-ultrasmall superparamagnetic iron oxide by target cells was further confirmed by Prussian blue staining and confocal laser scanning microscopy. PMID- 23796631 TI - Bone regeneration potential of the new chitosan-based alloplastic biomaterial. AB - Over the last few years, alloplastic bone substitute materials are raising much interest as an alternative to autologic transplants and xenogenic materials especially in oral surgery. These non-immunogenic and completely resorbable biomaterials are becoming the basis for complete and predictable guided bone regeneration in many cases. The objective of our research was to evaluate the dynamics of bone formation in rats' skulls after implantation of the new chitosan/tricalcium phosphate/alginate biomaterial in comparison to the commercially available alloplastic bone graft. A total of 45 adult male rats weighing 300-400 g were used for the study. The 85-mm-diameter defects in calvaria bone were prepared with a trephine bur, and then filled with the bone substitute materials: chitosan/tricalcium phosphate/alginate or easy-graft Classic (Degradable Solutions AG) (EA) or left just with the blood clot. Animals were sacrificed at 1 and 3 months for histological, histomorphometrical and micro tomographic evaluations. Histological evaluation at 1 month showed early new bone formation, observed around the experimental biomaterial (CH/TCP/Alg). There were no features of purulent inflammation and necrosis or granulomatous inflammation. Microscopic examination after 3 months following the surgery revealed trabecular bone formation around chitosan-based bone graft with no significant inflammatory response. Less satisfactory and differing results were observed for the commercially available EA and control blood clot. The tested material (chitosan) showed a high degree of biocompatibility and osteoconductivity in comparison with the control groups. Additionally, it seemed to be a "user-friendly" material for oral surgeons. PMID- 23796632 TI - Possible misinterpretations of nonalcoholic fatty liver disease and intra abdominal fat in prepubertal children born small for gestational age. PMID- 23796634 TI - Cognitive components in mice and humans: combining genetics and touchscreens for medical translation. AB - Human disorders of cognition arise from hundreds of gene mutations and mice serve as models for developing and testing therapeutic approaches. Recent advancements using touchscreen psychological tests that measure similar components of cognition in mice and humans can be combined with genetics. These experiments formally demonstrate that different components of cognition in humans and mice are not merely analogous, but homologous, sharing common descent and genetic constitution. They also show that it is possible to genetically dissect different behaviours and identify their underlying molecular mechanisms. Using these methods as standardised approaches offers the prospect of understanding the genetic architecture of the cognitive repertoire and the identification of new targets for drug development. Rigorously defining homologous mechanisms using genetics and touchscreen tests may also improve drug trial design. Recommendations for mouse clinical trial protocols combined with human genetics are proposed. PMID- 23796635 TI - Systematic review on daily vitamin B12 losses and bioavailability for deriving recommendations on vitamin B12 intake with the factorial approach. AB - AIMS: To systematically review the literature on daily losses and bioavailability of vitamin B12. These estimates could be used for deriving recommendations on vitamin B12 intake for adults and elderly. METHODS: We identified publications on daily vitamin B12 losses (July 2011) and publications on the bioavailability of vitamin B12 from foods or diets (June 2010) in MEDLINE, EMBASE and the Cochrane Library. RESULTS: A pooled analysis of five studies (52 subjects) showed that 0.13 +/- 0.03% of the total body store is lost per day. Absorption of vitamin B12 ranged from 4.5 (dose of 38 ug from consumption of liver) to 83% (dose of 3.0 ug from consumption of mutton meat). Data from eight studies including 83 subjects suggested that the amount of vitamin B12 absorbed from food (Ai) increased with increasing doses of vitamin B12 (Di) as described by the equation: ln(Ai) = 0.7694 * ln(Di) - 0.9614. CONCLUSION: Daily vitamin B12 losses in apparently healthy adults and elderly probably range from 1.4 to 5.1 ug. Vitamin B12 intakes needed to compensate for these losses seem to range from 3.8 to 20.7 ug. More evidence is needed on the relationships between biochemical markers of vitamin B12 status, vitamin B12 body store and long-term health outcomes to evaluate whether current recommendations on vitamin B12 intake (1.4-3 ug) need to be changed. PMID- 23796636 TI - Meiosis and its deviations in polyploid animals. AB - We review the different modes of meiosis and its deviations encountered in polyploid animals. Bisexual reproduction involving normal meiosis occurs in some allopolyploid frogs with variable degrees of polyploidy. Aberrant modes of bisexual reproduction include gynogenesis, where a sperm stimulates the egg to develop. The sperm may enter the egg but there is no fertilization and syngamy. In hybridogenesis, a genome is eliminated to produce haploid or diploid eggs or sperm. Ploidy can be elevated by fertilization with a haploid sperm in meiotic hybridogenesis, which elevates the ploidy of hybrid offspring such that they produce diploid gametes. Polyploids are then produced in the next generation. In kleptogenesis, females acquire full or partial genomes from their partners. In pre-equalizing hybrid meiosis, one genome is transmitted in the Mendelian fashion, while the other is transmitted clonally. Parthenogenetic animals have a very wide range of mechanisms for restoring or maintaining the mother's ploidy level, including gamete duplication, terminal fusion, central fusion, fusion of the first polar nucleus with the product of the first division, and premeiotic duplication followed by a normal meiosis. In apomictic parthenogenesis, meiosis is replaced by what is effectively mitotic cell division. The above modes have different evolutionary consequences, which are discussed. See also the sister article by Grandont et al. in this themed issue. PMID- 23796637 TI - Synthesis and biological activity of thiazolyl-acetic acid derivatives as possible antimicrobial agents. AB - 5a-h, a series of (5-substituted-2-methyl-1,3-thiazole-4-yl) acetic acids as heterocyclic acetic acid derivatives, was designed and synthesized from ethyl acetoacetate. The synthesized compounds were screened for their antimicrobial activities against bacterial and fungal strains, and their characteristics were investigated by assays under various temperature and pH conditions. Cytotoxicity was evaluated with the use of sheep erythrocytes and human neonate dermal fibroblasts. Similarly, agents such as lauric acid 6 and parabens 7a-b, which are used as preservative agents for commercial cosmetics and detergents, were assayed for comparison. Although the structure of 5a is simple, comprising a thiazole attached with an octyl group and acetic acid moiety, the compound showed stronger and broader antibacterial and antifungal activities among the 5 series against the tested microbes other than gram-negative bacteria. Interestingly, 5a overcame the weak antifungal activity of parabens 7a-b. Also, the cytotoxicity of 5a was less than that of parabens 7a-b, especially to human dermal fibroblasts. These results suggest that thiazolyl-acetic acid 5a is a potentially effective biocide, and that it could be used as a preservative agent in commercially sold cosmetics and detergents, facilitated by the hydrophilic and charge properties of its carboxylic acid moiety. PMID- 23796638 TI - Novel system to detect bacteria in real time in aquatic environments. AB - Bacteria tests are conducted for quality control in many different industries. However, the cultivation method takes a long period of time to obtain results and there are more than a few bacteria that are difficult to cultivate. We have focused on the autofluorescence substance in the bacteria to detect them, and developed a sensor to measure the bacteria in real-time, without any pretreatments or addition of any reagents. This system uses a 405nm laser focused on the sample flowing through the flow-cell in order to detect the fluorescent light from the bacteria as well as scattered light. Fluorescent light and scattered light are separated by a dichroic mirror, and the number of viable particles (bacteria) and that of non-viable particles are obtained. We tested this system using fluorescent polystyrene latex particles and several bacterial strains, and confirmed that it had good detection capability. We believe that this system will become a next-generation bacteria detection system and help the introduction of PAT (process analytical technology) to all areas where real time and on-site detection is needed. PMID- 23796633 TI - Cellular, molecular, and epigenetic mechanisms in non-associative conditioning: implications for pain and memory. AB - Sensitization is a form of non-associative conditioning in which amplification of behavioral responses can occur following presentation of an aversive or noxious stimulus. Understanding the cellular and molecular underpinnings of sensitization has been an overarching theme spanning the field of learning and memory as well as that of pain research. In this review we examine how sensitization, both in the context of learning as well as pain processing, shares evolutionarily conserved behavioral, cellular/synaptic, and epigenetic mechanisms across phyla. First, we characterize the behavioral phenomenon of sensitization both in invertebrates and vertebrates. Particular emphasis is placed on long-term sensitization (LTS) of withdrawal reflexes in Aplysia following aversive stimulation or injury, although additional invertebrate models are also covered. In the context of vertebrates, sensitization of mammalian hyperarousal in a model of post-traumatic stress disorder (PTSD), as well as mammalian models of inflammatory and neuropathic pain is characterized. Second, we investigate the cellular and synaptic mechanisms underlying these behaviors. We focus our discussion on serotonin-mediated long-term facilitation (LTF) and axotomy mediated long-term hyperexcitability (LTH) in reduced Aplysia systems, as well as mammalian spinal plasticity mechanisms of central sensitization. Third, we explore recent evidence implicating epigenetic mechanisms in learning- and pain related sensitization. This review illustrates the fundamental and functional overlay of the learning and memory field with the pain field which argues for homologous persistent plasticity mechanisms in response to sensitizing stimuli or injury across phyla. PMID- 23796639 TI - In vitro bactericidal activity of photo-irradiated oxydol products via hydroxyl radical generation. AB - The oxidative power of hydroxyl radicals has been applied to disinfection systems for the purpose of oral hygiene by utilizing blue light-induced photolysis of hydrogen peroxide (H2O2) in our laboratory. In the present study, the bactericidal potential of blue light-irradiated oxydol products via hydroxyl radical generation was compared with that of 3% (w/v) H2O2. Eleven commercially available oxydol products were used in the present study. Even though a few of the products that contained ethanol, a hydroxyl radical scavenger, as an additive showed slightly lower hydroxyl radical yield as compared with 3% (w/v) H2O2, the blue-light irradiation of each oxydol product for 3 min showed similar or superior bactericidal activity against Staphylococcus aureus to that of 3% (w/v) H2O2. The results strongly suggest that any of the oxydol products tested in the present study can be used as a source of hydroxyl radicals for the disinfection technique developed in our laboratory. PMID- 23796640 TI - Prediction of Salmonella Enteritidis growth in pasteurized and unpasteurized liquid egg products with a growth model. AB - Growth prediction of a four-strain cocktail of Salmonella Enteritidis in commercial products of pasteurized and unpasteurized liquid whole egg was studied with the new logistic model that we developed. The growth data of the pathogen in the liquid egg products at constant temperatures in our recent study (Sakha and Fujikawa, Biocont. Sci., 2012) were used for prediction. With estimated values of the parameters in the model, it successfully predicted the Salmonella growth in the liquid egg products at dynamic temperature conditions in the high and low ranges. The Baranyi model, which is well known worldwide, could predict Salmonella growth in the pasteurized product at the dynamic temperature conditions in the high range only. This study would be, in our knowledge, the first report on the prediction of Salmonella growth in both pasteurized and unpasteurized liquid egg products at dynamic temperature conditions with a mathematical model. PMID- 23796641 TI - Evaluation of a new chromogenic agar medium for Alicyclobacillus acidoterrestris. AB - Spoilage of fruit juices by a thermoacidophilic spore-forming bacterium, Alicyclobacillus acidoterrestris, is a big problem for fruit juice industries worldwide. We have developed a novel chromogenic selective agar medium (EAATSM) for the isolation and enumeration of A. acidoterrestris. A. acidoterrestris strains appeared as blue colonies on the EAATSM. Other Alicyclobacillus strains appeared as white colonies or were inhibited. A study comparing EAATSM and YSG agar was carried out using artificially contaminated samples of 50 fruit juice products. The correlation coefficient between EAATSM and YSG was 0.991. PMID- 23796642 TI - Potential use of Lactobacillus cell density in feces as a non-invasive bio indicator for evaluating environmental stress during mouse breeding. AB - From the viewpoint of the quality assurance of laboratory animals, it is important to guarantee that they have not accidentally been exposed to any stress during breeding. In this study, we investigated non-invasive indicators of the exposure of mice to stress. The stress of horizontal shaking and no-bedding was applied to mice and the intestinal bacterial flora in their feces was analyzed. The cell density of total lactic acid bacteria was influenced by the shaking stress but not affected by the no-bedding stress. In contrast, the cell density of Lactobacillus, a member of lactic acid bacteria, decreased significantly to 1/10 at 48 h under both types of stress. Therefore, the cell density of Lactobacillus in feces may be used as a non-invasive bio-indicator of the stress exposure of mice. PMID- 23796643 TI - Characteristics of an orange-pigmented bacterium isolated from a hot spring in Kagoshima, Japan. AB - In May 2012, strain HNN-6 (=JCM 18566) , a Gram-negative, non-spore-forming, motile and strictly aerobic rod, which produces a pale orange pigment, was isolated from a hot spring water sample obtained in Kagoshima, Japan, by a plating method using R2A medium at 30 degrees C for 7 d. The 16S rRNA gene sequences (1,437bp) of this strain (accession number: AB731137) had a close similarity (99.1%) to Hydrotalea sandarakina AF-51T (JF739858) . Growth occurred at 25-45 degrees C and pH 5.0-8.0, with optimal growth at 40 degrees C and pH 6.0 7.0. Growth did not occur in the presence of ?2% NaCl. The API 20NE identification system gave positive results for nitrate, aesculin, gelatin, 4 nitrophenyl-beta-D-galactopyranoside, D-glucose, D-mannose, maltose and oxidase (API code number 1472204) . The dominant cellular fatty acids of strain HNN-6 were iso-C15:0 (32.6%) , iso-C17:0 3-OH (24.2%) and iso-C16:0 (8.4%) . The guanine-plus-cytosine (G+C) content of DNA was 36.2 mol%. This article is the first report to describe the characteristics of an orange-pigmented bacterium isolated from a hot spring water sample in Japan. PMID- 23796644 TI - A novel chromogenic screening medium for isolation of enterohemorrhagic Escherichia coli. AB - EHEC-chrom, a novel chromogenic screening agar medium for enterohemorrhagic Escherichia coli (EHEC) , was developed. A total of 52 EHEC strains, which were studied for the inclusivity study, grew and formed blue-green colored colonies on EHEC-chrom. When 43 gram-negative bacteria other than EHEC were inoculated for the exclusivity study, 10 strains grew and formed colorless colonies. A total of 28 gram-positive bacteria failed to grow and 1 yeast strain grew as colorless colonies. EHEC-chrom was compared with CHROMagarTM STEC, XM-EHEC agar and CT MacConkey base agar with a specific sugar (CT-SorbitolMAC, CT-rhamnoseMAC and CT sorboseMAC) as commercially available selective agar using 100 food samples artificially contaminated with low levels (<10 logCFU/25g) of EHEC. Numbers of samples from which EHEC was recovered by using EHEC-chrom, CHROMagarTM STEC, XM EHEC agar and CT-MacConkey base agar with specific sugar were 62, 58, 59 and 60, respectively. Our results suggested EHEC-chrom was a useful alternative for EHEC screening in food. PMID- 23796645 TI - Staging laparoscopy for the management of early-stage ovarian cancer: a metaanalysis. PMID- 23796646 TI - Discussion: 'Adherence to hormonal contraception among women veterans,' by Borrero et al. AB - In the roundtable that follows, clinicians discuss a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. Article discussed: Borrero S, Zhao X, Mor MK, et al. Adherence to hormonal contraception among women veterans: differences by race/ethnicity and contraceptive supply. Am J Obstet Gynecol 2013;209:103.e1-11. PMID- 23796647 TI - Ectopic pregnancy rates in a non-Medicaid population are lower than previously reported. PMID- 23796648 TI - Reply: To PMID 23583213. PMID- 23796651 TI - Optimization of intravenous immunoglobulin in chronic inflammatory demyelinating polyneuropathy evaluated by grip strength measurement. AB - BACKGROUND: Optimal dose and timing of repeated intravenous immunoglobulin therapy (IVIg) for intractable chronic inflammatory demyelinating polyneuropathy (CIDP) patients have not been determined. The aim of this study was to optimize dose and timing of IVIg for CIDP patients who need frequent IVIg using daily grip strength measurement. METHODS: Repeated IVIg were administered for two intractable CIDP patients. Grip strength was recorded at home every day to access the clinical change in symptoms, and dose and timing of IVIg were optimized based on the results. RESULTS: The decrement on grip strength was a sensitive indicator of symptom exacerbation. 100 g of IVIg had a limited effect for each patient. In one patient, symptoms maintained after monthly 60 g of IVIg. In another, 100 g of IVIg every 7 weeks resulted in a marked improvement. After receiving 20 g of IVIg weekly, each patient showed further improvement. CONCLUSION: Optimal dose and timing possibly vary in each individual patient. Dose titration of IVIg is necessary to avoid over- and undertreatment. The daily self-monitoring of grip strength is a helpful tool for clinical assessment in CIDP. PMID- 23796650 TI - Sexual orientation differences in teen pregnancy and hormonal contraceptive use: an examination across 2 generations. AB - OBJECTIVE: To examine whether sexual orientation is associated with disparities in teen pregnancy and hormonal contraception use among adolescent females in 2 intergenerational cohorts. STUDY DESIGN: Data were collected from 91,003 women in the Nurses' Health Study II (NHSII), born between 1947-1964, and 6463 of their children, born between 1982-1987, enrolled in the Growing Up Today Study (GUTS). Log-binomial models were used to estimate risk ratios for teen pregnancy and hormonal contraception use in sexual minorities compared with heterosexuals and metaanalysis techniques were used to compare the 2 cohorts. RESULTS: Overall, teen hormonal contraception use was lower and teen pregnancy was higher in NHSII than GUTS. In both cohorts, lesbians were less likely, whereas the other sexual minorities were more likely, to use hormonal contraception as teenagers compared with their heterosexual peers. All sexual minority groups in both cohorts, except NHSII lesbians, were at significantly increased risk for teen pregnancy, with risk ratios ranging from 1.61 (95% confidence interval, 0.40-6.55) to 5.82 (95% confidence interval, 2.89-11.73). Having an NHSII mother who was pregnant as a teen was not associated with teen pregnancy in GUTS participants. Finally, significant heterogeneity was found between the 2 cohorts. CONCLUSION: Adolescent sexual minorities have been, and continue to be, at increased risk for pregnancy. Public health and clinical efforts are needed to address teen pregnancy in this population. PMID- 23796652 TI - Intraoperative hyperthermic intraperitoneal chemotherapy as adjuvant chemotherapy for advanced gastric cancer patients with serosal invasion. AB - BACKGROUND: To evaluate hyperthermic intraperitoneal chemotherapy (HIPEC) as an adjuvant chemotherapy in advanced gastric cancer (AGC) patients with serosal invasion. METHODS: Patients who received radical surgery and palliative surgery between January 2002 and December 2010 were retrospectively examined. Patients were divided into two groups, namely, one group that underwent surgery and another group that underwent surgery with HIPEC. All patients who received HIPEC had suspected serosal invasion on an abdominal computed tomography or by the surgeon's assessment during the operation. RESULTS: The prophylactic groups included 83 patients who underwent gastrectomy alone. A total of 29 patients underwent gastrectomy with HIPEC. The 5-year survival rates were 10.7% and 43.9%, respectively. The 5-year mean survival times were 22.66 (17.55-25.78) and 34.81 (24.97-44.66) months (p = 0.029), respectively. There were 52 patients who had a recurrence of carcinomatosis among 133 patients who had resections (52/133, 39.1%). The 3-year disease-free survival rate for carcinomatosis was 28.87% in the group that received surgery alone, whereas it was 66.03% in the group that received HIPEC. There was no significant difference in the rate of complication between the two groups in the prophylactic group (p = 0.542). Thus, curative surgery with HIPEC had a better prognosis for AGC with serosal invasion. The carcinomatosis recurrence time was longer in patients who underwent gastrectomy with HIPEC and received R0 resection. CONCLUSION: The survival benefit of HIPEC as an adjuvant therapy for gastric cancer patients with serosal invasion should be validated in a large cohort. PMID- 23796653 TI - [Situational leadership in nursing in a health institution in Bucaramanga, Colombia]. AB - INTRODUCTION: In nursing, it is crucial to know the leadership style required in each situation to act as a leader. The clinical nurse must have an effective leadership style that suits the situations presented during the performance of their functions, in order to achieve the objectives in the care of the patient and family. OBJECTIVES: To describe the situational leadership styles present in nurses in hospital departments, including intensive care, according to the theory of Hersey and Blanchard and to determine the relationship between leadership styles and occupational variables. METHODOLOGY: A cross-sectional descriptive study was conducted on a sample population of 107nurses working in clinical areas of hospital and intensive care in two health institutions. The Dr. Herman Bachenheimer situational leadership tool was applied to nursing staff. RESULTS: The nurses at the hospital area (61) and intensive care (46) have mainly a guide leadership style (35.4%), followed by a participative style (33.9%) and manager style (27.9%). Delegation leadership style (2.8%) was not present in clinical nurses. There is no significant relationship between leadership styles and the time working in the institution. A statistically significant relationship was found between leadership styles and length of management experience in the clinical area (P=.011). CONCLUSIONS: The predominant leadership style of hospital nurses is to guide, and for intensive care nurses it is participatory. PMID- 23796654 TI - Propidium monoazide combined with real-time quantitative PCR to quantify viable Alternaria spp. contamination in tomato products. AB - Alternaria is a common contaminating genus of fungi in fruits, grains, and vegetables that causes severe economic losses to farmers and the food industry. Furthermore, it is claimed that Alternaria spp. are able to produce phytotoxic metabolites, and mycotoxins that are unsafe for human and animal health. DNA amplification techniques are being increasingly applied to detect, identify, and quantify mycotoxigenic fungi in foodstuffs, but the inability of these methods to distinguish between viable and nonviable cells might lead to an overestimation of mycotoxin-producing living cells. A promising technique to overcome this problem is the pre-treatment of samples with nucleic acid intercalating dyes, such as propidium monoazide (PMA), prior to quantitative PCR (qPCR). PMA selectively penetrates cells with a damaged membrane inhibiting DNA amplification during qPCRs. In our study, a primer pair (Alt4-Alt5) to specifically amplify and quantify Alternaria spp. by qPCR was designed. Quantification data of qPCR achieved a detection limit of 10(2)conidia/g of tomato. Here, we have optimized for the first time a DNA amplification-based PMA sample pre-treatment protocol for detecting viable Alternaria spp. cells. Artificially inoculated tomato samples treated with 65MUM of PMA, showed a reduction in the signal by almost 7cycles in qPCR between live and heat-killed Alternaria spp. conidia. The tomato matrix had a protective effect on the cells against PMA toxicity, reducing the efficiency to distinguish between viable and nonviable cells. The results reported here indicate that the PMA-qPCR method is a suitable tool for quantifying viable Alternaria cells, which could be useful for estimating potential risks of mycotoxin contamination. PMID- 23796655 TI - Development of a time-to-detect growth model for heat-treated Bacillus cereus spores. AB - The microbiological safety and quality of Refrigerated Processed Foods of Extended Durability (REPFEDs) relies on a combination of mild heat treatment and refrigeration, sometimes in combination with other inhibitory agents that are ineffective when used alone. In this context, a predictive model describing the time-to-detect growth (measured by turbidimetry) of psychrotrophic Bacillus cereus spores submitted to various combinations of pH, water activity (aw), heat treatment and storage temperature was developed. As the inoculum was high, the time-to-detect growth was the sum of two times: for a large part of the spore lag time (time before germination and outgrowth) and to a lesser extent of the time to have subsequent vegetative cells growing up to a detectable level. A dataset of 434 combinations (of pH, aw, heat treatment, storage temperature and B. cereus strain), originally collected at Ghent University to build a growth/no-growth model for two Bacillus cereus strains, was re-interpreted as time-to-detect growth values. In the growth area (223 combinations) the time-to-detect growth was set as the longest time where none, or only one, of the 8 replicated wells showed growth. In the no-growth area (211 combinations) the time-to-detect growth was set as longer than the time where the experiment was stopped (60days or more) and analysed as a censored response. The factors of variation were heat-treatment intensity (85 degrees C, 87 degrees C and 90 degrees C in a time range of 1 to 38min), storage temperature (8-30 degrees C), pH (5.2-6.4) and aw (0.973-0.995). Two different strains were analysed. The model had a Gamma multiplicative structure; it was solved by Bayesian inference with informative prior distributions. To be implemented in a decision tool, for instance to calculate the process and formulation conditions required to achieve a given detection time, each Gamma term had some constraints: they had to be monotonous, continuous and algebraically simple mathematical functions (i.e. having analytical solution). Overall, the cumulative effect of various stressful conditions (pasteurisation process, low temperature, and low pH) enables to extend the time to-detect growth up to 60days or more, whereas the heat-treatment on its own did not have a similar effect. For example, with the most heat resistant strain (strain 1, FF140), for a product at aw0.99, stored at 10 degrees C, heat-treated at 90 degrees C for 10min, a time-to-detect growth of 2days was expected when the pH equalled 6.5. Under the same conditions, if the pH was reduced to 5.8, the time-to-detect growth was predicted to be 11days (and 33days at pH5.5). After a pasteurisation at 90 degrees C for 10min, for a product kept at 10 degrees C, combinations of pH and aw such as pH6.0-aw0.97, pH5.7-aw0.98 or pH5.5-aw0.99 were predicted to extend the time-to-detect growth up to 30days. The developed model is a useful tool for REPFED producers to guarantee the safety of their products towards psychrotrophic B. cereus. PMID- 23796656 TI - Primary aldosteronism: emerging trends. AB - Primary aldosteronism (PA) is the most common etiology of endocrine hypertension (HTN), and recent prevalence studies suggest that it may be under-diagnosed. Indications for screening have been expanded with recognition that many patients with PA do not have hypokalemia and that the disease may be familial. The aldosterone:renin ratio (ARR) is the preferred screening test for PA. The ARR can be interpreted in patients on most anti-hypertensive agents, and can be used to guide medical therapy of HTN even in patients without PA. Once PA is confirmed, adrenal venous sampling (AVS) should be performed to determine if PA is due to bilateral disease or a unilateral adenoma, if surgery is being considered. Targeted medical or surgical therapy improves patient outcomes. PMID- 23796658 TI - Commentary on article "Effectiveness of cast immobilization in comparison to the gold-standard self-removal orthotic intervention for closed mallet fingers: a randomized clinical trial" (Tocco et al., 2013). PMID- 23796659 TI - Myosin heavy chain-2b transcripts and isoform are expressed in human laryngeal muscles. AB - Three fast myosin heavy chain (MyHC) isoforms, i.e. MyHC-2a, -2x and -2b, are expressed in skeletal muscles of smaller mammals. In contrast, only MyHC-2a and 2x have been revealed in humans so far. The expression of MyHC isoforms is known to be wider in the functionally more specialized laryngeal muscles. Though mRNA transcripts of the MyHC-2b gene were found to be expressed in certain human skeletal and laryngeal muscles, the corresponding isoform has not been demonstrated in these muscles. To our knowledge, we are the first to demonstrate not only the expression of MyHC-2b transcripts using an in situ hybridization technique but also the corresponding protein, i.e. the MyHC-2b isoform, in some human laryngeal muscles by immunohistochemistry but not by polyacrylamide gel electrophoresis. Using a set of antibodies specific to MyHC isoforms, we demonstrated that MyHC-2b was always co-expressed with the major MyHC isoforms, not only with the fast ones (MyHC-2a and -2x) but with the slow isoform (MyHC-1) as well. PMID- 23796660 TI - Abeta increases neural stem cell activity in senescence-accelerated SAMP8 mice. AB - Neurogenesis persists in the adult brain as a form of plasticity due to the existence of neural stem cells (NSCs). Alterations in neurogenesis have been found in transgenic Alzheimer's disease (AD) mouse models, but NSC activity and neurogenesis in sporadic AD models remains to be examined. We herein describe a remarkable increase in NSC proliferation in the forebrain of SAMP8, a non transgenic mouse strain that recapitulates the transition from healthy aging to AD. The increase in proliferation is transient, precedes AD-like symptoms such as amyloid beta 1-42 [Abeta(1-42)] increase or gliosis, and is followed by a steep decline at later stages. Interestingly, in vitro studies indicate that secreted Abeta(1-42) and PI3K signaling may account for the early boost in NSC proliferation. Our results highlight the role of soluble Abeta(1-42) peptide and PI3K in the autocrine regulation of NSCs, and further suggest that over proliferation of NSCs before the appearance of AD pathology may underlie neurogenic failure during the age-related progression of the disease. These findings have implications for therapeutic approaches based on neurogenesis in AD. PMID- 23796661 TI - Age-dependent alterations in the number, volume, and localization of islands of Calleja within the olfactory tubercle. AB - The incidence of olfactory perceptual dysfunction increases substantially with aging. Putative mechanisms for olfactory sensory loss are surfacing, including neuroanatomical modifications within brain regions responsible for odor information processing. The islands of Calleja (IC) are dense cell clusters localized within the olfactory tubercle, a cortical structure receiving monosynaptic input from the olfactory bulb. The IC are hypothesized to be important for intra- and extra-olfactory tubercle information processing, and thus olfaction. However, whether the anatomy of the IC are affected throughout normal aging remains unclear. By examining the IC of C57bl/6 mice throughout adulthood and early aging (4-18 months of age), we found that the number of IC decreases significantly with aging. Stereological analysis revealed that the remaining IC in 18-month-old mice were significantly reduced in estimated volume compared with those in 4- month-old mice. We additionally found that whereas young adults (4 months of age) possess greater numbers of IC within the posterior parts of the olfactory tubercle, by 18 months of age, a greater percentage of IC are found within the anterior-most part of the olfactory tubercle, perhaps providing a substrate for the differential access of the IC to odor information throughout aging. These results show that the IC are highly plastic components of the olfactory cortex, changing in volume, localization, and even number throughout normal aging. We predict that modifications among the IC throughout aging and age-related neurodegenerative disorders might be a novel contributor to pathological changes in olfactory cortex function and olfactory perception. PMID- 23796663 TI - Fuel burnup calculation of Ghana MNSR using ORIGEN2 and REBUS3 codes. AB - Ghana Research Reactor-1 core is to be converted from HEU fuel to LEU fuel in the near future and managing the spent nuclear fuel is very important. A fuel depletion analysis of the GHARR-1 core was performed using ORIGEN2 and REBUS3 codes to estimate the isotopic inventory at end-of-cycle in order to help in the design of an appropriate spent fuel cask. The results obtained for both codes were consistent for U-235 burnup weight percent and Pu-239 build up as a result of burnup. PMID- 23796664 TI - Vitamin D levels in children born to vitamin D-deficient mothers. AB - AIM: To determine whether a standard daily dose of 400 IU vitamin D is sufficient to normalize vitamin D levels in infants born to vitamin D-deficient mothers. METHODS: The children were recruited from a study cohort of 68 immigrant and 51 non-immigrant pregnant women living in Stockholm. The women were monitored at 12 weeks of pregnancy, at delivery and together with their children, 6-18 months after birth. During pregnancy, most immigrant women (78%) had 25(OH)D3 levels <25 nmol/l. We here report the outcome of 25 infants born to these mothers. All infants received a daily supplementation dose of 400 IU vitamin D from 2 weeks of age. RESULTS: At birth, most children in the immigrant group were vitamin D deficient (23.3 nmol/l (12-54); mean and range) while at 6-18 months of age vitamin D levels were essentially normalized (82.8 nmol/l (38-142)) although 4 children still had subnormal levels consistent with vitamin D insufficiency. CONCLUSION: A daily recommended supplementation dose of 400 IU vitamin D is sufficient in most children of vitamin D-deficient immigrant women living in Sweden. PMID- 23796662 TI - Amyloid beta immunization worsens iron deposits in the choroid plexus and cerebral microbleeds. AB - Anti-amyloid beta (Abeta) immunotherapy provides potential benefits in Alzheimer's disease patients. Nevertheless, strategies based on Abeta1-42 peptide induced encephalomyelitis and possible microhemorrhages. These outcomes were not expected from studies performed in rodents. It is critical to determine if other animal models better predict side effects of immunotherapies. Mouse lemur primates can develop amyloidosis with aging. Here we used old lemurs to study immunotherapy based on Abeta1-42 or Abeta-derivative (K6Abeta1-30). We followed anti-Abeta40 immunoglobulin G and M responses and Abeta levels in plasma. In vivo magnetic resonance imaging and histology were used to evaluate amyloidosis, neuroinflammation, vasogenic edema, microhemorrhages, and brain iron deposits. The animals responded mainly to the Abeta1-42 immunogen. This treatment induced immune response and increased Abeta levels in plasma and also microhemorrhages and iron deposits in the choroid plexus. A complementary study of untreated lemurs showed iron accumulation in the choroid plexus with normal aging. Worsening of iron accumulation is thus a potential side effect of Abeta immunization at prodromal stages of Alzheimer's disease, and should be monitored in clinical trials. PMID- 23796665 TI - Droplet breakup in subsurface oil releases--part 1: experimental study of droplet breakup and effectiveness of dispersant injection. AB - Size distribution of oil droplets formed in deep water oil and gas blowouts have strong impact on the fate of the oil in the environment. However, very limited data on droplet distributions from subsurface releases exist. The objective of this study has been to establish a laboratory facility to study droplet size versus release conditions (rates and nozzle diameters), oil properties and injection of dispersants (injection techniques and dispersant types). This paper presents this facility (6 m high, 3 m wide, containing 40 m(3) of sea water) and introductory data. Injection of dispersant lowers the interfacial tension between oil and water and cause a significant reduction in droplet size. Most of this data show a good fit to existing Weber scaling equations. Some interesting deviations due to dispersant treatment are further analyzed and used to develop modified algorithms for predicting droplet sizes in a second paper (Johansen et al., 2013). PMID- 23796666 TI - Trace element content of seagrasses in the Leschenault Estuary, Western Australia. AB - Estuarine environments are particularly vulnerable to human impacts. In this study, trace elements in Ruppia megacarpa, Halophila ovalis, sediment and porewater were analysed to assess the potential contamination of the Leschenault Estuary, Western Australia, from a primarily agricultural drain. Sediment concentrations of Cd, Cu, Mn, and Ni and were highest nearest the drain while Al, As, Cr, Fe and Zn and were highest further from the drain. H. ovalis showed greater accumulation of Fe, Al, and As than R. megacarpa. Concentrations of Fe, Al, As, and Ni were generally higher in below-ground plant parts than above, suggesting uptake of these trace elements via the sediment-route pathway. This study suggested that the drain was a source of Cu and Mn, with these elements entering the estuary through water inflows. As and Fe, were highest furthest from the drain suggesting input of trace elements from sources other than the drain under study. PMID- 23796667 TI - Toxic responses and antioxidative enzymes activity of Scenedesmus obliquus exposed to fenhexamid and atrazine, alone and in mixture. AB - Laboratory studies were conducted to determine the effects of different concentrations of fenhexamid and atrazine (25, 50 and 100 ug L(-1)) on growth and oxidative stress on Scenedesmus obliquus (microalgae) after exposure for 24, 48, and 96 h. In addition, residues of fenhexamid and atrazine were determined in the culture medium after 96 h; 52%, 44% and 43% of fenhexamid remained in the medium for the lowest, middle and highest concentrations, respectively. Atrazine concentration decreased significantly in the medium with time. The reduction was faster with the lowest concentration (-53%), than in the highest concentration ( 46%), while it was intermediate with 50 ug L(-1) (-47%). The antioxidative enzyme activities were used as biomarkers to evaluate the toxic effects of fenhexamid and atrazine on the microalgae. Enzymatic activities were measured in the presence of each compound alone after 24, 48 and 96 h and also in mixture after 24h exposure. The results showed that fenhexamid and atrazine induced antioxidative enzyme activities (GST, CAT and GR) at different concentrations. Catalase activities (CAT) in both pesticides treated-algae were significantly increased. Additionally, an increase in gulathione-S-transferase (GST) was observed in algae after 24, 48 and 96 h of exposure to both fenhexamid and atrazine. Antioxidative enzymes in fenhexamid and atrazine mixture treatment showed an antagonistic interaction after 24h of exposure in algae. PMID- 23796668 TI - Vermicomposting of toxic weed--Lantana camara biomass: chemical and microbial properties changes and assessment of toxicity of end product using seed bioassay. AB - This work illustrates the results of vermicomposting trials of noxious weed - Lantana camara (LL) leaf litter spiked with cow dung (CD) in different ratios (0%, 20%, 40%, 60% and 80%) using Eisenia fetida. A total of five treatments were established and changes in chemical and microbial properties of vermibeds have been observed for 60 days. In all treatments, a decrease in pH (19.5-30.7%), total organic carbon (TOC) (12-23%) and C:N ratio (25-35%), but increase in ash content (16-40%), total N(N(tot)) (11-32%), available phosphorous (P(avail)) (445 629%), exchangeable potassium (K(exch)) (63-156%) exchangeable calcium (Ca(exch)) (67-94%),and N-NO3(-) (164-499%) was recorded. Vermibeds with 40-60% LL (T2 and T3) showed better mineralization rate. The number of fungi, bacteria and actinomycetes showed 0.33-1.67-fold, 0.72-2.33-fold and 2.03-2.99-fold increase, respectively after vermicomposting process. The germination index (GI) was between 47% and 83% in all vermicomposts as indicated by seed bioassay test. Results thus suggested that Lantana may be a potential source for vermicompost production for sustainable agriculture. PMID- 23796669 TI - Evolution of fetal subependymal cysts throughout gestation. AB - Subependymal cysts are secondary to brain germinal matrix hemorrhage or infarction and are associated with fetal chromosomal and metabolic conditions, as well as infections. They are found in 1-3% of neonates in the first days of life and have been described in fetuses, although much less frequently. We report the prenatal diagnosis of a case of subependymal cysts first visualized at 12 weeks' gestation and its evolution throughout pregnancy and after birth. As far as we know, this is the first time that such a condition is described before 16 weeks' gestation as well as its longitudinal evolution. Knowledge that subependymal cysts can be seen as early as 12 weeks' gestation and their natural evolution is important to avoid equivocal diagnoses. The prognosis of isolated subependymal cysts remains uncertain. PMID- 23796670 TI - Synaptic plasticity alterations associated with memory impairment induced by deletion of CB2 cannabinoid receptors. AB - In this study, the role of CB2r on aversive memory consolidation was further evaluated. Mice lacking CB2r (CB2KO) and their corresponding littermates (WT) were exposed to the step-down inhibitory avoidance test (SDIA). MAP2, NF200 and synaptophysin (SYN)-immunoreactive fibers were studied in the hippocampus (HIP) of both genotypes. The number of synapses, postsynaptic density thickness and the relation between the synaptic length across the synaptic cleft and the distance between the synaptic ends were evaluated in the HIP (dentate gyrus (DG) and CA1 fields) by electron microscopy. Brain-derived neurotrophic factor (BDNF), glucocorticoid receptor (NR3C1) gene expressions and mTOR/p70S6K signaling cascade were evaluated in the HIP and prefrontal cortex (PFC). Finally, the effects of acute administration of CB2r-agonist JWH133 or CB2r-antagonist AM630 on memory consolidation were evaluated in WT mice by using the SDIA. The lack of CB2r impaired aversive memory consolidation, reduced MAP2, NF200 and SYN immunoreactive fibers and also reduced the number of synapses in DG of CB2KO mice. BDNF and NR3C1 gene expression were reduced in the HIP of CB2KO mice. An increase of p-p70S6K (T389 and S424) and p-AKT protein expression was observed in the HIP and PFC of CB2KO mice. Interestingly, administration of AM630 impaired aversive memory consolidation, whereas JWH133 enhanced it. Further functional and molecular assessments would have been helpful to further support our conclusions. These results revealed that CB2r are involved in memory consolidation, suggesting that this receptor could be a promising target for developing novel treatments for different cognitive impairment-related disorders. PMID- 23796671 TI - Efficacy of high-dose methylprednisolone in patients with Crimean-Congo haemorrhagic fever and severe thrombocytopenia. AB - Crimean-Congo haemorrhagic fever (CCHF) is an acute viral haemorrhagic disease that is now endemic in south eastern Iran. The most important factor associated with mortality is a platelet count of less than 50,000/mL. The purpose of this study is to compare treated cases with severe thrombocytopenia using ribavirin with high-dose methylprednisolone (HDMP) with patients receiving ribavirin without HDMP. A clinical trial was conducted for confirmed patients with CCHF and severe thrombocytopenia (platelet count less than 50,000/mL) admitted to Boo-Ali Hospital in Zahedan between January 2010 and October 2011. The intervention group was given oral ribavirin, supportive managements and HDMP and the controls were treated with ribavirin and supportive management. Following HDMP therapy in hospitalized patients with severe thrombocytopenia, the platelet count increased within 36 h and the leukocyte count within 48 h of the beginning of treatment. Fewer in the intervention group required a transfusion of blood products than in the controls (P < 0.001). No one in the intervention group died. It seems that high-dose methylprednisolone is effective in the treatment of patients with CCHF. The increased platelet count and reduction of blood product requirement for severe CCHF patients after receiving HDMP are promising results. Further investigation is necessary in order to determine the efficacy of corticosteroid and its effect on outcome. PMID- 23796672 TI - The diagnosis of uterine cervical polyps in a low resource setting: the positive predictive value of clinical judgment--a series of 192 cases at the Yaounde Gynaeco-Obstetric and Paediatric Hospital, Cameroon. AB - As far as we know, the accuracy of clinical judgment in diagnosing uterine cervical polyps has not been assessed in sub-Saharan Africa. Our objective was to discover the positive predictive value (PPV) of clinical judgment in the diagnosis of cervical polyps. This is a retrospective descriptive study of 192 patients, carried out by the Departments of Pathology and Gynaecology of the Yaounde Gynaeco-Obstetric and Paediatric Hospital, Cameroon. The diagnosis of cervical polyp was confirmed by histopathology examination in 169 patients, giving a PPV rate of 88.0%. The PPV of clinical judgment in the diagnosis of cervical polyps is acceptable in our setting but the frequency of premalignant and malignant lesions encountered is too high (10.4%), even in the presence of a confirmed cervical polyp (8.9%). Even in areas where there are limited resources, we recommend a systematic histopathology examination of any clinically suspected cervical polyp. PMID- 23796673 TI - Dengue hepatitis sans dysfunction: experience of a single tertiary referral centre in the north Indian state of Uttarakhand. AB - Hepatic involvement is uncommon in dengue viral infections and is traditionally thought to be associated with severe disease in terms of morbidity and mortality. This study was conducted in order to assess the liver function in patients with dengue virus infection and to analyse its effect upon patient outcome. Three hundred and twenty-seven consecutive patients with dengue virus were categorized into groups A, B, C and D on the basis of elevation of either of the hepatic transaminases (normal, <3, 3-10 and >10 times, respectively). Primary and secondary outcome measures related to morbidity and mortality were studied. Hepatitis was seen in ~3/4 patients; an increasing grade of liver involvement was significantly associated with fewer platelets (P < 0.001). Recovery of platelets, bleeding manifestations, renal dysfunction, platelet recovery and duration of hospitalization were similar in all groups. Among the patients with manifest bleeding, the platelet count did not differ significantly but the platelet recovery was significantly slower (P = 0.044) with increasing grade. Hepatic dysfunction is self-limited without any increase in morbidity and mortality. PMID- 23796674 TI - Multi-drug resistance tuberculosis (MDR-TB) in Kassala State, Eastern Sudan. AB - This study investigates the prevalence of drug resistance and mutations in rpoB gene among Mycobacterium tuberculosis isolates from Kassala State, Sudan. In a cross-sectional study during 2011, sputum specimens (n = 90) were examined microscopically and grown cultures were identified by analysing IS6110 insertion sequence. Antimicrobial sensitivity and mutations in the rpoB gene were determined. Of the 90 specimens found which were positive for acid-fast bacilli (AFB), 65 (72.2%) showed growth of mycobacteria. Sixty (66.7%) of these were M. tuberculosis, 5 (5.6%) were rapidly growing mycobacteria and 10 (11.1%) revealed no growth. Of the 60 M. tuberculosis, 31 (51.7%) were drug resistant, including 18 multidrug resistant TB (30%), and 15 (83.3%) demonstrated mutations in the rpoB gene. Isoniazid and rifampicin revealed the highest resistance rates (64.5%, 61.3%, respectively). In conclusion, drug resistance M. tuberculosis in Kassala State was high (30%) and was found to be mainly (83.3%) due to mutations in the rpoB gene. PMID- 23796675 TI - Sonographic response in the liver and urinary bladder of children 14 months after treatment for schistosomiasis. AB - After praziquantel treatment for schistosomiasis, parasitological cure rates of 60%-90% are usual. Does this response to treatment correlate with the improvement in liver and bladder changes seen on ultrasound in children? This study shows that ultrasound is an effective way to evaluate liver and bladder changes caused by schistosomiasis infection in children and to assess treatment effects after mass treatment programmes. PMID- 23796676 TI - Primary small bowel volvulus in adults can be fatal: a report of two cases and brief review of the subject. AB - Primary small bowel volvulus is a relatively rare cause of small bowel obstruction but can be fatal. The chief problem is in differentiating it from other causes of obstruction that can be treated conservatively. We report two cases of primary small bowel volvulus in a regional hospital in the south west region of Cameroon within a 2 month period and briefly review the literature. PMID- 23796677 TI - Single and multiple liver abscesses in adults in Delhi are amoebic in origin: a clinical and microbiological study. AB - Single and multiple liver abscesses in Delhi are predominantly amoebic and must be distinguished from pyogenic abscesses which frequently require drainage. Mixed abscesses are larger, harbouring Gram negative rods. Multiple abscesses are not always pyogenic and presence of bacteria does not imply a primary pyogenic source. PMID- 23796678 TI - Fulminant amoebic colitis: a rare fierce presentation of a common pathology. AB - We conducted a retrospective study of patients with fulminant amoebic colitis (FAC) over a 20 year period in an urban tertiary care hospital in Pakistan. After consideration for inclusion and exclusion criteria 25 cases were identified as FAC with the most common presentations being abdominal pain (84%). Nineteen (76%) underwent laparotomy for peritonitis with evidence of: colonic perforation in 10 (40%); faecal peritonitis in eight (32%); bowel gangrene in one (4%); and intra abdominal abscess in two (8%). Nine (36%) deaths were recorded in the series - eight (53%) in the operated group and one (16.6%) in the medically-treated group. The optimal outcome can be achieved in FAC with aggressive resuscitation, intravenous broad-spectrum antibiotics, including metronidazole, and total colectomy without anastomosis in patients with peritonitis. PMID- 23796679 TI - Plasmodium vivax malaria presenting as acute respiratory distress syndrome: a case report. AB - Severe pulmonary involvement in malaria has been frequently reported in cases of Plasmodium falciparum infection but rarely in vivax malaria. We look at a case of a 38-year-old man living in a malaria endemic area who presented with acute respiratory distress syndrome (ARDS) caused by P. vivax. DNA polymerase chain reaction (PCR) confirmed that it was not a mixed infection. After specific antimalarial therapy and intensive supportive care, the patient was discharged from the hospital. This case illustrates that P. vivax-induced ARDS is not uncommon and should be readily recognized by the treating physicians. A confirmatory test with PCR is required in order to exclude P. falciparum co infection. PMID- 23796680 TI - Post-malaria neurological syndrome: a rare manifestation of common disease. AB - Several systemic and neurological complications can occur with Plasmodium falciparum malaria, of which cerebral malaria is well known and is the most serious. Rarely, patients may suffer a neurological disorder that occurs after complete recovery from P. falciparum infection, an entity known as post-malaria neurological syndrome (PMNS). It is a rare and transient clinical syndrome in which patients with symptomatic malaria infection, after parasitic clearance from the peripheral blood, develop neurological symptoms within 2 months of recovery. We report a case of PMNS manifesting as bilateral common peroneal nerve palsy leading to foot drop. PMID- 23796681 TI - Atypical small bowel obstruction following repair of inguinal hernia: a case of intestinal stenosis of Garre. AB - We report an atypical case of small bowel obstruction 10 days after the repair of an inguinal hernia that had been recurrently reduced. A preoperative diagnosis of the rare intestinal stenosis of Garre is difficult, and was based on the clinical, operative and pathological findings. Forced reduction of a hernia is not recommended because of the risk of rendering its contents ischaemic with subsequent fibrotic stenosis, or reducing a strangulated bowel into the abdominal cavity with subsequent perforation and peritonitis. PMID- 23796682 TI - To Buruli or not to Buruli. PMID- 23796683 TI - Occupation-based strategy training for adults with traumatic brain injury: a pilot study. AB - OBJECTIVE: To evaluate, before undertaking a larger trial, feasibility of the study processes to determine the effectiveness of occupation-based strategy training for producing changes on trained real-world behaviors, and to determine whether far transfer of training effects to measures of real-world impact, including participation in everyday life, could be achieved. DESIGN: Partially randomized controlled trial with pre- and postintervention assessments done by assessors masked to the treatment arm. SETTING: Testing occurred at a research institute, interventions at participants' homes. PARTICIPANTS: People (N=13) with chronic traumatic brain injury (TBI), 7 in the experimental group (mean age, 42.6y; mean time post-TBI, 9.8y; 4 men) and 6 in the control arm (mean age, 40.5y; mean time post-TBI, 10.8y; 3 men), were assessed immediately before and after the intervention phase. INTERVENTION: Occupation-based strategy training, an adapted version of the Cognitive Orientation to daily Occupational Performance (CO-OP), was provided in two 1-hour sessions per week for 10 weeks. MAIN OUTCOME MEASURES: Canadian Occupational Performance Measure, Dysexecutive Questionnaire, Mayo-Portland Adaptability Inventory-4 Participation Index, and Assessment of Motor and Process Skills. RESULTS: The study processes (testing and intervention) were acceptable to all participants. Evidence of far transfer was found as the experimental group improved significantly more than the control group on performance and satisfaction with performance ratings on untrained goals (P<.05), and reported increased levels of participation (P<.01). CONCLUSIONS: Findings must be interpreted with caution since the sample is small and comparisons are made with a no-treatment control. Nevertheless, they suggest that the training is feasible and a larger trial warranted. PMID- 23796684 TI - The six-minute walk test cannot predict peak cardiopulmonary fitness in ambulatory adolescents and young adults with cerebral palsy. AB - OBJECTIVES: To determine whether the 6-minute walk test (6MWT) is predictive of peak oxygen consumption (Vo(2)peak) and whether the 6MWT is a clinically applicable alternative to cardiopulmonary exercise testing (CPET) in ambulatory adolescents and young adults with cerebral palsy (CP). DESIGN: Cross-sectional. SETTING: University hospital and rehabilitation centers. PARTICIPANTS: Adolescents and young adults with CP (N=41) classified in Gross Motor Function Classification System (GMFCS) level I or II. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The covered distance during 6 minutes was measured with a 6MWT. The Vo(2)peak was obtained with CPET on a cycle ergometer. RESULTS: Univariate linear regression analysis was used to study the relationship between the outcomes of both tests. A multiple linear regression analysis was performed to determine whether Vo(2)peak could be predicted by the 6MWT, sex, body mass, and GMFCS level. A significant relationship (P<.01) was found between the outcomes of the 6MWT and CPET, with an explained variance of 21%. The multiple linear regression analysis showed an explained variance of 58% and a standard error of estimate (SEE) corresponding to 18% of the mean Vo(2)peak. CONCLUSIONS: The 6MWT is poorly related to Vo(2)peak in ambulatory adolescents and young adults with CP. Because of a high SEE, the multiple regression model did not allow for prediction of Vo(2)peak from the 6MWT in ambulatory adolescents and young adults with CP. PMID- 23796685 TI - Muscle energy technique versus corticosteroid injection for management of chronic lateral epicondylitis: randomized controlled trial with 1-year follow-up. AB - OBJECTIVE: To determine the short- and long-term effectiveness of the muscle energy technique (MET) compared with corticosteroid injections (CSIs) for chronic lateral epicondylitis (LE). DESIGN: Randomized controlled trial with 1 year of follow-up. SETTING: Outpatient clinic of a university's department of physical medicine and rehabilitation. PARTICIPANTS: Patients with chronic LE (N=82; 45 women, 37 men). INTERVENTIONS: Eight sessions of MET, or a single CSI was applied. MAIN OUTCOME MEASURES: Grip strength, pain intensity, and functional status were assessed using the pain-free grip strength (PFGS), a visual analog scale (VAS), and the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire, respectively. Measurements were performed before beginning treatment and at 6, 26, and 52 weeks afterward. RESULTS: When the baseline PFGS, VAS, and DASH scores were compared with the scores at the 52-week follow-up, statistically significant improvements were observed in both groups over time. The patients who received a CSI showed significantly better effects at 6 weeks according to the PFGS and VAS scores, but declined thereafter. At the 26- and 52 week follow-ups, the patients who received the MET were statistically significantly better in terms of grip strength and pain scores. At 52 weeks, the mean PFGS score in the MET group was significantly higher (75.08+/-26.19 vs 62.24+/-21.83; P=.007) and the mean VAS score was significantly lower (3.28+/ 2.86 vs 4.95+/-2.36; P=.001) than those of the CSI group. Although improvements in the DASH scores were more pronounced in the MET group, the differences in DASH scores between the groups were not statistically significant. CONCLUSIONS: This study showed that while both MET and CSI improved measures of strength, pain, and function compared with baseline, subjects receiving MET had better scores at 52 weeks for PFGS and the VAS for pain. We conclude that MET appears to be an effective intervention in the treatment of LE. PMID- 23796686 TI - Motor recovery of the ipsilesional upper limb in subacute stroke. AB - OBJECTIVE: To investigate the time-related changes in motor performance of the ipsilesional upper limb in subacute poststroke patients by using clinical and kinematic assessments. DESIGN: Observational, longitudinal, prospective, monocentric study. SETTING: Physical medicine and rehabilitation department. PARTICIPANTS: Stroke patients (n=19; mean age, 62.9y) were included less than 30 days after a first unilateral ischemic/hemorrhagic stroke. The control group was composed of age-matched, healthy volunteers (n=9; mean age, 63.1y). INTERVENTIONS: Clinical and kinematic assessments were conducted once a week during 6 weeks and 3 months after inclusion. Clinical measures consisted of Fugl Meyer Assessment, Box and Block Test (BBT), Nine-Hole Peg Test (9HPT), and Barthel Index. We used a 3-dimensional motion recording system during a reach-to grasp task to analyze movement smoothness, movement time, and peak velocity of the hand. Healthy controls performed both clinical (BBT and 9HPT) and kinematic evaluation within a single session. MAIN OUTCOME MEASURES: BBT and 9HPT. RESULTS: Recovery of ipsilesional upper arm capacities increased over time and leveled off after a 6-week period of rehabilitation, corresponding to 9 weeks poststroke. At study discharge, patients demonstrated similar ipsilesional clinical scores to controls but exhibited less smooth reaching movements. We found no effect of the hemispheric side of the lesion on ipsilesional motor deficits. CONCLUSIONS: Our findings provide evidence that ipsilesional motor capacities remain impaired at least 3 months after stroke, even if clinical tests fail to detect the impairment. Focusing on this lasting ipsilesional impairment through a more detailed kinematic analysis could be of interest to understand the specific neural network underlying ipsilesional upper-limb impairment. PMID- 23796687 TI - Sensibility of the stump in adults with an acquired major upper extremity amputation. AB - OBJECTIVES: To compare the sensibility of the stump in adults with an acquired major upper extremity amputation with the sensibility of the unaffected side and with the corresponding body parts of healthy controls, as well as to relate the sensibility of the stump to daily functioning. DESIGN: A survey with matched controls. SETTING: A tertiary referral center. PARTICIPANTS: A referred sample of patients (n=30) with an acquired upper extremity amputation, at least 1 year after amputation, and control subjects (n=30) matched for age, sex, and hand dominance were evaluated. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Three different modalities of sensibility were measured: (1) touch-pressure sensibility, tested using Semmes-Weinstein monofilaments; (2) stereognosis, detected using the Shape and Texture Identification test; and (3) kinesthesia. Daily functioning was assessed using the Upper Extremity Functional Status Module of the Orthotics and Prosthetics Users' Survey. RESULTS: The mean time +/- SD since amputation was 20+/-17.8 years. Twenty patients used a prosthesis. The stump sensibility was similar to that of unaffected hands and tended to be less than that of unaffected arms (P=.08). The patients using a prosthesis had significantly poorer touch-pressure sensibility in the stump compared with the nonusers (P=.04). However, touch-pressure sensibility and stereognosis were worse in the patients than in controls (P<.001 and P=.03, respectively). Two patients were able to identify shapes using their stump. Kinesthesia of the shoulders and elbows did not differ between the affected and unaffected side. Moreover, daily functioning was not related to sensibility. CONCLUSIONS: The touch-pressure sensibility in the stumps of patients using prostheses was poorer than the sensibility in nonusers, and remarkably, the unaffected extremities of the amputees were less sensitive than the extremities of the controls. PMID- 23796688 TI - Screening and characterization of reactive compounds with in vitro peptide trapping and liquid chromatography/high-resolution accurate mass spectrometry. AB - The present study describes a novel methodology for the detection of reactive compounds using in vitro peptide-trapping and liquid chromatography-high resolution accurate mass spectrometry (LC-HRMS). Compounds that contain electrophilic groups can covalently bind to nucleophilic moieties in proteins and form adducts. Such adducts are thought to be associated with drug-mediated toxicity and therefore represent potential liabilities in drug discovery programs. In addition, reactive compounds identified in biological screening can be associated with data that can be misinterpreted if the reactive nature of the compound is not appreciated. In this work, to facilitate the triage of hits from high-throughput screening (HTS), a novel assay was developed to monitor the formation of covalent peptide adducts by compounds suspected to be chemically reactive. The assay consists of in vitro incubations of test compounds (under conditions of physiological pH) with synthetically prepared peptides presenting a variety of nucleophilic moieties such as cysteine, lysine, histidine, arginine, serine, and tyrosine. Reaction mixtures were analyzed using full-scan LC-HRMS, the data were interrogated using postacquisition data mining, and modified amino acids were identified by subsequent LC-HRMS/mass spectrometry. The study demonstrated that in vitro nucleophilic peptide trapping followed by LC-HRMS analysis is a useful approach for screening of intrinsically reactive compounds identified from HTS exercises, which are then removed from follow-up processes, thus obviating the generation of data from biochemical activity assays. PMID- 23796689 TI - A label-free LC/MS/MS-based enzymatic activity assay for the detection of genuine caspase inhibitors and SAR development. AB - The resurgence of interest in caspases (Csp) as therapeutic targets for the treatment of neurodegenerative diseases prompted us to examine the suitability of published nonpeptidic Csp-3 and Csp-6 inhibitors for our medicinal chemistry programs. To support this effort, fluorescence-based Csp-2, Csp-3, and Csp-6 enzymatic assays were optimized for robustness against apparent enzyme inhibition caused by redox-cycling or aggregating compounds. The data obtained under these improved conditions challenge the validity of previously published data on Csp-3 and Csp-6 inhibitors for all but one series, namely, the isatins. Furthermore, in this series, it was observed that the nature of the rhodamine-labeled substrate, typically used to measure caspase activity, interfered with the pharmacological sensitivity of the Csp-2 assay. As a result, a liquid chromatography/tandem mass spectrometry-based assay that eliminates label-dependent assay interference was developed for Csp-2 and Csp-3. In these label-free assays, the activity values of the Csp-2 and Csp-3 reference inhibitors were in agreement with those obtained with the fluorogenic substrates. However, isatin 10a was 50-fold less potent in the label-free Csp-2 assay compared with the rhodamine-based fluorescence format, thus proving the need for an orthogonal readout to validate inhibitors in this class of targets highly susceptible to artifactual inhibition. PMID- 23796690 TI - Melanoma. Shall we move away from the sun and focus more on embryogenesis, body weight and longevity? AB - There are many observations regarding the behaviour of melanoma which points away from sunshine as the main cause of this tumour. Incidence data shows that the increase is mostly seen for thin melanomas which cannot be attributed to sun exposure but increasing screening over the last 20 years. Melanoma behaves in a similar fashion all over the world regarding age of onset, gender differences and histological subtypes. An excess of naevi is the strongest risk factor for melanoma and their appearance and involution throughout life, and the differences in naevus distribution according to gender is giving us a lot of clues about melanoma biology. Melanoma like all cancers is a complex disease with the involvement of many common and low penetrance genes many of them involved in pigmentation and naevogenesis but these only explain a very small portion of melanoma susceptibility. Genes involved in melanocyte differentiation early on in embryogenesis are also becoming relevant for melanoma initiation and progression. Reduced senescence and longevity as well as body weight and energy expenditure are also relevant for melanoma susceptibility. These observations with links between melanoma and non-sun related phenotypes as well as gene discoveries should help to assess the relative contribution of genetic and environmental factors in its causation. PMID- 23796691 TI - Overview: cellular plasticity, cancer stem cells and metastasis. AB - Recently, a number of hypotheses have converged into a unified theoretical framework which addresses the most vexing aspects of cancer: metastasis, relapse and therapeutic resistance. The central component of this framework is the new paradigm of cellular differentiation, once viewed as a unidirectional process, but now recognized as a plastic process in which cancer cells can dedifferentiate into more primitive, stem-like phenotypes. This plasticity is controlled by both intrinsic biochemical processes and bi-directional environmental cues involving cancer-associated non-cancerous cells. Such plastic phenotypic shifts may influence the discontinuous behavior of cancers, in which some cancers remain dormant for months or years after therapy, only to relapse and wreak havoc. This Special Issue of Cancer Letters assembles a collection of mini-reviews describing the current knowledge of cellular plasticity and its relationship to cancer "stemness" and progression, illuminating how progress in this field may yield major benefits in overcoming resistance and thwarting metastasis. PMID- 23796692 TI - miR-146b-5p inhibits glioma migration and invasion by targeting MMP16. AB - miR-146b-5p is frequently down-regulated in solid tumours, including prostate cancer, pancreatic cancer, and glioblastoma. However, the tumour-suppressive effects of miR-146b-5p in malignant gliomas have not been investigated thoroughly. Here, we found that decreased miR-146b-5p expression was strongly correlated with chromosome 10q loss in gliomas, especially glioblastomas. The overexpression of miR-146b-5p in glioblastoma cell lines led to MMP16 mRNA silencing, MMP2 inactivation, and the inhibition of tumour cell migration and invasion. Our results suggest that the restoration of miR-146b-5p expression may be a feasible approach for inhibiting the migration and invasion of malignant gliomas. PMID- 23796693 TI - The efficacy of micronutrient-fortified sorghum meal in improving the immune status of HIV-positive adults. AB - BACKGROUND: Micronutrient deficiencies are common and compound the effects of human immunodeficiency virus (HIV) infection in Africa. Nutritional interventions, particularly vitamin A supplementation, may improve immune functioning and delay disease progression. AIM: To investigate the effect of fortified sorghum meal provided for 12 months on the immune status of adults with HIV. METHODS: HIV-infected men and women were enrolled in a double-blind randomized placebo-controlled trial in Kanye, Botswana, to receive either sorghum meal fortified with micronutrients including vitamin A (n = 67) or control (n = 65). Serum retinol, iron, zinc, albumin, CD4 cell count and HIV viral load were assessed at baseline and every 3 months. RESULTS: Baseline serum retinol levels were 1.6 umol/l in both groups and no significant difference was observed at the end of the intervention (control group: 1.5 umol/l; experimental group: 1.6 umol/l). In addition, there was no significant difference in the mean (Q1, Q3) CD4 cell count; 348 (220, 456) cells/mm(3) for the control group versus 338 (228, 426) cells/mm(3) in the experimental group after intervention. CONCLUSION: In this study, fortified sorghum meal did not influence serum retinol, CD4 cell count and HIV viral load. Future intervention studies should carefully consider the composition and dosing of food supplements needed to improve immune status and delay disease progression. PMID- 23796694 TI - Improving the spectral analysis of Fluorescence Resonance Energy Transfer in live cells: application to interferon receptors and Janus kinases. AB - The observed Fluorescence Resonance Energy Transfer (FRET) between fluorescently labeled proteins varies in cells. To understand how this variation affects our interpretation of how proteins interact in cells, we developed a protocol that mathematically separates donor-independent and donor-dependent excitations of acceptor, determines the electromagnetic interaction of donors and acceptors, and quantifies the efficiency of the interaction of donors and acceptors. By analyzing large populations of cells, we found that misbalanced or insufficient expression of acceptor or donor as well as their inefficient or reversible interaction influenced FRET efficiency in vivo. Use of red-shifted donors and acceptors gave spectra with less endogenous fluorescence but produced lower FRET efficiency, possibly caused by reduced quenching of red-shifted fluorophores in cells. Additionally, cryptic interactions between jellyfish FPs artefactually increased the apparent FRET efficiency. Our protocol can distinguish specific and nonspecific protein interactions even within highly constrained environments as plasma membranes. Overall, accurate FRET estimations in cells or within complex environments can be obtained by a combination of proper data analysis, study of sufficient numbers of cells, and use of properly empirically developed fluorescent proteins. PMID- 23796695 TI - TNF-alpha promoter methylation in peripheral white blood cells: relationship with circulating TNFalpha, truncal fat and n-6 PUFA intake in young women. AB - The aim of this article is to assess the potential relationships between TNFalpha gene promoter methylation in peripheral white blood cells and central adiposity (truncal fat), metabolic features and dietary fat intake. A group of 40 normal weight young women (21 +/- 3y; BMI 21.0 +/- 1.7 kg/m(2)) was included in this cross-sectional study. Anthropometric, biochemical and dietary data were assessed using validated procedures. DNA from white blood cells was isolated and 5 methylcytosine levels of the CpGs sites present in TNFalpha gene promoter (from 170 to +359 pb) were analyzed by Sequenom EpiTyper. Those women with high truncal fat (>=52.3%) showed lower 5-methylcytosine levels (P<0.05) in the site CpG13 (at position +207) and CpG19 (+317 pb) of the TNFalpha gene promoter when were compared to women with lower truncal adiposity. The methylation levels of CpG13 were also correlated with circulating TNFalpha levels, which were higher in those women with greater truncal adiposity. In a linear regression model, truncal fat, HDL-cholesterol, insulin, plasma TNFalpha, and daily n-6 PUFA intake explained the methylation levels of CpG13 site +207 by 48% and the average of CpG13 and CpG19 by 43% (P<0.001). In conclusion, women with higher truncal fat showed lower methylation levels of TNFalpha promoter in peripheral white blood cells and higher plasma TNFalpha concentrations. DNA methylation levels of TNFalpha promoter were associated with some metabolic features and with n-6 PUFA intake, suggesting a complex nutriepigenomic network in the regulation of this recognized pro-inflammatory marker. PMID- 23796696 TI - Spontaneous elevation of a ping-pong fracture: case report and review of the literature. AB - Depressed skull fractures compromise 7-10% of the children admitted to hospital with a head injury. Depressed skull fractures that occur in children younger than 1 year are different from those found in older children. In neonates and infants, a depressed fracture forms an inward buckling of the bones forming a 'cup shape', termed a 'ping-pong fracture'. In neonates, spontaneous elevation of a ping-pong fracture after birth trauma is well documented. However, in infants, spontaneous elevation of a ping-pong fracture following head injury is extremely rare. Here, we present the case of an 11-month-old child, in whom a ping-pong fracture was spontaneously elevated within 2 h. In addition, the relevant literature is reviewed and discussed. PMID- 23796697 TI - Occurrence and analysis of rare cfiA-bft doubly positive Bacteroides fragilis strains. AB - We detected four cfiA-bft1 doubly positive Bacteroides fragilis strains out of 486 B. fragilis isolates analyzed for antibiotic susceptibilities and antibiotic resistance genes from a recent pan-European survey. The prevalence of the enterotoxin bft genes was roughly equal among cfiA-negative and -positive B. fragilis strains. We also demonstrated that the cfiA-bft doubly positive strains had the most common B. fragilis genomic pattern (I.1.). Thus we concluded that the bft-carrying CTn86 conjugative transposons are mobile accounting for this unexpected simultaneous occurrence of the cfiA and bft genes. PMID- 23796698 TI - [The conflict between obturator nerve and ovary: a cadaveric and radioanatomic study]. AB - The aim of this study was to describe the anatomical relationships between the ovary and the obturator nerve in its intrapelvic portion. Seven embalmed cadavers were dissected; 20 MRIs were then analyzed. The main distance between the lateral pole of the ovary and the obturator nerve was 29 mm. The authors describe various etiologies responsible for obturator neuralgia. An underdiagnosed cause is gonadal hypertrophy. PMID- 23796699 TI - [Geometrical growth models of the fetal forebrain, cerebellum, brainstem and change of the cranial base angles during fetal period]. AB - INTRODUCTION: Brain growth plays likely an important role for the skull growth. In the fetus, there exists an heterochrony for the growth of supratentorial (forebrain) and infratentorial regions (brainstem and cerebellum). The aim of the study was thus to model geometrically the growth of these two regions and to compare it with the inflection of the base of skull. MATERIAL AND METHODS: Brain growth measurements were performed from midsagittal photographs of fetal brains obtained from an Anatomical Atlas over a period from 10 to 40 amenorrhea weeks (AW). After countouring and pointing anatomical and geometrical landmarks, we have developed a linear growth model based on principal component analysis (PCA). Besides, the variation of the sphenoidal and clivo-foraminal angles was studied from anatomical midsagittal slices of fetal heads sampled over a period from 16 to 39 AW. RESULTS: The PCA model brings to light the radial expansion of the forebrain growth (first component) associated with an inferior and posterior rotation of the occipital lobe. The growth of the infratentoriel region presents an inferior and posterior expansion associated with a second component corresponding to inferior and anterior expansions. From the 17 AW, appears an heterochrony between the supra- and infratentorial growths and an inversion of the ratio between the infra- and supratentorial dimensions after 30 AW. The sphenoidal and clivo-foraminal angles decrease slightly until 25 AW, and then increase quickly until the 39 AW. CONCLUSIONS: The growth of brain is accompanied by morphological change between the compartments supra- and infratentoriel but also on the level of the base of skull. The possible interactions will be discussed. PMID- 23796700 TI - [Usefulness of capsule endoscopy in the diagnosis of gastrointestinal involvement in Bean syndrome]. PMID- 23796701 TI - Neuromelanin magnetic resonance imaging in Parkinson's disease and multiple system atrophy. AB - Pigmented neurons in the substantia nigra pars compacta (SNc) and locus coeruleus (LC) show decreased numbers differentially in Parkinson's disease (PD) and multiple system atrophy (MSA). Recent reports have described that fast spin-echo T1-weighted magnetic resonance imaging (MRI) by a 3-tesla machine can visualize neuromelanin-related contrast of the noradrenergic and dopaminergic neurons respectively in the LC and the SNc. Using neuromelanin MRI at 3 T, we investigated possible alterations of these catecholaminergic neurons in 32 PD and 9 MSA patients, and compared the results with those of 23 normal volunteers. The contrast ratio of the LC and SNc was decreased in MSA and PD patients, most prominently in the LC in MSA patients. The contrast ratio of the SNc was correlated with the Hoehn-Yahr stage of PD and the severity of neuroradiological abnormalities in MSA. These results indicate a potential diagnostic value of neuromelanin MRI to distinguish MSA patients from normal and PD patients. PMID- 23796702 TI - A novel nonsense mutation in exon 1 of HSD17B3 gene in an Egyptian 46,XY adult female presenting with primary amenorrhea. AB - 17-beta-Hydroxysteroid dehydrogenase type 3 deficiency is a rare autosomal recessive cause of 46,XY disorder of sex development. Worldwide, about 30 mutations in the hydroxysteroid (17-beta) dehydrogenase 3 (HSD17B3) gene have been reported, involving all exons except exon 1. Herein, we investigated an Egyptian female with 46,XY karyotype and low testosterone/Delta4-androstenedione ratio. Genomic DNA was extracted from blood samples, and then, direct DNA sequencing of HSD17B3 gene was performed. The patient had a homozygous mutation c.198G>A in exon 1 resulting in a stop codon (p.W50X). The study presents the first mutation to be reported in exon 1 of the HSD17B3 gene. PMID- 23796703 TI - Mechanical problem-solving strategies in left-brain damaged patients and apraxia of tool use. AB - Left brain damage (LBD) can impair the ability to use familiar tools (apraxia of tool use) as well as novel tools to solve mechanical problems. Thus far, the emphasis has been placed on quantitative analyses of patients' performance. Nevertheless, the question still to be answered is, what are the strategies employed by those patients when confronted with tool use situations? To answer it, we asked 16 LBD patients and 43 healthy controls to solve mechanical problems by means of several potential tools. To specify the strategies, we recorded the time spent in performing four kinds of action (no manipulation, tool manipulation, box manipulation, and tool-box manipulation) as well as the number of relevant and irrelevant tools grasped. We compared LBD patients' performance with that of controls who encountered difficulties with the task (controls-) or not (controls+). Our results indicated that LBD patients grasped a higher number of irrelevant tools than controls+ and controls-. Concerning time allocation, controls+ and controls- spent significantly more time in performing tool-box manipulation than LBD patients. These results are inconsistent with the possibility that LBD patients could engage in trial-and-error strategies and, rather, suggest that they tend to be perplexed. These findings seem to indicate that the inability to reason about the objects' physical properties might prevent LBD patients from following any problem-solving strategy. PMID- 23796704 TI - Grasping without vision: time normalizing grip aperture profiles yields spurious grip scaling to target size. AB - The analysis of normalized movement trajectories is a popular and informative technique used in investigations of visuomotor control during goal-directed acts like reaching and grasping. This technique typically involves standardizing measures against the amplitude of some other variable - most typically time. Here, we show that this normalizing technique can lead to some surprising results. In the first of two experiments, we asked participants to grasp target objects without ever seeing them from trial to trial. In the second experiment, participants were given a brief preview of the target and were then cued 3s later to pick it up while vision was prevented. Critically, on some trials during the delay period and unbeknownst to the participants, the previewed target was swapped for a new unseen one. The results of both experiments show that time normalized measures of grip aperture during the closing phase of the movement appear to be scaled to target size well before the fingers make contact with the target - even though participants had no idea what the size of the target was that they were grasping. In contrast, a classical measure of anticipatory grip scaling, maximum grip aperture, did not show scaling to target size. As we demonstrate, however, in both experiments, movement time was longer for the larger target than the smaller ones. Thus, the comparisons of time-normalized grip aperture, particularly during the closing phase of the movements, were made across different points in real time. Taken together, the results of these experiments highlight a need for caution when investigators interpret differences in time-normalized dependent measures - particularly when the effect of interest is correlated with the dependent measure and a third variable (e.g., movement time) that is used to standardize the dependent measure. PMID- 23796705 TI - Action modulated cognition: the influence of sensori-motor experience on the global processing bias. AB - Whether we are aware of it or not, cognition is inherently biased. Researchers have attempted to modulate these biases using prism adaptation in both healthy and patient populations. Recent research suggests that prisms themselves might not be necessary; simply interacting with one side of space can produce similar effects (Dupierrix, Alleysson, Ohlmann and Chokron (2008). Brain Research, 1214, 127-135). Here we tested whether sensori-motor interaction with the environment affects aspects of cognition that should at first glance appear to be unrelated. While previous research involved tasks that were largely directional in nature (e.g., line bisection), we chose a task without a directional component, the hierarchical figures task (Navon, (1977). Cognitive Psychology, 9, 353-383). In a sample of healthy young adults, we found that after 5min of lateralized pointing (pointing solely to the left or right side of space), performance on the hierarchical figures task varied significantly as a function of pointing direction: interference from irrelevant global information increased after interacting with the left side of space and decreased after interacting with the right side of space. We discuss the results in relation to a "hemispheric imbalance" hypothesis. Our findings demonstrate that cognition can be readily influenced by interactions with the environment even without artificially distorting normal perceptuo-motor relationships. PMID- 23796706 TI - Serum markers in small cell lung cancer: opportunities for improvement. AB - Lung cancer is one of the leading causes of death from malignancy worldwide. In particular small cell lung cancers, which comprise about 15-20% of all lung cancers, are extremely aggressive and cure rates are extremely low. Therefore, new treatment modalities are needed and detection at an early stage of disease, as well as adequate monitoring of treatment response is essential in order to improve outcome. In this respect, the use of non-invasive tools for screening and monitoring has gained increasing interest and the clinical applicability of reliable, tumor-related substances that can be detected as tumor markers in easily accessible body fluids is subject of intense investigation. Some of these indicators, such as high LDH levels in serum as a reflection of the disease, have been in use for a long time as a general tumor marker. To allow for improved monitoring of the efficacy of new therapeutic modalities and for accurate subtyping, there is a strong need for specific and sensitive markers that are more directly related to the biology and behavior of small cell lung cancer. In this review the current status of these potential markers, like CEA, NSE, ProGRP, CK-BB, SCC, CgA, NCAM and several cytokeratins will be critically analyzed with respect to their performance in blood based assays. Based on known cleavage sites for cytoplasmic and extracellular proteases, a prediction of stable fragments can be obtained and used for optimal test design. Furthermore, insight into the synthesis of specific splice variants and neo-epitopes resulting from protein modification and cleavage, offers further opportunities for improvement of tumor assays. Finally, we discuss the possibility that detection of SCLC related autoantibodies in paraneoplastic disease can be used as a very early indicator of SCLC. PMID- 23796707 TI - Effects of a multidisciplinary childhood obesity treatment intervention on adipocytokines, inflammatory and growth mediators. AB - BACKGROUND/AIMS: To examine the effects of a 3-month multidisciplinary intervention on anthropometric measures, physical activity patterns and fitness, inflammatory cytokines, adipocytokines, and growth mediators in obese children. METHODS: 21 obese subjects completed the 3-month intervention and were compared with 20 age-, gender- and maturity-matched controls. Subjects underwent anthropometric measurements (weight, height, BMI percentile and waist circumference), blood tests (IL-6, CRP, leptin, adiponectin, insulin, IGF-I and glucose), a progressive treadmill exercise test to evaluate fitness, and habitual activity assessment before and after the intervention. RESULTS: The intervention led to a significant change of differences in body weight (-1.3 +/- 4.1 vs. 2.5 +/- 3.3 kg), BMI percentile (-0.96 +/- 1.29 vs. 0.19 +/- 0.8), waist circumference (-2.1 +/- 2.7 vs. 2.9 +/- 3.0 cm) and running time (149.9 +/- 86.3 vs. -8.2 +/- 88.0 s) in the intervention compared to control. There was a significant increase in leisure-time physical activity (Godin questionnaire, 29.04 +/- 6.8 vs. -1.3 +/- 9.2) and a decrease in sedentary activity (-1.4 +/- 0.73 vs. 0.02 +/- 0.62 h/day) in the intervention compared to control. Significant change differences in adiponectin (2,308 +/- 1,640 vs. -801 +/- 465 ng/ml), IGF-I (33.8 +/- 37.8 vs. -1.0 +/- 36.2 ng/ml), CRP (-0.06 +/- 0.29 vs. 0.5 +/- 0.86 mg/dl) and HOMA-IR (-0.15 +/- 0.57 vs. 0.55 +/- 0.84) were found in the intervention group compared to control. CONCLUSIONS: Our results highlight the short-term beneficial effects of a childhood obesity multidisciplinary intervention on anthropometrics, habitual activity, fitness, inflammatory and metabolic measures. The longer-term effects of these changes on obesity associated metabolic risks are yet to be determined. PMID- 23796708 TI - MT1-MMP regulates MMP-2 expression and angiogenesis-related functions in human umbilical vein endothelial cells. AB - Membrane type 1 (MT1)-MMP is a member of matrix metalloproteinases (MMPs) that regulates extracellular matrix remodeling. In addition, MT1-MMP also serves as a multi-functional protein. However, the functional role of MT1-MMP in human endothelial cells remains unclear. In this study we use real-time PCR and Western blotting to demonstrate for the first time that MMP-2 expression is regulated by MT1-MMP in human endothelial cells. Moreover, MMP-2 activity is also modulated by MT1-MMP. In addition we found that endothelial cells, ECM adhesion and human endothelial cell tube formation, which are known to be regulated by MMP-2, are blocked by MT1-MMP siRNA. These results suggest that MT1-MMP plays an important role in regulating angiogenesis in human endothelial cells. PMID- 23796709 TI - Piperlongumine selectively kills glioblastoma multiforme cells via reactive oxygen species accumulation dependent JNK and p38 activation. AB - Piperlongumine (PL), a natural alkaloid isolated from the long pepper, may have anti-cancer properties. It selectively targets and kills cancer cells but leaves normal cells intact. Here, we reported that PL selectively killed glioblastoma multiforme (GBM) cells via accumulating reactive oxygen species (ROS) to activate JNK and p38. PL at 20MUM could induce severe cell death in three GBM cell lines (LN229, U87 and 8MG) but not astrocytes in cultures. PL elevated ROS prominently and reduced glutathione levels in LN229 and U87 cells. Antioxidant N-acetyl-L cysteine (NAC) completely reversed PL-induced ROS accumulation and prevented cell death in LN229 and U87 cells. In LN229 and U87 cells, PL-treatment activated JNK and p38 but not Erk and Akt, in a dosage-dependent manner. These activations could be blocked by NAC pre-treatment. JNK and p38 specific inhibitors, SB203580 and SP600125 respectively, significantly blocked the cytotoxic effects of PL in LN229 and U87 cells. Our data first suggests that PL may have therapeutic potential for one of the most malignant and refractory tumors GBM. PMID- 23796710 TI - Isolation and characterization of human breast cancer cells with SOX2 promoter activity. AB - Sex determining region Y-box 2 (SOX2) is well known as one of the "stemness" factors and is often expressed in cancers including breast cancer. In this study, we developed a reporter system using fluorescent protein driven by the promoter for SOX2 gene to detect and isolate living SOX2-positive cells. Using this system, we determined that SOX2 promoter activities were well correlated with SOX2 mRNA expression levels in 5 breast cancer cell lines, and that the cell population with positive SOX2 promoter activity (pSp-T(+)) isolated from one of the 5 cell lines, MCF-7 cells, showed a high SOX2 protein expression and high sphere-forming activity compared with very low promoter activity (pSp-T(low/-)). The pSp-T(+) population expressed higher mRNA levels of several stemness-related genes such as CD44, ABCB1, NANOG and TWIST1 than the pSp-T(low/-) population whereas the two populations expressed CD24 at similar levels. These results suggest that the cell population with SOX2 promoter activity contains cancer stem cell (CSC)-like cells which show different expression profiles from those of CSC marker genes previously recognized in human breast cancers. PMID- 23796711 TI - CHD4/NuRD maintains demethylation state of rDNA promoters through inhibiting the expression of the rDNA methyltransferase recruiter TIP5. AB - Despite the well-established fact that NuRD (nucleosome remodeling and histone deacetylase) is incapable of actively demethylating DNA, the complex is surprisingly showed to be required for the establishment of unmethylated state at promoters of ribosomal genes. But the molecular mechanism underlying how NuRD mediates unmethylation at rDNA promoters remains obscure. Here we show that NuRD directly binds to the promoter of rDNA transcription silencer TIP5 (TTF-I interacting protein 5), one of the components of nucleolar remodeling complex NoRC that silences rRNA genes by recruiting DNA methyltransferase to rDNA promoters and increasing DNA methylation. NuRD negatively regulates TIP5 expression, thereby inhibiting rDNA methylation and maintaining demethylation state of rDNA promoters. The deficiency of NuRD components in reprogrammed cells activates TIP5 expression, resulting in the increased fraction of heterochromatic rRNA genes and transcriptional silencing. Thus, NuRD is able to control methylation status of rDNA promoters through crosstalking with NoRC complex. PMID- 23796712 TI - p53 regulates glucose metabolism by miR-34a. AB - Cancer cells rely mainly on glycolysis rather than mitochondrial respiration for energy production, which is called the Warburg effect. p53 mutations are observed in about half of cancer cases, and p53 controls the cell cycle and cell death in response to cellular stressors. p53 has been emphasized as a metabolic regulator involved in glucose, glutamine, and purine metabolism. Here, we demonstrated metabolic changes in cancer that occurred through p53. We found that p53 inducible microRNA-34a (miR-34a) repressed glycolytic enzymes (hexokinase 1, hexokinase 2, glucose-6-phosphate isomerase), and pyruvate dehydrogenase kinase 1. Treatment with an anti-miR-34a inhibitor relieved the decreased expression in these enzymes following DNA damage. miR-34a-mediated inhibition of these enzymes resulted in repressed glycolysis and enhanced mitochondrial respiration. The results suggest that p53 has a miR-34a-dependent integrated mechanism to regulate glucose metabolism. PMID- 23796713 TI - MicroRNA-124 targets CCNA2 and regulates cell cycle in STHdh(Q111)/Hdh(Q111) cells. AB - Mutation in huntingtin (HTT) gene causes Huntington's disease (HD). Expression of many micro RNAs is known to alter in cell, animal models and brains of HD patients, but their cellular effects are not known. Here, we show that expression of microRNA-124 (miR-124) is down regulated in HD striatal mutant STHdh(Q111)/Hdh(Q111) cells, a cell model of HD compared to STHdh(Q7)/Hdh(Q7) cells. STHdh(Q7)/Hdh(Q7) and STHdh(Q111)/Hdh(Q111) cells express endogenously full length wild type and mutant HTT respectively. We confirmed this result in R6/2 mouse, an animal model of HD, expressing mutant HTT. Gene Ontology terms related to cell cycle were enriched significantly with experimentally validated targets of miR-124. We observed that expression of Cyclin A2 (CCNA2), a putative target of miR-124 was increased in mutant STHdh(Q111)/Hdh(Q111) cells and brains of R6/2 mice. Fraction of cells in S phase was higher in asynchronously growing mutant STHdh(Q111)/Hdh(Q111) cells compared to wild type STHdh(Q7)/Hdh(Q7) cells and could be altered by exogenous expression or inhibition of miR-124. Exogenous expression or knock down of CCNA2, a target of miR-124, also alters proportion of cells in S phase of HD cell model. In summary, decreased miR-124 expression could increase CCNA2 in cell and animal model of HD and is involved in deregulation of cell cycle in STHdh(Q111)/Hdh(Q111) cells. PMID- 23796715 TI - In vivo gliding and contact characteristics of the sigmoid notch and the ulna in forearm rotation. AB - PURPOSE: To investigate shifting of the contact center over the surfaces of 2 opposing bones of the distal radioulnar joint during forearm rotation. METHODS: We recruited 8 volunteers and used their right wrists. Serial computed tomography scans were obtained with the forearm at neutral position and 6 other positions of forearm rotation. We reconstructed 3-dimensional images and mapped contact regions of both the sigmoid notch and ulnar head by calculating the shortest distance between the 2 opposing bones. The center of contact was also defined and plotted against the distal radioulnar joint rotation to determine the sliding distance over the surfaces of the 2 bones. RESULTS: During forearm rotation, the maximal sliding of the sigmoid notch over the ulnar head was 7.4 mm in forearm pronation and 9.2 mm in forearm supination, which occurred in volar-dorsal direction primarily. Sliding of the ulnar head over the sigmoid notch was more limited, measuring 4.7 mm during pronation and 2.3 mm during supination. Most of the motion occurred between 30 degrees pronation and 60 degrees supination. In the proximal-distal direction, the contact site of the sigmoid notch with the ulnar head translated distally 1.6 mm during pronation and proximally 0.7 mm during supination. CONCLUSIONS: During forearm rotation, the sigmoid notch slides substantially against the ulnar head at each part of the forearm rotation arc. The sliding of the ulnar head over the sigmoid notch is smaller, most of which is at the range from moderate forearm pronation to slight supination. The contact site of the sigmoid notch with the ulnar head moves slightly distally during forearm pronation and proximally during supination. CLINICAL RELEVANCE: The in vivo findings provide more detailed information and insight into distal radioulnar joint motion kinematics. PMID- 23796716 TI - Angioleiomyoma of the upper extremity. AB - PURPOSE: To determine the outcomes of surgical excision in the management of angioleiomyomas of the upper extremity. METHODS: We retrospectively reviewed the medical records of 26 patients undergoing a surgical excision of an angioleiomyoma in the upper extremity between 1975 and 2012, who had at least 1 year of follow-up. There were 12 men and 14 women, with an average age of 55 +/- 20 years. The most common location was the hand (n = 14). The onset of symptoms was on average 6 +/- 5 years before presentation. The most common problem was a painful mass (19 of 26 patients). Average tumor size was 10 +/- 7 mm. RESULTS: Patients over the age of 60 years tended to have smaller tumors. There was no significant difference between average preoperative and postoperative grip strength in the affected and unaffected extremities. None of the lesions was diagnosed based on radiographic imaging. There was 1 postoperative complication. No recurrence was noted at an average 8.6-year follow-up (range, 1.0-21.0 y). CONCLUSIONS: Angioleiomyomas present as a small, painful masses that can be reliably treated with marginal surgical excision. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 23796717 TI - Report of the 8th International Congress on Vascular Access, Prague, Czech Republic, April 25-27, 2013. PMID- 23796714 TI - Systems biological approaches to measure and understand vaccine immunity in humans. AB - Recent studies have demonstrated the utility of using systems approaches to identify molecular signatures that can be used to predict vaccine immunity in humans. Such approaches are now being used extensively in vaccinology, and are beginning to yield novel insights about the molecular networks driving vaccine immunity. In this review, we present a broad review of the methodologies involved in these studies, and discuss the promise and challenges involved in this emerging field of "systems vaccinology." PMID- 23796718 TI - Practical quantification of necrosis in histological whole-slide images. AB - Since the histological quantification of necrosis is a common task in medical research and practice, we evaluate different image analysis methods for quantifying necrosis in whole-slide images. In a practical usage scenario, we assess the impact of different classification algorithms and feature sets on both accuracy and computation time. We show how a well-chosen combination of multiresolution features and an efficient postprocessing step enables the accurate quantification necrosis in gigapixel images in less than a minute. The results are general enough to be applied to other areas of histological image analysis as well. PMID- 23796719 TI - Evaluation of an immunochromatographic test for the identification of Legionella genus and Legionella pneumophila serogroups 1-15 from cultures. PMID- 23796720 TI - Efficacy of combined levonorgestrel-releasing intrauterine system with gonadotropin-releasing hormone analog for the treatment of adenomyosis. AB - OBJECTIVES: To evaluate the clinical outcomes of gonadotropin-releasing hormone analog (GnRHa) combined with implantation of a levonorgestrel-releasing intrauterine system (LNG-IUS) in adenomyosis patients with significantly enlarged uteruses. SUBJECTS AND METHODS: Twenty-one adenomyosis patients whose uterine volumes were greater in size than at 12 weeks' gestation were recruited for the study. Subcutaneous injection of GnRHa was administrated at an interval of 28 days for a total of 3-4 cycles when uterine length was determined to be less than 10 cm by ultrasound measurement. At 3, 6 and 12 months after LNG-IUS implantation, follow-up was performed to document the clinical values such as uterine volume, degree of dysmenorrhea and menstrual flow. RESULTS: Twelve months after implantation, the menstrual flow was significantly lower than baseline values (53.8 +/- 11.7 vs. 100, p = 0.03). The degree of dysmenorrhea (pain) was relieved 12 months after implantation (58.2 +/- 11.5 vs. 93.7 +/- 0.2, p = 0.005). Uterine volume was also below pre-GnRHa levels after implantation (276.6 +/- 32.1 vs. 311.4 +/- 32.3, p = 0.005). LNG-IUS was expelled in 3 patients, giving an expulsion rate of 14%. Side effects of GnRHa combined with LNG-IUS implantation were few. CONCLUSION: The findings indicate that combined GnRHa and LNG-IUS treatment was efficacious in patients with enlarged adenomyosis. PMID- 23796721 TI - [Challenge of the management of severe trauma of cervical spine in sub-developed country]. AB - BACKGROUND AND PURPOSE: The management of cervical spine injuries requires a multidisciplinary approach based on emergency management and rehabilitation. In our context this chain fails, especially on the post-hospital care. Our goal is to explain the difficulties we had in the management of these patients in Dakar. METHODS: This retrospective cohort study (2005-2009) included 99 patients admitted for severe cervical spinal cord injury in two hospitals in Dakar. The clinical signs, treatment and outcome were studied. The follow up was between 3 and 54 months. RESULTS: The average age of patients was 36.1 years and the traffic accidents were the main etiology (73.7%). Medical transport of patients was done in 65.7% with an admission average time of 64.86 hours. On admission, 57.6% of patients had Frankel score A or B. Dislocations (59.6%) and Tear drop fractures (16.2%) were the main lesions. The surgery was performed in 83.8% with a mean interval of 128.84 hours after the trauma. Outpatient rehabilitation was offered whatever the patient's neurological status. Recovery was complete in 20.2% and partial in 31.3% with a mortality rate of 37.4%. Most deaths occurred between 1 and 6 months (59.5%) mainly due to decubitus complications (56.8%). CONCLUSION: The efficacy of the management of severe spinal cord injuries is based on reducing the preoperative time and rehabilitation. PMID- 23796722 TI - Human hepatocyte transplantation in patients with hepatic failure awaiting a graft. AB - BACKGROUND: Hepatocyte transplantation (HT) has the potential to become a promising treatment to temporarily support liver function in patients with liver failure. METHODS: Two patients, who had already received a liver transplant (LT) in the past, with an end-stage liver disease due to recurrent hepatitis C virus cirrhosis, suffering acute-on-chronic liver failure while on the waiting list for an LT, received HT as a bridge to whole-organ retransplantation. After HT and during intensive care unit admission, blood tests and ammonia levels were determined every 12 and 24 h, respectively, before and after each hepatocyte infusion. RESULTS: The present study describes monitoring of analytical and clinical parameters and improvement of liver function following HT. In both patients, we managed to lower the blood ammonia levels and clinically improve the degree of hepatic encephalopathy, thus serving as a bridge to liver retransplantation in 1 patient. CONCLUSIONS: We believe that this therapy may be an alternative treatment in patients with chronic liver disease who suffer episodes of acute decompensation as a bridge to conventional LT. PMID- 23796723 TI - Overexpression of a tomato carotenoid epsilon-hydroxylase gene alleviates sensitivity to chilling stress in transgenic tobacco. AB - Chilling is one of the most serious environmental stresses that disrupt the metabolic balance of cells and enhance the production of reactive oxygen species (ROS). Lutein plays important roles in dissipating excess excitation energy and eliminating ROS to maintain the normal physiological function of cells. A tomato carotenoid epsilon-ring hydroxylase gene (LeLUT1) was isolated, and the LeLUT1 GFP fusion protein was localized in the chloroplast of Arabidopsis mesophyll protoplast. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis indicated that the expression of LeLUT1 was the highest in the leaves and was down-regulated by various abiotic stresses in tomato. The transgenic tobacco plants overexpressing LeLUT1 had higher lutein content, which was decreased in cold condition. Under chilling stress, the non-photochemical quenching (NPQ) values were higher in the transgenic plants than in the wild type (WT) plants. Compared with the WT plants, the transgenic plants showed lower levels of hydrogen peroxide (H2O2), superoxide radical (O2(.-)), relative electrical conductivity, and malondialdehyde content (MDA), and relatively higher values of maximal photochemical efficiency of photosystem II (Fv/Fm), oxidizable P700 of PSI, and net photosynthetic rate (Pn). Therefore, the transgenic seedlings were less suppressed in growth and lost less cotyledon chlorophyll than the WT seedlings. These results suggested that the overexpression of LeLUT1 had a key function in alleviating photoinhibition and photooxidation, and decreased the sensitivity of photosynthesis to chilling stress. PMID- 23796724 TI - Biochemical and physiological responses of oil palm to bud rot caused by Phytophthora palmivora. AB - In recent years, global consumption of palm oil has increased significantly, reaching almost 43 million tons in 2010. The sustainability of oil palm (Elaeis guineensis) cultivation has been compromised because of the bud rot disease whose initial symptoms are caused by Phytophthora palmivora. There was a significant incidence of the disease, from an initial stage 1 of the disease to the highest stage 5, that affected photosynthetic parameters, content of pigments, sugars, polyamines, enzymatic antioxidant activities, phenylalanine ammonia-lyase (PAL, EC 4.3.1.5) and beta-(1,3) glucanase (beta-Gluc, EC 3.2.1.39). In healthy palms photosynthesis was 13.29 MUmol CO2 m(-2) s(-1) in average, while in stage 5 the average photosynthesis was around 3.66 MUmol CO2 m(-2) s(-1). Additionally, total chlorophyll was reduced by half at the last stage of the disease. On the contrary, the contents of putrescine, spermine and spermidine increased three, nine and twelve times with respect to stage 5, respectively. Antioxidant enzyme activities, as well as the phenylalanine ammonia-lyase and beta-(1,3) glucanase showed an increase as the severity of the disease increased, with the latter increasing from 0.71 EAU in healthy palms to 2.60 EAU in plants at stage 5 of the disease. The peroxidase (POD, EC 1.11.1.7) enzymatic activity and the content of spermidine were the most sensitive indicators of disease. PMID- 23796725 TI - Antiproliferative activity of Rhinella marina and Rhaebo guttatus venom extracts from Southern Amazon. AB - The venom of amphibians is a fascinating source of active substances. In view of their medical importance and aiming to explore the amazing Brazilian biodiversity, we conducted bioprospecting of antiproliferative activity in extracts of Rhinella marina and Rhaebo guttatus toads occurring in the Southern Amazon of Mato Grosso, Brazil. LC-MS and HPLC analysis of the venom extracts of R. marina revealed four bufadienolides (telocinobufagin, marinobufagin, bufalin and resibufogenin. R. guttatus venom extracts contained only marinobufagin. First, R. marina and R. guttatus venom extracts were evaluated for cytotoxicity against tumor cell lines by the MTT assay. All extracts revealed cytotoxicity, where R. marina extracts were comparable to doxorubicin (IC50 values ranging from 0.01 to 0.23 MUg/mL). Only extracts of R. guttatus toad venom caused membrane disruption of human erythrocytes. The extracts were investigated for selective activity by determining their effect on stimulated human peripheral blood mononuclear cells (PBMC) with the Alamar BlueTM assay. The extracts were up to 80 fold more selective against leukemia cells when compared to dividing leukocytes. Aiming to confirm these antiproliferative effects, BrdU incorporation into DNA was measured in HL-60 treated cells with R. marina venom extracts. These extracts decreased BrdU incorporation at both concentrations tested. In summary, nine extracts of R. marina and R. guttatus venom showed pronounced lethal and discriminating effects on tumor lines, especially those from R. marina, highlighting toad parotoid gland secretions as a promising source for novel lead anticancer chemicals. PMID- 23796726 TI - Feasibility studies into the production of gamma-irradiated oyster tissue reference materials for paralytic shellfish poisoning toxins. AB - A study was conducted to assess the feasibility for the production of sterile, stable and homogenous shellfish reference materials containing known concentrations of paralytic shellfish poisoning (PSP) toxins. Pacific oysters were contaminated with toxins following mass culturing of toxic algae and shellfish feeding experiments. Live oysters were shucked and tissues homogenised, before measuring into multiple aliquots, with one batch subjected to gamma irradiation treatment and the other remaining untreated. The homogeneity of both batches of samples was assessed using a pre-column oxidation liquid chromatography with fluorescence detection (Pre-COX LC-FLD) method and shown to be within the limits of normal within-batch repeatability. A twelve-month stability experiment was conducted for both untreated and gamma irradiated batches, specifically examining the effects of long term storage at -20 degrees C, +4 degrees C and +40 degrees C. Results indicated mostly good stability of PSP toxins in both materials when stored frozen at -20 degrees C, but with the instability of GTX2&3 concentrations in the untreated tissues eliminated in the irradiated tissues. Analysis using a post-column oxidation (PCOX) LC-FLD method also showed epimerisation in both GTX1&4 and GTX2&3 epimeric pairs in untreated samples after only 6 months frozen storage. This issue was not present in the tissues irradiated before long term storage. Biological activity testing confirmed the absence of bacteria in the irradiated samples throughout the 12 month study period. With such results there was clear evidence for the potential of increasing the scale of the mass culturing and shellfish feeding for the production of large batches of tissue suitable for the preparation of a certified matrix reference material. Overall results demonstrated the feasibility for production of oyster reference materials for PSTs, with evidence for prolonged stability following gamma irradiation treatment and storage at -20 degrees C. PMID- 23796727 TI - Cytotoxic, genotoxic/antigenotoxic and mutagenic/antimutagenic effects of the venom of the wasp Polybia paulista. AB - Hymenoptera venoms are constituted by a complex mixture of chemically or pharmacologically bioactive agents, such as phospholipases, hyaluronidases and mastoparans. Venoms can also contain substances that are able to inhibit and/or diminish the genotoxic or mutagenic action of other compounds that are capable of promoting damages in the genetic material. Thus, the present study aimed to assess the effect of the venom of Polybia paulista, a neotropical wasp, by assays with HepG2 cells maintained in culture. The cytotoxic potential of the wasp venom, assessed by the methyl thiazolyl tetrazolium assay (MTT assay), was tested for the concentrations of 10 MUg/mL, 5 MUg/mL and 1 MUg/mL. As these concentrations were not cytotoxic, they were used to evaluate the genotoxic (comet assay) and mutagenic potential (micronucleus test) of the venom. In this study, it was verified that these concentrations induced damages in the DNA of the exposed cells, and it was necessary to test lower concentrations until it was found those that were not considered genotoxic and mutagenic. The concentrations of 1 ng/mL, 100 pg/mL and 10 pg/mL, which did not induce genotoxicity and mutagenicity, were used in four different treatments (post-treatment, pre treatment, simultaneous treatment with and without incubation), in order to evaluate if these concentrations were able to inhibit or decrease the genotoxic and mutagenic action of methyl methanesulfonate (MMS). None of the concentrations was able to inhibit and/or decrease the MMS activity. The genotoxic and mutagenic activity of the venom of P. paulista could be caused by the action of phospholipase, mastoparan and hyaluronidase, which are able to disrupt the cell membrane and thereby interact with the genetic material of the cells or even facilitate the entrance of other compounds of the venom that can act on the DNA. Another possible explanation for the genotoxicity and mutagenicity of the venom can be the presence of substances able to trigger inflammatory process and, consequently, generate oxygen reactive species that can interact with the DNA of the exposed cells. PMID- 23796728 TI - Reply to Jamilloux et al. about the article "Online home self-assessment: a tool for improving future treatment trials?", Joint Bone Spine 2013;80:5-7. PMID- 23796729 TI - Treatment persistence and changes in fracture risk, back pain, and quality of life amongst patients treated with teriparatide in routine clinical care in France: results from the European Forsteo Observational Study. AB - OBJECTIVES: The European Forsteo Observational Study assessed the clinical fracture incidence, back pain, quality of life (QoL), and treatment persistence amongst post-menopausal women, who were prescribed teriparatide in routine care in eight European countries. We present the results for France, with health insurance reimbursement criteria channel teriparatide to women with severe disease and limit treatment to 18 months. METHODS: A representative sample of women initiating teriparatide in France was followed in routine care for 36 months. We described patients' characteristics at baseline and persistence to teriparatide (Kaplan-Meier analysis), fracture incidence, back pain, and QoL (EQ 5D) at baseline, 18 and 36 months follow-up (last-observation-carried-forward (LOCF) and mixed-models-for-repeated-measures (MMRM). RESULTS: One hundred and sixteen rheumatologists included 309 patients, of whom 290 (93.9%) had at least one follow-up visit. Women's mean age (standard deviation) was 74.5 years (7.4) and 296 (95.8%) had greater or equal to two vertebral fractures prior to teriparatide initiation. Clinical fracture incidence, mainly vertebral fractures, decreased around 6 months after teriparatide initiation, and was sustained at 36 months (P=0.013) when most patients were treated by anti-resorptives. Back pain and EQ-5D measures improved significantly at 18 and 36 months (P<0.0001) in the LOCF analyses but did not improve in the EQ-5D VAS measure after covariate adjustment in the MMRM model. Median treatment duration was 17.4 months. CONCLUSION: French women initiating teriparatide in routine care had severe osteoporosis and showed good treatment persistence, consistent with France's insurance reimbursement criteria. Improvements in fracture risk and back pain began soon after treatment and was maintained at 36 months follow-up. PMID- 23796730 TI - Carpal and tarsal osteolysis. PMID- 23796731 TI - Vascular effects of nonsteroidal antiinflammatory drugs. AB - The effect of nonsteroidal antiinflammatory drugs (NSAIDs) on the risk of cardiovascular events remains controversial. Among NSAIDs, only low-dose aspirin exerts protective vascular effects. Low-dose aspirin has been proven effective for secondary prevention. For primary prevention, the usefulness of low-dose aspirin is debated, as illustrated by the differences in recommendations across countries. NSAIDs other than aspirin, whether COX-2 selective or nonselective, increase the risk of cardiovascular events. Among them, naproxen is associated with the smallest risk increase. In patients with a history of coronary artery disease, diclofenac seems to carry the greatest risk, but all NSAIDs should be avoided. Uncertainties persist about aspirin interactions with other NSAIDs and with proton pump inhibitors. An adverse effect of acetaminophen on the risk of cardiovascular disease cannot be completely ruled out. PMID- 23796732 TI - 25-hydroxyvitamin D status does not affect the clinical rituximab response in rheumatoid arthritis. PMID- 23796733 TI - Dysregulation of diurnal salivary cortisol production is associated with spontaneous preterm delivery: a pilot study. AB - OBJECTIVES: The purpose of this study was to evaluate whether the diurnal fluctuation of salivary cortisol and its overall diurnal secretion are associated with the length of gestation in patients who were admitted to the hospital with an assigned diagnosis of possible preterm labor (PL) at a gestational age of 28 33 weeks. METHODS: In 22 patients, maternal saliva samples were collected for a cortisol assay 4 times per day (8 AM, 12 AM, 4 PM and 8 PM) on day 4 and day 6 after antenatal corticosteroid prophylaxis to prevent neonatal respiratory distress syndrome. RESULTS: Eight patients who ultimately delivered before term (32.6 +/- 1.7 gestation weeks) showed an inverted fluctuation of salivary cortisol on both days 4 and 6, morning cortisol levels being significantly lower than evening levels. In contrast, in 14 patients who delivered at term (39.5 +/- 0.6 gestation weeks), the physiological diurnal fluctuation of salivary cortisol was maintained. In addition, a distinctive feature of women delivering before term was a significantly hampered salivary cortisol diurnal production measured on day 6. CONCLUSIONS: Corticoadrenal activity is dysregulated and anticipates very preterm delivery in women with an assigned diagnosis of possible PL. PMID- 23796734 TI - Evidence for the diagnosis and treatment of acute uncomplicated sinusitis in children: a systematic review. AB - In 2001, the American Academy of Pediatrics published clinical practice guidelines for the management of acute bacterial sinusitis (ABS) in children. The technical report accompanying those guidelines included 21 studies that assessed the diagnosis and management of ABS in children. This update to that report incorporates studies of pediatric ABS that have been performed since 2001. Overall, 17 randomized controlled trials of the treatment of sinusitis in children were identified and analyzed. Four randomized, double-blind, placebo controlled trials of antimicrobial therapy have been published. The results of these studies varied, likely due to differences in inclusion and exclusion criteria. Because of this heterogeneity, formal meta-analyses were not performed. However, qualitative analysis of these studies suggests that children with greater severity of illness at presentation are more likely to benefit from antimicrobial therapy. An additional 5 trials compared different antimicrobial therapies but did not include placebo groups. Six trials assessed a variety of ancillary treatments for ABS in children,and 3 focused on subacute sinusitis. Although the number of pediatric trials has increased since 2001, there are still limited data to guide the diagnosis and management of ABS in children. Diagnostic and treatment guidelines focusing on severity of illness at the time of presentation have the potential to identify those children most likely to benefit from antimicrobial therapy and at the same time minimize unnecessary use of antibiotics PMID- 23796735 TI - Variation in definitions of urinary tract infections in spina bifida patients: a systematic review. AB - OBJECTIVE: Urinary tract infections (UTIs) are a common source of morbidity among children with spina bifida (SB) and are a frequently reported outcome in studies of this patient population. However, the criteria for a diagnosis of UTI are often not stated. We evaluated the literature on SB patients for the criteria that authors use to define parameters in reporting UTI outcomes. METHODS: Embase and Medline were queried with the medical subject heading terms "spinal dysraphism," "myelomeningocele," "infection,"and "urinary tract infection." A second search with the exploded term"spina bifida" and "urinary tract infection" was performed. Original research studies reporting a UTI outcome in SB patients were included and evaluated by 2 independent reviewers for the presence of a UTI definition and diagnostic criteria. RESULTS: We identified 872 publications, of which 124 met inclusion criteria. Forty-five of 124 (36.3%) studies reporting UTI as an outcome provided a definition of UTI. Of 124 studies, 28 (22.6%) were published in pediatric journals and 69 (55.6%) in urology journals. A definition of UTI was provided in 11 (39.3%) and 26 (37.7%) studies, respectively. "Fever,culture, and symptoms" defined a UTI in 17 of 45 studies. Journal category and presence of UTI definitions did not correlate (P = .71). CONCLUSIONS: Explicit definitions for UTI are heterogeneous and infrequently applied in studies of SB patients, limiting study reliability and estimates of true UTI rates in this population. Future studies will benefit from the development and application of a standard definition for UTI in this population. PMID- 23796736 TI - Cardiorespiratory fitness and adiposity in metabolically healthy overweight and obese youth. AB - OBJECTIVE: Controversy exists surrounding the contribution of fitness and adiposity as determinants of the Metabolically Healthy Overweight(MHO) phenotype in youth. This study investigated the independent contribution of cardiorespiratory fitness and adiposity to the MHO phenotype among overweight and obese youth. METHODS: This cross-sectional study included 108 overweight and obese youth classified as MHO (no cardiometabolic risk factors) or non-MHO (>=1 cardiometabolic risk factor), based on age- and gender specific cut-points for fasting glucose, triglycerides, high-density lipoprotein cholesterol, systolic and diastolic blood pressure, and hepaticsteatosis. RESULTS: Twenty-five percent of overweight and obese youth were classified as MHO. This phenotype was associated with lower BMIz-score (BMI z-score: 1.8 +/- 0.3 vs 2.1 +/- 0.4, P = .02) and waist circumference (99.7 +/- 13.2 vs 106.1 +/- 13.7 cm, P = .04) compared with non-MHO youth. When matched for fitness level and stratified by BMI z-score (1.6 +/- 0.3 vs 2.4 +/- 0.2), the prevalence of MHO was four fold higher in the low BMI z-score group (27% vs 7%; P = .03).Multiple logistic regression analyses revealed that the best predictor of MHO was the absence of hepatic steatosis even after adjusting for waist circumference (odds ratio 0.57, 95% confidence interval 0.40-0.80) or BMI z-score (odds ratio 0.59, 95% confidence interval 0.43-0.80). CONCLUSIONS: The MHO phenotype was present in 25% of overweight and obese youth and is strongly associated with lower levels of adiposity,and the absence of hepatic steatosis, but not with cardiorespiratory fitness. PMID- 23796738 TI - Statement of Endorsement: Defining Pediatric Malnutrition. PMID- 23796737 TI - Office-based care for lesbian, gay, bisexual, transgender, and questioning youth. AB - The American Academy of Pediatrics issued its last statement on homosexuality and adolescents in 2004. This technical report reflects the rapidly expanding medical and psychosocial literature about sexual minority youth. Pediatricians should be aware that some youth in their care may have concerns or questions about their sexual orientation or that of siblings, friends, parents, relatives, or others and should provide factual, current, nonjudgmental information in a confidential manner. Although most lesbian, gay, bisexual, transgender, and questioning(LGBTQ) youth are quite resilient and emerge from adolescence as healthy adults, the effects of homophobia and heterosexism can contribute to increased mental health issues for sexual minority youth. LGBTQ and MSM/WSW (men having sex with men and women having sex with women) adolescents, in comparison with heterosexual adolescents,have higher rates of depression and suicidal ideation, high errates of substance abuse, and more risky sexual behaviors. Obtaining a comprehensive, confidential, developmentally appropriate adolescent psychosocial history allows for the discovery of strengths and assets as well as risks. Pediatricians should have offices that are teen-friendly and welcoming to sexual minority youth. This includes having supportive, engaging office staff members who ensure that there are no barriers to care. For transgender youth, pediatricians should provide the opportunity to acknowledge and affirm their feelings of gender dysphoria and desires to transition to the opposite gender. Referral of transgender youth to a qualified mental health professional is critical to assist with the dysphoria, to educate them,and to assess their readiness for transition. With appropriate assistance and care, sexual minority youth should live healthy, productive lives while transitioning through adolescence and young adulthood. PMID- 23796739 TI - Transitioning HIV-infected youth into adult health care. AB - With advances in antiretroviral therapy, most HIV-infected children survive into adulthood. Optimal health care for these youth includes a formal plan for the transition of care from primary and/or subspecialty pediatric/adolescent/family medicine health care providers (medical home) to adult health care provider(s). Successful transition involves the early engagement and participation of the youth and his or her family with the pediatric medical home and adult health care teams in developing a formal plan. Referring providers should have a written policy for the transfer of HIV-infected youth to adult care, which will guide in the development of an individualized plan for each youth. The plan should be introduced to the youth in early adolescence and modified as the youth approaches transition. Assessment of developmental milestones is important to define the readiness of the youth in assuming responsibility for his or her own care before initiating the transfer. Communication among all providers is essential and should include both personal contact and a written medical summary. Progress toward the transition should be tracked and,once completed, should be documented and assessed. PMID- 23796740 TI - Imiquimod, molluscum, and the need for a better "best pharmaceuticals for children" act. PMID- 23796741 TI - Implementation of a parental tobacco control intervention in pediatric practice. AB - OBJECTIVE: To test whether routine pediatric outpatient practice can be transformed to assist parents in quitting smoking. METHODS: Cluster RCT of 20 pediatric practices in 16 states that received either CEASE intervention or usual care. The intervention gave practices training and materials to change their care delivery systems to provide evidence-based assistance to parents who smoke. This assistance included motivational messaging; proactive referral to quitlines; and pharmacologic treatment of tobacco dependence. The primary outcome, assessed at an exit interview after an office visit,was provision of meaningful tobacco control assistance, defined as counseling beyond simple advice (discussing various strategies to quit smoking), prescription of medication, or referral to the state quitline, at that office visit. RESULTS: Among 18 607 parents screened after their child's office visit between June 2009 and March 2011, 3228 were eligible smokers and 1980 enrolled (999 in 10 intervention practices and 981 in 10 control practices). Practices' mean rate of delivering meaningful assistance for parental cigarette smoking was 42.5% (range 34%-66%) in the intervention group and 3.5% (range 0%-8%) in the control group (P < .0001).Rates of enrollment in the quitline (10% vs 0%); provision of smoking cessation medication (12% vs 0%); and counseling for smoking cessation(24% vs 2%) were all higher in the intervention group compared with the control group (P < .0001 for each). CONCLUSIONS: A system-level intervention implemented in 20 outpatient pediatric practices led to 12-fold higher rates of delivering tobacco control assistance to parents in the context of the pediatric office visit. PMID- 23796742 TI - Clinical practice guideline for the diagnosis and management of acute bacterial sinusitis in children aged 1 to 18 years. AB - OBJECTIVE: To update the American Academy of Pediatrics clinical practice guideline regarding the diagnosis and management of acute bacterial sinusitis in children and adolescents. METHODS: Analysis of the medical literature published since the last version of the guideline (2001). RESULTS: The diagnosis of acute bacterial sinusitis is made when a child with an acute upper respiratory tract infection (URI) presents with (1) persistent illness (nasal discharge [of any quality] or daytime cough or both lasting more than 10 days without improvement), (2) a worsening course (worsening or new onset of nasal discharge, daytime cough, or fever after initial improvement), or (3) severe onset (concurrent fever[temperature >=39 degrees C/102.2 degrees F] and purulent nasal discharge for at least 3 consecutive days). Clinicians should not obtain imaging studies of any kind to distinguish acute bacterial sinusitis from viral URI, because they do not contribute to the diagnosis; however, a contrast-enhanced computed tomography scan of the paranasal sinuses should be obtained whenever a child is suspected of having orbital or central nervous system complications. The clinician should prescribe antibiotic therapy for acute bacterial sinusitis in children with severe onset or worsening course. The clinician should either prescribe antibiotic therapy or offer additional observation for 3 days to children with persistent illness. Amoxicillin with or without clavulanate is the firstline treatment of acute bacterial sinusitis. Clinicians should reassess initial management if there is either a caregiver report of worsening(progression of initial signs/symptoms or appearance of new signs/symptoms) or failure to improve within 72 hours of initial management.If the diagnosis of acute bacterial sinusitis is confirmed in a child with worsening symptoms or failure to improve, then clinicians may change the antibiotic therapy for the child initially managed with antibiotic or initiate antibiotic treatment of the child initially managed with observation. CONCLUSIONS: Changes in this revision include the addition of a clinical presentation designated as "worsening course," an option to treat immediately or observe children with persistent symptoms for 3 days before treating, and a review of evidence indicating that imaging is not necessary in children with uncomplicated acute bacterial sinusitis. PMID- 23796743 TI - Racial and ethnic disparities in ADHD diagnosis from kindergarten to eighth grade. AB - OBJECTIVE: Whether and to what extent racial/ethnic disparities inattention deficit/hyperactivity disorder (ADHD) diagnosis occur across early and middle childhood is currently unknown. We examined the over-time dynamics of race/ethnic disparities in diagnosis from kindergarten to eighth grade and disparities in treatment in fifth and eighth grade. METHODS: Analyses of the nationally representative Early Childhood Longitudinal Study, Kindergarten Class of 1998 1999 (N = 17 100)using discrete-time hazard modeling. RESULTS: Minority children were less likely than white children to receive an ADHD diagnosis. With time invariant and -varying confounding factors statistically controlled the odds of ADHD diagnosis for African Americans, Hispanics, and children of other races/ethnicities were 69% (95% confidence interval [CI]: 60%-76%), 50% (95% CI: 34%-62%), and 46% (95% CI: 26%-61%) lower, respectively, than for whites. Factors increasing children's risk of an ADHD diagnosis included being a boy,being raised by an older mother, being raised in an English-speaking household, and engaging in externalizing problem behaviors. Factors decreasing children's risk of an ADHD diagnosis included engaging in learning-related behaviors (eg, being attentive), displaying greater academic achievement, and not having health insurance. Among children diagnosed with ADHD, racial/ethnic minorities were less likely than whites to be taking prescription medication for the disorder. CONCLUSIONS: Racial/ethnic disparities in ADHD diagnosis occur by kindergarten and continue until at least the end of eighth grade. Measured confounding factors do not explain racial/ethnic disparities in ADHD diagnosis and treatment. Culturally sensitive monitoring should be intensified to ensure that all children are appropriately screened, diagnosed,and treated for ADHD. PMID- 23796745 TI - Enrollment in early intervention programs among infants born late preterm, early term, and term. AB - OBJECTIVE: To compare the prevalence of and characteristics associated with early intervention (EI) program enrollment among infants born late preterm (34-36 weeks' gestation), early term (37-38 weeks' gestation), and term (39-41 weeks' gestation). METHODS: A Massachusetts cohort of 554 974 singleton infants born during 1998 through 2005 and survived the neonatal period was followed until the third birthday of each infant. Data came from the Pregnancy to Early Life Longitudinal Data System that linked birth certificates, birth hospital discharge reports, death certificates, and EI program enrollment records. We calculated prevalence and adjusted risk ratios to compare differences and understand associations. RESULTS: The prevalence of EI program enrollment increased with each decreasing week of gestation before 41 weeks (late preterm [23.5%],early term [14.9%], and term [11.9%]. In adjusted analyses, the strongest predictors of EI enrollment (adjusted risk ratio >=1.20) for all gestational age groups were male gender, having a congenital anomaly, and having mothers who were >=40 years old, non high school graduates, and recipients of public insurance. CONCLUSIONS: Infants born late preterm and early term have higher prevalence of EI program services enrollment than infants born at term,and may benefit from more frequent monitoring for developmental delays or disabilities. PMID- 23796746 TI - Office-based care for lesbian, gay, bisexual, transgender, and questioning youth. AB - The American Academy of Pediatrics issued its last statement on homosexuality and adolescents in 2004. Although most lesbian, gay, bisexual, transgender, and questioning (LGBTQ) youth are quite resilient and emerge from adolescence as healthy adults, the effects of homophobia and heterosexism can contribute to health disparities in mental health with higher rates of depression and suicidal ideation, higher rates of substance abuse, and more sexually transmitted and HIV infections. Pediatricians should have offices that are teen-friendly and welcoming to sexual minority youth. Obtaining a comprehensive, confidential, developmentally appropriate adolescent psychosocial history allows for the discovery of strengths and assets as well as risks. Referrals for mental health or substance abuse may be warranted. Sexually active LGBTQ youth should have sexually transmitted infection/HIV testing according to recommendations of the Sexually Transmitted Diseases Treatment Guidelines of the Centers for Disease Control and Prevention based on sexual behaviors. With appropriate assistance and care, sexual minority youth should live healthy, productive lives while transitioning through adolescence and young adulthood. PMID- 23796747 TI - Improving on-time start of day and end of day for a pediatric surgical service. AB - BACKGROUND AND OBJECTIVE: In multicase pediatric ear, nose, and throat operating rooms (ORs), brief delays in early case start times often produce a cascading effect of lengthy delays by the end of the day and can often lead to patient, family, and staff dissatisfaction and increased labor costs due to unplanned overtime. We sought to improve actual end of day relative to scheduled end of day from 40% to 60%. METHODS: Key drivers of the process included case scheduling, ordering of sedative medications, and nurse availability in the post anesthesia care unit to receive the patient from the anesthesia provider. A multidisciplinary team conducted a series of tests of change addressing the various key drivers. Data were collected by using an independent, impartial data collector as well as being extracted from the hospital information technology system. Data were analyzed by using control charts and statistical process control methods. RESULTS: The percentage of ORs ending on time increased from 40% to 60%. Appropriate scheduling of complex cases increased from 10% to 87%, and accurate scheduling of case duration improved from 21% to 48%. Timely premedication increased from 55% to 90% and immediate availability of a nurse in the postanesthesia care unit from 68% to.90%. CONCLUSIONS: By applying quality improvement methods, significant improvements were made in a multicase pediatric ear, nose, and throat OR. The impact can be significant by reducing wait times for patients, as well as staff overtime for the institution. PMID- 23796748 TI - Novel roles for complement receptors in T cell regulation and beyond. AB - Complement receptors are expressed on cells of the innate and the adaptive immune system. They play important roles in pathogen and danger sensing as they translate the information gathered by complement fluid phase sensors into cellular responses. Further, they control complement activation on viable and apoptotic host cells, clearance of immune complexes and mediate opsonophagocytosis. More recently, evidence has accumulated that complement receptors form a complex network with other innate receptors systems such as the Toll-like receptors, the Notch signaling system, IgG Fc receptors and C-type lectin receptors contributing to the benefit and burden of innate and adaptive immune responses in autoimmune and allergic diseases as well as in cancer and transplantation. Here, we will discuss recent developments and emerging concepts of complement receptor activation and regulation with a particular focus on the differentiation, maintenance and contraction of effector and regulatory T cells. PMID- 23796749 TI - Functional analysis of an ATP-binding cassette transporter protein from Aspergillus fumigatus by heterologous expression in Saccharomyces cerevisiae. AB - Aspergillus fumigatus is the major filamentous fungal pathogen in humans. Although A. fumigatus can be treated with many of the available antifungal drugs, including azole compounds, drug resistant isolates are being recovered at an increasing rate. In other fungal pathogens such as the Candida species, ATP binding cassette (ABC) transporter proteins play important roles in development of clinically-significant azole resistance phenotypes. Central among these ABC transporter proteins are homologues of the Saccharomyces cerevisiae Pdr5 multidrug transporter. In this work, we test the two A. fumigatus genes encoding proteins sharing the highest degree of sequence similarity to S. cerevisiae Pdr5 for their ability to be function in a heterologous pdr5Delta strain of S. cerevisiae. Expression of full-length cDNAs for these two Afu proteins failed to suppress the drug sensitive phenotype of a pdr5Delta strain and no evidence could be obtained for their expression as green fluorescent protein (GFP) fusions. To improve the expression of one of these Afu ABC transporters (XP_755847), we changed the sequence of the cDNA to use codons corresponding to the major tRNA species in S. cerevisiae. This codon-optimized (CO Afu abcA) cDNA was efficiently expressed in pdr5Delta cells and able to be detected as a GFP fusion protein. The CO Afu abcA did not correct the drug sensitivity of the pdr5Delta strain and exhibited a high degree of perinuclear fluorescence suggesting that this fusion protein was localized to the S. cerevisiae ER. Interestingly, when these experiments were repeated at 37 degrees C, the CO Afu abcA was able to complement the drug sensitive phenotype of pdr5Delta cells and exhibited less intracellular fluorescence. Additionally, we found that the CO Afu abcA was able to reduce resistance to drugs like phytosphingosine that act via causing mislocalization of amino acid permeases in fungi. These data suggest that the Afu abcA protein can carry out two different functions of Pdr5: drug transport and regulation of protein internalization from the plasma membrane. PMID- 23796750 TI - Malvidin-3-O-beta glucoside, major grape anthocyanin, inhibits human macrophage derived inflammatory mediators and decreases clinical scores in arthritic rats. AB - Polyphenolic anthocyanins are major colorful compounds in red fruits, known to prevent cardiovascular and other diseases. Grape polyphenols are a mixture of various molecules and their exact contribution to above bioactivities remains to be clarified. In the present study, we first analyzed the effect of purified grape-derived compounds on human peripheral blood mononuclear cell (PBMC) survival, proliferation, as well as for their ability to inhibit the activation of human normal macrophages. Data indicated that malvidin-3-O-beta glucoside (Malbetag), the major grape anthocyanin, is bioactive with no toxicity on human PBMC. Malbetag decreased the transcription of genes encoding inflammatory mediators, confirmed by the inhibition of TNFalpha, IL1, IL-6 and iNOS-derived nitric oxide (NO) secretion from activated macrophages. As Malbetag also inhibited inflammatory response of rat macrophages, we investigated the anti inflammatory potential of Malbetag in chronic rat adjuvant-induced arthritis (AIA). Malbetag significantly diminished inflammatory cachexia and arthritic paw scores in AIA rats at both therapeutic and preventive levels. In vivo effects of Malbetag correlated with down-regulation of NO generation from AIA rats' peritoneal macrophages ex vivo. These data indicate that Malbetag, major grape anthocyanin, is a potent anti-inflammatory agent in vitro and in vivo, without detectable toxic effect. PMID- 23796752 TI - Morphine mediates a proinflammatory phenotype via MU-opioid receptor-PKCE-Akt ERK1/2 signaling pathway in activated microglial cells. AB - Anti-nociceptive tolerance to opioids severely limits their clinical efficacy for the treatment of chronic pain syndromes. Glia has a central role in the development of morphine tolerance. Here, we characterized the receptor-proximal signaling events that link MU-opioid receptors to activation of Akt and ERKs in lipopolysaccharide (LPS)-stimulated murine microglial cells with the aim to define the molecular mechanism contributing to the ability of morphine to increase inflammatory mediators such as nitric oxide (NO), tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6 in activated microglial cells. In particular, the role of PKCE isoform in MU-opioid-induced inflammatory response in microglia was investigated. The results indicate that morphine increases the LPS-induced expression and activation of PKCE and stimulates Akt pathway upstream of ERK1/2 and iNOS. Furthermore, we found that morphine enhanced the release of IL-1beta, TNF-alpha, IL-6, and of NO via MU-opioid receptor-PKCE signaling pathway in activated microglial cells, mediating a proinflammatory phenotype in mouse microglial cells. Together, these data suggest that the modulation of MU opioid receptor signaling on microglia through PKCE selective inhibition may provide a means to attenuate glial activation and, as a consequence, to treat opioid development of tolerance and dependence. PMID- 23796751 TI - Nicotinic modulation of intrinsic brain networks in schizophrenia. AB - The nicotinic receptor is a promising drug target currently being investigated for the treatment of cognitive symptoms in schizophrenia. A key step in this process is the development of noninvasive functional neuroimaging biomarkers that can be used to determine if nicotinic agents are eliciting their targeted biological effect, ideally through modulation of a fundamental aspect of neuronal function. To that end, neuroimaging researchers are beginning to understand how nicotinic modulation affects "intrinsic" brain networks to elicit potentially therapeutic effects. An intrinsic network is a functionally and (often) structurally connected network of brain areas whose activity reflects a fundamental neurobiological organizational principle of the brain. This review summarizes findings of the effects of nicotinic drugs on three topics related to intrinsic brain network activity: (1) the default mode network, a group of brain areas for which activity is maximal at rest and reduced during cognitive tasks, (2) the salience network, which integrates incoming sensory data with prior internal representations to guide future actions and change predictive values, and (3) multi-scale complex network dynamics, which describe these brain's ability to efficiency integrate information while preserving local functional specialization. These early findings can be used to inform future neuroimaging studies that examine the network effects of nicotinic agents. PMID- 23796753 TI - Characterization of a novel proinflammatory effect mediated by BK and the kinin B2 receptor in human preadipocytes. AB - Obesity and adipose tissue contribute to local and systemic inflammation. However the role of the inflammatory mediator bradykinin (BK) in this context is not known. We therefore evaluated the effect of BK on adipokines secretion in human preadipocytes during the course of differentiation and characterized the receptors involved. Results obtained from antibody array and ELISA experiments showed that several adipokines are released by human preadipocytes under basal conditions while BK specifically stimulated the production of interleukin(IL)-6 and IL-8. The effect of BK diminished with the progression of differentiation, being almost inactive on adipocytes. In preadipocytes, BK also induced a rapid and transient [Ca2+](i) mobilization, a rapid and sustained increase in ERK1/2 activation and enhanced forskolin-stimulated cAMP accumulation. BK was without effect on cell proliferation and viability as assessed by bromodeoxyuridine incorporation, WST-1 conversion, or lactate dehydrogenase leakage and was without effect on adipogenesis as measured by triglyceride accumulation, GPDH activity and leptin release. The B1 receptor agonist, Lys-[des-Arg9]-BK, displayed poor activity or was without effect while overall BK effects were prevented by the selective B2 receptor antagonist, fasitibant chloride, but not by the B1 selective antagonist, Lys-[Leu8][des-Arg9]-BK. Immunoblot analysis and immunofluorescence studies showed that the kinin B2 receptor was essentially expressed at the beginning of the differentiation program. In conclusion, human preadipocytes expressed kinin B2 receptors linked to multiple signaling pathways, IL-6 and IL-8 production, and BK proinflammatory response in adipose tissue could be prevented by fasitibant chloride. PMID- 23796754 TI - Immune response variations to Salmonella enterica serovar Typhi recombinant porin proteins in mice. AB - OBJECTIVES: Typhoid fever is caused by Salmonella enterica serovar Typhi. OmpC, OmpF and OmpA, the three major outer membrane proteins (OMPs), could serve as vaccine candidates. METHODS: The porins antigenicity was predicted in silico. The OMP genes were amplified, cloned and expressed. Sero-reactivities of the recombinant proteins purified by denaturing method were assayed by ELISA. BALB/c mice were immunized with the recombinant porins followed by bacterial challenge. RESULTS: Bacterial challenge of the animal model brought about antibody triggering efficacy of the antigen in OmpF > OmpC > OmpA order. Experimental findings validated the in silico results. None of the antigens had synergic or antagonistic effects on each other from immune system induction points of view. Despite their high immunogenicity, none of the antigens was protective. However, administration of two or three antigens simultaneously resulted in retardation of lethal effect. Porins, in addition to their specific functions, share common functions. Hence, they can compensate for each other's functions. CONCLUSIONS: The produced antibodies could not eliminate the pathogenicity by blockade of one or some of the antigens. Porin antigens are not suitable vaccine candidates alone or in denatured forms. Native forms of the antigens maybe studied for protective immunogenicity. PMID- 23796755 TI - Validation of a parental questionnaire to identify atopic dermatitis in a population-based sample of children up to 2 years of age. AB - BACKGROUND: Validated eczema questionnaires have been available for schoolchildren only, but the incidence of atopic dermatitis (AD) is highest during infancy. OBJECTIVE: To validate a parental questionnaire to identify AD in children up to 2 years of age. METHODS: Parents of 476 children answered a written questionnaire prior to an examination by a physician. Sensitivity, specificity, predictive values and test-retest reliability of the questionnaire were assessed. RESULTS: A total of 245 (51%) girls and 231 (49%) boys, aged 1-24 months, with and without physician-diagnosed AD participated. Seventy-one children (15%) had physician-diagnosed AD. Validation of the questionnaire by comparisons with physicians' diagnoses showed a sensitivity of 0.87 (95% confidence interval, CI, 0.77-0.94) and a specificity of 0.98 (95% CI, 0.96 0.99). The positive predictive value was 0.90 (95% CI, 0.80-0.96) and the negative predictive value was 0.98 (95% CI, 0.96-0.99). CONCLUSION: The questionnaire identified AD in children aged 0-2 years with high accuracy. PMID- 23796756 TI - Variables influencing the frictional behaviour of in vivo human skin. AB - In the past decades, skin friction research has focused on determining which variables are important to affect the frictional behaviour of in vivo human skin. Until now, there is still limited knowledge on these variables. This study has used a large dataset to identify the effect of variables on the human skin, subject characteristics and environmental conditions on skin friction. The data are obtained on 50 subjects (34 males and 16 females). Friction measurements represent the friction between in vivo human skin and an aluminium sample, assessed on three anatomical locations. The coefficient of friction increased significantly (p<0.05) with increasing age, increasing ambient temperature and increasing relative air humidity. A significant inversely proportional relationship was found between friction and both the amount of hair present on the skin and the height of the subject. Other outcome variables in this study were the hydration of the skin and the skin temperature. PMID- 23796757 TI - The root of reduced fertility in aged women and possible therapentic options: current status and future perspects. AB - It is well known that maternal ageing not only causes increased spontaneous abortion and reduced fertility, but it is also a high genetic disease risk. Although assisted reproductive technologies (ARTs) have been widely used to treat infertility, the overall success is still low. The main reasons for age-related changes include reduced follicle number, compromised oocyte quality especially aneuploidy, altered reproductive endocrinology, and increased reproductive tract defect. Various approaches for improving or treating infertility in aged women including controlled ovarian hyperstimulation with intrauterine insemination (IUI), IVF/ICSI-ET, ovarian reserve testing, preimplantation genetic diagnosis and screening (PGD/PGS), oocyte selection and donation, oocyte and ovary tissue cryopreservation before ageing, miscarriage prevention, and caloric restriction are summarized in this review. Future potential reproductive techniques for infertile older women including oocyte and zygote micromanipulations, derivation of oocytes from germ stem cells, ES cells, and iPS cells, as well as through bone marrow transplantation are discussed. PMID- 23796758 TI - Effects of phytate on thyroid gland of rats intoxicated with cadmium. AB - Cadmium (Cd) is one of the most dangerous occupational and environmental toxins. The objective of the present study is to examine the potential prophylactic effects of phytic acid (PA) on thyroid hormones of male rats intoxicated with Cd. The male albino rats were divided into five groups: group I (control) was fed with the basal diet, group II was intoxicated with Cd in drinking water, groups III, IV, and V were intoxicated with Cd in drinking water and fed with the diet containing 3.5, 7, and 10 g of PA/kg, respectively. The results indicated that the serum calcium, iron (Fe), and total Fe binding capacity levels and serum T3 and T4 in Cd-treated rats of group II were decreased when compared with the control group, while PA-administered groups with Cd showed a significant improvement when compared with the Cd-treated rats only. Serum thyroid stimulating hormone (TSH) level was significantly increased in Cd-treated rats compared with the control group, while the addition of PA in diet decreased the high levels of TSH. These results indicated a prophylactic effect of PA against Cd-induced toxicity in rats. PMID- 23796759 TI - Amelioration of carbon tetrachloride-induced pulmonary toxicity with Oxalis corniculata. AB - This research work was planned to investigate the antioxidant potential of methanolic crude extract of Oxalis corniculata (OCME) against lung injuries initiated by carbon tetrachloride (CCl4) in rats at histological and biochemical level. A total of 42 female Sprague Dawley rats were randomly distributed in to seven groups and each group comprised of six rats. Experiment was completed in 22 days (10 doses at alternate days). Group I was not treated (control rats), while group II was administered with vehicles (olive oil and dimethyl sulfoxide), groups III, IV, and V were treated with 1 ml kg(-1) body weight (b.w.) of CCl4 (20% in olive oil). Group III received only CCl4, whereas groups IV and V were administered with 100 and 200 mg kg(-1) b.w. of OCME, respectively. Group VI was administered with OCME (200 mg kg(-1) b.w.) alone. Group VII was treated with sylimarin (50 mg kg(-1) b.w.). CCl4 enhanced the lipid peroxidation while reduced the glutathione in lung samples. Activities of antioxidant enzymes, catalase, peroxidase, superoxide dismutase, and glutathione-S-transferase decreased in lung homogenates with CCl4. Treatment of CCl4 induced deleterious changes in the microanatomy of lungs by rupturing the alveolar septa, thickening of alveolar walls, and damaging the cells with subsequent collapse of blood vessels due to the accumulation of degenerated blood cells. OCME, dose dependently, prevented the alterations in these parameters. These results suggest that OCME protected the lungs due to its intrinsic properties by scavenging of free radicals generated by CCl4. PMID- 23796760 TI - Synergistic effect of black tea and curcumin in improving the hepatotoxicity induced by aflatoxin B1 in rats. AB - Aflatoxin B1 (AFB1) is a toxic compound commonly found as a contaminant in human food. It is carcinogenic due its potential in inducing the oxidative stress and distortion of the most antioxidant enzymes. Since black tea possesses strong antioxidant activity, it protects cells and tissues against oxidative stress. Curcumin (CMN), a naturally occurring agent, has a combination of biological and pharmacological properties that include antioxidant activity. Therefore, the present study was carried out to investigate the possible role of separate and mixed supplementation of black tea extract and CMN in the hepatotoxicity induced by AFB1 in rats. A total of 48: adult male Sprague Dawley rats were randomly divided into eight groups with six rats in each group. Group 1 (normal control) includes rats that received no treatment. Groups 2, 3, and 4 (positive control) include rats that received olive oil, black tea extract, and CMN, respectively. Group 5 includes rats that received AFB1 at a dose of 750 MUg/kg body weight (b.w.) dissolved in olive oil. Groups 6, 7, and 8 include rats that received AFB1 along with 2% black tea extract, CMN at a dose of 200 mg/kg b.w., and both black tea extract and CMN at the same previous doses, respectively. After 90 days, biochemical and histopathological examination was carried out for the blood samples and liver tissues. A significant decrease in the antioxidant enzymes and a significant increase in the lipid peroxidation and hydrogen peroxide in the rats treated with AFB1 were observed. Moreover, there were dramatic changes in the liver function biomarkers, lipid profile, and liver architecture. Supplementation of black tea extract or CMN showed an efficient role in repairing the distortion of the biochemical and histological changes induced by AFB1 in liver. This improvement was more pronounced when both CMN and black tea were used together. PMID- 23796761 TI - Recall strategies for the verbal fluency test in patients with multiple sclerosis. AB - Multiple sclerosis (MS) is a neurodegenerative disease characterised by inflammation and demyelination. It generates irreversible myelin changes, which in turn give rise to physical and cognitive disorders. The verbal fluency test (VF) has been shown to be a sensitive tool for detecting cognitive impairment in these patients. OBJECTIVE: To compare quantitative and qualitative aspects of performance on semantic and phonological fluency tests between MS patients and healthy controls by analysing total words produced and strategies used (clusters and switching). METHOD: We evaluated 46 patients with MS and 33 healthy controls using the VF test. RESULTS: The semantic VF task revealed no significant differences between groups; for the phonological task, patients demonstrated reduced word production (F [77]=2.286 P<.001) and poorer use of grouping strategies, resulting in more frequent switching (F [77]=3.808 P<.005). CONCLUSIONS: These results support using qualitative analysis for recall strategies, since the technique provides data about which components of the task are affected by brain damage. Clusters depend on the integrity of semantic memory, while switching has to do with developing effective search strategies, cognitive flexibility, and the ability to modify responses. Frontal lobe damage has been reported in MS, and this is consistent with results from the phonological VF test. PMID- 23796762 TI - Collet-Sicard syndrome. PMID- 23796763 TI - 'Born in Michigan? You're in the biobank': engaging population biobank participants through Facebook advertisements. AB - BACKGROUND/AIMS: Despite a broad call for biobanks to use social media, data is lacking regarding the capacity of social media tools, especially advertising, to engage large populations on this topic. METHODS: We used Facebook advertising to engage Michigan residents about the BioTrust for Health. We conducted a low budget (=20% reduction from baseline) for 2 consecutive visits after 3 months, vision-threatening complications, de novo glaucoma procedures, or loss of light perception. Secondary outcome measures include IOP, medication use, visual acuity, complications, and interventions. RESULTS: A total of 238 patients were enrolled and randomized; 124 received the Ahmed implant and 114 received the Baerveldt implant. Baseline characteristics were similar in both groups. Half the study group had secondary glaucoma, and 37% had previously failed trabeculectomy. The mean preoperative IOP was 31.4+/-10.8 mmHg on 3.1+/-1.0 glaucoma medications. Median baseline Snellen visual acuity was 20/100. At 3 years, the cumulative probability of failure was 51% in the Ahmed group and 34% in the Baerveldt group (P = 0.03). Mean IOP was 15.7+/-4.8 mmHg in the Ahmed group (49% reduction) and 14.4+/-5.1 mmHg in the Baerveldt group (55% reduction; P = 0.09). Mean number of glaucoma medications was 1.8+/-1.4 in the Ahmed group (42% reduction) and 1.1+/ 1.3 in the Baerveldt group (65% reduction; P = 0.002). There was a moderate but similar decrease in visual acuity in both groups (P< 0.001). The 2 groups had similar complication rates (52% Ahmed, 62% Baerveldt; P = 0.12); however, the Baerveldt group had a higher rate of hypotony-related vision-threatening complications (0% Ahmed, 6% Baerveldt; P = 0.005). More interventions were required in the Baerveldt group, although the difference did not reach statistical significance (38% Ahmed, 50% Baerveldt; P = 0.07). Most complications were transient, and most interventions were slit-lamp procedures. CONCLUSIONS: Both devices were effective in reducing IOP and glaucoma medications. The Baerveldt group had a lower failure rate and required fewer medications than the Ahmed group after 3 years, but it experienced more hypotony-related vision threatening complications. PMID- 23796765 TI - Ciliary body medulloepithelioma: analysis of 41 cases. AB - PURPOSE: To describe the clinical features, histopathology, treatment, and outcomes of ciliary body medulloepithelioma. DESIGN: Retrospective study. PARTICIPANTS: Forty-one patients with medulloepithelioma. INTERVENTION: Cryotherapy, plaque radiotherapy, external beam radiotherapy, tumor removal by partial lamellar sclerouvectomy (PLSU), or enucleation. MAIN OUTCOME MEASURES: Metastasis and death. RESULTS: Of 41 patients with ciliary body medulloepithelioma, the median age at diagnosis was 5 years. The mean tumor basal diameter was 11 mm, and the mean tumor thickness was 7 mm. Related features included secondary glaucoma (n = 18, 44%), iris neovascularization (n = 21, 51%), cataract (n = 19, 46%), lens subluxation (n = 11, 27%), lens coloboma (n = 8, 20%), retrolental neoplastic cyclitic membrane (n = 21, 51%), intratumoral cysts (n = 25, 61%), and extraocular extension (n = 4, 10%). There was systemic association with pleuropulmonary blastoma in 2 cases (5%). Primary tumor treatment included enucleation (n = 21, 60%), tumor removal by PLSU (n = 8, 23%), plaque radiotherapy (n = 3, 9%), external beam radiotherapy (n = 1, 3%), cryotherapy (n = 1, 3%), or palliative chemotherapy (n = 1, 3%). In 1 case, medulloepithelioma was diagnosed histopathologically after inadvertent evisceration for blind painful eye. Subsequent treatment for residual or recurrent tumor in cases treated conservatively/inappropriately (n = 15) was necessary in 7 cases (47%). Histopathology disclosed benign features in 6 cases (20%), malignant features in 24 cases (80%), teratoid features in 11 cases (37%), and nonteratoid features in 19 cases (63%). In the 26 enucleated eyes, other features included retrolental neoplastic cyclitic membrane (n = 18, 69%), neoplastic epiretinal membrane (n = 6, 23%), and persistent hyaloid artery (n = 6, 23%). Systemic metastasis occurred in 3 cases (8%) over a mean follow-up of 49 months, all of whom presented with extrascleral extension of tumor due to mean delay in diagnosis by 39 months. CONCLUSIONS: Medulloepithelioma most commonly occurs in children. Systemic association with pleuropulmonary blastoma rarely is found. Patients with extrascleral medulloepithelioma are at risk for metastasis. PMID- 23796766 TI - Ophthalmic surgery simulator training improves resident performance of capsulorhexis in the operating room. AB - PURPOSE: To assess the effect of a Capsulorhexis Intensive Training Curriculum (CITC) on the rates of errant, continuous, curvilinear capsulorhexes (CCCs) during cataract surgery among resident surgeons at a teaching hospital. DESIGN: Retrospective educational interventional case series. PARTICIPANTS AND CONTROLS: A total of 1037 consecutive cataract surgeries performed at Harbor-UCLA Medical Center during 4 consecutive academic years were considered. The baseline cohort consists of 434 cataract surgeries performed during the 2 academic years before the intervention. The postintervention cohort consists of 603 cataract surgeries performed during the following 2 consecutive academic years. INTERVENTION: The principal intervention was the introduction of the CITC for residents on the Eyesi (VRmagic, Mannheim, Germany) ophthalmic virtual reality surgical simulator. MAIN OUTCOME MEASURES: The main outcome measure was the rate of errant CCCs among the capsulorhexes performed during resident surgical cases. Errant CCCs were defined as attempted CCCs that resulted in the attending physician taking over, radialization of the CCC, conversion to can-opener capsulorhexis, or any combination of the 3 aforementioned conditions. Secondary measures included the use of trypan blue during CCC and correlating errant CCC and surgeons' level of training (postgraduate year [PGY]). RESULTS: There were 68 errant CCCs (15.7%) in the baseline cohort and 30 errant CCCs (5.0%; P<0.0001) in the postintervention cohort, a 3.2-fold or 68% reduction. The use of trypan blue increased from 55.3% in the baseline cohort to 76.0% in the postintervention cohort (P<0.00001), but within each cohort there was no significant difference in the rate of errant CCCs whether trypan blue was used or not. In the baseline cohort, there was a statistical trend toward fewer errant CCCs among PGY 4 (14.6%) compared with PGY 3 (22.8%) surgeons (P = 0.12). The postintervention cohort showed no significant difference in errant CCC rates between PGY 3 (4.4%) and PGY 4 (5.1%) surgeons (P = 1.00). CONCLUSIONS: This study strongly suggests that virtual reality surgical simulation training with the CITC on the Eyesi reduces the rate of errant capsulorhexes. The incorporation of a formal program for surgical training via virtual reality simulation should be strongly considered in ophthalmology resident surgical education to reduce the unnecessary risk of complications for live patients. PMID- 23796768 TI - Design and synthesis of conformationally restricted capsaicin analogues based in the 1, 3, 4-thiadiazole heterocycle reveal a novel family of transient receptor potential vanilloid 1 (TRPV1) antagonists. AB - 4-hydroxy-3-methoxybenzaldehyde was used as starting material to obtain a number of 1, 3, 4-thiadiazole alkylamide derivatives. The pharmacological properties of these conformationally restricted capsaicin analogues were evaluated on HEK-293T cells transiently expressing TRPV1 receptor. By means of a highthroughput calcium imaging assay we find that 1, 3, 4-thiadiazoles (compounds 8-15) act as potent antagonists of the capsaicin receptor, inhibiting both, the capsaicin- and temperature-dependent activation. Docking studies suggested a different binding orientation on the vanilloid binding site when compared with capsaicin analogues, such as 5-iodononivamide. Overall, our studies suggest that 1, 3, 4-thiadiazoles interact with capsaicin's binding region of the receptor, although using a different set of interactions within the vanilloid binding pocket. PMID- 23796767 TI - A novel one-pot synthesis and preliminary biological activity evaluation of cis restricted polyhydroxy stilbenes incorporating protocatechuic acid and cinnamic acid fragments. AB - A series of new stilbenes 4a-e, 5 were synthesized through a novel one-pot Perkin like reaction between 6,7-dimethoxyhomophthalic anhydride and aromatic aldehydes, followed by treatment with BBr3. This synthesis is straightforward and allows polyhydroxylated cis-stilbenes gathering two well-known pharmacophoric fragments to be obtained in good yields and for short reaction times. The structure of the newly synthesized compounds was established by spectroscopic methods ((1)H NMR, (13)C NMR, IR and HRMS) and the double bond configuration was unequivocally elucidated by means of gated decoupling (13)C NMR spectra and 2D NOESY experiments. Preliminary differentiating screening of their radical scavenging, antibacterial, anti-fungal and tyrosinase inhibitory activity was further performed. The results obtained suggest that the tested compounds possess a triple biological action as potent radical scavengers, antifungal agents and tyrosinase inhibitors in micromolar concentration. The most promising bioactive compound amongst the others was 4a, acting as excellent radical scavenger against DPPH(*) radical (IC50 <= 10 MUM), antifungal agent suppressing the growth of Fusarium graminearum (89% inhibition at 0.17 MUmol/mL), and tyrosinase inhibitor showing higher activity than hydroquinone at 23 MUM. PMID- 23796769 TI - Dermatology life quality index and side effects after topical photodynamic therapy of actinic keratosis. AB - BACKGROUND: Photodynamic therapy (PDT) is an excellent treatment option for actinic keratosis. However the side effects lead to an impairment of the patients' quality of life. OBJECTIVES: To evaluate the impact of PDT on patients' quality of life and to determine the frequency and intensity of side effects over the course of 4 weeks post PDT. PATIENTS AND METHODS: 22 patients with actinic keratosis in the face were included into this prospective study. Pain was measured using a visual analog scale immediately and 8 h after PDT. The Dermatology Life Quality Index (DLQI) was assessed at screening, after treatment as well as 2 and 4 weeks after PDT. The physician and patient evaluated the intensity of side effects during the treatment, 2 and 4 weeks post PDT. Additionally, the patient documented side effects daily from the 1st to the 14th day after PDT and on day 28 post PDT, using a diary. RESULTS: We observed a significant (p < 0.001) increase in the DLQI from 1.6 +/- 1.7 prior to PDT to 7.3 +/- 4.9 post PDT. The DLQI normalized in the following 4 weeks. Immediately and 8 h after PDT mean pain was 4.3 +/- 2.5 and 2.3 +/- 2.1. Side effects documented by the patients were erythema (100%), pain, burning, edema (90.9%), itching (86.4%), scaling (81.8%) and pustules (59.1%). No scar formation, hyper-/hypopigmentation or infections were observed. CONCLUSION: PDT has a significant temporary impact on patients' DLQI. Transitory side effects are common and show typical kinetics. PMID- 23796770 TI - Intermedin modulates hypoxic pulmonary vascular remodeling by inhibiting pulmonary artery smooth muscle cell proliferation. AB - BACKGROUND: Hypoxic pulmonary arterial hypertension (PAH) is a disabling disease with limited treatment options. Hypoxic pulmonary vascular remodeling is a major cause of hypoxic PAH. Pharmacological agents that can inhibit the remodeling process may have great therapeutic value. OBJECTIVE: To examine the effect of intermedin (IMD), a new calcitonin gene-related peptide family of peptide, on hypoxic pulmonary vascular remodeling. METHODS: Rats were exposed to normoxia or hypoxia (~10% O(2)), or exposed to hypoxia and treated with IMD, administered by an implanted mini-osmotic pump (6.5 MUg/rat/day), for 4 weeks. The effects of IMD infusion on the development of hypoxic PAH and right ventricle (RV) hypertrophy, on pulmonary vascular remodeling, on pulmonary artery smooth muscle cell (PASMC) proliferation and apoptosis, and on the activations of l-arginine nitric oxide (NO) pathway and endoplasmic reticulum stress apoptotic pathway were examined. RESULTS: Rats exposed to hypoxia developed PAH and RV hypertrophy. IMD treatment alleviated PAH and prevented RV hypertrophy. IMD inhibited hypoxic pulmonary vascular remodeling as indicated by reduced wall thickness and increased lumen diameter of pulmonary arterioles, and decreased muscularization of distal pulmonary vasculature in hypoxia-exposed rats. IMD treatment inhibited PASMC proliferation and promoted PASMC apoptosis. IMD treatment increased tissue level of constitutive NO synthase activity and tissue NO content in lungs, and enhanced l-arginine uptake into pulmonary vascular tissues. IMD treatment increased cellular levels of glucose-regulated protein (GRP) 78 and GRP94, two major markers of endoplasmic reticulum (ER) stress, and increased caspase-12 expression, the ER stress-specific caspase, in lungs and cultured PASMCs. CONCLUSIONS: These results demonstrate that IMD treatment attenuates hypoxic pulmonary vascular remodeling, and thereby hypoxic PAH mainly by inhibiting PASMC proliferation. Promotion of PASMC apoptosis may also contribute to the inhibitory effect of IMD. Activations l-arginine-NO pathway and of ER stress-specific apoptosis pathway could be the mechanisms mediating the anti-proliferative and pro-apoptotic effects of IMD. PMID- 23796771 TI - Reinforcing and discriminative stimulus properties of music in goldfish. AB - This paper investigated whether music has reinforcing and discriminative stimulus properties in goldfish. Experiment 1 examined the discriminative stimulus properties of music. The subjects were successfully trained to discriminate between two pieces of music--Toccata and Fugue in D minor (BWV 565) by J. S. Bach and The Rite of Spring by I. Stravinsky. Experiment 2 examined the reinforcing properties of sounds, including BWV 565 and The Rite of Spring. We developed an apparatus for measuring spontaneous sound preference in goldfish. Music or noise stimuli were presented depending on the subject's position in the aquarium, and the time spent in each area was measured. The results indicated that the goldfish did not show consistent preferences for music, although they showed significant avoidance of noise stimuli. These results suggest that music has discriminative but not reinforcing stimulus properties in goldfish. PMID- 23796772 TI - Habitat richness affects home range size in a monogamous large rodent. AB - In monogamous species, after pair formation, the main reason for ranging movements is not searching for a mate, but for other important resources e.g. food. We monitored a total of 20 radio-tagged adult, paired crested porcupines in four areas of different habitat richness. No sexual size dimorphism was assessed. Body mass and habitat richness showed collinearity. For both sexes, home range size was correlated to habitat richness, with a significant inverse exponential regression. Opposite to natural foragers, living in poor habitats, crop foragers had smaller home ranges, with their dens significantly closer to cultivations. Both availability of food resources and den sites are key variables to determine home range size. PMID- 23796774 TI - Rapid, accurate time estimation in zebrafish (Danio rerio). AB - Zebrafish were tested in an appetitive Pavlovian delayed conditioning task. After an intertrial interval of k*T s (k=11.25; T=8, 16 or 32 s), a small, translucent vertical pole was illuminated (CS) for T s. Food was presented at T/2 s. Pole biting response latencies from CS onset were a linear function of the food delay T/2, with slope approximating unity (proportional timing), and standard deviation proportional to latency (scalar timing). Response latencies tracked changes in food delays even when they changed every other day. These findings are significant because the zebrafish genome has recently been sequenced, opening the door to studies in the genetics of interval timing. PMID- 23796773 TI - Variation in social and sexual behaviour in four species of aposematic seed bugs (Hemiptera: Lygaeidae): the role of toxic and non-toxic food. AB - Understanding variation in social behaviour both within and among species continues to be a challenge. Evolutionary or ecological theory typically predicts the optimal behaviour for an animal under a given set of circumstances, yet the real world presents much greater variation in behaviour than predicted. This variation is apparent in many social and sexual interactions, including mate choice, and has led to a renewed focus on individual variation in behaviour. Here we explore within and among species variation in social behaviour in four species of aposematic seed bug (Lygaeidae: Hemiptera). These species are Mullerian mimics, with characteristic warning colouration advertising their chemical toxicity. We examine the role of diet in generating variation in two key behaviours: social aggregation of nymphs and mate choice. We test how behaviour varies with exposure to either milkweed (a source of defensive compounds) or sunflower (that provides no defence). We show that although the four species vary in their food preferences, and diet influences their life-history (as highlighted by body size), social aggregation and mate choice is relatively unaffected by diet. We discuss our findings in terms of the evolution of aposematism, the importance of automimicry, and the role of diet in generating behavioural variation. PMID- 23796775 TI - Is killer whale dialect evolution random? AB - The killer whale is among the few species in which cultural change accumulates over many generations, leading to cumulative cultural evolution. Killer whales have group-specific vocal repertoires which are thought to be learned rather than being genetically coded. It is supposed that divergence between vocal repertoires of sister groups increases gradually over time due to random learning mistakes and innovations. In this case, the similarity of calls across groups must be correlated with pod relatedness and, consequently, with each other. In this study we tested this prediction by comparing the patterns of call similarity between matrilines of resident killer whales from Eastern Kamchatka. We calculated the similarity of seven components from three call types across 14 matrilines. In contrast to the theoretical predictions, matrilines formed different clusters on the dendrograms made by different calls and even by different components of the same call. We suggest three possible explanations for this phenomenon. First, the lack of agreement between similarity patterns of different components may be the result of constraints in the call structure. Second, it is possible that call components change in time with different speed and/or in different directions. Third, horizontal cultural transmission of call features may occur between matrilines. PMID- 23796780 TI - An ERP study of motor compatibility effects in action language. AB - This ERP study explores the brain's response to the manipulation of motor compatibility in action-related language. In Experiment 1 participants read sentences in which a protagonist performed two different manual actions either simultaneously or consecutively (e.g. While/after cleaning the wound he unrolled the bandage...). The ERPs were measured in the second-clause verb (e.g. unrolled) and noun (e.g. bandage). Notably, only the noun showed compatibility effects, namely a larger N400 in the simultaneous (incompatible) version than in the consecutive (compatible) version, suggesting that readers need to integrate the meaning of the whole sentence to evaluate the feasibility of the actions. In Experiment 2, motor compatibility was manipulated in a different way: all the sentences described the protagonist as performing two simultaneous actions that were both manual (While cleaning the wound he unrolled the bandage), or one action that was perceptual and the other manual (While looking at the wound he unrolled the bandage). The N400 effects for the former incompatible condition were replicated, again in the second-clause noun. The results demonstrated that readers of action language employ their pragmatic world knowledge to test the feasibility of motor actions, taking into account the embodied constraints of such actions. PMID- 23796781 TI - Oxygen and glucose deprivation (OGD)-induced spreading depression in the Substantia Nigra. AB - Spreading depression (SD) is a profound depolarization of neurons and glia that propagates in a wave-like manner across susceptible brain regions, and can develop during periods of compromised cellular energy such as ischemia, when it influences the severity of acute neuronal damage. Although SD has been well characterized in the cerebral cortex and hippocampus, little is known of this event in the Substantia Nigra (SN), a brainstem nucleus engaged in motor control and reward-related behavior. Transverse brain slices (250 MUm; P21-23 rats) containing the SN were subject to oxygen and glucose deprivation (OGD) tests, modeling brain ischemia. SD developed in lateral aspects of the SN within 3.3+/ 0.2 min of OGD onset, and spread through the Substantia Nigra pars reticulata (SNr), as indicated by fast-occurring and propagating increased tissue light transmittance and negative shift of extracellular DC potential. These events were associated with profound mitochondrial membrane depolarization (DeltaPsim) throughout the SN, as demonstrated by increased Rhodamine 123 fluorescence. Extracellular recordings from individual SNr neurons indicated rapid depolarization followed by depolarizing block, while dopaminergic neurons in the Substantia Nigra pars compacta (SNc) showed inhibition of firing associated with hyperpolarization. SD evoked in the SNr was similar to OGD-induced SD in the CA1 region in hippocampal slices. In the hippocampus, SD also developed during anoxia or aglycemia alone (associated with less profound DeltaPsim than OGD), while these conditions rarely led to SD in the SNr. Our results demonstrate that OGD consistently evokes SD in the SN, and that this phenomenon only involves the SNr. It remains to be established whether nigral SD contributes to neuronal damage associated with a sudden-onset form of Parkinson's disease known as 'vascular parkinsonism'. PMID- 23796782 TI - Irradiance encoding in the suprachiasmatic nuclei by rod and cone photoreceptors. AB - Light information is transmitted to the central clock of the suprachiasmatic nuclei (SCN) for daily synchronization to the external solar cycle. Essential for synchronization is the capacity of SCN neurons to respond in a sustained and irradiance-dependent manner to light. Melanopsin has been considered to mediate this photosensory task of irradiance detection. By contrast, the contribution of the classical photoreceptors in irradiance encoding is less clear. Here we investigate the role of classical photoreceptors by in vivo electrophysiological responses in freely moving animals to specific wavelengths of light (UV, lambdamax 365 nm; blue, lambdamax 467 nm; and green, lambdamax 505 nm) in both melanopsin-deficient (Opn4(-/-)) mice and mice lacking rods and cones (rd/rd cl). Short- and long-wavelength light induced sustained irradiance-dependent responses in congenic wild-type mice (+19.6%). Unexpectedly, sustained responses to light persisted in Opn4(-/-) mice (+18.4%). These results provide unambiguous evidence that classical photoreceptors can transmit irradiance information to the SCN. In addition, at light intensities that would stimulate rod and cone photoreceptors, the SCN of rd/rd cl mice showed greatly reduced sustained responses to light (+7.8%). Collectively, our data demonstrate a role for classical photoreceptors in illuminance detection by the SCN. PMID- 23796784 TI - alpha1,6-Fucosylation regulates neurite formation via the activin/phospho-Smad2 pathway in PC12 cells: the implicated dual effects of Fut8 for TGF-beta/activin mediated signaling. AB - It is well known that alpha1,6-fucosyltransferase (Fut8) and its products, alpha1,6-fucosylated N-glycans, are highly expressed in brain tissue. Recently, we reported that Fut8-knockout mice exhibited multiple behavioral abnormalities with a schizophrenia-like phenotype, suggesting that alpha1,6-fucosylation plays important roles in the brain and neuron system. In the present study, we screened several neural cell lines and found that PC12 cells express the highest levels of alpha1,6-fucosylation. The knockdown (KD) of Fut8 promoted a significant enhancement of neurite formation and induction of neurofilament expression. Surprisingly, the levels of phospho-Smad2 were greatly increased in the KD cells. Finally, we found that the activin-mediated signal pathway was essential for these changes in KD cells. Exogenous activin, not TGF-beta1, induced neurite outgrowth and phospho-Smad2. In addition, the alpha1,6-fucosylation level on the activin receptors was greatly decreased in KD cells, while the total expression level was unchanged, suggesting that alpha1,6-fucosylation negatively regulated activin-mediated signaling. Furthermore, inhibition of activin receptor-mediated signaling or restoration of Fut8 expression rescued cell morphology and phospho Smad2 levels, which were enhanced in KD cells. Considering the fact that alpha1,6 fucosylation is important for TGF-beta-mediated signaling, the results of this study strongly suggest that Fut8 plays a dual role in TGF-beta/activin-mediated signaling. PMID- 23796783 TI - Small GTPase Rab14 down-regulates UT-A1 urea transport activity through enhanced clathrin-dependent endocytosis. AB - The UT-A1 urea transporter plays an important role in the urinary concentration mechanism. However, the molecular mechanisms regarding UT-A1 trafficking, endocytosis, and degradation are still unclear. In this study, we identified the small GTPase Rab14 as a binding partner to the C terminus of UT-A1 in a yeast 2 hybrid assay. Interestingly, UT-A1 binding is preferential for the GDP-bound inactive form of Rab14. Coinjection of Rab14 in Xenopus oocytes results in a decrease of UT-A1 urea transport activity, suggesting that Rab14 acts as a negative regulator of UT-A1. We subsequently found that Rab14 reduces the cell membrane expression of UT-A1, as evidenced by cell surface biotinylation. This effect is blocked by chlorpromazine, an inhibitor of the clathrin-mediated endocytic pathway, but not by filipin, an inhibitor of the caveolin-mediated endocytic pathway. In kidney, Rab14 is mainly expressed in IMCD epithelial cells with a pattern identical to UT-A1 expression. Consistent with its role in participating in clathrin-mediated endocytosis, Rab14 localizes in nonlipid raft microdomains and codistributes with Rab5, a marker of the clathrin-mediated endocytic pathway. Taken together, our study suggests that Rab14, as a novel UT A1 partner, may have an important regulatory function for UT-A1 urea transport activity in the kidney inner medulla. PMID- 23796785 TI - The Arp2/3 complex mediates multigeneration dendritic protrusions for efficient 3 dimensional cancer cell migration. AB - Arp2/3 is a protein complex that nucleates actin filament assembly in the lamellipodium in adherent cells crawling on planar 2-dimensional (2D) substrates. However, in physiopathological situations, cell migration typically occurs within a 3-dimensional (3D) environment, and little is known about the role of Arp2/3 and associated proteins in 3D cell migration. Using time resolved live-cell imaging and HT1080, a fibrosarcoma cell line commonly used to study cell migration, we find that the Arp2/3 complex and associated proteins N-WASP, WAVE1, cortactin, and Cdc42 regulate 3D cell migration. We report that this regulation is caused by formation of multigeneration dendritic protrusions, which mediate traction forces on the surrounding matrix and effective cell migration. The primary protrusions emanating directly from the cell body and prolonging the nucleus forms independent of Arp2/3 and dependent on focal adhesion proteins FAK, talin, and p130Cas. The Arp2/3 complex, N-WASP, WAVE1, cortactin, and Cdc42 regulate the secondary protrusions branching off from the primary protrusions. In 3D matrices, fibrosarcoma cells as well as migrating breast, pancreatic, and prostate cancer cells do not display lamellipodial structures. This study characterizes the unique topology of protrusions made by cells in a 3D matrix and show that these dendritic protrusions play a critical role in 3D cell motility and matrix deformation. The relative contribution of these proteins to 3D migration is significantly different from their role in 2D migration. PMID- 23796787 TI - Adenoviral-mediated gene transfer into bone marrow: an effective surgical technique in rat. AB - BACKGROUND: The role of transforming growth factor-beta 1 (TGF-beta1) in the onset of bone marrow fibrosis has been confirmed in some animal models. To further understand the genetic expression of some myeloproliferative disorders affecting marrow stem cells, however, it is necessary to develop a specific and reliable procedure to deliver modified adenoviral vectors into the bone marrow cavity. The aim of this paper is to report a surgical technique designed to deliver an adenoviral vector-mediated gene expressing TGF-beta1 into the bone marrow of rat femurs. METHODS: Forty-two Sprague-Dawley rats were used in the study. Rat femurs were exposed and the compact and trabecular bones at the proximal head removed. An intrabone marrow injection of a mutated TGF-beta1 adenoviral vector, a null adenoviral vector, or PBS was delivered into the bone. Three groups were accounted (n = 14 per group): fibrogenic and positive and negative controls. The quality of the surgical entrance was assessed by means of computerized tomography and histological changes were assessed by histochemistry. The concentration of TGF-beta1 in the bone marrow was determined by ELISA. RESULTS: The surgical technique was conducted under ideal timing (approx. 10 min) and no surgical or postsurgical complications were observed. Computerized tomography revealed no changes in the bone tissue and a clean entrance was delimited through the bone to the bone marrow. HE and Masson's trichrome staining indicated highly fibrotic areas in the profibrotic group and bone marrow lavage reported a significantly higher concentration of TGF-beta1 (p < 0.05) in that same group. CONCLUSIONS: The present study confirmed that the proposed surgical technique is an effective method to deliver adenoviral vectors into the femoral bone marrow to investigate the physiopathology of bone marrow fibrosis in rats. PMID- 23796786 TI - Skin microbiome imbalance in patients with STAT1/STAT3 defects impairs innate host defense responses. AB - BACKGROUND: Chronic mucocutaneous candidiasis (CMC) and hyper-IgE syndrome (HIES) are primary immunodeficiencies mainly caused by mutations in STAT1 and STAT3, respectively. CMC and HIES patients have an increased risk for skin and mucosal infections with fungal pathogens and Staphylococcus aureus. However, it is unknown whether the genetic defects in these patients also affect the skin and mucosal microbiome, which in turn may influence host defense mechanisms. METHODS: The skin and oral microbiome of CMC and HIES patients was compared to that of healthy controls at five body sites using 16S rRNA sequencing. The influence of skin colonizers on the immune response was investigated using in vitro experiments. RESULTS: The microbiome of CMC and HIES patients contained more Gram negative bacteria, especially Acinetobacter spp., and less of the normal Corynebacterium spp. compared to healthy controls. Exposure of human primary leukocytes to Acinetobacter suppressed the cytokine response to Candida albicans and S. aureus, while the normal corynebacteria did not suppress cytokine responses. DISCUSSION: These results demonstrate that central mediators of immune responses like STAT1 and STAT3 not only directly influence immune responses, but also result in changes in the skin microbiome that in turn can amplify the defective immune response against fungal and microbial pathogens. PMID- 23796788 TI - Effects of Newcastle disease virus vaccine antibodies on the shedding and transmission of challenge viruses. AB - Different genotypes of avian paramyxovirus serotype-1 virus (APMV-1) circulate in many parts of the world. Traditionally, Newcastle disease virus (NDV) is recognized as having two major divisions represented by classes I and II, with class II being further divided into sixteen genotypes. Although all NDV are members of APMV-1 and are of one serotype, antigenic and genetic diversity is observed between the different genotypes. Reports of vaccine failure from many countries and reports by our lab on the reduced ability of classical vaccines to significantly decrease viral replication and shedding have created renewed interest in developing vaccines formulated with genotypes homologous to the virulent NDV (vNDV) circulating in the field. We assessed how the amount and specificity of humoral antibodies induced by inactivated vaccines affected viral replication, clinical protection and evaluated how non-homologous (heterologous) antibody levels induced by live NDV vaccines relate to transmission of vNDV. In an experimental setting, all inactivated NDV vaccines protected birds from morbidity and mortality, but higher and more specific levels of antibodies were required to significantly decrease viral replication. It was possible to significantly decrease viral replication and shedding with high levels of antibodies and those levels could be more easily reached with vaccines formulated with NDV of the same genotype as the challenge viruses. However, when the levels of heterologous antibodies were sufficiently high, it was possible to prevent transmission. As the level of humoral antibodies increase in vaccinated birds, the number of infected birds and the amount of vNDV shed decreased. Thus, in an experimental setting the effective levels of humoral antibodies could be increased by (1) increasing the homology of the vaccine to the challenge virus, or (2) allowing optimal time for the development of the immune response. PMID- 23796789 TI - Alternative splicing of the trout Pax5 gene and identification of novel B cell populations using Pax5 signatures. AB - Pax5 is an alternatively spliced transcription factor that regulates B cell development and activation. The function of specific Pax5 isoforms is unknown. Here we report the existence of seven alternatively spliced isoforms of Pax5 in the rainbow trout. We hypothesized that B cells differentially express specific Pax5 isoforms as a means of modulating Pax5 activity during cell maturation. Flow cytometric analyses using Pax5-specific antibodies recognizing the paired domain, a central (exon 6-encoding) domain, or the C-terminus, revealed the existence of distinct Pax5-expressing cell populations in trout immune tissues. Additionally, using the transcription factor EBF, we show that Pax5 isoforms lacking a paired domain are already expressed at the earliest stages of trout (B) lymphopoiesis, and unexpectedly, that minor populations of such cells reside in blood and spleen. These data support use of differentially expressed Pax5 isoforms to identify novel B cell subsets in the form of Pax5 tissue signatures, and as such, provides new biomarkers for malignancy, infectious disease, and disease resistance in trout and humans. PMID- 23796790 TI - A bifunctional invertebrate-type lysozyme from the disk abalone, Haliotis discus discus: genome organization, transcriptional profiling and biological activities of recombinant protein. AB - Lysozyme is an important enzyme in the innate immune system that plays a vital role in fighting microbial infections. In the current study, we identified, cloned, and characterized a gene that encodes an invertebrate-type lysozyme from the disk abalone, Haliotis discus discus (abLysI). The full-length cDNA of abLysI consisted of 545 bp with an open reading frame of 393 bp that encodes 131 amino acids. The theoretical molecular mass of mature abLysI was 12.3 kDa with an isoelectric point of 8.03. Conserved features in other homologs, such as catalytic sites for lytic activity (Glu(30) and Asp(41)), isopeptidase activity (His(107)), and ten cysteine residues were identified in abLysI. Genomic sequence analysis with respect to its cDNA showed that abLysI was organized into four exons interrupted by three introns. Several immune-related transcription factor binding sites were discovered in the putative promoter region. Homology and phylogeny analysis of abLysI depicted high identity and closer proximity, respectively, with an annelid i-type lysozyme from Hirudo medicinalis, and indicated that abLysI is a novel molluscan i-type lysozyme. Tissue-specific expressional studies revealed that abLysI is mainly transcribed in hepatopancreas followed by mantle. In addition, abLysI mRNA expression was induced following bacterial (Vibrio parahaemolyticus and Listeria monocytogenes) and viral (viral hemorrhagic septicemia virus) challenges. Recombinantly expressed abLysI [(r)abLysI] demonstrated strong lytic activity against Micrococcus lysodeikticus, isopeptidase activity, and antibacterial activity against several Gram-positive and Gram-negative bacteria. Moreover, (r)abLysI showed optimum lytic activity at pH 4.0 and 60 degrees C, while exhibiting optimum isopeptidase activity at pH 7.0. Taken together, these results indicate that abLysI is potentially involved in immune responses of the disk abalone to protect it from invaders. PMID- 23796792 TI - [Metacarpal osteoarticular injuries in children]. AB - Metacarpal fractures and dislocations in the fingers are common injuries in children's hands. Most of these can be treated successfully non-operatively, although a subset requires more aggressive treatment. Results following appropriate care in children are generally good. Twenty percent of them need a reduction, need for surgical stabilization is rare. Each injury is presented, including diagnostic, therapeutic principles, pitfalls to prevent and potential complications. PMID- 23796791 TI - Peptidoglycan recognition proteins in Drosophila immunity. AB - Innate immunity is the front line of self-defense against infectious non-self in vertebrates and invertebrates. The innate immune system is mediated by germ-line encoding pattern recognition molecules (pathogen sensors) that recognize conserved molecular patterns present in the pathogens but absent in the host. Peptidoglycans (PGN) are essential cell wall components of almost all bacteria, except mycoplasma lacking a cell wall, which provides the host immune system an advantage for detecting invading bacteria. Several families of pattern recognition molecules that detect PGN and PGN-derived compounds have been indentified, and the role of PGRP family members in host defense is relatively well-characterized in Drosophila. This review focuses on the role of PGRP family members in the recognition of invading bacteria and the activation and modulation of immune responses in Drosophila. PMID- 23796793 TI - Colorectal cancer screening with blood-based biomarkers: cost-effectiveness of methylated septin 9 DNA versus current strategies. AB - BACKGROUND: Screening reduces colorectal cancer mortality, but many persons remain unscreened. Screening with a blood test could improve screening rates. We estimated the comparative effectiveness and cost-effectiveness of colorectal cancer screening with emerging biomarkers, illustrated by a methylated Septin 9 DNA plasma assay ((m)SEPT9), versus established strategies. METHODS: We conducted a cost-utility analysis using a validated decision analytic model comparing (m)SEPT9, fecal occult blood testing (FOBT), fecal immunochemical testing (FIT), sigmoidoscopy, and colonoscopy, projecting lifetime benefits and costs. RESULTS: In the base case, (m)SEPT9 decreased colorectal cancer incidence by 35% to 41% and colorectal cancer mortality by 53% to 61% at costs of $8,400 to $11,500/quality-adjusted life year gained versus no screening. All established screening strategies were more effective than (m)SEPT9. FIT was cost saving, dominated (m)SEPT9, and was preferred among all the alternatives. Screening uptake and longitudinal adherence rates over time strongly influenced the comparisons between strategies. At the population level, (m)SEPT9 yielded incremental benefit at acceptable costs when it increased the fraction of the population screened more than it was substituted for other strategies. CONCLUSIONS: (m)SEPT9 seems to be effective and cost-effective compared with no screening. To be cost-effective compared with established strategies, (m)SEPT9 or blood-based biomarkers with similar test performance characteristics would need to achieve substantially higher uptake and adherence rates than the alternatives. It remains to be proven whether colorectal cancer screening with a blood test can improve screening uptake or long-term adherence compared with established strategies. IMPACT: Our study offers insights into the potential role of colorectal cancer screening with blood-based biomarkers. PMID- 23796794 TI - Ectopic expression of miR160 results in auxin hypersensitivity, cytokinin hyposensitivity, and inhibition of symbiotic nodule development in soybean. AB - Symbiotic root nodules in leguminous plants result from interaction between the plant and nitrogen-fixing rhizobia bacteria. There are two major types of legume nodules, determinate and indeterminate. Determinate nodules do not have a persistent meristem, while indeterminate nodules have a persistent meristem. Auxin is thought to play a role in the development of both these types of nodules. However, inhibition of rootward auxin transport at the site of nodule initiation is crucial for the development of indeterminate nodules but not determinate nodules. Using the synthetic auxin-responsive DR5 promoter in soybean (Glycine max), we show that there is relatively low auxin activity during determinate nodule initiation and that it is restricted to the nodule periphery subsequently during development. To examine if and what role auxin plays in determinate nodule development, we generated soybean composite plants with altered sensitivity to auxin. We overexpressed microRNA393 to silence the auxin receptor gene family, and these roots were hyposensitive to auxin. These roots nodulated normally, suggesting that only minimal/reduced auxin signaling is required for determinate nodule development. We overexpressed microRNA160 to silence a set of repressor auxin response factor transcription factors, and these roots were hypersensitive to auxin. These roots were not impaired in epidermal responses to rhizobia but had significantly reduced nodule primordium formation, suggesting that auxin hypersensitivity inhibits nodule development. These roots were also hyposensitive to cytokinin and had attenuated expression of key nodulation-associated transcription factors known to be regulated by cytokinin. We propose a regulatory feedback loop involving auxin and cytokinin during nodulation. PMID- 23796795 TI - Visualization of BRI1 and BAK1(SERK3) membrane receptor heterooligomers during brassinosteroid signaling. AB - The leucine-rich repeat receptor-like kinase BRASSINOSTEROID-INSENSITIVE1 (BRI1) is the main ligand-perceiving receptor for brassinosteroids (BRs) in Arabidopsis (Arabidopsis thaliana). Binding of BRs to the ectodomain of plasma membrane (PM) located BRI1 receptors initiates an intracellular signal transduction cascade that influences various aspects of plant growth and development. Even though the major components of BR signaling have been revealed and the PM was identified as the main site of BRI1 signaling activity, the very first steps of signal transmission are still elusive. Recently, it was shown that the initiation of BR signal transduction requires the interaction of BRI1 with its SOMATIC EMBRYOGENESIS RECEPTOR-LIKE KINASE (SERK) coreceptors. In addition, the resolved structure of the BRI1 ectodomain suggested that BRI1-ASSOCIATED KINASE1 [BAK1](SERK3) may constitute a component of the ligand-perceiving receptor complex. Therefore, we investigated the spatial correlation between BRI1 and BAK1(SERK3) in the natural habitat of both leucine-rich repeat receptor-like kinases using comparative colocalization analysis and fluorescence lifetime imaging microscopy. We show that activation of BR signaling by exogenous ligand application resulted in both elevated colocalization between BRI1 and BAK1(SERK3) and an about 50% increase of receptor heterooligomerization in the PM of live Arabidopsis root epidermal cells. However, large populations of BRI1 and BAK1(SERK3) colocalized independently of BRs. Moreover, we could visualize that approximately 7% of the BRI1 PM pool constitutively heterooligomerizes with BAK1(SERK3) in live root cells. We propose that only small populations of PM located BRI1 and BAK1(SERK3) receptors participate in active BR signaling and that the initiation of downstream signal transduction involves preassembled BRI1 BAK1(SERK3) heterooligomers. PMID- 23796797 TI - Environmental and genomic factors as well as interventions influencing smoking cessation: a systematic review of reviews and a proposed working model. AB - BACKGROUND: Smoking behaviour is a major public health problem worldwide. Several sources have confirmed the implication of genomic factors in smoking behaviour. These factors interact both with environmental factors and interventions to develop a certain behaviour. OBJECTIVES: Describing the environmental and genomic factors as well as the interventions influencing smoking cessation (SC) and developing a working model incorporating the different factors influencing SC were our main objectives. METHODS: Two systematic reviews were conducted using articles in English from the Cochrane library, PubMed and HuGENet from January 2000 to September 2012: (1) a systematic review of systematic reviews and meta analyses and (2) a systematic review of original research for genomic factors. The proposed working model was developed by making use of previous models of SC and applying an iterative process of discussion and re-examination by the authors. RESULTS: We confirmed the importance of the 4 main factors influencing SC: (1) environmental factors, (2) genomic factors, (3) gene-environment interactions, and (4) evidence-based interventions. The model demonstrates the complex network of factors influencing SC. CONCLUSION: The working model of SC proposed a global view of factors influencing SC, warranting future research in this area. Future testing of the model will consolidate the understanding of the different factors affecting SC and will help to improve interventions in this field. PMID- 23796796 TI - Neural mechanisms of cognitive reappraisal in remitted major depressive disorder. AB - BACKGROUND: Down-regulation of negative emotions by cognitive strategies relies on prefrontal cortical modulation of limbic brain regions, and impaired frontolimbic functioning during cognitive reappraisal has been observed in affective disorders. However, no study to date has examined cognitive reappraisal in unmedicated euthymic individuals with a history of major depressive disorder relative to symptom-matched controls. Given that a history of depression is a critical risk factor for future depressive episodes, investigating the neural mechanisms of emotion regulation in remitted major depressive disorder (rMDD) may yield novel insights into depression risk. METHOD: We assessed 37 individuals (18 rMDD, 19 controls) with functional magnetic resonance imaging (fMRI) during a task requiring cognitive reappraisal of sad images. RESULTS: Both groups demonstrated decreased self-reported negative affect after cognitive reappraisal and no group differences in the effects of cognitive reappraisal on mood were evident. Functional MRI results indicated greater paracingulate gyrus (rostral anterior cingulate cortex, Brodmann area 32) activation and decreased right midfrontal gyrus (Brodmann area 6) activation during the reappraisal of sad images. LIMITATIONS: Trial-by-trial ratings of pre-regulation affect were not collected, limiting the interpretation of post-regulation negative affect scores. CONCLUSIONS: Results suggest that activation of rostral anterior cingulate cortex, a region linked to the prediction of antidepressant treatment response, and of the right midfrontal gyrus, a region involved in cognitive control in the context of cognitive reappraisal, may represent endophenotypic markers of future depression risk. Future prospective studies will be needed to validate the predictive utility of these neural markers. PMID- 23796798 TI - The lateral view head-neck index (LVHNI): a diagnostic tool for the sequelae of slipped capital femoral epiphysis. AB - INTRODUCTION: It is a well-known fact that slipped capital femoral epiphysis (SCFE) is one of the causes of premature hip osteoarthritis and anterior femoroacetabular impingement. But there are no reliable, published diagnostic methods to measure the residual deformity of slipped capital femoral epiphysis. We propose using the lateral view head-neck index (LVHNI) measurement on a specific lateral X-ray view of the hip for this purpose. HYPOTHESIS: The LVHNI can detect and quantify the posterior translation of the femoral head and this index can be measured reliably. MATERIALS AND METHODS: A prospective radiography study was performed by three observers. The hip X-rays of patients who were being treated by arthroplasty for hip osteoarthritis (total hip replacement or hip resurfacing) between January 2010 and December 2011 were analyzed. The LVHNI, which quantifies the posterior translation of the femoral head, was measured on a lateral view of the hip in 45 degrees flexion/45 degrees abduction/30 degrees external rotation. The presence of a pistol grip deformity on A/P X-rays was also assessed. RESULTS: The analysis was performed on 131 hips in 120 patients having an average age of 61 years (range 37-91). The chosen LVHNI threshold of 9% resulted in a sensitivity of 89.1% (95% CI: 78.8%-95.5%) and a specificity of 82.4% (95% CI: 71.2%-89.7%) for detecting the presence of a pistol grip deformity. Twenty percent of the hips with no visible deformity on A/P X-rays had a pathological index value. The inter-observer reproducibility was good for the LHNI [intraclass correlation coefficient (ICC): 0.61; 95% CI: 0.51-0.71] and for detecting a pistol grip deformity (ICC: 0.74; 95% CI: 0.62-0.85). The intra observer reproducibility was excellent for the LHNI (ICC: 0.78; 95% CI: 0.57 0.88) and the pistol grip deformity (ICC: 0.85; 95% CI: 0.74-0.92). CONCLUSION: The LVHNI is a reliable and reproducible tool to identify deformities secondary to SCFE on specific lateral femoral neck X-rays. If the index value is greater than 9%, SCFE sequelae may be present. In addition, this study showed that 20% of hips with normal A/P X-rays had a pathological index. LEVEL OF EVIDENCE: Level IV, prospective diagnostic study without control group. PMID- 23796799 TI - Single nucleotide polymorphisms in the FTO gene and their association with growth and meat quality traits in rabbits. AB - Fat mass and obesity associated (FTO) gene is an excellent candidate to affect the fatness and growth-related traits in pig and cattle. The aim of this study was to reveal the association between FTO and growth and meat quality traits in rabbits. A total of eight coding SNPs were detected, and four SNPs of them in exon 3 were further genotyped for association analysis in 442 rabbits from three breeds, including 248 New Zealand rabbits, 92 Ira rabbits, and 102 Champagne rabbits. Because there were significant differences for the allele and genotype frequencies among breeds, the association analysis was independently conducted in each breed only for these SNPs with minor allele frequency >5.0%. The results revealed that non-synonymous SNP c.499G>A (p.A167T) was significantly associated with body weight (BW) at 35, 70, and 84 days of age in New Zealand rabbits (P<0.01). The CC genotype of synonymous SNP c.660T>C was significantly associated with higher BW84, average daily weight gain, and intramuscular fat content of longissimus lumborum than TT and TC genotypes in Ira rabbits (P<0.05). There were no associations between the four SNPs and growth and meat quality traits in Champagne rabbits. Meanwhile, FTO SNPs were not associated with meat pH value. Our data indicated that FTO gene could be a candidate gene associated with growth and meat quality traits in rabbits. However, the breed-specific effect should be carefully taken into consideration. PMID- 23796800 TI - The distribution of recombination repair genes is linked to information content in bacteria. AB - The concept of a 'proteomic constraint' proposes that the information content of the proteome exerts a selective pressure to reduce mutation rates, implying that larger proteomes produce a greater selective pressure to evolve or maintain DNA repair, resulting in a decrease in mutational load. Here, the distribution of 21 recombination repair genes was characterized across 900 bacterial genomes. Consistent with prediction, the presence of 17 genes correlated with proteome size. Intracellular bacteria were marked by a pervasive absence of recombination repair genes, consistent with their small proteome sizes, but also consistent with alternative explanations that reduced effective population size or lack of recombination may decrease selection pressure. However, when only non intracellular bacteria were examined, the relationship between proteome size and gene presence was maintained. In addition, the more widely distributed (i.e. conserved) a gene, the smaller the average size of the proteomes from which it was absent. Together, these observations are consistent with the operation of a proteomic constraint on DNA repair. Lastly, a correlation between gene absence and genome AT content was shown, indicating a link between absence of DNA repair and elevated genome AT content. PMID- 23796801 TI - Associations of the PTEN -9C>G polymorphism with insulin sensitivity and central obesity in Chinese. AB - BACKGROUND: Phosphatase and tensin homolog on chromosome 10 gene (PTEN) is known as a tumor-suppressor gene. Previous studies demonstrated that PTEN dysfunction affects the function of insulin. However, investigations of PTEN single nucleotide polymorphisms (SNPs) and IR-related disease associations are limited. The aim of the present study was to investigate whether its polymorphism could be involved in the risk of metabolic syndrome (MetS). METHODS: The genotype frequency of PTEN -9C>G polymorphism was determined by using a Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF MS) method in 530 subjects with MetS and 202 healthy control subjects of the Han Ethnic Chinese population in a case-control analysis. RESULTS: The PTEN -9C>G polymorphism was not associated with MetS or its hyperglycemia, hypertension and hypertriglyceridemia components. In the control individuals aged <60 years or >=60 years, the CG genotype individuals had lower insulin sensitivity than CC individuals (P<0.05). In the <60-year-old MetS group and normal glucose tolerance (NGT) subgroup, the CG individuals had lower insulin sensitivity and higher waist circumference (WC) and waist-height-ratio (WHtR) than CC individuals (P<0.05). Multiple linear regression analysis showed that the PTEN polymorphism (P=0.001) contributed independently to 4.2% (adjusted R(2)) of insulin sensitivity variance (estimated by Matsuda ISI), while age (P=0.004), gender (P=0.000) and the PTEN polymorphism (P=0.032) contributed independently to 5.6% (adjusted R(2)) of WHtR variance. CONCLUSIONS: The CG genotype of PTEN -9C>G polymorphism was not associated with MetS and some of its components as well. However, it may not only decrease insulin sensitivity in the healthy control and MetS in pre-elderly or NGT subjects, but may also increase the risk of central obesity among these MetS individuals. PMID- 23796802 TI - Dioxin-induced acute cardiac mitochondrial oxidative damage and increased activity of ATP-sensitive potassium channels in Wistar rats. AB - The environmental dioxin 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is classified as a Group 1 human carcinogen and teratogenic agent. We hypothesize that TCDD induced oxidative stress may also interfere with mitochondrial ATP-sensitive potassium channels (mitoKATP), which are known to regulate and to be regulated by mitochondrial redox state. We investigated the effects of an acute treatment of male Wistar rats with TCDD (50 MUg/kg i.p.) and measured the regulation of cardiac mitoKATP. While the function of cardiac mitochondria was slightly depressed, mitoKATP activity was 52% higher in animals treated with TCDD. The same effects were not observed in liver mitochondria isolated from the same animals. Our data also shows that regulation of mitochondrial ROS production by mitoKATP activity is different in both groups. To our knowledge, this is the first report to show that TCDD increases mitoKATP activity in the heart, which may counteract the increased oxidative stress caused by the dioxin during acute exposure. PMID- 23796803 TI - Attentional focus of feedback for improving performance of reach-to-grasp after stroke: a randomised crossover study. AB - OBJECTIVE: To investigate whether feedback inducing an external focus (EF) of attention (about movement effects) was more effective for retraining reach-to grasp after stroke compared with feedback inducing an internal focus (IF) of attention (about body movement). It was predicted that inducing an EF of attention would be more beneficial to motor performance. DESIGN: Crossover trial where participants were assigned at random to two feedback order groups: IF followed by EF or EF followed by IF. SETTING: Research laboratory. PARTICIPANTS: Forty-two people with upper limb impairment after stroke. INTERVENTION: Participants performed three reaching tasks: (A) reaching to grasp a jar; (B) placing a jar forwards on to a table; and (C) placing a jar on to a shelf. Ninety six reaches were performed in total over one training session. MAIN OUTCOME MEASURES: Kinematic measures were collected using motion analysis. Primary outcome measures were movement duration, peak velocity of the wrist, size of peak aperture and peak elbow extension. RESULTS: Feedback inducing an EF of attention produced shorter movement durations {first feedback order group: IF mean 2.53 seconds [standard deviation (SD) 1.85]; EF mean 2.12 seconds (SD 1.63), mean difference 0.41 seconds; 95% confidence interval -0.68 to 1.5; P=0.008}, an increased percentage time to peak deceleration (P=0.01) when performing Task B, and an increased percentage time to peak velocity (P=0.039) when performing Task A compared with feedback inducing an IF of attention. However, an order effect was present whereby performance was improved if an EF of attention was preceded by an IF of attention. CONCLUSIONS: Feedback inducing an EF of attention may be of some benefit for improving motor performance of reaching in people with stroke in the short term; however, these results should be interpreted with caution. Further research using a randomised design is recommended to enable effects on motor learning to be assessed. PMID- 23796805 TI - Life span and life course approaches to dermatological disease. AB - Social and behavioral scientists have long been interested in cumulative, life course processes. This chapter reviews prototypical questions and methods from the life span approach in psychology as well as the life course approach in sociology. Their relevance for understanding the unfolding lives of those who suffer from skin disorders is then considered. Key themes extracted from these approaches are how skin disease impacts life course development, how skin disorders influence personal agency and social networks, whether the historical context surrounding dermatological disease is changing, how accumulation processes occur over time, and the need to consider multiple life pathways, involving both profiles of vulnerability and resilience. PMID- 23796804 TI - Non-cryogenic ultra-low field MRI of wrist-forearm area. AB - Ultra-low field (ULF) MRI as an alternative to high field MRI can find some niche applications where high field is a liability. Previously we demonstrated hand images with a non-cryogenic ULF MRI system, but such a system was restrictive to the size of the imaging objects. We have modified the previous setup to increase the imaging volume and demonstrate the image of human hand near the wrist area. One goal for the demonstration is the evaluation of quality of larger bone structure to project image quality to other parts of extremities, such as elbows, shoulders, and knees. We found that after 12 min of acquisition, the image quality was quite satisfactory. To achieve this image quality, several problems were solved that appeared in the new system. The increase in the imaging volume size led to an increase in transient time and various measures were taken to reduce this time. We also explored a method of overcoming the artifacts and image quality reduction arising from field drifts present in the system due to heating of the coils. We believe that our results can be useful for evaluation of diagnostic capability of non-cryogenic ULF MRI of extremities and other parts of the body. The system can be also applied to image animals and tissues. PMID- 23796806 TI - Two key concepts in the life course approach in medicine: allostatic load and cumulative life course impairment. AB - According to the biopsychosocial model, psychosocial and biological factors interact in a number of ways influencing onset and course of medical disease. In a longitudinal perspective, such factors may elicit different effects on health depending on their accumulation mechanisms and timing of exposure over the life course. These aspects have become particularly relevant in the field of chronic diseases such as chronic dermatological conditions, where complete healing is unlikely to occur. Two key concepts may aid understanding of chronic medical conditions in a more comprehensive manner. In the first place, the concept of allostatic load may represent the link between the cumulative effect of various challenging situations and the disease onset through the progressive 'wear and tear' induced by chronic exposure to fluctuating allostatic responses. In addition, the allostatic overload model emphasizes the fact that the cumulative interaction of stressors, psychological symptoms and impaired psychological well being may constitute a danger to health. In the second place, the concept of cumulative life course impairment, which takes into account the multiple dimensions of chronic disease, underlines the fact that illness is only one of many recordable parameters which ultimately determine, through their mutual interaction, the 'life trajectory of individuals'. In a broader sense, both concepts of allostatic load and cumulative life course impairment allow more light to be shed on a new perspective on illness - the life course perspective - and on its interactions with psychological, social and environmental factors. This perspective may ultimately result not only in a substantial improvement of clinical care, but also in a different and long-lasting approach to interventions in chronic illness, with wide economic, political and social consequences whose entity has yet to be appreciated. PMID- 23796807 TI - Mathematical modeling in life course research. AB - Approaching (chronic) diseases within a 'life course' framework provides primarily answers to two main questions: What are the long-term effects on health of life events and of previous exposures to risk (or protecting) factors during sensitive periods (e.g. childhood, adolescence) of life? What are the effects of the onset (and course) of a chronic disease on all other variables (such as social and economic pathway, marital status, etc.) that define a life trajectory and how can this influence be modulated by medical and social interventions? In order to tackle such ambitious questions, to collect epidemiological data related to them and to attempt to provide forecasts concerning the effect of interventions, it will be necessary to represent life course trajectories by formal means within a mathematical model in order to render the trajectories classifiable and 'measurable'. We outline briefly some important concepts and techniques that can be applied to the purpose of modeling life course, such as multistate models, Markov models, latent class analysis and sequence analysis. PMID- 23796808 TI - Life course impairment and quality of life over time. AB - The concepts of cumulative life course impairment (CLCI) and health-related quality of life (QoL) are analyzed, in order to find shared and divergent aspects. The concept of QoL includes the patients' perception of their health and their personal experiences concerning the psychosocial impact of the disease on their life. CLCI aims to investigate the impact of a chronic disease on the milestones of life, such as education, work, relationships, children, social life, (briefly - on the whole trajectory of life) and on how the disease influenced the possibility of patients of living their life up to its full potential. QoL is a cross-sectional measure, while CLCI takes into account the lifetime. However, it is clear that the possibility of reaching one's full life potential and QoL at a certain time are correlated. There are few studies in dermatology in this field; however, both in the case of atopic dermatitis and of vitiligo it has been shown that patients with a severe condition in childhood endured severe psychosocial and physical consequences in adulthood and experienced a profound negative impact of the disease on their current quality of life. It is thus important to take into account both CLCI and QoL when evaluating the impact of a chronic condition on a patient's life. PMID- 23796809 TI - Concept of major life-changing decisions in life course research. AB - Chronic diseases can severely impair patients' quality of life but little information is available about the long-term impact of chronic diseases. The chronic nature of disease may decrease patients' psychosocial well-being, may change their attitude towards life goals and influence major life-changing decisions (MLCDs). Understanding of the impact on MLCDs is largely missing from health outcomes research. It is potentially important in the assessment of the overall burden and cumulative impact of chronic disease. This chapter reviews the concepts of life events, life transition, life goals concepts and what constitutes a long-term impact, essential background to this area. We also describe the relationship of the concept of MLCD with the concept of cumulative life course impairment. Chronic disease has long-term impact on patients' lives, particularly by influencing MLCDs related to career, job, relationships, education, having children and early retirement. We describe qualitative research carried out in Cardiff that has sought to give more detailed insight into what decisions constitute MLCDs, in patients both from dermatology and from several general medical disciplines. We have also proposed the MLCD Profile to measure the number of MLCDs that an individual patient may have experienced as being influenced by chronic disease. Adding the domain of MLCDs to how we think about the burden of disease experienced by an individual, could broaden understanding of the true extent of disease impact. PMID- 23796810 TI - Setting up a life course questionnaire. AB - In order to give a practical meaning to a concept, it is necessary to measure it. In this chapter, some guidelines for the creation of a life course questionnaire are given, starting from the concept of measurement and all the properties (validity, reliability, responsiveness and interpretability) that an instrument must have, to be defined as a measurement tool. The first step is to define the construct to be measured. Cumulative life course impairment (CLCI) assumes impairment over time of the life course of individuals; key concepts of CLCI are accumulation of risk as well as timing of risk exposure. CLCI is a longitudinal construct, and in order to measure it, it is imperative to take the role of time into account. Questionnaires administered at a certain moment during the patient's life will investigate the impact the disease had on his/her life from the beginning until that moment. Items to be assessed in patients suffering from chronic condition will be, among others, physical and psychological comorbidities, feelings of stigmatization and coping style. Together with the given personality, and other personal and clinical characteristics, they may contribute to changes in the life trajectory compared to a hypothetical 'unaffected average life course'. At the end of the chapter, an example of life course questionnaire is proposed. PMID- 23796811 TI - Cumulative life course impairment: identifying patients at risk. AB - Cumulative life course impairment (CLCI) is a multidimensional construct, which reflects the overall increasing burden posed on patients by chronic (dermatological) disease. As such, CLCI can, to date, neither be directly measured nor can the patients' risk for CLCI be assessed by univocally defined screening scales. Presently, patients at risk for CLCI need to be identified by clinical, personal and psychosocial indicators and predictors of CLCI which need to be individually applied. Among those factors, the following are to be considered: (1) clinical disease severity; (2) chronic course of disease; (3) early onset of psoriasis; (4) perception of stigmatization; (5) lack of social support; (6) negative impact on profession; (7) 'negative' mood/personality trait; (8) coping strategy; (9) quality of life; (10) behaviors putting the patient at risk, and (11) comorbidities. Each of these factors requires accurate assessment either by clinical considerations or by specific tools. In particular, apart from other any single objectifiable risk factors, personality and social support of the patient can markedly affect the extent of CLCI and thus modulate the risks. PMID- 23796812 TI - Cumulative life course impairment: evidence for psoriasis. AB - Psoriasis is a disease state that may present significant cumulative life course impairment (CLCI). The impact of psoriasis on CLCI can be divided into social factors such as stigmatization, psychological factors such as depression, and physical factors such as pruritis, pain and arthritis. With a bimodal age range at first presentation, psoriasis tends to affect those in the second and fifth decades of life. In accordance with the CLCI model, the age of first presentation may substantially affect an individuals' life course, with younger patients more susceptible to CLCI. Social, psychological, and physical factors also provide protection from CLCI: personality, coping mechanisms, social support, and treatment or therapy may act as positive factors and mitigate these damaging effects. As the time course of most clinical trials encompasses a fraction of a patients' life, the true nature of this impact has not been easily captured. Longitudinal CLCI data in psoriasis is limited and continued life course data is needed. PMID- 23796813 TI - Cumulative life course impairment by epidermolysis bullosa. AB - Inherited epidermolysis bullosa, which encompasses at least 30 distinctive genetic diseases, may be associated with marked functional impairment, the result of the presence of severe cutaneous and extracutaneous manifestations or complications in some of its subtypes. PMID- 23796814 TI - Cumulative life course impairment in vitiligo. AB - Vitiligo is an acquired, idiopathic skin disease characterized by the mostly progressive loss of the inherited skin color leading to white patches and in some cases to total depigmentation. The course of this ancient disease is still unknown. The worldwide prevalence range is 0.5-1%. The disease burden includes stigmatization, depression, impaired quality of life, lack of self-confidence, embarrassment and self-consciousness. To the best of our knowledge, the extent to which this chronic disease may exert an influence upon the life course of affected individuals has, to date, not been investigated. The material presented herein is the result of an accurate analysis of published literature. Moreover, we included our own data collected in two studies. To apply the concept of cumulative life course impairment in vitiligo, we looked at possible trigger factors, role of patient's age and the age at disease onset, disease duration and stigmatization. Stigmatization had the strongest impact. It is common in patients with an early disease onset, often leading to other disturbances. Our data revealed that older patients or those with a disease onset later in life adjust better to this chronic skin disorder and that they are less socially avoidant. However, long disease duration can also lead to impaired quality of life and obsession, while this group seems to be less depressed or embarrassed. Results from our own work with peer groups of these patients strongly support a positive long-lasting effect of treatment on quality of life of children, adolescents and adults. To which extent vitiligo may contribute to a cumulative life course impairment remains to be shown. PMID- 23796815 TI - Cumulative life course impairment in melanoma and nonmelanoma skin cancer. AB - Patients with skin cancer remain at risk for disease progression or relapse for many years. Therefore, skin cancer may be considered a chronic, life-threatening disease. It could impact on patients lifestyles and social and professional activities. Although no direct study of cumulative life course impairment (CLCI) in skin cancer patients has been carried out, a few studies suggest that skin cancer may strongly impair quality of life and eventually determine a significant CLCI (melanoma more than nonmelanoma skin cancer). Obviously, the life course of patients with melanoma at an advanced stage of the disease may change considerably. A number of cancer-associated problems may determine a CLCI, including familial or professional changes and a reduction of life expectancy may eventually lead to social withdrawal and depressive disorders. Even patients with a low stage disease may experience an important impairment of quality of life and in some cases a CLCI. Some skin cancer patients may have physical and psychological after effects from their cancer surgery. Several patients complain about lymphedema, discomfort experienced from wearing surgical stockings, and diminished range of physical motion postsurgery. A few are concerned about their body image due to surgical scars, and they may consider changing their job position because of the supposed negative impact of scars in visible sites on their ability to perform their job. Some female melanoma survivors may have a reduced desire of having children in the future. PMID- 23796816 TI - Cumulative life course impairment in chronic wounds. AB - Chronic wounds such as leg ulcers, diabetic or ischemic foot ulcers and pressure ulcers are a heterogeneous group of chronic tissue defects which share the stagnation of wound healing due to an underlying disease. Most patients suffer from marked reductions of quality of life, including pain, physical discomfort, functional limitations, social burden as well as psychological distress. In some countries, a negative socioeconomic impact for the patients is another strain. Most patients complain about the additional burden due to treatment. Given the long period of disease and the even longer-lasting comorbidity, chronic wounds can be associated with marked cumulative life course impairments. It is thus essential to detect any early signs of wound disease and psychosocial burden in patients at risk of chronic wounds. Though specific instruments have not yet been developed for the detection of cumulative life course impairment in chronic wounds, patients at risk can be identified by using validated disease-specific instruments for quality of life. Moreover, in specific situations, psychological instruments can be of additional diagnostic help. PMID- 23796817 TI - Cumulative life course impairment in other chronic or recurrent dermatologic diseases. AB - Skin diseases are visible, and identifying abnormal skin generally does not require specialist knowledge. Dermatology is therefore a ripe field for studies of cumulative life course impairment, because of the many diseases that affect not only the patients, but also their psychosocial interaction with others. Dermatological patients are visibly sick. The stigma associated with visible as well as hidden skin diseases is considerable and may have a major negative impact on the life course of patients. Stigma and psychosocial relations are however not the only sources of impairment for patients with dermatological diseases. Hand eczema is a prototypical example of a skin disease that causes life course impairment not only due to stigmatization, but also to a major loss of function. The impairment therefore occurs through several mechanisms increasing the potential impact of hand eczema on patients. The list of skin diseases where an assessment of cumulative life course impairment is relevant can be enlarged considerably. Diseases with functional impairment such as, e.g. scleroderma, diseases with prominent subjective symptoms such as acne or hidradenitis, and diseases with limited physical impairment but massive psychosocial impairment in specific communities such as vitiligo, are all suitable for further studies. Life course studies are particularly suitable for skin diseases due to their often chronic recurrent course, low mortality and their psychosocial aspects. The development of a stronger empirical framework is welcomed, and may lead to considerable benefits for patients. PMID- 23796818 TI - Cumulative life course impairment across cultures and medical systems. AB - Life course epidemiology is very important in the evaluation of chronic diseases and their long term physical, psychological, cognitive and social consequences. However, chronic dermatologic diseases can have a different impact on quality of life depending on patients' cultures and medical systems. Conversely, cultural, social and economic factors over life may lead to even greater health disparities. Moreover, individuals with same diseases and disease severities, but with diverse cultural backgrounds and medical systems, may value health differently and this has to be taken into account when performing multinational studies of cumulative life course impairment. Some processes and concepts involved in cross-cultural comparison of quality of life studies are described here, including the small number of international studies that have been performed to evaluate quality of life instruments across different cultures to date. Cross-cultural impact of dermatologic diseases on subjects' life as well as studies evaluation of different dermatology-specific quality of life instruments are discussed. PMID- 23796819 TI - Patients' narratives. AB - Patients who suffer from inflammatory skin disease are at risk of stigmatisation and physical and psychological co-morbidities. To an extent these issues can be offset by effective coping strategies. The cumulative balance of these interactions will often lead to impairment, especially in those whose coping mechanisms are maladaptive or do not exist. When this situation arises, the detrimental effect of these various morbidities is termed 'cumulative life course impairment' (CLCI). We present 2 typical cases, one of a patient suffering from severe psoriasis and another of a patient suffering severe atopic eczema, as examples of how patients with inflammatory skin disease may be affected by CLCI. Their experiences demonstrate that the presence of inflammatory skin disease changes key life choices with resultant effect on career and relationships, amongst others. Although longitudinal evidence to support this CLCI is lacking, these patient narratives add support to the concept of CLCI. PMID- 23796820 TI - Bioavailability and potential carcinogenicity of polycyclic aromatic hydrocarbons from wood combustion particulate matter in vitro. AB - Due to increasing energy demand and limited fossil fuels, renewable energy sources have gained in importance. Particulate matter (PM) in general, but also PM from the combustion of wood is known to exert adverse health effects in human. These are often related to specific toxic compounds adsorbed to the PM surface, such as polycyclic aromatic hydrocarbons (PAH), of which some are known human carcinogens. This study focused on the bioavailability of PAHs and on the tumor initiation potential of wood combustion PM, using the PAH CALUX(r) reporter gene assay and the BALB/c 3T3 cell transformation assay, respectively. For this, both cell assays were exposed to PM and their respective organic extracts from varying degrees of combustion. The PAH CALUX(r) experiments demonstrated a concentration response relationship matching the PAHs detected in the samples. Contrary to expectations, PM samples from complete (CC) and incomplete combustion (IC) provided for a stronger and weaker response, respectively, suggesting that PAH were more readily bioavailable in PM from CC. These findings were corroborated via PAH spiking experiments indicating that IC PM contains organic components that strongly adsorb PAH thereby reducing their bioavailability. The results obtained with organic extracts in the cell transformation assay presented the highest potential for carcinogenicity in samples with high PAH contents, albeit PM from CC also demonstrated a carcinogenic potential. In conclusion, the in vitro assays employed emphasize that CC produces PM with low PAH content however with a general higher bioavailability and thus with a nearly similar carcinogenic potential than IC PM. PMID- 23796821 TI - A discussion on the investigation of an autologous blood treatment strategy for temporomandibular joint hypermobility in a pig model. PMID- 23796822 TI - Ambient temperature and nutritional stress influence fatty acid composition of structural and fuel lipids in Japanese quail (Coturnix japonica) tissues. AB - In birds, fatty acids (FA) serve as the primary metabolic fuel during exercise and fasting, and their composition affects metabolic rate and thus energy requirements. To ascertain the relationship between FAs and metabolic rate, a distinction should be made between structural and fuel lipids. Indeed, increased unsaturation of structural lipid FAs brings about increased cell metabolism, and changes in the FA composition of fuel lipids affects metabolic rate through selective mobilization and increasing availability of specific FAs. We examined the effects of acclimation to a low ambient temperature (Ta: 12.7+/-3.0 degrees C) and nutritional status (fed or unfed) on the FA composition of four tissues in Japanese quail, Coturnix japonica. Differentiating between neutral (triglycerides) and polar (phospholipids) lipids, we tested the hypothesis that both acclimation to low Ta and nutritional status modify FA composition of triglycerides and phospholipids. We found that both factors affect FA composition of triglycerides, but not the composition of phospholipids. We also found changes in liver triacylglyceride FA composition in the low-Ta acclimated quail, namely, the two FAs that differed, oleic acid (18:1) and arachidonic acid (20:4), were associated with thermoregulation. In addition, the FAs that changed with nutritional status were all reported to be involved in regulation of glucose metabolism, and thus we suggest that they also play a role in the response to fasting. PMID- 23796823 TI - Effects of dietary arginine on endocrine growth factors of channel catfish, Ictalurus punctatus. AB - Thyroid (TH) and growth (GH) hormones, and insulin-like growth factor I (IGF-I) are anabolic regulators in fish and responsive to nutrient intake. A study was conducted to determine if previously reported growth effects of dietary arginine (ARG) in channel catfish were related to the activation of endocrine axes. In a first experiment, catfish were fed incremental levels of ARG (0.5 - 4% of diet) for 6 weeks and sampled at 2-week intervals. In a second experiment, fasted (48h) fish were fed a single ration of ARG (0.5 or 4% of diet) and sampled at various intervals (0 to 72h postprandial, PP). Experiment 1 did not reveal any influence of ARG on circulating TH, GH, or IGF-I despite the significantly increased growth of fish fed ARG-enriched diets. In experiment 2, feeding the 4% ARG diet significantly increased the amplitude of pulsatile plasma GH levels and also significantly increased IGF-I mRNA in liver and muscle, (at 2h PP) and plasma IGF I levels (at 6h PP). Although relatively infrequent sampling failed to reveal alterations in TH or GH levels in response to ARG-induced growth activation, PP high frequency sampling unveiled high amplitude pulsatile GH secretions and may be important in activating IGF production in target tissues. Additionally, expressed and secreted IGF-I exhibited discernible patterns which closely correlate with ARG-induced growth effects in catfish. PMID- 23796824 TI - The blue globular pattern in dermoscopy. AB - BACKGROUND: Seborrheic keratosis (SK) is a frequent benign epithelial skin tumor. Generally its diagnosis is clinical, however SK can sometimes clinically simulate a melanocytic lesion; therefore we need dermoscopy to reach a correct diagnosis. Milia-like cysts and comedo-like openings are the common dermoscopic features of SK, but it is not a rare finding that SK can display one or more dermoscopic patterns suggestive of a melanocytic origin. OBJECTIVES: We describe a case series of SKs with a blue globular pattern simulating a melanocytic lesion. METHODS: We retrospectively evaluated 224 SKs seen during 2011 at the Dermatoscopy Unit of the Department of Dermatology, University of Rome 'Sapienza'. RESULTS: Five SKs showed a blue globular pattern, without the SK main features generally seen in dermoscopy; globules were multiple, round or oval, well-demarcated, small and medium-sized, blue-colored and equally distributed within the lesion. Histopathologic examination was consistent with acanthotic SK. CONCLUSIONS: Identification of the blue globular pattern can be helpful for the dermoscopic diagnosis of SK, especially when its common dermoscopic features are absent. PMID- 23796825 TI - Active hip and spine ROM differs when comparing unconstrained motion with voluntary segmental constraint. AB - BACKGROUND: Active range of motion trials are frequently used as a baseline for normalizing other data. However, previous research has not focused on methods utilized to achieve maximum active range of motion. METHODS: Twenty-seven males (age 20-38 years) participated in this study. Active hip extension in upright standing was compared to active lumbar extension with regards to degrees of total hip and spine extension obtained. Similarly, active spine rotation whereby participants attempted to constrain associated pelvis and hip rotation was compared to rotation trials in which the pelvis and hips were free to rotate concurrently. An infra-red motion capture system and associated software were used to capture movement and determine joint angles. FINDINGS: Results indicate that average degrees of hip extension did not differ between the two methods (p = 0.138), nor did either method result more frequently in the highest measurement. Spine extension values were significantly greater in the active spine extension manoeuvre compared to the associated back extension that occurred when participants were asked to actively extend their hip (p < 0.001). Average degrees of spine rotation were greater in the unconstrained trials: when concurrent hip and pelvis rotation were allowed to take place (p < 0.001). Of the 27 participants, 23 obtained maximum rotation during the unconstrained trials. INTERPRETATION: To obtain maximum active hip joint extension, both hip and back extension trials should be collected. Maximum spine rotation is more likely to occur when the pelvis and hips are unconstrained. PMID- 23796826 TI - Measurement of salivary cortisol as a marker of stress in newborns in a neonatal intensive care unit. AB - AIMS: The study was designed to evaluate the newborn (NB) stress response during the inpatient time in the neonatal intensive care unit. METHODS: A quantitative, prospective, observational study was conducted with two NB groups. The first group consisted of 12 NB patients in the neonatal intensive care unit as the experimental group (EG), and the second included 43 NBs who were sent to their own homes and were considered the control group (CG). The EG's salivary cortisol concentration was measured on the 2nd day (D2) and 9th day (D9) of life. The CG's salivary cortisol concentration was measured on the 14th day of life at the child's own home. RESULTS: The salivary cortisol concentration levels for the EG on D2 and D9 and for the CG were 4.3151 +/- 2.6492, 1.826 +/- 1.2252, and 1.0166 +/- 0.8300 ng/dl, respectively. These findings indicated the presence of an adrenal response to stress during the first inpatient days. CONCLUSIONS: The salivary cortisol concentration is an accurate method to indicate neonatal stress. The glucocorticoids frequently used in the prenatal period suppress the adrenal glands and interfere with the stress response. PMID- 23796827 TI - Inpatients with schizophrenia report impaired situational motivation but intact global and social motivation. AB - It is well established that individuals with schizophrenia are less active and engaged than healthy control subjects, and motivation deficits are considered a core symptom of the disease. However, it remains unclear if schizophrenia individuals perceive themselves as less motivated than others, and there is a scarcity in research examining the relationship between perceived motivation, psychopathology and personality traits. Eighty-six inpatients with schizophrenia and 45 non-patient control participants completed the Motivation and Energy Inventory, which consists of Global Motivation, Social Motivation and Situational Motivation (the motivation individuals experience when they are engaging in an activity). Participants also completed personality questionnaires and an affective evocative task. Compared to controls, schizophrenia participants reported lower situational motivation, and comparable global and social motivation. Situational motivation was negatively predicted by negative temperament, affective ambivalence and depression level. Our results are consistent with the idea that schizophrenia individuals are not impaired in their motivational disposition but lack energy during the implementation of their goals. This may reflect impairment in the prediction, maintenance and/or modulation of required effort and energy during goal-directed actions, and is predicted by some affective processes. Improving situational motivation may be an effective therapeutic approach in people with schizophrenia. PMID- 23796828 TI - Hyaluronidase enzyme core-5-fluorouracil-loaded chitosan-PEG-gelatin polymer nanocomposites as targeted and controlled drug delivery vehicles. AB - This study examines the performance of novel hyaluronidase enzyme core-5 fluorouracil-loaded chitosan-polyethylene glycol-gelatin polymer nanocomposites, which were prepared using an ionic gelation technique, as targeted and controlled drug delivery vehicles. These hyaluronidase-loaded nanoparticles have recently been proposed as targeted and controlled drug delivery vehicle systems to tissues due to their ability to loosen the intercellular connective matrix of hyaluronic acid. The encapsulation efficiency and loading capacities of the nanoparticles demonstrated that these nanocomposites displayed sufficient binding ability, which depends on the pH and initial concentration of the drug. The cytotoxic effects of the chitosan-hyaluronidase-5-fluorouracil (CS-HYL-5-FU), chitosan hyaluronidase-5-fluorouracil polyethylene glycol (CS-HYL-5-FU-PEG), and chitosan hyaluronidase-5-fluorouracil polyethylene glycol-gelatin (CS-HYL-5-FU-PEG-G) nanoparticles were assessed using MTT assays, and the nanovectors were found to be less cytotoxic than the chemotherapeutic 5-FU after incubation for 3-12h. The particle sizes of the CS-HYL-5-FU, CS-HYL-5-FU-PEG and CS-HYL-5-FU-PEG-G polymer composites were between 300 and 580 nm, as determined by a Zetasizer. Scanning electron microscopy (SEM) analysis indicated that the nanocomposites exhibit a clear, smooth surface and fine morphology. Linkages of the polymers, enzyme, and drug were confirmed by FTIR spectroscopy. Atomic fluorescence microscopy (AFM) analysis confirmed the size of the polymer composite nanoparticles. Therefore, this work established that the drug can be successfully encapsulated in chitosan polyethylene glycol-gelatin-accompanied hyaluronidase nanoparticles with a homogeneous distribution. These nanoparticles can be potential carriers for targeted and controlled drug delivery to cancer cells. PMID- 23796829 TI - Whey protein and alginate hydrogel microparticles for insulin intestinal absorption: evaluation of permeability enhancement properties on Caco-2 cells. AB - The evaluation of encapsulated insulin intestinal absorption enhancement was investigated by in vitro methods. Insulin-loaded microparticles (INS-MP) made of whey protein (WP) and alginate (ALG) were prepared by a cold gelation technique. Effect of INS encapsulation toward trypsin and chymotrypsin degradation was performed. Permeability studies using in vitro (Caco-2 cells) experiments were conducted. INS was partially protected by encapsulation toward enzymatic degradation. Moreover INS transport experiments showed that WP and, in lesser extent, ALG were able to enhance INS absorption both as MP and as polymeric solutions by opening the tight junctions. These experiments reinforced the interest of encapsulation in WP/ALG hydrogel combination. PMID- 23796830 TI - N-terminal mono-PEGylation of growth hormone antagonist: correlation of PEG size and pharmacodynamic behavior. AB - Growth hormone antagonist (GHA), an analog of growth hormone (GH), can inhibit GH action and treat acromegaly. However, GHA suffers from a short plasma half-life of 15-20 min that has limited its clinical application. PEGylation, conjugation with polyethylene glycol (PEG), can increase the plasma half-life of GHA. Single PEG attachment (mono-PEGylation) at N-terminus of GHA has the advantages of product homogeneity and minimization of the bioactivity loss. Conjugation of large PEG molecule may increase the plasma half-life but could potentially decrease the bioactivity of GHA, due to the steric shielding effect of PEG. Thus, N-terminal mono-PEGylation of GHA with 20 kDa and 40 kDa PEG were used to look for a balance of the two competing factors. Sedimentation velocity analysis suggested that 40 kDa PEG was more efficient than 20 kDa PEG to elongate the molecular shape of the conjugate. As reflected by marginal suppression of insulin like growth factor I (IGF-I), GHA conjugated with 40 kDa PEG was statistically indistinguishable from the saline solution that could not inhibit GH action. In contrast, GHA conjugated with 20kDa PEG can apparently inhibit GH action, as reflected by IGF-I suppression of 30-43%. Thus, our work demonstrated the effective therapeutic potency of N-terminally mono-PEGylated GHA. PMID- 23796831 TI - Design of sustained release fine particles using two-step mechanical powder processing: particle shape modification of drug crystals and dry particle coating with polymer nanoparticle agglomerate. AB - We attempted to prepare sustained release fine particles using a two-step mechanical powder processing method; particle-shape modification and dry particle coating. First, particle shape of bulk drug was modified by mechanical treatment to yield drug crystals suitable for the coating process. Drug crystals became more rounded with increasing rotation speed, which demonstrates that powerful mechanical stress yields spherical drug crystals with narrow size distribution. This process is the result of destruction, granulation and refinement of drug crystals. Second, the modified drug particles and polymer coating powder were mechanically treated to prepare composite particles. Polymer nanoparticle agglomerate obtained by drying poly(meth)acrylate aqueous dispersion was used as a coating powder. The porous nanoparticle agglomerate has superior coating performance, because it is completely deagglomerated under mechanical stress to form fine fragments that act as guest particles. As a result, spherical drug crystals treated with porous agglomerate were effectively coated by poly(meth)acrylate powder, showing sustained release after curing. From these findings, particle-shape modification of drug crystals and dry particle coating with nanoparticle agglomerate using a mechanical powder processor is expected as an innovative technique for preparing controlled-release coated particles having high drug content and size smaller than 100 MUm. PMID- 23796832 TI - Synthesis of surfactant free PCL-PEG brushed nanoparticles with tunable degradation kinetics. AB - A delivery system based on polymer nanoparticles (NPs) is developed and tested in relevant biological conditions for breast cancer treatment. E-Caprolactone (CL) and polyethylene glycol (PEG) copolymers have been used for the one pot synthesis of surfactant free PEGylated NPs which are monodispersed, stable in physiological conditions and have size in the range 90-250 nm. The degradation behavior of these NPs has been investigated in cell medium and a relation between degradation time and molecular weight of the starting CL-based material has been established. This allows producing NPs with controlled degradation kinetics. Finally, selected NPs have been tested in 4T1 breast cancer cells to check their toxicity and to investigate the uptake process, in order to validate their use as targeted vectors for breast cancer treatment. PMID- 23796833 TI - A novel lipid-based solid dispersion for enhancing oral bioavailability of Lycopene--in vivo evaluation using a pig model. AB - Lycopene is a potent anti-oxidant, which has been widely reported for its potential benefits at reducing the risks of certain types of cancer e.g. prostate cancer. The oral bioavailability of this highly lipophilic carotenoid is low and highly influenced by the extent of intestinal lymphatic uptake. The aim of this study was to develop an optimised formulation, which allows for efficient absorption following oral administration. A self-emulsifying drug delivery system (SEDDS) and solid dispersion of Lycopene were developed initially. Subsequently, a novel lipid based solid dispersion (LBSD) was designed. Processing via a solid dispersion approach was found to alter the solid state characteristics of Lycopene, as determined by differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The bioavailability of Lycopene was significantly increased after oral administration of LBSD to fasted pigs, relative to the commercial product (Lycovit((r))). A clear distinction in terms of Cmax and AUC was observed between Lycovit((r)) and LBSD. In conclusion, a novel LBSD formulation was developed to enhance the oral bioavailability of the model lipophilic compound, Lycopene, by enhancing dissolution in the gastrointestinal tract and promoting intestinal lymphatic uptake utilising digestible lipid excipients. PMID- 23796834 TI - Acid-cleavable ketal containing poly(beta-amino ester) for enhanced siRNA delivery. AB - The safe and effective intracellular delivery of nucleic acids remains the most challenging obstacle to the broad application of gene therapy in clinic. Endosomal escape of nucleic acids is also a major barrier for efficient gene delivery. Ketal linkage is known to readily cleave at the acidic pH of endosomal compartments. Here, we report ketal containing poly(beta-amino ester) (KPAE) as an acid-cleavable non-viral siRNA delivery system. KPAE efficiently condensed siRNA into nanocomplexes with a diameter of ~ 150 nm, which are stable under neutral conditions but rapidly dissociate to release siRNA at acidic pH. KPAE had a buffering capacity due to the presence of secondary amines in its backbone, confirmed by acid-base titration. Moreover, the studies of confocal fluorescence imaging using calcein and LysoTracker Red revealed that KPAE disrupted endosomes by colloid osmotic mechanism and "proton sponge" effects. Cell culture studies demonstrated that KPAE can deliver tumor necrosis factor-alpha (TNF-alpha) siRNA to lipopolysaccharide (LPS)-stimulated macrophages and significantly inhibit the expression of TNF-alpha. The results demonstrate that acid-cleavable KPAE has great potential as gene delivery systems based on its excellent biocompatibility, pH sensitivity and high gene delivery efficiency. PMID- 23796835 TI - Crystallization of a new polymorph of acetohexamide from 2-hydroxybutyl-beta cyclodextrin solution: form VI with a high aqueous solubility. AB - A new polymorph of acetohexamide (Form VI) was prepared via the formation of a complex with 2-hydoxybutyl-beta-cyclodextrin (HB-beta-CD) in aqueous solution. An alkaline solution of acetohexamide and HB-beta-CD was adjusted to pH 4.0 by titration with hydrochloric acid. The resulting opaque solution was filtered through paper and allowed to stand at 4 degrees C for 24h. The resulting precipitate was isolated on a filter and analyzed for polymorph content by powder X-ray diffractometry and thermal analysis. The diffraction pattern and thermal behavior of the precipitate was different from those of previously reported acetohexamide polymorphs (Forms I, III, IV and V), indicating that a new polymorph of the drug, i.e. Form VI was produced. This new polymorph was fairly stable against conversion to a stable form even at accelerated storage conditions. Crystalline Form VI was highly soluble in water and dissolved more rapidly than the other known polymorphs. This property was reflected in the blood concentrations of the drug after oral administration to rats. PMID- 23796836 TI - Drug delivery to the ocular posterior segment using lipid emulsion via eye drop administration: effect of emulsion formulations and surface modification. AB - This work explored submicron-sized lipid emulsion as potential carriers for intraocular drug delivery to the posterior segment via eye drops. The effects of physicochemical properties of lipid emulsion on drug delivery were evaluated in vivo using mice. Different formulations of submicron-sized lipid emulsions were prepared using a high pressure homogenization system. Using coumairn-6 as a model drug and fluorescent marker, fluorescence could be observed in the retina after administration of the lipid emulsion. The fluorescence intensity observed after administration of medium chain triglycerides containing the same amount of coumarin-6 was much lower than that observed after administration of lipid emulsions. The inner oil property and phospholipid emulsifier did not affect the drug delivery efficiency to the retina. However, compared with unmodified emulsions, the fluorescence intensity in the retina increased by surface modification using a positive charge inducer and the functional polymers chitosan (CS) and poloxamer 407 (P407). CS-modified lipid emulsions could be electrostatically interacted with the eye surface. By its adhesive property, poloxamer 407, a surface modifier, possibly increased the lipid emulsion retention time on the eye surface. In conclusion, we suggested that surface modified lipid emulsions could be promising vehicles of hydrophobic drug delivery to the ocular posterior segment. PMID- 23796837 TI - Design and evaluation of biodegradable enteric microcapsules of amifostine for oral delivery. AB - Amifostine is the first FDA approved cytoprotective and chemoprotective agent in the treatment of cancer. However, it is not used widely because of its ineffectiveness when administered orally. The objective of this study was to prepare and evaluate the radioprotective efficacy of orally active amifostine enteric microcapsules (amifostine mc). The microcapsules were prepared by spray drying technique using Eudragit L100-55, and the yield was more than 80%. The particle size and surface morphology were determined by particle analyzer and scanning electron microscopy. Thermal characterization and infrared spectroscopy were evaluated as well. In vitro release assay found that more than 60% amifostine was released during the first 4h and the cumulative release ratio was up to approximately 90% in 24h at 37 degrees C. The radioprotective efficacy was determined by 30-day survival study in mice acutely exposed to 6 Gy gamma-ray irradiation. The results showed that all dose groups of amifostine microcapsules could significantly improve survival animal numbers and time. Furthermore, tissue distribution studies indicated the concentrations of the active metabolite WR 1065 in mice tissues of microcapsule group were higher than that of oral amifostine group at 180 min (p<0.01). These results demonstrated that oral administration of amifostine microcapsules provided effective radioprotection compared to the bulk drug. PMID- 23796838 TI - Interactions of N'-acetyl-rifabutin and N'-butanoyl-rifabutin with lipid bilayers: a synchrotron X-ray study. AB - This work focuses on the interaction of N'-acetyl-rifabutin (RFB2) and N' butanoyl-rifabutin (RFB3) with human and bacterial cell membrane models under physiological conditions. The effect of RFB2 and RFB3 on human cell membrane models was assessed using multilamellar vesicles (MLVs) composed of 1,2 dimyristoyl-rac-glycero-3-phosphocholine (DMPC). In order to mimic the bacterial cell membrane, MLVs of 1,2-dimyristoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DMPG) and a mixture of 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE) and 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DPPG) (8:2 molar ratio) were chosen. Small and wide-angle X-ray scattering (SAXS and WAXS) were used to study the effect of these antimycobacterial compounds on the structure formed in aqueous lipid dispersions. This study contributes to understanding the molecular mechanisms of the drugs delivery through the human and bacterial cells and the effect of these antimycobacterial compounds on the membrane lipids organization, which is related with their antibiotic efficacy and toxic effects. PMID- 23796840 TI - [Lung isolation using EZ-Blocker bronchial block in a patient during a bilateral endoscopic thoracic sympathectomy]. PMID- 23796839 TI - Evaluation of some compression aids in tableting of roller compacted swellable core drug layer. AB - Swellable core technology (SCT) represents a broadly applicable oral osmotic drug delivery platform for the controlled release of drugs. SCT tablets control drug delivery by using osmosis to regulate the influx of water into the tablet's core. The tablet consists of two layers; drug layer and sweller layer, with a semi permeable membrane coating and delivery port located in the drug layer side of the tablet. The key component of SCT formulations is polyethylene oxide (PEO), which is typically wet granulated with organic solvents to prevent rapid gel hydration observed during contact with aqueous environments. However, the use of organic solvents has their own environmental and cost considerations which make this form of processing undesirable. To overcome this issue, dry granulation can be employed. However, PEO is a very plastic material and problems may be encountered during the tableting process, when work hardening occurs upon double compression. The addition of compression aids to the drug layer will help to increase the roll force when generating ribbons - reducing fines and segregation potential - while also reducing work hardening effects which impact tablet friability. The five compression aids used in this study were microcrystalline cellulose (MCC), xylitol, di-calcium phosphate (anhydrous), lactose monohydrate and starch. The work undertaken here studies the compression properties of the drug layer blends with different levels of the five compression aids as part of the formulation. Roller compaction properties are also varied to provide granules with differing solid fractions. The results of this study indicate that addition of microcrystalline cellulose in the formulation in levels between 10% and 30% significantly improve the tablet hardness at lower tablet compression forces. Further work is required to investigate the impact on dissolution. PMID- 23796841 TI - Takotsubo cardiomyopathy and anaesthesia: case report and review of the literature. AB - Takotsubo cardiomyopathy is an acute syndrome characterized by cardiac failure from disturbances in the contractility of the left ventricle. It is presumably caused by sympathetic over stimulation. We describe a case of postoperatively developed Takotsubo cardiomyopathy in a 69-year-old female. The syndrome developed in connection with awareness during complete residual paralysis. The literature on this syndrome is reviewed and implications for anaesthesia described. PMID- 23796842 TI - [Giant meningioma with supra and infratentorial components. Anesthetic implications]. PMID- 23796843 TI - Tumors of central and peripheral nervous system associated with inherited genetic syndromes. AB - There are several genetic syndromes that predispose to the development of tumors of the nervous system. In the present study, we provide a review of the tumors that are associated with neurofibromatosis type 1, neurofibromatosis type 2, tuberous sclerosis complex, von Hippel-Lindau disease, Li-Fraumeni syndrome, Cowden disease, Turcot syndrome, nevoid basal cell carcinoma syndrome (Gorlin syndrome) and rhabdoid predisposition syndrome, which are the most common. PMID- 23796844 TI - Endoscopic management of complications in digestive surgery. AB - Endoscopy has an ever-increasing role in the treatment of complications in digestive surgery. Endoscopic treatment is essentially used for (i) fistula or intra-abdominal collection secondary to anastomotic dehiscence and (ii) anastomotic stricture, especially esophagogastric, but also sometimes after colorectal surgery. First intention treatment of fistula following esophagogastric surgery is the insertion of an extractable self-expandable metallic stent (partially or entirely covered); this is supported by a low level of scientific evidence, but clinical experience has been satisfactory. Other techniques for treatment of anastomotic leak have also been reported anecdotally (clip placement, sealing with glue). There are few data available in the literature on endoscopic management (stents essentially) of postoperative colonic fistula. Whatever the approach chosen to treat a postoperative digestive tract fistula, management is medico-surgical and cannot be limited to simple closure of the digestive tube wall defect. Drainage of any collections by endoscopic, radiologic or surgical approach, systemic treatment of infection and nutritional support are essential adjuvant treatment modalities. Treatment of postoperative esophageal or colonic strictures is essentially endoscopic and is based on initial dilatation (endoscopic with hydrostatic balloon or bougie), and placement of extractable metallic stents (partially or entirely covered) in case of refractory outcome. PMID- 23796845 TI - A five-year study of particulate matter (PM2.5) and cerebrovascular diseases. AB - Cerebrovascular accidents, or strokes, are the second leading cause of mortality and the leading cause of morbidity in both Chile and the rest of the world. However, the relationship between particulate matter pollution and strokes is not well characterized. The association between fine particle concentration and stroke admissions was studied. Data on hospital admissions due to cerebrovascular accidents were collected from the Ministry of Health. Air quality and meteorological data were taken from the Air Quality database of the Santiago Metropolitan Area. Santiago reported 33,624 stroke admissions between January 1, 2002 and December 30, 2006. PM2.5 concentration was markedly seasonal, increasing during the winter. This study found an association between PM2.5 exposure and hospital admissions for stroke; for every PM2.5 concentration increase of 10 MUg m(-3), the risk of emergency hospital admissions for cerebrovascular causes increased by 1.29% (95% CI 0.552%-2.03%). PMID- 23796846 TI - HPLC-ESI-MS/MS analysis of hemoglobin peptides in tryptic digests of dried-blood spot extracts detects HbS, HbC, HbD, HbE, HbO-Arab, and HbG-Philadelphia mutations. AB - BACKGROUND: Hemoglobinopathies are mutations resulting in abnormal globin chain structure; some have clinically significant outcomes such as anemia or reduced lifespan. Five beta-globin mutations are (c.20A>T, p.E6V), (c.19G>A, p. E6K), (c.79G>A, p.E26K), (c.364G>C, p.E121Q), and (c.364G>A, p.E121K), resulting in HbS (sickle-cell hemoglobin), HbC, HbE, HbD-Los Angeles, and HbO-Arab, respectively. One alpha-globin mutation is (c.[207C>G or 207C>A], p.N68K), resulting in HbG Philadelphia. METHODS: HPLC-ESI-MS/MS analysis of dried-blood spot (DBS) punches from newborns extracted with a trypsin-containing solution provides greater than 90% coverage of alpha-, beta-, and gamma-globin amino acid sequences. Because the (c.20A>T, p.E6V), (c.19G>A, p. E6K), (c.79G>A, p.E26K), (c.364G>C, p.E121Q), (c.364G>A, p.E121K), and (c.[207C>G or 207C>A], p.N68K) mutations generate globin peptides with novel amino acid sequences, detecting one of these peptides in DBS extracts is indicative of the presence of a hemoglobinopathy in the newborn. RESULTS: The method described here can distinguish normal beta-globin peptides from the mutant HbS, HbC, HbE, HbD-Los Angeles and HbO-Arab peptides, as well as normal alpha-globin peptide from the mutant HbG-Philadelphia peptide, allowing the identification of unaffected heterozygotes such as HbAS, and of compound heterozygotes such as HbASG-Philadelphia. CONCLUSIONS: This HPLC-ESI-MS/MS analytical approach provides information that is not available from traditional hemoglobin analyses such as isoelectric focusing and HPLC-UV. It is also capable of determining the amino acid sequence of hemoglobin peptides, potentially allowing the detection of numerous hemoglobinopathies resulting from point mutations. PMID- 23796847 TI - Cervical spine injury biomechanics: Applications for under body blast loadings in military environments. AB - BACKGROUND: While cervical spine injury biomechanics reviews in motor vehicle and sports environments are available, there is a paucity of studies in military loadings. This article presents an analysis on the biomechanics and applications of cervical spine injury research with an emphasis on human tolerance for underbody blast loadings in the military. METHODS: Following a brief review of published military studies on the occurrence and identification of field trauma, postmortem human subject investigations are described using whole body, intact head-neck complex, osteo-ligamentous cervical spine with head, subaxial cervical column, and isolated segments subjected to differing types of dynamic loadings (electrohydraulic and pendulum impact devices, free-fall drops). FINDINGS: Spine injuries have shown an increasing trend over the years, explosive devices are one of the primary causal agents and trauma is attributed to vertical loads. Injuries, mechanisms and tolerances are discussed under these loads. Probability based injury risk curves are included based on loading rate, direction and age. INTERPRETATION: A unique advantage of human cadaver tests is the ability to obtain fundamental data to delineate injury biomechanics and establish human tolerance and injury criteria. Definitions of tolerances of the spine under vertical loads based on injuries have implications in clinical and biomechanical applications. Primary outputs such as forces and moments can be used to derive secondary variables such as the neck injury criterion. Implications are discussed for designing anthropomorphic test devices that may be used to predict injuries in underbody blast environments and improve the safety of military personnel. PMID- 23796848 TI - Some parameters affecting the diffusion of SO4(2-) used in iron gall ink: preliminary findings. AB - A systematic evaluation of the effect of components of the ink, types of the paper, temperature and humidity of environment and the direction of the paper fibers on the diffusion percentage of SO4(2-) was made. The results showed that the diffusion percentage of SO4(2-) was associated with all factors mentioned above. The general rule is that the higher the humidity and temperature, the greater the diffusion percentage; the smaller the basis weight of paper, the greater the diffusion percentage of SO4(2-); diffusion percentages of SO4(2-) in strokes perpendicular to the paper's fiber is more bigger than ones of strokes parallel to the paper fibers. In order to estimate the age of iron gall ink entries, it is necessary to select a suitable sample, which used for comparison should be the same as those of the document in question. PMID- 23796849 TI - Abstracts of the International Heart Forum. Beijing, China. August 11-14, 2011. PMID- 23796850 TI - Cloning, expression promoter analysis of vasa gene in Japanese flounder (Paralichthys olivaceus). AB - Vasa is a DEAD box helicase and has shown essential functions during gametogenesis and embryogenesis. In most species, research revealed a specific expression of vasa gene in the germ cells. Thus, vasa has become the candidate gene in identifying germ cells. In this study, the vasa gene was isolated from gonads of Japanese flounder (Paralichthys olivaceus). In the 11.4kb genomic sequence, 23 exons were identified besides 5' and 3' flanking regions. The promoter region contained several putative TF binding sites which may have the function of regulating vasa expression. Quantitative real-time PCR analysis showed that vasa gene expression was restricted to adult gonads, with a higher level in the ovary. Development expression profiling revealed a maternal deposit and constant embryonic expression at early stages, but the relative mRNA amount decreased after gastrula. Nine other PoVasa transcripts were detected and their expression in gonads and during early development was not all the same, implying potential different functions during gametogenesis or early embryonic development. These results together confirmed the feasibility of using vasa as a marker of germ cells and that vasa gene had an important role in spermatogenesis and oogenesis. Furthermore, our study laid the groundwork for identifying fish primordial germ cells (PGCs) and investigating germ cell biology. PMID- 23796851 TI - Understanding glucose uptake during methionine deprivation in incubated rainbow trout (Oncorhynchus mykiss) hepatocytes using a non-radioactive method. AB - The role of methionine supplementation in fish metabolism remains largely unexplored. This study investigates the effects of methionine deprivation (MD) on glucose uptake in rainbow trout (Oncorhynchus mykiss) hepatocytes. To this end, primary hepatocytes were incubated in the presence (+M) or the absence (-M) of methionine for 48h and glucose uptake was assessed using a novel non-radioactive, fluorescent-linked enzymatic assay. Evidence indicated that glucose uptake increased under methionine deprivation, primarily due to the increased abundance of membrane bound sodium-glucose transporter 2 (SGLT2), which was likely facilitated by the cellular reduction in [ATP] resulting from increased mitochondrial uncoupling, as supported by elevated transcript levels of uncoupling protein 2a (UCP2a). This study is the first to suggest that the mechanisms responsible for the rapid glucose uptake associated with MR are facilitated by the greater abundance of SGLT2 glucose transporter and mitochondrial uncoupling. PMID- 23796852 TI - Role of mechanical forces in hand nail configuration asymmetry in hemiplegia: an analysis of four hundred thumb nails. AB - OBJECTIVE: To assess the relationship between nail configuration and mechanical force, the nail morphology and pinch strengths of the paralyzed and non-paralyzed sides of patients with hemiplegia were measured. METHODS: Study 1: Analysis of nail configuration. Both thumb nails of 100 subjects with hemiplegia and 100 healthy volunteers (400 thumb nails) were enrolled. The left and right thumb nails were compared in terms of configuration, namely the curve index (defined as nail height/width). Study 2: Measurement of pinch strength. In 10 subjects with hemiplegia and 10 healthy volunteers, the pinch strengths of both sides were compared. RESULTS: Study 1: In the subjects with hemiplegia, the palsy side had a significantly higher curve index than the non-palsy side (32.7 +/- 8.3 vs. 24.4 +/- 6.5%). The two sides of the healthy volunteers did not differ significantly in terms of the curve index. Study 2: In all hemiplegia cases, the non-palsy side had a higher pinch strength. The differences were statistically significant (4.40 +/- 1.90 vs. 0.05 +/- 0.16 kg). In the healthy volunteers, the dominant and non dominant sides did not differ significantly. CONCLUSION: Mechanical forces may affect the nail configuration and could participate in the pathophysiology of nail deformities. PMID- 23796853 TI - Preface. PMID- 23796854 TI - Seizure risk factors in shunted hydrocephalic patients. AB - OBJECTIVE: There are controversies about seizure risk factors in shunted hydrocephalic patients which can be due to having merged two different types of seizure (preshunt and postshunt seizures) in previous studies. Also, it is not known whether a considerable change in ventricular size after shunting can be a risk factor of postshunt seizures. METHODS: 150 hydrocephalic patients who underwent shunting from 2006 to 2011 in the Children's Hospital Medical Center in Tehran, Iran, were visited at least 1 year after shunting to assess risk factors of preshunt and postshunt seizures. Ventricular size was assessed by using a radiologic index of bifrontal ratio (BFR). RESULTS: Preshunt seizures were higher in patients with postinfectious hydrocephalus and intraventricular hemorrhage. Early shunting, history of shunt complications and shunt infection, and a high number of shunt revisions were significant risk factors for developing postshunt seizures. The change in BFR after shunting was not a significant risk factor of postshunt seizures. CONCLUSION: The difference between risk factors of preshunt seizures and postshunt seizures shows that they are two different types of seizures with different natures. Preshunt seizures are hard to prevent as they are related to the underlying disease of the brain or the etiology of hydrocephalus. However, postshunt seizures are related to the shunt and might be decreased by preventing shunt complications. PMID- 23796855 TI - Mindfulness-based therapy: a comprehensive meta-analysis. AB - BACKGROUND: Mindfulness-based therapy (MBT) has become a popular form of intervention. However, the existing reviews report inconsistent findings. OBJECTIVE: To clarify these inconsistencies in the literature, we conducted a comprehensive effect-size analysis to evaluate the efficacy of MBT. DATA SOURCES: A systematic review of studies published in journals or in dissertations in PubMED or PsycINFO from the first available date until May 10, 2013. REVIEW METHODS: A total of 209 studies (n=12,145) were included. RESULTS: Effect-size estimates suggested that MBT is moderately effective in pre-post comparisons (n=72; Hedge's g=.55), in comparisons with waitlist controls (n=67; Hedge's g=.53), and when compared with other active treatments (n=68; Hedge's g=.33), including other psychological treatments (n=35; Hedge's g=.22). MBT did not differ from traditional CBT or behavioral therapies (n=9; Hedge's g=-.07) or pharmacological treatments (n=3; Hedge's g=.13). CONCLUSION: MBT is an effective treatment for a variety of psychological problems, and is especially effective for reducing anxiety, depression, and stress. PMID- 23796856 TI - Evaluation of an endorectal electrode for performing focused irreversible electroporation ablations in the Swine rectum. AB - PURPOSE: To study the feasibility of a novel endorectal electrode for the creation of focal ablations of the rectal wall with the use of irreversible electroporation (IRE). MATERIALS AND METHODS: A monopolar electrode with a grounding pad (10 ablations in five pigs) and a bipolar electrode (two ablations in one pig) were evaluated in healthy swine rectum. A two-dimensional model of the electrode in the rectum was created and used to solve the Laplace equation to determine field strength. Simulation was used to identify treatment settings for superficial ablation (mucosal layers) or transmural ablation of rectal wall. Animals were euthanized within 4 hours after treatment. RESULTS: Treatment was successfully completed without treatment-related complications. Eleven of 12 lesions were successfully located and extracted for pathologic analysis. All lesions were characterized by necrotic cell death with mild inflammation and hyperemia, with a sharp demarcation between ablated and adjacent normal tissue. Depth of lesions corresponded with numeric simulation. Histologic analysis and measurements indicated that lesion creation with the superficial treatment setting resulted in ablation of mucosal and submucosal layers with superficial or no injury to the muscularis propria (9.97 mm +/- 0.31 length, 3.3 mm +/- 2.92 depth), and that lesion creation with the transmural treatment setting resulted in full-thickness ablation (12.43 mm +/- 3.85 length, 4.97 mm +/- 2.89 depth) of the rectal wall. CONCLUSIONS: An endorectal electrode can be used to deliver IRE and create limited focal ablations in the rectal wall. Treatment parameters can be determined through numeric modeling to control the depth of penetration of ablation. PMID- 23796857 TI - Contrast-enhanced US-guided radiofrequency ablation of hepatocellular carcinoma. AB - PURPOSE: Contrast-enhanced ultrasound (US) has been shown to be an efficient imaging modality in guiding radiofrequency (RF) ablation of hepatocellular carcinomas (HCC). The purpose of the present study was to assess the usefulness of contrast-enhanced US in guiding RF ablation in patients with early-stage HCC that was not clearly visible on grayscale US or noncontrast computed tomography (CT). MATERIALS AND METHODS: During a 17-month period, contrast-enhanced US guided RF ablation was performed in 14 patients with 19 early-stage lesions that were poorly defined on grayscale US and noncontrast CT. Contrast-enhanced US was repeated after 30 minutes, and complete ablation was defined as absence of any arterial-phase enhancement within the ablated lesion. Patients were followed periodically with clinical evaluation, liver function tests, alpha-fetoprotein measurement, and multiphasic CT or magnetic resonance (MR) imaging for a minimum of 1 year after ablation to look for local recurrence or disease progression. Survival probability was estimated with the Kaplan-Meier method. RESULTS: Complete tumor ablation was achieved in all 19 lesions, with no evidence of residual or recurrent tumor in the ablated areas after a mean follow-up of 16 months. No major complications were observed in any patient. However, new lesions developed in other parts of the liver on follow-up scans in three patients, and were accordingly treated with RF ablation. Two patients died of disease progression or liver failure within the 1-year follow-up. CONCLUSIONS: For early stage HCCs not well visualized on unenhanced US or CT, contrast-enhanced US provides an additional tool to guide RF ablation. PMID- 23796858 TI - Treatment of medically inoperable non-small-cell lung cancer with stereotactic body radiation therapy versus image-guided tumor ablation: can interventional radiology compete? AB - Patients with medically inoperable stage IA non-small-cell lung cancer have treatment options that include image-guided tumor ablation or stereotactic body radiation therapy. Literature to date with both techniques suggests similar overall survival; however, local control rates appear to be higher with SBRT. It is important for interventional radiologists to understand the differences and similarities between these two techniques. Future research is important to determine which patients would benefit from these therapies. This review summarizes the two techniques and available clinical literature, provides relevant commentary, and suggests future directions for research in this area. PMID- 23796859 TI - Chemical composition and antioxidant activities in immumosuppressed mice of polysaccharides isolated from Mosla chinensis Maxim cv. jiangxiangru. AB - Polysaccharide MP was isolated from Mosla chinensis Maxim cv. jiangxiangru. It was composed of rhamnose, arabinose, xylose, mannose, glucose and galactose in a molar ratio of 5.364:12.260:3.448:12.260:32.567:30.651, with 11.00%+/-0.24% uronic acid and 9.046%+/-0.04% protein. Its antioxidant activity on the cyclophosphamide-induced immunosuppressed mice was investigated. The spleen and the thymus indices were investigated, and the biochemical parameters were evaluated in three organs (liver, heart and kidney). MP was able to overcome the cyclophosphamide-induced immunosuppression and can significantly raise the T-AOC, CAT, SOD and GSH-PX level. It also raised the spleen and thymus indices and decreased the MDA level in mice. MP could play an important role during the prevention process of oxidative damage in immunological system. PMID- 23796860 TI - Kin, daytime associations, or preferred sleeping sites? Factors influencing sleep site selection in captive chimpanzees (Pan troglodytes). AB - Chimpanzee nesting behaviours and the factors that may influence these behaviours are rarely studied in captive settings. In the present study, the daytime associations, sleeping site selections and nesting groups of 11 zoo-housed chimpanzees over a 29-day period were analysed. Neither daytime associations nor presence of kin influenced sleeping site selection in females. Daytime associations did influence sleeping arrangements in males. Nighttime spatial arrangements and individual preferences for specific sleeping areas were broadly comparable to nesting patterns reported in free-living chimpanzee communities. In the interests of captive ape welfare, we conclude that exhibits should incorporate multilevel nesting areas and a choice of several potential sleeping sites. PMID- 23796861 TI - Epileptic spasms in tuberous sclerosis complex. AB - PURPOSE: To characterize epileptic spasms (ES) occurring after the age of two years in patients with tuberous sclerosis complex (TSC), particularly treatment response to vigabatrin (VGB), which is extremely effective for infantile spasms (IS) in TSC. METHODS: The authors retrospectively reviewed 19 patients with TSC and ES. Medical records were assessed for clinical and treatment data, neurocognitive, EEG, MRI data, and genetic analyses. RESULTS: Of 391 patients with TSC, 19 (4.8%) had ES. Of those with detailed clinical data, six had infantile spasms that persisted after 2 years old, six recurred after an initial remission of infantile spasms (range 2-24 years old), and four occurred de novo over the age of two (range 2-20 years old). All concurrently had other seizure types. One had hypsarrhythmia on EEG. All had brain MRI stigmata typical of TSC. Thirteen had a mutation in TSC2, and one in TSC1. Six patients became spasm-free with medication treatment, including four with VGB, one with VGB in combination with the low glycemic index dietary treatment, and one with felbamate. Five became spasm-free after epilepsy surgery. VGB was not effective for seven patients. The majority continued to have refractory epilepsy. CONCLUSIONS: ES are not uncommon in patients with TSC, especially those with TSC2 mutations. ES in TSC occur in the setting of other seizure types and refractory epilepsy. Hypsarrhythmia is rare. VGB can be effective, but the success of VGB for ES in TSC is not equivalent to that of IS in TSC. PMID- 23796862 TI - Long-term retention of lacosamide in a large cohort of people with medically refractory epilepsy: a single centre evaluation. AB - Lacosamide (LCM) is a recently licensed antiepileptic drug available in the UK since 2008. It is thought to act through modulation of sodium channel slow inactivation. Its efficacy and tolerability have been shown in several regulatory randomised controlled trials, but assessments of its performance in large naturalistic settings are rare. We assessed a large cohort of consecutive people who started LCM at a single tertiary epilepsy centre, from June 2008 to June 2011. Forty-five percent of the 376 people included were still taking LCM at last follow-up, with estimated retention was 62% at one year, 45% at two years and 35% at three years. Eighteen percent reported a period of improvement in terms of significant seizure reduction or seizure freedom of at least six months duration whilst on LCM, of whom four people were seizure free for at least one year. Long term efficacy in our centre appears similar to zonisamide and pregabalin when compared to historical controls. Adverse events were reported by 61%, CNS-related in the vast majority. Most clinical factors did not affect retention; withdrawal occurred more often because of inefficacy than because of adverse events. Retention rates for LCM, when compared to historical controls appear similar to lamotrigine, topiramate, pregabalin, zonisamide, higher than gabapentin, and lower than levetiracetam. PMID- 23796863 TI - Anti-HBV treatment induces novel reverse transcriptase mutations with reflective effect on HBV S antigen. AB - INTRODUCTION: The identification of novel reverse-transcriptase (RT) drug resistance mutations is critical in predicting the probability of success to anti HBV treatment. Furthermore, due to HBV-RT/HBsAg gene-overlap, they can have an impact on HBsAg-detection and quantification. METHODS: 356 full-length HBV-RT sequences from 197 drug-naive patients and 159 patients experiencing virological breakthrough to nucleoside/nucleotide-analogs (NUCs) were analyzed. Mutants and wild-type HBs-antigens were expressed in HuH7-hepatocytes and quantified in cell supernatants and cell-lysates by Architect HBsAg-assay. RESULTS: Ten novel RT mutations (rtN53T-rtS78T-rtS85F-rtS135T-rtA181I-rtA200V-rtK212Q-rtL229V/F rtM309K) correlated with specific NUC-treatments and classical drug-resistance mutations on divergent evolutionary pathways. Some of them reduced RT-binding affinity for anti-HBV drugs and altered S-antigen structure. Indeed, rtS78T (prevalence: 1.1% in drug-naive and 12.2% in adefovir-failing patients) decreased the RT-affinity for adefovir more than the classical adefovir-resistance mutations rtA181 T/V (WT:-9.63 kcal/mol, rtA181T:-9.30 kcal/mol, rtA181V:-7.96 kcal/mol, rtS78T:-7.37 kcal/mol). Moreover, rtS78T introduced a stop-codon at HBsAg-position 69, and completely abrogated HBsAg-quantification in both supernatants and cell-lysates, indicating an impaired HBsAg-secretion/production. Furthermore, the HBsAg-mutation sP217L, silent in RT, significantly correlated with M204V/I-related virological-breakthrough and increased HBsAg-quantification in cell-lysate. CONCLUSIONS: Mutations beyond those classically known can affect drug-binding affinity of mutated HBV-RT, and may have potential effects on HBsAg. Their cumulative effect on resistance and HBV-pathogenicity indicates the importance of preventing therapeutic failures. PMID- 23796864 TI - Evaluating pleural ADA, ADA2, IFN-gamma and IGRA for diagnosing tuberculous pleurisy. AB - OBJECTIVE: Conventional methods for diagnosing tuberculous pleurisy (TB pleurisy) are either invasive or have a long turn-around-time. Performances of pleural adenosine deaminase (ADA), ADA2, interferon-gamma (IFN-gamma), and interferon gamma release assays (IGRA) as diagnostic tools for TB pleurisy were evaluated. METHODS: Eighty-eight patients with lymphocyte-predominant pleural exudates between June 2010 and March 2011, including 31 with clinically diagnosed TB pleurisy, were prospectively studied. Pleural ADA and ADA2 activity were measured by colorimetric method, IFN-gamma levels by enzyme-linked immuno-sorbent assay, and IGRA by enzyme-linked immuno-spot (T-SPOT.TB) assay. RESULTS: Pleural ADA, ADA2, and IFN-gamma levels, but not the proportion of positive T-SPOT.TB assay, were significantly higher in patients with TB pleurisy than in those without TB pleurisy. The area under the receiver-operating-characteristic (ROC) curve was 0.920, 0.893, 0.875, and 0.544 for IFN-gamma, ADA2, ADA, and T-SPOT.TB assay, respectively. The combination of ADA >= 40 IU/L and IFN-gamma >= 75 pg/mL yielded a specificity of 100%. CONCLUSIONS: Pleural ADA, ADA2 and IFN-gamma, but not T SPOT.TB assay, are all sensitive and specific for TB pleurisy. In patients with lymphocyte-predominant pleural exudates, ADA >= 40 IU/L and IFN-gamma >= 75 pg/mL in pleural effusion imply a very high probability of TB pleurisy. PMID- 23796865 TI - Added value of PCR-testing for confirmation of invasive meningococcal disease in England. AB - OBJECTIVES: In England, national guidance recommends that all patients with suspected invasive meningococcal disease (IMD) should be investigated by blood culture and polymerase chain reaction (PCR) testing. The Meningococcal Reference Unit (MRU) provides a national service for meningococcal species confirmation and PCR-testing of clinical samples. We performed a population-level assessment of the added value of PCR-testing for IMD to augment traditional culture confirmation. METHODS: We analysed all PCR-samples and invasive meningococcal isolates received by MRU in 2009 and 2010. We assumed that all patients with PCR samples submitted to MRU also had blood cultures performed and that positive blood cultures were referred to MRU. We confirmed this assertion by case ascertainment. RESULTS: In total, 25,379 specimens from 22,039 patients were submitted for PCR-testing and 1492 (6.8%) tested PCR-positive. MRU received 825 invasive meningococcal isolates; 393 confirmed by PCR and culture, 405 without a PCR-specimen submitted and 27 with a PCR-negative result. Thus, of 1924 reported IMD cases, 1099 (57.1%) were confirmed by PCR only, 432 (22.5%) by culture only and 393 (20.4%) by both tests. CONCLUSION: More than half of all confirmed IMD cases were confirmed by PCR only, indicating this service ensures high case ascertainment for national surveillance. PMID- 23796866 TI - Respiratory infections in Enepa Amerindians are related to malnutrition and Streptococcus pneumoniae carriage. AB - OBJECTIVES: High acute respiratory tract infection (ARTI) rates are observed in indigenous populations. We assessed the role of viral infections and nasopharyngeal bacterial carriage in ARTIs in Enepa Amerindians from Venezuela. METHODS: In 40 children aged 0-10 years with ARTIs, healthy nearest-age sibling controls and their mothers the presence of Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Moraxella catarrhalis, Mycoplasma pneumoniae, Chlamydophila pneumoniae/psittachi and 15 respiratory viruses was investigated. RESULTS: S. pneumoniae was the most frequently detected pathogen, with carriage rates of 75% and 38% in children and mothers respectively. In children, S. pneumoniae carriage was associated with ARTI risk in multivariate analysis (OR 14.1, 95% CI 1.4-137.7). Viral infections were not associated with ARTI risk. S. pneumoniae carriage was common in children of all ages while viral co-infections were more frequently present in children under 4 years compared to older children (46% vs. 17%, p < 0.01). An increase of one unit height-for-age Z score (i.e. improved chronic nutritional status) was associated with decreased odds of S. pneumoniae colonization in multivariate analysis (OR 0.66, 95% CI 0.44-0.99). CONCLUSIONS: In Enepa children high S. pneumoniae carriage rates associated with a poor nutritional status contribute to the development of ARTIs. PMID- 23796867 TI - Factors influencing discordant results of the QuantiFERON-TB Gold In-tube test in patients with active TB. AB - OBJECTIVES: Indeterminate or negative results from the QuantiFERON-TB Gold In tube test (QFT-GIT) for TB-confirmed patients indicate the lower sensitivity of this method. The aim of this study was to determine the factors associated with indeterminate and negative QFT-GIT results in active TB patients. METHODS: We analyzed retrospectively the laboratory and clinical data of patients diagnosed with TB between December 2009 and April 2012 at a tertiary university hospital in Seoul, Korea. RESULTS: Among 1301 patients who underwent QFT-GIT, TB-PCR and TB culture, 168 (12.9%), those with positive TB-PCR or TB-culture were diagnosed with TB. Thirty-nine (23.2%) had indeterminate or negative results by QFT-GIT assay, which did not correlate with positive results of TB-PCR or TB-culture. These patients were older, had lower lymphocyte, total protein and albumin levels, and showed significantly higher CRP levels than the positive group. Multivariate logistic regression analysis showed that the probability of indeterminate and negative QFT-GIT results increased as CRP (odd ratio, 1.069; 95% CI, 1.013-1.127; P = 0.014) or age (1.030, 1.005-1.056, 0.02) increases. CONCLUSIONS: When levels of markers of inflammation, such as CRP, are high or the patient is older, QFT-GIT results should be interpreted carefully and correlated with additional tests for TB. PMID- 23796868 TI - QuantiFERON to diagnose infection by Mycobacterium tuberculosis: performance in infants and older children. AB - OBJECTIVES: QuantiFERON value to diagnose tuberculosis (TB) in young children remains to be clarified. To this aim QF-TB-IT performance was evaluated in a large series of immunocompetent children that were stratified according to age and clinical conditions. METHODS: QF-TB-IT reactivity was analyzed in 226 immunocompetent children (0-15 years old): 31 were uninfected despite TB contact; 51 presented TB disease; 39 had Latent TB (LTBI) and 105 had TB disease suspected but an alternative diagnosis (TB excluded). RESULTS: QF-TB-IT specificity was 100% in TB excluded. In TB disease, low sensitivity of QF-TB-IT in infants (40%) increased with aging (77% in 1-<5 years and 82% in 5-<15 years old subgroups). In LTBI, agreement between TST and QF-TB-IT was 0% in infants, 40% in 1-<5 years and 57% in children >5 years old. Finally, the incidence of indeterminate results was high (24%) in children <5 years old with TB excluded, especially with non-TB pneumonitis (61%), but was low (0-6%) regardless of age group in TB disease, LTBI and uninfected contact cases. CONCLUSIONS: In our low burden country, i) QF-TB-IT specificity was 100%, ii) QF-TB-IT sensitivity was low in infants but commensurable to adult values in older children, and iii) indeterminate results mostly relied on ongoing infections unrelated to TB. PMID- 23796869 TI - Lamivudine-resistant HBV strain rtM204V/I in acute hepatitis B. AB - AIMS: To detect HBV rtM204V/I lamivudine-resistant strains in serum of patients with acute hepatitis B and to assess their biological and clinical significance. METHODS: Eighty HBV DNA-positive patients with symptomatic acute hepatitis B observed from 1999 to 2010 were enrolled. A plasma sample obtained at the first observation was tested for HBV mutants in the polymerase region by direct sequencing; the antiviral drug-resistant rtM204V/I mutations, the most frequent HBV mutants in Italy, were also sought by the more sensitive allele-specific polymerase chain reaction (PCR). RESULTS: No HBV mutation associated with resistance to nucleos(t)ide analogues was identified by direct sequencing, whereas allele-specific PCR identified HBV strains carrying the substitution rtM204V/I in 11 (13.7%) patients. Compared with those with the HBV wild strain, patients with rtM204V/I more frequently showed severe acute hepatitis B (36.4% vs 8.7%; p < 0.05) and lower values of serum HBV DNA (1.77 * 10(6) +/- 4.76 * 10(6) vs. 1.68 * 10(8) +/- 5.46 * 10(8)). In addition, a multivariate analysis identified the presence of a pre-existing HCV chronic infection as independently associated with severe acute hepatitis B (p < 0.05). CONCLUSIONS: HBV rtM204V/I lamivudine-resistant strains were detected in serum of 11 (13.7%) patients with acute hepatitis B by allele-specific polymerase chain reaction. The frequent association of rtM204V/I with a more severe acute hepatitis B and with a lower viral load may suggest that greater and/or more prolonged immune pressure might have induced their selection. PMID- 23796870 TI - Commercial MPT64-based tests for rapid identification of Mycobacterium tuberculosis complex: a meta-analysis. AB - OBJECTIVE: We did a systematic review and meta-analysis of published studies to evaluate the accuracy of commercial MPT64-based immunochromatographic tests for rapid identification of Mycobacterium tuberculosis complex. METHODS: We identified studies by searching Pubmed, BIOSIS Previews and Web of Science, and included studies using predetermined inclusion criteria. The data were pooled using the DerSimonian-Laird random effects model. RESULTS: A total of 28 studies were included in the final analysis. Pooled estimates were 97% (confidence interval [CI] 96-97%) for sensitivity and 98% (CI 98-99%) for specificity. The summary receiver operating characteristic curve showed an area of 0.9968 and a Q* of 0.98. Subgroup analysis showed that test accuracy did not depend on commercial kit, reference test and medium. CONCLUSIONS: Commercial MPT64-based immunochromatographic tests are highly sensitive and specific for rapid identification of M. tuberculosis complex. They are good alternatives to biochemical test and molecular assays. Nevertheless, additional studies are required in setting with high prevalence of mpt64 mutations or high contamination of cultures. PMID- 23796871 TI - Impact of hepatitis B and delta virus co-infection on liver disease in Mauritania: a cross sectional study. AB - OBJECTIVES: Mauritania is a highly endemic region for hepatitis B (HBV) and delta (HDV) viruses. No data are available on HDV's impact on the severity of liver disease in consecutive HBV-infected patients in Africa. This study evaluated the degree of liver fibrosis in a cohort of chronic HBV carriers. METHODS: Three hundred consecutive HBV-infected Mauritanian patients were checked for HDV infection via the detection of anti-HDV antibodies (Ab) and viral RNA. HBV- vs. HBV/HDV-infected patients were compared by physical examination, biological analyses, and the APRI (aspartate aminotransferase to platelet ratio index) and FibroMeter tests for determination of liver fibrosis. RESULTS: More than 30% of the patients had anti-HDVAb. Among these, 62.2% were HDV-RNA positive. Co infected patients were older (>8-years) than HBV-mono-infected patients. They had more liver tests abnormalities and clinical or ultrasound signs of liver fibrosis. APRI and FibroMeter scores were also significantly increased in these patients. In multivariate analysis, beyond HDVAb, male gender and HBV-VL >3.7 log IU/mL were the only markers linked to significant liver fibrosis. CONCLUSIONS: In Mauritania, HDV co-infection worsens liver disease, both clinically and biologically, as confirmed by the APRI and FibroMeter tests. These tests may be useful for the management of delta hepatitis, which is a major health problem in Mauritania. PMID- 23796872 TI - Rapid progression and brain atrophy in anti-AMPA receptor encephalitis. AB - Anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor encephalitis is an anti-neuronal surface antigen autoimmune encephalitis that is rarely reported. Our study evaluated the first known patient who developed anti AMPA receptor encephalitis during pregnancy. Initial brain MRI revealed bilateral limbic encephalitis. However, rapid brain atrophy on MRI with extensive hypometabolism of cerebral cortices, caudate nuclei and brain stem hypoperfusion on (18)F-FDG PET developed when clinically progressed. IgG index of serial CSF studies reflected the clinical improvements after plasmapheresis and plasma exchange. The clinical spectrum of anti-AMPA receptor encephalitis may be expanded from limited limbic involvement to extended central nervous system. PMID- 23796873 TI - TRPM4 mRNA expression levels in peripheral blood mononuclear cells from multiple sclerosis patients. AB - Recent studies have suggested a role of the cation channel TRPM4 in mediating neurodegeneration in experimental autoimmune encephalomyelitis and multiple sclerosis (MS). We aimed to extrapolate central nervous system findings to the blood compartment by determining TRPM4 expression in peripheral blood mononuclear cells from 12 healthy controls (HC) and 64 untreated MS patients. TRPM4 mRNA expression levels were comparable between HC and MS patients with primary progressive MS (n=17), secondary progressive MS (n=19), and relapsing-remitting MS during clinical remission (n=21) and relapses (n=7). These findings do not support a role of TRPM4 in the peripheral blood compartment of MS patients. PMID- 23796874 TI - Filling the gap: estimating physicochemical properties of the full array of polybrominated diphenyl ethers (PBDEs). AB - Physicochemical properties of PBDE congeners are important for modeling their transport, but data are often missing. The quantitative structure-property relationship (QSPR) approach is utilized to fill this gap. Individual research groups often report piecemeal properties through experimental measurements or estimation techniques, but these data seldom satisfy fundamental thermodynamic relationships because of errors. The data then lack internal consistency and cannot be used directly in environmental modeling. This paper critically reviews published experimental data to select the best QSPR models, which are then extended to all 209 PBDE congeners. Properties include aqueous solubility, vapor pressure, Henry's law constant, octanol-water partition coefficient and octanol air partition coefficient. Their values are next adjusted to satisfy fundamental thermodynamic equations. The resulting values then take advantage of all measurements and provide quick references for modeling and PBDE-contaminated site assessment and remediation. PCBs are also compared with respect to their properties and estimation methods. PMID- 23796875 TI - A fraction of stem bark extract of Entada africana suppresses lipopolysaccharide induced inflammation in RAW 264.7 cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Entada africana is a plant used in African traditional medicine for the treatment of stomachache, fever, liver related diseases, wound healing, cataract and dysentery. AIMS OF THE STUDY: This study aimed at evaluating the anti-inflammatory activity of fractions of the stem bark extract of the plant using lipopolysaccharide (LPS)-induced inflammation in RAW 264.7 macrophages model. MATERIALS AND METHODS: The crude extract was prepared using the mixture CH2Cl2/MeOH (1:1, v/v) and fractionated by flash chromatography using solvents of increasing polarity to obtain five different fractions. The effects of the fractions on the cells viability were studied by the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and their inhibitory activity against LPS-induced nitric oxide (NO) production screened by Griess test. The most active fraction was further investigated for its effects on reactive oxygen species (ROS) production using flux cytometry, the expression of inducible nitric oxide synthase (iNOS), pro-and anti-inflammatory cytokines (IL1beta, TNFalpha, IL6, IL10 and IL13) by RT-PCR, and the activity of the enzyme p38 MAPK kinase by enzyme-linked immunosorbent assay (ELISA). RESULTS: The fractions presented no significant effect on the viability of macrophages at 100 MUg/ml after 24h incubation. The CH2Cl2/MeOH 5% (Ea5) fraction was found to be the most potent in inhibiting NO production with a half inhibition concentration (IC50)=18.36 MUg/ml, and showed the highest inhibition percentage (89.068%) in comparison with Baicalin (63.34%), an external standard at 50 MUg/ml. Ea5, as well as Baicalin significantly (P<0.05) inhibited the expression of TNFalpha, IL6 and IL1beta mRNA, attenuated mRNA expression of inducible NO synthase in a concentration-dependent manner, stimulated the expression of anti-inflammatory cytokines (IL10 and IL13), and showed a 30% inhibition of the activity of p38 MAPK kinase. CONCLUSION: The results of the present study indicate that the fraction Ea5 of Entada africana possesses most potent in vitro anti-inflammatory activity and may contain compounds useful as a therapeutic agent in the treatment of inflammatory related diseases cause by over-activation of macrophages. PMID- 23796876 TI - Efficacy of Withania somnifera on seminal plasma metabolites of infertile males: a proton NMR study at 800 MHz. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Indian systems of medicine use roots of Withania somnifera for impotence, infertility treatment, stress, and the aging process. Although Withania somnifera improves semen quality by regulating reproductive hormone levels and oxidative stress, the molecular mechanism is not clear. AIM OF THE STUDY: Our study uses high-resolution Nuclear Magnetic Resonance (NMR) spectroscopy to explore the scientific basis to reveal the pre- and post-treatment efficacy of Withania somnifera on seminal plasma of infertile men-which remains unexplored to date. MATERIALS AND METHODS: A total of 180 infertile male patients were administered Withania somnifera root powder at the rate of 5 g/d for a 3-month period. The study included age-matched, healthy men as a control (n=50) group. Proton NMR spectroscopy was used to measure lactate, alanine, glutamate, glutamine, citrate, lysine, choline, glycerophosphocholine (GPC), glycine, tyrosine, histidine, phenylalanine, and uridine in all seminal plasma samples. To appraise infertility levels, we also measured sperm concentration, motility, lipid peroxide, and hormonal perturbation. RESULTS: Withania somnifera therapy repairs the disturbed concentrations of lactate, alanine, citrate, GPC, histidine, and phenylalanine in seminal plasma and recovers the quality of semen of post-treated compared to pre-treated infertile men. Serum biochemistry was also improved over post-therapy in infertile men. Our findings reveal that Withania somnifera not only reboots enzymatic activity of metabolic pathways and energy metabolism but also invigorates the harmonic balance of seminal plasma metabolites and reproductive hormones in infertile men. CONCLUSION: The results suggest that Withania somnifera may be used as an empirical therapy for clinical management and treatment of infertility. PMID- 23796877 TI - Toxicity evaluation of standardized extract of Gynostemma pentaphyllum Makino. AB - ETHNOPHARMACOLOGICAL RELEVANCE: To evaluate the safety of standardized extract of Gynostemma pentaphyllum in rats. MATERIALS AND METHODS: The water extract of Gynostemma pentaphyllum was prepared and standardized, the dry powder yielded 6% gypenosides. In the acute oral toxicity test, the single oral dose of 5000 mg/kg of Gynostemma pentaphyllum extract was given to female Sprague-Dawley rats. In subchronic toxicity test, the oral dose of 1000 mg/kg/day of the extract was given to rats in treatment and satellite groups for 90 days. Satellite groups of both sexes were kept for additional 28 days after 90-day treatment. Control rats received distilled water. RESULTS: Standardized extract of Gynostemma pentaphyllum did not cause death or any toxic signs in rats. The daily administration of the extract for 90 days did not produce lethal or harmful effects. Although certain hematological and blood chemistry values (i.e., neutrophil, monocyte, glucose, and serum alkaline phosphatase levels) were found to be statistically different from the control group, however; these values were within the ranges of normal rats. CONCLUSION: Standardized extract of Gynostemma pentaphyllum did not produce mortality or any abnormality in rats. PMID- 23796878 TI - Lilium lancifolium Thunb. extract attenuates pulmonary inflammation and air space enlargement in a cigarette smoke-exposed mouse model. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Lilium lancifolium Thunb. (Liliaceae) has long been used as a traditional medicine in Korea and China to treat bronchitis, pneumonia, and other pulmonary ailments. AIM OF THE STUDY: Cigarette smoke (CS) is a major risk factor for the development of pulmonary inflammatory response; it also triggers pulmonary alveoli enlargement. In the present study, we investigate the effects of Lilium lancifolium Thunb. root extract on pulmonary inflammatory responses in a CS-exposed mouse model. MATERIALS AND METHODS: Water extract of Lilium lancifolium Thunb. root was fed to C57BL/6 mice prior CS exposure every day for 3 weeks. The numbers of macrophages and neutrophils in bronchoalveolar lavage fluid (BALF) were counted. The relative inflammatory factors, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-1 beta (IL 1beta), monocyte chemotactic protein-1 (MCP-1), and matrix metalloproteinase-12 (MMP-12) were measured by real-time PCR, ELISA, or Western blot analysis. The average alveoli size was determined by lung histology. RESULTS: Lilium lancifolium Thunb. root extract was found to significantly inhibit the numbers of macrophages and neutrophils in BALF due to CS exposure. Lilium lancifolium Thunb. root extract also reduced the protein secretion levels of TNF-alpha, IL-6, IL 1beta, and MCP-1 in BALF and the RNA expression levels of TNF-alpha, IL-6, IL 1beta, MCP-1, and MMP-12 in lung tissue compared with mice only exposed to CS. Moreover, MMP-12 in serum was down regulated in Lilium lancifolium Thunb. root extract treated mice compared with CS-exposed mice. Finally, a morphometric analysis of the lungs of Lilium lancifolium Thunb. root extract treated mice demonstrated a significant reduction in airspace size compared to mice only exposed to CS. CONCLUSION: Our results show that Lilium lancifolium Thunb. root extract reduces lung inflammation and airspace enlargement in a CS-exposed mouse model. These data indicate that Lilium lancifolium Thunb. root extract is a therapeutic candidate for pulmonary inflammation and emphysema caused by CS. PMID- 23796879 TI - The chemical bases of human sociality. AB - Communication is the foundation of sociality and is made possible by a diverse set of media. Research on human communication has primarily focused on auditory and visual modalities. Here, we discuss the role of the olfactory modality as an important medium of human communication and highlight the significance of interpersonal chemosignaling in the context of emerging research that investigates the adaptive effects of human chemosignals on cognitive-affective processes. PMID- 23796880 TI - Beyond metaphor: contrasting mechanisms of social and physical pain. AB - Physical pain can be clearly distinguished from other states of distress. In recent years, however, the notion that social distress is experienced as physically painful has permeated the scientific literature and popular media. This conclusion is based on the overlap of brain regions that respond to nociceptive input and sociocultural distress. Here we challenge the assumption that underlies this conclusion - that physical pain can be easily inferred from a particular pattern of activated brain regions - by showing that patterns of activation commonly presumed to constitute the 'pain matrix' are largely unspecific to pain. We then examine recent analytical advances that may improve the specificity of imaging for parsing pain from a broad range of perceptually unique human experiences. PMID- 23796881 TI - Ischemia-modified albumin, a predictive marker of major adverse cardiovascular events in continuous ambulatory peritoneal dialysis patients. AB - OBJECTIVES: The aim of this study was to evaluate the efficiency of ischemia modified albumin (IMA) for predicting major adverse cardiovascular events (MACE) in continuous ambulatory peritoneal dialysis (CAPD) patients. DESIGN AND METHODS: A prospective observational study was conducted with 120 CAPD patients and 37 healthy volunteers. Demographic and clinical data were collected. The primary end point is the occurrence of MACE. RESULTS: A total of 157 participants with a mean age of 43.64 years finally completed this study. The CAPD patients had a significantly high rate of MACE (P=0.001) and high levels of IMA than healthy controls (P<0.001). Compared with CAPD patients with normal levels of IMA, the CAPD patients with high levels of IMA (>85 kU/L) had lower non-MACE survival rate (P<0.001), which indicated that the high IMA CAPD patients may suffer a high rate of MACE. In addition, the high IMA CAPD patients also had a low level of serum albumin (P<0.001) and hemoglobin (P=0.018). The correlation analysis showed that the serum albumin level was the most effective factor influencing IMA (B=-0.967, P<0.001). CONCLUSIONS: CAPD patients with high levels of IMA had a high incidence rate of MACE. IMA was a good predictive marker of MACE and might be important in cardiovascular risk stratification of CAPD patients. PMID- 23796882 TI - FLAIR lesion segmentation: application in patients with brain tumors and acute ischemic stroke. AB - BACKGROUND: Lesion size in fluid attenuation inversion recovery (FLAIR) images is an important clinical parameter for patient assessment and follow-up. Although manual delineation of lesion areas considered as ground truth, it is time consuming, highly user-dependent and difficult to perform in areas of indistinct borders. In this study, an automatic methodology for FLAIR lesion segmentation is proposed, and its application in patients with brain tumors undergoing therapy; and in patients following stroke is demonstrated. MATERIALS AND METHODS: FLAIR lesion segmentation was performed in 57 magnetic resonance imaging (MRI) data sets obtained from 44 patients: 28 patients with primary brain tumors; 5 patients with recurrent-progressive glioblastoma (rGB) who were scanned longitudinally during anti-angiogenic therapy (18 MRI scans); and 11 patients following ischemic stroke. RESULTS: FLAIR lesion segmentation was obtained in all patients. When compared to manual delineation, a high visual similarity was observed, with an absolute relative volume difference of 16.80% and 20.96% and a volumetric overlap error of 24.87% and 27.50% obtained for two raters: accepted values for automatic methods. Quantitative measurements of the segmented lesion volumes were in line with qualitative radiological assessment in four patients who received anti anogiogenic drugs. In stroke patients the proposed methodology enabled identification of the ischemic lesion and differentiation from other FLAIR hyperintense areas, such as pre-existing disease. CONCLUSION: This study proposed a replicable methodology for FLAIR lesion detection and quantification and for discrimination between lesion of interest and pre-existing disease. Results from this study show the wide clinical applications of this methodology in research and clinical practice. PMID- 23796883 TI - Abstracts of the International Heart Forum. Beijing, China. August 9-12, 2012. PMID- 23796884 TI - In silico models for predicting ready biodegradability under REACH: a comparative study. AB - REACH (Registration Evaluation Authorization and restriction of Chemicals) legislation is a new European law which aims to raise the human protection level and environmental health. Under REACH all chemicals manufactured or imported for more than one ton per year must be evaluated for their ready biodegradability. Ready biodegradability is also used as a screening test for persistent, bioaccumulative and toxic (PBT) substances. REACH encourages the use of non testing methods such as QSAR (quantitative structure-activity relationship) models in order to save money and time and to reduce the number of animals used for scientific purposes. Some QSAR models are available for predicting ready biodegradability. We used a dataset of 722 compounds to test four models: VEGA, TOPKAT, BIOWIN 5 and 6 and START and compared their performance on the basis of the following parameters: accuracy, sensitivity, specificity and Matthew's correlation coefficient (MCC). Performance was analyzed from different points of view. The first calculation was done on the whole dataset and VEGA and TOPKAT gave the best accuracy (88% and 87% respectively). Then we considered the compounds inside and outside the training set: BIOWIN 6 and 5 gave the best results for accuracy (81%) outside training set. Another analysis examined the applicability domain (AD). VEGA had the highest value for compounds inside the AD for all the parameters taken into account. Finally, compounds outside the training set and in the AD of the models were considered to assess predictive ability. VEGA gave the best accuracy results (99%) for this group of chemicals. Generally, START model gave poor results. Since BIOWIN, TOPKAT and VEGA models performed well, they may be used to predict ready biodegradability. PMID- 23796885 TI - Trigeminal neuralgia associated with cerebellopontine angle lipoma in childhood. AB - Cerebellopontine angle lipomas are rare and more rarely associated with trigeminal neuralgia especially in childhood. Medical treatment provides relief from the pain; however, the effect may not be permanent. Surgical treatment is associated with a high morbidity rate; therefore, surgery should be considered only in intractable cases. In this article we describe the clinical course and radiological features of a 6-year-old girl with a cerebellopontine angle lipoma who presented with a 4-year history of left-side trigeminal neuralgia, especially in the mandibular area. Magnetic resonance imaging revealed an extra-axial fatty mass at the level of the 'dorsal-entry zone' of the trigeminal nerve. The pain improved with carbamazepine therapy. PMID- 23796886 TI - Diffuse pulmonary meningotheliomatosis diagnosed by transbronchial lung biopsy. AB - Minute pulmonary meningothelial-like nodules (MPMNs) are usually unique lesions in the lung parenchyma. Diffuse pulmonary meningotheliomatosis, which is presented as multiple MPMNs, has been less frequently described. MPMNs are mainly asymptomatic and are diagnosed after lung surgery or during autopsy. We report on a patient with multiple and bilateral pulmonary nodules, some of which were cavitated, diagnosed with diffuse pulmonary meningotheliomatosis by transbronchial lung biopsy. Diffuse pulmonary meningotheliomatosis should be included in the differential diagnosis of bilateral lung nodules. PMID- 23796887 TI - Fertility-sparing surgery in ovarian cancer extended beyond the ovaries: a case report and review of the literature. AB - BACKGROUND: Much attention has been recently focused on the role of fertility sparing surgery in patients with ovarian cancer. However, few data are currently available on the feasibility of conservative approaches in women with disease extending beyond the ovaries. AIM: This review article aims at summarizing the oncologic and obstetric outcome of patients with stage II-III ovarian cancer treated with fertility-sparing surgery. We also describe a successful conservative management of a stage IIC endometrioid ovarian carcinoma. METHODS: A literature search through Medline was carried out to locate published articles using the following keywords for selection: 'Fertility-sparing surgery and ovarian cancer'. From every single case series, we retrieved data on patients with stage II-III disease submitted to conservative surgery. RESULTS: We identified 21 patients with stage II-III disease receiving fertility-sparing surgery. Recurrent disease was observed in 9 women (42.8%), and 5 (23.8%) of them died of disease. In contrast, a successful obstetric outcome has been reported in 3 cases (14.2%). CONCLUSIONS: Radical surgical staging remains the standard of care for all women with stage II-III disease. A fertility-sparing approach may be considered only in the presence of a favorable histology and a very strong fertility desire. PMID- 23796889 TI - Biochar mitigates negative effects of salt additions on two herbaceous plant species. AB - Addition of pyrolyzed biomass ("biochar") to soils has commonly been shown to increase crop yields and alleviate plant stresses associated with drought and exposure to toxic materials. Here we investigate the ability of biochar (at two dosages: 5 and 50 t ha(-1)) to mitigate salt-induced stress, simulating road salt additions in a factorial glasshouse experiment involving the broadleaved herbaceous plants Abutilon theophrasti and Prunella vulgaris. Salt additions of 30 g m(-2) NaCl to unamended soils resulted in high mortality rates for both species. Biochar (Fagus grandifolia sawdust pyrolyzed at 378 degrees C), when applied at 50 t ha(-1) as a top dressing, completely alleviated salt-induced mortality in A. theophrasti and prolonged survival of P. vulgaris. Surviving A. theophrasti plants that received both 50 t ha(-1) biochar and salt addition treatments showed growth rates and physiological performance similar to plants without salt addition. Biochar treatments alone also substantially increased biomass of P. vulgaris, with a ~50% increase relative to untreated controls at both biochar dosages. Biochar did not significantly affect photosynthetic carbon gain (Amax), water use efficiency, or chlorophyll fluorescence (Fv/Fm) in either species. Our results indicate that biochar can ameliorate salt stress effects on plants through salt sorption, suggesting novel applications of biochar to mitigate effects of salinization in agricultural, urban, and contaminated soils. PMID- 23796888 TI - Molecular mechanisms of muscle atrophy in myotonic dystrophies. AB - Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) are multisystemic diseases that primarily affect skeletal muscle, causing myotonia, muscle atrophy, and muscle weakness. DM1 and DM2 pathologies are caused by expansion of CTG and CCTG repeats in non-coding regions of the genes encoding myotonic dystrophy protein kinase (DMPK) and zinc finger protein 9 (ZNF9) respectively. These expansions cause DM pathologies through accumulation of mutant RNAs that alter RNA metabolism in patients' tissues by targeting RNA binding proteins such as CUG-binding protein 1 (CUGBP1) and Muscle blind-like protein 1 (MBNL1). Despite overwhelming evidence showing the critical role of RNA binding proteins in DM1 and DM2 pathologies, the downstream pathways by which these RNA-binding proteins cause muscle wasting and muscle weakness are not well understood. This review discusses the molecular pathways by which DM1 and DM2 mutations might cause muscle atrophy and describes progress toward the development of therapeutic interventions for muscle wasting and weakness in DM1 and DM2. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. PMID- 23796890 TI - The voluntary-threat approach to control nonpoint source pollution under uncertainty. AB - This paper extends the voluntary-threat approach of Segerson and Wu (2006) to the case that the ambient level of nonpoint source pollution is stochastic. It is shown that when the random component is bounded from the above, fine-tuning the cutoff value of the tax payments avoids the actual imposition of the tax while the threat of such payments retains necessary incentive for the polluters to engage in abatements at the optimal level. If the random component is not bounded, the imposition of the tax cannot be completely avoided but the probability can be reduced by setting a higher cutoff value. It is also noted that the regulator has additional flexibility in randomizing the tax imposition but the randomization process has to be credible. PMID- 23796891 TI - Pulmonary venous wedge pressure: a rare indication in a heart transplant candidate. PMID- 23796892 TI - Treatment of Staphylococcus aureus endocarditis with high doses of trimethoprim/sulfamethoxazole and clindamycin-Preliminary report. PMID- 23796893 TI - Alternative natural sources for a new generation of antibacterial agents. AB - The huge challenge posed by antibiotic resistance would be well served by the discovery and development of a new wave of antibacterial drugs. Natural products have been the mainstay of anti-infective drug discovery since the early days of the antibiotic era, but mining of valuable natural resources has been all but abandoned by the major pharmaceutical players in favour of synthetic chemistry. The search for naturally occurring antibacterial agents has continued in academe, but activities need to be repositioned to take advantage of exciting advances in genomics and advanced genetic engineering. This review evaluates the potential of microbial communities in underexplored environmental niches to yield new antibiotics and the harnessing of biomembrane-interactive plant-derived agents as supplements to conventional antibacterial chemotherapy. PMID- 23796894 TI - Prevalence and characterisation of plasmid-mediated quinolone resistance and mutations in the gyrase and topoisomerase IV genes among Shigella isolates from Henan, China, between 2001 and 2008. AB - A total of 293 Shigella isolates were isolated from patients with diarrhoea in four villages of Henan, China. This study investigated the prevalence of the plasmid-mediated quinolone resistance (PMQR) genes qnrA, qnrB, qnrS, qepA and aac(6')-Ib-cr and compared the polymorphic quinolone resistance-determining regions (QRDRs) of gyrA, gyrB, parC and parE. Of the isolates, 292 were found to be resistant to nalidixic acid and pipemidic acid, whereas 77 were resistant to ciprofloxacin (resistance rate of 26.3%). Resistance of the Shigella isolates to ciprofloxacin significantly increased from 2001 to 2008 (P<0.05). A mutation in gyrA was present in 277 (94.5%) of the isolates and a mutation in parC was present in 19 (6.5%) of the isolates. Moreover, 168 (57.3%) of the isolates contained only the gyrA (Ser83Leu) mutation. In addition, 107 isolates had two gyrA point mutations (Ser83Leu and either Asp87Gly, Asp87Asn or Asp113Tyr) and 13 isolates had two gyrA point mutations (Ser83Leu and Asp87Gly or Gly214Ala) and one parC mutation (Ser80Ile). In addition, qepA and aac(6')-Ib-cr were present in 6 (2.05%) and 19 (6.48%) of the isolates, respectively. All but one of the PMQR positive isolates with a ciprofloxacin minimum inhibitory concentration in the range 4-32MUg/mL had a mutation in the QRDR. It is known that PMQR-positive Shigella isolates are common in China. This study found that there was a significant increase in mutation rates of the QRDR and the resistant rates to ciprofloxacin. Other mechanisms may be present in the isolates that also contribute to their resistance to ciprofloxacin. PMID- 23796895 TI - Extensive investigation of antimicrobial resistance in Vibrio parahaemolyticus from shellfish and clinical sources, Italy. PMID- 23796896 TI - MicroRNA-138 and SIRT1 form a mutual negative feedback loop to regulate mammalian axon regeneration. AB - Regulated gene expression determines the intrinsic ability of neurons to extend axons, and loss of such ability is the major reason for the failed axon regeneration in the mature mammalian CNS. MicroRNAs and histone modifications are key epigenetic regulators of gene expression, but their roles in mammalian axon regeneration are not well explored. Here we report microRNA-138 (miR-138) as a novel suppressor of axon regeneration and show that SIRT1, the NAD-dependent histone deacetylase, is the functional target of miR-138. Importantly, we provide the first evidence that miR-138 and SIRT1 regulate mammalian axon regeneration in vivo. Moreover, we found that SIRT1 also acts as a transcriptional repressor to suppress the expression of miR-138 in adult sensory neurons in response to peripheral nerve injury. Therefore, miR-138 and SIRT1 form a mutual negative feedback regulatory loop, which provides a novel mechanism for controlling intrinsic axon regeneration ability. PMID- 23796897 TI - A survey of intragenic breakpoints in glioblastoma identifies a distinct subset associated with poor survival. AB - With the advent of high-throughput sequencing technologies, much progress has been made in the identification of somatic structural rearrangements in cancer genomes. However, characterization of the complex alterations and their associated mechanisms remains inadequate. Here, we report a comprehensive analysis of whole-genome sequencing and DNA copy number data sets from The Cancer Genome Atlas to relate chromosomal alterations to imbalances in DNA dosage and describe the landscape of intragenic breakpoints in glioblastoma multiforme (GBM). Gene length, guanine-cytosine (GC) content, and local presence of a copy number alteration were closely associated with breakpoint susceptibility. A dense pattern of repeated focal amplifications involving the murine double minute 2 (MDM2)/cyclin-dependent kinase 4 (CDK4) oncogenes and associated with poor survival was identified in 5% of GBMs. Gene fusions and rearrangements were detected concomitant within the breakpoint-enriched region. At the gene level, we noted recurrent breakpoints in genes such as apoptosis regulator FAF1. Structural alterations of the FAF1 gene disrupted expression and led to protein depletion. Restoration of the FAF1 protein in glioma cell lines significantly increased the FAS-mediated apoptosis response. Our study uncovered a previously underappreciated genomic mechanism of gene deregulation that can confer growth advantages on tumor cells and may generate cancer-specific vulnerabilities in subsets of GBM. PMID- 23796899 TI - Phase errors in FSE signals due to low frequency electromagnetic interference. AB - OBJECTIVE: To quantitatively evaluate induced phase errors in fast spin echo (FSE) signals due to low frequency electromagnetic inference (EMI). METHODS: Specific form of Bloch equation is numerically solved in time domain for two different FSE pulse sequences (ETL=8) with two different bandwidths. A single spin is modeled at x=10cm, EMI frequencies are simulated from 1 to 1000Hz and phase errors at different echo times are calculated. RESULTS: Phase errors in the received echo signals induced by EMI are significantly higher at low frequencies (<200Hz) than at high frequencies and the phase errors at low frequencies can be effectively reduced by using high receiving bandwidth. CONCLUSION: Pulse sequence bandwidth can be used to control the phase errors in the FSE signals due to low frequency EMI. PMID- 23796898 TI - An IKKalpha-E2F1-BMI1 cascade activated by infiltrating B cells controls prostate regeneration and tumor recurrence. AB - Androgen-deprived prostate cancer (PCa) is infiltrated by B lymphocytes that produce cytokines that activate IkappaB kinase alpha (IKKalpha) to accelerate the emergence of castration-resistant tumors. We now demonstrate that infiltrating B lymphocytes and IKKalpha are also required for androgen-dependent expansion of epithelial progenitors responsible for prostate regeneration. In these cells and in PCa cells, IKKalpha phosphorylates transcription factor E2F1 on a site that promotes its nuclear translocation, association with the coactivator CBP, and recruitment to critical genomic targets that include Bmi1, a key regulator of normal and cancerous prostate stem cell renewal. The IKKalpha-BMI1 pathway is also activated in human PCa. PMID- 23796900 TI - Surgical excision of sialoblastoma in the parotid gland in newborn. AB - OBJECTIVES: To evaluate outcome of surgical excision of sialoblastoma in the parotid gland in newborn. PATIENTS AND METHODS: This was a retrospective review of 3 pediatric patients with sialoblastoma in the parotid gland that underwent surgical resections. All patients are newborn boys. The lesions ranged from 5 cm * 5 cm to 8 cm * 5 cm in size. The tumor was resected en bloc, and the facial nerve was preserved. RESULTS: None surgical complications occurred. The mean follow-up was 34 months; none patients had recurrent lesions. CONCLUSION: Surgical dissection of sialoblastoma in the parotid gland in the newborn is most efficient and safe. PMID- 23796901 TI - Gaining insight of fetal brain development with diffusion MRI and histology. AB - Human brain is extraordinarily complex and yet its origin is a simple tubular structure. Its development during the fetal period is characterized by a series of accurately organized events which underlie the mechanisms of dramatic structural changes during fetal development. Revealing detailed anatomy at different stages of human fetal brain development provides insight on understanding not only this highly ordered process, but also the neurobiological foundations of cognitive brain disorders such as mental retardation, autism, schizophrenia, bipolar and language impairment. Diffusion tensor imaging (DTI) and histology are complementary tools which are capable of delineating the fetal brain structures at both macroscopic and microscopic levels. In this review, the structural development of the fetal brains has been characterized with DTI and histology. Major components of the fetal brain, including cortical plate, fetal white matter and cerebral wall layer between the ventricle and subplate, have been delineated with DTI and histology. Anisotropic metrics derived from DTI were used to quantify the microstructural changes during the dynamic process of human fetal cortical development and prenatal development of other animal models. Fetal white matter pathways have been traced with DTI-based tractography to reveal growth patterns of individual white matter tracts and corticocortical connectivity. These detailed anatomical accounts of the structural changes during fetal period may provide the clues of detecting developmental and cognitive brain disorders at their early stages. The anatomical information from DTI and histology may also provide reference standards for diagnostic radiology of premature newborns. PMID- 23796903 TI - Mummy, A UDP-N-acetylglucosamine pyrophosphorylase, modulates DPP signaling in the embryonic epidermis of Drosophila. AB - The evolutionarily conserved JNK/AP-1 (Jun N-terminal kinase/activator protein 1) and BMP (Bone Morphogenetic Protein) signaling cascades are deployed hierarchically to regulate dorsal closure in the fruit fly Drosophila melanogaster. In this developmental context, the JNK/AP-1 signaling cascade transcriptionally activates BMP signaling in leading edge epidermal cells. Here we show that the mummy (mmy) gene product, which is required for dorsal closure, functions as a BMP signaling antagonist. Genetic and biochemical tests of Mmy's role as a BMP-antagonist indicate that its function is independent of AP-1, the transcriptional trigger of BMP signal transduction in leading edge cells. pMAD (phosphorylated Mothers Against Dpp) activity data show the mmy gene product to be a new type of epidermal BMP regulator - one which transforms a BMP ligand from a long- to a short-range signal. mmy codes for the single UDP-N-acetylglucosamine pyrophosphorylase in Drosophila, and its requirement for attenuating epidermal BMP signaling during dorsal closure points to a new role for glycosylation in defining a highly restricted BMP activity field in the fly. These findings add a new dimension to our understanding of mechanisms modulating the BMP signaling gradient. PMID- 23796902 TI - Quantitative evaluation of brain development using anatomical MRI and diffusion tensor imaging. AB - The development of the brain is structure-specific, and the growth rate of each structure differs depending on the age of the subject. Magnetic resonance imaging (MRI) is often used to evaluate brain development because of the high spatial resolution and contrast that enable the observation of structure-specific developmental status. Currently, most clinical MRIs are evaluated qualitatively to assist in the clinical decision-making and diagnosis. The clinical MRI report usually does not provide quantitative values that can be used to monitor developmental status. Recently, the importance of image quantification to detect and evaluate mild-to-moderate anatomical abnormalities has been emphasized because these alterations are possibly related to several psychiatric disorders and learning disabilities. In the research arena, structural MRI and diffusion tensor imaging (DTI) have been widely applied to quantify brain development of the pediatric population. To interpret the values from these MR modalities, a "growth percentile chart," which describes the mean and standard deviation of the normal developmental curve for each anatomical structure, is required. Although efforts have been made to create such a growth percentile chart based on MRI and DTI, one of the greatest challenges is to standardize the anatomical boundaries of the measured anatomical structures. To avoid inter- and intra-reader variability about the anatomical boundary definition, and hence, to increase the precision of quantitative measurements, an automated structure parcellation method, customized for the neonatal and pediatric population, has been developed. This method enables quantification of multiple MR modalities using a common analytic framework. In this paper, the attempt to create an MRI- and a DTI-based growth percentile chart, followed by an application to investigate developmental abnormalities related to cerebral palsy, Williams syndrome, and Rett syndrome, have been introduced. Future directions include multimodal image analysis and personalization for clinical application. PMID- 23796905 TI - Tissue factor pathway inhibitor-2: a novel gene involved in zebrafish central nervous system development. AB - Tissue factor pathway inhibitor-2 (Tfpi-2) is an important serine protease inhibitor in the extracellular matrix (ECM), but its precise physiological significance remains unknown. This work is part of a series of studies intended to investigate functional roles of Tfpi-2 and explore the underlying molecular mechanisms. First, we cloned and identified zebrafish Tfpi-2 (zTfpi-2) as an evolutionarily conserved protein essential for zebrafish development. We also demonstrated that ztfpi-2 is mainly expressed in the central nervous system (CNS) of zebrafish, and embryonic depletion of ztfpi-2 caused severe CNS defects. In addition, changes of neural markers, including pax2a, egr2b, huC, ngn1, gfap and olig2, confirmed the presence of developmental abnormalities in the relevant regions of ztfpi-2 morphants. Using microarray analysis, we found that members of the Notch pathway, especially her4 and mib, which mediate lateral inhibition in CNS development, were also downregulated. Intriguingly, both her4 and mib were able to partially rescue the ztfpi-2 morphant phenotype. Furthermore, Morpholino knockdown of ztfpi-2 resulted in upregulation of neuronal markers while downregulation of glial markers, providing evidence that the Notch pathway is probably involved in ztfpi-2-mediated CNS development. PMID- 23796904 TI - Atoh1 directs hair cell differentiation and survival in the late embryonic mouse inner ear. AB - Atoh1 function is required for the earliest stages of inner ear hair cell development, which begins during the second week of gestation. Atoh1 expression in developing hair cells continues until early postnatal ages, but the function of this late expression is unknown. To test the role of continued Atoh1 expression in hair cell maturation we conditionally deleted the gene in the inner ear at various embryonic and postnatal ages. In the organ of Corti, deletion of Atoh1 at E15.5 led to the death of all hair cells. In contrast, deletion at E16.5 caused death only in apical regions, but abnormalities of stereocilia formation were present throughout the cochlea. In the utricle, deletion at E14.5 or E16.5 did not cause cell death but led to decreased expression of myosin VIIa and failure of stereocilia formation. Furthermore, we show that maintained expression of Barhl1 and Gfi1, two transcription factors implicated in cochlear hair cell survival, depends upon continued Atoh1 expression. However, maintained expression of Pou4f3 and several hair cell-specific markers is independent of Atoh1 expression. These data reveal novel late roles for Atoh1 that are separable from its initial role in hair cell development. PMID- 23796906 TI - Mortality in patients with IgA nephropathy. AB - BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis globally. Few studies have investigated mortality in patients with IgAN compared with the age- and sex-adjusted general population. STUDY DESIGN: Cohort study with record linkage between the Norwegian Kidney Biopsy Registry, Norwegian Cause of Death Registry, and Norwegian Renal Registry. SETTING & PARTICIPANTS: 633 patients diagnosed with IgAN in 1988-2004. PREDICTOR: Estimated glomerular filtration rate (eGFR), age, and sex. OUTCOMES: Deaths and causes of death before and after the onset of end-stage renal disease through 2008. RESULTS: Mean follow-up was 11.8 (range, 0-20.8) years. During the observation period, the observed number of deaths was 80 and the expected number was 42.1, resulting in a standardized mortality ratio (SMR) of 1.9 (95% CI, 1.5 2.4). Risk stratification based on initial eGFR showed that SMR was 1.0 (95% CI, 0.6-1.6) if eGFR was >=60 mL/min/1.73 m(2), 1.9 (95% CI, 1.3-2.8) if eGFR was 30 60 mL/min/1.73 m(2), and 3.6 (95% CI, 2.6-5.0) in patients with eGFR <30 mL/min/1.73 m(2). Renal replacement therapy (RRT) was initiated in 146 patients and 35 of the 80 deaths occurred after the start of RRT. The age- and sex adjusted SMR was not increased significantly in the pre-RRT period (1.3; 95% CI, 1.0-1.7), but was increased after initiation of RRT (4.9; 95% CI, 3.5-7.0). The most common cause of death was cardiovascular disease, accounting for 45% of all deaths. LIMITATIONS: Treatment during follow-up is not known. CONCLUSIONS: Mortality in patients with IgAN was twice the expected rate, but not significantly increased before RRT. The risk of end-stage renal disease was substantially higher than risk of death. PMID- 23796907 TI - Cystic kidney disease in a patient with systemic toxicity from long-term D penicillamine use. AB - D-penicillamine, used to treat cystinuria, is known to cause impaired collagen deposition and dysfunction in elastic fibers. D-penicillamine also has been associated with glomerular abnormalities, typically membranous glomerulonephritis. We describe a patient with severe bilateral cystic kidney disease that developed after long-term D-penicillamine use for treatment of cystinuria. The cysts in the kidneys were noted during an evaluation for acute kidney injury. The patient had no evidence of cysts on prior renal imaging at a time when his kidney function was normal. Simultaneously, he presented with multiorgan manifestations of D-penicillamine toxicity, including the skin findings of cutix laxa and elastosis perforans serpiginosa. Consequently, D penicillamine treatment was discontinued, after which the progression of cystic kidney disease gradually ceased, along with the other systemic manifestations of toxicity. To our knowledge, this is the first report of cystic kidney disease associated with and perhaps caused by long-term d-penicillamine therapy. The proposed mechanism of cyst formation is the malfunction of the extracellular matrix of the kidney by d-penicillamine that leads to an impaired repair process after kidney injury. PMID- 23796908 TI - Biosynthetic machinery of ionophore polyether lasalocid: enzymatic construction of polyether skeleton. AB - Diversity of natural polycyclic polyethers originated from very simple yet versatile strategy consisting of epoxidation of linear polyene followed by epoxide opening cascade. To understand two-step enzymatic transformations at molecular basis, a flavin containing monooxygenase (EPX) Lsd18 and an epoxide hydrolase (EH) Lsd19 were selected as model enzymes for extensive investigation on substrate specificity, catalytic mechanism, cofactor requirement and crystal structure. This pioneering study on prototypical lasalocid EPX and EH provides insight into detailed mechanism of ionophore polyether assembly machinery and clarified remaining issues for polyether biosynthesis. PMID- 23796909 TI - Target identification of biologically active small molecules via in situ methods. AB - The identification of potential cellular targets of small molecules is important in biomedical research and drug discovery, but has been challenging due to a lack of proteome-based methods that enable direct investigation of small molecule protein interaction in live cells. This review summarizes some of the recent advances in target identification of bioactive molecules (including drugs and natural products) using in situ methods for cell-based proteome profiling of potential on and off targets. PMID- 23796911 TI - Effect of fatigue loading on the screw joint stability of zirconium abutment. AB - PURPOSE: This study evaluated the effect of fatigue loading on the screw joint stability of a zirconium abutment connected to an external hexagon implant in vitro. MATERIALS AND METHODS: Fifteen titanium and 15 zirconia abutments of 3 different heights (5, 8, and 11 mm) were connected to external titanium implants with titanium screws. A torque gauge was used to measure the reverse torque values before and after loading. An air cylindrical loading device was used to simulate mastication at a 45-degree angle to the longitudinal axis of the implant. RESULTS: There were significant differences (P<0.05) before and after the loading of titanium (5mm) and zirconia (5, 8, and 11 mm) abutments. CONCLUSION: Zirconia abutments for external hexagon implants had durability rates similar to those of titanium abutments after repeating load on the reverse torque of the abutment screw, indicating that the zirconia abutment could be reliably used instead of the titanium abutment. PMID- 23796910 TI - A modified Hargreaves' method for assessing threshold temperatures for heat nociception. AB - This study describes a modified Hargreaves' method for assessing paw withdrawal threshold temperatures for heat (PWT-H) nociception in the hind paws of rats. This method utilises radiant heat to maintain controlled lamp temperatures (CLTs) on a glass floor beneath the rat hind paw. An ascending series of CLTs were applied for 10s, with 5-10min intervals between applications, until characteristic withdrawal behaviour was observed or a cutoff CLT was reached. The average plantar epicutaneous temperatures measured from anaesthetised rats corresponding to CLTs and withdrawal latencies were used for determining PWT-H. The mean PWT-H in 2-month-old (mo) naive Sprague-Dawley rats (n=38) was 47.6+/ 0.2 degrees C, which is comparable to the noxious threshold temperature for human glabrous skin (46.5+/-0.5 degrees C). The PWT-H was consistent between trials and daily assessments over four consecutive days. No significant differences were observed between the PWT-H in 2-, 6- to 8-, and >24-mo F344 rats, but the PWT-H in 1-mo rats was significantly reduced. Three hours following plantar incision, the PWT-H decreased to 37.5+/-0.2 degrees C, consistent with previous observations of C-fibre afferents from incised glabrous skin firing at 36.7+/-3.6 degrees C. Parallel testing, using the current method and an electronic von Frey device, illustrated similar degrees of incision-induced hyperalgesia, gradual improvements in hyperalgesia, and reversals induced through morphine and gabapentin. In conclusion, the present method facilitates a comparison of PWT-H using electrophysiological and human psychophysical studies involving thermosensation, and as a behavioural assay identical to von Frey testing, this method also measures the threshold for nociception. PMID- 23796912 TI - Chemical denaturation as a tool in the formulation optimization of biologics. AB - Biologics have become the fastest growing segment in the pharmaceutical industry. As is the case with all proteins, biologics are susceptible to denature or to aggregate; conditions that, if present, preclude their use as pharmaceuticals. Identifying the solvent conditions that maximize their structural stability is crucial during development. Since the structural stability of a protein is susceptible to different chemical and physical conditions, the use of several complementary techniques can be expected to provide the best answers. Stability measurements that rely on temperature or chemical [urea or guanidine hydrochloride (GuHCl)] denaturation have been the preferred ones in research laboratories and together provide a thorough evaluation of protein stability. In this review, we will discuss chemical denaturation as a tool in the optimization of formulation conditions for biologics, and how chemical denaturation complements the role of thermal denaturation for this purpose. PMID- 23796913 TI - The future is here: tumour profiling in day-to-day clinical practice. PMID- 23796914 TI - Fire eater's lung: retrospective analysis of 123 cases reported to a National Poison Center. AB - BACKGROUND: Fire eater's lung (FEL) is a distinct form of acute chemical toxic pneumonitis, which is caused by aspiration of flammable petrochemical derivatives used by street performers for 'fire eating'. The optimal management of this condition has not yet been determined. OBJECTIVE: The aim of this study was to investigate patient characteristics, clinical features, treatment, and outcome of FEL. METHODS: A single-center retrospective review of consecutive cases of FEL in children and adults reported to a national poison center (the Swiss Toxicological Information Center) between 1995 and 2012. RESULTS: 123 cases (83.7% males, mean age 21.9 years) were included. The most frequently reported symptom was cough (50.4%), followed by chest pain (45.5%), and fever (35.8%). Dyspnea was reported by 23.6%. Cough (p = 0.002) and chest pain (p = 0.02) were significantly more prevalent in subjects reporting to have aspirated the fuel compared to those who have swallowed it or who did not perceive poison exposure. A pulmonary infiltrate was detected in 83% of the cases in whom chest X-ray was performed. Overall, 22% were treated with an antibiotic agent for a mean duration of 10.4 days. Corticosteroids were administered in 4.9%. All showed complete recovery irrespective of the therapeutic management. CONCLUSION: The combination of intense pleuritic chest pain, cough, dyspnea, and fever, or any of these symptoms after 'fire eating' or erroneous swallowing of a petroleum distillate should alert the clinician to the diagnosis of FEL. Early antibiotic treatment of severe cases seems justified, considering that clinical, laboratory, and radiologic findings of FEL are overlapping with bacterial superinfection. PMID- 23796915 TI - Hyperuricemia and cardiovascular disease: is this relationship independent of the etiology of hyperuricemia? PMID- 23796918 TI - HYBRID - evaluating new radiation technology in patients with unmet needs. PMID- 23796916 TI - Tumor necrosis factor alpha promoter polymorphism and severity of acute kidney injury. AB - BACKGROUND: Tumor necrosis factor-alpha is a proinflammatory cytokine that has been implicated in the pathobiology of acute kidney injury (AKI). METHODS: We explored the association of a functional polymorphism in the promoter region (rs1800629) of the TNFA gene with severity of AKI, as defined by level of glomerular filtration (serum cystatin C and creatinine) and tubular injury (urinary NAG, KIM-1, alpha-GST, and pi-GST) markers, in 262 hospitalized adults. RESULTS: In unadjusted analyses, compared with the GG genotype, the TNFA GA and AA genotype groups tended to have higher enrollment (p = 0.08), peak (p = 0.004), and discharge (p = 0.004) serum creatinine levels, and the AA genotype tended to have a higher enrollment serum cystatin C level (p = 0.04). Compared with the GG genotype, the TNFA GA and AA genotype groups tended to have a higher urinary KIM 1 level (p = 0.03), and the AA genotype group tended to have a higher urinary pi GST level (p = 0.03). After adjustment for sex, race, age, baseline estimated glomerular filtration rate, sepsis, and dialysis requirement, compared with the GG genotype, the TNFA minor A-allele group had a higher peak serum creatinine of 1.03 mg/dl (0.43, 1.63; p = 0.001) and a higher urinary KIM-1 (relative ratio: 1.73; 95% CI: 1.16, 2.59; p = 0.008). The TNFA minor A-allele group also had a higher Multiple Organ Failure score of 0.26 (95% CI: 0.03, 0.49; p = 0.024) after adjustment for sex, race, age, and sepsis. CONCLUSIONS: The TNFA rs1800629 gene polymorphism is associated with markers of kidney disease severity and distant organ dysfunction among patients with AKI. Larger studies are needed to confirm these relationships. PMID- 23796919 TI - Antifungal Activity of the Noncytotoxic Human Peptide Hepcidin 20 against Fluconazole-Resistant Candida glabrata in Human Vaginal Fluid. AB - Vaginal infections caused by Candida glabrata are difficult to eradicate due to this species' scarce susceptibility to azoles. Previous studies have shown that the human cationic peptide hepcidin 20 (Hep-20) exerts fungicidal activity in sodium phosphate buffer against a panel of C. glabrata clinical isolates with different levels of susceptibility to fluconazole. In addition, the activity of the peptide was potentiated under acidic conditions, suggesting an application in the topical treatment of vaginal infections. To investigate whether the peptide activity could be maintained in biological fluids, in this study the antifungal activity of Hep-20 was evaluated by a killing assay in (i) a vaginal fluid simulant (VFS) and in (ii) human vaginal fluid (HVF) collected from three healthy donors. The results obtained indicated that the activity of the peptide was maintained in VFS and HVF supplemented with EDTA. Interestingly, the fungicidal activity of Hep-20 was enhanced in HVF compared to that observed in VFS, with a minimal fungicidal concentration of 25 MUM for all donors. No cytotoxic effect on human cells was exerted by Hep-20 at concentrations ranging from 6.25 to 100 MUM, as shown by 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5 carboxanilide tetrazolium salt (XTT) reduction assay and propidium iodide staining. A piece of indirect evidence of Hep-20 stability was also obtained from coincubation experiments of the peptide with HVF at 37 degrees C for 90 min and for 24 h. Collectively, these results indicate that this peptide should be further studied as a novel therapeutic agent for the topical treatment of vaginal C. glabrata infections. PMID- 23796920 TI - Restrictive Streptomycin Resistance Mutations Decrease the Formation of Attaching and Effacing Lesions in Escherichia coli O157:H7 Strains. AB - Streptomycin binds to the bacterial ribosome and disrupts protein synthesis by promoting misreading of mRNA. Restrictive mutations on the ribosomal subunit protein S12 confer a streptomycin resistance (Strr) phenotype and concomitantly increase the accuracy of the decoding process and decrease the rate of translation. Spontaneous Strr mutants of Escherichia coli O157:H7 have been generated for in vivo studies to promote colonization and to provide a selective marker for this pathogen. The locus of enterocyte effacement (LEE) of E. coli O157:H7 encodes a type III secretion system (T3SS), which is required for attaching and effacing to the intestinal epithelium. In this study, we observed decreases in both the expression and secretion levels of the T3SS translocated proteins EspA and EspB in E. coli O157:H7 Strr restrictive mutants, which have K42T or K42I mutations in S12. However, mildly restrictive (K87R) and nonrestrictive (K42R) mutants showed slight or indistinguishable changes in EspA and EspB secretion. Adherence and actin staining assays indicated that restrictive mutations compromised the formation of attaching and effacing lesions in E. coli O157:H7. Therefore, we suggest that E. coli O157:H7 strains selected for Strr should be thoroughly characterized before in vivo and in vitro experiments that assay for LEE-directed phenotypes and that strains carrying nonrestrictive mutations such as K42R make better surrogates of wild-type strains than those carrying restrictive mutations. PMID- 23796921 TI - Fitness Consequences of Plasmodium falciparum pfmdr1 Polymorphisms Inferred from Ex Vivo Culture of Ugandan Parasites. AB - Polymorphisms in the Plasmodium falciparum multidrug resistance 1 (pfmdr1) gene impact sensitivity to multiple antimalarials. In Africa, polymorphisms at N86Y and D1246Y are common and have various impacts on sensitivity to different drugs. To gain insight into the fitness consequences of these polymorphisms, we cultured parasites isolated from children with malaria in Tororo, Uganda, where the multiplicity of infection is high, and used pyrosequencing to follow polymorphism prevalences in culture over time. Of 71 cultures, parasites in 69 were successfully analyzed at N86Y and parasites in 68 were successfully analyzed at D1246Y over 3 to 36 days of culture. For position 86, the sequences of 39/69 (56.5%) parasites remained stable (>90% prevalence over 2 to 17 time points), with 82.1% of these being stable for the 86Y mutation. For position 1246, the sequences of 31/68 (45.6%) parasites remained stable, with 64.5% of these being stable for the wild-type D1246 sequence (P = 0.0002 for comparison of stable mutant genotypes for the two alleles). Defining allele selection as a >=15% change in prevalence between the first and last samples assessed, for position 86, 11 samples showed selection, with selection toward 86Y occurring in 72.7% of alleles; for position 1246, 14 samples showed selection, with selection toward D1246 occurring in 64.3% of alleles (P = 0.11 for comparison of selection of mutations at the two alleles). Among the 7 samples with selection at both alleles, 5 showed selection for both 86Y and D1246. Overall, consistent trends in the direction of selection were seen, although differences were not statistically significant. Our results suggest fitness advantages for parasites with the pfmdr1 86Y mutation and wild-type D1246, highlighting the complex interplay between drug resistance and fitness in malaria parasites. (This study has been registered at ClinicalTrials.gov under registration no. NCT00948896 and NCT00993031.). PMID- 23796922 TI - Resistance Genes Underlying the LSA Phenotype of Staphylococcal Isolates from France. AB - There exist numerous genes disseminated by mobile elements that can confer cross resistance to lincosamides and streptogramin A compounds in staphylococci. This study investigated the nature and means of dissemination of genes responsible for LSA resistance among 24 French clinical isolates screened for reduced susceptibility to lincomycin. The vga(A)v gene was found to be the most prevalent determinant of LSA resistance, while Tn5406 appeared to be its exclusive gene support. PMID- 23796923 TI - Reducing the Level of Undecaprenyl Pyrophosphate Synthase Has Complex Effects on Susceptibility to Cell Wall Antibiotics. AB - Undecaprenyl pyrophosphate synthase (UppS) catalyzes the formation of the C55 lipid carrier (UPP) that is essential for bacterial peptidoglycan biosynthesis. We selected here a vancomycin (VAN)-resistant derivative of Bacillus subtilis W168 that contains a single-point mutation in the ribosome-binding site of the uppS gene designated uppS1 Genetic reconstruction experiments demonstrate that the uppS1 allele is sufficient to confer low-level VAN resistance and causes reduced UppS translation. The decreased level of UppS renders B. subtilis slightly more susceptible to many late-acting cell wall antibiotics, including beta-lactams, but significantly more resistant to fosfomycin and d-cycloserine, antibiotics that interfere with the very early steps of cell wall synthesis. We further show that the uppS1 allele leads to slightly elevated expression of the sigmaM regulon, possibly helping to compensate for the stress caused by a decrease in UPP levels. Notably, the uppS1 mutation increases resistance to VAN, fosfomycin, and d-cycloserine in wild-type cells, but this effect is greatly reduced or eliminated in a sigM mutant background. Our findings suggest that, although UppS is an attractive antibacterial target, incomplete inhibition of UppS function may lead to increased resistance to some cell wall-active antibiotics. PMID- 23796924 TI - Antileishmanial activity, uptake, and biodistribution of an amphotericin B and poly(alpha-Glutamic Acid) complex. AB - A noncovalent, water-soluble complex of amphotericin B (AMB) and poly(alpha glutamic acid) (PGA), with AMB loadings ranging from 25 to 55% (wt/wt) using PGA with a molecular weight range of 50,000 to 70,000, was prepared as a potential new treatment for visceral leishmaniasis (VL). The AMB-PGA complex was shown to be as active as Fungizone (AMB deoxycholate) against intracellular Leishmania donovani amastigotes in differentiated THP-1 cells. The in vitro uptake of the AMB-PGA complex by differentiated THP-1 cells was similar to that of Fungizone and higher than that of AmBisome (liposomal AMB). The AMB-PGA complex also displayed a dose-response profile similar to that of AmBisome in vivo in BALB/c mice against L. donovani, with 50% effective doses (ED50s) of 0.24 +/- 0.03 mg/kg of body weight for the AMB-PGA complex and 0.24 +/- 0.06 mg/kg for AmBisome. A biodistribution study with mice indicated that the AMB-PGA complex cleared more rapidly from plasma than AmBisome, with a comparable low level of distribution to the kidneys. PMID- 23796925 TI - Antibiotic Resistance in Salmonella enterica Serovar Typhimurium Associates with CRISPR Sequence Type. AB - Salmonella enterica subsp. enterica serovar Typhimurium is a leading cause of food-borne salmonellosis in the United States. The number of antibiotic-resistant isolates identified in humans is steadily increasing, suggesting that the spread of antibiotic-resistant strains is a major threat to public health. S Typhimurium is commonly identified in a wide range of animal hosts, food sources, and environments, but little is known about the factors mediating the spread of antibiotic resistance in this ecologically complex serovar. Previously, we developed a subtyping method, CRISPR-multi-virulence-locus sequence typing (MVLST), which discriminates among strains of several common S. enterica serovars. Here, CRISPR-MVLST identified 22 sequence types within a collection of 76 S Typhimurium isolates from a variety of animal sources throughout central Pennsylvania. Six of the sequence types were identified in more than one isolate, and we observed statistically significant differences in resistance among these sequence types to 7 antibiotics commonly used in veterinary and human medicine, such as ceftiofur and ampicillin (P < 0.05). Importantly, five of these sequence types were subsequently identified in human clinical isolates, and a subset of these isolates had identical antibiotic resistance patterns, suggesting that these subpopulations are being transmitted through the food system. Therefore, CRISPR-MVLST is a promising subtyping method for monitoring the farm-to-fork spread of antibiotic resistance in S Typhimurium. PMID- 23796926 TI - Radiologic Responses in Cynomolgus Macaques for Assessing Tuberculosis Chemotherapy Regimens. AB - Trials to test new drugs currently in development against tuberculosis in humans are impractical. All animal models to prioritize new regimens are imperfect, but nonhuman primates (NHPs) infected with Mycobacterium tuberculosis develop active tuberculosis (TB) disease with a full spectrum of lesion types seen in humans. Serial 2-deoxy-2-[18F]-fluoro-d-glucose (FDG) positron emission tomography (PET) with computed tomography (CT) imaging was performed on cynomolgus macaques during infection and chemotherapy with individual agents or the four-drug combination therapy most widely used globally. The size and metabolic activity of lung granulomas varied among animals and even within a single animal during development of disease. Individual granulomas within untreated animals had highly local and independent outcomes, some progressing in size and FDG uptake, while others waned, illustrating the highly dynamic nature of active TB. At necropsy, even untreated animals were found to have a proportion of sterile lesions consistent with the dynamics of this infection. A more marked reduction in overall metabolic activity in the lungs (decreased FDG uptake) was associated with effective treatment. A reduction in the size of individual lesions correlated with a lower bacterial burden at necropsy. Isoniazid treatment was associated with a transient increase in metabolic activity in individual lesions, whereas a net reduction occurred in most lesions from rifampin-treated animals. Quadruple-drug therapy resulted in the highest decrease in FDG uptake. The findings of PET-CT imaging may provide an important early correlate of the efficacy of novel combinations of new drugs that can be directly translated to human clinical trials. PMID- 23796927 TI - Targeting the "Rising DAMP" during a Francisella tularensis Infection. AB - Antibiotic efficacy is greatly enhanced the earlier it is administered following infection with a bacterial pathogen. However, in a clinical setting antibiotic treatment usually commences following the onset of symptoms, which in some cases (e.g., biothreat agents) may be too late. In a BALB/c murine intranasal model of infection for Francisella tularensis SCHU S4 infection, we demonstrate during a time course experiment that proinflammatory cytokines and the damage-associated molecular pattern HMGB1 were not significantly elevated above naive levels in tissue or sera until 72 h postinfection. HMGB1 was identified as a potential therapeutic target that could extend the window of opportunity for the treatment of tularemia with antibiotics. Antibodies to HMGB1 were administered in conjunction with a delayed/suboptimal levofloxacin treatment of F. tularensis We found in the intranasal model of infection that treatment with anti-HMGB1 antibody, compared to an isotype IgY control antibody, conferred a significant survival benefit and decreased bacterial loads in the spleen and liver but not the lung (primary loci of infection) 4 days into infection. We also observed an increase in the production of gamma interferon in all tested organs. These data demonstrate that treatment with anti-HMGB1 antibody is beneficial in enhancing the effectiveness of current antibiotics in treating tularemia. Strategies of this type, involving antibiotics in combination with immunomodulatory drugs, are likely to be essential for the development of a postexposure therapeutic for intracellular pathogens. PMID- 23796928 TI - Efficacy of Amphotericin B at Suboptimal Dose Combined with Voriconazole in a Murine Model of Aspergillus fumigatus Infection with Poor In Vivo Response to the Azole. AB - The combination of amphotericin B at a suboptimal dose (0.3 mg/kg) with voriconazole has shown efficacy in prolonging survival and reducing tissue burden in a murine model of disseminated infection by an isolate of Aspergillus fumigatus that had showed a poor in vivo response to the azole. The efficacy of the combined treatment was higher than that obtained with amphotericin B at 0.8 mg/kg. PMID- 23796929 TI - Clinical Outcomes in Patients with Heterogeneous Vancomycin-Intermediate Staphylococcus aureus Bloodstream Infection. AB - The prevalence of heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) infections varies in the literature, a problem complicated by the lack of routine screening procedures; however, limited data suggest that hVISA has been associated with persistent bloodstream infections (BSI) and vancomycin failure, yet these studies have been confounded by design issues. We conducted this study to compare the characteristics of patients with BSI caused by hVISA with those with vancomycin-susceptible Staphylococcus aureus (VSSA) treated with vancomycin. This retrospective, multicenter matched (1:1) cohort study compared the clinical characteristics and outcomes of hVISA and VSSA. Patients with hVISA methicillin resistant Staphylococcus aureus (MRSA) BSI from 2004 to 2012 were matched to VSSA MRSA BSI patients. The primary outcome was failure of vancomycin treatment, defined as a composite of persistent bacteremia (>=7 days), persistent signs and symptoms, change of MRSA antibiotic, recurrent BSI, or MRSA-related mortality. We identified 122 matched cases. The overall vancomycin failure rate was 57% (82% hVISA versus 33% VSSA; P < 0.001). The individual components of failure in hVISA versus VSSA were persistent bacteremia, 59% versus 21% (P < 0.001); change in MRSA therapy, 54% versus 25% (P = 0.001); MRSA-related mortality, 21% versus 10% (P = 0.081); and recurrence of BSI, 26% versus 2% (P < 0.001). Using logistic regression analysis and adjusting for covariates, hVISA (adjusted odds ratio [aOR], 11.1; 95% confidence interval [CI], 4.3 to 28.7) and intensive care unit (ICU) admission (aOR, 4.5; 95% CI, 1.8 to 11.6) were still independently associated with vancomycin failure. Relative to VSSA BSI, patients with hVISA were more likely to experience failure of vancomycin treatment, including persistent bacteremia and recurrence. Our results indicate that hVISA was responsible for considerable morbidity. PMID- 23796930 TI - Amphiphilic Antimony(V) Complexes for Oral Treatment of Visceral Leishmaniasis. AB - The need for daily parenteral administration is an important limitation in the clinical use of pentavalent antimonial drugs against leishmaniasis. In this study, amphiphilic antimony(V) complexes were prepared from alkylmethylglucamides (L8 and L10, with carbon chain lengths of 8 and 10, respectively), and their potential for the oral treatment of visceral leishmaniasis (VL) was evaluated. Complexes of Sb and ligand at 1:3 (SbL8 and SbL10) were obtained from the reaction of antimony(V) with L8 and L10, as evidenced by elemental and electrospray ionization-tandem mass spectrometry (ESI-MS) analyses. Fluorescence probing of hydrophobic environment and negative-staining transmission electron microscopy showed that SbL8 forms kinetically stabilized nanoassemblies in water. Pharmacokinetic studies with mice in which the compound was administered by the oral route at 200 mg of Sb/kg of body weight indicated that the SbL8 complex promoted greater and more sustained Sb levels in serum and liver than the levels obtained for the conventional antimonial drug meglumine antimoniate (Glucantime [Glu]). The efficacy of SbL8 and SbL10 administered by the oral route was evaluated in BALB/c mice infected with Leishmania infantum after a daily dose of 200 mg of Sb/kg for 20 days. Both complexes promoted significant reduction in the liver and spleen parasite burdens in relation to those in the saline-treated control group. The extent of parasite suppression (>99.96%) was similar to that achieved after Glu given intraperitoneally at 80 mg of Sb/kg/day. As expected, there was no significant reduction in the parasitic load in the group treated orally with Glu at 200 mg of Sb/(kg day). In conclusion, amphiphilic antimony(V) complexes emerge as an innovative and promising strategy for the oral treatment of VL. PMID- 23796931 TI - In Vitro Activity of Retapamulin against Staphylococcus aureus Resistant to Various Antimicrobial Agents. AB - Retapamulin and six other antimicrobial agents were evaluated against 155 methicillin-resistant Staphylococcus aureus (MRSA) isolates, including strains resistant to vancomycin, linezolid, daptomycin, and mupirocin by microdilution tests. Time-kill assays were performed against representative MRSA, vancomycin intermediate S. aureus (VISA), and vancomycin-resistant S. aureus (VRSA) isolates. Retapamulin and mupirocin demonstrated MIC90s of 0.12 MUg/ml and 8 MUg/ml, respectively, with resistance seen in 2.6% and 10% of isolates, respectively. Retapamulin maintained good activity against 94% (15/16) of mupirocin-resistant isolates. PMID- 23796932 TI - Evaluation of Combinations of 4'-Ethynyl-2-Fluoro-2'-Deoxyadenosine with Clinically Used Antiretroviral Drugs. AB - Drug combination studies of 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) with FDA approved drugs were evaluated by two different methods, MacSynergy II and CalcuSyn. Most of the combinations, including the combination of the two adenosine analogs EFdA and tenofovir, were essentially additive, without substantial antagonism or synergism. The combination of EFdA and rilpivirine showed apparent synergism. These studies provide information that may be useful for the design of EFdA combination regimens for initial and salvage therapy assessment. PMID- 23796933 TI - Daptomycin In Vitro Activity against Methicillin-Resistant Staphylococcus aureus Is Enhanced by d-Cycloserine in a Mechanism Associated with a Decrease in Cell Surface Charge. AB - The killing activity of daptomycin against an isogenic pair of daptomycin susceptible and daptomycin-nonsusceptible (DNS) methicillin-resistant Staphylococcus aureus (MRSA) strains was enhanced by the addition of certain cell wall agents at 1* MIC. However, when high inocula of the DNS strain were used, no significant killing was observed in our experiments. Cytochrome c binding assays revealed d-cycloserine as the only agent associated with a reduction in the cell surface charge for both strains at the concentrations used. PMID- 23796934 TI - In Vivo Effects of Cefazolin, Daptomycin, and Nafcillin in Experimental Endocarditis with a Methicillin-Susceptible Staphylococcus aureus Strain Showing an Inoculum Effect against Cefazolin. AB - Several reports have implicated the inoculum effect that some strains of type A beta-lactamase (Bla)-producing, methicillin-susceptible Staphylococcus aureus (MSSA) show against cefazolin as the cause for clinical failures in certain serious deep-seated infections. Here, using a previously reported MSSA strain displaying this phenotype (TX0117), we obtained a Bla-cured derivative (TX0117c) with a combination of novobiocin and high temperature. Both isolates were then used in a rat endocarditis model and treated with cefazolin, nafcillin, and daptomycin, given to simulate human dosing. Animals were treated for 3 days and either sacrificed at 24 h after the last antibiotic dose (standard group) or left untreated for an additional 3 days (relapse group). With TX0117 in the standard treatment group, daptomycin and nafcillin were both significantly better than cefazolin in reducing CFU/g of vegetations, achieving mean log10 reductions compared to levels in untreated rats of 7.1, 5.3, and 1.8, respectively (cefazolin versus daptomycin, P < 0.0001; cefazolin versus nafcillin, P = 0.005; daptomycin versus nafcillin, P = 0.053). In addition, cefazolin was significantly more effective in reducing vegetation titers of TX0117c than of TX0117 (mean log10 reduction of 1.4 versus 5.5, respectively; P = 0.0001). Similar results were observed with animals in the relapse group. Thus, these data show that there can be an in vivo consequence of the in vitro inoculum effect that some MSSA strains display against cefazolin and indicate a specific role for Bla production using a Bla-cured derivative strain against which cefazolin regained both in vitro and in vivo activity. PMID- 23796935 TI - Characterization of TEM-1 beta-Lactamase-Producing Kingella kingae Clinical Isolates. AB - Kingella kingae is a human pathogen that causes pediatric osteoarticular infections and infective endocarditis in children and adults. The bacterium is usually susceptible to beta-lactam antibiotics, although beta-lactam resistance has been reported in rare isolates. This study was conducted to identify beta lactam-resistant strains and to characterize the resistance mechanism. Screening of a set of 90 K. kingae clinical isolates obtained from different geographic locations revealed high-level resistance to penicillins among 25% of the strains isolated from Minnesota and Iceland. These strains produced TEM-1 beta-lactamase and were shown to contain additional >=50-kb plasmids. Ion Torrent sequencing of extrachromosomal DNA from a beta-lactamase-producing strain confirmed the plasmid location of the blaTEM gene. An identical plasmid pattern was demonstrated by multiplex PCR in all beta-lactamase producers. The porin gene's fragments were analyzed to investigate the relatedness of bacterial strains. Phylogenetic analysis revealed 27 single-nucleotide polymorphisms (SNPs) in the por gene fragment, resulting in two major clusters with 11 allele types forming bacterial strain subclusters. beta-Lactamase producers were grouped together based on por genotyping. Our results suggest that the beta-lactamase-producing strains likely originate from a single plasmid-bearing K. kingae isolate that traveled from Europe to the United States, or vice versa. This study highlights the prevalence of penicillin resistance among K. kingae strains in some regions and emphasizes the importance of surveillance for antibiotic resistance of the pathogen. PMID- 23796936 TI - Determination of In Vitro Activities of Solithromycin at Different pHs and Its Intracellular Activity against Clinical Isolates of Neisseria gonorrhoeae from a Laboratory Collection. AB - We evaluated the activity of solithromycin against 196 clinical gonococcal isolates collected at the Public Health Ontario Laboratories, Toronto, Canada, including isolates with different levels of azithromycin resistance, as well as the role of pH in MIC determinations using pH-adjusted agar plates (pH range, 5.6 to 7.6). In vitro invasion assays were performed using monolayers of HeLa epithelial cells and clinical gonococci displaying different azithromycin MICs; infected cultures were treated with solithromycin, and its intracellular activity was determined by CFU assays after 3 and 20 h of exposure. Solithromycin displayed a MIC50 and MIC90 of 0.0625 and 0.125 MUg/ml, respectively, making its activity at least 4-fold higher than that of azithromycin. Clinical isolates with elevated MICs for azithromycin (MICs of >=2,048 MUg/ml and 4 to 8 MUg/ml) showed solithromycin MIC values of 8 and 0.5 MUg/ml, respectively. In contrast to azithromycin, solithromycin MICs were not significantly affected by acidic pHs, suggesting more stability at lower pH. Moreover, when intracellular Neisseria gonorrhoeae isolates were incubated with solithromycin at 4 times, 1 times, and one-fourth of the MIC, the exposure to solithromycin resulted in the progressive loss of viability of most isolates over time. The intracellular activity of solithromycin, combined with the low MICs to this agent, indicates that it may be an attractive option for gonorrhea treatment if clinical trials in development reveal that this drug can be used safely in adult indications, especially when multidrug-resistant clinical isolates are now emerging. PMID- 23796937 TI - Polymyxin B Induces Apoptosis in Kidney Proximal Tubular Cells. AB - The nephrotoxicity of polymyxins is a major dose-limiting factor for treatment of infections caused by multidrug-resistant Gram-negative pathogens. The mechanism(s) of polymyxin-induced nephrotoxicity is not clear. This study aimed to investigate polymyxin B-induced apoptosis in kidney proximal tubular cells. Polymyxin B-induced apoptosis in NRK-52E cells was examined by caspase activation, DNA breakage, and translocation of membrane phosphatidylserine using Red-VAD-FMK [Val-Ala-Asp(O-Me) fluoromethyl ketone] staining, a terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assay, and double staining with annexin V-propidium iodide (PI). The concentration dependence (50% effective concentration [EC50]) and time course for polymyxin B induced apoptosis were measured in NRK-52E and HK-2 cells by fluorescence activated cell sorting (FACS) with annexin V and PI. Polymyxin B-induced apoptosis in NRK-52E cells was confirmed by positive labeling from Red-VAD-FMK staining, TUNEL assay, and annexin V-PI double staining. The EC50 (95% confidence interval [CI]) of polymyxin B for the NRK-52E cells was 1.05 (0.91 to 1.22) mM and was 0.35 (0.29 to 0.42) mM for HK-2 cells. At lower concentrations of polymyxin B, minimal apoptosis was observed, followed by a sharp rise in the apoptotic index at higher concentrations in both cell lines. After treatment of NRK-52E cells with 2.0 mM polymyxin B, the percentage of apoptotic cells (mean +/ standard deviation [SD]) was 10.9% +/- 4.69% at 6 h and reached plateau (>80%) at 24 h, whereas treatment with 0.5 mM polymyxin B for 24 h led to 93.6% +/- 5.57% of HK-2 cells in apoptosis. Understanding the mechanism of polymyxin B induced apoptosis will provide important information for discovering less nephrotoxic polymyxin-like lipopeptides. PMID- 23796938 TI - Prototypical Recombinant Multi-Protease-Inhibitor-Resistant Infectious Molecular Clones of Human Immunodeficiency Virus Type 1. AB - The many genetic manifestations of HIV-1 protease inhibitor (PI) resistance present challenges to research into the mechanisms of PI resistance and the assessment of new PIs. To address these challenges, we created a panel of recombinant multi-PI-resistant infectious molecular clones designed to represent the spectrum of clinically relevant multi-PI-resistant viruses. To assess the representativeness of this panel, we examined the sequences of the panel's viruses in the context of a correlation network of PI resistance amino acid substitutions in sequences from more than 10,000 patients. The panel of recombinant infectious molecular clones comprised 29 of 41 study-defined PI resistance amino acid substitutions and 23 of the 27 tightest amino acid substitution clusters. Based on their phenotypic properties, the clones were classified into four groups with increasing cross-resistance to the PIs most commonly used for salvage therapy: lopinavir (LPV), tipranavir (TPV), and darunavir (DRV). The panel of recombinant infectious molecular clones has been made available without restriction through the NIH AIDS Research and Reference Reagent Program. The public availability of the panel makes it possible to compare the inhibitory activities of different PIs with one another. The diversity of the panel and the high-level PI resistance of its clones suggest that investigational PIs active against the clones in this panel will retain antiviral activity against most if not all clinically relevant PI-resistant viruses. PMID- 23796939 TI - Nasal Carriage of Epidemic Methicillin-Resistant Staphylococcus aureus 15 (EMRSA 15) Clone Observed in Three Chicago-Area Long-Term Care Facilities. AB - The spread of pandemic methicillin-resistant Staphylococcus aureus (MRSA) clones such as USA300 and EMRSA-15 is a global health concern. As a part of a surveillance study of three long-term care facilities in the Greater Chicago area, phenotypic and molecular characterization of nasal MRSA isolates was performed. We report a cluster of pandemic EMRSA-15, an MRSA clone rarely reported from the United States, detected during this study. PMID- 23796940 TI - Expansion of Salmonella enterica Serovar Typhimurium ST34 Clone Carrying Multiple Resistance Determinants in China. PMID- 23796941 TI - Species-Dependent Blood-Brain Barrier Disruption of Lipopolysaccharide: Amelioration by Colistin In Vitro and In Vivo. AB - The aim of this study was to use in vitro and in vivo models to assess the impact of lipopolysaccharide (LPS) from two different bacterial species on blood-brain barrier (BBB) integrity and brain uptake of colistin. Following repeated administration of LPS from Pseudomonas aeruginosa, the brain-to-plasma ratio of [14C]sucrose in Swiss outbred mice was not significantly increased. Furthermore, while the brain uptake of colistin in mice increased 3-fold following administration of LPS from Salmonella enterica, LPS from P. aeruginosa had no significant effect on colistin brain uptake. This apparent species-dependent effect did not appear to correlate with differences in plasma cytokine levels, as the concentrations of tumor necrosis factor alpha and interleukin-6 following administration of each LPS were not different (P > 0.05). To clarify whether this species-specific effect of LPS was due to direct effects on the BBB, human brain capillary endothelial (hCMEC/D3) cells were treated with LPS from P. aeruginosa or S. enterica and claudin-5 expression was measured by Western blotting. S. enterica LPS significantly (P < 0.05) reduced claudin-5 expression at a concentration of 7.5 MUg/ml. In contrast, P. aeruginosa LPS decreased (P < 0.05) claudin-5 expression only at the highest concentration tested (i.e., 30 MUg/ml). Coadministration of therapeutic concentrations of colistin ameliorated the S. enterica LPS-induced reduction in claudin-5 expression in hCMEC/D3 cells and the perturbation in BBB function in mice. This study demonstrates that BBB disruption induced by LPS is species dependent, at least between P. aeruginosa and S. enterica, and can be ameliorated by colistin. PMID- 23796942 TI - Vancomycin Use for Pediatric Clostridium difficile Infection Is Increasing and Associated with Specific Patient Characteristics. AB - In adults with Clostridium difficile infection (CDI), enteral vancomycin is considered the preferred initial regimen for severe disease; however, patterns of antimicrobial use for children with CDI are unknown. We sought to describe trends in and predictors of vancomycin use for the treatment of children with CDI admitted to tertiary-care children's hospitals in the United States. We used a database of freestanding children's hospitals to identify patients 1 to 18 years old with CDI between January 2006 and June 2011. The first hospitalization with a diagnosis of CDI for each patient was identified, and CDI-directed therapy was assessed. Generalized estimating equations were used to identify predictors of vancomycin receipt, controlling for clustering within hospitals. Vancomycin use has increased significantly (P = 0.005), with substantial variability between hospitals (0 to 16%). In multivariate analyses, vancomycin use was more common in children age 7 to 13 years old (versus children 1 to 2 years old: adjusted odds ratio [AOR] = 1.57; 95% confidence interval [CI] = 1.13 to 2.18), 14 to 18 years old (AOR = 1.40; 95% CI = 1.11 to 1.76), in an ICU (AOR = 1.37; 95% CI = 1.05 to 1.80), or with chronic gastrointestinal conditions (AOR = 2.01; 95% CI = 1.44 to 2.81). Vancomycin use was less common in black (AOR = 0.53; 95% CI = 0.39 to 0.73) and Hispanic (AOR = 0.63; 95% CI = 0.47 to 0.84) patients and in children with malignancies (AOR = 0.57; 95% CI = 0.36 to 0.89). Despite a lack of empirical evidence to suggest superiority, vancomycin use for pediatric CDI is increasing. Furthermore, there is substantial variability in vancomycin use between hospitals. Further studies are needed to explore potential racial and ethnic differences in CDI management and to investigate clinicians' rationale for using vancomycin for initial therapy in selected populations. PMID- 23796943 TI - Vibrational spectra and dispersion analysis of K2Ni(SeO4)2.6H2O Tutton salt single crystal doped with K2Ni(SO4)2.6H2O. AB - Dispersion analysis of the polarized IR reflectance spectra of K2Ni(SeO4)2.6H2O doped with K2Ni(SO4)2.6H2O has been performed. Vibrational parameters like oscillator strength, attenuation constant and frequency of the transversal phonons for the modes of Au symmetry type plus the orientation of the transition dipole moments for the modes of Bu symmetry type in the ac crystal plane have been obtained. The spectra-structure correlation of the H2O stretching vibrations show that bands appearing in the spectra for polarization of the external radiation oriented along the b axis are mainly due to the H2O stretching vibrations of one of the three crystallographically distinct sets of water molecules. The orientation of the transition dipoles of stretching vibrations of the selenate ion differ from the characteristic spectra of the sulfate analog in that no mutually perpendicular transition dipoles are found in the ac crystal plane. Water librational bands masked with the bands of the nu4(SO4(2-)) mode in the sulfate analog have now been unveiled and assigned. The ratio between the oscillator strength and the attenuation constant appears to be a helpful tool in the assignment of the sulfate stretching vibrations and water librations. The vibrational and orientational characteristics of the nu4(SeO4(2-)) modes were obtained. The nu3(SO4(2-)) frequency region of the isomorphously isolated SO4(2-) ion in the K2Ni(SeO4)2.6H2O matrix was investigated in some detail. Contrary to the expected three, four bands can be identified. Three of them were assigned to nu3(SO4(2-)) based on the orientation of the transition dipole moments. On the basis of the IR, but also Raman spectra of the pure and mixed crystals, a discussion of the influence of the potential field and the hydrogen bonds with the change in the volume of the unit cell is given. PMID- 23796944 TI - Transient osteoporosis of the hip in pregnancy associated with generalized low bone mineral density--a case report. AB - Transient osteoporosis of the hip (TOH) in pregnancy is characterized by severe pain in unilateral or bilateral hips and has been diagnosed as localized osteopenia. However, we evaluated a case of unilateral TOH with generalized profound osteoporosis involving both the hips and the lumbar vertebrae by dual energy X-ray absorptiometry. The diagnosis was based on the clinical course and confirmed by magnetic resonance imaging. Three-dimensional helical computed tomography (3D-CT), which has not been used in patients with TOH, revealed a markedly thin bilateral proximal femoral cortex, particularly in the symptomatic femoral head. Despite the difference in the severity of bone destruction between the two femora, they both showed the same pattern of damage on 3D-CT. Furthermore, despite continuing treatment with the same dose of alendronate and calcitriol, a high rate of bone mineral density gain, involving both the femora and lumbar vertebrae, was limited to the early postpartum months. A majority of reported female patients with TOH are pregnant. Thus, the association between TOH and pregnancy was not considered to be fortuitous, and chemical or hormonal factors related to pregnancy may play an etiologic role in this disease. The possible etiologies of TOH in pregnancy are also discussed. PMID- 23796945 TI - Testing promotes long-term learning via stabilizing activation patterns in a large network of brain areas. AB - The testing effect refers to the phenomenon that repeated retrieval of memories promotes better long-term retention than repeated study. To investigate the neural correlates of the testing effect, we used event-related functional magnetic resonance imaging methods while participants performed a cued recall task. Prior to the neuroimaging experiment, participants learned Swahili-German word pairs, then half of the word pairs were repeatedly studied, whereas the other half were repeatedly tested. For half of the participants, the neuroimaging experiment was performed immediately after the learning phase; a 1-week retention interval was inserted for the other half of the participants. We found that a large network of areas identified in a separate 2-back functional localizer scan were active during the final recall of the word pair associations. Importantly, the learning strategy (retest or restudy) of the word pairs determined the manner in which the retention interval affected the activations within this network. Recall of previously restudied memories was accompanied by reduced activation within this network at long retention intervals, but no reduction was observed for previously retested memories. We suggest that retrieval promotes learning via stabilizing cue-related activation patterns in a network of areas usually associated with cognitive and attentional control functions. PMID- 23796946 TI - Long-chain omega-3 fatty acids improve brain function and structure in older adults. AB - Higher intake of seafish or oil rich in long-chain omega-3 polyunsaturated fatty acids (LC-n3-FA) may be beneficial for the aging brain. We tested in a prospective interventional design whether high levels of supplementary LC-n3-FA would improve cognition, and addressed potential mechanisms underlying the effects. Sixty-five healthy subjects (50-75 years, 30 females) successfully completed 26 weeks of either fish oil (2.2 g/day LC-n3-FA) or placebo intake. Before and after the intervention period, cognitive performance, structural neuroimaging, vascular markers, and blood parameters were assayed. We found a significant increase in executive functions after LC-n3-FA compared with placebo (P = 0.023). In parallel, LC-n3-FA exerted beneficial effects on white matter microstructural integrity and gray matter volume in frontal, temporal, parietal, and limbic areas primarily of the left hemisphere, and on carotid intima media thickness and diastolic blood pressure. Improvements in executive functions correlated positively with changes in omega-3-index and peripheral brain-derived neurotrophic factor, and negatively with changes in peripheral fasting insulin. This double-blind randomized interventional study provides first-time evidence that LC-n3-FA exert positive effects on brain functions in healthy older adults, and elucidates underlying mechanisms. Our findings suggest novel strategies to maintain cognitive functions into old age. PMID- 23796948 TI - Massive modulation of brain areas after mechanical pain stimulation: a time resolved FMRI study. AB - To date, relatively little is known about the spatiotemporal aspects of whole brain blood oxygenation level-dependent (BOLD) responses to brief nociceptive stimuli. It is known that the majority of brain areas show a stimulus-locked response, whereas only some are characterized by a canonical hemodynamic response function. Here, we investigated the time course of brain activations in response to mechanical pain stimulation applied to participants' hands while they were undergoing functional magnetic resonance imaging (fMRI) scanning. To avoid any assumption about the shape of BOLD response, we used an unsupervised data-driven method to group voxels sharing a time course similar to the BOLD response to the stimulus and found that whole-brain BOLD responses to painful mechanical stimuli elicit massive activation of stimulus-locked brain areas. This pattern of activations can be segregated into 5 clusters, each with a typical temporal profile. In conclusion, we show that an extensive activity of multiple networks is engaged at different time latencies after presentation of a noxious stimulus. These findings aim to motivate research on a controversial topic, such as the temporal profile of BOLD responses, the variability of these response profiles, and the interaction between the stimulus-related BOLD response and ongoing fluctuations in large-scale brain networks. PMID- 23796947 TI - Neuroelectrical decomposition of spontaneous brain activity measured with functional magnetic resonance imaging. AB - Spontaneous activity in the human brain occurs in complex spatiotemporal patterns that may reflect functionally specialized neural networks. Here, we propose a subspace analysis method to elucidate large-scale networks by the joint analysis of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) data. The new approach is based on the notion that the neuroelectrical activity underlying the fMRI signal may have EEG spectral features that report on regional neuronal dynamics and interregional interactions. Applying this approach to resting healthy adults, we indeed found characteristic spectral signatures in the EEG correlates of spontaneous fMRI signals at individual brain regions as well as the temporal synchronization among widely distributed regions. These spectral signatures not only allowed us to parcel the brain into clusters that resembled the brain's established functional subdivision, but also offered important clues for disentangling the involvement of individual regions in fMRI network activity. PMID- 23796949 TI - A perspective on recurrent vertigo. AB - The recurrent nature of the 3 most common vestibulopathies suggests a recurrent cause. Histopathology in temporal bones from patients with these syndromes - vestibular neuronitis (VN, n = 7), Meniere's disease (MD, n = 8) and benign paroxysmal positional vertigo (BPPV, n = 5) - shows focal degeneration of vestibular nerve axons and degenerated nearby facial nerve meatal ganglion cells. Transmission electron microscopic confirmation of intracytoplasmic viral particles in surgically excised vestibular nerves from patients with VN and MD support a viral etiology in these vestibulopathies. Antiviral treatment of these syndromes in a series of 211 patients with a 3- to 8-year follow-up resulted in complete control of vertigo in VN (88%), MD (90%) and BPPV (60%). PMID- 23796950 TI - Meta-analysis of toxicity and teratogenicity of 133 chemicals from zebrafish developmental toxicity studies. AB - Zebrafish developmental toxicity testing is an emerging field, which faces considerable challenges regarding data meta-analysis and the establishment of standardized test protocols. Here, we present an initial correlation study on toxicity of 133 chemicals based on data in the literature to ascertain predictive developmental toxicity endpoints. We found that the physical properties of chemicals (BCF or logP) did not fully predict lethality or developmental outcomes. Instead, individual outcomes such as pericardial edema and yolk sac edema were more reliable indicators of developmental toxicity. In addition, we ranked the chemicals based on toxicity with the Toxicological Priority Index (ToxPi) program and via a teratogenic ratio, and found that perfluorooctane sulfonate (PFOS) had the highest ToxPi score, triphenyltin acetate had the highest average ToxPi score (corrected for missing data and having more than 4 outcomes), and N-methyl-dithiocarbamate had the highest teratogenic ratio. PMID- 23796951 TI - A category approach to predicting the developmental (neuro) toxicity of organotin compounds: the value of the zebrafish (Danio rerio) embryotoxicity test (ZET). AB - Zebrafish embryos were exposed to different organotin compounds during very early development (<100h post fertilization). Morphology, histopathology and swimming activity (in a motor activity test) were the endpoints analyzed. DBTC was, by far, the most embryotoxic compound at all time points and endpoints studied. In fact, we observed a clear concordance between the effects observed in our zebrafish embryo model, and those observed with these compounds in full rodent in vivo studies. All organotin compounds classified as developmental (neuro) toxicants in vivo, were correctly classified in the present assay. Together, our results support the ZET model as a valuable tool for providing biological verification for a grouping and a read-across approach to developmental (neuro) toxicity. PMID- 23796952 TI - CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer. AB - The functional roles of SNPs within the 8q24 gene desert in the cancer phenotype are not yet well understood. Here, we report that CCAT2, a novel long noncoding RNA transcript (lncRNA) encompassing the rs6983267 SNP, is highly overexpressed in microsatellite-stable colorectal cancer and promotes tumor growth, metastasis, and chromosomal instability. We demonstrate that MYC, miR-17-5p, and miR-20a are up-regulated by CCAT2 through TCF7L2-mediated transcriptional regulation. We further identify the physical interaction between CCAT2 and TCF7L2 resulting in an enhancement of WNT signaling activity. We show that CCAT2 is itself a WNT downstream target, which suggests the existence of a feedback loop. Finally, we demonstrate that the SNP status affects CCAT2 expression and the risk allele G produces more CCAT2 transcript. Our results support a new mechanism of MYC and WNT regulation by the novel lncRNA CCAT2 in colorectal cancer pathogenesis, and provide an alternative explanation of the SNP-conferred cancer risk. PMID- 23796954 TI - Optimization of adenovirus 40 and 41 recovery from tap water using small disk filters. AB - Currently, the U.S. Environmental Protection Agency's Information Collection Rule (ICR) for the primary concentration of viruses from drinking and surface waters uses the 1MDS filter, but a more cost effective option, the NanoCeram(r) filter, has been shown to recover comparable levels of enterovirus and norovirus from both matrices. In order to achieve the highest viral recoveries, filtration methods require the identification of optimal concentration conditions that are unique for each virus type. This study evaluated the effectiveness of 1MDS and NanoCeram filters in recovering adenovirus (AdV) 40 and 41 from tap water, and optimized two secondary concentration procedures the celite and organic flocculation method. Adjustments in pH were made to both virus elution solutions and sample matrices to determine which resulted in higher virus recovery. Samples were analyzed by quantitative PCR (qPCR) and Most Probable Number (MPN) techniques and AdV recoveries were determined by comparing levels of virus in sample concentrates to that in the initial input. The recovery of adenovirus was highest for samples in unconditioned tap water (pH 8) using the 1MDS filter and celite for secondary concentration. Elution buffer containing 0.1% sodium polyphosphate at pH 10.0 was determined to be most effective overall for both AdV types. Under these conditions, the average recovery for AdV40 and 41 was 49% and 60%, respectively. By optimizing secondary elution steps, AdV recovery from tap water could be improved at least two-fold compared to the currently used methodology. Identification of the optimal concentration conditions for human AdV (HAdV) is important for timely and sensitive detection of these viruses from both surface and drinking waters. PMID- 23796955 TI - Hand surgery for Multicentric Reticulohistiocytosis: A new avenue of treatment and review of the literature. AB - INTRODUCTION: Multicentric Reticulohistiocytosis (MRH) is a rare non-Langerhans cell histiocytosis characterised by destructive polyarthritis and violaceous skin papules. PRESENTATION OF CASE: In 2010, a 70-year-old woman with Palindromic Rheumatism was diagnosed with MRH. Within a few months, she developed ankylosis of the small joints of both hands which resulted in severe fixed flexion deformities of the fingers and thumbs. The joint disease failed to respond to medical therapies and the palmar skin of her left hand was becoming increasingly macerated. Therefore, she elected to undergo arthrodesis of the metacarpophalangeal joints to allow hand hygiene. DISCUSSION: To-date, this is the first report of a surgical intervention for this rare condition and represents a novel avenue of potential therapy. Medical therapies for MRH are usually ineffective in preventing the debilitating small joint disease which often develops and there is on-going research into newer agents and alternative surgical techniques. CONCLUSION: Once medical therapies are exhausted, clinicians should consider the input of Hand Surgeons in managing the inevitable and mutilating joint disease of this rare condition. PMID- 23796953 TI - Prostaglandin receptor EP2 in the crosshairs of anti-inflammation, anti-cancer, and neuroprotection. AB - Modulation of a specific prostanoid synthase or receptor provides therapeutic alternatives to nonsteroidal anti-inflammatory drugs (NSAIDs) for treating pathological conditions governed by cyclooxygenase-2 (COX-2 or PTGS2). Among the COX-2 downstream signaling pathways, the prostaglandin E2 (PGE2) receptor EP2 subtype (PTGER2) is emerging as a crucial mediator of many physiological and pathological events. Genetic ablation strategies and recent advances in chemical biology provide tools for a better understanding of EP2 signaling. In the brain, the EP2 receptor modulates some beneficial effects, including neuroprotection, in acute models of excitotoxicity, neuroplasticity, and spatial learning via cAMP PKA signaling. Conversely, EP2 activation accentuates chronic inflammation mainly through the cAMP-Epac pathway, likely contributing to delayed neurotoxicity. EP2 receptor activation also engages beta-arrestin in a G-protein-independent pathway that promotes tumor cell growth and migration. Understanding the conditions under which multiple EP2 signaling pathways are engaged might suggest novel therapeutic strategies to target this key inflammatory prostaglandin receptor. PMID- 23796956 TI - Implicating the role of plasma membrane localized calcium channels and exchangers in stress-induced deleterious effects. AB - Stress-induced increase in intracellular calcium (Ca(2+)) has been demonstrated to produce various deleterious effects in the body. The rise in intracellular Ca(2+) (particularly neuronal) in response to stress has been mainly attributed to opening of voltage gated L-type Ca(2+) channels. The role of P/Q-, N-, R- and T-type Ca(2+)channels, and plasma membrane localized exchangers such as Na(+)/Ca(2+) exchanger and Ca(2+) ATPase has also been implicated in increasing intracellular Ca(2+) in response to stress. Stress-induced changes in Ca(2+) currents has been mainly attributed to increased release of corticosterone (activation of glucocorticoid receptors in the hippocampus) and catecholamine release as a consequence of activation of Hypothalamic-Pituitary-Adrenal (HPA) axis and sympathetic neural system, respectively. Stress-induced increase intracellular Ca(2+) may trigger various deleterious signaling pathway including free radical generation, apoptosis, increased synaptic release of glutamate and synthesis/release of cytotoxic cytokines that may be responsible for damaging effects associated with stress. The present review discusses the mechanisms involved in stress-induced rise in intracellular Ca(2+) levels and subsequent implications of increased Ca(2+) levels in stress. PMID- 23796958 TI - Symptom correlates of facial emotion recognition impairment in schizophrenia. AB - BACKGROUND: The ability to facial emotion recognition (FER), a key component of socioemotional competence, is often impaired in schizophrenic disorders. The purpose of the present study was to examine the relationship between emotion recognition performance and symptoms in a group of patients with schizophrenia spectrum disorders. SAMPLING AND METHODS: Seventy-nine patients meeting DSM-IV-TR criteria for schizophrenia, schizophreniform disorder and schizoaffective disorder were assessed by the Positive and Negative Syndrome Scale and a FER task. In schizophrenia patients and healthy control subjects, FER performance was compared. In order to avoid a possible confounding role of cognitive impairment, we carried out partial correlations corrected for an index of global cognition. RESULTS: Patients performed worse than a healthy control group on all negative emotions. Partial correlations showed that cognitive/disorganized symptoms correlated with a worse performance in the FER task, whereas no correlations were found with positive, negative, excitement and depressive symptoms. CONCLUSIONS: Our findings support that in schizophrenia FER impairment is specific for negative emotions and that there is a relationship between this deficit and cognitive/disorganized symptoms, regardless of the general cognitive level. PMID- 23796957 TI - Folic acid modulates eNOS activity via effects on posttranslational modifications and protein-protein interactions. AB - Folic acid enhances endothelial function and improves outcome in primary prevention of cardiovascular disease. The exact intracellular signalling mechanisms involved remain elusive and were therefore the subject of this study. Particular focus was placed on folic acid-induced changes in posttranslational modifications of endothelial nitric oxide synthase (eNOS). Cultured endothelial cells were exposed to folic acid in the absence or presence of phosphatidylinositol-3' kinase/Akt (PI3K/Akt) inhibitors. The phosphorylation status of eNOS was determined via western blotting. The activities of eNOS and PI3K/Akt were evaluated. The interaction of eNOS with caveolin-1, Heat-Shock Protein 90 and calmodulin was studied using co-immunoprecipitation. Intracellular localisation of eNOS was investigated using sucrose gradient centrifugation and confocal microscopy. Folic acid promoted eNOS dephosphorylation at negative regulatory sites, and increased phosphorylation at positive regulatory sites. Modulation of phosphorylation status was concomitant with increased cGMP concentrations, and PI3K/Akt activity. Inhibition of PI3K/Akt revealed specific roles for this kinase pathway in folic acid-mediated eNOS phosphorylation. Regulatory protein and eNOS protein associations were altered in favour of a positive regulatory effect in the absence of bulk changes in intracellular eNOS localisation. Folic acid-mediated eNOS activation involves the modulation of eNOS phosphorylation status at multiple residues and positive changes in important protein-protein interactions. Such intracellular mechanisms may in part explain improvements in clinical vascular outcome following folic acid treatment. PMID- 23796960 TI - Hemodialysis-induced acute myocardial dyssynchronous impairment in children. AB - In adults, recurrent hemodialysis (HD)-induced cardiac injury results in ischemic myocardial dysfunction. Uremic children, like adults, share the full complement of uremia-related cardiovascular abnormalities but without significant atheromatous coronary artery disease. The aim of this study was, to assess the impact of HD on left ventricular (LV) myocardial function in children. METHOD: We assessed all single-center chronic HD patients (n = 15, range 1-17 years) excluding those with overt cardiac disease. Regional LV function and mechanical synchronicity was measured echographically by two-dimensional segmental longitudinal, circumferential and radial myocardial strain. All patients were assessed pre-dialysis and at the end of dialysis. In addition, we scanned age matched controls at rest. RESULTS: The peak longitudinal strain was lower in uremic patients compared with controls with a significant fall during HD (mean peak strain -19.9 controls, -17.9 pre-HD, -15.3 end of HD, p < 0.05). Radial strain was lower in uremic patients and increased during HD. Circumferential strain was preserved in uremic patients and fell during HD. Intrasegmental deformation synchronicity was progressively worse pre-dialysis and end of dialysis compared with controls. Intradialytic peak longitudinal strain reduction was significantly associated with systolic blood pressure and ultrafiltrate volume (p < 0.05). CONCLUSION: Uremic children have impaired regional LV function, with a predisposition to longitudinal axis dysfunction and LV mechanical dyssynchrony, both of which are established markers of ischemic injury. This is further evidence for a characteristic cardiovascular phenotype in uremic patients that predisposes them to subclinical demand ischemia during dialysis. PMID- 23796961 TI - Over-activation in bilateral superior temporal gyrus correlated with subsequent forgetting effect of Chinese words. AB - We evaluated the subsequent memory and forgotten effects for Chinese using event related fMRI. Sixteen normal subjects were recruited and performing incidental memory tasks where semantic decision was required during memory encoding. Consistent with previous studies, our results showed bilateral frontal regions as the main locus for the subsequent memory effect. However, contrast between miss and hit responses revealed larger activation in bilateral superior temporal gyrus. We proposed that larger activation in the superior temporal gyrus may reflect alteration of self-monitoring process which resulted in unsuccessful memory encoding for the miss items. PMID- 23796962 TI - Predictive value of serum uric acid levels on mortality in acute coronary syndrome patients with chronic kidney disease after drug-eluting stent implantation. AB - OBJECTIVES: Despite optimal treatments, prognosis in acute coronary syndrome (ACS) patients with chronic kidney disease (CKD) remains poor. Elevated serum uric acid (SUA) levels may predict worse outcomes in these patients. The objective was to assess the predictive value of SUA levels on mortality in ACS patients with CKD after drug-eluting stent (DES) implantation. METHODS: We retrospectively assessed ACS patients with CKD who underwent successful DES implantation between January 2007 and December 2009. Patients were followed up from January to March 2012. CKD was defined as an estimated glomerular filtration rate <60 ml/min/1.73 m(2). We assessed the association between SUA levels and mortality. RESULTS: A total of 1,132 patients were included. The mean age was 67.7 years. During a mean follow-up of 38.5 months, 145 patients died: 50 from cardiac diseases, 28 from cerebral diseases, 14 from renal diseases and 53 from other causes. After adjustment for confounders, SUA levels increased the risk of all-cause, cerebral and other-cause mortality. Adjusted hazard ratios for quartiles 3 and 4 versus quartile 1 of SUA were: all-cause, 1.66 [95% confidence interval (CI) 1.08-2.78] and 1.99 (95% CI 1.21-3.23); cerebral, 2.24 (95% CI 0.43 11.7) and 5.89 (95% CI 1.30-26.6); and other causes, 2.81 (95% CI 1.17-6.78) and 3.89 (95% CI 1.63-9.29), respectively. SUA levels had no impact on cardiac and renal mortality rates. CONCLUSIONS: High SUA levels are associated with all cause, cerebral and other-cause mortality rates in ACS patients with CKD after DES implantation. Future research is needed to determine if lowering SUA levels will decrease mortality in these patients. PMID- 23796963 TI - A life history view of mutualistic viral symbioses: quantity or quality for cooperation? AB - Mutualistic symbioses between viruses and their hosts do not employ a straightforward rule by viral genome characteristics, transmission mechanisms or host genotypes. In this review we propose that reproduction rates and environmental carrying capacity of hosts may play a major role in maintaining the mutualism. Depending on how host life history shifts following establishment of the symbiosis, a symbiosis can be classified as quality-selected mutualism or quantity-selected mutualism. Quality-selected mutualism is described with modified Lotka-Volterra models. Both our models and previous empirical examples support the hypothesis that quality-selected mutualism can reach stable equilibrium under certain conditions. Quantity-selected mutualism is rare and is not supported by our model. With increasing attention to mutualistic viral ecology, we will have a better understanding of how viruses drive evolution. PMID- 23796964 TI - Multinucleation regulated by the Akt/PTEN signaling pathway is a survival strategy for HepG2 cells. AB - Hepatocellular carcinoma (HCC) is non-responsive to many chemotherapeutic agents including etoposide. The aim of this study was to examine the survival strategy of the HCC cell line HepG2 after etoposide treatment. Here we analyzed and compared spontaneous and etoposide-induced DNA damage in HepG2 (alpha-fetoprotein (AFP)-positive) and Chang Liver (AFP-negative) cell lines. Compared to Chang Liver cells, HepG2 cells exhibited a significantly higher degree of micronucleation and a higher nuclear division index, as determined by the cytokinesis-block micronucleus assay, following exposure to etoposide. HepG2 cells were also more resistant to etoposide-induced cytotoxicity compared to Chang Liver cells. We also establish that increased etoposide-induced multinucleation in HepG2 cells is dependent on the catalytic activity of Akt, as phosphatidylinositol-3-kinase inhibitors as well as the overexpression of kinase defective Akt reversed this phenotype. Moreover, ectopic expression of wild type PTEN reduced the frequency of etoposide-induced multinucleated HepG2 cells, and restored HepG2 etoposide sensitivity. Taken together, these results implicate the Akt/PTEN cellular axis as a major determinant of the etoposide resistance of HCC cells. PMID- 23796965 TI - Fine structure of Telonema subtilis Griessmann, 1913: a flagellate with a unique cytoskeletal structure among eukaryotes. AB - Telonema is a genus of heterotrophic flagellates with two flagella that occurs in marine environments. Although some aspects of the morphology and ultrastructure of Telonema have been reported in previous studies, several characters have been described incompletely or not at all. In the present study, we identify and describe several of these characteristics, such as extrusomes, telonemosome, adhesive fibers and the intricate cytoskeleton structure of T. subtilis using serial ultra-thin sections in transmission electron-microscopy. The extrusomes are scattered throughout the cell. Their structure in transverse section is similar to those of several monadofilosan cercozoa, but are distinguished by a longitudinal element. The telonemosome is an enigmatic organelle surrounded by a single membrane. It contains many thin tubular structures and resembles the K bodies found in oomycetes. The complex cytoskeletal structure is multilayered and unique among eukaryotes, although the posterior half resembles the penetrating/feeding apparatus found in apicomplexans, protoalveolates and kathablepharids. The proposed function and distribution pattern of the adhesive fibers in Telonema resemble those of the fibrous structures of Microheliella maris (Heliozoa). Our observations provide a more complete understanding of the characteristics of Telonema and support the conclusion from molecular studies that Telonema is a lineage without a clear sister group among the eukaryotes. PMID- 23796966 TI - A Kampo (traditional Japanese herbal) medicine, Hochuekkito, pretreatment in mice prevented influenza virus replication accompanied with GM-CSF expression and increase in several defensin mRNA levels. AB - A Kampo medicine, Hochuekkito (TJ-41), with an influenza virus-preventing effect had life-extending effectiveness, and immunological responses other than interferon (IFN)-alpha release were examined. TJ-41 (1 g/kg) was given to C57BL/6 male mice orally once a day for 2 weeks. Mice were then intranasally infected with influenza virus. After infection, virus titers and various parameters, mRNA levels and protein expression, for immunoresponses in the bronchoalveolar lavage fluid or removed lung homogenate, were measured by plaque assay, quantitative RT PCR and ELISA. IFN-alpha and -beta levels of TJ-41-treated mice were higher than those of the control. Toll-like receptor TLR7 and TLR9 mRNAs were elevated after infection, but retinoic acid-inducible gene (RIG-1) family mRNA levels, RIG-1, melanoma differentiation-associated gene 5 and Leishmania G protein 2 showed no response in either TJ-41 or control groups. Interferon regulatory transcription factor (IRF)-3 mRNA levels to stimulate type I (alpha/beta) IFN were increased, but IRF-7 did not change. Only granulocyte-macrophage colony-stimulating factor (GM-CSF) after Hochuekkito treatment was significantly elevated 2 and 3 days after infection. The mRNA levels of 7 defensins after infection increased compared to preinfection values. The key roles of TJ-41 were not only stimulation of type I IFN release but also GM-CSF-derived anti-inflammation activity. Furthermore, defensin (antimicrobial peptide) mRNA levels increased by infection and were further enhanced by TJ-41 treatment. Defensin might prevent influenza virus replication. PMID- 23796967 TI - Dopamine receptor (D4) polymorphism is related to comorbidity between marijuana abuse and depression. AB - The rates of marijuana abuse are steadily increasing in the U.S. Data suggest that comorbid marijuana abuse and depression is associated with worse outcomes than either diagnosis. Genetic studies independently link the DRD4 gene polymorphism to substance use and to internalizing disorders, but no study has examined whether the DRD4 polymorphism is linked to comorbid marijuana use and depression in a population sample. This study examined associations between the DRD4 gene 48bp VNTR polymorphism and comorbidity between marijuana use frequency and depression in a diverse, non-clinical adolescent sample (n=1882; ages 14 to 18) from the National Longitudinal Study of Adolescent Health (Add Health). Multinomial regression analyses indicated that the odds of being comorbid for depressive symptoms and marijuana use are approximately 2.5>= with the >=7R/>=7R genotype than youths who carry the <7R/<7R genotype, controlling for the effects of ethnicity, gender, age, violent victimization, and alcohol related problems. Findings provide genetic clues for psychopathology characterized by prominent externalizing and internalizing features. PMID- 23796968 TI - The Golgi Apparatus: Panel Point of Cytosolic Ca(2+) Regulation. AB - The Golgi apparatus (GA), an intermediate organelle of the cell inner membrane system, plays a key role in protein glycosylation and secretion. In recent years, this organelle has been found to act as a vital intracellular Ca(2+) store because different Ca (2+) regulators, such as the inositol-1,4,5-triphosphate receptor, sarco/endoplasmic reticulum Ca(2+) -ATPase and secretory pathway Ca 2+ ATPase, were demonstrated to localize on their membrane. The mechanisms involved in Ca(2+) release and uptake in the GA have now been established.Here, based on careful backward looking on compartments and patterns in GA Ca (2+) regulation, we review neurological diseases related to GA calcium remodeling and propose a modified cytosolic Ca(2+) adjustment model, in which GA acts as part of the panel point. PMID- 23796969 TI - Behaviors related to physical activity and nutrition among U.S. high school students. AB - PURPOSE: National data related to physical activity (PA) and nutrition among adolescents are needed to help develop effective obesity prevention programs. The 2010 National Youth Physical Activity and Nutrition Study (NYPANS) was conducted to provide nationally representative data on behaviors and behavioral correlates related to healthy eating and PA. METHODS: NYPANS used a three-stage cluster sample design to obtain data representative of public- and private-school students in grades 9 through 12 in the United States (n = 11,429). Students completed an anonymous, self-administered questionnaire in their classrooms during a regular class period. Trained data collectors directly measured the students' height and weight at school using a standard protocol. RESULTS: Analyses revealed that 19.0% of students were obese and 17.8% were overweight. Students participated in a range of physical activities during the 12 months before the survey; prevalence ranged from 5.0% for ice hockey to 83.9% for walking. In addition, 52.5% of students enjoyed the physical education classes they took at school. During the 7 days before the survey, 74.8% of students ate at least one meal or snack from a fast food restaurant, with black students more likely than white and Hispanic students to have done so. Forty-one percent of students always or most of the time have a TV on while eating dinner at home. CONCLUSIONS: These and other NYPANS results can be used to develop obesity prevention programs that address specific behaviors and behavioral correlates, and target subgroups in which behaviors and behavioral correlates related to obesity are most prevalent. PMID- 23796970 TI - The prevalence of falling and status of physical function among elderly individuals with locomotive and visual/hearing disorders. AB - In a super-aged society, the need for prevention of locomotor dysfunction is growing, and evidence for feasible preventive measures is thus required. This study aimed to examine the relationship between these disorders and the prevalence rates for falling and physical function status. Participants included 1182 community-dwelling elderly Japanese individuals aged 60 and older. Subjects were classified into four groups on the basis of the presence or absence of locomotive and visual/hearing disorders. Locomotive and visual/hearing organs disorders and physical function were assessed using a self-rated questionnaire. Competence level with activities of daily living (ADL) was used to assess physical function. Locomotive disorder was more prevalent in females than in males, and the presence of such disorders tended to have more influence on the risk of falling and decline in ADL function in females than in males. Locomotive disorders may have a greater effect on the lives of elderly females compared with elderly males. Although there was no significant odds ratio in the presence of multiple disorders, the prevalence rate of the multiple disorders increased with age and this increased the risk of falling also increases with age. PMID- 23796971 TI - Low brain DHA content worsens sensorimotor outcomes after TBI and decreases TBI induced Timp1 expression in juvenile rats. AB - The effects of dietary modulation of brain DHA content on outcomes after TBI were examined in a juvenile rat model. Long-Evans rats with normal or diet-induced decreases in brain DHA were subjected to a controlled cortical impact or sham surgery on postnatal day 17. Rats with the greatest decreases in brain DHA had the poorest sensorimotor outcomes after TBI. Ccl2, Gfap, and Mmp 9 mRNA levels, and MMP-2 and -9 enzymatic activities were increased after TBI regardless of brain DHA level. Lesion volume was not affected by brain DHA level. In contrast, TBI-induced Timp1 expression was lower in rats on the Deficient diet and correlated with brain DHA level. These data suggest that decreased brain DHA content contributes to poorer sensorimotor outcomes after TBI through a mechanism involving modulation of Timp1 expression. PMID- 23796973 TI - Lesions of the nucleus accumbens disrupt reinforcement omission effects in rats. AB - The reinforcement omission effects (ROEs) have been attributed to both motivational and attentional consequences of the surprising reinforcement omission. Some studies have been showed amygdala is part of a circuit involved in the ROEs modulation. The view that amygdala lesions interfere with the ROEs is supported by evidence involving amygdala in responses correlated with motivational processes. These processes depend on the operation of separate amygdala areas and their connections with other brain systems. It has been suggested the interaction between the amygdala and the nucleus accumbens (NAC) is important to the modulation of motivational processes. Recent neuroimaging studies in human revealed reward delivery enhances activity of subcortical structures (NAC and amygdala), whereas reward omission reduces the activity in these same structures. The present study aimed to clarify whether the mechanisms related to ROEs depend on NAC. Prior to acquisition training, rats received bilateral excitotoxic lesions of NAC (NAC group) or sham lesions (Sham group). Following postoperative recovery, the rats were trained on a fixed-interval with limited hold signaled schedule of reinforcement. After acquisition of stable performance, the training was changed from 100% to 50% schedule of reinforcement. Both NAC and Sham groups presented the ROEs. However, after nonreinforcement, the response rates of the NAC group were lower than those registered in the Sham group. The performance of the NAC group decreased in the period following nonreinforcement when compared to the period preceding reinforcement omission. These findings suggest the NAC is part of the neural substrate involved in the ROEs modulation. PMID- 23796972 TI - The context dependency of extinction negates the effectiveness of cognitive enhancement to reduce cocaine-primed reinstatement. AB - With respect to the treatment of addiction, the objective of extinction training is to decrease drug-seeking behavior by repeatedly exposing the patient to cues in the absence of unconditioned reinforcement. Such exposure therapy typically takes place in a novel (clinical) environment. This is potentially problematic, as the effects of extinction training include a context dependent component and therefore diminished efficacy is expected upon the patient's return to former drug-seeking/taking environments. We have reported that treatment with the NMDAR coagonist d-serine is effective in facilitating the effects of extinction to reduce cocaine-primed reinstatement. The present study assesses d-serine's effectiveness in reducing drug-primed reinstatement under conditions in which extinction training occurs in a novel environment. After 22 days of cocaine self administration (0.5 mg/kg) in context "A", animals underwent 5 extinction training sessions in context "B". Immediately after each extinction session in "B", animals received either saline or d-serine (60 mg/kg) treatment. Our results indicate that d-serine treatment following extinction in "B" had no effect on either IV or IP cocaine-primed reinstatement conducted in "A". These results stand in contrast to our previous findings where extinction occurred in "A", indicating that d-serine's effectiveness in facilitating extinction training to reduce drug-primed reinstatement is not transferable to a novel extinction environment. This inability of d-serine treatment to reduce the context specificity of extinction training may explain the inconsistent effects observed in clinical studies published to date in which adjunctive cognitive enhancement treatment has been combined with behavioral therapy without significant benefit. PMID- 23796974 TI - What is the impact of Helicobacter pylori density on the success of eradication therapy: a clinico-histopathological study. AB - BACKGROUND AND OBJECTIVE: To investigate the presence of any possible association between H. pylori density in the stomach and the efficacy of triple (lansoprazole 30 mg b.i.d., clarithromycin 500 mg b.i.d. and amoxicillin 1g b.i.d. for 14 days) and bismuth-containing quadruple (colloidal bismuth subcitrate 300 mg q.i.d., lansoprazole 30 mg b.i.d., tetracycline 500 mg q.i.d. and metronidazole 500 mg t.i.d. for 14 days) eradication therapies. METHODS: Eighty-five cases with H. pylori infection (proved by rapid urease test and histology) were studied. In each case, the density of H. pylori colonization was graded according to the updated Sydney classification. H. pylori eradication was determined via the (14)C Urea breath test performed 4 weeks after the end of therapy. RESULTS: The eradication rate of H. pylori was 50% (30 out of 60) in the triple therapy and 92% (23 of 25) in the quadruple therapy group. In the triple therapy group, the eradication rate of H. pylori decreased as the initial density of H. pylori increased (density of H. pylori: 1, 58.3%; 2, 54.5%; 3, 52.4%; 4, 38.5%; 5, 33.3%). In two cases with eradication failure after quadruple therapy, the grades of bacterial density were 1 and 3. CONCLUSION: H. pylori density, as assessed by histological grading, may predict the usefulness of triple therapy. The higher the H. pylori density, the less effective triple therapy will be at successful eradication of H. pylori. Quadruple therapy does not seem to be negatively affected by bacterial density. PMID- 23796975 TI - Metastatic distant lymph nodes in gastric adenocarcinoma should be determined before excluding curative treatment. PMID- 23796976 TI - Significance of correlation between interferon-gamma and soluble intercellular adhesion molecule-1 and interleukin-17 in hepatitis B virus-related cirrhosis. AB - BACKGROUND AND OBJECTIVE: Hepatitis B virus (HBV)-related cirrhosis is known to be associated with chronic hepatic inflammation. The present study aimed to examine the correlation between inflammatory mediators INF-gamma, IL-17, and sICAM-1 in HBV cirrhotic patients. METHODS: The levels of sICAM-1, interleukin 17, and IFN-gamma were measured with enzyme-linked immunosorbent assays in 120 cirrhotic patients with HBV and 270 sex- and age-matched healthy controls. Total bilirubin (TB) was measured and the association between TB and IFN-gamma, sICAM 1, interleukin-17 were analyzed. The levels of these cytokines in serum and the association between IFN-gamma and sICAM-1 as well as interleukin-17 were investigated. Relationships between these cytokines and Child-Pugh classes were analyzed in patients. RESULTS: Age and sex were similar, but TB values were significantly different between the two groups (P<0.001). Serum levels of sICAM 1, interleukin-17, and IFN-gamma were significantly higher in cirrhotic patients with HBV than in controls (P<0.001 for both). TB levels were positively correlated with IFN-gamma, interleukin-17 and sICAM-1 levels. Significantly positive correlations were also found between IFN-gamma and interleukin-17 as well as sICAM-1 (r=0.817 and r=0.561, respectively, P<0.01). There were significant differences between the studied cytokines (sICAM-1, interleukin-17, and IFN-gamma) and Child-Pugh classes (P<0.01). CONCLUSIONS: The increased IFN gamma level was correlated with both IL-17 and sICAM-1, and it may primarily play a role as cytokines trigger in liver injury. Both IL-17 and sICAM-1 may synergistically contribute to liver damage. PMID- 23796977 TI - Posterior reversible encephalopathy syndrome: a unique presentation. AB - We present a case of a patient presenting with posterior reversible encephalopathy syndrome to the emergency department. We discuss the various symptoms that lead to the identification of posterior reversible encephalopathy syndrome and the important clinical clues. Posterior reversible encephalopathy syndrome is a very uncommon diagnosis/clinical presentation that requires the understanding of the condition and awareness in distinct/specific patient populations. Without this understanding, the diagnosis may be missed and appropriate management delayed. PMID- 23796978 TI - Conversion of recent onset atrial fibrillation: which drug is faster? PMID- 23796979 TI - What is the clinical significance of chest CT when the chest x-ray result is normal in patients with blunt trauma? AB - BACKGROUND: Computed tomography (CT) has been shown to detect more injuries than plain radiography in patients with blunt trauma, but it is unclear whether these injuries are clinically significant. STUDY OBJECTIVES: This study aimed to determine the proportion of patients with normal chest x-ray (CXR) result and injury seen on CT and abnormal initial CXR result and no injury on CT and to characterize the clinical significance of injuries seen on CT as determined by a trauma expert panel. METHODS: Patients with blunt trauma older than 14 years who received emergency department chest imaging as part of their evaluation at 2 urban level I trauma centers were enrolled. An expert trauma panel a priori classified thoracic injuries and subsequent interventions as major, minor, or no clinical significance. RESULTS: Of 3639 participants, 2848 (78.3%) had CXR alone and 791 (21.7%) had CXR and chest CT. Of 589 patients who had chest CT after a normal CXR result, 483 (82.0% [95% confidence interval [CI], 78.7-84.9%]) had normal CT results, and 106 (18.0% [95% CI, 15.1%-21.3%]) had CTs diagnosing injuries-primarily rib fractures, pulmonary contusion, and incidental pneumothorax. Twelve patients had injuries classified as clinically major (2.0% [95% CI, 1.2%-3.5%]), 78 were clinically minor (13.2% [95% CI, 10.7%-16.2%]), and 16 were clinically insignificant (2.7% (95% CI, 1.7%-4.4%]). Of 202 patients with CXRs suggesting injury, 177 (87.6% [95% CI, 82.4%-91.5%]) had chest CTs confirming injury and 25 (12.4% [95% CI, 8.5%-17.6%]) had no injury on CT. CONCLUSION: Chest CT after a normal CXR result in patients with blunt trauma detects injuries, but most do not lead to changes in patient management. PMID- 23796980 TI - Retrospective analysis of acute fatty liver of pregnancy: twenty-eight cases and discussion of anesthesia. AB - AIMS: To summarize the clinical features, perioperative management and maternal and neonatal outcomes of patients with acute fatty liver of pregnancy (AFLP) and to discuss the management of anesthesia in these patients. METHODS: This study was a retrospective review over a period of 5 years and 9 months; 28 cases from the Shanghai Public Health Clinical Center were included. Records were reviewed for symptoms, signs, laboratory findings, clinical courses, perioperative management and maternal and neonatal outcomes. RESULTS: Of the AFLP cases analyzed in the present study, 75.0% occurred in primipara and 63.3% occurred with male fetuses. Prodromic symptoms included the sudden onset of fatigue, nausea, vomiting, anorexia and jaundice. Laboratory results indicated liver function abnormalities, coagulopathy, hypoglycemia, leukocytosis and negative urine bilirubin. There were 2 maternal deaths (7.1%) without fetal deaths. Cesarean sections were performed in 16 cases under neuraxial anesthesia and in 12 cases under general anesthesia with rapid-sequence induction. CONCLUSION: Early diagnosis, prompt delivery and intensive supportive treatment are critical for improving the prognosis of AFLP. Anesthesia selection should be individualized and general anesthesia with rapid-sequence induction may be the best choice for patients with severe coagulopathy. PMID- 23796982 TI - beta-Thujaplicinol inhibits hepatitis B virus replication by blocking the viral ribonuclease H activity. AB - Hepatitis B virus (HBV) is a hepatotropic DNA virus that replicates by reverse transcription. It chronically infects >350 million people and kills about 1 million patients annually. Therapy primarily employs nucleos(t)ide analogs that suppress viral DNA synthesis by the viral reverse transcriptase very well but that rarely cure the infection, so additional therapies are needed. Reverse transcription requires the viral ribonuclease H (RNAseH) to destroy the viral RNA after it has been copied into DNA. We recently produced active recombinant HBV RNAseH and demonstrated that Human Immunodeficiency Virus (HIV) RNAseH antagonists could inhibit the HBV enzyme at a high frequency. Here, we extended these results to beta-thujaplicinol, a hydroxylated tropolone which inhibits the HIV RNAseH. beta-Thujaplicinol inhibited RNAseHs from HBV genotype D and H in biochemical assays with IC50 values of 5.9+/-0.7 and 2.3+/-1.7 MUM, respectively. It blocked replication of HBV genotypes A and D in culture by inhibiting the RNAseH activity with an estimated EC50 of ~5 MUM and a CC50 of 10.1+/-1. 7 MUM. Activity of beta-thujaplicinol against RNAseH sequences from multiple HBV genotypes implies that if chemical derivatives of beta-thujaplicinol with improved efficacy and reduced toxicity can be identified, they would have promise as anti-HBV agents. PMID- 23796983 TI - Coping with chronic social stress in mice: hypothalamic-pituitary-adrenal/ sympathetic-adrenal-medullary axis activity, behavioral changes and effects of antalarmin treatment: implications for the study of stress-related psychopathologies. AB - The aim of this study was to analyze the individual differences that lead to the development of psychopathological changes in response to chronic social stress. We also assessed the ability of an antagonist of the corticotrophin-releasing hormone (CRH) receptors to reverse the effects of stress. Male adult mice were exposed to repeated defeat experiences for 21 days using a sensorial contact model. After 18 days of defeat, two groups of subjects were established (active and passive), according to their behaviors during social confrontation. Antalarmin treatment was given for 4 and 6 days. The results corroborated previous data indicating that subjects who adopted a passive coping strategy had higher corticosterone levels after 21 days of defeat and decreased resting levels 3 days later. Moreover, they showed higher resting expression levels of hypothalamic CRH than their active counterparts. On day 24, the experimental animals were subjected to another social defeat to determine whether the stress response remained. The increase in corticosterone and hypothalamic CRH levels was similar for all of the stressed subjects, but the passive subjects also had a greater CRH response in the amygdala. Passive subjects had decreased levels of adrenal dopamine beta-hydroxylase, tyrosine hydroxylase and plasma adrenaline compared to the active subjects, and lower plasma noradrenaline levels than manipulated controls. The passive profile of physiological changes in both the hypothalamic-pituitary-adrenal and sympathetic-adrenal-medullary (SAM) axes has been associated with changes related to mood disorders, such as posttraumatic stress disorder and depression. The active coping profile is characterized by similar corticosterone resting levels to controls and increased SAM activity. Both profiles showed alterations in the novel palatable and forced swimming tests, with the passive profile being the most vulnerable to the effects of stress in this last test. Pharmacological treatment with antalarmin failed to reverse the effects of stress. PMID- 23796981 TI - The influenza virus NS1 protein as a therapeutic target. AB - Nonstructural protein 1 (NS1) of influenza A virus plays a central role in virus replication and blockade of the host innate immune response, and is therefore being considered as a potential therapeutic target. The primary function of NS1 is to dampen the host interferon (IFN) response through several distinct molecular mechanisms that are triggered by interactions with dsRNA or specific cellular proteins. Sequestration of dsRNA by NS1 results in inhibition of the 2' 5' oligoadenylate synthetase/RNase L antiviral pathway, and also inhibition of dsRNA-dependent signaling required for new IFN production. Binding of NS1 to the E3 ubiquitin ligase TRIM25 prevents activation of RIG-I signaling and subsequent IFN induction. Cellular RNA processing is also targeted by NS1, through recognition of cleavage and polyadenylation specificity factor 30 (CPSF30), leading to inhibition of IFN-beta mRNA processing as well as that of other cellular mRNAs. In addition NS1 binds to and inhibits cellular protein kinase R (PKR), thus blocking an important arm of the IFN system. Many additional proteins have been reported to interact with NS1, either directly or indirectly, which may serve its anti-IFN and additional functions, including the regulation of viral and host gene expression, signaling pathways and viral pathogenesis. Many of these interactions are potential targets for small-molecule intervention. Structural, biochemical and functional studies have resulted in hypotheses for drug discovery approaches that are beginning to bear experimental fruit, such as targeting the dsRNA-NS1 interaction, which could lead to restoration of innate immune function and inhibition of virus replication. This review describes biochemical, cell-based and nucleic acid-based approaches to identifying NS1 antagonists. PMID- 23796984 TI - Ultrasonic-assisted drop-to-drop solvent microextraction in a capillary tube coupled with GC-FID for trace analysis of phthalate esters. AB - An easy-to-use, rapid, robust and inexpensive technique termed ultrasonic assisted drop-to-drop solvent microextraction (USA-DDSME) in a capillary tube was used to extract trace phthalate esters in the dipping solution of plastic samples, followed by determination by using gas chromatography-flame ionization detection. Extraction conditions were optimized, including type and volume of extraction solvent, sample volume, extraction time and effect of salt concentration. The method showing the best extraction performance was used to obtain optimized conditions: 20 uL of solution sample; extraction solvent, 5.00 uL of dichloromethane; segments of extraction phase, five equal divisions; extraction time, 10 min; no added salt. The linearity of the method was determined by analyzing spiked water samples over a concentration range of 0.1 300 ug/L. All calibration curves were found to be linear, with correlation coefficients > 0.9965. The limit of detection was 0.02 ug/L. The recovery values were in the range of 68.91 to 124.8% and relative standard deviations were not higher than 14.2%. Thus, the USA-DDSME method is suitable for the extraction of trace phthalate esters in complicated samples. PMID- 23796985 TI - Distribution of parvalbumin, calbindin and calretinin containing neurons and terminal networks in relation to sleep associated nuclei in the brain of the giant Zambian mole-rat (Fukomys mechowii). AB - To broaden the understanding of the neural control and evolution of the sleep wake cycle in mammals, the distribution and interrelations of sleep associated nuclei with neurons and terminal networks expressing the calcium-binding proteins parvalbumin, calbindin and calretinin were explored in a rodent that lacks a significant visual system. The sleep-associated nuclei explored include the cholinergic basal forebrain and pontine nuclei, the catecholaminergic locus coeruleus complex, the serotonergic dorsal raphe nuclear complex, the hypothalamic orexinergic nuclei, and the thalamic reticular nucleus. Zambian mole rat brains were sectioned and stained in a one in nine series for Nissl, myelin, choline acetyltransferase (ChAT), tyrosine hydroxylase (TH), serotonin (5HT), orexin (OrxA), calbindin (CB), calretinin (CR) and parvalbumin (PV). We observed that while the density of immunopositive calbindin (CB+) neurons and terminal networks varied in the different sleep related nuclei, they were found in all nuclei apart from the compact and diffuse subdivisions of the subcoeruleus, which lacked CB+ neurons but evinced a CB+ terminal network. The density of calretinin immunopositive (CR+) neurons and terminal networks varied between the sleep related nuclei, but was present in all nuclei examined. Neurons and terminal networks associated with PV immunoreactivity were the most sparsely distributed in these nuclei, but were present in the majority of nuclei. The thalamic reticular nucleus had the highest density of PV+ neurons and terminal networks, while PV+ neurons were absent in the cholinergic pontine nuclei, and PV+ neurons and terminal networks were absent in the orexinergic nuclei. The increased presence of neurons and terminal networks expressing the calcium binding proteins in comparison to that seen in the laboratory rat, specifically in the brainstem, may account for the prominent muscle twitches during REM sleep previously observed in this subterranean African rodent. PMID- 23796986 TI - [Radial collateral artery perforator (RCAP)-based propeller flap: "discussion"]. PMID- 23796987 TI - Treatment-related mortality in patients with advanced-stage hodgkin lymphoma: an analysis of the german hodgkin study group. AB - PURPOSE: The introduction of BEACOPP(escalated) (escalated-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) has significantly improved tumor control and overall survival in patients with advanced-stage Hodgkin lymphoma. However, this regimen has also been associated with higher treatment-related mortality (TRM). Thus, we analyzed clinical course and risk factors associated with TRM during treatment with BEACOPP(escalated). PATIENTS AND METHODS: In this retrospective analysis, we investigated incidence, clinical features, and risk factors for BEACOPP(escalated)-associated TRM in the German Hodgkin Study Group trials HD9, HD12, and HD15. RESULTS: Among a total of 3,402 patients, TRM of 1.9% (64 of 3,402) was mainly related to neutropenic infections (n = 56; 87.5%). Twenty of 64 events occurred during the first course of BEACOPP(escalated) (31.3%). Higher risk of TRM was seen in patients age >= 40 years with poor performance status (PS) and in patients age >= 50 years. PS and age were then used to construct a new risk score; those with a score >= 2 had TRM of 7.1%, whereas patients who scored 0 or 1 had TRM of 0.9%. CONCLUSION: The individual risk of TRM associated with BEACOPP(escalated) can be predicted by a simple algorithm based on age and PS. High-risk patients should receive special clinical attention. PMID- 23796988 TI - Revised International Prognostic Scoring System (IPSS) predicts survival and leukemic evolution of myelodysplastic syndromes significantly better than IPSS and WHO Prognostic Scoring System: validation by the Gruppo Romano Mielodisplasie Italian Regional Database. AB - PURPOSE: The definition of disease-specific prognostic scores plays a fundamental role in the treatment decision-making process in myelodysplastic syndrome (MDS), a group of myeloid disorders characterized by a heterogeneous clinical behavior. PATIENTS AND METHODS: We applied the recently published Revised International Prognostic Scoring System (IPSS-R) to 380 patients with MDS, registered in an Italian regional database, recruiting patients from the city of Rome (Gruppo Romano Mielodisplasie). Patients were selected based on the availability of IPSS R prognostic factors, including complete peripheral-blood and bone marrow counts, informative cytogenetics, and follow-up data. RESULTS: We validated the IPSS-R score as a significant predictor of overall survival (OS) and leukemia-free survival (LFS) in MDS (P < .001 for both). When comparing the prognostic value of the International Prognostic Scoring System (IPSS), WHO Prognostic Scoring System (WPSS), and IPSS-R, using the Cox regression model and the likelihood ratio test, a significantly higher predictive power for LFS and OS became evident for the IPSS-R, compared with the IPSS and WPSS (P < .001 for both). The multivariate analysis, including IPSS, WPSS, age, lactate dehydrogenase, ferritin concentration, Eastern Cooperative Oncology Group performance status, transfusion dependency, and type of therapy, confirmed the significant prognostic value of IPSS-R subgroups for LFS and OS. Treatment with lenalidomide and erythropoiesis stimulating agents was shown to be an independent predictor of survival in the multivariate analysis. CONCLUSION: Our data confirm that the IPSS-R is an excellent prognostic tool in MDS in the era of disease-modifying treatments. The early recognition of patients at high risk of progression to aggressive disease may optimize treatment timing in MDS. PMID- 23796989 TI - Can't see the forest for the care plan: a call to revisit the context of care planning. PMID- 23796990 TI - Solitary brain metastasis as first manifestation of small-cell parotid gland carcinoma with high sensitivity to temozolomide therapy on basis of tumor O6 methylguanine-DNA-methyltransferase expression. PMID- 23796991 TI - Two birds with one stone: octreotide treatment for acromegaly and breast cancer. PMID- 23796992 TI - Deficits in physical function among young childhood cancer survivors. AB - PURPOSE: Childhood cancer survivors (CCSs) are at risk for physical disability. The aim of this investigation was to characterize and compare physical performance among CCSs and a group of siblings age < 18 years and determine if diagnosis, treatment, and physical activity levels were associated with lower performance scores. METHODS: CCSs >= 5 years from diagnosis and a sibling comparison group were recruited and evaluated for strength, mobility, and fitness. Physical performance measures were compared in regression models between survivors and siblings by diagnosis and among survivors by treatment exposures and physical activity levels. RESULTS: CCSs (n = 183; mean age +/- standard deviation [SD], 13.5 +/- 2.5 years; 53% male) scored lower than siblings (n = 147; mean age +/- SD, 13.4 +/- 2.4 years; 50% male) on lower-extremity strength testing, the timed up-and-go (TUG) test, and the 6-minute walk (6MW) test, despite reporting similar levels and types of habitual physical activity. The lowest scores were prevalent among survivors of CNS tumors and bone and soft tissue sarcomas on strength testing (score +/- SD: CNS tumors, 76.5 +/- 4.7; sarcoma 67.1 +/- 7.2 v siblings, 87.3 +/- 2.4 Newton-meters quadricep strength at 90 degrees per second; P = .04 and .01, respectively) and among CNS tumor survivors on the TUG (score +/- SD: 5.1 +/- 0.1 v siblings, 4.4 +/- 0.1 seconds; P < .001) and 6MW tests (score +/- SD: 533.3 +/- 15.6 v siblings, 594.1 +/- 8.3 m; P < .001). CONCLUSION: CCSs may have underlying physiologic deficits that interfere with function that cannot be completely overcome by participation in regular physical activity. These survivors may need referral for specialized exercise interventions in addition to usual counseling to remain physically active. PMID- 23796993 TI - Long-term remission after multiple relapses in an elderly patient with lymphomatoid granulomatosis after rituximab and high-dose cytarabine chemotherapy without stem-cell transplantation. PMID- 23796994 TI - Bisphosphonate-related osteonecrosis of jaw in the adjuvant breast cancer setting: risks and perspective. PMID- 23796995 TI - Rare case of precursor B-cell acute lymphoblastic leukemia presenting as a solitary paraspinal mass alone. PMID- 23796996 TI - Ablation of a site of progression with stereotactic body radiation therapy extends sunitinib treatment from 14 to 22 months. PMID- 23796997 TI - Bone marrow transplantation (BMT) in myelodysplastic syndromes: to BMT or not to BMT--that is the question. PMID- 23796998 TI - Osteonecrosis of the jaw and oral health-related quality of life after adjuvant zoledronic acid: an adjuvant zoledronic acid to reduce recurrence trial subprotocol (BIG01/04). AB - PURPOSE: In patients with early breast cancer, adjuvant zoledronic acid (zoledronate) may reduce recurrence and improve survival. However, zoledronate is associated with the occasional development of osteonecrosis of the jaw (ONJ). We report on the frequency of ONJ and investigate oral health-related quality of life (Oral-QoL) in a large randomized trial (Adjuvant Zoledronic Acid to Reduce Recurrence [AZURE]). PATIENTS AND METHODS: Three thousand three hundred sixty women with stage II or III breast cancer were randomly assigned to receive standard adjuvant systemic therapy alone or with zoledronate administered at a dose of 4 mg for 19 doses over 5 years. All potential occurrences of ONJ were reported as serious adverse events and centrally reviewed. Additionally, we invited 486 study participants to complete the Oral Health Impact Profile-14 (OHIP-14) to assess Oral-QoL around the time the patients completed 5 years on study. Multivariable linear regression was used to calculate mean scores and 95% CIs in addition to identifying independent prognostic factors. RESULTS: With a median follow-up time of 73.9 months (interquartile range, 60.7 to 84.2 months), 33 possible cases of ONJ were reported, all in the zoledronate-treated patients. Twenty-six cases were confirmed as being consistent with a diagnosis of ONJ, representing a cumulative incidence of 2.1% (95% CI, 0.9% to 3.3%) in the zoledronate arm. Three hundred sixty-two patients (74%) returned the OHIP-14 questionnaire. Neither the prevalence nor severity of impacts on Oral-QoL differed significantly between zoledronate patients and control patients. CONCLUSION: Adjuvant zoledronate used in the intensive schedule studied in the AZURE trial is associated with a low incidence of ONJ but does not seem to adversely affect Oral-QoL. PMID- 23796999 TI - Chromosomal abnormalities are major prognostic factors in elderly patients with multiple myeloma: the intergroupe francophone du myelome experience. AB - PURPOSE: Chromosomal abnormalities, especially t(4;14) and del(17p), are major prognostic factors in patients with multiple myeloma (MM). However, this has been especially demonstrated in patients age < 66 years treated with intensive approaches. The goal of this study was to address this issue in elderly patients treated with conventional-dose chemotherapy. PATIENTS AND METHODS: To answer this important question, we retrospectively analyzed a series of 1,890 patients (median age, 72 years; range, 66 to 94 years), including 1,095 with updated data on treatment modalities and survival. RESULTS: This large study first showed that the incidence of t(4;14) was not uniform over age, with a marked decrease in the oldest patients. Second, it showed that both t(4;14) and del(17p) retained their prognostic value in elderly patients treated with melphalan and prednisone-based chemotherapy. CONCLUSION: t(4;14) and del(17p) are major prognostic factors in elderly patients with MM, both for progression-free and overall survival, indicating that these two abnormalities should be investigated at diagnosis of MM, regardless of age. PMID- 23797001 TI - Hairy-cell leukemia presenting as lytic bone lesions. PMID- 23797000 TI - Role of reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation in older patients with de novo myelodysplastic syndromes: an international collaborative decision analysis. AB - PURPOSE: Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders that are more common in patients aged >= 60 years and are incurable with conventional therapies. Reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation is potentially curative but has additional mortality risk. We evaluated RIC transplantation versus nontransplantation therapies in older patients with MDS stratified by International Prognostic Scoring System (IPSS) risk. PATIENTS AND METHODS: A Markov decision model with quality-of-life utility estimates for different MDS and transplantation states was assessed. Outcomes were life expectancy (LE) and quality-adjusted life expectancy (QALE). A total of 514 patients with de novo MDS aged 60 to 70 years were evaluated. Chronic myelomonocytic leukemia, isolated 5q- syndrome, unclassifiable, and therapy related MDS were excluded. Transplantation using T-cell depletion or HLA mismatched or umbilical cord donors was also excluded. RIC transplantation (n = 132) stratified by IPSS risk was compared with best supportive care for patients with nonanemic low/intermediate-1 IPSS (n = 123), hematopoietic growth factors for patients with anemic low/intermediate-1 IPSS (n = 94), and hypomethylating agents for patients with intermediate-2/high IPSS (n = 165). RESULTS: For patients with low/intermediate-1 IPSS MDS, RIC transplantation LE was 38 months versus 77 months with nontransplantation approaches. QALE and sensitivity analysis did not favor RIC transplantation across plausible utility estimates. For intermediate-2/high IPSS MDS, RIC transplantation LE was 36 months versus 28 months for nontransplantation therapies. QALE and sensitivity analysis favored RIC transplantation across plausible utility estimates. CONCLUSION: For patients with de novo MDS aged 60 to 70 years, favored treatments vary with IPSS risk. For low/intermediate-1 IPSS, nontransplantation approaches are preferred. For intermediate-2/high IPSS, RIC transplantation offers overall and quality-adjusted survival benefit. PMID- 23797002 TI - Culture matters as well. PMID- 23797003 TI - Diffusely metastatic digital papillary adenocarcinoma 11 years after initial presentation treated with palliative chemotherapy and radiotherapy. PMID- 23797004 TI - ALK amplification and protein expression predict inferior prognosis in neuroblastomas. AB - BACKGROUND: ALK gene has been identified as a major neuroblastoma (NBL) predisposition gene. But ALK gene copy number and protein expression in ganglioneuroblastoma (GNBL) and ganglioneuroma (GN) are poorly described in the literature. Furthermore, there are controversies on the correlation between ALK protein expression and clinical outcome in NBL. METHODS: We evaluated MYCN/ALK gene copy number by fluorescence in situ hybridization (FISH) and detected ALK protein expression by immunohistochemistry (IHC) in 188 NBL, 52 GNBL and 6 GN samples and analyzed their association with clinical outcome of the patients. RESULTS: Although ALK gene copy number increase is a recurrent genetic aberration of neuroblastic tumors (NTs) (39.1%, 96/246), ALK amplification was only present in three NBLs (1.2%, 3/246). The frequency of ALK positivity in NBL (50.5%, 51/101) was significantly higher than in GNBL (22.6%, 7/31) and in GN (0.0%, 0/4) (P<0.05). In addition, ALK positivity also significantly correlates with MYCN/ALK gene copy number increases (P<0.05). Kaplan-Meier survival analysis indicated that MYCN/ALK amplification is correlated with decreased overall survival in NBL. A better prognosis trend was observed in patients with MYCN/ALK gain tumors compared with those with MYCN/ALK normal tumors. Furthermore, ALK positivity significantly correlated with inferior survival in NBL (P=0.044). CONCLUSION: ALK positivity in NTs correlated with advanced tumor types and MYCN/ALK gene copy number increases. ALK positivity predicts inferior prognosis in NBL and IHC is a simplified strategy to screen ALK positivity in clinical practice. PMID- 23797005 TI - Optimized pregelatinized starch technique for cell block preparation in cell cultures. AB - The aim of the present study was to optimize the pregelatinized starch technique for cell block preparation and apply this approach in cultured cells of all types of growing forms, suspension and adherent. In order to evenly mix the starch powder and the cell suspension, we crafted a special plastic dropper. To prove the effectiveness of this optimized technique we used different cell lines, NCI H69, NCI-H345, HCT-116, SKBR3 and MDA-MB-231. The morphology features, immunocytochemistry (ICC) and fluorescent/chromogenic in-situ hybridization (FISH/CISH) on the cell block sections were evaluated. The morphology features, the ICC and ISH results of cell block sections prepared by the new method were satisfactory comparing with the results obtained in biopsies, the gold standard test for this kind of analysis. The most attractive advantage of our optimized pregelatinized starch technique is that this new method is based on cell suspensions instead of cell sediment, so with our technique every section will contain cells due to the even distribution of the starch powder and the cells forming a homogeneous cell block. To the authors' knowledge, this is the first description on cell block preparation based on cell suspension. PMID- 23797006 TI - Effect of salivary phosphate-binding chewing gum on serum phosphate in chronic kidney disease. AB - BACKGROUND/AIMS: Serum phosphate (P) has been linked to adverse events in patients with chronic kidney disease. Salivary phosphate (Psal) has been proposed as a potential target of therapy with a chitosan-containing chewing gum. METHODS: We conducted several pilot studies to characterize Psal and its relationship with kidney function and subsequently conducted two clinical efficacy studies: a double-blind placebo-controlled trial in patients with end-stage renal disease (ESRD) and an open-label trial in those with stage 3-4 CKD. RESULTS: Pilot studies demonstrated no relationship between the level of kidney function and Psal. Mean Psal was approximately 6.46 mmol/l across the entire spectrum of kidney function. Passive saliva collection demonstrated higher Psal concentration as compared to active collection. There was no evidence of diurnal variation in Psal. Twice daily 20 mg chitosan gum over 4 weeks reduced serum P by 0.065 mmol/l in the double-blind, placebo-controlled trial in ESRD (p = NS vs. placebo). In an open-label extension in these subjects, 40 mg chitosan gum three times daily reduced serum P by 0.065 mmol/l (p = 0.03 vs. end of washout). In a 2-week open label trial in patients with CKD not on dialysis, 20 mg chitosan gum given three times daily reduced serum P by 0.05 mmol/l (p = 0.003 vs. day 1). Neither trial demonstrated any significant change in Psal with chitosan gum. CONCLUSIONS: Psal concentration is approximately 4-5 times that of serum P and is not related to glomerular filtration rate. Chitosan chewing gum resulted in a reduction of serum P by approximately 0.05-0.065 mmol/l but had no effect on Psal concentration. PMID- 23797007 TI - Lemierre syndrome from a neck abscess due to methicillin-resistant Staphylococcus aureus. AB - Lemierre syndrome is characterized by acute septic thrombophlebitis of the internal jugular vein (IJV) that develops after an oropharyngeal infection, and can be complicated by septic emboli to lungs and other organs. The most frequent causative agent is Fusobacterium necrophorum, an anaerobic bacillus found in normal oropharyngeal flora. Staphylococcus aureus has emerged as a cause of Lemierre syndrome in the last decade. We report a case of a 24-year-old man who developed septic IJV thrombosis and necrotizing pneumonia due to S. aureus from an infected hematoma in the right sternocleidomastoid muscle. Antibiotics are the mainstay of therapy with few cases needing anticoagulation. A good outcome is dependent upon an awareness of the condition, a high index of suspicion, and prompt initiation of antibiotic therapy. Recognition of S. aureus as a cause of Lemierre syndrome can guide the choice of initial antibiotics to cover this virulent pathogen. PMID- 23797008 TI - Differential gene expressions of the MAPK signaling pathway in enterovirus 71 infected rhabdomyosarcoma cells. AB - BACKGROUND: Mitogen-activated protein kinase (MAPK) signaling pathway plays an important role in response to viral infection. The aim of this study was to explore the function and mechanism of MAPK signaling pathway in enterovirus 71 (EV71) infection of human rhabdomyosarcoma (RD) cells. METHODS: Apoptosis of RD cells was observed using annexin V-FITC/PI binding assay under a fluorescence microscope. Cellular RNA was extracted and transcribed to cDNA. The expressions of 56 genes of MAPK signaling pathway in EV71-infected RD cells at 8h and 20h after infection were analyzed by PCR array. The levels of IL-2, IL-4, IL-10, and TNF-alpha in the supernatant of RD cells infected with EV71 at different time points were measured by ELISA. RESULTS: The viability of RD cells decreased obviously within 48h after EV71 infection. Compared with the control group, EV71 infection resulted in the significantly enhanced releases of IL-2, IL-4, IL-10 and TNF-alpha from infected RD cells (p<0.05). At 8h after infection, the expressions of c-Jun, c-Fos, IFN-beta, MEKK1, MLK3 and NIK genes in EV71-infected RD cells were up-regulated by 2.08-6.12-fold, whereas other 19 genes (e.g. AKT1, AKT2, E2F1, IKK and NF-kappaB1) exhibited down-regulation. However, at 20h after infection, those MAPK signaling molecules including MEKK1, ASK1, MLK2, MLK3, NIK, MEK1, MEK2, MEK4, MEK7, ERK1, JNK1 and JNK2 were up-regulated. In addition, the expressions of AKT2, ELK1, c-Jun, c-Fos, NF-kappaB p65, PI3K and STAT1 were also increased. CONCLUSION: EV71 infection induces the differential gene expressions of MAPK signaling pathway such as ERK, JNK and PI3K/AKT in RD cells, which may be associated with the secretions of inflammatory cytokines and host cell apoptosis. PMID- 23797009 TI - Trends in bacterial resistance in a tertiary university hospital over one decade. AB - The objective of this study was to investigate bacterial resistance trends, infection sites and the relationship between resistance and admittance to the intensive care unit (ICU). A total of 53,316 bacteria identified between 1999 and 2008 were evaluated. Multidrug resistance was characterized when gram-negative bacilli (GNB) presented resistance to two or more classes of antibiotics. Gram positive cocci (CPC) were assessed for resistance to penicillin, oxacillin and vancomycin. GNB were the most common (66.1%) isolate. There was a 3.7-fold overall increase in multidrug resistant GNB over the study period; Acinetobacter baumanii and Staphylococcus aureus were the most prevalent. Highest increases were recorded for Klebsiella pneumoniae (14.6-fold) and enterococci (73-fold). The resistance rates for GNB and GPC were 36% and 51.7%, respectively. Most multidrug resistant GNB and GPC were recovered from ICU patients (p-value<0.001). Vancomycin-resistant enterococci were isolated during this decade with an increase of 18.7% by 2008. These data confirm the worldwide trend in multidrug bacterial resistance. PMID- 23797010 TI - A structural model of PpoA derived from SAXS-analysis-implications for substrate conversion. AB - In plants and mammals, oxylipins may be synthesized via multi step processes that consist of dioxygenation and isomerization of the intermediately formed hydroperoxy fatty acid. These processes are typically catalyzed by two distinct enzyme classes: dioxygenases and cytochrome P450 enzymes. In ascomycetes biosynthesis of oxylipins may proceed by a similar two-step pathway. An important difference, however, is that both enzymatic activities may be combined in a single bifunctional enzyme. These types of enzymes are named Psi-factor producing oxygenases (Ppo). Here, the spatial organization of the two domains of PpoA from Aspergillus nidulans was analyzed by small-angle X-ray scattering and the obtained data show that the enzyme exhibits a relatively flat trimeric shape. Atomic structures of the single domains were obtained by template-based structure prediction and docked into the enzyme envelope of the low resolution structure obtained by SAXS. EPR-based distance measurements between the tyrosyl radicals formed in the activated dioxygenase domain of the enzyme supported the trimeric structure obtained from SAXS and the previous assignment of Tyr374 as radical site in PpoA. Furthermore, two phenylalanine residues in the cytochrome P450 domain were shown to modulate the specificity of hydroperoxy fatty acid rearrangement. PMID- 23797011 TI - Influence of hypoxia on endothelium-derived NO-mediated relaxation in rat carotid, mesenteric and iliac arteries. AB - Individual vascular beds exhibit differences in vascular reactivity. The present study examined the influence of hypoxia on endothelium-dependent, especially nitric oxide (NO)-mediated, relaxation in the isolated rat common carotid, superior mesenteric and external iliac arteries. Hypoxia for 1 and 3 h had no effects on the relaxations caused by acetylcholine (ACh) and sodium nitroprusside (SNP) in common carotid and external iliac arteries. In addition, NO synthase inhibitor N(G)-nitro-L-arginine (L-NA, 10 MUmol/l)-resistant, endothelium dependent relaxations by ACh were also unaffected by hypoxia in these arteries. On the other hand, ACh-induced relaxation in superior mesenteric arteries was significantly impaired by exposure to hypoxia, while this condition did not affect the relaxation induced by SNP or ACh in the presence of L-NA. This impairment was partially prevented by treatment with tempol (3 mmol/l), a superoxide scavenger. These findings demonstrate a marked heterogeneity in response to hypoxia in rat arteries. Briefly, acute hypoxia induces impairment of endothelium-derived NO-mediated relaxation through the decrease in its bioavailability in the superior mesenteric, but not in common carotid or external iliac, arteries. Furthermore, superoxide seems to be one causal factor responsible for the undesirable effect of hypoxia. PMID- 23797012 TI - Urethro-ejaculatory duct reflux, a complication of peno-bulbar urethral stricture: case report with review of the literature. AB - Urethro-ejaculatory duct reflux (UEDR) is an uncommonly discussed entity that may result in devastating complications. We discuss the case of a young married male with obstructive voiding symptoms along with intermittent left scrotal pain for last the 2 years. On voiding cystourethrography, he had intravasation of contrast into the prostatic ducts, vas deferens and epididymal ducts suggestive of UEDR which might be the cause of his scrotal pain due to recurrent episodes of epididymitis. Complete resolution of voiding symptoms and recurrent scrotal pain occurred after management of urethral stricture. The possibility of UEDR should be kept in mind while dealing with men suffering from recurrent prostatitis, seminal vesiculitis, epididymitis or, less commonly, infertility. PMID- 23797013 TI - Bleeding complications in percutaneous coronary interventions. PMID- 23797014 TI - Attitudes of meat retailers to animal welfare in Spain. AB - This study analyzes retailer attitude towards animal welfare in Spain, and how this attitude has changed over recent years (2006-2011). Retailers were concerned about animal welfare issues but a declining trend is observed recently, probably due to the financial crisis. The concern about animal welfare was affected by sex, with women retailers expressing a more positive attitude towards animal welfare issues than men. Retailers, based on their experience, perceive a low level of willingness to pay more for welfare friendly products (WFP) on behalf of their customers. This fact is reflected in the sales of the WFP, which declined from 2006 to 2011. The main reason for consumers to buy WFP, according to retailer perception, is organoleptic quality, with improved welfare being second. The results obtained provide a pessimistic picture in relation to the current market positioning of WFP, which is probably a consequence of market contraction. PMID- 23797015 TI - Characterizing salt substitution in beef meat processing by vibrational spectroscopy and sensory analysis. AB - In this investigation, the effect of NaCl, KCl and MgSO4 on bovine meat was studied, where the salts were used in standard marinades in 5.5% concentration. The effect of salts on secondary structure of the myofibrillar proteins, protein water interactions, WHC, and sensory properties of the meat was followed by carrying out FTIR and NIR measurements, cooking loss and sensory analysis. The information obtained by spectroscopic analysis was integrated by using CPCA. This revealed that MgSO4 increased ratio of alpha-helices and CO and NH groups (followed by FTIR) that are involved in H-bonding with surrounding water molecules (followed by NIR). This was also supported by increased WHC. Conversely, KCl reduced WHC of meat and was correlated to non-hydrogenated CO and NH groups. Furthermore, the sensory analysis confirmed that MgSO4 was acceptable only when the share of this salt in the mixture was one third. PMID- 23797016 TI - Effect of IGF-II genotype and pig rearing system on the final characteristics of dry-cured Iberian hams. AB - The effect of the IGF-II genotype (AG vs. GG) on the morphological and compositional parameters, the fatty acid composition of intramuscular fat, the odour concentration (analysed by dynamic olfactometry) and the volatile compound profile (analysed by proton transfer reaction time-of-flight mass spectrometry) of dry-cured Iberian ham was studied for the first time, and compared to the effect of pig rearing system (high-oleic concentrated feed vs. acorn and grass). The IGF-II genotype had no effect on most variables. However, it influenced the concentration of some odorants (methanethiol and octanal), although it did not affect odour concentration. Conversely, the rearing system had a significant effect on a large number of ham variables. Results indicate a negligible effect of the IGF-II genotype on the final ham quality and confirm that the rearing system has a marked effect. PMID- 23797017 TI - Antioxidant action of ganghwayakssuk (Artemisia princeps Pamp.) in combination with ascorbic acid to increase the shelf life in raw and deep fried chicken nuggets. AB - Raw and deep fried chicken nuggets containing various levels of ganghwayakssuk ethanolic extract (GE) in combination with ascorbic acid (Aa) were evaluated for shelf-life during refrigerated storage (4 degrees C). The pH and color (lightness, redness, and yellowness) values of raw and deep fried samples were significantly affected by the addition of GE (P<0.05). All antioxidant combinations except for Aa+GE 0.01 were effective at delaying lipid oxidation (CD, POV, and TBARS) when compared to the control or Aa. Raw samples with GE 0.2 and Aa+GE 0.1 exhibited lower bacterial populations during storage. The sensory characteristics (color, juiciness, flavor, tenderness, and overall acceptability) did not differ significantly in all deep fried chicken nugget samples, except color, whereas storage time had a significant effect (P<0.05). The results suggest the possibility of utilizing raw and deep fried chicken nuggets with a mixture of ganghwayakssuk and ascorbic acid for the increase of shelf-life and quality. PMID- 23797018 TI - Left ventricular basal region involvement in noncompaction cardiomyopathy. AB - A previously healthy 16-year-old woman experienced progressive dyspnea on exertion. The echocardiogram and cardiac magnetic resonance imaging showed a significant increase in cardiac chambers, severe biventricular systolic dysfunction, and prominent ventricular trabeculations suggesting noncompaction cardiomyopathy (NCC). The patient underwent heart transplantation 5 years after the NCC diagnosis, and the anatomopathological examination evidenced diffuse biventricular hypertrabeculation compromise, including the basal region of the biventricular wall. There is no consensus about the gold-standard diagnostic criteria, which demands a conceptual review and attention to another point: the relation of trabeculation volume and prognosis. PMID- 23797019 TI - Use of natalizumab in patients with active relapsing-remitting multiple sclerosis in Kuwait. AB - OBJECTIVE: To evaluate the outcomes of patients with multiple sclerosis (MS) who were treated with natalizumab in Kuwait. MATERIALS AND METHODS: A retrospective study using the MS registry to identify patients who were treated with natalizumab was conducted. Patients' demographics, clinical characteristics and treatment parameters were collected at baseline and last follow-up visit. Primary outcome was the proportion of relapse-free patients at the last follow-up while secondary outcomes were the change in the mean annual relapse rate, Expanded Disability Status Scale (EDSS) and the proportion of patients with magnetic resonance imaging (MRI) activity at the last follow-up visit. Forty-four patients were included in the study. RESULTS: Of the 44 patients, 27 (61.4%) were females and the remaining 17 (38.6%) males. Mean age of patients and mean disease duration were 29.05 +/- 7.25 and 5.71 +/- 3.37 years, respectively. The mean number of natalizumab infusions was 18.14. The proportion of relapse-free patients significantly increased from 11.36 to 90.91% (p < 0.0001). The EDSS significantly improved from 4.76 to 3.15 (p < 0.0001) over the observational period. There was no significant difference between patients with EDSS <3 compared to those with EDSS >= 3 (p < 0.67). The proportion of patients with MRI activity was significantly reduced from 95.5 to 18.2% (p < 0.0001) at their last visit. Six patients discontinued the drug, 5 due to positive JC virus and 1 due to pregnancy. CONCLUSIONS: Natalizumab induced a suppression of disease activity and was responsible for a significant improvement in disability status in highly active MS patients. PMID- 23797020 TI - Operative treatment for scaphoid osteonecrosis (Preiser disease): salvage or excision? Report on two cases and a review of the literature. AB - Idiopathic avascular necrosis of the scaphoid, or Preiser disease, is a rare condition. Both the etiology and the pathology are still not well understood. We here present 2 cases with this disease and discuss the recommended treatment according to the stage of disease progression and by reference to previous studies in the literature. Similar to Kienbock disease, the recommended treatment should be selected according to the degree of disease progression. We believe that vascularized bone graft should be restricted to Herbert stage I or II cases with no evidence of radiocarpal arthritis or carpal instability. Our first case showed excellent revascularization following vascularized bone graft, as revealed by magnetic resonance image findings. The presence of arthrosis of the radiocarpal or mid-carpal joints is an indication for scaphoid excision with midcarpal fusion or proximal row carpectomy. PMID- 23797022 TI - Self-inflicted burns in soldiers. AB - BACKGROUND: Self-inflicted burns are a multidisciplinary medical challenge. In contrast to the more common motive of attempted suicide in self-infliction of a burn, usually of a serious degree, a second motive is malingering. Motivation of this nature has been exhibited among Israeli soldiers who inflict on themselves low- to moderate-degree burns to obtain dismissal from mandatory military service. The purpose of our study is to investigate and define this phenomenon. METHODS: A retrospective analysis was performed on a population of 75 soldiers admitted to our Medical Center during the year 2010 with the diagnosis of any sort of burn. We set up a database including all relevant information about the burns including date and time of occurrence, cause, body location, depth of burn injury, area and shape of burn, etiology, and prescribed treatment. RESULTS: The summer was found to be the season with the highest incidence of burns. As far as the day of the week was influential, we found that the greater percentage of burns occurred at the beginning of the week. Most of the burns involved a minor surface area on the dorsal aspect of the foot. Scalding with hot water was the most common cause of burn. Eighty-one percent of the burns were atypical, being well demarcated.Most of the burn cases happened at home with no witnesses to the event. Sixty-one percent of the patients were not admitted to the hospital and were conservatively treated. CONCLUSIONS: Israeli soldiers tend to inflict burns on themselves for ulterior motives. Such burns are almost always minor with a small trauma area and sharp demarcations, and hence can be differentiated from other self-inflicted burns described in the literature. We found that most of the burns occur when the soldiers are on vacation at home. This is probably because the privacy allows them to carry out their act undisturbed. It is important to raise the awareness of attending physicians to the characteristics of these burns. Such patients should be evaluated by medical teams including mental health professionals to help them psychologically and to eliminate this unfortunate problem. PMID- 23797023 TI - Confirmatory factor analysis of the Michigan Hand Questionnaire. AB - BACKGROUND: When the Michigan Hand Questionnaire (MHQ) was originally developed, an exploratory factor analysis (EFA) was used to reduce the originally large number of generated items to the 63 items currently present on the questionnaire. Confirmation of the implied factor model of the existing MHQ has never been performed. The objective of this study was to confirm the factor model used to create the existing MHQ, and to possibly shorten the existing MHQ using factor analysis. METHODS: Patients attending the Plastic Surgery Clinic at the QEII Health Sciences Centre with a hand complaint were asked to complete the MHQ. Confirmatory factor analysis was performed to explore the implied factor structure of the original EFA and to examine the interplay between the MHQ subscales. Further item-reduction was performed using clinically guided decisions as well as factor analysis-guided statistics. RESULTS: Initial confirmatory factor analysis showed that original EFA model does not optimally explain the relationships between items in the existing MHQ and their corresponding factors. Our abbreviated model of the MHQ consists of 23 items, and performed more favorably in all goodness-of-fit parameters than the original 63-item questionnaire. CONCLUSIONS: The factor model of the existing MHQ does not fully take advantage of the relationship between items in the MHQ and the proposed factors. This study proposes a shortened version of the MHQ that more accurately reflects hand health as well as a factor-based interpretation of the subscales that takes interdependent relationships into account. PMID- 23797024 TI - Surgical treatment for congenital curved nail of the fourth toe. AB - Since congenital curved nail of the fourth toe (CNFT) was reported by Iwasawa et al in 1991, there have been only 19 cases of CNFT in 6 reports, which were from Japan and Taiwan. We performed surgery on 4 patients with CNFT and report here good results. There has been no previous detailed report on surgical treatment for this condition. This report will describe the treatment, mainly the surgical procedure. PMID- 23797025 TI - A 3-dimensional model for teaching local flaps using porcine skin. AB - The European Working Time Directive and streamlined training has led to reduced training time. Surgery, as an experience-dependent craft specialty is affected more than other medical specialties. Trainees want to maximize all training opportunities in the clinical setting, and having predeveloped basic skills acquired on a simulated model can facilitate this.Here we describe the use of a novel model to design and raise local flaps in the face and scalp regions. The model consists of mannequin heads draped with porcine skin which is skewered with pins at strategic points to give a 3-dimensional model which closely resembles a cadaveric head.The advantages of this model are that it is life size and incorporates all the relevant anatomical features, which can be drawn on if required.This model was used on a recent course, Intermediate Skills in Plastic Surgery: Flaps Around the Face, at the Royal College of Surgeons England. The trainees found that practicing on the porcine skin gave them an opportunity to master the basics of flap design and implementation.In summary, this innovative 3 dimensional training model has received high levels of satisfaction and is currently as close as we can get to cadaveric dissection without the constraints and cost of using human tissue. PMID- 23797026 TI - Childhood death attributable to trauma: is there a difference between accidental and abusive fatal injuries? AB - BACKGROUND: Trauma is a leading cause of death among children worldwide. Detailed knowledge of the epidemiology of childhood fatal injuries is necessary for preventing injuries. OBJECTIVE: To determine clinical differences between children who were treated in an emergency department for accidental or abusive injuries. METHODS: A retrospective review of all deceased patients who were treated in two urban pediatric emergency departments between 1998 and 2010 was performed. Patients were categorized into two groups, accidental and abusive, for comparison. RESULTS: A total of 1498 patients died during the study period, with 124 deaths being attributable to injury for a rate of 9.5 injury-related deaths per year. Most fatal injuries were accidental. Children with abusive fatal injuries were younger and more likely to have been seen for an injury in a clinic or emergency department within 2 months of their death. Eighty-two percent of abusive fatal injuries had documented subdural hematomas, whereas only 7.2% of accidental fatal injuries had a subdural hematoma documented. Nearly 50% of abusive fatal injuries had retinal hemorrhages reported, although no child with an accidental fatal injury had this type of injury documented. CONCLUSION: Younger children, especially those previously seen in an emergency department or clinic for injury, are more likely to sustain an abusive fatal injury. Sentinel physical findings associated with abusive fatal injuries include subdural hematomas and retinal hemorrhages, and the presence of these findings should prompt an investigation into the circumstances of injury. PMID- 23797027 TI - Estimating the glomerular filtration rate in the general population using different equations: effects on classification and association. AB - BACKGROUND/AIMS: Several formulas for glomerular filtration rate (GFR) estimation, based on serum creatinine or cystatin C, have been proposed. We assessed the impact of some of these equations on estimated GFR (eGFR) and chronic kidney disease (CKD) prevalence, and on the association with cardiovascular risk factors, in a general population sample characterized by a young mean age. METHODS: We studied 1,199 individuals from three Alpine villages enrolled into the MICROS study. eGFR was obtained with the 4- and 6-parameter MDRD study equations, the Virga equation, and with the three CKD-EPI formulas for creatinine, cystatin C, and the combination of creatinine and cystatin C. We assessed the concordance between quantitative eGFR levels, CKD prevalence, and in terms of association with total, LDL, and HDL cholesterol. RESULTS: The highest and lowest eGFR levels corresponded to the cystatin C-based and MDRD-4 equations, respectively. CKD prevalence varied from 1.8% (Virga) to 5.8% (MDRD-4). The CKD EPI based on creatinine showed the highest agreement with all other equations. Agreement between methods was higher at lower eGFR levels, older age, and in the presence of diabetes and hypertension. Creatinine-based estimates of eGFR were associated with total and low-density lipoprotein but not high-density lipoprotein cholesterol. The opposite was observed for the cystatin C-based GFR. CONCLUSION: GFR estimation is strongly affected by the chosen equation. Differences are more pronounced in healthy and younger individuals. To identify CKD risk factors, the choice of the equation is of secondary importance to the choice of the biomarker used in the formula. If eGFR is not calibrated to a gold standard GFR in the general population, reports about CKD prevalence should be considered with caution. PMID- 23797028 TI - Interstitial leukocyte migration in vivo. AB - Rapid leukocyte motility is essential for immunity and host defense. There has been progress in understanding the molecular signals that regulate leukocyte motility both in vitro and in vivo. However, a gap remains in understanding how complex signals are prioritized to result in directed migration, which is critical for both adaptive and innate immune function. Here we focus on interstitial migration and how external cues are translated into intracellular signaling pathways that regulate leukocyte polarity, directional sensing and motility in three-dimensional spaces. PMID- 23797029 TI - Integrins in mechanotransduction. AB - Forces acting on cells govern many important regulatory events during development, normal physiology, and disease processes. Integrin-mediated adhesions, which transmit forces between the extracellular matrix and the actin cytoskeleton, play a central role in transducing effects of forces to regulate cell functions. Recent work has led to major insights into the molecular mechanisms by which these adhesions respond to forces to control cellular signaling pathways. We briefly summarize effects of forces on organs, tissues, and cells; and then discuss recent advances toward understanding molecular mechanisms. PMID- 23797031 TI - Scientific publications: present and future. PMID- 23797030 TI - Role of adhesion receptor trafficking in 3D cell migration. AB - This review discusses recent advances in our understanding of adhesion receptor trafficking in vitro, and extrapolates them as far as what is currently possible towards an understanding of migration in three dimensions in vivo. Our specific focus is the mechanisms for endocytosis and recycling of the two major classes of cell-matrix adhesion receptors, integrins and syndecans. We review the signalling networks that are employed to regulate trafficking and conversely the effects of trafficking on signalling itself. We then define the contribution that this element of the migration process makes to processes such as wound healing and tumour invasion. PMID- 23797032 TI - Roles of ChlR1 DNA helicase in replication recovery from DNA damage. AB - The ChlR1 DNA helicase is mutated in Warsaw breakage syndrome characterized by developmental anomalies, chromosomal breakage, and sister chromatid cohesion defects. However, the mechanism by which ChlR1 preserves genomic integrity is largely unknown. Here, we describe the roles of ChlR1 in DNA replication recovery. We show that ChlR1 depletion renders human cells highly sensitive to cisplatin; an interstrand-crosslinking agent that causes stalled replication forks. ChlR1 depletion also causes accumulation of DNA damage in response to cisplatin, leading to a significant delay in resolution of DNA damage. We also report that ChlR1-depleted cells display defects in the repair of double-strand breaks induced by the I-PpoI endonuclease and bleomycin. Furthermore, we demonstrate that ChlR1-depeleted cells show significant delays in replication recovery after cisplatin treatment. Taken together, our results indicate that ChlR1 plays an important role in efficient DNA repair during DNA replication, which may facilitate efficient establishment of sister chromatid cohesion. PMID- 23797034 TI - Oxidative stress in atherosclerosis: the role of microRNAs in arterial remodeling. AB - Atherosclerosis is the underlying condition in most cardiovascular diseases. Among the highly specific cellular and molecular responses, endothelial dysfunction plays a key role in disease initiation and progression. These events coincide with the occurrence of oxidative stress. Increased reactive oxygen species production and oxidization of low-density lipoprotein are detected throughout atherosclerosis progression. MicroRNAs (miRNAs) have emerged as important regulators of gene expression that posttranscriptionally modify cellular responses and function. Accumulating studies indicate an integrated miRNA network in the molecular mechanisms that control cellular homeostasis, vascular inflammation, and metabolism. Experimental models of atherosclerosis highlight a direct link between altered miRNA expression profiles and the pathophysiology of the disease and identify putative miRNA candidates for the development of novel therapeutic strategies. In this review, we provide an overview of the role of miRNA regulatory networks in oxidative stress in atherosclerosis and arterial remodeling and discuss their potential therapeutic implications. PMID- 23797035 TI - In silico methods to predict drug toxicity. AB - This review describes in silico methods to characterize the toxicity of pharmaceuticals, including tools which predict toxicity endpoints such as genotoxicity or organ-specific models, tools addressing ADME processes, and methods focusing on protein-ligand docking binding. These in silico tools are rapidly evolving. Nowadays, the interest has shifted from classical studies to support toxicity screening of candidates, toward the use of in silico methods to support the expert. These methods, previously considered useful only to provide a rough, initial estimation, currently have attracted interest as they can assist the expert in investigating toxic potential. They provide the expert with safety perspectives and insights within a weight-of-evidence strategy. This represents a shift of the general philosophy of in silico methodology, and it is likely to further evolve especially exploiting links with system biology. PMID- 23797036 TI - Targeting MET: why, where and how? AB - Despite the initial skepticism, targeted therapies represent a new perspective in the treatment of cancer. Tyrosine kinases, and in particular receptor tyrosine kinases (RTKs), are considered ideal targets for this type of therapy. MET, the tyrosine kinase receptor for the Hepatocyte Growth Factor (HGF), has recently become a very interesting and studied target in oncology. In this review we discuss firstly 'why' the MET/HGF pathway can be considered a target in human tumors; secondly 'where' MET/HGF inhibition can be useful in cancer treatment and finally 'how' MET and HGF can be inhibited using either monoclonal antibodies or tyrosine kinase inhibitors. We also highlight some questions in the anti-MET/HGF targeted therapy field that are still waiting for an answer. PMID- 23797037 TI - Biosynthesis and biological actions of pineal neurosteroids in domestic birds. AB - The central and peripheral nervous systems have the capacity of synthesizing steroids de novo from cholesterol, the so-called 'neurosteroids'. De novo synthesis of neurosteroids from cholesterol appears to be a conserved property across the subphylum vertebrata. Until recently, it was generally believed that neurosteroids are produced in neurons and glial cells in the central and peripheral nervous systems. However, our recent studies on birds have demonstrated that the pineal gland, an endocrine organ located close to the brain, is an important site of production of neurosteroids de novo from cholesterol. 7alpha-Hydroxypregnenolone is a major pineal neurosteroid that stimulates locomotor activity of juvenile birds, connecting light-induced gene expression with locomotion. The other major pineal neurosteroid allopregnanolone is involved in Purkinje cell survival by suppressing the activity of caspase-3, a crucial mediator of apoptosis during cerebellar development. This review is an updated summary of the biosynthesis and biological actions of pineal neurosteroids. PMID- 23797038 TI - Role of crustacean hyperglycemic hormone (CHH) in the environmental stressor exposed intertidal copepod Tigriopus japonicus. AB - To identify and characterize CHH (TJ-CHH) gene in the copepod Tigriopus japonicus, we analyzed the full-length cDNA sequence, genomic structure, and promoter region. The full-length TJ-CHH cDNA was 716 bp in length, encoding 136 amino acid residues. The deduced amino acid sequences of TJ-CHH showed a high similarity of the CHH mature domain to other crustaceans. Six conserved cysteine residues and five conserved structural motifs in the CHH mature peptide domain were also observed. The genomic structure of the TJ-CHH gene contained three exons and two introns in its open reading frame (ORF), and several transcriptional elements were detected in the promoter region of the TJ-CHH gene. To investigate transcriptional change of TJ-CHH under environmental stress, T. japonicus were exposed to heat treatment, UV-B radiation, heavy metals, and water accommodated fractions (WAFs) of Iranian crude oil. Upon heat stress, TJ-CHH transcripts were elevated at 30 degrees C and 35 degrees C for 96 h in a time course experiment. UV-B radiation led to a decreased pattern of the TJ-CHH transcript 48 h and more after radiation (12 kJ/m(2)). After exposure of a fixed dose (12 kJ/m(2)) in a time-course experiment, TJ-CHH transcript was down regulated in time-dependent manner with a lowest value at 12h. However, the TJ CHH transcript level was increased in response to five heavy metal exposures for 96 h. Also, the level of the TJ-CHH transcript was significantly up-regulated at 20% of WAFs after exposure to WAFs for 48 h and then remarkably reduced in a dose dependent manner. These findings suggest that the enhanced TJ-CHH transcript level is associated with a cellular stress response of the TJ-CHH gene as shown in decapod crustaceans. This study is also helpful for a better understanding of the detrimental effects of environmental changes on the CHH-triggered copepod metabolism. PMID- 23797039 TI - Determination of Mycophenolic acid in the vitreous humor using the HPLC-ESI-MS/MS method: application of intraocular pharmacokinetics study in rabbit eyes with ophthalmic implantable device. AB - Mycophenolic acid (MPA) is an immunosuppressive agent widely used in the treatment of solid organ transplant rejection. The success of MPA in the treatment of inflammatory intraocular diseases has been reported in recent literature. The treatment of inflammatory eye diseases in the posterior chamber is a challenge due to the anatomy of the eye, which presents certain barriers to drug access. Thus, the bioavailability of drugs in the eye is quite low, and successful drug delivery may well represent a key limiting factor to attaining a successful therapeutic strategy. Ophthalmic controlled drug delivery offers the potential to enhance the efficacy of treatment for pathological conditions. Thus, a novel delivery system based on a biodegradable polymeric device, which can be implanted inside the eye and deliver MPA directly to the target, is being developed. Specific analytical methods to determine the use of effective drugs within the eye are needed to characterize this device. A liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) method for the quantitation of MPA in the vitreous humor of rabbits was developed and validated. The vitreous was collected from rabbits, extracted by a protein precipitation extraction procedure and then separated on a C18 column with a mobile phase comprised of 0.15% aqueous acetic acid and methanol (60:40, v/v). The calibration curve was constructed within the range of 3-10,000 ng/mL for MPA. The mean R.S.D. values for the intra-run and inter-run precision were 5.15% and 4.35%. The mean accuracy value was 100.16%. The validated method was successfully applied to determine the MPA concentration in the vitreous humor of rabbits treated with an ocular implantable device. PMID- 23797040 TI - Quantification of a pegylated interferon-alpha2a product by a customised and validated reverse phase-high performance liquid chromatography method. AB - There is increasing development of pegylated proteins as clinical products for therapeutic interventions in human disease. Quantification of such products relies on appropriately calibrated traditional methods, including reverse phase high performance liquid chromatography (RP-HPLC). However, currently available pharmacopoeia calibrants, e.g., chemical reference substances (CRS), are highly purified non-pegylated proteins of known concentration. These are uncertain to be suitable for calibration purposes where the precise quantification of the mass of pegylated proteins, often heterogeneous with respect to polyethylene glycol (PEG) chain size, structure, attachment sites and isomer numbers and proportions, is required. In this study, a customised RP-HPLC method was developed and validated for the analysis of a pegylated IFN-alpha2a product having a linear 20kDa PEG chain (PEG20-IFN-alpha2a; Reiferon Retard((r))). Since the PEG20 moiety generated no signal at the detection wavelength of 210nm, the concentration of the base IFN alpha2a molecules in PEG-IFN-alpha2a could be determined. By calculating the UV absorbance at 210nm of peak areas in their respective chromatographic profiles, a high correlation (r(2) >= 0.995) of PEG20-IFN-alpha2a concentrations with equal concentrations of the CRS of IFN-alpha2a, or of a well-characterised PEG20-IFN alpha2a internal reference substance (IRS) was found. This finding confirmed the suitability of this CRS as a primary calibrant for mass determinations of PEG20 IFN-alpha2a by the customised RP-HPLC method. Application of this method to the quantitative analysis of 10 batches of Reiferon Retard((r)) yielded accurate and consistent results, indicating its utility for mass determinations of current and future Reiferon Retard((r)) batches. PMID- 23797033 TI - Clinical perspective on oxidative stress in sporadic amyotrophic lateral sclerosis. AB - Sporadic amyotrophic lateral sclerosis (ALS) is one of the most devastating neurological diseases; most patients die within 3 to 4 years after symptom onset. Oxidative stress is a disturbance in the pro-oxidative/antioxidative balance favoring the pro-oxidative state. Autopsy and laboratory studies in ALS indicate that oxidative stress plays a major role in motor neuron degeneration and astrocyte dysfunction. Oxidative stress biomarkers in cerebrospinal fluid, plasma, and urine are elevated, suggesting that abnormal oxidative stress is generated outside of the central nervous system. Our review indicates that agricultural chemicals, heavy metals, military service, professional sports, excessive physical exertion, chronic head trauma, and certain foods might be modestly associated with ALS risk, with a stronger association between risk and smoking. At the cellular level, these factors are all involved in generating oxidative stress. Experimental studies indicate that a combination of insults that induce modest oxidative stress can exert additive deleterious effects on motor neurons, suggesting that multiple exposures in real-world environments are important. As the disease progresses, nutritional deficiency, cachexia, psychological stress, and impending respiratory failure may further increase oxidative stress. Moreover, accumulating evidence suggests that ALS is possibly a systemic disease. Laboratory, pathologic, and epidemiologic evidence clearly supports the hypothesis that oxidative stress is central in the pathogenic process, particularly in genetically susceptive individuals. If we are to improve ALS treatment, well-designed biochemical and genetic epidemiological studies, combined with a multidisciplinary research approach, are needed and will provide knowledge crucial to our understanding of ALS etiology, pathophysiology, and prognosis. PMID- 23797041 TI - HPLC method for determination of lipoxygenase positional specific products. AB - Mammalian lipoxygenases (LOXs) play an important role in physiological and pathological processes through the biosynthesis of lipid mediators-leukotrienes, lipoxins and other arachidonic acid derivatives.There are four major families of LOXs that can be analyzed through the production of hydroxyeicosatetraenoic acids (HETEs). No analytical method to detect 5-, 8-, 12- and 15-HETE in one run has been published to date. The HPLC method combines reversed-phase separative column Nucleosil 120-5 C18 and NP column Zorbax Rx.SIL for identification. This conjunction enables separation of 12-HETE and 15-HETE to the baseline which is essential in 12/15-LOX research and elution of all four HETEs in one run. The method was successfully tested on partially purified LOXs from rat lung cytosol. PMID- 23797042 TI - Progress towards the 'Golden Age' of biotechnology. AB - Biotechnology uses substances, materials or extracts derived from living cells, employing 22 million Europeans in a ? 1.5 Tn endeavour, being the premier global economic growth opportunity this century. Significant advances have been made in red biotechnology using pharmaceutically and medically relevant applications, green biotechnology developing agricultural and environmental tools and white biotechnology serving industrial scale uses, frequently as process feedstocks. Red biotechnology has delivered dramatic improvements in controlling human disease, from antibiotics to overcome bacterial infections to anti-HIV/AIDS pharmaceuticals such as azidothymidine (AZT), anti-malarial compounds and novel vaccines saving millions of lives. Green biotechnology has dramatically increased food production through Agrobacterium and biolistic genetic modifications for the development of 'Golden Rice', pathogen resistant crops expressing crystal toxin genes, drought resistance and cold tolerance to extend growth range. The burgeoning area of white biotechnology has delivered bio-plastics, low temperature enzyme detergents and a host of feedstock materials for industrial processes such as modified starches, without which our everyday lives would be much more complex. Biotechnological applications can bridge these categories, by modifying energy crops properties, or analysing circulating nucleic acid elements, bringing benefits for all, through increased food production, supporting climate change adaptation and the low carbon economy, or novel diagnostics impacting on personalized medicine and genetic disease. Cross-cutting technologies such as PCR, novel sequencing tools, bioinformatics, transcriptomics and epigenetics are in the vanguard of biotechnological progress leading to an ever-increasing breadth of applications. Biotechnology will deliver solutions to unimagined problems, providing food security, health and well-being to mankind for centuries to come. PMID- 23797044 TI - Building bridges: future directions for medical error disclosure research. AB - OBJECTIVE: The disclosure of medical errors has attracted considerable research interest in recent years. However, the research to date has lacked interdisciplinary dialog, making translation of findings into medical practice challenging. This article lays out the disciplinary perspectives of the fields of medicine, ethics, law and communication on medical error disclosure and identifies gaps and tensions that occur at these interdisciplinary boundaries. METHODS: This article summarizes the discussion of an interdisciplinary error disclosure panel at the 2012 EACH Conference in St. Andrews, Scotland, in light of the current literature across four academic disciplines. RESULTS: Current medical, ethical, legal and communication perspectives on medical error disclosure are presented and discussed with particular emphasis on the interdisciplinary gaps and tensions. CONCLUSION: The authors encourage interdisciplinary collaborations that strive for a functional approach to understanding and improving the disclosure of medical errors with the ultimate goal to improve quality and promote safer medical care. PRACTICE IMPLICATIONS: Interdisciplinary collaborations are needed to reconcile the needs of the stakeholders involved in medical error disclosure. A particular challenge is the effective translation of error disclosure research into practice. Concrete research questions are provided throughout the manuscript to facilitate a resolution of the tensions that currently impede interdisciplinary progress. PMID- 23797045 TI - Ocular pulse amplitude as a dynamic parameter and its relationship with 24-h intraocular pressure and blood pressure in glaucoma. AB - Abnormal ocular blood flow (OBF) has been suspected as one of the underlying mechanisms of glaucoma. The ocular pulse amplitude (OPA) is considered a possible surrogate parameter for ocular blood flow (OBF) measurement and has been studied in its association with glaucoma. Although there have been several studies that reported various ocular and systemic factors in association with OPA, all of these studies were based on a single measurement of these factors as well as OPA. The purpose of this study was to determine the 24-h (h) dynamic variability and any associations between OPA and intraocular pressure (IOP) and blood pressure (BP) variables using 24-h data collected from untreated patients with normal tension glaucoma (NTG). One hundred and forty-four patients with NTG were consecutively enrolled. All patients underwent 24-h monitoring of IOP, OPA, and BP variables. A cosinor model was used to describe the patterns and statistical significance of the 24-h OPA rhythm, as well as the IOP and BP variables. Associations between 24-h OPA data, IOP and BP variables, and ocular and demographic factors were also assessed using the generalized estimating equation. Over the course of 24-h, OPA (p = 0.007) demonstrated significant dynamic diurnal rhythms that were similar to the other dynamic variables (all p < 0.05). Based on the 24-h data, IOP (p < 0.001), arterial pulse pressure (p = 0.034), and the spherical equivalent (p < 0.001) positively correlated with the OPA, whilst male sex (p < 0.001) negatively correlated with the OPA. These results indicate that OPA is primarily influenced by IOP as well as arterial pulse pressure, spherical equivalent, and gender. In conclusion, OPA is a dynamic ocular parameter that demonstrates a 24-h short-time fluctuation in NTG patients. PMID- 23797046 TI - Characterization of the normal microbiota of the ocular surface. AB - The ocular surface is continually exposed to the environment and as a consequence to different types of microbes, but whether there is a normal microbiota of the ocular surface remains unresolved. Using traditional microbial culture techniques has shown that <80% of swabs of the conjunctiva yield cultivable microbes. These usually belong to the bacterial types of the coagulase-negative staphylococci, Propionibacterium sp., with low frequency of isolation of bacteria such as Staphylococcus aureus, Micrococcus sp., Gram-negative bacteria or fungi. Even when these are grown, the numbers of colony forming units (cfu) per swab of the conjunctiva is usually much less than 100 cfu. Swabs of the lid more commonly result in microbial growth, of the same species as from the conjunctiva and slightly higher cfu. Contact lenses have also been cultured, and they yield similar microbial types. Microbes can be isolated from the ocular surface almost immediately after birth. The advent of molecular techniques for microbial identification based on 16S rRNA sequencing has opened up the possibility of determining whether there are non-cultivable microbes that can colonise the ocular surface. Additionally, use of these techniques with cross-sectional and longitudinal studies may help to understand whether the ocular surface harbours its own unique microbiota, or whether the microbiota are only transiently present. PMID- 23797047 TI - One-year follow-up of dermoscopy education on the ability of medical students to detect skin cancer. AB - BACKGROUND: Learning skin cancer detection skills is important, yet many medical schools lack a standardized skin cancer examination (SCE) curriculum. OBJECTIVE: To determine medical students' skills in discriminating benign from malignant skin lesions on a 10-item image-based test one year after receiving a SCE intervention. METHODS: Cohort 1 received SCE teaching only. Cohort 2 received SCE teaching with dermoscopy tutorial, and a dermatoscope. The same test was given to assess students post-intervention and one year later. RESULTS: 43% (n = 145) and 38% (n = 143) of cohorts 1 and 2, respectively, participated one year later. Both cohorts improved or maintained their scores to correctly classify all lesions from post-intervention to one-year follow-up. After one year, cohort 2 maintained higher scores for successful identification of both benign and malignant lesions as compared to cohort 1. CONCLUSION: Medical students receiving a SCE intervention can improve their diagnostic skills after one year, especially with the aid of dermoscopy. PMID- 23797048 TI - Retroperitoneal bleeding after cardiac catheterization: a 7-year descriptive single-center experience. AB - BACKGROUND: Retroperitoneal bleeding (RPB) is an unusual but potentially fatal vascular complication occurring after cardiac catheterization (CC). Contemporary data of RPB in the era of dual antiplatelet therapy and vascular closure devices are lacking. METHODS: We retrospectively examined all RPB cases that occurred after CC in the Rabin Medical Center between the years 2005 and 2011. RESULTS: Of 26,487 patients who underwent CC, a total of 48 patients (mean age 60.9 +/- 13.8 years, 52.1% female) with RPB were identified (0.18%). The indication for CC was acute coronary syndrome (43.7%), myocardial infarction (35.4%), stable angina pectoris (8.3%), hemodynamic studies for valvular heart disease (10.4%) and others (2.1%). Coronary intervention was performed in 34 patients (70.9%) and a vascular closure device (VCD) was used in 16 patients (33.3%). Seventy-seven percent of patients were treated with clopidogrel, 20.8% with glycoprotein IIb IIIa inhibitors and 85.4% with anticoagulation during CC. Median time to diagnosis of bleeding was 9.0 h, while the median time to bleeding differed between patients with and without a VCD (12 vs. 5 h, respectively). The clinical presentation of RPB was hemorrhagic shock in 39.6% of patients and 50.0% required at least one blood transfusion. Patients were managed either with conservative treatment (79.2%), angiography stenting (14.6%) or vascular surgery (6.2%). A total of 3 patients died during hospitalization, of which RPB was the etiology in 2 (4.2%). CONCLUSIONS: RPB which is a rare complication of CC is associated with younger age and female gender, as compared to patients without RPB. Onset of bleeding can be delayed in patients with VCDs. With careful and early diagnosis, most patients with RPB after CC can be managed conservatively. PMID- 23797049 TI - GDF15 is related to anemia and hepcidin in kidney allograft recipients. AB - Anemia is more prevalent in renal transplant recipients than in GFR-matched chronic kidney disease patients. Hepcidin is a small defensin-like peptide whose production by hepatocytes is modulated in response to anemia, hypoxia or inflammation. Growth differentiation factor 15 (GDF15) was recently identified as a hepcidin-suppression factor that is expressed at high levels in patients with ineffective erythropoiesis. The aim of the study was to assess GDF15 levels with relation to iron parameters in 62 stable kidney allograft recipients maintained on triple immunosuppressive therapy. METHODS: Complete blood count, urea, creatinine, and iron status were assessed by standard methods. We measured GDF15, hepcidin, hemojuvelin, IL-6 and NGAL with commercially available assays. RESULTS: Mean levels of GDF15, NGAL, hepcidin and hemojuvelin were significantly higher in kidney allograft recipients when compared to the control group (p < 0.001 for all). GDF15 was significantly higher in patients with anemia according to the WHO definition when compared to their nonanemic counterparts (p < 0.05). GDF15 levels were not dependent on the type of immunosuppressive therapy. In univariate analysis GDF15 was related to kidney function (creatinine r = 0.39, p < 0.01, eGFR by MDRD r = -0.37, p < 0.01), urea (r = 0.39, p < 0.01), uric acid (r = 0.42, p < 0.01), hepcidin (r = -0.32, p < 0.01), IL-6 (r = 0.28, p < 0.05), hemoglobin (r = -0.32, p < 0.05), and NGAL (r = -0.35, p < 0.01). GDF15 was not related to serum iron, or ferritin. In multivariate analysis, hepcidin was found to be a predictor of GDF15. In conclusion, our preliminary data may suggest possible mutual relations between GDF15 and hepcidin in patients with kidney disease and that GDF15 might be involved in the pathogenesis of anemia in kidney allograft recipients. However, the role of inflammation should be also elucidated. PMID- 23797050 TI - Expression of fibroblast growth factor 9 in normal human lung and idiopathic pulmonary fibrosis. AB - The fibroblast growth factor (FGF) family of signaling ligands contributes significantly to lung development and maintenance in the adult. FGF9 is involved in control of epithelial branching and mesenchymal proliferation and expansion in developing lungs. However, its activity and expression in the normal adult lung and by epithelial and interstitial cells in fibroproliferative diseases like idiopathic pulmonary fibrosis (IPF) are unknown. Tissue samples from normal organ donor human lungs and those of a cohort of patients with mild to severe IPF were sectioned and stained for the immunolocalization of FGF9. In normal lungs, FGF9 was confined to smooth muscle surrounding airways, alveolar ducts and sacs, and blood vessels. In addition to these same sites, lungs of IPF patients expressed FGF9 in a population of myofibroblasts within fibroblastic foci, hypertrophic and hyperplastic epithelium of airways and alveoli, and smooth muscle cells surrounding vessels embedded in thickened interstitium. The results demonstrate that FGF9 protein increased in regions of active cellular hyperplasia, metaplasia, and fibrotic expansion of IPF lungs, and in isolated human lung fibroblasts treated with TGF-beta1 and/or overexpressing Wnt7B. The cellular distribution and established biologic activity of FGF9 make it a potentially strong candidate for contributing to the progression of IPF. PMID- 23797051 TI - Reduced FHIT expression is associated with mismatch repair deficient and high CpG island methylator phenotype colorectal cancer. AB - Colorectal cancer (CRC) is a heterogeneous disease and a major contributor to world cancer mortality rates. Molecular subtypes of CRC have become standards for CRC classification and have established prognostic potential. Here, we attempt to corroborate and provide further insight pertinent to the fragile histidine triad (FHIT) gene in microsatellite instable (MSI), microsatellite stable (MSS), and CpG island methylator phenotype (CIMP) CRC subtypes. We employed array comparative genomic hybridization and multiplex ligation-dependent probe amplification (MLPA) techniques to survey genomic aberrations in FHIT gene and their effects on FHIT protein expression using immunohistochemistry (IHC) in a CRC cohort. We further studied FHIT protein expression by IHC in a larger CRC cohort defined for its mismatch repair (MMR) protein expression and genomic methylation profiles. Our results show FHIT genomic deletions centered in exons 4 and 5 in most of MSI-CRC samples. Moreover, we confirmed the significant association of FHIT protein expression diminution (p=0.035) with MSI-CRC. In the larger cohort, reduced FHIT protein expression was significantly associated with CIMP-high subtype of CRC (p=0.009) and loss of PMS2 protein expression (p=0.017). We conclude that FHIT expression may be a valuable marker for CRC subtyping, and its diagnostic, prognostic, and therapeutic potential should be perused. PMID- 23797052 TI - Small human sperm vacuoles observed under high magnification are pocket-like nuclear concavities linked to chromatin condensation failure. AB - Since an embryo's ability to grow to the blastocyst stage and implant can be improved by selection of a normal spermatozoon with a vacuole-free head, this study set out to determine the nature of small sperm vacuoles observed under high magnification (>*6300). For 15 infertile men with various sperm profiles, high magnification microscopy was used to select motile, morphometrically normal spermatozoa with no vacuoles (n=450) or more than two small vacuoles (each of which occupied less than 4% of the head's area; n=450). Spermatozoa acrosome reaction status and degree of chromatin condensation were analysed. Three dimensional deconvolution microscopy was used to accurately image the nucleus and acrosome at all depths in all spermatozoa. In all 450 spermatozoa with small vacuoles, the latter were seen to be abnormal, DNA-free nuclear concavities. Spermatozoa with small vacuoles were significantly more likely than vacuole-free spermatozoa to have noncondensed chromatin (39.8% versus 9.3%, respectively; P<0.0001). There was no significant difference between the two groups of spermatozoa in terms of acrosome reaction status. No association between chromatin condensation and acrosome reaction status was observed. Small human sperm vacuoles observed under high magnification are pocket-like nuclear concavities related to failure of chromatin condensation. PMID- 23797053 TI - Validation of the iHealth BP5 wireless upper arm blood pressure monitor for self measurement according to the European Society of Hypertension International Protocol revision 2010. AB - OBJECTIVE: The aim of this study was to validate the iHealth BP5 wireless upper arm blood pressure (BP) monitor according to the European Society of Hypertension International Protocol (ESH-IP) revision 2010. MATERIALS AND METHODS: The ESH-IP revision 2010 for validation of BP measuring devices in adults was followed precisely. A total of 99 pairs of test device and reference BP measurements (three pairs for each of the 33 participants) were obtained in the study. RESULTS: The device produced 71, 89, and 97 measurements within 5, 10, and 15 mmHg for systolic blood pressure (SBP) and 73, 90, and 99 mmHg for diastolic blood pressure (DBP), respectively. The mean +/- SD device-observer difference was -1.21 +/- 5.87 mmHg for SBP and -1.04 +/- 5.28 mmHg for DBP. The number of participants with two or three device-observer differences within 5 mmHg was 25 for SBP and 28 for DBP. In addition, three participants had no device-observer difference within 5 mmHg for SBP and none of the participants had the same for DBP. CONCLUSION: According to the validation results on the basis of the ESH-IP revision 2010, the iHealth BP5 wireless upper arm BP monitor can be recommended for self/home measurement in an adult population. PMID- 23797054 TI - Home blood pressure measurement in elderly patients with cognitive impairment: comparison of agreement between relative-measured blood pressure and automated blood pressure measurement. AB - OBJECTIVES: Home blood pressure measurement (HBPM) is recommended by guidelines for hypertension management. However, this method might be difficult to use in elderly individuals with cognitive disorders. Our aim was to assess the agreement and the feasibility of HBPM by a relative as compared with 24-h ambulatory blood pressure monitoring (ABPM) in elderly patients with dementia. METHODS: Sixty outpatients with dementia aged 75 years and older with office hypertension (>=140/90 mmHg) were subjected successively to HBPM by a trained relative and 24 h ABPM. The order of the two methods was randomized. Current guidelines' thresholds for the diagnosis of hypertension were used. RESULTS: The mean (SD) age of the patients was 80.8 (6.1) years (55% women) and the mean (SD) mini mental state examination score was 20.1 (6.9). The feasibility of relative-HBPM was very high, with a 97% success rate (defined by >=12/18 measurements reported). The blood pressure measurements were highly correlated between the two methods (r=0.75 and 0.64 for systolic blood pressure and diastolic blood pressure, respectively; P<0.001 for both). The agreement between the methods for the diagnosis of sustained hypertension and white-coat hypertension was excellent (overall agreement, 92%; kappa coefficient, 0.81; 95% CI, 0.61-0.93). Similar results were found for daytime-ABPM. CONCLUSION: In cognitively impaired elderly patients, HBPM by a relative using an automated device was a good alternative to 24-h ABPM. PMID- 23797056 TI - In vitro, in vivo and ex vivo models for studying particle deposition and drug absorption of inhaled pharmaceuticals. AB - Delivery of therapeutic agents via the pulmonary route has gained significant attention over the past few decades because this route of administration offers multiple advantages over traditional routes that include localized action, non invasive nature and favorable lung-to-plasma ratio. However, assessment of post administration behavior of inhaled pharmaceuticals-such as deposition of particles over the respiratory airways, interaction with the respiratory fluid and movement across the air-blood barrier-is challenging because the lung is a very complex organs that is composed of airways with thousands of bifurcations with variable diameters. Thus, much effort has been put forward to develop models that mimic human lungs and allow evaluation of various pharmaceutical and physiological factors that influence the deposition and absorption profiles of inhaled formulations. In this review, we sought to discuss in vitro, in vivo and ex vivo models that have been extensively used to study the behaviors of airborne particles in the lungs and determine the absorption of drugs after pulmonary administration. We have provided a summary of lung cast models, cascade impactors, noninvasive imaging, intact animals, cell culture and isolated perfused lung models as tools to evaluate the distribution and absorption of inhaled particles. We have also outlined the limitations of currently used models and proposed future studies to enhance the reproducibility of these models. PMID- 23797055 TI - Associations between PBDEs in office air, dust, and surface wipes. AB - Increased use of flame-retardants in office furniture may increase exposure to PBDEs in the office environment. However, partitioning of PBDEs within the office environment is not well understood. Our objectives were to examine relationships between concurrent measures of PBDEs in office air, floor dust, and surface wipes. We collected air, dust, and surface wipe samples from 31 offices in Boston, MA. Correlation and linear regression were used to evaluate associations between variables. Geometric mean (GM) concentrations of individual BDE congeners in air and congener specific octanol-air partition coefficients (Koa) were used to predict GM concentrations in dust and surface wipes and compared to the measured concentrations. GM concentrations of PentaBDEs in office air, dust, and surface wipes were 472pg/m(3), 2411ng/g, and 77pg/cm(2), respectively. BDE209 was detected in 100% of dust samples (GM=4202ng/g), 93% of surface wipes (GM=125pg/cm(2)), and 39% of air samples. PentaBDEs in dust and air were moderately correlated with each other (r=0.60, p=0.0003), as well as with PentaBDEs in surface wipes (r=0.51, p=0.003 for both dust and air). BDE209 in dust was correlated with BDE209 in surface wipes (r=0.69, p=0.007). Building (three categories) and PentaBDEs in dust were independent predictors of PentaBDEs in both air and surface wipes, together explaining 50% (p=0.0009) and 48% (p=0.001) of the variation respectively. Predicted and measured concentrations of individual BDE congeners were highly correlated in dust (r=0.98, p<0.0001) and surface wipes (r=0.94, p=002). BDE209 provided an interesting test of this equilibrium partitioning model as it is a low volatility compound. Associations between PentaBDEs in multiple sampling media suggest that collecting dust or surface wipes may be a convenient method of characterizing exposure in the indoor environment. The volatility of individual congeners, as well as physical characteristics of the indoor environment, influence relationships between PBDEs in air, dust, and surface wipes. PMID- 23797057 TI - Osteogenic effect of local, long versus short term BMP-2 delivery from a novel SPU-PLGA-betaTCP concentric system in a critical size defect in rats. AB - A concentric delivery system, composed of the three biomaterials SPU, PLGA, and betaTCP (segmented polyurethane, poly[lactic-co-glycolic acid], and beta tricalcium phosphate) was fabricated as an external, porous ring of betaTCP with a pasty core of a new SPU, mixed with PLGA microspheres. The regenerative effects of two distinct doses of either immediately available or continuously released rhBMP-2 were evaluated in an 8mm, critical calvaria defect in rats. Protein dose and release kinetics affected material resorption rates and the progression of the regeneration process. Groups treated with the empty system alone or in conjunction with free rhBMP-2 did not respond. By contrast, after 12 weeks, approximately 20% and 60% of the defects implanted with systems loaded with 1.6 MUg and 6.5 MUg rhBMP-2, respectively were healed, with all the growth factor being released in the course of 6 weeks. The NMR, FTIR, GPC, DSC, and histological analyses showed that PLGA microsphere degradation occurred independently of the regenerative process. However, the resorption rate of the SPU and betaTCP did depend on the regeneration process, which was governed by dose and release rate of rhBMP-2. Furthermore, the biocompatibility and high capacity of adaptation to the defect convert the herein proposed, new SPU polymer into a potential material for applications in tissue engineering and regenerative medicine. PMID- 23797058 TI - cAMP inhibits migration, ruffling and paxillin accumulation in focal adhesions of pancreatic ductal adenocarcinoma cells: effects of PKA and EPAC. AB - We demonstrated that increasing intracellular cAMP concentrations result in the inhibition of migration of PANC-1 and other pancreatic ductal adenocarcinoma (PDAC) cell types. The rise of cAMP was accompanied by rapid and reversible cessation of ruffling, by inhibition of focal adhesion turnover and by prominent loss of paxillin from focal adhesions. All these phenomena develop rapidly suggesting that cAMP effectors have a direct influence on the cellular migratory apparatus. The role of two primary cAMP effectors, exchange protein activated by cAMP (EPAC) and protein kinase A (PKA), in cAMP-mediated inhibition of PDAC cell migration and migration-associated processes was investigated. Experiments with selective activators of EPAC and PKA demonstrated that the inhibitory effect of cAMP on migration, ruffling, focal adhesion dynamics and paxillin localisation is mediated by PKA, whilst EPAC potentiates migration. PMID- 23797059 TI - The three alpha1-adrenoceptor subtypes show different spatio-temporal mechanisms of internalization and ERK1/2 phosphorylation. AB - We analyzed the kinetic and spatial patterns characterizing activation of the MAP kinases ERK 1 and 2 (ERK1/2) by the three alpha1-adrenoceptor (alpha1-AR) subtypes in HEK293 cells and the contribution of two different pathways to ERK1/2 phosphorylation: protein kinase C (PKC)-dependent ERK1/2 activation and internalization-dependent ERK1/2 activation. The different pathways of phenylephrine induced ERK phosphorylation were determined by western blot, using the PKC inhibitor Ro 31-8425, the receptor internalization inhibitor concanavalin A and the siRNA targeting beta-arrestin 2. Receptor internalization properties were studied using CypHer5 technology and VSV-G epitope-tagged receptors. Activation of alpha1A- and alpha1B-ARs by phenylephrine elicited rapid ERK1/2 phosphorylation that was directed to the nucleus and inhibited by Ro 31-8425. Concomitant with phenylephrine induced receptor internalization alpha1A-AR, but not alpha1B-AR, produced a maintained and PKC-independent ERK phosphorylation, which was restricted to the cytosol and inhibited by beta-arrestin 2 knockdown or concanavalin A treatment. alpha1D-AR displayed constitutive ERK phosphorylation, which was reduced by incubation with prazosin or the selective alpha1D antagonist BMY7378. Following activation by phenylephrine, alpha1D-AR elicited rapid, transient ERK1/2 phosphorylation that was restricted to the cytosol and not inhibited by Ro 31-8425. Internalization of the alpha1D-AR subtype was not observed via CypHer5 technology. The three alpha1-AR subtypes present different spatio-temporal patterns of receptor internalization, and only alpha1A-AR stimulation translates to a late, sustained ERK1/2 phosphorylation that is restricted to the cytosol and dependent on beta-arrestin 2 mediated internalization. PMID- 23797063 TI - How B cells capture, process and present antigens: a crucial role for cell polarity. AB - B cells are key components of the adaptive immune response. Their differentiation into either specific memory B cells or antibody-secreting plasma cells is a consequence of activation steps that involve the processing and presentation of antigens. The engagement of B cell receptors by surface-tethered antigens leads to the formation of an immunological synapse that coordinates cell signalling events and that promotes antigen uptake for presentation on MHC class II molecules. In this Review, we discuss membrane trafficking and the associated molecular mechanisms that are involved in antigen extraction and processing at the B cell synapse, and we highlight how B cells use cell polarity to coordinate the complex events that ultimately lead to efficient humoral responses. PMID- 23797065 TI - Best determinants of nonalcoholic fatty liver disease and intra-abdominal fat in prepubertal children born small for gestational age: ultrasound technique versus anthropometric data. PMID- 23797066 TI - Myeloid-derived suppressor cells in cancer: recent progress and prospects. AB - Immunosuppressive cells, mainly myeloid-derived suppressor cells (MDSCs) and T regulatory cells, downregulate antitumour immunity and cancer immunotherapy. MDSCs are a heterogeneous group of immature myeloid cells that negatively regulate the immune responses during tumour progression, inflammation and infection. Whilst there have been extensive laboratory investigations aimed at characterising the MDSC subsets in cancer, there remains a significant gap in our understanding of their phenotypical and functional heterogeneity. In this article, we review data concerning the phenotypical and functional role of MDSCs in cancers. Importantly, we analyse the value of MDSCs as a prognostic factor in various clinical settings and the possible therapeutic approaches towards elimination of their immunosuppressive activity and enhancement of beneficial antitumour immune responses. MDSCs promote tumour immune evasion by inhibiting T cell responses, as well as by supporting tumour progression. Accumulation of MDSCs is associated with the progression of human cancers, and their elimination was shown to improve anti-tumour immune responses. Phenotypical characterisation of MDSCs has been poorly investigated in many human cancers and lacks comprehensive clinicopathological correlation data. Although the need for effective therapeutic agents to eliminate the MDSC suppressive effect is immense, their role has been examined only in a few clinical settings. PMID- 23797064 TI - Unravelling the mechanisms of durable control of HIV-1. AB - Untreated HIV-1 infection typically progresses to AIDS within 10 years, but less than 1% of infected individuals remain healthy and have normal CD4(+) T cell counts and undetectable viral loads; some individuals have remained this way for 35 years and counting. Through a combination of large population studies of cohorts of these 'HIV-1 controllers' and detailed studies of individual patients, a heterogeneous picture has emerged regarding the basis for this remarkable resistance to AIDS progression. In this Review, we highlight the host genetic factors, the viral genetic factors and the immunological factors that are associated with the controller phenotype, we discuss emerging methodological approaches that could facilitate a better understanding of spontaneous HIV-1 immune control in the future, and we delineate implications for a 'functional cure' of HIV-1 infection. PMID- 23797067 TI - The multifunctional alarmin HMGB1 with roles in the pathophysiology of sepsis and cancer. AB - Although originally described as a highly conserved nuclear protein involved in DNA replication, transcription and repair, high-mobility group box-1 protein (HMGB1) has emerged as a key mediator in the regulation of immune responses to infection and sterile injury by exhibiting all the properties of a prototypic 'alarmin'. These include rapid passive release in response to pathogenic infection and/or traumatic injury, active secretion providing for chemotactic and cytokine-like function and an ability to resolve inflammation, including tissue repair and remodelling. In this review, we will give an overview of the post translational modifications necessary for such diversity in biological activity, concentrating particularly on how differences in oxidation of highly conserved redox-sensitive cysteine residues can potentiate inflammatory responses and dictate cellular fate. We will also review the most recent literature on HMGB1 and its involvement in the pathophysiology of sepsis and cancer, as well as cancer therapy-induced mucositis. PMID- 23797068 TI - Full functional activity of SSL7 requires binding of both complement C5 and IgA. AB - Staphylococcus aureus is an opportunistic bacterial pathogen responsible for a range of diseases, from local skin infections through to life-threatening illnesses such as toxic shock syndrome. S. aureus produces an assortment of molecules designed to evade or subvert the host immune system. One example is the 23 kDa staphylococcal superantigen-like protein 7 (SSL7) that simultaneously binds immunoglobulin A (IgA) and complement C5 to inhibit complement-mediated hemolytic and bactericidal activity. The avirulent bacterium Lactococcus lactis was engineered to express SSL7 so that its role in bacterial survival could be assessed without interference from other virulence factors. Expression of SSL7 by L. lactis led to significantly enhanced bacterial survival in whole human blood and prevented the membrane attack complex (C5b-9) forming on the cell wall. To further understand the mechanism of action of SSL7, the activity of wild-type SSL7 protein was compared with a panel of mutant proteins lacking the capacity to bind IgA, C5, or both IgA and C5. SSL7 potently inhibited in vitro chemotaxis of inflammatory myeloid cells in response to a pathogenic stimulus and when injected into mice, SSL7 blocked the migration of neutrophils into the peritoneum in response to an inoculum of heat-killed S. aureus. Mutagenesis of the C5-binding site on SSL7 abolished all inhibitory activity, while mutation of the IgA-binding site had only partial effects, indicating that while IgA binding enhances activity it is not essential. SSL7 is an important staphylococcal virulence factor with potent anti-inflammatory properties, which are mediated by targeting complement C5 and IgA. PMID- 23797069 TI - Tripartite immune cell co-operation in the Bacillus Calmette Guerin-induced activation of gammadelta T cells. AB - gammadelta T cells contribute to immunosurveillance of pathogenic infections and malignant transformations; however, mechanisms of activation have yet to be fully defined. In this study we demonstrate a novel mechanism by which human Vdelta2(+) gammadelta T cells are activated by the model pathogen Bacillus Calmette Guerin (BCG). We show in vitro that Vdelta2 cell cytokine production and cytotoxic activity in response to BCG are dependent on both dendritic cells (DCs) and memory CD4(+) alphabeta T cells (CD4 T cells). We found that Vdelta2 cells are indirectly activated by BCG in an interleukin (IL)-12p70-dependent manner, and that DC production of the IL-12p70 responsible for Vdelta2 cell activation requires Toll-like receptor 2/4 ligands from BCG and interferon (IFN)-gamma from memory CD4 T cells. Our data suggest that Vdelta2 cell responses to BCG are dependent on the activation of IFN-gamma-producing memory CD4 T cells, and provide novel insight into the complex interplay between cells of the innate and adaptive immune response. PMID- 23797070 TI - Skin-resident memory T cells keep herpes simplex virus at bay. PMID- 23797071 TI - Nutrition and disease: lessons learnt from Gallipoli. PMID- 23797072 TI - Meningococcal disease in New Zealand. PMID- 23797073 TI - A nutritional analysis of New Zealand military food rations at Gallipoli in 1915: likely contribution to scurvy and other nutrient deficiency disorders. AB - BACKGROUND: Amongst New Zealand soldiers in Gallipoli in 1915 there were reports of poor food quality and cases of scurvy. But no modern analysis of the military food rations has ever been conducted to better understand potential nutritional problems in this group. METHODS: We analysed the foods in the military rations for 1915 using food composition data on the closest equivalents for modern foods. We compared these results with other plausible diets and various optimised ones using linear programming. RESULTS: Historical accounts provide evidence for poor food quality supplied to these soldiers. The nutrient analysis suggested that the military rations were below modern requirements for vitamins A, C and E; potassium; selenium; and dietary fibre. If military planners had used modest amounts of the canned vegetables and fruit available in 1915, this would probably have eliminated four of these six deficits. The results from the uncertainty analyses for vitamin C (e.g., 95% uncertainty interval [UI]: 5.5 to 6.7 mg per day), was compatible with the range known to cause scurvy, but the UI for vitamin A intake was only partly in the range for causing night blindness. To indicate the gap with the ideal, an optimised diet (using foods available in 1915), could have achieved all nutrient requirements for under half the estimated purchase cost of the 1915 military rations. CONCLUSIONS: There is now both historical and analytic evidence that the military rations provided to these soldiers were nutritionally inadequate in vitamin C, and probably other nutrients such as vitamin A. These deficits are likely to have caused cases of scurvy and may have contributed to the high rates of other illnesses experienced at Gallipoli. Such problems could have been readily prevented by providing rations that included some canned fruit or vegetables (e.g., as manufactured by New Zealand at the time). PMID- 23797074 TI - The Northland emergency meningococcal C vaccination programme. AB - AIM: This paper describes an emergency meningococcal C vaccination programme implemented in Northland, New Zealand in 2011. The programme aimed to reduce the impact of a meningococcal group C outbreak on the Northland population, through vaccination of 85% of children and youth 12 months to <20 years with a meningococcal serogroup C conjugate vaccine. METHOD: The emergency vaccination programme targeted an estimated population of 44,000 children and youth. Vaccinations were promoted and delivered by Northland District Health Board Public Health Nursing Service, Primary Health Organisations, General Practice, and Maori provider services, at schools, general practice clinics, via community clinics and outreach home-based vaccination services. RESULTS: 32,410 children and youth were vaccinated. Overall coverage reached 73% (72% Maori, 75% non Maori). Coverage differed across age, ethnic groups, school decile and geographic location. Vaccination coverage was highest for children 5 to <13 years at 84% for Maori and 81% for non-Maori. Coverage was lowest for the 17 to <20 year age group at 46% for Maori and 63% for non-Maori. In the pre-school population, 67% of Maori and 76% of non-Maori children 12 months to <5 years received vaccination. The 13 to <17 year age group reached 71% coverage for Maori and 70% for non Maori. CONCLUSION: Equitable, high vaccination coverage is attainable in an emergency vaccination programme in New Zealand. However a range of service options, including community outreach, are necessary to reduce access barriers for some groups. The programme presented useful insights into what is possible with focussed attention to adapting services to meet diverse needs. PMID- 23797075 TI - Unanswered questions, the epidemiology of a community outbreak: meningococcal C disease in Northland, New Zealand, 2011. AB - AIM: We describe the epidemiology of a community outbreak of Meningococcal C disease in Northland in 2011, and national trends in serogroup C disease in New Zealand. METHODS: Notification data from EpiSurv for all meningococcal C cases were analysed for 2011 for Northland and for the period 2001-2011 nationally. RESULTS: In 2011, the rate of group C meningococcal disease for the population in the Whangarei district aged less than 20 years was 27.6 cases per 100,000 population (6 cases) compared with 17.6 cases per 100,000 population under 20 years (8 cases) in the Northland District Health Board (DHB). All except one case were under 20 years of age. The case fatality rate was 33%. Nationally the rate of meningococcal C disease has fluctuated over the last decade, with an increasing trend apparent since 2007. There has been a noticeable increase over the last 3 years of group C cases infected with the C:P1.5-1,10-8 strain (including all of the Northland cases). This strain has also been associated with a higher case fatality rate (16% in the period 2007-2011). CONCLUSION: Meningococcal C disease in New Zealand, although still less common than group B, is poorly understood. The relationships between carriage, invasive disease and community outbreaks deserve greater study. Active monitoring of surveillance data is warranted to ensure timely funded introduction of the highly effective meningococcal C conjugate vaccine on to the national immunisation schedule when appropriate, given increasing disease rates, the high case fatality rate and significant Maori non-Maori inequities in disease incidence. PMID- 23797076 TI - The epidemiology of acute rheumatic fever in Northland, 2002-2011. AB - AIM: An audit of rheumatic fever surveillance in Northland was carried out for the period 2002-2011. The aim of the audit was to establish the accuracy and completeness of surveillance of Acute Rheumatic Fever in Northland, and to provide a robust baseline for future comparison given current rheumatic fever prevention efforts. METHODS: Cases of acute rheumatic fever (2002-2011) were identified and evaluated through auditing Northland hospital discharges, the Northland Rheumatic Fever secondary penicillin prophylaxis register and the national EpiSurv database. Cases were included in the audit if they met diagnostic criteria according to the 2008 Heart Foundation guidelines. RESULTS: A total of 114 acute rheumatic fever cases met the audit criteria, an annualised incidence of 7.7/100,000 in Northland. 95% of all cases were Maori with a large disparity between Maori (24.8/100,000) and non-Maori (0.6/100,000). Acute rheumatic fever cases were strongly associated with living in high deprivation areas. This audit noted both under- and over-notification of acute rheumatic fever. CONCLUSION: Acute rheumatic fever rates in Northland Maori children aged 5 14 (78/100000) are similar to those seen in developing countries and nearly double the rates seen other New Zealand audits. The findings highlight the urgent need to address crowding, poverty and inequitable primary care access if rheumatic fever is to be eliminated. PMID- 23797077 TI - Nurse-led school-based clinics for skin infections and rheumatic fever prevention: results from a pilot study in South Auckland. AB - AIM: To assess the acceptability and feasibility of delivering targeted primary health care in a decile one primary school setting. METHOD: A pilot public health nurse (PHN)-led clinic was set up in a South Auckland primary school (roll approximately 400). The clinic was based on a previous sore throat clinic model with modifications aimed at improving programme feasibility and effectiveness. The timely identification and treatment of Group A Streptococcal (GAS) throat infections to prevent rheumatic fever (RF), and the prevention and treatment of four skin infections (cellulitis, impetigo, infected eczema and scabies) were the focus. The pilot ran for 15 weeks from April to July 2011. Evaluation included documentation review, key school and healthcare stakeholder interviews and parent questionnaires. RESULTS: The consent rate was 92.2%. Of a total 722 throat swabs taken from 337 students, 94 were GAS positive. Ninety-eight assessments of skin conditions were completed at which 76 had a skin infection diagnosed, the most common infection being impetigo (n=46). Thirty-one skin infections were diagnosed in the first week of the pilot. PHN workload was high with a total of 539 phone calls, 137 home visits and 51 school-based parent consultations. The approach was highly acceptable to the majority of key stakeholders. Extrapolating pilot costs results in an estimated annual cost of $510 per student for the programme. CONCLUSION: It is likely to be both acceptable and feasible to take this model of delivering targeted primary health care to school aged children and use it on a larger scale. The complexity of providing this type of service should not be underestimated and it is essential that robust processes are in place to ensure smooth, safe running of such a programme. Long-term outcome evaluation will be vital to assess programme effectiveness. PMID- 23797078 TI - Temperature management in haematology patients with febrile neutropenia: a practice survey. AB - AIM: To assess the attitudes of clinicians to temperature management in haematology patients with febrile neutropenia. METHOD: An online scenario-based survey was circulated to consultant members of the New Zealand branch of the Haematology Society of Australia and New Zealand, to haematology advanced trainees, and to nursing representatives at each haematology department in New Zealand. RESULTS: Eighty-eight responses were obtained, from 34 doctors and 54 nurses. Most respondents would advise a neutropenic patient to take paracetamol as needed for pain. Median temperature intervention threshold for an asymptomatic patient with febrile neutropenia was higher for doctors than for nurses (38.5 versus 38.0 degrees Celcius), despite considerable heterogeneity. Both groups indicated they would intervene at a median 38.0 degrees Celcius for a patient with rigors. Paracetamol was the preferred first-line cooling measure, with physical methods second-line, and pethidine third-line. All respondents favoured oral over intravenous or rectal paracetamol. Most believed a clinical trial of antipyretic treatment for febrile neutropenia was warranted, and indicated willingness to enrol their patients in such a study. CONCLUSION: This survey documents clinicians' preferred temperature intervention thresholds and methods for haematology patients with neutropenic fever, and shows considerable variation in practice. Most respondents supported a trial of antipyretic management in febrile neutropenia. PMID- 23797079 TI - The influenza pandemic of 1918-1919 in two remote island nations: Iceland and New Zealand. AB - AIM: Nations varied in their experience of, and response to, the 1918-19 influenza pandemic. Island communities can provide unique opportunities to study the epidemiology of infectious diseases. We aimed to compare the epidemiology and public health response to this pandemic in two remote island nations, on opposite sides of the globe: Iceland and New Zealand (NZ). METHOD: Historical accounts in both nations were reviewed, along with recent analysis of the pandemics impact and course. RESULTS: Marked similarities were noted in epidemic timing, failure of border control, shape of epidemic curves, and delayed use of public health interventions. However, amongst the exposed European populations, Iceland experienced a significantly higher mortality rate (830 vs 550 per 100,000) compared to NZ (rate ratio: 1.5, 95%CI: 1.4-1.6). There is evidence that some public health measures in specific areas of both nations resulted in lower mortality rates. In particular, Iceland's use of travel restrictions and ship quarantining, appeared to protect 36% of the population. CONCLUSION: The epidemiology of the 1918-19 influenza pandemic was fairly similar for the exposed European populations of Iceland and NZ. Nevertheless, major differences were the significantly higher overall mortality rate in Iceland and the success of Iceland's use of travel restrictions. PMID- 23797080 TI - Isolation of Mycobacterium thermoresistible from a mesh used in an incisional hernia repair. AB - We present a case of Mycobacterium thermoresistible infection from a hernia repair mesh, the first reported case of this infection in New Zealand. Mycobacterium thermoresistible infection is rare, with only seven recorded cases in the literature. The presence of this isolate has implications for antibiotic regime and treatment duration. In this report we detail the case particulars and a brief summary of the previously documented cases. PMID- 23797081 TI - Active tuberculosis (TB) with a negative interferon gamma release assay: failure of this test to rule out TB. AB - This report describes a patient with pulmonary tuberculosis in whom the interferon gamma release assay (IGRA) was negative at presentaion. It became positive following treatment. This illustrates that this test cannot be used to rule out tuberculosis, even in a low incidence country. PMID- 23797082 TI - A timely reminder--rheumatic fever. AB - Rheumatic fever is a disease diagnosed using the Jones criteria. The Jones criteria were designed using data from areas with a low prevalence of rheumatic fever. In New Zealand there is a high prevalence of rheumatic fever amongst Maori and Pacific peoples. A case is presented where a child of Samoan ethnicity is diagnosed and treated for rheumatic fever without fulfilling the Jones criteria. Evidence supporting the broadening of the diagnostic criteria in high prevalence areas is highlighted. PMID- 23797083 TI - Medical image. An unusual complication of a pyrexia. PMID- 23797084 TI - Lessons from the February 2011 Christchurch Earthquake for the training and preparation of Post Graduate Year 1 doctors. PMID- 23797085 TI - Decline in echocardiographic optimisation of cardiac resynchronisation therapy (CRT) devices at Christchurch Hospital. PMID- 23797086 TI - Whakatane Hospital Laboratory. PMID- 23797087 TI - Molecular epidemiology of human tuberculosis in New Zealand and potential insights for disease control. PMID- 23797089 TI - The novel somatostatin receptor 2/dopamine type 2 receptor chimeric compound BIM 23A758 decreases the viability of human GOT1 midgut carcinoid cells. AB - The majority of neuroendocrine tumors (NETs) of the gastroenteropancreatic system coexpress somatostatin receptors (SSTRs) and dopamine type 2 receptors (D2R), thus providing a rationale for the use of novel SSTR2/D2R chimeric compounds in NET disease. Here we investigate the antitumor potential of the SSTR2/D2R chimeric compounds BIM-23A760 and BIM-23A758 in comparison to the selective SSTR2 agonist BIM-23023 and the selective D2R agonist BIM-53097 on human NET cell lines of heterogeneous origin. While having only minor effects on human pancreatic and bronchus carcinoid cells (BON1 and NCI-H727), BIM-23A758 induced significant antitumor effects in human midgut carcinoid cells (GOT1). These effects involved apoptosis induction as well as inhibition of mitogen-activated protein kinase and Akt signaling. Consistent with their antitumor response to BIM-23A758, GOT1 cells showed relatively high expression levels of SSTR2 and D2R mRNA. In particular, GOT1 cells highly express the short transcript variant of D2R. In contrast to BIM 23A758, the SSTR2/D2R chimeric compound BIM-23A760 as well as the individual SSTR2 and D2R agonistic compounds BIM-23023 and BIM-53097 induced no or only minor antitumor responses in the examined NET cell lines. Taken together, our findings suggest that the novel SSTR2/D2R chimeric compound BIM-23A758 might be a promising substance for the treatment of NETs highly expressing SSTR2 and D2R. In particular, a sufficient expression of the short transcript variant of DR2 might play a pivotal role for effective treatment. PMID- 23797088 TI - Circadian clocks and neurodegenerative diseases: time to aggregate? AB - The major neurodegenerative diseases are characterised by a disabling loss of the daily pattern of sleep and wakefulness, which may be reflective of a compromise to the underlying circadian clock that times the sleep cycle. At a molecular level, the canonical property of neurodegenerative diseases is aberrant aggregation of otherwise soluble neuronal proteins. They can thus be viewed as disturbances of proteostasis, raising the question whether the two features - altered daily rhythms and molecular aggregation - are related. Recent discoveries have highlighted the fundamental contribution of circadian clocks to the correct ordering of daily cellular metabolic cycles, imposing on peripheral organs such as the liver a strict programme that alternates between anabolic and catabolic states. The discovery that circadian mechanisms are active in local brain regions suggests that they may impinge upon physiological and pathological elements that influence pro-neurodegenerative aggregation. This review explores how introducing the dimension of circadian time and the circadian clock might refine the analysis of aberrant aggregation, thus expanding our perspective on the cell biology common to neurodegenerative diseases. PMID- 23797090 TI - Dermoscopy of necrobiosis lipoidica and granuloma annulare. AB - BACKGROUND: Dermoscopy is traditionally used for the diagnosis of skin tumors, but it has also gained increasing interest as an adjunct in the clinical diagnosis of inflammatory skin diseases. OBJECTIVE: To evaluate the dermoscopic patterns of necrobiosis lipoidica (NL) and granuloma annulare (GA) and to compare these findings with other granulomatous skin disorders. METHODS: This is a retrospective analysis of patient data and clinical and dermoscopic images of histopathologically diagnosed cases of NL and GA. RESULTS: A total of 24 cases, including 12 cases of NL and 12 cases of GA, were evaluated. In all cases of NL, dermoscopy revealed evident, sharply focused, elongated and serpentine telangiectasias, which were typically located over a whitish, structureless background. In contrast, all cases of GA were dermoscopically typified by peripheral, structureless orange-reddish borders, which were associated in 5 cases with isolated, unfocussed small vessels. CONCLUSION: Our study suggests that NL and GA reveal different dermoscopic patterns, which may aid the correct diagnosis. In addition, the dermoscopic patterns of NL and GA appear to differ from other forms of granulomatous diseases. PMID- 23797092 TI - Shp1 regulates T cell homeostasis by limiting IL-4 signals. AB - The protein-tyrosine phosphatase Shp1 is expressed ubiquitously in hematopoietic cells and is generally viewed as a negative regulatory molecule. Mutations in Ptpn6, which encodes Shp1, result in widespread inflammation and premature death, known as the motheaten (me) phenotype. Previous studies identified Shp1 as a negative regulator of TCR signaling, but the severe systemic inflammation in me mice may have confounded our understanding of Shp1 function in T cell biology. To define the T cell-intrinsic role of Shp1, we characterized mice with a T cell specific Shp1 deletion (Shp1fl/fl CD4-cre). Surprisingly, thymocyte selection and peripheral TCR sensitivity were unaltered in the absence of Shp1. Instead, Shp1(fl/fl) CD4-cre mice had increased frequencies of memory phenotype T cells that expressed elevated levels of CD44. Activation of Shp1-deficient CD4+ T cells also resulted in skewing to the Th2 lineage and increased IL-4 production. After IL-4 stimulation of Shp1- deficient T cells, Stat 6 activation was sustained, leading to enhanced Th2 skewing. Accordingly, we observed elevated serum IgE in the steady state. Blocking or genetic deletion of IL-4 in the absence of Shp1 resulted in a marked reduction of the CD44hi population. Therefore, Shp1 is an essential negative regulator of IL-4 signaling in T lymphocytes. PMID- 23797093 TI - Tob1 plays a critical role in the activation of encephalitogenic T cells in CNS autoimmunity. AB - Reliable biomarkers corresponding to disease progression or therapeutic responsiveness in multiple sclerosis (MS) have not been yet identified. We previously reported that low expression of the antiproliferative gene TOB1 in CD4+ T cells of individuals presenting with an initial central nervous system (CNS) demyelinating event (a clinically isolated syndrome), correlated with high risk for progression to MS. We report that experimental autoimmune encephalomyelitis (EAE) in Tob1-/ - mice was associated with augmented CNS inflammation, increased infiltrating CD4+ and CD8+ T cell counts, and increased myelin-reactive Th1 and Th17 cells, with reduced numbers of regulatory T cells. Reconstitution of Rag1-/ -mice with Tob1-/- CD4+ T cells recapitulated the aggressive EAE phenotype observed in Tob1-/- mice. Furthermore, severe spontaneous EAE was observed when Tob1-/- mice were crossed to myelin oligodendrocyte glycoprotein-specific T cell receptor transgenic (2D2) mice. Collectively, our results reveal a critical role for Tob1 in adaptive T cell immune responses that drive development of EAE, thus providing support for the development of Tob1 as a biomarker for demyelinating disease activity. PMID- 23797094 TI - T cell-derived inducible nitric oxide synthase switches off Th17 cell differentiation. AB - RORgammat is necessary for the generation of TH17 cells but the molecular mechanisms for the regulation of TH17 cells are still not fully understood. We show that activation of CD4+ T cells results in the expression of inducible nitric oxide synthase (iNOS). iNOS-deficient mice displayed enhanced T(H)17 cell differentiation but without major effects on either T(H)1 or T(H)2 cell lineages, whereas endothelial NOS (eNOS) or neuronal NOS (nNOS) mutant mice showed comparable T(H)17 cell differentiation compared with wild-type control mice. The addition of N6-(1-iminoethyl)-l-lysine dihydrochloride (L-NIL), the iNOS inhibitor, significantly enhanced TH17 cell differentiation, and S-nitroso-N acetylpenicillamine (SNAP), the NO donor, dosedependently reduced the percentage of IL-17-producing CD4+ T cells. NO mediates nitration of tyrosine residues in RORgammat, leading to the suppression of RORgammat-induced IL-17 promoter activation, indicating that NO regulates IL-17 expression at the transcriptional level. Finally, studies of an experimental model of colitis showed that iNOS deficiency results in more severe inflammation with an enhanced T(H)17 phenotype. These results suggest that NO derived from iNOS in activated T cells plays a negative role in the regulation of T(H)17 cell differentiation and highlight the importance of intrinsic programs for the control of T(H)17 immune responses. PMID- 23797097 TI - Electrical impedance monitoring of photothermal porated mammalian cells. AB - To transfer large cargo into mammalian cells, we recently provided a new approach called a photothermal nanoblade. Micron-sized membrane pores generated by the nanoblade are surprisingly well repaired with little cell death, suggesting rapid membrane-resealing dynamics. Here, we report the resealing time of photothermal porated mammalian cell plasma membranes using an electrical impedance sensor. Cell membrane pores were generated by high-speed cavitation bubbles induced by laser pulsing of metallic microdisks on a pair of transparent indium tin oxide electrodes. Electrical responses from the sensor electrodes were obtained with a signal voltage of 500 mV and a frequency at 500 kHz. Real-time impedance measurements show that membrane resealing and impedance recovery take a surprisingly long 1 to 2 min after laser pulsing. A nonrecovering impedance shift is also detected for cells after high-energy laser pulsing. This impedance response is also confirmed by a separate experiment in which thin-film gold electrodes are used to trigger cavitation bubbles for opening transient membrane pores on cells cultured on electrodes. Overall, our study platform provides new insight for micron-sized membrane defect repair dynamics to maintain cell viability. PMID- 23797095 TI - Induction and stability of human Th17 cells require endogenous NOS2 and cGMP dependent NO signaling. AB - Nitric oxide (NO) is a ubiquitous mediator of inflammation and immunity, involved in the pathogenesis and control of infectious diseases, autoimmunity, and cancer. We observed that the expression of nitric oxide synthase-2 (NOS2/iNOS) positively correlates with Th17 responses in patients with ovarian cancer (OvCa). Although high concentrations of exogenous NO indiscriminately suppress the proliferation and differentiation of Th1, Th2, and Th17 cells, the physiological NO concentrations produced by patients' myeloid-derived suppressor cells (MDSCs) support the development of RORgammat(Rorc)+IL-23R+IL-17+ Th17 cells. Moreover, the development of Th17 cells from naive-, memory-, or tumor-infiltrating CD4+ T cells, driven by IL-1beta/IL-6/IL-23/NO-producing MDSCs or by recombinant cytokines (IL-1beta/IL-6/IL-23), is associated with the induction of endogenous NOS2 and NO production, and critically depends on NOS2 activity and the canonical cyclic guanosine monophosphate (cGMP)-cGMP-dependent protein kinase (cGK) pathway of NO signaling within CD4+ T cells. Inhibition of NOS2 or cGMP-cGK signaling abolishes the de novo induction of Th17 cells and selectively suppresses IL-17 production by established Th17 cells isolated from OvCa patients. Our data indicate that, apart from its previously recognized role as an effector mediator of Th17-associated inflammation, NO is also critically required for the induction and stability of human Th17 responses, providing new targets to manipulate Th17 responses in cancer, autoimmunity, and inflammatory diseases. PMID- 23797096 TI - Identification of beryllium-dependent peptides recognized by CD4+ T cells in chronic beryllium disease. AB - Chronic beryllium disease (CBD) is a granulomatous disorder characterized by an influx of beryllium (Be)-specific CD4+ T cells into the lung. The vast majority of these T cells recognize Be in an HLA-DP-restricted manner, and peptide is required for T cell recognition. However, the peptides that stimulate Be-specific T cells are unknown. Using positional scanning libraries and fibroblasts expressing HLA-DP2, the most prevalent HLA-DP molecule linked to disease, we identified mimotopes and endogenous self-peptides that bind to MHCII and Be, forming a complex recognized by pathogenic CD4+ T cells in CBD. These peptides possess aspartic and glutamic acid residues at p4 and p7, respectively, that surround the putative Be-binding site and cooperate with HLA-DP2 in Be coordination. Endogenous plexin A peptides and proteins, which share the core motif and are expressed in lung, also stimulate these TCRs. Be-loaded HLA-DP2 mimotope and HLA-DP2-plexin A4 tetramers detected high frequencies of CD4+ T cells specific for these ligands in all HLADP2+ CBD patients tested. Thus, our findings identify the first ligand for a CD4+ T cell involved in metal-induced hypersensitivity and suggest a unique role of these peptides in metal ion coordination and the generation of a common antigen specificity in CBD. PMID- 23797098 TI - Phenomenological study of ICU nurses' experiences caring for dying patients. AB - This existential phenomenological study explored caring for the dying based on the philosophical works of Merleau-Ponty. Fourteen critical care nurses were asked to describe lived experiences of caring for dying patients. An encompassing theme of Promises to Keep emerged, with five subthemes, including the following: (a) promise to be truthful: "Nurses are in the game of reality," (b) promise to provide comfort: "I'll make him comfortable," (c) promise to be an advocate: "Just one more day," (d) "Promise that couldn't be kept," and (e) "Promise to remain connected." The essence of intensive care nurses' lived experience of caring for dying patients is captured in the theme Promises to Keep. Nurses accept the reality of death and express strong commitment to making it as comfortable, peaceful, and dignified as possible, despite critical care unit environments that foster a "paradigm of curing" rather than a "paradigm of caring.". PMID- 23797099 TI - Motivational interviewing to reduce cardiovascular risk in African American and Latina women. AB - Cardiovascular disease (CVD) is the leading cause of death for women, and disproportionally so for African American and Latina women. CVD is largely preventable and many risks can be attributable to health behaviors, implementing and sustaining positive health behaviors is a challenge. Motivational interviewing is one promising intervention for initiating behavior change. The purpose of this review was to identify, synthesize, and critically analyze the existing literature on the use of motivational interviewing as a behavioral intervention to reduce CVD risk among African American and Latina women. Seven studies were identified that met inclusion criteria. Results of this review suggest that motivational interviewing has mixed results when used to reduce cardiovascular risk factors in African American and Latina women. More research using a standardized motivational interviewing approach is needed to definitively determine if it is an effective behavioral intervention to reduce CVD risk when used in populations of African American and Latina women. PMID- 23797100 TI - Strategies for a successful PhD program: words of wisdom from the WJNR Editorial Board. AB - Nursing doctoral programs prepare students for research-focused careers within academic settings. The purpose of this Editorial Board Special Article is to provide PhD students and advisors with suggestions for making the most of their doctoral experience. Editorial Board members provide their individual insights on the skills and attributes students must acquire during the course of their doctoral education in order to succeed. The authors provide practical tips and advice on how to excel in a PhD program, including how to select an advisor and a dissertation committee, the importance of attending conferences to increase visibility and develop a network of colleagues, presenting and publishing research while still a student, and balancing work and personal life. Students who take full advantage of the opportunities available to them during the course of their doctoral programs will graduate well prepared to take on the multiple responsibilities of research, teaching, and leadership. PMID- 23797101 TI - Do transactive memory and participative teamwork improve nurses' quality of work life? AB - Improvement in nurses' quality of work life (QWL) has become a major issue in health care organizations. We hypothesized that the level of transactive memory (defined as the way groups collectively encode, store, and retrieve knowledge) and participative teamwork (an organizational model of care based on vocational training, a specific service's care project, and regular interdisciplinary staffing) positively affect nurses' QWL. This cross-sectional study enrolled 84 ward-based psychiatric nurses. We assessed transactive memory, participative teamwork, perceived organizational justice, perceived organizational support, and QWL using psychometrically reliable and valid scales. Participative teamwork and transactive memory were positively associated with nurses' QWL. Perceived organizational support and organizational justice fully mediated the relationship between participative teamwork and QWL, but not between transactive memory and QWL. Improved transactive memory could directly improve nurses' QWL. Improved participative teamwork could improve nurses' QWL through better perceived organizational support and perceived organizational justice. PMID- 23797102 TI - Caenorhabditis elegans histone deacetylase hda-1 is required for morphogenesis of the vulva and LIN-12/Notch-mediated specification of uterine cell fates. AB - Chromatin modification genes play crucial roles in development and disease. In Caenorhabditis elegans, the class I histone deacetylase family member hda-1, a component of the nucleosome remodeling and deacetylation complex, has been shown to control cell proliferation. We recovered hda-1 in an RNA interference screen for genes involved in the morphogenesis of the egg-laying system. We found that hda-1 mutants have abnormal vulva morphology and vulval-uterine connections (i.e., no uterine-seam cell). We characterized the vulval defects by using cell fate-specific markers and found that hda-1 is necessary for the specification of all seven vulval cell types. The analysis of the vulval-uterine connection defect revealed that hda-1 is required for the differentiation of the gonadal anchor cell (AC), which in turn induces ventral uterine granddaughters to adopt pi fates, leading to the formation of the uterine-seam cell. Consistent with these results, hda-1 is expressed in the vulva and AC. A search for hda-1 target genes revealed that fos-1 (fos proto-oncogene family) acts downstream of hda-1 in vulval cells, whereas egl-43 (evi1 proto-oncogene family) and nhr-67 (tailless homolog, NHR family) mediate hda-1 function in the AC. Furthermore, we showed that AC expression of hda-1 plays a crucial role in the regulation of the lin 12/Notch ligand lag-2 to specify pi cell fates. These results demonstrate the pivotal role of hda-1 in the formation of the vulva and the vulval-uterine connection. Given that hda-1 homologs are conserved across the phyla, our findings are likely to provide a better understanding of HDAC1 function in development and disease. PMID- 23797103 TI - Evaluating adaptive divergence between migratory and nonmigratory ecotypes of a salmonid fish, Oncorhynchus mykiss. AB - Next-generation sequencing and the application of population genomic and association approaches have made it possible to detect selection and unravel the genetic basis to variable phenotypic traits. The use of these two approaches in parallel is especially attractive in nonmodel organisms that lack a sequenced and annotated genome, but only works well when population structure is not confounded with the phenotype of interest. Herein, we use population genomics in a nonmodel fish species, rainbow trout (Oncorhynchus mykiss), to better understand adaptive divergence between migratory and nonmigratory ecotypes and to further our understanding about the genetic basis of migration. Restriction site-associated DNA (RAD) tag sequencing was used to identify single-nucleotide polymorphisms (SNPs) in migrant and resident O. mykiss from two systems, one in Alaska and the other in Oregon. A total of 7920 and 6755 SNPs met filtering criteria in the Alaska and Oregon data sets, respectively. Population genetic tests determined that 1423 SNPs were candidates for selection when loci were compared between resident and migrant samples. Previous linkage mapping studies that used RAD DNA tag SNPs were available to determine the position of 1990 markers. Several significant SNPs are located in genome regions that contain quantitative trait loci for migratory-related traits, reinforcing the importance of these regions in the genetic basis of migration/residency. Annotation of genome regions linked to significant SNPs revealed genes involved in processes known to be important in migration (such as osmoregulatory function). This study adds to our growing knowledge on adaptive divergence between migratory and nonmigratory ecotypes of this species; across studies, this complex trait appears to be controlled by many loci of small effect, with some in common, but many loci not shared between populations studied. PMID- 23797104 TI - Variation in meiotic recombination frequencies between allelic transgenes inserted at different sites in the Drosophila melanogaster genome. AB - Meiotic crossovers are distributed nonrandomly across the genome. Classic studies in Drosophila suggest that the position of a gene along a chromosome arm can affect the outcome of the recombination process, with proximity to the centromere being associated with lower crossing over. To examine this phenomenon molecularly, we developed an assay that measures meiotic crossovers and noncrossover gene conversions between allelic transgenes inserted into different genomic positions. To facilitate collecting a large number of virgin females, we developed a useful genetic system that kills males and undesired classes of females. We found that the recombination frequency at a site in the middle of the X chromosome, where crossovers are normally frequent, was similar to the frequency at the centromere-proximal end of the euchromatin, where crossovers are normally infrequent. In contrast, we recovered no recombinants--crossovers or noncrossovers--at a site on chromosome 4 and at a site toward the distal end of the X chromosome. These results suggest that local sequence or chromatin features have a stronger impact on recombination rates in this transgene assay than position along the chromosome arm. PMID- 23797105 TI - Mutational analysis of Sse1 (Hsp110) suggests an integral role for this chaperone in yeast prion propagation in vivo. AB - The yeast Hsp110 chaperone Sse1 is a conserved protein that is a noncanonical member of the Hsp70 protein superfamily. Sse1 influences the cellular response to heat stress and has also been implicated in playing a role in the propagation of prions in yeast. Sse1 can seemingly exert its effects in vivo through direct or indirect actions by influencing the nucleotide exchange activity of canonical cytosolic Hsp70s. Using a genetic screen based on the inability to propagate the yeast [PSI(+)] prion, we have identified 13 new Sse1 mutants that are predicted to alter chaperone function through a variety of different mechanisms. Not only are these new Sse1 mutants altered in the ability to propagate and cure yeast prions but also to varying degrees in the ability to grow at elevated temperatures. The expression levels of chaperone proteins known to influence yeast prion propagation are unaltered in the Sse1 mutants, suggesting that the observed phenotypic effects are caused by direct functional alterations in these mutants. Mapping the location of the mutants onto the Sse1 crystal structure suggests that more than one functional alteration in Sse1 may result in changes in prion propagation and ability to function at elevated temperatures. All Sse1 mutants isolated provide essential functions in the cell under normal growth conditions, further demonstrating that essential chaperone functions in vivo can to some degree at least be detached from those related to propagation of prions. Our results suggest that Sse1 can influence prion propagation through a variety of different mechanisms. PMID- 23797106 TI - Evolutionarily stable attenuation by genome rearrangement in a virus. AB - Live, attenuated viruses provide many of the most effective vaccines. For the better part of a century, the standard method of attenuation has been viral growth in novel environments, whereby the virus adapts to the new environment but incurs a reduced ability to grow in the original host. The downsides of this approach were that it produced haphazard results, and even when it achieved sufficient attenuation for vaccine production, the attenuated virus was prone to evolve back to high virulence. Using bacteriophage T7, we apply a synthetic biology approach for creating attenuated genomes and specifically study their evolutionary stability. Three different genome rearrangements are used, and although some initial fitness recovery occurs, all exhibit greatly impaired abilities to recover wild-type fitness over a hundred or more generations. Different degrees of stable attenuation appear to be attainable by different rearrangements. Efforts to predict fitness recovery using the extensive background of T7 genetics and biochemistry were only sometimes successful. The use of genome rearrangement thus offers a practical mechanism of evolutionary stable viral attenuation, with some progress toward prediction. PMID- 23797107 TI - Inferring selection intensity and allele age from multilocus haplotype structure. AB - It is a challenging task to infer selection intensity and allele age from population genetic data. Here we present a method that can efficiently estimate selection intensity and allele age from the multilocus haplotype structure in the vicinity of a segregating mutant under positive selection. We use a structured coalescent approach to model the effect of directional selection on the gene genealogies of neutral markers linked to the selected mutant. The frequency trajectory of the selected allele follows the Wright-Fisher model. Given the position of the selected mutant, we propose a simplified multilocus haplotype model that can efficiently model the dynamics of the ancestral haplotypes under the joint influence of selection and recombination. This model approximates the ancestral genealogies of the sample, which reduces the number of states from an exponential function of the number of single-nucleotide polymorphism loci to a quadratic function. That allows parameter inference from data covering DNA regions as large as several hundred kilo-bases. Importance sampling algorithms are adopted to evaluate the probability of a sample by exploring the space of both allele frequency trajectories of the selected mutation and gene genealogies of the linked sites. We demonstrate by simulation that the method can accurately estimate selection intensity for moderate and strong positive selection. We apply the method to a data set of the G6PD gene in an African population and obtain an estimate of 0.0456 (95% confidence interval 0.0144-0.0769) for the selection intensity. The proposed method is novel in jointly modeling the multilocus haplotype pattern caused by recombination and mutation, allowing the analysis of haplotype data in recombining regions. Moreover, the method is applicable to data from populations under exponential growth and a variety of other demographic histories. PMID- 23797108 TI - Drosophila as a model for intractable epilepsy: gilgamesh suppresses seizures in para(bss1) heterozygote flies. AB - Intractable epilepsies, that is, seizure disorders that do not respond to currently available therapies, are difficult, often tragic, neurological disorders. Na(+) channelopathies have been implicated in some intractable epilepsies, including Dravet syndrome (Dravet 1978), but little progress has been forthcoming in therapeutics. Here we examine a Drosophila model for intractable epilepsy, the Na(+) channel gain-of-function mutant para(bss1) that resembles Dravet syndrome in some aspects (parker et al. 2011a). In particular, we identify second-site mutations that interact with para(bss1), seizure enhancers, and seizure suppressors. We describe one seizure-enhancer mutation named charlatan (chn). The chn gene normally encodes an Neuron-Restrictive Silencer Factor/RE1 Silencing Transcription factor transcriptional repressor of neuronal-specific genes. We identify a second-site seizure-suppressor mutation, gilgamesh (gish), that reduces the severity of several seizure-like phenotypes of para(bss1)/+ heterozygotes. The gish gene normally encodes the Drosophila ortholog of casein kinase CK1g3, a member of the CK1 family of serine-threonine kinases. We suggest that CK1g3 is an unexpected but promising new target for seizure therapeutics. PMID- 23797109 TI - Miniature short hairpin RNA screens to characterize antiproliferative drugs. AB - The application of new proteomics and genomics technologies support a view in which few drugs act solely by inhibiting a single cellular target. Indeed, drug activity is modulated by complex, often incompletely understood cellular mechanisms. Therefore, efforts to decipher mode of action through genetic perturbation such as RNAi typically yields "hits" that fall into several categories. Of particular interest to the present study, we aimed to characterize secondary activities of drugs on cells. Inhibiting a known target can result in clinically relevant synthetic phenotypes. In one scenario, drug perturbation could, for example, improperly activate a protein that normally inhibits a particular kinase. In other cases, additional, lower affinity targets can be inhibited as in the example of inhibition of c-Kit observed in Bcr-Abl-positive cells treated with Gleevec. Drug transport and metabolism also play an important role in the way any chemicals act within the cells. Finally, RNAi per se can also affect cell fitness by more general off-target effects, e.g., via the modulation of apoptosis or DNA damage repair. Regardless of the root cause of these unwanted effects, understanding the scope of a drug's activity and polypharmacology is essential for better understanding its mechanism(s) of action, and such information can guide development of improved therapies. We describe a rapid, cost-effective approach to characterize primary and secondary effects of small molecules by using small-scale libraries of virally integrated short hairpin RNAs. We demonstrate this principle using a "minipool" composed of shRNAs that target the genes encoding the reported protein targets of approved drugs. Among the 28 known reported drug-target pairs, we successfully identify 40% of the targets described in the literature and uncover several unanticipated drug-target interactions based on drug-induced synthetic lethality. We provide a detailed protocol for performing such screens and for analyzing the data. This cost effective approach to mammalian knockdown screens, combined with the increasing maturation of RNAi technology will expand the accessibility of similar approaches in academic settings. PMID- 23797110 TI - FijiWings: an open source toolkit for semiautomated morphometric analysis of insect wings. AB - Development requires coordination between cell proliferation and cell growth to pattern the proper size of tissues, organs, and whole organisms. The Drosophila wing has landmark features, such as the location of veins patterned by cell groups and trichome structures produced by individual cells, that are useful to examine the genetic contributions to both tissue and cell size. Wing size and trichome density have been measured manually, which is tedious and error prone, and although image processing and pattern-recognition software can quantify features in micrographs, this approach has not been applied to insect wings. Here we present FijiWings, a set of macros designed to perform semiautomated morphophometric analysis of a wing photomicrograph. FijiWings uses plug-ins installed in the Fiji version of ImageJ to detect and count trichomes and measure wing area either to calculate trichome density of a defined region selected by the user or generate a heat map of overall trichome densities. For high throughput screens we have developed a macro that directs a trainable segmentation plug-in to detect wing vein locations either to measure trichome density in specific intervein regions or produce a heat map of relative intervein areas. We use wing GAL4 drivers and UAS-regulated transgenes to confirm the ability of these tools to detect changes in overall tissue growth and individual cell size. FijiWings is freely available and will be of interest to a broad community of fly geneticists studying both the effect of gene function on wing patterning and the evolution of wing morphology. PMID- 23797111 TI - Design and implementation of an imprinted material for the extraction of the endocrine disruptor bisphenol A from milk. AB - This paper describes the determination of bisphenol A (BPA) in milk samples, using a novel molecularly imprinted polymer. The imprinted polymer was developed using a rational design approach, and pre-polymerization interactions were investigated using molecular dynamics simulations and X-ray crystallography. A hydroquinone-imprinted polymer was used for solid phase extraction (SPE) clean-up of samples. BPA was quantified by high performance liquid chromatography (HPLC) and fluorescence (FLD) detection. Following validation, the method described was capable of determining bisphenol A in milk down to a limit of detection of 1.32MUgkg(-1). The method was applied to a survey (n=27) of commercial milk products; BPA was detected in one of the samples, at a level of 176MUgkg(-1). Test results were confirmed by a parallel UHPLC-MS/MS analytical method. This demonstrates the utility of the hydroquinone-imprinted polymer for application to selective sample clean-up and analysis of bisphenol A in milk, avoiding possible detrimental affects associated with template bleeding and without the need for expensive or difficult-to-obtain template. PMID- 23797112 TI - Determination of leelamine in mouse plasma by LC-MS/MS and its pharmacokinetics. AB - Leelamine may be applicable to treat diabetes and is known to inhibit pyruvate dehydrogenase kinase 4. In this study, we developed and validated a quantification method using liquid chromatography (LC) coupled with tandem mass spectrometry analysis, which was applied to a pharmacokinetic investigation in mouse plasma. Leelamine transition ions in multiple reaction-monitoring modes using positive ionization were observed at m/z 286.4 to m/z 173.2. LC was performed using an ACE 5 C18 column, and a mixture of acetonitrile and water containing 0.1% formic acid was used as the mobile phase at a flow rate of 0.22mL/min. Leelamine and the internal standard (reserpine) had retention times of 4.1 and 3.9min, respectively. Acceptable linearity (r(2)=0.995) was observed over the concentration range of 10-3000ng/mL, with a lower limit of quantification of 10ng/mL in mouse plasma. The intra-day and inter-day accuracy and precision were less than 15%, which was sufficient for quality-control purposes. This method was used to determine leelamine concentrations in mouse plasma and showed that the oral bioavailability of leelamine was 7.6%. PMID- 23797113 TI - Ionic-liquid based dispersive liquid-liquid microextraction followed by high performance liquid chromatographic determination of anti-hypertensives in rat serum. AB - A novel, simple and eco-friendly ionic liquid based dispersive liquid-liquid microextraction followed by HPLC determination of anti-hypertensive drugs viz., eprosartan, valasartan, irbesartan, losartan and telmisartan in rat serum has been developed and validated. Experimental parameters influencing the extraction efficiency, nature and volume of the ionic liquid, dispenser solvent, extraction time and effect of salt were optimized. Under the optimum conditions, the extraction recoveries were between 92.85 and 98.50%. The relative standard deviations of intra-and inter-day accuracy varied between 1.9 and 9.1% (n=3). The linearity of the proposed method was 0.1-20MUg/mL with coefficients of determination varying between 0.9979 and 0.9992. PMID- 23797114 TI - Single particle detection, manipulation and analysis with resonant optical trapping in photonic crystals. AB - We demonstrate a resonant optical trapping mechanism based on two-dimensional hollow photonic crystal cavities. This approach benefits simultaneously from the resonant nature and unprecedented field overlap with the trapped specimen. The photonic crystal structures are implemented in a 30 mm * 12 mm optofluidic chip consisting of a patterned silicon substrate and an ultrathin microfluidic membrane for particle injection and control. Firstly, we demonstrate permanent trapping of single 250 and 500 nm-sized particles with sub-mW powers. Secondly, the particle induces a large resonance shift of the cavity mode amounting up to several linewidths. This shift is exploited to detect the presence of a particle within the trap and to retrieve information on the trapped particle. The individual addressability of multiple cavities on a single photonic crystal device is also demonstrated. PMID- 23797115 TI - Interfaces and controversies in gastroenterology / Challenges of liver cirrhosis and tumors: prevent it, treat it, manage consequences. Preface. PMID- 23797116 TI - Eosinophilic esophagitis: a bulk of mysteries. AB - Eosinophilic esophagitis (EoE), which was first described in the early 1990s, has rapidly evolved as a distinctive chronic inflammatory esophageal disease. The diagnosis is based clinically on the presence of symptoms related to esophageal dysfunction and histologically by an eosinophil-predominant inflammation once other conditions leading to esophageal eosinophilia are excluded. This striking male-prevalent disease has an increasing incidence and prevalence in the Westernized countries. Currently, EoE represents the main cause of dysphagia and bolus impaction in adult patients. Despite the fact that EoE often occurs in atopic patients, the value of allergic testing is still under discussion. Topical corticosteroids lead to a rapid improvement of active EoE clinically and histologically; they are therefore regarded as first-line drug therapy. Elimination diets have similar efficacy as topical corticosteroids, but their long-term use is limited by practical issues. Esophageal dilation of EoE-induced strictures can also be effective in improving symptoms, but this therapy has no effect on the underlying inflammation. Neither the diagnostic nor the long-term therapeutic strategies have been fully defined. Currently, the list of unsolved issues--or mysteries--is still long and a concerted effort on behalf of clinicians and scientists is required to improve the understanding and the therapeutic management of this mysterious disease. PMID- 23797117 TI - Barrett's esophagus: the American perspective. AB - The American Gastroenterological Association (AGA) defines Barrett's esophagus as the condition in which any extent of metaplastic columnar epithelium that predisposes to cancer development replaces the squamous epithelium that normally lines the distal esophagus. Although cardiac mucosa may be metaplastic, its malignant predisposition is not clear, and the AGA still requires the demonstration of intestinal metaplasia (with goblet cells) for a diagnosis of Barrett's esophagus. The AGA generally recommends endoscopic eradication therapy for patients with high-grade dysplasia, who otherwise develop esophageal adenocarcinoma at the rate of 6% per year. Endoscopic therapy is often curative for mucosal neoplasms in Barrett's esophagus because the risk of lymph node metastases is only 1-2%. American gastroenterologists generally do not recommend endoscopic therapy for patients whose neoplasms involve any portion of the submucosa because of the high rate of lymph node metastases that has been described in these cases. The management of low-grade dysplasia is disputed because of poor agreement among pathologists on the diagnosis and because of contradictory data on the natural history, but the AGA recommends that radiofrequency ablation (RFA) should be a therapeutic option for patients with confirmed low-grade dysplasia in Barrett's esophagus. Arguments for using RFA to treat nondysplastic Barrett's metaplasia are based on the premise that RFA decreases cancer risk, but no study has established that premise. In the absence of definitive data, concerns about the frequency and importance of buried metaplastic glands and recurrent metaplasia should temper enthusiasm for treating nondysplastic Barrett's esophagus with RFA. PMID- 23797118 TI - Nonneoplastic and neoplastic Barrett's esophagus: the European perspective. AB - The cancer risk of nondysplastic Barrett's esophagus is very low (0.33-0.5 per year). Therefore, any endoscopic ablation technique is an overtreatment. Patients with low-grade intraepithelial neoplasia confirmed by a specialized GI pathologist seem to have a significant risk for developing high-grade intraepithelial neoplasia (HGIN) or cancer. Therefore, endoscopic treatment in this case seems to be justified. However, up to now there has been no prospective study supporting this. In recent years, endoscopic treatment of HGIN and mucosal Barrett's cancer has become a widely accepted treatment approach and even the therapy of choice in many countries. Endoscopic resection (ER) is the best validated treatment method in patients with HGIN and mucosal Barrett's cancer, and is widely used all over the world. In contrast to ablative treatment methods like argon plasma coagulation and radiofrequency ablation, ER allows histological assessment of the resected specimen in order to assess the depth of infiltration of the tumor. However, ER of the neoplastic lesions should always be followed by ablation of the nondysplastic remaining Barrett's esophagus in order to reduce the risk of recurrence or metachronous neoplasia. The long-time complete remission rate with this two-step strategy is >=95%. A matter of continuing debate is whether patients with Barrett's cancer infiltrating the upper third of the mucosal layer (pT1sm1) can be treated by ER. Data from our and other centers indicate that a subgroup of patients with pT1sm1 adenocarcinomas without the presence of risk factors (poor differentiation grade, lymph or blood vessel infiltration, size >20 mm, ulcerated lesion) have a very low risk for lymph node metastasis (<2%) and endoscopic therapy can be an alternative to radical surgery. PMID- 23797119 TI - Evolution in surgical management of esophageal cancer. AB - Esophageal resection remains the primary treatment for local regional esophageal cancer, although its role in superficial (T1A) cancers and squamous cell cancer is in evolution. Mortality associated with esophagectomy has historically been high but is improving with the current expectation of in-hospital mortality rates of 2-4% in high-volume centers. Most patients with regional cancers (T2-4 N0-3) are recommended for neoadjuvant therapy, which most commonly involves radiochemotherapy. Some centers have proposed treating with definitive chemoradiation and reserving surgery for patients who have persistent or recurrent disease. 'Salvage resections' are possible but are associated with higher levels of perioperative morbidity and mortality, and treatment decisions should routinely be based on multidisciplinary discussion in the tumor board. Although open surgical resection (both transthoracic and transhiatal operations) remain the most common approach, minimally invasive or hybrid operations are being done in up to 30% of procedures internationally. There are some indications that minimally invasive esophagectomy may decrease the incidence of respiratory complications and decrease length of stay. At this point, oncologic outcomes appear equivalent between open and minimally invasive procedures. Recent reviews from high-volume esophagectomy centers demonstrate that elderly patients can selectively undergo esophagectomy with the expectation of increased complications but similar mortality and survival to younger patients. Multiple studies confirm that quality of life following esophagectomy can be equivalent to the general population when surgery is done in experienced centers. Patients requiring surgical treatment of esophageal cancer should be referred to high-volume centers, especially those with established care pathways or enhanced recovery programs to improve outcomes including morbidity, mortality, survival, and quality of life. PMID- 23797120 TI - The role of radiotherapy in the multimodal management of esophageal cancer. AB - Despite recent improvements in surgery and radiotherapy, and refinements of systemic treatment options, including incorporation of targeted agents, long-term survival remains poor for patients with esophageal cancer. While surgical resection alone constitutes the standard approach for early-stage disease (stage I), multimodality therapy, including perioperative chemotherapy and neoadjuvant or definitive chemoradiotherapy (CRT), are internationally accepted treatment options for patients with locally advanced disease. In lower esophageal and esophagogastric junction adenocarcinomas, data from large, randomized phase III trials and meta-analyses support the use of both perioperative chemotherapy alone or neoadjuvant concurrent CRT. In patients with locally advanced squamous cell carcinoma (SCC) of the esophagus, neoadjuvant CRT but not neoadjuvant chemotherapy alone is the preferred treatment approach. Definitive CRT without surgery has also emerged as a useful option for the treatment of resectable SCC of the esophagus, avoiding potential surgical morbidity and mortality, with salvage surgery reserved for those with persistent disease. Functional imaging modalities, such as PET-CT, may create new opportunities for a more adequate therapy response assessment and patient selection. Patients with SCC that show clinical response by PET-CT are considered to have a more favorable outcome, regardless of whether surgery will be performed or not. In nonresponding patients, salvage surgery improves survival, especially if complete resection is achieved. Recent technological advances in radiotherapy, such as intensity modulated radiotherapy, image guided-radiotherapy and PET-CT-based radiotherapy planning, may further improve the therapeutic ratio of CRT. Moreover, the traditional backbone of CRT, platinum plus fluorouracil, may be supplanted by more modern and easier-to-administer regimens incorporating taxanes, irinotecan and targeted agents. PMID- 23797121 TI - MALT lymphoma: forget surgery? AB - Treatment of gastric marginal zone B cell lymphoma of MALT (mucosa-associated lymphoid tissue) is nowadays standardized as outlined in the German S3 guideline of 2009 and the European (EGILS) consensus report of 2011. The first choice of treatment is Helicobacter pylori eradication in any case irrespective of H. pylori status and lymphoma stage. Some 70-80% of patients reveal complete remission of MALT lymphoma following successful eradication of the bacterium. Those patients with histologically persisting lymphoma residuals are managed by a watch-and-wait strategy. Nonresponders to H. pylori eradication are referred to radiation with a curative intention in stages I and II. The rare cases of MALT lymphoma of stage III and IV should be treated by chemotherapy. Surgery no longer plays a role in the therapy of gastric MALT lymphoma except for very rare complications such as perforation or bleeding that cannot be controlled endoscopically. Diffuse large B cell lymphoma (DLBCL) is the second most common gastric lymphoma. H. pylori eradication may lead to regression of DLBCL in the individual case. However, immunochemotherapy by a combination of rituximab and the CHOP protocol represents the standard treatment approach in patients with DLBCL and offers a good curative chance. PMID- 23797122 TI - Conservative treatment of chronic pancreatitis. AB - BACKGROUND: Chronic pancreatitis is a progressive inflammatory disease giving rise to several complications that need to be treated accordingly. Because pancreatic surgery has significant morbidity and mortality, less invasive therapy seems to be an attractive option. AIM: This paper reviews current state-of-the art strategies to treat chronic pancreatitis without surgery and the current guidelines for the medical therapy of chronic pancreatitis. RESULTS: Endoscopic therapy of complications of chronic pancreatitis such as pain, main pancreatic duct strictures and stones as well as pseudocysts is technically feasible and safe. The long-term outcome, however, is inferior to definitive surgical procedures such as resection or drainage. On the other hand, the medical therapy of pancreatic endocrine and exocrine insufficiency is well established and evidence based. CONCLUSIONS: Endoscopic therapy may be an option to bridge for surgery and in children/young adolescents and those unfit for surgery. Pain in chronic pancreatitis as well as treatment of pancreatic exocrine insufficiency follows established guidelines. PMID- 23797123 TI - Pancreatic cancer: advances in treatment, results and limitations. AB - BACKGROUND/AIMS: Pancreatic cancer remains a therapeutic challenge. Surgery is the only treatment with the chance of cure. The aim of this review is to summarize the present state-of-the-art surgical procedures in pancreatic cancer. METHODS: The current literature was reviewed with regard to surgical approaches in pancreatic cancer. A focus was put on high-quality studies, reviews, systematic reviews and meta-analyses as well as recruiting studies highlighting innovative approaches. RESULTS: Today, standard resections can be performed with mortality rates below 5% in specialized high-volume institutions. Extended approaches for locally advanced cancer are technically feasible, including venous resections, multivisceral resections and recurrence surgery. They can be carried out without increased morbidity and mortality, are not compromised by higher R1 or N+ rates, and can improve survival. Arterial tumor invasion is still regarded controversially and is oncologically questionable. All surgical approaches should be part of interdisciplinary multimodal treatment concepts to improve the patients' prognosis. CONCLUSION: Surgery is the backbone of pancreatic cancer treatment in localized disease. Extended approaches are feasible in centers and show--except for arterial resections--good long-term outcome. Interdisciplinary therapy is an essential supplementation of all surgical approaches. PMID- 23797124 TI - Gluten-free diet in gluten-related disorders. AB - A gluten-free diet (GFD) is recommended for all patients with coeliac disease (CD). The spectrum of gluten-related disorders in the early 1980s was simple: CD and dermatitis herpetiformis. In the last few years, wheat allergy, gluten ataxia and noncoeliac gluten sensitivity have become new gluten-related topics. Adherence to GFDs in CD is limited and factors influencing adherence are poorly understood. Noncoeliac gluten sensitivity has stimulated the GFD food industry not only in Australia but all over the world. This article provides an overview of GFD in daily practice. PMID- 23797125 TI - Modern imaging techniques: which--when--why? AB - Within the last decade, the technological development improved the diagnostic work-up of small bowel diseases. In addition to abdominal ultrasound and radiological methods, the importance of endoscopy is increasing. Nowadays, five nonsurgical flexible endoscopy techniques are available for small bowel endoscopy: push enteroscopy and balloon-guided enteroscopy for evaluation of the proximal small bowel, balloon-assisted enteroscopy using two balloons (double balloon enteroscopy) or one balloon (single-balloon enteroscopy), and spiral enteroscopy for evaluation of the deep small bowel. Intraoperative enteroscopy has become a reserve method. PMID- 23797126 TI - Appendicitis/diverticulitis: diagnostics and conservative treatment. AB - Appendicitis and diverticulitis are very common entities that show some similarities in diagnosis and course of disease. Both are widely believed to be simple clinical diagnoses, which is in contrast to scientific evidence. An accurate diagnosis has to describe not only the initial detection, but particularly the severity of the disease. It is based mainly on cross-sectional imaging by ultrasound (US) and computed tomography (CT). Appendectomy is the standard treatment for acute appendicitis and is mandatory in complicated cases. Antibiotic therapy is similarly effective in uncomplicated appendicitis, but long term results are not sufficiently known. Treatment of diverticulitis is related to the disease status. Complications such as perforation and bleeding require intervention. Uncomplicated diverticulitis as graded by US or CT are subject to conservative management, in the form of outpatient or hospital care. It is an unresolved debate as to whether antibiotic treatment offers benefits. Mesalazine seems at least to improve pain. The real challenge is treatment of recurrent diverticulitis. Lifestyle measures such as nutritional habits and physical activity are found to influence diverticular disease. Besides immunosuppression, obesity is a significant risk factor for complicated diverticulitis. Whether any medication such as chronic antibiotics, probiotics or mesalazine offers benefits is unclear. The indication for sigmoid resection has changed; it is no longer given by the number of attacks, but rather by structural changes as depicted by cross-sectional imaging. PMID- 23797127 TI - Appendicitis/diverticulitis: minimally invasive surgery. AB - Complicated intra-abdominal infections such as acute appendicitis and complicated diverticulitis represent both diagnostic and therapeutic challenges. Both diseases, although different in many ways, are caused by the obstruction of a blind pouch leading to inflammation, abscesses, and perforation of surrounding tissues. For many decades, acute appendicitis was managed through a conventional surgical incision in the right iliac fossa. As for other diseases, there is a significant tendency to propose less invasive treatments. For many teams, laparoscopy, which leads to less postoperative pain, a shorter hospital stay, and a quicker recovery, represents the standard of care for appendectomy. For selected cases, a medical approach can be proposed with satisfactory outcomes. Additionally, the management of complicated diverticulitis is also quickly moving towards less invasive procedures than the deleterious '3-phase surgery', which is Hartmann's procedure, followed by reversal protected with a stoma, and finally stoma closure. Benefiting from the evolution of antimicrobial therapy and interventional radiology, many complicated cases classified as Hinchey stage I and Hinchey stage II complicated diverticulitis are now treated medically. CT images allow the identification of patients requiring radiological drainage of localized abscesses or collections over 5 cm in size. Patients with Hinchey stage III sigmoiditis may benefit from an initial laparoscopic exploration allowing, in some cases, a conservative nonresective approach that will prevent laparotomy and stoma. Major resection leading to temporary or definitive stoma is usually indicated for stage IV complications and is required only in exceptional cases. Although a surgical intervention can be the definitive treatment for complicated intra-abdominal infections, multidisciplinary management including radiology, medical treatment, and laparoscopic surgery may limit the severe consequences of an acute surgical approach in patients suffering from complicated appendicitis and diverticulitis. Today, the ultimate goal of acutely infected abdomen management is to reduce hospital stay, disability, and numerous operations for these patients. PMID- 23797128 TI - Top-down or step-up treatment in Crohn's disease? AB - In recent years, a change in the treatment goals for patients with Crohn's disease (CD) has come under intense discussion. Whereas 10 years ago treatment was initiated mainly in reaction to acute flares of the disease aimed to improve clinical symptoms, the focus now has changed to the prevention of damage to the intestinal wall. The prevention of structural damage by achievement of 'mucosal healing', however, is associated with the more 'aggressive' treatment and an earlier use of immunosuppressants and biologicals. The use of immunosuppressants and biologicals especially in patients with CD has decreased the rates of surgery and hospitalizations, indicating that there is a group of patients definitely profiting from such an early use of immunosuppressive treatment. In this group of patients, the benefits outweigh the disadvantages of immunosuppression: the increased risk of severe infections. However, it remains questionable whether this improvement can only be achieved by completely reversing established treatment strategies. The dispute has been condensed to the questions whether 'top-down' (e.g. start with a combination of biological and immunosuppressant and 'de-escalate' if possible) or 'step-up' treatment (e.g. start with topical steroids, step up to systemic steroid, go to immunosuppression and biologicals if necessary) may be better. In general, in an upcoming era of individualized and personalized medicine, a 'one-size-fits-all' approach does not appear to be desirable. CD patients definitely should not be undertreated (which is still frequently the case) or remain on steroid treatment (which is inappropriate); however, overtreatment (putting patients at risk of side effects without benefit) is against a fundamental principle of medicine: nihil nocere (do no harm). PMID- 23797129 TI - Ulcerative colitis: current and future treatment strategies. AB - Since the incidence of inflammatory bowel diseases including ulcerative colitis is continuously increasing worldwide, there is a strong need for effective treatment strategies. However, there is no therapy allowing for healing ulcerative colitis; consequently, the available medications will have to be applied at their best. The preferred option for mild pan- or left-sided colitis is still mesalazine. One can only emphasize that the formulations allowing for once daily dosing are not only equally effective, but even facilitate the implication of long-term therapy in daily life. In case steroids are frequently required to control disease, further immunosuppressive therapy should be introduced in order to minimize steroid exposure. Thiopurines represent the first choice immunosuppressive medication. In more severe cases, early escalation to combinatory therapies with anti-TNF antibodies should be considered with the possibility of therapy deescalation after induction of remission. Major difficulties arise with steroid-refractory acute flares. Here cyclosporine as well as anti-TNF strategies can be initiated. However, in case of severe disease, the high 1-year colectomy rate of about 50% should be considered. If short-term surgery is an option due to disease severity, cyclosporine might be advantageous since the half-life is short compared to infliximab or adalimumab. The central problem of all therapeutic approaches is that because we chase after the disease, solid markers that allow for prediction of the future disease course are desirable. In fact, the CD8+ transcriptome might fill this gap and will potentially lead to the classification of patients in low- and high-risk groups. PMID- 23797130 TI - The size of the problem: clinical algorithms. AB - Hepatocellular carcinoma (HCC) is a highly prevalent and lethal neoplasia. Current data show that it is the main cause of death in patients with cirrhosis. A better knowledge of the natural history of the tumor and the development of staging systems have led to a better prediction of prognosis and to a most appropriate treatment approach. The Barcelona Clinic Liver Cancer (BCLC) system has become the preferred staging system since it takes into account the characteristics of the tumor, the degree of liver impairment and the physical performance. In addition, it is the only one that links prognosis assessment with treatment recommendation. Curative therapies such as resection, transplantation and ablation can improve survival in patients diagnosed at an early HCC stage and may offer a long-term cure. Patients with intermediate-stage HCC benefit from chemoembolization and those diagnosed at an advanced stage benefit from sorafenib, an oral available, multikinase inhibitor with antiangiogenic and antiproliferative effects. Further efforts are needed to improve the survival of this lethal neoplasia. PMID- 23797131 TI - Systemic therapy and synergies by combination. AB - After years of therapeutic nihilism due to the inefficacy of conventional cytotoxic chemotherapy, the multikinase inhibitor sorafenib was the first agent to demonstrate a significant improvement in the survival of patients with advanced hepatocellular carcinoma (HCC). However, survival benefits on sorafenib treatment remain modest in clinical practice and developing more effective systemic therapies is challenging. No other targeted agent or regimen has proven efficacy to improve survival in a phase III trial in the first- or second-line setting, and no standard treatment option currently exists outside of clinical trials for patients with acquired resistance or intolerance to sorafenib. In contrast to other malignancies, no oncogene addiction has been identified in hepatocarcinogenesis thus far, which may explain why currently tested agents do not achieve sustained partial or complete response in the majority of patients. Several agents with mainly antiangiogenic properties are currently in phase II and III development, including brivanib, ramucirumab, everolimus, tivantinib and resminostat. In addition, the role of molecularly targeted therapy (MTT) in earlier stages of the disease in combination with transcatheter arterial chemoembolization or in the adjuvant setting after potentially curative approaches is under investigation. The identification of the key driver mutations and the assessment of relevant targets for specific subpopulations of patients according to their biomarker-based profile will hopefully lead to a more personalized medicine. This article attempts to provide a concise overview on recent developments of MTT in the phase II-III setting in advanced HCC with an additional focus on synergistic combinations and combined treatment approaches. PMID- 23797132 TI - Multimodal treatment strategies in patients undergoing surgery for hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the major health problems worldwide, and continues to grow because of its association with hepatitis B and C viruses. In patients with HCC, liver transplantation (LT) and liver resection are the only two curative treatment options. LT remains the best option since it not only removes the tumor, but also the underlying disease. The prerequisite for long term success of LT for HCC depends on the tumor load and strict selection criteria with regard to the size and number of existing HCC lesions. The need to obtain the optimal benefit from a limited number of grafts has prompted the implementation of well-defined selection criteria that identify patients with early HCC who may benefit from better long-term outcome after LT. Unfortunately, LT can only be proposed in approximately 30% of patients with HCC due to limitations in donor graft availability. In this particular setting, open and laparoscopic surgical resection represent reasonable treatment modalities in noncirrhotic HCC patients. The decision-making process for liver resection should integrate the tumor stage, quality and function of the underlying liver parenchyma, volume of the future liver remnant, and general condition of the patient. In patients with favorable features (solitary tumor, compensated Child Pugh A cirrhosis, no portal hypertension), the reported 5-year survival rates range between 50 and 70%. In specific cases, liver resection and LT may be combined in the same patient. PMID- 23797133 TI - Primary sclerosing cholangitis and cholangiocarcinoma: pathogenesis and modes of diagnostics. AB - Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease caused by progressive inflammation of the intra- and extrahepatic bile duct system. PSC patients have an increased risk to develop hepatobiliary as well as extrahepatic malignancies. The goal of a surveillance strategy for hepatobiliary malignancy in these patients is the detection of early cancer which will allow a potentially curative therapy. Here, we focus on a conceptual review of the pathogenesis of cholangiocellular carcinoma and gallbladder cancer and we will discuss a rational approach for the surveillance of these malignancies in PSC patients. PMID- 23797134 TI - Liver transplantation for perihilar cholangiocarcinoma. AB - Perihilar cholangiocarcinoma is a complex and devastating disease. Its complexity in part arises from the difficulty of establishing a diagnosis, especially in primary sclerosing cholangitis (PSC) patients. We have found fluorescent in situ hybridization (FISH) of cytologic specimens to be helpful in establishing a diagnosis of cholangiocarcinoma. In particular, FISH polysomy is useful in establishing a diagnosis of this malignancy. Endoscopic ultrasound with fine needle aspirates of regional lymph nodes has high utility in identifying patients who have advanced disease with lymph node metastases. Patients who are resectable by conventional surgical techniques are referred for surgery. However, patients who are not resectable or who have PSC and meet highly selective criteria become eligible for liver transplantation. The protocol employs external beam radiation therapy followed by brachytherapy, and then capecitabine until a staging laparotomy is performed. There is a high dropout rate while patients await liver transplantation of approximately 30% at 12 months, due to tumor progression. Overall, survival rates are approximately 65-70% at 5 years. The disease recurrence rate is 20%. Patients who have masses greater than 3 cm or who do not meet the criteria identified above have worse outcomes. These survival rates are better than those following surgical resection. Vascular complications occur frequently after liver transplantation. Portal venous anastomotic strictures are very common and can be managed by stent placement. In summary, neoadjuvant chemoradiation plus liver transplantation achieves excellent survival for patients with early-stage perihilar cholangiocarcinoma. PMID- 23797135 TI - Hepatobiliary malignancies: lessons from Asia. AB - With the higher incidences of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) in the East compared with the West, Asian centers have made significant contributions to the management of these malignancies. The major risk factor for HCC is hepatitis B infection in Asia in contrast to hepatitis C in Western populations. Barcelona Clinic for Liver Cancer (BCLC) staging that guides the treatment of patients with HCC in the West is considered too conservative by many Asian centers. In Asia, liver resection is widely offered to patients with multifocal, bilobar tumor or tumor invasion to the portal vein. The criteria for liver transplantation for HCC are also often more extended in Asian centers. Asian surgeons pioneered the development of living donor liver transplantation, which plays a major role in the management of early HCC associated with severe cirrhosis in Asia due to shortage of deceased donor graft. Asian centers have also made significant contributions to the modern management of CCA. A more aggressive surgical approach is generally adopted in Asia, including radical lymphadenectomy for intrahepatic CCA and simultaneous hepatic artery and portal vein resection with hepatectomy for hilar CCA. Eastern and Western centers should collaborate in further studies to establish the optimal treatment strategies for hepatobiliary malignancies. PMID- 23797136 TI - Direct effects of hepatitis B virus-encoded proteins and chronic infection in liver cancer development. AB - Hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer-related death worldwide with currently limited treatment options. Chronic hepatitis B virus (HBV) infection accounts for HCC development in more than 50% of cases. The lifetime risk of HBV carriers to develop cirrhosis, liver failure or HCC is estimated to be as high as 15-40%. Although several pathways and triggers contributing to HCC development have been described, many features of hepatocellular carcinogenesis and the attributed direct role of viral factors remain elusive. Host genetic factors, the geographic area and epidemiologic factors, as well as the direct risk related to chronic HBV and hepatitis C virus (HCV) infections, account for geographical and gender differences of HCC prevalence. There is growing evidence that hepatocarcinogenesis is a multistep process. Human HCC is typically preceded by chronic inflammation and apoptotic and nonapoptotic cell death with compensatory liver proliferation. However, we still lack a thorough understanding of the common underlying molecular mechanisms. High levels of HBV replication and chronicity of inflammation are known to independently increase the risk for HCC. A direct carcinogenic role of viral factors is very likely to contribute to liver cancer since HCC is known to also occur in noncirrhotic livers of individuals with an inactive chronic or even with occult HBV infection with no significant histological signs of inflammation or cytopathic effects. Furthermore, synergistic or independent viral risk factors for primary liver cancer development have been described, such as HBV genotype, integration of viral DNA into the host genome and direct effects of viral proteins. A broader understanding of these viral factors in hepatocarcinogenesis might give rise to new diagnostic and therapeutic means in the future. We review the current state of research in liver cancer development and focus on the role of direct viral factors in HBV infection. PMID- 23797137 TI - Cholestatic liver disease. AB - Cholestasis develops as a consequence of impaired bile formation and/or bile flow and can be classified as intra- or extrahepatic. Chronic cholestatic diseases are mostly intrahepatic with the exception of primary and secondary sclerosing cholangitis affecting intra- and extrahepatic bile ducts. Recent genome-wide association studies have confirmed major histocompatibility complex associations and discovered multiple susceptibility loci in primary biliary cirrhosis and primary sclerosing cholangitis, providing new insights into disease pathogenesis, which may translate into more precise therapeutic prevention and intervention in the future. Diagnostic steps in cholestatic conditions comprise a thorough patient history, abdominal imaging and distinct serological studies including antimitochondrial antibodies and IgG4 levels; if the diagnosis remains unclear, liver biopsy is warranted. Genetic testing should also be considered, as mutations in the hepatobiliary transporters ATP8B1, ABCB11 and ABCB4 are causative for three different forms of familial intrahepatic cholestasis. Disease severity is dependent on the genotypic variants of these transporters, ranging from mildly elevated liver enzymes in adults to cirrhosis in early childhood. Ligands of nuclear receptors, which represent important regulators of hepatobiliary transporters, and modified bile salts are new promising therapeutic options in cholestatic liver disease and are currently being investigated in clinical trials. PMID- 23797138 TI - Autoimmune hepatitis. AB - Autoimmune hepatitis (AIH) was the first chronic liver disease in which remission was achieved by immunosuppression. Prognosis is poor when left untreated. Since the original description in 1950 by Waldenstrom, the initially reported treatment option has remained until today and is the core of the basic therapeutic strategy of inducing remission with steroids and azathioprine. Immunosuppression as a treatment concept spans different situations including the induction and maintenance of remission, treatment of nonresponders, avoidance of side effects, perioperative treatment of liver transplantation candidates and the issue of withdrawal. Alternative immunosuppressive drugs such as transplantation immunosuppressants have been administered and reported in small series. In an attempt to optimize side effect management, a recent large multicenter prospective treatment trial suggests that budesonide may offer an alternative for noncirrhotic AIH patients with lower steroid side effects. With an early diagnosis and effective therapy, only 4% of transplant candidates are transplanted for AIH. After liver transplantation there is a considerable risk for graft loss because of recurrent AIH, and lifelong vigilance and therapeutic attention is important. PMID- 23797139 TI - Liver transplantation: an appraisal of the present situation. AB - Liver transplantation (LT) is an established approach to treatment of end-stage liver diseases, metabolic diseases and early hepatocellular carcinoma, and the results of this procedure have improved considerably. MELD allocation and the great number of transplant centers had a negative influence on outcome in Germany. Typical surgical issues following transplantation are vascular thrombosis and the development of biliary lesions. Nonanastomotic strictures impact graft survival and cause considerable posttransplant morbidity. Nonsurgical issues in LT are hepatitis C reinfection, selection of appropriate patients with hepatocellular carcinoma and individualized immunosuppression. In hepatitis C the new antiviral drugs (protease and polymerase inhibitors) are promising tools to prevent reinfection. Nephrotoxicity caused by calcineurin inhibitors - which remain the mainstay of immunosuppression - can only partially be avoided. So far, alternative forms of treatment using mycophenolic acid and mTOR inhibitors cannot totally replace calcineurin inhibitors. In view of graft scarcity, we need to think about a benefit-based model of liver allocation which focuses on the optimal use of this resource. Deciding on this form of organ allocation requires an ethical consensus: not the most urgent patient is the first candidate to receive a graft, but rather the patient who is supposed to have the greatest benefit. PMID- 23797140 TI - Familial amyloid polyneuropathy. AB - Familial amyloid polyneuropathy (FAP; also known as familiar amyloidosis and hereditary amyloidosis) is an autosomal dominant inherited disease due to mutations of the transthyretin (TTR) gene coding for the corresponding protein, consisting of 127 amino acids. The gene is located on chromosome 18q. More than 100 different mutations are known. Other mutant precursor proteins produced in the liver, such as apolipoprotein I and II, lysozyme and fibrinogen Aalpha, may be of etiological importance as well. Amyloidogenic mutations of the TTR gene lead to decreased stability of the corresponding protein and subsequently to extracellular deposition of amyloid in several tissues (peripheral and autonomic nerves, walls of the gastrointestinal tract, heart, etc.). The Val30Met mutation is the most prevalent cause of FAP worldwide. There are endemic regions in Portugal, Sweden and Japan. The onset of symptoms is usually between 25 and 35 years of age, but late-onset families are also known. The most common clinical symptoms are polyneuropathy of the lower limbs, rhythmological disturbances and diarrhea/obstipation. TTR amyloid is predominantly produced in the liver; only as few as 5% are synthesized in the retina and choroid plexus. Therefore, liver transplantation has become widely accepted as the ultimate curative treatment of this disease in order to prevent the ultimately fatal outcome and ameliorate disabling symptoms. Because of shortage of donor grafts, livers of FAP patients are used for domino liver transplantation. Last year, a new therapeutic option was approved by the European Medical Authority (EMA) for therapy of early-stage FAP. The first results of a multicenter-controlled trial have been published and show a benefit in patients with an early stage of disease regarding neurological symptoms as well as modified BMI. There are several other pharmacologic approaches that have been reported in the last years which may lead to stabilization of the TTR tetramer. Therefore, this might be the beginning of new therapeutic options with pharmacological therapies in patients with FAP. PMID- 23797143 TI - Molecular typing of the local HIV-1 epidemic in Serbia. AB - Worldwide HIV-1 pandemic is becoming increasingly complex, with growing heterogeneity of subtypes and recombinant viruses. Previous studies have documented HIV-1 subtype B as the predominant one in Serbia, with limited presence and genetic diversity of non B subtypes. In recent years, MSM transmission has become the most frequently reported risk for HIV infection among newly diagnosed patients in Serbia, but very little is known of the network structure and dynamics of viral transmission in this and other risk groups. To gain insight about the HIV-1 subtypes distribution pattern as well as characteristics of HIV-1 transmission clusters in Serbia, we analyzed the genetic diversity of the pol gene segment in 221 HIV-1-infected patients sampled during 2002-2011. Subtype B was found to still be the most prevalent one in Serbia, accounting for over 90% of samples, while greater diversity of other subtypes was found than previously reported, including subtypes G, C, A, F, CRF01 and CRF02. In total, 41.3% of analyzed subtype B sequences were found associated in transmission clusters/network, that are highly related with MSM transmission route. PMID- 23797145 TI - Visual information constrains early and late stages of spoken-word recognition in sentence context. AB - Audiovisual speech perception has been frequently studied considering phoneme, syllable and word processing levels. Here, we examined the constraints that visual speech information might exert during the recognition of words embedded in a natural sentence context. We recorded event-related potentials (ERPs) to words that could be either strongly or weakly predictable on the basis of the prior semantic sentential context and, whose initial phoneme varied in the degree of visual saliency from lip movements. When the sentences were presented audio visually (Experiment 1), words weakly predicted from semantic context elicited a larger long-lasting N400, compared to strongly predictable words. This semantic effect interacted with the degree of visual saliency over a late part of the N400. When comparing audio-visual versus auditory alone presentation (Experiment 2), the typical amplitude-reduction effect over the auditory-evoked N100 response was observed in the audiovisual modality. Interestingly, a specific benefit of high- versus low-visual saliency constraints occurred over the early N100 response and at the late N400 time window, confirming the result of Experiment 1. Taken together, our results indicate that the saliency of visual speech can exert an influence over both auditory processing and word recognition at relatively late stages, and thus suggest strong interactivity between audio-visual integration and other (arguably higher) stages of information processing during natural speech comprehension. PMID- 23797144 TI - Visceral fat is associated with lower executive functioning in adolescents. AB - BACKGROUND: Obesity, a major risk factor for cardiometabolic disease, is associated with lower cognitive performance from childhood to senescence, especially on tasks of executive function. In the cardiovascular domain, fat stored viscerally rather than elsewhere in the body carries particularly high risk. It is unknown whether this is also true in case of obesity-cognition relationships. The aim of this study was to assess the cross-sectional relationship between visceral fat (VF) and cognitive performance in a community sample of healthy adolescents. METHODS: In a community-based sample of 983 adolescents (12-18 years old, 480 males), VF was quantified using magnetic resonance imaging, total body fat was measured using a multifrequency bioimpedance, and cognitive performance was assessed using a battery of cognitive tests measuring executive function and memory. RESULTS: We found that larger volumes of VF were associated with lower performance on six measures of executive function (P=0.0001-0.02). We also found that the association of VF with executive function was moderated by sex for a subset of measures, such that relationship was present mainly in female subjects and not in male subjects (sex-by-VF interaction: P=0.001-0.04). These relationships were independent of the quantity of total body fat and a number of potential confounders, including age, puberty stage and household income. CONCLUSIONS: Our results suggest that the adverse association between obesity and executive function may be attributed to fat stored viscerally and not to fat stored elsewhere in the body. They also suggest that female subjects compared with male subjects may be more sensitive to the potentially detrimental effects of VF on cognition. PMID- 23797146 TI - EEG coherence during mental rotation of letters, hands and scenes. AB - The purpose of the present study was to investigate differences in the electrocortical synchronization pattern during mental rotation of three different object categories as well as six different rotation angles. Therefore, event related coherence of the electroencephalographic (EEG) activity between selective frontal and parietal electrode pairs of ten subjects was measured during the performance of a mental rotation task consisting of rotation of letters, hands and scenes. Statistical analysis showed an increased coherence of frontal and parietal electrode pairs for the condition LETTER in comparison to the other conditions in the alpha1- (8.5-10 Hz) and alpha2-band (10, 5-12 Hz) supporting the notion of different mental rotation mechanisms for externally and internally represented objects. Additionally decreased coherence of the frontal and parietal electrode pairs was found for the rotation angles 30 degrees to 150 degrees in comparison to the 0 degrees and 180 degrees rotations for the alpha1- and alpha2-band as well as the gamma frequency band (30-45 Hz). It is assumed that this decrease of synchronization reflects the mental rotation process implying that the mental rotation process of 180 degrees differs from the rotation process of all other rotation angles. PMID- 23797147 TI - Sleep deprivation and neurobehavioral functioning in children. AB - Sleep deprivation can result in significant impairments in daytime neurobehavioral functioning in children. Neural substrates impacted by sleep deprivation include the prefrontal cortex, basal ganglia and amygdala and result in difficulties with executive functioning, reward anticipation and emotional reactivity respectively. In everyday life, such difficulties contribute to academic struggles, challenging behaviors and public health concerns of substance abuse and suicidality. In this article, we aim to review 1) core neural structures impacted by sleep deprivation; 2) neurobehavioral problems associated with sleep deprivation; 3) specific mechanisms that may explain the relationship between sleep disturbances and neurobehavioral dysfunction; and 4) sleep problems reported in common neurodevelopmental disorders including attention deficit hyperactivity disorder (ADHD) and autistic spectrum disorders (ASDs). PMID- 23797148 TI - How do taxonomic versus thematic relations impact similarity and difference judgments? An ERP study. AB - Taxonomically related concepts like "bee" and "butterfly" and thematically related concepts like "bee" and "honey" have different roles in similarity judgments. We examined the complex impact of taxonomic and thematic relations on similarity and difference judgments via ERPs in a S1-S2 paradigm. Subjects were required to remember a word denoting some object or animal (S1), and compare that to a second word (S2) that was either thematically related, taxonomically related or unrelated to S1, making a "high" or "low" similarity and difference judgments in separate blocks. We found two main differences that suggest thematic and taxonomic relations engage distinct neural processes. The first difference is an N400 effect peaking between 300 ms and 400 ms that is more negative for unrelated words than for thematically and taxonomically related words. The second difference is a frontally distributed P600 peaking between 500 ms and 600 ms that is larger for taxonomically related words than for both unrelated and thematically related words. These results suggest that the dual process model for perceiving similarity is superior to the comparison only model of similarity judgments, and furthermore, provide evidence that the thematic relations are dissociative from taxonomic relations in making similarity and difference judgments. PMID- 23797149 TI - The relationship between mental and physical health: insights from the study of heart rate variability. AB - Here we review our recent body of work on the impact of mood and comorbid anxiety disorders, alcohol dependence, and their treatments on heart rate variability (HRV), a psychophysiological marker of mental and physical wellbeing. We have shown that otherwise healthy, unmedicated patients with these disorders display reduced resting-state HRV, and that pharmacological treatments do not ameliorate these reductions. Other studies highlight that tricyclic medications and the serotonin and noradrenaline reuptake inhibitors in particular may have adverse cardiovascular consequences. Reduced HRV has important functional significance for motivation to engage social situations, social approach behaviours, self regulation and psychological flexibility in the face of stressors. Over the longer-term, reduced HRV leads to immune dysfunction and inflammation, cardiovascular disease and mortality, attributable to the downstream effects of a poorly functioning cholinergic anti-inflammatory reflex. We place our research in the context of the broader literature base and propose a working model for the effects of mood disorders, comorbid conditions, and their treatments to help guide future research activities. Further research is urgently needed on the long term effects of autonomic dysregulation in otherwise healthy psychiatric patients, and appropriate interventions to halt the progression of a host of conditions associated with morbidity and mortality. PMID- 23797150 TI - Mindfulness meditation, well-being, and heart rate variability: a preliminary investigation into the impact of intensive Vipassana meditation. AB - Mindfulness meditation has beneficial effects on brain and body, yet the impact of Vipassana, a type of mindfulness meditation, on heart rate variability (HRV) - a psychophysiological marker of mental and physical health - is unknown. We hypothesised increases in measures of well-being and HRV, and decreases in ill being after training in Vipassana compared to before (time effects), during the meditation task compared to resting baseline (task effects), and a time by task interaction with more pronounced differences between tasks after Vipassana training. HRV (5-minute resting baseline vs. 5-minute meditation) was collected from 36 participants before and after they completed a 10-day intensive Vipassana retreat. Changes in three frequency-domain measures of HRV were analysed using 2 (Time; pre- vs. post-Vipassana)* 2 (Task; resting baseline vs. meditation) within subjects ANOVA. These measures were: normalised high-frequency power (HF n.u.), a widely used biomarker of parasympathetic activity; log-transformed high frequency power (ln HF), a measure of RSA and required to interpret normalised HF; and Traube-Hering-Mayer waves (THM), a component of the low frequency spectrum linked to baroreflex outflow. As expected, participants showed significantly increased well-being, and decreased ill-being. ln HF increased overall during meditation compared to resting baseline, while there was a time*task interaction for THM. Further testing revealed that pre-Vipassana only ln HF increased during meditation (vs. resting baseline), consistent with a change in respiration. Post Vipassana, the meditation task increased HF n.u. and decreased THM compared to resting baseline, suggesting post-Vipassana task-related changes are characterised by a decrease in absolute LF power, not parasympathetic-mediated increases in HF power. Such baroreflex changes are classically associated with attentional load, and our results are interpreted in light of the concept of 'flow' - a state of positive and full immersion in an activity. These results are also consistent with changes in normalised HRV reported in other meditation studies. PMID- 23797151 TI - Rechallenge with mTOR inhibitors in metastatic renal cell carcinoma patients who progressed on previous mTOR inhibitor therapy. AB - OBJECTIVE: To determine if mammalian target of rapamycin (mTOR) inhibitor (everolimus or temsirolimus) rechallenge in the third- or fourth-line setting after sequential use of a vascular endothelial growth factor receptor (VEGF) targeted agent and an mTOR inhibitor is a feasible and effective treatment strategy in patients with metastatic renal cell carcinoma (mRCC). METHODS: Patients who received a VEGF-targeted agent, an mTOR inhibitor and rechallenge with a second mTOR inhibitor at 2 institutions (Hopital Europeen Georges-Pompidou and Vienna Medical School) between 30 March 2001 and 15 September 2011 were included. Analyses of radiographic images were performed according to the Response Evaluation Criteria in Solid Tumors, version 1.0, to determine the objective response rate and treatment duration (TD). RESULTS: Twelve patients met the inclusion criteria. Following 1 or 2 VEGF receptor-tyrosine kinase inhibitors, 7 patients firstly received everolimus and 5 patients received temsirolimus. Irrespective of treatment sequence, 6 of 12 patients (50%) responded to everolimus and 4 of 12 patients (33%) responded to temsirolimus; 3 patients (25%) did not respond to either. Median TDs (95% confidence interval) for everolimus -> temsirolimus and temsirolimus -> everolimus sequences were 10.3 months (8.8-19.2 months) and 5.8 months (2.9-19.3 months), respectively. CONCLUSIONS: Despite the limited number of patients, this highlights the feasibility of utilizing mTOR rechallenge as an integral part of sequential treatment strategies in mRCC. PMID- 23797152 TI - Oligodendrocyte differentiation and signaling after transferrin internalization: a mechanism of action. AB - Oligodendrocytes are the cells producing the myelin membrane around the axons in the central nervous system and, although apotransferrin (aTf) is required for oligodendrocyte differentiation, the underlying mechanisms are not fully understood. Fyn tyrosine kinase, a member of the Src family of proteins, has been shown to play an important role in myelination by up-regulating the expression of myelin basic protein; however, a molecular link between aTf and Fyn kinase signaling pathway during oligodendrocytes differentiation has not been established yet. Our aim was to investigate whether Fyn kinase, MEK/ERK and PI3K/Akt signaling pathways are required for aTf-stimulation of oligodendrocyte differentiation and also to determine if the transferrin receptor is involved in these mechanisms. Treatment of primary cultures of oligodendroglial precursor cells with aTf leads to Fyn kinase activation by a mechanism that involves transferrin receptor. In turn, Fyn kinase activation promotes MEK-mediated transient phosphorylation of ERK1/2. On the other hand, transferrin receptor internalization also produces rapid and sustained activation of Akt, which involves phosphatidylinositol 3-kinase (PI3K) activation. Finally, aTf incorporated through clathrin-mediated endocytosis increases myelin basic protein, F3-contactin and beta-tubulin through Fyn/MEK/ERK pathways, as well as an activation of the PI3K/Akt pathway. Our results also demonstrate that the activation of the pathways necessary for oligodendroglial precursor cell maturation is dependent on AP2 recruitment onto the plasma membrane for clathrin mediated endocytosis of transferrin receptor. PMID- 23797155 TI - Expanded hepatitis C virus screening recommendations promote opportunities for care and cure. PMID- 23797154 TI - A mouse model of the slow channel myasthenic syndrome: Neuromuscular physiology and effects of ephedrine treatment. AB - In the slow channel congenital myasthenic syndrome mutations in genes encoding the muscle acetylcholine receptor give rise to prolonged ion channel activations. The resulting cation overload in the postsynaptic region leads to damage of synaptic structures, impaired neuromuscular transmission and fatigable muscle weakness. Previously we identified and characterised in detail the properties of the slow channel syndrome mutation epsilonL221F. Here, using this mutation, we generate a transgenic mouse model for the slow channel syndrome that expresses mutant human epsilon-subunits harbouring an EGFP tag within the M3-M4 cytoplasmic region, driven by a ~1500 bp region of the CHRNB promoter. Fluorescent mutant acetylcholine receptors are assembled, cluster at the motor endplates and give rise to a disease model that mirrors the human condition. Mice demonstrate mild fatigable muscle weakness, prolonged endplate and miniature endplate potentials, and variable degeneration of the postsynaptic membrane. We use our model to investigate ephedrine as a potential treatment. Mice were assessed before and after six weeks on oral ephedrine (serum ephedrine concentration 89 +/- 3 ng/ml) using an inverted screen test and in vivo electromyography. Treated mice demonstrated modest benefit for screen hang time, and in measures of compound muscle action potentials and mean jitter that did not reach statistical significance. Ephedrine and salbutamol show clear benefit when used in the treatment of DOK7 or COLQ congenital myasthenic syndromes. Our results highlight only a modest potential benefit of these beta2-adrenergic receptor agonists for the treatment of the slow channel syndrome. PMID- 23797153 TI - Paxillin phosphorylation counteracts proteoglycan-mediated inhibition of axon regeneration. AB - In the adult central nervous system, the tips of axons severed by injury are commonly transformed into dystrophic endballs and cease migration upon encountering a rising concentration gradient of inhibitory proteoglycans. However, intracellular signaling networks mediating endball migration failure remain largely unknown. Here we show that manipulation of protein kinase A (PKA) or its downstream adhesion component paxillin can reactivate the locomotive machinery of endballs in vitro and facilitate axon growth after injury in vivo. In dissociated cultures of adult rat dorsal root ganglion neurons, PKA is activated in endballs formed on gradients of the inhibitory proteoglycan aggrecan, and pharmacological inhibition of PKA promotes axon growth on aggrecan gradients most likely through phosphorylation of paxillin at serine 301. Remarkably, pre-formed endballs on aggrecan gradients resume forward migration in response to PKA inhibition. This resumption of endball migration is associated with increased turnover of adhesive point contacts dependent upon paxillin phosphorylation. Furthermore, expression of phosphomimetic paxillin overcomes aggrecan-mediated growth arrest of endballs, and facilitates axon growth after optic nerve crush in vivo. These results point to the importance of adhesion dynamics in restoring endball migration and suggest a potential therapeutic target for axon tract repair. PMID- 23797156 TI - Secreted calmodulin-like skin protein ameliorates scopolamine-induced memory impairment. AB - Humanin, a short bioactive peptide, inhibits cell death in a variety of cell based death models through Humanin receptors in vitro. In vivo, Humanin ameliorates both muscarinic receptor antagonist-induced memory impairment in normal mice and memory impairment in Alzheimer's disease (AD)-relevant mouse models including aged transgenic mice expressing a familial AD-linked gene. Recently, calmodulin-like skin protein (CLSP) has been shown to be secreted from skin tissues, contain a region minimally similar to the core region of Humanin, and inhibit AD-related neuronal death through the heterotrimeric Humanin receptor on the cell surface in vitro. As CLSP is much more potent than Humanin and efficiently transported through blood circulation across the blood-brain barrier to the central nervous system, CLSP is considered as a physiological agonist that binds to the heterotrimeric Humanin receptor and triggers the Humanin-induced signals in central nervous system. However, it remains unknown whether CLSP ameliorates memory impairment in mouse dementia models as Humanin does. In this study, we show that recombinant CLSP, administered intracerebroventricularly or intraperitoneally, ameliorates scopolamine-induced dementia in mice. PMID- 23797158 TI - The pathological features of bronchoscopic lung volume reduction using sealant treatment assessed in lung explants of patients who underwent lung transplantation. PMID- 23797157 TI - Heterotaxy syndrome: impact of ventricular morphology on resource utilization. AB - Patients with heterotaxy syndrome (HS) have significant cardiac and extracardiac anomalies that impact outcome. To improve the management of this complex patient population, we performed a comprehensive analysis of their anatomic and clinical features along with an evaluation of resource utilization data. The objectives were to describe anatomic and clinical features of patients with HS syndrome treated at a single center from 1992 to 2011 focusing on the impact of ventricular morphology (univentricular [UV] vs. biventricular [BV]) on clinical outcomes and resource utilization. Clinical and echocardiographic data from patients with HS were abstracted from medical records. Health care costs were indexed to inflation. Seventy-eight patients were identified with HS ranging in age from 1 day to 29 years old. UV morphology was present in 46 patients (59 %), most commonly with right-ventricular dominance (36 of 46). The presence of extra cardiac anomalies did not differ between the UV and BV groups (82 vs. 78 %) nor did morbidities, such as need for enteral tube feedings (47 vs. 25 %) or pacemaker placement (24 vs. 25 %). Mortality was 28 % in the entire cohort: 39 % in univentricuar patients versus 10.5 % in those with biventricular anatomy. Hospital length of stay for medical illnesses was similar in both groups, but length of stay after surgery was significantly longer in UV than BV patients. Among survivors, UV patients had greater median hospital costs (TeX 67,732, p < 0.001), but when this was adjusted for mortality and variable follow-up, there were no differences in health care costs within the first year of life. Significant health care dollars are used to manage children with HS, the majority of which involve expenses related to surgical care. Although patients with biventricular morphology have better survival, morbidity and resource utilization are similar to those for UV patients especially within the first year of life. PMID- 23797159 TI - Thymosin alpha1 activates complement receptor-mediated phagocytosis in human monocyte-derived macrophages. AB - Thymosin alpha1 (Talpha1) is a naturally occurring thymic peptide used worldwide in clinical trials for the treatment of infectious diseases and cancer. The immunomodulatory activity of Talpha1 on innate immunity effector cells has been extensively described, but its mechanism of action is not completely understood. We report that Talpha1-exposed human monocyte-derived macrophages (MDMs) assume the typical activated morphology also exhibited by lipopolysaccharide-activated MDMs, but show a comparatively higher ability of internalizing fluorescent beads and zymosan particles. Talpha1 exposure also promptly and dramatically stimulates MDM phagocytosis and killing of Aspergillus niger conidia starting as soon as 30 min after challenge. The effect is dose dependent and early coupled to low transcription of the proinflammatory cytokines tumor necrosis factor alpha and interleukin-6 and unmodified Toll-like receptor expression. The Talpha1 stimulated phagocytosis is strictly dependent on the integrity of the microtubule network and protein kinase C activity and occurs by a variation in the classic zipper model, with recruitment of vinculin and actin at the phagosome exhibiting a punctate distribution. These findings indicate that, in human mature MDMs, Talpha1 implements pathogen internalization and killing via the stimulation of the complement receptor-mediated phagocytosis. Our observations document that Talpha1 is an early and potent activator of innate immunity and reinforce the concept of its pleiotropy. PMID- 23797160 TI - Team clinician variability in return-to-play decisions. AB - OBJECTIVE: To describe the variability in the return-to-play (RTP) decisions of experienced team clinicians and to assess their clinical opinion as to the relevance of 19 factors described in a RTP decision-making model. DESIGN: Survey questionnaire. SETTING: Advanced Team Physician Course. PARTICIPANTS: Sixty-seven of 101 sports medicine clinicians completed the questionnaire. MAIN OUTCOME MEASURES: Results were analyzed using descriptive statistics. For categorical variables, we report percentage and frequency. For continuous variables, we report mean (SD) if data were approximately normally distributed and frequencies for clinically relevant categories for skewed data. RESULTS: The average number of years of clinical sports medicine experience was 13.6 (9.8). Of the 62 clinicians who responded fully, 35% (n = 22) would "clear" (vs "not clear") an athlete to participate in sport even if the risk of an acute reinjury or long term sequelae is increased. When respondents were given 6 different RTP options rather than binary choices, there were increased discrepancies across some injury risk scenarios. For example, 8.1% to 16.1% of respondents who chose to clear an athlete when presented with binary choices, later chose to "not clear" an athlete when given 6 graded RTP options. The respondents often considered factors of potential importance to athletes as nonimportant to the RTP decision process if risk of reinjury was unaffected (range, n = 4 [10%] to n = 19 [45%]). CONCLUSIONS: There is a high degree of variability in how different clinicians weight the different factors related to RTP decision making. More precise definitions decrease but do not eliminate this variability. PMID- 23797161 TI - Bilateral osteochondrosis of the primary patellar ossification centers in a young athlete: a case report. AB - : Osteochondroses are a group of idiopathic self-limited conditions seen in skeletally immature individuals. The term describes disturbances in endochondral ossification affecting either the primary or secondary ossification centers. Osteochondrosis of the tarsal navicular was first described by Kohler in 1908; the eponym "Kohler's disease" is commonly used to refer to this condition. In his original paper, Kohler also described one instance of an osteochondrosis of the primary patellar ossification center, a clinical entity that has since rarely been reported. We present a case of isolated bilateral "Kohler's disease of the patellae" in an approximately 7-year-old male athlete demonstrated clinically and radiographically by both plain radiographs and magnetic resonance imaging. PMID- 23797164 TI - Time to redefine the duration of antimicrobial treatment in male patients with urinary infections. PMID- 23797165 TI - Time to redefine the duration of antimicrobial treatment in male patients with urinary infections--reply. PMID- 23797166 TI - The demise of the "evil specialists": class warfare of specialists vs primary care physicians fostered by elimination of the consultation code. PMID- 23797167 TI - Physicians' health practices are better than patients'. PMID- 23797168 TI - Physicians' health practices are better than patients'--reply. PMID- 23797169 TI - Transfusion in myocardial infarction: bloodcurdling? PMID- 23797170 TI - Patient-level vs group-level data to adjust meta-analysis on transfusion and mortality. PMID- 23797171 TI - Patient-level vs group-level data to adjust meta-analysis on transfusion and mortality--reply. PMID- 23797172 TI - Effects of vertical muscle surgery on differences in the orientation of Listing's plane in patients with superior oblique palsy. AB - BACKGROUND: Although scleral search coils are widely and accurately used for the measurement of Listing's plane in both eyes, they require specialized equipment and are invasive. In this study, we describe a convenient and less invasive method that uses a synoptometer to analyze the differences in orientation of Listing's plane (difLP), and the effects of vertical muscle surgery on the difLP tilt in patients with superior oblique palsy (SOP). METHODS: Seventeen patients with unilateral congenital SOP (CSOP) and four patients with unilateral acquired SOP (ASOP) who had not undergone any strabismus surgeries were examined. Cyclodeviations of 13 vertical and horizontal gaze points within 30 degrees were measured with a synoptometer, and the difLP tilts in the yaw and pitch planes were analyzed before and after vertical muscle surgery. RESULTS: The difLP tilt in the CSOP patients was significantly tilted nasally (p = 0.02) and forward on the lower side (p = 0.001), whereas that in ASOP patients tended to tilt temporally (p = 0.15). Ipsilateral inferior oblique recession (IOR) performed in seven CSOP patients tended to improve the difLP tilt in both the yaw (p = 0.07) and pitch (p = 0.09) planes, whereas contralateral inferior rectus recession (IRR) performed in three CSOP patients significantly improved the difLP tilt in the pitch plane (p = 0.015). The mean excyclodeviations in the 13 gaze points were significantly improved with both procedures (p < 0.0001 for both). CONCLUSIONS: The difLP tilt in the SOP patients could be analyzed with a convenient and less invasive method using a synoptometer, and dissimilar difLP tilts were confirmed in the ASOP and CSOP patients. The results of this study suggest that both IOR and IRR are reasonable treatments for improving the difLP tilt in CSOP patients. IOR should be selected for patients with a steep preoperative difLP tilt to the nasal side, whereas IRR should be selected for patients with a gentle preoperative difLP tilt. PMID- 23797174 TI - Marine microbiology: drilling deeper. PMID- 23797175 TI - Microbiome: with a little help from my phage friends. PMID- 23797173 TI - Molecular pathogenesis of the obligate intracellular bacterium Coxiella burnetii. AB - The agent of Q fever, Coxiella burnetii, is an obligate intracellular bacterium that causes acute and chronic infections. The study of C. burnetii pathogenesis has benefited from two recent fundamental advances: improved genetic tools and the ability to grow the bacterium in extracellular media. In this Review, we describe how these recent advances have improved our understanding of C. burnetii invasion and host cell modulation, including the formation of replication permissive Coxiella-containing vacuoles. Furthermore, we describe the Dot/Icm (defect in organelle trafficking/intracellular multiplication) system, which is used by C. burnetii to secrete a range of effector proteins into the host cell, and we discuss the role of these effectors in remodelling the host cell. PMID- 23797176 TI - Impact of octreotide long-acting release on tumour growth control as a first-line treatment in neuroendocrine tumours of pancreatic origin. AB - BACKGROUND: Somatostatin analogues (SSA) are widely used in the treatment of patients with functioning and non-functioning neuroendocrine tumours (NET). The aim of our investigation was to evaluate the antiproliferative effect of SSA in patients with pancreatic NET. METHODS: We retrospectively analysed records of 43 patients with pancreatic NET treated at our clinic with octreotide long-lasting release as a first-line therapy. The aim of our study was to investigate the overall best response according to the RECIST criteria, overall best response defined as disease control rate (SD+PR), response and disease control rate at 12 months, and time to tumour progression (TTP). RESULTS: The mean age (+/- SD) of the patients (16 female/27 male) at initial diagnosis was 54.7 +/- 11.86 years. At the start of therapy, 39 of 43 patients were classified as stage IV according to ENETS-TNM. Tumours were graded, based on MiB-1/Ki67 staining, as G1 (n = 8), G2 (n = 30) or unknown (n = 5). The octreoscan was positive in 37 patients, negative in 2 and unknown in 4 cases. Nineteen patients had functioning tumours, 24 patients had non-functioning tumours. Median overall survival was 98 months, and median TTP was 13 months. Analysis of grading showed a statistically significant influence on TTP when comparing the median TTP for Ki67 >10% with Ki67 <5% (p = 0.009) and Ki67 5-10% (p = 0.036). CONCLUSION: SSA may be considered as a first-line treatment for antiproliferative purposes in metastatic NET of the pancreas. Patients with a proliferation index <10% displayed a more durable response compared to those with a higher proliferation index. PMID- 23797179 TI - A phase I dose escalation study to determine the optimal biological dose of irosustat, an oral steroid sulfatase inhibitor, in postmenopausal women with estrogen receptor-positive breast cancer. AB - Steroid sulfatase (STS) inhibition may have a therapeutic role in suppression of endocrine-responsive breast cancer. This study aimed to determine the optimal biological dose and recommended dose (RD) of the STS inhibitor irosustat. A three part, open-label, multicenter, dose escalation study of irosustat in estrogen receptor-positive breast cancer patients involved administration of a single dose of irosustat with a 7-day observation period; followed by a daily oral dose of irosustat for 28 days; and an extension phase, in which the daily oral dose of irosustat was continued at the discretion of the investigator and as long as the patient was benefitting from the treatment. Five doses of irosustat were tested (1, 5, 20, 40, and 80 mg) in 50 patients. After 28 days of daily administration of irosustat, all the evaluated patients in the 5, 20, 40, and 80 mg cohorts achieved >=95 % STS inhibition in peripheral blood mononuclear cells and corresponding endocrine suppression. The maximum tolerated dose was not reached, and the 40 mg dose was established as the RD. The median time to disease progression in the 40 mg cohort was 11.2 weeks. Disease stabilization was achieved in 10 % of patients potentially indicative of drug activity. Dry skin was the most frequent adverse event. The RD of irosustat is 40 mg. Disease stabilization occurred in 10 % of this heavily pretreated patient population. A larger study is required to define an accurate response rate to irosustat as a single agent and whether co-administration with an aromatase inhibitor is needed. PMID- 23797180 TI - Fat necrosis of the breast in the accelerated partial breast irradiation era: the need for a universal grading system. AB - Fat necrosis of the breast is increasingly reported and used as a trial endpoint in the treatment of breast cancer with accelerated partial breast irradiation (APBI). Yet, there is no universal toxicity scoring system within the latest version of the Common Terminology Criteria for Adverse Events (CTCAE v4.0). This requires investigators to adopt their own scoring system or improperly use those that exist, and limits accurate reporting of this entity. Fat necrosis of the breast also creates diagnostic uncertainty among clinicians and concern of recurrence among patients. In this review, we address the question of increasing incidence of fat necrosis through the comparison of recent APBI trials and literature. The pathogenesis, symptoms, clinical and radiologic diagnosis, clinical predictors of developing fat necrosis, management and follow-up are also discussed.Lastly, we propose a simplified and universal scoring system for the reporting of fat necrosis. PMID- 23797178 TI - Weight, inflammation, cancer-related symptoms and health related quality of life among breast cancer survivors. AB - Maintaining weight is important for better prognosis of breast cancer survivors. The associations between weight and cancer-related symptoms are not known. We examined associations among weight, weight change, inflammation, cancer-related symptoms, and health-related quality of life (HRQOL) in a cohort of stage 0-IIIA breast cancer survivors. Participants were recruited on average 6 months (2-12 months) after diagnosis. Height, weight, and C-reactive protein (CRP) were assessed at approximately 30 months post-diagnosis; cancer-related symptoms (chest wall and arm symptoms, vasomotor symptoms, urinary incontinence, vaginal symptoms, cognition/mood problems, sleep, sexual interest/function), and HRQOL (SF-36) were assessed at approximately 40 months post-diagnosis. Weight was measured at baseline in a subset. Data on 661 participants were evaluable for body mass index (BMI); 483 were evaluable for weight change. We assessed associations between BMI (<25.0, 25.0-29.9, >=30.0 kg/m2), post-diagnosis weight change (lost >=5 %, weight change <5 %, gained >=5 %), and CRP (tertile) with cancer-related symptoms and HRQOL using analysis of covariance. Higher symptoms scores indicate more frequent or severe symptoms. Higher HRQOL scores indicate better HRQOL. Compared with those with BMI <25 kg/m2, women with BMI >=30 kg/m2 had the following scores: increased for arm symptoms (+25.0 %), urinary incontinence (+40.0 %), tendency to nap (+18.9 %), and poorer physical functioning (-15.6 %, all p < 0.05). Obese women had lower scores in trouble falling asleep (-9.9 %; p < 0.05). Compared with weight change <5 %, participants with >=5 % weight gain had lower scores in physical functioning (-7.2 %), role physical (-15.5 %) and vitality (-11.2 %), and those with weight loss >=5 % had lower chest wall (-33.0 %) and arm symptom scores (-35.5 %, all p < 0.05). Increasing CRP tertile was associated with worse scores for chest wall symptoms, urinary incontinence, physical functioning, role-physical, vitality and physical component summary scores (all P trend < 0.05). Future studies should examine whether interventions to maintain a healthy weight and reduce inflammation could alleviate cancer-related symptoms and improve HRQOL. PMID- 23797181 TI - Prophylactic supraclavicular radiotherapy after surgery in high-risk n1 breast cancer. AB - OBJECTIVES: To evaluate the role of prophylactic supraclavicular radiotherapy (RT) by comparing the clinical outcomes of locoregional recurrence (LRR) in high risk N1 breast cancer. METHODS: We performed a retrospective comparison study of 250 high-risk N1 breast cancer patients treated at two institutions. Patients were considered to be high-risk when they had more than two of the following risk factors: lymphovascular invasion, extracapsular extension, metastasis to more than two axillary lymph nodes (ALNs), or level II or higher ALN metastasis. We compared two groups treated with different adjuvant RT fields for the purpose of prophylactic supraclavicular RT (SCRT). RESULTS: Among the 250 patients, 97 patients received SCRT while 153 did not. During follow-up, 32 patients (7 in the SCRT and 25 in the no-SCRT group) had recurrence, and LRR developed in 19 patients, 18 of whom had not received SCRT. In multivariate analysis, SCRT [hazard ratio (HR) 0.072; p = 0.011] and chemotherapy regimen (cyclophosphamide, Adriamycin, and taxane; TAC) were the significant prognostic factors in LRR-free survival (HR 0.385; p = 0.046), and chemotherapy regimen also showed significance for distant metastasis-free survival (HR 0.399; p = 0.037). CONCLUSIONS: Use of prophylactic SCRT may reduce the risk of LRR in patients with high-risk N1 breast cancer. PMID- 23797183 TI - Motor unit activity in upper airway muscles genioglossus and tensor palatini. AB - Common oscillatory inputs to genioglossus (GG) and tensor palatini (TP) motoneurons were assessed using coherence analysis. Oscillations in the ranges 0 5 Hz (common drive) and 10-30 Hz (short term synchrony) were analyzed. GG and TP electromyograms were recorded via intramuscular fine wire electrodes in 32 subjects during wakefulness. Coherence analysis was conducted on 201 pairs of motor units paired according to their discharge patterns. Results were similar for the two muscles. Common drive was significantly higher for unilateral than bilateral pairs of units (p<.001), and was highest in Inspiratory Tonic pairs and lowest in Tonic pairs (p<.001). Pairs constructed from one muscle had higher common drive than pairs from two muscles (p<.001), the difference being greater for tonic pairs (interaction effect, p=.003). Short term synchrony was weak. The results indicate strong common drive to GG and TP phasic motoneurons, while common drive to Tonic motoneurons was weaker and idiosyncratic to each muscle. PMID- 23797182 TI - A prospective study of factors affecting recovery from musculoskeletal injuries. AB - PURPOSE: Research suggests the importance of psychosocial factors in recovery from musculoskeletal injuries. The objective of this study was to identify predictors of recovery among U.S. Marines who had musculoskeletal injuries of the back, knee, or shoulder. METHODS: A sample of 134 participants was assessed at baseline and followed for 1 year to determine outcome information. RESULTS: The strongest predictor of injury recovery at the 1-year follow-up was recovery expectations. In a multivariate logistic model with key demographic and psychosocial factors controlled, individuals who had high recovery expectations at baseline were over five times as likely to be recovered at follow-up as individuals who had low expectations (OR = 5.18, p?.01). CONCLUSIONS: This finding is consistent with a large body of research that has linked recovery expectations with better recovery outcomes in patients with musculoskeletal injuries as well as with research linking recovery expectations with better outcomes across a wide range of medical conditions.Applied to military populations, interventions designed to modify recovery expectations may have the potential to improve rates of return to duty and to reduce rates of disability discharge. PMID- 23797184 TI - Computational fluid dynamics model of avian tracheal temperature control as a model for extant and extinct animals. AB - Respiratory evaporative cooling is an important mechanism of temperature control in bird. A computational simulation of the breathing cycle, heat and water loss in anatomical avian trachea/air sac model has not previously been conducted. We report a first attempt to simulate a breathing cycle in a three-dimensional model of avian trachea and air sacs (domestic fowl) using transient computational fluid dynamics. The airflow in the trachea of the model is evoked by changing the volume of the air sacs based on the measured tidal volume and inspiratory/expiratory times for the domestic fowl. We compare flow parameters and heat transfer results with in vivo data and with our previously reported results for a two-dimensional model. The total respiratory heat loss corresponds to about 13-19% of the starvation metabolic rate of domestic fowl. The present study can lend insight into a possible thermoregulatory function in species with long necks and/or a very long trachea, as found in swans and birds of paradise. Assuming the structure of the sauropod dinosaur respiratory system was close to avian, the simulation of the respiratory temperature control (using convective and evaporative cooling) in the extensively experimentally studied domestic fowl may also help in making simulations of respiratory heat control in these extinct animals. PMID- 23797185 TI - The respiratory neuromuscular system in Pompe disease. AB - Pompe disease is due to mutations in the gene encoding the lysosomal enzyme acid alpha-glucosidase (GAA). Absence of functional GAA typically results in cardiorespiratory failure in the first year; reduced GAA activity is associated with progressive respiratory failure later in life. While skeletal muscle pathology contributes to respiratory insufficiency in Pompe disease, emerging evidence indicates that respiratory neuron dysfunction is also a significant part of dysfunction in motor units. Animal models show profound glycogen accumulation in spinal and medullary respiratory neurons and altered neural activity. Tissues from Pompe patients show central nervous system glycogen accumulation and motoneuron pathology. A neural mechanism raises considerations about the current clinical approach of enzyme replacement since the recombinant protein does not cross the blood-brain-barrier. Indeed, clinical data suggest that enzyme replacement therapy delays symptom progression, but many patients eventually require ventilatory assistance, especially during sleep. We propose that treatments which restore GAA activity to respiratory muscles, neurons and networks will be required to fully correct ventilatory insufficiency in Pompe disease. PMID- 23797186 TI - Gender considerations in ventilatory and metabolic development in rats: special emphasis on the critical period. AB - In rats, a critical period exists around postnatal day (P) 12-13, when an imbalance between heightened inhibition and suppressed excitation led to a weakened ventilatory and metabolic response to acute hypoxia. An open question was whether the two genders follow the same or different developmental trends throughout the first 3 postnatal weeks and whether the critical period exists in one or both genders. The present large-scale, in-depth ventilatory and metabolic study was undertaken to address this question. Our data indicated that: (1) the ventilatory and metabolic rates in both normoxia and acute hypoxia were comparable between the two genders from P0 to P21; thus, gender was never significant as a main effect; and (2) the age effect was highly significant in all parameters studies for both genders, and both genders exhibited a significantly weakened response to acute hypoxia during the critical period. Thus, the two genders have comparable developmental trends, and the critical period exists in both genders in rats. PMID- 23797187 TI - Ultrasound-guided peripheral regional anaesthesia: a feasibility study in obese versus normal-weight women. AB - BACKGROUND AND OBJECTIVES: In particular, obese patients may profit from peripheral regional anaesthesia due to avoidance of general anaesthesia. Currently, ultrasound (US) guidance is described as the golden standard in regional anaesthesia, but no studies have so far evaluated the US behaviour of peripheral nerve structures in obese versus normal-weight patients. To be able to perform such studies, it is necessary to develop new and more objective methods to quantify nerve visibility by US. We therefore designed a prospective, observational, comparative and blinded study to investigate the visibility of peripheral nerves in obese versus normal-weight patients by using a novel method based on histogram grey-scale values. METHODS: We scanned the median and sciatic nerves in 40 obese and normal-weight female patients and calculated differences of histogram grey-scale values between nerves and surrounding tissues. RESULTS: Histogram value analysis showed less US visibility of sciatic nerves in obese versus normal-weight study patients, which is caused by higher surrounding tissue histogram values. No differences could be detected for median nerves. CONCLUSIONS: The novel technique of comparing histogram grey-scale values to determine the visibility of the peripheral nerve in different patient categories was found feasible. Median nerves are appropriately visible by US in both normal and obese subjects, whereas sciatic nerves are less visible in obese as compared with normal-weight women. Our results serve as the rationale behind difficulties in peripheral regional anaesthesia in obese patients. PMID- 23797189 TI - Mild cognitive impairment, risk factors and magnetic resonance volumetry: role of probable Alzheimer's disease in the family. AB - BACKGROUND/AIMS: Late-onset Alzheimer's disease (LOAD) comprises sporadic LOAD and familial LOAD. We wanted to determine whether total plasma homocysteine (Hcy), cardiovascular risk factors and volumetric analyses of cerebral magnetic resonance imaging (MRI) were differently associated with mild cognitive impairment (MCI) in subjects from families with aggregation of LOAD (probable familial LOAD) and MCI in subjects from families without LOAD (probable sporadic LOAD). METHODS: A total of 103 subjects with MCI without known stroke or other apparent causative diseases were included as cases together with 58 controls. The cases were stratified into 3 groups according to the number of biological relatives with probable LOAD on one side of the family. Cerebral MRI was obtained from all. The case groups were compared to the control group in sex-specific analyses of covariance. RESULTS: Hcy was significantly elevated in all cases compared to controls, except for women with probable familial LOAD. These women also had significantly smaller hippocampal volume and significantly larger lateral ventricles, unlike the women in the other case groups. CONCLUSIONS: Our findings suggest that research on Hcy, cardiovascular risk factors and other potential risk factors for LOAD might benefit from distinguishing between sporadic and familial LOAD. PMID- 23797188 TI - A comparison of South Asian specific and established BMI thresholds for determining obesity prevalence in pregnancy and predicting pregnancy complications: findings from the Born in Bradford cohort. AB - OBJECTIVE: To describe how maternal obesity prevalence varies by established international and South Asian specific body mass index (BMI) cut-offs in women of Pakistani origin and investigate whether different BMI thresholds can help to identify women at risk of adverse pregnancy and birth outcomes. DESIGN: Prospective bi-ethnic birth cohort study (the Born in Bradford (BiB) cohort). SETTING: Bradford, a deprived city in the North of the UK. PARTICIPANTS: A total of 8478 South Asian and White British pregnant women participated in the BiB cohort study. MAIN OUTCOME MEASURES: Maternal obesity prevalence; prevalence of known obesity-related adverse pregnancy outcomes: mode of birth, hypertensive disorders of pregnancy (HDP), gestational diabetes, macrosomia and pre-term births. RESULTS: Application of South Asian BMI cut-offs increased prevalence of obesity in Pakistani women from 18.8 (95% confidence interval (CI) 17.6-19.9) to 30.9% (95% CI 29.5-32.2). With the exception of pre-term births, there was a positive linear relationship between BMI and prevalence of adverse pregnancy and birth outcomes, across almost the whole BMI distribution. Risk of gestational diabetes and HDP increased more sharply in Pakistani women after a BMI threshold of at least 30 kg m(-2), but there was no evidence of a sharp increase in any risk factors at the new, lower thresholds suggested for use in South Asian women. BMI was a good single predictor of outcomes (area under the receiver operating curve: 0.596-0.685 for different outcomes); prediction was more discriminatory and accurate with BMI as a continuous variable than as a binary variable for any possible cut-off point. CONCLUSION: Applying the new South Asian threshold to pregnant women would markedly increase those who were referred for monitoring and lifestyle advice. However, our results suggest that lowering the BMI threshold in South Asian women would not improve the predictive ability for identifying those who were at risk of adverse pregnancy outcomes. PMID- 23797191 TI - Telling the patient's story with electronic health records. PMID- 23797192 TI - You missed a spot! Disinfecting shared mobile phones. PMID- 23797193 TI - Piloting patient rounding as a quality improvement initiative. PMID- 23797194 TI - Freezing the process: implementing bedside report. PMID- 23797196 TI - Strike! Preparing nursing departments for work stoppage. PMID- 23797197 TI - DNP-prepared APRNs: leading the Magnet(r) charge. PMID- 23797198 TI - Leadership Q&A. PMID- 23797199 TI - Impact of pharmacy student and resident-led discharge counseling on heart failure patients. AB - PURPOSE: Many health systems have implemented interventions to reduce the rate of heart failure readmissions. Pharmacists have the training and expertise to provide effective medication-related education. However, few studies have examined the impact of discharge education provided by pharmacy students and residents on patients hospitalized with heart failure exacerbations. METHODS: This was a nonrandomized intervention study evaluating the impact of a pharmacy student and resident-led discharge counseling program on heart failure readmissions. The primary end point was the 30-day heart failure readmission rate. Secondary end points included self-reported patient understanding of medications, number of medication errors documented, and estimated associated cost avoidance. RESULTS: A total of 86 and 94 patients were enrolled into the intervention and control groups, respectively. No statistically significant difference in readmission rates was detected between the intervention and the control groups. Thirty-four medication errors and discrepancies were documented, or 1 for every 2.5 patients counseled, resulting in an estimated cost avoidance of $4241 for the institution. Eighty-nine percent of patients who received discharge counseling agreed they had a better understanding of their medications after speaking with a pharmacy resident or student. CONCLUSIONS: There was no statistically significant difference in readmission rates; however, several medication errors were prevented, and a large percentage of patients expressed an improved understanding of their medications. PMID- 23797201 TI - Transplantation: Urine--but not serum--suPAR might predict FSGS recurrence. PMID- 23797202 TI - Dialysis: Membrane flux, dialysate purity and cardiovascular outcomes. PMID- 23797203 TI - Glomerular disease: ANCA-associated GN--to PLEX or not to PLEX? PMID- 23797204 TI - Screening for Hepatitis C Virus Infection in Adults: U.S. Preventive Services Task Force Recommendation Statement. PMID- 23797206 TI - Abstracts from Nippon Eiseigaku Zasshi (Japanese Journal of Hygiene) vol. 68, no. 2. PMID- 23797205 TI - Immunostaining of pulpal nerve fibre bundle/arteriole associations in ground serial sections of whole human teeth embedded in technovit(r) 9100. AB - A technique for embedding human undecalcified tooth specimens in Technovit(r) 9100 was developed, which permits immunohistological evaluation of pulp tissue in serial ground sections. Human molars were divided into 14-18 sections of about 23 um thickness. Immunohistological double staining for S-100 and CD34 revealed unique associations of myelinated nerve fibre bundles with arterioles, which continued through the entire tooth pulp. These arterioles were not only accompanied by, but partially or totally enveloped in longitudinally orientated myelinated nerve fibre bundles. We speculate that this unique arrangement may mechanically support the arterioles and alleviate detection or regulation of their contraction state by sensory nerve cells. PMID- 23797207 TI - Longitudinal changes in total body creatine pool size and skeletal muscle mass using the D3-creatine dilution method. AB - BACKGROUND: We recently validated in cross-sectional studies a new method to determine total body creatine pool size and skeletal muscle mass based on D3 creatine dilution from an oral dose and detection of urinary creatinine enrichment by isotope ratio mass spectrometry (IRMS). Routine clinical use of the method in aging and disease will require repeated application of the method, with a more widely available technology than IRMS, to enable determination of change in skeletal muscle mass in longitudinal studies. We therefore adapted the method to liquid chromatography-tandem mass spectrometry (LC-MS/MS) technology, and sought to establish proof of concept for the repeated application of the method in a longitudinal study. Because the turnover of creatine is slow, it was also critical to determine the impact of background enrichment from an initial dose of oral D3-creatine on subsequent, longitudinal measurements of change in muscle mass. METHODS: Rats were given an oral tracer dose of D3-creatine (1.0 mg/kg body weight) at 10 and 17 weeks of age. LC-MS/MS was used to determine urinary D3 creatine, and urinary D3-creatinine enrichment, at time intervals after D3 creatine administration. Total body creatine pool size was calculated from urinary D3-creatinine enrichment at isotopic steady state 72 h after administration of D3-creatine tracer. RESULTS: At 10 weeks of age, rat lean body mass (LBM) measured by quantitative magnetic resonance correlated with creatine pool size (r = 0.92, P = 0.0002). Over the next 7 weeks, the decline in urinary D3-creatinine enrichment was slow and linear, with a rate constant of 2.73 +/- 0.06 %/day. Subtracting background urinary D3-creatinine enrichment from the elevated enrichment following a second dose of D3-creatine at 17 weeks permitted repeat calculations of creatine pool size. As at 10 weeks, 17-week LBM correlated with creatine pool size (r = 0.98, P <0.0001). In addition, the change in creatine pool size was correlated with the change in LBM during the 7 weeks of rat growth between measurements (r = 0.96, P <0.0001). CONCLUSION: The LC-MS/MS based D3-creatine dilution method can be applied repeatedly to measure total body creatine skeletal muscle mass change in longitudinal study. PMID- 23797209 TI - Disrupted cortical network as a vulnerability marker for obsessive-compulsive disorder. AB - Morphological alterations of brain structure are generally assumed to be involved in the pathophysiology of obsessive-compulsive disorder (OCD). Yet, little is known about the morphological connectivity properties of structural brain networks in OCD or about the heritability of those morphological connectivity properties. To better understand these properties, we conducted a study that defined three different groups: OCD group with 30 subjects, siblings group with 19 subjects, and matched controls group with 30 subjects. A structural brain network was constructed using 68 cortical regions of each subject within their respective group (i.e., one brain network for each group). Both small-worldness and modularity were measured to reflect the morphological connectivity properties of each constructed structural brain network. When compared to the matched controls, the structural brain networks of patients with OCD indeed exhibited atypical small-worldness and modularity. Specifically, small-worldness showed decreased local efficiency, and modularity showed reduced intra-connectivity in Module III (default mode network) and increased interconnectivity between Module I (executive function) and Module II (cognitive control/spatial). Intriguingly, the structured brain networks of the unaffected siblings showed similar small worldness and modularity as OCD patients. Based on the atypical structural brain networks observed in OCD patients and their unaffected siblings, abnormal small worldness and modularity may indicate a candidate endophenotype for OCD. PMID- 23797208 TI - A direct anterior cingulate pathway to the primate primary olfactory cortex may control attention to olfaction. AB - Behavioral and functional studies in humans suggest that attention plays a key role in activating the primary olfactory cortex through an unknown circuit mechanism. We report that a novel pathway from the anterior cingulate cortex, an area which has a key role in attention, projects directly to the primary olfactory cortex in rhesus monkeys, innervating mostly the anterior olfactory nucleus. Axons from the anterior cingulate cortex formed synapses mostly with spines of putative excitatory pyramidal neurons and with a small proportion of a neurochemical class of inhibitory neurons that are thought to have disinhibitory effect on excitatory neurons. This novel pathway from the anterior cingulate is poised to exert a powerful excitatory effect on the anterior olfactory nucleus, which is a critical hub for odorant processing via extensive bilateral connections with primary olfactory cortices and the olfactory bulb. Acting on the anterior olfactory nucleus, the anterior cingulate may activate the entire primary olfactory cortex to mediate the process of rapid attention to olfactory stimuli. PMID- 23797210 TI - Boron neutron capture therapy for advanced salivary gland carcinoma in head and neck. AB - PURPOSE: Boron neutron capture therapy (BNCT) is among the radiation treatments known to have a selective lethal effect on tumor cells. This study summarizes the tumor responses and the acute and late adverse effects of BNCT in the treatment of patients with both recurrent and newly diagnosed T4 salivary gland carcinoma. METHODS: Two patients with recurrent cancer and 3 with newly diagnosed T4 advanced malignancy were registered between October 2003 and September 2007, with the approval of the medical ethics committees of Kawasaki Medical School and Kyoto University. BNCT was performed, in a single fraction using an epithermal beam, at Japan Research Reactor 4. RESULTS: All patients achieved a complete response within 6 months of treatment. The median duration of the complete response was 24.0 months; the median overall survival time was 32.0 months. Three of the 5 patients are still alive; the other 2 died of distant metastatic disease. Open biopsy of the parotid gland after BNCT was performed in 1 patient and revealed no residual viable cancer cells and no serious damage to the normal glandular system. Although mild alopecia, xerostomia, and fatigue occurred in all patients, there were no severe adverse effects of grade 3 or greater. CONCLUSIONS: Our preliminary results demonstrate that BNCT is a potential curative therapy for patients with salivary gland carcinoma. The treatment does not cause any serious adverse effects, and may be used regardless of whether the primary tumor has been previously treated. PMID- 23797211 TI - Usefulness of CT-lymphography in sentinel lymph node navigation. AB - BACKGROUND: There are many methods for sentinel lymph node (SLN) navigation. The methods using radioisotopes and blue dyes are performed mainly for the identification of SLN. Our current method for SLN biopsy is a combination of three techniques with 99mTc-phytate, patent blue V dye, and preoperative CT lymphography (CTLG). PATIENTS AND METHODS: Iomeprol (Iomeron(r)) as a water soluble contrast agent is diluted twofold with 1 % lidocaine and intradermally injected into a few sites (2-5 ml at each site) around the tumor. After the injection, CT imaging is performed using a 64-row MDCT system (Siemens SOMATOM Definition AS+). We performed CTLG in 34 patients (16 men, 18 women) between September 2008 and March 2013. RESULTS: CTLG clearly visualized the SLN and the lymphatic drainage in 21 out of 34 patients. CONCLUSIONS: We can detect the SLN and lymphatic flow near to tumors without shine-through effect, especially in the head and neck regions. It is thought that CTLG may be useful to determine the range of lymph node dissection. PMID- 23797213 TI - Noninvasive estimation of the input function for dynamic mouse 18F-FDG microPET studies. AB - A new noninvasive estimation method for the plasma time-activity curve, i.e., input function (IF) of the tracer kinetic model in dynamic (18)F-FDG microPET mouse studies, is proposed and validated. This estimation method comprises of four steps. First, a novel constraint nonnegative matrix factorization segmentation algorithm was applied to extract the left ventricle (Lv) and myocardium (Myo) time activity curves (TACs). Second, we modeled the IF as a seven-parameter mathematical equation and constructed a dual-output model of the real TAC in Lv and Myo accounting for the partial-volume and spillover effects. Then, we fit the image-derived Lv and Myo TACs to the dual-output model to estimate the parameters of the IF. Finally, the IF was validated by comparing it to the gold standard IF while considering the delay and dispersion effects. Our method was verified based on 20 mice datasets from the Mouse Quantitation Program database, provided by UCLA. The error of the areas under the curves between the delayed and dispersed estimated IF and the gold standard IF was 7.237% +/- 6.742% (r = 0.969), and the error of the (18)F-FDG influx constant Ki of the Myo was 4.910% +/- 6.810% ( r = 0.992). The results demonstrated the effectiveness of the proposed method. PMID- 23797214 TI - A parametric method to measure time-varying linear and nonlinear causality with applications to EEG data. AB - A linear and nonlinear causality detection method called the error-reduction ratio causality (ERRC) test is introduced in this paper to investigate if linear or nonlinear models should be considered in the study of human electroencephalograph (EEG) data. In comparison to the traditional Granger methods, one significant advantage of the ERRC approach is that it can effectively detect the time-varying linear and nonlinear causalities between two signals without fitting a complete nonlinear model. Two numerical simulation examples are employed to compare the performance of the new method with other widely used methods in the presence of noise and in tracking time-varying causality. Finally, an application to measure the linear and nonlinear relationships between two EEG signals from different cortical sites for patients with childhood absence epilepsy is discussed. PMID- 23797215 TI - Heart rate turbulence analysis based on photoplethysmography. AB - The goal of this paper is to determine whether the photoplethysmography (PPG) can replace the ECG-based detection of heart rate turbulence. Using the PPG, classification of ventricular premature beats (VPBs) is accomplished with a linear classifier. The two conventional parameters turbulence onset and slope are studied together with a recently introduced parameter characterizing turbulence shape. Performance is studied on a dataset with 4131 VPBs, recorded from a total of 27 patients in different clinical contexts (hemodialysis treatment, intensive care monitoring, and electrophysiological study). The sensitivity/specificity of VPB classification was found to be 90.5/99.9%, with an accuracy of 99.3%, suggesting that classification of VPBs can be reliable made from the PPG. The main difference between the two types of turbulence analysis stems from the fact that the pulse transit time varies largely immediately after the VPB. Out of the 22 patients which had a sufficient number of VPBs, the outcome of the ECG- and PPG-based analysis was identical in 21. It is concluded that the PPG may serve as a surrogate technique for the ECG in turbulence analysis. PMID- 23797216 TI - Purification and partial characterization of a novel beta-1,3-endoglucanase from Streptomyces rutgersensis. AB - A beta-1,3-endoglucanase produced by Streptomyces rutgersensis was purified to a homogeneity by the fractional precipitation with ammonium sulfate, ion exchange chromatography on Q-Sepharose and hydrophobic chromatography on Butyl Sepharose. A typical procedure provided 11.74-fold purification with 12.53 % yield. SDSPAGE of the purified protein showed one protein band. The exact molecular mass of the enzyme obtained by mass spectrometry was 41.25 kDa; the isoelectric point was between pH 4.2-4.4. The optimal beta-glucanase catalytic activity was at pH 7 and 50 degrees C. An enzyme was only active toward glucose polymers containing beta 1,3 linkages and hydrolyzed Saccharomyces cerevisiae cell wall beta-glucan in an endo-like way: reaction products were different molecular size beta-glucans, which were larger than glucose. PMID- 23797217 TI - Identification of incidental hepatic malignancy as photopenic defect on 99mTc sestamibi myocardial perfusion imaging. AB - A 63-year-old male patient undergoing cardiac SPECT examination was incidentally found to have a large, photopenic (tracer-deficient) region in the right lobe of the liver. Follow-up abdominal CT scan demonstrated a corresponding large (7.8 cm * 6.9 cm), hypodense hepatic lesion. Subsequent CT-guided biopsy revealed metastatic carcinoma of uncertain primary source. PMID- 23797218 TI - The role of 11C-choline PET imaging in the early detection of recurrence in surgically treated prostate cancer patients with very low PSA level <0.5 ng/mL. AB - PURPOSE: This study aims to evaluate the role of (11)C-choline PET/CT in patients with biochemical relapse after radical prostatectomy (RP) showing prostate specific antigen (PSA) values lower than 0.5 ng/mL. METHODS: We performed (11)C choline PET/CT in 71 consecutive patients previously treated with RP showing PSA values lower than 0.5 ng/mL. (11)C-Choline PET/CT was performed following standard procedure. (11)C-Choline PET/CT-positive findings were validated by transrectal ultrasonography + biopsy, repeated (11)C-choline PET/CT, other conventional imaging modality, and histology. RESULTS: (11)C-Choline PET/CT was true positive in 15/71 (21.1%). (11)C-Choline uptake was observed in pelvic lymph nodes (7/71; 9.9%), in the prostatic bed (7/71; 9.9%), and in bone (1/71; 1.4%). Mean PSA, PSA doubling time (PSAdt), and PSA velocity (PSAvel) values +/- SD in (11)C-choline PET/CT-positive patients was 0.37 +/- 0.1 ng/mL, 3.4 +/- 2.1 months, and 0.05 +/- 0.1 ng/mL/yr, respectively. (11)C-Choline PET/CT was false negative in 2 patients and false positive in 1 patient. Among all variables, only PSAdt and the ongoing hormonal treatment were statistically significant in the prediction of a positive (11)C-choline PET/CT at multivariate analysis. CONCLUSIONS: (11)C-Choline PET/CT could be used early after biochemical failure even if PSA values are very low, preferentially in hormonal resistant patients showing fast PSA kinetics. An early detection of the site of relapse could lead to a personalized and tailored treatment. PMID- 23797219 TI - Hypoxia imaging with 18F-fluoroerythronitroimidazole integrated PET/CT and immunohistochemical studies in non-small cell lung cancer. AB - PURPOSE: (18)F-fluoroerythronitroimidazole ((18)F-FETNIM) PET/CT allows a noninvasive assessment of tumor hypoxia. The purpose of this study was to evaluate a noninvasive and simplicity parameter for quantization of (18)F-FETNIM uptake with expectations to predict survival in non-small cell lung cancer surgical patients and investigate the relationship between (18)F-FETNIM uptake and molecular markers related to hypoxia, glucose metabolism, and angiogenesis. PATIENTS AND METHODS: Thirty-two patients with biopsy-proven non-small cell lung cancer for surgical treatment were enrolled from March 2007 to February 2011. All patients had PET/CT studies with (18)F-FETNIM and subsequently underwent surgery. Twenty-five patients had stage II disease of surgical staging only for statistical analysis. The tumor-to-mediastinum (T/Me) ratio was calculated and correlated with survival and immunohistochemical staining of hypoxia inducible factor 1alpha (HIF-1alpha), glucose transporter 1 (GLUT-1), and vascular endothelial growth factor (VEGF). RESULTS: The actuarial survival was worse for patients showing a high T/Me ratio, the best discriminative cutoff value being 1.9. A statistically significant worse survival was noted in patients having a tumor with a T/Me ratio of 1.9 or greater, compared with patients showing a tumor with a T/Me ratio of less than 1.9, a 3-year survival of 43.8% and 88.9%, respectively (P = 0.034). There was a positive correlation between T/Me ratio and HIF-1alpha (P = 0.023), GLUT-1 (P = 0.035), and VEGF (P = 0.042). CONCLUSIONS: T/Me ratio provides a noninvasive parameter for quantization of (18)F-FETNIM uptake on PET/CT. T/Me ratio is correlated with a worse outcome and with the expression of HIF-1alpha, GLUT-1, and VEGF, all up-regulated under hypoxic conditions. PMID- 23797220 TI - Unexpected diagnosis of thyroid storm in a young child referred for urgent lung perfusion imaging. AB - A 2-year-old girl with cardiorespiratory distress and suspected pulmonary embolism (PE) was referred for urgent lung perfusion scintigraphy, proven negative for perfusion defects but unexpectedly revealing an enlarged orthotopic thyroid. This finding was, under the circumstances, considered as suggestive of thyroid storm (TS), subsequently confirmed by thyroid hormones measurement. A (99m)TcO(4)(-) thyroid scan 1 week later showed a homogenously enlarged thyroid with high tracer uptake. Both PE and TS are rare but serious pediatric conditions with partially overlapping presentations. In the present case, the unbounded (99m)Tc fraction avidly taken by the overfunctioning thyroid suggested the correct, clinically unsuspected, diagnosis. PMID- 23797221 TI - Portal shunt scintigraphy (PSS) in the evaluation of patients suspected of hereditary hemorrhagic telangiectasia. AB - Vascular malformations of the liver in hereditary hemorrhagic telangiectasia may develop high output cardiac failure. Currently, the treatment for refractory hepatic vascular shunts includes hepatic artery embolization. However, hepatic or biliary necrosis may occur if inadequate portal blood flow supplies the liver. In this study, we applied noninvasive portal shunt scintigraphy to determine the portal shunt index for their evaluation. We present a case of the patient with a high PSI value and another case with a normal PSI value (<10%). PMID- 23797222 TI - Preoperative detection of sentinel lymph nodes in endometrial cancer using SPECT/CT. AB - We report the use of SPECT/CT in sentinel lymph node biopsy in endometrial cancer. The patient was a 54-year-old woman with the diagnosis of endometrial adnenocarcinoma, grade 2. Preoperative MRI and transvaginal ultrasound scans revealed tumor infiltrating more than 50% of the myometrium. The patient was qualified for total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic/paraaortic lymphadenectomy. Before the surgery, 2 cervical injections of the (99m)Tc-labeled nanocolloid (0.5 mCi) were administered and the SPECT/CT was performed using a standard dual-head gamma camera and a 6-slice spiral CT component. PMID- 23797223 TI - Detection of meningioma metastasis to liver and lung using somatostatin receptor scintigraphy. AB - Extracranial meningioma metastasis is rare. We report a case of a 74-year-old Caucasian man with intracranial recurrence of atypical meningioma treated with a combination of surgical resection and gamma knife radiotherapy over a 4-year period. Somatostatin receptor scintigraphy using (111)In pentreotide for surveillance of tumor recurrence showed multiple pulmonary and hepatic metastases. PMID- 23797224 TI - Segmental "misty mesentery" on FDG PET/CT: an uncommon manifestation of mesenteric lymphoma. AB - Mesenteric lymphomas are commonly seen as bulky hypermetabolic nodal masses on F FDG PET/CT. Very rarely, these are seen as mesenteric haziness due to localized hyperattenuation of fat, known as "misty mesentery", which morphological imaging wise has other differentials as well. We report a unique imaging finding of segmental misty mesentery with hypermetabolic mesenteric nodes on FDG PET/CT in a patient who was kept on observation due to inconclusive biopsy, which on follow up imaging progressed to extensive lymphomatous involvement. Thus, in retrospect, this imaging feature on baseline PET/CT was diagnostic for mesenteric lymphoma. PMID- 23797225 TI - PET or PET/CT for detection of peritoneal carcinomatosis: a meta-analysis. AB - The present study assessed the diagnostic performances of (18)F-FDG PET or PET/CT in detecting peritoneal carcinomatosis in patients with cancer. METHODS: Through a search of MEDLINE (January 1998 to September 2012), an overall weighted average for sensitivity and specificity was calculated using the weighted averages of the sample sizes in each relevant study. Pooled estimates of positive and negative likelihood ratios were calculated using fixed and random effects models, respectively, according to the heterogeneity among studies. A summary receiver operating characteristics (sROC) curve was constructed and the area under the sROC curve (AUC) was calculated. To explore heterogeneity, due to sources other than threshold effects, I-square was calculated. RESULTS: The present study included analyses of patients (n = 513) from 7 studies. Results indicated a significant heterogeneity for sensitivity and specificity (I(2) > 50% and P < 0.05). The overall pooled estimates for sensitivity and specificity of FDG PET or PET/CT scans in the detection of peritoneal carcinomatosis were 72.4% (95% CI, 64.4%-79.5%) and 96.7% (95% CI, 94.4%-98.3%), respectively. The positive likelihood ratio was 10.414 (95% CI, 6.195-17.506) and the negative likelihood ratio 0.312 (95% CI, 0.159-0.612). The AUC was 0.9404. The overall diagnostic accuracy (Q* index) was 87.8%. CONCLUSION: The high specificity may provide the reliability of a positive FDG PET or PET/CT to detect peritoneal carcinomatosis in patients with cancer. FDG PET or PET/CT has only weak power to exclude the presence of peritoneal carcinomatosis. By a good overall diagnostic accuracy, FDG PET or PET/CT may prove beneficial to surgeons when selecting appropriate patients on whom to perform laparoscopy or laparotomy. PMID- 23797226 TI - Transposition of the great arteries: a myocardial perfusion PET-CT study. AB - We report the case of a 20-year-old woman with surgically corrected transposition of the great arteries, pulmonary valve defects, and absence of left coronary ostium at a previous cardiac catheterization. Because of worsening dyspnea, she underwent myocardial perfusion PET/CT study with 13N-ammonia at rest and during pharmacological stress, which showed extensive ischemia in the left coronary territory and signs of severe left ventricle dysfunction. Quantitative PET data showed impaired regional coronary flow reserve (<2.0) in the left coronary territory, thus allowing a precise and reliable evaluation of the myocardial perfusion defect because of the absence of left coronary ostium. PMID- 23797227 TI - Inflammatory myofibroblastic tumor: FDG PET/CT findings with pathologic correlation. AB - PURPOSE: The aim of this study was to evaluate retrospectively F-FDG PET/CT findings of inflammatory myofibroblastic tumor (IMT) and their correlation with the pathologic findings. PATIENTS AND METHODS: FDG PET/CT findings were reviewed in 5 patients with IMT and 1 patient with spindle cell sarcoma transformed from IMT. PET/CT scans were performed in all 6 patients before surgery. Follow-up FDG PET/CT scan was performed in 1 patient. The location, size, maximal standardized uptake value (SUVmax), and pathologic findings of the tumors were reviewed. The correlation between the FDG uptake and pathologic findings were analyzed. RESULTS: A total of 10 lesions were detected in all 6 patients. The tumor locations were liver (n = 3), retroperitoneum (n = 2), spleen (n = 1), lung (n = 1), and bone (n = 3). Seven IMTs and 1 spindle cell sarcoma transformed from IMT were confirmed by pathology. The mean SUVmax of the pathologically proven tumors was 10.9 +/- 5.5, with a high variability of SUVmax among tumors ranging from 3.3 to 20.8. The tumors (n = 7) with high cellularity had stronger FDG uptake, while the tumors (n = 1) with low cellularity had relatively low FDG uptake. The tumors with nuclear atypia and relatively high proliferative index had very strong FDG uptake, while those with low proliferative index or negative Ki-67 staining had relatively lower FDG uptake. One small tumor with abundant plasma cells showed high FDG uptake, while 1 large tumor with focal inflammatory cell infiltrate showed lower FDG uptake. One patient developed local recurrences and distant metastases revealed by the second FDG PET/CT scan 7 months after resection. CONCLUSIONS: FDG uptake in IMTs varied from low to high FDG uptake, which may be due to tumor cellularity, biological behaviors of the tumor cells, the composition and the proportion of inflammatory cells, and the extent of activation of the inflammatory cells. FDG PET/CT may be useful for detection of the primary tumors, local recurrences, and distant metastases. PMID- 23797228 TI - Radiation exposure to family caregivers and nurses of pediatric neuroblastoma patients receiving 131I-metaiodobenzylguanidine (131I-MIBG) therapy. AB - PURPOSE: (131)I-MIBG provides molecularly targeted radiotherapy for pediatric neuroblastoma patients with relapsed or refractory disease. At our institution, designated family caregivers and nurses participate in the care of the child during hospital isolation for approximately 3-5 days post-administration. The purpose of this study was to measure radiation exposure to family caregivers and nurses caring for children with neuroblastoma during their stay in the hospital for (131)I-MIBG therapy. METHODS: Iodine-(131)I-MIBG therapy was administered to 14 children (mean age 6.7 +/- 3.8 years, range 3-13 years) for relapsed or refractory neuroblastoma from 2009 to 2010. The administered activity ranged from 5.92 to 23.31 GBq (mean 13.65 +/- 5.22 GBq). The mean administered activities were 8.77 +/- 2.07 GBq (range 5.92-11.1 GBq) and 17.32 +/- 3.4 GBq (range 11.84 23.31 GBq) for children less than 7 and 7 years or older, respectively. One or two designated caregivers received specific radiation safety training prior to treatment. One caregiver was allowed to stay in a room adjacent to the child to provide general patient care as instructed by nursing. Nurses assigned to the care of the patient also received specific radiation instructions. The total caregiver and nursing whole body radiation dose was determined using real-time personal dosimetry. RESULTS: There was no correlation between caregiver (r = 0.068, P = 0.817) or nursing (r = -0.031, P = 0.916) whole-body radiation dose and the patient-administered activity. The overall mean caregiver radiation dose was 1.79 +/- 1.04 mSv, but the range of caregiver radiation doses varied by more than an order of magnitude (0.35-3.81 mSv), with no caregiver receiving more than 4.0 mSv. The overall mean nursing radiation dose was 0.44 +/- 0.27 mSv per treatment, ranging from 0.15 to 1.08 mSv, with no nurse receiving more than 1.1 mSv. When grouped by patient age, there was no significant difference (P = 0.673) in the mean caregiver exposure for children less than 7 years, 1.94 +/- 1.17 mSv (n = 6, range 0.7-3.81 mSv), compared to 1.69 +/- 0.99 mSv (n = 8, range 0.35 3.37 mSv) for children 7 years or older. Similarly, there was no significant difference (P = 0.511) in mean nursing exposure for children less than 7 years, 0.5 +/- 0.31 mSv (n = 6, range 0.18-1.08 mSv), compared to 0.4 +/- 0.24 mSv (n = 8, range 0.15-0.94 mSv) for children 7 years or older. CONCLUSION: There was no significant correlation between caregiver or nursing radiation exposure and patient-administered activity or no significant difference between patient age. This may suggest that older children who tend to receive higher administered activities may require less direct caregiver support during their hospital stay. Most importantly, all caregivers and nurses received radiation doses allowed under current regulations for individuals exposed to therapy patients during hospital isolation (<5.0 mSv), although this does not include exposure the caregivers may receive once the patient leaves the hospital. PMID- 23797229 TI - 99mTc-HYNIC-TOC (99mTc-hydrazinonicotinyl-Tyr3-octreotide) scintigraphy identifying two separate causative tumors in a patient with tumor-induced osteomalacia (TIO). AB - Tumors that cause osteomalacia are generally benign fibroblast growth factor-23 producing mesenchymal tumors which can be detected by octreoscan. A 45-year-old man underwent (99m)Tc-HYNIC-TOC scan to detect a possible culprit causing osteomalacia. The images showed abnormal activity in the left humerus and in the right foot. The lesion of the right foot was confirmed pathologically as phosphaturic mesenchymal tumor. After surgical removal of the tumor in the right foot, the patient's symptoms were promptly improved. However, the improvement was transient due to the unresected tumor in the left humerus. PMID- 23797230 TI - 18F sodium fluoride PET/CT detects osseous metastases from breast cancer missed on FDG PET/CT with marrow rebound. AB - Intense FDG uptake by bone marrow following recent chemotherapy limits evaluation for osseous metastases. The impact of marrow rebound on accuracy of (18)F fluoride PET/CT is unclear. A 73-year-old woman with breast cancer presented for restaging FDG PET/CT, which showed intense activity throughout almost the entire axial skeleton and no osseous metastases. An (18)F-fluoride PET/CT performed 7 days later identified multiple osseous metastases in the spine, ribs, and pelvis. This case demonstrates that (18)F-fluoride PET/CT should be considered for the evaluation of osseous metastases in patients with rebound marrow uptake on FDG PET/CT. PMID- 23797231 TI - A rare case of mucinous cystadenoma of the lung mimicking malignancy at 18F-FDG PET/CT. AB - We describe a rare case of pulmonary mucinous cystadenoma (PMCA) detected F-FDG PET/CT and mimicking a malignancy. A 60-year-old female patient underwent F-FDG PET/CT for metabolic characterization of a left pulmonary nodule which showed increased F-FDG uptake (SUVmax = 3.7). Based on this PET/CT finding, the patient underwent a cuneiform resection of the left pulmonary nodule. Histology demonstrated the presence of a PMCA. In our case, F-FDG PET/CT has been useful in detecting this rare pulmonary tumor. PMID- 23797232 TI - FDG PET/CT findings of superficial angiomyxoma. AB - Superficial angiomyxoma, also known as cutaneous myxoma, is a rare but distinctive soft tissue tumor characterized by a sparse proliferation of spindle shaped cells in a prominent myxoid matrix with numerous thin-walled blood vessels. We present a case of a pathologically proven superficial angiomyxoma arising in the first web space of the left hand of a 39-year-old man. Integrated PET/CT images showed mild focal FDG uptake in a subcutaneous soft tissue mass, with a maximum standardized uptake value of 2.94. PMID- 23797233 TI - Breast cancer patient with an uncommon lymphatic drainage evidenced by SPECT/CT. AB - SPECT/CT reinforces the role of lymphoscintigraphy in breast cancer by solving some cases with difficult reading on planar scintigraphy. An 80-year-old woman was referred to our institution for management of a screen-detected, nonpalpable, invasive lobular carcinoma of lower inner quadrant of the left breast. Lymphoscintigraphy was performed before surgery. Planar images showed an axillary sentinel node and 2 medially located hot spots. SPECT/CT allowed determining that one of the extra-axillary drainage sites was to the internal mammary basin, while the second corresponded to a mediastinal lymph node. Although this drainage was unexpected, mediastinum is a common site of breast cancer recurrence. PMID- 23797234 TI - SPECT/CT of metastatic struma ovarii. AB - A 41-year-old woman presented with multiple right lower quadrant masses which were removed and consistent with metastatic follicular thyroid cancer. Thyroidectomy revealed no primary malignancy and evaluation of her ovaries was positive for struma ovarii. The patient was diagnosed with metastatic struma ovarii stage IV. Nine days following the patient's second therapy with I for recurrent disease, planar and SPECT/CT imaging demonstrated multiple I avid peritoneal nodules. At least one of them, located along the medial margin of the spleen, would have been difficult to diagnose without hybrid SPECT/CT imaging. PMID- 23797235 TI - Fit and motivated: outcome predictors in patients starting a program for lifestyle change. AB - BACKGROUND: In previous pilot studies we have demonstrated that the Treatment Motivation and Readiness Test (TRE-MORE) is capable of predicting the outcome of obesity therapy and that a higher muscle mass (MM) is associated with a greater weight loss. Purposes of the present study were: to confirm the predictive value of TRE-MORE scores and MM, using a standardized non-pharmacologic intervention for weight loss; to explore the relationship between TRE-MORE and MM; to discriminate predictors of attendance from predictors of final therapeutic success. METHODS: A consecutive series of 331 patients was enrolled and addressed to a standardized treatment protocol. RESULTS: Mean weight loss at 6 months was 5.03%. Among participants, 48.7% lost at least 5% initial body weight after 6 months and had significantly higher TRE-MORE total scores and MM. Weight loss was significantly associated with baseline MM, TRE-MORE-3, and a lower number of previous diets. Significantly lower TRE-MORE-3 scores were associated with drop out. CONCLUSION: The present study confirms that therapeutic success is predicted by TRE-MORE scores and, independently from these, by estimated MM (after adjustment for BMI). TRE-MORE total score is a predictor of failure, but not of attendance, whereas drop-out patients showed a lower score only in TREMORE-3 subscale which investigates lifestyle habits. PMID- 23797236 TI - Adult acute lymphoblastic leukemia: a cancer with no standard of care. PMID- 23797237 TI - Methylation markers for prostate cancer prognosis: a systematic review. AB - PURPOSE: We conducted a systematic review to summarize current evidence on the prognostic utility of DNA methylation markers in prostate cancer and ascertain knowledge gaps to inform future research. METHODS: We identified relevant studies using combined key search against PubMed database. Inclusion criteria were studies of human subjects that examined the association between DNA methylation markers and prostate cancer disease outcomes. The methodological quality of each study was systematically evaluated. Findings were qualitatively summarized. Due to heterogeneity and concerns of internal validity, no meta-analysis was performed. RESULTS: Twenty studies were reviewed; sample size ranged from 35 to 605 men in the prognostic analyses. Sixteen studies examined methylation markers in prostate cancer tissue and four examined circulating DNA methylation markers. Of all genes reviewed, paired-like homeodomain transcription factor 2 (PITX2) methylation was examined in two more rigorously designed studies and was found to be associated with biochemical recurrence. Common limitations in current literature included small sample sizes,lack of adequate adjustment for established prognostic factors, and poor reporting quality. CONCLUSION: Evidence on the prognostic utility of methylation markers in prostate cancer is inconclusive. Future research should ascertain large samples with adequate follow up and include patients of racial/ethnic minority and those treated with modalities other than prostatectomy(e.g., using prostate cancer diagnostic biopsy as tissue source). PMID- 23797238 TI - Benchmarking HEp-2 cells classification methods. AB - In this paper, we report on the first edition of the HEp-2 Cells Classification contest, held at the 2012 edition of the International Conference on Pattern Recognition, and focused on indirect immunofluorescence (IIF) image analysis. The IIF methodology is used to detect autoimmune diseases by searching for antibodies in the patient serum but, unfortunately, it is still a subjective method that depends too heavily on the experience and expertise of the physician. This has been the motivation behind the recent initial developments of computer aided diagnosis systems in this field. The contest aimed to bring together researchers interested in the performance evaluation of algorithms for IIF image analysis: 28 different recognition systems able to automatically recognize the staining pattern of cells within IIF images were tested on the same undisclosed dataset. In particular, the dataset takes into account the six staining patterns that occur most frequently in the daily diagnostic practice: centromere, nucleolar, homogeneous, fine speckled, coarse speckled, and cytoplasmic. In the paper, we briefly describe all the submitted methods, analyze the obtained results, and discuss the design choices conditioning the performance of each method. PMID- 23797240 TI - Dynamic contrast-enhanced MRI-based early detection of acute renal transplant rejection. AB - A novel framework for the classification of acute rejection versus nonrejection status of renal transplants from 2-D dynamic contrast-enhanced magnetic resonance imaging is proposed. The framework consists of four steps. First, kidney objects are segmented from adjacent structures with a level set deformable boundary guided by a stochastic speed function that accounts for a fourth-order Markov Gibbs random field model of the kidney/background shape and appearance. Second, a Laplace-based nonrigid registration approach is used to account for local deformations caused by physiological effects. Namely, the target kidney object is deformed over closed, equispaced contours (iso-contours) to closely match the reference object. Next, the cortex is segmented as it is the functional kidney unit that is most affected by rejection. To characterize rejection, perfusion is estimated from contrast agent kinetics using empirical indexes, namely, the transient phase indexes (peak signal intensity, time-to-peak, and initial up slope), and a steady-phase index defined as the average signal change during the slowly varying tissue phase of agent transit. We used a kn-nearest neighbor classifier to distinguish between acute rejection and nonrejection. Performance of our method was evaluated using the receiver operating characteristics (ROC). Experimental results in 50 subjects, using a combinatoric kn-classifier, correctly classified 92% of training subjects, 100% of the test subjects, and yielded an area under the ROC curve that approached the ideal value. Our proposed framework thus holds promise as a reliable noninvasive diagnostic tool. PMID- 23797239 TI - Including spatial information in nonlinear inversion MR elastography using soft prior regularization. AB - Tissue displacements required for mechanical property reconstruction in magnetic resonance elastography (MRE) are acquired in a magnetic resonance imaging (MRI) scanner, therefore, anatomical information is available from other imaging sequences. Despite its availability, few attempts to incorporate prior spatial information in the MRE reconstruction process have been reported. This paper implements and evaluates soft prior regularization (SPR), through which homogeneity in predefined spatial regions is enforced by a penalty term in a nonlinear inversion strategy. Phantom experiments and simulations show that when predefined regions are spatially accurate, recovered property values are stable for SPR weighting factors spanning several orders of magnitude, whereas inaccurate segmentation results in bias in the reconstructed properties that can be mitigated through proper choice of regularization weighting. The method was evaluated in vivo by estimating viscoelastic mechanical properties of frontal lobe gray and white matter for five repeated scans of a healthy volunteer. Segmentations of each tissue type were generated using automated software, and statistically significant differences between frontal lobe gray and white matter were found for both the storage modulus and loss modulus . Provided homogeneous property assumptions are reasonable, SPR produces accurate quantitative property estimates for tissue structures which are finer than the resolution currently achievable with fully distributed MRE. PMID- 23797243 TI - Visual and Contextual Modeling for the Detection of Repeated Mild Traumatic Brain Injury. AB - Currently, there is a lack of computational methods for the evaluation of mild traumatic brain injury (mTBI) from magnetic resonance imaging (MRI). Further, the development of automated analyses has been hindered by the subtle nature of mTBI abnormalities, which appear as low contrast MR regions. This paper proposes an approach that is able to detect mTBI lesions by combining both the high-level context and low-level visual information. The contextual model estimates the progression of the disease using subject information, such as the time since injury and the knowledge about the location of mTBI. The visual model utilizes texture features in MRI along with a probabilistic support vector machine to maximize the discrimination in unimodal MR images. These two models are fused to obtain a final estimate of the locations of the mTBI lesion. The models are tested using a novel rodent model of repeated mTBI dataset. The experimental results demonstrate that the fusion of both contextual and visual textural features outperforms other state-of-the-art approaches. Clinically, our approach has the potential to benefit both clinicians by speeding diagnosis and patients by improving clinical care. PMID- 23797242 TI - Framework to co-register longitudinal virtual histology-intravascular ultrasound data in the circumferential direction. AB - Considerable efforts have been directed at identifying prognostic markers for rapidly progressing coronary atherosclerotic lesions that may advance into a high risk (vulnerable) state. Intravascular ultrasound (IVUS) has become a valuable clinical tool to study the natural history of coronary artery disease (CAD). While prospectively IVUS studies have provided tremendous insight on CAD progression, and its association with independent markers (e.g., wall shear stress), they are limited by the inability to examine the focal association between spatially heterogeneous variables (in both circumferential and axial directions). Herein, we present a framework to automatically co-register longitudinal (in-time) virtual histology-intravascular ultrasound (VH-IVUS) imaging data in the circumferential direction (i.e., rotate follow-up image so circumferential basis coincides with corresponding baseline image). Multivariate normalized cross correlation was performed on paired images (n = 636) from five patients using three independent VH-IVUS defined parameters: artery thickness, VH IVUS defined plaque constituents, and VH-IVUS perivascular imaging data. Results exhibited high correlation between co-registration rotation angles determined automatically versus manually by an expert reader ( r(2) = 0.90). Furthermore, no significant difference between automatic and manual co-registration angles was observed ( 91.31 +/-1.04( degrees ) and 91.07 +/-1.04( degrees ), respectively; p = 0.48) and Bland-Altman analysis yielded excellent agreement ( bias = 0.24( degrees ), 95% CI +/- 16.33( degrees )). In conclusion, we have developed, verified, and validated an algorithm that automatically co-registers VH-IVUS imaging data that will allow for the focal examination of CAD progression. PMID- 23797241 TI - Assessment of cardiac motion effects on the fiber architecture of the human heart in vivo. AB - The use of diffusion tensor imaging (DTI) for studying the human heart in vivo is very challenging due to cardiac motion. This paper assesses the effects of cardiac motion on the human myocardial fiber architecture. To this end, a model for analyzing the effects of cardiac motion on signal intensity is presented. A Monte-Carlo simulation based on polarized light imaging data is then performed to calculate the diffusion signals obtained by the displacement of water molecules, which generate diffusion weighted (DW) images. Rician noise and in vivo motion data obtained from DENSE acquisition are added to the simulated cardiac DW images to produce motion-induced datasets. An algorithm based on principal components analysis filtering and temporal maximum intensity projection (PCATMIP) is used to compensate for motion-induced signal loss. Diffusion tensor parameters derived from motion-reduced DW images are compared to those derived from the original simulated DW images. Finally, to assess cardiac motion effects on in vivo fiber architecture, in vivo cardiac DTI data processed by PCATMIP are compared to those obtained from one trigger delay (TD) or one single phase acquisition. The results showed that cardiac motion produced overestimated fractional anisotropy and mean diffusivity as well as a narrower range of fiber angles. The combined use of shifted TD acquisitions and postprocessing based on image registration and PCATMIP effectively improved the quality of in vivo DW images and subsequently, the measurement accuracy of fiber architecture properties. This suggests new solutions to the problems associated with obtaining in vivo human myocardial fiber architecture properties in clinical conditions. PMID- 23797244 TI - Unsupervised segmentation, clustering, and groupwise registration of heterogeneous populations of brain MR images. AB - Population analysis of brain morphology from magnetic resonance images contributes to the study and understanding of neurological diseases. Such analysis typically involves segmentation of a large set of images and comparisons of these segmentations between relevant subgroups of images (e.g., "normal" versus "diseased"). The images of each subgroup are usually selected in advance in a supervised way based on clinical knowledge. Their segmentations are typically guided by one or more available atlases, assumed to be suitable for the images at hand. We present a data-driven probabilistic framework that simultaneously performs atlas-guided segmentation of a heterogeneous set of brain MR images and clusters the images in homogeneous subgroups, while constructing separate probabilistic atlases for each cluster to guide the segmentation. The main benefits of integrating segmentation, clustering and atlas construction in a single framework are that: 1) our method can handle images of a heterogeneous group of subjects and automatically identifies homogeneous subgroups in an unsupervised way with minimal prior knowledge, 2) the subgroups are formed by automatical detection of the relevant morphological features based on the segmentation, 3) the atlases used by our method are constructed from the images themselves and optimally adapted for guiding the segmentation of each subgroup, and 4) the probabilistic atlases represent the morphological pattern that is specific for each subgroup and expose the groupwise differences between different subgroups. We demonstrate the feasibility of the proposed framework and evaluate its performance with respect to image segmentation, clustering and atlas construction on simulated and real data sets including the publicly available BrainWeb and ADNI data. It is shown that combined segmentation and atlas construction leads to improved segmentation accuracy. Furthermore, it is demonstrated that the clusters generated by our unsupervised framework largely coincide with the clinically determined subgroups in case of disease-specific differences in brain morphology and that the differences between the cluster specific atlases are in agreement with the expected disease-specific patterns, indicating that our method is capable of detecting the different modes in a population. Our method can thus be seen as a comprehensive image-driven population analysis framework that can contribute to the detection of novel subgroups and distinctive image features, potentially leading to new insights in the brain development and disease. PMID- 23797245 TI - The spectrum of MOG autoantibody-associated demyelinating diseases. AB - Myelin oligodendrocyte glycoprotein (MOG) has been identified as a target of demyelinating autoantibodies in animal models of inflammatory demyelinating diseases of the CNS, such as multiple sclerosis (MS). Numerous studies have aimed to establish a role for MOG antibodies in patients with MS, although the results have been controversial. Cell-based immunoassays using MOG expressed in mammalian cells have demonstrated the presence of high-titre MOG antibodies in paediatric patients with acute disseminated encephalomyelitis, MS, aquaporin-4-seronegative neuromyelitis optica, or isolated optic neuritis or transverse myelitis, but only rarely in adults with these disorders. These studies indicate that MOG antibodies could be associated with a broad spectrum of acquired human CNS demyelinating diseases. This Review article discusses the current literature on MOG antibodies, their potential clinical relevance, and their role in the pathogenesis of MOG antibody-associated demyelinating disorders. PMID- 23797246 TI - Neurodegenerative disease: 'fifty shades of grey' in the Huntington disease gene. PMID- 23797247 TI - Mechanism and therapeutic strategy of secondary failure to anti-tumor necrosis factor-alpha monoclonal antibody treatment for Crohn's disease. AB - It is not too much to say that infliximab has revolutionized the treatment of Crohn's disease. However, there is the problem of 'secondary failure' wherein the effect may diminish during treatment. This is a much-discussed topic. For example, not all patients with secondary failure can maintain remission with dose intensification to 10 mg/kg. It is also important to make the appropriate drug selection and to clarify the optimal timing of dose intensification for achieving long-term maintenance of remission, including discussion of the first priority use of adalimumab. PMID- 23797248 TI - A combined microphone and camera calibration technique with application to acoustic imaging. AB - We present a calibration technique for an acoustic imaging microphone array, combined with a digital camera. Computer vision and acoustic time of arrival data are used to obtain microphone coordinates in the camera reference frame. Our new method allows acoustic maps to be plotted onto the camera images without the need for additional camera alignment or calibration. Microphones and cameras may be placed in an ad-hoc arrangement and, after calibration, the coordinates of the microphones are known in the reference frame of a camera in the array. No prior knowledge of microphone positions, inter-microphone spacings, or air temperature is required. This technique is applied to a spherical microphone array and a mean difference of 3 mm was obtained between the coordinates obtained with this calibration technique and those measured using a precision mechanical method. PMID- 23797249 TI - Pose estimation with segmentation consistency. AB - In this paper, we propose a novel method that treats pose estimation as a problem with the constraints of human segmentation consistency from single images. Different from the previous paper, we integrate pose estimation and object segmentation into a joint optimization. With the support of segmentation consistency, we can obtain more reliable pose results. Through analyzing the energy function of pose estimation and human segmentation, we convert the pose estimation into a binary optimization problem that has the same formation as segmentation. The top-down pose shape cues, bottom-up visual cues, and the consistency constraints that penalize the mismatching of pose and human foreground are incorporated into our final objective function. Qualitative and quantitative experimental results demonstrate the merits of our method in pose estimation on Ramanan benchmark and Buffy data sets. PMID- 23797250 TI - Noise-resistant local binary pattern with an embedded error-correction mechanism. AB - Local binary pattern (LBP) is sensitive to noise. Local ternary pattern (LTP) partially solves this problem. Both LBP and LTP, however, treat the corrupted image patterns as they are. In view of this, we propose a noise-resistant LBP (NRLBP) to preserve the image local structures in presence of noise. The small pixel difference is vulnerable to noise. Thus, we encode it as an uncertain state first, and then determine its value based on the other bits of the LBP code. It is widely accepted that most of the image local structures are represented by uniform codes and noise patterns most likely fall into the non-uniform codes. Therefore, we assign the value of an uncertain bit hence as to form possible uniform codes. Thus, we develop an error-correction mechanism to recover the distorted image patterns. In addition, we find that some image patterns such as lines are not captured in uniform codes. Those line patterns may appear less frequently than uniform codes, but they represent a set of important local primitives for pattern recognition. Thus, we propose an extended noise-resistant LBP (ENRLBP) to capture line patterns. The proposed NRLBP and ENRLBP are more resistant to noise compared with LBP, LTP, and many other variants. On various applications, the proposed NRLBP and ENRLBP demonstrate superior performance to LBP/LTP variants. PMID- 23797251 TI - A novel fractal image compression scheme with block classification and sorting based on Pearson's correlation coefficient. AB - Fractal image compression (FIC) is an image coding technology based on the local similarity of image structure. It is widely used in many fields such as image retrieval, image denoising, image authentication, and encryption. FIC, however, suffers from the high computational complexity in encoding. Although many schemes are published to speed up encoding, they do not easily satisfy the encoding time or the reconstructed image quality requirements. In this paper, a new FIC scheme is proposed based on the fact that the affine similarity between two blocks in FIC is equivalent to the absolute value of Pearson's correlation coefficient (APCC) between them. First, all blocks in the range and domain pools are chosen and classified using an APCC-based block classification method to increase the matching probability. Second, by sorting the domain blocks with respect to APCCs between these domain blocks and a preset block in each class, the matching domain block for a range block can be searched in the selected domain set in which these APCCs are closer to APCC between the range block and the preset block. Experimental results show that the proposed scheme can significantly speed up the encoding process in FIC while preserving the reconstructed image quality well. PMID- 23797252 TI - Multiview-video-plus-depth coding based on the advanced video coding standard. AB - This paper presents a multiview-video-plus-depth coding scheme, which is compatible with the advanced video coding (H.264/AVC) standard and its multiview video coding (MVC) extension. This scheme introduces several encoding and in-loop coding tools for depth and texture video coding, such as depth-based texture motion vector prediction, depth-range-based weighted prediction, joint inter-view depth filtering, and gradual view refresh. The presented coding scheme is submitted to the 3D video coding (3DV) call for proposals (CfP) of the Moving Picture Experts Group standardization committee. When measured with commonly used objective metrics against the MVC anchor, the proposed scheme provides an average bitrate reduction of 26% and 35% for the 3DV CfP test scenarios with two and three views, respectively. The observed bitrate reduction is similar according to an analysis of the results obtained for the subjective tests on the 3DV CfP submissions. PMID- 23797253 TI - User-action-driven view and rate scalable multiview video coding. AB - We derive an optimization framework for joint view and rate scalable coding of multi-view video content represented in the texture plus depth format. The optimization enables the sender to select the subset of coded views and their encoding rates such that the aggregate distortion over a continuum of synthesized views is minimized. We construct the view and rate embedded bitstream such that it delivers optimal performance simultaneously over a discrete set of transmission rates. In conjunction, we develop a user interaction model that characterizes the view selection actions of the client as a Markov chain over a discrete state-space. We exploit the model within the context of our optimization to compute user-action-driven coding strategies that aim at enhancing the client's performance in terms of latency and video quality. Our optimization outperforms the state-of-the-art H.264 SVC codec as well as a multi-view wavelet based coder equipped with a uniform rate allocation strategy, across all scenarios studied in our experiments. Equally important, we can achieve an arbitrarily fine granularity of encoding bit rates, while providing a novel functionality of view embedded encoding, unlike the other encoding methods that we examined. Finally, we observe that the interactivity-aware coding delivers superior performance over conventional allocation techniques that do not anticipate the client's view selection actions in their operation. PMID- 23797254 TI - Digital multi-focusing from a single photograph taken with an uncalibrated conventional camera. AB - The demand to restore all-in-focus images from defocused images and produce photographs focused at different depths is emerging in more and more cases, such as low-end hand-held cameras and surveillance cameras. In this paper, we manage to solve this challenging multi-focusing problem with a single image taken with an uncalibrated conventional camera. Different from all existing multi-focusing approaches, our method does not need to include a deconvolution process, which is quite time-consuming and will cause ringing artifacts in the focused region and low depth-of-field. This paper proposes a novel systematic approach to realize multi-focusing from a single photograph. First of all, with the optical explanation for the local smooth assumption, we present a new point-to-point defocus model. Next, the blur map of the input image, which reflects the amount of defocus blur at each pixel in the image, is estimated by two steps. 1) With the sharp edge prior, a rough blur map is obtained by estimating the blur amount at the edge regions. 2) The guided image filter is applied to propagate the blur value from the edge regions to the whole image by which a refined blur map is obtained. Thus far, we can restore the all-in-focus photograph from a defocused input. To further produce photographs focused at different depths, the depth map from the blur map must be derived. To eliminate the ambiguity over the focal plane, user interaction is introduced and a binary graph cut algorithm is used. So we introduce user interaction and use a binary graph cut algorithm to eliminate the ambiguity over the focal plane. Coupled with the camera parameters, this approach produces images focused at different depths. The performance of this new multi-focusing algorithm is evaluated both objectively and subjectively by various test images. Both results demonstrate that this algorithm produces high quality depth maps and multi-focusing results, outperforming the previous approaches. PMID- 23797255 TI - Low latency secondary transforms for intra/inter prediction residual. AB - In this paper, we present a transform scheme where a secondary transform is applied after the conventional DCT for intra as well as inter prediction residues. Our approach is applicable to any block-based video codec that employs transforms along the horizontal and vertical direction separably. The secondary transform is applied to the lower K ( K=4 or 8) frequency coefficients of the output of conventional DCT at block with dimensions 8 and larger. The proposed transform scheme has low complexity as it is applied only to the top-left portion of the DCT output, especially in the context of large blocks such as 32 * 32 where an alternate non-DCT 32 * 32 transform would have a prohibitive implementation hardware cost. The proposed technique is single-pass, and the choice of whether to use the secondary transform is solely based on the prediction direction for intra residue, and on transform unit location in the prediction unit for the inter residue. The scheme requires no additional signaling information or R-D search. Our simulation results show that the proposed transform scheme provides significant BD-rate improvement over the conventional DCT-based coding scheme. Finally, we also show how to implement the proposed secondary transforms with low latency in hardware. PMID- 23797256 TI - Reducing integrability error of color tensor gradients for image fusion. AB - To overcome the difficulties in applying gradient-based operators to color images, Di Zenzo introduced the color tensor, an operator that provides a gradient field for multichannel images. An elegant application for this operator was developed in the domain of multichannel image visualization: Socolinsky and Wolff proposed to reintegrate Di Zenzo's gradient by solving a Poisson equation, yielding a greyscale representation of the multispectral contrast of the input image. Di Zenzo's gradients are, however, generally not integrable and some approximation must be introduced. Thus, the resulting image can suffer from artifacts such as the smearing of edges. In this paper, we focus on the integrability of Di Zenzo's gradients. We show that the integrability of the obtained field can be improved dramatically through a simple desaturation of the color image (as in the HSV color space). This result can be readily extended to multispectral images by defining an analogue to saturation. We present several results explaining what happens to color tensors as the saturation changes. Significantly we show that small changes of the saturation in the linear image space can result in large improvements in the integrability of tensor gradients calculated in logarithmic color space. This result is important for two reasons. 1) Log-differences are more perceptually meaningful. 2) In log-space we can operate with retinex algorithms, which are well known techniques for contrast enhancement. We propose that they can be used to "put back" any contrast that might be lost in the desaturation step and, more importantly, they can enhance contrast at the same time as reintegrating the gradient field because of their relation to partial differential equations. Finally, we evaluate our method psychophysically. Compared with other commonly used image fusion methods, experiments show that our data fusion using the Di Zenzo color tensor after desaturating the image and where a simple contrast boost is applied is strongly preferred. PMID- 23797257 TI - An iterative linear expansion of thresholds for l1-based image restoration. AB - This paper proposes a novel algorithmic framework to solve image restoration problems under sparsity assumptions. As usual, the reconstructed image is the minimum of an objective functional that consists of a data fidelity term and an l1 regularization. However, instead of estimating the reconstructed image that minimizes the objective functional directly, we focus on the restoration process that maps the degraded measurements to the reconstruction. Our idea amounts to parameterize the process as a linear combination of few elementary thresholding functions (LET) and to solve the linear weighting coefficients by minimizing the objective functional. It is then possible to update the thresholding functions and to iterate this process ( i-LET). The key advantage of such a linear parametrization is that the problem size reduces dramatically--each time we only need to solve an optimization problem over the dimension of the linear coefficients (typically less than 10) instead of the whole image dimension. With the elementary thresholding functions satisfying certain constraints, a global convergence of the iterated LET algorithm is guaranteed. Experiments on several test images over a wide range of noise levels and different types of convolution kernels clearly indicate that the proposed framework usually outperforms state-of the-art algorithms in terms of both the CPU time and the number of iterations. PMID- 23797258 TI - A curve evolution approach for unsupervised segmentation of images with low depth of field. AB - In this paper, we describe a novel algorithm for unsupervised segmentation of images with low depth of field (DOF). First of all, a multi-scale reblurring model is used to detect the object of interest (OOI) in saliency space. Then, to determine the boundary of OOI, an active contour model based on hybrid energy function is proposed. In this model, a global energy item related with the saliency map is adopted to find the global minimum, and a local energy term regarding the low DOF image is used to improve the segmentation precision. In addition, an adaptive parameter is attached to this model to balance the weight of global and local energy. Furthermore, an unsupervised curve initialization method is designed to reduce the number of evolution iterations. Finally, we conduct experiments on various low DOF images, and the results demonstrate the high robustness and precision of the proposed approach. PMID- 23797259 TI - C4: a real-time object detection framework. AB - A real-time and accurate object detection framework, C(4), is proposed in this paper. C(4) achieves 20 fps speed and the state-of-the-art detection accuracy, using only one processing thread without resorting to special hardware such as GPU. The real-time accurate object detection is made possible by two contributions. First, we conjecture (with supporting experiments) that contour is what we should capture and signs of comparisons among neighboring pixels are the key information to capture contour cues. Second, we show that the CENTRIST visual descriptor is suitable for contour based object detection, because it encodes the sign information and can implicitly represent the global contour. When CENTRIST and linear classifier are used, we propose a computational method that does not need to explicitly generate feature vectors. It involves no image preprocessing or feature vector normalization, and only requires O(1) steps to test an image patch. C(4) is also friendly to further hardware acceleration. It has been applied to detect objects such as pedestrians, faces, and cars on benchmark data sets. It has comparable detection accuracy with state-of-the-art methods, and has a clear advantage in detection speed. PMID- 23797260 TI - DSIM: a DisSIMilarity-based image clutter metric for targeting performance. AB - Previous image clutter metrics were proposed on the thought that clutter was just a perceptual effect, while we identify clutter as both perceptual and cognitive effects. Under this identification, we give a new definition of image clutter metric by analyzing the research results in the fields of visual psychology and psychophysics. According to the definition, we further put forward a DisSIMilarity (DSIM) based image clutter metric, which can also be taken as a kind of HVS-based signal-to-clutter ratio. The earlier image clutter metrics produced limited success in predicting targeting performance mainly since they did not consider brain cognitive characteristics. We develop a brain cognitive dissimilarity measure (BCDM) as a quantitative estimate of the selection weights which are allocated by brain attentional mechanism to affect visual selection processes. A human vision perceptual dissimilarity measure (VPDM), fully embodying vision perceptual properties, is first established between the target and clutter images, and then we utilize the BCDM between the two images as selection weights to pool the VPDM to be a clutter metric, which can be called DSIM metric. The metric is tested in Search_2 dataset provided by TNO Human Factors Research Institute of Netherlands. Error analysis and correlation tests demonstrate that the DSIM metric makes a more significant improvement than previously proposed metrics in predicting 62 observers' targeting performances including detection probability, false alarm probability and search time. PMID- 23797261 TI - 3D superalloy grain segmentation using a multichannel edge-weighted centroidal Voronoi tessellation algorithm. AB - Accurate grain segmentation on 3D superalloy images is very important in materials science and engineering. From grain segmentation, we can derive the underlying superalloy grains' micro-structures, based on how many important physical, mechanical, and chemical properties of the superalloy samples can be evaluated. Grain segmentation is, however, usually a very challenging problem because: 1) even a small 3D superalloy sample may contain hundreds of grains; 2) carbides and noises may degrade the imaging quality; and 3) the intensity within a grain may not be homogeneous. In addition, the same grain may present different appearances, e.g., different intensities, under different microscope settings. In practice, a 3D superalloy image may contain multichannel information where each channel corresponds to a specific microscope setting. In this paper, we develop a multichannel edge-weighted centroidal Voronoi tessellation (MCEWCVT) algorithm to effectively and robustly segment the superalloy grains from 3D multichannel superalloy images. MCEWCVT performs segmentation by minimizing an energy function, which encodes both the multichannel voxel-intensity similarity within each cluster in the intensity domain and the smoothness of segmentation boundaries in the 3D image domain. In the experiment, we first quantitatively evaluate the proposed MCEWCVT algorithm on a four-channel Ni-based 3D superalloy data set (IN100) against the manually annotated ground-truth segmentation. We further evaluate the MCEWCVT algorithm on two synthesized four-channel superalloy data sets. The qualitative and quantitative comparisons of 18 existing image segmentation algorithms demonstrate the effectiveness and robustness of the proposed MCEWCVT algorithm. PMID- 23797262 TI - Navigation domain representation for interactive multiview imaging. AB - Enabling users to interactively navigate through different viewpoints of a static scene is a new interesting functionality in 3D streaming systems. While it opens exciting perspectives toward rich multimedia applications, it requires the design of novel representations and coding techniques to solve the new challenges imposed by the interactive navigation. In particular, the encoder must prepare a priori a compressed media stream that is flexible enough to enable the free selection of multiview navigation paths by different streaming media clients. Interactivity clearly brings new design constraints: the encoder is unaware of the exact decoding process, while the decoder has to reconstruct information from incomplete subsets of data since the server generally cannot transmit images for all possible viewpoints due to resource constrains. In this paper, we propose a novel multiview data representation that permits us to satisfy bandwidth and storage constraints in an interactive multiview streaming system. In particular, we partition the multiview navigation domain into segments, each of which is described by a reference image (color and depth data) and some auxiliary information. The auxiliary information enables the client to recreate any viewpoint in the navigation segment via view synthesis. The decoder is then able to navigate freely in the segment without further data request to the server; it requests additional data only when it moves to a different segment. We discuss the benefits of this novel representation in interactive navigation systems and further propose a method to optimize the partitioning of the navigation domain into independent segments, under bandwidth and storage constraints. Experimental results confirm the potential of the proposed representation; namely, our system leads to similar compression performance as classical inter-view coding, while it provides the high level of flexibility that is required for interactive streaming. Because of these unique properties, our new framework represents a promising solution for 3D data representation in novel interactive multimedia services. PMID- 23797263 TI - Chronic sulforaphane oral treatment accentuates blood glucose impairment and may affect GLUT3 expression in the cerebral cortex and hypothalamus of rats fed with a highly palatable diet. AB - Obesity and insulin resistance are the key factors underlying the etiology of major health problems such as hypertension, diabetes and stroke. These important health issues lead researchers to investigate new approaches to prevent and treat obesity and insulin resistance. Good candidates are the phytochemical compounds that have been extensively studied in the field. Therefore, the aim of this study was to test whether sulforaphane (SFN, 1 mg kg-1, 4 months treatment), a potent inducer of antioxidant enzymes present in cruciferous vegetables, had some beneficial effects on obesity and insulin resistance induced by a highly palatable (HP) diet in male Wistar rats. Glucose tolerance, serum and hepatic lipid levels, lipid profile, ALT, AST, urea and creatinine, GLUT1 and GLUT3 levels in the cerebral cortex, hippocampus and hypothalamus were analyzed. Glucose tolerance was lower in the HP diet groups, especially in the HP group treated with SFN. Except for the liver triacylglycerols, no differences were found in serum lipids, hepatic and kidney markers of the HP diet groups. Although expression of GLUT1 was similar between groups for all three brain structures analyzed, expression of GLUT3 in the cortex and hypothalamus had a tendency to decrease in the HP diet group treated with SFN. In conclusion, SFN at the specific dose was able to accentuate glucose intolerance and may affect GLUT3 expression in the cerebral cortex and hypothalamus. PMID- 23797264 TI - Hormone therapy in younger women and cognitive health. PMID- 23797265 TI - Pulmonary manifestations of Sjogren's syndrome. AB - Sjogren's syndrome (SS) is primarily defined by its impact on the oral and ocular system resulting in xerostomia and xerophthalmia. However, SS can also manifest throughout the respiratory system. Subclinical pulmonary involvement is common. Clinically significant involvement can result in a 4-fold increased risk of death. Thus, recognizing the many potential presentations of SS in the lung is critical in caring for patients with SS. Additionally, SS should be included in the differential diagnosis of a number of forms of interstitial lung disease. PMID- 23797266 TI - Neuromodulation of vegetative state through spinal cord stimulation: where are we now and where are we going? AB - BACKGROUND: Vegetative state (VS) is a complex condition that represents a challenging frontier for medicine and neuroscience research. Nowadays there is no scientifically validated treatment for VS patients, and their chronic long-term assistance is very demanding for healthcare systems worldwide. OBJECTIVES: The present paper is a systematic review of the role of spinal cord stimulation (SCS) as a treatment of patients with VS. METHODS: Published literature on this topic was analyzed systematically. Clinical and epidemiological characteristics of VS, present therapeutic options and social costs of VS were also evaluated. RESULTS: Only 10 papers have been published since 1988, and overall 308 VS patients have been treated with SCS worldwide; 51.6% displayed a clinical improvement and an amelioration of the environmental interaction. These effects are probably mediated by the stimulation of the reticular formation-thalamus-cortex pathway and by cerebral blood flow augmentation induced by SCS. CONCLUSIONS: The experience on this topic is still very limited, and on this basis it is still hard to make any rigorous assessment. However, the most recent experiments represent significant progress in the research on this topic and display SCS as a possible therapeutic tool in the treatment of VS. PMID- 23797267 TI - Knee extensor muscle strength and index of renal function associated with an exercise capacity of 5 metabolic equivalents in male chronic heart failure patients with chronic kidney disease. AB - BACKGROUND: The goal of the present study was to determine knee extensor muscle strength (KEMS) and degree of renal dysfunction associated with an exercise capacity of >=5 metabolic equivalents (METs) in male chronic heart failure (CHF) patients with chronic kidney disease (CKD). METHODS: In this cross-sectional study of 75 male CHF patients with CKD (65.3 +/- 11.6 years), we measured clinical characteristics, peak [Formula: see text], estimated glomerular filtration rate (eGFR), and KEMS. Patients were divided into two groups by exercise capacity: >=5 METs group (n = 41) and <5 METs group (n = 34). Cutoff values for KEMS and eGFR resulting in an exercise capacity of >=5 METs were selected with ROC curves. Patients were divided into four groups according to cutoff values, and numbers of patients attaining an exercise capacity of >=5 METs were compared between groups. RESULTS: Age was significantly higher although eGFR, Hb, and KEMS were lower in the <5 METs versus >=5 METs group (P < 0.001). Multiple logistic regression analysis revealed a positive significant relation between KEMS and eGFR and exercise capacity of >=5 METs. Exercise capacity of >=5 METs was associated with KEMS of approximately 1.69 Nm/kg and an eGFR of 45.7 mL/min/1.73 m(2). The number of patients attaining an exercise capacity of >=5 METs in the patients who did not reach both cutoff values was significantly lower than that in any other patients (P < 0.001). CONCLUSION: KEMS and eGFR may be useful indices for predicting attainment of exercise capacity of >=5 METs in male CHF patients with CKD. PMID- 23797268 TI - Effects of pre-pregnancy obesity, race/ethnicity and prematurity. AB - To investigate the association between maternal pre-pregnancy obesity, race/ethnicity and prematurity. Retrospective cohort study of maternal deliveries at a single regional center from 2009 to 2010 time period (n = 11,711). Generalized linear models were used for the analysis to estimate an adjusted odds ratio with 95% confidence interval of the association between maternal pre pregnancy obesity, race/ethnicity and prematurity. Analysis controlled for diabetes, chronic hypertension, previous preterm birth, smoking and insurance status. The demographics of the study population were as follows, race/ethnicity had predominance in the White/Non-Hispanic population with 60.1%, followed by the Black/Non-Hispanic population 24.2%, the Hispanic population with 10.3% and the Asian population with 5.4%. Maternal pre-pregnancy weight showed that the population with a normal body mass index (BMI) was 49.4%, followed by the population being overweight with 26.2%, and last, the population which was obese with 24.4%. Maternal obesity increased the odds of prematurity in the White/Non Hispanic, Hispanic and Asian population (aOR 1.40, CI 1.12-1.75; aOR 2.20, CI 1.23-3.95; aOR 3.07, CI 1.16-8.13, respectively). Although the Black/Non-Hispanic population prematurity rate remains higher than the other race/ethnicity populations, the Black/Non-Hispanic population did not have an increased odds of prematurity in obese mothers (OR 0.87; CI 0.68-1.19). Unlike White/Non-Hispanic, Asian and Hispanic mothers, normal pre-pregnancy BMI in Black/Non-Hispanic mothers was not associated with lower odds for prematurity. The odds for mothers of the White/Non-Hispanic, Hispanic and Asian populations, for delivering a premature infant, were significantly increased when obese. Analysis controlled for chronic hypertension, diabetes, insurance status, prior preterm birth and smoking. Obesity is a risk factor for prematurity in the White/Non-Hispanic, Asian and Hispanic population, but not for the Black/Non-Hispanic population. The design and evaluation of weight-based maternal health programs that aggregate race/ethnicity may not be sufficient. The optimal method to address maternal pre pregnancy and intra-pregnancy weight-related health disorders may need to be stratified along race/ethnicity adjusted strategies and goals. However, a more global preventative strategy that encompasses the social determinants of health may be needed to reduce the higher rates of prematurity among the Black/Non Hispanic population. PMID- 23797270 TI - L-Proline catalyzed reaction of N-confused porphyrin and active methylene compounds. AB - Active methylene compounds such as acetone, butanone, cyclopentanone, nitromethane, malononitrile, ethyl 2-cyanoacetate, diethyl malonate, and ethyl acetylacetate react with the C3 position of N-confused porphyrin in the presence of L-proline in refluxing THF-EtOH affording a variety of N-confused porphyrin derivatives in moderate yield. L-Proline catalyzes the reaction facilitating the formation of the carbanion derived from an active methylene compound simultaneously delivering protons to the N-confused porphyrin. Both processes are key factors of this reaction. PMID- 23797269 TI - Women's longitudinal smoking patterns from preconception through child's kindergarten entry: profiles of biological mothers of a 2001 US birth cohort. AB - To identify longitudinal patterns of women's smoking during the pre-conception, perinatal, and early parenting period and describe risk factors distinguishing the different profiles. We conducted longitudinal latent class analysis of maternal smoking status over a 6-7 year period in a sample of 8,650 biological mothers of the Early Childhood Longitudinal Study-Birth Cohort, nationally representative of US births in 2001. Five latent classes were identified: pregnancy-inspired quitters (4.3 %), delayed initiators (5.1 %), persistent smokers (8.5 %), temporary quitters (10.4 %), and nonsmokers (71.7 %). These classes were distinguished by age, race/ethnicity, education, poverty status, marital status, parity, drinking behavior, and depression. For example, when compared to those with college degrees, those with less than a high school degree were at least five times as likely to be in the delayed initiator, temporary quitter, or persistent smoker classes (vs. the nonsmoker class). Heterogeneous longitudinal smoking patterns indicate the need for both prevention messages and cessation treatment continuing past parturition, tailored to fit individual profiles in order to achieve better health outcomes for both mothers and children. PMID- 23797271 TI - Aging-dependent reduction in glyoxalase 1 delays wound healing. AB - Methylglyoxal (MG), the major dicarbonyl substrate of the enzyme glyoxalase 1 (GLO1), is a reactive metabolite formed via glycolytic flux. Decreased GLO1 activity in situ has been shown to result in an accumulation of MG and increased formation of advanced glycation endproducts, both of which can accumulate during physiological aging and at an accelerated rate in diabetes and other chronic degenerative diseases. To determine the physiological consequences which result from elevated MG levels and the role of MG and GLO1 in aging, wound healing in young (<=12 weeks) and old (>=52 weeks) wild-type mice was studied. Old mice were found to have a significantly slower rate of wound healing compared to young mice (74.9 +/- 2.2 vs. 55.4 +/- 1.5% wound closure at day 6; 26% decrease; p < 0.0001). This was associated with decreases in GLO1 transcription, expression and activity. The importance of GLO1 was confirmed in mice by inhibition of GLO1. Direct application of MG to the wounds of young mice, decreased wound healing by 24% compared to untreated mice, whereas application of BSA modified minimally by MG had no effect. Treatment of either young or old mice with aminoguanidine, a scavenger of free MG, significantly increased wound closure by 16% (66.8 +/- 1.6 vs. 77.2 +/- 3.1%; p < 0.05) and 64% (40.4 +/- 7.9 vs. 66.4 +/- 5.2%; p < 0.05), respectively, by day 6. As a result of the aminoguanidine treatment, the overall rate of wound healing in the old mice was restored to the level observed in the young mice. These findings were confirmed in vitro, as MG reduced migration and proliferation of fibroblasts derived from young and old, wild-type mice. The data demonstrate that the balance between MG and age-dependent GLO1 downregulation contributes to delayed wound healing in old mice. PMID- 23797272 TI - Aortic 18F-FDG PET/CT uptake pattern at 60 min (early) and 180 min (delayed) acquisition in a control population: a visual and semiquantitative comparative analysis. AB - 18F-Fluoro-2-deoxy-D-glucose (F-FDG) PET/CT acquisition is generally performed 60 min after injection. The normal biodistribution pattern of F-FDG includes activity in the aortic territory due to blood pool activity, which could interfere in the diagnosis of aortic diseases by overlapping the wall uptake. The aim of the study was to evaluate the change over time of F-FDG uptake by the aortic wall and the activity in the lumen in a control population and to establish normal reference values. This prospective study included 15 control patients (mean age: 58.2 years). PET/CT was acquired 60 min (early scan) and 180 min (delayed scan) after an F-FDG injection at a dose of 7 MBq/kg. A visual and semiquantitative analysis of the F-FDG aortic wall uptake was carried out, and lumen activity and the aortic wall to lumen ratio [target-to-background ratio (TBR)] were determined. In the visual analysis all patients showed F-FDG activity at the aortic territory at 60 and 180 min. The pattern of uptake at 60 min was diffuse in all 15 patients (100%), without delineation of the aortic wall uptake; however, at 180 min the uptake pattern of the aortic wall changed to lineal in 14 patients (93.3%). The aortic wall maximum standardized uptake value decreased from 2.07+/-0.34 to 1.7+/-0.46 during the delayed acquisition (P=0.0279) and the lumen maximum standardized uptake value decreased highly significantly (1.99+/ 0.35 vs. 1.36+/-0.32, P=0.0001). Therefore, TBR also increased highly significantly from 1.04+/-0.06 to 1.25+/-0.16 (P<0.0001). The high decrease in blood pool activity from 60 to 180 min provides a better delineation of the aortic wall uptake, which corresponds to the normal pattern at that time. The TBR increased significantly at 180 min, and 1.25+/-0.16 is suggested as the threshold for diagnostic purposes, especially for the diagnosis of vasculitis. PMID- 23797273 TI - Diagnostic value of metabolic tumor volume assessed by 18F-FDG PET/CT added to SUVmax for characterization of thyroid 18F-FDG incidentaloma. AB - BACKGROUND: The objective of the study was to investigate whether metabolic tumor volume (MTV) measured by fluorine-18 fluorodeoxyglucose (F-FDG) PET/computed tomography (PET/CT) after stratification of serum thyroid stimulating hormone (TSH) levels could predict malignancy in patients with thyroid F-FDG incidentaloma. MATERIALS AND METHODS: A total 262 patients with focal thyroid F FDG incidentaloma undergoing cancer evaluation for nonthyroid cancer or a health checkup were enrolled in this study. We retrospectively evaluated the relationship of the maximum standardized uptake value (SUVmax) and MTV in the prediction of malignant thyroid F-FDG incidentaloma. RESULTS: The prevalence of malignancy was 20.9% (37/177). Malignant thyroid incidentaloma had a statistically significant higher value of SUVmax (malignant: median 4.6, range 1.9-34.9; benign: median 4.1, range 0-28; P=0.030). The value of MTV4 in malignant thyroid incidentaloma was significantly higher than that of benign thyroid incidentaloma (malignant: median 0.16, range 0.02-1.19; benign: median 0.10, range 0-0.65; P=0.032). However, the values of MTV3.5, MTV3, and MTV2.5 did not differ significantly between the groups. After stratification of serum TSH levels (an SUVmax>5 was used as the cutoff point) the sensitivity and specificity for prediction of malignancy were found to be 61.1% [95% confidence interval (CI): 35.7-82.7%] and 68.7% (95% CI: 56.2-79.4%), respectively. The area under the curve (AUC) was 0.655 (95% CI: 0.545-0.755; P=0.0239). When MTV4 greater than 0.07 cm was used as the cutoff point, the sensitivity and specificity for prediction of malignancy were 81.2% (95% CI: 54.4-96.0%) and 50.0% (95% CI: 37.0 63.0%), respectively. The AUC was 0.650 (95% CI: 0.534-0.755; P=0.0451). On comparison receiver operating characteristic curve analysis, no significant difference was found between SUVmax and MTV4 in the prediction of thyroid carcinoma (P=0.4346). However, a combination of SUVmax and MTV4 resulted in an AUC of 0.669 (95% CI: 0.554-0.772; P=0.0183). CONCLUSION: The SUVmax and MTV4 measured by F-FDG PET/CT after stratification of serum TSH levels could predict thyroid cancer in patients with thyroid F-FDG incidentaloma. A combination of SUVmax and MTV4 may be more useful for the differentiation of malignant from benign thyroid incidentaloma. PMID- 23797274 TI - Diet pills, powders, and liquids: predictors of use by healthy weight females. AB - About 35% of healthy weight adolescent females describe themselves as overweight, and 66% report planning to lose weight.Body weight dissatisfaction is associated with unhealthy weight loss practices including diet pill/powder/liquid (PPL) use. Few studies have examined diet PPL use in healthy weight adolescent females; therefore, Youth Risk Behavior Survey data (n =247) were analyzed to identify predictors of use. Descriptive statistics and logistic regression analyses were conducted using Statistical Package for the Social Sciences Complex Samples software. Social cognitive theory served as the framework guiding the analysis. Approximately 8% of healthy weight females reported using diet PPL for weight loss. Describing self as overweight, planning to lose weight, being offered drugs at school, fasting to lose weight, cigarette/alcohol use, vomiting, and laxative use were significantly associated (p < .05) with diet PPL use. Health professionals, including school nurses, must assess for unhealthy weight loss practices in healthy weight females, in order to adequately address related issues. PMID- 23797275 TI - Establishment of Tunga trimamillata (Siphonaptera: Tungidae) in Brazil. AB - Tunga trimamillata is a species of sand flea occurring in Ecuador and Peru parasitizing cattle, goat, sheep, swine, and man. This is the first report of this species in Brazil, having been found on the hooves of cows in Barretos, Sao Paulo State, and Felixlandia, Minas Gerais State, and previously misidentified as Tunga penetrans. A previous report concerning Hydrochoerus hydrochaeris from Rio Novo, Minas Gerais State, may also be attributed to that species of sand flea, a possible the primary host. Given the large geographical distribution of T. trimamillata, the vast cattle population in Brazil, and the high number of individuals subject to the risk of tungiasis, the number of cases attributed to this sand flea will most likely increase over time. PMID- 23797276 TI - Synergistic effect of inhibitors of fatty acid desaturases on Trypanosoma parasites. AB - The pathway for unsaturated fatty acid biosynthesis is essential in trypanosomatid parasites and has been a key target in our work on the discovery and analysis of several inhibitory compounds. Here, we show the effect of novel inhibitors of stearoyl-CoA desaturase (SCD) and oleate desaturase (OD), alone and in combination, on the growth rate of parasite cultures. GS-456332, an inhibitor of human Delta9 desaturase, efficiently inhibited growth of both Trypanosoma cruzi epimastigotes and Trypanosoma brucei bloodstream form cells, with EC50 values of 136.9 +/- 24.2 and 9.4 +/- 3.1 nM, respectively. This effect was specific for SCD. Stearolic acid (9-octadecynoic acid) was also able to arrest T. cruzi and T. brucei growth by specific inhibition of their OD, with EC50 values of 1.0 +/- 0.2 MUM and 0.1 +/- 0.01 MUM, respectively. When these compounds were administered simultaneously, a clearly synergistic effect was observed for both Trypanosoma species, with EC50 values in the low nanomolar range. These results demonstrate the feasibility of using combinations of drugs, inhibiting different enzymes on the same metabolic pathway, for the development of more efficient chemotherapeutic strategies against neglected diseases caused by these parasites. PMID- 23797277 TI - Therapeutic cytodifferentiation in alveolar rhabdomyosarcoma without genetic change of the PAX3-FKHR chimeric fusion gene: a case study. AB - Alveolar rhabdomyosarcoma (ARMS) is a subtype of rhabdomyosarcoma and usually occurs in childhood and adolescence. ARMS is characterized by its aggressive behavior and poor prognosis. To improve the unfavorable prognosis, new therapeutic developments and the establishment of methods for precise prognostic prediction are required. We describe a case of ARMS, solid variant, which occurred in a 10-year-old boy. After chemotherapy and radiotherapy, the tumor morphologically and immunohistochemically showed marked cytodifferentiation, whereas the exact same PAX3-FKHR chimeric fusion gene transcript was detected in samples before and after treatment. The result of this study seems to indicate that therapeutic cytodifferentiation does not always correlate with genetic change and favorable prognosis in ARMS. PMID- 23797278 TI - Newly established human liver cell line: a potential cell source for the bioartificial liver in the future. AB - The clinical use of a bioartificial liver (BAL) device strongly depends on the development of human liver cell lines. The aim of this study was to establish and assess the potential use of the stable HepG2 cell line expressing human augmenter of liver regeneration (hALR). The cDNA encoding hALR protein was inserted into pcDNA3.1 to generate pcDNA3.1/hALR, following which pcDNA3.1/hALR was transfected to HepG2 to establish a cell line that stably expressed hALR (HepG2 hALR). A total of 800 million HepG2 hALR cells were loaded into laboratory-scale BAL bioreactors and cultured for 4 days, during which time the parameters of hepatocyte-specific function and general metabolism were determined. The cell line that stably expressed human ALR was successfully established. The expression of recombinant hALR was higher in the HepG2 hALR cell line than in the HepG2 cell line based on immunofluorescence and immunoblot assays. In samples removed from the BAL bioreactor on day 4, compared to HepG2 cells, HepG2 hALR cells produced significantly more alpha-fetoprotein (127.3 %; P < 0.05) and urea (128.8 %; P < 0.05) and eliminated more glucose (135.7 %; P < 0.05); the level of human albumin was also higher (117 %) in HepG2 hALR cells, but the difference was not significant (P > 0.05). After 24 h of culture, the mean lidocaine removal rate was 65.1 and 57.3 % in culture supernatants of HepG2 hALR and HepG2 cell lines, respectively (P < 0.01). Based on these results, we conclude that HepG2 hALR cells showed liver-specific functionality when cultured inside the bioreactor and would therefore be a potential cell source for BAL. PMID- 23797279 TI - Alcohol outlet density and violence: the role of risky retailers and alcohol related expenditures. AB - AIMS: The aim of the study was to assess the association between alcohol outlet density and violence controlling for alcohol expenditures and the density of other retailers. METHODS: Cross-sectional ecological study of 1816 block groups in Philadelphia. We obtained 2010 data for aggravated assaults, alcohol outlets, alcohol expenditures, business points, land use and socioeconomic and demographic characteristics. We mapped the spatial distribution of alcohol outlets and aggravated assaults using a geographic information system. We estimated the association between assault density and total, on-premise and off-premise alcohol outlet densities using spatial regression models and controlling for the covariates of urban crime rates, alcohol expenditures, and the presence of other general and risky commercial retail outlets. RESULTS: The strong and positive association between alcohol outlet density and violence remained after controlling for alcohol expenditures and the density of other retailers. CONCLUSION: Findings support the concept that off-premise alcohol outlets in the neighborhood environment may impact health and social outcomes. The positive outlet-violence association in the face of these controls means it is not an association due solely to alcohol availability or to retail density. It also suggests that there is something unique about alcohol outlets or their density that makes them crime generators and links them to violence. PMID- 23797280 TI - Ethanol consumption increases endothelin-1 expression and reactivity in the rat cavernosal smooth muscle. AB - AIMS: We investigated the effects of chronic ethanol consumption on the cavernosal smooth muscle (CSM) reactivity to endothelin-1 (ET-1) and the expression of ET system components in this tissue. METHODS: Male Wistar rats were treated with heavy dose of ethanol (20% v/v) for 6 weeks. Reactivity experiments were performed in the isolated rat CSM. Plasma and CSM nitrate generation and also superoxide anion generation in rat CSM were measured by chemiluminescence. Protein and mRNA levels of pre-pro-ET-1, endothelin-converting enzyme-1 (ECE-1), ETA and ETB receptors, eNOS, nNOS and iNOS were assessed by western immunoblotting and quantitative real-time polymerase chain reaction, respectively. RESULTS: Chronic ethanol consumption increased plasma ET-1 levels and the contractile response induced by this peptide in the isolated CSM. The relaxation induced by acetylcholine, but not IRL1620, a selective ETB receptor agonist, was reduced in CSM from ethanol-treated rats. BQ123, a selective ETA receptor antagonist, produced a rightward displacement of the ET-1 concentration response curves in CSM from control, but not ethanol-treated rats. Reduced levels of nitrate were found in the plasma and CSM from ethanol-treated rats. Ethanol consumption increased superoxide anion generation in the rat CSM. The mRNA levels of pre-pro-ET-1, ECE-1, ETA and ETB receptors, eNOS, nNOS and iNOS were not altered by ethanol consumption. Protein levels of ET-1, ETA receptor and iNOS were higher in the CSM from rats chronically treated with ethanol. CONCLUSION: The major findings of the present study are that heavy ethanol consumption increases plasma ET-1 levels and the contraction induced by the peptide in the CSM. Increased CSM reactivity to ET-1 and altered protein levels of ET-1 and ETA receptors could play a role in the pathogenesis of erectile dysfunction associated with chronic ethanol consumption. PMID- 23797282 TI - Patterns of shoulder muscle coordination vary between wheelchair propulsion techniques. AB - This study investigated changes in the coordination patterns of shoulder muscles and wheelchair kinetics with different propulsion techniques by comparing wheelchair users' self-selected propulsion patterns with a semicircular pattern adopted after instruction. Wheelchair kinetics data were recorded by Smart(Wheel) on an ergometer, while EMG activity of seven muscles was recorded with surface electrodes on 15 able-bodied inexperienced participants. The performance data in two sessions, first using a self-selected and then the learned semicircular pattern, were compared with a paired t-test. Muscle coordination patterns across seven muscles were analyzed by principal component analysis. The semicircular pattern was characterized by significantly lower push frequency, significantly longer push length, push duration and push distance (p < 0.05, all cases) without a significant increase in push force, when compared with the self-selected pattern. In addition, our results show that in the semicircular propulsion technique, synergistic muscles were recruited in distinct phases and displayed a clearer separation between activities in the push phase and recovery phase muscles. An instruction session in semicircular propulsion technique is recommended for the initial use of a wheelchair after an injury. PMID- 23797281 TI - Metabolic abnormalities in lobar and subcortical brain regions of abstinent polysubstance users: magnetic resonance spectroscopic imaging. AB - AIMS: The aim of the study was to explore neurometabolic and associated cognitive characteristics of patients with polysubstance use (PSU) in comparison with patients with predominant alcohol use using proton magnetic resonance spectroscopy. METHODS: Brain metabolite concentrations were examined in lobar and subcortical brain regions of three age-matched groups: 1-month-abstinent alcohol dependent PSU, 1-month-abstinent individuals dependent on alcohol alone (ALC) and light drinking controls (CON). Neuropsychological testing assessed cognitive function. RESULTS: While CON and ALC had similar metabolite levels, persistent metabolic abnormalities (primarily higher myo-inositol) were present in temporal gray matter, cerebellar vermis and lenticular nuclei of PSU. Moreover, lower cortical gray matter concentration of the neuronal marker N-acetylaspartate within PSU correlated with higher cocaine (but not alcohol) use quantities and with a reduced cognitive processing speed. CONCLUSIONS: These metabolite group differences reflect cellular/astroglial injury and/or dysfunction in alcohol dependent PSU. Associations of other metabolite concentrations with neurocognitive performance suggest their functional relevance. The metabolic alterations in PSU may represent polydrug abuse biomarkers and/or potential targets for pharmacological and behavioral PSU-specific treatment. PMID- 23797283 TI - A post-stroke rehabilitation system integrating robotics, VR and high-resolution EEG imaging. AB - We propose a system for the neuro-motor rehabilitation of upper limbs in stroke survivors. The system is composed of a passive robotic device (Trackhold) for kinematic tracking and gravity compensation, five dedicated virtual reality (VR) applications for training of distinct movement patterns, and high-resolution EEG for synchronous monitoring of cortical activity. In contrast to active devices, the Trackhold omits actuators for increased patient safety and acceptance levels, and for reduced complexity and costs. VR applications present all relevant information for task execution as easy-to-understand graphics that do not need any written or verbal instructions. High-resolution electroencephalography (HR EEG) is synchronized with kinematic data acquisition, allowing for the epoching of EEG signals on the basis of movement-related temporal events. Two healthy volunteers participated in a feasibility study and performed a protocol suggested for the rehabilitation of post-stroke patients. Kinematic data were analyzed by means of in-house code. Open source packages (EEGLAB, SPM, and GMAC) and in-house code were used to process the neurological data. Results from kinematic and EEG data analysis are in line with knowledge from currently available literature and theoretical predictions, and demonstrate the feasibility and potential usefulness of the proposed rehabilitation system to monitor neuro-motor recovery. PMID- 23797284 TI - Accelerometry-based gait analysis and its application to Parkinson's disease assessment- part 2: a new measure for quantifying walking behavior. AB - Gait analysis is a valuable tool for obtaining quantitative information on motor deficits in Parkinson's disease (PD). Since the characteristic gait patterns of PD patients may not be fully identified by brief examination in a clinic, long term, and unobtrusive monitoring of their activities is essential, especially in a nonclinical setting. This paper describes a single accelerometer-based gait analysis system for the assessment of ambulatory gait properties. Acceleration data were recorded continuously for up to 24 h from normal and PD subjects, from which gait peaks were picked out and the relationship between gait cycle and vertical gait acceleration was evaluated. By fitting a model equation to the relationships, a quantitative index was obtained for characterizing the subjects' walking behavior. The averaged index for PD patients with gait disorder was statistically smaller than the value for normal subjects. The proposed method could be used to evaluate daily gait characteristics and thus contribute to a more refined diagnosis and treatment of the disease. PMID- 23797285 TI - A preliminary assessment of legged mobility provided by a lower limb exoskeleton for persons with paraplegia. AB - This paper presents an assessment of a lower limb exoskeleton for providing legged mobility to people with paraplegia. In particular, the paper presents a single-subject case study comparing legged locomotion using the exoskeleton to locomotion using knee-ankle-foot orthoses (KAFOs) on a subject with a T10 motor and sensory complete injury. The assessment utilizes three assessment instruments to characterize legged mobility, which are the timed up-and-go test, the Ten Meter Walk Test (10 MWT), and the Six-Minute Walk Test (6 MWT), which collectively assess the subject's ability to stand, walk, turn, and sit. The exertion associated with each assessment instrument was assessed using the Physiological Cost Index. Results indicate that the subject was able to perform the respective assessment instruments 25%, 70%, and 80% faster with the exoskeleton relative to the KAFOs for the timed up-and-go test, the 10 MWT, and the 6 MWT, respectively. Measurements of exertion indicate that the exoskeleton requires 1.6, 5.2, and 3.2 times less exertion than the KAFOs for each respective assessment instrument. The results indicate that the enhancement in speed and reduction in exertion are more significant during walking than during gait transitions. PMID- 23797286 TI - Naturally selected rilpivirine-resistant HIV-1 variants by host cellular immunity. AB - BACKGROUND: Rilpivirine is listed as an alternative key drug in current antiretroviral therapy (ART) guidelines. E138G/A/K in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) are rilpivirine resistance associated mutations and can be identified in a few ART-naive patients, although at low frequency. The 138th position in HIV-1 RT is located in one of the putative epitopes of human leukocyte antigen (HLA)-B*18-restricted cytotoxic T lymphocytes (CTLs). CTL-mediated immune pressure selects escape mutations within the CTL epitope. Here we tested whether E138G/A/K could be selected by HLA-B*18 restricted CTLs. METHODS: The amino acid variation at the 138th position was compared between ART-naive HIV-1-infected patients with and without HLA-B*18. The optimal epitope containing the 138th position was determined and the impact of E138G/A/K on CTL response was analyzed by epitope-specific CTLs. The effect of E138G/A/K on drug susceptibility was determined by constructing recombinant HIV-1 variants. RESULTS: The prevalence of E138G/A/K was 21% and 0.37% in 19 and 1088 patients with and without HLA-B*18, respectively (odds ratio, 72.3; P = 4.9 * 10( 25)). The CTL response was completely abolished by the substitution of E138G/A/K in the epitope peptide. E138G/A/K conferred 5.1-, 7.1-, and 2.7-fold resistance to rilpivirine, respectively. CONCLUSIONS: E138G/A/K can be selected by HLA-B*18 restricted CTLs and confer significant rilpivirine resistance. We recommend drug resistance testing before the introduction of rilpivirine-based ART in HLA-B*18 positive patients. PMID- 23797287 TI - Editorial Commentary: a tale of 2 realities: what are the challenges and solutions to improving Engagement in HIV care? PMID- 23797289 TI - The state of engagement in HIV care in the United States: from cascade to continuum to control. AB - The National HIV/AIDS Strategy and the promise of treatment as prevention have garnered considerable attention from the policy, practice, and scientific communities, with the treatment cascade becoming the sentinel image illustrating the domestic human immunodeficiency virus (HIV) epidemic. The cascade depicts prevalence estimates for sequential steps from HIV diagnosis through viral suppression, the most striking of which is that >50% of persons diagnosed with HIV are not in medical care. This heterogeneous group includes individuals not linked to medical care following HIV diagnosis and those entering care who are not retained, requiring reengagement from a range of community settings. This review synthesizes the state of engagement in HIV care in the United States, focusing on research, practice, and policy considerations. Included are conceptual frameworks, a review of health implications, measurement, monitoring, and evidence-based intervention approaches, and a look to the future in addressing the greatest challenge and opportunity facing our domestic HIV epidemic. PMID- 23797288 TI - Optimizing care for HIV-infected people who use drugs: evidence-based approaches to overcoming healthcare disparities. AB - Substance use disorders (SUDs) and human immunodeficiency virus (HIV) are pervasive epidemics that synergize, resulting in negative outcomes for HIV infected people who use drugs (PWUDs). The expanding epidemiology of substance use demands a parallel evolution of the HIV specialist-beyond HIV to diagnosis and management of comorbid SUDs. The purpose of this paper is to describe healthcare disparities for HIV-infected PWUDs along each point of a continuum of care, and to suggest evidence-based strategies for overcoming these healthcare disparities. Despite extensive dedicated resources and availability of antiretroviral therapy (ART) in the United States, PWUDs continue to experience delayed HIV diagnosis, reduced entry into and retention in HIV care, delayed initiation of ART, and inferior HIV treatment outcomes. Overcoming these healthcare disparities requires integrated packages of clinical, pharmacological, behavioral, and social services, delivered in ways that are cost-effective and convenient and include, at a minimum, screening for and treatment of underlying SUDs. PMID- 23797290 TI - Hyper-CVAD regimen in routine management of adult acute lymphoblastic leukemia: a retrospective multicenter study. AB - Treatment of acute lymphoblastic leukemia is unsatisfactory in adults due to disease and patient-related factors and probably because adult chemotherapy regimens are weaker than pediatric protocols. Worries about inadequacy of adult regimens urged many hematologists, including us, to reconsider their routine treatment practices. In this retrospective multicenter study, we aimed to evaluate results of hyper-CVAD treatment in comparison to other intensive protocols. All patients aged <=65 years who were commenced on intensive induction chemotherapy between 1999 and 2011 were included in the study. Sixty-eight of 166 patients received hyper-CVAD, 65 were treated with CALGB-8811 regimen and 33 with multiple other protocols. Limited number of patients who were treated with other intensive protocols and mature B-acute lymphoblastic leukemia cases who were mostly given hyper-CVAD were eliminated from the statistical analyses. In spite of a favorable complete remission rate (84.2%), overall (26.3 vs. 44.2% at 5 years, p = 0.05) and disease-free (24.9 vs. 48.2%, p = 0.001) survival rates were inferior with hyper-CVAD compared to CALGB-8811 due to higher cumulative nonrelapse mortality risk (29.7 vs. 5.9%, p = 0.003) and no superiority in cumulative relapse incidence comparison (45% for both arms, p = 0.44). Hyper CVAD, in its original form, was a less favorable regimen in our practice. PMID- 23797291 TI - Taxonomic Profiling and Metagenome Analysis of a Microbial Community from a Habitat Contaminated with Industrial Discharges. AB - Industrial units, manufacturing dyes, chemicals, solvents, and xenobiotic compounds, produce liquid and solid wastes, which upon conventional treatment are released in the nearby environment and thus are the major cause of pollution. Soil collected from contaminated Kharicut Canal bank (N 22 degrees 57.878'; E 072 degrees 38.478'), Ahmedabad, Gujarat, India was used for metagenomic DNA preparation to study the capabilities of intrinsic microbial community in dealing with xenobiotics. Sequencing of metagenomic DNA on the Genome Sequencer FLX System using titanium chemistry resulted in 409,782 reads accounting for 133,529,997 bases of sequence information. Taxonomic analyses and gene annotations were carried out using the bioinformatics platform Sequence Analysis and Management System for Metagenomic Datasets. Taxonomic profiling was carried out by three different complementary approaches: (a) 16S rDNA, (b) environmental gene tags, and (c) lowest common ancestor. The most abundant phylum and genus were found to be "Proteobacteria" and "Pseudomonas," respectively. Metagenome reads were mapped on sequenced microbial genomes and the highest numbers of reads were allocated to Pseudomonas stutzeri A1501. Assignment of obtained metagenome reads to Gene Ontology terms, Clusters of Orthologous Groups of protein categories, protein family numbers, and Kyoto Encyclopedia of Genes and Genomes hits revealed genomic potential of indigenous microbial community. In total, 157,024 reads corresponded to 37,028 different KEGG hits, and amongst them, 11,574 reads corresponded to 131 different enzymes potentially involved in xenobiotic biodegradation. These enzymes were mapped on biodegradation pathways of xenobiotics to elucidate their roles in possible catalytic reactions. Consequently, information obtained from the present study will act as a baseline which, subsequently along with other "-omic" studies, will help in designing future bioremediation strategies in effluent treatment plants and environmental clean-up projects. PMID- 23797292 TI - Identification of bacterial infection in neotropical primates. AB - Emerging infectious diseases usually arise from wild animal populations. In the present work, we performed a screening for bacterial infection in natural populations of New World primates. The blood cell bulk DNAs from 181 individuals of four Platyrrhini genera were PCR screened for eubacterial 16S rRNA genes. Bacteria were detected and identified in 13 distinct individuals of Alouatta belzebul, Alouatta caraya, and Cebus apella monkeys from geographically distant regions in the states of Mato Grosso and Para, Brazil. Sequence analyses showed that these Platyrrhini bacteria are closely related not only to human pathogens Pseudomonas spp. but also to Pseudomonas simiae and sheep-Acari infecting Pseudomonas spp. The identified Pseudomonas possibly represents a group of bacteria circulating in natural monkey populations. PMID- 23797295 TI - Left ventricular fat deposition on CT in patients without proven myocardial disease. AB - To analyze computed tomography (CT) characteristics of left ventricle (LV) fat deposition in patients without proven myocardial disease and to correlate these CT findings with electrocardiogram (ECG) and echocardiography data. We retrospectively searched our database of 14,470 consecutive coronary CT scans performed in the past 4 years for LV fat deposition in patients without proven myocardial disease. In total, we identified 25 patients (0.2 %; 10 males, 15 females; mean age 63 years) involving 91 cardiac segments. Pattern and location of LV fat deposition on CT were analyzed and compared to ECG and echocardiographic data. LV fat deposition can be categorized into 3 patterns: fat deposits in an apical cap (pattern I, n = 14), localized fat accumulation (pattern II, n = 12), and diffuse linear accumulation (pattern III, n = 6). Both patterns I and II were seen in 7 patients. The most common locations were apical segments (40 %) and the mid-myocardial layer (70 %). No patients had ECG findings positive for left-dominant arrhythmogenic dysplasia. Regional wall-motion abnormalities and decreased LV function (ejection fraction < 50 %) were only observed in 33 % of pattern III cases. LV fat deposition on CT can be seen in patients without proven myocardial disease. LV fat depositions were most commonly seen in the mid-myocardial location and apical segments. Diffuse linear fat deposition in the LV may correlates with decreased regional and global function. PMID- 23797297 TI - Determination of waste decay rate for a large Finnish landfill by calibrating methane generation models on the basis of methane recovery and emissions. AB - The aim of this study was to determine the methane (CH(4)) generation factor (k) and CH(4) generation potential (L) for bulk waste in order to calibrate a CH(4) generation model (USEPA Landgem 3.02) and provide information on the remaining CH(4) generation potential in a large (54 ha) municipal solid waste landfill located in a boreal climate. The CH(4) generation model was calibrated by actual CH(4) recovery and emission measurement data. Moreover, waste characterisation information from a previous study was considered.The appropriate k for bulk waste was 0.18 in the studied landfill, which indicated a higher rate of degradation than proposed by the Intergovernmental Panel on Climate Change as a default k value of 0.09 for wet conditions in boreal and temperate climes, whereas the calibrated L of 100 m(3)/t was lower than estimated on the basis of a previous waste characterisation study. The results demonstrate the importance of model calibration, as inappropriate model parameters may result in a large discrepancy (approximately 100 % or 119 million m(3) having an energy equivalent of nearly 1.2 TWh) in cumulative CH(4) generation estimates within a 18-year timescale (2012-30) at the studied landfill. PMID- 23797298 TI - Proposed water balance equation for municipal solid waste landfills in Jordan. AB - This article presents a water balance equation for predicting leachate generation in municipal solid waste (MSW) landfills located in semi-arid areas, using the Akaider landfill in Jordan as an example. HYDRUS-2D/3D software was used to model the effect of co-disposal of wastewater into the landfill on the leachate production rates and for comparison with the results of the simulation of the proposed water balance equation parameters. A series of simulations was carried out for a 30-year period. The suggested water balance equation predicted that leachate will percolate to a depth of 50 m in the simulated period. The result indicates that the co-disposed wastewater plays a major role in controlling the rate and magnitude of the contaminants that percolate from the MSW leachate. As the initial water content of the waste increases, there is greater mobilisation of salts. The concentration of chloride at a given location increased and the time required for the chloride to reach this location decreased as a consequence. However, eliminating the co-disposed wastewater will significantly minimise leachate generation and decrease possible groundwater contamination. This equation is applicable to areas that have geological and hydrological properties similar to Jordan. PMID- 23797299 TI - Climate co-benefits of energy recovery from landfill gas in developing Asian cities: a case study in Bangkok. AB - Landfilling is the most common and cost-effective waste disposal method, and it is widely applied throughout the world. In developing countries in Asia there is currently a trend towards constructing sanitary landfills with gas recovery systems, not only as a solution to the waste problem and the associated local environmental pollution, but also to generate revenues through carbon markets and from the sale of electricity. This article presents a quantitative assessment of climate co-benefits from landfill gas (LFG) to energy projects, based on the case of Bangkok Metropolitan Administration, Thailand. Life cycle assessment was used for estimating net greenhouse gas (GHG) emissions, considering the whole lifespan of the landfill. The assessment found that the total GHG mitigation of the Bangkok project would be 471,763 tonnes (t) of carbon dioxide (CO(2))-equivalents (eq) over its 10-year LFG recovery period.This amount is equivalent to only 12% of the methane (CH(4)) generated over the whole lifespan of the landfill. An alternative scenario was devised to analyse possible improvement options for GHG mitigation through LFG-to-energy recovery projects. This scenario assumes that LFG recovery would commence in the second year of landfill operation and gas extraction continues throughout the 20-year peak production period. In this scenario, GHG mitigation potential amounted to 1,639,450 tCO(2)-eq during the 20 year project period, which is equivalent to 43% of the CH(4) generated throughout the life cycle. The results indicate that with careful planning, there is a high potential for improving the efficiency of existing LFG recovery projects which would enhance climate co-benefits, as well as economic benefits. However, the study also shows that even improved gas recovery systems have fairly low recovery rates and, in consequence, that emissions of GHG from such landfills sites are still considerable. PMID- 23797300 TI - Implementing an advanced waste separation step in an MBT plant: assessment of technical, economic and environmental impacts. AB - Heavy fractions resulting from mechanical treatment stages of mechanical biological waste treatment plants are posing very specific demands with regard to further treatment (large portions of inert and high-caloric components). Based on the current Austrian legal situation such a waste stream cannot be landfilled and must be thermally treated. The aim of this research was to evaluate if an inert fraction generated from this waste stream with advanced separation technologies, two sensor-based [near-infrared spectroscopy (NIR), X-ray transmission (XRT)] and two mechanical systems (wet and dry) is able to be disposed of. The performance of the treatment options for separation was evaluated by characterizing the resulting product streams with respect to purity and yield. Complementing the technical evaluation of the processing options, an assessment of the economic and global warming effects of the change in waste stream routing was conducted. The separated inert fraction was evaluated with regard to landfilling. The remaining high-caloric product stream was evaluated with regard to thermal utilization. The results show that, in principal, the selected treatment technologies can be used to separate high-caloric from inert components. Limitations were identified with regard to the product qualities achieved, as well as to the economic expedience of the treatment options. One of the sensor-based sorting systems (X-ray) was able to produce the highest amount of disposeable heavy fraction (44.1%), while having the lowest content of organic (2.0% C biogenic per kg waste input) components. None of the high-caloric product streams complied with the requirements for solid recovered fuels as defined in the Austrian Ordinance on Waste Incineration. The economic evaluation illustrates the highest specific treatment costs for the XRT (? 23.15 per t), followed by the NIR-based sorting system (? 15.67 per t), and the lowest costs for the air separation system (? 10.79 per t). Within the ecological evaluation it can be shown that the results depend strongly on the higher heating value of the high caloric light fraction and on the content of C biogenic of the heavy fraction. Therefore, the XRT system had the best results for the overall GWP [-14 kg carbon dioxide equivalents (CO2 eq) per t of input waste] and the NIR-based the worst (193 kg CO2 eq per t of input waste). It is concluded that three of the treatment options would be suitable under the specific conditions considered here. Of these, sensor-based sorting is preferable owing to its flexibility. PMID- 23797302 TI - Longer length of first stay in intermittent residential programmes is associated with larger weight loss at 1 and 2 years. AB - OBJECTIVE: To determine if length of first stay impacts on weight loss and cardiovascular fitness, at 1 and 2 years in severely obese patients enrolled in intermittent residential programs. METHODS: In a retrospective follow-up study, we assessed weight loss and changes in cardiovascular fitness (VO2 peak) at 1 and 2 years in 179 severely obese adults who participated in two intermittent residential programmes. Both programmes consisted of five stays at the Roros Rehabilitation Centre over a 2-year period, but programme A consisted of a much longer first stay compared with programme B (8 vs. 2 weeks). RESULTS: Of 179 participants (BMI 44 +/- 6 kg/m2), 162 completed 1-year and 117 2-year evaluation. Programme A led to significantly larger weight reduction (-20.7 +/- 10.8 vs. -13.5 +/- 8.1 kg and -16.0 +/- 12.7 vs. -7.9 +/- 11.2 kg, p < 0.0001) and improvement in VO2 peak (7.8 vs. 3.6 ml/kg/min (p < 0.0001) and 5.6 vs. 2.5 ml/kg/min (p < 0.01)) at both 1 and 2 years, compared with programme B. Intention to-treat analysis showed similar results. CONCLUSION: A residential intermittent programme with a longer initial stay is associated with better weight loss and improvement in cardiovascular fitness at both 1 and 2 years. A longer follow-up is needed to clearly establish the sustainability of these programmes. PMID- 23797304 TI - Supervisory control system for monitoring a pharmaceutical hot melt extrusion process. AB - Continuous pharmaceutical manufacturing processes are of increased industrial interest and require uni- and multivariate Process Analytical Technology (PAT) data from different unit operations to be aligned and explored within the Quality by Design (QbD) context. Real-time pharmaceutical process verification is accomplished by monitoring univariate (temperature, pressure, etc.) and multivariate (spectra, images, etc.) process parameters and quality attributes, to provide an accurate state estimation of the process, required for advanced control strategies. This paper describes the development and use of such tools for a continuous hot melt extrusion (HME) process, monitored with generic sensors and a near-infrared (NIR) spectrometer in real-time, using SIPAT (Siemens platform to collect, display, and extract process information) and additional components developed as needed. The IT architecture of such a monitoring procedure based on uni- and multivariate sensor systems and their integration in SIPAT is shown. SIPAT aligned spectra from the extrudate (in the die section) with univariate measurements (screw speed, barrel temperatures, material pressure, etc.). A multivariate supervisory quality control strategy was developed for the process to monitor the hot melt extrusion process on the basis of principal component analysis (PCA) of the NIR spectra. Monitoring the first principal component and the time-aligned reference feed rate enables the determination of the residence time in real-time. PMID- 23797303 TI - Freeze-dried targeted mannosylated selenium-loaded nanoliposomes: development and evaluation. AB - The aim of this investigation was to develop and evaluate freeze-dried mannosylated liposomes for the targeted delivery of selenium. Dipalmitoylphosphatidylcholine, distearoylphosphatidylglycerol, and cholesterol were dissolved in a chloroform and methanol mixture and allowed to form a thin film within a rotatory evaporator. This thin film was hydrated with a sodium selenite (5.8 MUM) solution to form multilamellar vesicles and homogenized under high pressure to yield unilamellar nanoliposomes. Se-loaded nanoliposomes were mannosylated by 0.1% w/v mannosamine (Man-Lip-Se) prior to being lyophilized. Mannosamine concentration was optimized with cellular uptake studies in M receptor expressing cells. Non-lyophilized and lyophilized Man-Lip-Se were characterized for size, zeta potential, and entrapment efficiency. The influence of liposomal composition on the characteristics of Man-Lip-Se were evaluated using acidic and basic medium for 24 h. Thermal analysis and powder X-ray diffraction were used to determine the interaction of components within the Man Lip-Se. The size, zeta potential and entrapment efficiency of the optimum Man-Lip Se were observed to be 158 +/- 28.9 nm, 33.21 +/- 0.89 mV, and 77.27 +/- 2.34%, respectively. An in vitro Se release of 70-75% up to 24 h in PBS pH 6.8 and <8% Se release in acidic media (0.1 N HCl) in 1 h was observed. The Man-Lip-Se were found to withstand gastric-like environments and showed sustained release. Stable freeze-dried Man-Lip-Se were successfully formulated with a size of <200 nm, ~ 75% entrapment, and achieved controlled release of Se with stability under acidic media, which may be of importance in the targeted delivery of Se to the immune system. PMID- 23797305 TI - Increased in situ intestinal absorption of phytoestrogenic diarylheptanoids from Curcuma comosa in nanoemulsions. AB - Curcuma comosa has long been used as a gynecological medicine. Several diarylheptanoids have been purified from this plant, and their pharmacological effects were proven. However, there is no information about the absorption of C. comosa components to support the formulation usage. In the present study, C. comosa hexane extract and the mixture of its two major compounds, (4E,6E)-1,7 diphenylhepta-4,6-dien-3-ol (DA1) and (6E)-1,7-diphenylhept-6-en-3-ol (DA2), were formulated into nanoemulsions. The physical properties of the nanoemulsions and the in situ intestinal absorptions of DA1 and DA2 were evaluated. The results demonstrated the mean particle sizes at 0.207 +/- 0.001 and 0.408 +/- 0.014 MUm, and the zeta potential at -14.57 +/- 0.85 and -10.47 +/- 0.32 mV for C. comosa nanoemulsion (C.c-Nano) and mixture of diarlylheptanoid nanoemulsions (DA-Nano), respectively. The entrapments of DA1 and DA2 were 76.61% and 75.41%, and 71.91% and 71.63% for C.c-Nano and DA-Nano, respectively. The drug loading ratios of DA1 and DA2 were 351.47 and 614.53 MUg/mg, and 59.48 and 126.72 MUg/mg for C.c-Nano and DA-Nano. The intestinal absorption rates of DA1 and DA2 were 0.329 +/- 0.015 and 0.519 +/- 0.026 MUg/min/cm2 in C.c-Nano, and 0.380 +/- 0.006 and 0.428 +/- 0.036 MUg/min/cm2 in DA-Nano, which were five to ten times faster than those in oil. In conclusion, the formulation in nanoemulsion forms obviously increased the intestinal absorption rate of diarylheptanoids. PMID- 23797306 TI - Mortality for publicly reported conditions and overall hospital mortality rates. AB - IMPORTANCE: Federal efforts about public reporting and quality improvement programs for hospitals have focused primarily on a small number of medical conditions. Whether performance on these conditions accurately predicts the quality of broader hospital care is unknown. OBJECTIVE: To determine whether mortality rates for publicly reported medical conditions are correlated with hospitals' overall performance. METHODS: Using national Medicare data, we compared hospital performance at 2322 US acute care hospitals on 30-day risk adjusted mortality, aggregated across the 3 publicly reported conditions (acute myocardial infarction, congestive heart failure, and pneumonia), with performance on a composite risk-adjusted mortality rate across 9 other common medical conditions, a composite mortality rate across 10 surgical conditions, and both composites combined. We also examined the relationship between alternative surrogates of quality (hospital size and teaching status) and performance on these composite outcomes. RESULTS: Our sample included 6,670,859 hospitalizations for Medicare fee-for-service beneficiaries from 2008 through 2009. Hospitals in the top quartile of performance on publicly reported conditions had a 3.6% lower absolute risk-adjusted mortality rate on the combined medical-surgical composite than those in the bottom quartile (9.4% vs 13.0%; P < .001). These top performers on publicly reported conditions had 5 times greater odds of being in the top quartile on the overall combined composite risk-adjusted mortality rate (odds ratio [OR], 5.3; 95% CI, 4.3-6.5). Mortality rates for the index condition were predictive of medical (OR, 8.4; 95% CI, 6.8-10.3) and surgical (2.7; 2.2-3.3) performance when these groups were considered separately. In comparison, large size (OR, 1.9; 95% CI, 1.5-2.4) and teaching status (2.4; 1.8-3.2) showed weaker relationships with overall hospital mortality rates. CONCLUSIONS AND RELEVANCE: Hospital performance on publicly reported conditions can potentially be used as a signal of overall hospital mortality rates. PMID- 23797307 TI - Spondyloarthritis: Is it time to replace BASDAI with ASDAS? PMID- 23797308 TI - Connective tissue diseases: Immunosuppressive cells identified in mouse models of SLE. PMID- 23797310 TI - Lupus nephritis: a rituximab-based regimen might enable oral steroid avoidance in lupus nephritis. PMID- 23797309 TI - Bedfellows: mycobacteria and rheumatoid arthritis in the era of biologic therapy. AB - In modern times a relationship between tuberculosis (TB) and rheumatoid arthritis (RA) has been firmly recognized, and is primarily attributable to the immunosuppressive therapies used to treat RA. Whereas TB can complicate the successful management of RA, nontuberculous mycobacteria have now perhaps become as important as (if not more so than) TB in the setting of RA, and can represent an even greater challenge to the rheumatologist wishing to use immunosuppressive therapies. This article reviews our most recent understanding of the epidemiological and clinical aspects of mycobacterial disease as it relates to RA, and the existing and emerging immunosuppressive therapies used to treat this disease. PMID- 23797311 TI - A Nonlinear Adaptive Level Set for Image Segmentation. AB - In this paper, we present a novel level set method (LSM) for image segmentation. By utilizing the Bayesian rule, we design a nonlinear adaptive velocity and a probability-weighted stopping force to implement a robust segmentation for objects with weak boundaries. The proposed method is featured by the following three properties: 1) it automatically determines the curve to shrink or expand by utilizing the Bayesian rule to involve the regional features of images; 2) it drives the curve evolve with an appropriate speed to avoid the leakage at weak boundaries; and 3) it reduces the influence of false boundaries, i.e., edges far away from objects of interest. We applied the proposed segmentation method to artificial images, medical images and the BSD-300 image dataset for qualitative and quantitative evaluations. The comparison results show the proposed method performs competitively, compared with the LSM and its representative variants. PMID- 23797312 TI - Symmetry constraint for foreground extraction. AB - Symmetry as an intrinsic shape property is often observed in natural objects. In this paper, we discuss how explicitly taking into account the symmetry constraint can enhance the quality of foreground object extraction. In our method, a symmetry foreground map is used to represent the symmetry structure of the image, which includes the symmetry matching magnitude and the foreground location prior. Then, the symmetry constraint model is built by introducing this symmetry structure into the graph-based segmentation function. Finally, the segmentation result is obtained via graph cuts. Our method encourages objects with symmetric parts to be consistently extracted. Moreover, our symmetry constraint model is applicable to weak symmetric objects under the part-based framework. Quantitative and qualitative experimental results on benchmark datasets demonstrate the advantages of our approach in extracting the foreground. Our method also shows improved results in segmenting objects with weak, complex symmetry properties. PMID- 23797313 TI - Discriminative exemplar coding for sign language recognition with Kinect. AB - Sign language recognition is a growing research area in the field of computer vision. A challenge within it is to model various signs, varying with time resolution, visual manual appearance, and so on. In this paper, we propose a discriminative exemplar coding (DEC) approach, as well as utilizing Kinect sensor, to model various signs. The proposed DEC method can be summarized as three steps. First, a quantity of class-specific candidate exemplars are learned from sign language videos in each sign category by considering their discrimination. Then, every video of all signs is described as a set of similarities between frames within it and the candidate exemplars. Instead of simply using a heuristic distance measure, the similarities are decided by a set of exemplar-based classifiers through the multiple instance learning, in which a positive (or negative) video is treated as a positive (or negative) bag and those frames similar to the given exemplar in Euclidean space as instances. Finally, we formulate the selection of the most discriminative exemplars into a framework and simultaneously produce a sign video classifier to recognize sign. To evaluate our method, we collect an American sign language dataset, which includes approximately 2000 phrases, while each phrase is captured by Kinect sensor with color, depth, and skeleton information. Experimental results on our dataset demonstrate the feasibility and effectiveness of the proposed approach for sign language recognition. PMID- 23797314 TI - Image annotation by multiple-instance learning with discriminative feature mapping and selection. AB - Multiple-instance learning (MIL) has been widely investigated in image annotation for its capability of exploring region-level visual information of images. Recent studies show that, by performing feature mapping, MIL can be cast to a single instance learning problem and, thus, can be solved by traditional supervised learning methods. However, the approaches for feature mapping usually overlook the discriminative ability and the noises of the generated features. In this paper, we propose an MIL method with discriminative feature mapping and feature selection, aiming at solving this problem. Our method is able to explore both the positive and negative concept correlations. It can also select the effective features from a large and diverse set of low-level features for each concept under MIL settings. Experimental results and comparison with other methods demonstrate the effectiveness of our approach. PMID- 23797315 TI - Kernel Density Estimation, Kernel Methods, and Fast Learning in Large Data Sets. AB - Kernel methods such as the standard support vector machine and support vector regression trainings take O(N(3)) time and O(N(2)) space complexities in their naive implementations, where N is the training set size. It is thus computationally infeasible in applying them to large data sets, and a replacement of the naive method for finding the quadratic programming (QP) solutions is highly desirable. By observing that many kernel methods can be linked up with kernel density estimate (KDE) which can be efficiently implemented by some approximation techniques, a new learning method called fast KDE (FastKDE) is proposed to scale up kernel methods. It is based on establishing a connection between KDE and the QP problems formulated for kernel methods using an entropy based integrated-squared-error criterion. As a result, FastKDE approximation methods can be applied to solve these QP problems. In this paper, the latest advance in fast data reduction via KDE is exploited. With just a simple sampling strategy, the resulted FastKDE method can be used to scale up various kernel methods with a theoretical guarantee that their performance does not degrade a lot. It has a time complexity of O(m(3)) where m is the number of the data points sampled from the training set. Experiments on different benchmarking data sets demonstrate that the proposed method has comparable performance with the state-of art method and it is effective for a wide range of kernel methods to achieve fast learning in large data sets. PMID- 23797316 TI - Racial/Ethnic and regional differences in the prevalence of inflammatory bowel disease in the United States. AB - BACKGROUND: The magnitude of racial/ethnic and regional differences in the prevalence of inflammatory bowel disease (IBD) in the United States remains largely unknown. AIMS: To estimate differences in the prevalence of IBD by race/ethnicity and region. METHODS: The Medical Expenditure Panel Survey, a nationally representative survey of US households and medical conditions, was used. A multivariate logistic model was used in statistical analysis. RESULTS: Among 202,468 individuals surveyed during 1996-2007, 316 were diagnosed with IBD (26 Blacks, 21 Hispanics, and 5 Asians). The prevalence of IBD was higher in Whites [Crohn's disease: 154; ulcerative colitis (UC): 89] than Blacks (Crohn's disease: 68; UC: 25), Hispanics (Crohn's disease: 15; UC: 35), and Asians (Crohn's: 45; UC: 40) (all p < 0.05, except for UC in Asians). The differences in Crohn's disease between Whites and minorities and the difference in UC between Whites and Blacks remained significant in multivariate analysis. In multivariate analysis, there was no regional difference in the prevalence of Crohn's disease, but the prevalence of UC was higher in the Northeast than the South (p < 0.05). CONCLUSIONS: There were significant racial/ethnic differences in the prevalence of IBD in the USA. The underlying etiology of these differences warrants additional research. PMID- 23797317 TI - Spinal cord stimulation for vegetative state: is this ready for prime time? PMID- 23797318 TI - Neuroprotective effect of quercetin in ectoenzymes and acetylcholinesterase activities in cerebral cortex synaptosomes of cadmium-exposed rats. AB - This study investigated the effect of quercetin on nucleoside triphosphate diphosphohydrolase (NTP-Dase), 50-nucleotidase, adenosine deaminase (ADA), and acetylcholinesterase (AChE) activities in synaptosomes from cerebral cortex of adult rats exposed to cadmium (Cd). Rats were exposed to Cd (2.5 mg/Kg) and quercetin (5, 25 or 50 mg/Kg) by gavage for 45 days. Rats were randomly divided into eight groups (n = 8-10): saline/ethanol, saline/Querc 5 mg/kg, saline/Querc 25 mg/kg, saline/Querc 50 mg/kg, Cd/ethanol, Cd/Querc 5 mg/kg, Cd/Querc 25 mg/kg, and Cd/Querc 50 mg/kg. Results demonstrated that AChE activity increased in the Cd/ethanol group when compared to saline/ethanol group. Treatment with quercetin prevented the increase in AChE activity when compared to Cd/ethanol group. Quercetin treatment prevented the cadmium-induced increase in NTPDase, 5 nucleotidase, and ADA activities in Cd/ethanol group when compared to saline/ethanol group. Our data showed that quercetin have a protector effect against Cd intoxication. This way, is a promising candidate among the flavonoids to be investigated as a therapeutic agent to attenuate neurological disorders associated with Cd intoxication. PMID- 23797319 TI - MK-2206 induces cell cycle arrest and apoptosis in HepG2 cells and sensitizes TRAIL-mediated cell death. AB - It has become evident that AKT inhibitors have great potential in cancer treatment. In this study, we investigate the anticancer activity of MK-2206, a novel AKT inhibitor, on HepG2 hepatocellular carcinoma cell, and to show whether MK-2206 enhances the apoptosis-inducing potential of tumor necrosis factor related apoptosis-inducing ligand (TRAIL). The cell growth inhibition was evaluated by MTT assay and colony formation assay. Cell cycle distribution was assessed by propidium iodide flow cytometry. Apoptosis was determined by AnnexinV FITC/PI double staining assay and caspase-9, casapse-7, caspase-3, and PARP cleavage. The results of present study showed that MK-2206-induced G1-phase arrest was associated with a marked decrease in the protein expression of cyclin D1 with concomitant induction of p21 and p27. MK-2206-induced apoptosis was characterized by cleavage of a pro-caspase in a concentration-dependent manner. Moreover, the MAP family kinases p38 kinase and JNK were activated by exposure to MK-2206. SB203580, an p38-specific inhibitor, partially blocked MK-2206-induced death of HepG2 cells and caspase activation. A combination of MK-2206 with TRAIL significantly inhibited growth of TRAIL resistant HepG2 cells. Taken together, our findings provide a new insight to better understand anticancer mechanisms of MK-2206, at least in HepG2 cell. Using of MK-2206 as a potent sensitizer to TRAIL induced apoptotic cell death offers a promising means of enhancing the efficacy of TRAIL-based HCC treatments. PMID- 23797320 TI - Transcriptional directionality of the human insulin-degrading enzyme promoter. AB - Unidirectional promoters dominate among mammalian genomes. However, the mechanism through which the transcriptional directionality of promoters is accomplished remains to be clarified. Insulin-degrading enzyme (IDE) is a ubiquitously expressed zinc metalloprotease, whose promoter contains a CpG island. We previously showed that the basal promoter region of mouse IDE has bidirectional transcriptional activity, but an upstream promoter element blocks its antisense transcription. Therefore, we wonder whether the human IDE promoter contains an analogous element. Similarly, the basal promoter region of human IDE (-102 ~ +173 and -196 ~ +173 relative to the transcription start site) showed bidirectional transcriptional activity. However, the region from -348 to +173 could only be transcribed from the normal orientation, implying that an upstream promoter element between -348 and -196 blocks the antisense transcription of the human IDE promoter. Through promoter deletion and mutagenesis analysis, we mapped this element precisely and found that the upstream promoter element locates between 318 and -304. Furthermore, the transcription-blocking elements in the mouse and human IDE promoters inhibited the transcription of the SV40 promoter when put downstream of it. In conclusion, we identify an upstream promoter element which blocks the antisense transcription of the human IDE promoter. Our studies are helpful to clarify the transcriptional directionality of promoters. PMID- 23797321 TI - miR-155 inhibits oxidized low-density lipoprotein-induced apoptosis of RAW264.7 cells. AB - Macrophage apoptosis is a prominent feature of advanced atherosclerotic plaques. Here, we examined the hypothesis that the apoptotic machinery is regulated by microRNA-155 (miR-155). Constitutive expression of miR-155 was detected in RAW264.7 cells, which was increased following stimulation with oxidized low density lipoprotein (OxLDL) in a dose- and time-dependent manner. OxLDL-treated RAW264.7 cells showed a marked time- and dose-dependent increase in apoptosis, which was suppressed in the presence of mimics and increased with antagonists of miR-155. Bioinformatics analysis revealed Fas-associated death domain-containing protein (FADD) as a putative target of miR-155. Luciferase reporter assay and Western blot further disclosed that miR-155 inhibits FADD expression by directly targeting the 3'-UTR region. We propose that miR-155 attenuates the macrophage apoptosis, at least in part, through FADD regulation, since forced expression of FADD blocked the ability of miR-155 to inhibit apoptosis. Our results collectively suggest that miR-155 attenuates apoptosis of OxLDL-mediated RAW264.7 cells by targeting FADD, supporting a possible therapeutic role in atherosclerosis. PMID- 23797324 TI - Evidence for dynamic and multiple roles for huntingtin in Ciona intestinalis. AB - Although mutations in the huntingtin gene (HTT) due to poly-Q expansion cause neuropathology in humans (Huntington's disease; HD), the normal function(s) of the gene and its protein (HTT) remain obscure. With new information from recently sequenced invertebrate genomes, the study of new animal models opens the possibility of a better understanding of HTT function and its evolution. To these ends, we studied huntingtin expression pattern and dynamics in the invertebrate chordate Ciona intestinalis. Ciona huntingtin (Ci-HTT) shows a biphasic expression pattern during larval development and prior to metamorphosis. A single form of huntingtin protein is present until the early larval stages, at which time two different mass proteins become evident in the metamorphically competent larva. An antibody against Ci-HTT labeled 50 cells in the trunk mesenchyme regions in pre-hatching and hatched larvae and probably represents the distribution of the light form of the protein. Dual labeling with anti-Ci-HTT and anti-aldoketoreductase confirmed the presence of Ci-HTT in mesenchyme cells. Suppression of Ci-HTT RNA by a morpholino oligonucleotide reduced the number and apparent mobility of Ci-HTT positive cells. In Ciona, HTT expression has a dynamic temporal and spatial expression pattern that in ontogeny precedes metamorphosis. Although our results may reflect a derived function for the protein in pre- and post-metamorphic events in Ciona, we also note that as in vertebrates, there is evidence for multiple differential temporal expression, indicating that this protein probably has multiple roles in ontogeny and cell migration. PMID- 23797323 TI - Pharmacogenomics of anti-platelet and anti-coagulation therapy. AB - Arterial thrombosis is a major component of vascular disease, especially myocardial infarction (MI) and stroke. Current anti-thrombotic therapies such as warfarin and clopidogrel are effective in inhibiting cardiovascular events; however, there is great inter-individual variability in response to these medications. In recent years, it has been recognized that genetic factors play a significant role in drug response, and, subsequently, common variants in genes responsible for metabolism and drug action have been identified. These discoveries along with new diagnostic targets and therapeutic strategies hold promise for more effective individualized anti-coagulation and anti-platelet therapy. PMID- 23797325 TI - Motor Function in MPTP-Treated Tree Shrews (Tupaia belangeri chinensis). AB - The tree shrew, a new experimental animal model, has been used to study a variety of diseases, especially diseases of the nervous system. 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) is the gold standard for toxin-based animal models of Parkinson's disease (PD) because MPTP treatment replicates almost all of the pathological hallmarks of PD. Therefore, in this study, the effects of MPTP on the motor function of the tree shrew were examined. After five daily injections of a 3 mg/kg dose of MPTP, the motor function of MPTP-injected tree shrews decreased significantly, and the classic Parkinsonian symptoms of action and resting tremor, bradykinesia, posture abnormalities, and gait instability were observed in most MPTP-injected tree shrews. HPLC results also showed significantly reduced striatal dopamine and 3,4-dihydroxyphenylacetic acid levels in tree shrews after MPTP injection. Increased oxidative stress levels are usually considered to be the cause of dopaminergic neuron depletion in the presence of MPTP and were observed in the substantia nigra of MPTP-treated tree shrews, as indicated by a significant reduction in superoxide dismutase and glutathione peroxidase activity and increased levels of malondialdehyde. In addition, elevated alpha-synuclein mRNA levels in the midbrain of MPTP-treated tree shrews were observed. Furthermore, MPTP-treated tree shrews showed the classic Parkinsonian symptoms at a lower MPTP dosage compared with other animal models. Thus, the MPTP-treated tree shrew may be a potential animal model for studying the pathogenesis of PD. PMID- 23797326 TI - Special Section on Pharmacogenomics: recent advances and future directions. PMID- 23797328 TI - Human periventricular grey somatosensory evoked potentials suggest rostrocaudally inverted somatotopy. AB - BACKGROUND: Somatosensory homunculi have been demonstrated in primary somatosensory cortex and ventral posterior thalamus but not periaqueductal and periventricular grey matter (PAVG), a therapeutic target for deep brain stimulation (DBS) in chronic pain. AIMS: The study is an investigation of somatotopic representation in PAVG and assessment for a somatosensory homunculus. METHODS: Five human subjects were investigated using electrical somatosensory stimulation and deep brain macroelectrode recording. DBS were implanted in the contralateral PAVG. Cutaneous arm, leg and face regions were stimulated while event-related potentials were recorded from deep brain electrodes. Electrode contact positions were mapped using MRI and brain atlas information. RESULTS: Monopolar P1 somatosensory evoked potential amplitudes were highest and onset latencies shortest in contralateral caudal PAVG with facial stimulation and rostral with leg stimulation, in agreement with reported subjective sensation during intra-operative electrode advancement. CONCLUSIONS: A rostrocaudally inverted somatosensory homunculus exists in the human PAVG region. Objective human evidence of PAVG somatotopy increases understanding of a brainstem region important to pain and autonomic control that is a clinical target for both pharmacological and neurosurgical therapies. Such knowledge may assist DBS target localisation for neuropathic pain syndromes related to particular body regions like brachial plexopathies, anaesthesia dolorosa and phantom limb pain. PMID- 23797329 TI - A new cytochrome P450 system from Bacillus megaterium DSM319 for the hydroxylation of 11-keto-beta-boswellic acid (KBA). AB - In the genome of Bacillus megaterium DSM319, a strain who has recently been sequenced to fully exploit its potential for biotechnological purposes, we identified a gene encoding the cytochrome P450 CYP106A1 as well as genes encoding potential redox partners of CYP106A1. We cloned, expressed, and purified CYP106A1 and five potential autologous redox partners, one flavodoxin and four ferredoxins. The flavodoxin and three ferredoxins were able to support the activity of CYP106A1 displaying the first cloned natural redox partners of a cytochrome P450 from B. megaterium. The CYP106A1 system was able to convert the pentacyclic triterpene 11-keto-beta-boswellic acid (KBA) belonging to the main bioactive constituents of Boswellia serrata gum resin extracts, which are used to treat inflammatory disorders and arthritic diseases. In order to provide sufficient amounts of the KBA products to characterize them structurally by NMR spectroscopy, recombinant whole-cell biocatalysts were constructed based on B. megaterium MS941. The main product has been identified as 7beta-hydroxy-KBA, while the side product (~20%) was shown to be a mixture of 7beta,15alpha dihydroxy-KBA and 15alpha-hydroxy-KBA. Without further optimization 560.7 mg l-1 day-1 of the main product, 7beta-hydroxy-KBA, could be obtained thus providing a suitable starting point for the efficient production of modified KBA by chemical tailoring to produce novel KBA derivatives with increased bioavailability and this way more efficient drugs. PMID- 23797330 TI - Heterologous expression, characterization and evaluation of the matrix protein from Newcastle disease virus as a target for antiviral therapies. AB - Newcastle disease virus (NDV) is an infectious agent of a large variety of birds, including chicken, which poses a real threat to the agriculture industry. Matrix (M) proteins of NDV and many other viruses perform critical functions during viral assembly and budding from the host cell. M-proteins are well conserved and therefore are potential targets for antiviral therapies. To validate this, we expressed the NDV M-protein in its native form in Saccharomyces cerevisiae and in inclusion bodies in Escherichia coli. Proper refolding of the recombinant protein produced in E. coli was verified using circular dichroism and infrared spectroscopies and electron microscopy. Immunization of chickens with the NDV M protein elicited significant serum antibody titers. However, the antibodies conferred little protection against the ND following lethal viral challenges. We conclude that the M-protein is not exposed on the surface of the host cell or the virus at any stage during its life cycle. We discuss how the conserved M-protein can further be exploited as an antiviral drug target. PMID- 23797331 TI - Fermentation of biodiesel-derived glycerol by Bacillus amyloliquefaciens: effects of co-substrates on 2,3-butanediol production. AB - Cultivation in glycerol instead of sugars inhibits 2,3-butanediol (2,3-BD) production by Bacillus amyloliquefaciens. In this study, we report that B. amyloliquefaciens readily produces 2,3-BD from biodiesel-derived glycerol in the presence of beet molasses as a co-substrate. Unexpectedly, the molasses stimulated 2,3-BD production and simultaneously reduced the duration of fermentation. Productivity of 2,3-BD was enhanced at the start of fermentation, and yields increased under continuous molasses supply. Subsequently, 2,3-BD production in molasses-supplemented fed-batch culture was observed. Prior to inoculation of fed-batch fermentation culture, 15 g/l of molasses was added to the bioreactor. After 6 h of incubation, the bioreactor was fed with a solution containing 80 % glycerol and 15 % molasses. The 2,3-BD concentration, yield, and productivity significantly improved, reaching 83.3 g/l, 0.42 g/g, and 0.87 g/l.h, respectively. To our knowledge, these results are the highest report for 2,3-BD fermentation from biodiesel-derived glycerol. PMID- 23797332 TI - Design and evaluation of improved magnetic stir bars for single-mode microwave reactors. AB - Magnetic stirring in sealed cylindrical vessels designed for use in single-mode microwave instruments is typically less than optimal, and is not comparable to the efficient agitation that can be generally obtained in a round-bottomed flask fitted with a suitable magnetic stir bar or using overhead mechanical stirring systems. A new "vertical blade" stir bar design that improves the stirring performance in the very narrow, flow-constricting microwave vessels has been developed and evaluated for several different transformations where stirring and efficient agitation are known to be of importance. The better performance of these novel stirrers compared to the traditional cylindrical stir bar design is not only due to the geometry of the stirrer but also to the utilization of a magnetic material with a stronger magnetic transmission force (Sm2Co17) compared to standard ferrite or AlNiCo alloys. For all three tested cases involving solid/liquid, liquid/liquid and highly viscous reaction systems, the new vertical blade stirrers showed a distinctively improved performance resulting in higher conversions and/or product yields. PMID- 23797334 TI - Tailup plays multiple roles during cardiac outflow assembly in Drosophila. AB - The Drosophila LIM-homeodomain transcription factor Tailup and its vertebrate counterpart Islet1 are expressed in cardiac progenitor cells where they play a specification role. Loss of function of Islet1 leads to a complete absence of the right ventricle and affects the development of the cardiac outflow tract in mouse embryos. Similarly, tailup mutant embryos display a reduced number of cardiac cells but the role of tailup in cardiac outflow formation in Drosophila remains unknown. Here, we show that tailup is expressed in the main Drosophila cardiac outflow components, i.e., heart anchoring cells (HANC) and cardiac outflow muscles (COM) and that loss of its function and/or tissue-specific knockdowns dramatically affect cardiac outflow morphogenesis. Our data demonstrate that tailup plays many roles and is required for the acquisition of HANC and COM properties. We also show that tailup regulates HANC motility, COM shapes and their attachment to the heart tip and genetically interacts with ladybird, shotgun and slit, which are known to be involved in cardiac outflow assembly. Furthemore, using tissue-specific overexpression of dominant negative tailup constructs lacking sequences encoding either the homeodomain or the LIM domain, we demonstrate that tailup can exert its function not only in transcription factor mode but also via its protein-protein interaction domain. We identify Tailup as an evolutionarily-conserved regulator of cardiac outflow formation and provide further evidence for its conserved role in heart development. PMID- 23797335 TI - A candidate of organum vasculosum of the lamina terminalis with neuronal connections to neurosecretory preoptic nucleus in eels. AB - Systemic angiotensin II (Ang II) is a dipsogen in terrestrial vertebrates and seawater teleosts. In eels, Ang II acts on the area postrema, a sensory circumventricular organ (CVO) and elicits water intake but other sensory CVOs have not yet been found in the eel forebrain. To identify sensory CVOs in the forebrain, eels were peripherally injected with Evans blue, which immediately binds to albumin, or a rabbit IgG protein. Extravasation of these proteins, which cannot cross the blood-brain barrier (BBB), was observed in the brain parenchyma of the anteroventral preoptic recess (PR) walls. Fenestrated capillaries were observed in the parenchymal margin of the ventral wall of the PR, confirming a deficit of the BBB in the eel forebrain. Immunostaining for tyrosine hydroxylase (TH) and choline acetyltransferase (ChAT) detected neurons in the lateral region of the anterior parvocellular preoptic nucleus (PPa), which were strongly stained by BBB-impermeable N-hydroxysulfosuccinimide. In the periventricular region of the PPa, many neurons incorporated biotinylated dextran amine conjugated to fluorescein, a retrograde axonal tracer, injected into the magnocellular preoptic nucleus (PM), indicating neuronal connections from the PPa to the PM. The mammalian paraventricular and supraoptic nuclei, homologous to the teleost PM, receive principal neuronal projections from the organum vasculosum of the lamina terminalis (OVLT). These results strongly suggest that the periventricular subpopulation of the PPa, which is most likely to be a component of the OVLT, serves as a functional window of access for systemic signal molecules such as Ang II. PMID- 23797336 TI - Neuropeptide Y mRNA and peptide in the night-migratory redheaded bunting brain. AB - This study investigated the distribution of neuropeptide Y (NPY) in the brain of the night-migratory redheaded bunting (Emberiza bruniceps). We first cloned the 275-bp NPY gene in buntings, with >=95% homology with known sequences from other birds. The deduced peptide sequence contained all conserved 36 amino acids chain of the mature NPY peptide, but lacked 6 amino acids that form the NPY signal peptide. Using digosigenin-labeled riboprobe prepared from the cloned sequence, the brain cells that synthesize NPY were identified by in-situ hybridization. The NPY peptide containing cell bodies and terminals (fibers) were localized by immunocytochemistry. NPY mRNA and peptide were widespread throughout the bunting brain. This included predominant pallial and sub-pallial areas (cortex piriformis, cortex prepiriformis, hyperpallium apicale, hippocampus, globus pallidus) and thalamic and hypothalamic nuclei (organum vasculosum laminae terminalis, nucleus (n.) dorsolateralis anterior thalami, n. rotundus, n. infundibularis) including the median eminence and hind brain (n. pretectalis, n. opticus basalis, n. reticularis pontis caudalis pars gigantocellularis). The important structures with only NPY-immunoreactive fibers included the olfactory bulb, medial and lateral septal areas, medial preoptic nucleus, medial suprachiasmatic nucleus, paraventricular nucleus, ventromedial hypothalamic nucleus, optic tectum, and ventro-lateral geniculate nucleus. These results demonstrate that NPY is possibly involved in the regulation of several physiological functions (e.g. daily timing feeding, and reproduction) in the migratory bunting. PMID- 23797338 TI - Genetic modulation of the serotonergic pathway: influence on weight reduction and weight maintenance. AB - The serotonergic pathway plays a major role in the development of obesity. Its activity can be modulated by the 5-HT transporter-linked polymorphic region in the SLC6A4 gene and the upstream variable number of tandem repeats polymorphism in the MAOA gene. We studied whether these genetic modulations have an influence on weight reduction and weight maintenance in a one-year weight reduction program (OPTIFAST(r)52). The polymorphisms were genotyped by PCR in a sample of 135 female and 67 male subjects with severe obesity (44 +/- 13 years, 122.3 +/- 22.2 kg, BMI: 41.7 +/- 6.7 kg/m2). The program leads to a total weight loss of 19.9 +/ 9.8 kg (16.9 +/- 8.3 %) in women and 27.4 +/- 13.6 kg (20.4 +/- 9.9 %) in men. Anthropometric measurements and blood levels were determined at the start of the program (T0), after the weight reduction phase (T1) and after the subsequent weight maintenance phase at the end of the program (T2). Each polymorphism alone did not significantly influence weight loss or weight maintenance neither in men nor in women. However, women carrying both risk genotypes (SS and 3/3) displayed a lower total weight loss during the program (p = 0.05). This effect derived mainly from difficulties in the weight maintenance phase (p = 0.11), while the weight reduction phase was not affected (p = 0.61). No influence was found in men (p = 0.93). Modulation of the serotonergic pathway by carrying both risk alleles seems to influence success of weight loss programs in women with severe obesity due to problems in stabilizing body weight after weight reduction. PMID- 23797339 TI - GRPR antagonists for prostate cancer--prospects and caveats. PMID- 23797340 TI - Prostate cancer: stratifying intermediate-risk patients for radiotherapy. PMID- 23797341 TI - Overview of the latest treatments for castration-resistant prostate cancer. AB - Over the past few years, we have developed an increased understanding of the molecular mechanisms that underlie prostate cancer progression and castration resistance and expanded our repertoire of therapeutic options for castration resistant prostate cancer (CRPC). Four new agents (cabazitaxel, abiraterone acetate, enzalutamide, and radium-233) have been shown to prolong overall survival in patients with CRPC in the postchemotherapy setting. Targeting the androgen receptor pathway continues to have an important role in the treatment of CRPC, with abiraterone acetate and enzalutamide being the most exciting developments. Cabazitaxel is now considered the standard-of-care second-line chemotherapy for men with metastatic CRPC (mCRPC). Bone-targeted therapy is an active area of research, with denosumab being the first bone-targeted agent able to significantly delay the appearance of bone metastases in patients with CRPC and radium-223 being the first radiopharmaceutical agent to improve survival in patients with mCRPC. PMID- 23797342 TI - Economic costs of childhood lead exposure in low- and middle-income countries. AB - BACKGROUND: Children's blood lead levels have declined worldwide, especially after the removal of lead in gasoline. However, significant exposure remains, particularly in low- and middle-income countries. To date, there have been no global estimates of the costs related to lead exposure in children in developing countries. OBJECTIVE: Our main aim was to estimate the economic costs attributable to childhood lead exposure in low- and middle-income countries. METHODS: We developed a regression model to estimate mean blood lead levels in our population of interest, represented by each 1-year cohort of children < 5 years of age. We used an environmentally attributable fraction model to estimate lead-attributable economic costs and limited our analysis to the neurodevelopmental impacts of lead, assessed as decrements in IQ points. Our main outcome was lost lifetime economic productivity due to early childhood exposure. RESULTS: We estimated a total cost of $977 billions of international dollars in low- and middle-income countries, with economic losses equal to $134.7 billion in Africa [4.03% of gross domestic product (GDP)], $142.3 billion in Latin America and the Caribbean (2.04% of GDP), and $699.9 billion in Asia (1.88% of GDP). Our sensitivity analysis indicates a total economic loss in the range of $728.6 1162.5 billion. CONCLUSIONS: We estimated that, in low- and middle-income countries, the burden associated with childhood lead exposure amounts to 1.20% of world GDP in 2011. For comparison, in the United States and Europe lead attributable economic costs have been estimated at $50.9 and $55 billion, respectively, suggesting that the largest burden of lead exposure is now borne by low- and middle-income countries. PMID- 23797343 TI - Immunogenicity of monoclonal antibodies against tumor necrosis factor used in chronic immune-mediated Inflammatory conditions: systematic review and meta analysis. AB - IMPORTANCE: Knowledge of the immunogenicity of biologic agents may be helpful for the development of strategies for treatment of chronic immune-mediated inflammatory diseases. OBJECTIVE: To summarize the influence of antibodies against biologic agents (AABs [seropositivity]) on efficacy and safety in immune mediated inflammatory diseases. DATA SOURCES MEDLINE, EMBASE, Cochrane Library, and the Web of Knowledge were searched for articles published in English, Spanish, French, Italian, or Portuguese between 2000 and March 2012. The search strategy focused on synonyms of diseases, immunogenicity, and biologic agents. Abstracts from 2001 to 2011 of the European League Against Rheumatism and American College of Rheumatology congresses were also included. STUDY SELECTION: The selection criteria were (1) observational or interventional studies in rheumatoid arthritis, juvenile idiopathic arthritis, inflammatory bowel disease, spondyloarthritis, and psoriasis; (2) studies including patients who received biologic agents; and (3) studies collecting data on AABs. DATA EXTRACTION AND SYNTHESIS: Data collected included publication details, study design, characteristics of patients and treatments, presence of antibodies, and definition of response. MAIN OUTCOMES AND MEASURES: The primary end point was the association of AABs with response to treatment. Secondary end points were the association of AABs with safety, the association of AABs with concentration of the drug, and the influence of use of concomitant immunosuppressive therapy in the formation of AABs. RESULTS: The search captured 10 728 articles and abstracts. By hand and reverse search, 31 articles were additionally included. After evaluation of the full reports, 60 references were selected. They included 59 studies of anti-tumor necrosis factor monoclonal antibodies: 1 with etanercept, 2 with rituximab, and 2 with abatacept. In rheumatoid arthritis but not in inflammatory bowel disease or spondyloarthritis, seropositive patients presented worse clinical response at 6 months or less (odds ratio [OR], 0.03; 95% CI, 0.01-0.21), and at 6 months or more (0.03; 0.00-0.30) by meta-analysis. In rheumatoid arthritis, discontinuation of the biologic agent for all reasons was more common in seropositive patients (OR, 3.53; 95% CI, 1.60-7.82). In all conditions, seropositive patients had a higher risk of hypersensitivity reactions (OR, 3.97; 95% CI, 2.36-6.67). Overall, concomitant treatment with disease modifying antirheumatic drugs, including azathioprine, decreased the risk of seropositivity (OR, 0.32; 95% CI, 0.25-0.42). CONCLUSIONS AND RELEVANCE: Presence of antibodies against anti-tumor necrosis factor monoclonal antibodies confers a risk of discontinuation of treatment in rheumatoid arthritis and a risk of development of hypersensitivity reactions in all immune-mediated inflammatory diseases. The combined use of anti-tumor necrosis factor monoclonal antibodies and disease-modifying antirheumatic drugs reduces the development of antibodies and subsequent risks. Information on other biologic agents is fragmentary. PMID- 23797344 TI - Hospital to Home with Mechanical Circulatory Support. AB - Mechanical circulatory support (MCS) is becoming the mainstay of therapy for patients with advanced heart failure, both for patients needing support as a bridge to transplantation and for those who require the device as a destination therapy. As more and more devices are implanted, there is a need to address effective discharge planning, arrange appropriate follow-up, anticipate and address complications, and develop strategies for long-term care. In this article, we will discuss issues surrounding discharge and challenges of managing patients with MCS in the outpatient setting. PMID- 23797345 TI - What is the optimal place for heart failure treatment and care: home or hospital? AB - This article examines the role of home versus hospital clinic-based management of heart failure to achieve the best outcomes for affected individuals and their carer/families. It also considers the role of remote management strategies. Overall, the evidence in favor of home-based strategies is quite compelling. However, persistently high levels of heart-failure-related morbidity and mortality, combined with inconsistent application of key components of care, mandate greater efforts to develop more standardized and cost-effective forms of heart failure support services. PMID- 23797346 TI - Crisis? What crisis? PMID- 23797347 TI - Role of fresh-frozen plasma in angioedema: progress and problems. PMID- 23797348 TI - Morbidly obese patients in emergency department: are we ready to face the challenge? PMID- 23797349 TI - The Use of the Medical Dictionary for Regulatory Activities in the Identification of Mitochondrial Dysfunction in HIV-Infected Children. AB - OBJECTIVE: To demonstrate the utility of a medical terminology-based method for identifying cases of possible mitochondrial dysfunction (MD) in a large cohort of youths with perinatal HIV infection and to describe the scoring algorithms. METHODS: Medical Dictionary for Regulatory Activities (MedDRA)(r) version 6 terminology was used to query clinical criteria for mitochondrial dysfunction by two published classifications, the Enquete Perinatale Francaise (EPF) and the Mitochondrial Disease Classification (MDC). Data from 2,931 participants with perinatal HIV infection on PACTG 219/219C were analyzed. Data were qualified for severity and persistence, after which clinical reviews of MedDRA-coded and other study data were performed. RESULTS: Of 14,000 data records captured by the EPF MedDRA query, there were 3,331 singular events. Of 18,000 captured by the MDC query, there were 3,841 events. Ten clinicians blindly reviewed non MedDRA-coded supporting data for 15 separate clinical conditions. We used the Statistical Analysis System (SAS) language to code scoring algorithms. 768 participants (26%) met the EPF case definition of possible MD; 694 (24%) met the MDC case definition, and 480 (16%) met both definitions. LIMITATIONS: Subjective application of codes could have affected our results. MedDRA terminology does not include indicators of severity or persistence. Version 6.0 of MedDRA did not include Standard MedDRA Queries, which would have reduced the time needed to map MedDRA terms to EPF and MDC criteria. CONCLUSION: Together with a computer-coded scoring algorithm, MedDRA terminology enabled identification of potential MD based on clinical data from almost 3000 children with substantially less effort than a case by case review. The article is accessible to readers with a background in statistical hypothesis testing. An exposure to public health issues is useful but not strictly necessary. PMID- 23797350 TI - Chorea paralytica: a videotape case with rapid recovery and good long-term outcome. AB - Chorea paralytica (or chorea mollis) is a very rare variant of Sydenham's chorea, characterized by a profound hypotonia, resulting in severe disability. Given the rarity of this condition, data on its prognosis are lacking. Most reports suggest that the delay from onset to recover total autonomy is long, usually several weeks to months which strongly affects the quality of life of these children. We report a videotape case of a 14-year-old girl, who became rapidly bedridden because of severe generalized chorea paralytica. Her clinical picture was totally improved 7 days only after initiation of an "aggressive" treatment, combining steroid pulse, haloperidol and long-term penicillin G, with no relapse after 4 year follow-up. We believe that the best care of this rare and severe form of Sydenham's chorea, should combine pathophysiological treatment with corticosteroids, preferably by pulse-therapy, symptomatic antichoreic treatment by neuroleptics, associated with a long-term antibiotic use to reduce recurrence risk. PMID- 23797351 TI - Behavioral and neurophysiological study of attentional and inhibitory processes in ADHD-combined and control children. AB - This study compares behavioral and electrophysiological (P300) responses recorded in a cued continuous performance task (CPT-AX) performed by children with attention deficit hyperactivity disorder-combined subtype (ADHD-com) and age matched healthy controls. P300 cognitive-evoked potentials and behavioral data were recorded in eight children with ADHD (without comorbidity) and nine control children aged 8-12 years while performing a CPT-AX task. Such task enables to examine several kinds of false alarms and three different kinds of P300 responses: the "Cue P300", the "Go P300" and the "NoGo P300", respectively, associated with preparatory processing/attentional orienting, motor/response execution and motor/response inhibition. Whereas hit rates were about 95% in each group, ADHD children made significantly more false alarm responses (inattention- and inhibition-related) than control children. ADHD children had a marginally smaller Cue P300 than the control children. Behavioral and electrophysiological findings both highlighted inhibition and attention deficits in ADHD-com children in the CPT-AX task. A rarely studied kind of false alarm, the "Other" FA, seems to be a sensitive FA to take into account, even if its interpretation remains unclear. PMID- 23797352 TI - Fetal cerebral hemodynamic in gestational diabetic versus normal pregnancies: a Doppler velocimetry of middle cerebral and umbilical arteries. AB - Gestational diabetes mellitus (GDM) is one of the most common complications in pregnancies. Evaluating other conditions, including intra uterine growth restriction and pre-eclampsia, some studies have shown significant changes in blood flow velocity of fetal middle cerebral artery (MCA). Our study is one of the few that has aimed to assess the effects of GDM on Doppler parameters of the fetal MCA and umbilical artery (UA) and to compare with normal pregnancies. This cross-sectional study was performed on 66 pregnant women, including 33 women with GDM and the others without it, in Akbar-Abadi University Hospital in Tehran, Iran during 2010-2011. Peak systolic and diastolic velocities, pulsatility index (PI), resistance index (RI) and systolic diastolic ratio (SD) were recorded in UA as well as both right and left fetal MCAs for every recruited pregnant women by means of Doppler ultrasonography. The mean gestational age at the time of examination was 34.45 (SD = 2.62) weeks in GDM group. Although all of the measured Doppler parameters had higher values in GDM pregnancies, the differences were not significant between two groups of study; except for the left fetal MCA PI, which was significantly higher in GDM group [2.07 (SD = 0.07) vs. 1.85 (SD = 0.74), P = 0.03]. Our results show that gestational diabetes may contribute to an elevated PI in the fetal MCA. Although there is not yet strong proof for the effect of GDM on the fetal brain hemodynamics, the significant higher MCA-PI warrants more attention towards better controlling of the hyperglycemia during pregnancy. PMID- 23797354 TI - Challenges in the provision of skin in the UK: the use of human deceased donor skin in burn care relating to mass incidents in the UK. AB - This article aims to discuss the role of deceased donor skin within the treatment of burn injuries with particular reference to the management of major burn disasters. The article begins with a review of wound healing before progressing to outline the development of the current modern day approach to burns surgery from its historical origins and the role of deceased donor skin within this. A detailed review of mass disasters within the UK over the past 29 years provides an indication as to the frequency and extent of mass disasters that might be predicted to occur. Combining this with a recent review of allograft requirements within burns surgery at a regional UK centre allows for more accurate planning and stockpiling of deceased donor skin reserves. UK awareness and emergency preparedness for major burn disasters can thus be improved. PMID- 23797355 TI - Correlation of active contact positions with the electrophysiological and anatomical subdivisions of the subthalamic nucleus in deep brain stimulation. AB - BACKGROUND: The most effective contacts in subthalamic nucleus (STN) deep brain stimulation are reported to be dorsolateral, and suppression of synchronized oscillatory activity might be a mechanism of action. OBJECTIVES: To analyze the optimal contact position in regard to the anatomical and electrophysiological position and to determine whether oscillatory and bursty activity is more frequent around the active contact. METHODS: In 21 patients, the clinically most effective contacts were analyzed according to their relative position to the anatomical and electrophysiological STN center, which was assessed by T2-weighted MRI and microrecording. In 12 out of 21 consecutive patients, autocorrelograms of the action potentials within the vicinity of the active contact were compared to the most ventromedial reference contact. RESULTS: The isocenter of the anatomical and electrophysiological STN had a mean deviation of 0.8 mm (SD 1.45). Thirty-two out of 42 active contacts were found dorsal to the anatomical isocenter of the STN. None of the active contacts were ventral to the STN. Synchronized oscillatory or bursty activity was found in 67% of the patients within the vicinity of the active contact. In 64% of the patients, the ventromedial reference contact showed irregular activity. CONCLUSIONS: Synchronized activity in the autocorrelogram correlates with the most effective contact. The optimal localization of the finally stimulated contact is dorsal to the STN isocenter. PMID- 23797356 TI - Glassy dynamics of soft matter under 1D confinement: how irreversible adsorption affects molecular packing, mobility gradients and orientational polarization in thin films. AB - The structural dynamics of polymers and simple liquids confined at the nanometer scale has been intensively investigated in the last two decades in order to test the validity of theories on the glass transition predicting a characteristic length scale of a few nanometers. Although this goal has not yet been reached, the anomalous behavior displayed by some systems--e.g. thin films of polystyrene exhibit reductions of Tg exceeding 70 K and a tremendous increase in the elastic modulus--has attracted a broad community of researchers, and provided astonishing advancement of both theoretical and experimental soft matter physics. 1D confinement is achieved in thin films, which are commonly treated as systems at thermodynamic equilibrium where free surfaces and solid interfaces introduce monotonous mobility gradients, extending for several molecular sizes. Limiting the discussion to finite-size and interfacial effects implies that film thickness and surface interactions should be sufficient to univocally determine the deviation from bulk behavior. On the contrary, such an oversimplified picture, although intuitive, cannot explain phenomena like the enhancement of segmental mobility in proximity of an adsorbing interface, or the presence of long-lasting metastable states in the liquid state. Based on our recent work, we propose a new picture on the dynamics of soft matter confined in ultrathin films, focusing on non-equilibrium and on the impact of irreversibly chain adsorption on the structural relaxation. We describe the enhancement of dynamics in terms of the excess in interfacial free volume, originating from packing frustration in the adsorbed layer (Guiselin brush) at t(*) ? 1, where t(*) is the ratio between the annealing time and the time scale of adsorption. Prolonged annealing at times exceeding the reptation time (usually t(*) ? 1 induces densification, and thus reduces the deviation from bulk behavior. In this Colloquium, after reviewing the experimental approaches permitting to investigate the structural relaxation of films with one, two or no free surfaces by means of dielectric spectroscopy, we propose several methods to determine gradients of mobility in thin films, and then discuss on the unexploited potential of analyses based on the time, temperature and thickness dependence of the orientational polarization via the dielectric strength. PMID- 23797357 TI - Protein packing defects "heat up" interfacial water. AB - Ligands must displace water molecules from their corresponding protein surface binding site during association. Thus, protein binding sites are expected to be surrounded by non-tightly-bound, easily removable water molecules. In turn, the existence of packing defects at protein binding sites has been also established. At such structural motifs, named dehydrons, the protein backbone is exposed to the solvent since the intramolecular interactions are incompletely wrapped by non polar groups. Hence, dehydrons are sticky since they depend on additional intermolecular wrapping in order to properly protect the structure from water attack. Thus, a picture of protein binding is emerging wherein binding sites should be both dehydrons rich and surrounded by easily removable water. In this work we shall indeed confirm such a link between structure and dynamics by showing the existence of a firm correlation between the degree of underwrapping of the protein chain and the mobility of the corresponding hydration water molecules. In other words, we shall show that protein packing defects promote their local dehydration, thus producing a region of "hot" interfacial water which might be easily removed by a ligand upon association. PMID- 23797358 TI - Anomalous drying dynamics of a polymer solution on a substrate. AB - When a polymer solution with volatile solvent is exposed to open air, an elastic layer (called a skin) is often formed at the surface of the solution due to evaporation of the solvent. After such a skin is formed, further extraction of the solvent from the solution caused by evaporation has generally been considered to reduce the pressure in the solution. We have found that, in PMMA/acetone droplet placed on a substrate, the liquid below the skin layer is pushed out as the solvent evaporates further. These phenomena indicate that the pressure in the solution increases by solvent evaporation. It is considered to be caused by the shrinkage and other structural changes taking place in the skin layer. PMID- 23797359 TI - Patients' causal beliefs about diabetic retinopathy. AB - PURPOSE: This study explored patients' understanding of the risk factors for diabetic retinopathy (DR) and their personal beliefs about the cause and controllability of their own DR, as well as health professionals' perceptions of patients' understanding of DR and its cause. METHODS: Eight focus groups and 18 semistructured interviews were conducted with 57 patients with DR, and seven semistructured interviews were conducted with diabetes and ophthalmic specialists. Sessions were transcribed verbatim and iteratively analyzed using the constant comparative method and NVIVO software. RESULTS: Nearly 50% of participants had proliferative DR, and most patients had undergone laser treatment. Patients had a reasonable understanding of the basic risk factors for DR such as diabetes control, although they were less clear about specific risk factors such as blood pressure and lipid control. Regarding their own disease, most patients attributed their DR either to poor diabetes control or to failings of the health care system. Some patients believed that their DR was a result of health aspects beyond their control or environmental factors, whereas others were unsure about the cause. Diabetes and ophthalmic specialists believed that many patients lacked understanding about the cause of their DR and the goal and outcome of laser treatment. Difficulty communicating the abstract concept of laser treatment outcomes in the face of concrete (yet erroneous) anecdotal evidence of the detrimental impact of laser on visual acuity was highlighted as a major barrier to mitigating patients' harmful beliefs about treatment. CONCLUSIONS: This study revealed some important gaps in patients' knowledge and potentially damaging beliefs about the cause and treatment of DR despite most patients having considerable exposure to eye health professionals and DR treatment. Improving patients' understanding of the major risk factors for DR and the realistic outcomes of laser treatment may improve patients' coping mechanisms, adaption to disease, and ocular outcomes. PMID- 23797360 TI - Dynamics of connective-tissue localization during chronic Borrelia burgdorferi infection. AB - The etiologic agent of Lyme disease, Borrelia burgdorferi, localizes preferentially in the extracellular matrix during persistence. In chronically infected laboratory mice, there is a direct association between B. burgdorferi and the proteoglycan decorin, which suggests that decorin has a role in defining protective niches for persistent spirochetes. In this study, the tissue colocalization of B. burgdorferi with decorin and the dynamics of borrelial decorin tropism were evaluated during chronic infection. Spirochetes were found to colocalize absolutely with decorin, but not collagen I in chronically infected immunocompetent C3H mice. Passive immunization of infected C3H-scid mice with B. burgdorferi-specific immune serum resulted in the localization of spirochetes in decorin-rich microenvironments, with clearance of spirochetes from decorin-poor microenvironments. In passively immunized C3H-scid mice, tissue spirochete burdens were initially reduced, but increased over time as the B. burgdorferi specific antibody levels waned. Concurrent repopulation of the previously cleared decorin-poor microenvironments was observed with the rising tissue spirochete burden and declining antibody titer. These findings indicate that the specificity of B. burgdorferi tissue localization during chronic infection is determined by decorin, driven by the borrelia-specific antibody response, and fluctuates with the antibody response. PMID- 23797361 TI - PepT1 expressed in immune cells has an important role in promoting the immune response during experimentally induced colitis. AB - We and others have shown that the dipeptide cotransporter PepT1 is expressed in immune cells, including macrophages that are in close contact with the lamina propria of the small and large intestines. In the present study, we used PepT1 knockout (KO) mice to explore the role played by PepT1 in immune cells during dextran sodium sulfate (DSS)-induced colitis. DSS treatment caused less severe body weight loss, diminished rectal bleeding, and less diarrhea in PepT1-KO mice than in wild-type (WT) animals. A histological examination of colonic sections revealed that the colonic architecture was less disrupted and the extent of immune cell infiltration into the mucosa and submucosa following DSS treatment was reduced in PepT1-KO mice compared with WT animals. Consistent with these results, the DSS-induced colitis increase in colonic myeloperoxidase activity was significantly less in PepT1-KO mice than in WT littermates. The colonic levels of mRNAs encoding the inflammatory cytokines CXCL1, interleukin (IL)-6, monocyte chemotactic protein-1, IL-12, and interferon-gamma were significantly lower in DSS-treated PepT1-KO mice than in DSS-treated WT animals. Colonic immune cells from WT had significantly higher level of proinflammatory cytokines then PepT1 KO. In addition, we observed that knocking down the PepT1 expression decreases chemotaxis of immune cells recruited during intestinal inflammation. Antibiotic treatment before DSS-induced colitis eliminated the differential expression of inflammatory cytokines between WT and PepT1-KO mice. In conclusion, PepT1 in immune cells regulates the secretion of proinflammatory cytokines triggered by bacteria and/or bacterial products, and thus has an important role in the induction of colitis. PepT1 may transport small bacterial products, such as muramyl dipeptide and the tripeptide L-Ala-gamma-D-Glu-meso-DAP, into macrophages. These materials may be sensed by members of the nucleotide-binding site-leucine-rich repeat family of intracellular receptors, ultimately resulting in altered homeostasis of the intestinal microbiota. PMID- 23797362 TI - [Foreword]. PMID- 23797363 TI - [CNS metastases--an interdisciplinary challenge]. PMID- 23797364 TI - [Immune oncology in focus]. PMID- 23797365 TI - [Supply legal and regulatory structure for restructuring the drug market]. PMID- 23797366 TI - Temperature-dependent shifts in phenology contribute to the success of exotic species with climate change. AB - PREMISE OF THE STUDY: The study of how phenology may contribute to the assembly of plant communities has a long history in ecology. Climate change has brought renewed interest in this area, with many studies examining how phenology may contribute to the success of exotic species. In particular, there is increasing evidence that exotic species occupy unique phenological niches and track climate change more closely than native species. METHODS: Here, we use long-term records of species' first flowering dates from fi ve northern hemisphere temperate sites (Chinnor, UK and in the United States, Concord, Massachusetts; Fargo, North Dakota; Konza Prairie, Kansas; and Washington,D.C.) to examine whether invaders have distinct phenologies. Using a broad phylogenetic framework, we tested for differences between exotic and native species in mean annual flowering time, phenological changes in response to temperature and precipitation,and longer-term shifts in first flowering dates during recent pronounced climate change ("flowering time shifts"). KEY RESULTS: Across North American sites, exotic species have shifted flowering with climate change while native species, on average, have not. In the three mesic systems, exotic species exhibited higher tracking of interannual variation in temperature,such that flowering advances more with warming, than native species. Across the two grassland systems, however, exotic species differed from native species primarily in responses to precipitation and soil moisture, not temperature. CONCLUSIONS: Our findings provide cross-site support for the role of phenology and climate change in explaining species' invasions.Further, they support recent evidence that exotic species may be important drivers of extended growing seasons observed with climate change in North America. PMID- 23797367 TI - The cascade radical cyclisation approach to prenylated alkaloids: synthesis of stephacidin A and notoamide B. AB - A strategy for the synthesis of members of the prenylated indole alkaloid family is described, which involves a radical cascade process of an appropriately substituted diketopiperazine (DKP) core structure. Several approaches to the generation of the initial radical were explored, with the most successful involving treatment of a sulfenyl substituted DKP under classical reductive conditions by heating with Bu3SnH and a radical initiator. The required, fully substituted, radical precursor DKP structures were prepared using regio- and stereocontrolled enolate chemistry of simpler proline-tryptophan derived DKPs. The new approach allowed rapid access to a key polycyclic indoline structure, which was converted into either of the natural products stephacidin A or notoamide B. PMID- 23797368 TI - Observations on the effects of inhaled isoflurane in long-term sedation of critically Ill children using a modified AnaConDa(c)-system. AB - Long-term intravenous sedation may present problems due to dependence and side effects. Medical records of children who were administered isoflurane were reviewed. 15 patients (9 boys, 6 girls) with a mean age of 11.8 month (+2.4) were analysed.Analgesia and sedation was given in mean 9.7+1.1 days before commencing inhalation using a modified application device (AnaConDa(c)). Administration was given over a period of 7.2+1.4 days. Depth of sedation was monitored by using Comfort- and Hartwig-scores. Observations included continuous monitoring of heart rate, pulse oxymetry, blood pressure and cerebral tissue oxygenation.Within 4 h post administration of isoflurane a satisfactory increase in the depth of sedation was seen and kept till extubation. 6/15 patients received tracheostomies during the observation period. None of the patients observed suffered life critical events of the modified application of isoflurane proceeded without complications. Ketamine and clonidine infusion rates were significantly reduced (p<0.005) as well as the use and overall infusion rate of midazolam, gamma hydroxy butyrate, fentanyl and morphine (p<0.05).Isoflurane inhalation may provide an additional option for long-term sedation in a specific group of critically ill infants but neurodegenerative toxic effects will have to be taken into account when using volatile anesthetics at any time during infancy. PMID- 23797370 TI - Correlation of MRI with arthroscopy for the evaluation of the subscapularis tendon: a musculoskeletal division's experience. AB - OBJECTIVE: To determine the accuracy of MR imaging for the evaluation of the subscapularis tendon as well as define imaging findings that will increase accuracy. MATERIALS AND METHODS: Retrospective review of the MR and operative (OR) reports of 286 patients was conducted and reviewed for the presence/degree (partial (PT)/full-thickness (FT)) of tearing; only PT articular tears were included. The presence of a supraspinatus tear and time interval between surgery and MRI were also documented. All of the PT tears called on MRI were also reviewed to see if there was a statistically significant association between certain imaging characteristics and the presence of a tear in surgery. Statistical analysis included 95 % confidence intervals, Fisher's exact, and exact Mann-Whitney tests. RESULTS: A total of 244 patients were included in the study with a total of 25 subscapularis tears, 16 PT and nine FT, and 219 intact tendons in arthroscopy; 20/25 tears and 200 intact sensitivity of 80%, specificity of 91%, accuracy of 90%, positive predictive value of 51%, and negative predictive value of 98 %. There was a significant association between the presence of a PT tear during arthroscopy and fluid-like signal within the tendon on more than one imaging plane (p<0.001) with an accuracy of 90%. CONCLUSIONS: This study reflects a musculoskeletal radiology section's experience with the diagnosis of subscapularis tendon pathology, demonstrating that MRI could be used to accurately evaluate the subscapularis tendon. An understanding of certain imaging pitfalls and the presence of fluid-like signal on multiple imaging planes should increase the diagnostic accuracy of the radiologist evaluating the subscapularis tendon for the presence of a tear. PMID- 23797369 TI - Right ventricular dysfunction in systemic sclerosis-associated pulmonary arterial hypertension. AB - BACKGROUND: Systemic sclerosis-associated pulmonary artery hypertension (SScPAH) has a worse prognosis compared with idiopathic pulmonary arterial hypertension (IPAH), with a median survival of 3 years after diagnosis often caused by right ventricular (RV) failure. We tested whether SScPAH or systemic sclerosis-related pulmonary hypertension with interstitial lung disease imposes a greater pulmonary vascular load than IPAH and leads to worse RV contractile function. METHODS AND RESULTS: We analyzed pulmonary artery pressures and mean flow in 282 patients with pulmonary hypertension (166 SScPAH, 49 systemic sclerosis-related pulmonary hypertension with interstitial lung disease, and 67 IPAH). An inverse relation between pulmonary resistance and compliance was similar for all 3 groups, with a near constant resistance*compliance product. RV pressure-volume loops were measured in a subset, IPAH (n=5) and SScPAH (n=7), as well as SSc without PH (n=7) to derive contractile indexes (end-systolic elastance [Ees] and preload recruitable stroke work [Msw]), measures of RV load (arterial elastance [Ea]), and RV pulmonary artery coupling (Ees/Ea). RV afterload was similar in SScPAH and IPAH (pulmonary vascular resistance=7.0+/-4.5 versus 7.9+/-4.3 Wood units; Ea=0.9+/-0.4 versus 1.2+/-0.5 mm Hg/mL; pulmonary arterial compliance=2.4+/-1.5 versus 1.7+/-1.1 mL/mm Hg; P>0.3 for each). Although SScPAH did not have greater vascular stiffening compared with IPAH, RV contractility was more depressed (Ees=0.8+/-0.3 versus 2.3+/-1.1, P<0.01; Msw=21+/-11 versus 45+/-16, P=0.01), with differential RV-PA uncoupling (Ees/Ea=1.0+/-0.5 versus 2.1+/-1.0; P=0.03). This ratio was higher in SSc without PH (Ees/Ea=2.3+/-1.2; P=0.02 versus SScPAH). CONCLUSIONS: RV dysfunction is worse in SScPAH compared with IPAH at similar afterload, and may be because of intrinsic systolic function rather than enhanced pulmonary vascular resistive and pulsatile loading. PMID- 23797373 TI - [Interventional Mitral valve repair with the MitraClip(r) procedure. Patient selection criteria]. AB - In current practice the MitraClip(r) procedure is increasingly being used for patients unsuitable or at high risk for cardiac surgery. This article initially describes the patient groups that are suitable for percutaneous edge-to-edge repair. For this purpose the echocardiographic criteria for severe mitral regurgitation are first characterized and treatment algorithms for patients with primary as well as secondary mitral regurgitation according to current guidelines are illustrated. Basic anatomical requirements for the successful implantation of a MitraClip(r) are described and a distinction is made between various valve morphologies ranging from optimal to unsuitable anatomical conditions. Finally, three patient groups eligible for percutaneous edge-to-edge repair considering clinical and anatomical criteria are defined: (1) optimal for MitraClip(r), (2) MitraClip(r) could be considered and (3) MitraClip(r) only in exceptional cases. PMID- 23797372 TI - High BNP level as risk factor for acute kidney injury and predictor of all-cause mortality in STEMI patients. AB - OBJECTIVES: The aim of this study was to evaluate the predictive value of brain natriuretic peptide (BNP) in the development of acute kidney injury (AKI) and 6 month all-cause mortality after primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) in a modest-risk population. BACKGROUND: The prognostic value of BNP has been well documented in patients with acute coronary syndrome. However, its value in development of AKI and 6-month all cause mortality in patients with STEMI undergoing primary PCI remains unclear. METHODS: We prospectively enrolled 424 consecutive STEMI patients (mean age 53.6 +/- 12.1 years) undergoing primary PCI. The population was divided into two groups: a high (n = 110) and a low (n = 314) admission BNP group according to the cut-off value (> 88.7 pg/ml) determined by ROC analysis to have the best predictive accuracy for 6-month all-cause mortality. The clinical characteristics as well as the in-hospital and 6-month outcomes of patients undergoing primary PCI were analyzed. RESULTS: Cox multivariate analysis showed that a high admission BNP value (> 88.7 pg/ml) was an independent predictor of AKI development (odds ratio, 1.002; 95 % confidence interval, 1.000-1.003; p = 0.02) and 6-month all-cause mortality (odds ratio, 1.003; 95 % confidence interval; 1.001-1.004; p = 0.004). CONCLUSION: These results suggest that a high-admission BNP level is associated with an increased risk of AKI development and 6-month all cause mortality in patients with STEMI undergoing primary PCI. PMID- 23797374 TI - [TRAMI (Transcatheter Mitral Valve Interventions) register. The German mitral register]. AB - The transcatheter mitral valve interventions (TRAMI) registry was established in 2010 in order to assess the safety and efficacy of percutaneous mitral valve therapy in Germany and to document baseline characteristics and decision-making in different subgroups of patients. The TRAMI registry is available to all German sites performing percutaneous mitral valve therapy. Follow-up is scheduled at 30 days, 1, 3, and 5 years. In addition, patients can be enrolled retrospectively without predefined times of follow-up. The vast majority of patients enrolled in TRAMI underwent MitraClip(r) therapy. As of March 2013, a total of 1,064 patients treated with MitraClip(r) have been enrolled at 21 different German sites. Preliminary results show that patients treated with MitraClip(r) in Germany were mainly elderly patients with significant comorbidities and high or inacceptable risk of surgery. The majority of patients had secondary mitral regurgitation and a large proportion of patients had reduced left ventricular ejection fraction (LV EF). Nevertheless, MitraClip(r) was found to be safe and established risk factors for conventional cardiac mitral valve surgery, such as advanced age (>=76 years), female gender, severely reduced LV-EF (<30%) and high logistic EuroScore (>=20%) were not predictive for mortality or major complication rates. In contrast, severely reduced renal function was predictive for adverse outcome. The TRAMI registry is the largest real world cohort of patients treated with MitraClip(r). As long as randomized studies in this high-risk cohort of patients are lacking, TRAMI provides important information on outcomes after MitraClip(r) therapy. The data are important for hypothesis generation for randomized trials and TRAMI is an important tool for quality assurance after percutaneous mitral valve therapy in Germany. PMID- 23797375 TI - Complications during percutaneous edge-to-edge mitral valve repair. AB - Transcatheter edge-to-edge mitral valve repair is an approach for treating mitral regurgitation, which is an alternative for surgery in patients with a high surgical risk. Although the safety and efficacy of the technique have been demonstrated, it is still associated with potentially life-threatening complications. The aim of this paper is to discuss the nature, management, and prevention of the most important procedural complications associated with this procedure. PMID- 23797376 TI - Gastroparesis: from concepts to management. AB - While the symptoms of gastroparesis are common, an accurate diagnosis is based on a combination of those symptoms with a documented delay in gastric emptying. Typical symptoms include nausea, vomiting, early satiety, postprandial fullness, bloating, and abdominal discomfort. Patients with gastroparesis face many diagnostic and therapeutic challenges. The most common origins of gastroparesis are idiopathic causes and diabetes mellitus. The increased use of certain medications in medicine today, including opiates and drugs with anticholinergic properties, can alter gastrointestinal functions and mimic symptoms of gastroparesis. Accordingly, alternative explanations for symptoms and altered gastrointestinal function need to be considered. Numerous clinical sequelae, including weight loss and severe protein-calorie malnutrition, may be seen in advanced stages of gastroparesis. This article provides an overview of gut sensorimotor function to help the reader better understand the clinical presentation of patients with dyspepsia and those who may have accompanying delayed gastric emptying that meets criteria for gastroparesis. Techniques available for diagnosing motor dysfunction and the principles of gastroparesis management are reviewed. Nutrition recommendations and a review of pharmacologic agents, nonpharmacologic techniques, and novel treatment modalities are provided. PMID- 23797377 TI - Combination HIV prevention: the value and interpretation of mathematical models. AB - Mathematical models of HIV prevention interventions often provide critical insights related to programmatic design and economic efficiency. One recent dynamic model by Long et al. highlights that a combination prevention approach - with testing, treatment, circumcision, microbicides and PrEP - may decrease transmissions by over 60% and may be very cost-effective in South Africa. In this analysis, the authors introduce the critical concept of joint effectiveness of preventions programs and demonstrate how some programs operate synergistically (HIV screening coupled with early treatment) while others may create redundancies (microbicides coupled with pre-exposure prophylaxis). Whether combination HIV prevention programs perform with additive, multiplicative or maximal effectiveness will be important to consider in anticipation of their combined transmission impact. PMID- 23797378 TI - Application of a peripheral nerve block technique in laser treatment of the entire facial skin and evaluation of its analgesic effect. AB - BACKGROUND: The aim was to develop a technique for peripheral nerve block anesthesia (PNB) for the skin of the entire face and neck, considering the nerves anesthetized, injection sites, use of an injection method assisted by computer controlled local anesthetic delivery (CCLAD), and to evaluate the analgesic effects of the PNB technique. METHODS: 50 patients who suffered from large nevus of Ota lesions or port-wine stains on their facial and neck skin and who required laser treatment were included. This study was designed as a non-randomized self control trial. All the patients received the laser treatment under topical anesthesia in the first phase and three to six months later, they received the same treatment under the PNB using CCLAD. The differences in scores from the visual analogue scale of pain for the two phases were analyzed by the t-test. P values <0.05 were considered to be statistically significant. RESULTS: The peripheral nerve block technique was simple to execute and easy to learn, the anesthetic injection site was generally located at a subcutaneous depth of 0.5 1.0 cm. The analgesic effect of PNB was significant, the mean pain score (2.8 +/- 2.2) was significantly lower than that with topical anesthesia (P<0.0001). Patients during the PNB phase did not experience injection pain following CCLAD. CONCLUSION: The peripheral nerve block technique can greatly ease the pain that occurs during laser treatment, especially for patients with larger lesions. CCLAD will allow PNB to be broadly applied in laser treatments. PMID- 23797380 TI - ? PMID- 23797379 TI - Contraindicated initiation of beta-blocker therapy in patients hospitalized for heart failure. PMID- 23797381 TI - [Areas of work of a biopsychosocial oriented psychiatric consultation-liaison service: results from a prospective 2-year survey]. AB - BACKGROUND: Since the establishment of the European Association of Consultation Liaison Psychiatry and Psychosomatics in 1992, C/L psychiatry in European countries has been increasingly recognized as a subspecialty of clinical psychiatry and psychosomatic medicine. The study explored the areas of work of the biopsychosocial oriented psychiatric consultation - liaison (C/L) service at the university hospital LKH Graz (Austria). METHODS: We conducted two prospective 1-year surveys over two years of observation. Survey I comprised 1,505 consecutive new consultations, and the more recent Survey II extended over 1,478 consecutive new referrals to our C/L service. Psychiatric referrals were analyzed with regard to demographic characteristics, referring departments, principal reasons for referral, diagnostic characteristics, and intervention patterns. RESULTS: In both surveys, the most common patient to be referred was a middle aged woman. Internal medicine consistently accounted for almost one third of all referrals, followed by neurology. The most prominent reasons for biopsychosocial referral were any signs of abnormal mood, behaviour, psychotic symptoms or cognitive impairments. The most common mental disorders according to ICD-10 were adjustment disorders, depressive disorders, and delirium. Psychopharmacotherapy and combined psycho- and pharmacotherapy were the most frequent actions in both surveys, followed by biopsychosocial evaluation pretransplant. CONCLUSIONS: To ameliorate the provision of biopsychosocial care for general hospital patients, the need for specially planned biopsychosocial C/L services with equal involvement of specialists in medical psychology, C/L psychiatry, and clinical psychology should be underscored. PMID- 23797383 TI - Two-year weight-loss maintenance in primary care-based Diabetes Prevention Program lifestyle interventions. AB - OBJECTIVE: To investigate whether the effects on weight loss and cardiometabolic risk factor reduction of two technology-mediated lifestyle interventions for 15 months in a primary care-based translation trial sustained at 24 months (that is, 9 months after the end of intervention). DESIGN: This study analyzed data from an extended follow-up of participants in the original 'E-LITE' (Evaluation of Lifestyle Interventions to Treat Elevated Cardiometabolic Risk in Primary Care) randomized controlled trial, which demonstrated the effectiveness of two adapted Diabetes Prevention Program (DPP) lifestyle interventions compared with usual primary care. SUBJECTS: E-LITE randomized 241 overweight or obese participants with pre-diabetes and/or metabolic syndrome to receive usual care alone (n=81) or usual care plus a coach-led (n=79) or self-directed intervention (n=81). The interventions provided coach-led group behavioral weight-loss treatment or a take home, self-directed DVD using the same 12-week curriculum, followed by 12 additional months of technology-mediated coach contact and self-monitoring support. Participants received no further intervention after month 15. A blinded assessor conducted 24-month visits by following the measurement protocols of the original trial. Measurements include weight and cardiometabolic risk factors (waist circumference, fasting plasma glucose, resting blood pressure, triglycerides, high- and low-density lipoprotein cholesterol, total cholesterol and triglyceride to high-density lipoprotein cholesterol ratio). RESULTS: At month 24, mean+/-s.e. changes in body mass index (trial primary outcome) and weight (kg) from baseline were -1.9+/-0.3 (P=0.001) and -5.4+/-0.9 (P<0.001) in the coach-led intervention, and -1.6+/-0.3 (P=0.03) and -4.5+/-0.9 (P=0.001) in the self-directed intervention, compared with -0.9+/-0.3 and 2.4+/-0.9 in the usual care group. In addition, both interventions led to a greater percentage of participants maintaining ?7% weight loss and sustained improvements in waist circumference and fasting plasma glucose levels than usual care. CONCLUSION: This study shows sustained benefits of the two primary care-based, technology-mediated DPP lifestyle interventions. The findings warrant replication in long-term studies involving diverse populations. PMID- 23797384 TI - The cost-effectiveness of shopping to a predetermined grocery list to reduce overweight and obesity. AB - BACKGROUND: Pre-commitment strategies can encourage participants to commit to a healthy food plan and have been suggested as a potential strategy for weight loss. However, it is unclear whether such strategies are cost-effective. OBJECTIVE: To analyse whether pre-commitment interventions that facilitate healthier diets are a cost-effective approach to tackle obesity. METHODS: Effectiveness evidence was obtained from a systematic review of the literature. For interventions demonstrating a clinically significant change in weight, a Markov model was employed to simulate the long-term health and economic consequences. The review supported modelling just one intervention: grocery shopping to a predetermined list combined with standard behavioural therapy (SBT). SBT alone and do nothing were used as comparators. The target population was overweight or obese adult women. A lifetime horizon for health effects (expressed as quality-adjusted life years (QALYs)) and costs from the perspective of the UK health sector were used to calculate incremental cost-effectiveness ratios (ICERs). RESULTS: In the base case analysis, the pre-commitment strategy of shopping to a list was found to be more effective and cost saving when compared against SBT, and cost-effective when compared against 'do nothing' (ICER=L166 per QALY gained). A sensitivity analysis indicated that shopping to a list remained dominant or cost-effective under various scenarios. CONCLUSION: Our findings suggest grocery shopping to a predetermined list combined with SBT is a cost-effective means for reducing obesity and its related health conditions. PMID- 23797385 TI - Acute sleep deprivation delays the glucagon-like peptide 1 peak response to breakfast in healthy men. AB - OBJECTIVE: Previous experiments have demonstrated that acute sleep loss impairs glucose homeostasis and increases food intake in humans. The incretin hormone glucagon-like peptide 1 (GLP-1) enhances postprandial insulin secretion and promotes satiety. Hypothesizing that the detrimental metabolic effects of sleep curtailment imply alterations in GLP-1 signaling, we investigated 24-h serum total GLP-1 concentrations during total sleep deprivation (TSD) and a normal sleep/wake cycle (comprising ~8 h of sleep) in 12 healthy young men. METHODS: Sessions started at 1800 h, and subjects were provided with standardized meals. Assessments of serum GLP-1 took place in 1.5- to 3-h intervals, focusing on the response to breakfast intake (3.8 MJ). RESULTS: Across conditions, 24-h concentration profiles of GLP-1 were characterized by the expected postprandial increases (P<0.001). Although there were no differences in magnitude between conditions (P>0.11), the postprandial GLP-1 peak response to breakfast intake was delayed by ~90 min following sleep loss in comparison with regular sleep (P<0.02). CONCLUSIONS: RESULTS indicate that acute TSD exerts a mild, but discernible effect on the postprandial dynamics of circulating GLP-1 concentrations in healthy men. PMID- 23797382 TI - The non-coding road towards cardiac regeneration. AB - Our understanding of cardiovascular disease has evolved rapidly, leading to a number of treatments that have improved patient quality of life and mortality rates. However, there is still no cure for heart failure. This has led to the pursuit of cardiac regeneration to prevent, and ultimately cure, this debilitating condition. To this end, several approaches have been proposed, including activation of cardiomyocyte proliferation, activation of endogenous or exogenous stem/progenitor cells, delivery of de novo cardiomyocytes, and in situ direct reprogramming of cardiac fibroblasts. While these different methodologies are currently being intensely investigated, there are still a number of caveats limiting their application in the clinic. Given the emerging regulatory potential of non-coding RNAs for controlling diverse cellular processes, these molecules may offer potential solutions in this pursuit of cardiac regeneration. In this concise review, we discuss the potential role of non-coding RNAs in a variety of different cardiac regenerative approaches. PMID- 23797386 TI - Atherosclerosis and cardiac function assessment in low-density lipoprotein receptor-deficient mice undergoing body weight cycling. AB - BACKGROUND: Obesity has become an epidemic in many countries and is supporting a billion dollar industry involved in promoting weight loss through diet, exercise and surgical procedures. Because of difficulties in maintaining body weight reduction, a pattern of weight cycling often occurs (so called 'yo-yo' dieting) that may result in deleterious outcomes to health. There is controversy about cardiovascular benefits of yo-yo dieting, and an animal model is needed to better understand the contributions of major diet and body weight changes on heart and vascular functions. Our purpose is to determine the effects of weight cycling on cardiac function and atherosclerosis development in a mouse model. METHODS: We used low-density lipoprotein receptor-deficient mice due to their sensitivity to metabolic syndrome and cardiovascular diseases when fed high-fat diets. Alternating ad libitum feeding of high-fat and low-fat (rodent chow) diets was used to instigate weight cycling during a 29-week period. Glucose tolerance and insulin sensitivity tests were done at 22 and 24 weeks, echocardiograms at 25 weeks and atherosclerosis and plasma lipoproteins assessed at 29 weeks. RESULTS: Mice subjected to weight cycling showed improvements in glucose homeostasis during the weight loss cycle. Weight-cycled mice showed a reduction in the severity of atherosclerosis as compared with high-fat diet-fed mice. However, atherosclerosis still persisted in weight-cycled mice as compared with mice fed rodent chow. Cardiac function was impaired in weight-cycled mice and matched with that of mice fed only the high-fat diet. CONCLUSION: This model provides an initial structure in which to begin detailed studies of diet, calorie restriction and surgical modifications on energy balance and metabolic diseases. This model also shows differential effects of yo-yo dieting on metabolic syndrome and cardiovascular diseases. PMID- 23797387 TI - Enhancing family resilience through family narrative co-construction. AB - We draw upon family resilience and narrative theory to describe an evidence-based method for intervening with military families who are impacted by multiple wartime deployments and psychological, stress-related, or physical parental injuries. Conceptual models of familial resilience provide a guide for understanding the mechanics of how families respond and recover from exposure to extreme events, and underscore the role of specific family processes and interaction patterns in promoting resilient capabilities. Leading family theorists propose that the family's ability to make meaning of stressful and traumatic events and nurture protective beliefs are critical aspects of resilient adaptation. We first review general theoretical and empirical research contributions to understanding family resilience, giving special attention to the circumstances, challenges, needs, and strengths of American military families. Therapeutic narrative studies illustrate the processes through which family members acquire meaning-making capacities, and point to the essential role of parents' in facilitating discussions of stressful experiences and co-constructing coherent and meaningful narratives. This helps children to make sense of these experiences and develop capacities for emotion regulation and coping. Family based narrative approaches provide a structured opportunity to elicit parents' and children's individual narratives, assemble divergent storylines into a shared family narrative, and thereby enhance members' capacity to make meaning of stressful experiences and adopt beliefs that support adaptation and growth. We discuss how family narratives can help to bridge intra-familial estrangements and re-engage communication and support processes that have been undermined by stress, trauma, or loss. We conclude by describing a family-based narrative intervention currently in use with thousands of military children and families across the USA. PMID- 23797388 TI - Posterior dislocation of the Oxford knee meniscal bearing: a treatment option. AB - Unicompartmental knee replacement (UKR) is now established as a treatment for medial compartment arthritis. The Oxford UKR (Biomet Orthopedics, Inc, Warsaw, IN, USA) has a mobile-bearing system, which minimizes wear. This has been shown to provide excellent long-term results. Dislocation of the mobile-bearing device is rare with an incidence of 1 in 200 (0.5 %). The treatment usually involves exploration of the knee through the original anteromedial incision, removal of the dislocated bearing and rectification of the underlying cause for the dislocation. We describe two cases of a posterior dislocation in which the mobile bearing could not be retrieved and was left in situ. In both cases a good outcome was achieved. We conclude that in extremely rare cases where a dislocated bearing has migrated posteromedially and cannot be retrieved, it can be left in place rather than exploring the joint acutely through a separate posterior incision. PMID- 23797389 TI - Spica cast as an alternative to general anesthesia for lower limb MRI in young children. AB - BACKGROUND: The conventional approach for MRI procedures in very young children is to use general anesthesia which comes with inherent risks. Non-pharmacological strategies to reduce anxiety in children have also been described, but they all require patient cooperation. The purpose of the study was to evaluate the ability to complete diagnosis using temporary spica cast immobilization (TSCI) in children less than 3 years old undergoing MRI procedures for lower limb disorders. MATERIALS AND METHODS: A retrospective review identified 14 children under 3 years old that had required an MRI for a lower limb disorder, using TSCI. The MRI procedure was performed for evaluation of hip dysplasia, bone infections, limping, evaluation of soft tissue tumor and femoral head osteonecrosis. A spica cast was fitted by the pediatric orthopedic team. The MRI procedure was subsequently performed. RESULTS: Diagnosis was achieved in all cases. The radiologist identified movement artifacts (14 %) that did not impair the image quality enough to prevent interpretation. CONCLUSION: TSCI is a safe, effective and costless procedure avoiding general anesthesia for young patients under 3 years old who require MRI for pelvis or lower limb disorders. LEVEL OF EVIDENCE: IV. PMID- 23797390 TI - Combined edaravone and D1-3-n-butylphthalide antioxidant therapy for paraquat poisoning. PMID- 23797391 TI - Inter-rater agreement of the triage system RETTS-HEV. AB - OBJECTIVE: The purpose of this study was to evaluate the inter-rater agreement among nurses using the triage system RETTS-HEV (rapid emergency triage and treatment system - hospital unit west) in a Danish emergency department (ED). BACKGROUND: The use of triage systems in Denmark has been implemented recently together with structural changes in hospital organization. Testing and evaluation is therefore needed. The RETTS-HEV is a five-scale triage system being used in the ED of Herning, Denmark, since May 2010. The ED is semilarge, with 29 000 annual visits. MATERIALS AND METHODS: Consecutive patients presenting to the ED were assessed by both a duty and a study nurse using RETTS-HEV. Nurses did not receive training before the study. In all, 146 patients were enroled and a blinded, paired and simultaneous triage was conducted independently to evaluate inter-rater agreement using Fleiss kappa. RESULTS: A total of 155 patients were triaged over a 10-day period and complete data were available for 146 patients. We found the overall agreement to be good [Fleiss kappa 0.60 (95% confidence interval 0.48; 0.72)]. The kappa estimate was higher for the group of patients who required immediate attention [0.83 (95% confidence interval 0.18; 1.47)]. CONCLUSION: The study found good inter-rater agreement between two independent observers not receiving any new triage training before the study. PMID- 23797392 TI - Staphylococcus epidermidis biofilm formation and structural organization on different types of intraocular lenses under in vitro flow conditions. AB - AIM: To compare the adherence and structural organization of Staphylococcus epidermidis biofilm on intraocular lenses (IOLs). METHODS: IOLs made of 3 different biomaterials [polymethyl methacrylate (PMMA), hydrophilic acrylic or hydrophobic acrylic] were incubated into an S. epidermidis bacterial solution. Scanning electron microscopy was used to count the bound bacteria and to analyze the structural biofilm architecture. RESULTS: After 4-6 h of incubation, adherence was statistically weakest on the hydrophilic acrylic polymer. On the hydrophobic acrylic material, the bacterial cells tended to cover the substratum in a horizontal spread in a continuous monolayer. On the hydrophilic acrylic material or on the PMMA material bacterial cells tended to form only few, small scattered cell clusters. CONCLUSIONS: The data suggest that the pattern of S. epidermidis adhesion varies with the IOL biomaterial. Hydrophobic IOLs seem to be more permissive to S. epidermidis adhesion. PMID- 23797393 TI - Clinical guidelines and systematic reviews. PMID- 23797394 TI - Systematic review and evidence-based clinical recommendations for dosing of pediatric supported standing programs. AB - PURPOSE: There is a lack of evidence-based recommendations for effective dosing of pediatric supported standing programs, despite widespread clinical use. METHODS: Using the International Classification of Functioning, Disability, and Health (Child and Youth Version) framework, we searched 7 databases, using specific search terms. RESULTS: Thirty of 687 studies located met our inclusion criteria. Strength of the evidence was evaluated by well-known tools, and to assist with clinical decision-making, clinical recommendations based on the existing evidence and the authors' opinions were provided. CONCLUSIONS AND RECOMMENDATIONS FOR CLINICAL PRACTICE: Standing programs 5 days per week positively affect bone mineral density (60 to 90 min/d); hip stability (60 min/d in 30 degrees to 60 degrees of total bilateral hip abduction); range of motion of hip, knee, and ankle (45 to 60 min/d); and spasticity (30 to 45 min/d). PMID- 23797395 TI - Effects of passive versus dynamic loading interventions on bone health in children who are nonambulatory. AB - PURPOSE: To investigate the effectiveness of a novel dynamic standing intervention compared with a conventional passive standing intervention on bone health in children with cerebral palsy who are nonambulatory. METHODS: Four children in passive standers and 5 in dynamic standers were followed for 15 months (standing 30 min/d, 5 d/wk). Dual-energy x-ray absorptiometry scans of the distal femur were obtained at 3-month intervals to measure changes in bone mineral density (BMD), bone mineral content, and area. RESULTS: Increases in BMD were observed during dynamic standing (P < .001), whereas passive standing appeared to maintain the baseline BMD. Increases in bone mineral content were observed in each standing intervention (P < .001), with dynamic standing inducing greater increases. Increases in area were comparable between interventions (P = .315). CONCLUSIONS: Dynamic standing demonstrated the potential of moderate magnitude, low-frequency loading to increase cortical BMD. Further investigations could provide insight into the mechanisms of bone health induced through loading interventions. PMID- 23797396 TI - Commentary on "Effects of passive versus dynamic loading interventions on bone health in children who are nonambulatory". PMID- 23797397 TI - Commentary on "A longitudinal evaluation of maturational effects on lower extremity strength in female adolescent athletes". PMID- 23797398 TI - Commentary on "Muscle activation patterns in infants with myelomeningocele stepping on a treadmill". PMID- 23797399 TI - Comparison of measures of physical performance among young children who are healthy weight, overweight, or obese. AB - PURPOSE: To determine the differences in gait, balance, muscle strength, and physical activity in young children who are healthy weight (HW), overweight (OW), or obese. METHODS: Participants (n = 70; 5-9 years) were classified according to their body mass index as OW/obese (n = 29) or HW (n = 41). Data were collected on gait parameters, 1-leg stance test (OLST), handgrip strength, vertical jump (VJ) height, and physical activity. An independent t test, Mann-Whitney U test, analysis of covariance (ANCOVA), and regression analyses were carried out. RESULTS: Being OW/obese resulted in a significantly increased base of support while walking (P < .05), decreased OLST performance (P < .05), and decreased VJ height (P < .01) compared with peers of HW. CONCLUSION: These findings suggest that in young children, being OW/obese may lead to an increased base of support while walking, decreased balance, and decreased leg explosive strength. PMID- 23797400 TI - Commentary on "Comparison of measures of physical performance among young children who are healthy weight, overweight, or obese". PMID- 23797401 TI - Factors affecting parental adherence to an intervention program for congenital torticollis. AB - PURPOSE: Identify factors related to parental adherence to an intervention program for congenital torticollis. METHODS: Sixty-five mothers of infants referred to physical therapy served as subjects. Attitudes toward health care styles, satisfaction with and trust in the therapist, expectations and belief in treatment credibility, and maternal perceptions of the severity of the torticollis and the potential effect of treatment on the infant's future function were measured with questionnaires. Adherence was measured by attendance, exercise compliance, and reason for treatment termination. RESULTS: Adherence correlated with maternal perceptions of the severity of the functional effect of the torticollis and the importance of the intervention program on future function (P = .005). The independent variables assessed by the questionnaires were not significantly correlated to adherence. CONCLUSIONS: Maternal perceptions of the effect of torticollis on her infant's activities and the program's importance for the infant's future function were the only predictors of adherence. PMID- 23797402 TI - Commentary on "Factors affecting parental adherence to an intervention program for congenital torticollis". PMID- 23797403 TI - Commentary on "Perceived effectiveness and barriers to physical therapy services for families and children with Friedreich ataxia". PMID- 23797404 TI - Differences in function among children with sensory processing disorders, physical disabilities, and typical development. AB - PURPOSE: To examine the capability and performance of children with sensory processing disorders (SPD) compared with children who are developing typically and those with physical disabilities (PD). METHODS: Participants included parents/caregivers of 81 children ranging in age from 1 to 7.3 years; 57% were boys. The child's therapist interviewed the parents using the Pediatric Evaluation of Disability Inventory (PEDI) to measure functional performance. RESULTS: Children with SPD demonstrated significant differences from children in the other groups in functional skills and caregiver assistance within 3 domains (self-care, mobility, social function). CONCLUSIONS: The PEDI can be used to (1) identify functional delays in young children with SPD, which can affect participation in age-appropriate self-care, mobility, and social skills, and (2) determine appropriate referrals for early intervention. PMID- 23797405 TI - Commentary on "Differences in function among children with sensory processing disorders, physical disabilities, and typical development". PMID- 23797406 TI - The use of video clips in teleconsultation for preschool children with movement disorders. AB - PURPOSE: To investigate the reliability and validity of video clips in assessing movement disorders in preschool children. METHODS: The study group included 27 children with neuromotor concerns. The explorative validity group included children with motor problems (n = 21) or with typical development (n = 9). Hempel screening was used for live observation of the child, full recording, and short video clips. The explorative study tested the validity of the clinical classifications "typical" or "suspect." RESULTS: Agreement between live observation and the full recording was almost perfect; Agreement for the clinical classification "typical" or "suspect" was substantial. Agreement between the full recording and short video clips was substantial to moderate. The explorative validity study, based on short video clips and the presence of a neuromotor developmental disorder, showed substantial agreement. CONCLUSION: Hempel screening enables reliable and valid observation of video clips, but further research is necessary to demonstrate the predictive value. PMID- 23797407 TI - Commentary on "The use of video clips in teleconsultation for preschool children with movement disorders". PMID- 23797409 TI - Mistletoe specialist frugivores: latterday "Johnny Appleseeds" or self-serving market gardeners? AB - Many plants use birds to disperse their propagules, but mistletoes are especially reliant on their services. As aerial parasites, mistletoe seeds need to be deposited upon branches of suitable hosts, and mistletoe specialist frugivores (from eight different avian families) have long been regarded as their coevolved dispersers. Like the pioneer Johnny 'Appleseed' Chapman who established nurseries that helped open up land for settlement, these birds are considered benevolent dispersers of this keystone resource and often invoked as illustrative examples of mutualistic interactions. We have compared recent research on these specialists with studies of other birds with broader diets (generalists) which also disperse mistletoe seed. Rather than mutualists, we suggest that mistletoe specialist frugivores are better considered exploitative, with multiple lineages evolving independently to capitalize on this reliable, nutritious resource. Although mistletoe specialist frugivores are quantitatively important seed dispersers in some regions, their specialized diet restricts them to areas with high mistletoe densities, resulting in contagious dispersal patterns. By intensifying existing infections, mistletoe specialist frugivores increase their own medium-term food security-akin to market gardeners profiting from intensive cultivation. Exploring the ecological and evolutionary implications of this proposition, we evaluate the consequences of different dispersal patterns on mistletoe fitness and highlight the neglected role of dietary generalists in the stabilization of plant-animal interactions. PMID- 23797410 TI - Weak vertical canopy gradients of photosynthetic capacities and stomatal responses in a fertile Norway spruce stand. AB - The sensitivity of carbon (C) assimilation to within-canopy nitrogen (N) allocation and of stomatal conductance (g s) to environmental variables were investigated along a vertical canopy gradient in a fertile Norway spruce [Picea abies (L.) Karst.] stand. Maximum rates of ribulose bisphosphate-saturated carboxylation (V (cmax)) and electron transport (J (max)) exhibited weak relationships with needle N content. Using these relationships together with a combined stomatal-photosynthesis model, it was found that the sensitivity of C assimilation of 12 1-year old shoots to within-canopy N allocation pattern was very weak. Modelled C assimilation based on optimal compared to observed N allocation pattern increased by only 1-2 %, and altering total needle N content by +/- 30 % resulted in a 2-4 % change in modelled C assimilation. C assimilation was more sensitive to water use and changed by 8-12 % in response to +/- 30 % altered stomatal conductance. No indications of significant limitations of photosynthesis by other nutrients or non-optimal within-canopy allocation of water were detected. The sensitivity of g s to photosynthetic photon flux density (PPFD) was found to be stronger in the lower canopy, while no significant within canopy variation was observed in light-saturated g( s) or stomatal sensitivity to vapour pressure deficit (VPD). The results of this study show that, at this N rich site, photosynthesis integrated for shoots at different canopy positions is only marginally affected by N allocation pattern and that increased stand-scale N availability would only be truly beneficial to canopy photosynthesis if it resulted in increased leaf area. PMID- 23797411 TI - Females better face senescence in the wandering albatross. AB - Sex differences in lifespan and aging are widespread among animals. Since investment in current reproduction can have consequences on other life-history traits, the sex with the highest cost of breeding is expected to suffer from an earlier and/or stronger senescence. This has been demonstrated in polygynous species that are highly dimorphic. However in monogamous species where parental investment is similar between sexes, sex-specific differences in aging patterns of life-history traits are expected to be attenuated. Here, we examined sex and age influences on demographic traits in a very long-lived and sexually dimorphic monogamous species, the wandering albatross (Diomedea exulans). We modelled within the same model framework sex-dependent variations in aging for an array of five life-history traits: adult survival, probability of returning to the breeding colony, probability of breeding and two measures of breeding success (hatching and fledging). We show that life-history traits presented contrasted aging patterns according to sex whereas traits were all similar at young ages. Both sexes exhibited actuarial and reproductive senescence, but, as the decrease in breeding success remained similar for males and females, the survival and breeding probabilities of males were significantly more affected than females. We discuss our results in the light of the costs associated to reproduction, age related pairing and a biased operational sex-ratio in the population leading to a pool of non-breeders of potentially lower quality and therefore more subject to death or breeding abstention. For a monogamous species with similar parental roles, the patterns observed were surprising and when placed in a gradient of observed age/sex-related variations in life-history traits, wandering albatrosses were intermediate between highly dimorphic polygynous and most monogamous species. PMID- 23797412 TI - Growth and stable isotope signals associated with drought-related mortality in saplings of two coexisting pine species. AB - Drought-induced events of massive tree mortality appear to be increasing worldwide. Species-specific vulnerability to drought mortality may alter patterns of species diversity and affect future forest composition. We have explored the consequences of the extreme drought of 2005, which caused high sapling mortality (approx. 50 %) among 10-year-old saplings of two coexisting pine species in the Mediterranean mountains of Sierra Nevada (Spain): boreo-alpine Pinus sylvestris and Mediterranean P. nigra. Sapling height growth, leaf delta(13)C and delta(18)O, and foliar nitrogen concentration in the four most recent leaf cohorts were measured in dead and surviving saplings. The foliar isotopic composition of dead saplings (which reflects time-integrated leaf gas-exchange until mortality) displayed sharp increases in both delta(13)C and delta(18)O during the extreme drought of 2005, suggesting an important role of stomatal conductance (g(s)) reduction and diffusional limitations to photosynthesis in mortality. While P. nigra showed decreased growth in 2005 compared to the previous wetter year, P. sylvestris maintained similar growth levels in both years. Decreased growth, coupled with a sharper increase in foliar delta(18)O during extreme drought in dead saplings, indicate a more conservative water use strategy for P. nigra. The different physiological behavior of the two pine species in response to drought (further supported by data from surviving saplings) may have influenced 2005 mortality rates, which contributed to 2.4-fold greater survival for P. nigra over the lifespan of the saplings. This species specific vulnerability to extreme drought could lead to changes in dominance and distribution of pine species in Mediterranean mountain forests. PMID- 23797413 TI - Little evidence for niche partitioning among ectomycorrhizal fungi on spruce seedlings planted in decayed wood versus mineral soil microsites. AB - Ectomycorrhizal fungal (EMF) communities vary among microhabitats, supporting a dominant role for deterministic processes in EMF community assemblage. EMF communities also differ between forest and clearcut environments, responding to this disturbance in a directional manner over time by returning to the species composition of the original forest. Accordingly, we examined EMF community composition on roots of spruce seedlings planted in three different microhabitats in forest and clearcut plots: decayed wood, mineral soil adjacent to downed wood, or control mineral soil, to determine the effect of retained downed wood on EMF communities over the medium and long term. If downed and decayed wood provide refuge habitat distinct from that of mineral soil, we would expect EMF communities on seedlings in woody habitats in clearcuts to be similar to those on seedlings planted in the adjacent forest. As expected, we found EMF species richness to be higher in forests than clearcuts (P <= 0.01), even though soil nutrient status did not differ greatly between the two plot types (P >= 0.05). Communities on forest seedlings were dominated by Tylospora spp., whereas those in clearcuts were dominated by Amphinema byssoides and Thelephora terrestris. Surprisingly, while substrate conditions varied among microsites (P <= 0.03), especially between decayed wood and mineral soil, EMF communities were not distinctly different among microhabitats. Our data suggest that niche partitioning by substrate does not occur among EMF species on very young seedlings in high elevation spruce-fir forests. Further, dispersal limitations shape EMF community assembly in clearcuts in these forests. PMID- 23797414 TI - Regularity in daily mood stabilizer dosage taken by patients with bipolar disorder. AB - OBJECTIVE: The aim of this study was to investigate regularity in the daily mood stabilizer dosage taken by patients with bipolar disorder, and identify factors associated with irregularity. METHODS: Self-reported daily mood and medication data were available from 206 patients who took the same mood stabilizer for >=100 days. Approximate entropy (ApEn) was used to measure serial regularity in daily mood stabilizer dosage. Generalized estimating equations (GEE) were used to estimate if demographic or clinical variables were associated with ApEn. RESULTS: There was a wide range of regularity in the daily mood stabilizer dosage. The mean percent of days of missing doses was 13.6%. The number of psychotropic medications (p=0.007), pill burden (p=0.004) and percent of days with depressed mood (p=0.013) were associated with more irregularity, while the percent of days euthymic (p=0.014) was associated with less irregularity. The percent of days missing doses was not associated with the number of medications, pill burden or mood ratings. DISCUSSION: Patients may have irregularity in daily dosage in spite of a low percent of days missing doses. Psychotropic medication regimen complexity and depression are associated with increased dosage irregularity. Research is needed on how irregularity in daily dosage impacts the continuity of drug action of mood stabilizers. PMID- 23797416 TI - The contemporary practice of psychiatric surgery: results from a global survey of functional neurosurgeons. AB - BACKGROUND: Interest in neurosurgery for psychiatric diseases (NPD) has grown globally. We previously reported the results of a survey of North American functional neurosurgeons that evaluated general attitudes towards NPD and the future directions of the field. OBJECTIVES: The purpose of this study was to expand on our previous work and obtain a snapshot in time of global attitudes towards NPD among practicing functional neurosurgeons. We measure general and regional trends in functional neurosurgery and focus specifically on surgery for mind and mood, while exploring the future prospects of the field. METHODS: We designed an online survey and distributed it electronically to 881 members of the following international organizations: World Society for Stereotactic and Functional Neurosurgery, European Society for Stereotactic and Functional Neurosurgery, Asian-Australasian Society for Stereotactic Functional Neurosurgery and the South and Latin American Society for Stereotactic and Functional Neurosurgery. Subsequent statistical and thematic analysis was performed on the data obtained. RESULTS: Of 881 surveys distributed, 106 were returned (12.8%). Eighty-two percent of functional neurosurgeon respondents were fellowship trained, with movement disorders and pain making up the majority of their practice. Psychiatric indications are the most frequently treated conditions for 34% of survey respondents, and over half of participants (51%) perform epilepsy surgery. Of the psychiatric conditions, obsessive-compulsive disorder and depression are the most common disorders treated. The majority of respondents (90%) felt optimistic about the future of NPD. Two thirds cited the reluctance of psychiatrists to refer patients as the greatest obstacle facing the field, and a majority reported that a cultural stigma surrounding psychiatric diseases exists in their community. In response to hypothetical situations involving cognitive and personality enhancement, opinions varied, but the majority opposed enhancement interventions. Regional variations were examined as well and uncovered distinct attitudinal differences depending on geographic location. CONCLUSIONS: Surgery for psychiatric conditions is an expanding field within functional neurosurgery. The opinions of international functional neurosurgeons were largely in line with those of their North American colleagues. Optimism regarding the future of NPD predominates, and future editions of this survey can be used to track the evolution of neurosurgeons' attitudes towards NPD and neuroenhancement. PMID- 23797415 TI - Ankylosing spondylitis: Chinese perspective, clinical phenotypes, and associated extra-articular systemic features. AB - Ankylosing spondylitis (AS) is a common rheumatic disease in the Chinese population, which is the largest population in the world associated with the global burden of health care. Herein we review and report the epidemiology and specific clinical characteristics of Chinese AS. More than 90 % of Chinese AS patients are HLA-B27 positive with the predominant HLA-B*2704 subtype; the incidence of HLA-B27 positivity ranges from 4 to 8 % in the general Chinese population. The first-degree relatives of AS probands often develop atypical AS with relatively mild disease and particularly undifferentiated spondyloarthropathy in females. Chinese AS patients have higher frequencies of juvenile-onset AS and peripheral arthritis. Of extra-articular manifestations, AS patients have earlier onset and more recurrent attacks of HLA-B27-related acute anterior uveitis. Cardiac arrhythmias or other cardiovascular disorders and metabolic syndrome are not infrequently found. Importantly, apical lung diseases in Chinese AS patients are also frequently associated with tuberculosis infection. PMID- 23797418 TI - Bacteria under pressure, calcium channel internalization, and why cockroaches avoid glucose-baited traps. PMID- 23797419 TI - The D50N mutation and syndromic deafness: altered Cx26 hemichannel properties caused by effects on the pore and intersubunit interactions. AB - Mutations in the GJB2 gene, which encodes Cx26, are the most common cause of sensorineural deafness. In syndromic cases, such as keratitis-ichthyosis-deafness (KID) syndrome, in which deafness is accompanied by corneal inflammation and hyperkeratotic skin, aberrant hemichannel function has emerged as the leading contributing factor. We found that D50N, the most frequent mutation associated with KID syndrome, produces multiple aberrant hemichannel properties, including loss of inhibition by extracellular Ca(2+), decreased unitary conductance, increased open hemichannel current rectification and voltage-shifted activation. We demonstrate that D50 is a pore-lining residue and that negative charge at this position strongly influences open hemichannel properties. Examination of two putative intersubunit interactions involving D50 suggested by the Cx26 crystal structure, K61-D50 and Q48-D50, showed no evidence of a K61-D50 interaction in hemichannels. However, our data suggest that Q48 and D50 interact and disruption of this interaction shifts hemichannel activation positive along the voltage axis. Additional shifts in activation by extracellular Ca(2+) remained in the absence of a D50-Q48 interaction but required an Asp or Glu at position 50, suggesting a separate electrostatic mechanism that critically involves this position. In gap junction (GJ) channels, D50 substitutions produced loss of function, whereas K61 substitutions functioned as GJ channels but not as hemichannels. These data demonstrate that D50 exerts effects on Cx26 hemichannel and GJ channel function as a result of its dual role as a pore residue and a component of an intersubunit complex in the extracellular region of the hemichannel. Differences in the effects of substitutions in GJ channels and hemichannels suggest that perturbations in structure occur upon hemichannel docking that significantly impact function. Collectively, these data provide insight into Cx26 structure-function and the underlying bases for the phenotypes associated with KID syndrome patients carrying the D50N mutation. PMID- 23797420 TI - Insights on the mechanisms of Ca(2+) regulation of connexin26 hemichannels revealed by human pathogenic mutations (D50N/Y). AB - Because of the large size and modest selectivity of the connexin hemichannel aqueous pore, hemichannel opening must be highly regulated to maintain cell viability. At normal resting potentials, this regulation is achieved predominantly by the physiological extracellular Ca(2+) concentration, which drastically reduces hemichannel activity. Here, we characterize the Ca(2+) regulation of channels formed by wild-type human connexin26 (hCx26) and its human mutations, D50N/Y, that cause aberrant hemichannel opening and result in deafness and skin disorders. We found that in hCx26 wild-type channels, deactivation kinetics are accelerated as a function of Ca(2+) concentration, indicating that Ca(2+) facilitates transition to, and stabilizes, the closed state of the hemichannels. The D50N/Y mutant hemichannels show lower apparent affinities for Ca(2+)-induced closing than wild-type channels and have more rapid deactivation kinetics, which are Ca(2+) insensitive. These results suggest that D50 plays a role in (a) stabilizing the open state in the absence of Ca(2+), and (b) facilitating closing and stabilization of the closed state in the presence of Ca(2+). To explore the role of a negatively charged residue at position 50 in regulation by Ca(2+), this position was substituted with a cysteine residue, which was then modified with a negatively charged methanethiosulfonate reagent, sodium (2-sulfanoethyl) methanethiosulfonate (MTSES)(-). D50C mutant hemichannels display properties similar to those of D50N/Y mutants. Recovery of the negative charge with chemical modification by MTSES(-) restores the wild-type Ca(2+) regulation of the channels. These results confirm the essential role of a negative charge at position 50 for Ca(2+) regulation. Additionally, charge swapping mutagenesis studies suggest involvement of a salt bridge interaction between D50 and K61 in the adjacent connexin subunit in stabilizing the open state in low extracellular Ca(2+). Mutant cycle analysis supports a Ca(2+) sensitive interaction between these two residues in the open state of the channel. We propose that disruption of this interaction by extracellular Ca(2+) destabilizes the open state and facilitates hemichannel closing. Our data provide a mechanistic understanding of how mutations at position 50 that cause human diseases are linked to dysfunction of hemichannel gating by external Ca(2+). PMID- 23797421 TI - Contribution of the KCa3.1 channel-calmodulin interactions to the regulation of the KCa3.1 gating process. AB - The Ca(2+)-activated potassium channel of intermediate conductance, KCa3.1, is now emerging as a therapeutic target for a large variety of health disorders. The Ca(2+) sensitivity of KCa3.1 is conferred by the Ca(2+)-binding protein calmodulin (CaM), with the CaM C-lobe constitutively bound to an intracellular domain of the channel C terminus. It was proposed on the basis of the crystal structure obtained for the C-terminal region of the rat KCa2.2 channel (rSK2) with CaM that the binding of Ca(2+) to the CaM N-lobe results in CaM interlocking the C-terminal regions of two adjacent KCa3.1 subunits, leading to the formation of a dimeric structure. A study was thus undertaken to identify residues of the CaM N-lobe-KCa3.1 complex that either contribute to the channel activation process or control the channel open probability at saturating Ca(2+) (Pomax). A structural homology model of the KCa3.1-CaM complex was first generated using as template the crystal structure of the C-terminal region of the rat KCa2.2 channel with CaM. This model was confirmed by cross-bridging residues R362 of KCa3.1 and K75 of CaM. Patch-clamp experiments were next performed, demonstrating that the solvation energy of the residue at position 367 in KCa3.1 is a key determinant to the channel Pomax and deactivation time toff. Mutations of residues M368 and Q364 predicted to form anchoring points for CaM binding to KCa3.1 had little impact on either toff or Pomax. Finally, our results show that channel activation depends on electrostatic interactions involving the charged residues R362 and E363, added to a nonpolar energy contribution coming from M368. We conclude that electrostatic interactions involving residues R362 and E363 and hydrophobic effects at M368 play a prominent role in KCa3.1 activation, whereas hydrophobic interactions at S367 are determinant to the stability of the CaM-KCa3.1 complex throughout gating. PMID- 23797423 TI - Fluorescein aldehyde with disulfide functionality as a fluorescence turn-on probe for cysteine and homocysteine in HEPES buffer. AB - We developed a fluorescein aldehyde probe with disulfide functionality for the fluorescence detection of biologically important thiols. The probe displayed highly selective responses to cysteine (Cys) and homocysteine (Hcy) over glutathione (GSH) due to the rapid ring formation reaction of Cys and Hcy with the aldehyde group of the probe and the concomitant cleavage of the disulfide group followed by subsequent intramolecular cyclization. The fluorescent probe also exhibited a highly sensitive fluorescence turn-on response to Hcy with a detection limit of 2.4 MUM Hcy in HEPES buffer. PMID- 23797422 TI - The mechanoelectrical response of the cytoplasmic membrane of Vibrio cholerae. AB - Persistence of Vibrio cholerae in waters of fluctuating salinity relies on the capacity of this facultative enteric pathogen to adapt to varying osmotic conditions. In an event of osmotic downshift, osmolytes accumulated inside the bacterium can be quickly released through tension-activated channels. With the newly established procedure of giant spheroplast preparation from V. cholerae, we performed the first patch-clamp characterization of its cytoplasmic membrane and compared tension-activated currents with those in Esherichia coli. Saturating pressure ramps revealed two waves of activation belonging to the ~1-nS mechanosensitive channel of small conductance (MscS)-like channels and ~3-nS mechanosensitive channel of large conductance (MscL)-like channels, with a pressure midpoint ratio p0.5MscS/p0.5MscL of 0.48. We found that MscL-like channels in V. cholerae present at a density three times higher than in E. coli, and yet, these vibrios were less tolerant to large osmotic downshocks. The Vibrio MscS-like channels exhibit characteristic inward rectification and subconductive states at depolarizing voltages; they also adapt and inactivate at subsaturating tensions and recover within 2 s upon tension release, just like E. coli MscS. Trehalose, a compatible internal osmolyte accumulated under hypertonic conditions, significantly shifts activation curves of both MscL- and MscS-like channels toward higher tensions, yet does not freely partition into the channel pore. Direct electrophysiology of V. cholerae offers new avenues for the in situ analysis of membrane components critical for osmotic survival and electrogenic transport in this pathogen. PMID- 23797424 TI - [Editorial]. PMID- 23797425 TI - Novel approaches to heart rate modulation in chronic heart failure. PMID- 23797426 TI - The effect of doubling the dose of acetylsalicylic acid (ASA) on platelet function parameters in patients with type 2 diabetes and platelet hyperreactivity during treatment with 75 mg of ASA: a subanalysis of the AVOCADO study. AB - BACKGROUND: Individuals with diabetes are at 2- to 4-fold higher risk of cardiovascular disease than those without diabetes. High platelet reactivity (HPR) plays a pivotal role in atherothrombotic complications of diabetes. Polish and American diabetes associations recommend treating high-risk diabetic patients with low doses of acetylsalicylic acid (ASA) in primary and secondary prevention of cardiovascular events. Unfortunately, some patients show HPR despite treatment with ASA. AIM: To determine the effect of doubling the dose of ASA on platelet reactivity in patients with type 2 diabetes and HPR despite treatment of with 75 mg of ASA. METHODS: 304 type 2 diabetes patients treated with 75 mg of ASA were enrolled into the prospective, randomised, open-label Aspirin Versus/Or Clopidogrel in Aspirin-resistant Diabetics inflammation Outcomes (AVOCADO) study. Platelet reactivity was assessed by Platelet Function Analyser (PFA)-100(r), VerifyNow(r) Aspirin Assay, and serum thromboxane B2 (sTXB2) and urinary 11 dehydrothromboxane B2 (u11dhTXB2) level measurements. Patients with HPR determined by collagen/epinephrine-induced closure time (CEPI-CT) measured by PFA 100(r) were randomised in a 2:3 ratio to receive 150 mg of ASA (Group 1) or 75 mg of clopidogrel (Group 2), respectively. Platelet reactivity was assessed at baseline and after 8 weeks of treatment. RESULTS: Complete clinical data and blood samples were ultimately available for 260 of 304 patients initially enrolled to the study. Subsequently, six patients were excluded from the analysis based on suspected ASA non-compliance (sTXB2 level > 7200 pg/mL). Among 254 patients finally included into analysis, HPR was found in 90 (35.4%) patients of whom 38 patients were randomised to Group 1 and 52 patients to Group 2. Doubling the dose of ASA resulted in a significant CEPI-CT prolongation (Delta 111 s, p < 0.001) and reduction of sTXB2 level (Delta -101.3 pg/mL, p = 0.001) but did not significantly affect results of other platelet function tests. CONCLUSIONS: Doubling the dose of ASA improved platelet reactivity in patients with type 2 diabetes and HPR. PMID- 23797427 TI - Effect of various forms of physical training on the autonomic nervous system activity in patients with acute myocardial infarction. AB - BACKGROUND: A shift in the dynamic autonomic nervous system (ANS) balance towards sympathetic activity in patients with acute myocardial infarction (AMI) predisposes them to life-threatening ventricular arrhythmias. Improvement of unfavourable changes in ANS can be expected in such patients as a result of physical training. A beneficial shift in ANS balance towards parasympathetic activity could be confirmed by demonstrating increased baroreceptor reflex sensitivity (BRS) as well as favourable changes in heart rate variability (HRV) parameters. AIM: To analyse the effect of different forms of physical training on ANS activity in patients with AMI after hospital discharge. METHODS: The study included 38 patients with AMI (aged 59 +/- 8 years) subjected to 2-month exercise training. Group 1 (n = 19)underwent 3-week supervised in-hospital cardiac rehabilitation followed by 5-week home-based training, and Group 2 (n = 19) underwent 8-week home-based training. BRS and HRV were determined based on a 10 min recording of systolic arterial pressure and the cardiac cycle. Measurements were performed one day before discharge (R1) and after 2 months of training (R2). RESULTS: A significant increase in the mean values of TP (total power), HF (high frequency power), rMSSD (square root of the mean of the squared differences between successive R-R intervals), and pNN50 (proportion of differences between successive R-R intervals that are greater than 50 ms) was observed in the overall study group, along with trends for higher SDNN (standard deviation of the mean of sinus rhythm R-R intervals) and HFnu (normalised HF power), and for lower LFnu (normalised LF power). Additionally, a significant increase in BRS (from 2.2 +/- 0.6 to 5.1 +/- 2.2 ms/mm Hg, p = 0.01) was found in patients with baseline BRS <= 3 ms/mm Hg. A significant increase in rMSSD, pNN50, HF and HFnu, as well as a decrease in LFnu and LF/HF (LF to HF ratio) was observed in Group 1. In contrast, a significant increase in BRS was noted in Group 2. CONCLUSIONS: Various forms of 2-month physical training led to a favourable shift in autonomic balance towards parasympathetic activity. Our findings suggest a clinically important effect of physical activity in patients after AMI. PMID- 23797428 TI - Intima-media thickness correlates with features of metabolic syndrome in young people with a clinical diagnosis of familial hypercholesterolaemia. AB - BACKGROUND: Familial hypercholesterolaemia (FH) is a monogenic lipid metabolism disorder characterised by markedly elevated serum low-density lipoprotein (LDL) cholesterol level due to a mutation in the LDL receptor gene. Clinical features of FH include premature atherosclerosis and coronary artery disease. AIM: To explore associations between noninvasive markers of atherosclerosis including intima-media thickness (IMT) and pulse wave velocity (PWV) and blood lipids, blood pressure (BP) and obesity in a group of young patients with FH. METHODS: Study population included 36 patients aged < 35 years with the diagnosis of FH based on the Simon Broome Register criteria, and their 49 relatives who comprised the control group free of FH. RESULTS: Mean IMT values were higher in FH patients than controls (0.60 +/- 0.19 vs. 0.53 +/- 0.07 mm, respectively, p < 0.05).Mean body mass index (BMI) and waist circumference were similar in patients and controls. The prevalence of carotid atherosclerotic plaques was significantly higher among FH patients (n = 6) than in controls (n = 1) (21.4% vs. 2.6%, p = 0.012). Arterial hypertension was present in 27.8% of patients with FH and 16.3% of subjects in the control group. Systolic blood pressure (SBP) in FH patients correlated significantly with age (r = 0.35), BMI (r = 0.48) and waist circumference (r = 0.47), and diastolic blood pressure (DBP) correlated with BMI (r = 0.42) and waist circumference (r = 0.41). PWV correlated significantly with age (r = 0.44), SBP (r = 0.63) and DBP (r = 0.52). We did not find any correlations between IMT and serum lipids, BP or obesity indices in FH patients. CONCLUSIONS: Our findings show a higher rate of arterial hypertension in young FH patients compared to their relatives free of FH, with significant associations between BP and indices of obesity and arterial stiffness. Intensive lipid lowering and antihypertensive therapy along with a reduction in central fat may be considered a mandatory treatment strategy in young FH patients to prevent atherosclerosis and increased arterial stiffness. PMID- 23797429 TI - Association between physical exercise and quality of erection in men with ischaemic heart disease and erectile dysfunction subjected to physical training. AB - BACKGROUND: In addition to a beneficial effect on exercise tolerance and an associated reduction of global cardiovascular risk, modification of physical activity has a positive effect on the quality of life, reducing, among other things, the severity of erectile dysfunction (ED). AIM: The specific nature of sexual activity, which combines the need to maintain appropriate exercise tolerance and good erection quality, prompted us to evaluate the association between exercise tolerance and severity of ED in an intervention group of subjects with ischaemic heart disease (IHD) and ED in the context of cardiac rehabilitation (CR). METHODS: A total of 138 men treated invasively for IHD (including 99 treated with percutaneous coronary intervention and 39 treated with coronary artery bypass grafting) who scored 21 or less in the initial IIEF-5 test were investigated. Subjects were randomised into two groups. The study group included 103 subjects (mean age 62.07 +/- 8.59 years) who were subjected to a CR cycle. The control group included 35 subjects (mean age 61.43 +/- 8.81 years) who were not subjected to any CR. All subjects filled out an initial and final IIEF-5 questionnaire and were evaluated twice with a treadmill exercise test. The CR cycle was carried out for a period of 6 months and included interval endurance training on a cycle ergometer (three times a week) and general fitness exercises and resistance training (twice a week). RESULTS: The CR cycle in the study group resulted in a statistically significant increase in exercise tolerance (7.15 +/- 1.69 vs. 9.16 +/- 1.84 METs,p < 0.05) and an increase in erection quality (12.51 +/- 5.98 vs. 14.39 +/- 6.82, p < 0.05) which was not observed in the control group. A significant effect of age on a progressive decrease in exercise tolerance and erection quality was found in the study group. Exercise tolerance and erection quality were also negatively affected by hypertension and smoking. A significant correlation between exercise tolerance and erection quality prior to the rehabilitation cycle indicates better erection quality in patients with better effort tolerance. The improvement in exercise tolerance did not correlate significantly with initial exercise tolerance or age of the subjects. In contrast, a significantly higher increase in erection quality was observed in younger subjects with the lowest baseline severity of ED.The relative increase in exercise tolerance in the group subjected to CR was significantly higher than the relative increase in erection quality but these two effects were not significantly correlated with each other. CONCLUSIONS: 1. In subjects with IHD and ED, erection quality is significantly correlated with exercise tolerance. 2. Exercise training had a positive effect on both exercise tolerance and erection quality but the size of these two effects was different and they ran independently of each other. PMID- 23797430 TI - Pulmonary artery growth in univentricular physiology patients. AB - BACKGROUND: A Fontan-type operation, i.e. a connection of the systemic veins and pulmonary arteries without subpulmonary ventricle, with different surgical techniques, is nowadays the only treatment option for patients with a functionally univentricular heart (UVH). Understanding the development of pulmonary arteries in patients who are considered for the Fontan procedure is important clinically. AIM: To evaluate the development of pulmonary arteries in patients with univentricular circulation. METHODS: Between 1995 and 2007, 111 patients underwent a bidirectional Glenn procedure. In all patients, preoperative catheterisation was performed to assess the anatomy and haemodynamics of UVH, especially the size of the pulmonary arteries. Ninety nine patients were included in the bidirectional Glenn group; 62 of these underwent repeat catheterisation before Fontan completion. The late results, after one stage extracardiac total cavopulmonary anastomosis performed in 24 patients between 1992 and 2002, were reinvestigated (one-stage Fontan group). We assessed the changes in the McGoon ratio and Nakata index for the whole cohort of patients. McGoon ratio is the sum of the diameter of pulmonary arteries divided by the diameter of the aorta. Nakata index is the sum of the cross-sectional area of the pulmonary arteries divided by the body surface area. RESULTS: During cardiac catheterisation prior to Glenn procedure, the mean Nakata index was 351.9 (range 131.2-886) mm2/m2 and was higher in patients with increased pulmonary flow (p = 0.0135). Mean McGoon ratio was 2.5 (range 1.1-4.9). An average 40.3 months after Glenn procedure, the Nakata index and McGoon ratio decreased significantly to 226.4 +/- 125 mm2/m2 (p < 0.003), and to 2.14 +/- 0.58 (p < 0.008) respectively. In the group of patients after one-stage Fontan in late follow-up, mean 7.4 years after procedure, the Nakata index decreased from 318.7 +/- 159.1 mm2/m2 to 120 +/- 40 mm2/m2 (p < 0.0001) and McGoon ratio from 2.4 +/- 0.6 to 1.4 +/- 0.27 (p < 0.0001). Only size of pulmonary arteries before Glenn procedure, in the bidirectional Glenn group, or before Fontan operation, in the one-stage Fontan group,were inversely correlated with the changes of size of pulmonary arteries (p = 0.0015 and p = 0.0012). CONCLUSIONS: The relative decrease of the size of pulmonary arteries in the inter-stage period (between bidirectional Glenn anastomosis and Fontan completion) and after Fontan completion may indicate that pulmonary artery sizes should probably not bean absolute limiting factor in the decision on treatment of functionally UVH patients, especially at the stage of Fontan approach. PMID- 23797431 TI - Evaluation of plasma oxidative status in patients with slow coronary flow. AB - BACKGROUND: Slow coronary flow (SCF) is a coronary microvascular disorder characterised by delayed opacification of coronary vessels in a normal coronary angiogram. Coronary endothelial dysfunction plays an important pathogenetic role in patients with SCF. Oxidative stress is associated with cardiovascular diseases. AIM: To assess the total antioxidant capacity (TAC) and total oxidative status (TOS) in patients with SCF. METHODS: The study included 36 patients with SCF. An age- and gender-matched control group was composed of 30 patients with normal coronary arteries and normal coronary flow. We measured plasma TAC and TOS levels and oxidative stress index(OSI) value in patients and control subjects. Linear regression analysis was performed to identify factors associated with the mean TIMI frame count (TFC). RESULTS: Plasma TOS level and OSI value were significantly higher in the SCF group compared to the control group (p = 0.005 and p = 0.004, respectively). However, there was no significant difference in plasma TAC levels between the groups (p = 0.104). Factors associated with mean TFC were plasma TOS levels (beta = 0.425, p = 0.002) and fasting glucose levels (beta = 0.099, p = 0.01) in linear regression analysis. CONCLUSIONS: We found that plasma TOS and OSI were significantly higher in SCF compared to the control group and plasma TOS levels were independently associated with mean TFC. PMID- 23797432 TI - Comparison of endoscopic versus conventional internal mammary harvesting regarding unligated side branches. AB - BACKGROUND: In an effort to minimise access in cardiac surgery, endoscopic vessel harvesting has become more popular. The endoscopic approach, however, allows for only the harvest of the mid to distal internal mammary artery (IMA), leaving the more proximal branches of the conduit available for collateral flow away from the coronary bed. AIM: To compare the number and anatomic variation of remaining side branches in thoracoscopic vs. conventional IMA harvesting. METHODS: 199 fresh cadavers were randomly divided into two groups. Group A (n = 100) underwent endoscopic IMA harvesting. In Group B (n = 99), IMAs were harvested using an open conventional approach. In both groups during surgery, side branches of the IMA were isolated and identified. RESULTS: The two groups were comparable with regard to mean age and age distribution, male sex (56% vs. 63%, respectively), cause of death and coronary risk factors including smoking, diabetes, dyslipidaemia and hypertension. 24 of 199 cadavers(12%) had a lateral costal branch. The left IMA arose from the third part of the subclavian artery in 6%, and from the thyrocervical trunk in 7% of the cadavers. There were significantly more unligated side branches in Group B compared to Group A (14 branches vs. 3 branches, p < 0.01). The first intercostal artery and lateral costal artery were found unligated in 3% and 5% of cadavers in Group B, whereas no side branch remained unligated in Group A. There was no subclavian artery or IMA injury in either group. Internal mammary vein was damaged in 2% of cadavers in Group B. CONCLUSIONS: Thoracoscopic left IMA harvesting is more accurate in finding and ligating the side branches of IMA. PMID- 23797433 TI - Correlation between clinical parameters of periodontal disease and mean platelet volume in patients with coronary artery disease: a pilot study. AB - BACKGROUND: Cardiovascular diseases as well as periodontitis can be regarded as current epidemics and have become a social problem. Mean platelet volume (MPV) is a simple, routinely assessed biochemical parameter, which is becoming regarded asa new, independent risk factor of acute coronary syndromes and stroke. AIM: Assessment of a potential relationship between clinical indices of periodontal disease and MPV in relation to the presence of coronary artery disease (CAD) and chronic periodontitis. METHODS: The study included 57 individuals aged from 50 to 65 years. Patients were divided into three groups. Group 1 consisted of 19 patients with previously diagnosed CAD and coexisting chronic periodontitis. Group 2 included 18 patients with diagnosed chronic periodontitis with excluded CAD. Group 3 was a control group and consisted of 20 healthy individuals without CAD or periodontitis. RESULTS: Unsatisfactory oral hygiene defined by plaque index (PI) was observed in all patients. Mean PI was significantly higher in Groups 1 and 2 than in Group 3 (76.7% vs. 45.7%, p < 0.01). Mean bleeding index (BI) was significantly higher in Group 2 than in Groups 1 and 3 (46.4% vs. 29.8%, p < 0.05). Mean periodontal pocket depths (PD) (2.75 mm, 2.93 mm,1.97 mm, respectively, p < 0.05, p < 0.01) and clinical attachment loss (CAL) were significantly higher in Groups 1 and 2 than in Group 3 (5.13 mm, 4.79 mm, 1.31 mm, respectively, p < 0.01). Mean WBC, fibrinogen and hsCRP were not significantly different among the examined groups (WBC 6.81 G/L vs. 6.71 G/L vs. 6.18 G/L, fibrinogen concentration 4.31 g/L vs. 3.94 g/L vs. 3.67 g/L; hsCRP concentration 4.08 mg/dL vs. 6.61 mg/dL vs. 4.33 mg/dL). In Group 1, MPV was significantly higher than in Group 3 (10.39 fL vs. 9.39 fL, p < 0.01). There was a weak, although significant, correlation between periodontal parameters and MPV and correlations between MPV and PD as well as CAL (MPV-PD: r = 0.45, p < 0.05; MPV-CAL: r = 0.42, p < 0.05). CONCLUSIONS: Chronic periodontitis in patients with CAD results in an increased MPV that may suggest increased platelet activity. This observation could indicate a potential pathophysiological link between chronic periodontitis and an increased risk of acute coronary syndromes. PMID- 23797434 TI - [Heart failure due to chronic hypoparathyroidism in patient with acute coronary syndrome]. AB - Severe heart failure can be a rare symptom of hypocalcemia. We report a case of a 58 year-old male admitted with a diagnosis of acute coronary syndrome. The ECG showed prolonged QTc interval with severly impared left ventricular ejection fraction recognised in echocardiography. During the hospitalisation hypocalcemia due to primary hypoparathyreoidism was revealed to be the cause of those symptoms. PMID- 23797435 TI - [The effect of hypocalcemia on the cardiovascular system]. PMID- 23797436 TI - [Acute coronary syndrome suspicion in patient with left coronary artery arising from right coronary sinus]. AB - We present a case of 73 year-old patient who underwent coronary angiography due to suspicion of acute coronary syndrome without persistent ST segment elevation. The angiographic result showed no lesions that could cause recurrent chest pain,but it also revealed a seldom coronary artery abnormality - left coronary artery arising from right coronary sinus. Performed computed tomography of the chest confirmed the result of the coronarography. But apart from that it found the signs of neoplastic disease which was probably responsible for clinical presentation. PMID- 23797437 TI - Surgical removal of stent from multiply stented vessel: problem with choice of place for anasthomosis - one year follow-up. AB - Since the advent of percutaneous coronary intervention there have been increasing numbers of patients with so-called 'full metal jacket' coronary arteries disease. This is creating a challenging problem for the cardiac surgeon. A 73 year-old woman after the implantation of two metal stents to the left anterior descending artery (LAD) and four to the right coronary artery (RCA), with ejection fraction of 28%, significant mitral and tricuspid insufficiency, and high systolic pulmonary pressure, was admitted to our department with unstable angina and with symptoms of pulmonary oedema. Coronary angiogram revealed restenosis in all stents. She agreed to a coronary artery bypass graft (CABG) with mitral and tricuspid valve reconstruction. The RCA was opened just above the postero-lateral branch. Due to lack of space, the metal stent was removed and saphenous bypass graft performed.Six months later, control angiography showed a properly working LITA-LAD graft; the stents in the RCA had been occluded above anasthomosis and the venous graft to RCA had been stenosed. Percutaneous cardiac intervention was performed and the metal stent was implanted with good early effect. After a further six months, coronarography revealed in stent stenosis in the place of venous anasthomosis. The patient was qualified for conservative treatment. Long term results after such procedures are hard to predict;we believe patients should be qualified earlier for CABG and that doctors should avoid implanting too many stents into one artery. PMID- 23797438 TI - [Magnetic resonance imaging in a patient with an implantable cardioverter defibrillator]. AB - The number of patients with cardiac pacemakers (PM), implantable cardioverter defibrillators (ICD) and cardiac resynchronisation therapy PM systems is increasing. The number of magnetic resonance imaging (MRI) examinations is also growing and amounts to about 60 million tests per year worldwide. The presence of an ICD is still considered to be an absolute contraindication to MRI by most experts. We present a patient with an implanted ICD who successfully underwent brain MRI with use of special precautions. PMID- 23797439 TI - [Peripartum cardiomyopathy, acute autoimmune pancreatitis and periadipose tissue inflammation - autoimmune reaction?]. AB - A case of 26 year-old female with peripartum cardiomyopathy, acute pancreatitis, periadipose tissue inflammation due to unknown cause and multiple organ dysfunction syndrome complication is presented. PMID- 23797440 TI - [Cardiovascular electronic device infections]. PMID- 23797441 TI - [One patient - many faces of myocardial ischaemia]. AB - We present the case of a woman treated with coronary angioplasty due to non-ST segment elevation myocardial infarction,then again because of restenosis, who continued to complain of chest pain and syncope. Holter electrocardiogram recording revealed atrioventricular block related to ST-segment elevations and variant angina was diagnosed. Despite administered medications, the patient required pacemaker implantation. PMID- 23797442 TI - [Editorial comment]. PMID- 23797443 TI - [Bilateral bundle branch block during treatment with amitriptyline]. AB - A 57 year-old man treated with amitriptyline was admitted because of several episodes of syncope. In ECG, the incomplete left bundle branch block was masked by the complete right bundle branch block and left anterior fascicular block. PMID- 23797444 TI - [Editorial comment]. PMID- 23797445 TI - [Aortic diseases in contemporary imaging. Expert consensus statement of the Polish Clinical Forum for Cardiovascular Imaging]. PMID- 23797446 TI - Acute myocardial infarction in a patient with chronic renal failure and endocarditis. AB - We report a case of a 55 year-old female with chronic renal failure who received routine haemodialysis and suffered from acute myocardial infarction of inferior wall. Based on coronary angiogram, transoesophageal echocardiography, and autopsy,coronary embolisation with vegetations in the course of infective endocarditis was identified as a rare cause of ST-segment elevation myocardial infarction. PMID- 23797447 TI - Acute left main occlusion during transcatheter aortic valve implantation. AB - We present a case of a 92 year-old female with severe aortic stenosis who underwent TAVI. The procedure resulted with acute left main coronary artery occlusion requiring an immediate percutaneous coronary intervention. PMID- 23797448 TI - Radiofrequency ablation of numerous premature ventricular contractions in a cardiac resynchronisation therapy patient: a long-term follow-up. AB - We present a case study of a patient with dilated cardiomyopathy and a cardiac resynchronisation therapy (CRT) device who was repeatedly hospitalised due to heart failure (HF) exacerbations. A successful radiofrequency ablation of numerous premature ventricular contractions enabled the proper action of CRT and stabilised the patient's condition in NYHA II without HF subsequent hospitalisations during a 30 month follow-up. PMID- 23797449 TI - Evaluation of aneurysm after coronary stent implantation by optical coherence tomography. PMID- 23797450 TI - An adult patient with patent ductus arteriosus: multimodality diagnostic approach. PMID- 23797451 TI - [Transcatheter valve-in-valve implantation in mitral valve bioprosthesis]. PMID- 23797452 TI - Multiple cardiovascular complications in a patient with missed small apical myocardial infarction caused by a coronary artery thrombus of uncertain origin. PMID- 23797453 TI - Dissecting aortic aneurysm in a 23 year-old hypertensive woman. PMID- 23797454 TI - Transcatheter implantation of self-expanding valve for failed stentless aortic root bioprosthesis. PMID- 23797455 TI - [Initial experience with the use of cardioverter-defibrillator leads with DF-4 connector in the resynchronisation therapy]. PMID- 23797456 TI - Finite element analysis of the pelvis after modular hemipelvic endoprosthesis reconstruction. PMID- 23797457 TI - Response to comment on Gagala et al.: Clinical and radiological outcomes of treatment of avascular necrosis of the femoral head using autologous osteochondral transfer (mosaicplasty). Preliminary report. PMID- 23797458 TI - [Liver dysfunctions in intensive care patients--consequences for the treatment of invasive Candida infections]. AB - Liver dysfunction is common among patients on intensive care units (ICU) due to sepsis, chronic liver disease, ischemic hepatitis, drug toxicity and intensive care measures. Critically ill patients with invasive fungal infections should therefore be treated with antifungals that are not metabolized by the liver. This may help to avoid therapeutic complications by drug accumulation, inadequate dosages or drug-drug interactions. Echinocandins are established as the antifungal class of choice in the treatment of invasive Candida infections. Anidulafungin is not hepatically metabolized and may be used without dose adjustments in patients with severe liver dysfunction. It has no known clinically relevant drug interactions. In the primary endpoint of the randomized pivotal trial in patients with candidemia or invasive candidiasis, anidulafungin was statistically superior versus the former standard therapy (fluconazole), with a favourable overall safety profile. More recent study data particularly in ICU patients confirm the efficacy of anidulafungin for these patient groups. Therefore, anidulafungin is an important antifungal treatment option for patients with liver dysfunction. PMID- 23797459 TI - Smooth pursuit eye movement training promotes recovery from auditory and visual neglect: a randomized controlled study. AB - BACKGROUND: No treatment for auditory neglect and no randomized controlled trial evaluating smooth pursuit eye movement therapy (SPT) for multimodal neglect are available. OBJECTIVE: To compare the effects of SPT and visual scanning therapy (VST) on auditory and visual neglect in chronic stroke patients with neglect. METHODS: A randomized, prospective trial was conducted. Fifty patients with left auditory and visual neglect were randomly assigned. Twenty-four patients completed SPT therapy and 21 patients VST. Five patients (4 VST, 1 SPT) were lost. Each group received 1-hour sessions of neglect therapy for 5 consecutive days totaling 5 hours. Outcome measures in visual neglect (digit cancellation, visuoperceptual- and motor line bisection, paragraph reading) and auditory neglect (auditory midline) were assessed twice before therapy, thereafter, and at 2-week follow-up. The SPT group practiced smooth pursuit eye movements while tracking stimuli moving leftward. The VST group systematically scanned the same but static stimuli. Both groups were divided into subgroups, and effects were separately investigated for mild and severe neglect. RESULTS: Both groups did not differ before therapy in clinical/demographic variables or neglect severity (auditory/visual). After treatment, the SPT group showed significant and lasting improvements in all visual measures and normal performance in the auditory midline. Neither visual nor auditory neglect impairments changed significantly after VST. Moreover, the treatment effect sizes (Cohen's d) were considerably higher for visual and auditory neglect after SPT versus VST, both for mild and severe neglect. CONCLUSIONS: Repetitive contralesional, smooth pursuit training induces superior, multimodal therapeutic effects in mild and severe neglect. PMID- 23797460 TI - Interleukin 17, interleukin 22 and FoxP3 expression in tissue and serum of non segmental vitiligo: a case- controlled study on eighty-four patients. AB - BACKGROUND: Skewing of responses towards T helper (Th) 17 and away from T regulatory cells (T-regs) has been suggested to be partially involved in autoimmune diseases like vitiligo. AIMS: Clarify the possible role and relationship between Th17 and T-regs in vitiligo by measuring tissue, systemic levels of interleukin (IL)-17, IL-22 and Forkhead box P3. PATIENTS AND METHODS: 84 non-segmental vitiligo patients and 80 controls were included. Vitiligo Area Scoring Index, Vitiligo Disease Activity and stress score were determined. Skin biopsies underwent immunohistochemical staining for IL-17, IL-22 and FoxP3 and their systemic levels were determined by ELISA and quantitative real time PCR. RESULTS: Mean area % of +ve immunostaining and serum levels of IL-17 (34.12 +/- 5.12, 23.62 +/- 8.17 pg/mL) and IL-22 (48.63 +/- 19.23, 43.53 +/- 11.95 pg/mL) were significantly higher in patients compared to controls (15.33 +/- 4.19, 12.83 +/- 3.29 pg/mL) (13.44 +/- 3.82, 9.92 +/- 4.7 pg/mL) (P<0.001). Mean area % of +ve immunostaining and peripheral blood levels of FoxP3 were significantly lower in patients (2.67 +/- 0.54, 0.574 +/- 0.32) compared to controls (7.12 +/- 0.18, 1.48 +/- 0.49) (P<0.001). In patients, a positive correlation between IL-17 and IL-22 was detected (r = 0.671, P<0.001), each showing negative correlation with FoxP3 (r = -0.548, P<0.001), (r = -0.382, P<0.001). VASI, VIDA and stress score correlated positively with IL-17, IL-22 and negatively with FoxP3. CONCLUSION: Th17 and T-regs are intertwined in the complexity of vitiligo giving hope of treatment through adjuvant therapies controlling the delicate balance between them. PMID- 23797461 TI - Extracting BI-RADS Features from Portuguese Clinical Texts. AB - In this work we build the first BI-RADS parser for Portuguese free texts, modeled after existing approaches to extract BI-RADS features from English medical records. Our concept finder uses a semantic grammar based on the BIRADS lexicon and on iterative transferred expert knowledge. We compare the performance of our algorithm to manual annotation by a specialist in mammography. Our results show that our parser's performance is comparable to the manual method. PMID- 23797462 TI - Image analysis quantification of sticking and picking events of pharmaceutical powders compressed on a rotary tablet press simulator. AB - PURPOSE: The aim of this work was to develop a quantification method based on image analysis, able to characterize sticking during pharmaceutical tableting. Relationship between image analysis features and relevant mechanical parameters recorded on an instrumented tablet press simulator were investigated. METHODS: Image analysis, based on gray levels co-occurrence matrices (GLCM), generated textural features of the tablet surface. The tableting simulator (Stylcam(r) 200R, Medelpharm), instrumented with force and displacement transducers, provided accurate records. The tablet defects and compaction process parameters were studied using three pharmaceutical powders (Fast-Flo(r) lactose, anhydrous Emcompress(r) and Avicel(r) PH200 microcrystalline cellulose), five compression pressures (60 to 250 MPa), five lubricating levels, and three types of punches (standard steel, amorphous hard carbon and anti-sticking punches). RESULTS: Texture parameters made it possible to quantify with precision tablets' aspect. The selected parameter IC2 (Information on Correlation 2) plotted versus the ratio between the ejection shear stress (Esh) and the compression pressure (Cp) let appear a relevant knowledge space where it was possible to identify a normal and a degraded tableting mode. A positive link between those two parameters was shown. CONCLUSION: Since the Esh/Cp ratio was related to image analysis results, it proved to be an interesting defect tag. PMID- 23797463 TI - Development of Solid SEDDS, V: Compaction and Drug Release Properties of Tablets Prepared by Adsorbing Lipid-Based Formulations onto Neusilin(r) US2. AB - PURPOSE: To develop tablet formulations by adsorbing liquid self-emulsifying drug delivery systems (SEDDS) onto Neusilin(r)US2, a porous silicate. METHODS: Nine SEDDS were prepared by combining a medium chain monoglyceride, Capmul MCM EP, a medium chain triglyceride, Captex 355 EP/NF, or their mixtures with a surfactant Cremophor EL, and a model drug, probucol, was then dissolved. The solutions were directly adsorbed onto Neusilin(r)US2 at 1:1 w/w ratio. Content uniformity, bulk and tap density, compressibility index, Hausner ratio and angle of repose of the powders formed were determined. The powders were then compressed into tablets. The dispersion of SEDDS from tablets was studied in 250 mL of 0.01NHCl (USP dissolution apparatus; 50 RPM; 37 degrees C) and compared with that of liquid SEDDS. RESULTS: After adsorption of liquid SEDDS onto Neusilin(r)US2, all powders demonstrated acceptable flow properties and content uniformity for development into tablet. Tablets with good tensile strength (>1 MPa) at the compression pressure of 45 to 135 MPa were obtained. Complete drug release from tablets was observed if the SEDDS did not form gels in contact with water; the gel formation clogged pores of the silicate and trapped the liquid inside pores. CONCLUSION: Liquid SEDDS were successfully developed into tablets by adsorbing them onto Neusilin(r)US2. Complete drug release from tablets could be obtained. PMID- 23797464 TI - Development of Solid SEDDS, IV: Effect of Adsorbed Lipid and Surfactant on Tableting Properties and Surface Structures of Different Silicates. AB - PURPOSE: To compare six commonly available silicates for their suitability to develop tablets by adsorbing components of liquid lipid-based drug delivery systems. METHODS: The tabletability of Aerosil(r) 200, Sipernat(r) 22, Sylysia(r) 350, Zeopharm(r) 600, Neusilin(r) US2 and Neusilin(r) UFL2 were studied by compressing each silicate into tablets in the presence of 20% microcrystalline cellulose and measuring the tensile strength of tablets produced. Three components of lipid based formulations, namely, Capmul(r) MCM EP (glycerol monocaprylocaprate), Captex(r) 355 EP/NF (caprylic/capric triglycerides) and Cremophor(r) EL (PEG-35 castor oil), were adsorbed individually onto the silicates at 1:1 w/w, and the mixtures were then compressed into tablets. The SEM photomicrographs of neat silicates and their 1:1 w/w mixtures (also 1:2 and 1:3 for Neusilin(r) US2 and Neusilin(r) UFL2) with one of the liquids (Cremophor(r) EL) were recorded. RESULTS: Neat Aerosil(r) 200, Sipernat(r) 22 and Sylysia(r) 350 were non-tabletable to the minimum acceptable tensile strength of 1 MPa, and they were also non-tabletable in presence of liquid. While Zeopharm(r) 600, Neusilin(r) US2 and Neusilin(r) UFL2 were tabletable without the addition of liquids, only Neusilin(r) US2 retained acceptable tabletability with 1:1 liquid. The SEM images of silicate-liquid mixtures indicated that, except for Neusilin(r) US2, much of the adsorbed liquid distributed primarily at the surface of particles rather than inside pores, which hindered their compaction into tablets. CONCLUSION: Among the six silicates studied, Neusilin(r) US2 was the only silicate able to produce tablets with acceptable tensile strength in presence of a lipid component at 1:1 w/w ratio due to the fact that the liquid was mostly adsorbed into the pores of the silicate rather than at the surface. PMID- 23797465 TI - Targeted delivery of nano-therapeutics for major disorders of the central nervous system. AB - Major central nervous system (CNS) disorders, including brain tumors, Alzheimer's disease, Parkinson's disease, and stroke, are significant threats to human health. Although impressive advances in the treatment of CNS disorders have been made during the past few decades, the success rates are still moderate if not poor. The blood-brain barrier (BBB) hampers the access of systemically administered drugs to the brain. The development of nanotechnology provides powerful tools to deliver therapeutics to target sites. Anchoring them with specific ligands can endow the nano-therapeutics with the appropriate properties to circumvent the BBB. In this review, the potential nanotechnology-based targeted drug delivery strategies for different CNS disorders are described. The limitations and future directions of brain-targeted delivery systems are also discussed. PMID- 23797467 TI - Association of epidermal growth factor receptor mutations with human papillomavirus 16/18 E6 oncoprotein expression in non-small cell lung cancer. AB - BACKGROUND: Lung cancers in women, in nonsmokers, and in patients with adenocarcinoma from Asia have more prevalent mutations in the epidermal growth factor receptor (EGFR) gene than their counterparts. However, the etiology of EGFR mutations in this population remains unclear. The authors hypothesized that the human papillomavirus (HPV) type 16/18 (HPV16/18) E6 oncoprotein may contribute to EGFR mutations in Taiwanese patients with lung cancer. METHODS: One hundred fifty-one tumors from patients with lung cancer were enrolled to determine HPV16/18 E6 and EGFR mutations using immunohistochemistry and direct sequencing, respectively. Levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo dG) in lung tumors and cells were evaluated using immunohistochemistry and liquid chromatography-mass spectrometry/mass spectrometry. An supF mutagenesis assay was used to determine H2 O2 -induced mutation rates of lung cancer cells with or without E6 expression. RESULTS: Patients with E6-positive tumors had a greater frequency of EGFR mutations than those with E6-negative tumors (41% vs 20%; P = .006). Levels of 8-oxo-dG were correlated with EGFR mutations (36% vs 16%; P = .012). Two stable clones of E6-overexpressing H157 and CL-3 cells were established for the supF mutagenesis assay. The data indicated that the cells with high E6 overexpression had higher H2 O2 -induced SupF gene mutation rates compared with the cells that expressed lower levels of E6 and compared with vector control cells. CONCLUSIONS: HPV16/18 E6 may contribute in part to EGFR mutations in lung cancer, at least in the Taiwanese population. PMID- 23797466 TI - Challenges of using in vitro data for modeling P-glycoprotein efflux in the blood brain barrier. AB - The efficacy of central nervous system (CNS) drugs may be limited by their poor ability to cross the bloodbrain barrier (BBB). Transporters, such as p glycoprotein, may affect the distribution of many drugs into the CNS in conjunction with the restricted paracellular pathway of the BBB. It is therefore important to gain information on unbound drug concentrations in the brain in drug development to ensure sufficient drug exposure from plasma at the target site in the CNS. In vitro methods are routinely used in drug development to study passive permeability and p-glycoprotein efflux of new drugs. This review discusses the challenges in the use of in vitro data as input parameters in physiologically based pharmacokinetic (PBPK) models of CNS drug disposition of p-glycoprotein substrates. Experience with quinidine demonstrates the variability in in vitro parameters of passive permeability and active pglycoprotein efflux. Further work is needed to generate parameter values that are independent of the model and assay. This is a prerequisite for reliable predictions of drug concentrations in the brain in vivo. PMID- 23797468 TI - The Ku70 DNA-repair protein is involved in centromere function in a grasshopper species. AB - The Ku70 protein is involved in numerous cell functions, the nonhomologous end joining (NHEJ) DNA repair pathway being the best known. Here, we report a novel function for this protein in the grasshopper Eyprepocnemis plorans. We observed the presence of large Ku70 foci on the centromeres of meiotic and mitotic chromosomes during the cell cycle stages showing the highest centromeric activity (i.e., metaphase and anaphase). The fact that colchicine treatment prevented centromeric location of Ku70, suggests a microtubule-dependent centromeric function for Ku70. Likewise, the absence of Ku70 at metaphase-anaphase centromeres from three males whose Ku70 gene had been knocked down using interference RNA, and the dramatic increase in the frequency of polyploid spermatids observed in these males, suggest that the centromeric presence of Ku70 is required for normal cytokinesis in this species. The centromeric function of Ku70 was not observed in 14 other grasshopper and locust species, or in the mouse, thus suggesting that it is an autapomorphy in E. plorans. PMID- 23797470 TI - Moxifloxacin in complicated skin and skin structure infections (cSSSIs): A prospective, international, non-interventional, observational study. AB - INTRODUCTION: ARTOS was an international, prospective, non-interventional, non controlled observational study designed to determine the effectiveness, safety, and tolerability of moxifloxacin under daily-life conditions in patients with complicated skin and skin structure infections (cSSSIs) treated in Europe, the Middle East, and Asia-Pacific region. METHODS: Eligible patients included males and females who were hospitalized patients or outpatients requiring antibiotic therapy for cSSSIs and for whom the treating physician had elected to begin moxifloxacin therapy in accordance with its approved indications. Patients were assessed before therapy and then at one or two follow-up visits. Effectiveness was assessed with respect to improvement and resolution of signs and symptoms of cSSSIs and safety with respect to the nature and frequency of adverse events and adverse drug reactions. RESULTS: A total of 6,594 patients were enrolled of whom 5,444 had data available for analysis; 4,692 patients received sequential intravenous/oral (IV/PO) moxifloxacin and 752 exclusively IV therapy. A majority of patients were aged between 40 and 79 years and had one or more comorbid conditions. Post-surgical wound infection, skin abscess, and diabetic foot infection were the cSSSIs most frequently diagnosed and treated with moxifloxacin, with almost 90% of infections rated moderate or severe. Treating physicians chose sequential moxifloxacin 400 mg for most patients, switching from IV to PO after 3-4 days. On average, treatment was maintained for 10 days. Treatment with moxifloxacin was associated with rapid relief in symptoms, with 93.2% of patients experiencing either complete resolution of symptoms or improvement at follow-up. Moxifloxacin was well tolerated with adverse drug reactions occurring in only 2% of patients. CONCLUSIONS: This study, conducted in a 'real-world' setting, confirms the effectiveness and safety of moxifloxacin in the treatment of a wide spectrum of cSSSIs seen in routine clinical practice. PMID- 23797469 TI - Long-term effects on cognitive function of postmenopausal hormone therapy prescribed to women aged 50 to 55 years. AB - IMPORTANCE: Postmenopausal hormone therapy with conjugated equine estrogens (CEEs) may adversely affect older women's cognitive function. It is not known whether this extends to younger women. OBJECTIVE: To test whether prescribing CEE based hormone therapy to postmenopausal women aged 50 to 55 years has longer-term effects on cognitive function. DESIGN: Trained, masked staff assessed participants with an annual telephone-administered cognitive battery that included measures of global and domain-specific cognitive functions. Cognitive testing was conducted an average of 7.2 years after the trials ended, when women had a mean age of 67.2 years, and repeated 1 year later. Enrollment occurred from 1996 through 1999. SETTING: Forty academic research centers. PARTICIPANTS: The study population comprised 1326 postmenopausal women, who had begun treatment in 2 randomized placebo-controlled clinical trials of hormone therapy when aged 50 to 55 years. INTERVENTION: The clinical trials in which the women had participated had compared 0.625 mg CEE with or without 2.5 mg medroxyprogesterone acetate over a mean of 7.0 years. MAIN OUTCOMES AND MEASURES: The primary outcome was global cognitive function. Secondary outcomes were verbal memory, attention, executive function, verbal fluency, and working memory. RESULTS: Global cognitive function scores from women who had been assigned to CEE-based therapies were similar to those from women assigned to placebo: mean (95% CI) intervention effect of 0.02 (-0.08 to 0.12) standard deviation units (P = .66). Similarly, no overall differences were found for any individual cognitive domain (all P > .15). Prespecified subgroup analyses found some evidence that CEE-based therapies may have adversely affected verbal fluency among women who had prior hysterectomy or prior use of hormone therapy: mean treatment effects of -0.17 (-0.33 to -0.02) and -0.25 (-0.42 to -0.08), respectively; however, this may be a chance finding. CONCLUSIONS AND RELEVANCE: CEE-based therapies produced no overall sustained benefit or risk to cognitive function when administered to postmenopausal women aged 50 to 55 years. We are not able to address whether initiating hormone therapy during menopause and maintaining therapy until any symptoms are passed affects cognitive function, either in the short or longer term. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01124773. PMID- 23797471 TI - Complementing insulin therapy to achieve glycemic control. AB - INTRODUCTION: Most patients with type 2 diabetes mellitus (T2DM) will need incrementally more complex therapeutic regimens to control hyperglycemia as the disease progresses. Insulin is very effective in reducing hyperglycemia and may improve beta-cell function in patients with T2DM. However, insulin therapy is associated with weight gain and increased risk of hypoglycemia. Adding other antidiabetes medications to insulin can improve glycemic control and potentially lower the required insulin dose, resulting in less weight gain and lower risk for hypoglycemia. This article summarizes the advantages and disadvantages of different classes of commonly used antidiabetes agents, with emphasis on newer classes, for use as add-on therapy to insulin in patients with T2DM inadequately controlled on insulin therapy. METHODS: A PubMed search from July 1, 2003 to April 15, 2013 for peer-reviewed clinical and review articles relevant to insulin combination or add-on therapy in T2DM was conducted. Search terms included "insulin combination therapy," "add-on therapy diabetes," "dipeptidyl peptidase-4 (DPP-4) inhibitors," "glucagon-like peptide-1 (GLP-1) receptor agonist," "sodium glucose cotransporter 2 (SGLT2) inhibitors", "insulin metformin," "insulin sulfonylurea," and "insulin thiazolidinedione." Bibliographies from retrieved articles were also searched for relevant articles. Study design, clinical relevance, and effect on insulin combination therapy were analyzed. RESULTS: Therapies used as add-on to insulin include agents associated with weight gain (thiazolidinediones and sulfonylureas) and/or hypoglycemia (sulfonylureas), which, therefore, may exacerbate risks already present with insulin. GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT2 inhibitors improve glycemic control when added to insulin and have a low propensity for hypoglycemia and cause no change (DPP-4 inhibitors) or a reduction (GLP-1 receptor agonists, SGLT2 inhibitors) in body weight. CONCLUSION: GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT2 inhibitors improve glycemic control when combined with insulin. They also have low propensity for weight gain and hypoglycemia and so may be preferred treatment options for insulin combination when compared with traditional therapies. PMID- 23797473 TI - Insufficient stromal support in MDS results from molecular and functional deficits of mesenchymal stromal cells. AB - Ineffective hematopoiesis is a major characteristic of myelodysplastic syndromes (MDS) causing relevant morbidity and mortality. Mesenchymal stromal cells (MSC) have been shown to physiologically support hematopoiesis, but their contribution to the pathogenesis of MDS remains elusive. We show that MSC from patients across all MDS subtypes (n=106) exhibit significantly reduced growth and proliferative capacities accompanied by premature replicative senescence. Osteogenic differentiation was significantly reduced in MDS-derived MSC, indicated by cytochemical stainings and reduced expressions of Osterix and Osteocalcin. This was associated with specific methylation patterns that clearly separated MDS-MSC from healthy controls and showed a strong enrichment for biological processes associated with cellular phenotypes and transcriptional regulation. Furthermore, in MDS-MSC, we detected altered expression of key molecules involved in the interaction with hematopoietic stem and progenitor cells (HSPC), in particular Osteopontin, Jagged1, Kit-ligand and Angiopoietin as well as several chemokines. Functionally, this translated into a significantly diminished ability of MDS derived MSC to support CD34+ HSPC in long-term culture-initiating cell assays associated with a reduced cell cycle activity. Taken together, our comprehensive analysis shows that MSC from all MDS subtypes are structurally, epigenetically and functionally altered, which leads to impaired stromal support and seems to contribute to deficient hematopoiesis in MDS. PMID- 23797474 TI - Ave atque vale to the next editor-in-chief. PMID- 23797475 TI - CORR Insights(r): incidence and risk factors for pulmonary embolism after primary musculoskeletal tumor surgery. PMID- 23797472 TI - STAT transcription factors in hematopoiesis and leukemogenesis: opportunities for therapeutic intervention. AB - Signal transducer and activator of transcription (STAT) proteins comprise a family of transcription factors that are activated by cytokines, hormones and growth factors. The activation of STAT proteins plays a key role in the production of mature hematopoietic cells via effects on cellular proliferation, survival and lineage-specific differentiation. Emerging evidence also demonstrates frequent, constitutive activation of STATs in primary leukemia specimens. Moreover, roles for STATs in promoting leukemia development have been delineated in numerous preclinical studies. This review summarizes our current understanding of STAT protein involvement in normal hematopoiesis and leukemogenesis, as well as recent advances in the development and testing of novel STAT inhibitors. PMID- 23797476 TI - Tumor-associated soluble uPAR-directed endothelial cell motility and tumor angiogenesis. AB - The expression of urokinase-type plasminogen activator (uPA) receptor (uPAR) correlates with the malignant phenotype of various cancers. The soluble form of uPAR (s-uPAR) is present in the circulation of cancer patients, but the role of s uPAR in endothelial cell migration is poorly understood. Therefore, we examined the role of tumor-associated s-uPAR on endothelial cell motility and angiogenesis. Here, we present evidence that tumor-associated s-uPAR augments the migration of human umbilical vein endothelial cells (HUVECs). When grown on tumor conditioned medium, the membrane fraction of HUVECs had increased localization of s-uPAR onto its cell membrane. Colocalization studies for GM1 ganglioside receptor and uPAR further demonstrated s-uPAR recruitment onto lipid rafts of HUVECs. Immunoblot analysis for uPAR in lipid raft fractions confirmed s-uPAR recruiting onto HUVECs' membrane. Further, s-uPAR induced Rac1-mediated cell migration while either function-blocking uPAR antibodies or dominant-negative mutant Rac1 expression in HUVECs-mitigated s-uPAR-enhanced cell migration. In addition, orthotopic implantation of uPAR-overexpressing cells resulted in a significant increase in circulating s-uPAR in blood serum and invasive nature of tumor and tumor vasculature in mice. Collectively, this data provide insight into tumor-associated s-uPAR-directed migration of endothelial cells and its subsequent influence on tumor angiogenesis. PMID- 23797477 TI - Altered redox status in Escherichia coli cells enhances pyruvate production in pH-adjusting culture with a fermenter. AB - Improvements in pyruvate production process were examined using Escherichia coli BW25113Dpta/ pHfdh strain carrying the formate dehydrogenase gene of Mycobacterium vaccae to change the redox status of the cells. Glucose and formate concentrations, and oxygenation levels determined previously in a shake-flask culture were applied for pyruvate production in a 1 l fermenter. However, pyruvate was not produced under the examined conditions. Detailed pH measurements during the fermenter culture using CaCO3 revealed that maintaining the pH value around 6.0 plays an important role in stabilizing the pyruvate accumulation. In the pH-adjusting culture around 6.0 with NaOH solution, the concentration and yield of pyruvate were 8.96 g l-1 and 0.48 g pyruvate g glucose-1, respectively, which were significantly higher than the values reported in the shake-flask culture (6.79 g l-1 and 0.32 g pyruvate g glucose-1). PMID- 23797479 TI - Preoperative magnetoencephalographic sensory cortex mapping. AB - The use of functional neuroimaging holds the promise of improving neurosurgical outcomes by providing preoperative localization of critical brain functions. The brain representation of somatosensory function can be effectively localized using magnetoencephalography (MEG) in both normal subjects and in patients with tumors, vascular malformation, and epilepsy. This study investigates the pattern of somatosensory localization in 45 patients. Thirty-two of these patients underwent subsequent resective surgery for brain pathologies. Electrical stimulation of the median nerve was conducted, and the most prominent somatosensory peak in the resultant averaged data was localized using the single equivalent current dipole technique. Results showed that this peak localized either to the central or postcentral sulcus of the somatosensory cortex. We found that neither age nor the presence of brain pathologies had significant effect on the recognition of the somatosensory cortex. Patients who underwent surgery after presurgical planning using MEG suffered no new somatosensory deficits, indicating the valuable role of pre-surgical mapping using MEG in the surgical planning. PMID- 23797480 TI - Anaphylaxis caused by ingestion of jellyfish. AB - Although anaphylaxis caused by foods is well known, an immediate allergic reaction due to jellyfish ingestion has never been reported. We report a 32-year old Japanese female, who developed anaphylaxis after eating salt-preserved jellyfish. The patient was a surfer and had frequently been stung by jellyfish. Thirty minutes after eating salted jellyfish, she showed wheals and oral stinging sensation and 60 minutes later when she was dancing the hula, she showed an asthma-like attack, hypotension, nausea, vomiting and abdominal pain. Prick-to prick test for the salted jellyfish produced a positive reaction as strong as that induced by histamine. Immunoblot analysis revealed that IgE antibodies in the patient serum reacted with an approximately 200 kDa protein in extracts from tentacle and umbrella of living jellyfish and in extract from the salted jellyfish, as well as a 25 kDa protein only in extracts from living jellyfish. This patient is considered to be the first reported case of anaphylaxis caused by intake of jellyfish. It is speculated that the patient was first sensitized through the skin by jellyfish stings and then jellyfish intake induced generalized attack of anaphylaxis. The 200 kDa unknown jellyfish protein may be the causative allergen. PMID- 23797481 TI - Does 11C-choline PET-CT contribute to multiparametric MRI for prostate cancer localisation? AB - BACKGROUND AND PURPOSE: The aim of this work was to determine whether 11C-choline positron emission tomography (PET)-computed tomography (CT) makes a positive contribution to multiparametric magnetic resonance imaging (MRI) for localisation of intraprostatic tumour nodules. PATIENTS AND METHODS: A total of 73 patients with biopsy-proven intermediate- and high-risk prostate cancer were enrolled in a prospective imaging study consisting of T2-weighted (T2w), dynamic contrast enhanced (DCE) and diffusion-weighted (DW) MRI and 11C-choline PET-CT before radical prostatectomy. Cancerous regions were delineated on the whole-mount prostatectomy sections and on the different MRI modalities and analysed in 24 segments per patient (3 sections, 8 segments each). To analyse PET-CT images, standardized uptake values (SUV) were calculated per segment. RESULTS: In total, 1,752 segments were analyzed of which 708 (40.4%) were found to be malignant. A high specificity (94.7, 93.6 and 92.2%) but relatively low sensitivity (31.2, 24.9 and 44.1%) for tumour localisation was obtained with T2w, DCE and DW MRI, respectively. Sensitivity values significantly increased when combining all MRI modalities (57.2%). For PET-CT, mean SUVmax of malignant octants was significantly higher than mean SUVmax of benign octants (3.68+/-1.30 vs. 3.12+/ 1.02, p<0.0001). In terms of accuracy, the benefit of adding PET-CT to (multiparametric) MRI was less than 1%. CONCLUSION: The additional value of 11C choline PET-CT to MRI in localising intraprostatic tumour nodules is limited, especially when multiparametric MRI is used. PMID- 23797483 TI - Impacts of dung combustion on the carbon cycle of alpine grassland of the north Tibetan plateau. AB - Alpine grassland of Tibet is a frangible ecosystem in terms of carbon (C) emission. Yak dung is an important resident energy with about 80 % of yak dung combusted for energy in the north Tibetan plateau. This paper investigated the impact of dung combustion on the C cycle of the alpine grassland ecosystem in north Tibet, China. During the growing season of 2011, from a field survey and household questionnaires, the main impacts of dung collection for fuel on the C cycle of the ecosystem were identified. (1) The C sequestration and storage capacity, including the dung-derived C stored in soil and C captured by vegetation, decreased. The net primary production decreased remarkably because of the reduction of dung returned to soil. (2) In a given period, more C was emitted to the atmosphere in the dung combustion situation than that in the dung returned to soil situation. (3) The energy grazing alpine meadow ecosystem changed into a net C source, and the net biome production of the ecosystem dropped to -15.18 g C/m2 year in the dung combustion situation, 42.95 g C/m2 year less than that in the dung returned situation. To reduce the CO2 emission derived from dung use, the proportion of dung combustion should be reduced and alternative renewable energy such as solar, wind, or hydro energy should be advocated, which is suitable for, and accessible to, the north Tibetan plateau. PMID- 23797484 TI - Land management versus natural factors in land instability: some examples in northern Spain. AB - The objective of this work is to test a hypothesis formulated on the basis of former results which considers that there might be a ''global geomorphic change,'' due to activities related to land management and not determined by climate change, which could be causing an acceleration of geomorphic processes. Possible relationships between some geomorphic processes related to land instability (landslides or sediment generation) and potential triggering factors are analyzed in study areas in northern Spain. The analysis is based on landslide inventories covering different periods, as well as the determination of sedimentation rates. Temporal landslide and sedimentation rate trends are compared with different indicators of human activities (land-use change, logging, forest fires) and with potential natural triggers (rainfall, seismicity). The possible influence of the road network in the distribution of landslides is also analyzed. Results obtained show that there is a general increase of both landslide and sedimentation rates with time that cannot be explained satisfactorily by observed rainfall trends and even less by seismicity. Land use change appears to be by far the main factor leading to land instability, with some changes producing up to a 12-fold increase of landslide rate. A relationship between road network and the spatial distribution of landslides has also been observed. These results do confirm the existence of an acceleration of geomorphic processes in the region, and also suggest that climate-related factors play a limited role in the changes observed. PMID- 23797486 TI - Misunderstanding the ''nature'' of co-management: a geography of regulatory science and indigenous knowledges (IK). AB - Governments, NGOs, and natural scientists have increased research and policy making collaborations with Indigenous peoples for governing natural resources, including official co-management regimes. However, there is continuing dissatisfaction with such collaborations, and calls for better communication and mutual learning to create more ''adaptive'' co-management regimes. This, however, requires that both Western and Indigenous knowledge systems be equal participants in the ''co-production'' of regulatory data. In this article, I examine the power dynamics of one co-management regulatory regime, conducting a multi-sited ethnography of the practices of researching and managing one transnational migratory species, greater white-fronted geese (Anser albifrons frontalis), who nest where Koyukon Athabascans in Alaska, USA, practice subsistence. Analyzing the ethnographic data through the literatures of critical geography, science studies and Indigenous Studies, I describe how the practice of researching for co management can produce conflict. ''Scaling'' the data for the co-management regime can marginalize Indigenous understandings of human- environment relations. While Enlightenment-based practices in wildlife biology avoid ''anthropomorphism,'' Indigenous Studies describes identities that operate through non-modern, deeply imbricated human-nonhuman identities that do not separate ''nature'' and ''society'' in making knowledge. Thus, misunderstanding the ''nature'' of their collaborations causes biologists and managers to measure and research the system in ways that erase how subsistence- based Indigenous groups already ''manage'' wildlife: by living through their ethical commitments to their fellow beings. At the end of the article, I discuss how managers might learn from these ontological and epistemologicaldifferences to better ''co produce'' data for co-management. PMID- 23797485 TI - Evaluation and selection of indicators for land degradation and desertification monitoring: methodological approach. AB - An approach to derive relationships for defining land degradation and desertification risk and developing appropriate tools for assessing the effectiveness of the various land management practices using indicators is presented in the present paper. In order to investigate which indicators are most effective in assessing the level of desertification risk, a total of 70 candidate indicators was selected providing information for the biophysical environment, socio-economic conditions, and land management characteristics. The indicators were defined in 1,672 field sites located in 17 study areas in the Mediterranean region, Eastern Europe, Latin America, Africa, and Asia. Based on an existing geo referenced database, classes were designated for each indicator and a sensitivity score to desertification was assigned to each class based on existing research. The obtained data were analyzed for the various processes of land degradation at farm level. The derived methodology was assessed using independent indicators, such as the measured soil erosion rate, and the organic matter content of the soil. Based on regression analyses, the collected indicator set can be reduced to a number of effective indicators ranging from 8 to 17 in the various processes of land degradation. Among the most important indicators identified as affecting land degradation and desertification risk were rain seasonality, slope gradient, plant cover, rate of land abandonment, land-use intensity, and the level of policy implementation. PMID- 23797487 TI - Stream nitrogen sources apportionment and pollution control scheme development in an agricultural watershed in eastern China. AB - A modeling system that couples a land-usebased export coefficient model, a stream nutrient transport equation, and Bayesian statistics was developed for stream nitrogen source apportionment. It divides a watershed into several sub catchments, and then considers the major landuse categories as stream nitrogen sources in each subcatchment. The runoff depth and stream water depth are considered as the major factors influencing delivery of nitrogen from land to downstream stream node within each sub-catchment. The nitrogen sources and delivery processes are lumped into several constant parameters that were calibrated using Bayesian statistics from commonly available stream monitoring and land-use datasets. This modeling system was successfully applied to total nitrogen (TN) pollution control scheme development for the ChangLe River watershed containing six sub-catchments and four land-use categories. The temporal (across months and years) and spatial (across sub-catchments and land use categories) variability of nonpoint source (NPS) TN export to stream channels and delivery to the watershed outlet were assessed. After adjustment for in stream TNretention, the time periods and watershed areas with disproportionately high-TN contributions to the stream were identified. Aimed at a target stream TN level of 2 mg L-1, a quantitative TN pollution control scheme was further developed to determine which sub-catchments, which land-use categories in a sub catchment, which time periods, and how large of NPS TN export reduction were required. This modeling system provides a powerful tool for stream nitrogen source apportionment and pollution control scheme development at the watershed scale and has only limited data requirements. PMID- 23797489 TI - Blood donation as a public good: an empirical investigation of the free rider problem. AB - A voluntary blood donation system can be seen as a public good. People can take advantage without contributing and have a free ride. We empirically analyse the extent of free riding and its determinants. Interviews of the general public in Spain (n = 1,211) were used to ask whether respondents were (or have been) regular blood donors and, if not, the reason. Free riders are defined as those who are medically capable to donate blood but do not. In addition, we distinguish four different types of free riding depending on the reason given for not donating. Binomial and multinomial logit models estimate the effect of individual characteristics on the propensity to free ride and the likelihood of the free rider types. Amongst those who are able to donate, there is a 67 % probability of being a free rider. The most likely free rider is female, single, with low/no education and abstained from voting in a recent national election. Gender, age, religious practice, political participation and regional income explain the type of free rider. PMID- 23797490 TI - Increased hospital length of stay attributable to Clostridium difficile infection in patients with four co-morbidities: an analysis of hospital episode statistics in four European countries. AB - Hospital-onset Clostridium difficile infection (CDI) places a significant burden on health care systems throughout Europe, estimated at around ?3 billion per annum. This burden is shared between national payers and hospitals that support additional bed days for patients diagnosed with CDI while in hospital or patients re-admitted from a previous hospitalisation. This study was performed to quantify additional hospital stay attributable to CDI in four countries, England, Germany, Spain, and The Netherlands, by analysing nationwide hospital-episode data. We focused upon patients at increased risk of CDI: with chronic obstructive pulmonary disease, heart failure, diabetes, or chronic kidney disease, and aged 50 years or over. Multivariate regression and propensity score matching models were developed to investigate the impact of CDI on additional length of hospital stay, controlling for confounding factors such as underlying disease severity. Patients in England had the longest additional hospital stay attributable to CDI at 16.09 days, followed by Germany at 15.47 days, Spain at 13.56 days, and The Netherlands at 12.58 days, derived using regression analysis. Propensity score matching indicated a higher attributable length of stay of 32.42 days in England, 15.31 days in Spain, and 18.64 days in The Netherlands. Outputs from this study consistently demonstrate that in European countries, for patients whose hospitalisation is complicated by CDI, the infection causes a statistically significant increase in hospital length of stay. This has implications for optimising resource allocation and budget setting at both the national and hospital level to ensure that levels of CDI-complicated hospitalisations are minimised. PMID- 23797491 TI - [Early diagnosis and therapy in pulmonary hypertension--aspects of a vision]. AB - In patients with pulmonary hypertension progressive vascular changes in the lung precede the clinical and hemodynamic manifestations of the disease. Therefore, early diagnosis and timely treatment of the disease are crucial. This has been the topic of an expert meeting in Greifswald, Germany in June 2012. The current definition of pulmonary hypertension requires a mean pulmonary artery pressure >= 25 mmHg at rest, a hemodynamic abnormality already reflecting pulmonary vascular changes beyond early disease. There is increasing evidence supporting the concept that a lower pressure threshold at rest or an abnormal pressure response with exercise better characterize early disease. While right heart catheterization at rest remains the diagnostic gold standard other methods for detecting early disease are explored with echocardiography being the most frequently used technique. Targeted therapy has been approved for patients with pulmonary arterial hypertension (PAH, WHO-group I) in functional class II-IV. Preliminary data in functional class I patients suggest therapeutic potential of theses drugs in early disease as well. Current guidelines propose therapeutic goals based on parameters with prognostic importance. However, these recommendations are based on mostly retrospective analyses of pre-treatment data obtained in patients with pulmonary hypertension in functional class II-IV. Therefore, evidence-based therapeutic goals for early interventions in functional class I patients are lacking. PMID- 23797492 TI - [Medication adherence in asthma therapy--a structured review]. AB - BACKGROUND: The adherence level of Asthma therapy is low. We provide a literature overview about the determinants of adherence in asthma therapy, and potential options that lead to an improvement of adherence. We also discuss cost issues of poor adherence. METHODS: A systematic literature search was conducted and 53 articles were identified. RESULTS: The most prominent driving factors of adherence are patient beliefs, comorbidities, physician-patient relationship, and medication regimen. The cost effectiveness of adherence improving measures has yet to be shown. CONCLUSION: As asthma control is primarily depended on adherence, cost effective adherence programs need to be developed that respond to patients' individual needs. PMID- 23797494 TI - Relationship of macrophage migration inhibitory factor levels in PBMCs, lesional skin and serum with disease severity and activity in vitiligo vulgaris. AB - Melanocyte loss in vitiligo vulgaris is believed to be an autoimmune process. Macrophage migration inhibitory factor (MIF) is involved in many autoimmune skin diseases. We determined the possible role of MIF in the pathogenesis of vitiligo vulgaris, and describe the relationship between MIF expressions and disease severity and activity. Serum MIF concentrations and mRNA levels in PBMCs were measured in 44 vitiligo vulgaris patients and 32 normal controls, using ELISA and real-time RT-PCR. Skin biopsies from 15 patients and 6 controls were analyzed by real-time RT-PCR. Values are reported as median (25th-75th percentile). Serum MIF concentrations were significantly increased in patients [35.81 (10.98-43.66) ng/mL] compared to controls [7.69 (6.01-9.03) ng/mL]. MIF mRNA levels were significantly higher in PBMCs from patients [7.17 (3.59-8.87)] than controls [1.67 (1.23-2.42)]. There was also a significant difference in MIF mRNA levels in PBMCs between progressive and stable patients [7.86 (5.85-9.13) vs 4.33 (2.23 8.39)] and in serum MIF concentrations [40.47 (27.71-46.79) vs 26.80 (10.55 36.07) ng/mL]. In addition, the vitiligo area severity index scores of patients correlated positively with changes of both serum MIF concentrations (r = 0.488) and MIF mRNA levels in PBMCs (r = 0.426). MIF mRNA levels were significantly higher in lesional than in normal skin [2.43 (2.13-7.59) vs 1.18 (0.94-1.83)] and in patients in the progressive stage than in the stable stage [7.52 (2.43-8.84) vs 2.13 (1.98-2.64)]. These correlations suggest that MIF participates in the pathogenesis of vitiligo vulgaris and may be useful as an index of disease severity and activity. PMID- 23797496 TI - Preliminary Study to Assess the Performance of Mengovirus Elution from Sludge. AB - In the virus detection protocol for sludge, the viral elution step from solids to solution is critical. In this study, mengoviruses were detected in artificially contaminated sludge with a qRT-PCR assay. The viral yields ranged between 19 and 66 % for 60 % sludge. This study demonstrates that mengovirus can be used as a sample process control for analysis of sewage sludge. PMID- 23797495 TI - The epigenetic modifiers 5-aza-2'-deoxycytidine and trichostatin A influence adipocyte differentiation in human mesenchymal stem cells. AB - Epigenetic mechanisms such as DNA methylation and histone modification are important in stem cell differentiation. Methylation is principally associated with transcriptional repression, and histone acetylation is correlated with an active chromatin state. We determined the effects of these epigenetic mechanisms on adipocyte differentiation in mesenchymal stem cells (MSCs) derived from bone marrow (BM-MSCs) and adipose tissue (ADSCs) using the chromatin-modifying agents trichostatin A (TSA), a histone deacetylase inhibitor, and 5-aza-2'-deoxycytidine (5azadC), a demethylating agent. Subconfluent MSC cultures were treated with 5, 50, or 500 nM TSA or with 1, 10, or 100 uM 5azadC for 2 days before the initiation of adipogenesis. The differentiation was quantified and expression of the adipocyte genes PPARG and FABP4 and of the anti-adipocyte gene GATA2 was evaluated. TSA decreased adipogenesis, except in BM-MSCs treated with 5 nM TSA. Only treatment with 500 nM TSA decreased cell proliferation. 5azadC treatment decreased proliferation and adipocyte differentiation in all conditions evaluated, resulting in the downregulation of PPARG and FABP4 and the upregulation of GATA2. The response to treatment was stronger in ADSCs than in BM MSCs, suggesting that epigenetic memories may differ between cells of different origins. As epigenetic signatures affect differentiation, it should be possible to direct the use of MSCs in cell therapies to improve process efficiency by considering the various sources available. PMID- 23797497 TI - Induced Pluripotent Stem Cells and Disorders of the Nervous System: Progress, Problems, and Prospects. AB - Advances in cellular reprograming have shown that the delivery of specific transcription factors can result in the shift of one cell type to another. Brief forced expression of the four Yamanaka reprogramming factors (Klf4, Sox2, c-Myc, and Oct4) is able to convert many cell types into induced pluripotent stem cells, whereas some lineage specific transcription factors can convert cells from one type directly to another. Numerous strategies have already been developed for deriving neural cell types, with the hopes of better understanding/alleviating neurodegenerative disease. These cells facilitate drug discovery and constitute an autologous source of cells for brain repair, thus, avoiding rejection issues faced by allografts derived from embryonic stem cells. However, proper characterization of the various types of reprogrammed cells and an understanding of how these cells acquire neural fate is necessary before their translation into the clinic. Here, we review the progress, problems, and prospects with reprogrammed cell types with regards to neurodegenerative disease. PMID- 23797498 TI - Lumbar spinous process splitting decompression provides equivalent outcomes to conventional midline decompression in degenerative lumbar canal stenosis: a prospective, randomized controlled study of 51 patients. AB - STUDY DESIGN: Prospective, randomized controlled study. OBJECTIVE: To compare the functional outcomes and extent of paraspinal muscle damage between 2 decompressive techniques for lumbar canal stenosis. SUMMARY OF BACKGROUND DATA: Lumbar spinous process splitting decompression (LSPSD) preserves the muscular and liga-mentous attachments of the posterior elements of the spine. It can potentially avoid problems such as paraspinal muscle atrophy and trunk extensor weakness that can occur after conventional midline decompression. However, large series prospective randomized controlled studies are lacking. METHODS: Patients with lumbar canal stenosis were randomly allocated into 2 groups: LSPSD (28 patients) and conventional midline decompression (23 patients). The differences in operative time, blood loss, time to comfortable mobilization, and hospital stay were studied. Paraspinal muscle damage was assessed by postoperative rise in creatine phosphokinase and C-reactive protein levels. Functional outcome was evaluated at 1 year by Japanese Orthopaedic Association score, neurogenic claudication outcome score, and visual analogue scale for back pain and neurogenic claudication. RESULTS: Fifty-one patients of mean age 56 years were followed-up for a mean 14.2 +/- 2.9 months. There were no significant differences in the operative time, blood loss, and hospital stay. Both the groups showed significant improvement in the functional outcome scores at 1 year. Between the 2 groups, the Japanese Orthopaedic Association score, neurogenic claudication outcome score improvement, visual analogue scale for back pain, neurogenic claudication visual analogue scale, and the postoperative changes in serum C reactive protein and creatine phosphokinase levels did not show any statistically significant difference. On the basis of the Japanese Orthopaedic Association recovery rate, it was found that 73.9% of conventional midline decompression group had good outcomes compared with only 60.7% after LSPSD. CONCLUSION: The functional outcome scores, back pain, and claudication pain in the immediate period and at the end of 1 year are similar in both the techniques. More patients had better functional outcomes after conventional decompression than the LSPSD technique. On the basis of this study, the superiority of one technique compared with the other is not established, mandating the need for further long-term studies. LEVEL OF EVIDENCE: 2. PMID- 23797499 TI - Inhibition of nitric oxide mediated protein nitration: therapeutic implications in experimental radiculopathy. AB - STUDY DESIGN: Experimental animal study. OBJECTIVE: This study investigated whether nitric oxide (NO) mediated protein nitration is involved in the pathogenesis of radiculopathy and whether the symptoms can be relieved by its suppression. SUMMARY OF BACKGROUND DATA: It has been reported that nitration of protein mediated by NO is involved in the degenerative neurological disorders, but its involvement is not clear in the radiculopathy. METHODS: Two kinds of rat models of radiculopathy were used. Radiculopathy was induced either by ligation of spinal nerve roots or transplantation of autologous nucleus pulposus. In separate groups of rats, aminoguanidine, a potent nitric oxide synthetase inhibitor, was administered just before induction of radiculopathy, to suppress NO production and resultant nitration of protein. Sensation of the hind limb was evaluated by plantar stimulation test, and motor weakness was assessed by observation of gait pattern. Nitrotyrosine, product of protein nitration, was assayed quantitatively by Western immunoblotting. RESULTS: Mechanical allodynia was observed in both compression and nucleus pulposus groups, but motor weakness was observed only in the compression group. Preoperative administration of aminoguanidine attenuated mechanical allodynia and motor weakness. Optical densities of nitrotyrosine bands increased significantly in radiculopathy groups, but they were lowered by administration of aminoguanidine. CONCLUSION: NO mediated protein nitration contributes to the development of both types of radiculopathies. Suppression of NO production can decrease protein nitration and relieve neural dysfunctions of radiculopathy. LEVEL OF EVIDENCE: N/A. PMID- 23797500 TI - Automatic Cobb angle determination from radiographic images. AB - STUDY DESIGN: Automatic measurement of Cobb angle in patients with scoliosis. OBJECTIVE: To test the accuracy of an automatic Cobb angle determination method from frontal radiographical images. SUMMARY OF BACKGROUND DATA: Thirty-six frontal radiographical images of patients with scoliosis. METHODS: A modified charged particle model is used to determine the curvature on radiographical spinal images. Three curve fitting methods, piece-wise linear, splines, and polynomials, each with 3 variants were used and evaluated for the best fit. The Cobb angle was calculated out of these curve fit lines and compared with a manually determined Cobb angle. The best-automated method is determined on the basis of the lowest mean absolute error and standard deviation, and the highest R2. RESULTS: The error of the manual Cobb angle determination among the 3 observers, determined as the mean of the standard deviations of all sets of measurements, was 3.37 degrees . For the automatic method, the best piece-wise linear method is the 3-segments method. The best spline method is the 10-steps method. The best polynomial method is poly 6. Overall, the best automatic methods are the piece-wise linear method using 3 segments and the polynomial method using poly 6, with a mean absolute error of 4,26 degrees and 3,91 degrees a standard deviation of 3,44 degrees and 3,60 degrees , and a R2 of 0.9124 and 0.9175. The standard measurement error is significantly lower than the upper bound found in the literature (11.8 degrees ). CONCLUSION: The automatic Cobb angle method seemed to be better than the manual methods described in the literature. The piece-wise linear method using 3 segments and the polynomial method using poly 6 yield the 2 best results because the mean absolute error, standard deviation, and R2 are the best of all methods. LEVEL OF EVIDENCE: 3. PMID- 23797501 TI - New, clinically more relevant model for nerve root injury in the rat. AB - STUDY DESIGN: Exposure to nucleus pulposus and displacement of intraspinal nervous structures with assessment of spontaneous behavioral changes in rats. OBJECTIVE: To develop a controlled, experimental model for nerve root injury. SUMMARY OF BACKGROUND DATA: There are a number of experimental models presented for studies on radiculopathies. One frequently used model is based on exposure to nucleus pulposus and displacement of the dorsal root ganglion (DRG). However, it is clinically more common that the nerve roots are displaced/compressed than the DRG. In this study, we developed a model for displacement of the nerve root by modifying the DRG model. METHODS: After removing the left L3-L4 facet joint, the underlying disc was punctured, and the L4 nerve root was displaced laterally by an injection needle (n = 10). In sham experiments, the same procedure was performed without disc puncture and displacement (n = 10). In 10 rats, the left L4-L5 facet joint was removed. The underlying disc was punctured and the L4 DRG was displaced medially by an injection needle. Assessment of spontaneous behavioral changes was performed on days 1, 3, 7, 14, and 21, postsurgery. RESULTS: There was a clear increase in duration of the behavior "unloading of the paw" after displacement of the DRG that was most pronounced on day 1 and then gradually declined. There was a similar pattern for this behavior induced by nerve root displacement, although the duration was higher than that for the DRG displacement. No apparent trends in behavioral changes were observed for the other behaviors studied. CONCLUSION: Displacement of the nerve root induced more changes in the pain behavior than displacement of the DRG, but only for the behavior unloading of the paw. Because nerve root injury is more common than DRG injury, this model may be more clinically relevant than the DRG model. LEVEL OF EVIDENCE: N/A. PMID- 23797502 TI - Incidence and risk factors for postoperative delirium after lumbar spine surgery. AB - STUDY DESIGN: Retrospective database analysis. OBJECTIVE: A population-based database was analyzed to characterize the incidence, hospital costs, mortality, and risk factors associated with postoperative delirium after lumbar decompression (LD) and lumbar fusion (LF) surgical procedures. SUMMARY OF BACKGROUND DATA: Postoperative delirium is a common complication after surgery in the elderly that leads to increased hospitalization, cost, and other adverse outcomes. The incidence of delirium after lumbar spine surgery has not been discussed in this literature. METHODS: Data from the Nationwide Inpatient Sample were obtained from 2002-2009. Patients undergoing LD or LF for degenerative pathologies were identified. Patient demographics, comorbidities, length of stay, discharge disposition, costs, and mortality were assessed. SPSS version 20 was used for statistical analysis using independent T tests for discrete variables and chi2 tests for categorical data. Logistic regression was performed to identify independent predictors of delirium. A P value of less than 0.001 was used to denote significance. RESULTS: A total of 578,457 LDs and LFs were identified in the United States from 2002-2009. Of these, 292,177 were LDs and 286,280 were LFs. The overall incidence of delirium was 8.4 events per 1000 cases. Patients undergoing LF had a statistically greater incidence of delirium than patients undergoing LD (11.8 vs. 5.0 per 1000; P < 0.001). Patients experiencing delirium were significantly older and more likely to be female than nonaffected patients (P < 0.001). Patients with delirium in both cohorts demonstrated significantly greater comorbidities, length of stay, greater costs, and more frequent discharge to skilled nursing facilities (P < 0.001). The presence of delirium in LD-treated patients was associated with an increased mortality rate (6.1 vs. 0.8 per 1000; P < 0.001). Logistic regression demonstrated that independent predictors of delirium included older age (>=65 yr), alcohol/drug abuse, depression, psychotic disorders, neurological disorders, deficiency anemia, fluid/electrolyte disorders, and weight loss. CONCLUSION: The results of our study demonstrated an overall incidence of 8.4 events per 1000 lumbar spine surgical procedures. Overall analysis demonstrated an increased incidence of delirium in older females with greater comorbid conditions. Delirium was found to be associated with increased length of stay, costs, and mortality in all patients undergoing lumbar spine surgery. We recommend that physicians put greater effort into recognizing risk factors of delirium and diagnosing it in a timely manner to mitigate its effects. LEVEL OF EVIDENCE: 3. PMID- 23797503 TI - Posteriorly directed shear loads and disc degeneration affect the torsional stiffness of spinal motion segments: a biomechanical modeling study. AB - STUDY DESIGN: Finite element study. OBJECTIVE: To analyze the effects of posterior shear loads, disc degeneration, and the combination of both on spinal torsion stiffness. SUMMARY OF BACKGROUND DATA: Scoliosis is a 3-dimensional deformity of the spine that presents itself mainly in adolescent girls and elderly patients. Our concept of its etiopathogenesis is that an excess of posteriorly directed shear loads, relative to the body's intrinsic stabilizing mechanisms, induces a torsional instability of the spine, making it vulnerable to scoliosis. Our hypothesis for the elderly spine is that disc degeneration compromises the stabilizing mechanisms. METHODS: In an adult lumbar motion segment model, the disc properties were varied to simulate different aspects of disc degeneration. These models were then loaded with a pure torsion moment in combination with either a shear load in posterior direction, no shear, or a shear load in anterior direction. RESULTS: Posteriorly directed shear loads reduced torsion stiffness, anteriorly directed shear loads increased torsion stiffness. These effects were mainly caused by a later (respectively earlier) onset of facet joint contact. Disc degeneration cases with a decreased disc height that leads to slackness of the annular fibers and ligaments caused a significantly decreased torsional stiffness. The combination of this stage with posterior shear loading reduced the torsion stiffness to less than half the stiffness of a healthy disc without shear loads. The end stage of disc degeneration increased torsion stiffness again. CONCLUSION: The combination of a decreased disc height, that leads to slack annular fibers and ligaments, and posterior shear loads very significantly affects torsional stiffness: reduced to less than half the stiffness of a healthy disc without shear loads. Disc degeneration, thus, indeed compromises the stabilizing mechanisms of the elderly spine. A combination with posteriorly directed shear loads could then make it vulnerable to scoliosis. LEVEL OF EVIDENCE: N/A. PMID- 23797504 TI - Comparative study of lumbopelvic sagittal alignment between patients with and without sacroiliac joint pain after lumbar interbody fusion. AB - STUDY DESIGN: A retrospective case-control study. OBJECTIVE: To elucidate the role of changes of lumbopelvic sagittal alignment in the pathogenesis of sacroiliac joint (SIJ) pain after posterior lumbar interbody fusion (PLIF) by comparing these values with the control, patients without SIJ pain. SUMMARY OF BACKGROUND DATA: There has been no study specifically addressing the relation between lumbopelvic sagittal alignment and SIJ pain after PLIF. METHODS: Among 346 patients who underwent PLIF between June 2009 and April 2012, patients with postoperative SIJ pain who responded to SIJ block were enrolled. For a control group, patients who were matched for sex, age group, the number of fused level, and fusion to sacrum were randomly selected. The patients were assessed using clinical and radiological parameters including age, sex, diagnosis, bone mineral density, body mass index, lumbar lordosis (LL), pelvic incidence (PI), pelvic tilt, and sacral slope. Target LL (PI + 9 degrees ), achieved rate of LL (postoperative LL/target LL * 100), and LL-PI mismatch (Delta) were also calculated and compared between 2 groups. RESULTS: Twenty-three patients (9 males and 14 females) with SIJ pain and 46 patients (18 males and 28 females) without SIJ pain were assessed. Postoperatively, the SIJ pain group showed significantly greater pelvic tilt (19.88 +/- 10.42 degrees , P = 0.03), smaller achieved rate of LL (64.3%, P = 0.02), and substantial residual LL-PI mismatch (-14.45 +/- 12.16 degrees , P = 0.03) than the non-SIJ pain group (14.25 +/- 7.68 degrees , 73.2%, and -8.26 +/- 9.12 degrees , respectively). The degree of correlation between LL and PI in both the SIJ pain group and the non-SIJ pain group was positive preoperatively (r = 0.569; P = 0.003, r = 0.591; P = 0.000, respectively). Although correlation of the SIJ pain group remained positive postoperatively (r = 0.601, P = 0.002), it became strongly positive in the non SIJ pain group (r = 0.856, P = 0.000). CONCLUSION: This study indicates that lumbopelvic sagittal imbalance inferred from greater pelvic tilt and inadequately restored LL may play a central role in the development of SIJ pain after PLIF. Thus, it is important to restore lumbopelvic sagittal balance and to evaluate PI to determine the ideal LL that is needed to prevent postoperative SIJ pain. LEVEL OF EVIDENCE: 3. PMID- 23797505 TI - Novel 3-dimensional motion analysis method for measuring the lumbar spine range of motion: repeatability and reliability compared with an electrogoniometer. AB - STUDY DESIGN: Repeatability and reliability for measuring methods for real-time lumbar range of motion. OBJECTIVE: We established a novel set of marker positions for 3-dimensional motion analysis (VICON system) to determine lumbar spine range of motion (LROM) and lumbar motion precisely; we compared the repeatability and reliability of VICON system with those of an electrogoniometer. SUMMARY OF BACKGROUND DATA: The assessment of the LROM using x-ray is still one of the most precise methods, despite the radiation exposure. To avoid this, alternative methods, such as the VICON system and electrogoniometer, have been widely used. No study has reported the repeatability and reliability of LROM measurements using a VICON system and electrogoniometer. METHODS: The VICON system and electrogoniometer measured LROM and lumbar motion in 7 healthy males during 7 days. Differences between both systems were analyzed using Bland-Altman plots. Repeatability and reliability of the LROM measurements was assessed using coefficients of multiple correlations and intraclass correlation coefficients, respectively. Standard error of measurement was calculated to quantify the systematic error in LROM measurements. RESULTS: The mean maximum LROM values using the VICON system/electrogoniometer were 42 degrees /52 degrees for flexion, 17 degrees /24 degrees for extension, 16 degrees /16 degrees for lateral bending, and 8 degrees /2 degrees for axial rotation, respectively. Between VICON system and the electrogoniometer, Bland-Altman plots revealed no discrepancies in LROM values except for flexion.Coefficients of multiple correlations for LROM showed excellent repeatability. LROM measurements with VICON system showed excellent reliability for flexion and extension and fair-to good reliability for other motions. LROM measurements with the electrogoniometer showed excellent reliability for flexion and fair-to-good reliability for other motions. Except for axial rotation, maximum intraclass correlation coefficients using VICON system were more reliable than the electrogoniometer for measuring lumbar motion. CONCLUSION: VICON system with our novel marker set allows practical and reliable longitudinal assessment of dynamic LROM. LEVEL OF EVIDENCE: N/A. PMID- 23797506 TI - Diagnostic advancement of axial loaded lumbar spine MRI in patients with clinically suspected central spinal canal stenosis. AB - STUDY DESIGN: Case series study. OBJECTIVE: To define diagnostic advancement of L spine magnetic resonance with axial loading device in patients with clinically suspected central spinal canal stenosis, and to show a relationship of facet joint instability with aggravated central spinal canal stenosis in axial loaded studies. SUMMARY OF BACKGROUND DATA: Although the axial loading device has been used for several years, there have been few reports about the usefulness of the axial loading device in clinical settings. Also, there has been no report about the relationship between facet arthrosis and dynamic central spinal canal stenosis. METHODS: Lumbar magnetic resonance image (MRI) with axial loading device was obtained in 54 patients. Axial images were evaluated with attention to (1) gross change of central spinal canal stenosis, (2) findings of facet joint, including arthrosis, effusion, effacement of effusion, and (3) formation of ventral synovial cyst after axial loading. In addition, dural sac cross-sectional area was measured in L3-L4, L4-L5, and L5-LS1 levels to quantify the change of stenosis. Changes of neural foraminal stenosis, curvature, and spondylolisthesis were evaluated with sagittal images. RESULTS: With a use of axial loading device, the additional diagnosis of severe central spinal canal stenosis was made in 13 patients (25%) in both gross interpretation and quantitative study (dural sac cross-sectional area <75 mm). The significant decrease of dural sac cross sectional area was demonstrated in 22 patients (42%). The significant decrease was related to facet joint effusion and effacement of effusion. CONCLUSION: Measurable advancement in diagnosis of severe central spinal canal stenosis was possible with axial loaded MRI. Patients with facet joint instability had a tendency to show significant changes in the central spinal canal area. LEVEL OF EVIDENCE: 4. PMID- 23797507 TI - Enzymatic hydrolysis and succinic acid fermentation from steam-exploded corn stalk at high solid concentration by recombinant Escherichia coli. AB - Steam-exploded corn stalk biomass was used as the substrate for succinic acid production via lignocellulose enzymatic hydrolysis and fermentation. Succinic acid fermentation was investigated in Escherichia coli strains overexpressing cyanobacterium Anabaena sp. 7120 ecaA gene encoding carbonic anhydrase (CA). For the washed steam-exploded corn stalk at 30 % substrate concentration, i.e., 30 % water-insoluble solids (WIS), enzymatic hydrolysis yielded 97.5 g/l glucose solution and a cellulose conversion of 73.6 %, thus a high succinic acid level up to 38.6 g/l. With the unwashed steam-exploded corn stalk, though a cellulose conversion of 71.2 % was obtained in hydrolysis at 30 % solid concentration (27.9 % WIS), its hydrolysate did not ferment at all, and the hydrolysate of 25 % solid loading containing 3.8 g/l acetic acid and 168.2 mg/l furfural exerted a strong inhibition on succinic acid production. PMID- 23797508 TI - Enantioconvergent biohydrolysis of racemic styrene oxide to R-phenyl-1, 2 ethanediol by a newly isolated filamentous fungus Aspergillus tubingensis TF1. AB - An effort was made to isolate biocatalysts hydrolyzing epoxides from various ecological niches of northeast India, a biodiversity hot spot zone of the world and screened for epoxide hydrolase activity to convert different racemic epoxides to the corresponding 1, 2-vicinal diols. Screening of a total of 450 microorganisms isolated was carried out using NBP colorimetric assay. One of the strains TF1, after internal transcribed spacer sequence analysis, identified as Aspergillus tubingensis, showed promising enantioconvergent epoxide hydrolase activity. The hydrolysis of unsubstituted styrene oxide (1) occurred to give 97 % ee of R-(-)-1-phenylethane-1, 2-diol (6) with more than 99 % conversion within 45 min incubation. It is shown to be a cheap and practical biocatalyst for one step asymmetric synthesis of chiral R-diol. The other representative substrates (2-5), although underwent hydrolysis with more than 99 % conversion beyond 15 h, exhibited poor enantioselectivity. PMID- 23797509 TI - Enhancement of the Enzymatic Digestibility and Ethanol Production from Sugarcane Bagasse by Moderate Temperature-Dilute Ammonia Treatment. AB - In this study, sugarcane bagasse was pretreated with ammonium hydroxide, and the effectiveness of the pretreatment on enzyme hydrolysis and ethanol production was examined. Bagasse was soaked in ammonium hydroxide and water at a ratio of 1:0.5:8 for 0-4 days at 70 degrees C. Approximately, 14-45 % lignin, 2-6 % cellulose, and 13-22 % hemicellulose were removed during a 0.5- to 4-day ammonia soaking period. The highest glucan conversion of sugarcane bagasse soaked in dilute ammonia at moderate temperature by cellulase was accomplished at 78 % with 75 % of the theoretical ethanol yield. Under the same conditions, untreated bagasse resulted in a cellulose digestibility of 29 and 27 % of the theoretical ethanol yield. The increased enzymatic digestibility and ethanol yields after dilute ammonia pretreatment was related to a combined effect of the removal of lignin and increase in the surface area of fibers. PMID- 23797510 TI - beta-D-xylosidase from Geobacillus thermoleovorans IT-08: biochemical characterization and bioinformatics of the enzyme. AB - The gene encoding a thermostable beta-D-xylosidase (GbtXyl43B) from Geobacillus thermoleovorans IT-08 was cloned in pET30a and expressed in Escherichia coli; additionally, characterization and kinetic analysis of GbtXyl43B were carried out. The gene product was purified to apparent homogeneity showing M r of 72 by sodium dodecyl sulfate polyacrylamide gel electrophoresis. The enzyme exhibited an optimum temperature and pH of 60 degrees C and 6.0, respectively. In terms of stability, GbtXyl43B was stable at 60 degrees C at pH 6.0 for 1 h as well as at pH 6-8 at 4 degrees C for 24 h. The enzyme had a catalytic efficiency (k cat/K M) of 0.0048 +/- 0.0010 s(-1) mM(-1) on p-nitrophenyl-beta-D-xylopyranoside substrate. Thin layer chromatography product analysis indicated that GbtXyl43B was exoglycosidase cleaving single xylose units from the nonreducing end of xylan. The activity of GbtXyl43B on insoluble xylan was eightfold higher than on soluble xylan. Bioinformatics analysis showed that GbtXyl43B belonging to glycoside hydrolase family 43 contained carbohydrate-binding module (CBM; residues 15 to 149 forming eight antiparallel beta-strands) and catalytic module (residues 157 to 604 forming five-bladed beta-propeller fold with predicted catalytic residues to be Asp287 and Glu476). CBM of GbtXyl43B dominated by the Phe residues which grip the carbohydrate is proposed as a novel CBM36 subfamily. PMID- 23797511 TI - Synergistic antibacterial and antibiofilm effect between (+)-medioresinol and antibiotics in vitro. AB - In this study, antibacterial effects of (+)-Medioresinol isolated from stem bark of Sambucus williamsii and its synergistic activities in combination with antibiotics such as ampicillin, cefotaxime, and chloramphenicol were tested by antibacterial susceptibility testing and checkerboard assay. (+)-Medioresinol possessed antibacterial effects against antibiotics-susceptible- or antibiotics resistant strains. Most of combinations between (+)-Medioresinol and each antibiotic showed synergistic interaction (fractional inhibitory concentration index <= 0.5) against bacterial strains including antibiotics-resistant Pseudomonas aeruginosa. Furthermore, the antibiofilm effect of (+)-Medioresinol alone or in combination with each antibiotic was investigated. The results indicated that not only (+)-Medioresinol but also its combination with each antibiotic had antibiofilm activities. It concludes that (+)-Medioresinol has potential as a therapeutic agent and adjuvant for treatment of bacterial infection. PMID- 23797512 TI - Syncope-Quiz Case: A Tale of Two Triggers. PMID- 23797513 TI - Solar spectral conversion for improving the photosynthetic activity in algae reactors. AB - Sustainable biomass production is expected to be one of the major supporting pillars for future energy supply, as well as for renewable material provision. Algal beds represent an exciting resource for biomass/biofuel, fine chemicals and CO2 storage. Similar to other solar energy harvesting techniques, the efficiency of algal photosynthesis depends on the spectral overlap between solar irradiation and chloroplast absorption. Here we demonstrate that spectral conversion can be employed to significantly improve biomass growth and oxygen production rate in closed-cycle algae reactors. For this purpose, we adapt a photoluminescent phosphor of the type Ca0.59Sr0.40Eu0.01S, which enables efficient conversion of the green part of the incoming spectrum into red light to better match the Qy peak of chlorophyll b. Integration of a Ca0.59Sr0.40Eu0.01S backlight converter into a flat panel algae reactor filled with Haematococcus pluvialis as a model species results in significantly increased photosynthetic activity and algae reproduction rate. PMID- 23797514 TI - The process of efficiency. PMID- 23797515 TI - Impact of the 2011 FDA transvaginal mesh safety update on AUGS members' use of synthetic mesh and biologic grafts in pelvic reconstructive surgery. AB - OBJECTIVE: To describe the frequency of use and recent change in use of synthetic mesh and biologic grafts in pelvic organ prolapse (POP) and stress urinary incontinence surgery by American Urogynecology Society (AUGS) members. METHODS: An electronic survey of AUGS members was conducted between December 2011 and January 2012. Frequency of graft use in POP (overall and by transvaginal and transabdominal approaches) and stress urinary incontinence surgery was queried relative to the timing of the 2011 Food and Drug Administration (FDA) safety update. Rates of materials' use before and after the statement were compared using Wilcoxon signed rank test. RESULTS: Fifty-three percent (507/962) of AUGS members responded and were included in analysis; 79% were urogynecologists. Before the FDA warning, in POP surgery, most (90%) used synthetic mesh and fewer (34%) used biologic grafts; 99% used synthetic mesh slings. After the FDA statement, respondents reported an overall decrease in the percent of POP cases in which they used synthetic mesh (P < 0.001) but no change in biologic graft use for POP (P = 0.37) or synthetic mesh sling use (P = 0.10). Specifically, transvaginal mesh use decreased: 40% reported decreased use and 12% stopped use. However, transvaginal mesh was still used by 61% of respondents in at least some cases. No change (62%) or increased use (12%) of mesh was reported for transabdominal POP procedures. CONCLUSIONS: Synthetic mesh use in transvaginal POP surgery decreased after the 2011 FDA safety update, but synthetic mesh use for transabdominal POP repair and sling procedures and overall biologic graft use in POP surgery did not decrease. PMID- 23797516 TI - Position statement on restriction of surgical options for pelvic floor disorders: the American Urogynecologic Society Board of Directors. PMID- 23797517 TI - Recurrence of prolapse after transvaginal mesh excision. AB - OBJECTIVE: Recurrence of pelvic organ prolapse (POP) is a potential complication after mesh removal. We evaluated anatomical and functional outcomes preoperatively and postoperatively in patients undergoing mesh excision. MATERIALS AND METHODS: We conducted a retrospective cohort analysis of consecutive patients who underwent mesh excision from years 2005 to 2009. Anatomical outcomes were evaluated using the POP quantification (POP-Q) system. Recurrence of prolapse was defined as stage II or higher-stage prolapse on the POP-Q system, reoperation for prolapse, or postoperative use of a pessary for prolapse reduction. Functional outcomes were assessed using the pelvic floor distress inventory and pelvic floor impact questionnaire scores. RESULTS: Data were analyzed from 71 patients who underwent either partial or complete mesh excision. Most (44/70 [63%]) of the patients underwent partial mesh excision, and 26 patients (37%) underwent total mesh removal. Nineteen patients (26.7%) had preoperative prolapse and 27 (38.0%) of the 71 patients underwent concomitant native tissue prolapse repair. Overall change in POP-Q stage in women who underwent partial removal (median, 0 [-1 to 2]) was less advanced than in women with total excision. (median, -1 [-3 to 0]; P = 0.006) at 1 year postoperatively. Four patients prolapsed to the hymen, with all patients having defects in the anterior compartment. No patients required a second surgery, and one patient was treated with a pessary.Total pelvic floor distress inventory and pelvic floor impact questionnaire scores before mesh excision were significantly improved 6 months after mesh removal (P < 0.05). Dyspareunia improved significantly after mesh excision (P = 0.034). CONCLUSION: In our patient population, total and partial mesh excision is associated with re-treatment of POP in 1.4% of the patients. Patient functional outcomes significantly improved after mesh removal. PMID- 23797518 TI - Exploring predictors of mesh exposure after vaginal prolapse repair. AB - OBJECTIVES: To evaluate clinical, demographic, and surgical factors that may be associated with mesh exposure after vaginal repair of pelvic organ prolapse (POP). METHODS: Records of women who underwent POP repair with Elevate or Prolift were retrospectively reviewed. Body mass index (BMI), prolapse grade, smoking history, diabetes, steroid and estrogen use, parity, compartment repaired, concurrent hysterectomy, operative time, postoperative pain, change in hemoglobin (DeltaHgb) and other characteristics were evaluated for associations with mesh exposure.Categorical variables were examined using Pearson chi test where appropriate, or the Fisher exact test was used. The continuous variables were examined using Wilcoxon rank tests. A multivariable logistic regression analysis was completed to examine predictors of mesh exposure. All analyses used SAS for Windows version 9.2 (Cary, NC). RESULTS: Three hundred thirty-five women underwent repair from 2006 to 2011. Vaginal mesh exposure was identified in 27 (8.1%) of the 335 women. Patients with exposure had longer median follow-up than the group with no exposure (357 vs 145 days; P = 0.0003). The median time to exposure was 96 days (15-1129 days). Mesh exposure was associated with lower BMI (25.2 +/- 2.5 vs 27.4 +/- 5.1; P = 0.020) and greater DeltaHgb (-3.7 +/- 1.7 mg/dL vs -2.5 +/-1.3; P = 0.0011). Change in hemoglobin decreased over time (P = 0.0005). Exposure rates also decreased over time (17% in 2005 to 12% in 2006, then 5%-8% in 2006-2011) but were not statistically significant (P = 0.49). CONCLUSIONS: In this study, vaginal mesh exposure was only associated with DeltaHgb and lower BMI. PMID- 23797519 TI - The rapidly increasing usefulness of social media in urogynecology. AB - OBJECTIVE: We assessed the availability and quality of urinary incontinence and pelvic organ prolapse information in social medias and the growth of such information in the past 13 months. METHODS: We focused on the most popular social medias (Facebook, Twitter, and YouTube) to evaluate the key words "urogynecology," "pelvic organ prolapse," "stress incontinence," "urge incontinence," and "incontinence." Initial evaluation included top 30 search results for key word "incontinence" to compare with our study in 2010, followed by a secondary search using the top 100 items. Results were classified as useful or not useful and then further categorized by health care providers, others, commercial, or humorous in intent. Results with the intent of providing information were presumed to be informative. RESULTS: Comparative search over a 13-month period showed a stable amount of useful information, 40% to 39%, but an increase in the number of health professionals (22% vs 13%). However, of the 817 search results, 406 (50%) were medically useful. Only 28% were written by health professionals, but of the informative results, 56% were written by health professionals. Finally, specific search terms provided the highest relevant and useful information, but also limited the number of search items found. CONCLUSIONS: Over 13 months, there was an increase in useful information presented from health professionals. These changes may reflect the medical community's growing awareness of the usefulness of social media. If these trends continue, we predict the use of these medias for medical purposes will continue to increase among medical professionals. PMID- 23797520 TI - Can visuospatial ability predict performance and learning curves on a robotic surgery simulator? AB - OBJECTIVE: This study aimed to examine the correlation between visuospatial ability, measured with the Perceptual Ability Test (PAT), and da Vinci robot simulator performance on the da Vinci Skills Simulator. METHODS: Twenty-five consenting medical students naive to both the PAT and the da Vinci robot completed the PAT and then performed a single simulation (Ring-walk 2) 10 consecutive times. Raw PAT scores were compared with composite simulator scores for all subjects. Participants were divided into those with high and low visuospatial ability based on whether they scored above or below (or equal) to the median on the PAT. We compared the mean composite simulator scores and the time to complete each exercise between the high and the low PAT performers. RESULTS: The mean (SD) raw PAT score (out of 90) was 45.5 (18.3) (median, 43.0). The mean composite simulator score was 65.5 (24.1) (median, 72.2). The high (n = 12) and low (n = 13) PAT performers had a mean (SD) (median) simulator score of 79.1 (9.8) (80.3) and 53.0 (26.7) (65.9), respectively. On average, the high PAT performers scored 26.1 points (95% confidence interval, 9.2-43.0, P = 0.005), or 49.2%, higher on the simulation than the low PAT performers. The high PAT performers completed the exercise in 96.5 seconds (95% confidence interval, 26.0 167.0; P = 0.009), or 36.2%, faster than the low PAT performers. CONCLUSIONS: Better visuospatial ability relates to improved performance on a robotic surgery simulator. PMID- 23797521 TI - Pelvic floor muscle training for urinary incontinence: a comparison of outcomes in premenopausal versus postmenopausal women. AB - OBJECTIVES: Previous studies examining the effectiveness of pelvic floor muscle training (PFMT) for urinary incontinence in premenopausal and postmenopausal women have shown ambiguous results. The aim of this study was to compare subjective PFMT outcome in premenopausal versus postmenopausal women. METHODS: This is a retrospective study including premenopausal and postmenopausal women after PFMT for urodynamically proven stress urinary incontinence, mixed urinary incontinence, or urgency urinary incontinence from January 2003 to December 2008, with assessment of the need of an incontinence surgery in a follow-up time of least 24 months. Patients evaluated the change of their urinary incontinence on a 4-point Likert scale (1, no improvement; 2, slightly better; 3, no relevant incontinence; 4, excellent outcome; no incontinence at all) and their goal attainment on a 3-point Likert scale (1, less than expected; 2, as expected; and 3, more than expected). RESULTS: Successful outcome was reported by 59% of the premenopausal patients and 70% of the postmenopausal patients (P = 0.16), the attainment of the subjective goal by 68% and 81% (P = 0.09), and the need of an incontinence operation in a follow-up of 30 to 102 months by 15% and 14% (P = 1.0), respectively. None of the outcome parameters reached significance. CONCLUSIONS: In comparing premenopausal to postmenopausal women, we could not detect any statistically significant difference with regard to patients' satisfaction for the outcome of PFMT. PMID- 23797522 TI - Perceptions and practice patterns of general gynecologists regarding urogynecology and pelvic reconstructive surgery. AB - OBJECTIVES: The purpose of this study was to describe the current practice patterns of general gynecologists regarding management of various urogynecologic conditions. METHODS: A 15-item Web-based survey was sent to obstetrician and gynecologists in 2011. Subjects who chose to participate answered questions about their comfort level with management of various urogynecologic conditions, their perceptions of the need for a pelvic reconstructive surgeon in their community, and when they feel it is appropriate to refer to a specialist. RESULTS: Two hundred ninety-four obstetrics/gynecology generalists responded to the survey with overall 33% response rate. There was a wide range of comfort level depending on the complexity of the condition. Most of the subjects felt comfortable in the management of stress and urge incontinence, cystocele, rectocele, and uterine prolapse. On the other hand, most of the subjects were uncomfortable with management of intrinsic sphincter deficiency, fecal incontinence, recurrent incontinence after failed surgery, and complications of vaginal mesh surgery. In addition, there was wide variation in types of surgical options offered by different practitioners. When we compared the results by age, younger gynecologists have a smaller repertoire of procedures they offer for treatment of urogynecologic conditions. Burch colposuspension, uterosacral ligament suspension, and colpocleisis were performed more often by older surgeons than younger surgeons. On the other hand, cystoscopy was performed more commonly by the younger group. CONCLUSIONS: Among general gynecologists, there is a wide range in both comfort level for management of different urogynecologic conditions and types of urogynecologic services performed. PMID- 23797523 TI - Pathologic evaluation of explanted vaginal mesh: interdisciplinary experience from a referral center. AB - OBJECTIVES: In light of vaginal mesh safety concerns, we reviewed our institutional experience with analytic processes and pathologic findings of explanted vaginal mesh to identify problems and opportunities to facilitate improved documentation and research. METHODS: We reviewed gross and microscopic pathology reports and archival slides of explanted mesh specimens from January 2010 through February 2012. Specimen requisition clinical history, number of mesh specimens per case, and type of examination (gross or histologic) were abstracted from pathology records using the initial search word "mesh". RESULTS: One hundred two cases were reviewed. Explanted mesh specimens included tissue in 97%. Forty eight percent of these cases were submitted for histopathologic evaluation (as opposed to gross examination only). Specimen requisitions listed clinical history as pain (28.4%), vaginal mesh erosion (24.5%), erosion (17.6%), urinary retention (5.9%), and infection (2.9%). When no history was provided (24.5%), the case was more frequently submitted for histologic examination (74% vs 41%, P = 0.05). In all but 2 cases, the mesh material was polypropylene; no requisition mentioned this information. Gross descriptions of mesh varied significantly; in 18% of the cases, mesh was inaccurately described as "metallic". No cases of neoplasm were diagnosed histologically; all tissue diagnoses described benign reactive processes. CONCLUSIONS: Our experience suggests that either gross or histopathologic examination is appropriate for mesh explants. Documentation of clinical history, mesh product, and material was frequently incomplete and associated with increased submission of tissue for histologic examination and inaccurate gross impression of material type. We recommend improved documentation to aid pathologic examination and enable future pathophysiologic study of mesh complications. PMID- 23797524 TI - Minimally invasive diagnosis and treatment of endometrial cancer after LeFort colpocleisis. AB - BACKGROUND: Endometrial carcinoma is rare after LeFort colpocleisis. Standards for its diagnosis and treatment have not been established. CASE: A 74-year-old woman presented with postmenopausal bleeding 14 months after LeFort colpocleisis. Here, we describe the use of the colpocleisis channels in our novel 2-stage approach. In the first stage, endometrial carcinoma was diagnosed with vaginohysteroscopy and dilatation and curettage via the channels. In the second stage, the cancer was optimally treated with total robotic hysterectomy, bilateral salpingo-oophorectomy, and lymph node dissection. Assistance and specimen retrieval were achieved through the vaginal channels. The patient recovered without compromise to the pelvic floor. CONCLUSIONS: Endometrial cancer after LeFort colpocleisis can be diagnosed and treated with minimally invasive approaches without disrupting the colpocleisis or the pelvic floor support. PMID- 23797525 TI - Transobturator taping for the treatment of incontinence after neobladder reconstruction. AB - Incontinence in the patients with neobladder is a distressing condition. Although conservative management may be helpful in some, a significant number of patients require some form of surgical intervention. Any surgical intervention, especially from the abdominal route can be significantly morbid in these patients because of extensive surgery done previously. There is a need for a technique that can take care of the postoperative incontinence without subjecting the patient to significant surgical risk. Artificial sphincters have been used in male patients but their use in female patients can be technically difficult. There are limited options available for women like transurethral bulking agents and pubovaginal slings. These procedures do not have very good results and female patients often end up with a cutaneous stoma. We, in this report, describe a female patient with incontinence after orthotopic neobladder reconstruction that could be successfully treated with transobturator taping. PMID- 23797526 TI - A case of silicone mesh extrusion into the bladder associated with robotic sacrocolpopexy. AB - BACKGROUND: Over the past several years, the daVinci robot has been used in gynecologic surgery as a new surgical approach. The literature is being slowly populated with pros and cons of this technology. CASE: We report a 60-year-old woman with a history of pelvic organ prolapse who had a robotic sacrocolpopexy. She presented with mesh extrusion into her vagina, which was removed by exploratory laparotomy. Two years later, she presented with mesh erosion into her bladder, which was removed. CONCLUSION: This case report provides an example of significant mesh complication associated with robotic sacrocolpopexy 4 years after surgery and then again 2 years later. PMID- 23797527 TI - Urinary tract injury at the time of laparoscopic and robotic surgery: presentation and management. AB - OBJECTIVE: To report a series of urinary tract injuries resultant of laparoscopic or robotic procedures performed for a gynecologic indication. METHODS: We identified 16 patients with urinary tract fistulas after laparoscopic or robotic gynecologic procedures between 2009 and 2012. We extracted demographic data and prior surgical data as well as reviewed our management of each case. RESULTS: Thirteen subjects had undergone robotic procedures, 2 traditional laparoscopies, and a single-port laparoscopy with time to presentation from 2 days to 9 months postoperatively. Seven patients presented with vesicovaginal fistulas (43%), of which one healed spontaneously. Eight patients had ureterovaginal fistulas. Two patients (25%) were managed with ureteroneocystotomy, 2 patients (25%) were managed with Boari flap, and 4 patients (50%) were managed with double-J stent placement. One patient had a vesicocervical fistula managed via trachelectomy and partial cystectomy. CONCLUSION: The authors have seen an increase in referrals for urinary tract fistulas in minimally invasive surgery. It is imperative to investigate the effect of a steep learning curve, unfamiliarity with new energy sources, or poor patient selection as contributing factors. PMID- 23797528 TI - Robotic versus vaginal urogynecologic surgery: a retrospective cohort study of perioperative complications in elderly women. AB - OBJECTIVES: The primary objective was to compare perioperative complications after robotic surgery (RS) versus vaginal surgery (VS) for apical prolapse repair in elderly women. The secondary objectives were to (1) assess whether tools designed to predict surgical morbidity, the American Society of Anesthesiologists (ASA) class and the Charlson Comorbidity Index (CCI), are useful in the elderly urogynecologic population and (2) to classify complications during urogynecologic apical procedures using the Dindo classification system. METHODS: We reviewed medical records of women 65 years or older who underwent RS or VS between March 2006 and April 2011. Procedures included robotic sacrocolpopexy and sacrocervicopexy, vaginal uterosacral ligament suspension, sacrospinous ligament suspension, colpocleisis, and Uphold vaginal mesh placement. We assessed preoperative risks using ASA and CCI classification and complications using Dindo grade. RESULTS: There were 136 eligible cases (RS, 70; and VS, 66) during the 5 year study period. Women who underwent RS were younger (70 vs 74 years; P < 0.001). Vaginal surgery had more severe comorbidities as measured by the CCI (P = 0.012) but similar ASA profiles (P = 0.10). Robotic surgery had longer operative times (P < 0.001) but a lower estimated blood loss (P < 0.001). There were fewer postoperative complications in RS (P = 0.005). However, complication severity based on Dindo grade was similar between RS and VS, with most surgeries having no complications. CONCLUSIONS: In the elderly women, RS was associated with fewer postoperative complications than VS. Overall, all procedures were associated with few complications, and either route may be reasonable in the elderly population. PMID- 23797529 TI - The role of CYP2C8 genotypes in dose requirement and levels of everolimus after heart transplantation. AB - Everolimus is an immunosuppressive drug metabolized by enzymes of the CYP family. A common variant of the CYP2C8 gene, CYP2C8*3, results in strongly decreased CYP2C8 activity, but its role for the pharmacogenetics of everolimus remains unclear. Aim of the present study was to examine the role of CYP2C8 variants in everolimus dose and drug levels after heart transplantation. The present study comprised 30 patients with everolimus based maintenance therapy after heart transplantation. CYP2C8 genotypes were determined and correlated with clinical data. In all, 21 subjects carried the CYP2C8 *1/*1 genotype and 9 subjects carried the CYP2C8 *1/*3 genotype. Neither everolimus dose nor everolimus levels were associated with CYP2C8 genotype at any point of time (p < 0.05). During follow-up, graft rejection reactions were observed in two patients and infections were observed in seven patients. In one patient, type 2 diabetes was diagnosed during follow-up. None of these adverse events were significantly associated with CYP2C8 genotypes. We conclude that in adult patients after heart transplantation, CYP2C8 genotypes are not associated with dose requirements or levels of everolimus. PMID- 23797531 TI - Incidence and analysis of open fractures of the midshaft and distal femur. AB - BACKGROUND: The purpose of this study was to determine whether different forms of stabilization for open femur fractures can be performed without influencing outcome, in particular infection and delayed unions/nonunions. Although the traditional management of these injuries is external fixation, a trend toward definitive stabilization techniques has evolved in the current literature. METHODS: All open fractures of the femur shaft and the distal femur presenting to our urban Level I trauma center during a 10 year period were reviewed. A total of 40 patients (41 fractures) were initially treated at the above institution within 6 h of injury. All patients underwent emergent wound irrigation, debridement, and antibiothic theraphy. The method of fracture immobilization was left to the discretion of the attending trauma surgent. Study population consited of 12 (29 %) GI, 10 (25 %) GII, and 19 (46 %) GIII fractures. RESULTS: Initially, fracture management was performed with external fixation (EF) 19 (43.2 %), intramedullary nailing (IM) 18 (38.6 %), plating (PL) 3 (6.8 %), screw fixation (SF) 1 (2.3 %) and without treatment 4 (9.1 %). In all, 3 (6.8 %) fractures were complicated by infection, 7 (15.9 %) had implant failure, and 5 (11.4 %) developed delayed union. CONCLUSIONS: Using external fixation in acute fracture treatment for open femur fractures is a safe and effective surgical technique. Based on our results, external fixation might be superior to intramedullary nailing or plating when evaluating outcome parameters and complications. PMID- 23797530 TI - [Periprocedual management of vitamin K antagonist's with low molecular weight heparins during invasive procedures--Consensus of experts]. AB - Interruption of an ongoing therapy with vitamin K antagonists (VKAs) is necessary in almost all patients undergoing major surgery. The purpose of the following expert recommendations is to provide easy to use guidance for the periprocedural management of patients on VKAs based on current evidence from the literature. Management of anticoagulation during the time of interruption of VKAs is based on balancing the thromboembolic (TE) risk of underlying conditions against the bleeding risk of the surgical procedure. VKAs should be stopped 3-7days prior to surgery. Low molecular weight heparin (LMWH) is used to cover ("bridge") the progressive pre-operative loss of anticoagulation and the slow post-operative onset of anticoagulant activity of VKAs. Patients with high risk of TE should receive a therapeutic dose of LMWH, patients with a moderate risk of TE should receive half of this dose. Patients with a low risk of TE do not need bridging therapy with LMWH. In case of an uneventful postoperative course, patients with a therapeutic pre-operative dose should be treated post-operatively with the same dose, starting on day 4 in case of major surgery and on day 2 in case of minor procedures. Patients with a half-therapeutic preoperative dose should be treated post-operatively with the same dose, starting on day 3 in case of major surgery and on day 1 in case of minor procedures. Therapy with VKAs should be re instituted on the second post-operative day based on the preoperative dosage. Procedure-related post-operative thromboprophylaxis should be given irrespective of these recommendations on days without "bridging" anticoagulation. PMID- 23797533 TI - Evaluation of perinatal arterial ischemic stroke using noninvasive arterial spin labeling perfusion MRI. AB - BACKGROUND: Arterial spin labeling (ASL) magnetic resonance imaging (MRI) can evaluate brain perfusion in neonates noninvasively. The aim of this study was to investigate whether ASL MRI can demonstrate perfusion abnormalities in neonates diagnosed with perinatal arterial ischemic stroke (PAIS). METHODS: Pulsed ASL perfusion MR images were acquired in the subacute stage (5-6 d after birth) and at follow-up (13 d to 16 wk after birth) in four PAIS patients. Images were visually evaluated for hypo- and hyperperfusion. In addition, cerebral oxygenation was monitored using near infrared spectroscopy (NIRS). RESULTS: In three PAIS patients, ASL images showed hypoperfusion in the stroke area. In one of these, hyperperfusion was visualized in the periphery of the stroke area. In one PAIS patient, hyperperfusion was seen in the stroke area. In all infants, cerebral oxygenation was higher in the infarcted hemisphere as compared with the contralateral hemisphere. Follow-up ASL images showed partial recovery of perfusion in the stroke area. CONCLUSION: ASL perfusion MRI is able to reliably detect hypo- and hyperperfusion in PAIS patients and can be used to monitor the evolution of perfusion after an ischemic event. PMID- 23797532 TI - Longitudinal trajectory of vitamin D status from birth to early childhood in the development of food sensitization. AB - BACKGROUND: Increasing evidence supports the immunomodulatory effect of vitamin D on allergic diseases. The combined role of prenatal and postnatal vitamin D status in the development of food sensitization (FS) and food allergy remains understudied. METHODS: Plasma 25-hydroxyvitamin D (25(OH)D) levels of 460 children in the Boston Birth Cohort (BBC) were measured at birth and early childhood, and the subjects were genotyped for rs2243250 (C-590T) in the IL4 gene. We defined FS as specific IgE levels of >=0.35 kUA/l to any of eight common food allergens; we defined persistently low vitamin D status as cord blood 25(OH)D <11 ng/ml and postnatal 25(OH)D <30 ng/ml. RESULTS: We observed a moderate correlation between cord blood 25(OH)D at birth and venous blood 25(OH)D measured at 2-3 y (r = 0.63), but a weak correlation at <1 y (r = 0.28). There was no association between low vitamin D status and FS at any single time point alone. However, in combination, persistence of low vitamin D status at birth and in early childhood increased the risk of FS (odds ratio (OR) = 2.03, 95% confidence interval (CI): 1.02-4.04), particularly among children carrying the C allele of rs2243250 (OR = 3.23, 95% CI: 1.37-7.60). CONCLUSION: Prenatal and early postnatal vitamin D levels, along with individual genetic susceptibility, should be considered in assessing the role of vitamin D in the development of FS and food allergy. PMID- 23797534 TI - Novel noninvasive anthropometric measure in preterm and full-term infants: normative values for waist circumference:length ratio at birth. AB - BACKGROUND: Waist circumference:length ratio (WLR) and ponderal index (PI) appear to be useful markers of visceral and total adiposity, respectively. However, there are no normative birth data across the full range of gestational ages. METHODS: In this retrospective cohort study of 500 preterm and 1,426 full-term infants, born in 1998 and 2008 at three military hospitals, the percentile growth curves for WLR and PI were calculated. There were no sex differences, and results were combined to obtain values from 26 to 42 wk gestation. RESULTS: Between 26 and 42 wk gestation, median birth WLR increased from 0.55 to 0.62, and median PI increased from 21.1 to 25.6. The adjusted mean WLR at birth among infants born <34 wk increased from 0.55 in 1998 to 0.58 in 2008 (P = 0.048), suggesting that early-preterm infants born in 2008 had greater abdominal adiposity than those born in 1998. CONCLUSION: We report normative birth data for WLR and PI in preterm and full-term infants by gestational age and sex. WLR and PI may be useful as clinical markers of visceral and overall adiposity. In conjunction with other anthropometric measures, WLR and PI may be useful to monitor postnatal nutrition and growth and assess risk for later obesity and cardiometabolic disorders. PMID- 23797536 TI - Improved luminescence and temperature sensing performance of Ho(3+)-Yb(3+) Zn(2+):Y2O3 phosphor. AB - The codoping effect of Zn(2+) ions on luminescence emission in visible and near infrared (NIR) regions of Y2O3:Ho(3+)-Yb(3+) phosphor prepared by low temperature combustion process have been investigated under 980 nm and 448 nm excitations. The phase and crystallite size of the prepared phosphor were determined by X-ray diffraction analysis and processes involved in the upconversion mechanism have been discussed in detail via pump power dependence, decay curve analysis and a suitable energy level diagram. The temperature sensing performance of the developed material has also been investigated by measuring the fluorescence intensity ratio of the blue upconversion emission bands centred at 465 nm and 491 nm up to 673 K. It is found that by using fluorescence intensity ratio technique, appreciable sensitivity for temperature measurement can be achieved from the present phosphor material, which indicates its applicability as a high temperature sensing probe. The fabrication of green LEDs using the developed phosphor material has also been suggested. PMID- 23797535 TI - Pharmacokinetics and pharmacodynamics of anticoagulants in paediatric patients. AB - Given the rising incidence of thrombotic complications in paediatric patients, understanding of the pharmacologic behaviour of anticoagulant drugs in children has gained importance. Significant developmental differences between children and adults in the haemostatic system and pharmacologic parameters for individual drugs highlight potentially unique aspects of anticoagulant pharmacology in this special and vulnerable population. This review focuses on pharmacologic information relevant to the dosing of unfractionated heparin, low molecular weight heparin, warfarin, bivalirudin, argatroban and fondaparinux in paediatric patients. The bulk of clinical experience with paediatric anticoagulation rests with the first three of these agents, each of which requires higher bodyweight based dosing for the youngest patients, compared with adults, in order to achieve comparable pharmacodynamic effects, likely related to an inverse correlation between age and bodyweight-normalized clearance of these drugs. Whether extrapolation of therapeutic ranges targeted for adult patients prescribed these agents is valid for children, however, is unknown and a high priority for future research. Novel oral anticoagulants, such as dabigatran, rivaroxaban and apixaban, hold promise for future use in paediatrics but require further pharmacologic study in infants, children and adolescents. PMID- 23797537 TI - Tie2-dependent VHL knockdown promotes airway microvascular regeneration and attenuates invasive growth of Aspergillus fumigatus. AB - Microvascular ischemia and infections are associated with the development of chronic rejection following lung transplantation. The von Hippel-Lindau protein (VHL) controls protein levels of hypoxia-inducible factors (HIFs), regulates vascular repair, and improves tissue perfusion. Here, we studied the role of VHL in microvascular repair by orthotopically transplanting tracheas into mice with VHL haplodeficiency in Tie2 lineage cells. We showed that VHL haplodeficiency prolonged airway microvascular perfusion and promoted tissue blood flow through the production of the angiogenic factors, SDF-1 and angiopoietin 1. VHL haplodeficient pulmonary endothelial cells exhibited increased angiogenic activity, resistance to serum deprivation-induced cell death, and enhanced microvascular repair. By contrast, in recipient mice with HIF-1alpha deficiency in Tie2 lineage cells, microvascular repair was significantly diminished and suggested that recipient-derived HIF-1alpha normally participates in the repair of alloimmune-mediated microvascular damage. To evaluate the translational impact of our findings, we compared VHL-haplodeficient mice with wild-type controls using a model of Aspergillus airway infection. In 83% of the VHL-haplodeficient recipients, Aspergillus fumigatus was noninvasive in contrast to 75% of wild-type mice in which the mold was deeply invasive. Our study demonstrated that stabilization of HIF-1alpha in angiogenic cells, through Tie2 cell VHL haplodeficiency, promoted airway microvascular regeneration and vascular normalization and thereby minimized tissue ischemia and hypoxia. By also mitigating the virulence of A. fumigatus, a common pathogen and itself a risk factor for the development of lung transplant rejection, the selective enhancement of HIF-1alpha expression has the prospect of offering several novel therapeutic effects to transplant recipients. PMID- 23797539 TI - Occupational stress and self-rated health among nurses. AB - OBJECTIVE: To analyze the association between job stress and self-rated health among nurses in public hospital emergency units. METHODS: This is a cross sectional study undertaken through the administration of a self-administered questionnaire in a sample of 134 health professionals, using the brief version of the Job Stress Scale. Descriptive analyses of the socio-demographic, health and work variables were undertaken, as was multivariate analysis through unconditional logistic regression for adjustment of the association between job stress and poor self-rated health, in accordance with potential confounding variables, with a level of significance of 5%. RESULTS: 70% of the interviewees were classified as passive workers or as with high strain. Poor self-rated health was significantly greater among health professionals with high demand and low control, compared to those with low strain, after adjusting for co-variables. CONCLUSIONS: Low control, allied with low demand, can serve as a demotivating factor, contributing to the increase in professional dissatisfaction. It is recommended that institutions should adopt a policy of planning and managing human resources so as to encourage the participation of health professionals in decision-making, with a view to reducing job stress among nurses. PMID- 23797538 TI - Electronic library REV@ENF of the Network VHL Nursing International. PMID- 23797540 TI - Associations among occupational roles, independence, assistive technology, and purchasing power of individuals with physical disabilities. AB - OBJECTIVE: to verify whether there are associations among occupational roles, independence to perform Activities of Daily Living, purchasing power, and assistive technology for individuals with physical disabilities. METHOD: 91 individuals with physical disabilities participated in the study. The instruments used were: Role Checklist, Brazilian Economic Classification Criterion, Barthel Index, and a Questionnaire to characterize the subjects. RESULTS: an association with a greater number of roles was found among more independent individuals using a lower number of technological devices. Higher purchasing power was associated with a lower functional status of dependence. CONCLUSION: even though technology was not directly associated with independence, the latter was associated with a greater number of occupational roles, which requires reflection upon independence issues when considering the participation in occupational roles. These findings support interdisciplinary actions designed to promote occupational roles in individuals with physical disabilities. PMID- 23797541 TI - Nursing intervention/activity mapping at a Chemotherapy Center: an instrument for workload assessment. AB - OBJECTIVES: identify the interventions/activities nurses develop at a Chemotherapy Center (CTC) using standardized language and validate their contents. METHOD: data triangulation was used through the combination of three information sources: semistructured interview, document analysis and questionnaire. The instrument, constructed in accordance with the Nursing Interventions Classification (NIC) taxonomy, was submitted to content validation through meetings with the participants. RESULTS: Thirty-five interventions and 48 activities were mapped and validated, organized in five domains (physiological: basic and physiological: complex, behavioral, safety and health system) and 11 classes. CONCLUSION: The identification of nurses' interventions/activities at CTC supports the determination of the time consumed and permits measuring the workload. It also helps to define these professionals' role, which permits the redesign of the work process and optimizes productivity. PMID- 23797542 TI - Nursing care based on risk assessment and classification: agreement between nurses and the institutional protocol. AB - OBJECTIVE: to verify the degree of agreement between the levels of priority given by baccalaureate nurses in care based on risk assessment and classification and the institutional protocol, and also among peers. METHOD: descriptive study, using a questionnaire with thirty fictitious clinical cases based on the institutional protocol, which is considered the gold standard, answered by twenty baccalaureate nurses. RESULTS: the agreement analysis through the Kappa Coefficient concluded that the agreement between baccalaureate nurses and the institutional protocol in relation to prioritizing the levels of severity was moderate. When the agreement among peers was evaluated, it was low, as represented by the colorimetric density in shades of light gray. CONCLUSION: in Brazil, some institutions have developed their own protocol, which makes it necessary to develop tools in order to evaluate the accuracy of professionals in relation to the protocols, highlighting the need for capable people to perform this activity, thus contributing to patient safety. PMID- 23797543 TI - Social and environmental factors associated with the hospitalization of tuberculosis patients. AB - OBJECTIVE: to identify social and environmental factors associated with hospitalization of tuberculosis (TB) patients in Manaus, Amazonas, during 2010. METHODS: this is a quantitative cross-sectional epidemiological study, with primary data collection and analysis of human immunodeficiency virus (HIV), based on seropositive status. RESULTS: Among social factors for TB-HIV co-infection, the association between alcohol use and dependence was significant for employed workers; among non-co-infections, the association between income less than one minimum wage (U.S. $200) and retired people, Bolsa Familia Program [Family Allowance]/other social benefits was significant. Regarding environmental factors, the association was significant for TB-HIV co-infection among those not having their own house, having masonry housing and daily garbage collection; and among non-co-infection, owning their own house, no masonry housing and lack of daily garbage collection was significant. CONCLUSION: The findings indicated that not only social factors, but also environmental ones are associated with hospitalization of tuberculosis patients, and such associations differ according to TB-HIV co-infection. Findings revealed that the non-biological factors associated with hospitalization of tuberculosis patients should be considered when caring patients with this disease. PMID- 23797544 TI - Socio-demographic characteristics and quality of life of elderly patients with systemic arterial hypertension who live in rural areas: the importance of nurses' role. AB - OBJECTIVE: To describe the socio-demographic characteristics and quality of life of elderly patients with systemic arterial hypertension; to correlate the quality of life with the time of diagnosis and number of medication, as well as to compare the quality of life with the type of medication. METHOD: In this cross sectional home survey design, 460 elderly people from rural areas were involved. The data was collected with the use of the following instruments: World Health Organization Quality of Life-bref and World Health Organization Quality of Life Olders. A descriptive analysis, Pearson correlation and t-Student test (p<0.05) were undertaken. RESULTS: Predominant patient characteristics were: women between the age of 60 and 70, married, four to eight years of formal education, income of one minimum wage, living with their partners. The time of diagnosis was associated with lower quality of life in the physical domain. Elderly patients who used Inhibitors and Angiotensin Converting Enzyme and who did not use AT1 blocker had lower scores in relation to functioning of the senses. Those who used calcium channel blocker scored higher in relation to autonomy. CONCLUSION: there is a need for actions to control systemic arterial hypertension and its associated complications, with the purpose of improving quality of life. PMID- 23797545 TI - Nursing diagnoses for the elderly using the International Classification for Nursing Practice and the activities of living model. AB - OBJECTIVE: To develop nursing diagnosis statements for the elderly based on the Activities of Living Model and on the International Classification for Nursing Practice. METHOD: Descriptive and exploratory study, put in practice in two stages: 1) collection of terms and concepts that are considered clinically and culturally relevant for nursing care delivered to the elderly, in order to develop a database of terms and 2) development of nursing diagnosis statements for the elderly in primary health care, based on the guidelines of the International Council of Nurses and on the database of terms for nursing practice involving the elderly. RESULTS: 414 terms were identified and submitted to the content validation process, with the participation of ten nursing experts, which resulted in 263 validated terms. These terms were submitted to cross mapping with the terms of the International Classification for Nursing Practice, resulting in the identification of 115 listed terms and 148 non-listed terms, which constituted the database of terms, from which 127 nursing diagnosis statements were prepared and classified into factors that affect the performance of the elderly's activities of living - 69 into biological factors, 19 into psychological, 31 into sociocultural, five into environmental, and three into political-economic factors. CONCLUSIONS: After clinical validation, these statements can serve as a guide for nursing consultations with elderly patients, without ignoring clinical experience, critical thinking and decision-making. PMID- 23797546 TI - Living with intestinal stoma: the construction of autonomy for care. AB - OBJECTIVE: to investigate the care undertaken in the health services for people with intestinal stoma, from the perspective of articulating the actions proposed in the Amplified and Shared Clinic, with a view to promoting autonomy. METHOD: qualitative study. PARTICIPANTS: 10 people who received a stoma, and their family members. Data was collected between 10th January and 30th June 2011, through two semi-structured interviews. Analysis was through the stages: anxiety, synthesis, theorization and recontextualization. RESULTS: presented in the categories: (1) the need to carry out stoma care; (2) receiving health support and care after discharge from hospital; (3) returning to daily activities and social reinsertion. CONCLUSION: the study identified common factors which influence the process of development of autonomy and the relationship which health professionals have with this achievement. PMID- 23797547 TI - The use of religious/spiritual coping among patients with cancer undergoing chemotherapy treatment. AB - OBJECTIVE: to investigate the use of religious/spiritual coping among people with cancer undergoing chemotherapy. METHODS: a quantitative, descriptive and cross sectional study of 101 patients undergoing intravenous chemotherapy in an oncology outpatients center in a public hospital in Minas Gerais, made in the first semester of 2011. For data collection, an interview was held, using a questionnaire for characterizing the sample and the Brief Spiritual/Religious Coping Scale. RESULTS: all subjects made use of religious/spiritual coping (mean=3.67; sd=0.37); the younger individuals, those with no religion and those who consider spiritual support unimportant tend to use coping negatively; individuals who would like to receive spiritual support and who participate in support groups for cancer patients, on the other hand, use coping positively. CONCLUSIONS: the study reinforces that religious/spiritual coping is an important strategy for coping with cancer, and contributes to an understanding of the same as a useful tool for spiritual care. PMID- 23797548 TI - Evaluation of pre-natal care from the perspective of different models in primary care. AB - OBJECTIVES: to evaluate the quality of the pre-natal care delivered in primary care, comparing the traditional model and the Family Health Strategy. METHOD: a service evaluation study, grounded in the public health policies. The data was obtained from interviews with managers, observation in the health centers, and analysis of patient records of pregnant women, selected at random. Differences in the indicators for structure and process were evaluated using the Chi-squared test, adopting p<0.05 as the critical value, calculation of the odds ratio, and confidence intervals of 95%. RESULTS: Similar structures were evidenced in both models of care. Synthesis indicators for the process created in the present study, and those indicated by the public policies, indicated that the situation is more favorable in Family Health Centers. Regarding the set of activities called for in pre-natal care, the performance was flawed in both models, although it was slightly better in the Family Health Centers. CONCLUSION: the results indicate the need for actions to improve pre-natal care in the two models of primary care evaluated in the municipality. PMID- 23797549 TI - Assessing the care of children under one year old in Primary Health Care. AB - OBJECTIVE: to analyze the presence and extent of Primary Health Care attributes and the strength of affiliation of children under one year old in a Family Health Unit. METHOD: cross-sectional, descriptive study conducted between October 25, 2010 and May 14, 2011 with 44 mothers, using the Primary Care Assessment Tool to collect data. Data were analyzed by calculating the Essential Primary Health Care and General Primary Health Care scores. RESULTS: mothers recognized and experienced aspects of accessibility, comprehensive care and coordination of care, as well as community guidance, marked by a concern and involvement on the part of the health team in the children's care, their families and community. CONCLUSION: The Primary Health Care team makes efforts to approach the community and meet their health needs, seeking instruments that aid the promotion of qualified care to children. PMID- 23797550 TI - Family network of children with special health needs: implications for nursing. AB - OBJECTIVE: to describe appropriate sources and resources for caregivers of children with special health needs in the community. METHOD: A qualitative study that used the creativity and sensitivity dynamics speaking map, part of the sensitive creative method, involving 11 caregivers of children with special health needs who are assisted in a university hospital located in the South of Brazil. RESULTS: the maps graphically represented through the genogram and ecomap showed that the caregiving women consistently and regularly use the resources of the internal and external family network; they eventually and irregularly access the community social network for physical and psychological support. CONCLUSION: the reclusive nature of care for these children inside the family circle contributes to their social invisibility. Based on this new information, it is recommended that Nursing participate in the care that is focused on these children's families, with particular attention to their socio-cultural conditions. PMID- 23797551 TI - Parental role conflict: the nursing diagnosis in mothers of hospitalized newborns. AB - OBJECTIVE: To verify if mothers of newborns hospitalized recognize the defining characteristics of "parental role conflict" as representative of that experience. METHODS: A cross-sectional and descriptive study, developed in a neonatal unit of a public teaching hospital in the state of Sao Paulo. The sample consisted of 100 women who assigned scores of 1 to 5 to the defining characteristics of the diagnosis, where 1 meant "not at all characteristic" and 5 meant "completely characteristic of what I am experiencing." RESULT: Of the total sample, 96 women self-identified with the diagnosis. The most prevalent defining characteristics were: "anxiety," "mother expresses concern(s) in relation to changes in maternal role"; "verbalizes feelings of frustration," "reports concern about family" and "fear". Women who were with their children less often during hospitalization had a higher number of defining characteristics. CONCLUSION: There was a high prevalence of the defining characteristics of the studied diagnosis, suggesting the relevance of the topic and the need for further studies to be developed in the neonatal unit. PMID- 23797552 TI - Institutional shelter to protect adolescent victims of domestic violence: theory or practice? AB - OBJECTIVE: To understand and analyze, from the perspective of adolescent victims of domestic violence who were cared for in an institution in Campinas-SP, the protective factors to which they are submitted and / or have access. METHOD: This was qualitative research, with data collection occurring through focus groups with 17 adolescents, and semistructured interviews with seven of them; the data analysis was based on content analysis, using a thematic modality. RESULTS: Two themes emerged, entitled Four Walls and Trust. We discuss the context of institutional care, that despite the efforts made contemporaneously, still maintains an authoritarian environment; the importance of the bond and trust established with some employees, acting as protective factors for the adolescents and the protective aspect of religiosity. CONCLUSIONS: It is understood that these considerations should be valued and reinforced through the healthcare services provided to children and adolescents, as they contribute to the promotion of the physical and mental health of this population. PMID- 23797553 TI - Health vulnerabilities in adolescence: socioeconomic conditions, social networks, drugs and violence. AB - OBJECTIVE: to analyze the health vulnerabilities in adolescence associated with socioeconomic conditions, social networks, drugs and violence from the perspective of students. METHOD: cross-sectional study with 678 students between 14-15 years old in Contagem, Brazil. A self-administered questionnaire divided into modules by subject was used. Quantitative, descriptive and stratified analyses were performed by sex. RESULTS: high percentage of adolescents (40.4%) were beneficiaries of Government financial support called "Bolsa Familia" and 14.6% had a job, 57.1% and 23.6% had tried alcohol and tobacco, respectively. We identified 15% of aggression and 26.7% of bullying. The majority informed they never/rarely talk to parents about the daily difficulties (64.5%) and 22% reported insomnia and/or feelings of loneliness. CONCLUSION: the results indicated that there is a need to intensify educational activities that seek to develop cognitive, affective and social skills aimed at improving the way adolescents face the vulnerabilities, in these activities, nursing has a fundamental role. PMID- 23797554 TI - Content validation of the Self-perception of Family Health Status scale using the Delphi technique. AB - OBJECTIVE: To ascertain the content validity of the Self-perception of Family Health Status scale. METHOD: A validation study of an instrument with an online Delphi panel using the consensus technique. Eighteen experts in the subject were intentionally selected, with a multidisciplinary origin and representing different professional fields. Each of the proposed items was assessed using a five-point scale, and open-ended questions, to modify or propose items. Descriptive analysis was performed of the sample and the items, applying criteria of validation/elimination. RESULTS: The first round had a response rate of 83.3% and validated 75 of the 96 proposed items; the second had a response rate of 80%, and validated the 21 newly created items, concluding the panel of experts. CONCLUSIONS: We present an instrument to measure self-perception of family health status, from a nursing perspective. This may be an advance in scientific knowledge, to facilitate the assessment of the state of health of the family unit, enabling detection of alterations, and to facilitate interventions to prevent consequences to the family unit and its members. It can be used in clinical care, research or teaching. PMID- 23797555 TI - Validation of the Brazilian version of the Attentional Function Index. AB - OBJECTIVES: To assess the reliability and validity of the Brazilian version of the Attentional Function Index. METHOD: Methodological study. The sample was made up of 138 students from an undergraduate nursing course. The psychometric properties were assessed through the convergent construct validity, using the Brazilian version of the Attentional Function Index and the Portuguese-language version of the Profile of Mood States instrument, while the reliability was measured by its internal consistency, expressed by the Cronbach Alpha Coefficient. RESULTS: The Cronbach Alpha Coefficient was 0.86 for the total score, and varied from 0.64 to 0.86 in the three subscales. A strong significant negative correlation (r=-0.64; p<0.0001) was obtained for the convergent validity. CONCLUSION: The Brazilian version of the Attentional Function Index resulted in satisfactory levels of validity and reliability, demonstrating its viability for use in practice and in undertaking further research. PMID- 23797556 TI - Cultural adaptation and internal consistency analysis of the MISSCARE Survey for use in Brazil. AB - OBJECTIVE: The aims of this methodological research were to culturally adapt the MISSCARE Survey instrument to Brazil and analyze the internal consistency of the adapted version. METHOD: The instrument consists of 41 items, presented in two parts. Part A contains 24 items listing elements of missed nursing care. Part B is comprised of 17 items, related to the reasons for not delivering care. The research received ethics committee approval and was undertaken in two phases. The first was the cultural adaptation process, in which a committee of five experts verified the face and content validity, in compliance with the steps recommended in the literature. The second was aimed at analyzing the internal consistency of the instrument, involving 60 nursing team professionals at a public teaching hospital. RESULTS: According to the experts, the instrument demonstrated face and content validity. Cronbach's alpha coefficients for parts A and B surpassed 0.70 and were considered appropriate. CONCLUSION: The adapted version of the MISSCARE Survey demonstrated satisfactory face validity and internal consistency for the study sample. PMID- 23797557 TI - Effectiveness of disinfection with alcohol 70% (w/v) of contaminated surfaces not previously cleaned. AB - OBJECTIVE: To evaluate the disinfectant effectiveness of alcohol 70% (w/v) using friction, without previous cleaning, on work surfaces, as a concurrent disinfecting procedure in Health Services. METHOD: An experimental, randomized and single-blinded laboratory study was undertaken. The samples were enamelled surfaces, intentionally contaminated with Serratia marcescens microorganisms ATCC 14756 106 CFU/mL with 10% of human saliva added, and were submitted to the procedure of disinfection WITHOUT previous cleaning. The results were compared to disinfection preceded by cleaning. RESULTS: There was a reduction of six logarithms of the initial microbial population, equal in the groups WITH and WITHOUT previous cleaning (p=0.440) and a residual microbial load <= 102 CFU. CONCLUSION: The research demonstrated the acceptability of the practice evaluated, bringing an important response to the area of health, in particular to Nursing, which most undertakes procedures of concurrent cleaning /disinfecting of these work surfaces. PMID- 23797558 TI - Bipolar disorder and medication: adherence, patients' knowledge and serum monitoring of lithium carbonate. AB - OBJECTIVES: this study featured patients with affective bipolar disorder who were making use of lithium and received care at an outpatient care center located in a country town in the state of Sao Paulo in 2009; it assessed the adherence and knowledge of these patients in relation to the medication prescribed to them and verified the proportion of blood tests performed per year in the service, for each individual, to measure lithium levels in the blood. METHOD: descriptive study with quantitative approach, involving 36 participants. Structured interviews and review of medical records were used for data collection and descriptive statistics for data analysis. RESULTS: difficulties in reporting the dosage of the medication prescribed and a high rate of non-adherence were identified among the participants. None of the participants in the study was submitted to two tests a year to measure lithium levels in the blood, which is the minimum proportion of tests recommended by the literature for maintenance treatment using lithium carbonate. CONCLUSION: this study highlights the critical factors for the promotion of patients' safety in monitoring lithium drug therapy. PMID- 23797559 TI - The use of music in group educational activities in Family Health. AB - OBJECTIVE: describe how music is used in the development of group educational activity in Family Health. METHODS: a qualitative, descriptive and exploratory study, developed with 10 group coordinators, distributed in five basic care units in Belo Horizonte, Minas Gerais, Brazil. Data were collected from March to July, 2009, with non participant observation in the group itself, and semi-structured interviews with the coordinators. Information was organized and categorized according to thematic analysis. To interpret the data, the Snyderian concepts in addition to theoretical references about music, communication and health education were used. RESULTS: three thematic nuclei were found: the affective dimension of music; recreative dimension of music and the reflexive dimension of music. CONCLUSION: an attempt by the coordinators was observed, to overcome the pathological barriers with the use of music, considering the group as a whole. As advancement for the production of knowledge, this study shows the need for qualification of these coordinators, by means of workshops and constant follow-up of their musical practices. PMID- 23797560 TI - English in the nursing degree: a pending subject. AB - OBJECTIVE: The new competence profile of nursing professionals, scientific and medical development, the free circulation of health professionals worldwide, and the increasing social and cultural diversity requires that nurses have specific abilities in spoken and written English. The objective of this research is to describe the characteristics of the English language training required for a Bachelors of Nursing in Spain. METHOD: A descriptive cross-sectional observational study has been performed in forty-six Spanish universities that offer the Bachelor in nursing degree. RESULTS: In line with the directives of the European Higher Education Area, all universities contemplate the mandatory credit of a second language emphasizing English, although there is considerable variability in the emphasis: 39.4% do not include any English subject, and of the remaining 60.6% who do include it, 60% considered it an elective subject, 32.5% basic education, and 7.5% mandatory. CONCLUSIONS: The English training has different characteristics in each university, which implies a different commitment from each center for this learning. This fact questions the adequacy of the education in relation to the new competence profile required by the European Higher Education Area, which may adversely affect future professional development. PMID- 23797561 TI - Predictive markers of response to isotretinoin in female acne. AB - BACKGROUND: Acne vulgaris is a common and chronic disorder of the pilosebaceous unit. Female acne may be a subtype differing from teenager acne. Isotretinoin is the only therapy impacting on all the major acne-related aetiological factors. All clinical studies demonstrating isotretinoin efficacy in acne patients have been performed either in teenagers or in a mixed population of teenagers and adults. OBJECTIVE: To evaluate isotretinoin efficiency and tolerance in a cohort of females with acne, aged 20+ years. METHODS: Study of 32 women prescribed isotretinoin according to the European recommendations (0.5 mg/kg) in two dermatology departments (France and Greece). The ECLA scale and a global evaluation using the GEA grading were used to evaluate isotretinoin efficacy. The correlation between the clinical response and the different epidemiological factors was determined. RESULTS: Complete response reached 59% on the face, 78% on the trunk and 43% on both the face and trunk. A significant correlation was observed between the facial response and body mass index (p = 0.02), the high glycemic-load diet (p = 0.0009), tobacco (p = 0.05) and age at acne onset (p = 0.05). CONCLUSION: Isotretinoin at 0.5mg/kg is effective and well tolerated in mild-to-moderate acne in females over 20 years old and results were similar to those of teenagers and men. We can propose positive predictive markers of response to isotretinoin in female acne, including a low body mass index, low glycemic-load diet, no tobacco, absence of early acne onset and of lesions on the neck. PMID- 23797562 TI - Electric in-plane polarization in multiferroic CoFe2O4/BaTiO3 nanocomposite tuned by magnetic fields. AB - Ferrimagnetic CoFe2O4 nanopillars embedded in a ferroelectric BaTiO3 matrix are an example for a two-phase magnetoelectrically coupled system. They operate at room temperature and are free of any resource-critical rare-earth element, which makes them interesting for potential applications. Prior studies succeeded in showing strain-mediated coupling between the two subsystems. In particular, the electric properties can be tuned by magnetic fields and the magnetic properties by electric fields. Here we take the analysis of the coupling to a new level utilizing soft X-ray absorption spectroscopy and its associated linear dichroism. We demonstrate that an in-plane magnetic field breaks the tetragonal symmetry of the (1,3)-type CoFe2O4/BaTiO3 structures and discuss it in terms of off-diagonal magnetostrictive-piezoelectric coupling. This coupling creates staggered in-plane components of the electric polarization, which are stable even at magnetic remanence due to hysteretic behaviour of structural changes in the BaTiO3 matrix. The competing mechanisms of clamping and relaxation effects are discussed in detail. PMID- 23797563 TI - Mesenchymal stem cell differentiation on electrochemically modified titanium: an optimized approach for biomedical ?applications. AB - PURPOSE: To speed up the osteointegration process, surface-treated titanium has been widely used in dental and orthopedic applications. The present work describes a new silicon-based anodic spark deposition (ASD) treatment and investigates the properties of the surfaces obtained, focusing on their capability to modulate the osteogenic differentiation potential of adult mesenchymal stem cells (MSCs). METHODS: The surfaces examined were obtained from commercially pure grade 2 titanium by a single-step ASD (SUM) eventually followed by a thermal treatment in alkali solution (SUMNa), while acid-etched titanium (AE; NextMaterials s.r.l.) was selected as a control. Their morphology, elemental composition, crystallographic structure of the Ti2O layer, wettability and topography were evaluated by scanning electron microscopy, energy-dispersive X ray spectroscopy, thin-film X-ray diffraction, contact angle measurements and laser profilometry, respectively. MSCs' response to surface properties was assessed by examining cell morphology and viability by scanning electron microscopy and Alamar Blue assay(r), while their osteogenic differentiation potential was investigated by evaluating the levels of the enzyme alkaline phosphatase (ALP) and the degree of calcium accumulation by Alizarin Red-S (AR-S) staining. RESULTS: The proposed ASD treatment has allowed the obtaining of surfaces with round-shaped micrometric pores, enriched in calcium, phosphorus and silicon and significantly more wettable than controls; furthermore, the treatment has been shown to promote MSC proliferation and the degree of in vitro mineralization. CONCLUSIONS: The described ASD treatment may be an effective technique to modify the surface cues of titanium implants, aiming at enhancing the conveying of osteoprogenitor cells and their functional differentiation in bone cells. PMID- 23797564 TI - The development and validation of the Family Reported Outcome Measure (FROM 16)(c) to assess the impact of disease on the partner or family member. AB - PURPOSE: The impact of patients' illness on family members has proven to be both widespread and severe. Currently, there is no generic instrument that can be used to measure the impact of illnesses on the partner or family members of patients. This study describes the development of the Family Reported Outcome Measure (FROM 16)(c). METHODS: A total of 30 items were generated from the content of previous interviews with family members. Qualitative and quantitative feedback from expert panels was collected. Items were reduced using both Rasch analysis and factor analysis, and full psychometric testing was carried out including construct validity and reliability. RESULTS: Collapsing response categories, removing misfitting items and combining residually correlating items produced a good fit to the Rasch model (n = 240, total chi2 = 56.6, df = 48, p = 0.18). Factor analysis produced a 16-item measure with two factors. The FROM showed high internal consistency (n = 120, Cronbach's alpha = 0.80-0.89), high reproducibility (n = 51, intraclass correlation = 0.85-0.92) and a mean completion time of 2 min. Construct validity was proven through the correlation between the FROM and the WHOQOL-BREF total scores (n = 119, r = -0.53-0.52, p < 0.001), and the correlation between the FROM and the patient's overall health score (n = 120, r = -0.45-0.48, p < 0.001). CONCLUSION: The FROM-16 is both reliable and valid for use. It has a potential for wide use, including clinical (healthcare professionals or researchers in all medical specialties), industrial and social sciences. The FROM can be used to identify areas where family members need further support, as well as identify those individuals most affected by the patient's illness. PMID- 23797565 TI - Individual and community-level socioeconomic position and its association with adolescents experience of childhood sexual abuse: a multilevel analysis of six countries in Sub-Saharan Africa. AB - BACKGROUND: Childhood sexual abuse (CSA) is a substantial global health and human rights problem and consequently a growing concern in sub-Saharan Africa. We examined the association between individual and community-level socioeconomic status (SES) and the likelihood of reporting CSA. METHODS: We applied multiple multilevel logistic regression analysis on Demographic and Health Survey data for 6,351 female adolescents between the ages of 15 and 18 years from six countries in sub-Saharan Africa, between 2006 and 2008. RESULTS: About 70% of the reported cases of CSA were between 14 and 17 years. Zambia had the highest proportion of reported cases of CSA (5.8%). At the individual and community level, we found that there was no association between CSA and socioeconomic position. This study provides evidence that the likelihood of reporting CSA cut across all individual SES as well as all community socioeconomic strata. CONCLUSIONS: We found no evidence of socioeconomic differentials in adolescents' experience of CSA, suggesting that adolescents from the six countries studied experienced CSA regardless of their individual- and community-level socioeconomic position. However, we found some evidence of geographical clustering, adolescents in the same community are subject to common contextual influences. Further studies are needed to explore possible effects of countries' political, social, economic, legal, and cultural impact on childhood sexual abuse. PMID- 23797567 TI - The diagnostic value of monoclonal gastric cancer 7 antigen: a systematic review with meta-analysis. AB - The aim of this study is to explore the clinical characteristic and the diagnostic role of MG7-Ag in detecting gastric cancer (GC) through a systematic review and meta-analysis. Relevant manuscripts aiming at the application of serum MG7-Ag level in GC diagnosis were searched in PubMed, Embase, Chinese National Knowledge Infrastructure, VIP, and Wan Fang Data independently,which were published between January 1, 1980 and February 28, 2013. The pooled sensitivity, specificity,positive diagnostic likelihood ratio (DLR+), negative diagnostic likelihood ratio (DLR-), diagnostic odds ratio,and the area under the summary receiver operating characteristic(AUC) were used to evaluate the value of serum MG7-Ag in diagnosis of GC by using the Meta-DiSc and STATA 11.0 statistical software. 410 manuscripts were retrieved, and 7 manuscripts of high quality including 652 patients were of high quality in this meta-analysis. Overall,the pooled sensitivity, specificity, DLR+, DLR-, and AUC were 0.73 (95 % CI 0.63 0.82), 0.91 (95 % CI 0.84-0.94), 8.59 (95 % CI 5.62-13.11), 0.29 (95 % CI 0.21 0.42), and 0.92 (95 % CI 0.89-0.94), respectively. MG7-Ag is a potential biomarker for the diagnosis of GC.However, more studies are needed to confirm the standard criteria. PMID- 23797568 TI - Early low-frequency stimulation of the pudendal nerve can inhibit detrusor overactivity and delay progress of bladder fibrosis in dogs with spinal cord injuries. AB - OBJECTIVES: To determine the inhibitory effects of pudendal nerve stimulation (5 Hz) on bladder overactivity at the early stage of spinal cord injury (SCI) in dogs, and to explore the possible effects on delayed progression of bladder fibrosis after SCI. METHODS: The study was performed using six dogs with spinal cord transection at the T9-T10 level. Group 1 (three dogs) under went low frequency electrical stimulation of the pudendal nerve 1 day after spinal cord transection. Group 2 (three dogs) underwent only spinal cord transection. All dogs underwent urodynamic examination at 1 and 3 months after SCI. The bladders were removed for histological examination of fibrosis at 3 months after SCI. RESULTS: Bladder capacity and compliance were significantly increased (P<0.05) by pudendal nerve stimulation in group 1 when compared with group 2 at 1 and 3 months after SCI. Non-voiding contractions (NVCs) were inhibited in group 1 compared with group 2. Collagen fibers were significantly increased and elastic fibers were significantly decreased (P<0.05) in group 2 when compared with group 1. CONCLUSION: Early low-frequency pudendal nerve stimulation can inhibit detrusor overactivity (DO), increase bladder capacity and delay the progression of bladder fibrosis. PMID- 23797569 TI - Response to 'Onabotulinum toxin injection in neurogenic detrusor overactivity: intradetrusor versus suburothelial'. PMID- 23797571 TI - Syncope-Discussion. PMID- 23797570 TI - The effect of long-term oral tadalafil treatment on corpus cavernosum function in an experimental spinal cord transection rat model. AB - OBJECTIVES: The aim of this study was to investigate the pharmacological effects of long-term oral tadalafil treatment on the corpus cavernosum function in rats subjected to experimental spinal cord transection (SCT). METHODS: Thirty young adult, male Sprague-Dawley rats were randomly divided into five groups (n1/4 6, each), as follows: (1) Control,(2) Control surgery (Sham), (3) Tadalafil (Td), (4) Experimental SCT, and (5) SCT + Tadalafil (SCT + Td). SCT rat model: after removal of T8-T9 spinal processes and laminates, a full-thickness scalpel incision was made in the spinal cord. SCT + Td rat model:rats subjected to SCT were given tadalafil (5mg kg(-1), p.o.) for 4 weeks. Next, the penile cavernous tissues obtained by en blocexcision were trimmed free of the surrounding tissue to isolate cavernosal smooth muscle strips, which were then transferred into the isolated organ baths to investigate isometric tension changes in response to various bioactive agents and electrical field stimulation (EFS). RESULTS: The relaxation response to acetylcholine at 0.01 mM concentration was significantly less in the SCT group compared with other groups. EFS-induced relaxation in the basal and precontracted cavernous tissue preparations was greater in the SCT + Td group than in the SCT group. CONCLUSION: This study demonstrated that long-term tadalafil administration preserves relaxation responses probably by affecting through the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway in SCT-applied rats. This treatment strategy might preserve the erectile process and prevent the SCT-induced permanent damage in the cavernosal tissue. PMID- 23797572 TI - Inherent difficulties of measuring the burden of surgical disease in resource poor settings: reply. PMID- 23797573 TI - Synthesis and structural determination of zinc complexes based on an anilido aldimine ligand containing an O-donor pendant arm: zinc alkoxide derivative as an efficient initiator for ring-opening polymerization of cyclic esters. AB - Zinc complexes bearing the anilido-aldiminate AA(OMe) ligand (AA(OMe)-H = (E)-2,6 diisopropyl-N-(2-(((2-methoxyethyl)imino)methyl)phenyl)aniline) were synthesized in a stepwise method and were structurally characterized. The reaction of AA(OMe) H (1) with one equivalent of diethyl zinc (ZnEt2) furnishes a three-coordinated and mononuclear zinc complex [(AA(OMe))ZnEt] (2). Further reaction of 2 with a stoichiometric amount of benzyl alcohol (BnOH) affords a four-coordinated and dinuclear zinc benzylalkoxide complex [(AA(OMe))Zn(MU-OBn)]2 (3). In the presence of two equivalents of AA(OMe)-H with ZnEt2, a homoleptic and four-coordinated zinc complex [(AA(OMe))2Zn] (4) is formed. The geometry around the zinc centres of 3 and 4 are both distorted tetrahedrals, while 2 adopts a different coordination mode with a slightly distorted trigonal planar geometry. The variable-temperature (1)H NMR studies of 3 illustrate that 3 exhibits a dinuclear structure in solution at low temperature as well as in the solid state. While raising the temperature, it drifts towards dissociation to form a mononuclear zinc benzylalkoxide species, which coexists in solution. The ring-opening polymerizations of epsilon-caprolactone (epsilon-CL) and beta-butyrolactone (beta BL) catalyzed by complexes 3 and 4 are investigated. The epsilon-CL and beta-BL polymerizations initiated by zinc alkoxide 3 were demonstrated to have living characteristics and to proceed in a controlled manner with narrow polydispersity indices (PDIs < 1.12). An efficient catalytic performance for the beta-BL polymerization with a high monomer-to-initiator ratio (1200/1) initiated by 3 has also been reported. PMID- 23797574 TI - Retroportal proper hepatic artery with malrotated gut. AB - he celiac trunk is the artery supplying the upper abdominal organs, mainly the lower part of esophagus, stomach, parts of duodenum, liver, gallbladder, spleen and pancreas. It normally trifurcates into the left gastric artery (LGA), the common hepatic artery (CHA) and the splenic artery (SA) at the superior border of the pancreas. This 'normal variant' of the vessel has been observed in 89.8 % cadaveric dissections in the Japanese population by Chen et al. (2009). Prakash et al. (2012) reported a normally trifurcating celiac trunk in 86 % of the south Indian population. The CHA branches from the celiac trunk, forms the gastroduodenal artery (GDA) and a proper hepatic artery (PHA), which further divides distally into right and left hepatic arteries. This normal origin and branching of CHA has been observed in 52-80 % of individuals (Michels 1966; Nelson et al. 1988; Hiatt et al. 1994; Koops et al. 2004; Chen et al. 2009). In a large series of 604 selective celiac and superior mesenteric angiographies, aberrant or anomalous vasculature was reported in 20.9 % of individuals by Koops et al. (2004). This knowledge and recognition of anomalous/aberrant or accessory vasculature in the upper abdomen, occurring in about one-fifth of the population is of vital importance to the hepatico-biliary-pancreatic surgeon to avoid iatrogenic injuries and complications, as well as to the interventional radiologist performing trans-arterial chemo-ablative procedures. PMID- 23797575 TI - Humoral and cellular immunity in chromium picolinate-supplemented lambs. AB - The effects of oral supplementation of chromium picolinate (CrPic) on humoral and cellular immunity in sheep were investigated. Twenty-four male lambs divided into four treatments and received different dosages of CrPic: placebo (0), 0.250, 0.375, and 0.500 mg of chromium/animal/day during 84 days. The base ration was Panicum maximum cv Massai hay and concentrate. Blood samples were collected fortnightly for total and differential leukocyte counts. On days 28 and 56, the lambs were challenged with chicken ovalbumin I.M. Serum samples were collected on days 46 and 74 and subjected to an indirect enzyme-linked immunosorbent assay to measure IgG anti-ovalbumin. The cell-mediated immune response was determined by a delay-type hypersensitivity test using phytohemagglutinin. CrPic did not significantly affect humoral immunity in lambs but there was a negative effect on cellular immunity (P < 0.05) as Cr supplementation increased. Therefore, the level of Cr supplementation for lambs must be better studied to address its effect on stressed animals or the possible toxic effects of Cr on the animal itself or its immune system. PMID- 23797576 TI - Biomonitoring with honeybees of heavy metals and pesticides in nature reserves of the Marche Region (Italy). AB - The aim of this study was to carry out biomonitoring with honeybees (Apis mellifera L.) to assess the presence of pesticides and heavy metals (cadmium, chromium, nickel, lead) in all of the ten nature reserves of the Marche Region (central-eastern Italy). The study was carried out during the spring and summer seasons when the honeybees were active, over 3 years (2008-2010). Twenty-two colonies of honeybees bred in hives were used. Samples of live and dead honeybees and of honey were collected from 11 sampling stations from May to October in each year. No pesticide pollution was found. Significant differences in heavy metal concentrations were found among years, months and sites, and in particular situations. The analysis reveals that high heavy-metal concentrations occurred exclusively in live honeybees. For the seasonal averages, the most detected heavy metal was chromium, which exceeded the threshold more often than for the other elements, followed by cadmium and lead; nickel never exceeded the threshold. The data are discussed with an evaluation of the natural and anthropic sources taken from the literature and from local situations that were likely to involve heavy metal pollution. PMID- 23797578 TI - Improving the stability of anticancer drugs. PMID- 23797590 TI - The effects of antioxidants on gene expression following gamma-radiation (GR) and proton radiation (PR) in mice in vivo. AB - Ionizing radiation (IR) generates free radicals that interact randomly with a range of intracellular biomolecules that can result in lethal cellular injury. Therefore, IR-inflicted damage is a highly complex interplay of vastly different pathophysiological processes, including inflammation, epithelial regeneration, tissue remodeling, and fibrosis. The development of safe and effective radioprotectors that protect normal tissues following IR exposure is highly desirable. It was previously shown that dietary supplementation with an antioxidant (AOX) diet containing SeM (0.06 MUg/g diet), alpha-lipoic acid (85.7 MUg/g diet), NAC (171.4 MUg/g diet), sodium ascorbate (142.8 MUg/g diet), and vitamin E succinate (71.4MUg/ g diet) was an effective countermeasure to lethality in mice following gamma-radiation (GR) and proton radiation (PR). ( 1) (,) ( 2) Here we are examining the effect of the AOX diet on global gene expression following RBE-weighted doses of GR (7.0 Gy) and PR (6.4 Gy) in an attempt to gain further insight into the molecular mechanism of action of AOX diet in the context of radiation exposure. The AOX diet altered the expression pattern of several pro- and anti-apoptotic genes. Our data suggest that the AOX diet may alter IL6 signaling following GR and completely block the expression of the prokineticin PROK2, the ligand to the G protein-coupled receptors PROKR1 and PROKR2, which are involved in a number of pathophysiological processes. PMID- 23797596 TI - [Spanish job-exposure matrix: MatEmESp]. PMID- 23797597 TI - [Documenting occupation in the medical chart of a public hospital system: 2006 2010]. AB - OBJECTIVE: To describe the frequency of recording of a patient's occupation and/or employment status in the medical charts of a Barcelona hospital system by age, sex, department and type of medical record. METHODS: We reviewed the medical records of a random sample of 495 patients age 18 years and older, admitted between 2006 and 2010 in nine hospital departments (dermatology, pulmonary diseases, ophthalmology, oncology, otolaryngology, radiation therapy, rehabilitation, traumatology and urology). For each department and each year, 11 hard copy and 11 different electronic records were reviewed. In all cases we collected information on recording of occupation and/or employment status, age, sex and recording year. RESULTS: 57% of reviewed records were from male patients, 40% of the charts were hard copy and 60% were electronic. Overall, information on the patient's occupation and/or employment status was found in 32% of cases, more often for male patients and in the hard copy records. The rehabilitation department exhibited the highest completion rate (47%), whereas the ophthalmology department exhibited the lowest (16%). CONCLUSION: Information on a hospitalized patient's occupation and/or employment status is low, being present in less than one-third of cases, which is consistent with previous studies conducted in Spain and elsewhere. Specific initiatives are needed to improve this important shortcoming. PMID- 23797577 TI - A systematic review of health-related quality of life instruments in patients with cancer cachexia. AB - PURPOSE: Assessing the health-related quality of life (HRQOL) of cancer patients with cachexia is particularly important because treatments for cachexia are currently aimed at palliation and treatment efficacy must be measured in ways other than survival. The aim of this systematic review was to evaluate HRQOL assessment in cancer patients with cachexia. METHODS: Using guidance from the Centre for Reviews and Dissemination, relevant databases were searched from January 1980 to January 2012 with terms relating to cancer, cachexia and HRQOL for papers including adult cancer patients with cachexia or documented weight loss at baseline. RESULTS: We found one cachexia-specific instrument, the Functional Assessment of Anorexia/Cachexia Therapy, but the tool has not been fully validated, does not cover all the relevant domains and the consensus-based standards for the selection of health status measurement instruments checklist highlighted a number of weaknesses in the methodological quality of the validation study. Sixty-seven studies assessed HRQOL in cachectic or weight losing cancer patients. Most used generic cancer HRQOL instruments, limiting the amount of useful information they provide. A modified version of the Efficace minimum data checklist demonstrated that the quality of reporting on HRQOL tool use was inadequate in many of the studies. A negative relationship between HRQOL and weight loss was found in 23 of the 27 studies which directly examined this. CONCLUSION: There is a pressing need for a well-designed HRQOL tool for use with this patient group in both clinical trials and clinical practice. PMID- 23797598 TI - [Gender differences in the relationship between long working hours and health status in Catalonia]. AB - OBJECTIVES: To analyze gender differences in the relationship of long working hours with type of contract, psychosocial risk factors and health status in Catalonia. METHODS: Cross sectional study of a representative sample of the working population in Catalonia who worked up to 60 hours per week, interviewed in the 2005 I Survey of Working Conditions in Catalonia (1624 men and 1221 women). The analysis was conducted separately by sex and multivariate logistic regression models were fitted. The reference category was employees working 30-40 hours per week. RESULTS: In both sexes, working 41 to 60 hours per week was associated with non fixed term temporary contracts, low autonomy, low support from colleagues and high skill discretion. In addition, among women, they were also associated with high psychological demands. No relationship with self perceived health status was observed, but working 41 to 60 hours a week was associated with job dissatisfaction in both sexes (crude odds ratio, 95% confidence intervals: cOR=1.52; 95%CI 1.05 to 2.18 for men; cOR=2.53; 95% CI 1.44 to 4.45 for women) and in women also with nervous disorders/depression (cOR=3.41; 95%CI 1.42 to 8.22). After adjustment for psychosocial risk factors, these associations disappeared among men but not in women. CONCLUSIONS: Long working hours are associated with non-fixed term temporary contracts and more psychosocial hazards, as well as with some health indicators, primarily among women. It is likely that the association with health status in women is partially explained by the sum of hours of paid and domestic and family work. PMID- 23797599 TI - [Measurement of muscular activity by surface electromyography during use of an emergency evacuation chair]. AB - OBJECTIVE: To compare the different techniques used by paramedics in handling an emergency evacuation chair and to identify themore ergonomically favourable technique, based on an analysis ofmuscular activity using surface electromyography. METHODS: The trial was based on descending stairs, through four possible arrangements for the same transport operation, where the study variables were: worker anthropometrics (5th and 95th percentiles, corresponding to the extremes of the normal height-weight distribution curve), worker location during chair transport (upper or lower end of the chair), and the position of the individual at the lower end (facing front or backwards during descent). RESULTS: For both workers participating in the study, the more favourable working position during chair descent was at the lower end of the chairwhile facing forward, as this was associated with less muscular activity. In general, physical demands on the various muscles studied was greater for the worker corresponding to the 5th percentile (i.e., lower height-weight), except for the paravertebral musculature which, for certain maneuvers involving manipulation was significantly greater than the 95th percentile. CONCLUSIONS: When descending stairs while transporting an emergency evacuation chair, the position involving least muscular activity is located at the lower end of the chair, and descending while facing forwards. PMID- 23797600 TI - Identification of qRBS1, a QTL involved in resistance to bacterial seedling rot in rice. AB - Bacterial seedling rot (BSR), a destructive disease of rice (Oryza sativa L.), is caused by the bacterial pathogen Burkholderia glumae. To identify QTLs for resistance to BSR, we conducted a QTL analysis using chromosome segment substitution lines (CSSLs) derived from a cross between Nona Bokra (resistant) and Koshihikari (susceptible). Comparison of the levels of BSR in the CSSLs and their recurrent parent, Koshihikari, revealed that a region on chromosome 10 was associated with resistance. Further genetic analyses using an F5 population derived from a cross between a resistant CSSL and Koshihikari confirmed that a QTL for BSR resistance was located on the short arm of chromosome 10. The Nona Bokra allele was associated with resistance to BSR. Substitution mapping in the Koshihikari genetic background demonstrated that the QTL, here designated as qRBS1 (quantitative trait locus for RESISTANCE TO BACTERIAL SEEDLING ROT 1), was located in a 393-kb interval (based on the Nipponbare reference genome sequence) defined by simple sequence repeat markers RM24930 and RM24944. PMID- 23797601 TI - Purification of contaminated paddy fields by clean water irrigation over two decades. AB - Paddy fields near a mining site in north part of Guangdong Province, PR China, were severely contaminated by heavy metals as a result of wastewater irrigation from the tailing pond. The following clean water irrigation for 2 decades produced marked rinsing effect, especially on Pb and Zn. Paddy fields continuously irrigated with wastewater ever since mining started (50 years) had 1,050.0 mg kg-1 of Pb and 810.3 mg kg-1 of Zn for upper 20 cm soil, in comparison with 215.9 mg kg-1 of Pb and 525.4 mg kg-1 of Zn, respectively, with clean water irrigation for 20 years. Rinsing effect mainly occurred to a depth of upper 40 cm, of which the soil contained highest metals. Copper and Cd in the farmlands were also reduced due to clean water irrigation. Higher availability of Pb might partly account for more Pb transferred from the tailing pond to the farmland and also more Pb removal from the farmland as a result of clean water irrigation. Neither rice in the paddy field nor dense weeds in the uncultivated field largely took up the metals. However, they might contribute to activate metals differently, leading to a different purification extent. Rotation of rice and weed reduced metal retention in the farmland soil, in comparison with sole rice growth. Harvesting of rice grain (and partially rice stalk) only contributed small fraction of total amount of removed metal. In summary, heavy metal in paddy field resulting from irrigation of mining wastewater could be largely removed by clean water irrigation for sufficient time. PMID- 23797603 TI - The Additional Value of an E-Mail to Inform Healthcare Professionals of a Drug Safety Issue: A Randomized Controlled Trial in the Netherlands. AB - BACKGROUND: The usefulness and the impact of Direct Healthcare Professional Communications (DHPCs, or 'Dear Doctor letters') in changing the clinical behaviour of physicians have been debated. Changes in the current risk communication methods should preferably be based on the preferences of the healthcare professionals, to optimize the uptake of the message. OBJECTIVE: The aim of this study was to assess whether safety issues are communicated more effectively with an additional e-mail sent by the Dutch Medicines Evaluation Board (MEB) than with the DHPC only. METHODS: A randomized controlled trial was conducted amongst ophthalmologists and hospital pharmacists in the Netherlands, who were the target group of a DHPC that was issued for pegaptanib, a drug that is administered intra-ocularly in patients with macular degeneration. The intervention group (N = 110) received the pegaptanib DHPC, as well as the MEB e mail. The control group (N = 105) received the traditional paper-based DHPC only. Two weeks later, the study population received an invitation to fill out an online questionnaire. Questions were asked about the respondents' knowledge and attitude regarding the pegaptanib issue, and any action they had consequently taken. Additional questions were asked about their satisfaction with the DHPC and the e-mail, and their preferred source of such information. RESULTS: Forty respondents (18.6%) completed the questionnaire. Eighty-one percent of the respondents in the intervention group (N = 21) and 47% of the control group (N = 19) correctly indicated that a serious increase in intra-ocular pressure could be caused by pegaptanib injections (Fishers' exact test, p = 0.046). Nine respondents in the intervention group versus none of the control group respondents indicated that they had taken action in response to the pegaptanib safety issue (Fishers' exact test, p = 0.01). The majority of both the intervention group and the control group confirmed that they would like to receive an MEB e-mail with safety information about drugs in the future (90 and 95 %, respectively). CONCLUSION: The results of this study indicate that an additional e-mail might strengthen the uptake of the safety information provided to healthcare professionals, who prefer to receive an e-mail from the MEB as a source of such information, as well as the DHPC. This study may serve as a starting point for new strategies to improve risk communication regarding safety issues associated with drugs and its impact on prescribing. PMID- 23797604 TI - Risk of bladder cancer in diabetic patients treated with rosiglitazone or pioglitazone: a nested case-control study. AB - BACKGROUND: Evidence has emerged that pioglitazone may increase the risk of bladder cancer, but the association has not been confirmed. This potential risk also has not been evaluated in users of rosiglitazone. OBJECTIVE: Using Taiwan's National Health Insurance Research Database (NHIRD), this large population-based nested case-control study was conducted to explore the relationship between the use of rosiglitazone or pioglitazone and risk of bladder cancer in diabetic patients. METHODS: We identified 3,412 cases of newly diagnosed bladder cancer and 17,060 controls (1:5 matched by age and sex) among a diabetic patient cohort from the NHIRD.We defined an index date for each case as the date of first hospitalization for bladder cancer. Each control was assigned the index date of their corresponding case. Multivariable conditional logistic regressions were used to estimate the association between exposure (timing and duration) to rosiglitazone or pioglitazone and bladder cancer. We defined rosiglitazone or pioglitazone exposure as ''current'' if the prescription duration covered the index date or ended at 90 days before, as ''recent'' if it ended 91-180 days before the index date, or as ''past'' if the last prescription ended more than 180 days before. Duration of rosiglitazone or pioglitazone use was defined based on the cumulative days of exposure prior to the index date: < 1, 1-2 and >= 2 years. RESULTS: Rosiglitazone and pioglitazone use were associated with risk of bladder cancer and the associations were stronger with a longer term of exposure (pioglitazone < 1 year odds ratio [OR] 1.45 [95 % CI 1.12-1.87, p < 0.01], 1-2 years OR 1.74 [95 % CI 1.05-2.90, p = 0.03] and >= 2 years OR 2.93 [95 % CI 1.59 5.38, p < 0.01]; rosiglitazone < 1 year OR 0.98 [95 % CI0.82-1.17, p = 0.81], 1-2 years OR 1.78 [95 % CI 1.31-2.39, < 0.01] and >= 2 years OR 2.00 [95 % CI 1.37 2.92, p < 0.01]). CONCLUSIONS: Long-term exposures to pioglitazone and rosiglitazone were associated with higher odds of bladder cancer, and the highest odds were seen in users with >= 2 years of exposure. PMID- 23797602 TI - PHF20 regulates NF-kappaB signalling by disrupting recruitment of PP2A to p65. AB - Constitutive NF-kappaB activation in cancer cells is caused by defects in the signalling network responsible for terminating the NF-kappaB response. Here we report that plant homeodomain finger protein 20 (PHF20) maintains NF-kappaB in an active state in the nucleus by inhibiting the interaction between PP2A and p65. We show that PHF20 induces canonical NF-kappaB signalling by increasing the DNA binding activity of NF-kappaB subunit p65. In PHF20 overexpressing cells, the termination of tumour necrosis factor-induced p65 phosphorylation is impaired whereas upstream signalling events triggered by tumour necrosis factor are unaffected. This effect strictly depends on the interaction between PHF20 and methylated lysine residues of p65, which hinders recruitment of PP2A to p65, thereby maintaining p65 in a phosphorylated state. We further show that PHF20 levels correlate with p65 phosphorylation levels in human glioma specimens. Our work identifies PHF20 as a novel regulator of NF-kappaB activation and suggests that elevated expression of PHF20 may drive constitutive NF-kappaB activation in some cancers. PMID- 23797606 TI - Neglected role of hookah and opium in gastric carcinogenesis: a cohort study on risk factors and attributable fractions. AB - A recent study showed an association between hookah/opium use and gastric cancer but no study has investigated the relationship with gastric precancerous lesions. We examined the association between hookah/opium and gastric precancerous lesions and subsequent gastric cancer. In a population-based cohort study, 928 randomly selected, healthy, Helicobacter pylori-infected subjects in Ardabil Province, Iran, were followed for 10 years. The association between baseline precancerous lesions and lifestyle risk factors (including hookah/opium) was analyzed using logistic regression and presented as odds ratios (ORs) and 95% confidence intervals (CIs). We also calculated hazard ratios (HRs) and 95% CIs for the associations of lifestyle risk factors and endoscopic and histological parameters with incident gastric cancers using Cox regression models. Additionally, the proportion of cancers attributable to modifiable risk factors was calculated. During 9,096 person-years of follow-up, 36 new cases of gastric cancer were observed (incidence rate: 3.96/1,000 persons-years). Opium consumption was strongly associated with baseline antral (OR: 3.2; 95% CI: 1.2-9.1) and body intestinal metaplasia (OR: 7.3; 95% CI: 2.5-21.5). Opium (HR: 3.2; 95% CI: 1.4 7.7), hookah (HR: 3.4; 95% CI: 1.7-7.1) and cigarette use (HR: 3.2; 95% CI: 1.4 7.5), as well as high salt intake, family history of gastric cancer, gastric ulcer and histological atrophic gastritis and intestinal metaplasia of body were associated with higher risk of gastric cancer. The fraction of cancers attributable jointly to high salt, low fruit intake, smoking (including hookah) and opium was 93% (95% CI: 83-98). Hookah and opium use are risk factors for gastric cancer as well as for precancerous lesions. Hookah, opium, cigarette and high salt intake are important modifiable risk factors in this high-incidence gastric cancer area. PMID- 23797607 TI - Interleukin-1beta suppresses activity of an inwardly rectifying K+ channel in human renal proximal tubule cells. AB - We investigated the effect of interleukin-1beta (IL-1beta) on activity of an inwardly rectifying K+ channel in cultured human proximal tubule cells (RPTECs), using the patch-clamp technique and Fura-2 Ca2+ imaging. IL-1beta (15 pg/ml) acutely reduced K+ channel activity in cell-attached patches. This effect was blocked by the IL-1 receptor antagonist (20 ng/ml), an inhibitor of phospholipase C, neomycin (300 MUM), and an inhibitor of protein kinase C (PKC), GF109203X (500 nM). The Fura-2 Ca2+ imaging revealed that IL-1beta increased intracellular Ca2+ concentration even after removal of extracellular Ca2+, which was blocked by an inhibitor of inositol 1,4,5-trisphosphate receptors, 2-aminoethoxydiphenyl borate (2-APB, 1 MUM). Moreover, IL-1beta suppressed channel activity in the presence of 2-APB without extracellular Ca2+. These results suggest that IL-1beta suppresses K+ channel activity in RPTECs through binding to its specific receptor and activation of the PKC pathway even though intracellular Ca2+ does not increase. PMID- 23797608 TI - Efficacy of repetitive transcranial magnetic stimulation in the treatment of patients with chronic primary insomnia. AB - This study assessed the efficacy of repetitive transcranial magnetic stimulation (rTMS) in the treatment of patients with chronic primary insomnia. Hundred and twenty patients with chronic primary insomnia were randomly assigned to three study groups (n = 40 per group): rTMS, medication, or psychotherapy treatment (both latter as controls). The treatments proceeded for 2 weeks, after which treatment efficacies were assessed in each study group based on changes in polysomnography parameters, Pittsburgh sleep quality index, and indices of HPA and HPT axes (serum cortisol, adrenocorticotropic hormone, highly sensitive thyrotropin, free T3, and free T4). Further, the relapse and recurrence rates within 3 months after respective treatments were also measured. rTMS treatment significantly better (p < 0.05) improved stage III sleep and REM sleep cycle compared with both control groups. Further, rTMS treatment group was more advantageous in improving the indices of HPA and HPT axes (p < 0.05 vs. both control groups). In addition, the relapse and recurrence rates were also the lowest in rTMS treatment group. In conclusion, rTMS treatment is more advantageous than both medication and psychotherapy treatments in improving the sleep architecture. Further, rTMS significantly decreases the body awakening level and provides a better long-term treatment effect. PMID- 23797611 TI - Vitreous humor rheology after Nd:YAG laser photo disruption. AB - This work aimed to consider the hazardous side effect of eye floaters treatment with Q-switched Nd:YAG laser on the protein and viscoelastic properties of the vitreous humor, and evaluate the protective role of vitamin C against laser photo disruption. Five groups of New Zealand rabbits were divided as follows: control group for (n = 3) without any treatment, the second group (n = 9) treated with Q switched Nd:YAG laser energy of 5 mJ * 100 pulse delivered to the anterior, middle, and posterior vitreous, respectively (n = 3 for each). The third group (n = 9) received a daily dose of 25 mg/kg body weight vitamin C for 2 weeks, and then treated with laser as the previous group. The fourth group (n = 9) treated with 10 mJ 9 50 pulse delivered to the anterior, middle, and posterior vitreous, respectively (n = 3 rabbits each). The fifth group (n = 9) received a daily dose of 25 mg/kg body weight vitamin C for 2 weeks, and then treated with laser as the previous group. After 2 weeks of laser treatment, the protein content, refractive index (RI), and the rheological properties of vitreous humor, such as consistency, shear stress, and viscosity, were determined. The results showed that, the anterior vitreous group exposed to of 5 mJ * 100 pulse and/or supplemented with vitamin C, showed no obvious change. Furthermore, all other treated groups especially for mid-vitreous and posterior vitreous humor showed increase in the protein content, RI and the viscosity of vitreous humor. The flow index remained below unity indicating the non-Newtonian behavior of the vitreous humor. Application of Q-switched Nd:YAG laser should be restricted to the anterior vitreous humor to prevent the deleterious effect of laser on the gel state of the vitreous humor. PMID- 23797609 TI - The WD40-repeat protein-containing deubiquitinase complex: catalysis, regulation, and potential for therapeutic intervention. AB - Ubiquitination has emerged as an essential signaling mechanism in eukaryotes. Deubiquitinases (DUBs) counteract the activities of the ubiquitination machinery and provide another level of control in cellular ubiquitination. Not surprisingly, DUBs are subjected to stringent regulations. Besides regulation by the noncatalytic domains present in the DUB sequences, DUB-interacting proteins are increasingly realized as essential regulators for DUB activity and function. This review focuses on DUBs that are associated with WD40-repeat proteins. Many human ubiquitin-specific proteases (USPs) were found to interact with WD40-repeat proteins, but little is known as to how this interaction regulates the activity and function of USPs. In recent years, significant progress has been made in understanding a prototypical WD40-repeat protein-containing DUB complex that comprises USP1 and USP1-associated factor 1 (UAF1). It has been shown that UAF1 activates USP1 through a potential active-site modulation, and the complex formation between USP1 and UAF1 is regulated by serine phosphorylation. Recently, human USPs have been recognized as a promising target class for inhibitor discovery. Small molecule inhibitors targeting several human USPs have been reported. USP1 is involved in two major DNA damage response pathways, DNA translesion synthesis and the Fanconi anemia pathway. Inhibiting the USP1/UAF1 deubiquitinase complex represents a new strategy to potentiate cancer cells to DNA-crosslinking agents and to overcome resistance that has plagued clinical cancer chemotherapy. The progress in inhibitor discovery against USPs and the WD40-repeat protein-containing USP complex will be discussed. PMID- 23797612 TI - Initial clinical findings of a mathematical model to predict survival of head and neck cancer. AB - OBJECTIVES: (1) Identify clinical features that impact survival for head and neck cancer. (2) Determine the individual contribution to mortality of significant clinical features. (3) Develop a web-based calculator to integrate clinical features and predict survival outcome for individual patients. STUDY DESIGN: Analysis of a national cancer database. We fit patient data to the binary biological model of cancer lethality, a mathematical model designed to predict cancer outcome. The model predicts the risk of cancer death, using information on tumor size, nodal status, and other prognostic factors. SUBJECTS AND METHODS: Analysis was carried out on a cohort of ~50,000 patients with head and neck cancer from the Survey, Epidemiology and End-Results (SEER) 2009 data set and validated with a cohort of ~1300 patients from an institutional Massachusetts General Hospital/Massachusetts Eye and Ear Infirmary database. We developed a web based calculator written in JavaScript, PHP, and HTML. RESULTS: The risk of death due to head and neck cancer increases monotonically with tumor size. Each positive lymph node is associated with ~14% extra risk of death. Anatomical site, age, race, tumor extension, N stage, and extracapsular spread contribute to mortality. The lethal impact of these prognostics factors can be accurately estimated by the Size + Nodes + PrognosticMarkers (SNAP) method. CONCLUSIONS: This predictive cancer model and web-based calculator provide a basis for estimating the risk of death for head and neck cancer patients by assigning values to the lethal contributions of tumor size, number of positive nodes, anatomical site, tumor extension, N stage, extracapsular spread, age at diagnosis, and race. PMID- 23797610 TI - Differential expression of dicer, miRNAs, and inflammatory markers in diabetic Ins2+/- Akita hearts. AB - Diabetic cardiomyopathy is a leading cause of morbidity and mortality, and Insulin2 mutant (Ins2+/-) Akita is a genetic mice model of diabetes relevant to humans. Dicer, miRNAs, and inflammatory cytokines are associated with heart failure. However, the differential expression of miRNAs, dicer, and inflammatory molecules are not clear in diabetic cardiomyopathy of Akita. We measured the levels of miRNAs, dicer, pro-inflammatory tumor necrosis factor alpha (TNFalpha), and anti-inflammatory interleukin 10 (IL-10) in C57BL/6J (WT) and Akita hearts. The results revealed increased heart to body weight ratio and robust expression of brain natriuretic peptide (BNP: a hypertrophy marker) suggesting cardiac hypertrophy in Akita. The multiplex RT-PCR, qPCR, and immunoblotting showed up regulation of dicer, whereas miRNA array elicited spread down regulation of miRNAs in Akita including dramatic down regulation of let-7a, miR-130, miR-142 3p, miR-148, miR-338, miR-345-3p, miR-384-3p, miR-433, miR-450, miR-451, miR-455, miR-494, miR-499, miR-500, miR-542-3p, miR-744, and miR-872. Conversely, miR-295 is induced in Akita. Cardiac TNFalpha is upregulated at mRNA (RT-PCR and qPCR), protein (immunoblotting), and cellular (immunohistochemistry and confocal microscopy) levels, and is robust in hypertrophic cardiomyocytes suggesting direct association of TNFalpha with hypertrophy. Contrary to TNFalpha, cardiac IL 10 is downregulated in Akita. In conclusion, induction of dicer and TNFalpha, and attenuation of IL-10 and majority of miRNA are associated with cardiomyopathy in Akita and could be used for putative therapeutic target for heart failure in diabetics. PMID- 23797613 TI - Reference laboratory values for digoxin following publication of Digitalis Investigation Group (DIG) trial data. PMID- 23797614 TI - Analysis of possible sexual assault or abuse in a 67-year-old female with early dementia post-brain attack. AB - The case analysis explores an emergency department visit by a 67-year-old female with early dementia post-brain attack, with complaints of possible sexual assault or abuse. This patient resides in a long-term skilled nursing facility. The case outlines the forensic care provided by the Advanced Practice Forensic Nurse (APFN) once medically cleared by the emergency department Advanced Practice Nurse (APN). The case discussion includes issues related to sexuality in aging populations, consent, sexual abuse or assault in institutions, and forensic care of older persons. Expected genital injuries in older women that result from sexual assault and abuse are also explored. The case discussion will analyze the key elements for critical thinking and clinical reasoning and demonstrate standards of care for the APFN and APN practice. PMID- 23797615 TI - Comminuted pelvic fracture with retroperitoneal bleed in a geriatric patient: a case study. AB - The case study presented involved an 87-year-old Hispanic man who was transferred to the emergency department (ED) of an acute care hospital. The patient was complaining of left hip pain and hitting his head. The patient had fallen backward upon standing from a wheelchair, lost his balance, and suffered an occipital laceration with hematoma. There was a brief loss of consciousness after hitting his head. An external pelvic stabilizer was placed on the patient's pelvis in an attempt to stabilize the comminuted pelvic fractures. Because of the patient's comorbidities and unstable condition, the consulting physician specialists determined that the patient was not a surgical or interventional candidate. Self-tamponed of retroperitoneal bleeding occurred without intervention of angiogram with embolization or laparotomy. A decision was made among the patient, the patient's stepchildren, and the attending physicians for a do-not-resuscitate order. The patient was then transferred to a palliative care unit outside the hospital. This case discusses the physiological changes in geriatric patients and the management of geriatric patients with pelvic trauma and retroperitoneal bleeding. PMID- 23797616 TI - Bihemispheric repetitive transcranial magnetic stimulation combined with intensive occupational therapy for upper limb hemiparesis after stroke: a preliminary study. AB - We investigated the safety, feasibility, and efficacy of the combination of bihemispheric repetitive transcranial magnetic stimulation (rTMS) and intensive occupational therapy (OT) for upper limb hemiparesis in poststroke patients. The study participants were eight poststroke patients with upper limb hemiparesis (age at intervention: 62.8+/-4.9 years, time after stroke: 84.3+/-87.2 months, mean+/-SD). During 15 days of hospitalization, each patient received 10 sessions of 40-min bihemispheric rTMS and 240-min intensive OT (120-min one-to-one training and 120-min self-training). One session of bihemispheric rTMS comprised the application of both 1 and 10 Hz rTMS (2000 stimuli for each hemisphere). The Fugl-Meyer Assessment, Wolf Motor Function Test, and the Modified Ashworth Scale were administered on the day of admission and at discharge. All patients completed the treatment without any adverse effects. Motor function of the affected upper limb improved significantly, on the basis of changes in Fugl-Meyer Assessment and Wolf Motor Function Test (P<0.05, each). A significant decrease in the Modified Ashworth Scale score was noted in the elbow, wrist, and finger flexors of the affected upper limb (P<0.05, each). The combination of bihemispheric rTMS and intensive OT was safe and feasible therapy for poststroke hemiparetic patients, and improved motor function of the hemiparetic upper limb in poststroke patients. The findings provide a new avenue for the treatment of patients with poststroke hemiparesis. PMID- 23797617 TI - Attenuated live vaccine (Bartha-K16) caused pseudorabies (Aujeszky's disease) in sheep. AB - Pseudorabies (PR, Aujeszky's disease) is an acute, contagious viral disease that affects a wide range of domestic and wild species. In the present study, an outbreak of PR in sheep induced by attenuated live vaccine (Bartha-K16) was diagnosed and analyzed in China. The presence of PR virus (PRV) in brain samples from infected sheep was confirmed by gC gene polymerase chain reaction amplification and PRV-like particle observation by electron microscopy. The molecular characterization of the PRV was performed with homology analysis and phylogenetic tree construction based on the gC gene. This is the first description of an outbreak of PR induced by a live attenuated vaccine (Bartha K16), indicating that this vaccine is unsuitable for use in sheep. PMID- 23797618 TI - A simple mathematical model for manganese oxide-coated montmorillonite as a catalyst for water oxidation: from nano to macro sized manganese oxide. AB - Here, we propose a mathematical model that gives a good fit to the experimental data for water oxidation by Mn oxide-coated montmorillonite with different Mn content. Our data show that the water oxidation may progress by cooperation among only neighbor Mn ions on montmorillonite. It is a promising model for finding more about the mechanism of multi-electron reactions. PMID- 23797619 TI - No significant displacement of basal brain structures upon head movement: Kinematic MRI morphometry relevant to neuroendoscopy. AB - BACKGROUND: An appreciation of normal intracranial anatomy allows optimal planning of trajectories necessary for safe and effective neuroendoscopy. Little information exists on displacement of the caudal brain relative to the skull upon head movement; this could have important implications for planning and performance of neuroendoscopic procedures. We used kinematic magnetic resonance imaging (MRI) studies to examine the morphometric displacement and changing anatomical relationships between the clivus and basal brain structures, intracranial vessels, and subarachnoid spaces. PATIENTS: We retrospectively analyzed 15 patients undergoing sagittal T2 kinematic MRI of the head and neck in modest flexion and extension. The angle between a horizontal axial reference plane and a line between the opisthion and the hard palate defined the degree of flexion and extension. We then measured in flexion and extension (1) the cervicomedullary angle (CMA), (2) displacement of the ventral surface of the brainstem (i.e., depth of the prepontine and premedullary cisterns), (3) total sagittal area of the combined suprasellar and ventral brainstem cisterns, and (4) the basilar tip to tuber cinereum distance. RESULTS: Relative to neutral head position, a mean extension angle of -15.8 degrees was achieved in all 15 patients, and a mean flexion angle of +9.9 degrees was achieved in 6 patients. The mean CMA was 146 degrees in flexion and 158 degrees in extension. The mean reduction in prepontine and premedullary cistern depth was 0.7 mm and 0.5 mm, respectively, upon flexion from extension. The combined area of suprasellar and ventral brainstem cisterns was minimally reduced from 402 mm2 in flexion to 399 mm(2) in extension. The basilar tip did not move significantly from its position in flexion to extension, 5.3 mm to 5.2 mm respectively from the tuber cinereum. CONCLUSION: Kinematic MRI shows minimal brainstem-to-clivus displacement even within minor physiological changes in head flexion. Importantly, these movements are small and there is no significant shift in the position of the basilar tip in modest flexion or extension. These results should be useful for presurgical planning of optimal patient positioning during neuroendoscopic procedures such as third ventriculostomy and the expanded endonasal transsphenoidal approach to the retroclival space. PMID- 23797620 TI - Intraspecies variation in dominance style of Macaca fuscata. AB - Knowledge of intraspecific variation is important to test the evolutionary basis of covariation in primate social systems, yet few reports have focused on it, even in the best-studied species of the Macaca genus. We conducted a comparative study of the dominance styles among three provisioned, free-ranging groups of Japanese macaques at Shodoshima Island, Takasakiyama Mountain and Shiga Heights, and collected standard data on aggressive and affiliative behavior during a period of 5 years. Our data in the Takasakiyama and Shiga groups support previous studies showing that Japanese macaques typically have despotic social relations; nevertheless, our data in the Shodoshima group are inconsistent with the norm. The social traits of Shodoshima monkeys suggested that: (1) their dominance style is neither despotic nor tolerant but is intermediate between the two traits; (2) some measures of dominance style, e.g., frequency and duration of social interactions, covary as a set of tolerant traits in Shodoshima monkeys. This study suggests broad intraspecific variation of dominance style in Japanese macaques as can be seen in some other primate species. PMID- 23797621 TI - Cytokine pathways and interactions in alopecia areata. AB - Alopecia areata (AA) is an autoimmune disease resulting in the premature arrest of the follicular growth cycle clinically resulting in patchy, non-scarring hair loss. The presence of a dense follicular T cell infiltrate and variations in cytokines have led to the hypothesis that T cell activation and alterations in inflammatory mediators are crucial participants in the etiopathogenesis of the disease. Various studies suggest that the AA pathogenesis has a dominant TH1 mediated component, with potential involvement of the TH17 pathway. However, a fully integrated view of intersecting cytokine networks that support the autoimmune response in AA is lacking. A more precise understanding of cytokine pathways in disease is required to rationally explore cytokine targeted treatment strategies. Here, we comprehensively and critically review the current literature to provide a working framework regarding the complexity of T cell-cytokine interactions in AA, emphasizing the areas necessitating further research, particularly for the development of novel therapeutic options. PMID- 23797622 TI - A novel method for semen collection and artificial insemination in large parrots (Psittaciformes). AB - The paper described a novel technique for semen collection in large psittacines (patent pending), a procedure which was not routinely possible before. For the first time, a large set of semen samples is now available for analysis as well as for artificial insemination. Semen samples of more than 100 psittacine taxa were collected and analysed; data demonstrate large differences in the spermatological parameters between families, indicating an ecological relationship with breeding behaviour (polygamous versus monogamous birds). Using semen samples for artificial insemination resulted in the production of offspring in various families, such as Macaws and Cockatoos, for the first time ever. The present technique represents a breakthrough in species conservation programs and will enable future research into the ecology and environmental factors influencing endangered species. PMID- 23797623 TI - Colony stimulating factors (including erythropoietin, granulocyte colony stimulating factor and analogues) for stroke. AB - BACKGROUND: Colony stimulating factors (CSFs), also called haematopoietic growth factors, regulate bone marrow production of circulating red and white cells, and platelets. Some CSFs also mobilise the release of bone marrow stem cells into the circulation. CSFs have been shown to be neuroprotective in experimental stroke. OBJECTIVES: To assess (1) the safety and efficacy of CSFs in people with acute or subacute ischaemic or haemorrhagic stroke, and (2) the effect of CSFs on circulating stem and blood cell counts. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (last searched September 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 4), MEDLINE (1985 to September 2012), EMBASE (1985 to September 2012) and Science Citation Index (1985 to September 2012). In an attempt to identify further published, unpublished and ongoing trials we contacted manufacturers and principal investigators of trials (last contacted April 2012). We also searched reference lists of relevant articles and reviews. SELECTION CRITERIA: We included randomised controlled trials recruiting people with acute or subacute ischaemic or haemorrhagic stroke. CSFs included stem cell factor (SCF), erythropoietin (EPO), granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), macrophage-colony stimulating factor (M-CSF, CSF-1), thrombopoietin (TPO), or analogues of these. The primary outcome was functional outcome at the end of the trial. Secondary outcomes included safety at the end of treatment, death at the end of follow-up, infarct volume and haematology measures. DATA COLLECTION AND ANALYSIS: Two review authors (TE and NS) independently extracted data and assessed trial quality. We contacted study authors for additional information. MAIN RESULTS: We included a total of 11 studies involving 1275 participants. In three trials (n = 782), EPO therapy was associated with a significant increase in death by the end of the trial (odds ratio (OR) 1.98, 95% confidence interval (CI) 1.19 to 3.3, P = 0.009) and a non significant increase in serious adverse events. EPO significantly increased the red cell count with no effect on platelet or white cell count, or infarct volume. Two small trials of carbamylated EPO have been completed but have yet to be reported. We included eight small trials (n = 548) of G-CSF. G-CSF was associated with a non-significant reduction in early impairment (mean difference (MD) -0.4, 95% CI -1.82 to 1.01, P = 0.58) but had no effect on functional outcome at the end of the trial. G-CSF significantly elevated the white cell count and the CD34+ cell count, but had no effect on infarct volume. Further trials of G-CSF are ongoing. AUTHORS' CONCLUSIONS: There are significant safety concerns regarding EPO therapy for stroke. It is too early to know whether other CSFs improve functional outcome. PMID- 23797624 TI - Effect of clonidine added to lidocaine for sub-Tenon's (episcleral) anesthesia in cataract surgery. AB - PURPOSE: We aimed to evaluate the duration of anesthesia, analgesia and ocular akinesia of clonidine added to lidocaine in sub-Tenon's anesthesia in patients undergoing cataract surgery. METHODS: Forty patients were prospectively enrolled. They were randomized to two sub-Tenon's anesthesia groups: group L (6 ml of lidocaine 2 %, 1 ml of 0.9 % saline and 25 UI/ml of hyaluronidase), and group C (6 ml lidocaine 2 %, clonidine 1 MUg/kg, 1 ml of 0.9 % saline and 25 UI/ml of hyaluronidase). Duration of sensory anesthesia, ocular akinesia in all directions, akinesia of the levator palpebrae superioris and orbicularis oculi muscles, the duration of analgesia (time to the first postoperative use of analgesics), the overall use of analgesics and the presence of adverse effects were recorded . RESULTS: The duration of sensory anesthesia and akinesia of the four rectus, levator palpebrae superioris, and orbicularis oculi muscles was significantly longer in group C (p < 0.05). The number of patients who required analgesics was similar between the groups but the duration of analgesia was longer in group C (p < 0.05). No significant adverse effects were observed. CONCLUSION: The addition of clonidine 1 MUg/kg to 2 % lidocaine in sub-Tenon's anesthesia for cataract surgery increased the duration of sensory anesthesia, ocular akinesia, and the duration of analgesia. PMID- 23797627 TI - [Archivos de Prevencion de Riesgos Laborales in MEDLINE/PubMed]. PMID- 23797625 TI - The inhibitory effects of bupivacaine, levobupivacaine, and ropivacaine on K2P (two-pore domain potassium) channel TREK-1. AB - PURPOSE: Bupivacaine, levobupivacaine, and ropivacaine are amide local anesthetics. Levobupivacaine and ropivacaine are stereoisomers of bupivacaine and were developed to circumvent the bupivacaine's severe toxicity. The recently characterized background potassium channel, K(2P) TREK-1, is a well-known target for various local anesthetics. The purpose of study is to investigate the differences in inhibitory potency and stereoselectivity among bupivacaine, levobupivacaine, and ropivacaine on K(2P) TREK-1 channels overexpressed in COS-7 cells. METHODS: We investigated the effects of bupivacaine, levobupivacaine, and ropivacaine (10, 50, 100, 200, and 400 MUM) on TREK-1 channels expressed in COS-7 cells by using the whole cell patch clamp technique with a voltage ramp protocol ranging from -100 to 100 mV for 200 ms from a holding potential of -70 mV. RESULTS: Bupivacaine, levobupivacaine, and ropivacaine showed reversible inhibition of TREK-1 channels in a concentration-dependent manner. The half maximal inhibitory concentrations (IC(50)) of bupivacaine, levobupivacaine, and ropivacaine were 95.4 +/- 14.6, 126.1 +/- 24.5, and 402.7 +/- 31.8 MUM, respectively. IC(50) values indicated a rank order of potency (bupivacaine > levobupivacaine > ropivacaine) with stereoselectivity. Hill coefficients were 0.84, 0.93, and 0.89 for bupivacaine, levobupivacaine, and ropivacaine, respectively. CONCLUSION: Inhibitory effects on TREK-1 channels by bupivacaine, levobupivacaine, and ropivacaine demonstrated stereoselectivity: bupivacaine was more potent than levobupivacaine and ropivacaine. Inhibition of TREK-1 channels and consecutive depolarization of the cell membrane by bupivacaine, levobupivacaine, and ropivacaine may contribute to the blockade of neuronal conduction and side effects. PMID- 23797628 TI - [Non-occupational temporary sickness absence in Catalonia, 2007-2010]. AB - OBJECTIVES: To describe nonoccupational temporary sickness absence episodes registered in Catalonia between 2007 and 2010. METHODS: We analysed 4,273,601 sickness absence episodes (SA) that came to closure between 2007 and 2010, registered through Catalonian Primary Health centers. Annual incidence rates per 100 workers, and median and mean duration of days lost per worker were examined by gender, age, province, social security scheme, and major ICD-10 diagnostic groups. RESULTS: There was a consistent downward trend in mean duration of days lost per worker (from 12.2 days in 2007 to 10.8 in 2010), and in incidence rates (from 34.4 to 30.4 cases per 100 workers). This pattern was observed in both men and women, although overall men had a lower incidence, median duration and mean days lost per worker than women. The most frequent diagnostic groups were respiratory diseases (about 7 episodes per 100 workers), musculoskeletal disorders (decreasing from 6.9 to 3.2 over the study period), and infections (about 4 episodes per 100 workers). The longest median durations were those associated with neoplasms (about 50 days), mental disorders (30 days) and cardiovascular diseases (between 20 and 30 days). CONCLUSIONS: These trends may serve as a baseline for planning and evaluating policies directed at better management of sickness absence in Spain. PMID- 23797629 TI - [Trends in occupational injuries in employees affiliated with MC Mutual in Spain, 2005-2009]. AB - OBJECTIVES: In recent years, occupational injury rates are declining significantly. This study analyzes temporal trends of nonfatal occupational injuries among employees affiliated with MC Mutual in the period 2005-2009, by sex, age, activity of the company and duration of sick leave. METHODS: Time series. We calculated the annual incidence rate adjusted by sex, age and activity of the company through direct standardization, as well as changes in annual and overall rates, together with stratified analysis by duration of sick leave. RESULTS: The standardized incidence of occupational injuries decreased from 74.8 per 1000 workers-year in 2005 to 48.3 in 2009 (a 35.4% reduction). The highest standardized incidence and rate of reduction was observed among sick leave processes lasting between 4 and 15 days, which decreased from 41.1 in 2005 to 25.2 in 2009 (a 38.6% reduction). Changes in trends were not consistent when considering the duration of the sick leave. CONCLUSIONS: There was a significant reduction in nonfatal occupational injuries resulting in sick leave during the study period, after considering age and sex of workers and the economic activity of affiliated companies, mainly at the expense of sick leave processes of short duration. PMID- 23797630 TI - [Evaluation of a grant program for improving health and safety in small and medium companies in Andalusia (Spain)]. AB - OBJECTIVES: To evaluate a grant program for the development and support of occupational safety projects in small and medium companies (SMC) in Andalusia. The analysis includes data and results of the program between 2006 and 2008. METHODS: We analyzed the program characteristics in terms of budget, proposals submitted and projects financed. The views of participating companies regarding the program were evaluated through a voluntary and anonymous postal survey. Occupational injury rates in 2006 and 2007 in a subgroup of companies that had obtained a grant in 2006 were calculated. RESULTS: Public investment in the program (> 17 million euros) covered 44% of the investment in occupational health projects proposed by participating companies. Nearly 50% of the projects presented received grant funding. The survey was completed by 573 companies (24% of the submitted questionnaires). Among grantee companies, 89% considered the investment to have been effective and 87% considered that working conditions in the company had improved. Most of the companies (>90%) considered that lack of economic resources is an obstacle for prevention activities and that these kinds of public subsidies are necessary. Occupational injury rates decreased between 2006 and 2007 (incidence rate 0.93; 95%confidence interval, 0.78-1.11). CONCLUSIONS: The grant program was viewed positively by participating companies and was accompanied by a reduction of occupational injury rates among grantee companies. These programs should incorporate evaluation criteria and indicators in their design. PMID- 23797631 TI - Pattern classification by memristive crossbar circuits using ex situ and in situ training. AB - Memristors are memory resistors that promise the efficient implementation of synaptic weights in artificial neural networks. Whereas demonstrations of the synaptic operation of memristors already exist, the implementation of even simple networks is more challenging and has yet to be reported. Here we demonstrate pattern classification using a single-layer perceptron network implemented with a memrisitive crossbar circuit and trained using the perceptron learning rule by ex situ and in situ methods. In the first case, synaptic weights, which are realized as conductances of titanium dioxide memristors, are calculated on a precursor software-based network and then imported sequentially into the crossbar circuit. In the second case, training is implemented in situ, so the weights are adjusted in parallel. Both methods work satisfactorily despite significant variations in the switching behaviour of the memristors. These results give hope for the anticipated efficient implementation of artificial neuromorphic networks and pave the way for dense, high-performance information processing systems. PMID- 23797632 TI - Cold-induced activity of brown adipose tissue in young lean men of South-Asian and European origin. AB - AIMS/HYPOTHESIS: South Asians have a disproportionately high risk of developing abdominal obesity, insulin resistance and type 2 diabetes. Brown adipose tissue (BAT) has been identified as a possible target to fight obesity and protect against metabolic disturbance. We explored whether lower BAT activity in South Asians compared with Europids may contribute to the high risk of metabolic disturbance. METHODS: We studied 20 healthy men (ten Europids/ten South Asians, BMI 19-25 kg/m(2), age 18-32 years). Following 2 h of cold exposure (16-18 degrees C) after an overnight fast, (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography-computed tomography (CT) and (123)I-metaiodobenzylguanidine ((123)I-MIBG) single-photon emission computed tomography-CT were performed to visualise metabolic BAT activity and sympathetic stimulation of BAT. Metabolic BAT activity was defined as maximal standardised uptake value (SUV(max)) of (18)F FDG, and sympathetic stimulation of BAT as semiquantitative uptake value (SQUV) of (123)I-MIBG. We performed hyperinsulinaemic-euglycaemic clamps to assess insulin sensitivity. Spearman's correlations for SUV(max) of (18)F-FDG and both SQUV of (123)I-MIBG and insulin sensitivity were determined. RESULTS: The median (interquartile range) SUV(max) of (18)F-FDG in South Asians (7.5 [2.2-10.6] g/ml) was not different from the median SUV(max) obtained in Europids (4.5 [2.2-8.4] g/ml; p = 0.59). There was no correlation between BAT activity and insulin sensitivity. Correlations between SQUV of (123)I-MIBG and SUV(max) of (18)F-FDG were positive, both in the total population (rho = 0.80, p < 0.001) and after stratification by ethnicity (Europids, rho = 0.65, p = 0.04; South Asians, rho = 0.83, p = 0.01). CONCLUSIONS/INTERPRETATION: This is the first study to prospectively investigate ethnic differences in metabolic BAT activity during cold exposure. We did not find differences in BAT activity between South Asians and Europids. Therefore, it seems unlikely that BAT plays an important role in the development of unfavourable metabolic profiles in South Asians. PMID- 23797633 TI - Mortality among veterans with type 2 diabetes initiating metformin, sulfonylurea or rosiglitazone monotherapy. AB - AIMS/HYPOTHESES: Despite oral hypoglycaemic medications being the most commonly used pharmacological treatments for type 2 diabetes, research is limited on their comparative safety, particularly their effects on overall mortality. We compared mortality risk with monotherapy initiation of four oral hypoglycaemic medications in a nationwide cohort of US veterans with type 2 diabetes. METHODS: We identified new users of oral hypoglycaemic medication monotherapy between 2004 and 2009 who received care for at least 1 year from the Veterans Health Administration.Patients were followed until initial monotherapy discontinuation,addition of another diabetes pharmacotherapy, death or end of follow-up. Mortality HRs were estimated using Cox regression adjusted for potential confounding factors. RESULTS: Among new users of metformin, sulfonylureas and rosiglitazone (185,360 men, 7,812 women), 4,256 (2.2%) died during follow-up. Average duration of medication use ranged from 1.4 to 1.7 years. Significantly higher mortality risk was seen for glibenclamide (known as glyburide in the USA and Canada) (HR 1.38, 95% CI 1.27, 1.50) or glipizide (HR 1.55,95% CI 1.43, 1.67) compared with metformin monotherapy,and for glipizide compared with rosiglitazone (HR 1.27, 95%CI 1.01, 1.59) or glibenclamide monotherapy (HR 1.12, 95%CI 1.02, 1.23). A significant sex-rosiglitazone interaction was seen (p=0.034) compared with metformin monotherapy, with women having a higher HR (HR 4.36, 95% CI 1.34, 14.20)than men (HR 1.19, 95% CI 0.95, 1.49). CONCLUSIONS/INTERPRETATIONS: Significantly higher mortality was associated with glibenclamide, glipizide and rosiglitazone use compared with metformin, and with glipizide use compared with rosiglitazone or glibenclamide. The potential for residual confounding by indication should be considered in interpreting these results. PMID- 23797634 TI - Small effects of a large sediment contamination with heavy metals on aquatic organisms in the vicinity of an abandoned lead and zinc mine. AB - The effects of the long-term contamination of water reservoirs with mine effluents were investigated at an abandoned mine site in Upper Silesia, southern Poland. The studies covered metal content and mobility in bottom sediments as well as water chemistry in relation to the content of metals in selected macrophytes and their physiology and the composition of phyto- and zooplankton communities. Although it is 40 years since mining ceased, reservoir sediments are still heavily contaminated with cadmium, zinc and lead with concentrations (mg/kg), which vary roughly between 130-340, 10,000-50,000 and 4,000-12,000, respectively. About 50-80 % of these elements are associated with the reducible phase, and only a small percentage, <10%, is present in the most mobile exchangeable phase. Despite the high total metal concentration in sediments, their content in the submerged plants Myriophyllum spicatum and the emerged plants Phragmites australis was low. The observed effects of heavy metal contamination on photosynthetic activity in the leaves of P. australis were negligible, whereas those in M. spicatum show up only as a difference in the distribution of photosynthetic activity in leaves of different ages, which seems to be related to the very good water quality and to the generally small concentrations of metals in pond water. The physicochemical properties of water also seem to control the presence of planktonic species more than does sediment contamination. However, a shift toward groups of species known to be more resistant to heavy metals (diatoms, green algae and Rotifera) indicates some adaptative changes related to the longlasting contamination of ponds. PMID- 23797635 TI - Spatial patterns of heavy metals in soil under different geological structures and land uses for assessing metal enrichments. AB - One hundred and thirty composite soil samples were collected from Hamedan county, Iran to characterize the spatial distribution and trace the sources of heavy metals including As, Cd, Co, Cr, Cu, Ni, Pb, V, Zn, and Fe. The multivariate gap statistical analysis was used; for interrelation of spatial patterns of pollution, the disjunctive kriging and geoenrichment factor (EF(G)) techniques were applied. Heavy metals and soil properties were grouped using agglomerative hierarchical clustering and gap statistic. Principal component analysis was used for identification of the source of metals in a set of data. Geostatistics was used for the geospatial data processing. Based on the comparison between the original data and background values of the ten metals, the disjunctive kriging and EF(G) techniques were used to quantify their geospatial patterns and assess the contamination levels of the heavy metals. The spatial distribution map combined with the statistical analysis showed that the main source of Cr, Co, Ni, Zn, Pb, and V in group A land use (agriculture, rocky, and urban) was geogenic; the origin of As, Cd, and Cu was industrial and agricultural activities (anthropogenic sources). In group B land use (rangeland and orchards), the origin of metals (Cr, Co, Ni, Zn, and V) was mainly controlled by natural factors and As, Cd, Cu, and Pb had been added by organic factors. In group C land use (water), the origin of most heavy metals is natural without anthropogenic sources. The Cd and As pollution was relatively more serious in different land use. The EF(G) technique used confirmed the anthropogenic influence of heavy metal pollution. All metals showed concentrations substantially higher than their background values, suggesting anthropogenic pollution. PMID- 23797636 TI - Assessment of methane emission and oxidation at Air Hitam Landfill site cover soil in wet tropical climate. AB - Methane (CH4) emissions and oxidation were measured at the Air Hitam sanitary landfill in Malaysia and were modeled using the Intergovernmental Panel on Climate Change waste model to estimate the CH4 generation rate constant, k. The emissions were measured at several locations using a fabricated static flux chamber. A combination of gas concentrations in soil profiles and surface CH4 and carbon dioxide (CO2) emissions at four monitoring locations were used to estimate the CH4 oxidation capacity. The temporal variations in CH4 and CO2 emissions were also investigated in this study. Geospatial means using point kriging and inverse distance weight (IDW), as well as arithmetic and geometric means, were used to estimate total CH4 emissions. The point kriging, IDW, and arithmetic means were almost identical and were two times higher than the geometric mean. The CH4 emission geospatial means estimated using the kriging and IDW methods were 30.81 and 30.49 gm(-2) day(-1), respectively. The total CH4 emissions from the studied area were 53.8 kg day(-1). The mean of the CH4 oxidation capacity was 27.5 %. The estimated value of k is 0.138 year(-1). Special consideration must be given to the CH4 oxidation in the wet tropical climate for enhancing CH4 emission reduction. PMID- 23797637 TI - Biodegradation or simple adsorption to the support material? Development of a simple, fast and low-cost technique. AB - Biofilms are present in several areas and are studied in microbiology, medical sciences, biology and, of course, sanitary engineering. Biofilms are used for the treatment of municipal wastewater, and their application was even before the invention of the activated sludge process. The main objective of this work was to develop a simple, fast and low-cost technique to evaluate the nature of the first decay in the concentration of an organic compound in the presence of a solid material. Though simple, the technique developed has allowed the clarification of whether the initial concentration decay is due to adsorption to the support material or a result of biodegradation. The results show that, with two different support materials, adsorption does not take place, and the biodegradation processes are responsible for the first decay in the organic concentration. The technique used offers a fast and low-cost way of studying the existence of adsorption. Two feed concentration solutions and two different support materials were used. PMID- 23797638 TI - The significance of free light chain measurements in the diagnosis of myelomatous pleural effusion. PMID- 23797639 TI - Inflammation and disease duration have a cumulative effect on the risk of dysplasia and carcinoma in IBD: a case-control observational study based on registry data. AB - Patients with long-standing inflammatory bowel disease (IBD) have an increased risk for colorectal carcinoma (CRC). Earlier studies suggest that the severity of inflammation is an independent risk factor for CRC in ulcerative colitis (UC). We investigated the role of histological inflammation as a risk factor for colorectal dysplasia or CRC to better target dysplasia surveillance in IBD. By combining our hospital patient registry and pathology database between 1996 and 2008, we identified 183 IBD patients with dysplasia or CRC. The control group was collected from our registry of IBD patients. Histological severe inflammation was present in 41.4% of patients with dysplasia and in 24.1% of patients with CRC, but in only 4.3% of controls. Severe inflammation had an odds ratio (OR) of 31.8 [95% confidence interval (CI): 15.6-64.9] for dysplasia or carcinoma compared to patients with no inflammation. Among patients with mild to moderate inflammation, the OR was 2.6 (95% CI: 1.6-4.1). Disease duration increased the annual risk for dysplasia or CRC by 4.5%. Coexisting primary sclerosing cholangitis (PSC) did not elevate the risk, whereas use of thiopurines (OR = 0.09, 95% CI: 0.02-0.33) and also 5-aminosalicylic acid (OR 0.17, 95% CI: 0.017-1.01) protected against CRC. As conclusion, degree of inflammation and duration of disease cumulatively increase the risk for dysplasia and CRC. PSC was not identified as a risk factor. We demonstrated that use of thiopurines strongly protects against CRC. These results can be applied to better target dysplasia surveillance in IBD patients. PMID- 23797641 TI - The chronic inflammation of obesity and its effects on surgery and anesthesia. PMID- 23797642 TI - Preoperative screening for obstructive sleep apnea in morbidly obese patients. PMID- 23797643 TI - Airway management in patients with morbid obesity. PMID- 23797640 TI - The hyper IgM syndromes. AB - The hyper IgM syndromes are a group of rare inherited immune deficiency disorders characterized by impairment of immunoglobulin isotype switching resulting from defects in the CD40 ligand/CD40 signaling pathway. X-linked forms of hyper IgM are caused by defects in the CD40 ligand gene or NF-kappaB essential modulator, while autosomal recessive forms of hyper IgM are caused by defects in CD40 or downstream signaling molecules including activation-induced cytidine deaminase, uracil N glycosylase or postmeiotic segregation increased 2. The loss of interaction between CD40 and its ligand results in an impairment of T cell function, of B cell differentiation and of monocyte function while only B cell differentiation appears to be affected in defects of sinaling molecules downstream of CD40 with the exception of defects of the NF-kappaB complex, which mediates signaling via multiple receptor pathways. With many genetic defects in the hyper IgM syndrome identified, it is possible to diagnose patients definitively, to perform genetic screening, and to delineate the clinical manifestations of the different diseases in this syndrome. Stem cell transplantation is an available therapeutic option for defects that result in a combined immunodeficiency while antibody replacement appears sufficient for the strictly humoral immunodeficiencies. PMID- 23797644 TI - Pulmonary physiology of the morbidly obese and the effects of anesthesia. PMID- 23797645 TI - Pharmacology and obesity. PMID- 23797646 TI - Perioperative pain. PMID- 23797647 TI - Intraoperative fluid management and bariatric surgery. PMID- 23797648 TI - Obesity and regional anesthesia. PMID- 23797649 TI - The morbidly obese patient undergoing outpatient surgery. PMID- 23797650 TI - The obese parturient. PMID- 23797651 TI - Critical care management of obese patients. PMID- 23797652 TI - Bariatric surgery. PMID- 23797654 TI - Obesity. PMID- 23797655 TI - Phthalic acid chemical probes synthesized for protein-protein interaction analysis. AB - Plasticizers are additives that are used to increase the flexibility of plastic during manufacturing. However, in injection molding processes, plasticizers cannot be generated with monomers because they can peel off from the plastics into the surrounding environment, water, or food, or become attached to skin. Among the various plasticizers that are used, 1,2-benzenedicarboxylic acid (phthalic acid) is a typical precursor to generate phthalates. In addition, phthalic acid is a metabolite of diethylhexyl phthalate (DEHP). According to Gene_Ontology gene/protein database, phthalates can cause genital diseases, cardiotoxicity, hepatotoxicity, nephrotoxicity, etc. In this study, a silanized linker (3-aminopropyl triethoxyslane, APTES) was deposited on silicon dioxides (SiO2) particles and phthalate chemical probes were manufactured from phthalic acid and APTES-SiO2. These probes could be used for detecting proteins that targeted phthalic acid and for protein-protein interactions. The phthalic acid chemical probes we produced were incubated with epithelioid cell lysates of normal rat kidney (NRK-52E cells) to detect the interactions between phthalic acid and NRK-52E extracted proteins. These chemical probes interacted with a number of chaperones such as protein disulfide-isomerase A6, heat shock proteins, and Serpin H1. Ingenuity Pathways Analysis (IPA) software showed that these chemical probes were a practical technique for protein-protein interaction analysis. PMID- 23797656 TI - Metasin-an intra-operative RT-qPCR assay to detect metastatic breast cancer in sentinel lymph nodes. AB - Nodal status is one of the most important prognostic factors in breast cancer. Established tests such as touch imprint cytology and frozen sections currently used in the intra-operative setting show variations in sensitivity and specificity. This limitation has led to the development of molecular alternatives, such as GeneSearch, a commercial intra-operative real-time quantitative Polymerase Chain Reaction (RT-qPCR) assay that allows the surgeon to carry out axillary clearance as a one-step process. Since GeneSearch has been discontinued, we have developed the replacement Metasin assay, which targets the breast epithelial cell markers CK19 and mammaglobin mRNA and identifies metastatic disease in sentinel lymph nodes. The optimised assay can be completed within 32 min (6 min for RNA preparation and 26 min instrument run time), making its use feasible in the intraoperative setting. An analysis by Metasin of 154 archived lymph node homogenates previously analysed by both parallel histology and GeneSearch showed concordance for 148 cases. The sensitivity and specificity of Metasin compared with GeneSearch were 95% (CI 83%-99%) and 97% (CI 91%-99%) respectively; compared with histology they were 95% (CI 83%-99%) and 97% (CI 91% 99%), respectively. The sensitivity and specificity of GeneSearch compared with histology were 90% (CI 77%-96%) and 97% (CI 93%-99%) respectively. The positive predictive value of Metasin was 90% and negative predictive value was 98% for both histology and GeneSearch. The positive predictive value of GeneSearch was 92% and the negative predictive value was 97% compared to histology. The discordance rates of Metasin with both GeneSearch and histology were 3.89%. In comparison, the discordance rate of GeneSearch with histology was 4.5%. Metasin's robustness was independently evaluated on 193 samples previously analysed by GeneSearch from the Jules Bordet Institute, where Metasin yielded comparable results. PMID- 23797657 TI - Bending of layer-by-layer films driven by an external magnetic field. AB - We report on optimized architectures containing layer-by-layer (LbL) films of natural rubber latex (NRL), carboxymethyl-chitosan (CMC) and magnetite (Fe3O4) nanoparticles (MNPs) deposited on flexible substrates, which could be easily bent by an external magnetic field. The mechanical response depended on the number of deposited layers and was explained semi-quantitatively with a fully atomistic model, where the LbL film was represented as superposing layers of hexagonal graphene-like atomic arrangements deposited on a stiffer substrate. The bending with no direct current or voltage being applied to a supramolecular structure containing biocompatible and antimicrobial materials represents a proof-of principle experiment that is promising for tissue engineering applications in biomedicine. PMID- 23797658 TI - Significant decline in Galactomannan Signal during storage of clinical serum samples. AB - Galactomannan (GM) is widely used for detection of invasive aspergillosis in high risk haemato-oncology patients. Recent publications have reported a lack of repeatability of GM detection. The objective of this retrospective study was to assess the repeatability of GM levels during storage of clinical samples. In a GM screening strategy, positive sera were repeat tested as per manufacturer's recommendations. Short-term (ST) storage of samples was at +4 degrees C while long-term (LT) storage was at -80 degrees C. Bronchoalveolar (BAL) fluid was also repeating tested after ST storage and LT storage. Wilcoxon Signed Ranks Test was employed to assess the repeatability of GM levels. In a subset of 14 GM positive sera, repeat testing was performed on both the original serum and ethylenediaminetetraacetic acid (EDTA) pre-treated sample. There was a significant reduction in GM signals on repeat testing following ST storage (median GM index: 0.65 vs. 0.19; p < 0.001) and LT storage (median GM index: 0.56 vs. 0.10; p < 0.001) of serum samples. Of samples that were initially GM positive, an average GM index reduction of 50% was seen, with approximately two thirds becoming GM negative on repeat testing of the same sample. In contrast, GM signal loss was not seen on repeat testing of BAL fluid following ST or LT storage. When GM positive serum samples were repeat tested using EDTA pre-treated serum from the first step of the testing protocol, all samples remained GM positive. In contrast, when the same samples were repeat tested from the original collected serum, 9 samples (64%) became GM negative. The significant reduction in GM signals during ST and LT storage of serum samples has implications for clinical management. Although the reasons for GM decline are unknown, they occur prior to the EDTA pre-treatment stage, indicating that the time from phlebotomy to testing should be minimized. BAL fluid GM index values remain stable. PMID- 23797659 TI - Achillea millefolium L. essential oil inhibits LPS-induced oxidative stress and nitric oxide production in RAW 264.7 Macrophages. AB - Achillea millefolium L. is a member of the Asteraceae family and has been used in folk medicine in many countries. In this study, 19 compounds in A. millefolium essential oil (AM-EO) have been identified; the major components are artemisia ketone (14.92%), camphor (11.64%), linalyl acetate (11.51%) and 1,8-cineole (10.15%). AM-EO can suppress the inflammatory responses of lipopolysaccharides (LPS)-stimulated RAW 264.7 macrophages, including decreased levels of cellular nitric oxide (NO) and superoxide anion production, lipid peroxidation and glutathione (GSH) concentration. This antioxidant activity is not a result of increased superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities, but rather occurs as a result of the down-regulation of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and heme oxygenase-1 (HO-1) expression, thus reducing the inflammatory response. Therefore, AM-EO can be utilized in many applications, including the treatment of inflammatory diseases in the future. PMID- 23797660 TI - Enzymatic properties of Populus alpha- and beta-NAD-ME recombinant proteins. AB - Plant mitochondrial NAD-malic enzyme (NAD-ME), which is composed of alpha- and beta-subunits in many species, participates in many plant biosynthetic pathways and in plant respiratory metabolism. However, little is known about the properties of woody plant NAD-MEs. In this study, we analyzed four NAD-ME genes (PtNAD-ME1 through PtNAD-ME4) in the genome of Populus trichocarpa. PtNAD-ME1 and -2 encode putative alpha-subunits, while PtNAD-ME3 and -4 encode putative beta subunits. The Populus NAD-MEs were expressed in Escherichia coli cells as GST tagged fusion proteins. Each recombinant GST-PtNAD-ME protein was purified to near homogeneity by glutathione-Sepharose 4B affinity chromatography. Milligram quantities of each native protein were obtained from 1 L bacterial cultures after cleavage of the GST tag. Analysis of the enzymatic properties of these proteins in vitro indicated that alpha-NAD-MEs are more active than beta-NAD-MEs and that alpha- and beta-NAD-MEs presented different kinetic properties (Vmax, kcat and kcat/Km). The effect of different amounts of metabolites on the activities of Populus alpha- and beta-NAD-MEs was assessed in vitro. While none of the metabolites evaluated in our assays activated Populus NAD-ME, oxalacetate and citrate inhibited all alpha- and beta-NAD-MEs and glucose-6-P and fructose inhibited only the alpha-NAD-MEs. PMID- 23797661 TI - Anti-tumor effects of Mfn2 in gastric cancer. AB - Mitofusin-2 (Mfn2) is a mitochondrial outer membrane protein involved in mitochondrial fusion. Its mutation can cause Charcot-Marie-Tooth disease. Recent studies of Mfn2 in cancer research have not included gastric cancer. We confirmed that Mfn2 expression was lower in tumor tissue than in normal gastric mucosal tissue and that it was negatively correlated with tumor size, indicating an anti tumor role for Mfn2. In vitro experiments showed that Mfn2 overexpression suppressed gastric cancer cell proliferation and colony formation, weakened the invasion and migratory ability of cancer cells by downregulating MMP-2 and MMP-9, halted the cell cycle and induced apoptosis. Western blotting indicated the likely involvement of P21 and PI3K/Akt signaling. Therefore, Mfn2 is a potential anti-tumor gene and a potential therapeutic target for treating gastric cancer. The progress of gastric cancer may be delayed by controlling Mfn2 expression. PMID- 23797662 TI - Birth plans: tickets to the OR? AB - Although some nurses and physicians might suggest that women who write birth plans are at greater risk of a cesarean birth, research has not supported this myth. The research studies on this topic have suggested, actually, that women who write birth plans do not have higher cesarean rates or worse obstetric outcomes. Birth plans have been shown to inform and empower women, and lead to more satisfaction with their birth experiences. The purpose of this article is to present the existing evidence on perinatal outcomes in women with birth plans and to explore the phenomenon of divergent perceptions among care givers. PMID- 23797663 TI - The ultrasound-guided retrolaminar block. AB - PURPOSE: Paravertebral blocks have gained in popularity and offer the possible benefit of reduced adverse effects when compared with epidural analgesia. Nevertheless, pulmonary complications in the form of inadvertent pleural puncture are still a recognized risk. Also, the traditional paravertebral blocks are often technically difficult even with ultrasound guidance and constitute deep non compressible area injections. We present our experience with the first three patients receiving ultrasound-guided retrolaminar blocks for managing the pain associated with multiple rib fractures. CLINICAL FEATURES: The vertebral laminae are identified by ultrasound imaging in a paramedian sagittal plane by sequentially visualizing the pleura and ribs, transverse processes, and the corresponding laminae (from lateral to medial). The block needle is guided to contact the lamina, and the local anesthetic injectate is visualized under real time imaging. A catheter is inserted and used for continuous analgesia. In three consecutive patients, verbal rating scale (VRS) pain scores were reduced from 10/10 to less than 5/10, and no technical difficulties, complications, or adverse effects were encountered. CONCLUSIONS: Successful analgesia was achieved in all three cases utilizing continuous infusion and intermittent boluses with ultrasound-guided retrolaminar blocks. These results show the feasibility of this approach for patients with multiple rib fractures. PMID- 23797664 TI - Academic medicine in the 21st century. AB - The achievements of academic medical centers in improving clinical care, advancing scientific discovery, and training the next generation of scientists and clinicians have been remarkable. But today, academic medicine is in great danger from shrinking support for each of its core missions--clinical care, research, and education. This unprecedented crisis also brings a unique opportunity for radical change in the culture, organization, and operation of academic medical centers. PMID- 23797665 TI - Unraveling the geometry dependence of in-nozzle cavitation in high-pressure injectors. AB - Cavitation is an intricate multiphase phenomenon that interplays with turbulence in fluid flows. It exhibits clear duality in characteristics, being both destructive and beneficial in our daily lives and industrial processes. Despite the multitude of occurrences of this phenomenon, highly dynamic and multiphase cavitating flows have not been fundamentally well understood in guiding the effort to harness the transient and localized power generated by this process. In a microscale, multiphase flow liquid injection system, we synergistically combined experiments using time-resolved x-radiography and a novel simulation method to reveal the relationship between the injector geometry and the in-nozzle cavitation quantitatively. We demonstrate that a slight alteration of the geometry on the micrometer scale can induce distinct laminar-like or cavitating flows, validating the multiphase computational fluid dynamics simulation. Furthermore, the simulation identifies a critical geometric parameter with which the high-speed flow undergoes an intriguing transition from non-cavitating to cavitating. PMID- 23797666 TI - BAFF- and APRIL-dependent maintenance of antibody titers after immunization with T-dependent antigen and CD1d-binding ligand. AB - CD1d-restricted invariant NKT (iNKT) cells boost humoral immunity to T-dependent Ags that are coadministered with the CD1d-binding glycolipid Ag alpha galactosylceramide (alpha-GC). Observations that mice lacking iNKT cells have decaying Ab responses following vaccination have led to the hypothesis that iNKT cells express plasma cell (PC) survival factors that sustain specific Ab titers. Bone marrow chimeric mice in which the entire hematopoietic compartment or iNKT cells selectively lacked BAFF, a proliferation-inducing ligand (APRIL), or both BAFF and APRIL were created and immunized with nitrophenol hapten-conjugated keyhole limpet hemocyanin adsorbed to Imject aluminum hydroxide-containing adjuvant or mixed with alpha-GC. In comparison with BAFF- or APRIL-sufficient bone marrow chimeras, absence of hematopoietic compartment- and iNKT-derived BAFF and APRIL was associated with rapidly decaying Ab titers and reduced PC numbers. The iNKT cell-derived BAFF or APRIL assumed a greater role in PC survival when alpha-GC was used as the adjuvant for immunization. These results show that iNKT cell-derived BAFF and APRIL each contribute to survival of PCs induced by immunization. This study sheds new light on the mechanisms through which iNKT cells impact humoral immunity and may inform design of vaccines that incorporate glycolipid adjuvants. PMID- 23797667 TI - Pulmonary expression of oncostatin M (OSM) promotes inducible BALT formation independently of IL-6, despite a role for IL-6 in OSM-driven pulmonary inflammation. AB - Inducible BALT (iBALT) is associated with immune responses to respiratory infections as well as with local pathology derived from chronic inflammatory lung diseases. In this study, we assessed the role of oncostatin M (OSM) in B cell activation and iBALT formation in mouse lungs. We found that C57BL/6 mice responded to an endotracheally administered adenovirus vector expressing mouse OSM, with marked iBALT formation, increased cytokine (IL-4, IL-5, IL-6, IL-10, TNF-alpha, and IL-12), and chemokine (CXCL13, CCL20, CCL21, eotaxin-2, KC, and MCP-1) production as well as inflammatory cell accumulation in the airways. B cells, T cells, and dendritic cells were also recruited to the lung, where many displayed an activated phenotype. Mice treated with control adenovirus vector (Addl70) were not affected. Interestingly, IL-6 was required for inflammatory responses in the airways and for the expression of most cytokines and chemokines. However, iBALT formation and lymphocyte recruitment to the lung tissue occurred independently of IL-6 and STAT6 as assessed in gene-deficient mice. Collectively, these results support the ability of OSM to induce B cell activation and iBALT formation independently of IL-6 and highlight a role for IL-6 downstream of OSM in the induction of pulmonary inflammation. PMID- 23797669 TI - Antibody and antigen contact residues define epitope and paratope size and structure. AB - A total of 111 Ag-Ab x-ray crystal structures of large protein Ag epitopes and paratopes were analyzed to inform the process of eliciting or selecting functional and therapeutic Abs. These analyses illustrate that Ab contact residues (CR) are distributed in three prominent CR regions (CRR) on L and H chains that overlap but do not coincide with Ab CDR. The number of Ag and Ab CRs per structure are overlapping and centered around 18 and 19, respectively. The CR span (CRS), a novel measure introduced in this article, is defined as the minimum contiguous amino acid sequence containing all CRs of an Ag or Ab and represents the size of a complete structural epitope or paratope, inclusive of CR and the minimum set of supporting residues required for proper conformation. The most frequent size of epitope CRS is 50-79 aa, which is similar in size to L (60-69) and H chain (70-79) CRS. The size distribution of epitope CRS analyzed in this study ranges from ~20 to 400 aa, similar to the distribution of independent protein domain sizes reported in the literature. Together, the number of CRs and the size of the CRS demonstrate that, on average, complete structural epitopes and paratopes are equal in size to each other and similar in size to intact protein domains. Thus, independent protein domains inclusive of biologically relevant sites represent the fundamental structural unit bound by, and useful for eliciting or selecting, functional and therapeutic Abs. PMID- 23797668 TI - Distinct chemokine receptor axes regulate Th9 cell trafficking to allergic and autoimmune inflammatory sites. AB - Migration of Th cells to peripheral sites of inflammation is essential for execution of their effector function. The recently described Th9 subset characteristically produces IL-9 and has been implicated in both allergy and autoimmunity. Despite this, the migratory properties of Th9 cells remain enigmatic. In this study, we examined chemokine receptor usage by Th9 cells and demonstrate, in models of allergy and autoimmunity, that these cells express functional CCR3, CCR6, and CXCR3, chemokine receptors commonly associated with other, functionally opposed effector Th subsets. Most Th9 cells that express CCR3 also express CXCR3 and CCR6, and expression of these receptors appears to account for the recruitment of Th9 cells to disparate inflammatory sites. During allergic inflammation, Th9 cells use CCR3 and CCR6, but not CXCR3, to home to the peritoneal cavity, whereas Th9 homing to the CNS during experimental autoimmune encephalomyelitis involves CXCR3 and CCR6 but not CCR3. To our knowledge, these data provide the first insights into regulation of Th9 cell trafficking in allergy and autoimmunity. PMID- 23797670 TI - IL-23 receptor expression on gammadelta T cells correlates with their enhancing or suppressive effects on autoreactive T cells in experimental autoimmune uveitis. AB - We have previously reported that, depending on their activation status, mouse gammadelta T cells can either enhance or inhibit the activity of IL-17(+) autoreactive T cells in experimental autoimmune uveitis. In this study, we showed that gammadelta T cells in naive C57BL/6 (B6) mouse do not express the IL-23R, whereas in immunized mice, it is expressed on >50% of gammadelta T cells. In vitro studies showed that IL-23R expression on gammadelta T cells is modulated by their state of activation, as weakly activated gammadelta T cells expressed the IL-23R, but highly activated gammadelta T cells did not. Functional studies showed that IL-23R(+) gammadelta T cells had the strongest suppressive effect on IL-17(+) autoreactive T cells, and that this effect was inhibited when the IL-23R was blocked by anti-IL-23R Ab or in the presence of excessive amounts of exogenous IL-23. We conclude that the balance between the enhancing and inhibitory effects of gammadelta T cells is regulated by their level of IL-23R expression. The expression of variable IL-23R levels allows gammadelta T cells to have different regulatory effects on adaptive immune responses, conceivably as a result of alphabeta and gammadelta T cells competing for IL-23. PMID- 23797671 TI - Mast cell-restricted, tetramer-forming tryptases induce aggrecanolysis in articular cartilage by activating matrix metalloproteinase-3 and -13 zymogens. AB - Mouse mast cell protease (mMCP)-6-null C57BL/6 mice lost less aggrecan proteoglycan from the extracellular matrix of their articular cartilage during inflammatory arthritis than wild-type (WT) C57BL/6 mice, suggesting that this mast cell (MC)-specific mouse tryptase plays prominent roles in articular cartilage catabolism. We used ex vivo mouse femoral head explants to determine how mMCP-6 and its human ortholog hTryptase-beta mediate aggrecanolysis. Exposure of the explants to recombinant hTryptase-beta, recombinant mMCP-6, or lysates harvested from WT mouse peritoneal MCs (PMCs) significantly increased the levels of enzymatically active matrix metalloproteinases (MMP) in cartilage and significantly induced aggrecan loss into the conditioned media, relative to replicate explants exposed to medium alone or lysates collected from mMCP-6-null PMCs. Treatment of cartilage explants with tetramer-forming tryptases generated aggrecan fragments that contained C-terminal DIPEN and N-terminal FFGVG neoepitopes, consistent with MMP-dependent aggrecanolysis. In support of these data, hTryptase-beta was unable to induce aggrecan release from the femoral head explants obtained from Chloe mice that resist MMP cleavage at the DIPEN?FFGVG site in the interglobular domain of aggrecan. In addition, the abilities of mMCP 6-containing lysates from WT PMCs to induce aggrecanolysis were prevented by inhibitors of MMP-3 and MMP-13. Finally, recombinant hTryptase-beta was able to activate latent pro-MMP-3 and pro-MMP-13 in vitro. The accumulated data suggest that human and mouse tetramer-forming tryptases are MMP convertases that mediate cartilage damage and the proteolytic loss of aggrecan proteoglycans in arthritis, in part, by activating the zymogen forms of MMP-3 and MMP-13, which are constitutively present in articular cartilage. PMID- 23797673 TI - Macrophage migration inhibitory factor potentiates autoimmune-mediated neuroinflammation. AB - Macrophage migration inhibitory factor (MIF) is a multipotent cytokine that is associated with clinical worsening and relapses in multiple sclerosis (MS) patients. The mechanism through which MIF promotes MS progression remains undefined. In this study, we identify a critical role for MIF in regulating CNS effector mechanisms necessary for the development of inflammatory pathology in a mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Despite the ability to generate pathogenic myelin-specific immune responses peripherally, MIF deficient mice have reduced EAE severity and exhibit less CNS inflammatory pathology, with a greater percentage of resting microglia and fewer infiltrating inflammatory macrophages. We demonstrate that MIF is essential for promoting microglial activation and production of the innate soluble mediators IL-1beta, IL 6, TNF-alpha, and inducible NO synthase. We propose a novel role for MIF in inducing microglial C/EBP-beta, a transcription factor shown to regulate myeloid cell function and play an important role in neuroinflammation. Intraspinal stereotaxic microinjection of MIF resulted in upregulation of inflammatory mediators in microglia, which was sufficient to restore EAE-mediated inflammatory pathology in MIF-deficient mice. To further implicate a role for MIF, we show that MIF is highly expressed in human active MS lesions. Thus, these results illustrate the ability of MIF to influence the CNS cellular and molecular inflammatory milieu during EAE and point to the therapeutic potential of targeting MIF in MS. PMID- 23797674 TI - Antiepileptics other than gabapentin, pregabalin, topiramate, and valproate for the prophylaxis of episodic migraine in adults. AB - BACKGROUND: Some antiepileptic drugs but not others are useful in clinical practice for the prophylaxis of migraine. This might be explained by the variety of actions of these drugs in the central nervous system. The present review is part of an update of a Cochrane review first published in 2004, and previously updated (conclusions not changed) in 2007. OBJECTIVES: To describe and assess the evidence from controlled trials on the efficacy and tolerability of antiepileptic drugs other than gabapentin, pregabalin, topiramate, and valproate (which are the subjects of separate Cochrane reviews) for preventing migraine attacks in adult patients with episodic migraine. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2012, Issue 12), PubMed/MEDLINE (1966 to 15 January 2013), MEDLINE In-Process (current week, 15 January 2013), and EMBASE (1974 to 15 January 2013) and handsearched Headache and Cephalalgia through January 2013. SELECTION CRITERIA: Studies were required to be prospective, controlled trials of antiepileptic drugs other than gabapentin, pregabalin, topiramate, and valproate taken regularly to prevent the occurrence of migraine attacks, to improve migraine-related quality of life, or both. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data. For headache frequency data, we calculated mean differences (MDs) between antiepileptic drugs and comparators (placebo, active control, or same drug in a different dose) for individual studies and pooled these across studies. For dichotomous data on responders (patients with >= 50% reduction in headache frequency), we calculated odds ratios (ORs) and numbers needed to treat (NNTs). We also summarised data on adverse events from placebo-controlled trials and calculated risk differences (RDs) and numbers needed to harm (NNHs). MAIN RESULTS: Eleven papers describing 10 unique trials met the inclusion criteria. The 10 trials reported results for nine antiepileptic drugs other than gabapentin, pregabalin, topiramate, and valproate. Six of the eight drugs investigated in placebo-controlled trials were not better than placebo in reducing headache frequency per 28-day period during treatment (clonazepam, lamotrigine, oxcarbazepine, and vigabatrin) and/or in the proportion of responders (acetazolamide, carisbamate, lamotrigine, oxcarbazepine). One prospective, randomised, double-blind, single cross-over trial of 48 patients demonstrated a significant superiority of carbamazepine over placebo in the proportion of responders (OR 11.77; 95% confidence interval (CI) 3.92 to 35.32). The NNT was 2 (95% CI 2 to 3). In a small prospective, randomised, double-blind, parallel-group trial, levetiracetam 1000 mg was significantly superior to placebo in reducing headache frequency per 28-day period during treatment (MD -2.40; 95% CI -4.52 to -0.28; 26 patients), as well as in the proportion of responders (OR 26.07; 95% CI 1.30 to 521.91; 26 patients). The NNT was 2 (95% CI 1 to 4). The same trial examined levetiracetam 1000 mg versus topiramate 100 mg and found a small but significant difference favouring topiramate in headache frequency per 28-day period during treatment (MD 1.40; 95% CI 0.14 to 2.66; 28 patients). There was no significant difference between levetiracetam and topiramate in the proportion of responders (OR 0.71; 95% CI 0.16 to 3.23; 28 patients). Finally, one trial with 75 participants examined zonisamide versus topiramate (200 and 100 mg, respectively) and found no significant difference between them in reduction of headache frequency from baseline during the third month of treatment. Adverse events for active treatment versus placebo were available for all investigated drugs except levetiracetam, vigabatrin, and zonisamide. A high prevalence of adverse events was noted for carbamazepine, with a NNH of only 2 (95% CI 2 to 4). AUTHORS' CONCLUSIONS: Available evidence does not allow robust conclusions regarding the efficacy of antiepileptic drugs other than gabapentin, pregabalin, topiramate, and valproate in the prophylaxis of episodic migraine among adults. Acetazolamide, carisbamate, clonazepam, lamotrigine, oxcarbazepine, and vigabatrin were not more effective than placebo in reducing headache frequency. In one trial each, carbamazepine and levetiracetam were significantly superior to placebo in reducing headache frequency, and there was no significant difference in proportion of responders between zonisamide and active comparator. These three positive studies suffer from considerable methodological limitations. PMID- 23797672 TI - The role of JAK-3 in regulating TLR-mediated inflammatory cytokine production in innate immune cells. AB - The role of JAK-3 in TLR-mediated innate immune responses is poorly understood, although the suppressive function of JAK3 inhibition in adaptive immune response has been well studied. In this study, we found that JAK3 inhibition enhanced TLR mediated immune responses by differentially regulating pro- and anti- inflammatory cytokine production in innate immune cells. Specifically, JAK3 inhibition by pharmacological inhibitors or specific small interfering RNA or JAK3 gene knockout resulted in an increase in TLR-mediated production of proinflammatory cytokines while concurrently decreasing the production of IL-10. Inhibition of JAK3 suppressed phosphorylation of PI3K downstream effectors including Akt, mammalian target of rapamycin complex 1, glycogen synthase kinase 3beta (GSK3beta), and CREB. Constitutive activation of Akt or inhibition of GSK3beta abrogated the capability of JAK3 inhibition to enhance proinflammatory cytokines and suppress IL-10 production. In contrast, inhibition of PI3K enhanced this regulatory ability of JAK3 in LPS-stimulated monocytes. At the transcriptional level, JAK3 knockout lead to the increased phosphorylation of STATs that could be attenuated by neutralization of de novo inflammatory cytokines. JAK3 inhibition exhibited a GSK3 activity-dependent ability to enhance phosphorylation levels and DNA binding of NF-kappaB p65. Moreover, JAK3 inhibition correlated with an increased CD4(+) T cell response. Additionally, higher neutrophil infiltration, IL-17 expression, and intestinal epithelium erosion were observed in JAK3 knockout mice. These findings demonstrate the negative regulatory function of JAK3 and elucidate the signaling pathway by which JAK3 differentially regulates TLR-mediated inflammatory cytokine production in innate immune cells. PMID- 23797675 TI - Gabapentin or pregabalin for the prophylaxis of episodic migraine in adults. AB - BACKGROUND: Some antiepileptic drugs but not others are useful in clinical practice for the prophylaxis of migraine. This might be explained by the variety of actions of these drugs in the central nervous system. The present review is part of an update of a Cochrane review first published in 2004, and previously updated (conclusions not changed) in 2007. OBJECTIVES: To describe and assess the evidence from controlled trials on the efficacy and tolerability of gabapentin/gabapentin enacarbil or pregabalin for preventing migraine attacks in adult patients with episodic migraine. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2012, Issue 12), PubMed/MEDLINE (1966 to 15 January 2013), MEDLINE In-Process (current week, 15 January 2013), and EMBASE (1974 to 15 January 2013) and handsearched Headache and Cephalalgia through January 2013. SELECTION CRITERIA: Studies were required to be prospective, controlled trials of gabapentin/gabapentin enacarbil or pregabalin taken regularly to prevent the occurrence of migraine attacks, to improve migraine-related quality of life, or both. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data. For headache frequency data, we calculated mean differences (MDs) between gabapentin and comparator (placebo, active control, or gabapentin in a different dose) for individual studies and pooled these across studies. For dichotomous data on responders (patients with >= 50% reduction in headache frequency), we calculated odds ratios (ORs) and numbers needed to treat (NNTs). We also summarised data on adverse events from all single dosage studies and calculated risk differences (RDs) and numbers needed to harm (NNHs). MAIN RESULTS: Five trials on gabapentin and one trial on its prodrug gabapentin enacarbil met the inclusion criteria; no reports on pregabalin were identified. In total, data from 1009 patients were considered. One trial each of gabapentin 900 mg (53 patients), and gabapentin titrated to 1200 mg (63 patients) and 1800 mg (122 patients) failed to show a statistically significant reduction in headache frequency in the active treatment group as compared to the placebo group, whereas one trial of gabapentin titrated to 1800 to 2400 mg (113 patients) demonstrated a small but statistically significant superiority of active treatment for this outcome (MD -0.80; 95% confidence interval (CI) -1.55 to -0.05). The pooled results of these four studies (MD -0.44; 95% CI -1.43 to 0.56; 351 patients) do not demonstrate a significant difference between gabapentin and placebo. One trial of gabapentin titrated to 1800 mg (122 patients) failed to demonstrate a significant difference between active treatment and placebo in the proportion of responders (OR 0.97; 95% CI 0.45 to 2.11), whereas one trial of gabapentin titrated to 1800 to 2400 mg (113 patients) demonstrated a small but statistically significant superiority of active treatment for this outcome (OR 2.79; 95% CI 1.09 to 7.17). The pooled results of these two studies (OR 1.59; 95% CI 0.57 to 4.46; 235 patients) do not demonstrate a significant difference between gabapentin and placebo. Comparisons from one study (135 patients) suggest that gabapentin 2000 mg is no more effective than gabapentin 1200 mg. One trial of gabapentin enacarbil (523 participants) failed to demonstrate a significant difference versus placebo or between doses for gabapentin enacarbil titrated to between 1200 mg and 3000 mg with regard to proportion of responders; there was also no evidence of a dose response trend. Adverse events, most notably dizziness and somnolence, were common with gabapentin. AUTHORS' CONCLUSIONS: The pooled evidence derived from trials of gabapentin suggests that it is not efficacious for the prophylaxis of episodic migraine in adults. Since adverse events were common among the gabapentin-treated patients, it is advocated that gabapentin should not be used in routine clinical practice. Gabapentin enacarbil is not efficacious for the prophylaxis of episodic migraine in adults. There is no published evidence from controlled trials of pregabalin for the prophylaxis of episodic migraine in adults. PMID- 23797676 TI - Topiramate for the prophylaxis of episodic migraine in adults. AB - BACKGROUND: Some antiepileptic drugs but not others are useful in clinical practice for the prophylaxis of migraine. This might be explained by the variety of actions of these drugs in the central nervous system. The present review is part of an update of a Cochrane review first published in 2004, and previously updated (conclusions not changed) in 2007. OBJECTIVES: To describe and assess the evidence from controlled trials on the efficacy and tolerability of topiramate for preventing migraine attacks in adult patients with episodic migraine. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2012, Issue 12), PubMed/MEDLINE (1966 to 15 January 2013), MEDLINE In-Process (current week, 15 January 2013), and EMBASE (1974 to 15 January 2013) and handsearched Headache and Cephalalgia through January 2013. SELECTION CRITERIA: Studies were required to be prospective, controlled trials of topiramate taken regularly to prevent the occurrence of migraine attacks, to improve migraine-related quality of life, or both. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data. For headache frequency data, we calculated mean differences (MDs) between topiramate and comparator (placebo, active control, or topiramate in a different dose) for individual studies and pooled these across studies. For dichotomous data on responders (patients with >= 50% reduction in headache frequency), we calculated odds ratios (ORs) and, in select cases, risk ratios (RRs); we also calculated numbers needed to treat (NNTs). We calculated MDs for selected quality of life instruments. Finally, we summarised data on adverse events from placebo controlled trials and calculated risk differences (RDs) and numbers needed to harm (NNHs). MAIN RESULTS: Twenty papers describing 17 unique trials met the inclusion criteria. Analysis of data from nine trials (1737 participants) showed that topiramate reduced headache frequency by about 1.2 attacks per 28 days as compared to placebo (MD -1.20; 95% confidence interval (CI) -1.59 to -0.80). Data from nine trials (1190 participants) show that topiramate approximately doubled the proportion of responders relative to placebo (RR 2.02; 95% CI 1.57 to 2.60; NNT 4; 95% CI 3 to 6). Separate analysis of different topiramate doses produced similar MDs versus placebo at 50 mg (-0.95; 95% CI -1.95 to 0.04; three studies; 520 participants), 100 mg (-1.15; 95% CI -1.58 to -0.71; six studies; 1620 participants), and 200 mg (-0.94; 95% CI -1.53 to -0.36; five studies; 804 participants). All three doses significantly increased the proportion of responders relative to placebo; ORs were as follows: for 50 mg, 2.35 (95% CI 1.60 to 3.44; three studies; 519 participants); for 100 mg, 3.49 (95% CI 2.23 to 5.45; five studies; 852 participants); and for 200 mg, 2.49 (95% CI 1.61 to 3.87; six studies; 1025 participants). All three doses also significantly improved three or more domains of quality of life as compared to placebo. Meta-analysis of the three studies that included more than one dose of topiramate suggests that 200 mg is no more effective than 100 mg. With regard to mean headache frequency and/or responder rate, seven trials using active comparators found (a) no significant difference between topiramate and amitriptyline (one study, 330 participants); (b) no significant difference between topiramate and flunarizine (one study, 83 participants); (c) no significant difference between topiramate and propranolol (two studies, 342 participants); (d) no significant difference between topiramate and relaxation (one study, 61 participants); but (e) a slight significant advantage of topiramate over valproate (two studies, 120 participants). Relaxation improved migraine-specific quality of life significantly more than topiramate. In trials of topiramate against placebo, seven adverse events (AEs) were reported by at least three studies. These were usually mild and of a non serious nature. Except for taste disturbance and weight loss, there were no significant differences in the frequency of AEs in general, or of the seven specific AEs, between placebo and topiramate 50 mg. AEs in general and all of the specific AEs except nausea were significantly more common on topiramate 100 mg than on placebo, with NNHs varying from 3 to 25, and the RDs versus placebo were even higher for topiramate 200 mg, with NNHs varying from 2 to 17. AUTHORS' CONCLUSIONS: Meta-analysis demonstrates that topiramate in a 100 mg/day dosage is effective in reducing headache frequency and reasonably well-tolerated in adult patients with episodic migraine. This provides good evidence to support its use in routine clinical management. More studies designed specifically to compare the efficacy or safety of topiramate versus other interventions with proven efficacy in the prophylaxis of migraine are needed. PMID- 23797677 TI - Valproate (valproic acid or sodium valproate or a combination of the two) for the prophylaxis of episodic migraine in adults. AB - BACKGROUND: Some antiepileptic drugs but not others are useful in clinical practice for the prophylaxis of migraine. This might be explained by the variety of actions of these drugs in the central nervous system. The present review is part of an update of a Cochrane review first published in 2004, and previously updated (conclusions not changed) in 2007. OBJECTIVES: To describe and assess the evidence from controlled trials on the efficacy and tolerability of valproate (valproic acid or sodium valproate or a combination of the two) for preventing migraine attacks in adult patients with episodic migraine. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2012, Issue 12), PubMed/MEDLINE (1966 to 15 January 2013), MEDLINE In-Process (current week, 15 January 2013), and EMBASE (1974 to 15 January 2013) and handsearched Headache and Cephalalgia through January 2013. SELECTION CRITERIA: Studies were required to be prospective, controlled trials of valproate taken regularly to prevent the occurrence of migraine attacks, to improve migraine-related quality of life, or both. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data. For headache frequency data, we calculated mean differences (MDs) between valproate and comparator (placebo, active control, or valproate in a different dose) for individual studies and pooled these across studies. For dichotomous data on responders (patients with >= 50% reduction in headache frequency), we calculated odds ratios (ORs) and, in select cases, risk ratios (RRs); we also calculated numbers needed to treat (NNTs). We calculated MDs for Migraine Disability Assessment (MIDAS) scores. We also summarised data on adverse events from placebo controlled trials and calculated risk differences (RDs) and numbers needed to harm (NNHs). MAIN RESULTS: Ten papers describing 10 unique trials met the inclusion criteria. Analysis of data from two trials (63 participants) showed that sodium valproate reduced headache frequency by approximately four headaches per 28 days as compared to placebo (MD -4.31; 95% confidence interval (CI) -8.32 to -0.30). Data from four trials (542 participants) showed that divalproex sodium (a stable combination of sodium valproate and valproic acid in a 1:1 molar ratio) more than doubled the proportion of responders relative to placebo (RR 2.18; 95% CI 1.28 to 3.72; NNT 4; 95% CI 2 to 11). One study of sodium valproate (34 participants) versus placebo supported the latter findings (RR for responders 2.83; 95% CI 1.27 to 6.31; NNT 3; 95% CI 2 to 9). There was no significant difference in the proportion of responders between sodium valproate versus flunarizine (one trial, 41 participants) or between divalproex sodium versus propranolol (one trial, 32 participants). Pooled analysis of post-treatment mean headache frequencies in two trials (88 participants) demonstrates a slight but significant advantage for topiramate 50 mg over valproate 400 mg (MD -0.90; 95% CI -1.58 to -0.22). For placebo-controlled trials of sodium valproate and divalproex sodium, NNHs for clinically important adverse events ranged from 7 to 14. AUTHORS' CONCLUSIONS: Valproate is effective in reducing headache frequency and is reasonably well tolerated in adult patients with episodic migraine. PMID- 23797678 TI - Is the BTS/SIGN guideline confusing? A retrospective database analysis of asthma therapy. AB - BACKGROUND: The British guideline on the management of asthma produced by the British Thoracic Society (BTS) and the Scottish Intercollegiate Guidelines Network (SIGN) describes five steps for the management of chronic asthma. Combination therapy of a long acting beta2-agonist (LABA) and an inhaled corticosteroid (ICS) is recommended as first-line therapy at step 3, although the dose of ICS at which to add a LABA is subject to debate. AIMS: To classify the inhaled therapy prescribed to patients with asthma in NHS Forth Valley according to two interpretations of the BTS/SIGN guideline and to evaluate the use of combination therapy in this population. METHODS: A retrospective analysis including patients from 46 general practitioner surgeries was conducted. Patients with physician diagnosed asthma were classified according to the BTS/SIGN guideline based on treatment prescribed during 2008. Patient characteristics were evaluated for the overall step classification, and specifically for therapy in step 3. RESULTS: 12,319 patients were included. Guideline interpretation resulted in a shift of 9.2% of patients (receiving medium-dose ICS alone) between steps 2 and 3. The largest proportion of patients (32.3%) was classified at step 4. Age, sex, smoking status, chronic obstructive pulmonary disease co-morbidity, and utilisation of short-acting beta2-agonists and oral corticosteroids all correlated with step; however, no differences in these characteristics were evident between low-dose combination therapy and medium-dose ICS alone at step 3. CONCLUSIONS: Further studies are needed to evaluate prescribing decisions in asthma. Guideline recommendations regarding the use of ICS dose escalation versus combination therapy need to be clarified relative to the published evidence. PMID- 23797679 TI - Barriers to, and facilitators for, referral to pulmonary rehabilitation in COPD patients from the perspective of Australian general practitioners: a qualitative study. AB - BACKGROUND: Pulmonary rehabilitation (PR) is recommended in the management of people with chronic obstructive pulmonary disease (COPD), but referral to this service is low. AIMS: To identify barriers to, and facilitators for, referral to PR programmes from the perspective of Australian general practitioners. METHODS: Semi-structured interviews were conducted with general practitioners involved in the care of people with COPD. Interview questions were informed by a validated behavioural framework and asked about participants' experience of referring people with COPD for PR, and barriers to, or facilitators of, this behaviour. Interviews were audiotaped, transcribed verbatim, and analysed using content analysis. RESULTS: Twelve general practitioners participated in this study, 10 of whom had never referred a patient to a PR programme. Four major categories relating to barriers to referral were identified: low knowledge of PR for COPD; low knowledge of how to refer; actual or anticipated access difficulties for patients; and questioning the need to do more to promote exercise behaviour change. Awareness of benefit was the only current facilitator. Three major categories of potential facilitators were identified: making PR part of standard COPD care through financial incentive; improving information flow with regard to referrals and services; and informing patients and public. CONCLUSIONS: Significant barriers to referral exist, but opportunities to change the organisation of practice and information management were identified. Behaviour change strategies which directly target these barriers and incorporate facilitators should make up the key components of interventions to improve referral to PR by general practitioners who care for people with COPD. PMID- 23797680 TI - Reactivity differences between 2,4- and 2,5-disubstituted zirconacyclopentadienes: a highly selective and general approach to 2,4 disubstituted phospholes. AB - Mixtures of 2,4- and 2,5-disubstituted zirconacyclopentadienes were obtained by the reductive dimerisation of terminal alkynes using the Cp2ZrCl2/lanthanum system. Reactions of dihalophosphines with these mixtures afforded selectively the corresponding 2,4-disubstituted phospholes and 1,4-disubstituted butadienes. A new series of phospholes was characterized by multi-nuclear NMR spectroscopy and X-ray analysis. A possible explanation for the observed selectivity was obtained from X-ray studies and DFT analysis of the intermediate zirconacyclopentadienes. PMID- 23797681 TI - [Assisted peritoneal dialysis: home-based renal replacement therapy for the elderly patient]. AB - The number of elderly patients with end stage renal disease is constantly increasing. Conventional hamodiaylsis as the mainstay of renal replacement therapy is often poorly tolerated by frail eldery patients with multiple comorbidities. Although many of these patients would prefer a home based dialysis treatment, the number of elderly patients using peritoneal dialysis (PD) is still low. Impaired physical and cognitive function often generates insurmountable barriers for self care peritoneal dialysis. Assisted peritoneal dialysis can overcome many of these barriers and give elderly patients the ability of a renal replacement therapy in their own homes respecting their needs. PMID- 23797683 TI - ? PMID- 23797682 TI - Merkel cell carcinoma: a review and update on aetiopathogenesis, diagnosis and treatment approaches. AB - Merkel cell carcinoma (MCC) or primary cutaneous neuroendocrine carcinoma is a relatively uncommon form of skin cancer. It is an aggressive neoplasm with high tendency for local recurrence and lymph node and distant metastasis, whose incidence has been rising in the last 2 decades.A novel polyomavirus (MCPyV) has been found in a significant proportion of MCCs, and this finding significantly contributed to the understanding of its pathogenesis.It is fairly consensual at the current state of know-ledge that appropriate staging, including sentinel lymph node biopsy, is very important in order to plan adequate treatment. Treatment includes aggressive surgery of the primary tumour and lymph node basin, commonly combined with adjuvant radiotherapy. Chemotherapy is usually reserved for distant metastasis.In the present article, the authors review the current knowledge about MCC with special emphasis on the new pathogenetic findings and current recommendations regarding management. PMID- 23797684 TI - IgA pemphigus with non-pustular erythematous lesions and IgA antibodies to desmocollins 1 and 2. AB - IgA pemphigus is a rare variant of pemphigus. IgA pemphigus is subdivided into intraepidermal neutrophilic IgA dermatosis-type (IEN-type), whose target antigen is still an enigma, and subcorneal pustular dermatosis-type, whose target antigen is desmocollin 1 (Dsc1). We report a 56-year-old Japanese male with IgA pemphigus showing atypical erythema. One month after erythema developed, the patient visited his private physician, and was tentatively diagnosed as having erythema multiforme. The patient had been intermittently treated with a low dose of oral prednisolone for a year without benefit before visiting our hospital. Clinical examination revealed irregularly-shaped and partially edematous erythema over the trunk and extremities without mucosal involvement. Neither bullae nor pustules were seen during the course. Direct immunofluorescence showed IgA deposition on cell surfaces of keratinocytes in the upper two thirds of the epidermis. Indirect immunofluorescence of monkey esophagus sections revealed IgA and IgG anti-cell surface antibodies. Our new enzyme-linked immunosorbent assays using eukaryotic recombinant proteins of human Dsc 1-3 detected IgA antibodies to Dsc1 and Dsc2. Although no apparent bullae were observed, the diagnosis of IgA pemphigus was made. Prednisolone 30 mg daily was required to control erythematous lesions. Although the pathomechanism for the unique skin lesion is unknown, the possibility that IgA pemphigus has a prodromal phase and that early administration of low dose prednisolone suppressed the development of pustules or bullae were considered. PMID- 23797686 TI - Validation of tumour models for use in anticancer nanomedicine evaluation: the EPR effect and cathepsin B-mediated drug release rate. AB - PURPOSE: Intravenously (i.v.) administered nanomedicines have the potential for tumour targeting due to the enhanced permeability and retention (EPR) effect, but in vivo tumour models are rarely calibrated with respect to functional vascular permeability and/or mechanisms controlling intratumoural drug release. Here the effect of tumour type and tumour size on EPR-mediated tumour localisation and cathepsin B-mediated drug release was studied. METHODS: Evans Blue (10 mg/kg) and an N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-doxorubicin (Dox) conjugate (FCE28068) (5 mg/kg Dox-equiv) were used as probes and tumour levels (and Dox release) measured at 1 h after i.v. administration in a panel of murine and human xenograft tumours. RESULTS: Evans Blue and FCE28068 displayed similar tumour levels in the range of 2-18 % dose/g at 1 h for B16F10 and L1210. Approximately half of the tumour models evaluated exhibited tumour size-dependent accumulation of FCE28068; smaller tumours had the highest accumulation. Administration of free Dox (5 mg/kg) produced tumour levels of ?2.5 % dose/g independent of tumour size. Whereas the degree of EPR-mediated targeting showed *12-fold difference across the tumour models evaluated, Dox release from FCE28068 at 1 h displayed *200-fold variation. CONCLUSIONS: Marked heterogeneity was seen in terms of EPR effect and Dox release rate, underlining the need to carefully calibrate tumour models used to benchmark nanomedicines against known relevant standard agents and for optimal development of strategies for late pre-clinical and clinical development. PMID- 23797687 TI - Molecular adsorption induces the transformation of rhombohedral- to Bernal stacking order in trilayer graphene. AB - The Bernal (ABA)-stacked graphene trilayer is presumed to be thermodynamically more stable than the rhombohedral (ABC) counterpart. However, the thermal transformation from ABC to ABA domains does not occur at a temperature lower than 1,000 degrees C. Here we report that ABC-stacked trilayers are transformed to ABA-stacked layers after an organic molecule triazine is evaporated onto graphene surfaces at 150 degrees C. The transformation is found to always initiate at the ABA-ABC domain boundaries. Simulations based on density function theory considering the van der Waals interaction suggest that after triazine decoration the energy difference between ABA and ABC domains is larger, providing a driving force for stacking transformation. The molecular dynamics simulation results further suggest that the triazine decoration on the wrinkles at the ABC-ABA domain boundary activates the wrinkle sliding toward the ABC domains, leading to the stacking transformation from ABC to ABA. PMID- 23797688 TI - The frequency of alpha4beta7(high) memory CD4+ T cells correlates with susceptibility to rectal simian immunodeficiency virus infection. AB - BACKGROUND: Integrin alpha4beta7(high) (alpha4beta7(high)) mediates the homing of CD4+ T cells to gut-associated lymphoid tissues, which constitute a highly favorable environment for HIV expansion and dissemination. HIV and simian immunodeficiency virus (SIV) envelope proteins bind to and signal through alpha4beta7(high) and during acute infection SIV preferentially infects alpha4beta7(high) CD4+ T cells. We postulated that the availability of these cells at the time of challenge could influence mucosal SIV transmission and acute viral load (VL). METHODS: We challenged 17 rhesus macaques with 3000 TCID50 of SIVmac239 rectally and followed the subsets of alpha4beta7(high) T cells and dendritic cells (DCs) by flow cytometry in blood and tissues, before and after challenge. RESULTS: We found that the frequency of memory CD4+ T cells that expressed high levels of alpha4beta7(high) (alpha4beta7(high) memory CD4+ T cells) in blood before challenge correlated strongly with susceptibility to infection and acute VL. Notably, not only at the time of challenge but also their frequency 3 weeks before challenge correlated with infection. This association extended to the rectal tissue as we observed a strong direct correlation between the frequency of alpha4beta7(high) memory CD4+ T cells in blood and rectum before and after challenge. The frequency of alpha4beta7 myeloid DCs and alpha4beta7(high) CD80+ DCs also correlated with infection and acute VL, whereas blood CCR5+ and CD69+ CD4+ T cells could not be associated with infection. CONCLUSIONS: Our results suggest that animals with higher frequency of alpha4beta7(high) CD4+ T cells in circulation and in rectal tissue could be more susceptible to SIV rectal transmission. PMID- 23797689 TI - Microbial translocation in HIV infection is associated with dyslipidemia, insulin resistance, and risk of myocardial infarction. AB - OBJECTIVE: Microbial translocation has been suggested to be a driver of immune activation and inflammation. It is hypothesized that microbial translocation may be related to dyslipidemia, insulin resistance, and the risk of coronary heart disease in HIV-infected individuals. DESIGN: Cross-sectional study of 60 HIV infected patients on combination antiretroviral therapy with viral suppression >2 years and 31 healthy age-matched controls. METHODS: Lipopolysaccharide (LPS) was analyzed by limulus amebocyte lysate colorimetric assay. Lipids, including cholesterol, low-density lipoprotein (LDL), and triglycerides, were measured. Glucose metabolism was determined using an oral glucose tolerance test. Body composition was determined using whole-body dual-energy x-ray absorptiometry scans and magnetic resonance imaging. The Framingham risk score was used to assess risk of cardiovascular disease and myocardial infarction. RESULTS: HIV infected patients had higher level of LPS compared with controls (64 pg/mL vs. 50 pg/mL, P = 0.002). Likewise, HIV-infected patients had higher triglycerides, LDL, and fasting insulin as well as evidence of lower insulin sensitivity compared with controls. Among HIV-infected patients, high LPS was associated with a higher level of triglycerides and LDL and with lower insulin sensitivity. Importantly, among HIV-infected patients, high LPS was associated with a higher Framingham risk score. CONCLUSIONS: HIV-infected patients with suppressed viral replication had increased level of microbial translocation as measured by LPS. LPS was associated with cardiometabolic risk factors and increased Framingham risk score. Hence, the gastrointestinal mucosal barrier may be a potential therapeutic target to prevent dyslipidemia and future cardiovascular complications in HIV infection. PMID- 23797690 TI - Increasing rate of TAMs and etravirine resistance in HIV-1-infected adults between 12 and 24 months of treatment: the VOLTART cohort study in Cote d'Ivoire, West Africa. AB - BACKGROUND: In sub-Saharan Africa, most HIV-infected patients receive antiretroviral therapy (ART) without virological monitoring. Longitudinal data on secondary resistance are rare. METHODS: We conducted a prospective cohort study of HIV-1-infected adults initiating ART in 3 clinics using computerized monitoring systems. Patients had plasma HIV-1 RNA viral load (VL) tests at months 12 (M12) and 24 (M24) after ART initiation and HIV-1 resistance genotype tests if VL was detectable (>=300 copies/mL). RESULTS: Overall, 1573 patients initiated ART with stavudine/zidovudine plus lamivudine plus nevirapine/efavirenz. At M12 and M24, 944 and 844 patients, respectively, remained in active follow-up. Among them, 25% (M12) and 27% (M24) had detectable VLs and 12% (M12) and 19% (M24) had virus resistant to at least 1 antiretroviral drug, accounting for 54% (M12) and 75% (M24) of patients with detectable VLs. Among the resistant strains, 95% (M12) and 97% (M24) were resistant to lamivudine/emtricitabine, efavirenz, and/or nevirapine, the frequency of thymidine analog mutations increased from 8.1% (M12) to 14.7% (M24) and etravirine resistance increased from 13.5% (M12) to 24.5% (M24). CONCLUSIONS: Of the patients with detectable VLs at M24, 25% still did not harbor resistant virus. Preventing mutations from emerging with adherence reinforcement in patients with detectable VLs remains important beyond M24. Switching therapy early in patients with resistance to 3 TC/FTC and/or to nonnucleoside reverse transcriptase inhibitors to prevent extended resistance to nucleoside reverse transcriptase inhibitors and etravirine resistance from occurring is also a major challenge. PMID- 23797691 TI - Virologic response, early HIV-1 decay, and maraviroc pharmacokinetics with the nucleos(t)ide-free regimen of maraviroc plus darunavir/ritonavir in a pilot study. AB - OBJECTIVE: To address the need for nucleos(t)ide reverse transcriptase inhibitor (NRTI)-sparing regimens, we explored the virologic and pharmacokinetic characteristics of maraviroc plus ritonavir-boosted darunavir in a single-arm, open-label, 96-week study. METHODS: Twenty-four antiretroviral-naive R5 HIV-1 infected participants received maraviroc 150 mg and darunavir/ritonavir (DRV/r) 800/100 mg (MVC/DRV/r) once daily. The primary outcome was virologic failure (VF) = confirmed viral load (VL) >50 copies per milliliter at week 24 in the modified intent-to-treat population. To determine viral dynamics, participant-specific first- and second-phase empirical Bayes estimates were compared with decay rates from efavirenz (EFV) plus lopinavir/ritonavir, lopinavir/ritonavir plus 2NRTIs, and EFV plus 2NRTIs. Maraviroc plasma concentrations were determined at weeks 2, 4, 12, 24, and 48. RESULTS: Baseline median (Q1, Q3) CD4 count and VL were 455 (299, 607) cells per cubic millimeter and 4.62 (4.18, 4.80) log10 copies per milliliter, respectively. VF occurred in 3 of 24 participants {12.5% [95% confidence interval (CI): 2.7 to 32.4]} at week 24. One of these resuppressed, yielding a week 48 VF rate of 2/24 [8.3% (95% CI: 1.0 to 27.0)]. The week 48 failures were 2 of the 4 participants (50%) with baseline VL >100,000 copies per milliliter. Week 96 VF rate was 2/20 [10% (95% CI: 1.2 to 31.7)]. Phase 1 decay was faster with MVC/DRV/r than reported for ritonavir-boosted lopinavir plus 2NRTIs (P = 0.0063) and similar to EFV-based regimens. Individual maraviroc trough concentrations collected between 20 and 28 hours post dose (n = 59) was 13.7 to 130 ng/mL (Q1, 23.4 ng/mL; Q3, 46.5 ng/mL), and modeled steady-state concentration was 128 ng/mL. CONCLUSIONS: MVC/DRV/r 150/800/100 mg once daily has potential for treatment-naive patients with R5 HIV-1. PMID- 23797692 TI - Treatment outcomes in AIDS-related diffuse large B-cell lymphoma in the setting roll out of combination antiretroviral therapy in South Africa. AB - BACKGROUND: Long-term survival for patients with AIDS-related diffuse large B cell lymphoma (DLBCL) is feasible in settings with available combination antiretroviral therapy (cART). However, given limited oncology resources, outcomes for AIDS-associated DLBCL in South Africa are unknown. METHODS: We performed a retrospective analysis of survival in patients with newly diagnosed AIDS-related DLBCL treated at a tertiary teaching hospital in Cape Town, South Africa, with cyclophosphamide, doxorubicin, vincristine, and oral prednisone (CHOP) or CHOP-like chemotherapy (January 2004 until December 2010). HIV-related and lymphoma-related prognostic factors were evaluated. RESULTS: Thirty-six patients evaluated; median age 37.3 years, 52.8% men, and 61.1% black South Africans. Median CD4 count 184 cells per microliter (in 27.8% this was <100 cells/MUL), 80% high risk according to the age-adjusted International Prognostic Index. Concurrent Mycobacterium tuberculosis in 25%. Two-year overall survival (OS) was 40.5% (median OS 10.5 months, 95% confidence interval: 6.5 to 31.8). Eastern Cooperative Oncology Group performance status of 2 or more (25.4% vs 50.0%, P = 0.01) and poor response to cART (18.0% vs 53.9%, P = 0.03) predicted inferior 2-year OS. No difference in 2-year OS was demonstrated in patients coinfected with M. tuberculosis (P = 0.87). CONCLUSIONS: Two-year OS for patients with AIDS-related DLBCL treated with CHOP like regimens and cART is comparable to that seen in the United States and Europe. Important factors effecting OS in AIDS related DLBCL in South Africa include performance status at presentation and response to cART. Patients with comorbid M. tuberculosis or hepatitis B seropositivity seem to tolerate CHOP in our setting. Additional improvements in outcomes are likely possible. PMID- 23797693 TI - Early infection HIV-1 envelope V1-V2 genotypes do not enhance binding or replication in cells expressing high levels of alpha4beta7 integrin. AB - It has been postulated that HIV-1 envelope properties, such as shorter and less glycosylated V1-V2 loops commonly observed among non-subtype B early-transmitted viruses, promote utilization of the gut homing integrin alpha4beta7. This property potentially confers an advantage to some HIV-1 variants early after acquisition. We found that replication-competent recombinant viruses incorporating HIV-1 subtype A compact and less-glycosylated early versus chronic phase V1-V2 loops demonstrated no significant difference in binding to alpha4beta7 high CD8+ T cells or replication in alpha4beta7 high CD4+ T cells. Integrin alpha4beta7 usage does not select for shorter less-glycosylated envelopes during transmission. PMID- 23797694 TI - Prediction of hepatic fibrosis in patients coinfected with HIV and hepatitis C virus based on genetic markers. AB - OBJECTIVE: To assess the ability of the cirrhosis risk score (CRS) to predict liver fibrosis progression in HIV/hepatitis C virus (HCV)-coinfected patients. DESIGN: Retrospective follow-up study. METHODS: Based on a minimum follow-up time of 10 years with HCV infection, 190 HIV/HCV-coinfected patients were classified according to their METAVIR score: (1) 25 nonprogressor patients who did not develop fibrosis (F0) and (2) 165 progressor patients who developed fibrosis (F >= 1). Seven polymorphisms of CRS signature and IL28B genotype were performed using the GoldenGate assay. The CRS signature was calculated by naive Bayes formula as previously described. RESULTS: Nonprogressors had CRS values significantly lower than progressors (0.61 versus 0.67; P = 0.043). Among the progressors, we observed similar CRS values through all the fibrosis stages (F1/F2/F3/F4). The percentage of patients with CRS > 0.70 (high risk of developing fibrosis) was higher in progressors than in nonprogressors; but the percentages with values between 0.50 and 0.70 (intermediate risk) and <0.50 (low risk) were quite similar for each of the fibrosis stages (P = 0.047). The area under the receiver-operating characteristic curve of CRS for discriminating nonprogressor versus progressor was 0.625 (P = 0.043). When clinical variables were considered (age at HCV infection, intravenous drug use, gender, IL28B, and HCV genotype), the area under the receiver-operating characteristic curve of CRS improved up to 0.739 (P < 0.001). CONCLUSIONS: CRS itself seems not to be a good marker for identifying HIV/HCV-coinfected patients who are at high risk of developing liver fibrosis. However, CRS score coupled with clinical factors might help to distinguish between nonprogressors and progressors patients. PMID- 23797695 TI - Understanding the disparity: predictors of virologic failure in women using highly active antiretroviral therapy vary by race and/or ethnicity. AB - BACKGROUND: Stark racial/ethnic disparities in health outcomes exist among those living with HIV in the United States. One of 3 primary goals of the National HIV/AIDS Strategy is to reduce HIV-related disparities and health inequities. METHODS: Using data from HIV-infected women participating in the Women's Interagency HIV Study from April 2006 to March 2011, we measured virologic failure (HIV RNA >200 copies/mL) after suppression (HIV RNA < 80 copies/mL) on highly active antiretroviral therapy. We identified predictors of virologic failure using discrete time survival analysis and calculated racial/ethnic specific population-attributable fractions (PAFs). RESULTS: Of 887 eligible women, 408 (46%) experienced virologic failure during the study period. Hispanic and white women had significantly lower hazards of virologic failure than African American women [Hispanic hazard ratio, (HR) = 0.8, 95% confidence interval: (0.6 to 0.9); white HR = 0.7 (0.5 to 0.9)]. The PAF of virologic failure associated with low income was higher in Hispanic [adjusted hazard ratios (aHR) = 2.2 (0.7 to 6.5), PAF = 49%] and African American women [aHR = 1.8 (1.1 to 3.2), PAF = 38%] than among white women [aHR = 1.4 (0.6 to 3.4), PAF = 16%]. Lack of health insurance compared with public health insurance was associated with virologic failure only among Hispanic [aHR = 2.0 (0.9 to 4.6), PAF = 22%] and white women [aHR = 1.9 (0.7 to 5.1), PAF = 13%]. By contrast, depressive symptoms were associated with virologic failure only among African-American women [aHR = 1.6 (1.2 to 2.2), PAF = 17%]. CONCLUSIONS: In this population of treated HIV-infected women, virologic failure was common, and correlates of virologic failure varied by race/ethnicity. Strategies to reduce disparities in HIV treatment outcomes by race/ethnicity should address racial/ethnic-specific barriers including depression and low income to sustain virologic suppression. PMID- 23797697 TI - Reproductive recovery of a common eider Somateria mollissima population following reductions in discharges of polycyclic aromatic hydrocarbons (PAHs). AB - Polycyclic aromatic hydrocarbons (PAHs) are widely distributed toxic compounds in marine ecosystems, but the effects of such pollutants on populations of aquatic birds are poorly known. This study examined the reproductive biology of a marine duck, the common eider (Somateria mollissima), in a Norwegian fjord that received high input of PAHs over several decades. Numbers of breeding females and post hatch duckling mortality were compared between the years before and after termination of PAH discharges (1989/1990). Moreover, 5 years after the pollution was terminated, reproductive parameters were compared between the polluted fjord and a nearby unpolluted area, to investigate long-term effects. The environmental impact of the pollution peaked in the 1980s, and during this time the number of breeding eiders was halved in the study colony. The duckling mortality was very high, peaking in 1991 when about 8 % of all hatched ducklings were found dead in or near the nest. Since 1993 the ratio of dead ducklings per breeding female stabilized at about one third of the level before the termination of the PAH discharges. Moreover, between 1994 and 1999 the numbers of breeding females increased by 50 %, and in 1995 females in the polluted colony were in better condition, laid larger eggs and had shorter incubation periods than females in the unpolluted area. This study indicates that in the 1980s, PAH pollution affected the reproduction of the eiders in the polluted fjord, although other natural factors may also have influenced eider reproduction. A few years after the pollution level dropped, reproductive output improved strongly, but the number of ducklings dying in the nest was still relatively high compared to unpolluted areas. PMID- 23797696 TI - Novel oral anticoagulants and stroke prevention in atrial fibrillation and chronic heart failure. AB - Heart failure (HF) and atrial fibrillation (AF) frequently coexist and share a reciprocal relationship. The presence of AF increases the propensity to HF and can worsen its severity as well as escalating the risk of stroke. Despite the proven efficacy of vitamin K antagonists and warfarin for stroke prevention in AF, their use is beset by numerous problems. These include their slow onset and offset of action, unpredictability of response, the need for frequent coagulant monitoring and serious concerns around the increased risks of intracranial and major bleeding. Three recently approved novel anticoagulants (dabigatran, rivaroxaban and apixaban) are already challenging warfarin use in AF. They have a predictable therapeutic response and a wide therapeutic range and do not necessitate coagulation monitoring. In this article, the relationship between HF and AF and the mechanisms for their compounded stroke risk are reviewed. The evidence to support the use of these three NOACs amongst patients with AF and HF is further explored. PMID- 23797698 TI - Sarcosine and other metabolites along the choline oxidation pathway in relation to prostate cancer--a large nested case-control study within the JANUS cohort in Norway. AB - Methyl group donors and intermediates of one-carbon metabolism affect DNA synthesis and DNA methylation, and may thereby affect prostate carcinogenesis. Choline, the precursor of betaine, and the one-carbon metabolite sarcosine have been associated with increased prostate cancer risk. Within JANUS, a prospective cohort in Norway (n = 317,000) with baseline serum samples, we conducted a nested case-control study among 3,000 prostate cancer cases and 3,000 controls. Using conditional logistic regression, odds ratios (ORs) and 95% confidence intervals (CIs) for prostate cancer risk were estimated according to quintiles of circulating betaine, dimethylglycine (DMG), sarcosine, glycine and serine. High sarcosine and glycine concentrations were associated with reduced prostate cancer risk of borderline significance (sarcosine: highest vs. lowest quintile OR = 0.86, CI = 0.72-1.01, p(trend) = 0.03; glycine: OR = 0.83, CI = 0.70-1.00, p(trend) = 0.07). Serum betaine, DMG and serine were not associated with prostate cancer risk. However, individuals with a high glycine/serine ratio were at decreased prostate cancer risk (OR = 0.74, CI = 0.69-0.85, p(trend) < 0.001). This population-based study suggested that men with high serum sarcosine or glycine concentrations have modestly reduced prostate cancer risk. Ratios of metabolites reflecting one-carbon balance may be associated with prostate cancer risk, as demonstrated for the glycine/serine ratio, and should be explored in future studies. PMID- 23797685 TI - Purinergic signalling and cancer. AB - Receptors for extracellular nucleotides are widely expressed by mammalian cells. They mediate a large array of responses ranging from growth stimulation to apoptosis, from chemotaxis to cell differentiation and from nociception to cytokine release, as well as neurotransmission. Pharma industry is involved in the development and clinical testing of drugs selectively targeting the different P1 nucleoside and P2 nucleotide receptor subtypes. As described in detail in the present review, P2 receptors are expressed by all tumours, in some cases to a very high level. Activation or inhibition of selected P2 receptor subtypes brings about cancer cell death or growth inhibition. The field has been largely neglected by current research in oncology, yet the evidence presented in this review, most of which is based on in vitro studies, although with a limited amount from in vivo experiments and human studies, warrants further efforts to explore the therapeutic potential of purinoceptor targeting in cancer. PMID- 23797699 TI - Early major worsening in ischemic stroke: predictors and outcome. AB - INTRODUCTION: We aimed to investigate the characteristics and outcome of patients suffering early major worsening (EMW) after acute ischemic stroke (AIS) and assess the parameters associated with it. METHODS: All consecutive patients with AIS in the ASTRAL registry until 10/2010 were included. EMW was defined as an NIHSS increase of >=8 points within the first 24 h after admission. The Bootstrap version of the Kolmogorov-Smirnov test and the chi(2)-test were used for the comparison of continuous and categorical covariates, respectively, between patients with and without EMW. Multiple logistic regression analysis was performed to identify independent predictors of EMW. RESULTS: Among 2155 patients, 43 (2.0 %) had an EMW. EMW was independently associated with hemorrhagic transformation (OR 22.6, 95 % CI 9.4-54.2), cervical artery dissection (OR 9.5, 95 % CI 4.4-20.6), initial dysarthria (OR 3.7, 95 % CI 1.7 8.0), and intravenous thrombolysis (OR 2.1, 95 % CI 1.1-4.3), whereas a negative association was identified with initial eye deviation (OR 0.4, 95 % CI 0.2-0.9). Favorable outcome at 3 and 12 months was less frequent in patients with EMW compared to patients without (11.6 vs. 55.3 % and 16.3 vs. 50.7 %, respectively), and case fatality was higher (53.5 vs. 12.9 % and 55.8 vs. 16.8 %, respectively). Stroke recurrence within 3 months in surviving patients was similar between patients with and without EMW (9.3 vs. 9.0 %, respectively). CONCLUSIONS: Worsening of >=8 points in the NIHSS score during the first 24 h in AIS patients is related to cervical artery dissection and hemorrhagic transformation. It justifies urgent repeat parenchymal and arterial imaging. Both conditions may be influenced by targeted interventions in the acute phase of stroke. PMID- 23797700 TI - Evaluation of relationship between retinal nerve fiber layer thickness progression and visual field progression in patients with glaucoma. AB - PURPOSE: To evaluate the capability of optical coherence tomography (OCT), retinal nerve fiber layer (RNFL) thickness, and visual field (VF) measurements in glaucoma progression detection. METHODS: The study examined 62 eyes of 37 glaucoma patients observed over a 3-year period. All eyes underwent at least four serial RNFL measurements performed by Cirrus OCT, with the first and last measurements separated by at least 3 years. VF testing was performed by using the Swedish interactive threshold algorithm (SITA) Standard 30-2 program of the Humphrey field analyzer (HFA) on the same day as the RNFL imaging. Both serial RNFL thicknesses and VF progression were assessed by the guided progression analysis (GPA) software program. RNFL thickness progression was evaluated by event analysis. Total deviation (TD) in the superior or inferior hemifield was also examined. RESULTS: A total of 295 OCT scans and 295 VFs were analyzed. Five eyes exhibited progression by OCT only and 8 eyes exhibited progression by VF GPA only. When the analysis was based on the combined measurement findings, progression was noted in 6 eyes. The average of the progressive hemifield TD at baseline for combined RNFL and VF progression was -3.21+/-1.38 dB, while it was 2.17+/-1.14 dB for RNFL progression and -9.12+/-3.75 dB for VF progression. The average of the progressive hemifield TD indicated a significant advancement of VF progression as compared to RNFL progression (P=0.002). CONCLUSIONS: When a mild VF defect is present, OCT RNFL thickness measurements are important in helping discern glaucoma progression. PMID- 23797702 TI - Performance measures: better outcomes, not better grades. PMID- 23797701 TI - Application of "papillary-like main pancreatic duct invaginated" pancreaticojejunostomy for normal soft pancreas cases. AB - Pancreaticojejunostomy is the key procedure of pancreaticoduodenectomy. Our study introduced a new pancreaticojejunal (PJ) anastomosis named "papillary-like main pancreatic duct invaginated" pancreaticojejunostomy. Nighty-two patients underwent pancreaticojejunostomy with either conventional duct-to-mucosa pancreaticojejunostomy or the new "papillary-like main pancreatic duct invaginated" techniques were analyzed retrospectively from January 2010 to September 2012. The incidence of pancreatic fistula was 15.7% (8/51) for the "papillary-like main pancreatic duct invaginated" group and 19.5% (8/41) for the duct-to-mucosa fashion respectively. It is noteworthy that the rate of grade B/C postoperative pancreatic fistula (POPF) in the "papillary-like main pancreatic duct invaginated" group was significantly lower than that of the duct-to-mucosa group (P = 0.039). There were no differences in the incidence of postoperative morbidity and mortality such as postoperative hemorrhage, delayed gastric emptying or remnant pancreatitis. The "papillary-like main pancreatic duct invaginated" pancreaticojejunostomy could provide a feasible option to pancreatic surgeons for patients with normal soft pancreas. PMID- 23797703 TI - Bioactive phenylpropanoid glycosides from Tabebuia avellanedae. AB - Three novel phenylpropanoid glycosides 2, 5, 6 were isolated from water extract of Tabebuia avellanedae, together with three known phenylpropanoid glycosides 1, 3, 4. All compounds were identified on the basis of spectroscopic analysis and chemical methods and, for known compounds, by comparison with published data. All isolated compounds showed strong antioxidant activity in the DPPH assay, and compound 5 give the highest antioxidant activity among all compounds, with an IC50 of 0.12 uM. All compounds exhibited moderate inhibitory effect on cytochrome CYP3A4 enzyme. PMID- 23797704 TI - Regulation of TIMP3 in diabetic nephropathy: a role for microRNAs. AB - Diabetic nephropathy (DN) is the major cause of chronic kidney disease in developed countries and contributes significantly to increased morbidity and mortality among diabetic patients. Morphologically, DN is characterized by tubulo interstitial fibrosis, thickening of the glomerular basement membrane and mesangial expansion mainly due to accumulation of extracellular matrix (ECM). ECM turnover is regulated by metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs) activities. In diabetic conditions, TIMP3 expression in kidney is strongly reduced, but the causes of this reduction are still unknown. The aim of this study was to elucidate at least one of these mechanisms which relies on differential expression of TIMP3-targeting microRNAs (miRs) in a hyperglycemic environment either in vitro (MES13 cell line) or in vivo (mouse kidney and human biopsies). Among the TIMP3-targeting miRs, miR-21 and miR-221 were significantly upregulated in kidneys from diabetic mice compared to control littermates, and in a mesangial cell line grown in high glucose conditions. In human samples, only miR-21 expression was increased in kidney biopsies from diabetic patients compared to healthy controls. The expression of miR-217, which targets TIMP3 indirectly through downregulation of SirT1, was also increased in diabetic kidney and MES13 cell line. In agreement with these result, SirT1 expression was reduced in mouse and human diabetic kidneys as well as in MES13 mesangial cell line. TIMP3 deficiency has recently emerged as a hallmark of DN in mouse and human. In this study, we demonstrated that this reduction is due, at least in part, to increased expression of certain TIMP3-targeting miRs in diabetic kidneys compared to healthy controls. Unveiling the post-transcriptional mechanisms responsible for TIMP3 downregulation in hyperglycemic conditions may orient toward the use of this protein as a possible therapeutic target in DN. PMID- 23797705 TI - Different distribution of phenotypes and glucose tolerance categories associated with two alternative proposed cutoffs of insulin resistance. AB - We investigated whether two alternative HOMA-IR thresholds recently proposed identify similar phenotype and have the same impact on gluco-metabolic risk. The two IR cutoffs, IR1 and IR2 (IR1: HOMA-IR >5.9 and IR2: HOMA-IR between 2.8 and 5.9 with HDL-C <51 mg/dl), were applied to a database of 2,360 outpatients, and their association with phenotypes, glucose tolerance, lipids and metabolic syndrome (MetS) was examined. IR1 group showed 5.5% of overweight versus 27.8% of IR2 subjects, and obesity was present in 92.3 versus 68.4%, respectively. We observed the major prevalence of pathological waist in IR1 compared to IR2 subjects: 96.0 versus 80.5% (p < 0.001). After OGTT, IR1 patients presented higher prevalence of impaired glucose tolerance (IGT: 25.8 vs. 20.2%, p < 0.001) and DM2 was diagnosed in 39.7% of IR1 versus 11.3% of IR2 patients (p < 0.001) with odds ratio (OR) 8.3 (95% CI 6.1-11.6) versus 0.8 (0.6-1.2), respectively. IR1 versus IR2 cutpoint showed higher significant (mean +/- SEM) total cholesterol (224.8 +/- 2.6 vs. 213.1 +/- 1.7 mg/dl, p < 0.001) and triglyceride (208.1 +/- 12.3 vs. 177.4 +/- 4.8 mg/dl, p < 0.001) levels. MetS prevalence was significantly higher in IR1 than IR2 (89.0 vs. 78.3%, p < 0.001). The IR1 cutpoint was associated with a higher OR of MetS 7.3 (5.3-10.2) versus 5.2 (2.8 9.5) of IR2. In summary, the two alternative HOMA-IR cutoffs identify subjects with different distribution of phenotypes and gluco-metabolic risk. The IR1 patients are characterized by higher prevalence of obesity, pathological waist, MetS, dyslipidemia and IGT/DM2. PMID- 23797706 TI - Revisions to the derivation of the Australian and New Zealand guidelines for toxicants in fresh and marine waters. AB - The Australian and New Zealand Guidelines for Fresh and Marine Water Quality are a key document in the Australian National Water Quality Management Strategy. These guidelines released in 2000 are currently being reviewed and updated. The revision is being co-ordinated by the Australian Department of Sustainability, Environment, Water, Population and Communities, while technical matters are dealt with by a series of Working Groups. The revision will be evolutionary in nature reflecting the latest scientific developments and a range of stakeholder desires. Key changes will be: increasing the types and sources of data that can be used; working collaboratively with industry to permit the use of commercial-in confidence data; increasing the minimum data requirements; including a measure of the uncertainty of the trigger value; improving the software used to calculate trigger values; increasing the rigour of site-specific trigger values; improving the method for assessing the reliability of the trigger values; and providing guidance of measures of toxicity and toxicological endpoints that may, in the near future, be appropriate for trigger value derivation. These changes will markedly improve the number and quality of the trigger values that can be derived and will increase end-users' ability to understand and implement the guidelines in a scientifically rigorous manner. PMID- 23797707 TI - Arbuscular mycorrhizal fungi induced differential Cd and P phytoavailability via intercropping of upland kangkong (Ipomoea aquatica Forsk.) with Alfred stonecrop (Sedum alfredii Hance): post-harvest study. AB - A post-harvest experiment was conducted further to our previous greenhouse pot study on upland kangkong (Ipomoea aquatica Forsk.) and Alfred stonecrop (Sedum alfredii Hance) intercropping system in Cd-contaminated soil inoculated with arbuscular mycorrhizal (AM) fungi. Previously, four treatments were established in the intercropping experiment, including monoculture of kangkong (control), intercropping with stonecrop (IS), and IS plus inoculation with Glomus caledonium (IS+Gc) or Glomus versiforme (IS+Gv). Both kangkong and stonecrop plants were harvested after growing for 8 weeks. Then, the tested soils were reclaimed for growing post-harvest kangkong for 6 weeks. In the post-harvest experiment, there were no significant differences between the IS and control treatments, except for a significantly decreased (p<0.05) soil available P concentration with IS treatment. Compared with IS, both IS+Gc and IS+Gv significantly decreased (p<0.05) soil DTPA-extractable (phytoavailable) Cd concentrations, but not total Cd, by elevating soil pH, causing significantly lower (p<0.05) Cd concentrations in both the root and shoot of kangkong. In addition, both Gc and Gv significantly increased (p<0.05) soil acid phosphatase activities and available P concentrations and hence resulted in significantly higher (p<0.05) plant P acquisitions. However, only Gv significantly increased (p<0.05) kangkong yield, while Gc only significantly elevated (p<0.05) the shoot P concentration. It suggested that AM fungi have played key roles in Cd stabilization and P mobilization in the intercropping system, and such positive responses seemed to be sustainable and valuable in post-harvest soils. PMID- 23797708 TI - A combined approach of physicochemical and biological methods for the characterization of petroleum hydrocarbon-contaminated soil. AB - Main physicochemical and microbiological parameters of collected petroleum contaminated soils with different degrees of contamination from DaGang oil field (southeast of Tianjin, northeast China) were comparatively analyzed in order to assess the influence of petroleum contaminants on the physicochemical and microbiological properties of soil. An integration of microcalorimetric technique with urease enzyme analysis was used with the aim to assess a general status of soil metabolism and the potential availability of nitrogen nutrient in soils stressed by petroleum-derived contaminants. The total petroleum hydrocarbon (TPH) content of contaminated soils varied from 752.3 to 29,114 mg kg(-1). Although the studied physicochemical and biological parameters showed variations dependent on TPH content, the correlation matrix showed also highly significant correlation coefficients among parameters, suggesting their utility in describing a complex matrix such as soil even in the presence of a high level of contaminants. The microcalorimetric measures gave evidence of microbial adaptation under highest TPH concentration; this would help in assessing the potential of a polluted soil to promote self-degradation of oil-derived hydrocarbon under natural or assisted remediation. The results highlighted the importance of the application of combined approach in the study of those parameters driving the soil amelioration and bioremediation. PMID- 23797709 TI - Modelling the phytoplankton dynamics in a nutrient-rich solar saltern pond: predicting the impact of restoration and climate change. AB - An ecological model for the solar saltern of Sfax (Tunisia) was established and validated by comparing simulation results to observed data relative to horizontal distributions of temperature, nutrients and phytoplankton biomass. Sensitivity analysis was performed in order to assess the influence of the main ecological model parameters. First applied at the saltern's pond A1, the model was calibrated with field data measured over 4 years of study (from 2000 to 2003), which allowed an evaluation of parameters such as maximum growth rate of phytoplankton, optimal growth temperature and constant of half saturation for P/N assimilation by phytoplankton. Simulation results showed that the model allowed us to predict realistic phytoplankton variations of the study area, though we were unable to accurately reproduce the nutrient variation. The model was then applied to simulations of the impact of changes in phytoplankton biomass through scenarios such as hypothetic climate changes and saltern restoration. PMID- 23797710 TI - Promotion of oxygen reduction by a bio-inspired tethered iron phthalocyanine carbon nanotube-based catalyst. AB - Electrocatalysts for oxygen reduction are a critical component that may dramatically enhance the performance of fuel cells and metal-air batteries, which may provide the power for future electric vehicles. Here we report a novel bio inspired composite electrocatalyst, iron phthalocyanine with an axial ligand anchored on single-walled carbon nanotubes, demonstrating higher electrocatalytic activity for oxygen reduction than the state-of-the-art Pt/C catalyst as well as exceptional durability during cycling in alkaline media. Theoretical calculations suggest that the rehybridization of Fe 3d orbitals with the ligand orbitals coordinated from the axial direction results in a significant change in electronic and geometric structure, which greatly increases the rate of oxygen reduction reaction. Our results demonstrate a new strategy to rationally design inexpensive and durable electrochemical oxygen reduction catalysts for metal-air batteries and fuel cells. PMID- 23797711 TI - Ultrastructural changes in photorejuvenation induced by photodynamic therapy in a photoaged mouse model. AB - BACKGROUND: Photoaging is defined as premature aging of the skin induced by ultraviolet (UV) irradiation. Photodynamic therapy (PDT) has been shown to be a non-invasive but effective technique for photoaged skin. OBJECTIVE: We observed histological and ultrastructural changes of photoaging and photorejuvenating effects of 5-aminolevulinic acid (ALA)-PDT in a UV-irradiated mice model. METHODS: A total of 20 mice were divided into a control (group A) group and a UV irradiated (photoaging) group. The photoaging group was divided according to the following interventions: photoaging only (group B), ALA application only (group C), light-emitting diode (LED) irradiation only (group D), and ALA-PDT with a light dose of 20 J/cm(2) (group E). Serial skin biopsies were performed from day 2 to day 21, and transmission electron microscopic (TEM) studies were performed. RESULTS: After UV irradiation, the amount of dermal collagen fibers decreased, and the quantity of elastotic materials increased. Following ALA-PDT application, the amount of collagen fibers increased from day 2 to day 21 and the increased elastotic materials during the photoaging period were normalized. With TEM, the decreased collagen fibers during photoaging were restored after PDT application. Also, distended dermal fibroblasts with distended endoplasmic reticulum by UV irradiation were normalized after PDT application. CONCLUSION: This study provides histologic evidence of the beneficial effects of ALA-PDT, even in photodamaged skin. ALA-PDT induces deposition of collagen in the dermis, normalizes elastotic materials which were induced by photoaging and may even have a direct effect on the normalization of the morphology of fibroblasts. PMID- 23797712 TI - Breast cancer knowledge and related behaviors among women in Abha City, southwestern Saudi Arabia. AB - Breast cancer is the most common malignancy among women in Saudi Arabia. A cross sectional study was conducted on 1,092 women attending urban primary health care centers in Abha City southwestern Saudi Arabia about breast cancer knowledge, attitudes, and related practices. Only 22.0% heard about mammography, and 41.5% heard about breast self-examination (BSE). More than half of the women in the study identified changes occurring in case of breast cancer and identified risk factors. Only 8.3% were examined by clinical breast examination (CBE), 6.2% were examined by mammography, and 29.7% performed BSE. The study points to the insufficient knowledge of women and the low practice of BSE, CBE, and mammography. Public awareness should be enhanced by all available means including mass media, schools, social gatherings, and waiting areas in primary health care centers. There is an urgent need for continuing medical education programs for health care workers in the region concerning breast cancer. PMID- 23797713 TI - The Wnt signaling pathway is involved in the regulation of phagocytosis of virus in Drosophila. AB - Phagocytosis is crucial for triggering host defenses against invading pathogens in animals. However, the receptors on phagocyte surface required for phagocytosis of virus have not been extensively explored. This study demonstrated that white spot syndrome virus (WSSV), a major pathogen of shrimp, could be engulfed but not digested by Drosophila S2 cells, indicating that the virus was not recognized and taken up by a pathway that was silent and would not activate the phagosome maturation and digestion pathway. The results showed that the activation of receptors on S2 cell surface by lipopolysaccharide or peptidoglycan resulted in the phagocytosis of S2 cells against WSSV virions. Gene expression profiles revealed that the dally-mediated Wnt signaling pathway was involved in S2 phagocytosis. Further data showed that the Wnt signaling pathway played an essential role in phagocytosis. Therefore, our study contributed novel insight into the molecular mechanism of phagocytosis in animals. PMID- 23797714 TI - The Relationship Between Clinical Presentation and Unusual Sensory Interests in Autism Spectrum Disorders: A Preliminary Investigation. AB - Unusual responses to sensory stimuli have been described in autism spectrum disorder (ASD).The study examined the frequencies of 'unusual sensory interests' and 'negative sensory responses' and their relation to functioning in a large ASD population (n = 679). Having 'unusual sensory interests' was reported in 70.4 % and 'negative sensory responses' in 66.0 % of the ASD group. Having 'unusual sensory interests' was associated with more severe reported and observed autism symptoms, lower cognitive ability and lower adaptive skills. In contrast, having 'negative sensory responses' was only associated with more severe reported stereotyped behaviors. It is suggested that having 'unusual sensory interests' is a part of a primary more severe type of ASD involving numerous developmental domains that might have a unique neurobiological origin. PMID- 23797715 TI - Evaluating the potential for the environmentally sustainable control of foot and mouth disease in Sub-Saharan Africa. AB - Strategies to control transboundary diseases have in the past generated unintended negative consequences for both the environment and local human populations. Integrating perspectives from across disciplines, including livestock, veterinary and conservation sectors, is necessary for identifying disease control strategies that optimise environmental goods and services at the wildlife-livestock interface. Prompted by the recent development of a global strategy for the control and elimination of foot-and-mouth disease (FMD), this paper seeks insight into the consequences of, and rational options for potential FMD control measures in relation to environmental, conservation and human poverty considerations in Africa. We suggest a more environmentally nuanced process of FMD control that safe-guards the integrity of wild populations and the ecosystem dynamics on which human livelihoods depend while simultaneously improving socio economic conditions of rural people. In particular, we outline five major issues that need to be considered: 1) improved understanding of the different FMD viral strains and how they circulate between domestic and wildlife populations; 2) an appreciation for the economic value of wildlife for many African countries whose presence might preclude the country from ever achieving an FMD-free status; 3) exploring ways in which livestock production can be improved without compromising wildlife such as implementing commodity-based trading schemes; 4) introducing a participatory approach involving local farmers and the national veterinary services in the control of FMD; and 5) finally the possibility that trans frontier conservation might offer new hope of integrating decision-making at the wildlife-livestock interface. PMID- 23797716 TI - Contribution of preventable acute care spending to total spending for high-cost Medicare patients. AB - IMPORTANCE: A small proportion of patients account for the majority of US health care spending, and understanding patterns of spending among this cohort is critical to reducing health care costs. The degree to which preventable acute care services account for spending among these patients is largely unknown. OBJECTIVE: To quantify preventable acute care services among high-cost Medicare patients. DESIGN, SETTING, AND PARTICIPANTS: We summed standardized costs for each inpatient and outpatient service contained in standard 5% Medicare files from 2009 and 2010 across the year for each patient in our sample, and defined those in the top decile of spending in 2010 as high-cost patients and those in the top decile in both 2009 and 2010 as persistently high-cost patients. We used standard algorithms to identify potentially preventable emergency department (ED) visits and acute care inpatient hospitalizations. A total of 1,114,469 Medicare fee-for-service beneficiaries aged 65 years or older were included. MAIN OUTCOMES AND MEASURES: Proportion of acute care hospital and ED costs deemed preventable among high-cost patients. RESULTS: The 10% of Medicare patients in the high-cost group were older, more often male, more often black, and had more comorbid illnesses than non-high-cost patients. In 2010, 32.9% (95% CI, 32.9%-32.9%) of total ED costs were incurred by high-cost patients. Based on validated algorithms, 41.0% (95% CI, 40.9%-41.0%) of these costs among high-cost patients were potentially preventable compared with 42.6% (95% CI, 42.6%-42.6%) among non high-cost patients. High-cost patients accounted for 79.0% (95% CI, 79.0%-79.0%) of inpatient costs, 9.6% (95% CI, 9.6%-9.6%) of which were due to preventable hospitalizations; 16.8% (95% CI, 16.8%-16.8%) of costs within the non-high-cost group were due to preventable hospitalizations. Comparable proportions of ED spending (43.3%; 95% CI, 43.3%-43.3%) and inpatient spending (13.5%; 95% CI, 13.5%-13.5%) were preventable among persistently high-cost patients. Regions with high primary care physician supply had higher preventable spending for high-cost patients. CONCLUSIONS AND RELEVANCE: Among a sample of patients in the top decile of Medicare spending in 2010, only a small percentage of costs appeared to be related to preventable ED visits and hospitalizations. The ability to lower costs for these patients through better outpatient care may be limited. PMID- 23797717 TI - Loss of Foxp3 is associated with CD30 expression in the anaplastic large cell subtype of adult T-cell leukemia/lymphoma (ATLL) in US/Caribbean patients: potential therapeutic implications for CD30 antibody-mediated therapy. AB - Adult T-cell leukemia/lymphoma (ATLL) is caused by the HTLV-1 virus, endemic to Japan and the Caribbean, and is likely derived from cells with the T-regulatory phenotype. The malignant cells express IL2 receptor alpha (CD25), and the majority express transcription factor Forkhead box P3 (Foxp3), in addition to T cell markers. Occasional cases express CD30. Whereas Japanese cases are predominantly of the acute and chronic leukemic types, the less well-studied Caribbean cases are more often lymphomatous. We performed immunohistochemical analysis for CD25, Foxp3, and CD30 on samples from 42 US/Caribbean ATLL patients and correlated these markers with morphologic subtype and clinical characteristics. In the 16/42 patients who had successive biopsies, we determined the expression stability of these markers. Foxp3 was expressed in 26 of the 42 (62%) initial biopsies, and its intensity correlated with CD25 expression. It was more frequent in pleomorphic small-sized and medium-sized cell types than in large cell tumors but did not correlate with patients' clinical attributes. Foxp3 expression and morphology were unchanged in successive biopsies in 13 of 16 patients. Four initial biopsies had features of anaplastic large cell T lymphomas, all of which were Foxp3. Successive biopsies from 2 patients with pleomorphic medium cell variant showed diminishing expression of originally weak Foxp3 expression and de novo CD30 expression, whereas they showed morphologic progression to the anaplastic cell variant. A third patient's second biopsy revealed progression from pleomorphic medium to anaplastic large cell morphology with loss of Foxp3, but it remained CD30. Foxp3 expression correlates with pleomorphic small and medium cell types and may be lost with large cell transformation. The evolution of the latter type can be associated with the gain of CD30 expression; such ATLL tumors might respond to anti-CD30 monoclonal antibody therapies. PMID- 23797718 TI - BRAFV600E immunohistochemistry facilitates universal screening of colorectal cancers for Lynch syndrome. AB - BRAFV600E mutation in microsatellite-unstable (MSI) colorectal carcinomas (CRCs) virtually excludes Lynch syndrome (LS). In microsatellite-stable (MSS) CRCs it predicts poor prognosis. We propose a universal CRC LS screening algorithm using concurrent reflex immunohistochemistry (IHC) for BRAFV600E and mismatch-repair (MMR) proteins. We compared BRAFV600E IHC with multiplex polymerase chain reaction (PCR) and matrix-assisted laser desorption/ionization-time of flight mass spectrometry in 216 consecutive CRCs from 2011. Discordant cases were resolved with real-time PCR. BRAFV600E IHC was performed on 51 CRCs from the Australasian Colorectal Cancer Family Registry (ACCFR), which were fully characterized for BRAF mutation by allele-specific PCR, MMR status (MMR IHC and MSI), MLH1 promoter methylation, and germline MLH1 mutation. We then assessed MMR and BRAFV600E IHC on 1403 consecutive CRCs. By matrix-assisted laser desorption/ionization-time of flight mass spectrometry 15 cases did not yield a BRAF result, whereas 38/201 (19%) were positive. By IHC 45/216 (20%) were positive. Of the 7 discordant cases, real-time PCR confirmed the IHC result in 6. In the 51 CRCs from the ACCFR, IHC was concordant with allele-specific PCR in 50 cases. BRAFV600E and MSI IHC on 1403 CRCs demonstrated the following phenotypes: BRAF/MSS (1029 cases, 73%), BRAF/MSS (98, 7%), BRAF/MSI (183, 13%), and BRAF/MSI (93, 7%). All 11/1403 cancers associated with proven LS were BRAF/MSI. We conclude that BRAF IHC is highly concordant with 2 commonly used PCR-based BRAFV600E assays; it performed well in identifying MLH1 mutation carriers from the ACCFR and identified all cases of proven LS among the 1403 CRCs. Reflex BRAFV600E and MMR IHC are simple cheap tests that facilitate universal LS screening and identify the poor prognosis of the BRAFV600E-mutant MSS CRC phenotype. PMID- 23797719 TI - Outcomes of atypical spitz tumors with chromosomal copy number aberrations and conventional melanomas in children. AB - Death due to melanoma in childhood (up to 20 y of age) is a rare event, with an average of 18 cases reported annually in the United States. In this study we evaluated 2 subgroups of high-risk melanocytic neoplasms in childhood, specifically atypical Spitz tumors (ASTs) with chromosomal copy number changes and conventional melanomas. We analyzed the clinical, histologic, and molecular features of all cases and performed the Fisher exact test, logistic regression, and multivariate analysis to evaluate features associated with aggressive clinical behavior in these cases. Among the ASTs, all of which had 1 or more chromosomal copy number aberrations, the presence of homozygous 9p21 deletions and a positive sentinel lymph node were each found to be correlated with tumor extension beyond the sentinel lymph node, with P-values of 0.046 and 0.01, respectively. Two patients with ASTs that had homozygous 9p21 deletions developed brain metastasis, one of whom died of disease. Among the 21 conventional melanomas, 3 patients developed distant metastasis and died of disease. Chromosomal copy number aberrations evaluated by fluorescence in situ hybridization were present in the majority of the cases (16/18). Among conventional melanomas, we did not identify any clinical, histologic, or molecular features associated with aggressive behavior. The presence of 8q24 gains was seen almost exclusively in 6 amelanotic small cell melanomas in children of whom 1 died of disease. Characteristic chromosomal copy number aberrations may occur in specific subtypes of melanocytic neoplasms in children and may help with the classification and prognostication of these rare tumors. PMID- 23797720 TI - Papillary squamous cell carcinoma of the head and neck: clinicopathologic and molecular features with special reference to human papillomavirus. AB - A relationship between human papillomavirus (HPV) infection and papillary squamous cell carcinoma (PSCC) has been suggested. However, to date, no studies have thoroughly and directly evaluated for transcriptional activity of the virus or the clinicopathologic significance of HPV-positive PSCC. Forty-eight cases of PSCC were retrieved from our surgical pathology database and were reviewed by 4 study pathologists, with tumors defined as SCC with a significant component of papillary growth in the tumor. Immunohistochemical analysis for p16 and p53 was performed. Overexpression of p16 was used as a surrogate marker of transcriptionally active HPV. Transcriptional activity was also directly evaluated using RNA in situ hybridization to detect high-risk HPV E6/E7 mRNA. Clinical follow-up data were obtained by chart review. Seven cases were located in the oral cavity, 19 in the oropharynx, and 22 in the larynx. Two morphologic types of PSCC were identified: keratinizing type, in which the epithelial cells showed a maturation trend with minimal surface parakeratin, and nonkeratinizing type, in which the papillae were completely covered by immature basaloid cells. Transcriptionally active HPV was present in 23 of 43 (53.4%) tumors. The majority of tumors harboring transcriptionally active HPV arose in the oropharynx, showed nonkeratinizing morphology, were p16 positive, and p53 negative. Transcriptionally active HPV was also present in many laryngeal and oral cavity PSCCs. Overall survival, disease-specific survival, and disease-free survival were favorable and did not significantly differ by anatomic subsite. However, HPV related tumors showed a trend toward better survival. PMID- 23797721 TI - Diagnosis of congenital CMV using PCR performed on formalin-fixed, paraffin embedded placental tissue. AB - Congenital cytomegalovirus (CMV) infection may be asymptomatic until hearing loss manifests in childhood. Because diagnosis of congenital CMV requires viral detection within an infant's first 21 days of life, CMV polymerase chain reaction (PCR) on formalin-fixed, paraffin-embedded (FFPE) placental tissue provides a unique opportunity to identify congenital exposure in cases in which CMV is not initially suspected. To assess the utility of this approach, a database of all CMV cultures performed from July 2001 to March 2012 was used to identify infants in whom urine CMV cultures were obtained within 100 days of life. Corresponding placentas were then identified through the pathology database. The database was also queried to identify placentas in which CMV immunohistochemical analysis had been performed. CMV PCR was positive in FFPE placental tissue from 100% (5/5) of cases in which the first urine culture collected before the first 21 days of life was positive. Placentas from 20 infants with negative CMV urine cultures were CMV PCR negative. Interestingly, CMV was detected in 12.5% (1/8) of placentas in which the first CMV-positive urine culture was collected after the first 21 days of life. Furthermore, 4% (1/26) of placentas with chronic villitis by histology (no urine cultures available) were CMV PCR positive. In the 10 CMV PCR-positive placentas, including 3 cases of fetal demise, CMV immunohistochemistry was positive in just 6 cases. These results suggest that the confirmation of CMV exposure in utero by PCR of FFPE placental tissue provides a useful adjunct to histologic evaluation and may identify infants requiring close clinical follow up. PMID- 23797722 TI - Diffuse intrapulmonary malignant mesothelioma masquerading as interstitial lung disease: a distinctive variant of mesothelioma. AB - Malignant mesothelioma typically encases lungs as a thick rind, while relatively sparing lung parenchyma. We describe an unusual presentation of mesothelioma characterized by diffuse intrapulmonary growth, with absent or inconspicuous pleural involvement, clinically simulating interstitial lung disease (ILD). We identified 5 patients (median age 56 y, all men) with diffuse intrapulmonary malignant mesothelioma in our pathology consultation practice from 2009 to 2012. Clinical history, imaging, and pathology materials were reviewed. Symptoms included chronic dyspnea (4 cases), cough (3), and acute dyspnea with bilateral pneumothorax (1). Chest imaging showed irregular opacities (5), reticulation (4), pleural effusions (2), and subpleural nodular densities (1), without radiologic evidence of pleural disease or masses. A clinicoradiologic diagnosis of ILD was made in all cases, and wedge biopsies were performed. Histologic evaluation revealed a neoplastic proliferation of bland epithelioid or spindled cells, showing various growth patterns simulating silicotic nodules, desquamative interstitial pneumonia, organizing pneumonia, and Langerhans cell histiocytosis. Some areas mimicked adenocarcinoma, with lepidic, acinar, micropapillary, and solid patterns. Initial diagnoses by referring pathologists included reactive changes (1), hypersensitivity pneumonitis versus drug reaction (1), desquamative interstitial pneumonia versus neoplasm (1), and mesothelioma (2). Microscopic pleural involvement was identified in 4 cases. Immunohistochemistry confirmed the characteristic immunophenotype of mesothelioma in all cases. Median survival of 3 patients treated with chemotherapy was 28 months. Two patients received no therapy and survived 3 and 4 weeks, respectively. "Diffuse intrapulmonary malignant mesothelioma" is a rare variant with a distinctive presentation that clinically mimics ILD. Recognition is essential to avoid misdiagnosis. PMID- 23797723 TI - Molecular and histopathologic characteristics of multifocal papillary thyroid carcinoma. AB - Papillary thyroid carcinoma (PTC) is frequently multifocal, which can represent either intraglandular spread from a single primary tumor or multiple synchronous primary tumors (MSPTs). To distinguish and characterize these entities, we investigated whether multifocal PTCs contain genetically similar or different mutations and have particular histopathologic characteristics. In 60 cases of PTC with 2 to 4 discrete tumor foci, each focus was tested for BRAF, NRAS, HRAS, and KRAS point mutations and RET/PTC1 and RET/PTC3 rearrangements and analyzed for various histopathologic features. Overall, BRAF mutations were found in 43% of tumors, RAS in 27%, and RET/PTC in 2%. Four different patterns of mutation occurrence were identified: (i) 2 foci containing different mutations (30%); (ii) 1 tumor containing a mutation and another carrying no mutations (32%); (iii) both/all tumors containing the same mutation (25%); (iv) all tumors having no mutations (13%). The 30% of cases with 2 different mutations represent a group of tumors that are unequivocally MSPT. These tumors more commonly occurred in different lobes, although they could be located as close as 0.6 cm from each other. Moreover, MSPTs typically demonstrated distinct histologic variants/microscopic features, were encapsulated or had a smooth border, and showed no microscopic peritumoral dissemination. In conclusion, we demonstrate that at least 30% of multifocal PTCs represent unequivocal MSPTs that develop through distinct molecular alterations and that as many as 60% of multifocal PTCs are likely MSPTs. Histopathologically, MSPTs are typically located in different lobes, have distinct growth patterns, and do not show microscopic peritumoral dissemination. PMID- 23797724 TI - Malignant perivascular epithelioid cell neoplasm (PEComa) of the urinary bladder with TFE3 gene rearrangement: clinicopathologic, immunohistochemical, and molecular features. AB - Recently, a small subgroup of PEComas has been recognized to harbor rearrangements involving TFE3, a gene also involved in rearrangements in translocation-associated renal cell carcinomas and alveolar soft part sarcomas. The few TFE3 rearrangement-associated PEComas reported have exhibited distinctive pathologic characteristics contrasting to PEComas in general, including predominantly epithelioid nested or alveolar morphology and underexpression of muscle markers by immunohistochemistry. In this study, we report the clinicopathologic, immunohistochemical, and molecular features of a primary urinary bladder PEComa diagnosed by transurethral resection in a 55-year-old woman that clinically mimicked urothelial carcinoma. Light microscopy demonstrated mixed spindle cell and epithelioid morphology with the epithelioid component preferentially associated with blood vessels. Immunohistochemistry revealed positive staining for HMB45, tyrosinase, MiTF, cathepsin K, smooth muscle actin, and TFE3 protein. Fluorescence in situ hybridization for the TFE3 gene revealed a split signal pattern, indicating TFE3 rearrangement. X chromosome inactivation analysis demonstrated a clonal pattern despite the heterogenous appearance of the tumor. Unfortunately, despite surgical resection and sarcoma directed therapy, the patient died of metastatic disease 12 months after diagnosis. This report adds to the known data regarding urinary bladder PEComas and PEComas with TFE3 rearrangement, indicating that both can pursue an aggressive course. Although the few reported TFE3-rearranged PEComas have predominantly lacked a spindle cell component and expression of smooth muscle actin and MiTF by immunohistochemistry, the findings in this study indicate that these features are sometimes present in TFE3-rearranged PEComas. PMID- 23797725 TI - Identification of succinate dehydrogenase-deficient bladder paragangliomas. AB - A significant number of patients with paragangliomas harbor germline mutations in one of the succinate dehydrogenase (SDH) genes (SDHA, B, C, or D). Tumors with mutations in SDH genes can be identified using immunohistochemistry. Loss of SDHB staining is seen in tumors with a mutation in any one of the SDH genes, whereas loss of both SDHB and SDHA expression is seen only in the context of an SDHA mutation. Identifying an SDH-deficient tumor can be prognostically significant, as tumors with SDHB mutations are more likely to pursue a malignant course. Although the rate of SDH deficiency in paragangliomas in general is known to be approximately 30%, there are only rare reports of SDH-deficient bladder paragangliomas. Therefore, the aim of this study was to determine the rate of SDH deficiency in bladder paragangliomas. Eleven cases of bladder paragangliomas were identified. Hematoxylin and eosin-stained slides of all tumors were reviewed, and immunohistochemical analysis for SDHB and SDHA was performed. For cases with loss of SDHA expression by immunohistochemistry, mutation analysis of the SDHA gene was performed. Loss of SDHB staining was seen in 3 (27%) cases (2 with loss of SDHB only, 1 with loss of SDHB and SDHA). Patients with SDH-deficient tumors were younger than those with tumors with intact SDH expression (mean age at presentation 39 y and 58 y, respectively). Of the 2 patients with SDHB-deficient and SDHA-intact tumors, one was found to have a germline SDHB mutation, and the other had a family history of a malignant paraganglioma. Both patients developed metastatic disease. The one patient with a tumor that was deficient for both SDHB and SDHA had no family history of paragangliomas and no evidence of metastatic disease. Sequencing of this tumor revealed a deleterious heterozygous single-base pair substitution in exon 10 of SDHA (c.1340 A>G; p.His447Arg) in both the tumor and normal tissue, indicative of a germline SDHA mutation, and a deleterious single-base pair substitution in exon 5 of SDHA (c.484 A>T; p.Arg162*) in 1 allele of the tumor only. No patients with intact SDH expression had a family history of paragangliomas; 1 had a synchronous paraganglioma, but none developed metastatic disease. A significant subset of bladder paragangliomas is SDH deficient. It is essential to identify SDH-deficient tumors, as the presence of an SDH mutation has prognostic implications and is important in guiding genetic counseling. PMID- 23797726 TI - Foamy gland carcinoma of the prostate in needle biopsy: incidence, Gleason grade, and comparative alpha-methylacyl-CoA racemase vs. ERG expression. AB - Foamy gland carcinoma is a variant of prostatic acinar adenocarcinoma characterized by abundant, foamy cytoplasm, frequently showing small, pyknotic nuclei. The incidence and Gleason grade of foamy gland carcinoma in a large prostate needle biopsy series have not been established. Foamy gland carcinoma may be deceptively benign appearing and missed on needle biopsy. Immunohistochemical staining for basal cells and alpha-methylacyl-CoA racemase (AMACR) can support a diagnosis of foamy gland carcinoma, but the sensitivity of AMACR for foamy gland carcinoma has been reported to be lower than that for usual acinar carcinoma. The utility of ERG immunohistochemistry in the diagnosis of foamy gland carcinoma has not been explored. The aim of this study was to characterize the incidence and Gleason grade of foamy gland carcinoma in a large consecutive series of prostate needle biopsy cases. We also assessed ERG expression in foamy gland carcinoma, in comparison with AMACR expression, to determine whether ERG expression provides added diagnostic value beyond AMACR expression. We evaluated a consecutive series of 476 prostatic adenocarcinoma needle core biopsy cases for presence, linear extent, and Gleason grade of foamy gland carcinoma. A selected block from each case containing foamy gland carcinoma was evaluated for AMACR and ERG expression by immunohistochemistry. Of the 476 cases, 17% contained a foamy gland carcinoma component, with 2% of the cases showing pure foamy gland carcinoma. Two cases of pure foamy gland carcinoma had a total linear extent of <3 mm. The majority (80%) of cases had a Gleason score 3+3=score of 6. Sensitivity of AMACR for foamy gland carcinoma was 92%, and sensitivity of ERG was 42%. No AMACR-negative case was ERG positive. Low AMACR expression was detected in 24 of 72 cases (33%), and of these cases ERG was positive in 5 (21%). In summary, foamy gland carcinoma features are relatively common in prostate needle core biopsies, the foamy gland carcinoma is admixed with usual acinar carcinoma in the majority of cases, and is usually not of high Gleason grade, although 20% are Gleason score 7 or greater. ERG immunohistochemistry did not provide added value beyond AMACR expression in most cases, suggesting that it need not be initially utilized in addition to basal cell markers and AMACR when immunohistochemistry is needed to substantiate a diagnosis of foamy gland malignancy. This is an important consideration in this era of cost-consciousness in application of immunohistochemistry. Sensitivity of AMACR for foamy gland carcinoma was comparable to that seen in studies of usual acinar carcinoma and is an excellent marker for foamy gland carcinoma of the prostate. ERG immunohistochemistry could be considered in a second round of immunostaining of select difficult cases of foamy gland carcinoma with low AMACR expression. PMID- 23797727 TI - Intrabiliary growth of liver metastases: clinicopathologic features, prevalence, and outcome. AB - Intrabiliary growth by metastatic colorectal carcinoma (CRC) is an unusual finding that can clinically mimic cholangiocarcinoma. We evaluated prevalence of intrabiliary growth by retrospective review of 1596 diagnostic reports and by prospective evaluation of 223 hepatectomies. Positive cases were scored for extent of intrabiliary growth (major vs. minor duct involvement), architectural pattern (colonization of biliary epithelium and/or intrabiliary tumor plugs), and secondary sclerosing cholangitis in non-neoplastic parenchyma. By retrospective review, we identified intrabiliary growth in 41 (3.6%) of 1144 metastatic CRCs but only 3 (0.7%) of 452 noncolorectal tumors (P<0.001). Prospectively, we found intrabiliary growth in 18 (10.6%) of 170 metastatic CRCs and 1 (1.9%) of 53 other tumors (P=0.05). Among our final population of 43 CRCs with intrabiliary growth, 24 (56%) had major and 19 (44%) had minor duct involvement, 35 (81%) showed colonization of biliary epithelium, and 35 (81%) showed intrabiliary tumor plugs. Compared with minor duct involvement and 51 controls without intrabiliary growth, major duct involvement was more likely to produce obstructive liver chemistries (P=0.004), radiographic evidence of biliary disease (P<0.0001), and sclerosing cholangitis in non-neoplastic liver (P<0.0001). However, there was no impact on overall survival. Clinically, 5 (21%) cases of major duct involvement resulted in diagnostic uncertainty between metastatic CRC and cholangiocarcinoma. These findings underscore the frequency of intrabiliary growth by metastatic CRCs and its rarity with other metastases. Major duct involvement should be recognized because of its distinctive clinical features, which can overlap with cholangiocarcinoma. PMID- 23797728 TI - To bring consumers to the table, simplify the review. PMID- 23797730 TI - Decreased inhibitory neuronal activity in patients with frontal lobe brain tumors with seizure presentation: Preliminary study using magnetoencephalography. AB - BACKGROUND: Although 30-50 % of patients with brain tumors experience epileptic seizure as the presenting clinical symptom, and another 10-30 % are at risk for developing epilepsy in the later stages of the disease, the mechanisms of tumor related epileptogenesis are poorly understood. We used magnetoencephalography (MEG) to investigate sensory evoked fields (SEFs) in patients with frontal lobe brain tumors as a means of evaluating the neuronal activity of peri-tumoral cortex. METHODS: Twelve patients with frontal lobe brain tumors underwent MEG. We calculated the equivalent current dipole strength of two components of the primary sensory cortical response (N20m and P35m) and compared the P35m/N20m ratio in the tumor hemisphere vs. the normal hemisphere. There were two subsets of patients: group I, in which P35m/N20m was higher in the tumor hemisphere (n= 7), and group II, in which P35m/N20m was higher in the normal hemisphere (n=5). We looked for associations between clinical factors and P35m/N20m within each group. RESULTS: All patients with seizure presentation were in group I, whereas only two patients without seizure presentation were in group I (Fisher exact test, p=0.028). No other clinical factors were related to P35m/N20m. The mean ratio of P35m/N20m equivalent current dipole strength in patients with seizure presentation was 4.07 +/- 2.38 in the tumor hemisphere and 2.00 +/- 0.55 in the normal hemisphere. This difference was statistically significant (Mann-Whitney test, p=0.030). CONCLUSION: The paradoxical increase in P35m/N20m in patients with seizure presentation suggests that decreased inhibitory neuronal activity is a potential cause of tumorrelated epilepsy. PMID- 23797729 TI - Trends in Triathlon Performance: Effects of Sex and Age. AB - The influences of sex and age upon endurance performance have previously been documented for both running and swimming. A number of recent studies have investigated how sex and age influence triathlon performance, a sport that combines three disciplines (swimming, cycling and running), with competitions commonly lasting between 2 (short distance: 1.5-km swim, 40-km cycle and 10-km run) and 8 h (Ironman distance: 3.8-km swim,180-km cycle and 42-km run) for elite triathletes. Age and sex influences upon performance have also been investigated for ultra-triathlons, with distances corresponding to several Ironman distances and lasting several days, and for off-road triathlons combining swimming, mountain biking and trail running. Triathlon represents an intriguing alternative model for analysing the effects of age and sex upon endurance and ultra-endurance ([6 h) performance because sex differences and age-related declines in performance can be analysed in the same individuals across the three separate disciplines. The relative participation of both females and masters athletes (age[40 years) in triathlon has increased consistently over the past 25 years. Sex differences in triathlon performance are also known to differ between the modes of locomotion adopted (swimming, cycling or running) for both elite and non elite triathletes. Generally, time differences between sexes in swimming have been shown to be smaller on average than during cycling and running. Both physiological and morphological factors contribute to explaining these findings. Performance density (i.e. the time difference between the winner and tenth-placed competitor) has progressively improved (time differences have decreased) for international races over the past two decades for both males and females, with performance density now very similar for both sexes. For age-group triathletes, sex differences in total triathlon performance time increases with age. However,the possible difference in age-related changes in the physiological determinants of endurance and ultra-endurance performances between males and females needs further investigation. Non-physiological factors such as low rates of participation of older female triathletes may also contribute to the greater age-related decline in triathlon performance shown by females. Total triathlon performance has been shown to decrease in a curvilinear manner with advancing age. However, when triathlon performanceis broken down into its three disciplines, there is a smaller age-related decline in cycling performance than in running and swimming performances. Age-associated changes in triathlon performance are also related to the total duration of triathlon races. The magnitude of the declines in cycling and running performances with advancing age for short triathlons are less pronounced than for longer Ironman distance races. Triathlon distance is also important when considering how age affects the rate of the decline in performance. Off-road triathlon performances display greater decrements with age than road-based triathlons, suggesting that the type of discipline (road vs. mountain bike cycling and road vs. trail running) is an important factor in age-associated changes in triathlon performance.Finally, masters triathletes have shown relative improvements in their performances across the three triathlon disciplines and total triathlon event times during Ironman races over the past three decades. This raises an important issue as to whether older male and female triathletes have yet reached their performance limits during Ironman triathlons PMID- 23797731 TI - What does fluorescence depict in glioma surgery? PMID- 23797732 TI - A New Experimental Model for Neuronal and Glial Differentiation Using Stem Cells Derived from Human Exfoliated Deciduous Teeth. AB - Stem cells isolated from human adult tissues represent a promising source for neural differentiation studies in vitro. We have isolated and characterized stem cells from human exfoliated deciduous teeth (SHEDs). These originate from the neural crest and therefore particularly suitable for induction of neural differentiation. We here established a novel three-stage protocol for neural differentiation of SHEDs cells. After adaptation to a serum-free and neurogenic environment, SHEDs were induced to differentiate. This resulted in the formation of stellate or bipolar round-shaped neuron-like cells with subpopulations expressing markers of sensory neurons (Brn3a, peripherin) and glia (myelin basic protein). Commercial PCR array analyses addressed the expression profiles of genes related to neurogenesis and cAMP/calcium signalling. We found distinct evidence for the upregulation of genes regulating the specification of sensory (MAF), sympathetic (midkine, pleitrophin) and dopaminergic (tyrosine hydroxylase, Nurr1) neurons and the differentiation and support of myelinating and non myelinating Schwann cells (Krox24, Krox20, apolipoprotein E). Moreover, for genes controlling major developmental signalling pathways, there was upregulation of BMP (TGF beta-3, BMP2) and Notch (Notch 2, DLL1, HES1, HEY1, HEY2) in the differentiating SHEDs. SHEDs treated according to our new differentiation protocol gave rise to mixed neuronal/glial cell cultures, which opens new possibilities for in vitro studies of neuronal and glial specification and broadens the potential for the employment of such cells in experimental models and future treatment strategies. PMID- 23797733 TI - The expression of FBP1 after traumatic brain injury and its role in astrocyte proliferation. AB - Far upstream element binding protein 1 (FBP1) has been identified as an upstream gene of p27kip1 (p27), which is a key regulator of mammalian cell cycle regulation and neurogenesis. To elucidate the expression and function of FBP1 in central nervous system lesion and repair, we performed a traumatic brain injury (TBI) model in adult rats. We observed that FBP1 protein level significantly reduced at day 3 after injury, and the downregulation of FBP1 was predominant in astrocytes, which were largely proliferated after injury. Furthermore, in vitro, overexpression of FBP1 was concomitant with the up-regulation of p27 and reduction of PCNA in LPS-induced astrocyte proliferation. These results suggest that a decreased level of FBP1 in brain is involved in the proliferation of glial cells after TBI. PMID- 23797734 TI - Involvement of upregulated p53-induced death domain protein (PIDD) in neuronal apoptosis after rat traumatic brain injury. AB - Traumatic brain injury (TBI) initiates a series of complicated pathological events that could eventually lead to neuronal apoptosis. Recent studies indicated that p53 played a crucial role in neuronal apoptosis and regeneration following TBI. However, the detailed mechanism of p53-induced neuronal apoptosis in TBI remains largely elusive. In this study, we identified that p53-induced death domain protein (PIDD), whose transcription could be rapidly induced by p53 activation, was significantly upregulated after TBI. Western blot and immunohistochemistrical analyses revealed that the expression of PIDD was gradually increased, reached a peak at 3 days, and then decreased gradually to basal level after brain trauma. Further, double immunofluorescent analysis showed that PIDD was distributed predominantly in neurons, and the number of PIDD positive neurons was significantly elevated in injured brain cortex. In addition, we found that PIDD was mainly distributed in active caspase-3-positive neurons, implicating a possible involvement of PIDD in the regulation of neuronal apoptosis during TBI. Finally, we showed that the expressions of p53 and Bax were altered correlatively with PIDD after brain trauma, implying that the upregulation of PIDD after TBI might be a result of p53 activation. Taken together, these findings suggested that PIDD might be an important regulator and potential therapeutic target of TBI. PMID- 23797735 TI - Perchlorate reduction from a highly contaminated groundwater in the presence of sulfate-reducing bacteria in a hydrogen-fed biofilm. AB - We used a hydrogen (H2 )-based biofilm to treat a groundwater contaminated with perchlorate (ClO(4)(-) ) at ~10 mg/L, an unusually high concentration. To enhance ClO(4)(-) removal, we either increased the H2 pressure or decreased the electron acceptor surface loading. The ClO(4)(-) removal increased from 94% to 98% when the H2 pressure was increased from 1.3 to 1.7 atm when the total acceptor surface loading was 0.49 g H2 /m(2) day. We then decreased the acceptor surface loading stepwise from 0.49 to 0.07 g H2 /m(2) day, and the ClO(4)(-) removal improved to 99.6%, giving an effluent ClO(4)(-) concentration of 41 ug/L. However, the tradeoff was that sulfate (SO(4)(2-) ) reduction occurred, reaching 85% conversion at the lowest acceptor surface loading (0.07 g H(2) /m(2) day). In two steady states with the highest ClO(4)(-) reduction, we assayed for the presence of perchlorate-reducing bacteria (PRB), denitrifying bacteria (DB), and sulfate reducing bacteria (SRB) by quantitative polymerase chain reaction (qPCR) targeting characteristic reductases. The qPCR results documented competition between PRB and SRB for space within the biofilm. A simple model analysis for a steady-state biofilm suggests that competition from SRB pushed the PRB to locations having a higher detachment rate, which prevented them from driving the ClO(4)(-) concentration below 41 ug/L. PMID- 23797736 TI - Integrated molecular analysis of clear-cell renal cell carcinoma. AB - Clear-cell renal cell carcinoma (ccRCC) is the most prevalent kidney cancer and its molecular pathogenesis is incompletely understood. Here we report an integrated molecular study of ccRCC in which >=100 ccRCC cases were fully analyzed by whole-genome and/or whole-exome and RNA sequencing as well as by array-based gene expression, copy number and/or methylation analyses. We identified a full spectrum of genetic lesions and analyzed gene expression and DNA methylation signatures and determined their impact on tumor behavior. Defective VHL-mediated proteolysis was a common feature of ccRCC, which was caused not only by VHL inactivation but also by new hotspot TCEB1 mutations, which abolished Elongin C-VHL binding, leading to HIF accumulation. Other newly identified pathways and components recurrently mutated in ccRCC included PI3K-AKT mTOR signaling, the KEAP1-NRF2-CUL3 apparatus, DNA methylation, p53-related pathways and mRNA processing. This integrated molecular analysis unmasked new correlations between DNA methylation, gene mutation and/or gene expression and copy number profiles, enabling the stratification of clinical risks for patients with ccRCC. PMID- 23797737 TI - Calycosin entered HUVECs and ameliorated AGEs-promoted cell apoptosis via the Bcl 2 pathway. AB - Endothelial cell (EC) apoptosis plays a pivotal role in the progression of diabetic complications. Abundant studies have demonstrated the pivotal role of advanced glycation end products (AGEs) on the development of diabetes. The aim of the present study was to investigate the effect of calycosin, a phytoestrogen, on AGEs-induced human umbilical vein endothelial cell (HUVEC) apoptosis. Fluorescence polarization and fluorescence absorption assays indicated that calycosin interacted with AGEs in a time-dependent manner. Further studies found that calycosin entered the cells as detected by HPLC. The MTT method demonstrated that calycosin ameliorated AGEs-induced HUVEC apoptosis in a dose-dependent manner, and statistical significance was observed at 1 * 10(-8) M of calycosin; this behavior was further demonstrated by acridine orange/ethidium bromide staining in that the presence of calycosin dramatically reduced AGEs-induced red staining in HUVECs. Further studies found that pre-incubation with calycosin at 1 * 10(-8) M dramatically increased anti-apoptotic Bcl-2 while decreased pro apoptotic Bax and Bad expressions as detected by immunocytochemistry, and the effect of calycosin on rebalancing the ratio of Bcl-2/Bax was more significant than that of its glycoside, calycosin-7-O-beta-D-glucopyranoside (CG). Furthermore, calycosin slightly reversed AGEs-induced cell oxidative stress at 1 * 10(-8) M, but its antioxidative stress effect was less significant than that of CG. The present study strongly indicates that calycosin can enter the cell and modulate endothelial cell dysfunction by ameliorating AGEs-induced cell apoptosis. PMID- 23797738 TI - CD82 regulates STAT5/IL-10 and supports survival of acute myelogenous leukemia cells. AB - We recently reported that adhesion molecule CD82 is aberrantly expressed in CD34(+) /CD38(-) leukemia stem cells (LSCs). Here, we report the results of a functional analysis of CD82 in CD34(+) /CD38(-) acute myelogenous leukemia (AML) cells. Short hairpin (sh)RNA-mediated downregulation of CD82 resulted in a decrease in the level of IL-10. In contrast, forced expression of CD82 in CD34(+)/CD38(+) AML cells by transduction with CD82-expressing lentiviral particles resulted in an increase in the levels of IL-10. Notably, exposure of CD34(+)/CD38(-) AML cells to IL-10 stimulated clonogenic growth of these cells. Moreover, downregulation of CD82 by a shRNA dephosphorylated STAT5 in CD34(+)/CD38(-) AML cells. On the other hand, forced expression of CD82 resulted in increase in the levels of p-STAT5 in CD34(+)/CD38(+) AML cells. Chromatin immunoprecipitation (ChIP) assay results indicated that STAT5A binds to the promoter region of the IL-10 gene, while reporter gene assay results indicated stimulation of IL-10 expression at the transcriptional level. These results suggest that CD82 positively regulates the STAT5/IL-10 signaling pathway. Moreover, shRNA-mediated downregulation of CD82 expression in CD34(+)/CD38(-) AML cells dephosphorylated STAT5 in immunodeficient mice. Taken together, our data suggest that the CD82/STAT5/IL-10 signaling pathway is involved in the survival of CD34(+)/CD38(-) AML cells and may thus be a promising therapeutic target for eradication of AML LSCs. PMID- 23797739 TI - Context management platform for tourism applications. AB - The notion of context has been widely studied and there are several authors that have proposed different definitions of context. However, context has not been widely studied in the framework of human mobility and the notion of context has been imported directly from other computing fields without specifically addressing the tourism domain requirements. In order to store and manage context information a context data model and a context management platform are needed. Ontologies have been widely used in context modelling, but many of them are designed to be applied in general ubiquitous computing environments, do not contain specific concepts related to the tourism domain or some approaches do not contain enough concepts to represent context information related to the visitor on the move. That is why we propose a new approach to provide a better solution to model context data in tourism environments, adding more value to our solution reusing data about tourist resources from an Open Data repository and publishing it as Linked Data. We also propose the architecture for a context information management platform based on this context data model. PMID- 23797740 TI - Fabrication of a polyaniline ultramicroelectrode via a self assembled monolayer modified gold electrode. AB - Herein, we report a simple and inexpensive way for the fabrication of an ultramicroelectrode and present its characterization by electrochemical techniques. The fabrication of polyaniline UME involves only two steps: modification of a gold (Au) electrode by self assembled monolayers (SAM) and then electrodeposition of polyaniline film on this thiol-coated Au electrode by using cyclic voltammetry and constant potential electrolysis methods. Two types of self assembled monolayers (4-mercapto-1-butanol, MB, and 11-mercaptoundecanoic acid, MUA) were used, respectively, to see the effect of chain length on microelectrode formation. Microelectrode fabrication and utility of the surface was investigated by cyclic voltammetric measurements in a redox probe. The thus prepared polyaniline microelectrode was then used for DNA immobilization. Discrimination between double-stranded DNA (dsDNA) and single-stranded DNA (ssDNA) was obtained with enhanced electrochemical signals compared to a polyaniline-coated Au electrode. Different modifications on the electrode surfaces were examined using scanning electron microscopy (SEM). PMID- 23797741 TI - Transcatheter aortic valve replacement for bioprosthetic aortic valve failure: the valve-in-valve procedure. PMID- 23797742 TI - Mitral valve injury after radiofrequency ablation for Wolff-Parkinson-White syndrome. PMID- 23797743 TI - Optical coherence tomography findings in an acquired coronary fistula. PMID- 23797744 TI - Coronary intravascular ultrasound. PMID- 23797745 TI - Letter by Zaugg and Lucchinetti regarding article, "Randomized comparison of sevoflurane versus propofol to reduce perioperative myocardial ischemia in patients undergoing noncardiac surgery". PMID- 23797746 TI - Letter by Zhang et al regarding article, "Randomized comparison of sevoflurane versus propofol to reduce perioperative myocardial ischemia in patients undergoing noncardiac surgery". PMID- 23797747 TI - Letter by Ruggieri et al regarding article, "Randomized comparison of sevoflurane versus propofol to reduce perioperative myocardial ischemia in patients undergoing noncardiac surgery". PMID- 23797748 TI - [Unclear focal hepatic mass.] PMID- 23797749 TI - Trends in hospitalizations of children with inflammatory bowel disease within the United States from 2000 to 2009. AB - BACKGROUND: The incidence and prevalence of pediatric inflammatory bowel disease (IBD) seems to be increasing in North America and Europe. Our objective was to evaluate hospitalization rates in children with IBD in the United States during the decade 2000 to 2009. METHODS: We analyzed cases with a discharge diagnosis of Crohn disease (CD) and ulcerative colitis (UC) within the Healthcare Cost and Utilization Project Kids' Inpatient Database, Agency for Healthcare Research and Quality. RESULTS: We identified 61,779 pediatric discharges with a diagnosis of IBD (CD, 39,451 cases; UC, 22,328 cases). The number of hospitalized children with IBD increased from 11,928 to 19,568 (incidence, 43.5-71.5 cases per 10,000 discharges per year; P < 0.001). For CD, the number increased from 7757 to 12,441 (incidence, 28.3-45.0; P < 0.001) and for UC, 4171 to 7127 (15.2-26.0; P < 0.001). Overall, there was a significant increasing trend for pediatric hospitalizations with IBD, CD, and UC (P < 0.001). In addition, there was an increase in IBD-related complications and comorbid disease burden (P < 0.01). CONCLUSION: There was a significant increase in the number and incidence of hospitalized children with IBD in the United States from 2000 to 2009. PMID- 23797750 TI - Carotid proliferative plaque formation in a canine model of chronic hypertension. AB - BACKGROUND: There are few reports describing arterial plaque formation induced by hypertension alone. The aim of this study was to establish a canine model of chronic hypertension and investigate carotid plaque development. METHODS: Ten beagles were studied; 5 underwent bilateral renal artery constriction via a novel vascular clip, and 5 sham-operated animals served as controls. Systolic blood pressure (SBP), diastolic blood pressure (DBP), lipid values, the intima-media thickness, and the carotid artery plaque score were investigated during 1 year after placement of the clips. RESULTS: The mean SBP and DBP over time were significantly greater in the constriction group (P < 0.001 for SBP, P < 0.01 for DBP). There were no significant differences in blood lipid levels or other biochemical parameters. Carotid plaques were demonstrated at 4 months postoperation in the constriction group; and in the constriction group, intima media thickness became significantly greater at 4 months (P < 0.05), and plaque scores became significantly higher at 8 months (P = 0.034) after clip placement. Carotid stenosis was proved by digital subtraction angiography 1 year after clip placement, and histological examination revealed that the plaques were mainly comprised of smooth muscle cells, proteoglycans, and collagen fibers, but few macrophages and little lipid. CONCLUSIONS: Carotid proliferative plaques were developed in a canine model of chronic hypertension induced by a novel vascular clip. The plaques were mainly comprised of smooth muscle cells, proteoglycans, and collagen fibers. PMID- 23797751 TI - Postoperative pain medication requirements in patients undergoing computer assisted ("Robotic") and standard laparoscopic procedures for newly diagnosed endometrial cancer. AB - PURPOSE: Laparoscopy (LSC) offers superior patient outcomes compared to laparotomy. Small retrospective/prospective series have suggested robotics offers further reduction in postoperative pain and pain medication use compared to standard LSC. Our objective was to compare postoperative pain in patients undergoing robotically assisted (RBT) versus standard LSC for newly diagnosed endometrial cancer. METHODS: All preoperative endometrial cancer cases scheduled for RBT and LSC from May 1, 2007 to June 9, 2010 were identified. For this analysis, we only included cases not requiring conversion to laparotomy. All patients were offered intravenous (IV) patient-controlled analgesia (PCA) postoperatively. Intraoperative equivalent fentanyl doses (IEFDs) and pain scores in the postanesthesia care unit (PACU) were assessed. RESULTS: IV PCA was used in 206 RBTs (86 %) and 208 LSCs (88 %). Median IEFD was 425 MUg for LSCs and 500 MUg for RBTs (P = 0.03). Median pain scores on PACU arrival were similar in both groups. Median highest pain score was 5 for LSCs and 4 for RBTs (P = 0.007). Linear regression demonstrated that the IEFD was not correlated with the highest pain score (R = 0.09; P = 0.07). Fentanyl was used postoperatively in 196 of 206 RBTs (95 %) and 187 of 208 LSCs (90 %). The total fentanyl doses were 242.5 (range 0-2705) MUg and 380 (range 0-2625) MUg, respectively (P < 0.001). The median hourly fentanyl doses were 16.7 (range 0-122.5) MUg and 23.5 (range 0 132.4) MUg, respectively (P = 0.005). Simultaneous multiple regression analysis further demonstrated RBT was independently associated with a lower total fentanyl dose compared to LSC (P = 0.02). CONCLUSIONS: RBT is independently associated with significantly lower postoperative pain and pain medication requirements compared to LSC. The amount of intraoperative fentanyl analgesia does not appear to correlate with postoperative pain.Endometrial cancer is the most common gynecologic malignancy in the United States, with an estimated 47,130 new cases in 2012.1 An estimated 287,100 women were diagnosed with endometrial cancer worldwide in 2008.2 Surgery is the primary treatment of choice for the majority of these women.3 The standard surgical approach has been total abdominal hysterectomy, bilateral salpingo-oophorectomy, and staging via laparotomy. Multiple retrospective series have shown that a less invasive surgical approach via laparoscopy (LSC) is feasible and safe, and also associated with improved perioperative outcomes compared to laparotomy in these patients.4 The Gynecologic Oncology Group (GOG) published results of the largest randomized trial (LAP2) comparing LSC to laparotomy in patients with newly diagnosed endometrial carcinoma in 2009.5,6 This landmark study essentially changed the accepted standard surgical approach in this group. Postoperative complications, median blood loss, and median length of stay (LOS), despite increased operative time, were significantly lower in LSC patients despite 25 % requiring conversion to laparotomy.5 The first 802 eligible patients randomized in LAP2 also participated in a quality-of-life (QOL) study. Within 6 weeks of surgery, patients assigned to LSC reported significantly better QOL on all scales other than fear of recurrence.6 Overall, during this 6-week postoperative period, patients assigned to LSC had superior QOL, fewer physical symptoms, less pain and pain-related interference with functioning, better physical functioning and emotional state, earlier resumption of normal activities, earlier return to work, and better body image compared to those assigned to laparotomy.6 Recurrence-free and overall survivals were the same in both groups.7 Multiple published retrospective series have shown possible benefits, such as reduced postoperative pain, using the robotic (RBT) platform compared to LSC or laparotomy in patients with endometrial cancer.8-11 In a randomized trial, LSC was found to be associated with less postoperative pain compared to vaginal approaches in patients undergoing hysterectomy for benign gynecologic disease.12 A small retrospective series reported further reductions in postoperative pain in patients who had undergone an RBT hysterectomy compared to a standard total LSC hysterectomy for benign indications.13 A recent cost analysis suggested that patients experienced less pain and required less pain medication use after RBT procedures compared to LSC for endometrial cancer.14 Based on these reports, we sought to analyze postoperative pain and the use of pain medication in patients undergoing RBT compared to standard transperitoneal LSC procedures for newly diagnosed endometrial cancer during a concurrent time period. Of note, current RBT surgery is not truly robotic in that it is not autonomous. A more appropriate term is "computer-assisted surgery," but to satisfy current convention, we refer to it as "robotic surgery" in this manuscript. PMID- 23797752 TI - Prognostic gene signatures for hepatocellular carcinoma: what are we measuring? PMID- 23797754 TI - Usefulness of stroke volume index obtained with the FloTrac/ Vigileo system for the prediction of acute kidney injury after radical esophagectomy. AB - PURPOSE: To assess the impact of stroke volume index (SVI) at the end of esophagectomy upon postoperative renal function. METHODS: We reviewed medical records of 128 patients undergoing esophagectomy. Intraoperative hemodynamics were monitored with the FloTrac sensor/Vigileo monitor system in addition to standard monitors. Patients were divided into two groups according to SVI at the end of surgery: the normal SVI group (n = 76), with SVI >= 35 ml/m2, and the low SVI group (n = 52), with SVI<35 ml/m2. We compared postoperative renal function, indicated by serum creatinine and estimated glomerular filtration rate, on post operative days 0 through 3. We also compared numbers of patients who developed postoperative acute kidney injury (AKI). RESULTS: Although there were no intergroup differences in preoperative renal function or other intraoperative hemodynamic variables, including arterial pressure, central venous pressure, stroke volume variation, a volume of infusion, urine output, and the total intraoperative in-out balance, estimated glomerular filtration rate was significantly lower and serum creatinine was significantly higher in the low SVI group than in the normal SVI group on postoperative days 1 and 2 (P<0.05). In addition, more patients developed postoperative AKI in the low SVI group than in the normal SVI group (12 of 52 vs. 5 of 76, P = 0.015). CONCLUSIONS: Low SVI at the end of esophagectomy may represent a risk factor for AKI in the early postoperative period. Further studies are required to examine whether maintaining SVI above 35 ml/m2 reduces the incidence of AKI after esophagectomy. PMID- 23797753 TI - Prognostic impact of body mass index in patients with squamous cell carcinoma of the esophagus. AB - PURPOSE: To clarify the prognostic impact of body mass index (BMI) in patients with esophageal squamous cell carcinoma (ESCC). METHODS: Two hundred forty-three patients who underwent esophagectomy for ESCC from April 2005 through December 2010 were eligible. Prognoses of the patients were compared between groups stratified according to BMI. We also analyzed the survival difference using propensity score matching to adjust differences in staging and treatment. RESULTS: Low, normal, and high BMI groups had 35, 177, and 31 patients, respectively. The low BMI group included more advanced cases than did the normal BMI group, while tumor stage was equivalent in the normal and high BMI groups. Disease-free survival of the low and high BMI groups was significantly worse than that of the normal BMI group (P<0.0001 between the low and normal BMI groups; P = 0.0076 between the normal and high BMI groups). Disease-free survival of the high BMI group was significantly worse than that of the normal BMI group in the propensity score-matched cohort (P = 0.0020). Multivariate analysis in this cohort demonstrated that high BMI was an independent prognostic factor (hazard ratio 2.949, 95% confidence interval, 1.132-7.683). CONCLUSIONS: High BMI was an independent prognostic factor after curative esophagectomy for ESCC. Although further analysis is required to clarify the influence of overweight on the biological features of ESCC, glucose metabolism may be a therapeutic target for ESCC. PMID- 23797755 TI - Multistage regression, a novel method for making better predictions from your efficacy data. AB - Multistage regression is rarely used in therapeutic research, despite the multistage pattern of many medical conditions. Using an example of an efficacy study of a new laxative, path analysis and the 2-stage least square method were compared with standard linear regression. Standard linear regression showed a significant effect of the predictor "noncompliance" on drug efficacy at P=0.005. However, after adjustment for the covariate "counseling," the magnitude of the regression coefficient fell from 0.70 to 0.29, and the P value rose to 0.10. Path analysis was valid, given the significant correlation between the two predictors (P=0.024) and produced an increase of the regression coefficient between "noncompliance" and "drug efficacy" by 60.0%. The 2-stage least squares method, using counseling as instrumental variable, produced, similarly, an increase of the overall correlation by 66.7%. A bivariate path analysis with "quality of life" as the second outcome variable increased the magnitude of the path statistic further by 47.1%, and, thus, enabled to make still better use of the predicting variables. We conclude that (1) multistage regression methods, as used in the present article produced much better predictions about the drug efficacy than did standard linear regression; (2) the inclusion of additional outcome variables enables to make still better use of the predicting variables; (3) multistage regression must always be preceded by usual linear regression to exclude weak predictors. We recommend that researchers analyzing efficacy data of new treatments more often apply multistage regression. PMID- 23797756 TI - Central effects of lipoic acid associated with paroxetine in mice. AB - Antidepressants, including selective serotonin reuptake inhibitors, are commonly prescribed for the treatment of affective disorders such as anxiety and depression. The purpose of this study was to investigate the central effects of acute administration of paroxetine (PXT) combined with lipoic acid (LA) on various behavioral models in mice. Paroxetine (10 and 20 mg/kg), LA (100 mg/kg), or vehicle was administered, intraperitoneally, 30 minutes before the tests. The results showed that PXT (10 mg/kg) alone and in combination with LA increased locomotor activity. In the anxiety models studied, an anxiolytic effect was observed after the administration of LA and PXT. In the tail suspension test, PXT at both doses and in combination with LA caused a significant decrease in immobility time. These results indicate possible anxiolytic and antidepressant effects of LA associated with PXT. These data suggest that coadministration of LA and PXT may improve anxiolytic and antidepressant responses, and being more effective than each drug alone. However, further studies are necessary to investigate the mechanism by which antioxidants exert antidepressant or anxiolytic action. PMID- 23797757 TI - Late-onset advanced heart block due to vagal nerve stimulation. AB - Vagal nerve stimulation (VNS) is widely accepted as an effective and safe therapy for refractory seizure disorders. Significant cardiac complications, such as complete heart block or symptomatic bradycardia, are extremely rare. We present a case report of a 40-year-old man with drug-resistant epilepsy, treated with VNS, who developed the late-onset (12 months after implant), stimulation-related, symptomatic advanced heart block that was initially misinterpreted for a new type of seizure. The patient was otherwise free from other stimulation-related side effects. To our knowledge, this is the first case report of late-onset advanced heart block due to VNS. PMID- 23797758 TI - Coronary Artery Disease in the Human Immunodeficiency Virus Seropositive Population. AB - The development of efficient combined antiretroviral therapies has lengthened the mean life span of the population affected with human immunodeficiency virus (HIV) transforming this terminal infection to a chronic yet manageable disease. Nonetheless, patients with HIV--treatment naive or not--exhibit larger risks for coronary artery disease than the noninfected population. Moreover, coronary atherosclerosis/arteriosclerosis may be the most prevalent condition in the HIV infected population that is being accentuated by the effects of viral agents and the antiretroviral drugs, especially protease inhibitors. Nonetheless, generalized metabolic dysfunctions and premature senescence are often attributed to the viremia caused by the HIV infection directly and primarily. Therefore, a multifactorial approach is to be considered when attempting to explain the strong correlation between HIV and coronary artery disease, including co-opportunistic viremias and vitamin D insufficiency/deficiency. PMID- 23797759 TI - Corticosteroid Monotherapy Is Usually Insufficient Treatment for Idiopathic Inflammatory Myopathy. AB - Idiopathic inflammatory myopathies (IIM) are a rare group of autoimmune diseases characterized by muscle inflammation. High-dose corticosteroids are conventionally used as the first-line therapy for IIM, but early introduction of noncorticosteroid immunosuppressive agents has become increasingly common in recent years despite a paucity of compelling evidence to support this. Here, we systematically analyze therapeutic practice patterns of IIM in a large municipal safety net medical center. We conducted a retrospective chart review of all adult patients attending rheumatology clinics at the Cook County Health and Hospital Systems from 2006 to 2011 with a diagnosis of IIM. Data collected included patient demographics, diagnosis, immunosuppressive therapies, serial serum creatine kinase (CK) measurements, and serial muscle strength testing. One hundred eight patients fulfilled eligibility criteria. The mean duration of follow-up was 62 months (range, 1-351 months). At presentation, the mean strength in the weakest muscle group was rated as 3.6 out of 5 (range, 1-5; SD 0.9), the mean initial CK was 4720 U/L (range, 23-38, 461; SD 6, 795), and initial mean prednisone dosage was 48 mg/d (range, 0-100, SD 22). At the end of the follow-up period, mean strength in the weakest muscle group was 4.6 out of 5 (range, 2-5; SD 0.7), mean peak CK was 412 (24-7533; SD 875), and the mean prednisone dosage was 12.7 mg (0-80; SD 17.5). Only 15 patients (14%) received exclusively corticosteroid monotherapy during the follow-up period. Ninety-three patients (86%) received additional immunosuppressive agents. Over the course of their illness, only a minority of patients in our cohort of IIM patients was treated with corticosteroids alone. It is unlikely we will determine optimal therapy in the absence of a large controlled study comparing corticosteroids versus a combination regimen, but it seems that rheumatologists favor addition of second line immunosuppressive agents. PMID- 23797760 TI - Genetic properties of endemic Chinese porcine epidemic diarrhea virus strains isolated since 2010. AB - Acute diarrhea outbreaks caused by porcine epidemic diarrhea virus (PEDV) have been observed in various pig-breeding provinces of China since December 2010. Endemic strains of PEDV were isolated from different areas, and the complete genome sequences of 10 isolates were determined. Our objective in this study was to genetically characterize current Chinese field isolates of PEDV to better understand their epidemiology and genetic diversity. Sequence analysis showed that 10 post-2010 isolates shared high homology with each other and were always clustered together with the virulent DR13 strains (South Korea) and/or one earlier Chinese strain, CH-S, in phylogenetic analysis. All post-2010 isolates possessed common sequence changes in each gene. Our results suggest that current Chinese PEDV isolates originated from either South Korean and/or Chinese ancestors that underwent some genetic variation, thereby forming a new PEDV genotype in China. PMID- 23797761 TI - [Prescription of antibiotic drugs for children at the Brazzaville University Hospital Center (Congo)]. AB - Antibiotics are a class of drugs commonly prescribed in pediatric practice, often inappropriately. OBJECTIVE: To determine the prevalence of antibiotic prescription in hospitalized children, assess the quality of prescribing, and identify factors related to inappropriate prescriptions. METHODS: This retrospective study was conducted from July through December 2009 (6 months). It included data about 464 children aged from 1 month-16 years who received antibiotic therapy. RESULTS: Antibiotics were prescribed to 61.5% of the children admitted to the hospital. Their mean age was 18.6 +/- 20.2 months, and most (78%) were younger than 2 years. The indications for antibiotics were dominated by acute respiratory infections (46%), diarrhea (16%), and severe sepsis (12%). The prescriptions were written by pediatricians in 179 cases (38.6%), and by residents or interns in the other cases. The beta-lactam antibiotics (79%), aminoglycosides (8%) and sulfonamides (7%) were prescribed most often. The initial antibiotic therapy was changed in 82 cases. The indication for antibiotic therapy was correct in 325 cases and the type chosen appropriate in 229, the dosage correct in 437 cases, and the duration correct in 390. The route of administration was intravenous in 243 cases (40.3%), oral in 194 (41.8%), and intramuscular in 37 (7.9%). The qualification of the prescriber was associated with relevance, choice and dosage. The dosage was correct when the drug was administered parenterally in 248 cases (56.8%); in contrast, it was incorrect in 189 cases (43.7%; p>0.05) of oral administration. The route of administration was related to the choice of antibiotic. Thus, it was appropriate when the route was parenteral in 162 cases (70.7%) and in only 67 cases (29.3%) for the oral route (p <0.001). CONCLUSION: Errors in antibiotic prescriptions could be improved by standardized treatment guidelines, compliance with international recommendations, a consistent approach to diagnosis, and better laboratory performance. PMID- 23797762 TI - Metformin impairs glucose consumption and survival in Calu-1 cells by direct inhibition of hexokinase-II. AB - The anti-hyperglycaemic drug metformin has important anticancer properties as shown by the direct inhibition of cancer cells proliferation. Tumor cells avidly use glucose as a source for energy production and cell building blocks. Critical to this phenotype is the production of glucose-6-phosphate (G6P), catalysed by hexokinases (HK) I and II, whose role in glucose retention and metabolism is highly advantageous for cell survival and proliferation. Here we show that metformin impairs the enzymatic function of HKI and II in Calu-1 cells. This inhibition virtually abolishes cell glucose uptake and phosphorylation as documented by the reduced entrapment of 18F-fluorodeoxyglucose. In-silico models indicate that this action is due to metformin capability to mimic G6P features by steadily binding its pocket in HKII. The impairment of this energy source results in mitochondrial depolarization and subsequent cell death. These results could represent a starting point to open effective strategies in cancer prevention and treatment. PMID- 23797763 TI - [Cuff tear arthropathy - long-term results of reverse total shoulder arthroplasty]. AB - The results after reverse total shoulder arthroplasty for cuff tear arthropathy are superior and the complications fewer than for other etiologies, such as rheumatoid arthritis, fracture, fracture sequelae or even revision. The improvements in function and pain are excellent whereas rotation may be unaffected. Revisions and complications can be encountered in the first 3 years and the survival curve of the prosthesis is still good after 10 years with 90%. Progressive functional and radiological deterioration is observed after 9 years in approximately 30% of the patients without apparent problems with the prosthesis. Notching is progressive with incidence and size over time, without a proven correlation to the functional results but remains a major concern. Modification of the implants, the operative techniques and experience could significantly improve the results and reduce the rate of complications. Lateralization of the center of rotation and smaller inclination angles have a positive effect on the rate of notching and the range of motion, especially for the rotation. New prosthetic designs and operative techniques attempt to implement a combination of the biomechanical improvements. Reverse shoulder arthroplasty remains a challenging operation with a high rate of complications. The results depend on the etiology and the function of the remaining muscles and therefore on the experience and the skill of the surgeon to implement the appropriate biomechanical factors. Because of the concerns regarding the longevity, reverse shoulder arthroplasty should be reserved for the elderly over 70 years of age. PMID- 23797764 TI - [Reverse shoulder arthroplasty for fracture sequelae]. AB - Posttraumatic fracture sequelae of the proximal humerus represent an extremely heterogeneous pathology. In severe cases they are often associated with marked soft tissue scarring, osseous defects and insufficiency of the rotator cuff, resulting in a static instability of the humeral head. The aim of this article is to demonstrate the possibilities and early results of reverse shoulder arthroplasty for the operative management of this complex injury pattern. PMID- 23797765 TI - Effectiveness of the new injection program 'saline test injection mode' for use power injector in pediatric contrast CT. AB - To improve the safety of the use of a power injector for pediatric contrast CT, we newly developed a saline test injection mode for a power injector and investigated its usefulness. We used an injection route and investigated the relationship of the injection pressure to the injection rate of saline and the contrast medium. From this relationship, we investigated it was possible to estimate the change of pressure injection of contrast medium from the pressure change of saline injection. The correlation between the saline test injection pressure and the contrast medium injection pressure was investigated in 64 clinical cases. The detection rate of side effects from the saline test injection was investigated in 473 patients. Regarding the correlation between the injection rate and pressure for both saline and contrast, the pressure rose as the rate increased. The contrast medium injection pressure could be estimated from the correlation observed with saline. The clinical data were obtained had a relationship similar to that with phantom data. The detection rate of side effects from the saline test injection was 4.4% in the clinical cases. In these cases, examinations were completed by re-establishing an injection route or administering hypnotics. Our results suggest that contrast medium pressure can be estimated from a saline test injection, thus aiding in prediction of the risk of injection abnormality. Reactions to injections could be observed in the present study, facilitating the prevention of examination failure. Countermeasures can be taken against the cause of the reaction, and the examination can be performed after confirming the absence of a reaction to injection. Therefore, a saline test injection may be useful in pediatric contrast CT. PMID- 23797766 TI - Scintillating advances on somatic cell nuclear transfer and the implications for human ARTs. PMID- 23797767 TI - New evidence supports, challenges, and informs the ambitions of health reform. PMID- 23797768 TI - Drugs for bacterial infections. PMID- 23797769 TI - Association between human papillomavirus and endometrial adenocarcinoma. AB - Several studies have suggested a possible role of human papillomavirus (HPV) in the pathogenesis of endometrial carcinoma. The aim of the study was to investigate the presence of HPV DNA in endometrium cancers and nonneoplastic endometrium. Sixty endometrial adenocarcinomas with and without squamous differentiation and the nonneoplastic endometrium tissue of fifty-six of the same patients were analyzed for the presence of family 16 and family 6 HPV DNA by using chromogenic in situ hybridization technique on formalin-fixed and paraffin embedded archival samples, and the results were confirmed by polymerase chain reaction method. HPV DNA was not detected either in the endometrial adenocarcinoma with or without squamous differentiation, or in the nonneoplastic endometrium tissue. It appears that HPV does not play any role in the pathogenesis of endometrial carcinoma, since endometrium may not to be a suitable host for HPV replication. PMID- 23797770 TI - Co-expression of AQP3 and AQP5 in esophageal squamous cell carcinoma correlates with aggressive tumor progression and poor prognosis. AB - To investigate the expression patterns of aquaporin 3 (AQP) 3 and AQP5, to evaluate their relationships with clinicopathological characteristics, and to determine their correlations with survival in esophageal squamous cell carcinoma (ESCC) patients, expression levels of AQP3 and AQP5 proteins in 126 ESCC patients were detected by immunohistochemistry. Then, paired Student's t-test, chi-square test, Spearman's rank correlation, Kaplan-Meier plots, and Cox proportional hazards regression model were used to analyze their associations with clinicopathological characteristics and survivals of ESCC patients. Both AQP3 and AQP5 proteins were localized on the cell membrane of tumor cells in ESCC tissues. The expression levels of two proteins in ESCC tissues were significantly higher than those in adjacent normal tissues (both P < 0.001). Additionally, high expression of AQP3 and AQP5 was both correlated with advanced invasion depth (both P = 0.01), aggressive lymph node status (P = 0.02 and 0.01, respectively), and positive distant metastasis (both P = 0.01). However, the overexpression of AQP3 and AQP5 alone did not influence the prognosis. Furthermore, ESCC patients with the co-expression of AQP3 and AQP5 showed the poorest prognosis in overall (P = 0.002) and disease-free survival (P < 0.001). Multivariate analysis showed that the co-expression of AQP3 and AQP5 was an independent prognostic factors of overall (P = 0.01) and disease-free survival (P = 0.01) in ESCC. Our data demonstrate for the first time that high expression of both AQP3 and AQP5, not each alone, is an independent poor prognostic factor in ESCC patients. Combined detection of the two proteins' expression may help to predict the progression and the prognosis of ESCC patients. PMID- 23797771 TI - Combined therapy in untreated patients improves outcome in nasal NK/T lymphoma: results of a clinical trial. AB - Nasal NK/T-cell lymphoma is a rare presentation of T-cell lymphoma in USA and in Europe, but is the most common presentation in Latin America. The lymphoma is associated with a worse prognosis even in the early stage. Until now, a better treatment has not been determined. We performed a prospective, open-label, controlled clinical trial to assess the efficacy and toxicity of the most common treatment options. We treated 427 patients, of whom 109 patients received radiotherapy (RT), 116 patients received chemotherapy (C), and 202 patients received combined therapy (CT), which were balanced according to stage and prognostic factors. Complete response was achieved in 91 % (95 % confidence interval CI 88-102 %) in CT arm 69 % (95 % CI 61-75 %) in RT arm; and 59 % (95 % CI 48-64 %) in C arm (p < 0.01). A progression-free disease was 91 % (95 % CI 83 96 %); 78 % (95 % CI 69-86 %); and 40 % (95 % CI 32-46 %), respectively (p < 0.01). Actuarial curves of overall survival at 5 years were as follows: 86 % (95 % CI 81-90 %), for CT; 64 % (95 % CI 59-70 %) for RT; and 45 % (95 % CI 39-51 %) for C (p < 0.001). Toxicity was mild and well tolerated. To our knowledge, this is the first controlled clinical trial, with a large number of patients and longer follow-up. Thus, we conclude that CT is the best therapeutic option in this setting of patients. PMID- 23797772 TI - Correlation of EGFR mutation and predominant histologic subtype according to the new lung adenocarcinoma classification in Chinese patients. AB - A new lung adenocarcinoma classification proposed by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) has recently been published. However, the relationship between EGFR mutations and subtype of adenocarcinoma remains unclear. A total of 161 surgically resected lung adenocarcinomas in Zhejiang Cancer Hospital were reviewed using the new classification system. Epidermal growth factor receptor (EGFR) mutations were observed in 67 cases (41.6 %). EGFR mutations were found to be closely associated with the micropapillary predominant subtype (P = 0.0068) and lepidic component (P = 0.005). The frequency of EGFR mutation was found to be lower in the solid predominant subtype than other subtype (P = 0.04). In conclusion, histologic subtyping was found to be associated with EGFR mutations. The EGFR mutation frequency of micropapillary and lepidic predominant subtypes was found to be more pronounced than that of other subtypes. PMID- 23797773 TI - Down-regulation of ribosomal protein L22 in non-small cell lung cancer. AB - Ribosomal protein L22 (RPL22), an RNA-binding protein, is a constituent of the 60S large ribosomal subunit. As reported, RPL22 is not required in protein synthesis, and mutations of RPL22 were the main cause of macrolide resistance in bacteria. In vertebrates, RPL22 mutation might increase the proliferation of cells and then increase cancer risk. However, to our knowledge, RPL22 has not been implicated in any lung diseases, especially in lung cancer. In this study, we compared the expression of RPL22 gene in non-small cell lung cancer (NSCLC) tissues, plasma as well as human lung cancer cell line LTEP-a-2 with that in normal lung tissues and cells, using real-time RT-qPCR, Western blot, quantitative immunohistochemistry analysis, and ELISA. Our studies showed that the expression of RPL22 was significantly down-regulated in mRNA and protein expression level in NSCLC; however, there was no significant difference of RPL22 levels in plasma between normal and NSCLC patients. Further analysis indicated that down-regulation of RPL22 might be involved in the carcinogenesis of NSCLC, yet not an effective biomarker in plasma for early diagnosis. PMID- 23797774 TI - The type of patients who would benefit from anti-androgen withdrawal therapy: could it be performed safely for aggressive prostate cancer? AB - This study was designed to detect the factors that were significantly associated with the results of anti-androgen withdrawal (AAWD) therapy, and to examine whether patients with aggressive prostate cancer demonstrating a short prostate specific antigen (PSA)-doubling time (DT) could benefit from it without even greater exacerbation of the disease. We conducted a retrospective chart review study of 121 patients who received AAWD therapy due to failed combined androgen blockade (CAB) therapy. A reduction in the serum PSA level after AAWD was observed in 35 patients (28.9 %), and a greater than 50 % decrease from the baseline serum PSA level was observed in 16 patients (13.2 %). Shortening of PSA DT after AAWD was observed in 48 patients (39.7 %). Univariate and multivariate analyses demonstrated that only a long duration of prior anti-androgen treatment was selected as a significant predictor for a good response to AAWD therapy. With respect to exacerbation after AAWD, we found that patients with a short baseline PSA-DT conversely had a low risk of subsequent shortening of PSA-DT. Using these two factors, we could stratify the patients into four groups, and patients with prior duration of anti-androgen >18 months and PSA-DT <=3 months demonstrated the best results with a good response rate (67.9 %) and a low risk for a worsening of the disease (14.3 %). We conclude that AAWD would be effective especially for patients whose cancer progressed rapidly (short PSA-DT) after a long stable period under CAB and should be recommended before embarking on the next therapeutic maneuver. PMID- 23797775 TI - Harvesting microalgae cultures with superabsorbent polymers: desulfurization of Chlamydomonas reinhardtii for hydrogen production. AB - It is presented in this work a new methodology to harvest fresh water microalgae cultures by extracting the culture medium with superabsorbent polymers (SAPs). The microalgae Chlamydomonas reinhardtii were grown in the Sueoka culture medium, harvested with polyacrylic SAPs and re-suspended in the culture medium tris acetate-potassium without sulfur (TAP-S) to generate hydrogen (H2 ) under anoxic conditions. The H2 production as an alternative fuel is relevant since this gas has high-energy recovery without involving carbon. Before microalgae harvesting, a number of range diameters (1-7 mm) for SAPs spherical particles were tested, and the initial rate (V0 ) and the maximal capacity (Qmax ) were determined for the Sueoka medium absorption. The SAP particles with the diameter range 2.0-2.5 mm performed the best and these were employed for the rest of the experiments. The Sueoka medium has a high salt content and the effect of the ionic strength was also studied for different medium concentrations (0-400%). The SAPs were reused in consecutive absorption/desorption cycles, maintaining their absorption capacity. Although the Sueoka medium reduces the SAPs absorption capacity to 40% compared with deionized water, the use of SAPs was very significant for the desulfurization process of C. reihardtii. The presence of C. reinhardtii at different concentrations does not affect the absorption capacity of the Sueoka culture medium by the SAPs. In order to reduce the time of the process, an increase of the SAPs concentration was tested, being 20 g of SAP per liter of medium, a condition to harvest the microalgae culture in 4 h. There were no evident cell ruptures during the harvesting process and the cells remained alive. Finally, the harvested biomass was re-suspended in TAP-S medium and kept under anaerobic conditions and illumination to produce H2 that was monitored by a PEM fuel cell. The use of SAPs for microalgae harvesting is a feasible non-invasive procedure to obtain high concentrations of functional biomass at low cost; it offers an attractive alternative due to its versatility and simplicity. PMID- 23797776 TI - Human papillomavirus infections as a marker to predict overall survival in lung adenocarcinoma. AB - Human papillomavirus (HPV) has been implicated in multiple cancers, but its significance in lung cancer has remained controversial. As the prevalence of HPV 16/18 infection was higher in lung adenocarcinoma among Taiwanese females, the aim of our study was to evaluate the clinical impact of HPV infections in lung adenocarcinoma. Two hundred and ten patients were enrolled to investigate the associations of HPV status in tumors with clinical characteristics as well as its impact on overall survival. The methods to assess HPV status were by immunohistochemistry for HPV L1 capsid protein and E6 protein and by nested polymerase chain reaction for HPV 16 and HPV 18. HPV infections were identified in 35.2% of patients, and associated with localized and smaller sized tumors (p = 0.022 and p = 0.002, respectively). Patients with HPV infections had a significantly better survival (p = 0.023, by log-rank test) and a significantly reduced mortality risk after adjustments of age, tumor extent, epidermal growth factor receptor (EGFR) mutations status and treatments [adjusted hazard ratio = 0.68, 95% confidence interval (CI) = 0.49-0.96, p = 0.026, by multivariate Cox proportional hazards models]. Specifically, patients with both HPV infections and EGFR mutations had the best survival outcome [1-year survival rate, 68.5% (95% CI = 52.2-4.8%)]. Our findings indicate that HPV infections represent an independent prognostic factor for overall survival in patients with lung adenocarcinoma. PMID- 23797777 TI - Out of Academics: Education, Entrepreneurship and Enterprise. AB - The author started a niche biotech company in 1985 called Flexcell(r) to distribute an enabling technology, mechanobiology devices, to the field. He was the first University of North Carolina faculty member to start a company and stay with it as he pursued his career in academics. That was an unpopular route at that time, but a path he was driven to navigate. Those interests, merged with his training, led to the design and manufacture of mechanobiology devices such as the Flexercell(r) Strain Unit and the BioFlex(r) flexible bottom culture plates to study fundamental responses of cells to strain. Principles in these devices were also incorporated into bioreactors for tissue engineering, which are standard in the marketplace today. In this article, the major roadblocks will be chronicled that were overcome to help build the field of mechanobiology and create a small biotechnology company. Through example, the author's formula for achieving milestones will be discussed including, the DRIVE it takes to get there ["DRIVE": Determination (Confidence), Research and Development (R&D) and Risk-Taking, Innovation (Imagination) and Intellectual Property, achieving Victory, and Enterprise]. PMID- 23797778 TI - New perspectives in human movement variability. PMID- 23797779 TI - Study of the efficacy of mizoribine in lupus nephritis in Chinese patients. AB - We conducted a clinical study in China on the efficacy and safety of mizoribine (MZR) in lupus nephritis. Eleven subjects with proteinuria (>=2 g/day) who had undergone renal biopsy confirming a diagnosis of lupus nephritis (class III: 1 subject; class IV: 6 subjects; class V: 4 subjects) were enrolled. Nine of the subjects were treatment- naive patients who received remission induction therapy, and the other two were switched from cyclophosphamide (CTX) or mycophenolate mofetil due to lack of efficacy. MZR 150 mg was administered once a day. After 6 months, the remission rate was 72.7% (2 subjects achieved complete remission, and 9 partial remission). After 3 and 6 months, significant reductions (p < 0.01) were obtained in 24-h proteinuria (g/day). In the subjects switched to MZR due to lack of efficacy with CTX, the dose was increased from MZR 150-200 mg due to inadequate improvement in proteinuria, and this dose escalation resulted in complete remission after 6 months. It is believed that this kind of dose escalation is one possible treatment option for lupus nephritis. In this study, no adverse events occurred in any of the subjects. We therefore concluded that this first use in China as remission induction therapy in lupus nephritis patients of MZR, which is recognized as an effective maintenance therapy in Japan, was effective. The results also suggest that MZR could be effective in patients for whom other drugs have been insufficiently effective. PMID- 23797780 TI - Gout: a critical analysis of scientific development. AB - In recent years, scientific efforts on the topic "gout" have focused on pathogenetic aspects. This has opened new strategies of anti-inflammatory therapy and has improved urate-lowering therapy. So far, a scientometric analysis of the topic "gout" has not been generated despite an increased need for it in times of modified evaluation criteria for academic personnel and a subsequent tendency to co-authorship and author self-citation. The study aims to evaluate quality and quantity of scientific research dealing with the topic "gout" and to contribute to distinguish relevant research output. The current study uses scientometric methods and large-scale data analysis to evaluate quality and quantity of scientific efforts in the field of "gout." Data were gained from PubMed and ISI Web. In the last 22 years (1990-2012), 4,424 items were published by 71 countries, of which the USA have been the most productive supplier with 32 % of all publications, followed in considerable distance by the United Kingdom, Japan, Spain and Germany, respectively. The USA have established their position as center of international cooperation. The most prolific journals in the field of gout were "Arthritis and Rheumatism," "Annals of the Rheumatic diseases" and the "Journal of Rheumatology." Our analysis specifies the most productive authors and institutions engaged with the topic, the most successful international and national cooperation and the most prolific journals and subject areas. Nevertheless, scientometric indicators, such as h-index, citation rate and impact factor, commonly used for assessment of scientific quality, should be seen critically due to distortion by bias of self-citation and co-authorship. PMID- 23797781 TI - Relationship between pulse wave velocity and serum YKL-40 level in patients with early rheumatoid arthritis. AB - Subclinical atherosclerosis has been demonstrated in patients with early rheumatoid arthritis (ERA) without any signs of cardiovascular disease (CVD). The aim of this study was to investigate the relationship between serum YKL-40 level and arterial stiffness in patients with ERA. Forty two patients with ERA and 35 healthy controls with no history or current sign of CVD were included in the study. ERA patients with active disease, defined as DAS28 >= 3.2, and symptoms onset <12 months were recruited. Arterial stiffness was evaluated by carotid femoral pulse wave velocity (CF-PWV), and the intima-media thickness carotid (IMT C) was measured by carotid ultrasonography. Serum YKL-40 levels were measured by an enzyme-linked immunoassay method. The mean age was 43.1 +/- 5.8 years in ERA patients and 41.0 +/- 5.9 years in control group. The CFPWV and IMT-C of the ERA patients were determined significantly higher than the control group (P = .001, P < .001, respectively). YKL-40 levels were significantly elevated in ERA patients than controls (P = .008). The serum levels of YKL-40 in the ERA patients showed a strong correlation with CF-PWV (r = .711, P < .001) and IMT-C (r = .733, P < .001). Multiple linear regression analysis revealed that CF-PWV could be explained by serum YKL-40 levels (adjusted R2 = .493, P < .001). We have shown that patients with ERA had increased CF-PWV and serum YKL-40 levels. In addition, there was an association between CF-PWV values and serum YKL-40 levels in patients with ERA. As a result, we believe that serum YKL-40 level and CF-PWV might reflect early atherosclerosis in patients with ERA. PMID- 23797782 TI - Computational microscopy of cyclodextrin mediated cholesterol extraction from lipid model membranes. AB - Beta-cyclodextrins (beta-CDs) can form inclusion complexes with cholesterol, and are commonly used to manipulate cholesterol levels of biomembranes. In this work, we have used multiscale molecular dynamics simulations to provide a detailed view on the interaction between beta-CDs and lipid model membranes. We show that cholesterol can be extracted efficiently upon adsorption of beta-CD dimers at the membrane/water interface. However, extraction is only observed to occur spontaneously in membranes with high cholesterol levels. Free energy calculations reveal the presence of a kinetic barrier for cholesterol extraction in the case of low cholesterol content. Cholesterol uptake is facilitated in case of (poly)unsaturated lipid membranes, which increases the free energy of the membrane bound state of cholesterol. Comparing lipid/cholesterol compositions typical of liquid-disordered (L(d)) and liquid-order (L(o)) domains, we furthermore show that cholesterol is preferentially extracted from the disordered regions, in line with recent experimental data. PMID- 23797783 TI - Pediatric stroke, health disparities, and biological differences in disease pathophysiology. PMID- 23797785 TI - Histaminylation of fibrinogen by tissue transglutaminase-2 (TGM-2): potential role in modulating inflammation. AB - Plasma fibrinogen plays an important role in hemostasis and inflammation. Fibrinogen is converted to fibrin to impede blood loss and serves as the provisional matrix that aids wound healing. Fibrinogen also binds to cytokine activated endothelial cells and promotes the binding and migration of leukocytes into tissues during inflammation. Tissue transglutaminase (TGM-2) released from injured cells could cross-link fibrinogen to form multivalent complexes that could promote adhesion of platelets and vascular cells to endothelium. Histamine released by mast cells is a potent biogenic amine that promotes inflammation. The covalent attachment of histamine to proteins (histaminylation) by TGM-2 could modify local inflammatory reactions. We investigated TGM-2 crosslinking of several biogenic amines (serotonin, histamine, dopamine and noradrenaline) to fibrinogen. We identified histaminylation of fibrinogen by TGM-2 as a preferred reaction in solid and solution phase transglutaminase assays. Histamine caused a concentration-dependent inhibition of fibrinogen cross-linking by TGM-2. Fibrinogen that was not TGM-2 crosslinked bound to unactivated endothelial cells with low affinity. However, the binding was increased by sevenfold when fibrinogen was cross-linked by TGM-2. Histaminylation of fibrinogen also inhibited TGM-2 crosslinking of fibrinogen and the binding to un-activated HUVEC cells by 75-90 %. In summary, the histaminylation of fibrinogen by TGM-2 could play a role in modifying inflammation by sequestering free histamine and by inhibiting TGM-2 crosslinking of fibrinogen. PMID- 23797786 TI - Family-centered ICU care may be good for everyone. PMID- 23797787 TI - How to interpret a randomized controlled study stopped early. PMID- 23797788 TI - Predicting aortic complications after endovascular aneurysm repair. AB - BACKGROUND: Lifelong surveillance is standard after endovascular repair of abdominal aortic aneurysm (EVAR), but remains costly, heterogeneous and poorly calibrated. This study aimed to develop and validate a scoring system for aortic complications after EVAR, informing rationalized surveillance. METHODS: Patients undergoing EVAR at two centres were studied from 2004 to 2010. Preoperative morphology was quantified using three-dimensional computed tomography according to a validated protocol, by investigators blinded to outcomes. Proportional hazards modelling was used to identify factors predicting aortic complications at the first centre, and thereby derive a risk score. Sidak tests between risk quartiles dichotomized patients to low- or high-risk groups. Aortic complications were reported by Kaplan-Meier analysis and risk groups were compared by log rank test. External validation was by comparison of aortic complications between risk groups at the second centre. RESULTS: Some 761 patients, with a median age of 75 (interquartile range 70-80) years, underwent EVAR. Median follow-up was 36 (range 11-94) months. Physiological variables were not associated with aortic complications. A morphological risk score incorporating maximum aneurysm diameter (P < 0.001) and largest common iliac diameter (measured 10 mm from the internal iliac origin; P = 0.004) allocated 75 per cent of patients to a low-risk group, with excellent discrimination between 5-year rates of aortic complication in low- and high-risk groups at both centres (centre 1: 12 versus 31 per cent, P < 0.001; centre 2: 12 versus 45 per cent, P = 0.002). CONCLUSION: The risk score uses commonly available morphological data to stratify the rate of complications after EVAR. The proposals for rationalized surveillance could provide clinical and economic benefits. PMID- 23797789 TI - A graph-based approach for the approximate solution of the chemical master equation. AB - The chemical master equation (CME) represents the accepted stochastic description of chemical reaction kinetics in mesoscopic systems. As its exact solution-which gives the corresponding probability density function-is possible only in very simple cases; there is a clear need for approximation techniques. Here, we propose a novel perturbative three-step approach, which draws heavily on graph theory: (i) we expand the eigenvalues of the transition state matrix in the CME as a series in a nondimensional parameter that depends on the reaction rates and the reaction volume; (ii) we derive an analogous series for the corresponding eigenvectors via a graph-based algorithm; (iii) we combine the resulting expansions into an approximate solution to the CME. We illustrate our approach by applying it to a reversible dimerization reaction; then we formulate a set of conditions, which ensure its applicability to more general reaction networks, and we verify those conditions for two common catalytic mechanisms. Comparing our results with the linear-noise approximation (LNA), we find that our methodology is consistently more accurate for sufficiently small values of the nondimensional parameter. This superior accuracy is particularly evident in scenarios characterized by small molecule numbers, which are typical of conditions inside biological cells. PMID- 23797790 TI - Discrete epidemic models with arbitrary stage distributions and applications to disease control. AB - W.O. Kermack and A.G. McKendrick introduced in their fundamental paper, A Contribution to the Mathematical Theory of Epidemics, published in 1927, a deterministic model that captured the qualitative dynamic behavior of single infectious disease outbreaks. A Kermack-McKendrick discrete-time general framework, motivated by the emergence of a multitude of models used to forecast the dynamics of epidemics, is introduced in this manuscript. Results that allow us to measure quantitatively the role of classical and general distributions on disease dynamics are presented. The case of the geometric distribution is used to evaluate the impact of waiting-time distributions on epidemiological processes or public health interventions. In short, the geometric distribution is used to set up the baseline or null epidemiological model used to test the relevance of realistic stage-period distribution on the dynamics of single epidemic outbreaks. A final size relationship involving the control reproduction number, a function of transmission parameters and the means of distributions used to model disease or intervention control measures, is computed. Model results and simulations highlight the inconsistencies in forecasting that emerge from the use of specific parametric distributions. Examples, using the geometric, Poisson and binomial distributions, are used to highlight the impact of the choices made in quantifying the risk posed by single outbreaks and the relative importance of various control measures. PMID- 23797791 TI - Association of intensive morphine treatment and increased stroke incidence in prostate cancer patients: a population-based nested case-control study. AB - OBJECTIVES: We address the potential problem of stroke induced by morphine exposure by comparing the incidence of stroke in cancer patients treated with and without morphine. METHODS: We performed a population-based nested case-control retrospective analysis on the Longitudinal Health Insurance Database 2000 and Registry for Catastrophic Illness Patients of Taiwan. This study is based on a malignancy cohort of 31 611 patients without a history of stroke, and 1208 patients who subsequently developed stroke served as the stroke group. Four controls of matched age, sex, entry year and entry month for each case were selected from the malignancy cohort from the non-stroke group. We used logistic regression to estimate the odds ratios and 95% confidence intervals, and applied the multivariable model to control for age, sex, hypertension, diabetes, hyperlipidemia and cardiovascular disease. RESULTS: Cancer patients who received morphine had a 12% higher risk of developing stroke than non-morphine users. However, the difference was nonsignificant. A significant difference only appears in prostate cancer patients, where morphine users have a 3.02-fold (4.24- and 2.90-fold for hemorrhagic and ischemic strokes, respectively) higher risk of suffering from stroke. The risk increased significantly as the morphine dosage increased to 170 mg/year of treatment. CONCLUSIONS: Intense morphine treatment may be associated with an increased stroke incidence in patients with malignancy, and the association is particularly significant for prostate cancer patients. PMID- 23797792 TI - Imaging modalities for the early diagnosis of acute aortic syndrome. AB - The term acute aortic syndrome (AAS) incorporates aortic dissection, intramural haematoma, and penetrating atherosclerotic ulcer. The common feature of these entities is disruption of the medial layer of the aortic wall. Owing to the life threatening nature of these conditions, prompt and accurate diagnosis is of paramount importance--misdiagnosis can be fatal. The noninvasive imaging techniques that have a fundamental role in the diagnosis and management of patients with AAS include CT, MRI, transoesophageal echocardiography (TEE), and transthoracic echocardiography (TTE). CT is the most-commonly used imaging modality owing to its wide availability, accuracy, and large field of view. CT plus TTE is the best combination for diagnosing AAS and its complications, and allows important morphological and dynamic aspects of AAS to be assessed and appropriately managed. Ideally, TEE should be performed immediately before surgery or endovascular treatment, in the operating theatre and under general anaesthesia. In stable patients with an uncertain diagnosis of intramural haematoma despite high clinical suspicion, MRI is the technique of choice to make a definitive diagnosis. Imaging techniques have an important role in the primary diagnosis, treatment strategy, and risk stratification of patients with AAS. PMID- 23797793 TI - Anticoagulation therapy: Warfarin dosing--novel SNP identified. PMID- 23797795 TI - [Profile of adenopathies in a tropical setting: 78 observations in Gabon]. AB - OBJECTIVE: To determine the main causes of lymphadenopathies and their clinical characteristics in Gabon. MATERIAL AND METHOD: This retrospective study analyzed the records of patients hospitalized in the medical department at the Military Hospital of Libreville (Gabon) from January 2010 through December 2011 who presented one or more lymphadenopathies. RESULTS: The study included 78 patients (45 men, 33 women), with a mean age of 42.2 +/- 15.9 years. Lymphadenopathies were superficial in 67.9% of cases, abdominal in 42% of cases and mediastinal in 24% of cases. Both deep and superficial locations were noted in 26% (20 cases). Weight loss (63%), fever (56%), asthenia (54%), hepatomegaly (26%), and splenomegaly (20%) were the clinical signs most frequently associated with lymphadenopathy. The main diagnoses were tuberculosis (52%, 41 cases) and non Hodgkin's lymphoma (11%, 9 cases). Infection with human immunodeficiency virus (HIV) was found in 47% of cases. CONCLUSION: Tuberculosis remains the most frequent cause of lymphadenopathy in our setting. HIV testing should be routinely performed in all patients with lymphadenopathy. PMID- 23797796 TI - Liptruzet: a combination of ezetimibe and atorvastatin. PMID- 23797797 TI - Nutritional supplements for age-related macular degeneration revisited. PMID- 23797794 TI - Exercise: friend or foe? AB - Physical activity and exercise have been associated with reduced cardiovascular risk, morbidity, and mortality, as well as all-cause mortality, both in the general population and in patients with various forms of cardiovascular disease. Increasing amounts of exercise are associated with incremental reductions in mortality, but considerable benefits have been found even with a low level of exercise. Exercise is beneficial for most individuals, but risks exist. Exercise is associated with reduced long-term morbidity and mortality, but acute exercise can transiently increase the risk of fatal or nonfatal cardiovascular events. Although tragic, these events are very rare, and even to some extent preventable with screening programmes. Low-intensity physical activity is important and beneficial to all individuals, including those with a high risk of adverse cardiovascular events. In individuals who are physically fit and who do not have genetic predisposition to, or signs of, cardiovascular disease, the greater the intensity and amount of exercise, the greater the health benefits. Nevertheless, effective strategies to encourage exercise in the population are lacking. A sustained increase in physical activity is likely to require more than individual advice, and needs to include urban planning and possibly even legislation. PMID- 23797798 TI - Tobramycin inhalation powder (Tobi Podhaler) for cystic fibrosis. PMID- 23797799 TI - Plan B One-Step OTC. PMID- 23797800 TI - Enhanced killing of therapy-induced senescent tumor cells by oncolytic measles vaccine viruses. AB - Therapy-induced senescence (TIS) as a permanent growth arrest can be induced by various stimuli, including anticancer compounds. TIS emerged as a promising strategy to overcome resistance phenomena. However, senescent cancer cells might regain proliferation activity in vivo or even secrete tumor-promoting cytokines. Therefore, successful exploitation of TIS in cancer treatment simultaneously requires the development of effective strategies to eliminate senescent cancer cells. Virotherapy aims to selectively hit tumor cells, thus a combination with senescence-inducing drugs was explored. As a model, we chose measles vaccine virus (MeV), which does not interfere with cellular senescence by itself. In different tumor cell types, such as hepatoma, pancreatic and mammary gland carcinoma, we demonstrate efficient viral replication and lysis after TIS by gemcitabine, doxorubicin or taxol. Applying real time imaging, we even found an accelerated lysis of senescent cancer cells, supporting an enhanced viral replication with an increase in cell-associated and released infectious MeV particles. In summary, we show as a proof-of-concept that senescent tumor cells can be efficiently exploited as virus host cells by oncolytic MeV. These observations open up a new field for preclinical and clinical research to further investigate TIS and oncolytic viruses as an attractive combinatorial future treatment approach. PMID- 23797801 TI - Parthenolide enhances dacarbazine activity against melanoma cells. AB - Dacarbazine induces a clinical response only in 15% of melanoma patients. New treatment strategies may involve combinations of drugs with different modes of action to target the tumor heterogeneity. We aimed to determine whether the combined treatment of heterogeneous melanoma cell populations in vitro with the alkylating agent dacarbazine and the nuclear factor-kappaB inhibitor parthenolide could be more effective than either drug alone. A panel of melanoma cell lines, including highly heterogeneous populations derived from surgical specimens, was treated with dacarbazine and parthenolide. The effect of drugs on the viable cell number was examined using an acid phosphatase activity assay, and the combination effect was determined by median-effect analysis. Cell death and cell-cycle arrest were assessed by flow cytometry. Gene expression was measured by real-time PCR and changes in the protein levels were evaluated by western blotting. Secretion of vascular endothelial growth factor and interleukin-8 was determined using an enzyme-linked immunosorbent assay. The self-renewing capacity was assessed using a clonogenic assay. Dacarbazine was less effective in heterogeneous melanoma populations than in the A375 cell line. Parthenolide and dacarbazine synergistically reduced the viable cell numbers. Both drugs induced cell-cycle arrest and apoptotic cell death. Importantly, parthenolide abrogated the baseline and dacarbazine-induced vascular endothelial growth factor secretion from melanoma cells in heterogeneous populations, whereas interleukin-8 secretion was not significantly affected by either drug. Parthenolide eradicated melanoma cells with self-renewing capacity also in cultures simultaneously treated with dacarbazine. The combination of parthenolide and dacarbazine might be considered as a new therapeutic modality against metastatic melanoma. PMID- 23797802 TI - Galloflavin suppresses lactate dehydrogenase activity and causes MYC downregulation in Burkitt lymphoma cells through NAD/NADH-dependent inhibition of sirtuin-1. AB - Activation of the myc oncogene in cancer cells upregulates lactate dehydrogenase A (LDH-A) expression, leading to a sustained glycolytic flux that is needed to produce ATP under hypoxic conditions. We studied the effects of galloflavin (GF), a recently identified LDH inhibitor, on myc overexpressing Burkitt lymphoma (BL) cells. Epstein-Barr virus-infected lymphoblasts were used as a non-neoplastic control. Our results showed that myc overactivation induced a two- to seven-fold increase in LDH-A expression in BL cells compared with non-neoplastic lymphoblasts; this result is consistent with previously reported data. Moreover, GF treatment suppressed LDH activity and inhibited BL cell replication but did not affect lymphoblast viability. Surprisingly, we found that increased levels of the MYC and LDH-A proteins did not lead to a metabolic shift in BL cells toward glycolytic ATP generation. BL cells were treated with GF at doses that achieved 50% inhibition of cell growth and lactate production, and ATP levels were scarcely affected after GF treatment. The same results were also obtained by suppressing LDH activity with oxamate, an LDH specific inhibitor. Our data suggest that LDH activity is important for maintaining a correct NAD/NADH balance in BL cells. LDH inhibition led to decreased NAD cellular levels, which resulted in sirtuin-1 inhibition. Confirming previous studies, sirtuin-1 inhibition caused a reduction in MYC protein levels, depriving BL cells of their most important survival signal. This study further describes the biological functions of the LDH enzyme and suggests that LDH inhibition could be useful for the treatment of cancer. PMID- 23797803 TI - Specific disgust sensitivities differentially predict interest in careers of varying procedural-intensity among medical students. AB - Mismatches between the needs of public health systems and student interests have led to renewed study on the factors predicting career specializations among medical students. While most work examines career and lifestyle values, emotional proclivities may be important; disgust sensitivity may help explain preferences for careers with greater and lesser degrees of procedural content. In the study, 294 students completed measures assessing: (1) demographics, (2) career interest or intention regarding emergency medicine, internal medicine, obstetrics/gynecology, and pediatric medicine, (3) traditional determinants of career intention/interest, and (4) core/bodily product, animal reminder, contamination, and sexual/moral disgust sensitivity. As predicted, logistic regressions controlling for demographics and traditional career predictors, showed that greater animal reminder disgust predicted reduced interest in emergency medicine but greater interest in pediatric medicine. Conversely, greater core/bodily product disgust predicted lower interest in obstetrics/gynecology and pediatric medicine; greater contamination and sexual/moral disgust both predicted increased odds of interest in internal medicine. Overall, specific disgust sensitivities were the best predictors of specialization intention in multivariate models. Specific disgust sensitivities appear to differentially deter and/or predispose self-selection into specific trajectories varying in procedural content. Such findings may permit the early identification of specialty fit and provide guidance in career counseling. PMID- 23797804 TI - Studying genetic variability of pomegranate (Punica granatum L.) based on chloroplast DNA and barcode genes. AB - Chloroplast DNA has been used extensively to analyze plant phylogenies at different taxonomic levels because of its size, organization and sequence conservation. In the present research, two chloroplastic regions, petA-psaJ, trnC trnD and four DNA barcodes (trnH-psbA, ITS, rbcL, matK), were used to introduce suitable regions for the assessment of genetic diversity among P. granatum L. genotypes. Analysis of psbE-petL in petA-psaJ region revealed 1,300 nucleotides with 4.29 % genetic diversity among genotypes, while trnC-petN in trnC-trnD region showed 1.8 % genetic diversity. Therefore, despite the results obtained from the study of other plants, the trnC-trnD region had a low potential for the evaluation of diversity among pomegranate genotypes. Analysis of DNA barcodes in pomegranate showed that trnH-psbA (genetic diversity 2.91 %) provides the highest intra-species variation, followed by ITS (genetic diversity 0.44 %). Eighteen genotypes from different geographical origins of Iran were used to investigate psbE-petL and trnH-psbA potential as novel barcodes to determine genetic polymorphism and characterize pomegranate genotypes. The results suggested that two regions, psbE-petL and trnH-psbA, were more suitable for determining intra species relationships of pomegranate. PMID- 23797805 TI - Characterization of a hexameric exo-acting GH51 alpha-l-arabinofuranosidase from the mesophilic Bacillus subtilis. AB - alpha-l-Arabinofuranosidases (alpha-l-Abfases, EC 3.2.1.55) display a broad specificity against distinct glycosyl moieties in branched hemicellulose and recent studies have demonstrated their synergistic use with cellulases and xylanases for biotechnological processes involving plant biomass degradation. In this study, we examined the structural organization of the arabinofuranosidase (GH51 family) from the mesophilic Bacillus subtilis (AbfA) and its implications on function and stability. The recombinant AbfA showed to be active over a broad temperature range with the maximum activity between 35 and 50 degrees C, which is desirable for industrial applications. Functional studies demonstrated that AbfA preferentially cleaves debranched or linear arabinan and is an exo-acting enzyme producing arabinose from arabinoheptaose. The enzyme has a canonical circular dichroism spectrum of alpha/beta proteins and exhibits a hexameric quaternary structure in solution, as expected for GH51 members. Thermal denaturation experiments indicated a melting temperature of 53.5 degrees C, which is in agreement with the temperature-activity curves. The mechanisms associated with the unfolding process were investigated through molecular dynamics simulations evidencing an important contribution of the quaternary arrangement in the stabilization of the beta-sandwich accessory domain and other regions involved in the formation of the catalytic interface of hexameric Abfases belonging to GH51 family. PMID- 23797806 TI - Selective worsening of brain injury biomarker abnormalities in cognitively normal elderly persons with beta-amyloidosis. AB - IMPORTANCE: The appearance of beta-amyloidosis and brain injury biomarkers in cognitively normal (CN) persons is thought to define risk for the future development of cognitive impairment due to Alzheimer disease (AD), but their interaction is poorly understood. OBJECTIVE: To test the hypothesis that the joint presence of beta-amyloidosis and brain injury biomarkers would lead to more rapid neurodegeneration. DESIGN Longitudinal cohort study. SETTING: Population based Mayo Clinic Study of Aging. PARTICIPANTS: One hundred ninety-one CN persons (median age, 77 years; range, 71-93 years) in the Mayo Clinic Study of Aging who underwent magnetic resonance, fludeoxyglucose F 18 (FDG) positron emission tomography (PET), and Pittsburgh Compound B (PiB) PET imaging at least twice 15 months apart. Participants were grouped according to the recommendations of the National Institute on Aging-Alzheimer Association preclinical AD criteria based on the presence of beta-amyloidosis, defined as a PiB PET standardized uptake value ratio (SUVr) greater than 1.5, alone (stage 1) or with brain injury (stage 2 + 3), defined as hippocampal atrophy or FDG hypometabolism. We also studied a group of patients with mild cognitive impairment (n = 17) or dementia (n = 9) from the Mayo Clinic Study of Aging or the Mayo Alzheimer Center with similar follow-up times who had undergone comparable imaging and had a PiB PET SUVr greater than 1.5. MAIN OUTCOMES AND MEASURES: Rate of change of cortical volume on volumetric magnetic resonance images and rate of change of glucose metabolism on FDG PET scan results. RESULTS: There were 25 CN participants with both high PiB retention and low hippocampal volume or FDG hypometabolism at baseline (preclinical AD stages 2 + 3). On follow-up scans, the preclinical AD stage 2 + 3 participants had greater loss of medial temporal lobe volume and greater glucose hypometabolism in the medial temporal lobe compared with the other CN groups. The changes were similar to those in the cognitively impaired participants. Extratemporal regions did not show similar changes. CONCLUSIONS AND RELEVANCE: Higher rates of medial temporal neurodegeneration occur in CN individuals who, on their initial scans, had abnormal levels of both beta-amyloid and brain injury biomarkers. Although preclinical AD is currently only a research topic, the description of its brain structural changes will be critical for trials designed to prevent or forestall dementia due to AD. PMID- 23797807 TI - Novel kinetic trapping in charged colloidal clusters due to self-induced surface charge organization. AB - Colloidal clusters are an unusual state of matter where tunable interactions enable a sufficient reduction in their degrees of freedom that their energy landscapes can become tractable - they form a playground for statistical mechanics and promise unprecedented control of structure on the submicron lengthscale. We study colloidal clusters in a system where a short-ranged polymer induced attraction drives clustering, while a weak, long-ranged electrostatic repulsion prevents extensive aggregation. We compare experimental yields of cluster structures with theory which assumes simple addition of competing isotropic interactions between the colloids. Here we show that for clusters of size 4 <= m <= 7, the yield of minimum energy clusters is much less than expected. We attribute this to an anisotropic self-organized surface charge distribution which leads to unexpected kinetic trapping. We introduce a model for the coupling between counterions and binding sites on the colloid surface with which we interpret our findings. PMID- 23797808 TI - Parent conversations about healthful eating and weight: associations with adolescent disordered eating behaviors. AB - IMPORTANCE: The prevalence of weight-related problems in adolescents is high. Parents of adolescents may wonder whether talking about eating habits and weight is useful or detrimental. OBJECTIVE: To examine the associations between parent conversations about healthful eating and weight and adolescent disordered eating behaviors. DESIGN: Cross-sectional analysis using data from 2 linked multilevel population-based studies. SETTING: Anthropometric assessments and surveys completed at school by adolescents and surveys completed at home by parents in 2009-2010. PARTICIPANTS: Socioeconomically and racially/ethnically diverse sample (81% ethnic minority; 60% low income) of adolescents from Eating and Activity in Teens 2010 (EAT 2010) (n = 2793; mean age, 14.4 years) and parents from Project Families and Eating and Activity in Teens (Project F-EAT) (n = 3709; mean age, 42.3 years). EXPOSURE Parent conversations about healthful eating and weight/size. MAIN OUTCOMES AND MEASURES: Adolescent dieting, unhealthy weight control behaviors, and binge eating. RESULTS: Mothers and fathers who engaged in weight-related conversations had adolescents who were more likely to diet, use unhealthy weight-control behaviors, and engage in binge eating. Overweight or obese adolescents whose mothers engaged in conversations that were focused only on healthful eating behaviors were less likely to diet and use unhealthy weight control behaviors. Additionally, subanalyses with adolescents with data from 2 parents showed that when both parents engaged in healthful eating conversations, their overweight or obese adolescent children were less likely to diet and use unhealthy weight-control behaviors. CONCLUSIONS AND RELEVANCE: Parent conversations focused on weight/size are associated with increased risk for adolescent disordered eating behaviors, whereas conversations focused on healthful eating are protective against disordered eating behaviors. PMID- 23797809 TI - Changes in PTSD symptomatology and mental health during pregnancy and postpartum. AB - Changes in mental health symptoms throughout pregnancy and postpartum may impact a woman's experience and adjustment during an important time. However, few studies have investigated these changes throughout the perinatal period, particularly changes in posttraumatic stress disorder (PTSD) symptoms. The purpose of this study was to examine longitudinal changes in PTSD, depression, and anxiety symptomatology during pregnancy and postpartum. Pregnant women of ethnically diverse backgrounds receiving services for prenatal care at an outpatient obstetric-gynecology clinic or private physicians' office were assessed by interview on symptoms of PTSD, depression, anxiety, and general stress up to four times, including their first, second, and third trimester, and postpartum visits. Overall, during pregnancy there was a declining trend of PTSD symptoms. For anxiety, there was no overall significant change over time; however, anxiety symptoms were individually variable in the rate of change. For both depression and general stress symptoms, there was a declining trend, which was also variable in the individual rate of change among women during their pregnancy. Visual and post hoc analyses also suggest a possible peak in PTSD symptoms in the weeks prior to delivery. While most mental health symptoms may generally decrease during pregnancy, given the individual variability among women in the rate of change in symptoms, screening and monitoring of symptom fluctuations throughout the course of pregnancy may be needed. Further studies are needed to examine potential spiking of symptoms in the perinatal period. PMID- 23797810 TI - Integrin alpha6beta1 is the main receptor for vascular laminins and plays a role in platelet adhesion, activation, and arterial thrombosis. AB - BACKGROUND: Laminins are major components of basement membranes, well located to interact with platelets upon vascular injury. Laminin-111 (alpha1beta1gamma1) is known to support platelet adhesion but is absent from most blood vessels, which contain isoforms with the alpha2, alpha4, or alpha5 chain. Whether vascular laminins support platelet adhesion and activation and the significance of these interactions in hemostasis and thrombosis remain unknown. METHODS AND RESULTS: Using an in vitro flow assay, we show that laminin-411 (alpha4beta1gamma1), laminin-511 (alpha5beta1gamma1), and laminin-521 (alpha5beta2gamma1), but not laminin-211 (alpha2beta1gamma1), allow efficient platelet adhesion and activation across a wide range of arterial wall shear rates. Adhesion was critically dependent on integrin alpha6beta1 and the glycoprotein Ib-IX complex, which binds to plasmatic von Willebrand factor adsorbed on laminins. Glycoprotein VI did not participate in the adhesive process but mediated platelet activation induced by alpha5-containing laminins. To address the significance of platelet/laminin interactions in vivo, we developed a platelet-specific knockout of integrin alpha6. Platelets from these mice failed to adhere to laminin-411, laminin-511, and laminin-521 but responded normally to a series of agonists. alpha6beta1 Deficient mice presented a marked decrease in arterial thrombosis in 3 models of injury of the carotid, aorta, and mesenteric arterioles. The tail bleeding time and blood loss remained unaltered, indicating normal hemostasis. CONCLUSIONS: This study reveals an unsuspected important contribution of laminins to thrombus formation in vivo and suggests that targeting their main receptor, integrin alpha6beta1, could represent an alternative antithrombotic strategy with a potentially low bleeding risk. PMID- 23797811 TI - Drug-eluting balloon in peripheral intervention for below the knee angioplasty evaluation (DEBATE-BTK): a randomized trial in diabetic patients with critical limb ischemia. AB - BACKGROUND: The 1-year restenosis rate after balloon angioplasty of long lesions in below-the-knee arteries may be as high as 70%. Our aim was to investigate the efficacy of a paclitaxel drug-eluting balloons versus conventional percutaneous transluminal angioplasty (PTA) for the reduction of restenosis in diabetic patients with critical limb ischemia undergoing endovascular intervention of below-the-knee arteries. METHODS AND RESULTS: The Drug-Eluting Balloon in Peripheral Intervention for below the knee angioplasty evaluation (DEBATE-BTK) is a randomized, open-label, single-center study comparing drug-eluting balloons and PTA. Inclusion criteria were diabetes mellitus, critical limb ischemia (Rutherford class 4 or higher), significant stenosis or occlusion >40 mm of at least 1 below-the-knee vessel with distal runoff, and life expectancy >1 year. Binary in-segment restenosis at a 1-year angiographic or ultrasonographic follow up was the primary end point. Clinically driven target lesion revascularization, major amputation, and target vessel occlusion were the secondary end points. One hundred thirty-two patients with 158 infrapopliteal atherosclerotic lesions were enrolled. Mean length of the treated segments was 129+/-83 mm in the drug-eluting balloon group compared with 131+/-79 mm in the PTA group (P=0.7). Binary restenosis, assessed by angiography in >90% of patients, occurred in 20 of 74 lesions (27%) in the drug-eluting balloon group compared with 55 of 74 lesions (74%) in the PTA group (P<0.001); target lesion revascularization, in 12 (18%) versus 29 (43%; P=0.002); and target vessel occlusion, in 12 (17%) versus 41 (55%; P<0.001). Only 1 major amputation occurred, in the PTA group (P=0.9). CONCLUSIONS: Drug-eluting balloons compared with PTA strikingly reduce 1-year restenosis, target lesion revascularization, and target vessel occlusion in the treatment of below-the-knee lesions in diabetic patients with critical limb ischemia. PMID- 23797812 TI - Evaluating stem and cancerous biomarkers in CD15+CD44+ KYSE30 cells. AB - Digestive system cancers are listed among the ten top causes of cancer-related death worldwide. Cancer stem cells (CSCs) are malignant cells that share some of their characteristics with normal stem cells, including self-renewal and multipotency, and also cancer cells, such as drug resistance and metastasis. Despite many reports on CSCs with digestive system origin, identification and characterization of esophageal CSCs have remained elusive. To examine the validity of routine SC, cancer cell and CSC markers in KYSE30 cells, derived from esophageal carcinoma, cells were first characterized by immunofluorescence and RT PCR techniques, and then the significance of candidate biomarkers was evaluated in retinoic acid-treated cells by flow cytometry and/or real-time RT-PCR. Meanwhile, to study CD15 (a newly introduced CSC marker) expression in digestive tract cancers, human normal and tumoral tissues of esophagus, stomach, and colon were analyzed by immunohistochemistry. Using several experimental approaches, we show that CD44, but not CD15, could serve as a reliable marker for undifferentiated malignant squamous cells of esophagus. In conclusion, our study confirms the role of CD44 as a CSC marker in KYSE30 cells, an esophageal squamous cell carcinoma cell line, and for the first time indicates the expression of CD15 in non-neural stem-like cancer cells. Although the importance of CD15 was not indicated in diagnosis of digestive cancers, further studies are needed to better understand the biological identity and function of this molecule in non-neural malignancies. PMID- 23797813 TI - Video-assisted thoracoscopic surgery for stage I non-small cell lung cancer: long term survival and prognostic factors. AB - The purpose of this study was to evaluate the long-term outcomes of video assisted thoracoscopic surgery (VATS) major pulmonary resection in patients with stage I non-small cell lung cancer (NSCLC). Of the 411 stage I patients, 318 (77.4 %) underwent complete VATS (c-VATS), while 89 (21.7 %) underwent assisted VATS (a-VATS). There were no intraoperative deaths. There were three deaths (0.7 %) within 30 postoperative days. The 1-, 3-, and 5-year survival rates were 95.1 % (95 % CI, 92.9-97.3 %), 83.1 % (95 % CI, 79.2-87.0 %), and 73.4 % (95 % CI, 68.1-78.7 %), respectively. Univariate analysis by log-rank test revealed that tumor-node-metastasis (TNM) stage, primary tumor (pT) status, and type of resection were statistically significant factors affecting overall survival (OS; P = 0.029, P = 0.025, and P = 0.005, respectively). Less acute TNM stage and less extensive resection were significantly predictive for longer OS by multivariate analysis as well (P = 0.024 and P = 0.006, respectively). In experienced hands, c VATS or a-VATS can be considered as an alternative to traditional incision in patients with stage I NSCLC. Lower TNM stage and less extensive resection were significantly predictive for better OS. A prospective randomized controlled study on a larger scale is required to reach definitive conclusions regarding the efficacy of VATS relative to other techniques. PMID- 23797814 TI - Abnormal expression of insulin-like growth factor-I receptor in hepatoma tissue and its inhibition to promote apoptosis of tumor cells. AB - Abnormal signaling of insulin-like growth factor I receptor (IGF-IR) is associated with hepatocellular carcinoma, but the underlying molecular mechanisms remain largely unknown. The objective of this study was to investigate IGF-IR's role as a signaling molecule, its pathological alteration in hepatoma tissues, and its effect on hepatoma cell proliferation when inhibited. As measured by immunohistochemical analysis, the incidence of hepatic IGF-IR expression in cancerous tissue was 80.0 % (24 of 30), which was significantly higher (P < 0.05) than 43.3 % (13 of 30) occurrence in the surrounding tissue and the nondetectable (0 of 30) frequency in the distal cancerous tissue. Hepatoma IGF-IR expression was correlated to the differentiation degree and not to the number or size of tumors, HBV infection, and AFP level. The in vitro IGF-IR expression in hepatoma cells was down-regulated significantly by picropodophyllin, a specific kinase inhibitor, in a time- and dose-dependent manner. Cell proliferation was inhibited through typical mechanisms of promoting apoptosis and cell cycle arrest (G2/M phase). Up-regulation of IGF-IR in hepatocarcinogenesis suggests that the down regulation of IGF-IR expression could be a specific molecular target for hepatoma cell proliferation. PMID- 23797815 TI - PLCE1 rs2274223 A>G polymorphism and cancer risk: a meta-analysis. AB - Phospholipase C epsilon 1 gene (PLCE1) encodes a phospholipase enzyme which regulates various physiological processes (cell growth, differentiation, and apoptosis) and is supposed to play a critical role in carcinogenesis. Recently, a single nucleotide polymorphism (rs2274223 A>G) in PLCE1 was reported as a novel susceptibility locus for esophageal and gastric cancers by genome-wide association studies performed in Chinese population. However, individual association studies replicating this finding showed inconclusive results. Therefore, we performed a meta-analysis of eligible studies to derive precise estimation of the association of PLCE1 rs2274223 A>G polymorphism with cancer risk. We performed pooled analysis of 12 case-control studies including 7,622 cases and 9,555 controls. Odds ratios and 95 % confidence interval were calculated to assess strength of association in overall studies and in subgroup analysis stratified by ethnicity, cancer types, and source of controls. All statistical analyses were performed by MIX 2.0 software. We found that PLCE1 rs2274223 A>G polymorphism was significantly associated with increased risk of cancer in log additive/dominant model and at allele level (GG vs. AA: OR = 1.24, 95 % CI = 1.01-1.53, P = 0.039; AG vs. AA: OR = 1.24, 95 % CI = 1.16-1.32, P < 0.001; AG + GG vs. AA: OR = 1.22, 95 % CI = 1.12-1.34, P < 0.001; and G vs. A allele: OR = 1.15, 95 % CI = 1.05-1.25, P = 0.002). Further, stratified analysis showed elevated risk of only gastric and esophageal tumors. Sub-group analysis based on ethnicity suggests PLCE1 polymorphism conferred significant risk among Asian (Chinese) but not in Caucasian. In conclusion, PLCE1 rs2274223 polymorphism may be used as potential biomarker for cancer susceptibility particularly for esophageal/gastric cancer and for the Chinese population. PMID- 23797817 TI - Neuroendocrinology: regulated secretory cells go to the BAR for a bud. AB - Syndromes caused by insufficient secretion of peptide hormones originate either from an inadequate population of endocrine secretory cells or from deficiencies in the secretory process. Two remarkable new studies highlight the importance of PICK1 and ICA69 in creating the protein storage organelles needed for regulated exocytosis, independent of stimulus-secretion coupling. PMID- 23797818 TI - Paediatrics: surgical strategy and quality of life in craniopharyngioma. AB - Management of childhood craniopharyngioma remains controversial. Aggressive primary surgery is associated with an increased risk of severe obesity, but hypothalamus-sparing surgery might increase the need for reoperation and/or irradiation. Nevertheless, hypothalamus-sparing strategies decreased occurrence of obesity-a risk factor for impaired quality of life-without increasing recurrence rates in a new study. PMID- 23797816 TI - MicroRNAs in osteosarcoma: diagnostic and therapeutic aspects. AB - MicroRNAs (miRNAs) are small RNA molecules, which can interfere with the expression of several genes and act as gene regulator. miRNAs have been proved as a successful diagnostic and therapeutic tool in several cancers. In this review, the differential expression of miRNAs in osteosarcoma and their possibility to be used as diagnostic and therapeutic tools have been discussed. Osteosarcoma is the most common primary bone tumor that mainly affects children and adolescents. The current treatment of osteosarcoma remains difficult, and osteosarcoma causes many deaths because of its complex pathogenesis and resistance to conventional treatments. Several studies demonstrated that the differential expression patterns of miRNAs are a promising tool for the diagnosis and treatment of osteosarcoma. Although some aspect of the mechanism of action of miRNAs in controlling osteosarcoma has been identified (e.g., targeting the Notch signaling pathway), it is far beyond to the clear understanding of miRNA targets in osteosarcoma. Identification of the specific target of miRNAs may aid molecular targets for drug development and future relief of osteosarcoma. PMID- 23797819 TI - Reproductive endocrinology: novel mutations linked to central precocious puberty. PMID- 23797820 TI - Epidemiology: work-related stress and the risk of type 2 diabetes mellitus. AB - A new cohort study links work-related stress to an increased risk of developing type 2 diabetes mellitus (T2DM) in women, but the findings are less clear in men. Randomized controlled studies are now needed to determine whether management of stress could be used to reduce the risk of developing T2DM. PMID- 23797821 TI - Obesity: effect of maternal obesity on neonatal outcomes. PMID- 23797823 TI - ROC operating point selection for classification of imbalanced data with application to computer-aided polyp detection in CT colonography. AB - PURPOSE: Computer-aided detection and diagnosis (CAD) of colonic polyps always faces the challenge of classifying imbalanced data. In this paper, three new operating point selection strategies based on receiver operating characteristic curve are proposed to address the problem. METHODS: Classification on imbalanced data performs inferiorly because of a major reason that the best differentiation threshold shifts due to the degree of data imbalance. To address this decision threshold shifting issue, three operating point selection strategies, i.e., shortest distance, harmonic mean and anti-harmonic mean, are proposed and their performances are investigated. RESULTS: Experiments were conducted on a class imbalanced database, which contains 64 polyps in 786 polyp candidates. Support vector machine (SVM) and random forests (RFs) were employed as basic classifiers. Two imbalanced data correcting techniques, i.e., cost-sensitive learning and training data down sampling, were applied to SVM and RFs, and their performances were compared with the proposed strategies. Comparing to the original thresholding method, i.e., 0.488 sensitivity and 0.986 specificity for RFs and 0.526 sensitivity and 0.977 specificity for SVM, our strategies achieved more balanced results, which are around 0.89 sensitivity and 0.92 specificity for RFs and 0.88 sensitivity and 0.90 specificity for SVM. Meanwhile, their performance remained at the same level regardless of whether other correcting methods are used. CONCLUSIONS: Based on the above experiments, the gain of our proposed strategies is noticeable: the sensitivity improved from 0.5 to around 0.88 for RFs and 0.89 for SVM while remaining a relatively high level of specificity, i.e., 0.92 for RFs and 0.90 for SVM. The performance of our proposed strategies was adaptive and robust with different levels of imbalanced data. This indicates a feasible solution to the shifting problem for favorable sensitivity and specificity in CAD of polyps from imbalanced data. PMID- 23797824 TI - Transient insomnia versus chronic insomnia: a comparison study of sleep-related psychological/behavioral characteristics. AB - OBJECTIVES: Vulnerability to transient insomnia is regarded as a predisposing factor for chronic insomnia. However, most individuals with transient insomnia do not develop chronic insomnia. The current study investigated the differential contributing factors for these two conditions to further the understanding of this phenomenon. METHOD: Chronic insomnia patients and normal sleepers with high and low vulnerability to transient insomnia completed measures of pre-sleep arousal, dysfunctional sleep beliefs, and sleep-related safety behaviors. RESULTS: Both cognitive and somatic pre-sleep arousals were identified as significant predictors for transient insomnia. Dysfunctional beliefs regarding worry about insomnia and cognitive arousal were predictors for chronic insomnia. Sleep-related safety behavior, although correlated with insomnia severity, was not a significant predictor for both conditions. CONCLUSIONS: Dysfunctional beliefs associated with worry and losing control over sleep are the most critical factors in differentiating chronic insomnia from transient insomnia. These factors should be addressed to help prevent individuals with high sleep vulnerability from developing chronic sleep disturbance. PMID- 23797822 TI - Testosterone and insulin resistance in the metabolic syndrome and T2DM in men. AB - Obesity, type 2 diabetes mellitus and the metabolic syndrome are major risk factors for cardiovascular disease. Studies have demonstrated an association between low levels of testosterone and the above insulin-resistant states, with a prevalence of hypogonadism of up to 50% in men with type 2 diabetes mellitus. Low levels of testosterone are also associated with an increased risk of all-cause and cardiovascular mortality. Hypogonadism and obesity share a bidirectional relationship as a result of the complex interplay between adipocytokines, proinflammatory cytokines and hypothalamic hormones that control the pituitary testicular axis. Interventional studies have shown beneficial effects of testosterone on components of the metabolic syndrome, type 2 diabetes mellitus and other cardiovascular risk factors, including insulin resistance and high levels of cholesterol. Biochemical evidence indicates that testosterone is involved in promoting glucose utilization by stimulating glucose uptake, glycolysis and mitochondrial oxidative phosphorylation. Testosterone is also involved in lipid homeostasis in major insulin-responsive target tissues, such as liver, adipose tissue and skeletal muscle. PMID- 23797826 TI - Rapidly in situ forming adhesive hydrogel based on a PEG-maleimide modified polypeptide through Michael addition. AB - Polyethylene glycol-maleimide modified epsilon-polylysine (EPL-PEG-MAL) with a unique comb-shaped structure was designed and used as a novel crosslinker for thiolated chitosan (CSS). Novel polysaccharide/polypeptide bionic hydrogels based on CSS and EPL-PEG-MAL could form rapidly in situ within 1 min via Michael addition under physiological conditions. Rheological studies showed that introduction of PEG can dramatically improve the storage modulus (G') of the hydrogels and the optimal hydrogel system showed superior G' of 1,614 Pa. The maximum adhesion strength reached 148 kPa, six times higher than that of fibrin glue. Cytotoxicity test indicated that the hydrogel is nontoxic toward growth of L929 cells. Gelation time, swelling ratio, storage modulus and adhesion strength of the hydrogels can be modulated by the content of PEG-maleimide, CSS concentration and molar ratio of maleimide group to thiol group. Benefiting from the fast gelation behaviors, desirable mechanical properties, relatively high adhesive performance and no cytotoxicity, these hydrogels have the potential applications as promising biomaterials for tissue adhesion and sealing. PMID- 23797827 TI - A superabsorbent polymer-containing wound dressing efficiently sequesters MMPs and inhibits collagenase activity in vitro. AB - Superabsorbent polymer (SAP)-containing wound dressings present a valuable and unique category of wound management products. An in vitro approach was used to assess the effects of a new SAP dressing in treatment of non-healing wounds. It was shown that the SAP dressing possesses a significant binding capacity for MMP 2 and MMP-9 in vitro (P?0.001). The inclusion of the bound proteases was so strong that no MMP-2 and only marginal amounts of MMP-9 were released from the dressing samples in a subsequent elution step. In addition, the SAP dressing was able to take up collagenase and reduce its activity in vitro. However, collagenase was not completely inactivated upon binding and enzyme-mediated substrate turnover could be observed at the dressings. In conclusion, in vitro data confirm the positive effect of the SAP wound dressing observed in vivo. The findings suggest that it should be specifically useful for highly exuding wounds with an elevated proteolytic activity that needs to be reduced to support healing. PMID- 23797828 TI - Investigation of the mechanisms governing doxorubicin and irinotecan release from drug-eluting beads: mathematical modeling and experimental verification. AB - Drug-eluting beads (DEBs) are embolising devices in clinical use for the treatment of liver cancer by transarterial chemoembolisation. In this study, release kinetics of doxorubicin (DOX) and irinotecan (IRI) were investigated by experimental evaluations and mathematical modeling, based on Langmuir isotherm and two phenomenological models (Boyd/Bhaskar) developed to determine the actual mechanisms controlling drug release rate. The model was validated through release studies, in particular by assessing how drug loading, ionic strength of the release medium and device swelling during release influence drug release kinetics. Results demonstrated that IRI is released much faster than DOX, and that DEB volume strongly depends upon drug loading and fractional release. This effect was properly taken into account in developing the mathematical model. Experimental results were well fit by numerical simulations, and two different rate-controlling mechanisms were found to govern DOX and IRI delivery. PMID- 23797829 TI - The pH-controlled nanoparticles size of polydopamine for anti-cancer drug delivery. AB - A facile method was used to prepare polydopamine (PDA) nanoparticles. The effect of the initial pH of the dopamine solution on the formation kinetics, chemical structure, and biocompatibility of PDA nanoparticles was evaluated. Additionally, camptothecin (CPT) was chosen as a model anti-cancer drug with which to evaluate the efficiency of drug loading and release behavior of PDA nanoparticles. The results indicated that the size and yield of PDA nanoparticles, consisting of quinoid and indoline species, were closely related to the pH value of the precursor solution. At a reaction time of 6 h, the uniform particle sizes of PDA nanoparticles were ~400, 250, 150, and 75 nm in solutions with initial pH values of 7.5, 8, 8.5, and 9, respectively, and with corresponding yields of 3, 7, 20, and 34 %. The amounts of CPT loaded in 1 mg of PDA nanoparticles synthesized at pH values of 7.5, 8, 8.5, and 9 for 6 h were 10.85, 11.81, 10.17, and 6.19 lg, respectively. After the first day, 19, 20, 25, and 36 % of the CPT was released from PDA nanoparticles synthesized at pH values of 7.5, 8, 8.5, and 9, respectively, depending on the particle size. The PDA nanoparticles had excellent haemocompatibility: there was no apparent hemolysis, and they did not cause acute toxicity in A549 and HeLa cells. The loading of CPT into PDA nanoparticles significantly reduced the viability of A549 and HeLa cells, comparable to free CPT. It can be concluded that the PDA nanoparticles prepared by our facile method are potential carriers of anticancer drugs for cancer therapy. PMID- 23797830 TI - Association study between gene polymorphisms in PPAR signaling pathway and porcine meat quality traits. AB - There is increasing evidence suggesting that fatty acids biosynthesis and metabolism are regulated by peroxisome proliferator-activated receptors (PPARs), mostly through the PPAR signaling pathway at the transcriptomic level. We hypothesized that the genetic variants of the enzymes in the PPAR signaling pathway may be associated with the traits of porcine meat quality (PMQ). We mined 77 potentially functional single nucleotide polymorphisms in the PPAR signaling pathway of the pig. There were 13 TagSNPs in 13 different genes mapped within the reported pig quantitative trait loci (QTLs) regions related to PMQ based on the Pig QTL database. Based on the association study with ten measured PMQ traits in both the pathway level and the SNP level, we tested eight significantly associated traits with additive effect in the PPAR signaling pathway and explored only one significant TagSNP in gene RXRB, which is directly associated with the trait of skin weight. Moreover, several interactions of TagSNPs were also significantly related to some of PMQ traits. In this large and comprehensive candidate gene set study, we found a modest association of genes and SNPs in the PPAR signaling pathway with PMQ. Further investigation of these gene polymorphisms jointly with fatty acid measures and other genetic factors would help us better understand the regulation mechanisms of PMQ. PMID- 23797832 TI - The effect of exposures to policing on syringe sharing among people who inject drugs in Bangkok, Thailand. AB - While intensive drug law enforcement is recognized as a social-structural driver of HIV epidemics among people who inject drugs (IDU), few studies have investigated the effects of direct encounters with police, particularly in Asian settings. Using multivariate log-binomial regression, we examined the relationship between syringe sharing and exposures to two types of policing practices among IDU in Bangkok, Thailand: having been beaten by police and having been tested for illicit drugs by police. Between July and October 2011, 435 IDU participated in the study, with 75 (17.2 %) participants reporting syringe sharing in the past 6 months. In multivariate analyses, exposures to the two types of policing practices had an independent effect on syringe sharing, with experiencing both practices showing the greatest effect. These findings highlight the importance of addressing the policy and social environment surrounding IDU as a means of HIV prevention. PMID- 23797831 TI - "People knew they could come here to get help": an ethnographic study of assisted injection practices at a peer-run 'unsanctioned' supervised drug consumption room in a Canadian setting. AB - People who require help injecting are disproportionately vulnerable to drug related harm, including HIV transmission. North America's only sanctioned SIF operates in Vancouver, Canada under an exemption to federal drug laws, which imposes operating regulations prohibiting assisted injections. In response, the Vancouver Area Network of Drug Users (VANDU) launched a peer-run unsanctioned SIF in which trained peer volunteers provide assisted injections to increase the coverage of supervised injection services and minimize drug-related harm. We undertook qualitative interviews (n = 23) and ethnographic observation (50 h) to explore how this facility shaped assisted injection practices. Findings indicated that VANDU reshaped the social, structural, and spatial contexts of assisted injection practices in a manner that minimized HIV and other health risks, while allowing people who require help injecting to escape drug scene violence. Findings underscore the need for changes to regulatory frameworks governing SIFs to ensure that they accommodate people who require help injecting. PMID- 23797833 TI - [History of human epidemic and endemic diseases in the southwest Indian Ocean]. AB - Smallpox has been known in the Mascarene Islands since 1729, and in 1898, the vaccinogenic and anti-rabies Institute of Tananarive, the future Pasteur Institute of Madagascar, was created to combat it. Cholera first arrived in the Mascarenes in 1819, but did not affect the Comoros Islands and Madagascar until the current pandemic. Bubonic plague has beset the ports of Madagascar and the Mascarenes since 1898. Girard and Robic developed the anti-plague vaccine in 1931 at the Pasteur Institute of Madagascar. The Mascarenes lost their reputation as Eden when malaria arrived in 1841, and this disease remains prominent in Madagascar and Comoros. Leprosy has been known in La Reunion since 1726 and is still very present in Mayotte, Anjouan, and Madagascar. Leptospirosis is a public health problem, except in Madagascar and the Comoros. Dengue, chikungunya, and Rift Valley fever are also present. HIV/AIDS is not a major concern, except in Mauritius, where it was spread by injection drug use, in the Seychelles and in Madagascar's largest cities. Madagascar is the principal site worldwide of chromoblastomycosis, first described there in 1914. PMID- 23797843 TI - An LC-MS based study of the metabolic profile of primaquine, an 8-aminoquinoline antiparasitic drug, with an in vitro primary human hepatocyte culture model. AB - The 8-aminoquinoline drug primaquine (PQ) is currently the only drug in use against the persistent malaria caused by the hypnozoite-forming strains P. vivax and P. ovale. However, despite decades of research, its complete metabolic profile is still poorly understood. In the present study, the metabolism of PQ was evaluated by incubating the drug with pooled human hepatocytes cultured in vitro as well as with recombinant cytochrome P450 (CYP) iso- enzymes, monoamine oxidases (MAO), and flavin-containing monooxygenases (FMO). Targeted LC-MS/MS analysis of hepatocyte incubations using chemical inhibitors indicated that PQ was predominantly metabolized by CYPs 3A4, 1A2 and 2D6, MAO-A, -B and FMO-3. Confirmation of these results was sought by incubation of PQ with the corresponding recombinant enzymes. Small amounts of carboxyprimaquine (CPQ), the major observed PQ metabolite in vivo, were detected in recombinant MAO-A incubations along with another peak at m/z 261, and no significant formation of CPQ with any other recombinant enzymes was observed. Incubations with all recombinant enzymes identified as potentially active towards PQ from the hepatocyte-based assay resulted in significant parent loss over the course of 1 h. These results suggest that several enzymes, including CYPs in combination with FMOs and MAOs, play a role in the overall metabolism of PQ and indicate a major role for MAO-A. Future studies to elucidate the potential role in cytotoxicity and/or efficacy of the PQ metabolite observed at m/z 261, as observed in MAO-A isoenzyme studies, are needed. PMID- 23797845 TI - Ultrafast energy transfer in ultrathin organic donor/acceptor blend. AB - It is common knowledge that poly(3-hexylthiophene) (P3HT)/[6,6]-phenyl-C61 butyric acid methyl ester (PCBM) blend, a prototype system for bulk heterojunction (BHJ) solar cells, consists of a network of tens of nanometers large donor-rich and acceptor-rich phases separated by extended finely intermixed border regions where PCBM diffuse into P3HT. Here we specifically address the photo-induced dynamics in a 10 nm thin P3HT/PCBM blend that consists of the intermixed region only. Using the multi-pass transient absorption technique (TrAMP) that enables us to perform ultra high sensitive measurements, we find that the primary process upon photoexcitation is ultrafast energy transfer from P3HT to PCBM. The expected charge separation due to hole transfer from PCBM to P3HT occurs in the 100 ps timescale. The derived picture is much different from the accepted view of ultra-fast electron transfer at the polymer/PCBM interface and provides new directions for the development of efficient devices. PMID- 23797844 TI - Evidence that alpha-9 human papillomavirus infections are a major etiologic factor for oropharyngeal carcinoma in black South Africans. AB - Human papillomavirus (HPV) infection, most commonly genotype 16 of the alpha-9 family, is implicated in the etiology of a subset of oropharyngeal squamous cell carcinomas (OPSC) worldwide. Data are scarce regarding OPSC in South Africans, and three prior studies suggest no significant etiologic role for HPV. We aimed to investigate for evidence of HPV etiology in OPSCs from black South Africans by polymerase chain reaction (PCR) methodologies with determination of HPV subtype by sequencing, in situ hybridization (ISH), and p16INK4a immunohistochemistry (IHC), as a surrogate marker for an HPV-driven tumor. It was hypothesized that HPV-driven tumors would be positive by PCR plus IHC and/or ISH whereas OPSCs with HPV background infections (HPV-passenger) would be positive by PCR alone. Formalin-fixed, paraffin embedded tissues from 51 OPSCs collected between 2005 and 2010 from 41 patients were analyzed for HPV by GP5?6? PCR (targeting the HPV L1 region), pU-1M/pU- 2R PCR (targeting the HPV E6/E7 region) and HPV-31 specific PCR (targeting the E5 region), chromogenic ISH, and p16INK4a IHC. All cases positive by PCR were subject to sequencing to determine HPV genotype. The patient mean age was 58.0 years and 88 % were male. Of the 51 evaluable tumors, 48 (94.1 %) were positive for HPV DNA by PCR: 25 (49.1 %) met criteria for an HPV-driven tumor, 23 (45.1 %) for HPV-passenger, and 3 (5.9 %) were HPV unrelated. Sequencing of the PCR-positive cases revealed the following genotypes: combined HPV-16 and 31 (41.7 %), HPV-31 (25.0 %), HPV-16 (22.9 %), combined HPV-16 and 18 (6.3 %), and a single case each of HPV 18 and HPV 33. Studies via ISH were negative in all cases. In accordance with worldwide trends but contrary to prior South African data, HPV likely plays an etiologic role in a significant subset (at least 49.1 %) of OPSC in black South Africans. We found that the alpha-9 HPV family, particularly HPV-16 and 31 either in combination or separately, to predominate in our sample tumors. The use of multiple PCR primers increased sensitivity of viral detection, and a HPV-31 specific primer confirmed the presence of this genotype in many samples. Further studies including HPV E6/E7 mRNA assays are needed to better elucidate the pathogenic role of HPV in black South African OPSCs. PMID- 23797834 TI - New developments in the diagnosis and treatment of thyroid cancer. AB - Thyroid cancer exists in several forms. Differentiated thyroid cancers include those with papillary and follicular histologies. These tumors exist along a spectrum of differentiation, and their incidence continues to climb. A number of advances in the diagnosis and treatment of differentiated thyroid cancers now exist. These include molecular diagnostics and more advanced strategies for risk stratification. Medullary cancer arises from the parafollicular cells and not the follicular cells. Therefore, diagnosis and treatment differs from those of differentiated thyroid tumors. Genetic testing and newer adjuvant therapies have changed the diagnosis and treatment of medullary thyroid cancer. This review will focus on the epidemiology, diagnosis, workup, and treatment of both differentiated and medullary thyroid cancers, focusing specifically on newer developments in the field. PMID- 23797846 TI - Changing ethnic disparity in ischemic stroke mortality in US children after the STOP trial. AB - IMPORTANCE: A prior report showed higher stroke mortality in US black children compared with white children (1979-1998), a disparity likely due in part to sickle cell disease, which leads to a high risk of childhood ischemic stroke. We hypothesized that this disparity has diminished since the publication of the Stroke Prevention Trial in Sickle Cell Anemia (STOP trial) in 1998 demonstrating the efficacy of long-term blood transfusions for primary stroke prevention. OBJECTIVE: To evaluate the demographics and secular trends in mortality from ischemic and hemorrhagic stroke (as a primary cause of death) in US children (<20 years) and determine if there has been a decrease in the disparity between white and black children since the publication of the STOP trial in 1998. DESIGN: We used death certificate data from the National Center for Health Statistics, 1988 through 2007. SETTING: United States. PARTICIPANTS: Children who died in 1988 through 2007 in the United States. INTERVENTION: Publication of the STOP trial. MAIN OUTCOME MEASURES: Incidence rate ratios were calculated as the measure of relative risk. RESULTS: Among 1.6 billion person-years of US children (1988 2007), there were 4425 deaths attributed to stroke, yielding an average of 221 deaths per year; 20% were ischemic; 67%, hemorrhagic; and 12%, unspecified. The relative risk of ischemic stroke mortality for black vs white children dropped from 1.74 from 1988 through 1997 to 1.27 from 1998 through 2007. The ethnic disparity in hemorrhagic stroke mortality, however, remained relatively stable between these 2 periods: black vs white relative risk, 1.90 (1988-1997) and 1.97 (1998-2007). CONCLUSIONS AND RELEVANCE: The excess risk of death from ischemic, but not hemorrhagic, stroke in US black children has decreased over the past decade. This may be related to the implementation of an effective ischemic stroke prevention strategy for children with sickle cell disease. PMID- 23797847 TI - Comparison between various fracture risk assessment tools. AB - The suboptimal performance of bone mineral density as the sole predictor of fracture risk and treatment decision making has led to the development of risk prediction algorithms that estimate fracture probability using multiple risk factors for fracture, such as demographic and physical characteristics, personal and family history, other health conditions, and medication use. We review theoretical aspects for developing and validating risk assessment tools, and illustrate how these principles apply to the best studied fracture probability tools: the World Health Organization FRAX(r), the Garvan Fracture Risk Calculator, and the QResearch Database's QFractureScores. Model development should follow a systematic and rigorous methodology around variable selection, model fit evaluation, performance evaluation, and internal and external validation. Consideration must always be given to how risk prediction tools are integrated into clinical practice guidelines to support better clinical decision making and improved patient outcomes. Accurate fracture risk assessment can guide clinicians and individuals in understanding the risk of having an osteoporosis related fracture and inform their decision making to mitigate these risks. PMID- 23797849 TI - Postmortem radiography of gastromalacia: case reports. AB - Gastromalacia is a postmortem artifact resulting from autolysis of the gastric walls. Gastromalacia is autolytic rupture of the stomach caused by endogenous enzymes, and it is devoid of any vital reactions. The left leaf of the diaphragm is occasionally perforated by a ragged fenestration, with escape of gastric contents into the pleural cavity. This rupture may lead to pneumoperitoneum or pneumothorax. For diagnostic radiologists, gastromalacia is rarely encountered. Therefore, they should be aware of this entity to avoid misdiagnosis when performing postmortem radiography. PMID- 23797848 TI - Copper deficit as a potential pathogenic factor of reduced bone mineral density and severe tooth wear. AB - The study evaluated if men and women with severe tooth wear were at increased risk of general bone loss. Enamel biopsies obtained from 50 subjects aged 47.5 +/ 5 years showed decreased copper content, which was associated with reduced spine bone mineral density, suggesting deficits of this trace element contributing to bone demineralization, enamel attrition, and deteriorated quality of mineralized tissues. INTRODUCTION: The objective of this cross-sectional study was to assess associations between enamel trace minerals and bone mineral density (BMD) in severe tooth wear. We hypothesized that similar factors contributed to both the excessive abrasion of dental enamel and reduced BMD in subjects with tooth wear. METHODS: Fifty patients aged 47.5 +/- 5 years with severe tooth wear and 20 age-, sex-, and body mass index (BMI)-matched healthy volunteers with normal dental status were studied regarding dietary intakes of trace elements, serum and salivary copper (Cu), zinc (Zn), and calcium (Ca) concentrations, and serum PTH, osteocalcin, and hydroxyvitamin D levels. Tooth wear was determined using clinical examination based on standard protocol according to Smith and Knight. In all subjects, acid biopsies of the maxillary central incisors were carried out to assess mineral composition of the enamel. Atomic absorption spectroscopy with an air/acetylene flame was used to measure Ca and Zn, and graphite furnace atomic absorption spectroscopy was used to analyze Cu content. BMD was examined using dual energy X-ray absorptiometry. RESULTS: Tooth wear patients had reduced lumbar spine, but not femoral, BMD relative to controls (p < 0.001). No differences were found in enamel Ca concentration and Zn content was slightly higher in tooth wear patients than in controls whereas Cu content was significantly decreased in the patients: 19.59 +/- 16.4 vs 36.86 +/- 26.1 MUg/l (p = 0.01) despite similar levels of Cu in serum and saliva. The differences were independent of serum 25-OH D, osteocalcin concentrations or PTH either. CONCLUSION: Severe tooth wear is associated with reduced spinal BMD. Enamel in adult individuals with severe tooth wear is low in copper content. Therefore, further work is needed to determine whether copper plays a role in bone pathophysiology in these patients. PMID- 23797850 TI - Novel phage display-derived mycolic acid-specific antibodies with potential for tuberculosis diagnosis. AB - Tuberculosis is a major cause of mortality and morbidity due to infectious disease. However, current clinical diagnostic methodologies such as PCR, sputum culture, or smear microscopy are not ideal. Antibody-based assays are a suitable alternative but require specific antibodies against a suitable biomarker. Mycolic acid, which has been found in patient sputum samples and comprises a large portion of the mycobacterial cell wall, is an ideal target. However, generating anti-lipid antibodies using traditional hybridoma methodologies is challenging and has limited the exploitation of this lipid as a diagnostic marker. We describe here the isolation and characterization of four anti-mycolic acid antibodies from a nonimmune antibody phage display library that can detect mycolic acids down to a limit of 4.5ng. All antibodies were specific for the methoxy subclass of mycolic acid with weak binding for alpha mycolic acid and did not show any binding to closely related lipids or other Mycobacterium tuberculosis (Mtb) derived lipids. We also determined the clinical utility of these antibodies based on their limit of detection for mycobacteria colony forming units (CFU). In combination with an optimized alkaline hydrolysis method for rapid lipid extraction, these antibodies can detect 10(5) CFU of Mycobacterium bovis BCG, a close relative of Mtb and therefore represent a novel approach for the development of diagnostic assays for lipid biomarkers. PMID- 23797851 TI - Gene expression: Disentangling DNA methylation. PMID- 23797852 TI - Genome evolution: Adaptive human regulatory variation. PMID- 23797854 TI - Metagenomics: With a little help from my phage friends. PMID- 23797853 TI - PIWI-interacting RNAs: from generation to transgenerational epigenetics. AB - Small-RNA-guided gene regulation is a recurring theme in biology. Animal germ cells are characterized by an intriguing small-RNA-mediated gene-silencing mechanism known as the PIWI pathway. For a long time, both the biogenesis of PIWI interacting RNAs (piRNAs) as well as their mode of gene silencing has remained elusive. A recent body of work is shedding more light on both aspects and implicates PIWI in the establishment of transgenerational epigenetic states. In fact, the epigenetic states imposed by PIWI on targets may actually drive piRNA production itself. These findings start to couple small RNA biogenesis with small RNA-mediated epigenetics. PMID- 23797855 TI - The gating charge pathway of an epilepsy-associated potassium channel accommodates chemical ligands. AB - Voltage-gated potassium (Kv) channels derive their voltage sensitivity from movement of gating charges in voltage-sensor domains (VSDs). The gating charges translocate through a physical pathway in the VSD to open or close the channel. Previous studies showed that the gating charge pathways of Shaker and Kv1.2-2.1 chimeric channels are occluded, forming the structural basis for the focused electric field and gating charge transfer center. Here, we show that the gating charge pathway of the voltage-gated KCNQ2 potassium channel, activity reduction of which causes epilepsy, can accommodate various small molecule ligands. Combining mutagenesis, molecular simulation and electrophysiological recording, a binding model for the probe activator, ztz240, in the gating charge pathway was defined. This information was used to establish a docking-based virtual screening assay targeting the defined ligand-binding pocket. Nine activators with five new chemotypes were identified, and in vivo experiments showed that three ligands binding to the gating charge pathway exhibit significant anti-epilepsy activity. Identification of various novel activators by virtual screening targeting the pocket supports the presence of a ligand-binding site in the gating charge pathway. The capability of the gating charge pathway to accommodate small molecule ligands offers new insights into the gating charge pathway of the therapeutically relevant KCNQ2 channel. PMID- 23797857 TI - A comparative study of blade plate fixation and external fixation in osteotomies for slipped capital femoral epiphysis. AB - We have performed corrective osteotomies for moderate or severe slipped capital femoral epiphysis (SCFE) using an original blade plate (BP) until 2006 and using a hybrid external fixator (EF) since 2007. We designed a comparative study of the short-term results between BP and EF devices in the treatment of proximal femoral osteotomies in SCFE. Nineteen SCFE patients (12 BP; seven EF) who underwent corrective osteotomies at our institution were included. Clinical and radiographic valuables including the operative time, intraoperative blood loss, postoperative improvement of head shaft angle, and posterior tilting angle, Harris hip score, limb-length discrepancy, and associated complications were compared between the two groups. Although there were no significant differences between the two groups in postoperative improvement of head shaft angle and posterior tilting angle, Harris hip score, and limb-length discrepancy, the EF group showed significantly shorter operative time and less intraoperative blood loss. Serious complications were observed in two patients of the BP group (deep infection and chondrolysis, respectively) and one of the EF group (chondrolysis). Percutaneous proximal femoral osteotomy using an EF appears to be safe, easy, and effective in correcting multiplanar deformities associated with SCFE. It has potential advantages over commonly used open techniques in terms of simplicity and less invasiveness. PMID- 23797858 TI - Abstracts of Tight Junctions, Interdisciplinary Rheumatological /Dermatological Research Symposium . November 2-3, 2012. Germany. PMID- 23797856 TI - Subepicardial endothelial cells invade the embryonic ventricle wall to form coronary arteries. AB - Coronary arteries bring blood flow to the heart muscle. Understanding the developmental program of the coronary arteries provides insights into the treatment of coronary artery diseases. Multiple sources have been described as contributing to coronary arteries including the proepicardium, sinus venosus (SV), and endocardium. However, the developmental origins of coronary vessels are still under intense study. We have produced a new genetic tool for studying coronary development, an AplnCreER mouse line, which expresses an inducible Cre recombinase specifically in developing coronary vessels. Quantitative analysis of coronary development and timed induction of AplnCreER fate tracing showed that the progenies of subepicardial endothelial cells (ECs) both invade the compact myocardium to form coronary arteries and remain on the surface to produce veins. We found that these subepicardial ECs are the major sources of intramyocardial coronary vessels in the developing heart. In vitro explant assays indicate that the majority of these subepicardial ECs arise from endocardium of the SV and atrium, but not from ventricular endocardium. Clonal analysis of Apln-positive cells indicates that a single subepicardial EC contributes equally to both coronary arteries and veins. Collectively, these data suggested that subepicardial ECs are the major source of intramyocardial coronary arteries in the ventricle wall, and that coronary arteries and veins have a common origin in the developing heart. PMID- 23797860 TI - DSM-5: call for commentaries on gender dysphoria, sexual dysfunctions, and paraphilic disorders. PMID- 23797859 TI - Rotavirus genotypes in children in the community with diarrhea in Madagascar. AB - In the context of the possible introduction of a preventive vaccine against rotaviruses in Madagascar, the G and P genotypes distribution of the rotaviruses circulating in the children in Madagascar was studied, and the presence of emerging genotypes and unusual strains were assessed. From February 2008 to May 2009, 1,679 stools specimens were collected from children <=5 years old with diarrhea. ELISA was used for antigen detection, and molecular amplification of VP7 and VP4 gene fragments was used for genotyping. Rotavirus antigen was detected in 104 samples (6.2%). Partial sequences of VP7 and VP4 genes were obtained from 81 and 80 antigen-positive stools, respectively. The most frequent G and P types combinations detected were G9P[8] (n = 51; 64.6%), followed by G1P[8] (n = 15; 18.9%), and G1P[6] (n = 8; 10.1%). A few unusual G-P combinations, such as G4P[6] (n = 3; 3.8%), G9P[6] (n = 1; 1.3%), and G3P[9] reassortant feline human virus (n = 1; 1.3%) were identified. Both VP4 and VP7 sequences in one of the three G4P[6] isolates were closely related to those in porcine strains, and one was a reassortant human porcine virus. These findings give an overview of the strains circulating in Madagascar and should help public health authorities to define a vaccine strategy. PMID- 23797861 TI - Extending the dynamic range of the ion trap by differential mobility filtration. AB - A miniature, planar, differential ion mobility spectrometer (DMS) was interfaced to an LCQ classic ion trap to conduct selective ion filtration prior to mass analysis in order to extend the dynamic range of the trap. Space charge effects are known to limit the functional ion storage capacity of ion trap mass analyzers and this, in turn, can affect the quality of the mass spectral data generated. This problem is further exacerbated in the analysis of mixtures where the indiscriminate introduction of matrix ions results in premature trap saturation with non-targeted species, thereby reducing the number of parent ions that may be used to conduct MS/MS experiments for quantitation or other diagnostic studies. We show that conducting differential mobility-based separations prior to mass analysis allows the isolation of targeted analytes from electrosprayed mixtures preventing the indiscriminate introduction of matrix ions and premature trap saturation with analytically unrelated species. Coupling these two analytical techniques is shown to enhance the detection of a targeted drug metabolite from a biological matrix. In its capacity as a selective ion filter, the DMS can improve the analytical performance of analyzers such as quadrupole (3D or linear) and ion cyclotron resonance (FT-ICR) ion traps that depend on ion accumulation. PMID- 23797862 TI - Induced dual-nanospray: a novel internal calibration method for convenient and accurate mass measurement. AB - Accurate mass information is of great importance in the determination of unknown compounds. An effective and easy-to-control internal mass calibration method will dramatically benefit accurate mass measurement. Here we reported a simple induced dual-nanospray internal calibration device which has the following three advantages: (1) the two sprayers are in the same alternating current field; thus both reference ions and sample ions can be simultaneously generated and recorded. (2) It is very simple and can be easily assembled. Just two metal tubes, two nanosprayers, and an alternating current power supply are included. (3)With the low-flow-rate character and the versatility of nanoESI, this calibration method is capable of calibrating various samples, even untreated complex samples such as urine and other biological samples with small sample volumes. The calibration errors are around 1 ppm in positive ion mode and 3 ppm in negative ion mode with good repeatability. This new internal calibration method opens up new possibilities in the determination of unknown compounds, and it has great potential for the broad applications in biological and chemical analysis. PMID- 23797863 TI - Analysis of a soluble (UreD:UreF:UreG)2 accessory protein complex and its interactions with Klebsiella aerogenes urease by mass spectrometry. AB - Maturation of the nickel-containing urease of Klebsiella aerogenes is facilitated by the UreD, UreF, and UreG accessory proteins along with the UreE metallo chaperone. A fusion of the maltose binding protein and UreD (MBP-UreD) was co isolated with UreF and UreG in a soluble complex possessing a (MBPUreD: UreF:UreG)2 quaternary structure. Within this complex a UreF:UreF interaction was identified by chemical cross-linking of the amino termini of its two UreF protomers, as shown by mass spectrometry of tryptic peptides. A preactivation complex was formed by the interaction of (MBP-UreD:UreF:UreG)2 and urease. Mass spectrometry of intact protein species revealed a pathway for synthesis of the urease pre-activation complex in which individual hetero-trimer units of the (MBP UreD:UreF:UreG)2 complex bind to urease. Together, these data provide important new insights into the structures of protein complexes associated with urease activation. PMID- 23797864 TI - Multiple mass analysis using an ion trap array (ITA) mass analyzer. AB - A novel ion trap array (ITA) mass analyzer with six ion trapping and analyzing channels was investigated. It is capable of analyzing multiple samples simultaneously. The ITA was built with several planar electrodes made of stainless steel and 12 identical parallel zirconia ceramic substrates plated with conductive metal layers. Each two of the opposing ceramic electrode plates formed a boundary of an ion trap channel and six identical ion trapping and analyzing channels were placed in parallel without physical electrode between any two adjacent channels. The electric field distribution inside each channel was studied with simulation. The new design took the advantage of high precision machining attributable to the rigidity of ceramic, and the convenience of surface patterning technique. The ITA system was tested by using a two-channel electrospray ionization source, a multichannel simultaneous quadruple ion guide, and two detectors. The simultaneous analysis of two different samples with two adjacent ITA channels was achieved and independent mass spectra were obtained. For each channel, the mass resolution was tested. Additional ion trap functions such as mass-selected ion isolation and collision-induced dissociation (CID) were also tested. The results show that one ITA is well suited for multiple simultaneous mass analyses. PMID- 23797865 TI - In vitro circadian period is associated with circadian/sleep preference. AB - Evaluation of circadian phenotypes is crucial for understanding the pathophysiology of diseases associated with disturbed biological rhythms such as circadian rhythm sleep disorders (CRSDs). We measured clock gene expression in fibroblasts from individual subjects and observed circadian rhythms in the cells (in vitro rhythms). Period length of the in vitro rhythm (in vitro period) was compared with the intrinsic circadian period, tau, measured under a forced desynchrony protocol (in vivo period) and circadian/sleep parameters evaluated by questionnaires, sleep log, and actigraphy. Although no significant correlation was observed between the in vitro and in vivo periods, the in vitro period was correlated with chronotype, habitual sleep time, and preferred sleep time. Our data demonstrate that the in vitro period is significantly correlated with circadian/sleep preference. The findings suggest that fibroblasts from individual patients can be utilized for in vitro screening of therapeutic agents to provide personalized therapeutic regimens for CRSD patients. PMID- 23797866 TI - [Prenatal care in the city of Marrakech]. AB - The data reported here come from a survey conducted in 2008, in direct interviews, according to a standard questionnaire, of 1712 women visiting 15 health centers in Marrakech. We selected 1202 women who gave birth during the past five years to examine the impact of socioeconomic and biodemographic determinants on access to prenatal care in this city. We also identified 309 women in our sample who were pregnant during the survey and studied the quality and content of their prenatal care. Around 90% of pregnant women consulted at least once during pregnancy. These results indicate that women in Marrakesh use prenatal care at higher rates than the national and regional population. This is likely to be explained by the large number of public health centers relatively well distributed throughout the city of Marrakech, although periurban areas are much less well endowed. Our analysis nonetheless indicates that 10% of the women in Marrakech do not consult at any time during pregnancy, although free care is provided in public health centers and outreach programs of the Department of Health encourage women to be monitored. Multiple sociocultural, socioeconomic, and biodemographic factors promote recourse to prenatal care. The most vulnerable pregnant women, that is, multiparous women living in periurban areas, the less educated women, and women of rural origin, are also those the least monitored. Most of the obstacles raised by the interviewees are maternal barriers, that is, related to the women themselves. These include indifference, recklessness, and ignorance of the risks: these barriers are related to maternal illiteracy and to a failure to understand the importance of medical surveillance. PMID- 23797867 TI - Positioning microanalysis: studying the self through the exploration of dialogical processes. AB - Self-multiplicity is a widely recognized phenomenon within psychology. The study of how self-continuity emerges amidst self-multiplicity remains a crucial issue, however. Dialogical approaches are widely viewed as suitable for developing this field of study but they demand coherent methods compatible with their theoretical bases. After reviewing the available methods for the study of the dialogical self, as well as other dialogical methods for the study of psychotherapy, we conclude that we still lack a method which can be used by external observers and is devoted to the systematic tracing of the dialogical dynamics of self-positions as they unfold over time. A new method, positioning microanalysis, is described in detail as a possible way to overcome current limitations in methods focused on the dialogicality inherent in selfhood processes. Positioning microanalysis takes a genetic-developmental perspective on dialogical processes in the self and allows for the depiction of microgenetic movements of self-positions over time and the establishment of more or less stable sequences or patterns of positions. This is illustrated by its application to an emotion-focused therapy session. PMID- 23797868 TI - Extracapsular spread in head and neck carcinoma: impact of site and human papillomavirus status. AB - BACKGROUND: Extracapsular spread (ECS) in cervical lymph node metastases from head and neck squamous cell carcinoma (SCC) is regarded as an adverse prognostic factor and is often used to select patients who may benefit from adjuvant therapy. The prognostic value of ECS was evaluated for patients with oropharyngeal SCC (OPC; with known p16/human papillomavirus [HPV] status) and for patients with SCC of the oral cavity (OCC). METHODS: Disease-specific survival (DSS) was assessed among SCC patients with cervical lymph node metastases (n = 347, including 133 patients with OPC and 214 patients with OCC). All patients were treated surgically between 1983 and 2009. ECS status was determined by pathologists at the time of initial pathologic evaluation and confirmed for this study. HPV status of patients with OPC was determined via immunohistochemistry for p16 and in situ hybridization. RESULTS: Among OCC patients, ECS was a significant, independent factor influencing DSS. For OCC patients with ECS, 3 year DSS was 45% (95% confidence interval [CI], 36%-56%); for those without ECS, 3-year DSS was 71% (95% CI, 62%-81%; P = .0018). The effect of ECS was independent of the number of positive lymph nodes as well as other clinical, pathologic, and treatment variables. Of the 133 OPC patients, 76 (57%) were p16 positive and 57 (43%) were p16-negative. ECS status did not correlate with DSS among p16-positive or p16-negative OPC patients. CONCLUSION: ECS was not associated with worse DSS in p16-positive or p16-negative OPC patients. Adverse prognostic value of ECS in OCC patients was confirmed. Cancer 2013;119:3302-8. (c) 2013 American Cancer Society. PMID- 23797869 TI - Cancer: Importance of oncofetal gene, SALL4, in a subset of hepatocellular carcinoma. PMID- 23797871 TI - Pancreas: Reconstruction methods after pancreaticoduodenectomy. PMID- 23797872 TI - Gallbladder: High levels of bilirubin as a risk factor for symptomatic gallstone disease. PMID- 23797873 TI - SET-domain bacterial effectors target heterochromatin protein 1 to activate host rDNA transcription. AB - Transcription of rRNA genes (rDNAs) in the nucleolus is regulated by epigenetic chromatin modifications including histone H3 lysine (de)methylation. Here we show that LegAS4, a Legionella pneumophila type IV secretion system (TFSS) effector, is targeted to specific rDNA chromatin regions in the host nucleolus. LegAS4 promotes rDNA transcription, through its SET-domain (named after Drosophila Su(var)3-9, enhancer of zeste [E(z)], and trithorax [trx]) histone lysine methyltransferase (HKMTase) activity. LegAS4's association with rDNA chromatin is mediated by interaction with host HP1alpha/gamma. L. pneumophila infection potently activates rDNA transcription in a TFSS-dependent manner. Other bacteria, including Bordetella bronchiseptica and Burkholderia thailandensis, also harbour nucleolus-localized LegAS4-like HKMTase effectors. The B. thailandensis type III effector BtSET promotes H3K4 methylation of rDNA chromatin, contributing to infection-induced rDNA transcription and bacterial intracellular replication. Thus, activation of host rDNA transcription might be a general bacterial virulence strategy. PMID- 23797874 TI - The chromatin remodelling complex NoRC safeguards genome stability by heterochromatin formation at telomeres and centromeres. AB - Constitutive heterochromatin is crucial for the integrity of chromosomes and genomic stability. Here, we show that the chromatin remodelling complex NoRC, known to silence a fraction of rRNA genes, also establishes a repressive heterochromatic structure at centromeres and telomeres, preserving the structural integrity of these repetitive loci. Knockdown of NoRC leads to relaxation of centromeric and telomeric heterochromatin, abnormalities in mitotic spindle assembly, impaired chromosome segregation and enhanced chromosomal instability. The results demonstrate that NoRC safeguards genomic stability by coordinating enzymatic activities that establish features of repressive chromatin at centromeric and telomeric regions, and this heterochromatic structure is required for sustaining genomic integrity. PMID- 23797876 TI - Concurrent video-rate color and near-infrared fluorescence laparoscopy. AB - The visual identification and demarcation of tumors and tumor margins remains challenging due to the low optical contrast of cancer cells over surrounding tissues. Fluorescence molecular imaging was recently considered clinically for improving cancer detection during open surgery. We present herein a next step in the development of fluorescence molecular guidance by describing a novel video rate imaging laparoscope capable of concurrently recording color and near infrared fluorescence images and video. Video-rate operation is based on graphics processing unit-based image processing. We examine the optical characteristics of the system developed and provide performance metrics related to intra-operative endoscopic guidance, showcased on phantoms and endoscopic color and fluorescence molecular imaging of tumors in a mouse model of the human disease. PMID- 23797875 TI - Wnk kinases are positive regulators of canonical Wnt/beta-catenin signalling. AB - Wnt/beta-catenin signalling is central to development and its regulation is essential in preventing cancer. Using phosphorylation of Dishevelled as readout of pathway activation, we identified Drosophila Wnk kinase as a new regulator of canonical Wnt/beta-catenin signalling. WNK kinases are known for regulating ion co-transporters associated with hypertension disorders. We demonstrate that wnk loss-of-function phenotypes resemble canonical Wnt pathway mutants, while Wnk overexpression causes gain-of-function canonical Wnt-signalling phenotypes. Importantly, knockdown of human WNK1 and WNK2 also results in decreased Wnt signalling in mammalian cell culture, suggesting that Wnk kinases have a conserved function in ensuring peak levels of canonical Wnt signalling. PMID- 23797877 TI - In vivo imaging of orthotopic prostate cancer with far-red gene reporter fluorescence tomography and in vivo and ex vivo validation. AB - Fluorescence gene reporters have recently become available for excitation at far red wavelengths, enabling opportunities for small animal in vivo gene reporter fluorescence tomography (GRFT). We employed multiple projections of the far-red fluorescence gene reporters IFP1.4 and iRFP, excited by a point source in transillumination geometry in order to reconstruct the location of orthotopically implanted human prostate cancer (PC3), which stably expresses the reporter. Reconstruction was performed using a linear radiative-transfer-based regularization-free tomographic method. Positron emission tomography (PET) imaging of a radiolabeled antibody-based agent that targeted epithelial cell adhesion molecule overexpressed on PC3 cells was used to confirm in vivo GRFT results. Validation of GRFT results was also conducted from ex vivo fluorescence imaging of resected prostate tumor. In addition, in mice with large primary prostate tumors, a combination of GRFT and PET showed that the radiolabeled antibody did not penetrate the tumor, consistent with known tumor transport limitations of large (~150 kDa) molecules. These results represent the first tomography of a living animal using far-red gene reporters. PMID- 23797870 TI - Serotonin signalling in the gut--functions, dysfunctions and therapeutic targets. AB - Serotonin (5-HT) has been recognized for decades as an important signalling molecule in the gut, but it is still revealing its secrets. Novel gastrointestinal functions of 5-HT continue to be discovered, as well as distant actions of gut-derived 5-HT, and we are learning how 5-HT signalling is altered in gastrointestinal disorders. Conventional functions of 5-HT involving intrinsic reflexes include stimulation of propulsive and segmentation motility patterns, epithelial secretion and vasodilation. Activation of extrinsic vagal and spinal afferent fibres results in slowed gastric emptying, pancreatic secretion, satiation, pain and discomfort, as well as nausea and vomiting. Within the gut, 5 HT also exerts nonconventional actions such as promoting inflammation and serving as a trophic factor to promote the development and maintenance of neurons and interstitial cells of Cajal. Platelet 5-HT, originating in the gut, promotes haemostasis, influences bone development and serves many other functions. 5-HT3 receptor antagonists and 5-HT4 receptor agonists have been used to treat functional disorders with diarrhoea or constipation, respectively, and the synthetic enzyme tryptophan hydroxylase has also been targeted. Emerging evidence suggests that exploiting epithelial targets with nonabsorbable serotonergic agents could provide safe and effective therapies. We provide an overview of these serotonergic actions and treatment strategies. PMID- 23797878 TI - Mifepristone treatment affects the response to repeated amphetamine injections, but does not attenuate the expression of sensitization. AB - Rationale Glucocorticoid hormones facilitate sensitization to repeated administration of psychostimulants, an effect that is mediated by glucocorticoid receptors (GRs). It is still unclear, however, at which stage of psychomotor sensitization are stress and GR-mediated effects involved. OBJECTIVES: In the present study, we have tested the hypothesis that GR-mediated effects during the phase of repeated amphetamine injections play a crucial role in the long-term expression of sensitization. For this purpose, we used DBA/2 mice, an inbred strain commonly used for the study of stress effects on psychostimulant sensitization. METHODS: Animals were treated with the GR antagonist mifepristone (200 mg/kg) at 2.5 h before each daily injection of amphetamine (2.5 mg/kg) or saline in a 5-day protocol. The amphetamine or saline injections were given in the home or a novel context. This was followed by a 2.5-week withdrawal period, without any drug delivery. Following the withdrawal period, two low-dose amphetamine challenges (1.25 mg/kg) were given subsequently, without additional mifepristone. RESULTS: The animals receiving amphetamine in the novel context showed a higher expression of sensitization at challenge as compared to those in the home condition. Mifepristone treatment influenced locomotor response to repeated amphetamine injections, but this effect during the initial phase did not affect the expression of sensitization after a withdrawal period. CONCLUSION: Our results indicate that GR-related processes during the initial phase of sensitization are involved in, but not crucial for, the development of long-term sensitization. PMID- 23797879 TI - Elongated styloid process as a cause of transient ischemic attacks. PMID- 23797880 TI - Laparoscopic repair of hiatal hernia after esophagectomy. AB - BACKGROUND: Herniation of abdominal contents via the diaphragmatic hiatus is a potentially life-threatening complication of esophagectomy. Mounting evidence suggests that hiatal hernias are more common following minimally invasive esophagectomy. Therefore, post-esophagectomy hiatal hernia and its treatment bear increasing significance. METHODS: We retrospectively reviewed the records of five patients with hiatal hernia following esophagectomy over a 5-year period. RESULTS: Successful laparoscopic reduction of a post-esophagectomy hiatal hernia was done without mesh reinforcement in three patients. One patient underwent mesh reinforcement. One patient was found to have carcinomatosis upon laparoscopic inspection, and repair of the hiatal hernia was abandoned. There were no perioperative deaths or complications. One patient developed a recurrent hiatal hernia 14 months after repair of the initial hiatal hernia. Patients were discharged within a mean of 1.75 days after surgical repair. DISCUSSION: We have successfully used laparoscopy to treat hiatal hernias after esophagectomy. The benefits conferred by laparoscopy, including better visualization of the right gastroepiploic artery supplying the gastric conduit, minimally invasive evaluation of the field for metastasis, and shorter recovery time, make it our favored approach. Here, we describe our experience with hiatal hernia following esophagectomy and our operative technique. PMID- 23797882 TI - Sister Mary Joseph's nodule presenting as large bowel obstruction: a case report and brief review of the literature. PMID- 23797881 TI - Perineural invasion in extrahepatic cholangiocarcinoma: prognostic impact and treatment strategies. AB - BACKGROUND: The significance of perineural invasion in extrahepatic cholangiocarcinoma has not been fully elucidated. This study aims to determine the prognostic impact of and optimal treatment strategy for perineural invasion in patients with extrahepatic cholangiocarcinoma. METHODS: Medical records of 133 patients with extrahepatic cholangiocarcinoma who underwent curative resection were reviewed retrospectively. Ninety-eight patients had perineural invasion and 35 patients did not. Univariate and multivariate survival analyses were performed to clarify the prognostic impact of and optimal treatment strategy for perineural invasion. RESULTS: Only tumor differentiation (P=0.024) was independently associated with perineural invasion in the multivariate logistic regression model. Multivariate survival analysis revealed that perineural invasion (P=0.002), resection margin status(P=0.016), and International Union Against Cancer (UICC) pT factor (P=0.015) were independent prognostic factors of overall survival. Overall 5-year survival rates for patients with and without perineural invasion were 28 and 74 %, respectively. Among 98 patients with perineural invasion, the use of adjuvant chemotherapy (P=0.003), lymph node status (P=0.015), resection margin status (P=0.008), and UICC pT factor (P=0.016) were independently associated with overall survival by multivariate analysis. Overall 5-year survival rates for patients with perineural invasion who did and did not receive adjuvant chemotherapy were 33 and 21 %, respectively (P=0.023). CONCLUSIONS: Perineural invasion is a potent prognostic factor in extrahepatic cholangiocarcinoma. Adjuvant chemotherapy may improve the overall survival of patients with perineural invasion. PMID- 23797883 TI - Splenic vein thrombosis is associated with an increase in pancreas-specific complications and reduced survival in patients undergoing distal pancreatectomy for pancreatic exocrine cancer. AB - Distal pancreatectomy and splenectomy (DPS) is the procedure of choice for the surgical treatment of pancreatic exocrine cancer localized to the body and tail of the pancreas. Splenic vein thrombosis (SVT) can occur in patients with malignant pancreatic exocrine tumors secondary to direct tumor invasion or compression of the splenic vein by mass effect. This study examines the effect of preoperative SVT on postoperative outcomes. In this retrospective cohort study, we queried our pancreatic surgery database to identify patients who underwent DPS from October 2005 to June 2011. These cases were evaluated for evidence of preoperative SVT on clinical records and cross-sectional imaging (CT,MRI, endoscopic US). Outcomes for patients with and without SVT were compared. From an overall cohort of 285 consecutive patients who underwent DPS during the study period, data were evaluated for 70 subjects who underwent surgery for pancreatic exocrine cancer (27 with SVT, 43 without SVT). The preoperative demographics and co-morbidities were similar between the groups, except the average age was higher for those without SVT (p<0.05). The median estimated blood loss was significantly higher in the SVT group (675 versus 250 ml, p=<0.001).While the overall morbidity rates were similar between the two groups (48 % SVT versus 56% no SVT, p=NS), the group with SVT had a significantly higher rate of pancreas-specific complications, including pancreatic fistula (33 versus 7 %,p<0.01) and delayed gastric emptying (15 versus 0%, p<0.02). Hospital readmission rates were similar between the groups(30 versus 28 %, p=NS). Patients without SVT had a trend toward longer median survival (40 versus 20.8 months),although the difference was not statistically significant (p=0.1). DPS for pancreatic ductal adenocarcinoma can be performed safely in patients with SVT, but with higher intraoperative blood loss, increased pancreas-specific complications, and a trend towards lower long term survival rates. This paper was presented as a poster at the 53rd annual meeting of the Society for Surgery of the Alimentary Tract and at the 46th annual meeting of the Pancreas Club, San Diego, CA, May 2012. PMID- 23797884 TI - Esophageal perforation and rupture: a comprehensive medicolegal examination of 59 jury verdicts and settlements. AB - BACKGROUND: Consequences accompanying esophageal perforation make this complication a prime litigation target. We characterize factors in jury verdicts and settlements regarding esophageal perforation, including operative procedure, patient demographics, alleged cause(s) of malpractice, outcome, and other factors. METHODS: Pertinent court records were examined for the aforementioned factors. RESULTS: Gastroenterologists, general surgeons, and anesthesiologists were the most commonly named defendants. Two thirds of outcomes were for the defendant, and 11.9 % were settled (median--$650,000); 20.3% resulted in awarded damages (median--$1.2 M). Esophagogastroduodenoscopy was the most commonly litigated procedure, followed by intubation and Nissen fundoplication. Necessity of repair, delayed diagnosis, death, and inadequate consent were the most frequently cited factors in litigation. CONCLUSIONS: An understanding of the factors important in determining legal responsibility is of great interest for practitioners in multiple specialties. The requirement of surgical repair and a delay in diagnosis are two of the most common factors present in litigated cases resulting in a payment. The importance of explicitly listing esophageal perforation in the informed consent for esophagogastroduodenoscopy, abdominal surgery, and any patients at risk of intubation injury needs to be emphasized. PMID- 23797885 TI - Novel liver visualization and surgical simulation system. AB - BACKGROUND: Successful liver surgery requires an understanding of the patient's particular liver characteristics, including shape and vessel distribution. In clinical medicine, there is a high demand for surgical assistance systems to assess individual patients. Our aims in this study were to segment the liver based on computed tomography volume data and to develop surgical plans for individual patients. METHODS: The hepatic vessels were semi-automatically extracted from the segmented liver images, and the 3D shape of the liver and extracted vessel distribution were visualized using a surgical simulation system. RESULTS: The 3D visualization of the liver allowed easy recognition of vessel and tumor location and selection of these structures with the 3D pointing device. The surgeon's prior knowledge and clinical experience were integrated into the visualization system to create a practical virtual surgery, leading to improved functionality and accuracy of information recognition in the surgical simulation system. CONCLUSIONS: The 3D visualization demonstrated details of individual liver structure, resulting in better understanding and practical surgical simulation. PMID- 23797886 TI - Evidence-based treatment of gallstone disease. PMID- 23797887 TI - Giant GIST of the small intestine in a young man. AB - Gastrointestinal stromal tumors (GISTs) represent a rare group of neoplasms of the digestive tract deriving from the mesenchyme. Giant GISTs (over 10 cm in diameter) represent only 20 % of all cases and are associated with a high risk of malignancy. We present the case of a giant GIST of the jejunum successfully treated by surgical resection and adjuvant therapy with imatinib. PMID- 23797888 TI - Complete clinical response after neoadjuvant chemoradiotherapy for squamous cell cancer of the thoracic oesophagus: is surgery always necessary? AB - BACKGROUND: Neoadjuvant chemoradiotherapy (CT-RT) before oesophagectomy is standard management for squamous cell carcinoma(SCC) of the thoracic oesophagus. The aim of this study was to compare the outcome of patients who had clinical complete response(CR) with neoadjuvant CT-RT + oesophagectomy with the survival of patients who had clinical CR and were not operated on. PATIENTS AND METHODS: Seventy-seven consecutive patients with SCC of the thoracic oesophagus with CR with neoadjuvant CT-RT presenting at the Regional Center of Esophageal Diseases from 1992 to 2008 were included in this retrospective study on a prospectively collected database. Thirty-nine patients underwent oesophagectomy (CT-RT + oesophagectomy), while 38(CT-RT) were not operated on because they were considered unfit for surgery or refused the operation. Patients' outcome and survival were compared. RESULTS: In the CT-RT + oesophagectomy group, clinical CR was confirmed after histological examination of the surgical specimen in 27/39 (69.2 %) patients. Five-year overall survival rates were 50.0 % in the CT-RT + oesophagectomy group and 57.0 % in the CT-RT group (p=0.99); 5-year disease-free survival rates were 55.5%in the CT-RT + oesophagectomy group and 34.6%in the CTRT group (p=0.15). Even after adjusting for propensity score, age, ASA and clinical stage, the treatment regimen did not show a statistically significant effect on overall survival (adjusted p=0.65) nor on disease-free survival (adjusted p=0.15). CONCLUSION: In our group of patients with clinical CR after neoadjuvant CT-RT for SCC of the thoracic oesophagus, waiting for recurrence and then using salvage surgery did not negatively impact their survival compared to patients treated with surgery. More accurate restaging protocols are warranted to improve decision making after CR with neoadjuvant CT-RT. PMID- 23797889 TI - Testing three different sequential mediational interpretations of Beck's cognitive model of the development of depression. AB - OBJECTIVES: This study tested and compared three sequential interpretations of Beck's cognitive model of the development of depression (1996). The causal mediational interpretation identifies dysfunctional attitudes as most distal to depressive symptoms, followed by cognitive distortions, the cognitive triad, and negative automatic thoughts, with each construct successively more proximal to depressive symptoms. By contrast, the symptom model reverses the causal chain with negative automatic thoughts as the most proximal consequence and dysfunctional attitudes as the most distal consequence of depression. The bidirectional model merges both interpretations into one model. Previous studies on sequential interpretations of Beck's model have not included cognitive distortions or the cognitive triad and did not test the bidirectional model finding contradictory empirical evidence for the sequential order. METHOD: In the 3-wave longitudinal study, 308 German university students without clinically significant depressive symptoms (245 female, average age: 23.69 years) completed self-report questionnaires measuring their dysfunctional attitudes, cognitive distortions, cognitive triad, negative automatic thoughts, and depressive symptoms. RESULTS: The bidirectional model with partial mediation fit the data best and cognitive distortions mediated the relationship between dysfunctional attitudes and negative automatic thoughts and vice versa. CONCLUSIONS: The findings have important consequences for the prevention of depression. Prevention programs may want to focus on cognitive distortions, the only construct in Beck's model that influences every other construct in the model. PMID- 23797890 TI - Probiotic Lactobacillus casei Zhang ameliorates high-fructose-induced impaired glucose tolerance in hyperinsulinemia rats. AB - AIM: To evaluate the preventive and therapeutic effects of Lactobacilluscasei Zhang on impaired glucose tolerance (IGT) by using fructose-induced hyperinsulinemia rats. METHODS: Rats were fed 25 % fructose solution for hyperinsulinemia with L.casei Zhang for prevention or therapy. Serum levels of insulin, glucagon-like peptide-2 (GLP-2), osteocalcin, malondialdehyde (MDA), total intestinal bile acids and hepatic glycogen contents were determined by assay kits. The major bacteria from feces and liver expression of adiponectin receptor 2 (AdipoR2), liver X receptor-alpha (LXR-alpha), peroxisome proliferator activated receptor gamma (PPAR-gamma) and vitamin K epoxide reductase complex subunit 1 mRNA were assessed by RT-PCR. Pancreas injury was evaluated by histological analysis. RESULTS: Lactobacilluscasei Zhang significantly increased numbers of Lactobacillus and Bifidobacterium and decreased Clostridium in the intestine (p < 0.01). Meanwhile, liver glycogen contents were significantly decreased (p < 0.05). In preventive group, accompanied by significantly lower insulin and GLP-2 levels (p < 0.05), L.casei Zhang prevented rats from an increase in oral glucose tolerance area under curve (AUC) which was significant in hyperinsulinemia group (p < 0.05). In therapeutic group, L.casei Zhang administration possessed improved glucose tolerance (p < 0.05), which were associated with increased osteocalcin level (p < 0.01), improved intestinal bile acids secretion (p = 0.060), decreased serum MDA levels (p < 0.05) and upregulation of LXR-alpha, PPAR-gamma and AdipoR2 gene expression, as well as an increase in Bacteroides fragilis (p < 0.05). CONCLUSIONS: Lactobacilluscasei Zhang administration exert both preventive and ameliorative effect on oral glucose tolerance AUC in IGT rats but may be via different mechanisms. L.casei Zhang could prevent rats from increased AUC through GLP-2 lowering, while the ameliorative effect in high-fructose-fed post-adolescent rats may be via B. fragilis enriched vitamin K2-dependent osteocalcin mechanism in which AdipoR2, LXR-alpha and PPAR-gamma signaling were involved. PMID- 23797894 TI - Combined spectrophotometry and tensile measurements of human connective tissues: potentials and limitations. AB - Strain-dependent transmission data of nine iliotibial tract specimens are determined using a custom-built optical setup with a halogen light source and an industrial norm material testing machine. Polarized light microscopy and hematoxylin-eosin staining indicated that lateral contraction of collagen structures is responsible for total intensity variations during a 20-cycle preconditioning and a 5-cycle tensile test. Tensile force progress is opposite to total transmission progress. Due to dehydration, wavelength-specific radiation intensity shifting is determined during the test, primarily noticeable in a water absorption band between 1400 and 1500 nm. The results show the capability of integrating spectrophotometry technology into biomechanics for determining structural alterations of human collagen due to applied strain. Being more sensitive to drying, spectrophotometry may likely serve as a quality control in stress-strain testing of biological structures. PMID- 23797895 TI - Three-dimensional model for human anterior corneal surface. AB - The anterior corneal asphericity (Q) with the tangential radius is calculated, and a three-dimensional (3-D) anterior corneal model is constructed. Tangential power maps from Orbscan II are acquired for 66 young adult subjects. The Q-value of each semimeridian in the near-horizontal region is calculated with the tangential radius. Polynomial fitting is used to model the 360-semimeridional variation of Q-values, and to fit the Q-values in the near-vertical region. Furthermore, a customized 3-D anterior corneal model is constructed. The 360 semimeridional variation of Q-values is well fitted with a seventh-degree polynomial function for all subjects. The goodness of fit of the polynomial function was >0.9, and the median value was 0.94. The Q-value distribution of the anterior corneal surface showed bimodal variation. Additionally, the Q-values gradually become less negative from the horizontal to the vertical semimeridians in the four quadrants. The 3-D surface plot of the anterior corneal surface approximated a prolate ellipsoid. Using a method to calculate the Q-value with the tangential radius combined with polynomial fitting, we are able to obtain the Q-value of any semimeridian. Compared with general models, this method generates a complete shape of the anterior corneal surface using asphericity. PMID- 23797893 TI - Hepatitis A and hepatitis B infection prevalence and associated risk factors in men who have sex with men, Bangkok, 2006-2008. AB - Despite the availability of safe and effective vaccines, little is known about prevalence and risk factors for hepatitis A (HAV) and hepatitis B virus (HBV) infection among Thai men who have sex with men. The prevalence of HAV and HBV infection among men who have sex with men cohort in Bangkok was assessed. Baseline blood specimens were drawn and demographic and behavioral data were collected. Bivariate and multivariate logistic regression analysis was used to analyze risk factors for prevalent HAV and HBV infection. One thousand two hundred ninety-nine Thai men who have sex with men 18 years and older were enrolled. Among those with results, 349/1,291 (27.0%) had evidence of past or current hepatitis A infection. Of the 1,117 (86.5%) men with unambiguous HBV test results, 442 (39.6%) had serologic evidence of past/current infection, 103 (9.2%) were immune due to hepatitis B vaccination, 572 (51.2%) had no evidence of immunological exposure to HBV or vaccine. Of those with past/current HBV infection, 130 (29.4%) were HIV positive. Age >35 years was independently associated with both HAV and HBV infection. University education was protective against both HAV and HBV infection. Increased alcohol consumption, number of lifetime male sexual partners >=10, and prevalent HIV infection were also independently associated with HBV infection. The prevalence of past/current HAV and HBV infection was high in Bangkok men who have sex with men. Age-cohorts with a higher prevalence of hepatitis B vaccine induced immunity may be expected in the future. Hepatitis A and B vaccination is recommended. PMID- 23797896 TI - Investigating line- versus point-laser excitation for three-dimensional fluorescence imaging and tomography employing a trimodal imaging system. AB - The adoption of axially oriented line illumination patterns for fluorescence excitation in small animals for fluorescence surface imaging (FSI) and fluorescence optical tomography (FOT) is being investigated. A trimodal single photon-emission-computed-tomography/computed-tomography/optical-tomography (SPECT CT-OT) small animal imaging system is being modified for employment of point- and line-laser excitation sources. These sources can be arbitrarily positioned around the imaged object. The line source is set to illuminate the object along its entire axial direction. Comparative evaluation of point and line illumination patterns for FSI and FOT is provided involving phantom as well as mouse data. Given the trimodal setup, CT data are used to guide the optical approaches by providing boundary information. Furthermore, FOT results are also being compared to SPECT. Results show that line-laser illumination yields a larger axial field of view (FOV) in FSI mode, hence faster data acquisition, and practically acceptable FOT reconstruction throughout the whole animal. Also, superimposed SPECT and FOT data provide additional information on similarities as well as differences in the distribution and uptake of both probe types. Fused CT data enhance further the anatomical localization of the tracer distribution in vivo. The feasibility of line-laser excitation for three-dimensional fluorescence imaging and tomography is demonstrated for initiating further research, however, not with the intention to replace one by the other. PMID- 23797897 TI - Near-infrared-excited confocal Raman spectroscopy advances in vivo diagnosis of cervical precancer. AB - Raman spectroscopy is a unique optical technique that can probe the changes of vibrational modes of biomolecules associated with tissue premalignant transformation. This study evaluates the clinical utility of confocal Raman spectroscopy over near-infrared (NIR) autofluorescence (AF) spectroscopy and composite NIR AF/Raman spectroscopy for improving early diagnosis of cervical precancer in vivo at colposcopy. A rapid NIR Raman system coupled with a ball lens fiber-optic confocal Raman probe was utilized for in vivo NIR AF/Raman spectral measurements of the cervix. A total of 1240 in vivo Raman spectra [normal (n=993), dysplasia (n=247)] were acquired from 84 cervical patients. Principal components analysis (PCA) and linear discriminant analysis (LDA) together with a leave-one-patient-out, cross-validation method were used to extract the diagnostic information associated with distinctive spectroscopic modalities. The diagnostic ability of confocal Raman spectroscopy was evaluated using the PCA-LDA model developed from the significant principal components (PCs) [i.e., PC4, 0.0023%; PC5, 0.00095%; PC8, 0.00022%, (p<0.05)], representing the primary tissue Raman features (e.g., 854, 937, 1095, 1253, 1311, 1445, and 1654 cm(-1)). Confocal Raman spectroscopy coupled with PCA-LDA modeling yielded the diagnostic accuracy of 84.1% (a sensitivity of 81.0% and a specificity of 87.1%) for in vivo discrimination of dysplastic cervix. The receiver operating characteristic curves further confirmed that the best classification was achieved using confocal Raman spectroscopy compared to the composite NIR AF/Raman spectroscopy or NIR AF spectroscopy alone. This study illustrates that confocal Raman spectroscopy has great potential to improve early diagnosis of cervical precancer in vivo during clinical colposcopy. PMID- 23797898 TI - Relationship between the chemical and morphological characteristics of human dentin after Er:YAG laser irradiation. AB - The effects of laser etching on dentin are studied by microenergy-dispersive x ray fluorescence spectrometry (MU-EDXRF) and scanning electron microscopy (SEM) to establish the correlation of data obtained. Fifteen human third molars are prepared, baseline MU-EDXRF mappings are performed, and ten specimens are selected. Each specimen received four treatments: acid etching (control-CG) or erbium:yttrium-aluminum-garnet (Er:YAG) laser irradiation (I-100 mJ, II-160 mJ, and III-220 mJ), and maps are done again. The Ca and P content are significantly reduced after acid etching (p<0.0001) and increased after laser irradiation with 220 mJ (Ca: p<0.0153 and P: p=0.0005). The Ca/P ratio increased and decreased after CG (p=0.0052) and GI (p=0.0003) treatments, respectively. CG treatment resulted in lower inorganic content (GI: p<0.05, GII: p<0.01, and GIII: p<0.01) and higher Ca/P ratios than laser etching (GI: p<0.001, GII: p<0.01, and GIII: p<0.01). The SEM photomicrographies revealed open (CG) and partially open dentin tubules (GI, GII, and GIII). MU-EDXRF mappings illustrated that acid etching created homogeneous distribution of inorganic content over dentin. Er:YAG laser etching (220 mJ) produced irregular elemental distribution and changed the stoichiometric proportions of hydroxyapatite, as showed by an increase of mineral content. Decreases and increases of mineral content in the MU-EDXRF images are correlated to holes and mounds, respectively, as found in SEM images. PMID- 23797900 TI - A specific cell-penetrating peptide induces apoptosis in SKOV3 cells by down regulation of Bcl-2. AB - Peptides are emerging as pharmaceutical agents in cancer therapy. The peptide, TLSGAFELSRDK (TLS) is a targeting ligand that can specifically triggers cellular uptake by binding to SKOV3 cells. Cell surface proteins and the C-terminal basic residues of the TLS are required for effective cell penetration, and the uptake process is energy-dependent. It inhibited the proliferation of SKOV3 cells and induced early-stage apoptosis by down-regulation of Bcl-2 expression mediated through a caspase-dependent pathway. The synergistic anti-proliferative effects of the peptide TLS and doxorubicin on SKOV3 cells were further investigated. Taken together, TLS, acting as a combination of a targeted ligand and a therapeutic agent, was a promising candidate for the development of peptide-based therapies in ovarian cancer. PMID- 23797899 TI - Divergence between human and murine peroxisome proliferator-activated receptor alpha ligand specificities. AB - Peroxisome proliferator-activated receptor alpha (PPARalpha) belongs to the family of ligand-dependent nuclear transcription factors that regulate energy metabolism. Although there exists remarkable overlap in the activities of PPARalpha across species, studies utilizing exogenous PPARalpha ligands suggest species differences in binding, activation, and physiological effects. While unsaturated long-chain fatty acids (LCFA) and their thioesters (long-chain fatty acyl-CoA; LCFA-CoA) function as ligands for recombinant mouse PPARalpha (mPPARalpha), no such studies have been conducted with full-length human PPARalpha (hPPARalpha). The objective of the current study was to determine whether LCFA and LCFA-CoA constitute high-affinity endogenous ligands for hPPARalpha or whether there exist species differences for ligand specificity and affinity. Both hPPARalpha and mPPARalpha bound with high affinity to LCFA-CoA; however, differences were noted in LCFA affinities. A fluorescent LCFA analog was bound strongly only by mPPARalpha, and naturally occurring saturated LCFA was bound more strongly by hPPARalpha than mPPARalpha. Similarly, unsaturated LCFA induced transactivation of both hPPARalpha and mPPARalpha, whereas saturated LCFA induced transactivation only in hPPARalpha-expressing cells. These data identified LCFA and LCFA-CoA as endogenous ligands of hPPARalpha, demonstrated species differences in binding specificity and activity, and may help delineate the role of PPARalpha as a nutrient sensor in metabolic regulation. PMID- 23797901 TI - Prevention of human papillomavirus-related malignancy: access is the answer. PMID- 23797902 TI - Fluorescent microscopy beyond diffraction limits using speckle illumination and joint support recovery. AB - Structured illumination microscopy (SIM) breaks the optical diffraction limit by illuminating a sample with a series of line-patterned light. Recently, in order to alleviate the requirement of precise knowledge of illumination patterns, structured illumination microscopy techniques using speckle patterns have been proposed. However, these methods require stringent assumptions of the speckle statistics: for example, speckle patterns should be nearly incoherent or their temporal average should be roughly homogeneous. Here, we present a novel speckle illumination microscopy technique that overcomes the diffraction limit by exploiting the minimal requirement that is common for all the existing super resolution microscopy, i.e. that the fluorophore locations do not vary during the acquisition time. Using numerical and real experiments, we demonstrate that the proposed method can improve the resolution up to threefold. Because our proposed method succeeds for standard fluorescence probes and experimental protocols, it can be applied in routine biological experiments. PMID- 23797903 TI - Role of meaning in the prediction of depressive symptoms among trauma-exposed and nontrauma-exposed emerging adults. AB - OBJECTIVES: This study investigated the role of searching for meaning, finding meaning, trauma exposure, and their interaction in the prediction of depressive symptoms among trauma-exposed and nontrauma-exposed emerging adults. METHOD: Eight thousand seven hundred and eighty-four college students (73% female; mean age of 19.8 years) completed self-report measures. Hierarchical regression analysis was conducted to evaluate the three-way interaction in the prediction of depressive symptoms. RESULTS: Searching for and finding meaning as well as the three-way interaction significantly contributed to the prediction of depression. Specifically, searching for meaning was associated with increased symptoms, irrespective of meaning levels among nontrauma-exposed and low frequency trauma exposed emerging adults. Among high frequency trauma-exposed individuals, an increase in the search-by-find meaning interaction predicted fewer symptoms. CONCLUSIONS: The findings suggest that searching for and finding meaning are important mechanisms in the prediction of depression among emerging adults facing daily stressors and traumatic events. Clinical implications are discussed. PMID- 23797904 TI - Emotional dampening in persons with elevated blood pressure: affect dysregulation and risk for hypertension. AB - BACKGROUND: Persons with higher blood pressure have emotional dampening in some contexts. This may reflect interactive changes in central nervous system control of affect and autonomic function in the early stages of hypertension development. PURPOSE: The purpose of this study is to determine the independence of cardiovascular emotional dampening from alexithymia to better understand the role of affect dysregulation in blood pressure elevations. METHODS: Ninety-six normotensives were assessed for resting systolic and diastolic (DBP) blood pressure, recognition of emotions in faces and sentences using the Perception of Affect Task (PAT), alexithymia, anxiety, and defensiveness. RESULTS: Resting DBP significantly predicted PAT emotion recognition accuracy in men after adjustment for age, self-reported affect, and alexithymia. CONCLUSIONS: Cardiovascular emotional dampening is independent of alexithymia and affect in men. Dampened emotion recognition could potentially influence interpersonal communication and psychosocial distress, thereby further contributing to BP dysregulation and increased cardiovascular risk. PMID- 23797906 TI - Identification of circulating microRNA signatures for breast cancer detection. AB - PURPOSE: There is a quest for novel noninvasive diagnostic markers for the detection of breast cancer. The goal of this study is to identify circulating microRNA (miRNA) signatures using a cohort of Asian Chinese patients with breast cancer, and to compare miRNA profiles between tumor and serum samples. EXPERIMENTAL DESIGN: miRNA from paired breast cancer tumors, normal tissue, and serum samples derived from 32 patients were comprehensively profiled using microarrays or locked nucleic acid real-time PCR panels. Serum samples from healthy individuals (n = 22) were also used as normal controls. Significant serum miRNAs, identified by logistic regression, were validated in an independent set of serum samples from patients (n = 132) and healthy controls (n = 101). RESULTS: The 20 most significant miRNAs differentially expressed in breast cancer tumors included miRNA (miR)-21, miR-10b, and miR-145, previously shown to be dysregulated in breast cancer. Only 7 miRNAs were overexpressed in both tumors and serum, suggesting that miRNAs may be released into the serum selectively. Interestingly, 16 of the 20 most significant miRNAs differentially expressed in serum samples were novel. MiR-1, miR-92a, miR-133a, and miR-133b were identified as the most important diagnostic markers, and were successfully validated; receiver operating characteristic curves derived from combinations of these miRNAs exhibited areas under the curves of 0.90 to 0.91. CONCLUSION: The clinical use of miRNA signatures as a noninvasive diagnostic strategy is promising, but should be further validated for different subtypes of breast cancers. PMID- 23797905 TI - An imbalance between excitatory and inhibitory neurotransmitters in amyotrophic lateral sclerosis revealed by use of 3-T proton magnetic resonance spectroscopy. AB - IMPORTANCE: A lack of neuroinhibitory function may result in unopposed excitotoxic neuronal damage in amyotrophic lateral sclerosis (ALS). OBJECTIVE: To determine whether there are reductions in gamma-aminobutyric acid (GABA) levels and elevations in glutamate-glutamine (Glx) levels in selected brain regions of patients with ALS by use of proton magnetic resonance spectroscopy. DESIGN: Case control study using short echo time and GABA-edited proton magnetic resonance spectroscopy at 3 T with regions of interest in the left motor cortex, left subcortical white matter, and pons; data analyzed using logistic regression, t tests, and Pearson correlations; and post hoc analyses performed to investigate differences between riluzole-naive and riluzole-treated patients with ALS. SETTING: Tertiary referral center. PARTICIPANTS: Twenty-nine patients with ALS and 30 age- and sex-matched healthy controls. EXPOSURE: Fifteen patients were taking 50 mg of riluzole twice a day as part of their routine clinical care for ALS. MAIN OUTCOMES AND MEASURES: Levels of GABA, Glx, choline (a marker of cell membrane turnover), creatine (a marker of energy metabolism), myo-inositol (a marker of glial cells), and N-acetylaspartate (a marker of neuronal integrity). RESULTS: Patients with ALS had significantly lower levels of GABA in the motor cortex than did healthy controls (P < .01). Patients with ALS also had significantly lower levels of N-acetylaspartate in the motor cortex (P < .01), subcortical white matter (P < .05), and pons (P < .01) and higher levels of myo inositol in the motor cortex (P < .001) and subcortical white matter (P < .01) than did healthy controls. Riluzole-naive patients with ALS had higher levels of Glx than did riluzole-treated patients with ALS (P < .05 for pons and motor cortex) and healthy controls (P < .05 for pons and motor cortex). Riluzole-naive patients with ALS had higher levels of creatine in the motor cortex (P < .001 for both comparisons) and subcortical white matter (P <= .05 for both comparisons) than did riluzole-treated patients with ALS and healthy controls. Riluzole-naive patients with ALS had higher levels of N-acetylaspartate in the motor cortex than did riluzole-treated patients with ALS (P < .01). CONCLUSIONS AND RELEVANCE: There are reduced levels of GABA in the motor cortex of patients with ALS. There are elevated levels of Glx in riluzole-naive patients with ALS compared with riluzole-treated patients with ALS and healthy controls. These results point to an imbalance between excitatory and inhibitory neurotransmitters as being important in the pathogenesis of ALS and an antiglutamatergic basis for the effects of riluzole, although additional research efforts are needed. PMID- 23797907 TI - Molecular pathways: YAP and TAZ take center stage in organ growth and tumorigenesis. AB - The evolution of a solid tumor is fueled by genetic aberrations. Yet, the tumor environment often dominates over the effects of genetics: normal tissues have powerful tumor-suppressive properties that constantly tame or eliminate cells carrying transforming mutations. Critical elements of such a suppressive microenvironment are structural characteristics of normal cells and tissues, such as cell polarity, attachment to the extracellular matrix (ECM), and epithelial organization. Once these tissue-level checkpoints have been overcome, tumor growth is enhanced by recruitment of stromal cells and remodeling of the ECM. Genetic inactivation in mouse models indicates the Hippo pathway as a fundamental inhibitor of organ growth during development and as a critical tumor suppressor in epithelial tissues, such as the liver, skin, and ovaries, and soft tissues. At the centerpiece of this pathway lie two related transcriptional coactivators, YAP and TAZ, that promote tissue proliferation and the self-renewal of normal and cancer stem cells, and incite metastasis. Strikingly, YAP and TAZ are controlled by the same architectural features that first inhibit and then foster cancer growth, such as ECM elasticity, cell shape, and epithelial-to-mesenchymal transition. These findings open unexpected opportunities for the development of new cancer therapeutics targeting key YAP/TAZ regulatory inputs such as Wnt signaling, cytoskeletal contractility, G-protein-coupled receptors, or YAP/TAZ regulated transcription. PMID- 23797908 TI - Use, analysis, and regulation of pesticides in natural extracts, essential oils, concretes, and absolutes. AB - Natural extracts used by the fragrance and cosmetics industries, namely essential oils, concretes, resinoids, and absolutes, are produced from natural raw materials. These are often cultivated by use of monoculture techniques that involve the use of different classes of xenobiotica, including pesticides. Because of these pesticides' potential effect on public health and the environment, laws regarding permitted residual levels of pesticides used in cultivation of raw materials for fragrance and cosmetic products are expected to become stricter. The purpose of this review is to present and classify pesticides commonly used in the cultivation of these natural raw materials. We will summarize the most recent regulations, and discuss publications on detection of pesticides via chemical analysis of raw natural extracts. Advances in analytical chemistry for identification and quantification of pesticides will be presented, including both sample preparation and modern separation and detection techniques, and examples of the identification and quantification of individual pesticides present in natural extracts, for example essential oils, will be provided. PMID- 23797909 TI - Increasing the depth of mass spectrometry-based glycomic coverage by additional dimensions of sulfoglycomics and target analysis of permethylated glycans. AB - Hog or porcine gastric mucin resembles the human source in carrying not only blood group antigens but also the rather rare alpha4-GlcNAc-capped terminal epitope functionally implicated in protection against Helicobacter pylori infection. Being more readily available and reasonably well characterized, it serves as a good reagent for immunobiological studies, as well as a standard for analytical methodology developments. Current approaches in mass spectrometry (MS) based glycomic mapping remain vastly inadequate in revealing the full complexity of glycosylation, particularly for cases such as the extremely heterogeneous O glycosylation of mucosal mucins that can be further sulfated. We demonstrate here a novel concerted workflow that extends the conventional matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS) mapping of permethylated glycans in positive ion mode to include a further step of sulfoglycomic analysis in negative ion mode. This was facilitated by introducing a mixed-mode solid phase extraction step, which allows direct cleanup and simultaneous fractionation of the permethylated glycans into separate non-sulfated and sulfated pools in one single step. By distinct MALDI-MS/MS fragmentation patterns, all previously known structural features of porcine gastric mucin including the terminal epitopes and location of sulfates could be readily defined. We additionally showed that both arms of the core 2 structures could be extended via 6-O-sulfated GlcNAc to yield a series of disulfated O-glycans not previously reported, thus expanding its current glycomic coverage. However, a targeted LC-MSn analysis was required and best suited to dig even deeper into validating the occurrence of very minor structural isomers carrying the Lewis Y epitope implicated by positive antibody binding. PMID- 23797910 TI - In silico and in vitro metabolism studies support identification of designer drugs in human urine by liquid chromatography/quadrupole-time-of-flight mass spectrometry. AB - Human phase I metabolism of four designer drugs, 2-desoxypipradrol (2-DPMP), 3,4 dimethylmethcathinone (3,4-DMMC), alpha-pyrrolidinovalerophenone (alpha-PVP), and methiopropamine (MPA), was studied using in silico and in vitro metabolite prediction. The metabolites were identified in drug abusers' urine samples using liquid chromatography/quadrupole-time-of-flight mass spectrometry (LC/Q-TOF/MS). The aim of the study was to evaluate the ability of the in silico and in vitro methods to generate the main urinary metabolites found in vivo. Meteor 14.0.0 software (Lhasa Limited) was used for in silico metabolite prediction, and in vitro metabolites were produced in human liver microsomes (HLMs). 2-DPMP was metabolized by hydroxylation, dehydrogenation, and oxidation, resulting in six phase I metabolites. Six metabolites were identified for 3,4-DMMC formed via N demethylation, reduction, hydroxylation, and oxidation reactions. alpha-PVP was found to undergo reduction, hydroxylation, dehydrogenation, and oxidation reactions, as well as degradation of the pyrrolidine ring, and seven phase I metabolites were identified. For MPA, the nor-MPA metabolite was detected. Meteor software predicted the main human urinary phase I metabolites of 3,4-DMMC, alpha PVP, and MPA and two of the four main metabolites of 2-DPMP. It assisted in the identification of the previously unreported metabolic reactions for alpha-PVP. Eight of the 12 most abundant in vivo phase I metabolites were detected in the in vitro HLM experiments. In vitro tests serve as material for exploitation of in silico data when an authentic urine sample is not available. In silico and in vitro designer drug metabolism studies with LC/Q-TOF/MS produced sufficient metabolic information to support identification of the parent compound in vivo. PMID- 23797911 TI - Impressions of the Indiana Global Health Research Conference: an editor's account. PMID- 23797912 TI - Bringing big data to personalized healthcare: a patient-centered framework. AB - Faced with unsustainable costs and enormous amounts of under-utilized data, health care needs more efficient practices, research, and tools to harness the full benefits of personal health and healthcare-related data. Imagine visiting your physician's office with a list of concerns and questions. What if you could walk out the office with a personalized assessment of your health? What if you could have personalized disease management and wellness plan? These are the goals and vision of the work discussed in this paper. The timing is right for such a research direction--given the changes in health care, reimbursement, reform, meaningful use of electronic health care data, and patient-centered outcome mandate. We present the foundations of work that takes a Big Data driven approach towards personalized healthcare, and demonstrate its applicability to patient centered outcomes, meaningful use, and reducing re-admission rates. PMID- 23797913 TI - Taking stock of the ethical foundations of international health research: pragmatic lessons from the IU-Moi Academic Research Ethics Partnership. AB - It is a sine qua non that research and health care provided in international settings raise profound ethical questions when different cultural and political values are implicated. Yet ironically, as international health research expands and as research on ethical issues in international health research broadens and deepens, we appear to have moved away from discussing the moral foundations of these activities. For international health research to thrive and lead to the kind of benefits it is capable of, it is helpful to occasionally revisit the foundational premises that justify the enterprise as a whole. We draw on the experience of the Indiana University-Moi University Academic Research Ethics Partnership, an innovative bioethics training program co-located in Indianapolis and Eldoret, Kenya to highlight the changing nature of ethical issues in international health research and the ongoing practical challenges. PMID- 23797914 TI - The global role of health care delivery science: learning from variation to build health systems that avoid waste and harm. AB - This paper addresses the fourth theme of the Indiana Global Health Research Working Conference, Clinical Effectiveness and Health Systems Research. It explores geographic variation in health care delivery and health outcomes as a source of learning how to achieve better health outcomes at lower cost. It focuses particularly on the relationship between investments made in capacities to deliver different health care services to a population and the value thereby created by that care for individual patients. The framing begins with the dramatic variation in per capita health care expenditures across the nations of the world, which is largely explained by variations in national wealth. The 1978 Declaration of Alma Ata is briefly noted as a response to such inequities with great promise that has not as yet been realized. This failure to realize the promise of Alma Ata grows in significance with the increasing momentum for universal health coverage that is emerging in the current global debate about post-2015 development goals. Drawing upon work done at Dartmouth over more than three decades, the framing then turns to within-country variations in per capita expenditures, utilization of different services, and health outcomes. A case is made for greater attention to the question of value by bringing better information to bear at both the population and individual levels. Specific opportunities to identify and reduce waste in health care, and the harm that is so often associated with it, are identified by learning from outcome variations and practice variations. PMID- 23797915 TI - Laboratory support of global health research. AB - Laboratory generated data are used in support of several types of global health research. Routinely obtained clinical diagnostic data are used for disease surveillance, epidemiologic analysis of frequencies and trends, health outcomes research, and sponsored research projects. Clinical data from research laboratories is also collected in support of sponsored research projects. Whether the initial purpose of the testing is in support of research protocols or the data are retrospectively reviewed, the quality of the laboratory data is essential to drawing correct conclusions. The types and use of data generated by on-site, routine diagnostic, research diagnostic and basic science laboratories will be described, with a focus on quality-related issues. Full integration of laboratory management as a partner is essential to successful research planning and execution. PMID- 23797916 TI - "These are good problems to have...": establishing a collaborative research partnership in East Africa. AB - In the context of a long-term institutional 'twinning' partnership initiated by Indiana and Moi Universities more than 22 years ago, a vibrant program of research has arisen and grown in size and stature. The history of the AMPATH (Academic Model Providing Access to Healthcare) Research Program is described, with its distinctive attention to Kenyan-North American equity, mutual benefit, policies that support research best practices, peer review within research working groups/cores, contributions to clinical care, use of healthcare informatics, development of research infrastructure and commitment to research workforce capacity. In the development and management of research within our partnership, we describe a number of significant challenges we have encountered that require ongoing attention, many of which are "good problems" occasioned by the program's success and growth. Finally, we assess the special value a partnership program like ours has created and end by affirming the importance of organizational diversity, solidarity of purpose, and resilience in the 'research enterprise.' PMID- 23797917 TI - More than a walk in the park: The Indiana Global Health Research meeting. AB - The Indiana Global Health Research Working Conference of October 2012 was convened by a planning committee representing Indiana's research-intensive universities (Indiana University, Purdue University,and the University of Notre Dame). The event was organized as an open-space meeting with six thematic emphases and pre-conference keynote papers. Within their domains of common interest, attendees developed for me fruste research project abstracts that represent a future-oriented agenda for global health research. The organizational principles and purposes of this meeting are explicated with a concluding commentary on the agenda for research. PMID- 23797918 TI - Capsule Commentary on Percac-Lima et al., Decreasing Disparities in Breast Cancer Screening in Refugee Women Using Culturally-tailored Patient Navigation. PMID- 23797919 TI - Capsule commentary on Betz et al., "I wish we could normalize driving health": a qualitative study of clinician discussions with older drivers. PMID- 23797920 TI - The impact of neighborhood socioeconomic status and race on the prescribing of opioids in emergency departments throughout the United States. AB - BACKGROUND: Racial and ethnic disparities in opioid prescribing in the emergency department (ED) are well described, yet the influence of socioeconomic status (SES) remains unclear. OBJECTIVES: (1) To examine the effect of neighborhood SES on the prescribing of opioids for moderate to severe pain; and (2) to determine if racial disparities in opioid prescribing persist after accounting for SES. DESIGN: We used cross-sectional data from the National Hospital Ambulatory Medical Care Survey between 2006 and 2009 to examine the prescribing of opioids to patients presenting with moderate to severe pain (184 million visits). We used logistic regression to examine the association between the prescribing of opioids, SES, and race. Models were adjusted for age, sex, pain-level, injury status, frequency of emergency visits, hospital type, and region. MAIN MEASURES: Our primary outcome measure was whether an opioid was prescribed during a visit for moderate to severe pain. SES was determined based on income, percent poverty, and educational level within a patient's zip code. RESULTS: Opioids were prescribed more frequently at visits from patients of the highest SES quartile compared to patients in the lowest quartile, including percent poverty (49.0 % vs. 39.4 %, P<0.001), household income (47.3 % vs. 40.7 %, P<0.001), and educational level (46.3 % vs. 42.5 %, P=0.01). Black patients were prescribed opioids less frequently than white patients across all measures of SES. In adjusted models, black patients (AOR 0.73; 95 % CI 0.66-0.81) and patients from poorer areas (AOR 0.76; 95 % CI 0.68-0.86) were less likely to receive opioids after accounting for pain-level, age, injury-status, and other covariates. CONCLUSIONS: Patients presenting to emergency departments from lower SES regions were less likely to receive opioids for equivalent levels of pain than those from more affluent areas. Black and Hispanic patients were also less likely to receive opioids for equivalent levels of pain than whites, independent of SES. PMID- 23797921 TI - Specialty, Political Affiliation, and Perceived Social Responsibility Are Associated with U.S. Physician Reactions to Health Care Reform Legislation. AB - BACKGROUND: Little is known about how U.S. physicians' political affiliations, specialties, or sense of social responsibility relate to their reactions to health care reform legislation. OBJECTIVE: To assess U.S. physicians' impressions about the direction of U.S. health care under the Affordable Care Act (ACA), whether that legislation will make reimbursement more or less fair, and examine how those judgments relate to political affiliation and perceived social responsibility. DESIGN: A cross-sectional, mailed, self-reported survey. PARTICIPANTS: Simple random sample of 3,897 U.S. physicians. MAIN MEASURES: Views on the ACA in general, reimbursement under the ACA in particular, and perceived social responsibility. KEY RESULTS: Among 2,556 physicians who responded (RR2: 65 %), approximately two out of five (41 %) believed that the ACA will turn U.S. health care in the right direction and make physician reimbursement less fair (44 %). Seventy-two percent of physicians endorsed a general professional obligation to address societal health policy issues, 65 % agreed that every physician is professionally obligated to care for the uninsured or underinsured, and half (55 %) were willing to accept limits on coverage for expensive drugs and procedures for the sake of expanding access to basic health care. In multivariable analyses, liberals and independents were both substantially more likely to endorse the ACA (OR 33.0 [95 % CI, 23.6-46.2]; OR 5.0 [95 % CI, 3.7-6.8], respectively), as were physicians reporting a salary (OR 1.7 [95 % CI, 1.2-2.5]) or salary plus bonus (OR 1.4 [95 % CI, 1.1-1.9) compensation type. In the same multivariate models, those who agreed that addressing societal health policy issues are within the scope of their professional obligations (OR 1.5 [95 % CI, 1.0-2.0]), who believe physicians are professionally obligated to care for the uninsured / under-insured (OR 1.7 [95 % CI, 1.3-2.4]), and who agreed with limiting coverage for expensive drugs and procedures to expand insurance coverage (OR 2.3 [95 % CI, 1.8-3.0]), were all significantly more likely to endorse the ACA. Surgeons and procedural specialists were less likely to endorse it (OR 0.5 [95 % CI, 0.4-0.7], OR 0.6 [95 % CI, 0.5-0.9], respectively). CONCLUSIONS: Significant subsets of U.S. physicians express concerns about the direction of U.S. health care under recent health care reform legislation. Those opinions appear intertwined with political affiliation, type of medical specialty, as well as perceived social responsibility. PMID- 23797922 TI - Physician trainees' interactions with the pharmaceutical industry. PMID- 23797923 TI - [Colonic amoebiasis simulating a cecal tumor: case report]. AB - Colonic ameboma is a rare inflammatory pseudo-tumor of the colon that can mimic cancer development. This case was located in the cecum and appeared malignant from a macroscopic view. Accordingly a right hemicolectomy was performed, followed by an end-to-side ileocolic anastomosis. The pathology study enabled us to correct the diagnosis and affirm its amebic origin. PMID- 23797925 TI - Influence of malocclusion on social perceptions of adolescents at public and private schools. AB - OBJECTIVE: To determine whether malocclusion influences adolescents' perception when judging their colleagues from the aspects of athletics, social and health status, leadership and academic skills. METHODOLOGY: Front view photographs of the smile of eight adolescent volunteers (non-ideal smile) were altered to create an image with aligned teeth (ideal smile). Two parallel groups were programmed with the subjects' photographs. When the image of an ideal smile of one of the subjects appeared in one of the groups, the image of the non-ideal appeared in the other. Two hundred adolescents were evaluators, half of the students being from private and half from public schools. They classified the group images indicating their social perception with respect to skills in sports, leadership, academic activities, popularity and the health conditions of each subject. RESULTS: The majority of photographs of subjects with an ideal smile were evaluated as being better when compared with photographs of the non-ideal smile. The differences in the evaluations between the ideal and non-ideal smiles were significant for the perception of popularity, intelligence, leadership capability and health, differently from the performance in sports, as this aspect did not attain statistical relevance. CONCLUSIONS: Malocclusion has influence on the perception of adolescents of different social levels when judging youngsters with or without malocclusion from the aspects of athletics, social and health status, leadership and academic skills. PMID- 23797926 TI - Aetiology of molar-incisor hypomineralisation (MIH) in Brazilian children. AB - AIM: To determine the potential aetiological factors related to molar-incisor hypomineralisation (MIH) in Brazilian children. METHODS: A total of 1,151 children aged 7-12 years (mean 8.86 +/- 1.28), born and living in the urban area of Araraquara, Brazil, were examined by two examiners evaluating the presence of MIH according to criteria suggested by the European Academy of Paediatric Dentistry (2003). Their mothers completed a structured questionnaire about medical history, from pregnancy to the first 3 years of the children's life. Descriptive analyses of data and odds ratios (OR) with 95 % test-based confidence intervals (CI) were estimated. Chi-square test was used to evaluate the differences between groups. RESULTS: The prevalence of MIH in the children was 12.3 %. The interviewing response rate was 90.4 %. The prevalence of miscarriage history (25 vs. 15.4 %; OR = 1.21; 95 % CI 0.30-4.92) and occurrence of anaemia (23 vs. 12.4 %; OR = 2.07; 95 % CI 0.50-8.63) were higher in mothers from MIH group than those from non-MIH group. However, these associations were not statically significant. In the children's medical history, rhinitis, bronchitis (56.5 vs. 52.5 %; OR = 1.17; 95 % CI 0.82-1.68), and high fever (20.4 vs. 18.2 %; OR = 1.14; 0.73-1.76) were more prevalent in MIH group, but there were no significant differences between the groups (p > 0.05). CONCLUSIONS: No possible aetiological factor investigated was associated with MIH. Prospective studies are needed to define the aetiological factors involved with MIH. PMID- 23797927 TI - Bone-like material growth in a replanted immature central incisor following avulsion. AB - BACKGROUND: Avulsion is one of the most complicated types of trauma to the teeth. After replantation of an avulsed immature tooth, numerous pulpo-dentinal responses may occur. CASE REPORT: This study reports a case of a seven-and-a-half year-old boy in whom an immature maxillary permanent central incisor was replanted following avulsion due to a fall from a tree, and a bone-like growth was observed in the pulp chamber 6 months after the trauma, with a thin radiolucent line on the inner surface of the dentinal walls. The bone-like structure eventually filled the pulp chamber of the tooth. FOLLOW-UP: The tooth was followed up 4 years after the replantation with no evidence of pathology. CONCLUSION: This case demonstrates an immature avulsed tooth which did not present positive vital signs, but still maintains the potential of survival, and endodontic intervention may not be required. Instead, follow-up visits are recommended as long as there are no pathologic signs, especially in teeth with questionable prognosis. PMID- 23797929 TI - The effect of range of motion after single-level discover cervical artificial disk replacement. AB - STUDY DESIGN: A biomechanical study of cervical artificial disk replacement (CADR). OBJECTIVE: This study aimed to investigate the range of motion (ROM) of the treated segment, the ROM of the adjacent segments, the global ROM in the sagittal plane, and the total neck ROM in the 3 cardinal planes after single level Discover CADR. SUMMARY OF BACKGROUND DATA: CADR could theoretically preserve the motion function of the treated segment without affecting the adjacent segments significantly. Although previous studies have reported excellent clinical outcomes and ROM of the treated segment after CADR, few studies have focused on the ROM of the adjacent segments, the global ROM, and the total neck motion. METHODS: C5/6 Discover CADR was performed in 58 patients (37 male and 21 female) between September 2008 and September 2010. Anteroposterior, lateral, and flexion-extension lateral radiographies were performed before operation and at the 1-year follow-up. Clinical parameters, including the Japanese orthopedic association score, the neck disability index, and the visual analogue scale, were evaluated. The ROM of the treated segment (C5/6) and the adjacent segments (C4/5 and C6/7) and the global ROM (C2/7) were measured by radiography. To evaluate the total neck ROM, the cervical ROM device was advocated. Preoperative and postoperative data were compared using the paired t test. RESULTS: The Japanese orthopedic association score was 14.3 at the 1-year follow-up as compared with the preoperative score of 8.7. Other scoring systems had improved postoperatively, including the neck disability index from 85.1 to 68.6 and the visual analogue scale from 7.8 to 3.3. Compared with the preoperative ROM, the postoperative ROM increased by 3.0 degrees (27.0%) in C5/6, 1.3 degrees (13.7%) in C4/5, and 1.8 degrees (17.6%) in C6/7. The postoperative global ROM also increased by 6.7 degrees (15.2%) compared with preoperative global data. Compared with the preoperative total neck motion, the postoperative total neck motion increased by 8.3 degrees (9.3%) in the sagittal plane and 6.1 degrees (7.7%) in the coronal plane. There was an insignificant increase of 0.8 degrees (0.6%) in the horizontal plane. CONCLUSIONS: This study demonstrated that the single-level Discover CADR increased the ROM of the treated segment and the adjacent segments. There was also an increase in the global ROM and the total neck motion in the sagittal and the coronal planes, although there was no significant difference in the horizontal plane before and after operation. PMID- 23797928 TI - Effects of mitiglinide, a short-acting insulin secretagogue, on daily glycemic variability and oxidative stress markers in Japanese patients with type 2 diabetes mellitus. AB - BACKGROUND AND OBJECTIVE: The objective of this study was to clarify the effects of mitiglinide on daily glycemic variability and oxidative stress markers in outpatients with type 2 diabetes mellitus that is insufficiently controlled by diet and/or non-insulin secretagogues. METHODS: We enrolled 24 patients with type 2 diabetes whose glycemic control had been suboptimal [i.e. glycosylated hemoglobin (HbA(1c)) >= 6.9 %]. The patients were treated with mitiglinide 10 mg three times daily for 16 weeks. If their glycemic control was not improved at week 8, the dose of mitiglinide was increased to 20 mg three times daily. Daily glycemic variability was assessed by 7-point self-monitoring of blood glucose for 2 days, and standard deviation (SD), M value, and mean of daily differences(MODD) were calculated. Oxidative stress was assessed by oxidized low-density lipoprotein, pentosidine,urinary 8-iso-prostaglandin F2 alpha, and urinary 8 hydroxydeoxy guanosine. RESULTS: After 16 weeks of mitiglinide treatment, the HbA(1c) level was significantly decreased (mean +/- SD,7.4 +/- 0.7 to 6.8 +/- 0.5 %, P < 0.0001). Postprandial glucose excursion and glycemic variability were also significantly improved after mitiglinide treatment (all P < 0.05). The reductions in SD, M value, and MODD were 17, 50,and 48 %, respectively. There was a significant positive correlation between the change in HbA(1c) and change in SD during the study (r = 0.454, P = 0.03). There were no significant changes in oxidative stress markers. CONCLUSIONS: The present study supports the notion that mitiglinide improves postprandial glucose excursion and HbA(1c) level in patients with type 2 diabetes. In addition,we demonstrated that mitiglinide also effectively improves daily glycemic variability. The effect of mitiglinide on oxidative stress needs further investigation. PMID- 23797930 TI - Chemical ecology mediated by fungal endophytes in grasses. AB - Defensive mutualism is widely accepted as providing the best framework for understanding how seed-transmitted, alkaloid producing fungal endophytes of grasses are maintained in many host populations. Here, we first briefly review current knowledge of bioactive alkaloids produced by systemic grass-endophytes. New findings suggest that chemotypic diversity of the endophyte-grass symbiotum is far more complex, involving multifaceted signaling and chemical cross-talk between endophyte and host cells (e.g., reactive oxygen species and antioxidants) or between plants, herbivores, and their natural enemies (e.g., volatile organic compounds, and salicylic acid and jasmonic acid pathways). Accumulating evidence also suggests that the tight relationship between the systemic endophyte and the host grass can lead to the loss of grass traits when the lost functions, such as plant defense to herbivores, are compensated for by an interactive endophytic fungal partner. Furthermore, chemotypic diversity of a symbiotum appears to depend on the endophyte and the host plant life histories, as well as on fungal and plant genotypes, abiotic and biotic environmental conditions, and their interactions. Thus, joint approaches of (bio)chemists, molecular biologists, plant physiologists, evolutionary biologists, and ecologists are urgently needed to fully understand the endophyte-grass symbiosis, its coevolutionary history, and ecological importance. We propose that endophyte-grass symbiosis provides an excellent model to study microbially mediated multirophic interactions from molecular mechanisms to ecology. PMID- 23797931 TI - Priming of anti-herbivore defense in tomato by arbuscular mycorrhizal fungus and involvement of the jasmonate pathway. AB - Mycorrhizas play a vital role in soil fertility, plant nutrition, and resistance to environmental stresses. However, mycorrhizal effects on plant resistance to herbivorous insects and the related mechanisms are poorly understood. This study evaluated effects of root colonization of tomato (Solanum lycopersicum Mill.) by arbuscular mycorrhizal fungi (AMF) Glomus mosseae on plant defense responses against a chewing caterpillar Helicoverpa arimigera. Mycorrhizal inoculation negatively affected larval performance. Real time RT-PCR analyses showed that mycorrhizal inoculation itself did not induce transcripts of most genes tested. However, insect feeding on AMF pre-inoculated plants resulted in much stronger defense response induction of four defense-related genes LOXD, AOC, PI-I, and PI II in the leaves of tomato plants relative to non-inoculated plants. Four tomato genotypes: a wild-type (WT) plant, a jasmonic acid (JA) biosynthesis mutant (spr2), a JA-signaling perception mutant (jai1), and a JA-overexpressing 35S::PS plant were used to determine the role of the JA pathway in AMF-primed defense. Insect feeding on mycorrhizal 35S::PS plants led to higher induction of defense related genes relative to WT plants. However, insect feeding on mycorrhizal spr2 and jai1 mutant plants did not induce transcripts of these genes. Bioassays showed that mycorrhizal inoculation on spr2 and jai1 mutants did not change plant resistance against H. arimigera. These results indicates that mycorrhizal colonization could prime systemic defense responses in tomato upon herbivore attack, and that the JA pathway is involved in defense priming by AMF. PMID- 23797932 TI - Evaluation of three different surgical approaches in repairing paravaginal support defects: a comparative trial. AB - OBJECTIVES: Paravaginal defects have been shown to account for 60-80% of anterior compartment prolapse and its repair offers the chance of a more effective cure of such defect. There is no good evidence to suggest the superiority of a particular route of paravaginal repair. The objective of this study was to evaluate the effectiveness of abdominal (APVR), vaginal (VPVR) and laparoscopic (LPVR) approaches in the repair of such defects. STUDY DESIGN: This is a prospective comparative study of patients, referred over a 2-year period, with symptomatic stage II-IV anterior compartment prolapse due to paravaginal support defects. Patients were assessed subjectively by direct verbal questioning, and objectively, using POP-Q system for staging, at 1, 6 and 12 months postoperatively. Analysis of data was performed using SPSS for Windows (V9) software package. RESULTS: Forty-five patients were recruited to the study. There was no significant difference in the subjective and objective outcomes of APVR (n = 20) and VPVR (n = 20) groups. The laparoscopic approach had to be abandoned after five patients only, as the degree of improvement in prolapse stage was less than in the other two approaches. CONCLUSION: The effectiveness of paravaginal repair procedure is similar whether the abdominal or vaginal approaches were adopted in patients with anterior compartment prolapse due to paravaginal support defects. In our experience, the laparoscopic approach was associated with the least favourable outcome. PMID- 23797933 TI - The use of different size-hysteroscope in office hysteroscopy: our experience. AB - PURPOSE: To evaluate the successful rate and patient acceptance of different sized hysteroscope in office hysteroscopy. METHODS: We retrospectively evaluated 900 office hysteroscopy performed in ambulatory setting using three different hysteroscopes: 5 mm Hamou II (n = 300), 5 mm Bettocchi (n = 300) and 4 mm Bettocchi (n = 300). Endpoints of our study were the successful rate of hysteroscopy, the eventual side effects/complication and the pain intensity experience from the patients using visual analog scale (VAS). RESULTS: Use of 4 mm Bettocchi leads to a higher rate of successfully performed hysteroscopy (99%, n = 297) and statistically significant when compared to the 5 mm Hamou (95%, n = 285) and to the 5 mm Bettocchi (96%, n = 288) (4 mm Bettocchi vs. 5 mm Bettocchi p < 0.05; 4 mm Bettocchi vs. 5 mm Hamou II p < 0,001; 5 mm Bettocchi vs. 5 mm Hamou II ns). Moreover, the VAS score was higher using 5 mm Hamou II (5.72 +/- 1.99) and statistically significant when compared to the 4 mm Bettocchi (3.06 +/- 2.14) and to the 5 mm Bettocchi (4.27 +/- 1.88) (A vs. B p < 0.05; A vs. C p < 0.001; B vs. C p < 0.001). CONCLUSIONS: Our result suggests that the hysteroscope size plays a pivotal role in the acceptance and for the success of office hysteroscopy. PMID- 23797934 TI - Fostering innovation in health promotion research: the critical role of the IUHPE. PMID- 23797935 TI - The call to action: health promotion in The Gambia - closing the implementation gap? AB - This paper discusses the difficulties facing the development of health promotion in The Gambia, and in 'closing the implementation gap' noted by the WHO 7(th) Global Conference on Health Promotion (2009, Nairobi). The Gambia has achieved a great deal so far, but health promotion as a discipline has not really informed the development of its approach to health. There is not a central concern with determinants of health and tackling health inequalities and there is no well developed health promotion infrastructure. The difficulties facing sub-Saharan Africa generally can be extrapolated from the paper, with the conclusion that sub Saharan Africa faces many disease and health challenges not experienced by richer countries and thus not only does the discourse of health promotion need to take this into account, but also the basic needs of Africa need to be placed at the forefront. PMID- 23797936 TI - Everyday life and health concepts among blue-collar female workers in Denmark: implications for health promotion aiming at reducing health inequalities. AB - This article introduces a perspective on the health of women with low levels of education in terms of organisation of their everyday life. The aim is to demonstrate the ways in which the women's concept of health is contingent on the conditions encountered in everyday life. A qualitative study based on interviews with the women forms the basis for the discussion. The analysis shows that the women find it difficult to adopt the official discourse on health and its foundation in a biomedical tradition. The article argues that it is necessary to move away from the educational approach focusing on risk and lifestyle with the goal of regulating individual behaviour. Instead, an approach is suggested which can provide the women with the opportunity to gain control of the everyday health determinants which are normally beyond their immediate reach. This is based on the argument that it is necessary to work with a health promotion and education strategy capable of operating within the various interactive patterns between 'environment' and 'individual' which form the foundation for health. PMID- 23797937 TI - Beyond the accolades: a postcolonial critique of the foundations of the Ottawa Charter. AB - INTRODUCTION: The Ottawa Charter is undeniably of pivotal importance in the history of ideas associated with the establishment of health promotion. There is much to applaud in a charter which responds to the need to take action on the social and economic determinants of health and which seeks to empower communities to be at the centre of this. Such accolades tend to position the Ottawa Charter as 'beyond critique'; a taken-for-granted 'given' in the history of health promotion. In contrast, we argue it is imperative to critically reflect on its 'manufacture' and assess the possibility that certain voices have been privileged, and others marginalized. METHODS: This paper re-examines the 1986 Ottawa Conference including its background papers from a postcolonial standpoint. We use critical discourse analysis as a tool to identify the enactment of power within the production of the Ottawa health promotion discourse. This exercise draws attention to both the power to ensure the dominant presence of privileged voices at the conference as well as the discursive strategies deployed to 'naturalize' the social order of inequality. RESULTS: Our analysis shows that the discourse informing the development of the Ottawa Charter strongly reflected Western/colonizer centric worldviews, and actively silenced the possibility of countervailing Indigenous and developing country voices. CONCLUSION: The Ottawa Charter espouses principles of participation, empowerment and social justice. We question then whether the genesis of the Ottawa Charter lives up to its own principles of practice. We conclude that reflexive practice is crucial to health promotion, which ought to include a preparedness for health promotion to more critically acknowledge its own history. PMID- 23797938 TI - The salutogenic model of health in health promotion research. AB - Despite health promotion's enthusiasm for the salutogenic model of health, researchers have paid little attention to Antonovsky's central ideas about the ease/dis-ease continuum, defined in terms of 'breakdown' (the severity of pain and functional limitations, and the degree medical care is called for, irrespective of specific diseases). Rather, salutogenesis research has a strong focus on how sense of coherence relates to a wide range of specific diseases and illness endpoints. We address two questions: Why has Antonovsky's health concept failed to stimulate research on breakdown, and how can the present emphasis on disease be complemented by an emphasis on positive well-being in the salutogenic model? We show that (i) the breakdown concept of health as specified by Antonovsky is circular in definition, (ii) it is not measured on the 'required' ease/dis-ease continuum, (iii) it is not measureable by any validated or reliability-tested assessment tool, and (iv) it has not so much been rejected by health promotion, as it has not been considered at all. We show that Antonovsky came to view breakdown as but one aspect of well-being. He was open to the idea of well-being as something more positive than the absence of pain, suffering and need for medical care. We suggest ways to move salutogenesis research in the direction of well-being in its positive sense. PMID- 23797939 TI - Reducing social inequities in health through settings-related interventions -- a conceptual framework. AB - INTRODUCTION: The creation of supportive environments for health is a basic action principle of health promotion, and equity is a core value. A settings approach offers an opportunity to bridge these two, with its focus on the interplay between individual, environmental and social determinants of health. METHODS: We conducted a scoping review of the literature on theoretical bases and practical applications of the settings approach. Interventions targeting social inequities in health through action on various settings were analyzed to establish what is done in health equity research and action as it relates to settings. RESULTS: Four elements emerged as central to an equity-focused settings approach: a focus on social determinants of health, addressing the needs of marginalized groups, effecting change in a setting's structure, and involving stakeholders. Each came with related challenges. To offer potential solutions to these challenges we developed a conceptual framework that integrates theoretical and methodological approaches, along with six core guiding principles, into a 'settings praxis'. CONCLUSIONS: Reducing social inequities in health through the creation of supportive environments requires the application of the settings approach in an innovative way. The proposed conceptual framework can serve as a guide to do so, and help develop, implement and evaluate equity-focused settings related interventions. PMID- 23797941 TI - Stimulating innovative research in health promotion. AB - The Global Working Group on Health Promotion Research (GWG HPR) of the International Union for Health Promotion and Education (IUHPE) presents a collection of four articles illustrating innovative avenues for health promotion research. This commentary synthesizes the contributions of these articles while attempting to define the contours of research in health promotion. We propose that innovation in research involves the adoption of a reflexive approach wherein consideration of context plays different roles. The reflexive process consists of questioning what is taken for granted in the conceptualization and operationalization of research. It involves linking research findings and its theoretical foundations to characteristics and goals of the field and observed realities, while orienting reflection on specific objects. The reflexive nature of the research activity is of paramount importance for innovation in health promotion. With the publication of this series, the GWG HPR wishes to strengthen health promotion research capacity at the global level and reaffirm health promotion as a specific research domain. PMID- 23797940 TI - Reorienting health services in the Northern Territory of Australia: a conceptual model for building health promotion capacity in the workforce. AB - INTRODUCTION: Reorienting work practices to include health promotion and prevention is complex and requires specific strategies and interventions. This paper presents original research that used 'real-world' practice to demonstrate that knowledge gathered from practice is relevant for the development of practice based evidence. The paper shows how practitioners can inform and influence improvements in health promotion practice. Practitioner-informed evidence necessarily incorporates qualitative research to capture the richness of their reflective experiences. METHODS: Using a participatory action research (PAR) approach, the research question asked 'what are the core dimensions of building health promotion capacity in a primary health care workforce in a real-world setting?' PAR is a method in which the researcher operates in full collaboration with members of the organisation being studied for the purposes of achieving some kind of change, in this case to increase the amount of health promotion and prevention practice within this community health setting. The PAR process involved six reflection and action cycles over two years. Data collection processes included: survey; in-depth interviews; a training intervention; observations of practice; workplace diaries; and two nominal groups. The listen/reflect/act process enabled lessons from practice to inform future capacity-building processes. RESULTS: This research strengthened and supported the development of health promotion to inform 'better health' practices through respectful change processes based on research, practitioner-informed evidence, and capacity-building strategies. A conceptual model for building health promotion capacity in the primary health care workforce was informed by the PAR processes and recognised the importance of the determinants approach. CONCLUSION: Practitioner-informed evidence is the missing link in the evidence debate and provides the links between evidence and its translation to practice. New models of health promotion service delivery can be developed in community settings recognising the importance of involving practitioners themselves in these processes. PMID- 23797942 TI - An inter-professional 'advocacy and activism in global health': module for the training of physician-advocates. AB - Medical students typically learn about the role of physicians as health advocates through a component of the health professionalism curriculum. Recently, there has been a call for increased exposure to health advocacy in undergraduate medical education so that students can develop the interest, knowledge, skills, and attitudes that they will utilize throughout their careers as physician-advocates. We developed a four-session Advocacy and Activism training module that consisted of formal didactic teaching, training in basic skills, debate and discussion, and the development and presentation of advocacy projects. There were several uniquely innovative aspects of this module, including its structure, content, and inter-professional approach that included students of medicine, nursing, and public health. However, this approach also resulted in some important and unexpected limitations. We were encouraged by the quality of student participation during the module, as well as specific feedback regarding the format and content. The module was a low-cost, easy-to-implement, and academically rigorous model that can be implemented by interested students and faculty at other schools. We plan to continue to develop this program in the future, and we believe that other medical institutions should consider a similar model for introducing students to their future role as health advocates. PMID- 23797943 TI - The importance of context in the evolution of health promotion. AB - The world has changed dramatically since the Ottawa Charter was developed in 1986. Contemporary health promotion responses continue to evolve and become more sophisticated in response to the multiple challenges created by an ever-changing world. This commentary discusses some of the challenges facing health promotion professionals today and some of the responses that are being developed to address them. The importance of contextual considerations for both the worker and the work of health promotion are emphasised. The author then suggests ways that organisations and individuals can meet modern-day health promotion challenges through specific courses of action. PMID- 23797947 TI - Serial evaluation of microcirculatory dysfunction in patients with Takotsubo cardiomyopathy by myocardial contrast echocardiography. AB - BACKGROUND: Stress cardiomyopathy manifests as reversible left ventricular apical ballooning in the absence of epicardial coronary obstruction. Transient microcirculatory dysfunction has been proposed as a potential putative mechanism. This study aimed to understand the natural history of this dysfunction using readily available noninvasive methods. HYPOTHESIS: Stress cardiomyopathy presents with profound microvascular dysfunction that improves quickly over a period of 3 to 4 weeks. METHODS: Nine consecutive patients with Takotsubo cardiomyopathy were followed serially with myocardial perfusion echocardiograms at 24 hours, within 1 week, and 3 to 6 months after index admission. RESULTS: The mean left ventricular ejection fraction (LVEF) steadily improved from 38% at baseline to 48% within 1 week to 67% by the end of 3 to 6 months follow-up. The number of wall segments with reduced or absent perfusion decreased from 4.1 at baseline to 2 at 1 week. By 3 to 6 months, perfusion had returned to normal in all but 1 segment in 1 patient. At 1 week, the relative improvement in mean LVEF was 26%, whereas perfusion had improved by nearly 50%, suggesting a fairly pronounced improvement in microcirculatory function prior to recovery of wall motion. CONCLUSIONS: Patients with Takotsubo cardiomyopathy present with significant acute microcirculatory dysfunction that recovers quickly prior to the recovery of regional wall motion abnormalities. PMID- 23797948 TI - The relationship between depressive symptoms and error monitoring during response switching. AB - Heightened sensitivity to failure and negative information is thought to be an important maintenance mechanism for symptoms of depression. However, the specific neural and behavioral correlates of the abnormal reactions to errors associated with depression are not yet well understood. The present study was designed to shed new light on this issue by examining how depressive symptoms relate to error monitoring in the context of different task demands. We used a modified flanker task in which the stimulus-response (S-R) mappings were reversed between blocks, differentiating relatively easy nonreversal blocks from the more-demanding S-R reversal blocks. Undergraduates performed this task and then completed a self report measure of anhedonic depression. The results revealed that depressive symptoms were related to poorer posterror accuracy in the more-difficult S-R reversal blocks, but not in the easier nonreversal blocks. Event-related brain potentials (ERPs) within a subsample of these participants further indicated that depressive symptoms were associated with reduced error positivity (Pe) amplitudes in both block types, suggesting that depressive symptoms were related to reduced attention allocation to errors across the easy and hard blocks. Finally, brain behavior correlations indicated that highly depressed individuals failed to display a relationship between Pe amplitude and posterror accuracy in the S-R reversal blocks, a relationship that was intact in the low-depression group. Together, these results suggest that task demands play a critical role in the emergence of error-monitoring abnormalities in depression. PMID- 23797949 TI - Usefulness of biochemical parameters in decision-making on the start of emergency treatment in patients with propionic acidemia. AB - BACKGROUND: Recurrent acute and life-threatening metabolic decompensations are thought to be the major cause of mortality and morbidity in patients with propionic acidemia (PA). Since metabolic decompensations in these patients usually develop gradually, there is considerable uncertainty about the beginning and when emergency treatment should be initiated. The major aim of this study was to evaluate the usefulness of biochemical parameters for improving decision making on the start of emergency treatment. METHODS: We analysed data of 16 PA patients continuously followed in our centre. Metabolic decompensation was defined clinically by the occurrence of at least one of three alarming symptoms: vomiting, food refusal or impaired consciousness. Thirty-eight biochemical parameters were analysed. RESULTS: A total of 259 metabolic decompensations were documented and compared with 625 routine visits. Among the symptoms used to clinically define metabolic decompensations, vomiting was most frequent (87 %). In total, 19 biochemical parameters differentiated between metabolic decompensations and routine visits. Among them ammonia, acid-base balance and anion gap were most reliable to identify a metabolic decompensation, and to estimate its severity. A comparative analysis of patients with PA and methylmalonic acidemia during metabolic decompensation showed similar results. CONCLUSIONS: Ammonia, acid-base balance and anion gap are important biochemical parameters to identify an (impending) metabolic decompensation and to assess its severity in PA patients. The identified biochemical parameters should be integrated in an algorithm for clinical decision-making on emergency treatment and should be tested in a prospective trial. PMID- 23797950 TI - Microsomal epoxide hydrolase (EPHX1) polymorphisms are associated with aberrant promoter methylation of ERCC3 and hematotoxicity in benzene-exposed workers. AB - Benzene is an important industrial chemical and widespread environmental pollutant known to induce leukemia and other blood disorders. To be carcinogenic, benzene must be metabolized to produce toxic metabolites. To investigate whether single nucleotide polymorphisms (SNPs) in the metabolic enzyme genes are associated with benzene-induced alterations in DNA methylation and hematotoxicity, we genotyped four commonly studied SNPs in three metabolic enzymes genes CYP1A1, EPHX1 and NQO1; and analyzed promoter DNA methylation status in 11 genes which have been reported to be associated with benzene-induced hematotoxicity (BLM, CYP1A1, EPHX1, ERCC3, NQO1, NUDT1, p15, p16, RAD51, TP53 and WRAP53) in 77 benzene-exposed workers and 25 unexposed controls in China. ERCC3, a DNA repair gene, showed a small but statistically significant increase of promoter DNA methylation in the exposed group compared with the unexposed group (mean +/- SD: 4.73 +/- 3.46% vs. 3.63 +/- 1.96%, P = 0.048). We also observed that an increased number of C allele for rs1051740 in EPHX1 was associated with decreased ERCC3 methylation levels in benzene-exposed workers (P(trend) = 0.001), but not in unexposed controls (P(trend) = 0.379). Interestingly, another EPHX1 SNP (rs2234922) was associated with lower white blood cell (WBC) counts (P(trend) = 0.044) in benzene-exposed workers. These associations remained the same when ERCC3 promoter methylation and WBCs were dichotomized according to the 90th percentile (>=6%) of methylation levels in controls and a leucopenia cutoff (<4 * 10(9) /L), respectively. Our findings suggest that benzene exposure may be associated with hypermethylation in ERCC3, and that genetic variants in EPHX1 may play an important role in epigenetic changes and hematotoxicity among benzene exposed workers. PMID- 23797951 TI - Examination of proposed DSM-5 changes to pathological gambling in a helpline sample. AB - OBJECTIVES: To examine the effect of proposed the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) changes to pathological gambling relative to DSM-IV criteria in a large gambling helpline sample (N = 2,750). Changes in prevalence rates, the diagnostic utility of the illegal acts criterion, and severity of alternative diagnostic formulation thresholds were examined. METHOD: Callers to the helpline completed a semistructured interview and DSM-IV criteria were assessed. RESULTS: Without lowering the diagnostic threshold, removal of the illegal acts criterion resulted in loss of diagnostic status in less than 2% of helpline callers. The DSM-IV prevalence rate in this sample was 81.2%, and DSM-5 formulations with lowered thresholds of 4, 3, and 2 symptoms increased prevalence rates by 9% to 17%. However, item-level symptom endorsement suggested that subclinical gamblers experience significant adverse consequences. CONCLUSIONS: Lowered thresholds may lead to earlier provision of treatment to gamblers and prevent escalation of the disorder, while being more consistent with diagnostic thresholds of other addiction disorders. PMID- 23797952 TI - Financial crisis and collapsed banks: psychological distress and work related factors among surviving employees--a nation-wide study. AB - AIM: The study considered psychological distress among surviving bank employees differently entangled in downsizing and restructuring following the financial crisis of 2008. METHODS: A cross-sectional, nationwide study was conducted among surviving employees (N = 1880, response rate 68%). Multivariate analysis was conducted to assess factors associated with psychological distress. RESULTS: In the banks, where all employees experienced rapid and unpredictable organizational changes, psychological distress was higher among employees most entangled in the downsizing and restructuring process. Being subjected to downsizing within own department, salary cut, and transfer to another department, was directly related to increased psychological distress, controlling for background factors. The associations between downsizing, restructuring, and distress were reduced somewhat by adding job demands, job control, and empowering leadership to the model, however, adding social support had little effect on these associations. CONCLUSION: Employees most entangled in organizational changes are the most vulnerable and should be prioritized in workplace interventions during organizational changes. PMID- 23797953 TI - Abstracts of the 37th Annual Congress of the Italian Urodynamic Society (Continence, Neuro-Urology, Pelvic Floor). Latina, Italy. June 20-22, 2013. PMID- 23797954 TI - High-dosage ascorbic acid treatment in Charcot-Marie-Tooth disease type 1A: results of a randomized, double-masked, controlled trial. AB - IMPORTANCE: No current medications improve neuropathy in subjects with Charcot Marie-Tooth disease type 1A (CMT1A). Ascorbic acid (AA) treatment improved the neuropathy of a transgenic mouse model of CMT1A and is a potential therapy. A lower dosage (1.5 g/d) did not cause improvement in humans. It is unknown whether a higher dosage would prove more effective. OBJECTIVE: To determine whether 4-g/d AA improves the neuropathy of subjects with CMT1A. DESIGN: A futility design to determine whether AA was unable to reduce worsening on the CMT Neuropathy Score (CMTNS) by at least 50% over a 2-year period relative to a natural history control group. SETTING: Three referral centers with peripheral nerve clinics (Wayne State University, Johns Hopkins University, and University of Rochester). PARTICIPANTS: One hundred seventy-four subjects with CMT1A were assessed for eligibility; 48 did not meet eligibility criteria and 16 declined to participate. The remaining 110 subjects, aged 13 to 70 years, were randomly assigned in a double-masked fashion with 4:1 allocation to oral AA (87 subjects) or matching placebo (23 subjects). Sixty-nine subjects from the treatment group and 16 from the placebo group completed the study. Two subjects from the treatment group and 1 from the placebo group withdrew because of adverse effects. INTERVENTIONS: Oral AA (4 g/d) or matching placebo. MAIN OUTCOMES AND MEASURES: Change from baseline to year 2 in the CMTNS, a validated composite impairment score for CMT. RESULTS: The mean 2-year change in the CMTNS was -0.21 for the AA group and -0.92 for the placebo group, both better than natural history (+1.33). This was well below 50% reduction of CMTNS worsening from natural history, so futility could not be declared (P > .99). CONCLUSIONS AND RELEVANCE: Both treated patients and those receiving placebo performed better than natural history. It seems unlikely that our results support undertaking a larger trial of 4-g/d AA treatment in subjects with CMT1A. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00484510. PMID- 23797956 TI - Direct high-resolution label-free imaging of cellular nanostructure dynamics in living cells. AB - We report the application of an optical microscope equipped with a high resolution dark-field condenser for detecting dynamic responses of cellular nanostructures in real time. Our system provides an easy-to-use technique to visualize biological specimens without any staining. This system can visualize the dynamic behavior of nanospheres and nanofibers, such as F-actin, at the leading edges of adjacent neuronal cells. We confirmed that the nanofibers imaged with this high-resolution optical microscopic technique are F-actin by using fluorescence microscopy after immunostaining the F-actin of fixed cells. Furthermore, cellular dynamics are enhanced by applying noncontact electric field stimulation through a transparent graphene electric field stimulator. High resolution label-free optical microscopy enables the visualization of nanofiber dynamics initiated by filopodial nanofiber contacts. In conclusion, our optical microscopy system allows the visualization of nanoscale cellular dynamics under various external stimuli in real time without specific staining. PMID- 23797955 TI - Sleep disturbance, distress, and quality of life in ovarian cancer patients during the first year after diagnosis. AB - BACKGROUND: Sleep disturbance is a common clinical complaint of oncology patients and contributes to substantial morbidity. However, because most sleep studies have been cross-sectional, associations between sleep quality and distress in patients with ovarian cancer over time remain unclear. This prospective longitudinal study examined rates of sleep disturbance; contributions of depression, anxiety, and medication use in sleep disturbance; and associations between sleep quality and quality of life (QOL) during the first year after diagnosis among women with ovarian cancer. METHODS: Women with a pelvic mass completed measures of sleep quality, depression, anxiety, and QOL before surgery. Those diagnosed with primary epithelial ovarian, fallopian tube, or peritoneal cancer repeated surveys at 6 months and 1 year after diagnosis. Mixed modeling was used to examine trajectories of psychosocial measures over time, as well as associations between changes in distress and sleep quality. Relationships between changes in sleep and QOL were also examined. RESULTS: The majority of patients reported disturbed global sleep (Pittsburgh Sleep Quality Index > 5) at all 3 time points. Medications for sleep and pain were associated with worse sleep at all time points. Greater increases in depression were associated with increased disturbances in sleep quality over time (P < .04). Worsening sleep was also associated with declines in QOL over time (P < .001). CONCLUSIONS: Sleep disturbance is common and persistent in women with ovarian cancer, and is linked to depressive symptoms and QOL. Pharmacologic treatment does not appear to adequately address this problem. Results highlight the need for ongoing screening and intervention for sleep disturbance in this population. PMID- 23797957 TI - First reported case of compound heterozygosity for HbA2-Yialousa (HBD: c.82 G>C) and HbA2-Wrens (HBD: c.295 G>A) in Oman. AB - We report the presence of two different dglobin gene mutations causing d? thalassemia in association with homozygous (-a3.7/-a3.7) genotype for the first time in an Omani child with a low hemoglobin A2 (HbA2) of 0.8 %. Direct nucleotide sequencing revealed compound heterozygote mutations in the patient's d globin genes: HbA2-Yialousa (HBD: c.82G[C) and HbA2- Wrens (HBD: c.295G[A). In Oman, where a and b-thalassemia and HbS are prevalent, an awareness of the presence of different d-globin gene mutations is important as complex interactions between these hemoglobinopathies can lead to the misdiagnosis of b thalassemia carriers. PMID- 23797958 TI - High early death rate in elderly patients with acute promyelocytic leukemia treated with all-trans retinoic acid combined chemotherapy. PMID- 23797959 TI - Daycase bariatric surgery--just how much experience is potentially lost to trainees? PMID- 23797960 TI - Viral ocular manifestations: a broad overview. AB - The viruses able to affect the eye are taxonomically diverse, ranging from double stranded DNA viruses, to single stranded RNA viruses, to retroviruses. Any part of the eye may be affected, frequently producing blepharitis, conjunctivitis, keratitis, uveitis, cataract and retinitis. The more common ocular viral infections include the Herpesviruses such as HSV-1, VZV and CMV. The HIV pandemic is placing a serious burden on ophthalmology clinics, particularly in sub-Saharan Africa as the number of viral ocular diseases is increasing. In particular, CMV retinitis is becoming more prevalent where antiretroviral therapy is not available and is replaced by immune-recovery uveitis where antiretrovirals are given. This review aims to improve knowledge of the common viral ocular diseases, their diagnosis and management, as well as the fairly uncommon viral ocular diseases that may also cause considerable morbidity. PMID- 23797963 TI - Inhaled iloprost in preterm infants with severe respiratory distress syndrome and pulmonary hypertension. AB - OBJECTIVE: Many vasodilator drugs, including inhaled iloprost, are used to treat insufficient pulmonary vasodilatation, which is the main issue in pulmonary hypertension in newborns. STUDY DESIGN: The safety and efficacy of inhaled iloprost for the treatment of pulmonary hypertension were evaluated retrospectively in 15 preterm infants diagnosed with respiratory distress syndrome and pulmonary hypertension. RESULTS: The infants were unresponsive to surfactant and conventional mechanical ventilation and thus were treated with inhaled iloprost. Oxygenation parameters and hypoxemia improved rapidly after treatment. There was no decline in systemic blood pressure, no need for increased doses of vasopressor, and no side effects during treatment. One patient died of sepsis during treatment. CONCLUSION: In the treatment of severely sick premature babies with pulmonary hypertension, inhaled iloprost has high tolerability and a low incidence of systemic side effects. Based on the benefits of inhaled iloprost in preterm infants with pulmonary hypertension in this case series, further studies are required to evaluate its efficacy and safety in the preterm population. PMID- 23797962 TI - Adrenomedullin signaling pathway polymorphisms and adverse pregnancy outcomes. AB - OBJECTIVE: Reduced maternal plasma levels of the peptide vasodilator adrenomedullin have been associated with adverse pregnancy outcomes. We measured the extent to which genetic polymorphisms in the adrenomedullin signaling pathway are associated with birth weight, glycemic regulation, and preeclampsia risk. STUDY DESIGN: We genotyped 1,353 women in the Pregnancy, Infection, and Nutrition Postpartum Study for 37 ancestry-informative markers and for single-nucleotide polymorphisms in adrenomedullin (ADM), complement factor H variant (CFH), and calcitonin receptor-like receptor (CALCRL). We used linear and logistic regression to model the association between genotype and birth weight, glucose loading test (GLT) results, preeclampsia, and gestational diabetes (GDM). All models were adjusted for pregravid body mass index, maternal age, and probability of Yoruban ancestry. p values of < 0.05 were considered statistically significant. RESULTS: Among Caucasian women, ADM rs57153895, a proxy for rs11042725, was associated with reduced birth weight z-score. Among African American women, ADM rs57153895 was associated with increased birth weight z score. Two CALCRL variants were associated with GDM risk. CFH rs1061170 was associated with higher GLT results and increased preeclampsia risk. CONCLUSION: Consistent with studies of plasma adrenomedullin and adverse pregnancy outcomes, we found associations between variants in the adrenomedullin signaling pathway and birth weight, glycemic regulation, and preeclampsia. PMID- 23797964 TI - A slow life history is related to a negative attitude towards cousin marriages: a study in three ethnic groups in Mexico. AB - Little is known about current attitudes towards cousin marriages. Using data from a rural population in the Mexican state of Oaxaca, the present research examined how life history was related to attitudes towards cousin marriages in various ethnic groups. Participants were 205 parents from three ethnic groups. i.e., Mestizos (people of mixed descent, n = 103), indigenous Mixtecs (n = 65), and Blacks (n = 35). Nearly all men in this study were farm workers or fishermen. Participants reported more negative than positive attitudes towards cousin marriage, and women reported more negative attitudes than did men. The main objection against marrying a cousin was that it is wrong for religious reasons, whereas the risk of genetic defects was considered relatively unimportant. Cousin marriage was not considered to contribute to the quality and unity of marriage and the family. The three ethnic groups did not differ in their attitude towards cousin marriages. However, a slower life history was related to a more negative attitude towards cousin marriages, especially among Blacks, less so among Mixtecs, and not at all among Mestizos. In addition, and independent of the effect of life history, with increasing levels of parental control over mate choice, the attitude towards cousin marriage was more positive, but among men the attitude was more negative the more religious they were. The results are discussed in the context of theorizing on life history theory and the benefits and costs of cousin marriages. PMID- 23797965 TI - 3-dimensional ultrasound assisted counseling for conjoined twins. PMID- 23797966 TI - Letters to the editor. PMID- 23797967 TI - Extensive use of FRET in biological imaging. AB - Forster resonance energy transfer (FRET) is a phenomenon used for bioimaging ranging from single molecules to in vivo scale. A large variety of organic dyes and fluorescent proteins are available for FRET probes. In this review, we introduce the representative pairs of FRET probes developed thus far. The efficiency of FRET is depending on the spectral overlap of donor emission and acceptor absorption, the orientation of donor and acceptor and their distance. For FRET-based indicators composed of fluorescent proteins, their orientation and dimeric property of donor and acceptor largely affect the FRET efficiency, indicating the effect for the performance of indicators. In addition, three major applications of FRET, including genetically encoded indicators, single-molecule FRET, and enhancement of chemiluminescent proteins, have been introduced and their functions have also been discussed. PMID- 23797968 TI - TRIP steel microstructure visualized by slow and very slow electrons. AB - The aim of the present paper is to demonstrate the ability of the scanning low energy electron microscopy to visualize the transformed induced plasticity steel microstructure with extremely high sensitivity. Using the retarding mode in the scanning electron microscope, the high contrast between the individual phases has been obtained, which enables us to differentiate the retained austenite and the other phases. The sets of the micrographs have been collected from the sample at a wide range of landing energies of primary electrons from 50 eV to 10 keV and the dependence of the contrast between the phases on the landing energy has been calculated. Upon a comparison of these contrast curves, the optimal conditions for achieving of maximum contrast have been established. PMID- 23797969 TI - Phase-locking of oscillating images using laser-induced spin-polarized pulse TEM. AB - Pulse-mode operation was realized in spin-polarized transmission electron microscopy (SP-TEM) using a laser-driven electron gun with a GaAs-GaAsP strained layer-superlattice photocathode. TEM images were acquired with a pulsed electron beam with a 5-MUs pulse duration. Phase locking of wobbling TEM images was demonstrated using a pulsed beam with a 1-kHz repetition frequency, which matched the image wobbling frequency. It was found that in composite images formed by superimposing 2 * 10(4) separate single-pulse exposures, the amount of image blurring due to wobbling was a linear function of the pulse duration. These results suggest the possibility of pump-probe measurements in SP-TEM using the pulsed electron beam as a probe, allowing nanometer-scale time-resolved spin mapping. PMID- 23797970 TI - Radiotherapy for T1a glottic cancer: the influence of smoking cessation and fractionation schedule of radiotherapy. AB - The objective of the presented study is to report on retrospectively collected data on long-term outcome and toxicity and prospective assessment of quality of life (QoL) and Voice-Handicap Index (VHI) of patients with T1a glottic cancer treated with radiotherapy. Between 1985 and 2011, 549 patients were treated. Endpoints were local control (LC), toxicity, QoL and VHI. After a median follow up of 93 months, the actuarial rates of LC were 91, and 90 % at 5- and 10-years, respectively. Continuing smoking (p < 0.001) and anaemia (p = 0.02) were significantly correlated with poor LC on univariate analysis and fractionation schedule did not show significant correlation (p = 0.08). On multivariate analysis, only continuing smoking retained significance (p = 0.001). These patients had also significantly increased incidence of second primary tumour and lower overall survival rates. The incidence of grade >=2 late xerostomia and dysphagia were 10 and 6 %, respectively. Slight and temporary deterioration of QoL-scores was reported. The scores on the EROTC-QOL-H&N35 dysphagia and xerostomia at 24 months were -2 and -3, compared to baseline, respectively. VHI improved significantly from 34 at baseline to 21 at 24 months. Patients who continued smoking had significantly worse VHI. In conclusion, excellent outcome with good QoL and VHI were reported. Patients who continued smoking after radiotherapy had significantly poor LC and worse VHI. The current study emphasizes the importance of smoking cessation and the non-inferiority of hypofractionated schemes in terms of outcome and VHI. At our institution, phase II study is going to evaluate the role of single vocal cord irradiation with high fraction dose. PMID- 23797971 TI - Prior knowledge is more predictive of error correction than subjective confidence. AB - Previous research has demonstrated that, when given feedback, participants are more likely to correct confidently-held errors, as compared with errors held with lower levels of confidence, a finding termed the hypercorrection effect. Accounts of hypercorrection suggest that confidence modifies attention to feedback; alternatively, hypercorrection may reflect prior domain knowledge, with confidence ratings simply correlated with this prior knowledge. In the present experiments, we attempted to adjudicate among these explanations of the hypercorrection effect. In Experiments 1a and 1b, participants answered general knowledge questions, rated their confidence, and received feedback either immediately after rating their confidence or after a delay of several minutes. Although memory for confidence judgments should have been poorer at a delay, the hypercorrection effect was equivalent for both feedback timings. Experiment 2 showed that hypercorrection remained unchanged even when the delay to feedback was increased. In addition, measures of recall for prior confidence judgments showed that memory for confidence was indeed poorer after a delay. Experiment 3 directly compared estimates of domain knowledge with confidence ratings, showing that such prior knowledge was related to error correction, whereas the unique role of confidence was small. Overall, our results suggest that prior knowledge likely plays a primary role in error correction, while confidence may play a small role or merely serve as a proxy for prior knowledge. PMID- 23797972 TI - Pad weight testing in the evaluation of urinary incontinence. AB - AIM: To present the teaching module "Pad Weight Testing in the Evaluation of Urinary Incontinence." This teaching module embodies a presentation, in combination with this manuscript. This manuscript serves as a scientific background review; the evidence base made available on ICS website to summarize current knowledge and recommendations. METHODS: This review has been prepared by a Working Group of The ICS Urodynamics Committee. The methodology used included comprehensive literature review, consensus formation by the members of the Working Group, and review by members of the ICS Urodynamics Committee core panel. RESULTS: The pad test is a non-invasive diagnostic tool for urinary incontinence. It is an easy to perform, inexpensive test with utilization in both the daily patient care and clinical research. Despite it is clear value in initial diagnosis, selection of treatment, and follow-up evaluation, only less than 10% of urologists perform the test routinely. A number of testing protocols with varying lengths of recording time exist, however, only a 1-hr pad test has been standardized. One-hour pad tests are most suitable in establishing initial diagnosis, the 24-hr test serves most often for evaluation of treatment outcomes, and longer pad tests are used in clinical studies. CONCLUSIONS: The pad test is clearly underutilized. Well-designed studies providing level one evidence are lacking. Numerous variations in how the test is performed by individual urologists make the evaluation of published literature difficult. Future research goals should include randomized studies leading to establishment of optimal protocols of testing for clinical research and daily care. PMID- 23797973 TI - Adolescent identity development and distress in a clinical sample. AB - OBJECTIVE: The purpose of this study was to examine the relationships of identity development and identity distress to psychological adjustment within adolescents affected by psychological problems. METHOD: Participants included 88 adolescents (43.2% female) ranging from 11 to 20 years of age who were receiving services from a community mental health center. RESULTS: A high proportion of the participants (22.7%) met the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition Text Revision criteria for Identity Problem. Regression analyses found psychopathology symptom score was associated with identity distress, identity exploration, and identity commitment, while identity distress was only related to psychopathology symptom score and not the other two identity variables. CONCLUSIONS: Adolescents with a clinical diagnosis may report significant levels of identity distress. Given that the relationship between psychopathology and identity distress may be reciprocal, assessing for identity issues might be prudent when conducting clinical diagnostic interviews and useful in treatment planning. PMID- 23797974 TI - Proteomics analysis of human pericardial fluid. AB - Pericardial fluid (PF) is considered as a biochemical window of heart. To date, there have been limited attempts to perform an in-depth analysis of the PF proteome. In this study, an SDS-PAGE-LC-MS/MS platform was utilized to explore depleted PF, which showed great coverage of low-abundant proteins. In total, 1007 nonredundant proteins were identified with at least two peptides. This is the first comprehensive analysis of human PF proteome and provides a foundation for further application of PF in cardiovascular research. The data have been deposited to the ProteomeXchange with identifier PXD000194. PMID- 23797975 TI - DNA adducts and combinations of multiple lung cancer at-risk alleles in environmentally exposed and smoking subjects. AB - Interindividual variation in DNA adduct levels in individuals exposed to similar amounts of environmental carcinogens may be due to genetic variability. We analysed the influence of genes involved in determining/modifying DNA damage, including microsomal epoxide hydrolase1 (EPHX1) His139Arg, N-acetyl-transferase, NAD(P)H:quinone oxidoreductase1 (NQO1) Pro187Ser, manganese superoxide dismutase2 (MnSOD2) Val16Ala, and apurinic/apyrimidinic endonuclease1 (APE1) Asp148Glu polymorphisms in blood of 120 smokers. Subsequently, we examined the effects of the combinations of the variant alleles of EPHX, NQO1 and MnSOD2 together with the wild type allele of APE1 on DNA damage by calculating the "sum of at-risk alleles." We reviewed the studies examining the relationships of DNA adducts with at-risk alleles in environmentally exposed subjects. Our findings showed that smokers carrying the EPHX1-139Arg and the NQO1-187Ser variants were significantly more likely to have higher adduct levels. Null associations were found with the other variants. Nevertheless, DNA adduct levels in smokers with >=5 at-risk alleles were significantly different from those with fewer than two alleles. A similar picture emerged from studies of DNA adducts and at-risk alleles in environmentally exposed and smoking subjects. Certain at-risk allele combinations may confer a greater likelihood of increased levels of adducts after environmental insults. The increase in DNA adduct levels in susceptible subjects exposed to environmental carcinogens may reflect changes in the mechanisms that protect cells from the accumulation of genetic damage. Alterations of the physiological processes designed to maintain homeostasis may reduce the individual "genotoxic tolerance" to environmental challenges and result in phenotypes characterized by high levels of DNA adducts. PMID- 23797976 TI - The burden of mortality with costs in productivity loss from occupational cancer in Italy. AB - BACKGROUND: The costs of productivity loss due to occupational cancer mortality are rarely investigated. An estimate of occupational cancer deaths in Italy in 2006 and an approximation of the resultant costs from medical and non-medical expenditures together with figures of remuneration lost are provided. METHODS: Occupational cancer deaths, obtained from the application of the attributable fraction (AF) to mortality data (source: Italian National Institute of Statistics), were used to calculate the Potential Years of Life Lost (PYLLs), the Potential Years of Working Life Lost (PYWLLs) and the costs of the loss of productive life. The health care costs for any cancer was applied to the estimated number of occupational cancer cases to obtain the total cost. RESULTS: Around 8,000-8,500 deaths/year from occupational cancer are estimated to occur in Italy, corresponding to 170,000 PYLLs and more than 16,000 PYWLLs, leading to around 360,000,000 euros in indirect economic loss. Health care costs of occupational cancer are estimated at 456,000,000 euros. CONCLUSIONS: Occupational cancer is of major concern in terms of mortality and economic productivity loss. Preventive efforts in evaluating ongoing risks and current exposures are strongly recommended to health policy-makers. PMID- 23797977 TI - Whither hope for pharmacological treatment of Charcot-Marie-Tooth disease type 1A? PMID- 23797978 TI - Risk and outcome of non-Hodgkin lymphoma among classical Hodgkin lymphoma survivors. AB - BACKGROUND: Survivors of classical Hodgkin lymphoma (cHL) are at an increased risk of developing secondary non-Hodgkin lymphomas (sNHLs). To the authors' knowledge, the outcome of patients with sNHL compared with their de novo counterparts (dnNHL) is unknown. METHODS: Data from 26,826 cases of HL from the Surveillance, Epidemiology, and End Results (SEER) program that were diagnosed between 1992 and 2009 were used to obtain the risk of further development of different subtypes of sNHL. The survival of patients with sNHL was compared with that of matched patients with dnNHL. RESULTS: The estimated cumulative incidence of sNHL was 2.50% (95% confidence interval [95% CI], 2.10-2.89) at 15 years from the diagnosis of cHL. The standardized incidence ratio was 10.5 (95% CI, 8.9 12.4) for aggressive B-cell NHL, 4.0 (95% CI, 3.1-5.1) for indolent B-cell NHL, and 14.6 (95% CI, 10.3-20.1) for T-cell NHL. Patients with indolent B-cell sNHL had a worse overall survival compared with their dnNHL counterparts (hazards ratio [HR] of death, 2.7; 95% CI, 1.3-5.7). Survival was not significantly different between patients with sNHL and those with dnNHL with regard to aggressive B-cell NHL (HR, 1.3; 95% CI, 0.6-2.7) or T-cell NHL (HR, 0.8; 95% CI, 0.3-1.8). CONCLUSIONS: The risk of developing sNHL after cHL is substantial. Although patients with indolent B-cell sNHL have inferior survival, patients with aggressive B-cell sNHL and T-cell sNHL have survival comparable to that of their de novo counterparts. PMID- 23797979 TI - Identification and expression profiles of IL-8 in bighead carp (Aristichthys nobilis) in response to microcystin-LR. AB - Microcystin-LR (MCLR) is a widespread cyanotoxin and has immunotoxicity to animals, including fish. Chemokines are considered to play important roles in inflammatory response induced by MCLR. In this study, we cloned the full-length cDNA of interleukin-8 (IL-8) from bighead carp (Aristichthys nobilis) for the first time. The full-length IL-8 cDNA was 552 bp and contained a 297-bp open reading frame that encoded for a 98-amino acid protein. The deduced IL-8 protein had a typical aspartic acid (D)-leucine (L)-arginine (R) and a CXC motif at the N terminal, which were conserved in most fish species. Phylogenetic analysis showed that bighead carp IL-8 protein was grouped in the teleost IL-8 lineage 2. Under normal conditions, the expression of IL-8 is constitutive and weak in all tested tissues. However, MCLR treatment could significantly increase the transcription of IL-8 in bighead carp in a temporal- and dose-dependent pattern. The present study will help us to understand more about the evolution of IL-8 and its function in the MCLR induced proinflammatory response in bighead carp. PMID- 23797980 TI - Mutagenicity, genotoxicity, and estrogenic activity of river porewaters. AB - We investigated mutagenicity, genotoxicity, and estrogenic activity in the porewaters of two river basins in southern Italy that had different features. Three samples from each site were collected in different seasons from 7 sites for a total of 21 samples. Mutagenicity was measured with the Ames test with and without metabolic activation (S9) using Salmonella typhimurium TA98 and TA100 strains. Genotoxicity was measured with two tests: one involved a chromophore that detected DNA damage in Escherichia coli PQ37 (SOS chromotest), and the other measured micronuclei formation in the root cells of Vicia faba. Estrogenic activity was measured with a yeast-based estrogen receptor assay and an MCF-7 cell-based, estrogen-sensitive proliferation assay. We also applied chemical analyses to detect alkylphenols, pesticides, natural and synthetic hormones, and heavy metals. The porewaters of both river sediments showed mutagenic/genotoxic activity on V. faba test and Ames test, the latter both with and without S9 liver fraction. The SOS chromotest without metabolic activation was not sufficiently sensitive to detect genotoxicity of the porewaters, but the SOS DNA repair system in E. coli PQ37 was activated in the presence of S9 mix. Good correlations were found between mutagenicity/genotoxicity and the concentration of cadmium and between estrogenic activity and the presence of copper. This study assessed the chemical concentrations of some bioavailable pollutants in porewater and detected the overall effects of multiple pollutants that contributed to mutagenicity, genotoxicity, and estrogenic activity of these two basin porewaters, thus increasing our understanding of the environmental consequences of polluted aquatic ecosystems. PMID- 23797982 TI - Atrial fibrillation after coronary artery bypass grafting. PMID- 23797983 TI - Rupture of right sinus of Valsalva aneurysm into the pulmonary artery. AB - Rupture of a sinus of Valsalva aneurysm is an uncommon lesion that can occur in any cardiac chamber since the aortic valve occupies a central position in the base of the heart. However, rupture into the pulmonary artery is extremely rare. We describe a case of rupture of an aneurysm of right sinus of Valsalva into the pulmonary artery of a 51-year-old woman. She had been treated by patch closure of a sub-pulmonary ventricular septal defect and aortic valve replacement due to right coronary cusp prolapse 26 years previously. A massive shunt from Valsalva sinus into pulmonary artery indicated the need of radical operation. The defect in the pulmonary artery wall was closed through a pulmonary arteriotomy with a satisfactory outcome. As far as we know, a case of rupture of a sinus of Valsalva aneurysm into pulmonary artery after the previous operation for VSD has not been reported. PMID- 23797984 TI - Use of case-time-control design in pharmacovigilance applications: exploration with high-risk medications and unplanned hospital admissions in the Western Australian elderly. AB - PURPOSE: To use a case-time-control design to derive preliminary estimates of unplanned hospitalisations attributable to suspected high-risk medications in elderly Western Australians. METHODS: Using pharmaceutical claims linked to inpatient and other health records, the study applied a case-time-control design and conditional logistic regression to estimate odds ratios (ORs) for unplanned hospital admissions associated with anticoagulants, antirheumatics, opioids, corticosteroids and four major groups of cardiovascular drugs. Attributable fractions (AFs) were derived from the ORs to estimate the number and proportion of admissions associated with drug exposure. Results were compared with those obtained from a more conventional method using International Classification of Diseases (ICD) external cause codes to identify admissions related to adverse drug events. RESULTS: The study involved 1 899 699 index hospital admissions. Six of the eight drug groups were associated with an increased risk of unplanned hospitalisation, opioids (adjusted OR = 1.81, 95%CI 1.75-1.88; AF = 44.9%) and corticosteroids (1.48, 1.42-1.54; 32.2%) linked with the highest risks. For all six, the estimated number of hospitalisations attributed to the medication in the exposed was higher (two to 31-fold) when derived from the case-time-control design compared with identification from ICD codes. CONCLUSIONS: This study provides an alternative approach for identifying potentially harmful medications and suggests that the use of ICD external causes may underestimate adverse drug events. It takes drug exposure into account, can be applied to individual medications and may overcome under-reporting issues associated with conventional methods. The approach shows great potential as part of a post-marketing pharmacovigilance monitoring system in Australia and elsewhere. PMID- 23797985 TI - What is new in dealing with esophageal atresia. PMID- 23797987 TI - Synthesis, crystal structure, optical properties and antibacterial evaluation of novel imidazo[1, 5-a]pyridine derivatives bearing a hydrazone moiety. AB - A series of novel imidazo[1,5-a]pyridine-hydrazone derivatives were synthesized and characterized by infrared spectroscopy (IR), 1H NMR, 13C NMR and high resolution mass spectrometer (HRMS). Typically, the spatial structure of compound 3j was determined using X-ray diffraction analysis. The UV-vis absorption and fluorescence spectral characteristics of the compounds in dichloromethane and acetonitrile were investigated. Absorption peaks could be observed in the wavelength range 290-450 nm. It can also be seen that they display very similar maximum emission. The group attached to hydrazone hardly influenced the maximum emission. Furthermore, all the compounds were evaluated for antibacterial activity and were found to be more effective against Staphylococcus aureus, Listeria monocytogenes, Escherichia coli, Salmonella typhimurium, Pseudomonas aeruginosa and Shigella compared with chloramphenicol. PMID- 23797986 TI - High-resolution three-dimensional imaging of red blood cells parasitized by Plasmodium falciparum and in situ hemozoin crystals using optical diffraction tomography. AB - We present high-resolution optical tomographic images of human red blood cells (RBC) parasitized by malaria-inducing Plasmodium falciparum (Pf)-RBCs. Three dimensional (3-D) refractive index (RI) tomograms are reconstructed by recourse to a diffraction algorithm from multiple two-dimensional holograms with various angles of illumination. These 3-D RI tomograms of Pf-RBCs show cellular and subcellular structures of host RBCs and invaded parasites in fine detail. Full asexual intraerythrocytic stages of parasite maturation (ring to trophozoite to schizont stages) are then systematically investigated using optical diffraction tomography algorithms. These analyses provide quantitative information on the structural and chemical characteristics of individual host Pf-RBCs, parasitophorous vacuole, and cytoplasm. The in situ structural evolution and chemical characteristics of subcellular hemozoin crystals are also elucidated. PMID- 23797988 TI - Diferential DNA synthesis in Anopheles albimanus tissues induced by immune challenge with different microorganisms. AB - The induction of DNA synthesis in various tissues of Anopheles albimanus, in response to challenge with Saccharomyces cerevisiae, Micrococcus luteus, and Serratia marcescens, was analyzed by 5-bromo-2-deoxy-uridine (BrdU) incorporation. Microorganism-inoculated mosquitoes were fed with a sucrose solution containing BrdU and maintained alive for 5 days. Alternatively, abdominal carcasses of microorganisms-inoculated mosquitoes were cultivated in Roswell Park Memorial Institute (RPMI) medium supplemented with BrdU for 5 days. Control groups were inoculated with RPMI alone. In both experiments, DNA synthesis, evidenced by epifluorescence with an anti-BrdU fluorescein-labeled antibody, occurred in fat body, epithelial cells of pleural membranes, dorsal vessel, and the oviducts. Relative quantification of DNA synthesis, evaluated by ELISA using an anti-BrdU peroxidase-labeled antibody, was higher in abdomen tissues of microorganisms-inoculated mosquitoes than controls in in vitro and in vivo experiments. The intensity of DNA synthesis varied among the different microorganism challenges, but was higher in in vivo experiments, compared to cultured samples. These differences in DNA synthesis suggest a compartmentalization of the immune response, probably mediated by different signaling pathways. PMID- 23797989 TI - Multimodally specified energy expenditure and action-based distance judgments. AB - Previous research has demonstrated that perceived self-motion can be manipulated by the relation between optic flow rate and walking rate. Other studies have revealed that verbal reports of perceived distance are influenced by the energy that would be expended to traverse the distance in question. In an effort to integrate these findings, we investigated how action-based distance judgments are influenced by multimodally specified energy expenditure (MSEE)--the metabolic cost associated with traversing an optically specified distance--using a virtual reality treadmill environment. The energy expenditure associated with walking, measured as the volume of oxygen consumed, was manipulated by changing treadmill speed or grade. Optically specified distance was manipulated by changing the virtual optic flow rate. All three manipulations of MSEE (walking rate, grade, and optic flow rate) influenced distance reports in the predicted directions and to equivalent degrees. PMID- 23797990 TI - Rapid separation of fatty acids using a poly(vinyl alcohol) coated capillary in nonaqueous capillary electrophoresis with contactless conductivity detection. AB - The determination of fatty acids by nonaqueous CZE with capacitively coupled contactless conductivity detection was investigated. A new deoxycholate-based BGE, which had previously been found to give significantly improved baseline stability in the determination of lipophilic organic ammonium ions, was found to be similarly beneficial for the determination of the anions. The use of a PVA coated capillary was required for suppression of the EOF and to obtain well reproducible results. The complete separation of 12 fatty acids could be achieved with 10 mM DOC in methanol within 6 min under optimized conditions. The PVA coated capillary demonstrated outstanding stability over 300 runs with no sign of depletion of the PVA layer. Method validation showed a good linearity range from 0.75 to 25 MUM with correlation coefficients between 0.9949 and 0.9979. The LOD was determined as 0.5 MUM for all fatty acids. The developed approach was successfully demonstrated for the separation of free fatty acids in commercial and home-made edible oil. PMID- 23797991 TI - In silico analysis of mt 16S rRNA sequences of ocypodid crabs. AB - The family Ocypodidae comprises of four sub-families Dotillinae, Heloeciinae, Macrophthalminae and Ocypodinae. Ocypodidae mt 16S rRNA sequences were analysed for studying the conserved regions and phylogeny. Conserved regions will be helpful in molecular identification at the sub-family level and in interpretation of the species relationships in a better way. In the current phylogeny, the Ocypodidae family exhibits different lineages, indicating the family is polyphyletic along with its sub-families Dotillinae and Ocypodinae. The genera Ilyoplax of Dotillinae, with three different lineages, and the Uca genera of Ocypodinae, with four different lineages, exhibit polyphyly. Ocypode and Uca show a close relationship within the sub-family Ocypodinae. PMID- 23797992 TI - A new greedy randomised adaptive search procedure for Multiple Sequence Alignment. AB - The Multiple Sequence Alignment (MSA) is one of the most challenging tasks in bioinformatics. It consists of aligning several sequences to show the fundamental relationship and the common characteristics between a set of protein or nucleic sequences; this problem has been shown to be NP-complete if the number of sequences is >2. In this paper, a new incomplete algorithm based on a Greedy Randomised Adaptive Search Procedure (GRASP) is presented to deal with the MSA problem. The first GRASP's phase is a new greedy algorithm based on the application of a new random progressive method and a hybrid global/local algorithm. The second phase is an adaptive refinement method based on consensus alignment. The obtained results are very encouraging and show the feasibility and effectiveness of the proposed approach. PMID- 23797993 TI - Exploitation of in silico potential in prediction, validation and elucidation of mechanism of anti-angiogenesis by novel compounds: comparative correlation between wet lab and in silico data. AB - This study describes in silico validation of the wet lab data from aeroplysinin 1, curcumin and halofuginone using Autodock Tools 4.0. The inhibition patterns of the vascular endothelial cell differentiation and capillary tube formation mediated by anti-angiogenic growth factors from these test compounds were found quite comparable with the in silico results using angiogenic targets (EFGR, bFGF and VEGFR-1). Successful validation of the wet lab results of the selected angiogenic targets by in silico method has led to exploit the hidden potential of in silico tools in preliminary screening of the unknown compounds for anti angiogenic potential in a cost-effective manner. PMID- 23797994 TI - In silico analysis of putative miRNAs and their target genes in sorghum (Sorghum bicolor). AB - MicroRNAs (miRNAs) are small endogenous genes regulators which regulate different processes underlying plant adaptation to abiotic stresses. To gain a deep understanding of role of miRNAs in plants, in the present study, we computationally analyzed different sorghum miRNAs in the drought-induced gene sequences. Homologous miRNA were identified using different plant miRNA databases. Using previously established genes databases, various targets of sorghum miRNAs were predicted viz: transcription factors, chaperonins, metabolic enzymes and other gene targets necessary for proper plant development. Analysis of cis-elements provides molecular evidence for the possible involvement of miRNAs in the process of abiotic stress tolerance in sorghum. Based on these results, it was suggested that miRNAs may play an important role in water stress tolerance. PMID- 23797996 TI - Serial fusion of Random Subspace ensemble for subcellular phenotype images classification. AB - Subcellular localisation is a key functional characteristic of proteins. In this paper, we apply Haralick texture analysis and Curvelet Transform for feature description and propose a cascade Random Subspace (RS) ensemble with rejection options for subcellular phenotype classification. Serial fusions of RS classifier ensembles much improve classification reliability. The rejection option is implemented by relating the consensus degree from majority voting to a confidence measure and abstaining to classify ambiguous samples if the consensus degree is lower than a threshold. Using the public 2D HeLa cell images, classification accuracy 93% is obtained with rejection rate 2.7% from the proposed system. PMID- 23797995 TI - Identifying radiation exposure biomarkers from mouse blood transcriptome. AB - Ionising radiation is a pleiotropic stress agent that may induce a variety of adverse effects. Molecular biomarker approaches possess promise to assess radiation exposure, however, the pleiotropic nature of ionising radiation induced transcriptional responses and the historically poor inter-laboratory performance of omics-derived biomarkers serve as barriers to identification of unequivocal biomarker sets. Here, we present a whole-genome survey of the murine transcriptomic response to physiologically relevant radiation doses, 2 Gy and 8 Gy. We used this dataset with the Random Forest algorithm to correctly classify independently generated data and to identify putative metabolite biomarkers for radiation exposure. PMID- 23797997 TI - Efficient calculation of compound similarity based on maximum common subgraphs and its application to prediction of gene transcript levels. AB - Properties of a chemical entity, both physical and biological, are related to its structure. Since compound similarity can be used to infer properties of novel compounds, in chemoinformatics much attention has been paid to ways of calculating structural similarity. A useful metric to capture the structural similarity between compounds is the relative size of the Maximum Common Subgraph (MCS). The MCS is the largest substructure present in a pair of compounds, when represented as graphs. However, in practice it is difficult to employ such a metric, since calculation of the MCS becomes computationally intractable when it is large. We propose a novel algorithm that significantly reduces computation time for finding large MCSs, compared to a number of state-of-the-art approaches. The use of this algorithm is demonstrated in an application predicting the transcriptional response of breast cancer cell lines to different drug-like compounds, at a scale which is challenging for the most efficient MCS-algorithms to date. In this application 714 compounds were compared. PMID- 23797998 TI - Turning wrong into right: the 2013 lung allocation controversy. PMID- 23797999 TI - Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing remitting multiple sclerosis: subgroup analyses of the DEFINE study. AB - In the double-blind, placebo-controlled, Phase 3 DEFINE study in patients with relapsing-remitting multiple sclerosis, oral BG-12 (dimethyl fumarate) significantly reduced the proportion of patients relapsed (primary endpoint), the annualized relapse rate (ARR), and confirmed disability progression (secondary endpoints) at two years compared with placebo. We investigated the efficacy of BG 12 240 mg twice daily (BID) and three times daily (TID) in patient subgroups stratified according to baseline demographic and disease characteristics including gender, age, relapse history, McDonald criteria, treatment history, expanded disability status scale score, T2 lesion volume, and gadolinium enhancing lesions. The clinical efficacy of BG-12 was generally consistent across patient subgroups and reflected positive findings in the overall DEFINE study population. Treatment with BG-12 BID and TID reduced the proportion of patients relapsed and the ARR at two years compared with placebo in all patient subgroups. Reductions in the risk of relapse with BG-12 BID vs. placebo ranged from 68% [hazard ratio 0.32 (95% confidence interval (CI) 0.16-0.62)] to 26% [0.74 (0.51 1.09)] and from 66% [0.34 (0.23-0.50)] to 25% [0.75 (0.42-1.36)] with BG-12 TID vs. placebo. BG-12 also reduced the risk of disability progression at two years compared with placebo in most subgroups of patients treated with the BID dosing regimen and in all subgroups treated with the TID regimen. These analyses indicate that treatment with BG-12 is consistently effective across a wide spectrum of patients with relapsing-remitting multiple sclerosis with varied demographic and disease characteristics. PMID- 23798000 TI - Recent advances in Parkinson's disease genetics. AB - The last 5 years have seen rapid progress in Parkinson's disease (PD) genetics, with the publication of a series of large-scale genome wide association studies for PD, and evaluation of the roles of the LRRK2 and GBA genes in the aetiology of PD. We are beginning to develop a coherent picture of the interplay of Mendelian and non-Mendelian factors in PD. Pathways involved in mitochondrial quality control (mitophagy), lysosomal function and immune function are emerging as important in the pathogenesis of PD. These pathways represent a target for therapeutic intervention and a way in which the heterogeneity of disease cause, as well as disease mechanism, can be established. In the future, there is likely to be an individualised basis for the treatment of PD, linked to the identification of specific genetic factors. PMID- 23798001 TI - Oncogene-induced cellular senescence elicits an anti-Warburg effect. AB - Cellular senescence, an irreversible cell cycle arrest induced by a diversity of stimuli, has been considered as an innate tumor suppressing mechanism with implications and applications in cancer therapy. Using a targeted proteomics approach, we show that fibroblasts induced into senescence by expression of oncogenic Ras exhibit a decrease of global acetylation on all core histones, consistent with formation of senescence-associated heterochromatic foci. We also detected clear increases in repressive markers (e.g. >50% elevation of H3K27me2/3) along with decreases in histone marks associated with increased transcriptional expression/elongation (e.g. H3K36me2/3). Despite the increases in repressive marks of chromatin, 179 loci (of 2206 total) were found to be upregulated by global quantitative proteomics. The changes in the cytosolic proteome indicated an upregulation of mitochondrial proteins and downregulation of proteins involved in glycolysis. These alterations in primary metabolism are opposite to the well-known Warburg effect observed in cancer cells. This study significantly improves our understanding of stress-induced senescence and provides a potential application for triggering it in antiproliferative strategies that target the primary metabolism in cancer cells. PMID- 23798002 TI - Occupational exposure to trichloroethylene and serum concentrations of IL-6, IL 10, and TNF-alpha. AB - To evaluate the immunotoxicity of trichloroethylene (TCE), we conducted a cross sectional molecular epidemiology study in China of workers exposed to TCE. We measured serum levels of IL-6, IL-10, and TNF-alpha, which play a critical role in regulating various components of the immune system, in 71 exposed workers and 78 unexposed control workers. Repeated personal exposure measurements were taken in workers before blood collection using 3 M organic vapor monitoring badges. Compared to unexposed workers, the serum concentration of IL-10 in workers exposed to TCE was decreased by 70% (P = 0.001) after adjusting for potential confounders. Further, the magnitude of decline in IL-10 was >60% and statistically significant in workers exposed to <12 ppm as well as in workers with exposures >= 12 ppm of TCE, compared to unexposed workers. No significant differences in levels of IL-6 or TNF-alpha were observed among workers exposed to TCE compared to unexposed controls. Given that IL-10 plays an important role in immunologic processes, including mediating the Th1/Th2 balance, our findings provide additional evidence that TCE is immunotoxic in humans. PMID- 23798003 TI - Depression in Parkinson's disease: identification and management. AB - Depression is a common psychiatric comorbidity in Parkinson's disease (PD) and contributes to significant impairments in cognitive, functional, motor, and social performance. This results in reduced quality of life, higher levels of care dependency, and increased caregiver burden. When treating depression, it is important to ensure that the patient's response to treatment will be adequately monitored. This can be accomplished in neurology or primary care settings, or in clinical settings with interdisciplinary treatment teams. Mental health services should be engaged early as a component of ongoing comprehensive care. This article reviews a general approach to treating the pharmacotherapy of depression in PD. Ultimately, clinicians should rely on empiric assessments of known risks and putative benefits to guide treatment decisions and should include a targeted and individualized multimodal approach that utilizes psychotherapeutic interventions along with pharmacologic therapies. PMID- 23798004 TI - Electrical measurement of red blood cell deformability on a microfluidic device. AB - This paper describes a microfluidic system and a technique for electrically measuring the deformability of red blood cells (RBCs). RBCs are deformed when they flow through a small capillary (microfluidic channel). The microfluidic device consists of two stages of microchannels as two measurement units for measuring cell size/volume and cell deformability. A low frequency voltage signal is established across the microfluidic channel, and electrical current signal is sampled continuously when RBCs pass through the measurement areas. Mechanical opacity is defined to mitigate the coupled effect of cell size/volume and deformability. The system performed tests on controlled, glutaraldehyde-treated, and heated RBCs using a number of driving pressures. The experimental results proved the capability of the system for distinguishing different RBC populations based on their deformability with a throughput of ~10 cells s(-1). PMID- 23798005 TI - Relations between hopelessness, depressive symptoms and suicidality: mediation by reasons for living. AB - OBJECTIVE: The present study examined whether reasons for living (RFL) would partially account for the associations between traditional risk factors (depressive symptoms, hopelessness) and suicidal ideation and attempts. METHOD: Data were collected from 1,075 undergraduate college students who completed a battery of online assessments. RESULTS: Results from a series of simultaneous mediational models indicated that the relations between risk factors and current suicidal ideation were partially mediated by total RFL (and Coping Beliefs and Self-Evaluation subscales). Further, total RFL (and the Coping Beliefs subscale) fully mediated the relation between hopelessness and past-year suicide attempt, and partially mediated the depressive symptoms-suicide attempt relation. CONCLUSIONS: This study demonstrates the importance of assessing for the presence of these suicide risk and protective factors. Implications for the improved identification and treatment of young adults at risk for suicide are discussed. PMID- 23798006 TI - Defining the optimal approach to the patient with postradiation prostate-specific antigen recurrence using outcome data from a prospective randomized trial. AB - BACKGROUND: Optimal management remains unknown following prostate-specific antigen (PSA) failure when considering comorbidity and PSA kinetics at recurrence. In order to define randomized controlled trials (RCTs) that can address this issue, this study examined factors associated with the risk of death following PSA failure. METHODS: Of 206 men randomized to RT with or without 6 months of androgen suppression therapy (AST), 108 sustained PSA failure and began AST when PSA approached 10 ng/mL and formed the study cohort. Cox regression multivariable analysis was used to determine factors associated with death following PSA failure. RESULTS: After a median follow-up of 10.3 years of 108 men with PSA failure, 64 (59%) died, with 22 (34%) dying of prostate cancer (PC). Increasing PSA velocity at recurrence was associated with a significant increase in the risk of death (adjusted hazard ratio, 1.21; 95% confidence interval, 1.02 1.45; P = .03). Among men with no/minimal versus moderate/severe comorbidity, PC comprised 42% (20 of 48) versus 12.5% (2 of 16) of all deaths, respectively. Estimates of PC-specific and all-cause death were significantly higher when PSA velocity was greater than as compared with the median or less in men with no/minimal (P < .008) but not moderate/severe comorbidity (P > .15). CONCLUSIONS: Despite unfavorable PSA kinetics at recurrence, unhealthy men may not benefit from AST; RCTs examining intermittent AST versus surveillance are needed. For healthy men with unfavorable PSA kinetics at recurrence, PC death rates are high despite AST, which warrants RCTs to evaluate the impact on death when adding agents that prolong survival in men with metastatic castration-resistant PC to AST. PMID- 23798007 TI - Introduction: Neurodevelopmental issues in inborn errors of metabolism. PMID- 23798008 TI - Peroxisome biogenesis disorders: Biological, clinical and pathophysiological perspectives. AB - The peroxisome biogenesis disorders (PBD) are a heterogeneous group of autosomal recessive disorders in which peroxisome assembly is impaired, leading to multiple peroxisome enzyme deficiencies, complex developmental sequelae and progressive disabilities. Mammalian peroxisome assembly involves the protein products of 16 PEX genes; defects in 14 of these have been shown to cause PBD. Three broad phenotypic groups are described on a spectrum of severity: Zellweger syndrome is the most severe, neonatal adrenoleukodystrophy is intermediate and infantile Refsum disease is less severe. Another group is Rhizomelic chondrodysplasia punctata spectrum. Recently, atypical phenotypes have been described, indicating that the full spectrum of these disorders remains to be identified. For most patients, there is a correlation between clinical severity and effect of the mutation on PEX protein function. Diagnosis relies on biochemical measurements of peroxisome functions and PEX gene sequencing. There are no targeted therapies, although management protocols have been suggested and research endeavors continue. In this review we will discuss peroxisome biology and PBD, and research contributions to pathophysiology and treatment. PMID- 23798009 TI - Sterol metabolism disorders and neurodevelopment-an update. AB - Cholesterol has numerous quintessential functions in normal cell physiology, as well as in embryonic and postnatal development. It is a major component of cell membranes and myelin, and is a precursor of steroid hormones and bile acids. The development of the blood brain barrier likely around 12-18 weeks of human gestation makes the developing embryonic/fetal brain dependent on endogenous cholesterol synthesis. Known enzyme defects along the cholesterol biosynthetic pathway result in a host of neurodevelopmental and behavioral findings along with CNS structural anomalies. In this article, we review sterol synthesis disorders in the pre- and post-squalene pathway highlighting neurodevelopmental aspects that underlie the clinical presentations and course of Smith-Lemli-Opitz Syndrome (SLOS), mevalonic aciduria (MVA) or the milder version hyper-immunoglobulinemia D and periodic fever syndrome (HIDS), Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (ABS1), congenital hemidysplasia with icthyosiform nevus and limb defects (CHILD) syndrome, CK syndrome, sterol C4 methyl oxidase (SC4MOL) deficiency, X-linked dominant chondrodysplasia punctata 2(CDPX2)/ Conradi Hunermann syndrome, lathosterolosis and desmosterolosis, We also discuss current controversies and share thoughts on future directions in the field. PMID- 23798010 TI - Congenital disorders of glycosylation and intellectual disability. AB - The congenital disorders of glycosylation (CDG) are a rapidly growing group of inborn errors of metabolism that result from defects in the synthesis of glycans. Glycosylation is a major post-translational protein modification and an estimated 2% of the human genome encodes proteins for glycosylation. The molecular bases for the current 60 disorders, affecting approximately 800 individuals, have been identified, many in the last 5 years. CDG should be considered in any multi system syndrome or single tissue disorder not explained by the identification of another disorder. The initial clinical presentation varies significantly among individuals, even between affected siblings. However, two thirds of the known CDGs are associated with intellectual disabilities and most affected individuals need support services throughout their lives. Additional disorders of glycosylation are likely to be characterized over time. PMID- 23798011 TI - Neuronopathic lysosomal storage diseases: clinical and pathologic findings. AB - BACKGROUND: The lysosomal-autophagocytic system diseases (LASDs) affect multiple body systems including the central nervous system (CNS). The progressive CNS pathology has its onset at different ages, leading to neurodegeneration and early death. METHODS: Literature review provided insight into the current clinical neurological findings, phenotypic spectrum, and pathogenic mechanisms of LASDs with primary neurological involvement. CONCLUSIONS: CNS signs and symptoms are variable and related to the disease-specific underlying pathogenesis. LAS dysfunction leads to diverse global cellular consequences in the CNS ranging from specific axonal and dendritic abnormalities to neuronal death. Pathogenic mechanisms for disease progression vary from impaired autophagy, massive storage, regional involvement, to end-stage inflammation. Some of these features are also found in adult neurodegenerative disorders, for example, Parkinson's and Alzheimer's diseases. Lack of effective therapies is a significant unmet medical need. PMID- 23798012 TI - Newborn screening for lysosomal storage disorders and other neuronopathic conditions. AB - Newborn screening (NBS) is a public health program aimed at identifying treatable conditions in presymptomatic newborns to avoid premature mortality, morbidity, and disabilities. Currently, every newborn in the Unites States is screened for at least 29 conditions where evidence suggests that early detection is possible and beneficial. With new or improved treatment options and development of high throughput screening tests, additional conditions have been proposed for inclusion into NBS programs. Among those are several conditions with a strong neuronopathic component. Some of these conditions have already been added to a few national and international screening programs, whereas others are undergoing pilot studies to determine the test performance metrics. Here, we review the current state of NBS for 13 lysosomal storage disorders, X-adrenoleukodystrophy, Wilson disease, and Friedreich ataxia. PMID- 23798013 TI - The neuronal ceroid-lipofuscinoses. AB - The neuronal ceroid-lipofuscinoses (NCL's, Batten disease) represent a group of severe neurodegenerative diseases, which mostly present in childhood. The phenotypes are similar and include visual loss, seizures, loss of motor and cognitive function, and early death. At autopsy, there is massive neuronal loss with characteristic storage in remaining neurons. Neurons appear to die because of increased rates of apoptosis and altered autophagy. Ten genes have been identified so far that result in an NCL (CLN1-10). The most common forms are CLN1, CLN2, and CLN3, which were previously known as Infantile, Late-Infantile, and Juvenile NCL's, respectively. CLN1 and CLN2 result from mutations in soluble lysosomal enzymes palmitoyl-protein thioesterase (PPT) and tripeptidyl peptidase 1 (TPP1), which can be measured in white blood cells for clinical diagnosis. Molecular diagnostic testing is routinely available for CLN1, CLN2, and CLN3. Sequencing of other NCL genes may be required to establish a diagnosis when the common forms are ruled out. The pathogenesis of NCL neuronal loss resulting from loss of function of any of the NCL gene products remains unknown and no treatment options are presently available. PMID- 23798015 TI - Neuroimaging of lipid storage disorders. AB - Lipid storage diseases, also known as the lipidoses, are a group of inherited metabolic disorders in which there is lipid accumulation in various cell types, including the central nervous system, because of the deficiency of a variety of enzymes. Over time, excessive storage can cause permanent cellular and tissue damage. The brain is particularly sensitive to lipid storage as the contents of the central nervous system must occupy uniform volume, and any increases in fluids or deposits will lead to pressure changes and interference with normal neurological function. In addition to primary lipid storage diseases, lysosomal storage diseases include the mucolipidoses (in which excessive amounts of lipids and carbohydrates are stored in the cells and tissues) and the mucopolysaccharidoses (in which abnormal glycosylated proteins cannot be broken down because of enzyme deficiency). Neurological dysfunction can be a manifestation of these conditions due to substrate deposition as well. This review will explore the modalities of neuroimaging that may have particular relevance to the study of the lipid storage disorder and their impact on elucidating aspects of brain function. First, the techniques will be reviewed. Next, the neuropathology of a few selected lipid storage disorders will be reviewed and the use of neuroimaging to define disease characteristics discussed in further detail. Examples of studies using these techniques will be discussed in the text. PMID- 23798014 TI - Neuropsychological outcomes in fatty acid oxidation disorders: 85 cases detected by newborn screening. AB - Mitochondrial fatty acid oxidation disorders include conditions in which the transport of activated acyl-Coenzyme A (CoA) into the mitochondria or utilization of these substrates is disrupted or blocked. This results in a deficit in the conversion of fat into energy. Most patients with fatty acid oxidation defects are now identified through newborn screening by tandem mass spectrometry. With earlier identification and preventative treatments, mortality and morbidity rates have improved. However, in the absence of severe health and neurological effects from these disorders, subtle developmental delays or neuropsychological deficits have been noted. Medical records were reviewed to identify outcomes in 85 children with FAOD's diagnosed through newborn screening and followed at one metabolic center. Overall, 54% of these children identified through newborn screening experienced developmental challenges. Speech delay or relative weakness in language was noted in 26 children (31%) and motor delays were noted in 24 children (29%). The majority of the 46 children receiving psychological evaluations performed well within the average range, with only 11% scoring <85 on developmental or intelligence tests. These results highlight the importance of screening children with fatty acid oxidation disorders to identify those with language, motor, or cognitive delay. Although expanded newborn screening dramatically changes the health and developmental outcomes in many children with fatty acid oxidation disorders, it also complicates the interpretation of biochemical and molecular findings and raises questions about the effectiveness or necessity of treatment in a large number of cases. Only by systematically evaluating developmental and neuropsychological outcomes using standardized methods will the true implications of newborn screening, laboratory results, and treatments for neurocognitive outcome in these disorders become clear. PMID- 23798016 TI - [Well-being self-determined]. PMID- 23798017 TI - Slice accelerated diffusion-weighted imaging at ultra-high field strength. AB - PURPOSE: Diffusion magnetic resonance imaging (dMRI) data with very high isotropic resolution can be obtained at 7T. However, for extensive brain coverage, a large number of slices is required, resulting in long acquisition times (TAs). Recording multiple slices simultaneously (SMS) promises to reduce the TA. METHODS: A combination of zoomed and parallel imaging is used to achieve high isotropic resolution dMRI data with a low level of distortions at 7T. The blipped-CAIPI (controlled aliasing in parallel imaging) approach is used to acquire several slices simultaneously. Due to their high radiofrequency (RF) power deposition and ensuing specific absorption rate (SAR) constraints, the commonly used multiband (MB) RF pulses for SMS imaging are inefficient at 7T and entail long repetition times, counteracting the usefulness of SMS acquisitions. To address this issue, low SAR multislice Power Independent of Number of Slices RF pulses are employed. RESULTS: In vivo dMRI results with and without SMS acceleration are presented at different isotropic spatial resolutions at ultra high field strength. The datasets are recorded at a high angular resolution to detect fiber crossings. CONCLUSION: From the results and compared with earlier studies at these resolutions, it can be seen that scan time is significantly reduced, while image quality is preserved. PMID- 23798018 TI - [Proctology]. PMID- 23798019 TI - [Evidence-based treatment of hemorrhoidal disease]. AB - Hemorrhoidal disease represents a prevalent benign condition of the lower gastrointestinal tract. As a common and early symptom of hemorrhoids, patients present with painless rectal bleeding during or after defecation. For the treatment of hemorrhoidal disease, a large variety of operative and non-operative therapeutic options exists. In the present article, the authors aim to provide guidance for stage-directed therapy of hemorrhoidal disease based on up-to-date knowledge and the authors' own clinical experience. PMID- 23798020 TI - [Surgical treatment of fistula-in-ano--a journey between Skylla and Charybdis]. AB - This review discusses the pathogenesis, symptomatology, diagnostic work-up, and treatment options for fistula-in-ano, which is a common condition that affects ~ 20 in 100,000 per year with a predominance for young males. Fistula-in-ano normally presents as an acute anorectal abscess that subsequently becomes established as a chronic discharging fistula. The illness is characterized by chronic perianal discharge and intermittent pain. The aim of surgical treatment is permanent cure of the fistula whilst maintaining patient continence. This principle forms the basis of surgical decision-making and means that treatment options often have to be individualized for each patient. Low, simple fistulae may be treated by fistulotomy because of the low risk of incontinence. In contrast, high fistulae that contain a greater proportion of sphincter muscle demand more complex operations. Traditional reconstructive techniques (transanal advancement flap, primary sphincter reconstruction) aim to eradicate the fistula whilst leaving the sphincter muscle intact or readapted, whilst newer techniques (biosynthetic plugs) provide a scaffold to encourage normal tissue ingrowth with fistula occlusion. The newer procedures preserve the sphincter ideally. On the other hand success rates of these techniques are somewhat disappointing. PMID- 23798021 TI - [Therapy of pilonidal sinus--is more always better]. AB - Nowadays the etiology of pilonidal sinus is explained as an acquired disease in form of ruptured hair follicles. It occurs most frequently in the proximal rima ani. Pilonidal disease is common in young men. Acute abscess formation and chronic discharge from the fistula represent indications for surgery. Surgical therapy has evolved from radical excision followed by months of open wound healing towards procedures causing less morbidity. In case of an acute abscess it is important to separate time-wise incision of the abscess in local anaesthesia from definitive excision of the fistula. Two surgical methods are compelling. First the minimal-invasive sinusectomy with sparse excision of the pori and the fistula preserving intact subcutaneous tissue. This procedure can be performed in local anaesthesia in an outpatient setting. The recurrence rate after 4 years is 7 %. Alternatively there is the possibility of a primary plastic wound closure by a rotation flap. Open wound healing can be avoided and the recurrence rate is as low as 3 %. To prevent recurrences a laser epilation has to be considered on individual decision. PMID- 23798022 TI - [Acute anal pain]. AB - Acute anal pain is a common proctological problem. A detailed history together with the clinical examination are crucial for the diagnosis. An acute perianal vein thrombosis can be successfully excised within the first 72 hours. Acute anal fissures are best treated conservatively using stool regulation and topical medications reducing the sphincter spasm. A chronic anal fissure needs surgery. Perianal abscesses can very often be incised and drained in local anesthesia. Proctalgia fugax and the levator ani syndrome are exclusion diagnoses and are treated symptomatically. PMID- 23798023 TI - [Fecal incontinence--a treatable problem!]. AB - Faecal incontinence has an enormous negative impact on patients' quality of life. Although the causes for faecal incontinence may vary (idiopatic, neurogenic, due to pregnancy, birth trauma or anorectal surgery), nowadays different therapies are available to cure or support patients after failure of conservative treatment. During the past decade, sacral nerve stimulation has shown to provide major improvement to patients with faecal incontinence. Regardless of the underlying disease (sphincter defect, diabetes mellitus, multiple sclerosis or idiopathic) the success rate of SNS lies over 80 %. The operation is performed under local anaesthesia and has a low morbidity rate. Not only its good long time results but also its cost effectiveness is based on scientific evidence. PMID- 23798024 TI - [Anorectal manifestations of sexually transmitted infections]. AB - The incidence of sexually transmitted infections is rising in Europe and in Switzerland since the beginning of the third millenium. Many organisms may affect the perianal skin and the anorectum. While some of these infections are a result of contigous spread from genital infection, most result from receptive anal intercourse affecting males who have sex with males but is seen increasingly in females as well since there is evidence of the increasing popularity of anal sex among heterosexuals. The symptoms of specific infections are largely dependent on the route and site of inoculation. Organisms that cause typical genital symptoms such as syphilis, chancroid, herpes simplex or HPV-infection - result in similar symptoms when the perianal skin, the anoderm or the distal anal canal are the site of infection. Patients with proctitis may have unspecific signs in various degrees including mucous discharge, rectal bleeding, anorectal pain, superficial ulcers and sometimes generalized lymphadenopathy and fever. It is of utmost importance to include STIs (e. g. lymphogranuloma venereum, gonorrhea, non-LGV chlamydia and herpes simplex) in the differential diagnosis in these patients. Unfortunately rectal infection with chlamydia and gonorrhea is asymptomatic in the majority of cases of men having sex with men and in high-risk females. A careful history and physical examination is essential in establishing a correct diagnosis, usually supported by proctoscopy, culture, PCR, serology and histology. Certain organisms, more commonly thought of as food- or water-borne disease may be sexually transmitted by direct or indirect fecal-oral contact from various sexual practices. PMID- 23798025 TI - [Perianal Crohn's disease]. AB - In patients with Crohn's disease, perianal lesions can be found at presentation in 20 - 30 % of all cases and a majority will have fistulas or abscesses. If a fistula is suspected, careful inspection of the perianal region will often confirm the diagnosis. Further investigation should be done by magnet-resonance imaging or anal endosonography to guide preoperative planing and minimize recurrence rates. Simple, uncomplicated fistulas are primarily treated with antibiotics. For complex fistulas combined with medication and surgical treatment usually offers the best treatment. Treatment of complex fistulas by surgery alone is rarely curative and may have significant morbidity, while medical treatment has the disadvantage of high recurrence rates and significant costs for long-term therapy. In trans-, supra- and extrasphincteric fistulas, immunosuppressants or anti-TNF alpha blockers will lead to sustained clinical remission with fistula closure in 30 - 50 %. However, 25 % of all patients with perianal Croh's disease will still need surgery during the course of their disease. Fistulotomy is used for subcutaneous or short intersphincteric fistulas while it should be avoided in fistulas with significant involvmenet of the sphincter muscles to avoid fecal incontinence. Seton drainage may be used as definitve treatment or as a bridge to a secondary surgical therapy. Minimally invasive precedures, such as the anal fistula plug have also been used in Crohn's disease. Although recurrence rates are high, the procedure is easy to perform and carries a low risk of incontinence and may therefore be used as primary treatment option for complex fistulas. The fistulectomy and closure of the inner fistula opening, e. g. with a mucosal advancement flap, is still considered the standard procedure, especially for complex fistulas. Anal fissures, ulcers and strictures are non-fistulating perianal lesions of Crohn's disease. PMID- 23798026 TI - Screening for hepatitis C virus infection in adults: U.S. Preventive Services Task Force recommendation statement. AB - DESCRIPTION: Update of the 2004 U.S. Preventive Services Task Force (USPSTF) recommendation on screening for and treatment of hepatitis C virus (HCV) infection in asymptomatic adults. METHODS: The Agency for Healthcare Research and Quality commissioned 2 systematic reviews on screening for and treatment of HCV infection in asymptomatic adults, focusing on evidence gaps identified in the previous USPSTF recommendation and new studies published since 2004. The evidence on screening for HCV in pregnant women was also considered. POPULATION: This recommendation applies to all asymptomatic adults without known liver disease or functional abnormalities. RECOMMENDATION: The USPSTF recommends screening for HCV infection in persons at high risk for infection. The USPSTF also recommends offering 1-time screening for HCV infection to adults born between 1945 and 1965. (B recommendation). PMID- 23798027 TI - Stress induces plant somatic cells to acquire some features of stem cells accompanied by selective chromatin reorganization. AB - BACKGROUND: Previous data suggested that senescing cells or cells exposed to acute stress may acquire stem cell properties characterized by open chromatin conformation and by promiscuous expression of transcription factor genes. To further explore the link between stress response and dedifferentiation, we generated transgenic plants in which a reporter AtMBD6-GFP is controlled by a meristem-specific promoter derived from the ANAC2 gene together with the analysis of chromatin conformation. RESULTS: We found that ANAC2 promoter is essentially active in the shoot and the root apical meristems including leaf primordia. ANAC2 was activated in mature leaves following exposure to various stress conditions including protoplasting and dark. This activity was associated with decondensation of pericentric but not of centromeric chromatin. Using epigenetic mutants, ddm1 and kyp/suvh4, we found that compaction at centromeric chromatin persists despite a significant reduction in DNA and histone methylation. CONCLUSIONS: Our results suggest that extreme environmental signals trigger plant somatic cells to acquire stem cell properties before assuming a new cell fate. Results also pointed to distinct mechanisms involved in controlling chromatin compaction at chromocenter and that compaction of centromeric chromatin may not be dependent on epigenetic means driven by DDM1 and KYP/SUVH4 chromatin modifier proteins. PMID- 23798028 TI - Fractal analysis illuminates the form of connectionist structural gradualness. AB - We examine two connectionist networks-a fractal learning neural network (FLNN) and a Simple Recurrent Network (SRN)-that are trained to process center-embedded symbol sequences. Previous work provides evidence that connectionist networks trained on infinite-state languages tend to form fractal encodings. Most such work focuses on simple counting recursion cases (e.g., anbn), which are not comparable to the complex recursive patterns seen in natural language syntax. Here, we consider exponential state growth cases (including mirror recursion), describe a new training scheme that seems to facilitate learning, and note that the connectionist learning of these cases has a continuous metamorphosis property that looks very different from what is achievable with symbolic encodings. We identify a property-ragged progressive generalization-which helps make this difference clearer. We suggest two conclusions. First, the fractal analysis of these more complex learning cases reveals the possibility of comparing connectionist networks and symbolic models of grammatical structure in a principled way-this helps remove the black box character of connectionist networks and indicates how the theory they support is different from symbolic approaches. Second, the findings indicate the value of future, linked mathematical and empirical work on these models-something that is more possible now than it was 10 years ago. PMID- 23798029 TI - Preclinical and phase I results of decitabine in combination with midostaurin (PKC412) for newly diagnosed elderly or relapsed/refractory adult patients with acute myeloid leukemia. AB - PURPOSE: To determine the preclinical activity, clinical maximum tolerated dose (MTD), and recommended phase II dose of midostaurin (MS) combined either sequentially or concurrently with intravenous decitabine (DAC) in newly diagnosed patients 60 years or older or relapsed/refractory adult patients (18 years or older) with acute myeloid leukemia (AML). PATIENTS AND METHODS: Cultured and primary AML cells were treated with DAC and/or MS and analyzed by flow cytometry and immunoblot analyses. In the phase I study, 16 patients were enrolled; 8 were newly diagnosed patients 60 years or older and 8 were 18 years or older with relapsed AML. Only 2 of 16 patients (13%) had FLT3-internal tandem duplication (ITD) mutations, and no patient had KIT mutations. RESULTS: Compared with treatment with either agent alone, sequential treatment with DAC and MS exerted superior anti-AML activity in cultured and primary FLT3-ITD-expressing AML cells. In the subsequent phase I study, the MTD and schedule of administration of the combination was identified as DAC followed by MS. Three patients developed dose limiting toxicities: two patients developed pulmonary edema requiring mechanical ventilation and one patient developed a prolonged QTc greater than 500 msec. Based on an intent-to-treat analysis, 57% of the patients achieved stable disease or better while enrolled in the trial; 25% had a complete hematologic response. Pharmacokinetic analysis revealed results similar to those previously reported for MS. CONCLUSION: The in vitro combination of DAC and MS is synergistically active against FLT3-ITD mutations expressing AML cells. In a clinical setting, the combination of sequentially administered DAC followed by MS is possible without significant unexpected toxicity, but the concurrent administration of DAC and MS led to pulmonary toxicity after only a few doses. On the basis of these results, additional studies exploring the sequential combination of untreated AML in elderly patients are warranted to further evaluate this combination at the MTD. PMID- 23798030 TI - Sensory and cognitive influences on the training-related improvement of reading speed in peripheral vision. AB - Reading speed in normal peripheral vision is slow but can be increased through training on a letter-recognition task. The aim of the present study is to investigate the sensory and cognitive factors responsible for this improvement. The visual span is hypothesized to be a sensory bottleneck limiting reading speed. Three sensory factors-letter acuity, crowding, and mislocations (errors in the spatial order of letters)-may limit the size of the visual span. Reading speed is also influenced by cognitive factors including the utilization of information from sentence context. We conducted a perceptual training experiment to investigate the roles of these factors. Training consisted of four daily sessions of trigram letter-recognition trials at 10 degrees in the lower visual field. Subjects' visual-span profiles and reading speeds were measured in pre- and posttests. Effects of the three sensory factors were isolated through a decomposition analysis of the visual span profiles. The impact of sentence context was indexed by context gain, the ratio of reading speeds for ordered and unordered text. Following training, visual spans increased in size by 5.4 bits of information transmitted, and reading speeds increased by 45%. Training induced a substantial reduction in the magnitude of crowding (4.8 bits) and a smaller reduction for mislocations (0.7 bits), but no change in letter acuity or context gain. These results indicate that the basis of the training-related improvement in reading speed is a large reduction in the interfering effect of crowding and a small reduction of mislocation errors. PMID- 23798031 TI - The temporal characteristics of the early and late stages of L- and M-cone pathways that signal brightness. AB - Flickering 560-nm light appears brighter and less saturated than steady light of the same average intensity. The changes in appearance are consistent with the visual signal's being distorted at some nonlinear site (or sites) within the visual pathway at which new temporal components, not part of the original waveform, are produced. By varying the input stimulus to manipulate these new temporal components--called distortion products--and measuring our observers' sensitivity in detecting them, we derived the temporal attenuation characteristics of the early (prenonlinearity) and late (post-nonlinearity) stages of the L- and M-cone pathway that signals brightness. We found that the early stage acts like a band-pass filter peaking at 10-15 Hz with sensitivity losses at both lower and higher frequencies, whereas the late stage acts like a two-stage low-pass filter with a corner frequency near 3 Hz. Although brightness is often associated with the fast achromatic or luminance pathway, these filter characteristics, and particularly those of the late filter, are consistent with comparable features of the L-M chromatic pathway that produce mainly chromatic distortion products (Petrova, Henning, & Stockman, 2013). A plausible site for the nonlinearity is after surround antagonism from horizontal cells. Modeling suggested the form of the nonlinearity to be initially expansive but possibly with a hard limit at the highest input levels. PMID- 23798032 TI - Brightness and transparency in the early visual cortex. AB - Several psychophysical studies have shown that transparency can have drastic effects on brightness and lightness. However, the neural processes generating these effects have remained unresolved. Several lines of evidence suggest that the early visual cortex is important for brightness perception. While single cell recordings suggest that surface brightness is represented in the primary visual cortex, the results of functional magnetic resonance imaging (fMRI) studies have been discrepant. In addition, the location of the neural representation of transparency is not yet known. We investigated whether the fMRI responses in areas V1, V2, and V3 correlate with brightness and transparency. To dissociate the blood oxygen level-dependent (BOLD) response to brightness from the response to local border contrast and mean luminance, we used variants of White's brightness illusion, both opaque and transparent, in which luminance increments and decrements cancel each other out. The stimuli consisted of a target surface and a surround. The surround luminance was always sinusoidally modulated at 0.5 Hz to induce brightness modulation to the target. The target luminance was constant or modulated in counterphase to null brightness modulation. The mean signal changes were calculated from the voxels in V1, V2, and V3 corresponding to the retinotopic location of the target surface. The BOLD responses were significantly stronger for modulating brightness than for stimuli with constant brightness. In addition, the responses were stronger for transparent than for opaque stimuli, but there was more individual variation. No interaction between brightness and transparency was found. The results show that the early visual areas V1-V3 are sensitive to surface brightness and transparency and suggest that brightness and transparency are represented separately. PMID- 23798033 TI - Thermodynamic and functional characteristics of deep-sea enzymes revealed by pressure effects. AB - Hydrostatic pressure analysis is an ideal approach for studying protein dynamics and hydration. The development of full ocean depth submersibles and high pressure biological techniques allows us to investigate enzymes from deep-sea organisms at the molecular level. The aim of this review was to overview the thermodynamic and functional characteristics of deep-sea enzymes as revealed by pressure axis analysis after giving a brief introduction to the thermodynamic principles underlying the effects of pressure on the structural stability and function of enzymes. PMID- 23798034 TI - Genetic and environmental influence on DNA strand break repair: a twin study. AB - Accumulation of DNA damage deriving from exogenous and endogenous sources has significant consequences for cellular survival, and is implicated in aging, cancer, and neurological diseases. Different DNA repair pathways have evolved in order to maintain genomic stability. Genetic and environmental factors are likely to influence DNA repair capacity. In order to gain more insight into the genetic and environmental contribution to the molecular basis of DNA repair, we have performed a human twin study, where we focused on the consequences of some of the most abundant types of DNA damage (single-strand breaks), and some of the most hazardous lesions (DNA double-strand breaks). DNA damage signaling response (Gamma-H2AX signaling), relative amount of endogenous damage, and DNA-strand break repair capacities were studied in peripheral blood mononuclear cells from 198 twins (94 monozygotic and 104 dizygotic). We did not detect genetic effects on the DNA-strand break variables in our study. PMID- 23798035 TI - Premenstrual disorders and rumination. AB - OBJECTIVES: Premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) involve emotional, behavioral, and physical symptoms; however, there is little understanding of psychological factors that contribute to these disorders. It was hypothesized that rumination, a form of depressive self-focused attention, is related to premenstrual distress. METHOD: Study 1 involved women (N = 735) meeting criteria for No/Mild PMS, Moderate/Severe PMS, and PMDD using retrospective self-report. Study 2 involved women (N = 85) meeting diagnostic criteria for PMS or PMDD (i.e., PMD group) and healthy controls (i.e., No PMD group) following 60-day symptom monitoring. Participants in both studies completed questionnaires of rumination, anxiety sensitivity, and coping styles. RESULTS: Rumination was strongly related to premenstrual disorders using both retrospective and prospective reports, as well as both categorical and continuous approaches to classification of premenstrual distress. CONCLUSIONS: Rumination, a transdiagnostic factor in psychopathology, may contribute to the onset and maintenance of premenstrual distress. PMID- 23798038 TI - Tumor perfusion-related parameter of diffusion-weighted magnetic resonance imaging: correlation with histological microvessel density. AB - PURPOSE: We obtained intravoxel incoherent motion (IVIM) parameters through biexponential analysis on diffusion-weighted MR imaging (DWI) using multiple b values. Correlation was evaluated between these parameters and histological microvessel density (MVD) for the possibility of noninvasive evaluation of MVD with DWI. METHODS: Twenty-five nude mice with the HT29 colorectal cancer cells implanted were analyzed after undergoing DWI with multiple b values (0, 50, 100, 300, 500, 700, and 1000 s/mm(2)). Tissue diffusivity (D(t)), pseudo-diffusion coefficient (D(p)), and perfusion fraction (f(p)) were calculated using a biexponential analysis, and these parameters were correlated with MVD. The MVD was determined with the CD31 stain. For statistical analysis, Spearman's rank correlation was applied. RESULTS: The mean value and correlation coefficient with MVD for each IVIM parameter were as follows: D(t) = 0.98 +/- 0.06 * 10(-3) mm(2)/s with r = 0.139 (P = 0.508); D(p) = 23.70 +/- 7.94 * 10(-3) mm(2)/s with r = 0.782 (P < 0.001); and f(p) = 15.58 +/- 5.7% with r = 0.749 (P < 0.001). D(p) and f(p) showed significant correlation with MVD, but D(t) did not. CONCLUSION: The IVIM parameters, D(p) and f(p), on DWI might be used in the noninvasive evaluation of MVD. PMID- 23798039 TI - Use of digital technologies for nasal prosthesis manufacturing. AB - BACKGROUND AND AIM: Digital technology is becoming more accessible for common use in medical applications; however, their expansion in prosthetic and orthotic laboratories is not large because of the persistent image of difficult applicability to real patients. This article aims to offer real example in the area of human facial prostheses. TECHNIQUE: This article describes the utilization of optical digitization, computational modelling, rapid prototyping, mould fabrication and manufacturing of a nasal silicone prosthesis. This technical note defines the key points of the methodology and aspires to contribute to the introduction of a certified manufacturing procedure. DISCUSSION: The results show that the used technologies reduce the manufacturing time, reflect patient's requirements and allow the manufacture of high-quality prostheses for missing facial asymmetric parts. The methodology provides a good position for further development issues and is usable for clinical practice. Clinical relevance Utilization of digital technologies in facial prosthesis manufacturing process can be a good contribution for higher patient comfort and higher production efficiency but with higher initial investment and demands for experience with software tools. PMID- 23798040 TI - Effect of custom-made and prefabricated orthoses on grip strength in persons with carpal tunnel syndrome. AB - BACKGROUND: Based on the literature, patients with carpal tunnel syndrome are suggested to wear a custom-made wrist orthosis immobilizing the wrist in a neutral position. Many prefabricated orthoses are available on the market, but the majority of those do not assure neutral wrist position. OBJECTIVES: We hypothesized that the use of orthosis affects grip strength in persons with carpal tunnel syndrome in a way that supports preference for custom-made orthoses with neutral wrist position over prefabricated orthoses. STUDY DESIGN: Experimental. METHODS: Comparisons of grip strength for three types of grips (cylindrical, lateral, and pinch) were made across orthosis types (custom-made, prefabricated with wrist in 20 degrees of flexion, and none) on the affected side immediately after fitting, as well as between affected side without orthosis and nonaffected side. RESULTS: Orthosis type did not significantly affect grip strength (p = 0.661). Cylindrical grip was by far the strongest, followed by lateral and pinch grips (p < 0.050). The grips of the affected side were weaker than those of the nonaffected side (p = 0.002). CONCLUSIONS: In persons with carpal tunnel syndrome, neither prefabricated orthoses with 20 degrees wrist extension nor custom-made wrist orthoses with neutral wrist position influenced grip strength of the affected hand. Compared to the nonaffected side, the grips of the affected side were weaker. CLINICAL RELEVANCE: The findings from this study can be used to guide application of orthoses to patients with carpal tunnel syndrome. PMID- 23798041 TI - Prediction of the skeletal medio-lateral dimension using non-invasive anthropometric measurements for the provision of ischial containment sockets: a pilot study. AB - BACKGROUND: Great emphasis is placed on the skeletal medio-lateral to maintain the normal adduction of the remnant femur and to ensure coronal plane stability in an ischial containment socket. Given the invasiveness of the skeletal medio lateral measurement, an alternative approach using prediction based on non invasive measures would be welcomed. OBJECTIVES: Determine the accuracy with which the skeletal medio-lateral dimension could be predicted using sex, stature, anterior-posterior dimension and iliofemoral angle. STUDY DESIGN: Cross sectional. METHOD: Anthropometric measurements on 77 persons were recorded and used as input data into a standard multiple regression. RESULTS: The regression model explained 59% of the variance in skeletal medio-lateral (r(2) = 0.59) that was statistically significant (F(4,72) = 25.37, p = 0.000). Only sex contributed significantly to the prediction of skeletal medio-lateral (beta = 0.67, t = 6.15, p = 0.00). The degree of error associated with the regression model (sum of squared errors = 0.009) indicated that the actual skeletal medio-lateral could be predicted within +/-18 mm in 95% of the cases. CONCLUSION: The regression model is not sufficiently accurate to predict skeletal medio-lateral for clinical purposes. Accuracy of the prediction could be improved with more accurate input data from computed tomography scans and use of other independent variables that explain the unique variance not already described by the participants' sex. Clinical relevance This pilot study demonstrates potential for the skeletal medio lateral to be predicted using non-invasive anthropometric measurements. Given this proof of concept, future investigators should use more accurate input data from computed tomography scans and identify alternative independent variables that explain the variance in the skeletal medio-lateral not attributable to sex. PMID- 23798042 TI - Incidence of lower limb amputation in Australian hospitals from 2000 to 2010. AB - BACKGROUND: Contemporary literature reports that the incidence of lower limb amputation has declined in many countries. This impression may be misleading given that many publications only describe the incidence of lower limb amputations above the ankle and fail to include lower limb amputations below the ankle. OBJECTIVES: To describe trends in the incidence of different levels of lower limb amputation in Australian hospitals over a 10-year period. STUDY DESIGN: Descriptive. METHOD: Data describing the age-standardised incidence of lower limb amputation were calculated from the Australian National Hospital Morbidity database and analysed for trends over a 10-year period. RESULTS: The age-standardised incidence of lower limb amputation remained unchanged over time (p = 0.786). A significant increase in the incidence of partial foot amputations (p = 0.001) and a decline in the incidence of transfemoral (p = 0.00) and transtibial amputations (p = 0.00) were observed. There are now three lower limb amputations below the ankle for every lower limb amputation above the ankle. CONCLUSION: While the age-standardised incidence of all lower limb amputation has not changed, a shift in the proportion of lower limb amputations above the ankle and lower limb amputations below the ankle may be the result of improved management of precursor disease that makes partial foot amputation a more commonly utilised alternative to lower limb amputations above the ankle. Clinical relevance This article highlights that although the incidence of lower limb amputation has remained steady, the proportion of amputations above the ankle and below the ankle has changed dramatically over the last decade. This has implications for how we judge the success of efforts to reduce the incidence of lower limb amputation and the services required to meet the increasing proportion of persons with amputation below the ankle. PMID- 23798043 TI - The Araz medial linkage orthosis: a new orthosis for walking in patients with spinal cord injury: a single patient study. AB - BACKGROUND: This article describes the development and evaluation of a new medial linkage orthosis to potentially assist paraplegic patients to ambulate. CASE DESCRIPTION AND METHODS: The orthosis was initially designed using the solid works program and was subsequently evaluated when used by a spinal cord injury subject to test the structure during standing and walking. Gait analysis was used to compare the medial linkage orthosis to a standard hip-knee-ankle-foot orthosis. FINDINGS AND OUTCOMES: The results demonstrated improvements in gait velocity, step length, and decreased compensatory motions in the new orthosis compared to the hip-knee-ankle-foot orthosis. CONCLUSIONS: The results propose that this new Araz medial linkage orthosis could be used to assist paraplegic subjects who have adequate ranges of motion and also with weakness or reduced tone to stand and walk. Clinical relevance The Araz medial linkage orthosis can potentially provide standing and walking assistance for spinal cord injury patients. PMID- 23798044 TI - Assessment of aerobic capacity and walking economy of unilateral transfemoral amputees. AB - BACKGROUND: Studies of the maximal oxygen uptake (VO(2max)) of transfemoral amputees have mostly used protocols that activate a relatively small muscle mass. Consequently, transfemoral amputee VO(2max) may be systematically underestimated, and the validity of these test protocols is questionable. OBJECTIVES: (1) Investigate validity and reliability of a VO(2max) walking protocol and (2) compare the VO(2max) of a transfemoral amputee group with a group of matching controls. STUDY DESIGN: (1) Randomized crossover study: walking versus running VO(2max) for the control group and (2) case-control study: transfemoral amputees versus control group VO(2max). METHODS: Twelve transfemoral amputees and control participants performed a walking VO(2max) test with increasing treadmill inclinations to voluntary exhaustion. The control group also completed a running ("gold-standard") VO(2max) test. RESULTS: Mean (standard deviation) control group VO(2max) following walking and running was similar, that is, 2.99 (0.6) L min(-1) and 3.09 (0.7) L min(-1), respectively. Mean (standard deviation) transfemoral amputee walking VO(2max) was 2.14 (0.8) L min(-1) (compared to CON; p < 0.01). Mean intraclass correlation coefficient of repeated VO(2) measurements was 0.97, and within-subjects standard deviation was 60 mL min(-1). CONCLUSIONS: The walk protocol is valid. Walking VO(2max) of transfemoral amputees was 40% lower compared to control group. Reliability of the walking protocol is comparable to other walking protocols. Clinical relevance The design, alignment, and materials of prostheses are important for effective ambulation. Cardio-respiratory fitness is, however, also important in this regard, and a low fitness may compromise health and independent living. Hence, transfemoral amputees with low physical fitness should engage in regular physical activity to improve health, gait capacity, and independency. PMID- 23798045 TI - The effect of ankle-foot orthoses on self-reported balance confidence in persons with chronic poststroke hemiplegia. AB - BACKGROUND: One intervention often used to address physical impairments post stroke is an ankle-foot orthosis. Ankle-foot orthoses may improve walking speed, stride length, and gait pattern. However, effects on balance, crucial for safe ambulation, are thus far inconclusive. One aspect of balance shown to contribute to functional ability is self-efficacy. Self-efficacy, defined as the belief in one's ability to succeed in particular situations, has been shown to be more strongly associated with activity and participation (as defined by the International Classification of Functioning, Disability, and Health) than physical performance measures of gait or balance. OBJECTIVES: We investigated whether self-efficacy, or balance confidence when referred to in the context of balance capabilities, is improved with ankle-foot orthosis use. STUDY DESIGN: Repeated measures study design. METHODS: Balance confidence was measured using the Activities-specific Balance Confidence Scale in 15 persons with chronic poststroke hemiplegia, with and without their regular ankle-foot orthosis. RESULTS: Activities-specific Balance Confidence Scale scores were significantly higher (p <= 0.01) for the ankle-foot orthosis condition compared to no ankle foot orthosis. CONCLUSIONS: One mechanism by which ankle-foot orthosis use may influence balance is improved balance confidence. Future work should explore the specific mechanisms underlying this improvement in self-efficacy. Clinical relevance Self-efficacy may be an important factor to consider when evaluating functioning post stroke. Rehabilitative interventions that improve balance confidence may help restore participation and overall functioning in pathological populations, particularly in the fall-prone poststroke population. Study results provide evidence for improvements in balance confidence with ankle-foot orthosis use. PMID- 23798046 TI - A phase 2 trial of intravenous and intraperitoneal paclitaxel combined with S-1 for treatment of gastric cancer with macroscopic peritoneal metastasis. AB - BACKGROUND: The prognosis of patients with gastric cancer with peritoneal metastasis is extremely poor. This phase 2 study evaluated the benefits and tolerability of weekly intravenous and intraperitoneal paclitaxel (PTX) treatment combined with oral S-1 in patients with gastric cancer who had macroscopic peritoneal metastasis. METHODS: Patients with gastric cancer who had primary tumors with macroscopic peritoneal metastasis were enrolled. PTX was administered intravenously at 50 mg/m2 and intraperitoneally at 20 mg/m2 on days 1 and 8, respectively. S-1 was administered at 80 mg/m2 per day for 14 consecutive days, followed by 7 days of rest. The primary endpoint was the 1-year overall survival (OS) rate. The secondary endpoints were the response rate, efficacy against malignant ascites, and safety. RESULTS: Thirty-five patients were enrolled. The median number of treatment courses was 11 (range, 2-35). The 1-year OS rate was 77.1% (95% confidence interval, 60.5-88.1). The overall response rate was 71% in 7 patients with target lesions. Malignant ascites disappeared or decreased in 15 of 22 (68%) patients. The frequent grade 3/4 toxic effects were neutropenia (34%), leukopenia (23%), and anemia (9%). CONCLUSIONS: Combination chemotherapy consisting of intravenous and intraperitoneal PTX with S-1 is well-tolerated and effective in patients with gastric cancer who have macroscopic peritoneal metastasis. PMID- 23798047 TI - 100 years of vitamins. PMID- 23798048 TI - The discovery of the vitamins. AB - The discovery of the vitamins was a major scientific achievement in our understanding of health and disease. In 1912, Casimir Funk originally coined the term "vitamine". The major period of discovery began in the early nineteenth century and ended at the mid-twentieth century. The puzzle of each vitamin was solved through the work and contributions of epidemiologists, physicians, physiologists, and chemists. Rather than a mythical story of crowning scientific breakthroughs, the reality was a slow, stepwise progress that included setbacks, contradictions, refutations, and some chicanery. Research on the vitamins that are related to major deficiency syndromes began when the germ theory of disease was dominant and dogma held that only four nutritional factors were essential: proteins, carbohydrates, fats, and minerals. Clinicians soon recognized scurvy, beriberi, rickets, pellagra, and xerophthalmia as specific vitamin deficiencies, rather than diseases due to infections or toxins. Experimental physiology with animal models played a fundamental role in nutrition research and greatly shortened the period of human suffering from vitamin deficiencies. Ultimately it was the chemists who isolated the various vitamins, deduced their chemical structure, and developed methods for synthesis of vitamins. Our understanding of the vitamins continues to evolve from the initial period of discovery. PMID- 23798049 TI - Micronutrients - a global perspective on intake, health benefits and economics. AB - The link between a sufficient intake of vitamins and long term health, cognition, healthy development and aging is increasingly supported by experimental animal, human and epidemiology studies. In low income countries billions of people still suffer from the burden of malnutrition and micronutrient deficiencies. However, inadequate micronutrient status might also be an issue in industrialized countries. Recent results from nutritional surveys in countries like the United States, Germany, and Great Britain indicate that the recommended intake of micronutrients is not reached. This notably concerns certain vulnerable population groups, such as pregnant women, young children and the elderly, but also greatly influences the general healthcare costs. An overview is provided on the gap that exists between current vitamin intakes and requirements, even in countries where diverse foods are plentiful. Folic acid and vitamin D intake and status are evaluated in more detail, providing insight on health and potential impact on health care systems. PMID- 23798050 TI - Vitamin D - from essentiality to functionality. AB - Vitamin D is essential in bone and muscle health. Severe deficiency (25 hydroxyvitamin D serum levels < 25 nmol/l) can result in rickets and osteomalacia, fractures, myopathy and falls. All recent recommendations on vitamin D agree that children and adults should reach a target 25-hydroxyvitamin D range of at least 50 nmol/l (threshold for normal vitamin D status) and 50 % of the population may be below that threshold. A vitamin D intake of 600 to 800 IU per day as recommended today will prevent about 97 % of children and adults from vitamin D deficiency. Notably, a higher 25-hydroxyvitamin D threshold of more than 60 nmol/l is needed for optimal functionality, fall and fracture in adults age 65 and older. PMID- 23798051 TI - Vitamins - wrong approaches. AB - Deficiencies of essential nutrients have been responsible for many epidemic outbreaks of deficiency diseases in the past. Large observational studies point at possible links between nutrition and chronic diseases. Low intake of antioxidant vitamins e. g. have been correlated to increased risk of cardiovascular diseases or cancer. The main results of these studies are indications that an intake below the recommendation could be one of the risk factors for chronic diseases. There was hardly any evidence that amounts above the RDA could be of additional benefit. Since observational studies cannot prove causality, the scientific community has been asking for placebo-controlled, randomized intervention trials (RCTs). Thus, the consequences of the epidemiological studies would have been to select volunteers whose baseline vitamin levels were below the recommended values. The hypothesis of the trial should be that correcting this risk factor up to RDA levels lowers the risk of a disease like CVD by 20 - 30 %. However, none of the RCTs of western countries was designed to correct a chronic marginal deficiency, but they rather tested whether an additional supplement on top of the recommended values would be beneficial in reducing a disease risk or its prognosis. It was, therefore, not surprising that the results were disappointing. As a matter of fact, the results confirmed the findings of the observational studies: chronic diseases are the product of several risk factors, among them most probably a chronic vitamin deficiency. Vitamin supplements could only correct the part of the overall risk that is due to the insufficient vitamin intake. PMID- 23798052 TI - Discovery-based nutritional systems biology: developing N-of-1 nutrigenomic research. AB - The progress in and success of biomedical research over the past century was built on the foundation outlined in R.A. Fisher's The Design of Experiments (1935), which described the theory and methodological approach to designing research studies. A key tenet of Fisher's treatise, widely adopted by the research community, is randomization, the process of assigning individuals to random groups or treatments. Comparing outcomes or responses between these groups yields "risk factors" called population attributable risks (PAR), which are statistical estimates of the percentage reduction in disease if the risk were avoided or in the case of genetic associations, if the gene variant were not present in the population .High throughput metabolomics, proteomic and genomic technologies provide 21st century data that humans cannot be randomized into groups: individuals are genetically and biochemically distinct. Gene-environment interactions caused by unique dietary and lifestyle factors contribute to heterogeneity in physiologies observed in human studies. The risk factors determined for populations (i.e., PAR) cannot be applied to the individual. Developing individual risk or benefit factors in light of the genetic diversity of human populations, the complexity of foods, culture and lifestyle, and the variety of metabolic processes that lead to health or disease are significant challenges for personalizing dietary advice for healthy or medical treatments for individuals with chronic disease. PMID- 23798053 TI - Vitamins for the first 1000 days: preparing for life. AB - Vitamins are essential nutrients for many body functions and particularly important during growth. Adequate supply in pregnancy and in early infancy is therefore crucial, but there is still a lack of knowledge about the needed amounts of vitamins of children older than six months and also during pregnancy. Recommendations for intake levels are generally derived by extrapolation from data for infants based in turn on the contents in breast milk and those for adults. A vitamin of particular importance in pregnancy is folic acid due to its role in the development of the brain and nerve system and the prevention of fetal neural tube defects (NTD). Mandatory fortification of flour and certain other grain products in many countries has been associated with a reduction in NTD incidence. However, other deficiencies or suboptimal status of B vitamins, especially B6 and B12 have been repeatedly reported in pregnant women also in high-income countries. Vitamin A is one of the three most critical micronutrients globally and pregnant women and young children are especially vulnerable to deficiencies. Night blindness, anemia, and immunodeficiency are major consequences of inadequate supply in these populations. Much attention has recently been accorded vitamin D that is also critical in pregnant women and young children for instance because of its involvement in bone mineralization but also its more recently discovered immune-modulating function that is thought to prevent development of autoimmune diseases like diabetes mellitus type I. A healthy balanced diet provides the best basis for optimal pregnancy outcome, lactation performance, and complementary feeding. However, supplements or fortified foods may be needed to cover the high requirements especially of critical vitamins such as vitamin D and folic acid and to correct unfavorable dietary patterns in women or to adapt foods to the needs of young children. PMID- 23798054 TI - Nutrition throughout life: folate. AB - Scientific evidence supports a number of roles for folate in maintaining health from early life to old age. Folate is required for one-carbon metabolism, including the remethylation of homocysteine to methionine; thus elevated plasma homocysteine reflects functional folate deficiency. Optimal folate status has an established role in preventing NTD and there is strong evidence indicating that it also has a role in the primary prevention of stroke. The most important genetic determinant of homocysteine in the general population is the common 677C > T variant in the gene encoding the folate-metabolising enzyme, MTHFR; homozygous individuals (TT genotype) have reduced enzyme activity and elevated plasma homocysteine concentrations. Meta-analyses indicate that the TT genotype carries a 14 to 21 % increased risk of CVD, but there is considerable geographic variation in the extent of excess CVD risk. A novel interaction between this folate polymorphism and riboflavin (a co-factor for MTHFR) has recently been identified. Intervention with supplemental riboflavin targeted specifically at individuals with the MTHFR 677TT genotype was shown to result in significant lowering of blood pressure in hypertensive people and in patients with CVD. This review considers the established and emerging roles for folate throughout the lifecycle, and some public health issues related to optimising folate status. PMID- 23798055 TI - The role of vitamins in aging societies. AB - Raising numbers of elderly lead to a dramatic shift in demographics, accompanied by an increase in non-communicable diseases such as cancer, cardiovascular disease and dementia. All these conditions are thought to be modifiable by diet to some degree and mounting evidence indicates that improved intakes of certain vitamins can slow their progress. Strong evidence exists for the beneficial effect of vitamin D on the risk of bone fractures. Moreover, as chromosomal damage is a risk factor for dementia, supplementation with nutrients preventing these impairments are thought to have a beneficial effect on cognitive decline. However, the aging progress strongly affects nutrient intakes and utilisation due to social, physical and psychological changes. Data from dietary surveys suggest that many of the elderly in Europe have intakes for various vitamins that are well below the recommendations. The situation appears to be even more critical for elderly in institutions such as care homes. Given the increasing number of elderly and the importance of an adequate supply with vitamins, more research is warranted to find nutritional solutions to improve their wellbeing and health - which in the long run can be expected to contribute to reduce the ever increasing health care costs. PMID- 23798056 TI - Vitamins: preparing for the next 100 years. AB - The insights gained from the last 100 years of vitamin research and applications have contributed substantially to our fundamental understanding of biology and importantly to the promotion of human health. There is no reason to think that the next 100 years will be any less fruitful if we are committed to preparing for them, particularly by changing four critical nutrition paradigms. First, we must move beyond the concept of preventing vitamin deficiencies and inadequacies to establishing health and, further, to creating optimal physiological functions. Each essential vitamin possesses different concentration thresholds for its variety of effects and the required balance necessary to achieving each has yet to be fully defined. Second, we must apply the research approaches and methods of ?-omics,? systems biology, and imaging technologies to define the dynamic role of vitamins and their broad array of genomic, molecular, biochemical, and functional interactions. Such work is necessary to understand the multiplicity of vitamin actions and ultimately apply them directly at the level of the individual. Third, we must revise the concept of evidence-based nutrition away from its current hierarchical system to recognize in a comprehensive and integrated way the attributes of each type of approach to research. To adhere to a single gold standard of the randomized clinical trial ignores both how we have moved forward so productively during the last 100 years and the vital information to be gained from basic research and other human studies; further, it acts to stifle innovation in both scientific and regulatory affairs. Fourth, we must understand that changes in the supply and distribution of food during the next century are likely to be at least as dramatic as those which have occurred over this last one. For example, inevitable environmental constraints will require more food protein be derived from plant than animal sources, a shift that will directly impact the dietary sources for vitamins. To meet the challenge of achieving global health in 2113 among a population of 9 billion people, effectively managing these four changes demands new and creative ways in which those in academia, government and non-government organizations, and industry must work together. PMID- 23798057 TI - Founder mutation in RSPH4A identified in patients of Hispanic descent with primary ciliary dyskinesia. AB - Primary ciliary dyskinesia (PCD) is a rare, autosomal recessive, genetically heterogeneous disorder characterized by ciliary dysfunction resulting in chronic oto-sino-pulmonary disease, respiratory distress in term neonates, laterality (situs) defects, and bronchiectasis. Diagnosis has traditionally relied on ciliary ultrastructural abnormalities seen by electron microscopy. Mutations in radial spoke head proteins occur in PCD patients with central apparatus defects. Advances in genetic testing have been crucial in addressing the diagnostic challenge. Here, we describe a novel splice-site mutation (c.921+3_6delAAGT) in RSPH4A, which leads to a premature translation termination signal in nine subjects with PCD (seven families). Loss-of-function was confirmed with quantitative ciliary ultrastructural analysis, measurement of ciliary beat frequency and waveform, and transcript analysis. All nine individuals carrying c.921+3_6delAAGT splice-site mutation in RSPH4A were Hispanic with ancestry tracing to Puerto Rico. This mutation is a founder mutation and a common cause of PCD without situs abnormalities in patients of Puerto Rican descent. PMID- 23798059 TI - Lower risk of major cardiovascular events associated with adherence to colesevelam HCI. AB - STUDY OBJECTIVE: To examine the relationship between adherence to colesevelam and the risk of major cardiovascular events (acute myocardial infarction [AMI] and stroke) among patients newly treated with colesevelam. DESIGN: Retrospective cohort study using administrative claims data. DATA SOURCE: MarketScan commercial and Medicare databases (2005-2011). PATIENTS: A total of 42,549 adults with hyperlipidemia and/or type 2 diabetes mellitus who newly started colesevelam between January 1, 2005, and September 30, 2011, and who had continuous enrollment in employer-sponsored commercial health insurance or Medicare supplemental benefit plans for at least 6 months before and 12 months after the date of colesevelam initiation. MEASUREMENTS AND MAIN RESULTS: Adherence was measured as the proportion of days covered (PDC) by prescription claims for colesevelam during the 1-year period after the drug initiation date. Patients were assigned to one of three adherence cohorts: adherent, PDC of 0.8 or more; partially adherent,PDC of 0.5-0.8; or nonadherent, PDC of less than 0.5. The primary outcome was time to the first hospitalization with a primary diagnosis for AMI or stroke during the follow-up period. Association of colesevelam adherence with the primary outcome was examined by multivariate Cox regression models, adjusting for demographics, comorbidity, and concomitant drugs. A sensitivity analysis between propensity score-matched cohorts was conducted to compare the outcome between adherent and nonadherent groups. Of the 42,549 patients included in the analysis, 7968 (18.7%) were adherent, 6197 (14.6%) were partially adherent, and 28,384 (66.7%) were nonadherent. Compared with nonadherent patients, adherent patients were older, more likely to be male and from the Northeast or North Central regions of the United States, and had more cardiovascular risk factors and concomitant drugs. Controlling for patient demographic and clinical characteristics, adherent patients were about 43% less likely to experience an AMI or stroke hospitalization during the follow-up period compared with nonadherent patients (hazard ratio 0.57, 95% confidence interval[CI] 0.44-0.73, p<0.0001). Results of the sensitivity analysis using propensity score matching techniques were consistent. CONCLUSION: Adherence to colesevelam was associated with lower risk of major cardiovascular events (AMI and stroke) among patients with hyperlipidemia and/or type 2 diabetes. Research to assess interventions to improve adherence to colesevelam and subsequently to evaluate the effects of these interventions on cardiovascular outcomes is warranted. PMID- 23798058 TI - Effect of laparoscopic surgery for moderate and severe endometriosis on depression, relationship satisfaction and sexual functioning: comparison of patients with and without bowel resection. AB - STUDY QUESTION: Is there a difference between women with endometriosis who underwent laparoscopic surgery with bowel resection or without bowel resection regarding depressive symptoms, relational adjustment and sexual functioning? SUMMARY ANSWER: Radical surgery for endometriosis in both groups improved the levels of depression and sexual functioning, but only the bowel resection patients showed improvements in relationship satisfaction. WHAT IS KNOWN ALREADY?: The frequent pain symptoms in endometriosis patients can have an impact on psychological issues, relationships and sexual functioning. There are no data available on depression and relationship adjustment after endometriosis surgery. Sexual dysfunction problems have been described after bowel resection for rectal cancer, but no data are available for endometriosis surgery. STUDY DESIGN, SIZE, DURATION: This prospective cohort study included 203 consecutive women operated at the Leuven University Fertility Center (LUFC) between 1 September 2006 and 30 September 2008 for moderate (n = 67) or severe (n = 136) endometriosis. The preoperative response rate was respectively 84% in the bowel resection group and 79% in the no bowel resection group. PARTICIPANTS, SETTING, METHODS: The beck depression inventory (BDI) measured depression, the dyadic adjustment scale (DAS) measured relationship satisfaction and the short sexual functioning scale (SSFS) measured sexual functioning before and 6, 12 and 18 months after women had laparoscopic surgery at the LUFC, a tertiary referral centre for fertility exploration, treatment and surgery. MAIN RESULTS AND THE ROLE OF CHANCE: Both groups had better post-operative outcomes when compared with the preoperative assessments. Mean BDI and DAS levels were comparable with the normal population. Overall assessment points, the bowel resection patients had better outcomes for DAS (P < 0.05) and SSFS 'arousal' (P < 0.05) than the no bowel resection patients. At 6 months after the operation, when compared with the no bowel resection group, the bowel resection group reported lower mean levels of BDI (P < 0.05), a lower incidence of SSFS 'pain during intercourse' and 'orgasm problems' (P < 0.05), and a lower proportion of patients with severe orgasm problems (P < 0.05). The data show that radical but fertility sparing surgery, with or without bowel resection, for the treatment of endometriosis results in comparable and good psychological outcomes concerning depression levels, relationship satisfaction and sexual functioning. LIMITATIONS, REASONS FOR CAUTION: Although the initial response rate was good, response dropped over time and was significantly higher for bowel resection patients compared with the no bowel resection patients (P = 0.05). A responder/non-responder analysis for the whole study population showed no significant differences concerning pain problems. This reduces the possible risk of (positive) bias in the results. WIDER IMPLICATIONS OF THE FINDINGS: Endometriosis is a complex condition and the focus should not be on a one-dimensional end-organ gynaecological outcome, but should take into account the role of psychological factors in pain-related outcome. To this end, more prospective data are needed on sexual functioning and psychological outcomes. PMID- 23798060 TI - Laser exposure of gold nanorods can induce intracellular calcium transients. AB - Uncoated and poly(styrene sulphonate) (PSS)-coated gold nanorods were taken up by NG108-15 neuronal cells. Exposure to 780 nm laser light at the plasmon resonance wavelength of the gold nanorods was found to induce intracellular Ca(2+) transients. The higher Ca(2+) peaks were observed at lower laser doses, with the highest levels obtained at a radiant exposure of 0.33 J/cm(2) . In contrast, the cells without nanoparticles showed a consistently small response, independent of the laser dose. These initial results open up new opportunities for peripheral nerve regeneration treatments and for more efficient optical stimulation techniques. PMID- 23798061 TI - Global child health update in 2012. PMID- 23798062 TI - A Correction to the Perspective Titled: "STIMulating Stress Fibers in Endothelial Cells". PMID- 23798063 TI - Laboratory detection of MRSA. PMID- 23798064 TI - Author response to laboratory detection of MRSA. Comment on "Antibiotic susceptibility of vancomyin and nitrofurantoin in Staphylococcus aureus isolated from burnt patients in Sulaimaniyah, Iraqi Kurdistan". PMID- 23798065 TI - Biophysics. Introduction. PMID- 23798066 TI - [Lipopolysaccharide induced expression of peroxiredoxin 1 in airway epithelial cell]. AB - OBJECTIVE: To investigate the effect of lipopolysaccharide (LPS) on expression of peroxiredoxin 1 (prdx1) in airway epithelial cells. METHODS: The airway epithelium cell line BEAS-2B was cultivated, and the cells were stimulated with 0, 1, and 10 mg/L of LPS for 12 hours and 24 hours, and then were harvested for prdx1 expression detection. The mRNA expression of prdx1 was detected by reverse transcription-polymerase chain reaction (RT-PCR).The airway epithelium cells were stimulated with 0, 0.1 , 0.5, 1 , 5, and 10 mg/L of LPS for 12 hours, and were collected for determination of prdx 1 protein expression by Western blotting. RESULTS: RT-PCR results showed that the prdx1 mRNA expression was significantly increased within 12 hours of stimulation with elevation of the dosage of LPS. The prdx1 mRNA expression at 12 hours of stimulation by 10 mg/L LPS was significantly higher than that in control group (2.014 +/- 0.197 vs. 0.644 +/- 0.178, P<0.05). However, with prolongation of LPS stimulation time, the prdx1 mRNA expression at 24 hours was slightly declined. Western blotting results showed that the prdx1 protein expression was gradually increased with elevation of dosage of LPS. The prdx1 protein expression at 12 hours of stimulation with 5 mg/L LPS was significantly higher than that in control group (1.069 +/- 0.175 vs. 0.328 +/- 0.010, P<0.05), and the expression remained at high level at 12 hours of stimulation with 10 mg/L LPS (0.984 +/- 0.220 ). CONCLUSION: 10 mg/Lof LPS can induce the mRNA and protein expression of prdx1 in BEAS-2B cell after 12 hours of stimulation. PMID- 23798067 TI - [Remifentanil for analgesia and sedation in mechanically ventilated patients in intensive care unit]. AB - OBJECTIVE: To prospectively assess the effect of remifentanil for analgesia and sedation, the impact on sustenance duration of mechanical ventilation and hemodynamics, and also its adverse reaction in the mechanically ventilated patients in the intensive care unit (ICU). METHODS: Sixty patients with invasive mechanical ventilation forever 24 hours after tumor operation were randomly allocated to fentanyl group (n = 30) or remifentanil group n = 30) to receive a persistent infusion of either fentanyl or remifentanil for sedation and analgesia. The level of analgesia was assessed according to facial pain scale (FPS), while the level of sedation was assessed according to the Ramsay score (RS). A propofol infusion was started if additional sedation was necessary. During the therapy, the daily awakening procedure was performed, and the scores of FPS and RS and the vital signs were recorded respectively before and after medication. The number of patients receiving additional propofol infusion, and number of daily interruption of medication and that of daily arousal, the duration of mechanical ventilation, ICU length of stay, and ICU cost were recorded. Furthermore, the incidence of adverse reactions was documented. RESULTS: The ideal targets of analgesia and sedation were reached in both groups. There were nearly no significant differences between the groups with respect to the effect of sedation and analgesia. However, the FPS scores in fentanyl group at the 30 minutes of the medication were. obviously higher than those of remifentanil group (3. 70 +/- 1.20 vs. 2.70 +/- 1.17, P<0.05). The mean arterial pressure (MAP,mm Hg, I mm Hg = 0.133 kPa) of remifentanil group at 30 minutes was significantly lower than that of fentanyl group (72.9 +/- 6.9 vs. 77.6 +/- 9.1, P<0.05). There was no difference between two groups with respect to the other vital signs. More patients in fentanyl group needed the additional propofol infusion (9 vs. 8) and interruption of medication (12 vs. 4, both P<0.05). The spontaneous breathing frequency (RRs, bpm) in patients of remifentanil group was lower obviously at 30 minutes and 1, 6, 24 hours than that of fentanyl group (7.0 +/- 2.8 vs. 10.4 +/- 3.5, 5.4 +/- 3.4 vs. 10.6 +/- 3.6, 5.4 +/- 3.0 vs. 7.2 +/- 3.1 , 6.1 +/- 3.0 vs. 9.2 +/- 3.4, all P< 0.05) . The duration of mechanical ventilation (hours) and ICU length of stay (hours) were shortened in remifentanil group comparted with fentanyl group (73.6 +/- 26.7 vs. 94.9 +/- 37.3, 125.9 +/- 37.1 vs. 150.8 +/- 50.9, both P<0.05). With respect to the cost of hospitalization (10 thousand), no significant difference was found between two groups (6.06 +/- 2.29 vs. 5.83 +/- 2.38, P>0.05). The number of patients showing hypotension was much more in remifentanil group than that of fentanyl group (8 vs. 2, P<0.05). CONCLUSIONS: The effect of remifentanil was similar to that of the conventional therapy. Remifentanil gives rapid effect, shortens the duration of mechanical ventilation, reduces the dosage of propofol, and has no severe adverse effect. PMID- 23798068 TI - Interradicular radiolucency. Hybrid giant cell granuloma and odontogenic fibroma. PMID- 23798069 TI - CD83 antigen expression and its role in the progression of systemic malignancies. PMID- 23798070 TI - Odontogenic cell culture in PEGDA hydrogel scaffolds for use in tooth regeneration protocols. AB - In order to obtain a tooth-like structure, embryonic oral ectoderm cells (EOE) and bone marrow-derived stem cells (BMSC) were stratified within a synthetic hydrogel matrix (PEGDA) and implanted in the ileal mesentery of adult male Lewis rats. Whole-mount in situ hybridization was used to evaluate the expression of Pitx2, Shh and Wnt10a signals indicative of tooth initiation. In rats, expression of the three markers was present in the oral ectoderm starting at embryonic stage E12.5. which was therefore selected for cell harvesting. Embryos were obtained by controlled service of young female Lewis rats in which estrus was detected by impedance reading. At E12.5, pregnant rats were humanely euthanized and embryos were collected. The mandibular segment of the first branchial arch was dissected and the mesenchyme separated from the ectoderm by enzymatic digestion with pancreatin trypsin solution. BMSCs were collected by flushing the marrow of tibiae and femurs of adult Lewis rats with alpha-MEM and cultured in alpha-MEM in 25 cm2 flasks. Second passage BMSC's were recombined with competent oral ectoderm (E12.5-E13) stratifying them within a 3D PEGDA scaffold polymerized by exposure to UV (365 nm) inside a pyramidal polypropylene mold. Constructs were incubated from 24 to 48 hrs in alpha-MEM and then implanted for four to six weeks in the mesentery of adult male (3-6 month old) Lewis rats. 76 constructs were implanted (37 experimental, 27 negative controls and 12 positive controls). Upon maturation, constructs were harvested, fixed in buffered formalin, processed and stained with hematoxylin eosin (HE). Histological evaluation of the experimental and negative constructs showed that BMSCs underwent an apoptotic process due to lack of matrix interactions, known as anoikis, and were thus incapable of interacting with the competent ectoderm. In contrast, embryonic oral ectoderm was able to proliferate during the mesenteric implantation. In conclusion, PEGDA scaffolds are incompatible with BMSCs, therefore it is essential to continue the search for an ideal scaffold that allows proper tissue interactions. PMID- 23798071 TI - Effect of disinfectant solutions on a denture base acrylic resin. AB - The aim of this study was to evaluate the hardness, roughness and mass loss of an acrylic denture base resin after in vitro exposure to four disinfectant solutions. Forty specimens (Classico, Brazil) were prepared and randomly assigned to 4 groups n = 10) according to the disinfectant solution: G1: control, stored in distilled water at 37 degrees C; G2: 1% sodium hypochlorite; G3: 2% glutaraldehyde; G4: 4% chlorhexidine. G2 to G4 were immersed for 60 minutes in the disinfectant solution. Measurements were carried out both before and after immersion in the solution. The surface was analyzed with a surface roughness tester (Surfcorder SE 1700 KOZAKALAB), a microdurometer FM-700 (Future Tech) and a scanning electron microscope (DSM 962-ZEISS). Loss of mass was determined with a digital weighing scale. After disinfection procedures, values were analyzed statistically. The acrylic denture base resin may be vulnerable to surface changes after in vitro immersion in the disinfectant solutions studied. PMID- 23798072 TI - Functional impairment in submandibular gland of rats induced by 5-fluorouracil and calcium leucovorin. AB - One of the main clinical problems during chemotherapy is the occurrence of severe systemic toxicities, including those related to the stomatognathic system, which contribute to reducing the patient's quality of life. The most frequent oral complications are mucositis, dysgeusia, inflammation, gingival bleeding and decreased salivary flow or hyposalivation, a factor that predisposes to xerostomia, and other local complications that alter the homeostasis of the system. The purpose of this study was to evaluate the functional activity of salivary glands in Wistar rats subject to chemotherapy by measuring salivary flow, glycogen levels and glandular tissue response to autonomic nervous system agonists. Five experimental groups were used: 1) Control group fed "ad libitum"; 2) 5-fluorouracil (20 mg/kg body weight); 3) Calcium leucovorin (10 mg/kg body weight); 4) 5-fluorouracil + calcium leucovorin (20 and 10 mg/kg, respectively) by intraperitoneal injection for five consecutive days and 5) control with paired diet. Groups 1 and 5 did not receive drugs. Treatment with fluorouracil + leucovorin produced an increase in stimulated salivary flow and a higher response to increasing doses of beta agonists compared to other experimental groups. In both groups treated with cytostatic drugs, blocking of glycogen consumption at the end of the experimental period was observed. Our work suggests that salivary secretion may be affected by a dual mechanism: the first would be toxicity induced by 5-FU, which would cause depression of the process of glucose utilization. The second mechanism would affect the sympathetic autonomic reflex arc. In this instance, the synergistic action of 5-FU + LV would have a negative effect on the nerve activity with a reduction of salivary secretion. This would explain the hyposalivation, cited by several authors in patients undergoing the 5 FU + LV scheme in the treatment of colon carcinoma. PMID- 23798073 TI - Early Childhood Oral Health Impact Scale (ECOHIS). Translation and validation in Spanish language. AB - Health is currently recognized as lying in the individual process rooted in genes, personal habits, the social model and the understanding of the ideological standpoint from which it is viewed. The aim of this study was to validate the Early Childhood Oral Health Impact Scale (ECOHIS) for use in Latin American communities, in order to demonstrate its efficacy for determining the impact of dental condition on children under 5 years of age and their families. The ECOHIS explores two domains: impact on children (9 questions) and on families (4 questions). Validation in Spanish was done in four stages. Stage I included translation and back-translation of the questionnaire (English-Spanish-English). Stage II was a pilot test on families in Venezuela to test stability (test retest) and make semantic adjustments. Stage III included validation of the questionnaire applied to a Venezuelan sample (n = 50) and two Argentine samples (A and B, made up of families with and without social risk, respectively; n = 95), and consisted of statistical analysis to check the questionnaire's internal consistency and discriminant capacity. In the final stage, parents were given feedback on the results and significance of each domain in the questionnaire. From the results of this study it may be concluded that the Spanish version of the ECOHIS was reliable and valid for administering to populations with homogeneous social risk, and that parents without social risk factors (AC/B) have significantly greater perception of the impact of oral health on the family's quality of life. The trends recorded suggest that (a) larger samples should be used, including variables for diagnosing social vulnerability or general risk, (b) the association with dental condition should be established by applying indicators to discriminate distinct cut-off points in the dental caries process and (c) it should be ascertained whether there are changes in perception of the impact on quality of life before and after dental treatments, including impact on general health condition. PMID- 23798074 TI - Composite resin restorations of non-carious cervical lesions in patients with diabetes mellitus and periodontal disease: pilot study. AB - Diabetes mellitus is a set of metabolic diseases characterized by hyperglycemia resulting from absolute or relative deficiency in insulin secretion by the pancreas and/or impaired insulin action in target tissues. Oral health maintenance through health care, as well as metabolic control are important measures for the overall health of diabetic patients. The objective of this study was to determine the relationship between biocompatibility of composite resin restorations with different nanoparticles, polishing in abfraction lesions in anterior and posterior teeth with periodontal tissues in patients with diabetes mellitus. We selected 20 patients--10 patients with diabetes mellitus and 10 patients without diabetes mellitus-, but with a total of 30 restorations in each group receiving composite resin restorations, who were evaluated for periodontal purposes: Plaque Index, Gingival Index; Probing Depth, Clinical Attachment Level and Bleeding on Probing. In addition, the restorations will receive assessments according to criteria for Marginal Adaptation, Anatomical Shape, Marginal Discoloration, ormation of caries, Post-operative Sensitivity and Retention. The total period was 90 days. The results showed a significant improvement in periodontal parameters assessed (p < 0.05) in both groups. With regard to assessments of the restorations, it was observed that there was no statistically significant difference (p > 0.05) among all criteria evaluated within the 90-day period. Thus, we conclude that in a short period (90 days) there is clinical biocompatibility of composite resin with nanoparticles restorations in abfraction lesions and periodontal tissues of patients with diabetes mellitus, regardless the type of polish these restorations receive. PMID- 23798075 TI - In vitro activity of Schinus terebinthifolius (Brazilian pepper tree) on Candida tropicalis growth and cell wall formation. AB - The aim of this study was to evaluate the in vitro antifungal activity of Schinus terebinthifolius (Brazilian pepper tree) tincture on planktonic Candida tropicalis (ATCC 40042), which is a microorganism associated to oral cavity infections. Minimum Inhibitory Concentration (MIC) and Minimum Fungicidal Concentration (MFC) were determined through the microdilution technique. Possible action of the tincture on fungal cell wall formation was also studied by adding an osmotic protector (0.8M sorbitol) to the microplates. Nystatin was used as standard control and tests were performed in triplicate. S. terebinthifolius was found to have MIC and MFC values of 625 microg/mL on the strain assayed, whereas nystatin showed MIC and MFC of 6.25 microg/mL. Results suggest that S. terebinthifolius tincture acts on fungal cell walls, since the sorbitol test indicated a MIC of 1.250 microg/mL. It may be concluded that S. terebinthifolius has potential in vitro antifungal activity against C. tropicalis strains, and probably acts by inhibiting fungal cell wall formation. PMID- 23798076 TI - Oral health in psychiatric adults in Argentina. AB - This cross-sectional descriptive study was performed at neuropsychiatric institutions in Buenos Aires Province. A randomized sample was selected of 384 20 to 65-year-old adults: 56 with mental disorders and undergoing a process of deinstitutionalization (DG), 220 institutionalized (IG) and 108 ambulatory adults with no diagnosis of mental disorder considered as the control group (CG). Inclusion criterion was receiving oral healthcare at the same dentistry facility. To estimate the endogenous variable (oral health) we used DMFT Loe y Silness plaque index and gingival index (PI - GI). Diagnosed mental conditions were classified according to DSM IV criteria. Mean DMFT was 18.75 +/- 6.19 for DG and 19.67 +/- 8.24 for IG. The difference between groups DG and IG was not significant (P = 0.7818). For CG the value was 14.54 +/- 5.96. The correlation analysis between DMFT and age showed significant association and the values were: DG r = 0.4423, IG r = 0.5056 and CG r = 0.3372. Missing teeth account for 80% in DG 81.12% in IG and 48.76% in CG. Mean PI-GI values were 1.66 +/- 0.72, 1.12 +/- 0.52 in GD; 2.13 +/- 0.55, 1.76 +/- 0.47 in IG and 1.51 +/- 0.52, 1.02 +/- 0.38 in CG. The discrepancy between IP means for DG and IG were not significant (P > 0.05), whereas the GI values for both groups differed significantly at 5% (P < 0.05). Data analysis describes the loss of teeth as a residual consequence of oral disease, and the need to include rehabilitation in a healthcare model for the deinstitutionalization process in psychiatric adults. PMID- 23798077 TI - Can ultrasound application influence the bond strength of self-adhesive resin cements to dentin? AB - The aim of this study was to evaluate the influence of ultrasound application on the bond strength of self-adhesives resin cements to dentin. Twenty-four third molars were randomly divided into 4 groups (n = 6/group): G1 - RelyX Unicem; G2 - Maxcem Elite; G3 - RelyX Unicem and ultrasound application; G4 - Marcem Elite and ultrasound application. Composite resin blocks were luted to flat dentin with a load of 500 g for 2 min, followed by light polymerization in G1 and G2. In G3 and G4, the ultrasound device was applied for 20 s on the composite resin block, followed by 500 g load for 1 min and 40 s, and light polymerization. After storage in distilled water at 37 degrees C for 24 h, six tooth/resin sets were cut parallel to the long axis of the tooth, in the x and y directions, with a cross section area of -0.80 mm2. Twenty-four specimens were obtained for each group and submitted to microtensile bond strength (microTBS) testing in a universal testing machine at 0.5 mm/min crosshead speed. According to two-way ANOVA, resin cement (p = 0.000) and cementation method (p = 0.002) were significant. Interaction was not significant (p = 0.676). According to Student's t test (alpha = 0.05), the microTBS mean with ultrasound application (13.74 MPa) was statistically higher than without it (10.57 MPa). The microTBS mean of RelyX Unicem (13.95 MPa) was statistically higher than Maxcem Elite (10.36 MPa). The ultrasound application increased the microTBS of the RelyX Unicem and Maxcem Elite to dentin. PMID- 23798078 TI - Use of anorganic bovine bone matrix in an experimental model of bone healing. AB - The dimensions of the alveolar bone surrounding the tooth are not maintained post tooth-extraction probably as a consequence of the bone remodeling process and the biomechanical demands on bone. The use of biomaterials as bone substitutes in the post-tooth-extraction socket promotes bone repair, regardless of damage to bone structures during the surgical procedures. The aim of the present study was to evaluate the effectiveness of anorganic bovine bone matrix (ABBM) as a bone substitute, in an experimental model of post-tooth extraction bone healing in the rat. Radiographic follow-up was performed at 7, 14, and 30 days, and showed persistence of the biomaterial inside the experimental alveoli. At 14 and 30 days post-tooth extraction, particles surrounded by bone tissue were observed in the middle sector of the alveoli. The osteoconductive property of ABBM was demonstrated using the present experimental model of active osteogenesis, thus showing its usefulness as a bone substitute. Persistence of the particles at the studied experimental time points did not affect post-tooth extraction bone healing. PMID- 23798079 TI - Influence of different flasking and polymerizing methods on the occlusal vertical dimension of complete dentures. AB - The flasking and polymerization technique for resins can introduce stresses during processing which may lead to denture base distortions, artificial teeth displacement and increases in the occlusal vertical dimension (OVD). This study investigated whether the association of microwave heat-activation (MH) and bimaxillary flasking (BF) minimizes the possible increases in OVD after prostheses processing. Forty pairs of complete dentures were waxed with the artificial teeth in closed occlusion and divided into four groups according to investing and heating methods: G1 (control) = monomaxillary/water bath; G2 = monomaxillary/microwave; G3 = bimaxillary/water bath and G4 = bimaxillary/microwave. OVD was measured using a digital caliper before and after prostheses processing. Results were submitted to statistical analysis (Student's t-test for multiple comparisons and post hoc ANOVA, alpha = 0.05). Comparison of values before and after processing showed that OVD increased in all groups after polymerization (p < 0.001), regardless of flasking and polymerization methods. Statistically, G2 had the greatest difference in OVD when compared to G1 (p = 0.014), G3 (p = 0.019) and G4 (p = 0.024). G3 and G4 showed similar results statistically when compared to G1 (control). Both investing and heating methods resulted in an increase in OVD after processing. However, the prostheses invested in bimaxillary flasks showed the lowest changes in OVD, regardless of the polymerization method. PMID- 23798080 TI - Comparative study of changes in arterial pressure and heart rate during dental treatment under local anesthesia in hypertensive patients versus normotensive patients. AB - The aim of this study was to determine changes in arterial pressure (AP) and heart rate (HR) during dental treatment under local infiltration anesthesia (LIA) in patients with controlled arterial hypertension (AHT) versus normotensive patients. A longitudinal comparative study involving repeated measurements in well-controlled hypertensive (cases) and normotensive patients (controls) was conducted. All patients received standardized preventive periodontal treatment under LIA (1.8 ml of 4% articaine with 1:100000 L-Adrenaline). AP and HR were determined at 5 different phases of treatment. The study comprised 82 patients, 46.3% of whom were hypertensive, 61% were female. Systolic (SAP) and diastolic (DAP) arterial pressure and HR increased as the procedure advanced and then returned to initial values in both groups. Average HR values were lower in normotensive than in hypertensive patients (p < 0.001). Significant differences in AP and HR were observed among initial, mid-procedure, and final values (p < 0.001). Both groups exhibited highest SAP values post-LIA administration (p < 0.01). Average HR was higher in normotensive than in hypertensive patients. The hypertensive patients tended to develop AHT (> 140/90 mmHg) more frequently throughout the procedure (p = 0.002), SHOWING a 4.93-fold higher risk. Logistic regression analysis showed that sex (p < 0.032) and AH (p < 0.007) were associated with a tendency to develop AHT during treatment. Controlled hypertensive patients with normal AP values at the onset of dental treatment were found to be at a 5-fold higher risk of developing AHT during the course of dental treatment under local infiltration anesthesia. The observed increases in AP, however, did not reach clinically significant levels. The HR values tended to increase with the progress of dental treatment in all patients. HR was lower in hypertensive patients probably due a drug effect. PMID- 23798081 TI - Nasal carriage of Staphylococcus aureus and Candida species in immunocompetent individuals. AB - The aim of this study was to analyze the prevalence of Staphylococcus aureus and Candida species in samples of nasal mucosa from 100 immunocompetent subjects of both sexes, aged 18-70 years, during stomatological clinical examination. Samples were taken from the mucosa of both nasal fossae using sterile swabs. Samples were observed fresh, stained with Gram and Giemsa, and cultured on selective differential media at 37 degrees C to isolate and identify the selected microorganisms; conventional biochemical tests and commercial equipment and molecular studies using PCR were performed. A digital thermometer-hygrometer was used to measure room temperature at the time of sampling, which was on average 25 +/- 2 degrees C, with relative ambient humidity 66 +/- 11%. S. aureus was isolated from 38% of the samples; 4% of the samples were methicillin-resistant (MRSA) strains, with 2% identified genetically as community-acquired (CA-MRSA) and 2% as hospital-acquired (HA-MRSA). Candida was identified in 23% of the samples, with prevalence of C. albicans (19%) followed by C. dubliniensis (3%) and C. krusei (1%). There was significant association between Candida and S. aureus (Chi-squared = 27.75; df = 1; (p < 0.001). The nasal cavity is a reservoir and the identification of genus and species contributes to adequate epidemiological surveillance. PMID- 23798082 TI - Allergy situation in India: what is being done? PMID- 23798083 TI - Adherence and acquired drug-resistance in tuberculosis: wisdom stood on its head. PMID- 23798084 TI - Prevalence of rhinitis symptoms among 16 to 18 years old adolescents in Saudi Arabia. AB - OBJECTIVE: The present study was designed to estimate the prevalence of rhinitis symptoms among secondary school students in Saudi Arabia METHODS: A cross sectional study was conducted among children from secondary schools in the city of Riyadh. The study utilised the International Study of Asthma and Allergies in Children (ISAAC) questionnaire. RESULTS: Among the 3073 students (1504 boys and 1569 girls), the prevalence of life-time rhinitis, rhinitis in the past 12 months, and hay fever were 43.8%, 38.6% and 21.3%, respectively. There was a significant difference between boys and girls in the prevalence of life-time rhinitis (41% versus 46.5%, p = 0.02) and the prevalence of rhinitis in the past 12 months (35.1% versus 41.9%, p = 0.001). There was no significant difference between boys and girls in the prevalence of hay fever (22.5% versus 20.2%, p = 0.144). The prevalence of asthma symptoms among students with life-time rhinitis and hay fever were 35.4% and 39.9%, respectively. Asthma symptoms were strongly linked with life-time rhinitis (Odds Ratio [OR] = 2.5, p < 0.001) and hay fever (OR = 2.4, p value < 0.001). CONCLUSIONS: The prevalence of rhinitis symptoms is high among 16 to 18 years old adolescents in Saudi Arabia, and symptoms are more common in girls compared to boys. Rhinitis symptoms are also associated with a high frequency of asthma symptoms. PMID- 23798085 TI - Clinical presentation of patients with seasonal influenza and pandemic influenza A (H1N1-2009) requiring hospitalisation. AB - BACKGROUND: A sudden increase in the number of novel influenza A virus (pH1N1 2009) infection prompted us to compare the clinical presentation and outcomes of patients infected with pH1N1-2009 and seasonal influenza A virus during the post pandemic phase. METHODS: During the period August 13 to September 27, 2010, case records of 106 patients with severe influenza like illness (ILI) and respiratory complications who underwent diagnostic testing by real-time polymerase chain reaction (RT-PCR) for confirmation of pH1N1-2009 were retrospectively studied. RESULTS: Nineteen (17.9%) patients were tested positive for pH1N1-2009 and 78 (73.6%) were tested positive for seasonal influenza A virus. The mean age of patients infected with pH1N1-2009 was 45.2 +/- 15.3 years (range of 22 to 80 years). Common presenting symptoms included fever in 17 (89.4%), cough in 16 (84.2%), myalgia in 15 (78.9%) and breathlessness in 10 (52.6%) patients. The most common comorbidities included bronchial asthma/bronchitis/chronic obstructive pulmonary disease (COPD) in 4 (21%); followed by hypertension in 3 (15.8%) and diabetes in 3 (15.8%) patients. Overall, of the 97 influenza infected patients, 9 (9.3%) needed hospitalisation to the intensive care unit (ICU); one patient with COPD died due to multi-organ failure. CONCLUSIONS: Both the pandemic and seasonal strains were found to be co-circulating in the community. Patients with severe hypoxia, hypertension, acute respiratory distress syndrome and shock required ICU care. PMID- 23798086 TI - Combined pleural fluid cholesterol and total protein in differentiation of exudates and transudates. AB - BACKGROUND: The management strategy to be adopted in pleural effusion depends on whether an effusion is a transudate or exudate. OBJECTIVE: To evaluate the usefulness of pleural fluid cholesterol and/or total protein measurements for differentiating between exudates and transudates, and to compare it with Light's criteria. METHODS: In this prospective study 60 patients with pleural effusion were included. Pleural fluid total protein, lactate dehydrogenase (LDH) and cholesterol as well as serum total protein and LDH levels along with other investigations were studied. Clinical classification of transudate or exudate was done on the basis of aetiology. RESULTS: Based on clinical signs and symptoms, chest radiograph, other investigations and response to treatment, 49 of these effusions were classified as exudates and 11 as transudates. Using pleural fluid cholesterol levels at a cut-off point of greater than 60 mg/dL and/or total protein at a cut-off point of greater than 3 g/dL for distinguishing transudates and exudates, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV), were 100 percent. Using Light's criteria for discriminating transudates and exudates, sensitivity, specificity, PPV and NPV were found to be 98%; 100%; 100% and 92%, respectively. The differences resulted from a mis-classification of one expected exudate as transudate by Light's criteria. CONCLUSION: Pleural fluid cholesterol and total protein are simple, cost-effective, and useful parameters in distinguishing pleural transudates from exudates, with the advantage of requiring only two laboratory determinations and no simultaneous blood sample, compared to the use of Light's criteria. PMID- 23798087 TI - Pneumoconioses. AB - Occupational lung diseases are caused or made worse by exposure to harmful substances in the work-place. "Pneumoconiosis" is the term used for the diseases associated with inhalation of mineral dusts. While many of these broad-spectrum substances may be encountered in the general environment, many occur in the work place for greater amounts as a result of industrial processes; therefore, a range of lung reactions may occur as a result of work-place exposure. Physicians in metropolitan cities are likely to encounter pneumoconiosis for two reasons: (i) patients coming to seek medical help from geographic areas where pneumoconiosis is common, and (ii) pneumoconiosis caused by unregulated small-scale industries that are housed in poorly ventilated sheds within the city. A sound knowledge about the various pneumoconioses and a high index of suspicion are necessary in order to make a diagnosis. Identifying the disease is important not only for treatment of the individual case but also to recognise and prevent similar disease in co-workers. PMID- 23798088 TI - Primary achalasia with pneumoesophagus and bronchopleural fistula causing right lung collapse and bronchiectasis. PMID- 23798089 TI - Adenocarcinoma (somatic-type malignancy) in mature teratoma of anterior mediastinum. AB - Mature teratoma is a common anterior mediastinal tumour. However, occurrence of transformed malignant component within it is very rare. We report a case of a 32 year-old female presenting with dry cough and chest pain. Contrast-enhanced computed tomography (CT) showed a large thin-walled cystic lesion measuring 11.4 cm x 10.6 cm x 10.0 cm in the anterior mediastinum. Right postero-lateral thoracotomy was performed and the tumour was completely excised. Histopathological examination of the excised specimen was suggestive of mature teratoma with transformed malignant component, adenocarcinoma (somatic-type malignancy). PMID- 23798090 TI - Haemoptysis after four years of lobectomy for aspergilloma. AB - We present a case of a 26-year-old male who underwent lobectomy for life threatening haemoptysis due to aspergilloma in an old tuberculosis left upper lobe cavity who presented with recurrence of haemoptysis four years after the surgery. Fibreoptic bronchoscopy revealed Aspergillus colonisation in the ectatic residual bronchus which is an uncommon complication of lobectomy. The patient was successfully managed with antifungal agents. PMID- 23798091 TI - A case of Staphylococcus toxic shock syndrome presenting with multiple pneumatocoeles in the chest. AB - Staphylococcus toxic shock syndrome is a severe illness caused by infection with toxin producing Staphylococcus aureus and is associated with a poor outcome. We report a case of Staphylococcus TSS presenting with cough and expectoration along with multiple pneumatoceles visible on the chest radiograph that progressed to acute respiratory distress syndrome with eventual foci in brain. The patient was aggressively managed and recovered completely. PMID- 23798092 TI - Pulmonary renal syndrome in a case of Wegener's granulomatosis. AB - We report a case of a 42-year-old patient who presented with Wegener's granulomatosis complicated by pulmonary renal syndrome, i.e., diffuse alveolar haemorrhage and rapidly progressive crescentic glomerulonephritis. The patient was treated with plasmapheresis and immunosuppressive drugs--intravenous cyclophosphamide and methyl prednisolone. The clinical, haematological and biochemical parameters improved substantially and remission is achieved. PMID- 23798093 TI - Treatment practices in pulmonary tuberculosis by private sector physicians of Meerut, Uttar Pradesh. PMID- 23798094 TI - The author's reply. PMID- 23798095 TI - [Water-soluble inorganic salts in ambient aerosol particles in Tangshan]. AB - To investigate the levels, seasonal variation and size distributions of water soluble inorganic components, samples were collected with an Andersen cascade sampler in Tangshan from Sep. 2010 to Aug. 2011, and were analyzed by IC. The results showed that the secondary inorganic components (SO4(2-), NO3(-) and NH4(+)) were the major contributors to PM9 and PM2.1, accounting for 68% and 77% of the total water soluble salts in PM9 and PM2.1, respectively. The total concentrations of these three ions in spring, summer, autumn, and winter were 35.0, 84.7, 67.3 and 61.6 microg x m(-3) in PM9, and 23.2, 64.8, 52.7 and 49.6 microg x m(-3) in PM2.1. About 70%, 75% and 94% of SO4(2-), NO3(-) and NH4(+) were found in the fine mode of aerosol, respectively. Ca2+ and Mg2+ were unimodal and mostly concentrated in the coarse mode. Those results indicated that the pollution caused by atmospheric particles is serious in Tangshan. It is urgent to control the anthropogenic emissions sources, such as vehicle emission, coal and biomass burning. Meanwhile, it is necessary to strengthen the greening and reinforce the management of the road construction. PMID- 23798096 TI - [Characterization of water-soluble ions in PM2.5 at Dinghu Mount]. AB - To study the characteristics and source of aerosol in the background region of the Pearl River Delta, PM2.5 samples were collected with a high volume sampler from Jan. 2007 to Dec. 2008 at Dinghu Mountain. Water-soluble ions in PM2.5 were analyzed by ion chromatography (IC). The results showed that the annual concentrations of total water-soluble ions was (36.3 +/- 16.4) microg x m(-3) The three major ions SO4(2-), NH4(+) and NO3(-), accounted for 89% of the total water soluble ions. The correction of Na+ and Cl- was significantly enhanced in summer by the marine air mass, and the correlation coefficient R2 was 0.91. The mean value of NO3(-)/SO(2-) was 0.32, indicating that stationary sources had more contributions to Dinghu Mountain. The range of sigma cation/ sigma anion was 0.44 - 2.59, with a mean of 1.03 in PM2.5. The charge of water-soluble ions almost achieved balance in PM2.5 PMID- 23798097 TI - [Characteristics of mass size distributions of water-soluble, inorganic ions during summer and winter haze days of Beijing]. AB - To investigate the size distribution characteristics of water soluble inorganic ions in haze days, the particle samples were collected by two Andersen cascade impactors in Beijing during summer and winter time and each sampling period lasted two weeks. Online measurement of PM10 and PM2.5 using TEOM were also conducted at the same time. Sources and formation mechanism of water soluble inorganic ions were analyzed based on their size distributions. The results showed that average concentrations of PM10 and PM 2.5 were (245.5 +/- 8.4) microg x m(-3) and (120.2 +/- 2.0) microg x m(-3) during summer haze days (SHD), and were (384.2 +/- 30.2) microg x m(-3) and (252.7 +/- 47.1) microg x m(-3) during winter haze days (WHD), which suggested fine particles predominated haze pollution episode in both seasons. Total water-soluble inorganic ions concentrations were higher in haze days than those in non-haze days, especially in fine particles. Furthermore, concentrations of secondary inorganic ions (SO4(2 ), NO3(-) and NH4(+)) increased quicker than other inorganic ions in fine particles during haze days, indicating secondary inorganic ions played an important role in the formation of haze pollution. Similar size distributions were found for all Sinorganic water soluble ions except for NO3(-), during SHD and WHD. SO4(2-) and NH4(+) dominated in the fine mode (PM1.0) while Mg2+ and Ca2+ accumulated in coarse fraction, Na+, Cl- and K+ showed a bimodal distribution. For NO3(-), however, it showed a bimodal distribution during SHD and a unimodal distribution dominated in the fine fraction was found during WHD. The average mass median aerodynamic diameter (MMAD) of SO4(2-) was 0.64 microm in SHD, which suggested the formation of SO4(2-) was mainly attributed to in-cloud processes. Furthermore, a higher apparent conversion rate of sulfur dioxide (SOR) was found in SHD, indicating more fine particles were produced by photochemical reaction in haze days than that in non-haze days. The MMAD of SO4(2-) increased to 0.89 microm in WHD, local emission of SO2 and the subsequently heterogeneous reaction became the main source of SO4(2-) during winter time. The average MMADs of NO3(-) were 2.85 microm and 0.80 microm in SHD and WHD, respectively. Influenced by the seasonal temperature difference, NO3(-) mainly existed in the form of calcium nitrate in coarse mode during SHD while the fine mode nitrate was associated with ammonium during WHD. PMID- 23798098 TI - [Characterising seasonal variation and spatial distribution of PM2.5 species in Shenzhen]. AB - To investigate the effect of meteorological characteristics on PM2.5 chemical composition and the spatial distribution of different PM2.5 species in Shenzhen, 24-h PM2.5 samples were collected every six days from December 2008 to December 2009. The sampling network included an industrial site at Baoan, an urban site at Luohu and a seaside site at Yantian. Water-soluble inorganic ions and carbonaceous material (organic carbon and elemental carbon) were analyzed. The industrial site showed a much higher concentration than that of other two sites of organic matter, elemental carbon and nitrate, which presented the obvious difference of local emissions. But for the concentration of sulfate and ammonium of three different sites nearly stayed at the same level and indicated that they were mainly influenced by regional transport. OC/EC had the characteristics of the industrial site < the urban site < the seaside site, which implied that the industrial site had less secondary organic matter and more primary pollution sources. As the subtropical maritime monsoon climate is the dominant meteorological feature of the Pearl River Delta with a southwesterly transport and abundant rain in spring and summer, in contrast to a northwesterly transport and little rain in fall and winter, the PM2.5 pollution was much more serious in winter than in summer. Compared with the results of the similar experiment in 2004, the concentration of sulfate in PM2.5 has significantly declined because of the measures of reducing the emission of sulfer dioxide. But the pollution of vehicle emissions has become significant. PMID- 23798099 TI - [Characteristics of PAHs in the atmosphere in winter and summer in the urban and suburban of Fuzhou]. AB - Air samples from four sampling sites in urban and suburban in Fuzhou were collected by Hi-vol air samplers in winter and summer in 2010, and concentrations of PAHs were analyzed by GC-MSD. The total (particle and gas phase) PAHs concentrations in ambient air were in the range of 115.45-187.76 ng x m(-3) in winter and 45.55-59.20 ng x m(-3) in summer. PAHs in the gas phase were significantly higher than those in the particle phase, and PAHs in winter were higher than those in summer. No significantly difference was found between urban and suburban, with little higher PAHs in urban in winter and lower PAHs in summer. The ratios of PAHs in the gas phase to particle phase in summer were significantly higher than those in winter. The 2-4 rings PAHs were the dominant components in the gas phase while PAHs in the particle phase were dominated by 4 6 rings. The 3 rings PAHs were the dominant components in the gas phase in winter while 3 and 4 rings in summer. No significantly seasonal trends of PAHs components were found in the particle phase. The toxic equivalence factor (TEF) assessment showed that the pollution of PAHs in Fuzhou city was at a low level. Source analysis indicated that PAHs mainly came from combustion and diesel fuel was the predominant fuel in Fuzhou. PMID- 23798100 TI - [Seasonal variation and spatial distribution of typical organochlorine pesticides in the atmosphere of Hexi Corridor and Lanzhou, northwest China]. AB - Air samples were seasonally collected in Hexi Corridor and Lanzhou, Gansu province, using polyurethane foam (PUF) based passive air samplers for a year and determined hexachlorocyclohexanes (HCHs) and dichlorodiphenyltrichloroethanes (DDTs). Atmospheric concentrations of sigma HCHs (alpha-HCH +beta-HCH +gamma-HCH +delta-HCH) and sigma DDTs (p,p'-DDT + o,p'-DDT + p,p'-DDE + p,p'-DDD) were 86.22 pg x m(-3) and 34.06 pg x m(-3) in Hexi Corridor and Lanzhou with background concentrations of 54.41 pg x m(-3) and 21.56 pg x m(-3), respectively, which were lower than previously reported values elsewhere. In general, the seasonal pollution characteristics of sigma HCHs and sigma DDTs exhibited higher levels with the average concentrations of 127.4 pg x m(-3) and 47.06 pg x m(-3) in autumn, respectively. Furthermore, relatively higher residual concentrations of HCHs and DDTs were found in Jiuquan, Anxi and Zhangye, relating to their more arable lands and more intensively historical usage. Source apportionment indicated HCHs were mainly originated from historical technical-HCHs residues and recent Lindane usage. Recently introduced technical-DDTs was highly responsible for DDTs contamination, whereas the higher concentrations of o,p'-DDT observed in Jiuquan and Anxi may be attributed to dicofol usage. In addition, human exposure to HCHs and DDTs in Hexi Corridor and Lanzhou via inhalation could be relatively low. PMID- 23798101 TI - [Simulation of air pollution characteristics and estimates of environmental capacity in Zibo City]. AB - To develop a new pattern of air pollution control that is based on the integration of "concentration control, total amount control, and quality control", and in the context of developing national (2011-2015 air pollution control plan for key areas) and (Environmental protection plan of Zibo municipality for the "12th Five-Year Plan" period), a simulation of atmospheric dispersion of air pollutants in Zibo City and its peripheral areas is carried out by employing CALPUFF model, and the atmospheric environmental capacity of SO2, NO(x) and PM10 is estimated based on the results of model simulation and using multi-objective linear programming optimization. The results indicates that the air pollution in Zibo City is significantly related to the pollution sources outside of Zibo City, which contributes to the annual average concentration of SO2, NO2 and PM10 in Zibo City by 26.34%, 21.23%, and 14.58% respectively. There is a notable interaction between districts and counties of Zibo municipality, in which the contribution of SO2, NO(x) and PM10 emissions in surrounding counties and districts to the annual average concentrations of SO2, NO2 and PM10 in downtown area are 35.96%, 43.17%, and 17.69% respectively. There is a great variation in spatial sensitivity of air pollutant emission, and the environmental impact of unit pollutant emissions from Zhoucun, Huantai, Zhangdian and Zichuan is greater than that released from other districts/counties. To meet the requirement of (Ambient air quality standard) (GB 3095-2012), the environmental capacities of SO2, NO(x) and PM10 of Zibo City are only 8.03 x 10(4) t, 19.16 x 10(4) t and 3.21 x 10(4) t, respectively. Therefore, it is imperative to implement regional air pollution joint control in Shandong peninsula in order to ensure the achievement of air quality standard in Zibo City. PMID- 23798102 TI - [Diurnal changes in greenhouse gases at water-air interface of Xiangxi River in autumn and their influencing factors]. AB - With the closed chamber and gas chromatography method, a 24-hour continuous monitoring was carried out to understand the greenhouse gases fluxes across the water-air interface of the Xiangxi River Bay, the Three-Gorges Reservoir in Autumn. Results indicated that the fluxes of CO2, CH4 and N2O across the water air interface showed an obvious diurnal variation. The absorption and emission process of CH4 showed strong diurnal variation during the experimental period, reaching the highest emission at 1 am, whereas CO2 and N2O were emitted all day. The fluxes of CO2 ranged from 20.1-97.5 mg x (m2 x h)(-1) at day and 32.7-42.5 mg x (m2 x h)(-1) at night, the fluxes of N2O ranged from 18.4-133.7 microg x (m2 x h)(-1) at day and 42.1-102.6 microg x (m2 x h)(-1) at night. The fluxes of CO2 had positive correlation with wind speed and negative correlation with pH. The fluxes of N2O had positive correlation with pH. PMID- 23798103 TI - [Influence of human activities on groundwater environment based on coefficient variation method]. AB - Groundwater system in the plain area of Beijing can be divided into six subsystems. Due to the different hydrogeological conditions of the subsystems, the degrees to which human activities affect the subsystems are also diverse. In order to evaluate the influence of human activities on each subsystem, the first and second aquifer with relatively poor water quality were chosen to be the evaluating positions, based on the data of groundwater sampled in September, 2011. With respect to human activities affect index such as total hardness, TDS, sulfate and ammonium, variation coefficient methods were used to calculate the weight of each index. Then scores were obtained for each index with national standard as reference, and superposition calculations were used to gain comprehensive scores, finally the groundwater quality conditions were evaluated. Contrast analyses were used to evaluate the incidence of human activities with groundwater subsystems as evaluation unit and water quality partitions as evaluation factors. The results indicate that the influence of human activities on the first aquifer is greater than that of the second aquifer, the Yongding river groundwater subsystems and the Chaobai river groundwater subsystems are affected more than other groundwater subsystems. PMID- 23798104 TI - [Nitrogen non-point source pollution identification based on ArcSWAT in Changle River]. AB - The ArcSWAT (Soil and Water Assessment Tool) model was adopted for Non-point source (NPS) nitrogen pollution modeling and nitrogen source apportionment for the Changle River watershed, a typical agricultural watershed in Southeast China. Water quality and hydrological parameters were monitored, and the watershed natural conditions (including soil, climate, land use, etc) and pollution sources information were also investigated and collected for SWAT database. The ArcSWAT model was established in the Changle River after the calibrating and validating procedures of the model parameters. Based on the validated SWAT model, the contributions of different nitrogen sources to river TN loading were quantified, and spatial-temporal distributions of NPS nitrogen export to rivers were addressed. The results showed that in the Changle River watershed, Nitrogen fertilizer, nitrogen air deposition and nitrogen soil pool were the prominent pollution sources, which contributed 35%, 32% and 25% to the river TN loading, respectively. There were spatial-temporal variations in the critical sources for NPS TN export to the river. Natural sources, such as soil nitrogen pool and atmospheric nitrogen deposition, should be targeted as the critical sources for river TN pollution during the rainy seasons. Chemical nitrogen fertilizer application should be targeted as the critical sources for river TN pollution during the crop growing season. Chemical nitrogen fertilizer application, soil nitrogen pool and atmospheric nitrogen deposition were the main sources for TN exported from the garden plot, forest and residential land, respectively. However, they were the main sources for TN exported both from the upland and paddy field. These results revealed that NPS pollution controlling rules should focus on the spatio-temporal distribution of NPS pollution sources. PMID- 23798105 TI - [Study on the content and carbon isotopic composition of water dissolved inorganic carbon from rivers around Xi'an City]. AB - In this study, the content and isotopic compositions of water dissolved inorganic carbon (DIC) from four typical rivers (Chanhe, Bahe, Laohe and Heihe) around Xi'an City were studied to trace the possible sources of DIC. The results of this study showed that the content of DIC in the four rivers varied from 0.34 to 5.66 mmol x L(-1) with an average value of 1.23 mmol x L(-1). In general, the content of DIC increased from the headstream to the river mouth. The delta13C(DIC) of four rivers ranged from -13.3 per thousand to -7.2 per thousand, with an average value of -10.1 per thousand. The delta13C(DIC) values of river water were all negative (average value of -12.6 per thousand) at the headstream of four rivers, but the delta13C(DIC) values of downstream water were more positive (with an average value of -9.4 per thousand). In addition, delta13C(DIC) of river water showed relatively negative values (the average value of delta13C(DIC) was -10.5 per thousand) near the estuary of the rivers. The variation of the DIC content and its carbon isotope suggested that the DIC sources of the rivers varied from the headstream to the river mouth. The negative delta13C(DIC) value indicated that the DIC may originate from the soil CO2 at the headstream of the rivers. On the other hand, the delta13C(DIC) values of river water at the middle and lower reaches of rivers were more positive, and it showed that soil CO2 produced by respiration of the C4 plants (like corn) and soil carbonates with positive delta13C values may be imported into river water. Meanwhile, the input of pollutants with low delta13C(DIC) values may result in a decrease of delta13C(DIC) values in the rivers. The study indicated that the DIC content and carbon isotope may be used to trace the sources of DIC in rivers around Xi'an City. Our study may provide some basic information for tracing the sources of DIC of rivers in the small watershed area in the Loess Plateau of China. PMID- 23798106 TI - [First flush effects of storm events of Baoxiang River in Lake Dianchi Watershed]. AB - To understand riverine process of non-point source effectively, first flush effects of storm events were investigated at Baoxiang River of Lake Dianchi Watershed. Three sampling stations were selected along Baoxiang River for observing the flow rate and pollutant concentrations of the first three storm events from June 2009 to August 2009. Net discharged volume, net discharged loading, and net event mean concentration (EMC(n)) were proposed with their calculation methods. According to the analysis of three storm events at three stations, the following results colcd be extracted: (1) the larger the percent of impervious land and population density were, the higher EMC(n) of TSS, TN, TP, permanganate index and their cumulative curves [M(V)] were along the river; (2) TSS, TP loadings as well as their M (V) were positively correlated to the storm intensity, while TN and permanganate index loadings were consistent with the total rainfall of each storm event, where the percent of NO3(-) -N in total nitrogen decreased gradually when the number of storm events increased; (3) compared to tradition EMC, EMC(n) was proven to be a better indicator to accurately uncover and magnify the differences in first flush effects of storm events among different stations or storm events. PMID- 23798107 TI - [Estimation of releasing fluxes of sediment phosphorous in the Three Gorges Reservoir during late autumn and early winter]. AB - In order to investigate the internal contamination load sources in the Three Gorges Reservoir (TGR), a field sampling campaign was carried out in November and December 2010. Phosphate contents (PO4(3-) -P) were determined in 6 mainstream and 9 estuary sediment cores of sediment-water interface in the TGR. The results showed that the PO4(3-) -P concentrations of pore water in sediments from tributaries and the corresponding overlying water were higher than those from the mainstream. The PO4(3-) -P contents in tributaries and mainstream ranged from 9.59-29.79 microg x L(-1) and 9.01-25.36 microg x L(-1), respectively. Based on calculations using the Fick's First Law, sediments located at GuoJiaba and Xiaojiang estuaries were the 'sink' of P, and the fluxes of sediment PO4(3-) -P were estimated to be -0.63 mg x (m2 x a)(-1) and -0.60 mg x (m2 x a)(-1), respectively. In other areas, PO4(3-) -P diffused from the pore water to the overlying water, and the diffusive fluxes were in the range of 0.15-2.47 mg x (m2 x a)(-1). With the assumption that molecular diffusion was the main process by which nutrients were transported from the pore water to the overlying water and the water body in the TGR was evenly mixed, the contribution of sediment phosphorus to the water body was only -0.011-0.098%. So far, with the Three Gorges Reservoir sediments as the internal contamination load sources, the phosphorous release didn't significantly influence the water quality. The sediments in the TGR may be a large P source in a period of future time after the external P source is controlled efficiently. PMID- 23798108 TI - [Distributions and pollution status of heavy metals in the suspended particles of the estuaries and coastal area of eastern Hainan]. AB - The distributions and pollution status of heavy metals in the suspended particles were investigated in the Wanquan and Wenchang/Wenjiao estuaries and the coastal area of eastern Hainan in July 2008. The concentrations of metal elements (Al, Fe, Mn, Cr, Cu, Ni, V, Zn) were determined by ICP-AES after microwave digestion. Multivariate statistical methods (e. g. correlation analysis and principal factor analysis) were used to discuss the major factors controlling the variability of heavy metal concentrations and the pollution status in those areas. There was an obvious variability in particulate metal concentrations from upstream to estuary of both rivers. The concentrations first increased with increasing salinity and then decreased with further increase of the salinity; the concentrations were slightly higher at the coastal area in the east. The variability of particulate metal concentrations reduced significantly after the normalization by Al, indicating the effects of grain size. Enrichment factor calculation results showed that there was heavy metal pollution (especially Cu, Ni) in the Wenchang/Wenjiao River and estuary, while the situation in Wanquan River remained at pristine level. Concentrations of particulate metals in the study area were mainly controlled by source geology and provenance, as well as contamination from the discharge of waste water and biological activity. PMID- 23798110 TI - [Distribution and potential ecological risk assessment of heavy metals in sediments of Zhalong Wetland]. AB - This study investigated the concentrations of heavy metals in the sediments of the Zhalong Wetland using ICP-MS, analyzed their spatial distributions, evaluated the potential ecological risk, and explored the pollution sources and environmental influencing factors. The results can be summarized as the followings: (1) The concentrations of Hg, Cd, As, Cu, Pb, Zn and Cr were 0.065, 0.155, 10.26, 18.20, 21.35, 52.08 and 46.47 mg x kg(-1), respectively, which were all above the soil background values of the Songnen Plain. Their spatial distributions were distinctly different. The concentration of heavy metals in the north was higher than that in the south, and the east was higher than the west. Particularly in the eastern region, the concentrations of Hg and Cd were 20.8 and 32.4 times the minimum values of the whole area. And in the core zone, the concentration was relatively low. (2) The sequence of the potential ecological risk posed by the metals was Hg > Cd > As > Pb > Cu > Cr > Zn. The average potential ecological risk index (RI) of the Zhalong Wetland was 171.9 (ranged from 76.9-473.5), suggesting a moderate ecological risk. However, the potential ecological risk was extremely high in the east which should be treated as the major heavy metal pollution prevention site in the future. (3) Except for Hg and Pb, the concentrations of all heavy metals were significantly correlated to each other, indicating that those heavy metals had homology. (4) Organic matter was the major environmental influencing factor. However, the trend of land salinization in the Zhalong Wetland has been intensified, indicating a higher risk of heavy metal releasing from the sediments, to which the local authorities should pay enough attention. PMID- 23798109 TI - [Environmental characteristics of heavy metals in surface sediments from the Huanghe estuary]. AB - The contents of Cu, Pb, Zn, Cr, As and Hg in surface sediment from 14 sampling sites in the Huanghe estuary during July-August, 2011 were measured to investigate environmental geochemical characteristics of heavy metals related to multiple factors. The distribution, relationship with fine fraction and TOC, and sediment quality assessment concerning heavy metals were analyzed. The results showed that average concentrations of Cu, Pb, Zn, Cr, As and Hg in the Huanghe estuary were (16.5 +/- 2.7), (16.0 +/- 3.4), (21.0 +/- 3.3), (17.4 +/- 3.1), (6.5 +/- 1.2), (0.0444 +/- 0.0307) mg x kg(-1), respectively, which were lower than those in other typical areas along the coast of China. The distribution of metals displayed higher profiles in south than that in north of the Huanghe estuary, with a trend of increase seaward, especially for stations in southwest of the Laizhou bay. The insignificant correlation among metals indicated the complex sources of heavy metals in flood season. Pearson correlation was also conducted between metal contents and percentage of fine particulates and TOC, which was also insignificant, suggesting heavy metal concentration and distribution in the study region were also controlled by other factors except grain size and TOC. There was a good correlation between clay fraction and TOC (r = 0.724, P < 0.05), indicating TOC tends to accumulate in clay. Compared with variety of background values and an internationally used consensus-based sediment quality guidelines (CBSQGs) for saltwater ecosystem, heavy metals in surface sediments from the Huanghe estuary implied a low probability of toxic effect, despite a sharp contamination trend pertaining to Hg and Pb since 1980s. PMID- 23798111 TI - [Ecological risk evaluation of heavy metals of the typical dredged mud in Shanghai]. AB - In order to discuss the potential ecological risk of heavy metals of the typical dredged mud in Shanghai, the Hakanson potential ecological risks method was used to analyse and assess the potential ecological risks of heavy metals, including Hg, Cd, Cu, Pb, As,Cr and Zn in dredged mud from the following three areas-the dock apron of Huangpu River, the mouth of the Yangtze River and inland waterways. The results showed that the mean values of ecological risk index (Er(i)) of the seven heavy metals are 20.05, 17.49, 8.82, 5.71, 4.68, 1.74 and 1.13, respectively, all of which belonged to the low ecological risk; Cd (one location in inland waterways) and Hg (three locations in the mouth of the Yangtze River and one location in inland waterways) are the most hazardous elements, with the Er(i) > 40, which belonged to the medium ecological risk or the high ecological risk, and other elements belonged to the low ecological risk. From the results of ecological risk indices(ERI) of the heavy metals in Shanghai dredged mud, the risk of the heavy metals belonged to the low ecological risk. The ERI of inland waterways, the mouth of the Yangtze River and the dock apron of the Huangpu River were 81.4, 57.7 and 52.5, respectively, which all belong to the low ecological risk. PMID- 23798112 TI - [Pollution characteristics of heavy metals in sludge from wastewater treatment plants and sludge disposal in Chinese coastal areas]. AB - Thirteen sludge samples from Guangzhou, Shanghai and Dalian were collected and analysed for heavy metals to investigate the distribution and variation trend of heavy metals in sludge from wastewater treatment plants in Chinese coastal areas. The results showed that contents of heavy metals in sludge varied significantly, and the average contents exhibited an order of Cr > Zn > Cu > Pb > As > Hg > Cd. Additionally, contents of Cr, Cu and As exceeded their corresponding standard levels. Compared with contents of heavy metals in 2006 and 2001, content of Zn in sludge increased while contents of Cr, Cu and As decreased. Results also indicated that the industrial sludge was more seriously polluted than domestic sludge in terms of Zn, Cu and As. Only 23% sludge samples exceeded the standards for fertilization of sludge, suggesting that most of the sludge could be disposed by land application. These results also provide further information about the establishment of ocean disposal assessment for sludge. PMID- 23798113 TI - [Comparison of the estrogenic activity of organic compounds in source water and finished water from the Yangtze River and Taihu Lake in certain areas of Jiangsu Province]. AB - A total of 43 source water and finished water samples were collected from the Yangtze River and Taihu Lake in WX and SZ areas of Jiangsu Province from October 2010 to March 2012. The XAD-2 resin was applied to absorb the organic compounds in each water sample respectively. After the procedure of elution, concentration and drying, nonvolatile organic compounds (NVOCs) were obtained. The recombinant yeast estrogen screen test was then applied to evaluate the estrogenic activities of NVOCs in each water sample. The results showed that all of the source water collected from the Yangtze River and Taihu Lake possessed estrogenic activities. The EEQ values of source water from Taihu Lake were 0.04-2.07 ng x L(-1), and the volume of EC(25-E2) were 9.06-31.62 mL; the EEQ values of source water from Yangtze River were 0.69-1.15 ng x L(-1), and the volume of EC(25-E2) were 9.06 31.62 mL. The samples from Taihu Lake in SZ area had higher estrogenic activities than the samples collected from WX area. No estrogenic activity was detected in 58.3% of the finished water samples after the treatment in water plants. The water plants which collected source water from the Yangtze River and from Taihu Lake reduced the estrogenic activities by 80.3% -100% and 55.5% -100%, respectively. PMID- 23798114 TI - [Occurrence and fate of phthalates in wastewater treatment plants in Beijing, China]. AB - Three waste water treatment plants (WWTPs) in Beijing were selected as cases to study the occurrence and fate of phthalates. Contents of di-methyl phthalate (DMP), di-ethyl phthalate (DEP), di-butyl phthalate (DBP), butyl-benzyl phthalate (BBP), di-octyl phthalate (DOP) and di-(2-ehtylhexyl) phthalate (DEHP) in influent, effluent of secondary setting tank and excess sludge in those WWTPs were determined. The mean concentration of DMP, DEP, DBP and DEHP are 0.98, 0.21 x 10(2), 0.27 x 10(2) and 0.15 x 10(2) microg x L(-1) respectively. BBP and DOP were not found in those WWTPs. Only DBP and DEHP were detected in dewatered sludge with mean concentration of 0.37 microg x kg(-1) and 0.31 x 10(3) microg x kg(-1) DW. The removal efficiency of DMP, DEP, DBP and DEHP varied from 68.3% 82.6%, 94.5% - 98.2%, 74.7% -95.0% and 90.5% -90.7% respectively. The main removal mechanism should be biodegradation and volatilization to the air. Higher concentration of DBP and DEHP in effluent and dewatered sludge should be concerned. PMID- 23798115 TI - [Research on sludge toxicity caused by DMF biodegradation and toxicity spatial distribution in sludge flocs]. AB - The aerobic sequencing batch activated sludge system (SBR) was used to remove the toxic and refractory organic pollutant, N,N-dimethylformamide (DMF). The formation property and spatial distribution of the organic toxicity in sludge were studied. The operation parameters were controlled as follows: influent COD was about 300 mg x L(-1), every DMF concentration phase lasted 30 d(40 mg x L( 1), 80 mg x L(-1), 120 mg x L(-1)), the SBR cycle lasted 12 h, and DO was 2.0-3.0 mg x L(-1). The results showed that the sludge toxicity increased in the beginning and then decreased to a steady range at each DMF concentration phase; there was a positive correlation between the sludge toxicity and the initial DMF concentration; most of the sludge organic toxicity was caused by DMF biodegradation and existed in the inner extracellular polymeric substances (EPS) and intracellular section of sludge flocs. PMID- 23798116 TI - [Study on the ecological risk of wild veined rapa whelk (Rapana venosa) exposured to organotin compounds in Bohai Bay, China]. AB - The present study evaluated the potential ecological risk of organotin compounds (OTs) to wild veined rapa whelk (Rapana Venosa) population in Bohai Bay. The results showed that the imposex rate was 12.5% and 6.48% in Dashentang and Nanpaihe coastal areas, with relative penis size index of 9.61 and 12.45, respectively. The concentrations of butyltin compounds and phenyltin compounds were 39.04 ng x g(-1) dw and 46.48 ng x g(-1) dw in muscle tissues, and 32.09 ng x g(-1) dw and 109.03 ng x g(-1) dw in digest gland, respectively. Based on TBT levels in the muscles of all samples, a risk quotient of 0.024 was derived, indicating certain risk of OTs at current levels to wild veined rapa whelk populations in Bohai Bay. PMID- 23798117 TI - [Bioaccumulation of mercury in Crassostrea sp. exposed to waste seawater discharged from a coal-fired power plant equipped with a seawater flue-gas desulfurization system]. AB - A field experiment was conducted to study mercury (Hg) bioaccumulation in Crassostrea sp. exposed to waste seawater discharged from a coal-fired power plant equipped with a flue gas desulfurization system. Oysters were cultured in the discharge outlet of the power plant (studying site) and a control site, respectively. The total Hg (THg) concentrations (all counted as dry weight) of seawater in the studying and control sites were determined as (120.6 +/- 55.5) ng x L(-1) (n = 5) and (2.7 +/- 1.0) ng x L(-1) (n = 5), respectively, while methyl Hg (MeHg) concentrations were (0.30 +/- 0.44) ng x L(-1) (n = 5) and (0.28 +/- 0.31) ng x L(-1) (n = 5), respectively. The THg in oyster at the studying site increased dramatically from (138.3 +/- 14.3) ng x g(-1) (n = 6) to (3 012 +/- 289) ng x g(-1) (n = 6) within 7 d, and remained at high levels of 2 935-4 490 ng x g(-1) for the next 34 d. In contrast, the THg in oyster at the control site showed no significant change, and kept at low levels of 60.7-137.5 ng x g(-1). After 41 d exposure, the MeHg in oyster at the studying site had no significant change, ranging from 55.4 ng x g(-1) to 73.1 ng x g(-1), and the content at the control site showed a slight decrease, ranging from 15.6 to 55.6 ng x g(-1). The study showed that THg in the waste seawater discharged at the coal-fired power plant could be quickly bioaccumulated by oyster to a great extent, the potential risk can thus not be ignored. MeHg concentration in the waste seawater was quite low, and no obvious bioaccumulation was found in oyster. Under the study conditions, no self-synthesis of MeHg or transformation of inorganic Hg into MeHg was found. PMID- 23798118 TI - [Effects of imidazolium chloride ionic liquids on the acute toxicity and weight of earthworm]. AB - Standard contact filter paper test of OECD and artificial soil test were used to study the acute lethal effect of three imidazolium chloride ionic liquids, 1 butyl- 3-methylimidazolium chloride ([Bmim] Cl), 1-hexyl- 3-methylimidazolium chloride ([Hmim] Cl), and 1-octyl- 3-methylimidazolium chloride ([Omim] Cl) on earthworm (Eisenia fetida), and the weight of the earthworms was measured after subtle exposure. The 24 h-LC50 values of [Bmim] Cl, [Hmim] Cl and [Omim] Cl using the contact filter paper method were 109.60, 50.38 and 7.94 microg x cm(-2), respectively. The 48 h-LC50 values were 98.52, 39.14 and 3.61 microg x cm(-2), respectively. Using the artificial soil method, the 7 d-LC50 values of [Bmim] Cl, [Hmim] Cl and [Omim] Cl were 447.78, 245.56 and 180.51 mg x kg(-1), respectively, and the 14 d-LC50 values were 288.42, 179.75, 150.35 mg x kg(-1), respectively. There were differences in poisoning symptoms of the three ionic liquids on earthworms. The growth of Eisenia fetida was inhibited and declined with increasing ionic liquid concentration. The toxicity of ionic liquids on Eisenia fetida increased with the length of carbon chain. PMID- 23798120 TI - [Removal of DON in micro-polluted raw water by coagulation and adsorption using activated carbon]. AB - Dissolved organic nitrogen as a precursor of new type nitrogenous disinfection by products in drinking water attracted gradually the attention of scholars all over the world. In order to explore the mechanism of DON removal in micro-polluted raw water by coagulation and adsorption, water quality parameters, such as DON, DOC, NH4(+) -N, UV254, pH and dissolved oxygen, were determined in raw water and the molecular weight distribution of the DON and DOC was investigated. The variations in DON, DOC and UV254 in the coagulation and adsorption tests were investigated, and the changes of DON in raw water were characterized using three-dimensional fluorescence spectroscopy. The results showed that DON, DOC and UV254 were 1.28 mg x L(-1), 8.56 mg x L(-1), 0.16 cm(-1), and DOC/DON and SUVA were 6.69 mg x mg( 1), 1.87 m(-1) x (mg x L(-1))(-1) in raw water, respectively. The molecular weight distribution of the DON in raw water showed a bimodal distribution. The small molecular weight (< 6 000) fractions accounted for a high proportion of 68% and the large (> 20 000) fractions accounted for about 22%. The removal of DON, DOC and UV254 was about 20%, 26% and 70%, respectively, in the coagulation test and the dosage of coagulant was 10 mg x L(-1). The removal of DON, DOC and UV254 was about 60%, 35% and 100%, respectively, in the adsorption test and the dosage of activated carbon was 1.0 g. In the combination of coagulation and adsorption, the removal of DON and DOC reached approximately 82% and 64%, respectively. 3DEEM revealed that the variation of DON in the coagulation and adsorption tests depended intimately on tryptophan protein-like substances, aromatic protein-like substances and fulvic acid-like substances. PMID- 23798119 TI - [Influencing factors and mechanism of arsenic removal during the aluminum coagulation process]. AB - Aluminum coagulants are widely used in arsenic (As) removal during the drinking water treatment process. Aluminium chloride (AlCl3) and polyaluminium chloride (PACl) which contains high content of Al13 were used as coagulants. The effects of aluminum species, pH, humic acid (HA) and coexisting anions on arsenic removal were investigated. Results showed that AlCl3 and PACl were almost ineffective in As(II) removal while the As(V) removal efficiency reached almost 100%. pH was an important influencing factor on the arsenic removal efficiency, because pH influenced the distribution of aluminum species during the coagulation process. The efficiency of arsenic removal by aluminum coagulants was positively correlated with the content of Al13 species. HA and some coexisting anions showed negative impact on arsenic removal because of the competitive adsorption. The negative influence of HA was more pronounced at low coagulant dosages. PO4(3-) and F(-) showed marked influence during arsenic removal, but there was no obvious influence when SiO3(2-), CO3(2-) and SO4(2-) coexisted. The present study would be helpful to direct arsenic removal by enhanced coagulation during the drinking water treatment. PMID- 23798121 TI - [Mechanism of catalytic ozonation for the degradation of paracetamol by activated carbon]. AB - The degradation of paracetamol (APAP) in aqueous solution was studied with ozonation integrated with activated carbon (AC). The synergistic effect of ozonation/AC process was explored by comparing the degradation efficiency of APAP in three processes (ozonation alone, activated carbon alone and ozonation integrated with activated carbon). The operational parameters that affected the reaction rate were carefully optimized. Based on the intermediates detected, the possible pathway for catalytic degradation was discussed and the reaction mechanism was also investigated. The results showed that the TOC removal reached 55.11% at 60 min in the AC/O3 system, and was significantly better than the sum of ozonation alone (20.22%) and activated carbon alone (27.39%), showing the great synergistic effect. And the BOD5/COD ratio increased from 0.086 (before reaction) to 0.543 (after reaction), indicating that the biodegradability was also greatly improved. The effects of the initial concentration of APAP, pH value, ozone dosage and AC dosage on the variation of reaction rate were carefully discussed. The catalytic reaction mechanism was different at different pH values: the organic pollutions were removed by adsorption and direct ozone oxidation at acidic pH, and mainly by catalytic ozonation at alkaline pH. PMID- 23798122 TI - [Reductive degradation of chlorophenols in aqueous solution by gamma irradiation]. AB - Because chlorine is an electron withdrawing group, the highly chlorinated phenols may react quickly with hydrated electrons rather than with hydroxyl radicals. The process of reactions of four chlorophenols (4-CP, 2-CP, 2,4-DCP, 2,4,6-TCP) with e(aq)(-) was investigated in aqueous solutions by detecting the concentration of CPs, Cl- and intermediates. In the e(aq)(-) reductive system, the experimental results showed that the order of four kinds of chlorophenol degradation and dechlorination was 2,4,6-TCP > 2,4-DCP > 2-CP > 4-CP. The greater the chlorine content was the higher reactivity of hydrated electrons towards chlorophenols was. Furthermore, hydrated electrons may preferentially attack the ortho-position of chlorine atom rather than the para-position of chlorine atom. Phenol and Cl- were detected as the final product of the reductive reaction. Additionally, processes of degradation and dechlorination of CPs were observed as the pseudo first-order kinetics. The reaction constant of degradation of 4-CP, 2-CP, 2,4-DCP and 2,4,6-TCP were 0.154, 0.253, 0.750 and 1.188 kGy(-1), respectively. Meanwhile, the dechlorination of 4-CP, 2-CP, 2,4-DCP and 2,4,6-TCP were 0.137, 0.219, 0.251 and 0.306 kGy(-1), respectively. PMID- 23798123 TI - [Effect of C/N ratio on nitrite accumulation during denitrification process]. AB - Effect of C/N (COD/NO3(-) -N) ratio on nitrite accumulation during denitrification process was investigated in a sequencing batch reactor (SBR) with acetic sodium as the electron donor. The nitrite accumulation ratio was 45% at a C/N ratio of 3 during operation in SBR with HRT at 6 h. According to the results of batch experiments, Nitrite accumulation ratios were higher at C/N ratios of 2.5 and 3.0, and the values were 47.50% +/- 1.005% and 45.28% +/- 5.469%, respectively. The nitrite specific accumulation rate was (30.17 +/- 1.70) mg x (g x h)(-1) at a C/N ratio of 2.5, and was (29.92 +/- 1.90) mg x (g x h)(-1) at a C/N ratio of 3.0. C/N ratios of 2.5-4.0 did not affect the nitrate reduction rate but obviously affected the nitrite accumulation rate. C/N ratios of 2.5 and 3.0 were favorable for nitrite accumulation, and a C/N ratio > or = 3.5 would lead to decrease in nitrite accumulation (SBR). PMID- 23798124 TI - [Nitrous oxide emission during denitrification for activated sludge acclimated with methanol as the organic carbon]. AB - Denitrification of wastewater is one of the important sources of nitrous oxide (N2O). In this study, denitrifies were acclimated in a sequencing batch reactor with methanol and nitrate (NO3(-) -N) as the electron donor and acceptor, respectively. N2O emission during denitrification was examined both in typical cycles and in batch experiments under conditions of different electron acceptors, carbon/nitrogen (C/N) ratios and initial nitrite (NO2(-)-N) concentrations. With methanol as the organic carbon, the N2O emission was high with NO2(-)-N as the electron acceptor and the N2O emission was low with NO3(-) -N as the electron acceptor. The C/N ratios affected the emission of N2O by affecting activities of denitrifiers, and both the activity of denitrifiers and the emission of N2O decreased with decreasing C/N ratios. The N2O emission increased with increasing initial NO2(-) -N concentrations, and a certain range of NO2(-) -N concentrations enhanced the activity of denitrifiers. The N2O emission could be correlated very well with initial NO2(-) -N concentrations. PMID- 23798125 TI - [Comparison and optimization of cellulose carbon source for denitrification filter]. AB - The quantity and quality of carbon released by four agriculture wastes included of cotton, rice hull, rice straw and corncob was analyzed for selecting a suitable cellulose filter medium as well as the carbon source in advanced denitrification of the reclaimed water. And the long-term denitrification efficiency and bio-attachment capability of four agriculture wastes was contrastively estimated by running denitrification experiments in laboratory scale. The results showed that DOM amount released by corncob was the highest at the beginning, and the DOM quality was also beneficial for microorganism growth and biofilm formation. The running denitrification experiments showed that corncob had better denitrification efficiency than that of other three carbon sources, and 284.544 g nitrate was removed by 2.5 g corncob within 46 days. Cotton and rice hull had better denitrification efficiency than corncob in the early time, but the long-term denitrification efficiency was lower than that of corncob. Rice straw can hardly be used by microorganism so as to have the lowest denitrification. Therefore, corncob was more suitable to be the denitrification biofilter filter medium and the carbon source in advanced denitrification of the reclaimed water. PMID- 23798126 TI - [A novel municipal wastewater treating process for energy production and autotrophic nitrogen removal based on ANAMMOX]. AB - Using a innovative system consisted of methanogenesis,partial nitritation and anaerobic ammonium oxidation (ANAMMOX) reactors, simultaneous methane production and autotrophic nitrogen removal from domestic sewage was successfully achieved. The results showed that the effluent NH4(+) -N of the combined treatment process was below the detection limit. The effluent NO3(-)-N and NO2(-) -N were less than 0.5 mg x L(-1) and 3.6 mg x L(-1), respectively. The effluent COD of the combined treatment process was 10 mg x L(-1) and a COD removal rate of 98% was achieved. More than 80% COD was removed by the up-flow anaerobic sludge fixed bed (UAFB) and the anaerobic gas production was 3.3 L x d(-1) with a methane yield of 0.3 L x g(-1). About 39.2% of influent COD was removed in form of methane and about 6.52% was transferred to VFAs. Partial nitritation with high nitrite accumulation efficiency of 97% was realized in a Sequencing Batch Reactor (SBR). Ammonium was partly oxidized to nitrite with an ammonium: nitrite ratio of 1: 1.13, which was suitable for the sub-sequent ANAMMOX reaction. In terms of N balance, the N conversion rate of SBR was 36.59% while the anaerobic ammonium oxidation (ANAMMOX) reactor, which was the major system in nitrogen removal, removed 56.91% of N. The TN removal rate of the ANAMMOX reactor was 0.62 kg x (m3 x.d)(-1) and the ratio of NH4(+)-N removal: NO2(-) -N removal: NO3(-) -N generation was 1: 1.18: 1.25. The new process achieves energy recovery by reclaiming methane and autotrophic nitrogen removal by the partial nitritation-ANAMMOX process, and provides a new approach and technology for reforming of domestic wastewater treatment plants. PMID- 23798127 TI - [Modeling and dynamic simulation of the multimode anaerobic/anoxic/aerobic wastewater treatment process]. AB - Mathematical modeling is a useful tool for professional education, process development, design evaluation, operational optimization and automatic control of the wastewater treatment system, and has been extensively applied in numerous full-scale wastewater treatment plants. The ASM2d model was calibrated by the process data, and used to simulate 15 operational test runs of the multimode anaerobic/anoxic/aerobic (AAO) process. After calibration, the model was capable of simulating the sludge concentrations and effluent data in 15 test runs of the multimode AAO system. The dynamic simulation results showed an overall good agreement between the measured and simulated data, for both effluent data and sludge concentrations, with a good reproduction of dynamic processes in AO test runs. PMID- 23798128 TI - [Comparing microbial community of high ammonia wastewater and municipal sewage in a partial nitrification system]. AB - Nitritation is an important part of the biological nitrogen removal process, and the performance of the process was determined by the microbial community structure. To explore the microbial adaptability to different sewage, the microbial diversity and the amount of bacteria were investigated in a high ammonia wastewater treatment process and a sewage treatment process using the clone library of bacterial 16S rDNA, the phospholipid fatty acid method (PLFA) and the quantitative PCR. The clone library results showed that there was a significantly difference in bacterial community structure of these two processes, although the dominant bacteria belong to the Proteobacteria and Bacteroidete, there were more clusters in the sewage treatment process. The PLFAs results showed that the microbial diversity index and the evenness index of the high ammonium wastewater treatment process were significantly low. The quantitative PCR results showed that amounts of ammonia oxidizing bacteria (AOB) and nitrite oxidizing bacteria (NOB) in the high ammonium wastewater treatment process were higher than these in sewage treatment process. The copy number of AOB was higher than the copy number of NOB in the high ammonia wastewater treatment process by three orders magnitude. The copy number of AOB was higher than the copy number of NOB in sewage treatment process by two orders of magnitude. PMID- 23798129 TI - [Analysis of the fractal structure of activated sludge flocs]. AB - The small-angle light scattering (SALS) experiment was executed to calculate the fractal region, and the data of particle size distribution was fitted by Gamma equation. Besides, the atomic force microscope (AFM) and confocal laser scanning microscopy (CLSM) were used to observe the morphology of the microstructure of the sludge flocs under different scales. The results showed that the sluge floc was constituted by a series of clusters with different sizes. The surface of the floc was unsmooth with various "holes" and "gaps" and there were a range of pore structures within the sludge floc. For sludge flocs at large scales, a variety of pore texture coexisted, forming a transport channel for the nutrients and water in the sludge. The results also showed that the fractal structure was present in sludge flocs in the size range of 0.5-50 microm and the particle size distribution was fitted to the Gamma equation distribution model, indicating that the sludge floc formation process is a process dominated by Cluster-Cluster flocculation. PMID- 23798130 TI - [Rapid cultivation of aerobic nitrifying granular sludge with alternate loading method]. AB - The nitrifying granular sludge was cultivated in three Sequencing Batch Reactors (SBR), R1, R2 and R3, respectively. There were two new cultivating methods applied in R1 and R2, which alternately changed the influent nitrogen loading and the influent carbon and nitrogen loading, respectively. The traditional method of step-increasing nitrogen loading was adopted in R3. The results showed that the full-sense nitrifying granular sludge could be cultivated successfully after 70 days in R1 and R2, while it took 147 days in R3. The denser granules with higher activity of nitrifying bacteria and better denitrifying performance could be rapidly obtained by alternately changing the influent carbon and nitrogen loading simultaneously. The removal rates of ammonia nitrogen and total nitrogen were about 95% and 70%, respectively, under the stable operation conditions. Overall, the physical and chemical properties of granules and the performance of denitrification were outstanding in R2. From the comparison results, it indicates that the increasing influent organic loading can speed up the formation of granules and their growth at the early cultivation stage. PMID- 23798131 TI - [Acceleration of the formation of aerobic granules in SBR by inoculating different proportions and different diameters of mature aerobic granules]. AB - In the SBR reactor, the mixed traditional activated sludge and aerobic granules were used as seed sludge to cultivate aerobic granular sludge. The whole research can be divided into two phases. In the first stage, different proportions of aerobic granules (ten, fifteen and twenty percent) were added to three SBR reactors, respectively. In the second stage, aerobic granules of different sizes (unscreened, smaller than or equal to 1 mm in diameter, larger than 1 mm in diameter) were added to three SBR reactors with the proportion of twenty percent, respectively. During the cultivation, the morphological change of the sludge, variation of particle size, maturity time and removal rate of pollutants were studied. The mechanism of fast cultivation was also discussed. The results showed that the reactor with twenty percent aerobic granules had the shortest maturity time of 24 days in the first stage and the reactor with unscreened aerobic granules had the shortest maturity time of 30 days in the second stage. All the cultivated aerobic granules had a good settling property and detergency performance, with the SVI distinctly below 40 mL x g(-1) and the COD removal rate staying above 90%. The formation of aerobic granules could be divided into two stages: the accelerated disintegration stage and the disintegration and rapid forming stage. PMID- 23798132 TI - [Mechanisms of the improvement in dewaterability of alkaline fermented sludge by simultaneous ammonium and phosphate recovery]. AB - Simultaneous ammonium and phosphate recovery could notably improve the dewaterability of alkaline fermented sludge, the mechanisms of which, however, remains unclear at present. The influence of zeta potential, divalent ions, extracellular polymeric substances (EPS), dissolved polymers and struvite were studied in batch experiments. Under the optimal ammonium and phosphate recovery condition [i. e. pH =10.0, n(P)/n(N) = 1.3 mol x mol(-1), n(Mg)/n(N) = 1.9 mol x mol(-1)], it was found that magnesium ion could not only decrease the absolute value of zeta potential to 14 mV, but also reduce the monovalent to divalent ions ratio to 9 mol x mol(-1), which promoted the dewaterability of alkaline fermented sludge; also, the dissolved polymers and EPS, especially the dissolved protein and the loosely bound EPS, reduced remarkably. Results showed that all the factors above promoted sludge dewatering. Furthermore, the struvite formed during ammonium and phosphate recovery improved the dewaterability. PMID- 23798133 TI - [Use of flow cytometric sorting to assess the diversity of eukaryotic picophytoplankton of lakes]. AB - A novel approach based on flow cytometric sorting followed by construction of 18S rRNA clone libraries was used to study the diversity of eukaryotic picophytoplankton of lakes. The composition of eukaryotic picophytoplankton community appeared highly variable in three lakes. Eukaryotic picophytoplankton was dominated by Cryptophyta in the Lake Xuanwu, and was mainly composed of Cryptophyta and Chrysophyta in the Lake Zixia. In the Lake Taihu, four phyla were discovered, including Cryptophyta, Chrysophyta, Bacillariophyta and Chlorophyta. Meanwhile, the diversity of eukaryotic picophytoplankton differed in various lake regions. In the Meiliang Bay, Chrysophyta was the dominant, and the other three phyla were found in the Gonghu Bay. In the central lake, all of those four phyla were discovered, implying this region contained the highest diversity. The canonical correspondence analysis between the diversity of eukaryotic picophytoplankton and environmental factors revealed the concentration of total phosphorus had the highest important impact on the eukaryotic picophytoplankton communities. PMID- 23798134 TI - [Allelopathy effects of ferulic acid and coumarin on Microcystis aeruginosa]. AB - The inhibitory effects and allelopathy mechanism of ferulic acid and coumarin on Microcystis aeruginosa were investigated by measuring the D680 value, the content of chlorophyll-a, the electrical conductivity (EC) and superoxide anion radical O*- value. Ferulic acid and coumarin had allelopathic effects on the growth of M. aeruginosa and promoted the physiological metabolism at low concentrations while inhibited the metabolism at high concentrations. Obvious inhibitory effects were observed when the concentration of ferulic acid or coumarin was over 100 mg x L( 1). The average inhibitory rates reached 80.3% and 58.0% after six days when the concentration of ferulic acid or coumarin was 200 mg x L(-1). The content of chlorophyll-a was decreased while the EC value and O2*- concentration were promoted by higher concentrations of ferulic acid or coumarin, suggesting that the growth of algae was inhibited probably by the damage of cell membrane, increase in the content of O2*- and decrease in the content of chlorophyll-a. In addition, seed germination test elucidated that Ferulic acid was safer than Coumarin. PMID- 23798135 TI - [Spatiotemporal characteristics of zooplankton community structure and diversity in the strong temperature increment seawaters near Guohua power plant in Xiangshan Bay]. AB - To explore the spatiotemporal characteristics of the zooplankton community structure and diversity in the strong temperature increment seawaters near a power plant, zooplankton samples were seasonally collected in duplicate by the type II net with mesh size of 160 microm at 10 stations near Guohua power plant in Xiangshan Bay in 2011. The results showed that a total of 62 species (including larvae) were identified in the samples, and the average abundance was 9 531.1 ind x m(-3). In the seawaters, zooplankton communities were mainly composed of copepods and pelagic larvae, and pelagic larvae were the dominant with an average percentage of abundance reached up to 66.6%. Analysis of similarities demonstrated that significant differences existed in zooplankton community structures among different months (P < 0.01). In these zooplankton communities, there were 18 dominant species controlling these community structures, among which the most important discriminating species were Centropages tenuiremis, Oithona similis, Oithona fallax, Acartia clausi, Clausocalanus furcatus, Paracalanus aculeatus and Paracalanus parvwus. GLM analysis indicated that diversity indices were also significantly different among different months (P < 0.01). According to the calculation results, the inflection point, where the diversity index began to decrease with increasing water temperature, fell within 20.31-22.31 degrees C. In sections, the average water temperature in the 0.2 km section (D02), away from the outfall, was 2.16: higher than that in the 2 km section. Driven by temperature, the main dominant species such as C. tenuiremis and O. similis tended to move into the 0.2 km section, while A. clause and especially large zooplankton tended to stay away from the outfall, and then gathered in the 1.2 km section. As a result, the number of species (33 species) and abundance (5 522.8 ind x m(-3)) were minimum in the section D02, while the number of species (53 species) and abundance (16 491.0 ind x m(-3)) reached the highest in the 1.2 km section. Meanwhile, diversity indices in the 0.2 km section were also obviously lower than those in other sections. Linear regression analysis showed that the diversity indices significantly decreased with increasing water temperature (P < 0.01). The zooplankton richness decreased by 12.3% when the water temperature increased by 1 degrees C. PMID- 23798136 TI - [Screening of epoxy-degrading halophiles and their application in high-salt wastewater treatment]. AB - In this study, two halophilic bacteria were isolated from activated sludge in the epoxy wastewater treatment system. The strains were identified, and the growth and degradation characteristics were investigated. Strain J1 and J2 was identified respectively by morphological observation and 16S rDNA sequence alignment analysis. It was found that both strains belong to the Bacillus genus (Bacillus sp.) and branch Bacillus (Virgibacillus sp.). The optimized growth condition of strain J1 and J2 in the high salt CM culture medium was as follows: solution temperature 30 degrees C, pH 7.0 and 5-50 g x L(-1) of NaCl. Furthermore, the best degradation condition of the organic epoxy wastewater was: temperature 30 degrees C, pH 7.0 and NaCl concentration 30 g x L(-1). When the volume ratio of bacterial suspension mixture of J1 and J2 was 2:1 and the inoculum size of the composite strains was 10%, the highest COD removal efficiency was achieved in the epoxy wastewater treatment. PMID- 23798137 TI - [Biodegradation of decabromodiphenyl ether by intracellular enzyme obtained from Pseudomonas aeruginosa]. AB - The degradation characteristics of decabromodiphenyl ether (BDE-209) by crude enzyme from Pseudomonas aeruginosa were investigated. The results revealed that the degradation efficiency of the intracellular enzyme excreted from this bacterial strain reached 69.22% after incubation with 1 mg x L(-1) BDE-209 for 12 h. Temperature, pH, enzyme concentration and BDE-209 concentration all influenced the ability of crude enzyme to degrade BDE-209. When the BDE-209 concentration was 1 mg x L(-1), the optimal condition for enzymatic degradation was temperature 30 degrees C and pH 7.5, and the degradation rate increased with increasing enzyme concentration. The degradation process of BDE-209 by intracellular enzyme of the strain conformed to the first-order kinetic model. The highest reaction rate was achieved when the initial concentration of BDE-209 was 1 mg x L(-1) and the half-life of this substrate was 6.9 h. In addition, the biodegradation of BDE 209 can be well described by enzymatic reaction of high concentration substrate inhibition, with a maximum substrate utilization rate of 0.133 mg x (L x h)(-1), a Michaelis-Menten constant of 0.642 mg x L(-1), and an inhibitory constant of 1.558 mg x L(-1), respectively. PMID- 23798138 TI - [Influence of yeast extract on the fermentation of glucose by the demulsifying strain Alcaligenes sp. S-XJ-1]. AB - The demulsifying strain Alcaligenes sp. S-XJ-1, isolated from oil contaminated soil, was cultivated with glucose as the carbon source. The influences of yeast extract on the growth, demulsifying ability and the element composition of the strain were investigated. The results showed that the yeast extract could increase the biomass and enhance the glucose utilization of Alcaligenes sp. S-XJ 1. When the concentration of the yeast extract was 5 g x L(-1), the biomass was increased up to 3.0 g x L(-1), and the glucose utilization achieved 58%. The demulsifying ability of the strain was improved with increasing yeast extract concentration. When the concentration of the yeast extract was 10 g x L(-1), the demulsification ratio of the obtained cell was 76%. While the C/N ratio of the cells decreased with the increasing concentration of yeast extract. The proteins of cells were extracted and measured. The results showed that the proteins of the obtained cell increased with the increasing concentration of yeast extract, in accordance with the increased concentrations of proteins on the surface of the cells as measured by FTIR. It is estimated that the increase of the proteins leads to the improvement of the demulsifying ability of the demulsifying strain and theses proteins play essential roles in the demulsifying process. PMID- 23798139 TI - [Phylogenetic analysis of methanogenic corn stalk degrading microbial communities]. AB - Methanogenic corn stalk degrading enrichment cultures were constructed using corn stalk as the sole carbon source and eight types of environmental samples as inocula. All the cultures could degrade corn stalk within 30-50 days and the total solids (TS) removal rates were in the range of 30%-40%. In six out of eight cultures, the cumulative methane yields per gram TS were 62.1-118.4 mL x g(-1), with acetate, propionate and butyrate as the major volatile fatty acids (100-500 mg x L(-1)), and the final pH were 6.5-6.7. In the other two cultures, the cumulative methane yields per gram TS were 8.5-9.7 mL xg(-1), while the concentrations of acetate were high (1200 mg x L(-1)), and the final pH were low (5.6-5.9). The bacterial and archaeal structures in eight enrichments were investigated with a 16S rRNA genes-based clone library method. Clones belonging to the bacterial phyla Firmicutes, Bacteroidetes, Synergistetes and Thermotogae were observed in abundance within the bacterial clone libraries, which accounted for 37.8%, 34.3%, 11.6% and 6.4% of the total number of bacterial clones, respectively. Within the domain Archaea, clones affiliated with the classes Methanomicrobia and Methanobacteria were found to be abundant in the archaeal clone libraries, which accounted for 61.1% and 38.9% of the total number of archaeal clones, respectively. PMID- 23798140 TI - [Inhibition of methanogenium by erythromycin and its domestation]. AB - Erythromycin is a kind of antibiotic drugs with certain biological toxicity. In order to investigate the inhibitory effect of erythromycin on methanogens and its acclimation capacity, Anaerobic Toxicity Assay (ATA) and continuous experiment were conducted in anaerobic bottles and the Up-flow Anaerobic Sludge Blanket Reactor (UASB), respectively, to determine the accumulated methane production, ratio of methane production rate, COD removal efficiency, and methane content. The results showed that the methane production ratio was reduced to 56.1% in the presence of 150 mg x L(-1) of erythromycin and it was reduced by 99% when the erythromycin reached 250 mg x L(-1), indicating that the activity was completely inhibited. Keeping the erythromycin at an concentration of 20 mg x L(-1) in the process of continuous operation for 60d, the COD removal efficiency and methane content reached up to 81.4% and 64.2%, respectively. The results suggested that erythromycin had an inhibitory effect on methane bacteria, and the half inhibitory concentration was 150 mg x L(-1) (IC50:150 mg x L(-1)). The COD removal efficiency and methane content were increased by 15.13% and 22.05%, respectively, after domestication for 60 d. PMID- 23798141 TI - [Sand box study on fingering front morphology for NAPLs infiltrated in homogeneous porous media]. AB - Abstract: 1,2-dichloroethane and tetrachlorethylene were studied in four different unsaturated porous media to determine the impact of the properties of media and fluids on the infiltration aided by digital image analysis technique. The results indicated that the whole process of NAPLs migration can be recorded dynamically using the digital image analysis technique. The unstable flow "fingering" occurred in the process of infiltration. Fingering mechanisms such as splitting, coalescing, and shielding were observed in the process of fingering. Front morphology of the infiltration was influenced by the properties of porous media and fluids. The vertical migration rates and the growth rates of area development were positively correlated to the size of medium particle and the density of the NAPLs (except for toluene) in the process of infiltrating. The number of fingers and the wavelength of fingering were also closely correlated with the properties of media and fluid. DNAPLs infiltrated faster compared with LNAPLs, which resulted in larger pollution area within the same infiltration time. It can be concluded that the environmental risk of DNAPLs is significantly greater than the LNAPLs. PMID- 23798142 TI - [Vertical distribution and possible sources of polycyclic aromatic hydrocarbon in sewage area soil]. AB - Nine profile soil samples were collected from Xiaodian sewage irrigation area, Taiyuan city, China. The concentrations of 16 polycyclic aromatic hydrocarbons (PAHs) were analyzed by gas chromatography equipped with a mass spectrometry detector (GC/ MS). The rank order of the average concentrations of PAHs in the 0 10 cm upper soil layer was background area < swamp area < groundwater irrigation area < sewage irrigation area. The concentrations of PAHs in most profile soils decreased with the increase of depth, and the PAHs were mainly accumulated in the surface soil layer (0-40 cm). 4-6 rings of PAHs were mainly accumulated in the 0 50 cm soil layer, and the accumulation capacity in groundwater-irrigation area was better than that in sewage irrigation area. The correlation between different rings of PAHs and TOC was positive (r(max) = 0.791, P = 0), and the same situation was found for PAHs and sand (r(max) = 0. 882, P = 0). The correlation between PAHs and pH was negative (r(min) = -0.1, P = 0.702). The main source of PAHs in the surface soil layer (0-40 cm) of study area was coal combustion. There were two pollution ways of PAHs in soil, one was settled into soil directly, the other was first settled into water and absorbed on the surface of solid particles, and then got enrichment in soil as irrigation water flew. PMID- 23798143 TI - [Characteristic and evaluation of soil pollution by heavy metal in different functional zones of Hohhot]. AB - The residential areas, cultural and educational areas, city parks, commercial areas, urban roads, industrial zones, and development zones in Hohhot were selected as the research objects. Sixty-two soil samples were collected by triple subsampling technique in the seven functional zones. The aim of this study is to control the soil heavy metal pollution of Hohhot and provide the basic information. To investigate and analyze the heavy metal pollution in soil in different functional zones of Hohhot, the pollution of heavy metal was assessed with single factor pollution index and Nemerow integrated pollution index, and the pollution sources were discriminated by Principal Component Analysis. Contents of seven kinds of heavy metals were analyzed in different functional zones of Hohhot. The mean contents of heavy metals in soil samples exceeded the corresponding background values in the Inner Mongolia Autonomous Region. The mean contents of Cu and Zn were 2. 33 and 1. 85 times, respectively, as high as the soil background values of the Inner Mongolia Autonomous Region. Single factor pollution index showed that the urban soil in Hohhot has been polluted by heavy metals. The Cu pollution was the most severe in commercial areas, and the pollution degree was in the following order: Cu > Zn > Cr > Mn > As > Ni > Pb. Nemerow integrated pollution index showed that soils from the commercial areas were seriously contaminated by heavy metals. The soil of urban roads was moderately polluted. The soils from cultural and educational areas and the city parks were slightly polluted. The Nemerow integrated pollution index of the seven areas ranked as follows: commercial areas (3.03) > urban roads (2.12) > residential areas (1.98) > cultural and educational areas (1.81) > industrial zones (1.72) > development zones (1.36) > city parks (1. 28). The results of Principal Component Analysis showed that the heavy metals in soil of Hohhot came from different sources. Cr, Cu, Mn, Pb and Zn were mainly originated from anthropogenic sources while Ni and As were mainly controlled by natural sources. The healthy development of urban ecosystem has been threatened by soil heavy metal pollution in Hohhot. PMID- 23798144 TI - [Distribution characteristics of rice photosynthesized carbon in soil aggregates of different size and density]. AB - Rice growth affects the distribution of organic matter in soils and soil fractions, and is thus an important factor to control the storage of soil organic matter. The aims of our study were to quantify the photosynthesized C in soil fraction pools of different size and density during the rice growth, and also to offer data evidence not only in the mechanisms of SOC accumulation, but also in C sequestration potential in paddy soils. Therefore, the microcosm experiment was carried out to quantify the input and distribution of photo-assimilated carbon (C) in soils size and density aggregates pools by using continuous 14C labeling technique. Destructive samplings of rice (Oryza sativa) were conducted after labeling for 80 days. The allocation of 14C-labeled photosynthates in soil C pools was examined in rice-planted soil over the 14C labeling span using the size (250-2 000 microm, 20-250 microm, < 20 microm) and density (light and heavy) fractionation procedure. The amount of 14C in the soil organic C (SOC14) in the 250-2 000 microm particle size was dependent on the soils, ranged from 118.23 mg x kg(-1) to 309.94 mg x kg(-1), accounting for 0.52%-1.55% of its SOC, respectively, which was much larger than those of aggregates with the other two sizes (20-250 microm, < 20 microm). Moreover, the amounts of SOC14 in light fractions of 250-2 000 microm and 20-250 microm particle size aggregate were significantly greater than those in their heavy fractions (P < 0.05). The data suggested that rice photosynthesize C mainly entered into the light fraction of 250-2 000 microm particle size aggregate by rhizodeposition, which enhanced the contents of SOC. There was a significant positive correlation between the light and heavy fraction and 250-2000 microm particle size aggregate, 20-250 microm and < 20 microm particle size aggregate of SOC14, although significant negative correlation between light fractions in < 20 microm, 20-250 microm aggregates was observed. PMID- 23798145 TI - [Profile of soil microbial biomass carbon in different types of subtropical paddy soils]. AB - The soil microbial biomass carbon (C(mic)), one of the most active components of soil organic carbon (C(org)), is an effective indicator of soil quality. In the present study, five subtropical paddy soils developed from different parent materials were selected, and the distribution of C(mic) through the profiles was studied, as well as the relationship of C(mic) with C(org) and soil nutrients. The results showed that the contents of C(org) and C(mic) decreased markedly with increasing soil depth, ranging from 2.45 g x kg(-1) to 26.19 g x kg(-1) and from 4.55 mg x kg(-1) to 1 691.75 mg x kg(-1), respectively. They mainly concentrated in the surface layer (plough horizon and plough pan). The content of C(mic) varied significantly in paddy soils developed from different parent materials, with the highest one in yellow clayey soil, and the lowest ones in alluvial sandy soil and reddish yellow clayey soil. This was on the contrary to the distribution of C(org) in the surface paddy soils, since the reddish yellow clayey soil and alluvial sandy soil showed higher contents while other types of paddy soils exhibited similar contents of C(org). Notwithstanding, C(mic) was still controlled by the quantity of C(org) and positively correlated with C(org). The ratio of C(mic) to C(org)(C(mic)/C((org)) decreased with increasing soil depth and differed in the plough horizon between different paddy soils, with lower values in alluvial sandy soil (2.11%) and reddish yellow clayey soil (1.37%) but higher value in reddish yellow clayey soil I (8.24%). It indicated that the microbial substrate availability in alluvial sandy soil and reddish yellow clayey soil was lower than those in reddish yellow clayey soils. The content of C(mic) was significantly positively correlated with total nitrogen, alkali-hydrolyzable N and Olsen-P, but was irrelevant to available K. It is implied that the C(mic) was not only controlled by C(org), but also complicatedly interacted with soil nutrients in paddy soils. PMID- 23798146 TI - [Effect of composting organic fertilizer supplies on hexachlorobenzene dechlorination in paddy soils]. AB - A rice pot experiment was conducted in two soils, Hydragric Acrisols (Ac) and Gleyi-Stagnic Anthrosols (An). Three treatments including control and additions of 1% or 2% composting organic fertilizer were designed for each soil. The objective of this research was to evaluate the reductive dechlorination of hexachlorobenzene (HCB) as affected by organic fertilizer supplies in planted paddy soils, and to analyze the relationship between methane production and HCB dechlorination. The results showed that the HCB residues were decreased by 28.6% 30.1% of the initial amounts in Ac, and 47.3% -61.0% in An after 18 weeks of experiment. The amount of HCB and its metabolite uptake by rice plants was only a few thousandths of the initial HCB amount in soils. The main product of HCB dechlorination was pentachlorobenzene (PeCB). The rates of HCB dechlorination in An were higher than those in Ac, which was mainly attributed to the higher pH and dissolved organic carbon (DOC) content of An. The applications of both 1% and 2% composting organic fertilizer showed significant inhibition on PeCB production after the 6th and 10th week in Ac and An, respectively. In both tested soils, no significant difference of PeCB production rates was observed between the applications of 1% and 2% composting organic fertilizer. The role of methanogenic bacteria in HCB dechlorination was condition-dependent. PMID- 23798147 TI - [Remediation of Cu-Pb-contaminated loess soil by leaching with chelating agent and biosurfactant]. AB - Because of its strong chelation, solubilization characteristics, the chelating agents and biosurfactant are widely used in remediation of heavy metals and organic contaminated soils. Ethylenediamine tetraacetic acid (EDTA), citric acid (CIT) and dirhamnolipid (RL2) were selected as the eluent. Batch experiments and column experiments were conducted to investigate the leaching effect of the three kinds of eluent, as well as the mixture of biosurfactant and chelating agent for Cu, Pb contaminated loess soil. The results showed that the leaching efficiencies of different eluent on Cu, Pb contaminated loess soil followed the sequence of EDTA > CIT > RL2. At an eluent concentration of 0.02 mol x L(-1), the Cu leaching efficiency was 62.74% (EDTA), 52.28% (CIT) and 15.35% (RL2), respectively; the Pb leaching efficiency was 96.10% (EDTA), 23.08% (CIT) and 14.42% (RL2), respectively. When the concentration of RL2 was 100 CMC, it had synergistic effects on the other two kinds of chelating agent in Cu leaching, and when the concentration of RL2 was 200 CMC, it had antagonism effects. The effect of RL2 on EDTA in Pb leaching was similar to that in Cu leaching. Pb leaching by CIT was inhibited in the presence of RL2. EDTA and CIT could effectively remove Cu and Pb in exchangeable states, adsorption states, carbonate salts and organic bound forms; RL2 could effectively remove Cu and Pb in exchangeable and adsorbed states. PMID- 23798148 TI - [Effects of different temperatures biochar on adsorption of Pb(II) on variable charge soils]. AB - Effects of incorporation of the biochars generated from rice straw and peanut straw at different temperatures on soil pH and Pb(II) adsorption were investigated with two variable charge soils. The soil pH increased by 1.04-3.00 units, and the increase in soil pH increased with the rise of pyrolysis temperature of the biochar. Results from adsorption isotherm experiments indicated that the incorporation of the biochar enhanced the adsorption of Pb(II) by two soils. The adsorption of Pb(II) was increased by 12.6% -57.6%, when the initial concentration of Pb(II) is 2 mmol x L(-1). The adsorption also increased with rising pH. Freundlich and Langmuir equations can be used to fit the adsorption isotherms of Pb(II), but the Freundlich equation fitted the adsorption data better, the r-values are above 0.94. Soils incorporated with peanut straw char have a greater adsorption capacity for Pb(II) than these incorporated with rice straw char as predicted by the parameters of k and Q(m) in Freundlich and Langmuir equations, respectively. The biochars generated at 400 degrees C have a greater enhancement on Pb(II) adsorption by soils than 300 degrees C and 500 degrees C. Desorption results showed that the desorption of Pb(II) for the treatments with biochar added was greater than that for the control, but the amount of desorbed Pb(II) was much lower than that of adsorbed Pb(II). These results suggested that the enhanced adsorption of Pb(II) by incorporation of the biochars involved at least two mechanisms: electrostatic adsorption and non electrostatic adsorption. PMID- 23798149 TI - [Preparation and performance investigation of Trichoderma viride-modified corn stalk as sorbent materials for oil spills]. AB - This work aims at preparing oil spill sorbent (TCS, Trichoderma viride-modified corn stalk) through solid-state fermentation of corn stalk by Trichoderma viride. Single-factor experiments, including the effect of modification time, solid liquid ratio of modification and modification temperature, and adsorption experiments simulating oil spill condition, were carried out. The results indicated that the maximum oil adsorption of TCS, 13.84 g x g(-1), could be obtained under the conditions of 6 days of modification, with a solid-liquid ratio of 1:4 and a modification temperature of 25 degrees C. This oil absorption was 110.33% of that of the raw material (RCS, Raw Corn Stalk). Comparing RCS and TCS by means of Scanning Electron Microscopy (SEM), Fourier Transform Infrared Spectroscopy (FT-IR) and X-ray Diffraction (XRD), the results separately showed that TCS had rougher surface, lower cellulose content and higher instability, which explains the increase of oil absorption. Also, the component analysis indicated that bio-modification could reduce the contents of celluloses and hemicelluloses from corn stalk. Besides, sorption kinetics and oil retention performance test showed that, TCS, which could reach adsorption equilibrium after 1 h of 80 r x min(-1) oscillating, had fast oil adsorption rate, and it also had good oil retention performance, which could keep 74. 87% of the initial adsorption rate when trickling 10 min after reaching adsorption equilibrium. PMID- 23798150 TI - [Removal of PO4(3-) from solution, wastewater and seawater by modification and granulation magnesium and aluminium layered double hydroxide]. AB - Powder layered double hydroxide of Mg-Al LDH were prepared by hydrothermal technology with 500 kg x batch(-1), modified and granulated (MG Mg-Al CLDH) by deposition method. After the modification and granulation, the fixed bed can not be accumulated and clogged by the adsorbents. The PO4(3-) is removed from aqueous solution, wastewater and seawater by MG Mg-Al CLDH with column experiments. It shows that MG Mg-Al CLDH is an effective adsorbent. After removal, the water quality can satisfy with the first degree of integrated wastewater discharge or seawater standards. The mechanism of removal PO4(3-) is ion exchange and 'memory effect'. The breakthrough adsorption capacity of PO4(3-) from solution is 13.49 mg x g(-1), more than 6 times higher than that by Mg-Al LDH without modification. The exhausted MG Mg-Al CLDH can be desorbed with 0.1 mol x L(-1) NaOH and 3 mol x L(-1) NaCl and regenerated with 25% MgCl2. The regeneration rate is 126.24%. The breakthrough curves are influenced by bed depth, flow rate, initial concentration and initial pH. The adsorption processes are controlled by film diffusion. When the initial concentration is as low as 0.38 micromol x L(-1), PO4(3-) can be removed from seawater to satisfy with the first degree of seawater quality. So this work is very useful for the practical application of Mg-Al LDH and the removal of phosphorus. PMID- 23798151 TI - [Influence of carboxylic carbon nanotube supported platinum catalyst on cathode oxygen reduction performance of MFC]. AB - The cathodic catalyst plays an important role in the electricity generation of the microbial fuel cell (MFC). In order to evaluate the efficiency of oxygen reduction on the carbon nanotube (CNT) functionalized with different carboxylic groups supported Pt, carboxylic CNTs under the conditions of 80 degrees C and 95 degrees C were prepared, respectively. Pt/CNT catalysts (Pt/CNT-80 and Pt/CNT-95) was prepared by the dipping-precipitation method and their oxygen reduction efficiency was tested in the MFC (MFC-80, MFC-95 and MFC-C) with the air cathode. The results showed that the maximum power output densities of the MFC-95 and MFC 80 were 568.8 mWx m(-2) and 412.8 mWx m(-2), internal resistances were 204.7 omega and 207.7 omega, and open circuit potentials were 0.719 V and 0.651 V, respectively. However, the maximum power output density of the control MFC-C was only 5.4 mW x m(-2), and its internal resistance was 826.2 omega. XPS and XRD analysis results demonstrate that the efficiency of Pt/CNT-95 catalyst is better than Pt/CNT-80 may result from the surface of carboxylic CNT in the 95 degrees C introduced rich oxygen containing groups. PMID- 23798152 TI - [Flue gas desulfurization by a novel biomass activated carbon]. AB - A novel biomass columnar activated carbon was prepared from walnut shell and pyrolusite was added as a catalyst. The activated carbon prepared was used for flue gas desulphurization in a fixed-bed reactor with 16 g of activated carbon. The impact of operating parameters such as SO2 inlet concentration, space velocity, bed temperature, moisture content and O2 concentration on the desulfurization efficiency of activated carbon was investigated. The results showed that both the breakthrough sulfur capacity and breakthrough time of activated carbon decreased with the increase of SO2 inlet concentration within the range of 0.1% -0.3%. The breakthrough sulfur capacity deceased with the increase of space velocity, with optimal space velocity of 600 h(-1). The optimal bed temperature was 80 degrees C, and the desulfurization efficiency can be reduced if the temperature continue to increase. The presence of moisture and oxygen greatly promoted the adsorption of SO2 onto the activated carbon. The best moisture content was 10%. When the oxygen concentrations were between 10% and 13%, the desulfurization performance of activated carbon was the highest. Under the optimal operating conditions, the sulfur capacity of activated carbon was 252 mg x g(-1), and the breakthrough time was up to 26 h when the SO2 inlet concentration was 0.2%. PMID- 23798153 TI - [Method for grading industrial sectors in energy consumption and its application]. AB - Energy is mainly consumed by the urban industry system, thus grading industrial sectors for their energy consumption may help to identify the concerned industrial sectors and provide necessary information for industrial energy management in China's industrialization and urbanization. In present article, based on a review of the fundamental relationships between energy consumption and industrial sectors, the contribution rates and energy efficiency of industrial sectors are chosen as typical parameters for energy consumption. The concept of distance index of industrial sectors for energy consumption is defined through China's average level as a reference base. The grade of industrial sectors in energy consumption is classed into 9 types from extreme advantage to extreme disadvantage according to the scope of distance index values, and the types of industrial sectors that need to be more concerned are pointed out. Taking Chongqing as a case study, the application for grading industrial sectors for their energy consumption was exhibited, by which, the main industrial sectors are grated and the industrial sectors that should be special concerned in energy management are determined. PMID- 23798154 TI - [Dynamics and environmental load of food carbon consumption during urbanization: a case study of Xiamen City, China]. AB - With the rapid urbanization, city plays a more and more significant role in the carbon cycle of urban ecosystem. The contribution of household food carbon consumption to urban carbon cycle has become increasingly important, and has been the hot issues of the urban carbon cycle study. We analyzed the dynamics of the food carbon consumption in Xiamen City from 1988 to 2010, evaluated and forecasted the trends of food carbon consumption and its environmental load. The results showed that, from 1988 to 2010, per capita food consumption and per capita food carbon consumption declined by 6% and 25%, respectively. However, due to the rapid growth of population, the total food consumption and total food carbon consumption increased by 116% and 70%, respectively. The rising of total food carbon consumption led to the increasing environmental load of food carbon. The environmental load of food carbon increased from 98 800 t to 166 200 t, particularly there is a dramatic increase of carbon input into soil in recent years. From 2011 to 2024, total food carbon consumption and environmental load will continue to rise and then decline in 2025. Per capita food carbon consumption will decline continuously from 2011. The analysis of household food consumption showed that per household food carbon consumption was affected by household income, food cost and household persons. High food carbon consumption household usually had in average three persons eating at home, spent in average 3 125 yuan x month(-1) on food, the per household food carbon consumption was 1 134.91 kg,and the per capita food carbon consumption was 378.30 kg. Per capita food carbon consumption of high-consumption family was 4.84 times higher than that of low-consumption family. PMID- 23798155 TI - "Back our campaign and put patient safety first". PMID- 23798156 TI - "Talking" pilot to improve culture. PMID- 23798157 TI - "With Francis' main concerns ignored, expect more scandals". PMID- 23798158 TI - "Hospice funding must reflect the number of deaths that occur there". PMID- 23798159 TI - Training to promote disciplinary working. AB - The Better Training Better Care programme incorporates recommendations from Sir John Temple's report Time for Training and John Collins' review Foundation for Excellence to improve multiprofessional training and working. This article describes some of the programme pilots under way in the UK and looks at how they can be disseminated through the rest of the health service to improve patient care throughout. PMID- 23798160 TI - How interprofessional learning improves care. AB - Students from different health disciplines often have little idea of what each other's roles entail. Interprofessional learning increase this knowledge, as well as giving students an understanding of the interpersonal skills needed for liaison and communication. IPL has been shown to create teams that work together better and improve patient experience. It has been introduced successfully at the University of East Anglia and at other higher education institutions. PMID- 23798161 TI - Legal protection for healthcare workers from sharps injuries. AB - The implementation of the sharps directive is the result of a negotiated agreement at European level between employers' organisations and trade unions. In the UK, NHS Employers, health service unions--including Unison and the Royal College of Nursing--and others have worked with the Health and Safety Executive to try to ensure that the new rules are workable at local level. PMID- 23798162 TI - A skills development pathway for HCAs. AB - Recommendations by the Willis Commission for trusts to review processes for healthcare assistant development were echoed in the Francis report. HCAs are not regulated nationally, nor do they have a guaranteed standard of training. Liverpool Heart and Chest Hospital has responded to this challenge by setting up an HCA development pathway focusing on quality and patient safety. This article explains how it was implemented. PMID- 23798163 TI - Health risks for students on overseas placements. AB - Health profession students are encouraged to take an elective during training and many do this overseas in tropical, low-income countries. Higher education institutions should offer advice and support on organising these placements but this varies and students may present for pre-travel health advice at their general practice or travel clinic. This article discusses how they should be advised. PMID- 23798164 TI - Improving use of systematic reviews. PMID- 23798165 TI - Top-rated service for children. PMID- 23798166 TI - [Classic and specialty areas of wound taken into account]. PMID- 23798167 TI - [The bottom line is positive]. PMID- 23798168 TI - [We need more specialized wound centers (interview by Christian Heinemeyer)]. PMID- 23798169 TI - [Achieving long-term behavior changes]. PMID- 23798170 TI - [Taking the special needs of children's skin into consideration]. PMID- 23798171 TI - [Avoiding misperceptions]. PMID- 23798172 TI - [Patients with chronic ulcers profit from clinical pathways which ensure evidence based wound management]. PMID- 23798173 TI - [Inflamed, edematous and painful]. PMID- 23798174 TI - [Supplementing modern wound care]. PMID- 23798175 TI - [Measuring self care of patients with heart failure]. PMID- 23798176 TI - [How effective are silver wound dressings? Wound healing of critically colonized and infected wounds]. PMID- 23798177 TI - [Supporting and promoting desirable processes]. PMID- 23798178 TI - [In the systemic balance]. PMID- 23798179 TI - [Deliberate and clever research]. PMID- 23798180 TI - [Assessing, cleansing, dressing]. PMID- 23798181 TI - [Drugs and driving]. AB - Driving requires alertness at every moment. If everybody knows that between drink and drive, you must choose, few people know that many drugs can have an adverse effect on their ability to drive a vehicle. Most often it is because they can cause drowsiness, make them less attentive or slow reflexes that some drugs increase the risk of accidents, but they can also affect the ability of judgment, impair the view or cause dizziness what becomes dangerous when you're on the road. It is the responsibility of the pharmacist to attract the attention of the patient during the provision of these drugs on the negative impact they can have on driving. PMID- 23798182 TI - [Recommendations for the use of insect repellents by pregnant women and children]. PMID- 23798183 TI - [Opinions and attitudes of Flemish pharmacists and general practitioners towards INN prescribing. A survery in Antwerp and East Flanders]. AB - INTRODUCTION: Since 2002 in Belgium, physicians are allowed to prescribe by International Non-proprietary Name (INN). In 2005, the conditions for this decree were set. Examples from other countries have shown that INN prescribing can significantly contribute to controlling pharmaceutical expenditures. The share of INN prescriptions remains low in Belgium (7% in 2011). OBJECTIVE: To formulate an answer to the question: what are the opinions and attitudes of pharmacists and general practitioners [GP's] with regards to INN prescribing? METHOD: In the winter of 2011-2012, a questionnaire with closed-ended questions was send to pharmacists and GP's in the provinces of Antwerp and East-Flanders, through training days and personal visits. Pharmacists and GP's scored a list of statements with a 5-point Likert scale. The themes of the statements related to: delivering INN prescriptions, legislation, impact on expenditures, choices regarding patient concerns and interprofessional relations. RESULTS: In total, 353 questionnaires were completed and returned of which 228 165%1 were by pharmacists and 125 (35%1 by GP's. Although both declared to be sufficiently up to date with regulations to prescribe (84%) or to deliver (95%] a INN prescription, only 13% of the pharmacists said all prescription they receive contain the correct information. Less GP's [36%) than pharmacists (82%] feel aided by their software program when prescribing or delivering an INN prescription. GP's rely mostly on NIHDI (National Institute for Health and Disability Insurance) as the main source for information on INN prescribing, pharmacists rely on the [Local) pharmacists association. The pharmacists and GP's in the study who relied on NIHDI as main information source, were less aware of legislation concerning INN [N2, p<0,05] than those who rely on the local professional association [N2, p<0,0001]. All pharmacists in the study said to consider the patients medication history when delivering an INN prescription for chronic treatment. However, 57% of the GP's preferred not to prescribe by INN for the reason that they are not sure whether the pharmacist will always consider the patients medication history in case of an INN prescription. Although the GP's showed certain motivation to prescribe by INN, it was no greater than for generic prescribing. And INN prescribing has no added value compared to generic prescribing, according to the GP's. For the pharmacists, INN prescribing does contain an opportunity. With the increase in numbers of dosages and sorts of packaging of generic products, it becomes more and more difficult for pharmacists to manage their stock. In case of an INN prescription, the pharmacist can choose between the different packages in his stock. This offers opportunities especially for acute conditions. CONCLUSION: INN prescribing is a good example of where the collaboration between pharmacists and GP's still contains a lot of opportunities, as well for the two professions, as the government and the patient in terms of controlling the pharmaceutical expenditures. Also the education for pharmacist or GP can further contribute to the sensitization of INN prescribing. In practice, there remain a number of issues and differences in opinions between pharmacists and general practitioners regarding INN prescribing. GP's feel few motivation to prescribe by INN and the government has put no imperative demands towards prescribers. Further evaluation of the practicaL feasibility of the current conditions for prescribing and delivering INN prescriptions is needed. PMID- 23798184 TI - [Implementation of computerized phisician order entry in a hospital setting: what are the keys to success?]. AB - INTRODUCTION: A software of computerized physician order entry [CPOE] was developed by a data-processing company in collaboration with the Mont-Godinne University Hospital By 2006, parallel to the evolution of the software, the progressive implementation of CPOE was carried out, and currently covers 16 wards, the emergency room, the recovery rooms and the center of medical care [day hospital] as well as the day surgical center OBJECTIVES: Complete computerization of the drug supply chain, including the regulation by the physician, the pharmaceutical validation, the delivery and the follow-up of stocks by pharmacy, the validation of the administration by the nurse and the tariffing of the drugs. METHOD AND RESULTS: In 2006, a working group was created in order to validate specifications allowing the development of a software of CPOE, Linked to the computerized medical record. A data-processing company was selected in order to develop this software. Two beds were computerized in the pneumology ward, in order to test and validate the software. From 2007 to 2009, 3 additional wards were computerized [geriatrics, neurosurgery, revalidation]. A steering committee of CPOE, composed of various members (direction, doctors, pharmacists, nurses, data processing specialistsl is created. This committee allows the installation of the means necessary to the deployment of CPOE in the Institution. Structured teams for the deployment are created: medical and nurse coaches. From 2009 to 2012, the deployment of the software is carried out, covering 16 wards, the emergency room, the recovery room and the day-hospitals. CONCLUSION: The computerization of the drug supply chain is a challenge which concerns the institutional level. The assets of our hospital and our project were: - a strong management committee, making of this project a priority entering the strategical planning of the institution; - a steering committee allowing each type of actor to express his needs, and of prioriser requests; - a closer medical coaching; - teams of nurses coaches, accompanying each ward, during and after the deployment; - a dynamic IT team allowing a relay between the Institution and the data processing company. These points appeared essential and are as many keys for a successful deployment. PMID- 23798185 TI - [Tafluprost (Saflutan) ophthalmic use]. PMID- 23798186 TI - [Chronic diseases: the politician must engage himself]. PMID- 23798187 TI - [Hypoglycemia and diabetes treatment: the return to normal glucose level is not always the best therapeutic strategy]. AB - Recent clinical trials with type 2 diabetic patients and the quest of normal glyceamic values, have revealed difficulties and limitations. These too normal glyceamic targets corresponding to the physiological standards are associated with very high rate of hypoglycemia and an increase of mortality. A too simplistic view of treatment: "the lowest, the better is in the diabetes" is no longer defensible. The knowledge from complex systems behavior invites us to search targets adapted to a new state of equilibrium due to loss of self regulation. These targets should not aim the physiological standards but to be adapted to patient's situation. Shared decision-making and consensus are the two pillars of this new strategy supported by the new ADA-EASD guidelines. PMID- 23798188 TI - [Non diabetic hypoglycemia: diagnosis and management]. AB - Organic or non diabetic hypoglycemia (NDH) is a rare disease when it is confirmed, but is often confounded with low blood glucose concentration (between 3 and 4 mmol/I), which is much more frequent. NDH's definition requires the Whipple triad (plasma glucose level <2.8 mmol/l, symptoms of neuroglycopenia and their relief with administration of sugar). The diagnostic approach needs to differentiate the healthy from the sick patient, who's hypoglycemia causes are multiple and frequent, such as: toxic (medicament, OH), organ deficiency, denutrition and sepsis. When hypoglycemia is suspected, without evident causes in healthy persons, it should be investigated by a 72 h fast test, in order to guide the diagnosis. After confirmation of an endogen hyperinsulinism only, sophisticated imaging should be done to localize the tumor and/or to exclude alternatives diagnosis. PMID- 23798189 TI - [Diabetes in elderly: a tailored management]. AB - In developed countries, 12-25 % of the aged population (>65 years old) have diabetes. Treatment of the old diabetic patients is less well studied compared to younger patients although diabetic and geriatric medical associations have issued specific treatment and priority guidelines for these patients. Treatment and targets of glycemic control must be adapted to the functional condition of the patients, prevent symptoms and complications of the geriatric syndrome. Prevention and screening of chronic complication of diabetes have to be integrated in the overall care of aged diabetic patients to optimize their quality of life and health state. PMID- 23798190 TI - [Sport and type 1 diabetes]. AB - Physical activity is recognised to be an efficient measure in improving glycemic control in the treatment of type 2 diabetes. This evidence is lacking in type I diabetes but type 1I diabetics benefit from the same advantages like the general population. For many type I diabetics, especially younger patients, sport represents an important modality in the treatment of their disease but also of their quality of life. However, this is often a challenge for the patient as well as for the physician regarding the metabolic consequences (hypo- but also hyperglycemia) which can appear in relation with physical activity. There are existing general recommendations concerning the intake of carbohydrates and the reduction of insulin doses but those have to be adapted individually for each patient and depend significantly on different sports and on the intensity of sport. PMID- 23798191 TI - [How to tackle the epidemic of diabetes: strategy at cantonal level]. AB - Switzerland is affected by a "diabetes epidemic". It is estimated that one in fifteen adult is affected by this disease. The human costs are consistent with more than 2/3 of the costs of diabetes related to complications. To reduce the impact of the disease on the population of the canton of Vaud, the "Cantonal Diabetes Program" is a program to slow the increasing incidence of the disease (primary prevention) and to improve the care to patients. The secondary prevention strategy is divided into three areas: daily life support to the diabetic patients, improvement of the interdisciplinary work and consolidation of proximity care structures. The innovative approach of this program, which aims to enhance partnerships by strengthening the autonomy of patients and caregivers interdisciplinary work, could be applied to other chronic diseases. PMID- 23798192 TI - [Charcot osteoarthropathy: don't miss it!]. AB - Charcot neuropathic osteoarthropathy (CNO) is a destructive process affecting the bone and joint structure of diabetic patients and resulting from peripheral neuropathy. It is a limb threatening condition resulting in dramatic deformities associated with severe morbi-mortality. The diagnosis is mostly made by the observation of inflammatory signs and higlight the importance of prompt foot evaluation. Imaging studies may help confirm the diagnosis and the severity of the condition but lack of specificity. The goal of the treatment is to maintain or achieve structural stability of the foot and ankle to prevent further deformity and plantar dislocation. The scientific evidences aren't strong enough to recommend bisphosphonates or acute surgical treatment. Surgery is unanimusly recommended to prevent secondary ulceration. PMID- 23798193 TI - [Contrast-induced nephropathy]. AB - Iodine and gadolinium-based contrast induced nephropathy is the third leading cause of hospital-acquired acute kidney injury. It is essentially observed in patients with defined risk factors and is associated with increased morbidity and mortality. The prevention of contrast induced nephropathy consists in volume expansion through intravenous sodium chloride 0.9% or sodium bicarbonate 1.4%. Comparative randomized controlled trials appear to show a benefit in favor of sodium bicarbonate over saline fluids. According to last evidence, N acetylcysteine does not provide additional benefit over intravenous fluids. PMID- 23798194 TI - [Vitamin D: without danger?]. PMID- 23798195 TI - [SanteSuisse does not care about the citizens and the physicians. That's enough!]. PMID- 23798196 TI - [Caffe lungo]. PMID- 23798197 TI - [Tobacco: an industrial epidemic, to be treated as such]. PMID- 23798198 TI - [Welcoming democratic eugenics?]. PMID- 23798199 TI - [About sexes, races and all the angels]. PMID- 23798200 TI - [Medical record: an already exceeded project goal?]. PMID- 23798201 TI - NOTCH1 genetic variants in patients with tricuspid calcific aortic valve stenosis. AB - BACKGROUND AND AIM OF THE STUDY: Calcific aortic valve stenosis (AS) affects 2-5% of the population aged > 65 years. Functional DNA variants at the NOTCH1 locus result in bicuspid aortic valve (BAV) and severe valve calcification. The contribution of these variants to AS in the population with tricuspid aortic valve (TAV) remains to be determined. METHODS: Fourteen genetic variants surrounding the NOTCH1 gene were genotyped, including rare mutations previously reported, and common polymorphisms. The study involved 457 French Canadian patients with severe tricuspid AS. Genotyping was carried out using the Illumina BeadXpress platform. Allele frequencies of common single nucleotide polymorphisms (SNPs) for patients with AS were compared to a shared control group of European ancestry (n = 3,294). In total, 88 ancestry-informative markers were used to correct for population stratification. RESULTS: The mutation R1107X, previously associated with AS and BAV, was identified in a relatively young patient (aged 58 years). The mutations R1279H and V2285I were detected in 18 and 14 heterozygotes, respectively. A common polymorphism (rs13290979) located in intron 2 was significantly associated with AS (p = 0.003), which remained significant after correction for multiple testing. However, this association was no longer significant after accounting for population stratification (p = 0.088). CONCLUSION: In this study, rare functional variants were found in the NOTCH1 gene in a French Canadian population of patients with severe tricuspid AS. This also suggests, for the first time, the presence of a common polymorphism in this gene conferring susceptibility to AS. PMID- 23798202 TI - A pilot project of familial screening in patients with bicuspid aortic valve disease. AB - BACKGROUND AND AIM OF THE STUDY: Bicuspid aortic valve (BAV) is a common congenital cardiac abnormality, is often familial, and is associated with dilatation of the aortic root. The risk of dissection is significantly higher than that in the general population, occurring at a younger age than in patients with idiopathic aortic aneurysms. Current ACC/AHA guidelines recommend familial echocardiographic screening which, to the present authors' knowledge, is not performed routinely and uniformly. The aim of this pilot project was to explore the practicalities of running such a program. METHODS: An initial cohort of 47 patients who had undergone surgery for BAV disease and/or associated aneurysmal aortic dilatation were offered counseling and familial screening. Referred first degree relatives (FDR) underwent aortic valve and root assessment by standard two dimensional echocardiography. RESULTS: Twenty-four index patients (51%) referred a total of 75 FDR (approximately three per patient) who wished to undergo echocardiography, of whom 52 (70%) attended for review. The pick-up rate of newly detected BAV was 8% (four of 52 relatives). One of these asymptomatic individuals had a significant ascending aortic aneurysm, which required prompt surgery. In the families of the 24 index patients, there was a total of eight cases (14% prevalence) of aortic valve disease, either known or newly detected via screening. CONCLUSION: This pilot study confirmed the relatively high prevalence of BAV among FDR of patients who have undergone surgery for BAV-associated pathology. Patients should be made aware of the condition's pattern of inheritance, and familial screening should be actively pursued to reduce the potential morbidity and mortality associated with BAV and its related aortopathy. A number of important and practical considerations for setting-up a familial screening program are discussed. PMID- 23798204 TI - Circulating collagen metabolites, myocardial fibrosis and heart failure in aortic valve stenosis. AB - BACKGROUND AND AIM OF THE STUDY: Myocardial fibrosis predisposes to heart failure in aortic valve stenosis. The study aim was to determine the value of: (i) circulating collagen metabolites as biomarkers of left ventricular fibrosis and heart failure in aortic stenosis; and (ii) myocardial fibrosis as a predictor of postoperative outcome. METHODS: Among a total of 132 patients (mean age 68 +/- 10 years) with severe aortic stenosis, measurements were made of circulating N terminal propeptide of procollagen I (PINP), C-terminal telopeptide of collagen I (CITP) and N-terminal propeptide of procollagen III (PIIINP). Cardiac catheterization, echocardiography and a 6-min walk test were also performed. The aorta-to-coronary sinus concentration gradients of collagen metabolites were determined in 45 patients. Patients free from coronary artery disease (n = 85) underwent left ventricular biopsies for the assessment of myocardial fibrosis, one-year postoperative echocardiography and a 6-min walk test, and a long-term follow up for mortality. RESULTS: Neither peripheral collagen metabolites nor their transcardiac concentration gradients correlated with the extent of myocardial fibrosis. PIIINP demonstrated a net release from the heart, while PINP and CITP showed consistent falls in transcardiac concentrations that suggested extraction rather than release by the heart. Peripheral PIIINP correlated directly with the pulmonary wedge pressure (r = 0.50, p < 0.001) and inversely with the left ventricular ejection fraction (r = -0.40, p = 0.00001) and 6-min walk (r = -0.29, p = 0.001). Similar associations with heart failure were found for CITP, but not for PINP. One-year postoperative changes in exercise capacity and left ventricular mass and function were independent of myocardial fibrosis, as was mortality over a median of 8.8 years. CONCLUSION: Circulating collagen metabolites are not reliable surrogate measures of myocardial fibrosis in aortic stenosis, despite CITP and PIIINP being associated strongly with heart failure and left ventricular dysfunction. The results of surgery, including long-term survival, appear independent of the extent of myocardial fibrosis. PMID- 23798203 TI - Comparison of transesophageal echocardiographic analysis and circulating biomarker expression profile in calcific aortic valve disease. AB - BACKGROUND AND AIM OF THE STUDY: Aortic valve sclerosis (AVSc), the early asymptomatic stage of calcific aortic valve disease (CAVD), is characterized by a progressive thickening of the aortic cusps without obstruction of the left ventricular outflow. In spite of its high prevalence, there are no molecular markers to characterize the early stages of CAVD before it progresses to a severe, symptomatic stage of aortic valve stenosis (AVS). The study aim was to identify any correlation between circulating biomarkers and transesophageal echocardiography (TEE) evaluation. METHODS: A total of 330 patients with various degrees of CAVD was enrolled into the study. Blood was collected from each patient prior to surgery, and analyzed using ELISA kits following the manufacturers' instructions. RESULTS: Significantly higher plasma osteopontin (OPN) levels were observed in AVSc patients (72.7 +/- 1.8 ng/ml; p < 0.001) and AVS patients (64.3 +/- 5.1 ng/ml; p < 0.001) when compared to controls (30.3 +/- 1.8 ng/ml). Parathyroid hormone (PTH) levels in AVSc and AVS patients (164.1 +/- 16.5 and 134.3 +/- 14.6 pg/ml; p < 0.001 and p = 0.04, respectively) were also significantly higher than in controls (61.8 +/- 4.92 pg/ml). Upon further analysis, plasma levels of OPN (p < 0.001) and PTH (p < 0.001) were found to be significantly higher in asymptomatic AVSc patients, even before calcium deposition was detected on TEE evaluation. Fetuin-A levels were lower at all stages of CAVD when compared to controls (p < 0.001 and p < or = 0.05, respectively), but were comparable among the patient groups. NT-proBNP levels were significantly higher in AVS patients than in controls (p < or = 0.01). CONCLUSION: Serum levels of OPN, PTH, and fetuin-A showed a significant association with different stages of CAVD, with variations in their levels occurring before calcium nodules are visualized during TEE evaluation. The study results may help not only to provide a better understanding of the progression of CAVD but also to develop new tools that can be used to stage these patients. PMID- 23798205 TI - Impact of concomitant coronary artery bypass grafting on in-hospital outcome in octogenarians undergoing aortic valve replacement. AB - BACKGROUND AND AIM OF THE STUDY: Abundant data are available reporting excellent in-hospital outcomes after surgical aortic valve replacement (AVR) in octogenarians. However, there is a paucity of studies reporting the in-hospital outcome of concomitant AVR and coronary artery bypass grafting (CABG) in this group of patients. Hence, a comparison was made of the impact of concomitant AVR and CABG versus isolated AVR on in-hospital outcome in octogenarians. METHODS: Between January 2001 and October 2011, a total of 114 consecutive octogenarians undergoing combined AVR and CABG were compared with a control group of octogenarians (n = 68) undergoing isolated AVR. A retrospective analysis was performed of a prospectively collected cardiac surgery database. In addition, the medical notes and charts of all study patients were reviewed. RESULTS: The two groups had a similar mean age (AVR 82.3 +/- 2.4 years versus AVR + CABG 82.6 +/- 2.1 years; p = 0.91), demographics and EuroSCORE (AVR 11.4 versus AVR + CABG 13.2; p = 0.12). The aortic cross-clamp and cardiopulmonary bypass times were longer for AVR + CABG patients (p < 0.001). In-hospital mortality (7.4% after isolated AVR, 9.6% after AVR + CABG; p = 0.35 between groups) and major clinical outcomes for the two groups were found to be similar except for an increased need for hemofiltration in AVR + CABG patients (p = 0.02). CONCLUSION: In-hospital outcomes for concomitant AVR and CABG in octogenarians are comparable to those of isolated AVR, justifying the performance of combined AVR and CABG in this high risk group of carefully selected patients. PMID- 23798206 TI - Impact of smoking status on early and late outcomes after isolated aortic valve replacement surgery. AB - BACKGROUND AND AIM OF THE STUDY: Currently, insufficient data exist relating to the impact of smoking status on outcomes after isolated aortic valve replacement (AVR) surgery. METHODS: Data obtained prospectively between June 2001 and December 2009 by the Australian and New Zealand Society of Cardiac and Thoracic Surgeons (SCTS) Cardiac Surgery Database Program was analyzed retrospectively. Demographic and operative data were compared between patients who were non smokers, previous smokers and current smokers, using chi-square and t-tests. The independent impact of smoking status on 14 short-term complications and long-term mortality was determined using binary logistic and Cox regression, respectively. RESULTS: Isolated AVR surgery was performed in 2,790 patients; smoking status was recorded in 2,784 cases (99.8%). Of these patients 1,346 (48.3%) had no previous smoking history, 1,232 (44.3%) were previous smokers, and 206 (7.4%) were current smokers. The 30-day mortality rate was 2.3% in nonsmokers, 2.7% in previous smokers, and 0.5% in current smokers (p = NS). The incidence of perioperative complications was generally similar in the three groups, but current smokers were at an increased risk of pneumonia (p = 0.030) and postoperative myocardila infarction (p = 0.007). The mean follow up period for the study was 37 months (range: 0-105 months). After adjusting for differences in patient variables, the incidence of late mortality was not higher in previous smokers (HR 1.13; 95% CI 0.87-1.46; p = 0.372) or current smokers (HR 1.25; 95% CI 0.66-2.36; p = 0.494) compared to non-smokers. CONCLUSION: Smoking status does not necessarily portend a poorer perioperative outcome in patients undergoing isolated AVR. PMID- 23798207 TI - Mid-term echocardiographic progression of patients with moderate aortic regurgitation: implications for aortic valve surgery. AB - BACKGROUND AND AIM OF THE STUDY: Replacement of the aortic valve for moderate aortic regurgitation (AR) as an adjunct to another cardiac surgery, primarily for coronary artery bypass grafting (CABG) or mitral valve replacement or repair, remains the subject of much debate. The study aim was to monitor the progression rate of moderate AR by means of echocardiography, and to reveal the need for future surgical intervention. METHODS: A total of 262 consecutive patients (162 males, 100 females; mean age 65 +/- 15 years; range: 21-93 years) with moderate AR and no more than mild aortic stenosis, were followed for a mean of 42 +/- 31 months. AR resulted from disease of the aortic leaflets in 145 patients (55%) and was secondary to dilatation of the aortic root in 70 patients (27%). The cause of AR could not be determined in 47 patients (18%). RESULTS: Progression to severe AR occurred in 18 patients (6.9%), an average progression rate of 1.9% per year. Patients in whom the main pathology was aortic dilatation had a significantly higher rate of progression to severe AR (9/70; 3.7%/year) compared to those with leaflet pathology (7/145; 1.4%/year, p < 0.03). Only three patients were referred for aortic valve replacement during follow up (yearly rate 0.3%); all of these patients had aortic dilatation as the cause of AR. In total, 26 patients (9.9%) died during the follow up, representing an annual all-cause mortality rate of 2.8%. CONCLUSION: In the face of a slow progression and a low event rate, there is no support for 'prophylactic' valve replacement in patients with moderate AR who have been referred for CABG or mitral valve surgery. PMID- 23798208 TI - Pulmonary artery conduit in vivo dimensional requirements in a growing ovine model: comparisons with the ascending aorta. AB - BACKGROUND AND AIM OF THE STUDY: The pulmonary trunk (PT) structure and function are abnormal in multiple congenital cardiovascular diseases. Existing surgical treatments of congenital malformations of the right ventricular outflow tract and PT do not provide a long-term replacement that can adapt to normal growth. Although there is strong interest in developing tissue-engineered approaches for PT conduit replacement, there remains an absence of any complete investigation of the native geometric growth patterns of the PT to serve as a necessary benchmark. METHODS: Eleven Dorset sheep (aged 4-12 months) underwent a single cardiac magnetic resonance imaging study, from which luminal arterial surface points were obtained using a novel semi-automated segmentation technique. The three dimensional shapes of the PT and ascending aorta (AA) were measured over the same time period to gain insight into differences in the geometric changes between these two great vessels. RESULTS: The volumetric growth of the PT appeared to be a linear function of age, whereas its surface geometry demonstrated non-uniform growth patterns. While tortuosity was maintained with age, the cross-sectional shape of the main pulmonary artery (MPA) evolved from circular in young animals to elliptical at 12 months. In addition, the distal MPA near the pulmonary artery bifurcation tapered with age. CONCLUSION: It can be concluded that postnatal growth of the PT is not a simple proportionate (i.e. isotropic) size increase, but rather exhibits complex three-dimensional geometric features during somatic growth. PMID- 23798209 TI - Outcomes of transcatheter aortic valve implantation compared to surgical aortic valve replacement following previous surgery. AB - BACKGROUND AND AIM OF THE STUDY: Surgical aortic valve replacement remains the 'gold standard' treatment for aortic valve disease. An increasing number of elderly patients with multiple comorbidities are referred for transcatheter aortic valve implantation (TAVI), partly due to the perceived high risks of surgery. These include in particular patients who have had previous cardiac surgery. The study aim was to compare the outcomes of patients with aortic valve disease and previous cardiac surgery who underwent TAVI, with those who had redo surgery. METHODS: Patients were identified with aortic valve disease and previous cardiac surgery referred to the authors' multidisciplinary meeting. Patient characteristics were noted, together with their allocation to either re-do surgery or TAVI. A total of 20 patients who had undergone previous cardiac surgery was allocated to TAVI; these were matched to 20 patients who had undergone previous surgery and subsequently had redo surgery. Treatment modalities were chosen for individual patients according to their EuroSCORE, together with other factors not accounted for in traditional scoring systems. RESULTS: Between June 2008 and March 2010, a total of 191 patients was discussed; of these patients, 63 underwent TAVI, 20 of whom had undergone previous cardiac surgery. There was no significant difference in the EuroSCORE between groups (18 +/- 2 versus 19 +/- 3.0, p = 0.91). TAVI patients had a higher body mass index (27.1 +/- 3.9 versus 21.8 +/- 0.5 kg/m2, p = 0.0001). There were no deaths at 30 days in either group. One patient (5%) in the TAVI group had a transient ischemic attack following the procedure, and one (5%) had a hematoma at the site of arterial puncture. There were more pacemaker implantations in the TAVI group than in the redo group (25% versus 0%, p = 0.02). CONCLUSION: Improved risk stratification and its understanding in patients with aortic valve disease and previous cardiac surgery is required. Despite the perceived high risks in the surgically treated group, there were no deaths and redo surgery patients had lower rates of stroke and pacemaker implantation than did those who underwent TAVI. PMID- 23798210 TI - Outcomes of pericardial bovine xenografts for right ventricular outflow tract reconstruction in children and young adults. AB - BACKGROUND AND AIM OF THE STUDY: A variety of valve substitutes has been used for right ventricular outflow tract (RVOT) reconstruction in children and young adults following previous RVOT surgery that has led to significant pulmonary insufficiency and/or stenosis. Herein, the authors' experience with pulmonary valve replacement (PVR) using a stented bovine pericardial xenograft late after previous RVOT surgery was reviewed. METHODS: Between 2000 and 2011, a total of 49 patients (mean age 22.4 +/- 12.3 years; range: 5-50 years) underwent PVR using stented bovine pericardial xenografts. All patients had prior RVOT reconstruction; these patients averaged two prior operations (range: 1-4) for the following diagnoses: tetralogy of Fallot (n = 28), pulmonary atresia (n = 6), pulmonary stenosis (n = 6), transposition of the great arteries (n = 3), truncus arteriosus (n = 1), and others (n = 5). Of these patients, 24 (49%) underwent additional procedures at the time of pulmonary valve insertion. RESULTS: There was no early death, but six late deaths. The overall survival rate was 88% at 10 years. All surviving patients were well at a mean follow up of 4.0 +/- 2.3 years (range: 6 months to 10 years). Echocardiography showed trivial or no pulmonary insufficiency in 22 patients (56%). The calculated mean peak systolic RVOT gradient at the last follow up by echocardiography was 22.7 +/- 6.6 mmHg. Freedom from RVOT reintervention and xenograft explantation was 94% and 98% at 10 years, respectively. CONCLUSION: The stented bovine pericardial xenografts demonstrated excellent intermediate-term results for repeat RVOT reconstruction. The hemodynamic characteristics of this valve are comparable to those of allografts, and the xenograft represents is an attractive alternative given the limited availability of allografts. The stented bovine pericardial xenograft remains an ideal valve choice for teenagers and young adults with congenital abnormalities of the RVOT, especially for redo as a second or third choice. PMID- 23798211 TI - Short-term and mid-term results with the Sorin Freedom Solo aortic valve. AB - BACKGROUND AND AIM OF THE STUDY: The study aim was to present the short- and mid term results for patients who underwent aortic valve replacement (AVR) with the Sorin Freedom Solo third-generation stentless prosthetic valve. METHODS: AVR with a Sorin Freedom Solo valve was performed in 14 patients between March 2006 and March 2011. Patients aged > or = 60 years (male:female ratio 6:8; mean age 73.28 +/- 5.42 years) who required AVR with the Sorin Freedom Solo valve according to the surgeon's choice were included in the study. The valvular prosthesis was implanted in the supra-annular position, using a single suture line. RESULTS: Eight patients underwent an isolated AVR; combined interventions were carried out in the other patients due to concomitant cardiac disease. One patient died during the immediate perioperative period, and two more during the follow up, from non cardiac causes. The mean maximum transvalvular gradient of patients with aortic stenosis was 88.1 +/- 20.2 mmHg, and this fell to 26.4 +/- 7.6 mmHg during the early postoperative period. The mean gradient at one year of follow up was further decreased to 19.4 +/- 5.3 mmHg. The left ventricular end-diastolic and end-systolic diameters were also significantly reduced, from 4.8 +/- 0.9 to 4.3 +/- 0.6 cm and from 3.2 +/- 0.6 to 2.8 +/- 5.3 cm, respectively. The average left ventricular ejection fraction was 60.2 +/- 4.9% preoperatively, and 63.2 +/- 2.1% at one year after surgery (p = NS). No paravalvular leakage, endocarditis, prosthesis failure or neurologic events were reported among patients. CONCLUSION: The Sorin Freedom Solo stentless valve has provided good early and intermediate term results. Implantation of the prosthesis is straightforward, with low rates of morbidity and mortality. However, these data require further support from larger patient series and long-term follow up. PMID- 23798212 TI - Anti-alpha-Gal antibody response following xenogeneic heart valve implantation in adults. AB - BACKGROUND AND AIM OF THE STUDY: The study aim was to investigate the xenoreactive immune response directed at Galalpha1, 3-Galbeta1-4GlcNAc-R (alpha Gal) which is known to be a major barrier in xenotransplantation, and to identify factors such as age, gender, ABO group and type of implanted tissue that might affect the anti-alpha-Gal immune response in adults subjected to bioprosthetic heart valve (BHV) implantation. METHODS: A total of 103 early survivors aged > 20 years who underwent cardiac surgery using cardiopulmonary bypass was enrolled. Among the patients (45 males, 58 females; mean age 62.8 years), 66 who underwent BHV implantation were assigned as a study group, while the remainder were assigned to a control group. Serum samples were obtained from all patients on three occasions: before surgery (TO); on postoperative day 1 (T1); and on postoperative day 14 or at discharge (T2). A serum sample was also obtained from 31 patients in the study group at the out-patient clinic (T3) at a mean of 38 days after surgery. RESULTS: Anti-alpha-Gal antibody reactivity at TO was higher in patients aged < 65 years. Anti-alpha-Gal IgM and IgG reactivity at T2 was higher in the study group when compared to that in controls. In the study group, anti-alpha-Gal IgM and IgG reactivities were decreased at T1, but then increased at T2 when compared to that at TO. Anti-alpha-Gal IgG reactivity remained elevated at T3, but the IgM reactivity declined in the study group. None of the factors, including age, gender, ABO group and type of implanted tissue, had any effect on the anti-alpha-Gal immune response after BHV implantation. CONCLUSION: BHV implantation in adults elicits an increased formation of anti-alpha-Gal antibodies, with different patterns for each isotype. Based on the study results, host factors including age, gender and blood type might be less important in the anti-alpha-Gal immune response following BHV implantation in adults. PMID- 23798213 TI - Minimally invasive aortic valve replacement with self-anchoring Perceval valve. AB - BACKGROUND AND AIM OF THE STUDY: Although minimally invasive aortic valve replacement (AVR) has been proposed to cause less morbidity in patients, it still has not seen broad application. The study aim was to evaluate the implantation of the self-anchoring aortic valve (Perceval S; Sorin) via a mini-sternotomy. METHODS: As a part of a multicenter, European, prospective, non-randomized, clinical trial, 35 patients (30 females, five males; mean age 80 +/- 4 years) with isolated aortic valve stenosis (mean gradient 48 +/- 21 mm Hg) were operated on at the authors' center. Perceval S self-anchoring valves were implanted following a mini-sternotomy, extracorporeal circulation (ECC), aortic cross clamping, cardioplegic arrest and removal of the calcified native valve. The mean EuroSCORE and STS score were 12 +/- 9% and 4 +/- 2%, respectively. RESULTS: There were no failures of deployment, and nor was there any intra-procedure or 30-day mortality. The mean ECC-time was 70 +/- 24 min, and cross-clamp time 34 +/- 10 min. The valve implantation time was 9 +/- 5 min. Perioperative echocardiography revealed no significant aortic insufficiency or paravalvular leakage. The postoperative mean gradient was 16 +/- 6 mmHg. At follow up, there was no paravalvular leakage or significant valvular insufficiency. No migration or dislodgement of the prosthesis occurred. CONCLUSION: This trial highlights the advantages of the Perceval S self-anchoring valve which, technically is a more reproducible alternative for minimally invasive AVR. As the valve does not need to be sutured, the limited exposure is not a disadvantage even in patients with calcified or small aortic roots. This also potentially reduces the cross-clamp and ECC-times. This valve may enable a broader application of minimally invasive AVR. PMID- 23798214 TI - Computed tomography image processing to detect the real mechanism of bioprosthesis failure: implication for valve-in-valve implantation. AB - BACKGROUND AND AIM OF THE STUDY: Transcatheter valve-in-valve implantation is an emerging option for patients with structural deterioration of an aortic bioprosthesis and who are at a high surgical risk. The present case underlines the need for dedicated imaging to accurately understand the mechanism of valve failure, and the feasibility of a valve-in-valve procedure. METHODS: A patient with structural bioprosthetic deterioration at echocardiography was investigated using computed tomography (CT) scanning and novel 3D slicer software. The findings were compared with those revealed at intraoperative pathology. RESULTS: Post-processed CT images showed the bulk of calcifications to be located at the subvalvular level, suggesting the presence of calcified pannus. Pathology of the explanted valve confirmed that the valve stenosis was due primarily to pannus. Misdiagnosed calcified pannus represents a major threat during valve-in-valve procedures, due mainly to embolic risk. CONCLUSION: The 3D slicer elaboration of CT images may be invaluable in providing a precise definition of the mechanism of valve failure, and also to establish the feasibility of either a valve-in-valve procedure or conventional surgery. PMID- 23798215 TI - Evaluation of nutritional screening tools among patients scheduled for heart valve surgery. AB - BACKGROUND AND AIM OF THE STUDY: The study aim was to detect the most sensitive nutritional screening tool and to assess its prognostic value with regards to an adverse clinical course in patients with heart valve disease undergoing cardiopulmonary bypass (CPB). METHODS: This prospective cohort study included 441 adult patients who were screened using four nutritional screening tools: Nutritional Risk Screening 2002 (NRS-2002); Malnutrition Universal Screening Tool (MUST); Mini Nutritional Assessment (MNA); and Short Nutritional Assessment Questionnaire (SNAQ). Nutritional assessment was performed using a Subjective Global Assessment (SGA). In-hospital mortality, postoperative complications, and duration of hospital stay were each analyzed. RESULTS: With regards to the detection of malnutrition, the sensitivities of MUST, SNAQ, MNA and NRS-2002 were 100%, 92%, 84.6% and 43.6%, respectively. Malnutrition identified by MUST and MNA were associated with postoperative complications (OR 1.63, p = 0.033 and OR 1.6, p = 0.035) and prolonged hospitalization (OR 1.57, p = 0.048 and OR 1.7, p = 0.02). According to multivariate logistic regression analysis, along with well known age and duration of CPB, malnutrition identified by MUST and MNA was associated with a risk of development of complications (OR 1.6, p = 0.049 and OR 1.6, p = 0.04, respectively). The sensitivities of SNAQ, MUST, NRS-2002 and MNA with regards to postoperative complications were 26.8%, 28.8%, 10%, and 31.6%, respectively. CONCLUSION: The MUST tool is preferable with regards to the detection of malnutrition. Both, MUST and MNA independently predicted postoperative complications. SNAQ and NRS-2002 proved insensitive with regards to the postoperative course among patients with heart valve disease who were scheduled for cardiothoracic surgery. PMID- 23798216 TI - Retrospective evaluation of infective endocarditis over ten years in Taiwan. AB - BACKGROUND AND AIM OF THE STUDY: The echocardiographic findings, microbiological profiles, risk factors for mortality, and outcomes of intravenous drug (IVD) users and non-users with infective endocarditis (IE) in Taiwan were evaluated. METHODS: In this retrospective study, the charts of IVD users and non-users who were treated for IE between January 1999 and December 2009 in a hospital in Taiwan were reviewed. RESULTS: A total of 108 patients (including 26 IVD users) with definite diagnoses of IE according to the modified Duke criteria were enrolled in the study. Typically, IVD users were significantly more likely to be infected with Staphylococcus aureus (p < 0.001). A greater proportion of IVD users had higher levels of hemoglobin (84.6% versus 62.2%; p = 0.033) and a lower percentage had high platelet counts (42.3% versus 73.2%; p = 0.004) when compared to non-users. A higher percentage of IVD users had hepatitis C compared to non users (73.1% versus 11%; p < 0.001). Most non-users had vegetations in the mitral and aortic valves (40/74; 54.1% and 35/74; 47.3%, respectively), whereas IVD users had significantly more vegetations in the tricuspid valve (10/18; 55.6%). The overall in-hospital mortality rate was 33.3% (36/108), but the rate for IVD users (11.5%; 3/26) was significantly lower than that for non-users (40.2%; 33/82) (p = 0.007). Multivariate analysis showed that age > 40 years and serum creatinine level > or = 1.2 mg/dl were significantly associated with higher mortality [odds ratios (ORs) 1.06 and 7.49, respectively; p < 0.001 for both]. When the entire patient group was analyzed, a significantly better survival was associated with IVD use and surgical intervention (ORs 0.19 and 0.11; p = 0.012 and 0.011, respectively). CONCLUSION: The clinical features, microbiological spectra and outcomes of IVD users with IE were different from those of non-users. Among all patients, a higher age and elevated serum creatinine levels were significant risk factors for mortality, whereas IVD use and surgical intervention were associated with higher rates of survival. PMID- 23798217 TI - Large pseudoaneurysm of the sinus of Valsalva after surgery for aortic valve endocarditis. AB - Patients who undergo prosthetic aortic valve replacement for infective endocarditis and have no recurrent infection after surgery, rarely develop pseudoaneurysm of either the aortic root or the sinus of Valsalva (SV). Pseudoaneurysm of the SV can have fatal complications, including rupture. The case is reported of a large pseudoaneurysm of the SV that developed after surgical intervention for aortic valve endocarditis, and which was successfully treated. PMID- 23798218 TI - Late severe left ventricular dysfunction after successful transapical aortic valve implantation: a cause for concern. AB - An 88-year-old man with severe aortic stenosis and normal left ventricular ejection fraction underwent transcatheter aortic valve implantation via a transapical approach, without periprocedural complications. Some 16 months later the patient was readmitted because of worsening dyspnea, when left ventricular dysfunction due to apical akinesia was identified. A gated, rest-only myocardial single-photon emission computed tomography (G-SPECT) demonstrated apical hypoperfusion that persisted after attenuation correction. Necrosis involved the apical and mid-inferior wall, the apical lateral wall, and the apical segment. PMID- 23798219 TI - Transcatheter aortic valve implantation and four-year follow up in a 99-year-old patient. AB - Transcatheter aortic valve implantation (TAVI) has emerged as a life-saving therapy in patients with severe aortic valve stenosis who are considered to be high-risk surgical candidates. However, there is a paucity of data on the long term survival and quality-of-life in very old patients undergoing TAVI. Here, the case is reported of a now 104-year-old patient who underwent percutaneous transfemoral TAVI with a CoreValve prosthesis at the age of 99 years; details of his four-year outcome data are also provided. To best of the authors' knowledge, this patient is the oldest reported to have undergone TAVI, and is currently living with good functional status more than four years after the intervention. PMID- 23798220 TI - Double-balloon valvuloplasty of calcified bioprosthetic pulmonary valve twenty three years after implantation. AB - Balloon valvuloplasty to dilate stenotic bioprosthetic valves is rarely used, but has been applied successfully to dilate bioprosthetic mitral, aortic, tricuspid and, to a lesser extent, pulmonary valves. The case is reported of a 45-year-old male patient with right-sided heart failure who underwent a successful dilatation of a stenotic, calcific bioprosthetic pulmonary valve using double-balloon valvuloplasty. PMID- 23798221 TI - Optimised design of siRNA based on multi-featured comparison and analysis of H1N1 virus. AB - A promising method for flu treatment is small interfering RNAs (siRNAs) designed against conserved sequences in influenza virus. In this study, we developed a computational method for designing therapeutics siRNA and applied in the recent HIN1 influenza virus based on its biological characteristics that are substantially different from seasonal influenza virus. We first compared the PA fragments between the H IN1 virus in 2009 and the seasonal influenza virus genes in 2008, and the comparison found significant differences between them not only in sequence features but also in RNA secondary structures. In particular, the RNA secondary structures only share 76.8% identity, which suggests major changes in biological characteristics. Furthermore, we designed a metric of 'structure coefficient' to measure the effectiveness of siRNA based on the secondary structure of its target. Our study provides an improved approach for siRNA design and it may help developing siRNA-based therapeutics for seasonal epidemics and reoccurring pandemics of flu. PMID- 23798222 TI - Eigenspectra, a robust regression method for multiplexed Raman spectra analysis. AB - With the latest development of Surface Enhanced Raman Scattering (SERS) nanoparticles, Raman spectroscopy now can be extended to bioimaging and biosensing. In this study, we demonstrate the ability of Raman spectroscopy to separate multiple spectral fingerprints using Raman nanotags. A machine learning method is proposed to estimate the mixing ratios of sources from mixture signals. It decomposes the mixture signals into components for both best representation and most relating to mixing ratios. Then regression coefficients are calculated for the prediction. The robustness of the method was compared with least squares and weighted least squares methods. PMID- 23798223 TI - Gene expression rule discovery and multi-objective ROC analysis using a neural genetic hybrid. AB - Microarray data allows an unprecedented view of the biochemical mechanisms contained within a cell although deriving useful information from the data is still proving to be a difficult task. In this paper, a novel method based on a multi-objective genetic algorithm is investigated that evolves a near-optimal trade-off between Artificial Neural Network (ANN) classifier accuracy (sensitivity and specificity) and size (number of genes). This hybrid method is shown to work on four well-established gene expression data sets taken from the literature. The results provide evidence for the rule discovery ability of the hybrid method and indicate that the approach can return biologically intelligible as well as plausible results and requires no pre-filtering or pre-selection of genes. PMID- 23798224 TI - Protein contact map prediction using committee machine approach. AB - Protein contact map is a simplified representation of a protein's spatial structure. The Committee Machine is a machine learning method that allots the learning task to a number of learners and divides the input space into subspaces. Learners' responses to an input are combined to produce the system's final response, which is more accurate than any single individual's response. In this study, we propose a novel method called CMP_model, for contact map prediction based on the committee machine. The results of the proposed model in comparison with two other models, show considerable gain (an accuracy improvement from 0.05 to 0.15). PMID- 23798225 TI - Comprehensive detection of cancer gene expression profiles and gene networks are impacted by the choice of pre-processing algorithm and gene-selection method. AB - Pre-processing algorithms (PPA) and gene-selection methods (GSM) are commonly employed to select Differentially Expressed Genes (DEGs) from microarray data. Previous studies established that different combinations of PPAs and GSMs are intrinsically different in their performance to select biologically relevant DEGs. In this study, we evaluated eight combinations of PPAs and GSMs for their ability to select DEGs for prioritising gene-networks. Although the different combinations yielded dissimilar DEG-lists, all DEG-lists selected could segregate tumour from normal. Nevertheless, the DEG-list selected significantly impacted the prioritisation of cancer-associated gene-networks; hence the initial choice of PPA and GSM is crucial for subsequent interactome investigations. PMID- 23798226 TI - The conformational changes analysis of maltodextrin binding protein based on elastic network model. AB - Maltodextrin Binding Protein (MBP) has provided a model system for investigating open-closed conformation transition based on two coarse-grained elastic network models. GNM results show that the open and closed forms have the same motion hinge axes and the open-closed conformational transition mainly exhibits as a large movement of the N-domain. ANM calculation shows a transition from open/closed to closed/open, which is helpful for ligand binding or release. During the open-closed transition, the residues within the domains move in a highly coupled way, and this indicates that the hinge connecting the domains is flexible, while the domains themselves are rigid. PMID- 23798227 TI - PIMiner: a web tool for extraction of protein interactions from biomedical literature. AB - Information on Protein Interactions (Pls) is valuable for biomedical research, but often lies buried in the scientific literature and cannot be readily retrieved. While much progress has been made over the years in extracting Pls from the literature using computational methods, there is a lack of free, public, user-friendly tools for the discovery of Pls. We developed an online tool for the extraction of PI relationships from PubMed-abstracts, which we name PIMiner. Protein pairs and the words that describe their interactions are reported by PIMiner so that new interactions can be easily detected within text. The interaction likelihood levels are reported too. The option to extract only specific types of interactions is also provided. The PIMiner server can be accessed through a web browser or remotely through a client's command line. PIMiner can process 50,000 PubMed abstracts in approximately 7 min and thus appears suitable for large-scale processing of biological/biomedical literature. PMID- 23798228 TI - [The occupational physician, global advisor for the protection of workers' health]. PMID- 23798229 TI - [The importance of upper limb diseases in occupational medicine]. AB - BACKGROUND AND OBJECTIVES: In this work the authors analyse the results of the clinical evaluation of patients affected by suspected work related musculo skeletal disorders (WMSDs), observed throughout 2008-2009 in the specific ambulatory of Occupational Medicine Division of Ospedali Riuaniti di Bergamo. The aim is to illustrate the epidemiological relevance of upper limb (UL) WMSDs. METHODS: We observed 430 patients (mean age 46,9 years, DS 9,3; mean working seniority 29 years, DS 10,4), investigating 600 disorders in diferent musculoskeletal segments. Most of the patients (66%) got to the division for a clinical consultation requested by general practitioners, 29,8% by occupational physicians, 4,2% by national insurance for occupational injuries and diseases (INAIL). RESULTS: Most of the patients (38,4%) were employed in construction industry. Among the 600 disorders investigated, 34,5% was at lumbar spine, 74,5% was at upper limb. The clinical diagnosis was already clear at the first consultation for 81,6% of subjects with low back pain and for 56,5% of patients with upper limb disorders; for the others was necessary to prescribe some instrumental exams or specialistic (neurologic, physiatric, orthopaedic) medical examination. We concluded for a diagnosis of WMSDs in 48,3% of the 600 cases: the percentage is 50,2% if we consider only disorders at lumbar spine and 52,5% among disorders at upper limb. The most frequent reason of refusing occupational aetiology, in the cases of low back pain, was the concomitant presence of other diseases at the segment; on the contrary, for the cases of upper limb disorders, was the lack of correlation between type of disease and professional exposure. DISCUSSION: All physicians demonstrate a high attention about upper limb disorders, topical subject of great epidemiological interest. General practitioners and occupational physicians have to take more advantage of diagnostic support and clinical evaluations offered by Occupational Medicine Divisions an Universities about WMSDs. In consideration of the dificulties to diagnose upper limb disorders and proving correlation with professional exposure is useful to promote specific courses for general practitioners and occupational physicians. PMID- 23798230 TI - [The intention to leave a hospital: individual, occupational and organizational charactersitics of a sample of nurses in Northern Italy]. AB - Turnover represents a problematic phenomenon due to both staff management and costs related to the quality of care. Turnover is quite studied in other Countries, but it is still little studied in Italy. The aim of this study was to analyzing psychosocial factors related to intention to leave the hospital, by using theoretical models from literature and applying them in the health context. The study involved 1295 nurses from North-Italy. The results showed that intention to leave may be considered the most direct predictor of turnover behavior. In fact, the demand for mobility to another hospital was requested by nurses with high level of intention to leave. Among examined individual and organizational characteristics, we found that young nurses with high education had higher turnover intention than old nurses. Moreover, nurses with high level of intention to leave not only perceived a low affective commitment to the unit, but also a low quality of relationship with both supersiors and physicians. The findings have important implications for both nurses and hospitals by helping to promote effective work environments, thus reducing turnover intention. PMID- 23798231 TI - [Experimental evaluation of the occupational exposure to static magnetic fields on a 3 T magnetic resonance scanner]. AB - The recent postponement until 31 October 2013 of the deadline for transposition of the EU Directive 2004/40/EC, concerning the minimum health requirementsfor the exposure of workers to the risks arising from electromagnetic fields between 0 and 300 GHz, keeps on suspending the Italian law which was aimed to implement the EU regulations on the occupational exposure to electromagnetic fields, including those generated by Magnetic Resonance Imaging (MRI) units. Waiting for the revision of the exposure limits proposed by the EU Directive taking into account results from new studies and evolution of knowledge, the time-weighted values of static magnetic field proposed by the Italian Ministry of Health (D.M 02/08/91) still survive as limits for worker's exposure. The comparison between the proposed thresholds and the time required to position patients allows to calculate how long the MRI staff can stay at different values of static magnetic field, i.e. the maximum workload of each worker. In order to evaluate more accurately how many time the members of MRI staff are near the magnet bore and the real value of worker's exposure to the static magnetic field during the handling of patients, a teslameter Metrolab THM1176-PDA was used. Personal exposure measurements on the radiologists and the radiographers who worked on a 3 T GE Healthcare Discovery 750 MR were carried out during the positioning of self sufficient and collaborative patients. The sensor was worn at the chest level on the side that was nearest to the magnet bore. Results show wide variations occurring between individual working procedures concerning the handling of patients, especially during the initial position phase. The mean values of the time spent by radiographers inside the magnet room (B > 0.5 mT) to place the patient and to take him outside at the end of the exam were respectively 220 and 127 seconds. The mean value of the time spent by radiologists was 162 seconds when they had to insert a peripheral vein access (arm) and inject contrast medium. The time fraction spent in magnetic flux density above 200 mT was near 31% for radiographers and about 7% for radiologists. The maximum of the static magnetic field recorded was 1550 mT for radiographers and 409 mT for radiologists. The measuring system has proven to be useful in evaluating the compliance with time weighted exposure limit stated by Italian law and also to find the maximum magnetic flux density to which the staff is actually exposed. This is the quantity of significance in evaluating workers' exposure following international guidelines. PMID- 23798232 TI - [Intelligence and neurocognitive tests among students living in a industrialized region of Sardinia with relatively low blood levels of lead]. AB - In several recent epidemiological studies blood lead levels (BLLs) even below the current CDC intervention level of 10 microg/dl have been associated with reduced neurocognitive capacities of children, with no clear evidence of a "safe" threshold. We analyzed the relationship between the BLLs and the neurocognitive capacities of 205 Sardinian students aged 11 to 15 years, using 2 tests of the Swedish Performance Evaluating System (SPES) and the full-scale Intelligence Quotient (IQ) derived from the Wechsler Intelligence Scale for Children (WISC). The studied population included 104 children (61 males and 43 females) living in Portoscuso, a town 2 Km far from a lead smelter (mean BLLs: 5.98 +/- 2.2; max 11.5 microg/dl), and 101 age-matched students (55 males and 46 females) living in Sant'Antioco, a town about 20 Km far from the same smelter (mean BLLs: 2.08 +/- 0.8; max 4.5 microg/dl). Subjects with BLLs above 4 microg/dl performed worse in the SPES tests and scored about 5.0 points less on the full-scale IQ compared to the students with lower BLLs. The adjusted regression coefficients derived from the multivariate analysis showed that higher BLLs were significantly associated with worse performances in the SPES tests and with reduced IQ (0.94 points for each microg/dl of BLL). This study confirms the potential neurotoxicity of low levels of lead suggesting the need of lowering the actual CDC "limit of concern" for children to values lower than 4 microg/dl, improving at the same time the environmental primary prevention for limiting the lead exposure of subjects living near the lead smelter. PMID- 23798233 TI - The Italian Society of Physical and Rehabilitation Medicine (SIMFER) recommendations for neck pain. AB - The paper represents the Italian Society of Physical " and Rehabilitation Medicine (SIMFER) recommendations to Neck Pain. We searched the principal scientific databases for papers concerning the main approaches to NP, including international guidelines, clinical trials of high methodological value and systematic reviews without any temporal limits. The recommendations were graded on the basis of the National Plan for Guidelines of the Italian Istituto Superiore di Sanita, which includes the level of evidence and strength of the recommendation. The principal sections of the recommendations deal with the Evaluation and Therapy for Neck Pain. The first describes the main evidence concerning the evaluation of patients with NP with or without limb involvement and/or headache: medical history, physical examination, neurological examination, laboratory tests, electrodiagnostics, diagnostic imaging and self-administered questionnaires. The second describes the best evidence synthesis concernig the therapy for Neck Pain: education, exercise, medical therapy, manual therapy, traction, physical therapy, acupuncture, orthoses, multimodal treatment, behavioural treatment. PMID- 23798234 TI - Motor and sensory rehabilitation after lower limb amputation: state of art and perspective of change. AB - The rehabilitation of the amputated patient is based on a coordinated sequence of diagnostic, prognostic and therapeutic procedures carried out by an interdisciplinary rehabilitation team, that works globally on all patient problems. The objectives of the different phases of the rehabilitation treatment were reviewed. Due to their relevance in conditioning the final outcome of the treatment, aspects requiring further studies and remarks, were also reviewed. Among these the psychological aspects, the alterations of all sensory inputs, the secondary alterations at the bone, articular and muscular level, pain of the residual limb and the phantom limb. Finally, the basic criteria to be used to choose the kind of prosthesis in relation to the characteristics and expectations of the amputated person, and the results of the recovery of the autonomy and walking ability, will be schematically described. PMID- 23798235 TI - [Letter to the Editors: Still on Asbestos. A Brief Review]. PMID- 23798236 TI - [Attributes of non-participants aged 40-59 years in specific health check-ups]. PMID- 23798237 TI - [The association between lifestyle and body proportion in primary school children]. AB - OBJECTIVES: To investigate the association between lifestyle and body proportion in children. METHODS: The subjects were 499 students at "B" primary school, located in "A" prefecture. Data were obtained by analyzing the results of routine health checkups carried out in the fiscal year 2007 by using self-reported questionnaires on lifestyle. For the analysis of body proportion, the degree of obesity (overweight degree) divided by sex, age, and body height was calculated using a standard weight-based criterion; values greater than +20% indicated an inclination toward obesity, and values smaller than -20% indicated a tendency toward underweight. To analyze the relation between body proportion and lifestyle, binomial logistic regression analysis was performed using body proportion ("normal group" and "obesity inclination/underweight group") as the dependent variable and lifestyle as the independent variable. In addition, lifestyle factors common to and unrelated to both the obesity-inclined and the underweight groups were examined. RESULTS: Comparison between the incidences of children with an inclination toward either obesity or underweight with national averages in the same fiscal year revealed that the overall inclination toward obesity was high in boys. Among other factors, influence by lifestyle habits such as insufficient chewing and the habit of watching TV for long periods was suggested. The incidence of children tending toward underweight or obesity was high among boys in the fourth and fifth grades and in girls in the fifth grade. Logistic regression analysis showed that the occurrence of unhealthy lifestyle habits such as "insufficient chewing" (2.1 times the number of those who chew well; P = 0.016) and "TV watching for more than 2 hours per day" (1.9 times the number of those who do not watch TV for more than 2 hours per day; P = 0.071) were highly correlated with the incidence of underweight or obesity. In addition, when we categorized the relationship between lifestyle and body proportion into 3 types ("tendency to underweight", "normal," and "obesity inclination"), we found a high incidence of the unhealthy lifestyle factor "insufficient chewing" in the groups that tended toward underweight or obesity and "TV watching for more than 2 hours per day" in the group that was inclined toward obesity. CONCLUSION: When considering lifestyle issues, children inclined toward being either obese or underweight are often perceived to be contradictory to their external appearance. However, the results of the present study suggest that children with a tendency to be underweight and those with an inclination toward obesity share several lifestyle habits such as insufficient chewing. PMID- 23798238 TI - [Social concern and the present state of intergenerational programs. An analysis of newspaper articles and a survey of organizations]. AB - OBJECTIVES: The objectives of this study were (1) to clarify changes in social concern in intergenerational programs and (2) to determine the current state of and issues affecting intergenerational programs. METHODS: Articles including the words "intergenerational programs" were selected from 3 major Japanese newspapers (Asahi Shimbun, Yomiuri Shimbun, and Mainichi Shimbun) using an online database (399 articles). Content analysis was conducted to check changes in the number and content of articles. A total of 56 cases of intergenerational programs were selected, and a questionnaire survey was conducted with the responsible organization. The problems were classified using cluster analysis. RESULTS: Content analysis revealed that the number of articles relating to this topic increased towards the end of the 1990s, which corresponds with a change in social policy. The questionnaire survey revealed that most of the intergenerational programs were either annual or periodic activities. Furthermore, it was shown that the 4 main issues facing current intergenerational programs were the intergenerational gap, operating problems, activity selection, and lack of participants. CONCLUSION: In summary, social concern regarding the intergenerational programs has increased. However, most intergenerational programs were infrequent and quite time-intensive. Furthermore, the 4 issues mentioned above must be addressed in order to create programs that have wide ranging benefits for each community. Resolving the problem of compartmentalized administration and appointing local coordinators is necessary to solve these problems. PMID- 23798239 TI - [Training programs for staff at local Infectious Disease Surveillance Centers: the needs and usefulness]. AB - OBJECTIVES: The objective of this study was to assess the need for and usefulness of training programs for Local Infectious Disease Surveillance Center (LIDSC) staff. METHODS: A structured questionnaire survey was conducted to assess the needs and usefulness of training programs. The subjects of the survey were participants of a workshop held after an annual conference for the LIDSC staff. Data on demographic information, the necessity of training programs for LIDSC staff, the themes and contents of the training program, self-assessment of knowledge on epidemiology and statistics were covered by the questionnaire. RESULTS: A total of 55 local government officials responded to the questionnaire (response rate: 100%). Among these, 95% of participants believed that the training program for the LIDSC staff was necessary. Basic statistical analysis (85%), descriptive epidemiology (65%), outline of epidemiology (60%), interpretation of surveillance data (65%), background and objectives of national infectious disease surveillance in Japan (60%), methods of field epidemiology (60%), and methods of analysis data (51%) were selected by over half of the respondents as suitable themes for training programs. A total of 34 LIDSC staff answered the self-assessment question on knowledge of epidemiology. A majority of respondents selected "a little" or "none" for all questions about knowledge. Only a few respondents had received education in epidemiology. CONCLUSION: The results of this study indicate that LIDSC staff have basic demands for fundamental and specialized education to improve their work. Considering the current situation regarding the capacity of LIDSC staff, these training programs should be started immediately. PMID- 23798240 TI - Our common humanity. PMID- 23798241 TI - Creativity at the opening of the 21st century. PMID- 23798242 TI - Transdisciplinarity: an innovative approach to nursing knowledge. AB - A common complaint heard in many quarters is, "Things are moving so fast that it's hard to keep up." A natural response is to narrow our field of expertise to a smaller and smaller sphere. Even then, the rate of knowledge expansion necessitates regular modification; thus, our spheres continue to shrink. What we gain in a semblance of control, we lose in a grasp of the whole. Transdisciplinarity offers an alternative solution to ever-increasing complexity. This article is an exploration of transdisciplinarity and its potential benefits for the profession of nursing. PMID- 23798243 TI - Resistance to change in the nursing profession: creative transdisciplinary solutions. AB - This article offers a definition of the transdisciplinary inquiry approach (Montuori, 2010) and demonstrates how this approach can benefit the nursing profession in our process of shifting our paradigm toward caring, love, and healing. The article provides an example of a transdisciplinary approach to change process in nursing. It considers the phenomenon of resistance to change in nursing academia, which has created obstacles to revising pedagogical processes, resulting in ongoing difficulties in creating change in the practice setting. A model based on transdisciplinary practices for creative change in nursing is described. PMID- 23798244 TI - A portrait of holistic nurse educators. AB - Nurse educators are stewards of the future of the profession of nursing and, ultimately, of the delivery of holistic health care and the welfare of all individuals. Educators have the social responsibility to empower their students and to reenvision the goals of nursing curricula to encompass holistic health and healing. PMID- 23798245 TI - Stories are like water: an academic writing workshop for nurses. AB - Traditionally, there is very little formal instruction in academic writing for nurses in graduate programs. We, the writing scholar and a nurse educator and PhD student at a major Canadian university, describe how we collaborated on developing and delivering a 1-day academic writing workshop for incoming master of nursing students. By sharing this description, we hope to motivate nursing faculty to offer similar workshops to address the dearth of writing instruction for graduate students in nursing and to improve scholarship outcomes. PMID- 23798246 TI - A new way of thinking: a creative conversation with Marie Manthey, MNA, FRCN, and Berenice Bleedorn, PhD. Interview by Lori Steffen. PMID- 23798247 TI - Thinking styles and creativity preferences in nursing. AB - This article describes a study using a descriptive approach of cross-sectional correlation to explore the association between thinking styles and creativity in a group of nursing professionals and students. A thinking style is a characteristic way of thinking. The hypothesis was that the most creative subjects would present thinking styles that enhance and express their creativity. De la Torre and Violant (2006) argue that creativity is not only a personal value, insofar as it recognizes and stimulates the transforming potential of the individual, but is also an educational value because it generates abilities and attitudes toward improvement. The study results show that a legislative thinking style encourages innovation and creativity and should be encouraged both during education and training and in the professional domain. PMID- 23798248 TI - Broken communication in nursing can kill: teaching communication is vital. AB - Nursing communication is vital to quality and safe nursing care. Evidence continues to increase that communication breakdowns are responsible for medication errors, unnecessary costs, and inadequate patient care. Nursing students can be taught enhanced communication skills during clinical conferences using innovative teaching strategies, examples of which are described in this article. PMID- 23798249 TI - Many kinds of diversity. PMID- 23798250 TI - A message from the editor-in-chief. Health care management leadership, leveraging research and evidence, and frameworks and innovations. PMID- 23798251 TI - The role of values-based leadership in sustaining a culture of caring. AB - At the heart of healthcare are fundamental values like caring and compassion as well as the duty shared by healthcare organizations to address the care needs of those in their communities who are vulnerable, injured, or ill. A concern being raised by some political analysts in Canada is that fundamental values are being challenged by current economic and political influences that are reshaping the landscape of healthcare in this country. Influences from industry, technology, and business have significantly shifted healthcare from its moral foundations. A culture of caring is also challenged by the values and behaviours of individuals that negatively impact staff morale and inter-professional collaboration in many work settings. If a "culture of caring" is to survive the canons of cost containment, the impact of recurrent political wrangling, and other substantive influences, then healthcare must be guided by committed values-based leadership. Using case illustrations, this article attempts to explain the characteristics and role of values-based leaders in promoting those values that inspire a culture of caring. PMID- 23798252 TI - Building physician capacity for transformational leadership--revisited. AB - In 2001, St. Joseph's Health Centre reported on its efforts to design and deliver a physician leadership program. The program was launched in Fall 2010 and has just completed its second cohort with a total of 29 physicians participating. The results and associated learning have been very encouraging. PMID- 23798253 TI - Evaluating the success of a hospital's community engagement process. AB - This case study outlines how an Ontario hospital initiated an intensive Citizens' Advisory Panel related to budget and service provision decisions. The article describes the community and management context, community engagement process, resulting recommendations, and board response. It article further identifies the process and findings of a concurrent independent evaluation and highlights important takeaways, such as the required time commitment, the need for skilled facilitators, and the value of transparent board decisions. PMID- 23798254 TI - Building organizational capacity for evidence use: the experience of two Canadian healthcare organizations. AB - The use of evidence to inform decisions at the program level within healthcare organizations is a priority. The purpose of this article is to provide an overview of an innovative collaboration between two Canadian healthcare organizations to build organizational capacity for evidence use in program planning, implementation, and evaluation. The lessons learned from the initiative suggest that other healthcare organizations would find the capacity-building strategies identified and developed through the initiative useful. PMID- 23798255 TI - A method for identifying research priorities for health systems research on health and aging. AB - A rapid and feasible priority-setting method conducted within a limited budget was used to identify research topics that would have an influence on health services for older adults. Health and aging researchers, policy makers, and caregivers were recruited to complete Delphi surveys that generated and ranked topics and identified other potential researchers. An interdisciplinary team of researchers was selected to produce and submit a proposal to a peer-review granting agency. This method can be adapted by organizations to determine the focus of their research agenda and to engage individuals for collaboration on future research projects. PMID- 23798256 TI - Increasing revenue through idea generation at University Health Network. AB - To enhance products and services provided to researchers and generate external revenue, research operations at the University Health Network implemented an ideation revenue generation framework for evaluation of product ideas for launch to external market. The framework consists of coordinated cross-functional teamwork in idea development and formal evaluation by research operations senior management based on standard criteria. The framework accelerates launch to market of products and services, facilitates due diligence review, increases staff competencies and engagement, and helps foster innovative thinking. PMID- 23798257 TI - From framework to the frontline: designing a structure and process for drug supply shortage planning. AB - Drug shortages are not new; they have been managed through conservation, procurement of alternatives, and redistribution of stock The Sandoz shortage in 2012 has caused a radical reduction of generic injectables. In Newfoundland and Labrador, our response has led to the development of the framework, structure, and process outlined in this paper. The efforts have eased the concerns of clinicians and leaders, as they are aware of the decision-making resource for situations of drug and technology shortage. PMID- 23798258 TI - A mental health initiative to enhance schizophrenia treatment efficacy. AB - Improving patient outcomes while containing costs can be a challenging goal to achieve. This article describes the initiatives undertaken by one mental health department to improve medication adherence among patients with schizophrenia by increasing psychoeducation, psychosocial services, and use of long-acting injectable antipsychotic agents. Achievement of this objective depended on a sustained departmental education program. The successful clinical outcome also significantly reduced the hospitalization and costs. PMID- 23798259 TI - Individual and organizational ethical practices. PMID- 23798260 TI - Lesson learned. PMID- 23798261 TI - Supporting the next generation of physicians. PMID- 23798262 TI - First experience at the simulation center. PMID- 23798263 TI - School illness absenteeism during 2009 influenza A (H1N1) pandemic--South Dakota, 2009-2010. AB - Schools are important amplification settings of influenza virus transmission. We demonstrated correlation of school absenteeism (due to any illness) with other influenza A (H1N1) activity surveillance data during the 2009 pandemic. We collected nonspecific illness student absenteeism data from August 17, 2009 through April 3, 2010 from 187 voluntarily participating South Dakota schools using weekly online surveys. Relative risks (RR) were calculated as the ratio of the probability of absenteeism during elevated weeks versus the probability of absenteeism during the baseline weeks (RR = 1.89). We used Pearson correlation to associate absenteeism with laboratory-confirmed influenza cases, influenza cases diagnosed by rapid tests, influenza-associated hospitalizations and deaths reported in South Dakota during the 2009 H1N1 pandemic period. School-absenteeism data correlated strongly with data from these other influenza surveillance sources. PMID- 23798264 TI - Successful fusion of remote type II odontoid fracture using anterior screw fixation of the odontoid and rhBMP-2: report of two cases. AB - Anterior screw fixation of the odontoid is contraindicated in remote type II fractures. The alternative surgical treatment consists of a posterior C1 to C2 or an occiput to C3 fusion, which is met with much resistance by patients as this option limits head motion, especially rotational movement. Furthermore, elderly patients may not be medically fit to undergo surgery of this magnitude. This report presents two remote type II odontoid fractures in elderly patients (67 and 73 years of age) who were successfully treated by means of anterior screw fixation of the odontoid along with an injection of recombinant human bone morphogenic protein (rhBMP-2) (Medtronic Inc.) into the fracture line with infiltration of the fibrous union tissue and adjacent anterior longitudinal ligament. To our knowledge, this is the first documented report of solid fusion of remote type II odontoid fracture treated with rhBMP-2 and anterior screw fixation. The authors believe that this technique may be a viable alternative for the treatment of failed odontoid fractures older than six months. PMID- 23798266 TI - Patient education. The dance of parenting. PMID- 23798265 TI - Prescription drug monitoring programs. PMID- 23798267 TI - DAKOTACARE update: Let's continue our work to save a million hearts. PMID- 23798268 TI - Quality focus: care transitions data update. PMID- 23798269 TI - Occupational injury and disease: standards in the healthcare workplace. PMID- 23798271 TI - Workplace safety--emergency preparedness: would you know what to do? PMID- 23798270 TI - Needlestick injuries continue to be a challenge in healthcare facilities. PMID- 23798272 TI - Whistle while you work. PMID- 23798273 TI - AHRQ report identifies 22 proven safety strategies. PMID- 23798274 TI - Risk factors predicting fractures in early postmenopausal women. AB - Abstract Few studies exist evaluating fracture prediction in women aged 50-59. Clinical risk factors are important determinants for fracture prediction in younger postmenopausal women since most fractures occur outside the range of an osteoporotic bone mineral density. Although fracture incidence rates in this age group are about one-half of those aged 60-69, considerable costs and loss of quality-adjusted life years are still incurred in this age group. We sought to determine what clinical risk factors would predict subsequent fractures. Questionnaires were mailed out to 546 rural women who underwent osteoporosis screening 8.3 years previously by bone densitometry and a 24-item clinical risk factor assessment. Our survey had a 55% response rate and found that 11.9% of respondents had subsequent fractures. A prior fracture history, self-reported rheumatoid arthritis, and menopause age <40 were significantly associated with subsequent fractures. A logistic regression analyses showed only a prior fracture history and menopause age 600 ml obtained significantly higher serum albumin and cholinesterase levels at one year after PSE compared to those with less than 600 ml (P-values were 0.029 in both). CONCLUSION: A large preoperative splenic volume was the useful predictive marker for an effective PSE-induced liver functional improvement. PMID- 23798316 TI - A reciprocal translocation dissects roles of Pax6 alternative promoters and upstream regulatory elements in the development of pancreas, brain, and eye. AB - Pax6 encodes a transcription factor with key roles in the development of the pancreas, central nervous system, and eye. Gene expression is orchestrated by several alternative promoters and enhancer elements that are distributed over several hundred kilobases. Here, we describe a reciprocal translocation, called 1Gso, which disrupts the integrity of transcripts arising from the 5'-most promoter, P0, and separates downstream promoters from enhancers active in pancreas and eye. Despite this fact, 1Gso animals exhibit none of the dominant Pax6 phenotypes, and the translocation complements recessive brain and craniofacial phenotypes. However, 1Gso fails to complement Pax6 recessive effects in lacrimal gland, conjunctiva, lens, and pancreas. The 1Gso animals also express a corneal phenotype that is related to but distinct from that expressed by Pax6 null mutants, and an abnormal density and organization of retinal ganglion cell axons; these phenotypes may be related to a modest upregulation of Pax6 expression from downstream promoters that we observed during development. Our investigation maps the activities of Pax6 alternative promoters including a novel one in developing tissues, confirms the phenotypic consequences of upstream enhancer disruption, and limits the likely effects of the P0 transcript null mutation to recessive abnormalities in the pancreas and specific structures of the eye. PMID- 23798317 TI - Mapping aortic hemodynamics using 3D cine phase contrast magnetic resonance parallel imaging: evaluation of an anisotropic diffusion filter. AB - PURPOSE: To propose and evaluate an anisotropic diffusion filter to improve visualization and analysis of the thoracic aorta local hemodynamics from phase contrast MRI sensitivity encoding imaging. METHODS: The filter parameters were tailored to the phase-contrast MRI sensitivity encoding data, using a simple calibration procedure. The filter was applied to 20 phase-contrast MR image studies (five subjects acquired with four different sensitivity encoding reduction factors). The filter effect was estimated with respect to image quality (noise in velocity images, sigma(n)), regularity of the velocity fields (divergence; relative error in velocity magnitude, and absolute error in flow direction), aorta flow pattern visualization (streamlines, secondary flows) and flow rate quantification. RESULTS: sigma(n) decreased up to three times, divergence, error in velocity magnitude, and absolute error in flow direction decreased (by at least 313, 40, and 10%, respectively), indicating less noisy and more regular velocity fields after filtering. Streamline analysis confirmed the beneficial effect of anisotropic diffusion filter, both visually and quantitatively (streamline numbers increased by 207% in whole cardiac cycle and by 180% in systolic phase). A high correlation (r = 0.99) between the prefiltering and postfiltering aortic flow rate values was found. CONCLUSION: The anisotropic diffusion filter approach can be considered effective in improving the visualization and analysis of the thoracic aorta hemodynamics from phase contrast MRI sensitivity encoding images. PMID- 23798319 TI - Long-term outcomes for men with high-risk prostate cancer treated definitively with external-beam radiotherapy with or without androgen deprivation. PMID- 23798318 TI - A reduced computational and geometrical framework for inverse problems in hemodynamics. AB - The solution of inverse problems in cardiovascular mathematics is computationally expensive. In this paper, we apply a domain parametrization technique to reduce both the geometrical and computational complexities of the forward problem and replace the finite element solution of the incompressible Navier-Stokes equations by a computationally less-expensive reduced-basis approximation. This greatly reduces the cost of simulating the forward problem. We then consider the solution of inverse problems both in the deterministic sense, by solving a least-squares problem, and in the statistical sense, by using a Bayesian framework for quantifying uncertainty. Two inverse problems arising in hemodynamics modeling are considered: (i) a simplified fluid-structure interaction model problem in a portion of a stenosed artery for quantifying the risk of atherosclerosis by identifying the material parameters of the arterial wall on the basis of pressure measurements; (ii) a simplified femoral bypass graft model for robust shape design under uncertain residual flow in the main arterial branch identified from pressure measurements. PMID- 23798320 TI - Patient satisfaction with services provided by multidisciplinary anticoagulation clinics. AB - STUDY OBJECTIVE: To assess patients' perception of care delivery by anticoagulation clinics (ACs) throughout Alberta, Canada. DESIGN: Prospective postal survey. SETTING: Therapy provision by an AC to ambulatory-based patients for a minimum of 3 months across the province. PATIENTS: A total of 1687 patients (67.9%) receiving warfarin therapy from 6 ACs for a minimum of 3 months responded. MEASUREMENT AND MAIN RESULTS: The 25-item survey had responses grouped into domains of patient preference, knowledge, and service delivery. A 5-point Likert scale enabled each response to be assigned a numerical value from 1 (strongly disagree) to 5 (strongly agree). Overall, the mean response for patient satisfaction was 4.54, indicating most patients were satisfied with the AC care they received. Among those who had received care outside of an AC, 70.4% preferred AC care compared with 18.4% for family physician care. Mean responses for knowledge and service delivery exceeded 4.0, demonstrating positive responses in favor of AC care. CONCLUSIONS: This study demonstrates that most patients were greatly satisfied with AC care and preferred the care received from an AC to that provided by their family physician. Service delivery across Alberta is well perceived by patients. PMID- 23798321 TI - Steady-state plasma concentration of donepezil enantiomers and its stereoselective metabolism and transport in vitro. AB - The aim of the present study was to elucidate the differences in the plasma concentration of two enantiomers of donepezil in Chinese patients with Alzheimer's disease (AD) and investigate in vitro stereoselective metabolism and transport. Donepezil enantiomers were separated and determined by LC-MS/MS using D5-donepezil as an internal standard on a Sepax Chiralomix SB-5 column. In vitro stereoselective metabolism and transport of donepezil were investigated in human liver microsomes and MDCKII-MDR1 cell monolayer. Pre-dose (Css-min) plasma concentrations were determined in 52 patients. The mean plasma level of (R) donepezil was 14.94 ng/ml and that of (S)-donepezil was 23.37 ng/ml. One patient's plasma concentration of (R)-donepezil was higher than (S)-donepezil and the ratio is 1.51. The mean plasma levels of (S)-donepezil were found to be higher than those of (R)-donepezil in 51 patients and the ratio of plasma (R)- to (S)-donepezil varies from 0.34 to 0.85. In the in vitro microsomal system, (R) donepezil degraded faster than (S)-donepezil. V(max) of (R)-donepezil was significantly higher than (S)-donepezil. The P-gp inhibition experiment shown that the P(app) of the two enantiomers was higher than 200 and the efflux ratios were 1.11 and 0.99. The results of the P-gp inhibition identification experiment showed IC50 values of 35.5 and 20.4 MUM, respectively, for the two enantiomers. The results indicate that donepezil exhibits stereoselective hepatic metabolism that may explain the differences in the steady-state plasma concentrations observed. Neither (R)- nor (S)-donepezil was a P-gp substance and the two enantiomers are highly permeable through the blood-brain barrier. PMID- 23798322 TI - MS(n) , LC-MS-TOF and LC-PDA studies for identification of new degradation impurities of bupropion. AB - Three new degradation impurities of bupropion were characterized through high performance liquid chromatography coupled to photodiode array detection and to time-of-flight mass spectrometry. Bupropion was subjected to the ICH prescribed stress conditions. It degraded to seven impurities (I-VII) in alkaline hydrolytic conditions which were optimally resolved on an XTerra C18 column (250 * 4.6 mm, 5 um) with a ternary mobile phase comprising ammonium formate (20 mm, pH 4.0), methanol and acetonitrile (75:10:15, v/v). The degradation impurities (III-V and VII) were characterized on the basis of mass fragmentation pattern of drug, accurate mass spectral and photodiode array data of the drug and degradation impurities. Compound V was found to be a known degradation impurity [1-hydroxy-1 (3-chlorophenyl)propan-2-one], whereas III, IV and VII were characterized as 2 hydroxy-2-(3'-chlorophenyl)-3,5,5-trimethylmorpholine, (2,4,4-trimethyl-1,3 oxazolidin-2-yl)(3-chlorophenyl)-methanone and 2-(3'-chlorophenyl)-3,5,5 trimethylmorphol-2-ene, respectively. Compound III was a known metabolite of the drug. This additional information on the degradation impurities can help in the development of a new stability-indicating assay method to monitor the stability of the drug product during its shelf-life as well as in development of a drug product with increased shelf-life. PMID- 23798323 TI - Time domain removal of irrelevant magnetization in chemical exchange saturation transfer Z-spectra. AB - PURPOSE: To evaluate the possibility of processing Z-spectra using time domain analysis. METHODS: An inverse Fourier transform (IFT) is applied on Z-spectra, thus transforming the chemical exchange saturation transfer (CEST) data into the time domain. Here, large interfering signals from solvent and semisolid magnetization transfer can be fit and filtered out. The method is demonstrated on a range of phantoms (creatine, a para-CEST agent, and hen egg white) and also in vivo on a mouse brain. RESULTS: Using time domain analysis, signal components in Z-spectra could be fit very well, thus enabling irreverent or nuisance components to be removed. The method worked equally well for samples in a solution or a gel where the large contribution from conventional magnetization transfer contrast (MTC) was easily separated out. Results from egg white and mouse brain in vivo data showed that the large water resonance could easily be removed thus allowing the remaining signal to be analyzed without interference from direct water saturation. CONCLUSIONS: This method successfully filtered out the large nuisance signals from bulk water and MTC in Z-spectra in a large variety of phantom types and also in vivo. It is expected to be a potentially powerful tool for CEST studies without needing asymmetry analysis. PMID- 23798324 TI - Liver transplantation with a strongly positive crossmatch: case study and literature review. AB - A positive crossmatch has been associated with increased risk in liver transplantation. To study the clinical significance of preformed donor-specific human leukocyte antigen antibodies (DSAs) in liver transplantation, we reviewed patients who underwent liver transplantation with a strongly positive flow cytometry crossmatch. DSAs were evaluated with a Luminex solid phase assay. The complement-fixing ability of DSAs was tested with a complement component 1q (C1q) assay. Using an assay correlation between complement-dependent cytotoxicity crossmatch, flow cytometry crossmatch, and DSA results, we reviewed the effects of DSAs on the outcomes of our patients as well as reported cases in the literature. Five of 69 liver recipients had a strongly positive crossmatch: 4 had a positive T cell crossmatch [median channel shift (MCS) = 383.5 +/- 38.9], and 5 had a positive B cell crossmatch (MCS = 408.8 +/- 52.3). The DSAs were class I only in 1 patient, class I and II in 3 patients, and class II only in 1 patient. Cholestasis, acute rejection, or both were observed in 3 of the 4 patients with a positive T cell crossmatch with an MCS approximately greater than 300. The C1q assay was positive for 3 patients. Two had either persistent cholestasis or early acute rejection. One patient who was treated with preemptive intravenous immunoglobulin had an unremarkable outcome despite a positive C1q result. One of the 2 patients with a negative C1q assay experienced persistent cholestasis and early and recurrent acute rejection; the other had an unremarkable outcome. None of the patients died or lost a graft within the first year of transplantation. Our study suggests that human leukocyte antigen antibody screening, flow cytometry crossmatch MCS levels, DSA mean fluorescent intensity levels, and C1q assays may be useful in assessing the risk of antibody-mediated rejection and timely interventions in liver transplantation. PMID- 23798326 TI - Severity and prognostic assessment of the endotoxin activity assay in biliary tract infection. AB - BACKGROUND: Acute cholangitis and cholecystitis (AC) often progress to severe septic conditions. We evaluated the endotoxin activity assay (EAA) for assessment and prediction of the severity of AC. METHODS: We retrospectively reviewed 98 patients diagnosed with AC. We divided them into low (<0.4) and high (>=0.4) groups based on EAA values. RESULTS: Endotoxin levels showed no correlation with EAA values. Serum C-reactive protein (8.57 vs. 5.23 mg/dl, P = 0.02), procalcitonin (2.45 vs. 0.48 ng/ml, P = 0.004), and the positive culture rate of blood (50% vs. 15%, P < 0.001) were significantly higher in the high group than in the low group. Platelet counts were significantly lower in the high group than in the low group (23.9 vs. 13.5 10(4) /ml, P = 0.004). The ratio of patients with a Japanese Association for Acute Medicine disseminated intravascular coagulation score >=4 (32% vs. 14%, P = 0.032) was significantly higher in the high group than in the low group. There was a significantly higher percentage of patients with a severe grade of AC in the high group than patients with a mild or moderate grade (32% vs. 15%, P = 0.05). CONCLUSIONS: Endotoxin activity assay is useful for assessment and early prediction of septic conditions due to AC. PMID- 23798325 TI - Sensorimotor-independent prefrontal activity during response inhibition. AB - A network of brain regions involving the ventral inferior frontal gyrus/anterior insula (vIFG/AI), presupplementary motor area (pre-SMA) and basal ganglia has been implicated in stopping impulsive, unwanted responses. However, whether this network plays an equal role in response inhibition under different sensorimotor contexts has not been tested systematically. Here, we conducted an fMRI experiment using the stop signal task, a sensorimotor task requiring occasional withholding of the planned response upon the presentation of a stop signal. We manipulated both the sensory modality of the stop signal (visual versus auditory) and the motor response modality (hand versus eye). Results showed that the vIFG/AI and the preSMA along with the right middle frontal gyrus were commonly activated in response inhibition across the various sensorimotor conditions. Our findings provide direct evidence for a common role of these frontal areas, but not striatal areas in response inhibition independent of the sensorimotor contexts. Nevertheless, these three frontal regions exhibited different activation patterns during successful and unsuccessful stopping. Together with the existing evidence, we suggest that the vIFG/AI is involved in the early stages of stopping such as triggering the stop process while the preSMA may play a role in regulating other cortical and subcortical regions involved in stopping. PMID- 23798327 TI - Vancomycin trough concentrations in overweight or obese pediatric patients. AB - STUDY OBJECTIVES: To compare vancomycin trough concentrations in overweight or obese pediatric patients to those with normal body habitus, after initial dosing based on total body weight (TBW). DESIGN: Retrospective observational case control study. SETTING: Free-standing academic pediatric hospital. PATIENTS: Forty-two overweight or obese pediatric patients were matched to 84 children of normal body habitus (NBH). MEASUREMENTS AND MAIN RESULTS: Empiric vancomycin dosing was based on TBW and guided by an age-stratified dosing algorithm previously developed at our center. Initial steady-state vancomycin trough concentrations were retrieved from the electronic medical record. Overweight and obese children had significantly higher initial vancomycin trough concentrations compared with children who had an NBH (median 14.4 MUg/ml vs 10.5 MUg/ml, p<0.001). Initial vancomycin trough concentrations above 20 MUg/ml occurred more often in overweight and obese children (p=0.016). Our dosing algorithm suggested that initial vancomycin trough concentrations below 10 MUg/ml occurred significantly more often in children with NBH (p<0.001). CONCLUSIONS: Overweight and obese pediatric patients may have elevated initial vancomycin trough concentrations when empiric dosing is based on TBW. Special attention to therapeutic drug monitoring is warranted in all children. PMID- 23798330 TI - Theoretical study of N-heterocyclic carbenes-catalyzed cascade annulation of benzodienones and enals. AB - Growing attention in developing new N-heterocyclic carbene (NHC)-mediated reactions involving homoenolate intermediates has prompted our interest in exploring the mechanistic details of the related reactions. In this work, we carried out a detailed theoretical study for the NHC-catalyzed annulation reaction of cinnamaldehyde (A) and benzodi(enone) (B) in the presence of 1,8 diazabicyclo[5.4.0]undec-7-ene (DBU). By performing density functional theory calculations, we show clearly the detailed reaction mechanism and rationalize the experimental observation. The reaction of A and B falls into two stages: the formation of homoenolate intermediate and the annulation of homoenolate with B. In the homoenolate formation stage, three possible paths are characterized. The pathway involving the DBU-assisted 1,2-proton transfer with a stepwise mechanism is kinetically more favorable, and the DBU-assisted C1 proton departure is the rate-determining step of the total reaction. The annulation of homoenolate with B involves four elementary steps. The conformational difference of homoenolate (cis and trans) leads to two slightly different reaction processes. In the total reaction, the process involving cis-conformation of A is kinetically more feasible. This can be clearly understood through the frontier molecular orbital analysis and the electronic inductive effect. The calculated results are expected to offer valuable information for further design and development of NHC-mediated reactions. PMID- 23798329 TI - The demarcation between younger and older acute myeloid leukemia patients: a pooled analysis of 3 prospective studies. AB - BACKGROUND: Contemporary treatment protocols for adult acute myeloid leukemia (AML) are age-specific, and older patients are generally treated less intensively than younger patients. However, it remains uncertain whether older but fit patients with AML really need to have their treatment attenuated. METHODS: To evaluate the contribution of age to outcome for patients with AML receiving intensive chemotherapy, data were analyzed for 2276 patients aged less than 65 years who were treated uniformly, regardless of age, in 3 consecutive prospective studies conducted by the Japan Adult Leukemia Study Group. RESULTS: A substantial drop in overall survival (OS) between patients aged 40 to 49 years and 50 to 64 years led to a focus on 2 comparisons: 1) age < 50 versus >= 50 years; and 2) age 50 to 54 versus 55 to 59 versus 60 to 64 years. OS was significantly better for patients aged < 50 years than that for those aged >= 50 years (49.6% and 37.0% at 5 years; P < .001); older patients were more susceptible to relapse, but not to early death or nonrelapse mortality. The significant differences in OS between these 2 age groups were equally seen for patients with favorable, intermediate, and adverse cytogenetics (P < .001 each). Outcomes for those aged 50 to 54, 55 to 59, and 60 to 64 years were similar, with 5-year OS rates of 38.2%, 35.1%, and 38.0%, respectively (P = .934), and no differences in early death or nonrelapse mortality were observed among these age groups. CONCLUSIONS: These findings justify the use of intensive chemotherapy without dose attenuation toward older but fit patients with AML, at least up to the age of 64 years. PMID- 23798328 TI - Computational modeling of chemo-electro-mechanical coupling: a novel implicit monolithic finite element approach. AB - Computational modeling of the human heart allows us to predict how chemical, electrical, and mechanical fields interact throughout a cardiac cycle. Pharmacological treatment of cardiac disease has advanced significantly over the past decades, yet it remains unclear how the local biochemistry of an individual heart cell translates into global cardiac function. Here, we propose a novel, unified strategy to simulate excitable biological systems across three biological scales. To discretize the governing chemical, electrical, and mechanical equations in space, we propose a monolithic finite element scheme. We apply a highly efficient and inherently modular global-local split, in which the deformation and the transmembrane potential are introduced globally as nodal degrees of freedom, whereas the chemical state variables are treated locally as internal variables. To ensure unconditional algorithmic stability, we apply an implicit backward Euler finite difference scheme to discretize the resulting system in time. To increase algorithmic robustness and guarantee optimal quadratic convergence, we suggest an incremental iterative Newton-Raphson scheme. The proposed algorithm allows us to simulate the interaction of chemical, electrical, and mechanical fields during a representative cardiac cycle on a patient-specific geometry, robust and stable, with calculation times on the order of 4 days on a standard desktop computer. PMID- 23798331 TI - Clinical and histologic studies of olfactory outcomes after nasoseptal flap harvesting. AB - OBJECTIVES/HYPOTHESIS: Since the introduction of an endonasal endoscopic approach in transsphenoidal pituitary surgery, reports of perioperative olfactory changes have presented conflicting results. We examined the incidence of olfactory loss in cases of endoscopic transsphenoidal pituitary surgery with skull base repair using the nasoseptal flap (NSF) and the effects of monopolar electrocautery commonly used in designing the NSF. STUDY DESIGN: Case-control study. METHODS: Fifteen patients who underwent endoscopic transsphenoidal pituitary surgery with skull base reconstruction using the NSF were divided into cold knife (n = 8) and electrocautery (n = 7) groups according to the device used in the superior incision of the NSF. Patients were followed regularly to monitor the need for dressing or adhesiolysis around the olfactory cleft. All subjects received olfactory tests before and 6 months after surgery. Septal mucosa specimens obtained during posterior septectomy were incised with different devices, and the degree of mucosal damage was evaluated. RESULTS: One patient in the electrocautery group demonstrated olfactory dysfunction postoperatively, but the other 14 patients showed no decrease in olfaction. In histologic analyses, 55.8% and 76.9% of the mucosal surface showed total epithelial loss when the mucosa was cut with cutting- and coagulation-mode electrocautery, respectively. In contrast, only 20% of the mucosal surface exhibited total epithelial loss when the mucosa was cut with a cold knife (P < .01). CONCLUSIONS: Olfactory impairment is not common after use of the NSF. Use of the cold knife in making superior incision may reduce tissue damage with better olfactory outcomes. PMID- 23798332 TI - Development and validation of automated SPE-LC-MS/MS method for determination of indapamide in human whole blood and its application to real study samples. AB - A fast and simple liquid chromatography-electrospray ionization tandem mass spectrometry method for determination of indapamide in human whole blood was developed and validated. The sample extraction of indapamide from human whole blood was achieved using automated solid-phase extraction. Chromatographic separation was performed on Kinetex C18 column (100 * 2.1 mm, 1.7 um particle size) using acetonitrile and 2 mm ammonium formate in ratio 90:10 (v/v) as a mobile phase. The mass spectrometer was operated in the multiple reaction monitoring mode using positive electrospray ionization for indapamide and the internal standard (zolpidem tartarate). The total run time was 2.5 min. The present method was found to be linear in the concentration range of 1-50 ng/mL with the coefficient of determination 0.9987. The absolute recoveries of indapamide were 90.51-93.90%. The method was validated according the recommendations for validation of bioanalytical methods of European Medicines Agency guideline and was successfully used to analyze human whole blood samples for application in a pharmacokinetic study. PMID- 23798333 TI - Feasibility of T2 -weighted turbo spin echo imaging of the human prostate at 7 tesla. AB - PURPOSE: To demonstrate that high quality T2 -weighted (T2w) turbo spin-echo (TSE) imaging of the complete prostate can be achieved routinely and within safety limits at 7 T, using an external transceive body array coil only. METHODS: Nine healthy volunteers and 12 prostate cancer patients were scanned on a 7 T whole-body system. Preparation consisted of B0 and radiofrequency shimming and localized flip angle calibration. T1 and T2 relaxation times were measured and used to define the T2w-TSE protocol. T2w imaging was performed using a TSE sequence (pulse repetition time/echo time 3000-3640/71 ms) with prolonged excitation and refocusing pulses to reduce specific absorption rate. RESULTS: High quality T2w TSE imaging was performed in less than 2 min in all subjects. Tumors of patients with gold-standard tumor localization (MR-guided biopsy or prostatectomy) were well visualized on 7 T imaging (n = 3). The number of consecutive slices achievable within a 10-g averaged specific absorption rate limit of 10 W/kg was >=28 in all subjects, sufficient for full prostate coverage with 3-mm slices in at least one direction. CONCLUSION: High quality T2w TSE prostate imaging can be performed routinely and within specific absorption rate limits at 7 T with an external transceive body array. PMID- 23798334 TI - Subject-level matching for imbalance in cluster randomized trials with a small number of clusters. AB - In a cluster randomized controlled trial (RCT), the number of randomized units is typically considerably smaller than in trials where the unit of randomization is the patient. If the number of randomized clusters is small, there is a reasonable chance of baseline imbalance between the experimental and control groups. This imbalance threatens the validity of inferences regarding post-treatment intervention effects unless an appropriate statistical adjustment is used. Here, we consider application of the propensity score adjustment for cluster RCTs. For the purpose of illustration, we apply the propensity adjustment to a cluster RCT that evaluated an intervention to reduce suicidal ideation and depression. This approach to adjusting imbalance had considerable bearing on the interpretation of results. A simulation study demonstrates that the propensity adjustment reduced well over 90% of the bias seen in unadjusted models for the specifications examined. PMID- 23798335 TI - Advanced glycation end products impair glucose-induced insulin secretion from rat pancreatic beta-cells. AB - BACKGROUND: Advanced glycation end products (AGEs) are derivative compounds generated from non-enzymatic glycosylation and oxidation. In comparison with glucose-derived AGEs (Glu-AGEs), glyceraldehyde-derived AGEs (Glycer-AGEs) have stronger toxicity to living systems. In this study, we compared the effects of Glu-AGE and Glycer-AGE on insulin secretion. METHOD: Rat pancreatic islets were isolated by collagenase digestion and primary-cultured in the presence of 0.1 mg/ml bovine serum albumin (BSA) or 0.1 mg/ml Glu-AGE or Glycer-AGE-albumin. After 48 h of culture, we performed an insulin secretion test and identified the defects by a battery of rescue experiments [corrected]. Also, mRNA expression of genes associated with insulin secretion was measured. RESULTS: Insulin secretion induced by a high glucose concentration was 164.1 +/- 6.0, 124.4 +/- 4.4 (P < 0.05) and 119.8 +/- 7.1 (P < 0.05) MUU/3 islets/h in the presence of BSA, Glu AGE, and Glycer-AGE, respectively. Inhibition of insulin secretion by Glu-AGE or Glycer-AGE was rescued by a high extracellular potassium concentration, tolbutamide and alpha-ketoisocaproic acid, but not by glyceraldehyde, dihydroxacetone, methylpyruvate, glucagon-like peptide-1 and acetylcholine. Glu AGE or Glycer-AGE reduced the expression of the malate dehydrogenase (Mdh1/2) gene, which plays a critical role in the nicotinamide adenine dinucleotide (NADH) shuttle. CONCLUSION: Despite its reported cytotoxicity, the effects of Glycer-AGE on insulin secretion are similar to those of Glu-AGE. PMID- 23798336 TI - Clinical laboratory-based assay methodologies may underestimate and increase variability of vancomycin protein binding in hospitalized patients. AB - STUDY OBJECTIVE: To evaluate and compare the percent protein binding of vancomycin in hospitalized patients by using a clinical or research laboratory derived assay methodology, and to evaluate potential patient characteristics accounting for alterations in protein binding. DESIGN: Prospective noninterventional cohort study. SETTING: Single-center tertiary care medical center. PATIENTS: A total of 55 hospitalized adults who were receiving vancomycin for a suspected or documented infection between August and November 2011 and required therapeutic drug monitoring. MEASUREMENTS AND MAIN RESULTS: Vancomycin protein-binding studies were conducted by using ultracentrifugation of 63 blood samples collected from the 55 patients for therapeutic drug monitoring as part of clinical practice. Total and free drug concentrations were assayed in the research laboratory by using high-performance liquid chromatography (HPLC) and in the clinical laboratory by using fluorescence polarization immunoassay (FPIA). Multivariate linear regression analysis was performed to identify patient variables that were predictive of vancomycin protein binding. The average protein binding was statistically significantly lower and more variable when assayed by FPIA compared with HPLC (mean +/- SD 47.3 +/- 13.0% vs 54.6 +/- 9.5%, p<0.001). Multivariate analyses showed that after controlling for days of vancomycin therapy, patients in the intensive care unit (ICU) had a protein binding value that was 8.4% lower than non-ICU patients (p=0.005). CONCLUSION: Using research laboratory-based HPLC methodology, we identified an average vancomycin protein binding of 54.6% with considerably less variability than reported in the literature using clinical-based assay methodologies. Further, we identified patient factors that may likewise have an impact on this value. Future studies of vancomycin protein binding should consider use of a nonclinical assay to minimize methodological-induced variability. PMID- 23798337 TI - Investigating brain community structure abnormalities in bipolar disorder using path length associated community estimation. AB - In this article, we present path length associated community estimation (PLACE), a comprehensive framework for studying node-level community structure. Instead of the well-known Q modularity metric, PLACE utilizes a novel metric, Psi(PL), which measures the difference between intercommunity versus intracommunity path lengths. We compared community structures in human healthy brain networks generated using these two metrics and argued that Psi(PL) may have theoretical advantages. PLACE consists of the following: (1) extracting community structure using top-down hierarchical binary trees, where a branch at each bifurcation denotes a collection of nodes that form a community at that level, (2) constructing and assessing mean group community structure, and (3) detecting node level changes in community between groups. We applied PLACE and investigated the structural brain networks obtained from a sample of 25 euthymic bipolar I subjects versus 25 gender- and age-matched healthy controls. Results showed community structural differences in posterior default mode network regions, with the bipolar group exhibiting left-right decoupling. PMID- 23798338 TI - Long-term outcomes for men with high-risk prostate cancer treated definitively with external beam radiotherapy with or without androgen deprivation. AB - BACKGROUND: Men with high-risk prostate cancer are often thought to have very poor outcomes in terms of disease control and survival even after definitive treatment. However, results after external beam radiotherapy have improved significantly through dose escalation and the use of androgen deprivation therapy (ADT). This report describes long-term findings after low-dose (< 75.6 Gy) or high-dose (>= 75.6 Gy) external beam radiation, with or without ADT. METHODS: This analysis included 741 men with high-risk prostate cancer (clinical classification >= T3, Gleason score >= 8, or prostate-specific antigen level >= 20 ng/mL) treated with external beam radiotherapy at a single tertiary institution from 1987 through 2004. The radiation dose ranged from 60 to 79.3 Gy (median, 70 Gy); 295 men had received ADT for >= 2 years, and the median follow up time was 8.3 years. RESULTS: The 5- and 10-year actuarial overall survival rates were significantly better for men treated with the higher radiation dose (no ADT plus >= 75.6 Gy, 87.3% and 72.0%, respectively; and ADT plus >= 75.6 Gy, 92.3% and 72%, respectively) (P = .0035). The corresponding 5- and 10-year biochemical failure-free survival rates were significantly better for patients treated with both ADT and higher radiation dose (82% and 77%, P < .0001). At 5 years, men who had not received ADT and had received radiation dose < 75.6 Gy had higher clinical local failure rates than those given ADT and radiation dose >= 75.6 Gy (24.2% versus 0%, P < .0001). The 10-year symptomatic local failure rate was only 2% for all patients. CONCLUSIONS: Contrary to lingering historical perceptions, treatment of high-risk prostate cancer with modern, high-dose, external beam radiotherapy and ADT can produce better biochemical, clinical, and survival outcomes over those from previous eras. Specifically, symptomatic local failure is uncommon, and few men die of prostate cancer even 10 or more years after treatment. PMID- 23798339 TI - Validation of an open source framework for the simulation of blood flow in rigid and deformable vessels. AB - We discuss in this paper the validation of an open source framework for the solution of problems arising in hemodynamics. The proposed framework is assessed through experimental data for fluid flow in an idealized medical device with rigid boundaries and a numerical benchmark for flow in compliant vessels. The core of the framework is an open source parallel finite element library that features several algorithms to solve both fluid and fluid-structure interaction problems. The numerical results for the flow in the idealized medical device (consisting of a conical convergent, a narrow throat, and a sudden expansion) are in good quantitative agreement with the measured axial components of the velocity and pressures for three different flow rates corresponding to laminar, transitional, and turbulent regimes. We emphasize the crucial role played by the accuracy in performing numerical integration, mesh, and time step to match the measurements. The numerical fluid-structure interaction benchmark deals with the propagation of a pressure wave in a fluid-filled elastic tube. The computed pressure wave speed and frequency of oscillations, and the axial velocity of the fluid on the tube axis are close to the values predicted by the analytical solution associated with the benchmark. A detailed account of the methods used for both benchmarks is provided. PMID- 23798340 TI - Pleomorphic adenoma of the major salivary glands: diagnostic utility of FNAB and MRI. AB - OBJECTIVES/HYPOTHESIS: Pleomorphic adenoma (PA) is the most common, benign tumor of the major salivary glands. Surgical resection is the treatment of choice. Initial preoperative workup of major salivary gland neoplasms often includes fine needle aspiration biopsy (FNAB) and magnetic resonance imaging (MRI) of the head and neck. Our objective was to assess the positive predictive value of FNAB and MRI in the evaluation of PA arising from within the major salivary glands. STUDY DESIGN: Retrospective chart review. METHODS: All patients with a FNAB diagnosis of PA of the major salivary glands and who underwent surgical excision at our institution from 2001 to 2011 were identified. FNAB slides from these cases were reviewed by a cytopathologist for findings suggestive of PA: fibrillary stroma, mesenchymal elements, plasmacytoid myoepithelial cells, epithelial cells forming ducts or tubules, and the absence of nuclear atypia. For those patients with a preoperative MRI, the MRI studies were reviewed by a neuroradiologist for findings suggestive of PA, including homogenous T2 hyperintensity, well circumscribed borders, and solid contrast enhancement. Positive predictive value (PPV) of these specific FNAB and MRI findings were calculated using chi-squared testing. RESULTS: One hundred forty-six patients met inclusion criteria, and 68 had preoperative MRI. PPV of a FNAB diagnosis of PA was 97.8%. Characteristic features of PA on FNAB (fibrillary stroma, mesenchymal elements, plasmacytoid myoepithelial cells, epithelial cells forming ducts or tubules, and the absence of nuclear atypia) and MRI (homogenous T2 hyperintensity, well-circumscribed borders, and solid contrast enhancement) all demonstrated PPVs of 95% or greater in patients with FNA diagnosis of PA. CONCLUSIONS: PPV of a FNAB diagnosis of PA in the major salivary glands is high. Among patients with a FNAB diagnosis of PA, specific MRI characteristics also have a high PPV. The diagnostic accuracy of these studies in combination allows for the confident preoperative diagnosis of PA. PMID- 23798341 TI - Highly efficient asymmetric additions of diethylzinc to aldehydes triply activated by chiral phosphoramide-Zn(II) complexes derived from cinchona alkaloids. AB - New chiral phosphoramide ligands derived from cinchona alkaloids were developed, which react with diethylzinc to form chiral phosphoramide-Zn(II) complexes containing two Lewis bases and one Lewis acid. These trifunctional complexes can serve as highly efficient chiral catalysts for triple activation of enantioselective addition reactions of diethylzinc with aldehydes to give desired alcohol products with excellent yields and enantiomeric excess (ee) values up to 99%. PMID- 23798342 TI - Development and validation of a sensitive LC-MS/MS-ESI method for the determination of ivabradine in human plasma: application to a pharmacokinetic study. AB - A sensitive, rapid assay method for estimating ivabradine in human plasma has been developed and validated using liquid chromatography coupled to tandem mass spectrometry with electrospray ionization in the positive-ion mode. The procedure involved extraction of ivabradine and the internal standard (IS) from human plasma by solid-phase extraction. Chromatographic separation was achieved using an isocratic mobile phase (0.1% formic acid-methanol, 60:40, v/v) at a flow rate of 1.0 mL/min on an Aglient Eclipse XDB C8 column (150 * 4.6 mm, 5 um; maintained at 35 degrees C) with a total run time of 4.5 min. Detection was achieved using an Applied Biosystems MDS Sciex (Concord, Ontario, Canada) API 3200 triple quadrupole mass spectrometer. The MS/MS ion transitions monitored were 469-177 for ivabradine and 453-177 for IS. Method validation was performed according to Food and Drug Administration guidelines, and the results met the acceptance criteria. The calibration curve was linear over a concentration range of 0.1-200 ng/mL. The lower limit of quantitation achieved was 0.1 ng/mL. Intra- and inter day precisions were in the range of 1.23-14.17% and 5.26-8.96%, respectively. Finally, the method was successfully used in a pharmacokinetic study that measured ivabradine levels in healthy volunteers after a single 5 mg oral dose of ivabradine. Copyright (c) 2013 John Wiley & Sons, Ltd. PMID- 23798343 TI - Feasibility of 39-potassium MR imaging of a human brain at 9.4 Tesla. AB - PURPOSE: To demonstrate the feasibility of performing 39-potassium MR imaging of a human brain. METHODS: 39-Potassium magnetic resonance imaging of a human brain was performed at 9.4 T using a flexible twisted projection imaging acquisition with a nominal isotropic spatial resolution of 10 mm in 40 min using a single tuned birdcage radiofrequency coil. Co-registered sodium imaging with a nominal isotropic spatial resolution of 3.5 mm was performed on the same subject in 10 min. RESULTS: The 39-potassium flexible twisted projection imaging imaging had a signal-to-noise ratio of 5.2 in brain paranchyma. This qualitative imaging showed the expected features when compared to co-registered high- and low-resolution sodium imaging of the same subject. CONCLUSION: Potassium MR images may offer complementary information to that of sodium MR images by sampling the intracellular rather that interstitial environment. Quantification will require additional improvement in signal-to-noise ratio to produce clinically useful bioscales as are developing for sodium MR imaging. PMID- 23798344 TI - Initial testing (Stage 1) of the antibody-maytansinoid conjugate, IMGN901 (Lorvotuzumab mertansine), by the pediatric preclinical testing program. AB - BACKGROUND: IMGN901 (lorvotuzumab mertansine) is an antibody-drug conjugate composed of a humanized antibody that specifically binds to CD56 (NCAM, neural cell adhesion molecule) and that is conjugated to the maytansinoid, DM1 (a microtubule targeting agent). PROCEDURES: IMGN901 and DM1-SMe (unconjugated DM1 as a mixed disulfide with thiomethane to cap its sulfhydryl group) were tested in vitro at concentrations ranging from 0.01 nM to 0.1 uM and 0.3 pM to 3 nM, respectively. IMGN901 was tested against a subset of PPTP solid tumor xenografts focusing on those with high CD56 expression.The combination of IMGN901 with topotecan was also evaluated. RESULTS: Neuroblastoma models expressed CD56 at or above the median expression level for all PPTP xenografts and cell lines. Neuroblastoma cell lines demonstrated relatively low sensitivity to DM1-SMe compared to other cell lines, but the sensitivity of neuroblastoma cell lines to IMGN901 was comparable to that of non-neuroblastoma cell lines. In vivo, objective responses were observed in 9 of 24 (38%) models including, three of seven neuroblastoma xenografts, and two of seven rhabdomyosarcoma xenografts. All xenografts with objective responses showed homogeneous high-level staining by IHC for CD56, but not all xenografts with homogenous high-level staining had objective responses. Combined with topotecan, IMGN901 demonstrated therapeutic enhancement against two of four neuroblastoma models. CONCLUSIONS: IMGN901 has anti-tumor activity against some CD56 expressing pediatric cancer models. High expression of CD56 is a biomarker for in vivo response, but resistance mechanisms to IMGN901 in some high CD56 expressing lines need to be defined. PMID- 23798345 TI - Acute exposure to diesel exhaust impairs nitric oxide-mediated endothelial vasomotor function by increasing endothelial oxidative stress. AB - Exposure to diesel exhaust was recently identified as an important cardiovascular risk factor, but whether it impairs nitric oxide (NO)-mediated endothelial function and increases production of reactive oxygen species (ROS) in endothelial cells is not known. We tested these hypotheses in a randomized, controlled, crossover study in healthy male volunteers exposed to ambient and polluted air (n=12). The effects of skin microvascular hyperemic provocative tests, including local heating and iontophoresis of acetylcholine and sodium nitroprusside, were assessed using a laser Doppler imager. Before local heating, skin was pretreated by iontophoresis of either a specific NO-synthase inhibitor (L-N-arginine-methyl ester) or a saline solution (Control). ROS production was measured by chemiluminescence using the lucigenin technique in human umbilical vein endothelial cells preincubated with serum from 5 of the subjects. Exposure to diesel exhaust reduced acetylcholine-induced vasodilation (P<0.01) but did not affect vasodilation with sodium nitroprusside. Moreover, the acetylcholine/sodium nitroprusside vasodilation ratio decreased from 1.51 +/- 0.1 to 1.06 +/- 0.07 (P<0.01) and was correlated to inhaled particulate matter 2.5 (r=-0.55; P<0.01). NO-mediated skin thermal vasodilatation decreased from 466 +/- 264% to 29 +/- 123% (P<0.05). ROS production was increased after polluted air exposure (P<0.01) and was correlated with the total amount of inhaled particulate matter <2.5 MUm (PM2.5). In healthy subjects, acute experimental exposure to diesel exhaust impaired NO-mediated endothelial vasomotor function and promoted ROS generation in endothelial cells. Increased PM2.5 inhalation enhances microvascular dysfunction and ROS production. PMID- 23798346 TI - Plasma lipidomic profile signature of hypertension in Mexican American families: specific role of diacylglycerols. AB - Both as a component of metabolic syndrome and as an independent entity, hypertension poses a continued challenge with regard to its diagnosis, pathogenesis, and treatment. Previous studies have documented connections between hypertension and indicators of lipid metabolism. Novel technologies, such as plasma lipidomic profiling, promise a better understanding of disorders in which there is a derangement of the lipid metabolism. However, association of plasma lipidomic profiles with hypertension in a high-risk population, such as Mexican Americans, has not been evaluated before. Using the rich data and sample resource from the ongoing San Antonio Family Heart Study, we conducted plasma lipidomic profiling by combining high-performance liquid chromatography with tandem mass spectroscopy to characterize 319 lipid species in 1192 individuals from 42 large and extended Mexican American families. Robust statistical analyses using polygenic regression models, liability threshold models, and bivariate trait analyses implemented in the SOLAR software were conducted after accounting for obesity, insulin resistance, and relative abundance of various lipoprotein fractions. Diacylglycerols, in general, and the DG 16:0/22:5 and DG 16:0/22:6 lipid species, in particular, were significantly associated with systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP), as well as liability of incident hypertension measured during 7140.17 person years of follow-up. Four lipid species, including the DG 16:0/22:5 and DG 16:0/22:6 species, showed significant genetic correlations with the liability of hypertension in bivariate trait analyses. Our results demonstrate the value of plasma lipidomic profiling in the context of hypertension and identify disturbance of diacylglycerol metabolism as an independent biomarker of hypertension. PMID- 23798348 TI - Plasma lipidomic profile signature of hypertension in mexican american families. PMID- 23798347 TI - Increased circulating inflammatory endothelial cells in blacks with essential hypertension. AB - Morbidity and mortality attributable to hypertension are higher in black essential hypertensive (EH) compared with white EH patients, possibly related to differential effects on vascular injury and repair. Although circulating endothelial progenitor cells (EPCs) preserve endothelial integrity, inflammatory endothelial cells (IECs) detach from sites of injury and represent markers of vascular damage. We hypothesized that blood levels of IECs and inflammatory markers would be higher in black EH compared with white EH patients. Inferior vena cava and renal vein levels of CD34+/KDR+ (EPC) and VAP-1+ (IEC) cells were measured by fluorescence-activated cell sorting in white EH and black EH patients under fixed sodium intake and blockade of the renin-angiotensin system, and compared with systemic levels in normotensive control subjects (n=19 each). Renal vein and inferior vena cava levels of inflammatory cytokines and EPC homing factors were measured by Luminex. Blood pressure, serum creatinine, lipids, and antihypertensive medications did not differ between white and black EH patients, and EPC levels were decreased in both. Circulating IEC levels were elevated in black EH patients, and inversely correlated with EPC levels (R(2)=0.58; P=0.0001). Systemic levels of inflammatory cytokines and EPC homing factors were higher in black EH compared with white EH patients, and correlated directly with IECs. Renal vein inflammatory cytokines, EPCs, and IECs did not differ from their circulating levels. Most IECs expressed endothelial markers, fewer expressed progenitor cell markers, but none showed lymphocyte or phagocytic cell markers. Thus, increased release of cytokines and IECs in black EH patients may impair EPC reparative capacity and aggravate vascular damage, and accelerate hypertension related complications. PMID- 23798349 TI - Aortic stiffness determines diastolic blood flow reversal in the descending thoracic aorta: potential implication for retrograde embolic stroke in hypertension. AB - Aortic stiffening often precedes cardiovascular diseases, including stroke, but the underlying pathophysiological mechanisms remain obscure. We hypothesized that such abnormalities could be attributable to altered central blood flow dynamics. In 296 patients with uncomplicated hypertension, Doppler velocity pulse waveforms were recorded at the proximal descending aorta and carotid artery to calculate the reverse/forward flow ratio and diastolic/systolic flow index, respectively. Tonometric waveforms were recorded on the radial artery to estimate aortic pressure and characteristic impedance (Z0) and to determine carotid-femoral (aortic) and carotid-radial (peripheral) pulse wave velocities. In all subjects, the aortic flow waveform was bidirectional, comprising systolic forward and diastolic reverse flows. The aortic reverse/forward flow ratio (35 +/- 10%) was positively associated with parameters of aortic stiffness (including pulse wave velocity, Z0, and aortic/peripheral pulse wave velocity ratio), independent of age, body mass index, aortic diameter, and aortic pressure. The carotid flow waveform was unidirectional and bimodal with systolic and diastolic maximal peaks. There was a positive relationship between the carotid diastolic/systolic flow index (28 +/- 9%) and aortic reverse/forward flow ratio, which remained significant after adjustment for aortic stiffness and other related parameters. The Bland-Altman plots showed a close time correspondence between aortic reverse and carotid diastolic flow peaks. In conclusion, aortic stiffness determines the extent of flow reversal from the descending aorta to the aortic arch, which contributes to the diastolic antegrade flow into the carotid artery. This hemodynamic relationship constitutes a potential mechanism linking increased aortic stiffness, altered flow dynamics, and increased stroke risk in hypertension. PMID- 23798350 TI - Attention bias to threat faces in severe mood dysregulation. AB - BACKGROUND: We used a dot-probe paradigm to examine attention bias toward threat (i.e., angry) and happy face stimuli in severe mood dysregulation (SMD) versus healthy comparison (HC) youth. The tendency to allocate attention to threat is well established in anxiety and other disorders of negative affect. SMD is characterized by the negative affect of irritability, and longitudinal studies suggest childhood irritability predicts adult anxiety and depression. Therefore, it is important to study pathophysiologic connections between irritability and anxiety disorders. METHODS: SMD patients (N = 74) and HC youth (N = 42) completed a visual probe paradigm to assess attention bias to emotional faces. Diagnostic interviews were conducted and measures of irritability and anxiety were obtained in patients. RESULTS: SMD youth differed from HC youth in having a bias toward threatening faces (P < .01). Threat bias was positively correlated with the severity of the SMD syndrome and depressive symptoms; degree of threat bias did not differ between SMD youth with and without co-occurring anxiety disorders or depression. SMD and HC youth did not differ in bias toward or away from happy faces. CONCLUSIONS: SMD youth demonstrate an attention bias toward threat, with greater threat bias associated with higher levels of SMD symptom severity. Our findings suggest that irritability may share a pathophysiological link with anxiety and depressive disorders. This finding suggests the value of exploring further whether attention bias modification treatments that are effective for anxiety are also helpful in the treatment of irritability. PMID- 23798351 TI - Peripheral blood sCD3- CD4+ T cells: a useful diagnostic tool in angioimmunoblastic T cell lymphoma. AB - Angioimmunoblastic T cell lymphoma (AITL) belongs to the subgroup of mature T cell lymphomas according to the World Health Organization and is one of the common T cell lymphomas in Western countries. Particularly in cases in which histological confirmation cannot be easily achieved, immunophenotyping of peripheral blood can give important information for the differential diagnosis of AITL. sCD3- CD4+ T cells are a typical feature of AILT in flow cytometry of peripheral blood. In this retrospective study, the diagnostic value of flow cytometry for the diagnosis 'AITL' was assessed by comparing the frequency of sCD3- CD4+ T cells in leukemic AITL patients and in patients with other leukemic CD4+ T cell lymphomas. Immunophenotyping of peripheral blood by flow cytometry was performed in a lymphocyte gate using fluorochrome-labelled antibodies against CD3, CD2, CD4, CD5, CD7, CD8, CD10, CD14, CD16, CD19, CD56, CD57 and T cell receptor. In 17/17 leukemic AITL patients, a small but distinct population of sCD3- CD4+ T cells was detected (mean percentage of sCD3- CD4+ T cells in the lymphocyte gate: 11.9 +/- 15.4%, range 0.1-51.8%). In contrast, sCD3- CD4+ T cells were found in only 1/40 patients with other leukemic CD4+ T cell lymphomas (one patient with mycosis fungoides). sCD3- CD4+ T cells have a high positive predictive value (94%) for the diagnosis 'AITL'. Flow cytometry is particularly useful in the differential diagnosis of AITL, even if the aberrant T cell population has a very low frequency. Further biological characterization of this subfraction of lymphoma cells is warranted. PMID- 23798352 TI - Factors associated with early cancer-related death after curative hepatectomy for solitary small hepatocellular carcinoma without macroscopic vascular invasion. AB - BACKGROUND: Unexpected early cancer-related death (ECRD) within 2 years due to recurrence after curative hepatectomy for solitary small (<5 cm) hepatocellular carcinoma without macroscopic vascular invasion (SSHCC) is occasionally observed. METHOD: A total of 415 patients were enrolled (19 patients with ECRD and 396 patients with non-ECRD) to elucidate the risk factors of ECRD after curative hepatectomy for SSHCC. They were initially compared by limiting variables to preoperative factors to reveal predictors that could enable the modification of primary treatment. Subsequently, the same analysis was performed with all variables, including perioperative and histological factors. RESULTS: In the preoperative factors, tumor size > 3 cm and elevation of tumor marker level were independent predictors of ECRD. In the analysis with all variables, excessive intraoperative blood loss, poor differentiation, and microscopic vascular invasion were predictors of ECRD. In the recurrence patterns, 79% of ECRD presented as advanced (four or more lesions) or extra-hepatic recurrence, whereas these accounted for 18% in the non-ECRD. CONCLUSION: Excessive blood loss during the operation and histopathological findings of microscopic vascular invasion and poor differentiation are predictive factors of cancer-related death within 2 years of a hepatectomy for SSHCC. PMID- 23798354 TI - 10th International Conference on Brain Energy Metabolism. Preface. PMID- 23798356 TI - Gravity loading induces adenosine triphosphate release and phosphorylation of extracellular signal-regulated kinases in human periodontal ligament cells. AB - AIM: The periodontal ligament (PDL) receives mechanical stress (MS) from dental occlusion or orthodontic tooth movement. Mechanical stress is thought to be a trigger for remodeling of the PDL and alveolar bone, although its signaling mechanism is still unclear. So we investigated the effect of MS on adenosine triphosphate (ATP) release and extracellular signal-regulated kinases (ERK) phosphorylation in PDL cells. METHODS: Mechanical stress was applied to human PDL cells as centrifugation-mediated gravity loading. Apyrase, Ca(2+)-free medium and purinergic receptor agonists and antagonists were utilized to analyze the contribution of purinergic receptors to ERK phosphorylation. RESULTS: Gravity loading and ATP increased ERK phosphorylation by 5 and 2.5 times, respectively. Gravity loading induced ATP release from PDL cells by tenfold. Apyrase and suramin diminished ERK phosphorylation induced by both gravity loading and ATP. Under Ca(2+)-free conditions the phosphorylation by gravity loading was partially decreased, whereas ATP-induced phosphorylation was unaffected. Receptors P2Y4 and P2Y6 were prominently expressed in the PDL cells. CONCLUSION: Gravity loading induced ATP release and ERK phosphorylation in PDL fibroblasts, and ATP signaling via P2Y receptors was partially involved in this phosphorylation, which in turn would enhance gene expression for the remodeling of PDL tissue during orthodontic tooth movement. PMID- 23798353 TI - Stereotactic ablative radiotherapy: a potentially curable approach to early stage multiple primary lung cancer. AB - BACKGROUND: Surgical resection has been the standard treatment for early stage multiple primary lung cancer (MPLC). However, a significant proportion of patients with MPLC cannot undergo surgery. For this report, the authors explored the role of stereotactic ablative radiotherapy (SABR) for patients with MPLC. METHODS: Patients with MPLC who received SABR (50 grays [Gy] in 4 fractions or 70 Gy in 10 fractions) for the second tumor were reviewed. Four-dimensional, computed tomography-based, planning/volumetric image-guided treatment was used for all patients. Treatment outcomes/toxicities were analyzed. RESULTS: For the 101 patients who received SABR, at a median follow-up of 36 months and with a median overall survival (OS) of 46 months, the 2-year and 4-year in-field local control rates were 97.4% and 95.7%, respectively. The 2-year and 4-year OS rates were 73.2% and 47.5%, respectively; and the progression-free survival (PFS) rates were 67% and 58%, respectively. Patients who had metachronous tumors had better OS and PFS than patients who had synchronous tumors (2-year OS: 80.6% metachronous vs 61.5% synchronous; 4-year OS: 52.7% vs 39.7%, respectively; P = .047; 2-year PFS: 84.7% vs 49.4%, respectively; 4-year PFS: 75.6% vs 30.4%, respectively; P = .0001). For patients who either underwent surgery or received SABR for an index tumor, the incidence of grade >= 3 radiation pneumonitis was 3% (2 of 71 patients); however, this increased to 17% (5 of 30 patients) for those who received conventional radiotherapy for an index tumor. Other grade >= 3 toxicities included grade 3 chest wall pain (3 of 101 patients; 3%) and grade 3 skin toxicity (1 of 101 patients; 1%). CONCLUSIONS: SABR achieves promising long term tumor control and survival and may be a potential curative treatment for early stage MPLC. PMID- 23798358 TI - (S)-(-)-(2-MeBu)N(Pr)2MeI salt as template in the enantioselective synthesis of the enantiopure two-dimensional (S)-(-)-(2-MeBu)N(Pr)2Me[LambdaMnDeltaCr(C2O4)3] ferromagnet. AB - We describe herein the synthesis of (rac)- or enantiopure (S)-(-)-(2 MeBu)N(Pr)2MeI ammonium salts. These racemic and enantiopure ammonium salts were used as cationic templates to obtain new two-dimensional (2D) ferromagnets [(rac) (2-MeBu)N(Pr)2Me][MnCr(C2O4)3] and [(S)-(-)-(2-MeBu)N(Pr)2Me][DeltaMnLambda nCr(C2O4)3]. The absolute configuration of the hexacoordinated Cr(III) metallic ion in the enantiopure 2D network was determined by a circular dichroism measurement. The structure of [(2-MeBu)N(Pr)2Me][MnCr(C2O4)3], established by single crystal X-ray diffraction, belongs to the chiral P63 space group. According to direct current (dc) magnetic measurements, these compounds are ferrromagnets with a temperature Tc = 6 degrees K. PMID- 23798357 TI - Pharmacokinetics of methyl salicylate-2-O-beta-D-lactoside, a novel salicylic acid analog isolated from Gaultheria yunnanensis, in dogs. AB - Methyl salicylate-2-O-beta-D-lactoside (MSL), a natural salicylate derivative of Gaultheria yunnanensis (Franch.) Rehder (G. yunnanensis), has been shown to provide a beneficial anti-inflammatory effect in animal models. Studies on the pharmacokinetics and bioavailability of MSL can provide both a substantial foundation for understanding its mechanism and empirical evidence to support its use in clinical practice. A simple and sensitive high-performance liquid chromatography (HPLC) method, coupled with ultraviolet analyte detection, was developed for determining the concentration of MSL and its metabolite in beagle plasma. Chromatographic separation was achieved on a Agilent Zorbax SB-C18 column (5 MUM,4.6 * 250 mm). The mobile phase consisted of aqueous solution containing 0.1% phosphoric acid and acetonitrile (82:90, v/v), at a flow rate of 1 mL/min. Validation of the assay demonstrated that the developed HPLC method was sensitive, accurate and selective for the determination of MSL and its metabolite in dog plasma. After orally administering three doses of MSL, it could no longer be detected in dog plasma and its metabolite, salicylic acid, was detected. Salicylic acid showed a single peak in the plasma concentration-time curves and linear pharmacokinetics following the three oral doses (r(2) > 0.99). In contrast, only MSL was detected in plasma following intravenous administration. These results will aid in understanding the pharmacological significance of MSL. The developed method was successfully used for evaluation of the oral and intravenous pharmacokinetic profile of MSL in dogs. PMID- 23798359 TI - Gaze avoidance in social anxiety disorder. AB - BACKGROUND: The relationship between gaze avoidance and social anxiety has been examined previously using eye-tracking and static social images. Overall, findings to date highlight increased gaze avoidance as a behavioral marker of social anxiety. The purpose of the present study was to better elucidate the relationship between gaze avoidance and social anxiety disorder (SAD) symptoms via covert eye tracking of gaze tendencies in response to a dynamic computerized social interaction simulation. On the basis of the bivalent fear of evaluation (BFOE) model of social anxiety,([1]) it was expected that participants with SAD, compared to nonsocially anxious control (NSAC) participants, would exhibit gaze avoidance in response to both positive and negative social feedback. METHODS: Participants with SAD (n = 20), and a sample of demographically equivalent NSAC (n = 19), were administered clinical diagnostic interviews and a computerized social simulation task. The simulation task consisted of viewing 26 dynamic videos (13 positive and 13 negative), each 12 s in duration. All participants were covertly eye tracked during the simulation. RESULTS: SAD participants exhibited greater global gaze avoidance in response to both the positive and negative video clips in comparison to the controls. Moreover, the SAD group exhibited equivalent gaze avoidance in response to stimuli of both emotional valences. CONCLUSIONS: These results provide additional support for gaze avoidance as a behavioral marker of SAD, as well as additional support for the BFOE model. Implications for the assessment of SAD are discussed. PMID- 23798361 TI - Outcomes for patients with congenital hepatoblastoma. AB - BACKGROUND: Congenital hepatoblastoma, diagnosed in the first month of life, has been reported to have a poor prognosis; however, a comprehensive evaluation of this entity is lacking. PROCEDURE: We retrospectively reviewed two patients from the senior authors' personal series and 25 cases identified in the databases of several multicenter group studies (INT-0098, P9645, 881, P9346, HB 89, HB94, and HB 99). We compared this series with cases of congenital hepatoblastoma previously published in the literature. RESULTS: The 3-year survival in our case series was 86% (18/21) with a follow-up of 44-230 months (median 85.5 months). Presentation and treatment were not substantially different from hepatoblastoma cohorts unselected for age. Survival was comparable to the reported disease free survival for a similar cohort of hepatoblastoma patients unselected for age between 1986 and 2002 (82.5%) [von Schweinitz et al., Eur J Cancer 1997; 33:1243 1249]. The 2-year survival of cases reported in the literature was 0% (0/9) and 42% (10/24) for patients reported before and after 1990, respectively. CONCLUSIONS: Congenital hepatoblastoma does not appear to confer a worse prognosis. The improved survival of our current series of patients, collected from the past 20 years of German and American multicenter trials and personal series, suggests that the outcome of hepatoblastoma at this young age is much better than has been historically reported. More rigorous analysis should be conducted in future multicenter trials. It is possible that congenital hepatoblastoma should be treated like all other patients with hepatoblastoma provided that the child is stable enough to proceed with surgery and chemotherapy. PMID- 23798360 TI - Dynamic slice-dependent shim and center frequency update in 3 T breast diffusion weighted imaging. AB - PURPOSE: To demonstrate dynamic slice-dependent shim update as a simple method to reduce susceptibility-induced B0 inhomogeneity and associated pixel shift artifacts in diffusion-weighted echo planar imaging (DW-EPI) in 3 T breast imaging. METHODS: Dynamic slice-dependent update of linear shim and center frequency was implemented in a dual-echo B0 mapping sequence and a DW-EPI sequence. Multi-slice axial B0 maps and diffusion-weighted images were obtained from four volunteers with both conventional and dynamic shim methods. The two shim methods were compared in terms of B0 homogeneity and EPI pixel shift artifacts. RESULTS: In all volunteers the B0 maps showed significantly improved homogeneity; the left-right asymmetry was reduced by 79% and within-slice B0 standard deviation was reduced by 20% on the average. The improvements were better than what was previously reported for conventional (static) third-order shim in bilateral breast. Anatomy-referenced apparent diffusion coefficient (ADC) maps showed reduced overall image registration error obtainable with dynamic shim. CONCLUSIONS: Dynamic shim is an effective method to improve B0 shimming and DW-EPI image quality in 3 T bilateral breast imaging. Magn Reson Med 71:1813 1818, 2014. (c) 2013 Wiley Periodicals, Inc. PMID- 23798362 TI - Effects of pancrelipase on nonalcoholic fatty liver disease after pancreaticoduodenectomy. AB - BACKGROUND: Postoperative nonalcoholic fatty liver disease (NAFLD) after pancreaticoduodenectomy (PD) has recently become recognized. However, the pathoetiology of postoperative NAFLD is largely unknown. Furthermore, the optimal treatment has not been established. The aim of this prospective study was to clarify whether pancrelipase, which contains digestive pancreatic enzymes, could reverse NAFLD. METHODS: A collaborative clinical trial has been conducted (UMIN000006841). A total of 30 patients who developed NAFLD after PD were prospectively treated with pancrelipase. NAFLD was defined and evaluated by the liver-to-spleen attenuation ratio on computed tomography (CT). Clinical symptoms and laboratory findings were also assessed. RESULTS: The mean liver-to-spleen CT ratio before surgery in 30 patients was 1.233. It declined to 0.453 at diagnosis of NAFLD. It was significantly improved by the treatment and the CT ratios at 1, 3 and 6 months after treatment were 0.762, 0.958 and 0.904, respectively (vs. pretreatment, P < 0.001). The mild liver dysfunction was also improved. Total protein, albumin and total cholesterol levels were significantly improved by the treatment. Importantly, relatively severe diarrhea seen in 11 patients was also ameliorated. CONCLUSIONS: Pancrelipase has a significant beneficial impact on NAFLD after PD. Maldigestion after pancreatic surgery may be a main cause for the development of postoperative NAFLD. PMID- 23798364 TI - The impact of neo-osteogenesis on disease control in chronic rhinosinusitis after primary surgery. AB - BACKGROUND: Osteitic bone is a feature of chronic rhinosinusitis (CRS), potentially playing a role in pathogenesis. Although seen after previous endoscopic sinus surgery (ESS), it is also a de novo feature in patients without prior interventions. In these patients, osteitis is associated with high tissue and serum eosinophilia. However, the impact of osteitis on prognosis is unclear. This study investigates the clinical and endoscopic outcomes between patients with and without osteitis after primary ESS. METHODS: A prospective study of a cohort of previously unoperated patients with CRS undergoing ESS was performed. The sinuses were scored radiologically for osteitis using the Global Osteitis Score (GOS) and Kennedy Osteitis Score (KOS) preoperatively and were also scored dichotomously for the presence or absence of osteitis. Disease-specific quality of life (22-item Sino-Nasal Outcomes Test [SNOT-22]), nasal symptom score (NSS), endoscopic score (Lund-Kennedy), and clinical outcomes-including oral steroid use, frequency of nasal steroid irrigation, and infective exacerbations-were collected at baseline and 1 year postsurgery. The presence and extent of osteitis was assessed relative to clinical outcome. RESULTS: Fifty-three patients were included (41.5% female, age 47.4 +/- 13.8 years), 42.9% of which had radiologic osteitis. There was no significant association between the presence or severity of osteitis at the time of surgery and SNOT-22, NSS, or endoscopy scores at 12 months postsurgery. However, the presence of osteitis was associated with the need for a course of oral steroid postsurgery (odds ratio [OR]=4.17; p = 0.026). High tissue eosinophilia could not predict this alone (p = 0.55). There was no significant relationship between osteitis and the frequency of steroid irrigations or infective exacerbations. CONCLUSION: Osteitis in CRS is associated with the degree of eosinophilia and as a independent process it was associated with the need for a course of systemic corticosteroid over a 12-month period, but did it not affect overall disease control. PMID- 23798363 TI - Efficacy and safety of rituximab given at 1,000 mg on days 1 and 15 compared to the standard regimen to treat adult immune thrombocytopenia. AB - Rituximab (RTX) is used off-label to treat immune thrombocytopenia (ITP) but the regimen now commonly used in rheumatoid arthritis has not been evaluated in ITP. The aim of this large French multicenter retrospective study was to compare the efficacy and safety of two RTX regimens in adult's ITP. The efficacy of two (RTX) regimens: standard therapy of 375 mg/m(2) weekly for 4 weeks vs. a rheumatoid arthritis (RA) regimen of 1,000 mg on days 1 and 15, to treat ITP was compared. We included adults patients with previously primary ITP treated with RTX instead of treated primary ITP. (CR) was defined as a platelet count >100 * 10(9) /L, and a response (R) by a platelet count of >30 * 10(9) /L with a least a doubling of the baseline value. Of the 107 patients included, 61 (57%) received the standard regimen and 46 (43%) the RA regimen. Baseline characteristics and overall response rates at 3 month (M3) and 12 months (M12) were not significantly different between the groups. At M12, 22/61 patients (36%) treated with the standard regimen and 23/46 (50%) with the RA regimen achieved an overall response (R + CR). The initial pattern of response at M3 was associated with a later pattern of response by M12 in both groups. In multivariate analysis, both a younger age and a low number of previous therapies were associated with a higher likelihood of overall response at M12. Tolerance was good and comparable between the two groups. The RA regimen is an effective and safe alternative to the standard regimen to treat adults with ITP. PMID- 23798365 TI - Sub-10 nm Graphene Nanoribbon Array field-effect transistors fabricated by block copolymer lithography. AB - Sub-10 nm Graphene Nanoribbon Arrays are fabricated over large areas by etching CVD-grown graphene. A mask is used made by the directed self-assembly of a cylindrical PS-b-PDMS block copolymer under solvent annealing guided by a removable template. The optimized solvent annealing process, surface-modified removable polymeric templates, and high Flory-Huggins interaction parameters of the block copolymer enable a highly aligned array of nanoribbons with low line edge roughness to be formed. This leads to a higher on/off ratio and stronger temperature dependence of the current for nanoribbon FETs, and a photocurrent which is 30 times larger compared to unpatterned graphene. PMID- 23798366 TI - Efficient synthesis and antioxidant evaluation of 2-aryl-3-(pyrimidin-2-yl) thiazolidinones. AB - In the present study, we reported the efficient synthesis of 11 3-(pyrimidin-2 yl)-thiazolidinones in good yields using molecular sieve as the desiccant agent. In addition, we have evaluated the antioxidant capacity of the synthesized compounds by the 2,2-diphenyl-2-picrylhydrazyl hydrate (DPPH*) and the 2,2 azinobis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS(+*) ) radicals scavenging assay. Six compounds showed antioxidant activity towards DPPH* (EC50 between 16.13 and 49.94 ug/mL) and also demonstrated excellent activity regarding ABTS(+*) (TEAC: 10.32-53.52). These results showed that compounds 3-(pyrimidin-2-yl)-thiazolidinones may be easily synthesized by a less expensive procedure and could be a good starting point to the development of new antioxidant compounds. PMID- 23798367 TI - Patients with recurrent biliary tract cancer have a better prognosis than those with unresectable disease: retrospective analysis of a multi-institutional experience with patients of advanced biliary tract cancer who received palliative chemotherapy. AB - BACKGROUND: Prognostic factors for patients with advanced biliary tract cancer (BTC) who received palliative chemotherapy have not been fully established. Especially, the status of unresectable/recurrent disease has not been well studied because of a small number of patients with recurrent BTC in previous studies. METHODS: This multicenter retrospective study was conducted in 18 institutions in Japan. We retrospectively reviewed data regarding 403 patients with pathologically proven BTC who received palliative chemotherapy between April 2006 and March 2009. One hundred and ninety-two patients with recurrent BTC were included. Univariate and multivariate analyses were performed to identify prognostic factors. RESULTS: The median overall survival was significantly longer in the recurrent BTC patients than in the unresectable BTC patients (398 days vs. 323 days, P = 0.004). After adjustment using multivariate analysis, the status of recurrent/unresectable disease remained an independent prognostic factor (hazard ratio 1.33, 95% confidence interval 1.04-1.70, P = 0.022) in addition to performance status, extent of disease, carbohydrate antigen 19-9 levels, and carcinoembryonic antigen levels. CONCLUSIONS: The status of unresectable/recurrent disease was shown as an independent prognostic factor in the BTC patients. This result may help to predict life expectancy of BTC patients and design future clinical trials evaluating palliative chemotherapy in BTC. PMID- 23798368 TI - Peering into the future: hepcidin testing. AB - Hepcidin, a small 25 amino acid peptide, has been well established as the iron regulatory hormone. Its expression is upregulated in response to iron and inflammatory cytokines, and downregulated in anemic or hypoxic states. Hepcidin decreases iron export into the plasma by binding to and inducing the degradation of ferroportin, an iron channel located on macrophages and the basolateral surface of enterocytes. This leads to decreased absorption of parental iron by the enterocytes, reduced recycling of erythrocyte iron by macrophages, and increased iron stores in the hepatocytes. Although hepcidin assays are not currently approved for clinical use in the United States, there is much interest in the potential use of this biomarker for management of iron related medical conditions. This review briefly summarizes the current hepcidin test platforms under investigation and the challenges associated with development of a clinical assay for this biomarker. In addition, selected potential future applications hepcidin testing in the clinical setting are addressed. PMID- 23798369 TI - Noninvasive tumor hypoxia measurement using magnetic resonance imaging in murine U87 glioma xenografts and in patients with glioblastoma. AB - PURPOSE: There is a clinical need for noninvasive, nonionizing imaging biomarkers of tumor hypoxia and oxygenation. We evaluated the relationship of T1 -weighted oxygen-enhanced magnetic resonance imaging (OE-MRI) measurements to histopathology measurements of tumor hypoxia in a murine glioma xenograft and demonstrated technique translation in human glioblastoma multiforme. METHODS: Preclinical evaluation was performed in a subcutaneous murine human glioma xenograft (U87MG). Animals underwent OE-MRI followed by dynamic contrast-enhanced MRI (DCE-MRI) and histological measurement including reduced pimonidazole adducts and CD31 staining. Area under the curve (AUC) was measured for the R1 curve for OE-MRI and the gadolinium concentration curve for DCE-MRI. Clinical evaluation in five patients used analogous imaging protocols and analyses. RESULTS: Changes in AUC of OE-MRI (AUCOE ) signal were regionally heterogeneous across all U87MG tumors. Tumor regions with negative AUCOE typically had low DCE-MRI perfusion, had positive correlation with hypoxic area (P = 0.029), and had negative correlation with vessel density (P = 0.004). DCE-MRI measurements did not relate to either hypoxia or vessel density in U87MG tumors. Clinical data confirmed comparable signal changes in patients with glioblastoma. CONCLUSION: These data support further investigation of T1 -weighted OE-MRI to identify regional tumor hypoxia. The quantification of AUCOE has translational potential as a clinical biomarker of hypoxia. PMID- 23798370 TI - Site-specific differentiation of neural stem cell regulated by micropatterned multicomponent interfaces. AB - Stem cell microenvironments are enriched by signals from a variety of components, which cooperate spatially and temporally to regulate cellular function. In vitro recapitulating such complexity in a well-controlled manner is elusive. Here, a platform for patterning multiple bio-active proteins on a single substrate is developed and optimized, and is used it to study the cooperative involvement of cell-matrix interaction and cell-cell signaling in regulating neural stem cell (NSC) function. An affinity-capturing-based multi-step microcontact printing is used to pattern, extracellular matrix proteins, and cell-cell signaling ligands, as intersecting lines on a nonadhesive background. Such design provides spatial segregation of signals from different extrinsic components, while allowing cell traffic between them during their proliferation and differentiation processes. Rat embryonic neural stem cells are cultured and characterized on the multicomponent substrates patterned with different combinations of fibronectin, N cadherin, and Jagged1 proteins and allow to proliferate and differentiate over long term. It is found that local presentation of Notch signaling ligand (Jagged1) or cell adhesion molecule (N-cadherin) effectively modulate the balance between cell-cell and cell-matrix interaction, and significantly change the overall spatial remodeling of NSC differentiation. This platform provides an unambiguous approach to study the spatial and temporal cooperative involvement of different extrinsic components in regulating stem cell behavior. It is also readily expandable for inclusion of extra components and applicable to use with other types of cells, which provide a powerful tool for basic study of cell material interaction or advanced tissue-interface engineering. PMID- 23798371 TI - Environmental consequences of the desire to dominate and be superior. AB - A belief in human dominance over nature lies at the heart of current environmental problems. In this article, we extend the theoretical scope of social dominance theory by arguing that social dominance orientation (SDO) is an important variable in understanding person-environment relations. We argue that individuals high in SDO are more willing to exploit the environment in unsustainable ways because SDO promotes human hierarchical dominance over nature. Four studies provide support for this perspective. High SDO was associated with lower levels of environmental concern in a nationally representative New Zealand sample (Study 1) and in country-level data across 27 nations (Study 2). SDO was also positively related to utilization attitudes toward nature (Study 3) and mediated the gender difference in beliefs about anthropogenic climate change (Study 4), and both occurred independently of right-wing authoritarianism. Implications for the human-dominated view of nature subscribed to by those high in SDO are discussed. PMID- 23798372 TI - "Show me the money": vulnerability to gambling moderates the attractiveness of money versus suspense. AB - Do people take risks to obtain rewards or experience suspense? We hypothesized that people vulnerable to gambling are motivated more by the allure of winning money whereas people less vulnerable to gambling are motivated more by the allure of suspense. Consistent with this hypothesis, participants with high scores on a subscale of the Gambling Attitudes and Beliefs Survey--a measure of vulnerability to gambling--reported more of a motivation to earn money (pilot study), were more likely to accept a certain or near-certain amount of money than to gamble for that same amount (Studies 1-2), and worked harder to earn money (Study 3). People vulnerable to gambling also made more accurate predictions about how much they would gamble. People less vulnerable to gambling, in contrast, gambled more than people vulnerable to gambling, but did not know that they would. PMID- 23798373 TI - How large are actor and partner effects of personality on relationship satisfaction? The importance of controlling for shared method variance. AB - Previous research suggests that the personality of a relationship partner predicts not only the individual's own satisfaction with the relationship but also the partner's satisfaction. Based on the actor-partner interdependence model, the present research tested whether actor and partner effects of personality are biased when the same method (e.g., self-report) is used for the assessment of personality and relationship satisfaction and, consequently, shared method variance is not controlled for. Data came from 186 couples, of whom both partners provided self- and partner reports on the Big Five personality traits. Depending on the research design, actor effects were larger than partner effects (when using only self-reports), smaller than partner effects (when using only partner reports), or of about the same size as partner effects (when using self- and partner reports). The findings attest to the importance of controlling for shared method variance in dyadic data analysis. PMID- 23798374 TI - Mood and threat to attitudinal freedom: delineating the role of mood congruency and hedonic contingency in counterattitudinal message processing. AB - The present research examined when happy individuals' processing of a counterattitudinal message is guided by mood-congruent expectancies versus hedonic considerations. Recipients in positive, neutral, or negative mood read a strong or weak counterattitudinal message which either contained a threat to attitudinal freedom or did not contain such a threat. As expected, a freedom threatening counterattitudinal message was more mood threatening than a counterattitudinal message not threatening freedom. Furthermore, as predicted by the mood-congruent expectancies approach, people in positive mood processed a nonthreatening counterattitudinal message more thoroughly than people in negative mood. Message processing in neutral mood lay in between. In contrast, as predicted by the hedonic-contingency view, a threatening counterattitudinal message was processed less thoroughly in positive mood than in neutral mood. In negative mood, processing of a threatening counterattitudinal message was as low as in positive mood. These findings suggest that message processing is determined by mood congruency unless hedonic considerations override expectancy-based processing inclinations. PMID- 23798375 TI - Weak > strong: the ironic effect of argument strength on supportive advocacy. AB - When people seek support for a cause, they typically present the strongest case they can muster. The present research suggests that under some conditions, the opposite strategy may be superior-in particular, presenting weak rather than strong arguments might stimulate greater advocacy and action. Across four studies, we show that when individuals already agree with a cause (i.e., it is pro-attitudinal), receiving weak arguments in its favor can prompt them into advocating more on its behalf. Perceived argumentation efficacy mediates this effect such that people exposed to weak arguments are more likely to think they have something valuable to contribute. Moreover, consistent with the notion that it is driven by feelings of increased efficacy, the effect is more likely to emerge when initial argumentation efficacy and attitude certainty are moderate or low. Individuals with high argumentation efficacy and high certainty generally advocate more, regardless of the strength of arguments received. PMID- 23798376 TI - Examining temporal processes in diary studies. AB - Researchers have long recognized the utility of the diary method for studying variations in thoughts, feelings, and behaviors. Drawing on the idea that daily events have consequences that are realized both "in the moment" and prospectively over time, we describe a conceptual and statistical framework emphasizing the temporal aspect of diary data. Including temporal effects (i.e., Lagged and concurrent * Lagged terms) expands the scope of the hypothesis being tested by allowing the researcher to examine the association between prior day's event on the current day's outcome, as well as the extent to which a prior day's event makes an individual more or less responsive to an event today. Finally, we provide a detailed description of the procedures necessary to prepare the dataset, and secondary analysis of data from a recently published study illustrates our recommendations. PMID- 23798377 TI - Mapping of trap densities and hotspots in pentacene thin-film transistors by frequency-resolved scanning photoresponse microscopy. AB - Frequency-resolved scanning photoresponse microscopy of pentacene thin-film transistors is reported. The photoresponse pattern maps the in-plane distribution of trap states which is superimposed by the level of trap filling adjusted by the gate voltage of the transistor. Local hotspots in the photoresponse map thus indicate areas of high trap densities within the pentacene thin film. PMID- 23798378 TI - Clinicopathologic analysis of undifferentiated carcinoma of the gallbladder. AB - BACKGROUND: Undifferentiated carcinoma (UC) of the gallbladder (GB) is a rare malignant neoplasm and there have only been sparse case reports without precise description. We analyzed eight cases of UC of GB and compared with gallbladder carcinoma (GBC) in the aspects of clinicopathologic characteristics and prognosis. METHODS: We found eight UC cases out of 238 surgically resected GBCs. Patients with stage-matched GBC were selected (1:4) for comparative analysis of the clinicopathologic features and survival of UC. RESULTS: Histologically, UC cases were composed of four sarcomatoid, two pleomorphic, one small cell, and one osteoclast-like giant cell types. There was no difference between UC and ordinary GBC in clinicopathologic parameters, except for tumor size. It was significantly larger in UC (median; 5.0 cm, ranging 1.3-10.0 cm) compared to GBC (median; 3.0 cm, ranging 1.5-9.0 cm, P = 0.01). UC presented frequent intraluminal polypoid mass (87.5%: 7/8). UC showed significantly poor overall survival rate (37.5%, 37.5% and 18.8% at 1, 3, and 5 years), than GBC (84.4%, 65.6% and 52.1%, respectively) (P = 0.005). Pathologic findings of UC were an independent prognostic factor for poor survival in GBC (HR 7.242, 95% confidence interval: 1.799-29.147). CONCLUSIONS: Undifferentiated carcinoma of the gallbladder was a rare highly malignant neoplasm and frequently presented a large intraluminal polypoid tumor. It showed a significantly larger tumor size and poorer survival than GBC. PMID- 23798379 TI - Myelofibrosis, diffuse alveolar hemorrhage and radiation treatment. PMID- 23798380 TI - Quantitative liver 31P magnetic resonance spectroscopy at 3T on a clinical scanner. AB - PURPOSE: The aims of this study were (i) to establish a robust and fast method to quantify hepatocellular phosphorus compounds in molar concentration on a 3T clinical scanner, (ii) to evaluate its reproducibility, and (iii) to test its feasibility for a use in large cohort studies. METHOD: Proton-decoupled (31) P magnetic resonance spectroscopy of liver (31) P compounds were acquired on 85 healthy subjects employing image selected in-vivo spectroscopy localization in 13 min of acquisition at 3T. Absolute quantification was achieved using an external reference and double-matching phantoms (inorganic phosphates and adenosine triphosphate (ATP) solutions). Reproducibility of the method was also examined. RESULTS: This method showed a high intra- and interday as well as inter- and intraobserver reproducibility (r > 0.98; P < 0.001), with a high signal to noise ratio (SNR) (i.e., mean SNR of gamma-ATP: 16). The mean liver concentrations of 85 healthy subjects were assessed to be 1.99 +/- 0.51 and 2.74 +/- 0.55 mmol/l of wet tissue volume for Pi and gamma-ATP, respectively. CONCLUSION: This method reliably quantified molar concentrations of liver (31) P compounds on 85 subjects with a short total examination time (~25 min) on a 3T clinical scanner. Thus, the current method can be readily utilized for a clinical study, such as a large cohort study. PMID- 23798381 TI - Distearoyl anchor-painted erythrocytes with prolonged ligand retention and circulation properties in vivo. AB - Red blood cells (RBCs) attract significant interest as carriers of biomolecules, drugs, and nanoparticles. In this regard, versatile technologies to attach molecules and ligands to the RBC surface are of great importance. Reported here is a fast and efficient surface painting strategy to attach ligands to the surface of RBCs, and the factors that control the stability and circulation properties of the modified RBCs in vivo. Distearoyl phosphatidylethanolamine anchor-conjugated immunoglobulin (IgG) efficiently incorporates in the RBC membrane following 15-30 min incubation. The optimized RBCs show prolonged circulation in vivo (70% of the injected dose after 48 h) and efficient retention of IgG in the membrane with terminal half-life of 73 h. The IgG construct is gradually lost from the RBCs mainly due to the transfer to plasma components, liver endothelial cells, and Kupffer cells. The ligand retention efficiency is partially dictated by ligand type, anchor type, and ligand concentration in the membrane, while RBC half-life is determined by initial concentration of the ligand in the membrane and presence of PEG linker between the ligand and the anchor. This work provides important guidance for non-covalent surface painting of RBCs as well as other types of blood borne cells for in vivo therapeutic and targeting applications. PMID- 23798382 TI - STAT3 promotes motor neuron differentiation by collaborating with motor neuron specific LIM complex. AB - The motor neuron (MN)-hexamer complex consisting of LIM homeobox 3, Islet-1, and nuclear LIM interactor is a key determinant of motor neuron specification and differentiation. To gain insights into the transcriptional network in motor neuron development, we performed a genome-wide ChIP-sequencing analysis and found that the MN-hexamer directly regulates a wide array of motor neuron genes by binding to the HxRE (hexamer response element) shared among the target genes. Interestingly, STAT3-binding motif is highly enriched in the MN-hexamer-bound peaks in addition to the HxRE. We also found that a transcriptionally active form of STAT3 is expressed in embryonic motor neurons and that STAT3 associates with the MN-hexamer, enhancing the transcriptional activity of the MN-hexamer in an upstream signal-dependent manner. Correspondingly, STAT3 was needed for motor neuron differentiation in the developing spinal cord. Together, our studies uncover crucial gene regulatory mechanisms that couple MN-hexamer and STAT activating extracellular signals to promote motor neuron differentiation in vertebrate spinal cord. PMID- 23798383 TI - Shox2 is a molecular determinant of depot-specific adipocyte function. AB - Visceral and s.c. fat exhibit different intrinsic properties, including rates of lipolysis, and are associated with differential risk for the development of type 2 diabetes. These effects are in part related to cell autonomous differences in gene expression. In the present study, we show that expression of Shox2 (Short stature homeobox 2) is higher in s.c. than visceral fat in both rodents and humans and that levels are further increased in humans with visceral obesity. Fat specific disruption of Shox2 in male mice results in protection from high fat diet-induced obesity, with a preferential loss of s.c. fat. The reduced adipocyte size is secondary to a twofold increase in the expression of beta3 adrenergic receptor (Adrb3) at both the mRNA and protein level and a parallel increase in lipolytic rate. These effects are mimicked by knockdown of Shox2 in C3H10T1/2 cells. Conversely, overexpression of Shox2 leads to a repression of Adrb3 expression and decrease lipolytic rate. Shox2 does not affect differentiation but directly interacts with CCAAT/enhancer binding protein alpha and attenuates its transcriptional activity of the Adrb3 promoter. Thus, Shox2 can regulate the expression of Adrb3 and control the rate of lipolysis and, in this way, exerts control of the phenotypic differences between visceral and s.c. adipocytes. PMID- 23798384 TI - Optogenetic dissection reveals multiple rhythmogenic modules underlying locomotion. AB - Neural networks in the spinal cord known as central pattern generators produce the sequential activation of muscles needed for locomotion. The overall locomotor network architectures in limbed vertebrates have been much debated, and no consensus exists as to how they are structured. Here, we use optogenetics to dissect the excitatory and inhibitory neuronal populations and probe the organization of the mammalian central pattern generator. We find that locomotor like rhythmic bursting can be induced unilaterally or independently in flexor or extensor networks. Furthermore, we show that individual flexor motor neuron pools can be recruited into bursting without any activity in other nearby flexor motor neuron pools. Our experiments differentiate among several proposed models for rhythm generation in the vertebrates and show that the basic structure underlying the locomotor network has a distributed organization with many intrinsically rhythmogenic modules. PMID- 23798385 TI - Decorin causes autophagy in endothelial cells via Peg3. AB - Soluble decorin affects the biology of several receptor tyrosine kinases by triggering receptor internalization and degradation. We found that decorin induced paternally expressed gene 3 (Peg3), an imprinted tumor suppressor gene, and that Peg3 relocated into autophagosomes labeled by Beclin 1 and microtubule associated light chain 3. Decorin evoked Peg3-dependent autophagy in both microvascular and macrovascular endothelial cells leading to suppression of angiogenesis. Peg3 coimmunoprecipitated with Beclin 1 and LC3 and was required for maintaining basal levels of Beclin 1. Decorin, via Peg3, induced transcription of Beclin 1 and microtubule-associated protein 1 light chain 3 alpha genes, thereby leading to a protracted autophagic program. Mechanistically, decorin interacted with VEGF receptor 2 (VEGFR2) in a region overlapping with its natural ligand VEGFA, and VEGFR2 was required for decorin-evoked Beclin 1 and microtubule-associated protein 1 light chain 3 alpha expression as well as for Peg3 induction in endothelial cells. Moreover, decorin induced VEGFR2-dependent mitochondrial fragmentation and loss of mitochondrial membrane potential. Thus, we have unveiled a mechanism for a secreted proteoglycan in inducing Peg3, a master regulator of macroautophagy in endothelial cells. PMID- 23798387 TI - An exogenous retrovirus isolated from koalas with malignant neoplasias in a US zoo. AB - Leukemia and lymphoma account for more than 60% of deaths in captive koalas (Phascolarctos cinereus) in northeastern Australia. Although the endogenizing gammaretrovirus koala endogenous retrovirus (KoRV) was isolated from these koalas, KoRV has not been definitively associated with leukemogenesis. We performed KoRV screening in koalas from the San Diego Zoo, maintained for more than 45 y with very limited outbreeding, and the Los Angeles Zoo, maintained by continuously assimilating captive-born Australian koalas. San Diego Zoo koalas are currently free of malignant neoplasias and were infected with only endogenous KoRV, which we now term subtype "KoRV-A," whereas Los Angeles Zoo koalas with lymphomas/leukemias are infected in addition to KoRV-A by a unique KoRV we term subtype "KoRV-B." KoRV-B is most divergent in the envelope protein and uses a host receptor distinct from KoRV-A. KoRV-B also has duplicated enhancer regions in the LTR associated with increased pathology in gammaretroviruses. Whereas KoRV A uses the sodium-dependent phosphate transporter 1 (PiT1) as a receptor, KoRV-B employs a different receptor, the thiamine transporter 1 (THTR1), to infect cells. KoRV-B is transmitted from dam to offspring through de novo infection, rather than via genetic inheritance like KoRV-A. Detection of KoRV-B in native Australian koalas should provide a history, and a mode for remediation, of leukemia/lymphoma currently endemic in this population. PMID- 23798386 TI - S-nitrosylation therapy to improve oxygen delivery of banked blood. AB - From the perspectives of disease transmission and sterility maintenance, the world's blood supplies are generally safe. However, in multiple clinical settings, red blood cell (RBC) transfusions are associated with adverse cardiovascular events and multiorgan injury. Because ~85 million units of blood are administered worldwide each year, transfusion-related morbidity and mortality is a major public health concern. Blood undergoes multiple biochemical changes during storage, but the relevance of these changes to unfavorable outcomes is unclear. Banked blood shows reduced levels of S-nitrosohemoglobin (SNO-Hb), which in turn impairs the ability of stored RBCs to effect hypoxic vasodilation. We therefore reasoned that transfusion of SNO-Hb-deficient blood may exacerbate, rather than correct, impairments in tissue oxygenation, and that restoration of SNO-Hb levels would improve transfusion efficacy. Notably in mice, administration of banked RBCs decreased skeletal muscle pO2, but infusion of renitrosylated cells maintained tissue oxygenation. In rats, hemorrhage-induced reductions in muscle pO2 were corrected by SNO-Hb-repleted RBCs, but not by control, stored RBCs. In anemic awake sheep, stored renitrosylated, but not control RBCs, produced sustained improvements in O2 delivery; in anesthetized sheep, decrements in hemodynamic status, renal blood flow, and kidney function incurred following transfusion of banked blood were also prevented by renitrosylation. Collectively, our findings lend support to the idea that transfusions may be causally linked to ischemic events and suggest a simple approach to prevention (i.e., SNO-Hb repletion). If these data are replicated in clinical trials, renitrosylation therapy could have significant therapeutic impact on the care of millions of patients. PMID- 23798389 TI - Nucleostemin deletion reveals an essential mechanism that maintains the genomic stability of stem and progenitor cells. AB - Stem and progenitor cells maintain a robust DNA replication program during the tissue expansion phase of embryogenesis. The unique mechanism that protects them from the increased risk of replication-induced DNA damage, and hence permits self renewal, remains unclear. To determine whether the genome integrity of stem/progenitor cells is safeguarded by mechanisms involving molecules beyond the core DNA repair machinery, we created a nucleostemin (a stem and cancer cell enriched protein) conditional-null allele and showed that neural-specific knockout of nucleostemin predisposes embryos to spontaneous DNA damage that leads to severe brain defects in vivo. In cultured neural stem cells, depletion of nucleostemin triggers replication-dependent DNA damage and perturbs self-renewal, whereas overexpression of nucleostemin shows a protective effect against hydroxyurea-induced DNA damage. Mechanistic studies performed in mouse embryonic fibroblast cells showed that loss of nucleostemin triggers DNA damage and growth arrest independently of the p53 status or rRNA synthesis. Instead, nucleostemin is directly recruited to DNA damage sites and regulates the recruitment of the core repair protein, RAD51, to hydroxyurea-induced foci. This work establishes the primary function of nucleostemin in maintaining the genomic stability of actively dividing stem/progenitor cells by promoting the recruitment of RAD51 to stalled replication-induced DNA damage foci. PMID- 23798388 TI - miR-9 is an essential oncogenic microRNA specifically overexpressed in mixed lineage leukemia-rearranged leukemia. AB - MicroRNAs (miRNAs), small noncoding RNAs that regulate target gene mRNAs, are known to contribute to pathogenesis of cancers. Acute myeloid leukemia (AML) is a group of heterogeneous hematopoietic malignancies with various chromosomal and/or molecular abnormalities. AML with chromosomal translocations involving the mixed lineage leukemia (MLL) gene are usually associated with poor survival. In the present study, through a large-scale, genomewide miRNA expression assay, we show that microRNA-9 (miR-9) is the most specifically up-regulated miRNA in MLL rearranged AML compared with both normal control and non-MLL-rearranged AML. We demonstrate that miR-9 is a direct target of MLL fusion proteins and can be significantly up-regulated in expression by the latter in human and mouse hematopoietic stem/progenitor cells. Depletion of endogenous miR-9 expression by an appropriate antagomiR can significantly inhibit cell growth/viability and promote apoptosis in human MLL-rearranged AML cells, and the opposite is true when expression of miR-9 is forced. Blocking endogenous miR-9 function by anti miRNA sponge can significantly inhibit, whereas forced expression of miR-9 can significantly promote, MLL fusion-induced immortalization/transformation of normal mouse bone marrow progenitor cells in vitro. Furthermore, forced expression of miR-9 can significantly promote MLL fusion-mediated leukemogenesis in vivo. In addition, a group of putative target genes of miR-9 exhibited a significant inverse correlation of expression with miR-9 in a series of leukemia sample sets, suggesting that they are potential targets of miR-9 in MLL rearranged AML. Collectively, our data demonstrate that miR-9 is a critical oncomiR in MLL-rearranged AML and can serve as a potential therapeutic target to treat this dismal disease. PMID- 23798390 TI - Quantitative dissection of hydrogen bond-mediated proton transfer in the ketosteroid isomerase active site. AB - Hydrogen bond networks are key elements of protein structure and function but have been challenging to study within the complex protein environment. We have carried out in-depth interrogations of the proton transfer equilibrium within a hydrogen bond network formed to bound phenols in the active site of ketosteroid isomerase. We systematically varied the proton affinity of the phenol using differing electron-withdrawing substituents and incorporated site-specific NMR and IR probes to quantitatively map the proton and charge rearrangements within the network that accompany incremental increases in phenol proton affinity. The observed ionization changes were accurately described by a simple equilibrium proton transfer model that strongly suggests the intrinsic proton affinity of one of the Tyr residues in the network, Tyr16, does not remain constant but rather systematically increases due to weakening of the phenol-Tyr16 anion hydrogen bond with increasing phenol proton affinity. Using vibrational Stark spectroscopy, we quantified the electrostatic field changes within the surrounding active site that accompany these rearrangements within the network. We were able to model these changes accurately using continuum electrostatic calculations, suggesting a high degree of conformational restriction within the protein matrix. Our study affords direct insight into the physical and energetic properties of a hydrogen bond network within a protein interior and provides an example of a highly controlled system with minimal conformational rearrangements in which the observed physical changes can be accurately modeled by theoretical calculations. PMID- 23798391 TI - Correlations in ion channel expression emerge from homeostatic tuning rules. AB - Experimental observations reveal that the expression levels of different ion channels vary across neurons of a defined type, even when these neurons exhibit stereotyped electrical properties. However, there are robust correlations between different ion channel expression levels, although the mechanisms that determine these correlations are unknown. Using generic model neurons, we show that correlated conductance expression can emerge from simple homeostatic control mechanisms that couple expression rates of individual conductances to cellular readouts of activity. The correlations depend on the relative rates of expression of different conductances. Thus, variability is consistent with homeostatic regulation and the structure of this variability reveals quantitative relations between regulation dynamics of different conductances. Furthermore, we show that homeostatic regulation is remarkably insensitive to the details that couple the regulation of a given conductance to overall neuronal activity because of degeneracy in the function of multiple conductances and can be robust to "antihomeostatic" regulation of a subset of conductances expressed in a cell. PMID- 23798394 TI - On revenue maximization for selling multiple independently distributed items. AB - Consider the revenue-maximizing problem in which a single seller wants to sell k different items to a single buyer, who has independently distributed values for the items with additive valuation. The k = 1 case was completely resolved by Myerson's classical work in 1981, whereas for larger k the problem has been the subject of much research efforts ever since. Recently, Hart and Nisan analyzed two simple mechanisms: selling the items separately, or selling them as a single bundle. They showed that selling separately guarantees at least a c/log2 k fraction of the optimal revenue; and for identically distributed items, bundling yields at least a c/log k fraction of the optimal revenue. In this paper, we prove that selling separately guarantees at least c/log k fraction of the optimal revenue, whereas for identically distributed items, bundling yields at least a constant fraction of the optimal revenue. These bounds are tight (up to a constant factor), settling the open questions raised by Hart and Nisan. The results are valid for arbitrary probability distributions without restrictions. Our results also have implications on other interesting issues, such as monotonicity and randomization of selling mechanisms. PMID- 23798393 TI - Probing vasoocclusion phenomena in sickle cell anemia via mesoscopic simulations. AB - Vasoocclusion crisis is a key hallmark of sickle cell anemia. Although early studies suggest that this crisis is caused by blockage of a single elongated cell, recent experiments have revealed that vasoocclusion is a complex process triggered by adhesive interactions among different cell groups in multiple stages. However, the quantification of the biophysical characteristics of sickle cell anemia remains an open issue. Based on dissipative particle dynamics, we develop a multiscale model for the sickle red blood cells (SS-RBCs), accounting for diversity in both shapes and cell rigidities, to investigate the precise mechanism of vasoocclusion. First, we investigate the adhesive dynamics of a single SS-RBC in shear flow and static conditions, and find that the different cell groups (SS2: young-deformable SS-RBCs, ISCs: rigid-irreversible SS-RBCs) exhibit heterogeneous adhesive behavior due to the diverse cell morphologies and membrane rigidities. We quantify the observed adhesion behavior (in static conditions) in terms of a balance of free energies due to cell adhesion and deformation, and propose a power law that relates the free-energy increase as a function of the contact area. We further simulate postcapillary flow of SS-RBC suspensions with different cell fractions. The more adhesive SS2 cells interact with the vascular endothelium and trap ISC cells, resulting in vasoocclusion in vessels less than 12-14 MUm depending on the hematocrit. Under inflammation, adherent leukocytes may also trap ISC cells, resulting in vasoocclusion in even larger vessels. PMID- 23798392 TI - Default mode network connectivity distinguishes chemotherapy-treated breast cancer survivors from controls. AB - Breast cancer (BC) chemotherapy is associated with cognitive changes including persistent deficits in some individuals. We tested the accuracy of default mode network (DMN) resting state functional connectivity patterns in discriminating chemotherapy treated (C+) from non-chemotherapy (C-) treated BC survivors and healthy controls (HC). We also examined the relationship between DMN connectivity patterns and cognitive function. Multivariate pattern analysis was used to classify 30 C+, 27 C-, and 24 HC, which showed significant accuracy for discriminating C+ from C- (91.23%, P < 0.0001) and C+ from HC (90.74%, P < 0.0001). The C- group did not differ significantly from HC (47.06%, P = 0.60). Lower subjective memory function was correlated (P < 0.002) with greater hyperplane distance (distance from the linear decision function that optimally separates the groups). Disrupted DMN connectivity may help explain long-term cognitive difficulties following BC chemotherapy. PMID- 23798395 TI - Strain solitons and topological defects in bilayer graphene. AB - Bilayer graphene has been a subject of intense study in recent years. The interlayer registry between the layers can have dramatic effects on the electronic properties: for example, in the presence of a perpendicular electric field, a band gap appears in the electronic spectrum of so-called Bernal-stacked graphene [Oostinga JB, et al. (2007) Nature Materials 7:151-157]. This band gap is intimately tied to a structural spontaneous symmetry breaking in bilayer graphene, where one of the graphene layers shifts by an atomic spacing with respect to the other. This shift can happen in multiple directions, resulting in multiple stacking domains with soliton-like structural boundaries between them. Theorists have recently proposed that novel electronic states exist at these boundaries [Vaezi A, et al. (2013) arXiv:1301.1690; Zhang F, et al. (2013) arXiv:1301.4205], but very little is known about their structural properties. Here we use electron microscopy to measure with nanoscale and atomic resolution the widths, motion, and topological structure of soliton boundaries and related topological defects in bilayer graphene. We find that each soliton consists of an atomic-scale registry shift between the two graphene layers occurring over 6-11 nm. We infer the minimal energy barrier to interlayer translation and observe soliton motion during in situ heating above 1,000 degrees C. The abundance of these structures across a variety of samples, as well as their unusual properties, suggests that they will have substantial effects on the electronic and mechanical properties of bilayer graphene. PMID- 23798396 TI - Gut bacteria facilitate adaptation to crop rotation in the western corn rootworm. AB - Insects are constantly adapting to human-driven landscape changes; however, the roles of their gut microbiota in these processes remain largely unknown. The western corn rootworm (WCR, Diabrotica virgifera virgifera LeConte) (Coleoptera: Chrysomelidae) is a major corn pest that has been controlled via annual rotation between corn (Zea mays) and nonhost soybean (Glycine max) in the United States. This practice selected for a "rotation-resistant" variant (RR-WCR) with reduced ovipositional fidelity to cornfields. When in soybean fields, RR-WCRs also exhibit an elevated tolerance of antiherbivory defenses (i.e., cysteine protease inhibitors) expressed in soybean foliage. Here we show that gut bacterial microbiota is an important factor facilitating this corn specialist's (WCR's) physiological adaptation to brief soybean herbivory. Comparisons of gut microbiota between RR- and wild-type WCR (WT-WCR) revealed concomitant shifts in bacterial community structure with host adaptation to soybean diets. Antibiotic suppression of gut bacteria significantly reduced RR-WCR tolerance of soybean herbivory to the level of WT-WCR, whereas WT-WCR were unaffected. Our findings demonstrate that gut bacteria help to facilitate rapid adaptation of insects in managed ecosystems. PMID- 23798397 TI - Encoded multisite two-photon microscopy. AB - The advent of scanning two-photon microscopy (2PM) has created a fertile new avenue for noninvasive investigation of brain activity in depth. One principal weakness of this method, however, lies with the limit of scanning speed, which makes optical interrogation of action potential-like activity in a neuronal network problematic. Encoded multisite two-photon microscopy (eMS2PM), a scanless method that allows simultaneous imaging of multiple targets in depth with high temporal resolution, addresses this drawback. eMS2PM uses a liquid crystal spatial light modulator to split a high-power femto-laser beam into multiple subbeams. To distinguish them, a digital micromirror device encodes each subbeam with a specific binary amplitude modulation sequence. Fluorescence signals from all independently targeted sites are then collected simultaneously onto a single photodetector and site-specifically decoded. We demonstrate that eMS2PM can be used to image spike-like voltage transients in cultured cells and fluorescence transients (calcium signals in neurons and red blood cells in capillaries from the cortex) in depth in vivo. These results establish eMS2PM as a unique method for simultaneous acquisition of neuronal network activity. PMID- 23798398 TI - Intrinsic connectivity networks in healthy subjects explain clinical variability in Alzheimer's disease. AB - Although previous studies have emphasized the vulnerability of the default mode network (DMN) in Alzheimer's disease (AD), little is known about the involvement of other functional networks and their relationship to clinical phenotype. To test whether clinicoanatomic heterogeneity in AD is driven by the involvement of specific networks, network connectivity was assessed in healthy subjects by seeding regions commonly and specifically atrophied in three clinical AD variants: early-onset AD (age at onset, <65 y; memory and executive deficits), logopenic variant primary progressive aphasia (language deficits), and posterior cortical atrophy (visuospatial deficits). Four-millimeter seed regions of interest were used to obtain intrinsic connectivity maps in 131 healthy controls (age, 65.5 +/- 3.5 y). Atrophy patterns in independent cohorts of AD variant patients and their correspondence to connectivity networks in controls were also assessed. The connectivity maps of commonly atrophied regions of interest support posterior DMN and precuneus network involvement across AD variants, whereas seeding regions specifically atrophied in each AD variant revealed distinct, syndrome-specific connectivity patterns. Goodness-of-fit analysis of each connectivity map with network templates showed the highest correspondence between the early-onset AD seed connectivity map and anterior salience and right executive-control networks, the logopenic aphasia seed connectivity map and the language network, and the posterior cortical atrophy seed connectivity map and the higher visual network. Connectivity maps derived from controls matched regions commonly and specifically atrophied in the patients. Our findings indicate that the posterior DMN and precuneus network are commonly affected in AD variants, whereas syndrome-specific neurodegenerative patterns are driven by the involvement of specific networks outside the DMN. PMID- 23798399 TI - Mechanics of the Toxoplasma gondii oocyst wall. AB - The ability of microorganisms to survive under extreme conditions is closely related to the physicochemical properties of their wall. In the ubiquitous protozoan parasite Toxoplasma gondii, the oocyst stage possesses a bilayered wall that protects the dormant but potentially infective parasites from harsh environmental conditions until their ingestion by the host. None of the common disinfectants are effective in killing the parasite because the oocyst wall acts as a primary barrier to physical and chemical attacks. Here, we address the structure and chemistry of the wall of the T. gondii oocyst by combining wall surface treatments, fluorescence imaging, EM, and measurements of its mechanical characteristics by using atomic force microscopy. Elasticity and indentation measurements indicated that the oocyst wall resembles common plastic materials, based on the Young moduli, E, evaluated by atomic force microscopy. Our study demonstrates that the inner layer is as robust as the bilayered wall itself. Besides wall mechanics, our results suggest important differences regarding the nonspecific adhesive properties of each layer. All together, these findings suggest a key biological role for the oocyst wall mechanics in maintaining the integrity of the T. gondii oocysts in the environment or after exposure to disinfectants, and therefore their potential infectivity to humans and animals. PMID- 23798400 TI - On the mechanism of recombination hotspot scanning during double-stranded DNA break resection. AB - Double-stranded DNA break repair by homologous recombination is initiated by resection of free DNA ends to produce a 3'-ssDNA overhang. In bacteria, this reaction is catalyzed by helicase-nuclease complexes such as AddAB in a manner regulated by specific recombination hotspot sequences called Crossover hotspot instigator (Chi). We have used magnetic tweezers to investigate the dynamics of AddAB translocation and hotspot scanning during double-stranded DNA break resection. AddAB was prone to stochastic pausing due to transient recognition of Chi-like sequences, unveiling an antagonistic relationship between DNA translocation and sequence-specific DNA recognition. Pauses at bona fide Chi sequences were longer, were nonexponentially distributed, and resulted in an altered velocity upon restart of translocation downstream of Chi. We propose a model for the recognition of Chi sequences to explain the origin of pausing during failed and successful hotspot recognition. PMID- 23798401 TI - Numerical ability predicts mortgage default. AB - Unprecedented levels of US subprime mortgage defaults precipitated a severe global financial crisis in late 2008, plunging much of the industrialized world into a deep recession. However, the fundamental reasons for why US mortgages defaulted at such spectacular rates remain largely unknown. This paper presents empirical evidence showing that the ability to perform basic mathematical calculations is negatively associated with the propensity to default on one's mortgage. We measure several aspects of financial literacy and cognitive ability in a survey of subprime mortgage borrowers who took out loans in 2006 and 2007, and match them to objective, detailed administrative data on mortgage characteristics and payment histories. The relationship between numerical ability and mortgage default is robust to controlling for a broad set of sociodemographic variables, and is not driven by other aspects of cognitive ability. We find no support for the hypothesis that numerical ability impacts mortgage outcomes through the choice of the mortgage contract. Rather, our results suggest that individuals with limited numerical ability default on their mortgage due to behavior unrelated to the initial choice of their mortgage. PMID- 23798402 TI - Molecular basis for chromatin binding and regulation of MLL5. AB - The human mixed-lineage leukemia 5 (MLL5) protein mediates hematopoietic cell homeostasis, cell cycle, and survival; however, the molecular basis underlying MLL5 activities remains unknown. Here, we show that MLL5 is recruited to gene rich euchromatic regions via the interaction of its plant homeodomain finger with the histone mark H3K4me3. The 1.48-A resolution crystal structure of MLL5 plant homeodomain in complex with the H3K4me3 peptide reveals a noncanonical binding mechanism, whereby K4me3 is recognized through a single aromatic residue and an aspartate. The binding induces a unique His-Asp swapping rearrangement mediated by a C-terminal alpha-helix. Phosphorylation of H3T3 and H3T6 abrogates the association with H3K4me3 in vitro and in vivo, releasing MLL5 from chromatin in mitosis. This regulatory switch is conserved in the Drosophila ortholog of MLL5, UpSET, and suggests the developmental control for targeting of H3K4me3. Together, our findings provide first insights into the molecular basis for the recruitment, exclusion, and regulation of MLL5 at chromatin. PMID- 23798403 TI - Crystal structure of Ca2+/H+ antiporter protein YfkE reveals the mechanisms of Ca2+ efflux and its pH regulation. AB - Ca(2+) efflux by Ca(2+) cation antiporter (CaCA) proteins is important for maintenance of Ca(2+) homeostasis across the cell membrane. Recently, the monomeric structure of the prokaryotic Na(+)/Ca(2+) exchanger (NCX) antiporter NCX_Mj protein from Methanococcus jannaschii shows an outward-facing conformation suggesting a hypothesis of alternating substrate access for Ca(2+) efflux. To demonstrate conformational changes essential for the CaCA mechanism, we present the crystal structure of the Ca(2+)/H(+) antiporter protein YfkE from Bacillus subtilis at 3.1-A resolution. YfkE forms a homotrimer, confirmed by disulfide crosslinking. The protonated state of YfkE exhibits an inward-facing conformation with a large hydrophilic cavity opening to the cytoplasm in each protomer and ending in the middle of the membrane at the Ca(2+)-binding site. A hydrophobic "seal" closes its periplasmic exit. Four conserved alpha-repeat helices assemble in an X-like conformation to form a Ca(2+)/H(+) exchange pathway. In the Ca(2+) binding site, two essential glutamate residues exhibit different conformations compared with their counterparts in NCX_Mj, whereas several amino acid substitutions occlude the Na(+)-binding sites. The structural differences between the inward-facing YfkE and the outward-facing NCX_Mj suggest that the conformational transition is triggered by the rotation of the kink angles of transmembrane helices 2 and 7 and is mediated by large conformational changes in their adjacent transmembrane helices 1 and 6. Our structural and mutational analyses not only establish structural bases for mechanisms of Ca(2+)/H(+) exchange and its pH regulation but also shed light on the evolutionary adaptation to different energy modes in the CaCA protein family. PMID- 23798404 TI - Increased stray gas abundance in a subset of drinking water wells near Marcellus shale gas extraction. AB - Horizontal drilling and hydraulic fracturing are transforming energy production, but their potential environmental effects remain controversial. We analyzed 141 drinking water wells across the Appalachian Plateaus physiographic province of northeastern Pennsylvania, examining natural gas concentrations and isotopic signatures with proximity to shale gas wells. Methane was detected in 82% of drinking water samples, with average concentrations six times higher for homes <1 km from natural gas wells (P = 0.0006). Ethane was 23 times higher in homes <1 km from gas wells (P = 0.0013); propane was detected in 10 water wells, all within approximately 1 km distance (P = 0.01). Of three factors previously proposed to influence gas concentrations in shallow groundwater (distances to gas wells, valley bottoms, and the Appalachian Structural Front, a proxy for tectonic deformation), distance to gas wells was highly significant for methane concentrations (P = 0.007; multiple regression), whereas distances to valley bottoms and the Appalachian Structural Front were not significant (P = 0.27 and P = 0.11, respectively). Distance to gas wells was also the most significant factor for Pearson and Spearman correlation analyses (P < 0.01). For ethane concentrations, distance to gas wells was the only statistically significant factor (P < 0.005). Isotopic signatures (delta(13)C-CH4, delta(13)C-C2H6, and delta(2)H-CH4), hydrocarbon ratios (methane to ethane and propane), and the ratio of the noble gas (4)He to CH4 in groundwater were characteristic of a thermally postmature Marcellus-like source in some cases. Overall, our data suggest that some homeowners living <1 km from gas wells have drinking water contaminated with stray gases. PMID- 23798405 TI - Energy-dependent motion of TonB in the Gram-negative bacterial inner membrane. AB - Gram-negative bacteria acquire iron with TonB-dependent uptake systems. The TonB ExbBD inner membrane complex is hypothesized to transfer energy to outer membrane (OM) iron transporters. Fluorescence microscopic characterization of green fluorescent protein (GFP)-TonB hybrid proteins revealed an unexpected, restricted localization of TonB in the cell envelope. Fluorescence polarization measurements demonstrated motion of TonB in living cells, which likely was rotation. By determining the anisotropy of GFP-TonB in the absence and presence of inhibitors, we saw the dependence of its motion on electrochemical force and on the actions of ExbBD. We observed higher anisotropy for GFP-TonB in energy-depleted cells and lower values in bacteria lacking ExbBD. However, the metabolic inhibitors did not change the anisotropy of GFP-TonB in DeltaexbBD cells. These findings demonstrate that TonB undergoes energized motion in the bacterial cell envelope and that ExbBD couples this activity to the electrochemical gradient. The results portray TonB as an energized entity in a regular array underlying the OM bilayer, which promotes metal uptake through OM transporters by a rotational mechanism. PMID- 23798406 TI - Interannual variation of water isotopologues at Vostok indicates a contribution from stratospheric water vapor. AB - Combined measurements of water isotopologues of a snow pit at Vostok over the past 60 y reveal a unique signature that cannot be explained only by climatic features as usually done. Comparisons of the data using a general circulation model and a simpler isotopic distillation model reveal a stratospheric signature in the (17)O-excess record at Vostok. Our data and theoretical considerations indicate that mass-independent fractionation imprints the isotopic signature of stratospheric water vapor, which may allow for a distinction between stratospheric and tropospheric influences at remote East Antarctic sites. PMID- 23798407 TI - Probing the transient dark state of substrate binding to GroEL by relaxation based solution NMR. AB - The mechanism whereby the prototypical chaperonin GroEL performs work on substrate proteins has not yet been fully elucidated, hindered by lack of detailed structural and dynamic information on the bound substrate. Previous investigations have produced conflicting reports on the state of GroEL-bound polypeptides, largely due to the transient and dynamic nature of these complexes. Here, we present a unique approach, based on combined analysis of four complementary relaxation-based NMR experiments, to probe directly the "dark" NMR invisible state of the model, intrinsically disordered, polypeptide amyloid beta (Abeta40) bound to GroEL. The four NMR experiments, lifetime line-broadening, dark-state exchange saturation transfer, relaxation dispersion, and small exchange-induced chemical shifts, are dependent in different ways on the overall exchange rates and populations of the free and bound states of the substrate, as well as on residue-specific dynamics and structure within the bound state as reported by transverse magnetization relaxation rates and backbone chemical shifts, respectively. Global fitting of all the NMR data shows that the complex is transient with a lifetime of <1 ms, that binding involves two predominantly hydrophobic segments corresponding to predicted GroEL consensus binding sequences, and that the structure of the bound polypeptide remains intrinsically and dynamically disordered with minimal changes in secondary structure propensity relative to the free state. Our results establish a unique method to observe NMR invisible dynamic states of GroEL-bound substrates and to describe at atomic resolution the events between substrate binding and encapsulation that are crucial for understanding the normal and stress-related metabolic function of chaperonins. PMID- 23798408 TI - Transformation of the neural code for tactile detection from thalamus to cortex. AB - To understand how sensory-driven neural activity gives rise to perception, it is essential to characterize how various relay stations in the brain encode stimulus presence. Neurons in the ventral posterior lateral (VPL) nucleus of the somatosensory thalamus and in primary somatosensory cortex (S1) respond to vibrotactile stimulation with relatively slow modulations (~100 ms) of their firing rate. In addition, faster modulations (~10 ms) time-locked to the stimulus waveform are observed in both areas, but their contribution to stimulus detection is unknown. Furthermore, it is unclear whether VPL and S1 neurons encode stimulus presence with similar accuracy and via the same response features. To address these questions, we recorded single neurons while trained monkeys judged the presence or absence of a vibrotactile stimulus of variable amplitude, and their activity was analyzed with a unique decoding method that is sensitive to the time scale of the firing rate fluctuations. We found that the maximum detection accuracy of single neurons is similar in VPL and S1. However, VPL relies more heavily on fast rate modulations than S1, and as a consequence, the neural code in S1 is more tolerant: its performance degrades less when the readout method or the time scale of integration is suboptimal. Therefore, S1 neurons implement a more robust code, one less sensitive to the temporal integration window used to infer stimulus presence downstream. The differences between VPL and S1 responses signaling the appearance of a stimulus suggest a transformation of the neural code from thalamus to cortex. PMID- 23798409 TI - Caenorhabditis elegans centriolar protein SAS-6 forms a spiral that is consistent with imparting a ninefold symmetry. AB - Centrioles are evolutionary conserved organelles that give rise to cilia and flagella as well as centrosomes. Centrioles display a characteristic ninefold symmetry imposed by the spindle assembly abnormal protein 6 (SAS-6) family. SAS-6 from Chlamydomonas reinhardtii and Danio rerio was shown to form ninefold symmetric, ring-shaped oligomers in vitro that were similar to the cartwheels observed in vivo during early steps of centriole assembly in most species. Here, we report crystallographic and EM analyses showing that, instead, Caenorhabotis elegans SAS-6 self-assembles into a spiral arrangement. Remarkably, we find that this spiral arrangement is also consistent with ninefold symmetry, suggesting that two distinct SAS-6 oligomerization architectures can direct the same output symmetry. Sequence analysis suggests that SAS-6 spirals are restricted to specific nematodes. This oligomeric arrangement may provide a structural basis for the presence of a central tube instead of a cartwheel during centriole assembly in these species. PMID- 23798410 TI - Structural and functional insights into caseinolytic proteases reveal an unprecedented regulation principle of their catalytic triad. AB - Caseinolytic proteases (ClpPs) are large oligomeric protein complexes that contribute to cell homeostasis as well as virulence regulation in bacteria. Although most organisms possess a single ClpP protein, some organisms encode two or more ClpP isoforms. Here, we elucidated the crystal structures of ClpP1 and ClpP2 from pathogenic Listeria monocytogenes and observe an unprecedented regulation principle by the catalytic triad. Whereas L. monocytogenes (Lm)ClpP2 is both structurally and functionally similar to previously studied tetradecameric ClpP proteins from Escherichia coli and Staphylococcus aureus, heptameric LmClpP1 features an asparagine in its catalytic triad. Mutation of this asparagine to aspartate increased the reactivity of the active site and led to the assembly of a tetradecameric complex. We analyzed the heterooligomeric complex of LmClpP1 and LmClpP2 via coexpression and subsequent labeling studies with natural product-derived probes. Notably, the LmClpP1 peptidase activity is stimulated 75-fold in the complex providing insights into heterooligomerization as a regulatory mechanism. Collectively, our data point toward different preferences for substrates and inhibitors of the two ClpP enzymes and highlight their structural and functional characteristics. PMID- 23798411 TI - Permeation rates of penicillins indicate that Escherichia coli porins function principally as nonspecific channels. AB - Small, hydrophilic compounds such as beta-lactams diffuse across the outer membrane of Gram-negative bacteria through porin channels, which were originally thought to be nonspecific channels devoid of any specificity. However, since the discovery of an ampicillin-binding site within the OmpF channel in 2002, much attention has been focused on the potential specificity of the channel, where the binding site was assumed either to facilitate or to retard the penetration of beta-lactams. Since the earlier studies on porin permeability were done without the knowledge of the contribution of multidrug efflux pumps in the overall flux process across the cell envelope, in this study we have carefully studied both the porin permeability and active efflux of ampicillin and benzylpenicillin. We found that the influx occurs apparently by a spontaneous passive diffusion without any indication of specific binding within the concentration range relevant to the antibiotic action of these drugs, and that the higher permeability for ampicillin is totally as expected from the gross property of this drug as a zwitterionic compound. The active efflux by AcrAB was more effective for benzylpenicillin due to the stronger affinity and high degree of positive cooperativity. Our data now give a complete quantitative picture of the influx, efflux, and periplasmic degradation (catalyzed by AmpC beta-lactamase) of these two compounds, and correlate closely with the susceptibility of Escherichia coli strains used here, thus validating not only our model but also the parameters obtained in this study. PMID- 23798412 TI - Molecular consequences of the R453C hypertrophic cardiomyopathy mutation on human beta-cardiac myosin motor function. AB - Cardiovascular disorders are the leading cause of morbidity and mortality in the developed world, and hypertrophic cardiomyopathy (HCM) is among the most frequently occurring inherited cardiac disorders. HCM is caused by mutations in the genes encoding the fundamental force-generating machinery of the cardiac muscle, including beta-cardiac myosin. Here, we present a biomechanical analysis of the HCM-causing mutation, R453C, in the context of human beta-cardiac myosin. We found that this mutation causes a ~30% decrease in the maximum ATPase of the human beta-cardiac subfragment 1, the motor domain of myosin, and a similar percent decrease in the in vitro velocity. The major change in the R453C human beta-cardiac subfragment 1 is a 50% increase in the intrinsic force of the motor compared with wild type, with no appreciable change in the stroke size, as observed with a dual-beam optical trap. These results predict that the overall force of the ensemble of myosin molecules in the muscle should be higher in the R453C mutant compared with wild type. Loaded in vitro motility assay confirms that the net force in the ensemble is indeed increased. Overall, this study suggests that the R453C mutation should result in a hypercontractile state in the heart muscle. PMID- 23798413 TI - Use of anion-aromatic interactions to position the general base in the ketosteroid isomerase active site. AB - Although the cation-pi pair, formed between a side chain or substrate cation and the negative electrostatic potential of a pi system on the face of an aromatic ring, has been widely discussed and has been shown to be important in protein structure and protein-ligand interactions, there has been little discussion of the potential structural and functional importance in proteins of the related anion-aromatic pair (i.e., interaction of a negatively charged group with the positive electrostatic potential on the ring edge of an aromatic group). We posited, based on prior structural information, that anion-aromatic interactions between the anionic Asp general base and Phe54 and Phe116 might be used instead of a hydrogen-bond network to position the general base in the active site of ketosteroid isomerase from Comamonas testosteroni as there are no neighboring hydrogen-bonding groups. We have tested the role of the Phe residues using site directed mutagenesis, double-mutant cycles, and high-resolution X-ray crystallography. These results indicate a catalytic role of these Phe residues. Extensive analysis of the Protein Data Bank provides strong support for a catalytic role of these and other Phe residues in providing anion-aromatic interactions that position anionic general bases within enzyme active sites. Our results further reveal a potential selective advantage of Phe in certain situations, relative to more traditional hydrogen-bonding groups, because it can simultaneously aid in the binding of hydrophobic substrates and positioning of a neighboring general base. PMID- 23798414 TI - Cognitive relevance of the community structure of the human brain functional coactivation network. AB - There is growing interest in the complex topology of human brain functional networks, often measured using resting-state functional MRI (fMRI). Here, we used a meta-analysis of the large primary literature that used fMRI or PET to measure task-related activation (>1,600 studies; 1985-2010). We estimated the similarity (Jaccard index) of the activation patterns across experimental tasks between each pair of 638 brain regions. This continuous coactivation matrix was used to build a weighted graph to characterize network topology. The coactivation network was modular, with occipital, central, and default-mode modules predominantly coactivated by specific cognitive domains (perception, action, and emotion, respectively). It also included a rich club of hub nodes, located in parietal and prefrontal cortex and often connected over long distances, which were coactivated by a diverse range of experimental tasks. Investigating the topological role of edges between a deactivated and an activated node, we found that such competitive interactions were most frequent between nodes in different modules or between an activated rich-club node and a deactivated peripheral node. Many aspects of the coactivation network were convergent with a connectivity network derived from resting state fMRI data (n = 27, healthy volunteers); although the connectivity network was more parsimoniously connected and differed in the anatomical locations of some hubs. We conclude that the community structure of human brain networks is relevant to cognitive function. Deactivations may play a role in flexible reconfiguration of the network according to cognitive demand, varying the integration between modules, and between the periphery and a central rich club. PMID- 23798415 TI - Patterning droplets with durotaxis. AB - Numerous cell types have shown a remarkable ability to detect and move along gradients in stiffness of an underlying substrate--a process known as durotaxis. The mechanisms underlying durotaxis are still unresolved, but generally believed to involve active sensing and locomotion. Here, we show that simple liquid droplets also undergo durotaxis. By modulating substrate stiffness, we obtain fine control of droplet position on soft, flat substrates. Unlike other control mechanisms, droplet durotaxis works without imposing chemical, thermal, electrical, or topographical gradients. We show that droplet durotaxis can be used to create large-scale droplet patterns and is potentially useful for many applications, such as microfluidics, thermal control, and microfabrication. PMID- 23798416 TI - Ligands that interact with putative MOR-mGluR5 heteromer in mice with inflammatory pain produce potent antinociception. AB - The low effectiveness of morphine and related mu opioid analgesics for the treatment of chronic inflammatory pain is a result of opioid-induced release of proinflammatory cytokines and glutamate that lower the pain threshold. In this regard, the use of opioids with metabotropic glutamate-5 receptor (mGluR5) antagonist has been reported to increase the efficacy of morphine and prevent the establishment of adverse effects during chronic use. Given the presence of opioid receptors (MORs) and mGluR5 in glia and neurons, together with reports that suggest coexpressed MOR/mGluR5 receptors in cultured cells associate as a heteromer, the possibility that such a heteromer could be a target in vivo was addressed by the design and synthesis of a series of bivalent ligands that contain mu opioid agonist and mGluR5 antagonist pharmacophores linked through spacers of varying length (10-24 atoms). The series was evaluated for antinociception using the tail-flick and von Frey assays in mice pretreated with lipopolysaccharide (LPS) or in mice with bone cancer. In LPS-pretreated mice, MMG22 (4c, 22-atom spacer) was the most potent member of the series (intrathecal ED50 ~9 fmol per mouse), whereas in untreated mice its ED50 was more than three orders of magnitude higher. As members of the series with shorter or longer spacers have >=500-fold higher ED50s in LPS-treated mice, the exceptional potency of MMG22 may be a result of the optimal bridging of protomers in a putative MOR mGluR5 heteromer. The finding that MMG22 possesses a >10(6) therapeutic ratio suggests that it may be an excellent candidate for treatment of chronic, intractable pain via spinal administration. PMID- 23798417 TI - Manganese-oxidizing photosynthesis before the rise of cyanobacteria. AB - The emergence of oxygen-producing (oxygenic) photosynthesis fundamentally transformed our planet; however, the processes that led to the evolution of biological water splitting have remained largely unknown. To illuminate this history, we examined the behavior of the ancient Mn cycle using newly obtained scientific drill cores through an early Paleoproterozoic succession (2.415 Ga) preserved in South Africa. These strata contain substantial Mn enrichments (up to ~17 wt %) well before those associated with the rise of oxygen such as the ~2.2 Ga Kalahari Mn deposit. Using microscale X-ray spectroscopic techniques coupled to optical and electron microscopy and carbon isotope ratios, we demonstrate that the Mn is hosted exclusively in carbonate mineral phases derived from reduction of Mn oxides during diagenesis of primary sediments. Additional observations of independent proxies for O2--multiple S isotopes (measured by isotope-ratio mass spectrometry and secondary ion mass spectrometry) and redox-sensitive detrital grains--reveal that the original Mn-oxide phases were not produced by reactions with O2, which points to a different high-potential oxidant. These results show that the oxidative branch of the Mn cycle predates the rise of oxygen, and provide strong support for the hypothesis that the water-oxidizing complex of photosystem II evolved from a former transitional photosystem capable of single electron oxidation reactions of Mn. PMID- 23798418 TI - Identifying host species driving transmission of schistosomiasis japonica, a multihost parasite system, in China. AB - Understanding disease transmission dynamics in multihost parasite systems is a research priority for control and potential elimination of many infectious diseases. In China, despite decades of multifaceted control efforts against schistosomiasis, the indirectly transmitted helminth Schistosoma japonicum remains endemic, partly because of the presence of zoonotic reservoirs. We used mathematical modeling and conceptual frameworks of multihost transmission ecology to assess the relative importance of various definitive host species for S. japonicum transmission in contrasting hilly and marshland areas of China. We examine whether directing control interventions against zoonotic reservoirs could further reduce incidence of infection in humans or even eliminate transmission. Results suggest that, under current control programs, infections in humans result from spillover of transmission among zoonotic reservoirs. Estimates of the basic reproduction number within each species suggest that bovines (water buffalo and cattle) maintained transmission in the marshland area and that the recent removal of bovines from this area could achieve local elimination of transmission. However, the sole use of antifecundity S. japonicum vaccines for bovines, at least at current efficacies, may not achieve elimination in areas of comparable endemicity where removal of bovines is not a feasible option. The results also suggest that rodents drive transmission in the hilly area. Therefore, although targeting bovines could further reduce and potentially interrupt transmission in marshland regions of China, elimination of S. japonicum could prove more challenging in areas where rodents might maintain transmission. In conclusion, we show how mathematical modeling can give important insights into multihost transmission of indirectly transmitted pathogens. PMID- 23798420 TI - Evolutionary lag times and recent origin of the biota of an ancient desert (Atacama-Sechura). AB - The assembly of regional biotas and organismal responses to anthropogenic climate change both depend on the capacity of organisms to adapt to novel ecological conditions. Here we demonstrate the concept of evolutionary lag time, the time between when a climatic regime or habitat develops in a region and when it is colonized by a given clade. We analyzed the time of colonization of four clades (three plant genera and one lizard genus) into the Atacama-Sechura Desert of South America, one of Earth's driest and oldest deserts. We reconstructed time calibrated phylogenies for each clade and analyzed the timing of shifts in climatic distributions and biogeography and compared these estimates to independent geological estimates of the time of origin of these deserts. Chaetanthera and Malesherbia (plants) and Liolaemus (animal) invaded arid regions of the Atacama-Sechura Desert in the last 10 million years, some 20 million years after the initial onset of aridity in the region. There are also major lag times between when these clades colonized the region and when they invaded arid habitats within the region (typically 4-14 million years). Similarly, hyperarid climates developed ~8 million years ago, but the most diverse plant clade in these habitats (Nolana) only colonized them ~2 million years ago. Similar evolutionary lag times may occur in other organisms and habitats, but these results are important in suggesting that many lineages may require very long time scales to adapt to modern desertification and climatic change. PMID- 23798419 TI - Calcium-dependent N-cadherin up-regulation mediates reactive astrogliosis and neuroprotection after brain injury. AB - Brain injury induces phenotypic changes in astrocytes, known as reactive astrogliosis, which may influence neuronal survival. Here we show that brain injury induces inositol 1,4,5-trisphosphate (IP3)-dependent Ca(2+) signaling in astrocytes, and that the Ca(2+) signaling is required for astrogliosis. We found that type 2 IP3 receptor knockout (IP3R2KO) mice deficient in astrocytic Ca(2+) signaling have impaired reactive astrogliosis and increased injury-associated neuronal death. We identified N-cadherin and pumilio 2 (Pum2) as downstream signaling molecules, and found that brain injury induces up-regulation of N cadherin around the injured site. This effect is mediated by Ca(2+)-dependent down-regulation of Pum2, which in turn attenuates Pum2-dependent translational repression of N-cadherin. Furthermore, we show that astrocyte-specific knockout of N-cadherin results in impairment of astrogliosis and neuroprotection. Thus, astrocytic Ca(2+) signaling and the downstream function of N-cadherin play indispensable roles in the cellular responses to brain injury. These findings define a previously unreported signaling axis required for reactive astrogliosis and neuroprotection following brain injury. PMID- 23798421 TI - QnAs with Detlef Weigel. Interview by Sandeep Ravindran. PMID- 23798422 TI - Tuning gene expression with synthetic upstream open reading frames. AB - We engineered short ORFs and used them to control the expression level of recombinant proteins. These short ORFs, encoding a two-amino acid peptide, were placed upstream of an ORF encoding a protein of interest. Insertion of these upstream ORFs (uORFs) resulted in suppression of protein expression. By varying the base sequence preceding the uORF, we sought to vary the translation initiation rate of the uORF and subsequently control the degree of this suppression. Using this strategy, we generated a library of RNA sequence elements that can specify protein expression over a broad range of levels. By also using multiple uORFs in series and non-AUG start codons, we were able to generate particularly low expression levels, allowing us to achieve expression levels spanning three orders of magnitude. Modeling supported a mechanism where uORFs shunt the flow of ribosomes away from the downstream protein-coding ORF. With a lower translation initiation rate at the uORF, more ribosomes "leak" past the uORF; consequently, more ribosomes are able to reach and translate the downstream ORF. We report expression control by engineering uORFs and translation initiation to be robust, predictable, and reproducible across all cell types tested. We propose control of translation initiation as a primary method of choice for tuning expression in mammalian systems. PMID- 23798423 TI - Quality of early parent input predicts child vocabulary 3 years later. AB - Children vary greatly in the number of words they know when they enter school, a major factor influencing subsequent school and workplace success. This variability is partially explained by the differential quantity of parental speech to preschoolers. However, the contexts in which young learners hear new words are also likely to vary in referential transparency; that is, in how clearly word meaning can be inferred from the immediate extralinguistic context, an aspect of input quality. To examine this aspect, we asked 218 adult participants to guess 50 parents' words from (muted) videos of their interactions with their 14- to 18-mo-old children. We found systematic differences in how easily individual parents' words could be identified purely from this socio visual context. Differences in this kind of input quality correlated with the size of the children's vocabulary 3 y later, even after controlling for differences in input quantity. Although input quantity differed as a function of socioeconomic status, input quality (as here measured) did not, suggesting that the quality of nonverbal cues to word meaning that parents offer to their children is an individual matter, widely distributed across the population of parents. PMID- 23798424 TI - Physical linkage of metabolic genes in fungi is an adaptation against the accumulation of toxic intermediate compounds. AB - Genomic analyses have proliferated without being tied to tangible phenotypes. For example, although coordination of both gene expression and genetic linkage have been offered as genetic mechanisms for the frequently observed clustering of genes participating in fungal metabolic pathways, elucidation of the phenotype(s) favored by selection, resulting in cluster formation and maintenance, has not been forthcoming. We noted that the cause of certain well-studied human metabolic disorders is the accumulation of toxic intermediate compounds (ICs), which occurs when the product of an enzyme is not used as a substrate by a downstream neighbor in the metabolic network. This raises the hypothesis that the phenotype favored by selection to drive gene clustering is the mitigation of IC toxicity. To test this, we examined 100 diverse fungal genomes for the simplest type of cluster, gene pairs that are both metabolic neighbors and chromosomal neighbors immediately adjacent to each other, which we refer to as "double neighbor gene pairs" (DNGPs). Examination of the toxicity of their corresponding ICs shows that, compared with chromosomally nonadjacent metabolic neighbors, DNGPs are enriched for ICs that have acutely toxic LD50 doses or reactive functional groups. Furthermore, DNGPs are significantly more likely to be divergently oriented on the chromosome; remarkably, ~40% of these DNGPs have ICs known to be toxic. We submit that the structure of synteny in metabolic pathways of fungi is a signature of selection for protection against the accumulation of toxic metabolic intermediates. PMID- 23798425 TI - Acetylated histone H3K56 interacts with Oct4 to promote mouse embryonic stem cell pluripotency. AB - The presence of acetylated histone H3K56 (H3K56ac) in human ES cells (ESCs) correlates positively with the binding of Nanog, Sox2, and Oct4 (NSO) transcription factors at their target gene promoters. However, the function of H3K56ac there has been unclear. We now report that Oct4 interacts with H3K56ac in mouse ESC nuclear extracts and that perturbing H3K56 acetylation decreases Oct4 H3 binding. This interaction is likely to be direct because it can be recapitulated in vitro in an H3K56ac-dependent manner and is functionally important because H3K56ac combines with NSO factors in chromatin immunoprecipitation sequencing to mark the regions associated with pluripotency better than NSO alone. Moreover, reducing H3K56ac by short hairpin Asf1a decreases expression of pluripotency-related markers and increases expression of differentiation-related ones. Therefore, our data suggest that H3K56ac plays a central role in binding to Oct4 to promote the pluripotency of ESCs. PMID- 23798426 TI - Rational modification of protein stability by targeting surface sites leads to complicated results. AB - The rational modification of protein stability is an important goal of protein design. Protein surface electrostatic interactions are not evolutionarily optimized for stability and are an attractive target for the rational redesign of proteins. We show that surface charge mutants can exert stabilizing effects in distinct and unanticipated ways, including ones that are not predicted by existing methods, even when only solvent-exposed sites are targeted. Individual mutation of three solvent-exposed lysines in the villin headpiece subdomain significantly stabilizes the protein, but the mechanism of stabilization is very different in each case. One mutation destabilizes native-state electrostatic interactions but has a larger destabilizing effect on the denatured state, a second removes the desolvation penalty paid by the charged residue, whereas the third introduces unanticipated native-state interactions but does not alter electrostatics. Our results show that even seemingly intuitive mutations can exert their effects through unforeseen and complex interactions. PMID- 23798427 TI - Structural basis for dynamic mechanism of proton-coupled symport by the peptide transporter POT. AB - Proton-dependent oligopeptide transporters (POTs) are major facilitator superfamily (MFS) proteins that mediate the uptake of peptides and peptide-like molecules, using the inwardly directed H(+) gradient across the membrane. The human POT family transporter peptide transporter 1 is present in the brush border membrane of the small intestine and is involved in the uptake of nutrient peptides and drug molecules such as beta-lactam antibiotics. Although previous studies have provided insight into the overall structure of the POT family transporters, the question of how transport is coupled to both peptide and H(+) binding remains unanswered. Here we report the high-resolution crystal structures of a bacterial POT family transporter, including its complex with a dipeptide analog, alafosfalin. These structures revealed the key mechanistic and functional roles for a conserved glutamate residue (Glu310) in the peptide binding site. Integrated structural, biochemical, and computational analyses suggested a mechanism for H(+)-coupled peptide symport in which protonated Glu310 first binds the carboxyl group of the peptide substrate. The deprotonation of Glu310 in the inward open state triggers the release of the bound peptide toward the intracellular space and salt bridge formation between Glu310 and Arg43 to induce the state transition to the occluded conformation. PMID- 23798428 TI - Transformation of epithelial cells through recruitment leads to polyclonal intestinal tumors. AB - Intestinal tumors from mice and humans can have a polyclonal origin. Statistical analyses indicate that the best explanation for this source of intratumoral heterogeneity is the presence of interactions among multiple progenitors. We sought to better understand the nature of these interactions. An initial progenitor could recruit others by facilitating the transformation of one or more neighboring cells. Alternatively, two progenitors that are independently initiated could simply cooperate to form a single tumor. These possibilities were tested by analyzing tumors from aggregation chimeras that were generated by fusing together embryos with unequal predispositions to tumor development. Strikingly, numerous polyclonal tumors were observed even when one genetic component was highly, if not completely, resistant to spontaneous tumorigenesis in the intestine. Moreover, the observed number of polyclonal tumors could be explained by the facilitated transformation of a single neighbor within 144 MUm of an initial progenitor. These findings strongly support recruitment instead of cooperation. Thus, it is conceivable that these interactions are necessary for tumors to thrive, so blocking them might be a highly effective method for preventing the formation of tumors in the intestine and other tissues. PMID- 23798429 TI - Cell geometric constraints induce modular gene-expression patterns via redistribution of HDAC3 regulated by actomyosin contractility. AB - Physical forces in the form of substrate rigidity or geometrical constraints have been shown to alter gene expression profile and differentiation programs. However, the underlying mechanism of gene regulation by these mechanical cues is largely unknown. In this work, we use micropatterned substrates to alter cellular geometry (shape, aspect ratio, and size) and study the nuclear mechanotransduction to regulate gene expression. Genome-wide transcriptome analysis revealed cell geometry-dependent alterations in actin-related gene expression. Increase in cell size reinforced expression of matrix-related genes, whereas reduced cell-substrate contact resulted in up-regulation of genes involved in cellular homeostasis. We also show that large-scale changes in gene expression profile mapped onto differential modulation of nuclear morphology, actomyosin contractility and histone acetylation. Interestingly, cytoplasmic-to nuclear redistribution of histone deacetylase 3 modulated histone acetylation in an actomyosin-dependent manner. In addition, we show that geometric constraints altered the nuclear fraction of myocardin-related transcription factor. These fractions exhibited hindered diffusion time scale within the nucleus, correlated with enhanced serum-response element promoter activity. Furthermore, nuclear accumulation of myocardin-related transcription factor also modulated NF-kappaB activity. Taken together, our work provides modularity in switching gene expression patterns by cell geometric constraints via actomyosin contractility. PMID- 23798430 TI - Negative regulation of Toll-like receptor 4 signaling by IL-10-dependent microRNA 146b. AB - Toll-like receptors (TLRs) play key roles in detecting pathogens and initiating inflammatory responses that, subsequently, prime specific adaptive responses. Several mechanisms control TLR activity to avoid excessive inflammation and consequent immunopathology, including the anti-inflammatory cytokine IL-10. Recently, several TLR-responsive microRNAs (miRs) have also been proposed as potential regulators of this signaling pathway, but their functional role during the inflammatory response still is incompletely understood. In this study, we report that, after LPS engagement, monocytes up-regulate miR-146b via an IL-10 mediated STAT3-dependent loop. We show evidence that miR-146b modulates the TLR4 signaling pathway by direct targeting of multiple elements, including the LPS receptor TLR4 and the key adaptor/signaling proteins myeloid differentiation primary response (MyD88), interleukin-1 receptor-associated kinase 1 (IRAK-1), and TNF receptor-associated factor 6 (TRAF6). Furthermore, we demonstrate that the enforced expression of miR-146b in human monocytes led to a significant reduction in the LPS-dependent production of several proinflammatory cytokines and chemokines, including IL-6, TNF-alpha, IL-8, CCL3, CCL2, CCL7, and CXCL10. Our results thus identify miR-146b as an IL-10-responsive miR with an anti inflammatory activity based on multiple targeting of components of the TLR4 pathway in monocytes and candidate miR-146b as a molecular effector of the IL-10 anti-inflammatory activity. PMID- 23798431 TI - Regional variations in the health, environmental, and climate benefits of wind and solar generation. AB - When wind or solar energy displace conventional generation, the reduction in emissions varies dramatically across the United States. Although the Southwest has the greatest solar resource, a solar panel in New Jersey displaces significantly more sulfur dioxide, nitrogen oxides, and particulate matter than a panel in Arizona, resulting in 15 times more health and environmental benefits. A wind turbine in West Virginia displaces twice as much carbon dioxide as the same turbine in California. Depending on location, we estimate that the combined health, environmental, and climate benefits from wind or solar range from $10/MWh to $100/MWh, and the sites with the highest energy output do not yield the greatest social benefits in many cases. We estimate that the social benefits from existing wind farms are roughly 60% higher than the cost of the Production Tax Credit, an important federal subsidy for wind energy. However, that same investment could achieve greater health, environmental, and climate benefits if it were differentiated by region. PMID- 23798432 TI - Molecular circuit involving KLK4 integrates androgen and mTOR signaling in prostate cancer. AB - The androgen receptor (AR) and the phosphoinositide 3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin (mTOR) signaling are two of the major proliferative pathways in a number of tissues and are the main therapeutic targets in various disorders, including prostate cancer (PCa). Previous work has shown that there is reciprocal feedback regulation of PI3K and AR signaling in PCa, suggesting that cotargeting both pathways may enhance therapeutic efficacy. Here we show that proteins encoded by two androgen-regulated genes, kallikrein related peptidase 4 (KLK4) and promyelocytic leukemia zinc finger (PLZF), integrate optimal functioning of AR and mTOR signaling in PCa cells. KLK4 interacts with PLZF and decreases its stability. PLZF in turn interacts with AR and inhibits its function as a transcription factor. PLZF also activates expression of regulated in development and DNA damage responses 1, an inhibitor of mTORC1. Thus, a unique molecular switch is generated that regulates both AR and PI3K signaling. Consistently, KLK4 knockdown results in a significant decline in PCa cell proliferation in vitro and in vivo, decreases anchorage-independent growth, induces apoptosis, and dramatically sensitizes PCa cells to apoptosis inducing agents. Furthermore, in vivo nanoliposomal KLK4 siRNA delivery in mice bearing PCa tumors results in profound remission. These results demonstrate that the activities of AR and mTOR pathways are maintained by KLK4, which may thus be a viable target for therapy. PMID- 23798433 TI - Interfering with Gal-1-mediated angiogenesis contributes to the pathogenesis of preeclampsia. AB - Preeclampsia (PE) is a pregnancy-specific disorder characterized by sudden onset of hypertension and proteinuria in the second half of pregnancy (>20 wk). PE is strongly associated with abnormal placentation and an excessive maternal inflammatory response. Galectin-1 (Gal-1), a member of a family of carbohydrate binding proteins, has been shown to modulate several processes associated with placentation and to promote maternal tolerance toward fetal antigens. Here, we show that Gal-1 exhibits proangiogenic functions during early stages of pregnancy, promoting decidual vascular expansion through VEGF receptor 2 signaling. Blocking Gal-1-mediated angiogenesis or lectin, galactoside-binding, soluble, 1 deficiency results in a spontaneous PE-like syndrome in mice, mainly by deregulating processes associated with good placentation and maternal spiral artery remodeling. Consistent with these findings, we observed a down-regulation of Gal-1 in patients suffering from early onset PE. Collectively, these results strengthen the notion that Gal-1 is required for healthy gestation and highlight Gal-1 as a valuable biomarker for early PE diagnosis. PMID- 23798434 TI - Vibrational imaging of newly synthesized proteins in live cells by stimulated Raman scattering microscopy. AB - Synthesis of new proteins, a key step in the central dogma of molecular biology, has been a major biological process by which cells respond rapidly to environmental cues in both physiological and pathological conditions. However, the selective visualization of a newly synthesized proteome in living systems with subcellular resolution has proven to be rather challenging, despite the extensive efforts along the lines of fluorescence staining, autoradiography, and mass spectrometry. Herein, we report an imaging technique to visualize nascent proteins by harnessing the emerging stimulated Raman scattering (SRS) microscopy coupled with metabolic incorporation of deuterium-labeled amino acids. As a first demonstration, we imaged newly synthesized proteins in live mammalian cells with high spatial-temporal resolution without fixation or staining. Subcellular compartments with fast protein turnover in HeLa and HEK293T cells, and newly grown neurites in differentiating neuron-like N2A cells, are clearly identified via this imaging technique. Technically, incorporation of deuterium-labeled amino acids is minimally perturbative to live cells, whereas SRS imaging of exogenous carbon-deuterium bonds (C-D) in the cell-silent Raman region is highly sensitive, specific, and compatible with living systems. Moreover, coupled with label-free SRS imaging of the total proteome, our method can readily generate spatial maps of the quantitative ratio between new and total proteomes. Thus, this technique of nonlinear vibrational imaging of stable isotope incorporation will be a valuable tool to advance our understanding of the complex spatial and temporal dynamics of newly synthesized proteome in vivo. PMID- 23798435 TI - Amphetamine actions at the serotonin transporter rely on the availability of phosphatidylinositol-4,5-bisphosphate. AB - Nerve functions require phosphatidylinositol-4,5-bisphosphate (PIP2) that binds to ion channels, thereby controlling their gating. Channel properties are also attributed to serotonin transporters (SERTs); however, SERT regulation by PIP2 has not been reported. SERTs control neurotransmission by removing serotonin from the extracellular space. An increase in extracellular serotonin results from transporter-mediated efflux triggered by amphetamine-like psychostimulants. Herein, we altered the abundance of PIP2 by activating phospholipase-C (PLC), using a scavenging peptide, and inhibiting PIP2-synthesis. We tested the effects of the verified scarcity of PIP2 on amphetamine-triggered SERT functions in human cells. We observed an interaction between SERT and PIP2 in pull-down assays. On decreased PIP2 availability, amphetamine-evoked currents were markedly reduced compared with controls, as was amphetamine-induced efflux. Signaling downstream of PLC was excluded as a cause for these effects. A reduction of substrate efflux due to PLC activation was also found with recombinant noradrenaline transporters and in rat hippocampal slices. Transmitter uptake was not affected by PIP2 reduction. Moreover, SERT was revealed to have a positively charged binding site for PIP2. Mutation of the latter resulted in a loss of amphetamine-induced SERT mediated efflux and currents, as well as a lack of PIP2-dependent effects. Substrate uptake and surface expression were comparable between mutant and WT SERTs. These findings demonstrate that PIP2 binding to monoamine transporters is a prerequisite for amphetamine actions without being a requirement for neurotransmitter uptake. These results open the way to target amphetamine-induced SERT-dependent actions independently of normal SERT function and thus to treat psychostimulant addiction. PMID- 23798436 TI - Fungal adhesion protein guides community behaviors and autoinduction in a paracrine manner. AB - Microbes live mostly in a social community rather than in a planktonic state. Such communities have complex spatiotemporal patterns that require intercellular communication to coordinate gene expression. Here, we demonstrate that Cryptococcus neoformans, a model eukaryotic pathogen, responds to an extracellular signal in constructing its colony morphology. The signal that directs this community behavior is not a molecule of low molecular weight like pheromones or quorum-sensing molecules but a secreted protein. Znf2, a master regulator of morphogenesis in Cryptococcus, is necessary and sufficient for the production of this signal protein. Cfl1, a prominent Znf2-downstream adhesion protein (adhesin), was identified to be responsible for the paracrine communication. Consistent with its role in communication, Cfl1 is highly induced during mating colony differentiation, and some of the Cfl1 proteins undergo shedding and are released from the cell wall. The released Cfl1 is enriched in the extracellular matrix and acts as an autoinduction signal to stimulate neighboring cells to phenocopy Cfl1-expressing cells via the filamentation signaling pathway. We further demonstrate the importance of an unannotated and yet conserved domain in Cfl1's signaling activity. Although adhesion proteins have long been considered to be mediators of microbial pathogenicity and the structural components of biofilms, our work presented here provides the direct evidence supporting the signaling activation by microbial adhesion/matrix proteins. PMID- 23798437 TI - Rasip1 mediates Rap1 regulation of Rho in endothelial barrier function through ArhGAP29. AB - Rap1 is a small GTPase regulating cell-cell adhesion, cell-matrix adhesion, and actin rearrangements, all processes dynamically coordinated during cell spreading and endothelial barrier function. Here, we identify the adaptor protein ras interacting protein 1 (Rasip1) as a Rap1-effector involved in cell spreading and endothelial barrier function. Using Forster resonance energy transfer, we show that Rasip1 interacts with active Rap1 in a cellular context. Rasip1 mediates Rap1-induced cell spreading through its interaction partner Rho GTPase-activating protein 29 (ArhGAP29), a GTPase activating protein for Rho proteins. Accordingly, the Rap1-Rasip1 complex induces cell spreading by inhibiting Rho signaling. The Rasip1-ArhGAP29 pathway also functions in Rap1-mediated regulation of endothelial junctions, which controls endothelial barrier function. In this process, Rasip1 cooperates with its close relative ras-association and dilute domain-containing protein (Radil) to inhibit Rho-mediated stress fiber formation and induces junctional tightening. These results reveal an effector pathway for Rap1 in the modulation of Rho signaling and actin dynamics, through which Rap1 modulates endothelial barrier function. PMID- 23798438 TI - Tailored fatty acid synthesis via dynamic control of fatty acid elongation. AB - Medium-chain fatty acids (MCFAs, 4-12 carbons) are valuable as precursors to industrial chemicals and biofuels, but are not canonical products of microbial fatty acid synthesis. We engineered microbial production of the full range of even- and odd-chain-length MCFAs and found that MCFA production is limited by rapid, irreversible elongation of their acyl-ACP precursors. To address this limitation, we programmed an essential ketoacyl synthase to degrade in response to a chemical inducer, thereby slowing acyl-ACP elongation and redirecting flux from phospholipid synthesis to MCFA production. Our results show that induced protein degradation can be used to dynamically alter metabolic flux, and thereby increase the yield of a desired compound. The strategy reported herein should be widely useful in a range of metabolic engineering applications in which essential enzymes divert flux away from a desired product, as well as in the production of polyketides, bioplastics, and other recursively synthesized hydrocarbons for which chain-length control is desired. PMID- 23798439 TI - Genome of a SAR116 bacteriophage shows the prevalence of this phage type in the oceans. AB - The abundance, genetic diversity, and crucial ecological and evolutionary roles of marine phages have prompted a large number of metagenomic studies. However, obtaining a thorough understanding of marine phages has been hampered by the low number of phage isolates infecting major bacterial groups other than cyanophages and pelagiphages. Therefore, there is an urgent requirement for the isolation of phages that infect abundant marine bacterial groups. In this study, we isolated and characterized HMO-2011, a phage infecting a bacterium of the SAR116 clade, one of the most abundant marine bacterial lineages. HMO-2011, which infects "Candidatus Puniceispirillum marinum" strain IMCC1322, has an ~55-kb dsDNA genome that harbors many genes with novel features rarely found in cultured organisms, including genes encoding a DNA polymerase with a partial DnaJ central domain and an atypical methanesulfonate monooxygenase. Furthermore, homologs of nearly all HMO-2011 genes were predominantly found in marine metagenomes rather than cultured organisms, suggesting the novelty of HMO-2011 and the prevalence of this phage type in the oceans. A significant number of the viral metagenome sequences obtained from the ocean surface were best assigned to the HMO-2011 genome. The number of reads assigned to HMO-2011 accounted for 10.3%-25.3% of the total reads assigned to viruses in seven viromes from the Pacific and Indian Oceans, making the HMO-2011 genome the most or second-most frequently assigned viral genome. Given its ability to infect the abundant SAR116 clade and its widespread distribution, Puniceispirillum phage HMO-2011 could be an important resource for marine virus research. PMID- 23798440 TI - Anxiety-associated alternative polyadenylation of the serotonin transporter mRNA confers translational regulation by hnRNPK. AB - The serotonin transporter (SERT) is a major regulator of serotonergic neurotransmission and anxiety-related behaviors. SERT is expressed in two alternative polyadenylation forms that differ by an evolutionarily conserved element in the 3' untranslated region of its mRNA. Expression of SERT mRNA containing the distal polyadenylation element is associated with decreased anxiety-related behaviors in mice and humans, suggesting that this element has behaviorally relevant modulatory effects on SERT expression. We have identified heterogeneous nuclear ribonucleoprotein K (hnRNPK), a protein known to integrate multiple signal transduction pathways with gene expression, as a SERT distal polyadenylation element binding protein. This interaction is functionally meaningful because genetic manipulation of hnRNPK alters expression of the SERT protein. Furthermore, the trophic factor S100beta induces Src-family kinase mediated tyrosine phosphorylation of hnRNPK and increased SERT expression. These results identify a previously unknown mechanism of regulated SERT expression and provide a putative mechanism by which the SERT distal polyadenylation element modulates anxiety-related behaviors. PMID- 23798441 TI - Vibrio effector protein, VopQ, forms a lysosomal gated channel that disrupts host ion homeostasis and autophagic flux. AB - Defects in normal autophagic pathways are implicated in numerous human diseases- such as neurodegenerative diseases, cancer, and cardiomyopathy--highlighting the importance of autophagy and its proper regulation. Herein we show that Vibrio parahaemolyticus uses the type III effector VopQ (Vibrio outer protein Q) to alter autophagic flux by manipulating the partitioning of small molecules and ions in the lysosome. This effector binds to the conserved Vo domain of the vacuolar-type H(+)-ATPase and causes deacidification of the lysosomes within minutes of entering the host cell. VopQ forms a gated channel ~18 A in diameter that facilitates outward flux of ions across lipid bilayers. The electrostatic interactions of this type 3 secretion system effector with target membranes dictate its preference for host vacuolar-type H(+)-ATPase-containing membranes, indicating that its pore-forming activity is specific and not promiscuous. As seen with other effectors, VopQ is exploiting a eukaryotic mechanism, in this case manipulating lysosomal homeostasis and autophagic flux through transmembrane permeation. PMID- 23798443 TI - Structural basis of cargo recognitions for class V myosins. AB - Class V myosins (MyoV), the most studied unconventional myosins, recognize numerous cargos mainly via the motor's globular tail domain (GTD). Little is known regarding how MyoV-GTD recognizes such a diverse array of cargos specifically. Here, we solved the crystal structures of MyoVa-GTD in its apo-form and in complex with two distinct cargos, melanophilin and Rab interacting lysosomal protein-like 2. The apo-MyoVa-GTD structure indicates that most mutations found in patients with Griscelli syndrome, microvillus inclusion disease, or cancers or in "dilute" rodents likely impair the folding of GTD. The MyoVa-GTD/cargo complex structure reveals two distinct cargo-binding surfaces, one primarily via charge-charge interaction and the other mainly via hydrophobic interactions. Structural and biochemical analysis reveal the specific cargo binding specificities of various isoforms of mammalian MyoV as well as very different cargo recognition mechanisms of MyoV between yeast and higher eukaryotes. The MyoVa-GTD structures resolved here provide a framework for future functional studies of vertebrate class V myosins. PMID- 23798442 TI - MS/MS networking guided analysis of molecule and gene cluster families. AB - The ability to correlate the production of specialized metabolites to the genetic capacity of the organism that produces such molecules has become an invaluable tool in aiding the discovery of biotechnologically applicable molecules. Here, we accomplish this task by matching molecular families with gene cluster families, making these correlations to 60 microbes at one time instead of connecting one molecule to one organism at a time, such as how it is traditionally done. We can correlate these families through the use of nanospray desorption electrospray ionization MS/MS, an ambient pressure MS technique, in conjunction with MS/MS networking and peptidogenomics. We matched the molecular families of peptide natural products produced by 42 bacilli and 18 pseudomonads through the generation of amino acid sequence tags from MS/MS data of specific clusters found in the MS/MS network. These sequence tags were then linked to biosynthetic gene clusters in publicly accessible genomes, providing us with the ability to link particular molecules with the genes that produced them. As an example of its use, this approach was applied to two unsequenced Pseudoalteromonas species, leading to the discovery of the gene cluster for a molecular family, the bromoalterochromides, in the previously sequenced strain P. piscicida JCM 20779(T). The approach itself is not limited to 60 related strains, because spectral networking can be readily adopted to look at molecular family-gene cluster families of hundreds or more diverse organisms in one single MS/MS network. PMID- 23798444 TI - Trade-off between curvature tuning and position invariance in visual area V4. AB - Humans can rapidly recognize a multitude of objects despite differences in their appearance. The neural mechanisms that endow high-level sensory neurons with both selectivity to complex stimulus features and "tolerance" or invariance to identity-preserving transformations, such as spatial translation, remain poorly understood. Previous studies have demonstrated that both tolerance and selectivity to conjunctions of features are increased at successive stages of the ventral visual stream that mediates visual recognition. Within a given area, such as visual area V4 or the inferotemporal cortex, tolerance has been found to be inversely related to the sparseness of neural responses, which in turn was positively correlated with conjunction selectivity. However, the direct relationship between tolerance and conjunction selectivity has been difficult to establish, with different studies reporting either an inverse or no significant relationship. To resolve this, we measured V4 responses to natural scenes, and using recently developed statistical techniques, we estimated both the relevant stimulus features and the range of translation invariance for each neuron. Focusing the analysis on tuning to curvature, a tractable example of conjunction selectivity, we found that neurons that were tuned to more curved contours had smaller ranges of position invariance and produced sparser responses to natural stimuli. These trade-offs provide empirical support for recent theories of how the visual system estimates 3D shapes from shading and texture flows, as well as the tiling hypothesis of the visual space for different curvature values. PMID- 23798445 TI - Self-organization of bacterial biofilms is facilitated by extracellular DNA. AB - Twitching motility-mediated biofilm expansion is a complex, multicellular behavior that enables the active colonization of surfaces by many species of bacteria. In this study we have explored the emergence of intricate network patterns of interconnected trails that form in actively expanding biofilms of Pseudomonas aeruginosa. We have used high-resolution, phase-contrast time-lapse microscopy and developed sophisticated computer vision algorithms to track and analyze individual cell movements during expansion of P. aeruginosa biofilms. We have also used atomic force microscopy to examine the topography of the substrate underneath the expanding biofilm. Our analyses reveal that at the leading edge of the biofilm, highly coherent groups of bacteria migrate across the surface of the semisolid media and in doing so create furrows along which following cells preferentially migrate. This leads to the emergence of a network of trails that guide mass transit toward the leading edges of the biofilm. We have also determined that extracellular DNA (eDNA) facilitates efficient traffic flow throughout the furrow network by maintaining coherent cell alignments, thereby avoiding traffic jams and ensuring an efficient supply of cells to the migrating front. Our analyses reveal that eDNA also coordinates the movements of cells in the leading edge vanguard rafts and is required for the assembly of cells into the "bulldozer" aggregates that forge the interconnecting furrows. Our observations have revealed that large-scale self-organization of cells in actively expanding biofilms of P. aeruginosa occurs through construction of an intricate network of furrows that is facilitated by eDNA. PMID- 23798446 TI - Diarylcoumarins inhibit mycolic acid biosynthesis and kill Mycobacterium tuberculosis by targeting FadD32. AB - Infection with the bacterial pathogen Mycobacterium tuberculosis imposes an enormous burden on global public health. New antibiotics are urgently needed to combat the global tuberculosis pandemic; however, the development of new small molecules is hindered by a lack of validated drug targets. Here, we describe the identification of a 4,6-diaryl-5,7-dimethyl coumarin series that kills M. tuberculosis by inhibiting fatty acid degradation protein D32 (FadD32), an enzyme that is required for biosynthesis of cell-wall mycolic acids. These substituted coumarin inhibitors directly inhibit the acyl-acyl carrier protein synthetase activity of FadD32. They effectively block bacterial replication both in vitro and in animal models of tuberculosis, validating FadD32 as a target for antibiotic development that works in the same pathway as the established antibiotic isoniazid. Targeting new steps in well-validated biosynthetic pathways in antitubercular therapy is a powerful strategy that removes much of the usual uncertainty surrounding new targets and in vivo clinical efficacy, while circumventing existing resistance to established targets. PMID- 23798447 TI - Biophysical mechanisms for large-effect mutations in the evolution of steroid hormone receptors. AB - The genetic and biophysical mechanisms by which new protein functions evolve is a central question in evolutionary biology, biochemistry, and biophysics. Of particular interest is whether major shifts in protein function are caused by a few mutations of large effect and, if they are, the mechanisms that mediate these changes. Here we combine ancestral protein reconstruction with genetic manipulation and explicit studies of protein structure and dynamics to dissect an ancient and discrete shift in ligand specificity in the steroid receptors, a family of biologically essential hormone-controlled transcription factors. We previously found that the ancestor of the entire steroid receptor family was highly specific for estrogens, but its immediate phylogenetic descendant was sensitive only to androgens, progestogens, and corticosteroids. Here we show that this shift in function was driven primarily by two historical amino acid changes, which caused a ~70,000-fold change in the ancestral protein's specificity. These replacements subtly changed the chemistry of two amino acids, but they dramatically reduced estrogen sensitivity by introducing an excess of interaction partners into the receptor/estrogen complex, inducing a frustrated ensemble of suboptimal hydrogen bond networks unique to estrogens. This work shows how the protein's architecture and dynamics shaped its evolution, amplifying a few biochemically subtle mutations into major shifts in the energetics and function of the protein. PMID- 23798449 TI - Heterogeneous-gold-catalyzed acceptorless cross-dehydrogenative coupling of hydrosilanes and isocyanic acid generated in situ from urea. PMID- 23798448 TI - Oxytocin blunts social vigilance in the rhesus macaque. AB - Exogenous application of the neuromodulatory hormone oxytocin (OT) promotes prosocial behavior and can improve social function. It is unclear, however, whether OT promotes prosocial behavior per se, or whether it facilitates social interaction by reducing a state of vigilance toward potential social threats. To disambiguate these two possibilities, we exogenously delivered OT to male rhesus macaques, which have a characteristic pattern of species-typical social vigilance, and examined their performance in three social attention tasks. We first determined that, in the absence of competing task demands or goals, OT increased attention to faces and eyes, as in humans. By contrast, OT reduced species typical social vigilance for unfamiliar, dominant, and emotional faces in two additional tasks. OT eliminated the emergence of a typical state of vigilance when dominant face images were available during a social image choice task. Moreover, OT improved performance on a reward-guided saccade task, despite salient social distractors: OT reduced the interference of unfamiliar faces, particularly emotional ones, when these faces were task irrelevant. Together, these results demonstrate that OT suppresses vigilance toward potential social threats in the rhesus macaque. We hypothesize that a basic role for OT in regulating social vigilance may have facilitated the evolution of prosocial behaviors in humans. PMID- 23798450 TI - Hydrophobic anticancer drug delivery by a 980 nm laser-driven photothermal vehicle for efficient synergistic therapy of cancer cells in vivo. AB - A novel 980 nm laser-driven hydrophobic anticancer drug-delivery platform based on hollow CuS nanoparticles is constructed in this work. The excellent synergistic therapy combining drug treatment and photothermal ablation of cancer cells both in vitro and in vivo is demonstrated, which opens up new opportunities for biological and medical applications. PMID- 23798451 TI - An unusual cause of empyema in a teenage boy. PMID- 23798452 TI - Federal Wi-Fi panel criticized for undisclosed conflict. PMID- 23798453 TI - Variation of a test's sensitivity and specificity with disease prevalence. AB - BACKGROUND: Anecdotal evidence suggests that the sensitivity and specificity of a diagnostic test may vary with disease prevalence. Our objective was to investigate the associations between disease prevalence and test sensitivity and specificity using studies of diagnostic accuracy. METHODS: We used data from 23 meta-analyses, each of which included 10-39 studies (416 total). The median prevalence per review ranged from 1% to 77%. We evaluated the effects of prevalence on sensitivity and specificity using a bivariate random-effects model for each meta-analysis, with prevalence as a covariate. We estimated the overall effect of prevalence by pooling the effects using the inverse variance method. RESULTS: Within a given review, a change in prevalence from the lowest to highest value resulted in a corresponding change in sensitivity or specificity from 0 to 40 percentage points. This effect was statistically significant (p < 0.05) for either sensitivity or specificity in 8 meta-analyses (35%). Overall, specificity tended to be lower with higher disease prevalence; there was no such systematic effect for sensitivity. INTERPRETATION: The sensitivity and specificity of a test often vary with disease prevalence; this effect is likely to be the result of mechanisms, such as patient spectrum, that affect prevalence, sensitivity and specificity. Because it may be difficult to identify such mechanisms, clinicians should use prevalence as a guide when selecting studies that most closely match their situation. PMID- 23798455 TI - Piezogenic pedal papules. PMID- 23798456 TI - Cyclotron production of medical isotopes scales up. PMID- 23798457 TI - Blood pressure targets in chronic kidney disease: does proteinuria dictate how low we go? PMID- 23798458 TI - Health Canada's new clinical trials database should be mandatory, says expert. PMID- 23798460 TI - Patent ruling expands access to genetic tests and treatments. PMID- 23798459 TI - Effects of intensive blood pressure lowering on the progression of chronic kidney disease: a systematic review and meta-analysis. AB - BACKGROUND: Recent guidelines suggest lowering the target blood pressure for patients with chronic kidney disease, although the strength of evidence for this suggestion has been uncertain. We sought to assess the renal and cardiovascular effects of intensive blood pressure lowering in people with chronic kidney disease. METHODS: We performed a systematic review and meta-analysis of all relevant reports published between 1950 and July 2011 identified in a search of MEDLINE, Embase and the Cochrane Library. We included randomized trials that assigned patients with chronic kidney disease to different target blood pressure levels and reported kidney failure or cardiovascular events. Two reviewers independently identified relevant articles and extracted data. RESULTS: We identified 11 trials providing information on 9287 patients with chronic kidney disease and 1264 kidney failure events (defined as either a composite of doubling of serum creatinine level and 50% decline in glomerular filtration rate, or end stage kidney disease). Compared with standard regimens, a more intensive blood pressure-lowering strategy reduced the risk of the composite outcome (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.68-0.98) and end-stage kidney disease (HR 0.79, 95% CI 0.67-0.93). Subgroup analysis showed effect modification by baseline proteinuria (p = 0.006) and markers of trial quality. Intensive blood pressure lowering reduced the risk of kidney failure (HR 0.73, 95% CI 0.62-0.86), but not in patients without proteinuria at baseline (HR 1.12, 95% CI 0.67-1.87). There was no clear effect on the risk of cardiovascular events or death. INTERPRETATION: Intensive blood pressure lowering appears to provide protection against kidney failure events in patients with chronic kidney disease, particularly among those with proteinuria. More data are required to determine the effects of such a strategy among patients without proteinuria. PMID- 23798461 TI - Nutrition information noticed in restaurants if on menu. PMID- 23798463 TI - An extended dysfunctional area in the congestive area of the remnant liver after hemi-hepatectomy with middle hepatic vein resection for liver cancers evaluated on the gadoxetic acid disodium-enhanced magnetic resonance imaging. AB - BACKGROUND: The aim of the present study was to evaluate the liver function in the congestive area of the remnant liver after hemi-hepatectomy with middle hepatic vein (MHV) resection for liver cancers. METHODS: From November 2009 through December 2012, 18 patients underwent hemi-hepatectomy including the MHV for liver cancers. Post-hepatectomy, the volume of the congestive area, which appeared as a hyper-intense area on T2-weighted images and dysfunctional area, which appeared as a low intensity area on hepatobiliary phase images in the remnant liver was evaluated in all patients by gadoxetic acid disodium-enhanced magnetic resonance imaging. RESULTS: Fifteen of 18 patients showed a congestive area, and 16 of 18 patients showed a dysfunctional area in the remnant liver. The dysfunctional rate (median 11%) was significantly larger than the congestive rate (median 5%, P = 0.0004). The dysfunctional rate was associated with tumor invasion to the root of the MHV, and no tumor invasion to the root of the MHV was identified as a significant predictor of a larger dysfunctional area (odds ratio 25.888, P = 0.0267) on multivariate analysis. CONCLUSION: Hemi-hepatectomy with MHV resection for liver cancers should be performed considering the dysfunctional area in the remnant liver, which is associated with tumor invasion to the root of the MHV. PMID- 23798464 TI - Rising stars and sinking ships: consequences of status momentum. AB - Differences in rank are a ubiquitous feature of social life. Moving beyond the traditional static view of social hierarchy, five studies spanning multiple contexts examined how intertemporal changes in rank influenced people's status judgments. When final rank was held constant, people, products, and institutions were judged as higher status when they had arrived at this position by ascending, rather than descending, the hierarchy; moreover, these judgments affected downstream pricing recommendations, willingness to pay for products, and influence accepted from others. This impact of rank history on status judgments was accounted for by expectations of future status and moderated by the involvement of the self: The self and others are afforded an equivalent status boost for ascending to a given rank; however, only the self is pardoned the status tax that is levied on others for descending to the same rank. The theoretical utility of a dynamic approach to social hierarchy is discussed. PMID- 23798466 TI - Feedback field control improves linewidths in in vivo magnetic resonance spectroscopy. AB - PURPOSE: Magnetic resonance spectroscopy (MRS) experiments rely on a homogeneous and stable magnetic field within the sample. Field homogeneity is typically optimized by static B0 shimming while reproducible effects from dynamic field variation are commonly diminished by means of gradient system calibration as well as calibration based on non-water suppressed reference data. However, residual encoding deficiencies from incomplete calibration and nonreproducible field perturbations deteriorate the quality of the obtained data. To overcome this problem, we propose to adapt higher-order feedback field control based on NMR field probes for its application in MRS. METHODS: To allow for field measurements simultaneously with the spectroscopy readout, radiofrequency-shielded field probes were employed. The setup was evaluated in vitro and tested in vivo for single-voxel MRS at 7T to correct for field perturbations that occur due to subject breathing and limb motion. RESULTS: The in vitro experiments showed an effective field control during the MRS sequence. The resulting spectroscopy data were free of spurious signal and the achieved field stabilization improved the spectral resolution in vitro and in vivo. CONCLUSION: High-field MRS is limited by nonreproducible field perturbations for which spatiotemporal field feedback provides a solution without compromising sequence timing and efficiency. PMID- 23798465 TI - Common polymorphic deletion of glutathione S-transferase theta predisposes to acquired aplastic anemia: Independent cohort and meta-analysis of 609 patients. AB - Acquired aplastic anemia (AA) is a rare life-threatening bone marrow failure syndrome, caused by autoimmune destruction of hematopoietic stem and progenitor cells. Epidemiologic studies suggest that environmental exposures and metabolic gene polymorphisms contribute to disease pathogenesis. Several case-control studies linked homozygous deletion of the glutathione S-transferase theta (GSTT1) gene to AA; however, the role of GSTT1 deletion remains controversial as other studies failed to confirm the association. We asked whether a more precise relationship between the GSTT1 null polymorphism and aplastic anemia could be defined using a meta-analysis of 609 aplastic anemia patients, including an independent cohort of 67 patients from our institution. We searched PubMed, Embase, and the Cochrane Database for studies evaluating the association between GSTT1 null genotype and development of AA. Seven studies, involving a total of 609 patients and 3,914 controls, fulfilled the eligibility criteria. Meta analysis revealed a significant association of GSTT1 null genotype and AA, with an OR = 1.74 (95% CI 1.31-2.31, P < 0.0001). The effect was not driven by any one individual result, nor was there evidence of significant publication bias. The association between AA and GSTT1 deletion suggests a role of glutathione conjugation in AA, possibly through protecting the hematopoietic compartment from endogenous metabolites or environmental exposures. We propose a model whereby protein adducts generated by reactive metabolites serve as neo-epitopes to trigger autoimmunity in aplastic anemia. PMID- 23798467 TI - Sedation in infant pulmonary function testing. PMID- 23798468 TI - Fabrication and assembly of magneto-responsive, anisotropic, and hybrid microparticles of variable size and shape. PMID- 23798469 TI - Dielectrophoretically aligned carbon nanotubes to control electrical and mechanical properties of hydrogels to fabricate contractile muscle myofibers. AB - Dielectrophoresis is used to align carbon nanotubes (CNTs) within gelatin methacrylate (GelMA) hydrogels in a facile and rapid manner. Aligned GelMA-CNT hydrogels show higher electrical properties compared with pristine and randomly distributed CNTs in GelMA hydrogels. The muscle cells cultured on these materials demonstrate higher maturation compared with cells cultured on pristine and randomly distributed CNTs in GelMA hydrogels. PMID- 23798470 TI - Hypoxia inducible factor-1 alpha plays a pivotal role in hepatic metastasis of pancreatic cancer: an immunohistochemical study. AB - BACKGROUND: Hypoxia is an important condition to promote angiogenesis that is essential to tumor progression, including pancreatic ductal adenocarcinoma (PDAC). We evaluated whether the immunohistochemistry for hypoxia inducible factor-1alpha (HIF-1alpha) was correlated with hepatic metastases in PDAC. METHODS: We examined the expression of HIF-1alpha, vascular endothelial growth factor-A (VEGF-A), thymidine phosphorylase (TP) and basic fibroblast growth factor (bFGF) in a total of 100 paraffin-embedded PDAC primary tumors using immunohistochemical staining, and assessed their clinicopathological correlations. We determined microvessel count (MVC) and apoptotic index (AI), and assessed their correlations with hepatic metastases. Student's t-test, the Mann Whitney U-test, and Spearman correlation coefficients were used to validate the model, and regression analysis was used to test the model. RESULTS: Hypoxia inducible factor-1alpha expression induced the expression of multiple angiogenic factors, leading to a higher MVC and a lower AI. HIF-1alpha expression (P = 0.0087) and angiogenic factors (P = 0.0079) were significantly associated with not only the microvessel status (P = 0.022) but also the high incidence of hepatic metastasis (P = 0.02), resulting in the worse survival of PDAC patients (P < 0.05). CONCLUSIONS: Hypoxia inducible factor-1alpha plays a pivotal role in hepatic metastasis through its association with the expression of angiogenic factors in PDAC patients. These results may contribute future therapeutic strategies to prevent pancreatic cancer metastasis. PMID- 23798471 TI - Chaperone-like effects of a scFv antibody on the folding of human muscle creatine kinase. AB - Molecular chaperones play an essential role in assisting the folding of a myriad of nascent peptides to form different biologically active proteins. Therefore, their low substrate specificity is important for the functions of these housekeeping proteins. However, discovering chaperones which assist the folding of a particular protein can shed new light on the folding pathway of the protein, offering an interesting approach for developing specific therapeutic agents to treat protein-misfolding diseases. Screening of antibodies with chaperone-like function represents a novel strategy to meet the challenges. In this study, some single-chain variable fragment (scFv) antibodies were selected from a high capacity phage antibody library using human muscle creatine kinase (HCK) as antigen. A scFv antibody (scFv A4) was determined to inhibit aggregation and favor recovery of the native conformation of HCK during its refolding. This antibody also increased the stability of HCK during its heat-induced unfolding process. Our findings demonstrate that scFv A4 has dual-chaperone-like activities: assisting in correct protein folding as well as protecting the native protein from unfolding. A molecular mechanism by which scFv A4 exhibits chaperone like effects on HCK was proposed. This study demonstrates that phage antibody libraries can lead to chaperone-like proteins, and the specificity of the resulting antibody toward its antigen could provide new molecular details regarding how the chaperone interacts with the protein's unfolding and folding pathways. PMID- 23798472 TI - Everolimus treatment of refractory epilepsy in tuberous sclerosis complex. AB - OBJECTIVE: Epilepsy is a major manifestation of tuberous sclerosis complex (TSC). Everolimus is an mammalian target of rapamycin complex 1 inhibitor with demonstrated benefit in several aspects of TSC. We report the first prospective human clinical trial to directly assess whether everolimus will also benefit epilepsy in TSC patients. METHODS: The effect of everolimus on seizure control was assessed using a prospective, multicenter, open-label, phase I/II clinical trial. Patients>=2 years of age with confirmed diagnosis of TSC and medically refractory epilepsy were treated for a total of 12 weeks. The primary endpoint was percentage of patients with a >=50% reduction in seizure frequency over a 4 week period before and after treatment. Secondary endpoints assessed impact on electroencephalography (EEG), behavior, and quality of life. RESULTS: Twenty three patients were enrolled, and 20 patients were treated with everolimus. Seizure frequency was reduced by >=50% in 12 of 20 subjects. Overall, seizures were reduced in 17 of the 20 by a median reduction of 73% (p<0.001). Seizure frequency was also reduced during 23-hour EEG monitoring (p=0.007). Significant reductions in seizure duration and improvement in parent-reported behavior and quality of life were also observed. There were 83 reported adverse events that were thought to be treatment-related, all of which were mild or moderate in severity. INTERPRETATION: Seizure control improved in the majority of TSC patients with medically refractory epilepsy following treatment with everolimus. Everolimus demonstrated additional benefits on behavior and quality of life. Treatment was safe and well tolerated. Everolimus may be a therapeutic option for refractory epilepsy in this population. PMID- 23798473 TI - Hyperpolarized butyrate: a metabolic probe of short chain fatty acid metabolism in the heart. AB - PURPOSE: Butyrate, a short chain fatty acid, was studied as a novel hyperpolarized substrate for use in dynamic nuclear polarization enhanced magnetic resonance spectroscopy experiments, to define the pathways of short chain fatty acid and ketone body metabolism in real time. METHODS: Butyrate was polarized via the dynamic nuclear polarization process and subsequently dissolved to generate an injectable metabolic substrate. Metabolism was initially assessed in the isolated perfused rat heart, followed by evaluation in the in vivo rat heart. RESULTS: Hyperpolarized butyrate was generated with a polarization level of 7% and was shown to have a T1 relaxation time of 20 s. These physical characteristics were sufficient to enable assessment of multiple steps in its metabolism, with the ketone body acetoacetate and several tricarboxylic acid cycle intermediates observed both in vitro and in vivo. Metabolite to butyrate ratios of 0.1-0.4% and 0.5-2% were observed in vitro and in vivo respectively, similar to levels previously observed with hyperpolarized [2-(13) C]pyruvate. CONCLUSIONS: In this study, butyrate has been demonstrated to be a suitable hyperpolarized substrate capable of revealing multi-step metabolism in dynamic nuclear polarization experiments and providing information on the metabolism of fatty acids not currently achievable with other hyperpolarized substrates. PMID- 23798475 TI - Infrared spectra of cyanoacetaldehyde (NCCH2CHO): a potential prebiotic compound of astrochemical interest. AB - Cyanoacetaldehyde (NC-CH2CH=O) and its isomer, cyanovinylalcohol (NC-CH=CH-OH), as possible components of the interstellar medium, comets, or planetary atmospheres, exist in equilibrium in the gas phase, although the latter compound is very much in the minority (2%). The recording and analysis of the gas-phase infrared spectrum of the former compound within the 4000-500 cm(-1) spectroscopic range and the potential presence of the latter isomer, which could be vital for their detection in these media, are reported. CCSD(T) and G4 high-level ab initio methods, as well as density functional theory calculations, predict the existence of two stable rotamers of cyanoacetaldehyde. The global minimum has a structure with an unusual O-C-C-C dihedral angle (150 degrees ) that falls between the antiperiplanar (180 degrees ) and anticlinal forms (120 degrees ). The second rotamer, which is about 4.0 kJ mol(-1) less stable in terms of free energy, has a planar structure that corresponds to the synperiplanar form (O-C-C-C dihedral angle: 0 degrees ). The absorption vibrational bands of the two aldehyde rotamers that are present in the mixture lead to a spectrum with a very complex structure in the region of deformation movements, in which several low-intensity bands overlap. A complete and unambiguous assignment of the experimental spectrum has been achieved by using the calculated harmonic and anharmonic vibrational frequencies. PMID- 23798474 TI - Diffuse lung disease in children: summary of a scientific conference. AB - A multi-disciplinary scientific conference focused on diffuse and interstitial lung diseases in children was held in La Jolla, CA in June 2012. The conference brought together clinicians (including Pediatric and Adult Pulmonologists, Neonatologists, Pathologists, and Radiologists), clinical researchers, basic scientists, government agency representatives, patient advocates, as well as children affected by diffuse lung disease (DLD) and their families, to review recent scientific developments and emerging concepts in the pathophysiology of childhood DLD. Invited speakers discussed translational approaches, including genetics and proteomics, epigenetics and epigenomics, models of DLD, including animal models and induced pluripotent stem cells, and regenerative medicine approaches. The presentations of the invited speakers are summarized here. PMID- 23798476 TI - Facile fabrication of single-crystal-diamond nanostructures with ultrahigh aspect ratio. AB - A robust and facile approach for making single-crystal-diamond MEMS and NEMS devices is presented. The approach relies entirely on commercial diamond material and standard cleanroom processes. As an example, batch fabrication of cantilever beams of thickness down to 45 nm and aspect ratios exceeding 2000:1 is demonstrated. PMID- 23798477 TI - Successful single-session endosonography-based endoscopic retrograde cholangiopancreatography without fluoroscopy in pregnant patients with suspected choledocholithiasis: a case series. AB - PURPOSE: Same session endosonography (EUS) immediately prior to scheduled endoscopic retrograde cholangiopancreatography (ERCP) may eliminate the need for ERCP and its associated risks in pregnant patients with no evidence of choledocholithiasis on EUS. In patients with choledocholithiasis, EUS provides information regarding the location, size and number of stones present, which helps guide biliary interventions and confirm stone clearance without the use of fluoroscopy. METHODS: We retrospectively identified 10 pregnant patients referred to our tertiary endoscopy center for suspected choledocholithiasis between June 2008 and January 2012. All patients underwent same-session EUS-based ERCP. RESULTS: Of 10 pregnant patients managed with EUS-guided ERCP, six were found to have common bile duct stones and went on to ERCP. Four patients with no evidence of choledocholithiasis on EUS did not undergo ERCP. Patients with confirmed choledocholithiasis underwent ERCP without the use of fluoroscopy using the additional information provided by EUS. CONCLUSIONS: Same-session EUS immediately prior to scheduled ERCP may eliminate the need for ERCP and its risks in pregnant patients with no evidence of choledocholithiasis on EUS. In patients with confirmed choledocholithiasis, EUS provided additional information regarding the location, number and size of bile duct stones, which enabled the successful clearance of the bile duct without the use of fluoroscopy. PMID- 23798478 TI - Recent temporal trends in sleep duration, domain-specific sedentary behaviour and physical activity. A survey among 25-79-year-old Danish adults. AB - BACKGROUND: Prevalence of sedentary behaviour is high in many countries, but little is known about temporal trends in sitting time. OBJECTIVE: To examine temporal changes in sleep and domain-specific sedentary behaviour and moderate to vigorous leisure time physical activity (MVPA). METHODS: Two cross-sectional population-based surveys of 25-79-year-old inhabitants were conducted in The Capital Region of Denmark in 2007 (N = 69.800, response rate 52.3%) and 2010 (N = 77.517, response rate 54.8%). Information on sedentary behaviour and physical activity was obtained from self-report questionnaire and sociodemographic information from central registers. Data were weighted for survey design and for non-response and were analysed by multiple regression analyses. RESULTS: In 2007, the entire survey population reported a mean daily sleeping duration of 7.4 hours, leisure time sitting of 3.4 hours per day, occupational sitting of 4.4 hours per day, MVPA of 0.87 hours per day and a total 24-hour energy expenditure of 40.12 METs per day. In 2010, duration of sleep was unaltered (p = 0.1), sedentary leisure time and sedentary work time had increased by 12.6 minutes (p < 0.0001) and 13.2 minutes (p < 0.0001) per day, respectively. Time spent on MVPA had increased by 2.9 minutes per day (p < 0.0001). The 24-hour energy expenditure had decreased by 0.41 METs (p < 0.0001). CONCLUSIONS: Adult Danish men and women spend an increased amount of time sitting down at work and during leisure time, but also on leisure time MVPA. As duration of sleep is unaltered findings suggest that low intensity physical activity may be displaced in everyday life. PMID- 23798479 TI - Airway inflammation and bronchial hyperreactivity in steroid naive children with intermittent and mild persistent asthma. AB - BACKGROUND: Intermittent and mild persistent asthma are defined according to symptom frequency and spirometry and treated differently. To our knowledge, there is no study comparing airway inflammation between intermittent and mild persistent asthmatic children. MATERIALS AND METHODS: Children aged 7-16 years, referred to our pediatric allergy clinic for recurrent respiratory complaints underwent a detailed clinical history and spirometry with reversibility. None of the subjects had been using regular anti-inflammatory treatment. After a 2-week run-in period during which asthma symptoms were recorded, exhaled NO measurement, bronchial provocation test with adenosine monophosphate and methacholine and sputum induction were performed. Data of patients with intermittent and mild persistent asthma and a control group were compared. RESULTS: Thirty intermittent, 26 mild persistent asthmatic children, and 21 control subjects were studied. Sputum was obtained from 19 of intermittent asthmatics (63.3%), 18 of mild persistent asthmatics (69.2%), and 13 of control subjects (61.9%). Eosinophil count and exhaled nitric oxide were not different between asthmatic groups. Neutrophil count of children with mild persistent asthma was higher than the intermittent asthmatic group (P = 0.003). Geometric mean of PC20 methacoline values were not different between groups (P = 0.058). Geometric mean of PC20 AMP was lower among patients with mild persistent asthma (P = 0.102). CONCLUSION: Eosinophilic airway inflammation and direct BHR may not be significantly different in intermittent asthmatic children from their peers with mild persistent disease. Neutrophilic airway inflammation and BHR to an indirect stimuli are more pronounced in the mild persistent group. PMID- 23798480 TI - Novel likelihood ratio tests for screening gene-gene and gene-environment interactions with unbalanced repeated-measures data. AB - There has been extensive literature on modeling gene-gene interaction (GGI) and gene-environment interaction (GEI) in case-control studies with limited literature on statistical methods for GGI and GEI in longitudinal cohort studies. We borrow ideas from the classical two-way analysis of variance literature to address the issue of robust modeling of interactions in repeated-measures studies. While classical interaction models proposed by Tukey and Mandel have interaction structures as a function of main effects, a newer class of models, additive main effects and multiplicative interaction (AMMI) models, do not have similar restrictive assumptions on the interaction structure. AMMI entails a singular value decomposition of the cell residual matrix after fitting the additive main effects and has been shown to perform well across various interaction structures. We consider these models for testing GGI and GEI from two perspectives: likelihood ratio test based on cell means and a regression-based approach using individual observations. Simulation results indicate that both approaches for AMMI models lead to valid tests in terms of maintaining the type I error rate, with the regression approach having better power properties. The performance of these models was evaluated across different interaction structures and 12 common epistasis patterns. In summary, AMMI model is robust with respect to misspecified interaction structure and is a useful screening tool for interaction even in the absence of main effects. We use the proposed methods to examine the interplay between the hemochromatosis gene and cumulative lead exposure on pulse pressure in the Normative Aging Study. PMID- 23798481 TI - Polyglucosan body myopathy caused by defective ubiquitin ligase RBCK1. AB - Glycogen storage diseases are important causes of myopathy and cardiomyopathy. We describe 10 patients from 8 families with childhood or juvenile onset of myopathy, 8 of whom also had rapidly progressive cardiomyopathy, requiring heart transplant in 4. The patients were homozygous or compound heterozygous for missense or truncating mutations in RBCK1, which encodes for a ubiquitin ligase, and had extensive polyglucosan accumulation in skeletal muscle and in the heart in cases of cardiomyopathy. We conclude that RBCK1 deficiency is a frequent cause of polyglucosan storage myopathy associated with progressive muscle weakness and cardiomyopathy. PMID- 23798482 TI - The "megalencephaly-capillary malformation" (MCAP) syndrome: the nomenclature of a highly recognizable multiple congenital anomaly syndrome. PMID- 23798483 TI - Recent advances and problems in the management of pancreaticobiliary maljunction: feedback from the guidelines committee. AB - Clinical practice guidelines on how to deal with pancreaticobiliary maljunction (PBM) were made in Japan in 2012, representing a world first. Using a narrow definition, congenital biliary dilatation involves only Todani type I (except type Ib) and type IV-A, both of which are accompanied by PBM in almost all cases. Prospective ultrasonographic study revealed that the maximum diameter of the common bile duct increased with age. Pathophysiological conditions due to pancreatobiliary reflux occur in patients with high confluence of the pancreaticobiliary ducts, a common channel >= 6 mm long and occlusion of communication during contraction of the sphincter of Oddi. Since PBM can be diagnosed by magnetic resonance cholangiopancreatography, multi-planar reconstruction multi-detector row computed tomography and endoscopic ultrasonography, the current diagnostic criteria should be revised to take these diagnostic imaging modalities into consideration. According to a nationwide survey, biliary cancer occurred in 21.6% of adult patients with PBM with biliary dilatation and 42.2% of patients with PBM without biliary dilatation. In biliary cancer associated with PBM without biliary dilatation, 88.1% were gallbladder cancer. Treatment for PBM with biliary dilatation is prophylactic flow-diversion surgery, but further investigations and surveillance studies are needed to clarify the appropriate surgical strategy for PBM without biliary dilatation. PMID- 23798486 TI - High-performance ZnO transistors processed via an aqueous carbon-free metal oxide precursor route at temperatures between 80-180 degrees C. AB - An aqueous and carbon-free metal-oxide precursor route is used in combination with a UV irradiation-assisted low-temperature conversion method to fabricate low voltage ZnO transistors with electron mobilities exceeding 10 cm(2) /Vs at temperatures <180 degrees C. Because of its low temperature requirements the method allows processing of high-performance transistors onto temperature sensitive substrates such as plastic. PMID- 23798485 TI - Much of late life cognitive decline is not due to common neurodegenerative pathologies. AB - OBJECTIVE: The pathologic indices of Alzheimer disease, cerebrovascular disease, and Lewy body disease accumulate in the brains of older persons with and without dementia, but the extent to which they account for late life cognitive decline remains unknown. We tested the hypothesis that these pathologic indices account for the majority of late life cognitive decline. METHODS: A total of 856 deceased participants from 2 longitudinal clinical-pathologic studies, Rush Memory and Aging Project and Religious Orders Study, completed a mean of 7.5 annual evaluations, including 17 cognitive tests. Neuropathologic examinations provided quantitative measures of global Alzheimer pathology, amyloid load, tangle density, macroscopic infarcts, microinfarcts, and neocortical Lewy bodies. Random coefficient models were used to examine the linear relation of pathologic indices with global cognitive decline. In subsequent analyses, random change point models were used to examine the relation of the pathologic indices with the onset of terminal decline and rates of preterminal and terminal decline (ie, nonlinear decline). RESULTS: Cognition declined a mean of about 0.11 U per year (estimate = -0.109, standard error [SE] = 0.004, p < 0.001), with significant individual differences in rates of decline; the variance estimate for the individual slopes was 0.013 (SE = 0.112, p < 0.001). In separate analyses, global Alzheimer pathology, amyloid, tangles, macroscopic infarcts, and neocortical Lewy bodies were associated with faster rates of decline and explained 22%, 6%, 34%, 2%, and 8% of the variation in decline, respectively. When analyzed simultaneously, the pathologic indices accounted for a total of 41% of the variation in decline, and the majority remained unexplained. Furthermore, in random change point models examining the influence of the pathologic indices on the onset of terminal decline and the preterminal and terminal components of the cognitive trajectory, the common pathologic indices accounted for less than a third of the variation in the onset of terminal decline and rates of preterminal and terminal decline. INTERPRETATION: The pathologic indices of the common causes of dementia are important determinants of cognitive decline in old age and account for a large proportion of the variation in late life cognitive decline. Surprisingly, however, much of the variation in cognitive decline remains unexplained, suggesting that other important determinants of cognitive decline remain to be identified. Identification of the mechanisms that contribute to the large unexplained proportion of cognitive decline is urgently needed to prevent late life cognitive decline. PMID- 23798487 TI - Free light chain content in culture media reflects recombinant monoclonal antibody productivity and quality. AB - Monoclonal antibodies (mAbs) are currently the dominant class of biopharmaceuticals. Due to the high dosage requirements of most mAb therapeutics, high productivity and low aggregation are prevailing criteria during cell line generation and process development. Given that light chains (LCs) play an important role in antibody folding and assembly, and that most mAb producing cell lines also manufacture free LCs, we sought to investigate whether there was a relationship between free LC levels in cell culture media and mAb productivity/quality. To this end, a series of analytical methods were developed in order to quantify free LC content in cell culture media and assess mAb productivity and aggregation levels. Afterwards, conditioned media samples from different cell lines at identical culturing conditions and a single clone under varying culturing conditions were analyzed. Higher LC expression was found to correlate with higher cell viability, higher mAb productivity, and lower aggregation. While LC expression cannot yet be definitively considered the root cause of these phenomena, these results are consistent with the role of LCs in mAb production, suggesting that free LC expression levels may potentially serve as a parameter for cell line generation and cell culture process optimization. PMID- 23798488 TI - Body mass index (BMI): the case for condition-specific cut-offs for overweight and obesity in skeletal dysplasias. PMID- 23798484 TI - Statistical genetic analysis of serological measures of common, chronic infections in Alaska Native participants in the GOCADAN study. AB - This paper describes genetic investigations of seroreactivity to five common infectious pathogens in the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) study. Antibody titers and seroprevalence were available for 495 to 782 (depending on the phenotype) family members at two time points, approximately 15 years apart, for Chlamydophila pneumoniae, Helicobacter pylori, cytomegalovirus (CMV), herpes simplex virus 1 (HSV-1), and herpes simplex virus 2 (HSV-2). Seroprevalence rates indicate that infections with most of these pathogens are common (>=20% for all of them, >80% for H. pylori, CMV, and HSV-1). Seropositive individuals typically remain seropositive over time, with seroreversion rates of <1% to 10% over ~15 years. Antibody titers were significantly heritable for most pathogens, with the highest estimate being 0.61 for C. pneumoniae. Significant genome-wide linkage evidence was obtained for C. pneumoniae on chromosome 15 (logarithm of odds, LOD score of 3.13). These results demonstrate that individual host genetic differences influence antibody measures of common infections in this population, and further investigation may elucidate the underlying immunological processes and genes involved. PMID- 23798489 TI - eFG: an electronic resource for Fusarium graminearum. AB - Fusarium graminearum is a plant pathogen, which causes crop diseases and further leads to huge economic damage worldwide in past decades. Recently, the accumulation of different types of molecular data provides insights into the pathogenic mechanism of F. graminearum, and might help develop efficient strategies to combat this destructive fungus. Unfortunately, most available molecular data related to F. graminearum are distributed in various media, where each single source only provides limited information on the complex biological systems of the fungus. In this work, we present a comprehensive database, namely eFG (Electronic resource for Fusarium graminearum), to the community for further understanding this destructive pathogen. In particular, a large amount of functional genomics data generated by our group is deposited in eFG, including protein subcellular localizations, protein-protein interactions and orthologous genes in other model organisms. This valuable knowledge can not only help to disclose the molecular underpinnings of pathogenesis of the destructive fungus F. graminearum but also help the community to develop efficient strategies to combat this pathogen. To our best knowledge, eFG is the most comprehensive functional genomics database for F. graminearum until now. The eFG database is freely accessible at http://csb.shu.edu.cn/efg/ with a user-friendly and interactive interface, and all data can be downloaded freely. DATABASE URL: http://csb.shu.edu.cn/efg/ PMID- 23798490 TI - Virus immobilization on biomaterial scaffolds through biotin-avidin interaction for improving bone regeneration. AB - To spatially control therapeutic gene delivery for potential tissue engineering applications, a biotin-avidin interaction strategy was applied to immobilize viral vectors on biomaterial scaffolds. Both adenoviral vectors and gelatin sponges were biotinylated and avidin was applied to link them in a virus-biotin avidin-biotin-material (VBABM) arrangement. The tethered viral particles were stably maintained within scaffolds and SEM images illustrated that viral particles were evenly distributed in three-dimensional (3D) gelatin sponges. An in vivo study demonstrated that transgene expression was restricted to the implant sites only and transduction efficiency was improved using this conjugation method. For an orthotopic bone regeneration model, adenovirus encoding BMP-2 (AdBMP2) was immobilized to gelatin sponges before implanting into critical-sized bone defects in rat calvaria. Compared to gelatin sponges with AdBMP2 loaded in a freely suspended form, the VBABM method enhanced gene transfer and bone regeneration was significantly improved. These results suggest that biotin-avidin immobilization of viral vectors to biomaterial scaffolds may be an effective strategy to facilitate tissue regeneration. PMID- 23798491 TI - Modulation of homomeric and heteromeric kainate receptors by the auxiliary subunit Neto1. AB - The ionotropic glutamate receptors are primary mediators of fast excitatory neurotransmission, and their properties are determined both by their subunit composition and their association with auxiliary subunits. The neuropilin and tolloid-like 1 and 2 proteins (Neto1 and Neto2) have been recently identified as auxiliary subunits for kainate-type glutamate receptors. Heteromeric kainate receptors (KARs) can be assembled from varying combinations of low-affinity (GluK1-GluK3) and high-affinity (GluK4-GluK5) subunits. To better understand the functional impact of auxiliary subunits on KARs, we examined the effect of Neto1 on the responses of recombinant homomeric and heteromeric KARs to varying concentrations of glutamate. We found that co-expression of Neto1 with homomeric GluK2 receptors had a small effect on sensitivity of the receptors to glutamate, but decreased the onset of desensitization while speeding recovery from desensitization. In the absence of Neto1, addition of GluK5 subunits to form GluK2/GluK5 heteromeric receptors slowed the onset of desensitization at low glutamate concentrations, compared with GluK2 homomers. Co-expression of Neto1 with GluK2/GluK5 receptors further enhanced these effects, essentially eliminating desensitization at MUm glutamate concentrations without altering the EC50 for activation by glutamate. In addition, a prominent rebound current was observed upon removal of the agonist. The rate of recovery from desensitization was increased to the same degree by Neto1 for both homomeric GluK2 and heteromeric GluK2/GluK5 receptors. Expression of Neto1 with GluK1/GluK5, GluK3/GluK5 or GluK2/GluK4 receptors produced qualitatively similar effects on whole-cell currents, suggesting that the impact of Neto1 on the desensitization properties of heteromeric receptors was not subunit dependent. These results provide greater insight into the functional effects of the auxiliary subunit Neto1 on both homomeric and heteromeric KARs. Alteration of the characteristics of desensitization at both sub-maximal and saturating glutamate concentrations could influence the responsiveness of these receptors to repeated stimuli. As a result, assembly of KARs with the Neto auxiliary subunits could change the kinetic properties of the neuronal response to glutamatergic input. PMID- 23798492 TI - Placement of implantable cardioverter-defibrillators in paediatric and congenital heart defect patients: a pipeline for model generation and simulation prediction of optimal configurations. AB - There is currently no reliable way of predicting the optimal implantable cardioverter-defibrillator (ICD) placement in paediatric and congenital heart defect (CHD) patients. This study aimed to: (1) develop a new image processing pipeline for constructing patient-specific heart-torso models from clinical magnetic resonance images (MRIs); (2) use the pipeline to determine the optimal ICD configuration in a paediatric tricuspid valve atresia patient; (3) establish whether the widely used criterion of shock-induced extracellular potential (Phie) gradients >=5 V cm(-1) in >=95% of ventricular volume predicts defibrillation success. A biophysically detailed heart-torso model was generated from patient MRIs. Because transvenous access was impossible, three subcutaneous and three epicardial lead placement sites were identified along with five ICD scan locations. Ventricular fibrillation was induced, and defibrillation shocks were applied from 11 ICD configurations to determine defibrillation thresholds (DFTs). Two configurations with epicardial leads resulted in the lowest DFTs overall and were thus considered optimal. Three configurations shared the lowest DFT among subcutaneous lead ICDs. The Phie gradient criterion was an inadequate predictor of defibrillation success, as defibrillation failed in numerous instances even when 100% of the myocardium experienced such gradients. In conclusion, we have developed a new image processing pipeline and applied it to a CHD patient to construct the first active heart-torso model from clinical MRIs. PMID- 23798493 TI - The coupling of plasma membrane calcium entry to calcium uptake by endoplasmic reticulum and mitochondria. AB - Cross-talk between organelles and plasma membrane Ca(2+) channels is essential for modulation of the cytosolic Ca(2+) ([Ca(2+)]C) signals, but such modulation may differ among cells. In chromaffin cells Ca(2+) entry through voltage-operated channels induces calcium release from the endoplasmic reticulum (ER) that amplifies the signal. [Ca(2+)]C microdomains as high as 20-50 MUm are sensed by subplasmalemmal mitochondria, which accumulate large amounts of Ca(2+) through the mitochondrial Ca(2+) uniporter (MCU). Mitochondria confine the high-Ca(2+) microdomains (HCMDs) to beneath the plasma membrane, where exocytosis of secretory vesicles happens. Cell core [Ca(2+)]C is much smaller (1-2 MUm). By acting as a Ca(2+) sink, mitochondria stabilise the HCMD in space and time. In non-excitable HEK293 cells, activation of store-operated Ca(2+) entry, triggered by ER Ca(2+) emptying, also generated subplasmalemmal HCMDs, but, in this case, most of the Ca(2+) was taken up by the ER rather than by mitochondria. The smaller size of the [Ca(2+)]C peak in this case (about 2 MUm) may contribute to this outcome, as the sarco-endoplasmic reticulum Ca(2+) ATPase has much higher Ca(2+) affinity than MCU. It is also possible that the relative positioning of organelles, channels and effectors, as well as cytoskeleton and accessory proteins plays an important role. PMID- 23798494 TI - Regulation of miRNAs in human skeletal muscle following acute endurance exercise and short-term endurance training. AB - The identification of microRNAs (miRNAs) has established new mechanisms that control skeletal muscle adaptation to exercise. The present study investigated the mRNA regulation of components of the miRNA biogenesis pathway (Drosha, Dicer and Exportin-5), muscle enriched miRNAs, (miR-1, -133a, -133b and -206), and several miRNAs dysregulated in muscle myopathies (miR-9, -23, -29, -31 and -181). Measurements were made in muscle biopsies from nine healthy untrained males at rest, 3 h following an acute bout of moderate-intensity endurance cycling and following 10 days of endurance training. Bioinformatics analysis was used to predict potential miRNA targets. In the 3 h period following the acute exercise bout, Drosha, Dicer and Exportin-5, as well as miR-1, -133a, -133-b and -181a were all increased. In contrast miR-9, -23a, -23b and -31 were decreased. Short term training increased miR-1 and -29b, while miR-31 remained decreased. Negative correlations were observed between miR-9 and HDAC4 protein (r=-0.71; P=0.04), miR 31 and HDAC4 protein (r=-0.87; P=0.026) and miR-31 and NRF1 protein (r=-0.77; P=0.01) 3 h following exercise. miR-31 binding to the HDAC4 and NRF1 3 untranslated region (UTR) reduced luciferase reporter activity. Exercise rapidly and transiently regulates several miRNA species in muscle. Several of these miRNAs may be involved in the regulation of skeletal muscle regeneration, gene transcription and mitochondrial biogenesis. Identifying endurance exercise mediated stress signals regulating skeletal muscle miRNAs, as well as validating their targets and regulatory pathways post exercise, will advance our understanding of their potential role/s in human health. PMID- 23798495 TI - Ranolazine recruits muscle microvasculature and enhances insulin action in rats. AB - Ranolazine, an anti-anginal compound, has been shown to significantly improve glycaemic control in large-scale clinical trials, and short-term ranolazine treatment is associated with an improvement in myocardial blood flow. As microvascular perfusion plays critical roles in insulin delivery and action, we aimed to determine if ranolazine could improve muscle microvascular blood flow, thereby increasing muscle insulin delivery and glucose use. Overnight-fasted, anaesthetized Sprague-Dawley rats were used to determine the effects of ranolazine on microvascular recruitment using contrast-enhanced ultrasound, insulin action with euglycaemic hyperinsulinaemic clamp, and muscle insulin uptake using (125)I-insulin. Ranolazine's effects on endothelial nitric oxide synthase (eNOS) phosphorylation, cAMP generation and endothelial insulin uptake were determined in cultured endothelial cells. Ranolazine-induced myographical changes in tension were determined in isolated distal saphenous artery. Ranolazine at therapeutically effective dose significantly recruited muscle microvasculature by increasing muscle microvascular blood volume (~2-fold, P < 0.05) and increased insulin-mediated whole body glucose disposal (~30%, P = 0.02). These were associated with an increased insulin delivery into the muscle (P < 0.04). In cultured endothelial cells, ranolazine increased eNOS phosphorylation and cAMP production without affecting endothelial insulin uptake. In ex vivo studies, ranolazine exerted a potent vasodilatatory effect on phenylephrine pre-constricted arterial rings, which was partially abolished by endothelium denudement. In conclusion, ranolazine treatment vasodilatates pre capillary arterioles and increases microvascular perfusion, which are partially mediated by endothelium, leading to expanded microvascular endothelial surface area available for nutrient and hormone exchanges and resulting in increased muscle delivery and action of insulin. Whether these actions contribute to improved glycaemic control in patients with insulin resistance warrants further investigation. PMID- 23798497 TI - Lentiform fork sign and fluctuating, reversible parkinsonism in a patient with uremic encephalopathy. PMID- 23798496 TI - Altered Ca2+ concentration, permeability and buffering in the myofibre Ca2+ store of a mouse model of malignant hyperthermia. AB - Malignant hyperthermia (MH) is linked to mutations in the type 1 ryanodine receptor, RyR1, the Ca2+ channel of the sarcoplasmic reticulum (SR) of skeletal muscle. The Y522S MH mutation was studied for its complex presentation, which includes structurally and functionally altered cell 'cores'. Imaging cytosolic and intra-SR [Ca2+] in muscle cells of heterozygous YS mice we determined Ca2+ release flux activated by clamp depolarization, permeability (P) of the SR membrane (ratio of flux and [Ca2+] gradient) and SR Ca2+ buffering power (B). In YS cells resting [Ca2+]SR was 45% of the value in normal littermates (WT). P was more than doubled, so that initial flux was normal. Measuring [Ca2+]SR(t) revealed dynamic changes in B(t). The alterations were similar to those caused by cytosolic BAPTA, which promotes release by hampering Ca2+-dependent inactivation (CDI). The [Ca2+] transients showed abnormal 'breaks', decaying phases after an initial rise, traced to a collapse in flux and P. Similar breaks occurred in WT myofibres with calsequestrin reduced by siRNA; calsequestrin content, however, was normal in YS muscle. Thus, the Y522S mutation causes greater openness of the RyR1, lowers resting [Ca2+]SR and alters SR Ca2+ buffering in a way that copies the functional instability observed upon reduction of calsequestrin content. The similarities with the effects of BAPTA suggest that the mutation, occurring near the cytosolic vestibule of the channel, reduces CDI as one of its primary effects. The unstable SR buffering, mimicked by silencing of calsequestrin, may help precipitate the loss of Ca2+ control that defines a fulminant MH event. PMID- 23798498 TI - Fabrication of 3D microstructures from interactions of immiscible liquids with a structured surface. AB - A new lithography technique is presented that exploits the interactions of immiscible liquids with a structured surface. This highly parallel, "low-tech" method requires no dedicated equipment and easily produces curved and/or multi level structures out of a variety of photoactive and non-photoactive materials. PMID- 23798499 TI - Modeling of transient flow through a viscoelastic preparative chromatography packing. AB - The common method for purification of macromolecular bioproducts is preparative packed-bed chromatography using polymer-based, compressible, viscoelastic resins. Because of a downstream processing bottleneck, the chromatography equipment is often operated at its hydrodynamic limit. In this case, the resins may exhibit a complex behavior which results in compression-relaxation hystereses. Up to now, no modeling approach of transient flow through a chromatography packing has been made considering the viscoelasticity of the resins. The aim of the present work was to develop a novel model and compare model calculations with experimental data of two agarose-based resins. Fluid flow and bed permeability were modeled by Darcy's law and the Kozeny-Carman equation, respectively. Fluid flow was coupled to solid matrix stress via an axial force balance and a continuity equation of a deformable packing. Viscoelasticity was considered according to a Kelvin-Voigt material. The coupled equations were solved with a finite difference scheme using a deformable mesh. The model boundary conditions were preset transient pressure drop functions which resemble simulated load/elution/equilibration cycles. Calculations using a homogeneous model (assuming constant variables along the column height) gave a fair agreement with experimental data with regard to predicted flow rate, bed height, and compression-relaxation hysteresis for symmetric as well as asymmetric pressure drop functions. Calculations using an inhomogeneous model gave profiles of the bed porosity as a function of the bed height. In addition, the influence of medium wall support and intraparticle porosity was illustrated. The inhomogeneous model provides insights that so far are not easily experimentally accessible. PMID- 23798500 TI - Customized high resolution CGH-array for clinical diagnosis reveals additional genomic imbalances in previous well-defined pathological samples. AB - High-resolution array comparative genomic hybridization (aCGH) is a powerful molecular cytogenetic tool that is being adopted for diagnostic evaluation of genomic imbalances and study disease mechanisms and pathogenesis. We report on the design and use, of a custom whole-genome oligonucleotide-based array (called KaryoArray(r)v3.0; Agilent-based 8 * 60 K) for diagnostic setting, which was able to detect new and unexpected rearrangements in 11/63 (~17.5%) of previous known pathological cases associated with known genetic disorders, and in the second step it identified at least one causal genomic imbalance responsible of the phenotype in ~20% of patients with psychomotor development delay and/or intellectual disability. To validate the array, first; we blindly tested 120 samples; 63 genomic imbalances that had previously been detected by karyotyping, FISH and/or MLPA, and 57 sex-matched control samples from healthy individuals; secondly a prospective study of 540 patients with intellectual disabilities, autism spectrum disorder and multiple congenital anomalies were evaluated to confirm the utility of the tool. These data indicate that implementation of array technologies as the first-tier test may reveal that additional genomic imbalances could co-exist in patients with trisomies and classical del/dup syndromes, suggesting that aCGH may also be indicated in these individuals, at least when phenotype does not match completely with genotype. PMID- 23798501 TI - Usefulness of the Montreal Cognitive Assessment (MoCA) in Huntington's disease. AB - BACKGROUND: The Montreal Cognitive Assessment (MoCA) is a brief screening instrument for dementia that is sensitive to executive dysfunction. This study examined its usefulness for assessing cognitive performance in mild, moderate, and severe Huntington's disease (HD), compared with the use of the Mini-Mental State Examination (MMSE). METHODS: We compared MoCA and MMSE total scores and the number of correct answers in 5 cognitive-specific domains in 104 manifest HD patients and 100 matched controls. RESULTS: For the total HD sample, and for the moderate and severe patients, significant differences between both MoCA and MMSE total scores and almost all cognitive-specific domains emerged. Even mild HD subjects showed significant differences with regard to total score and several cognitive domains on both instruments. CONCLUSIONS: We conclude that the MoCA, although not necessarily superior to the MMSE, is a useful instrument for assessing cognitive performance over a broad level of functioning in HD. PMID- 23798502 TI - Breast epithelial cell infiltration in enhanced electrospun silk scaffolds. AB - In the present study, the effects of air-flow impedance electrospinning and air flow rates on silk-based scaffolds for biological tissues were investigated. First, the properties of scaffolds obtained from 7% and 12% silk concentrations were defined. In addition, cell infiltration and viability of MCF-10A breast epithelial cells cultured onto these scaffolds were used to determine the biological suitability of these nanostructures. Air-flow impedance electrospun scaffolds resulted in an overall larger pore size than scaffolds electrospun on a solid mandrel, with the largest pores in 7% silk electrospun with an air pressure of 100 kPa and in 12% silk electrospun with an air pressure of 400 kPa (13.4 +/- 0.67 and 26.03 +/- 1.19 um, respectively). After 14 days in culture, the deepest MCF-10A cell infiltration (36.58 +/- 2.28 um) was observed into 7% silk air-flow impedance electrospun scaffolds subjected to an air pressure of 100 kPa. In those scaffolds MCF-10A cell viability was also highest after 14 days in culture. Together, these results strongly support the use of 7% silk-based scaffolds electrospun with a 100 kPa air-flow as the most suitable microenvironment for MCF 10A infiltration and viability. PMID- 23798503 TI - Characterization of miR-210 in 3T3-L1 adipogenesis. AB - Although accumulating evidences indicate that miRNA emerge as a vital player in cell growth, development, and differentiation, how they contribute to the process of adipocyte differentiation remains elusive. In the present study, we revealed that the expression level of miR-210 was dramatically upregulated during 3T3-L1 adipogenesis. Ectopic introduction of miR-210 into 3T3-L1 cells promoted terminal differentiation as well as the expression of adipogenic markers. MTT assay showed that miR-210 significantly inhibited cell proliferation whereas the BrdU incorporation assay and flow cytometry analysis showed that miR-210 did not impair G1/S phase transition. Further experiments demonstrated that enhanced expression of miR-210 in 3T3-L1 cells provoked adipocyte differentiation via activation of PI3K/Akt pathway by targeting SHIP1, a negative regulator of PI3K/Akt pathway. Moreover, blockade of endogenous miR-210 during adipogenesis significantly repressed adipocyte differentiation. In summary, we have identified miR-210 as an important positive regulator in adipocyte differentiation through the activation of PI3K/Akt pathway. PMID- 23798504 TI - Genome-scale prediction of proteins with long intrinsically disordered regions. AB - Proteins with long disordered regions (LDRs), defined as having 30 or more consecutive disordered residues, are abundant in eukaryotes, and these regions are recognized as a distinct class of biologically functional domains. LDRs facilitate various cellular functions and are important for target selection in structural genomics. Motivated by the lack of methods that directly predict proteins with LDRs, we designed Super-fast predictor of proteins with Long Intrinsically DisordERed regions (SLIDER). SLIDER utilizes logistic regression that takes an empirically chosen set of numerical features, which consider selected physicochemical properties of amino acids, sequence complexity, and amino acid composition, as its inputs. Empirical tests show that SLIDER offers competitive predictive performance combined with low computational cost. It outperforms, by at least a modest margin, a comprehensive set of modern disorder predictors (that can indirectly predict LDRs) and is 16 times faster compared to the best currently available disorder predictor. Utilizing our time-efficient predictor, we characterized abundance and functional roles of proteins with LDRs over 110 eukaryotic proteomes. Similar to related studies, we found that eukaryotes have many (on average 30.3%) proteins with LDRs with majority of proteomes having between 25 and 40%, where higher abundance is characteristic to proteomes that have larger proteins. Our first-of-its-kind large-scale functional analysis shows that these proteins are enriched in a number of cellular functions and processes including certain binding events, regulation of catalytic activities, cellular component organization, biogenesis, biological regulation, and some metabolic and developmental processes. A webserver that implements SLIDER is available at http://biomine.ece.ualberta.ca/SLIDER/. PMID- 23798505 TI - Fe-doped MnxOy with hierarchical porosity as a high-performance lithium-ion battery anode. AB - Fe-doped Mnx Oy with hierarchical porosity is prepared from a nanocasting technique using amine-functionalized bromomethylated poly (2,6-dimethyl-1,4 phenylene oxide) (BPPO) membranes as the sacrificial template. The synergistic coupling of a percolating macroporous network, uniformly distributed mesopores, and optimal iron doping is used to improve the electronic and ionic wirings of manganese oxides for Li(+) storage via the conversion reaction. Very impressive Li(+) storage capabilities are shown. PMID- 23798507 TI - Research with parthenogenetic stem cells will help decide whether a safer clinical use is possible. AB - The derivation and use of parthenogenetic stem cells (pESCs) are envisaged as a reliable alternative to conventional embryonic stem cells. Similar to embryonic stem cells in their proliferation, expression of pluripotency markers and capacity to multilineage differentiation, pESCs are at a lower risk of immune rejection within stem cell-based therapeutics. Moreover, pESCs represent an important model system to study the effect of paternally imprinted genes on cell differentiation. However, currently available information about the genetic and epigenetic behaviour of pESCs is limited. Thus, a detailed look at the biology of parthenogenetic (PG) embryos and PG-derived cell lines would allow gaining insight into the full potential of pESC in biotechnology. In this commentary article we review some features related to the biology of PG embryos and pESCs. In addition, novel traits on bovine pESCs (bpESCs) are discussed. PMID- 23798506 TI - Characterisation of the nuclear proteome of a dehydration-sensitive cultivar of chickpea and comparative proteomic analysis with a tolerant cultivar. AB - Water deficit or dehydration hampers plant growth and development, and shrinks harvest size of major crop species worldwide. Therefore, a better understanding of dehydration response is the key to decipher the regulatory mechanism of better adaptation. In recent years, nuclear proteomics has become an attractive area of research, particularly to study the role of nucleus in stress response. In this study, a proteome of dehydration-sensitive chickpea cultivar (ICCV-2) was generated from nuclei-enriched fractions. The LC-MS/MS analysis led to the identification of 75 differentially expressed proteins presumably associated with different metabolic and regulatory pathways. Nuclear localisation of three candidate proteins was validated by transient expression assay. The ICCV-2 proteome was then compared with that of JG-62, a tolerant cultivar. The differential proteomics and in silico analysis revealed cultivar-specific differential expression of many proteins involved in various cellular functions. The differential tolerance could be attributed to altered expression of many structural proteins and the proteins involved in stress adaptation, notably the ROS catabolising enzymes. Further, a comprehensive comparison on the abiotic stress-responsive nuclear proteome was performed using the datasets published thus far. These findings might expedite the functional determination of the dehydration-responsive proteins and their prioritisation as potential molecular targets for better adaptation. PMID- 23798508 TI - Including deaf and hard-of-hearing students with co-occurring disabilities in the accommodations discussion. AB - Students who are deaf or hard of hearing (SDHH) are a low-incidence group of students; however, SDHH also have a high incidence of additional disabilities (SDHH+). Many SDHH and SDHH+ require accommodations for equal access to classroom instruction and assessment, particularly in mainstreamed educational settings where spoken English is the primary language. Accommodations for SDHH, overall, have increased under federal legislation including the Individuals with Disabilities Education Improvement Act and the No Child Left Behind Act. Unfortunately, specific practice recommendations for SDHH+ and their unique needs are often lacking in the research literature. This article presents findings regarding accommodations use by SDHH and SDHH+ from the National Longitudinal Transition Study 2. Initial logistic regression analysis found no differences in accommodations use of SDHH and SDHH+. However, logistic regression analysis that compared specific additional disability groups with the larger overall SDHH group did find differences in accommodations use for two SDHH+ groups: students who had a learning disability and students with attention deficit hyperactivity disorder. This article includes a discussion of the implications of these findings for both research and practice. PMID- 23798509 TI - Intelligibility of clear speech: effect of instruction. AB - PURPOSE: The authors investigated how clear speech instructions influence sentence intelligibility. METHOD: Twelve speakers produced sentences in habitual, clear, hearing impaired, and overenunciate conditions. Stimuli were amplitude normalized and mixed with multitalker babble for orthographic transcription by 40 listeners. The main analysis investigated percentage-correct intelligibility scores as a function of the 4 conditions and speaker sex. Additional analyses included listener response variability, individual speaker trends, and an alternate intelligibility measure: proportion of content words correct. RESULTS: Relative to the habitual condition, the overenunciate condition was associated with the greatest intelligibility benefit, followed by the hearing impaired and clear conditions. Ten speakers followed this trend. The results indicated different patterns of clear speech benefit for male and female speakers. Greater listener variability was observed for speakers with inherently low habitual intelligibility compared to speakers with inherently high habitual intelligibility. Stable proportions of content words were observed across conditions. CONCLUSIONS: Clear speech instructions affected the magnitude of the intelligibility benefit. The instruction to overenunciate may be most effective in clear speech training programs. The findings may help explain the range of clear speech intelligibility benefit previously reported. Listener variability analyses suggested the importance of obtaining multiple listener judgments of intelligibility, especially for speakers with inherently low habitual intelligibility. PMID- 23798510 TI - The effect of hearing loss on the perception of infant- and adult-directed speech. AB - PURPOSE: Infant-directed speech (IDS) facilitates language learning in infants with normal hearing, compared to adult-directed speech (ADS). It is well established that infants with normal hearing prefer to listen to IDS over ADS. The purpose of this study was to determine whether infants with hearing impairment (HI), like their NH peers, show a listening preference for IDS over ADS. METHOD: A total of 36 infants-9 HI infants (mean chronological age of 19.1 with mean listening age of 7.7 months), 9 NH infants with similar average listening age (7.8 months), and 9 NH infants with similar average chronological age (18.6 months)-were tested on their listening preference for IDS compared with ADS using the central fixation preference procedure. RESULTS: Infants with HI significantly preferred listening to IDS over ADS. The preference for IDS was also seen in the younger NH infants, but not older NH controls. Additionally, HI infants showed shorter overall looking times as compared to either NH group. CONCLUSION: Although infants with hearing loss displayed a shorter looking time to speech compared to NH controls, HI infants nonetheless appear to have sufficient access to the speech signal to display a developmentally appropriate preference for IDS over ADS. PMID- 23798511 TI - Triennial Reproduction Symposium: deficiencies in the uterine environment and failure to support embryonic development. AB - Pregnancy failure in livestock can result from failure to fertilize the oocyte or embryonic loss during gestation. The focus of this review is on cattle and factors affecting and mechanisms related to uterine insufficiency for pregnancy. A variety of factors contribute to embryonic loss and it may be exacerbated in certain animals, such as high-producing lactating dairy cows, and in some cattle in which estrous synchronization and timed AI was performed, due to reduced concentrations of reproductive steroids. Recent research in beef cattle induced to ovulate immature follicles and in lactating dairy cows indicates that deficient uterine function is a major factor responsible for infertility in these animals. Failure to provide adequate concentrations of estradiol before ovulation results in prolonged effects on expression and localization of uterine genes and proteins that participate in regulating uterine functions during early gestation. Furthermore, progesterone concentrations during early gestation affect embryonic growth, interferon-tau production, and uterine function. Therefore, an inadequate uterine environment induced by insufficient steroid concentrations before and after ovulation could cause early embryonic death either by failing to provide an adequate uterine environment for recognition of embryo signaling, adhesion, and implantation or by failing to support appropriate embryonic growth, which could lead to decreased conceptus size and failed maternal recognition of pregnancy. PMID- 23798512 TI - Triennial Reproduction Symposium: limitations in uterine and conceptus physiology that lead to fetal losses. AB - Conceptus losses in livestock occur throughout gestation. The uterus and the embryo-placenta-fetus play interconnected roles in these losses, the details of which depend on the period of gestation and the species. Studies in sheep and pigs have indicated that the uterine glands are essential for full fertility, based on experiments where gland development was reduced through the use of exogenous hormones. In sheep and cattle, normally the uterus is well able to support more than a single fetus although these species differ in the consequences of multiple births. When 2 conceptuses are present, the placentas of cattle often anastomose, putting 1 fetus at risk if the other is lost. One likely reason this does not occur in sheep is because sheep embryos undergo intrauterine migration, similar to pigs. In pigs, the relatively equidistant separation of conceptuses is likely to be essential for optimizing conceptus survival as is the simultaneous and uniform elongation of blastocysts that occurs during the time of maternal recognition of pregnancy. Other studies in pigs have indicated that the size of the uterus influences litter size and therefore fetal losses. In response to crowded intrauterine conditions in the pig, increased conceptus losses begin to occur between d 30 and 40 of pregnancy, and further losses occur sporadically during later gestation. There is evidence that improved fetal erythropoiesis can reduce these losses. Other studies indicated that profound changes in placental development occurred under crowded intrauterine conditions that may contribute to losses during late gestation. Reductions in placental stroma formation may compromise the ability of the pig placenta to adapt to reduced uterine space. Consistent with this, both hyaluronan and hyaluronidase activity are decreased in the placentas of small compared with large fetuses. These results indicate that improvements in placental stroma formation could improve placental ability to compensate for reduced intrauterine space, resulting in increased placental function and reduced fetal losses during late gestation. PMID- 23798513 TI - Breed and dietary linseed affect gene expression of enzymes and transcription factors involved in n-3 long chain polyunsaturated fatty acids synthesis in longissimus thoracis muscle of bulls. AB - N-3 long-chain (LC) PUFA are known to be beneficial for human development and health. These properties explain the increasing interest in promoting n-3 LC PUFA deposition in bovine muscles, leading to healthier meats. In this context, this study aimed to identify possible limiting steps in the bioconversion of 18:3n-3 into n-3 LC PUFA in the longissimus thoracis (LT) muscle of 36 Aberdeen Angus, Limousin, and Blond d'Aquitaine bulls (n = 12 per breed) that were fed, for the 105-d finishing period, either a concentrate-based diet (25% molasses straw to 75% concentrate, on a raw basis; CON) or the same CON diet supplemented with extruded linseed (44.5 g lipid/kg diet DM) mixed into the concentrate (LINS). The fatty acid (FA) composition of the LT muscle was determined by GLC, and the mRNA abundances for enzymes and transcription factors involved in n-3 LC PUFA synthesis were determined by quantitative real-time PCR. The total lipid concentration in the LT muscle was approximately 2.4-fold greater (P < 0.001) in Angus bulls than in the other breeds and composed of the greatest n-3 PUFA content (P < 0.001) including 18:3n-3 (P < 0.001) and n-3 LC PUFA (P < 0.02), primarily 20:5n-3 (P < 0.007) and 22:5n-3 (P < 0.04). These data were associated with a lesser gene expression (P < 0.02) of 2 enzymes [acyl-CoA oxidase 1 (ACOX1) and L-bifunctional protein (L-PBE)] and 2 transcription factors [liver X receptors (LXR) alpha and beta] in the LT muscle of Angus bulls compared with gene expression in Limousin bulls. Moreover, the mRNA of elongase 5 was only present in trace amounts in the LT muscle of the 3 breeds. The addition of linseed to the diet resulted in greater deposition of 18:3n-3 (P < 0.001) in the LT muscles of the 3 breeds, without any major changes (P > 0.34) in the n-3 LC PUFA content. Dietary linseed stimulated (P < 0.04) the gene expression of all enzymes and transcription factors involved in n-3 LC PUFA synthesis except elongases 2 and 5 (P > 0.19), the expression of which remained weak and was not inducible. These results reveal a limited capacity for n-3 LC PUFA synthesis from 18:4n-3 (substrate of elongase 5) in the LT muscles of Blond d'Aquitaine, Limousin, and Angus bulls. Therefore, further investigations on the cellular regulation of elongase gene expression are needed to identify the physiological or nutritional factors that efficiently stimulate elongase expression in beef cattle. PMID- 23798514 TI - The effects of Capn1 gene inactivation on skeletal muscle growth, development, and atrophy, and the compensatory role of other proteolytic systems. AB - Myofibrillar protein turnover is a key component of muscle growth and degeneration, requiring proteolytic enzymes to degrade the skeletal muscle proteins. The objective of this study was to investigate the role of the calpain proteolytic system in muscle growth development using MU-calpain knockout (KO) mice in comparison with control wild-type (WT) mice, and evaluate the subsequent effects of silencing this gene on other proteolytic systems. No differences in muscle development between genotypes were observed during the early stages of growth due to the up regulation of other proteolytic systems. The KO mice showed significantly greater m-calpain protein abundance (P < 0.01) and activity (P < 0.001), and greater caspase 3/7 activity (P < 0.05). At 30 wk of age, KO mice showed increased protein:DNA (P < 0.05) and RNA:DNA ratios (P < 0.01), greater protein content (P < 0.01) at the expense of lipid deposition (P < 0.05), and an increase in size and number of fast-twitch glycolytic muscle fibers (P < 0.05), suggesting that KO mice exhibit an increased capacity to accumulate and maintain protein in their skeletal muscle. Also, expression of proteins associated with muscle regeneration (neural cell adhesion molecule and myoD) were both reduced in the mature KO mice (P < 0.05 and P < 0.01, respectively), indicating less muscle regeneration and, therefore, less muscle damage. These findings indicate the concerted action of proteolytic systems to ensure muscle protein homeostasis in vivo. Furthermore, these data contribute to the existing evidence of the importance of the calpain system's involvement in muscle growth, development, and atrophy. Collectively, these data suggest that there are opportunities to target the calpain system to promote the growth and/or restoration of skeletal muscle mass. PMID- 23798515 TI - Effects of dietary combinations of organic acids and medium chain fatty acids on the gastrointestinal microbial ecology and bacterial metabolites in the digestive tract of weaning piglets. AB - Organic short and medium chain fatty acids are used in diets for piglets because they have an impact on the digestive processes and the intestinal microbiota. In this study, 48 pens (2 piglets/pen) were assigned randomly to 4 diets, without additive (control), with organic acids (OA; 0.416% fumaric and 0.328% lactic acid), with medium chain fatty acids (MCFA; 0.15% caprylic and capric acid), and a combination of OA and MCFA, to assess changes in the gastrointestinal microbiota with 12 pens per diet. Eight to nine piglets from each group were euthanized after 4 wk. Organic acids, MCFA, and pH in the digesta were determined and the intestinal microbiota was quantified by real-time PCR. The different diets had no effect on the growth performance. Concentration of added fumaric acid was below the detection limit in the upper small intestine whereas the concentration of lactic acid in the digesta was not affected by the treatments. The added MCFA was recovered in the MCFA treated groups in the stomach, but the concentrations declined in the upper small intestine. Concentration of short chain fatty acids was reduced in the colon digesta in piglets fed diets with OA compared with those fed unsupplemented diets (P = 0.029). The MCFA resulted in a pH reduction of the digesta, likely because of the effect on bacterial acid production. The addition of OA increased cell counts of Bacteroides-Porphyromonas Prevotella group and clostridial clusters XIVa, I, and IV in the stomach, the clostridial cluster XIVa in the jejunum, and Bacteroides-Porphyromonas-Prevotella in the ileum and reduced counts of Streptococcus spp. in the colon (P < 0.05). The MCFA induced only minor changes in the gastrointestinal microbiota but increased cell counts for the Escherichia-Hafnia-Shigella group in the jejunum and the clostridial cluster XIVa in the colon digesta (P < 0.05). In the colon of piglets fed diets with organic OA, reduced mean cell counts of STb (est-II) positive Escherichia coli were found. In conclusion, OA and MCFA had effects on the intestinal microecology in piglets. The decrease of the intestinal pH and the reduction of E. coli virulence genes by OA could make the combination of short chain fatty acids and MCFA as interesting gut flora modifiers, which can eventually prevent postweaning diarrhea. PMID- 23798516 TI - Concentration of digestible and metabolizable energy and digestibility of amino acids in chicken meal, poultry byproduct meal, hydrolyzed porcine intestines, a spent hen-soybean meal mixture, and conventional soybean meal fed to weanling pigs. AB - Two experiments were conducted to determine the concentration of DE and ME and the standardized ileal digestibility (SID) of AA in chicken meal, poultry byproduct meal, hydrolyzed porcine intestines, a spent hen-soybean meal (SBM) mixture, and conventional SBM fed to weanling pigs. In Exp. 1, 48 barrows (initial BW: 14.6 +/- 2.2 kg) were placed in metabolism cages and allotted to 6 diets with 8 replicate pigs per diet in a randomized complete block design. Six corn-based diets were formulated. The basal diet contained 98.1% corn (as-fed basis) and 5 diets contained corn and 11 to 16% chicken meal, poultry byproduct meal, hydrolyzed porcine intestines, spent hen-SBM mixture, or SBM. All test ingredients were included in their respective diets at levels that were expected to result in similar concentrations of CP among diets. Feces and urine were collected for 5 d. The ME was 3,957, 3,816, 4,586, 4,298, 4,255, and 4,091 kcal/kg DM for corn, chicken meal, poultry byproduct meal, hydrolyzed porcine intestines, the spent hen-SBM mixture, and SBM, respectively. The ME in poultry byproduct meal was greater (P < 0.01) than in corn, chicken meal, the spent hen SBM mixture, and SBM, and the ME in hydrolyzed porcine intestines and the spent hen-SBM mixture was greater (P < 0.01) than in corn and chicken meal, but there was no difference among hydrolyzed porcine intestines, the spent hen-SBM mixture, and SBM. In Exp. 2, 12 barrows (initial BW: 12.2 +/- 1.5 kg) were equipped with a T-cannula in the ileum and allotted to a replicated 6 * 6 Latin square design. A N-free diet and a cornstarch-SBM based diet were formulated. Four additional diets were formulated by mixing cornstarch, sucrose, and SBM with chicken meal, poultry byproduct meal, hydrolyzed porcine intestines, or the spent hen-SBM mixture. The SID of CP and all AA, except Trp and Pro, was greater (P < 0.01) in SBM than in all other ingredients. The SID of CP and all indispensable AA in the spent hen-SBM mixture was also greater (P < 0.01) than in chicken meal and hydrolyzed porcine intestines, and with the exception of Arg and Val, SID values of all indispensable AA in the spent hen-SBM mixture were greater than in poultry byproduct meal. However, with the exception of Val and Lys, there were no differences between chicken meal and poultry byproduct meal. In conclusion, the ME in hydrolyzed porcine intestines and the spent hen-SBM mixture is greater than in chicken meal, but not different from the ME of SBM. Poultry by product meal provides more ME than SBM, chicken meal, and the spent hen-SBM mixture, and the SID of most indispensable AA is greater in the spent hen-SBM mixture than in chicken meal, poultry byproduct meal, and hydrolyzed porcine intestines, but less than in SBM. PMID- 23798517 TI - Effects of reduced-oil corn distillers dried grains with solubles composition on digestible and metabolizable energy value and prediction in growing pigs. AB - Two experiments were conducted to determine the DE and ME content of corn distillers dried grains with solubles (corn-DDGS) containing variable ether extract (EE) concentrations and to develop DE and ME prediction equations based on chemical composition. Ether extract content of corn-DDGS ranged from 4.88 to 10.88% (DM basis) among 4 corn-DDGS samples in Exp. 1 and from 8.56 to 13.23% (DM basis) among 11 corn-DDGS samples in Exp. 2. The difference in concentration of total dietary fiber (TDF) and NDF among the 4 corn-DDGS sources was 2.25 and 3.40 percentage units, respectively, in Exp. 1 but was greater among the 11 corn-DDGS sources evaluated in Exp. 2, where they differed by 6.46 and 15.18 percentage units, respectively. The range in CP and ash were from 28.97 to 31.19% and 5.37 to 6.14%, respectively, in Exp. 1 and from 27.69 to 32.93% and 4.32 to 5.31%, respectively, in Exp. 2. Gross energy content among corn-DDGS samples varied from 4,780 to 5,113 kcal/kg DM in Exp. 1 and from 4,897 to 5,167 kcal/kg DM in Exp. 2. In Exp. 1, the range in DE content was from 3,500 to 3,870 kcal/kg DM and ME content varied from 3,266 to 3,696 kcal/kg DM. There were no differences in ME:DE content among the 4 corn-DDGS sources in Exp. 1, but ME:GE content differed (P = 0.04) among sources (66.82 to 74.56%). In Exp. 2, the range in DE content among the 11 corn-DDGS sources was from 3,474 to 3,807 kcal/kg DM and ME content varied from 3,277 to 3,603 kcal/kg DM. However, there were no differences in DE:GE, ME:DE, or ME:GE among sources in Exp. 2. In Exp. 1, no ingredient physical or chemical measurement [bulk density (BD), particle size, GE, CP, starch, TDF, NDF, ADF, hemicellulose, EE, or ash)] was statistically significant at P <= 0.15 to predict DE or ME content in corn-DDGS. In Exp. 2, the best fit DE equation was DE (kcal/kg DM) = 1,601 - (54.48 * % TDF) + (0.69 * % GE) + (731.5 * BD) [R(2) = 0.91, SE = 41.25]. The best fit ME equation was ME (kcal/kg DM) = 4,558 + (52.26 * % EE) - (50.08 * % TDF) [R(2) = 0.85, SE = 48.74]. Apparent total tract digestibility of several nutritional components such as ADF, EE, and N were quite variable among corn-DDGS sources in both experiments. These results indicate that although EE may be a good predictor of GE content in corn-DDGS, it is not a primary factor for predicting DE or ME content. Measures of dietary fiber, such as ADF or TDF, are more important than EE in determining the DE or ME content of corn-DDGS for growing pigs. PMID- 23798518 TI - Effects of dietary soybean oil on pig growth performance, retention of protein, lipids, and energy, and the net energy of corn in diets fed to growing or finishing pigs. AB - The objectives of this experiment were 1) to determine if dietary soybean oil (SBO) affects the NE of corn when fed to growing or finishing pigs, 2) to determine if possible effects of dietary SBO on the NE of corn differ between growing and finishing pigs, and 3) to determine effects of SBO on pig growth performance and retention of energy, protein, and lipids. Forty-eight growing (initial BW: 27.3 +/- 2.5 kg) and 48 finishing (initial BW: 86.0 +/- 3.0 kg) barrows were used, and within each stage of growth, pigs were allotted to 1 of 6 groups. Two groups at each stage of growth served as an initial slaughter group. The remaining 4 groups were randomly assigned to 4 dietary treatments and pigs in these groups were harvested at the conclusion of the experiment. A low-lipid basal diet containing corn, soybean meal, and no added SBO and a high-lipid basal diet containing corn, soybean meal, and 8% SBO were formulated at each stage of growth. Two additional diets at each stage of growth were formulated by mixing 25% corn and 75% of the low-lipid basal diet or 25% corn and 75% of the high lipid basal diet. Results indicated that addition of SBO had no effects on growth performance, carcass composition, or retention of energy, protein, and lipids but increased (P < 0.05) apparent total tract digestibility of acid hydrolyzed ether extract and GE. Addition of SBO also increased (P < 0.05) DE and NE of diets, but had no effect on the DE and NE of corn. Finishing pigs had greater (P < 0.05) growth performance and retention of energy, protein, and lipids than growing pigs. A greater (P < 0.05) DE and NE of diets was observed for finishing pigs than for growing pigs and the DE and NE of corn was also greater (P < 0.05) for finishing pigs than for growing pigs. In conclusion, addition of SBO increases the DE and NE of diets but has no impact on the DE and NE of corn. Diets fed to finishing pigs have greater DE and NE values than diets fed to growing pigs and the DE and NE of corn are greater for finishing pigs than for growing pigs. PMID- 23798519 TI - Mitochondrial complex I protein differs among residual feed intake phenotype in beef cattle. AB - Four experiments were performed to determine if residual feed intake (RFI) was related to mitochondrial complex I (CI) protein. For Exp. 1, crossbred Angus steers (initial BW 270 +/- 2.0 kg) were fed for a total of 170 d (n = 72). For Exp. 2, crossbred Braunvieh steers (initial BW 280 +/- 3.0 kg) were fed for a total of 150 d (n = 50). For Exp. 3, crossbred Braunvieh heifers (initial BW 260 +/- 3.0 kg) were fed for a total of 160 d (n = 40). For Exp. 4, crossbred Angus steers (initial BW 290 +/- 3.0 kg) were fed for a total of 160 d (n = 40). All cattle in all experiments were fed the same diet. The variable RFI was calculated as the difference between predicted and actual DMI. Predicted DMI was calculated from regressing intake on ADG and metabolic body weight. Blood was collected, lymphocytes were isolated, and antibody used to capture CI. For Exp. 1, 2, and 3, CI quantity was measured using an ELISA commercial kit (Mitosciences, OR). For Exp. 4, CI subunits were separated by gel electrophoresis and bands were analyzed for differences in concentration (absorbance) among RFI phenotypes. For all 4 experiments, there was a significant difference (P < 0.05) between RFI and DMI but no difference (P > 0.05) was reported for ADG and metabolic midweight. For Exp. 1, 2, and 3, CI concentration in mitochondria was greater (P < 0.05) for low RFI compared with other treatments. For Exp. 4, animals with low RFI had a trend (P = 0.07) for greater concentration of Band I (protein S1) than high RFI. Correlation between RFI and Band I was -0.72 (P = 0.04). We concluded that mitochondrial function was at least in part responsible for differences among animals in metabolic efficiency. PMID- 23798520 TI - A rumen unprotected conjugated linoleic acid supplement inhibits milk fat synthesis and improves energy balance in lactating goats. AB - Feeding trans-10, cis-12 CLA supplements in a rumen-protected form has been shown to cause milk fat depression (MFD) in cows, ewes, and goats. Methyl esters of CLA were shown to be as effective as FFA in inducing MFD when infused postruminally, but their efficacy as a feed supplement has not been addressed in studies with lactating ruminants. In the present study, we investigated the effects of an unprotected trans-10, cis-12 CLA supplement as methyl esters on performance, milk composition, and energy status of dairy goats. Eighteen multiparous Toggenburg goats were randomly assigned to dietary treatments in a crossover experimental design (14 d treatment periods separated by a 7 d washout interval): 30 g/d of calcium salts of fatty acids (Control) or 30 g/d of a rumen unprotected CLA supplement containing 29.9% of trans-10, cis-12 CLA as methyl esters (CLA). Lipid supplements were mixed into a concentrate and fed individually to animals 3 times a day as a total mixed ration component. The DMI, milk yield, milk protein and lactose content and secretion, and somatic cell count were unaffected by CLA treatment. On the other hand, milk fat content and yield were reduced by 19.9 and 17.9% in CLA-fed goats. Reduced milk fat yield in CLA-fed goats was a consequence of a lower secretion of both preformed and de novo synthesized fatty acids. The CLA treatment also changed the milk fatty acid profile, which included a reduction in the concentration of SFA (2.5%), increased MUFA and PUFA (5.6 and 5.4%, respectively), and a pronounced increase (1576%) in milk fat trans-10, cis 12 CLA. Consistent with the high milk fat trans-10, cis-12 CLA content, all desaturase indexes were reduced in milk fat from CLA-fed goats. The MFD induced by CLA reduced the energy required for milk production by 22%, which was accompanied by an improvement in the estimated energy balance (P < 0.001), greater blood glucose concentration (P < 0.05), and a trend for increased BW (P = 0.08). Approximately 7.2% of trans-10, cis-12 CLA was estimated to escape from rumen biohydrogenation and indirect comparisons with data obtained from other studies suggest equivalent MFD between dietary CLA in the methyl ester form and rumen protected sources. Thus, despite the apparent low degree of rumen protection, our results suggest that methyl esters of CLA could be an alternative to rumen protected CLA supplements due to manufacturing and cost advantages. PMID- 23798521 TI - Effects of roughage concentration in dry-rolled corn-based diets containing wet distillers grains with solubles on performance and carcass characteristics of finishing beef steers. AB - Distillers grains and distillers solubles are by-products of grain fermentation used to produce ethanol and contain greater concentrations of NDF and ADF, compared with other grains and concentrates they replace in feedlot diets. Typical finishing diets in the United States contain 8.3% and 9.0% roughage. Therefore, it is plausible that the dietary concentration of roughage can be altered when distillers grains are included in feedlot diets. The effects of roughage concentration in dry-rolled, corn-based diets containing wet distillers grains with solubles (WDGS) were evaluated in steers (n = 128; initial BW = 339 kg), using Calan gates. Each diet was based on dry-rolled corn and contained 25% WDGS with coarsely ground alfalfa hay (AH), replacing corn at 2% (AH-2), 6% (AH 6), 10% (AH-10), and 14% (AH-14) of DM. Feed offered was recorded daily, orts were measured weekly, and BW was measured on d 0, 1, 35, 70, 105, 140, 174, and 175. After commercial harvest and chilling, carcasses were evaluated on-line with a beef carcass grading camera to assess marbling and yield grade traits. The data were analyzed using the Mixed Procedure of SAS, in which contrast statements were used to separate linear and quadratic effects of AH inclusion. Decreasing concentrations of AH in the finishing diet resulted in a tendency for a quadratic response (P = 0.07) in final BW, where BW increased from 2 to 6% AH inclusion but then decreased from 6 to 14% inclusion. Similarly, ADG from d 0 to end responded quadratically (P < 0.01), in which ADG increased from 2 to 6% yet subsequently decreased from 6 to 14% AH inclusion. Dry matter intake from d 0 to end increased linearly (P = 0.02) as AH inclusion increased in the diet, whereas G:F increased from 2 to 6% AH inclusion and then decreased linearly (P < 0.01) from 6 to 14% AH inclusion. Concentration of AH in the finishing diet did not affect HCW, marbling score, or the proportion of cattle grading USDA choice (P >= 0.18). However, dressing percent and LM area did respond in a quadratic manner (P < 0.02), in which they decreased from 2 to 10% AH inclusion and increased from 10 to 14% AH in the diet. Yield grade and adjusted 12th rib fat responded quadratically (P < 0.01), in which both increased from 2 to 6% AH inclusion and decreased from 6 to 14% inclusion. Analysis of responses of G:F and ADG on AH predict the apex at 3% and 7% for G:F and ADG, respectively, when fed in diets containing 25% WDGS. PMID- 23798522 TI - Supplemental vitamin D3 and zilpaterol hydrochloride. I. Effect on performance, carcass traits, tenderness, and vitamin D metabolites of feedlot steers. AB - Angus * Simmental steers (n = 210; initial BW 314 +/- 11 kg) were separated into heavy and light BW blocks and allotted evenly by BW to 6 treatments (3 heavy and 2 light pens per treatment) to determine the effect of supplemental vitamin D3: 0 IU (no D), 250,000 IU for 165 d (long-term D), or 5 * 10(6) IU for 10 d (short term D) on performance, carcass traits, vitamin D metabolites, and meat tenderness in steers fed either 0 (NZ) or 8.38 mg/kg zilpaterol hydrochloride (ZH) daily for 21 d. Placebo or ZH was added to the diet 24 d, and short-term D was added 13 d before slaughter. Vitamin D3, ZH, and placebo were all removed from the diet 3 d before slaughter. Steers fed ZH tended to have improved overall G:F compared with steers not fed ZH (P < 0.09). Overall performance was not affected by long-term D, with or without ZH (P = 0.11) compared with no D, with or without ZH. Short-term D decreased final BW, ADG, and G:F (P = 0.04) compared with no D, when ZH was not fed. Zilpaterol hydrochloride increased HCW, dressing percentage, and LM area (P < 0.01); and decreased fat thickness, yield grade, and marbling (P < 0.03). Carcass traits were not impacted by long-term D without ZH (P > 0.13), but long-term D with ZH decreased percentage KPH (P < 0.02). Compared with no D, short-term D tended to decrease HCW (P < 0.07), decreased fat thickness (P < 0.01), and tended to increase dressing percentage (P < 0.10) when ZH was not fed, yet did not impact carcass traits when ZH was fed (P < 0.13). Feeding ZH tended to decrease (P < 0.09) LM 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. The long-term D treatment increased LM vitamin D3 and 25 hydroxyvitamin D3 (25OHD3) 18- and 5-fold, respectively, when ZH was not fed (P < 0.04) and increased LM 25OHD3 by 4-fold when ZH was fed (P < 0.01). Short-term D increased LM vitamin D3 and 25OHD3 by 52- and 9-fold, respectively, when ZH was not fed (P < 0.01), and by 24- and 9-fold, respectively, when ZH was fed (P < 0.01). Also, short-term D increased LM 1,25(OH)2D3 by 2-fold (P < 0.04) when ZH was fed. Warner-Bratzler shear force (WBSF) was greater for ZH steaks than non-ZH steaks at 7, 14, and 21 d postmortem aging (P < 0.01). Vitamin D did not reduce WBSF (P = 0.18). When ZH was fed, long-term D tended to increase WBSF in steaks aged 21 d (P = 0.06). In conclusion, ZH improved carcass leanness and decreased tenderness, and vitamin D feeding increased vitamin D3 metabolites in LM, but did not improve tenderness in steers fed ZH. PMID- 23798523 TI - Supplemental vitamin D3 and zilpaterol hydrochloride. II. Effect on calcium concentration, muscle fiber type, and calpain gene expression of feedlot steers. AB - Two hundred and ten Angus * Simmental steers (initial BW 314 +/- 11 kg) were separated into heavy and light BW blocks and allotted evenly by BW to 6 treatments (3 heavy and 2 light pens per treatment) to determine the effect of supplemental vitamin D3: 0 IU (no D), 250,000 IU for 165 d (long-term D), or 5 * 10(6) IU for 10 d (short-term D) on plasma and muscle calcium concentrations and gene expression in steers fed either 0 (NZ) or 8.38 mg/kg (ZH) zilpaterol hydrochloride (ZH) daily for 21 d. Placebo or ZH was added to the diet 24 d, and short-term D was added 13 d before slaughter. Treatments were removed from all diets 3 d before slaughter. Plasma total calcium (Ca(2+)) was determined at study initiation, start of ZH and short-term D feedings, and at vitamin D3 and ZH withdrawal. Both plasma total and ionic Ca(2+) were determined when animals were sent to harvest. Longissimus muscle total and ionic Ca(2+) were determined in meat aged 7 and 4 d postmortem, respectively. When ZH was fed, long-term D decreased plasma total Ca(2+) at slaughter (P < 0.04). Short-term D increased (P < 0.01) plasma total and ionic Ca(2+) at slaughter regardless of ZH inclusion in the diet. Long- and short-term D, with or without ZH, did not affect (P > 0.28) LM total Ca(2+); however, both long- and short-term D increased LM ionic Ca(2+) when ZH was not fed (P < 0.01). Long-term D reduced LM ionic Ca(2+) when ZH was fed (P < 0.02). Neither long- nor short-term D affected PPARalpha or delta gene expression (P = 0.19) whether or not ZH was fed. Expression of MYH1 and 2A (P < 0.05) but not 2X (P = 0.21) was decreased in steers fed ZH. Long-term D had no effect on MYH2A expression (P = 0.21). Short-term D increased MYH2A expression when ZH was not fed (P < 0.03). Calpain mRNA tended to be lower in steers fed ZH (P = 0.09), but was not affected by long- or short-term D regardless of whether or not ZH was fed (P = 0.39). Expression of calpastatin did not differ with vitamin D supplementation (P = 0.35). In conclusion, ZH decreased oxidative myosin expression, and when combined with long-term D, ZH decreased LM ionic Ca(2+). Moreover, vitamin D3 supplementation did not increase calpain mRNA. These results help explain why vitamin D3 does not improve tenderness in steers fed ZH. PMID- 23798524 TI - Invited review: piglet mortality: management solutions. AB - Preweaning mortality varies greatly among herds and this is partly attributed to differences in farrowing house management. In this review, we describe the various management strategies than can be adopted to decrease mortality and critically examine the evidence that exists to support their use. First, we consider which management procedures are effective against specific causes of death: intrapartum stillbirth, hypothermia, starvation, disease, crushing, and savaging. The most effective techniques include intervention to assist dystocic sows, measures to prevent and treat sow hypogalactia, good farrowing house hygiene, providing newborn piglets with a warm microenvironment, early fostering of supernumerary piglets, methods that assist small and weak piglets to breathe and obtain colostrum, and intervention to prevent deaths from crushing and savaging. The provision of nest-building material and modifications to the pen to assist the sow when lying down may also be beneficial, but the evidence is less clear. Because most deaths occur around the time of farrowing and during the first few days of life, the periparturient period is a particularly important time for management interventions intended to reduce piglet mortality. A number of procedures require a stockperson to be present during and immediately after farrowing. Second, we consider the benefits of farrowing supervision for preweaning mortality in general, focusing particularly on methods for the treatment of dystocia and programs of piglet care that combine multiple procedures. Third, we discuss the need for good stockmanship if farrowing supervision is to be effective. Stockmanship refers not only to technical skills but also to the manner in which sows are handled because this influences their fearfulness of humans. We conclude that piglet survival can be improved by a range of management procedures, many of which occur in the perinatal period and require the supervision of farrowing by trained staff. Although this incurs additional labor costs, there is some evidence that this can be economically offset by improved piglet survival. PMID- 23798525 TI - Evaluation of total oxidative stress and total antioxidant status in cows with natural bovine herpesvirus-1 infection. AB - Viruses, including herpes viruses, can alter oxidative balance by either increasing the formation of free radicals or inhibiting synthesis of enzymes involved in oxidative defense within host cells. This study examined the occurrence of oxidative and antioxidative balance in cows naturally infected with bovine herpesvirus type 1 (BHV-1) under field conditions. Clinical history indicated that cows had been sick and showed mild to severe respiratory signs, characterized by dullness, coughing, and lacrimation, and a high febrile response. All samples obtained from the infected animals during clinical examination were confirmed as positive for bovine herpesvirus type 1 by PCR. Control cows showed no clinical abnormalities and PCR results were negative. Total antioxidative status, total oxidant status, oxidative stress index, and some biochemical parameters were measured. The level of total antioxidative status was significantly lower in infected animals, compared with the healthy control group (P = 0.025). However, there was no statistically significant difference between the 2 groups for total oxidant status and oxidative stress index levels. Furthermore, there was a significant decrease in the infected groups, with respect to concentrations of alkaline phosphatase, alanine transferase, gamma glutamyl transferase, monocyte, and erythrocyte (P < 0.05). On the other hand, aspartate aminotransferase and creatinine kinase concentrations significantly increased in the cows infected with BHV-1. In conclusion, the data obtained hereby explained that animals with infected BHV-1 seemed to have more oxidative stress and low antioxidant defense. Moreover, future research conductance is needed on antioxidative and oxidative balance to understand pathophysiology of BHV-1 infections. PMID- 23798526 TI - Group housing for lactating sows with electronically controlled crates: 1. Reproductive traits, body condition, and feed intake. AB - The aim was to compare a group housing system (GROUP) and a conventional single housing (SINGLE) for lactating sows with regard to the performance of sows and piglets. Data of 132 cross-breed sows were collected in 11 batches with 6 sows in GROUP and SINGLE in each batch. The GROUP had single pens (4.7 m(2)) with electronically controlled crates and a shared running area (13 m(2)). The sows in GROUP were retained in the crates 3 d prepartum until 1 d postpartum. Piglets were able to leave the single pens on d 5 postpartum. Recorded traits per litter included the number of piglets born alive and weaned, piglet losses, and individual BW at birth and weaning. In addition, body condition and back fat thickness before and after lactation (26 d) and the daily feed intake of the sows were measured. Gilts and sows were analyzed separately. The reproductive traits did not differ significantly (P > 0.05) between the farrowing systems with exception of the weaning weights (GROUP = 7.6 +/- 0.12 kg vs. SINGLE = 8.1 +/- 0.12 kg; P < 0.05). Group housed and SINGLE sows had 14.4 +/- 0.47 and 14.6 +/- 0.45 piglets born alive, respectively. In both housing systems, sows weaned 11.4 piglets (SEM = 0.14 and 0.13 for GROUP and SINGLE), respectively. Most piglet losses (72%) occurred during the first 3 d postpartum. At this point in time, piglets in GROUP and SINGLE were housed in single pens. In the single pens, GROUP sows could leave the farrowing crate whereas SINGLE sows were fixed in crates during the whole lactation. In total, piglet losses were not significantly different during lactation between GROUP and SINGLE treatments (2.2 +/- 0.05 and 2.4 +/- 0.05 piglets per litter, respectively). Sows housed in GROUP had a significantly lower (P < 0.05) BCS (2.2 +/- 0.05) after lactation compared with SINGLE sows (BCS = 2.4 +/- 0.05). This development could not be verified using the back fat thickness value at weaning (GROUP = 14.4 +/- 0.25 mm vs. SINGLE = 14.6 +/- 0.23 mm). Daily feed intake was significantly greater for GROUP sows (6.4 +/- 0.08 kg per day) than SINGLE sows (6.15 +/- 0.08 kg per day; P < 0.05). In conclusion, the performance of GROUP and SINGLE sows was similar with the exception of lighter weaning weights in GROUP housing. PMID- 23798527 TI - The effects of diet form and feeder design on the growth performance of finishing pigs. AB - Two studies were conducted to determine the effects of diet form (meal vs. pellet) and feeder design (conventional dry vs. wet/dry) on finisher pig performance. Experiments were arranged as 2 * 2 factorials with 11 replications per treatment and 26 to 29 pigs per pen. In Exp. 1, pigs (n = 1,290; initial BW 46.8 kg) were used in a 91-d study. Pelleted diets averaged approximately 35% fines throughout the study. Overall, pigs fed pelleted diets or via wet/dry feeders had greater (P < 0.07 and 0.001, respectively) ADG than pigs fed meal diets or fed with a dry feeder. Diet form * feeder interactions (P < 0.02) were observed for G:F. Pigs fed either meal or pelleted diets via a wet/dry feeder had similar G:F, but pigs fed pelleted diets in dry feeders had poorer G:F than pigs with meal diets in dry feeders. In Exp. 2, pigs (n = 1,146; initial BW 38.2 kg) were used in a 104-d study. From d 0 to 28, a diet form * feeder design interaction (P < 0.01) was observed for ADG, which was due to decreased ADG in pigs fed pelleted diets from a conventional dry feeder compared with pigs fed meal diets from the same feeder type whereas there was no difference in wet/dry feeders based on diet form. Pigs fed pelleted diets had poorer (P < 0.01) G:F than pigs fed meal diets. This result appeared to be due to poor pellet quality (39.6% fines). From d 42 to 86, pellet quality improved (4.4% fines) and a diet form * feeder interaction was observed for ADG in which pigs fed meal diets in a dry feeder had decreased (P < 0.05) ADG than pigs fed pelleted diets in dry feeders or pigs presented either diet in wet/dry feeders. Pigs fed pelleted diets had improved (P < 0.001) G:F. Pigs fed via wet/dry feeders had increased (P < 0.03) ADFI and G:F compared with pigs fed via dry feeders. Overall, pigs fed with wet/dry feeders had increased (P < 0.02) ADG and ADFI and poorer G:F than pigs with dry feeders whereas pigs given pelleted diets had improved (P = 0.05) G:F compared with pigs presented meal diets. These studies found that pigs fed from wet/dry feeders had increased ADG and ADFI compared with pigs fed via dry feeders regardless of diet form. Additionally, pellet quality appeared to influence responses because pigs fed high-quality pellets via dry feeders had better growth performance than pigs fed meal diets. Conversely, if pellet quality was poor, the feed efficiency benefits associated with pelleting were lost. PMID- 23798529 TI - Altered innate defenses in the neonatal gastrointestinal tract in response to colonization by neuropathogenic Escherichia coli. AB - Two-day-old (P2), but not 9-day-old (P9), rat pups are susceptible to systemic infection following gastrointestinal colonization by Escherichia coli K1. Age dependency reflects the capacity of colonizing K1 to translocate from gastrointestinal (GI) tract to blood. A complex GI microbiota developed by P2, showed little variation over P2 to P9, and did not prevent stable K1 colonization. Substantial developmental expression was observed over P2 to P9, including upregulation of genes encoding components of the small intestinal (alpha-defensins Defa24 and Defa-rs1) and colonic (trefoil factor Tff2) mucus barrier. K1 colonization modulated expression of these peptides: developmental expression of Tff2 was dysregulated in P2 tissues and was accompanied by a decrease in mucin Muc2. Conversely, alpha-defensin genes were upregulated in P9 tissues. We propose that incomplete development of the mucus barrier during early neonatal life and the capacity of colonizing K1 to interfere with mucus barrier maturation provide opportunities for neuropathogen translocation into the bloodstream. PMID- 23798530 TI - Synergistic and additive effects of chromosomal and plasmid-encoded hemolysins contribute to hemolysis and virulence in Photobacterium damselae subsp. damselae. AB - Photobacterium damselae subsp. damselae causes infections and fatal disease in marine animals and in humans. Highly hemolytic strains produce damselysin (Dly) and plasmid-encoded HlyA (HlyA(pl)). These hemolysins are encoded by plasmid pPHDD1 and contribute to hemolysis and virulence for fish and mice. In this study, we report that all the hemolytic strains produce a hitherto uncharacterized chromosome-encoded HlyA (HlyAch). Hemolysis was completely abolished in a single hlyAch mutant of a plasmidless strain and in a dly hlyApl hlyAch triple mutant. We found that Dly, HlyA(pl), and HlyAch are needed for full hemolytic values in strains harboring pPHDD1, and these values are the result of the additive effects between HlyApl and HlyAch, on the one hand, and of the synergistic effect of Dly with HlyApl and HlyAch, on the other hand. Interestingly, Dly-producing strains produced synergistic effects with strains lacking Dly production but secreting HlyA, constituting a case of the CAMP (Christie, Atkins, and Munch-Petersen) reaction. Environmental factors such as iron starvation and salt concentration were found to regulate the expression of the three hemolysins. We found that the contributions, in terms of the individual and combined effects, of the three hemolysins to hemolysis and virulence varied depending on the animal species tested. While Dly and HlyApl were found to be main contributors in the virulence for mice, we observed that the contribution of hemolysins to virulence for fish was mainly based on the synergistic effects between Dly and either of the two HlyA hemolysins rather than on their individual effects. PMID- 23798531 TI - Probiotic Lactobacillus reuteri attenuates the stressor-enhanced severity of Citrobacter rodentium infection. AB - Stressor exposure has been shown to enhance host susceptibility and the severity of a plethora of illnesses, including gastrointestinal disease. In mice, susceptibility to Citrobacter rodentium has been shown to be dependent on host genetics as well as the composition of the intestinal microbiota, but the effects of stressor exposure on this gastrointestinal pathogen have not been elucidated fully. Previously, our lab showed that exposure to the prolonged-restraint stressor prior to a challenge with C. rodentium alters the intestinal microbiota community structure, including a reduction of beneficial genera such as Lactobacillus, which may contribute to stressor-enhanced C. rodentium-induced infectious colitis. To test the effects of stressor exposure on C. rodentium infection, we exposed resistant mice to a prolonged-restraint stressor concurrent with pathogen challenge. Exposure to prolonged restraint significantly enhanced C. rodentium-induced infectious colitis in resistant mice, as measured by increases in colonic histopathology, colonic inflammatory mediator gene production, and pathogen translocation from the colon to the spleen. It was further tested if the beneficial bacterium Lactobacillus reuteri could reduce the stressor-enhanced susceptibility to C. rodentium-enhanced infectious colitis. While L. reuteri treatment did not reduce all aspects of stressor-enhanced infectious colitis, it did significantly reduce pathogen translocation from the colon to the spleen. Taken together, these data demonstrate the deleterious effects that prolonged stressor exposure can have at the onset of a gastrointestinal infection by its ability to render a resistant mouse highly susceptible to C. rodentium. Probiotic treatment ameliorated the systemic manifestations of stress on colonic infection. PMID- 23798532 TI - LacR mutations are frequently observed in Streptococcus intermedius and are responsible for increased intermedilysin production and virulence. AB - Streptococcus intermedius secretes a human-specific cytolysin, intermedilysin (ILY), which is considered to be the major virulence factor of this pathogen. We screened for a repressor of ily expression by using random gene disruption in a low-ILY-producing strain (PC574). Three independent high-ILY-producing colonies that had plasmid insertions within a gene that has high homology to lacR were isolated. Validation of these observations was achieved through disruption of lacR in strain PC574 with an erythromycin cassette, which also led to higher hemolytic activity, increased transcription of ily, and higher cytotoxicity against HepG2 cells, compared to the parental strain. The direct binding of LacR within the ily promoter region was shown by a biotinylated DNA probe pulldown assay, and the amount of ILY secreted into the culture supernatant by PC574 cells was increased by adding lactose or galactose to the medium as a carbon source. Furthermore, we examined lacR nucleotide sequences and the hemolytic activity of 50 strains isolated from clinical infections and 7 strains isolated from dental plaque. Of the 50 strains isolated from infections, 13 showed high ILY production, 11 of these 13 strains had one or more point mutations and/or an insertion mutation in LacR, and almost all mutations were associated with a marked decline in LacR function. These results strongly suggest that mutation in lacR is required for the overproduction of ILY, which is associated with an increase in pathogenicity of S. intermedius. PMID- 23798533 TI - The Trypanosoma brucei gambiense secretome impairs lipopolysaccharide-induced maturation, cytokine production, and allostimulatory capacity of dendritic cells. AB - Trypanosoma brucei gambiense, a parasitic protozoan belonging to kinetoplastids, is the main etiological agent of human African trypanosomiasis (HAT), or sleeping sickness. One major characteristic of this disease is the dysregulation of the host immune system. The present study demonstrates that the secretome (excreted secreted proteins) of T. b. gambiense impairs the lipopolysaccharide (LPS) induced maturation of murine dendritic cells (DCs). The upregulation of major histocompatibility complex class II, CD40, CD80, and CD86 molecules, as well as the secretion of cytokines such as tumor necrosis factor alpha, interleukin-10 (IL-10), and IL-6, which are normally released at high levels by LPS-stimulated DCs, is significantly reduced when these cells are cultured in the presence of the T. b. gambiense secretome. Moreover, the inhibition of DC maturation results in the loss of their allostimulatory capacity, leading to a dramatic decrease in Th1/Th2 cytokine production by cocultured lymphocytes. These results provide new insights into a novel efficient immunosuppressive mechanism directly involving the alteration of DC function which might be used by T. b. gambiense to interfere with the host immune responses in HAT and promote the infectious process. PMID- 23798534 TI - Staphopains modulate Staphylococcus aureus biofilm integrity. AB - Staphylococcus aureus is a known cause of chronic biofilm infections that can reside on medical implants or host tissue. Recent studies have demonstrated an important role for proteinaceous material in the biofilm structure. The S. aureus genome encodes many secreted proteases, and there is growing evidence that these enzymes have self-cleavage properties that alter biofilm integrity. However, the specific contribution of each protease and mechanism of biofilm modulation is not clear. To address this issue, we utilized a sigma factor B (DeltasigB) mutant where protease activity results in a biofilm-negative phenotype, thereby creating a condition where the protease(s) responsible for the phenotype could be identified. Using a plasma-coated microtiter assay, biofilm formation was restored to the DeltasigB mutant through the addition of the cysteine protease inhibitor E-64 or by using Staphostatin inhibitors that specifically target the extracellular cysteine proteases SspB and ScpA (called Staphopains). Through construction of gene deletion mutants, we determined that an sspB scpA double mutant restored DeltasigB biofilm formation, and this recovery could be replicated in plasma-coated flow cell biofilms. Staphopain levels were also found to be decreased under biofilm-forming conditions, possibly allowing biofilm establishment. The treatment of S. aureus biofilms with purified SspB or ScpA enzyme inhibited their formation, and ScpA was also able to disperse an established biofilm. The antibiofilm properties of ScpA were conserved across S. aureus strain lineages. These findings suggest an underappreciated role of the SspB and ScpA cysteine proteases in modulating S. aureus biofilm architecture. PMID- 23798535 TI - The Mycoplasma gallisepticum virulence factor lipoprotein MslA is a novel polynucleotide binding protein. AB - Although lipoproteins of mycoplasmas are thought to play a crucial role in interactions with their hosts, very few have had their biochemical function defined. The gene encoding the lipoprotein MslA in Mycoplasma gallisepticum has recently been shown to be required for virulence, but the biochemical function of this gene is not known. Although this gene has no significant sequence similarity to any gene of known function, it is located within an operon in M. gallisepticum that contains a homolog of a gene previously shown to be a nonspecific exonuclease. We mutagenized both genes to facilitate expression in Escherichia coli and then examined the functions of the recombinant proteins. The capacity of MslA to bind polynucleotides was examined, and we found that the protein bound single- and double-stranded DNA, as well as single-stranded RNA, with a predicted binding site of greater than 1 nucleotide but less than or equal to 5 nucleotides in length. Recombinant MslA cleaved into two fragments in vitro, both of which were able to bind oligonucleotides. These findings suggest that the role of MslA may be to act in concert with the lipoprotein nuclease to generate nucleotides for transport into the mycoplasma cell, as the remaining genes in the operon are predicted to encode an ABC transporter. PMID- 23798536 TI - Poison domains block transit of translocated substrates via the Legionella pneumophila Icm/Dot system. AB - Legionella pneumophila uses the Icm/Dot type 4B secretion system (T4BSS) to deliver translocated protein substrates to the host cell, promoting replication vacuole formation. The conformational state of the translocated substrates within the bacterial cell is unknown, so we sought to determine if folded substrates could be translocated via this system. Fusions of L. pneumophila Icm/Dot translocated substrates (IDTS) to dihydrofolate reductase (DHFR) or ubiquitin (Ub), small proteins known to fold rapidly, resulted in proteins with low translocation efficiencies. The folded moieties did not cause increased aggregation of the IDTS and did not impede interaction with the adaptor protein complex IcmS/IcmW, which is thought to form a soluble complex that promotes translocation. The translocation defect was alleviated with a Ub moiety harboring mutations known to destabilize its structure, indicating that unfolded proteins are preferred substrates. Real-time analysis of translocation, following movement during the first 30 min after bacterial contact with host cells, revealed that the folded moiety caused a kinetic defect in IDTS translocation. Expression of an IDTS fused to a folded moiety interfered with the translocation of other IDTS, consistent with it causing a blockage of the translocation channel. Furthermore, the folded protein fusions also interfered with intracellular growth, consistent with inefficient or impaired translocation of proteins critical for L. pneumophila intracellular growth. These studies indicate that substrates of the Icm/Dot T4SS are translocated to the host cytosol in an unfolded conformation and that folded proteins are stalled within the translocation channel, impairing the function of the secretion system. PMID- 23798537 TI - Immunization with the yersiniabactin receptor, FyuA, protects against pyelonephritis in a murine model of urinary tract infection. AB - Urinary tract infections (UTI) are common and represent a substantial economic and public health burden. Roughly 80% of these infections are caused by a heterogeneous group of uropathogenic Escherichia coli (UPEC) strains. Antibiotics are standard therapy for UTI, but a rise in antibiotic resistance has complicated treatment, making the development of a UTI vaccine more urgent. Iron receptors are a promising new class of vaccine targets for UTI, as UPEC require iron to colonize the iron-limited host urinary tract and genes encoding iron acquisition systems are highly expressed during infection. Previously, three of six UPEC siderophore and heme receptors were identified as vaccine candidates by intranasal immunization in a murine model of ascending UTI. To complete the assessment of iron receptors as vaccine candidates, an additional six UPEC iron receptors were evaluated. Of the six vaccine candidates tested in this study (FyuA, FitA, IroN, the gene product of the CFT073 locus c0294, and two truncated derivatives of ChuA), only FyuA provided significant protection (P = 0.0018) against UPEC colonization. Intranasal immunization induced a robust and long lived humoral immune response. In addition, the levels of FyuA-specific serum IgG correlated with bacterial loads in the kidneys [Spearman's rank correlation coefficient rho(14) = -0.72, P = 0.0018], providing a surrogate of protection. FyuA is the fourth UPEC iron receptor to be identified from our screens, in addition to IutA, Hma, and IreA, which were previously demonstrated to elicit protection against UPEC challenge. Together, these iron receptor antigens will facilitate the development of a broadly protective, multivalent UTI vaccine to effectively target diverse strains of UPEC. PMID- 23798538 TI - Vesicle-associated membrane protein 4 and syntaxin 6 interactions at the chlamydial inclusion. AB - The predominant players in membrane fusion events are the soluble N ethylmaleimide-sensitive factor attachment protein receptor (SNARE) family of proteins. We hypothesize that SNARE proteins mediate fusion events at the chlamydial inclusion and are important for chlamydial lipid acquisition. We have previously demonstrated that trans-Golgi SNARE syntaxin 6 localizes to the chlamydial inclusion. To investigate the role of syntaxin 6 at the chlamydial inclusion, we examined the localization and function of another trans-Golgi SNARE and syntaxin 6-binding partner, vesicle-associated membrane protein 4 (VAMP4), at the chlamydial inclusion. In this study, we demonstrate that syntaxin 6 and VAMP4 colocalize to the chlamydial inclusion and interact at the chlamydial inclusion. Furthermore, in the absence of VAMP4, syntaxin 6 is not retained at the chlamydial inclusion. Small interfering RNA (siRNA) knockdown of VAMP4 inhibited chlamydial sphingomyelin acquisition, correlating with a log decrease in infectious progeny. VAMP4 retention at the inclusion was shown to be dependent on de novo chlamydial protein synthesis, but unlike syntaxin 6, VAMP4 recruitment is observed in a species-dependent manner. Notably, VAMP4 knockdown inhibits sphingomyelin trafficking only to inclusions in which it localizes. These data support the hypothesis that VAMP proteins play a central role in mediating eukaryotic vesicular interactions at the chlamydial inclusion and, thus, support chlamydial lipid acquisition and chlamydial development. PMID- 23798539 TI - Promotion of colonization and virulence by cholera toxin is dependent on neutrophils. AB - The innate immune response to Vibrio cholerae infection is poorly understood, but this knowledge is critical for the design of safe, effective vaccines. Using an adult mouse intestinal infection model, this study examines the contribution of neutrophils to host immunity, as well as the effect of cholera toxin and other secreted factors on this response. Depletion of neutrophils from mice with anti Ly6G IA8 monoclonal antibody led to similar survival rates of mice infected with low or moderate doses of toxigenic V. cholerae El Tor O1. At a high dose, neutropenic mice showed increased rates of survival compared to neutrophil replete animals. Expression of cholera toxin was found to be protective to the neutropenic host, and this phenotype can be replicated by the administration of purified toxin. Neutrophils do not effectively clear colonizing bacteria from the small intestine, nor do they alter induction of early immune-modulating signals. In both neutropenic and neutrophil-replete animals, the local response to infection is characterized by expression of interleukin 6 (IL-6), IL-10, and macrophage inflammatory protein 2 alpha (MIP-2). Overall, these data indicate that the innate immune response to toxigenic V. cholerae infection differs dramatically from the host response to nontoxigenic infection or vaccination, where neutrophils are protective to the host. In the absence of neutrophils, cholera toxin induces immunomodulatory effects that increase host survival. In cholera toxin-producing strains, similar to nontoxigenic infection, accessory toxins are critical to virulence, indicating that cholera toxin and the other secreted toxins modulate the host response by different mechanisms, with both contributing to bacterial persistence and virulence. PMID- 23798540 TI - Adjuvant activity of naturally occurring monophosphoryl lipopolysaccharide preparations from mucosa-associated bacteria. AB - Natural heterogeneity in the structure of the lipid A portion of lipopolysaccharide (LPS) produces differential effects on the innate immune response. Gram-negative bacterial species produce LPS structures that differ from the classic endotoxic LPS structures. These differences include hypoacylation and hypophosphorylation of the diglucosamine backbone, both differences known to decrease LPS toxicity. The effect of decreased toxicity on the adjuvant properties of many of these LPS structures has not been fully explored. Here we demonstrate that two naturally produced forms of monophosphorylated LPS, from the mucosa-associated bacteria Bacteroides thetaiotaomicron and Prevotella intermedia, function as immunological adjuvants for antigen-specific immune responses. Each form of mucosal LPS increased vaccination-initiated antigen specific antibody titers in both quantity and quality when given simultaneously with vaccine antigen preparations. Interestingly, adjuvant effects on initial T cell clonal expansion were selective for CD4 T cells. No significant increase in CD8 T cell expansion was detected. MyD88/Toll-like receptor 4 (TLR4) and TRIF/TLR4 signaling pathways showed equally decreased signaling with the LPS forms studied here as with endotoxic LPS or detoxified monophosphorylated lipid A (MPLA). Natural monophosphorylated LPS from mucosa-associated bacteria functions as a weak but effective adjuvant for specific immune responses, with preferential effects on antibody and CD4 T cell responses over CD8 T cell responses. PMID- 23798541 TI - Human and mouse macrophages collaborate with neutrophils to kill larval Strongyloides stercoralis. AB - Macrophages are multifunctional cells that are active in TH1- and TH2-mediated responses. In this study, we demonstrate that human and mouse macrophages collaborate with neutrophils and complement to kill the parasite Strongyloides stercoralis in vitro. Infection of mice with worms resulted in the induction of alternatively activated macrophages (AAM) within the peritoneal cavity. These cells killed the worms in vivo and collaborated with neutrophils and complement during the in vitro killing process. AAM generated in vitro killed larvae more rapidly than naive macrophages, which killed larvae after a longer time period. In contrast, classically activated macrophages were unable to kill larvae either in vitro or in vivo. This study adds macrophages to the armamentarium of immune components that function in elimination of parasitic helminths and demonstrate a novel function by which AAM control large extracellular parasites. PMID- 23798542 TI - Elution-extrusion counter-current chromatography separation of two new benzyl ester glucosides and three other high-polarity compounds from the tubers of Pleione bulbocodioides. AB - INTRODUCTION: The tubers of Pleione bulbocodioides (Franch.) Rolfe, with gastrodin and benzyl ester glucosides as main components, have been used in traditional Chinese medicine for the treatment of various cancers and bacterial infections. Up to now, their official quality control method is still inadequate, and the difficulty of obtaining these high-polarity compounds is one of the major reasons. OBJECTIVE: To develop a rapid and efficient method for preparative separation of the high-polarity compounds gastrodin and benzyl ester glucosides. METHODS: An optimised solvent system composed of n-butanol:ethanol:water (20:1:20, v/v/v) was applied for the elution-extrusion counter-current chromatography (EECCC) separation. The upper phase was used as the stationary phase, and the lower phase was used as the mobile phase at a flow rate of 1.5 mL/min, a rotation speed of 850 rpm and a temperature of 35 degrees C. RESULTS: Five high-polarity glucosides, including two new compounds, (E)-4-beta-D glucopyranosyloxycinnamic acid 9-(4-beta-D-glucopyranosyloxybenzyl) ester (4 mg) and (Z)-2-(2-methylpropyl)butenedioic acid bis(4-beta-D-glucopyranosyloxybenzyl) ester (9 mg), and three main components, gastrodin (87 mg), dactylorhin A (60 mg) and militarine (15 mg), with HPLC purities of 95.4%, 96.4%, 91.1%, 97.2% and 95.5% respectively, were yielded from 400 mg of the prepared sample. CONCLUSION: Elution-extrusion counter-current chromatography could be used as a useful tool for the separation of high-polarity compounds such as gastrodin and benzyl ester glucosides and the enrichment of the minor ones. PMID- 23798543 TI - Proteome analysis reveals antiangiogenic environments in chronic wounds of diabetes mellitus type 2 patients. AB - In contrast to normal healing wounds, chronic wounds commonly show disturbances in proteins regulating wound healing processes, particularly those involved in cell proliferation and protein degradation. Multidimensional protein identification technology MS/MS was conducted to investigate and compare the protein composition of chronic diabetic foot exudates to exudates from split-skin donor sites of burn victims otherwise healthy. Spectral counting revealed 188 proteins differentially expressed (more than twofold and p-value <0.05) in chronic wounds. Most were involved in biological processes including inflammation, angiogenesis, and cell mortality. Increased expression of the inflammatory response stimulating S100 proteins, predominantly S100A8 and S100A9 (almost tenfold), was identified. Matrix metalloproteinases (MMPs) MMP1, MMP2, and MMP8 were identified to be elevated in chronic wounds with significant impact on collagen degradation and tissue destruction. Further, proteins with antiangiogenic properties were found at higher expression levels in chronic wounds. Reduced angiogenesis leads to drastic shortage in nutrition supply and causes increased cell death, demonstrated by Annexin A5 exclusively found in chronic wound exudates. However, excessive nucleic and cytosolic material infers cell death occurring not only by apoptosis but also by necrosis. In conclusion, mass spectrometric investigation of exudates from chronic wounds demonstrated dramatic impairment in wound repair with excessive inflammation, antiangiogenic environment, and accelerated cell death. PMID- 23798544 TI - Stability and oxidation products of hydrolysable tannins in basic conditions detected by HPLC/DAD-ESI/QTOF/MS. AB - INTRODUCTION: Hydrolysable tannins occur in plants that are used for food or medicine by humans or herbivores. Basic conditions can alter the structures of tannins, that is, the oxidation of phenolic groups can lead to the formation of toxic quinones. Previously, these labile quinones and other oxidation products have been studied with colorimetric or electron paramagnetic resonance methods, which give limited information about products. OBJECTIVE: To study the stability and oxidation products of hydrolysable tannins in basic conditions using HPLC with a diode-array detector (DAD) combined with electrospray ionisation (ESI) and quadrupole time-of-flight (QTOF) MS. METHODS: Three galloyl glucoses, four galloyl derivatives with different polyols and three ellagitannins were purified from plants. The incubation reactions of tannins were monitored by HPLC/DAD at five pH values and in reduced oxygen conditions. Reaction products were identified based on UV spectra and mass spectral fragmentation obtained with the high-resolution HPLC/DAD-ESI/QTOF/MS. The use of a base-resistant HPLC column enabled injections without the sample pre-treatment and thus detection of short lived products. RESULTS: Hydrolysable tannins were unstable in basic conditions and half-lives were mostly less than 10 min at pH 10. Degradation rates were faster at pH 11 but slower at milder pH. The HPLC analyses revealed that various products were formed and identified to be the result of hydrolysis, deprotonation and oxidation. Interestingly, the main hydrolysis product was ellagic acid; it was also formed from galloyl glucoses that do not contain oxidatively coupled galloyl groups in their initial structures. CONCLUSION: HPLD/DAD-ESI/QTOF/MS was an efficient method for the identification of polyphenol oxidation products and showed how different pH conditions determine the fate of hydrolysable tannins. PMID- 23798545 TI - Bottom-up proteome analysis of E. coli using capillary zone electrophoresis tandem mass spectrometry with an electrokinetic sheath-flow electrospray interface. AB - The Escherichia coli proteome was digested with trypsin and fractionated using SPE on a C18 SPE column. Seven fractions were collected and analyzed by CZE-ESI MS/MS. The separation was performed in a 60-cm-long linear polyacrylamide-coated capillary with a 0.1% v/v formic acid separation buffer. An electrokinetic sheath flow electrospray interface was used to couple the separation capillary with an Orbitrap-Velos operating in higher-energy collisional dissociation mode. Each CZE ESI-MS/MS run lasted 50 min and total MS time was 350 min. A total of 23 706 peptide spectra matches, 4902 peptide IDs, and 871 protein group IDs were generated using MASCOT with false discovery rate less than 1% on the peptide level. The total mass spectrometer analysis time was less than 6 h, the sample identification rate (145 proteins/h) was more than two times higher than previous studies of the E. coli proteome, and the amount of sample consumed (<1 MUg) was roughly fourfold less than previous studies. These results demonstrate that CZE is a useful tool for the bottom-up analysis of prokaryote proteomes. PMID- 23798546 TI - Fetal therapy: the need for well-designed collaborative research trials. PMID- 23798547 TI - Re: Fetal cardiac catheterization using a percutaneous transhepatic access technique: preliminary experience in a lamb model. A. Edwards, S. Menahem, A. Veldman, D. Schranz, Y. Chan, I. Nitsos and F. Wong. Ultrasound Obstet Gynecol 2013; 42: 58-63. PMID- 23798548 TI - Re: Intra- and interobserver reproducibility of assessment of Doppler ultrasound findings in adnexal masses. L. Zannoni , L. Savelli , L. Jokubkiene , A. Di Legge , G. Condous , A. C. Testa , P. Sladkevicius and L. Valentin . Ultrasound Obstet Gynecol 2013; 42: 93-101. PMID- 23798549 TI - Reply: To PMID 22323094. PMID- 23798550 TI - Does the presence of a uterine scar influence the site of placental implantation? PMID- 23798551 TI - Re: Predicting successful vaginal birth after Cesarean section using a model based on Cesarean scar features examined using transvaginal sonography. PMID- 23798552 TI - Reply: To PMID 23371440. PMID- 23798553 TI - Proteome and phosphoproteome of Africanized and European honeybee venoms. AB - Honey bee venom toxins trigger immunological, physiological, and neurological responses within victims. The high occurrence of bee attacks involving potentially fatal toxic and allergic reactions in humans and the prospect of developing novel pharmaceuticals make honey bee venom an attractive target for proteomic studies. Using label-free quantification, we compared the proteome and phosphoproteome of the venom of Africanized honeybees with that of two European subspecies, namely Apis mellifera ligustica and A. m. carnica. From the total of 51 proteins, 42 were common to all three subspecies. Remarkably, the toxins melittin and icarapin were phosphorylated. In all venoms, icarapin was phosphorylated at the (205) Ser residue, which is located in close proximity to its known antigenic site. Melittin, the major toxin of honeybee venoms, was phosphorylated in all venoms at the (10) Thr and (18) Ser residues. (18) Ser phosphorylated melittin-the major of its two phosphorylated forms-was less toxic compared to the native peptide. PMID- 23798554 TI - Critical differences between isoforms of securin reveal mechanisms of separase regulation. AB - Sister chromatid separation depends on the activity of separase, which in turn requires the proteolysis of its inhibitor, securin. It has been speculated that securin also supports the activation of separase. In this study, we found that PTTG1 was the major securin isoform expressed in most normal and cancer cell lines. Remarkably, a highly homologous isoform called PTTG2 was unable to interact with separase. Using chimeras between PTTG1 and PTTG2 and other approaches, we pinpointed a single amino acid that accounted for the loss of securin function in PTTG2. Mutation of the homologous position in PTTG1 (H(134)) switched PTTG1 from an inhibitor into an activator of separase. In agreement with this, PTTG1 lacking H(134) was able to trigger premature sister chromatid separation. Conversely, introduction of H(134) into PTTG2 is sufficient to allow it to bind separase. These data demonstrate that while the motif containing H(134) has a strong affinity for separase and is involved in inhibiting it, another domain(s) is involved in activating separase and has a weaker affinity for it. Although PTTG2 lacks securin function, its differences from PTTG1 provide evidence of independent inhibitory and activating functions of PTTG1 on separase. PMID- 23798555 TI - Oncogenic activity of retinoic acid receptor gamma is exhibited through activation of the Akt/NF-kappaB and Wnt/beta-catenin pathways in cholangiocarcinoma. AB - Aberrant expression and function of retinoic acid receptor gamma (RARgamma) are often involved in the progression of several cancers. However, the role of RARgamma in cholangiocarcinoma (CCA), chemoresistant bile duct carcinoma with a poor prognosis, remains unclear. In the present study, we found that RARgamma was frequently overexpressed in human CCA specimens. Its overexpression was associated with poor differentiation, lymph node metastasis, high serum carbohydrate antigen 19-9 level, and poor prognosis of CCA. Downregulation of RARgamma reduced CCA cell proliferation, migration, invasion, and colony formation ability in vitro and tumorigenic potential in nude mice. RARgamma knockdown resulted in upregulation of cell cycle inhibitor P21, as well as downregulation of cyclin D1, proliferating cell nuclear antigen, and matrix metallopeptidase 9, in parallel with suppression of the Akt/NF-kappaB pathway. Furthermore, overexpression of RARgamma contributed to the multidrug chemoresistance of CCA cells, at least in part due to upregulation of P glycoprotein via activation of the Wnt/beta-catenin pathway. Molecular mechanism studies revealed that RARgamma interacted with beta-catenin and led to beta catenin nuclear translocation. Taken together, our results suggested that RARgamma plays an important role in the proliferation, metastasis, and chemoresistance of CCA through simultaneous activation of the Akt/NF-kappaB and Wnt/beta-catenin pathways, serving as a potential molecular target for CCA treatment. PMID- 23798556 TI - The winged helix transcription factor Foxa3 regulates adipocyte differentiation and depot-selective fat tissue expansion. AB - Conversion of mesenchymal stem cells into terminally differentiated adipocytes progresses sequentially through regulated transcriptional steps. While it is clear that the late phases of adipocyte maturation are governed by the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma), less is known about the transcriptional control of the initial stages of differentiation. To identify early regulators, we performed a small interfering RNA (siRNA) screen of Forkhead-box genes in adipocytes and show here for the first time that the winged helix factor Foxa3 promotes adipocyte differentiation by cooperating with C/EBPbeta and -delta to transcriptionally induce PPARgamma expression. Furthermore, we demonstrate that mice with genetic ablation of Foxa3 have a selective decrease in epididymal fat depot and a cell-autonomous defect to induce PPARgamma specifically in their visceral adipocytes. In obese subjects, FOXA3 is differentially expressed in visceral and subcutaneous adipose depots. Overall, our study implicates Foxa3 in the regulation of adipocyte differentiation and depot-selective adipose tissue expansion. PMID- 23798557 TI - Loss of epithelial hypoxia-inducible factor prolyl hydroxylase 2 accelerates skin wound healing in mice. AB - Skin wound healing in mammals is a complex, multicellular process that depends on the precise supply of oxygen. Hypoxia-inducible factor (HIF) prolyl hydroxylase 2 (PHD2) serves as a crucial oxygen sensor and may therefore play an important role during reepithelialization. Hence, this study was aimed at understanding the role of PHD2 in cutaneous wound healing using different lines of conditionally deficient mice specifically lacking PHD2 in inflammatory, vascular, or epidermal cells. Interestingly, PHD2 deficiency only in keratinocytes and not in myeloid or endothelial cells was found to lead to faster wound closure, which involved enhanced migration of the hyperproliferating epithelium. We demonstrate that this effect relies on the unique expression of beta3-integrin in the keratinocytes around the tip of the migrating tongue in an HIF1alpha-dependent manner. Furthermore, we show enhanced proliferation of these cells in the stratum basale, which is directly related to their attenuated transforming growth factor beta signaling. Thus, loss of the central oxygen sensor PHD2 in keratinocytes stimulates wound closure by prompting skin epithelial cells to migrate and proliferate. Inhibition of PHD2 could therefore offer novel therapeutic opportunities for the local treatment of cutaneous wounds. PMID- 23798559 TI - Cognitive rehabilitation for executive dysfunction in adults with stroke or other adult nonprogressive acquired brain damage. PMID- 23798558 TI - Laminin, gamma 2 (LAMC2): a promising new putative pancreatic cancer biomarker identified by proteomic analysis of pancreatic adenocarcinoma tissues. AB - In pancreatic cancer, the incidence and mortality curves coincide. One major reason for this high mortality rate in pancreatic ductal adenocarcinoma (PDAC) patients is the dearth of effective diagnostic, prognostic, and disease monitoring biomarkers. Unfortunately, existing tumor markers, as well as current imaging modalities, are not sufficiently sensitive and/or specific for early stage diagnosis. There is, therefore, an urgent need for improved serum markers of the disease. Herein, we performed Orbitrap(r) mass spectrometry proteomic analysis of four PDAC tissues and their adjacent benign tissues and identified a total of 2190 nonredundant proteins. Sixteen promising candidates were selected for further scrutiny using a systematic scoring algorithm. Our preliminary serum verification of the top four candidates (DSP, LAMC2, GP73, and DSG2) in 20 patients diagnosed with pancreatic cancer and 20 with benign pancreatic cysts, showed a significant (p < 0.05) elevation of LAMC2 in pancreatic cancer serum. Extensive validation of LAMC2 in healthy, benign, and PDAC sera from geographically diverse cohorts (n = 425) (Japan, Europe, and USA) demonstrated a significant increase in levels in early-stage PDAC compared with benign diseases. The sensitivity of LAMC2 was comparable to CA19.9 in all data sets, with an AUC value greater than 0.85 in discriminating healthy patients from early-stage PDAC patients. LAMC2 exhibited diagnostic complementarity with CA19.9 by showing significant (p < 0.001 in two out of three cohorts) elevation in PDAC patients with clinically low CA19.9 levels. PMID- 23798560 TI - Endovascular treatment of intracranial aneurysms: current status. PMID- 23798564 TI - Knockdown of N-acetylglucosaminyl transferase V ameliorates hepatotoxin-induced liver fibrosis in mice. AB - Aberrant N-glycosylation caused by altered N-acetyl glucosaminyltransferase V (GnT-V) expression is known to regulate tumor invasion and metastasis by modulating multiple cytokine signaling pathways. However, the exact role of GnT-V in the development of liver fibrosis has not been clearly defined. Here, we induced mouse liver fibrosis by ip injections of carbon tetrachloride (CCl4) or thioacetamide (TAA) and observed significant increase of hepatic GnT-V during the processes of liver fibrogenesis. Meanwhile, upregulations of GnT-V were detected in the activated hepatic stellate cells (HSCs) and injured hepatocytes. To knock down hepatic GnT-V expression, adenovirus that expressed the GnT-V siRNA was injected via the tail vein. Adenovirus-mediated delivery of GnT-V siRNA dramatically reduced the GnT-V expression in fibrotic liver and activated HSC in vivo and consequently alleviated CCl4- or TAA-induced liver fibrosis as assessed through collagen deposition and profiles of profibrogenic markers. Furthermore, knockdown of GnT-V in HSCs reduced transforming growth factor beta (TGF beta)/Smad signaling and blunted the activated HSC phenotype. The suppression of TGF-beta/Smad signaling in HSCs correlated with the decrease of GnT-V-modified beta1,6-branched N-glycan on TGF-beta receptors. Knockdown of GnT-V also suppressed platelet-derived growth factor (PDGF)-induced HSC proliferation and migration through inhibiting PDGF/Erk signaling. Finally, we demonstrated that knockdown of GnT-V profoundly suppressed TGF-beta1-induced epithelial-mesenchymal transition (EMT) in hepatocytes by morphological assessment and reversal of EMT markers. In conclusion, this study demonstrates that GnT-V is implicated in hepatotoxin-induced liver fibrosis, and targeting GnT-V may be a feasible and promising approach for treating liver fibrosis. PMID- 23798565 TI - Suppression of acute graft-versus-host response by TCDD is independent of the CTLA-4-IFN-gamma-IDO pathway. AB - Activation of the aryl hydrocarbon receptor (AhR) by its prototypic ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), induces potent suppression of an acute graft-versus-host (GVH) response and prevents GVH disease (GVHD). Suppression is associated with development of a regulatory population of donor CD4(+) CD25(+)T-cells that express high levels of cytotoxic T-lymphocyte antigen 4 (CTLA-4). However, a direct link between these AhR-induced Tregs (AhR-Tregs) and suppression of GVHD remains to be shown. CTLA-4 is a negative regulator of T cell responses and is associated with the induction of tolerogenic dendritic cells (DCs) that produce indoleamine 2,3-dioxygenase (IDO). We hypothesized that AhR-Tregs mediate suppression via their enhanced expression of CTLA-4, which, in turn, induces IFN-gamma and IDO in host DCs. Subsequent depletion of tryptophan by IDO leads to termination of the donor T-cell response prior to development of effector CTL. Here, we show that despite increased expression of Ifng, Irf3, Irf7, Ido1, and Ido2 in the lymph nodes of TCDD-treated host mice, inhibition of IDO enzyme activity by 1-methyl-tryptophan was unable to relieve TCDD-mediated suppression of the GVH response. Furthermore, treatment with an anti-CTLA-4 antibody that blocks CTLA-4 signaling was also unable to alleviate TCDD-mediated suppression. Alternatively, we investigated the possibility that donor-derived AhR-Tregs produce IFN-gamma to suppress effector CTL development. However, suppression of GVHD by TCDD was not affected by the use of Ifng-deficient donor cells. Together, these results indicate that neither overexpression of CTLA-4 nor production of IFN-gamma by AhR-Tregs plays a major role in the manifestation of their immunosuppressive function in vivo. PMID- 23798567 TI - Dmdmdx/Largemyd: a new mouse model of neuromuscular diseases useful for studying physiopathological mechanisms and testing therapies. AB - Although muscular dystrophies are among the most common human genetic disorders, there are few treatment options available. Animal models have become increasingly important for testing new therapies prior to entering human clinical trials. The Dmd(mdx) mouse is the most widely used animal model for Duchenne muscular dystrophy (DMD), presenting the same molecular and protein defect as seen in humans with the disease. However, this mouse is not useful for clinical trials because of its very mild phenotype. The mouse model for congenital myodystrophy type 1D, Large(myd), harbors a mutation in the glycosyltransferase Large gene and displays a severe phenotype. To help elucidate the role of the proteins dystrophin and LARGE in the organization of the dystrophin-glycoprotein complex in muscle sarcolemma, we generated double-mutant mice for the dystrophin and LARGE proteins. The new Dmd(mdx)/Large(myd) mouse model is viable and shows a severe phenotype that is associated with the lack of dystrophin in muscle. We tested the usefulness of our new mouse model for cell therapy by systemically injecting them with normal murine mesenchymal adipose stem cells (mASCs). We verified that the mASCs were hosted in the dystrophic muscle. The new mouse model has proven to be very useful for the study of several other therapies, because injected cells can be screened both through DNA and protein analysis. Study of its substantial muscle weakness will also be very informative in the evaluation of functional benefits of these therapies. PMID- 23798566 TI - Studies in experimental autoimmune encephalomyelitis do not support developmental bisphenol a exposure as an environmental factor in increasing multiple sclerosis risk. AB - Multiple sclerosis (MS), a demyelinating immune-mediated central nervous system disease characterized by increasing female penetrance, is the leading cause of disability in young adults in the developed world. Epidemiological data strongly implicate an environmental factor, acting at the population level during gestation, in the increasing incidence of female MS observed over the last 50 years, yet the identity of this factor remains unknown. Gestational exposure to bisphenol A (BPA), an endocrine disruptor used in the manufacture of polycarbonate plastics since the 1950s, has been reported to alter a variety of physiological processes in adulthood. BPA has estrogenic activity, and we hypothesized that increased gestational exposure to environmental BPA may therefore contribute to the increasing female MS risk. To test this hypothesis, we utilized two different mouse models of MS, experimental autoimmune encephalomyelitis (EAE) in C57BL/6J mice (chronic progressive) and in SJL/J mice (relapsing-remitting). Dams were exposed to physiologically relevant levels of BPA in drinking water starting 2 weeks prior to mating and continuing until weaning of offspring. EAE was induced in adult offspring. No significant changes in EAE incidence, progression, or severity were observed with BPA exposure, despite changes in cytokine production by autoreactive T cells. However, endocrine disruption was evidenced by changes in testes development, and transcriptomic profiling revealed that BPA exposure altered the expression of several genes important for testes development, including Pdgfa, which was downregulated. Overall, our results do not support gestational BPA exposure as a significant contributor to the increasing female MS risk. PMID- 23798568 TI - Mutant Enpp1asj mice as a model for generalized arterial calcification of infancy. AB - Generalized arterial calcification of infancy (GACI), an autosomal recessive disorder, is characterized by early mineralization of blood vessels, often diagnosed by prenatal ultrasound and usually resulting in demise during the first year of life. It is caused in most cases by mutations in the ENPP1 gene, encoding an enzyme that hydrolyzes ATP to AMP and inorganic pyrophosphate, the latter being a powerful anti-mineralization factor. Recently, a novel mouse phenotype was recognized as a result of ENU mutagenesis - those mice developed stiffening of the joints, hence the mutant mouse was named 'ages with stiffened joints' (asj). These mice harbor a missense mutation, p.V246D, in the Enpp1 gene. Here we demonstrate that the mutant ENPP1 protein is largely absent in the liver of asj mice, and the lack of enzymatic activity results in reduced inorganic pyrophosphate (PPi) levels in the plasma, accompanied by extensive mineralization of a number of tissues, including arterial blood vessels. The progress of mineralization is highly dependent on the mineral composition of the diet, with significant shortening of the lifespan on a diet enriched in phosphorus and low in magnesium. These results suggest that the asj mouse can serve as an animal model for GACI. PMID- 23798569 TI - Ethanol metabolism and oxidative stress are required for unfolded protein response activation and steatosis in zebrafish with alcoholic liver disease. AB - Secretory pathway dysfunction and lipid accumulation (steatosis) are the two most common responses of hepatocytes to ethanol exposure and are major factors in the pathophysiology of alcoholic liver disease (ALD). However, the mechanisms by which ethanol elicits these cellular responses are not fully understood. Recent data indicates that activation of the unfolded protein response (UPR) in response to secretory pathway dysfunction can cause steatosis. Here, we examined the relationship between alcohol metabolism, oxidative stress, secretory pathway stress and steatosis using zebrafish larvae. We found that ethanol was immediately internalized and metabolized by larvae, such that the internal ethanol concentration in 4-day-old larvae equilibrated to 160 mM after 1 hour of exposure to 350 mM ethanol, with an average ethanol metabolism rate of 56 MUmol/larva/hour over 32 hours. Blocking alcohol dehydrogenase 1 (Adh1) and cytochrome P450 2E1 (Cyp2e1), the major enzymes that metabolize ethanol, prevented alcohol-induced steatosis and reduced induction of the UPR in the liver. Thus, we conclude that ethanol metabolism causes ALD in zebrafish. Oxidative stress generated by Cyp2e1-mediated ethanol metabolism is proposed to be a major culprit in ALD pathology. We found that production of reactive oxygen species (ROS) increased in larvae exposed to ethanol, whereas inhibition of the zebrafish CYP2E1 homolog or administration of antioxidants reduced ROS levels. Importantly, these treatments also blocked ethanol-induced steatosis and reduced UPR activation, whereas hydrogen peroxide (H2O2) acted as a pro-oxidant that synergized with low doses of ethanol to induce the UPR. Collectively, these data demonstrate that ethanol metabolism and oxidative stress are conserved mechanisms required for the development of steatosis and hepatic dysfunction in ALD, and that these processes contribute to ethanol-induced UPR activation and secretory pathway stress in hepatocytes. PMID- 23798570 TI - Endogenous progesterone levels and frontotemporal dementia: modulation of TDP-43 and Tau levels in vitro and treatment of the A315T TARDBP mouse model. AB - Frontotemporal dementia (FTD) is associated with motor neurone disease (FTD-MND), corticobasal syndrome (CBS) and progressive supranuclear palsy syndrome (PSPS). Together, this group of disorders constitutes a major cause of young-onset dementia. One of the three clinical variants of FTD is progressive nonfluent aphasia (PNFA), which is focused on in this study. The steroid hormone progesterone (PROG) is known to have an important role as a neurosteroid with potent neuroprotective and promyelination properties. In a case-control study of serum samples (39 FTD, 91 controls), low serum PROG was associated with FTD overall. In subgroup analysis, low PROG levels were significantly associated with FTD-MND and CBS, but not with PSPS or PNFA. PROG levels of >195 pg/ml were significantly correlated with lower disease severity (frontotemporal dementia rating scale) for individuals with CBS. In the human neuroblastoma SK-N-MC cell line, exogenous PROG (9300-93,000 pg/ml) had a significant effect on overall Tau and nuclear TDP-43 levels, reducing total Tau levels by ~1.5-fold and increasing nuclear TDP-43 by 1.7- to 2.0-fold. Finally, elevation of plasma PROG to a mean concentration of 5870 pg/ml in an Ala315Thr (A315T) TARDBP transgenic mouse model significantly reduced the rate of loss of locomotor control in PROG-treated, compared with placebo, mice. The PROG treatment did not significantly increase survival of the mice, which might be due to the limitation of the transgenic mouse to accurately model TDP-43-mediated neurodegeneration. Together, our clinical, cellular and animal data provide strong evidence that PROG could be a valid therapy for specific related disorders of FTD. PMID- 23798571 TI - Novel, gel-free proteomics approach identifies RNF5 and JAMP as modulators of GPCR stability. AB - The maturation and folding of G protein-coupled receptors are governed by mechanisms that remain poorly understood. In an effort to characterize these biological events, we optimized a novel, gel-free proteomic approach to identify partners of the beta2-adrenergic receptor (beta2AR). In addition to a number of known interacting proteins such as heterotrimeric G protein subunits, this allowed us to identify proteins involved in endoplasmic reticulum (ER) QC of the receptor. Among beta2AR-associated proteins is Ring finger protein 5 (RNF5), an E3 ubiquitin ligase anchored to the outer membrane of the ER. Coimmunoprecipitation assays confirmed, in a cellular context, the interaction between RNF5 and the beta2AR as well as the prostaglandin D2 receptor (DP). Confocal microscopy revealed that DP colocalized with RNF5 at the ER. Coexpression of RNF5 with either receptor increased levels of their expression, whereas small interfering RNA-mediated knockdown of endogenous RNF5 promoted the opposite. RNF5 did not modulate the ubiquitination state of beta2AR or DP. Instead, RNF5 ubiquitinated JNK-associated membrane protein (JAMP), a protein that recruits the proteasome to the ER membrane and that is negatively regulated by RNF5-mediated ubiquitination. JAMP coimmunoprecipitated with both beta2AR and DP and decreased total receptor protein levels through proteasomal degradation. Expression of DP, a receptor largely retained in the ER, promoted proteasome recruitment by JAMP. Degradation of both receptors via JAMP was increased when RNF5 was depleted. Our data suggest that RNF5 regulates the turnover of specific G protein-coupled receptors by ubiquitinating JAMP and preventing proteasome recruitment. PMID- 23798572 TI - Stimulation of proglucagon gene expression by human GPR119 in enteroendocrine L cell line GLUTag. AB - GPR119 is a G protein-coupled receptor expressed on enteroendocrine L-cells that synthesize and secrete the incretin hormone glucagon-like peptide-1 (GLP-1). Although GPR119 agonists stimulate L-cell GLP-1 secretion, there is uncertainty concerning whether GLP-1 biosynthesis is under the control of GPR119. Here we report that GPR119 is functionally coupled to increased proglucagon (PG) gene expression that constitutes an essential first step in GLP-1 biosynthesis. Using a mouse L-cell line (GLUTag) that expresses endogenous GPR119, we demonstrate that PG gene promoter activity is stimulated by GPR119 agonist AS1269574. Surprisingly, transfection of GLUTag cells with recombinant human GPR119 (hGPR119) results in a constitutive and apparently ligand-independent increase of PG gene promoter activity and PG mRNA content. These constitutive actions of hGPR119 are mediated by cAMP-dependent protein kinase (PKA) but not cAMP sensor Epac2. Thus, the constitutive action of hGPR119 to stimulate PG gene promoter activity is diminished by: 1) a dominant-negative Galphas protein, 2) a dominant negative PKA regulatory subunit, and 3) a dominant-negative A-CREB. Interestingly, PG gene promoter activity is stimulated by 6-Bn-cAMP-AM, a cAMP analog that selectively activates alpha and beta isoforms of type II, but not type I PKA regulatory subunits expressed in GLUTag cells. Finally, our analysis reveals that a specific inhibitor of Epac2 activation (ESI-05) fails to block the stimulatory action of 6-Bn-cAMP-AM at the PG gene promoter, nor is PG gene promoter activity stimulated by: 1) a constitutively active Epac2, or 2) cAMP analogs that selectively activate Epac proteins. Such findings are discussed within the context of ongoing controversies concerning the relative contributions of PKA and Epac2 to the control of PG gene expression. PMID- 23798573 TI - Metastasin S100A4 is a mediator of sex hormone-dependent formation of the cortical bone. AB - S100A4 is a Ca-binding protein participating in regulation of cell growth, survival, and motility. Here we studied the role of S100A4 protein in sex hormone regulated bone formation. Bone mineral density in the trabecular and cortical compartments was evaluated in female S100A4 knockout (KO), in matched wild-type (WT) counterparts, and in WT mice treated with lentiviral small hairpin RNA construct inhibiting the S100A4 gene transcription or with a nontargeting construct, by peripheral quantitative computed tomography. The effect of sex hormones on bone was measured 5 weeks after ovariectomy (OVX) and/or dehydroepiadrosterone treatment. S100A4KO had an excessive trabecular and cortical bone formation compared with the age- and sex-matched WT mice. S100A4KO had an increased periosteal circumference (P = .001), cortical thickness (P = .056), and cortical area (P = .003), which predicted 20% higher bone strength in S100A4KO (P = .013). WT mice treated with small hairpin RNA-S100A4 showed an increase of the cortical bone parameters in a fashion identical with S100A4KO mice, indicating the key role of S100A4 in the changed bone formation. S100A4KO mice had higher serum levels of osteocalcin and a higher number of osteocalcin positive osteoblasts under the periosteum. OVX-S100A4 resulted in the loss of the cortical bone supported by high CTX-I levels, whereas no such changes were observed in OVX-WT mice. S100A4KO mice resisted the dehydroepiadrosterone induced bone formation observed in the WT counterparts. Our study indicates that S100A4 is a regulator of bone formation, which inhibits bone excess in the estrogen-sufficient mice and prevents the cortical bone loss in the estrogen deprived mice. PMID- 23798574 TI - Research resource: novel structural insights bridge gaps in glycoprotein hormone receptor analyses. AB - The first version of a glycoprotein hormone receptor (GPHR) information resource was designed to link functional with structural GPHR information, in order to support sequence-structure-function analysis of the LH, FSH, and TSH receptors (http://ssfa-gphr.de). However, structural information on a binding- and signaling-sensitive extracellular fragment (~100 residues), the hinge region, had been lacking. A new FSHR crystal structure of the hormone-bound extracellular domain has recently been solved. The structure comprises the leucine-rich repeat domain and most parts of the hinge region. We have not only integrated the new FSHR/FSH structure and the derived homology models of TSHR/TSH, LHCGR/CG, and LHCGR/LH into our web-based information resource, but have additionally provided novel tools to analyze the advanced structural features, with the common characteristics and distinctions between GPHRs, in a more precise manner. The hinge region with its second hormone-binding site allows us to assign functional data to the new structural features between hormone and receptor, such as binding details of a sulfated tyrosine (conserved throughout the GPHRs) extending into a pocket of the hormone. We have also implemented a protein interface analysis tool that enables the identification and visualization of extracellular contact points between interaction partners. This provides a starting point for comparing the binding patterns of GPHRs. Together with the mutagenesis data stored in the database, this will help to decipher the essential residues for ligand recognition and the molecular mechanisms of signal transduction, extending from the extracellular hormone-binding site toward the intracellular G protein-binding sites. PMID- 23798575 TI - Androgen receptor drives transcription of rat PACAP in gonadotrope cells. AB - Gonadotropin expression is precisely regulated within the hypothalamic-pituitary gonadal axis through the complex interaction of neuropeptides, gonadal steroids. and both gonadal- and pituitary-derived peptides. In the anterior pituitary gland, the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) modulates gonadotropin biosynthesis and secretion, acting both alone and in conjunction with GnRH. Steroid hormone feedback also influences gonadotropin expression via both direct and indirect mechanisms. Evidence from nonpituitary tissues suggests that PACAP may be a target for gonadal steroid regulation. In the present study, we show that androgen markedly stimulates rat (r) PACAP promoter-reporter activity in the LbetaT2 mature mouse gonadotrope cell line. 5' Serial deletion analysis of reporter constructs identifies 2 regions of androgen responsiveness located at (-915 to -818) and (-308 to -242) of the rPACAP promoter. Androgen receptor (AR) binds directly to DNA cis-elements in each of these regions in vitro. Site-directed mutagenesis of 3 conserved hormone response element half-sites straddling the (-308 to -242) region dramatically blunts androgen-dependent PACAP promoter activity and prevents AR binding at the mutated promoter element. Chromatin immunoprecipitation demonstrates that endogenous AR binds the homologous region on mouse chromatin in LbetaT2 cells in both the presence and absence of androgen. These data demonstrate that androgen stimulates PACAP gene expression in the pituitary gonadotrope via direct binding of AR to a specific cluster of evolutionarily conserved hormone response elements in the proximal rPACAP gene promoter. Thus, androgen regulation of pituitary PACAP expression may provide an additional layer of control over gonadotropin expression within the hypothalamic-pituitary-gonadal axis. PMID- 23798577 TI - Genetic variants reducing MTR gene expression increase the risk of congenital heart disease in Han Chinese populations. AB - AIMS: Elevated homocysteine levels are known to be a risk factor for congenital heart disease (CHD), but the mechanism underlying this effect is unknown. During early embryonic development, homocysteine removal is dictated exclusively by the MTR activity. To examine the role of MTR in CHD risk, we identified genetic variants in MTR and investigated the mechanisms that affect its expression levels and that increase the risk of CHD in Chinese populations. METHODS AND RESULTS: The association between regulatory variants of the MTR gene and CHD was examined in three independent case-control studies in a total of 2340 patients with CHD and 2270 controls. The functional consequences of these variants were demonstrated using dual-luciferase assays, real-time polymerase chain reaction (PCR), electrophoretic mobility shift assays, surface plasma resonance, chromatin immunoprecipitation, and bisulfite sequencing, as well as by a group of predicted microRNAs using a gene reporter system. Two regulatory variants of MTR, -186T>G and +905G>A, were associated with an increased risk of CHD in both the separate and combined case-control studies (-186GG P = 1.32 * 10(-9); +905AA P = 6.35 * 10(-14)). Compared with the major allele, the -186G allele exhibited significantly lower promoter activity, decreased hnRNA and mRNA levels, reduced transcription factor binding affinity, and a more highly methylated promoter. The +905A allele exhibited a statistically stronger binding affinity to functional microRNAs that down regulate MTR expression at the translational level. Both of the minor alleles were correlated with elevated plasma homocysteine concentrations, indicating a genetic component for hyperhomocysteinaemia. CONCLUSIONS: Regulatory variants of the MTR gene increase CHD risk by reducing MTR expression and inducing the homocysteine accumulation and elevation. PMID- 23798576 TI - Minireview: Toward the establishment of a link between melatonin and glucose homeostasis: association of melatonin MT2 receptor variants with type 2 diabetes. AB - The existence of interindividual variations in G protein-coupled receptor sequences has been recognized early on. Recent advances in large-scale exon sequencing techniques are expected to dramatically increase the number of variants identified in G protein-coupled receptors, giving rise to new challenges regarding their functional characterization. The current minireview will illustrate these challenges based on the MTNR1B gene, which encodes the melatonin MT2 receptor, for which exon sequencing revealed 40 rare nonsynonymous variants in the general population and in type 2 diabetes (T2D) cohorts. Functional characterization of these MT2 mutants revealed 14 mutants with loss of Gi protein activation that associate with increased risk of T2D development. This repertoire of disease-associated mutants is a rich source for structure-activity studies and will help to define the still poorly understood role of melatonin in glucose homeostasis and T2D development in humans. Defining the functional defects in carriers of rare MT2 mutations will help to provide personalized therapies to these patients in the future. PMID- 23798578 TI - Less use of standard guideline-based treatment of myocardial infarction in patients with chronic kidney disease: a Danish nation-wide cohort study. AB - AIMS: The aim of this Danish nationwide study was to evaluate the treatment of myocardial infarction (MI) in patients with non-end-stage chronic kidney disease (CKD) and in patients requiring renal replacement therapy (RRT). Upgraded guidelines for the management of MI were implemented around 2004; hence, the treatment of MI in the time periods before and after 2004 was compared in order to evaluate the impact for patients with CKD. METHODS AND RESULTS: By linking nationwide registries by the personal registration number, we identified patients admitted to Danish hospitals with first time MI in the period 2000-09 (79 585 with no renal disease, 3144 with non-end-stage CKD, and 725 requiring RRT). Cox proportional hazards model was used to estimate the chance of invasive treatment within 60 days after MI and the chance of filling prescriptions on recommended post-MI drugs within 90 days before and after 2004. Significantly less use of relevant MI treatment in patients with non-end-stage CKD and patients requiring RRT compared with patients with no renal disease were seen; however, the absolute frequencies of invasive procedures and filled prescriptions on post-MI drugs increased after 2004 in all patients. CONCLUSIONS: After 2004, invasive and pharmacological treatment of first-time MI improved in patients with non-end stage CKD and patients requiring RRT; however, all CKD patients were less treated with standard MI care compared with patients with no renal disease. PMID- 23798579 TI - Role of imaging in assessment of atrial fibrosis in patients with atrial fibrillation: state-of-the-art review. AB - Atrial fibrillation (AF) is the most common arrhythmia in the world. Despite the large number of studies focused on the causes and mechanisms of AF, it remains a clinical challenge. Atrial electrical and structural remodelling caused by AF is responsible for the perpetuation of the arrhythmia. However, a validated noninvasive method for assessment of atrial fibrosis in clinical practice is lacking. In this review, we aim to present an update about the origins and mechanisms of atrial remodelling, particularly focusing on atrial fibrosis, and compare imaging techniques that can detect atrial changes and greatly contribute to the clinical management of patients with AF. PMID- 23798580 TI - Mobile subpulmonary membrane in a patient with hypertrophic cardiomyopathy and right ventricular mid-cavitary obstruction. PMID- 23798581 TI - Clinical and epidemiologic profile of cutaneous leishmaniasis in Colombian children: considerations for local treatment. AB - Treatment alternatives have seldom been evaluated in children with cutaneous leishmaniasis (CL). We examine the clinical/epidemiological profile of children with CL considering international guidelines for local treatment. Descriptive analyses were conducted using International Center for Medical Research and Training (CIDEIM) case reports of parasitologically diagnosed patients <= 14 years of age from 2004 to 2010. Eligibility for local treatment based on World Health Organization/Pan American Health Organization (WHO/PAHO) criteria was determined. Among 380 children, 90% presented lesions of < 3 months duration, 54% presented single lesions < 30 mm in diameter, and 45% were <= 5 years old. Lesions on the head and neck were more frequent among children 0-5 years, and lesions below the head/neck were more frequent among 11- to 14-year-old children (P = 0.004). Using PAHO and WHO criteria, 26% and 53% of children, respectively, were eligible for local treatment. Recommended local treatments for New World CL have potential but limited applicability in children. Individual risk-benefit assessment and effectiveness data in children may increase eligibility. PMID- 23798582 TI - Transplacental transmission of cutaneous Leishmania mexicana strain in BALB/c mice. AB - The vertical transmission of leishmaniasis has been reported in species that cause visceral leishmaniasis. However, this condition has scarcely been documented in species that cause cutaneous leishmaniasis. The aim of this study was to determine experimentally whether L. mexicana is transmitted vertically. A control group of BALB/c mice and a group infected with L. mexicana were mated, the gestation was monitored, and females were killed before delivery. Four resorptions (P = 0.023) and eight fetal deaths (P = 0.010) were observed in the infected female group; furthermore, the offspring body weight of the infected group was lower than the body weight of the healthy group (P = 0.009). DNA amplification by polymerase chain reaction (PCR) revealed that all placentas and maternal spleens as well as 39 of 110 fetal spleens obtained from the offspring of infected mothers tested positive for Leishmania. In conclusion, L. mexicana is transmitted transplacentally and causes fetal death, resorption, and reduction in offspring body weight. PMID- 23798583 TI - Economic burden of bacteremic melioidosis in eastern and northeastern, Thailand. AB - Melioidosis is among the most common causes of septicemia in Thailand, but data on economic burden are limited. We describe the economic impact of bacteremic melioidosis hospitalizations in two Thailand provinces during 2006-2008. Costs are presented in US dollars ($1 = 30.49 Thai Baht). The average annual incidence of bacteremic melioidosis cases per 100,000 persons in Sa Kaeo and Nakhon Phanom was 4.6 and 14.4, respectively. The annual cost of bacteremic melioidosis hospitalizations from the societal perspective, including direct and indirect costs, was $152,159 in Sa Kaeo and $465,303 in Nakhon Phanom. The average cost per fatal case was $14,182 and $14,858 in Sa Kaeo and Nakhon Phanom, respectively. In addition to the high morbidity and mortality, the substantial economic burden of melioidosis further supports the need for investments to identify improved prevention and control strategies for melioidosis. PMID- 23798584 TI - Recruiting trainees for a global health research workforce: the National Institutes of Health Fogarty International Clinical Research Scholars Program selection process. AB - Between 2004 and 2012, the National Institutes of Health Fogarty International Clinical Research Scholars (FICRS) Program provided 1-year mentored research training at low- and middle-income country sites for American and international health science doctoral students. We describe the centralized application process, US applicant characteristics, and predictors of selection/enrollment. FICRS received 1,084 applicants representing many health professions and biomedical disciplines at 132 US academic institutions; 219 students from 72 institutions were accepted and enrolled. Medical/osteopathic students comprised 88.9% of applicants and 85.8% of enrollees. Applicants from institutions with higher applicant numbers were two times as likely to be selected. In 2012, FICRS was decentralized among 20 institutions in five consortia (Global Health Fellows), with autonomous selection processes that emphasize post-doctoral trainees. If academia, government, or charitable foundations offer future opportunities to health professions students for international research, the FICRS experience predicts that they can attract substantial numbers of motivated trainees from diverse backgrounds. PMID- 23798585 TI - Molecular evidence of Trichostrongylus colubriformis and Trichostrongylus axei infections in humans from Thailand and Lao PDR. AB - Human trichostrongylosis has been reported in Thailand. Recent reports in Lao People's Democratic Republic concerning species identification urged us to investigate species distribution in Thailand. We report eight human cases in Thailand and Lao People's Democratic Republic that were found to be infected by Trichostrongylus colubriformis and T. axei identified and confirmed by molecular techniques. This evidence is the first molecular evidence of human T. colubriformis and T. axei infection in Thailand. Infection by these two species was apparently epidemic in these areas. It is necessary to proceed with more comprehensive veterinary and epidemiologic studies to enable the practical prevention and control of this parasitic zoonosis. PMID- 23798586 TI - Dispositional coping, coping effectiveness, and cognitive social maturity among adolescent athletes. AB - It is accepted among scholars that coping changes as people mature during adolescence, but little is known about the relationship between maturity and coping. The purpose of this paper was to assess a model, which included dispositional coping, coping effectiveness, and cognitive social maturity. We predicted that cognitive social maturity would have a direct effect on coping effectiveness, and also an indirect impact via dispositional coping. Two hundred forty-five adolescent athletes completed measures of dispositional coping, coping effectiveness, and cognitive social maturity, which has three dimensions: conscientiousness, peer influence on behavior, and rule following. Using structural equation modeling, we found support for our model, suggesting that coping is related to cognitive social maturity. This information can be used to influence the content of coping interventions for adolescents of different maturational levels. PMID- 23798587 TI - The effects of depleted self-control strength on skill-based task performance. AB - The purpose of this study was to examine the effects of depleted self-control strength on skill-based sports task performance. Sixty-two participants completed the following: a baseline dart-tossing task (20 tosses), with measures of accuracy, reaction time, and myoelectrical activity of the arms taken throughout; a self-control depletion (experimental) or a nondepletion (control) manipulation; and a second round of dart tossing. As hypothesized, participants in the experimental condition had poorer mean accuracy at Round 2 than control condition participants, and a significant decline in accuracy from Round 1 to Round 2. Experimental condition participants also demonstrated poorer consistency in accuracy compared with control condition participants at Round 2 and a significant deterioration in consistency from Round 1 to Round 2. In addition, consistency in reaction time improved significantly for the control group but not for the experimental group. The results of this study provide evidence that ego depletion effects occur in the performance of a skill-based sports task. PMID- 23798588 TI - Examination of visual information as a mediator of external focus benefits. AB - Attunement to visual information has been suggested to mediate the performance advantage associated with adopting an external focus of attention (e.g., Al Abood, Bennett, Moreno Hernandez, Ashford, & Davids, 2002; Magill, 1998). We tested this hypothesis by examining the extent to which online visual information underpins the external focus advantage. The study examined skilled golfers on a putting task under one of three attentional focus conditions: control (no instructions), irrelevant (tone counting), and external (movement effect focus), with either full or occluded vision. In addition to task performance, the effect of attentional focus and vision on between-trial movement variability was examined. We found a significant advantage for an external focus of attention in the absence of vision. The results of the movement variability analysis further indicated that external focus was not mediated by the online use of vision. We discuss these findings in the context of traditional cognitive perspectives to external focus effects. PMID- 23798589 TI - The expertise reversal effect for sequential presentation in dynamic soccer visualizations. AB - Cognitive load perspective was used as a theoretical framework to investigate effects of expertise and type of presentation of interacting elements of information in learning from dynamic visualizations. Soccer players (N = 48) were required to complete a recall reconstruction test and to rate their invested mental effort after studying a concurrent or sequential presentation of the elements of play. The results provided evidence for an expertise reversal effect. For novice players, the sequential presentation produced better learning outcomes. In contrast, expert players performed better after studying the concurrent presentation. The findings suggest that the effectiveness of different visual presentation formats depend on levels of learner expertise. PMID- 23798590 TI - Passion and coping: relationships with changes in burnout and goal attainment in collegiate volleyball players. AB - This study examined the relationship between harmonious and obsessive passion and coping, and assessed whether coping mediated the relationship between passion types and changes in burnout and goal attainment. College- and university-level volleyball players (N = 421) completed measures of passion, coping, burnout, and goal attainment at the start and end of a season. Results of structural equation modeling, using a true latent change approach, supported a model whereby types of passion were indirectly related to changes in burnout and goal attainment via coping. Harmonious passion was positively related to task-oriented coping which, in turn, was positively associated with change in goal attainment. Obsessive passion was positively associated with disengagement-oriented coping which, in turn, was positively and negatively associated with changes in burnout and goal attainment, respectively. This study identifies coping as a reason why passionate athletes may experience changes in burnout and goal attainment over the course of a season. PMID- 23798591 TI - Development and initial validation of the Impression Motivation in Sport Questionnaire-Team. AB - Impression motivation is an important individual difference variable that has been under-researched in sport psychology, partly due to having no appropriate measure. This study was conducted to design a measure of impression motivation in team-sport athletes. Construct validity checks decreased the initial pool of items, factor analysis (n = 310) revealed the structure of the newly developed scale, and exploratory structural equation modeling procedures (n = 406) resulted in a modified scale that retained theoretical integrity and psychometric parsimony. This process produced a 15-item, 4-factor model; the Impression Motivation in Sport Questionnaire-Team (IMSQ-T) is forwarded as a valid measure of the respondent's dispositional strength of motivation to use self-presentation in striving for four distinct interpersonal objectives: self-development, social identity development, avoidance of negative outcomes, and avoidance of damaging impressions. The availability of this measure has contributed to theoretical development, will facilitate research, and offers a tool for use in applied settings. PMID- 23798592 TI - Does priming really put the gloss on performance? AB - Priming has recently emerged in the literature as offering advantages in the preparation for skilled performance. Accordingly, the current study tested the efficacy of imagery against a priming paradigm as a means of enhancing motor performance: in essence, contrasting a preparation technique primarily under the conscious control of the performer to an unconscious technique promoting automaticity. The imagery intervention was guided by the PETTLEP model, while the priming intervention took the form of a scrambled sentence task. Eighteen skilled field-hockey players performed a dribbling task under imagery, priming, skill focus, and control conditions. Results revealed a significant improvement in speed and technical accuracy for the imagery condition as opposed to the skill focus, control, and priming conditions. In addition, there were no significant differences in performance times or technical accuracy between the priming and control conditions. The study provides further support for the efficacy of imagery to elicit enhanced motor skill performance but questions the emerging emphasis on priming as an effective tool in preparation for physical tasks. PMID- 23798593 TI - "Coveting thy neighbour's legs": a qualitative study of exercisers' experiences of intrinsic and extrinsic goal pursuit. AB - Goals are central to exercise motivation, although not all goals (e.g., health vs. appearance goals) are equally psychologically or behaviorally adaptive. Within goal content theory (Vansteenkiste, Niemiec, & Soenens, 2010), goals are adaptive to the extent to which they satisfy psychological needs for autonomy, competence, and relatedness. However, little is known about what exercisers pursuing different goals are feeling, doing, thinking, and paying attention to that may help to explain the association between goal contents and need satisfaction. Using semistructured interviews and interpretative phenomenological analysis, we explored experiences of exercise among 11 adult exercisers who reported pursuing either predominantly intrinsic or extrinsic goals. Four themes emerged: (a) observation of others and resulting emotions, (b) goal expectations and time perspective, (c) markers of progress and (d) reactions to (lack of) goal achievement. Intrinsic and extrinsic goal pursuers reported divergent experiences within these four domains. The findings illuminate potential mechanisms by which different goals may influence psychological and behavioral outcomes in the exercise context. PMID- 23798594 TI - Motor ability and inhibitory processes in children with ADHD: a neuroelectric study. AB - The purpose of the current study was to examine the relationship between motor ability and response inhibition using behavioral and electrophysiological indices in children with ADHD. A total of 32 participants were recruited and underwent a motor ability assessment by administering the Basic Motor Ability Test-Revised (BMAT) as well as the Go/No-Go task and event-related potential (ERP) measurements at the same time. The results indicated that the BMAT scores were positively associated with the behavioral and ERP measures. Specifically, the BMAT average score was associated with a faster reaction time and higher accuracy, whereas higher BMAT subset scores predicted a shorter P3 latency in the Go condition. Although the association between the BMAT average score and the No Go accuracy was limited, higher BMAT average and subset scores predicted a shorter N2 and P3 latency and a larger P3 amplitude in the No-Go condition. These findings suggest that motor abilities may play roles that benefit the cognitive performance of ADHD children. PMID- 23798596 TI - MiR-133a modulates osteogenic differentiation of vascular smooth muscle cells. AB - Arterial calcification is a key pathologic component of vascular diseases such as atherosclerosis, coronary artery disease, and peripheral vascular disease. A hallmark of this pathological process is the phenotypic transition of vascular smooth muscle cells (VSMCs) to osteoblast-like cells. Several studies have demonstrated that microRNAs (miRNAs) regulate osteoblast differentiation, but it is unclear whether miRNAs also regulate VSMC-mediated arterial calcification. In the present study, we sought to characterize the role of miR-133a in regulating VSMC-mediated arterial calcification. Northern blotting analysis of VSMCs treated with beta-glycerophosphate demonstrated that miR-133a was significantly decreased during osteogenic differentiation. Overexpression of miR-133a inhibited VSMC transdifferentiation into osteoblast-like cells as evidenced by a decrease in alkaline phosphatase activity, osteocalcin secretion, Runx2 expression, and mineralized nodule formation. Conversely, the knockdown of miR-133a using an miR 133a inhibitor promoted osteogenic differentiation of VSMCs by increasing alkaline phosphatase activity, osteocalcin secretion, and Runx2 expression. Runx2 was identified as a direct target of miR-133a by a cotransfection experiment in VSMCs with luciferase reporter plasmids containing wild-type or mutant 3' untranslated region sequences of Runx2. Furthermore, the pro-osteogenic effects of miR-133a inhibitor were abrogated in Runx2-knockdown cells, and the inhibition of osteogenic differentiation by pre-miR-133a was reversed by overexpression of Runx2, providing functional evidence that the effects of miR-133a in osteogenic differentiation were mediated by targeting Runx2. These results demonstrate that miR-133a is a key negative regulator of the osteogenic differentiation of VSMCs. PMID- 23798597 TI - Insights into the protective mechanisms of tamoxifen in radiotherapy-induced ovarian follicular loss: impact on insulin-like growth factor 1. AB - Radiotherapy is one of the most common and effective cancer treatments. However, it has a profound impact on ovarian function, leading to premature ovarian failure. With the hope of preserving fertility in cancer survivors, the need for an effective radioprotective therapy is evident. The present study investigated the mechanism of the potential radioprotective effect of tamoxifen (TAM) on gamma irradiation-induced ovarian failure on experimental rats and the impact of the IGF-1 in the underlying protective mechanisms. Female Sprague Dawley rats were either exposed to single whole-body irradiation (3.2 Gy; lethal dose [LD20]) and/or treated with TAM (1 mg/kg). gamma-Irradiation caused an array of ovarian dysfunction that was evident by assessment of hormonal changes, follicular development, proliferation marker (proliferating cell nuclear antigen), and oxidative stress as well as apoptotic markers. In addition, IGF-1/IGF-1 receptor axis expression was assessed using real-time RT-PCR and immunolocalization techniques. Furthermore, fertility assessment was performed. TAM significantly enhanced follicular development and restored the anti-Mullerian hormone level. Moreover, it ameliorated the deleterious effects of irradiation on oxidative stress, proliferating cell nuclear antigen expression, and apoptosis. Interestingly, TAM was shown to enhance the ovarian IGF-1 but not IGF-1 receptor, a property that contributed significantly to its radioprotective mechanisms. Finally, TAM regained the fertility that was lost after irradiation. In conclusion, TAM showed a radioprotective effect and saved the ovarian reserve and fertility through increasing anti-Mullerian hormone and the local IGF-1 level and counteracting the oxidative stress-mediated apoptosis. PMID- 23798598 TI - Oral administration of corn zein hydrolysate stimulates GLP-1 and GIP secretion and improves glucose tolerance in male normal rats and Goto-Kakizaki rats. AB - We have previously demonstrated that ileal administration of the dietary protein hydrolysate prepared from corn zein (ZeinH) stimulated glucagon-like peptide-1 (GLP-1) secretion and attenuated hyperglycemia in rats. In this study, to examine whether oral administration of ZeinH improves glucose tolerance by stimulating GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) secretion, glucose tolerance tests were performed in normal Sprague-Dawley male rats and diabetic Goto-Kakizaki (GK) male rats. The test solution was gavaged before ip glucose injection in normal rats or gavaged together with glucose in GK rats. Blood samples were collected from the tail vein or by using the jugular catheter to measure glucose, insulin, GLP-1, and GIP levels. In the ip glucose tolerance test, oral administration of ZeinH (2 g/kg) significantly suppressed the glycemic response accompanied by an immediate increase in plasma GLP-1 and GIP levels in normal rats. In contrast, oral administration of another dietary peptide, meat hydrolysate, did not elicit a similar effect. The glucose-lowering effect of ZeinH was attenuated by a GLP-1 receptor antagonist or by a GIP receptor antagonist. Furthermore, oral ZeinH induced GLP-1 secretion and reduced glycemic response in GK rats under the oral glucose tolerance test. These results indicate that the oral administration of the dietary peptide ZeinH improves glucose tolerance in normal and diabetic rats by its incretin-releasing activity, namely, the incretinotropic effect. PMID- 23798600 TI - The barley MATE gene, HvAACT1, increases citrate efflux and Al(3+) tolerance when expressed in wheat and barley. AB - BACKGROUND AND AIMS: Aluminium is toxic in acid soils because the soluble Al(3+) inhibits root growth. A mechanism of Al(3+) tolerance discovered in many plant species involves the release of organic anions from root apices. The Al(3+) activated release of citrate from the root apices of Al(3+)-tolerant genotypes of barley is controlled by a MATE gene named HvAACT1 that encodes a citrate transport protein located on the plasma membrane. The aim of this study was to investigate whether expressing HvAACT1 with a constitutive promoter in barley and wheat can increase citrate efflux and Al(3+) tolerance of these important cereal species. METHODS: HvAACT1 was over-expressed in wheat (Triticum aestivum) and barley (Hordeum vulgare) using the maize ubiquitin promoter. Root apices of transgenic and control lines were analysed for HvAACT1 expression and organic acid efflux. The Al(3+) tolerance of transgenic and control lines was assessed in both hydroponic solution and acid soil. KEY RESULTS AND CONCLUSIONS: Increased HvAACT1 expression in both cereal species was associated with increased citrate efflux from root apices and enhanced Al(3+) tolerance, thus demonstrating that biotechnology can complement traditional breeding practices to increase the Al(3+) tolerance of important crop plants. PMID- 23798599 TI - Uncovering novel roles of nonneuronal cells in body weight homeostasis and obesity. AB - Glial cells, which constitute more than 50% of the mass of the central nervous system and greatly outnumber neurons, are at the vanguard of neuroendocrine research in metabolic control and obesity. Historically relegated to roles of structural support and protection, diverse functions have been gradually attributed to this heterogeneous class of cells with their protagonism in crescendo in all areas of neuroscience during the past decade. However, this dramatic increase in attention bestowed upon glial cells has also emphasized our vast lack of knowledge concerning many aspects of their physiological functions, let alone their participation in numerous pathologies. This minireview focuses on the recent advances in our understanding of how glial cells participate in the physiological regulation of appetite and systemic metabolism as well as their role in the pathophysiological response to poor nutrition and secondary complications associated with obesity. Moreover, we highlight some of the existing lagoons of knowledge in this increasingly important area of investigation. PMID- 23798601 TI - Microsite affects willow sapling recovery from bank vole (Myodes glareolus) herbivory, but does not affect grazing risk. AB - BACKGROUND: Large herbivores are often removed or reduced as part of vegetation restoration programmes, but the resultant increase in vegetation biomass and changes in vegetation structure may favour small mammals. Small mammals may have large impacts on plant community composition via granivory and sapling herbivory, and increased small mammal populations may reduce any benefits of large herbivore removal for highly preferred species. This study tested the impacts of small mammal herbivory, microsite characteristics and their interaction on growth and survival of three montane willow species with differing chemical compositions, Salix lapponum, S. myrsinifolia and S. arbuscula. METHODS: In two separate years, 1-year-old saplings were planted within a 180 ha, large-mammal scrub regeneration exclosure, and either experimentally protected from or exposed to small mammals (bank voles). Saplings were planted in one of two microsite treatments, vegetation mown (to mimic a grazed sward) or disturbed (all above- and below ground competition removed), and monitored throughout the first year of growth. KEY RESULTS: Approximately 40 % of saplings planted out in each year were damaged by bank voles, but direct mortality due to damage was very low (<2 %). There were no strong species differences in susceptibility to vole damage. Microsite treatment had no impact on the proportion of saplings attacked, but in 2004 saplings in mown microsites were more severely damaged and had smaller increases in size than those in disturbed microsites. In 2003, saplings in mown microsites had smaller increases in stem diameter following attack than those in disturbed microsites. CONCLUSIONS: Planting 1-year-old willow saplings into disturbed microsites may aid growth, reduce the severity of small mammal damage and improve recovery following sub-lethal small mammal damage. Restoration management of montane willow scrub should therefore consider manipulating the planting site to provide disturbed areas of soil. PMID- 23798602 TI - Plastid DNA sequencing and nuclear SNP genotyping help resolve the puzzle of central American Platanus. AB - BACKGROUND AND AIMS: Recent research on the history of Platanus reveals that hybridization phenomena occurred in the central American species. This study has two goals: to help resolve the evolutive puzzle of central American Platanus, and to test the potential of real-time polymerase chain reaction (PCR) for detecting ancient hybridization. METHODS: Sequencing of a uniparental plastid DNA marker [psbA-trnH((GUG)) intergenic spacer] and qualitative and quantitative single nucleotide polymorphism (SNP) genotyping of biparental nuclear ribosomal DNA (nrDNA) markers [LEAFY intron 2 (LFY-i2) and internal transcribed spacer 2 (ITS2)] were used. KEY RESULTS: Based on the SNP genotyping results, several Platanus accessions show the presence of hybridization/introgression, including some accessions of P. rzedowskii and of P. mexicana var. interior and one of P. mexicana var. mexicana from Oaxaca (= P. oaxacana). Based on haplotype analyses of the psbA-trnH spacer, five haplotypes were detected. The most common of these is present in taxa belonging to P. orientalis, P. racemosa sensu lato, some accessions of P. occidentalis sensu stricto (s.s.) from Texas, P. occidentalis var. palmeri, P. mexicana s.s. and P. rzedowskii. This is highly relevant to genetic relationships with the haplotypes present in P. occidentalis s.s. and P. mexicana var. interior. CONCLUSIONS: Hybridization and introgression events between lineages ancestral to modern central and eastern North American Platanus species occurred. Plastid haplotypes and qualitative and quantitative SNP genotyping provide information critical for understanding the complex history of Mexican Platanus. Compared with the usual molecular techniques of sub-cloning, sequencing and genotyping, real-time PCR assay is a quick and sensitive technique for analysing complex evolutionary patterns. PMID- 23798603 TI - Comparative microscopic study of human and rat lungs after overexposure to welding fume. AB - Welding is a common industrial process used to join metals and generates complex aerosols of potentially hazardous metal fumes and gases. Most long-time welders experience some type of respiratory disorder during their time of employment. The use of animal models and the ability to control the welding fume exposure in toxicology studies have been helpful in developing a better understanding of how welding fumes affect health. There are no studies that have performed a side-by side comparison of the pulmonary responses from an animal toxicology welding fume study with the lung responses associated with chronic exposure to welding fume by a career welder. In this study, post-mortem lung tissue was donated from a long time welder with a well-characterized work background and a history of extensive welding fume exposure. To simulate a long-term welding exposure in an animal model, Sprague-Dawley rats were treated once a week for 28 weeks by intratracheal instillation with 2mg of a stainless steel, hard-surfacing welding fume. Lung tissues from the welder and the welding fume-treated rats were examined by light and electron microscopy. Pathological analysis of lung tissue collected from the welder demonstrated inflammatory cell influx and significant pulmonary injury. The poor and deteriorating lung condition observed in the welder examined in this study was likely due to exposure to very high levels of potentially toxic metal fumes and gases for a significant number of years due to work in confined spaces. The lung toxicity profile for the rats treated with welding fume was similar. For tissue samples from both the welder and treated rats, welding particle accumulations deposited and persisted in lung structures and were easily visualized using light microscopic techniques. Agglomerates of deposited welding particles mostly were observed within lung cells, particularly alveolar macrophages. Analysis of individual particles within the agglomerates showed that these particles were metal complexes with iron, chromium, and nickel being the most common metals present. In conclusion, long-term exposure to specific welding fume can lead to serious chronic lung disease characterized by significant particle deposition and persistence as demonstrated in both a human case study and rat model. Not only were the lung responses similar in the human and rat lungs, as evidenced by inflammatory cell influx and pulmonary disease, but the composition of individual welding particles and agglomerations in situ was comparable. PMID- 23798605 TI - Reverse engineering of the selective agonist TBPB unveils both orthosteric and allosteric modes of action at the M1 muscarinic acetylcholine receptor. AB - Recent interest in the M1 muscarinic acetylcholine (ACh) receptor (mAChR) has led to the discovery of various selective agonists for the receptor. The novel selective agonist 1-(1'-(2-methylbenzyl)-1,4'-bipiperidin-4-yl)-1H benzo[d]imidazol-2(3H)-1 (TBPB) displays unprecedented functional selectivity at the M1 mAChR. This functional selectivity has been described to stem from sole interaction with an allosteric site, although the evidence for such a mechanism is equivocal. To delineate TBPB's mechanism of action, several truncated variants of TBPB were synthesized and characterized. Binding experiments with [3H]N methylscopolamine at the M1, M2, M3, and M4 mAChRs revealed radioligand displacement in a manner consistent with a competitive binding mode at the orthosteric site by TBPB and fragment derivatives. Cell-based functional assays of fragment derivatives of TBPB identified both agonistic and antagonistic moieties, one of which, 1-(1-cyclohexylpiperidin-4-yl)-1H-benzo[d]imidazol-2(3H) 1 (VCP794), lost agonistic selectivity for the M1 mAChR. Further interaction experiments between TBPB or its antagonist fragments with ACh also indicated a mechanism consistent with competitive binding at mAChRs. However, interaction with an allosteric site by an antagonist fragment of TBPB was demonstrated via its ability to retard radioligand dissociation. To reconcile this dual orthosteric/allosteric pharmacological behavior, we propose that TBPB is a bitopic ligand, interacting with both the orthosteric site and an allosteric site, at the M1 mAChR. This mechanism may also be the case for other selective agonists for mAChRs, and should be taken into consideration in the profiling and classification of new novel selective agonists for this receptor family. PMID- 23798613 TI - Cancer patients and survivors: changing words or changing culture? PMID- 23798614 TI - Clinical relevance of cancer stem cells in bone marrow of early breast cancer patients. AB - BACKGROUND: Cancer stem cells (CSCs) are epithelial tumor cells that express CD44(+)CD24(-/lo). CSCs can be further divided into those that have aldehyde dehydrogenase (ALDH) activity (Aldefluor(+)) and those that do not. We hypothesized that if CSCs are responsible for tumor dissemination, their presence in bone marrow (BM) would be prognostic in early stages of breast cancer (EBC) patients. PATIENTS AND METHODS: BM aspirates were collected at the time of surgery from 108 patients with EBC. BM was analyzed for CSCs and ALDH activity by flow cytometry. Overall survival and disease-free survival (DFS) were calculated from the date of diagnosis and analyzed with Kaplan-Meier survival plots. Cox multivariate proportional hazards model was also carried out. RESULTS: Patients with CSCs in BM had a hazard ratio (HR) of 8.8 for DFS (P = 0.002); patients with Aldefluor(+) CSCs had a HR of 5.9 (P = 0.052) for DFS. All deceased patients (n = 7) had CSCs in BM. In multivariate analysis, the presence of CSCs in BM was a prognostic factor of DFS (HR = 15.8, P = 0.017). CONCLUSIONS: The presence of BM metastasis is correlated with CSCs and these CSCs irrespective of ALDH activity are an independent adverse prognostic factor in EBC patients. PMID- 23798615 TI - Acute tubular necrosis associated with mTOR inhibitor therapy: a real entity biopsy-proven. AB - BACKGROUND: The protein kinase mTOR (mammalian target of rapamycin) is a critical regulator of cellular metabolism, growth, and proliferation. Inhibitors of mTOR have immunosuppressive and anti-cancer effects, but their effects on the progression of kidney disease are not fully understood. Their most common side effects include stomatitis, rash, dyslipidemia, hyperglycemia, fatigue, and pneumonitis. However, to the best of our knowledge these agents have not been previously reported to cause severe acute kidney injury (AKI). CASE PRESENTATION: We describe four cases of patients with cancer who developed AKI after starting mTOR inhibitor therapy. A kidney biopsy showed acute tubular necrosis (ATN) with prominent tubular dysfunction. Withdrawal of the drug leads to a rapid recovery in two cases. However, a fixed renal dysfunction was noted in the other two cases, one of which will remain dialysis-dependent. Such patients lead to a broad differential diagnosis of AKI including prerenal AKI, ATN, cancer-related GN, and drug-induced acute interstitial nephritis. Accurate history, physical examination, laboratory data, and kidney biopsy are highlighted in establishing the correct diagnosis in such patients. CONCLUSIONS: ATN have not been reported with mTOR inhibitor use. These cases demonstrated a potentially new and serious adverse consequence occurring with the use of an mTOR inhibitor, of which physicians need to be aware. PMID- 23798617 TI - Simple estimators of false discovery rates given as few as one or two p-values without strong parametric assumptions. AB - Multiple comparison procedures that control a family-wise error rate or false discovery rate provide an achieved error rate as the adjusted p-value or q-value for each hypothesis tested. However, since achieved error rates are not understood as probabilities that the null hypotheses are true, empirical Bayes methods have been employed to estimate such posterior probabilities, called local false discovery rates (LFDRs) to emphasize that their priors are unknown and of the frequency type. The main approaches to LFDR estimation, relying either on fully parametric models to maximize likelihood or on the presence of enough hypotheses for nonparametric density estimation, lack the simplicity and generality of adjusted p-values. To begin filling the gap, this paper introduces simple methods of LFDR estimation with proven asymptotic conservatism without assuming the parameter distribution is in a parametric family. Simulations indicate that they remain conservative even for very small numbers of hypotheses. One of the proposed procedures enables interpreting the original FDR control rule in terms of LFDR estimation, thereby facilitating practical use of the former. The most conservative of the new procedures is applied to measured abundance levels of 20 proteins. PMID- 23798616 TI - N0539 phase II trial of fulvestrant and bevacizumab in patients with metastatic breast cancer previously treated with an aromatase inhibitor: a North Central Cancer Treatment Group (now Alliance) trial. AB - BACKGROUND: Based on preclinical studies, the vascular endothelial pathway is an important mechanism for estrogen receptor resistance. We conducted a phase II study of fulvestrant and bevacizumab in patients with aromatase inhibitor pretreated metastatic breast cancer. PATIENTS AND METHODS: A single-stage phase II study was conducted with these objectives: 6-month progression-free survival (PFS), tumor response, toxic effect, and overall survival. Regimen: 250 mg fulvestrant days 1 and 15 (cycle 1) then day 1 (cycle 2 and beyond) and 10 mg/kg bevacizumab days 1 and 15 of each 4-week cycle. RESULTS: At interim analysis, 20 eligible patients initiated treatment, 11 were progression free and on treatment at 3 months, not meeting the protocol-specified efficacy requirements (at least 12 of 20). Accrual remained open during interim analysis with 36 patients enrolling before final study closure. Among the 33 eligible patients, the median PFS was 6.2 months [95% confidence interval (CI) 3.6-10.1 months]. Of the 18 with measurable disease, 4 (22%) patients (95% CI 6% to 48%) had a confirmed tumor response (1 complete, 3 partial). The most common grade 3/4 adverse events were hypertension 3 (9%) and headache 3 (9%). CONCLUSIONS: The fulvestrant/bevacizumab combination is safe and tolerable; however, it did not meet its statistical end point. PMID- 23798618 TI - Comparison of PR3-ANCA specific assay performance for the diagnosis of granulomatosis with polyangiitis (Wegener's). AB - BACKGROUND: PR3-ANCA, the serological marker of granulomatosis with polyangiitis (GPA), is usually detected by immunometric assays, with purified PR3 directly coated onto the solid-phase. Novel methods for PR3-ANCA detection have been developed to improve the performance of traditional PR3-ANCA specific assays, but little is known about their diagnostic performance in real-life clinical settings. This study aimed to compare the performance of nine different commercial PR3-ANCA specific assays, including traditional and newer ones, for the diagnosis of GPA. METHODS: The evaluated assays for PR3-ANCA detection were representative of the first, second, and third generation tests (direct, capture and anchor assays, respectively). A third-generation assay employing both human and recombinant PR3 was also evaluated. The study population consisted of 55 GPA patients, 175 disease controls (representing most diseases in differential diagnosis with primary small-vessel vasculitis) including 52 with microscopic polyangiitis, and 20 healthy subjects. We performed the primary evaluation of test sensitivity using cut-off points which provided adequate and identical specificity for each test. RESULTS: Although specificity and area under the ROC curve did not differ significantly between the different assays, substantial differences in sensitivity at 98%-specificity were found in some instances (p<0.001). Compared to first generation direct PR3-ANCA specific assays, some of the second and third generation tests increased the positive predictive value (PPV) for GPA diagnosis. CONCLUSIONS: Some of the newer PR3-ANCA specific assays have better PPV than traditional ones. PMID- 23798619 TI - Reference interval studies: what is the maximum number of samples recommended? AB - BACKGROUND: Little attention has been paid to the maximum number of specimens for reference interval calculation, i.e., the number of specimens beyond which there is no further benefit in reference interval calculation. We present a model for the estimation of the maximum number of specimens for reference interval studies based on setting the 90% confidence interval of the reference limits to be equal to the analyte reporting interval. METHODS: Equations describing the bounds on the upper and lower 90% confidence intervals for logarithmically transformed and untransformed data were derived and applied to determine the maximum number of specimens required to calculate a reference interval for 12 common chemistry and hematology analytes. RESULTS: Maximum sample sizes ranged from 126 to 18,171 and depended on the standard deviation of the population, any transformation involved and on the chosen reporting interval. CONCLUSIONS: This paper demonstrates the importance of the influence of reporting interval on reference intervals. Using this technique can reduce the cost of determining a reference interval by identifying the maximum number of specimens required. PMID- 23798620 TI - A novel method for the direct determination of heparin concentration during cardiopulmonary bypass surgery. AB - BACKGROUND: Heparin is the standard drug for anticoagulation treatment and is used in many cardiac surgical interventions to prevent blood clotting. The anticoagulation status is controlled by various clotting tests. However, these tests depend on parameters like temperature, hemodilution etc. and are thus not applicable for a direct monitoring of the heparin concentration. The aim of this prospective study was to test a novel light scattering assay (LiSA) for the direct determination of heparin concentration during cardiopulmonary bypass (CPB) surgery and to compare the heparin concentrations with routinely determined activated clotting time (ACT). METHODS: The patient group consisted of 50 patients undergoing coronary bypass surgery with CPB. The coagulation status was monitored by the measurement of ACT, which was performed approximately every 30 min during surgery. Parallel to each ACT measurement, the heparin concentration was measured by LiSA. RESULTS: For 70% of the patients, ACT and heparin concentration measured by LiSA correlated reasonably over the entire time course of the intervention. For 30% of the patients, an insufficient correlation or even no correlation at all was observed. CONCLUSIONS: This study showed that LiSA enables the determination of intra-operative heparin levels. The lack of correlation between ACT and heparin concentration in a substantial group of patients shows that monitoring of heparin concentration is important. A more precise blood coagulation management, in particular, a precise administration of heparin and protamine, should be based on a combination of the measurement of heparin concentration and of ACT, but not on ACT alone. PMID- 23798622 TI - Mycalina: another crack in the Poecilosclerida framework. AB - This is the first phylogenetic analysis integrating both morphological and molecular data of the sponge suborder Mycalina (Poecilosclerida), which was erected in 1994. A cladistic analysis of morphology supported the monophyly of Cladorhizidae (including Euchelipluma), Guitarridae (excluding Euchelipluma), Isodictyidae, Latrunculiidae, and Podospongiidae but rejected monophyly for Desmacellidae, Esperiopsidae, Hamacanthidae, and Mycalidae. Analyses of partial 16S and partial 28S rRNA datasets combined, as well as that of a complete 18S rDNA dataset, suggest that Mycalina is not monophyletic; Biemnidae is only distantly related to other poecilosclerids; Merlia and Desmacella branch near the base of a diverse Poecilosclerida clade; Mycalidae is monophyletic (excluding Mycale [Anomomycale] titubans in 18S); and Esperiopsidae and Isodictyidae form a clade. Analyses of the two molecular datasets differed on the monophyly of Podospongiidae and about the relationship of Podospongiidae to Isodictyidae + Esperiopsidae. PMID- 23798621 TI - Acetylation of the cell-fate factor dachshund determines p53 binding and signaling modules in breast cancer. AB - Breast cancer is a leading form of cancer in the world. The Drosophila Dac gene was cloned as an inhibitor of the hyperactive epidermal growth factor (EGFR), ellipse. Herein, endogenous DACH1 co-localized with p53 in a nuclear, extranucleolar compartment and bound to p53 in human breast cancer cell lines, p53 and DACH1 bound common genes in Chip-Seq. Full inhibition of breast cancer contact-independent growth by DACH1 required p53. The p53 breast cancer mutants R248Q and R273H, evaded DACH1 binding. DACH1 phosphorylation at serine residue (S439) inhibited p53 binding and phosphorylation at p53 amino-terminal sites (S15, S20) enhanced DACH1 binding. DACH1 binding to p53 was inhibited by NAD dependent deacetylation via DACH1 K628. DACH1 repressed p21CIP1 and induced RAD51, an association found in basal breast cancer. DACH1 inhibits breast cancer cellular growth in an NAD and p53-dependent manner through direct protein-protein association. PMID- 23798623 TI - Efficacy of fixed low dose hydroxyurea in Indian children with sickle cell anemia: a single centre experience. AB - INTRODUCTION: Data on the efficacy of hydroxyurea (HU) in Indian children with sickle cell anaemia (SCA) is limited. Hence, we have evaluated the efficacy of fixed low dose HU in Indian children. METHODS: The study cohort consisted of 144 children (<18 years of age) with SCA having severe manifestations (>= 3 episodes of vasocclusive crisis or blood transfusions, or having >= 1 episode of acute chest syndrome or cerebrovascular stroke or sequestration crisis) who were started on fixed low dose HU (10 mg/kg/day). They were followed up for two years and monitored for the hematological and clinical efficacy and safety. RESULTS: There was significant increase in the fetal hemoglobin level (HbF%), total hemoglobin and mean corpuscular volume. Vasoocclusive crises, blood transfusions, acute chest syndrome, sequestration crises and hospitalizations decreased significantly. Baseline HbF% had significant positive correlation with HbF% at 24 months. There was significant negative correlation between baseline HbF% and change in HbF% from baseline to 24 months. No significant correlation was found between HbF% at baseline and clinical event rates per year after HU. No major adverse events occurred during the study period. CONCLUSIONS: Fixed low dose HU is effective and safe in Indian children with SCA. PMID- 23798624 TI - Pune low birth weight study - birth to adulthood - cognitive development. AB - OBJECTIVE: To assess the cognitive development of non-handicapped low birth weight (LBW) infants at 18 years. DESIGN: Prospective cohort study. SETTING: Infants born between 1987 - 1989 with birth weight less than 2000 g and discharged from a neonatal special care unit were followed up till the age of 18 years. METHODS: The intelligence quotient (IQ) was determined by Ravens progressive matrices. Assessment of adjustment and aptitude was done. RESULTS: The cohort of 161 LBW infants was divided into three groups according to their gestation - preterm SGA (n=61), full term SGA (n=30) and preterm AGA (n=70). 71 full term AGA infants served as controls. The IQ of the study group (Percentile 39.3) was significantly lower than that of controls (Percentile 54.9) (P=0.002). Preterm SGA subjects had the lowest IQ (Percentile 35.5), though just within normal limits. Males from the study group had significantly lower IQ than male controls (P=0.03). The IQ of PTSGA subjects of college educated mothers (P=0.004) and belonging to higher socio-economic class (P=0.04) was significantly higher. On the differential aptitude test, PTSGA subjects were poor in speed and mechanical reasoning. The 18 year IQ could be best predicted by IQ at 6 and 12 years. CONCLUSION: Preterm SGA children have the lowest IQ at 18 years, males have lower IQ. Maternal education and socio-economic status have great impact on cognitive development. Good prediction of the 18 year IQ can be done by the 6 and 12 year IQ. PMID- 23798625 TI - Effectiveness and safety of intravenous iloprost for severe persistent pulmonary hypertension of the newborn. AB - OBJECTIVE: The aims of this study were to determine the effectiveness (oxygenation), safety (hemodynamic status) and short term outcomes of intravenous iloprost (IVI) administration as a rescue therapy in severe persistent pulmonary hypertension of the newborn (PPHN). DESIGN: Retrospective medical records review. SETTING: Tertiary neonatal intensive care unit at Songklanagarind Hospital, Songkhla Province, Hat Yai, Thailand. PARTICIPANTS: Newborns who received IVI as an adjunctive therapy for treatment of severe PPHN, as defined by an oxygen index (OI) of >20 and without response to conventional therapies. MAIN OUTCOME MEASURES: The change of OI and alveolar-arterial oxygen difference before and after commencement of IVI. RESULTS: 33 neonates with severe PPHN at a median gestation of 39 weeks and a baseline OI of 40 (range, 21-101) received IVI. The median OI and alveolar-arterial oxygen difference had a statistically significant decrease after 2 hours of treatment and continued to decline thereafter (P<0.05). All infants received one or more inotropic medications and volume expanders to provide blood pressure support with no statistically significant difference of blood pressure and heart rate before and after IVI treatment. The mortality rate was 15.2%, all of them had initially severe hypoxemia with a median OI of 53.6. CONCLUSION: Triglyceride and non-high-density lipoprotein cholesterol are better than low-density lipoprotein cholesterol as predictors of cardiovascular disease risk factors in Chinese Han children and adolescents. PMID- 23798626 TI - Effect of kangaroo mother care vs expressed breast milk administration on pain associated with removal of adhesive tape in very low birth weight neonates: a randomized controlled trial. AB - OBJECTIVE: To compare the pain relief effect of Kangaroo Mother Care (KMC) and Expressed Breast Milk (EBM) on the pain associated with adhesive tape removal in very low birth weight (VLBW) neonates. DESIGN: Randomized Controlled Trial. SETTING: Neonatal intensive care unit of a tertiary care teaching hospital. PARTICIPANTS: 15 VLBW neonates who needed adhesive tape removal for the first part and 50 VLBW neonates needing adhesive tape removal for the second part. METHODS: In first stage of the study, we studied whether adhesive tape removal in VLBW neonates was painful. In the second stage, eligible VLBW neonates were randomised to compare the efficacy of KMC and EBM in reducing the pain during the procedure of adhesive tape removal. OUTCOME VARIABLES: Premature Infant Pain Profile (PIPP) Score, heart rate, oxygen saturation. RESULTS: There was significant increase in pain associated with the removal of adhesive tape (Mean pre-procedure PIPP score 3.47 +/- 0.74; post-procedure mean PIPP score 12.13 +/- 2.59; P<0.0001). The post intervention mean PIPP pain score was not significantly different between the KMC and EBM groups (P= 0.62). CONCLUSION: Removal of adhesive tape is a painful procedure for VLBW neonates. There was no difference between KMC and EBM in relieving pain associated with adhesive tape removal. PMID- 23798627 TI - Clinical profile and outcome of chronic pancreatitis in children. AB - OBJECTIVE: To evaluate the etiology, presentation, complications and management of chronic pancreatitis in children. DESIGN: Retrospective chart review. SETTING: Gastroenterology department at Christian Medical College and Hospital, Vellore, India between January 2005 and December 2010. PARTICIPANTS: 99 Children (>18 yrs) diagnosed with chronic pancreatitis based on clinical and imaging features. MAIN OUTCOME MEASURES: Etiology, clinical presentation, complications and management of chronic pancreatitis in children. RESULTS: Of 3887 children who attended the Gastroenterology department, 99(2.5%) had chronic pancreatitis, of which 60 (60.6%) were males. In 95(95.9%) patients no definite cause was detected and they were labeled as Idiopathic chronic pancreatitis. All patients had abdominal pain, while 9(9.1%) had diabetes mellitus. Of the 22 children tested for stool fat, 10(45.5%) had steatorrhea. Pancreatic calcification was seen in 69 (69.7%). 68 (71.6%) patients with idiopathic chronic pancreatitis had calcification. Calcific idiopathic chronic pancreatitis was more frequent in males (67.6% vs. 48.1%, P=0.07), and was more commonly associated with diabetes mellitus (13.2% vs. none, P=0.047) and steatorrhea (61.5% vs. 16.7%, P=0.069). Pseudocyst (17.1%) and ascites (9.1%) were the most common complications. All children were treated with pancreatic enzyme supplements for pain relief. 57 patients were followed up. With enzyme supplementation, pain relief was present in 32 (56.1%) patients. Of those who did not improve, 10 underwent endotherapy and 15 underwent surgery. Follow up of 8 patients who underwent endotherapy, showed that 5 (62.5%) had relief. Follow up of 11 patients who underwent surgery showed that only 3 (27%) had pain relief. There was no death. CONCLUSIONS: Idiopathic chronic pancreatitis is the predominant form of chronic pancreatitis in children and adolescents. It can present with or without calcification. The calcific variety is an aggressive disease characterized by early morphological and functional damage to the pancreas. PMID- 23798628 TI - Disease patterns of juvenile dermatomyositis from Western India. AB - A retrospective assessment of clinical characteristics, complications/ associations, laboratory investigations, treatment modalities and outcome in an inceptional cohort of 22 (male-13) children with juvenile dermatomyositis (JDM) receiving treatment at Jaslok Hospital, Mumbai during 1997- 2012 was performed . Mean age at diagnosis was 7.52 +/- 3.99 years. Typical skin rash and muscle weakness were present in all children. Common complications included cutaneous ulcers (27.27%), dysphagia (22.72%) and calcinosis (18.18%).All patients presented with at least one of the serum muscle enzymes elevated. Absence of mortality and cardio-pulmonary complications and a monocyclic course in 72.7% of our patients are at variance from Western series. PMID- 23798629 TI - Presence of hernia sac in prediction of postoperative outcome in congenital diaphragmatic hernia. AB - We conducted this study to assess the value of presence of hernia sac in prediction of postoperative outcome in congenital diaphragmatic hernia (CDH). Data were obtained form medical records of 70 children operated for CDH between 2002-12. Postoperative neonatal death occurred in 1/10 (10%) of infants with a hernia sac and 26/60 (43.3%) in cases without a hernia sac, respectively (P =0.04). Perinatal morbidity in surviving infants was lower in the group with a hernia sac although not significantly. We conclude that the presence of a hernia sac is associated with better postoperative outcome and overall prognosis of CDH. PMID- 23798630 TI - Fatty acid composition of breastmilk of Israeli mothers. AB - We conducted this study to determine the fatty acid composition of breastmilk of Israeli women and compare it with baby milk substitutes. Samples of mature breast milk, from 29 lactating Israeli Jewish mothers were collected during feedings. Total milk lipids extracts were transmethylated and analyzed by using an improved gas-chromatographic method. About 72% of the total fatty acids in the investigated breast milk comprised oleic (18:1c; 31+/-4%), palmitic (16:0; 21+/ 4%), and linoleic (18:2n-6; 20+/-4%) acids. Total saturated fatty acids represented 42+/-7% of total fatty acids. The monounsaturated fatty acids content was 33+/-5%, of which 94% was oleic acid, and the polyunsaturated fatty acids content was about 24+/-4%, of which 85% was linoleic acid. The a-linolenic acid level found in this study, 2.0+/-0.6%, was higher than the range of values reported for the world population (0.10-1.4%). The main fatty acids composition of the milk substitutes has very similar composition to the breast milk. Docosahexaenoic acid levels are particularly low among the population of Jewish nursing mothers in relation to the milk substitutes, containing docosahexaenoic acid in their formulations. PMID- 23798631 TI - Assessment of bronchodilator response in preschool children by pulmonary function tests. AB - We performed pulmonary function test to document bronchodilator response by using tidal breathing flow volume loop (TBFVL), rapid thoracic compression (RTC), and raised volume rapid thoracic compression (RVRTC) techniques. Thirty-nine children (mean age 45.2 months) were evaluated. The parameters that showed significant improvement after bronchodilator administration included TEF10/ PTEF ratio in TBFVL, and FEF25-75%, FEV1 and PEF in RVRTC. None of the parameters measured in RTC showed significant improvement. We conclude FEV1, PEF and FEF 25-75% in RVRTC have greater sensitivity for detection of airways changes. PMID- 23798632 TI - Cerebral infarction after mild head trauma in children. AB - We conducted this retrospective, case record review to determine the risk factors and clinical features associated with cerebral infarction after mild head trauma in children. The median age of the cohort was 2.18 years (range, 6 mo-8 y). Most (26/29) of the patients developed the neurological symptoms and signs within 72 hours after trauma, 51.7% within 30 minutes. The first symptoms included hemiparesis (20), facial paresis (7), and convulsion (7). 86.21% of the lesions lay in basal ganglia region. Pre-existing basal ganglia calcification was identified in 13 as a risk factor. PMID- 23798633 TI - Empyema thoracis in children: a short term outcome study. AB - This study prospectively evaluates clinical course of pyogenic empyema thoracis in 25 children (2 mo to 12 y) treated with injectable antibiotics and chest tube drainage, and followed for 6 weeks. The median (range) age at presentation was 3 y (4 mo to 11 y). The pleural fluid culture was positive in 24% of patients. Staphylococcus aureus was the most commonly isolated organism. The median (range) duration of injectable antibiotics was 14(14-52) d; median duration of total antibiotics (injectable and oral) was 4 weeks. The median (range) duration of chest tube insertion and hospital stay was 8(5-45) and 14(14-56) days, respectively. All patients were discharged without any surgical intervention besides chest tube drainage. At discharge, pleural thickening was present in 84% and crowding of ribs was seen in 60% of the subjects on radiological examination. All these patients were asymptomatic at discharge. Chest deformity was present in 20% of the patients at 6-weeks follow up. Antibiotics and chest tube drainage is an effective method of treating pyogenic empyema thoracis in children in resource poor settings. PMID- 23798635 TI - Aggressive parenteral nutrition in sick very low birth weight babies: a randomized controlled trial. AB - Survival of preterm neonates in developing world has improved. Developing countries lag behind in nutritional management in NICU especially parenteral nutrition (PN). This randomized controlled trial was done to evaluate the effect of aggressive parenteral nutrition on nitrogen retention of sick VLBW and extremely low birth weight (ELBW) babies. From September 2009 to February 2010, total 34 babies were randomized to receive aggressive parenteral nutrition (APN)(n=17) or standard parenteral nutrition (SPN) (n=17). The average daily total and PN calory intake of babies in APN group was significantly higher during first week. APN was well-tolerated; however, nitrogen retention was not significantly higher in APN group. Aggressive parenteral nutrition in sick VLBW babies is feasible in developing world, though it did not improve nitrogen retention in first week of life. PMID- 23798634 TI - Vitamin A status of low and normal birth weight infants at birth and in early infancy. AB - Serum retinol levels of low birth weight (LBW; birth weight < 2500 g) and normal birth weight (NBW; birth weight >= 2500 g) infants were evaluated at birth and 3 months using high performance liquid chromatography. At birth, levels were 13.3 +/- 8.2 ug/dL in LBW (n=146) and 14.0 +/- 6.2 ug/dL in NBW infants (n = 79; p = 0.51), with 41.1% of LBW and 24.1% of NBW infants having vitamin A deficiency (VAD, < 10 ug/dL; P = 0.01). At follow up, levels were 18.0 +/- 9.4 ug/dL in LBW (n = 83) and 20.0 +/- 7.3 ug/dL in NBW infants (n = 51; P = 0.19), with 18.1% of LBW and 3.9% of NBW infants having VAD (P = 0.02). PMID- 23798636 TI - Birthweight centile charts from rural community-based data from southern India. AB - OBJECTIVE: The objectives of the study were to estimate gestational age specific birthweight centiles from healthy pregnancies in a defined rural block and compare the under-two month mortality rates in those belonging to the lowest and highest centile groups. DESIGN: Retrospective chart review. SETTING: Routine data collected regarding all pregnancies, births and deaths occurring in Kaniyambadi, a rural block in Southern India, between 2003 to 2012. SUBJECTS: All singleton live newborns of women without known major antenatal risk factors. MAIN OUTCOME MEASURES: Gestational age- and sex-specific birthweight centile curves were created using the LMS method. Mortality rates for the first two months of life were calculated for those in various centile groups. RESULTS: The median birthweight at term was lower for the study subjects as compared to the median birth weights in the WHO child growth standards 2006, the US and the UK standards. Mortality rates for those with birthweights both below the 3rd centile as well as above the 97th centile higher than for those between 3rd and 97th centiles. CONCLUSIONS: While absolute values of birthweights were lower than the WHO 2006 child growth standards there was a J shaped curve of birthweight and mortality. This suggests that in a given population, mortality increases at extremes of birthweights, even if some of these birthweights may be considered normal by other standards. PMID- 23798637 TI - Variability of thinness and its relation to cardio-metabolic risk factors using four body mass index references in school-children from Delhi, India. AB - OBJECTIVES: To compare: (i) prevalences of thinness in school-children by four body mass index references in common use viz., Centre for Disease Control (CDC); Cole; Indian Academy of Pediatrics (IAP); World Health Organization (WHO); and (ii) relationship of thinness with absence of cardio-metabolic risk factors in these BMI references. DESIGN: Cross-sectional. SETTING: Schools in Delhi. PARTICIPANTS: Anthropometry and blood pressure were measured in 16,245 school children aged 5 to 18 years. Fasting lipids and blood sugar were estimated in 2796 subjects. OUTCOME MEASURES: Age and sex-specific prevalences of thinness and predictive ability of reference cut-off for detecting any cardio-metabolic risk factor were compared. RESULTS: Prevalence of thinness varied with the reference employed; more so for boys. Overall prevalence of thinness was least with IAP reference and highest with CDC cut-offs (6.6% to 16.9% in boys, 6.5% to 10.3% in girls). Children identified as thin by any reference had comparable, significantly lower risks (OR 0.59 to 0.73) of associated cardio-metabolic aberrations. In subjects with any cardio-metabolic or blood pressure aberration, the prevalence of thinness was highest with CDC and least with IAP definition. CONCLUSION: Prevalence of thinness varies considerably with the reference employed. Thin children, identified by any reference, have a lower risk of associated cardio-metabolic aberrations; however, thinness is a poor diagnostic test for this purpose. In populations undergoing nutrition transition, there is a need to link cardio-metabolic risk factors with recommended anthropometric criteria to define undernutrition. PMID- 23798638 TI - Intellectual disability in Indian children: experience with a stratified approach for etiological diagnosis. AB - OBJECTIVE: To study the clinico-etiological profile of children with intellectual disability using an algorithmic approach. DESIGN: Cross-sectional study. SETTING: Tertiary care centre in Northern India. PARTICIPANTS: Consecutive children aged 3 months to 12 years, presenting with intellectual disability, confirmed by Developmental Assessment Scale for Indian Infants, Binet Kulshreshtha Test and Vineland Social Maturity Scale. METHODS: All children were assessed on an internally validated structured proforma. A targeted approach included thyroid function tests, Brainstem evoked response audiometry, electroencephalogram, neuroimaging and metabolic screen done as a pre-decided schema. Genetic tests included karyotyping, molecular studies for Fragile X, Multiplex Ligation Dependent Probe Amplification and Array Comparative Genomic Hybridisation. RESULTS: Data of 101 children (median age 22 months) was analyzed. The etiological yield was 82.1% with genetic causes being the most common (61.4%) followed by perinatal acquired (20.4%), CNS malformations (12%), external prenatal (3.6%), and postnatal acquired (2.4%). Mild delay was seen in 11.7%, moderate in 21.7%, severe in 30.6% and profound in 35.6% CONCLUSIONS: It is possible to ascertain the diagnosis in most of the cases of intellectual disability using a judicious and sequential battery of tests. PMID- 23798639 TI - Survival and morbidity among two cohorts of extremely low birth weight neonates from a tertiary hospital in northern India. AB - This study was conducted to compare the survival and morbidity of extremely low birth weight neonates born during two different time periods (2009-10 and 2001 02) at a Level III referral neonatal unit in Northern India. All consecutive intramural extremely low birth weight neonates (<1000g), irrespective of gestation, and admitted to Intensive Care were enrolled. 149 and 123 neonates were enrolled during 2009-10 and 2001-02, respectively. The baseline characteristics were comparable except for mean birth weight, which was lower during 2009-10 (843+/-108g vs 885+/-126g, P=0.003). Surfactant therapy (54% vs 18%, P<0.001), non-invasive ventilation (28% vs 6%, P<0.001), high frequency ventilation (24% vs 4%, P=0.001), IVH (52% vs 25%, P<0.001) and PDA (34% vs 18%, P=0.004) were significantly more during 2009-10. Culture positive sepsis (33% vs 51%, P=0.003) and ROP rates (7% vs 23%, P=0.042) were significantly higher during 2001-02. Overall survival was similar; however, neonates between 28-30 weeks gestation had better survival (63%) during 2009-10 compared to 2001-02 (38%), P=0.009. Survival in neonates 28-30 weeks improved during this period while overall survival remained the same. PMID- 23798640 TI - Quality of life in symptomatic HIV infected children. AB - We conducted a case control study to compare the quality of life (QOL) in 40 cases of HIV infected children and 40 demographically matched controls with other chronic ailments at a referral hospital in Northern India. Quality of life among HIV infected children was significantly better in psychosocial (P=0.008), emotional (P=0.001) and school (P=0.039) functioning. Factors including age (P=0.07), gender (P=0.44), socioeconomic status (P=0.99), clinical (P=0.18) and immunological staging (P=-0.91) of HIV infection did not significantly influence QOL scores. Hence, quality of life in HIV infected children of North India was better than those suffering from other childhood chronic illness. PMID- 23798641 TI - Analysis of aortic valve commissural fusion after support with continuous-flow left ventricular assist device. AB - OBJECTIVES: Continuous-flow left ventricular assist devices (cf-LVADs) may induce commissural fusion of the aortic valve leaflets. Factors associated with this occurrence of commissural fusion are unknown. The aim of this study was to examine histological characteristics of cf-LVAD-induced commissural fusion in relation to clinical variables. METHODS: Gross and histopathological examinations were performed on 19 hearts from patients supported by either HeartMate II (n = 17) or HeartWare (n = 2) cf-LVADs and related to clinical characteristics (14 heart transplantation, 5 autopsy). RESULTS: Eleven of the 19 (58%) aortic valves showed fusion of single or multiple commissures (total fusion length 11 mm [4-20] (median [interquartile range]) per valve), some leading to noticeable nodular displacements or considerable lumen diameter narrowing. Multiple fenestrations were observed in one valve. Histopathological examination confirmed commissural fusion, with varying changes in valve layer structure without evidence of inflammatory infiltration at the site of fusion. Commissural fusion was associated with continuous aortic valve closure during cf-LVAD support (P = 0.03). LVAD-induced aortic valve insufficiency developed in all patients with commissural fusion and in 67% of patients without fusion. Age, duration of cf LVAD support and aetiology of heart failure (ischaemic vs dilated cardiomyopathy) were not associated with the degree of fusion. CONCLUSIONS: Aortic valve commissural fusion after support with cf-LVADs is a non-inflammatory process leading to changes in valve layer structure that can be observed in >50% of cf LVAD patients. This is the first study showing that patients receiving full cf LVAD support without opening of the valve have a significantly higher risk of developing commissural fusion than patients on partial support. PMID- 23798642 TI - Reduction of prostate intrafractional motion from shortening the treatment time. AB - This study aims to quantify the reduction of the intrafractional motion when the prostate intensity modulated radiation therapy (IMRT) treatment time is shortened. Prostate intrafractional motion data recorded by the Calypso system for 105 patients was analyzed. Statistical distributions of the prostate displacements for the regular IMRT treatment and the first 1, 2, 3 and 5 min of the treatment were calculated and used for treatment margin estimation for all the selected patients. The treatment margins estimated for the first 1, 2, 3 and 5 min were compared with those for the regular IMRT treatment to quantify the reduction of the motion. If the treatment can be completed within 5 (3) min, the standard deviation of the prostate displacement could be reduced by up to 45% and the required treatment margins could be reduced to 1.2 (1.1), 0.9 (0.8), 2.2 (1.9), 1.9 (1.5), 1.9 (1.7) and 2.8 (2.4) mm from 1.5, 1.1, 2.8, 3.0, 2.4 and 3.9 mm in the left, right, superior, inferior, anterior and posterior directions, respectively. The same work was also performed for 19 of the 105 patients who exhibited the largest motion with 30% of their treatment time having 3D motion more than 3 mm. For this group of patients, the required margins change to 1.4 (1.2), 0.8 (0.8), 1.8 (1.6), 2.3 (1.8), 1.7 (1.5) and 3.4 (2.8) mm from 1.9, 1.2, 1.7, 3.7, 1.6 and 4.9 mm in the six directions when the treatment time is reduced to 5 (3) min. The intrafractional motion effects on prostate treatment are significantly smaller and the required margins can be therefore reduced when the treatment is shortened. PMID- 23798643 TI - Dosimetric feasibility of MRI-guided external beam radiotherapy of the kidney. AB - At our institution a treatment for kidney tumours with an MRI-Linac is under development. In order to set inclusion criteria for this treatment the anatomical eligibility criteria and the influence of the motion compensation strategy on the delivered dose should be known. Twenty patients with a renal lesion underwent an MR-scan to image the kidney. Static treatment plans were made and the doses to the organs at risk were evaluated. Furthermore, to calculate the influence of remnant motion in a gated treatment, a convolution of the static dose plan with the residual motion in a gating window was done. For ten patients (50%) a static plan within the dose constraints could be obtained. For all patients where the kidney constraint was obeyed in the static plan, the dose to the gross tumour volume (GTV) and the ipsilateral kidney remained within limits for residual motion in a gating window up to and including 12 mm. For four patients (20%) no static plan without violation of the constraint to the ipsilateral kidney could be made. One of these patients had a tumour of 73 mm in the upper pole and the other patients had a tumour of at least 30 mm in the mid pole. In 6 patients (30%), where the bowels were within the planning target volume, the maximum dose to the bowels was above the limit used. Patient specific assessment might degrade this violation. For tumours smaller than 30 mm a clinically acceptable plan could be created. For other patients the feasibility depends on the geometry of the GTV and kidney. Neither the GTV coverage nor the ipsilateral kidney dose is compromised by breathing motion for gating with a gating window up to and including 12 mm. PMID- 23798644 TI - Improved event positioning in a gamma ray detector using an iterative position weighted centre-of-gravity algorithm. AB - An iterative position-weighted centre-of-gravity algorithm was developed and tested for positioning events in a silicon photomultiplier (SiPM)-based scintillation detector for positron emission tomography. The algorithm used a Gaussian-based weighting function centred at the current estimate of the event location. The algorithm was applied to the signals from a 4 * 4 array of SiPM detectors that used individual channel readout and a LYSO:Ce scintillator array. Three scintillator array configurations were tested: single layer with 3.17 mm crystal pitch, matched to the SiPM size; single layer with 1.5 mm crystal pitch; and dual layer with 1.67 mm crystal pitch and a 1/2 crystal offset in the X and Y directions between the two layers. The flood histograms generated by this algorithm were shown to be superior to those generated by the standard centre of gravity. The width of the Gaussian weighting function of the algorithm was optimized for different scintillator array setups. The optimal width of the Gaussian curve was found to depend on the amount of light spread. The algorithm required less than 20 iterations to calculate the position of an event. The rapid convergence of this algorithm will readily allow for implementation on a front end detector processing field programmable gate array for use in improved real time event positioning and identification. PMID- 23798645 TI - Innovative treatments for joint diseases. Foreword. PMID- 23798646 TI - Brillouin spectroscopy: a new tool to decipher viscoelastic properties of biological scaffold functionalized with nanoscale films. AB - BACKGROUND: In tissue engineering, the endothelialization of vascular scaffold can be a crucial step to improve graft patency. A functional cellularization requires coating surfaces. Since 2003, our group used polyelectrolyte multilayer films (PEMFs) made of poly(allylamine hydrochloride) and polystyren sulfonate to coat luminal surface of blood vessel. Previous results showed that PEMFs have remarkable effect on cellular behavior: adhesion, proliferation, differentiation. However, no method seems adapted for in vitro measurement of the viscoelastic shift after PEMFs buildup. OBJECTIVE: In this present work, we proposed to use a new analytical method based on Brillouin spectroscopy (BS) to investigate the influence PEMFs coating on vessel intrinsic viscoelasticy. METHODS: On human umbilical arteries and rabbit vessels, PEMFs were buildup and the luminal surfaces viscoelasticy were measuring by BS. RESULTS: It seems that these films do not alter dynamic functionality and BS could be an interesting method for understanding the role of the tissue architecture, the interrelation between the different structures constituting the wall and the influence of this architecture on the tissue behavior, especially with the characterized components of the different vascular wall. CONCLUSION: The ability of BS to characterize biological samples opens potential applications in tissue engineering field, especially as a tool for a better understanding of vascular diseases. PMID- 23798647 TI - Respective interest of T2 mapping and diffusion tensor imaging in assessing porcine knee cartilage with MR at 3 Teslas. AB - Non-invasive quantitative assessment of articular cartilage integrity is essential for early detection and evaluation of osteoarthritis (OA) and for the follow-up of stem-cell-driven cartilage engineering. In this study, we investigated the feasibility of exploiting diffusion tensor imaging (DTI) on porcine knee joints with a clinical magnetic resonance (MR) scanner to extract micro-structural information in order to complement biochemical information quantified by T2 maps. We propose an MR protocol for quantifying T2 and cartilage microstructure with diffusion MR on a clinical scanner. Preliminary results were obtained on four pig knee joints using a 3 T GE clinical MRI scanner and an 8 channel knee coil array. The measured cartilage volume, T2 values, apparent diffusion coefficient and fractional anisotropy (FA) of femoral and tibial cartilage were respectively 9.8/2.3 mm2, 67.0/56.1 ms, 1.3/1.3*10-3 mm2/s and 0.4/0.3. This new protocol has the potential to be combined in vivo with quantitative assessment of both cartilage degradation and restoration in osteoarthritis. PMID- 23798648 TI - Influence of serum percentage on the behavior of Wharton's jelly mesenchymal stem cells in culture. AB - BACKGROUND: Mesenchymal stem cells (MSCs) are multipotent cells able to differentiate into several lineages with valuable applications in regenerative medicine. MSCs differentiation is highly dependent on physicochemical properties of the culture substrate, cell density and on culture medium composition. OBJECTIVE: In this study, we assessed the influence of fetal bovine serum (FBS) level on Wharton's jelly (WJ)-MSCs behavior seeded on polyelectrolyte multilayer films (PEMF) made of four bilayers of poly-allylamine hydrochloride (PAH) as polycation and poly-styrene sulfonate (PSS) as polyanion. METHODS: MSCs isolated from WJ by explants method were amplified until the third passage. Their phenotypic characterization was performed by flow cytometry analyses. MSCs were seeded on PEMF, in Endothelial growth medium-2 (EGM-2) supplemented by either 5% or 2% FBS. Cell's behavior was monitored for 20 days by optical microscopy and immunofluorescence. RESULTS: Until 2 weeks on glass slides, no difference was observed whatever the FBS percentage. Then with 5% FBS, MSCs formed three dimensional spheroids on PSS/PAH after 20 days of culture with a nuclear aggregate. Whereas, with 2% FBS, these spheroids did not appear and cells grown in 2D conserved the fibroblast-like morphology. CONCLUSIONS: The decrease of FBS percentage from 5% to 2% avoids 3D cell spheroids formation on PAH/PSS. Such results could guide bioengineering towards building 2D structures like cell layers or 3D structures by increasing the osteogenic or chondrogenic differentiation potential of MSCs. PMID- 23798649 TI - Increasing the bioactivity of elastomeric poly(epsilon-caprolactone) scaffolds for use in tissue engineering. AB - BACKGROUND: Biodegradable polymers used in tissue engineering applications, such as poly(epsilon-caprolactone) (PCL), are hydrophobic leading to a lack of favorable cell signalization and finally to a poor cell adhesion, proliferation and differentiation. To overcome this problem, scaffolds undergo generally a surface modification. OBJECTIVE: Our laboratory has demonstrated that the grafting of poly(sodium styrene sulfonate) (pNaSS) onto titanium or poly(ethylene terephthalate) surfaces, leads to a more specific protein adsorption and a better control of cell proliferation. The objective of this work is to develop, through a straightforward way, bioactive elastomeric PCL scaffolds by grafting pNaSS. METHODS: Porous elastomeric PCL scaffolds were developed using a particulate leaching process. pNaSS was grafted into the scaffold by a "grafting from" technique. In vitro tests were carried out to assess cell adhesion and protein expression. RESULTS: pNaSS was grafted homogeneously onto PCL scaffolds without degrading the biodegradable polymer or the porous structure. The in vitro studies have shown that pNaSS grafted onto PCL improves the cell response with a better expression of collagen, fibronectin and integrin alpha1. CONCLUSIONS: The grafting of pNaSS onto biomaterial surfaces is a versatile method that can provide a new generation of biodegradable scaffolds which could be "biointegrable". PMID- 23798650 TI - PolyNaSS bioactivation of LARS artificial ligament promotes human ligament fibroblast colonisation in vitro. AB - BACKGROUND: Introduction of a new generation of artificial ligaments for ACL reconstruction, the Ligament Augmentation and Reconstruction System (LARS), gives promising clinical results [1]. The current literature supports the use of LARS from short to medium term. To go even further to improve the biocompatibility of this biomaterial, poly(sodium styrene sulfonate) (polyNaSS) was grafted onto its surface. Studies using sheep animal model showed improvement of knee functionalities with this grafted artificial ligament and a better adhesion of human cell lines. OBJECTIVES: To better understand this in vivo improvement of integration with the bioactivated artificial prosthesis, in vitro studies were leaded using human ligament fibroblasts. METHODS: Human ligament fibroblasts isolated from human ruptured ACL were amplified and seeded onto poly(NaSS) grafted and non-grafted PET scaffold (Lars ligament) under standard culture conditions. Cellularized fibers were observed under scanning electron microscopy and histological and immunohistological studies were performed. RESULTS: Cells are localized around the grafted PET fibers of the bioactive ligament and penetrate in the scaffold. On ungrafted fibers, cells stay around the scaffold. On grafted fibers, collagen I appears strongly organized whereas is thin and dispersed on non grafted fibers. Finally, grafting altered localization of decorin. CONCLUSIONS: PolyNaSS grafting enhances human ligament fibroblast organisation in vitro in contact with biomaterial and improves collagen and decorin deposits around fibers. PMID- 23798651 TI - Reversing charges or how to improve Wharton's jelly mesenchymal stem cells culture on polyelectrolyte multilayer films. AB - BACKGROUND: Polyelectrolyte multilayer (PEMs) films made of poly(allylamine hydrochloride) (PAH) as polycation and poly(styrene sulfonate) (PSS) as polyanion, with a PAH ending layer, can be used as a coating in order to improve the anti-thrombogenicity and patency of vascular grafts in vascular engineering field. They induce strong adhesion of mature endothelial cells on glass, expanded polytetrafluoroethylene and cryopreserved arteries. Despite their outstanding effect on mature and progenitor endothelial cells, PEMs ending with PAH showed a poor outcome on Wharton's jelly mesenchymal stem cells (WJ-MSCs) culture. OBJECTIVE: The aim of this work was to examine the influence of the ending charge of PEMs on WJ-MSCs behavior. METHODS: WJ-MSCs amplified until the 3rd passage were seeded and cultured on (PAH-PSS)3-PAH and on (PAH-PSS)4 coated glass for 10 days. Stem cell phenotype was checked by flow cytometry and cell morphology was followed by bright field microscopy. RESULTS: Flow cytometry analysis showed that WJ-MSCs were positive for MSC's markers CD73, CD90 and CD105 and negative for hematopoietic markers CD34 and CD45. Light microscopy showed development of nodule-like structures after 10 days of culture on (PAH-PSS)3-PAH, which resulted in a disturbance of cell monolayer. Whereas WJ-MSCs cultured on (PAH-PSS)4 ending with PSS showed a normal cell growth like on collagen and reached confluence after 10 days. CONCLUSION: The culture surface seems to have a determining role in WJ-MSC's "spatial" behavior, which could be considered in the field of tissue engineering. PMID- 23798657 TI - Editor's commentary. PMID- 23798652 TI - Hydroxyapatite incorporated into collagen gels for mesenchymal stem cell culture. AB - Collagen gels could be used as carriers in tissue engineering to improve cell retention and distribution in the defect. In other respect hydroxyapatite could be added to gels to improve mechanical properties and regulate gel contraction. The aim of this work was to analyze the feasibility to incorporate hydroxyapatite into collagen gels and culture mesenchymal stem cells inside it. Human bone marrow mesenchymal stem cells (hMSC-BM) were used in this study. Gels were prepared by mixing rat tail type I collagen, hydroxyapatite microparticles and MSCs. After polymerization gels were kept in culture while gel contraction and mechanical properties were studied. In parallel, cell viability and morphology were analyzed. Gels became free-floating gels contracted from day 3, only in the presence of cells. A linear rapid contraction phase was observed until day 7, then a very slow contraction phase took place. The incorporation of hydroxyapatite improved gel stability and mechanical properties. Cells were randomly distributed on the gel and a few dead cells were observed all over the experiment. This study shows the feasibility and biocompatibility of hydroxyapatite supplemented collagen gels for the culture of mesenchymal stem cells that could be used as scaffolds for cell delivery in osteoarticular regenerative medicine. PMID- 23798658 TI - Overcoming jet lag: optimizing aerosol delivery with and without jet nebulizers. PMID- 23798659 TI - Strategies to reduce mechanical ventilation and bronchopulmonary dysplasia in preterm infants. PMID- 23798660 TI - Physiologic dead space assessment: field of dreams or clinical paradigm? PMID- 23798661 TI - Physician-ordered aerosol therapy versus respiratory therapist-driven aerosol protocol: effect on resource utilization. PMID- 23798662 TI - Practice of excessive FIO2 and effect on pulmonary outcomes in mechanically ventilated patients with acute lung injury. PMID- 23798663 TI - Dead space fraction: one of many choices to assess PEEP titration. PMID- 23798664 TI - Synthetic shuffling and in vitro selection reveal the rugged adaptive fitness landscape of a kinase ribozyme. AB - The relationship between genotype and phenotype is often described as an adaptive fitness landscape. In this study, we used a combination of recombination, in vitro selection, and comparative sequence analysis to characterize the fitness landscape of a previously isolated kinase ribozyme. Point mutations present in improved variants of this ribozyme were recombined in vitro in more than 10(14) different arrangements using synthetic shuffling, and active variants were isolated by in vitro selection. Mutual information analysis of 65 recombinant ribozymes isolated in the selection revealed a rugged fitness landscape in which approximately one-third of the 91 pairs of positions analyzed showed evidence of correlation. Pairs of correlated positions overlapped to form densely connected networks, and groups of maximally connected nucleotides occurred significantly more often in these networks than they did in randomized control networks with the same number of links. The activity of the most efficient recombinant ribozyme isolated from the synthetically shuffled pool was 30-fold greater than that of any of the ribozymes used to build it, which indicates that synthetic shuffling can be a rich source of ribozyme variants with improved properties. PMID- 23798666 TI - Crystal structure of Schmallenberg orthobunyavirus nucleoprotein-RNA complex reveals a novel RNA sequestration mechanism. AB - Schmallenberg virus (SBV) is a newly emerged orthobunyavirus (family Bunyaviridae) that has caused severe disease in the offspring of farm animals across Europe. Like all orthobunyaviruses, SBV contains a tripartite negative sense RNA genome that is encapsidated by the viral nucleocapsid (N) protein in the form of a ribonucleoprotein complex (RNP). We recently reported the three dimensional structure of SBV N that revealed a novel fold. Here we report the crystal structure of the SBV N protein in complex with a 42-nt-long RNA to 2.16 A resolution. The complex comprises a tetramer of N that encapsidates the RNA as a cross-shape inside the protein ring structure, with each protomer bound to 11 ribonucleotides. Eight bases are bound in the positively charged cleft between the N- and C-terminal domains of N, and three bases are shielded by the extended N-terminal arm. SBV N appears to sequester RNA using a different mechanism compared with the nucleoproteins of other negative-sense RNA viruses. Furthermore, the structure suggests that RNA binding results in conformational changes of some residues in the RNA-binding cleft and the N- and C-terminal arms. Our results provide new insights into the novel mechanism of RNA encapsidation by orthobunyaviruses. PMID- 23798665 TI - Distinct binding interactions of HIV-1 Gag to Psi and non-Psi RNAs: implications for viral genomic RNA packaging. AB - Despite the vast excess of cellular RNAs, precisely two copies of viral genomic RNA (gRNA) are selectively packaged into new human immunodeficiency type 1 (HIV 1) particles via specific interactions between the HIV-1 Gag and the gRNA psi (psi) packaging signal. Gag consists of the matrix (MA), capsid, nucleocapsid (NC), and p6 domains. Binding of the Gag NC domain to psi is necessary for gRNA packaging, but the mechanism by which Gag selectively interacts with psi is unclear. Here, we investigate the binding of NC and Gag variants to an RNA derived from psi (Psi RNA), as well as to a non-psi region (TARPolyA). Binding was measured as a function of salt to obtain the effective charge (Zeff) and nonelectrostatic (i.e., specific) component of binding, Kd(1M). Gag binds to Psi RNA with a dramatically reduced Kd(1M) and lower Zeff relative to TARPolyA. NC, GagDeltaMA, and a dimerization mutant of Gag bind TARPolyA with reduced Zeff relative to WT Gag. Mutations involving the NC zinc finger motifs of Gag or changes to the G-rich NC-binding regions of Psi RNA significantly reduce the nonelectrostatic component of binding, leading to an increase in Zeff. These results show that Gag interacts with gRNA using different binding modes; both the NC and MA domains are bound to RNA in the case of TARPolyA, whereas binding to Psi RNA involves only the NC domain. Taken together, these results suggest a novel mechanism for selective gRNA encapsidation. PMID- 23798667 TI - Consolidation therapy for HBeAg-positive Asian chronic hepatitis B patients receiving lamivudine treatment: a multicentre study. AB - OBJECTIVES: For hepatitis B e antigen (HBeAg)-positive patients, continuing therapy (consolidation) for 6-12 months before cessation of nucleos(t)ide analogues (NAs) was recommended. This study aimed to investigate whether a longer period of lamivudine consolidation therapy leads to better outcomes and the clinical factors associated with response. METHODS: Combined response [HBeAg seroconversion and undetectable serum hepatitis B virus (HBV) DNA by PCR assay] 6 months [end of follow-up (EOF)] after cessation of therapy was assessed in 101 HBeAg-positive chronically infected patients who received continued long-term lamivudine treatment and achieved a combined response at the end of treatment. RESULTS: The rate of combined response at EOF was 40.6%. A lower pretreatment HBV DNA level, a longer duration of consolidation therapy, pretreatment hepatitis B surface antigen titre <1500 IU/mL and a higher proportion of consolidation duration of >18 months were significantly associated with combined response. A lower pretreatment HBV DNA level and a longer duration of consolidation therapy were independent factors associated with combined response at EOF by multivariate logistic regression analyses. The rate of combined response was 71.4%, 39.0% and 25.6% in patients with consolidation duration of >18 months, 12-18 months and <12 months, respectively (P = 0.001). Consolidation therapy for >18 months achieved a significantly higher rate of combined response at EOF in patients achieving combined response within or after 6 months. CONCLUSIONS: Consolidation therapy for >18 months significantly improved the outcome of lamivudine therapy, particularly for patients who achieved a combined response after 6 months. PMID- 23798668 TI - In vitro phenotypes to elvitegravir and dolutegravir in primary macrophages and lymphocytes of clonal recombinant viral variants selected in patients failing raltegravir. AB - OBJECTIVES: The cross-resistance profiles of elvitegravir and dolutegravir on raltegravir-resistant variants is still controversial or not available in macrophages and lack extensive evaluations on wide panels of clonal variants. Thus, a complete evaluation in parallel with all currently available integrase inhibitors (INIs) was performed. METHODS: The integrase coding region was RT-PCR amplified from patient-derived plasma samples and cloned into an HIV-1 molecular clone lacking the integrase region. Twenty recombinant viruses bearing mutations to all primary pathways of resistance to raltegravir were phenotypically evaluated with each integrase inhibitor in freshly purified CD4+ T cells or monocyte-derived macrophages. RESULTS: Y143R single mutants conferred a higher level of raltegravir resistance in macrophages [fold change (FC) 47.7-60.24] compared with CD4+ T cells (FC 9.55-11.56). All other combinations had similar effects on viral susceptibility to raltegravir in both cell types. Elvitegravir displayed a similar behaviour both in lymphocytes and macrophages with all the tested patterns. When compared with raltegravir, none to modest increases in resistance were observed for the Y143R/C pathways. Dolutegravir maintained its activity and cross-resistance profile in macrophages. Only Q148H/R variants had a reduced level of susceptibility (FC 5.48-18.64). No variations were observed for the Y143R/C (+/-T97A) or N155H variants. CONCLUSIONS: All INIs showed comparable antiretroviral activity in both cell types even if single mutations were associated with a different level of susceptibility in vitro to raltegravir and elvitegravir in macrophages. In particular, dolutegravir was capable of inhibiting with similar potency infection of raltegravir-resistant variants with Y143 or N155 pathways in both HIV-1 major cell reservoirs. PMID- 23798670 TI - Resistance phenotypes and genotypes of methicillin-resistant Staphylococcus aureus isolates from broiler chickens at slaughter and abattoir workers. AB - OBJECTIVES: To comparatively investigate the resistance phenotypes and genotypes of various methicillin-resistant Staphylococcus aureus (MRSA) isolates from broilers at slaughter and workers at the respective poultry slaughterhouses. METHODS: Forty-six MRSA isolates (28 from broilers and 18 from humans) obtained at four different slaughterhouses were included. In addition to previously determined sequence types (STs) and spa types, the isolates were characterized by dru typing, SCCmec typing and PFGE. Resistance phenotypes were determined by broth microdilution. Resistance genes and clonal complexes (CCs) were detected by DNA microarray or specific PCR assays. RESULTS: MRSA of CC398, spa type t011 and varying dru types represented 23/28 broiler isolates and 12/18 human isolates. Three ST9/t1430/dt10a isolates were each seen among the isolates from the abattoir workers and the broilers. In addition, two human CC398/ST1453/t4652/dt3c isolates, a single human CC398/t034/dt6j isolate and two chicken CC398/t108/dt11a isolates were detected. All CC398 isolates (including ST1453) and some of the ST9 isolates from chickens and humans showed resistance to four to nine classes of antimicrobial agents and carried a wide range of resistance genes. While the resistance phenotypes and genotypes of the chicken isolates of the same flock were closely related, they usually differed from the resistance phenotypes and genotypes of the isolates from the workers at the respective slaughterhouse. CONCLUSIONS: The apparent homogeneity of MRSA isolates from the same flock suggests exchange of isolates between the respective animals. The apparent heterogeneity of MRSA isolates from abattoir workers might reflect their occupational contact with animals from numerous chicken flocks. PMID- 23798669 TI - National sentinel surveillance of transmitted drug resistance in antiretroviral naive chronically HIV-infected patients in France over a decade: 2001-2011. AB - OBJECTIVES: As recommended by the French ANRS programme for the surveillance of HIV-1 resistance, we estimated the prevalence of transmitted drug resistance associated mutations (RAMs) in antiretroviral-naive, chronically HIV-1-infected patients. METHODS: RAMs were sought in samples from 661 newly diagnosed HIV-1 infected patients in 2010/11 at 36 HIV clinical care centres. Weighted analyses were used to derive representative estimates of the percentage of patients with RAMs. RESULTS: At patient inclusion, the prevalence of virus with protease (PR) or reverse transcriptase (RT) RAMs was 9.0% (95% CI 6.8%-11.2%). No integrase RAMs were observed. The prevalences of protease inhibitor, nucleoside RT inhibitor and non-nucleoside RT inhibitor RAMs were 1.8%, 6.2% and 2.4%, respectively. Resistance to one, two and three classes of antiretroviral agent was observed in 7.9%, 0.9% and 0.2% of patients, respectively. The frequency of RAMs was higher in patients infected with B compared with non-B subtype virus (11.9% versus 5.1%, P = 0.003). Baseline characteristics (gender, age, country of transmission, CD4 cell count and viral load) were not associated with the prevalence of transmitted RAMs. However, men having sex with men (MSM) were more frequently infected with resistant virus than were other transmission groups (12.5% versus 5.8%, P = 0.003). Compared with the 2006/07 survey, the overall prevalence of resistance remained stable. However, a significant decrease in the frequency of virus with PR RAMs was observed in 2010/11 compared with the 2006/07 survey (1.8% versus 5.0%, P = 0.003). CONCLUSIONS: In France in 2010/11, the global prevalence of transmitted drug-resistant variants was 9.0%, and the prevalence was stable compared with the 2006/07 survey. MSM and B subtype infected patients are the groups with a higher prevalence of drug resistance. PMID- 23798671 TI - Proteome profiles of vaginal fluids from women affected by bacterial vaginosis and healthy controls: outcomes of rifaximin treatment. AB - OBJECTIVES: This study was designed to characterize the proteome of vaginal fluid (VF) from women with bacterial vaginosis (BV) in comparison with that from healthy women, and to evaluate the effect exerted by rifaximin vaginal tablets. METHODS: Women with BV (n = 39) and matched healthy controls (n = 41) were included in the study. BV patients were distributed among four groups receiving different doses of rifaximin. Vaginal rinsings were collected at the screening visit from all the participants and at a follow-up visit from BV-affected women. The VF proteome was analysed by tandem mass spectrometry using an Orbitrap mass analyser. RESULTS: A large number of human proteins were differentially expressed in women with BV in comparison with healthy women (n = 118) and in BV-affected women treated with rifaximin (n = 284). In both comparisons, a high proportion of the dysregulated proteins (~20%) were involved in the innate immune response. Twenty-one of 24 proteins increased in abundance in women with BV versus healthy women and 31/59 proteins decreased after rifaximin treatment, suggesting a general reduction of the immune response resulting from the therapy. Major changes in protein abundance were found following treatment with 25 mg of rifaximin once daily for 5 days. CONCLUSIONS: BV is associated with a massive change in the VF proteome, mainly regarding the abundance of proteins involved in the innate immune response. Rifaximin at a dosage of 25 mg for 5 days modulated the vaginal proteome, counteracting the alterations associated with the BV condition. PMID- 23798672 TI - Chitosan-dextran sulphate nanocapsule drug delivery system as an effective therapeutic against intraphagosomal pathogen Salmonella. AB - OBJECTIVES: The ability to target conventional drugs efficiently inside cells to kill intraphagosomal bacteria has been a major hurdle in treatment of infective diseases. We aimed to develop an efficient drug delivery system for combating infection caused by Salmonella, a well-known intracellular and intraphagosomal pathogen. Chitosan-dextran sulphate (CD) nanocapsules were assessed for their efficiency in delivering drugs against Salmonella. METHODS: The CD nanocapsules were prepared using the layer-by-layer method and loaded with ciprofloxacin or ceftriaxone. Antibiotic-loaded nanocapsules were analysed in vitro for their ability to enter epithelial and macrophage cells to kill Salmonella. In vivo pharmacokinetics and organ distribution studies were performed to check the efficiency of the delivery system. The in vivo antibacterial activity of free antibiotic and antibiotic loaded into nanocapsules was tested in a murine salmonellosis model. RESULTS: In vitro and in vivo experiments showed that this delivery system can be used effectively to clear Salmonella infection. CD nanocapsules were successfully employed for efficient targeting and killing of the intracellular pathogen at a dosage significantly lower than that of the free antibiotic. The increased retention time of ciprofloxacin in the blood and organs when it was delivered by CD nanocapsules compared with the conventional routes of administration may be the reason underlying the requirement for a reduced dosage and frequency of antibiotic administration. CONCLUSIONS: CD nanocapsules can be used as an efficient drug delivery system to treat intraphagosomal pathogens, especially Salmonella infection. This delivery system might be used effectively for other vacuolar pathogens including Mycobacteria, Brucella and Legionella. PMID- 23798673 TI - Therapeutic windows and opportunity cost cast upon prostate cancer's fatal shore. PMID- 23798674 TI - Population shift underlies Ca2+-induced regulatory transitions in the sodium calcium exchanger (NCX). AB - In eukaryotic Na(+)/Ca(2+) exchangers (NCX) the Ca(2+) binding CBD1 and CBD2 domains form a two-domain regulatory tandem (CBD12). An allosteric Ca(2+) sensor (Ca3-Ca4 sites) is located on CBD1, whereas CBD2 contains a splice-variant segment. Recently, a Ca(2+)-driven interdomain switch has been described, albeit how it couples Ca(2+) binding with signal propagation remains unclear. To resolve the dynamic features of Ca(2+)-induced conformational transitions we analyze here distinct splice variants and mutants of isolated CBD12 at varying temperatures by using small angle x-ray scattering (SAXS) and equilibrium (45)Ca(2+) binding assays. The ensemble optimization method SAXS analysis demonstrates that the apo and Mg(2+)-bound forms of CBD12 are highly flexible, whereas Ca(2+) binding to the Ca3-Ca4 sites results in a population shift of conformational landscape to more rigidified states. Population shift occurs even under conditions in which no effect of Ca(2+) is observed on the globally derived Dmax (maximal interatomic distance), although under comparable conditions a normal [Ca(2+)]-dependent allosteric regulation occurs. Low affinity sites (Ca1-Ca2) of CBD1 do not contribute to Ca(2+)-induced population shift, but the occupancy of these sites by 1 mM Mg(2+) shifts the Ca(2+) affinity (Kd) at the neighboring Ca3-Ca4 sites from ~ 50 nM to ~ 200 nM and thus, keeps the primary Ca(2+) sensor (Ca3-Ca4 sites) within a physiological range. Thus, Ca(2+) binding to the Ca3-Ca4 sites results in a population shift, where more constraint conformational states become highly populated at dynamic equilibrium in the absence of global conformational transitions in CBD alignment. PMID- 23798675 TI - CXCR4 chemokine receptor signaling induces apoptosis in acute myeloid leukemia cells via regulation of the Bcl-2 family members Bcl-XL, Noxa, and Bak. AB - The CXCR4 chemokine receptor promotes survival of many different cell types. Here, we describe a previously unsuspected role for CXCR4 as a potent inducer of apoptosis in acute myeloid leukemia (AML) cell lines and a subset of clinical AML samples. We show that SDF-1, the sole ligand for CXCR4, induces the expected migration and ERK activation in the KG1a AML cell line transiently overexpressing CXCR4, but ERK activation did not lead to survival. Instead, SDF-1 treatment led via a CXCR4-dependent mechanism to apoptosis, as evidenced by increased annexin V staining, condensation of chromatin, and cleavage of both procaspase-3 and PARP. This SDF-1-induced death pathway was partially inhibited by hypoxia, which is often found in the bone marrow of AML patients. SDF-1-induced apoptosis was inhibited by dominant negative procaspase-9 but not by inhibition of caspase-8 activation, implicating the intrinsic apoptotic pathway. Further analysis showed that this pathway was activated by multiple mechanisms, including up-regulation of Bak at the level of mRNA and protein, stabilization of the Bak activator Noxa, and down-regulation of antiapoptotic Bcl-XL. Furthermore, adjusting expression levels of Bak, Bcl-XL, or Noxa individually altered the level of apoptosis in AML cells, suggesting that the combined modulation of these family members by SDF-1 coordinates their interplay to produce apoptosis. Thus, rather than mediating survival, SDF-1 may be a means to induce apoptosis of CXCR4-expressing AML cells directly in the SDF-1-rich bone marrow microenvironment if the survival cues of the bone marrow are disrupted. PMID- 23798676 TI - Degradome products of the matricellular protein CCN1 as modulators of pathological angiogenesis in the retina. AB - CCN1 is a matricellular protein involved in normal vascular development and tissue repair. CCN1 exhibits cell- and context-dependent activities that are reflective of its tetramodular structure phylogenetically linked to four domains found in various matrix proteins. Here, we show that vitreal fluids from patients with proliferative diabetic retinopathy (PDR) were enriched with a two-module form of CCN1 comprising completely or partially the insulin-like growth factor binding protein (IGFBP) and von Willebrand factor type C (vWC) domains. The two- and three-module forms comprising, in addition to IGFBP and vWC, the thrombospondin type 1 (TSP1) repeats are CCN1 degradome products by matrix metalloproteinase-2 and -14. The functional significance of CCN1 and its truncated variants was determined in the mouse model of oxygen-induced retinopathy, which simulates neovascular growth associated with PDR and assesses treatment outcomes. In this model, lentivirus-mediated expression of either CCN1 or the IGFBP-vWC-TSP1 form reduced ischemia-induced neovascularization, whereas ectopic expression of the IGFBP-vWC variant exacerbated pathological angiogenesis. The IGFBP-vWC form has potent proangiogenic properties promoting retinal endothelial cell growth, migration, and three-dimensional tubular structure formation, whereas the IGFBP-vWC-TSP1 variant suppressed cell growth and angiogenic gene expression. Both IGFBP-vWC and IGFBP-vWC-TSP1 forms exhibited predictable variations of their domain folding that enhanced their functional potential. These data provide new insights into the formation and activities of CCN1-truncated variants and raise the predictive value of the form containing completely or partially the IGFBP and vWC domains as a surrogate marker of CCN1 activity in PDR distinguishing pathological from physiological angiogenesis. PMID- 23798677 TI - Mutation of the salt bridge-forming residues in the ETV6-SAM domain interface blocks ETV6-NTRK3-induced cellular transformation. AB - The ETV6-NTRK3 (EN) chimeric oncogene is expressed in diverse tumor types. EN is generated by a t(12;15) translocation, which fuses the N-terminal SAM (sterile alpha-motif) domain of the ETV6 (or TEL) transcription factor to the C-terminal PTK (protein-tyrosine kinase) domain of the neurotrophin-3 receptor NTRK3. SAM domain-mediated polymerization of EN leads to constitutive activation of the PTK domain and constitutive signaling of the Ras-MAPK and PI3K-Akt pathways, which are essential for EN oncogenesis. Here we show through complementary biophysical and cellular biological techniques that mutation of Lys-99, which participates in a salt bridge at the SAM polymer interface, reduces self-association of the isolated SAM domain as well as high molecular mass complex formation of EN and abrogates the transformation activity of EN. We also show that mutation of Asp 101, the intermolecular salt bridge partner of Lys-99, similarly blocks transformation of NIH3T3 cells by EN, reduces EN tyrosine phosphorylation, inhibits Akt and Mek1/2 signaling downstream of EN, and abolishes tumor formation in nude mice. In contrast, mutations of Glu-100 and Arg-103, residues in the vicinity of the interdomain Lys-99-Asp-101 salt bridge, have little or no effect on these oncogenic characteristics of EN. Our results underscore the importance of specific electrostatic interactions for SAM polymerization and EN transformation. PMID- 23798678 TI - Interaction with Cfd1 increases the kinetic lability of FeS on the Nbp35 scaffold. AB - P-loop NTPases of the ApbC/Nbp35 family are involved in FeS protein maturation in nearly all organisms and are proposed to function as scaffolds for initial FeS cluster assembly. In yeast and animals, Cfd1 and Nbp35 are homologous P-loop NTPases that form a heterotetrameric complex essential for FeS protein maturation through the cytosolic FeS cluster assembly (CIA) pathway. Cfd1 is conserved in animals, fungi, and several archaeal species, but in many organisms, only Nbp35 is present, raising the question of the unique roles played by Cfd1 and Nbp35. To begin to investigate this issue, we examined Cfd1 and Nbp35 function in budding yeast. About half of each protein was detected in a heterocomplex in logarithmically growing yeast. Nbp35 readily bound (55)Fe when fed to cells, whereas (55)Fe binding by free Cfd1 could not be detected. Rapid (55)Fe binding to and release from Nbp35 was impaired by Cfd1 deficiency. A Cfd1 mutation that caused a defect in heterocomplex stability supported iron binding to Nbp35 but impaired iron release. Our results suggest a model in which Cfd1-Nbp35 interaction increases the lability of assembled FeS on the Nbp35 scaffold for transfer to target apo-FeS proteins. PMID- 23798679 TI - How metabolism generates signals during innate immunity and inflammation. AB - The interplay between immunity, inflammation, and metabolic changes is a growing field of research. Toll-like receptors and NOD-like receptors are families of innate immune receptors, and their role in the human immune response is well documented. Exciting new evidence is emerging with regard to their role in the regulation of metabolism and the activation of inflammatory pathways during the progression of metabolic disorders such as type 2 diabetes and atherosclerosis. The proinflammatory cytokine IL-1beta appears to play a central role in these disorders. There is also evidence that metabolites such as NAD(+) (acting via deacetylases such as SIRT1 and SIRT2) and succinate (which regulates hypoxia inducible factor 1alpha) are signals that regulate innate immunity. In addition, the extracellular overproduction of metabolites such as uric acid and cholesterol crystals acts as a signal sensed by NLRP3, leading to the production of IL-1beta. These observations cast new light on the role of metabolism during host defense and inflammation. PMID- 23798680 TI - Inhibition of HDAC6 deacetylase activity increases its binding with microtubules and suppresses microtubule dynamic instability in MCF-7 cells. AB - The post-translational modification of tubulin appears to be a highly controlled mechanism that regulates microtubule functioning. Acetylation of the epsilon amino group of Lys-40 of alpha-tubulin marks stable microtubules, although the causal relationship between tubulin acetylation and microtubule stability has remained poorly understood. HDAC6, the tubulin deacetylase, plays a key role in maintaining typical distribution of acetylated microtubules in cells. Here, by using tubastatin A, an HDAC6-specific inhibitor, and siRNA-mediated depletion of HDAC6, we have explored whether tubulin acetylation has a role in regulating microtubule stability. We found that whereas both pharmacological inhibition of HDAC6 as well as its depletion enhance microtubule acetylation, only pharmacological inhibition of HDAC6 activity leads to an increase in microtubule stability against cold and nocodazole-induced depolymerizing conditions. Tubastatin A treatment suppressed the dynamics of individual microtubules in MCF 7 cells and delayed the reassembly of depolymerized microtubules. Interestingly, both the localization of HDAC6 on microtubules and the amount of HDAC6 associated with polymeric fraction of tubulin were found to increase in the tubastatin A treated cells compared with the control cells, suggesting that the pharmacological inhibition of HDAC6 enhances the binding of HDAC6 to microtubules. The evidence presented in this study indicated that the increased binding of HDAC6, rather than the acetylation per se, causes microtubule stability. The results are in support of a hypothesis that in addition to its deacetylase function, HDAC6 might function as a MAP that regulates microtubule dynamics under certain conditions. PMID- 23798681 TI - miR-200s contribute to interleukin-6 (IL-6)-induced insulin resistance in hepatocytes. AB - By influencing the activity of the PI3K/AKT pathway, IL-6 acts as an important regulator of hepatic insulin resistance. miR-200s have been shown to control growth by regulating PI3K, but the role of miR-200s in the development of hepatic insulin resistance remains unclear. The present study showed that elevated serum concentration of IL-6 is associated with decreased levels of miR-200s, impaired activation of the AKT/glycogen synthase kinase (GSK) pathway, and reduced glycogenesis that occurred in the livers of db/db mice. As shown in the murine NCTC 1469 hepatocytes and the primary hepatocytes treated with 10 ng/ml IL-6 for 24 h and in 12-week-old male C57BL/6J mice injected with 16 MUg/ml IL-6 by pumps for 7 days, IL-6 administration induced insulin resistance through down regulation of miR-200s. Moreover, IL-6 treatment inhibited the phosphorylation of AKT and GSK and decreased the glycogenesis. The effects of IL-6 could be diminished by suppression of FOG2 expression. We concluded that IL-6 treatment may impair the activities of the PI3K/AKT/GSK pathway and inhibit the synthesis of glycogen, perhaps via down-regulating miR-200s while augmenting FOG2 expression. PMID- 23798682 TI - An unbiased approach to identifying tau kinases that phosphorylate tau at sites associated with Alzheimer disease. AB - Neurofibrillary tangles, one of the hallmarks of Alzheimer disease (AD), are composed of paired helical filaments of abnormally hyperphosphorylated tau. The accumulation of these proteinaceous aggregates in AD correlates with synaptic loss and severity of dementia. Identifying the kinases involved in the pathological phosphorylation of tau may identify novel targets for AD. We used an unbiased approach to study the effect of 352 human kinases on their ability to phosphorylate tau at epitopes associated with AD. The kinases were overexpressed together with the longest form of human tau in human neuroblastoma cells. Levels of total and phosphorylated tau (epitopes Ser(P)-202, Thr(P)-231, Ser(P)-235, and Ser(P)-396/404) were measured in cell lysates using AlphaScreen assays. GSK3alpha, GSK3beta, and MAPK13 were found to be the most active tau kinases, phosphorylating tau at all four epitopes. We further dissected the effects of GSK3alpha and GSK3beta using pharmacological and genetic tools in hTau primary cortical neurons. Pathway analysis of the kinases identified in the screen suggested mechanisms for regulation of total tau levels and tau phosphorylation; for example, kinases that affect total tau levels do so by inhibition or activation of translation. A network fishing approach with the kinase hits identified other key molecules putatively involved in tau phosphorylation pathways, including the G-protein signaling through the Ras family of GTPases (MAPK family) pathway. The findings identify novel tau kinases and novel pathways that may be relevant for AD and other tauopathies. PMID- 23798683 TI - Quantitative dissection of the binding contributions of ligand lysines of the receptor-associated protein (RAP) to the low density lipoprotein receptor-related protein (LRP1). AB - Although lysines are known to be critical for ligand binding to LDL receptor family receptors, relatively small reductions in affinity have been found when such lysines have been mutated. To resolve this paradox, we have examined the specific binding contributions of four lysines, Lys-253, Lys-256, Lys-270, and Lys-289, in the third domain (D3) of receptor-associated protein (RAP), by eliminating all other lysine residues. Using D3 variants containing lysine subsets, we examined binding to the high affinity fragment CR56 from LRP1. With this simplification, we found that elimination of the lysine pairs Lys-253/Lys 256 and Lys-270/Lys-289 resulted in increases in Kd of 1240- and 100,000-fold, respectively. Each pair contributed additively to overall affinity, with 61% from Lys-270/Lys-289 and 39% from Lys-253/Lys-256. Furthermore, the Lys-270/Lys-289 pair alone could bind different single CR domains with similar affinity. Within the pairs, binding contributions of Lys-270 ? Lys-256 > Lys-253 ~ Lys-289 were deduced. Importantly, however, Lys-289 could significantly compensate for the loss of Lys-270, thus explaining how previous studies have underestimated the importance of Lys-270. Calorimetry showed that favorable enthalpy, from Lys-256 and Lys-270, overwhelmingly drives binding, offset by unfavorable entropy. Our findings support a mode of ligand binding in which a proximal pair of lysines engages the negatively charged pocket of a CR domain, with two such pairs of interactions (requiring two CR domains), appropriately separated, being alone sufficient to provide the low nanomolar affinity found for most protein ligands of LDL receptor family members. PMID- 23798684 TI - Decomposition of slide helix contributions to ATP-dependent inhibition of Kir6.2 channels. AB - Regulation of inwardly rectifying potassium channels by intracellular ligands couples cell membrane excitability to important signaling cascades and metabolic pathways. We investigated the molecular mechanisms that link ligand binding to the channel gate in ATP-sensitive Kir6.2 channels. In these channels, the "slide helix" forms an interface between the cytoplasmic (ligand-binding) domain and the transmembrane pore, and many slide helix mutations cause loss of function. Using a novel approach to rescue electrically silent channels, we decomposed the contribution of each interface residue to ATP-dependent gating. We demonstrate that effective inhibition by ATP relies on an essential aspartate at residue 58. Characterization of the functional importance of this conserved aspartate, relative to other residues in the slide helix, has been impossible because of loss-of-function of Asp-58 mutant channels. The Asp-58 position exhibits an extremely stringent requirement for aspartate because even a highly conservative mutation to glutamate is insufficient to restore normal channel function. These findings reveal unrecognized slide helix elements that are required for functional channel expression and control of Kir6.2 gating by intracellular ATP. PMID- 23798685 TI - Pannexin 1 channels link chemoattractant receptor signaling to local excitation and global inhibition responses at the front and back of polarized neutrophils. AB - Neutrophil chemotaxis requires excitatory signals at the front and inhibitory signals at the back of cells, which regulate cell migration in a chemotactic gradient field. We have previously shown that ATP release via pannexin 1 (PANX1) channels and autocrine stimulation of P2Y2 receptors contribute to the excitatory signals at the front. Here we show that PANX1 also contributes to the inhibitory signals at the back, namely by providing the ligand for A2A adenosine receptors. In resting neutrophils, we found that A2A receptors are uniformly distributed across the cell surface. In polarized cells, A2A receptors redistributed to the back where their stimulation triggered intracellular cAMP accumulation and protein kinase A (PKA) activation, which blocked chemoattractant receptor signaling. Inhibition of PANX1 blocked A2A receptor stimulation and cAMP accumulation in response to formyl peptide receptor stimulation. Treatments that blocked endogenous A2A receptor signaling impaired the polarization and migration of neutrophils in a chemotactic gradient field and resulted in enhanced ERK and p38 MAPK signaling in response to formyl peptide receptor stimulation. These findings suggest that chemoattractant receptors require PANX1 to trigger excitatory and inhibitory signals that synergize to fine-tune chemotactic responses at the front and back of neutrophils. PANX1 channels thus link local excitatory signals to the global inhibitory signals that orchestrate chemotaxis of neutrophils in gradient fields. PMID- 23798686 TI - Towards the endgame and beyond: complexities and challenges for the elimination of infectious diseases. AB - Successful control measures have interrupted the local transmission of human infectious diseases such as measles, malaria and polio, and saved and improved billions of lives. Similarly, control efforts have massively reduced the incidence of many infectious diseases of animals, such as rabies and rinderpest, with positive benefits for human health and livelihoods across the globe. However, disease elimination has proven an elusive goal, with only one human and one animal pathogen globally eradicated. As elimination targets expand to regional and even global levels, hurdles may emerge within the endgame when infections are circulating at very low levels, turning the last mile of these public health marathons into the longest mile. In this theme issue, we bring together recurring challenges that emerge as we move towards elimination, highlighting the unanticipated consequences of particular ecologies and pathologies of infection, and approaches to their management. PMID- 23798687 TI - Rinderpest: the veterinary perspective on eradication. AB - Rinderpest was a devastating disease of livestock responsible for continent-wide famine and poverty. Centuries of veterinary advances culminated in 2011 with the UN Food and Agriculture Organization and the World Organization for Animal Health declaring global eradication of rinderpest; only the second disease to be eradicated and the greatest veterinary achievement of our time. Conventional control measures, principally mass vaccination combined with zoosanitary procedures, led to substantial declines in the incidence of rinderpest. However, during the past decades, innovative strategies were deployed for the last mile to overcome diagnostic and surveillance challenges, unanticipated variations in virus pathogenicity, circulation of disease in wildlife populations and to service remote and nomadic communities in often-unstable states. This review provides an overview of these challenges, describes how they were overcome and identifies key factors for this success. PMID- 23798689 TI - Think globally, act locally: the role of local demographics and vaccination coverage in the dynamic response of measles infection to control. AB - The global reduction of the burden of morbidity and mortality owing to measles has been a major triumph of public health. However, the continued persistence of measles infection probably not only reflects local variation in progress towards vaccination target goals, but may also reflect local variation in dynamic processes of transmission, susceptible replenishment through births and stochastic local extinction. Dynamic models predict that vaccination should increase the mean age of infection and increase inter-annual variability in incidence. Through a comparative approach, we assess national-level patterns in the mean age of infection and measles persistence. We find that while the classic predictions do hold in general, the impact of vaccination on the age distribution of cases and stochastic fadeout are mediated by local birth rate. Thus, broad scale vaccine coverage goals are unlikely to have the same impact on the interruption of measles transmission in all demographic settings. Indeed, these results suggest that the achievement of further measles reduction or elimination goals is likely to require programmatic and vaccine coverage goals that are tailored to local demographic conditions. PMID- 23798688 TI - The final stages of the global eradication of poliomyelitis. AB - The global incidence of poliomyelitis has dropped by more than 99 per cent since the governments of the world committed to eradication in 1988. One of the three serotypes of wild poliovirus has been eradicated and the remaining two serotypes are limited to just a small number of endemic regions. However, the Global Polio Eradication Initiative (GPEI) has faced a number of challenges in eradicating the last 1 per cent of wild-virus transmission. The polio endgame has also been complicated by the recognition that vaccination with the oral poliovirus vaccine (OPV) must eventually cease because of the risk of outbreaks of vaccine-derived polioviruses. I describe the major challenges to wild poliovirus eradication, focusing on the poor immunogenicity of OPV in lower-income countries, the inherent limitations to the sensitivity and specificity of surveillance, the international spread of poliovirus and resulting outbreaks, and the potential significance of waning intestinal immunity induced by OPV. I then focus on the challenges to eradicating all polioviruses, the problem of vaccine-derived polioviruses and the risk of wild-type or vaccine-derived poliovirus re-emergence after the cessation of oral vaccination. I document the role of research in the GPEI's response to these challenges and ultimately the feasibility of achieving a world without poliomyelitis. PMID- 23798690 TI - The elimination of fox rabies from Europe: determinants of success and lessons for the future. AB - Despite perceived challenges to controlling an infectious disease in wildlife, oral rabies vaccination (ORV) of foxes has proved a remarkably successful tool and a prime example of a sophisticated strategy to eliminate disease from wildlife reservoirs. During the past three decades, the implementation of ORV programmes in 24 countries has led to the elimination of fox-mediated rabies from vast areas of Western and Central Europe. In this study, we evaluated the efficiency of 22 European ORV programmes between 1978 and 2010. During this period an area of almost 1.9 million km² was targeted at least once with vaccine baits, with control taking between 5 and 26 years depending upon the country. We examined factors influencing effort required both to control and eliminate fox rabies as well as cost-related issues of these programmes. The proportion of land area ever affected by rabies and an index capturing the size and overlap of successive ORV campaigns were identified as factors having statistically significant effects on the number of campaigns required to both control and eliminate rabies. Repeat comprehensive campaigns that are wholly overlapping much more rapidly eliminate infection and are less costly in the long term. Disproportionally greater effort is required in the final phase of an ORV programme, with a median of 11 additional campaigns required to eliminate disease once incidence has been reduced by 90 per cent. If successive ORV campaigns span the entire affected area, rabies will be eliminated more rapidly than if campaigns are implemented in a less comprehensive manner, therefore reducing ORV expenditure in the longer term. These findings should help improve the planning and implementation of ORV programmes, and facilitate future decision-making by veterinary authorities and policy-makers. PMID- 23798691 TI - Progress towards eliminating canine rabies: policies and perspectives from Latin America and the Caribbean. AB - Human rabies transmitted by dogs is considered a neglected disease that can be eliminated in Latin America and the Caribbean (LAC) by 2015. The aim of this paper is to discuss canine rabies policies and projections for LAC regarding current strategies for achieving this target and to critically review the political, economic and geographical factors related to the successful elimination of this deadly disease in the context of the difficulties and challenges of the region. The strong political and technical commitment to control rabies in LAC in the 1980s, started with the regional programme coordinated by the Pan American Health Organization. National and subnational programmes involve a range of strategies including mass canine vaccination with more than 51 million doses of canine vaccine produced annually, pre- and post exposure prophylaxis, improvements in disease diagnosis and intensive surveillance. Rabies incidence in LAC has dramatically declined over the last few decades, with laboratory confirmed dog rabies cases decreasing from approximately 25 000 in 1980 to less than 300 in 2010. Dog-transmitted human rabies cases also decreased from 350 to less than 10 during the same period. Several countries have been declared free of human cases of dog-transmitted rabies, and from the 35 countries in the Americas, there is now only notification of human rabies transmitted by dogs in seven countries (Bolivia, Peru, Honduras, Haiti, Dominican Republic, Guatemala and some states in north and northeast Brazil). Here, we emphasize the importance of the political commitment in the final progression towards disease elimination. The availability of strategies for rabies control, the experience of most countries in the region and the historical ties of solidarity between countries with the support of the scientific community are evidence to affirm that the elimination of dog-transmitted rabies can be achieved in the short term. The final efforts to confront the remaining obstacles, like achieving and sustaining high vaccination coverage in communities that are most impoverished or in remote locations, are faced by countries that struggle to allocate sufficient financial and human resources for rabies control. Continent wide cooperation is therefore required in the final efforts to secure the free status of remaining countries in the Americas, which is key to the regional elimination of human rabies transmitted by dogs. PMID- 23798692 TI - Preventive chemotherapy as a strategy for elimination of neglected tropical parasitic diseases: endgame challenges. AB - Global efforts to address neglected tropical diseases (NTDs) were stimulated in January 2012 by the London declaration at which 22 partners, including the Bill & Melinda Gates Foundation, World Bank, World Health Organization (WHO) and major pharmaceutical companies committed to sustaining and expanding NTD programmes to eliminate or eradicate 11 NTDs by 2020 to achieve the goals outlined in the recently published WHO road map. Here, we present the current context of preventive chemotherapy for some NTDs, and discuss the problems faced by programmes as they consider the 'endgame', such as difficulties of access to populations in post-conflict settings, limited human and financial resources, and the need to expand access to clean water and improved sanitation for schistosomiasis and soil-transmitted helminthiasis. In the case of onchocerciasis and lymphatic filariasis, ivermectin treatment carries a significant risk owing to serious adverse effects in some patients co-infected with the tropical eye worm Loa loa filariasis. We discuss the challenges of managing complex partnerships, and maintain advocacy messages for the continued support for elimination of these preventable diseases. PMID- 23798693 TI - A sticky situation: the unexpected stability of malaria elimination. AB - Malaria eradication involves eliminating malaria from every country where transmission occurs. Current theory suggests that the post-elimination challenges of remaining malaria-free by stopping transmission from imported malaria will have onerous operational and financial requirements. Although resurgent malaria has occurred in a majority of countries that tried but failed to eliminate malaria, a review of resurgence in countries that successfully eliminated finds only four such failures out of 50 successful programmes. Data documenting malaria importation and onwards transmission in these countries suggests malaria transmission potential has declined by more than 50-fold (i.e. more than 98%) since before elimination. These outcomes suggest that elimination is a surprisingly stable state. Elimination's 'stickiness' must be explained either by eliminating countries starting off qualitatively different from non-eliminating countries or becoming different once elimination was achieved. Countries that successfully eliminated were wealthier and had lower baseline endemicity than those that were unsuccessful, but our analysis shows that those same variables were at best incomplete predictors of the patterns of resurgence. Stability is reinforced by the loss of immunity to disease and by the health system's increasing capacity to control malaria transmission after elimination through routine treatment of cases with antimalarial drugs supplemented by malaria outbreak control. Human travel patterns reinforce these patterns; as malaria recedes, fewer people carry malaria from remote endemic areas to remote areas where transmission potential remains high. Establishment of an international resource with backup capacity to control large outbreaks can make elimination stickier, increase the incentives for countries to eliminate, and ensure steady progress towards global eradication. Although available evidence supports malaria elimination's stickiness at moderate-to-low transmission in areas with well developed health systems, it is not yet clear if such patterns will hold in all areas. The sticky endpoint changes the projected costs of maintaining elimination and makes it substantially more attractive for countries acting alone, and it makes spatially progressive elimination a sensible strategy for a malaria eradication endgame. PMID- 23798694 TI - Dracunculiasis (guinea worm disease): eradication without a drug or a vaccine. AB - Dracunculiasis, commonly known as guinea worm disease, is a nematode infection transmitted to humans exclusively via contaminated drinking water. The disease prevails in the most deprived areas of the world. No vaccine or medicine is available against the disease: eradication is being achieved by implementing preventive measures. These include behavioural change in patients and communities -such as self-reporting suspected cases to health workers or volunteers, filtering drinking water and accessing water from improved sources and preventing infected individuals from wading or swimming in drinking-water sources- supplemented by active surveillance and case containment, vector control and provision of improved water sources. Efforts to eradicate dracunculiasis began in the early 1980s. By the end of 2012, the disease had reached its lowest levels ever. This paper reviews the progress made in eradicating dracunculiasis since the eradication campaign began, the factors influencing progress and the difficulties in controlling the pathogen that requires behavioural change, especially when the threat becomes rare. The challenges of intensifying surveillance are discussed, particularly in insecure areas containing the last foci of the disease. It also summarizes the broader benefits uniquely linked to interventions against dracunculiasis. PMID- 23798696 TI - Vaccine refusal and the endgame: walking the last mile first. AB - As multiple papers within this special issue illustrate, the dynamics of disease eradication are different from disease control. When it comes to disease eradication, 'the last mile is longest'. For social and ecological reasons such as vaccine refusal, further ending incidence of a disease when it has reached low levels is frequently complex. Issues of non-compliance within a target population often influence the outcome of disease eradication efforts. Past eradication efforts confronted such obstacles towards the tail end of the campaign, when disease incidence was lowest. This article provides a comparison of non compliance within polio, measles and smallpox campaigns, demonstrating the tendency of vaccine refusal to rise as disease incidence falls. In order to overcome one of the most intractable challenges to eradication, future disease eradication efforts must prioritize vaccine refusal from the start, i.e. 'walk the last mile first'. PMID- 23798695 TI - The impact of protein-conjugate polysaccharide vaccines: an endgame for meningitis? AB - The development and implementation of conjugate polysaccharide vaccines against invasive bacterial diseases, specifically those caused by the encapsulated bacteria Neisseria meningitidis, Haemophilus influenzae and Streptococcus pneumoniae, has been one of the most effective public health innovations of the last 25 years. These vaccines have resulted in significant reductions in childhood morbidity and mortality worldwide, with their effectiveness due in large part to their ability to induce long-lasting immunity in a range of age groups. At the population level this immunity reduces carriage and interrupts transmission resulting in herd immunity; however, these beneficial effects can be counterbalanced by the selection pressures that immunity against carriage can impose, potentially promoting the emergence and spread of virulent vaccine escape variants. Studies following the implementation of meningococcal serogroup C vaccines improved our understanding of these effects in relation to the biology of accidental pathogens such as the meningococcus. This understanding has enabled the refinement of the implementation of conjugate polysaccharide vaccines against meningitis-associated bacteria, and will be crucial in maintaining and improving vaccine control of these infections. To date there is little evidence for the spread of virulent vaccine escape variants of the meningococcus and H. influenzae, although this has been reported in pneumococci. PMID- 23798697 TI - Economic considerations for the eradication endgame. AB - An infectious disease will be eradicated only if it is eliminated everywhere, including in the hardest-to-reach, most vaccine-wary communities. If eradication is successful, it promises a dividend in the form of avoided infections and vaccinations. However, success is never certain unless and until eradication is achieved, and claiming the dividend means bearing the possibly great risk of re emergence. Economic analysis of eradication evaluates these risks and rewards relative to the alternative of 'optimal control', and also exposes the incentives for achieving and capitalizing on eradication. Eradication is a 'game', because some countries may be willing to eliminate the disease within their borders only if assured that all others will eliminate the disease within their borders. International financing is also a game, because each country would rather free ride than contribute. Finally, for diseases such as polio, capitalizing on eradication is a game, for should any country continue to vaccinate in the post eradication era using the live-attenuated polio vaccine, the countries that stop vaccinating will be exposed to the risk of vaccine-derived polioviruses. In the framework developed in this paper, eradication is a seductive goal, its attainment fraught with peril. PMID- 23798698 TI - Vacated niches, competitive release and the community ecology of pathogen eradication. AB - A recurring theme in the epidemiological literature on disease eradication is that each pathogen occupies an ecological niche, and eradication of one pathogen leaves a vacant niche that favours the emergence of new pathogens to replace it. However, eminent figures have rejected this view unequivocally, stating that there is no basis to fear pathogen replacement and even that pathogen niches do not exist. After exploring the roots of this controversy, I propose resolutions to disputed issues by drawing on broader ecological theory, and advance a new consensus based on robust mechanistic principles. I argue that pathogen eradication (and cessation of vaccination) leads to a 'vacated niche', which could be re-invaded by the original pathogen if introduced. Consequences for other pathogens will vary, with the crucial mechanisms being competitive release, whereby the decline of one species allows its competitors to perform better, and evolutionary adaptation. Hence, eradication can cause a quantitative rise in the incidence of another infection, but whether this leads to emergence as an endemic pathogen depends on additional factors. I focus on the case study of human monkeypox and its rise following smallpox eradication, but also survey how these ideas apply to other pathogens and discuss implications for eradication policy. PMID- 23798699 TI - Elimination of foot-and-mouth disease in South America: lessons and challenges. AB - Foot-and-mouth disease (FMD) is a highly transmissible and economically devastating disease of cloven-hoofed livestock. Although vaccines are available and have been instrumental in eliminating the disease from most of the South American animal population, viral circulation still persists in some countries and areas, posing a threat to the advances of the last 60 years by the official veterinary services with considerable support of the livestock sectors. The importance of the disease for the social and economic development of the American continent led to the establishment in 1951 of the Pan American Centre for Foot and-Mouth Disease (PANAFTOSA), which has been providing technical cooperation to countries for the elimination of the disease. The first FMD national elimination programmes were established in South America around the 1960s and 1970s. To advance the regional elimination efforts in the 1980s, countries agreed on a Plan of Action 1988-2009 of the Hemispheric Program for the Eradication of Foot-and Mouth Disease. The Plan of Action 1988-2009 did not reach the goal of elimination from the continent; and a new Plan of Action 2011-2020 was developed in 2010 based on the experience acquired by the countries and PANAFTOSA during the past 60 years. This plan is now being implemented; several challenges are still to be overcome to ensure the elimination of FMD from the Americas by 2020, however, the goal is achievable. PMID- 23798700 TI - Lessons from the eradication of smallpox: an interview with D. A. Henderson. AB - It has been more than 35 years since the last naturally occurring case of smallpox. Sufficient time has passed to allow an objective overview of what were the key factors in the success of the eradication effort and what lessons smallpox can offer to other campaigns. Professor D. A. Henderson headed the international effort to eradicate smallpox. Here, we present a summary of D. A. Henderson's perspectives on the eradication of smallpox. This text is based upon the Unither Baruch Blumberg Lecture, delivered by D. A. Henderson at the University of Oxford in November 2012 and upon conversations and correspondence with Professor Henderson. PMID- 23798701 TI - Breast feeding and intergenerational social mobility: what are the mechanisms? AB - OBJECTIVE: To investigate the association between breast feeding and intergenerational social mobility and the possible mediating role of neurological and stress mechanisms. DESIGN: Secondary analysis of data from the 1958 and the 1970 British Cohort Studies. SETTING: Longitudinal study of individuals born in Britain during 1 week in 1958 and 1970. PARTICIPANTS: 17 419 individuals participated in the 1958 cohort and 16 771 in the 1970 cohort. The effect of breast feeding on intergenerational social mobility from age 10/11 to age 33/34 was analysed after multiple imputations to fill in missing data and propensity score matching on a wide range of confounders measured in childhood (1958 cohort N=16 039-16 154; 1970 cohort N=16 255-16 361). MAIN OUTCOME MEASURES: Own Registrar General's Social Class (RGSC) at 33/34 years adjusted for father's RGSC at 10/11 years, gender and their interaction. RESULTS: Breastfed individuals were more likely to be upwardly mobile (1958 cohort: OR 1.24 95% CI 1.12 to 1.38; 1970 cohort: OR 1.24 95% CI 1.12 to 1.37) and less likely to be downwardly mobile (1958 cohort: OR 0.81 95% CI 0.73 to 0.90; 1970 cohort: OR 0.79 95% CI 0.71 to 0.88). In an ordinal regression model, markers of neurological development (cognitive test scores) and stress (emotional stress scores) accounted for approximately 36% of the relationship between breast feeding and social mobility. CONCLUSIONS: Breast feeding increased the odds of upward social mobility and decreased the odds of downward mobility. Consistent with a causal explanation, the findings were robust to matching on a large number of observable variables and effect sizes were alike for two cohorts with different social distributions of breast feeding. The effect was mediated in part through neurological and stress mechanisms. PMID- 23798702 TI - Oxygen-coupled redox regulation of the skeletal muscle ryanodine receptor/Ca2+ release channel (RyR1): sites and nature of oxidative modification. AB - In mammalian skeletal muscle, Ca(2+) release from the sarcoplasmic reticulum (SR) through the ryanodine receptor/Ca(2+)-release channel RyR1 can be enhanced by S oxidation or S-nitrosylation of separate Cys residues, which are allosterically linked. S-Oxidation of RyR1 is coupled to muscle oxygen tension (pO2) through O2 dependent production of hydrogen peroxide by SR-resident NADPH oxidase 4. In isolated SR (SR vesicles), an average of six to eight Cys thiols/RyR1 monomer are reversibly oxidized at high (21% O2) versus low pO2 (1% O2), but their identity among the 100 Cys residues/RyR1 monomer is unknown. Here we use isotope-coded affinity tag labeling and mass spectrometry (yielding 93% coverage of RyR1 Cys residues) to identify 13 Cys residues subject to pO2-coupled S-oxidation in SR vesicles. Eight additional Cys residues are oxidized at high versus low pO2 only when NADPH levels are supplemented to enhance NADPH oxidase 4 activity. pO2 sensitive Cys residues were largely non-overlapping with those identified previously as hyperreactive by administration of exogenous reagents (three of 21) or as S-nitrosylated. Cys residues subject to pO2-coupled oxidation are distributed widely within the cytoplasmic domain of RyR1 in multiple functional domains implicated in RyR1 activity-regulating interactions with the L-type Ca(2+) channel (dihydropyridine receptor) and FK506-binding protein 12 as well as in "hot spot" regions containing sites of mutation implicated in malignant hyperthermia and central core disease. pO2-coupled disulfide formation was identified, whereas neither S-glutathionylated nor sulfenamide-modified Cys residues were observed. Thus, physiological redox regulation of RyR1 by endogenously generated hydrogen peroxide is exerted through dynamic disulfide formation involving multiple Cys residues. PMID- 23798703 TI - Insights into the conformation of aminofluorene-deoxyguanine adduct in a DNA polymerase active site. AB - The active site conformation of the mutagenic fluoroaminofluorene-deoxyguanine adduct (dG-FAF, N-(2'-deoxyguanosin-8-yl)-7-fluoro-2-aminofluorene) has been investigated in the presence of Klenow fragment of Escherichia coli DNA polymerase I (Kfexo(-)) and DNA polymerase beta (pol beta) using (19)F NMR, insertion assay, and surface plasmon resonance. In a single nucleotide gap, the dG-FAF adduct adopts both a major-groove- oriented and base-displaced stacked conformation, and this heterogeneity is retained upon binding pol beta. The addition of a non-hydrolysable 2'-deoxycytosine-5'-[(alpha,beta) methyleno]triphosphate (dCMPcPP) nucleotide analog to the binary complex results in an increase of the major groove conformation of the adduct at the expense of the stacked conformation. Similar results were obtained with the addition of an incorrect dAMPcPP analog but with formation of the minor groove binding conformer. In contrast, dG-FAF adduct at the replication fork for the Kfexo(-) complex adopts a mix of the major and minor groove conformers with minimal effect upon the addition of non-hydrolysable nucleotides. For pol beta, the insertion of dCTP was preferred opposite the dG-FAF adduct in a single nucleotide gap assay consistent with (19)F NMR data. Surface plasmon resonance binding kinetics revealed that pol beta binds tightly with DNA in the presence of correct dCTP, but the adduct weakens binding with no nucleotide specificity. These results provide molecular insights into the DNA binding characteristics of FAF in the active site of DNA polymerases and the role of DNA structure and sequence on its coding potential. PMID- 23798704 TI - Characterization of the interaction between the Saccharomyces cerevisiae Rad51 recombinase and the DNA translocase Rdh54. AB - The Saccharomyces cerevisiae Rdh54 protein is a member of the Swi2/Snf2 family of DNA translocases required for meiotic and mitotic recombination and DNA repair. Rdh54 interacts with the general recombinases Rad51 and Dmc1 and promotes D-loop formation with either recombinase. Rdh54 also mediates the removal of Rad51 from undamaged chromatin in mitotic cells, which prevents formation of nonrecombinogenic complexes that can otherwise become toxic for cell growth. To determine which of the mitotic roles of Rdh54 are dependent on Rad51 complex formation, we finely mapped the Rad51 interaction domain in Rdh54, generated N terminal truncation variants, and characterized their attributes biochemically and in cells. Here, we provide evidence suggesting that the N-terminal region of Rdh54 is not necessary for the response to the DNA-damaging agent methyl methanesulfonate. However, truncation variants missing 75-200 residues at the N terminus are sensitive to Rad51 overexpression. Interestingly, a hybrid protein containing the N-terminal region of Rad54, responsible for Rad51 interaction, fused to the Swi2/Snf2 core of Rdh54 is able to effectively complement the sensitivity to both methyl methanesulfonate and excess Rad51 in rdh54 null cells. Altogether, these results reveal a distinction between damage sensitivity and Rad51 removal with regard to Rdh54 interaction with Rad51. PMID- 23798706 TI - Occupational external exposure to ionising radiation in France (2005-2011). AB - The Institute for Radiological Protection and Nuclear Safety (IRSN) produces the French annual report on occupational exposure to ionising radiation, collecting all national data and aggregating the results according to a unique activity classification expected to be shared by all involved in personal dosimetric monitoring (employers, external dosimetry services and IRSN). Nearly 344,000 monitored workers were counted in France in 2011, with a collective dose of 64.24 man.Sv. The average annual dose (as calculated over the number of measurably exposed workers) differed among the main activity fields: 0.54 mSv in medical and veterinary activities, 1.18 mSv in the nuclear field, 1.60 mSv in non-nuclear industry and 0.47 mSv in research activities. Because of improved knowledge about worker activities, the results for year 2011 are detailed per activity sectors in each field. Lasting limitations prevent from having complete and reliable worker activity information. Solutions are considered to reduce the inaccuracy in the annually published statistics. The evolution of occupational external exposure to ionising radiation from 2005 to 2011 in France is then presented for the main activity fields. PMID- 23798705 TI - Centrosomal Che-1 protein is involved in the regulation of mitosis and DNA damage response by mediating pericentrin (PCNT)-dependent Chk1 protein localization. AB - To combat threats posed by DNA damage, cells have evolved mechanisms, collectively termed DNA damage response (DDR). These mechanisms detect DNA lesions, signal their presence, and promote their repair. Centrosomes integrate G2/M checkpoint control and repair signals in response to genotoxic stress, acting as an efficient control mechanism when G2/M checkpoint function fails and mitosis begins in the presence of damaged DNA. Che-1 is an RNA polymerase II binding protein involved in the regulation of gene transcription, induction of cell proliferation, and DDR. Here we provide evidence that in addition to its nuclear localization, Che-1 localizes at interphase centrosomes, where it accumulates following DNA damage or spindle poisons. We show that Che-1 depletion generates supernumerary centrosomes, multinucleated cells, and multipolar spindle formation. Notably, Che-1 depletion abolishes the ability of Chk1 to bind pericentrin and to localize at centrosomes, which, in its turn, deregulates the activation of centrosomal cyclin B-Cdk1 and advances entry into mitosis. Our results reinforce the notion that Che-1 plays an important role in DDR and that its contribution seems to be relevant for the spindle assembly checkpoint. PMID- 23798707 TI - Measurement of indoor and outdoor radon concentrations during Superstorm Sandy. AB - Superstorm Sandy affected much of the US East Coast extending over 1800 km. It passed over the test location in the State of Maryland on 29 October 2012. Being 350 km away from the regions of highest intensity the storm was of lower intensity at the test location. Continuous radon monitors and passive radon monitors were used for the measurement. The test location was the basement of a single family home representing the indoor concentration. A partially opened garage of the same test home represented the outdoor radon concentration. In 24 h, the atmospheric pressure dropped from 990 to 960 mbar and the indoor radon concentration increased from 70 to 1500 Bq m(-3) and returned to the normal of 70 Bq m(-3) at the end of the storm. Throughout the storm, the outdoor radon concentration was not significantly affected. Probable reasons for such surprisingly large changes are discussed. However, the outdoor temperature dropped from 13 degrees C to 7 degrees C during the radon peak. PMID- 23798708 TI - Natural radioactivity in bottled mineral and thermal spring waters of Turkey. AB - Radiological assessment of bottled mineral waters and thermal spring waters collected from various natural sources in Turkey was carried out using gross alpha and gross beta counting techniques. For 40 samples of bottled mineral water, the mean gross alpha activity concentration was determined to be 164 mBq l(-1) (min.:7 mBq l(-1); max.: 3042 mBq l(-1)), whereas the gross beta activity concentration was found to be 555 mBq l(-1) (min.: 21 mBq l(-1); max.: 4845 mBq l(-1)). For 24 samples of thermal spring water, the mean gross alpha activity concentration was obtained to be 663 mBq l(-1) (min.: 18 mBq l(-1); max.: 3070 mBq l(-1)). The gross beta activity concentration for these samples, on the other hand, was determined to be 3314 mBq l(-1) (min.: 79 mBq l(-1); max.: 17955 mBq l( 1)). These values lead to the average annual effective doses of 313 uSv for mineral waters and 1805 uSv for thermal spa waters, which are found to be higher than those recommended for drinking waters by the World Health Organization. It should be noted, however, that one will get less dose from mineral waters since the daily consumption is much lower than 2 l that these calculations assume. PMID- 23798709 TI - Comparison of active and passive methods for radon exhalation from a high exposure building material. AB - The radon exhalation rates and radon concentrations in granite stones used in Iran were measured by means of a high-resolution high purity Germanium gamma spectroscopy system (passive method) and an AlphaGUARD model PQ 2000 (active method). For standard rooms (4.0 * 5.0 m area * 2.8 height) where ground and walls have been covered by granite stones, the radon concentration and the radon exhalation rate by two methods were calculated. The activity concentrations of (226)Ra in the selected granite samples ranged from 3.8 to 94.2 Bq kg(-1). The radon exhalation rate from the calculation of the (226)Ra activity concentration was obtained. The radon exhalation rates were 1.31-7.86 Bq m(-2)h(-1). The direction measurements using an AlphaGUARD were from 218 to 1306 Bq m(-3) with a mean of 625 Bq m(-3). Also, the exhalation rates measured by the passive and active methods were compared and the results of this study were the same, with the active method being 22 % higher than the passive method. PMID- 23798710 TI - Self-disorders and schizophrenia: a phenomenological reappraisal of poor insight and noncompliance. AB - Poor insight into illness is considered the primary cause of treatment noncompliance in schizophrenia. In this article, we critically discuss the predominant conceptual accounts of poor insight, which consider it as an ineffective self-reflection, caused either by psychological defenses or impaired metacognition. We argue that these accounts are at odds with the phenomenology of schizophrenia, and we propose a novel account of poor insight. We suggest that the reason why schizophrenia patients have no or only partial insight and consequently do not comply with treatment is rooted in the nature of their anomalous self-experiences (ie, self- disorders) and the related articulation of their psychotic symptoms. We argue that self-disorders destabilize the patients' experiential framework, thereby weakening their basic sense of reality (natural attitude) and enabling another sense of reality (solipsistic attitude) to emerge and coexist. This coexistence of attitudes, which Bleuler termed "double bookkeeping," is, in our view, central to understanding what poor insight in schizophrenia really is. We suggest that our phenomenologically informed account of poor insight may have important implications for early intervention, psychoeducation, and psychotherapy for schizophrenia. PMID- 23798712 TI - Introduction to a series of reviews on cancer-associated thrombotic disease. PMID- 23798711 TI - LIN28B-mediated expression of fetal hemoglobin and production of fetal-like erythrocytes from adult human erythroblasts ex vivo. AB - Reactivation of fetal hemoglobin (HbF) holds therapeutic potential for sickle cell disease and beta-thalassemias. In human erythroid cells and hematopoietic organs, LIN28B and its targeted let-7 microRNA family, demonstrate regulated expression during the fetal-to-adult developmental transition. To explore the effects of LIN28B in human erythroid cell development, lentiviral transduction was used to knockdown LIN28B expression in erythroblasts cultured from human umbilical cord CD34+ cells. The subsequent reduction in LIN28B expression caused increased expression of let-7 and significantly reduced HbF expression. Conversely, LIN28B overexpression in cultured adult erythroblasts reduced the expression of let-7 and significantly increased HbF expression. Cellular maturation was maintained including enucleation. LIN28B expression in adult erythroblasts increased the expression of gamma-globin, and the HbF content of the cells rose to levels >30% of their hemoglobin. Expression of carbonic anhydrase I, glucosaminyl (N-acetyl) transferase 2, and miR-96 (three additional genes marking the transition from fetal-to-adult erythropoiesis) were reduced by LIN28B expression. The transcription factor BCL11A, a well-characterized repressor of gamma-globin expression, was significantly down-regulated. Independent of LIN28B, experimental suppression of let-7 also reduced BCL11A expression and significantly increased HbF expression. LIN28B expression regulates HbF levels and causes adult human erythroblasts to differentiate with a more fetal-like phenotype. PMID- 23798713 TI - Tumor-derived tissue factor-positive microparticles and venous thrombosis in cancer patients. AB - Patients with cancer have an increased risk for venous thrombosis. Interestingly, different cancer types have different rates of thrombosis, with pancreatic cancer having one of the highest rates. However, the mechanisms responsible for the increase in venous thrombosis in patients with cancer are not understood. Tissue factor (TF) is a transmembrane receptor and primary initiator of blood coagulation. Tumor cells express TF and spontaneously release TF-positive microparticles (MPs) into the blood. MPs are small membrane vesicles that are highly procoagulant. It has been proposed that these circulating tumor-derived, TF-positive MPs may explain the increased rates of venous thrombosis seen in patients with cancer. In animal models, increased levels of tumor-derived, TF positive MPs are associated with activation of coagulation. Moreover, these MPs bind to sites of vascular injury and enhance thrombosis. We and others have found that patients with cancer have elevated levels of circulating TF-positive MPs. These MPs are derived from tumors because they express tumor markers and are decreased by tumor resection. Importantly, several studies have shown that increased levels of TF-positive MPs correlate with venous thrombosis in patients with cancer. Taken together, these results suggest that TF-positive MPs may be a useful biomarker to identify patients with cancer who are at high risk for thrombosis. PMID- 23798714 TI - CC chemokine receptor 8 potentiates donor Treg survival and is critical for the prevention of murine graft-versus-host disease. AB - The infusion of donor regulatory T cells (Tregs) has been used to prevent acute graft-versus-host disease (GVHD) in mice and has shown promise in phase 1 clinical trials. Previous work suggested that early Treg migration into lymphoid tissue was important for GVHD prevention. However, it is unclear how and where Tregs function longitudinally to affect GVHD. To better understand their mechanism of action, we studied 2 Treg-associated chemokine receptors in murine stem cell transplant models. CC chemokine receptor (CCR) 4 was dispensable for donor Treg function in the transplant setting. Donor Tregs lacking CCR8 (CCR8(-/ )), however, were severely impaired in their ability to prevent lethal GVHD because of increased cell death. By itself, CCR8 stimulation was unable to rescue Tregs from apoptosis. Instead, CCR8 potentiated Treg survival by promoting critical interactions with dendritic cells. In vivo, donor bone marrow-derived CD11c(+) antigen-presenting cells (APCs) were important for promoting donor Treg maintenance after transplant. In contrast, host CD11c(+) APCs appeared to be dispensable for early activation and expansion of donor Tregs. Collectively, our data indicate that a sustained donor Treg presence is critical for their beneficial properties, and that their survival depends on CCR8 and donor but not host CD11c(+) APCs. PMID- 23798716 TI - Pro-convulsant effects: a neglected dimension of psychotropic activity. PMID- 23798715 TI - Advanced drug delivery systems for antithrombotic agents. AB - Despite continued achievements in antithrombotic pharmacotherapy, difficulties remain in managing patients at high risk for both thrombosis and hemorrhage. Utility of antithrombotic agents (ATAs) in these settings is restricted by inadequate pharmacokinetics and narrow therapeutic indices. Use of advanced drug delivery systems (ADDSs) may help to circumvent these problems. Various nanocarriers, affinity ligands, and polymer coatings provide ADDSs that have the potential to help optimize ATA pharmacokinetics, target drug delivery to sites of thrombosis, and sense pathologic changes in the vascular microenvironment, such as altered hemodynamic forces, expression of inflammatory markers, and structural differences between mature hemostatic and growing pathological clots. Delivery of ATAs using biomimetic synthetic carriers, host blood cells, and recombinant fusion proteins that are activated preferentially at sites of thrombus development has shown promising outcomes in preclinical models. Further development and translation of ADDSs that spare hemostatic fibrin clots hold promise for extending the utility of ATAs in the management of acute thrombotic disorders through rapid, transient, and targeted thromboprophylaxis. If the potential benefit of this technology is to be realized, a systematic and concerted effort is required to develop clinical trials and translate the use of ADDSs to the clinical arena. PMID- 23798717 TI - Prevention of common mental disorders: what can we learn from those who have gone before and where do we go next? AB - OBJECTIVE: Prevention strategies have made a major contribution to the considerable successes in reductions in cardiovascular disease and cancer mortality seen in recent decades. However, in the field of psychiatry, similar population-level initiatives in the prevention of common mental disorders, depression and anxiety, are noticeably lacking. This paper aims to provide a brief overview of the existing literature on the topic of the prevention of common mental disorders and a commentary regarding the way forward for prevention research and implementation. METHODS: This commentary considers what we currently know, what we might learn from the successes and failures of those working in prevention of other high prevalence health conditions, and where we might go from here. Taking cognisance of previous preventive models, this commentary additionally explores new opportunities for preventive approaches to the common mental disorders. RESULTS: The consensus from a large body of evidence supports the contention that interventions to prevent mental disorders across the lifespan can be both effective and cost-effective. However, funding for research in the area of prevention of common mental disorders is considerably lower than that for research in the areas of treatment, epidemiology and neurobiology. Thus, there is a clear imperative to direct funding towards prevention research to redress this imbalance. Future prevention interventions need to be methodologically rigorous, scalable to the population level and include economic evaluation. Evidence-based knowledge translation strategies should be developed to ensure that all stakeholders recognise preventing mental disorders as an imperative, with appropriate resources directed to this objective. CONCLUSION: There has been a recent expansion of research into potentially modifiable risk factors for depression, and it is now timely to make a concerted effort to advance the field of prevention of common mental disorders. PMID- 23798718 TI - Longitudinal course and predictors of suicidal ideation in a rural community sample. AB - OBJECTIVE: Suicide rates in rural Australia are higher than in urban areas. No existing research has explored the long-term patterns and predictors of change in suicidal ideation within rural areas. This report uses longitudinal data and multiple time points to determine predictors of the trajectory of suicidal ideation in rural Australia. METHOD: Participants in the Australian Rural Mental Health Study (ARMHS) completed self-report surveys at baseline, 12 and 36 months, reporting their psychological and social well-being, and suicidal ideation. Generalised linear mixed models explored these factors as correlates and predictors of suicidal ideation across 3 years using multiple data points. RESULTS: A total of 2135 participants completed at least one wave of ARMHS, and hence were included in the current analysis. Overall, 8.1% reported suicidal ideation during at least one study wave, 76% of whom reported suicidal ideation intermittently rather than consistently across waves. Across the three time points, suicidal ideation was significantly associated with higher psychological distress (OR 1.30, 95% CI 1.23 to 1.37), neuroticism (OR 1.15, 95% CI 1.04 to 1.27), and availability of support (OR 0.80, 95% CI 0.69 to 0.92), with a non significant association with unemployment (OR 1.73, 95% CI 0.93 to 3.24) even after controlling for the effects of perceived financial hardship. Future suicidal ideation was significantly predicted by distress (OR 1.16, 95% CI 1.09 to 1.23) and neuroticism (OR 1.17, 95% CI 1.03 to 1.32), with a non-significant association with unemployment (OR 2.11, 95% CI 0.41 to 2.27). Predictive effects for marital status, social networks, sense of community and availability of support did not remain significant in the full multivariate analysis. CONCLUSIONS: Fluctuations in suicidal ideation are common, and may be associated with changes in psychological and social well-being. Public health strategies, focusing on encouraging help-seeking among those with higher psychological distress, lower social support, and unstable or absent employment opportunities, may be a useful long-term initiative to reduce the prevalence of suicidal ideation in the general rural community. PMID- 23798719 TI - Clinical practitioner's attitudes towards the use of Routine Outcome Monitoring within Child and Adolescent Mental Health Services: a qualitative study of two Child and Adolescent Mental Health Services. AB - Routine Outcome Monitoring (ROM) is held as a greatly important part of practice across many Health Care Services, both in the NHS and in private practice. Yet despite this, there has been little research into the attitudes of practitioners towards ROM. This paper looks at the attitudes of 50 clinicians from two Child and Adolescent Mental Health Services in greater London. The findings showed that although the practitioners were not overwhelming positive in their attitudes to ROM, neither were they overwhelming negative, and many of their concerns involved practical issues surrounding ROM that are potentially soluble. Practitioner engagement in ROM is key if ROM is to be used constructively to reflect on practice. PMID- 23798720 TI - Detection of mild to moderate influenza A/H7N9 infection by China's national sentinel surveillance system for influenza-like illness: case series. AB - OBJECTIVE: To characterise the complete case series of influenza A/H7N9 infections as of 27 May 2013, detected by China's national sentinel surveillance system for influenza-like illness. DESIGN: Case series. SETTING: Outpatient clinics and emergency departments of 554 sentinel hospitals across 31 provinces in mainland China. CASES: Infected individuals were identified through cross referencing people who had laboratory confirmed A/H7N9 infection with people detected by the sentinel surveillance system for influenza-like illness, where patients meeting the World Health Organization's definition of influenza-like illness undergo weekly surveillance, and 10-15 nasopharyngeal swabs are collected each week from a subset of patients with influenza-like illness in each hospital for virological testing. We extracted relevant epidemiological data from public health investigations by the Centers for Disease Control and Prevention at the local, provincial, and national level; and clinical and laboratory data from chart review. MAIN OUTCOME MEASURE: Epidemiological, clinical, and laboratory profiles of the case series. RESULTS: Of 130 people with laboratory confirmed A/H7N9 infection as of 27 May 2013, five (4%) were detected through the sentinel surveillance system for influenza-like illness. Mean age was 13 years (range 2 26), and none had any underlying medical conditions. Exposure history, geographical location, and timing of symptom onset of these five patients were otherwise similar to the general cohort of laboratory confirmed cases so far. Only two of the five patients needed hospitalisation, and all five had mild or moderate disease with an uneventful course of recovery. CONCLUSION: Our findings support the existence of a "clinical iceberg" phenomenon in influenza A/H7N9 infections, and reinforce the need for vigilance to the diverse presentation that can be associated with A/H7N9 infection. At the public health level, indirect evidence suggests a substantial proportion of mild disease in A/H7N9 infections. PMID- 23798721 TI - Restructuring health systems for an era of prolonged austerity: an essay by Richard B Saltman and Zachary Cahn. PMID- 23798722 TI - To boldly go from "computer says no" to an iNHS. PMID- 23798723 TI - GPs refer men with urological cancers more promptly than women. PMID- 23798724 TI - L28m bill for compromise agreements that left staff feeling "gagged," says UK watchdog. PMID- 23798725 TI - Lack of hemodynamic interaction between CGRP-receptor antagonist telcagepant (MK 0974) and sumatriptan: results from a randomized study in patients with migraine. AB - OBJECTIVE: The objective of this article is to assess the effects of sumatriptan monotherapy, telcagepant monotherapy, and their combination on blood pressure (BP) in migraine patients during a headache-free period. METHODS: A double-blind, placebo-controlled, four-period, single-dose, randomized crossover study in 24 migraine patients was conducted. In each period, patients received a single oral dose of sumatriptan 100 mg alone, telcagepant 600 mg alone, sumatriptan 100 mg coadministered with telcagepant 600 mg, or placebo. Semi-recumbent BP was measured pre-dose and at seven post-dose time points over a period of six hours. Individual time-weighted averages in mean arterial pressure (MAP) were evaluated using a linear mixed-effects model. The pharmacokinetics of sumatriptan alone and in the presence of telcagepant were also evaluated using limited sampling times. RESULTS: The mean difference in time-weighted (0-2.5 h) MAP (90% confidence interval) was 1.2 mmHg (-0.2, 2.7) between telcagepant and placebo, 4.0 mmHg (2.5, 5.5) between sumatriptan and placebo, and 1.5 mmHg (0.0, 3.0) between telcagepant with sumatriptan vs sumatriptan alone. When coadministered with telcagepant, the AUC0-6h and C(max) of sumatriptan were increased by 23% and 24%, respectively. The small MAP increases observed after coadministration could possibly be associated with the slight elevations in sumatriptan levels. CONCLUSION: Telcagepant does not elevate mean MAP, and coadministration of telcagepant with sumatriptan results in elevations in MAP similar to those observed following administration of sumatriptan alone in migraineurs during the interictal period. When coadministered, telcagepant slightly increases the plasma levels of sumatriptan, but without an apparent clinically meaningful effect. PMID- 23798726 TI - John Briggs: a closer look at HIV and coated vesicles. Interview by Caitlin Sedgwick. PMID- 23798727 TI - Imaging cell biology in live animals: ready for prime time. AB - Time-lapse fluorescence microscopy is one of the main tools used to image subcellular structures in living cells. Yet for decades it has been applied primarily to in vitro model systems. Thanks to the most recent advancements in intravital microscopy, this approach has finally been extended to live rodents. This represents a major breakthrough that will provide unprecedented new opportunities to study mammalian cell biology in vivo and has already provided new insight in the fields of neurobiology, immunology, and cancer biology. PMID- 23798728 TI - Replication and trafficking of a plant virus are coupled at the entrances of plasmodesmata. AB - Plant viruses use movement proteins (MPs) to modify intercellular pores called plasmodesmata (PD) to cross the plant cell wall. Many viruses encode a conserved set of three MPs, known as the triple gene block (TGB), typified by Potato virus X (PVX). In this paper, using live-cell imaging of viral RNA (vRNA) and virus encoded proteins, we show that the TGB proteins have distinct functions during movement. TGB2 and TGB3 established endoplasmic reticulum-derived membranous caps at PD orifices. These caps harbored the PVX replicase and nonencapsidated vRNA and represented PD-anchored viral replication sites. TGB1 mediated insertion of the viral coat protein into PD, probably by its interaction with the 5' end of nascent virions, and was recruited to PD by the TGB2/3 complex. We propose a new model of plant virus movement, which we term coreplicational insertion, in which MPs function to compartmentalize replication complexes at PD for localized RNA synthesis and directional trafficking of the virus between cells. PMID- 23798729 TI - Cyclin-dependent kinases regulate splice-specific targeting of dynamin-related protein 1 to microtubules. AB - Fission and fusion reactions determine mitochondrial morphology and function. Dynamin-related protein 1 (Drp1) is a guanosine triphosphate-hydrolyzing mechanoenzyme important for mitochondrial fission and programmed cell death. Drp1 is subject to alternative splicing of three exons with previously unknown functional significance. Here, we report that splice variants including the third but excluding the second alternative exon (x01) localized to and copurified with microtubule bundles as dynamic polymers that resemble fission complexes on mitochondria. A major isoform in immune cells, Drp1-x01 required oligomeric assembly and Arg residues in alternative exon 3 for microtubule targeting. Drp1 x01 stabilized and bundled microtubules and attenuated staurosporine-induced mitochondrial fragmentation and apoptosis. Phosphorylation of a conserved Ser residue adjacent to the microtubule-binding exon released Drp1-x01 from microtubules and promoted mitochondrial fragmentation in a splice form-specific manner. Phosphorylation by Cdk1 contributed to dissociation of Drp1-x01 from mitotic microtubules, whereas Cdk5-mediated phosphorylation modulated Drp1-x01 targeting to interphase microtubules. Thus, alternative splicing generates a latent, cytoskeletal pool of Drp1 that is selectively mobilized by cyclin dependent kinase signaling. PMID- 23798730 TI - Complete integrin headpiece opening in eight steps. AB - Carefully soaking crystals with Arg-Gly-Asp (RGD) peptides, we captured eight distinct RGD-bound conformations of the alphaIIbbeta3 integrin headpiece. Starting from the closed betaI domain conformation, we saw six intermediate betaI conformations and finally the fully open betaI with the hybrid domain swung out in the crystal lattice. The beta1-alpha1 backbone that hydrogen bonds to the Asp side chain of RGD was the first element to move followed by adjacent to metal ion dependent adhesion site Ca(2+), alpha1 helix, alpha1' helix, beta6-alpha7 loop, alpha7 helix, and hybrid domain. We define in atomic detail how conformational change was transmitted over long distances in integrins, 40 A from the ligand binding site to the opposite end of the betaI domain and 80 A to the far end of the hybrid domain. During these movements, RGD slid in its binding groove toward alphaIIb, and its Arg side chain became ordered. RGD concentration requirements in soaking suggested a >200-fold higher affinity after opening. The thermodynamic cycle shows how higher affinity pays the energetic cost of opening. PMID- 23798734 TI - Assisted dying: what happens after Vermont? PMID- 23798735 TI - Hundreds of doctors to be investigated for questionable prescribing practices. PMID- 23798731 TI - Physical limits of cell migration: control by ECM space and nuclear deformation and tuning by proteolysis and traction force. AB - Cell migration through 3D tissue depends on a physicochemical balance between cell deformability and physical tissue constraints. Migration rates are further governed by the capacity to degrade ECM by proteolytic enzymes, particularly matrix metalloproteinases (MMPs), and integrin- and actomyosin-mediated mechanocoupling. Yet, how these parameters cooperate when space is confined remains unclear. Using MMP-degradable collagen lattices or nondegradable substrates of varying porosity, we quantitatively identify the limits of cell migration by physical arrest. MMP-independent migration declined as linear function of pore size and with deformation of the nucleus, with arrest reached at 10% of the nuclear cross section (tumor cells, 7 um2; T cells, 4 um2; neutrophils, 2 um2). Residual migration under space restriction strongly depended upon MMP-dependent ECM cleavage by enlarging matrix pore diameters, and integrin- and actomyosin-dependent force generation, which jointly propelled the nucleus. The limits of interstitial cell migration thus depend upon scaffold porosity and deformation of the nucleus, with pericellular collagenolysis and mechanocoupling as modulators. PMID- 23798736 TI - A third of world's women have been sexually or physically abused by a partner, says WHO. PMID- 23798738 TI - Grant recipients don't need to declare opposition to prostitution, rules Supreme Court. PMID- 23798739 TI - New inquest into infant's death is ordered after coroner's verdict is quashed. PMID- 23798740 TI - Consumer organisation to fight for overhaul of NHS complaints system. PMID- 23798741 TI - Government has turned NHS into "Byzantine system" nobody wanted, Porter says. PMID- 23798742 TI - Gender inequalities in the promptness of diagnosis of bladder and renal cancer after symptomatic presentation: evidence from secondary analysis of an English primary care audit survey. AB - OBJECTIVES: To explore whether women experience greater delays in the diagnosis of bladder and renal cancer when first presenting to a general practitioner with symptoms caused by those cancers and potential reasons for such gender inequalities. DESIGN: Prospective national audit survey of cancer diagnosis. SETTING: English primary care (2009-2010). PARTICIPANTS: 920 patients with bladder and 398 patients with renal cancer (252 (27%) and 165 (42%), respectively, were women). PRIMARY AND SECONDARY OUTCOME MEASURES: Proportion of patients with three or more pre-referral consultations; number of days from first presentation to referral; proportion of patients who presented with haematuria and proportion of patients investigated in primary care. RESULTS: Women required three or more prereferral consultations more often than men (27% (95% CI 21% to 33%) vs 11% (9% to 14%) for bladder (p<0.001); and 30% (22% to 39%) vs 18% (13% to 25%) for renal cancer (p=0.025)) and had a greater number of days from presentation to referral. In multivariable analysis (adjusting for age, haematuria status and use of primary care-led investigations), being a woman was independently associated with higher odds of three or more pre-referral consultations (OR=3.29 (2.06 to 5.25, p<0.001) for bladder cancer; and OR=1.90 (1.06 to 3.42, p=0.031) for renal cancer). Although presentation with haematuria was associated with more timely diagnosis of bladder cancer, gender inequalities did not vary by haematuria status for either cancer (p=0.18 for bladder and p=0.27 for renal). Each year in the UK, approximately 700 women with either bladder or renal cancer experience a delayed diagnosis because of their gender, of whom more than a quarter (197, or 28%) present with haematuria. CONCLUSIONS: There are notable gender inequalities in the timeliness of diagnosis of urological cancers. There is a need to both reinforce existing guidelines on haematuria investigation and develop new diagnostic decision aids and tests for patients who present without haematuria. PMID- 23798743 TI - The last two years. PMID- 23798745 TI - Assessment of changes in left ventricular systolic function with oesophageal Doppler. AB - BACKGROUND: We tested the ability of mean acceleration (Acc) and peak velocity (V peak) of the aortic velocity signal measured by oesophageal Doppler to reflect left ventricular (LV) systolic performance. METHODS: We included critically ill patients in whom a fluid challenge (n=25) or the introduction of dobutamine, 5 ug kg(-1) min(-1) (n=25), was planned by the attending physician. Before and after therapeutic interventions, we measured Acc and V peak (CardioQ device) and LV ejection fraction (LVEF) using echocardiography. RESULTS: For all pairs of measurements, the absolute values of Acc and V peak correlated with LVEF (r=0.36 and 0.57, respectively). The correlation was significantly higher for V peak than for Acc. Volume expansion did not significantly change LVEF and Acc, but significantly increased V peak by 7 (8)%. Dobutamine increased LVEF by 30 (15)%, Acc by 33 (25)%, and V peak by 20 (10)%. Considering the pooled effects of volume expansion and dobutamine, changes in Acc and V peak and those of LVEF were correlated (r=0.53 and 0.67, respectively). When excluding changes <18% (i.e. the least significant change for LVEF), the concordance rate was 96% for Acc and 100% for V peak. CONCLUSIONS: V peak and, to a lesser extent, Acc measured by oesophageal Doppler behaved as markers of LV systolic performance as they were almost insensitive to fluid administration and changed to a much larger extent with dobutamine. These indices could be used to estimate LV systolic performance and to assess the effects of inotropic therapy. PMID- 23798746 TI - Does altering inclination alter effectiveness of treadmill training for gait impairment after stroke? A randomized controlled trial. AB - OBJECTIVE: To assess whether a downhill walking training programme is more effective than the same amount of training applied uphill in chronic stroke survivors. DESIGN: Randomized, single-blind study. SETTING: Outpatient rehabilitation service. METHODS: Thirty-eight adults with hemiplegia from stroke lasting more than three months were randomly allocated to one of the two groups: 'UP' - 45 minutes of physical therapy + 30 minutes of treadmill with 5% ascending slope; and 'DOWN' - 45 minutes of physical therapy + 30 minutes of treadmill with 5% descending slope. Both groups were treated 5 times a week for six weeks. Patients were evaluated before treatment, at the end of treatment and after three months. OUTCOME MEASURES: Primary outcome measure was the number of patients showing an improvement in 6-minute walking test (6MWT) greater than 50 m. Secondary outcome measures were: (1) number of patients showing a clinically relevant improvement of gait speed during 10-m walking test (10mWT); (2) number of patients showing an improvement in timed up and go (TUG) greater than minimal detectable change. RESULTS: Both groups had a significant improvement after treatment and at follow-up. At the end of treatment, compared to UP group, more patients in the DOWN group showed clinically significant improvements in primary and secondary outcomes (16/19 patients for 6MWT, 11/19 patients for 10mWT and 9/19 patients for TUG compared with 3/19, 4/19 and 2/19 patients, respectively, P < 0.01). At follow-up, results were similar except for 10mWT. CONCLUSIONS: In chronic stroke patients, downhill treadmill training produces a bigger effect than uphill training. PMID- 23798747 TI - A systematic review and meta-analysis of the effect of an ankle-foot orthosis on gait biomechanics after stroke. AB - OBJECTIVE: To systematically review the evidence on the effects of an ankle-foot orthosis on gait biomechanics after stroke. DATA SOURCES: The following databases were searched; AMED, CINHAL, Cochrane Library (Stroke section), Medline, PubMed, Science Direct and Scopus. Previous reviews, reference lists and citation tracking of the selected articles were screened and the authors of selected trials contacted for any further unpublished data. REVIEW METHODS: Controlled trials of an ankle-foot orthosis on gait biomechanics in stroke survivors were identified. A modified PEDro score evaluated trial quality; those scoring 4/8 or more were selected. Information on the trial design, population, intervention, outcomes, and mean and standard deviation values for the treatment and control groups were extracted. Continuous outcomes were pooled according to their mean difference and 95% confidence intervals in a fixed-effect model. RESULTS: Twenty trials involving 314 participants were selected. An ankle-foot orthosis had a positive effect on ankle kinematics (P < 0.00001-0.0002); knee kinematics in stance phase (P < 0.0001-0.01); kinetics (P = 0.0001) and energy cost (P = 0.004), but not on knee kinematics in swing phase (P = 0.84), hip kinematics (P < 0.18-0.89) or energy expenditure (P = 0.43). There were insufficient data for pooled analysis of individual joint moments, muscle activity or spasticity. All trials, except one, evaluated immediate effects only. CONCLUSIONS: An ankle-foot orthosis can improve the ankle and knee kinematics, kinetics and energy cost of walking in stroke survivors. PMID- 23798748 TI - Factors influencing participation in cardiac rehabilitation programmes after referral and initial attendance: qualitative systematic review and meta synthesis. AB - BACKGROUND: Greater participation in cardiac rehabilitation improves morbidity and mortality in people with coronary heart disease, but little is understood of patients' decisions to participate. METHODS: To develop interventions aimed at increasing completion of programmes, we conducted a qualitative systematic review and meta-synthesis to explore the complex factors and processes influencing participation in cardiac rehabilitation programmes after referral and initial access. To be included in the review, studies had to contain a qualitative research component, population specific data on programme participation in adults >18 years, and be published >=1995 as full articles or theses. Ten databases were searched (31 October 2011) using 100+ search terms. RESULTS: Of 2264 citations identified, 62 studies were included involving: 1646 patients (57% female; mean age 64.2), 143 caregivers, and 79 professionals. Patients' participation was most strongly influenced by perceptions of the nature, suitability and scheduling of programmes, social comparisons made possible by programmes, and the degree to which programmes, providers, and programme users met expectations. Women's experiences of these factors rendered them less likely to complete. Comparatively, perceptions of programme benefits had little influence on participation. CONCLUSIONS: Factors reducing participation in programmes are varied but amenable to intervention. Participation should be viewed as a 'consumer behaviour' and interventions should mobilize family support, promote 'patient friendly' scheduling, and actively harness the social, identity-related, and experiential aspects of participation. PMID- 23798749 TI - Introductory paragraph - volume 27, Issue 7. PMID- 23798751 TI - Percutaneous kyphoplasty combined with the posterior screw-rod system in treatment of osteoporotic thoracolumbar fractures. AB - BACKGROUND: The osteoporotic vertebral compression fractures (OVCF) have attracted more and more attention due to increase in life span globally and aging population. Percutaneous vertebroplasty (PVP) and percutaneous kyphoplasty (PKP) have been popularized rapidly by virtue of their unique advantage in minimal invasiveness. We analysed our results in osteoporotic thoracolumbar fractures using percutaneous kyphoplasty and posterior screw rod system. To investigate the possibility of treatment of rupture of the posterior vertebral osteoporotic fractures by means of kyphoplasty combined with the posterior screw-rod system. MATERIALS AND METHODS: Twenty six patients (65 years of age or older) with the single spine fractures included in study. The preoperative bone mineral density was measured by dual-energy X-ray. The PKP was done in all the cases. Decompression was done if neurological symptoms were present. RESULTS: The results demonstrated osteoporosis with BMD T value <= -2.5; injured posterior vertebral body (3 cases) had shown the whole damage accompanied by neurological symptoms through X-ray or CT. After 2 days, the remaining patients of back pain symptoms were relieved or disappeared except for three cases of patients with decompression incision. VAS score and Cobb angle changed from preoperative 8.23 +/- 0.17 and 28.7 +/- 0.33 degrees respectively to postoperative 3.77 +/- 0.44 and 3.8 +/- 0.2 degrees respectively. CONCLUSION: Treatment of rupture of the posterior vertebral osteoporotic thoracolumbar fractures by means of kyphoplasty combined with posterior screw-rod system is a safe, effective procedure. PMID- 23798750 TI - Current concepts and controversies on adolescent idiopathic scoliosis: Part II. AB - A new era in the surgical treatment of adolescent idiopathic scoliosis (AIS) opened with the introduction of pedicle screw instrumentation, which provides 3 column vertebral fixation and allows major deformity correction on the coronal, sagittal, and axial planes. A steep learning curve can be expected for spinal surgeons to become familiar with pedicle screw placement and correction techniques. Potential complications including injury to adjacent neural, vascular, and visceral structures can occur due to screw misplacement or pull-out during correction maneuvers. These major complications are better recognized as pedicle screw techniques become more popular and may result in serious morbidity and mortality. Extensive laboratory and clinical training is mandatory before pedicle screw techniques in scoliosis surgery are put to practice. Wider application, especially in developing countries, is limited by the high cost of implants. Refined correction techniques are currently developed and these utilize a lesser number of pedicle anchors which are strategically positioned to allow optimum deformity correction while reducing the neurological risk, surgical time, and blood loss, as well as instrumentation cost. Such techniques can be particularly attractive at a time when cost has major implications on provision of health care as they can make scoliosis treatment available to a wider population of patients. Pedicle screw techniques are currently considered the gold standard for scoliosis correction due to their documented superior biomechanical properties and ability to produce improved clinical outcomes as reflected by health-related quality-of-life questionnaires. Ongoing research promises further advances with the future of AIS treatment incorporating genetic counseling and possibly fusionless techniques. PMID- 23798752 TI - Percutaneous vertebroplasty in symptomatic hemangioma versus osteoporotic compression fracture. AB - BACKGROUND: Percutaneous vertebroplasty (PVP) is more commonly used for osteoporotic compression fractures (OCFs) and osteolytic vertebral body tumors. This study aimed to study the differences between OCFs and vertebral hemangiomas (VHs) treated with PVP. MATERIALS AND METHODS: Between September 2007 and January 2010, we prospectively treated 28 consecutive patients of OCFs (43 recently symptomatic OCFs) and 24 cases of VHs (26 VHs). We used visual analogue scale (VAS) pain and Oswestry Disability Index (ODI) to evaluate the patients. The followup period in group 1 and 2 were 25.1 months (range 12 - 31 months) and 21.3 months (range 14 - 28 months), respectively. Comparison of means was carried out with the Chi Square Tests, t-test, and N Par-Test for multiple comparisons, whenever appropriate. The level of statistical significance was set at P < 0.05. RESULTS: Following PVP the VAS score decreased to 4.57 and 4.17 in group 1 and 2, respectively. The ODI scores were 32.5% and 30%, respectively. This decrease in ODI scores lasted throughout the followup period. CONCLUSIONS: Although the preoperative scores were significantly different between group 1 and 2, there was no significant difference between two groups following the PVP. PMID- 23798753 TI - Pullout strength of misplaced pedicle screws in the thoracic and lumbar vertebrae - A cadaveric study. AB - BACKGROUND: The objective of this cadaveric study was to analyze the effects of iatrogenic pedicle perforations from screw misplacement on the mean pullout strength of lower thoracic and lumbar pedicle screws. We also investigated the effect of bone mineral density (BMD), diameter of pedicle screws, and the region of spine on the pullout strength of pedicle screws. MATERIALS AND METHODS: Sixty fresh human cadaveric vertebrae (D10-L2) were harvested. Dual-energy X-ray absorptiometry (DEXA) scan of vertebrae was done for BMD. Titanium pedicle screws of different diameters (5.2 and 6.2 mm) were inserted in the thoracic and lumbar segments after dividing the specimens into three groups: a) standard pedicle screw (no cortical perforation); b) screw with medial cortical perforation; and c) screw with lateral cortical perforation. Finally, pullout load of pedicle screws was recorded using INSTRON Universal Testing Machine. RESULTS: Compared with standard placement, medially misplaced screws had 9.4% greater mean pullout strength and laterally misplaced screws had 47.3% lesser mean pullout strength. The pullout strength of the 6.2 mm pedicle screws was 33% greater than that of the 5.2 mm pedicle screws. The pullout load of pedicle screws in lumbar vertebra was 13.9% greater than that in the thoracic vertebra (P = 0.105), but it was not statistically significant. There was no significant difference between pullout loads of vertebra with different BMD (P = 0.901). CONCLUSION: The mean pullout strength was less with lateral misplaced pedicle screws while medial misplaced pedicle screw had more pullout strength. The pullout load of 6.2 mm screws was greater than that of 5.2 mm pedicle screws. No significant correlation was found between bone mineral densities and the pullout strength of vertebra. Similarly, the pullout load of screw placed in thoracic and lumbar vertebrae was not significantly different. PMID- 23798754 TI - Massive lumbar disc herniation with complete dural sac stenosis. AB - BACKGROUND: Large lumbar disc herniation (LDH) has been reported to have a greater tendency to resolve in clinical and pathomorphological evolutions. However, various definitions of large LDH have been used without validation, and the clinical symptoms of large LDH have not been fully elucidated. We conducted a retrospective analysis to determine the clinical characteristics and treatment outcome of massive LDH with complete dural sac stenosis. MATERIALS AND METHODS: We retrospectively reviewed 33 cases of LDH with complete dural sac stenosis on magnetic resonance imaging. Complete dural sac stenosis was defined as no recognizable rootlet and cerebrospinal fluid signal on T2-weighed axial MR images. The clinical outcome parameters included back pain, leg pain, Oswestry disability index (ODI), and neurological dysfunction. The paired t-test and Wilcoxon's signed rank test were used to compare serial changes in back pain, leg pain and neurological dysfunction. RESULTS: Mean duration of followup was 66 months (range 24 - 108 months). There were 24 male and 9 female. The mean age was 37 years (range 20 - 53 years). At presentation, mean visual analogue scales for back pain and leg pain were 75.3 +/- 19.1 (range 12 - 100) and 80.2 +/- 14.6 (range 0 -100), respectively. Mean ODI was 67.1 +/- 18.8 (range 26 - 88). Neurological dysfunction was found in 9 patients (27.3%), and the bowel/bladder dysfunction was found in 2 patients (3.1%). Conservative treatment was performed in 21 patients (63.6%) with satisfactory results. Seven patients underwent decompressive surgery, and 5 underwent posterolateral fusion. CONCLUSIONS: A massive LDH with complete dural sac stenosis was found to be associated with severe back and leg pain at presentation, however surgical treatment can be deferred unless significant neurological symptoms occur. PMID- 23798755 TI - CT based evaluation of odontoid morphology in the Indian population. AB - BACKGROUND: Anterior fixation using two 3.5 mm screws is typically recommended for type II odontoid fractures. However, it is unsuitable in patients with an odontoid diameter of <9.0 mm. There is no data regarding the morphology of odontoid process in the Indian population. The aim of our study was to: a) Measure the external diameters of odontoid process in the Indian population using CT scan and thus determine the feasibility of two 3.5 mm screw fixation in them. b) Determine if any correlation exists between body height (Ht) and weight (Wt) and external odontoid diameters. MATERIALS AND METHODS: CT images of odontoid process of 100 consecutive patients were analyzed. Antero- posterior (AP) and transverse (TD), outer diameters of the odontoid process were measured from the base and at 1 mm interval upwards on axial CT images. RESULTS: The mean AP and mean TD were 11.52 mm and 9.85 mm, respectively. Fifty-five (55%) of the patients had at least one TD <9.0 mm. Five (5%) patients had at least one TD <7.4 mm. None of the patients had any diameter <5.5 mm. Body Ht correlated significantly with mean AP and mean TD of the odontoid process (AP: r = 0.276, P = 0.013; TD: r = 0.359, P = 0.001), whereas body Wt correlated significantly only with mean TD (AP: r = 0.162, P = 0.15; TD: r = 0.297, P = 0.007). CONCLUSION: More than half of the study population (55%) was unsuitable for two 3.5 mm screw fixation for type II odontoid fracture. Two 2.7 mm screws can be safely used in 95% of the population. A 4.5 mm Herbert screw can be safely used in the entire population. We recommend two 2.7 mm screws or a 4.5 mm Herbert screw for fixation of these fractures in the Indian population. Body height showed a significant correlation with external odontoid diameters, whereas weight showed significant correlation only with TD of the odontoid process. PMID- 23798756 TI - Comparison of the early results of transforaminal lumbar interbody fusion and posterior lumbar interbody fusion in symptomatic lumbar instability. AB - BACKGROUND: Transforaminal lumbar interbody fusion (TLIF) has been preferred to posterior lumbar interbody fusion (PLIF) for different spinal disorders but there had been no study comparing their outcome in lumbar instability. A comparative retrospective analysis of the early results of TLIF and PLIF in symptomatic lumbar instability was conducted between 2005 and 2011. MATERIALS AND METHODS: Review of the records of 102 operated cases of lumbar instability with minimum 1 year followup was done. A total of 52 cases (11 men and 41 women, mean age 46 years SD 05.88, range 40-59 years) underwent PLIF and 50 cases (14 men and 36 women, mean age 49 years SD 06.88, range 40-59 years) underwent TLIF. The surgical time, duration of hospital stay, intraoperative blood loss were compared. Self-evaluated low back pain and leg pain status (using Visual Analog Score), disability outcome (using Oswestry disability questionnaire) was analyzed. Radiological structural restoration (e.g., disc height, foraminal height, lordotic angle, and slip reduction), stability (using Posner criteria), fusion (using Hackenberg criteria), and overall functional outcome (using MacNab's criteria) were compared. RESULTS: Pain, disability, neurology, and overall functional status were significantly improved in both groups but PLIF required more operative time and caused more blood loss. Postoperative hospital stay, structural restoration, stability, and fusion had no significant difference but neural complications were relatively more with PLIF. CONCLUSIONS: Both methods were effective in relieving symptoms, achieving structural restoration, stability, and fusion, but TLIF had been associated with shorter operative time, less blood loss, and lesser complication rates for which it can be preferred for symptomatic lumbar instability. PMID- 23798757 TI - Slipped upper femoral epiphysis: Outcome after in situ fixation and capital realignment technique. AB - BACKGROUND: Slipped upper femoral epiphysis (SUFE) is the gradually acquired malalignment of the upper femoral epiphysis (capital) and the proximal femoral metaphysis. SUFE is uncommon in India, and there are no previous studies on outcome and clinical characteristics of patients with SUFE from India. This study evaluates the presentation, disease associations and outcome of SUFE from a tertiary care centre in India. MATERIALS AND METHODS: Twenty six consecutive children with SUFE seen over a period of 4 years were reviewed. The clinical presentations, severity of the slip, surgical interventions (n=30) were assessed. Twenty one boys and five girls with a mean age 13.1 years (range 10-16 years) were included in the study. Four children had bilateral involvement. There were 4 rural and 22 urban children from the eastern and southern states of the country. The presentation was acute in 7, acute on chronic in 5, and chronic in 14, with a mean duration of symptoms of 51 days (range 3-120 days). Slips were stable in 16 and unstable in 10 children. Two children had adiposogenital syndrome. Body mass index was high in 12 out of 23 children. Vitamin D levels were low in 20 out of 21 children, with a mean vitamin D level of 12.61 +/- 5 ng/ml. Eighteen children underwent in situ pinning. Eight children underwent capital realignment. RESULTS: Clinical outcome as assessed by Merle d' Aubigne score was excellent in 6, good in 10, fair in 6 and poor in 1. Half of the in situ fixation patients underwent osteoplasty procedure for femoroacetabular impingement and 5 more were symptomatic. The head neck offset and alpha angle after in situ pinning were 1.12 +/- 3 mm and 66.05 +/- 9.7 degrees , respectively and this improved to 8.7 mm and 49 degrees , respectively, after osteoplasty. One child in the pinning group had chondrolysis. Eight patients with severe slip underwent capital realignment. Mean followup was 20.15 months. The anterior head neck offset and alpha angle were corrected to 6.8 +/- 1.72 mm and 44.6 +/- 7.0 degrees mm, respectively. Two children with unstable slip in the capital realignment group had avascular necrosis which was diagnosed at presentation by bone scan. CONCLUSION: High BMI, vitamin D deficiency and endocrine disorders are associated with SUFE in India and should be evaluated as some of these are amenable to prevention and treatment. Most patients treated with in situ pinning developed femoroacetabular impingement. The early results after capital realignment procedure are encouraging and help to avoid a second procedure which is needed in a majority of patients who underwent in situ pinning. PMID- 23798758 TI - Long proximal femoral nail in ipsilateral fractures proximal femur and shaft of femur. AB - BACKGROUND: Ipsilateral fractures of the proximal femur and femoral shaft are extremely uncommon injuries which occur in young adults who sustain a high energy trauma. A variety of management modalities have been tried to treat this complex fracture pattern ranging from conservative approach to recently introduced reconstruction nails. All these approaches have their own difficulties. We studied the outcome of long proximal femoral nail (LPFN) in the management of concomitant ipsilateral fracture of the proximal femur and femoral shaft. MATERIALS AND METHODS: We analysed the prospective data of 36 consecutive patients who had sustained a high energy trauma (30 closed fractures and 6 open shaft fractures) who had concomitant ipsilateral fractures of the femoral shaft associated with proximal femur fractures treated with LPFN between December 2005 and December 2011. The mean age was 39 years (range 28-64 years). Twenty nine males and seven females were enrolled for this study. RESULTS: The patients were followed up at three, six, twelve, and eighteen months. The mean healing time for the neck fractures was 4.8 months and for the shaft fractures was 6.2 months. The greater trochanter was splintered and widened in two cases which eventually consolidated. Two patients had superficial infection, two patients had lateral migration of the screws with coxa vara which was due to severe osteoporosis detected during the followup. We had two cases of nonunion of shaft fracture and one case of nonunion of neck fracture. Two cases of avascular necrosis of femoral head were detected after 2 years of followup. No cases of implant failure were noted. Limb shortening of less than 2 cms was noted in four of our patients. The functional assessment system of Friedman and Wyman was used for evaluating the results. In our series 59.9% (n = 23) were rated as good, 30.6% (n = 11) as fair, and 5.5% (n = 2) as poor. CONCLUSION: Long PFN is a reliable option for concomitant ipsilateral diaphyseal and proximal femur fractures. PMID- 23798759 TI - Approach for measuring the angle of hallux valgus. AB - BACKGROUND: There is medium correlation between the current anthropometric method and the radiography in the angle of hallux valgus (AoH) measurement, so this study aimed at designing a reliable and more accurate approach to measure the AoH (AoH). MATERIALS AND METHODS: Fifteen age, body weight, and height matched male students were included and those with foot disorders, deformities, or injuries were excluded from the study. The dorsal protrusions of the first metatarsal and the hallux were marked by palpating from three experienced observers; then their barefoot model in standing was collected by a three dimensional laser scanning system. The AoH was defined in the X-Y plane by the angle between the line joining the marks of centre of head and centre of base of metatarsal shaft and the one connecting the marks of the centre of metatarsal head and the hallux. The same procedure was repeated a week later. Besides, other measures based on the footprint, outline, and the radiography were also available for comparisons. Paired t-test, linear regression, and reliability analysis were applied for statistical analysis with significant level of 0.05 and 95% confidence interval. RESULTS: There were no significant differences recorded between the new method and the radiographic method (P = 0.069). The AoH was superior to the methods of footprint and outline and it displayed a relative higher correlation with the radiographic method (r = 0.94, r (2) = 0.89). Moreover both the inter and intraobserver reliabilities of this method were proved to be good. CONCLUSION: This new method can be used for hallux valgus inspection and evaluation. PMID- 23798760 TI - Elbow dislocation with irreparable fracture radial head. AB - BACKGROUND: Treatment of elbow dislocation with irreparable radial head fracture needs replacement of radial head to achieve stability of elbow. An alternate method in cases of elbow dislocation with radial head fracture can be resection of radial head with repair of medial collateral ligament. We report a retrospective analysis of cases of elbow dislocation with irreparable radial head treated by excision head of radius and repair of MCL. MATERIALS AND METHODS: Nine patients of elbow dislocation with associated irreparable fractures of the head of the radius were included in this analysis (6 F:3 M, Age: 35-47 years). Radial head excision was done through the lateral approach and MCL was sutured using no 3 Ethibond using medial approach. Above elbow plaster was given for 6 weeks and gradual mobilization was done thereafter. All patients were assessed at final followup using Mayo elbow performance score (MEPS). RESULTS: Mean followup was 19.55 +/- 7.12 months (range 14-36 months). There was no extension deficit when compared to opposite side with mean range of flexion of 138.8 degrees +/- 6.97 degrees (range 130 -145 degrees ). Mean pronation was 87.7 degrees +/- 4.4 degrees (range 80-90 degrees ) and mean supination was 87.7 +/- 4.62 degrees (range 80-90 degrees ). The mean MEPS was 98.8 +/- 3.33 (range 90-100). No patient had pain, sensory complaints, subluxation or redislocation. All were able to carry out their daily activities without disability. CONCLUSION: Radial head excision with MCL repair is an acceptable option for treatment of patients with elbow dislocation and irreparable radial head fracture. PMID- 23798761 TI - Functional outcome of arthroscopic assisted fixation of distal radius fractures. AB - BACKGROUND: Many studies in literature have supported the role of wrist arthroscopy as an adjunct to the stable fixation of unstable intraarticular distal radial fractures. This article focuses on the surgical technique, indications, advantages, and results using wrist arthroscopy to assess articular reduction and evaluates the treatment of carpal ligament injuries and triangular fibrocartilage complex (TFCC) injuries in conjunction with the stable fixation of distal radial fractures. MATERIALS AND METHODS: We retrospectively evaluated 27 patients (16 males and 11 females), who underwent stable fixation of intraarticular distal radial fractures with arthroscopic evaluation of the articular reduction and repair of associated carpal injuries. As per the AO classification, they were 9 C 1, 12 C2, 2 C3, 3 B 1, and 1 B2 fractures. The final results were evaluated by modified Mayo wrist scoring system. The average age was 41 years (range: 18-68 years). The average followup was of 26 months (range 24-52 months). RESULTS: Five patients needed modification of the reduction and fixation after arthroscopic joint evaluation. Associated ligament lesions found during the wrist arthroscopy were TFCC tears (n=17), scapholunate ligament injury (n=8), and luno-triquetral ligament injury (n=1). Five patients had combined injuries i.e. included TFCC tear, scapholunate and/or lunotriquetral ligament tear. There were 20 excellent, 3 good, and 4 fair results using this score. CONCLUSION: The radiocarpal and mid carpal arthroscopy is a useful adjunct to stable fixation of distal radial fractures. PMID- 23798762 TI - Curettage of benign bone tumors and tumor like lesions: A retrospective analysis. AB - BACKGROUND: Curettage is one of the most common treatment options for benign lytic bone tumors and tumor like lesions. The resultant defect is usually filled. We report our outcome curettage of benign bone tumors and tumor like lesions without filling the cavity. MATERIALS AND METHODS: We retrospectively studied 42 patients (28 males and 14 females) with benign bone tumors who had undergone curettage without grafting or filling of the defect by any other bone graft substitute. The age of the patients ranged from 14 to 66 years. The most common histological diagnosis was that of giant cell tumor followed by simple bone cyst, aneurysamal bone cyst, enchondroma, fibrous dysplasia, chondromyxoid fibroma, and chondroblastoma and giant cell reparative granuloma. Of the 15 giant cell tumors, 4 were radiographic grade 1 lesions, 8 were grade 2 and 3 grade 3. The mean maximum diameter of the cysts was 5.1 (range 1.1-9 cm) cm and the mean volume of the lesions was 34.89 cm(3) (range 0.94-194.52 cm(3)). The plain radiographs of the part before and after curettage were reviewed to establish the size of the initial defect and the rate of reconstitution, filling and remodeling of the bone defect. Patients were reviewed every 3 monthly for a minimum period of 2 years. RESULTS: Most of the bone defects completely reconstituted to a normal appearance while the rest filled partially. Two patients had preoperative and three had postoperative fractures. All the fractures healed uneventfully. Local recurrence occurred in three patients with giant cell tumor who were then reoperated. All other patients had unrestricted activities of daily living after surgery. The rate of bone reconstitution, risk of subsequent fracture or the incidence of complications was related to the size of the cyst/tumor at diagnosis. The benign cystic bone lesions with volume greater than approximately 70 cm(3) were found to have higher incidence of complications. CONCLUSION: This study demonstrates the natural healing ability of bone without filling with bone grafts or bone graft substitutes. In selected sizes and locations of the benign lytic tumors and tumor like lesions extended curettage alone can be sufficient. PMID- 23798763 TI - Conjoint bicondylar Hoffa fracture in an adult. AB - Conjoint bicondylar Hoffa fracture is an extremely rare injury. Only one case has been reported previously in the pediatric age group. We describe this injury in a 17-year-old male who presented following a fall with direct impact on his semiflexed right knee. Plain radiographs were inadequate to define the exact pattern of injury. Computed tomographic (CT) scans demonstrated the coronal fracture involving both the femoral condyles which were joined by a bridge of intact bone. The patient was treated with open reduction and internal fixation using swashbuckler (modified anterior) approach. Union occurred within 3 months and at final followup (at 18 months) the patient had a good clinical outcome. The possible mechanism of injury is discussed. PMID- 23798764 TI - Open segmental fracture of both bone forearm and dislocation of ipsilateral elbow with extruded middle segment radius. AB - Extruded middle segment of radius with open segmental fracture both bone forearm and dislocation of ipsilateral elbow is a rare injury. A 12-year-old child presented to us within 4 hours following fall from tree. The child's mother was carrying a 12-cm-long extruded soiled segment of radius. The extruded bone was thoroughly washed. The medullary cavity was properly syringed with antiseptic solution. The bone was autoclaved and put in the muscle plane of the distal forearm after debridement of the wound. After 5 days, a 2.5-mm K-wire was introduced by retrograde method into the proximal radius by passing through the extruded segment. Another 2.5-mm K-wire was passed in ulna. The limb was evaluated clinicoradiologically every 2 weeks. The wound was healed by primary intention. At 4 months, the reposed bone appeared less dense radiologically and K wire seemed to be out of the bone. In the subsequent months, the roentgenograms show remodeling of the extruded fragment. After 20 weeks, the K-wires were removed (first ulnar and then radial). Complete union was achieved with full range of movement except loss of few degrees of extension of elbow and thumb. This case is reported to show a good outcome following successful incorporation of an extruded segment of radius in an open fracture. PMID- 23798765 TI - Old nutcracker fracture of cuboid. AB - Nutcracker fractures of the cuboid (compressed) are rare and often missed at an initial visit. We report a 21-year-old patient presented with a 9 months old cuboid fracture. He presented with a localized pain around his left foot. Radiograph revealed the shortening of the lateral column with old cuboid fracture. The lateral column of foot was reconstructed. The patient remained symptom-free and no radiographic evidence of recurrence was observed 1 year postsurgery. PMID- 23798766 TI - Localized nodular synovitis of the infrapatellar fat pad. AB - We report a case of localized nodular synovitis of the infrapatellar fat pad impinging on the patellofemoral joint causing limitation of extension. Arthroscopy involved use of a superolateral portal because location of lesion hindered access via a conventional anterior portal. The infrapatellar mass impinged in the patellofemoral joint upon knee extension and retracted upon flexion. Superior-superior triangulation allowed for complete excision of the mass. PMID- 23798767 TI - Soft tissue coverage in open fractures of tibia. PMID- 23798768 TI - Author's reply. PMID- 23798769 TI - Author's reply in response to letter to editor Indian J Orthop 2012;46:602 titled "Utility of combined abduction angle for hip surveillance in children with cerebral palsy". PMID- 23798770 TI - Author's reply in response to letter to editor Indian J Orthop 2012;46:728-9 titled "Tumor like swellings arising from Hoffa's fat pad: A series of three patients". PMID- 23798771 TI - Enhanced piezoelectric performance of composite sol-gel thick films evaluated using piezoresponse force microscopy. AB - Conventional composite sol-gel method has been modified to enhance the piezoelectric performance of ceramic thick films. Lead zirconate titanate (PZT) and lead magnesium niobate-lead titanate (PMN-PT) thick films were fabricated using the modified sol-gel method for ultrasonic transducer applications. In this work, piezoresponse force microscopy was employed to evaluate the piezoelectric characteristics of PZT and PMN-PT composite sol-gel thick films. The images of the piezoelectric response and the strain-electric field hysteresis loop behavior were measured. The effective piezoelectric coefficient (d33,eff) of the films was determined from the measured loop data. It was found that the effective local piezoelectric coefficient of both PZT and PMN-PT composite films is comparable to that of their bulk ceramics. The promising results suggest that the modified composite sol-gel method is a promising way to prepare the high-quality, crack free ceramic thick films. PMID- 23798772 TI - Perceived Stress, Anhedonia and Illusion of Control: Evidence for Two Mediational Models. AB - Illusion of control (IOC) refers to the perception that one has control over an outcome, that is, in actuality, uncontrollable; low IOC has been linked to depression. Prior studies in depression have mostly assessed IOC using paradigms involving positive outcomes, suggesting that IOC might be influenced by anhedonia. Recent evidence indicates that anhedonia, in turn, is linked to stress. To clarify such links, we examined putative relationships among perceived stress, anhedonia, and IOC (as assessed by a non-contingency task) in 63 participants. Perceived stress and anhedonia, but not general depressive symptoms, were associated with reduced IOC. Moreover, anhedonia fully mediated the relationship between stress perception and IOC, and perceived stress partially mediated the relationship between IOC and anhedonia. Findings suggest that (1) IOC is integrally related to hedonic capacity, (2) reward processing deficits may promote reduced IOC, and/or (3) a low IOC may promote depression via anhedonia-related mechanisms. PMID- 23798773 TI - Nitric oxide modulators: an emerging class of medicinal agents. AB - Nitric oxide, a unique messenger in biological system, is ubiquitously present virtually in all tissues revealing its versatile nature of being involved in diverse physiological functions such as vascular tone, inhibition of platelet aggregation, cell adhesion, neurotransmission and enzyme and immune regulation. The tremendous advancements made in the past few decades in this area suggests that the nitric oxide modulation either by its exogenous release through nitric oxide donors or inhibition of its synthesis by nitric oxide synthase inhibitors in physiological milieu may provide newer clinical strategies for the treatment of some diseases. In this review, an attempt is made to document and understand the biological chemistry of different classes of nitric oxide modulators that would prove to be a fruitful area in the years to come. PMID- 23798774 TI - Characterization and Antimicrobial Activity of N-Methyl-2-pyrrolidone-loaded Ethylene Oxide-Propylene Oxide Block Copolymer Thermosensitive Gel. AB - The purpose of this study is to investigate the effects of N-methyl-2-pyrrolidone on the thermosensitive properties of aqueous ethylene oxide-propylene oxide block copolymer (Lutrol((r)) F127) system. Due to the aqueous solubility enhancement and biocompatibility, N-methyl-2-pyrrolidone is an interesting solubilizer for the poorly water soluble drugs to be incorporated in the Lutrol((r)) F127 system. Effect of N-methyl-2-pyrrolidone on physicochemical properties of Lutrol((r)) F127 system was investigated using appearance, pH, gelation, gel melting temperature and rheology. The antimicrobial activity of the thermosensitive N methyl-2-pyrrolidone gel was also tested. Lower N-methyl-2-pyrrolidone amount (<=30%w/w) could shift the sol-gel transition to a lower temperature but the gel sol transition was shifted to a higher temperature. Higher N-methyl-2-pyrrolidone (>=40%w/w) could shift both sol-gel and gel-sol transitions of the system to a lower temperature. The amount of N-methyl-2-pyrrolidone >60% w/w could reverse the phase of the Lutrol((r)) F127 system to non-newtonian flow at 4 degrees and Newtonian flow at high temperature. Aqueous Lutrol((r)) F127 system containing N methyl-2-pyrrolidone exhibited antimicrobial activities against Staphylococcus aureus, Escherichia coli and Candida albicans with the N-methyl-2-pyrrolidone in a dose-dependent manner. PMID- 23798775 TI - Solubility Enhancement of a Poorly Water Soluble Drug by Forming Solid Dispersions using Mechanochemical Activation. AB - Mechanochemical activation is a practical cogrinding operation used to obtain a solid dispersion of a poorly water soluble drug through changes in the solid state molecular aggregation of drug-carrier mixtures and the formation of noncovalent interactions (hydrogen bonds) between two crystalline solids such as a soluble carrier, lactose, and a poorly soluble drug, indomethacin, in order to improve its solubility and dissolution rate. Samples of indomethacin and a physical mixture with a weight ratio of 1:1 of indomethacin and lactose were ground using a high speed vibrating ball mill. Particle size was determined by electron microscopy, the reduction of crystallinity was determined by calorimetry and transmission electron microscopy, infrared spectroscopy was used to find evidence of any interactions between the drug and the carrier and the determination of apparent solubility allowed for the corroboration of changes in solubility. Before grinding, scanning electron microscopy showed the drug and lactose to have an average particle size of around 50 and 30 MUm, respectively. After high speed grinding, indomethacin and the mixture had a reduced average particle size of around 5 and 2 MUm, respectively, showing a morphological change. The ground mixture produced a solid dispersion that had a loss of crystallinity that reached 81% after 30 min of grinding while the drug solubility of indomethacin within the solid dispersion increased by 2.76 fold as compared to the pure drug. Drug activation due to hydrogen bonds between the carboxylic group of the drug and the hydroxyl group of lactose as well as the decrease in crystallinity of the solid dispersion and the reduction of the particle size led to a better water solubility of indomethacin. PMID- 23798776 TI - Effect of various polymers concentrations on physicochemical properties of floating microspheres. AB - Floating microspheres have emerged as a potential candidate for gastroretentive drug delivery system. For developing a desired intragastric floatation system employing these microspheres, it is necessary to select an appropriate balance between buoyancy and drug releasing rate. These properties mainly depend on the polymers used in the formulation of the microspheres. Hence it is necessory to study the effect of these polymer concentrations on the various physicochemical properties of the microspheres. Floating microspheres were prepared by emulsion solvent evaporation technique utilising different polymers such as ethyl cellulose, Eudragit((r)) RS and Eudragit((r)) RL by dissolving them in a mixture of dichloromethane and methanol. Release modifiers studied were hydroxypropyl methylcellulose K4M, hydroxypropyl methylcellulose E50 LV and Eudragit((r)) EPO. Prepared microspheres were analysed for particle size, surface morphology, entrapment efficiency, buoyancy, differential scanning calorimetry and in-vitro drug release. Ethyl cellulose and Eudragit((r)) EPO resulted microspheres with high percentage yield, excellent spherical shape but had very less buoyancies with a high cumulative drug release. Ethyl cellulose microspheres prepared using hydroxypropyl methylcellulose K4M showed more sustained drug release and high buoyancies than that of the microspheres formulated with the hydroxypropyl methylcellulose E50 LV. Amongst these hydroxypropyl methylcellulose E50 LV showed good balance between buoyancy and the drug release. PMID- 23798777 TI - Development of Chitosan-based Dry Powder Inhalation System of Cisplatin for Lung Cancer. AB - Cisplatin, a platinum compound, exerts its cytotoxic effects by coordinating to DNA where it inhibits both replication and transcription, and induces programmed cell death. It is used in the treatment of non-small cell lung cancer. In the present study, an attempt was made to achieve better treatment of lung cancer by direct lung delivery of cisplatin microparticulate systems, which helps to localize the drug in the lungs, and also provide sustained action. Cisplatin loaded chitosan microspheres were prepared by emulsification and ionotropic gelation method, and characterized for drug content, particle size, densities, flow properties, moisture content, and surface topography by SEM and in vitro drug release was evaluated in simulated lung fluid at 37 degrees at pH 7.4. The respirable or fine particle fraction (FPF) was determined by using twin stage impinger (TSI). Further stability evaluation of cisplatin-loaded DPI systems was carried out at 25 degrees /60% RH and at 40 degrees /75% RH. PMID- 23798778 TI - Effects of highly hygroscopic excipients on the hydrolysis of simvastatin in tablet at high relative humidity. AB - Effects of highly hygroscopic sorbitol, citric acid, sodium carboxymethyl cellulose or polyvinylpolypyrrolidone, on the hydrolysis of simvastatin in tablets at 25 degrees /90% RH were studied. The simvastatin tablets were prepared by direct powder compression. Simvastatin and its hydrolyte, simvastatin acid, were quantitatively analysed by high performance liquid chromotography. The hygroscopicity, water swelling ratio, water solubility and pH of the four hygroscopic excipients were investigated. During the investigation period, the weight gain of sorbitol or citric acid increased faster than that of polyvinylpolypyrrolidone or sodium carboxymethyl cellulose at 25 degrees /90% RH, accordingly, the moisture sorption of the tablets containing citric acid or sorbitol (T-3 or T-6) were more than that of the tablets containing sodium carboxymethyl cellulose or polyvinylpolypyrrolidone (T-4 or T-5). The increase of simvastatin acid content with time at 25 degrees /90% RH for the tablets was in the following order: T-6 < T-4 < T-3 < T-5. The effects of the four excipients on the hydrolysis of simvastatin in tablet were related to not only their hygroscopicity but also their other properties, such as moisture retention capacity and pH. Sorbitol as hygroscopic excipient in tablet can most effectively prevent the hydrolysis of simvastatin in tablet. PMID- 23798779 TI - Comparative physicochemical evaluation of a marketed herbomineral formulation: naga bhasma. AB - In the practice of Ayurveda, where herbomineral formulations are said to be made biocompatible through specific processes like Shodhana and Marana, the western medical science on the contrary has raised the safety concerns of these formulations in the recent past. In the present study, comparative physico chemical analysis of Naga bhasma, a herbo-mineral preparation having a reputation of miraculous drug commonly used to treat several health disorders, was carried out using five marketed formulations through analytical methods like differential scanning calorimetry, X-ray difraction, thermogravimetric analysis, Fourier Transform infrared spectroscopy and also subjected for particle size analysis and estimation of trace and heavy metals to access the safety of these formulation. The results revealed variable observations regarding particle size, metal form and content of lead. The presence of free lead in five different formulations indicated towards the possible risk of severe side effects to the consumer. Present findings certainly put doubt over the safety of this formulation but at the same time, variation in the results with all five formulations also indicated that these formulations were not prepared as per the mentioned Ayurvedic text. Hence, enforcement of strict regulatory guidelines is strongly warranted before launching into the market. Further, a series of biological studies need to be conducted before taking any final verdict on the safety of this formulation. PMID- 23798780 TI - A novel and rapid method to determine doxycycline in human plasma by liquid chromatography tandem mass spectrometry. AB - A simple, rapid, specific and sensitive liquid chromatography tandem mass spectrometric method has been developed and validated for the determination of doxycycline from the human plasma. Doxycycline is extracted from human plasma by solid phase extraction. Demeclocycline was used as an internal standard. Detection was performed at transitions of 444.800->428.200 for doxycycline and 464.700->448.100 for demeclocycline using mass spectrometry. Chromatographic separation of analyte and internal standard were carried out using a reverse phase C18, column at 0.500 ml/min flow. The assay of doxycycline is linear over the range of 0.055-7.612 MUg/ml, with a precision <14.83%, regression coefficient (r(2))=0.9961 and the limit of quantification in plasma for doxycycline was 0.055 MUg/ml. Mean extraction recovery obtained was 95.55%. Samples are stable at room temperature for 6 h, processed samples were stable at least for 30.20 h and also stable at three freeze-thaw cycles. The method has been used to perform pharmacokinetic and bioequivalence studies in human plasma. PMID- 23798781 TI - Purification and Structural Characterization of Sulfated Polysaccharide from Sargassum myriocystum and its Efficacy in Scavenging Free Radicals. AB - Sulfated polysaccharides from marine algae are one of the commercially beneficial compounds with a range of pharmaceutical and biomedical applications. They are testified to be effective against free radicals and related health complications. This study aims to determine the antioxidant potential of the sulfated polysaccharide from Sargassum myriocystum, followed by its purification and structural characterization. Amount of extract obtained was 5% from 10 g of plant material. The carbohydrate and sulfate content were found to be 31 and 0.34 mg/10 g of plant material, respectively. Total sulfated polysaccharide extract showed a good radical scavenging activity at lower concentrations. The active principle from the total sulfated polysaccharide was fractionated in anion exchange and gel filtration columns followed by structural characterization using Fourier transform infrared and nuclear magnetic resonance spectroscopy. Fraction 12 closely matched with the Fourier transform infrared and nuclear magnetic resonance spectra of fucoidan. Based on the results obtained, we conclude that sulfated polysaccharide from Sargassum myriocystum is identified as Fucoidan with potential radical scavenging activity compared to butylated hydroxyl toluene. PMID- 23798782 TI - Oral Disintegration Tablets of Stavudine for HIV Management: A New Technological Approach. AB - Stavudine oral disintegration tablets were formulated to minimize the bitter taste and to reduce the first-pass hepatic metabolism. The various precompression parameters like the angle of repose, bulk density, compressibility index and Hausner's ratio were determined for the powder blend. In this study, 14 formulations of stavudine oral disintegration tablet were prepared by direct compression method. The tablets were evaluated for weight variation, percentage friability, disintegration time, hardness, wetting time and water absorption ratio. The in vitro dissolution study results of the batch S1 (stavudine+crospovidone+sodium starch glycollate) are encouraging as highest dissolution rate (99.2% in 100 min) and lowest time of disintegration (56 s) was achieved. The in vivo drug release studies were carried out in rabbits and the relative bioavailability of formulation S1 was found to be 2.83 times greater than that of conventional tablets. PMID- 23798784 TI - In situ Gel of Metoprolol Tartrate: Physicochemical Characterization, In vitro Diffusion and Histological Studies. AB - The purpose of the present investigation was to prepare an intranasal in situ gel with increased nasal residence time in order to improve bioavailability of metoprolol tartrate. The in situ gel systems containing carbopol, hydroxypropyl methylcellulose K4M and K15M in different concentrations were prepared. The samples were characterized for viscosity, rheological behavior, gelation behavior, gel strength, and mucoadhesion. The formulations F10 (0.4% w/v carbopol, 1% w/v hydroxylpropyl methylcellulose K15M) and F13 (0.3% w/v carbopol, 1% w/v hydroxypropyl methylcellulose K15M) showed gel strength of 40.33+/-0.47 and 43.00+/-1.41, respectively, and mucoadhesion strength 31.48+/-0.14*10(3) and 32.12+/-0.05*10(3) dyne/cm(2), respectively. In vitro release profiles showed initial burst followed by slow release. F10 and F13 released 88.08+/-0.98 and 91.18+/-1.09% drug in 8 h. R(2) value for F10 (0.9953) and F13 (0.9942) was maximum for Higuchi, showing mixed order kinetics while n value obtained on treatment with Korsemayer Pappas equation were near to 0.5, suggesting release by fickian diffusion mechanism. The nasal permeability of formulations F10 and F13 were found to be 0.057 and 0.063 cm/s, respectively. Histopathological examination revealed slight degeneration of nasal epithelium with increased vascularity by F10 but no inflammation by formulation F13. Thus, a pH triggered in situ gel system containing low concentration (0.3% w/v) of carbopol demonstrated sustained release of metoprolol tartrate without any destructive effect on the mucosa. PMID- 23798785 TI - Exploring knowledge and perceptions of generic medicines among drug retailers and community pharmacists. AB - The study was carried out to evaluate community pharmacists' and drug retailers' knowledge and perceptions about generic medicines. A cross-sectional descriptive study, with a questionnaire, was conducted to survey community pharmacists and drug retailers working in 39 randomly selected private pharmacies from two towns of Tamil Nadu, India. Among 66 respondents (pharmacists and drug retailers), 39 (59.1%) were drug retailers; 52 (78.8%) were self-employed; majority in the age group 31-40 (31.8%); and mostly males (83.3%). Overall, 21 respondents (31.8%) did not know what generic medicines were. About 30% of the respondents thought that generic medicines are of inferior quality compared to branded medicines. Only 63.6% of the surveyed pharmacists and drug retailers agreed that generic medicines can be considered therapeutically equivalent with the branded ones. A higher level of education had a direct relationship having correct knowledge of generic medicines (P<0.01). The majority of the respondents (80%) did not support generic substitution, even in case of prescribed medicines are not available. Many community pharmacists and drug retailers have misconceptions regarding generic medicines. Lack of knowledge may negatively affect the community pharmacists' support towards generic medicines in India. This issue should be addressed by academicians and other relevant bodies. PMID- 23798787 TI - A Validated RP-HPLC Method for the Estimation of Lapatinib in Tablet Dosage form using Gemcitabine Hydrochloride as an Internal Standard. AB - A simple, selective, rapid, precise and economical reverse-phase high-performance liquid chromatography method has been developed for the determination of lapatinib in tablet using gemcitabine hydrochloride as an internal standard. Chromatography was carried out on an ODS C-18 RP column (4.6 mm i.d. *250 mm) using a mixture of acetonitrile and water (50:50 v/v) as the mobile phase at a flow rate of 1.0 ml/min. The drug was monitored at 232 nm. The retention times for lapatinib and gemcitabine hydrochloride were found to be 4.25+/-0.05 and 6.10+/-0.05 min, respectively. The method produced linear responses in the concentration range of 2-60 MUg/ml of lapatinib. The limit of detection and limit of quantitation were 0.265 and 0.884 MUg/ml, respectively. PMID- 23798786 TI - Antifungal Activity of Leaves of Mangroves Plant Acanthus licifolius Against Aspergillus fumigatus. AB - The antifungal activity of chloroform extract of leaves of Acanthus ilicifolius was evaluated in Aspergillus fumigatus infected mice. Swiss albino mice (60) were divided into five groups. All the groups were immunosuppressed with cyclophosphamide and cortisone acetate couple of days prior to intranasal inoculation with Aspergillus fumigatus conidia (10(6)) in all the groups, except the first. Treatment was initiated at 24 h of fungal inoculation and continued up to day 14, and included amphotericin B (1 mg/kg orally) for group III and extract of Acanthus ilicifolius at 250 mg and 500 mg/kg for group IV and V, respectively. Groups I and II received sterile water orally for the same period. From each group, three mice were sacrificed after 1 h and the remaining mice on the 14(th) day of inoculation. One hour post-inoculation lung colony forming unit count confirmed the delivery of conidia into the lungs. Colony forming unit count, intensity of gross necropsy changes and histopathological changes were highest in group II. It improved in group III and also in groups IV and V in dose-dependent manner. Lesions were absent in the noninfected group. Lesions included maximum granulomatous inflammation of lung, multifocal diffused necrotic granulomas on kidney and moderate microgranulomas on liver. From this study, it was concluded that chloroform extract of Acanthus ilicifolius contains active principles that are absorbed after oral administration to produce systemic effects when given at 500 mg/kg dose. PMID- 23798788 TI - Estimation of quality of life in haemodialysis patients. AB - Since haemodialysis is an expensive treatment modality for chronic renal failure patients, it is very essential to assess the outcome of therapy in terms of quality of life. The primary objective of the study was to estimate the effect of patient counselling in quality of life of end stage renal disease patients opting haemodialysis using World Health Organisation Quality of life scale and to assess the variables affecting the quality of life of these patients. Quality of life was determined by World Health Organisation Quality of life scale questionnaire comprised of 26 items which measures four domains: physical, psychological, social and environmental domain. A total of 81 patients were selected and divided into test and control group and the test group patients received counselling regarding their disease, use of medications, importance of adherence and the complications experienced during and after dialysis. The quality of life data was collected at the interval of 1, 2, 3, 6 and 12 months and the patients were counselled at each interval. The demographic profiles revealed that majority of the patients were in the age group of 31-50 and there exists a male predominance. About the socioeconomic status, upper middle class people were mostly affected. Assessment of impact of patient counselling in the quality of life of haemodialysis indicated a significant improvement in each domain after counselling. And also found that the psychological domain showed a significant increase in the score compared to others. Patient counselling helped to gain benefits in terms of improvement in quality of life and delayed progression of renal failure. Early recognition and prevention is necessary to improve the quality of life of chronic renal failure patients. Patient counselling should be made mandatory by incorporating clinical pharmacist in the nephrology team to make the patient understand his illness and modifications in lifestyle also create a positive environment and result in better quality of life. PMID- 23798789 TI - Development and Validation of New RP-HPLC Method for the Determination of Dexrazoxane. AB - A new sensitive, precise, rapid and linear RP-HPLC method was developed and validated for the determination of dexrazoxane in formulations and human serum samples. Good chromatographic separation of dexrazoxane was achieved by using Kromasil C18 column. The system was operated at ambient temperature using a mobile phase consisting of methanol, 5% ortho phosphoric acid, 0.01M ammonium dihydrogen phosphate and tetrahydrofuran, pH 4.2 (10:40:30:20, v/v) isocratically at a flow rate of 1 ml/min. The method showed high sensitivity with good linearity (r(2)=0.9998) over the tested concentration range of 0.1 to 0.9 mg/ml. Detection was carried out at 272 nm and retention time was 7.005 min. The accuracy, formulation assay and percentage of RSD were 100.03, 97.48 and 0.03184, respectively with tailing factor (1.84). This method can be used for the routine quality control analysis. PMID- 23798790 TI - The Binding Interactions of the Macrolide Endectocide Ivermectin with the Antibiotics Ampicillin, Chloramphenicol and Tetracycline HCL. AB - Ivermectin, chloramphenicol, ampicillin and tetracycline HCl are common drugs in human and veterinary practice. The purpose of this study is to investigate the possible binding interactions between ivermectin and the antibiotics chloramphenicol, ampicillin and tetracycline HCl. Isothermal titration calorimetry was used to determine the binding interactions between ivermectin and these antibiotics. Results indicated that, about three molecules of ampicillin can bind to one molecule of ivermectin and about one molecule of chloramphenicol with one molecule of ivermectin. However, no binding stoichiometry can be detected with tetracycline HCl-ivermectin titration. Furthermore, the binding interactions were accompanied by various biophysical and biochemical mechanisms. This is the first report of such interactions of ivermectin with chloramphenicol, ampicillin and tetracycline HCl. There are possible binding interactions of ivermectin with chloramphenicol and ampicillin. Further studies are required for detecting the impact of this binding on biological aspects of drug actions. PMID- 23798791 TI - Phosphatase and tensin homologue deleted on chromosome 10. AB - Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a tumor suppressor gene deleted or mutated in many human cancers such as glioblastoma, spinal tumors, prostate, bladder, adrenals, thyroid, breast, endometrium, and colon cancers. They result from loss of heterozygosity (LOH) for the PTEN gene on chromosome 10q23. Previous studies reported that various drugs, chemicals, and foods can up-regulate PTEN mRNA and protein expression in different cell lines, and they may be useful in the future prevention and/or treatment of these cancers. PTEN has also been observed to have prognostic significance and is gradually being accepted as an independent prognostic factor. This will help in monitoring disease progression and/or recurrence, with a view to improving treatment outcomes and reducing the associated morbidity and mortality from these cancers. Neprilysin (NEP) is a zinc-dependent metallopeptidase that cleaves and inactivates some biologically active peptides thus switching off signal transduction at the cell surface. Decreased NEP expression in many cancers has been reported. NEP can form a complex with PTEN and enhance PTEN recruitment to the plasma membrane as well as stabilize its phosphatase activity. MicroRNA-21 (miR-21) post-transcriptionally down-regulates the expression of PTEN and stimulates growth and invasion in non-small cell lung cancer (NSCLC) (lung Ca), suggesting that this may be a potential therapeutic target in the future treatment of NSCLC. PTEN is a tumor suppressor gene associated with many human cancers. This has diagnostic, therapeutic, and prognostic significance in the management of many human cancers, and may be a target for new drug development in the future. PMID- 23798792 TI - Household cost of antenatal care and delivery services in a rural community of Kaduna state, northwestern Nigeria. AB - BACKGROUND: Maternal mortality remains a leading cause of death among women of reproductive age. While Nigeria has only two percent of the global population, it contributes 10% to the global maternal mortality burden. Antenatal care (ANC) reduces the incidence of maternal mortality. However, financial capability affects access to antenatal care. Thus, the rural poor are at a higher risk of maternal mortality. MATERIALS AND METHODS: A cross-sectional descriptive study involving 135 women (pregnant women and those who are 6 weeks postpartum). Structured interviewer-administered questionnaires were used for data collection. Data analysis was carried out using statistical package for social sciences software (version 17). RESULTS: The average amount spent on booking and initial laboratory investigations were N77 (half a dollar) and N316 ($2), respectively. Per ANC visit, average amount spent on drugs and transportation were N229 ($1.5) and N139 ($0.9) respectively. For delivery, the average amount spent was N1500 ($9.6). On an average, ANC plus delivery cost about N3,365.00 ($22). There was a statistically significant association between husband's income and ANC attendance (X(2) = 2.451, df = 2, P = 0.048). CONCLUSION: Cost of Antenatal care and delivery services were not catastrophic but were a barrier to accessing antenatal care and facility-based delivery services in the study area. ANC attendance was associated with the income of household heads. Pro-poor policies and actions are needed to address this problem, as it will go a long way in reducing maternal mortality in this part of the country. PMID- 23798793 TI - Beneficial effects of low dose Musa paradisiaca on the semen quality of male Wistar rats. AB - BACKGROUND: This study aimed at determining the effects of administration of mature green fruits of Musa paradisiaca on the semen quality of adult male Wistar rats. MATERIALS AND METHODS: THE ANIMALS USED FOR THE STUDY WERE GROUPED INTO THREE: the control group, given 2 ml of double distilled water, a low dose group given 500 mg/kg/day and a high dose group given 1000 mg/kg/day of the plantain fruits, which was made into flour, and dissolved in 2 ml of double distilled water for easy oral administration. RESULTS: Significant increment in the semen parameters was noticed in animals that received a lower dose of the plantain flour, but those animals who received the high dose had marked and very significant reduction in sperm cell concentration and percentage of morphologically normal spermatozoa. CONCLUSION: Musa paradisiaca should be consumed in moderate quantities in order to derive its beneficial effects of enhancing male reproductive functions. PMID- 23798794 TI - Anti-malaria prescription in pregnancy among general practitioners in Enugu state, south east Nigeria. AB - BACKGROUND: The national policy on malaria control recommends use of intermittent preventive treatment with sulfadoxine/pyrimethamine (IPT-SP) for chemoprophylaxis against malaria in pregnancy; and use of quinine and arthemisinin-based combination therapy (ACT) for acute treatment of malaria in the first, and second/third trimesters, respectively. In Nigeria, a large proportion of pregnant women are seen by the general practitioners (GPs). OBJECTIVE: To determine the pattern of anti-malaria prescription in pregnancy among GPs in Enugu state, and access the level of conformity with the national policy on malaria control. MATERIALS AND METHODS: Questionnaires were administered to a cross-section of 147 GPs that attended the 2010 Enugu state branch of the Nigeria Medical Association Scientific Conference/Annual General Meeting/Election. RESULTS: The mean age of the GPs was 37 +/- 3.6 (range 27-70) years. Quinine was the commonly (45.6% (n = 67)) prescribed anti-malaria drug in the first trimester while in the second/third trimester ACT was commonly (48.3% (n = 71)) prescribed. Seventy-six (51.7%) practitioners prescribed IPT-SP for chemoprophylaxis against malaria while the rest (48.3%) prescribed other drugs. GPs who obtained MBBS qualification less than or equal to 5 years prior to the survey were more likely to comply with the national policy on malaria control in their prescriptions (P < 0.05). CONCLUSION: The pattern of anti-malaria prescription among GPs in Enugu state is varied, and conformed poorly to the evidence-based national policy on malaria control. There is need for continuing professional development to keep the GPs abreast with current trends in malaria treatment during pregnancy. PMID- 23798795 TI - Effects of indomethacin on expression of PTEN tumour suppressor in human cancers. AB - BACKGROUND: Previous studies reported that Non-steroidal Anti-inflammatory Drugs (NSAIDs), chemicals, and food supplements can be used to up-regulate the PTEN mRNA and protein expression, suggesting that these substances may be used in prevention and/or treatment of various human cancers like spinal, brain, colon, breast, prostate, bladder and endometrial cancers. AIM: This was to study expression and sub-cellular localisation of PTEN protein, and review the effect(s) of indomethacin on PTEN's expression in cultured Human Endometrial Cancer (HEC 1B) cell line, which is known to express significant amounts of the wild-type PTEN. MATERIALS AND METHODS: This involves culture and incubation of artificial HEC 1B cells. All procedures were undertaken in the cell culture hood under the recommended sterile conditions. The cells were then incubated with different concentrations of indomethacin solution, for variable durations and finally fixed (with paraformaldehyde) and stained with fluorescein-labelled diluted secondary antibody (FITC). Immunocytochemistry (IHC) and fluorescent microscopy were then employed for the detection and localisation of the specific antigen (PTEN), using antibodies. RESULTS: The HEC 1B cells, which were cultured and incubated with different concentrations of indomethacin solution, expressed the PTEN protein, most of which was localised to the nucleus with minimal cytoplasmic expression. Increased PTEN expression was observed following treatment of the cells with various concentrations of the solution for variable durations, although there was cell death at higher concentrations and longer duration. This procedure was repeated several times, in order to have consistency and to validate the results. CONCLUSION: This study agrees with previous studies in similar human cell lines and supports the idea that NSAIDs and other drugs may be used in the future for prevention of human cancers. However, more studies need to be carried out to substantiate these observations. PMID- 23798796 TI - Teething myths among nursing mothers in a Nigerian community. AB - BACKGROUND: Many symptoms had been associated with teething in children with the possibility of overlooking potentially fatal condition. Symptoms that had been associated with teething include diarrhoea, fever, vomiting and cough. The possibility that any of these symptoms could have been due to other causes call for thorough investigation of the child before concluding that it is only "teething". OBJECTIVES: The study was carried out to assess the beliefs of nursing mothers concerning symptoms that are associated with teething among children and to identify those that would seek medical treatments in case of their children having such symptoms during teething. MATERIALS AND METHODS: Two hundred and ninety nursing mothers whose children had erupted at least a tooth were interviewed in the immunisation clinics of the University College Hospital and Adeoyo Maternity Teaching Hospital, both in Ibadan, Nigeria, on their beliefs and practice concerning teething in children. RESULTS: One hundred and eighty eight (64.8%) of the mothers associated symptoms such as fever, cough, catarrh and diarrhoea with eruption of teeth in their children. Over half of the women agreed that a child having either fever (51.0%), ear infection (57.6%) or cough (50.3%) should be promptly taken for medical consultation and not be tagged "teething", while for other symptoms such as gum pain (74.5%), sleepless night (56.6%), vomiting (51.4%) and diarrhoea (51.7%), over half of the mothers believed that the symptoms will resolve following the eruption of the teeth. CONCLUSION: The study demonstrated that mothers in the study attributes several symptoms to teething, which could be detrimental to the survival of their children as the symptom could have been due to other causes. There is, therefore, need for public enlightenment to create awareness on the possible effect of presumptuous belief that childhood diseases are due to teething process. PMID- 23798797 TI - Indications and findings at colonoscopy in Ilorin, Nigeria. AB - BACKGROUND: Colonoscopy is a safe and effective means of visual inspection of the large bowel from the distal rectum to the caecum. It may be carried out for diagnostic and or therapeutic reasons. There is a paucity of data on this procedure in Nigeria. We, therefore, determined the indications, findings, and diagnostic yield in Nigerians at colonoscopy. MATERIALS AND METHODS: This was a hospital-based cross-sectional study carried out at the Endoscopy unit of Crescent hospital, Ilorin from January 2010 to May, 2012. The endoscopy register was reviewed, and the biodata, indications and colonoscopic findings were recorded on a pro forma. RESULTS: A total of 103 patients had colonoscopy. Seventy (68.0%) were males while 33 (32.0%) were females. The indications for colonoscopy were rectal bleeding 41 (39.8%), suspected colon cancer 32 (31.1%), chronic constipation and chronic diarrhoea nine each (8.7%), abdominal/anal pain five (4.9%), suspected anorectal cancer and enterocutaneous fistula two each (1.9%), faecal incontinence, occult gastrointestinal bleeding, post-colostomy for Hirschsprung disease one each (1.0%). Endoscopic findings were normal findings 21 (20.4%), diverticulosis 17 (16.5%), polyps 16 (15.5%), haemorrhoids 16 (15.5%), anorectal cancer 13 (12.6%), angiodysplasia 12 (11.7%), colon cancer eight (7.8%), colitis 7 (6.8%), anorectal ulcer 4 (3.9%), anal warts two (1.9%), anal fissure, caecal tumour, faecal impaction and proctitis one each (1.0%). The diagnostic yield was 79.6%. CONCLUSIONS: The commonest indication for colonoscopy was rectal bleeding, while the most frequent pathology was diverticulosis. The diagnostic yield was high. PMID- 23798798 TI - Impact of health education intervention on malaria prevention practices among nursing mothers in rural communities in Nigeria. AB - INTRODUCTION: Malaria is the most prevalent parasitic endemic disease in Africa, which is preventable, treatable and curable. This study aims to assess the effect of health education intervention on the knowledge, attitude, and prevention practices amongst mothers of under-five children in a rural area of Ogun State, Nigeria. MATERIALS AND METHODS: The study design was a quasi-experimental study carried out in Ijebu North Local Government Area of Ogun State. A multistage random sampling technique was used in choosing the required samples and a semi structured questionnaire was used to collect relevant information. A total of 400 respondents were recruited into the study with 200 each in both the experimental and control groups and were followed up for a period of 3 months. RESULTS: There was no statistically significant differences observed between the experimental and control groups. Knowledge of indoor spraying increased from 14.7% to 58.2% (P < 0.001) and window and door nets increased from 48.3% to 74.8% (P < 0.001). The proportion of those with ITN use increased from 50.8% to 87.4% (P < 0.001) while those with practice of maintaining clean environment also increased from 40.4% to 54.5% (P < 0.001). There were no significant changes in all the practice of malaria prevention methods in the control group. CONCLUSION: This suggests that malaria control can be significantly improved in rural areas, if the caregivers are adequately empowered through appropriate health education intervention though change in attitude and belief may require a longer and persistent effort. PMID- 23798799 TI - Cranial computed tomographic findings in Nigerian women with metastatic breast cancer. AB - INTRODUCTION: Brain metastases (BM) occur in up to one-fifth of patients with metastatic breast cancer (MBC). Imaging plays a key role in diagnosis. The pattern and distribution of these changes are also crucial to their management. These patterns have not been fully studied in Nigerian women. MATERIALS AND METHODS: Retrospective analysis of the findings on the cranial Computed Tomography (CT) scans performed in 59 breast cancer patients with suspected BM treated at the University Teaching Hospital in Ibadan, between 2005 and 2010. The imaging features were evaluated in relation to their clinical characteristics. RESULTS: In the 59 patients studied (mean age 50.9 years +/- 11.75 SD), headache (40.7%) and hemiparesis/hemiplegia (16.9%) were the commonest clinical presentation. Lytic skull lesions were seen in 15 patients (25.4%), most commonly in the parietal bones. Thirty-nine patients (66.1%), had parenchymal brain lesions, and only 8 (20.5%) of these were single lesions. Most of the lesions were isodense (19/39; 51.4%) the parietal lobe was the most common site with 50.8% (30/59) occurrence and the leptomeninges the least with 13.6% (8/59). Orbital or sellar region involvement occurred in only two patients. The size of the lesions, was <2 cm in 17 (28.8%), 2-5 cm in 14 (23.7%) and >5 cm in 5 patients. Sixteen (27.1%) patients were free of any lesion either in the skull or brain. Patient presenting with multiple brain lesions were more likely to have skull lesions though this was not statistically significant (P = 0.584). CONCLUSION: The brain continues to be a sanctuary site for breast cancer metastases and CT imaging remains an invaluable tool in the clinical evaluation and therapeutic management of Nigerian women with BM from MBC. It also appears that the demographic and imaging findings in these patients are similar to other racial groups. PMID- 23798800 TI - Stroke risk factors, subtypes, and 30-day case fatality in Abuja, Nigeria. AB - BACKGROUND: Stroke is the second leading cause of death and the leading cause of adult disability worldwide. A better understanding of stroke risk factors and outcome may help guide efforts at reducing the community burden of stroke. This study aimed to understand stroke risk factors, imaging subtypes, and 30-day outcomes among adult Nigerians. MATERIALS AND METHODS: We prospectively recruited all patients presenting with acute stroke at the National Hospital Abuja between January 2010 and June 2012. We assessed clinical and laboratory variables, as well as brain computerized tomography, magnetic resonance imaging, and carotid Doppler ultrasound scans. We also assessed case fatality and functional outcome at 30 days after stroke. RESULTS: Of 272 patients studied, 168 (61.8%) were males. Age at presentation (mean +/- standard deviation) was 56.4 +/- 12.7 years in males and 52.9 +/- 14.8 years in females (P = 0.039). Neuroimaging was obtained in 96.7% patients, revealing cerebral infarction (61.8%), intracerebral hemorrhage (ICH) (34.8%), and subarachnoid hemorrhage (SAH) (3.4%). Carotid plaques or stenosis >=50% were detected in 53.2% patients with cerebral infarction. Stroke risk factors included hypertension (82.7%), obesity (32.6%), diabetes (23.5%), hyperlipidemia (18.4%), atrial fibrillation (9.2%), and cigarette smoking (7.7%). At 30 days after stroke, case-fatality rate was 18.8%, whereas modified Rankin Scale (mRS) scores for cerebral infarction, ICH, and SAH were 3.71, 4.21, and 4.56, respectively. Atrial fibrillation, a previous stroke, and age older than 50 years were all associated with worse mRS scores at 30 days. CONCLUSION: Although hypertension, obesity, diabetes mellitus, and atrial fibrillation were important stroke risk factors, in many patients, these were detected only after a stroke. While the commonest stroke subtype was cerebral infarction, observed in almost two-third of patients, SAH was associated with the highest case-fatality rate at 30 days of 44.4%. Larger population-based studies may provide additional data on stroke incidence and outcome among Nigerians. PMID- 23798801 TI - MR urography: Anatomical and quantitative information on congenital malformations in children. AB - BACKGROUND AND AIM: Magnetic resonance urography (MRU) is considered to be the next step in uroradiology. This technique combines superb anatomical images and functional information in a single test. In this article, we aim to present the topic of MRU in children and how it has been implemented in Northern Greece so far. The purpose of this study is to demonstrate the potential of MRU in clinical practice. We focus both on the anatomical and the quantitative information this technique can offer. MATERIALS AND METHODS: MRU was applied in 25 children (ages from 3 to 11 years) diagnosed with different types of congenital malformations. T1 and T2 images were obtained for all patients. Dynamic, contrast-enhanced data were processed and signal intensity versus time curves were created for all patients from regions of interest (ROIs) selected around the kidneys in order to yield quantitative information regarding the kidneys function. RESULTS: From the slopes of these curves we were able to evaluate which kidneys were functional and from the corticomedullary cross-over point to determine whether the renal system was obstructed or not. CONCLUSION: In all 25 cases MRU was sufficient, if not superior to other imaging modalities, to establish a complete diagnosis. PMID- 23798802 TI - That dyspepsia in the young could be cancer. AB - Malignant tumour of the stomach is not common in young adults. When it does occur, it is associated with a high morbidity and mortality. The objective of this report is to document our experience with three cases of gastric adenocarcinoma in young adult Nigerians seen over a period of 18 months in our centre. PMID- 23798803 TI - Parkinson's disease in the elderly and the comprehensive geriatric assessment. PMID- 23798804 TI - Early stage visual-orthographic processes predict long-term retention of word form and meaning: a visual encoding training study. AB - Adult learners of Chinese learned new characters through writing, visual chunking or reading-only. Following training, ERPs were recorded during character recognition tasks, first shortly after the training and then three months later. We hypothesized that the character training effects would be seen in ERP components associated with word recognition and episodic memory. Results confirmed a larger N170 for visual chunking training than other training and a larger P600 for learned characters than novel characters. Another result was a training effect on the amplitude of the P100, which was greater following writing training than other training, suggesting that writing training temporarily lead to increased visual attention to the orthographic forms. Furthermore, P100 amplitude at the first post-test was positively correlated with character recall 3 months later. Thus the marker of early visual attention (P100) was predictive of retention of orthographic knowledge acquired in training. PMID- 23798805 TI - "Bird-Wing" abdominal phalloplasty: A novel surgical technique for penile reconstruction. AB - AIM: To describe a technique of phalloplasty that is devoid of donor site scarring and suitable for urethral inlay and penile prosthesis in subsequent stages in cases of aphallia. MATERIALS AND METHODS: Four patients with various disorders of sex development with 46 XY and severe penile deficiency, including one with complete androgen insensitivity syndrome who was initially raised as female, have been operated using a "Bird Wing" lower abdominal skin crease incision. RESULTS: The patients' age ranged from 6 to 17 years with preoperative stretched penile lengths between 1 and 2.5 cm. Phallic sizes between 7.5 and 12.5 cm was achieved leaving the donor site unremarkable with lower abdominal skin crease linear scar and excellent postoperative recovery. CONCLUSIONS: This phalloplasty technique can be utilized as a definitive procedure in many situations of penile insufficiency. Subsequent stages of urethral repair and insertion of penile prosthesis can be easily added. PMID- 23798806 TI - Nephrectomy in children: Comparison of stress response to laparoscopic and open methods. AB - AIM: To evaluate and compare the extent of surgical stress following laparoscopic nephrectomy (LN) and open nephrectomy (ON) in children. MATERIALS AND METHODS: Twenty consecutive children undergoing nephrectomy were randomized to LN or ON groups. Acid-base balance, blood glucose, acute phase proteins (C-reactive protein [CRP]) and inflammatory markers (interleukin-6 [IL-6]) were measured pre operatively, as well as 4 and 24 h after surgery. The differences between the two groups were analyzed statistically (significance value for P < 0.05). RESULTS: The overall acid base status was more stable in LN. The fall in pH 4 h after surgery was more in ON (P = 0.440) and the difference in pH in ON 4 h and 24 h post-operatively was statistically significant (P = 0.002). In LN, significant difference was found in the base excess mean pre-surgery (mean -3.280 mEq/L) and 4 h post-surgery (mean -7.480 mEq/L) (P = <0.05), as well as between 4 h and 24 h after surgery (mean -2.660 mEq/L) (P = 0.011). The acute rise in CRP 24 h post operatively in the ON (88.972 mg/L) was significantly higher when compared to both the pre-operative and 4 h post-operative values (P < 0.05). This rise was however, not statistically significant when compared to the 24 h post-operative value in LN (46.399 mg/L) (P = 0.062). The rise in IL-6, 24 h post-procedure in LN (mean 44.444 pg/ml) was statistically lower than that in the open group (mean 343.333 pg/ml) (P = 0.041). CONCLUSIONS: The stable acid-base status and lesser rise of CRP and IL-6 in LN lead to the conclusion that surgical stress caused by LN is less than ON. PMID- 23798807 TI - Effect of ipsilateral ureteric obstruction on contralateral kidney and role of renin angiotensin system blockade on renal recovery in experimentally induced unilateral ureteric obstruction. AB - AIMS: To study, the effects of ipsilateral ureteric obstruction on contralateral kidney and the role of renin angiotensin system (RAS) blockade on renal recovery in experimentally induced unilateral ureteric obstruction. MATERIALS AND METHODS: Unilateral upper ureteric obstruction was created in 96 adult Wistar rats that were reversed after pre-determined intervals. Losartan and Enalapril were given to different subgroups of rats following relief of obstruction. RESULTS: The severity of dilatation on the contralateral kidney varied with duration of ipsilateral obstruction longer the duration more severe the dilatation. There is direct correlation between renal parenchymal damage, pelvi-ureteric junction (PUJ) fibrosis, inflammation and severity of pelvi-calyceal system dilatation of contralateral kidney with duration of ipsilateral PUJ obstruction. CONCLUSIONS: Considerable injury is also inflicted to the contralateral normal kidney while ipsilateral kidney remains obstructed. Use of RAS blocking drugs has been found to significantly improve renal recovery on the contralateral kidney. It can, thus, be postulated that contralateral renal parenchymal injury was mediated through activation of RAS. PMID- 23798808 TI - Modified tubularized incised plate urethroplasty. AB - AIM: To share our experience of doing tubularized incised plate urethroplasty with modifications. MATERIALS AND METHODS: This is a single surgeon personal series from 2004 to 2009. One hundred patients of distal hypospadias were subjected for Snodgrass urethroplasty with preputioplasty. The age range was 1 to 5 year with mean age of 2.7 years. Selection criteria were good urethral plate, without chordee and torsion needing complete degloving. Main technical modification from original Snodgrass procedure was spongioplasty, preputioplasty, and dorsal slit when inability to retract prepuce during surgery. RESULTS: Average follow-up period is 23 months. Seven (7%) patients developed fistula and one patient had complete preputial dehiscence. Phimosis developed in three (3%) patients and required circumcision. Dorsal slit was required in seven patients. One patient developed meatal stenosis in postoperative period. All other patients are passing single urinary stream and have cosmesis that is acceptable. CONCLUSIONS: Modified tubularized incised plate urethroplasty with preputioplasty effectively gives cosmetically normal looking penis with low complications. PMID- 23798809 TI - Calretinin immunohistochemistry: A new cost-effective and easy method for diagnosis of Hirschsprung's disease. AB - AIM: To evaluate the efficacy of calretinin immunostaining in diagnosing Hirschsprung's disease (HD). MATERIALS AND METHODS: Sixty cases were studied over a period of 1 year (July 2010-June 2011). There were 36 full-thickness biopsies and 24 resected specimens. Calretinin processing was done on the paraffin embedded blocks after routine histopathological examination. RESULTS: Of the 36 biopsy specimens, in 19 cases HD was diagnosed by hematoxylin and eosin (H and E) staining earlier. In 2 patients, ganglion cells were seen and HD was ruled out. In 15 cases, there was a diagnostic dilemma and calretinin was used. Ganglion cells were found in 3 specimens and nerve fibers in 5. In all 24 resected specimens, calretinin correlated with the findings on H and E staining. CONCLUSIONS: Calretinin was extremely useful in solving the suspicious and indeterminate cases of HD. It can serve as a valuable cost-effective diagnostic aid in the centers where acetylcholinesterase enzyme histochemistry is not available. PMID- 23798810 TI - Bladder exstrophy: Comparison of anatomical bladder neck repair with innervation preserving sphincteroplasty versus Young-Dees-Leadbetter bladder neck reconstruction. AB - AIM: To evaluate the outcome of innervation preserving sphincteroplasty along with anatomical bladder neck reconstruction (IPS-ABNR) compared to classic Young Dees-Leadbetter (YDL) bladder neck reconstruction in exstrophy with insufficient bladder capacity requiring detubularized-ileocystoplasty. MATERIALS AND METHODS: Sixteen male patients of exstrophy bladder who required ileocystoplasty from 2004 to 2010 were randomized into group A (n = 7) and group B (n = 9). After detubularized-ileocystoplasty with Mitrofanoff stoma and ureteric reimplantation in all, group A received YDL bladder neck repair while group B received IPS-ABNR repair through a midline scrotoperineal approach. Outcome measurement included operative and postoperative problems, continence, and upper tract status. RESULTS: In group A, two had incompetent bladder neck with gross incontinence, while four had a dry interval of more than 3 h without the ability of voiding per urethra. In group B, seven patients had dry interval of more than 3 h with an ability of urethral voiding and midstream holding in five. CONCLUSIONS: Exstrophy patients requiring augmentation cystoplasty and repaired with IPS-ABNR can achieve dynamic bladder outlet resistance with adequate leak point pressure and ability to void voluntarily with midstream holding capability. The children had the satisfaction of voiding per urethra with ability to stop in midstream similar to that in normal children. PMID- 23798811 TI - Posterior urethral valves: Persistent renin angiotensin system activation after valve ablation and role of pre-emptive therapy with angiotensin converting enzyme inhibitors on renal recovery. AB - AIM: To study renin angiotensin system (RAS) activity after posterior urethral valve ablation and the role of early induction of angiotensin converting enzyme inhibitors (ACE-I) on the outcome of renal function. MATERIALS AND METHODS: Thirty four children underwent valve ablation in which therapy with ACE-I was started 40.5 +/- 4.1 (range 32-47 months) formed the study group. Post-ACE-I data were collected after mean duration of 18.2 +/- 4.0 (12-28 months). Plasma renin activity (PRA), urinary micro albumin, glomerular filtration rate (GFR), and serum creatinine, before and after therapy were monitored. RESULTS: Therapy with ACE-I resulted in a fall in micro albuminuria by 45.7% and 42.0% in patients without and with vesico ureteral reflux, respectively, and improvement in split renal function by 6.6% and 5.9% GFR respectively. A similar response was noted in patients without and with renal scars. CONCLUSION: The decline in renal function after valve ablation is accompanied by activation of RAS reflected in a gradual rise in PRA. Therapy with ACE-I stabilizes and then improves renal function, thereby, retarding the pace of renal damage. PMID- 23798812 TI - Prune belly syndrome with congenital pouch colon. AB - We report a rare case of prune belly syndrome associated with congenital pouch colon, which was managed successfully. PMID- 23798813 TI - Congenital pouch colon in a girl associated with bilateral atresia of cervix uteri and uterus didelphys. AB - This report describes a girl with congenital pouch colon (CPC), uterus didelphys with septate vagina, and a cloacal anomaly. The girl underwent cloacal reconstruction at the age of 15 months. Subsequently, at puberty, the child had primary amenorrhea with severe cyclic abdominal pain due to endometriosis of both the uteruses and adnexal cysts with hematometra and hematosalpinx. Laparotomy with removal of both uteri and the left fallopian tube was performed. Both uteri had atresia of the cervix uteri. This report emphasizes the need for comprehensive evaluation and a long-term management strategy for associated gynecologic anomalies in girls with CPC, especially with regard to patency of the outflow tract. PMID- 23798814 TI - Isolated inferior mesenteric portal hypertension with giant inferior mesenteric vein and anomalous inferior mesenteric vein insertion. AB - Extrahepatic portal hypertension is not an uncommon disease in childhood, but isolated inferior mesenteric portal varices and lower gastrointestinal (GI) bleed have not been reported till date. A 4-year-old girl presented with lower GI bleed. Surgical exploration revealed extrahepatic portal vein obstruction with giant inferior mesenteric vein and colonic varices. Inferior mesenteric vein was joining the superior mesenteric vein. The child was treated successfully with inferior mesenteric - inferior vena caval anastomosis. The child was relieved of GI bleed during the follow-up. PMID- 23798815 TI - Primary paratesticular yolk sac tumor: A case report and review of literature. AB - Paratesticular germ cell tumors are extremely rare. A 12-month-old boy with yolk sac tumor involving only the paratesticular tissue is reported. Pre-operatively raised alpha fetoprotein levels fell to normal levels after high inguinal orchiectomy. This appears to be the youngest and only the 3(rd) case reported in the English literature. PMID- 23798816 TI - Unilobar Caroli's disease and its management in an 8-year-old girl. AB - A case of unilobar Caroli's disease in an 8-year-old girl treated with left hepatectomy is reported here. PMID- 23798817 TI - Comment on persistent hyperinsulinemic hypoglycemia of infancy. PMID- 23798818 TI - Awareness about management of 'avulsed teeth' among primary contact doctors. PMID- 23798819 TI - Retraction note: Penile strangulation by metallic rings. PMID- 23798820 TI - From the Editor's desk. PMID- 23798821 TI - Bizzare plasma cell - mott cell. PMID- 23798822 TI - Estimation of plasma lipids and its significance on histopathological grades in oral cancer: Prognostic significance an original research. AB - BACKGROUND OBJECTIVES: Alterations in the lipid profile have long been associated with various cancers because lipids play a key role in maintenance of cell integrity. This study was to estimate the plasma lipid levels in patients with oral cancer and to correlate the values with the histopathological grades. MATERIALS AND METHODS: The study group included 50 patients with oral cancer aged between 20 and 60 years who had visited the Department of Oral Medicine and Radiology during the period of September 2005 to July 2007. After the histotopathological confirmation, their plasma lipid levels were estimated using auto analyzer and the data was statistically analyzed. RESULTS: The study revealed a significant decrease in the total plasma lipid levels in patients with oral cancer in comparison with the standard values. Comparing the plasma lipid levels with the histopathological grades, we observed a significant variation in the levels of total cholesterol, very low density lipoprotein, low-density lipoprotein, high-density lipoprotein and triglycerides. CONCLUSION: The variation in the levels of plasma cholesterol and other lipid constituents in patients with cancer might be due to their increased utilization by neoplastic cells for new membrane biosynthesis. This study was an attempt to estimate the plasma lipids in oral cancer patients and its significance on histopathological grades. We observed a relationship between lower plasma lipids and oral cancer. The result of our study strongly warrants an in-depth research with larger samples and a longer follow-up to consider the low plasma lipid status in oral cancer patients as a useful indicator to assess the course and prognosis of the disease. PMID- 23798823 TI - Analysis of the changes in the basal cell region of oral lichen planus: An ultrastructural study. AB - CONTEXT: Oral lichen planus (OLP) affects 0.5-1% of the total world's population. The histological features of oral lichen planus were first described by Dubreuill in 1906. Despite the advent of various techniques, the etiology of lichen planus remains obscure, although many theories for the etiology have been proposed. AIMS: By studying OLP electron microscopically, we shall be emphasizing on the cells and its interactions in specific/altered surroundings which would help us in hypothesizing the effects of its specific cell-to-cell interactions. MATERIALS AND METHODS: A total of 20 cases of oral lichen planus were selected and categorized into erosive and nonerosive forms based upon clinical pattern and confirmed as lichen planus by histopathological analysis. Tissue specimens thus obtained were cut into two halves and fixed in appropriate fixatives, i.e., neutral buffered formalin for paraffin-embedded hematoxylin and eosin stained sections and 2.5% glutaraldehyde and 2% paraformaldehyde for electron microscopic purpose respectively. RESULTS: Ultrastructural comparison among the two forms showed significant differences between them. The basal layer showed cytoplasmic processes, intercellular spaces, desmosomes, nuclei, and signs of degeneration. The erosive form showed elongated, narrow or irregular cytoplasmic projections whereas the nonerosive showed short and broad based projections. CONCLUSIONS: The present study confirms the ultrastructural findings of basal cells in OLP with previous authors findings. Besides this, the categorization of the ultrastructural differences between erosive and nonerosive has raised the question of difference in the probable cellular and molecular mechanism between erosive and nonerosive forms. PMID- 23798824 TI - Impact of highly active antiretroviral therapy on salivary flow in patients with human-immuno deficiency virus disease in Southern India. AB - AIMS: To ascertain and compare between highly active antiretroviral therapy (HAART) and non-HAART patients, the stimulated salivary flow rates and unstimulated salivary flow rates (USFR and SSFR) and to correlate the salivary flow rates with immune suppression. MATERIALS AND METHODS: One hundred human immuno deficiency virus seropositive patients attending RAGAS-YRG CARE were examined and divided into two groups, a HAART group (patients on combination antiretroviral therapy) comprising 50 patients and a non-HAART group comprising 50 patients. The HAART group was followed every 3 months after the baseline visit (0) for a period of 9 months, during which a clinical oral examination and collection of unstimulated and stimulated saliva was done. Their salivary gland function was assessed using a xerostomia inventory during each visit. The study on non-HAART group was cross-sectional. STATISTICAL ANALYSIS: Statistical analysis were performed with the aid of the Statistical Package for the Social Sciences (SPSS version 10.05) software. RESULTS: There was no significant difference in mean SSFR and USFR between the two groups at baseline. In the HAART group, the mean stimulated salivary flow rate increased from baseline to 3 months (P = 0.02), with the increase being maintained at 6 months and 9 months. When salivary flow rates were correlated with Cluster of Differentiation, CD4 counts, patients in the HAART group with a CD4 <= 200 at 6 months visit had a higher mean stimulated salivary flow rate when compared with patients with CD4 >= 200 (P = 0.02). The xerostomia inventory did not reveal any significant difference between the two groups and HAART was not significantly associated with xerostomia. CONCLUSION: In our study HAART was neither associated with xerostomia nor a reduction in salivary flow rate and immune suppression was not a significant factor for decreasing the salivary flow rate. PMID- 23798825 TI - Comparing modified papanicolaou stain with ayoub-shklar and haematoxylin-eosin stain for demonstration of keratin in paraffin embedded tissue sections. AB - AIM: The aim of the present study was to stain the known keratin containing tissues by Haematoxylin and eosin stain (H-E), ayoub-shklar (A/S) and modified Papanicolaou (PAP) stain and to compare the efficacy of modified PAP staining procedure with that of A/S stain and H-E staining technique, so as to device a staining procedure which is easy and effective for keratin. MATERIALS AND METHODS: A Total Number of 60 paraffin embedded tissue sections of known keratin containing tissues including normal keratinized oral mucosa (NKOM), Keratinized Odontogenic Keratocyst (OKC), Verrucous Carcinoma (VC) and Well differentiated Squamous Cell Carcinoma (WDSCC) were taken and 3 sections of 4 microns thickness of each block were cut and stained with above mentioned three stains. RESULTS: Surface keratin was stained distinctly and uniformly in all the three staining techniques in NKOM, OKC, and VC and WDSCC. But results were statistically significant in WDSCC when Amount of keratin pearls and Pattern of staining were compared in all 3 staining procedures and p value was p=0.000 and p=0.001 respectively. CONCLUSION: Based on the above findings we conclude that the efficacy of modified PAP is comparable with that of H-E stain and A-S stain for surface keratin and thus be used effectively to stain Surface keratin. Whereas to know the exact pattern of cytokeratin expression in SCC a more sensitive tool like immunohistochemical method can be applied. PMID- 23798826 TI - An immunohistochemical study of basement membrane heparan sulfate proteoglycan (perlecan) in oral epithelial dysplasia and squamous cell carcinoma. AB - BACKGROUND: Basement membrane heparan sulfate proteoglycan (perlecan) has been demonstrated in precancer lesions and carcinomas of oral cavity. It helps in malignant transformation of epithelial cells. The aim of our study was to understand the immuno-localization of perlecan in oral dysplastic epithelium and oral carcinomas. MATERIALS AND METHODS: A total of 50 cases comprising 10 normal mucosa, 20 dysplastic mucosa, and 20 oral squamous cell carcinomas (OSCC) were included in the retrospective study. They were examined for the presence of perlecan protein core by immunohistochemistry using monoclonal antibody. Interpretation of the pattern of staining was done, and majority of the observations were taken for statistical analysis. RESULTS: In normal epithelium, perlecan was found to be present in basal layer at the cell border. In dysplastic epithelium, it was present in suprabasal layers also. With the increase in severity of dysplasia, its expression was more in suprabasal layers, and the immuno-localization was found to be at cell border and cytoplasm. In OSCC cases, perlecan was present in stroma and tumor islands. CONCLUSION: It was deduced from the above results that perlecan helps potentially in dysplastic changes of epithelial cells. It gets accumulated within the cell and intercellular spaces and serves as a reservoir for various growth factors. In OSCC, it breaks down and releases growth factors, which help in tumor progression, angiogenesis, and metastasis of the carcinoma. PMID- 23798827 TI - Fibro-osseous lesions of the oral and maxillo-facial region: Retrospective analysis for 20 years. AB - BACKGROUND: Fibro-osseous lesions (FOLs) are one of the commonest entities reported in the head and neck region. However, studies on these groups of lesions on Indian population were not carried out before. So this motivated us to analyze the clinico-pathologic correlation of fibro-osseous lesions reported at our hospital. MATERIALS AND METHODS: A retrospective review was made of all the lesions surgically treated in our hospital. A total of 6,175 biopsies were performed during the study period. All the cases which were histopathologically diagnosed as FOLs were included in the study. The demographic data, radiographic features, and histopathologic findings were analyzed and compared with similar studies on other races. RESULTS AND CONCLUSION: We could find 80 cases diagnosed as fibro-osseous lesions and information about them was documented. The most common FOL reported in the region was cemento-ossifying fibroma (COF) (75%) than fibrous dysplasia (FD) (25%). These were commonly occurring in 2(nd) decade without any sex or site predilection. However, COF was showing a slight female predominance and FD with a definite male predominance. COF was commonly seen in mandible (posterior region) whereas FD mainly confined to the maxilla (as a whole bone). Radiographically, most of COF showed well-defined mixed opaque and lucent areas whereas FD showed diffuse borders. Cortical plate expansion and resorption of associated teeth was a frequent finding in COF when compared with FD. Histopathologically, stroma was fibrocellular in many cases of COF, whereas most FDs showed fibrous stroma, interspersed with mainly woven bone. PMID- 23798828 TI - Histopathologic evaluation of follicular tissues associated with impacted lower third molars. AB - CONTEXT: Previous studies have reported that the dental follicular tissues associated with impacted lower third molars (ILTMs) may undergo cystic degeneration and/or neoplastic transformation. This is especially likely when the pericoronal space is >2.5 mm on intraoral radiographs and >3 mm on panoramic radiographs and to examine dental follicular tissue for pathological changes in patients with ILTMs and pericoronal radiolucencies of <2.5 mm. AIM: Histopathological evaluation of follicular tissues associated with ILTMs. MATERIALS AND METHODS: The morphology of the hematoxylin and eosin-stained follicular tissues of 146 such impactions were studied. RESULTS: On microscopy, no cystic structures with fibrous walls were identified. 85 cases (58%) showed fibrous or myxomatous connective tissue and no epithelial elements. 61 cases (42%) showed epithelial elements in addition to fibrocollagenous tissue. Of these, 16 cases exhibited epithelium, of which 13 cases showed reduced enamel epithelium and three cases showed squamous metaplasia/non-keratinized stratified squamous epithelium. CONCLUSIONS: All asymptomatic unerupted third molars with pericoronal radiolucency of <2.5 mm should be retained since they do not exhibit cyst formation microscopically. PMID- 23798829 TI - Clinico-epidemiological profile of oral potentially malignant and malignant conditions among areca nut, tobacco and alcohol users in Eastern India: A hospital based study. AB - CONTEXT: With an increase in the abuse of various oral habitual products in India over the past few decades; the incidence of oral potentially malignant conditions as leukoplakia, oral submucous fibrosis and squamous cell carcinoma (SCC) rates have also increased. No recent study has been conducted reporting the scenario of oral cancer and potentially malignant conditions in Eastern India (specifically Kolkata). AIMS: The present study was conducted at Dr. R. Ahmed Dental College, Kolkata during 2010-2011 to find a possible correlation between the effects of the different oral habits, age, sex and the different types of oral mucosal lesions among patients reported to the hospital. This study also enabled us to see the predilection of the various histopathological stages of the lesions for different sites of the oral cavity. SUBJECTS AND METHODS: The study group consisted of 698 patients having either oral potentially malignant or malignant lesion. The control group consisted of 948 patients who had reported to the hospital for different oral/dental problems and had the habit of tobacco, areca nut and/or alcohol usage for at least 1 year. STATISTICAL ANALYSIS: The unadjusted odds ratio, the 95% confidence interval, and the P value were calculated to correlate patients with/without different kinds of habit and having/not having various kinds of oral lesions. RESULTS: Our study shows that for males having the habit of taking smokeless tobacco or mixed habit poses the highest risk for developing SCC. For females, significant risk of developing SCC was found in patients habituated to processed areca nut chewing. CONCLUSION: This study presents probably for the first time in recent years the occurrence of oral potentially malignant and malignant conditions amongst patients having deleterious habits in a hospital based population of Kolkata. PMID- 23798830 TI - c-Myc oncogene expression in selected odontogenic cysts and tumors: An immunohistochemical study. AB - AIM: To investigate the role of c-Myc oncogene in selected odontogenic cysts and tumors. MATERIALS AND METHODS: Ten cases each of ameloblastoma, adenomatoid odontogenic tumor (AOT), odontogenic keratocyst (OKC), dentigerous cyst, and radicular cyst were selected and primary monoclonal mouse anti-human c-Myc antibody was used in a dilution of 1: 50. Statistical Analysis was performed using Mann Whitney U test. RESULTS: 80% positivity was observed in ameloblastoma, AOT and OKC; 50% positivity in radicular cyst and 20% positivity in dentigerous cyst. Comparison of c-Myc expression between ameloblastoma and AOT did not reveal significant results. Similarly, no statistical significance was observed when results of OKC were compared with ameloblastoma and AOT. In contrast, significant differences were seen on comparison of dentigerous cyst with ameloblastoma and AOT and radicular cyst with AOT. CONCLUSION: From the above data we conclude that (1) Ameloblastoma and AOT have similar proliferative potential and their biologic behavior cannot possibly be attributed to it. (2) OKC has an intrinsic growth potential which is absent in other cysts and reinforces its classification as keratocystic odontogenic tumor. PMID- 23798831 TI - Revealing anti-cariogenic efficacy of smokeless tobacco: A pilot study. AB - BACKGROUND: The tobacco plant, Nicotiana tabacum, has been responsible for more deaths than any other herb. However, the literature has also been endowed with its use as "holy herb" since the pre-Columbian era. Used for treating pain, poisonous bites, ulcers, nasal polyps, and basal cell carcinoma; it also acts as an important ingredient of commercially available toothpastes; and even used as tobacco vaccines against Streptococcus species as highlighted in the literature. AIMS AND OBJECTIVES: (1) To elicit the anti-microbial property of tobacco against Streptococcus mutans, if any, in raw smokeless tobacco. (2) To study the relationship of duration and growth inhibition efficacy of smokeless tobacco. MATERIALS AND METHODS: Extracts were prepared by centrifugation of mixed raw smokeless tobacco with Ringer's lactate solution and with saliva. The extracts were placed in wells prepared on Mitis salivarius culture plate and incubated at 37 degrees C for 24 h after 0 h, 1 h, and 2 h of extract preparation. The inhibition zones were measured on the underside of plate using the vernier calipers. RESULTS: Smokeless tobacco has a statistically significant zone of inhibition, which proves its anti-microbial activity against S. mutans. However, the mean zones of inhibition were greater for Ringer's lactate and tobacco group as compared to test samples (saliva and tobacco) with subsequent reduction of inhibition zones with an increase in duration. CONCLUSION: The anti-microbial property of extensive tobacco resources can be utilized from their extracts in order to balance the deterioration it had caused to mankind. PMID- 23798832 TI - Fluorescence in-situ hybridization technique as a diagnostic and prognostic tool in oral squamous cell carcinoma. AB - BACKGROUND AND OBJECTIVES: Early diagnosis and appropriate management are of prime importance for oral squamous cell carcinoma (OSCC) in the present scenario. Molecular changes in OSCC are well documented with the occurrence of a wide range of genetic damage. Identification of the genetic damage in OSCC using various diagnostic aids is mandatory, and one of the important advances in this field is cytogenetics using fluorescence in-situ hybridization (FISH). The aim of the present study is to analyze the genetic alteration in OSCC using FISH as a diagnostic aid. MATERIALS AND METHODS: Peripheral blood was analyzed in 20 clinically and histopathologically proven OSCC cases and 10 healthy controls for chromosomal alteration under standardized conditions. RESULTS: Of the 20 OSCC cases, 7 (35%) cases showed chromosomal alterations. No cases from the control group showed any chromosomal changes. Of the positive cases in OSCC, 30% cases showed increased copy number of cyclin D1 gene and 1 (5%) case showed positivity indicating extra copy of chromosome 11p11.11-q11 region. INTERPRETATION AND CONCLUSION: Increased genetic damage in OSCC which is a prominent feature can be identified by the use of FISH as seen from the present study. The findings suggest that FISH can be used as a diagnostic aid in the detection of genetic changes occurring in OSCC. The present study also suggests the importance of peripheral blood as a medium for assessing cytogenetic damage in OSCC. PMID- 23798833 TI - Art of reading a journal article: Methodically and effectively. AB - BACKGROUND: Reading scientific literature is mandatory for researchers and clinicians. With an overflow of medical and dental journals, it is essential to develop a method to choose and read the right articles. OBJECTIVE: To outline a logical and orderly approach to reading a scientific manuscript. By breaking down the task into smaller, step-by-step components, one should be able to attain the skills to read a scientific article with ease. METHODS: The reader should begin by reading the title, abstract and conclusions first. If a decision is made to read the entire article, the key elements of the article can be perused in a systematic manner effectively and efficiently. A cogent and organized method is presented to read articles published in scientific journals. CONCLUSION: One can read and appreciate a scientific manuscript if a systematic approach is followed in a simple and logical manner. PMID- 23798834 TI - Metastatic tumors to the jaws and oral cavity. AB - Cancer is a disease involving complex multiple sequential irreversible dysregulated processes showing metastasis that results in morbidity and mortality. Metastasis is a complex biological course that begins with detachment of tumor cells from the primary tumor, spreading into the distant tissues and/or organs, invading through the lymphovascular structures followed by their survival in the circulation. Metastatic tumors to the oro-facial region are uncommon and may occur in the oral soft tissues or jawbones. The clinical presentation of metastatic tumors can be variable, which may lead to erroneous diagnosis or may create diagnostic dilemma. Therefore, they should be considered in the differential diagnosis of inflammatory and reactive lesions that are common to the oral region. Most of the literature on oral metastases involves either single case reports or reviews of these reported cases from scattered geographical areas. Hence this present article is an attempt to provide a detailed review of pathogenesis, epidemiological details including clinical and radiographic presentations, microscopic features and treatment of metastatic tumors to the jaws and oral cavity. PMID- 23798835 TI - Human immunodeficiency virus vaccine an update. AB - Since the discovery of acquired immuno deficiency syndrome (AIDS) in late1980s, the spread of human immunodeficiency virus (HIV) has reached pandemic proportions, representing a global developmental and public health threat. Finding of a safe, globally effective and affordable HIV vaccine offers the best hope for the future control of the disease pandemic. Significant progress has been made over the past years in the areas of basic virology, immunology, and pathogenesis of HIV/AIDS and the development of anti-retroviral drugs. However, the search for an HIV vaccine faces formidable scientific challenges related to the high genetic variability of the virus, the lack of immune correlates of protection, limitations with the existing animal models and logistical problems associated with the conduct of multiple clinical trials. Most of the vaccine approaches developed so far aim at inducing cell-mediated immune responses. Multiple vaccine concepts and vaccination strategies have been tested, including DNA vaccines, subunit vaccines, live vectored recombinant vaccines, various prime boost vaccine combinations and vaccine based on broadly neutralizing human anti HIV Antibody 2G12. This article reviews the state of the art in HIV vaccine research, summarizes the results obtained so far and discusses the challenges to be met in the development of a successful HIV vaccine. PMID- 23798836 TI - Hidden keys in stroma: Unlocking the tumor progression. AB - Malignancy is considered as a pathological imbalance of tissue-cell societies, a state that emerges from tumor-host microenvironment in which host participates in induction, selection and expansion of the neoplastic cells. Invasion of these malignancies can be viewed as a derangement in the proper sorting of cell populations, causing a violation of normal tissue boundaries. This violation is carried out by certain stromal cells like carcinoma associated fibroblasts (CAFs), tumor associated macrophage (TAMs), endothelial cells (ECs) leucocytes, bone marrow derived cells, etc. Tumor cells may alter the surrounding stroma and in turn, stromal cells may promote cancer progression and invasion. Thus, this review compares the role of CAFs, TAMs and ECs in tumor microenvironment towards tumor progression. This compilation aims to collate existing literature on stromal cell with particular emphasis on their role in tumor invasiveness and summarize experimental studies, trials and literature of last 10 years collected from pubmed central indexed journals. PMID- 23798837 TI - Clear cell odontogenic carcinoma of maxilla: A case report and mini review. AB - Clear cell odontogenic carcinoma is a rare odontogenic tumor occurring predominantly in posterior mandible during 5(th)-7(th) decades with a female predilection. It is a potentially aggressive tumor, capable of frequent recurrences and loco-regional and distant metastases. Till date, only 73 cases have been reported in the literature. Current case is of a 55-year-old woman with tumor mass extending from canine to molar region on the left maxillary arch. Being locally aggressive tumor with the capacity to metastasize, it demands to be distinguished from other primary and metastatic clear cell tumors of the oral and maxillofacial region. A brief compilation of the reported cases is being attempted in the current article to better understand the behavior of the tumor. PMID- 23798838 TI - Sialolipoma of the parotid gland: Case report with literature review comparing major and minor salivary gland sialolipomas. AB - Sialolipoma is a rare tumor found within both major and minor salivary glands. Here we discuss sialolipoma of the parotid gland and briefly review the English literature. Including our case, a total of 35 sialolipomas have been reported, 18 within major salivary glands and 17 within minor salivary glands. Major gland sialolipomas most often are presented in the parotid gland (77%) and those from minor glands were most often seen in the palate (41%). All lesions were well circumscribed and contained mature adipose tissue intimately admixed with benign salivary gland components. Ductal dilatation was found in 100% of minor salivary gland sialolipomas but in only 28% of major salivary gland tumors. Nerve entrapment has also rarely been noted in major salivary glands (14%) whereas myxoid degeneration has been identified in rare minor salivary glands tumors (13%). Treatment is surgical excision and is curative with no reports of recurrence. PMID- 23798839 TI - Adenoid cystic carcinoma on the dorsum of the tongue. AB - Adenoid cystic carcinoma is a relatively rare epithelial tumor of the salivary glands accounting for about 5-10% of all salivary gland neoplasms. Approximately, 31% of salivary gland neoplasms affect minor salivary glands particularly the palate. It involves tongue in only 19.8% of cases and even rarely the dorsum of the tongue. We report such a rare case that affected dorsum of the tongue in a 45 year-old-female patient. PMID- 23798840 TI - Primary clear cell carcinoma of parotid gland: Case report and review of literature. AB - Clear cell carcinoma (CCC) is a rare low-grade carcinoma that represents only 1% to 2% of all salivary glands tumors. The finding of a clear cell tumor in a parotid gland involves the necessity of differential diagnosis between primary clear cell parotid tumors and metastases, mainly from kidney. The biological behavior is not very aggressive and development, which is very slow, is usually asymptomatic and indeed, the tumor often reaches considerable dimensions before being diagnosed. The treatment of choice is the surgical excision. There are rare cases of local recurrence and distant metastases. The aim of this article is to report a primary CCC in the parotid gland that microscopically closely resembled a metastatic CCC of renal origin, making microscopic differentiation difficult. PMID- 23798841 TI - Multisystem Langerhans cell histiocytosis presenting as an oral lesion. AB - Langerhans cell histiocytosis (LCH) is a rare proliferative disorder in which the pathologic Langerhans cells infiltrate and destroy the tissues. Patients with LCH present varied clinical manifestations. Cutaneous lesions in LCH manifest as vesiculopapular eruptions that often mimic various infectious diseases particularly in infants. We present a case of a female infant with an ulcerative lesion intraorally. The baby was asymptomatic otherwise. A detailed history revealed the presence of cutaneous lesions that was overlooked by her parents. CONCLUSION: This report tries to briefly discuss the current concepts regarding the etiology of LCH. An attempt has been made to emphasis the need for a through systemic examination. The protocol of investigative procedures to be adopted in LCH is also discussed. PMID- 23798842 TI - Clear cell variant of squamous cell carcinoma of skin: A report of a case. AB - Clear cell squamous cell carcinoma (SCC) is a rare variant of SCC of skin in which ultraviolet radiation has been suggested as possible etiology. This case is that of a 62-year-old male concrete block maker/bricklayer who presented with a 6 months history of a non-healing ulcer on the left side of his face. Histology showed features of malignant epithelial neoplasm composed of islands of large oval to polyhedral malignant squamous cells with eosinophilic to amphophilic cytoplasm and vesicular nuclei and there were areas showing clear cell differentiation and isolated areas of keratin pearl formation. The lesion was also negative for periodic acid schiff, mucicarmine, and alcian blue stains but was strongly positive for AE1/AE3 (immuno-stain). This case showed an aggressive and bizarre clinical presentation but more report of cases are needed to have a better characterization of the clinical presentation and prognosis of this variant of SCC. PMID- 23798843 TI - Amelanotic melanoma of the tongue. AB - Malignant melanoma of the oral cavity is a rare lesion, with an incidence of about 0.2% to 0.8% of all melanomas. Melanoma of tongue is still rarer and represents less than 2% of oro-nasal melanoma cases. We report a rare case of amelanotic melanoma of the tongue in a young man. The importance of consideration of melanoma in the differential diagnosis of oral cavity lesions is discussed since mucosal melanoma carries a bad prognosis and early diagnosis is vital. PMID- 23798844 TI - Keloid: A case report and review of pathophysiology and differences between keloid and hypertrophic scars. AB - Keloids extend beyond the borders of the original wound invading normal skin. Usually appear as firm nodules, often pruritic and painful, and generally do not regress spontaneously. Most often occur on the chest, shoulders, upper back, back of the neck, and earlobes. The aim of the paper is to discuss a case of keloid, review the pathophysiology and also to highlight the differences between keloid and hypertrophic scars. A 26-year-old female complains of swelling on ear lobe since 3 years. Swelling was firm, non-tender, dumbell-shaped with central wooden stick still present, measuring 3 cm in diameter medial to the inferior part of the helix. A clinical diagnosis of keloid was given. Histopathological sections showed hyperorthokeratinized stratified squamous epithelium with deep dermal sclerosis showing large dense bundle of glassy collagen diagnostic of Keloid. Special stain like Van Gieson's was used to identify collagen bundles. The sections were also subjected to immunohistochemical markers such as alpha-SMA (alpha Smooth muscle actin), Desmin, and S-100. Despite decades of research, the pathophysiology of keloids remains incompletely understood. Recent studies indicate that TGF-beta (Transforming growth factor beta) and PDGF (Platelet derived growth factor) play an integral role in the formation of keloids. In future, development of selective inhibitors of TGF-beta might produce new therapeutic tools with enhanced efficacy and specificity for the treatment of keloids. Patients with a previous history of keloid or other risk-factors should avoid body piercing and elective cosmetic procedures. Keloid scars should be sent for histopathology in order to avoid missing potentially malignant conditions particularly those showing unusual features. PMID- 23798845 TI - Intraosseous myofibroma of mandible: A rarity of jaws: With clinical, radiological, histopathological and immunohistochemical features. AB - Myofibroma is an uncommon benign mesenchymal neoplasm composed of myofibroblasts, but it can be confused with more aggressive spindle cell tumors. Solitary myofibroma is common in soft tissues of head and neck, but rare in the jaw bones with only 38 cases of central myofibroma of mandible reported in English medical literature. When encountered in the jaws, lesions exhibit clinical and radiographic features suggestive of odontogenic cysts/tumors or other neoplastic conditions. We hereby present the 39(th) case of intraosseous myofibroma of the mandible which had been reported to our institution. A 16-year-old male reported with a chief complaint of swelling in the right side of face. Intraorally there was a firm, nontender swelling in the right buccal aspect of the mandible. Radiologically the lesion was osteolytic, destroying the buccal cortical plate. Histologically, characteristic biphasic pattern of myofibroma was noticed. Immunoreactivity was positive for vimentin and alphaSMA but negative for desmin, thus confirming our diagnosis. The patient was treated by local-wide surgical excision of the lesion. A 3-year follow-up revealed no signs of recurrence. Occurrence of myofibroma involving the jaw bones is common in the younger age groups and represents a unique diagnostic and therapeutic challenge. Differentiating this lesion from other benign and malignant neoplasms is crucial in deciding between a radical and a conservative treatment approach. PMID- 23798846 TI - Intraosseous lipoma of mandible presenting as a swelling. AB - Lipomas are the most common form of benign mesenchymal tumors and are composed of mature adipocytes. They can occur anywhere in the body where fat is found and thus, called as the 'universal tumor' or the 'ubiquitous tumor'. Intraosseous lipomas (IOL) are among the rarest (0.1%) of primary bone tumors and are very rarely seen in head and neck bones. They have been subdivided based on the site of origin within bone, into intramedullary and intracortical. Of the two, few cases of intramedullary lipoma have been reported intraorally and none of the latter. Intraosseous lipomas are usually asymptomatic and are detected incidentally on radiographs taken for other complaints. Here, we report a case of intraosseous lipoma in the mandible presenting as a large swelling. PMID- 23798847 TI - Malignant peripheral nerve sheath tumor of facial nerve: Presenting as parotid mass. AB - Malignant peripheral nerve sheath tumor (MPNST) is very uncommon tumor of parotid gland and it is an uncommon spindle cell sarcoma accounting for approximately 5% of all soft-tissue sarcoma. There is strong association between MPNSTs and neurofibromatosis (NF-1) and previous irradiation. Structural abnormality of chromosome 17 is associated with NF-1 and so MPNST. We present a case of a 78 year-old male presenting with slowly growing parotid mass who underwent tumor resection. PMID- 23798848 TI - Ellis-van Creveld syndrome: A rare clinical entity. AB - Ellis-van Creveld (EVC) syndrome is a genetic disorder with autosomal recessive transmission, which may clinically present as small stature, short limbs, fine sparse hair, hypoplastic fingernails, multiple musculofibrous frenula, conical teeth, hypoplasia of the enamel, hypodontia, and malocclusion. Heart defects, especially abnormalities of atrial septation, have been found in about 60% of cases. The mutation in EVC and EVC2 gene is responsible for this syndrome. The presence of multiple orodental findings makes this syndrome important for dentists. The aim of this article is to present a rare case of EVC syndrome in a 10-year-old girl along with the review of literature. PMID- 23798849 TI - Clear cell hidradenoma: An unusual tumor of the oral cavity. AB - Clear cell hidradenoma (CCH) is a benign tumor of skin appendage. This lesion is commonly seen on the head, face, extremities and rarely in the oral cavity. The clinical appearance of this lesion is not specific and differential diagnosis from other lesions, both benign and malignant, can only be made after complete removal of the lesion. Histopathology of these lesions is often confused with tumors of salivary glands because of their striking resemblance. In this case of oral CCH, histopathology was an important aid in the diagnosis and hence, CCH should be considered in the differential diagnosis of lesions of the oral cavity. PMID- 23798850 TI - Disseminated histoplasmosis with oral and cutaneous manifestations. AB - Histoplasmosis is a systemic mycotic infection caused by the dimorphic fungus, Histoplasma capsulatum. Systemic histoplasmosis has emerged as an important opportunistic infection in human immunodeficiency virus (HIV) patients and those in endemic areas. Reported cases of histoplasmosis have been low in India with less than 50 cases being reported. We are reporting a case of disseminated histoplasmosis with oral and cutaneous involvement in an HIV seronegative patient. PMID- 23798851 TI - Histomorphological array in odontogenic keratocyst. PMID- 23798852 TI - Molluscum contagiosum. PMID- 23798853 TI - Granular cell tumor of the tongue: Report of a case. AB - Granular cell tumor (GCT) is a benign lesion characterized by the accumulation of plump cells with abundant granular cytoplasm. The formation of a granular cell tumor is a neoplastic process and the lesions formed are of neural derivation, as supported by immunophenotypic and ultra structural evidence. This type of tumor has been found to be both benign and malignant although malignancy is rare and comprises only 2% of all granular cell tumors. Here we report a case of GCT in a 40 year old male patient on the posterolateral border of tongue. PMID- 23798854 TI - Epidermoid cyst localized in the palatine tonsil. AB - Epidermoid and dermoid cysts are benign, developmental lesions that can be encountered anywhere in the body. Our literature search did not result in a finding of any report of an epidermoid cyst located in the palatine tonsils. This is a report of a 42-year-old female patient who underwent a tonsillectomy for diagnostic purposes because of an epidermoid cyst arising from the tonsil which was confirmed by histology. PMID- 23798855 TI - Spindle cell lipoma of the tongue: A case report of unusual occurrence. AB - Spindle cell lipoma (SCL) is a benign lipomatous tumor predominantly occurring at the posterior neck and shoulder area. Face, forehead, scalp, cheek, perioral area, and upper arm are less common sites. In oral cavity, it is a relatively uncommon neoplasm, particularly in tongue, which is relatively devoid of fat cells. We present a case report of SCL located on the left lateral border of the tongue in a 64-year-old Caucasian female patient with diabetes mellitus type 2 and arterial hypertension. PMID- 23798856 TI - Leimyosarcoma of the buccal mucosa and review of literature. AB - Leiomyosarcoma (LMS) is an uncommon malignant spindle cell tumor of the head and neck region. The occurrence is particularly rare in the buccal mucosa of the oral cavity. It is a rapidly growing tumor with aggressive behavior and poor prognosis. METHOD: This article presents a rare case of primary leimyosarcoma of the buccal mucosa in a 35 year old female and retrospective analysis of primary oral LMS published in the English literature since past 20 years is done. Diagnosis was confirmed by immunohistochemistry profile showing positivity for vimentin, smooth muscle actin (SMA), high proliferative index displayed by Ki-67, focal positivity for pan-CK and negativity for S-100. CONCLUSION: Based on the presence of malignant spindle cells showing positivity for vimentin and SMA, a diagnosis of leiomyosarcoma was made. PMID- 23798857 TI - Ameloblastic fibroma in one-year-old girl. AB - Ameloblastic fibroma (AF) is a relatively rare, slow growing benign mixed odontogenic tumor, comprising of 1.5-4.5% of all odontogenic tumors. It is usually asymptomatic except for the eventual expansion of the jaw. AFs are most common in adolescents and young adults, mostly affecting the mandible as a well defined uni or multilocular radiolucency. The effective surgical treatment includes enucleation and curettage of the surrounding bone and removal of the affected teeth. Although recurrence of AF is rare, a long term follow up is recommended. This report describes a 1-year-old girl with AF in the mandible and discusses its clinical, radiographic and histological findings. PMID- 23798858 TI - Florid cemento-osseous dysplasia. AB - Floridcemento-osseous dysplasia (FCOD) is a"fibro-osseouslesion" that characteristically affects the jaw bones of the middle-aged with multi-quadrant radiopaque cementum-like masses. In thepast, the condition was known with a variety of names causing confusion in diagnosis and treatment. The condition is usually asymptomatic and needs no treatment as such. The diagnosis of FCOD is made on the basis of typical clinico-radiological features and biopsy is usually not recommended due to the risk of postoperative infection. This paper reports a rare case of FCOD affecting mandible bilaterally in a forty-two years old woman. PMID- 23798860 TI - Prophylactic antibiotic: The need for clear guidelines. PMID- 23798859 TI - Antibiotic prophylaxis for transurethral urological surgeries: Systematic review. AB - The use of antibiotic prophylaxis to prevent urinary tract infection and bacteremia (sepsis) following endoscopic urologic procedures is a controversial topic. Evidence in the literature revealed that urological instrumentation is associated with increased incidence of urinary tract infection and bacteremia. The aim of this review is to evaluate the effectiveness of antibiotic prophylaxis in reducing the risk of urinary tract infection in patients who had transurethral urological surgeries. We have selected all RCTs of adult population who underwent all different types of transurethral urological surgery, including cystoscopy, transurethral resection of prostate and transurethral resection of bladder tumor, and received prophylactic antibiotics or placebo/no treatment. At first, more than 3000 references were identified and reviewed; of which 42 studies with a total of 7496 patients were included in the final analysis. All those trials were analyzing antibiotic prophylaxis versus placebo/no treatment, and they were significantly favoring antibiotic use in reducing all outcomes, including bacteriuria (RR 0.36, 95% CI 0.29 to 0.46, P < 0.0001) with moderate heterogeneity detected (I(2) 48%), symptomatic UTI (RR 0.38, 95% CI 0.28 to 0.51, P < 0.0001) with no significant heterogeneity was detected (I(2)= 17%), bacteremia (RR 0.43, 95% CI 0.23 to 0.82, P < 0.0001) with no noted heterogeneity (I(2) = 0%), and fever >=38.5 Celsius (RR 0.41, 95% CI 0.23 to 0.73, P = 0.003); also, there was no noted heterogeneity (I(2) = 0%). However, using antibiotic prophylaxis did not reduce the incidence of low grade temperature (RR 0.82, 95% CI 0.61 to 1.11, P = 0.20) or in moderate grade temperature (RR 1.03, 95% CI 0.71 to 1.48, P = 0.89). Antibiotic prophylaxis appears to be an effective intervention in preventing urinary tract infections and its sequels following transurethral urological surgeries in patients with preoperative sterile urine. PMID- 23798861 TI - Increased rate of positive biopsies using a combination of MR-Tomography, spectroscopy and diffusion-weighted magnetic resonance imaging prior to prostate biopsies in patients with persistent elevated prostate-specific antigen values: A retrospective analysis. AB - PURPOSE: Persistently elevated prostate-specific antigen (PSA) values following negative biopsies result in a diagnostic dilemma. In order to improve detection rates in patients with former negative biopsies and persistently elevated PSA values, magnetic resonance tomography (MRT), magnetic resonance spectroscopy (MRS), and diffusion-weighted magnetic resonance imaging (DW-MRI) were performed prior to prostate rebiopsies. MATERIALS AND METHODS: Over a 14-month period, 67 patients (mean age of 66 years) with a history of 1-5 negative biopsies underwent endorectal magnetic resonance imaging (MRI) using T2-weighted MRT MRS and DW-MRI before an additional prostate biopsy was performed. Subsequently, 5 contrast enhanced transrectal ultrasound-guided biopsies were performed according to a 10 core systematic scheme. Out of the 67 men, 25 patients had positive biopsies and opted for radical prostatectomy. Histological evaluation of cancer localization, PSA, diameters of primary tumors, numbers and diameters of satellite tumors, prostate volume, and staging pathology was performed. These findings were compared with MRI and MRS results. RESULTS: Serum PSA levels ranged from 3.1 to 19.5 g/ml (median level of 7.96 ng/ml). After the 25 patients underwent radical prostatectomy, analysis of 20 whole-mount sections of 25 radical retropubic prostatectomy (RPE) specimens presented results agreeing with the tumor location from MRI and MRS data. CONCLUSIONS: The aim of image-guided diagnostics should be to provide more critical information prior to biopsy. Furthermore, the acquisition of such data is important for better risk stratification in therapeutic decisions. PMID- 23798863 TI - A step towards refining prognostication in individual patients with bladder cancer. PMID- 23798862 TI - CD10 and CA19.9 immunohistochemical expression in transitional cell carcinoma of the urinary bladder. AB - BACKGROUND: Transitional cell carcinoma of the bladder is the most common malignancy affecting the urinary tract ranking the 5(th) among males and the 9(th) among females' cancers in Iraq. The prognosis depends largely on the histological grade and stage of the tumor at diagnosis; however, there is no reliable parameter predicting the risk of recurrence or progression; molecular and immunological markers may be required to estimate the individual prognosis of patients as well as for effective diagnosis and treatment. OBJECTIVES: To evaluate CD10 and CA19.9 immunohistochemical expression in transitional cell carcinoma of the urinary bladder and to correlate this expression with the grade and stage of the tumor. MATERIALS AND METHODS: This study was retrospectively designed. Forty-nine cystoscopy specimens of urothelial carcinoma of the bladder were retrieved from the archival materials of the Specialized Surgical Hospital and Al-Khadhmiya Teaching Hospital in Baghdad for the period from January 2010 to June 2011. Three sections of 5-MUm thickness were taken from each case. One section was stained with Hematoxylin and Eosin; the other two were stained immunohistochemically with CA19.9 and CD10. RESULTS: Immunohistochemical expression of CA19.9 and CD10 had a significant correlation with WHO 2004 grade of urothelial carcinoma. There was no significant correlation between CA19.9 and CD10 immunohistochemical expression with stage. CONCLUSIONS: CA19.9 and CD10 immunohistochemical expression could be of value in assisting the differentiation between high and low-grade urothelial carcinoma cases and consequently in determining the prognosis in such cases. PMID- 23798864 TI - Management of impacted proximal ureteral stone: Extracorporeal shock wave lithotripsy versus ureteroscopy with holmium: YAG laser lithotripsy. AB - OBJECTIVE: PROSPECTIVE EVALUATION OF THE EFFICACY AND SAFETY OF THE EXTRACORPOREAL SHOCK WAVE LITHOTRIPSY (SWL) AND URETEROSCOPY WITH HOLMIUM: YAG laser lithotripsy (URSL) as a primary treatment for impacted stone in the proximal ureter. PATIENTS AND METHODS: A total of 82 patients with a single impacted stone in the proximal ureter were included in the study. Patients were allocated into two groups according to patient preference for either procedure. The first group included 37 patients who were treated by SWL and the second group included 45 patients treated by URSL. The preoperative data and treatment outcomes of both procedures were compared and analyzed. RESULTS: There was no difference as regards to patient and stone characters between the two groups. There was significantly higher mean session number and re-treatment rate in the SWL group in comparison to URSL group (1.5 +/- 0.8 vs. 1.02 +/- 0.15 session, and 43.2% vs. 2.2%, respectively). At one month, the stone-free rate of the URSL group was statistically significantly higher than that of the SWL group (80% vs. 67.6%, respectively). The stone-free rate at three months was still higher in the URSL group, but without statistically significant difference (80.2% vs. 78.4%, respectively). There was no statistically significant difference in the rate of complications between the SWL and URSL (24.3% vs. 15.6%, respectively). CONCLUSION: Both procedures can be used effectively and safely as a primary treatment for impacted stone in the proximal ureter; however, the URSL has a significantly higher initial stone-free rate and lower re-treatment rate. PMID- 23798865 TI - Chordee without hypospadias: Operative classification and its management. AB - CONTEXT: Developing countries. AIMS: To propose a operative classification of Chordee without hypospadias (CWH) with its management. SETTINGS AND DESIGN: Tertiary referral centre; Retrospective study from January 2000 to January 2011. MATERIALS AND METHODS: Total 26 patients were classified peroperatively into sixtypes (A: Cutaneous chordee-> Degloving skin and dartos (1/26); B: Fibrous chordee-> chordectomy (4/26);C: Corporocavernosalchordee-> Corporoplasty +/- Urethral mobilization (4/26); D: Urethral tethering with Hypoplastic urethra-> Urethral mobilization +/- urethral reconstruction because of hypoplastic urethra (14/26); E: Congenital short urethra-> excision of urethra from the meatus and urethroplasty (2/26); and F: Complex chordee-> Degloving +/- Corporoplasty +/- urethroplasty (1/26 patients). The follow-up over 6 months to 9 years were analyzed. STATISTICAL ANALYSIS: SPSS soft ware version 17.0 for Windows. RESULTS: The mean age of surgery was 5.33 +/- 0.11 years. The success rate defined on uroflowmetry and voiding cystourethrography was 65.6%. The coronal urethra cutaneous fistula developed in 26.9% (7/26) {including 7.7% (3/26) of associated metal stenosis}. The urethral stricture developed in 3.8% (1/26). CONCLUSIONS: CWH needs stepwise surgical management. The operative classification may help in better understanding and management of this difficult entity. Meticulous tissue handling and urethroplasty is needed for good and promising results. PMID- 23798866 TI - Do the values of prostate specific antigen obtained from fresh and dried urine reflect the serum measurements? AB - AIM: To investigate if free PSA (fPSA) and total PSA (tPSA) values obtained from simultaneously collected urine, fresh and dried on filter paper, reflect the serum free and total PSA. MATERIALS AND METHODS: The sera and 20 cc first voided urine from 33 consecutive men aged between 40 and 84 (mean 61 +/- 12), were collected in the morning and delivered to the laboratory. Three different aliquots of 100 microgram urine were taken with automatic pipette and dropped on 3 certain areas of a filter paper and allowed to dry for each patient. On each paper, borders of dried urine were marked. PSA values were obtained from the sera and fresh urine samples and recorded. Later on particular days dried urine samples were dissolved and eventually PSA values were derived and recorded again. The results were compared to each other. Correlations were evaluated by using an SPSS statistics program. RESULTS: Serum PSA values correlated weakly (r < 0.24) with fresh and dried urine PSA values. While PSA in fresh and dried urine samples showed strong correlation (0.5 < r < 0.74), a very strong correlation (r > 0.75) among PSA values of dried urine samples of 1-day, 7- and 28-days, were seen. CONCLUSIONS: We conclude that PSA values obtained from fresh and dried urine could not reflect serum PSA values. But, because dried urine on a filter paper can be stable for years, it could be used for forensic purposes. PMID- 23798867 TI - Urinary prostate specific antigen, usefulness is still a matter of controversy. PMID- 23798868 TI - Weekly intravesical bacillus Calmette-Guerin (BCG) alternating with epirubicin in Ta and T1 urothelial bladder cancer: An approach to decrease BCG toxicity. AB - CONTEXT: Bacillus Calmette-Guerin (BCG) therapy is the standard treatment for nonmuscle-invasive bladder cancer (NMIBC). However, its toxicity is a major concern. AIM: If we reduce the number of BCG doses by half and replace the second half with epirubicin, we may have a lower toxicity while maintaining the same efficacy of BCG. To test this hypothesis, we conducted this study as an update of our previous report. SETTING AND DESIGN: The study included 607 patients with Ta and T1 NMIBC between January 1994 and December 2008. MATERIALS AND METHODS: After transurethral resection of bladder tumor (TURBT), the patients received weekly doses of 120 mg BCG alternating with 50 mg epirubicin for six weeks (three weekly doses of each). Maintenance was given. Recurrence, progression rates, and toxicity were assessed. End points were progression, recurrence, and cancer specific survival. RESULTS: A total of 532 patients were eligible for evaluation (mean age: 58 years; median follow-up: 45 months). Of these, 291 (55%) were free, 157 (29.5%) showed recurrence, and 84 (15.8%) showed muscle-invasive progression. Toxicity developed in 221 patients. These were mild in the majority (167), whereas 10 developed hematuria, 30 severe cystitis, and five systemic complications. The rate of permanent therapy discontinuation was 3.8%. STATISTICAL ANALYSIS USED: SPSS package version 16 and Kaplan-Meier curves were used to evaluate survival. CONCLUSIONS: Reducing the frequency of BCG instillations by half and replacing the second half with epirubicin results in a similar efficacy and a lower toxicity compared with historical cases receiving BCG alone. However, further trials are required to support these results. PMID- 23798869 TI - Intravesical bacillus Calmette-Guerin for bladder cancer: What is known? What is not? What is next? PMID- 23798870 TI - Laparoscopy-assisted orchiopexy versus laparoscopic two-stage fowler stephens orchiopexy for nonpalpable testes: Comparative study. AB - BACKGROUND/PURPOSE: To assess the outcome of the primary laparoscopy-assisted orchiopexy (LAO) and the laparoscopic two-stage Fowler Stephens orchiopexy (FSO) for managing patients with nonpalpable testis in terms of safety, feasibility and efficacy. MATERIALS AND METHODS: This study included 94 patients (110 nonpalpable testes) who underwent laparoscopy at King Khalid University Hospital, Riyadh between July 1998 and June 2012. Patients were evaluated postoperatively to check the location and size of testes and to exclude any other complications. RESULTS: Mean age at presentation was 24+/-19 months (9-96 months). Orchiectomy was done for 5 atrophic testes. 36 open orchiopexy was done for 29 canalicular testes and 7 peeping testes. 35 LAO were done for 1 canalicular testis, 5 peeping testes, 16 low intraabdominal testes and 13 high intraabdominal testes. 34 FSO were done for 23 high intraabdominal testes, 9 low intraabdominal testes and 2 peeping testes. Median follow up was 12 months (1-84 months) and 6 patients were lost to follow up. The overall success rates for LAO and FSO were 88% and 63%, respectively. Overall testicular atrophy rates were 3% and 30% for LAO and FSO, respectively (OR 0.08 [95% CI, 0.01-0.69], P = 0.006). For high intraabdominal testes, the atrophy rates were 3% and 20% for LAO and FSO, respectively (OR 0.14 [95% CI, 0.02-1.21, P = 0.049).Testicular displacement rates were 9% and 7% for LAO and FSO, respectively (OR 1.5, 95% CI, 0.24-9.59, P = 0.514). CONCLUSIONS: Laparoscopy provides a safe and accurate modality for diagnosing and managing patients with nonpalpable testes. LAO appears to be feasible and effective in management of high intraabdominal testes. Further well-conducted comparative studies are needed. PMID- 23798871 TI - Composite pheochromocytoma-ganglioneuroma of the adrenal gland: A case report with immunohistochemical study. AB - Composite tumors of the adrenal medulla consisting of pheochromocytoma and ganglioneuroma are rare tumors accounting for less than 3% of all sympathoadrenal tumors. These tumors display more than one line of differentiation in which normal and neoplastic chromaffin cells are capable of differentiating into ganglion cells under the influence of nerve growth factors. To the best of our knowledge, we report the second case with a composite tumor of the adrenal medulla in a normotensive patient from India. PMID- 23798872 TI - Multilocular cystic renal cell carcinoma a diagnostic dilemma: A case report in a 30-year-old woman. AB - Multilocular cystic renal cell carcinoma (MCRCC), also known as multilocular clear cell renal cell carcinoma (RCC), is a rare cystic tumor of the kidney with an excellent outcome. It occurs in about 3.1-6% of the conventional RCC. It is usually included in the group of tumors of undetermined malignant potential with low nuclear grade. We present a case of MCRCC in a 30-year-old female patient presenting incidentally as an apparently benign-looking multicystic space occupying lesion in the upper pole of right kidney. Right-sided simple nephrectomy was performed, and on histopathologic examination it was found to be MCRCC, stage 1 with Fuhrman nuclear grade 1. Immunohistochemistry with epithelial membrane antigen and vimentin confirmed the diagnosis. PMID- 23798873 TI - Simultaneous renal clear cell carcinoma and gastrointestinal stromal tumor in one case. AB - Renal cell carcinoma is a tumor in kidney, while gastrointestinal stromal tumors are localized in the stomach and small intestine. They seldom occur simultaneously in sporadic case, both of which were suspective to sunitinib, a tyrosine kinases (RTKs) inhibitor. Our current case is novel in that concurrent RTK-related tumors are involved in one case. One possible explanation is the presence of some activating mutations. PMID- 23798874 TI - Umbilical cord prolapsed through urethra: An unusual presentation of a vesico uterine fistula. AB - Umbilical cord prolapse occurs when a loop of cord is present below the presenting part when the amniotic membranes are ruptured. The incidence is 0.2% of total births. The case presented here is unusual because the definition of cord prolapse cannot be applied to it and the lady did not complain of any history of urinary incontinence or hematuria. The presentation of umbilical cord through maternal urethra led to the speculation of an opening between the anterior uterine wall and the bladder. Fetal demise was diagnosed by abdominal ultrasound. At laprotomy, a communication was found between the bladder and the uterus thus letting the cord traverse through the bladder. PMID- 23798875 TI - Transmesocolic robotic extended pyelolithotomy of a large gas-containing renal stone: Case report and review of the literature. AB - We present the fifth case in the world literature of a gas-containing urinary stone. Our patient is a 31-year-old woman referred for left flank pain and gross hematuria who was noted on imaging to have a 6.5 cm left renal pelvis stone containing gas. Cultures revealed Escherichia coli from the urine and stone material. Chemistry revealed underlying gouty diathesis. The stone was removed using robotic extended pyelolithotomy. Overall, renal function remained unchanged while drainage improved on nucleotide renography. Review of the world literature suggests that gas-containing renal stones are invariably associated with emphysematous pyelonephritis commonly caused by E. coli and Klebsiella. Contributing factors to gas-containing stone formation include urinary stasis, metabolic mineral derangement and, in a minority of the cases, diabetes. PMID- 23798876 TI - An abnormally large prostatic utricle cyst associated with unilateral renal agenesis. AB - Prostatic utricle cyst is an uncommon congenital disorder associated with urogenital anomalies. We present a case of an abnormally large prostatic utricle cyst filling the whole of the abdominal cavity with unilateral renal agenesis in an 8-year-old male child. PMID- 23798877 TI - New triterpenoid acyl derivatives and biological study of Manilkara zapota (L.) Van Royen fruits. AB - beta-amyrin-3-(3'-dimethyl) butyrate, a new natural compound was isolated from the fruits of Manilkara zapota (L.) Van Royen, in addition to lupeol-3-acetate and 4-caffeoylquinic acid (cryptochlorogenic acid). The structures of these compounds were identified using different spectral methods (IR, MS, UV, (1)H-NMR, (13)C-NMR and 2D-NMR). The alcoholic and aqueous extracts of the unripe fruits, in addition to their aqueous homogenate exhibited antioxidant, antihyperglycemic and hypocholesterolemic activities. PMID- 23798878 TI - The effects of unripe grape extract on systemic blood pressure, nitric oxide production, and response to angiotensin II administration. AB - BACKGROUND: Hypertension is the most common disease in the world. In Iranian folk medicine, unripe grape juice has been used as antihypertention remedy, but no data is documented for this popular belief. This study was designed to determine the effect of unripe grape extract (UGE) on blood pressure and the response to angiotensin II in rat. MATERIALS AND METHODS: Unripe grape was collected, air dried, and extracted and concentrated. Four groups of Wistar rats received single doses of 125, 250, and 500 mg/kg of UGE or saline, respectively. The direct blood pressure and the serum nitrite level were measured one hour post UGE administration. The animals also were subjected to the infusion of various angiotensin II concentrations (100, 300, and 1000 MUg/kg/min), and blood pressure was determined. RESULTS: Mean arterial, systolic, and diastolic pressures (MAP, SP, and DP) in all UGE treated groups were less than the control group, but only at the dose of 125 mg/kg (Group 1) they were significantly different (P < 0.05). The level of nitrite in groups 1-3 were significantly greater than the control group (P < 0.05). No significant differences were detected for the MAP, SP, and DP to different concentrations of angiotensin II among these groups. CONCLUSION: UGE potentially attenuate MAP, SP, and DP via vasodilatation induced by nitric oxide production. PMID- 23798879 TI - Insulin secretion enhancing activity of roselle calyx extract in normal and streptozotocin-induced diabetic rats. AB - BACKGROUND AND OBJECTIVE: Our recent study revealed the antihyperglycemic activity of an ethanolic extract of roselle calyxes (Hibiscus sabdariffa) in diabetic rats. The present study had, therefore, an objective to investigate the mechanism underlying this activity. MATERIALS AND METHODS: Male Sprague Dawley rats were induced to be diabetes by intraperitoneal injection of 45 mg/kg streptozotocin (STZ). Normal rats as well as diabetic rats were administered with the ethanolic extract of H. sabdariffa calyxes (HS-EE) at 0.1 and 1.0 g/kg/day, respectively, for 6 weeks. Then, blood glucose and insulin levels, at basal and glucose-stimulated secretions, were measured. The pancreas was dissected to examine histologically. RESULTS: HS-EE 1.0 g/kg/day significantly decreased the blood glucose level by 38 +/- 12% in diabetic rats but not in normal rats. In normal rats, treatment with 1.0 g/kg HS-EE increased the basal insulin level significantly as compared with control normal rats (1.28 +/- 0.25 and 0.55 +/- 0.05 ng/ml, respectively). Interestingly, diabetic rats treated with 1.0 g/kg HS EE also showed a significant increase in basal insulin level as compared with the control diabetic rats (0.30 +/- 0.05 and 0.15 +/- 0.01 ng/ml, respectively). Concerning microscopic histological examination, HS-EE 1.0 g/kg significantly increased the number of islets of Langerhans in both normal rats (1.2 +/- 0.1 and 2.0 +/- 0.1 islet number/10 low-power fields (LPF) for control and HS-EE treated group, respectively) and diabetic rats (1.0 +/- 0.3 and 3.9 +/- 0.6 islet number/10 LPF for control and HS-EE treated group, respectively). CONCLUSION: The antidiabetic activity of HS-EE may be partially mediated via the stimulating effect on insulin secretion. PMID- 23798880 TI - Immune-stimulatory and anti-inflammatory activities of Curcuma longa extract and its polysaccharide fraction. AB - BACKGROUND: While curcuminoids have been reported to possess diverse biological activities, the anti-inflammatory activity of polar extracts (devoid of curcuminoids) of Curcuma longa (C. longa) has seldom been studied. In this study, we have investigated immune-stimulatory and anti-inflammatory activities of an aqueous based extract of C. longa (NR-INF-02) and its fractions in presence and absence of mitogens. MATERIALS AND METHODS: Effects of NR-INF-02 (TurmacinTM, Natural Remedies Pvt. Ltd., Bangalore, India) on proliferation, nitric oxide (NO), monocyte chemotactic protein-1 (MCP-1), interleukins (ILs) and prostaglandin (PGE2) levels of mouse splenocytes and mouse macrophage (RAW264.7) cells were determined. RESULTS: NR-INF-02 increased splenocytes number in presence and absence of lipopolysaccharide (LPS) or concanavalin A. Treatment of NR-INF-02 showed a significant increase of NO, IL-2, IL-6, IL-10, IL-12, interferon (IFN) gamma, tumor necrosis factor (TNF) alpha and MCP-1 production in unstimulated mouse splenocytes and mouse macrophages. Interestingly, NR-INF-02 showed potent inhibitory effect towards release of PGE2 and IL-12 levels in LPS stimulated mouse splenocytes. Further, NR-INF-02 was fractionated into polysaccharide fraction (F1) and mother liquor (F2) to study their immune modulatory effects. F1 was found to be more potent than F2 toward inhibiting PGE2 and IL-12 in LPS stimulated splenocytes. CONCLUSION: Present findings revealed the novel anti-inflammatory property of NR-INF-02 and its polysaccharide fraction by inhibiting the secretion of IL-12 and PGE2 in vitro. PMID- 23798881 TI - Secondary metabolites and bioactivities of Albizia anthelmintica. AB - BACKGROUND: Albizia species are rich in phenolics and terpenes in the different plant organs. They are widely used in traditional Chinese medicine. So this study investigated the phytochemical and biological activities of Albizia Anthelmintica. MATERIALS AND METHODS: Column chromatography has been performed for the isolation of compounds. Bioactivity studies of A. anthelmintica leaves were carried out on aqueous ethanol extract and some pure compounds were tested for their antioxidant activities. RESULTS: Eight compounds have been isolated for the first time from A. anthelmintica. The aqueous ethanol extract of A. anthelmintica showed moderate anti-inflammatory activity and significant for both analgesic and antioxidant activities. Quercetin-3-O-beta-D-glucopyranoside, kaempferol-3-O-beta-D-glucopyranoside, kaempferol-3-O-(6beta-O-galloyl-beta-D glucopyranoside and quercetin-3-O-(6beta-O-galloyl-beta-D-glucopyranoside) exhibited potent antioxidant scavenging activity towards diphenyl picrylhydrazine. PMID- 23798882 TI - Regeneration of multiple shoots from petiole callus of Viola serpens Wall. AB - Experiments were conducted to develop methodology for in vitro propagation and rapid multiplication of Viola serpens Wall. using petiole explant. The MS medium supplemented with 2, 4-D (6.78 MUm) was found most suitable for callus induction in petiole explant. The best growth response and higher rate of shoot regeneration from petiole callus was observed on MS medium containing BAP (11.10 MUm) as the average number of shoots could be increased to 36.4 on fourth successive subculturing. Higher rooting response with larger number of roots were observed in shoots inoculated on the half-strength MS medium supplemented with IBA (19.68 MUm). PMID- 23798884 TI - The heavy metal contents of some selected medicinal plants sampled from different geographical locations. AB - BACKGROUND: The levels of 5 minerals namely; lead, arsenic, mercury, cadmium, and aluminum were assessed in 10 medicinal plants sampled from 5 different geographical locations to determine the effect of location on the plants' mineral content. MATERIALS AND METHODS: Atomic absorption spectrophotometry (wet digestion) was used for the analyzes, and content of the minerals per sample was expressed as MUg/g. The levels of minerals were compared to their limit specification for herbs and daily total intake of these minerals. A two-way analysis of variance, which tends to look at the effect of the location and the medicinal plant itself on the plants mineral content, was used in the statistical analysis. RESULTS: Lead (Pb) was present in all plant species examined, except Ocimum gratissimum. One plant exceeded the maximum safety limit for lead. Cadmium was also detected in some of the medicinal plant species (44%) whilst majority were below the detection limit (0.002) representing 56%. 40% of the plant species exceeded the limit for cadmium. Mercury and arsenic in all the plant species were below the detection limit (0.001). Significant variation existed in mineral content for the various locations (P <= 0.05). CONCLUSION: The findings generally suggest the variation in mineral levels for the various locations. Thus, our study has shown that same species of medicinal plants, growing in different environments, accumulates different levels of heavy metals. PMID- 23798883 TI - Production of podophyllotoxin from roots and plantlets of Hyptis suaveolens cultivated in vitro. AB - BACKGROUND: Hyptis suaveolens was an important source of food and medicines in pre-hispanic Miotaxico and is actually used popularly to treat respiratory and skin diseases, fever, pain, and cramps, between other ailments. In 2008 the presence of podophyllotoxin (PTOX) was reported in this plant. OBJECTIVE: To establish in vitro cultures of H. suaveolens able to produce PTOX. MATERIALS AND METHODS: Explants of H. suaveolens were cultivated in Murashige and Skoog (MS) medium supplemented with different concentrations of the phytohormones 6 benzylaminopurine (6-BAP), 2,4-dichlorophenoxyacetic acid (2,4-D), 1 naphthaleneacetic acid (NAA) and kinetin (Kin), in order to induce the production of podophyllotoxin. Root cultures without hormones were also established and the quantification of PTOX was performed by HPLC analysis. RESULTS: The presence of growth regulators during in vitro cultivation of H. suaveolens, provoked morphological variations in explants, and induced the accumulation of different levels of PTOX. Roots grown without phytohormones accumulated PTOX at 0.013% dry weight (DW), while in three of the callus cultures cell lines growing together with roots, PTOX accumulated at concentrations of 0.003, 0.005 and 0.006% DW when NAA was combined with either Kin or BAP. In wild plant material PTOX was present in trace amounts in the aerial parts, while in the roots it was found at 0.005% DW. CONCLUSION: This study demonstrated that although it is possible to obtain PTOX in a variety of in vitro cultures of H. suaveolens, in vitro roots grown without the addition of growth regulators were better producers of PTOX. PMID- 23798885 TI - The triterpenoid fraction from Trichosanthes dioica root exhibits in vitro antileishmanial effect against Leishmania donovani promastigotes. AB - BACKGROUND: Trichosanthes dioica Roxb. (Cucurbitaceae), called pointed gourd in English is a dioecious climber found wild throughout the plains of the Indian subcontinent and traditionally used in India for several medicinal purposes. OBJECTIVE: The present study was aimed at the evaluation of in vitro antileishmanial effect of triterpenoid fraction from T. dioica root (CETD). MATERIALS AND METHODS: The antileishmanial activity of CETD was evaluated against Leishmania donovani (strain MHOM/IN/83/AG83)) promastigotes by in vitro promastigote cell toxicity assay by using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide). Potassium antimonyl tartrate was used as reference. RESULTS: Here, CETD markedly inhibited the growth of L. donovani promastigotes in vitro in a concentration dependent manner and demonstrated IC50 value of 18.75 MUg/ml. The reference drug potassium antimonyl tartrate exhibited IC50 of 7.52 MUg/ml. CONCLUSION: From the present study it can be inferred that the triterpenoid fraction of T. dioica root exhibited remarkable antileishmanial activity against Leishmania donovani promastigotes in vitro. PMID- 23798886 TI - Anti-arthritic activity of ethanolic extract of Tridax procumbens (Linn.) in Sprague Dawley rats. AB - OBJECTIVE: To determine the anti-arthritic effect of whole plant ethanolic extract of Tridax procumbens (Asteraceae) in female Sprague Dawley (SD) rats using the Freund's Complete Adjuvant (FCA) model. MATERIALS AND METHODS: The plant was collected from different regions of Madurai District, Tamil Nadu, and the phytoconstituents were identified through chemical tests. Ethanol (95%) was used to obtain the whole plant extraction through Soxhlet extractor. Female SD rats were used for anti-arthritic screening. Arthritis was induced using FCA, and the anti-arthritic effect of the ethanolic extract of T. procumbens was studied at doses of 250 and 500 mg/kg. The effects were compared with those of indomethacin (10 mg/kg). At the end of the study, the liver enzyme levels were determined and a radiological examination was carried out. RESULT: The preliminary phytochemical analysis of the ethanolic extract of T. procumbens indicated the presence of alkaloids, tannins, flavonoids and saponins. T. procumbens at 250 and 500 mg/kg significantly inhibited the FCA-induced arthritis in the rats. This was manifested by as a decrease in the paw volume. The arthritic control animals exhibited a significant decrease in body weight compared with control animals without arthritis. T. procumbens animals showed dose dependent reduction in decrees in body weight and arthritis. At the same time, T. procumbens significantly altered the biochemical and haematological changes induced by FCA (P < 0.05). The anti-arthritic effect of T. procumbens was comparable with that of indomethacin. CONCLUSION: The whole plant extract of T. procumbens showed significant anti-arthritic activity against FCA-induced arthritis in female SD rats. PMID- 23798887 TI - Volatile oil of Artemisia santolina decreased morphine withdrawal jumping in mice. AB - INTRODUCTION: Flowered aerial parts of Artemisia santolina Schrenk (Asteraceae), which is found in the central and western regions of Iran were collected from Khorasan province and the volatile oil extracted by hydro distillation. MATERIALS AND METHODS: The oil (0.5% v/w) was analyzed by GC and GC/MS using DB-5 column. The effect of this oil on the withdrawal syndrome was determined in mice. After induction of dependency by morphine, mice were intraperitoneally administered different concentrations of the oil. Morphine-withdrawal inducing by naloxone was assessed by recording the incidence of escape jumps for 60 min. RESULTS: The results indicated that a significant difference between the essential oil received group (at dose of 3.6 mg/kg) and control group was shown but the lower doses were not effective. Essential oil analysis showed that there were forty-six components, representing 95.4% of the oil. CONCLUSION: The oil of A. santolina which is rich in oxygenated monoterpenes with the major components, trans verbenol (34.6%) and p-mentha3-en-8-ol (13.1%), can decreased the number of withdrawal jumping in addicted mice. PMID- 23798888 TI - Anti-arthritic activity of root bark of Oroxylum indicum (L.) vent against adjuvant-induced arthritis. AB - BACKGROUND: Oroxylum indicum (Bignoniaceae) also known as Sonapatha is an indigenous medicinal plant widely used in Ayurvedic medicine for over thousands of years. It is an active ingredient of well-known Ayurvedic formulations such as Chyawanprash and Dasamula. Root bark of this plant has tonic and astringent properties and it is also used in rheumatism. OBJECTIVE: The present investigation was carried out to evaluate the anti-arthritic activity of different extracts of root bark of Oroxylum indicum against adjuvant - induced arthritis in rats. MATERIALS AND METHODS: Male Wistar rats were used in this study. Arthritis was induced by injecting 0.1 ml Freund's complete adjuvant intra dermally into the left hind paw of the rats. The paw volume, hematological, biochemical, radiographic and histopathological aspects were evaluated. RESULTS: The relative percentage inhibition potential of paw volume in rats treated with various extracts of Oroxylum indicum was found to be ethyl acetate extract (67.69%) >chloroform extract (64.61%) >n-butanol extract (58.46%) respectively. The hematological parameters like RBC count, hemoglobin content showed significant increase while there was a significant decrease in total WBC count and ESR in all the groups of animals pretreated with root bark extracts. The biochemical parameters such as catalase, glutathione contents showed a significant increase while the lipid peroxide and Cathepsin-D content decreased significantly only in case of ethyl acetate pretreated rats when compared to others. CONCLUSION: The present study suggests that the chloroform, ethyl acetate and n-butanol extracts of root bark of Oroxylum indicum exhibit anti-arthritic activity. The order of activity of extracts was found to be ethyl acetate >chloroform >n-butanol respectively. PMID- 23798889 TI - Anti-inflammatory and anti-hyperalgesic activities of Acanthopanax trifoliatus (L) Merr leaves. AB - CONTEXT: Acanthopanax trifoliatus is a ginseng-like plant, which has been widely used to treat various diseases including inflammatory-related diseases. AIMS: The present study has been designed to investigate the anti-inflammatory and anti hyperalgesic effects of various fractions of Acanthopanax trifoliatus leaves ethanolic extract in rats. MATERIALS AND METHODS: Anti-inflammatory activity was studied by using carrageenan-induced edema on rat paw whilst anti-hyperalgesic was assessed by using carrageenan-evoked thermal hyperalgesia on plantar test. STATISTICAL ANALYSIS USED: Data were analyzed using Student t-test to compare with control. Multiple comparisons for difference between control and extract treated groups were evaluated by Tukey HSD (Honestly Significant Difference) test. P values less than 0.05 (P < 0.05) is considered significant. RESULTS: Among three different fractions i.e., hexane, dichloromethane, and methanol tested, methanolic fraction displayed the most potent fraction amongst those three. It gave significant anti-inflammatory effect at highest dose, 500 mg/kg, with 77.24% of inhibition. Whilst for anti-hyperalgesic activity, methanolic fraction showed the highest efficacy at 375 mg/kg. Administration of methanolic fraction of Acanthopanax trifoliatus inhibited paw edema in a dose- dependent manner. The inhibition for both activities might be due to possible composition of polar compounds, which are flavonoids and phenolics content. CONCLUSIONS: Methanol fraction of Acanthopanax trifoliatus leaves has potential effect as anti inflammatory and anti-hyperalgesia in acute inflammation model. PMID- 23798890 TI - Isolation and identification of bacterial endophytes from pharmaceutical agarwood producing Aquilaria species. AB - BACKGROUND: Resins and gums are used in traditional medicine and do have potential applications in pharmacy and medicine. Agarwood is the fragrant resinous wood, which is an important commodity from Aquilaria species and has been used as a sedative, analgesic, and digestive in traditional medicine. Endophytic bacteria are potentially important in producing pharmaceutical compounds found in the plants. Hence, it was important to understand which types of endophytic bacteria are associated with pharmaceutical agarwood-producing Aquilaria species. OBJECTIVE: This study was undertaken to isolate and identify endophytic bacteria associated with agarwood-producing seven (7) Aquilaria species from Malaysia. MATERIALS AND METHODS: Botanical samples of seven Aquilaria species were collected, and endophytic bacteria were isolated from surface-sterilized-tissue samples. The 16S rRNA gene fragments were amplified using PCR method, and endophytic bacterial isolates (EBIs) were identified based on 16S rRNA gene sequence similarity based method. RESULTS: Culturable, 77 EBIs were analyzed, and results of 16S rRNA gene sequences analysis suggest that 18 different types of endophytic bacteria are associated with (seven) Aquilaria species. From 77 EBIs, majority (36.4%) of the isolates were of Bacillus pumilus. CONCLUSION: These findings indicate that agarwood-producing Aquilaria species are harboring 18 different types of culturable endophytic bacteria. PMID- 23798894 TI - Earthworms newly from Mongolia (Oligochaeta, Lumbricidae, Eisenia). AB - Two new megadrile earthworms from the steppes, the first species wholly from Outer Mongolia, are ascribed to the partially parthenogenetic Eisenia nordenskioldi (Eisen, 1879) species-complex. Taxonomic justification of sympatric Eisenia nordenskioldi mongol and Eisenia nordenskioldi onon ssp. n. are supported by mtDNA COI barcodes. The unreliability of molecular differentiation based on voucher names compared to definitive types is again demonstrated, as pertains to the ultimate Eisenia andrei Bouche, 1972 synonym of the Eisenia fetida (Savigny, 1826) sibling species-complex composed of more than a dozen prior names. Similar species described from Northeast China [formerly Manchuria] and North Korea are briefly considered, albeit they are intermittently held in synonymy of cosmopolitan Aporrectodea rosea (Savigny, 1826) along with many other taxa including some exotic lumbricids initially found in India. Japanese and North American lumbricids are also mentioned. Distributions are discussed and an annotated checklist of all nine Siberian/sub-arctic Eisenia nordenskioldi ssp. is appended. PMID- 23798891 TI - Family Intervention to Prevent Depression and Substance Use Among Adolescents of Depressed Parents. AB - Parental depression places offspring at elevated risk for multiple, co-occurring problems. The purpose of this study was to develop and preliminarily evaluate Project Hope, a family intervention for the prevention of both depression and substance use among adolescent-aged children (M = 13.9 years) of depressed parents. The program was created by blending two empirically supported interventions: one for depression and another for substance use. Thirty families were randomly assigned to either Project Hope (n = 16) or a wait-list control condition (n = 14). Pretests, posttests (n = 29), and 5-month follow-ups (n = 28) were conducted separately with parents and youth via phone interviews. Questions asked about the family depression experience, family interactions, family management, coping, adolescent substance use beliefs and refusal skills, adolescent depression, and adolescent substance use. Project Hope was fully developed, manualized, and implemented with a small sample of targeted families. Engagement in the program was relatively high. Preliminary outcome analyses were conducted using 2 (Group) *3 (Time) analyses of covariance. Results provided some evidence for significant improvements among intervention compared to control participants in indicators of the family depression experience, family management, and coping, and a statistically significant decrease from pretest to posttest in alcohol quantity for intervention compared to control youth. Next steps for this program of research are discussed. PMID- 23798895 TI - Genus Promalactis Meyrick (Lepidoptera, Oecophoridae) from China: Descriptions of twelve new species. AB - Sixteen species of the genus Promalactis Meyrick, 1908 from China are described. Among them, twelve species are described as new: Promalactis bifurciprocessa sp. n., Promalactis convexa sp. n., Promalactis papillata sp. n., Promalactis quadratitabularis sp. n., Promalactis quadriloba sp. n., Promalactis ramispinea sp. n., Promalactis scorpioidea sp. n., Promalactis serpenticapitata sp. n., Promalactis similiconvexa sp. n., Promalactis spinosicornuta sp. n., Promalactis strumifera sp. n. and Promalactis uncinispinea sp. n.; the previously unknown male of Promalactis dimolybda Meyrick, 1935 and female of Promalactis flavescens Wang, Zheng & Li, 1997 are described for the first time; Promalactis albipunctata Park & Park, 1998 and Promalactis dierli Lvovsky, 2000 are newly recorded for China. Adults and genitalia are illustrated. PMID- 23798896 TI - A taxonomic study of Chinese species of the alberti group of Metaphycus (Hymenoptera, Encyrtidae). AB - Ten alberti-group species of the genus Metaphycus Mercet from China are reviewed. Six species Metaphycus dorsalis sp. n., Metaphycus chinensis sp. n., Metaphycus wui sp. n., Metaphycus stylatus sp. n., Metaphycus fusiscapus sp. n. and Metaphycus fusiformis sp. n. are described as new to science. Four known species from China are redescribed. A key to the females of the Chinese species is given and photomicrographs are provided to illustrate morphological characters of these species. All specimens unless otherwise specified are deposited in the National Zoological Museum of China Institute of Zoology Chinese Academy of Sciences Beijing. PMID- 23798899 TI - A neotype designation for the bone-skipper Centrophlebomyia anthropophaga (Diptera, Piophilidae, Thyreophorina), with a review of the Palaearctic species of Centrophlebomyia. AB - The European bone-skippers (Diptera: Piophilidae: Thyreophorina), long considered extinct, have recently been the object of much interest by dipterists after their unexpected rediscovery. Considerable faunistic work has been done on these flies in recent years. However, some nomenclatural and taxonomic issues still require attention. A neotype is designated for Thyreophora anthropophaga Robineau Desvoidy, 1830 (now in the genus Centrophlebomyia Hendel, 1903) to fix the identity of this nominal species. Centrophlebomyia anthropophaga is recognized as a valid species. It is described and illustrated in detail, and information on its preimaginal instars is provided for the first time. Four Palaearctic species of Centrophlebomyia are recognized and reviewed and a key is provided for their identification. Centrophlebomyia orientalis Hendel, 1907 from northern India, is removed from synonymy with Centrophlebomyia anthropophaga and recognized as a valid species of Centrophlebomyia, stat. r. The nominal genus Protothyreophora Ozerov, 1984 is considered a junior synonym of Centrophlebomyia, syn. n. PMID- 23798897 TI - Generic revision and species classification of the Microdontinae (Diptera, Syrphidae). AB - With 552 species group names available (excluding misspellings), the Microdontinae constitute the smallest of the three subfamilies of Syrphidae. Paradoxically, this subfamily is taxonomically the least organized of the three: 388 species names were previously classified in a single genus, Microdon Meigen, 1803. The present paper introduces a new generic classification of the Microdontinae, relying partly on the results of phylogenetic analyses of morphological and molecular data as published in other papers, and partly on examination of primary type specimens of 347 taxa, plus additional material, and original descriptions. A total number of 67 genus group names (excluding misspellings) are evaluated, redescribed, diagnosed and discussed, with several implications for their taxonomic status. Of these, 43 names are considered as valid genera, 7 as subgenera, 17 as synonyms. Two generic names (Ceratoconcha Simroth, 1907, Nothomicrodon Wheeler, 1924) are left unplaced, because they are known from immature stages only and cannot be reliably associated with taxa known from adults. The following 10 new genera are described by Reemer: Domodon, Heliodon, Laetodon, Menidon, Mermerizon, Metadon, Peradon, Piruwa, Sulcodon and Thompsodon. A key to all genera, subgenera and species groups is given. A total number of 26 new species are described in the following genera: Archimicrodon Hull, 1945, Ceratrichomyia Seguy, 1951, Domodon, Furcantenna Cheng, 2008, Heliodon, Indascia Keiser, 1958, Kryptopyga Hull, 1944, Masarygus Brethes. 1908, Mermerizon, Metadon, Microdon, Paramixogaster Brunetti, 1923, Piruwa, Pseudomicrodon Hull, 1937, Rhopalosyrphus Giglio-Tos, 1891, and Thompsodon. New lectotypes are designated for Ceratrichomyia behara Seguy, 1951 and Microdon iheringi Bezzi, 1910. A total number of 267 new combinations of species and genera are proposed. New synonyms are proposed for 19 species group names. Three replacement names are introduced for primary and secondary junior homonyms: Microdon shirakii nom. n. (= Microdon tuberculatus Shiraki, 1968, primary homonym of Microdon tuberculatus de Meijere, 1913), Paramixogaster brunettii nom. n. (= Mixogaster vespiformis Brunetti, 1913, secondary homonym of Microdon vespiformis de Meijere, 1908), Paramixogaster sacki nom. n. (= Myxogaster variegata Sack, 1922, secondary homonym of Ceratophya variegata Walker, 1852). An attempt is made to classify all available species names into (sub)genera and species groups. The resulting classification comprises 454 valid species and 98 synonyms (excluding misspellings), of which 17 valid names and three synonyms are left unplaced. The paper concludes with a discussion on diagnostic characters of Microdontinae. PMID- 23798900 TI - The rediscovery of Passiflora kwangtungensis Merr. (subgenus Decaloba supersection Disemma): a critically endangered Chinese endemic. AB - Passiflora kwangtungensis is a critically endangered Chinese species known from Guangxi, Guangdong, and Jiangxi Provinces. The species belongs to Passiflora subgenus Decaloba, supersection Disemma, section Octandranthus. Field observations decreased rapidly during the 1970s to 1980s, and it was suspected that this species might have been extirpated due to repeated deforestation events throughout southern China. In recent years, however, small isolated populations of this species have been rediscovered in Hunan Province, representing new locality records for Passiflora kwangtungensis. New herbarium collections, color photographs, and silica gel collections have provided an unexpected opportunity to examine the evolutionary significance of this species. The current study presents a revised morphological description of Passiflora kwangtungensis based on fresh material, along with an updated distribution map. Using nrITS sequence data, preliminary insights into the phylogenetic position of Passiflora kwangtungensis are presented. Molecular data support the placement of Passiflora kwangtungensis within supersection Disemma section Octandranthus. However, the exact placement of Passiflora kwangtungensis within this lineage is unclear. The nrITS data suggest that Passiflora kwangtungensis may be sister to a clade containing Passiflora from China, Nepal, India, and Southeast Asia. Morphologically, Passiflora kwangtungensis displays the most similarity Passiflora geminiflora (Nepal, India) and Passiflora henryi (China). Lastly, conservation status and recommendations are made for Passiflora kwangtungensis following the IUCN Red List Criteria, where this species is classified as CR C1+C2a(i); D. PMID- 23798901 TI - Treatment of Severe Acute Asthma is Damage Control. PMID- 23798902 TI - Treatment of acute seizures: is intranasal midazolam a viable option? AB - Seizures in the pediatric population commonly occur, and when proper rescue medication is not administered quickly, the risk of neurologic compromise emerges. For many years, rectal diazepam has been the standard of care, but recent interest in a more cost-effective, safe alternative has led to the investigation of intranasal midazolam for this indication. Although midazolam and diazepam are both members of the benzodiazepine class, the kinetic properties of these 2 anticonvulsants vary. This paper will review available data pertaining to the efficacy, safety, cost, and pharmacokinetics of intranasal midazolam versus rectal diazepam as treatment for acute seizures for children in the prehospital, home, and emergency department settings. PMID- 23798904 TI - Hospital-acquired hyponatremia in pediatric patients: a review of the literature. AB - Hypotonic intravenous (IV) fluids in children are a mainstay of therapy based on a recommendation made in 1957 by Holliday and Segar. Since that time, hospital acquired hyponatremia caused by hypotonic IV fluids has been found to be an additional risk factor in the cause of death and neurological impairment in acutely ill children. This article reviews and critically evaluates the literature regarding the association of hyponatremia and hypotonic IV fluids in pediatric hospitalized, postoperative, and critical care patients. PMID- 23798905 TI - Validation of an improved pediatric weight estimation strategy. AB - OBJECTIVES: To validate the recently described Mercy method for weight estimation in an independent cohort of children living in the United States. METHODS: Anthropometric data including weight, height, humeral length, and mid upper arm circumference were collected from 976 otherwise healthy children (2 months to 14 years old). The data were used to examine the predictive performances of the Mercy method and four other weight estimation strategies (the Advanced Pediatric Life Support [APLS] method, the Broselow tape, and the Luscombe and Owens and the Nelson methods). RESULTS: THE MERCY METHOD DEMONSTRATED ACCURACY COMPARABLE TO THAT OBSERVED IN THE ORIGINAL STUDY (MEAN ERROR: -0.3 kg; mean percentage error: 0.3%; root mean square error: 2.62 kg; 95% limits of agreement: 0.83-1.19). This method estimated weight within 20% of actual for 95% of children compared with 58.7% for APLS, 78% for Broselow, 54.4% for Luscombe and Owens, and 70.4% for Nelson. Furthermore, the Mercy method was the only weight estimation strategy which enabled prediction of weight in all of the children enrolled. CONCLUSIONS: The Mercy method proved to be highly accurate and more robust than existing weight estimation strategies across a wider range of age and body mass index values, thereby making it superior to other existing approaches. PMID- 23798903 TI - Severe acute asthma exacerbation in children: a stepwise approach for escalating therapy in a pediatric intensive care unit. AB - OBJECTIVES: An increasing prevalence of pediatric asthma has led to increasing burdens of critical illness in children with severe acute asthma exacerbations, often leading to respiratory distress, progressive hypoxia, and respiratory failure. We review the definitions, epidemiology, pathophysiology, and clinical manifestations of severe acute asthma, with a view to developing an evidence based, stepwise approach for escalating therapy in these patients. METHODS: Subject headings related to asthma, status asthmaticus, critical asthma, and drug therapy were used in a MEDLINE search (1980-2012), supplemented by a manual search of personal files, references cited in the reviewed articles, and treatment algorithms developed within Le Bonheur Children's Hospital. RESULTS: Patients with asthma require continuous monitoring of their cardiorespiratory status via noninvasive or invasive devices, with serial clinical examinations, objective scoring of asthma severity (using an objective pediatric asthma score), and appropriate diagnostic tests. All patients are treated with beta-agonists, ipratropium, and steroids (intravenous preferable over oral preparations). Patients with worsening clinical status should be progressively treated with continuous beta-agonists, intravenous magnesium, helium-oxygen mixtures, intravenous terbutaline and/or aminophylline, coupled with high-flow oxygen and non-invasive ventilation to limit the work of breathing, hypoxemia, and possibly hypercarbia. Sedation with low-dose ketamine (with or without benzodiazepines) infusions may allow better toleration of non-invasive ventilation and may also prepare the patient for tracheal intubation and mechanical ventilation, if indicated by a worsening clinical status. CONCLUSIONS: Severe asthma can be a devastating illness in children, but most patients can be managed by using serial objective assessments and the stepwise clinical approach outlined herein. Following multidisciplinary education and training, this approach was successfully implemented in a tertiary-care, metropolitan children's hospital. PMID- 23798906 TI - Stability of extemporaneously prepared lansoprazole suspension at two temperatures. AB - OBJECTIVE: The purpose of this study was to examine the stability of a generic lansoprazole product in a 3 mg/mL sodium bicarbonate suspension under room temperature and refrigerated conditions. METHODS: Lansoprazole suspensions (3 mg/mL) were prepared in triplicate using an 8.4% sodium bicarbonate vehicle for each storage condition (room temperature and refrigerated). During 1 month, samples from each replicate were periodically removed and analyzed for lansoprazole concentration by liquid chromatography-tandem mass spectrometry (LC MS/MS). Each sample was spiked with 10 mg/L omeprazole to serve as the internal standard. A positive electrospray LC-MS/MS method was validated over the calibration range of 5 to 25 mg/L using Food and Drug Administration Guidance. The identities of the analyte and internal standard in the samples were verified by monitoring the MS/MS transitions of m/z 370 to m/z 252 and m/z 346 to m/z 198 for lansoprazole and omeprazole, respectively. Additionally, the pH of the suspensions was monitored throughout the study. RESULTS: The stability of lansoprazole in the oral sodium bicarbonate suspension under refrigeration is compromised prior to what has been previously reported in the literature. Samples kept at room temperature lost >10% of the lansoprazole after 48 hours compared with the refrigerated samples, which maintained integrity up to 7 days. No statistically significant difference was found between the pH of the room temperature and refrigerated suspension samples, indicating that this factor is not the cause for the differences in stability at these two conditions. CONCLUSIONS: This study suggests that the extemporaneously compounded lansoprazole oral suspension prepared in 8.4% sodium bicarbonate should not be stored in plastic oral syringes longer than 48 hours at room temperature and no longer than 7 days when refrigerated. These data indicate an expiration time earlier than that previously reported for the refrigerated product (14 days). PMID- 23798907 TI - Valproic Acid and topiramate induced hyperammonemic encephalopathy in a patient with normal serum carnitine. AB - A 17-year-old female developed hyperammonemic encephalopathy 2 weeks after valproic acid (VPA), 500 mg twice a day, was added to her regimen of topiramate (TPM), 200 mg twice a day. She presented to the emergency department (ED) with altered mental status, hypotension, bradycardia, and lethargy. Laboratory analysis showed mild non-anion gap hyperchloremic acidosis, serum VPA concentration of 86 mg/L, and urine drug screen result that was positive for marijuana. She was admitted to the pediatric intensive care unit for persistent symptoms, prolonged QTc, and medical history. Blood ammonia concentrations were obtained because of her persistent altered mental status, initially 94 MUmol/L and a peak of 252 MUmol/L. A serum carnitine profile was obtained at the time of hyperammonemia and was found to be normal (results were available postdischarge). VPA and TPM were discontinued on day 1 and day 2, respectively, as the patient's blood ammonia concentration remained elevated. On day 3, her mental status had returned to baseline, and blood ammonia concentrations trended downward; by day 4 her blood ammonia concentration was 23 MUmol/L. VPA has been associated with numerous side effects including hyperammonemia and encephalopathy. Recently, drug interactions with TPM and VPA have been reported; however, serum carnitine concentrations have not been available. We discuss the possible mechanisms that VPA and TPM may affect serum ammonia and carnitine concentrations and the use of levocarnitine for patients or treating toxicity. PMID- 23798908 TI - Stenotrophomonas infection in a patient with glucose-6-phosphate dehydrogenase deficiency. AB - The drug of choice for treatment of Stenotrophomonas maltophilia is sulfamethoxazole/trimethoprim, and second-line therapy usually consists of a fluoroquinolone. However, in patients with glucose-6-phosphate dehydrogenase deficiency, neither sulfamethoxazole/trimethoprim nor a fluoroquinolone is a preferred option as it may result in hemolysis. Currently, there is a paucity of data regarding treatment of S maltophilia infection in these patients. This case report presents a patient who was successfully treated with doxycycline and inhaled colistimethate. PMID- 23798909 TI - Pediatric news. PMID- 23798910 TI - Reconstructing the Hsp90/Tau Machine. AB - Imbalanced protein load within cells is a critical aspect for most diseases of aging. In particular, the accumulation of proteins into neurotoxic aggregates is a common thread for a host of neurodegenerative diseases. Recent work demonstrates that age-related changes to the cellular chaperone repertoire contributes to abnormal buildup of the microtubule-associated protein tau that accumulates in a group of diseases termed tauopathies, the most common being Alzheimer's disease (AD). The Hsp90 co-chaperone repertoire has diverse effects on tau stability; some co-chaperones stabilize tau while others facilitate its clearance. We propose that each of these proteins may be novel therapeutic targets. While targeting Hsp90 directly may be deleterious at the organismal level, perhaps targeting individual co-chaperone activities will be more tolerable. PMID- 23798911 TI - Focal neuropathies following percutaneous nephrolithotomy (PCNL)--preliminary study. AB - INTRODUCTION: Postoperative neurological complications in pelvic and renal surgery are a well-known clinical problem and their morbidities are important. We designed this study to determine prevalence and risk factors of such complications after percutaneous nephrolithotomy (PCNL) surgery. MATERIAL AND METHODS: A cross-sectional study was performed during February and July 2011 on 68 PCNL cases. Demographic data and surgery reports were gathered and comprehensive neurological physical examination carried out before and after surgery. Then, data was analyzed using software SPSS 18. RESULTS: The ultimate sample included 30 (46.2%) male and 35 (53.8%) female patients with a mean age of 47.9 +/- 11.47 years. In intercostal and lumbosacral plexus area, sensory neurological complications occurred in 8 patients (12.31%), 4 men and 4 women. The most common involved dermatomes and nerves were T12 (8 cases). There was a significant correlation between prolonged duration of surgery and prevalence of sensory complications (p<0.010). The highest hemoglobin value drop after surgery occurred in patients with neurological complications (p<0.001). There were no correlations between age, tracts used, diabetes mellitus, BMI, hypertension, positioning of patients and side of surgery with incidence of sensory neurological complications. No motor neurological complications occurred. CONCLUSION: Prolonged duration of PCNL and increased value of hemoglobin drop may lead to increased risk of neuropathy. Larger prospective studies with retroperitoneal imagings and patients' follow up is suggested for better understanding of this complication. PMID- 23798912 TI - Idiopathic colonic calcification: a case report. AB - We describe diffuse colonic calcification detected on CT scan of the abdomen in a young female patient who presented to our clinic with vague intermittent abdominal pain of four weeks duration. Her investigative profile was normal and her colonoscopy did not reveal any mucosal changes. Colonic calcification has been known to occur mostly as a result of ischemic phenomenon but the index case had no such features or any other predisposing factor. The patient is currently symptom-free and is following our clinic for the last 8 months. After the review of literature and thorough investigations her colonic calcification remains unexplained. PMID- 23798913 TI - Observation of lymphangioma of the duodenum by a magnifying endoscope with a narrow-band imaging system. AB - Among duodenal tumors, lymphangioma is relatively infrequent. In this case report, we describe the case of a 65-year-old Japanese man with duodenal lymphangioma diagnosed by esophagogastroduodenoscopy. Endoscopically, the tumor appeared as a soft submucosal tumor with white spots. When the white spots were grasped by biopsy forceps, milky liquid exuded from the tumor. Additionally, observation by a magnifying endoscope with narrow-band imaging revealed elongated microvessels on the surface. We speculated that this feature was formed because the duodenal villi were dilated and the microvessels were stretched due to the retention of chyle. These endoscopic findings are key features in the diagnosis of duodenal lymphangioma. PMID- 23798914 TI - Elevated serum aminotransferases secondary to rippling muscle disease. AB - A 43-year-old man was referred by his general practitioner to the hepatology clinic with deranged serum aminotransferases, discovered as part of routine blood tests. The objective was to identify the cause of elevated serum aminotransferases in this patient in a systematic manner. Thorough history and physical examination revealed a background history of rippling muscle disease secondary to caveolin-3 protein deficiency, with typical clinical signs. There was a positive family history of musculoskeletal disease in the patient's father and brother. Previous diagnostic tests performed to investigate the patient's musculoskeletal symptoms, including muscle biopsies, were revisited. Subsequent systematic investigations such as blood tests, liver ultrasound scan and Fibroscan((r)) were performed to exclude potential causes of the deranged serum aminotransferases. Liver biopsy was not performed. A consistent pattern of chronic low-grade elevations of serum aminotransferases, less than three times the upper limit of the normal range, was found. This was associated with a consistently elevated serum creatine kinase and normal renal function tests. Previous muscle biopsies had revealed chronic degenerative and regenerative changes suggestive of a focal necrotizing myopathy. Liver ultrasound scan and Fibroscan((r)) were normal. With exclusion of other liver diseases and identification of profoundly elevated serum creatine kinase concentration, the deranged aminotransferases were attributed to rippling muscle disease. PMID- 23798915 TI - Acute liver failure associated with propylthiouracil in a pregnant 26-year-old woman. AB - It seems appropriate to use propylthiouracil to treat maternal hyperthyroidism during the first trimester of pregnancy. We present the case of a 26-year-old woman with acute liver failure associated with propylthiouracil during the first trimester of pregnancy. She was successfully treated without liver transplantation. Attention should be paid to the possible occurrence of propylthiouracil-induced hepatotoxicity even during the first trimester of pregnancy. PMID- 23798916 TI - Prevalence study of clinical disorders in 6-year-old children across Iranian provinces: Findings of Iranian national health assessment survey. AB - OBJECTIVE: To assess the national prevalence of clinical disorders in 6-year-old Iranian children before school entry using a national health assessment survey. MATERIALS AND METHODS: In a cross-sectional nationwide survey, all Iranian children entering public and private elementary schools were asked to participate in a mandatory national screening program in Iran in 2009 in two levels of screening and diagnostic levels. RESULTS: The study population consisted of 955388 children (48.5% girls and 76.1% urban). Of the whole children, 3.1% of the 6-year-old children had impaired vision. In addition, 1.2, 1.8, 1.4, 10, 10.9, 56.7, 0.7, 0.8 and 0.6% had color blindness, hearing impaired, speech disorder, height to age retardation, body mass index extremes, decayed teeth, having disease with special needs, spinal disorders, and hypertension, respectively. The distribution of these disorders was unequally distributed across provinces. CONCLUSIONS: Our results confirmed that the prevalence of clinical disorders among 6-year-old children across Iranian provinces was not similar. The observed burden of these distributions among young children needs a comprehensive national policy with evidence-based province programs to identify the reason for different distribution among provinces. PMID- 23798917 TI - The prevalence of hypogonadism in diabetic men in Isfahan Endocrine and Metabolism Research Center, Isfahan, Iran. AB - OBJECTIVE: Low testosterone, with or without symptoms, reported in diabetic men in some studies. We investigated the prevalence of hypogonadism in Iranian type 2 diabetic men. MATERIALS AND METHODS: Total testosterone (TT) and sex hormone binding globulin (SHBG) concentrations were measured in 247 diabetic men >30 years who had symptoms of androgen deficiency, according to ADAMs questionnaire. The correlation between some parameters and total, free and bioavailable testosterone levels was determined using Pearson correlation coefficient. Free and bioavailable testosterone were calculated by electronic calculator. Four patients were excluded because of high testosterone level, due to unreported androgen use. Overt hypogonadism was defined as total testosterone <=8 nmol/l or calculated bioavailable testosterone (cBT)<=2.5 nmol/l and borderline hypogonadism was considered as TT 8-12 nmol/l or cBT 2.5-4nmol/l. RESULTS: The mean and SD of age was 59 (9.3) years. The mean TT, calculated free testosterone (cFT), and cBT and SHBG levels were 4.81 (1.7) nmol/l, 0.11 (0.06) nmol/l, 2.42 (1.17) nmol/l and 36.15 (18.3) nmol/l, respectively. According to TT and cBT, overt hypogonadism observed in 7.4% and 61.6% of men, respectively, and the prevalence of borderline hypogonadism was 9.9% and 36%, respectively. cFT <=0.16 nmol/l found in 227 diabetic men (96%). Hypogonadism (TT <=12 nmol/l) was not correlated with obesity, smoking, age,duration of diabetes, blood pressure, and HbA1c. CONCLUSION: Hypogonadism is highly prevalent in type 2 diabetes men. PMID- 23798918 TI - Effects of oral magnesium supplementation on inflammatory markers in middle-aged overweight women. AB - BACKGROUND: This study aimed to investigate whether magnesium supplementation might affect serum magnesium, high sensitive C-reactive protein (hs-CRP), plasma fibrinogen, and interleukin 6 (IL-6) levels in healthy middle-aged overweight women. The relationships, if any, between serum magnesium and the inflammatory markers were also examined cross-sectionally in the entire participants at the beginning of the study. MATERIALS AND METHODS: This double-blinded, placebo controlled, randomized trial included 74 middle-aged overweight women. Participants were randomly assigned to receive either 250 mg magnesium as magnesium oxide or placebo daily for 8 weeks. Serum magnesium, hs-CRP, fibrinogen and IL-6 concentrations were measured before and after the intervention. RESULTS: Serum magnesium was found to be inversely correlated with hs-CRP (rs =-0.22, P=0.05) in the entire participants at baseline. Serum hs-CRP declined significantly in both groups as compared with baseline values (median change=0.8 mg/L; PMagnesium= 0.03, PPlacebo < 0.001). Plasma fibrinogen decreased significantly, by 9%, in the magnesium group at the end of week 8 compared to baseline (P=0.001). Mean concentration of IL-6 was significantly increased in the magnesium group comparing the baseline value(P=0.001). However hs-CRP, fibrinogen and IL-6 levels at week 8 or any changes during the study were not statistically different between the two groups. Serum magnesium showed no significant changes in any groups. CONCLUSIONS: Serum magnesium had a significant inverse correlation with hs-CRP. In the present study, magnesium as magnesium oxide, 250 mg/day, for 8 weeks did not significantly attenuate inflammatory markers in the magnesium group as compared to the placebo. PMID- 23798919 TI - A study to investigate the relationship between difficult intubation and prediction criterion of difficult intubation in patients with obstructive sleep apnea syndrome. AB - BACKGROUND AND AIM: Obstructive sleep apnea (OSA) syndrome is predisposed to the development of upper airway obstruction during sleep, and it poses considerable problem for anesthetic management. Difficult intubation (DI) is an important problem for management of anesthesia. In this clinical research, we aim to investigate the relationship between DI and prediction criteria of DI in cases with OSA. MATERIALS AND METHODS: We studied 40 [OSA (Group O, n = 20) and non OSA, (Group C, n = 20)] ASA I-II, adult patients scheduled tonsillectomy under general anesthesia. Same anesthetic protocol was used in two groups. Intubation difficulties were assessed by Mallampati grading, Wilson sum score, Laryngoscopic grading (Cormack and Lehane), a line joining the angle of the mouth and tragus of the ear with the horizontal, sternomental distance, and tyromental distance. Demographic properties, time-dependent hemodynamic variables, doses of reversal agent, anesthesia and operation times, and recovery parameters were recorded. RESULTS: Significant difference was detected between groups in terms of BMI, Mallampati grading, Wilson weight scores, Laryngoscopic grading, sternomental distance, tyromental distance, doses of reversal agent, and recovery parameters. CONCLUSION: OSA patient's DI ratio is higher than that of non-OSA patients. BMI Mallampati grading, Wilson weight scores, Laryngoscopic grading, sternomental distance, and tyromental distance evaluation might be predictors for DI in patients with OSA. PMID- 23798920 TI - Ameliorative effects of metformin on renal histologic and biochemical alterations of gentamicin-induced renal toxicity in Wistar rats. AB - BACKGROUND: The aim of this study was to test the potential properties of metformin (MF) to protect the kidney from gentamicin (GM)-induced renal toxicity. MATERIALS AND METHODS: In this preclinical study, 50 male Wistar rats were randomly divided into five groups of 10 rats in each. In the first group (group I), they were kept in the same condition as others without receiving drugs for 10 days. In group II, the rats were injected intraperitoneally with 100 mg/kg/day of GM for 10 consecutive days. Group III rats received 100 mg/kg/day MF orally for 10 days. In group IV, the rats received GM (100 mg/kg; intraperitoneally) for 10 days and 100 mg/kg/day MF orally for the next 10 days. In the last group (group V), the rats received a combination of GM 100 mg/kg/day intraperitoneally and MF 100 mg/kg/day orally for 10 days simultaneously. Serum blood urea nitrogen (BUN) and creatinine (Cr) values were measured and renal tissues of the animals were processed for light microscope examination. RESULTS: The levels of BUN in groups II, IV, and V, and also the serum level of Cr in groups II and V were increased significantly after the experiment. Furthermore, post-treatment with MF or co treatment with MF could prevent the elevation of serum BUN and Cr induced by GM and also attenuates the damage score (P < 0.05). CONCLUSIONS: MF may prevent or ameliorate GM-induced acute renal failure, and therefore it might be beneficial in patients under treatment with this medicine. PMID- 23798921 TI - Effect of low calorie diet with rice bran oil on cardiovascular risk factors in hyperlipidemic patients. AB - BACKGROUND: Cardiovascular disease remains the leading cause of death and disability in industrialized and developing countries. The aim of this research was to determine the effect of rice bran oil, with a low-calorie diet, on lipid profiles, in hyperlipidemic patients. MATERIALS AND METHODS: This study was a parallel groups' randomized clinical trial with a pre- and post-test design. Fifty hyperlipidemic patients of both sexes and age range of 25 - 65 years had participated. The patients received a low-calorie diet based on 1400 kcal energy, 17% protein, 26% fat, and 57% carbohydrate per day for four weeks. The treatment group received a low-calorie diet including rice bran oil (30 g / day). Blood samples were obtained after an overnight (12 hours) fasting period before the study and on the last day of the intervention period. Anthropometric indices and levels of serum triacylglycerol, total cholesterol, low-density lipoprotein, and high-density lipoprotein were measured before and after the intervention. RESULTS: In both groups, weight, body mass index, waist, and hip circumferences were significantly reduced (P < 0.05) after four weeks. In comparison with the control group, the results of treatment with rice bran oil, with a low-calorie diet, showed that at the end of the fourth week, total cholesterol, low-density lipoprotein, and atherogenic ratio of total cholesterol / high-density lipoprotein were significantly decreased (P < 0.05). CONCLUSIONS: The results confirm that rice bran oil, when consumed as part of a healthy diet, is effective in improving risk factors for cardiovascular disease. PMID- 23798922 TI - Sildenafil citrate and uteroplacental perfusion in fetal growth restriction. AB - BACKGROUND: To determine whether the phosphodiesterase type 5 inhibitor, Sildenafil citrate, affects uteroplacental perfusion. MATERIALS AND METHODS: Based on a randomized double-blinded and placebo-controlled trial, forty one pregnant women with documented intrauterine growth retardation at 24-37 weeks of gestation were evaluated for the effect of a single dose of Sildenafil citrate on uteroplacental circulation as determined by Doppler ultrasound study of the umbilical and middle cerebral arteries. Statistical analysis included chi(2)-test to compare proportions, and independent-samples t-test and paired student's t test to compare continuous variables. RESULTS: Sildenafil group fetuses demonstrated a significant decrease in systolic/diastolic ratios (0.60 [SD 0.40] [95% Cl 0.37-0.84], P=0.000), and pulsatility index (0.12 [SD 0.15] [95% Cl 0.02 0.22], P=0.019) for the umbilical artery and a significant increase in middle cerebral artery pulsatility index (MCA PI) (0.51 [SD 0.60] [95% Cl 0.16-0.85], P=0.008). CONCLUSION: Doppler velocimetry index values reflect decreased placental bed vascular resistance after Sildenafil. Sildenafil citrate can improve fetoplacental perfusion in pregnancies complicated by intrauterine growth restriction. It could be a potential therapeutic strategy to improve uteroplacental blood flow in pregnancies with fetal growth restriction (FGR). PMID- 23798923 TI - The effect of quercetin supplementation on selected markers of inflammation and oxidative stress. AB - BACKGROUND: Athletes use flavonoids as antioxidant to enhance endurance and physical performance. In vitro data indicate flavonoids have antioxidative and antiinflammatory functions but data in human studies are limited. The aim of this study was to determine the effects of a 2-month flavonoid quercetin supplementation on oxidative stress and inflammatory biomarkers in nonprofessional athletes with regular exercise. MATERIALS AND METHODS: The randomized double-blind clinical trial was done among subjects with systematic and regular exercise for 8 weeks in four groups, each containing 15 individuals: 500 mg quercetin + 250 mg vitamin C as pro-oxidant (Q+C), 500 mg of quercetin alone (Q), 250 mg of vitamin C alone (C), and placebo (Control). IL-6, CRP, E selectin and F2-isoprostane were measured before and after intervention. RESULTS: In 60 participants with mean (+/-SD) age of 21.0 +/- 1.6 years, statistically significant within group differences were observed in IL-6 (P<0.1), CRP (P<0.01) and F2-isoprostane for group 1 and pre- and postchanges in E-selectin was marginally significant for all study groups (P<0.1). Group 1 had marginally smaller F2-isoprostane (P<0.1) and interleukin 6 than control group (P<0.05) and there were marginally differences in CRP between respondents in group 1 and 2 with the control group (P<0.1). CONCLUSIONS: Eight-week supplementation with quercein-vitamin C was effective in reducing oxidative stress and reducing inflammatory biomarkers including CRP and IL-6 with little effect on E-selectin in healthy subjects. PMID- 23798924 TI - Cardioprotective role of insulin: Advantage analogues. AB - AIM: Type II diabetes mellitus (DM) increases the risk of cardiovascular disease. Treatment with insulin substantially reduces C - reactive protein (CRP) because of its anti-atherosclerotic action. This study was designed to explore and compare the cardio protective role of regular human insulin (RHI), aspart and lispro insulin in type II DM. MATERIALS AND METHODS: A randomized, open, parallel group, comparative clinical study was conducted on 90 patients of type II DM. After baseline clinical assessment and investigations, RHI was prescribed to 30 patients, aspart insulin to 30 patients and lispro insulin to another 30 patients for 12 weeks. The efficacy variables were change in blood pressure, glycemic control, lipid profile, serum potassium, high-sensitivity CRP (hsCRP) and UKPDS 10-year CHD risk scoring over 12 weeks. At the end of the study, the patients were followed up and changes in variables from baseline were analyzed by statistical tools. RESULTS: Systolic blood pressure decreased significantly in aspart group (P = 0.008) whereas diastolic blood pressure was decreased significantly both in aspart (P < 0.001) and lispro group (P = 0.01). Fasting, postprandial blood glucose and HbA1c were decreased in all three groups significantly but change in aspart group was superior (P = 0.01). Triglyceride was significantly better controlled by lispro (P < 0.01) whereas aspart insulin was superior to decrease total cholesterol and LDL (P < 0.05). The extent of potassium loss was significantly more with RHI (P = 0.004) than others. CRP lowering effect (P = 0.017) and decrease in UKPDS risk scoring (P = 0.019) in aspart and lispro group was superior to RHI group. CONCLUSION: Short acting insulin analogues, especially aspart insulin have been found to have a better cardio protective role than RHI in type II DM. PMID- 23798925 TI - Cardiorespiratory response to aerobic exercise programs with different intensity: 20 weeks longitudinal study. AB - CONTEXT: participation in regular intensive exercise is associated with a modest increase in left ventricular wall thickness and cavity size. The magnitude of improvement depends on frequency, intensity, type, and duration of exercise program. AIMS: to determine the effect of sports training on LV morphology and function, lung function, and to know the intensity of the exercise program enough for these changes. SETTINGS AND DESIGN: this was a longitudinal study (20 weeks duration) done on the medical college students. MATERIAL AND METHODS: three groups, doing exercise at different intensities, high intensity group (HG) [74.9+/-3.9 %HRmax], low intensity group (LG) [59.46+/-4.1%HRmax] and no exercise group (NG) were made, and their assessments were done using the echocardiography and pulmonary function test three times, first before start of the exercise program, second at the end of 10th week, and then at the end of the 20th week. STATISTICAL ANALYSIS USED: 3 * 3 Anova test and Bonferroni's post-test using Graph pad prism5 software. RESULTS: significant improvement was seen in HG in majority of cardio respiratory parameters (VO2max, heart rate, LVIDD, LVIDS, EDV, MVV, PEFR, FVC) as compared to the LG (VO2max, heart rate, MVV, PEFR) and this improvement was specially seen at the end of the twentieth week. CONCLUSIONS: twenty weeks of training is helpful in improving aerobic power, MVV, and PEFR even the exercise is of moderate (LG) to high intensity (HG) but for overall cardio respiratory development physical training must be associated with very hard intensity if duration of the exercise program is short. PMID- 23798926 TI - Prevalence of occupational exposure to blood and body secretions and its related effective factors among health care workers of three Emergency Departments in Tehran. AB - BACKGROUND: Accidental exposure to blood and body secretions is frequent among health care workers (HCWs). They are at risk of acquiring blood-borne diseases. In this study, we have investigated the prevalence and risk factors of occupational exposure among the HCWs of the Emergency Departments (ED) at three teaching hospitals in Tehran. MATERIALS AND METHODS: We conducted this observational, descriptive, cross-sectional study using a self-reporting 25 question survey, related to occupational exposures, in February 2010. It was carried out among 200 HCWs (specialist physicians, residents, medical interns, nurses, laboratory personnel, housekeepers, cleaners, and others), who were working in the EDs of the three teaching hospitals of the Tehran University of Medical Sciences. The age, sex, and job category of the HCWs suffering from the injury were determined, as also the risk factors responsible for the exposure of the HCWs. RESULTS: One hundred and fifteen (57.5%) of the 200 HCWs had had at least one episode of blood or body fluid exposure in their professional life. Hollow-bore needles accounted for the highest amount of injuries, with 41.5%, followed by suture needles (18.5%). The most prevalent procedures associated with injuries were suturing (17.5%) and recapping used syringes (16.5%), respectively. All the specialist doctors in this study reported at least one exposure. The percentage of exposure in the other participants of our study was 74.3% for ED residents, 61.1% for laboratory technicians, 51.9% for nurses, and 51% for medical interns. Binary logistic regression analysis revealed that male gender, recapping needles, and job profession were independently associated with exposure to blood or body fluids. CONCLUSION: High prevalence of occupational exposure in this study emphasized the importance of promoting awareness, training, and education for the HCWs, for preventive strategies, and also reporting of occupational exposure to blood and body secretions. PMID- 23798927 TI - The effect of using musical mobiles on reducing pain in infants during vaccination. AB - BACKGROUND: Distraction during painful interventions may reduce pain perception, but results in the literature are inconsistent. The aim of the study was to test the effectiveness of a musical mobile as a distraction tool on pain reduction in infants during a vaccine injection. MATERIALS AND METHODS: The study based on a quasi-experimental model involving a test group and a control group was performed on 120 healthy infants, who were presented to the primary healthcare center for their first DaPT-IPV-Hib combined vaccination. The study was conducted in a room furnished with or without a musical mobile fixed to the head of the examination table, suspended at a distance of 20 - 25 cm from the infant's face. A question form was used to determine the infants' characteristics, and the Face, Legs, Activity, Cry, Consolability (FLACC) Pain Scale was used to assess their levels of pain. Data were collected between January 1 and May 15, 2008. RESULTS: The pain scores of the infants in the test group (during the procedure 5.13 +/- 2.11 and after the procedure 1.26 +/- 2.01) were lower than the scores of the infants in the control group (during the procedure 6.65 +/- 2.69 and after the procedure 3.61 +/- 2.27). The crying duration was also shorter among infants in the test group than among infants in the control group (23.53 +/- 18.38 vs. 30.88 +/- 22.78 seconds) during the vaccination injection. CONCLUSIONS: A lower pain score and shorter crying duration in response to vaccination in a room furnished with a musical mobile indicates that distracting attention via a musical mobile is a practical way to reduce pain during routine medical interventions in infants. PMID- 23798928 TI - The impact of a novel herbal Shirazi Thymus Vulgaris on primary dysmenorrhea in comparison to the classical chemical Ibuprofen. AB - OBJECTIVE: Primary dysmenorrhea is defined as painful cramps during menstruation with no pelvic pathology. Due to the adverse effects of Non-Steroidal Anti Inflammatory Drugs (NSAIDs) are considered as the most common pharmacological treatment for this disorder. The present study was conducted to assess the impact of Shirazi Thymus Vulgaris compared to that of Ibuprofen on primary dysmenorrhea. MATERIALS AND METHODS: A randomized, single-blind clinical trial was conducted amongst 120 female students ofIlam University of Medical Sciences, aged 18-25 years who suffered from primary dysmenorrhea. The participants were randomly divided into two groups; one received the herbal and the other classical treatments. The herbal group received 5 ml of the Shirazi Thymus Vulgaris medication that commercially called BronchoT.D, orally four times a day. The classic group received Ibuprofen orally three times a day. A visual analogue scale (VAS) was used to record pain severity. RESULTS: Pain severity was reduced in both herbal and classic groups with no significant differences. Pain duration at the first and second month of treatment was also similar between two groups. CONCLUSIONS: Shirazi Thymus Vulgaris decreased dysmenorrhea symptoms, which might be attributed to its antispasmodic effects. The herbal Shirazi Thymus Vulgaris can be recommended as an effective medication fortreatment of the primary dysmenorrhea disorder. PMID- 23798929 TI - Development of PCR-based method for detection of Enterobacteriaceae in septicemia. AB - OBJECTIVE: Sepsis is a systemic inflammatory response associated with high mortality rates in the clinical setting. A multiplex endpoint polymerase chain reaction (PCR) based assay for rapid detection of enterobacteriaceae involved in septicemia, which included Internal Control (IC) and 16S rDNA, is presented here. To develop a panel of primers for DNA fragments of 16S rDNA, enterobacteriaceae, IC, and evaluate analytical sensitivity and specificity of the test. MATERIALS AND METHODS: Primers for amplification of enterobacteriaceae, IC, and16S rDNA were designed, and then PCR was performed. Minimal analytical sensitivity was determined by cloning and colony PCR, and specificity was tested on the basis of their respective standard strains. This study is a cross-sectional Model. RESULTS: Our results showed the rpoB gene as the most promising target for detection of enterobacteriaceae by PCR amplification. Specificity and sensitivity of endpoint PCR were 100%, 100%, and 100%, and 10, 1, and 100 copies/reaction for enterobacteriaceae, IC, and 16S rDNA, respectively. CONCLUSION: The molecular panel presented offers the advantage of an easy, reliable, and cost-effective system when compared to other molecular detection methods. However, further evaluation is needed. Our assay holds promising for more rapid pathogens related in clinical sepsis. PMID- 23798930 TI - Which modifiable, non-modifiable, and socioeconomic factors have more effect on cardiovascular risk factors in overweight and obese women? AB - BACKGROUND: The aim of the present study was to assess which modifiable, non modifiable, and socioeconomic factors are good predictors for cardiovascular risk in overweight and obese Iranian women. MATERIALS AND METHODS: This clinical cross sectional study was conducted on 811 overweight and obese women of age 20-60 years in Islamic Republic of Iran. In this study, the dependent variables were fasting blood sugar (FBS) and lipid profile, and the independent variables were educational level, waist to hip ratio (WHR), body mass index (BMI), waist circumference (WC), age, fasting glycemia, and diabetes. RESULTS: Univariate analysis showed that the significant factors associated with FBS were age, BMI, education, and WHR, but the effect of age was more than that of others. For total cholesterol (TC), only glycemia had a significant effect [P = 0.004, odds ratio (OR) 1.9 vs. others independent variables' ORs]. Having diabetes, BMI >=30 kg/m(2), and education <=12 years were the significant factors associated with triglyceride (TG), but the effect of diabetes was more than that of others (OR: 2.7, 2.2, and 1.9 for diabetes, BMI, and education, respectively). The effect of age was more than that of other independent factors on low density lipoprotein cholesterol (LDL-C). There was not any significant association between independent variables and high density lipoprotein-cholesterol (HDL-C) in multiple logistic regression models. CONCLUSION: Based on the obtained results, in clinic, for overweight and obese women, age, glycemia, and having diabetes can be considered as predictors for FBS, and LDL-C, TC, and TG, respectively. PMID- 23798932 TI - Comparison of energy intake and requirement of young students in Isfahan, Iran. AB - BACKGROUND: Estimation of energy intakes is required for understanding of growth and disease in young students. This study was conducted to estimate the energy intake of young students and compare with their energy requirements. MATERIALS AND METHODS: In this cross-sectional study, using simple random sampling, 400 students, aged 14-18 years, were selected in 2010. Hariss-Benedict equations were used to estimate the energy requirement of each group. RESULTS: Mean and standard error of energy intake and requirements of males was 2155 +/- 30 and 1670 +/- 18, respectively, and of females was 2700 +/- 21, 2300 +/- 4 kcal, respectively. Differences of means, energy intake, and requirement in both sexes were significant (P < 0.001). CONCLUSION: Because of their age (14-18 years), which is called growth age, energy intake was lower than their needs. PMID- 23798931 TI - Optimization of production of recombinant human growth hormone in Escherichia coli. AB - BACKGROUND: Human growth hormone (hGH) is a single-chain polypeptide that participates in a wide range of biological functions such as metabolism of proteins, carbohydrates and lipids as well as in growth, development and immunity. Growth hormone deficiency in human occurs both in children and adults. The routine treatment for this condition is administration of recombinant human growth hormone (rhGH) made by prokaryotes. Since nonglycosylated human growth hormone is a biologically active protein, prokaryotic expression systems are preferred for its production. MATERIALS AND METHODS: Different strains of E.coli were transformed by plasmid containing human growth hormone gene and cultured in different conditions. After induction by IPTG, recombinant human growth hormone production was assessed using ELISA, dot blotting and western blotting techniques. RESULTS: High levels of rhGH were produced using E.coli prokaryotic protein production system. CONCLUSION: This simple and cost effective production process could be recruited for large scale production of rhGH. PMID- 23798933 TI - Bulimia nervosa and its relation to voice changes in young adults: A simple review of epidemiology, complications, diagnostic criteria and management. AB - BACKGROUND: Bulimia nervosa (BN) is a type of feeding disorder that starts in adolescence and presents a variety of symptoms, recurrent vomiting in the oral cavity that may reach down to the larynx - similarly to gastro-esophageal reflux, causing laryngeal and voice disorder alterations. OBJECTIVE: These studies aimed at surveying the literature and investigate the studies that considered BN a risk factor for voice disorders and its epidemiology, complications, diagnostic criteria, and management. MATERIALS AND METHODS: A review of the literature was done based on a survey of BIOMED CENTRAL and COCHRANE @ OVID databases, which are linked to the IMU ezproxy virtual library (http://ezp.imu.edu.my/menu). The keywords "bulimia nervosa", "teenage complications" and "voice changes" were used. Citations with summaries were chosen to limit the topic, for the period between 2000 and 2010, in English. RESULTS: Of the ninety three papers we found, twenty three were used as a basis for this review. Among them, only three discuss BN as an etiology factor associated with voice changes in adult women, and we did not find any paper associating this with bulimic teenagers. CONCLUSION: It is necessary to observe laryngeal and vocal signs and symptoms associated with BN, especially in teenagers whose voices are going through a period of change. The contribution of this type of investigation, which should begin with a clinical history, is essential for minimizing the complications of bulimia nervosa. Thus, adolescents and adults with voice disorders should be investigated in greater detail. PMID- 23798935 TI - Identifying challenges for effective evaluation in nursing education: A qualitative study. AB - BACKGROUND: Although nursing education in Iran has a positive trend in growth; it is still facing with multifaceted challenges. This study aims to explore the challenges for effective evaluation of nursing education perceived by academic managers. MATERIALS AND METHODS: A qualitative study was performed by using 21 face-to-face, in-depth interviews with academic managers in medical universities and at the Ministry of Health and Medical Education in Iran. All interviews were recorded digitally, transcribed verbatim, and analyzed by qualitative content analysis. RESULTS: The main challenges could be categorized under 3 themes, each included 3 subthemes: managerial issues (inefficacy of management, inadequacy of policies and strategies, ineffective evaluation planning); administrative issues (inefficient and affected evaluators, inappropriate implementation, and inefficacy of approaches and tools); and structural issues (inappropriate culture, clinical education complexity, lack of alumni follow-up system). CONCLUSIONS: The results emphasize the need for educational evaluation development in nursing, including systematic and regular educational evaluation planning focusing on efficient feedback system and regard to excellence models. The comprehensive educational evaluation requires participation, involvement, and collaboration among the Nursing Board, Nursing ministerial office, faculties of nursing, and Nursing Organization. Thus, it is necessary to better designate current educational evaluation systems, policies, approaches, methods, and procedures. PMID- 23798934 TI - How dietary patterns could have a role in prevention, progression, or management of diabetes mellitus? Review on the current evidence. AB - OBJECTIVE: To investigate the role of dietary patterns in prevention and management of type 2 diabetes mellitus. MATERIALS AND METHODS: A systematic review of databases which were published in ISI, Cochrane Central Register of Controlled Trials databases, PubMed, Iran Medex, and MagIran was performed. "Diabetes" and "dietary pattern" were used as the keywords. RESULTS: A total of 58 studies which aimed to focus on diabetes mellitus, insulin resistance, metabolic syndrome, dietary pattern, and other related key words were reviewed. More than 47,447 articles were found and 46,709 entries of the extracted studies were excluded on the basis of the title and abstracts. The major dietary patterns were: "Healthy", "Western", "Traditional", "Prudent", "Unhealthy", "Mediterranean", "Modern", and "Dietary Approach to Stop Hypertension" (DASH) diets. Comparison of the effects of different diets revealed that dietary patterns containing fiber-rich foods have a protective role in managing diabetes mellitus. "Healthy", "Mediterranean", "Prudent", and "DASH" dietary patterns were associated with lower risk of hyperglycemia. CONCLUSIONS: The adherence to the Mediterranean, Prudent, or DASH diets could control hyperglycemia. The higher intake of vegetables, fruits, nuts, whole grains, and lower intake of red meat could reduce the risk of type 2 diabetes mellitus. PMID- 23798936 TI - Synergistic effects of genetic polymorphism and air pollution on markers of endothelial dysfunction in children. AB - BACKGROUND: This study aims to determine the association of some genetic polymorphisms in the relationship of air pollutants on the serum levels of thrombomodulin (TM) and tissue factor (TF) in a population-based sample of children and adolescents. MATERIALS AND METHODS: This cross-sectional study was conducted among 110 participants (52.8% girls) with a mean age of 12.7 + 2.3 years, in Isfahan, Iran. Genotypes of TM G33-A and + 5466A > G polymorphisms were determined by the polymerase chain reaction - restriction length fragment polymorphism method (PCR-RFLP). The enzyme-linked immunosorbent assay (ELISA) was used for measurement of serum TM and TF. RESULTS: THE FOLLOWING GENOTYPES WERE IDENTIFIED FOR TM: GG in 69.2%, GA in27.2%, and AA in 3.6% of the participants. Considering TF, 108 participants were homozygous for the + 5466A allele, and two subjects had + 5466AG genotype. The mean pollution standards index (PSI) value was at a moderate level; the mean particulate matter measured up to 10 MUm (PM(10)); and ozone (O(3)), nitrogen dioxide, and sulfur dioxide were considerably high. The mean serum TF and TM levels were not significantly different among the participants with the aforementioned genotypes. Among participants exposed to high quartiles of O(3), PM(10), and PSI, the TM-33G / A polymorphism (GA + AA genotype) increased the Odds ratio (OR) of the low serum TM level. There was no statistically significant association in the areas of low pollution. CONCLUSION: The findings of our study support the synergistic effect of the TM-33G / A polymorphism and air pollutants on factors associated with the onset of the atherosclerosis. This might be confirmatory evidence for gene environment interaction, and related effects on atherogenesis from early life. PMID- 23798937 TI - The impact of acute hypothyroidism on lipid levels in athyreotic patients. AB - BACKGROUND: We investigated the effect of acute hypothyroidism on lipid concentrations especially on high density lipoprotein (HDL-cholesterol) level in athyroatic patients. MATERIALS AND METHODS: Thirty-one patients, with a history of differentiated thyroid carcinoma and total thyroidectomy, who were candidates of radioiodine therapy, enrolled in the study. Their lipid profiles and serum thyrotropin stimulating hormone (TSH) levels were measured before and two-to-six weeks after thyroid hormone withdrawal. The lipid concentrations were compared with the paired t test and serum TSH using the Wilcoxon singed rank test. P values < 0.05 were considered statistically significant. RESULTS: The median of TSH concentration was 0.06 mU / liter on thyroid hormone suppressive therapy and 102 mU / liter at the thyroid hormone withdrawal phase (P < 0.0001). The serum concentrations of all lipids were significantly increased after withdrawal (P < 0.0001). The mean (SD) of the HDL-cholesterol concentration rose from 44 +/- 9 mg / dL to 58 +/- 17 mg / dL. The levels of total cholesterol, LDL-cholesterol, HDL cholesterol, and triglyceride increased by 58, 75, 30, and 59%, respectively, during acute hypothyroidism. CONCLUSION: The present study showed that thyroid hormone withdrawal altered the lipid concentrations significantly, in a short period of time. The levels of both atherogenic (LDL-cholesterol) and cardioprotective (HDL-cholesterol) particles increased concurrently. Their clinical importance should be investigated in future. PMID- 23798938 TI - The effect of pretreatment with clonidine on propofol consumption in opium abuser and non-abuser patients undergoing elective leg surgery. AB - OBJECTIVE: Clonidine, an alpha-2 adrenergic agonist, increases the quality of perioperative sedation and analgesia with a few side effects. This study was designed to assess the effect of clonidine premedication on the anesthesics used for elective below knee surgeries in opium abusers and non-abusers. MATERIALS AND METHODS: In a randomized clinical trial, 160 patients were selected and assigned into four groups. Eighty patients among the opium abusers were divided randomly into clonidine and no clonidine groups, with 40 patients in each, and 80 among the non-abusers were again divided randomly into clonidine and no clonidine groups, with 40 patients in each group. All were anesthetized for elective orthopedic operation using the same predetermined method. The total administered dose of propofol and other variables were compared. RESULTS: THE TOTAL PROPOFOL DOSE IN A DECREASING ORDER WAS AS FOLLOWS: Abuser patients receiving placebo (862 +/- 351 mg), non-abuser patients receiving placebo (806 +/- 348 mg), abuser patients receiving clonidine (472 +/- 175 mg), and non-abuser patients receiving clonidine (448 +/- 160 mg). Hence, a statistically significant difference was observed among the four study groups (P value for ANOVA = 0.0001). CONCLUSION: Adding clonidine as a preoperative medication decreases the patient's anesthetic needs; this decrease was even more considerable on the anesthetic needs than the effect of opium abuse history on anesthetic dose. PMID- 23798939 TI - How does the impact of a community trial on cardio-metabolic risk factors differ in terms of gender and living area? Findings from the Isfahan healthy heart program. AB - OBJECTIVE: To assess the impact of gender and living area on cardiovascular risk factors in the context of a comprehensive lifestyle intervention program. DESIGN: Data from independent sample surveys before (2000--2001) and after (2007) a community trial, entitled the Isfahan Healthy Heart Program (IHHP) were used to compare differences in the intervention area (IA) and reference area (RA) by gender and living area. SETTING: The interventions targeted the population living in Isfahan and Najaf-Abad counties as IA and Arak as RA. PARTICIPANTS: Overall, 12 514 individuals who were more than 19 years of age were studied at baseline, and 9570 were studied in postintervention phase. INTERVENTIONS: Multiple activities were conducted in connection with each of the four main strategies of healthy nutrition, increasing physical activity, tobacco control, and coping with stress. MAIN OUTCOMES: Comparing serum lipids levels, blood pressure, blood glucose and obesity indices changes between IA and RA based on sex and living areas during the study. RESULTS: In IA, while the prevalence of hypertension declined in urban and rural females (P < 0.05). In IA, the prevalence of hypercholesterolemia and hypertriglyceridemia decreased in both females and males of urban and rural areas except for hypercholesterolemia in rural males (P < 0.01). In RA, the significant changes include both decrease in the hypercholesterolemia among rural males (P < 0.001) and hypertriglyceridemia in urban females (P < 0.01), while hypertriglyceridemia was significantly increased in rural females (P < 0.01). CONCLUSIONS: This comprehensive community trial was effective in controlling many risk factors in both sexes in urban and rural areas. These findings also reflect the transitional status of rural population in adopting urban lifestyle behaviors. PMID- 23798940 TI - An immunohistochemical study of EGFR expression in colorectal cancer and its correlation with lymph nodes status and tumor grade. AB - BACKGROUND: Colorectal cancer (CRC) is a common human malignancy. Epidermal growth factor receptor (EGFR) is expressed in wide variety of human malignancies and is of some therapeutic and prognostic utility. The relationship between EGFR expression and regional lymph nodes involvement, and tumor grade in CRC has not been cleared, thus we decided to show it in a case-control study. MATERIAL AND METHODS: We chose paraffin-embedded tissue blocks of 46 CRCs with regional lymph nodes involvement as case group, and 46 CRCs without lymph nodes involvement as control group and then performed immunohistochemical staining for both groups. Moderate to strong, and complete staining of more than 10% of tumor cells was regarded as EGFR-positive. In analysis, P-value less than 0.05 was considered as significant. RESULTS: EGFR expression was positive in 80.4% and 56.5% of patients in the case and the control groups, respectively, which the difference between them was statistically significant. EGFR was positive in 48% of grade I, 60% of grade II and 100% of grade III tumors. CONCLUSIONS: EGFR expression had relationship with lymph node involvement and tumor grade in CRC. Also, lymph node involved CRCs showed higher scores of EGFR staining than control group. Thus, EGFR may be an additional factor to develop more aggressive CRCs and may predict the probability of lymph node involvement in these tumors. PMID- 23798941 TI - Comparison of anterior subcutaneous and submuscular transposition of ulnar nerve in treatment of cubital tunnel syndrome: A prospective randomized trial. AB - BACKGROUND: This study was designed to compare two methods of surgery, anterior subcutaneous transposition (ASCT) and anterior submuscular transposition (ASMT) of the ulnar nerve in treatment of cubital tunnel syndrome. MATERIALS AND METHODS: This randomized trial study was conducted from October 2008 to March 2009 in the Department of Orthopedic Surgery at University Hospital. Forty-eight patients with confirmed cubital tunnel syndrome were randomized in two groups, and each patient received one of two different surgical treatment methods, either ASCT (n = 24) or ASMT (n = 24). In the ASCT technique, the ulnar nerve was transposed and retained in the subcutaneous bed, whereas in the ASMT, the nerve was retained deep in the transected muscular complex, near the median nerve. Patient outcomes, including pain, sensation, muscle strength, and muscle atrophy were compared between groups. RESULTS: The two groups were similar in baseline characteristics. However, those treated with ASMT had a statistically significant reduction in their pain levels compared with ASCT (21 (87.5%) vs 8 (33.3%), P < 0.05). There were no statistically significant differences between the two groups relative to sensation (11 (45.8%) vs 12 (50%)), muscle strength (17 (70.8%) vs 15 (62.5%)), or muscle atrophy (15 (62.5%) vs 17 (70.8%)) (P > 0.05). CONCLUSIONS: Our results indicate that ASMT are more efficient than ASCT for managing cubital tunnel syndrome. In patients who had ASMT, there were significant reductions of pain compared with ASCT. PMID- 23798942 TI - Determinants of mammography screening behavior in Iranian women: A population based study. AB - BACKGROUND: Breast cancer remains a substantial health concern in Iran due to delay and late stage at diagnosis and treatment. Despite the potential benefits of mammography screening for early detection of breast cancer, the performance of this screening among Iranian women is low. For planning appropriate intervention, this study was carried out to identify mammography rates and explore determinants of mammography screening behavior in females of Isfahan, Iran. MATERIALS AND METHODS: In this population-based study, 384 women of 40 years and older were interviewed by telephone. The Farsi version of Champion's Health Belief Model scale (CHBMS) was used to examine factors associated with mammography screening. The obtained data were analyzed by SPSS (version 16.0) using statistical Chi square, Fisher Exact test, t-test and multiple logistic regression model to identify the importance rate of socio-demographic and Health Belief Model (HBM) variables to predict mammography screening behavior. In all of tests, the level of significant was considered a = 0.05. RESULTS: Mean age +/- SD of women was 52.24 +/- 8.2 years. Of the 384 participants, 44.3% reported at least one mammogram in their lifetime. Logistic regression analysis indicated that women were more likely to have mammography if they heard/read about breast cancer (OR = 4.17, 95% CI 2.09, 8.34), menopause in lower age (OR = 0.2, 95% CI 0.87, 0.99) and history of breast problem (OR = 0.9, 95% CI 0.12, 0.32). Also, women who perceived more benefits of mammography (OR = 1.84, 95% CI 1.63, 2.09), fewer barriers of mammography (OR = 0.91, 95% CI 0.86, 0.96) and had more motivation for health (OR = 0.94, 95% CI 0.89, 1) were more likely to have mammography. CONCLUSION: The findings indicated that the rate of mammography screening among women in Isfahan province is low and highlights the need for developing a comprehensive national breast cancer control program, which should be considered as the first priority for healthcare providers. Also, identification of these factors can help to design an appropriate educational intervention that focuses on benefits of mammography screening, decreasing changeable barriers, improving access to mammography, increasing health motivation, promoting perceived self efficacy and mammography adherence. PMID- 23798943 TI - A comparison between cetirizine and ondansetron in preventing postoperative nausea and vomiting in adults. AB - BACKGROUND: Postoperative nausea and vomiting are some of the important and common side effects of anesthesia after surgery occurring in almost 20-30% of patients and is the second factor of a patient's complaint and inconvenience after pain. This study compares the effect of oral cetirizine and ondansetron in the prevention of postoperative nausea and vomiting in adults. MATERIALS AND METHODS: In a blind and prospective study in fall 2010, 300 patients aged 18-65 years who were among ASA I-II in Chamran Orthopedic Hospital were randomly divided into three equal groups receiving cetirizine, ondansetron, and placebo, respectively. General anesthesia was identical. After operation (after 1-2 h in the recovery room, after 2-12 and 12-24 h in the ward), the presence or absence and any nausea or vomiting was recorded. RESULTS: The postoperative nausea and vomiting (PONV) rate after 1-2 h in the recovery room, after 2-12 and 12-24 h in the ward in placebo, and both groups of cetirizine and ondansetron were 50%, 21%, and 11%, respectively while the difference was significant (P value < 0.05). Regarding the number of vomiting, the least was related to ondansetron (especially in the first 2-12 h) but the difference was not significant (P > 0.05). CONCLUSION: The PONV rate in cetirizine and ondansetron groups was less than the placebo group. PMID- 23798944 TI - Qualitative analysis of parents' experience of hearing loss of their school going children of a rural area of Nagpur. AB - INTRODUCTION: Qualitative research methods provide a means of collecting and interpreting narrative or observational data about such interactions, leading to a deeper understanding of the process of health care delivery. This approach was used to clarify key themes from parents' comments about challenges on paths to detect hearing impairment. MATERIALS AND METHODS: An exploratory descriptive qualitative research design is used. In-depth interviews by using a semi structured questionnaire and focus group discussions (FGD) were held with parents, and other study groups. A study was conducted in Deaf Dum Rural School, Saoner, Nagpur district, Maharashtra, India. Purposive voluntary sampling is utilized. Semi-structured and in-depth interviews and FGD were conducted in private rooms. A FGD guide covered open-ended comments to the set of questions. RESULTS: Parents of 65 children (59%) replied to the questionnaire. Out of them, 55 (85.6%) were the parents of school children resides in the hostel. The majority of the children have profound hearing impairment (75.86%). Theme analysis revealed perceptions about causes, ways, and means of early detection, and powerful emotions experienced by parents at FGD. CONCLUSIONS: Reaching beyond numerical analyses, qualitative studies allow for expression of junior doctors, Deaf and Dump School teacher and parents' thoughts, feelings, and experiences. This study provides a means of collecting and interpreting narrative or observational data. PMID- 23798945 TI - Prevalence of hemoglobinopathy, ABO and rhesus blood groups in rural areas of West Bengal, India. AB - BACKGROUND: Hemoglobinopathies are a group of inherited disorders of hemoglobin synthesis. It could be formed a fatal scenario in concern of lacking of actual information. Beside this, ABO and Rh blood grouping are also important matter in transfusion and forensic medicine and to reduce new born hemolytic disease (NHD). MATERIALS AND METHODS: The spectrum and prevalence of various hemoglobinopathies, ABO and rhesus (Rh) blood groups was screened among patients who visited B.S. Medical College and Hospital, Bankura, West Bengal, India. This study was carried out on 958 patients of different ages ranging from child to adults from January to June 2011. High-performance liquid chromatography (HPLC), complete blood count (CBC) and hemagglutination technique were performed for the assessment of abnormal hemoglobin variants, ABO and Rh blood groups, respectively. RESULTS: Results from this study had been shown that there was high prevalence of hemoglobinpathies (27.35%) where beta-thalassemia in heterozygous state occurred more frequent than other hemoglobinopathies. Out of 958 patients, 72.65% were HbAA and 27.35% were hemoglobinopathies individuals where 17.64% beta-thalassemia heterozygous, 2.92% beta-thalassemia homozygous, 3.86% HbAE, 1.15% HbAS trait, 1.25% HbE-beta thalassemia trait and 0.52% HbS-beta thalassemia trait were found. No incidence of HbSS, HbSC, HbCC, HbD and other variants of hemoglobinpathies were observed. The gene frequencies with respect to ABO systems had been shown as O > B > A > AB. Blood group O was the highest (35.8%) and the least percentage distribution was blood group AB (6.68%). Rhesus positive (Rh+) were 97.7%, while the remaining was 2.3% Rhesus negative (Rh-). The frequencies of A(+), B(+), AB(+,) and O(+) blood groups were 22.44%, 33.61%, 6.58%, and 35.07%, respectively. CONCLUSIONS: Remarkable percentages of hemoglobinopathies were prevalent from the present study. An extensive screening of the population is needed to assess the prevalence of hemoglobinopathies, which will help in identification of carriers of hemoglobinopathies and further it will be of assistance in taking adequate therapeutic and preventive measures. PMID- 23798946 TI - GERD related micro-aspiration in chronic mustard-induced pulmonary disorder. AB - BACKGROUND AND AIM: Bronchiolitis obliterans (BO) is the main pulmonary involvement resulting from sulfur mustard (SM) gas exposure that was used against Iranian civilians and military forces during the Iran-Iraq war. The present study aimed to investigate the prevalence of gastro-esophageal reflux (GER) and gastric micro-aspiration in SM gas injured patients with chronic pulmonary diseases and recurrent episodes of exacerbations. MATERIALS AND METHODS: This cross-sectional study was done at Baqiyatallah University of Medical Sciences, Tehran, Iran. Gastric micro-aspiration and GER were assessed in the enrolled patients by assessing bile acids, pepsin and trypsin in their bronchoalveolar lavage fluid. RESULTS: Our result showed that bile acids were found to be high in 21.4% patients, and low in 53.6% of patients. Only in 16% patients, no bile was detected in the BALF. Trypsin and pepsin were detected in BAL fluid of all patients. CONCLUSION: Most of BO patients after exposure to SM suffer GER, while none the etiologic factors of GER in post lung transplant BO are present. It would be hypothesized that GER per se could be considered as an aggregative factor for exacerbations in patients. Further studies will provide more advances to better understanding of pathophysiological mechanism regarding GER and BO and treatment. PMID- 23798947 TI - Evaluation of DNA damage of hydro-alcoholic and aqueous extract of Echium amoenum and Nardostachys jatamansi. AB - BACKGROUND: Today most of herbal medicines are marketing without any standard safety profiles. Although common assumption is that these products are nontoxic but this assumption may be incorrect and dangerous, so toxicological studies should be done for herbal drugs. According to the frequent use of Echium amoenum as immunostimulant and useful in conditions including pain, cough, sore throat and arthritis, and Nardostachys jatamansi as tranquilizer and sleep inducer and evidences of some toxicities, we assessed the probable effect of their extracts on DNA of hepG2 cells using the comet assay. MATERIALS AND METHODS: Different concentrations of above extracts of the plants are incubated with hepG2 cells for 24 h. A mixture of cell suspension and agarose gel were put on slides, then slides were embedded in a lysing solution and were put in electrophoresis buffer (pH = 13). Then the electrophoresis procedure took place in an alkaline solution and after neutralization stage, colorization was done by ethidium bromide and comets were observed using a fluorescence microscope. At least 100 cells of each sample were evaluated and three parameters including comet length, percent of DNA in tail, and tail moment were assessed. RESULTS: Both Aqueous and hydro-alcoholic extract of E. amoenum were genotoxic in the concentrations of 25 mg/ml and aqueous and hydro-alcoholic extract of N. jatamansi were genotoxic in the concentrations 5 and 10 mg/ml, respectively. CONCLUSIONS: Although E. amoenum and N. jatamansi are highly used in medicine, these herbs have genotoxic effects in determined concentrations and they should be used cautiously. PMID- 23798948 TI - Is there any difference between non-obese male and female in response to cardiac rehabilitation programs? AB - INTRODUCTION: Coronary artery disease (CAD) is the leading cause of death and disability all over the world. A sedentary lifestyle and dyslipidemia are known to be the major risk factors, which play an important role in the progression of coronary artery disease. Regarding gender differences, the risk of developing coronary heart disease is recognized as being different between non-obese males and non-obese females. Hence, the aim of this study is to assess the benefits of a comprehensive cardiac rehabilitation program (CRP) on the functional capacity and lipid profiles, such as, total cholesterol, triglycerides, low density lipoprotein cholesterol, and high density lipoprotein cholesterol in non-obese males and non-obese females with coronary artery disease, and comparing these groups. MATERIALS AND METHODS: We evaluated 585 non-obese males and females with coronary artery disease. All the participants completed the cardiac rehabilitation program for two months, which included 24 exercise training sessions, medical evaluation, and consultation. For investigation of the effects of the cardiac rehabilitation program on the functional capacity and lipid profiles, exercise tests were carried out by each patient, and also, their blood samples were taken on entrance and at the end of this period. RESULTS: The findings, following 24 sessions in the cardiac rehabilitation program, showed that the functional capacity (P = 0.00) and all lipid profiles had significantly improved in both the groups, except that the high density lipoprotein cholesterol did not show a significant difference in non-obese females. In addition, comparing the two groups did not show any significant differences in lipid profiles, but the changes in functional capacity were significant (P = 0.00) between the two groups, following the cardiac rehabilitation program. CONCLUSION: The CRP, which was performed by the patients under supervision of a physician and an exercise physiologist, plays a key role in improving the functional capacity (FC) and all lipid profiles in non-obese males and females with coronary artery disease, without any attention to gender differences. PMID- 23798949 TI - Inadequate investment on management of diabetes education. AB - AIMS: Reforming and improving the patient education process need more insight into the strengths and weaknesses of the existing education process. There is little documentation on patient education in National Diabetes Prevention and Control Program in Iran, so the present study aimed to describe patient education process in diabetes centers in one of the provinces of Iran. MATERIALS AND METHODS: This is a qualitative content analysis. Twelve nurses who work as diabetes nurse educators (DNEs) and an internal medicine specialist participated in this study. Data was obtained through semi-structured face-to-face interviews, a focus group, existing documents, field notes, and multiple observations. Data analysis was guided by the conventional approach of qualitative content analysis. RESULTS: Three main themes including unequipped trainers (insufficient knowledge and experience, lack of appropriate educational facilities, lack of time, lack of patient's interest), unstructured education (lack of educational need assessment, lack of evaluation, lack of continuing patient education), unmanaged education (lack of official planning for patient education and supervising the education process) emerged from qualitative content analysis. CONCLUSIONS: Although patient education is one of the important strategies in National Diabetes Prevention and Control Program, there however has not been necessary investment and adequate space to achieve it. Patient education was not structured and based on scientific principles. Training of diabetes nurse educators (DNEs) is neglected, and there is no supervision on patient education process. PMID- 23798950 TI - Plantar fasciitis. AB - Heel pain, mostly caused by plantar fasciitis (PF), is a common complaint of many patients who requiring professional orthopedic care and are mostly suffering from chronic pain beneath their heels. The present article reviews studies done by preeminent practitioners related to the anatomy of plantar fasciitis and their histo-pathological features, factors associated with PF, clinical features, imaging studies, differential diagnoses, and diverse treatment modalities for treatment of PF, with special emphasis on non-surgical treatment. Anti inflammatory agents, plantar stretching, and orthosis proved to have highest priority; corticosteroid injection, night splints and extracorporeal shock wave therapy were of next priority, in patients with PF. In patients resistant to the mentioned treatments surgical intervention should be considered. PMID- 23798951 TI - Gastrosplenic fistula due to splenic large B-cell lymphoma. AB - A gastrosplenic fistula (GSF) is an unusual complication arising from a variety of primary gastric or splenic malignant lesions and less commonly from benign diseases. Splenic large cell lymphoma may be a main cause of this distinctive complication. We report a case of 62-year-old male with spontaneous GSF due to pathologically proven splenic large cell lymphoma who was diagnosed by computed tomography and treated successfully by surgical management. PMID- 23798952 TI - Complete atrioventricular block in an adult with congenitally corrected transposition of the great arteries with interrupted inferior vena cava. AB - A 56-year-old man got admitted as he was suffering from dizziness for 3 days. Electrocardiogram (ECG) showed complete atrioventricular (AV) block with ventricular rhythm of 35/min. We found that he had no inferior vena cava (IVC) which drained into right atrium in the middle of temporary pacing lead insertion. Venous drainage into superior vena cava from dilated azygos vein was identified after venogram. Echocardiogram revealed a congenitally corrected transposition of the great arteries (CCTGA). Chest computed tomography (CT) angiogram revealed AV and ventriculoarterial discordance with reversed ventricles and interrupted IVC with azygos continuation. DDD pacemaker was implanted via left axillary vein without any problem. PMID- 23798953 TI - Villous adenoma of gallbladder in a patient with systemic lupus erythematosus. AB - Villous adenomas occur most frequently in the rectum and colon. These tumors are rarely seen in the gallbladder. We report a case of gallbladder villous adenomas in a 69-year-old patient who has systemic lupus erythematosus (SLE). The patient was admitted for investigation of a gallbladder mass. Ultrasonography, computed tomography, and magnetic resonance imaging showed two well-circumscribed lobulated masses in the gallbladder. Open cholecystectomy was performed and histological examination revealed typical features of villous adenoma. This report describes the first case of villous adenomas of gallbladder with SLE, and documents its imaging findings comprehensively. PMID- 23798954 TI - Sternal fractures: "Operative treatment" should be kept in mind. AB - Isolated sternal fracture is a benign condition which generally heals with conservative treatment. But sometimes surgical intervention is necessary due to pain, other organ injury and union problems. There are several ways for repair; however, the best method is not yet defined. In this report, we presented two cases who were treated surgically for different indications with different suture materials. When anatomically correction can be achieved, using suture materials is a safe and effective method. PMID- 23798955 TI - Clinico-mycological evaluation of dermatophytes and non-dermatophytes isolated from various clinical samples: A study from north India. PMID- 23798956 TI - Medical findings in women with anorexia nervosa in a korean population. AB - OBJECTIVE: Eating disorders are a common clinical problem among young women in Asian countries. The aim of this study is to determine the medical effects of anorexia nervosa (AN) in the Korean population. METHODS: We comprehensively investigated medical complications including haemodynamic, haematologic, endocrine, and bone density abnormalities in 67 Korean women with AN, together with 194 healthy Korean women of comparable age with a cross-sectional design. RESULTS: In AN, 36.9% were anaemic, 50.8% were leukopenic, 35.5% were hypoproteinemic, 7.9% were hypokalemic, 9.5% had increased alanine aminotransferase, 6.3% were hyperbilirubinemia, 14.5% were hypercholesterolemia, 14.8% had decreased triiodothyronine. Osteopenia at any one site was identified in 43.3% and an additional 13.4% had osteoporosis. The lowest-ever body mass index was the main determinant of bone mineral density. CONCLUSION: Our data in Korean patients with AN show high frequencies of laboratory abnormalities for medical complications. This study emphasizes the importance of recognizing AN as a medical risk in young Korean women. PMID- 23798957 TI - Mediating effect of executive function on memory in normal aging adults. AB - OBJECTIVE: We hypothesize that the effect of aging on memory is mediated by executive function. METHODS: Two hundred and thirty healthy adults (101 male, 129 female) were recruited for the study. We used a promising, newly developed, computerized neuropsychological test for the measurement of executive function and memory. The data were analyzed using structural equation modeling and path analysis. RESULTS: The full mediation model showed a good fit to the data. However, chi-squared (chi(2)) tests for model comparison indicated that the partial mediation model better fits our data. Thus, the partial mediation model was used as the final model. In terms of auditory-verbal memory, the effect of aging on memory was fully mediated by executive function. However, visuo-spatial memory was significantly affected both indirectly (through executive function) and directly (by aging). Gender differences were not significant in this model. CONCLUSION: This study demonstrated the importance of executive function in the memory functioning of normal aging adults. It is noteworthy that modality differences were found between auditory-verbal and visuo-spatial memory. Aging is not the only factor that drives memory decline, and its direct, adverse effect on memory was more prominent in the visuo-spatial memory task than auditory-verbal memory task. Since performance in both modalities is fully or partially mediated by executive function, it is important to train normal aging adults in executive control skills, such as planning, strategy formation, and rapid decision making. PMID- 23798958 TI - Comparison of brain activation in response to two dimensional and three dimensional on-line games. AB - OBJECTIVE: The present study assessed the difference in the brain activity of professional gamers (excessive players, but not addicts) in response to playing a 3-dimensional online game with an improved interface. METHODS: Twenty-three StarCraft I pro gamers and 16 StarCraft II pro gamers were recruited at Chung Ang University Medical Center. Brain activity in response to StarCraft I or II cues was assessed with a 1.5 Tesla Espree MRI scanner. RESULTS: StarCraft I pro gamers showed significantly greater activity in 4 clusters in response to the video game cues compared to StarCraft II pro gamers: right superior frontal gyrus, right medial frontal gyrus, right occipital lobe, and left medial frontal gyrus. StarCraft II pro gamers showed significantly greater activity in 3 clusters in response to the video game cues compared to StarCraft I pro gamers: left middle frontal gyrus, left temporal fusiform gyrus and left cerebellum. DISCUSSION: This is the first study to show the difference in brain activity between gamers playing either a 2-dimensional or 3-dimensional online game. Current brain imaging studies may confirm the pro gamers' experience when playing StarCraft II, a 3-dimensional game with an improved interface, relative to playing StarCraft I. PMID- 23798959 TI - Decreased cardiac vagal control in drug-naive patients with posttraumatic stress disorder. AB - OBJECTIVE: Decreased cardiac vagal control (CVC) has been proposed in posttraumatic stress disorder (PTSD), but the results are mixed. Analyses with larger sample sizes and better methodology are needed. METHODS: Thirty-two drug naive survivors with current PTSD, 32 survivors without PTSD and 192 matched controls were recruited for a case-control analysis. We used the PTSD checklist civilian version (PCL-C) to assess posttraumatic symptoms severity. Cardiac autonomic function was evaluated by measuring heart rate variability (HRV) parameters. Frequency-domain indices of HRV were obtained. The obtained results were evaluated in association with personality traits assessed by the Tridimensional Personality Questionnaire (TPQ). RESULTS: PTSD patients exhibited decreased LF-HRV and HF-HRV as compared to survivors without PTSD and to matched controls. The PTSD symptoms severity was associated with reduced mean RR intervals, Var-HRV, LF-HRV and HF-HRV. The harm avoidance score (which has been suggested to be associated with serotonergic activity) was negatively correlated with Var-HRV, LF-HRV and HF-HRV. CONCLUSION: These data suggest that PTSD is accompanied by decreased CVC, highlighting the importance of assessing HRV in PTSD patients. In view of the increased risk for cardiovascular diseases in these vulnerable individuals, one might consider the treatment to restore their autonomic function while reducing PTSD symptoms. PMID- 23798960 TI - The temperament and character of korean male conscripts with military maladjustment-a preliminary study. AB - OBJECTIVE: Recently, an increasing number of Korean male conscripts have been retiring because of military maladjustment despite the presence of qualifying medical and psychological screening tests in the Korean army. These problems suggest the presence of a common personality problem. To further examine this possibility, the present study used Cloninger's psychobiological model to investigate the temperament and character of soldiers suffering from military maladjustment. METHODS: Seventy-nine maladjusted male conscripts and eighty-seven controls enrolled at the 1596th unit from April 2011 to June 2012 participated in the present study. To measure participant personality, we used the Korean version of the Temperament and Character Inventory, Revised-Short. We used logistic regression analysis to examine the association between TCI-RS scores and risk of military maladjustment. RESULTS: The maladjustment group had a lower rank, socioeconomic status, education level, and a shorter duration of military service than the control group. The harm avoidance and self-transcendence scores were significantly higher in the maladjustment group, with lower scores for reward dependence, persistence, self-directedness, and cooperativeness scores. However, of these measures, only low cooperativeness was associated with an increased risk of military maladjustment. CONCLUSION: These results suggest that a low level of cooperativeness can predict military inadequacy. Maladjusted male conscripts may have different personality characteristics from normals. To validate our results, further follow-up or cohort studies with a larger sample will be required. PMID- 23798961 TI - Temperamental characteristics in adults with attention-deficit hyperactivity disorder: a comparison with bipolar disorder and healthy control groups. AB - OBJECTIVE: To date, the affective temperamental characteristics of adults with attention-deficit hyperactivity disorder (ADHD) have not been studied. The aim of this study is to explore those temperamental characteristics for adults diagnosed with ADHD as measured by the TEMPS-A and then to compare those results with results for individuals diagnosed with bipolar disorder (BD) and with healthy controls. METHODS: Forty adults with ADHD, 40 patients with BD, and 40 healthy controls were enrolled in this study. The groups were matched by age and gender. All patients were assessed using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID I), the Hamilton Depression Rating Scale, the Hamilton Anxiety Rating Scale, the Young Mania Rating Scale and the Wender Utah Rating Scale. Subjects' temperamental characteristics were examined using the Turkish version of the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-auto questionnaire (TEMPS-A). RESULTS: Ten subjects (25%) in the ADHD group and 15 subjects (30%) in the bipolar group had at least one dominant temperament. There was no identifiable dominant temperament in the control group. Compared to the control group, the ADHD group scored higher than other groups on all domains of the TEMPS-A: depressive cyclothymic, irritable and anxious. However, the hyperthymic domain was not higher for this group. Adults with ADHD scored higher on the irritable temperament scale as compared to the BD group. The ADHD and BD groups had similar mean scores for each of the other four temperaments. CONCLUSION: The adults diagnosed with ADHD in this study had different temperamental characteristics from the control group, and these temperamental characteristics were similar to those of the bipolar patients. Recognizing the role of temperamental characteristics in adults with ADHD may increase our understanding of ADHD. PMID- 23798962 TI - Can the Loudness Dependence of Auditory Evoked Potentials and Suicidality Be Used to Differentiate between Depressive Patients with and without Bipolarity. AB - OBJECTIVE: This study aimed to test the hypothesis that the loudness dependence of auditory evoked potentials (LDAEP) can be used to predict the presence of bipolarity in patients with major depressive episodes. METHODS: A cohort of 61 patients who met the criteria for major depressive disorder (MDD) following diagnosis using Axis I of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders-text revision, and who had no history of hypomanic or manic episodes was included in this study. The patients were stratified into two subgroups based on whether or not they achieved a positive score for the Korean versions of the Mood Disorder Questionnaire (K-MDQ). The LDAEP was evaluated by measuring the auditory event-related potentials before beginning medication with serotonergic agents. RESULTS: The Barratt Impulsiveness Scale (BIS) score was also higher for the positive screening group (81.24+/-11.87) than for the negative screening group (73.30+/-14.92; p=0.039, independent t-test). However, the LDAEP, Beck Depression Inventory, Hamilton Depression Rating Scale, Beck Hopelessness Scale (BHS), and Hamilton Anxiety Scale scores did not differ significantly between them. When binary logistic regression analysis was carried, the relationship between the positive or negative subgroups for K-MDQ and BIS or Beck Scale for Suicidal Ideation (BSS) score was also significant (respectively, p=0.017, p=0.038). CONCLUSION: We found that LDAEP was not significantly different between depressive patients with and without bipolarity. However, our study has revealed the difference between two subgroups based on whether or not they achieved a positive score for the K-MDQ in BIS or BSS score. PMID- 23798963 TI - Relationship between SSRIs and Metabolic Syndrome Abnormalities in Patients with Generalized Anxiety Disorder: A Prospective Study. AB - OBJECTIVE: SSRIs are some of the most widely prescribed medications in the world. In addition to their effectiveness, SSRIs were reported to be associated with the side effects of weight gain, sexual dysfunction, drug interactions, extrapyramidal symptoms and discontinuation symptoms. However, the effects of SSRIs on metabolic parameters are poorly understood. METHODS: This study aims to describe the effects of SSRIs on the metabolic parameters of drug-naive first episode patients with generalized anxiety disorder. Ninety-seven female patients aged 20-41 years without any metabolic or psychiatric comorbidity were included in the study. Fluoxetine, sertraline, paroxetine, citalopram and escitalopram were randomly given to the patients. Metabolic parameters, including BMI, waist circumference and the levels of fasting glucose, total cholesterol, triglyceride, HDL, LDL and blood pressure, were measured before and after 16 weeks of treatment. RESULTS: In the paroxetine group, there was a significant increase in the parameters of weight, BMI, waist circumference, fasting glucose, total cholesterol, LDL and triglyceride after 16 weeks of treatment. There were significant increases in the levels of triglyceride in the citalopram and escitalopram groups. In the sertraline group, the total cholesterol level increased after treatment. In the fluoxetine group, there were significant reductions in the parameters of weight, total cholesterol and triglyceride. CONCLUSION: To our knowledge, this study is the first to prospectively describe metabolic syndrome abnormalities in patients with first episode generalized anxiety disorder. Although the effectiveness of the different SSRIs is similar, clinicians should be more careful when prescribing SSRIs to patients who have cardiac risk factors. Larger and lengthier controlled clinical trials are needed to explore the associations between SSRI use and metabolic syndrome. PMID- 23798964 TI - Development and Standardization of Extended ChaeLee Korean Facial Expressions of Emotions. AB - OBJECTIVE: In recent years there has been an enormous increase of neuroscience research using the facial expressions of emotion. This has led to a need for ethnically specific facial expressions data, due to differences of facial emotion processing among different ethnicities. METHODS: FIFTY PROFESSIONAL ACTORS WERE ASKED TO POSE WITH EACH OF THE FOLLOWING FACIAL EXPRESSIONS IN TURN: happiness, sadness, fear, anger, disgust, surprise, and neutral. A total of 283 facial pictures of 40 actors were selected to be included in the validation study. Facial expression emotion identification was performed in a validation study by 104 healthy raters who provided emotion labeling, valence ratings, and arousal ratings. RESULTS: A total of 259 images of 37 actors were selected for inclusion in the Extended ChaeLee Korean Facial Expressions of Emotions tool, based on the analysis of results. In these images, the actors' mean age was 38+/-11.1 years (range 26-60 years), with 16 (43.2%) males and 21 (56.8%) females. The consistency varied by emotion type, showing the highest for happiness (95.5%) and the lowest for fear (49.0%). The mean scores for the valence ratings ranged from 4.0 (happiness) to 1.9 (sadness, anger, and disgust). The mean scores for the arousal ratings ranged from 3.7 (anger and fear) to 2.5 (neutral). CONCLUSION: We obtained facial expressions from individuals of Korean ethnicity and performed a study to validate them. Our results provide a tool for the affective neurosciences which could be used for the investigation of mechanisms of emotion processing in healthy individuals as well as in patients with various psychiatric disorders. PMID- 23798965 TI - Gender difference in event related potentials to masked emotional stimuli in the oddball task. AB - OBJECTIVE: We investigated gender differences in event-related potential (ERP) responses to subliminally presented threat-related stimuli. METHODS: Twenty-four participants were presented with threat-related and neutral pictures for a very brief period of time (17 ms). To explore gender differences in ERP responses to subliminally presented stimuli, we examined six ERP components [P1, N170, N250, P300, Early Posterior Negativity (EPN) and Late Positive Potential (LPP)]. RESULTS: The result revealed that only female participants showed significant increases in the N170 and the EPN in response to subliminally presented threat related stimuli compared to neutral stimuli. CONCLUSION: Our results suggest that female participants exhibit greater cortical processing of subliminally presented threat-related stimuli than male participants. PMID- 23798966 TI - Impact of the BDNF Val66Met Polymorphism on Regional Brain Gray Matter Volumes: Relevance to the Stress Response. AB - OBJECTIVE: Genetic imaging is used to investigate the mechanism by which genetic variants influence brain structure. In a previous study, a structural change of the dorsolateral prefrontal cortex was associated with symptom modulation in post traumatic stress disorder patients. This study examined the effect of a polymorphism in the gene encoding brain-derived neurotrophic factor (BDNF) on regional gray matter (GM) volumes and the correlations between the dorsolateral prefrontal GM volume and the stress level in healthy volunteers. METHODS: Sixty one volunteers underwent genotyping for the BDNF Val66Met single nucleotide polymorphism (SNP) and completed the Stress Response Inventory (SRI). Magnetic resonance images were also acquired, and the effect of each subject's BDNF genotype and SRI subscore on his or her dorsolateral prefrontal GM volume was evaluated. RESULTS: The Val/Val homozygotes had significantly larger GM volumes in the prefrontal cortex and the precuneus, the uncus, and the superior temporal and occipital cortices than Met carriers. The Met homozygotes demonstrated a higher stress response in depression domain than Val/Val and Val/Met groups. A negative correlation between the middle frontal cortex GM volume and the SRI depression subscore was found. CONCLUSION: These findings indicate an interaction between genes and brain structure, and they suggest that differences in dorsolateral prefrontal GM volume related to the BDNF Val66Met SNP are associated with resilience to stressful life events, particularly in the dimension of emotion. PMID- 23798967 TI - No effect of serotoninergic gene variants on response to interpersonal counseling and antidepressants in major depression. AB - OBJECTIVE: Gene variants within the serotonin pathway have been associated with major depressive disorder (MDD) treatment outcomes, however a possible different modulation on pharmacological or psychological treatments has never been investigated. METHODS: One hundred sixty MDD patients were partially randomized to either inter-personal counseling (IPC) or antidepressants. The primary outcome was remission at week 8. Five serotonergic polymorphisms were investigated (COMT rs4680, HTR1A rs6295, HTR2A rs2224721, HTR2A rs7997012 and SLC6A4 rs421417). RESULTS: IPC (n=43) and antidepressant (n=117) treated patients did not show any difference in remission rates at week 8 (corrected for baseline severity, age and center). None of the studied gene variants impacted on response and remission rates at week 8 neither in the IPC nor in the antidepressant group. An analysis of the whole sample showed a trend of association between rs7997012 AA genotype and a better treatment outcome. CONCLUSION: Our study confirms that IPC is an effective psychological intervention comparable to antidepressants in mild moderate MDD. Polymorphisms related to the serotonin system did not exert a major effect on clinical outcomes in none of the treatment groups. PMID- 23798968 TI - No Association between Serotonin Receptor 2C-759C/T Polymorphism and Weight Change or Treatment Response to Mirtazapine in Korean Depressive Patients. AB - OBJECTIVE: Activation of one or more serotonin (5-HT) receptors may play a role in mediating the antidepressant effects of serotonergic antidepressants. The serotonin 2C (5HT 2C) receptor is known to be associated with antidepressant action and weight gain. We sought to determine whether the 5-HTR 2C receptor 759C/T polymorphism was associated with weight gain and treatment response to mirtazapine in major depressive disorder (MDD) patients. METHODS: The 5-HT 2C receptor -759C/T polymorphism was analyzed in 323 MDD patients. All patients were evaluated using the 21-item Hamilton Depression Rating Scale at the beginning of the study and at 1, 2, 4, and 8 weeks of mirtazapine treatment. RESULTS: There was no significant difference in the 5-HT 2C receptor -759C/T genotype distribution between responder and non-responder groups. The 5-HT 2C receptor 759C/T polymorphism was not associated with weight change over time after mirtazapine administration. CONCLUSION: The 5-HT 2C receptor -759C/T polymorphism does not appear to be a predictor of treatment response to mirtazapine. This polymorphism was not associated with weight change after 8 weeks of mirtazapine treatment. Further investigation on other polymorphisms of the 5-HT 2C gene is required to determine whether the 5-HT 2C gene influences treatment response and weight change after mirtazapine administration in patients with major depressive disorder. PMID- 23798969 TI - The contingent negative variation in remitted paediatric bipolar patients: no evidence of abnormality. AB - Although the Contingent Negative Variation (CNV) paradigm has been useful in schizophrenia, limited research involving such paradigm in subjects with Bipolar Disorder (BD) has produced contradictory findings. To the best of our knowledge, no study has investigated CNV in Paediatric Bipolar Disorder (PBD) subjects. Thirty remitted PBD patients and thirty matched healthy control group subjects participated in the study. No significant between group main effect could be found for either CNV latency or amplitude. We propose that CNV is unlikely to be a true endophenotype of BD. However, absence of CNV finding during euthymic phase in BD may help us in advancing our understanding of BD and such finding may, in fact, have some specificity with regard to differentiating BD from schizophrenia. PMID- 23798970 TI - Two cases of hypersexuality probably associated with aripiprazole. AB - Sexual dysfunction is a common side effect in patients treated with antipsychotics but significant differences exist across different compounds. We report hypersexuality symptoms in two female patients with schizophrenia who were receiving treatment with aripiprazole. The patients experienced more frequent sexual desire and greater sexual preoccupation after taking aripiprazole. We discuss the potential neuro-chemical mechanisms for this and argue that aripiprazole's unique pharmacological profile, partial agonism with high affinity at dopamine D2-receptor, may have contributed to the development of these symptoms. PMID- 23798971 TI - "Attenuated psychosis syndrome" or "subthreshold prodromal state"? PMID- 23798972 TI - Understanding admixture patterns in supplemented populations: a case study combining molecular analyses and temporally explicit simulations in Atlantic salmon. AB - Genetic admixture between wild and introduced populations is a rising concern for the management of endangered species. Here, we use a dual approach based on molecular analyses of samples collected before and after hatchery fish introduction in combination with a simulation study to obtain insight into the mechanisms of admixture in wild populations. Using 17 microsatellites, we genotyped pre- and post-stocking samples from four Atlantic salmon populations supplemented with non-native fish to estimate genetic admixture. We also used individual-based temporally explicit simulations based on realistic demographic and stocking data to predict the extent of admixture. We found a low admixture by hatchery stocks within prestocking samples but moderate to high values in post stocking samples (from 12% to 60%). The simulation scenarios best fitting the real data suggested a 10-25 times lower survival of stocked fish relative to wild individuals. Simulations also suggested relatively high dispersal rates of stocked and wild fish, which may explain some high levels of admixture in weakly stocked populations and the persistence of indigenous genotypes in heavily stocked populations. This study overall demonstrates that combining genetic analyses with simulations can significantly improve the understanding of admixture mechanisms in wild populations. PMID- 23798973 TI - Evolved polygenic herbicide resistance in Lolium rigidum by low-dose herbicide selection within standing genetic variation. AB - The interaction between environment and genetic traits under selection is the basis of evolution. In this study, we have investigated the genetic basis of herbicide resistance in a highly characterized initially herbicide-susceptible Lolium rigidum population recurrently selected with low (below recommended label) doses of the herbicide diclofop-methyl. We report the variability in herbicide resistance levels observed in F1 families and the segregation of resistance observed in F2 and back-cross (BC) families. The selected herbicide resistance phenotypic trait(s) appear to be under complex polygenic control. The estimation of the effective minimum number of genes (N E), depending on the herbicide dose used, reveals at least three resistance genes had been enriched. A joint scaling test indicates that an additive-dominance model best explains gene interactions in parental, F1, F2 and BC families. The Mendelian study of six F2 and two BC segregating families confirmed involvement of more than one resistance gene. Cross-pollinated L. rigidum under selection at low herbicide dose can rapidly evolve polygenic broad-spectrum herbicide resistance by quantitative accumulation of additive genes of small effect. This can be minimized by using herbicides at the recommended dose which causes high mortality acting outside the normal range of phenotypic variation for herbicide susceptibility. PMID- 23798974 TI - Genetic variation and risks of introgression in the wild Coffea arabica gene pool in south-western Ethiopian montane rainforests. AB - The montane rainforests of SW Ethiopia are the primary centre of diversity of Coffea arabica and the origin of all Arabica coffee cultivated worldwide. This wild gene pool is potentially threatened by forest fragmentation and degradation, and by introgressive hybridization with locally improved coffee varieties. We genotyped 703 coffee shrubs from unmanaged and managed coffee populations, using 24 microsatellite loci. Additionally, we genotyped 90 individuals representing 23 Ethiopian cultivars resistant to coffee berry disease (CBD). We determined population genetic diversity, genetic structure, and admixture of cultivar alleles in the in situ gene pool. We found strong genetic differentiation between managed and unmanaged coffee populations, but without significant differences in within-population genetic diversity. The widespread planting of coffee seedlings including CBD-resistant cultivars most likely offsets losses of genetic variation attributable to genetic drift and inbreeding. Mixing cultivars with original coffee genotypes, however, leaves ample opportunity for hybridization and replacement of the original coffee gene pool, which already shows signs of admixture. In situ conservation of the wild gene pool of C. arabica must therefore focus on limiting coffee production in the remaining wild populations, as intensification threatens the genetic integrity of the gene pool by exposing wild genotypes to cultivars. PMID- 23798975 TI - Triangulating the provenance of African elephants using mitochondrial DNA. AB - African elephant mitochondrial (mt) DNA follows a distinctive evolutionary trajectory. As females do not migrate between elephant herds, mtDNA exhibits low geographic dispersal. We therefore examined the effectiveness of mtDNA for assigning the provenance of African elephants (or their ivory). For 653 savanna and forest elephants from 22 localities in 13 countries, 4258 bp of mtDNA was sequenced. We detected eight mtDNA subclades, of which seven had regionally restricted distributions. Among 108 unique haplotypes identified, 72% were found at only one locality and 84% were country specific, while 44% of individuals carried a haplotype detected only at their sampling locality. We combined 316 bp of our control region sequences with those generated by previous trans-national surveys of African elephants. Among 101 unique control region haplotypes detected in African elephants across 81 locations in 22 countries, 62% were present in only a single country. Applying our mtDNA results to a previous microsatellite based assignment study would improve estimates of the provenance of elephants in 115 of 122 mis-assigned cases. Nuclear partitioning followed species boundaries and not mtDNA subclade boundaries. For taxa such as elephants in which nuclear and mtDNA markers differ in phylogeography, combining the two markers can triangulate the origins of confiscated wildlife products. PMID- 23798976 TI - A resurrection study reveals rapid adaptive evolution within populations of an invasive plant. AB - The future spread and impact of an introduced species will depend on how it adapts to the abiotic and biotic conditions encountered in its new range, so the potential for rapid evolution subsequent to species introduction is a critical, evolutionary dimension of invasion biology. Using a resurrection approach, we provide a direct test for change over time within populations in a species' introduced range, in the Asian shade annual Polygonum cespitosum. We document, over an 11-year period, the evolution of increased reproductive output as well as greater physiological and root-allocational plasticity in response to the more open, sunny conditions found in the North American range in which the species has become invasive. These findings show that extremely rapid adaptive modifications to ecologically-important traits and plastic expression patterns can evolve subsequent to a species' introduction, within populations established in its introduced range. This study is one of the first to directly document evolutionary change in adaptive plasticity. Such rapid evolutionary changes can facilitate the spread of introduced species into novel habitats and hence contribute to their invasive success in a new range. The data also reveal how evolutionary trajectories can differ among populations in ways that can influence invasion dynamics. PMID- 23798977 TI - Interactive effects of inbreeding and endocrine disruption on reproduction in a model laboratory fish. AB - Inbreeding depression is expected to be more severe in stressful environments. However, the extent to which inbreeding affects the vulnerability of populations to environmental stressors, such as chemical exposure, remains unresolved. Here we report on the combined impacts of inbreeding and exposure to an endocrine disrupting chemical (the fungicide clotrimazole) on zebrafish (Danio rerio). We show that whilst inbreeding can negatively affect reproductive traits, not all traits are affected equally. Inbreeding depression frequently only became apparent when fish were additionally stressed by chemical exposure. Embryo viability was significantly reduced in inbred exposed fish and there was a tendency for inbred males to sire fewer offspring when in direct competition with outbred individuals. Levels of plasma 11-ketotestosterone, a key male sex hormone, showed substantial inbreeding depression that was unaffected by addition of the fungicide. In contrast, there was no effect of inbreeding or clotrimazole exposure on egg production. Overall, our data provide evidence that stress may amplify the effects of inbreeding on key reproductive traits, particularly those associated with male fitness. This may have important implications when considering the consequences of exposure to chemical pollutants on the fitness of wild populations. PMID- 23798978 TI - Linkage disequilibrium and effective population size when generations overlap. AB - Estimates of effective population size are critical for species of conservation concern. Genetic datasets can be used to provide robust estimates of this important parameter. However, the methods used to obtain these estimates assume that generations are discrete. We used simulated data to assess the influences of overlapping generations on the estimates of effective size provided by the linkage disequilibrium (LD) method. Our simulations focus on two factors: the degree of reproductive skew exhibited by the focal species and the generation time, without considering sample size or the level of polymorphism at marker loci. In situations where a majority of reproduction is achieved by a small fraction of the population, the effective number of breeders can be much smaller than the per-generation effective population size. The LD in samples of newborns can provide estimates of the former size, while our results indicate that the latter size is best estimated using random samples of reproductively mature adults. Using samples of adults, the downwards bias was less than approximately 15% across our simulated life histories. As noted in previous assessments, precision of the estimate depends on the magnitude of effective size itself, with greater precision achieved for small populations. PMID- 23798979 TI - Direct, indirect, and intangible costs after severe trauma up to occupational reintegration - an empirical analysis of 113 seriously injured patients. AB - AIM: Although seriously injured patients account for a high medical as well as socioeconomic burden of disease in the German health care system, there are only very few data describing the costs that arise between the days of accident and occupational reintegration. With this study, a comprehensive cost model is developed that describes the direct, indirect and intangible costs of an accident and their relationship with socioeconomic background of the patients. METHODS: This study included 113 patients who each had at least two injuries and a total Abbreviated Injury Scale (AIS) greater than or equal to five. We calculated the direct, indirect and intangible costs that arose between the day of the accident and occupational reintegration. Direct costs were the treatment costs at hospitals and rehabilitation centers. Indirect costs were calculated using the human capital approach on the basis of the work days lost due to injury, including sickness allowance benefits. Intangible costs were assessed using the Short Form Survey (SF-36) and represented in non-monetary form. Following univariate analysis, a bivariate analysis of the above costs and the patients' sociodemographic and socioeconomic characteristics was performed. RESULTS: At an average Injury Severity Score (ISS) of 19.2, the average direct cost per patient were ?35,661. An average of 185.2 work days were lost, resulting in indirect costs of ?17,205. The resulting total costs per patient were ?50,431. A bivariate analysis showed that the costs for hospital treatment were 58% higher in patients who graduated from lower secondary school [Hauptschule] (ISS 19.5) than in patients with qualification for university admission [Abitur] (ISS 19.4). CONCLUSIONS: The direct costs of treating trauma patients at the hospital appear to be lower in patients with a higher level of education than in the comparison group with a lower educational level. Because of missing data, the calculated indirect costs can merely represent a general trend, so that the bivariate analysis can only be seen as a starting point for further studies. PMID- 23798980 TI - Emotional ambivalence and post-traumatic stress disorder (PTSD) in soldiers during military operations. AB - OBJECTIVE: This pilot study examined the extent to which a specific mechanism of emotion regulation - namely, ambivalence concerning the expressiveness of German soldiers' emotions - affects the severity of PTSD symptoms after a military operation. METHODOLOGY: A survey was conducted at three points in time among 66 soldiers deployed on military crisis operations. The Harvard Trauma Questionaire (HTQ), the Ambivalence over Emotional Expressiveness Questionnaire (AEQ-G18), and a questionnaire on the particular stress of German soldiers during military operations were used. RESULTS: The study showed a significant correlation between emotional ambivalence and traumatization. Furthermore, it was shown that the subjective stress of soldiers leading up to deployment is more pronounced when emotional ambivalence is stronger in the context of military operations. This particular stress is greater before and during the military operation than after. Compared to a male control sample, the average AEQ-G18 scores of the soldier sample examined here are considerably lower. CONCLUSION: This pilot study clearly indicates that the AEQ-G18 could be a suitable predictor of the psychological burden on soldiers. The correlations between emotional ambivalence on the one hand and the particular and post-traumatic stressors on the other hand are not only statistically significant in the present pilot study, but may also be relevant as risk factors. It is, therefore, necessary to conduct more extensive studies on soldiers participating in military operations to verify the results of this pilot study. PMID- 23798981 TI - The effect of forced choice on facial emotion recognition: a comparison to open verbal classification of emotion labels. AB - OBJECTIVE: This article includes the examination of potential methodological problems of the application of a forced choice response format in facial emotion recognition. METHODOLOGY: 33 subjects were presented with validated facial stimuli. The task was to make a decision about which emotion was shown. In addition, the subjective certainty concerning the decision was recorded. RESULTS: The detection rates are 68% for fear, 81% for sadness, 85% for anger, 87% for surprise, 88% for disgust, and 94% for happiness, and are thus well above the random probability. CONCLUSION: This study refutes the concern that the use of forced choice formats may not adequately reflect actual recognition performance. The use of standardized tests to examine emotion recognition ability leads to valid results and can be used in different contexts. For example, the images presented here appear suitable for diagnosing deficits in emotion recognition in the context of psychological disorders and for mapping treatment progress. PMID- 23798982 TI - Novel approaches for treating musculoskeletal diseases: molecular orthopedics and systems medicine. AB - Molecular medicine uses knowledge about cell structure and function for disease, diagnostics, stage characterisation and treatment. The advent of genomic technologies is considerably leading to developments in the field of molecular medicine. The accumulation of detailed information about gene expression, epigenetic variability, protein transcription and functional modulation is contributing to a new era in medicine. Rapid and early diagnostic procedures, molecular characterisation of degenerative and proliferative diseases and personalized therapies are predicted to lead to advancements in health prevention and treatment of disease. Diagnostic tools and therapies based on local and /or general modulation of cellular processes for traumatic or degenerative musculoskeletal conditions are becoming available. A logical consequence of the information derived from extensive data gathering, systems biology and systemic medicine has lead to significant improvements in understanding biological structure and function in a simultaneous bottom top and integrative, holistic manner. The description of disease mechanism at an intimate, subcellular level has a dual benefit. A thorough understanding of the crosstalk involved in molecular pathways both in the normal and the diseased state are expanding scientific knowledge and simultaneously are enabling design cell-targeted and individualized therapies. This paper presents a brief overview of current molecular based treatments available to the orthopedic surgeon and introduces the concept of systemic medicine from the perspective of musculoskeletal pathology. PMID- 23798988 TI - The open access malaria box: a drug discovery catalyst for neglected diseases. AB - Historically, one of the key problems in neglected disease drug discovery has been identifying new and interesting chemotypes. Phenotypic screening of the malaria parasite, Plasmodium falciparum has yielded almost 30,000 submicromolar hits in recent years. To make this collection more accessible, a collection of 400 chemotypes has been assembled, termed the Malaria Box. Half of these compounds were selected based on their drug-like properties and the others as molecular probes. These can now be requested as a pharmacological test set by malaria biologists, but importantly by groups working on related parasites, as part of a program to make both data and compounds readily available. In this paper, the analysis and selection methodology and characteristics of the compounds are described. PMID- 23798989 TI - The human fetus preferentially secretes corticosterone, rather than cortisol, in response to intra-partum stressors. AB - CONTEXT: Fetal stress is relevant to newborn outcomes. Corticosterone is rarely quantified in human clinical endocrinology and is found at much lower concentrations than cortisol. However, fetal corticosterone is a candidate hormone as a fetal stress signal. OBJECTIVE: Test the hypothesis that preferential fetal corticosterone synthesis occurs in response to fetal intra partum stress. DESIGN: Cross-sectional comparison of paired serum corticosteroid concentrations in umbilical artery and vein from 300 women providing consent at admission to a General Hospital Labor and Delivery unit. Pre-term and multiple births were excluded, leaving 265 healthy deliveries. MAIN OUTCOME MEASURES: Corticosterone and cortisol concentrations determined by LC-MS/MS for umbilical cord venous (V) and arterial (A) samples and used to calculate fetal synthesis (A V) and proportional fetal synthesis ([A-V]/V). Chart-derived criteria stratified samples by type of delivery, maternal regional analgesia, augmentation of contractions, and clinical rationale for emergent Caesarian delivery. RESULTS: Cortisol concentrations were higher than corticosterone concentrations; however, the fetus preferentially secretes corticosterone (148% vs 49% proportional increase for cortisol) and differentially secretes corticosterone as fetal stress increases. Fetal corticosterone synthesis is elevated after passage through the birth canal relative to Caesarian deliveries. For vaginal deliveries, augmentation of contractions does not affect corticosteroid concentrations whereas maternal regional analgesia decreases venous (maternal) concentrations and increases fetal synthesis. Fetal corticosterone synthesis is also elevated after C-section indicated by cephalopelvic disproportion after labor, whereas cortisol is not. CONCLUSIONS: The full-term fetus preferentially secretes corticosterone in response to fetal stress during delivery. Fetal corticosterone could serve as a biomarker of fetal stress. PMID- 23798991 TI - Neutral theory predicts the relative abundance and diversity of genetic elements in a broad array of eukaryotic genomes. AB - It is universally true in ecological communities, terrestrial or aquatic, temperate or tropical, that some species are very abundant, others are moderately common, and the majority are rare. Likewise, eukaryotic genomes also contain classes or "species" of genetic elements that vary greatly in abundance: DNA transposons, retrotransposons, satellite sequences, simple repeats and their less abundant functional sequences such as RNA or genes. Are the patterns of relative species abundance and diversity similar among ecological communities and genomes? Previous dynamical models of genomic diversity have focused on the selective forces shaping the abundance and diversity of transposable elements (TEs). However, ideally, models of genome dynamics should consider not only TEs, but also the diversity of all genetic classes or "species" populating eukaryotic genomes. Here, in an analysis of the diversity and abundance of genetic elements in >500 eukaryotic chromosomes, we show that the patterns are consistent with a neutral hypothesis of genome assembly in virtually all chromosomes tested. The distributions of relative abundance of genetic elements are quite precisely predicted by the dynamics of an ecological model for which the principle of functional equivalence is the main assumption. We hypothesize that at large temporal scales an overarching neutral or nearly neutral process governs the evolution of abundance and diversity of genetic elements in eukaryotic genomes. PMID- 23798990 TI - Exercise challenge in Gulf War Illness reveals two subgroups with altered brain structure and function. AB - Nearly 30% of the approximately 700,000 military personnel who served in Operation Desert Storm (1990-1991) have developed Gulf War Illness, a condition that presents with symptoms such as cognitive impairment, autonomic dysfunction, debilitating fatigue and chronic widespread pain that implicate the central nervous system. A hallmark complaint of subjects with Gulf War Illness is post exertional malaise; defined as an exacerbation of symptoms following physical and/or mental effort. To study the causal relationship between exercise, the brain, and changes in symptoms, 28 Gulf War veterans and 10 controls completed an fMRI scan before and after two exercise stress tests to investigate serial changes in pain, autonomic function, and working memory. Exercise induced two clinical Gulf War Illness subgroups. One subgroup presented with orthostatic tachycardia (n = 10). This phenotype correlated with brainstem atrophy, baseline working memory compensation in the cerebellar vermis, and subsequent loss of compensation after exercise. The other subgroup developed exercise induced hyperalgesia (n = 18) that was associated with cortical atrophy and baseline working memory compensation in the basal ganglia. Alterations in cognition, brain structure, and symptoms were absent in controls. Our novel findings may provide an understanding of the relationship between the brain and post-exertional malaise in Gulf War Illness. PMID- 23798992 TI - Murine cell glycolipids customization by modular expression of glycosyltransferases. AB - Functional analysis of glycolipids has been hampered by their complex nature and combinatorial expression in cells and tissues. We report an efficient and easy method to generate cells with specific glycolipids. In our proof of principle experiments we have demonstrated the customized expression of two relevant glycosphingolipids on murine fibroblasts, stage-specific embryonic antigen 3 (SSEA-3), a marker for stem cells, and Forssman glycolipid, a xenoantigen. Sets of genes encoding glycosyltansferases were transduced by viral infection followed by multi-color cell sorting based on coupled expression of fluorescent proteins. PMID- 23798993 TI - Gene expression profiling specifies chemokine, mitochondrial and lipid metabolism signatures in leprosy. AB - Herein, we performed microarray experiments in Schwann cells infected with live M. leprae and identified novel differentially expressed genes (DEG) in M. leprae infected cells. Also, we selected candidate genes associated or implicated with leprosy in genetic studies and biological experiments. Forty-seven genes were selected for validation in two independent types of samples by multiplex qPCR. First, an in vitro model using THP-1 cells was infected with live Mycobacterium leprae and M. bovis bacillus Calmette-Guerin (BCG). In a second situation, mRNA obtained from nerve biopsies from patients with leprosy or other peripheral neuropathies was tested. We detected DEGs that discriminate M. bovis BCG from M. leprae infection. Specific signatures of susceptible responses after M. leprae infection when compared to BCG lead to repression of genes, including CCL2, CCL3, IL8 and SOD2. The same 47-gene set was screened in nerve biopsies, which corroborated the down-regulation of CCL2 and CCL3 in leprosy, but also evidenced the down-regulation of genes involved in mitochondrial metabolism, and the up regulation of genes involved in lipid metabolism and ubiquitination. Finally, a gene expression signature from DEG was identified in patients confirmed of having leprosy. A classification tree was able to ascertain 80% of the cases as leprosy or non-leprous peripheral neuropathy based on the expression of only LDLR and CCL4. A general immune and mitochondrial hypo-responsive state occurs in response to M. leprae infection. Also, the most important genes and pathways have been highlighted providing new tools for early diagnosis and treatment of leprosy. PMID- 23798994 TI - Dimensions of temperament modulate cue-controlled behavior: a study on Pavlovian to instrumental transfer in horses (Equus caballus). AB - Pavlovian to instrumental transfer (PIT) is a central factor in how cues influence animal behavior. PIT refers to the capacity of a Pavlovian cue that predicts a reward to elicit or increase a response intended to obtain the same reward. In the present study, using an equine model, we assessed whether PIT occurs in hoofed domestic animals and whether its efficacy can be modulated by temperamental dimensions. To study PIT, horses were submitted to Pavlovian conditioning whereby an auditory-visual stimulus was repeatedly followed by food delivery. Then, horses were submitted to instrumental conditioning during which they learned to touch with their noses an object signaled by the experimenter in order to obtain the same reward. During the PIT test, the Pavlovian conditioned stimulus was presented to the animal in the absence of reward. At the end of the experiment, a battery of behavioral tests was performed on all animals to assess five temperamental dimensions and investigate their relationships with instrumental performance. The results indicate that PIT can be observed in horses and that its efficacy is greatly modulated by individual temperament. Indeed, individuals with a specific pattern of temperamental dimensions (i.e., higher levels of gregariousness, fearfulness, and sensory sensitivity) exhibited the strongest PIT. The demonstration of the existence of PIT in domesticated animals (i.e., horses) is important for the optimization of its use by humans and the improvement of training methods. Moreover, because PIT may be implicated in psychological phenomena, including addictive behaviors, the observation of relationships between specific temperamental dimensions and PIT efficacy may aid in identifying predisposing temperamental attributes. PMID- 23798995 TI - Is dynamic autocrine insulin signaling possible? A mathematical model predicts picomolar concentrations of extracellular monomeric insulin within human pancreatic islets. AB - Insulin signaling is essential for beta-cell survival and proliferation in vivo. Insulin also has potent mitogenic and anti-apoptotic actions on cultured beta cells, with maximum effect in the high picomolar range and diminishing effect at high nanomolar doses. In order to understand whether these effects of insulin are constitutive or can be subjected to physiological modulation, it is essential to estimate the extracellular concentration of monomeric insulin within an intact islet. Unfortunately, the in vivo concentration of insulin monomers within the islet cannot be measured directly with current technology. Here, we present the first mathematical model designed to estimate the levels of monomeric insulin within the islet extracellular space. Insulin is released as insoluble crystals that exhibit a delayed dissociation into hexamers, dimers, and eventually monomers, which only then can act as signaling ligands. The rates at which different forms of insulin dissolve in vivo have been estimated from studies of peripheral insulin injection sites. We used this and other information to formulate a mathematical model to estimate the local insulin concentration within a single islet as a function of glucose. Model parameters were estimated from existing literature. Components of the model were validated using experimental data, if available. Model analysis predicted that the majority of monomeric insulin in the islet is that which has been returned from the periphery, and the concentration of intra-islet monomeric insulin varies from ~50-300 pM when glucose is in the physiological range. Thus, our results suggest that the local concentration of monomeric insulin within the islet is in the picomolar 'sweet spot' range of insulin doses that activate the insulin receptor and have the most potent effects on beta-cells in vitro. Together with experimental data, these estimations support the concept that autocrine/paracrine insulin signalling within the islet is dynamic, rather than constitutive and saturated. PMID- 23798996 TI - Aspergillus felis sp. nov., an emerging agent of invasive aspergillosis in humans, cats, and dogs. AB - We describe a novel heterothallic species in Aspergillus section Fumigati, namely A. felis (neosartorya-morph) isolated from three host species with invasive aspergillosis including a human patient with chronic invasive pulmonary aspergillosis, domestic cats with invasive fungal rhinosinusitis and a dog with disseminated invasive aspergillosis. Disease in all host species was often refractory to aggressive antifungal therapeutic regimens. Four other human isolates previously reported as A. viridinutans were identified as A. felis on comparative sequence analysis of the partial beta-tubulin and/or calmodulin genes. A. felis is a heterothallic mold with a fully functioning reproductive cycle, as confirmed by mating-type analysis, induction of teleomorphs within 7 to 10 days in vitro and ascospore germination. Phenotypic analyses show that A. felis can be distinguished from the related species A. viridinutans by its ability to grow at 45 degrees C and from A. fumigatus by its inability to grow at 50 degrees C. Itraconazole and voriconazole cross-resistance was common in vitro. PMID- 23798997 TI - Effectiveness of antenatal clinics to deliver intermittent preventive treatment and insecticide treated nets for the control of malaria in pregnancy in Kenya. AB - BACKGROUND: Malaria in pregnancy can have devastating consequences for mother and baby. Coverage with the WHO prevention strategy for sub-Saharan Africa of intermittent-preventive-treatment (IPTp) with two doses of sulphadoxine pyrimethamine (SP) and insecticide-treated-nets (ITNs) in pregnancy is low. We analysed household survey data to evaluate the effectiveness of antenatal clinics (ANC) to deliver IPTp and ITNs to pregnant women in Nyando district, Kenya. METHODS: We assessed the systems effectiveness of ANC to deliver IPTp and ITNs to pregnant women and the impact on low birthweight (LBW). Logistic regression was used to identify predictors of receipt of IPTp and ITN use during pregnancy. RESULTS: Among 89% of recently pregnant women who attended ANC at least once between 4-9 months gestation, 59% reported receiving one dose of SP and 90% attended ANC again, of whom 57% received a second dose, resulting in a cumulative effectiveness for IPTp of 27%, most of whom used an ITN (96%). Overall ITN use was 89%, and ANC the main source (76%). Women were less likely to receive IPTp if they had low malaria knowledge (0.26, 95% CI 0.08-0.83), had a child who had died (OR 0.36, 95% CI 0.14-0.95), or if they first attended ANC late (OR 0.20, 95% CI 0.06-0.67). Women who experienced side effects to SP (OR 0.18, CI 0.03-0.90) or had low malaria knowledge (OR 0.78, 95% CI 0.11-5.43) were less likely to receive IPTp by directly observed therapy. Ineffective delivery of IPTp reduced its potential impact by 231 LBW cases averted (95% CI 64-359) per 10,000 pregnant women. CONCLUSION: IPTp presents greater challenges to deliver through ANC than ITNs in this setting. The reduction in public health impact on LBW resulting from ineffective delivery of IPTp is estimated to be substantial. Urgent efforts are required to improve service delivery of this important intervention. PMID- 23798998 TI - Distinct microRNA expression profile in prostate cancer patients with early clinical failure and the impact of let-7 as prognostic marker in high-risk prostate cancer. AB - BACKGROUND: The identification of additional prognostic markers to improve risk stratification and to avoid overtreatment is one of the most urgent clinical needs in prostate cancer (PCa). MicroRNAs, being important regulators of gene expression, are promising biomarkers in various cancer entities, though the impact as prognostic predictors in PCa is poorly understood. The aim of this study was to identify specific miRNAs as potential prognostic markers in high risk PCa and to validate their clinical impact. METHODOLOGY AND PRINCIPAL FINDINGS: We performed miRNA-microarray analysis in a high-risk PCa study group selected by their clinical outcome (clinical progression free survival (CPFS) vs. clinical failure (CF)). We identified seven candidate miRNAs (let-7a/b/c, miR-515 3p/5p, -181b, -146b, and -361) that showed differential expression between both groups. Further qRT-PCR analysis revealed down-regulation of members of the let-7 family in the majority of a large, well-characterized high-risk PCa cohort (n = 98). Expression of let-7a/b/and -c was correlated to clinical outcome parameters of this group. While let-7a showed no association or correlation with clinical relevant data, let-7b and let-7c were associated with CF in PCa patients and functioned partially as independent prognostic marker. Validation of the data using an independent high-risk study cohort revealed that let-7b, but not let-7c, has impact as an independent prognostic marker for BCR and CF. Furthermore, we identified HMGA1, a non-histone protein, as a new target of let-7b and found correlation of let-7b down-regulation with HMGA1 over-expression in primary PCa samples. CONCLUSION: Our findings define a distinct miRNA expression profile in PCa cases with early CF and identified let-7b as prognostic biomarker in high risk PCa. This study highlights the importance of let-7b as tumor suppressor miRNA in high-risk PCa and presents a basis to improve individual therapy for high-risk PCa patients. PMID- 23798999 TI - Interleukin-22 mediates early host defense against Rhizomucor pusilluscan pathogens. AB - BACKGROUND: In recent years, the fungal infectious disease zygomycosis has increased in incidence worldwide, especially among the immunodeficient population. Despite the rates of zygomycosis-related death and deformation being very high, the mechanism(s) by which the fungal pathogens cause these severe manifestations remain unknown. METHODS: Using the associated Rhizomucor variabilis species, which can selectively induce cutaneous zygomycosis in otherwise healthy individuals, we investigated the host mechanisms of infection related responses, including cytokine and chemokine expression as well as contributions of particular T cell subsets. siRNA specifically targeting IL-22,IL 17 and IFN-gamma were used to down-regulate expression of those molecules. RESULTS: In mouse models of infection, IL-22 was implicated in development of Rhizomucor spp.-induced skin lesions. In cultured human peripheral blood monocytes, R. pusilluscan, which is often found in immunodeficient patients, induced the production of IL-22, while R. variabilis did not. Moreover, Rhizomucor spp.-induced secretion of Il-22 from CCR6(+)CCR4(+)CCR10(+) cells was down-regulated by knockdown of IL-22 related signaling receptors, RORC and ARH. CONCLUSION: Our data strongly suggest that avoidance of IL-22 may be one mechanism by which mucor species produce morbidity and mortality in infected individuals. PMID- 23799001 TI - When feeling skillful impairs coordination in a lottery selection task. AB - Choosing a major field of study to secure a good job after graduation is a tacit coordination problem that requires considering others' choices. We examine how feeling skillful, either induced (Experiment 1) or measured (Experiment 2), affects coordination in this type of task. In both experiments participants chose between two lotteries, one offering a larger prize than the other. Participants' entry into the chosen lottery was either related or unrelated to their skill, with the final prize allocated randomly to one of the entrants in each lottery. Importantly, across conditions skill was irrelevant to choosing between lotteries. Notwithstanding, when skill was related to determining lottery entrants, participants who felt highly skillful chose the high prize lottery excessively. Results further suggest that this stems from high confidence in self skill, rather than incorrect expectations regarding others. PMID- 23799000 TI - CD40 gene silencing reduces the progression of experimental lupus nephritis modulating local milieu and systemic mechanisms. AB - Lupus nephritis (LN) is an autoimmune disorder in which co-stimulatory signals have been involved. Here we tested a cholesterol-conjugated-anti-CD40-siRNA in dendritic cells (DC) in vitro and in a model of LPS to check its potency and tissue distribution. Then, we report the effects of Chol-siRNA in an experimental model of mice with established lupus nephritis. Our in vitro studies in DC show a 100% intracellular delivery of Chol-siRNA, with a significant reduction in CD40 after LPS stimuli. In vivo in ICR mice, the CD40-mRNA suppressive effects of our Chol-siRNA on renal tissue were remarkably sustained over a 5 days after a single preliminary dose of Chol-siRNA. The intra-peritoneal administration of Chol-siRNA to NZB/WF1 mice resulted in a reduction of anti-DNA antibody titers, and histopathological renal scores as compared to untreated animals. The higher dose of Chol-siRNA prevented the progression of proteinuria as effectively as cyclophosphamide, whereas the lower dose was as effective as CTLA4. Chol-siRNA markedly reduced insterstitial CD3+ and plasma cell infiltrates as well as glomerular deposits of IgG and C3. Circulating soluble CD40 and activated splenic lymphocyte subsets were also strikingly reduced by Chol-siRNA. Our data show the potency of our compound for the therapeutic use of anti-CD40-siRNA in human LN and other autoimmune disorders. PMID- 23799002 TI - Combining mTOR inhibition with radiation improves antitumor activity in bladder cancer cells in vitro and in vivo: a novel strategy for treatment. AB - PURPOSE: Radiation therapy for invasive bladder cancer allows for organ preservation but toxicity and local control remain problematic. As such, improving efficacy of treatment requires radiosensitization of tumor cells. The aim of study is to investigate if the mammalian Target of Rapamycin (mTOR), a downstream kinase of the phosphatidylinositol 3-kinase (PI3K)/AKT survival pathway, may be a target for radiation sensitization. EXPERIMENTAL DESIGN: Clonogenic assays were performed using 6 bladder cancer cell lines (UM-UC3, UM UC5, UM-UC6, KU7, 253J-BV, and 253-JP) in order to examine the effects of ionizing radiation (IR) alone and in combination with RAD001, an mTOR inhibitor. Cell cycle analysis was performed using flow cytometry. In vivo, athymic mice were subcutaneously injected with 2 bladder cancer cell lines. Treatment response with RAD001 (1.5 mg/kg, daily), fractionated IR (total 9Gy = 3Gy*3), and combination of RAD001 and IR was followed over 4 weeks. Tumor weight was measured at experimental endpoint. RESULTS: Clonogenic assays revealed that in all bladder cell lines tested, an additive effect was observed in the combined treatment when compared to either treatment alone. Our data indicates that this effect is due to arrest in both G1 and G2 phases of cell cycle when treatments are combined. Furthermore, our data show that this arrest is primarily regulated by changes in levels of cyclin D1, p27 and p21 following treatments. In vivo, a significant decrease in tumor weight was observed in the combined treatment compared to either treatment alone or control. CONCLUSIONS: Altering cell cycle by inhibiting the mTOR signaling pathway in combination with radiation have favorable outcomes and is a promising therapeutic modality for bladder cancer. PMID- 23799003 TI - Zinc finger nuclease mediated knockout of ADP-dependent glucokinase in cancer cell lines: effects on cell survival and mitochondrial oxidative metabolism. AB - Zinc finger nucleases (ZFN) are powerful tools for editing genes in cells. Here we use ZFNs to interrogate the biological function of ADPGK, which encodes an ADP dependent glucokinase (ADPGK), in human tumour cell lines. The hypothesis we tested is that ADPGK utilises ADP to phosphorylate glucose under conditions where ATP becomes limiting, such as hypoxia. We characterised two ZFN knockout clones in each of two lines (H460 and HCT116). All four clones had frameshift mutations in all alleles at the target site in exon 1 of ADPGK, and were ADPGK-null by immunoblotting. ADPGK knockout had little or no effect on cell proliferation, but compromised the ability of H460 cells to survive siRNA silencing of hexokinase-2 under oxic conditions, with clonogenic survival falling from 21+/-3% for the parental line to 6.4+/-0.8% (p = 0.002) and 4.3+/-0.8% (p = 0.001) for the two knockouts. A similar increased sensitivity to clonogenic cell killing was observed under anoxia. No such changes were found when ADPGK was knocked out in HCT116 cells, for which the parental line was less sensitive than H460 to anoxia and to hexokinase-2 silencing. While knockout of ADPGK in HCT116 cells caused few changes in global gene expression, knockout of ADPGK in H460 cells caused notable up-regulation of mRNAs encoding cell adhesion proteins. Surprisingly, we could discern no consistent effect on glycolysis as measured by glucose consumption or lactate formation under anoxia, or extracellular acidification rate (Seahorse XF analyser) under oxic conditions in a variety of media. However, oxygen consumption rates were generally lower in the ADPGK knockouts, in some cases markedly so. Collectively, the results demonstrate that ADPGK can contribute to tumour cell survival under conditions of high glycolytic dependence, but the phenotype resulting from knockout of ADPGK is cell line dependent and appears to be unrelated to priming of glycolysis in these lines. PMID- 23799004 TI - Proteomic and biochemical analyses of the cotyledon and root of flooding-stressed soybean plants. AB - BACKGROUND: Flooding significantly reduces the growth and grain yield of soybean plants. Proteomic and biochemical techniques were used to determine whether the function of cotyledon and root is altered in soybean under flooding stress. RESULTS: Two-day-old soybean plants were flooded for 2 days, after which the proteins from root and cotyledon were extracted for proteomic analysis. In response to flooding stress, the abundance of 73 and 28 proteins was significantly altered in the root and cotyledon, respectively. The accumulation of only one protein, 70 kDa heat shock protein (HSP70) (Glyma17g08020.1), increased in both organs following flooding. The ratio of protein abundance of HSP70 and biophoton emission in the cotyledon was higher than those detected in the root under flooding stress. Computed tomography and elemental analyses revealed that flooding stress decreases the number of calcium oxalate crystal the cotyledon, indicating calcium ion was elevated in the cotyledon under flooding stress. CONCLUSION: These results suggest that calcium might play one role through HSP70 in the cotyledon under flooding stress. PMID- 23799005 TI - Evidence of impaired brain activity balance after passive sensorimotor stimulation in multiple sclerosis. AB - OBJECTIVES: Examination of sensorimotor activation alone in multiple sclerosis (MS) patients may not yield a comprehensive view of cerebral response to task stimulation. Additional information may be obtained by examining the negative BOLD response (deactivation). Aim of this work was to characterize activation and deactivation patterns during passive hand movements in MS patients. METHODS: 13 relapsing remitting-MS patients (RRMS), 18 secondary progressive-MS patients (SPMS) and 15 healthy controls (HC) underwent an fMRI study during passive right hand movements. Activation and deactivation contrasts in the three groups were entered into ANOVA, age and gender corrected. Post-hoc analysis was performed with one-sample and two-sample t-tests. For each patient we obtained lesion volume (LV) from both T1- and T2-weighted images. RESULTS: Activations showed a progressive extension to the ipsilateral brain hemisphere according to the group and the clinical form (HC=18years were recruited. Receiver Operating Characteristic (ROC) analysis determined effectiveness of HbA1c and FPG to discriminate between groups. RESULTS: HbA1c reference ranges in subjects with GCK mutations were: 38-56 mmol/mol (5.6-7.3%) if aged <=40years; 41-60 mmol/mol (5.9-7.6%) if >40years. All patients (123/123) with a GCK mutation were above the lower limit of the HbA1c age-appropriate reference ranges. 69% (31/99) of controls were below these lower limits. HbA1c was also effective in discriminating those with a GCK mutation from those with T1D/T2D. Using the upper limit of the age-appropriate reference ranges to discriminate those with a mutation from those with T1D/T2D correctly identified 97% of subjects with a mutation. The majority (438/597 (73%)) with other types of young-onset diabetes had an HbA1c above the upper limit of the age appropriate GCK reference range. HbA1c >=48 mmol/mol classified more people with GCK mutations as having diabetes than FPG >=7 mmol/l (68% vs. 48%, p = 0.0009). CONCLUSIONS: Current HbA1c diagnostic criteria increase diabetes diagnosis in patients with a GCK mutation. We have derived age-related HbA1c reference ranges that can be used for discriminating hyperglycaemia likely to be caused by a GCK mutation and aid identification of probands and family members for genetic testing. PMID- 23799007 TI - Metabolomic analysis and phenylpropanoid biosynthesis in hairy root culture of tartary buckwheat cultivars. AB - Buckwheat, Fagopyrum tataricum Gaertn., is an important medicinal plant, which contains several phenolic compounds, including one of the highest content of rutin, a phenolic compound with anti-inflammatory properties. An experiment was conducted to investigate the level of expression of various genes in the phenylpropanoid biosynthetic pathway to analyze in vitro production of anthocyanin and phenolic compounds from hairy root cultures derived from 2 cultivars of tartary buckwheat (Hokkai T8 and T10). A total of 47 metabolites were identified by gas chromatography-time-of-flight mass spectrometry (GC-TOFMS) and subjected to principal component analysis (PCA) in order to fully distinguish between Hokkai T8 and T10 hairy roots. The expression levels of phenylpropanoid biosynthetic pathway genes, through qRT-PCR, showed higher expression for almost all the genes in T10 than T8 hairy root except for FtF3'H-2 and FtFLS-2. Rutin, quercetin, gallic acid, caffeic acid, ferulic acid, 4-hydroxybenzoic acid, and 2 anthocyanin compounds were identified in Hokkai T8 and T10 hairy roots. The concentration of rutin and anthocyanin in Hokkai T10 hairy roots of tartary buckwheat was several-fold higher compared with that obtained from Hokkai T8 hairy root. This study provides useful information on the molecular and physiological dynamic processes that are correlated with phenylpropanoid biosynthetic gene expression and phenolic compound content in F. tataricum species. PMID- 23799009 TI - Structural similarities between brain and linguistic data provide evidence of semantic relations in the brain. AB - This paper presents a new method of analysis by which structural similarities between brain data and linguistic data can be assessed at the semantic level. It shows how to measure the strength of these structural similarities and so determine the relatively better fit of the brain data with one semantic model over another. The first model is derived from WordNet, a lexical database of English compiled by language experts. The second is given by the corpus-based statistical technique of latent semantic analysis (LSA), which detects relations between words that are latent or hidden in text. The brain data are drawn from experiments in which statements about the geography of Europe were presented auditorily to participants who were asked to determine their truth or falsity while electroencephalographic (EEG) recordings were made. The theoretical framework for the analysis of the brain and semantic data derives from axiomatizations of theories such as the theory of differences in utility preference. Using brain-data samples from individual trials time-locked to the presentation of each word, ordinal relations of similarity differences are computed for the brain data and for the linguistic data. In each case those relations that are invariant with respect to the brain and linguistic data, and are correlated with sufficient statistical strength, amount to structural similarities between the brain and linguistic data. Results show that many more statistically significant structural similarities can be found between the brain data and the WordNet-derived data than the LSA-derived data. The work reported here is placed within the context of other recent studies of semantics and the brain. The main contribution of this paper is the new method it presents for the study of semantics and the brain and the focus it permits on networks of relations detected in brain data and represented by a semantic model. PMID- 23799008 TI - Active video games and health indicators in children and youth: a systematic review. AB - BACKGROUND: Active video games (AVGs) have gained interest as a way to increase physical activity in children and youth. The effect of AVGs on acute energy expenditure (EE) has previously been reported; however, the influence of AVGs on other health-related lifestyle indicators remains unclear. OBJECTIVE: This systematic review aimed to explain the relationship between AVGs and nine health and behavioural indicators in the pediatric population (aged 0-17 years). DATA SOURCES: Online databases (MEDLINE, EMBASE, psycINFO, SPORTDiscus and Cochrane Central Database) and personal libraries were searched and content experts were consulted for additional material. DATA SELECTION: Included articles were required to have a measure of AVG and at least one relevant health or behaviour indicator: EE (both habitual and acute), adherence and appeal (i.e., participation and enjoyment), opportunity cost (both time and financial considerations, and adverse events), adiposity, cardiometabolic health, energy intake, adaptation (effects of continued play), learning and rehabilitation, and video game evolution (i.e., sustainability of AVG technology). RESULTS: 51 unique studies, represented in 52 articles were included in the review. Data were available from 1992 participants, aged 3-17 years, from 8 countries, and published from 2006-2012. Overall, AVGs are associated with acute increases in EE, but effects on habitual physical activity are not clear. Further, AVGs show promise when used for learning and rehabilitation within special populations. Evidence related to other indicators was limited and inconclusive. CONCLUSIONS: Controlled studies show that AVGs acutely increase light- to moderate-intensity physical activity; however, the findings about if or how AVG lead to increases in habitual physical activity or decreases in sedentary behaviour are less clear. Although AVGs may elicit some health benefits in special populations, there is not sufficient evidence to recommend AVGs as a means of increasing daily physical activity. PMID- 23799010 TI - Anti-bacterial activity of recombinant human beta-defensin-3 secreted in the milk of transgenic goats produced by somatic cell nuclear transfer. AB - The present study was conducted to determine whether recombinant human beta defensin-3 (rHBD3) in the milk of transgenic goats has an anti-bacterial activity against Escherichia coli (E. coli), Staphylococcus aureus (S. aureus) and Streptococcus agalactiae (S. agalactiae) that could cause mastitis. A HBD3 mammary-specific expression vector was transfected by electroporation into goat fetal fibroblasts which were used to produce fourteen healthy transgenic goats by somatic cell nuclear transfer. The expression level of rHBD3 in the milk of the six transgenic goats ranged from 98 to 121 ug/ml at 15 days of lactation, and was maintained at 90-111 ug/ml during the following 2 months. Milk samples from transgenic goats showed an obvious inhibitory activity against E. coli, S. aureus and S. agalactiae in vitro. The minimal inhibitory concentrations of rHBD3 in milk against E. coli, S. aureus and S. agalactiae were 9.5-10.5, 21.8-23.0 and 17.3-18.5 ug/mL, respectively, which was similar to those of the HBD3 standard (P>0.05). The in vivo anti-bacterial activities of rHBD3 in milk were examined by intramammary infusion of viable bacterial inoculums. We observed that 9/10 and 8/10 glands of non-transgenic goats infused with S. aureus and E. coli became infected. The mean numbers of viable bacteria went up to 2.9*10(3) and 95.4*10(3) CFU/ml at 48 h after infusion, respectively; the mean somatic cell counts (SCC) in infected glands reached up to 260.4*10(5) and 622.2*10(5) cells/ml, which were significantly higher than the SCC in uninfected goat glands. In contrast, no bacteria was presented in glands of transgenic goats and PBS-infused controls, and the SSC did not significantly change throughout the period. Moreover, the compositions and protein profiles of milk from transgenic and non-transgenic goats were identical. The present study demonstrated that HBD3 were an effective anti-bacterial protein to enhance the mastitis resistance of dairy animals. PMID- 23799011 TI - Undecylprodigiosin induced apoptosis in P388 cancer cells is associated with its binding to ribosome. AB - Prodigiosins (PGs) are a family of natural red pigments with anticancer activity, and one member of the family has entered clinical phase II trials. However, the anticancer mechanisms of PGs remain largely unclear. This study was designed to investigate the molecular basis of anticancer activity of UP, a derivative of PGs, in P388 cells. By introducing pharmacological inhibitors and utilizing a variety of analytical approaches including western blotting, flow cytometry and confocal laser microscopy, we found that UP inhibited proliferation of P388 via arresting cells at G2/M phase and inducing cells apoptosis, which was related to the activation of P38, JNK rather than ERK1/2 signaling. ROS regeneration and acidification in cells appear not involved in UP induced apoptosis. Furthermore, utilizing mass spectrometry, sucrose density gradient fractionation and immunofluorescence staining, we discovered that UP was apparently located at ribosome. These results together indicate that ribosome may be the potential target of UP in cancer cells, which opened a new avenue in delineating the anticancer mechanism of PGs. PMID- 23799012 TI - Degraded time-frequency acuity to time-reversed notes. AB - Time-reversal symmetry breaking is a key feature of many classes of natural sounds, originating in the physics of sound production. While attention has been paid to the response of the auditory system to "natural stimuli," very few psychophysical tests have been performed. We conduct psychophysical measurements of time-frequency acuity for stylized representations of "natural"-like notes (sharp attack, long decay) and the time-reversed versions of these notes (long attack, sharp decay). Our results demonstrate significantly greater precision, arising from enhanced temporal acuity, for such sounds over their time-reversed versions, without a corresponding decrease in frequency acuity. These data inveigh against models of auditory processing that include tradeoffs between temporal and frequency acuity, at least in the range of notes tested and suggest the existence of statistical priors for notes with a sharp-attack and a long decay. We are additionally able to calculate a minimal theoretical bound on the sophistication of the nonlinearities in auditory processing. We find that among the best studied classes of nonlinear time-frequency representations, only matching pursuit, spectral derivatives, and reassigned spectrograms are able to satisfy this criterion. PMID- 23799013 TI - Region-based association analysis of human quantitative traits in related individuals. AB - Regional-based association analysis instead of individual testing of each SNP was introduced in genome-wide association studies to increase the power of gene mapping, especially for rare genetic variants. For regional association tests, the kernel machine-based regression approach was recently proposed as a more powerful alternative to collapsing-based methods. However, the vast majority of existing algorithms and software for the kernel machine-based regression are applicable only to unrelated samples. In this paper, we present a new method for the kernel machine-based regression association analysis of quantitative traits in samples of related individuals. The method is based on the GRAMMAR+ transformation of phenotypes of related individuals, followed by use of existing kernel machine-based regression software for unrelated samples. We compared the performance of kernel-based association analysis on the material of the Genetic Analysis Workshop 17 family sample and real human data by using our transformation, the original untransformed trait, and environmental residuals. We demonstrated that only the GRAMMAR+ transformation produced type I errors close to the nominal value and that this method had the highest empirical power. The new method can be applied to analysis of related samples by using existing software for kernel-based association analysis developed for unrelated samples. PMID- 23799014 TI - Inhibiting PTEN protects hippocampal neurons against stretch injury by decreasing membrane translocation of AMPA receptor GluR2 subunit. AB - The AMPA type of glutamate receptors (AMPARs)-mediated excitotoxicity is involved in the secondary neuronal death following traumatic brain injury (TBI). But the underlying cellular and molecular mechanisms remain unclear. In this study, the role of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in GluR2 lacking AMPARs mediated neuronal death was investigated through an in vitro stretch injury model of neurons. It was indicated that both the mRNA and protein levels of PTEN were increased in cultured hippocampal neurons after stretch injury, which was associated with the decreasing expression of GluR2 subunits on the surface of neuronal membrane. Inhibition of PTEN activity by its inhibitor can promote the survival of neurons through preventing reduction of GluR2 on membrane. Moreover, the effect of inhibiting GluR2-lacking AMPARs was similar to PTEN suppression-mediated neuroprotective effect in stretch injury-induced neuronal death. Further evidence identified that the total GluR2 protein of neurons was not changed in all groups. So inhibition of PTEN or blockage of GluR2 lacking AMPARs may attenuate the death of hippocampal neurons post injury through decreasing the translocation of GluR2 subunit on the membrane effectively. PMID- 23799015 TI - Increasing the contrast of the brain MR FLAIR images using fuzzy membership functions and structural similarity indices in order to segment MS lesions. AB - Segmentation is an important step for the diagnosis of multiple sclerosis (MS). This paper presents a new approach to the fully automatic segmentation of MS lesions in Fluid Attenuated Inversion Recovery (FLAIR) Magnetic Resonance (MR) images. With the aim of increasing the contrast of the FLAIR MR images with respect to the MS lesions, the proposed method first estimates the fuzzy memberships of brain tissues (i.e., the cerebrospinal fluid (CSF), the normal appearing brain tissue (NABT), and the lesion). The procedure for determining the fuzzy regions of their member functions is performed by maximizing fuzzy entropy through Genetic Algorithm. Research shows that the intersection points of the obtained membership functions are not accurate enough to segment brain tissues. Then, by extracting the structural similarity (SSIM) indices between the FLAIR MR image and its lesions membership image, a new contrast-enhanced image is created in which MS lesions have high contrast against other tissues. Finally, the new contrast-enhanced image is used to segment MS lesions. To evaluate the result of the proposed method, similarity criteria from all slices from 20 MS patients are calculated and compared with other methods, which include manual segmentation. The volume of segmented lesions is also computed and compared with Gold standard using the Intraclass Correlation Coefficient (ICC) and paired samples t test. Similarity index for the patients with small lesion load, moderate lesion load and large lesion load was 0.7261, 0.7745 and 0.8231, respectively. The average overall similarity index for all patients is 0.7649. The t test result indicates that there is no statistically significant difference between the automatic and manual segmentation. The validated results show that this approach is very promising. PMID- 23799016 TI - Celastrol prevents atherosclerosis via inhibiting LOX-1 and oxidative stress. AB - Celastrol is a triterpenoid compound extracted from the Chinese herb Tripterygium wilfordii Hook F. Previous research has revealed its anti-oxidant, anti inflammatory, anti-cancer and immunosuppressive properties. Here, we investigated whether celastrol inhibits oxidized low-density lipoprotein (oxLDL) induced oxidative stress in RAW 264.7 cells. In addition, the effect of celastrol on atherosclerosis in vivo was assessed in apolipoprotein E knockout (apoE(-/-)) mouse fed a high-fat/high-cholesterol diet (HFC). We found that celastrol significantly attenuated oxLDL-induced excessive expression of lectin-like oxidized low density lipoprotein receptor-1(LOX-1) and generation of reactive oxygen species (ROS) in cultured RAW264.7 macrophages. Celastrol also decreased IkappaB phosphorylation and degradation and reduced production of inducible nitric oxide synthase (iNOS), nitric oxide (NO) and proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha and IL-6. Celastrol reduced atherosclerotic plaque size in apoE(-/-) mice. The expression of LOX-1 within the atherosclerotic lesions and generation of superoxide in mouse aorta were also significantly reduced by celastrol while the lipid profile was not improved. In conclusion, our results show that celastrol inhibits atherosclerotic plaque developing in apoE(-/-) mice via inhibiting LOX-1 and oxidative stress. PMID- 23799017 TI - Role of electron microscopy in the diagnosis of cadasil syndrome: a study of 32 patients. AB - BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by NOTCH3 gene mutations that result in vascular smooth muscle cell (VSMC) degeneration. Its distinctive feature by electron microscopy (EM) is granular osmiophilic material (GOM) detected in VSMC indentations and/or the extracellular space close to VSMCs. Reports of the sensitivity of EM in detecting GOM in biopsies from CADASIL patients are contradictory. We present data from 32 patients clinically suspected to have CADASIL and discuss the role of EM in its diagnosis in this retrospective study. METHODS: Skin, skeletal muscle, kidney and pericardial biopsies were examined by EM; the NOTCH3 gene was screened for mutations. Skin and muscle biopsies from 12 patients without neurological symptoms served as controls. RESULTS AND DISCUSSION: All GOM-positive patients exhibited NOTCH3 mutations and vice versa. This study i) confirms that EM is highly specific and sensitive for CADASIL diagnosis; ii) extends our knowledge of GOM distribution in tissues where it has never been described, e.g. pericardium; iii) documents a novel NOTCH3 mutation in exon 3; and iv) shows that EM analysis is critical to highlight the need for comprehensive NOTCH3 analysis. Our findings also confirm the genetic heterogeneity of CADASIL in a small Italian subpopulation and emphasize the difficulties in designing algorithms for molecular diagnosis. PMID- 23799018 TI - Tumor endothelial cell-specific drug delivery system using apelin-conjugated liposomes. AB - BACKGROUND: A drug delivery system specifically targeting endothelial cells (ECs) in tumors is required to prevent normal blood vessels from being damaged by angiogenesis inhibitors. The purpose of this study was to investigate whether apelin, a ligand for APJ expressed in ECs when angiogenesis is taking place, can be used for targeting drug delivery to ECs in tumors. METHODS AND RESULTS: Uptake of apelin via APJ stably expressed in NIH-3T3 cells was investigated using TAMRA (fluorescent probe)-conjugated apelin. Both long and short forms of apelin (apelin 36 and apelin 13) were taken up, the latter more effectively. To improve efficacy of apelin- liposome conjugates, we introduced cysteine, with its sulfhydryl group, to the C terminus of apelin 13, resulting in the generation of apelin 14. In turn, apelin 14 was conjugated to rhodamine-encapsulating liposomes and administered to tumor-bearing mice. In the tumor microenvironment, we confirmed that liposomes were incorporated into the cytoplasm of ECs. In contrast, apelin non-conjugated liposomes were rarely found in the cytoplasm of ECs. Moreover, non-specific uptake of apelin-conjugated liposomes was rarely detected in other normal organs. CONCLUSIONS: ECs in normal organs express little APJ; however, upon hypoxic stimulation, such as in tumors, ECs start to express APJ. The present study suggests that apelin could represent a suitable tool to effectively deliver drugs specifically to ECs within tumors. PMID- 23799019 TI - Systemic administration of Abeta mAb reduces retinal deposition of Abeta and activated complement C3 in age-related macular degeneration mouse model. AB - Age-related macular degeneration (AMD) is a leading cause of legal blindness in the Western world. There are effective treatments for the vascular complications of neo-vascular AMD, but no effective therapies are available for the dry/atrophic form of the disease. A previously described transgenic CFH-gene deficient mouse model, (cfh-/-), shows hallmarks of early AMD. The ocular phenotype has been further analysed to demonstrate amyloid beta (Abeta) rich basement membrane deposits associated with activated complement C3. Cfh-/- mice were treated systemically in both prophylactic and therapeutic regimes with an anti-Abeta monoclonal antibody (mAb), 6F6, to determine the effect on the cfh-/- retinal phenotype. Prophylactic treatment with 6F6 demonstrated a dose dependent reduction in the accumulation of both Abeta and activated C3 deposition. A similar reduction in the retinal endpoints could be seen after therapeutic treatment. Serum Abeta levels after systemic administration of 6F6 show accumulation of Abeta in the periphery suggestive of a peripheral sink mechanism. In summary, anti-Abeta mAb treatment can partially prevent or reverse ocular phenotypes of the cfh-/- mouse. The data support this therapeutic approach in humans potentially modulating two key elements in the pathogenesis of AMD - Abeta and activated, complement C3. PMID- 23799020 TI - Atypical song reveals spontaneously developing coordination between multi-modal signals in brown-headed cowbirds (Molothrus ater). AB - The courtship and dominance behavior of brown-headed cowbirds (Molothrus ater) consists of a multi-modal display, including song as well as postural and wing movements. The temporal sequences of the acoustic and the visual display are coordinated. In adult male cowbirds the largest wing movements of the display are synchronized with silent periods of song, but it is unknown how this coordination emerges during song development. Here we investigate how visual display features are coordinated with song by using atypical song sequence structure of isolation reared male cowbirds. In birds with atypical song, all components of the visual display were highly similar to those of "normal" song displays, but their timing was slightly different. The number of maximal wing movement cycles of isolation reared males was linked to the number of sound units in the song, and was therefore reduced during the abbreviated song types of isolates. These data indicate that young cowbirds do not need to be exposed to a model of the visual display during ontogeny and that there is synchronization with the temporal structure of song. A physiological link between respiratory and syringeal control of silent periods between sound units and wing movement cycles may be driving this synchronization. PMID- 23799021 TI - Multilamellar structures and filament bundles are found on the cell surface during bunyavirus egress. AB - Inside cells, viruses build specialized compartments for replication and morphogenesis. We observed that virus release associates with specific structures found on the surface of mammalian cells. Cultured adherent cells were infected with a bunyavirus and processed for oriented sectioning and transmission electron microscopy. Imaging of cell basal regions showed sophisticated multilamellar structures (MLS) and extracellular filament bundles with attached viruses. Correlative light and electron microscopy confirmed that both MLS and filaments proliferated during the maximum egress of new viruses. MLS dimensions and structure were reminiscent of those reported for the nanostructures on gecko fingertips, which are responsible for the extraordinary attachment capacity of these lizards. As infected cells with MLS were more resistant to detachment than control cells, we propose an adhesive function for these structures, which would compensate for the loss of adherence during release of new virus progeny. PMID- 23799022 TI - Are women deciding against home births in low and middle income countries? AB - BACKGROUND: Although there is evidence to tracking progress towards facility births within the UN Millennium Development Goals framework, we do not know whether women are deciding against home birth over their reproductive lives. Using Demographic and Health Surveys (DHS) data from 44 countries, this study aims to investigate the patterns and shifts in childbirth locations and to determine whether these shifts are in favour of home or health settings. METHODS AND FINDINGS: The analyses considered 108,777 women who had at least two births in the five years preceding the most recent DHS over the period 2000-2010. The vast majority of women opted for the same place of childbirth for their successive births. However, about 14% did switch their place and not all these decisions favoured health facility over home setting. In 24 of the 44 countries analysed, a higher proportion of women switched from a health facility to home. Multilevel regression analyses show significantly higher odds of switching from home to a facility for high parity women, those with frequent antenatal visits and more wealth. However, in countries with high infant mortality rates, low parity women had an increased probability of switching from home to a health facility. CONCLUSIONS: There is clear evidence that women do change their childbirth locations over successive births in low and middle income countries. After two decades of efforts to improve maternal health, it might be expected that a higher proportion of women will be deciding against home births in favour of facility births. The results from this analysis show that is not the case. PMID- 23799023 TI - The immunoglobulin superfamily protein differentiation of embryonic stem cells 1 (dies1) has a regulatory role in preadipocyte to adipocyte conversion. AB - Differentiation of Embryonic Stem Cells 1 (Dies1) was recently identified as a novel type I immunoglobulin (IgG) domain-containing plasma membrane protein important for effective differentiation of a murine pluripotent embryonic stem cell line. In this setting, Dies1 enhances bone morphogenetic protein 4 (BMP4) signaling. Here we show Dies1 transcript expression is induced ~225-fold during in vitro adipogenesis of 3T3-L1 murine preadipocytes. Immunocytochemical imaging using ectopic expression of Flag-tagged Dies1 in 3T3-L1 adipocytes revealed localization to the adipocyte plasma membrane. Modulation of adipocyte phenotype with with tumor necrosis factor-alpha (TNFalpha) treatment or by siRNA knockdown of the master pro-adipogenic transcription factor peroxisome proliferator activated receptor gamma (PPARgamma) resulted in a 90% and 60% reduction of Dies1 transcript levels, respectively. Moreover, siRNA-mediated Dies1 knockdown in 3T3 L1 preadipocytes inhibited adipogenic conversion. Such cultures had a 35% decrease in lipid content and a 45%-65% reduction in expression of key adipocyte transcripts, including that for PPARgamma. The standard protocol for full in vitro adipogenic conversion of committed preadipocytes, such as 3T3-L1, does not include BMP4 treatment. Thus we posit the positive role of Dies1 in adipogenesis, unlike that for Dies1 in differentiation of embryonic stem cells, does not include its pro-BMP4 effects. In support of this idea, 3T3-L1 adipocytes knocked down for Dies1 did not evidence decreased phospho-Smad1 levels upon BMP4 exposure. qPCR analysis of Dies1 transcript in multiple murine and human tissues reveals high enrichment in white adipose tissue (WAT). Interestingly, we observed a 10-fold induction of Dies1 transcript in WAT of fasted vs. fed mice, suggesting a role for Dies1 in nutritional response of mature fat cells in vivo. Together our data identify Dies1 as a new differentiation-dependent adipocyte plasma membrane protein whose expression is required for effective adipogenesis and that may also play a role in regard to nutritional status in WAT. PMID- 23799024 TI - Adaptive induction of growth differentiation factor 15 attenuates endothelial cell apoptosis in response to high glucose stimulus. AB - Growth differentiation factor 15 (GDF15), a direct target gene of p53, is a multifunctional member of the TGF-beta/BMP superfamily. GDF15 can be induced and is implicated as a key secretory cytokine in response to multiple cellular stimuli. Accumulating evidence indicates that GDF15 is associated with the development and prognosis of diabetes mellitus, while whether GDF15 can be induced by high glucose is unknown. In the present study, we revealed that high glucose could induce GDF15 expression and secretion in cultured human umbilical vein endothelial cells in a ROS- and p53-dependent manner. Inhibition of high glucose-induced GDF15 expression by siRNA demonstrated that adaptively induced GDF15 played a protective role against high glucose-induced human umbilical vein endothelial cell apoptosis via maintaining the active state of PI3K/Akt/eNOS pathway and attenuating NF-kappaB/JNK pathway activation. The protective effects of GDF15 were probably achieved by inhibiting ROS overproduction in high glucose treated human umbilical vein endothelial cells in a negative feedback manner. Our results suggest that high glucose can promote GDF15 expression and secretion in human umbilical vein endothelial cells, which in turn attenuates high glucose induced endothelial cell apoptosis. PMID- 23799025 TI - Observation of bacterial type I pili extension and contraction under fluid flow. AB - Type I pili are proteinaceous tethers that mediate bacterial adhesion of uropathogenic Escherichia coli to surfaces and are thought to help bacteria resist drag forces imparted by fluid flow via uncoiling of their quaternary structure. Uncoiling and recoiling have been observed in force spectroscopy experiments, but it is not clear if and how this process occurs under fluid flow. Here we developed an assay to study the mechanical properties of pili in a parallel plate flow chamber. We show that pili extend when attached E. coli bacteria are exposed to increasing shear stresses, that pili can help bacteria move against moderate fluid flows, and characterize two dynamic regimes of this displacement. The first regime is consistent with entropic contraction as modeled by a freely jointed chain, and the second with coiling of the quaternary structure of pili. These results confirm that coiling and uncoiling happen under flow but the observed dynamics are different from those reported previously. Using these results and those from previous studies, we review the mechanical properties of pili in the context of other elastic proteins such as the byssal threads of mussels. It has been proposed that the high extensibility of pili may help recruit more pili into tension and lower the force acting on each one by damping changes in force due to fluid flow. Our analysis of the mechanical properties suggests additional functions of pili; in particular, their extensibility may reduce tension by aligning pili with the direction of flow, and the uncoiled state of pili may complement uncoiling in regulating the force of the terminal adhesin. PMID- 23799026 TI - Dating the diversification of the major lineages of Ascomycota (Fungi). AB - Establishing the dates for the origin and main diversification events in the phylogeny of Ascomycota is among the most crucial remaining goals in understanding the evolution of Fungi. There have been several analyses of divergence times in the fungal tree of life in the last two decades, but most have yielded contrasting results for the origin of the major lineages. Moreover, very few studies have provided temporal estimates for a large set of clades within Ascomycota. We performed molecular dating to estimate the divergence times of most of the major groups of Ascomycota. To account for paleontological uncertainty, we included alternative fossil constraints as different scenarios to enable a discussion of the effect of selection of fossils. We used data from 6 molecular markers and 121 extant taxa within Ascomycota. Our various 'relaxed clock' scenarios suggest that the origin and diversification of the Pezizomycotina occurred in the Cambrian. The main lineages of lichen-forming Ascomycota originated at least as early as the Carboniferous, with successive radiations in the Jurassic and Cretaceous generating the diversity of the main modern groups. Our study provides new information about the timing of the main diversification events in Ascomycota, including estimates for classes, orders and families of both lichenized and non-lichenized Ascomycota, many of which had not been previously dated. PMID- 23799027 TI - Clinical significance in oral cavity squamous cell carcinoma of pathogenic somatic mitochondrial mutations. AB - Somatic mutations affecting the mitochondrial DNA (mtDNA) have been frequently observed in human cancers and proposed as important oncological biomarkers. However, the clinical significance of mtDNA mutations in cancer remains unclear. This study was therefore performed to explore the possible clinical use in assessing oral squamous cell carcinoma (OSCC) of pathogenic mtDNA mutations. The entire mitochondrial genome of 300 OSCC with their matched control DNAs was screened by direct sequencing and criteria were set to define a pathogenic somatic mutation. The patients' TP53 R72P genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. The relationships between pathogenic somatic mutations, clinicopathogical features, TP53 R72P genotype and clinical prognosis were analyzed. Overall, 645 somatic mtDNA mutations were identified and 91 of these mutations were defined as pathogenic. About one quarter (74/300) of the OSCC tumor samples contained pathogenic mutations. Individuals with the TP53 R allele had a higher frequency of pathogenic somatic mutation than those with the PP genotype. Kaplan-Meier analysis indicated that TP53 R allele patients with pathogenic somatic mutations demonstrated a significant association with a poorer disease-free survival than other individuals (HR = 1.71; 95% CI, 1.15-2.57; p = 0.009) and this phenomenon still existed after adjusting for mtDNA haplogroup, tumor stage with treatment regimens, differentiation and age at diagnosis (HR = 1.59; 95% CI, 1.06-2.40; p = 0.03). Subgroup analyses showed that this phenomenon was limited to patients who received adjuvant radiotherapy/chemo-radiotherapy after surgery. The results strongly indicated that pathogenic mtDNA mutations are a potential prognostic marker for OSCCs. Furthermore, functional mitochondria may play an active role in cancer development and the patient's response to radiotherapy/chemo-radiotherapy. PMID- 23799028 TI - A study on factors affecting the degradation of magnesium and a magnesium-yttrium alloy for biomedical applications. AB - Controlling degradation of magnesium or its alloys in physiological saline solutions is essential for their potential applications in clinically viable implants. Rapid degradation of magnesium-based materials reduces the mechanical properties of implants prematurely and severely increases alkalinity of the local environment. Therefore, the objective of this study is to investigate the effects of three interactive factors on magnesium degradation, specifically, the addition of yttrium to form a magnesium-yttrium alloy versus pure magnesium, the metallic versus oxide surfaces, and the presence versus absence of physiological salt ions in the immersion solution. In the immersion solution of phosphate buffered saline (PBS), the magnesium-yttrium alloy with metallic surface degraded the slowest, followed by pure magnesium with metallic or oxide surfaces, and the magnesium yttrium alloy with oxide surface degraded the fastest. However, in deionized (DI) water, the degradation rate showed a different trend. Specifically, pure magnesium with metallic or oxide surfaces degraded the slowest, followed by the magnesium-yttrium alloy with oxide surface, and the magnesium-yttrium alloy with metallic surface degraded the fastest. Interestingly, only magnesium-yttrium alloy with metallic surface degraded slower in PBS than in DI water, while all the other samples degraded faster in PBS than in DI water. Clearly, the results showed that the alloy composition, presence or absence of surface oxide layer, and presence or absence of physiological salt ions in the immersion solution all influenced the degradation rate and mode. Moreover, these three factors showed statistically significant interactions. This study revealed the complex interrelationships among these factors and their respective contributions to degradation for the first time. The results of this study not only improved our understanding of magnesium degradation in physiological environment, but also presented the key factors to consider in order to satisfy the degradation requirements for next-generation biodegradable implants and devices. PMID- 23799029 TI - Solution structure and peptide binding of the PTB domain from the AIDA1 postsynaptic signaling scaffolding protein. AB - AIDA1 links persistent chemical signaling events occurring at the neuronal synapse with global changes in gene expression. Consistent with its role as a scaffolding protein, AIDA1 is composed of several protein-protein interaction domains. Here we report the NMR structure of the carboxy terminally located phosphotyrosine binding domain (PTB) that is common to all AIDA1 splice variants. A comprehensive survey of peptides identified a consensus sequence around an NxxY motif that is shared by a number of related neuronal signaling proteins. Using peptide arrays and fluorescence based assays, we determined that the AIDA1 PTB domain binds amyloid protein precursor (APP) in a similar manner to the X11/Mint PTB domain, albeit at reduced affinity (~10 uM) that may allow AIDA1 to effectively sample APP, as well as other protein partners in a variety of cellular contexts. PMID- 23799030 TI - Glial promoter selectivity following AAV-delivery to the immature brain. AB - Recombinant adeno-associated virus (AAV) vectors are versatile tools for gene transfer to the central nervous system (CNS) and proof-of-concept studies in adult rodents have shown that the use of cell type-specific promoters is sufficient to target AAV-mediated transgene expression to glia. However, neurological disorders caused by glial pathology usually have an early onset. Therefore, modelling and treatment of these conditions require expanding the concept of targeted glial transgene expression by promoter selectivity for gene delivery to the immature CNS. Here, we have investigated the AAV-mediated green fluorescent protein (GFP) expression driven by the myelin basic protein (MBP) or glial fibrillary acidic protein (GFAP) promoters in the developing mouse brain. Generally, the extent of transgene expression after infusion at immature stages was widespread and higher than in adults. The GFAP promoter-driven GFP expression was found to be highly specific for astrocytes following vector infusion to the brain of neonates and adults. In contrast, the selectivity of the MBP promoter for oligodendrocytes was poor following neonatal AAV delivery, but excellent after vector injection at postnatal day 10. To extend these findings obtained in naive mice to a disease model, we performed P10 infusions of AAV-MBP-GFP in aspartoacylase (ASPA)-deficient mouse mutants presenting with early onset oligodendrocyte pathology. Spread of GFP expression and selectivity for oligodendrocytes in ASPA-mutants was comparable with our observations in normal animals. Our data suggest that direct AAV infusion to the developing postnatal brain, utilising cellular promoters, results in targeted and long-term transgene expression in glia. This approach will be relevant for disease modelling and gene therapy for the treatment of glial pathology. PMID- 23799032 TI - COMT Val158Met genotype selectively alters prefrontal [18F]fallypride displacement and subjective feelings of stress in response to a psychosocial stress challenge. AB - Catechol-O-methyltransferase (COMT) plays an essential role in degradation of extracellular dopamine in prefrontal regions of the brain. Although a polymorphism in this gene, COMT Val(158)Met, affects human behavior in response to stress little is known about its effect on dopaminergic activity associated with the human stress response, which may be of interest for stress-related psychiatric disorders such as psychosis. We aimed to investigate the effect of variations in COMT genotype on in vivo measures of stress-induced prefrontal cortex (PFC) dopaminergic processing and subjective stress responses. A combined sample of healthy controls and healthy first-degree relatives of psychosis patients (n = 26) were subjected to an [(18)F]fallypride Positron Emission Tomography scan. Psychosocial stress during the scan was induced using the Montreal Imaging Stress Task and subjective stress was assessed every 12 minutes. Parametric t-maps, generated using the linear extension of the simplified reference region model, revealed an effect of COMT genotype on the spatial extent of [(18)F]fallypride displacement. Detected effects of exposure to psychosocial stress were unilateral and remained restricted to the left superior and right inferior frontal gyrus, with Met-hetero- and homozygotes showing less [(18)F]fallypride displacement than Val-homozygotes. Additionally, Met-hetero- and homozygotes experienced larger subjective stress responses than Val homozygotes. The direction of the effects remained the same when the data was analyzed separately for controls and first-degree relatives. The human stress response may be mediated in part by COMT-dependent dopaminergic PFC activity, providing speculation for the neurobiology underlying COMT-dependent differences in human behaviour following stress. Implications of these results for stress related psychopathology and models of dopaminergic functioning are discussed. PMID- 23799033 TI - Characterization of hair follicle development in engineered skin substitutes. AB - Generation of skin appendages in engineered skin substitutes has been limited by lack of trichogenic potency in cultured postnatal cells. To investigate the feasibility and the limitation of hair regeneration, engineered skin substitutes were prepared with chimeric populations of cultured human keratinocytes from neonatal foreskins and cultured murine dermal papilla cells from adult GFP transgenic mice and grafted orthotopically to full-thickness wounds on athymic mice. Non-cultured dissociated neonatal murine-only skin cells, or cultured human only skin keratinocytes and fibroblasts without dermal papilla cells served as positive and negative controls respectively. In this study, neonatal murine-only skin substitutes formed external hairs and sebaceous glands, chimeric skin substitutes formed pigmented hairs without sebaceous glands, and human-only skin substitutes formed no follicles or glands. Although chimeric hair cannot erupt readily, removal of upper skin layer exposed keratinized hair shafts at the skin surface. Development of incomplete pilosebaceous units in chimeric hair corresponded with upregulation of hair-related genes, LEF1 and WNT10B, and downregulation of a marker of sebaceous glands, Steroyl-CoA desaturase. Transepidermal water loss was normal in all conditions. This study demonstrated that while sebaceous glands may be involved in hair eruption, they are not required for hair development in engineered skin substitutes. PMID- 23799031 TI - Profiling of childhood adversity-associated DNA methylation changes in alcoholic patients and healthy controls. AB - The increased vulnerability to alcohol dependence (AD) seen in individuals with childhood adversity (CA) may result in part from CA-induced epigenetic changes. To examine CA-associated DNA methylation changes in AD patients, we examined peripheral blood DNA methylation levels of 384 CpGs in promoter regions of 82 candidate genes in 279 African Americans [AAs; 88 with CA (70.5% with AD) and 191 without CA (38.2% with AD)] and 239 European Americans [EAs; 61 with CA (86.9% with AD) and 178 without CA (46.6% with AD)] using Illumina GoldenGate Methylation Array assays. The effect of CA on methylation of individual CpGs and overall methylation in promoter regions of genes was evaluated using a linear regression analysis (with consideration of sex, age, and ancestry proportion of subjects) and a principal components-based analysis, respectively. In EAs, hypermethylation of 10 CpGs in seven genes (ALDH1A1, CART, CHRNA5, HTR1B, OPRL1, PENK, and RGS19) were cross validated in AD patients and healthy controls who were exposed to CA. P values of two CpGs survived Bonferroni correction when all EA samples were analyzed together to increase statistical power [CHRNA5_cg17108064: P(adjust) = 2.54*10(-5); HTR1B_cg06031989: P(adjust) = 8.98*10(-5)]. Moreover, overall methylation levels in the promoter regions of three genes (ALDH1A1, OPRL1 and RGS19) were elevated in both EA case and control subjects who were exposed to CA. However, in AAs, CA-associated DNA methylation changes in AD patients were not validated in healthy controls. Our findings suggest that CA could induce population-specific methylation alterations in the promoter regions of specific genes, thus leading to changes in gene transcription and an increased risk for AD and other disorders. PMID- 23799034 TI - Ovariectomized OVA-sensitized mice display increased frequency of CD4(+)Foxp3(+) T regulatory cells in the periphery. AB - It is well established that female sex hormones have a pivotal role in inflammation. For instance, our group has previously reported that estradiol has proinflammatory actions during allergic lung response in animal models. Based on these findings, we have decided to further investigate whether T regulatory cells are affected by female sex hormones absence after ovariectomy. We evaluated by flow cytometry the frequencies of CD4(+)Foxp3(+) T regulatory cells (Tregs) in central and peripheral lymphoid organs, such as the thymus, spleen and lymph nodes. Moreover, we have also used the murine model of allergic lung inflammation a to evaluate how female sex hormones would affect the immune response in vivo. To address that, ovariectomized or sham operated female Balb/c mice were sensitized or not with ovalbumin 7 and 14 days later and subsequently challenged twice by aerosolized ovalbumin on day 21. Besides the frequency of CD4(+)Foxp3(+) T regulatory cells, we also measured the cytokines IL-4, IL-5, IL-10, IL-13 and IL-17 in the bronchoalveolar lavage from lungs of ovalbumine challenged groups. Our results demonstrate that the absence of female sex hormones after ovariectomy is able to increase the frequency of Tregs in the periphery. As we did not observe differences in the thymus-derived natural occurring Tregs, our data may indicate expansion or conversion of peripheral adaptive Tregs. In accordance with Treg suppressive activity, ovariectomized and ovalbumine-sensitized and challenged animals had significantly reduced lung inflammation. This was observed after cytokine analysis of lung explants showing significant reduction of pro inflammatory cytokines, such as IL-4, IL-5, IL-13 and IL-17, associated to increased amount of IL-10. In summary, our data clearly demonstrates that OVA sensitization 7 days after ovariectomy culminates in reduced lung inflammation, which may be directly correlated with the expansion of Tregs in the periphery and further higher IL-10 secretion in the lungs. PMID- 23799035 TI - CSTP1, a novel protein phosphatase, blocks cell cycle, promotes cell apoptosis, and suppresses tumor growth of bladder cancer by directly dephosphorylating Akt at Ser473 site. AB - Akt/protein kinase B is a pivotal component downstream of phosphatidylinositol 3 kinase (PI3K) pathway, whose activity regulates the balance between cell survival and apoptosis. Phosphorylation of Akt occurs at two key sites either at Thr308 site in the activation loop or at Ser473 site in the hydrophobic motif. The phosphorylated form of Akt (pAkt) is activated to promote cell survival. The mechanisms of pAkt dephosphorylation and how the signal transduction of Akt pathway is terminated are still largely unknown. In this study, we identified a novel protein phosphatase CSTP1(complete s transactivated protein 1), which interacts and dephosphorylates Akt specifically at Ser473 site in vivo and in vitro, blocks cell cycle progression and promotes cell apoptosis. The effects of CSTP1 on cell survival and cell cycle were abrogated by depletion of phosphatase domain of CSTP1 or by expression of a constitutively active form of Akt (S473D), suggesting Ser473 site of Akt as a primary cellular target of CSTP1. Expression profile analysis showed that CSTP1 expression is selectively down-regulated in non-invasive bladder cancer tissues and over-expression of CSTP1 suppressed the size of tumors in nude mice. Kaplan-Meier curves revealed that decreased expression of CSTP1 implicated significantly reduced recurrence-free survival in patients suffered from non-invasive bladder cancers. PMID- 23799037 TI - Weak and habitat-dependent effects of nutrient pollution on macrofaunal communities of southeast Australian estuaries. AB - Among the impacts of coastal settlements to estuaries, nutrient pollution is often singled out as a leading cause of modification to the ecological communities of soft sediments. Through sampling of 48 sites, distributed among 16 estuaries of New South Wales, Australia, we tested the hypotheses that (1) anthropogenic nutrient loads would be a better predictor of macrofaunal communities than estuarine geomorphology or local sediment characteristics; and (2) local environmental context, as determined largely by sediment characteristics, would modify the relationship between nutrient loading and community composition. Contrary to the hypothesis, multivariate multiple regression analyses revealed that sediment grain size was the best predictor of macrofaunal assemblage composition. When samples were stratified according to median grain size, relationships between faunal communities and nitrogen loading and latitude emerged, but only among estuaries with sandier sediments. In these estuaries, capitellid and nereid polychaetes and chironomid larvae were the taxa that showed the strongest correlations with nutrient loading. Overall, this study failed to provide evidence of a differential relationship between diffuse nutrient enrichment and benthic macrofauna across a gradient of 7 degrees of latitude and 4 degrees C temperature. Nevertheless, as human population growth continues to place increasing pressure on southeast Australian estuaries, manipulative field studies examining when and where nutrient loading will lead to significant changes in estuarine community structure are needed. PMID- 23799036 TI - ToP: a trend-of-disease-progression procedure works well for identifying cancer genes from multi-state cohort gene expression data for human colorectal cancer. AB - Significantly expressed genes extracted from microarray gene expression data have proved very useful for identifying genetic biomarkers of diseases, including cancer. However, deriving a disease related inference from a list of differentially expressed genes has proven less than straightforward. In a systems disease such as cancer, how genes interact with each other should matter just as much as the level of gene expression. Here, in a novel approach, we used the network and disease progression properties of individual genes in state-specific gene-gene interaction networks (GGINs) to select cancer genes for human colorectal cancer (CRC) and obtain a much higher hit rate of known cancer genes when compared with methods not based on network theory. We constructed GGINs by integrating gene expression microarray data from multiple states--healthy control (Nor), adenoma (Ade), inflammatory bowel disease (IBD) and CRC--with protein protein interaction database and Gene Ontology. We tracked changes in the network degrees and clustering coefficients of individual genes in the GGINs as the disease state changed from one to another. From these we inferred the state sequences Nor-Ade-CRC and Nor-IBD-CRC both exhibited a trend of (disease) progression (ToP) toward CRC, and devised a ToP procedure for selecting cancer genes for CRC. Of the 141 candidates selected using ToP, ~50% had literature support as cancer genes, compared to hit rates of 20% to 30% for standard methods using only gene expression data. Among the 16 candidate cancer genes that encoded transcription factors, 13 were known to be tumorigenic and three were novel: CDK1, SNRPF, and ILF2. We identified 13 of the 141 predicted cancer genes as candidate markers for early detection of CRC, 11 and 2 at the Ade and IBD states, respectively. PMID- 23799038 TI - Idiopathic environmental intolerance attributed to electromagnetic fields: a content analysis of British newspaper reports. AB - Idiopathic environmental intolerance attributed to electromagnetic fields (IEI EMF) is a controversial condition in which people describe symptoms following exposure to electromagnetic fields from everyday electrical devices. However, double-blind experiments have found no convincing evidence that electromagnetic fields cause these symptoms. In this study, we assessed whether recent newspaper reporting in the UK reflected this scientific evidence. We searched a database of newspaper articles to identify all those that contained IEI-EMF related keywords and selected a random sample of 60 for content analysis. For our primary outcomes, we assessed how many articles mainly or wholly presented an electromagnetic cause for IEI-EMF and how many discussed unproven treatments for the condition such as strategies intended to reduce exposure to electromagnetic fields or the use of complementary and alternative therapies. We also assessed whether the type of information source used by a newspaper article (e.g. scientist, person with IEI-EMF, politician) or the type of newspaper (broadsheet, tabloid, local or regional) was associated with either outcome. Of the 60 articles, 43 (71.7%) presented a mainly electromagnetic cause, compared to 13 (21.7%) which presented mainly non-electromagnetic causes and 4 (6.7%) which did not discuss a cause. 29 (48.3%) did not mention any potential treatment, while 24 (40.0%) mentioned eletromagnetic field related strategies and 12 (20.0%) mentioned complementary or alternative therapies. Articles which quoted someone with IEI-EMF were significantly more likely to report an electromagnetic cause and to present unproven treatments. Those which used a scientist as a source were more likely to present a non-electromagnetic cause for the condition. The widespread poor reporting we identified is disappointing and has the potential for to encourage more people to misattribute their symptoms to electromagnetic fields. Scientists should remain engaged with the media to counteract this effect. PMID- 23799039 TI - Identification of inter-organ vascular network: vessels bridging between organs. AB - Development and homeostasis of organs and whole body is critically dependent on the circulatory system. In particular, the circulatory system, the railways shuttling oxygen and nutrients among various organs, is indispensible for inter organ humoral communication. Since the modern view of the anatomy and mechanics of the circulatory system was established in 17(th) century, it has been assumed that humoral factors are carried to and from organs via vascular branches of the central arteries and veins running along the body axis. Over the past few decades, major advances have been made in understanding molecular and cellular mechanisms underlying the vascularization of organs. However, very little is known about how each organ is linked by vasculature (i.e., inter-organ vascular networks). In fact, the exact anatomy of inter-organ vascular networks has remained obscure. Herein, we report the identification of four distinct vessels, V1(LP), V2(LP), V3(LP) and V4(LP), that bridge between two organs, liver and pancreas in developing zebrafish. We found that these inter-organ vessels can be classified into two types: direct and indirect types. The direct type vessels are those that bridge between two organs via single distinct vessel, to which V1(LP) and V2(LP) vessels belong. The indirect type bridges between two organs via separate branches that emanate from a stem vessel, and V3(LP) and V4(LP) vessels belong to this type. Our finding of V1(LP), V2(LP), V3(LP) and V4(LP) vessels provides the proof of the existence of inter-organ vascular networks. These and other yet-to-be-discovered inter-organ vascular networks may facilitate the direct exchange of humoral factors that are necessary for the coordinated growth, differentiation and homeostasis of the connected organs. It is also possible that the inter-organ vessels serve as tracks for their connected organs to follow during their growth to establish their relative positions and size differences. PMID- 23799040 TI - Automatic diagnosis of pathological myopia from heterogeneous biomedical data. AB - Pathological myopia is one of the leading causes of blindness worldwide. The condition is particularly prevalent in Asia. Unlike myopia, pathological myopia is accompanied by degenerative changes in the retina, which if left untreated can lead to irrecoverable vision loss. The accurate diagnosis of pathological myopia will enable timely intervention and facilitate better disease management to slow down the progression of the disease. Current methods of assessment typically consider only one type of data, such as that from retinal imaging. However, different kinds of data, including that of genetic, demographic and clinical information, may contain different and independent information, which can provide different perspectives on the visually observable, genetic or environmental mechanisms for the disease. The combination of these potentially complementary pieces of information can enhance the understanding of the disease, providing a holistic appreciation of the multiple risks factors as well as improving the detection outcomes. In this study, we propose a computer-aided diagnosis framework for Pathological Myopia diagnosis through Biomedical and Image Informatics(PM-BMII). Through the use of multiple kernel learning (MKL) methods, PM-BMII intelligently fuses heterogeneous biomedical information to improve the accuracy of disease diagnosis. Data from 2,258 subjects of a population-based study, in which demographic and clinical information, retinal fundus imaging data and genotyping data were collected, are used to evaluate the proposed framework. The experimental results show that PM-BMII achieves an AUC of 0.888, outperforming the detection results from the use of demographic and clinical information 0.607 (increase 46.3%, p<0.005), genotyping data 0.774 (increase 14.7%, P<0.005) or imaging data 0.852 (increase 4.2%, p=0.19) alone. The accuracy of the results obtained demonstrates the feasibility of using heterogeneous data for improved disease diagnosis through our proposed PM-BMII framework. PMID- 23799041 TI - CRISPLD2 is expressed at low levels during septic shock and is associated with procalcitonin. AB - INTRODUCTION: Previous studies have shown that cysteine-rich secretory protein containing LCCL domain 2 (CRISPLD2) is a novel lipopolysaccharide (LPS)-binding protein, and the upregulation of CRISPLD2 expression protects mice against LPS induced lethality. The aim of this study was to examine the expression of CRISPLD2 in patients with sepsis and characterize the association of this protein with procalcitonin. METHODS: The expression of CRISPLD2 was determined in 100 healthy volunteers and 119 septic patients. According to the definition of sepsis, patients were divided into three groups sepsis, severe sepsis, and septic shock. The relationship between CRISPLD2 levels and procalcitonin was also examined and statistically analyzed. RESULTS: The CRISPLD2 levels in healthy individuals were 219.3+/-69.1 ug/ml. Patients with sepsis exhibited higher CRISPLD2 levels than observed in healthy individuals (p = 0.001), but CRISPLD2 expression was not upregulated in patients with septic shock. No significant differences were observed between the levels of CRISPLD2 in surviving and non surviving spesis patients. CRISPLD2 levels were negatively correlated with procalcitonin levels (r = -0.334, p<0.001). CONCLUSIONS: The present study is the first to demonstrate the decreased expression of CRISPLD2 in septic shock and its association with PCT in sepsis. Further studies are needed to clarify the potential association between CRISPLD2 expression and clinical outcomes to determine if it could be used as a novel sepsis biomarker. PMID- 23799042 TI - TRPV1 and TRPV4 play pivotal roles in delayed onset muscle soreness. AB - Unaccustomed strenuous exercise that includes lengthening contraction (LC) often causes tenderness and movement related pain after some delay (delayed-onset muscle soreness, DOMS). We previously demonstrated that nerve growth factor (NGF) and glial cell line-derived neurotrophic factor (GDNF) are up-regulated in exercised muscle through up-regulation of cyclooxygenase (COX)-2, and they sensitized nociceptors resulting in mechanical hyperalgesia. There is also a study showing that transient receptor potential (TRP) ion channels are involved in DOMS. Here we examined whether and how TRPV1 and/or TRPV4 are involved in DOMS. We firstly evaluated a method to measure the mechanical withdrawal threshold of the deep tissues in wild-type (WT) mice with a modified Randall Selitto apparatus. WT, TRPV1-/- and TRPV4-/- mice were then subjected to LC. Another group of mice received injection of murine NGF-2.5S or GDNF to the lateral gastrocnemius (LGC) muscle. Before and after these treatments the mechanical withdrawal threshold of LGC was evaluated. The change in expression of NGF, GDNF and COX-2 mRNA in the muscle was examined using real-time RT-PCR. In WT mice, mechanical hyperalgesia was observed 6-24 h after LC and 1-24 h after NGF and GDNF injection. LC induced mechanical hyperalgesia neither in TRPV1-/- nor in TRPV4-/- mice. NGF injection induced mechanical hyperalgesia in WT and TRPV4-/- mice but not in TRPV1-/- mice. GDNF injection induced mechanical hyperalgesia in WT but neither in TRPV1-/- nor in TRPV4-/- mice. Expression of NGF and COX-2 mRNA was significantly increased 3 h after LC in all genotypes. However, GDNF mRNA did not increase in TRPV4-/- mice. These results suggest that TRPV1 contributes to DOMS downstream (possibly at nociceptors) of NGF and GDNF, while TRPV4 is located downstream of GDNF and possibly also in the process of GDNF up-regulation. PMID- 23799043 TI - Prognostic significance of HIF-1alpha expression in hepatocellular carcinoma: a meta-analysis. AB - AIM: Pilot studies have evaluated the correlation between hypoxia-inducible factor-1alpha (HIF-1alpha) overexpression and clinical outcome in hepatocellular carcinoma (HCC) patients. However, the results remain inconclusive. To comprehensively and quantitatively summarize the evidence on the suitability of HIF-1alpha to predict the prognosis of patients with HCC, a meta-analysis was carried out. METHODS: Systematic literature searches were applied to PubMed, Elsevier and Web of Science databases until Feb. 2013. Seven studies (953 patients) were included in this meta-analysis. Pooled measure was calculated from the available data to evaluate the association between tissue -based HIF-1alpha level and overall survival (OS) and disease-free survival (DFS) in HCC patients. The relation between HIF-1alpha expression and vascular invasion was also assessed. Data were synthesized with fixed or random effect model, hazard ration (HR) or odds ratio (OR) with its 95% confidence interval (CI) was used as the effect size estimate. RESULT: The combined data suggested that HIF-1alpha overexpression in HCC correlated with poor OS [HR = 1.65 (95% (CI): 1.38, 1.97)] and DFS [HR = 2.14 (95% CI: 1.39, 3.29)]. And high HIF-1alpha expression tended to be associated with vascular invasion [OR = 2.21 (95% CI: 1.06, 4.57)]. CONCLUSION: HIF-1alpha overexpression indicates a poor prognosis for patients with HCC, it may also have predictive potential for HCC invasion and metastasis. PMID- 23799044 TI - Contrasting roles of E2F2 and E2F3 in cardiac neovascularization. AB - Insufficient neovascularization, characterized by poor endothelial cell (EC) growth, contributes to the pathogenesis of ischemic heart disease and limits cardiac tissue preservation and regeneration. The E2F family of transcription factors are critical regulators of the genes responsible for cell-cycle progression and growth; however, the specific roles of individual E2Fs in ECs are not well understood. Here we investigated the roles of E2F2 and E2F3 in EC growth, angiogenesis, and their functional impact on myocardial infarction (MI). An endothelial-specific E2F3-deficient mouse strain VE-Cre; E2F3(fl/fl) was generated, and MI was surgically induced in VE-Cre; E2F3(fl/fl) and E2F2-null (E2F2 KO) mice and their wild-type (WT) littermates, VE-Cre; E2F3(+/+) and E2F2 WT, respectively. The cardiac function, infarct size, and vascular density were significantly better in E2F2 KO mice and significantly worse in VE-Cre; E2F3(fl/fl) mice than in their WT littermates. The loss of E2F2 expression was associated with an increase in the proliferation of ECs both in vivo and in vitro, while the loss of E2F3 expression led to declines in EC proliferation. Thus, E2F3 promotes while E2F2 suppresses ischemic cardiac repair through corresponding changes in EC proliferation; and differential targeting of specific E2F members may provide a novel strategy for therapeutic angiogenesis of ischemic heart disease. PMID- 23799046 TI - Efficient multiple object tracking using mutually repulsive active membranes. AB - Studies of social and group behavior in interacting organisms require high throughput analysis of the motion of a large number of individual subjects. Computer vision techniques offer solutions to specific tracking problems, and allow automated and efficient tracking with minimal human intervention. In this work, we adopt the open active contour model to track the trajectories of moving objects at high density. We add repulsive interactions between open contours to the original model, treat the trajectories as an extrusion in the temporal dimension, and show applications to two tracking problems. The walking behavior of Drosophila is studied at different population density and gender composition. We demonstrate that individual male flies have distinct walking signatures, and that the social interaction between flies in a mixed gender arena is gender specific. We also apply our model to studies of trajectories of gliding Myxococcus xanthus bacteria at high density. We examine the individual gliding behavioral statistics in terms of the gliding speed distribution. Using these two examples at very distinctive spatial scales, we illustrate the use of our algorithm on tracking both short rigid bodies (Drosophila) and long flexible objects (Myxococcus xanthus). Our repulsive active membrane model reaches error rates better than 5 x 10(-6) per fly per second for Drosophila tracking and comparable results for Myxococcus xanthus. PMID- 23799045 TI - Combining antiangiogenic therapy with adoptive cell immunotherapy exerts better antitumor effects in non-small cell lung cancer models. AB - INTRODUCTION: Cytokine-induced killer cells (CIK cells) are a heterogeneous subset of ex-vivo expanded T lymphocytes which are characterized with a MHC unrestricted tumor-killing activity and a mixed T-NK phenotype. Adoptive CIK cells transfer, one of the adoptive immunotherapy represents a promising nontoxic anticancer therapy. However, in clinical studies, the therapeutic activity of adoptive CIK cells transfer is not as efficient as anticipated. Possible explanations are that abnormal tumor vasculature and hypoxic tumor microenvironment could impede the infiltration and efficacy of lymphocytes. We hypothesized that antiangiogenesis therapy could improve the antitumor activity of CIK cells by normalizing tumor vasculature and modulating hypoxic tumor microenvironment. METHODS: We combined recombinant human endostatin (rh endostatin) and CIK cells in the treatment of lung carcinoma murine models. Intravital microscopy, dynamic contrast enhanced magnetic resonance imaging, immunohistochemistry, and flow cytometry were used to investigate the tumor vasculature and hypoxic microenvironment as well as the infiltration of immune cells. RESULTS: Our results indicated that rh-endostatin synergized with adoptive CIK cells transfer to inhibit the growth of lung carcinoma. We found that rh endostatin normalized tumor vasculature and reduced hypoxic area in the tumor microenvironment. Hypoxia significantly inhibited the proliferation, cytotoxicity and migration of CIK cells in vitro and impeded the homing of CIK cells into tumor parenchyma ex vivo. Furthermore, we found that treatment with rh-endostatin significantly increased the homing of CIK cells and decreased the accumulation of suppressive immune cells in the tumor tissue. In addition, combination therapy produced higher level of tumor-infiltration lymphocytes compared with other treatments. CONCLUSIONS: Our results demonstrate that rh-endostatin improves the therapeutic effect of adoptive CIK cells therapy against lung carcinomas and unmask the mechanisms of the synergistic antitumor efficacy, providing a new rationale for combining antiangiogenesis therapy with immunotherapy in the treatment of lung cancer. PMID- 23799047 TI - Learning oncogenetic networks by reducing to mixed integer linear programming. AB - Cancer can be a result of accumulation of different types of genetic mutations such as copy number aberrations. The data from tumors are cross-sectional and do not contain the temporal order of the genetic events. Finding the order in which the genetic events have occurred and progression pathways are of vital importance in understanding the disease. In order to model cancer progression, we propose Progression Networks, a special case of Bayesian networks, that are tailored to model disease progression. Progression networks have similarities with Conjunctive Bayesian Networks (CBNs) [1],a variation of Bayesian networks also proposed for modeling disease progression. We also describe a learning algorithm for learning Bayesian networks in general and progression networks in particular. We reduce the hard problem of learning the Bayesian and progression networks to Mixed Integer Linear Programming (MILP). MILP is a Non-deterministic Polynomial time complete (NP-complete) problem for which very good heuristics exists. We tested our algorithm on synthetic and real cytogenetic data from renal cell carcinoma. We also compared our learned progression networks with the networks proposed in earlier publications. The software is available on the website https://bitbucket.org/farahani/diprog. PMID- 23799048 TI - Performance of serum biomarkers for the early detection of invasive aspergillosis in febrile, neutropenic patients: a multi-state model. AB - BACKGROUND: The performance of serum biomarkers for the early detection of invasive aspergillosis expectedly depends on the timing of test results relative to the empirical administration of antifungal therapy during neutropenia, although a dynamic evaluation framework is lacking. METHODS: We developed a multi state model describing simultaneously the likelihood of empirical antifungal therapy and the risk of invasive aspergillosis during neutropenia. We evaluated whether the first positive test result with a biomarker is an independent predictor of invasive aspergillosis when both diagnostic information used to treat and risk factors of developing invasive aspergillosis are taken into account over time. We applied the multi-state model to a homogeneous cohort of 185 high-risk patients with acute myeloid leukemia. Patients were prospectively screened for galactomannan antigenemia twice a week for immediate treatment decision; 2,214 serum samples were collected on the same days and blindly assessed for (1->3)- beta-D-glucan antigenemia and a quantitative PCR assay targeting a mitochondrial locus. RESULTS: The usual evaluation framework of biomarker performance was unable to distinguish clinical benefits of beta-glucan or PCR assays. The multi-state model evidenced that the risk of invasive aspergillosis is a complex time function of neutropenia duration and risk management. The quantitative PCR assay accelerated the early detection of invasive aspergillosis (P = .010), independently of other diagnostic information used to treat, while beta-glucan assay did not (P = .53). CONCLUSIONS: The performance of serum biomarkers for the early detection of invasive aspergillosis is better apprehended by the evaluation of time-varying predictors in a multi state model. Our results provide strong rationale for prospective studies testing a preemptive antifungal therapy, guided by clinical, radiological, and bi-weekly blood screening with galactomannan antigenemia and a standardized quantitative PCR assay. PMID- 23799050 TI - The Campanian Ignimbrite eruption: new data on volcanic ash dispersal and its potential impact on human evolution. AB - The Campanian Ignimbrite (CI) volcanic eruption was the most explosive in Europe in the last 200,000 years. The event coincided with the onset of an extremely cold climatic phase known as Heinrich Event 4 (HE4) approximately 40,000 years ago. Their combined effect may have exacerbated the severity of the climate through positive feedbacks across Europe and possibly globally. The CI event is of particular interest not only to investigate the role of volcanism on climate forcing and palaeoenvironments, but also because its timing coincides with the arrival into Europe of anatomically modern humans, the demise of Neanderthals, and an associated major shift in lithic technology. At this stage, however, the degree of interaction between these factors is poorly known, based on fragmentary and widely dispersed data points. In this study we provide important new data from Eastern Europe which indicate that the magnitude of the CI eruption and impact of associated distal ash (tephra) deposits may have been substantially greater than existing models suggest. The scale of the eruption is modelled by tephra distribution and thickness, supported by local data points. CI ashfall extends as far as the Russian Plain, Eastern Mediterranean and northern Africa. However, modelling input is limited by very few data points in Eastern Europe. Here we investigate an unexpectedly thick CI tephra deposit in the southeast Romanian loess steppe, positively identified using geochemical and geochronological analyses. We establish the tephra as a widespread primary deposit, which blanketed the topography both thickly and rapidly, with potentially catastrophic impacts on local ecosystems. Our discovery not only highlights the need to reassess models for the magnitude of the eruption and its role in climatic transition, but also suggests that it may have substantially influenced hominin population and subsistence dynamics in a region strategic for human migration into Europe. PMID- 23799049 TI - Distinctive profile of IsomiR expression and novel microRNAs in rat heart left ventricle. AB - MicroRNAs (miRNAs) are single-stranded non-coding RNAs that negatively regulate target gene expression through mRNA cleavage or translational repression. There is mounting evidence that they play critical roles in heart disease. The expression of known miRNAs in the heart has been studied at length by microarray and quantitative PCR but it is becoming evident that microRNA isoforms (isomiRs) are potentially physiologically important. It is well known that left ventricular (patho)physiology is influenced by transmural heterogeneity of cardiomyocyte phenotype, and this likely reflects underlying heterogeneity of gene expression. Given the significant role of miRNAs in regulating gene expression, knowledge of how the miRNA profile varies across the ventricular wall will be crucial to better understand the mechanisms governing transmural physiological heterogeneity. To determinine miRNA/isomiR expression profiles in the rat heart we investigated tissue from different locations across the left ventricular wall using deep sequencing. We detected significant quantities of 145 known rat miRNAs and 68 potential novel orthologs of known miRNAs, in mature, mature* and isomiR formation. Many isomiRs were detected at a higher frequency than their canonical sequence in miRBase and have different predicted targets. The most common miR 133a isomiR was more effective at targeting a construct containing a sequence from the gelsolin gene than was canonical miR-133a, as determined by dual fluorescence assay. We identified a novel rat miR-1 homolog from a second miR-1 gene; and a novel rat miRNA similar to miR-676. We also cloned and sequenced the rat miR-486 gene which is not in miRBase (v18). Signalling pathways predicted to be targeted by the most highly detected miRNAs include Ubiquitin-mediated Proteolysis, Mitogen-Activated Protein Kinase, Regulation of Actin Cytoskeleton, Wnt signalling, Calcium Signalling, Gap junctions and Arrhythmogenic Right Ventricular Cardiomyopathy. Most miRNAs are not expressed in a gradient across the ventricular wall, with exceptions including miR-10b, miR-21, miR-99b and miR 486. PMID- 23799051 TI - Risk factors for late-life cognitive decline and variation with age and sex in the Sydney Memory and Ageing Study. AB - INTRODUCTION: An aging population brings increasing burdens and costs to individuals and society arising from late-life cognitive decline, the causes of which are unclear. We aimed to identify factors predicting late-life cognitive decline. METHODS: Participants were 889 community-dwelling 70-90-year-olds from the Sydney Memory and Ageing Study with comprehensive neuropsychological assessments at baseline and a 2-year follow-up and initially without dementia. Cognitive decline was considered as incident mild cognitive impairment (MCI) or dementia, as well as decreases in attention/processing speed, executive function, memory, and global cognition. Associations with baseline demographic, lifestyle, health and medical factors were determined. RESULTS: All cognitive measures showed decline and 14% of participants developed incident MCI or dementia. Across all participants, risk factors for decline included older age and poorer smelling ability most prominently, but also more education, history of depression, being male, higher homocysteine, coronary artery disease, arthritis, low health status, and stroke. Protective factors included marriage, kidney disease, and antidepressant use. For some of these factors the association varied with age or differed between men and women. Additional risk and protective factors that were strictly age- and/or sex-dependent were also identified. We found salient population attributable risks (8.7-49.5%) for older age, being male or unmarried, poor smelling ability, coronary artery disease, arthritis, stroke, and high homocysteine. DISCUSSION: Preventing or treating conditions typically associated with aging might reduce population-wide late-life cognitive decline. Interventions tailored to particular age and sex groups may offer further benefits. PMID- 23799053 TI - A physiology-based seizure detection system for multichannel EEG. AB - BACKGROUND: Epilepsy is a common chronic neurological disorder characterized by recurrent unprovoked seizures. Electroencephalogram (EEG) signals play a critical role in the diagnosis of epilepsy. Multichannel EEGs contain more information than do single-channel EEGs. Automatic detection algorithms for spikes or seizures have traditionally been implemented on single-channel EEG, and algorithms for multichannel EEG are unavailable. METHODOLOGY: This study proposes a physiology-based detection system for epileptic seizures that uses multichannel EEG signals. The proposed technique was tested on two EEG data sets acquired from 18 patients. Both unipolar and bipolar EEG signals were analyzed. We employed sample entropy (SampEn), statistical values, and concepts used in clinical neurophysiology (e.g., phase reversals and potential fields of a bipolar EEG) to extract the features. We further tested the performance of a genetic algorithm cascaded with a support vector machine and post-classification spike matching. PRINCIPAL FINDINGS: We obtained 86.69% spike detection and 99.77% seizure detection for Data Set I. The detection system was further validated using the model trained by Data Set I on Data Set II. The system again showed high performance, with 91.18% detection of spikes and 99.22% seizure detection. CONCLUSION: We report a de novo EEG classification system for seizure and spike detection on multichannel EEG that includes physiology-based knowledge to enhance the performance of this type of system. PMID- 23799052 TI - Dopamine receptors modulate cytotoxicity of natural killer cells via cAMP-PKA CREB signaling pathway. AB - Dopamine (DA), a neurotransmitter in the nervous system, has been shown to modulate immune function. We have previously reported that five subtypes of DA receptors, including D1R, D2R, D3R, D4R and D5R, are expressed in T lymphocytes and they are involved in regulation of T cells. However, roles of these DA receptor subtypes and their coupled signal-transduction pathway in modulation of natural killer (NK) cells still remain to be clarified. The spleen of mice was harvested and NK cells were isolated and purified by negative selection using magnetic activated cell sorting. After NK cells were incubated with various drugs for 4 h, flow cytometry measured cytotoxicity of NK cells against YAC-1 lymphoma cells. NK cells expressed the five subtypes of DA receptors at mRNA and protein levels. Activation of D1-like receptors (including D1R and D5R) with agonist SKF38393 enhanced NK cell cytotoxicity, but activation of D2-like receptors (including D2R, D3R and D4R) with agonist quinpirole attenuated NK cells. Simultaneously, SKF38393 elevated D1R and D5R expression, cAMP content, and phosphorylated cAMP-response element-binding (CREB) level in NK cells, while quinpirole reduced D3R and D4R expression, cAMP content, and phosphorylated CREB level in NK cells. These effects of SKF38393 were blocked by SCH23390, an antagonist of D1-like receptors, and quinpirole effects were abolished by haloperidol, an antagonist of D2-like receptors. In support these results, H89, an inhibitor of phosphokinase A (PKA), prevented the SKF38393-dependent enhancement of NK cells and forskolin, an activator of adenylyl cyclase (AC), counteracted the quinpirole-dependent suppression of NK cells. These findings show that DA receptor subtypes are involved in modulation of NK cells and suggest that D1-like receptors facilitate NK cells by stimulating D1R/D5R-cAMP-PKA-CREB signaling pathway and D2-like receptors suppress NK cells by inhibiting D3R/D4R cAMP-PKA-CREB signaling pathway. The results may provide more targets of therapeutic strategy for neuroimmune diseases. PMID- 23799054 TI - The C825T polymorphism of the G-protein beta3 subunit gene and its association with hypertension and stroke: an updated meta-analysis. AB - OBJECTIVE: Several epidemiological studies have evaluated the association between the GNB3 C825T polymorphism and hypertension or stroke. The results of these studies were inconsistent; therefore, we performed a meta-analysis to clarify these discrepancies. METHODS: We systematically searched the PubMed, Embase, Web of Science, CNKI, and CBM databases, and manually searched reference lists of relevant papers, meeting abstracts, and relevant journals. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for dominant, recessive, and allelic models. A fixed or random effects model was separately adopted depending on study heterogeneity. Subgroup and sensitivity analyses were performed to detect study heterogeneity and examine result stability, respectively. Publication bias was tested using funnel plots, the Egger's regression test, and Begg's test. RESULTS: We screened 66 studies regarding hypertension and eight concerning stroke. A combined analysis showed that only the allelic model found a marginal association with hypertension (OR = 1.07, 95% CI = 1.01-1.13) and female gender (OR = 1.11, 95% CI = 0.99-1.24). However, no comparison models found an association with stroke (allelic model: OR = 1.11, 95% CI = 0.94-1.32; dominant model: OR = 1.16, 95% CI = 0.92-1.48; and recessive model: OR = 1.05, 95% CI = 0.97-1.14). Sensitivity analysis suggested that all models did not yield a relationship to hypertension or stroke among Asians. Besides, there was a lack of statistical association with hypertension in Caucasians, which maybe due to a small sample size. When we restricted the included studies to normal populations according to the Hardy-Weinberg equilibrium, no association was found. CONCLUSIONS: There was no evidence indicating that the 825T allele or TT genotype was associated with hypertension or stroke in Asians or hypertension in Caucasians. However, further studies regarding Africans and other ethnicities are needed to identify further correlations. PMID- 23799055 TI - Genetic characterization of the Drosophila birt-hogg-dube syndrome gene. AB - Folliculin (FLCN) is a conserved tumor suppressor gene whose loss is associated with the human Birt-Hogg-Dube (BHD) syndrome. However, its molecular functions remain largely unknown. In this work, we generated a Drosophila BHD model through genomic deletion of the FLCN gene (DBHD(-) ). The DBHD mutant larvae grew slowly and stopped development before pupation, displaying various characteristics of malnutrition. We found the growth delay was sensitive to the nutrient supplies. It became more severe upon restrictions of the dietary yeast; while high levels of yeast significantly restored the normal growth, but not viability. We further demonstrated that leucine was able to substitute for yeast to provide similar rescues. Moreover, the human FLCN could partially rescue the DBHD(-) phenotypes, indicating the two genes are involved in certain common mechanisms. Our work provides a new animal model of the BHD syndrome and suggests that modulation of the local nutrient condition might be a potential treatment of the BHD lesions. PMID- 23799056 TI - Whole-brain functional connectivity identification of functional dyspepsia. AB - Recent neuroimaging studies have shown local brain aberrations in functional dyspepsia (FD) patients, yet little attention has been paid to the whole-brain resting-state functional network abnormalities. The purpose of this study was to investigate whether FD disrupts the patterns of whole-brain networks and the abnormal functional connectivity could reflect the severity of the disease. The dysfunctional interactions between brain regions at rest were investigated in FD patients as compared with 40 age- and gender- matched healthy controls. Multivariate pattern analysis was used to evaluate the discriminative power of our results for classifying patients from controls. In our findings, the abnormal brain functional connections were mainly situated within or across the limbic/paralimbic system, the prefrontal cortex, the tempo-parietal areas and the visual cortex. About 96% of the subjects among the original dataset were correctly classified by a leave one-out cross-validation approach, and 88% accuracy was also validated in a replication dataset. The classification features were significantly associated with the patients' dyspepsia symptoms, the self rating depression scale and self-rating anxiety scale, but it was not correlated with duration of FD patients (p>0.05). Our results may indicate the effectiveness of the altered brain functional connections reflecting the disease pathophysiology underling FD. These dysfunctional connections may be the epiphenomena or causative agents of FD, which may be affected by clinical severity and its related emotional dimension of the disease rather than the clinical course. PMID- 23799057 TI - Dynamic multiscale boundary conditions for 4D CT of healthy and emphysematous rats. AB - Changes in the shape of the lung during breathing determine the movement of airways and alveoli, and thus impact airflow dynamics. Modeling airflow dynamics in health and disease is a key goal for predictive multiscale models of respiration. Past efforts to model changes in lung shape during breathing have measured shape at multiple breath-holds. However, breath-holds do not capture hysteretic differences between inspiration and expiration resulting from the additional energy required for inspiration. Alternatively, imaging dynamically- without breath-holds--allows measurement of hysteretic differences. In this study, we acquire multiple micro-CT images per breath (4DCT) in live rats, and from these images we develop, for the first time, dynamic volume maps. These maps show changes in local volume across the entire lung throughout the breathing cycle and accurately predict the global pressure-volume (PV) hysteresis. Male Sprague-Dawley rats were given either a full- or partial-lung dose of elastase or saline as a control. After three weeks, 4DCT images of the mechanically ventilated rats under anesthesia were acquired dynamically over the breathing cycle (11 time points, <=100 ms temporal resolution, 8 cmH2O peak pressure). Non rigid image registration was applied to determine the deformation gradient--a numerical description of changes to lung shape--at each time point. The registration accuracy was evaluated by landmark identification. Of 67 landmarks, one was determined misregistered by all three observers, and 11 were determined misregistered by two observers. Volume change maps were calculated on a voxel-by voxel basis at all time points using both the Jacobian of the deformation gradient and the inhaled air fraction. The calculated lung PV hysteresis agrees with pressure-volume curves measured by the ventilator. Volume maps in diseased rats show increased compliance and ventilation heterogeneity. Future predictive multiscale models of rodent respiration may leverage such volume maps as boundary conditions. PMID- 23799058 TI - Neural activations during visual sequence learning leave a trace in post-training spontaneous EEG. AB - Recent EEG studies have shown that implicit learning involving specific cortical circuits results in an enduring local trace manifested as local changes in spectral power. Here we used a well characterized visual sequence learning task and high density-(hd-)EEG recording to determine whether also declarative learning leaves a post-task, local change in the resting state oscillatory activity in the areas involved in the learning process. Thus, we recorded hd-EEG in normal subjects before, during and after the acquisition of the order of a fixed spatial target sequence (VSEQ) and during the presentation of targets in random order (VRAN). We first determined the temporal evolution of spectral changes during VSEQ and compared it to VRAN. We found significant differences in the alpha and theta bands in three main scalp regions, a right occipito-parietal (ROP), an anterior-frontal (AFr), and a right frontal (RFr) area. The changes in frontal theta power during VSEQ were positively correlated with the learning rate. Further, post-learning EEG recordings during resting state revealed a significant increase in alpha power in ROP relative to a pre-learning baseline. We conclude that declarative learning is associated with alpha and theta changes in frontal and posterior regions that occur during the task, and with an increase of alpha power in the occipito-parietal region after the task. These post-task changes may represent a trace of learning and a hallmark of use-dependent plasticity. PMID- 23799059 TI - Long-term stabilization effects of leptin on brain functions in a leptin deficient patient. AB - CONTEXT: Congenital leptin deficiency, caused by a very rare mutation in the gene encoding leptin, leads to severe obesity, hyperphagia and impaired satiety. The only systemic treatment is the substitution with metreleptin leading to weight reduction based on hormonal changes. Several studies have also shown alterations in brain function after metreleptin therapy. In a previous study, we were able to show changes in homeostatic (hypothalamus) and reward-related brain areas (striatum, orbitofrontal cortex (OFC), substantia nigra/ventral tegmental area, amygdala) 3 days and 6 months after therapy start in a leptin-deficient adolescent girl. To further access the time course of functional brain activation changes, we followed the patient for 2 years after initiation of the therapy. DESIGN, PATIENT: Functional magnetic resonance imaging during visual stimulation with food (high- and low-caloric) and non-food pictures was performed 1 and 2 years after therapy start in the previously described patient. RESULTS: The comparison of 'food vs. non-food' pictures showed a stabilization of the long term effects in the amygdala and in the OFC. Therefore, no significant differences were observed between 6 months compared to 12 and 24 months in these regions. Additionally, a reduction of the frontopolar cortex activity over the whole time span was observed. For the comparison of high- and low-caloric pictures, long-term effects in the hypothalamus showed an assimilating pattern for the response to the food categories whereas only acute effects after 3 months were observed in hedonic brain regions. CONCLUSION: This follow-up study shows that the long lasting benefit of metreleptin therapy is also associated with activation changes in homeostatic, hedonic and frontal control regions in congenital leptin deficiency. PMID- 23799060 TI - Characterizing venous vasculatures of hepatocellular carcinoma using a multi breath-hold two-dimensional susceptibility weighted imaging. AB - The aim of our study is to characterize the venous vasculatures of hepatocellular carcinoma (HCC) using a multi-breath-hold two-dimensional (2D) susceptibility weighted imaging (SWI) in comparison with conventional Magnetic Resonance Imaging (MRI) sequences. Twenty-nine patients with pathologically confirmed HCC underwent MR examination at a 3.0 T scanner. The number of venous vascularity in or around the lesion was counted and the image quality was subjectively evaluated by two experienced radiologists independently based on four image sets: 1) SWI, 2) T1 weighted sequence, 3) T2-weighted sequence, and 4) T1-weighted dynamic contrast enhanced (DCE) sequence. Of the 29 patients, a total of 33 liver lesions were detected by both SWI and conventional MR sequences. In the evaluation of the conspicuity of venous vascularity, a mean of 10.7 tumor venous vessels per mass was detected by the SWI and 3.9 tumor vasculatures were detected by T1-weighted DCE (P<0.0001), while none was detected by T1-, T2-weighted sequences. The Pearson correlation coefficients between the lesion sizes and the number of tumor vasculatures detected by T1-weighted DCE was 0.708 (P<0.001), and 0.883 by SWI (P<0.001). Our data suggest that SWI appears to be a more sensitive tool compared to T1-weighted DCE sequence to characterize venous vasculature in liver lesions. PMID- 23799061 TI - Multiple sclerosis incidence associated with the soil lead and arsenic concentrations in Taiwan. AB - BACKGROUND: Few studies in the world have assessed the incidence of multiple sclerosis (MS) with soil heavy metal concentrations. We explored the association of soil heavy metal factors and the MS incidence in Taiwan. METHODS: There were 1240 new MS cases from the National Health Insurance Research Database and were verified with serious disabling disease certificates, 1997-2008. Soil heavy metal factors records included arsenic, mercury, cadmium, chromium, copper, nickel, lead and zinc in Taiwan from 1986 to 2002. Spatial regression was used to reveal the association of soil heavy metals and age- and gender-standardized incidence ratios for townships by controlling sunlight exposure hours, smoking prevalence and spatial autocorrelation. RESULTS: The lead (Pb) concentration in the soil positively correlated with the township incidence; on the other hand, the arsenic (As) concentration in soil negatively correlated with the township incidence and when found together controlled each other. The positive correlation of lead (Pb) predominated in males, whereas the negative correlation of arsenic (As) in soil predominated in females. CONCLUSIONS: We conclude that exposure to lead (Pb) in soil positive associated with incidence of MS in Taiwan, especially in males. Exposure to arsenic (As) in soil negative associated with MS in Taiwan, especially in females. PMID- 23799062 TI - Chloroquine treatment enhances regulatory T cells and reduces the severity of experimental autoimmune encephalomyelitis. AB - BACKGROUND: The modulation of inflammatory processes is a necessary step, mostly orchestrated by regulatory T (Treg) cells and suppressive Dendritic Cells (DCs), to prevent the development of deleterious responses and autoimmune diseases. Therapies that focused on adoptive transfer of Treg cells or their expansion in vivo achieved great success in controlling inflammation in several experimental models. Chloroquine (CQ), an anti-malarial drug, was shown to reduce inflammation, although the mechanisms are still obscure. In this context, we aimed to access whether chloroquine treatment alters the frequency of Treg cells and DCs in normal mice. In addition, the effects of the prophylactic and therapeutic treatment with CQ on Experimental Autoimmune Encephalomyelitis (EAE), an experimental model for human Multiple Sclerosis, was investigated as well. METHODOLOGY/PRINCIPAL FINDINGS: EAE was induced in C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein (MOG35-55) peptide. C57BL/6 mice were intraperitoneally treated with chloroquine. Results show that the CQ treatment provoked an increase in Treg cells frequency as well as a decrease in DCs. We next evaluated whether prophylactic CQ administration is capable of reducing the clinical and histopathological signs of EAE. Our results demonstrated that CQ treated mice developed mild EAE compared to controls that was associated with lower infiltration of inflammatory cells in the central nervous system CNS) and increased frequency of Treg cells. Also, proliferation of MOG35-55-reactive T cells was significantly inhibited by chloroquine treatment. Similar results were observed when chloroquine was administrated after disease onset. CONCLUSION: We show for the first time that CQ treatment promotes the expansion of Treg cells, corroborating previous reports indicating that chloroquine has immunomodulatory properties. Our results also show that CQ treatment suppress the inflammation in the CNS of EAE-inflicted mice, both in prophylactic and therapeutic approaches. We hypothesized that the increased number of regulatory T cells induced by the CQ treatment is involved in the reduction of the clinical signs of EAE. PMID- 23799063 TI - Rapid assessment of trachoma in underserved population of Car-Nicobar Island, India. AB - PURPOSE: To determine the burden of trachoma and its related risk factors amongst the native population of Car-Nicobar Island in India. METHODS: Rapid assessment for trachoma was conducted in ten villages of Car-Nicobar Island according to standard WHO guidelines. An average of 50 children aged 1-9 years were assessed clinically for signs of active trachoma and facial cleanliness in each village. Additionally, all adults above 15 years of age in these households were examined for evidence of trachomatous trichiasis and corneal opacity. Environmental risk factors contributing to trachoma like limited access to potable water & functional latrine, presence of animal pen and garbage within the Nicobari hut were also noted in all villages. RESULTS: Out of a total of fifteen villages in Car-Nicobar Island, ten villages were selected for trachoma survey depending on evidence of socio-developmental indicators like poverty and decreased access to water, sanitation and healthcare facilities. The total population of the selected clusters was 7277 in the ten villages. Overall, 251 of 516 children (48.6%;CI: 46.5-55.1) had evidence of follicular stage of trachoma and 11 children (2.1%;CI:1.0-3.4) had evidence of inflammatory stage of trachoma. Nearly 15%(CI:12.1-18.3) children were noted to have unclean faces in the ten villages. Trachomatous trichiasis was noted in 73 adults (1.0%;CI:0.8-1.2). The environmental sanitation was not found to be satisfactory in the surveyed villages mainly due to the co-habitance of Nicobari people with domestic animals like pigs, hens, goats, dogs, cats etc in most (96.4%) of the households. CONCLUSION: Active trachoma and trachomatous trichiasis was observed in all the ten villages surveyed, wherein trachoma control measures are needed. PMID- 23799064 TI - Heterologous expression and biochemical characterisation of fourteen esterases from Helicoverpa armigera. AB - Esterases have recurrently been implicated in insecticide resistance in Helicoverpa armigera but little is known about the underlying molecular mechanisms. We used a baculovirus system to express 14 of 30 full-length esterase genes so far identified from midgut cDNA libraries of this species. All 14 produced esterase isozymes after native PAGE and the isozymes for seven of them migrated to two regions of the gel previously associated with both organophosphate and pyrethroid resistance in various strains. Thirteen of the enzymes obtained in sufficient yield for further analysis all showed tight binding to organophosphates and low but measurable organophosphate hydrolase activity. However there was no clear difference in activity between the isozymes from regions associated with resistance and those from elsewhere in the zymogram, or between eight of the isozymes from a phylogenetic clade previously associated with resistance in proteomic and quantitative rtPCR experiments and five others not so associated. By contrast, the enzymes differed markedly in their activities against nine pyrethroid isomers and the enzymes with highest activity for the most insecticidal isomers were from regions of the gel and, in some cases, the phylogeny that had previously been associated with pyrethroid resistance. Phospholipase treatment confirmed predictions from sequence analysis that three of the isozymes were GPI anchored. This unusual feature among carboxylesterases has previously been suggested to underpin an association that some authors have noted between esterases and resistance to the Cry1Ac toxin from Bacillus thuringiensis. However these three isozymes did not migrate to the zymogram region previously associated with Cry1Ac resistance. PMID- 23799066 TI - Antibody levels to persistent pathogens and incident stroke in Mexican Americans. AB - BACKGROUND: Persistent pathogens have been proposed as risk factors for stroke; however, the evidence remains inconclusive. Mexican Americans have an increased risk of stroke especially at younger ages, as well as a higher prevalence of infections caused by several persistent pathogens. METHODOLOGY/PRINCIPAL: Findings Using data from the Sacramento Area Latino Study on Aging (n = 1621), the authors used discrete-time regression to examine associations between stroke risk and (1) immunoglobulin G antibody levels to Helicobacter pylori (H. pylori), Cytomegalovirus, Varicella Zoster Virus, Toxoplasma gondii and Herpes simplex virus 1, and (2) concurrent exposure to several pathogens (pathogen burden), defined as: (a) summed sero-positivity, (b) number of pathogens eliciting high antibody levels, and (c) average antibody level. Models were adjusted for socio demographics and stroke risk factors. Antibody levels to H. pylori predicted incident stroke in fully adjusted models (Odds Ratio: 1.58; 95% Confidence Interval: 1.09, 2.28). No significant associations were found between stroke risk and antibody levels to the other four pathogens. No associations were found for pathogen burden and incident stroke in fully adjusted models. CONCLUSIONS/SIGNIFICANCE: Our results suggest that exposure to H. pylori may be a stroke risk factor in Mexican Americans and may contribute to ethnic differences in stroke risk given the increased prevalence of exposure to H. pylori in this population. Future studies are needed to confirm this association. PMID- 23799065 TI - High-throughput system for the presentation of secreted and surface-exposed proteins from Gram-positive bacteria in functional metagenomics studies. AB - Complex microbial ecosystems are increasingly studied through the use of metagenomics approaches. Overwhelming amounts of DNA sequence data are generated to describe the ecosystems, and allow to search for correlations between gene occurrence and clinical (e.g. in studies of the gut microbiota), physico-chemical (e.g. in studies of soil or water environments), or other parameters. Observed correlations can then be used to formulate hypotheses concerning microbial gene functions in relation to the ecosystem studied. In this context, functional metagenomics studies aim to validate these hypotheses and to explore the mechanisms involved. One possible approach is to PCR amplify or chemically synthesize genes of interest and to express them in a suitable host in order to study their function. For bacterial genes, Escherichia coli is often used as the expression host but, depending on the origin and nature of the genes of interest and the test system used to evaluate their putative function, other expression systems may be preferable. In this study, we developed a system to evaluate the role of secreted and surface-exposed proteins from Gram-positive bacteria in the human gut microbiota in immune modulation. We chose to use a Gram-positive host bacterium, Bacillus subtilis, and modified it to provide an expression background that behaves neutral in a cell-based immune modulation assay, in vitro. We also adapted an E. coli-B. subtilis shuttle expression vector for use with the Gateway high-throughput cloning system. Finally, we demonstrate the functionality of this host-vector system through the cloning and expression of a flagellin-coding sequence, and show that the expression-clone elicits an inflammatory response in a human intestinal epithelial cell line. The expression host can easily be adapted to assure neutrality in other assay systems, allowing the use of the presented presentation system in functional metagenomics of the gut and other ecosystems. PMID- 23799067 TI - Identification of pharmacological modulators of HMGB1-induced inflammatory response by cell-based screening. AB - High mobility group box 1 (HMGB1), a highly conserved, ubiquitous protein, is released into the circulation during sterile inflammation (e.g. arthritis, trauma) and circulatory shock. It participates in the pathogenesis of delayed inflammatory responses and organ dysfunction. While several molecules have been identified that modulate the release of HMGB1, less attention has been paid to identify pharmacological inhibitors of the downstream inflammatory processes elicited by HMGB1 (C23-C45 disulfide C106 thiol form). In the current study, a cell-based medium-throughput screening of a 5000+ compound focused library of clinical drugs and drug-like compounds was performed in murine RAW264.7 macrophages, in order to identify modulators of HMGB1-induced tumor-necrosis factor alpha (TNFalpha) production. Clinically used drugs that suppressed HMGB1 induced TNFalpha production included glucocorticoids, beta agonists, and the anti HIV compound indinavir. A re-screen of the NIH clinical compound library identified beta-agonists and various intracellular cAMP enhancers as compounds that potentiate the inhibitory effect of glucocorticoids on HMGB1-induced TNFalpha production. The molecular pathways involved in this synergistic anti inflammatory effect are related, at least in part, to inhibition of TNFalpha mRNA synthesis via a synergistic suppression of ERK/IkappaB activation. Inhibition of TNFalpha production by prednisolone+salbutamol pretreatment was also confirmed in vivo in mice subjected to HMGB1 injection; this effect was more pronounced than the effect of either of the agents administered separately. The current study unveils several drug-like modulators of HMGB1-mediated inflammatory responses and offers pharmacological directions for the therapeutic suppression of inflammatory responses in HMGB1-dependent diseases. PMID- 23799068 TI - A computationally designed water-soluble variant of a G-protein-coupled receptor: the human mu opioid receptor. AB - G-protein-coupled receptors (GPCRs) play essential roles in various physiological processes, and are widely targeted by pharmaceutical drugs. Despite their importance, studying GPCRs has been problematic due to difficulties in isolating large quantities of these membrane proteins in forms that retain their ligand binding capabilities. Creating water-soluble variants of GPCRs by mutating the exterior, transmembrane residues provides a potential method to overcome these difficulties. Here we present the first study involving the computational design, expression and characterization of water-soluble variant of a human GPCR, the human mu opioid receptor (MUR), which is involved in pain and addiction. An atomistic structure of the transmembrane domain was built using comparative (homology) modeling and known GPCR structures. This structure was highly similar to the subsequently determined structure of the murine receptor and was used to computationally design 53 mutations of exterior residues in the transmembrane region, yielding a variant intended to be soluble in aqueous media. The designed variant expressed in high yield in Escherichia coli and was water soluble. The variant shared structural and functionally related features with the native human MUR, including helical secondary structure and comparable affinity for the antagonist naltrexone (Kd = 65 nM). The roles of cholesterol and disulfide bonds on the stability of the receptor variant were also investigated. This study exemplifies the potential of the computational approach to produce water-soluble variants of GPCRs amenable for structural and functionally related characterization in aqueous solution. PMID- 23799069 TI - Candidate genes that may be responsible for the unusual resistances exhibited by Bacillus pumilus SAFR-032 spores. AB - The spores of several Bacillus species, including Bacillus pumilus SAFR-032 and B. safensis FO-36b, which were isolated from the spacecraft assembly facility at NASA's Jet Propulsion Laboratory, are unusually resistant to UV radiation and hydrogen peroxide. In order to identify candidate genes that might be associated with these resistances, the whole genome of B. pumilus SAFR-032, and the draft genome of B. safensis FO-36b were compared in detail with the very closely related type strain B. pumilus ATCC7061(T). 170 genes are considered characteristic of SAFR-032, because they are absent from both FO-36b and ATCC7061(T). Forty of these SAFR-032 characteristic genes are entirely unique open reading frames. In addition, four genes are unique to the genomes of the resistant SAFR-032 and FO-36b. Fifty three genes involved in spore coat formation, regulation and germination, DNA repair, and peroxide resistance, are missing from all three genomes. The vast majority of these are cleanly deleted from their usual genomic context without any obvious replacement. Several DNA repair and peroxide resistance genes earlier reported to be unique to SAFR-032 are in fact shared with ATCC7061(T) and no longer considered to be promising candidates for association with the elevated resistances. Instead, several SAFR 032 characteristic genes were identified, which along with one or more of the unique SAFR-032 genes may be responsible for the elevated resistances. These new candidates include five genes associated with DNA repair, namely, BPUM_0608 a helicase, BPUM_0652 an ATP binding protein, BPUM_0653 an endonuclease, BPUM_0656 a DNA cytosine-5- methyltransferase, and BPUM_3674 a DNA helicase. Three of these candidate genes are in immediate proximity of two conserved hypothetical proteins, BPUM_0654 and BPUM_0655 that are also absent from both FO-36b and ATCC7061(T). This cluster of five genes is considered to be an especially promising target for future experimental work. PMID- 23799070 TI - Archaea and fungi of the human gut microbiome: correlations with diet and bacterial residents. AB - Diet influences health as a source of nutrients and toxins, and by shaping the composition of resident microbial populations. Previous studies have begun to map out associations between diet and the bacteria and viruses of the human gut microbiome. Here we investigate associations of diet with fungal and archaeal populations, taking advantage of samples from 98 well-characterized individuals. Diet was quantified using inventories scoring both long-term and recent diet, and archaea and fungi were characterized by deep sequencing of marker genes in DNA purified from stool. For fungi, we found 66 genera, with generally mutually exclusive presence of either the phyla Ascomycota or Basiodiomycota. For archaea, Methanobrevibacter was the most prevalent genus, present in 30% of samples. Several other archaeal genera were detected in lower abundance and frequency. Myriad associations were detected for fungi and archaea with diet, with each other, and with bacterial lineages. Methanobrevibacter and Candida were positively associated with diets high in carbohydrates, but negatively with diets high in amino acids, protein, and fatty acids. A previous study emphasized that bacterial population structure was associated primarily with long-term diet, but high Candida abundance was most strongly associated with the recent consumption of carbohydrates. Methobrevibacter abundance was associated with both long term and recent consumption of carbohydrates. These results confirm earlier targeted studies and provide a host of new associations to consider in modeling the effects of diet on the gut microbiome and human health. PMID- 23799071 TI - Enhanced transgene expression in sugarcane by co-expression of virus-encoded RNA silencing suppressors. AB - Post-transcriptional gene silencing is commonly observed in polyploid species and often poses a major limitation to plant improvement via biotechnology. Five plant viral suppressors of RNA silencing were evaluated for their ability to counteract gene silencing and enhance the expression of the Enhanced Yellow Fluorescent Protein (EYFP) or the beta-glucuronidase (GUS) reporter gene in sugarcane, a major sugar and biomass producing polyploid. Functionality of these suppressors was first verified in Nicotiana benthamiana and onion epidermal cells, and later tested by transient expression in sugarcane young leaf segments and protoplasts. In young leaf segments co-expressing a suppressor, EYFP reached its maximum expression at 48-96 h post-DNA introduction and maintained its peak expression for a longer time compared with that in the absence of a suppressor. Among the five suppressors, Tomato bushy stunt virus-encoded P19 and Barley stripe mosaic virus-encoded gammab were the most efficient. Co-expression with P19 and gammab enhanced EYFP expression 4.6-fold and 3.6-fold in young leaf segments, and GUS activity 2.3-fold and 2.4-fold in protoplasts compared with those in the absence of a suppressor, respectively. In transgenic sugarcane, co-expression of GUS and P19 suppressor showed the highest accumulation of GUS levels with an average of 2.7-fold more than when GUS was expressed alone, with no detrimental phenotypic effects. The two established transient expression assays, based on young leaf segments and protoplasts, and confirmed by stable transgene expression, offer a rapid versatile system to verify the efficiency of RNA silencing suppressors that proved to be valuable in enhancing and stabilizing transgene expression in sugarcane. PMID- 23799072 TI - Differential responses of CO2 assimilation, carbohydrate allocation and gene expression to NaCl stress in perennial ryegrass with different salt tolerance. AB - Little is known about the effects of NaCl stress on perennial ryegrass (Lolium perenne L.) photosynthesis and carbohydrate flux. The objective of this study was to understand the carbohydrate metabolism and identify the gene expression affected by salinity stress. Seventy-four days old seedlings of two perennial ryegrass accessions (salt-sensitive 'PI 538976' and salt-tolerant 'Overdrive') were subjected to three levels of salinity stress for 5 days. Turf quality in all tissues (leaves, stems and roots) of both grass accessions negatively and significantly correlated with GFS (Glu+Fru+Suc) content, except for 'Overdrive' stems. Relative growth rate (RGR) in leaves negatively and significantly correlated with GFS content in 'Overdrive' (P<0.01) and 'PI 538976' (P<0.05) under salt stress. 'Overdrive' had higher CO2 assimilation and Fv/Fm than 'PI 538976'. Intercellular CO2 concentration, however, was higher in 'PI 538976' treated with 400 mM NaCl relative to that with 200 mM NaCl. GFS content negatively and significantly correlated with RGR in 'Overdrive' and 'PI 538976' leaves and in 'PI 538976' stems and roots under salt stress. In leaves, carbohydrate allocation negatively and significantly correlated with RGR (r(2) = 0.83, P<0.01) and turf quality (r(2) = 0.88, P<0.01) in salt-tolerant 'Overdrive', however, the opposite trend for salt-sensitive 'PI 538976' (r(2) = 0.71, P<0.05 for RGR; r(2) = 0.62, P>0.05 for turf quality). A greater up regulation in the expression of SPS, SS, SI, 6-SFT gene was observed in 'Overdrive' than 'PI 538976'. A higher level of SPS and SS expression in leaves was found in 'PI 538976' relative to 'Overdrive'. Accumulation of hexoses in roots, stems and leaves can induce a feedback repression to photosynthesis in salt-stressed perennial ryegrass and the salt tolerance may be changed with the carbohydrate allocation in leaves and stems. PMID- 23799073 TI - Effects of glucose availability on expression of the key genes involved in synthesis of milk fat, lactose and glucose metabolism in bovine mammary epithelial cells. AB - As the main precursor for lactose synthesis, large amounts of glucose are required by lactating dairy cows. Milk yield greatly depends on mammary lactose synthesis due to its osmoregulatory property for mammary uptake of water. Thus, glucose availability to the mammary gland could be a potential regulator of milk production. In the present study, the effect of glucose availability on expression of the key genes involved in synthesis of milk fat, lactose and glucose metabolism in vitro was investigated. Bovine mammary epithelial cells (BMEC) were treated for 12 h with various concentrations of glucose (2.5, 5, 10 or 20 mmol/L). The higher concentrations of glucose (10-20 mmol/L) did not affect the mRNA expression of acetyl-CoA carboxylase, diacyl glycerol acyl transferase, glycerol-3 phosphate acyl transferase and alpha-lactalbumin, whereas fatty acid synthase, sterol regulatory element binding protein-1 and beta-1, 4-galactosyl transferase mRNA expression increased at 10 mmol/L and then decreased at 20 mmol/L. The content of lactose synthase increased with increasing concentration of glucose, with addition of highest value at 20 mmol/L of glucose. Moreover, the increased glucose concentration stimulated the activities of pyruvate kinase and glucose-6-phosphate dehydrogenase, and elevated the energy status of the BMEC. Therefore, it was deduced that after increasing glucose availability, the extra absorbed glucose was partitioned to entering the synthesis of milk fat and lactose by the regulation of the mRNA expression of key genes, promoting glucose metabolism by glycolysis and pentose phosphate pathway as well as energy status. These results indicated that the sufficient availability of glucose in BMEC may promote glucose metabolism, and affect the synthesis of milk composition. PMID- 23799074 TI - The chemokine CCL3 promotes experimental liver fibrosis in mice. AB - Liver fibrosis is associated with infiltrating immune cells and activation of hepatic stellate cells. We here aimed to investigate the effects of the CC chemokine CCL3, also known as macrophage inflammatory protein-1alpha, in two different fibrosis models. To this end, we treated mice either with carbon tetrachloride or with a methionine- and choline-deficient diet to induce fibrosis in CCL3 deficient and wild-type mice. The results show that the protein expression of CCL3 is increased in wild-type mice after chronic liver injury. Deletion of CCL3 exhibited reduced liver fibrosis compared to their wild-type counterparts. We could validate these results by treating the two mouse groups with either carbon tetrachloride or by feeding a methionine- and choline deficient diet. In these models, lack of CCL3 is functionally associated with reduced stellate cell activation and liver immune cell infiltration. In vitro, we show that CCL3 leads to increased proliferation and migration of hepatic stellate cells. In conclusion, our results define the chemokine CCL3 as a mediator of experimental liver fibrosis. Thus, therapeutic modulation of CCL3 might be a promising target for chronic liver diseases. PMID- 23799075 TI - Maternal control of PIN1 is required for female gametophyte development in Arabidopsis. AB - Land plants are characterised by haplo-diploid life cycles, and developing ovules are the organs in which the haploid and diploid generations coexist. Recently it has been shown that hormones such as auxin and cytokinins play important roles in ovule development and patterning. The establishment and regulation of auxin levels in cells is predominantly determined by the activity of the auxin efflux carrier proteins PIN-FORMED (PIN). To study the roles of PIN1 and PIN3 during ovule development we have used mutant alleles of both genes and also perturbed PIN1 and PIN3 expression using micro-RNAs controlled by the ovule specific DEFH9 (DEFIFICENS Homologue 9) promoter. PIN1 down-regulation and pin1-5 mutation severely affect female gametophyte development since embryo sacs arrest at the mono- and/or bi-nuclear stages (FG1 and FG3 stage). PIN3 function is not required for ovule development in wild-type or PIN1-silenced plants. We show that sporophytically expressed PIN1 is required for megagametogenesis, suggesting that sporophytic auxin flux might control the early stages of female gametophyte development, although auxin response is not visible in developing embryo sacs. PMID- 23799076 TI - CD8(+) T cell cross-reactivity profiles and HIV-1 immune escape towards an HLA B35-restricted immunodominant Nef epitope. AB - Antigen cross-reactivity is an inbuilt feature of the T cell compartment. However, little is known about the flexibility of T cell recognition in the context of genetically variable pathogens such as HIV-1. In this study, we used a combinatorial library containing 24 billion octamer peptides to characterize the cross-reactivity profiles of CD8(+) T cells specific for the immunodominant HIV-1 subtype B Nef epitope VY8 (VPLRPMTY) presented by HLA-B(*)35?01. In conjunction, we examined naturally occurring antigenic variations within the VY8 epitope. Sequence analysis of plasma viral RNA isolated from 336 HIV-1-infected individuals revealed variability at position (P) 3 and P8 of VY8; Phe at P8, but not Val at P3, was identified as an HLA-B(*)35?01-associated polymorphism. VY8 specific T cells generated from several different HIV-1-infected patients showed unique and clonotype-dependent cross-reactivity footprints. Nonetheless, all T cells recognized both the index Leu and mutant Val at P3 equally well. In contrast, competitive titration assays revealed that the Tyr to Phe substitution at P8 reduced T cell recognition by 50-130 fold despite intact peptide binding to HLA-B(*)35?01. These findings explain the preferential selection of Phe at the C terminus of VY8 in HLA-B(*)35?01(+) individuals and demonstrate that HIV-1 can exploit the limitations of T cell recognition in vivo. PMID- 23799077 TI - c-IAP1 and c-IAP2 redundancy differs between T and B cells. AB - Cellular Inhibitors of Apoptosis 1 and 2 (c-IAP1 and c-IAP2) are ubiquitin protein ligases (E3s) that constitutively ubiquitinate and induce proteasomal mediated degradation of NF-kappaB Inducing Kinase (NIK) and repress non-canonical NF-kappaB activation. Mice expressing an E3-inactive c-IAP2 mutant (c IAP2(H570A)) have constitutive activation of non-canonical NF-kappaB, resulting in B cell hyperplasia and T cell costimulation-independence. If, and if so to what extent, c-IAP1 and c-IAP2 are redundant in NF-kappaB regulation in these mice is not known. Here we have generated mice expressing a mutant c-IAP1 that lacks E3 activity (c-IAP1(H582A)). These mice were phenotypically normal and did not have constitutive NF-kappaB activation in B cells or MEFs. siRNA-mediated knockdown of c-IAP2 showed that accumulated c-IAP2, resulting from lack of c-IAP1 dependent degradation, compensated for absent c-IAP1 E3 activity. Surprisingly, c IAP1(H582A) T cells had a lower p100/p52 ratio than wild type T cells, and in the absence of costimulation proliferated to a degree intermediate between wild type and c-IAP2(H570A) T cells. Therefore, although c-IAP1 and c-IAP2 both can repress constitutive NF-kappaB activation, the relative importance of each varies according to cell type. PMID- 23799078 TI - Leucine-rich repeat kinase 2 (LRRK2)-deficient rats exhibit renal tubule injury and perturbations in metabolic and immunological homeostasis. AB - Genetic evidence links mutations in the LRRK2 gene with an increased risk of Parkinson's disease, for which no neuroprotective or neurorestorative therapies currently exist. While the role of LRRK2 in normal cellular function has yet to be fully described, evidence suggests involvement with immune and kidney functions. A comparative study of LRRK2-deficient and wild type rats investigated the influence that this gene has on the phenotype of these rats. Significant weight gain in the LRRK2 null rats was observed and was accompanied by significant increases in insulin and insulin-like growth factors. Additionally, LRRK2-deficient rats displayed kidney morphological and histopathological alterations in the renal tubule epithelial cells of all animals assessed. These perturbations in renal morphology were accompanied by significant decreases of lipocalin-2, in both the urine and plasma of knockout animals. Significant alterations in the cellular composition of the spleen between LRRK2 knockout and wild type animals were identified by immunophenotyping and were associated with subtle differences in response to dual infection with rat-adapted influenza virus (RAIV) and Streptococcus pneumoniae. Ontological pathway analysis of LRRK2 across metabolic and kidney processes and pathological categories suggested that the thioredoxin network may play a role in perturbing these organ systems. The phenotype of the LRRK2 null rat is suggestive of a complex biology influencing metabolism, immune function and kidney homeostasis. These data need to be extended to better understand the role of the kinase domain or other biological functions of the gene to better inform the development of pharmacological inhibitors. PMID- 23799079 TI - Induced tRNA import into human mitochondria: implication of a host aminoacyl-tRNA synthetase. AB - In human cell, a subset of small non-coding RNAs is imported into mitochondria from the cytosol. Analysis of the tRNA import pathway allowing targeting of the yeast tRNA(Lys)(CUU) into human mitochondria demonstrates a similarity between the RNA import mechanisms in yeast and human cells. We show that the cytosolic precursor of human mitochondrial lysyl-tRNA synthetase (preKARS2) interacts with the yeast tRNA(Lys)(CUU) and small artificial RNAs which contain the structural elements determining the tRNA mitochondrial import, and facilitates their internalization by isolated human mitochondria. The tRNA import efficiency increased upon addition of the glycolytic enzyme enolase, previously found to be an actor of the yeast RNA import machinery. Finally, the role of preKARS2 in the RNA mitochondrial import has been directly demonstrated in vivo, in cultured human cells transfected with the yeast tRNA and artificial importable RNA molecules, in combination with preKARS2 overexpression or downregulation by RNA interference. These findings suggest that the requirement of protein factors for the RNA mitochondrial targeting might be a conserved feature of the RNA import pathway in different organisms. PMID- 23799080 TI - Dynamics of DNA methylation during early development of the preimplantation bovine embryo. AB - There is species divergence in control of DNA methylation during preimplantation development. The exact pattern of methylation in the bovine embryo has not been established nor has its regulation by gender or maternal signals that regulate development such as colony stimulating factor 2 (CSF2). Using immunofluorescent labeling with anti-5-methylcytosine and embryos produced with X-chromosome sorted sperm, it was demonstrated that methylation decreased from the 2-cell stage to the 6-8 cell stage and then increased thereafter up to the blastocyst stage. In a second experiment, embryos of specific genders were produced by fertilization with X- or Y-sorted sperm. The developmental pattern was similar to the first experiment, but there was stage * gender interaction. Methylation was greater for females at the 8-cell stage but greater for males at the blastocyst stage. Treatment with CSF2 had no effect on labeling for DNA methylation in blastocysts. Methylation was lower for inner cell mass cells (i.e., cells that did not label with anti-CDX2) than for trophectoderm (CDX2-positive). The possible role for DNMT3B in developmental changes in methylation was evaluated by determining gene expression and degree of methylation. Steady-state mRNA for DNMT3B decreased from the 2-cell stage to a nadir for D 5 embryos >16 cells and then increased at the blastocyst stage. High resolution melting analysis was used to assess methylation of a CpG rich region in an intronic region of DNMT3B. Methylation percent decreased between the 6-8 cell and the blastocyst stage but there was no difference in methylation between ICM and TE. Results indicate that DNA methylation undergoes dynamic changes during the preimplantation period in a manner that is dependent upon gender and cell lineage. Developmental changes in expression of DNMT3B are indicative of a possible role in changes in methylation. Moreover, DNMT3B itself appears to be under epigenetic control by methylation. PMID- 23799081 TI - Effects of background fluid on the efficiency of inactivating yeast with non thermal atmospheric pressure plasma. AB - Non-thermal plasma at atmospheric pressure has been actively applied to sterilization. However, its efficiency for inactivating microorganisms often varies depending on microbial species and environments surrounding the microorganisms. We investigated the influence of environmental factors (surrounding media) on the efficiency of microbial inactivation by plasma using an eukaryotic model microbe, Saccharomyces cerevisiae, to elucidate the mechanisms for differential efficiency of sterilization by plasma. Yeast cells treated with plasma in water showed the most severe damage in viability and cell morphology as well as damage to membrane lipids, and genomic DNA. Cells in saline were less damaged compared to those in water, and those in YPD (Yeast extract, Peptone, Dextrose) were least impaired. HOG1 mitogen activated protein kinase was activated in cells exposed to plasma in water and saline. Inactivation of yeast cells in water and saline was due to the acidification of the solutions by plasma, but higher survival of yeast cells treated in saline may have resulted from the additional effect related to salt strength. Levels of hydroxyl radical (OH.) produced by plasma were the highest in water and the lowest in YPD. This may have resulted in differential inactivation of yeast cells in water, saline, and YPD by plasma. Taken together, our data suggest that the surrounding media (environment) can crucially affect the outcomes of yeast cell plasma treatment because plasma modulates vital properties of media, and the toxic nature of plasma can also be altered by the surrounding media. PMID- 23799082 TI - Large-scale variation in combined impacts of canopy loss and disturbance on community structure and ecosystem functioning. AB - Ecosystems are under pressure from multiple human disturbances whose impact may vary depending on environmental context. We experimentally evaluated variation in the separate and combined effects of the loss of a key functional group (canopy algae) and physical disturbance on rocky shore ecosystems at nine locations across Europe. Multivariate community structure was initially affected (during the first three to six months) at six locations but after 18 months, effects were apparent at only three. Loss of canopy caused increases in cover of non-canopy algae in the three locations in southern Europe and decreases in some northern locations. Measures of ecosystem functioning (community respiration, gross primary productivity, net primary productivity) were affected by loss of canopy at five of the six locations for which data were available. Short-term effects on community respiration were widespread, but effects were rare after 18 months. Functional changes corresponded with changes in community structure and/or species richness at most locations and times sampled, but no single aspect of biodiversity was an effective predictor of longer-term functional changes. Most ecosystems studied were able to compensate in functional terms for impacts caused by indiscriminate physical disturbance. The only consistent effect of disturbance was to increase cover of non-canopy species. Loss of canopy algae temporarily reduced community resistance to disturbance at only two locations and at two locations actually increased resistance. Resistance to disturbance-induced changes in gross primary productivity was reduced by loss of canopy algae at four locations. Location-specific variation in the effects of the same stressors argues for flexible frameworks for the management of marine environments. These results also highlight the need to analyse how species loss and other stressors combine and interact in different environmental contexts. PMID- 23799083 TI - Uptake and intracellular trafficking of superantigens in dendritic cells. AB - Bacterial superantigens (SAgs) are exotoxins produced mainly by Staphylococcus aureus and Streptococcus pyogenes that can cause toxic shock syndrome (TSS). According to current paradigm, SAgs interact directly and simultaneously with T cell receptor (TCR) on the T cell and MHC class II (MHC-II) on the antigen presenting cell (APC), thereby circumventing intracellular processing to trigger T cell activation. Dendritic cells (DCs) are professional APCs that coat nearly all body surfaces and are the most probable candidate to interact with SAgs. We demonstrate that SAgs are taken up by mouse DCs without triggering DC maturation. SAgs were found in intracellular acidic compartment of DCs as biologically active molecules. Moreover, SAgs co-localized with EEA1, RAB-7 and LAMP-2, at different times, and were then recycled to the cell membrane. DCs loaded with SAgs are capable of triggering in vitro lymphocyte proliferation and, injected into mice, stimulate T cells bearing the proper TCR in draining lymph nodes. Transportation and trafficking of SAgs in DCs might increase the local concentration of these exotoxins where they will produce the highest effect by promoting their encounter with both MHC-II and TCR in lymph nodes, and may explain how just a few SAg molecules can induce the severe pathology associated with TSS. PMID- 23799084 TI - Interferon regulatory factor 1 polymorphisms previously associated with reduced HIV susceptibility have no effect on HIV disease progression. AB - INTRODUCTION: Interferon regulatory factor 1 (IRF1) is induced by HIV early in the infection process and serves two functions: transactivation of the HIV-1 genome and thus replication, and eliciting antiviral innate immune responses. We previously described three IRF1 polymorphisms that correlate with reduced IRF1 expression and reduced HIV susceptibility. OBJECTIVE: To determine whether IRF1 polymorphisms previously associated with reduced HIV susceptibility play a role in HIV pathogenesis and disease progression in HIV-infected ART-naive individuals. METHODS: IRF1 genotyping for polymorphisms (619, MS and 6516) was performed by PCR in 847 HIV positive participants from a sex worker cohort in Nairobi, Kenya. Rates of CD4+ T cell decline and viral loads (VL) were analyzed using linear mixed models. RESULTS: Three polymorphisms in the IRF1, located at 619, microsatellite region and 6516 of the gene, previously associated with decreased susceptibility to HIV infection show no effect on disease progression, either measured by HIV-1 RNA levels or the slopes of CD4 decline before treatment initiation. CONCLUSION: Whereas these three polymorphisms in the IRF1 gene protect against HIV-1 acquisition, they appear to exert no discernable effects once infection is established. PMID- 23799085 TI - Cancer subtype discovery and biomarker identification via a new robust network clustering algorithm. AB - In cancer biology, it is very important to understand the phenotypic changes of the patients and discover new cancer subtypes. Recently, microarray-based technologies have shed light on this problem based on gene expression profiles which may contain outliers due to either chemical or electrical reasons. These undiscovered subtypes may be heterogeneous with respect to underlying networks or pathways, and are related with only a few of interdependent biomarkers. This motivates a need for the robust gene expression-based methods capable of discovering such subtypes, elucidating the corresponding network structures and identifying cancer related biomarkers. This study proposes a penalized model based Student's t clustering with unconstrained covariance (PMT-UC) to discover cancer subtypes with cluster-specific networks, taking gene dependencies into account and having robustness against outliers. Meanwhile, biomarker identification and network reconstruction are achieved by imposing an adaptive [Formula: see text] penalty on the means and the inverse scale matrices. The model is fitted via the expectation maximization algorithm utilizing the graphical lasso. Here, a network-based gene selection criterion that identifies biomarkers not as individual genes but as subnetworks is applied. This allows us to implicate low discriminative biomarkers which play a central role in the subnetwork by interconnecting many differentially expressed genes, or have cluster-specific underlying network structures. Experiment results on simulated datasets and one available cancer dataset attest to the effectiveness, robustness of PMT-UC in cancer subtype discovering. Moveover, PMT-UC has the ability to select cancer related biomarkers which have been verified in biochemical or biomedical research and learn the biological significant correlation among genes. PMID- 23799086 TI - A self-organizing model of the visual development of hand-centred representations. AB - We show how hand-centred visual representations could develop in the primate posterior parietal and premotor cortices during visually guided learning in a self-organizing neural network model. The model incorporates trace learning in the feed-forward synaptic connections between successive neuronal layers. Trace learning encourages neurons to learn to respond to input images that tend to occur close together in time. We assume that sequences of eye movements are performed around individual scenes containing a fixed hand-object configuration. Trace learning will then encourage individual cells to learn to respond to particular hand-object configurations across different retinal locations. The plausibility of this hypothesis is demonstrated in computer simulations. PMID- 23799087 TI - Cancer missense mutations alter binding properties of proteins and their interaction networks. AB - Many studies have shown that missense mutations might play an important role in carcinogenesis. However, the extent to which cancer mutations might affect biomolecular interactions remains unclear. Here, we map glioblastoma missense mutations on the human protein interactome, model the structures of affected protein complexes and decipher the effect of mutations on protein-protein, protein-nucleic acid and protein-ion binding interfaces. Although some missense mutations over-stabilize protein complexes, we found that the overall effect of mutations is destabilizing, mostly affecting the electrostatic component of binding energy. We also showed that mutations on interfaces resulted in more drastic changes of amino acid physico-chemical properties than mutations occurring outside the interfaces. Analysis of glioblastoma mutations on interfaces allowed us to stratify cancer-related interactions, identify potential driver genes, and propose two dozen additional cancer biomarkers, including those specific to functions of the nervous system. Such an analysis also offered insight into the molecular mechanism of the phenotypic outcomes of mutations, including effects on complex stability, activity, binding and turnover rate. As a result of mutated protein and gene network analysis, we observed that interactions of proteins with mutations mapped on interfaces had higher bottleneck properties compared to interactions with mutations elsewhere on the protein or unaffected interactions. Such observations suggest that genes with mutations directly affecting protein binding properties are preferably located in central network positions and may influence critical nodes and edges in signal transduction networks. PMID- 23799088 TI - Enterocyte-specific inactivation of SIRT1 reduces tumor load in the APC(+/min) mouse model. AB - SIRT1 is a mammalian NAD(+)-dependent histone deacetylase implicated in metabolism, development, aging and tumorigenesis. Prior studies that examined the effect of enterocyte-specific overexpression and global deletion of SIRT1 on polyp formation in the intestines of APC(+/min) mice, a commonly used model for intestinal tumorigenesis, yielded conflicting results, supporting either tumor suppressive or tumor-promoting roles for SIRT1, respectively. In order to resolve the controversy emerging from these prior in vivo studies, in the present report we examined the effect of SIRT1 deficiency confined to the intestines, avoiding the systemic perturbations such as growth retardation seen with global SIRT1 deletion. We crossed APC(+/min) mice with mice bearing enterocyte-specific inactivation of SIRT1 and examined polyp development in the progeny. We found that SIRT1-inactivation reduced total polyp surface (9.3 mm(2) vs. 23.3 mm(2), p = 0.01), average polyp size (0.24 mm(2) vs. 0.51 mm(2), p = 0.005) and the number of polyps >0.5 mm in diameter (14 vs. 23, p = 0.04), indicating that SIRT1 affects both the number and size of tumors. Additionally, tumors in SIRT1 deficient mice exhibited markedly increased numbers of cells undergoing apoptosis, suggesting that SIRT1 contributes to tumor growth by enabling survival of tumor cells. Our results indicate that SIRT1 acts as a tumor promoter in the APC(+/min) mouse model of intestinal tumorigenesis. PMID- 23799089 TI - Aerobic interval training partly reverse contractile dysfunction and impaired Ca2+ handling in atrial myocytes from rats with post infarction heart failure. AB - BACKGROUND: There is limited knowledge about atrial myocyte Ca(2+) handling in the failing hearts. The aim of this study was to examine atrial myocyte contractile function and Ca(2+) handling in rats with post-infarction heart failure (HF) and to examine whether aerobic interval training could reverse a potential dysfunction. METHODS AND RESULTS: Post-infarction HF was induced in Sprague Dawley rats by ligation of the left descending coronary artery. Atrial myocyte shortening was depressed (p<0.01) and time to relaxation was prolonged (p<0.01) in sedentary HF-rats compared to healthy controls. This was associated with decreased Ca(2+) amplitude, decreased SR Ca(2+) content, and slower Ca(2+) transient decay. Atrial myocytes from HF-rats had reduced sarcoplasmic reticulum Ca(2+) ATPase activity, increased Na(+)/Ca(2+)-exchanger activity and increased diastolic Ca(2+) leak through ryanodine receptors. High intensity aerobic interval training in HF-rats restored atrial myocyte contractile function and reversed changes in atrial Ca(2+) handling in HF. CONCLUSION: Post infarction HF in rats causes profound impairment in atrial myocyte contractile function and Ca(2+) handling. The observed dysfunction in atrial myocytes was partly reversed after aerobic interval training. PMID- 23799090 TI - Sesquiterpene lactones downregulate G2/M cell cycle regulator proteins and affect the invasive potential of human soft tissue sarcoma cells. AB - Soft tissue sarcomas (STS) represent a rare group of malignant tumors that frequently exhibit chemotherapeutic resistance and increased metastatic potential. Many studies have demonstrated the great potential of plant-derived agents in the treatment of various malignant entities. The present study investigates the effects of the sesquiterpene lactones costunolide and dehydrocostus lactone on cell cycle, MMP expression, and invasive potential of three human STS cell lines of various origins. Both compounds reduced cell proliferation in a time- and dose-dependent manner. Dehydrocostus lactone significantly inhibited cell proliferation, arrested the cells at the G2/M interface and caused a decrease in the expression of the cyclin-dependent kinase CDK2 and the cyclin-dependent kinase inhibitor p27(Kip1). In addition, accumulation of cells at the G2/M phase transition interface resulted in a significant decrease in cdc2 (CDK1) together with cyclin B1. Costunolide had no effect on the cell cycle. Based on the fact that STS tend to form daughter cell nests and metastasize, the expression levels of matrix metalloproteinases (MMPs), which play a crucial role in extracellular matrix degradation and metastasis, were investigated by Luminex(r) technology and real-time RT-PCR. In the presence of costunolide, MMP-2 and -9 levels were significantly increased in SW-982 and TE 671 cells. Dehydrocostus lactone treatment significantly reduced MMP-2 and -9 expression in TE-671 cells, but increased MMP-9 level in SW-982 cells. In addition, the invasion potential was significantly reduced after treatment with both sesquiterpene lactones as investigated by the HTS FluoroBlockTM insert system. PMID- 23799091 TI - Patterns of non-administration of ordered doses of venous thromboembolism prophylaxis: implications for novel intervention strategies. AB - BACKGROUND: Recent studies have documented high rates of non-administration of ordered venous thromboembolism (VTE) prophylaxis doses. Intervention strategies that target all patients have been effective, but prohibitively resource intensive. We aimed to identify efficient intervention strategies based on patterns of non-administration of ordered VTE prophylaxis. METHODS AND FINDINGS: In this retrospective review of electronic medication administration records, we included adult hospitalized patients who were ordered pharmacologic VTE prophylaxis with unfractionated heparin or enoxaparin over a seven-month period. The primary measure was the proportion of ordered doses of VTE prophylaxis not administered, assessed at the patient, floor, and floor type levels. Differences in non-administration rates between groups were assessed using generalized estimating equations. A total of 103,160 ordered VTE prophylaxis doses during 10,516 patient visits on twenty-nine patient floors were analyzed. Overall, 11.9% of ordered doses were not administered. Approximately 19% of patients missed at least one quarter and 8% of patients missed over one half of ordered doses. There was marked heterogeneity in non-administration rate at the floor level (range: 5 27%). Patients on medicine floors missed a significantly larger proportion (18%) of ordered doses compared to patients on other floor types (8%, Odds Ratio: 2.4, p<0.0001). However, more than half of patients received at least 86% of their ordered doses, even on the lowest performing floor. The 20% of patients who missed at least two ordered doses accounted for 80% of all missed doses. CONCLUSIONS: A substantial proportion of ordered doses of VTE prophylaxis were not administered. The heterogeneity in non-administration rate between patients, floors, and floor types can be used to target interventions. The small proportion of patients that missed multiple ordered doses accounted for a large majority of non-administered doses. This recognition of the Pareto principle provides opportunity to efficiently target a relatively small group of patients for intervention. PMID- 23799092 TI - rAAV-mediated subcellular targeting of optogenetic tools in retinal ganglion cells in vivo. AB - Expression of optogenetic tools in surviving inner retinal neurons to impart retinal light sensitivity has been a new strategy for restoring vision after photoreceptor degeneration. One potential approach for restoring retinal light sensitivity after photoreceptor degeneration is to express optogenetic tools in retinal ganglion cells (RGCs). For this approach, restoration of ON and OFF center-surround receptive fields in RGCs, a key feature of visual information processing, may be important. A possible solution is to differentially express depolarizing and hyperpolarizing optogenetic tools, such as channelrhodopsin-2 and halorhodopsin, to the center and peripheral regions of the RGC dendritic field by using protein targeting motifs. Recombinant adeno-associated virus (rAAV) vectors have proven to be a powerful vehicle for in vitro and in vivo gene delivery, including in the retina. Therefore, the search for protein targeting motifs that can achieve rAAV-mediated subcellular targeted expression would be particularly valuable for developing therapeutic applications. In this study, we identified two protein motifs that are suitable for rAAV-mediated subcellular targeting for generating center-surround receptive fields while reducing the axonal expression in RGCs. Resulting morphological dendritic field and physiological response field by center-targeting were significantly smaller than those produced by surround-targeting. rAAV motif-mediated protein targeting could also be a valuable tool for studying physiological function and clinical applications in other areas of the central nervous system. PMID- 23799093 TI - In vivo ultrasonic detection of polyurea crosslinked silica aerogel implants. AB - BACKGROUND: Polyurea crosslinked silica aerogels are highly porous, lightweight, and mechanically strong materials with great potential for in vivo applications. Recent in vivo and in vitro studies have demonstrated the biocompatibility of this type of aerogel. The highly porous nature of aerogels allows for exceptional thermal, electric, and acoustic insulating capabilities that can be taken advantage of for non-invasive external imaging techniques. Sound-based detection of implants is a low cost, non-invasive, portable, and rapid technique that is routinely used and readily available in major clinics and hospitals. METHODOLOGY: In this study the first in vivo ultrasound response of polyurea crosslinked silica aerogel implants was investigated by means of a GE Medical Systems LogiQe diagnostic ultrasound machine with a linear array probe. Aerogel samples were inserted subcutaneously and sub-muscularly in a) fresh animal model and b) cadaveric human model for analysis. For comparison, samples of polydimethylsiloxane (PDMS) were also imaged under similar conditions as the aerogel samples. CONCLUSION/SIGNIFICANCE: Polyurea crosslinked silica aerogel (X Si aerogel) implants were easily identified when inserted in either of the regions in both fresh animal model and cadaveric model. The implant dimensions inferred from the images matched the actual size of the implants and no apparent damage was sustained by the X-Si aerogel implants as a result of the ultrasonic imaging process. The aerogel implants demonstrated hyperechoic behavior and significant posterior shadowing. Results obtained were compared with images acquired from the PDMS implants inserted at the same location. PMID- 23799094 TI - Genetic polymorphism in PDE4D gene and risk of ischemic stroke in Chinese population: a meta-analysis. AB - BACKGROUND: Stroke is the second most common cause of death and major cause of disability worldwide. The SNP 83 in PDE4D gene has been suggested as a risk factor in ischemic stroke, but direct evidence from genetic association studies remains inconclusive even in Chinese population. METHODS: Meta-analysis of case control studies on the relationship between SNP 83 in PDE4D gene and susceptibility to ischemic stroke in Chinese population published domestically and abroad from January 2003 to September 2012. RESULTS: 9 case-control studies were selected. Meta-analysis results showed that the significant association between SNP 83 and ischemic stroke was found under the dominant model (OR = 1.34, 95% CI: 1.20-1.49) and recessive model (OR = 1.45, 95% CI: 1.19-1.76) in Chinese population. In subgroup meta-analysis, SNP 83 and atherothrombotic stroke, rather than lacunar stroke, showed the significant association under the dominant model (OR = 1.69, 95% CI: 1.41-2.01) and recessive model (OR = 1.47, 95% CI: 1.04 2.06). CONCLUSIONS: The results suggest that SNP 83 in PDE4D gene is significantly associated with susceptibility to ischemic stroke in Chinese population. PMID- 23799095 TI - Evaluating amyloid-beta oligomers in cerebrospinal fluid as a biomarker for Alzheimer's disease. AB - The current study evaluated amyloid-beta oligomers (Abetao) in cerebrospinal fluid as a clinical biomarker for Alzheimer's disease (AD). We developed a highly sensitive Abetao ELISA using the same N-terminal monoclonal antibody (82E1) for capture and detection. CSF samples from patients with AD, mild cognitive impairment (MCI), and healthy controls were examined. The assay was specific for oligomerized Abeta with a lower limit of quantification of 200 fg/ml, and the assay signal showed a tight correlation with synthetic Abetao levels. Three clinical materials of well characterized AD patients (n = 199) and cognitively healthy controls (n = 148) from different clinical centers were included, together with a clinical material of patients with MCI (n = 165). Abetao levels were elevated in the all three AD-control comparisons although with a large overlap and a separation from controls that was far from complete. Patients with MCI who later converted to AD had increased Abetao levels on a group level but several samples had undetectable levels. These results indicate that presence of high or measurable Abetao levels in CSF is clearly associated with AD, but the overlap is too large for the test to have any diagnostic potential on its own. PMID- 23799096 TI - Reducing the decline in physical activity during pregnancy: a systematic review of behaviour change interventions. AB - PURPOSE: Physical activity (PA) typically declines throughout pregnancy. Low levels of PA are associated with excessive weight gain and subsequently increase risk of pre-eclampsia, gestational diabetes mellitus, hypertension disorders, delivery by caesarean section and stillbirth. Systematic reviews on PA during pregnancy have not explored the efficacy of behaviour change techniques or related theory in altering PA behaviour. This systematic review evaluated the content of PA interventions to reduce the decline of PA in pregnant women with a specific emphasis on the behaviour change techniques employed to elicit this change. SEARCH AND REVIEW METHODOLOGY: Literature searches were conducted in eight databases. Strict inclusion and exclusion criteria were employed. Two reviewers independently evaluated each intervention using the behaviour change techniques (BCT) taxonomy to identify the specific behaviour change techniques employed. Two reviewers independently assessed the risk of bias using the guidelines from the Cochrane Collaboration. Overall quality was determined using the GRADE approach. FINDINGS: A total of 1140 potentially eligible papers were identified from which 14 studies were selected for inclusion. Interventions included counselling (n = 6), structured exercise (n = 6) and education (n = 2). Common behaviour change techniques employed in these studies were goal setting and planning, feedback, repetition and substitution, shaping knowledge and comparison of behaviours. Regular face-to-face meetings were also commonly employed. PA change over time in intervention groups ranged from increases of 28% to decreases of 25%. In 8 out of 10 studies, which provided adequate data, participants in the intervention group were more physically active post intervention than controls. CONCLUSIONS AND IMPLICATIONS: Physical activity interventions incorporating behaviour change techniques help reduce the decline in PA throughout pregnancy. Range of behaviour change techniques can be implemented to reduce this decline including goals and planning, shaping knowledge and comparison of outcomes. A lack of high quality interventions hampers conclusions of intervention effectiveness. PMID- 23799097 TI - Effects of auditory stimuli in the horizontal plane on audiovisual integration: an event-related potential study. AB - This article aims to investigate whether auditory stimuli in the horizontal plane, particularly originating from behind the participant, affect audiovisual integration by using behavioral and event-related potential (ERP) measurements. In this study, visual stimuli were presented directly in front of the participants, auditory stimuli were presented at one location in an equidistant horizontal plane at the front (0 degrees , the fixation point), right (90 degrees ), back (180 degrees ), or left (270 degrees ) of the participants, and audiovisual stimuli that include both visual stimuli and auditory stimuli originating from one of the four locations were simultaneously presented. These stimuli were presented randomly with equal probability; during this time, participants were asked to attend to the visual stimulus and respond promptly only to visual target stimuli (a unimodal visual target stimulus and the visual target of the audiovisual stimulus). A significant facilitation of reaction times and hit rates was obtained following audiovisual stimulation, irrespective of whether the auditory stimuli were presented in the front or back of the participant. However, no significant interactions were found between visual stimuli and auditory stimuli from the right or left. Two main ERP components related to audiovisual integration were found: first, auditory stimuli from the front location produced an ERP reaction over the right temporal area and right occipital area at approximately 160-200 milliseconds; second, auditory stimuli from the back produced a reaction over the parietal and occipital areas at approximately 360-400 milliseconds. Our results confirmed that audiovisual integration was also elicited, even though auditory stimuli were presented behind the participant, but no integration occurred when auditory stimuli were presented in the right or left spaces, suggesting that the human brain might be particularly sensitive to information received from behind than both sides. PMID- 23799099 TI - Antibacterial immune competence of honey bees (Apis mellifera) is adapted to different life stages and environmental risks. AB - The development of all honey bee castes proceeds through three different life stages all of which encounter microbial infections to a various extent. We have examined the immune strength of honey bees across all developmental stages with emphasis on the temporal expression of cellular and humoral immune responses upon artificial challenge with viable Escherichia coli bacteria. We employed a broad array of methods to investigate defence strategies of infected individuals: (a) fate of bacteria in the haemocoel; (b) nodule formation and (c) induction of antimicrobial peptides (AMPs). Newly emerged adult worker bees and drones were able to activate efficiently all examined immune reactions. The number of viable bacteria circulating in the haemocoel of infected bees declined rapidly by more than two orders of magnitude within the first 4-6 h post-injection (p.i.), coinciding with the occurrence of melanised nodules. Antimicrobial activity, on the other hand, became detectable only after the initial bacterial clearance. These two temporal patterns of defence reactions very likely represent the constitutive cellular and the induced humoral immune response. A unique feature of honey bees is that a fraction of worker bees survives the winter season in a cluster mostly engaged in thermoregulation. We show here that the overall immune strength of winter bees matches that of young summer bees although nodulation reactions are not initiated at all. As expected, high doses of injected viable E.coli bacteria caused no mortality in larvae or adults of each age. However, drone and worker pupae succumbed to challenge with E.coli even at low doses, accompanied by a premature darkening of the pupal body. In contrast to larvae and adults, we observed no fast clearance of viable bacteria and no induction of AMPs but a rapid proliferation of E.coli bacteria in the haemocoel of bee pupae ultimately leading to their death. PMID- 23799098 TI - Acute simvastatin inhibits K ATP channels of porcine coronary artery myocytes. AB - BACKGROUND: Statins (3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors) consumption provides beneficial effects on cardiovascular systems. However, effects of statins on vascular KATP channel gatings are unknown. METHODS: Pig left anterior descending coronary artery and human left internal mammary artery were isolated and endothelium-denuded for tension measurements and Western immunoblots. Enzymatically-dissociated/cultured arterial myocytes were used for patch-clamp electrophysiological studies and for [Ca(2+)]i, [ATP]i and [glucose]o uptake measurements. RESULTS: The cromakalim (10 nM to 10 uM)- and pinacidil (10 nM to 10 uM)-induced concentration-dependent relaxation of porcine coronary artery was inhibited by simvastatin (3 and 10 uM). Simvastatin (1, 3 and 10 uM) suppressed (in okadaic acid (10 nM)-sensitive manner) cromakalim (10 uM)- and pinacidil (10 uM)-mediated opening of whole-cell KATP channels of arterial myocytes. Simvastatin (10 uM) and AICAR (1 mM) elicited a time-dependent, compound C (1 uM)-sensitive [(3)H]-2-deoxy-glucose uptake and an increase in [ATP]i levels. A time (2-30 min)- and concentration (0.1-10 uM)-dependent increase by simvastatin of p-AMPKalpha-Thr(172) and p-PP2A-Tyr(307) expression was observed. The enhanced p-AMPKalpha-Thr(172) expression was inhibited by compound C, ryanodine (100 uM) and KN93 (10 uM). Simvastatin-induced p-PP2A Tyr(307) expression was suppressed by okadaic acid, compound C, ryanodine, KN93, phloridzin (1 mM), ouabain (10 uM), and in [glucose]o-free or [Na(+)]o-free conditions. CONCLUSIONS: Simvastatin causes ryanodine-sensitive Ca(2+) release which is important for AMPKalpha-Thr(172) phosphorylation via Ca(2+)/CaMK II. AMPKalpha-Thr(172) phosphorylation causes [glucose]o uptake (and an [ATP]i increase), closure of KATP channels, and phosphorylation of AMPKalpha-Thr(172) and PP2A-Tyr(307) resulted. Phosphorylation of PP2A-Tyr(307) occurs at a site downstream of AMPKalpha-Thr(172) phosphorylation. PMID- 23799100 TI - Variations in kinematics during clinical gait analysis in stroke patients. AB - In addition to changes in spatio-temporal and kinematic parameters, patients with stroke exhibit fear of falling as well as fatigability during gait. These changes could compromise interpretation of data from gait analysis. The aim of this study was to determine if the gait of hemiplegic patients changes significantly over successive gait trials. Forty two stroke patients and twenty healthy subjects performed 9 gait trials during a gait analysis session. The mean and variability of spatio-temporal and kinematic joint parameters were analyzed during 3 groups of consecutive gait trials (1-3, 4-6 and 7-9). Principal component analysis was used to reduce the number of variables from the joint kinematic waveforms and to identify the parts of the gait cycle which changed during the gait analysis session. The results showed that i) spontaneous gait velocity and the other spatio-temporal parameters significantly increased, and ii) gait variability decreased, over the last 6 gait trials compared to the first 3, for hemiplegic patients but not healthy subjects. Principal component analysis revealed changes in the sagittal waveforms of the hip, knee and ankle for hemiplegic patients after the first 3 gait trials. These results suggest that at the beginning of the gait analysis session, stroke patients exhibited phase of adaptation,characterized by a "cautious gait" but no fatigue was observed. PMID- 23799101 TI - A novel Lentinula edodes laccase and its comparative enzymology suggest guaiacol based laccase engineering for bioremediation. AB - Laccases are versatile biocatalysts for the bioremediation of various xenobiotics, including dyes and polyaromatic hydrocarbons. However, current sources of new enzymes, simple heterologous expression hosts and enzymatic information (such as the appropriateness of common screening substrates on laccase engineering) remain scarce to support efficient engineering of laccase for better "green" applications. To address the issue, this study began with cloning the laccase family of Lentinula edodes. Three laccases perfectio sensu stricto (Lcc4A, Lcc5, and Lcc7) were then expressed from Pichia pastoris, characterized and compared with the previously reported Lcc1A and Lcc1B in terms of kinetics, stability, and degradation of dyes and polyaromatic hydrocarbons. Lcc7 represented a novel laccase, and it exhibited both the highest catalytic efficiency (assayed with 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) [ABTS]) and thermostability. However, its performance on "green" applications surprisingly did not match the activity on the common screening substrates, namely, ABTS and 2,6-dimethoxyphenol. On the other hand, correlation analyses revealed that guaiacol is much better associated with the decolorization of multiple structurally different dyes than are the two common screening substrates. Comparison of the oxidation chemistry of guaiacol and phenolic dyes, such as azo dyes, further showed that they both involve generation of phenoxyl radicals in laccase-catalyzed oxidation. In summary, this study concluded a robust expression platform of L. edodes laccases, novel laccases, and an indicative screening substrate, guaiacol, which are all essential fundamentals for appropriately driving the engineering of laccases towards more efficient "green" applications. PMID- 23799102 TI - Alterations in skeletal muscle cell homeostasis in a mouse model of cigarette smoke exposure. AB - BACKGROUND: Skeletal muscle dysfunction is common in chronic obstructive pulmonary disease (COPD), a disease mainly caused by chronic cigarette use. An important proportion of patients with COPD have decreased muscle mass, suggesting that chronic cigarette smoke exposure may interfere with skeletal muscle cellular equilibrium. Therefore, the main objective of this study was to investigate the kinetic of the effects that cigarette smoke exposure has on skeletal muscle cell signaling involved in protein homeostasis and to assess the reversibility of these effects. METHODS: A mouse model of cigarette smoke exposure was used to assess skeletal muscle changes. BALB/c mice were exposed to cigarette smoke or room air for 8 weeks, 24 weeks or 24 weeks followed by 60 days of cessation. The gastrocnemius and soleus muscles were collected and the activation state of key mediators involved in protein synthesis and degradation was assessed. RESULTS: Gastrocnemius and soleus were smaller in mice exposed to cigarette smoke for 8 and 24 weeks compared to room air exposed animals. Pro-degradation proteins were induced at the mRNA level after 8 and 24 weeks. Twenty-four weeks of cigarette smoke exposure induced pro-degradation proteins and reduced Akt phosphorylation and glycogen synthase kinase-3beta quantity. A 60-day smoking cessation period reversed the cell signaling alterations induced by cigarette smoke exposure. CONCLUSIONS: Repeated cigarette smoke exposure induces reversible muscle signaling alterations that are dependent on the duration of the cigarette smoke exposure. These results highlights a beneficial aspect associated with smoking cessation. PMID- 23799103 TI - BMP7 gene transfer via gold nanoparticles into stroma inhibits corneal fibrosis in vivo. AB - This study examined the effects of BMP7 gene transfer on corneal wound healing and fibrosis inhibition in vivo using a rabbit model. Corneal haze in rabbits was produced with the excimer laser performing -9 diopters photorefractive keratectomy. BMP7 gene was introduced into rabbit keratocytes by polyethylimine conjugated gold nanoparticles (PEI2-GNPs) transfection solution single 5-minute topical application on the eye. Corneal haze and ocular health in live animals was gauged with stereo- and slit-lamp biomicroscopy. The levels of fibrosis [alpha-smooth muscle actin (alphaSMA), F-actin and fibronectin], immune reaction (CD11b and F4/80), keratocyte apoptosis (TUNEL), calcification (alizarin red, vonKossa and osteocalcin), and delivered-BMP7 gene expression in corneal tissues were quantified with immunofluorescence, western blotting and/or real-time PCR. Human corneal fibroblasts (HCF) and in vitro experiments were used to characterize the molecular mechanism mediating BMP7's anti-fibrosis effects. PEI2 GNPs showed substantial BMP7 gene delivery into rabbit keratocytes in vivo (2*10(4) gene copies/ug DNA). Localized BMP7 gene therapy showed a significant corneal haze decrease (1.68+/-0.31 compared to 3.2+/-0.43 in control corneas; p<0.05) in Fantes grading scale. Immunostaining and immunoblot analyses detected significantly reduced levels of alphaSMA (46+/-5% p<0.001) and fibronectin proteins (48+/-5% p<0.01). TUNEL, CD11b, and F4/80 assays revealed that BMP7 gene therapy is nonimmunogenic and nontoxic for the cornea. Furthermore, alizarin red, vonKossa and osteocalcin analyses revealed that localized PEI2-GNP-mediated BMP7 gene transfer in rabbit cornea does not cause calcification or osteoblast recruitment. Immunofluorescence of BMP7-transefected HCFs showed significantly increased pSmad-1/5/8 nuclear localization (>88%; p<0.0001), and immunoblotting of BMP7-transefected HCFs grown in the presence of TGFbeta demonstrated significantly enhanced pSmad-1/5/8 (95%; p<0.001) and Smad6 (53%, p<0.001), and decreased alphaSMA (78%; p<0.001) protein levels. These results suggest that localized BMP7 gene delivery in rabbit cornea modulates wound healing and inhibits fibrosis in vivo by counter balancing TGFbeta1-mediated profibrotic Smad signaling. PMID- 23799105 TI - Uncertainties in predicting species distributions under climate change: a case study using Tetranychus evansi (Acari: Tetranychidae), a widespread agricultural pest. AB - Many species are shifting their distributions due to climate change and to increasing international trade that allows dispersal of individuals across the globe. In the case of agricultural pests, such range shifts may heavily impact agriculture. Species distribution modelling may help to predict potential changes in pest distributions. However, these modelling strategies are subject to large uncertainties coming from different sources. Here we used the case of the tomato red spider mite (Tetranychus evansi), an invasive pest that affects some of the most important agricultural crops worldwide, to show how uncertainty may affect forecasts of the potential range of the species. We explored three aspects of uncertainty: (1) species prevalence; (2) modelling method; and (3) variability in environmental responses between mites belonging to two invasive clades of T. evansi. Consensus techniques were used to forecast the potential range of the species under current and two different climate change scenarios for 2080, and variance between model projections were mapped to identify regions of high uncertainty. We revealed large predictive variations linked to all factors, although prevalence had a greater influence than the statistical model once the best modelling strategies were selected. The major areas threatened under current conditions include tropical countries in South America and Africa, and temperate regions in North America, the Mediterranean basin and Australia. Under future scenarios, the threat shifts towards northern Europe and some other temperate regions in the Americas, whereas tropical regions in Africa present a reduced risk. Analysis of niche overlap suggests that the current differential distribution of mites of the two clades of T. evansi can be partially attributed to environmental niche differentiation. Overall this study shows how consensus strategies and analysis of niche overlap can be used jointly to draw conclusions on invasive threat considering different sources of uncertainty in species distribution modelling. PMID- 23799104 TI - Eukaryotic translation elongation factor 1-alpha 1 inhibits p53 and p73 dependent apoptosis and chemotherapy sensitivity. AB - The p53 family of transcription factors is a key regulator of cell proliferation and death. In this report we identify the eukaryotic translation elongation factor 1-alpha 1 (eEF1A1) to be a novel p53 and p73 interacting protein. Previous studies have demonstrated that eEF1A1 has translation-independent roles in cancer. We report that overexpression of eEF1A1 specifically inhibits p53-, p73- and chemotherapy-induced apoptosis resulting in chemoresistance. Short interfering RNA-mediated silencing of eEF1A1 increases chemosensitivity in cell lines bearing wild type p53, but not in p53 null cells. Furthermore, silencing of eEF1A1 partially rescues the chemoresistance observed in response to p53 or p73 knockdown, suggesting that eEF1A1 is a negative regulator of the pro-apoptotic function of p53 and p73. Thus, in the context of p53-family signaling, eEF1A1 has anti-apoptotic properties. These findings identify a novel mechanism of regulation of the p53 family of proteins by eEF1A1 providing additional insight into potential targets to sensitize tumors to chemotherapy. PMID- 23799106 TI - Synthesis of coral-like tantalum oxide films via anodization in mixed organic inorganic electrolytes. AB - We report a simple method to fabricate nano-porous tantalum oxide films via anodization with Ta foils as the anode at room temperature. A mixture of ethylene glycol, phosphoric acid, NH4F and H2O was used as the electrolyte where the nano porous tantalum oxide could be synthesized by anodizing a tantalum foil for 1 h at 20 V in a two-electrode configuration. The as-prepared porous film exhibited a continuous, uniform and coral-like morphology. The diameters of pores ranged from 30 nm to 50 nm. The pores interlaced each other and the depth was about 150 nm. After calcination, the as-synthesized amorphous tantalum oxide could be crystallized to the orthorhombic crystal system. As observed in photocatalytic experiments, the coral-like tantalum oxide exhibited a higher photocatalytic activity for the degradation of phenol than that with a compact surface morphology, and the elimination rate of phenol increased by 66.7%. PMID- 23799107 TI - Seawater-cultured Botryococcus braunii for efficient hydrocarbon extraction. AB - As a potential source of biofuel, the green colonial microalga Botryococcus braunii produces large amounts of hydrocarbons that are accumulated in the extracellular matrix. Generally, pretreatment such as drying or heating of wet algae is needed for sufficient recoveries of hydrocarbons from B. braunii using organic solvents. In this study, the Showa strain of B. braunii was cultured in media derived from the modified Chu13 medium by supplying artificial seawater, natural seawater, or NaCl. After a certain period of culture in the media with an osmotic pressure corresponding to 1/4-seawater, hydrocarbon recovery rates exceeding 90% were obtained by simply mixing intact wet algae with n-hexane without any pretreatments and the results using the present culture conditions indicate the potential for hydrocarbon milking. HIGHLIGHTS: Seawater was used for efficient hydrocarbon extraction from Botryococcus braunii. The alga was cultured in media prepared with seawater or NaCl. Hydrocarbon recovery rate exceeding 90% was obtained without any pretreatment. PMID- 23799108 TI - The neurogenic factor NeuroD1 is expressed in post-mitotic cells during juvenile and adult Xenopus neurogenesis and not in progenitor or radial glial cells. AB - In contrast to mammals that have limited proliferation and neurogenesis capacities, the Xenopus frog exhibit a great potential regarding proliferation and production of new cells in the adult brain. This ability makes Xenopus a useful model for understanding the molecular programs required for adult neurogenesis. Transcriptional factors that control adult neurogenesis in vertebrate species undergoing widespread neurogenesis are unknown. NeuroD1 is a member of the family of proneural genes, which function during embryonic neurogenesis as a potent neuronal differentiation factor. Here, we study in detail the expression of NeuroD1 gene in the juvenile and adult Xenopus brains by in situ hybridization combined with immunodetections for proliferation markers (PCNA, BrdU) or in situ hybridizations for cell type markers (Vimentin, Sox2). We found NeuroD1 gene activity in many brain regions, including olfactory bulbs, pallial regions of cerebral hemispheres, preoptic area, habenula, hypothalamus, cerebellum and medulla oblongata. We also demonstrated by double staining NeuroD1/BrdU experiments, after long post-BrdU administration survival times, that NeuroD1 gene activity was turned on in new born neurons during post metamorphic neurogenesis. Importantly, we provided evidence that NeuroD1 expressing cells at this brain developmental stage were post-mitotic (PCNA-) cells and not radial glial (Vimentin+) or progenitors (Sox2+) cells. PMID- 23799109 TI - The evolution of strategic timing in collective-risk dilemmas. AB - In collective-risk dilemmas, a group needs to collaborate over time to avoid a catastrophic event. This gives rise to a coordination game with many equilibria, including equilibria where no one contributes, and thus no measures against the catastrophe are taken. In this game, the timing of contributions becomes a strategic variable that allows individuals to interact and influence one another. Herein, we use evolutionary game theory to study the impact of strategic timing on equilibrium selection. Depending on the risk of catastrophe, we identify three characteristic regimes. For low risks, defection is the only equilibrium, whereas high risks promote equilibria with sufficient contributions. Intermediate risks pose the biggest challenge for cooperation. In this risk regime, the option to interact over time is critical; if individuals can contribute over several rounds, then the group has a higher chance to succeed, and the expected welfare increases. This positive effect of timing is of particular importance in larger groups, where successful coordination becomes increasingly difficult. PMID- 23799110 TI - Overexpression of RBBP6, alone or combined with mutant TP53, is predictive of poor prognosis in colon cancer. AB - Retinoblastoma binding protein 6 (RBBP6) plays an important role in chaperone mediated ubiquitination and interacts with TP53 in carcinogenesis. However, the clinicopathologic significance of RBBP6 expression in colon cancer is unknown; in particular, the prognostic value of RBBP6 combined with TP53 expression has not been explored. Therefore, quantitative real-time PCR and western blot analyses were performed to detect RBBP6 expression in colon cancer tissues. RBBP6 and TP53 expression were assessed by immunohistochemistry in a tissue microarray format, in which the primary colon cancer tissue was paired with noncancerous tissue. Tissue specimens were obtained from 203 patients. We found that RBBP6 was overexpressed in colon tumorous tissues and was significantly associated with clinical stage, depth of tumor invasion, lymph node metastasis (LNM), distant metastasis, and histologic grade. Further studies revealed that a corresponding correlation between RBBP6 overexpression and mutant TP53 was evident in colon cancer (r = 0.450; P<0.001). RBBP6 expression was an independent prognostic factor for overall survival (OS) and disease free survival (DFS). Interestingly, patients with tumors that had both RBBP6 overexpression and mutant TP53 protein accumulation relapsed and died within a significantly short period after surgery (P<0.001). Multivariate analysis showed that patients with LNM and patients with both RBBP6- and TP53-positive tumors had extremely poor OS (HR 6.75; 95% CI 2.63 17.35; P<0.001) and DFS (HR 8.08; 95% CI 2.80-23.30; P<0.001). These clinical findings indicate that the assessment of both RBBP6 and mutant TP53 expression will be helpful in predicting colon cancer prognosis. PMID- 23799111 TI - Activity of lipase and chitinase immobilized on superparamagnetic particles in a rotational magnetic field. AB - We immobilize hydrolases such as lipase and chitinase on superparamagnetic particles, which are subjected to a rotational magnetic field, and measure the activities of the enzymes. We find that the activities of lipase and chitinase increase in the rotational magnetic field compared to those in the absence of a magnetic field and reach maximum at certain frequencies. The present methodology may well be utilized for the design and development of efficient micro reactors and micro total analysis systems (MU-TASs). PMID- 23799112 TI - Regulation of RNA-dependent RNA polymerase 1 and isochorismate synthase gene expression in Arabidopsis. AB - BACKGROUND: RNA-dependent RNA polymerases (RDRs) function in anti-viral silencing in Arabidopsis thaliana and other plants. Salicylic acid (SA), an important defensive signal, increases RDR1 gene expression, suggesting that RDR1 contributes to SA-induced virus resistance. In Nicotiana attenuata RDR1 also regulates plant-insect interactions and is induced by another important signal, jasmonic acid (JA). Despite its importance in defense RDR1 regulation has not been investigated in detail. METHODOLOGY/PRINCIPAL FINDINGS: In Arabidopsis, SA induced RDR1 expression was dependent on 'NON-EXPRESSER OF PATHOGENESIS-RELATED GENES 1', indicating regulation involves the same mechanism controlling many other SA- defense-related genes, including pathogenesis-related 1 (PR1). Isochorismate synthase 1 (ICS1) is required for SA biosynthesis. In defensive signal transduction RDR1 lies downstream of ICS1. However, supplying exogenous SA to ics1-mutant plants did not induce RDR1 or PR1 expression to the same extent as seen in wild type plants. Analysing ICS1 gene expression using transgenic plants expressing ICS1 promoter:reporter gene (beta-glucuronidase) constructs and by measuring steady-state ICS1 transcript levels showed that SA positively regulates ICS1. In contrast, ICS2, which is expressed at lower levels than ICS1, is unaffected by SA. The wound-response hormone JA affects expression of Arabidopsis RDR1 but jasmonate-induced expression is independent of CORONATINE-INSENSITIVE 1, which conditions expression of many other JA-responsive genes. Transiently increased RDR1 expression following tobacco mosaic virus inoculation was due to wounding and was not a direct effect of infection. RDR1 gene expression was induced by ethylene and by abscisic acid (an important regulator of drought resistance). However, rdr1-mutant plants showed normal responses to drought. CONCLUSIONS/SIGNIFICANCE: RDR1 is regulated by a much broader range of phytohormones than previously thought, indicating that it plays roles beyond those already suggested in virus resistance and plant-insect interactions. SA positively regulates ICS1. PMID- 23799113 TI - Norovirus binding to intestinal epithelial cells is independent of histo-blood group antigens. AB - Human noroviruses (NoVs) are a major cause of non-bacterial gastroenteritis. Although histo-blood group antigens (HBGAs) have been implicated in the initial binding of NoV, the mechanism of that binding before internalization is not clear. To determine the involvement of NoVs and HBGAs in cell binding, we examined the localization of NoV virus-like particles (VLPs) and HBGAs in a human intestinal cell line and the human ileum biopsy specimens by immunofluorescence microscopy. The localizations of Ueno 7k VLPs (genogroup II.6) and each HBGA (type H1-, H2- and Le(b)-HBGAs) on the human intestinal cell line, Caco-2, were examined by confocal laser-scanning microscopy. To explore any interactions of NoVs and HBGAs in vivo, fresh biopsy specimens from human ileum were directly incubated with NoV VLPs and examined by immunofluorescence microscopy. We found that VLP binding depended on the state of cell differentiation, but not on the presence of HBGAs. In differentiated Caco-2 cells, we detected no type H1 HBGAs, but VLPs bound to the cells anyway. We incubated fresh biopsies of human ileum directly with VLPs, a model that better replicates the in vivo environment. VLPs mainly bound epithelial cells and goblet cells. Although the incubations were performed at 4 degrees C to hinder internalization, VLPs were still detected inside cells. Our results suggest that VLPs utilize molecule(s) other than HBGAs during binding and internalization into cells. PMID- 23799114 TI - Evaluation of small intestine grafts decellularization methods for corneal tissue engineering. AB - Advances in the development of cornea substitutes by tissue engineering techniques have focused on the use of decellularized tissue scaffolds. In this work, we evaluated different chemical and physical decellularization methods on small intestine tissues to determine the most appropriate decellularization protocols for corneal applications. Our results revealed that the most efficient decellularization agents were the SDS and triton X-100 detergents, which were able to efficiently remove most cell nuclei and residual DNA. Histological and histochemical analyses revealed that collagen fibers were preserved upon decellularization with triton X-100, NaCl and sonication, whereas reticular fibers were properly preserved by decellularization with UV exposure. Extracellular matrix glycoproteins were preserved after decellularization with SDS, triton X-100 and sonication, whereas proteoglycans were not affected by any of the decellularization protocols. Tissue transparency was significantly higher than control non-decellularized tissues for all protocols, although the best light transmittance results were found in tissues decellularized with SDS and triton X-100. In conclusion, our results suggest that decellularized intestinal grafts could be used as biological scaffolds for cornea tissue engineering. Decellularization with triton X-100 was able to efficiently remove all cells from the tissues while preserving tissue structure and most fibrillar and non fibrillar extracellular matrix components, suggesting that this specific decellularization agent could be safely used for efficient decellularization of SI tissues for cornea TE applications. PMID- 23799115 TI - No association between low birth weight and cardiovascular risk factors in early adulthood: evidence from Sao Paulo, Brazil. AB - BACKGROUND: A growing literature suggests that low birth weight increases the risk of poor health outcomes in adulthood. We tested this hypothesis among young adults living in Sao Paulo State, Brazil. METHODS AND FINDINGS: To identify the effects of low birth weight on young adulthood outcomes, a medical assessment of 297 individuals born between 1977 and 1989 was conducted at a primary care unit in Sao Paulo State, Brazil. We analyzed body mass index (BMI), waist-hip ratio, blood pressure, fasting glucose and total cholesterol levels using linear and logistic regressions. Low birth was negatively associated with BMI (beta = -2.0, 95% CI: -3.69, -0.27, p = 0.02), fasting glucose levels (beta = -1.9, 95% CI: 3.9, -0.07, p = 0.05), waist-hip ratio (beta = -0.03, 95% CI: -0.07, -0.01, p = 0.10), systolic blood pressure (beta = -3.32, 95% CI: -7.60, 0.96, p = 0.12), and total cholesterol levels (beta = -3.19, 95% CI: -16.43, 10.05, p = 0.636). Low birth weight was also associated with lower odds of young adults being overweight and obese, but neither association was statistically significant. Weight gain in the first 12 months of life was associated with higher adult BMI (beta = 0.79, 95% CI: -0.0455, 1.623, p = 0.064) and blood pressure (beta = 2.79, 95% CI: 0.22, 5.35, p = 0.034). No associations were found between low birth weight and early life (catch-up) growth. CONCLUSIONS: Low birth weight was not associated with poor health outcomes among young adults in Brazil. These results appear inconsistent with the original Barker hypothesis, but will need to be corroborated in larger samples with longer follow-ups to allow a more general evaluation of the validity of the hypothesis in low and middle income countries. PMID- 23799116 TI - SNAI1-mediated epithelial-mesenchymal transition confers chemoresistance and cellular plasticity by regulating genes involved in cell death and stem cell maintenance. AB - Tumor cells at the tumor margin lose epithelial properties and acquire features of mesenchymal cells, a process called epithelial-to-mesenchymal transition (EMT). Recently, features of EMT were shown to be linked to cells with tumor founding capability, so-called cancer stem cells (CSCs). Inducers of the EMT include several transcription factors, such as Snail (SNAI1) and Slug (SNAI2), as well as the secreted transforming growth factor (TGFbeta). In the present study, we found that EMT induction in MCF10A cells by stably expressing SNAI1 contributed to drug resistance and acquisition of stem/progenitor-like character as shown by increased cell population for surface marker CD44(+)/CD24(-) and mammosphere forming capacity. Using a microarray approach, we demonstrate that SNAI1 overexpression results in a dramatic change in signaling pathways involved in the regulation of cell death and stem cell maintenance. We showed that NF kappaB/MAPK signaling pathways are highly activated in MCF10A-SNAI1 cells by IL1beta stimulation, leading to the robust induction in IL6 and IL8. Furthermore, MCF10A-SNAI1 cells showed enhanced TCF/beta-catenin activity responding to the exogenous Wnt3a treatment. However, EMT-induced stem/progenitor cell activation process is tightly regulated in non-transformed MCF10A cells, as WNT5A and TGFB2 are strongly upregulated in MCF10A-SNAI1 cells antagonizing canonical Wnt pathway. In summary, our data provide new molecular findings how EMT contributes to the enhanced chemoresistance and the acquisition of stem/progenitor-like character by regulating signaling pathways. PMID- 23799117 TI - A unified proteochemometric model for prediction of inhibition of cytochrome p450 isoforms. AB - A unified proteochemometric (PCM) model for the prediction of the ability of drug like chemicals to inhibit five major drug metabolizing CYP isoforms (i.e. CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) was created and made publicly available under the Bioclipse Decision Support open source system at www.cyp450model.org. In regards to the proteochemometric modeling we represented the chemical compounds by molecular signature descriptors and the CYP-isoforms by alignment-independent description of composition and transition of amino acid properties of their protein primary sequences. The entire training dataset contained 63 391 interactions and the best PCM model was obtained using signature descriptors of height 1, 2 and 3 and inducing the model with a support vector machine. The model showed excellent predictive ability with internal AUC = 0.923 and an external AUC = 0.940, as evaluated on a large external dataset. The advantage of PCM models is their extensibility making it possible to extend our model for new CYP isoforms and polymorphic CYP forms. A key benefit of PCM is that all proteins are confined in one single model, which makes it generally more stable and predictive as compared with single target models. The inclusion of the model in Bioclipse Decision Support makes it possible to make virtual instantaneous predictions (~100 ms per prediction) while interactively drawing or modifying chemical structures in the Bioclipse chemical structure editor. PMID- 23799118 TI - Desflurane preconditioning induces oscillation of NF-kappaB in human umbilical vein endothelial cells. AB - BACKGROUND: Nuclear factor kappa B (NF-kappaB) has been implicated in anesthetic preconditioning (APC) induced protection against anoxia and reoxygenation (A/R) injury. The authors hypothesized that desflurane preconditioning would induce NF kappaB oscillation and prevent endothelial cells apoptosis. METHODS: A human umbilical vein endothelial cells (HUVECs) A/R injury model was used. A 30 minute desflurane treatment was initiated before anoxia. NF-kappaB inhibitor BAY11-7082 was administered in some experiments before desflurane preconditioning. Cells apoptosis was analyzed by flow cytometry using annexin V-fluorescein isothiocyanate staining and cell viability was evaluated by modified tertrozalium salt (MTT) assay. The cellular superoxide dismutases (SOD) activitiy were tested by water-soluble tetrazolium salt (WST-1) assay. NF-kappaB p65 subunit nuclear translocation was detected by immunofluorescence staining. Expression of inhibitor of NF-kappaB-alpha (IkappaBalpha), NF-kappaB p65 and cellular inhibitor of apoptosis 1 (c-IAP1), B-cell leukemia/lymphoma 2 (Bcl-2), cysteine containing aspartate specific protease 3 (caspases-3) and second mitochondrial-derived activator of caspase (SMAC/DIABLO) were determined by western blot. RESULTS: Desflurane preconditioning caused phosphorylation and nuclear translocation of NF kappaB before anoxia, on the contrary, induced the synthesis of IkappaBalpha and inhibition of NF-kappaB after reoxygenation. Desflurane preconditioning up regulated the expression of c-IAP1 and Bcl-2, blocked the cleavage of caspase-3 and reduced SMAC release, and decreased the cell death of HUVECs after A/R. The protective effect was abolished by BAY11-7082 administered before desflurane. CONCLUSIONS: The results demonstrated that desflurane activated NF-kappaB during the preconditioning period and inhibited excessive activation of NF-kappaB in reperfusion. And the oscillation of NF-kappaB induced by desflurane preconditioning finally up-regulated antiapoptotic proteins expression and protected endothelial cells against A/R. PMID- 23799119 TI - Scrub typhus meningitis in South India--a retrospective study. AB - BACKGROUND: Scrub typhus is prevalent in India although definite statistics are not available. There has been only one study on scrub typhus meningitis 20 years ago. Most reports of meningitis/meningoencephalitis in scrub typhus are case reports. METHODS: A retrospective study done in Pondicherry to extract cases of scrub typhus admitted to hospital between February 2011 and January 2012. Diagnosis was by a combination of any one of the following in a patient with an acute febrile illness--a positive scrub IgM ELISA, Weil-Felix test, and an eschar. Lumbar puncture was performed in patients with headache, nuchal rigidity, altered sensorium or cranial nerve deficits. RESULTS: Sixty five cases of scrub typhus were found, and 17 (17/65) had meningitis. There were 33 males and 32 females. Thirteen had an eschar. Median cerebrospinal fluid (CSF) cell count, lymphocyte percentage, CSF protein, CSF glucose/blood glucose, CSF ADA were 54 cells/uL, 98%, 88 mg/dL, 0.622 and 3.5 U/mL respectively. Computed tomography was normal in patients with altered sensorium and cranial nerve deficits. Patients with meningitis had lesser respiratory symptoms and signs and higher urea levels. All patients had received doxycycline except one who additionally received chloramphenicol. CONCLUSION: Meningitis in scrub typhus is mild with quick and complete recovery. Clinical features and CSF findings can mimic tuberculous meningitis, except for ADA levels. In the Indian context where both scrub typhus and tuberculosis are endemic, ADA and scrub IgM may be helpful in identifying patients with scrub meningitis and in avoiding prolonged empirical antituberculous therapy in cases of lymphocytic meningitis. PMID- 23799120 TI - Response to rhinovirus infection by human airway epithelial cells and peripheral blood mononuclear cells in an in vitro two-chamber tissue culture system. AB - Human rhinovirus (HRV) infections are associated with the common cold, occasionally with more serious lower respiratory tract illnesses, and frequently with asthma exacerbations. The clinical features of HRV infection and its association with asthma exacerbation suggest that some HRV disease results from virus-induced host immune responses to infection. To study the HRV-infection induced host responses and the contribution of these responses to disease, we have developed an in vitro model of HRV infection of human airway epithelial cells (Calu-3 cells) and subsequent exposure of human peripheral blood mononuclear cells (PBMCs) to these infected cells in a two-chamber trans-well tissue culture system. Using this model, we studied HRV 14 (species B) and HRV 16 (species A) induced cytokine and chemokine responses with PBMCs from four healthy adults. Infection of Calu-3 cells with either virus induced HRV-associated increases in FGF-Basic, IL-15, IL-6, IL-28A, ENA-78 and IP-10. The addition of PBMCs to HRV 14-infected cells gave significant increases in MIP-1beta, IL-28A, MCP-2, and IFN-alpha as compared with mock-infected cells. Interestingly, ENA-78 levels were reduced in HRV 14 infected cells that were exposed to PBMCs. Addition of PBMCs to HRV 16-infected cells did not induce MIP-1beta, IL-28A and IFN-alpha efficiently nor did it decrease ENA-78 levels. Our results demonstrate a clear difference between HRV 14 and HRV 16 and the source of PBMCs, in up or down regulation of several cytokines including those that are linked to airway inflammation. Such differences might be one of the reasons for variation in disease associated with different HRV species including variation in their link to asthma exacerbations as suggested by other studies. Further study of immune responses associated with different HRVs and PBMCs from different patient groups, and the mechanisms leading to these differences, should help characterize pathogenesis of HRV disease and generate novel approaches to its treatment. PMID- 23799121 TI - Development of a spontaneous liver disease resembling autoimmune hepatitis in mice lacking tyro3, axl and mer receptor tyrosine kinases. AB - Autoimmune hepatitis (AIH) is a severe type of chronic liver disease. The lack of appropriate animal models has resulted in a limited understanding regarding the etiology of AIH. Here, we demonstrated that mice deficient in Tyro3, Axl and Mer (TAM) receptor tyrosine kinases (RTKs) developed persistent inflammatory liver damage resembling AIH. Tyro3(-/-)Axl(-/-)Mer(-/-) triple mutant (TAM(-/-)) mice exhibited chronic hepatitis, manifested by progressive appearance of interface hepatitis, immune cell infiltrations and elevated inflammatory cytokine levels in the liver. Accordingly, increased levels of transaminases were observed. Moreover, characteristic autoantibodies and high levels of plasma immunoglobulin G for AIH were detected as TAM(-/-) mice aged. Finally, we provided evidence that the liver damage in TAM(-/-) mice mainly result from bone marrow-derived cells and could be rescued by transplantation of WT bone marrow cells. Results suggest that TAM RTKs play an important role in maintaining immune tolerance of the liver. PMID- 23799122 TI - Circulating lipocalin-2 and retinol-binding protein 4 are associated with intima media thickness and subclinical atherosclerosis in patients with type 2 diabetes. AB - BACKGROUND: The lipocalin family proteins, including lipocalin-2 and retinol binding protein 4 (RBP4), are adipokines closely associated with obesity-related metabolic disorders. In this study, we evaluated the association of serum lipocalin-2 and RBP4 with intima-media thickness (IMT) and subclinical atherosclerosis in type 2 diabetic patients. METHODS AND RESULTS: Serum levels of lipocalin-2 and RBP4 were measured in 284 type 2 diabetic patients. Subclinical atherosclerosis was assessed by IMT at carotid, femoral and iliac arteries with ultrasound. Patients with subclinical atherosclerosis showed significantly higher circulating concentrations of lipocalin-2 and RBP4 when compared to those without [112.9 (86.4 to 202.1) ug/L versus 77.2(55.0-150.4) ug/L, 37.1(32.3-40.8) mg/L versus 23.2(20.1-29.2) mg/L, respectively; P = 0.002, P<0.001, respectively]. Moreover, positive correlations were observed between carotid IMT and lipocalin-2 (r = 0.170, P = 0.018) or RBP4 (r = 0.132, P = 0.040), femoral IMT and lipocalin 2 (r = 0.160, P = 0.027), as well as between iliac IMT and RBP4 (r = 0.241, P<0.001). Multiple logistic regression analysis further demonstrated that these two adipokines were independent risk factors for subclinical atherosclerosis in type 2 diabetes. CONCLUSION: Circulating levels of lipocalin-2 and RBP4 are positively correlated with carotid IMT and subclinical atherosclerosis in type 2 diabetes, which suggests a potential role of these two lipid-binding chaperones in the pathogenesis of vascular complications of diabetes. PMID- 23799123 TI - Sub-diffraction nano manipulation using STED AFM. AB - In the last two decades, nano manipulation has been recognized as a potential tool of scientific interest especially in nanotechnology and nano-robotics. Contemporary optical microscopy (super resolution) techniques have also reached the nanometer scale resolution to visualize this and hence a combination of super resolution aided nano manipulation ineluctably gives a new perspective to the scenario. Here we demonstrate how specificity and rapid determination of structures provided by stimulated emission depletion (STED) microscope can aid another microscopic tool with capability of mechanical manoeuvring, like an atomic force microscope (AFM) to get topological information or to target nano scaled materials. We also give proof of principle on how high-resolution real time visualization can improve nano manipulation capability within a dense sample, and how STED-AFM is an optimal combination for this job. With these evidences, this article points to future precise nano dissections and maybe even to a nano-snooker game with an AFM tip and fluorospheres. PMID- 23799124 TI - One-step transepithelial topography-guided ablation in the treatment of myopic astigmatism. AB - PURPOSE: To evaluate one-step topography-guided transepithelial ablation in the treatment of low to moderate myopic astigmatism using a 1KHz excimer laser. METHODS: Retrospective study of 117 consecutive eyes available for evaluation 12 months after surgery. Pre- and post-operative visual and refractive data as well as post-operative pain and haze were analyzed. A novel technique integrating custom refractive- and epithelial- ablation in a single uninterrupted procedure was used. RESULTS: The mean pre-operative spherical equivalent (SE) and the mean cylinder were: -3.22 diopters (D) +/-1.54 (SD) (range -0.63 to -7.25 D) and -0.77 D +/-0.65 (range 0 to -4.50 D), respectively. At 12 months after surgery: no eyes lost >=2 lines of corrected distant visual acuity (CDVA). Safety and efficacy indexes were 1.27 and 1.09, respectively. Uncorrected distant visual acuity (UDVA) was >=20/20 in 96.6% of the eyes. Manifest refraction spherical equivalent was within +/-0.5 D of the desired refraction in 93.2% of the eyes. Average root mean square (RMS) wavefront error measured at central 6 mm, increased from 0.38 pre-operatively to 0.47 um post-operatively. Refractive stability was achieved and sustained 1 month after surgery. No visually significant haze was registered during the observation period. Post-operative pain was reported in 4.5% of patients. CONCLUSIONS: One-step transepithelial topography-guided treatment for low to moderate myopia and astigmatism performed with a 1 KHz laser, provided safe, effective, predictable and stable results with low pain and no visually significant haze. PMID- 23799125 TI - Expressed prostate secretions in the study of human papillomavirus epidemiology in the male. AB - INTRODUCTION: Exploring different sampling sites and methods is of interest for studies of the epidemiology of HPV infections in the male. Expressed prostate secretions (EPS) are obtained during digital rectal examination (DRE), a daily routine urological diagnostic procedure, following massage of the prostate. MATERIALS AND METHODS: Urethral swabs and EPS samples were obtained from a consecutive sample of 752 men (mean age 32.4 years; median life-time sex partners 34) visiting urology outpatient clinics in St. Petersburg, Russia and tested for HPV DNA by general primer PCR, followed by genotyping using Luminex. RESULTS: Overall, 47.9% (360/752) of men were HPV-positive, with 42.0% (316/752) being positive for high-risk (HR-) HPV and 12.6% (95/752) for multiple HPV types. HPV positivity in the EPS samples was 32.6% (27.7% HR-HPV) and in the urethral samples 25.9% (24.5% HR-HPV). 10.6% were HPV positive in both EPS and urethral samples. 6.4% had the same HPV-type in both EPS and urethral samples. 10.6% were HPV positive in both EPS and urethral samples. 6.4% had the same HPV-type in both EPS and urethral samples. The concordance between the urethral samples and EPS was 62.5% (470/752), with 80 cases double positive and 390 cases double negative in both sites. The sensitivity of urethral samples for overall HPV detection was 54.2% (195/360). Compared to analysis of urethral samples only, the analysis of EPS increased the HPV prevalence in this population with 26.2%. CONCLUSION: EPS represent informative sampling material for the study of HPV epidemiology in the male. PMID- 23799126 TI - A filtering method to generate high quality short reads using illumina paired-end technology. AB - Consensus between independent reads improves the accuracy of genome and transcriptome analyses, however lack of consensus between very similar sequences in metagenomic studies can and often does represent natural variation of biological significance. The common use of machine-assigned quality scores on next generation platforms does not necessarily correlate with accuracy. Here, we describe using the overlap of paired-end, short sequence reads to identify error prone reads in marker gene analyses and their contribution to spurious OTUs following clustering analysis using QIIME. Our approach can also reduce error in shotgun sequencing data generated from libraries with small, tightly constrained insert sizes. The open-source implementation of this algorithm in Python programming language with user instructions can be obtained from https://github.com/meren/illumina-utils. PMID- 23799127 TI - Evaluation of common methods for sampling invertebrate pollinator assemblages: net sampling out-perform pan traps. AB - Methods for sampling ecological assemblages strive to be efficient, repeatable, and representative. Unknowingly, common methods may be limited in terms of revealing species function and so of less value for comparative studies. The global decline in pollination services has stimulated surveys of flower-visiting invertebrates, using pan traps and net sampling. We explore the relative merits of these two methods in terms of species discovery, quantifying abundance, function, and composition, and responses of species to changing floral resources. Using a spatially-nested design we sampled across a 5000 km(2) area of arid grasslands, including 432 hours of net sampling and 1296 pan trap-days, between June 2010 and July 2011. Net sampling yielded 22% more species and 30% higher abundance than pan traps, and better reflected the spatio-temporal variation of floral resources. Species composition differed significantly between methods; from 436 total species, 25% were sampled by both methods, 50% only by nets, and the remaining 25% only by pans. Apart from being less comprehensive, if pan traps do not sample flower-visitors, the link to pollination is questionable. By contrast, net sampling functionally linked species to pollination through behavioural observations of flower-visitation interaction frequency. Netted specimens are also necessary for evidence of pollen transport. Benefits of net based sampling outweighed minor differences in overall sampling effort. As pan traps and net sampling methods are not equivalent for sampling invertebrate flower interactions, we recommend net sampling of invertebrate pollinator assemblages, especially if datasets are intended to document declines in pollination and guide measures to retain this important ecosystem service. PMID- 23799128 TI - Different immunity elicited by recombinant H5N1 hemagglutinin proteins containing pauci-mannose, high-mannose, or complex type N-glycans. AB - Highly pathogenic avian influenza H5N1 viruses can result in poultry and occasionally in human mortality. A safe and effective H5N1 vaccine is urgently needed to reduce the pandemic potential. Hemagglutinin (HA), a major envelope protein accounting for approximately 80% of spikes in influenza virus, is often used as a major antigen for subunit vaccine development. In this study, we conducted a systematic study of the immune response against influenza virus infection following immunization with recombinant HA proteins expressed in insect (Sf9) cells, insect cells that contain exogenous genes for elaborating N-linked glycans (Mimic) and mammalian cells (CHO). While the antibody titers are higher with the insect cell derived HA proteins, the neutralization and HA inhibition titers are much higher with the mammalian cell produced HA proteins. Recombinant HA proteins containing tri- or tetra-antennary complex, terminally sialylated and asialyated-galactose type N-glycans induced better protective immunity in mice to lethal challenge. The results are highly relevant to issues that should be considered in the production of fragment vaccines. PMID- 23799129 TI - A bio-inspired methodology of identifying influential nodes in complex networks. AB - How to identify influential nodes is a key issue in complex networks. The degree centrality is simple, but is incapable to reflect the global characteristics of networks. Betweenness centrality and closeness centrality do not consider the location of nodes in the networks, and semi-local centrality, leaderRank and pageRank approaches can be only applied in unweighted networks. In this paper, a bio-inspired centrality measure model is proposed, which combines the Physarum centrality with the K-shell index obtained by K-shell decomposition analysis, to identify influential nodes in weighted networks. Then, we use the Susceptible Infected (SI) model to evaluate the performance. Examples and applications are given to demonstrate the adaptivity and efficiency of the proposed method. In addition, the results are compared with existing methods. PMID- 23799130 TI - Expression of ST3GAL4 leads to SLe(x) expression and induces c-Met activation and an invasive phenotype in gastric carcinoma cells. AB - Sialyl-Lewis X (SLe(x)) is a sialylated glycan antigen expressed on the cell surface during malignant cell transformation and is associated with cancer progression and poor prognosis. The increased expression of sialylated glycans is associated with alterations in the expression of sialyltransferases (STs). In this study we determined the capacity of ST3GAL3 and ST3GAL4 sialyltransferases to synthesize the SLe(x) antigen in MKN45 gastric carcinoma cells and evaluated the effect of SLe(x) overexpression in cancer cell behavior both in vitro and in vivo using the chicken chorioallantoic membrane (CAM) model. The activation of tyrosine kinase receptors and their downstream molecular targets was also addressed. Our results showed that the expression of ST3GAL4 in MKN45 gastric cancer cells leads to the synthesis of SLe(x) antigens and to an increased invasive phenotype both in vitro and in the in vivo CAM model. Analysis of phosphorylation of tyrosine kinase receptors showed a specific increase in c-Met activation. The characterization of downstream molecular targets of c-Met activation, involved in the invasive phenotype, revealed increased phosphorylation of FAK and Src proteins and activation of Cdc42, Rac1 and RhoA GTPases. Inhibition of c-Met and Src activation abolished the observed increased cell invasive phenotype. In conclusion, the expression of ST3GAL4 leads to SLe(x) antigen expression in gastric cancer cells which in turn induces an increased invasive phenotype through the activation of c-Met, in association with Src, FAK and Cdc42, Rac1 and RhoA GTPases activation. PMID- 23799131 TI - Intraventricular injection of human dental pulp stem cells improves hypoxic ischemic brain damage in neonatal rats. AB - OBJECTIVE: To investigate the effect of intraventricular injection of human dental pulp stem cells (DPSCs) on hypoxic-ischemic brain damage (HIBD) in neonatal rats. METHODS: Thirty-six neonatal rats (postnatal day 7) were assigned to control, HIBD, or HIBD+DPSC groups (n = 12 each group). For induction of HIBD, rats underwent left carotid artery ligation and were exposed to 8% to 10% oxygen for 2 h. Hoechst 33324-labeled human DPSCs were injected into the left lateral ventricle 3 days after HIBD. Behavioral assays were performed to assess hypoxic ischemic encephalopathy (HIE), and on postnatal day 45, DPSC survival was assessed and expression of neural and glial markers was evaluated by immunohistochemistry and Western blot. RESULTS: The HIBD group showed significant deficiencies compared to control on T-maze, radial water maze, and postural reflex tests, and the HIBD+DPSC group showed significant improvement on all behavioral tests. On postnatal day 45, Hoechst 33324-labeled DPSC nuclei were visible in the injected region and left cortex. Subsets of DPSCs showed immunostaining for neuronal (neuron-specific enolase [NSE], Nestin) and glial markers (glial fibrillary acidic protein [GFAP], O4). Significantly decreased staining/expression for NSE, GFAP, and O4 was found in the HBID group compared to control, and this was significantly increased in the HBID+DPSC group. CONCLUSION: Intraventricular injection of human DPSCs improves HIBD in neonatal rats. PMID- 23799132 TI - Isolation and characterization of a primary proximal tubular epithelial cell model from human kidney by CD10/CD13 double labeling. AB - Renal proximal tubular epithelial cells play a central role in renal physiology and are among the cell types most sensitive to ischemia and xenobiotic nephrotoxicity. In order to investigate the molecular and cellular mechanisms underlying the pathophysiology of kidney injuries, a stable and well characterized primary culture model of proximal tubular cells is required. An existing model of proximal tubular cells is hampered by the cellular heterogeneity of kidney; a method based on cell sorting for specific markers must therefore be developed. In this study, we present a primary culture model based on the mechanical and enzymatic dissociation of healthy tissue obtained from nephrectomy specimens. Renal epithelial cells were sorted using co-labeling for CD10 and CD13, two renal proximal tubular epithelial markers, by flow cytometry. Their purity, phenotypic stability and functional properties were evaluated over several passages. Our results demonstrate that CD10/CD13 double-positive cells constitute a pure, functional and stable proximal tubular epithelial cell population that displays proximal tubule markers and epithelial characteristics over the long term, whereas cells positive for either CD10 or CD13 alone appear to be heterogeneous. In conclusion, this study describes a method for establishing a robust renal proximal tubular epithelial cell model suitable for further experimentation. PMID- 23799133 TI - A comparative analysis of transcription factor expression during metazoan embryonic development. AB - During embryonic development, a complex organism is formed from a single starting cell. These processes of growth and differentiation are driven by large transcriptional changes, which are following the expression and activity of transcription factors (TFs). This study sought to compare TF expression during embryonic development in a diverse group of metazoan animals: representatives of vertebrates (Danio rerio, Xenopus tropicalis), a chordate (Ciona intestinalis) and invertebrate phyla such as insects (Drosophila melanogaster, Anopheles gambiae) and nematodes (Caenorhabditis elegans) were sampled, The different species showed overall very similar TF expression patterns, with TF expression increasing during the initial stages of development. C2H2 zinc finger TFs were over-represented and Homeobox TFs were under-represented in the early stages in all species. We further clustered TFs for each species based on their quantitative temporal expression profiles. This showed very similar TF expression trends in development in vertebrate and insect species. However, analysis of the expression of orthologous pairs between more closely related species showed that expression of most individual TFs is not conserved, following the general model of duplication and diversification. The degree of similarity between TF expression between Xenopus tropicalis and Danio rerio followed the hourglass model, with the greatest similarity occuring during the early tailbud stage in Xenopus tropicalis and the late segmentation stage in Danio rerio. However, for Drosophila melanogaster and Anopheles gambiae there were two periods of high TF transcriptome similarity, one during the Arthropod phylotypic stage at 8-10 hours into Drosophila development and the other later at 16-18 hours into Drosophila development. PMID- 23799134 TI - Oral and craniofacial manifestations and two novel missense mutations of the NTRK1 gene identified in the patient with congenital insensitivity to pain with anhidrosis. AB - Congenital insensitivity to pain with anhidrosis (CIPA) is a rare inherited disorder of the peripheral nervous system resulting from mutations in neurotrophic tyrosine kinase receptor 1 gene (NTRK1), which encodes the high affinity nerve growth factor receptor TRKA. Here, we investigated the oral and craniofacial manifestations of a Chinese patient affected by autosomal-recessive CIPA and identified compound heterozygosity in the NTRK1 gene. The affected boy has multisystemic disorder with lack of reaction to pain stimuli accompanied by self-mutilation behavior, the inability to sweat leading to defective thermoregulation, and mental retardation. Oral and craniofacial manifestations included a large number of missing teeth, nasal malformation, submucous cleft palate, severe soft tissue injuries, dental caries and malocclusion. Histopathological evaluation of the skin sample revealed severe peripheral nerve fiber loss as well as mild loss and absent innervation of sweat glands. Ultrastructural and morphometric studies of a shed tooth revealed dental abnormalities, including hypomineralization, dentin hypoplasia, cementogenesis defects and a dysplastic periodontal ligament. Genetic analysis revealed a compound heterozygosity--c.1561T>C and c.2057G>A in the NTRK1 gene. This report extends the spectrum of NTRK1 mutations observed in patients diagnosed with CIPA and provides additional insight for clinical and molecular diagnosis. PMID- 23799136 TI - Diagnosed mild cognitive impairment due to Alzheimer's disease with PET biomarkers of beta amyloid and neuronal dysfunction. AB - The aim of this study is to identify mild cognitive impairment (MCI) due to Alzheimer's disease (AD) using amyloid imaging of beta amyloid (Abeta) deposition and FDG imaging of reflecting neuronal dysfunction as PET biomarkers. Sixty-eight MCI patients underwent cognitive testing, [11C]-PIB PET and [18F]-FDG PET at baseline and follow-up. Regions of interest were defined on co-registered MRI. PIB distribution volume ratio (DVR) was calculated using Logan graphical analysis, and the standardized uptake value ratio (SUVR) on the same regions was used as quantitative analysis for [18F]-FDG. Thirty (44.1%) of all 68 MCI patients converted to AD over 19.2+/-7.1 months. The annual rate of MCI conversion was 23.4%. A positive Abeta PET biomarker significantly identified MCI due to AD in individual MCI subjects with a sensitivity (SS) of 96.6% and specificity (SP) of 42.1%. The positive predictive value (PPV) was 56.8%. A positive Abeta biomarker in APOE epsilon4/4 carriers distinguished with a SS of 100%. In individual MCI subjects who had a prominent impairment in episodic memory and aged older than 75 years, an Abeta biomarker identified MCI due to AD with a greater SS of 100%, SP of 66.6% and PPV of 80%, compared to FDG biomarker alone or both PET biomarkers combined. In contrast, when assessed in precuneus, both Abeta and FDG biomarkers had the greatest level of certainty for MCI due to AD with a PPV of 87.8%. The Abeta PET biomarker primarily defines MCI due to AD in individual MCI subjects. Furthermore, combined FDG biomarker in a cortical region of precuneus provides an added diagnostic value in predicting AD over a short period. PMID- 23799135 TI - An enhanced heterologous virus-like particle for human papillomavirus type 16 tumour immunotherapy. AB - Cervical cancer is caused by high-risk, cancer-causing human papillomaviruses (HPV) and is the second highest cause of cancer deaths in women globally. The majority of cervical cancers express well-characterized HPV oncogenes, which are potential targets for immunotherapeutic vaccination. Here we develop a rabbit haemorrhagic disease virus (RHDV) virus-like particle (VLP)-based vaccine designed for immunotherapy against HPV16 positive tumours. An RHDV-VLP, modified to contain the universal helper T cell epitope PADRE and decorated with an MHC I restricted peptide (aa 48-57) from the HPV16 E6, was tested for its immunotherapeutic efficacy against the TC-1 HPV16 E6 and E7-expressing tumour in mice. The E6-RHDV-VLP-PADRE was administered therapeutically for the treatment of a pre-existing TC-1 tumour and was delivered with antibodies either to deplete regulatory T cells (anti-CD25) or to block T cell suppression mediated through CTLA-4. As a result, the tumour burden was reduced by around 50% and the median survival time of mice to the humane endpoint was almost doubled the compared to controls. The incorporation of PADRE into the RHDV-VLP was necessary for an E6 specific enhancement of the anti-tumour response and the co-administration of the immune modifying antibodies contributed to the overall efficacy of the immunotherapy. The E6-RHDV-VLP-PADRE shows immunotherapeutic efficacy, prolonging survival for HPV tumour-bearing mice. This was enhanced by the systemic administration of immune-modifying antibodies that are commercially available for use in humans. There is potential to further modify these particles for even greater efficacy in the path to development of an immunotherapeutic treatment for HPV precancerous and cancer stages. PMID- 23799137 TI - Are bogs reservoirs for emerging disease vectors? Evaluation of culicoides populations in the Hautes Fagnes Nature Reserve (Belgium). AB - Several species of Culicoides (Diptera: Ceratopogonidae) biting midges serve as biological vectors for the bluetongue virus (BTV) and the recently described Schmallenberg virus (SBV) in northern Europe. Since their recent emergence in this part of the continent, these diseases have caused considerable economic losses to the sheep and cattle industries. Much data is now available that describe the distribution, population dynamics, and feeding habits of these insects. However, little is known regarding the presence of Culicoides in unusual habitats such as peaty marshes, nor their potential vector capacity. This study evaluated Culicoides biting midges present in the bogs of a Belgian nature reserve compared to those residing at a nearby cattle farm. Culicoides were trapped in 2011 at four different sites (broadleaved and coniferous forested areas, open environments, and at a scientific station) located in the Hautes Fagnes Nature Reserve (Belgium). An additional light trap was operated on a nearby cattle farm. Very high numbers of biting midges were captured in the marshy area and most of them (70 to 95%) were Culicoides impunctatus, a potential vector of BTV and other pathogens. In addition, fewer numbers of C. obsoletus/C. scoticus species, C. chiopterus, and C. dewulfi were observed in the bogs compared to the farm. The wet environment and oligotrophic nature of the soil were probably responsible for these changes in the respective populations. A total of 297,808 Culicoides midges belonging to 27 species were identified during this study and 3 of these species (C. sphagnumensis, C. clintoni and C. comosioculatus) were described in Belgium for the first time. PMID- 23799138 TI - Holocephalan embryo provides new information on the evolution of the glossopharyngeal nerve, metotic fissure and parachordal plate in gnathostomes. AB - The phylogenetic relationships between the different groups of Paleozoic gnathostomes are still debated, mainly because of incomplete datasets on Paleozoic jawed vertebrate fossils and ontogeny of some modern taxa. This issue is illustrated by the condition of the glossopharyngeal nerve relative to the parachordal plate, the otic capsules and the metotic fissure in gnathostomes. Two main conditions are observed in elasmobranchs (shark and rays) and osteichthyans (bony fishes and tetrapods). The condition in the other chondrichthyan taxon, the holocephalans, is still poorly known, and without any information on this taxon, it remains difficult to polarize the condition in gnathostomes. Based on the anatomical study of an embryo of the holocephalan Callorhinchus milii by means of propagation X-Ray Synchrotron phase contrast microtomography using both holotomography and single distance phase retrieval process, we show that, contrary to what was previously inferred for holocephalans (i.e. an osteichthyan like condition), the arrangement of the glossopharyngeal nerve relative to the surrounding structure in holocephalans is more similar to that of elasmobranchs. Furthermore, the holocephalan condition represents a combination of plesiomorphic characters for gnathostomes (e.g., the glossopharyngeal nerve leaves the braincase via the metotic fissure) and homoplastic characters. By contrast, the crown osteichthyans are probably derived in having the glossopharyngeal nerve that enters the saccular chamber and in having the glossopharyngeal foramen separated from the metotic fissure. PMID- 23799139 TI - Widespread occurrence of chemical residues in beehive matrices from apiaries located in different landscapes of Western France. AB - BACKGROUND: The honey bee, Apis mellifera, is frequently used as a sentinel to monitor environmental pollution. In parallel, general weakening and unprecedented colony losses have been reported in Europe and the USA, and many factors are suspected to play a central role in these problems, including infection by pathogens, nutritional stress and pesticide poisoning. Honey bee, honey and pollen samples collected from eighteen apiaries of western France from four different landscape contexts during four different periods in 2008 and in 2009 were analyzed to evaluate the presence of pesticides and veterinary drug residues. METHODOLOGY/FINDINGS: A multi-residue analysis of 80 compounds was performed using a modified QuEChERS method, followed by GC-ToF and LC-MS/MS. The analysis revealed that 95.7%, 72.3% and 58.6% of the honey, honey bee and pollen samples, respectively, were contaminated by at least one compound. The frequency of detection was higher in the honey samples (n = 28) than in the pollen (n = 23) or honey bee (n = 20) samples, but the highest concentrations were found in pollen. Although most compounds were rarely found, some of the contaminants reached high concentrations that might lead to adverse effects on bee health. The three most frequent residues were the widely used fungicide carbendazim and two acaricides, amitraz and coumaphos, that are used by beekeepers to control Varroa destructor. Apiaries in rural-cultivated landscapes were more contaminated than those in other landscape contexts, but the differences were not significant. The contamination of the different matrices was shown to be higher in early spring than in all other periods. CONCLUSIONS/SIGNIFICANCE: Honey bees, honeys and pollens are appropriate sentinels for monitoring pesticide and veterinary drug environmental pollution. This study revealed the widespread occurrence of multiple residues in beehive matrices and suggests a potential issue with the effects of these residues alone or in combination on honey bee health. PMID- 23799140 TI - VEGFR1 and VEGFR2 involvement in extracellular galectin-1- and galectin-3-induced angiogenesis. AB - AIM: Accumulating evidence suggests that extracellular galectin-1 and galectin-3 promote angiogenesis. Increased expression of galectin-1 and/or galectin-3 has been reported to be associated with tumour progression. Thus, it is critical to identify their influence on angiogenesis. METHODS: We examined the individual and combined effects of galectin-1 and galectin-3 on endothelial cell (EC) growth and tube formation using two EC lines, EA.hy926 and HUVEC. The activation of vascular endothelial growth factor receptors (VEGFR1 and VEGFR2) was determined by ELISA and Western blots. We evaluated the VEGFR1 and VEGFR2 levels in endosomes by proximity ligation assay. RESULTS: We observed different responses to exogenous galectins depending on the EC line. An enhanced effect on EA.hy926 cell growth and tube formation was observed when both galectins were added together. Focusing on this enhanced effect, we observed that together galectins induced the phosphorylation of both VEGFR1 and VEGFR2, whereas galectin-1 and -3 alone induced VEGFR2 phosphorylation only. In the same way, the addition of a blocking VEGFR1 antibody completely abolished the increase in tube formation induced by the combined addition of both galectins. In contrast, the addition of a blocking VEGFR2 antibody only partially inhibited this effect. Finally, the addition of both galectins induced a decrease in the VEGFR1 and VEGFR2 endocytic pools, with a significantly enhanced effect on the VEGFR1 endocytic pool. These results suggest that the combined action of galectin-1 and galectin-3 has an enhanced effect on angiogenesis via VEGFR1 activation, which could be related to a decrease in receptor endocytosis. PMID- 23799141 TI - Is the oxidant/antioxidant status altered in CADASIL patients? AB - The altered aggregation of proteins in non-native conformation is associated with endoplasmic reticulum derangements, mitochondrial dysfunction and excessive production of reactive oxygen species. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary systemic vasculopathy, caused by NOTCH3 mutations within the receptor extracellular domain, that lead to abnormal accumulation of the mutated protein in the vascular wall. NOTCH3 misfolding could cause free radicals increase also in CADASIL. Aim of the study was to verify whether CADASIL patients have increased oxidative stress compared to unrelated healthy controls. We enrolled 15 CADASIL patients and 16 gender- and age-matched healthy controls with comparable cardiovascular risk factor. Blood and plasma reduced and total aminothiols (homocysteine, cysteine, glutathione, cysteinylglycine) were measured by HPLC and plasma 3-nitrotyrosine by ELISA. Only plasma reduced cysteine (Pr-Cys) and blood reduced glutathione (Br-GSH) concentrations differed between groups: in CADASIL patients Br-GSH levels were higher (p = 0.019) and Pr-Cys lower (p = 0.010) than in controls. No correlation was found between Br-GSH and Pr-Cys either in CADASIL patients (rho 0.25, P = 0.36) or in controls (rho -0.15, P = 0.44). Conversely, 3 nitrotyrosine values were similar in CADASIL and healthy subjects (p = 0.82). The high levels of antioxidant molecules and low levels of oxidant mediators found in our CADASIL population might either be expression of an effective protective action against free radical formation at an early stage of clinical symptoms or they could suggest that oxidative stress is not directly involved in the pathogenesis of CADASIL. PMID- 23799142 TI - Release of proteins from intact chloroplasts induced by reactive oxygen species during biotic and abiotic stress. AB - Plastids sustain life on this planet by providing food, feed, essential biomolecules and oxygen. Such diverse metabolic and biosynthetic functions require efficient communication between plastids and the nucleus. However, specific factors, especially large molecules, released from plastids that regulate nuclear genes have not yet been fully elucidated. When tobacco and lettuce transplastomic plants expressing GFP within chloroplasts, were challenged with Erwinia carotovora (biotic stress) or paraquat (abiotic stress), GFP was released into the cytoplasm. During this process GFP moves gradually towards the envelope, creating a central red zone of chlorophyll fluorescence. GFP was then gradually released from intact chloroplasts into the cytoplasm with an intact vacuole and no other visible cellular damage. Different stages of GFP release were observed inside the same cell with a few chloroplasts completely releasing GFP with detection of only red chlorophyll fluorescence or with no reduction in GFP fluorescence or transitional steps between these two phases. Time lapse imaging by confocal microscopy clearly identified sequence of these events. Intactness of chloroplasts during this process was evident from chlorophyll fluorescence emanated from thylakoid membranes and in vivo Chla fluorescence measurements (maximum quantum yield of photosystem II) made before or after infection with pathogens to evaluate their photosynthetic competence. Hydrogen peroxide and superoxide anion serve as signal molecules for generation of reactive oxygen species and Tiron, scavenger of superoxide anion, blocked release of GFP from chloroplasts. Significant increase in ion leakage in the presence of paraquat and light suggests changes in the chloroplast envelope to facilitate protein release. Release of GFP-RC101 (an antimicrobial peptide), which was triggered by Erwinia infection, ceased after conferring protection, further confirming this export phenomenon. These results suggest a novel signaling mechanism, especially for participation of chloroplast proteins (e.g. transcription factors) in retrograde signaling, thereby offering new opportunities to regulate pathways outside chloroplasts. PMID- 23799143 TI - Characterization of PUD-1 and PUD-2, two proteins up-regulated in a long-lived daf-2 mutant. AB - C. elegans PUD-1 and PUD-2, two proteins up-regulated in daf-2(loss-of-function) (PUD), are homologous 17-kD proteins with a large abundance increase in long lived daf-2 mutant animals of reduced insulin signaling. In this study, we show that both PUD-1 and PUD-2 are abundantly expressed in the intestine and hypodermis, and form a heterodimer. We have solved their crystal structure to 1.9 A resolution and found that both proteins adopt similar beta-sandwich folds in the V-shaped dimer. In contrast, their homologs PUD-3, PUD-4, PUDL-1 and PUDL-2 are all monomeric proteins with distinct expression patterns in C. elegans. Thus, the PUD-1/PUD-2 heterodimer probably has a function distinct from their family members. Neither overexpression nor deletion of pud-1 and pud-2 affected the lifespan of WT or daf-2 mutant animals, suggesting that their induction in daf-2 worms does not contribute to longevity. Curiously, deletion of pud-1 and pud-2 was associated with a protective effect against paralysis induced by the amyloid beta-peptide (1-42), which further enhanced the protection conferred by daf 2(RNAi) against Abeta. PMID- 23799144 TI - Association between the Pro12Ala polymorphism of the peroxisome proliferator activated receptor gamma gene and strength athlete status. AB - BACKGROUND: The 12Ala allele of the Peroxisome Proliferator-Activated Receptor gamma gene (PPARG) Pro12Ala polymorphism produces a decreased binding affinity of the PPARgamma2 protein, resulting in low activation of the target genes. The 12Ala allele carriers display a significantly improved insulin sensitivity that may result in better glucose utilisation in working skeletal muscles. We hypothesise that the PPARG 12Ala allele could be associated with strength athlete status in Polish athletes. METHODOLOGY: The genotype distribution of PPARG Pro12Ala was examined in 660 Polish athletes. The athletes were stratified into four subgroups: endurance, strength-endurance, sprint-strength and strength. Control samples were prepared from 684 unrelated sedentary volunteers. A chi(2) test was used to compare the PPARG Pro12Ala allele and genotype frequencies between the different groups of athletes and control subjects. Bonferroni's correction for multiple testing was applied. RESULTS: A statistically significant higher frequency of PPARG 12Ala alleles was observed in the subgroup of strength athletes performing short-term and very intense exertion characterised by predominant anaerobic energy production (13.2% vs. 7.5% in controls; P = 0.0007). CONCLUSION: The PPARG 12Ala allele may be a relevant genetic factor favouring strength abilities in professional athletes, especially in terms of insulin dependent metabolism, a shift of the energy balance towards glucose utilisation and the development of a favourable weight-to-strength ratio. PMID- 23799145 TI - Angiotensin II receptor blocker attenuates intrarenal renin-angiotensin-system and podocyte injury in rats with myocardial infarction. AB - The mechanisms and mediators underlying common renal impairment after myocardial infarction (MI) are still poorly understood. The present study aimed to test the hypothesis that angiotensin II type 1 receptor blockers (ARBs) provides renoprotective effects after MI by preventing augmented intrarenal renin angiotensin-system (RAS)-induced podocyte injury. Sprague-Dawley rats that underwent ligation of their coronary arteries were treated with losartan (20 mg/kg/d) or vehicle for 3 or 9 weeks. Renal function, histology and molecular changes were assessed. The current study revealed that MI-induced glomerular podocyte injury was identified by increased immunostaining for desmin and p16(ink4a), decreased immunostaining for Wilms' tumor-1 and podocin mRNA expression, and an induced increase of blood cystatin C at both 3 and 9 weeks. These changes were associated with increased intrarenal angiotensin II levels and enhanced expressions of angiotensinogen mRNA and angiotensin II receptor mRNA and protein. These changes were also associated with decreased levels of insulin-like growth factor (IGF-1) and decreased expressions of IGF-1 receptor (IGF-1R) protein and mRNA and phosphorylated(p)-Akt protein at 9 weeks, as well as increased expressions of 8-hydroxy-2'-deoxyguanosine at both time points. Treatment with losartan significantly attenuated desmin- and p16(ink4a)-positive podocytes, restored podocin mRNA expression, and decreased blood cystatin C levels. Losartan also prevented RAS activation and oxidative stress and restored the IGF-1/IGF-1R/Akt pathway. In conclusion, ARBs prevent the progression of renal impairment after MI via podocyte protection, partially by inhibiting the activation of the local RAS with subsequent enhanced oxidative stress and an inhibited IGF-1/IGF-1R/Akt pathway. PMID- 23799146 TI - Higher Chlamydia trachomatis prevalence in ethnic minorities does not always reflect higher sexual risk behaviour. AB - BACKGROUND: In affluent countries, the prevalence of Chlamydia trachomatis (CT) is often higher in certain ethnic minorities than in the majority population. In The Netherlands, we examined why CT prevalence is higher in Surinamese/Antilleans, the largest minority in the country. METHODS: Heterosexuals were recruited for a cross-sectional survey from May through August 2010 at the sexually transmitted infections (STI) clinic in Amsterdam. Participants completed a questionnaire and were tested for STI. A causal directed acyclic graph was assumed to investigate whether the association between ethnicity and CT could be explained by differences in sexual risk behaviour and socio-economic status. RESULTS: Subjects included 1044 with Dutch background and 335 with Surinamese/Antillean background. Median age for the combined population was 25 (IQR 22-30) years, and 55.4% was female. Sexual risk behaviour did not differ significantly between the two groups. CT was diagnosed in 17.9% of Surinamese/Antilleans and in 11.4% of Dutch. Surinamese/Antilleans were significantly more likely to have CT (OR 1.70; 95% CI 1.21-2.38). The association between ethnicity and CT remained statistically significant after adjusting for sexual risk behaviour, age, sex, and ethnic mixing (aOR 1.48; 95% CI 1.00-2.18), but not after adjusting for education and neighbourhood, markers of socio economic status (aOR 1.08; 95% CI 0.71-1.64). CONCLUSION: The difference in CT prevalence between the minority and majority groups was not explained by differences in sexual risk behaviour. The higher CT prevalence found among Surinamese/Antilleans appeared to reflect their lower educational level and neighbourhood, two markers of lower socio-economic status. We hypothesise that the effect results from lower health-seeking behaviour. PMID- 23799147 TI - Metabolic analysis of adaptation to short-term changes in culture conditions of the marine diatom Thalassiosira pseudonana. AB - This report describes the metabolic and lipidomic profiling of 97 low-molecular weight compounds from the primary metabolism and 124 lipid compounds of the diatom Thalassiosira pseudonana. The metabolic profiles were created for diatoms perturbed for 24 hours with four different treatments: (I) removal of nitrogen, (II) lower iron concentration, (III) addition of sea salt, (IV) addition of carbonate to their growth media. Our results show that as early as 24 hours after nitrogen depletion significant qualitative and quantitative change in lipid composition as well as in the primary metabolism of Thalassiosira pseudonana occurs. So we can observe the accumulation of several storage lipids, namely triacylglycerides, and TCA cycle intermediates, of which citric acid increases more than 10-fold. These changes are positively correlated with expression of TCA enzymes genes. Next to the TCA cycle intermediates and storage lipid changes, we have observed decrease in N-containing lipids and primary metabolites such as amino acids. As a measure of counteracting nitrogen starvation, we have observed elevated expression levels of nitrogen uptake and amino acid biosynthetic genes. This indicates that diatoms can fast and efficiently adapt to changing environment by altering the metabolic fluxes and metabolite abundances. Especially, the accumulation of proline and the decrease of dimethylsulfoniopropionate suggest that the proline is the main osmoprotectant for the diatom in nitrogen rich conditions. PMID- 23799148 TI - Treating cattle to protect people? Impact of footbath insecticide treatment on tsetse density in Chad. AB - BACKGROUND: In Chad, several species of tsetse flies (Genus: Glossina) transmit African animal trypanosomoses (AAT), which represents a major obstacle to cattle rearing, and sleeping sickness, which impacts public health. After the failure of past interventions to eradicate tsetse, the government of Chad is now looking for other approaches that integrate cost-effective intervention techniques, which can be applied by the stake holders to control tsetse-transmitted trypanosomoses in a sustainable manner. The present study thus attempted to assess the efficacy of restricted application of insecticides to cattle leg extremities using footbaths for controlling Glossina m. submorsitans, G. tachinoides and G. f. fuscipes in southern Chad. METHODOLOGY/PRINCIPAL FINDINGS: Two sites were included, one close to the historical human African trypanosomiasis (HAT) focus of Moundou and the other to the active foci of Bodo and Moissala. At both sites, a treated and an untreated herd were compared. In the treatment sites, cattle were treated on a regular basis using a formulation of deltamethrin 0.005% (67 to 98 cattle were treated in one of the sites and 88 to 102 in the other one). For each herd, tsetse densities were monthly monitored using 7 biconical traps set along the river and beside the cattle pen from February to December 2009. The impact of footbath treatment on tsetse populations was strong (p < 10(-3)) with a reduction of 80% in total tsetse catches by the end of the 6-month footbath treatment. CONCLUSIONS/SIGNIFICANCE: The impact of footbath treatment as a vector control tool within an integrated strategy to manage AAT and HAT is discussed in the framework of the "One Health" concept. Like other techniques based on the treatment of cattle, this technology should be used under controlled conditions, in order to avoid the development of insecticide and acaricide resistance in tsetse and tick populations, respectively. PMID- 23799149 TI - Dynamics of physical interaction between HIV-1 Nef and ASK1: identifying the interacting motif(s). AB - FasL mediated preferential apoptosis of bystander CTLs while protection of infected CD4(+)T cells remains one of the hallmarks of immune evasion during HIV infection. The property of infected host cells to evade cell-autonomous apoptosis emanates from ability of HIV-1Nef-protein to physically interact with ASK-1 and thereby inhibit its enzymatic activity. The specific domains of HIV-1Nef through which it may interact with ASK1 and thereby impair the ASK1 activity remain unidentified so far and represent a major challenge towards developing clear understanding about the dynamics of this interaction. Using mammalian two hybrid screen in association with site directed mutagenesis and competitive inhibitor peptides, we identified constituent minimal essential domain (152 DEVGEANN 159) through which HIV-1Nef interacts with ASK1 and inhibits its function. Furthermore our study also unravels a novel alternate mechanism underlying HIV-1 Nef mediated ASK1 functional modulation, wherein by potentiating the inhibitory ser(967) phosphorylation of ASK1, HIV-1Nef negatively modulated ASK1 function. PMID- 23799150 TI - Asparagine substitution at PB2 residue 701 enhances the replication, pathogenicity, and transmission of the 2009 pandemic H1N1 influenza A virus. AB - The 2009/2010 pandemic influenza virus (H1N1pdm) contains an avian-lineage PB2 gene that lacks E627K and D701N substitutions important in the pathogenesis and transmission of avian-origin viruses in humans or other mammals. Previous studies have shown that PB2-627K is not necessary because of a compensatory Q591R substitution. The role that PB2-701N plays in the H1N1pdm phenotype is not well understood. Therefore, PB2-D701N was introduced into an H1N1pdm virus (A/New York/1682/2009 (NY1682)) and analyzed in vitro and in vivo. Mini-genome replication assay, in vitro replication characteristics in cell lines, and analysis in the mouse and ferret models demonstrated that PB2-D701N increased virus replication rates and resulted in more severe pathogenicity in mice and more efficient transmission in ferrets. In addition, compared to the NY1682-WT virus, the NY1682-D701N mutant virus induced less IFN-lambda and replicated to a higher titer in primary human alveolar epithelial cells. These findings suggest that the acquisition of the PB2-701N substitution by H1N1pdm viruses may result in more severe disease or increase transmission in humans. PMID- 23799151 TI - Structural stability of Burkholderia cenocepacia biofilms is reliant on eDNA structure and presence of a bacterial nucleic acid binding protein. AB - Cystic fibrosis (CF) is the most common lethal inherited genetic disorder affection Caucasians. Even with medical advances, CF is life-shortening with patients typically surviving only to age 38. Infection of the CF lung by Burkholderia cenocepacia presents exceptional challenges to medical management of these patients as clinically this microbe is resistant to virtually all antibiotics, is highly transmissible and infection of CF patients with this microbe renders them ineligible for lung transplant, often the last lifesaving option. Here we have targeted two abundant components of the B. cenocepacia biofilm for immune intervention: extracellular DNA and DNABII proteins, the latter of which are bacterial nucleic acid binding proteins. Treatment of B. cenocepacia biofilms with antiserum directed at one of these DNABII proteins (integration host factor or IHF) resulted in significant disruption of the biofilm. Moreover, when anti-IHF mediated destabilization of a B. cenocepacia biofilm was combined with exposure to traditional antibiotics, B. cenocepacia resident within the biofilm and thereby typically highly resistant to the action of antibiotics, were now rendered susceptible to killing. Pre-incubation of B. cenocepacia with anti-IHF serum prior to exposure to murine CF macrophages, which are normally unable to effectively degrade ingested B. cenocepacia, resulted in a statistically significant increase in killing of phagocytized B. cenocepacia. Collectively, these findings support further development of strategies that target DNABII proteins as a novel approach for treatment of CF patients, particularly those whose lungs are infected with B. cenocepacia. PMID- 23799152 TI - WW domain containing E3 ubiquitin protein ligase 1 (WWP1) negatively regulates TLR4-mediated TNF-alpha and IL-6 production by proteasomal degradation of TNF receptor associated factor 6 (TRAF6). AB - BACKGROUND: Toll-like receptors (TLRs) play a pivotal role in the defense against invading pathogens by detecting pathogen-associated molecular patterns (PAMPs). TLR4 recognizes lipopolysaccharides (LPS) in the cell walls of Gram-negative bacteria, resulting in the induction and secretion of proinflammatory cytokines such as TNF-alpha and IL-6. The WW domain containing E3 ubiquitin protein ligase 1 (WWP1) regulates a variety of cellular biological processes. Here, we investigated whether WWP1 acts as an E3 ubiquitin ligase in TLR-mediated inflammation. METHODOLOGY/RESULTS: Knocking down WWP1 enhanced the TNF-alpha and IL-6 production induced by LPS, and over-expression of WWP1 inhibited the TNF alpha and IL-6 production induced by LPS, but not by TNF-alpha. WWP1 also inhibited the IkappaB-alpha, NF-kappaB, and MAPK activation stimulated by LPS. Additionally, WWP1 could degrade TRAF6, but not IRAK1, in the proteasome pathway, and knocking down WWP1 reduced the LPS-induced K48-linked, but not K63-linked, polyubiquitination of endogenous TRAF6. CONCLUSIONS/SIGNIFICANCE: We identified WWP1 as an important negative regulator of TLR4-mediated TNF-alpha and IL-6 production. We also showed that WWP1 functions as an E3 ligase when cells are stimulated with LPS by binding to TRAF6 and promoting K48-linked polyubiquitination. This results in the proteasomal degradation of TRAF6. PMID- 23799153 TI - Biosynthesis of UDP-GlcNAc, UndPP-GlcNAc and UDP-GlcNAcA involves three easily distinguished 4-epimerase enzymes, Gne, Gnu and GnaB. AB - We have undertaken an extensive survey of a group of epimerases originally named Gne, that were thought to be responsible for inter-conversion of UDP-N acetylglucosamine (UDP-GlcNAc) and UDP-N-acetylgalactosamine (UDP-GalNAc). The analysis builds on recent work clarifying the specificity of some of these epimerases. We find three well defined clades responsible for inter-conversion of the gluco- and galacto-configuration at C4 of different N-acetylhexosamines. Their major biological roles are the formation of UDP-GalNAc, UDP-N acetylgalactosaminuronic acid (UDP-GalNAcA) and undecaprenyl pyrophosphate-N acetylgalactosamine (UndPP-GalNAc) from the corresponding glucose forms. We propose that the clade of UDP-GlcNAcA epimerase genes be named gnaB and the clade of UndPP-GlcNAc epimerase genes be named gnu, while the UDP-GlcNAc epimerase genes retain the name gne. The Gne epimerases, as now defined after exclusion of those to be named GnaB or Gnu, are in the same clade as the GalE 4-epimerases for inter-conversion of UDP-glucose (UDP-Glc) and UDP-galactose (UDP-Gal). This work brings clarity to an area that had become quite confusing. The identification of distinct enzymes for epimerisation of UDP-GlcNAc, UDP-GlcNAcA and UndPP-GlcNAc will greatly facilitate allocation of gene function in polysaccharide gene clusters, including those found in bacterial genome sequences. A table of the accession numbers for the 295 proteins used in the analysis is provided to enable the major tree to be regenerated with the inclusion of additional proteins of interest. This and other suggestions for annotation of 4-epimerase genes will facilitate annotation. PMID- 23799154 TI - Probucol increases striatal glutathione peroxidase activity and protects against 3-nitropropionic acid-induced pro-oxidative damage in rats. AB - Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disease characterized by symptoms attributable to the death of striatal and cortical neurons. The molecular mechanisms mediating neuronal death in HD involve oxidative stress and mitochondrial dysfunction. Administration of 3 nitropropionic acid (3-NP), an irreversible inhibitor of the mitochondrial enzyme succinate dehydrogenase, in rodents has been proposed as a useful experimental model of HD. This study evaluated the effects of probucol, a lipid-lowering agent with anti-inflammatory and antioxidant properties, on the biochemical parameters related to oxidative stress, as well as on the behavioral parameters related to motor function in an in vivo HD model based on 3-NP intoxication in rats. Animals were treated with 3.5 mg/kg of probucol in drinking water daily for 2 months and, subsequently, received 3-NP (25 mg/kg i.p.) once a day for 6 days. At the end of the treatments, 3-NP-treated animals showed a significant decrease in body weight, which corresponded with impairment on motor ability, inhibition of mitochondrial complex II activity and oxidative stress in the striatum. Probucol, which did not rescue complex II inhibition, protected against behavioral and striatal biochemical changes induced by 3-NP, attenuating 3-NP-induced motor impairments and striatal oxidative stress. Importantly, probucol was able to increase activity of glutathione peroxidase (GPx), an enzyme important in mediating the detoxification of peroxides in the central nervous system. The major finding of this study was that probucol protected against 3-NP-induced behavioral and striatal biochemical changes without affecting 3-NP-induced mitochondrial complex II inhibition, indicating that long-term probucol treatment resulted in an increased resistance against neurotoxic events (i.e., increased oxidative damage) secondary to mitochondrial dysfunction. These data appeared to be of great relevance when extrapolated to human neurodegenerative processes involving mitochondrial dysfunction and indicates that GPx is an important molecular target involved in the beneficial effects of probucol. PMID- 23799155 TI - Selaginellatamariscina attenuates metastasis via Akt pathways in oral cancer cells. AB - BACKGROUND: Crude extracts of Selaginellatamariscina, an oriental medicinal herb, have been evidenced to treat several human diseases. This study investigated the mechanisms by which Selaginellatamariscina inhibits the invasiveness of human oral squamous-cell carcinoma (OSCC) HSC-3 cells. METHODOLOGY/PRINCIPAL FINDINGS: Herein, we demonstrate that Selaginellatamariscina attenuated HSC-3 cell migration and invasion in a dose-dependent manner. The anti-metastatic activities of Selaginellatamariscina occurred at least partially because of the down regulation of matrix metalloproteinases (MMP)-2 and MMP-9 gelatinase activity and the down-regulation of protein expression. The expression and function of both MMP-2 and MMP-9 were regulated by Selaginellatamariscina at a transcriptional level, as shown by quantitative real-time PCR and reporter assays. Chromatin immunoprecipitation (ChIP) data further indicated that binding of the cAMP response element-binding (CREB) protein and activating protein-1 (AP-1) to the MMP-2 promoter diminished at the highest dosage level of Selaginellatamariscina. The DNA-binding activity of specificity protein 1 (SP-1) to the MMP-9 promoter was also suppressed at the same concentration. Selaginellatamariscina did not affect the mitogen-activated protein kinase signaling pathway, but did inhibit the effects of gelatinase by reducing the activation of serine-threonine kinase Akt. CONCLUSIONS: These results demonstrate that Selaginellatamariscina may be a potent adjuvant therapeutic agent in the prevention of oral cancer. PMID- 23799156 TI - Structural and functional studies of FKHR-PAX3, a reciprocal fusion gene of the t(2;13) chromosomal translocation in alveolar rhabdomyosarcoma. AB - Alveolar rhabdomyosarcoma (ARMS) is an aggressive pediatric cancer of skeletal muscle. More than 70% of ARMS tumors carry balanced t(2;13) chromosomal translocation that leads to the production of two novel fusion genes, PAX3-FKHR and FKHR-PAX3. While the PAX3-FKHR gene has been intensely studied, the reciprocal FKHR-PAX3 gene has rarely been described. We report here the cloning and functional characterization of the FKHR-PAX3 gene as the first step towards a better understanding of its potential impact on ARMS biology. From RH30 ARMS cells, we detected and isolated three versions of FKHR-PAX3 cDNAs whose C terminal sequences corresponded to PAX3c, PAX3d, and PAX3e isoforms. Unlike the nuclear-specific localization of PAX3-FKHR, the reciprocal FKHR-PAX3 proteins stayed predominantly in the cytoplasm. FKHR-PAX3 potently inhibited myogenesis in both non-transformed myoblast cells and ARMS cells. We showed that FKHR-PAX3 was not a classic oncogene but could act as a facilitator in oncogenic pathways by stabilizing PAX3-FKHR expression, enhancing cell proliferation, clonogenicity, anchorage-independent growth, and matrix adhesion in vitro, and accelerating the onset of tumor formation in xenograft mouse model in vivo. In addition to these pro-oncogenic behaviors, FKHR-PAX3 also negatively affected cell migration and invasion in vitro and lung metastasis in vivo. Taken together, these functional characteristics suggested that FKHR-PAX3 might have a critical role in the early stage of ARMS development. PMID- 23799159 TI - RAS signaling pathways, mutations and their role in colorectal cancer. AB - Two of the main cellular pathways in which the RAS protein operates are the mitogen-activated protein kinases (MAPK) and phosphoinositide-3 kinase (PI3K) pathways. In a normal cell, these are important in controlling several functions, such as cell growth and survival. It becomes self-evident that these events will be disrupted in a malignant cell with a deregulated MAPK or PI3K pathway. Mutations in genes involved in these pathways and interacting with RAS, as well as RAS itself will be discussed. The second part of this review concentrates on how crucial RAS signaling is in colorectal cancer progression, with references to treatment response and prognosis when RAS or other related mutations are present. PMID- 23799158 TI - Targeted treatments for metastatic esophageal squamous cell cancer. AB - Squamous cell carcinoma, one of the two major sub-types of esophageal carcinomas, constitutes the great majority of tumors in the upper and middle third of the organ. Declining in incidence in western countries, it continues to be a significant public health problem in the far east. Targeted treatments are novel therapies introduced in the clinical therapeutic armamentarium of oncology in the last 10-15 years. They represent a rational way of treating various cancers based on their molecular lesions. Although no such agent has been approved so far for the treatment of esophageal squamous cell carcinomas (ESCC), several are in clinical trials and several others have displayed pre-clinical activity that would justify the efforts and risks of pursuing their clinical development in this disease. This paper discusses some of these targeted agents in more advanced development in metastatic ESCC, as well as some promising drugs with pre-clinical or initial clinical data in the disease. PMID- 23799160 TI - Clinical Value of Vestibular Evoked Myogenic Potential in Assessing the Stage and Predicting the Hearing Results in Meniere's Disease. AB - OBJECTIVES: Our goal was to find the clinical value of cervical vestibular evoked myogenic potential (VEMP) in Meniere's disease (MD) and to evaluate whether the VEMP results can be useful in assessing the stage of MD. Furthermore, we tried to evaluate the clinical effectiveness of VEMP in predicting hearing outcomes. METHODS: The amplitude, peak latency and interaural amplitude difference (IAD) ratio were obtained using cervical VEMP. The VEMP results of MD were compared with those of normal subjects, and the MD stages were compared with the IAD ratio. Finally, the hearing changes were analyzed according to their VEMP results. RESULTS: In clinically definite unilateral MD (n=41), the prevalence of cervical VEMP abnormality in the IAD ratio was 34.1%. When compared with normal subjects (n=33), the VEMP profile of MD patients showed a low amplitude and a similar latency. The mean IAD ratio in MD was 23%, which was significantly different from that of normal subjects (P=0.01). As the stage increased, the IAD ratio significantly increased (P=0.09). After stratification by initial hearing level, stage I and II subjects (hearing threshold, 0-40 dB) with an abnormal IAD ratio showed a decrease in hearing over time compared to those with a normal IAD ratio (P=0.08). CONCLUSION: VEMP parameters have an important clinical role in MD. Especially, the IAD ratio can be used to assess the stage of MD. An abnormal IAD ratio may be used as a predictor of poor hearing outcomes in subjects with early stage MD. PMID- 23799161 TI - Short term effects of repetitive transcranial magnetic stimulation in patients with catastrophic intractable tinnitus: preliminary report. AB - OBJECTIVES: The short-term effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) in the patients with catastrophic and intractable tinnitus were investigated. METHODS: Fifteen participants were recruited among patients with catastrophic intractable tinnitus to receive 1 Hz rTMS treatment. Tinnitus severity was assessed before rTMS and directly after sham or real rTMS using the tinnitus handicap inventory (THI) and visual analog scale (VAS). RESULTS: There was no statistical difference in the THI score before and after sham stimulation. However, after 5 replications of real rTMS there was statistically significant reduction in THI score. Eight patients showed a decrease of more than 10 in THI score. Patients who showed a vast change in THI score after rTMS also showed a large decrease in their VAS score (r=0.879, P<0.001). Duration of tinnitus and change of THI score showed statistically significant moderate negative correlation (r=-0.637, P=0.011). But in case of VAS, there was no significant difference between VAS and duration of tinnitus. CONCLUSION: Among total 15 patients with catastrophic intractable chronic tinnitus, eight patients showed some improvement in symptoms after 1 Hz rTMS. rTMS can be considered management modality for intractable tinnitus even with distress as severe as catastrophic stage. PMID- 23799162 TI - The effect of obstructive sleep apnea on DNA damage and oxidative stress. AB - OBJECTIVES: Obstructive sleep apnea syndrome (OSAS) is associated with repeated hypoxia and re-oxygenation. This characteristic of OSAS may cause oxidative stress and DNA damage. However, the link of OSAS with oxidative stress and DNA damage is still controversial. In the current study, we investigated whether OSAS causes DNA damage using alkaline single-cell gel electrophoresis (comet assay) and measuring oxidative stress by monitoring serum malondialdehyde (MDA) levels. METHODS: From March 2009 to August 2010, 51 patients who underwent polysomnography (PSG) during the night were enrolled in this study. We obtained serum from the patients at 6 AM. DNA damage and oxidative stress were evaluated using a comet assay and measuring serum MDA, respectively. We divided the patients into two groups according to the existence of comets appearing in the comet assay. Group 1 included 44 patients with negative assay results and group 2 consisted of seven patients with positive comet assay findings. We compared the age, gender proportion, PSG data (respiratory disturbance index [RDI], lowest O2 saturation level, and arousal index [AI]), time of disease onset, smoking habits, and serum MDA levels between the two groups. RESULTS: The average age and gender proportion of the two groups were not statistically different (P>0.05). The average of RDI for group 1 was 30.4+/-18.4 and 8.0+/-7.7 (P<0.01) for group 2. The average of lowest O2 saturation level for group 1 was 81.2+/-7.2 and 87.4+/ 6.5 (P<0.05) for group 2. The average AI for group 1 was 32.8+/-15.1 and 20.8+/ 7.7 (P<0.05) for group 2. Similarly, serum MDA levels of the two groups were not statistically different (P>0.05). No relationship between positive comet assay results and OSAS severity was identified. CONCLUSION: Results of the current study showed that OSAS was not associated with DNA damage as measured by comet assays or oxidative stress according to serum MDA levels. PMID- 23799163 TI - Effects of rhinophototherapy on quality of life in persistant allergic rhinitis. AB - OBJECTIVES: To investigate the effect of rhinophototherapy with medical therapy on quality of life in persistent allergic rhinitis. METHODS: A prospective, randomized study was being performed between December 2009 and March 2010. The study included 65 patients with persistent allergic rhinitis. The diagnosis was confirmed with positive skin tests. All of the patients had house dust mite allergies. We divided the patients into two groups. First group (n=33) was given topical mometasone furoate 200 mcg/day and levocetirizine 5 mg/day for a month. Rhinophototherapy was applied with the same medical therapy to the second group (n=32), twice a week for three weeks continuously. Rhinophototherapy included visible light, ultraviolet A and ultraviolet B. We evaluated patients before the treatment, at the first month and at the third month after treatment with rhinoconjunctivitis quality of life questionnaire, nasal symptom scores and visual analogue scale (VAS) scores. RESULTS: Improvements of all variables of the quality of life questionnaire, nasal symptom scores and VAS were statistically significant in the second group both on the first and the third months when compared with the first group. CONCLUSION: Allergic rhinitis is a social problem and impairs quality of life. Rhinophototherapy with medical therapy improves the quality of life in allergic rhinitis. PMID- 23799164 TI - Analysis of facial deformities in korean leprosy. AB - OBJECTIVES: The clinical features of various facial deformities in Korean leprosy patients were evaluated according to the type of leprosy. METHODS: One hundred ninety six patients with leprosy were examined for various facial deformities using a nasal speculum, endoscope, and digital camera. The frequency and severity of external nasal deformities and septal perforations were evaluated according to the type of leprosy. Eye deformities, ear deformities, and facial palsy were also assessed. RESULTS: Seventy-one patients (36.2%) displayed external nasal deformities: 28 minimal contractures, three cartilage contractures, two bony cartilage contractures, and 38 skin defects. The external nasal deformity and severe form deformity in lepromatous types were more frequent compared to other types (P<0.05 for each variable). Twenty-three patients (9%) displayed septal perforations, among whom 11 had cartilaginous perforations and 12 had bony cartilaginous perforations. The frequency of septal and bony-cartilaginous perforations did not differ significantly between the types of leprosy (P>0.05 for each variable). Sixty-one patients (31.1%) had eye deformities and 19 patients (9.7%) had facial nerve palsy, common in the borderline type. No cases of ear deformities were observed. CONCLUSION: Korean patients had characteristic deformities according to the type of leprosy. They were different from those seen in the prior analyses of Caucasian populations. PMID- 23799165 TI - Viability and Regeneration of Chondrocytes after Laser Cartilage Reshaping Using 1,460 nm Diode Laser. AB - OBJECTIVES: Cartilage reshaping by laser irradiation is used to correct septal and auricular cartilage deformities. Chondrocyte viability following laser irradiation and reshaping has been well established. However, the regeneration process of chondrocyte after laser irradiation has not been revealed yet. The aims of this study were to determine the mechanism of cartilaginous thermal injury and the regenerative process of damaged cartilage following laser irradiation. METHODS: Laser irradiation was performed on human septal cartilage and rabbit auricular cartilage using a 1,460-nm diode laser. We observed change in the shape of cartilage and evaluated the extent of cartilage injury using live/dead cell assay via confocal microscopy. Hoechst and propidium iodide (PI) staining was used to evaluate the mechanism of chondrocyte injury after laser irradiation. To evaluate the regeneration of cartilage, laser irradiated cartilages were reimplanted into a subperichondrial pocket and were harvested at 1, 2, and 4 weeks after reimplantation for viability assessment and histologic examination. RESULTS: Laser irradiation using a 1,460-nm diode laser produced a marked shape change in both human septal and rabbit auricular cartilages. Thermal damage on cartilage was correlated with the exposure time and the laser power. Hoechst and PI staining showed that chondrocyte death by laser irradiation was due to mainly necrosis, rather than apoptosis. In lower power treatment group (0.3 W and 0.5 W), all the chondrocytes regenerated within 4 weeks, however, in 1 W treatment group, chondrocytes could not regenerate until 4 weeks. CONCLUSION: Reshaping of cartilage using 1,460 nm diode laser was attained concurrently with the thermal injury to the chondrocytes. The extent of thermal damage on chondrocytes was dependent on the exposure time and the laser power and the damaged chondrocytes irradiated with lower level of laser power could be regenerated after reimplantation into subperichondrial pocket. PMID- 23799167 TI - Conversion from selective to comprehensive neck dissection: is it necessary for occult nodal metastasis? 5-year observational study. AB - OBJECTIVES: To compare the therapeutic results between selective neck dissection (SND) and conversion modified radical neck dissection (MRND) for the occult nodal metastasis cases in head and neck squamous cell carcinoma. METHODS: Forty-four cases with occult nodal metastasis were enrolled in this observational cohort study. For twenty-nine cases, SNDs were done and for fifteen cases, as metastatic nodes were found in the operative field, conversion from selective to MRNDs type II were done. Baseline data on primary site, T and N stage, extent of SND, extracapsular spread of occult metastatic node and type of postoperative adjuvant therapy were obtained. We compared locoregional control rate, overall survival rate and disease specific survival rate between two groups. RESULTS: Among the 29 patients who underwent SND, only one patient had a nodal recurrence which occurred in the contralateral undissected neck. On the other hand, among the 15 patients who underwent conversion MRND, two patients had nodal recurrences which occurred in previously undissected neck. According to the Kaplan Meier survival curve, there was no statistically significant difference for locoregional control rate, overall survival rate and disease specific survival rate between two groups (P=0.2719, P=0.7596, and P=0.2405, respectively). CONCLUSION: SND is enough to treat occult nodal metastasis in head and neck squamous cell carcinoma and it is not necessary to convert from SND to comprehensive neck dissection. PMID- 23799166 TI - Coblation vs. Electrocautery Tonsillectomy: A Prospective Randomized Study Comparing Clinical Outcomes in Adolescents and Adults. AB - OBJECTIVES: Coblation is operated in low temperature, so it is proposed that tonsillectomy with coblation involves less postoperative pain and allows accelerated healing of the tonsillar fossae compared with other methods involving heat driven processes. However, the results of the previous studies showed that the effect of coblation tonsillectomy has been equivocal in terms of postoperative pain and hemorrhage. Though, most of the previous studies which evaluated coblation tonsillectomy were performed in children. Recently, electrocautery tonsillectomy has been used most widely because of the reduced intraoperative blood loss and shorter operative time compared to other techniques. This prospective study compared intraoperative records and postoperative clinical outcomes in adolescents and adults following coblation and electrocautery tonsillectomies. METHODS: Eighty patients over 16 years of age with histories of recurrent tonsillitis were enrolled. The patients were randomly allocated into coblation (n=40) and electrocautery tonsillectomy groups (n=40). All operations were performed by one surgeon who was skilled in both surgical techniques. Intraoperative parameters and postoperative outcomes were checked. RESULTS: Postoperative pain and otalgia were not significantly different between the two groups; however, there was a tendency towards reduced pain and otalgia in the coblation group. More cotton balls for swabbing the operative field were used introoperatively in the electrocautery group (P=0.00). There was no significant difference in postoperative hemorrhage, wound healing, commencement of a regular diet, and foreign body sensation between the groups. CONCLUSION: Only cotton use, which represented the amount of blood loss, was less in the coblation tonsillectomy group. Coblation tonsillectomy warrants further study with respect to the decreased postoperative pain and otalgia. PMID- 23799168 TI - Syndromic Hearing Loss in Association with PTPN11-Related Disorder: The Experience of Cochlear Implantation in a Child with LEOPARD Syndrome. AB - Hearing loss (HL) is one of the most frequent clinical manifestations of patients who suffer with multi-systemic genetic disorders. HL in association with other physical stigmata is referred to as a syndromic form of HL. LEOPARD syndrome (LS) is one of the disorders with syndromic HL and it is caused by a mutation in the PTPN11 or RAF1 gene. In general, 5 year old children who undergo cochlear implantation usually show a marked change in behavior regarding sound detection within the first 6 months of implant use, but word identification may not be exhibited for at least another 6-12 months of implant use. We herein report on a 5-year-old girl with LS. Her clinical manifestations including bilateral sensorineural HL, which indicated the diagnosis of LS. We confirmed the diagnosis by identifying a disease-causing mutation in the PTPN11 gene, which was a heterozygous missense mutation Ala461Thr (c.1381G>A). She underwent cochlear implantation (CI) without complications and she is currently on regular follow-up at postoperative 1 year. This is the first reported case of CI in a patient with LS in the medical literature. PMID- 23799169 TI - Ethmoidal mucocele presenting as oculomotor nerve paralysis. AB - A 56-year-old male was admitted with an acute headache and sudden ptosis on the right side. No ophthalmological or neurological etiologies were apparent. A mucocele of the right posterior ethmoid sinus was observed with radiology. After the marsupialization of the mucocele via a transnasal endoscopic approach, the patient's symptoms (oculomotor nerve paralysis and headache) resolved in 4 weeks. Oculomotor paralysis is a rare symptom of an ethmoidal mucocele. In this article, we report this rare case along with a literature review. PMID- 23799170 TI - Sclerosing polycystic adenosis of the nasal septum: the risk of misdiagnosis. AB - Sclerosing polycyctic adenosis (SPA) is a rare lesion of unknown etiology morphologically resembling fibrocystic changes of the breast. To date, approximately 41 cases of SPA have been reported. Most cases of SPA have originated in the parotid and submandibular glands, with a few cases of intra oral minor salivary gland origin. This is the first reported case of sclerosing polycystic adenosis of nasal minor salivary gland origin. The differential diagnosis of SPA includes polycystic disease, sclerosing sialadenitis, and benign and malignant glandular neoplasias. Although atypia ranging from mild dysplasia to carcinoma in situ can occur in some cases, SPA has a favorable outcome. It is important to be familiar with SPA to avoid aggresive treatment that results from a misdiagnosis. We present a case of a 49-year-old man who had 1-year history of right nasal obstruction. PMID- 23799171 TI - Osteitis fibrosa cystica mistaken for malignant disease. AB - A 65-year-old man with back pain had plain radiographs that showed multiple osteolytic bone lesions of the pelvis, femur and L-spine; an magnetic resonance imaging scan of the L-spine showed extensive bony resorption with a posterior epidural mass involving the L1 spinous process; these findings suggested multiple myeloma or bony metastasis. However, all serology testing was negative. The parathyroid hormone and serum calcium levels were found to be abnormally elevated. A fine needle aspiration biopsy suggested that the L-spine lesion was consistent with the diagnosis of osteitis fibrosa cystica. A pathological fracture of the spine compressed the spinal cord, and surgical intervention was required. The neck computed tomography and Tc-99m sestamibi scan showed a solitary parathyroid mass. A minimally invasive parathyroidectomy using intraoperative parathyroid hormone monitoring was performed and two enlarged parathyroid glands identified. This case illustrates the importance of the consideration of a rare brown tumor associated with primary hyperparathyroidism in patients with the bone lesions suggestive of a malignancy. PMID- 23799172 TI - Carcinosarcoma of the maxillary sinus. AB - Carcinosarcoma is a highly malignant tumor characterized by dual malignant histologic differentiation of epithelial and mesenchymal components. The tumor is extremely rare in the sinonasal tract. We report a case of a 62-year-old man with carcinosarcoma involving the maxillary sinus. PMID- 23799174 TI - Editorial. PMID- 23799173 TI - Do Ames dwarf and calorie-restricted mice share common effects on age-related pathology? AB - Since 1996, aging studies using several strains of long-lived mutant mice have been conducted. Among these studies, Ames dwarf mice have been extensively examined to seek clues regarding the role of the growth hormone/insulin-like growth factor-1 axis in the aging process. Interestingly, these projects demonstrate that Ames dwarf mice have physiological characteristics that are similar to those seen with calorie restriction, which has been the most effective experimental manipulation capable of extending lifespan in various species. However, this introduces the question of whether Ames dwarf and calorie restricted (CR) mice have an extended lifespan through common or independent pathways. To answer this question, we compared the disease profiles of Ames dwarf mice to their normal siblings fed either ad libitum (AL) or a CR diet. Our findings show that the changes in age-related diseases between AL-fed Ames dwarf mice and CR wild-type siblings were similar but not identical. Moreover, the effects of CR on age-related pathology showed similarities and differences between Ames dwarf mice and their normal siblings, indicating that calorie restriction and Ames dwarf mice exhibit their anti-aging effects through both independent and common mechanisms. PMID- 23799175 TI - Non-viral transfection methods optimized for gene delivery to a lung cancer cell line. AB - BACKGROUND: Mehr-80 is a newly established adherent human large cell lung cancer cell line that has not been transfected until now. This study aims to define the optimal transfection conditions and effects of some critical elements for enhancing gene delivery to this cell line by utilizing different non-viral transfection Procedures. METHODS: In the current study, calcium phosphate (CaP), DEAE-dextran, superfect, electroporation and lipofection transfection methods were used to optimize delivery of a plasmid construct that expressed Green Fluorescent Protein (GFP). Transgene expression was detected by fluorescent microscopy and flowcytometry. Toxicities of the methods were estimated by trypan blue staining. In order to evaluate the density of the transfected gene, we used a plasmid construct that expressed the Stromal cell-Derived Factor-1 (SDF-1) gene and measured its expression by real-time PCR. RESULTS: Mean levels of GFP expressing cells 48 hr after transfection were 8.4% (CaP), 8.2% (DEAE-dextran), 4.9% (superfect), 34.1% (electroporation), and 40.1% (lipofection). Lipofection had the highest intense SDF-1 expression of the analyzed methods. CONCLUSION: This study has shown that the lipofection and electroporation methods were more efficient at gene delivery to Mehr-80 cells. The quantity of DNA per transfection, reagent concentration, and incubation time were identified as essential factors for successful transfection in all of the studied methods. PMID- 23799176 TI - Design of Small Molecules with HIV Fusion Inhibitory Property Based on Gp41 Interaction Assay. AB - BACKGROUND: Gp41 of HIV (Human Immunodeficiency Virus) is a protein that mediates fusion between viral and cellular membranes. The agent, T-20, which has been approved for HIV inhibition, can restrain Gp41 function in the fusion process; nevertheless, it has disadvantages like instability, high cost of production and injection form to be delivered twice a day. METHODS: Several molecules like NB-2 and NB-64 have been discovered that can inhibit HIV infection. These molecules were used as template compounds to design and develop more effective small molecules functioning as HIV-1 fusion inhibitors targeting Gp41. The process included in silico docking protocols using HEX and ArgusLab applications. A multisource database was created, after choosing the best molecules; they were tested in vitro for inhibitory activity by HIV-1 single-cycle model, transfected in HEK cells (293T). RESULTS: Computational analysis and experimental data were combined to explore molecular properties and the most potent ones were found, with the best suitable criteria for interaction with Gp41. Several examples (DAA 6, DAA-9 and DAA-12) could inhibit infection in vitro as effective as NB-2, NB 64. CONCLUSION: Since disadvantages of available fusion inhibitor (T-20), it seems necessary to find similar molecules to be approved and have small size providing suitable bioactivity profile. The molecules explored in this study can be good candidates for further investigations to be used as oral HIV fusion inhibitors in the future. PMID- 23799177 TI - Expression Enhancement in Trastuzumab Therapeutic Monoclonal Antibody Production using Genomic Amplification with Methotrexate. AB - BACKGROUND: Trastuzumab (Herceptin) is a humanized monoclonal antibody (mAb) which is used for specific treatment of metastatic breast cancer in patients with overexpression of HER2/neu receptor. In this study, we have attempted to develop a biosimilar version of trastuzumab mAb. METHODS: According to in silico studies, the heavy and light chains of trastuzumab mAb were designed and constructed. The recombinant constructs were co-transfected in CHO DG44 cell line. Stable transformants were selected on a semi solid medium. Genomic amplification with methotrexate was achieved for heavy chain gene amplification. Biological activity of produced antibody in comparison with Herceptin was tested by flow cytometry method. RESULTS: Three folds of amplification were obtained after seven rounds of methotrexate treatments. The results indicated the equal expression level of heavy and light chains. The yield of purified mAb was between 50 to 60 mg/l /day. According to the results, the produced mAb had similar affinity to HER2(+) tumor cells to that of Herceptin. CONCLUSION: High-level recombinant protein expression can be achieved by amplification of the recombinant gene with a selectable marker, such as Dihydrofolate Reductase (DHFR). It is usually accepted that DHFR gene can be amplified in DHFR(-) CHO cells, which consequently leads to amplification of the co-linked target gene, and finally amplification of recombinant protein. In this research, with the aim of producing a biosimilar version of herceptin, the effect of genomic amplification was investigated on the increasing the gene copy number using quantitative real-time PCR. PMID- 23799178 TI - Preparation and Cytotoxic Evaluation of Magnetite (Fe3O4) Nanoparticles on Breast Cancer Cells and its Combinatory Effects with Doxorubicin used in Hyperthermia. AB - BACKGROUND: Magnetic nanoparticles in a variable magnetic field are able to produce heat. This heat (42-45 degrees C) has more selective effect on fast dividing cancer cells than normal tissues. METHODS: In this work magnetite nanoparticles have been prepared via co-precipitation and phase identification was performed by powder x-ray diffraction (XRD). Magnetic parameters of the prepared nanoparticles were measured by a Vibrating Sample Magnetometer (VSM). A sensitive thermometer has been used to measure the increase of temperature in the presence of an alternating magnetic field. To evaluate the cytotoxicity of nanoparticles, the suspended magnetite nanoparticles in liquid paraffin, doxorubicin and a mixture of both were added to the MDA-MB-468 cells in separate 15 ml tubes and left either in the RT or in the magnetic field for 30 min. Cell survival was measured by trypan blue exclusion assay and flow cytometer. Particle size distribution of the nanoparticles was homogeneous with a mean particles size of 10 nm. A 15 degrees C temperature increase was achieved in presence of an AC magnetic field after 15 min irradiation. RESULTS: Biological results showed that magnetite nanoparticles alone were not cytotoxic at RT, while in the alternative magnetic filed more than 50% of cells were dead. Doxorubicin alone was not cytotoxic during 30 min, but in combination with magnetite more than 80% of the cells were killed. CONCLUSION: It could be concluded that doxorubicin and magnetite nanoparticles in an AC magnetic field had combinatory effects against cells. PMID- 23799179 TI - Comparison of proliferative and multilineage differentiation potential of sheep mesenchymal stem cells derived from bone marrow, liver, and adipose tissue. AB - BACKGROUND: BACKGROUND: Despite major progress in our general knowledge related to the application of adult stem cells, finding alternative sources for bone marrow Mesenchymal Stem Cells (MSCs) has remained to be challenged. In this study successful isolation, multilineage differentiation, and proliferation potentials of sheep MSCs derived from bone marrow, adipose tissue, and liver were widely investigated. METHODS: The primary cell cultures were prepared form tissue samples obtained from sheep 30-35 day fetus. Passage-3 cells were plated either at varying cell densities or different serum concentrations for a week. The Population Doubling Time (PDT), growth curves, and Colony Forming Unit (CFU) of MSCs was determined. The stemness and trilineage differentiation potential of MSCs were analyzed by using molecullar and cytochemical staining approaches. The data was analyzed through one way ANOVA using SigmaStat (ver. 2). RESULTS: The highest PDT and lowest CFU were observed in adipose tissue group compared with other groups (p<0.001). Comparing different serum concentrations (5, 10, 15, and 20%), irrespective of cell sources, the highest proliferation rate was achieved in the presence of 20% serum (p<0.001). Additionally, there was an inverse relation between cell seeding density at culture initiation and proliferation rate, except for L-MSC at 300 cell seeding density. CONCLUSION: All three sources of fetal sheep MSCs had the identical trilineage differentiation potential. The proliferative capacity of liver and bone marrow derived MSCs were similar at different cell seeding densities except for the higher fold increase in B-MSCs at 2700 cells/cm (2) density. Moreover, the adipose tissue derived MSCs had the lowest proliferative indices. PMID- 23799180 TI - Expression of Shigella flexneri ipaB Gene in Tobacco. AB - BACKGROUND: Shigellosis is a leading cause of diarrhea in many developing countries and although the disease can be controlled and managed with antibiotics, the constant emergence of resistant species requiring ever newer antibacterial drugs make development of an effective vaccine necessary. The bacteria are highly contagious and since immunity to Shigella is serotype specific a multi-serotype vaccine is required for adequate protection. Proteins encoded by Shigella invasion plasmid, which are part of the Type Three Secretion System (TTSS) of this bacteria, are good candidate as vaccine targets since they are both immunogenic and conserved between different Shigella species. The advent of molecular farming, which is a low cost system, has opened up new venues for production of recombinant proteins. In view of the difficulties encountered in expressing IpaB in Escherichia coli (E. coli), the feasibility of the expression of this protein in tobacco has been investigated. METHODS: The ipaB gene was cloned in place of the Hygromycin gene in pCambia1304 containing GFP as a reporter gene. The vector was then transferred into competent Agrobacterium tumefaciens (A. tumefaciens) strain LBA4404 which was used for agro-infiltration of Nicotiana tobaccum (N. tobaccum) leaves. Transformation was confirmed by expression of GFP. The gene was also cloned in pBAD/geneIII A and transformed E. coli host containing the construct was induced using different amounts of L arabinose as inducer. Expression of IpaB gene by both hosts was determined by Western blotting using anti-IpaB monoclonal antibody. RESULTS: The data obtained showed that IpaB was expressed in plant leaves but expression in E. coli was not detectable. CONCLUSION: This study showed that N. tobaccum is capable of expressing this protein without its specific chaperon and in levels detectable by Western blotting. PMID- 23799181 TI - Genotyping analysis of circulating fetal cells reveals high frequency of vanishing twin following transfer of multiple embryos. AB - BACKGROUND: Detection of Circulating Fetal Trophoblastic Cells (CFTC) by single cell genotyping not only allows to identify fetal cells from maternal blood, but also to characterize their bi-parental genome. METHODS: We have tested intact fetal trophoblastes recovered at 4th to 10th weeks of gestation (WG) from blood (10 ml per mother) of 13 women after In Vitro Fertilization (IVF) and transfer of one or several embryos. Large cells isolated from blood were individually microdissected and studied by genetic fingerprinting with a mean number of 3 Short Tandem Repeats (STR) markers, known to be informative by testing paternal and maternal blood DNA. RESULTS: CFTC were found in all mothers starting from the 5th WG. A mean number of 2.5 CFTC per ml of blood was found in all the analyzed samples collected at the different terms of pregnancy. All mothers who received the transfer of two or three embryos, including one who delivered twins and one with vanishing twin (identified by ultrasounds), were found to have CFTC with two or three different bi-parental genotypes, belonging to different embryos derived from the same parents. CONCLUSION: CFTC circulation is detectable starting from the 5th WG. A "vanishing twin" phenomenon frequently develops after IVF and transfer of multiple embryos, being undetectable by ultrasounds and revealed by genetic CFTC fingerprinting. PMID- 23799183 TI - In situ morphometric characterization of Aframomum melegueta accessions in Ghana. AB - In spite of the huge economic importance of Aframomum melegueta in the herbal and pharmaceutical industries, its production is limited by lack of planting materials (propagules). The plant also lacks scientific descriptors, which has often led to misidentification with adverse health implications. We therefore aimed at developing a descriptor list to facilitate the identification of A. melegueta using 34 morphometric traits comprising 18 quantitative and 16 qualitative characters. The morphological traits showed that A. melegueta has a characteristic stolon that produces tillers instead of rhizomes. The unweighted pair group method with arithmetic mean using both the nearest-neighbour and complete-linkage methods based on the 34 morphometric traits clustered the eight accessions into two main groups based on ecological location. The accessions from the Eastern and Ashanti regions were separated at similarity coefficients of 0.822 and 0.644, respectively, with a highly significant discriminant function. The Eastern accessions were further clustered into red or yellow fruits at similarity indexes of 0.936 and 0.865 using the nearest-neighbour and complete linkage methods, respectively. The present study has shown that morphometric traits of A. melegueta are greatly influenced by its ecological habitat. It is envisaged that the descriptor list developed coupled with a morphometric description would enhance its identification and utilization. PMID- 23799182 TI - Culture of Ovine IVM/IVF Zygotes in Isolated Mouse Oviduct: Effect of Basal Medium. AB - BACKGROUND: The basal medium that supports Isolated Mouse Oviduct (IMO) is important for supporting embryo development and quality. METHODS: The culture of ovine IVM/IVF zygotes was done in IMO using SOFaaciBSA and SOFaaBSA as basal medium of IMO and in SOFaaBSA alone as control. For preparation of IMO mature inbred strain C57BL/6 female mice were synchronized and mated with vasectomized males. The females with vaginal plug were sacrificed and the zygotes were transferred in to the isolated oviduct at 20 hpi. The oviducts were cultured with SOFaaciBSA and SOFaaBSA for 6 days. Another group of zygotes were cultured in SOFaaBSA alone as control. RESULTS: Culture of zygotes in the IMO with SOFaaciBSA and SOFaaBSA, did not significantly affect the development and quality of embryos (p > 0.05). The hatching rate, total and trophectoderm cells number in IMO groups' blastocysts were significantly higher than SOFaaBSA alone. The morphological appearance of IMO blastocysts was superior to SOFaaBSA alone. When the quality of oocytes was poor, IMO could better support ovine embryo development either with SOFaaBSA or SOFaaciBSA than SOFaaBSA alone and there was a significant difference in blastocyst formation at day 6 with SOFaaBSA alone. CONCLUSION: The culture of ovine IVM/IVF zygotes in IMO using two highly efficient ruminant embryo culture media not only could support development of ovine embryos similar to the level in non IMO culture system (SOFaaBSA alone) but also could improve the quality of resulting embryos. Additionally, IMO could better support the development of ovine embryos derived from poor quality oocytes compared to the SOFaaBSA alone. PMID- 23799184 TI - A common rule for integration and suppression of luminance contrast across eyes, space, time, and pattern. AB - Visual perception begins by dissecting the retinal image into millions of small patches for local analyses by local receptive fields. However, image structures extend well beyond these receptive fields and so further processes must be involved in sewing the image fragments back together to derive representations of higher order (more global) structures. To investigate the integration process, we also need to understand the opposite process of suppression. To investigate both processes together, we measured triplets of dipper functions for targets and pedestals involving interdigitated stimulus pairs (A, B). Previous work has shown that summation and suppression operate over the full contrast range for the domains of ocularity and space. Here, we extend that work to include orientation and time domains. Temporal stimuli were 15-Hz counter-phase sine-wave gratings, where A and B were the positive and negative phases of the oscillation, respectively. For orientation, we used orthogonally oriented contrast patches (A, B) whose sum was an isotropic difference of Gaussians. Results from all four domains could be understood within a common framework in which summation operates separately within the numerator and denominator of a contrast gain control equation. This simple arrangement of summation and counter-suppression achieves integration of various stimulus attributes without distorting the underlying contrast code. PMID- 23799185 TI - Paradoxical psychometric functions ("swan functions") are explained by dilution masking in four stimulus dimensions. AB - The visual system dissects the retinal image into millions of local analyses along numerous visual dimensions. However, our perceptions of the world are not fragmentary, so further processes must be involved in stitching it all back together. Simply summing up the responses would not work because this would convey an increase in image contrast with an increase in the number of mechanisms stimulated. Here, we consider a generic model of signal combination and counter suppression designed to address this problem. The model is derived and tested for simple stimulus pairings (e.g. A + B), but is readily extended over multiple analysers. The model can account for nonlinear contrast transduction, dilution masking, and signal combination at threshold and above. It also predicts nonmonotonic psychometric functions where sensitivity to signal A in the presence of pedestal B first declines with increasing signal strength (paradoxically dropping below 50% correct in two-interval forced choice), but then rises back up again, producing a contour that follows the wings and neck of a swan. We looked for and found these "swan" functions in four different stimulus dimensions (ocularity, space, orientation, and time), providing some support for our proposal. PMID- 23799186 TI - Spatial arrangement in texture discrimination and texture segregation. AB - We investigated the role of spatial arrangement of texture elements in three psychophysical experiments on texture discrimination and texture segregation. In our stimuli, oriented Gabor elements formed an iso-oriented and a randomly oriented texture region. We manipulated (1) the orientation similarity in the iso oriented region by adding orientation jitter to the orientation of each Gabor; (2) the spatial arrangement of the Gabors: quasi-random or regular; and (3) the shape of the edge between the two texture regions: straight or curved. In Experiment 1, participants discriminated an iso-oriented stimulus from a stimulus with only randomly oriented elements. Experiment 2 required texture segregation to judge the shape of the texture edge. Experiment 3 replicated Experiment 2 with Gabors of a smaller spatial extent in a denser arrangement. We found comparable performance levels with regular and quasi-random Gabor positions in the discrimination task but not in the segregation tasks. We conclude that spatial arrangement plays a role in a texture segregation task requiring shape discrimination of the texture edge but not in a texture discrimination task in which it is sufficient to discriminate an iso-oriented region from a completely random region. PMID- 23799187 TI - Look out, there is a triangle behind you! The effect of primitive geometric shapes on perceived facial dominance. AB - Previous research has shown that perceived facial valence is biased toward background valence. Here, we examine whether background dominance also affects perceived facial dominance. In particular, we hypothesized that downward-pointing triangles, which are known to convey threat, would affect perceived facial dominance. Participants judged perceived facial dominance of neutral faces presented overlaid on downward- or upward-pointing background triangles. Our results show that neutral faces are indeed judged more dominant when seen with a downward-pointing triangle in the background. The fact that simple geometric background shapes can affect facial judgments may have important implications for the design and experience of our daily environment and multimedia content. PMID- 23799188 TI - Judging whether it is aesthetic: Does equilibrium compensate for the lack of symmetry? AB - In two experiments, we explored whether compositions made up of two or three rectangles received high aesthetics ratings when the composition was equilibrated, that is, when the center of mass of the weights represented by the areas of the rectangles were in the center of the composition. We supposed that equilibrated stimuli might be appreciated as much as symmetric stimuli. We further wanted to find out whether aesthetics ratings, balance ratings, and weight ratings differ from each other, and which stimulus characteristics influence each rating. We observed that the position of the center of mass of the compositions influenced the aesthetics ratings only slightly whereas it influenced the weight ratings more strongly. In contrast with this, the variation of the overall shape of the rectangles making up the compositions influenced the aesthetics ratings more strongly than the weight ratings. At first sight, balance ratings appeared intermediate between the aesthetics ratings and the weight ratings. However, when we varied the area ratio of the rectangles making up the composition, we observed that the balance ratings were independent of the two other ratings. PMID- 23799189 TI - Neurophysiological studies may provide a misleading picture of how perceptual motor interactions are coordinated. AB - Neurophysiological measurement techniques like fMRI and TMS are increasingly being used to examine the perceptual-motor processes underpinning the ability to anticipate the actions of others. Crucially, these techniques invariably restrict the experimental task that can be used and consequently limit the degree to which the findings can be generalised. These limitations are discussed based on a recent paper by Tomeo et al. (2012) who sought to examine responses to fooling actions by using TMS on participants who passively observed spliced video clips where bodily information was, and was not, linked to the action outcome. We outline two particular concerns with this approach. First, spliced video clips that show physically impossible actions are unlikely to simulate a "fooling" action. Second, it is difficult to make meaningful inferences about perceptual motor expertise from experiments where participants cannot move. Taken together, we argue that wider generalisations based on these findings may provide a misunderstanding of the phenomenon such a study is designed to explore. PMID- 23799190 TI - A single unexpected change in target- but not distractor motion impairs multiple object tracking. AB - Recent research addresses the question whether motion information of multiple objects contributes to maintaining a selection of objects across a period of motion. Here, we investigate whether target and/or distractor motion information is used during attentive tracking. We asked participants to track four objects and changed either the motion direction of targets, the motion direction of distractors, neither, or both during a brief flash in the middle of a tracking interval. We observed that a single direction change of targets is sufficient to impair tracking performance. In contrast, changing the motion direction of distractors had no effect on performance. This indicates that target- but not distractor motion information is evaluated during tracking. PMID- 23799191 TI - Loss of color by afterimage masking. AB - When two images, one depicting colored disks and the other depicting colored windmill patterns, are displayed in succession, the color of the windmills is perceptually replaced by black. The illusion is striking. Experiments confirmed (1) that the luminance contrast between the target patterns and the background must be large and (2) that the disks and windmills must be static on the retina and in register. The illusion is weakened when the windmills and disks have different colors. PMID- 23799192 TI - Sugar and space? Not the case: Effects of low blood glucose on slant estimation are mediated by beliefs. AB - There is a current debate concerning whether people's physiological or behavioral potential alters their perception of slanted surfaces. One way to directly test this is to physiologically change people's potential by lowering their blood sugar and comparing their estimates of slant to those with normal blood sugar. In the first investigation of this (Schnall, Zadra, & Proffitt, 2010), it was shown that people with low blood sugar gave higher estimates of slanted surfaces than people with normal blood sugar. The question that arises is whether these higher estimates are due to lower blood sugar, per se, or experimental demand created by other aspects of the experiment. Here evidence was collected from 120 observers showing that directly manipulating physiological potential, while controlling for experimental demand effects, does not alter the perception of slant. Indeed, when experimental demand went against behavioral potential, it produced judgmental biases opposite to those predicted by behavioral potential in the low blood sugar condition. It is suggested that low blood sugar only affects slant judgments by making participants more susceptible to judgmental biases. PMID- 23799193 TI - Visual discomfort and depth-of-field. AB - Visual discomfort has been reported for certain visual stimuli and under particular viewing conditions, such as stereoscopic viewing. In stereoscopic viewing, visual discomfort can be caused by a conflict between accommodation and convergence cues that may specify different distances in depth. Earlier research has shown that depth-of-field, which is the distance range in depth in the scene that is perceived to be sharp, influences both the perception of egocentric distance to the focal plane, and the distance range in depth between objects in the scene. Because depth-of-field may also be in conflict with convergence and the accommodative state of the eyes, we raised the question of whether depth-of field affects discomfort when viewing stereoscopic photographs. The first experiment assessed whether discomfort increases when depth-of-field is in conflict with coherent accommodation-convergence cues to distance in depth. The second experiment assessed whether depth-of-field influences discomfort from a pre-existing accommodation-convergence conflict. Results showed no effect of depth-of-field on visual discomfort. These results suggest therefore that depth of-field can be used as a cue to depth without inducing discomfort in the viewer, even when cue conflicts are large. PMID- 23799194 TI - Attractiveness is influenced by the relationship between postures of the viewer and the viewed person. AB - Many factors influence physical attractiveness, including degree of symmetry and relative length of legs. We asked a sample of 112 young adults to rate the attractiveness of computer-generated female bodies that varied in terms of symmetry and leg-to-body ratio. These effects were confirmed. However, we also varied whether the person in the image was shown sitting or standing. Half of the participants were tested standing and the other half sitting. The difference in the posture of the participants increased the perceived attractiveness of the images sharing the same posture, despite the fact that participants were unaware that their posture was relevant for the experiment. We conclude that our findings extend the role of embodied simulation in social cognition to perception of attractiveness from static images. PMID- 23799195 TI - Illusory speed is retained in memory during invisible motion. AB - The brain can retain speed information in early visual short-term memory in an astonishingly precise manner. We investigated whether this (early) visual memory system is active during the extrapolation of occluded motion and whether it reflects speed misperception due to contrast and size. Experiments 1A and 2A showed that reducing target contrast or increasing its size led to an illusory speed underestimation. Experiments 1B, 2B, and 3 showed that this illusory phenomenon is reflected in the memory of speed during occluded motion, independent of the range of visible speeds, of the length of the visible trajectory or the invisible trajectory, and of the type of task. These results suggest that illusory speed is retained in memory during invisible motion. PMID- 23799196 TI - Zograscopic viewing. AB - The "zograscope" is a "visual aid" (commonly known as "optical machine" in the 18th century) invented in the mid-18th century, and in general use until the early 20th century. It was intended to view single pictures (thus not stereographic pairs) with both eyes. The optics approximately eliminates the physiological cues (binocular disparity, vergence, accommodation, movement parallax, and image blur) that might indicate the flatness of the picture surface. The spatial structure of pictorial space is due to the remaining pictorial cues. As a consequence, many (or perhaps most) observers are aware of a heightened "plasticity" of the pictorial content for zograscopic as compared with natural viewing. We discuss the optics of the zograscope in some detail. Such an analysis is not available in the literature, whereas common "explanations" of the apparatus are evidently nonsensical. We constructed a zograscope, using modern parts, and present psychophysical data on its performance. PMID- 23799197 TI - Haptic choice blindness. AB - Choice blindness is the failure to notice a mismatch between intention and outcome when making decisions. It is unknown whether choice blindness occurs when participants have extended interaction with real objects. Here, we examined the case when objects could be touched but not seen. Participants examined pairs of common, everyday objects inside a specially constructed box where a silent turntable was used to switch objects between initial choice and later justification. For similar pairs of objects, we found detection rates of around 22%, consistent with previous studies of choice blindness. For pairs consisting of more distinctive exemplars, the detection rate rose to 70%. Our results indicate that choice blindness does occur after haptic interaction with real objects, but is strongly modulated by similarity. PMID- 23799199 TI - Altered brain morphometry in carpal tunnel syndrome is associated with median nerve pathology. AB - OBJECTIVE: Carpal tunnel syndrome (CTS) is a common median nerve entrapment neuropathy characterized by pain, paresthesias, diminished peripheral nerve conduction velocity (NCV) and maladaptive functional brain neuroplasticity. We evaluated structural reorganization in brain gray (GM) and white (WM) matter and whether such plasticity is linked to altered median nerve function in CTS. METHODS: We performed NCV testing, T1-weighted structural MRI, and diffusion tensor imaging (DTI) in 28 CTS and 28 age-matched healthy controls (HC). Voxel based morphometry (VBM) contrasted regional GM volume for CTS versus HC. Significant clusters were correlated with clinical metrics and served as seeds to define associated WM tracts using DTI data and probabilistic tractography. Within these WM tracts, fractional anisotropy (FA), axial (AD) and radial (RD) diffusivity were evaluated for group differences and correlations with clinical metrics. RESULTS: For CTS subjects, GM volume was significantly reduced in contralesional S1 (hand-area), pulvinar and frontal pole. GM volume in contralesional S1 correlated with median NCV. NCV was also correlated with RD and was negatively correlated with FA within U-fiber cortico-cortical association tracts identified from the contralesional S1 VBM seed. CONCLUSIONS: Our study identified clear morphometric changes in the CTS brain. This central morphometric change is likely secondary to peripheral nerve pathology and altered somatosensory afference. Enhanced axonal coherence and myelination within cortico cortical tracts connecting primary somatosensory and motor areas may accompany peripheral nerve deafferentation. As structural plasticity was correlated with NCV and not symptomatology, the former may be a better determinant of appropriate clinical intervention for CTS, including surgery. PMID- 23799201 TI - Exploring targeted pulmonary delivery for treatment of lung cancer. AB - Lung cancer is the most malignant cancer today. The treatment of lung cancer continues to be a challenge for oncologists. The direct delivery of chemotherapeutic agents to the lungs could represent a novel therapeutic approach for patients with pulmonary metastases. The large alveolar surface area, the low thickness of the epithelial barrier, and an extensive vascularization make the pulmonary route an ideal route for administration of oncolytics. This paper reviews the research performed over the last and current decades on the delivery of various oncolytics for pulmonary delivery for the treatment of lung cancer. Inhaled drug delivery devices in cancer therapy are also discussed in the present manuscript. PMID- 23799200 TI - Novel gene delivery systems. AB - Gene therapy is an emerging field in medical and pharmaceutical sciences because of its potential in treating chronic diseases like cancer, viral infections, myocardial infarctions, and genetic disorders. Application of gene therapy is limited because of lack of suitable methods for proper introduction of genes into cells and therefore, this is an area of interest for most of the researchers. To achieve successful gene therapy, development of proper gene delivery systems could be one of the most important factors. Several nonviral and viral gene transfer methods have been developed. Even though the viral agents have a high transferring efficiency, they are difficult to handle due to their toxicity. To overcome the safety problems of the viral counterpart, several nonviral in vitro and in vivo gene delivery systems are developed. Out of these, the most promising and latest systems include polymer-based nonviral gene carriers, dendrimers, and physical means like electroporation, microinjection, etc., Shunning of possible immunogenicity and toxicity, and the feasibility of repeated administration are some of the merits of nonviral gene delivery systems over viral gene delivery. An ideal nonviral gene carrying system should possess all these merits without any compromise to its gene transferring efficiency. The viral gene delivery systems include lytic and nonlytic vectors for drug delivery. Inspite of its toxicity they are still preferred because of their long term expression, stability, and integrity. This review explores the recent developments and relevancy of the novel gene delivery systems in gene therapy. PMID- 23799202 TI - Quality risk management of top spray fluidized bed process for antihypertensive drug formulation with control strategy engendered by Box-behnken experimental design space. AB - INTRODUCTION: Lacidipine (LCDP) is a very low soluble and highly biovariable calcium channel blocker used in the treatment of hypertension. To increase its apparent solubility and to reduce its biovariability, solid dispersion fluid bed processing technology was explored, as it produces highly dispersible granules with a characteristic porous structure that enhances dispersibility, wettability, blend uniformity (by dissolving and spraying a solution of actives), flow ability and compressibility of granules for tableting and reducing variability by uniform drug-binder solution distribution on carrier molecules. MATERIALS AND METHODS: Main object of this quality risk management (QRM) study is to provide a sophisticated "robust and rugged" Fluidized Bed Process (FBP) for the preparation of LCDP tablets with desired quality (stability) and performance (dissolution) by quality by design (QbD) concept. RESULTS AND CONCLUSION: THIS STUDY IS PRINCIPALLY FOCUSING ON THOROUGH MECHANISTIC UNDERSTANDING OF THE FBP BY WHICH IT IS DEVELOPED AND SCALED UP WITH A KNOWLEDGE OF THE CRITICAL RISKS INVOLVED IN MANUFACTURING PROCESS ANALYZED BY RISK ASSESSMENT TOOLS LIKE: Qualitative Initial Risk-based Matrix Analysis (IRMA) and Quantitative Failure Mode Effective Analysis (FMEA) to identify and rank parameters with potential to have an impact on In Process/Finished Product Critical Quality Attributes (IP/FP CQAs). These Critical Process Parameters (CPPs) were further refined by DoE and MVDA to develop design space with Real Time Release Testing (RTRT) that leads to implementation of a control strategy to achieve consistent finished product quality at lab scale itself to prevent possible product failure at larger manufacturing scale. PMID- 23799203 TI - Formulation and evaluation of periodontal in situ gel. AB - BACKGROUND: The present study was aimed to develop and optimize in situ gel for the treatment of periodontal disease. MATERIALS AND METHODS: Temperature sensitive in situ gel containing 0.1% w/v Chlorhexidine hydrochloride was formulated by cold method using different polymers. Preliminary study was carried out to optimize different types and concentration of polymers such as Poloxamer 188, Poloxamer 407, Gellan gum, and Carbopol 934P. Central composite design was employed for optimization of the effect of independent variables such as Poloxamer 407 and Carbopol 934P on responses such as gelation temperature, spreadability, cumulative percentage release at 2 h, and time for 50% drug release (t50 %). Each formulations were evaluated for clarity, pH, gelation temperature, spreadability, drug content, in vitro drug release, t50 %, and cumulative percentage drug release at 2 h. RESULTS: Results of evaluation parameters revealed that the drug release, gelation temperature was considerably decreased with increasing t50 % as the concentration of each polymer was increased. The desirability function was utilized to find out optimized formulation of the factorial design. Formulation F6 showed the highest overall desirability of 0.6283 and, therefore, this formulation was considered to be the optimized formulation. The % relative error was calculated, which showed that observed responses were in close agreement with the predicted values calculated from the generated regression equations. CONCLUSION: The clarity, pH, drug content of all formulations was found to be satisfactory. Further, all the formulations showed sustained drug release for a period of 6 h, which satisfied to treat periodontal disease. PMID- 23799204 TI - Fabrication and in vitro evaluation of mucoadhesive ondansetron hydrochloride beads for the management of emesis in chemotherapy. AB - BACKGROUND: Mucoadhesive beads were fabricated and evaluated for controlled release of an antiemetic drug 'Ondansetron Hydrochloride'. Ondansetron hydrochloride is a serotonin 5-HT3 receptor antagonist mainly used for the treatment of emesis, which occurs as a side effect of chemotherapy. MATERIALS AND METHODS: The present work was to fabricate and evaluate ondansetron-loaded microbeads by using chitosan as mucoadhesive and sustained release polymer. Sodium tripolyphosphate (Na-TPP) was used as a cross-linking agent. The microbeads were successfully prepared by ionotropic gelation technique. The particle size, entrapment efficiency, and mucoadhesive strength of drug-loaded formulations was measured by an optical microscope, direct crushing method, and in vitro wash-off method, respectively. RESULTS: Particle size, entrapment efficiency, mucoadhesive strength, and in vitro drug release of optimized formulation was found to be 760.11 +/- 1.02 MUm, 75.09 +/- 2.40%, 95.14 +/- 0.27% and 87.45 +/- 1.21%, respectively. The data was fitted to different kinetic models to illustrate its anomalous (non-Fickian) diffusion. CONCLUSIONS: The results revealed that ondansetron HCl loaded microbeads are most suitable mode of drug delivery for promising therapeutic action. Ondansetron HCl-loaded microbeads can prove to be potential pharmaceutical dosage forms for sustaining the drug release and reducing the dose frequency. PMID- 23799205 TI - Formulation and evaluation of buccal film of Ivabradine hydrochloride for the treatment of stable angina pectoris. AB - BACKGROUND: Ivabradine hydrochloride is an anti-anginal drug with a biological half-life of about 2 h, and repeated daily administration is needed to maintain effective plasma level. Present investigation of buccal films of Ivabradine hydrochloride is an attempt to avoid the repeated administration and release of drug in more controlled fashion, thereby, to improve the bioavailability. MATERIALS AND METHODS: Buccal patches were fabricated by solvent casting technique and were evaluated for its physical properties like physical appearance, weight uniformity, thickness, swelling index, surface pH, mucoadhesive time, and folding endurance, in vitro and ex vivo release studies. RESULTS: A combination of hydroxypropyl methyl cellulose (HPMC) K15M and K100M with carbopol 940, PEG 6000 gave promising results. Further, the drug content of all the formulations was determined and was found to be uniform. All the formulations were subjected to in vitro release study using phosphate buffer pH 6.6. Patches exhibited drug release in the range of 90.36% +/- 0.854 to 98.37% +/ 0.589 at the end of six hrs. The best formulations (F2 and F5) containing the composition of HPMC K15-37.50 mg, carbopol-0.42 mg, PEG6000-16.87 mg, Aspertane 0.28 mg, Tween-0.0023 mg and HPMC K100-37.50 mg, carbopol-0.42 mg, PEG6000-16.87 mg, Aspertane-0.28 mg, Tween-0.0023 mg respectively exhibited in vitro drug release of 97.61% +/- 0.589 and 98.37% +/- 0.114 respectively. The results of ex vivo diffusion using goat cheek pouch revealed that the drug release rate was retarded up to seven hrs. Films prepared with permeation enhancer (Tween 80) showed faster drug release. Finally, stability studies were carried out by using human saliva for the optimized formulation (F2-F5). CONCLUSION: The present study indicated enormous potential of mucoadhesive buccal patches containing Ivabradine for systemic delivery with an added advantage of circumventing hepatic first pass metabolism. Further work is recommended to support its efficacy claims by long term pharmacokinetic and pharmacodynamic studies in human beings. PMID- 23799206 TI - Skin decontamination cream for radiological contaminants: Formulation development and evaluation. AB - BACKGROUND: Increased use of the radioactive materials in the field of research, medical, nuclear power plant, and industry has increased the risk of accidental exposure. Intentional use of the radioisotopes by terrorist organizations could cause exposure/contamination of a number of the population. In view of the accidental contamination, there is a need to develop self-usable decontamination formulations that could be used immediately after contamination is suspected. MATERIALS AND METHODS: Present work was planned to optimize and develop self usable radiation decontamination cream formulation. Various pharmaceutical parameters were characterized. (99m)Tc-sodium pertechnetate was used as radiocontaminant. Static counts were recorded before and after decontamination using single photon emission computed tomography. RESULTS: Decontamination efficacy of the cream was found to be 42% +/- 3% at 0-0.5 h after the exposure. Primary skin irritancy test was satisfactory as no erythema or edema was observed visually after 2 weeks of the formulation application. CONCLUSION: The decontamination studies proved the potential of EDTA to remove the radiological contaminants effectively. PMID- 23799207 TI - Comparative release profile of sustained release matrix tablets of verapamil HCl. AB - INTRODUCTION: Verapamil hydrochloride (VH) is a calcium channel blocking agent used in the treatment of hypertension, cardiac arrhythmia and angina pectoris. The short half-life and high frequency of administration of VH makes it a suitable candidate for designing sustained drug delivery system. The aim of the present investigation was to develop a sustained release matrix tablet of verapamil hydrochloride (VH) using ethyl cellulose, methyl cellulose, Eudragit RS 100, hydroxypropyl methylcellulose and carboxymethyl cellulose and to evaluate the drug release kinetics. MATERIALS AND METHODS: In order to achieve the required sustained release profile, the tablets were prepared by a wet granulation method using avicel PH 101 and magnesium stearate as binder and lubricant, respectively. RESULTS: The formulated tablets were characterized for pre-compression and post-compression parameters and they were in the acceptable limits. The drug release data obtained after an in vitro dissolution study was fitted to various release kinetic models in order to evaluate the release mechanism and kinetics. The criterion for selecting the best fit model was linearity (coefficient of correlation). Drug release mechanism was found to follow a complex mixture of diffusion, swelling and erosion. Furthermore, to minimize the initial burst drug release, batches were coated by using Eudragit RS100 polymer. After coating the tablets, a better release profile of the formulated tablets was expected and the release rate of the drug was compared with the marketed SR tablet of VH. CONCLUSION: The dosage form holds the potential to control the release rate of drug and extend the duration of action of a drug. PMID- 23799208 TI - Transplant rejection and risk: in search of the genetic dark matter. PMID- 23799209 TI - Endoscopic ultrasound-guided fine needle aspiration for solid pancreatic masses. Optimizing the diagnostic yield. PMID- 23799210 TI - Time for individualized colonoscopy bowel-prep regimens? A randomized controlled trial comparing sodium picosulphate and magnesium citrate versus 4-liter split dose polyethylene glycol. AB - BACKGROUND & AIMS: Good bowel cleansing is essential to achieving optimal endoscopic evaluation of the colon. There are many different regimens available, but none have shown consistently superior results in achieving a clean colon. We compared the efficiency of two regimens with regard to bowel cleansing and patient satisfaction. The study also aimed to identify patient-related factors that influenced the quality of the bowel cleansing. METHODS: We conducted a single-blind, multicenter, randomized controlled trial comparing sodium picosulphate and magnesium citrate versus 4-liter split-dose polyethylene glycol (PEG). Consecutive patients presenting for colonoscopy at two tertiary referral centers were invited to participate. The main outcomes were colon cleanliness and patient satisfaction with the preparation regimen. The quality of bowel cleansing was assessed by the endoscopist with the use of a 4-grade scale. Patients completed questionnaires evaluating their experience during the preparation process. Multivariate analysis was conducted in order to compare the two regimens and identify patient-related factors that influenced the main outcomes. RESULTS: One hundred eighty-one patients were randomized and 165 completed the trial (91.1%). PEG was slightly superior to sodium picosulphate with regard to bowel cleansing (p=0.01), while patient satisfaction was higher with sodium picosulphate (p=0.008). Patients with higher education and patients reporting high adherence to instructions achieved better colon cleansing using PEG. CONCLUSIONS: There seems to be no clear advantage for one bowel preparation solution over the other. However, by taking into account individual patient characteristics, opting for a particular regimen could increase the likelihood of achieving a cleaner colon. PMID- 23799211 TI - Levels of anti-double-strained DNA but not antinuclear antibodies are associated with treatment efficacy and adverse outcomes in Crohn's disease patients treated with anti-TNFalpha. AB - BACKGROUND & AIMS: Treatment of Crohn's disease (CD) by infliximab (IFX) has been associated with the induction of antinuclear (ANA) and anti-double strand DNA (dsDNA) autoantibodies and in some studies the formation of dsDNA antibodies was associated with lupus-like syndromes. The aims of this study were to analyse the relationship between the development of ANA and dsDNA antibodies during anti tumor necrosis factor (TNF)alpha therapy and the clinical efficacy or adverse outcome in patients with inflammatory bowel disease (IBD). METHODS: Data of 96 CD patients (age at presentation: 25.1 years, folow-up: 5 years, males/females 43/53) treated with anti-TNFalpha for at least one-year were analyzed. Records of a total of 198 one-year treatment cycles were collected and levels of autoantibodies were determined at induction and after one-year treatment periods. RESULTS: The majority of CD patients had ileocolonic (67.4%) and complicated disease (B2-B3: 72.6%) with perianal lesions (63.2%). At any time ANA or dsDNA positivity was 28.6% and 18%. Elevated level of ANA at induction or during anti TNFalpha therapy was not associated with treatment efficacy or development of adverse outcomes. In contrast, treatment efficacy (dsDNA positivity no/partial response vs. remission: 68.5% vs. 31.5%, P=0.003) was inferior and adverse outcomes were more frequent in patients with dsDNA positivity during the anti TNFalpha therapy in both univariate analysis and in logistic regression models (OR efficacy: 4.91, 95%CI: 1.15-20.8; OR adverse outcome: 3.81,95%CI 1.04-13.9). CONCLUSIONS: Our data suggest that development of dsDNA during biological therapy may be associated with suboptimal treatment efficacy and adverse outcomes in CD patients. PMID- 23799212 TI - ERCP on a cohort of 2,986 patients with cholelitiasis: a 10-year experience of a single center. AB - BACKGROUND & AIMS: Endoscopic Retrograde Cholangio-Pancreatography (ERCP) is the standard method of treatment for choledocholithiasis. We evaluated the diagnostic success rate and the outcomes of therapeutic ERCP for bile duct stones, in relation to the anatomical variants. METHOD: A total of 3,097 consecutive ERCPs were performed in 2,986 patients during a 10-year period (2002-2011) in our endoscopy department. The analysis of the results of therapy was performed in relation to the anatomical variants, patients' age, opacification of the Wirsung duct and recurrent lithiasis. RESULTS: The rate of successful cannulation was 98%. The patient's age and the diameter of the common bile duct were the factors influencing the probability of finding a gallstone: age over 74 years, AUC=0.547 (p<0.001) and a CBD diameter larger than 12 mm (AUC=0.735, p<0.001). The number of cases with opacification of the Wirsung duct, the use of precut papillotomy and the inability of finding a stone significantly decreased with the increasing experience of the operator (p<0.001). The stone removal was unsuccessful in 2.3%. Factors associated independently with unsuccessful extraction were previous surgical sphincteroplasty, stone size and Billroth I anastomosis. Ninety two patients (4.3%) were diagnosed with recurrent lithiasis. Factors associated independently with recurrence were stone size (p=0.002, OR=0.35), dilation of infundibulum (p=0.04, OR=0.13) and the presence of periampullary diverticula (p=0.004, OR=0.28). CONCLUSIONS: The endoscopic treatment of choledocholithiasis is highly effective. It is influenced partly by the experience of the operator. In experienced hands, the success rate is high even in cases of anatomical variants and difficult calculi. PMID- 23799213 TI - The role of 13C-methacetin breath test for the non-invasive evaluation of nonalcoholic fatty liver disease. AB - BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in many parts of the world. The 13C-methacetin breath test (MBT), a microsomal liver function test, enables quantitative evaluation of cytochrome P450-dependent liver function involved in NAFLD pathogenesis. The aim of our study was to evaluate the efficacy of MBT in differentiating patients with non-alcoholic steatohepatitis (NASH) from patients with simple steatosis (SS) and its ability to predict significant fibrosis in NAFLD patients. METHODS: We performed MBT in 64 patients with histologically proven NAFLD (ranging from SS to severe steatohepatitis) and in 20 healthy controls. Brunt scoring system for histological evaluation of NAFLD served as a reference. The correlation between MBT parameters and liver biopsy was tested using Spearman's coefficient. The overall validity was measured using the area under the receiver operating characteristic curve (AUROC) with 95%CI. RESULTS: 13C-MBT is a good tool for identifying patients with histologically proven NASH, with an AUROC of 0.824, 95% CI (0.723-0.926), a sensitivity of 95% and a specificity of 74%. The diagnosis accuracy of 13C-MBT for significant fibrosis (F >=2) has a validity of 91% (95% CI, AUROC = 0.830-0.989) with higher sensitivity (90%) and specificity (81%). 13C MBT values predicted better F3 or F4 fibrosis (AUROC were 0.936 and 0.973). CONCLUSION: Due to the impairment of microsomal function which occurs in NAFLD, 13C-MBT could be a reliable diagnostic and follow-up test for NAFLD patients. PMID- 23799214 TI - Performance of unidimensional transient elastography in staging chronic hepatitis C. Results from a cohort of 1,202 biopsied patients from one single center. AB - BACKGROUND & AIMS: The current study aimed to establish the liver stiffness (LS) cut-off values and their performance in the prediction of the fibrosis stage in chronic hepatitis C (CHC) patients, to find the anthropometric and biochemical factors leading to overestimation of the fibrosis stage and to analyze the factors leading to the technique failure. METHODS: 1,202 consecutive CHC patients were prospectively included in the study. All of them underwent percutaneous liver biopsy for grading and staging the disease (METAVIR) and were referred to LS measurement 1 day prior to biopsy. RESULTS: LS values varied between 2.8-75 kPa. Transient elastography success rate (SR) ranged between 0-100% (84.82 +/- 24.46%). In 27 patients (2.2%), no valid measurement was obtained; high BMI influenced independently the measurement failure. In 11.2% of cases, the SR was <60%, but 10 valid measurements were nevertheless recorded; the female sex and high BMI were the only factors independently leading to a SR<60%. AUROCs for the diagnosis of fibrosis F>=1, F>=2, F>=3, and F=4 were 0.879, 0.889, 0.941 and 0.970, for the cut-off values of 5.3 kPa, 7.4 kPa, 9.1 kPa and 13.2 kPa respectively, and they did not significantly differ from the adjusted AUROC values. The patients with false positive results were younger and had significantly higher serum aminotransferase (ALT, AST) and gamma glutamyl transpeptidase levels than the patients with concordant results. The multivariate analysis showed that only high ALT levels influenced independently the occurrence of false positive results. CONCLUSION: Transient elastography is a useful non invasive method for the assessment of fibrosis in CHC patients. However, it must be interpreted in the clinical and biochemical context, in order to insure high quality results. PMID- 23799215 TI - Association of transporter associated with antigen processing (TAP) gene polymorphisms in donors with acute cellular rejection in living donor liver transplantation. AB - BACKGROUND & AIMS: Despite improvements in immunosuppressive therapy, acute cellular rejection (ACR) remains an important cause of mortality and graft loss in patients undergoing liver transplantation. Recently, associations between gene polymorphisms and the incidence of ACR have been reported, though few studies have investigated those polymorphisms in donors. Transporter associated with antigen processing (TAP1 and TAP2) are involved in major histocompatibility complex (MHC) class I antigen-mediated processing and presentation to cytotoxic CD8+ T lymphocytes. The aim of this study was to determine whether TAP1 and TAP2 gene polymorphisms in the donor have affected on ACR incidence in living donor liver transplantation (LDLT). METHODS: We examined 155 LDLTs treated at Nagoya University or Kyoto University from 2004 to 2009 and analyzed the gene polymorphisms of TAP-1 p.Ile333Val, TAP-1 p.Asp697Gly, TAP-2 p.Arg651Cys, and TAP 2 p.Gln687Stop. RESULTS: Thirty-seven recipients developed early ACR. Of the investigated gene polymorphisms, the TAP-1 p.697Gly allele in donors was associated with incidence of early ACR (OR=2.97, 95%CI 1.33-6.63, p=0.008). CONCLUSIONS: The TAP-1 p.697Gly allele in donors was associated with increased incidence of early ACR following LDLT. The TAP-1 697 polymorphism in donors can be genotyped prior to LDLT, which may contribute to individualize immunosuppression strategies for recipients and donor selection. PMID- 23799217 TI - Repeat endoscopic ultrasound-guided fine needle aspiration for solid pancreatic lesions at a tertiary referral center will alter the initial inconclusive result. AB - BACKGROUND & AIMS: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is indispensable for the diagnosis of solid pancreatic lesions (SPLs). However, initial attempt of EUS-FNA can be inconclusive. We retrospectively evaluated the ability of repeat EUS-FNA at a tertiary referral hospital to obtain a conclusive cytological diagnosis after the initial inconclusive EUS-FNA results at referring facilities. METHODS: We identified patients who had undergone EUS-FNA for SPLs and with inconclusive cytological diagnosis at referring facilities. The diagnostic ability of EUS-FNA was defined as the percentage of cases with conclusive cytological diagnoses out of the total included cases in which initial results had been inconclusive. As a secondary outcome, we conducted sub-group analysis to reveal factors which might have assisted conclusive results at the University of Texas MD Anderson Cancer Center (MDA). RESULTS: We found 913 patients who underwent EUS-FNA for SPLs between 2005 and 2011. Among them, we recruited 84 patients who met the above criteria. Repeat EUS-FNA had ability to clarify the diagnosis in 82.1 % (69/84). No statistical differences were observed in tumor size (n = 50, 29.8 versus 29.4 mm, P-value = 0.84) and the number of needles passes (n = 40, 4.0 versus 3.4, P-value = 0.1) between outside MDA and MDA. Rapid on-site evaluation was present in less than half of cases outside MDA (n = 33, 42.4 versus 100%, P-value = 0.0001). MDA endosonographers had more years of experience compared to outside MDA (n = 50, 12.9 versus 10 years, P-value = 0.015). CONCLUSIONS: A repeat EUS-FNA for SPLs with initial inconclusive diagnosis at a tertiary referral center establishes a diagnosis in the majority of patients. PMID- 23799216 TI - Effect of body mass index on survival after curative therapy for non-B non-C hepatocellular carcinoma. AB - BACKGROUND & AIMS: The impact of obesity on survival after curative treatment for non-B non-C hepatocellular carcinoma (NBNC-HCC) remains unclear. This study examined the prognostic impact of obesity in patients who received curative therapy for NBNC-HCC. METHODS: A total of 260 patients with NBNC-HCC who underwent curative therapy were analyzed. They included 116 obese patients (44.6%) with a body mass index (BMI) >25 kg/m2 (obesity group) and 144 control patients (55.4%) with a BMI <25 kg/m2 (control group). Overall survival (OS) and recurrence-free survival (RFS) rates were compared. RESULTS: The median observation periods in the obesity and control groups were 3.1 and 3.0 years, respectively. The 1-, 3- and 5-year cumulative OS rates were 93.9%, 77.3% and 56.0% in the obesity group, and 98.8%, 77.3% and 62.1% in the control group, respectively (p = 0.955). The corresponding RFS rates were 74.6%, 28.0% and 19.0% in the obesity group, and 70.0%, 44.3% and 28.9%, in the control group, respectively (p = 0.128). Multivariate analyses identified a serum albumin >4.0 g/dL (hazard ratio [HR], 1.759; 95% confidence interval [CI], 1.007-3.074; p = 0.047) and des-gamma-carboxy prothrombin >100 mAU/mL (HR, 0.396; 95% CI, 0.243 0.646; p < 0.001) as independent factors linked to OS. Alkaline phosphatase>300 IU/L (HR, 0.549; 95% CI, 0.367-0.823; p = 0.004) and gamma-glutamyl transferase >100 IU/L (HR, 0.679; 95% CI, 0.471-0.978; p = 0.038) were significant adverse predictors linked to RFS. CONCLUSIONS: Obesity does not affect survival in patients with NBNC-HCC after curative therapy. PMID- 23799218 TI - Update on the management of alcoholic steatohepatitis. AB - Among heavy drinkers with liver disease, the development of severe alcoholic hepatitis (AH) is a serious complication. Prognosis is grave and associated with a high mortality due to liver failure, hepatorenal syndrome or intractable sepsis. Clinically, AH presents as a syndrome of progressive inflammatory liver injury in patients with recent or ongoing heavy alcohol consumption. Although approximately 20% of alcoholics undergoing liver biopsy reveal histological features of AH, only a minority progress to severe AH with markedly elevated serum liver enzymes, jaundice and impaired liver function. To establish the diagnosis of AH, histology is recommended but not mandatory. Prognostic scores include the Maddrey's discriminant function, the model of end-stage liver disease, the Glasgow Alcoholic Hepatitis score, and the ABIC score. While the former scores identify patients at risk of death or the need for corticosteroids, the response to corticosteroid therapy can be assessed using the Lille model. Treatments include abstinence and enteral nutrition, while pharmacotherapy using corticosteroids either with or without N-acetylcysteine may be indicated for patients with severe AH. Pentoxifylline was found to reduce the risk of hepatorenal syndrome, but data on mortality are limited. Although considered a contraindication in most transplant centers, recent evidence indicates that carefully selected patients with AH could be good candidates for liver transplantation with a prognosis comparable to other indications. PMID- 23799219 TI - The pleiotropic effects and therapeutic potential of the hydroxy-methyl-glutaryl CoA reductase inhibitors in gastrointestinal tract disorders: a comprehensive review. AB - The hydroxy-methyl-glutaryl-CoA reductase inhibitors (statins) are used extensively in the treatment of dyslipidemia, and for the prevention and treatment of coronary artery disease and stroke. They have also demonstrated a benefit in a variety of other disease processes through their non-lipid lowering properties, known as pleiotropic effects. Our paper serves as a focused and updated discussion of the pleiotropic effects of statins in gastrointestinal disorders. PMID- 23799220 TI - De-novo onset of eosinophilic esophagitis after large volume allergen exposures. AB - Eosinophilic esophagitis (EoE) is a chronic immune-mediated condition believed to have an allergic component, but the timing of the initial allergen triggers that cause the disease is poorly understood. While the clinical presentation of EoE is often of longstanding symptoms, in animal models, acute exposure to an allergen challenge successfully produces EoE. In this report, we present three cases of individuals who developed esophageal eosinophilia and EoE shortly after a clearly identified exposure to aeroallergens. These cases highlight the allergic etiology of EoE, and provide a link from humans to the previously described experimental mechanisms. PMID- 23799221 TI - Accidentally ingested foreign body associated with liver actinomycosis: the diagnostic value of imaging. AB - Accidental ingestion of foreign bodies is a relatively common situation, in the large majority of cases being followed by an unobserved passing of the objects through the digestive tract and their elimination in about a week. We present a patient with liver actinomycosis developed in relation with a gastric (antral) perforation secondary to accidental foreign body ingestion. The complexity of the case raised many problems concerning the imaging diagnosis, especially due to the pseudotumoral aspect of the liver lesion, which extensively involved the retroperitoneal area, the stomach and the pancreas. However, the presence of an image suggesting a foreign body into the gastric wall, in correlation with clinical, biological, morphological and imaging studies solved the case. PMID- 23799222 TI - Upper gastrointestinal bleeding in a young patient with Budd Chiari syndrome due to a mutation of factor V Leiden: a case report. AB - Budd Chiari syndrome or hepatic venous outflow obstruction is a complex entity with multiple etiologies and various clinical manifestations. It is often difficult to establish the diagnosis. The most common cause is a hypercoagulable state due to either genetic disorders of blood coagulation or several acquired conditions such as hematological diseases, tumors, infections, chronic inflammatory diseases, pregnancy. The most common clinical presentation is hepatomegaly, abdominal pain and ascites, but the onset can also be dramatical and life threatening with upper digestive bleeding due to portal hypertension through postsinusoidal blockage. We report the case of a young patient with a coagulation disorder secondary to a mutation of factor V Leiden, who presented with upper digestive bleeding as the first manifestation of Budd Chiari syndrome and who also was associated with myocardial infarction in his past medical history. PMID- 23799223 TI - Gall bladder malignancy: an unusual association. AB - Gall bladder malignancy predominantly comprises adenocarcinoma and is found mostly in a late stage whereas primary lymphoma of mucosa associated lymphoid tissue (MALT) within the gall bladder is exceedingly rare and has an incidental presentation. We report a case of well differentiated adenocarcinoma with MALT lymphoma of the gall bladder in an 83 year old woman. To our knowledge, this is the first case of a carcinoma and lymphoma occurring simultaneously in the gall bladder. PMID- 23799224 TI - Real-time elastography applications in liver pathology between expectations and results. AB - Real time elastography has very good results in differentiating tumors of the breast, thyroid, prostate, pancreas and lymph nodes. Because liver biopsy is invasive and has complications, the method has been tried in diffuse or localized liver pathology in the hope of similar results. However, the published studies are isolated and performed on small groups of patients and the working methodology differs from author to author, without a consensus regarding the establishing of the area of interest, the recording and data analysis. The appearance of the elastography software on the convex probe with high penetration, the possibility for elastography to visualize the liver entirely and the development of elastography measurement information programs opened new perspectives in the noninvasive assessment of liver pathology. PMID- 23799225 TI - On the treatment of new oral anticoagulant-associated gastrointestinal hemorrhage. AB - The recently introduced new oral anticoagulants (nOAC) carry a higher gastrointestinal bleeding risk compared to traditional antithrombotic therapy. Current diagnostic coagulation tests are not accurate enough to determine the level of coagulopathy. Besides that, the lack of a specific antidote leaves the endoscopist unsure how to achieve hemostasis during gastrointestinal hemorrhage. In this brief report, we address the (endoscopic) management, when facing a suspected nOAC-associated gastrointestinal hemorrhage. We recommend that specific coagulation tests such as diluted thrombin time and anti-Xa measurement should be made available. Furthermore, nOAC should be stopped. Finally, correcting coagulopathy with administration of prothrombin complex concentrate, recombinant factor VIIa and even hemodialysis should be considered, whereas fresh frozen plasma and vitamin K have no place. The generalizability of these recommendations needs to be confirmed in future studies. PMID- 23799226 TI - Comments on colorectal cancer screening. PMID- 23799227 TI - Endoscopic gastrointestinal lavage (EGIL): a new sampling technique for the untouchable patient. PMID- 23799228 TI - Seroclearance of Hepatitis B surface antigen after entecavir treatment. PMID- 23799229 TI - Hepatocellular carcinoma in Budd-Chiari syndrome after treatment with an expandable metallic stent. PMID- 23799230 TI - A target-induced fluorescent nanoparticle for in situ monitoring of Zn(II). AB - A target-induced fluorescent silica nanoparticle has been developed for the identification, enrichment and in situ determination of trace amounts of zinc(II). The nanoparticle combines the advantages of target-induced fluorescent compounds and the small size of the nanomaterial to produce a new, smarter nanosignaling material that is capable of selectively enriching a target and detecting a specific binding process in one step. As the target analyte, Zn(II), changes the fluorescence characteristics of the nanoparticle and effectively 'turns on' the fluorescence signal, no separation step is needed to confirm or quantify the binding process. The designed nanoparticle was characterized by several aspects prior to monitoring of Zn(II) in situ. The interferences from common metal ions were studied in detail. The photostability and reversibility of the sensing materials were investigated as well. The ability of this nanoparticle to detect the target Zn(II) provides a great advantage for in situ monitoring targets in biological samples under the fluorescence microscope. PMID- 23799231 TI - DNA assembly and enzymatic cutting in solutions: a gold nanoparticle based SERS detection strategy. AB - The ability to monitor biomolecular recognition such as DNA hybridization and enzymatic reactivity in solutions with high sensitivity is important for developing effective bioassay strategies. Surface enhanced Raman scattering (SERS) based on use of solid substrates to produce the SERS effect for the detection often requires substrate preparation which is ineffective for rapid monitoring. This report describes a new strategy exploiting a gold nanoparticle (AuNP) based interparticle "hot-spot" for SERS monitoring of DNA mediated assembly and enzyme induced cleavage of the assembly in solution phase. The DNAs consist of two different complementary DNA strands with a thiol modification for attachment to AuNPs of selected sizes. In a solution containing AuNPs conjugated with one of the single-stranded (ss) DNA and other AuNPs labeled with a Raman reporter molecule, 4-mercaptobenzoic acid (MBA), the introduction of the complementary DNA strand leads to a linkage of the two types of AuNPs, producing double-stranded (ds) DNA-AuNP assembly (ds-DNA-AuNPs) with an interparticle "hot spot" for SERS detection of the diagnostic bands of the reporter. Upon introducing a restriction enzyme (e.g. MspI) into the ds-DNA-AuNP assembly solution, the removal of the interparticle "hot-spot" due to restriction enzyme cleavage of the ds-DNA leads to a decrease of the SERS signals. While the detailed cleavage process may depend on the reaction time and the amount of enzyme, the viability of using gold nanoparticle "hot-spot" based SERS monitoring of DNA assembly and enzyme cleavage is clearly demonstrated, which has important implications for developing new strategies for bioassays. PMID- 23799232 TI - An AC voltammetry approach for the detection of droplets in microfluidic devices. AB - A simple electrochemical method using ac voltammetry to detect aqueous droplets up to 480 droplets per second in a flow-focusing microfluidic device is presented. The method offers a promising and versatile platform with simple and inexpensive instrumentation for droplets real time detection and preliminary characterization. PMID- 23799233 TI - Mapping of egg yolk and animal skin glue paint binders in Early Renaissance paintings using near infrared reflectance imaging spectroscopy. AB - In situ chemical imaging techniques are being developed to provide information on the spatial distribution of artists' pigments used in polychrome works of art such as paintings. The new methods include reflectance imaging spectroscopy and X ray fluorescence mapping. Results from these new methods have extended the knowledge obtained from site-specific chemical analyses widely in use. While these mapping methods have aided in determining the distribution of pigments, there is a growing interest to develop methods capable of identifying and mapping organic paint binders as well. Near infrared (NIR) reflectance spectroscopy has been extensively used in the remote sensing field as well as in the chemical industry to detect organic compounds. NIR spectroscopy provides a rapid method to assay organics by utilizing vibrational overtones and combination bands of fundamental absorptions that occur in the mid-IR. Here we explore the utility of NIR reflectance imaging spectroscopy to map organic binders in situ by examining a series of panel paintings known to have been painted using distemper (animal skin glue) and tempera (egg yolk) binders as determined by amino acid analysis of samples taken from multiple sites on the panels. In this report we demonstrate the success in identifying and mapping these binders by NIR reflectance imaging spectroscopy in situ. Three of the four panel paintings from Cosimo Tura's The Annunciation with Saint Francis and Saint Louis of Toulouse (ca. 1475) are imaged using a highly sensitive, line-scanning hyperspectral imaging camera. The results show an animal skin glue binder was used for the blue skies and blue robe of the Virgin Mary, and egg yolk tempera was used for the red robes and brown landscape. The mapping results show evidence for the use of both egg yolk and animal skin glue in the faces of the figures. The strongest absorption associated with lipidic egg yolk features visually correlates with areas that appear to have white highlights. The results are in agreement with prior site-specific amino acid analysis, underscoring the synergy of both methods. The work here demonstrates that NIR reflectance imaging spectroscopy is a useful technique that can identify and map paint binding media based on differences in chemical composition. PMID- 23799234 TI - Pt-Pd bimetallic nanoparticles dispersed in an ionic liquid and peroxidase immobilized on nanoclay applied in the development of a biosensor. AB - Pt-Pd bimetallic alloy nanoparticles (NPs) dispersed in the ionic liquid 1-butyl 3-methylimidazolium hexafluorophosphate (Pt-Pd-BMI.PF6) were employed together with a peroxidase (PO) enzyme from cauliflower immobilized on nanoclay for the development of a new biosensor for polyphenol determination by square-wave voltammetry (SWV). The biosensor demonstrated good repeatability and reproducibility, low limit of detection (LOD = 3.7 * 10(-7) mol L(-1) for caffeic acid (CA)), and adequate lifetime and stability (maintaining over 80% of the response over 80 days of evaluation, and allowing over 600 measurements by SWV for each electrode). Under optimized conditions, the proposed biosensor was applied in the determination of the bioelectrochemical polyphenolic index (BPI) for samples of commercial white wine, using CA as the phenolic compound standard. The recovery of CA from wine samples ranged from 95.5 to 108.3%. The values for the polyphenolic content obtained using the proposed biosensor showed a good correlation (r = 0.990) with those obtained with the reference spectrophotometric method (Folin-Ciocalteu method). Therefore, the proposed biosensor represents a useful tool for the rapid and accurate monitoring of polyphenolic content in wine samples and may also be applicable to other beverage samples, such as juices and teas. PMID- 23799235 TI - On the nature of DNA hyperchromic effect. AB - A combined theoretical-experimental study of the hyperchromic effect as occurring in the denaturation of a double stranded polyA-polyT is presented. Our theoretical/computational procedure allows us to reproduce the essential features of the experimental spectra and to characterize those molecular interactions responsible for the changes in the UV absorbance. We found that although excitonic intrastrand interactions strongly affect the absorbance, they are almost fully maintained in the single-stranded DNA. Our data indicate that hyperchromic effect originates from the higher delocalization of the excitonic states in the denaturated DNA with respect to the double-stranded conformation. PMID- 23799236 TI - Real-time subsecond voltammetric analysis of Pb in aqueous environmental samples. AB - Lead (Pb) pollution is an important environmental and public health concern. Rapid Pb transport during stormwater runoff significantly impairs surface water quality. The ability to characterize and model Pb transport during these events is critical to mitigating its impact on the environment. However, Pb analysis is limited by the lack of analytical methods that can afford rapid, sensitive measurements in situ. While electrochemical methods have previously shown promise for rapid Pb analysis, they are currently limited in two ways. First, because of Pb's limited solubility, test solutions that are representative of environmental systems are not typically employed in laboratory characterizations. Second, concerns about traditional Hg electrode toxicity, stability, and low temporal resolution have dampened opportunities for in situ analyses with traditional electrochemical methods. In this paper, we describe two novel methodological advances that bypass these limitations. Using geochemical models, we first create an environmentally relevant test solution that can be used for electrochemical method development and characterization. Second, we develop a fast-scan cyclic voltammetry (FSCV) method for Pb detection on Hg-free carbon fiber microelectrodes. We assess the method's sensitivity and stability, taking into account Pb speciation, and utilize it to characterize rapid Pb fluctuations in real environmental samples. We thus present a novel real-time electrochemical tool for Pb analysis in both model and authentic environmental solutions. PMID- 23799237 TI - Adolescents' perception of environmental features and its association with physical activity: results from de Azorean Physical Activity and Health Study II. AB - BACKGROUND: The aim of the current study was to verify if physical activity (PA) behavior (steps/day) was associated with environmental features that may be able to promote PA and walking in a sample of Portuguese adolescents living in the Azorean Archipelago. METHODS: The sample comprised 948 adolescents aged 15-18 years (543 girls) from the Azorean Physical Activity Health Study II. PA was objectively measured with pedometers. Participants were classified as active if they belong to percentile 75th (by age and gender) or more. Environmental perceptions were assessed with a questionnaire. Binary logistic regression analyzed relationships between PA and environmental perceptions controlling for age, body mass index, gender and socioeconomic status. RESULTS: Regression analysis showed that participants with a positive overall perception in the transportation dimension were 44.2% (OR = 1.442, P = .025) more likely to be classified as active than those with a negative overall perception. No significant results were found for safety, aesthetics and facilities dimensions. CONCLUSIONS: A positive overall perception of the transportation dimension was positively associated with PA in Azorean Adolescents. Future health promotion strategies aimed to increase PA in this population should consider the environmental features that are associated with PA levels. PMID- 23799238 TI - Recurrent oil sheens at the deepwater horizon disaster site fingerprinted with synthetic hydrocarbon drilling fluids. AB - We used alkenes commonly found in synthetic drilling-fluids to identify sources of oil sheens that were first observed in September 2012 close to the Deepwater Horizon (DWH) disaster site, more than two years after the Macondo well (MW) was sealed. While explorations of the sea floor by BP confirmed that the well was sound, they identified the likely source as leakage from an 80-ton cofferdam, abandoned during the operation to control the MW in May 2010. We acquired sheen samples and cofferdam oil and analyzed them using comprehensive two-dimensional gas chromatography. This allowed for the identification of drilling-fluid C16- to C18-alkenes in sheen samples that were absent in cofferdam oil. Furthermore, the spatial pattern of evaporative losses of sheen oil alkanes indicated that oil surfaced closer to the DWH wreckage than the cofferdam site. Last, ratios of alkenes and oil hydrocarbons pointed to a common source of oil found in sheen samples and recovered from oil-covered DWH debris collected shortly after the explosion. These lines of evidence suggest that the observed sheens do not originate from the MW, cofferdam, or from natural seeps. Rather, the likely source is oil in tanks and pits on the DWH wreckage, representing a finite oil volume for leakage. PMID- 23799240 TI - Effects of exergaming based exercise on urban children's physical activity participation and body composition. AB - BACKGROUND: Exergaming has been considered a fun solution to promoting a physically active lifestyle. This study examined the impact of an exergaming based program on urban children's physical activity participation, body composition and perceptions of the program. METHODS: A sample of 185 children's physical activity was measured in August 2009 (pretest), and percent body fat was used as index of body composition. Fourth graders were assigned to intervention group engaging in 30 minutes exergaming-based activities 3 times per week, while third and fifth graders were in comparison group. Measurements were repeated 9 months later (posttest). Interviews were conducted among 12 intervention children. RESULTS: ANCOVA with repeated measures revealed a significant main effect for intervention, F(1, 179) = 10.69, P < .01. Specifically, intervention children had significantly greater increased physical activity levels than comparison children. Logistic regression for body composition indicated intervention children did not differ significantly in percent body fat change from comparison children, Chi square = 5.42, P = .14. Children interviewed reported positive attitudes toward the intervention. CONCLUSIONS: The implementation of exergaming-based program could have a significantly positive effect on children's physical activity participation and attitudes. Meanwhile, long-term effect of the program on children's body composition deserves further investigation. PMID- 23799239 TI - Assessment of antigenemia assay for the diagnosis of cytomegalovirus gastrointestinal diseases in HIV-infected patients. AB - We conducted a single-center prospective study to evaluate the utility of cytomegalovirus (CMV) antigenemia assay for the diagnosis of CMV-gastrointestinal disease (GID). The study subjects were HIV-infected patients with CD4 count <=200 MUL/cells who had undergone endoscopy. A definite diagnosis of CMV-GID was made by histological examination of endoscopic biopsied specimen. CMV antigenemia assay (C10/C11 monoclonal antibodies), CD4 count, HIV viral load, history of HAART, and gastrointestinal symptoms as measured by 7-point Likert scale, were assessed on the same day of endoscopy. One hundred cases were selected for analysis, which were derived from 110 cases assessed as at high-risk for CMV-GID after endoscopy screening of 423 patients. Twelve patients were diagnosed with CMV-GID. Among the gastrointestinal symptoms, mean bloody stool score was significantly higher in patients with CMV-GID than in those without (2.5 vs. 1.7, p=0.02). The area under the receiver-operating characteristic curve of antigenemia was 0.80 (95%CI 0.64-0.96). The sensitivity, specificity, positive likelihood ratio (LR), and negative LR of antigenemia were 75.0%, 79.5%, 3.7, and 0.31, respectively, when the cutoff value for antigenemia was >=1 positive cell per 300,000 granulocytes, and 50%, 92.0%, 5.5, and 0.55, respectively, for >=5 positive cells per 300,000 granulocytes. In conclusion, CMV antigenemia seems a useful diagnostic test for CMV-GID in patients with HIV infection. The use of >=5 positive cells per 300,000 granulocytes as a cutoff value was associated with high specificity and high positive LR. Thus, a positive antigenemia assay with positive endoscopic findings should allow the diagnosis of CMV-GID without biopsy. PMID- 23799241 TI - Gas phase acidity measurement of local acidic groups in multifunctional species: controlling the binding sites in hydroxycinnamic acids. AB - The applicability of the extended kinetic method (EKM) to determine the gas phase acidities (GA) of different deprotonable groups within the same molecule was tested by measuring the acidities of cinnamic, coumaric, and caffeic acids. These molecules differ not only in the number of acidic groups but in their nature, intramolecular distances, and calculated GAs. In order to determine independently the GA of groups within the same molecule using the EKM, it is necessary to selectively prepare pure forms of the hydrogen-bound heterodimer. In this work, the selectivity was achieved by the use of solvents of different vapor pressure (water and acetonitrile), as well as by variation of the drying temperature in the ESI source, which affected the production of heterodimers with different solvation energies and gas-phase dissociation energies. A particularly surprising finding is that the calculated solvation enthalpies of water and the aprotic acetonitrile are essentially identical, and that the different gas-phase products generated are apparently the result of their different vapor pressures, which affects the drying mechanism. This approach for the selective preparation of heterodimers, which is based on the energetics, appears to be quite general and should prove useful for other studies that require the selective production of heterodimers in ESI sources. The experimental results were supported by density functional theory (DFT) calculations of both gas-phase and solvated species. The experimental thermochemical parameters (deprotonation DeltaG, DeltaH, and DeltaS) are in good agreement with the calculated values for the monofunctional cinnamic acid, as well as the multifunctional coumaric and caffeic acids. The measured GA for cinnamic acid is 334.5 +/- 2.0 kcal/mol. The measured acidities for the COOH and OH groups of coumaric and caffeic acids are 332.7 +/- 2.0, 318.7 +/- 2.1, 332.2 +/- 2.0, and 317.3 +/- 2.2 kcal/mol, respectively. PMID- 23799242 TI - Interaction and structure in polyelectrolyte/clay multilayers: a QCM-D study. AB - This study focuses on the investigation of the influence of the ionic strength on the internal structure, film forming behavior, and swelling properties of polyelectrolyte/clay multilayers. Layer-by-layer films were prepared with three different polyelectrolytes [polyethylenimine (PEI), polydiallyldimethylammoniumchloride (pDADMAC), and 2-hydroxy-3-trimethylammonium propyl chloride starch (HPMA starch)] in combination with laponite clay platelets on three different surfaces. All experiments were carried out at two different ionic strengths (30 mM or 500 mM NaCl). The experiments performed with strong polyelectrolytes revealed a higher film thickness and adsorbed masses of clay and polyelectrolyte at 500 mM NaCl. The films containing PEI showed different behavior and were considerably less sensitive to changes in the ionic strength. This was also reflected by the swelling behavior as demonstrated by quartz crystal microbalance with dissipation (QCM-D) measurements. Films comprising PEI showed, in contrast to the other polyelectrolytes, much lower swelling in water leading to more compact and stable films in humid environments which is important for numerous applications of LbL clay coatings. PMID- 23799243 TI - Effects of drop size and viscosity on spreading dynamics in DC electrowetting. AB - This study investigates the effects of drop size and viscosity on spreading dynamics, including response time, maximum velocity, and spreading pattern transition, in response to various DC voltages, based on both experiment and theoretical modeling. It is experimentally found that both switching time (i.e., time to reach maximum wetted radius) and settling time (i.e., time to reach equilibrium radius) are proportional to 1.5th power of the effective base radius. It is also found that the maximum velocity is slightly dependent on drop size but linearly proportional to the electrowetting number. The viscosity effect on drop spreading is investigated by observing spreading patterns with respect to applied voltages, and the critical viscosity at which a spreading pattern changes from under- to overdamped response is obtained. Theoretical models with contact angle hysteresis predict the spreading dynamics of drops with low and high viscosities fairly well. By fitting the theoretical models to experimental results, we obtain the friction coefficient, which is nearly proportional to 0.6th power of viscosity and is rarely influenced by applied voltage and drop size. Finally, we find that drop viscosity has a weak effect on maximum velocity but not a clear one on contact line friction. PMID- 23799244 TI - Understanding advanced theory of mind and empathy in high-functioning adults with autism spectrum disorder. AB - It has been argued that higher functioning individuals with autism spectrum disorders (ASDs) have specific deficits in advanced but not simple theory of mind (ToM), yet the questionable ecological validity of some tasks reduces the strength of this assumption. The present study employed The Awareness of Social Inference Test (TASIT), which uses video vignettes to assess comprehension of subtle conversational inferences (sarcasm, lies/deception). Given the proposed relationships between advanced ToM and cognitive and affective empathy, these associations were also investigated. As expected, the high-functioning adults with ASDs demonstrated specific deficits in comprehending the beliefs, intentions, and meaning of nonliteral expressions. They also had significantly lower cognitive and affective empathy. Cognitive empathy was related to ToM and group membership whereas affective empathy was only related to group membership. PMID- 23799245 TI - Mast cell mediators cause early allergic bronchoconstriction in guinea-pigs in vivo: a model of relevance to asthma. AB - One feature of allergic asthma, the EAR (early allergic reaction), is not present in the commonly used mouse models. We therefore investigated the mediators involved in EAR in a guinea-pig in vivo model of allergic airway inflammation. Animals were sensitized using a single OVA (ovalbumin)/alum injection and challenged with aerosolized OVA on day 14. On day 15, airway resistance was assessed after challenge with OVA or MCh (methacholine) using the forced oscillation technique, and lung tissue was prepared for histology. The contribution of mast cell mediators was investigated using inhibitors of the main mast cell mediators [histamine (pyrilamine) and CysLTs (cysteinyl-leukotrienes) (montelukast) and prostanoids (indomethacin)]. OVA-sensitized and challenged animals demonstrated AHR (airway hyper-responsiveness) to MCh, and lung tissue eosinophilic inflammation. Antigen challenge induced a strong EAR in the sensitized animals. Treatment with a single compound, or indomethacin together with pyrilamine or montelukast, did not reduce the antigen-induced airway resistance. In contrast, dual treatment with pyrilamine together with montelukast, or triple inhibitor treatment, attenuated approximately 70% of the EAR. We conclude that, as in humans, the guinea-pig allergic inflammation model exhibits both EAR and AHR, supporting its suitability for in vivo identification of mast cell mediators that contribute to the development of asthma. Moreover, the known mast cell mediators histamine and leukotrienes were major contributors of the EAR. The data also lend further support to the concept that combination therapy with selective inhibitors of key mediators could improve asthma management. PMID- 23799246 TI - Low physical activity levels and associated factors in Brazilian adolescents from public high schools. AB - BACKGROUND: Several studies have shown that physical activity levels have declined in many countries, even with the regular practice of physical education in schools. The purpose of this study was to identify the prevalence of low physical activity levels and associated factors in adolescents enrolled in public high schools in Northeastern Brazil. METHODS: The sample was composed of 2259 adolescents (62.3% female) aged 16.26 +/- 1.1 years. A questionnaire was applied to collect data on physical activity levels, sociodemographic information, tobacco use and alcohol consumption, nutritional status and sedentary behavior. Descriptive statistics and Poisson regression hierarchized model with Prevalence Rate (PR) and P <= .05 were used. RESULTS: Higher prevalence of low physical activity level (89.1%) was observed. It was observed that 19.6% of individuals did not attend physical education classes regularly. Association was identified between low physical activity level and older girls (P = .02) and not attending physical education classes (P < .01). In males, the group most likely to have that low physical activity level was those whose parents studied until three years (P = .04). CONCLUSIONS: Low physical activity level was present in most adolescents, more evident in girls. Lifestyle changes are needed, with substitution of sedentary activities for physical and sport activities in schools. PMID- 23799247 TI - Combined N-glycome and N-glycoproteome analysis of the Lotus japonicus seed globulin fraction shows conservation of protein structure and glycosylation in legumes. AB - Legume food allergy, such as allergy toward peanuts and soybeans, is a health issue predicted to worsen as dietary advice recommends higher intake of legume based foods. Lotus japonicus (Lotus) is an established legume plant model system for studies of symbiotic and pathogenic microbial interactions and, due to its well characterized genotype/phenotype and easily manipulated genome, may also be suitable for studies of legume food allergy. Here we present a comprehensive study of the Lotus N-glycoproteome. The global and site-specific N-glycan structures of Lotus seed globulins were analyzed using mass spectrometry-based glycomics and glycoproteomics techniques. In total, 19 N-glycan structures comprising high mannose (~20%), pauci-mannosidic (~40%), and complex forms (~40%) were determined. The pauci-mannosidic and complex N-glycans contained high amounts of the typical plant determinants beta-1,2-xylose and alpha-1,3-fucose. Two abundant Lotus seed N-glycoproteins were site-specifically profiled; a predicted lectin containing two fully occupied N-glycosylation sites carried predominantly pauci-mannosidic structures in different distributions. In contrast, Lotus convicilin storage protein 2 (LCP2) carried exclusively high mannose N-glycans similar to its homologue, Ara h 1, which is the major allergen in peanut. In silico investigation confirmed that peanut Ara h 1 and Lotus LCP2 are highly similar at the primary and higher protein structure levels. Hence, we suggest that Lotus has the potential to serve as a model system for studying the role of seed proteins and their glycosylation in food allergy. PMID- 23799248 TI - Authentication of the botanical and geographical origin of distillers dried grains and solubles (DDGS) by FT-IR spectroscopy. AB - Distillers dried grains and solubles (DDGS) were investigated with attenuated total reflection FT-IR spectroscopy both directly in their solid state and as the isolated oils (fat fractions). The collected spectra were evaluated in a first step with principal component analysis (PCA) according to the botanical origin (corn, rice, wheat) and the geographical origin (Canada, China, European Union, India, United States) of the DDGS. In a second step, statistical models were constructed for the characterization of the botanical and geographical origin using linear discriminant analysis (LDA) and soft independent modeling of class analogy (SIMCA). For this purpose, the botanical origin was investigated more deeply for corn and wheat as the most important raw materials used for DDGS production. Also, the geographical origin was investigated exemplary for corn DDGS, derived from China and the United States. Models were validated by a randomized batchwise procedure and showed satisfactory classification rates, in most cases better than 80% correct classification. PMID- 23799250 TI - Serial neuroimaging in infants with abusive head trauma: timing abusive injuries. AB - OBJECT: The appearance and evolution of neuroimaging abnormalities following abusive head trauma (AHT) is important for establishing the time frame over which these injuries might have occurred. From a legal perspective this frames the timing of the abuse and therefore identifies and excludes potential perpetrators. A previous pilot study involving 33 infants with AHT helped to refine the timing of these injuries but was limited by its small sample size. In the present study, the authors analyzed a larger group of 210 cases involving infants with AHT to chronicle the first appearance and evolution of radiological (CT, MRI) abnormalities. METHODS: All children younger than 24 months admitted to the Penn State Hershey Medical Center with AHT over a 10-year period were identified from a medical record review; the time of injury was determined through an evaluation of the clinical records. All imaging studies were analyzed, and the appearance and evolution of abnormalities were chronicled on serial neuroimaging studies obtained in the days and weeks after injury. RESULTS: One hundred five infants with specific injury dates and available imaging studies were identified; a subset of 43 children additionally had documented times of injury. In infants with homogeneously hyperdense subdural hematomas (SDHs) on initial CT scans, the first hypodense component appeared within the SDH between 0.3 and 16 days after injury, and the last hyperdense subdural component disappeared between 2 and 40 days after injury. In infants with mixed-density SDHs on initial scans, the last hyperdense component disappeared between 1 and 181 days. Parenchymal hypodensities appeared on CT scans performed as early as 1.2 hours, and all were visible within 27 hours after the injury. Rebleeding into SDHs was documented in 17 cases (16%) and was always asymptomatic. Magnetic resonance imaging of the brain was performed in 49 infants. Among those with SDH, 5 patterns were observed. Patterns I and II reflected homogeneous SDH; Pattern I (T1 hyperintensity and T2/FLAIR hypointensity, "early subacute") more commonly appeared on scans performed earlier after injury compared with Pattern II (T1 hyperintensity and T2/FLAIR hyperintensity, "late subacute"), although there was considerable overlap. Patterns III and IV reflected heterogeneous SDH; Pattern III contained relatively equal mixtures having different intensities, whereas Pattern IV had fluid that was predominantly T1 hypointense and T2/FLAIR hyperintense. Again, Pattern III more commonly appeared on scans performed earlier after injury compared with Pattern IV, although there was significant overlap. CONCLUSIONS: These data extend the preliminary data reported by Dias and colleagues and provide a framework upon which injuries in AHT can be timed as well as the limitations on such timing estimates. PMID- 23799251 TI - Method development and validation for cyprodinil and fludioxonil in blueberries by solid-phase microextraction gas chromatography, and their degradation kinetics. AB - A method of analysis for residues of cyprodinil and fludioxonil in blueberries was developed. Fungicide residues were determined by solid-phase microextraction coupled to GC with nitrogen-phosphorous detection. The effect of pH values and fibre coatings was studied. The solid-phase microextraction fibre coating selected was 100 um polydimethylsiloxane. The method was selective, with adequate precision and high accuracy and sensitivity. Apparent recoveries ranged within the 99-101% range for cyprodinil and the 98-100% range for fludioxonil; LODs and LOQs were 1.2 and 3.9 ug/kg for cyprodinil and 0.4 and 1.3 ug/kg for fludioxonil, respectively. Statistical parameters indicated a matrix effect; consequently, calibration was performed on spiked samples. Degradation of cyprodinil and fludioxonil was studied in a blueberry field located in Concordia (Argentina), with fruit from Emerald and Jewel varieties. The degradation of these fungicides in both blueberry varieties studied followed first-order rate kinetics for both fungicides, and the half-life for cyprodinil was 2.2 and 3.4 days for Emerald and Jewel cultivars, respectively, and for fludioxonil was 12.7 and 16.3 days, respectively. PMID- 23799249 TI - Protein-protein interaction regulates the direction of catalysis and electron transfer in a redox enzyme complex. AB - Protein-protein interactions are well-known to regulate enzyme activity in cell signaling and metabolism. Here, we show that protein-protein interactions regulate the activity of a respiratory-chain enzyme, CymA, by changing the direction or bias of catalysis. CymA, a member of the widespread NapC/NirT superfamily, is a menaquinol-7 (MQ-7) dehydrogenase that donates electrons to several distinct terminal reductases in the versatile respiratory network of Shewanella oneidensis . We report the incorporation of CymA within solid supported membranes that mimic the inner membrane architecture of S. oneidensis . Quartz-crystal microbalance with dissipation (QCM-D) resolved the formation of a stable complex between CymA and one of its native redox partners, flavocytochrome c3 (Fcc3) fumarate reductase. Cyclic voltammetry revealed that CymA alone could only reduce MQ-7, while the CymA-Fcc3 complex catalyzed the reaction required to support anaerobic respiration, the oxidation of MQ-7. We propose that MQ-7 oxidation in CymA is limited by electron transfer to the hemes and that complex formation with Fcc3 facilitates the electron-transfer rate along the heme redox chain. These results reveal a yet unexplored mechanism by which bacteria can regulate multibranched respiratory networks through protein-protein interactions. PMID- 23799252 TI - Advance directives, control, and quality of life for persons with disabilities. AB - BACKGROUND: Personal control over end-of-life (EOL) care via advance care planning is a key component of high-quality care. Although this desire for control has been well documented in some populations, EOL care issues are not well understood within the disabilities community. OBJECTIVE: The objective for this study was to describe the relationships between individual demographic characteristics, health-related quality of life, health locus of control, and attitudes toward advance directives (ADs) in individuals who are disabilities activists. METHODS: We surveyed 55 participants attending a disability conference. Instruments included a demographic data sheet, the Advance Directive Attitude Survey (ADAS), the Multidimensional Health Locus of Control scale, and the Functional Assessment of Non-Life Threatening Conditions quality of life (QOL) scale. RESULTS: Most participants were Hispanic females with some college education. About 46% had a disability. Group means revealed a high level of QOL (M=75.72, SD=19.09) and a positive attitude about ADs (M=66.49, SD=8.03). On the Opportunities for Treatment Choices subscale of the ADAS, activists without disabilities (M=14.23) were more positive about their control over EOL decisions than were the activists with disabilities (M=12.97) [t(2,52)=2.116, p<0.05]. CONCLUSIONS: Although participants were positive about ADs, differences in attitudes about control over opportunities for treatment choices between the nondisabled and disabled groups support previous findings that people with disabilities may have concerns regarding undertreatment for serious health conditions. Further study of EOL care issues for persons with disabilities is warranted. PMID- 23799253 TI - 13C-aminopyrine demethylation is decreased in cirrhotic patients with normal biochemical markers. AB - This study determined the rates of (13)C-aminopyrine metabolism in patients with varying degrees of liver cirrhosis as defined by clinical scores. Twenty-five cirrhotic patients and 18 healthy subjects underwent a (13)C-aminopyrine breath test. The cumulative per cent dose recovery (cPDR) of (13)C on breath expressed as a percentage of the administered dose at 2 h was significantly lower in cirrhotic patients than in healthy subjects (median: 1.7% versus 9.0%; p<.0001). Significant inverse associations between cPDR at 2 h and the model for end-stage liver disease score, Child-Pugh score, international normalised ratio and bilirubin (all p<.05), but not alanine aminotransferase or alkaline phosphatase were observed in the cirrhotic patients. Taking each biochemical marker independently, cirrhotic patients with normal biochemistry had a significantly lower cPDR at 2 h than healthy subjects (all p<.05). Differences in (13)C aminopyrine metabolism were evident in cirrhotic patients with less severe disease and may mark hepatic dysfunction when conventional biochemical markers appear unchanged. PMID- 23799254 TI - Utilizing the dynamic stark shift as a probe for dielectric relaxation in photosynthetic reaction centers during charge separation. AB - In photosynthetic reaction centers, the electric field generated by light-induced charge separation produces electrochromic shifts in the transitions of reaction center pigments. The extent of this Stark shift indirectly reflects the effective field strength at a particular cofactor in the complex. The dynamics of the effective field strength near the two monomeric bacteriochlorophylls (BA and BB) in purple photosynthetic bacterial reaction centers has been explored near physiological temperature by monitoring the time-dependent Stark shift during charge separation (dynamic Stark shift). This dynamic Stark shift was determined through analysis of femtosecond time-resolved absorbance change spectra recorded in wild type reaction centers and in four mutants at position M210. In both wild type and the mutants, the kinetics of the dynamic Stark shift differ from those of electron transfer, though not in the same way. In wild type, the initial electron transfer and the increase in the effective field strength near the active-side monomer bacteriochlorophyll (BA) occur in synchrony, but the two signals diverge on the time scale of electron transfer to the quinone. In contrast, when tyrosine is replaced by aspartic acid at M210, the kinetics of the BA Stark shift and the initial electron transfer differ, but transfer to the quinone coincides with the decay of the Stark shift. This is interpreted in terms of differences in the dynamics of the local dielectric environment between the mutants and the wild type. In wild type, comparison of the Stark shifts associated with BA and BB on the two quasi-symmetric halves of the reaction center structure confirm that the effective dielectric constants near these cofactors are quite different when the reaction center is in the state P(+)QA(-), as previously determined by Steffen et al. at 1.5 K (Steffen, M. A.; et al. Science 1994, 264, 810-816). However, it is not possible to determine from static, low-temperature measurments if the difference in the effective dielectric constant between the two sides of the reaction center is manifest on the time scale of initial electron transfer. By comparing directly the Stark shift dynamics of the ground-state spectra of the two monomer bacteriochlorophylls, it is evident that there is, in fact, a large dielectric difference between protein environments of the two quasi-symmetric electron-transfer branches on the time scale of initial electron transfer and that the effective dielectric constant in the region continues to evolve on a time scale of hundreds of picoseconds. PMID- 23799255 TI - Screen time increases risk of overweight and obesity in active and inactive 9 year-old Irish children: a cross sectional analysis. AB - BACKGROUND: Independent associations between screen time (ST)/physical activity (PA) and overweight (OW)/obesity have been demonstrated but little research exists on the role of ST among sufficiently active children. PURPOSE: To examine the combined influence of ST and PA on risk of OW/obesity in a nationally representative sample of 9-year-old Irish children. METHODS: The sample in this cross sectional analysis contained 8568 children. Self-report parent data were used to group children into ST and PA categories and related to OW/obesity using forced entry logistic regression. RESULTS: High ST (> 3 hours/day), bedroom TV and mobile phone ownership increased risk of OW/obesity in high and low active children (P < .05). Low PA (<9 bouts fortnightly) was also associated with OW/obesity. In combined analyses, OW/obesity was lowest in the reference low ST/high PA group with ORs of 1.38, 1.63, and 2.07, respectively, in the low ST/low PA, high ST/high PA, and high ST/low PA groups. Access to electronic media, low socioeconomic status, parental obesity, and not engaging in sports were all related to high ST (P < .05). CONCLUSION: This study supports findings that ST is associated with OW/Obesity demonstrating this separately in high and low active children. PMID- 23799256 TI - Epidemiology of injury among handlers and dogs competing in the sport of agility. AB - BACKGROUND: Little is known about the epidemiology of dog sport-related injuries. This study examines injuries among handlers and dogs in the sport of dog agility. METHODS: A cross-sectional pilot study captured data on demographics, exposures, and injury for a sample of agility handlers and dogs. Logistic regressions predicted odds of injury. RESULTS: Survey of 217 handlers and 431 dogs identified 31 handler injuries (1.55 training injuries per 1000 hours, 2.14 competition injuries per 1000 runs) and 38 dog injuries (1.74 training injuries per 1000 hours, 1.72 competition injuries per 1000 runs). Handlers most commonly injured knees (48.4%) and lower trunk (29.0%). Most common diagnoses were strains (51.6%) and sprains (32.3%). Obese handlers had increased odds of injury compared with normal weight handlers (OR = 5.5, P < .001). Dogs most commonly injured front paws (23.7%) and shoulders (15.8%). Most common diagnoses were strains (44.7%) and cut/scrapes (21.1%). Injury was positively associated with dog's age (P < .05). Handlers more commonly reported positive physical, emotional, and social motivations for participation than competitive. CONCLUSIONS: Despite many health benefits, dog agility poses a risk of injury to both handlers and dogs. Future research on specific mechanisms of injury should drive evidence-based injury prevention strategies. PMID- 23799257 TI - Physical activity level and lifestyle-related risk factors from Catalan physicians. AB - BACKGROUND: Physicians' own Physical Activity (PA) and other health-related habits influence PA promotion. The current study identifies the PA level, according to the current PA recommendations and other health-related habits of physicians from the Catalan Medical Council. METHODS: 2400 physicians (30-55 years) were randomly selected; each received a self-administered mailed questionnaire identifying medical specialization, work setting, health self perception, body mass index (BMI), PA, and smoking habits. RESULTS: 762 physicians responded (52% female). Almost 1 in 2 (49.3%) exercised sufficiently, nearly all self-perceived good health, while 80.5% were nonsmokers. Almost 6 in 10 males reported overweight or obesity (56.9%) versus 18.2% of females. Active physicians dominated specific groups: (1) aged 45-55 years, (2) specializing either in primary care or surgery, (3) working in the private sector, (4) BMI < 25 kg/m2, (5) perceiving themselves in good health, or (6) having free leisure time. CONCLUSIONS: Only half of Catalan physicians met current PA recommendations; male physicians were particularly at risk for overweight/obesity. Overweight and under-exercise were associated with private workplaces and positive health perceptions, meaning that it is it is now possible to target inactive and/or overweight Catalan physicians in future interventions. PMID- 23799258 TI - Motor coordination, activity, and fitness at 6 years of age relative to activity and fitness at 10 years of age. AB - BACKGROUND: Health benefits of physical activity (PA) and physical fitness (PF) are reasonably well established, but tracking studies of PA and PF in childhood have not ordinarily considered the role of motor coordination. OBJECTIVES: To compare the growth status, gross motor coordination (GMC), PA, and PF characteristics of children at 6 years of age relative to aerobic fitness (fit, unfit) and PA (active, sedentary) at 10 years. METHODS: 285 primary school children (142 girls, 143 boys) resident on the 4 main Azorean islands, Portugal, were measured annually (in the fall) from 6 to 10 years. ANOVA and t tests were computed with SPSS 17. RESULTS: Children with either high aerobic fitness or with high level of PA at 10 years of age tended to have a more favorable profile at 6 years compared with those with low fitness or low activity, respectively. Children who were both fit and active at 10 years of age had a more favorable activity and fitness profile and had better GMC at 6 years compared with children who were unfit and sedentary. CONCLUSIONS: Results highlight the need to consider not only PA, but also PF and GMC in health promotion through the primary school years. PMID- 23799259 TI - Smoking impact on grip strength and fatigue resistance: implications for exercise and hand therapy practice. AB - BACKGROUND: Grip strength assessment reflects on overall health of the musculoskeletal system and is a predictor of functional prognosis and mortality. The purpose of this study was: examine whether grip-strength and fatigue resistance are impaired in smokers, determine if smoking-related impairments (fatigue-index) can be predicted by demographic data, duration of smoking, packets smoked-per-day, and physical activity. METHODS: Maximum isometric grip strength (MIGS) of male smokers (n = 111) and nonsmokers (n = 66) was measured before/after induced fatigue using Jamar dynamometer at 5-handle positions. Fatigue index was calculated based on percentage change in MIGS initially and after induced fatigue. RESULTS: Number of repetitions to squeeze the soft rubber ball to induce fatigue was significantly lower in smokers compared with nonsmokers (t = 10.6, P < .001 dominant hand; t = 13.9, P < .001 nondominant), demonstrating a significantly higher fatigue-index for smokers than nonsmokers (t = -8.7, P < .001 dominant hand; t = -6.0, P < .001 nondominant). The effect of smoking status on MIGS scores was significantly different between smokers and nonsmokers after induced fatigue (beta = -3.98, standard error = 0.59, P < .001) where smokers experienced on average a reduction of nearly 4 MIGS less than nonsmokers before fatigue. Smoking status was the strongest significant independent predictor of the fatigue-index. CONCLUSIONS: Smokers demonstrated reduced grip strength and fast fatigability in comparison with nonsmokers. PMID- 23799260 TI - Proximal and distal environmental correlates of adolescent obesity. AB - BACKGROUND: The purpose of this study was to determine how proximal (home) and distal (neighborhood) environmental characteristics interact to influence obesity in early and middle adolescents. METHODS: This was a descriptive, cross-sectional study using the 2007 National Survey of Children's Health (NCSH). Participants were 39,542 children ages 11 to 17 years. Logistic regressions were used to examine the relationship between adolescent obesity and environmental factors, the relative strength of these factors, and the influence of age and gender. RESULTS: Proximal environmental factors were stronger correlates of adolescent obesity than distal environmental factors. Sedentary behavior related to TV watching time at home was the strongest correlate of adolescent obesity overall (OR 1.13, 95% CI 1.11-1.15). Parks and playgrounds (OR 0.86, 95% CI 0.08-0.92), as well as recreation centers (OR 0.91, 95% CI 0.85-0.97) were significant distal environmental factor correlates. Girls and middle adolescents were at less risk for obesity than boys and early adolescents (OR 0.51, 95% CI 0.68-0.82; OR 0.75, 95% CI 0.68-0.96). CONCLUSION: The results of this study reveal the importance of proximal environmental characteristics on adolescent obesity relative to distal environmental characteristics. Obesity intervention strategies for adolescents should target sedentary behavior and opportunities for physical activity with a focus on early adolescents and boys. PMID- 23799262 TI - Investigating motivational regulations and physical activity over 25 weeks. AB - BACKGROUND: Because motivation has been deemed a key barrier to physical activity, it is imperative that we know how motivational levels change over time and how that change relates to physical activity. Based in Self-Determination Theory, this study investigated fluctuations in physical activity and motivational regulations over 25 weeks and tested the relationship between these 2 variables. METHODS: Data from the Physical Activity Counseling trial were examined. Inactive adults recruited from a primary care center (N = 120) answered motivation and physical activity questionnaires during the intervention and postintervention phases. Hierarchical linear modeling was used to test the hypotheses. RESULTS: Quadratic changes were found for external regulation (gamma20= 0.02, P < .05) and physical activity (gamma20 = -2.64, P < .001), while identified (gamma10= 0.04, P = .03) and intrinsic (gamma10= 0.04, P = .01) regulations increased linearly over the course of the 25 weeks. Only identified regulation (gamma30= 3.15, P = .01) and intrinsic motivation (gamma30= 4.68, P < .001) were significantly and positively related with physical activity. CONCLUSION: Physical activity, external and identified regulations and intrinsic motivation changed over the 25 weeks. Intervention should aim at fostering identified regulation and intrinsic motivation as greater levels of these regulations were related with physical activity. PMID- 23799263 TI - Identifying similar and different factors effecting long-term cardiac exercise rehabilitation behavior modification between New Zealand and the United Kingdom. AB - BACKGROUND: Cardiac Rehabilitation (CR) programs are the most cost-effective measure for reducing morbidity associated with Coronary Vascular Disease (CVD). To be more effective there is a need to understand what influences the maintenance of healthy behaviors. This study identifies similar and different influences in CR of the United Kingdom (UK) and New Zealand (NZ). METHODS: A retrospective study. Participants had previously been discharged from CR for 6 to 12+ months within the UK (n = 22) and NZ (n = 21). Participant's attended a focus group. Discussions were digitally recorded, transcribed then thematically analyzed. The CR programs were observed over 2 months to enable comment on findings relating to 'theory in practice.' RESULTS: Similar positive patient experiences influencing behavior between groups and countries were; support, education, positive attitude, and motivation. Companionship and exercising alongside people with similar health problems was the major determinant for positive exercise behavior. Barriers to maintaining exercise included; physical disabilities, time constraints, and weather conditions. NZ participants were more affected by external factors (eg, opportunity, access, and time). CONCLUSION: Both CR programs were successful in facilitating the maintenance of healthy lifestyles. Exercising with other cardiac patients for support in a structured environment was the strongest influence in maintaining healthy lifestyles beyond CR programs. PMID- 23799264 TI - Individual, Psychosocial, and environmental correlates of 4-year declines in walking among middle-to-older aged adults. AB - BACKGROUND: We examined associations of individual, psychosocial and environmental characteristics with 4-year changes in walking among middle-to older aged adults; few such studies have employed prospective designs. METHODS: Walking for transport and walking for recreation were assessed during 2003-2004 (baseline) and 2007-2008 (follow-up) among 445 adults aged 50-65 years residing in Adelaide, Australia. Logistic regression analyses examined predictors of being in the highest quintile of decline in walking (21.4 minutes/day or more reduction in walking for transport; 18.6 minutes/day or more reduction in walking for recreation). RESULTS: Declines in walking for transport were related to higher level of walking at baseline, low perceived benefits of activity, low family social support, a medium level of social interaction, low sense of community, and higher neighborhood walkability. Declines in walking for recreation were related to higher level of walking at baseline, low self-efficacy for activity, low family social support, and a medium level of available walking facilities. CONCLUSIONS: Declines in middle-to-older aged adults' walking for transport and walking for recreation have differing personal, psychosocial and built environment correlates, for which particular preventive strategies may be developed. Targeted campaigns, community-based programs, and environmental and policy initiatives can be informed by these findings. PMID- 23799265 TI - Designing climate change mitigation plans that add up. AB - Mitigation plans to combat climate change depend on the combined implementation of many abatement options, but the options interact. Published anthropogenic emissions inventories are disaggregated by gas, sector, country, or final energy form. This allows the assessment of novel energy supply options, but is insufficient for understanding how options for efficiency and demand reduction interact. A consistent framework for understanding the drivers of emissions is therefore developed, with a set of seven complete inventories reflecting all technical options for mitigation connected through lossless allocation matrices. The required data set is compiled and calculated from a wide range of industry, government, and academic reports. The framework is used to create a global Sankey diagram to relate human demand for services to anthropogenic emissions. The application of this framework is demonstrated through a prediction of per-capita emissions based on service demand in different countries, and through an example showing how the "technical potentials" of a set of separate mitigation options should be combined. PMID- 23799266 TI - Tuning the bacterial detection sensitivity of nanostructured microelectrodes. AB - Fast, sensitive nucleic acid sensors that enable direct detection of bacteria and diagnosis of infectious disease would offer significant advantages over existing approaches that employ enzymatic amplification of nucleic acids. We have developed chip-based microelectrodes that are highly effective for bacterial detection and have shown that they can capture and permit the analysis of large slow moving mRNA targets. Here, we explore new approaches to tune their analytical sensitivity and investigate the effect of sensor size, material composition, and probe density on the electrochemical signals obtained in the presence of bacteria. Sensor size can be varied from 10 to 100 MUm, and this parameter can change detection limits obtained by a factor of 100. Changing the surface coating can also be used to tune sensitivity, with more nanostructured coatings yielding the most sensitive detectors. Moreover, we assessed performance of the sensors by tuning probe density. Varying the density of the immobilized probe had a dramatic effect on sensitivity, with sparse probe monolayers providing superior levels of performance. Overall, this study points to several factors that can be used to tune detection limits. PMID- 23799268 TI - Method validation and analysis of nine dithiocarbamates in fruits and vegetables by LC-MS/MS. AB - An analytical method for separation and quantitative determination of nine dithiocarbamates (DTCs) in fruits and vegetables by using LC-MS/MS was developed, validated and applied to samples purchased in local supermarkets. The nine DTCs were ziram, ferbam, thiram, maneb, zineb, nabam, metiram, mancozeb and propineb. Validation parameters of mean recovery for two matrices at two concentration levels, relative repeatability (RSDr), relative within-laboratory reproducibility (RSDR) and LOD were obtained for the nine DTCs. The results from the analysis of fruits and vegetables served as the basis for an exposure assessment within the given commodities and a risk assessment by comparing the calculated exposure to the acceptable daily intake and acute reference dose for various exposure groups. The analysis indicated positive findings of DTCs in apples, pears, plums, table grapes, papaya and broccoli at concentrations ranging from 0.03 mg/kg to 2.69 mg/kg expressed as the equivalent amount of CS2. None of the values exceeded the Maximum residue level (MRL) set by the European Union, and furthermore, it was not possible to state whether illegal use had taken place or not, because a clear differentiation between the various DTCs in the LC-MS/MS analysis was lacking. The exposure and risk assessment showed that only for maneb in the case of apples and apple juice, the acute reference dose was exceeded for infants in the United Kingdom and for children in Germany, respectively. PMID- 23799267 TI - Chlordane and heptachlor are metabolized enantioselectively by rat liver microsomes. AB - Chlordane, heptachlor, and their metabolites are chiral persistent organic pollutants that undergo enantiomeric enrichment in the environment. This study investigated the enantioselective metabolism of both chlordane isomers and heptachlor, major components of technical chlordane, by liver microsomes prepared from male rats treated with corn oil (CO) or inducers of CYP2B (PB; phenobarbital) and CYP3A enzymes (DX; dexamethasone), isoforms induced by chlordane treatment. The extent of the metabolism of all three parent compounds was dependent on the microsomal preparation used and followed the rank order PB > DX > CO. The mass balances ranged from 49 to 130% of the parent compound added to the microsomal incubations. Both cis- and trans-chlordane were enantioselectively metabolized to oxychlordane (EF = 0.45-0.89) and 1,2-dichlorochlordene (EF = 0.42 0.90). Heptachlor was metabolized enantioselectively, with heptachlor epoxide B (EF = 0.44-0.54) being the only metabolite. Interestingly, the direction on the enrichment for oxychlordane, 1,2-dichlorochlordene, and heptachlor epoxide differed depending on the microsomal preparation. These findings demonstrate that the direction and extent of the enantioselective metabolism of both chlordane isomers and heptachlor is P450 isoform-dependent and can be modulated by the induction of P450 enzymes. PMID- 23799269 TI - Comparison of confirmed inactive and randomly selected compounds as negative training examples in support vector machine-based virtual screening. AB - The choice of negative training data for machine learning is a little explored issue in chemoinformatics. In this study, the influence of alternative sets of negative training data and different background databases on support vector machine (SVM) modeling and virtual screening has been investigated. Target directed SVM models have been derived on the basis of differently composed training sets containing confirmed inactive molecules or randomly selected database compounds as negative training instances. These models were then applied to search background databases consisting of biological screening data or randomly assembled compounds for available hits. Negative training data were found to systematically influence compound recall in virtual screening. In addition, different background databases had a strong influence on the search results. Our findings also indicated that typical benchmark settings lead to an overestimation of SVM-based virtual screening performance compared to search conditions that are more relevant for practical applications. PMID- 23799270 TI - A discursive psychology analysis of emotional support for men with colorectal cancer. AB - Recent research into both masculinity and health, and the provision of social support for people with cancer has focused upon the variations that may underlie broad assumptions about masculine health behaviour. The research reported here pursues this interest in variation by addressing the discursive properties of talk about emotional support, by men with colorectal cancer - an understudied group in the social support and cancer literature. Semi-structured interviews were conducted with eight men with colorectal cancer, and the transcripts were analysed using an intensive discursive psychology approach. From this analysis, two contrasting approaches to this group of men's framing of emotional support in the context of cancer are described. First, talk about cancer was positioned as incompatible with preferred masculine identities. Second, social contact that affirms personal relationships was given value, subject to constraints arising from discourses concerning appropriate emotional expression. These results are discussed with reference to both the extant research literature on masculinity and health, and their clinical implications, particularly the advice on social support given to older male cancer patients, their families and friends. PMID- 23799271 TI - Determination of chiral jasmonates in flowers by GC/MS after monolithic material sorptive extraction. AB - A GC/MS method with monolithic material sorptive extraction (MMSE) pretreatment was developed to determine contents of the enantiomers of jasmonic acid and methyl jasmonate in flowers. To optimize MMSE extraction, several MMSE parameters were investigated, including extraction temperature, extraction time, and extraction solvent. Under the optimal conditions, extraction efficiency was good. Using the selected-ion monitoring mode, the limit of detection (LOD, S/N = 3) for methyl jasmonates was 0.257 ng/mL. The limit of quantitation (LOQ, S/N = 10) was 0.856 ng/mL. The linearity range was 1-100 ng/mL. The average recovery of methyl jasmonate at lower concentration was 116.8% (2 ng/mL). The relative standard deviation of methyl jasmonate contents determined within the linear range of detection was less than or equal to 15% of the mean determined level. The proposed method is rapid, sensitive, and competently applied to the determination of jasmonic acid and methyl jasmonate enantiomers in flowers. PMID- 23799272 TI - Electronically nonadiabatic dynamics in complex molecular systems: an efficient and accurate semiclassical solution. AB - Chemical reaction dynamics is always a central theme in chemistry research. In many important chemical processes, reaction dynamics is electronically nonadiabatic, i.e., dynamics involves coupled multiple electronic states. We demonstrate in this paper that a semiclassical (SC) treatment based on an initial value representation methodology and a classical mapping formalism for the electronic degrees of freedom is now able to provide a rigorous and practical solution to electronically nonadiabatic dynamics in complex molecular systems. The key component of this treatment is to incorporate a correlated importance sampling protocol in nonadiabatic SC calculations, which results in a speedup factor of 100 or more in comparison with that using the standard sampling approach. This is illustrated by application to a two-state model coupled with up to 10 nuclear bath modes for a benchmark nonadiabatic excitation energy transfer problem. This work provides great opportunities for the effectively theoretical investigations on reaction mechanisms in complex molecular systems, in which electronically nonadiabatic dynamics plays an importance role. PMID- 23799273 TI - Parental mastery of continuous subcutaneous insulin infusion skills and glycemic control in youth with type 1 diabetes. AB - OBJECTIVE: The purpose of this study is to determine whether parental knowledge of the continuous subcutaneous insulin infusion (CSII) device affects glycemic control as measured by hemoglobin A1c (A1C) level. SUBJECTS AND METHODS: Parents of children with type 1 diabetes mellitus (T1DM) using CSII completed a 14-item questionnaire. Questions 1-10 were knowledge-based questions that required the parent to extract specific information from their child's CSII device. Questions 11-14 asked parents to provide a self-assessment of their CSII knowledge. RESULTS: Twenty-two parents of youth with T1DM participated in the study. Ten of the youth were in the Low-A1C group (A1C<8%), and the other 12 were in the High A1C group (A1C>=8%). Parents of youth in the Low-A1C group scored statistically better on the 10-item performance survey than parents of youth in the High-A1C group. Most of the parents of children in the Low-A1C group responded that they knew their child's insulin pump "very well" and that their pump knowledge had "increased" since their child started on the insulin pump. CONCLUSIONS: Our findings reveal that youth with T1DM whose parents are more knowledgeable about pump functions have optimal glycemic control as evidenced by A1C. These findings underscore the importance of ongoing pump training for both pediatric patients and their parents. PMID- 23799274 TI - Relations between sedentary behavior and FITNESSGRAM healthy fitness zone achievement and physical activity. AB - PURPOSE: To investigate the relations between sedentary behaviors and health related physical fitness and physical activity in middle school boys and girls. METHODS: Students (n = 1515) in grades 6-8 completed the Youth Risk Behavior Survey sedentary behavior questions, the FITNESSGRAM physical fitness items, and FITNESSGRAM physical activity self-report questions. RESULTS: When students reported <= 2 hours per day of sedentary behaviors, their odds of achieving the FITNESSGRAM Healthy Fitness Zone for aerobic capacity, muscular strength and endurance, flexibility, and body composition increased. Similarly, the odds of achieving physical activity guidelines for children increased when students reported <= 2 hours per day of sedentary behaviors. CONCLUSIONS: Results illustrate the importance of keeping sedentary behaviors to <= 2 hours per day in middle school children, thus increasing the odds that the student will achieve sufficient health-related fitness benefits and be more likely to achieve the national physical activity guidelines. PMID- 23799275 TI - Chondrocyte migration affects tissue-engineered cartilage integration by activating the signal transduction pathways involving Src, PLCgamma1, and ERK1/2. AB - To determine the signal transduction pathways involved in chondrocyte migration and their effects on cartilage integration in autologous chondrocyte implantation. Articular chondrocytes were divided into three inhibitor groups pretreated with different inhibitors to Src, phospholipase Cgamma1 (PLCgamma1), and extracellular signal-regulated kinase (ERK)1/2 signaling pathways and one control group pretreated with vehicle. The effect of these pathways on chondrocyte migration was first explored by Boyden chamber assay, and then by an in vitro cell/ring integration model. Chondrocyte migration was visualized and quantified by cell tracking, and the activity of Src, PLCgamma1, and ERK1/2 was determined by Western blotting. The effect of these pathways on cartilage integration was evaluated histologically, biochemically, and biomechanically. Boyden chamber assay revealed that the number of migrated cells was significantly increased in the control group without inhibitors. In an in vitro integration model, the implanted chondrocytes were observed to migrate through the interface and infiltrate into the native cartilage. Additionally, chondrocyte migration could be improved in the absence of inhibitors After 4 weeks of culture, the control group demonstrated a significantly higher cellularity, larger amount of chemical content deposition, stronger extracellular matrix staining in the integration zone, and higher integrative strength as compared to the inhibitor groups. Western blotting demonstrated that the Src-PLCgamma1-ERK1/2 signaling pathway was promoted in the integration process. This study is the first to show that the Src-PLCgamma1-ERK1/2 signaling transduction pathway is involved in cartilage tissue integration by affecting chondrocyte migration. Our results raise the importance of the chondrocyte migration enhancement therapy or the development of new agents specifically targeting the pathways to ensure long-term functionality of the restored joint surface. PMID- 23799276 TI - Revisiting the chemistry of the actinocenes [(eta8-C8H8)2An] (An = U, Th) with neutral Lewis bases. Access to the bent sandwich complexes [(eta8-C8H8)2An(L)] with thorium (L = py, 4,4'-bipy, tBuNC, R4phen). AB - In stark contrast to uranocene, (Cot)2Th reacts with neutral mono- or bidentate Lewis bases to give the bent sandwich complexes (Cot)2Th(L) (L = py, 4,4'-bipy, tBuNC, phen, Me4phen). DFT calculations in the gas phase show that, for both U and Th, formation of the bent compound (Cot)2An(L) should be facile, the linear and bent forms being close in energy. PMID- 23799277 TI - Cardiac baroreflex gain is frequency dependent: insights from repeated sit-to stand maneuvers and the modified Oxford method. AB - Cardiac baroreflex gain is usually quantified as the reflex alteration in heart rate during changes in blood pressure without considering the effect of the rate of change in blood pressure on the estimated gain. This study sought to (i) characterize baroreflex gain as a function of blood pressure oscillation frequencies using a repeat sit-to-stand method and (ii) compare baroreflex gain values obtained using the sit-to-stand method against the modified Oxford method. Fifteen healthy individuals underwent the repeated sit-to-stand method in which blood pressure oscillations were driven at 0.03, 0.05, 0.07, and 0.1 Hz. Sixteen healthy participants underwent the sit-to-stand and modified Oxford methods to examine their agreement. Sit-to-stand baroreflex gain was highest at 0.05 Hz (8.8 +/- 3.2 ms.mm Hg(-1)) and lowest at 0.1 Hz (5.8 +/- 3.0 ms.mm Hg(-1)). Baroreflex gains at 0.03 Hz (7.7 +/- 3.0 ms.mm Hg(-1)) and 0.07 Hz (7.5 +/- 3.3 ms.mm Hg( 1)) were not different from the baroreflex gain at 0.05 Hz. There was moderate correlation between phenylephrine gain and sit-to-stand gain (r values ranged from 0.52 to 0.75; all frequencies, p < 0.05), but no correlation between sodium nitroprusside gain and sit-to-stand gain (r values ranged from -0.07 to 0.22; all p < 0.05). Bland-Altman analysis of phenylephrine gain and sit-to-stand gain showed poor agreement and a positive proportional bias. These results show that baroreflex gains derived from these 2 methods cannot be used interchangeably. Furthermore, cardiac baroreflex gain is frequency dependent between 0.03 Hz and 0.1 Hz, which challenges the conventional practice of summarizing baroreflex gain as a single number. PMID- 23799279 TI - Indocyanine dyes approach free rotation at the 3' terminus of A-RNA: a comparison with the 5' terminus and consequences for fluorescence resonance energy transfer. AB - Cyanine dyes are widely used to study the folding and structural transformations of nucleic acids using fluorescence resonance energy transfer (FRET). The extent to which FRET can be used to extract inter- and intramolecular distances has been the subject of considerable debate in the literature; the contribution of dye and linker dynamics to the observed FRET signal is particularly troublesome. We used molecular dynamics (MD) simulations to study the dynamics of the indocarbocyanine dyes Cy3 and Cy5 attached variously to the 3' or 5' terminal bases of a 16-base pair RNA duplex. We then used Monte Carlo modeling of dye photophysics to predict the results of single-molecule-sensitive FRET measurements of these same molecules. Our results show that the average value of FRET depends on both the terminal base and the linker position. In particular, 3' attached dyes typically explore a wide region of configuration space, and the relative orientation factor, kappa(2), has a distribution that approaches that of free-rotators. This is in contrast to 5' attached dyes, which spend a significant fraction of their time in one or more configurations that are effectively stacked on the ends of the RNA duplex. The presence of distinct dye configurations for 5' attached dyes is consistent with observations, made by others, of multiple fluorescence lifetimes of Cy3 on nucleic acids. Although FRET is frequently used as a molecular "ruler" to measure intramolecular distances, the unambiguous measurement of distances typically relies on the assumption that the rotational degrees of freedom of the dyes can be averaged out and that the donor lifetime in the absence of the acceptor is a constant. We demonstrate that even for the relatively free 3' attached dyes, the correlation time of kappa(2) is still too long to justify the use of a free-rotation approximation. We further explore the consequences of multiple donor lifetimes on the predicted value of FRET. PMID- 23799280 TI - A randomized trial comparing the VIPON tampon and ibuprofen for dysmenorrhea pain relief. AB - BACKGROUND: This study was conducted to evaluate the therapeutic efficacy of a device designed to deliver high-frequency vibratory stimulation through direct intravaginal tampon application (VIPON) compared with a low-dose over-the-counter pharmacologic treatment of dysmenorrhea. METHODS: A randomized, open-label, prospective study comparing the investigational device to an oral self administration of the over-the-counter dose of 200-400 mg of ibuprofen with the onset of menstrual discomfort was conducted at two academic medical centers in the Midwest region of the United States. Women age 18 and older with self reported dysmenorrhea were treated with either VIPON or a single dose of 200-400 mg of ibuprofen, randomized for each of the next four menstrual cycles, and pain reduction from baseline was measured according to the Melzack-McGill pain scale. RESULTS: Overall, both ibuprofen and VIPON have significant effects on pain reduction according to the Melzack-McGill pain scale. However, the VIPON group achieved statistically significant greater, and more rapid, pain relief at every time point when compared with the ibuprofen. CONCLUSION: VIPON tampon is a viable, nonpharmacologic option to traditional low-dose over-the-counter pharmacologic therapies for menstrual pain management with more rapid onset of action. PMID- 23799281 TI - Association between the cerebral inflammatory and matrix metalloproteinase responses after severe traumatic brain injury in humans. AB - An increasing number of preclinical investigations have suggested that the degree of expression of the matrix metalloproteinase (MMP) family of endopeptidases may explain some of the variability in neurological damage after traumatic brain injury (TBI). As cytokines are a prominent stimulus for MMP expression in animals, we conducted a prospective multimodal monitoring study and determined their association with temporal MMP expression after severe TBI in eight critically ill adults. High cutoff, cerebral microdialysis (n=8); external ventricular drainage (n=3); and arterial and jugular venous bulb catheters were used to measure the concentration of nine cytokines and eight MMPs in microdialysate, cerebrospinal fluid (CSF), and plasma over 6 days. Severe TBI was associated with a robust central inflammatory response, which was largely similar between microdialysate and CSF. At all time points after injury, this response was predominated by the pro-inflammatory cytokines interleukin-6 (IL-6) and IL-8. Use of univariate generalized estimating equations suggested that the concentration of several MMPs varied with cytokine levels in microdialysate. The largest of these changes included increases in microdialysate concentrations of MMP-8 and MMP-9 with increases in the levels of IL-1alpha and -2 and IL-1alpha and -2 and TNF-alpha, respectively. In contrast, the microdialysate level of MMP 7 decreased with increases in microdialysate concentrations of IL-1beta, -2, and 6. These findings support the observations of animal studies that cross-talk exists between the neuroinflammatory and MMP responses after acute brain injury. Further study is needed to determine whether this link between cerebral inflammation and MMP expression may have clinical relevance to the care of patients with TBI. PMID- 23799282 TI - Enhancing the learning of new words using an errorless learning procedure: evidence from typical adults. AB - Two experiments compared the efficacy of errorless and errorful training procedures in the acquisition of novel words in typical adults. One experiment involved learning novel names for novel objects, while a second involved learning obscure English words and their definitions. In both studies the errorless method led to significantly better learning as assessed by an immediate cued recall test. The errorless advantage was characterised by a reduction in extra experimental intrusion errors and was still present when learning was re-tested 3 4 days after training. In contrast there was no errorless advantage in recognition of word-to-object pairings. Taken together, these results suggest that errorless learning procedures improve retrieval by leading to the creation of better-specified, retrievable representations in long-term memory. PMID- 23799283 TI - Patterns of objectively measured moderate-to-vigorous physical activity in preschool children. AB - BACKGROUND: Identifying periods of the day which are susceptible to varying levels of physical activity (PA) may help identify key times to intervene and potentially change preschool children's PA behaviors. This study assessed variability of objectively measured moderate-to-vigorous physical activity (MVPA) during weekdays and weekend days among preschool children. METHODS: One hundred and eighty-eight children (aged 3 to 5 years; 53.2% boys) from a northwest English city wore uni-axial accelerometers for 7 consecutive days. RESULTS: Higher levels of MVPA were recorded in boys, particularly those who attended preschool for a half day. Children who attended preschool for a full day engaged in 11.1 minutes less MVPA than children who attended for a half day. After-school hours were characterized by a decrease in activity for all groups. Patterns of activity during the weekend were smoother with less variability. CONCLUSION: This study identified discrete segments of the week, specifically afterschool and during the weekend, when preschoolers engage in low levels of PA. Higher levels of MVPA among children who attended preschool for less time each day suggests that the structured preschool environment is related to decreased activity. Consequently, there is a need for interventions in young children to focus on school and home environments. PMID- 23799284 TI - Aluminum-ligand cooperative N-H bond activation and an example of dehydrogenative coupling. AB - Activation of N-H bonds by a molecular aluminum complex via metal-ligand cooperation is described. ((Ph)I2P(2-))AlH (1b), in which (Ph)I2P(2-) is a tridentate bis(imino)pyridine ligand, reacts with anilines to give the N-H activated products ((Ph)HI2P(-))AlH(NHAr) (2). When heated, 2 releases H2 and affords ((Ph)I2P(-))Al(NHAr) (3). Complex 1b catalyzes the dehydrogenative coupling of benzylamine to afford H2, NH3, and N (phenylmethylene)benzenemethanamine. PMID- 23799286 TI - Treatment of cerebral radiation necrosis with bevacizumab: the Cleveland clinic experience. AB - BACKGROUND: Cerebral radiation necrosis (RN) is a devastating complication of radiation therapy for brain tumors. Recent studies have explored the role of bevacizumab, a humanized monoclonal antibody directed against vascular endothelial growth factor in the treatment of RN of the brain. We report 24 patients with cerebral RN who were treated with bevacizumab. MATERIALS AND METHODS: Twenty-four patients diagnosed with cerebral RN and treated with different schedules of bevacizumab between July 2007 and June 2012, were identified from the Cleveland Clinic Brain Tumor and Neuro-Oncology Center's database. Pretreatment and posttreatment magnetic resonance imaging (MRI) studies were compared to evaluate bevacizumab efficacy. RESULTS: Posttreatment MRI demonstrated a radiographic improvement in 23 of 24 patients on the postcontrast T1-weighted MRI and fluid-attenuated inversion-recovery sequences. Using the McDonald criteria, the average change in the T1-weighted postcontrast MRI was a decrease of 48.1%, and the average change in the fluid-attenuated inversion recovery images was a decrease of 53.7%. There was a mean daily dose reduction of 9.4 mg of dexamethasone after initiation of bevacizumab in patients who were on steroids at the start of bevaciuzmab therapy for RN. Treatment with bevacizumab was well tolerated with only 1 grade 3 adverse event. CONCLUSIONS: The current study demonstrates that bevacizumab treatment results in excellent clinical and radiologic response in patients with RN caused by common forms of radiation therapy. The safety profile of bevacizumab use in RN is acceptable. In the current study, we found no difference between different schedules of bevacizumab in treatment outcomes. PMID- 23799285 TI - Concomitant Chemoradiotherapy With Image-guided Pulsed Dose Rate Brachytherapy as a Definitive Treatment Modality for Early-stage Cervical Cancer. AB - PURPOSE: Concurrent chemoradiotherapy (CRT) is the standard of care for patients with bulky cervical cancer. This study aimed to determine the feasibility, tolerance, and effectiveness of pulsed dose rate (PDR) image-guided brachytherapy (IGBT), utilizing magnetic resonance imaging (MRI) planning after CRT for stages IB2 and II cervix cancer patients. METHODS AND MATERIALS: This study planned to include patients with histologically confirmed stage IB2 and II cervical cancer who were treated with CRT followed by a PDR IGBT boost from January 2009 to December 2009 in our institution. All patients had at least a partial response after CRT before IGBT. The institutional review board approved the study. Patients received a 45-Gy external beam radiotherapy (EBRT) to the pelvis with concomitant weekly cisplatin (40 mg/m) for 5 cycles. All patients then underwent reimaging using MRI before BT. The IGBT boost was accomplished with one insertion using an MRI-compatible tandem and ovoid applicator delivering 30 to 35 Gy to a high-risk clinical target volume. Treatment-induced adverse events (AEs), dose parameters, local control, progression-free survival, and overall survival are reported. RESULTS: Forty patients were included in this study, with ages ranging from 31 to 65 years (median age, 45 y). Of all the patients, 12.5% and 5% experienced grade 3 to 4 acute gastrointestinal and genitourinary AEs, respectively, and 2.5% and 2.5% had grade 3 to 4 chronic gastrointestinal and genitourinary AEs, respectively. Within a median follow-up of 30 months (range, 7 to 40 mo), local control was 90%, progression-free survival was 87.5%, and overall survival was 100%. CONCLUSIONS: Intracavitary MRI PDR-IGBT boost after CRT is a feasible, tolerable, and effective treatment modality for patients with stages IB2 and II cervical cancer. PMID- 23799287 TI - Metastasis to the thyroid gland: report of a large series from the Mayo Clinic. AB - OBJECTIVES: Metastases to the thyroid gland are not as unusual as previously believed. This study reports the largest number of patients with metastatic disease of the thyroid to date, confirms the accuracy of fine-needle aspiration (FNA) in diagnosing metastasis, and reviews the incidence and management through our institutional experience. METHODS: This study entailed review of all thyroid FNAs performed at Mayo Clinic, Rochester during the period 1980 to 2010 and identified 97 patients with a metastatic solid neoplasm of the thyroid gland. RESULTS: Frequent primary tumor sites included kidney (22%), lung (22%), and head and neck (12%). The median age at discovery of thyroid metastasis was 63 years. The time from diagnosis of primary tumor to metastasis to the thyroid gland was most considerable for renal cell carcinoma (mean 113 mo). Forty-one patients underwent thyroid resection with an average tumor size of 3 cm. Median survival in all patients with metastases was 20 months (range, 1 to 228 mo). Patients who underwent thyroid resection had a median survival of 30 months (range, 3 to 171 mo), whereas survival in patients without thyroid surgery was 12 months (range, 1 to 228 mo, log-rank test P=0.09). CONCLUSIONS: Our experience over the last 30 years confirms that FNA remains a sensitive and specific method to detect metastases to the thyroid. In any patient with a history of a malignancy, a new thyroid mass should be promptly evaluated for recurrent malignancy as early diagnosis and surgical resection resulted in a nonstatistically significant increased median survival. PMID- 23799288 TI - Predictors of locoregional outcome in HER2-overexpressing breast cancer treated with neoadjuvant chemotherapy. AB - OBJECTIVES: We identified prognostic factors for locoregional recurrence (LRR) in a cohort of patients with HER2-overexpressing breast cancer treated with neoadjuvant chemotherapy (NACT). METHODS: We reviewed records of 157 patients with HER-overexpressing tumors who received NACT between May 1999 and December 2009 and collected demographics, disease/treatment characteristics, and clinical outcome. We estimated rate of LRR by the method of cumulative incidence. RESULTS: Presentation was 33% stage II and 67% stage III; 29.9% were clinically node positive. All patients received NACT, 94% trastuzumab containing. 90.4% had mastectomy and 6.4% breast-conserving surgery; 3.2% had no surgery. Among surgical patients, 48% were pathologically N0, 28.8% had 1 to 3 positive nodes, and 23.7% had >=4 positive nodes. 79.6% received radiation therapy (RT) to the breast/chest wall+/-supraclavicular field. Median follow-up was 43 months. Three year cumulative incidence of LRR was 8.2%; 50% of LRR had a regional component. Predictors for LRR included use of RT (HR=4.70, P=0.006), lymph node positivity (>=4 vs. 0 HR=19.99, P=0.008; 1 to 3 vs. 0 HR=10.8, P=0.031), and ER status (negative vs. positive HR=6.02, P=0.006). The only risk factor for regional failure specifically was residual nodal disease (>=4 HR=6.5, 1 to 3 HR=5.1, P=0.031). CONCLUSIONS: In a cohort with stage II to III HER2-overexpressing breast cancer treated predominantly with trastuzumab-containing NACT followed by mastectomy+/-RT, we identified omission of RT, negative ER status, and residual positive lymph nodes as significant predictors of LRR, with 50% of LRR having a regional component. PMID- 23799289 TI - Metastatic malignant transformation of teratoma to primitive neuroectodermal tumor (PNET): results with PNET-based chemotherapy. AB - BACKGROUND: Metastatic germ cell cancers are highly chemosensitive and have 80% cure rate with cisplatin-based chemotherapy. Postchemotherapy teratoma can usually be surgically resected. However, teratoma, which is pluripotent tissue, can undergo malignant transformation along mesodermal elements to primitive neuroectodermal tumor (PNET). Unlike teratoma, PNET can metastasize and render a patient unresectable and incurable. We report the results of treatment of patients with malignant transformation to PNET with cyclophosphamide+doxorubicin+vincristine (CAV) alternating with ifosfamide+etoposide (IE). METHODS: We reviewed 86 patients with histologically confirmed PNET transformed from testicular teratoma at Indiana University from 1998 to 2012. We identified 18 patients who were treated with chemotherapy comprising cyclophosphamide (1000 to 1200 mg/m), doxorubicin (50 to 75 mg/m), and vincristine (2 mg) alternating with ifosfamide (1.8 g/m) plus etoposide (100 mg/m) for 5 consecutive days. Treatment was given every 3 weeks with a maximum of 6 cycles or until progression or undue toxicity. Hematopoietic growth factors were usually incorporated. The remaining 68 patients underwent surgical resection. RESULTS: Twelve patients had unresectable disease and 6 were treated in an adjuvant setting. Median age was 29 years (range, 20 to 53 y). Nine of the 12 metastatic patients achieved objective response by RECIST criteria. Six of those were rendered with no evidence of disease (NED) with further surgery. Although 4 of the 6 patients subsequently relapsed, 1 patient remains alive and NED at 78 months. The 6 patients who received adjuvant treatment are alive with NED at 9 to 90 months with a median duration of 32.7 months. CONCLUSIONS: CAV and IE alternating chemotherapy has high objective response rate for PNET transformed from teratoma and results in occasional long-term disease-free survival when combined with subsequent resection. We recommend adjuvant CAV alternating with IE chemotherapy for patients with PNET after RPLND due to the high probability of recurrent disease and their high chemosensitivity to this regimen. PMID- 23799290 TI - Oncoplastic surgery and radiation therapy for breast conservation: early outcomes. AB - PURPOSE: To analyze a multidisciplinary community experience with oncoplastic breast surgery (OBS) and postoperative radiation therapy (RT). METHODS: The records of 79 patients with localized breast cancer who underwent OBS+RT were reviewed. OBS included immediate reconstruction and contralateral mammoreduction. All patients had negative surgical margins. Whole-breast RT was delivered without boost. A subset of 44 patients agreed to complete a validated quality of life survey pre-RT, post-RT, 6 months after RT, and at final follow-up assessing cosmesis and treatment satisfaction. RESULTS: Sixty-seven patients (85%) were white. Median age was 62 years. Median interval between OBS and RT start was 9.6 weeks. Median RT dose was 46 Gy. Fourteen patients (18%) developed surgical toxicities before RT. Five patients (6%) developed RT toxicities. Physician rating of cosmesis post-RT was: 3% excellent, 94% good, and 4% fair. Cosmesis was rated as excellent or good by 87% of patients pre-RT, 82% post-RT, 75% at 6 months, and 88% at the final follow-up. Treatment satisfaction was rated as "total" or "somewhat" by 97% of patients pre-RT, 93% post-RT, 75% at 6 months, and 96% at final follow-up. No significant relation was found between patient or treatment-related factors and toxicity. Local control is 100% at median follow-up of 2.9 years. CONCLUSIONS: OBS followed by RT resulted in acceptable toxicity and favorable physician-rated cosmesis in this large community series. Patients' ratings of cosmesis and treatment satisfaction were initially high, decreasing at 6 months, returning near baseline at final follow-up. PMID- 23799291 TI - Proteomic analysis of salt tolerance in sugar beet monosomic addition line M14. AB - Understanding the mechanisms of plant salinity tolerance can facilitate plant engineering for enhanced salt stress tolerance. Sugar beet monosomic addition line M14 obtained from the intercross between Beta vulgaris L. and Beta corolliflora Zoss exhibits tolerance to salt stress. Here we report the salt responsive characteristics of the M14 plants under 0, 200, and 400 mM NaCl conditions using quantitative proteomics approaches. Proteins from control and the salt treated M14 plants were separated using 2D-DIGE. Eighty-six protein spots representing 67 unique proteins in leaves and 22 protein spots representing 22 unique proteins in roots were identified. In addition, iTRAQ LC-MS/MS was employed to identify and quantify differentially expressed proteins under salt stress. Seventy-five differentially expressed proteins in leaves and 43 differentially expressed proteins in roots were identified. The proteins were mainly involved in photosynthesis, energy, metabolism, protein folding and degradation, and stress and defense. Moreover, gene transcription data obtained from the same samples were compared to the corresponding protein data. Thirteen proteins in leaves and 12 in roots showed significant correlation in gene expression and protein levels. These results suggest the important processes for the M14 tolerance to salt stress include enhancement of photosynthesis and energy metabolism, accumulation of osmolyte and antioxidant enzymes, and regulation of methionine metabolism and ion uptake/exclusion. PMID- 23799292 TI - Library approach for reliable synthesis and properties of DNA-gold nanorod conjugates. AB - We developed a library-based approach to chemically stabilize cetyltrimethylammonium bromide (CTAB)-coated gold nanorods for the synthesis of polyvalent DNA-gold nanorod conjugates (DNA-AuNRs). Eleven chemical reagents were carefully chosen to constitute an additive library and screened by UV-vis spectroscopy to evaluate their stabilizing capability for the CTAB-coated AuNRs. Interestingly, 5-bromosalicylic acid (5-BrSA) was determined to most significantly stabilize the AuNRs by inducing additional adsorption of CTAB on the rod. Importantly, these stabilized AuNRs with 5-BrSA were conjugated with thiol DNA in an exceptionally reproducible and reliable method, which led to the systematic investigation of their cooperative assembly and disassembly properties under various conditions, including different types and lengths of the DNA sequences. PMID- 23799293 TI - Direct coupling of thin-layer chromatography with a bioassay for the detection of estrogenic compounds: applications for effect-directed analysis. AB - The present study investigated the hypothesis that the coupling of high performance thin-layer chromatography with the yeast estrogen screen (planar-YES, p-YES) can be used as a screening tool for effect-directed analysis. Therefore, the proposed method was challenged for the first time with several real samples from various origins such as sediment pore water, wastewater, and sunscreens. It was possible to detect and quantify estrogenic effects in all investigated sample types, even in the presence of demanding matrixes. Furthermore, the specific agonistic effect of the estrogen receptor activation could be detected in samples exhibiting cytotoxic effects and at cytotoxic levels of analyzed estrogenic compounds, which is not possible with the classic YES. The analysis of samples by the p-YES results in profiles of estrogenic activity. By means of this profiles samples can be compared qualitatively and quantitatively with respect to different compositions of bioactive compounds in mixtures. In conclusion, the p YES approach seems to have a high potential to be used as a valuable screening tool for various applications in effect-directed analysis. PMID- 23799294 TI - Efficacy of gemcitabine plus platinum agents for biliary tract cancers: a meta analysis. AB - The objective of this study was to carry out a meta-analysis of the efficacy of gemcitabine+platinum agent regimens in the treatment of advanced biliary tract cancer (BTC). PubMed and Google Scholar were searched using the following combination of search terms: gemcitabine, oxaliplatin, cholangiocarcinoma, biliary, gallbladder, bile duct. Studies were eligible for inclusion in the meta analysis if they were randomized trials on the use of gemcitabine plus a platinum agent for the treatment of advanced (unresectable or metastatic cancer) BTC. Outcomes of interest were response rate, overall survival, and progression-free survival. Pooled odds ratios/differences in median survival and 95% confidence intervals (CIs) were determined for each outcome. A total of 47 records were identified in the initial search. Ultimately, three open-label randomized trials (two phase 2 and one phase 3) met the eligibility criteria and were included in the meta-analysis. Two studies compared gemcitabine plus cisplatin with gemcitabine alone, whereas the other study compared gemcitabine plus oxaliplatin with fluorouracil-folinic acid. The total number of patients in the studies ranged from 54 to 410. The overall analyses revealed that all survival outcomes assessed were significantly more favorable for patients treated with gemcitabine plus platinum agents than for patients not treated with this combination. Response rates: odds ratio=2.639, 95% CI=1.210-5.757, Z=2.439, P=0.015; pooled difference in median overall survival=3.822 months, 95% CI=1.798-5.845 months, Z=3.702, P<0.001; pooled difference in median progression-free survival=3.268 months, 95% CI=1.996-4.541 months, Z=5.035, P<0.001. Patients with advanced BTC who are treated with gemcitabine plus platinum agents may experience better survival outcomes compared with patients who are not treated with this combination of chemotherapy. PMID- 23799295 TI - Marker gene screening for human mesenchymal stem cells in early osteogenic response to bone morphogenetic protein 6 with DNA microarray. AB - AIMS: Microarray data were analyzed using bioinformatic tools to screen marker genes of human mesenchymal stem cells (hMSC) in response to bone morphogenetic protein 6 (BMP6). RESULTS: A total of 190 differentially expressed genes were identified. The interaction network was divided into three functional modules. These genes were connected with BMP signaling pathways and regulation of cell processes, while NOG and BMPR2 participated in the transforming growth factor beta signal pathway. Besides, several related small molecules were acquired. CONCLUSION: Marker genes in osteogenic responses to BMP6 treatment for hMSC were screened with microarray data along with elaborate function analysis by bioinformatics. NOG and BMPR2 showed potential to become indicators to monitor the directed differentiation of hMSC into osteoblasts, which can be used for bone disease treatment. Moreover, small molecules such as W-13 were retrieved and provided directions for future drug design. PMID- 23799296 TI - Using antiubiquitin antibodies to probe the ubiquitination state within rhTRIM5alpha cytoplasmic bodies. AB - The first line of defense protecting rhesus macaques from HIV-1 is the restriction factor rhTRIM5alpha, which recognizes the capsid core of the virus early after entry and normally blocks infection prior to reverse transcription. Cytoplasmic bodies containing rhTRIM5alpha have been implicated in the ubiquitin proteasome pathway, but the specific roles these structures play remain uncharacterized. Here, we examine the ubiquitination status of cytoplasmic body proteins. Using antibodies specific for different forms of ubiquitin, we show that ubiquitinated proteins are present in cytoplasmic bodies, and that this localization is altered after proteasome inhibition. A decrease in polyubiquitinated proteins localizing to cytoplasmic bodies was apparent after 1 h of proteasome inhibition, and greater differences were seen after extended proteasome inhibition. The decrease in polyubiquitin conjugates within cytoplasmic bodies was also observed when deubiquitinating enzymes were inhibited, suggesting that the removal of ubiquitin moieties from polyubiquitinated cytoplasmic body proteins after extended proteasome inhibition is not responsible for this phenomenon. Superresolution structured illumination microscopy revealed finer details of rhTRIM5alpha cytoplasmic bodies and the polyubiquitin conjugates that localize to these structures. Finally, linkage specific polyubiquitin antibodies revealed that K48-linked ubiquitin chains localize to rhTRIM5alpha cytoplasmic bodies, implicating these structures in proteasomal degradation. Differential staining of cytoplasmic bodies seen with different polyubiquitin antibodies suggests that structural changes occur during proteasome inhibition that alter epitope availability. Taken together, it is likely that rhTRIM5alpha cytoplasmic bodies are involved in recruiting components of the ubiquitin-proteasome system to coordinate proteasomal destruction of a viral or cellular protein(s) during restriction of HIV-1. PMID- 23799297 TI - Channel-mediated lactic acid transport: a novel function for aquaglyceroporins in bacteria. AB - MIPs (major intrinsic proteins), also known as aquaporins, are membrane proteins that channel water and/or uncharged solutes across membranes in all kingdoms of life. Considering the enormous number of different bacteria on earth, functional information on bacterial MIPs is scarce. In the present study, six MIPs [glpF1 (glycerol facilitator 1)-glpF6] were identified in the genome of the Gram positive lactic acid bacterium Lactobacillus plantarum. Heterologous expression in Xenopus laevis oocytes revealed that GlpF2, GlpF3 and GlpF4 each facilitated the transmembrane diffusion of water, dihydroxyacetone and glycerol. As several lactic acid bacteria have GlpFs in their lactate racemization operon (GlpF1/F4 phylogenetic group), their ability to transport this organic acid was tested. Both GlpF1 and GlpF4 facilitated the diffusion of D/L-lactic acid. Deletion of glpF1 and/or glpF4 in Lb. plantarum showed that both genes were involved in the racemization of lactic acid and, in addition, the double glpF1 glpF4 mutant showed a growth delay under conditions of mild lactic acid stress. This provides further evidence that GlpFs contribute to lactic acid metabolism in this species. This lactic acid transport capacity was shown to be conserved in the GlpF1/F4 group of Lactobacillales. In conclusion, we have functionally analysed the largest set of bacterial MIPs and demonstrated that the lactic acid membrane permeability of bacteria can be regulated by aquaglyceroporins. PMID- 23799298 TI - Dr. Heinrich Rohrer (1933-2013), founding father of nanotechnology. PMID- 23799299 TI - Implications of the French registry for engineered nanomaterials. PMID- 23799301 TI - Chemical mapping and quantification at the atomic scale by scanning transmission electron microscopy. AB - With innovative modern material-growth methods, a broad spectrum of fascinating materials with reduced dimensions-ranging from single-atom catalysts, nanoplasmonic and nanophotonic materials to two-dimensional heterostructural interfaces-is continually emerging and extending the new frontiers of materials research. A persistent central challenge in this grand scientific context has been the detailed characterization of the individual objects in these materials with the highest spatial resolution, a problem prompting the need for experimental techniques that integrate both microscopic and spectroscopic capabilities. To date, several representative microscopy-spectroscopy combinations have become available, such as scanning tunneling microscopy, tip enhanced scanning optical microscopy, atom probe tomography, scanning transmission X-ray microscopy, and scanning transmission electron microscopy (STEM). Among these tools, STEM boasts unique chemical and electronic sensitivity at unparalleled resolution. In this Perspective, we elucidate the advances in STEM and chemical mapping applications at the atomic scale by energy-dispersive X ray spectroscopy and electron energy loss spectroscopy with a focus on the ultimate challenge of chemical quantification with atomic accuracy. PMID- 23799302 TI - New implicit solvation models for dispersion and exchange energies. AB - Implicit solvation models provide a very efficient means to estimate solvation energies. For example, dielectric continuum models are commonly used to obtain the long-range electrostatic interactions. These may be parametrized to also include in some average manner short-range interactions such as dispersion and exchange, but it is preferable to instead develop additional implicit models specifically designed for the short-range interactions. This work proposes new models for dispersion and exchange interactions between solute and solvent by adapting approaches previously developed for treatment of gas-phase intermolecular forces. The new models are formulated in terms of the charge densities of the solutes and use only three adjustable parameters. To illustrate the performance of the models, electronic structure calculations are reported for a large number of solutes in two nonpolar solvents where short-range interactions dominate and different balances pertain between attractive dispersion and repulsive exchange contributions. After empirical optimization of the requisite parameters, it is found that the errors compared to experimental solvation free energies are only about 0.4 kcal/mol on average, which is better than previous approaches in the literature that invoke many more parameters. PMID- 23799303 TI - Gombamide A, a cyclic thiopeptide from the sponge Clathria gombawuiensis. AB - A new peptide, gombamide A (1), was isolated from the marine sponge Clathria gombawuiensis, collected from Korean waters. On the basis of the results of combined spectroscopic analyses, the structure of this compound was determined to be a cyclic C-terminally modified thiohexapeptide containing the unusual amino acid residues para-hydroxystyrylamide (pHSA) and pyroglutamic acid (pyroGlu). The absolute configurations of all amino acid residues were determined to be l by advanced Marfey's analysis. The new compound exhibited weak cytotoxicity against A549 and K562 cell lines as well as moderate inhibitory activity against Na(+)/K(+)-ATPase. PMID- 23799304 TI - Photoinduced electron and energy transfer and pH-induced modulation of the photophysical properties in homo- and heterobimetallic complexes of ruthenium(II) and rhodium(III) based on a heteroditopic phenanthroline-terpyridine bridge. AB - Homo- and heterobimetallic complexes of compositions [(bpy)2Ru(II)(phen-Hbzim tpy)Ru(II)(tpy/tpy-PhCH3/H2pbbzim)](4+) and [(bpy)2Ru(II)(phen-Hbzim tpy)Rh(III)(tpy-PhCH3/H2pbbzim)](5+), where phen-Hbzim-tpy = 2-[4-(2,6-dipyridin 2-ylpyridin-4-yl)phenyl]-1H-imidazole[4,5-f][1,10]phenanthroline, bpy = 2,2' bipyridine, tpy = 2,2':6',2"-terpyridine, tpy-PhCH3 = 4'-(4-methylphenyl) 2,2':6',2"-terpyridine, and H2pbbzim = 2,6-bis(benzimidazol-2-yl)pyridine, have been synthesized and characterized by elemental analyses, electrospray ionization mass spectrometry, and (1)H NMR spectroscopy. The absorption spectra, redox behavior, and luminescence properties of these bimetallic complexes have been thoroughly investigated and compared with those of monometallic [(bpy)2Ru(II)(phen-Hbzim-tpy)](2+) and [(tpy-PhCH3)Rh(III)(tpy-Hbzim-phen)](3+) model compounds. The electrochemistry of the complexes shows a reversible Ru(II/III) oxidation in the anodic region and an irreversible Rh(III/I) reduction and several ligand-based reductions in the cathodic region. Steady-state and time resolved luminescence data at room temperature show that an efficient intramolecular electronic energy transfer from the metal-to-ligand charge transfer (MLCT) excited state of the [(bpy)2Ru(II)(phen-Hbzim-tpy)] chromophore to the MLCT state of the tpy-containing chromophore [(phen-Hbzim tpy)Ru(II)(tpy/tpy-PhCH3/H2pbbzim)] occurs in all three unsymmetrical homobimetallic complexes. On the other hand, for both heterometallic dyads, an efficient intramolecular photoinduced electron transfer from the excited ruthenium moiety to the rhodium-based unit takes place. The rate constants for the energy- and electron-transfer processes have been determined by time-resolved emission spectroscopy. The influence of the pH on the absorption, steady-state, and time-resolved emission properties of complexes has been thoroughly investigated. The absorption titration data were used to determine the ground state pK values, whereas the luminescence data were utilized for determination of the excited-state acid dissociation constants. In effect, deprotonation of the azole NH moieties of the complexes leads to a substantial lowering of the MLCT absorption and emission band energies. PMID- 23799305 TI - Extraordinary shifts of the Leidenfrost temperature from multiscale micro/nanostructured surfaces. AB - In the present work, the effects of surface chemistry and micro/nanostructuring on the Leidenfrost temperature are experimentally investigated. The functional surfaces were fabricated on a 304 stainless steel surface via femtosecond laser surface processing (FLSP). The droplet lifetime experimental method was employed to determine the Leidenfrost temperature for both machine-polished and textured surfaces. A precision dropper was used to control the droplet size to 4.2 MUL and surface temperatures were measured by means of an embedded thermocouple. Extraordinary shifts in the Leidenfrost temperatures, as high as 175 degrees C relative to the polished surface, were observed with the laser-processed surfaces. These extraordinary shifts were attributed to nanoporosity, reduction in contact angle, intermittent liquid/solid contacts, and capillary wicking actions resulting from the presence of self-assembled nanoparticles formed on the surfaces. In addition to the shift in the Leidenfrost temperature, significant enhancement of the heat transfer in the film boiling regime was also observed for the laser-processed surfaces; water droplet evaporation times were reduced by up to 33% for a surface temperature of 500 degrees C. PMID- 23799307 TI - The true impact of a scientific paper. PMID- 23799306 TI - Enhanced osteogenesis in cocultures with human mesenchymal stem cells and endothelial cells on polymeric microfiber scaffolds. AB - In this work, human mesenchymal stem cells (hMSCs) and their osteogenically precultured derivatives were directly cocultured with human umbilical vein endothelial cells (HUVECs) on electrospun three-dimensional poly(E-caprolactone) microfiber scaffolds to evaluate the coculture's effect on the generation of osteogenic constructs. Specifically, cells were cultured on scaffolds for up to 3 weeks, and the cellularity, alkaline phosphatase (ALP) activity, and bone-like matrix formation were assessed. Constructs with cocultures and monocultures had almost identical cellularity after the first week, however, lower cellularity was observed in cocultures compared to monocultures during the subsequent 2 weeks of culture. Scaffolds with cocultures showed a significantly higher ALP activity, glycosaminoglycan and collagen production, as well as greater calcium deposition over the course of study compared to monocultures of hMSCs. Furthermore, the osteogenic outcome was equally robust in cocultures containing osteogenically precultured and non-precultured hMSCs. The results demonstrate that the combination of MSC and HUVEC populations within a porous scaffold material under osteogenic culture conditions is an effective strategy to promote osteogenesis. PMID- 23799308 TI - Familial hypercholesterolaemia: new treatment options. AB - Familial hypercholesterolaemia is a relatively frequently occurring disease that is strongly associated with vascular disease. Current treatment with cholesterol lowering agents is partly effective but shows variable responses between patients with familial hypercholesterolaemia. Recently, new cholesterol-lowering drugs have been developed. Here we describe the most promising of these new agents for which results from phase 2 or phase 3 trials are available. We will discuss the data regarding lipid-lowering potential and safety issues and speculate about the potential reductions of the residual risk of statin-treated FH patients. PMID- 23799309 TI - Haemodynamic monitoring of morbidly obese intensive care unit patients. AB - Because of technical and practical difficulties in relation to increased body size, haemodynamic monitoring of morbidly obese critically ill patients (i.e. body mass index ≥40 kg/m2) may be challenging. Obese and non-obese patients are not so different with respect to haemodynamic monitoring and goals. The critical care physician, however, should be aware of the basic principles of the monitoring tools used. The theoretical assumptions and calculations of these tools could be invalid because of the high body weight and fat distribution. Although the method of assessing haemodynamic data may be more complex in morbidly obese patients, its interpretation should not be different from that in non-obese patients. Indeed, when indexed for body surface area or (predicted) lean body mass, reliable haemodynamic data are comparable etween obese and non obese individuals. PMID- 23799310 TI - Immunoparalysis in sepsis. AB - Although therapeutic opportunities in medicine continuously improve, death is inevitable in some cases due to limitations in treatment. When patients die without a conclusive diagnosis, autopsy studies can provide essential information in order to improve athophysiological reasoning. We describe two patients who died after a prolonged course of sepsis and were diagnosed with the unsuspected presence of aspergillosis at autopsy. Literature review demonstrates that due to apoptosis and immunological interactions, septic patients become susceptible to opportunistic infections, a state described as immunoparalysis. PMID- 23799311 TI - Venous thromboembolism and prothrombotic parameters in Klippel-Trenaunay syndrome. AB - BACKGROUND: In Klippel-Trenaunay syndrome (KTS), a congenital combined vascular (capillary, venous and lymphatic) malformation with localised disturbed growth, venous thromboembolisms (VTEs) are frequently reported in small cohorts. DESIGN AND METHODS: We quantified the frequency of VTE by screening a large KTS-patient cohort with duplex compression ultrasonography. Additionally, we performed a case control study to evaluate whether coagulation alterations were related to VTE and magnitude of vascular malformations as quantified by magnetic resonance imaging (MRI). RESULTS: Twenty-nine (39%) of 75 patients had signs of current or previous VTE, including superficial venous thrombosis, six (8%) of whom had a deep venous thrombosis or a pulmonary embolism. Compared with 105 controls, 54 adult patients (both: median age 33 years) had higher plasma levels of D-dimer, medians 266 (IQR 195-366) versus 457 (IQR 270-3840) mg/l (p. PMID- 23799312 TI - Unexpected symptoms after rhTSH administration due to occult thyroid carcinoma metastasis. AB - 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) scintigraphy is a useful imaging technique in the evaluation of metastasised thyroid carcinoma. Administration of recombinant human thyrotropin (rhTSH, Thyrogen(r)) increases the diagnostic yield of this procedure. Here we present a 64-year-old male who was followed for Hurthle cell carcinoma of the thyroid with several intrapulmonary metastases. He developed sudden complaints of neck pain following rhTSH administration as part of the routine preparation for a diagnostic 18FDG PET/CT procedure. This investigation subsequently revealed a previously undetected metastatic lesion in the first cervical vertebra, with no signs of spinal cord compression. Treatment with a nonsteroidal anti-inflammatory drug reduced the symptoms sufficiently, and a few weeks later the neurosurgeon performed a complete resection of the metastasis. It is likely that the symptoms were caused by oedema and/or increased blood flow to the lesion. Physicians should be aware that rhTSH administration to patients with disseminated thyroid carcinoma may lead to sudden onset of symptoms caused by previously occult metastases. PMID- 23799313 TI - A 76-year-old male with a blue toe and livedo reticularis. PMID- 23799314 TI - A breathtaking response to tuberculosis therapy. PMID- 23799315 TI - Chronic blepharitis. PMID- 23799316 TI - A fatal rash. PMID- 23799317 TI - Chest pain in sickle cell disease. AB - The differential diagnosis of chest pain in a patient with sickle cell disease is difficult and may encompass several serious conditions, including chest syndrome, pulmonary embolism and infectious complications. In this manuscript we provide an overview on the various underlying diseases that may cause chest pain in patients with sickle cell disease and provide clues for a proper diagnostic workup. PMID- 23799318 TI - The challenge of multidisciplinary research: improving diabetic pregnancy together. AB - Improving diabetic pregnancy outcome is a goal shared by many involved specialists. Despite proper glucose control, the incidence of maternal and perinatal complications is very high, including a high risk for pre-eclampsia, congenital malformations, perinatal mortality and macrosomia. To improve outcome, not only collaborating in the doctor's office is required but also participation in critical evaluation of our treatment strategies by means of randomised clinical trials. PMID- 23799319 TI - Cost-minimisation in vitamin B12 deficiencies: expensive diagnostics can reduce spending. PMID- 23799320 TI - Strongylodiasis in a mine worker. PMID- 23799322 TI - Dehydrocostuslactone, a sesquiterpene lactone activates wild-type and DeltaF508 mutant CFTR chloride channel. AB - Cystic fibrosis transmembrane conductance regulator (CFTR) represents the main cAMP-activated Cl- channel expressed in the apical membrane of serous epithelial cells. Both deficiency and overactivation of CFTR may cause fluid and salt secretion related diseases. The aim of this study was to identify natural compounds that are able to stimulate wild-type (wt) and DeltaF508 mutant CFTR channel activities in CFTR-expressing Fischer rat thyroid (FRT) cells. We found that dehydrocostuslactone [DHC, (3aS, 6aR, 9aR, 9bS)-decahydro-3,6,9-tris (methylene) azuleno [4,5-b] furan-2(3H)-one)] dose dependently potentiates both wt and DeltaF508 mutant CFTR-mediated iodide influx in cell-based fluorescent assays and CFTR-mediated Cl- currents in short-circuit current studies, and the activations could be reversed by the CFTR inhibitor CFTRinh-172. Maximal CFTR mediated apical Cl- current secretion in CFTR-expressing FRT cells was stimulated by 100 MUM DHC. Determination of intracellular cAMP content showed that DHC modestly but significantly increased cAMP level in FRT cells, but cAMP elevation effects contributed little to DHC-stimulated iodide influx. DHC also stimulated CFTR-mediated apical Cl- current secretion in FRT cells expressing DeltaF508 CFTR. Subsequent studies demonstrated that activation of CFTR by DHC is forskolin dependent. DHC represents a new class of CFTR potentiators that may have therapeutic potential in CFTR-related diseases. PMID- 23799323 TI - Excited states of the inactive and active forms of the orange carotenoid protein. AB - The orange carotenoid protein (OCP) is a crucial player in the process of nonphotochemical quenching in a large number of cyanobacteria. This water-soluble protein binds one pigment only, the keto carotenoid 3'-hydroxyechinenone, and needs to be photoactivated by strong (blue-green) light in order to induce energy dissipation within or from the phycobilisome, the main light harvesting system of these organisms. We performed transient-absorption spectroscopy on OCP samples frozen in the inactive and active forms at 77 K. By making use of target analysis we determined the excited state properties of the active form. Our results show that OCP photoactivation modifies the carotenoid excited state energy landscape. More specifically the photoactivated OCP is characterized by one state with predominantly ICT character (ICT/S1) and a lifetime of 2.3 ps, and another state with mainly S1 character (S1/ICT) with a lifetime of 7.6 ps. We also show that the kinetic model is fully consistent with the RT data obtained earlier (Berera et al., J. Phys. Chem. B 2012, 116, 2568-2574). We propose that this ICT/S1 state acts as the quencher in the OCP mediated nonphotochemical quenching. PMID- 23799324 TI - On the robustness of prime response retrieval processes: evidence from auditory negative priming without probe interference. AB - Visual negative priming has been shown to depend on the presence of probe distractors, a finding that has been traditionally seen to support the episodic retrieval model of negative priming; however, facilitated prime-to-probe contingency learning might also underlie this effect. In four sound identification experiments, the role of probe distractor interference in auditory negative priming was investigated. In each experiment, a group of participants was exposed to probe distractor interference while another group ran the task in the absence of probe distractors. Experiments 1A, 1B, and 1C varied in the extent to which fast versus accurate responding was required. Between Experiments 1 and 2, the spatial cueing of the to-be-attended ear was varied. Whereas participants switched ears from prime to probe in Experiment 1, they kept a stable attentional focus throughout Experiment 2. For trials with probe distractors, a negative priming effect was present in all experiments. For trials without probe distractors, the only ubiquitous after-effect of ignoring a prime distractor was an increase of prime response errors in ignored repetition compared to control trials, indicating that prime response retrieval processes took place. Whether negative priming beyond this error increase was found depended on the stability of the attentional focus. The findings suggest that several mechanisms underlie auditory negative priming with the only robust one being prime response retrieval. PMID- 23799325 TI - Nutritional management of acute pancreatitis: the concept of 'gut rousing'. AB - PURPOSE OF REVIEW: Enteral nutrition has emerged as one of the most effective treatments in the early management of patients with acute pancreatitis. The original rationale for nutrition in acute pancreatitis, dating back to the mid 20th century, was to provide full nutritional requirements but avoid stimulating exocrine pancreatic secretion. The purpose of this article is to review the recent clinical studies of enteral nutrition in acute pancreatitis to revise the rationale and develop a contemporary conceptual framework for nutritional management of this disease. RECENT FINDINGS: Several recent randomized controlled trials dispel the outdated concept of 'pancreatic rest', which equates with gut neglect, and offer 'gut rousing' as a preferred concept. The new concept postulates that gastrointestinal (dys)function has a discernible impact on the outcomes of patients with acute pancreatitis. Further, timely administration of appropriate intraluminal modalities prevents or mitigates the gastrointestinal dysfunction. SUMMARY: Nutritional management in acute pancreatitis should aim primarily at maintaining the gastrointestinal function. Providing full nutritional requirements and avoiding pancreatic exocrine stimulation should be considered as secondary aims. PMID- 23799326 TI - Irisin: what promise does it hold? AB - PURPOSE OF REVIEW: The recently identified myokine, irisin has raised great expectations as a potential target in the conservative treatment of obesity. This review focuses on studies exploring the effects of irisin in humans. RECENT FINDINGS: Peroxisome proliferator-activated receptor gamma coactivator-1 alpha expression in skeletal muscles is induced by exercise followed by expression of the membrane protein fibronectin type III domain containing 5. After cleavage from fibronectin type III domain containing 5, irisin is secreted into blood increasing thermogenesis by browning of subcutaneous white/beige adipose tissue. Although clear-cut data have been reported in rodents, the thermogenic effect of irisin in humans remains controversial. The initially reported exercise-dependent increase of irisin in humans could not be confirmed in most studies. However, a robust finding in human studies is the association of irisin with BMI. SUMMARY: The discovery of irisin provides more insight into exercise-induced browning of adipose tissue, and therefore leads to a better understanding of mechanisms underlying body weight regulation and further down the road possibly may lead to treatment strategies of diseases with greatly altered body weight such as obesity or anorexia nervosa. PMID- 23799327 TI - Diarrhea in enterally fed patients: blame the diet? AB - PURPOSE OF REVIEW: Diarrhea has great impact on enteral nutrition. The purpose of this review is to identify the factors leading to diarrhea during enteral nutrition and to provide the published updates on diarrhea prevention through nutritional intervention. RECENT FINDINGS: Diarrhea in enteral fed patients is attributed to multiple factors, including medications (major contributor), infections, bacterial contamination, underlying disease, and enteral feeding. Diet management can alleviate diarrhea in enteral feeding. High content of fermentable oligosaccharides, disaccharides, and monosaccharides and polyols (FODMAPs) in enteral formula is postulated to induce diarrhea and lower FODMAPs formula may reduce the likelihood of diarrhea in enterally fed patients. Fiber enriched formula can reduce the incidence of diarrhea and produce short-chain fatty acids for colonocytes. Ingesting prebiotics, nonviable probiotics or probiotic derivatives, and human lactoferrin may provide alternatives for reducing/preventing diarrhea. SUMMARY: Enteral feeding is not generally considered the primary cause of diarrhea, which is frequently linked to prescribed medications. When diarrhea is apparent, healthcare members should evaluate the possible risk factors and systematically attempt to eliminate the underlying causes of diarrhea before reducing or suspending enteral feeding. Lower FODMAPs formula, prebiotics, probiotic derivatives, and lactoferrin may be used to manage enteral feeding-related diarrhea. PMID- 23799328 TI - Body composition in chemotherapy: the promising role of CT scans. AB - PURPOSE OF REVIEW: Reducing cancer-treatment toxicity was a largely ignored research agenda, which is now emerging as an active area of investigation. Studies of human body composition using computerized tomography scans have provided proof-of-concept that variability in drug disposition and toxicity profiles may be partially explained by different features in body composition. RECENT FINDINGS: Collectively, studies suggest that skeletal muscle depletion (regardless of body weight) is an independent predictor of severe toxicity, affecting cancer treatment and its outcomes. Although precise mechanisms are unknown, pharmacokinetic parameters such as variations in volume of distribution and increased drug exposure may explain such findings. SUMMARY: Computerized tomography scans are readily available in clinical databases of diagnostic images and provide feasible, reliable, and highly differentiated measurements of body composition. These images should be used to optimize screening and management of patients in order to prevent severe toxicity, and to improve the efficacy and cost-efficiency of chemotherapy treatments. PMID- 23799329 TI - Multiple drug hypersensitivity syndrome. AB - PURPOSE OF REVIEW: The multiple drug hypersensitivity syndrome (MDH) is a distinct clinical entity, different from cross-reactivity and flare-up reactions. Following its initial description in 1989 by Sullivan et al., several authors have addressed the issues surrounding this peculiar form of drug hypersensitivity. Whether this syndrome is single or can be further classified in several entities is still a matter of debate. RECENT FINDINGS: Case reports, case series or studies involving large populations on MDH are few. The use of this term in the literature is heterogeneous, and the definitions variable. Given the major advances in the study of drug hypersensitivities in general, and ongoing research regarding severe cutaneous adverse reactions in particular, careful study of the subgroup of patients with demonstrated immunological basis of MDH has enabled the generation of possible pathogenetic hypotheses. Together with the studies (despite their limitations) to estimate the prevalence of this syndrome in adult and paediatric patients these emerging data need confirmation through larger studies with well defined populations. SUMMARY: Bringing together the experience of groups involved in the field of drug allergy should help to move knowledge regarding this peculiar form of drug hypersensitivity forward. PMID- 23799330 TI - Toxic epidermal necrolysis: the year in review. AB - PURPOSE OF REVIEW: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening severe adverse drug reactions. Once thought to be idiosyncratic and unpredictable, there has been significant progress made in the understanding of the pathomechanism and pharmacogenetics of such reactions. These advances together with their clinical implications will be elaborated in this review. RECENT FINDINGS: It is now known that the human leukocyte antigen (HLA) association in SJS/TEN is more than just a genetic marker and has a functional role as well. This reaction is mediated by cytotoxic T lymphocytes (CTLs) in an HLA-restricted fashion. Certain drugs may bind directly to the HLA complex and facilitate the development of self-reactivity due to drug-modified HLA-peptide repertoire. The role of the drug-specific T cells and their T-cell receptors has also been clarified. Downstream cytotoxic signals have been elucidated with granulysin, a cytotoxic protein produced by CTLs or natural killer cells deemed to be the key mediator in the reaction. SUMMARY: Pharmacogenetic screening of HLA alleles prior to drug initiation has already been shown useful in the prevention of such reactions. The other advances in the disease mechanism will form the basis for better preventive and therapeutic strategies. PMID- 23799331 TI - Cross-reacting carbohydrate determinants and hymenoptera venom allergy. AB - PURPOSE OF REVIEW: Insect venom allergy is an important cause of anaphylaxis. Venom immunotherapy assume the clear identification of the culprit insect, but this is impeded by Immunoglobulin E (IgE) antibodies to cross reactive carbohydrate determinant (CCD) epitopes of common glycoproteins. Here we give an overview about inducers, importance, and relevance of anti-N-Glycan CCD IgE antibodies. RECENT FINDINGS: Pollen exposure and insect stings induce anti-CCD IgE antibodies interfering with in-vitro tests for allergy diagnosis due to extensive IgE cross-reactivity. Instead of being biologically active these antibodies are irrelevant for allergic reactions due to hymenoptera stings. The general response of the immune system to the ubiquitous exposure to N-glycan containing glycoproteins is still a matter of debate. CCD specific IgG antibodies in sera of bee keepers suggest tolerance induction due to high-dose exposure. Tolerance induction by pollen and food glycoproteins has not been proved. SUMMARY: Hymenoptera stings and pollen exposure induce anti-CCD IgE. In regard to anaphylaxis due to Hymenoptera stings these antibodies are not clinically relevant, but they are important for the specificity of in-vitro tests proving insect venom allergy. The introduction of component based diagnostic IgE testing improves the specificity of in-vitro tests if proteins devoid of CCD epitopes are used. PMID- 23799332 TI - Reactions to honeybee stings: an allergic prospective. AB - PURPOSE OF REVIEW: The purpose of this article is to provide a brief overview of the events involved in honeybee allergy and to concisely update the reader on progress toward knowledge of honeybee venom (HBV), strides in solving diagnostic difficulties, and advancements in improving safety and efficacy of HBV immunotherapy. RECENT FINDINGS: It is well known that honeybee allergy is unique in venom allergen and protein composition, diagnostic challenges, and immunotherapy safety and efficacy. Many new honeybee allergens have been recognized. Advances in testing, evaluation, and extract manipulation methods, many using recombinant technology, have allowed a greater ability to help with honeybee allergy diagnosis and resultant improvement in immunotherapy safety and evaluation of immunotherapy efficacy. SUMMARY: In an effort to address many honeybee allergy concerns, specific advances have been recently made. Some recently characterized honeybee allergens appear to be major contributors to honeybee allergy. In the setting of double-positivity, cross-reacting carbohydrate determinants and other cross-reacting components in HBV have made diagnosis of honeybee allergy challenging. Recombinant technology, including component-resolved diagnostics, and other evolving testing methods should help clarify double-positivity, if not now, in the very near future. Purified HBV and possibly depot formulations for immunotherapy appear to make it more well tolerated. Recombinant methods may help with evaluation of immunotherapy's safety and efficacy. PMID- 23799333 TI - Mitigating the allergic effects of fire ant envenomation with biologically based population reduction. AB - PURPOSE OF REVIEW: To describe the current efforts to use biological control agents to reduce fire ant population levels, thus ultimately reducing the number of human sting and allergic reaction incidents. RECENT FINDINGS: Climate change and worldwide fire ant expansion will increase the frequency of human encounters and allergenic events, putting additional pressure on the public health sector. Six species of fire ant decapitating flies are now established in the United States. The microsporidium Kneallhazia solenopsae is well established and new fire ant hosts have been identified. The fire ant virus Solenopsis invicta virus 3 shows good potential for use as an environmentally friendly biopesticide because of its virulence and host specificity. SUMMARY: During separate founding events in the United States, Australia, mainland China, and Taiwan, fire ants native to South America escaped their native pathogens and parasites. Consequently, fire ant populations in these introduced regions pose a serious public health threat to the human populations by envenomation and subsequent allergic reactions. Specific, self-sustaining biological control agents have been discovered, studied, and released into fire ant populations in the United States in an effort to re-establish an ecological/competitive balance, resulting in reduced fire ant densities and human exposure. PMID- 23799334 TI - Treatment of food anaphylaxis with traditional Chinese herbal remedies: from mouse model to human clinical trials. AB - PURPOSE OF REVIEW: To describe the development of a novel treatment for food allergy, named the food allergy herbal formula-2 (FAHF-2), that is based on traditional Chinese medicine. RECENT FINDINGS: FAHF-2 has proven to be well tolerated and effective for the treatment of food allergies in murine models of peanut and multiple food allergies. These results are accompanied by evidence of favorable immune modulation, and the effects are persistent after the discontinuation of treatment. Early clinical trials demonstrate the safety and tolerability of this formula in individuals with food allergies. An ongoing Phase II clinical trial will evaluate the efficacy of FAHF-2 in protecting individuals from allergen-induced allergic reactions during oral food challenges. SUMMARY: FAHF-2 is an herbal formula that has a high safety profile and has shown to prevent anaphylaxis in murine models of food allergy. Similar findings in clinical trials could bring a novel treatment for food allergies. PMID- 23799335 TI - Asthma pharmacogenetics: responding to the call for a personalized approach. AB - PURPOSE OF REVIEW: Asthma is a chronic, complex disease that is treated with a combination of different therapies. However, interindividual variability in clinical responses to different therapies complicates asthma management. A personalized approach to asthma management could identify appropriate responders to specific agents or those that might be at an increased risk for adverse responses. RECENT FINDINGS: Pharmacogenetic studies of genes from the leukotriene, glucocorticoid, and beta2-adrenergic receptor pathways have improved our understanding of how gene variation determines therapeutic responses to different classes of antiasthma therapies. Such studies have previously been limited to retrospective analyses of candidate genes in the leukotriene, glucocorticoid, and beta2-adrenergic receptor pathways in trial cohorts. However, prospective genotype-stratified trials in asthma have recently been done and recent genome-wide association studies have identified novel pharmacogenetic loci. SUMMARY: It will be important to replicate previous genotypic associations in large clinical trial cohorts as future pharmacogenetic studies continue to focus on genome-wide approaches and the study of novel therapeutic pathways. This review of the pharmacogenetics of asthma highlights the contributions of genomics research to the future of personalized medicine in asthma and draws attention to the role of genetic biomarkers in predicting clinical responses to specific therapies. PMID- 23799336 TI - Environmental control for asthma: recent evidence. AB - PURPOSE OF REVIEW: To review and interpret recent literature related to the role of environmental control in prevention and treatment of asthma. RECENT FINDINGS: Environmental control has a clearly established role in the management of asthma, but its role as a primary prevention tool is not supported by recent clinical trials. Although some of the interventions tested in these trials reduced the risk of asthma, the interventions often included dietary modification and those trials intervening only on environmental exposures were largely negative. Environmental interventions that target multiple asthma triggers, such as a laminar airflow device and relocation to high altitude, continue to demonstrate efficacy in asthma. Several studies highlight the efficacy of portable HEPA purifiers in reduction of indoor particulate matter and improving asthma outcomes. Several recently published practice parameters provide evidence-based recommendations for environmental control practices targeting furry pet, rodent, and cockroach allergens. Emerging work highlights the potential impact of spatial temporal aspects of exposure and the shape of the dose-response relationships on the indoor allergen exposure-asthma relationship. SUMMARY: Environmental interventions likely have no effect on the risk of developing atopic disease, but multifaceted interventions are generally of benefit in the management of asthma, particularly in children. PMID- 23799337 TI - Evidence of preventive effect of probiotics and prebiotics for infantile eczema. AB - PURPOSE OF REVIEW: Infantile eczema, and in particular atopic dermatitis are, in many children, the first manifestation of their predisposition to an atopic disease. Among existing prevention strategies, supplementation with probiotics and prebiotics belong to the most promising beneficial interventions. Highlighting the most recent literature, we review here the most recent studies on probiotics and prebiotics and hypothesize on the most efficient intervention strategies. RECENT FINDINGS: Various probiotics and prebiotics, either alone or in combinations, have been administered, in general, during the late phase of pregnancy and up to 6 months of age. In general, a combination of probiotics and prebiotics given from pregnancy until early infancy has a higher potential for protecting the infant from developing early manifestations of eczema than short administration of one specific microorganism. SUMMARY: The effect of probiotics and prebiotic supplementations on early manifestations of atopy such as infantile eczema are conflicting. Nevertheless, prevention strategies should aim for an enhanced efficacy by addressing not only interventions on the microbiota, but by combining them to other interventions, for example, to those aiming at actively inducing antigen-specific tolerance. PMID- 23799338 TI - Molecular profile clustering of IgE responses and potential implications for specific immunotherapy. AB - PURPOSE OF REVIEW: To summarize recent data on molecular profiles of IgE sensitization in allergic patients and discuss how they can influence our understanding of allergen specific immunotherapy. RECENT FINDINGS: In childhood, Immunoglobulin E (IgE) sensitization to grass pollen starts preclinically as a weak, mono or oligomolecular response and evolves rapidly to become strong, polymolecular and associated with clinical manifestations. This immunological phenomenon has been defined 'molecular spreading' and it makes the IgE sensitization profiles to complex allergenic sources highly heterogeneous in the population. SUMMARY: The recent findings raise new questions: do different molecular sensitization profiles (e.g. to grass pollen) underlie different clinical responses to allergen-specific immunotherapy? Should the allergen specific immunological intervention be anticipated at earlier stages of the IgE sensitization process? Should the regulatory rules for molecularly designed allergen-specific immunotherapy preparations consider the extreme heterogeneity of sensitization profiles in populations? PMID- 23799339 TI - Current world literature. Drug allergy. PMID- 23799341 TI - Serum 25-hydroxyvitamin D level is associated with arterial stiffness, left ventricle hypertrophy, and inflammation in newly diagnosed hypertension. AB - OBJECTIVES: Vitamin D may modulate vascular inflammation, vascular smooth muscle cell proliferation, the renin-angiotensin system, and cardiomyocyte proliferation, myocardial fibrosis, and proliferation. These mechanisms may play a role on arterial stiffness and left ventricle hypertrophy (LVH) in hypertensive patients. We aimed to evaluate the association between serum vitamin D with arterial stiffness and LVH in patients with hypertension. METHODS: We studied 133 patients with newly diagnosed hypertension [mean (SD) age, 62.9 (10.6) years]. Pulse wave velocity (PWV), which reflects arterial stiffness, was calculated using the single-point method via the Mobil-O-Graph ARCsolver algorithm. Left ventricular mass index (LVMI) was determined according to Deverux formula. The patients were divided into the following 2 groups according to serum vitamin D level: vitamin Dlow group with less than 20 ng/mL and vitamin Dhigh group with greater than or equal to 20 ng/mL. RESULTS: The highest PWV, high-sensitivity C reactive protein, and LVMI values were observed in vitamin Dlow group compared with vitamin Dhigh group. Multiple linear regression analysis showed that vitamin D level was independently associated with LVMI (beta = -0.235, P = 0.002) and PWV (beta = -0.432, P < 0.001). Adjustment for age, sex, parathyroid hormone level, body surface area, and mean blood pressure did not modify these associations. Vitamin D level was also independently associated with high-sensitivity C reactive protein (beta = -0.143, P = 0.047). However, adjustment for parathyroid hormone level or body surface area and mean blood pressure attenuate this association. CONCLUSIONS: Serum 25-hyroxyvitamin D is independently related with arterial stiffness, LVH, and inflammation. Vitamin D may play a role on pathogenesis of arterial stiffness and LVH in patient with newly diagnosed hypertension. PMID- 23799342 TI - Maternal attitudes and knowledge about newborn screening. AB - PURPOSE: To determine whether mothers of newborns understand basic facts about newborn screening (NBS), and how they feel about state retention of dried bloodspots (DBS) for research use. DESIGN: This study was a cross-sectional survey administered to 548 mothers of newborns in postpartum units in five different hospitals in north Texas after Institutional Review Board approval. Each participating site delivered and collected surveys using systems that were convenient for them. The survey instrument used in this study is the Maternal Attitudes and Knowledge about Newborn Screening Survey. The survey was developed by the investigators. Summary statistics were provided for each participating site and surveys were combined for final data analysis. Multiple regression analysis was used to quantify associations between responses and demographic variables. RESULTS: Overall, knowledge about details of NBS and DBS retention was inadequate. The most frequent source of information about NBS was the postpartum nurse. Mothers tended to believe that using newborn bloodspots for research was a good thing, but Medicaid recipients and minorities were more reluctant than others to share dried bloodspots for research. CLINICAL IMPLICATIONS: Mothers are not fully informed about NBS or the use of infant bloodspots for research. Bloodspot storage in Texas could shrink under new opt-in policies, constraining a resource needed for genetic and other research. Further research to design and test educational interventions that are sensitive to the concerns of parents about DBS storage and that can be efficiently implemented antenatally is needed. PMID- 23799343 TI - A sobering truth. PMID- 23799344 TI - The natural course of spontaneous osteonecrosis of the knee (SPONK): a 1- to 27 year follow-up of 40 patients. AB - BACKGROUND AND PURPOSE: Spontaneous osteonecrosis of the knee (SPONK) is a painful lesion in the elderly, frequently leading to osteoarthritis and subsequent knee surgery. We evaluated the natural course and long-term consequences of SPONK in terms of need for major knee surgery. METHODS: Between 1982 and 1988, 40 consecutive patients were diagnosed with SPONK. The short-term outcome has been reported previously (1991). After 1-7 years, 10 patients had a good radiographic outcome and 30 were considered failures, developing osteoarthritis. In 2012, all 40 of the patients were matched with the Swedish Knee Arthroplasty Register (SKAR) and their medical records were reviewed to evaluate the long-term need for major knee surgery. RESULTS: At the 2012 review, 33 of the 40 patients had died. The mean follow-up time from diagnosis to surgery, death, or end of study was 9 (1-27) years. 17 of 40 patients had had major knee surgery with either arthroplasty (15) or osteotomy (2). All operated patients but 1 were in the radiographic failure group and had developed osteoarthritis in the study from 1991. 6 of 7 patients with large lesions (> 40% of the AP radiographic view of the condyle) at the time of the diagnosis were operated. None of the 10 patients with a lesion of less than 20% were ever operated. INTERPRETATION: It appears that the size of the osteonecrotic lesion can be used to predict the outcome. Patients showing early signs of osteoarthritis or with a large osteonecrosis have a high risk of later major knee surgery. PMID- 23799345 TI - 1-stage primary arthroplasty of mechanically failed internally fixated of hip fractures with deep wound infection: good outcome in 16 cases. AB - BACKGROUND AND PURPOSE: Mechanically failed internal fixation following hip fracture is often treated by salvage arthroplasty. If deep wound infection is present, a 2-stage procedure is often used. We have used a 1-stage procedure in infected cases, and we now report the outcome. PATIENTS AND METHODS: We reviewed 16 cases of deep wound infection after mechanically failed hip fracture fixation, treated between 1994 and 2010. In all patients, a joint prosthesis was implanted in a 1-stage procedure. RESULTS: After an average follow-up period of 12 (2-18) years, no reinfection was detected. In 4 cases, a hip dislocation occurred and 3 of these needed further surgery. INTERPRETATION: A 1-stage procedure for arthroplasty of an infected, mechanically failed hip fracture fixation is feasible and carries a low risk of infection. PMID- 23799346 TI - Negative correlation between extent of physeal ablation after percutaneous permanent physiodesis and postoperative growth: volume computer tomography and radiostereometric analysis of 37 physes in 27 patients. AB - BACKGROUND AND PURPOSE: Percutaneous physiodesis in the knee region is a well established method for treating leg-length inequality. Longitudinal growth in the physis is believed to stop almost immediately after the operation. The extent of physis ablation required has never been investigated by any kind of tomography in humans. Using radiostereometric analysis (RSA), we determined when definite growth arrest occurred after surgery. We also studied the correlation between the extent of physis ablation and postoperative growth. Finally, we assessed any bone bridging across the physis. METHODS: 6, 12, and 30 weeks after surgery, we used RSA to measure longitudinal growth in 27 patients (37 physes) with a mean age of 13 years. CT scanning of the knee region was performed 12 weeks after surgery to measure the percentage of the ablated physis and to determine the distribution of bone bridges across the physis. RESULTS: RSA showed that growth rate was reduced to less than half of the expected rate after 6 weeks. During the next 6 weeks, the growth ceased completely. CT scans revealed a large variation in the extent of ablated physes (17-69%). In the ablated areas, tissues of various densities were mixed with mature bone. Bridges were found both laterally and medially across the physes in all of the patients. There was a negative correlation between the extent of ablation and total postoperative growth (rho = -0.37, p = 0.03). INTERPRETATION: Growth across the physis is effectively stopped by percutaneous physiodesis. RSA is well-suited for observation of this phenomenon. Volume CT scanning can be used to detect bone bridges that cross the physis and to calculate the extent of physis ablation. PMID- 23799347 TI - Risk factors for aseptic loosening of Muller-type straight stems: a registry based analysis of 828 consecutive cases with a minimum follow-up of 16 years. AB - Background and purpose Even small differences in design variables for the femoral stem may influence the outcome of a hip arthroplasty. We performed a risk factor analysis for aseptic loosening of 4 different versions of cemented Muller-type straight stems with special emphasis on design modifications (2 shapes, MSS or SL, and 2 materials, CoNiCrMo (Co) or Ti-6Al-7Nb (Ti)). Methods We investigated 828 total hip replacements, which were followed prospectively in our in-house register. All stems were operated in the same setup, using Sulfix-6 bone cement and a second-generation cementing technique. Demographic and design-specific risk factors were analyzed using an adjusted Cox regression model. Results The 4 versions showed marked differences in 15-year stem survival with aseptic loosening as the endpoint: 94% (95% CI: 89-99) for MSS Co, 83% (CI: 75-91) for SL Co, 81% (CI: 76-87) for MSS Ti and 63% (CI: 56-71) for SL Ti. Cox regression analysis showed a relative risk (RR) for aseptic loosening of 3 (CI: 2-5) for stems made of Ti and of 2 (CI: 1-2) for the SL design. The RR for aseptic stem loosening increased to 8 (CI: 4-15) when comparing the most and the least successful designs (MSS Co and SL Ti). Interpretation Cemented Muller-type straight stems should be MSS-shaped and made of a material with high flexural strength (e.g. cobalt-chrome). The surface finish should be polished (Ra < 0.4 um). These technical aspects combined with modern cementing techniques would improve the survival of Muller-type straight stems. This may be true for all types of cemented stems. PMID- 23799348 TI - Effect of femoral head size on risk of revision for dislocation after total hip arthroplasty: a population-based analysis of 42,379 primary procedures from the Finnish Arthroplasty Register. AB - BACKGROUND AND PURPOSE: Previous population-based registry studies have shown that larger femoral head size is associated with reduced risk of revision for dislocation. However, the previous data have not included large numbers of hip resurfacing arthroplasties or large metal-on-metal (> 36-mm) femoral head arthroplasties. We evaluated the association between femoral component head size and the risk of revision for dislocation after THA by using Finnish Arthroplasty Register data. PATIENTS AND METHODS: 42,379 patients who were operated during 1996-2010 fulfilled our criteria. 18 different cup/stem combinations were included. The head-size groups studied (numbers of cases) were 28 mm (23,800), 32 mm (4,815), 36 mm (3,320), and > 36 mm (10,444). Other risk factors studied were sex, age group (18-49 years, 50-59 years, 60-69 years, 70-79 years, and > 80 years), and time period of operation (1996-2000, 2001-2005, 2006-2010). RESULTS: The adjusted risk ratio in the Cox model for a revision operation due to dislocation was 0.40 (95% CI: 0.26-0.62) for 32-mm head size, 0.41 (0.24-0.70) for 36-mm head size, and 0.09 (0.05-0.17) for > 36-mm head size compared to implants with a head size of 28 mm. INTERPRETATION: Larger femoral heads clearly reduce the risk of dislocation. The difference in using heads of > 36 mm as opposed to 28-mm heads for the overall revision rate at 10 years follow-up is about 2%. Thus, although attractive from a mechanical point of view, based on recent less favorable clinical outcome data on these large heads, consisting mainly of metal-on-metal prostheses, one should be cautious using these implants. PMID- 23799349 TI - Good accuracy of the Phase III Oxford Mobile Bearing Unicompartmental Knee Instrumentation. AB - BACKGROUND AND PURPOSE: Unicompartmental knee arthroplasty (UKA) needs careful balancing of flexion/extension (F/E) gaps to prevent dislocation of the mobile meniscal bearing. Assessment of gaps is based on the surgeon's subjective insertion force of a feeler gauge with different thicknesses and/or the lift-off of a trial meniscal bearing. However, the accuracy of this method remains unclear. We assessed the accuracy of the technique. PATIENTS AND METHODS: A consecutive series of 33 UKAs in 32 patients (mean age 64 years, 24 women) were balanced using the Oxford Phase III (OP III) Instrumentation. The recommended technique for F/E gap assessment was performed using different feeler gauges with 1-mm increments and the meniscal bearing lift-off tests according to surgical technique. A tensiometer was inserted and both gaps were maximally distracted by hand. Measurements in mm were recorded and analyzed with a reading of 90 N for both gaps in 20 and 90 degrees of flexion. RESULTS: The gaps measured were 12 (11 18) mm in extension and 13 (11-18) mm in 90 degrees of flexion. The difference between the gaps was 0.4 (-0.5 to 1.0) mm (p < 0.001). There were no statistically significant gender differences regarding composite implant thickness, laxity, flexion gap, extension gap, or gap difference. INTERPRETATION: OP III instrumentation using feeler gauges and the lift-off test provides accurate balancing of F/E gaps with an accuracy of less than 1 mm. PMID- 23799350 TI - 10-year results following impaction bone grafting of major bone defects in 29 rotational and hinged knee revision arthroplasties: a follow-up of a previous report. AB - BACKGROUND AND PURPOSE: Substantial bone loss in revision total knee arthroplasty (TKA) is a challenging problem. We studied whether impaction bone grafting provides long-term restoration of bone stock in the treatment of major bone defects in revision surgery of rotational and hinged knee arthroplasties (LINK Endo-Model). PATIENTS AND METHODS: Between 1996 and 2006, 29 knees in 29 patients underwent revision procedures of rotational and hinged knee arthroplasties using impaction bone grafting (IBG) to reconstruct major bone defects. At the latest follow-up, the clinical examination included the Knee Society score (KSS), standardized radiographs, and a questionnaire for the WOMAC score. RESULTS: After a mean follow-up of 10 (6-13) years, 14 knees with 19 IBG reconstructions (5 total, 9 partial revisions) had failed. 12 knees were treated with re-revision surgery mean 5 (1-12) years after the first revision, due to mechanical failure and aseptic loosening of the components. In all these failed cases, the surgeon observed a lack of incorporation with bone graft resorption in the femur or tibia during the re-revision procedure. In all 15 knees that were not re-revised, with 21 reconstructions (6 total, 9 partial revisions), an improvement in the combined KSS score (knee score + function score) of 60 points (p < 0.001) was found at the latest follow-up. In 12 of these knees, a clear incorporation with no visible radiolucent lines around the component and no sign of substantial graft resorption was noted, while unclear radiographic graft incorporation was seen in 3 knees. INTERPRETATION: Our results clearly indicate that IBG alone is not a methodologically sound technique in the revision of rotational and hinged knee arthroplasties. PMID- 23799351 TI - Retaining well-fixed cementless stem in the treatment of infected hip arthroplasty. PMID- 23799352 TI - Variation in the femoral bow: a novel high-throughput analysis of 3922 femurs on cross-sectional imaging. AB - OBJECTIVES: To evaluate femoral radius of curvature in a large sample of computed tomography scans to definitively determine the relationship between radius of curvature and femoral length, age, gender, ethnicity, body mass index and cortical thickness. METHODS: A retrospective review was conducted of the electronic medical records and advanced imaging of 1961 patients who underwent pulmonary embolism protocol computed tomography scans between December 1999 and March 2010. The computed tomography scans were imported from the clinical picture archiving and communication system archive into a research image archive and analysis system. Each scan was processed by an automated system that algorithmically determined bony landmarks, adjusted for body position within the scanner and measured the radius of curvature. RESULTS: The mean medullary radius of curvature of 3922 femurs was 112 cm (SD = 26 cm). The mean anterior radius of curvature of the femurs was 145 cm (SD = 55 cm). There was a moderately strong positive correlation (0.36-0.39) between femoral length and radius of curvature (P < 0.0001) that was not affected by age, body mass index, cortical thickness, gender, or ethnicity. No significant relationship was found between either gender or ethnicity and radius of curvature independent of femoral length. CONCLUSIONS: Differences in radius of curvature based on ethnicity and gender exist primarily because of the variation in average height, and therefore femur length, that exists between ethnic groups and genders. These data may prove useful in the design of safer intramedullary implants that accommodate a greater spectrum of anatomic variation. PMID- 23799353 TI - Posterolateral approach for plating of tibial plateau fractures and the risk of injury to the anterior tibial vessels. PMID- 23799354 TI - Preemptive application of airway pressure release ventilation prevents development of acute respiratory distress syndrome in a rat traumatic hemorrhagic shock model. AB - BACKGROUND: Once established, the acute respiratory distress syndrome (ARDS) is highly resistant to treatment and retains a high mortality. We hypothesized that preemptive application of airway pressure release ventilation (APRV) in a rat model of trauma/hemorrhagic shock (T/HS) would prevent ARDS. METHODS: Rats were anesthetized, instrumented for hemodynamic monitoring, subjected to T/HS, and randomized into two groups: (a) volume cycled ventilation (VC) (n = 5, tidal volume 10 mL/kg; positive end-expiratory pressure 0.5 cmH(2)O) or (b) APRV (n = 4, P(high) = 15-20 cmH(2)O; T(high) = 1.3-1.5 s to achieve 90% of the total cycle time; T(low) = 0.11-0.14 s, which was set to 75% of the peak expiratory flow rate; P(low) = 0 cmH(2)O). Study duration was 6 h. RESULTS: Airway pressure release ventilation prevented lung injury as measured by PaO(2)/FIO(2) (VC 143.3 +/- 42.4 vs. APRV 426.8 +/- 26.9, P < 0.05), which correlated with a significant decrease in histopathology as compared with the VC group. In addition, APRV resulted in a significant decrease in bronchoalveolar lavage fluid total protein, increased surfactant protein B concentration, and an increase in epithelial cadherin tissue expression. In vivo microscopy demonstrated that APRV significantly improved alveolar patency and stability as compared with the VC group. CONCLUSIONS: Our findings demonstrate that preemptive mechanical ventilation with APRV attenuates the clinical and histologic lung injury associated with T/HS. The mechanism of injury prevention is related to preservation of alveolar epithelial and endothelial integrity. These data support our hypothesis that preemptive APRV, applied using published guidelines, can prevent the development of ARDS. PMID- 23799355 TI - A radiological comparison of Salter and Pemberton osteotomies to improve acetabular deformations in developmental dysplasia of the hip. AB - We investigated whether the following acetabular scores influence operative outcomes in patients with developmental dysplasia of the hip who underwent Salter innominate osteotomy (SIO) or Pemberton osteotomy (PO): the acetabular depth ratio (ADR), the acetabular index, the center-edge (CE) angle of Wiberg, and the femoral head migration rate (Reimer's index). A total of 47 hips were treated with SIO and 50 hips were treated with PO. Changes in ADR were greater in children who underwent PO compared with those who underwent SIO. However, the acetabular index, the center-edge angle, and Reimer's index did not differ between the groups at final follow-up. Children who underwent PO achieved an improved radiological ADR compared with those who underwent SIO on an average follow-up of 5 years after innominate osteotomy. PMID- 23799356 TI - Women's Health Initiative clinical trials: interaction of calcium and vitamin D with hormone therapy. AB - OBJECTIVE: This study aims to test the added value of calcium and vitamin D (CaD) in fracture prevention among women taking postmenopausal hormone therapy (HT). METHODS: This is a prospective, partial-factorial, randomized, controlled, double blind trial among Women's Health Initiative postmenopausal participants aged 50 to 79 years at 40 centers in the United States with a mean follow-up of 7.2 years. A total of 27,347 women were randomized to HT (0.625 mg of conjugated estrogens alone, or 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate daily), and 36,282 women were randomized to 1,000 mg of elemental calcium (carbonate) plus 400 IU of vitamin D3 daily, each compared with placebo. A total of 16,089 women participated in both arms. The predefined outcomes were adjudicated hip fractures and measured bone mineral density. RESULTS: Interaction between HT and CaD on hip fracture (P interaction = 0.01) was shown. The effect of CaD was stronger among women assigned to HT (hazard ratio [HR], 0.59; 95% CI, 0.38-0.93) than among women assigned to placebo (HR, 1.20; 95% CI, 0.85-1.69). The effect of HT on hip fracture was stronger among women assigned to active CaD (HR, 0.43; 95% CI, 0.28-0.66) than among women assigned to placebo (HR, 0.87; 95% CI, 0.60-1.26). CaD supplementation enhanced the antifracture effect of HT at all levels of personal calcium intake. There was no interaction between HT and CaD on change in hip or spine bone mineral density. CONCLUSIONS: Postmenopausal women at normal risk for hip fracture who are on CaD supplementation experience significantly reduced incident hip fractures beyond HT alone at all levels of personal baseline total calcium intake. PMID- 23799357 TI - Impact of hormone therapy on quality of life after menopause. AB - OBJECTIVE: Given the complexity of the literature on quality of life (QOL) and hormone therapy (HT) among women in the menopausal transition and postmenopause, the purposes of this integrative review were to (1) define QOL as a multidimensional construct; (2) review validated instruments for measurement of QOL; (3) review results of HT and QOL clinical trials that have used validated instruments; and (4) assess the effectiveness of HT on QOL, including health related QOL (HRQOL), menopause-specific QOL (MSQOL), and global QOL (GQOL). METHODS: The literature on HT and QOL was searched for definitions of QOL and validated instruments for measuring QOL, and the results were summarized. The purposes of this integrative review were to evaluate the effects of HT on HRQOL, differentiating the effects of HT on GQOL, HRQOL, and MSQOL. As a basis for this review, we searched for published controlled clinical trials in which the effects of HT on QOL were studied using validated QOL instruments, in particular menopause-specific validated instruments. RESULTS: Clear definitions are elucidated. Validated instruments for the measurements of HRQOL, GQOL, and MSQOL are summarized, and the necessity of their incorporation into future research and clinical practice is emphasized. The published effects on QOL of estrogens and progestogens administered to symptomatic and nonsymptomatic women in the menopausal transition and beyond are reviewed. CONCLUSIONS: The impact of various health state-related symptoms on HRQOL and GQOL is now an integral component of contemporary health care. Effects of HT include GQOL and HRQOL and should be menopause-specific. There is clearly a need for further studies on menopause and menopause-related therapies using appropriate and validated instruments. Literature review shows that HT provides a significant benefit for MSQOL in midlife women, mainly through relief of symptoms, but treatment also may result in a global increase in sense of well-being (GQOL). HRQOL benefits are contingent on symptom status, as are MSQOL outcomes. Women who are severely symptomatic experience a significant improvement in HRQOL and MSQOL, although this improvement is not significant among women without severe symptoms at baseline measures in clinical trials. PMID- 23799358 TI - beta-Cyclodextrin inclusion complex to improve physicochemical properties of pipemidic acid: characterization and bioactivity evaluation. AB - The aptitude of cyclodextrins (CDs) to form host-guest complexes has prompted an increase in the development of new drug formulations. In this study, the inclusion complexes of pipemidic acid (HPPA), a therapeutic agent for urinary tract infections, with native beta-CD were prepared in solid state by kneading method and confirmed by FT-IR and 1H NMR. The inclusion complex formation was also characterized in aqueous solution at different pH via UV-Vis titration and phase solubility studies obtaining the stability constant. The 1:1 stoichiometry was established by a Job plot and the inclusion mechanism was clarified using docking experiments. Finally, the antibacterial activity of HPPA and its inclusion complex was tested on P. aeruginosa, E. coli and S. aureus to determine the respective EC50s and EC90s. The results showed that the antibacterial activity of HPPA:beta-CD against E. coli and S. aureus is higher than that of HPPA. Furthermore, HPPA and HPPA:beta-CD, tested on human hepatoblastoma HepG2 and MCF-7 cell lines by MTT assay, exhibited, for the first time, antitumor activities, and the complex revealed a higher activity than that of HPPA. The use of beta-CD allows an increase in the aqueous solubility of the drug, its bioavailability and then its bioactivity. PMID- 23799359 TI - Sequestration of AS-DACA into acidic compartments of the membrane trafficking system as a mechanism of drug resistance in rhabdomyosarcoma. AB - The accumulation of weakly basic drugs into acidic organelles has recently been described as a contributor to resistance in childhood cancer rhabdomyosarcoma (RMS) cell lines with differential sensitivity to a novel topoisomerase II inhibitor, AS-DACA. The current study aims to explore the contribution of the endocytic pathway to AS-DACA sequestration in RMS cell lines. A 24-fold differential in AS-DACA cytotoxicity was detected between the RMS lines RD and Rh30. The effect of inhibitors of the endocytic pathway on AS-DACA sensitivity in RMS cell lines, coupled with the variations of endosomal marker expression, indicated the late endosomal/lysosomal compartment was implicated by confounding lines of evidence. Higher expression levels of Lysosomal-Associated Membrane Protein-1 (LAMP1) in the resistant RMS cell line, RD, provided correlations between the increased amount and activity of these compartments to AS-DACA resistance. The late endosomal inhibitor 3-methyladenine increased AS-DACA sensitivity solely in RD leading to the reduction of AS-DACA in membrane trafficking organelles. Acidification inhibitors did not produce an increase in AS-DACA sensitivity nor reduce its sequestration, indicating that the pH partitioning of weakly basic drugs into acidic compartments does not likely contribute to the AS-DACA sequestering resistance mechanism evident in RMS cells. PMID- 23799360 TI - New Labdane-type diterpenoids and anti-inflammatory constituents from Hedychium coronarium. AB - Four new labdane-type diterpenoids: hedychicoronarin (1), peroxycoronarin D (2), 7beta-hydroxycalcaratarin A (3), and (E)-7beta-hydroxy-6-oxo-labda-8(17),12-diene 15,16-dial (4), have been isolated from the rhizomes of Hedychium coronarium, together with 13 known compounds (5-17). The structures of these new compounds were determined through spectroscopic and MS analyses. Compounds 3, 5, 6, and 10 exhibited inhibition (IC50 values <=4.52 MUg/mL) of superoxide anion generation by human neutrophils in response to formyl-L-methionyl-L-leucyl-L phenylalanine/cytochalasin B (fMLP/CB). Compounds 3-6, 10, and 11 inhibited fMLP/CB-induced elastase release with IC50 values <=6.17 MUg/mL. PMID- 23799361 TI - MicroRNA regulation in renal pathophysiology. AB - MicroRNAs are small, noncoding RNA molecules that regulate a considerable amount of human genes on the post-transcriptional level, and participate in many key biological processes. MicroRNA deregulation has been found associated with major kidney diseases. Here, we summarize current knowledge on the role of microRNAs in renal glomerular and tubular pathologies, with emphasis on the mesangial cell and podocyte dysfunction in diabetic nephropathy, the proximal tubular cell survival in acute kidney injury, the transport function of the thick ascending limb in Ca++ imbalance diseases, and the regulation of salt, K+ and blood pressure in the distal tubules. Identification of microRNAs and their target genes provides novel therapeutic candidates for treating these diseases. Manipulation of microRNA function with its sense or antisense oligonucleotide enables coordinated regulation of the entire downstream gene network, which has effectively ameliorated several renal disease phenotypes. The therapeutic potentials of microRNA based treatments, though promising, are confounded by major safety issues related to its target specificity, which remain to be fully elucidated. PMID- 23799362 TI - Protective effects of hydrogen sulfide in hypoxic human umbilical vein endothelial cells: a possible mitochondria-dependent pathway. AB - The aim of the study was to investigate the protective effects of sodium hydrosulfide (NaHS), a H2S donor, against hypoxia-induced injury in human umbilical vein endothelial cells (HUVECs) and also to look into the possible mechanisms by which H2S exerts this protective effect. 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide (MTT) assay and scratch wound healing assay were chosen to measure the cell viability and migration-promoting effects. The fluorescent probe, DCFH-DA and 5,5',6,6'-Tetrachloro-1,1',3,3'-tetraethyl imidacarbocyanine iodide (JC-1) were applied to detect the reactive oxygen species (ROS) level and mitochondrial membrane potential (DeltaPsim). Furthermore, western blots were used to measure the expressions of the apoptosis related proteins. Under hypoxic conditions, 300 MUM and 600 MUM of H2S could protect HUVECs against hypoxia-induced injury, as determined by MTT assay. Following the treatment of 60 uM NaHS for 18 h, scratch wound healing assays indicated that the scratch became much narrower than control group. After treatment with 60 uM, 120 uM, and 600 uM NaHS, and hypoxia for 30 min, flow cytometry demonstrated that the ROS concentrations decreased to 95.08% +/- 5.52%, 73.14% +/- 3.36%, and 73.51% +/- 3.05%, respectively, compared with the control group. In addition, the JC-1 assay showed NaHS had a protective effect on mitochondria damage. Additionally, NaHS increased Bcl-2 expression and decreased the expression of Bax, Caspase-3 and Caspase-9 in a dose-dependent way. Our results suggest that H2S can protect endothelial cells and promote migration under hypoxic condition in HUVECs. These effects are partially associated with the preservation of mitochondrial function mediated by regulating the mitochondrial-dependent apoptotic pathway. PMID- 23799364 TI - Diagnosis of desmoplastic reaction by immunohistochemical analysis, in biopsy specimens of early colorectal carcinomas, is efficacious in estimating the depth of invasion. AB - The aim of our study was to evaluate the diagnosis of desmoplastic reaction (DR) by immunostaining for alpha-smooth muscle actin (alphaSMA) and desmin, for predicting the depth of submucosal invasion in biopsy specimens of early colorectal carcinomas (CRCs). Thirty-eight cases of non-pedunculated early CRCs were included in this study. Positive for DR was defined as alphaSMA-positive and desmin-negative stroma in the CRC. The depth of submucosal invasion was measured in endoscopically or surgically resected specimens and the lesions were subsequently divided into two groups: Group A (carcinoma in situ/intramucosal carcinoma and submucosal invasive carcinoma with a depth <1000 MUm) and Group B (submucosal invasion with a depth >=1000 MUm). Twenty-one cases were DR-positive and 17 were DR-negative. No statistical significance was found between the DR with regard to tumor size, location and histological type. All DR-positive cases belonged to Group B whereas 14 (82.4%) DR-negative lesions belonged to Group A (p < 0.001). The sensitivity, specificity, positive and negative predictive values and accuracy of DR positivity for diagnosis of Group B were 87.5%, 100%, 100%, 82.4% and 92.1%, respectively. Conclusively, detection of DR in biopsy specimens with ancillary immunohistochemistry (alphaSMA/desmin) would help in preoperative diagnosis for the depth of submucosal invasion of early CRC. PMID- 23799363 TI - Hormesis in aging and neurodegeneration-a prodigy awaiting dissection. AB - Hormesis describes the drug action of low dose stimulation and high dose inhibition. The hormesis phenomenon has been observed in a wide range of biological systems. Although known in its descriptive context, the underlying mode-of-action of hormesis is largely unexplored. Recently, the hormesis concept has been receiving increasing attention in the field of aging research. It has been proposed that within a certain concentration window, reactive oxygen species (ROS) or reactive nitrogen species (RNS) could act as major mediators of anti aging and neuroprotective processes. Such hormetic phenomena could have potential therapeutic applications, if properly employed. Here, we review the current theories of hormetic phenomena in regard to aging and neurodegeneration, with the focus on its underlying mechanism. Facilitated by a simple mathematical model, we show for the first time that ROS-mediated hormesis can be explained by the addition of different biomolecular reactions including oxidative damage, MAPK signaling and autophagy stimulation. Due to their divergent scales, the optimal hormetic window is sensitive to each kinetic parameter, which may vary between individuals. Therefore, therapeutic utilization of hormesis requires quantitative characterizations in order to access the optimal hormetic window for each individual. This calls for a personalized medicine approach for a longer human healthspan. PMID- 23799365 TI - The enzyme-mediated direct reversal of a dithymine photoproduct in germinating endospores. AB - Spore photoproduct lyase (SPL) repairs a special thymine dimer, 5-thyminyl-5,6 dihydrothymine, which is commonly called spore photoproduct, or SP, in germinating endospores. SP is the exclusive DNA photo-damaging product found in endospores; its generation and swift repair by SPL are responsible for the spores' extremely high UV resistance. Early in vivo studies suggested that SPL utilizes a direct reversal strategy to repair SP in the absence of light. Recently, it has been established that SPL belongs to the radical S adenosylmethionine (SAM) superfamily. The enzymes in this superfamily utilize a tri-cysteine CXXXCXXC motif to bind a [4Fe-4S] cluster. The cluster provides an electron to the S-adenosylmethionine (SAM) to reductively cleave its C5'-S bond, generating a reactive 5'-deoxyadenosyl (5'-dA) radical. This 5'-dA radical abstracts the proR hydrogen atom from the C6 carbon of SP to initiate the repair process; the resulting SP radical subsequently fragments to generate a putative thymine methyl radical, which accepts a back-donated H atom to yield the repaired TpT. The H atom donor is suggested to be a conserved cysteine141 in B. subtilis SPL; the resulting thiyl radical likely interacts with a neighboring tyrosine99 before oxidizing the 5'-dA to 5'-dA radical and, subsequently, regenerating SAM. These findings suggest SPL to be the first enzyme in the large radical SAM superfamily (>44,000 members) to utilize a radical transfer pathway for catalysis; its study should shed light on the mechanistic understanding of the SAM regeneration process in other members of the superfamily. PMID- 23799366 TI - DNA polymerase kappa-dependent DNA synthesis at stalled replication forks is important for CHK1 activation. AB - Formation of primed single-stranded DNA at stalled replication forks triggers activation of the replication checkpoint signalling cascade resulting in the ATR mediated phosphorylation of the Chk1 protein kinase, thus preventing genomic instability. By using siRNA-mediated depletion in human cells and immunodepletion and reconstitution experiments in Xenopus egg extracts, we report that the Y family translesion (TLS) DNA polymerase kappa (Pol kappa) contributes to the replication checkpoint response and is required for recovery after replication stress. We found that Pol kappa is implicated in the synthesis of short DNA intermediates at stalled forks, facilitating the recruitment of the 9-1-1 checkpoint clamp. Furthermore, we show that Pol kappa interacts with the Rad9 subunit of the 9-1-1 complex. Finally, we show that this novel checkpoint function of Pol kappa is required for the maintenance of genomic stability and cell proliferation in unstressed human cells. PMID- 23799367 TI - Threshold-controlled ubiquitination of the EGFR directs receptor fate. AB - How the cell converts graded signals into threshold-activated responses is a question of great biological relevance. Here, we uncover a nonlinear modality of epidermal growth factor receptor (EGFR)-activated signal transduction, by demonstrating that the ubiquitination of the EGFR at the PM is threshold controlled. The ubiquitination threshold is mechanistically determined by the cooperative recruitment of the E3 ligase Cbl, in complex with Grb2, to the EGFR. This, in turn, is dependent on the simultaneous presence of two phosphotyrosines, pY1045 and either one of pY1068 or pY1086, on the same EGFR moiety. The dose response curve of EGFR ubiquitination correlate precisely with the non-clathrin endocytosis (NCE) mode of EGFR internalization. Finally, EGFR-NCE mechanistically depends on EGFR ubiquitination, as the two events can be simultaneously re engineered on a phosphorylation/ubiquitination-incompetent EGFR backbone. Since NCE controls the degradation of the EGFR, our findings have implications for how the cell responds to increasing levels of EGFR signalling, by varying the balance of receptor signalling and degradation/attenuation. PMID- 23799368 TI - Spontaneous reduction and assembly of graphene oxide into three-dimensional graphene network on arbitrary conductive substrates. AB - Chemical reduction of graphene oxide (GO) is the main route to produce the mass graphene-based materials with tailored surface chemistry and functions. However, the toxic reducing circumstances, multiple steps, and even incomplete removal of the oxygen-containing groups were involved, and the produced graphenes existed usually as the assembly-absent precipitates. Herein, a substrate-assisted reduction and assembly of GO (SARA-GO) method was developed for spontaneous formation of 3D graphene network on arbitrary conductive substrates including active and inert metals, semiconducting Si, nonmetallic carbon, and even indium tin oxide glass without any additional reducing agents. The SARA-GO process offers a facile, efficient approach for constructing unique graphene assemblies such as microtubes, multi-channel networks, micropatterns, and allows the fabrication of high-performance binder-free rechargeable lithium-ion batteries. The versatile SARD-GO method significantly improves the processablity of graphenes, which could thus benefit many important applications in sensors and energy-related devices. PMID- 23799369 TI - Engineering robust polar chiral clathrate crystals. AB - The R-(+)-enantiomeric form of Dianin's compound and the S-(+)-enantiomeric form of its direct thiachroman analogue both obtained chromatographically employing a cellulose tris(3,5-dimethylphenylcarbamate) column, are shown to undergo supramolecular assembly to form a polar clathrate lattice which is stable even in the absence of a consolidating guest component. PMID- 23799370 TI - Biopsies: next-generation biospecimens for tailoring therapy. AB - The majority of samples in existing tumour biobanks are surgical specimens of primary tumours. Insights into tumour biology, such as intratumoural heterogeneity, tumour-host crosstalk, and the evolution of the disease during therapy, require biospecimens from the primary tumour and those that reflect the patient's disease in specific contexts. Next-generation 'omics' technologies facilitate deep interrogation of tumours, but the characteristics of the samples can determine the ultimate accuracy of the results. The challenge is to biopsy tumours, in some cases serially over time, ensuring that the samples are representative, viable, and adequate both in quantity and quality for subsequent molecular applications. The collection of next-generation biospecimens, tumours, and blood samples at defined time points during the disease trajectory--either for discovery research or to guide clinical decisions--presents additional challenges and opportunities. From an organizational perspective, it also requires new additions to the multidisciplinary therapeutic team, notably interventional radiologists, molecular pathologists, and bioinformaticians. In this Review, we describe the existing procedures for sample procurement and processing of next-generation biospecimens, and highlight the issues involved in this endeavour, including the ethical, logistical, scientific, informational, and financial challenges accompanying next-generation biobanking. PMID- 23799372 TI - Breast cancer: Stable breast cancer xenograft models. PMID- 23799373 TI - Liver cancer: SALL4--a cancer marker and target. PMID- 23799371 TI - Minimal residual disease in acute myeloid leukaemia. AB - Technological advances in the laboratory have led to substantial improvements in clinical decision making through the introduction of pretreatment prognostic risk stratification factors in acute myeloid leukaemia (AML). Unfortunately, similar progress has not been made in treatment response criteria, with the definition of 'complete remission' in AML largely unchanged for over half a century. Several clinical trials have demonstrated that high-sensitivity measurements of residual disease burden during or after treatment can be performed, that results are predictive for clinical outcome and can be used to improve outcomes by guiding additional therapeutic intervention to patients in clinical complete remission, but at increased relapse risk. We review these recent trials, the characteristics and challenges of the modalities currently used to detect minimal residual disease (MRD), and outline opportunities to both refine detection and improve clinical use of MRD measurements. MRD measurement is already the standard of care in other myeloid malignancies, such as chronic myelogenous leukaemia and acute promyelocytic leukaemia (APL). It is our belief that response criteria for non APL AML should be updated to include assessment for molecular complete remission and recommendations for post-consolidation surveillance should include regular monitoring for molecular relapse as standard of care. PMID- 23799374 TI - Collagen Type II is produced in healing pars tensa of perforated tympanic membranes: an experimental study in the rat. AB - HYPOTHESIS: Type II collagen is synthesized in the tympanic membrane during healing of a perforation. The time course and appearance of Type II collagen regrowth in the newly healed tympanic membrane is the subject of the present study. BACKGROUND: The arrangement of Type II collagen fibers in the tympanic membrane gives it a unique tensile strength important for sound conduction. Healing after tympanic membrane perforation can cause the tympanic membrane to lose its characteristic. At what phase Type II collagen in tympanic membrane is replaced during healing of a perforation has previously not been studied. METHODS: Rat tympanic membranes were perforated, and the animals were sacrificed 9 to 16 days after perforation. Tympanic membranes were stained with a Type II collagen antibody. RESULTS: At Day 9, a majority of the tympanic membranes had healed. Keratinizing epithelium and connective tissue had formed, but there was no Type II collagen. At Day 10, all tympanic membranes had healed, and staining for Type II collagen appeared. After Day 10, staining was more intense. Newly formed collagen did not show the parallel bundle arrangement seen in normal tympanic membranes but was more scattered in the tissue. CONCLUSION: Type II collagen was seen in tympanic membranes only after closure of the perforation. The fiber arrangement after healing was disturbed, which presumably has an impact on the function of the tympanic membrane. Understanding the formation of Type II collagen in the healing of tympanic membrane perforations could enable further research toward treating tympanic membrane perforations. PMID- 23799375 TI - Fetal Brain-directed AAV Gene Therapy Results in Rapid, Robust, and Persistent Transduction of Mouse Choroid Plexus Epithelia. AB - Fetal brain-directed gene addition represents an under-appreciated tool for investigating novel therapeutic approaches in animal models of central nervous system diseases with early prenatal onset. Choroid plexuses (CPs) are specialized neuroectoderm-derived structures that project into the brain's ventricles, produce cerebrospinal fluid (CSF), and regulate CSF biochemical composition. Targeting the CP may be advantageous for adeno-associated viral (AAV) gene therapy for central nervous system disorders due to its immunoprivileged location and slow rate of epithelial turnover. Yet the capacity of AAV vectors to transduce CP has not been delineated precisely. We performed intracerebroventricular injections of recombinant AAV serotype 5-green fluorescent protein (rAAV5-GFP) or rAAV9-GFP in embryonic day 15 (E15) embryos of CD-1 and C57BL/6 pregnant mice and quantified the percentages of GFP expression in CP epithelia (CPE) from lateral and fourth ventricles on E17, postnatal day 2 (P2), and P22. AAV5 was selective for CPE and showed significantly higher transduction efficiency in C57BL/6 mice (P = 0.0128). AAV9 transduced neurons and glial cells in both the mouse strains, in addition to CPE. We documented GFP expression in CPE on E17, within just 48 hours of rAAV administration to the fetal lateral ventricle, and expression by both the serotypes persisted at P130. Our results indicate that prenatal administration of rAAV5 and rAAV9 enables rapid, robust, and sustained transduction of mouse CPE and buttress the rationale for experimental therapeutics targeting the CP.Molecular Therapy-Nucleic Acids (2013) 2, e101; doi:10.1038/mtna.2013.27; published online 25 June 2013. PMID- 23799376 TI - Pay attention [to the road] or pay the price. PMID- 23799377 TI - Blood safety. PMID- 23799378 TI - Bacterial contamination of platelet concentrates produced in New Zealand. AB - AIMS: To identify the rate of bacterial contamination of platelet concentrates in New Zealand and compare with other countries who use the BacT/ALERT screening system. To report on septic transfusion reactions associated with platelet transfusion in New Zealand. METHODS: Six mL of platelet concentrate is inoculated into a BacT/ALERT BPA (aerobic culture) bottle on Day 2 post-collection. Bottles that are flagged as positive are sent to the microbiology laboratory, with the associated unit, for confirmatory testing. Platelet units that have expired are sampled again. Results from the four blood processing sites in New Zealand were reviewed. RESULTS: 59,461 (65%) platelet components were sampled on Day 2 and 15,560 (17%) were re-sampled post-expiry, between December 2003 and September 2011. The rate of confirmed bacterial contamination was 0.04% for Day 2 sampling and 0.04% for post-expiry sampling. The rate in the published literature ranges from 0.01-0.74% and is lower (0.01-0.18%) when diversion of the initial flow of blood is utilised. There were five bacterial transfusion transmitted infections associated with platelet transfusion reported during the study period. CONCLUSIONS: BacT/ALERT screening reduces the transfusion of bacterially contaminated platelet concentrates. Day 2 sampling does not identify all contaminated units. PMID- 23799379 TI - A tale of two cities: paradoxical intensity of traffic calming around Auckland schools. AB - BACKGROUND: The school journey is a common context for child pedestrian injuries in New Zealand, with children from low socioeconomic, Maori or Pacific families being at increased risk. The extent to which evidence-based environmental strategies that can address this problem are equitably implemented is unclear. AIM: To determine if there is a difference in the distribution of traffic-calming modifications around schools in areas of high and low socioeconomic deprivation in Auckland and Manukau Cities, New Zealand. METHODS: From a list of the most and least socioeconomically deprived schools in Auckland and Manukau Cities, 40 of each were randomly selected. The number of modifications within a 1 km radius of these schools was recorded in December 2009 or January 2010. The association of deprivation and region with the numbers of traffic-calming modifications was examined using a general linear model. RESULTS: Socioeconomically least deprived schools had more traffic-calming interventions than the most deprived schools (least square mean (LSM): 25 versus 18; p=0.05), and Auckland schools had more interventions than Manukau schools (LSM: 27 versus 16; p=0.001). CONCLUSION: Traffic-calming measures were observed more commonly in less deprived areas where the risks of child pedestrian injuries are generally lower. This apparent paradox could result in increasing socioeconomic inequities in the distribution of child pedestrian injuries. PMID- 23799380 TI - The San Francisco Syncope Rule performs well in a regional rural emergency department in New Zealand. AB - AIMS: To assess the utility of a decision rule for determining short-term risk in syncope patients presenting to the Emergency Department (ED) of Nelson Hospital (Nelson, New Zealand). METHODS: Sixty-eight of 83 eligible syncope patients who presented to the ED with syncope were consecutively enrolled. Follow-up for an adverse event within 7 days of index presentation was performed. Actual event rate was compared with the prediction tool known as the San Francisco Syncope Rule (SFSR). RESULTS: Sensitivity and specificity for the SFSR was 83% (95% Confidence Interval (CI) of 44-97%) and 82% (95%CI 71-91%) respectively. There was a negative predictive value of 98% (95% CI 90-99%). Positive and negative likelihood ratios were 4.7 (95% CI 2.5-9.0) and 0.2 (95% CI 0.03-01.22) respectively. CONCLUSION: Syncope patients who present to the ED with no obvious cause and who are being considered for discharge may benefit from application of the SFSR for short-term risk assessment. PMID- 23799381 TI - The high volume debate in a low volume country: centralisation of oesophageal resection in New Zealand. AB - AIM: Centralisation of oesophageal resection for cancer remains an area of debate. However, no consensus for the requirements of high volume centres yet exists and some low volume centres have been able to produce a comparable outcome. With the small population of New Zealand more than one high volume centre might not be achievable. We reviewed our series of oesophageal resections and compared them to outcomes in the literature to challenge the need for only high volume centres within New Zealand METHODS: A retrospective analysis of all consecutive oesophagogastrectomies performed in Christchurch Public Hospital (Christchurch City, New Zealand) from January 1998 until June 2009 was undertaken. RESULTS: Within this period 128 oesophagogastrectomies were performed. Median admission duration was 12 days. The overall complication rate was 53.9% of which 5.5% was an anastomotic leak. Combined in-hospital and 30-day mortality was 1.6% (2/128). The 5-year-survival was 32.4% for adenocarcinoma and 47.7% for squamous cell carcinoma. Conclusion This series has shown that a low volume centre within New Zealand is able to deliver a satisfactory level of care for oesophagectomy. Given New Zealand's low population density it is debatable to what extent care should be centralised for treatment of oesophageal carcinoma. PMID- 23799382 TI - Reduction mammaplasty and resource allocation--are patients being treated fairly? An examination of the current New Zealand situation, and looking towards the future. AB - AIM: To review the access to publically-funded reduction mammaplasty for New Zealand (NZ) women. Additionally, to evaluate quality of life gains from reduction mammaplasty and other surgical treatments of chronic conditions. Ultimately to determine whether access to surgical treatment for this condition is equitable. METHOD: Four tertiary referral centres for Plastic Surgery in NZ completed a survey to characterise patient access. A literature search was done to investigate the global situation and obtain quality of life information following breast reduction and other operations for chronic conditions. RESULTS: The survey showed there was significant inequity in allocation and access to breast reduction surgery in NZ over time and geographical location. There were hopes that the Ministry of Health Prioritisation Tool would ensure more equitable access to plastic surgical procedures nationally in the future. A similar situation exists in Europe in regards to allocation, and insurance companies dictate access in the US. There was overwhelming evidence to support quality of life gains with reduction mammaplasty, which are equal to if not greater than more accessible operations. CONCLUSION: In NZ there is inequitable access to surgery for patients who would be treated by breast reduction surgery, with substantial variation across geography and time. A new Prioritisation Tool may address this discrepancy. Much evidence exists that quality of life gains for reduction mammaplasty are equivalent to other surgical procedures, which are more readily available. The challenge is to improve equity of access across all surgical conditions. PMID- 23799383 TI - Murine typhus and leptospirosis presenting with undifferentiated symptoms of an acute febrile illness to Waikato Hospital, New Zealand, 2009-2010. AB - AIMS: This prospective observational study aimed to identify what proportion of patients presenting to Waikato Hospital with undifferentiated symptoms of an acute febrile illness (USFI) have leptospirosis or murine typhus infection, and to identify factors at presentation predictive of each infection. It also aimed to identify infecting rickettsial organism(s) causing murine typhus in the region. METHODS: Between 15/10/2009-15/10/2010 all adult patients presenting with USFI of greater than and equal to 72 hours with no clear diagnosis on presentation were invited to participate in the study. A structured questionnaire and examination were administered and acute and convalescent serology was performed. For patients returning positive murine typhus serology, rickettsial PCR analysis was performed on stored acute blood samples. RESULTS: Fifty-seven patients were recruited. Nine were diagnosed with leptospirosis, five with murine typhus, three with Epstein-Barr virus (EBV), two with cytomegalovirus (CMV), five with bacterial sepsis and six with other diagnoses. Twenty seven had an acute febrile illness for which no diagnosis was found. A low platelet count (p<0.001) was associated with murine typhus infection, and rural occupation (p<0.001) and a low lymphocyte count (p=0.001) with leptospiral infection. There was a trend towards rural residence being associated with murine tyhpus infection (p=0.059). Two of four patients with positive murine typhus serology returned positive PCR analysis for Rickettsia typhi. CONCLUSION: A significant proportion of patients presenting to Waikato Hospital with USFI had leptospirosis or murine typhus infection. A low platelet count and rural residence were associated with murine typhus infection, and rural occupation and a low lymphocyte count with leptospiral infection. R. typhi was identified as a rickettsial organism causing rickettsial fever in the Waikato region. PMID- 23799384 TI - Is it time to advocate for a vulnerable road user protection law in New Zealand? AB - After a spate of recent New Zealand cyclist deaths, cycle advocates and several policy makers have been pondering the issue of increased penalties aimed at drivers deemed at fault. A key question is whether vulnerable road users (VRUs), including pedestrians, workers, animal riders, stranded motorists, skateboarders, cyclists, and others, are likely to be protected through enhanced penalties for at fault drivers of motor vehicles. We explored current policy and the international literature to examine whether or not enhanced penalties would be likely to increase motor vehicle driver motivation to exercise greater caution around VRUs leading to improved road safety. PMID- 23799385 TI - Duck shooting injuries in Southland, New Zealand. AB - Duck shooting is a common sport in New Zealand. The opening weekend is anticipated and celebrated, often with significant alcohol intake which is cause for concern, and potentially very dangerous. Hunters are annually warned about the dangers. There have been few duck shooting incidents which lead to injury or death. In the last decade two duck shooters in New Zealand have been killed, while 16 suffered non fatal gunshot injuries. We present a series of injuries identified during the 2012 duck shooting season in Southland Province. PMID- 23799386 TI - Lead poisoning from Ayurvedic medicines. AB - A case of lead poisoning with established exposure to Ayurvedic medicines is presented. This patient migrated from India to New Zealand 8 years previously. He regularly visits India where he purchases "herbal remedies" for his wellbeing. PMID- 23799387 TI - Medical image. The lady who lost her marbles--food for thought. PMID- 23799388 TI - Medical image. Mediastinal air-fluid level with substernal pain: achalasia. PMID- 23799389 TI - Alcohol-related injuries requiring surgery. PMID- 23799390 TI - Cancellations on the day of elective gynaecological surgery: the Counties Manukau experience. PMID- 23799391 TI - Nutritional balance of ANZAC's military rations. PMID- 23799392 TI - Assessing preoperative nerve damage is the best predictor of outcome following carpal tunnel surgery. PMID- 23799393 TI - Down syndrome: the notion of expert. PMID- 23799394 TI - No smoker left behind--a policy mix for everyone. PMID- 23799395 TI - FIZZ: a new advocacy group to FIght Sugar in Soft-drinks. PMID- 23799396 TI - A "turn-on" fluorescent sensor for detection of Pb2+ based on graphene oxide and G-quadruplex DNA. AB - A rapid, sensitive and selective fluorescence sensor for detection of Pb(2+) was developed based on a Pb(2+)-induced G-quadruplex and graphene oxide. By using a specific G-rich DNA sequence, this strategy provided a promising alternative to Pb(2+) determination in the presence of Hg(2+) escaping from the use of a masking agent of Hg(2+). PMID- 23799397 TI - In-vivo single neuron axotomy triggers axon regeneration to restore synaptic density in specific cortical circuits. AB - To what extent, how and when axons respond to injury in the highly interconnected grey matter is poorly understood. Here we use two-photon imaging and focused ion beam-scanning electron microscopy to explore, at synaptic resolution, the regrowth capacity of several neuronal populations in the intact brain. Time-lapse analysis of >100 individually ablated axons for periods of up to a year reveals a surprising inability to regenerate even in a glial scar-free environment. However, depending on cell type some axons spontaneously extend for distances unseen in the unlesioned adult cortex and at maximum speeds comparable to peripheral nerve regeneration. Regrowth follows a distinct pattern from developmental axon growth. Remarkably, although never reconnecting to the original targets, axons consistently form new boutons at comparable prelesion synaptic densities, implying the existence of intrinsic homeostatic programmes, which regulate synaptic numbers on regenerating axons. Our results may help guide future clinical investigations to promote functional axon regeneration. PMID- 23799399 TI - Single-molecule force spectroscopy of G-protein-coupled receptors. AB - The applicability of single-molecule force spectroscopy (SMFS) to characterize membrane proteins in vitro is developing rapidly and opening a wide range of fascinating possibilities to study how intra- and intermolecular interactions determine their structural stability and functional state. In particular, understanding how molecular interactions contribute to the functional state of G protein-coupled receptors (GPCRs) is of importance because they mediate most of our physiological responses and act as therapeutic targets for a broad spectrum of diseases. In our review we focus on SMFS to characterize GPCRs embedded in their physiologically relevant membranes and exposed to physiologically relevant conditions. SMFS uses a molecularly sharp stylus to grasp the terminal end of a GPCR and to quickly unfold the receptor while recording interaction forces. The positional accuracy of SMFS localizes these interactions to structural segments of the GPCR whereas the sensitivity of SMFS enables their stabilizing interaction forces to be quantified. To further investigate the kinetic, energetic and mechanical properties of the structural segments, dynamic SMFS (DFS) probes their stability over a wide range of loading rates. These parameters provide insight into the energy landscape that provides information on the structural and functional properties of the GPCRs. Selected highlights exemplify the application of SMFS to characterize inter- and intramolecular interactions, which change the properties of GPCRs in relation to their functional state (e.g., ligand binding), diseased state (e.g., mutation), or lipid environment such as cholesterol. PMID- 23799400 TI - [Pathogenesis, prophylaxis and treatment of infections in patients with chronic lymphocytic leukemia]. AB - Chronic lymphocytic leukemia (CLL) patients are at high risk for infections. The pathogenesis of infection in patients with this leukemia is complex and multifactorial. Patients with CLL have a number of immune system defects, including disordered B-cell function with decreased production of normal B-cells and abnormal production of immunoglobulins, suppressed T-cell function and neutropenia. Other immune abnormalities present in CLL patients include neutrophil dysfunction, and complement deficiencies. In addition, further perturbations in immune function are related to the antileukemic therapies. Immune disturbance might be common prior to CLL diagnosis and infectious agents could trigger CLL development. Current chemotherapy-based regimens are not curative and often worsen this immune suppression. The introduction of new effective therapeutic agents such as the purine analogues and monoclonal antibodies has influenced the spectrum of infections diagnosed in CLL patients. Some conditions increase the risk for the development of infections including advanced age, decreased levels of immunoglobulins, advanced Binet stage, neutropenia and treatment with more than one line of chemotherapy. Until now it is debatable whether and when antibacterial prophylaxis could be useful in CLL patients. The prevention of infection includes antimicrobial prophylaxis, as well as immunoglobulin replacement and vaccination. Antibacterial prophylaxis should be given to CLL patients with previous severe and/or relapsing bacterial infections. This article reviews the immune defects in CLL and discusses strategies aimed at prophylaxis and treatment of infections in patients with CLL. PMID- 23799401 TI - [The role of biological clock in glucose homeostasis]. AB - The mechanism of the biological clock is based on a rhythmic expression of clock genes and clock-controlled genes. As a result of their transcripto-translational associations, endogenous rhythms in the synthesis of key proteins of various physiological and metabolic processes are created. The major timekeeping mechanism for these rhythms exists in the central nervous system. The master circadian clock, localized in suprachiasmatic nucleus (SCN), regulates multiple metabolic pathways, while feeding behavior and metabolite availability can in turn regulate the circadian clock. It is also suggested that in the brain there is a food entrainable oscillator (FEO) or oscillators, resulting in activation of both food anticipatory activity and hormone secretion that control digestion processes. Moreover, most cells and tissues express autonomous clocks. Maintenance of the glucose homeostasis is particularly important for the proper function of the body, as this sugar is the main source of energy for the brain, retina, erythrocytes and skeletal muscles. Thus, glucose production and utilization are synchronized in time. The hypothalamic excited orexin neurons control energy balance of organism and modulate the glucose production and utilization. Deficiency of orexin action results in narcolepsy and weight gain, whereas glucose and amino acids can affect activity of the orexin cells. Large scale genetic studies in rodents and humans provide evidence for the involvement of disrupted clock gene expression rhythms in the pathogenesis of obesity and type 2 diabetes. In general, the current lifestyle of the developed modern societies disturbs the action of biological clock. PMID- 23799402 TI - [Epicardial adipose tissue and its role in cardiac physiology and disease]. AB - Adipose tissue secretes a number of cytokines, referred to as adipokines. Intensive studies conducted over the last two decades showed that adipokines exert broad effects on cardiac metabolism and function. In addition, the available data strongly suggests that these cytokines play an important role in development of cardiovascular diseases. Epicardial adipose tissue (EAT) has special properties that distinguish it from other deposits of visceral fat. Overall, there appears to be a close functional and anatomic relationship between the EAT and the cardiac muscle. They share the same coronary blood supply, and there is no structure separating the adipose tissue from the myocardium or coronary arteries. The role of EAT in osierdziocardiac physiology remains unclear. Its putative functions include buffering coronary arteries against the torsion induced by the arterial pulse wave and cardiac contraction, regulating fatty acid homeostasis in the coronary microcirculation, thermogenesis, and neuroprotection of the cardiac autonomic ganglia and nerves. Obesity (particularly the abdominal phenotype) leads to elevated EAT content, and the available data suggests that high amount of this fat depot is associated with increased risk of ischemic heart disease, cardiac hypertrophy and diastolic dysfunction. The mass of EAT is small compared to other fat deposits in the body. Nevertheless, its close anatomic relationship to the heart suggests that this organ is highly exposed to EAT-derived adipokines which makes this tissue a very promising area of research. In this paper we review the current knowledge on the role of EAT in cardiac physiology and development of heart disease. PMID- 23799403 TI - The clinical course of late diagnosed fatal cases of A (H1N1) influenza in Poland. AB - INTRODUCTION: The most frequent complication of A (H1N1) influenza and the leading cause of death was pneumonia with a primary viral or mixed viral and bacterial etiology. 182 patients had died because of a pandemic influenza in Poland by 31st July 2010. MATERIAL AND METHODS: A retrospective study of 6 fatal cases of pandemic influenza, aged 23-41, including 3 women, hospitalised between November 2009 and February 2011 in different Polish medical centres. RESULTS: We present the clinical course of 6 late diagnosed cases of A (H1N1) influenza. All patients presented typical flu-like symptoms in the beginning. 4/6 patients had severe disease risk factors: pregnancy, arthritis, Wegener granulomatosis and obesity. All patients were seen by doctors, no one had received antiviral therapy, 4/5 were treated with antibiotics before they were hospitalized. One patient had nosocomial infection. Patients were admitted to the hospital on the 3rd to 8th day of the disease. They received oseltamivir treatment on the 4th to 9th day. All patients developed pneumonia complicated by acute respiratory distress syndrome. Death appeared between the 4th and 27th day after the onset of symptoms. Autopsies were performed in 5 cases and revealed haemorrhagic pneumonia in 2 patients. CONCLUSION: Delayed diagnosis and antiviral treatment initiation has a significant impact on mortality in A (H1N1) influenza. During the influenza epidemic, patients presenting typical symptoms should always be suspected of having influenza. Antiviral treatment has to be initiated immediately, especially if there are risk factors of severe disease. PMID- 23799404 TI - Strain effects on hydrogen storage in Ti decorated pyridinic N-doped graphene. AB - Strain-engineered adsorption of Ti on pyridinic nitrogen-doped graphene (PNG) and the hydrogen storage characteristics of Ti-decorated PNG are examined by using a first-principles approach using density functional theory (DFT) calculations. Under the strain from -5% to 5%, binding energy (Eb) of Ti on PNG was higher than cohesive energy of the Ti bulk. Thus, it is expected that Ti atoms prefer atomic dispersion in PNG to clustering in the applied strain range. For this Ti-PNG system, the Eb variation of the second and third adsorbed H2 molecule according to the strain was a large value of 0.217 and 0.254 eV, respectively. Therefore, strain-engineered Ti-decorated PNG is adaptable to diverse operation conditions of hydrogen storage systems for mobile applications. In addition, by applying compressive strain, this system can adsorb the fourth H2 molecule, suggesting that the compressive strain can be used to improve hydrogen storage capacity. Thus, it can be expected that strain-engineered Ti-decorated PNG can be considered to be a promising potential hydrogen storage medium. PMID- 23799405 TI - Rugby union: much potential for injury prevention but substantial resources are required now. PMID- 23799406 TI - Performance, penalties, and injuries in youth ice hockey. PMID- 23799407 TI - What dose of injectable corticosteroid for periarticular shoulder disorders? PMID- 23799408 TI - Interventions for relieving the symptoms of exercise-induced muscle damage: a review. PMID- 23799409 TI - In response to: acute management of auricular hematoma: a novel approach and retrospective review. PMID- 23799410 TI - Reply: To PMID 22695406. PMID- 23799411 TI - Effects of alcohol consumption on antigen-specific cellular and humoral immune responses to SIV in rhesus macaques. AB - BACKGROUND: Simian immunodeficiency virus (SIV) infection in macaques chronically receiving ethanol results in significantly higher plasma viral loads and more rapid progression to end-stage disease. We thus hypothesized that the increased plasma viral load in ethanol-treated, SIV-infected macaques would negatively correlate with antigen-specific immune responses. METHODS: Rhesus macaques were administered ethanol or sucrose (n = 12 per group) by indwelling gastric catheters for 3 months and then intravenously infected with SIVMAC251. Peripheral blood T- and B-cell immunophenotyping and quantification were performed. Plasma was examined for viremia, levels of SIVEnv-specific binding, and neutralizing antibodies. Virus-specific interferon gamma and tumor necrosis factor alpha cytokine responses to SIV-Nef, Gag, or Env peptide pools were measured in peripheral blood CD8 T cells. RESULTS: Macaques receiving ethanol had both higher plasma viremia and virus-specific cellular immune responses compared with the sucrose-treated group. The emergence of virus-specific cytokine responses temporally correlated with the decline in mean plasma viral load after 14 days postinfection in all SIV-infected animals. However, neither the breadth and specificity nor the magnitude of virus-specific CD8 T-cell responses correlated with early postpeak reductions in plasma viral loads. In fact, increased cytokine responses against Gag, gp120, and gp41 positively correlated with plasma viremia. Levels of SIV envelope-specific immunoglobulin G and neutralizing antibodies were similar over the disease course in both groups of macaques. CONCLUSIONS: Persistently higher antigen-specific cytokine responses in animals receiving ethanol are likely an effect of the higher viral loads and antigen persistence, rather than a cause of the increased viremia. PMID- 23799413 TI - Toll-like receptor-4 expression by stromal fibroblasts is associated with poor prognosis in colorectal cancer. AB - Because of the important role in inflammation and tissue regeneration, toll-like receptors (TLR) are likely candidates to mediate effects of the innate immune system on tumorigenesis. The aim of this study was to investigate the expression and clinical relevance of TLR in colorectal cancer (CRC). The expressions of TLR3, TLR4, TLR7, and TLR9 were analyzed in 104 patients with resectable CRC by immunohistochemistry. The evaluation of the expression consisted on measuring the overall level of TLR expression and by each cell type. The results showed a direct association between the histologic grade of tumor and TLR9 expression by tumor cells. TLR4 expression by tumor cells was significantly associated with a lower rate of tumor recurrence, whereas the expression by fibroblasts was significant and independently associated with a high rate of tumor recurrence and with a shortened overall survival in patients; particularly in tumors from left colon and rectum. Therefore, TLR4 expression by fibroblasts could be a useful prognostic marker in CRC. PMID- 23799412 TI - A dose-escalation study of recombinant human interleukin-18 in combination with rituximab in patients with non-Hodgkin lymphoma. AB - Interleukin-18 (IL-18) is an immunostimulatory cytokine with antitumor activity in preclinical models. Rituximab is a CD20 monoclonal antibody with activity against human B-cell lymphomas. A phase I study of recombinant human (rh) IL-18 given with rituximab was performed in patients with CD20+ lymphoma. Cohorts of 3 4 patients were given infusions of rituximab (375 mg/m2) weekly for 4 weeks with escalating doses of rhIL-18 as a 2-hour intravenous infusion weekly for 12 consecutive weeks. Toxicities were graded using standard criteria. Blood samples were obtained for safety, pharmacokinetic, and pharmacodynamic studies. Nineteen patients with CD20+ B-cell non-Hodgkin lymphoma were given rituximab in combination with rhIL-18 at doses of 1, 3, 10, 20, 30, and 100 MUg/kg. Common side effects included chills, fever, headache, and nausea. Common laboratory abnormalities included transient, asymptomatic lymphopenia, hyperglycemia, anemia, hypoalbuminemia, and bilirubin and liver enzyme elevations. No dose limiting toxicities were observed. Biologic effects of rhIL-18 included transient lymphopenia and increased expression of activation antigens on lymphocytes. Increases in serum concentrations of IFN-gamma, GM-CSF, and chemokines were observed after dosing. Objective tumor responses were seen in 5 patients, including 2 complete and 3 partial responses. rhIL-18 can be given in biologically active doses by weekly infusions in combination with rituximab to patients with lymphoma. A maximum tolerated dose of rhIL-18 plus rituximab was not determined. Further studies of rhIL-18 and CD20 monoclonal antibodies in B cell malignancies are warranted. PMID- 23799414 TI - Treatment efficacy and immune stimulation by AdCD40L gene therapy of spontaneous canine malignant melanoma. AB - Malignant melanoma is a serious disease in both humans and dogs, and the high metastatic potential results in poor prognosis for many patients. Its similarities with human melanoma make spontaneous canine melanoma an excellent model for comparative studies of novel therapies and tumor biology. We report a pilot study of local adenovector CD40L (AdCD40L) immunogene treatment in 19 cases of canine melanoma (14 oral, 4 cutaneous, and 1 conjunctival). Three patients were World Health Organization stage I, 2 were stage II, 10 stage III, and 4 stage IV. One to 6 intratumoral injections of AdCD40L were given every 7 days, followed by cytoreductive surgery in 9 cases and only immunotherapy in 10 cases. Tumor tissue was infiltrated with T and B lymphocytes after treatment, suggesting immune stimulation. The best overall response included 5 complete responses, 8 partial responses, and 4 stable and 2 progressive disease statuses according to the World Health Organization response criteria. Median survival was 160 days (range, 20-1141 d), with 3 dogs still alive at submission. Our results suggest that local AdCD40L therapy is safe and could have beneficial effects in dogs, supporting further treatment development. Clinical translation to human patients is in progress. PMID- 23799415 TI - Evidence and opinion in facial plastic surgery: surgical management of facial paralysis, nasal defects, and rhinoplasty. PMID- 23799416 TI - Implants in facial skeletal augmentation. AB - PURPOSE OF REVIEW: Alloplastic implants have demonstrated longstanding utility in the augmentation of the facial skeleton. Although their popularity may have waned in recent years, their established efficacy endures. This review summarizes the techniques, limitations, and complications associated with the use of facial implants. RECENT FINDINGS: Given the recognized utility of facial implants in the augmentation of the facial skeleton, they have received little attention in the recent literature. Contemporary reports have focused on the refinement of techniques--with renewed interest in the vertical transoral approach, and expanding the scope of facial implants--that is, the utility of facial implants as alternatives and/or adjuncts to orthognathic surgery. SUMMARY: Facial augmentation using alloplastic implants remains a tried, tested, and true means of correcting skeletal insufficiencies and abnormalities. Thus, what was once old will be new again, and a renaissance in the use of facial implants will undoubtedly occur. PMID- 23799417 TI - Craniofacial features of children with celiac disease. AB - BACKGROUND AND GOALS: Growth retardation is one of the most important signs of childhood celiac disease (CD); however, it is not very well known whether craniofacial growth is also affected. We aimed to carry out a detailed craniofacial morphological study to derive a conclusion on the craniofacial features of children with CD. PARTICIPANTS AND METHODS: Eighty-four 2-16-year-old children with biopsy-proven CD and 84 age-matched and sex-matched healthy children were included. Of these, 37 children (44.0%) had been newly diagnosed and 47 (56.0%) were on a gluten-free diet. Anteroposterior and lateral photographs were evaluated using the Scion Image software program for the measurements of the distances between reference points on the face. RESULTS: Except for nasofrontal angle (nfa), nasolabial angle (nla), pronasale height (prnh), nasal dorsum height (ndh), and nasal radix height (nrh), all measurements were significantly greater in patients compared with controls. In celiac children, all facial proportions except forehead/face height (t-gl/t-gn) and nose length/face height (n-ns/t-gn) were significantly different from those of controls. Except for nla, prnh, ndh, nrh, t-gl/t-gn, face height to total face height ratio (sn-gn/t-gn), n-sn/t-gn, ear length to face height ratio (s-sba/t gn), and face width to face height ratio (z-z/t-gn), all measurements were statistically different in those on a gluten-free diet and newly diagnosed children. CONCLUSION: Most of the facial measurements and proportions of celiac children were different from those of controls. Our data confirm those of a previous study reporting that the forehead proportion is not altered in childhood CD. Pathophysiological mechanisms underlying these alterations are not clear but disruptions of growth during certain critical periods may be responsible. PMID- 23799418 TI - Preoperative smoking status and postoperative complications: a systematic review and meta-analysis. AB - OBJECTIVE: To systematically review and summarize the evidence of an association between preoperative smoking status and postoperative complications elaborated on complication type. BACKGROUND: The conclusions of studies examining the association between preoperative smoking and postoperative complications are inconsistent, thus there is a need for a review and meta-analysis to summarize the existing evidence. METHODS: A systematic review and meta-analysis based on a search in MEDLINE, EMBASE, CINAHL, and PsycINFO. Included were original studies of the association between smoking status and postoperative complications occurring within 30 days of operation. In total, 9354 studies were identified and reviewed for eligibility and data were extracted. Forest plots and summarized relative risks (RR) including 95% confidence intervals (CIs) were estimated for various complication types. RESULTS: Of the 9354 identified studies, 107 studies were included in the meta-analyses and based on these, 157 data sets were extracted. Preoperative smoking was associated with an increased risk of various postoperative complications including general morbidity (RR=1.52, 95% CI: 1.33 1.74), wound complications (RR=2.15, 95% CI: 1.87-2.49), general infections (RR=1.54, 95% CI: 1.32-1.79), pulmonary complications (RR=1.73, 95% CI: 1.35 2.23), neurological complications (RR=1.38, 95% CI: 1.01-1.88), and admission to intensive care unit (RR=1.60, 95% CI: 1.14-2.25). Preoperative smoking status was not observed to be associated with postoperative mortality, cardiovascular complications, bleedings, anastomotic leakage, or allograft rejection. CONCLUSIONS: Preoperative smoking was found to be associated with an increased risk of the following postoperative complications: general morbidity, wound complications, general infections, pulmonary complications, neurological complications, and admission to the intensive care unit. PMID- 23799419 TI - T-tube or No T-tube in Cadaveric Orthotopic Liver Transplantation: The Type of Tube Really Matters. PMID- 23799420 TI - Predicting mortality from noncardiac surgery. PMID- 23799421 TI - Preoperative gemcitabine-based chemoradiation therapy for resectable and borderline resectable pancreatic cancer. AB - OBJECTIVE: To evaluate the outcome of preoperative gemcitabine-based chemoradiation therapy (CRT) for resectable and borderline resectable pancreatic cancer (PC), with a focus on the differences in surgical outcomes and patterns of recurrence between these 2 categories. BACKGROUND: Various multimodal treatment strategies have been proposed to improve the surgical outcomes of PC. Preoperative CRT and subsequent surgery is one of the promising strategies for resectable (PC-R) and borderline resectable (PC-BR) PC. METHODS: A total of 268 patients with PC-R and PC-BR received preoperative gemcitabine-based CRT. The numbers of PC-R and PC-BR cases were 188 and 80, respectively. We evaluated the following comparisons between patients with PC-R and those with PC-BR: (1) resection rate, (2) rate of margin-negative resection, (3) survival, and (4) pattern of the treatment failure, including local recurrence, peritoneal dissemination, and distant metastasis. RESULTS: The resection rate of patients with PC-R (87%) was higher than that of patients with PC-BR (54%) (P < 0.001). Pathological margin-negative resection was achieved in 99% and 98% of the patients with PC-R and PC-BR, respectively. The 5-year survival rates of the PC-R and PC-BR cases were 57% and 34%, respectively (P = 0.029). Although the 5-year cumulative incidence of local recurrence was comparable in both groups (15% and 13%, respectively; P = 0.508), the 5-year cumulative incidence of peritoneal and distant recurrence was significantly higher in the patients with PC-BR (43 and 76%) than in the patients with PC-R (17% and 43%). CONCLUSIONS: In the resected cases, the locoregional control was comparable between patients with PC-R and PC BR after preoperative CRT. The survival rate for the patients with PC-BR was lower than the rate for those with PC-R due to a higher incidence of peritoneal and distant recurrence in the patients with PC-BR. (UMIN000001804). PMID- 23799422 TI - Match analysis of U9 and U10 english premier league academy soccer players using a global positioning system: relevance for talent identification and development. AB - The purpose of this study was to examine the match activity profile of U9 and U10 elite soccer players and to establish if there were any differences between players who were subsequently retained or released by their clubs. Such information should prove valuable in the design of training programs for these very young players and in the talent identification and development process. A Global Positioning System was used to analyze 2-4 interacademy 6-a-side matches of English Premier League Academy players (U9: N = 22 and U10: N = 12) who trained 3 times a week (4.5 hours). Speed zones were created based on 5 and 10-m sprint times, and an independent sample t-test was employed for a statistical analysis. Both squads covered ~4,000 m in total or ~4,700 m.h during a match (p = NS between squads), with the U10 squad tending to cover a greater distance at moderate (p = 0.10) and high speeds (p = 0.08) than the U9 squad. Retained group covered a greater distance than released group (retained vs. released: 4,478 +/- 513 m vs. 4,091 +/- 462 m, p < 0.05) during a match and covered a greater distance during low-speed running in absolute (1,226 +/- 259 m vs. 1,005 +/- 221 m, p < 0.05) and relative (1,325 +/- 235 m.h vs. 1,132 +/- 210 m.h, p < 0.05) terms. Thus, U9 and U10 players cover over 4000 m in match play, and those players who are retained by academies cover a greater distance in total and at low speeds (2.1-3.1 m.s). This information may support the preparation of squad training programs and the talent identification and development process. PMID- 23799423 TI - Acute potentiating effect of depth jumps on sprint performance. AB - The purpose of this investigation was to determine whether the addition of 3 depth jumps to a dynamic warm-up (DYNDJ) protocol would significantly improve 20 m sprint performance when compared with a cardiovascular (C) warm-up protocol or a dynamic (DYN) stretching protocol alone. The first part of the study identified optimal drop height for all subjects using the maximum jump height method. The identified optimal drop heights were later used during the DYNDJ protocol. The second part compared the 3 warm-up protocols above to determine their effect on 20-m sprint performance. Twenty-nine subjects (age, 20.8 +/- 4.4 years; weight, 82.6 +/- 9.9 kg; height, 180.3 +/- 6.2 cm) performed 3 protocols of a C protocol, a DYN protocol, and a DYNDJ protocol in a randomized order. A 20-m sprint was performed 1 minute after the completion of each of the 3 protocols. Results displayed significant differences between each of the 3 protocols. A significant improvement (p = 0.001) of 2.2% was obtained in sprint time between the C protocol (3.300 +/- 0.105 seconds) and the DYN protocol (3.227 +/- 0.116 seconds), a further significant improvement of 5.01% was attained between the C and the DYNDJ protocols (3.300 +/- 0.10 vs. 3.132 +/- 0.120 seconds; p = 0.001). In addition, a significant improvement (p = 0.001) of 2.93% was observed between the DYN protocol (3.227 +/- 0.116 seconds) and the DYNDJ protocol (3.132 +/- 0.116 seconds). The data from this study advocate the use of DYNDJ protocol as a means of significantly improving 20-m sprint performance 1 minute after the DYNDJ protocol. PMID- 23799424 TI - Expansion of memory-type CD8+ T cells correlates with the failure of early immunosuppression withdrawal after cadaver liver transplantation using high-dose ATG induction and rapamycin. AB - BACKGROUND: We report on a pilot study investigating the feasibility of early immunosuppression withdrawal after liver transplantation (LT) using antithymocyte globulin (ATG) induction and rapamycin. METHODS: LT recipients received 3.75 mg/kg per day ATG from days 0 to 5 followed by rapamycin-based immunosuppression. In the absence of acute rejection (AR), rapamycin was withdrawn after month 4. Immunomonitoring included analysis of peripheral T-cell phenotypes and clonality, cytokine production in mixed lymphocyte reaction, and characterization of intragraft infiltrating cells. RESULTS: Ten patients were enrolled between October 2009 and July 2010. In the first three patients, complete withdrawal of immunosuppression after month 4 led to AR. No further withdrawals of immunosuppressive were attempted. Two AR occurred in the remaining seven patients. ATG induced profound T-cell depletion followed by CD8(+) T-cell reexpansion exhibiting memory/effector-like phenotype associated with progressive oligoclonal T-cell expansion (Vbeta/HPRT ratio) and gradually enhanced anti cytomegalovirus and anti-Epstein-Barr virus T-cell frequencies. Patients developing AR were characterized by decreased TCAIM expression. AR were associated with increased donor-specific production of interferon (IFN)-gamma and interleukin (IL)-17, increased intragraft expression of IFN-gamma mRNA, and significant CD8(+) T-cell infiltrates colocalizing with IL-17(+) cells. CONCLUSION: High-dose ATG followed by short-term rapamycin treatment failed to promote early operational tolerance to LT. AR correlates with expansion of memory type CD8(+) T cells and increased levels of IFN-gamma and IL-17 in mixed lymphocyte reaction and in the graft. This suggests that resistance and preferential expansion of effector memory T-cell in lymphopenic environment could represent the major barrier for establishment of tolerance to LT in approaches using T-cell-depleting induction. PMID- 23799425 TI - Modifiable factors in access to living-donor kidney transplantation among diverse populations. AB - BACKGROUND: We have observed a significant inequality in the number of living donor kidney transplants (LDKT) performed between patients of non-Western European origin and those of Western European origin. The aim of this study was to investigate modifiable factors that could be used as potential targets for an intervention in an attempt to reduce this inequality. METHODS: A questionnaire on knowledge, risk perception, communication, subjective norm, and willingness to accept LDKT was completed by 160 end-stage renal patients who were referred to the pretransplantation outpatient clinic (participation rate of 92%). The questionnaire was available in nine languages. Multivariate analyses of variance were conducted to explore differences between patients with and without a living donor. RESULTS: There were significantly fewer patients of non-Western descent (11 of 82) that brought a living donor to the outpatient clinic than patients of Western descent (38 of 78). After correcting for the unmodifiable sociodemographic factors non-Western descent, low knowledge, little communication about their kidney disease, and low willingness to communicate with individuals from the social network about LDKT were significantly associated with the absence of a living donor. CONCLUSIONS: Knowledge and communication are identified as modifiable factors that are associated with the likelihood of identifying a potential living donor for LDKT. This observation makes knowledge and communication targets for interventions to reduce inequality in access to LDKT. PMID- 23799426 TI - Cancer risk after ABO-incompatible living-donor kidney transplantation. AB - BACKGROUND: Recipients of ABO-incompatible (ABOi) living-donor kidney transplants often undergo more intense immunosuppression than their ABO-compatible counterparts. It is unknown if this difference leads to higher cancer risk after transplantation. Single-center studies are too small and lack adequate duration of follow-up to answer this question. METHODS: We identified 318 ABOi recipients in the Transplant Cancer Match Study, a national linkage between the Scientific Registry of Transplant Recipients and population-based U.S. cancer registries. Seven cancers (non-Hodgkin lymphoma, Merkel cell carcinoma, gastric adenocarcinoma, hepatocellular carcinoma, thyroid cancer, pancreatic cancer, and testicular cancer) were identified among ABOi recipients. We then matched ABOi recipients to ABO-compatible controls by age, gender, race, human leukocyte antigen mismatch, retransplantation, and transplant year. RESULTS: There was no demonstrable association between ABOi and cancer in unadjusted (incidence rate ratio, 0.83; 95% confidence interval, 0.33-1.71; P=0.3) or matched control (incidence rate ratio, 0.99; 95% confidence interval, 0.38-2.23; P=0.5) analyses. CONCLUSION: To the extent that could be determined in this registry study, current desensitization protocols are not associated with increased risk of cancer after transplantation. PMID- 23799427 TI - Delivery system reform--visualizing the future. PMID- 23799428 TI - The privilege gap in medicine. PMID- 23799429 TI - The privilege gap in medicine--in reply to Nahvi. PMID- 23799430 TI - Bring global health and global medicine home. PMID- 23799431 TI - Bring global health and global medicine home. PMID- 23799432 TI - Bring global health and global medicine home--in reply to Ventres and Page and to Asgary. PMID- 23799433 TI - Specialized residency programs may help stem the tide of physician burnout. PMID- 23799434 TI - Specialized residency programs may help stem the tide of physician burnout--in reply to Shah. PMID- 23799435 TI - Empowering medical students to design and execute advocacy projects. PMID- 23799436 TI - Empowering medical students to design and execute advocacy projects--in reply to Premkumar et al:. PMID- 23799437 TI - Chair of a department of medicine: now a different job. AB - The job of chair of a department of medicine, once seen as the apex in the career of an academic internist, has lost much of its allure, in part because of increasing administrative and financial obligations that require more of the time and effort of chairs than formerly. This is the impression the author gathered from interviewing 44 current and former chairs, deans, division chiefs, and hospital directors.He was told that chairs have lost some of their independence as departments have become increasingly dependent on the support of the executives at their university hospitals who, as the source of funds and facilities, can even specify which clinical services the chairs may develop. Conflict over the assignment of resources between dean and hospital CEO, which one interviewee stated can produce "incredible tensions," can complicate efforts of chairs to build clinical and research strength within their departments according to their own preferences. The growing administrative and financial duties of the job have forced some chairs to decrease their dedication to the classic responsibilities of teaching medical students and house officers.Recruiting outstanding leaders for departments of medicine challenges search committees and deans more than in the past because many suitable candidates do not choose to be considered and prefer to lead institutes, centers, or specialty divisions. The author suggests, however, that schools-by providing chairs with adequate administrative support and authority-can structure the job to improve its attractiveness and allow chairs more time to engage in traditional academic pursuits. PMID- 23799438 TI - Embrace the challenge: advice for current and prospective department chairs. AB - In this issue, Kastor discusses the challenges and responsibilities of a contemporary chair of medicine as described in interviews of 44 chairs. As a chair of surgery at the University of North Carolina at Chapel Hill for 17 years, the author of this commentary uses his own experiences to reflect on how the insights presented in Kastor's commentary can apply to department chairs in other specialties. Elements from Kastor's commentary, as well as additional observations from the author's tenure, may be sources of advice to future chairs of any department. The author concludes that, despite a changing health care environment and other significant leadership challenges, being a department chair is a rewarding job with many opportunities to pursue worthwhile objectives. PMID- 23799439 TI - Bigger chairs at smaller tables. AB - As noted in the commentary by Kastor, chairs of academic clinical departments in medical schools now find themselves beleaguered by issues and responsibilities and in reporting relationships-that are beyond the traditional scope of those positions. The situation is particularly acute in departments of medicine. This commentary suggests that departments of medicine have become too large and that chairs are no longer able to focus on the more traditional missions of the department of medicine, most notably direct clinical care and teaching. An argument is made for limiting the scope of departments' clinical and research programs, thereby enabling academic chairs to regain the level of prominence and satisfaction that has traditionally been associated with those distinguished positions. PMID- 23799440 TI - The woman in the mirror: humanities in medicine. AB - While the role of the sciences in medicine and medical training is unquestioned and should remain so, the traditional resistance of medical culture to the humanities and humanistic argument does not serve the medical profession well, nor does it do justice either to the challenges or rewards of clinical practice. PMID- 23799442 TI - The synergy of medicine and art in the curriculum. AB - This is a commentary in which a fourth-year medical student argues for the relevance of the arts and humanities and the need to sustain medical students' exposure to these through the medical curriculum. She writes that the point of incorporating the visual arts, literature, music, and other arts into the curriculum is not necessarily to "teach" professionalism but, rather, to offer students a viable, lifelong tool to reorient themselves as they move along in their training. The advantages that the humanities offer are multifactorial: They offer a space for discussion about topics such as death and dying-and coping with dying patients-such that students can feel safe and objective in sharing thoughts; they remind students of the patient experience; they eloquently distill muddy feelings into nuanced words; and they serve as an anchoring point for a state of mind that nurtures reflection over the disdain encouraged by the "hidden curriculum" of the wards. The author closes the commentary with excerpts from literature. PMID- 23799444 TI - Medicine and the arts. The face of pain by Jordan Doyle. Commentary. PMID- 23799445 TI - Body and soul: lessons from my third year in medical school. PMID- 23799446 TI - Culturally sensitive medical professionalism. PMID- 23799447 TI - AM last page: self-regulated learning--a dynamic, cyclical perspective. PMID- 23799448 TI - Solution NMR studies on the orientation of membrane-bound peptides and proteins by paramagnetic probes. AB - Many peptides and proteins are attached to or immersed in a biological membrane. In order to understand their function not only the structure but also their topology in the membrane is important. Solution NMR spectroscopy is one of the most often used approaches to determine the orientation and localization of membrane-bound peptides and proteins. Here we give an application-oriented overview on the use of paramagnetic probes for the investigation of membrane bound peptides and proteins. The examples discussed range from the large pool of antimicrobial peptides, bacterial toxins, cell penetrating peptides to domains of larger proteins or the calcium regulating protein phospholamban. Topological information is obtained in all these examples by the use of either attached or freely mobile paramagnetic tags. For some examples information obtained from the paramagnetic probes was included in the structure determination. PMID- 23799449 TI - Monolithic poly(N-vinylcarbazole-co-1,4-divinylbenzene) capillary columns for the separation of biomolecules. AB - Monolithic capillary columns were prepared by thermally initiated free radical copolymerization of N-vinylcarbazole (NVC) and 1,4-divinylbenzene (DVB) within the confines of 200 and 100 MUm i.d. fused silica capillaries. The reaction was carried out under the influence of inert micro-(toluene) and macroporogen (1 decanol) and alpha,alpha'-azoisobutyronitrile (AIBN) as a free radical initiator. The material proved high mechanical stability applying water and acetonitrile as mobile phases. The morphological and porous properties were studied by scanning electron microscopy (SEM), nitrogen sorption (BET) and mercury intrusion porosimetry (MIP). The homogeneity of the copolymerization process was confirmed by elemental analysis and monomer conversion measurements. The newly developed NVC/DVB monolithic supports showed high separation efficiency towards biomolecules, applying reversed-phase (RP) and ion-pair reversed-phase (IP-RP) separation modes, which is exemplified by the separations of peptides, proteins and oligonucleotides. Furthermore the maximum loading capacity was evaluated. The chromatographic performance under isocratic elution was determined in terms of theoretical plate number and plate height, where up to 41,000 plates per column and a minimum plate height value of 1.7 MUm were achieved, applying oligonucleotide separations. In gradient elution mode, peak capacities of 96 and 127 were achieved within a gradient time window of 60 min for protein and oligonucleotide separations, respectively. The material proved to have high permeability, good repeatability of the fabrication process and high surface areas in the range of 120-160 m(2) g(-1). PMID- 23799450 TI - The transition state structure for coupled binding and folding of disordered protein domains. AB - Intrinsically disordered proteins are abundant in the eukaryotic proteome, and they are implicated in a range of different diseases. However, there is a paucity of experimental data on molecular details of the coupled binding and folding of such proteins. Two interacting and relatively well studied disordered protein domains are the activation domain from the p160 transcriptional co-activator ACTR and the nuclear co-activator binding domain (NCBD) of CREB binding protein. We have analyzed the transition state for their coupled binding and folding by protein engineering and kinetic experiments (Phi-value analysis) and found that it involves weak native interactions between the N-terminal helices of ACTR and NCBD, but is otherwise "disordered-like". Most native hydrophobic interactions in the interface between the two domains form later, after the rate-limiting barrier for association. Linear free energy relationships suggest a cooperative formation of native interactions, reminiscent of the nucleation-condensation mechanism in protein folding. PMID- 23799451 TI - Novel CYP2D6 and CYP2C19 variants identified in a patient with adverse reactions towards venlafaxine monotherapy and dual therapy with nortriptyline and fluoxetine. AB - We present a case report of novel variants of CYP2D6 and CYP2C19 identified in a patient who experienced adverse effects during antidepressant therapy. CYP2D6 DNA sequencing revealed that the patient was most likely an intermediate metabolizer, owing to the presence of a novel variant (2579C>T), which gives rise to a premature stop codon in exon 5. Because defects in CYP2C19 may also be important, we sequenced the promoter region and all exons of CYP2C19 and identified a cluster of three novel variants (-13G>A, 7C>T and 10T>C) around exon 1, as well as the more common CYP2C19*2 allele. The presence of multiple genetic lesions in CYP2C19 implies that this patient is potentially a CYP2C19 poor metabolizer, and this was confirmed by haplotype analysis. Combined impairment of CYP2D6 and CYP2C19 activities, we believe, may have contributed to the development of the observed drug responses in the present report. PMID- 23799453 TI - Measurement of hepatic venous pressure gradient is feasible and safe in children. AB - BACKGROUND AND OBJECTIVES: Hepatic venous pressure gradient (HVPG) is an indirect measure of portal venous pressure in cirrhosis, which is valid in cirrhotic adults for evaluating the severity of portal hypertension, predicting outcomes, and guiding therapeutic decisions. Published data on the measurement of HVPG in children are sparse. The aim of the present study was to determine the feasibility and safety of undertaking HVPG measurements in children. METHODS: Children who underwent HVPG measurements between 2000 and 2011 were identified from our interventional radiology database. Medical charts were reviewed for clinical, procedural, and outcome data. RESULTS: A total of 49 patients (25 boys, mean age 8.2 +/- 5.6 years) underwent 52 HVPG measurements. Diagnoses included cirrhosis (n = 7), acute liver failure (n = 15), postliver transplant (n = 6), postbone marrow transplant (n = 9), vascular anomalies (n = 3), and others (n = 9). There were no complications related to HVPG measurement. HVPG values ranged between 0 and 28 mmHg, median 9.0 (range 0-28) mmHg, and were elevated >6 mmHg in 30 patients. CONCLUSIONS: HVPG measurement is feasible and safe in children with severe liver disease. The clinical use of HVPG measurements in managing children with portal hypertension or with acute liver diseases must now be determined. PMID- 23799452 TI - In vitro integration of ribosomal RNA synthesis, ribosome assembly, and translation. AB - Purely in vitro ribosome synthesis could provide a critical step towards unraveling the systems biology of ribosome biogenesis, constructing minimal cells from defined components, and engineering ribosomes with new functions. Here, as an initial step towards this goal, we report a method for constructing Escherichia coli ribosomes in crude S150 E. coli extracts. While conventional methods for E. coli ribosome reconstitution are non-physiological, our approach attempts to mimic chemical conditions in the cytoplasm, thus permitting several biological processes to occur simultaneously. Specifically, our integrated synthesis, assembly, and translation (iSAT) technology enables one-step co activation of rRNA transcription, assembly of transcribed rRNA with native ribosomal proteins into functional ribosomes, and synthesis of active protein by these ribosomes in the same compartment. We show that iSAT makes possible the in vitro construction of modified ribosomes by introducing a 23S rRNA mutation that mediates resistance against clindamycin. We anticipate that iSAT will aid studies of ribosome assembly and open new avenues for making ribosomes with altered properties. PMID- 23799454 TI - Percutaneous endoscopic gastrostomy in children: Is early feeding safe? AB - BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) is the preferred method to provide nutritional support for patients with normal gastrointestinal function but cannot be fed orally for a variety of reasons. Owing to safety concerns, the first feeding after PEG tube placement is generally delayed. Early feeding may be an option; however, childhood studies regarding early feeding after the PEG procedure are highly insufficient. METHODS: A prospective randomized controlled study was conducted to compare early (4th hour) and late (12th hour) feeding after the PEG procedure. The PEG process was performed with the standard pull technique. Prophylactic antimicrobial drugs were not used. Complications such as gastric residue after feeding, vomiting, fever, systemic signs of infection, and duration of hospital stay were recorded. Tube feeding training was given to parents during their stay in the hospital in both groups. In the first and third days following PEG, the patients were visited by an experienced nurse in their homes and evaluated in terms of potential complications. RESULTS: The study was completed with a total of 69 patients: 35 in the early feeding group and 34 in the late feeding group. The demographic characteristics of the groups were similar. Vomiting was rare and detected as similar in both groups (early feeding group 8.5% [3/35], late feeding group 8.8% [3/34], P = 1.00). Rarely, minor gastric residue was observed in both groups (early feeding group 11.4%, late feeding group 8.8% [P = 1.00]). The amount of gastric residue in the early feeding group was a maximum of 13.2 mL, whereas the late feeding group had a maximum of 14.3 mL. The average duration of stay in the hospital for the early and late feeding groups was calculated as 6.7 +/- 0.64 and 28.3 +/- 3.74 hours, respectively (P < 0.001). Leakage from gastrostomy fistulas, peritonitis, and aspiration were not observed in any patients. CONCLUSIONS: The feeding at the fourth hour after PEG placement was safe and well tolerated by patients and shortened the duration of the hospital stay. The use of prophylactic antibiotics seems to be unnecessary before the procedure. PMID- 23799455 TI - Systematic review of biliary atresia services: a case for medium-sized centres? PMID- 23799456 TI - Authors' response. PMID- 23799457 TI - Percutaneous liver biopsy: pathologic diagnosis and complications in children. AB - OBJECTIVE: The aim of this study was to determine patient factors that predict diagnostic failure or increased risk of bleeding complications following percutaneous liver biopsy in children. METHODS: A retrospective review of all children undergoing percutaneous liver biopsy at a single institution between July 2008 and July 2011 was performed. Demographics, comorbid conditions, preprocedural diagnoses/indications, procedural details, laboratory data, pathologic diagnosis, and complications were recorded. Continuous data were analyzed by Wilcoxon test and categorical data by Fisher exact test to determine statistical significance. RESULTS: Two hundred thirteen children (104 girls) with a median age of 7 years (range 1 week-22 years) underwent 328 percutaneous liver biopsies. Nine (4.2%) experienced a decrease in hemoglobin >2 g/dL, 7 required transfusion (3.3%), and 1 patient died (0.5%). Younger age (1.8 vs 84 months, P = 0.05) and lower preprocedural hematocrit (29.3 vs 34.3, P = 0.05) predicted bleeding complications, whereas the number of biopsies, comorbid conditions, and coagulopathy did not. Sixty-three (19.2%) biopsies were insufficient for definitive histologic evaluation on initial biopsy in 57 patients. Twenty-one of 57 patients (37%) underwent repeat percutaneous biopsy and 3 of 57 (8%) underwent surgical biopsy. Biopsy provided definitive diagnosis in 86% of cases when repeat biopsy was performed. Shorter specimen length (1.4 vs 1.7 cm, P < 0.01) and biopsies performed for unexplained elevation of liver function tests (34.9% vs 16.7%, P < 0.01) were predictive of nondiagnosis. CONCLUSIONS: Percutaneous liver biopsy is safe with a low rate of bleeding-related complications. Ensuring adequate sample length and careful patient selection may further increase the diagnostic yield. PMID- 23799458 TI - Successful application of electrohydraulic lithotripsy in a child with impacted esophageal foreign body (pill). PMID- 23799459 TI - ATP interferes with neural cell adhesion molecule-induced neurite outgrowth. AB - The neural cell adhesion molecule (NCAM) is a member of the immunoglobulin superfamily and involved in the development and regeneration of the nervous system. NCAM is expressed in three major isoforms. Two of them have large intracellular domains of different lengths and are named according to their apparent molecular weight as NCAM140 or NCAM180. NCAM140 is known to promote neurite outgrowth, whereas NCAM180 stabilizes cell-cell contacts. Beside its role in neurite outgrowth, NCAM also shows ATPase activity on its extracellular domain. Here, we quantified neurite outgrowth of neuroblastoma cells, which were transfected with either NCAM140 or NCAM180 in the absence or presence of ATP. We could confirm that NCAM140 strongly promotes neurite outgrowth, whereas NCAM180 stimulates neurite outgrowth only to a minor extent. Furthermore, application of ATP reduced the NCAM-induced neurite outgrowth to background levels in a concentration-dependent and isoform-dependent manner. PMID- 23799461 TI - Multichannel linear descriptors analysis for sustained attention-related electroencephalography. AB - This study investigated the differences in brain functional state between sustained attention and ignoring task conditions using the electroencephalography in association with sustained attention to response task (SART) performance. Multichannel electroencephalography data were obtained from 10 male healthy volunteers while performing the SART. Three multichannel linear descriptors, that is spatial complexity (Omega), field strength (Sigma), and frequency of field changes (Phi), were applied to analyze three frequency bands (theta, alpha, and beta) for sustained attention and ignoring task conditions. The experimental results showed that participants had a significantly lower Omega value in the theta and alpha band in the SART state. The Sigma value was significantly higher in each frequency band of interest in almost all region of interest areas during SART performance. In addition, the Phi value was significantly lower in the theta band and significantly higher in the beta band during the sustained attention condition. The results indicated that multichannel linear descriptors could show the differences in brain functions between sustained attention and ignoring task conditions, and might be used to evaluate disorders with an attentional dysfunction. PMID- 23799460 TI - Between-site reliability of startle prepulse inhibition across two early psychosis consortia. AB - Prepulse inhibition (PPI) and reactivity of the acoustic startle response are widely used biobehavioral markers in psychopathology research. Previous studies have demonstrated that PPI and startle reactivity exhibit substantial within-site stability; however, between-site stability has not been established. In two separate consortia investigating biomarkers of early psychosis, traveling participants studies were carried out as a part of quality assurance procedures to assess the fidelity of data across sites. In the North American Prodromal Longitudinal Studies (NAPLS) consortium, eight normal participants traveled to each of the eight NAPLS sites and were tested twice at each site on the startle PPI paradigm. In preparation for a binational study, 10 healthy participants were assessed twice in both San Diego and Mexico City. Intraclass correlations between and within sites were significant for PPI and startle response parameters, confirming the reliability of startle measures across sites in both consortia. There were between-site differences in startle magnitude in the NAPLS study that did not appear to be related to methods or equipment. In planning multisite studies, it is essential to institute quality assurance procedures early and establish between-site reliability to assure comparable data across sites. PMID- 23799462 TI - Advances in fluid resuscitation in critically ill patients: implications for clinical practice. PMID- 23799463 TI - The rapid response system and end-of-life care. AB - PURPOSE OF REVIEW: To review the recent observational studies reporting the role of the rapid response team (RRT) in end-of-life care (EOLC) planning for hospitalized patients. RECENT FINDINGS: Initial RRT studies focussed on its role in detecting and preventing avoidable morbidity. However, patients who are in the process of dying will also trigger RRT activation criteria. Single-centre studies from several countries reveal that up to 25% of RRT calls involve patients with a pre-existing limitation of medical therapy (LOMT) and 10% result in new implementation of a new LOMT. A recent seven hospital study revealed that such EOLC RRT calls occur in significantly older patients, who are less likely to be from home and more likely to be admitted with a nonsurgical condition. Importantly, almost 50% of patients subject to EOLC RRT call die in hospital, and in many cases the last RRT call occurs on the day of death. SUMMARY: Up to one third of RRT calls involve patients at the end of their life. Better understanding of the features of these patients may guide improved advance care and EOLC planning for hospitalized patients. PMID- 23799464 TI - Focus on neurotechniques. PMID- 23799465 TI - Recurrent networks learn to tell time. PMID- 23799466 TI - CRESTing the ALS mountain. PMID- 23799467 TI - Itching for relief. PMID- 23799468 TI - Dopamine signals mimic reward prediction errors. PMID- 23799469 TI - Pair-bonding through epigenetics. PMID- 23799470 TI - Opportunities and challenges of pluripotent stem cell neurodegenerative disease models. AB - Human neurodegenerative disorders are among the most difficult to study. In particular, the inability to readily obtain the faulty cell types most relevant to these diseases has impeded progress for decades. Recent advances in pluripotent stem cell technology now grant access to substantial quantities of disease-pertinent neurons both with and without predisposing mutations. While this suite of technologies has revolutionized the field of 'in vitro disease modeling', great care must be taken in their deployment if robust, durable discoveries are to be made. Here we review what we perceive to be several of the stumbling blocks in the use of stem cells for the study of neurological disease and offer strategies to overcome them. PMID- 23799471 TI - Seeing the forest tree by tree: super-resolution light microscopy meets the neurosciences. AB - Light microscopy can be applied in vivo and can sample large tissue volumes, features crucial for the study of single neurons and neural circuits. However, light microscopy per se is diffraction-limited in resolution, and the substructure of core signaling compartments of neuronal circuits--axons, presynaptic active zones, postsynaptic densities and dendritic spines-can be only insufficiently characterized by standard light microscopy. Recently, several forms of super-resolution light microscopy breaking the diffraction-imposed resolution limit have started to allow highly resolved, dynamic imaging in the cell-biologically highly relevant 10-100 nanometer range ('mesoscale'). New, sometimes surprising answers concerning how protein mobility and protein architectures shape neuronal communication have already emerged. Here we start by briefly introducing super-resolution microscopy techniques, before we describe their use in the analysis of neuronal compartments. We conclude with long-term prospects for super-resolution light microscopy in the molecular and cellular neurosciences. PMID- 23799472 TI - Immunogold cytochemistry in neuroscience. AB - The complexity of the central nervous system calls for immunocytochemical procedures that allow target proteins to be localized with high precision and with opportunities for quantitation. Immunogold procedures stand out as particularly powerful in this regard. Although these procedures have found wide application in the neuroscience community, they present limitations and pitfalls that must be taken into account. At the same time, these procedures offer potentials that remain to be fully realized. PMID- 23799473 TI - Targeting neurons and photons for optogenetics. AB - Optogenetic approaches promise to revolutionize neuroscience by using light to manipulate neural activity in genetically or functionally defined neurons with millisecond precision. Harnessing the full potential of optogenetic tools, however, requires light to be targeted to the right neurons at the right time. Here we discuss some barriers and potential solutions to this problem. We review methods for targeting the expression of light-activatable molecules to specific cell types, under genetic, viral or activity-dependent control. Next we explore new ways to target light to individual neurons to allow their precise activation and inactivation. These techniques provide a precision in the temporal and spatial activation of neurons that was not achievable in previous experiments. In combination with simultaneous recording and imaging techniques, these strategies will allow us to mimic the natural activity patterns of neurons in vivo, enabling previously impossible 'dream experiments'. PMID- 23799474 TI - Optogenetic pharmacology for control of native neuronal signaling proteins. AB - The optical neuroscience revolution is transforming how we study neural circuits. By providing a precise way to manipulate endogenous neuronal signaling proteins, it also has the potential to transform our understanding of molecular neuroscience. Recent advances in chemical biology have produced light-sensitive compounds that photoregulate a wide variety of proteins underlying signaling between and within neurons. Chemical tools for optopharmacology include caged agonists and antagonists and reversibly photoswitchable ligands. These reagents act on voltage-gated ion channels and neurotransmitter receptors, enabling control of neuronal signaling with a high degree of spatial and temporal precision. By covalently attaching photoswitch molecules to genetically tagged proteins, the newly emerging methodology of optogenetic pharmacology allows biochemically precise control in targeted subsets of neurons. Now that the tools for manipulating endogenous neuronal signaling proteins are available, they can be implemented in vivo to enhance our understanding of the molecular bases of brain function and dysfunctions. PMID- 23799475 TI - Probing perceptual decisions in rodents. AB - The study of perceptual decision-making offers insight into how the brain uses complex, sometimes ambiguous information to guide actions. Understanding the underlying processes and their neural bases requires that one pair recordings and manipulations of neural activity with rigorous psychophysics. Though this research has been traditionally performed in primates, it seems increasingly promising to pursue it at least partly in mice and rats. However, rigorous psychophysical methods are not yet as developed for these rodents as they are for primates. Here we give a brief overview of the sensory capabilities of rodents and of their cortical areas devoted to sensation and decision. We then review methods of psychophysics, focusing on the technical issues that arise in their implementation in rodents. These methods represent a rich set of challenges and opportunities. PMID- 23799476 TI - Opportunities and limitations of intrinsic functional connectivity MRI. AB - Intrinsic functional connectivity magnetic resonance imaging (fcMRI) has emerged as a powerful tool for mapping large-scale networks in the human brain. Robust and reliable functionally coupled networks can be detected in individuals that echo many known features of anatomical organization. Features of brain organization have been discovered, including descriptions of distributed large scale networks interwoven throughout association cortex, interactions (including anticorrelations) between brain networks and insights into the topography of subcortical structures. But interpreting fcMRI is complicated by several factors. Functional coupling changes dynamically, suggesting that it is constrained by, but not fully dictated by, anatomic connectivity. Critically to study of between group differences, fcMRI is sensitive to head motion and to differences in the mental states of participants during the scans. We discuss the potential of fcMRI in the context of its limitations. PMID- 23799478 TI - Risk factors for nosocomial burn wound infection caused by multidrug resistant Acinetobacter baumannii. AB - Acinetobacter baumannii infections in burn patients may lead to delays in wound healing, graft losses, and development of sepsis. Determining the risk factors for multidrug resistant A. baumannii (MDR-AB) infections is essential for infection control. In the present study, the authors aimed to evaluate risk factors for wound infections caused by A. baumannii in burn patients. The study was conducted at Dicle University Hospital Burn Center, from April 2011 to July 2012, to investigate the risk factors for MDR-AB infections. The data of both the case and control group patients and the result of wound cultures were recorded on a daily basis, on individual forms given for each patient, and analyzed. A total of 30 cases infected with MDR-AB, and 60 uninfected control patients, were included in the study. The mean age (+/-SD) was 7.7 +/- 15.4 years in infected patients and 11.4 +/- 16.5 years in uninfected patients. The mean total burn surface area was 13.5 +/- 10.9% in uninfected patients and 34.7 +/- 16.2% in infected patients. The mean total burn surface area, the abbreviated burn severity index, acute physiological and chronic health evaluation II score, day of admission to hospital, length of hospital stay, first excision day, prior usage of third-generation cephalosporins, and stay in intensive care unit of the infected patients were significantly higher (P < .001) than those of patients without infection. Univariate analysis found that high acute physiological and chronic health evaluation II score, first excision time of wound, invasive device usage, admission day to hospital, and prior usage of broad-spectrum antibiotics were risk factors for nosocomial infections. This study showed that multiple factors contribute to multidrug resistance in A. baumannii. A combination of an early diagnosis of wound infections, appropriate antimicrobial treatments, surgical debridement, and early wound closure may be effective in the management. PMID- 23799477 TI - Noninvasive brain stimulation: from physiology to network dynamics and back. AB - Noninvasive brain stimulation techniques have been widely used for studying the physiology of the CNS, identifying the functional role of specific brain structures and, more recently, exploring large-scale network dynamics. Here we review key findings that contribute to our understanding of the mechanisms underlying the physiological and behavioral effects of these techniques. We highlight recent innovations using noninvasive stimulation to investigate global brain network dynamics and organization. New combinations of these techniques, in conjunction with neuroimaging, will further advance the utility of their application. PMID- 23799479 TI - Citation classics in the burn literature during the past 55 years. AB - The objective of this study was to identify the 100 most cited, peer-reviewed burn-related articles over the past half century. Burn care presents ongoing challenges to both U.S. civilian and military healthcare personnel. Improvements in burn survival and quality of life are the result of advances in burn research. The Web of Science (including Science Citation Index) was searched for the most cited articles related to burn care, published from 1955 to the present. The most cited article was "Permanent coverage of large burn wounds with autologous cultured human epithelium," by G.G. Gallico et al, New England Journal of Medicine, 1984 (711 citations). Between the 1970s and the 1990s, there was a near doubling of the number of highly cited publications with each subsequent decade. A total of 85% of the articles were on the topics of pathophysiology (37%), wounds, tissue, or dressings (31%), or organ failure/sepsis (17%). B.A. Pruitt Jr. (2320 citations), D.N. Herndon (1972 citations), and A.D. Mason Jr. (1435 citations) were the most cited authors. This study identified some of the most important contributions to burn research and the areas of greatest scientific interest to the specialty during the past five decades, and highlights key research that has contributed to the evolution of modern burn care. PMID- 23799480 TI - Does the storage age of transfused blood affect outcome in burn patients? AB - Blood banks now store blood up to 42 days. With increasing duration of storage, units of red blood cells (RBCs) develop a storage lesion characterized by alterations in oxygen transport capability and heightened proinflammatory properties. However, there is considerable controversy as to whether the storage lesion affects outcomes in transfused patients and burn patients, which has not been studied. The purpose was to identify whether any relationship exists between the storage age of transfused blood and outcome in severely burned adults. This is a retrospective review of adults, with burns 20% or more TBSA, treated at an adult regional ABA-verified burn center, who received at least one RBC transfusion. Subjects were stratified a priori based on the mean age of all RBC units transfused during the first 30 days postburn, to either a Fresh Group (mean storage age <=28 days), or an Old Group (mean storage age >28 days). The Fresh Group (N = 89) did not differ significantly from the Old Group (N = 38) in baseline characteristics. The median (range) mean blood storage age was 22.2 (10.3-28) days in the Fresh Group and 31.5 (28.3-41) days in the Old Group, (P < .001). The Fresh Group had a significantly higher median daily transfusion rate when alive and in hospital, during the first 30 days postburn, than the Old Group (0.5 [range 0.03-5.5] units/day vs 0.35 [0.03-2.7] units/day; P = .04). There were no significant differences between the groups in mean daily sequential organ failure assessment (SOFA) score, peak SOFA score, delta SOFA score (peak admission SOFA), time to wound healing, length of stay, and 30-day mortality or in-hospital mortality. Linear regression revealed no significant effect of the mean age of transfused blood on mean daily SOFA score/first 30 days postburn. The Fresh Group had a significantly longer median duration of mechanical ventilation (29 [range 1-195] vs 17 [range 1-80] days, P = .03) and had significantly more sepsis episodes. Transfusion of RBCs with a mean storage age of more than 28 days was not associated with any worsened outcome compared with transfusion of blood with a mean storage age of less than 28 days, among this cohort of adult burn patients. These findings do not suggest the need to preferentially transfuse fresher blood to burn patients, but randomized prospective studies of this question are needed. PMID- 23799481 TI - Evaluation of burn injuries related to liquefied petroleum gas. AB - Liquefied petroleum gas (LPG) is a fuel that is widely used for domestic, agricultural, and industrial purposes. LPG is also commonly used in restaurants, industries, and cars; however, the home continues to be the main site for accidents. In Turkey, the increased usage of LPG as a cooking or heating fuel has resulted in many burn injuries from LPG mishaps. Between January 2000 and June 2011, 56 LPG-burned patients were compared with 112 flame-burned patients. There were no significant differences with respect to the mean age, sex, hospitalization time, and mortality in both groups. In the LPG-caused burn cases, 41 burns (73.2%) occurred at home, seven (12.5) were work-related mishaps, and eight (14.3) were associated with car accidents. The majority of the LPG burns (82%, 46 patients) resulted from a gas leak, and 18% of them were related to the failure to close LPG tubes in the patients' kitchens (10 patients). Burns to the face and neck (82 vs 67%, P = .039) and upper (62 vs 23%, P = .000) and lower (70 vs 45%, P = .002) extremities were significantly higher in LPG-caused burn cases than flame-burned cases. General awareness regarding the risk of LPG and first aid for burns appears to be lacking. The LPG delivery system should be standardized throughout countries that widely use LPG. PMID- 23799482 TI - Lightning burns. AB - We present the case of a lightning-strike victim. This case illustrates the importance of in-field care, appropriate referral to a burn center, and the tendency of lightning burns to progress to full-thickness injury. PMID- 23799483 TI - An update on the regional organizations of the american burn association. AB - In 1985, the American Burn Association (ABA) created 10 regions in the United States and charged the Chiefs of these regions with the development of regional disaster plans. Now more than 25 years after this mandate, the ABA's Organizational and Delivery of Burn Care Committee assessed the status of regional development. The extant region leaders were contacted by email and queried as to the activities of their region and their opinion as to the success or failure of the regionalization initiative. Several regional organizational meetings were attended at the annual ABA meeting and many phone interviews were conducted to clear up any conflicting information. The original map of the burn regions was based on the American College of Surgeons Committee on Trauma regions, but these have undergone significant redistricting. The organizational structure, age, and activities of the regions vary significantly. The financial costs of maintaining a regional organization and holding an annual meeting are a major concern for most regions. For the most part the regional organizations are a good source of professional networking and a cost-effective source of continuing medical education/continuing education units for burn centers. The regionalization experiment of the ABA been reasonably successful in its first 25 years, but the ABA and the regions should take this opportunity to consider the next steps for the regions in the coming 25 years. PMID- 23799484 TI - Mucormycosis: a rare fungal infection in tornado victims. AB - This article reviews four immunocompetent patients who developed a rare fungal infection, mucormycosis, secondary to multiple traumatic injuries sustained during an EF-5 tornado in Joplin, MO. Commonly found in soil and decaying organic matter, mucorales are fungi associated with soft tissue and cutaneous infections. Onset of this fungal infection can occur without clinical signs, presenting several days to several weeks after injury, delaying diagnosis. A multidisciplinary treatment approach including aggressive antifungal therapy and aggressive surgical debridement is critical. This diagnosis should be considered in all patients presenting with injuries sustained from high-velocity embedment of debris such as natural disasters or explosions. We present four cases of mucormycosis, species Apophysomyces trapeziformis. Data reported includes predisposing factors, number of days between injury and diagnosis of mucormycosis, surgical treatment, antifungal therapy, outcomes, and potential risk factors that may have contributed to the development of mucormycosis. PMID- 23799486 TI - How do burn patients feel about peer support? Preliminary data from the SHARE program. PMID- 23799485 TI - Burn rehabilitation outcomes: lessons learned from the uniform data system for medical rehabilitation. PMID- 23799487 TI - Optogenetics, visual prosthesis and electrostimulation for retinal dystrophies. AB - PURPOSE OF REVIEW: Outer retinal degenerations such as retinitis pigmentosa can cause profound vision loss. Various treatment strategies are being pursued to potentially restore functional vision in these patients. RECENT FINDINGS: Advances in retinal prostheses have restored some vision in patients previously blind from retinitis pigmentosa. Optogenetics is another area that shows promise for restoration of vision. Transcorneal electrostimulation shows some efficacy to treat these patients as well. SUMMARY: We review recent advances in optogenetics, visual prosthesis and electrostimulation to treat outer retinal degenerations. PMID- 23799488 TI - The computation of lipophilicities of 64Cu PET systems based on a novel approach for fluctuating charges. AB - A QSPR scheme for the computation of lipophilicities of 64Cu complexes was developed with a training set of 24 tetraazamacrocylic and bispidine-based Cu(II) compounds and their experimentally available 1-octanol-water distribution coefficients. A minimum number of physically meaningful parameters were used in the scheme, and these are primarily based on data available from molecular mechanics calculations, using an established force field for Cu(II) complexes and a recently developed scheme for the calculation of fluctuating atomic charges. The developed model was also applied to an independent validation set and was found to accurately predict distribution coefficients of potential 64Cu PET (positron emission tomography) systems. A possible next step would be the development of a QSAR-based biodistribution model to track the uptake of imaging agents in different organs and tissues of the body. It is expected that such simple, empirical models of lipophilicity and biodistribution will be very useful in the design and virtual screening of positron emission tomography (PET) imaging agents. PMID- 23799489 TI - Evaluation of an inpatient heart failure screening tool. AB - Heart failure is increasing in incidence, prevalence, and mortality. The purpose of this study was to test the predictive accuracy of a screening tool to identify inpatients with heart failure. The tool demonstrated statistical significance for predictability, with 68.3% sensitivity, 86% specificity, and overall accuracy of 77.5%. The tool facilitated heart failure screening and subsequent implementation of evidence-based therapies. PMID- 23799490 TI - Developing and implementing a computerized nursing quality control system in a tertiary general medical center in Israel. AB - This article describes the development and implementation of the Nursing Quality Indicators Scale and a quality control system for hospital nursing care, which allows universal access to all external and internal audit results, thus ensuring complete data transparency. Standardized indicators make departments' performance comparable. Key to the new system is nurses' self-audit and responsibility for making quality improvements at the ward level. PMID- 23799491 TI - An in-reflection strain sensing head based on a Hi-Bi photonic crystal fiber. AB - A photonic crystal fiber-based sensing head is proposed for strain measurements. The sensor comprises a Hi-Bi PCF sensing head to measure interferometric signals in-reflection. An experimental background study of the sensing head is conducted through an optical backscatter reflectometer confirming the theoretical predictions, also included. A cost effective setup is proposed where a laser is used as illumination source, which allows accurate high precision strain measurements. Thus, a sensitivity of ~7.96 dB/me was achieved in a linear region of 1,200 MUe. PMID- 23799492 TI - A robust self-alignment method for ship's strapdown INS under mooring conditions. AB - Strapdown inertial navigation systems (INS) need an alignment process to determine the initial attitude matrix between the body frame and the navigation frame. The conventional alignment process is to compute the initial attitude matrix using the gravity and Earth rotational rate measurements. However, under mooring conditions, the inertial measurement unit (IMU) employed in a ship's strapdown INS often suffers from both the intrinsic sensor noise components and the external disturbance components caused by the motions of the sea waves and wind waves, so a rapid and precise alignment of a ship's strapdown INS without any auxiliary information is hard to achieve. A robust solution is given in this paper to solve this problem. The inertial frame based alignment method is utilized to adapt the mooring condition, most of the periodical low-frequency external disturbance components could be removed by the mathematical integration and averaging characteristic of this method. A novel prefilter named hidden Markov model based Kalman filter (HMM-KF) is proposed to remove the relatively high-frequency error components. Different from the digital filters, the HMM-KF barely cause time-delay problem. The turntable, mooring and sea experiments favorably validate the rapidness and accuracy of the proposed self-alignment method and the good de-noising performance of HMM-KF. PMID- 23799493 TI - Stop-and-go mode: sensor manipulation as essential as sensor development in terrestrial laser scanning. AB - This study was dedicated to illustrating the significance of sensor manipulation in the case of terrestrial laser scanning, which is a field now in quick development. In fact, this quickness was mainly rooted in the emergence of new sensors with better performance, while the implications of sensor manipulation have not been fully recognized by the whole community. For this technical gap, the stop-and-go mapping mode can be reckoned as one of the potential solution plans. Stop-and-go was first proposed to handle the low efficiency of traditional static terrestrial laser scanning, and then, it was re-emphasized to improve the stability of sample collections for the state-of-the-art technology of mobile laser scanning. This work reviewed the previous efforts of trying the stop-and-go mode for improving the performance of static and mobile terrestrial laser scanning and generalized their principles respectively. This work also analyzed its advantages compared to the fully-static and fully-kinematic terrestrial laser scanning, and suggested the plans with more automatic measures for raising the efficacy of terrestrial laser scanning. Overall, this literature review indicated that the stop-and-go mapping mode as a case with generic sense can verify the presumption of sensor manipulation as essential as sensor development. PMID- 23799495 TI - Iodine-131 in sewage sludge from a small water pollution control plant serving a thyroid cancer treatment facility. AB - Iodine-131 (half-life = 8.04 d) is the most widely used radionuclide in medicine for therapeutic purposes. It is excreted by patients and is discharged directly to sewer systems. Despite considerable dilution in waste water and the relatively short half-life of I, it is readily measured in sewage. This work presents I concentrations in sewage sludge from three water pollution control plants (WPCPs) on Long Island, NY. Iodine-131 concentrations ranged from 0.027 +/- 0.002 to 148 +/- 4 Bq g dry weight. The highest concentrations were measured in the Stony Brook WPCP, a relatively small plant (average flow = 6.8 * 10 L d) serving a regional thyroid cancer treatment facility in Stony Brook, NY. Preliminary radiation dose calculations suggested further evaluation of dose to treatment plant workers in the Stony Brook WPCP based on the recommendations of the Interagency Steering Committee on Radiation Standards. PMID- 23799494 TI - Development of an ultrasensitive immunoassay for detecting tartrazine. AB - We have developed an ultrasensitive indirect competitive enzyme-linked immunosorbent assay for the determination of tartrazine. Two carboxylated analogues of tartrazine with different spacer lengths, and one derivative from commercial tartrazine after a little chemical modification, were synthesized as haptens in order to produce antibodies specific to tartrazine. The effect of sulfonic acid groups on the hapten structure of tartrazine was also studied carefully for the first time. A most specific monoclonal antibody against tartrazine was created and exhibited an IC50 value of 0.105 ng/mL and a limit of detection of 0.014 ng/mL, with no cross-reactivity to other structurally-related pigments. The established immunoassay was applied to the determination of tartrazine in fortified samples of orange juice and in real positive samples of carbonated beverages. PMID- 23799496 TI - A dynamic transfer model for the estimation of 14C radioactivity in Japanese radish (Daikon) plants. AB - A dynamic compartment model was developed to describe C accumulation in the Japanese radish plant, which is an important crop in the area around Japan's first commercial nuclear fuel reprocessing plant in Rokkasho, Aomori, Japan. Photosynthetically fixed carbon is distributed into the leaf and the root compartments, and a part of the carbon accumulated in the leaf compartment is redistributed to the root compartment. The model parameters were estimated by using data obtained from exposure of the plant to CO2. The model estimates were in good agreement with the experimental observations, showing that the newly developed compartment model is applicable to assessment of the accumulation of C in Japanese radish plants around the nuclear facility. In this study, respiration rate was set to be proportional to the carbon mass of the compartment, though the respiration rate has been assumed generally to be proportional to the growth rate of the compartment. While the estimates using both respiration rates differed only slightly from each other, the ratio of the respiratory rate of the root to that of the leaf was too high in the case of the respiratory rate proportional to the growth rate. PMID- 23799497 TI - Source terms and attenuation lengths for estimating shielding requirements or dose analyses of proton therapy accelerators. AB - Proton therapy accelerators in the energy range of 100-300 MeV could potentially produce intense secondary radiation, which must be carefully evaluated and shielded for the purpose of radiation safety in a densely populated hospital. Monte Carlo simulations are generally the most accurate method for accelerator shielding design. However, simplified approaches such as the commonly used point source line-of-sight model are usually preferable on many practical occasions, especially for scoping shielding design or quick sensitivity studies. This work provides a set of reliable shielding data with reasonable coverage of common target and shielding materials for 100-300 MeV proton accelerators. The shielding data, including source terms and attenuation lengths, were derived from a consistent curve fitting process of a number of depth-dose distributions within the shield, which were systematically calculated by using MCNPX for various beam target shield configurations. The general characteristics and qualities of this data set are presented. Possible applications in cases of single- and double layer shielding are considered and demonstrated. PMID- 23799498 TI - Workshop report on atomic bomb dosimetry-residual radiation exposure: recent research and suggestions for future studies. AB - There is a need for accurate dosimetry for studies of health effects in the Japanese atomic bomb survivors because of the important role that these studies play in worldwide radiation protection standards. International experts have developed dosimetry systems, such as the Dosimetry System 2002 (DS02), which assess the initial radiation exposure to gamma rays and neutrons but only briefly consider the possibility of some minimal contribution to the total body dose by residual radiation exposure. In recognition of the need for an up-to-date review of the topic of residual radiation exposure in Hiroshima and Nagasaki, recently reported studies were reviewed at a technical session at the 57th Annual Meeting of the Health Physics Society in Sacramento, California, 22-26 July 2012. A one day workshop was also held to provide time for detailed discussion of these newer studies and to evaluate their potential use in clarifying the residual radiation exposures to the atomic-bomb survivors at Hiroshima and Nagasaki. Suggestions for possible future studies are also included in this workshop report. PMID- 23799499 TI - TL behavior of topaz-glass composite in various irradiation fields. AB - Topaz is a natural hard silicate mineral that has the potential to be used as a thermoluminescent dosimeter (TLD). It is difficult to manufacture chips of topaz and problematic to use its powder as TLDs. Topaz-glass composite (in the form of pellets) can be made easily and applied for radiation dosimetry. To produce pellets of topaz-glass composite in 2:1 wt (%), topaz powder was combined with commercial glass. The pellets with 6 mm diameter and 1 mm thickness were sintered in a furnace at 900 degrees C for 1 h. The composite pellets were irradiated with x-ray and gamma photons and alpha and beta particles. The pellets yielded two peaks in the glow curve; Peak 1 at temperature range 150-160 degrees C and Peak 2 at 250-260 degrees C. The intensity of Peak 2 rose linearly with the increase in absorbed dose. The intensity of Peak 2 was comparable with peaks for photons and beta irradiation but relatively low for alpha exposure. The reproducibility of the intensity of Peak 2 was within 5-8%. Two months after irradiation of the pellets, the fading of the intensity of Peak 2 was found to be about 7%. The topaz-glass composite can be used effectively and efficiently for dosimetry of alpha, beta, and gamma radiation. PMID- 23799500 TI - Effect of contrast material on radiation dose in an adult cardiac dual-energy CT using retrospective ECG-gating. AB - The purpose of this study was to determine the effect of contrast material and retrospective ECG-gating on radiation dose in an adult cardiac dual-energy computed tomography (DECT). Sixty-two patients underwent CT cardiac examination with a Somatom Definition Flash DECT using tube voltages of 100 kV without filter and 140 kV with a tin filter (mean effective mA s: arterial 72.39 and 62.94, venous 93.21 and 78.45, and late phase 134.5 and 118.2). The arterial and late phases were examined with retrospective ECG-gating, but gating was not used for the venous phase. Seventy milliliters (70 ml) iodinated contrast material (CM) was injected into the patient during examination. The effective doses (ED) were calculated from dose-length-product (DLP) and computed tomographic dose index volume (CTDIvol) using the latest k-factor (0.028). Pearson's correlation coefficient was used for statistical tests on continuous variables. Mean CTDIvol and DLP were lower in the late phase (10.15 +/- 1.5 mGy and 202.9 +/- 23 mGy cm) compared to the arterial phase (19.69 +/- 3 mGy and 394 +/- 90 mGy cm). Differences between the arterial and late phase were statistically significant (p = 0.005), and mean values for the late phase were 48.5% lower than mean values for the arterial phase. Mean CTDIvol and DLP were lower in venous (7.72 +/- 1 mGy and 154.3 +/- 17 mGy cm) compared to late phase (10.15 +/- 1.5 mGy and 202.9 +/- 23 mGy cm). The difference between venous and late phase was statistically significant (p < 0.001). The mean results for the venous phase were 24% lower than those for the late phase. This study shows that contrast material (CM) absorbs radiation significantly and increases dose by 48.5% in an adult cardiac dual-energy CT with retrospective ECG-gating. Care must be taken to determine the type, concentration, and volume of CM used for the scan. The dual-energy non-ECG gated technique decreased radiation dose by 24% compared to the ECG-gated technique. ECG-gated cardiac examination should be limited to patients with strong clinical indications. SNR and HU increased with decreasing energy. The image noise values showed a negligible difference in the arterial and late phase datasets, and this did not affect the diagnostic quality of the image evaluation. PMID- 23799501 TI - Radiation risk of malignant neoplasms in organs of main deposition for plutonium in the cohort of Mayak workers with regard to histological types. AB - This paper presents the results of analyses of the incidence of malignant neoplasms in lung, liver, and bone and associated connective tissues among Mayak nuclear workers exposed to both internally incorporated plutonium and to external gamma radiation. The study cohort included 22,373 individuals employed at the reactors and radiochemical and plutonium production facilities of the Mayak nuclear complex during 1948-1982 and followed up to the end of 2004. All analyses were carried out by Poisson regression, and the doses used were derived using a recently available update of organ doses, Mayak doses-2008. There was clear evidence for the linear association between internal plutonium dose and the risk of lung cancer. For males, there was evidence of a significant internal plutonium dose response for all histological types of lung cancer evaluated (adenocarcinoma, squamous-cell, and other epithelial); the estimated excess relative risk (ERR)/Gy for adenocarcinoma was the largest (ERR/Gy = 32.5; 95% CI: 16.3; 71.9), about 11-fold higher than that for squamous-cell lung cancer (ERR/Gy = 3.1; 95% CI: 0.3; 9.1). The relationship between liver cancer risk and plutonium exposure was best described by a linear-quadratic (LQ) function, but the LQ effect was diminished after restricting internal doses <2 Gy. Hepatocellular cancer was the most frequently observed type of liver cancer associated with internal plutonium exposure, and hemangiosarcomas were exclusively observed only at high internal plutonium doses (>4 Gy). For malignant neoplasms of bone and associated connective tissues, the trend was not statistically significant in relation to internal plutonium dose, but a statistically significantly higher risk (RR=13.7; 95% CI= 3.0; 58.5) was found among unmonitored female plutonium workers who were employed in the most hazardous plutonium production facility commissioned prior to 1950. PMID- 23799502 TI - Radiofrequency energy exposure from the Trilliant smart meter. AB - This paper reviews radiofrequency (RF) field levels produced by electric utility meters equipped with RF transceivers (so-called Smart Meters), focusing on meters from one manufacturer (Trilliant, Redwood City, CA, USA, and Granby, QC, Canada). The RF transmission levels are summarized based on publicly available data submitted to the U.S. Federal Communications Commission supplemented by limited independent measurements. As with other Smart Meters, this meter incorporates a low powered radiofrequency transceiver used for a neighborhood mesh network, in the present case using ZigBee-compliant physical and medium access layers, operating in the 2.45 GHz unlicensed band but with a proprietary network architecture. Simple calculations based on a free space propagation model indicate that peak RF field intensities are in the range of 10 mW m or less at a distance of more than 1-2 m from the meters. However, the duty cycle of transmission from the meters is very low (< 1%). Limited measurements identified pulses from the meter that were consistent with data reported by the vendor to the U.S. Federal Communications Commission. Limited measurements conducted in two houses with the meters were unable to clearly distinguish emissions from the meters from the considerable electromagnetic clutter in the same frequency range from other sources, including Wi-Fi routers and, when it was activated, a microwave oven. These preliminary measurements disclosed the difficulties that would be encountered in characterizing the RF exposures from these meters in homes in the face of background signals from other household devices in the same frequency range. An appendix provides an introduction to Smart Meter technology. The RF transmitters in wireless-equipped Smart Meters operate at similar power levels and in similar frequency ranges as many other digital communications devices in common use, and their exposure levels are very far below U.S. and international exposure limits. PMID- 23799503 TI - Comparison of measured and calculated dose rates near nuclear medicine patients. AB - Widely used release criteria for patients receiving radiopharmaceuticals (NUREG 1556, Vol. 9, Rev.1, Appendix U) are known to be overly conservative. The authors measured external exposure rates near patients treated with I, Tc, and F and compared the measurements to calculated values using point and line source models. The external exposure dose rates for 231, 11, and 52 patients scanned or treated with I, Tc, and F, respectively, were measured at 0.3 m and 1.0 m shortly after radiopharmaceutical administration. Calculated values were always higher than measured values and suggested the application of "self-shielding factors," as suggested by Siegel et al. in 2002. The self-shielding factors of point and line source models for I at 1 m were 0.60 +/- 0.16 and 0.73 +/- 0.20, respectively. For Tc patients, the self-shielding factors for point and line source models were 0.44 +/- 0.19 and 0.55 +/- 0.23, and the values were 0.50 +/- 0.09 and 0.60 +/- 0.12, respectively, for F (all FDG) patients. Treating patients as unshielded point sources of radiation is clearly inappropriate. In reality, they are volume sources, but treatment of their exposures using a line source model with appropriate self-shielding factors produces a more realistic, but still conservative, approach for managing patient release. PMID- 23799504 TI - Enhanced analysis methods to derive the spatial distribution of 131I deposition on the ground by airborne surveys at an early stage after the Fukushima Daiichi nuclear power plant accident. AB - This paper applies both new and well tested analysis methods to aerial radiological surveys to extract the I ground concentrations present after the March 2011 Fukushima Daiichi nuclear power plant (NPP) accident. The analysis provides a complete map of I deposition, an important quantity incalculable at the time of the accident due to the short half-life of I and the complexity of the analysis. A map of I deposition is the first step in conducting internal exposure assessments, population dose reconstruction, and follow-up epidemiological studies. The short half-life of I necessitates the use of aerial radiological surveys to cover the large area quickly, thoroughly, and safely. Teams from the U.S. Department of Energy National Nuclear Security Administration (DOE/NNSA) performed aerial radiological surveys to provide initial maps of the dispersal of radioactive material in Japan. This work reports on analyses performed on a subset of the initial survey data by a joint Japan-U.S. collaboration to determine I ground concentrations. The analytical results show a high concentration of I northwest of the NPP, consistent with the previously reported radioactive cesium deposition, but also shows a significant I concentration south of the plant, which was not observed in the original cesium analysis. The difference in the radioactive iodine and cesium patterns is possibly the result of differences in the ways these materials settle out of the air. PMID- 23799505 TI - Decontamination of radionuclides from skin: an overview. AB - The accident in Fukushima has emphasized the need to increase the capacity of health protection for exposed workers, first responders, and the general public in a major accident situation with release of radioactivity. Skin contamination is one of the most probable risks following major nuclear or radiological incidents, but this risk also exists and incidents can happen in industry, research laboratories, or in nuclear medicine departments. The aim of this paper is to provide an overview of the products currently used after skin contamination in order to highlight the needs and ways to improve the medical management of victims. From this review, it can be observed that the current use of these radiological decontamination products is essentially based on empiricism. In addition, some of these products are harsh and irritating, even toxic, possibly damaging the skin barrier. In some emergency situations in which clean water is in short supply, most of the current products cannot be used. Research on the mechanisms of action of decontaminating products is needed to develop a decontamination strategy. PMID- 23799506 TI - Species-dependent effective concentration of DTPA in plasma for chelation of 241Am. AB - Diethylenetriaminepentaacetic acid (DTPA) is a chelating agent that is used to facilitate the elimination of radionuclides such as americium from contaminated individuals. Its primary site of action is in the blood, where it competes with various biological ligands, including transferrin and albumin, for the binding of radioactive metals. To evaluate the chelation potential of DTPA under these conditions, the competitive binding of Am between DTPA and plasma proteins was studied in rat, beagle, and human plasma in vitro. Following incubation of DTPA and Am in plasma, the Am-bound ligands were fractionated by ultrafiltration and ion-exchange chromatography, and each fraction was assayed for Am content by gamma scintillation counting. Dose response curves of DTPA for Am binding were established, and these models were used to calculate the 90% maximal effective concentration, or EC90, of DTPA in each plasma system. The EC90 were determined to be 31.4, 15.9, and 10.0 MUM in rat, beagle, and human plasma, respectively. These values correspond to plasma concentrations of DTPA that maximize Am chelation while minimizing excess DTPA. Based on the pharmacokinetic profile of DTPA in humans, after a standard 30 MUmol kg intravenous bolus injection, the plasma concentration of DTPA remains above EC90 for approximately 5.6 h. Likewise, the effective duration of DTPA in rat and beagle were determined to be 0.67 and 1.7 h, respectively. These results suggest that species differences must be considered when translating DTPA efficacy data from animals to humans and offer further insights into improving the current DTPA treatment regimen. PMID- 23799511 TI - Fluorescent carboxylic and phosphonic acids: comparative photophysics from solution to organic nanoparticles. AB - Phosphonic and carboxylic fluorescent nanoparticles have been fabricated by direct reprecipitation in water. Their fluorescence properties strongly differ from those of the corresponding esters where strong H-bonding formation is prohibited. Comparative experiments between the two acid derivatives, differing only in their acid functions while keeping the same alkyl chain, have evidenced the peculiar behavior of the phosphonic acid derivative compared to its carboxylic analog. A dramatic emission quenching for the phosphonic acid in aprotic toluene could be observed while a fivefold increase in the fluorescence signal was observed for molecules assembled as nanoparticles. Such properties have been attributed on the theoretical basis to the formation of folded conformers in solution, leading to deactivation of the radiative excited state through intramolecular H-bonding. These studies evidence for the first time through time-resolved fluorescence measurements the stronger H-donating character of phosphonic acids compared to the carboxylic ones, and provide information on the degree of structural heterogeneity within the nanoparticles. They should pave the way for the rational fabrication of chelating acid fluorophores, able to complex metal oxides to yield stiff hybrid magnetofluorescent nanoparticles which are attracting considerable attention in the growing fields of bimodal imaging and vectorization applications. PMID- 23799510 TI - FAK-heterozygous mice display enhanced tumour angiogenesis. AB - Genetic ablation of endothelial focal adhesion kinase (FAK) can inhibit pathological angiogenesis, suggesting that loss of endothelial FAK is sufficient to reduce neovascularization. Here we show that reduced stromal FAK expression in FAK-heterozygous mice unexpectedly enhances both B16F0 and CMT19T tumour growth and angiogenesis. We further demonstrate that cell proliferation and microvessel sprouting, but not migration, are increased in serum-stimulated FAK-heterozygous endothelial cells. FAK-heterozygous endothelial cells display an imbalance in FAK phosphorylation at pY397 and pY861 without changes in Pyk2 or Erk1/2 activity. By contrast, serum-stimulated phosphorylation of Akt is enhanced in FAK-heterozygous endothelial cells and these cells are more sensitive to Akt inhibition. Additionally, low doses of a pharmacological FAK inhibitor, although too low to affect FAK autophosphorylation in vitro, can enhance angiogenesis ex vivo and tumour growth in vivo. Our results highlight a potential novel role for FAK as a nonlinear, dose-dependent regulator of angiogenesis where heterozygous levels of FAK enhance angiogenesis. PMID- 23799512 TI - Facile synthesis of a Cu-based MOF confined in macroporous carbon hybrid material with enhanced electrocatalytic ability. AB - The Cu-based MOF loaded on macroporous carbon (MPC) creates novel Cu-MOF-MPC hybrids for the first time. The obtained Cu-MOF-MPC composites are used as electrocatalysts for the oxidation of NADH and reduction of H2O2 in neutral solution. PMID- 23799513 TI - Socioeconomic status accounts for rapidly increasing geographic variation in the incidence of poor fetal growth. AB - Fetal growth is an important risk factor for infant morbidity and mortality. In turn, socioeconomic status is a key predictor of fetal growth; however, other sociodemographic factors and environmental effects may also be important. This study modelled geographic variation in poor fetal growth after accounting for socioeconomic status, with a fixed effect for socioeconomic status and a combination of spatially-correlated and spatially-uncorrelated random effects. The dataset comprised 88,246 liveborn singletons, aggregated within suburbs in Perth, Western Australia. Low socioeconomic status was strongly associated with an increased risk of poor fetal growth. An increase in geographic variation of poor fetal growth from 1999-2001 (interquartile odds ratio among suburbs = 1.20) to 2004-2006 (interquartile odds ratio = 1.40) indicated a widening risk disparity by socioeconomic status. Low levels of residual spatial patterns strengthen the case for targeting policies and practices in areas of low socioeconomic status for improved outcomes. This study indicates an alarming increase in geographic inequalities in poor fetal growth in Perth which warrants further research into the specific aspects of socioeconomic status that act as risk factors. PMID- 23799514 TI - Comment on "The structure and formation of hydrogen-bonded molecular networks on Au(111) surfaces revealed by scanning tunnelling and torsional-tapping atomic force microscopy" by V. V. Korolkov, N. Mullin, S. Allen, C. J. Roberts, J. K. Hobbs and S. J. B. Tendler, Phys. Chem. Chem. Phys., 2012, 14, 15909. PMID- 23799516 TI - Mortality and long-term virologic outcomes in children and infants treated with lopinavir/ritonavir. AB - BACKGROUND: There is scant data on young children receiving protease inhibitor based therapy in real-life resource-limited settings and on the optimal timing of therapy among children who survive infancy. Our aim was to evaluate outcomes at the Hospital del Nino, Panama, where children have been routinely treated with lopinavir/ritonavir (LPV/r)-based therapy since 2002. METHODS: Retrospective cohort analysis of all HIV-infected children enrolled in care between January 1, 1991, and June 1, 2011. Kaplan-Meier method and Cox proportional hazards regression were used to evaluate death, virologic suppression and virologic rebound. RESULTS: Of 399 children contributing 1944 person-years of follow-up, 254 (63.7%) were treated with LPV/r and 94 (23.6%) were never treated with antiretrovirals (ARVs). Among infants, improved survival was associated with male gender (hazard rate of death[HRdeath] 0.54, 95% confidence interval [CI]: 0.32 0.92) and treatment with highly active antiretroviral therapy (HRdeath 0.32, 95% CI: 0.12-0.83), whereas residence outside of Panama City was associated with poorer survival (HRdeath 1.72, 95% CI: 1.01-2.94). Among children who survived to 1 year of age without exposure to ARVs, LPV/r-based therapy improved survival (HRdeath 0.07, 95% CI: 0.01-0.33). Virologic suppression was achieved in 42.1%, 70.5% and 85.1% by 12, 24 and 60 months of follow-up among children treated with LPV/r. Virologic suppression was not associated with prior ARV exposure or age at initiation of therapy but was associated with residence outside of Panama City (HR suppression 1.93, 95% CI: 1.19-3.14). Patients with a baseline viral load >100,000 copies/mL were less likely to achieve suppression (HR suppression 0.37, 95% CI: 0.21-0.66). No children who achieved virologic suppression after initiating LPV/r died. CONCLUSIONS: LPV/r-based therapy improved survival not only in infants but also in children over 1 year of age. Age at initiation of LPV/r-based therapy or prior ARVs did not impact virologic outcomes. PMID- 23799515 TI - Prevalence and predictors of elevated aspartate aminotransferase-to-platelet ratio index in Latin American perinatally HIV-infected children. AB - BACKGROUND: Chronic liver disease has emerged as an important problem in adults with longstanding HIV infection, but data are lacking for children. We characterized elevated aspartate aminotransferase-to-platelet ratio index (APRI), a marker of possible liver fibrosis, in perinatally HIV-infected children. METHODS: The National Institute of Child Health and Human Development International Site Development Initiative enrolled HIV-infected children (ages 0.1-20.1 years) from 5 Latin American countries in an observational cohort from 2002 to 2009. Twice yearly visits included medical history, physical examination and laboratory evaluations. The prevalence (95% confidence interval) of APRI > 1.5 was calculated, and associations with demographic, HIV-related and liver related variables were investigated in bivariate analyses. RESULTS: APRI was available for 1012 of 1032 children. APRI was >1.5 in 32 (3.2%, 95% confidence interval: 2.2%-4.4%) including 2 of 4 participants with hepatitis B virus infection. Factors significantly associated with APRI > 1.5 (P < 0.01 compared with APRI <= 1.5) included country, younger age, past or current hepatitis B virus, higher alanine aminotransferase, lower total cholesterol, higher log10 current viral load, lower current CD4 count, lower nadir CD4 count, use of hepatotoxic nonantiretroviral (ARV) medications and no prior ARV use. Rates of APRI > 1.5 varied significantly by current ARV regimen (P = 0.0002), from 8.0% for no ARV to 3.2% for non-protease inhibitor regimens to 1.5% for protease inhibitor-based regimens. CONCLUSIONS: Elevated APRI occurred in approximately 3% of perinatally HIV-infected children. Protease inhibitor-based ARVs appeared protective whereas inadequate HIV control appeared to increase risk of elevated APRI. Additional investigations are needed to better assess potential subclinical, chronic liver disease in HIV-infected children. PMID- 23799517 TI - Predictors of adverse outcomes in HIV-1-infected children receiving combination antiretroviral treatment: results from a DREAM cohort in sub-Saharan Africa. AB - BACKGROUND: HIV-infected children have less access to combination antiretroviral therapy as compared with adults in resource-limited settings. Growth faltering, loss to follow-up (LTFU) and high mortality are frequently seen. METHODS: A retrospective cohort study was performed with parameters extracted from the Drug Resource Enhancement against AIDS and Malnutrition database for HIV-infected, antiretroviral naive children under 15 years presenting for care at 17 Drug Resource Enhancement against AIDS and Malnutrition centers in Mozambique, Malawi and Guinea between January 2005 to December 2008. Predictors of time-to-death, time-to-LTFU and persistence of malnutrition by Cox's regression and Kaplan-Meier were determined. RESULTS: 2215 children presented to care with 1343 (61%) being <= 5 years. At baseline, stunting and malnutrition occurred in 40% and 25%, respectively; 75% of 2149 children had CD4 cell percentages less than 20; median HIV RNA, log10 cp/mL, was 4.97 in 1927 patients. Over time 238 children died (10.7%; 2.7% person-years [PY]) 63 were LTFU (2.8%; 0.7% PY). By multivariate analysis, mortality was associated with virus load (hazards ratio: 1.19; confidence interval: 1.01-1.402, P = 0.038) and reduced weight-for-age Z scores (hazards ratio: 0.590; confidence interval: 0.53-0.66, P < 0.001). LTFU was associated with low weight-for-height Z scores (hazards ratio: 0.71; confidence interval: 0.51-0.97, P = 0.031). At 12 months after combination antiretroviral therapy, anthropometric parameters significantly improved in 1226 children (P < 0.001); virus load declined to <400 copies/mL in over 60%. CONCLUSIONS: Despite advanced HIV disease, children initiating combination antiretroviral therapy had mortality rates of 2.7% p/PY with overall attrition rates of 11.7% p/100 PY, with significant reversal of negative anthropometric markers, and improvement of immunological and virological parameters in children with 12 months of follow-up. PMID- 23799518 TI - Immune responses in infants whose mothers received Tdap vaccine during pregnancy. AB - BACKGROUND: The effect of maternal Tdap vaccination on infant immunologic responses to routine pediatric vaccines is unknown. METHODS: This was a cohort study of infants whose mothers received or did not receive Tdap vaccine during pregnancy. Maternal and cord blood samples were collected at delivery; infant blood samples were collected before and after primary series and booster dose of diphtheria, tetanus, and acellular pertussis (DTaP) and other vaccines. Geometric mean antibody concentrations or titers to pertussis, hepatitis B, tetanus, diphtheria, Haemophilus influenzae type b and polio antigens were measured. Mean maternal-to-cord blood antibody ratios were calculated. RESULTS: At delivery, maternal and cord antibody concentrations to pertussis antigens were higher in the Tdap group (n=16) than control group (n=54; maternal: 1.9- to 20.4-fold greater; cord: 2.7- to 35.5-fold greater). Increased antibody concentrations persisted for infants at first DTaP (3.2- to 22.8-fold greater). After primary series, antibody concentrations to pertussis antigens were lower in Tdap group (0.7- to 0.8-fold lower), except for fimbriae types 2 and 3 (FIM) (1.5-fold greater). Antibody concentrations to pertussis antigens before and after booster dose were comparable (prebooster: Tdap group 1.0- to 1.2-fold higher than controls; postbooster: 0.9- to 1.0-fold lower). Differences in FIM values at these time points are difficult to interpret, due to varying FIM content among DTaP vaccines administered to infants in both groups. CONCLUSIONS: Maternal Tdap immunization resulted in higher pertussis antibody concentrations during the period between birth and the first vaccine dose. Although slightly decreased immune responses following the primary series were seen compared with controls, differences did not persist following the booster. PMID- 23799519 TI - Demonstration of permanent porosity in flexible and guest-responsive organic zeolite analogs (now called MOFs). AB - In the late 1990s rigorous proof of coordination polymer framework or MOF integrity in the absence of guest molecules still needed to be developed. A study by Kepert and Rosseinsky presented X-ray crystal structure refinements as one of the first definitive demonstrations of the retention of structural integrity of a porous coordination polymer framework upon complete desolvation and guest re adsorption. PMID- 23799520 TI - ITP: the dilemma of treatment. PMID- 23799522 TI - Pediatric ovarian dysgerminoma presenting with hypercalcemia and chronic constipation: a case report. AB - Malignancy-associated hypercalcemia is a common finding among adult malignancies. However, the incidence of malignancy-induced hypercalcemia associated with germ cell tumor among pediatric patients is very rare. We describe a 9-year-old girl with an ovarian dysgerminoma presenting with chronic constipation and hypercalcemia. We review some of the causes of malignancy-associated hypercalcemia described in literature and treatment strategies. We also recommend considering oncological processes in the presence of hypercalcemia. PMID- 23799521 TI - The effects of propofol and ketamine on the cytokine levels of children with acute lymphoblastic leukemia. AB - The immune system of children with acute lymphoblastic leukemia (ALL) is affected by both the underlying disease and the chemotherapy. Children with ALL receive sedation for diagnostic and therapeutic procedures, which may contribute to immune competence alteration. The effects of propofol-ketamine combination on the immune system of children with ALL have not been investigated. This cohort study was designed to assess the immunomodulatory activity of the propofol-ketamine combination on proinflammatory and anti-inflammatory cytokines of children with ALL undergoing painful procedures. We enrolled 20 children with ALL undergoing bone marrow aspiration (BMA) and lumbar puncture with methotrexate. All children received sedation with IV ketamine (0.5 mg/kg) and propofol (3+/-2 mg/kg). Plasma concentration of cytokines interleukin (IL)-1beta, IL-2, IL-6, IL-10, IL-8, IL 12p70, and interferon-gamma before sedation for BMA was represented as T0, during lumbar puncture with methotrexate sedation 6 hours after T0 was represented as T1, and 24 hours after BMA was represented as T2. Sedation with propofol-ketamine combination did not modify the plasma concentration of the most measured cytokines and the T helper 1/2 ratio in children with ALL. There was a significant reduction in IL-8 concentration 24 hours after BMA associated with the concomitant administration of steroids and methotrexate. These data suggest that sedation with propofol-ketamine combination may not affect the immediate outcome of children with ALL. PMID- 23799523 TI - Children and adolescents with ALL are taller than expected at diagnosis. AB - We investigated whether the relative increased height of childhood acute lymphoblastic leukemia (ALL) survivors at diagnosis was due to referral bias, the height of California children, socio-economic status, or race/ethnicity. We reviewed the records of all Pediatric Oncology referrals to our institution from 1988 to 2007. Height at diagnosis, sex, age at and date of diagnosis, date of birth, diagnosis, race/ethnicity, and socio-economic status were evaluated. Heights were standardized by z score from age and sex norms for US children. Of the 883 cases, 180 were excluded (Down syndrome, noncancer diagnosis, data at relapse only, incorrect height measurement, or major growth disturbance). ALL patients were taller than those with other cancers and US children. Age at and date of diagnosis and date of birth had no effect. Whites, boys, and those with private insurance had higher height z scores. Multivariable analysis identified diagnosis and race/ethnicity as significant. ALL children and adolescents were taller and black and Asian children shorter than white children. The mean height increase for those with ALL was 1.3 cm. The reason for the increased height of these patients is unknown, but is not due to referral patterns, having childhood cancer, or the racial/ethnic makeup of California children. PMID- 23799524 TI - Multicentric plasma cell type of castleman disease in a child: difficulty in diagnosis and treatment. AB - Multicentric plasma cell variant of Castleman disease (CD) has rarely been reported and the optimal therapeutic approach is unknown, especially in childhood. In this case report, we discuss the case of a 7-year-old boy with multicentric plasma cell variant of CD, who presented with cervical lymphadenopathies, autoimmune hemolytic anemia, bone marrow insufficiency, pulmonary, renal, hepatic, and gastrointestinal involvement, emphasizing the difficulty in diagnosis and treatment approach. PMID- 23799525 TI - Idiopathic myelofibrosis in children: primary myelofibrosis, essential thrombocythemia, or transient process? AB - We report 3 pediatric cases of primary/idiopathic myelofibrosis (PMF/IMF). Two cases exhibited clinical courses not typically observed in adult patients in whom this process is much more common. One of these cases exhibited spontaneous clinical and bone marrow resolution, whereas the other case achieved near resolution of myelofibrosis in response to cytoreductive therapy alone. However, the third case of IMF that met diagnostic criteria for essential thrombocythemia with a JAK2V617F mutation had central venous thrombosis that resulted in blindness. PMF/IMF, a rare finding in children, does not seem to portend the same level of risk as seen in adults with the same process, thus less aggressive management may be appropriate. However, delayed diagnosis of mutation-associated PMF or essential thrombocythemia can lead to devastating consequences. We review the literature and discuss the complexities surrounding diagnosis, risk stratification, and management of pediatric PMF/IMF. PMID- 23799526 TI - International cooperation for the cure and prevention of severe hemoglobinopathies. AB - Thalassemia major (TM) is the most frequent life-threatening noninfectious disease of childhood in the Middle East, South Asia, and Pacific Islands where it accounts for a significant proportion of childhood mortality, morbidity, and related health care expenses. In spite of major advances in supportive care during the last decade, many patients in low-income and middle-income countries still fare poorly because of high treatment costs and lack of accessible multidisciplinary teams, not to consider the risk of blood-borne infections, primarily hepatitis C. In selected low-risk patients with a compatible sibling, TM is highly curable by bone marrow transplantation (BMT), which also improves the quality of life and is cost-effective. Starting in 2008, the Cure2Children Foundation (C2C), an Italian Non-Governmental Organization, has supported a BMT network in Pakistan, which during 2012 was extended to India. The primary aim of this project was to assess feasibility, outcomes, and costs of matched-related BMT for thalassemia in young low-risk children using a well-established and tolerable strategy. A total of 100 matched-related BMTs have been performed to date by partner institutions within this C2C-supported network; in the 50 low risk cases with TM, over 90% disease-free survival was obtained with procedure expenses within 10,000 USD/BMT, that is, an outcome comparable to that obtained in affluent countries but with a fraction of the expenses. This cure rate was also obtained in start-up BMT centers (1 in Pakistan and 1 in India) within a structured and intensive cooperation program. Twinning and other international cooperation strategies based on shared principles and a common vision may substantially facilitate access to BMT. PMID- 23799527 TI - Placental mesenchymal dysplasia and fetal hematologic disorder. AB - Placental mesenchymal dysplasia (PMD) is a rare, recently recognized placental vascular anomaly. About 20% of patients with this placental anomaly have Beckwith Wiedemann syndrome. We report a case of a phenotypically normal neonate with anemia and thrombocytopenia associated with PMD. Histologic examination of the placenta showed findings consistent with PMD, including chorangioma. The patient's hematologic abnormalities resolved during the week following birth. Normal phenotypic fetuses with PMD seem to exhibit hematologic disorders at birth in some cases, especially in the presence of chorangioma. PMID- 23799531 TI - Copper and silver complexes bearing flexible hybrid scorpionate ligand mpBm. AB - The addition of flexible scorpionate ligand, [mpBm]-{i.e. HB(mt)2(mp), where mt = methyl-2-mercaptoimidazole and mp = 2-mercaptopyridine} to group eleven centres is reported for the first time. The coordination of this hybrid ligand to copper(I) and silver(I) centres in the presence of triphenylphosphine and trialkylphosphine co-ligands has been investigated. The trialkylphosphines coordinates to both copper and silver centres while the less basic triarylphosphine only successfully coordinates to the copper centre. Structural characterisation of [Cu{HB(mt)2(mp)}(PPh3)], [Cu{HB(mt)2(mp)}(PCy3)] and [Ag{HB(mt)2(mp)}(PCy3)] confirm kappa3-SSH coordination modes for ligand where one of the mt 'arms' and the mp 'arm' of the scorpionate ligand are coordinated to the metal centre. The second mt 'arm' remains uncoordinated in all three complexes. A comparison has been made with the parent sulfur based scorpionate ligand, [Tm]-{HB(mt)3}. PMID- 23799528 TI - Moderation of antipsychotic-induced weight gain by energy balance gene variants in the RUPP autism network risperidone studies. AB - Second-generation antipsychotic exposure, in both children and adults, carries significant risk for excessive weight gain that varies widely across individuals. We queried common variation in key energy balance genes (FTO, MC4R, LEP, CNR1, FAAH) for their association with weight gain during the initial 8 weeks in the two NIMH Research Units on Pediatric Psychopharmacology Autism Network trials (N=225) of risperidone for treatment of irritability in children/adolescents aged 4-17 years with autism spectrum disorders. Variants in the cannabinoid receptor (CNR)-1 promoter (P=1.0 * 10(-6)), CNR1 (P=9.6 * 10(-5)) and the leptin (LEP) promoter (P=1.4 * 10(-4)) conferred robust-independent risks for weight gain. A model combining these three variants was highly significant (P=1.3 * 10(-9)) with a 0.85 effect size between lowest and highest risk groups. All results survived correction for multiple testing and were not dependent on dose, plasma level or ethnicity. We found no evidence for association with a reported functional variant in the endocannabinoid metabolic enzyme, fatty acid amide hydrolase, whereas body mass index-associated single-nucleotide polymorphisms in FTO and MC4R showed only trend associations. These data suggest a substantial genetic contribution of common variants in energy balance regulatory genes to individual antipsychotic-associated weight gain in children and adolescents, which supersedes findings from prior adult studies. The effects are robust enough to be detected after only 8 weeks and are more prominent in this largely treatment naive population. This study highlights compelling directions for further exploration of the pharmacogenetic basis of this concerning multifactorial adverse event. PMID- 23799530 TI - Biomarkers in amyloid-beta immunotherapy trials in Alzheimer's disease. AB - Drug candidates directed against amyloid-beta (Abeta) are mainstream in Alzheimer's disease (AD) drug development. Active and passive Abeta immunotherapy is the principle that has come furthest, both in number and in stage of clinical trials. However, an increasing number of reports on major difficulties in identifying any clinical benefit in phase II-III clinical trials on this type of anti-Abeta drug candidates have caused concern among researchers, pharmaceutical companies, and other stakeholders. This has provided critics of the amyloid cascade hypothesis with fire for their arguments that Abeta deposition may merely be a bystander, and not the cause, of the disease or that the amyloid hypothesis may only be valid for the familial form of AD. On the other hand, most researchers argue that it is the trial design that will need refinement to allow for identifying a positive clinical effect of anti-Abeta drugs. A consensus in the field is that future trials need to be performed in an earlier stage of the disease and that biomarkers are essential to guide and facilitate drug development. In this context, it is reassuring that, in contrast to most brain disorders, research advances in the AD field have led to both imaging (magnetic resonance imaging (MRI) and PET) and cerebrospinal fluid (CSF) biomarkers for the central pathogenic processes of the disease. AD biomarkers will have a central role in future clinical trials to enable early diagnosis, and Abeta biomarkers (CSF Abeta42 and amyloid PET) may be essential to allow for testing a drug on patients with evidence of brain Abeta pathology. Pharmacodynamic Abeta and amyloid precursor protein biomarkers will be of use to verify target engagement of a drug candidate in humans, thereby bridging the gap between mechanistic data from transgenic AD models (that may not be relevant to the neuropathology of human AD) and large and expensive phase III trials. Last, downstream biomarker evidence (CSF tau proteins and MRI volumetry) that the drug ameliorates neurodegeneration will, together with beneficial clinical effects on cognition and functioning, be essential for labeling an anti-Abeta drug as disease modifying. PMID- 23799532 TI - Delayed time-point 18F-FDG PET CT imaging enhances assessment of atherosclerotic plaque inflammation. AB - OBJECTIVE: The aim of this study was to determine the ideal circulation time of fluorine-18 fluorodeoxyglucose (F-FDG) in order to detect and quantify atherosclerotic plaque inflammation with PET computed tomography (CT) imaging. METHODS: Fifteen patients underwent multiple time-point imaging at ~60, 120, and 180 min after F-FDG administration. For each time point, global assessment of aortic and carotid F-FDG uptake was determined qualitatively by visual assessment and semiquantitatively by calculation of the mean and maximum standardized uptake values (SUV) and the corresponding target-to-background ratio (TBR). RESULTS: Delayed imaging achieved significant improvement in visualization of atherosclerotic plaque inflammation [Friedman's chi statistic (d.f.=2, n=15)=24.13, P<0.001, Kendall's W=0.80]. This observation was confirmed by semiquantitative image analysis. At 1 h, the aortic and carotid SUVmean calculated TBR was 1.05 [95% confidence interval (CI)=0.98, 1.11] and 0.88 (95% CI=0.81, 0.96), respectively. At 3 h, the TBR significantly increased to 1.57 (95% CI=1.28, 1.86; P=0.001) for the aorta and to 1.61 (95% CI=1.36, 1.87; P<0.001) for the carotid arteries. SUVmax-calculated TBRs showed a similar increase over time. CONCLUSION: One- and 2-h F-FDG PET CT imaging is suboptimal for global assessment of atherosclerotic plaque inflammation compared with imaging at 3 h. Our data support the utilization of 3-h delayed imaging to obtain optimal data for the detection and quantification of atherosclerotic plaque inflammation in human arteries. PMID- 23799533 TI - Socioeconomic and early-life factors and risk of being overweight or obese in children of Swedish- and foreign-born parents. AB - BACKGROUND: Ethnic minorities/immigrants have differential health as compared with natives. The epidemic in child overweight/obesity (OW/OB) in Sweden is leveling off, but lower socioeconomic groups and immigrants/ethnic minorities may not have benefited equally from this trend. We investigated whether nonethnic Swedish children are at increased risk for being OW/OB and whether these associations are mediated by parental socioeconomic position (SEP) and/or early life factors such as birth weight, maternal smoking, BMI, and breastfeeding. METHODS: Data on 10,628 singleton children (51% boys, mean age: 4.8 y, born during the period 2000-2004) residing in Uppsala were analyzed. OW/OB was computed using the International Obesity Task Force's sex- and age-specific cutoffs. The mother's nativity was used as proxy for ethnicity. Logistic regression was used to analyze ethnicity-OW/OB associations. RESULTS: Children of North African, Iranian, South American, and Turkish ethnicity had increased odds for being overweight/obese as compared with children of Swedish ethnicity (adjusted odds ratio (OR): 2.60 (95% confidence interval (CI): 1.57-4.27), 1.67 (1.03-2.72), 3.00 (1.86-4.80), and 2.90 (1.73-4.88), respectively). Finnish children had decreased odds for being overweight/obese (adjusted OR: 0.53 (0.32 0.90)). CONCLUSION: Ethnic differences in a child's risk for OW/OB exist in Sweden that cannot be explained by SEP or maternal or birth factors. As OW/OB often tracks into adulthood, more effective public health policies that intervene at an early age are needed. PMID- 23799534 TI - Dose-dependent neuroprotection of VEGF165 in Huntington's disease striatum. AB - Huntington's disease (HD) is a devastating neurodegenerative disorder caused by abnormal polyglutamine expansion in the huntingtin protein (Exp-Htt). Currently, there are no effective treatments for HD. We used bidirectional lentiviral transfer vectors to generate in vitro and in vivo models of HD and to test the therapeutic potential of vascular endothelial growth factor 165 (VEGF165). Lentiviral-mediated expression of Exp-Htt caused cell death and aggregate formation in human neuroblastoma SH-SY5Y and rat primary striatal cultures. Lentiviral-mediated VEGF165 expression was found to be neuroprotective in both of these models. Unilateral stereotaxic vector delivery of Exp-Htt vector in adult rat striatum led to progressive inclusion formation and striatal neuron loss at 10 weeks post-transduction. Coinjection of a lower dose VEGF165 significantly attenuated DARPP-32(+) neuronal loss, enhanced NeuN staining and reduced Exp-Htt aggregation. A tenfold higher dose VEGF165 led to overt neuronal toxicity marked by tissue damage, neovascularization, extensive astrogliosis, vascular leakage, chronic inflammation and distal neuronal loss. No overt behavioral phenotype was observed in these animals. Expression of VEGF165 at this higher dose in the brain of wild-type rats led to early mortality with global neuronal loss. This report raises important safety concerns about unregulated VEGF165 CNS applications. PMID- 23799535 TI - Biodegradable lipids enabling rapidly eliminated lipid nanoparticles for systemic delivery of RNAi therapeutics. AB - In recent years, RNA interference (RNAi) therapeutics, most notably with lipid nanoparticle-based delivery systems, have advanced into human clinical trials. The results from these early clinical trials suggest that lipid nanoparticles (LNPs), and the novel ionizable lipids that comprise them, will be important materials in this emerging field of medicine. A persistent theme in the use of materials for biomedical applications has been the incorporation of biodegradability as a means to improve biocompatibility and/or to facilitate elimination. Therefore, the aim of this work was to further advance the LNP platform through the development of novel, next-generation lipids that combine the excellent potency of the most advanced lipids currently available with biodegradable functionality. As a representative example of this novel class of biodegradable lipids, the lipid evaluated in this work displays rapid elimination from plasma and tissues, substantially improved tolerability in preclinical studies, while maintaining in vivo potency on par with that of the most advanced lipids currently available. PMID- 23799537 TI - A heterozygous missense SCN5A mutation associated with early repolarization syndrome. AB - The genetic background of early repolarization syndrome (ERS) has not been fully understood. In this study, we identified a missense SCN5A mutation and a polymorphism in a patient with ERS and characterized the functional consequences of the two variants. The functional consequences of mutant channels were investigated with the patch-clamp technique, immunocytochemical studies and real time PCR. A 19-year-old female proband with recurrent syncope had a documented electrocardiogram with ventricular fibrillation (VF) proceeded by large J waves in leads I, II, III, aVF and V2-V6. Genetic analysis revealed that the patient carried a missense mutation of c.4297 G>C and a synonymous polymorphism of T5457C on the same allele of the SCN5A gene. Patch-clamp experiments demonstrated that the c.4297 G>C mutation significantly reduced the sodium current (INa) density and altered the channel kinetics. Immunocytochemical studies demonstrated that the mutation dramatically inhibited the expression of sodium channels in the cell membrane and in the cytoplasm, although the mRNA levels remained in the normal range. Noteworthy, the reduction in INa density may be partially restored from the co-existence of the T5457C polymorphism on the same allele by the upregulation of mRNA levels. In conclusion, our study indicated that the c.4297 G>C mutation caused the 'loss-of-function' of sodium channels that may account for the clinical phenotype of ERS. The reduction in INa density was due to a decreased number of sodium channels caused by abnormal translation processes. The T5457C polymorphism partially rescued the INa density of the mutant channels by the upregulation of mRNA levels. PMID- 23799536 TI - Scara1 deficiency impairs clearance of soluble amyloid-beta by mononuclear phagocytes and accelerates Alzheimer's-like disease progression. AB - In Alzheimer's disease, soluble amyloid-beta causes synaptic dysfunction and neuronal loss. Receptors involved in clearance of soluble amyloid-beta are not known. Here we use short hairpin RNA screening and identify the scavenger receptor Scara1 as a receptor for soluble amyloid-beta expressed on myeloid cells. To determine the role of Scara1 in clearance of soluble amyloid-beta in vivo, we cross Scara1 null mice with PS1-APP mice, a mouse model of Alzheimer's disease, and generate PS1-APP-Scara1-deficient mice. Scara1 deficiency markedly accelerates Abeta accumulation, leading to increased mortality. In contrast, pharmacological upregulation of Scara1 expression on mononuclear phagocytes increases Abeta clearance. This approach is a potential treatment strategy for Alzheimer's disease. PMID- 23799538 TI - Effect of Cd(II) and Se(IV) exposure on cellular distribution of both elements and concentration levels of glyoxal and methylglyoxal in Lepidium sativum. AB - In this work, the effect of cadmium (0-5.0 mg L(-1) as cadmium chloride, Cd(II)) and selenium (0-2.0 mg L(-1) as sodium selenite, Se(IV)) was studied in Lepidium sativum with specific focus on glyoxal (GO) and methylglyoxal (MGO) and on the cellular distribution of both elements under different exposure conditions. The concentrations of two reactive alpha-ketoaldehydes present as natural metabolites and as by-products of lipid peroxidation, were increased in plants treated with Cd(II), providng complementary experimental evidence on element phytotoxicity in garden cress, in terms of oxidative damage. Even though for higher than 1.0 mg L( 1) Se in medium similar adverse effect was found, under simultaneous exposure to both elements the changes in GO and MGO concentrations were clearly attenuated as compared to a single stressor treatment. This effect was accompanied by lower uptake of the two elements, significant decrease of their relative distribution in the fraction containing polar compounds and their increase in fraction corresponding to insoluble cell fragments/components, suggesting that the direct in vivo interaction between two element forms might be involved in the favorable effects of simultaneous treatment with Cd(II) + Se(IV). The fluorescence spectra obtained for biomass extracts corresponding to different exposure conditions suggested possible in vivo formation of CdSe quantum dots; however further studies are needed for ultimate identification and characterization of such nanoparticulate species. PMID- 23799539 TI - A microiterative intrinsic reaction coordinate method for large QM/MM systems. AB - Intrinsic reaction coordinate (IRC) computations are a valuable tool in theoretical studies of chemical reactions, but they can usually not be applied in their current form to handle large systems commonly described by quantum mechanics/molecular mechanics (QM/MM) methods. We report on a development that tackles this problem by using a strategy analogous to microiterative transition state optimization. In this approach, the IRC equations only govern the motion of a core region that contains at least the atoms directly involved in the reaction, while the remaining degrees of freedom are relaxed after each IRC step. This strategy can be used together with any existing IRC procedure. The present implementation covers the stabilized Euler, local quadratic approximation, and Hessian predictor-corrector algorithms for IRC calculations. As proof of principle, we perform tests at the QM level on small gas-phase systems and validate the results by comparisons with standard IRC procedures. The broad applicability of the method is demonstrated by IRC computations for two enzymatic reactions using standard QM/MM setups. PMID- 23799541 TI - Cytotoxic role of advanced glycation end-products in PC12 cells treated with beta amyloid peptide. AB - Alzheimer's disease (AD) is the most common type of dementia afflicting the elderly. Recent studies have increasingly suggested that a high concentration of advanced glycation end products (AGEs) may be important in AD pathogenesis. However, the mechanisms and pathways involved remain unknown. The aim of this study was to explore whether the mechanism of the effect of AGEs on Abeta-PC12 cells [PC12 cells treated with beta-amyloid (Abeta) peptide] was associated with oxidative stress; and to study whether inhibiting the activity of the receptor for AGE (RAGE) attenuated the toxic effect of AGEs and Abeta on PC12 cells. Several PC12 cells were pretreated with Abeta, and were then treated with different concentrations of AGEs. Other PC12 cells were treated with trypsin, a pancreatic protein enzyme and an inhibitor of RAGE, and were then treated with Abeta and AGEs. Apoptosis was measured by flow cytometry (FCM) and cell viability was measured by MTT assay. RAGE and nuclear factor-kappaB (NF-kappaB) were measured by reverse transcription-polymerase chain reaction (RT-PCR) assay. With an increase in AGE concentration, the viability of Abeta-PC12 cells treated with AGEs decreased. However, the Abeta-PC12 cell viability was greater in the trypsin group than in the non-trypsin group. Cell apoptosis rates and mRNA expression of RAGE and NF-kappaB in Abeta-PC12 cells treated with AGEs were significantly higher than in the Abeta-PC12 cells. AGEs and Abeta were neurotoxic, and RAGE triggered the neural cytotoxic role of AGEs in Abeta-PC12 cells. The molecular mechanisms may be connected with the expression of NF-kappaB and apoptosis mediated by RAGE. Inhibiting the activity of RAGE may mitigate the toxic effect of AGEs and Abeta on neural cells. PMID- 23799542 TI - Stability and in vitro digestibility of emulsions containing lecithin and whey proteins. AB - The effect of pH and high-pressure homogenization on the properties of oil-in water (O/W) emulsions stabilized by lecithin and/or whey proteins (WPI) was evaluated. For this purpose, emulsions were characterized by visual analysis, droplet size distribution, zeta potential, electrophoresis, rheological measurements and their response to in vitro digestion. Lecithin emulsions were stable even after 7 days of storage and WPI emulsions were unstable only at pH values close to the isoelectric point (pI) of proteins. Systems containing the mixture of lecithin and WPI showed high kinetic instability at pH 3, which was attributed to the electrostatic interaction between the emulsifiers oppositely charged at this pH value. At pH 5.5 and 7, the mixture led to reduction of the droplet size with enhanced emulsion stability compared to the systems with WPI or lecithin. The stability of WPI emulsions after the addition of lecithin, especially at pH 5.5, was associated with the increase of droplet surface charge density. The in vitro digestion evaluation showed that WPI emulsion was more stable against gastrointestinal conditions. PMID- 23799543 TI - A TaON nano-photocatalyst with low surface reduction defects for effective mineralization of chlorophenols under visible light irradiation. AB - TaON nanoparticles with low surface reduction defect sites were successfully constructed by a simple nitridation approach using Ta2O5.nH2O as a precursor. Large amounts of crystal water in Ta2O5.nH2O are considered as a parclose to prohibit Ta(5+) from being reduced in the nitridation process with NH3 gas. Urea was also used in the synthesis, acting as a co-nitridation agent together with NH3 but also as a porogen for creating nanopores in TaON frameworks. The as prepared TaON catalyst was evaluated by environmental purification of organic pollutants in water, as exemplified here by mineralization of phenol and its chloroderivatives in aqueous phase under visible light irradiation. Results revealed that a lower defect density of TaON, as well as its nanopore structure and smaller particle size, contribute to the promotion in both electron-hole separation and interfacial charge-transfer in materials surface/interface, being the main reasons for the enhanced photocatalytic performance. PMID- 23799544 TI - Assembly of naphthalenediimide conjugated peptides: aggregation induced changes in fluorescence. AB - Naphthalenediimide appended peptide based self-assembly was studied. Interestingly, an aggregation induced drastic change in the fluorescence property and gel formation were observed depending on the solvent composition (chloroform : methylcyclohexane) at a fixed concentration of 1.6 mM at room temperature. PMID- 23799545 TI - Lentiviral-mediated p38 MAPK RNAi attenuates aldosterone-induced myocyte apoptosis. AB - Aldosterone-induced myocyte apoptosis is an important component of cardiovascular disease. While the p38 mitogen-activated protein kinase (p38 MAPK) pathway has been shown to be crucial in myocyte apoptosis, whether aldosterone induces myocyte apoptosis through this pathway remains unclear. In the present study, three individual strands of p38 MAPK short hairpin RNA (ShRNA), delivered by lentiviral vectors (PGLV), were constructed and used to explore the role of p38 MAPK pathway activation in aldosterone-mediated myocyte apoptosis in cultured myocytes and normotensive rats. Aldosterone stimulation increased myocyte apoptosis, caspase-3 expression levels and p38 MAPK mRNA and protein expression levels in vitro and in vivo. PGLV-ShRNA3 transduction decreased aldosterone mediated myocyte apoptosis and p38 MAPK mRNA and protein expression levels in vitro (all P<0.01). PGLV-ShRNA3 transduction significantly decreased aldosterone mediated myocyte apoptosis, p38 MAPK mRNA and protein expression levels in normotensive rats (P<0.01, P<0.01 and P<0.05, respectively). Results from the present study suggest that aldosterone directly induces myocyte apoptosis through the p38 MAPK pathway and the gene silencing of p38 MAPK may protect cardiac myocytes from aldosterone-mediated apoptosis. PMID- 23799546 TI - Inhibition of late-stage autophagy synergistically enhances pyrrolo-1,5 benzoxazepine-6-induced apoptotic cell death in human colon cancer cells. AB - The pyrrolo-1,5-benzoxazepines (PBOXs) are a novel group of selective apoptotic agents displaying promising therapeutic potential in both ex vivo chemotherapy refractory patient samples and in vivo murine carcinoma models. In this report, we present novel data concerning the induction of autophagy by the PBOXs in adenocarcinoma-derived colon cancer cells. Autophagy is a lysosome-dependent degradative pathway recently associated with chemotherapy. However, whether autophagy facilitates cell survival in response to chemotherapy or contributes to chemotherapy-induced cell death is highly controversial. Autophagy was identified by enhanced expression of LC3B-II, an autophagosome marker, an increase in the formation of acridine orange-stained cells, indicative of increased vesicle formation and electron microscopic confirmation of autophagic structures. The vacuolar H+ ATPase inhibitor bafilomycin-A1 (BAF-A1) inhibited vesicle formation and enhanced the apoptotic potential of PBOX-6. These findings suggest a cytoprotective role of autophagy in these cells following prolonged exposure to PBOX-6. Furthermore, BAF-A1 and PBOX-6 interactions were determined to be synergistic and caspase-dependent. Potentiation of PBOX-6-induced apoptosis by BAF-A1 was associated with a decrease in the levels of the anti-apoptotic protein, Mcl-1. The data provide evidence that autophagy functions as a survival mechanism in colon cancer cells to PBOX-6-induced apoptosis and a rationale for the use of autophagy inhibitors to further enhance PBOX-6-induced apoptosis in colon cancer. PMID- 23799547 TI - Rosuvastatin prevents pressure overload-induced myocardial hypertrophy via inactivation of the Akt, ERK1/2 and GATA4 signaling pathways in rats. AB - Pressure overload-induced myocardial hypertrophy is associated with a poor prognosis in humans and contributes to the development of cardiac arrhythmias, diastolic dysfunction and ultimate congestive heart failure. 3-Hydroxy-3 methylglutaryl-CoA (HMG-CoA) reductase inhibitors, also known as statins, have been previously shown to induce regression of myocardial hypertrophy in aortic banding models. However, there is limited knowledge regarding the underlying molecular mechanisms. Therefore, we hypothesized that the myocardial hypertrophy related signaling pathways protein kinase B (Akt), extracellular signal-regulated kinases 1 or 2 (ERK1/2) and GATA binding protein 4 (GATA4) activation pathways constitute targets of rosuvastatin (RSV). Therefore, the above-mentioned activation pathways were hypothesized to be involved in the regression of pressure overload-induced myocardial hypertrophy treated by RSV. Twenty-eight Wistar rats were randomly allocated into 4 groups: the sham operation-vehicle (SH V), abdominal aortic constriction-vehicle (AAC-V), abdominal aortic constriction RSV 10 mg/kg/day (AAC-LO) and the abdominal aortic constriction-RSV 20 mg/kg/day (AAC-HI) group. Following the establishment of the abdominal aorta constriction model, we investigated the effect of RSV, a new hydrophilic statin, on abdominal aortic constriction-induced myocardial hypertrophy as well as the underlying intercellular signaling pathways after 5 days and 4 weeks of drug intervention. Moreover, echocardiographic features and the left ventricular weight to final body weight ratio (LVW/BW) were determined. Cross-sectional areas (CSAs) of cardiomyocytes were assessed by hematoxylin and eosin (H&E) staining. Atrial natriuretic factor (ANF), beta-myosin heavy chain (beta-MHC) and peroxisome proliferator-activated receptor alpha (PPARalpha) messenger RNA (mRNA) expression was assessed using RT-PCR. The phosphorylation of Akt, ERK1/2 and GATA4 were also examined using western blot analysis. Our results showed that RSV significantly attenuates pressure overload-induced myocardial hypertrophy by preventing myocardial hypertrophy-related activation of Akt, ERK1/2 and GATA4 signaling pathways. PMID- 23799548 TI - Immunomodulatory effects of polysaccharopeptide in immunosuppressed mice induced by cyclophosphamide. AB - Polysaccharopeptide (PSP) is well known for its immunoregulatory effects. In the present study, the effect of PSP on white blood cell (WBC) count, T lymphocyte subsets, B lymphocytes, Th1/Th2 balance and negative immune regulators was investigated using an immunosuppressed mouse model. The results demonstrated that the WBC count and the absolute number of CD3+CD4+ T cells, CD3+CD8+ T cells and CD3-CD19+ B cells in the peripheral blood were increased in PSP-treated groups as compared with the cyclophosphamide (Cy) group. In addition, PSP reduced interleukin (IL)-4 and GATA binding protein 3 (GATA-3) mRNA relative expression levels and elevated the ratios of IL-2/IL-4 and the transcription factors, T-box containing protein/GATA-3. The relative mRNA expression levels of the forkhead/winged-helix transcription factor box protein 3 (Foxp3), programmed death-1 (PD-1) and IL-10 were also downregulated by PSP. These observations indicate that the immunoregulatory effects of PSP are associated with restoration of WBC number, improving the absolute number of T lymphocyte subsets and B lymphocytes, inducing the Th1/Th2 response and downregulating the negative immune regulators, Foxp3, PD-1 and IL-10. PMID- 23799549 TI - The effect of MAPK inhibitors and ROS modulators on cell growth and death of H2O2 treated HeLa cells. AB - Reactive oxygen species (ROS) influence the signaling of mitogen-activated protein kinases (MAPKs) involved in cell survival and death. In the present study, the toxicological effect of hydrogen peroxide (H2O2) on HeLa cervical cancer cells was evaluated following treatment with MAPK inhibitors [MAP kinase or ERK kinase (MEK), c-Jun N-terminal kinase (JNK) or p38], N-acetyl cysteine (NAC) and propyl gallate (PG) (well-known antioxidants), or L-buthionine sulfoximine [BSO; an inhibitor of glutathione (GSH) synthesis]. Treatment with 100 uM H2O2 inhibited the growth of HeLa cells and induced cell death, which was accompanied by loss of the mitochondrial membrane potential (MMP; DeltaPsim). H2O2 did not induce any specific phase arrests of the cell cycle. ROS levels increased, while GSH levels decreased in H2O2-treated HeLa cells after 1 and 24 h of treatment. The MAPK inhibitors enhanced H2O2-induced HeLa cell death, while only p38 inhibitor increased ROS levels. Both NAC and PG attenuated H2O2-induced HeLa cell growth inhibition and death together with the suppression of ROS levels. BSO increased ROS levels in H2O2-treated HeLa cells without increasing cell death. The levels of MMP (DeltaPsim) loss and GSH depletion were not closely associated with the levels of apoptosis in HeLa cells treated with the MAPK inhibitors, NAC, PG or BSO, in the presence of H2O2. In conclusion, H2O2 induced HeLa cell growth inhibition and death. MAPK inhibitors generally enhanced H2O2 induced HeLa cell death. In particular, p38 inhibitor increased ROS levels in H2O2-treated HeLa cells, while NAC and PG attenuated H2O2-induced HeLa cell death by suppressing ROS levels. PMID- 23799550 TI - Evaluation of left ventricular systolic function with pulsed wave tissue Doppler in rheumatic mitral stenosis. AB - BACKGROUND: Mitral stenosis (MS) is still the most common complication of acute rheumatic fever in Turkey. Rheumatic carditis affects not only cardiac valves but also myocardium. In this study, we aimed to evaluate the subclinical left ventricular (LV) systolic dysfunction and contraction of short and long axial circumferential and longitudinal fibers by pulsed wave tissue Doppler in rheumatic MS patients who have preserved LV systolic function in 2D echocardiography. METHODS: Fifteen severe, 20 moderate rheumatic MS patients hospitalized for mitral balloon valvuloplasty, and 15 patients who had normal echocardiographic findings were included in the study. After routine conventional transthoracic echocardiographic examination, LV myocardial systolic velocities were evaluated with pulsed wave tissue Doppler in the short and long axis with simultaneous electrocardiographic monitoring. RESULTS: Long axis first systolic velocity (SW1) of mild-moderate and severe MS was much lower than normal group (10.7 +/- 2.3 in normal group vs. 7.9 +/- 1.3 in mild-moderate MS group vs. 6.2 +/- 1.4 in severe MS group, p < 0.001). Long axis Q-SW1 duration was longer in mild-moderate MS group (145 +/- 32 in normal group vs. 199 +/- 43 in mild moderate MS group, p = 0.001). Short axis Q-SW2 duration was longer in normal group compared to mild-moderate and severe MS groups (298 +/- 41 in normal group vs. 245 +/- 37 in mild-moderate MS group vs. 234 +/- 26 in severe MS group, p < 0.001). Significant correlation between mitral valve area and SW1, Q-SW1 was determined (p = 0.01). CONCLUSIONS: Even if LV functions are normal with conventional 2D echocardiography, subclinical systolic dysfunction exists in MS. Also, there is a dyssynchrony between contraction of longitudinal and circumferential myofibrils. PMID- 23799551 TI - Impaired global and segmental myocardial deformation assessed by two-dimensional speckle tracking echocardiography in patients with vitamin B12 deficiency. AB - BACKGROUND: Contrary effects of vitamin B12 deficiency have been shown on the cardiovascular system. Aim of our study was to analyze left ventricular (LV) myocardial deformation, by using the two dimensional (2D) speckle tracking echocardiography (STE) in patients with vitamin B12 deficiency and normal LV ejection fraction. METHODS: Twenty-five patients with vitamin B12 deficiency (B12 levels < 200 pg/mL; mean age: 29.6 +/- 8.2 years, 15 female), and 27 healthy controls (B12 levels > 200 pg/mL; mean age: 30.1 +/- 6.9 years, 13 female) were included in the study. 2D echocardiography images were transferred to a workstation for further offline analysis. Longitudinal peak systolic (LPSS) and global strain (LGS) was obtained from 4 chamber and apical long axis (APLAX) views. RESULTS: Standard echocardiographic parameters and tissue Doppler imaging (TDI) velocities were compared between the groups. All LPSS values in the patient group except for apical 4C septal wall longitudinal strain were significantly decreased than those in the control group. There was a positive correlation between B12 levels and strain values except apical 4C septal wall strain values. CONCLUSIONS: We found that in patients with vitamin B12 deficiency, global and segmental myocardial deformation was impaired and this impairment was correlated with the levels of vitamin B12. PMID- 23799552 TI - Impact of operator experience and wiring technique on procedural efficacy of trans-radial percutaneous chronic total occlusion recanalization performed by dedicated radialists. AB - BACKGROUND: The efficacy of trans-radial approach (TRA) in chronic total occlusions (CTO) percutaneous coronary interventions (PCI) is not well established. Thus, we sought to review the feasibility and long-term results of TRA for CTO PCI performed by dedicated TRA operatorsof our center. METHODS: CTO PCI performed by dedicated radialists were considered. Primary end-points were "PCI success" (stent implantation with residual stenosis < 20% and TIMI 3) and "patient success" (PCI success in a first or second attempt). Vascular complications and major adverse cardiac events (MACE) were also assessed. Procedures were divided into: Period 1 - no systematic adoption of TRA nor systematic wire selection, and Period 2 - systematic TRA with stepwise wire selection. The starting guidewire was initially an intermediate wire (Period 2a), and, thereafter, a tapered soft polymeric guidewire (Period 2b). RESULTS: Two operators performed 167 TRA PCI on CTO in 158 patients. PCI success rate was 74.3% and patient success rate was 78.5%. Drug-eluting stents were implanted in 95.1% of successful procedures. One (0.6%) patient had a (minor) vascular complication. After a mean follow-up of 580 days, 93.7% of patients were free from MACE. PCI success (57.1% in Period 1 vs. 76.5% in Period 2a vs. 80.5% in Period 2b, p = 0.029) and patient success (62.5% in Period 1 vs. 77.8% in Period 2a vs. 86.1% in Period 2b, p = 0.025) significantly improved during the study. CONCLUSIONS: CTO PCI by TRA is safe and feasible. Its efficacy seems to be strongly dependenton operator experience with CTO techniques and may be influenced by the strategy of guidewire selection. PMID- 23799553 TI - Comparison of the effects of carvedilol and nebivolol on diastolic functions of the left ventricle in patients with non-ischemic heart failure. AB - BACKGROUND: We investigated whether carvediolol or nebiovolol with vasodilator properties will produce different effects on diastolic function of the left ventricle (LV) in heart failure (HF) with low ejection fraction (EF). METHODS: Sixty-one non-ischemic HF patients with EF <=40% randomly received carvedilol (n = 31, 16 male) or nebivolol (n = 30, 19 male). Clinical and echocardiographic evaluations were performed at baseline, 3 and 6 months after therapy. Mitral inflow velocities (E and A waves), deceleration time of E wave (DT), isovolumetric relaxation time (IVRT), mitral annular velocities (Ea and Aa waves) were evaluated. Mitral E/A and E/Ea ratios were calculated. RESULTS: In carvediolol and nebivolol groups, mitral E/A ratio (from 1.08 +/- 0.31 to 0.87 +/ 0.30 vs. from 0.98 +/- 0.20 to 0.80 +/- 0.20, p = 0.30) and IVRT (from 108 +/- 13 to 94 +/- 10 ms vs. from 107 +/- 22 to 92 +/- 10 ms, p = 0.25) similarly decreased while DT prolonged (from 184 +/- 40 to 218 +/- 42 ms vs. from 193 +/- 37 to 222 +/- 36 ms, p = 0.71). Also, E/Ea ratio significantly decreased in each group (p = 0.01), but it was lower in nebivolol group than carvedilol group at 6 months (10.2 +/- 2 vs. 11.8 +/- 2, p = 0.01). Carvediolol and nebivolol reduced similarly N-terminal pro-B type natriuretic peptide level (from 666 to 137 vs. 661 to 123 pg/dL, p = 0.41, respectively) and improved functional capacity (p > 0.05). CONCLUSIONS: At 6 month follow-up, carvedilol and nebivolol appear to similarly improve LV diastolic functions in non-ischemic HF patients. PMID- 23799554 TI - Determinants of high sensitivity troponin T concentration in chronic stable patients with heart failure: Ischemic heart failure versus non-ischemic dilated cardiomyopathy. AB - BACKGROUND: Cardiac troponin T is a marker of myocardial injury, especially when measured by means of the high-sensitivity assay (hs-cTnT). The echocardiographic and clinical predictors of hs-cTnT may be different in ischemic heart failure (IHF) and non-ischemic dilated cardiomyopathy (DCM). METHODS: Sixty consecutive patients (19 female, 41 male; mean age 56.3 +/- 13.9 years) with stable congestive heart failure (33 patient with IHF and 27 patients with DCM), with New York Heart Association functional class I-II symptoms, and left ventricular ejection fraction < 40% were included. RESULTS: In patients with IHF peak early mitral inflow velocity (E), E/peak early diastolic mitral annular tissue Doppler velocity (Em) lateral, peak systolic mitral annular tissue Doppler velocity (Sm) lateral and logBNP were univariate predictors of hs-cTnT above median. But only E/Em lateral was an independent predictor of hs-cTnT above median (p = 0.04, HR: 1.2,CI: 1-1.4). In patients with DCM; left atrial volume index, male sex, Sm lateral and global longitudinal strain (LV-GLS) were included in multivariate model and LV-GLS was detected to be an independent predictor for hs-cTnT above median (p < 0.05, HR: 0.7, CI: 0.4-1.0). CONCLUSIONS: While LV-GLS is an independent predictor of hs-cTnT concentrations in patients with DCM, E/Em lateral predicted hs-TnT concentrations in patients with IHF. PMID- 23799555 TI - Serum fetuin-A levels are associated with carotid intima-media thickness in patients with normotensive chronic obstructive pulmonary disease. AB - BACKGROUND: There are contradictory reports about the relationship between fetuin A and atherosclerotic process. Coronary artery disease is the most important cause of mortality in patients with chronic obstructive pulmonary disease (COPD). We aimed to investigate the association of serum fetuin-A level with mean carotid intima-media thickness (cIMT) and ankle-brachial index (ABI) in COPD. METHODS: We evaluated the association of serum fetuin-A level, mean cIMT and ABI in normotensive subjects with COPD (n = 65) and with non-COPD (n = 50). RESULTS: Fetuin-A level was significantly lower (63.5 +/- 19.8 ng/mL, 72.9 +/- 16.2 ng/mL, p = 0.035) and C-reactive protein level higher (4 [1-10] vs. 3 [1-12] mg/dL, p = 0.034) in COPD patients than the control group. Compared to controls, fetuin-A level was significantly lower (63.5 +/- 19.8 ng/mL, 72.9 +/- 16.2 ng/mL, p = 0.035) and mean cIMT higher (0.69 [0.50-0.98] vs. 0.62 [0.44-0.98] mm, p = 0.034, respectively) in the COPD group. There was a significant negative correlation between mean cIMT and fetuin-A levels (r = -0.320, p = 0.032). Age (b +/- SE: 0.002 +/- 0.001, p = 0.008) and fetuin-A (b +/- SE: -0.002 +/- 0.001, p = 0.035) were decisive for the mean cIMT. CONCLUSIONS: There are increased cIMT values, decreased fetuin-A levels, but unchanged ABI values in patients with normotensive COPD. Age and fetuin-A were predictors for cIMT, while fetuin-A was negatively correlated with cIMT. PMID- 23799557 TI - Safety and effectiveness of transvenous lead extraction in elderly patients. AB - BACKGROUND: There is a considerable controversy regarding safety of transvenous lead extraction (TLE) in elderly patients due to their potentially worse general condition, more concomitant diseases, more difficult sedation or analgesia. Moreover, the present experience is not relevant. The aim of the study was the comparison of safety and feasibility of TLE in elderly and middle-aged patients. METHODS: We have extracted an ingrown pacemaker (PM)/implantable cardioverter defibrillator (ICD) leads from 1,060 adult patients (21-70 years) and 192 octogenarians (mean age 83.4 +/- 3.1 years) using standard mechanical systems within the last 7 years. We compared effectiveness and complications of the TLE procedures in the two mentioned groups of patients. RESULTS: There were more women in octogenarians referred for TLE (45.3% vs. 36.9%). In addition, more pocket infections (37.0% vs. 24.5%), less non-infective indications for PM (46.9% vs. 57.7%) and ICD systems (7.3% vs. 28.8%) TLE were observed in this group. Leads body dwelling time was similar (76.4 +/- 56.8 vs. 83.5 +/- 63.0) in both groups. Procedure efficacy (full radiological success 97.4% vs. 94.6%, partial radiological success 2.6% vs. 4.34%), safety measures (major complications 1.6% vs. 1.51%, minor complications 1.0% vs. 1.9%) were similar in both compared groups. CONCLUSIONS: Old age does not influence TLE effectiveness. Therefore, TLE can be safely and successfully performed in octogenarians. PMID- 23799556 TI - A prospective study about impact of renal dysfunction and morbidity and mortality on cardiovascular events after ischemic stroke. AB - BACKGROUND: The aim of our prospective study was to define the impact of renal dysfunction on future cardiovascular events and total mortality in 390 patients suffering from ischemic stroke. METHODS: A quantitative measurement of neurologic deficit according to National Institutes of Health Stroke Scale (NIHSS) score was performed. Blood parameters were measured. Diabetes, hypertension and smoking habits were defined. Estimated glomerular filtration rate was calculated. RESULTS: 153 (39.2%) patients had renal dysfunction. In the follow-up period in 36 (9.2%) patients acute coronary syndrome, in 102 (26.2%) recurrent ischemic stroke and in 44 (11.3%) peripheral arterial disease were documented. 191 (49%) patient died, 118 (30.3%) of whom died of cardiovascular events. Patients who died were older, had higher prevalence of renal dysfunction and NIHSS score. The Kaplan-Meier survival analysis showed that total mortality (p < 0.003) and cardiovascular mortality (p < 0.01) were higher in patients with renal dysfunction. According to Cox's regression analysis, renal dysfunction was the predictor of cardiovascular events, cardiovascular and total mortality. CONCLUSIONS: Patients with ischemic stroke and renal dysfunction are at higher risk for long term cardiovascular and total mortality. The patients with ischemic stroke and renal dysfunction are also at higher risk of new cardiovascular morbidity. Renal dysfunction should be added to the other known prognostic factors in patients with ischemic stroke. Our results also emphasize the importance of identification and management of renal dysfunction in stroke patients. PMID- 23799558 TI - Epidemiology, anticoagulant treatment and risk of thromboembolism in patients with valvular atrial fibrillation: Results from Atrial Fibrillation in Turkey: Epidemiologic Registry (AFTER). AB - BACKGROUND: The aim of this study was to perform a multicenter, prospective investigation regarding the epidemiology, the current effectiveness of therapeutic anticoagulation, and the risk of thromboembolism in patients with valvular atrial fibrillation (AF) based on the records of the Atrial Fibrillation in Turkey: Epidemiologic Registry (AFTER) study. METHODS: Patients were selected from a total of 2,242 consecutive admissions that presented with AF diagnosed via electrocardiogram. Those diagnosed with non-valvular AF were excluded from the AFTER study population, which left 497 patients with valvular AF for analysis. RESULTS: The etiology of valvular AF in patients was either attributed to rheumatic mitral valve stenosis (n = 217) or possessing a prosthetic heart valve (n = 280). Out of all the patients with valvular AF, 83.1% were taking warfarin for anticoagulation. Only 36.1% demonstrated a therapeutic international normalized ratio (INR), and among those patients it was found that 19.1% exhibited a labile INR. Multivariate analysis revealed that age was the only independent predictor of thromboembolic events in patients with valvular AF. CONCLUSIONS: Many valvular AF patients are not maintained at therapeutic INR levels, which poses a threat to patient health as they age and are at greater risk for thromboembolism. PMID- 23799559 TI - Usefulness of the Global Echo-Doppler Score (GEDS) in selection of patients with mitral stenosis for percutaneous balloon mitral valvuloplasty. AB - BACKGROUND: We aimed to create a novel modified score by combining anatomic and hemodynamic Doppler-echocardiographic measures for selection of suitable patients with mitral stenosis for percutaneous balloon mitral valvuloplasty (PBMV) and its impact in prediction of outcome. METHODS: 262 consecutive patients candidate for PBMV were enrolled. Wilkins score and a global score based on anatomical parameters (Wilkins score, posterior to anterior mitral leaflet ratio [PMVL/AMVL ratio]; left atrial diameter [LAD]) and hemodynamic parameters (mitral regurgitation [MR]; atrioventricular compliance [CN]; systolic pulmonary artery pressure [SPAP]) were assessed. Patients were classified into two groups according to their outcomes. RESULTS: Global Echo-Doppler Score (GEDS) for patients with favorable vs. those with unfavorable outcomes was (5.0 +/- 0.9 vs. 8.9 +/- 1.3; p < 0.001). Sensitivity, specificity, and accuracy of a GEDS >= 7 for prediction of cardiac events were 97.5%, 88%, and 97.5%, respectively. The area under the receiver operating characteristic curve was 0.95 (p < 0.001). The correlation coefficient was 0.852 (p < 0.0001) for GEDS 0.531 (p < 0.002), for Wilkins score 0.315 (p < 0.02), for PMVL/AMVL 0.460 (p < 0.01), for LAD; MR: Pre PBMV (r = 0.348, p < 0.03); CN [mL/mm Hg] (r = 0.579, p < 0.01) and SPAP [mm Hg] (r = 0.499, p < 0.01). In the regression analysis, GEDS, Wilkins score, and LAD were entered into the model. The regression coefficient (r = 0.695) of GEDS was much higher than those of the other 2 factors. CONCLUSIONS: GEDS is an independent predictor of PBMV success and clinical outcome and may be formulated in a scoring system that would help to identify the proper timing and best candidates for PBMV. PMID- 23799560 TI - Coronary sinus diameter by echocardiography to differentiate atrioventricular nodal reentrant tachycardia from atrioventricular reentrant tachycardia. AB - BACKGROUND: Coronary sinus (CS) has been shown to be larger in patients with atrioventricular nodal reentrant tachycardia (AVNRT). We sought to determine if echocardiographically measured CS diameter can help identify the mechanism of tachycardia in patients with narrow complex tachycardia without preexcitation before the invasive electrophysiology study. METHODS: Forty four patients with documented narrow complex, short RP tachycardia who were scheduled for an electrophysiology study were included. Based on the electrophysiology study, patients were divided into those with AVNRT and those with a concealed accessory pathway and atrioventricular reentrant tachycardia (AVRT). Proximal CS diameter (CSp) measured at the ostium and mid CS diameter (CSm) 1 cm distal to the ostium using transthoracic echocardiography. RESULTS: CSp was significantly larger in patients with AVNRT than AVRT (14.1 +/- 5 vs. 9.9 +/- 2 mm, p < 0.0001). CSm diameter was not significantly different between the two groups. A cut-off of CSp > 11.2 mm identified AVNRT with a sensitivity of 92.6% and specificity of 76.9%. CSp was a better discriminant (AUC 0.89, 95% CI 0.75-0.97) compared to age (AUC 0.74, 95% CI 0.58-0.87) or tachycardia rate (AUC 0.60, 95% CI 0.44-0.76). CONCLUSIONS: Echocardiographic measurement of the diameter of CS ostium can help in identifying the mechanism of the tachycardia before the invasive electrophysiology study. PMID- 23799561 TI - Atrial fibrillation practice patterns among cardiac electrophysiologists and cardiologists. AB - BACKGROUND: Treatment paradigms for atrial fibrillation (AF) are highly variable. This study explores the management practices for AF between general cardiologists and electrophysiologists in an academic institution. METHODS: One hundred and eighty eight patients with AF who had primary outpatient evaluation by either a cardiologist (n = 94) or electrophysiologist (n = 94) in 2008 were selected from the Northwestern electronic medical record and included in the study. Chart review was used to determine the type of therapy, methods of monitoring AF, antiarrhythmic drug use patterns and outcome. RESULTS: Patients seen by cardiologists vs. electrophysiologists were older (70.3 +/- 11.8 vs. 65.3 +/- 10.3, p = 0.002) and had more diabetes (21.3% vs. 10.6%, p = 0.046), renal disease (29.0% vs. 9.2%, p = 0.001) and coronary artery disease (40.4% vs. 23.4%, p = 0.01). A rate control strategy was used more often (80.9% vs. 54.3%, p < 0.001), and antiarrhythmics were prescribed less (10.6% vs. 31.9%, p < 0.001) by cardiologists than electrophysiologists. Antiarrhythmic choices were amiodarone (33.3%), sotalol (20.0%), flecainide (13.3%), propafenone (13.3%), and dofetilide (23.3%) for electrophysiologists, and were limited to amiodarone (80%) and sotalol (20%) for cardiologists. After a mean follow-up of 14.0 +/- 11.6 and 12.8 +/- 11.1 months (p = 0.44) for patients managed by cardiologists and electrophysiologists, mortality was 13.8% and 6.4% (p = 0.09), respectively. Long term ambulatory electrocardiogram monitoring was used more frequently by electrophysiologists (74.4%) than by cardiologists (55.6%, p = 0.15). CONCLUSIONS: Practice patterns for treatment of AF significantly differ between electrophysiologists and cardiologists. Understanding specialist treatment patterns will help optimize individualized therapy for treatment of AF. PMID- 23799562 TI - Training surgeon status is not associated with an increased risk of early or late mortality after isolated aortic valve replacement surgery. AB - BACKGROUND: Few studies have addressed the effect of "trainee surgeon" status on outcomes after isolated aortic valve replacement (AVR). METHODS AND RESULTS: A retrospective analysis of data, collected by the Australasian Society of Cardiac and Thoracic Surgeons Cardiac Surgery Database Program between June 2001 and December 2009 was performed. Patient demographics, intra-operative characteristics and early morbidity were compared between trainee and staff cases. Multivariate analyses were used to determine the independent association of training status with 30-day and late mortality. Isolated AVR was performed in 2747 patients; of these, 369 (13.4%) were by trainees. Compared to staff cases, trainee cases were less likely to present with renal failure (1.1% vs. 3.7%, p = 0.010) or in a critical preoperative state (1.4% vs. 3.7%, p = 0.020). The mean EuroSCORE was lower in trainee patients, compared to staff patients (8.11 +/- 2.80 vs. 8.81 +/- 3.09, p < 0.001). Trainee cases had longer mean perfusion (117.9 min vs. 98.9 min, p < 0.001) and cross-clamp (88.8 min vs. 73.2 min, p < 0.001) times. The incidence of early complications was similar between the two groups, except for post-operative myocardial infarction (1.1% vs. 0.3%, p = 0.008) and red blood cell transfusion (43.9 vs. 40.0%, p = 0.006). On multivariate analysis, trainee status was not associated with an increased risk of 30-day mortality (2.2% vs. 2.4%, p = 0.823). Moreover, there was no significant difference in long-term outcomes and 5-year survival was comparable in both groups (89.9% vs. 84.8%, p = 0.274). CONCLUSIONS: Isolated AVR can be safely and effectively performed by trainee surgeons who are strictly supervised in the operating theatre especially during the technically complex parts of the procedure. PMID- 23799564 TI - The endocrine pancreas: insights into development, differentiation, and diabetes. AB - In the developing embryo, appropriate patterning of the endoderm fated to become pancreas requires the spatial and temporal coordination of soluble factors secreted by the surrounding tissues. Once pancreatic progenitor cells are specified in the developing gut tube epithelium, epithelial-mesenchymal interactions, as well as a cascade of transcription factors, subsequently delineate three distinct lineages, including endocrine, exocrine, and ductal cells. Simultaneous morphological changes, including branching, vascularization, and proximal organ development, also influence the process of specification and differentiation. Decades of research using mouse genetics have uncovered many of the key factors involved in pancreatic cell fate decisions. When pancreas development or islet cell functions go awry, due to mutations in genes important for proper organogenesis and development, the result can lead to a common pancreatic affliction, diabetes mellitus. Current treatments for diabetes are adequate but not curative. Therefore, researchers are utilizing the current understanding of normal embryonic pancreas development in vivo, to direct embryonic stem cells toward a pancreatic fate with the goal of transplanting these in vitro generated 'islets' into patients. Mimicking development in vitro has proven difficult; however, significant progress has been made and the current differentiation protocols are becoming more efficient. The continued partnership between developmental biologists and stem cell researchers will guarantee that the in vitro generation of insulin-producing beta cells is a possible therapeutic option for the treatment of diabetes. PMID- 23799565 TI - Oscillatory gene expression and somitogenesis. AB - A bilateral pair of somites forms periodically by segmentation of the anterior ends of the presomitic mesoderm (PSM). This periodic event is regulated by a biological clock called the segmentation clock, which involves cyclic gene expression. Expression of her1 and her7 in zebrafish and Hes7 in mice oscillates by negative feedback, and mathematical models have been used to generate and test hypotheses to aide elucidation of the role of negative feedback in regulating oscillatory expression. her/Hes genes induce oscillatory expression of the Notch ligand deltaC in zebrafish and the Notch modulator Lunatic fringe in mice, which lead to synchronization of oscillatory gene expression between neighboring PSM cells. In the mouse PSM, Hes7 induces coupled oscillations of Notch and Fgf signaling, while Notch and Fgf signaling cooperatively regulate Hes7 oscillation, indicating that Hes7 and Notch and Fgf signaling form the oscillator networks. Notch signaling activates, but Fgf signaling represses, expression of the master regulator for somitogenesis Mesp2, and coupled oscillations in Notch and Fgf signaling dissociate in the anterior PSM, which allows Notch signaling-induced synchronized cells to express Mesp2 after these cells are freed from Fgf signaling. These results together suggest that Notch signaling defines the prospective somite region, while Fgf signaling regulates the pace of segmentation. It is likely that these oscillator networks constitute the core of the segmentation clock, but it remains to be determined whether as yet unknown oscillators function behind the scenes. PMID- 23799566 TI - Molecular mechanisms of liver and bile duct development. AB - The liver is derived from the ventral foregut endoderm. After hepatic specification, liver progenitor cells delaminate from the endoderm and invade the septum transversum mesenchyme to form the liver bud. In addition to proliferation and expansion, liver progenitor cells differentiate into two epithelial cell types, each arranged into unique structures with distinctive function. Growth, morphogenesis, and differentiation during liver development are regulated by a variety of factors that are expressed in a spatially and temporally specific manner. A comprehensive understanding of the regulatory mechanisms underlying the liver development has influenced the diagnosis of liver diseases and further progress will be critical for future advances in therapy. This review highlights some of the best understood steps of liver development, summarizing progress in our understanding of the molecular mechanisms that underlie differentiation, morphogenesis, and functional integration of the liver. PMID- 23799568 TI - Patterning the primary root in Arabidopsis. AB - The Arabidopsis root, with its ordered cell divisons and straightforward patterning, is a tractable model for understanding organ formation during plant development. Regular cell divisions in the root tip produce consistent cell type arrangements that can be followed through time. Root development occurs through the precise spatiotemporal control of transcription factors and phytohormone signaling networks. In this article, we provide a broad overview of the major events controlling embryonic and post-embryonic development within each major tissue and cell type in the primary root of Arabidopsis. PMID- 23799569 TI - Mathematical models of morphogen gradients and their effects on gene expression. AB - An introduction to mathematical models of pattern formation by morphogen gradients is presented, using the early embryo of the fruit fly Drosophila as the main experimental example. Analysis of morphogen gradient formation is based on the source-diffusion-degradation models and a formalism of local accumulation times. Transcriptional control by morphogens is discussed within the framework of thermodynamic site occupancy models of gene regulatory regions. PMID- 23799567 TI - Control of adult stem cells in vivo by a dynamic physiological environment: diet dependent systemic factors in Drosophila and beyond. AB - Adult stem cells are inextricably linked to whole-body physiology and nutrient availability through complex systemic signaling networks. A full understanding of how stem cells sense and respond to dietary fluctuations will require identifying key systemic mediators, as well as elucidating how they are regulated and integrated with local and intrinsic factors across multiple tissues. Studies focused on the Drosophila germline have generated valuable insights into how stem cells are controlled by diet-dependent pathways, and increasing evidence suggests that diverse adult stem cell populations respond to nutrients through similar mechanisms. Systemic signals, including nutrients themselves and diet-regulated hormones such as Insulin/Insulin-like growth factor or steroid hormones, can directly or indirectly affect stem cell behavior by modifying local cell-cell communication or intrinsic factors. The physiological regulation of stem cells in response to nutritional status not only is a fascinating biological problem, but also has clinical implications, as research in this field holds the key to noninvasive approaches for manipulating stem cells in vivo. In addition, given the known associations between diet, stem cells, and cancer risk, this research may inspire novel anticancer therapies. PMID- 23799570 TI - The role of noncoding RNAs in chromatin regulation during differentiation. AB - A myriad of nuclear noncoding RNAs (ncRNAs) have been discovered since the paradigm of RNAs as plain conveyors of protein translation was discarded. There is increasing evidence that at vital intersections of developmental pathways, ncRNAs target the chromatin modulating machinery to its site of action. However, the mechanistic details of processes involved are still largely unclear, and well characterized metazoan ncRNA species implicated in chromatin regulation during differentiation remain few. Nevertheless, four major categories are slowly emerging: cis-acting antisense ncRNAs that flag the neighboring genes for the propagation of chromatin marks; allele-specific ncRNAs that perform similar tasks, but target larger loci that typically vary in size from hundreds of thousands of base pairs to a whole chromosome; structural ncRNAs proposed to act as scaffolds that couple chromatin shaping complexes of distinct functionalities; and cofactor ncRNAs with a capacity to inhibit or activate essential components of the intertwined chromatin and transcription apparatuses. PMID- 23799571 TI - Primary cilia and graded Sonic Hedgehog signaling. AB - Cilia are evolutionary-conserved microtubule-containing organelles protruding from the surface of cells. They are classified into two types--primary and motile cilia. Primary cilia are nearly ubiquitous, at least in vertebrate cells, and it has become apparent that they play an essential role in the intracellular transduction of a range of stimuli. Most notable among these is Sonic Hedgehog. In this article we briefly summarize the structure and biogenesis of primary cilia. We discuss the evidence implicating cilia in the transduction of extrinsic signals. We focus on the involvement and molecular mechanism of cilia in signaling by Sonic Hedgehog in embryonic tissues, specifically the neural tube, and we discuss how cilia play an active role in the interpretation of gradients of Sonic Hedgehog (Shh) signaling. PMID- 23799572 TI - The evolution and development of mammalian flight. AB - Mammals have evolved a stunning diversity of limb morphologies (e.g., wings, flippers, hands, and paws) that allowed access to a wide range of habitats. Over 50 million years ago, bats (Order Chiroptera) evolved a wing (composed of a thin membrane encasing long digits) and thereby achieved powered flight. Unfortunately, the fossil record currently lacks any transitional fossils between a rodent-like ancestor and a winged bat. To reconstruct how this important evolutionary transition occurred, researchers have begun to employ an evolutionary developmental approach. This approach has revealed some of the embryological and molecular changes that have contributed to the evolution of the bat wing. For example, bat and mouse forelimb morphologies are similar during earliest limb development. Despite this, some key signaling centers for limb development are already divergent in bat and mouse at these early stages. Bat and mouse limb development continues to diverge, such that at later stages many differences are apparent. For example, at these later stages bats redeploy expression of toolkit genes (i.e., Fgf, Shh, Bmp, Grem) in a novel expression domain to inhibit apoptosis of the interdigital tissues. When results are taken together, a broad picture of the developmental changes that drove the transition from a hand to a wing over 50 million years ago is beginning to take shape. Moreover, studies seem to suggest that small changes in gene regulation during organogenesis can generate large evolutionary changes in phenotype. PMID- 23799573 TI - The Drosophila midgut: a model for stem cell driven tissue regeneration. AB - The Drosophila and mammalian digestive systems bear striking similarities in genetic control and cellular composition, and the Drosophila midgut has emerged as an amenable model for dissecting the mechanisms of tissue homeostasis. The Drosophila midgut is maintained by multipotent intestinal stem cells (ISCs) that give rise to all cell types in the intestinal epithelium and are required for long-term tissue homeostasis. ISC proliferation rate increases in response to a myriad of chemical and bacterial insults through the release of JAK-STAT and EGFR ligands from dying enterocytes that activate the JAK-STAT and EGFR pathways in ISCs. The Hippo and JNK pathways converge upon JAK-STAT and EGFR signaling, presumably in response to specific stresses, and JNK and insulin signaling have been shown to be critical in response to age-related stresses. This review details these emerging mechanisms of tissue homeostasis and the proliferative response of ISCs to epithelial damage, environmental stresses, and aging. PMID- 23799574 TI - Thymidine kinase/ganciclovir and cytosine deaminase/5-fluorocytosine suicide gene therapy-induced cell apoptosis in breast cancer cells. AB - The present study was conducted to explore the efficacy of suicide gene therapy with thymidine kinase (TK) in combination with cytosine deaminase (CD) for breast cancer. The expression of CD/TK was detected in the infected cells by RT-PCR. The killing effect on MCF-7 cells following treatment was analyzed by MTT assay. The morphological characteristics of the cells were observed by electron microscopy, and the distribution of the cell cycle was analyzed by flow cytometry. Caspase-3 and -8 activities were detected by absorption spectrometry. Cytotoxic assays showed that cells transfected with CD/TK became more sensitive to the prodrugs. Morphological features characteristic of apoptosis were noted in the MCF-7 cells via electron microscopy. The experimental data showed that the proportion of MCF 7 cells during the different phases of the cell cycle varied significantly following treatment with the prodrugs. The activity of caspase-3 gradually increased following treatment with increasing concentrations of the prodrugs. We conclude that the TK/ganciclovir and CD/5-fluorocytosine suicide gene system used here induces apoptosis in breast cancer cells, and provides a promising treatment modality for breast cancer. PMID- 23799576 TI - Differential effects of paclitaxel and docetaxel on gap junctions affects their cytotoxicities in transfected HeLa cells. AB - Gap junctions (GJs) enhance the cytotoxicity of specific cancer chemotherapeutic drugs and therefore, the inhibition of functional GJs may represent a mechanism by which the toxicity of chemotherapeutics in cancer cells can be reduced. In the present study, the effects and mechanisms of paclitaxel and docetaxel on GJ intercellular communication (GJIC) and the modulation of drug cytotoxicity were investigated in HeLa cells that were stably transfected with the connexin (Cx) 32 expression plasmid. Paclitaxel, but not docetaxel, was observed to inhibit dye coupling through junctional channels. Gating closure rather than the alteration of Cx32 expression or its membrane localization was responsible for the inhibitory action of paclitaxel on GJ function following short-term exposure. The results revealed that the cytotoxicity of paclitaxel or docetaxel increased in the presence of functional GJs compared with that observed when GJIC was suppressed. In addition, paclitaxel-induced downregulation of GJIC decreased the cytotoxicity of paclitaxel in the presence of functional GJs compared with that of docetaxel, which did not affect Cx32 channels. These observations demonstrated that the differential effects of paclitaxel and docetaxel on GJIC may affect the cytotoxicity of chemotherapeutic drugs. The present study provides a promising new approach to select antineoplastics and improve drug efficacy in carcinoma cells that form GJs. PMID- 23799577 TI - Changes in expression and distribution of attractin in the testes of rats at different developmental stages. AB - Attractin (Atrn), an autosomal recessive gene, is widely expressed in the body and displays multiple physiological and pathological functions in different types of tissues. The objective of this study was to localize Atrn protein and mRNA in the testis and epididymis of rats at different stages of maturation. Testis and epididymidis samples were obtained from the following 5 groups of Sprague Dawley (SD) rats in different developmental stages: newborn (8 h after birth), prepubertal (5 days), pubertal (20 days), postpubertal (50 days) and mature (70 days). Tissues were fixed and prepared for indirect immunofluorescence, immunohistochemistry, in situ hybridization, confocal laser scanning microscopy and western blot assays. A polyclonal antiserum against mouse Atrn and oligonucleotide riboprobes were used in the above assays. At the different stages of maturation, Atrn protein and mRNA were both widely expressed in the rat testis, including Leydig cells, primitive spermatogonia, primary spermatocytes, spermatids, Sertoli and peritubular myoid cells. Staining of the Atrn protein was mainly located on the cell membrane and in the cell cytoplasm while Atrn mRNA was distributed in both the nucleus and cytoplasm. No immunopositive staining was detected in spermatozoa and epididymides. In the epididymis, comprised of the caput, corpus and cauda, there was no definitive immunopositive staining within the efferent ductules or epididymal ducts. Taken together, Atrn protein and mRNA are both expressed widely in the rat testis at different stages of maturation, which suggests that Atrn protein is involved and plays an important role in the development of the reproductive system. In addition, the rat testis has the ability to synthesize Atrn protein throughout sexual development. PMID- 23799578 TI - The history and enduring contributions of planarians to the study of animal regeneration. AB - Having an almost unlimited capacity to regenerate tissues lost to age and injury, planarians have long fascinated naturalists. In the Western hemisphere alone, their documented history spans more than 200 years. Planarians were described in the early 19th century as being 'immortal under the edge of the knife', and initial investigation of these remarkable animals was significantly influenced by studies of regeneration in other organisms and from the flourishing field of experimental embryology in the late 19th and early 20th centuries. This review strives to place the study of planarian regeneration into a broader historical context by focusing on the significance and evolution of knowledge in this field. It also synthesizes our current molecular understanding of the mechanisms of planarian regeneration uncovered since this animal's relatively recent entrance into the molecular-genetic age. PMID- 23799580 TI - The Caenorhabditis elegans intestine. AB - The transcriptional regulatory hierarchy that controls development of the Caenorhabditis elegans endoderm begins with the maternally provided SKN-1 transcription factor, which determines the fate of the EMS blastomere of the four cell embryo. EMS divides to produce the posterior E blastomere (the clonal progenitor of the intestine) and the anterior MS blastomere, a major contributor to mesoderm. This segregation of lineage fates is controlled by an intercellular signal from the neighboring P2 blastomere and centers on the HMG protein POP-1. POP-1 would normally repress the endoderm program in both E and MS but two consequences of the P2-to-EMS signal are that POP-1 is exported from the E-cell nucleus and the remaining POP-1 is converted to an endoderm activator by complexing with SYS-1, a highly diverged beta-catenin. In the single E cell, a pair of genes encoding small redundant GATA-type transcription factors, END-1 and END-3, are transcribed under the combined control of SKN-1, the POP-1/SYS-1 complex, as well as the redundant pair of MED-1/2 GATA factors, themselves direct zygotic targets of SKN-1 in the EMS cell. With the expression of END-1/END-3, the endoderm is specified. END-1 and END-3 then activate transcription of a further set of GATA-type transcription factors that drive intestine differentiation and function. One of these factors, ELT-2, appears predominant; a second factor, ELT 7, is partially redundant with ELT-2. The mature intestine expresses several thousand genes, apparently all controlled, at least in part, by cis-acting GATA type motifs. PMID- 23799581 TI - Rare syndromes of the head and face-Pierre Robin sequence. AB - Pierre Robin sequence (PRS) is an association of clinical features consisting of mandibular hypoplasia, cleft secondary palate, and glossoptosis leading to obstructive apnea and feeding difficulties. PRS can occur as an isolated condition or can be found in association with a range of other features in a number of conditions including Treacher collins and Stickler syndromes. The frequent association of the PRS triad suggests a common underlying developmental mechanism which impacts on each of these tissues. Isolated PRS is typically sporadic but when familial usually exhibits autosomal dominant inheritance. The term PRS is applied on the basis of the pattern of malformation rather than etiology and growing evidence indicates that the initiating genetic lesion is variable. Various chromosomal anomalies have been associated with PRS including loci on chromosomes 2, 4, and 17. Associations with genes including SOX9, a number of collagen genes and work with animal models suggest the phenotype derives from a cartilage defect during early facial growth. However, alternative theories have been proposed and these highlight the difficulty of characterising congenital anomalies of craniofacial development in which multiple etiologies can result in very similar phenotypes. PMID- 23799579 TI - Understanding vascular development. AB - The vasculature of an organism has the daunting task of connecting all the organ systems to nourish tissue and sustain life. This complex network of vessels and associated cells must maintain blood flow, but constantly adapt to acute and chronic changes within tissues. While the vasculature has been studied for over a century, we are just beginning to understand the processes that regulate its formation and how genetic hierarchies are influenced by mechanical and metabolic cues to refine vessel structure and optimize efficiency. As we gain insights into the developmental mechanisms, it is clear that the processes that regulate blood vessel development can also enable the adult to adapt to changes in tissues that can be elicited by exercise, aging, injury, or pathology. Thus, research in vessel development has provided tremendous insights into therapies for vascular diseases and disorders, cancer interventions, wound repair and tissue engineering, and in turn, these models have clearly impacted our understanding of development. Here we provide an overview of the development of the vascular system, highlighting several areas of active investigation and key questions that remain to be answered. PMID- 23799583 TI - The 22q11 deletion: DiGeorge and velocardiofacial syndromes and the role of TBX1. AB - Hemizygous deletion of 22q11 affects approximately 1:4000 live births and may give rise to many different malformations but classically results in a constellation of phenotypes that receive a diagnosis of DiGeorge syndrome or velocardiofacial syndrome. Particularly affected are the heart and great vessels, the endocrine glands of the neck, the face, the soft palate, and cognitive development. Although up to 50 genes may be deleted, it is haploinsufficiency of the transcription factor TBX1 that is thought to make the greatest contribution to the disorder. Mouse embryos are exquisitely sensitive to varying levels of Tbx1 mRNA, and Tbx1 is required in all three germ layers of the embryonic pharyngeal region for normal development. TBX1 controls cell proliferation and affects cellular differentiation in a cell autonomous fashion, but it also directs non-cell autonomous effects, most notably in the signaling between pharyngeal surface ectoderm and the rostral neural crest. TBX1 interacts with several signaling pathways, including fibroblast growth factor, retinoic acid, CTNNB1 (formerly known as beta-catenin), and bone morphogenetic protein (BMP), and may regulate pathways by both DNA-binding and non-binding activity. In addition to the structural abnormalities seen in 22q11 deletion syndrome (DS) and Tbx1 mutant mouse models, patients reaching adolescence and adulthood have a predisposition to psychiatric illness. Whether this has a developmental basis and, if so, which genes are involved is an ongoing strand of research. Thus, knowledge of the genetic and developmental mechanisms underlying 22q11DS has the potential to inform about common disease as well as developmental defect. PMID- 23799582 TI - The etiology and molecular genetics of human pigmentation disorders. AB - Pigmentation, defined as the placement of pigment in skin, hair, and eyes for coloration, is distinctive because the location, amount, and type of pigmentation provides a visual manifestation of genetic heterogeneity in pathways regulating the pigment-producing cells, melanocytes. The scope of this genetic heterogeneity in humans ranges from normal to pathological pigmentation phenotypes. Clinically, normal human pigmentation encompasses a variety of skin and hair color as well as punctate pigmentation such as melanocytic nevi (moles) or ephelides (freckles), while abnormal human pigmentation exhibits markedly reduced or increased pigment levels, known as hypopigmentation and hyperpigmentation, respectively. Elucidation of the molecular genetics underlying pigmentation has revealed genes important for melanocyte development and function. Furthermore, many pigmentation disorders show additional defects in cells other than melanocytes, and identification of the genetic insults in these disorders has revealed pleiotropic genes, where a single gene is required for various functions in different cell types. Thus, unravelling the genetics of easily visualized pigmentation disorders has identified molecular similarities between melanocytes and less visible cell types/tissues, arising from a common developmental origin and/or shared genetic regulatory pathways. Herein we discuss notable human pigmentation disorders and their associated genetic alterations, focusing on the fact that the developmental genetics of pigmentation abnormalities are instructive for understanding normal pathways governing development and function of melanocytes. PMID- 23799584 TI - Beetle horns and horned beetles: emerging models in developmental evolution and ecology. AB - Many important questions in developmental biology increasingly interface with related questions in other biological disciplines such as evolutionary biology and ecology. In this article, we review and summarize recent progress in the development of horned beetles and beetle horns as study systems amenable to the integration of a wide range of approaches, from gene function analysis in the laboratory to population ecological and behavioral studies in the field. Specifically, we focus on three key questions at the current interface of developmental biology, evolutionary biology and ecology: (1) the developmental mechanisms underlying the origin and diversification of novel, complex traits, (2) the relationship between phenotypic diversification and the diversification of genes and transcriptomes, and (3) the role of behavior as a leader or follower in developmental evolution. For each question we discuss how work on horned beetles is contributing to our current understanding of key issues, as well as highlight challenges and opportunities for future studies. PMID- 23799585 TI - Molecular genetic control of cell patterning and fate determination in the developing ventral spinal cord. AB - The generation of neuronal diversity in the ventral spinal cord during development is a multistep process that occurs with precise and reproducible spatiotemporal order. The proper functioning of the central nervous system requires that this be carried out with extraordinary precision from the outset. Extrinsic influences such as the secreted Sonic hedgehog (SHH) protein provide positional cues that are read out genetically as specific patterns of gene expression in subsets of dividing progenitors, which is the first overt indication that they have begun to embark upon cell-type-specific differentiation programs. Cells generated from these segregated domains will ultimately share similar properties and functions. Recent work illustrates that SHH, which regulates target genes via the GLI transcription factors, directly controls a subset of progenitor fate determinant genes and that both derepression and activation play a role in shaping the differential response to this morphogen. PMID- 23799586 TI - Metallomics for drug development: an integrated CE-ICP-MS and ICP-MS approach reveals the speciation changes for an investigational ruthenium(III) drug bound to holo-transferrin in simulated cancer cytosol. AB - A method based on combining inductively coupled plasma mass spectrometry (ICP-MS) with capillary electrophoresis (CE) or an ultrafiltration step was developed to study the speciation of the serum-protein adducts of a ruthenium anticancer drug under in vitro intracellular conditions. The formation of a reactive Ru species in the cell, following the metal release from the protein, is thought to play an important role in the drug's mode of action. Glutathione and ascorbic acid at their cancer cytosol concentrations were shown to be capable of altering the metal speciation in the drug adduct with holo-transferrin but not that with albumin. The appearance of the additional peaks in ICP-MS electropherograms (by recording both Ru- and Fe-specific signals) was found to be dependent on time which allowed for kinetic assessment of the evolution of novel metal species. On the contrary, after the addition of citric acid the ruthenium ion (within the appropriately complexed scaffold) remained sequestered in the adduct. This was inferred as a proof of the speciation changes taking place by a virtue of a redox mechanism rather than due to ligand-exchange transformations. The protein-bound metallodrug was further characterized by direct ICP-MS assaying so as to confirm a partial release of ruthenium induced by glutathione. PMID- 23799587 TI - Cells, tissues, and organs on chips: challenges and opportunities for the cancer tumor microenvironment. AB - The transition to increasingly sophisticated microfluidic systems has led to the emergence of "organ-on-chip" technology that can faithfully recapitulate organ level function. Given the rapid progress at the interface between microfluidics and cell biology, there is need to provide a focused evaluation of the state-of the-art in microfluidic systems for cancer research to advance development, accelerate discovery of novel insights, and facilitate cooperation between engineers, biologists and oncologists in the clinic. Here, we provide a focused review of microfluidics technology from cells- and tissues- to organs-on-chips with application toward studying the tumor microenvironment. Key aspects of the tumor microenvironment including angiogenesis, hypoxia, biochemical gradients, tumor-stromal interactions, and the extracellular matrix are summarized for both solid tumors and non-solid hematologic malignancies. An overview of microfluidic systems designed specifically to answer questions related to different aspects of the tumor microenvironment is provided, followed by an examination of how these systems offer new opportunities to study outstanding challenges related to the major cancer hallmarks. Challenges also remain for microfluidics engineers, but it is hoped that cooperation between engineers and biologists at the intersection of their respective fields will lead to significant impact on the utility of organs-on-chips in cancer research. PMID- 23799588 TI - Expression profiling of lncRNAs in C3H10T1/2 mesenchymal stem cells undergoing early osteoblast differentiation. AB - Protein-coding genes and small non-coding microRNAs involved in the guidance of differentiation in mesenchymal stem cells (MSCs) into osteoblasts have been extensively investigated in previous studies. However, long non-coding RNAs (lncRNAs), which account for a large proportion of the genomic sequences in numerous species, have not yet been reported. In the present study, the lncRNA expression profile was analyzed using the Arraystar lncRNA array in C3H10T1/2 MSCs undergoing early osteoblast differentiation and 116 differentially expressed lncRNAs were identified between BMP-2 treated and untreated groups. Among these lncRNAs, 59 were upregulated and 57 were downregulated in BMP-2 treated groups. In addition, 24 cooperatively differentially expressed lncRNAs and nearby mRNA pairs were found. For example, mouselincRNA0231 and its nearby gene, EGFR, were downregulated, while lncRNA NR_027652 and its nearby gene, DLK1, were upregulated. These observations may be part of the regulatory mechanisms of lncRNAs in the control of osteoblast differentiaton. In conclusion, results of the present study indicate that lncRNA expression profiles are significantly altered in C3H10T1/2 undergoing early osteoblast differentiation and these results may provide insight into the mechanisms responsible for osteoblast differentiation. PMID- 23799589 TI - Expansion of decidual CD45RO+ T cells with high expression of CEACAM1 in the early stage of pregnancy. AB - The aim of the present study was to investigate the mechanism involved in the expansion of CD45RO+ T cells in the decidual microenvironment, and in the expression of the inhibitory carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) on the surface of decidual CD45RO+ T cells. Twenty-one healthy nonpregnant females and seventeen healthy pregnant females in the first trimester were included in the study. Peripheral blood samples from nonpregnant and pregnant females, and decidual tissues from pregnant females following elective abortion, were obtained and analyzed by flow cytometry. The percentages of CD45RO+ T cells and CEACAM1-expressing CD45RO+ T cells were significantly higher in first trimester human decidua than in the peripheral blood. Conditioned medium from the coculture of monocytes and the human trophoblast HTR8/SVneo cell line (MHM) was added to the model for the generation of CD45RO+ T cells in vitro. MHM caused an increase in the percentage of CD45RO+ T cells in a monocyte chemoattractant protein-1 (MCP-1)-dependent manner and an increase in the percentage of CEACAM1-expressing CD4+CD45RO+ T cells in the model. In conclusion, our results implied that trophoblast cells and monocytes may be involved in the increase of decidual CD45RO+ T cells and the high expression of CEACAM1 on their surfaces. PMID- 23799590 TI - Proteomic identification of keratin alterations with enhanced proliferation of oral carcinoma cells by loss of mucosa-associated lymphoid tissue 1 expression. AB - Progression of oral carcinomas associates with aberrant activation and inactivation of molecules that work in established or unknown pathways. Although mucosa-associated lymphoid tissue 1 (MALT1) expressed in normal oral epithelium is inactivated in the aggressive subset of carcinomas with worse prognosis, phenotypic changes of carcinoma cells upon the loss of expression is unknown. We performed a proteomic analysis to identify MALT1-regulated proteins in oral carcinoma cells. Four different keratins were included in the ten most abundantly changed proteins. K8/18 were upregulated in MALT1 stably-expressing carcinoma cells and K5/14 in MALT1-marginal control cells. K8/18 upregulation and K5/14 downregulation were MALT1 dose-dependent and observed in a series of oral carcinoma cells. MALT1 suppressed cell proliferation (0.52-fold, P<0.01) and its dominant-negative form stimulated it (1.33-fold, P<0.01). The decreased proliferation associated with reduction of cyclin D1, which was recovered by the short interfering RNA against MALT1. Taken together, loss of MALT1 expression alters keratin expression and enhances proliferation of carcinoma cells, and may progress oral carcinomas into the advanced state. PMID- 23799591 TI - Identification and analysis of microRNAs in the left ventricular myocardium of two-kidney one-clip hypertensive rats. AB - MicroRNAs (miRNAs) are involved in the regulation of numerous physiological and pathological processes. However, little information is available with regard to miRNAs in the left ventricular myocardium of the renovascular angiotensin dependent hypertensive rat. In this study, miRNA expression profiles in the left ventricular myocardium of two-kidney one-clip (2K1C) hypertensive rats were analyzed using a microarray. The roles of the differentially expressed miRNAs, their target genes and signaling pathways were analyzed using ingenuity pathway analysis (IPA) for the first time to further elucidate the molecular mechanisms of left ventricular remodeling. PMID- 23799592 TI - Overexpression of human telomerase reverse transcriptase promotes the motility and invasiveness of HepG2 cells in vitro. AB - Recent studies have indicated that telomerase activity promotes cancer invasion and metastasis, but the underlying mechanism remains unclear. Several studies have shown that expression of exogenous human telomerase reverse transcriptase (hTERT) can promote motility and invasiveness among telomerase-negative tumor cells, and inhibition of endogenous telomerase activity can reduce invasiveness in tumor cells. However, whether overexpression of hTERT can further enhance the motility and invasiveness of telomerase-positive tumor cells has yet to be determined. In the present study, we showed that stable overexpression of hTERT can increase telomerase activity and telomere length, which significantly promotes the invasive and metastatic potential of telomerase-positive HepG2 cells but does not affect cell proliferation. Further analysis suggested that enhanced invasiveness and metastasis may act through corresponding upregulation of mRNA and protein expression of matrix metalloproteinase 9 (MMP9) and Ras homolog gene family member C (RhoC). Our study indicated that exogenous expression of hTERT may promote invasiveness and metastasis through upregulation of MMP9 and RhoC. PMID- 23799594 TI - Requiem for tetrazepam. PMID- 23799595 TI - [Prenatal cerebrovascular accidents diagnosed in the early infant stage: a series of 10 patients]. AB - INTRODUCTION. A foetal or prenatal cerebrovascular accident (CVA) is defined as an ischaemic, thrombotic or arterial or venous haemorrhagic event that occurs between the 14th week of gestation and the onset of labour. PATIENTS AND METHODS. We report a retrospective study of a series of 10 patients suffering from a, presumably foetal, stroke that went unnoticed during the pregnancy and was diagnosed in the early infant stage. The symptoms and the age at which they were identified are highlighted. RESULTS. None of the 10 patients studied presented any relevant events in the mothers' medical history, but there were four threats of a preterm birth that were solved using the usual means and without the occurrence of any alterations that later affected the foetus. The studies that led to the diagnosis were carried out between the sixth and ninth months of life, and the reason for visiting was reported by the family as being a lower degree of mobility on one side of the body with respect to the other. Two patients presented thrombophilia. With a mean follow-up time of six years, all the patients have an associated infantile cerebral palsy, a third of them have epilepsy and 75% have learning difficulties or intellectual disability. CONCLUSIONS. When CVA are not detected in the prenatal period, it is important in primary care to look for and detect the warning signs of the psychomotor development of the infant at an early stage in order to begin a study of the case and to undertake rehabilitation as early as possible. PMID- 23799596 TI - [Comparison of bibliometric indicators for neuropaediatrics in Revista de Neurologia and Anales de Pediatria over one decade]. AB - AIM. Bibliometric analysis of neuropaediatrics articles published in Revista de Neurologia and Anales de Pediatria between 2000 and 2009. MATERIALS AND METHODS. We selected neuropaediatrics articles published in two journal during the last decade (n = 1,085). We investigated authorship, topic and bibliography, to calculate indices of isolation, Price, collaboration, productivity, transience and self-citations. Analyze citations received by Web of Knowledge (WOK): articles cited, sometimes cited and h-index. RESULTS. 1,085 articles were analyzed, 255 published in Anales de Pediatria (9.4% of the total in that period) and 830 in Revista de Neurologia (21.7% total). The collaboration index was 4.3. The 89.7% of the authors were medical care (96% hospital staff, 0,8% of primary care staff and 2.9% of both). The 11.9% ??of the articles were collaborative between regions and the 26% came from foreign centers. The originals were 29.8% (80.8% descriptive observational studies, analytical 18.3% and 0.8% clinical trials). The most frequent topics were paroxysmal disorders (15.9%) and developmental, learning and behavioral disorders (15%). The average number of citations per article was 27.6, with an isolation rate of 13.4% and a Price index of 41.7%. The profile of the articles published in both journals is different, finding significant differences in almost all parameters analyzed. According WOK, the 255 items of Anales de Pediatria have received 40 citations and h-index of 3 and the 830 Revista de Neurologia 2,234 citations with h-index of 13. CONCLUSIONS. There are differences in the pediatric neurology publications between the two magazines with more international projection of Revista de Neurologia. PMID- 23799597 TI - [Quality of life and perceived general health state related to seizure type and frequency, electroencephalographic findings, cognitive impairment, therapeutic response and secondary effects in persons with epilepsy]. AB - INTRODUCTION. The perceived quality of life (QoL) in persons with epilepsy has demonstrated to be a relevant factor for the continuity of treatment and for the patients' own general health perception. Currently, the positive concept of QoL is used to assess the psychosocial factors of the epilepsy, replacing the concept of stigma. AIM. To analyze the relationship between QoL and general health perception, with several relevant clinical parameters in a sample of persons with epilepsy, in order to draw conclusions that help to suggest a more global approach to the disease. PATIENTS AND METHODS. We applied the Spanish versions of the QOLIE-10, the GHQ-12, and MMSE, and registered the clinical parameters (diagnostic, years of illness, electroencephalographic patterns, seizure type and frequency, response to medication, and side effects) in a sample of 29 persons with epilepsy. RESULTS. QoL and perceived general health are two unrelated factors respect to the clinical features. QoL is closely related to the frequency and type of crisis, whilst the years of illness and the level of neurocognitive impairment are not related with QoL. CONCLUSIONS. From the clinical point of view, it must be taken into account the relationship between the persons with epilepsy perceived QoL with factors such as the seizure frequency, side effects of the medication, and the general health perception, in order to obtain the best response and treatment adherence. PMID- 23799598 TI - [Intraventricular arachnoid cyst]. AB - INTRODUCTION. Intracranial arachnoids cysts are considered benign developmental anomalies that occur within the arachnoid membrane and generally contain clear and colourless fluid resembling cerebrospinal fluid. The prevalence of these cysts is higher in the first two decades of life, and the incidence is widely quoted as approximately 1% of all space-occupying intracranial lesions. Arachnoids cysts in the elderly person are a rare occurrence. We report the unusual presentation of a woman with an intraventricular arachnoid cyst treated with endoscopic technique. CASE REPORT. A 75-year-old woman presented with progressive hemiparesis of two years duration. Cranial MR imaging showed a right parieto-occipital intraventricular cyst with local mass effect and moderate dilatation of lateral ventricles. A right-sided burr hole was made and the arachnoids cyst was reached and cysto-ventricle shunting was realized. This was followed by a septum pellucidum fenestration. There were no complications during the surgery and the patient presented no symptoms at time of discharge. CONCLUSIONS. The neuroendoscopic approach to intraventricular arachnoid cysts was effective with few complications. PMID- 23799599 TI - [Metabolomics in ischaemic stroke, new diagnostic and prognostic biomarkers]. AB - The study of biomarkers related with ischaemic stroke is becoming increasingly more important as a way to further our knowledge of the pathophysiological changes that occur in cerebrovascular disease and to make it easier to reach an early diagnosis. Within this field, metabolomics offers a novel approach. The field is defined as the study of the small-molecule metabolites derived from cell metabolism. Its interest lies in the fact that, using a biological sample, it offers a snapshot of the cellular changes that are taking place. Today, the application of metabolomics requires a complex methodology that includes the application of laboratory separation techniques, multivariant statistical analyses and the use of bioinformatic tools. A number of studies conducted within the field of cardiovascular disease have focused on the application of this approach. In recent years there has been a steady growth in the number of publications referring to the metabolic changes related with ischaemic stroke, both in animal models and in patients. Metabolomics makes it possible to obtain the profiles of metabolites that identify patients who have suffered an ischaemic stroke. Furthermore, since studies have been carried out that relate certain metabolites with the most common causations of ischaemic stroke, metabolomics may eventually play a significant role in the study of cryptogenic stroke. The most exhaustive knowledge of the changes in the metabolic pathways involved in cerebrovascular disease could lay the foundations for the development of new neuroprotector strategies. PMID- 23799601 TI - [Recurring arterial reocclusion following endovascular recanalisation in a patient with protein S deficiency]. PMID- 23799602 TI - [Post-herpetic segmental hypoesthesia-paresis with fast recovery]. PMID- 23799603 TI - [Orolingual angiooedema following intravenous thrombolysis]. PMID- 23799604 TI - [Spinal cord compression: a multidisciplinary approach to a real neuro oncological emergency]. PMID- 23799605 TI - [Spinal cord compression: a multidisciplinary approach to a real neuro oncological emergency. Reply]. PMID- 23799606 TI - Neuroprotectin D1 attenuates brain damage induced by transient middle cerebral artery occlusion in rats through TRPC6/CREB pathways. AB - Neuroprotectin D1 (NPD1) may serve an endogenous neuroprotective role in brain ischemic injury, yet the underlying mechanism involved is poorly understood. In the present study, we aimed to investigate whether intracerebroventricular (ICV) injection of NPD1 is neuroprotective against transient focal cerebral ischemia. We also sought to verify the neuroprotective mechanisms of NPD1. Rats subjected to 2 h ischemia followed by reperfusion were treated with NPD1 at 2 h after reperfusion. PD98059 was administered 20 min prior to surgery. Western blot analysis was performed to detect the protein levels of calpain-specific aII spectrin breakdown products of 145 kDa (SBDP145), transient receptor potential canonical (subtype) 6 (TRPC6) and phosphorylation of cAMP/Ca2+-response element binding protein (p-CREB) at 12, 24 and 48 h after reperfusion. The immunoreactivity of p-CREB and TRPC6 was measured by quantum dot-based immunofluorescence analysis. Infarct volume and neurological scoring were evaluated at 48 h after reperfusion. NPD1, when applied at 2 h after reperfusion, significantly reduced infarct volumes and increased neurological scores at 48 h after reperfusion, accompanied by elevated TRPC6 and p-CREB activity, and decreased SBDP145 activity. When mitogen-activated protein kinase kinase (MEK) activity was specifically inhibited, the neuroprotective effect of NPD1 was attenuated and correlated with decreased CREB activity. Our results clearly showed that ICV injection of NPD1 at 2 h after reperfusion improves the neurological status of middle cerebral artery occlusion (MCAO) rats through the inhibition of calpain-mediated TRPC6 proteolysis and the subsequent activation of CREB via the Ras/MEK/ERK pathway. PMID- 23799607 TI - High internal phase agar hydrogel dispersions in cocoa butter and chocolate as a route towards reducing fat content. AB - Reducing the fat content of chocolate formulations is a major challenge for the confectionery industry. We report the suspension of aqueous microgel agar particles of up to 80% v/v within sunflower oil, cocoa butter, and ultimately chocolate. The optimised emulsification process involves a shear-cooling step. We demonstrate the versatility of our method when applied to white, milk, and dark chocolate formulations, whilst preserving the desired polymorph V of the cocoa butter matrix. In addition, we show that this technology can be used as a strategy to disperse alcoholic beverages into chocolate confectionery. PMID- 23799608 TI - Inhibitory effects of low molecular weight polyphenolics from Inonotus obliquus on human DNA topoisomerase activity and cancer cell proliferation. AB - Low molecular weight (LMW) polyphenolics containing a polyhydroxylated benzyl moiety are abundant in medicinal plants. In the present study, we report on the activities of seven LMW polyphenolics isolated from Inonotus obliquus, a medicinal mushroom. The isolated compounds included caffeic acid (CA), 3,4 dihydroxybenzalacetone (DBL), gallic acid, syringic acid, protocatechuic acid, 3,4-dihydroxybenzaldehyde and 2,5-dihydroxyterephthalic acid. We analyzed their inhibitory effects on DNA polymerase (pol) and DNA topoisomerase (topo), and their effects on human cancer cell growth. All isolated compounds inhibited human topo II activity; the most potent were DBL and CA, which contain a catechol propanoid moiety. CA and DBL inhibited the activity of human topo I, whereas other compounds had no effect. No compound modulated the activities of 11 mammalian pol species or other DNA metabolic enzymes, including T7 RNA polymerase, mouse IMP dehydrogenase (type II), T4 polynucleotide kinase and bovine deoxyribonuclease I. CA and DBL markedly suppressed the proliferation of human colon HCT116 carcinoma cells with an LD50 of 70.0 and 49.4 uM, respectively, and halted the cell cycle in the G2/M phase. The suppressive effect of these compounds on cancer cell growth correlated with their ability to inhibit topo II. These results suggest that CA- and DBL-dependent decreases in cell proliferation are due to the inhibition of cellular topo II. The mechanism of action of these catechol propanoid compounds and the implication for their use as anticancer agents are discussed. PMID- 23799610 TI - Highly efficient alpha-C-sialylation promoted by (p-Tol)2SO/Tf2O with N-acetyl-5 N,4-O-oxazolidione protected thiosialoside as donor. AB - Based on a preactivation protocol with (p-Tol)2SO/Tf2O, a practical, straightforward, and high-yielding synthesis of alpha-sialyl C-glycosides was accomplished by coupling N-acetyl-5-N,4-O-oxazolidione protected thiosialoside with various trimethylsilyl enol ethers and allyltrimethylsilanes. High yields and excellent alpha-selectivities were obtained for the strong pi-nucleophiles with large nucleophilicity values (N = 4.4-9.0), irrespective of whether silyl enol ethers, silyl ketene acetals or allyltrimethylsilanes were used for the electrophilic C-sialylation. PMID- 23799609 TI - Serum microRNA expression levels can predict lymph node metastasis in patients with early-stage cervical squamous cell carcinoma. AB - Circulating microRNA expression levels can serve as diagnostic/prognostic biomarkers in several types of malignant tumors; however, to our knowledge, there have been reports describing their value in cervical squamous cell carcinoma (SCC). In this study, we used hybridization arrays to compare the microRNA expression profiles in cervical squamous cell carcinomas (SCC) samples among patients with lymph node metastasis (LNM) or without LNM; 89 microRNAs were found to fit our inclusion criteria. Using quantitative PCR (qPCR), we examined the expression levels of these microRNAs in cervical cancer tissue, as well as in serum from patients and healthy women. We compared the expression levels between patients with LNM (n=40) and those without LNM (n=40) and healthy controls (n=20). Using regression analysis, we generated a comprehensive set of marker microRNAs and drew the fitted binormal receiver operating characteristic (ROC) curves to access the predictive value. We identified 6 serum microRNAs that can predict LNM in cervical SCC patients; these microRNAs were miR-1246, miR-20a, miR 2392, miR-3147, miR-3162-5p and miR-4484. The area under the curve (AUC) of the comprehensive set of serum microRNAs predicting LNM was 0.932 (sensitivity, 0.856; specificity, 0.850). The predictive value of the serum microRNAs was inferior to that in tissue (AUC 0.992; sensitivity, 0.967; specificity, 0.950; P=0.018). We compared the LNM predictive value of serum microRNAs and SCC antigen (SCC-Ag) by drawing fitted binormal ROC curves However, serum microRNA analysis is by far superior to serum SCC-Ag analysis (AUC 0.713; sensitivity, 0.612; specificity, 0.700; P<0.0001). Serum microRNAs are a good predictor of LNM with clinical value in early-stage cervical SCC. PMID- 23799611 TI - Structural insights of SIR2rp3 proteins as promising biotargets to fight against Chagas disease and leishmaniasis. AB - Trypanosoma cruzi and Leishmania spp. are protozoan pathogens responsible for Chagas disease and leishmaniasis, respectively. Current therapies rely only on a very small number of drugs, most of them are inadequate because of their severe host toxicity or drug-resistance phenomena. In order to find therapeutic alternatives, the identification of new biotargets is highly desired. In this study, homology modelling, docking and molecular dynamics simulations have been used to generate robust 3D models of NAD(+)-dependent deacetylases from Trypanosoma and Leishmania spp., known as SIR2rp3, whose structures have never been described before. Molecular docking of known inhibitors revealed strong analogies with the mitochondrial human SIRT5 in terms of binding mode and interaction strength. On the other hand, by extending the analysis to the channel rims, regions of difference between host and parasitic targets, useful for future selective drug design projects, were pointed out. PMID- 23799612 TI - Mutations in the STAT1-interacting domain of the hepatitis C virus core protein modulate the response to antiviral therapy. AB - RNA viruses, such as hepatitis C virus (HCV), have markedly error-prone replication, resulting in high rates of mutagenesis. In addition, the standard treatment includes ribavirin, a base analog that is likely to cause mutations in different regions of the HCV genome, resulting in deleterious effects on HCV itself. The N-terminal region of the core protein is reported to block interferon (IFN) signaling by interaction with the STAT1-SH2 domain, resulting in HCV resistance to IFN therapy. In this study, mutations in the HCV core protein from IFN/ribavirin-treated patients were analyzed, with particular focus on the N terminal domain of the HCV core which is reported to interact with STAT1. HCV PCR positive patients enrolled in this study were either undergoing pegylated IFN/ribavirin bitherapy and had completed 12 weeks of initial treatment or were treatment-naive patients. The HCV core protein was cloned and sequenced from these patients and mutations observed in the STAT1-interacting domain of the core protein from treated patients were characterized using in silico interaction to depict the role of these mutations in disease outcomes. Our results suggest that the amino acids at positions 2, 3, 8, 16 and 23 of the HCV core protein are critical for core-STAT1 interaction and ribavirin-induced mutations at these positions interfere with the interaction, resulting in a better response of the treated patients. In conclusion, this study anticipates that HCV core residues 2, 3, 8, 16 and 23 directly interact with STAT1. We propose that IFN/ribavirin bitherapy-induced mutations in the STAT1-interacting domain of the HCV core protein may be responsible for the improved therapeutic response and viral clearance, thus amino acids 1-23 of the N-terminus of the core protein are an ideal antiviral target. However, this treatment may give rise to resistant variants that are able to escape the current therapy. We propose similar studies in responsive and non-responsive genotypes in order to gain a broader picture of this proposed mechanism of viral clearance. PMID- 23799613 TI - Inhibition of Wnt signaling induces cell apoptosis and suppresses cell proliferation in cholangiocarcinoma cells. AB - The aim of the present study was to explore possible gene therapy for hilar cholangiocarcinoma by detecting the activation of the Wnt signaling pathway in 4 cholangiocarcinoma cell lines and inhibiting its expression by RNA interference (RNAi) targeting key factors of this pathway. The expression levels of the Wnt pathway-related factors, Wnt2, Wnt3, beta-catenin and transcription factor 4, and its target genes, c-myc and cyclin D1, in 4 cholangiocarcinoma cell lines were detected by RT-PCR, western blotting and immunofluorescence microscopy. After transfection of siRNAs targeting Wnt2 and beta-catenin into FRH0201 cells, the expression of the Wnt pathway-related factors and its target genes was again detected, and the cell cycle distribution, apoptosis and proliferation were analyzed by flow cytometry and MTT assay. Activation of the Wnt pathway and the expression of its target genes were detected in all 4 cell lines at various levels. After siRNA transfection, the expression of the target genes in the FRH0201 cells was significantly downregulated. In addition, the Wnt pathway was blocked, cell apoptosis was enhanced and cell proliferation was suppressed. In conclusion, the Wnt signaling pathway is activated in cholangiocarcinoma cells. RNAi technology targeting Wnt2 and beta-catenin may be a possible gene therapy for hilar cholangiocarcinoma. PMID- 23799614 TI - Whole-exome sequencing to identify novel somatic mutations in squamous cell lung cancers. AB - Squamous cell lung cancer is a major histotype of non-small cell lung cancer (NSCLC) that is distinct from lung adenocarcinoma. We used whole-exome sequencing to identify novel non-synonymous somatic mutations in squamous cell lung cancer. We identified 101 single-nucleotide variants (SNVs) including 77 non-synonymous SNVs (67 missense and 10 nonsense mutations) and 11 INDELs causing frameshifts. We also found four SNVs located within splicing sites. We verified 62 of the SNVs (51 missense, 10 nonsense and 1 splicing-site mutation) and 10 of the INDELs as somatic mutations in lung cancer tissue. Sixteen of the mutated genes were also mutated in at least one patient with a different type of lung cancer in the Catalogue of Somatic Mutation in Cancer (COSMIC) database. Four genes (LPHN2, TP53, MYH2 and TGM2) were mutated in approximately 10% of the samples in the COSMIC database. We identified two missense mutations in C10orf137 and MS4A3 that also occurred in other solid-tumor tissues in the COSMIC database. We found another somatic mutation in EP300 that was mutated in 4.2% of the 2,020 solid tumor samples in the COSMIC database. Taken together, our results implicate TP53, EP300, LPHN2, C10orf137, MYH2, TGM2 and MS4A3 as potential driver genes of squamous cell lung cancer. PMID- 23799615 TI - Staphylococcal enterotoxin B and alpha-toxin induce the apoptosis of ECV304 cells via similar mechanisms. AB - Staphylococcal enterotoxin B (SEB) and alpha-toxin produced by Staphylococcus aureus (S. aureus) are important in the pathogenesis of diseases. In the present study, we investigated the effects of SEB and alpha-toxin on ECV304 cells. It was identified that both SEB and alpha-toxin were capable of inducing the apoptosis of ECV304 cells in a dose- and time-dependent manner. In addition, SEB and alpha toxin were able to induce the expression of TNF-alpha and the activation of caspase-3 and -8 in the ECV304 cells. The inhibition of TNF-alpha (with its neutralizing antibody) and caspase-3 and -8 [with the corresponding inhibitory peptides; z-N-acetyl-Asp-Glu-Val-Asp-aminomethyl-coumarin (DEVD)-fluoromethyl ketone (FMK) for inhibition of caspase-3 and z-N-acetyl-Ile-Glu-Thr-Asp (IETD) FMK) for inhibition of caspase-8] significantly decreased the rates of cell apoptosis induced by SEB and alpha-toxin, but was not able to completely block the induced cell apoptosis. These data suggest that SEB and alpha-toxin induce ECV304 cell apoptosis via a similar mechanism, which is partially mediated by the extrinsic death pathway involving TNF-alpha and caspase-8. These results provide insights into the synergistic pathogenicity of SEB and alpha-toxin during S. aureus infection. PMID- 23799616 TI - 1,3-beta-glucan affects the balance of Th1/Th2 cytokines by promoting secretion of anti-inflammatory cytokines in vitro. AB - 1,3-beta-glucan is considered a fungal biomarker and exposure to this agent induces lung inflammation. Previous studies have shown that 1,3-beta-glucan affects Th1 and Th2 immune responses. Interleukin (IL)-10 and transforming growth factor (TGF)-beta, as typical anti-inflammatory cytokines, suppress the Th1 immune response. To investigate the effects of 1,3-beta-glucan on the secretion of cytokines in co-cultured mouse macrophages and lymphocytes in vitro, mice were exposed to 1,3-beta-glucan or phosphate-buffered saline (PBS) by intratracheal instillation. Following extraction and co-culture of macrophages and lymphocytes, which were treated with or without 1,3-beta-glucan in vitro, enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of cytokines and real time reverse transcription (RT)-polymerase chain reaction (PCR) was used to investigate the mRNA expression of forkhead box p3 (Foxp3) in the cells. We showed that 1,3-beta-glucan exposure in vitro decreased the secretion of Th1 cytokines and increased the secretion of Th2 cytokines in the culture media. Furthermore, 1,3-beta-glucan exposure in vitro increased the secretion of IL-10 and TGF-beta in the culture media. According to these results, 1,3-beta-glucan exposure in vitro is suggested to promote the secretion of anti-inflammatory cytokines, which may lead to a decrease in the levels of Th1 cytokines and an increase in the levels of Th2 cytokines. 1,3-beta-glucan is suggested to induce regulatory lymphocytes, which partly contributes to an increased secretion of anti-inflammatory cytokines in co-cultured mouse macrophages and lymphocytes in vitro. PMID- 23799617 TI - Transcranial direct current stimulation (tDCS) for improving aphasia in patients after stroke. AB - BACKGROUND: Stroke is one of the leading causes of disability worldwide. Aphasia among stroke survivors is common. Current speech and language therapy (SLT) strategies have only limited effectiveness in improving aphasia. A possible adjunct to SLT for improving SLT outcomes might be non-invasive brain stimulation by transcranial direct current stimulation (tDCS) to modulate cortical excitability and hence to improve aphasia. OBJECTIVES: To assess the effects of tDCS for improving aphasia in patients after stroke. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (April 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, March 2012), MEDLINE (1948 to March 2012), EMBASE (1980 to March 2012), CINAHL (1982 to March 2012), AMED (1985 to April 2012), Science Citation Index (1899 to April 2012) and seven additional databases. We also searched trials registers and reference lists, handsearched conference proceedings and contacted authors and equipment manufacturers. SELECTION CRITERIA: We included only randomised controlled trials (RCTs) and randomised controlled cross-over trials (from which we only analysed the first period as a parallel group design) comparing tDCS versus control in adults with aphasia due to stroke. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted the data. If necessary, we contacted study authors for additional information. We collected information on dropouts and adverse events from the trials. MAIN RESULTS: We included five trials involving 54 participants. None of the included studies used any formal outcome measure for measuring functional communication, that is measuring aphasia in a real-life communicative setting. All five trials measured correct picture naming as a surrogate for aphasia. There was no evidence that tDCS enhanced SLT outcomes. No adverse events were reported and the proportion of dropouts was comparable between groups. AUTHORS' CONCLUSIONS: Currently there is no evidence of the effectiveness of tDCS (anodal tDCS, cathodal tDCS) versus control (sham tDCS). However, it appears that cathodal tDCS over the non-lesioned hemisphere might be the most promising approach. PMID- 23799618 TI - An improved postconditioning algorithm: gradually increased reperfusion provides improved cardioprotection in rats. AB - The aim of the present study was to investigate whether a gradually increasing reperfusion algorithm, in which the brief reperfusion was lengthened as the duration of each reperfusion/reocclusion cycle remained fixed, enhances cardioprotection. Rats were randomized into 5 groups: the sham, reperfusion injury (R/I), gradually decreased reperfusion (GDR; 30/10-25/15-15/25-10/30 sec of reperfusion/reocclusion), equal reperfusion (ER; 4 20/20-sec reperfusion/reocclusion cycles) and gradually increased reperfusion (GIR; 10/30 15/25-25/15-30/10 sec of reperfusion/reocclusion). The rats were sacrificed to measure serum markers, apoptotic indices and infarct size. Western blot analyses were used to analyze the expression of molecules involved in important signaling pathways. All the three postconditioning patterns were found to provide cardioprotection (P<0.05 compared with the R/I group). GIR provided optimum cardioprotection, followed by ER and then GDR. Apoptotic index and serum marker levels were significantly reduced in the GIR compared with the ER group (P<0.05). The enhanced cardioprotection provided by GIR was accompanied by significantly increased levels of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and Bcl-2, as well as lower levels of p38/c-Jun N-terminal kinase (JNK) phosphorylation, tumor necrosis factor alpha (TNFalpha), caspase-8, Bax, caspase-9 and cytochrome c (Cyt-c) in the cytoplasm of rats (P<0.05, all compared with ER). The infarct size in the rats of the GIR group was also smaller compared with that in the rats of the ER group, but this difference was not significant (16.30+/-5.22 vs. 20.57+/-6.32%, P>0.05). All the variables measured in the present study were significantly improved in the GIR group compared with the GDR group (P<0.05). In conclusion, the association between brief reperfusion and reocclusion is an important factor in postconditioning algorithms. Additionally, GIR results in improved cardioprotection compared with that achieved by the remaining algorithms examined. PMID- 23799619 TI - Postoperative serum troponin T concentration in patients undergoing aortic valve replacement does not predict early postoperative outcome. AB - BACKGROUND: The measurement of serum cardiac troponin T concentration (cTnT) after aortic valve replacement (AVR) provides the opportunity to assess the degree of myocardial damage and may have some prognostic value. AIM: To determine whether elevated troponin level is related to patient outcome. METHODS: We investigated patient outcome and postoperative serum concentration of troponin T in 79 patients who underwent AVR. Serum levels of cTnT were measured within 24 h of AVR. We searched for the occurrence of subsequent adverse events i.e. requirement for intraaortic ballon pump (IABP) or inotropic support, prolonged Intensive Care Unit (ICU) stay, and in-hospital death. RESULTS: Serum concentration of cTnT after AVR increased significantly compared to the preoperative value. We found significant positive correlations between aortic cross-clamp time (r = 0.23, p = 0.04), cardiopulmonary bypass time (r = 0.4,p = 0.00029), duration of the surgery (r = 0.30, p = 0.008), and postoperative cTnT level. Three (4%) patients required IABP support, 37 (46%) patients required inotropic support, and 11 (14%) patients had a prolonged ICU stay (> 48 h). Thirty eight (48%) patients required either inotropic support or IABP insertion. At least one adverse event occurred in 44 (56%) patients. Median postoperative serum cTnT concentration was 0.31 ng/mL (interquartile range 0.23-0.60 ng/mL). We failed to find a statistically significant difference in postoperative cTnT level between patients with and without adverse events. According to multiple logistic regression analysis, the postoperative serum level of troponin T was not independently associated with adverse patient outcome. Diabetes mellitus, patient age and left ventricular ejection fraction below 50% were significant independent predictors of adverse events after AVR. The area under receiver operating curve (AUROC) for postoperative serum troponin T concentration as a determinant of various adverse outcomes was never significantly different from 0.50. CONCLUSIONS: Serum cTnT concentration is frequently - if not universally - elevated after AVR. Serum level of troponin T measured on the first postoperative morning is a poor predictor of patient outcome after AVR and should not be relied on when planning postoperative care. PMID- 23799620 TI - Age, sex, and secondary prevention of ischaemic heart disease in everyday practice. AB - BACKGROUND: Many researchers have studied age- and sex-related differences in the management of patients with coronary artery disease. However, the results are inconsistent. AIM: To assess sex- and age-related bias in the secondary prevention in patients hospitalised due to ischaemic heart disease. METHODS: Five hospitals with departments of cardiology serving a city and surrounding districts in southern Poland participated in the study. Consecutive patients hospitalised from 1 April 2005 to 31 July 2006 due to acute coronary syndrome or for a myocardial revascularisation procedure and aged <= 80 years were recruited and interviewed 6-18 months after hospitalisation. RESULTS: The hospital records of 640 patients were reviewed and 513 (80.2%) patients participated in the follow-up interview. Women were older and less educated than their male counterparts. Sex was not independently associated with the control of major risk factors in the post-discharge period, whereas age was related to a higher probability of having high blood pressure and a lower chance of smoking. Multivariate analysis showed that females were prescribed calcium antagonists (odds ratio [OR] 2.13; 95% confidence intervals [CI] 1.34-3.39) and diuretics (OR 1.52; 95% CI 1.00-2.31) more often than males. Age was independently related to the prescription rate of diuretics (>= 70 years vs. < 60 years; OR 1.61; 95% CI 1.19-2.20). The prescription rate of antiplatelets, beta-blockers, angiotensin converting enzyme inhibitors/sartans, lipid-lowering drugs, and anticoagulants was not related to age or sex. CONCLUSIONS: We found no major sex-related difference in the frequency of achieving recommended goals in secondary prevention, whereas age was related to a lower prevalence of smoking and a higher probability of having high blood pressure in subjects after hospitalisation for coronary artery disease. PMID- 23799621 TI - Endovascular repair of traumatic thoracic aortic rupture: a single centre experience. AB - BACKGROUND: Thoracic aortic rupture is usually the result of a sudden deceleration caused by a traffic accident, fall or some other misfortune. Before the endovascular era, there was only one treatment option: open repair, burdened by high morbidity and significant mortality. Now, we have the ability to treat it with a stent graft. The advantages of this method include avoiding a thoracotomy or aorta cross-clamping and their associated complications. AIM: To present our experience and results of endovascular treatment of thoracic aortic ruptures. METHODS: Since 1998, we have performed endovascular treatment for aortic lesions in 1,598 patients. From this group, the indication for stent graft implantation in 31 patients was a traumatic aortic rupture or pseudoaneurysm caused by an injury. All patients had a history of blunt chest trauma. The sequence of injury treatment depended on the severity of each. In all but two patients, the first was an aortic stent graft implantation. The length of thoracic aorta covered ranged from 100-200 mm (mean 123 mm). We did not use any method of spinal cord ischaemia protection. Final angiography showed complete exclusion of the aortic disruption in all patients. RESULTS: All but one operation was successful. One patient died intraoperatively due to concomitant injuries. After the operation, none of the patients had signs of spinal cord ischaemia or any other complications through a follow-up period ranging from 12 to 96 months (mean 40 months). CONCLUSIONS: Our experience with traumatic thoracic aortic ruptures suggests that endovascular treatment should be the method of choice, especially in unstable multi-trauma patients. However, long-term studies are required to assess the durability of this technique after many years. PMID- 23799622 TI - Is there an association between depressive symptoms and coronary artery disease in the Polish adult population? AB - BACKGROUND: Evidence-based medicine has confirmed the role of psychosocial factors in the pathogenesis of many diseases, both cardiovascular (CVD) and metabolic. On the other hand, CVD patients often suffer from concomitant diseases. Depression was found to be an independent predictor of coronary artery disease (CAD) in many populations. AIM: To evaluate the association between depressive symptoms (DS) and CAD in the Polish adult population. METHODS: A random sample of the Polish population (6392 men and 7153 women), aged 20-74 years, was examined in 2003-2005 for the presence of DS using the Beck Depression Inventory. RESULTS: In the examined population, CAD was found in 12.1% of men and 11.0% of women. Persons with CAD were older, more often finished their education at the level of primary school and lived in large communes, and more often had obesity, hypertension, diabetes and hyperlipidaemia compared to those without CAD. DS were found twice more often in persons with CAD compared to those without CAD, both in men and women. Subjects with DS were twice more likely to have CAD (men: odds ratio [OR] 2.14, 95% confidence interval [CI] 1.78-2.56; women: OR 2.03, 95% CI 1.70-2.43) and arrhythmia (women), and 1.5-fold more likely to report myocardial infarction and arrhythmia. CONCLUSIONS: A significant association between DS and CAD, myocardial infarction and arrhythmia independent of CVD risk factors was found in the Polish adult population. PMID- 23799623 TI - Aspirin antagonizes the cytotoxic effect of methotrexate in lung cancer cells. AB - Methotrexate (MTX) has been widely used for the treatment of cancer and rheumatoid arthritis (RA). Aspirin (ASA) is a non-selective cyclooxygenase (COX) inhibitor that contributes to the treatment of inflammatory conditions such as RA. It has been observed that the antitumor effect of ASA can be attributed to inhibition of cell cycle progression, induction of apoptosis and inhibition of angiogenesis. In the present study, we revealed that the treatment with a combination of MTX and ASA resulted in antagonism of the cytotoxic effect as demonstrated by SRB and colony formation assays. ASA alleviated the MTX-mediated S phase accumulation and recovered the G1 phase. MTX-mediated accumulation of the S phase marker cyclin A was also alleviated by ASA. Notably, FAS protein levels were upregulated by MTX in A549 cells. The antagonism of MTX efficacy caused by ASA was accompanied by altered expression of caspase-3, Bcl-2 and FAS but not dihydrofolate reductase (DHFR). This suggests that the alteration of caspase-3, Bcl-2 and FAS was involved in the antagonism between ASA and MTX. Exogenously added folic acid reversed the MTX-mediated DHFR inhibition following either MTX or MTX + ASA treatments. Most importantly, we demonstrated for the first time that the commonly used non-steroidal anti-inflammatory drug for headache ASA and possibly other COX-1/2 inhibitors can produce a strong antagonistic effect on the growth inhibition of lung cancer cells when administered in combination with MTX. The clinical implication of our finding is obvious, i.e., the clinical efficacy of MTX therapy can be compromised by ASA and their concomitant use should be avoided. PMID- 23799626 TI - Testis formation in the fetal mouse: dynamic and complex de novo tubulogenesis. AB - Soon after Sry initiates male sex determination, cells in XY gonads undergo an unusual process of de novo cord formation that results in the organization of Sertoli cells into epithelial tubules enclosing germ cells and partitioning mesenchymal cells and vasculature to the interstitial space of the testis. Recent experiments investigating this dynamic process in four dimensions have begun to shed new light on the collective interactions of multiple cell types during morphogenesis of testis cords. PMID- 23799625 TI - The molecular basis of human congenital limb malformations. AB - This review focuses predominantly on the human congenital malformations caused by alterations affecting the morphoregulatory gene networks that control early limb bud patterning and outgrowth. Limb defects are among the most frequent congenital malformations in humans that are caused by genetic mutations or teratogenic effects resulting either in abnormal, loss of, or additional skeletal elements. Spontaneous and engineered mouse models have been used to identify and study the molecular alterations and disrupted gene networks that underlie human congenital limb malformations. More recently, mouse genetics has begun to reveal the alterations that affect the often-large cis-regulatory landscapes that control gene expression in limb buds and cause devastating effects on limb bud development. These findings have paved the way to identifying mutations in cis regulatory regions as causal to an increasing number of congenital limb malformations in humans. In these cases, no mutations in the coding region of a presumed candidate were previously detected. This review highlights how the current understanding of the molecular gene networks and interactions that control mouse limb bud development provides insight into the etiology of human congenital limb malformations. PMID- 23799627 TI - The evolution of the neural crest: new perspectives from lamprey and invertebrate neural crest-like cells. AB - The neural crest is an embryonic cell population that gives rise to an array of tissues and structures in adult vertebrates including most of the head skeleton. Because neural crest cells (NCCs), and many of their derivatives, are unique to vertebrates, the evolution of the neural crest is thought to have potentiated vertebrate origins and diversification. However, the lack of clear NCC homologs in invertebrate chordates has made it difficult to reconstruct the evolutionary history of modern NCCs. In this review, the development of NCCs in the basal jawless vertebrate, lamprey, is compared with the development of neural crest like cells in a range of invertebrates to deduce features of the first NCCs and their evolutionary precursors. These comparisons demonstrate that most of the defining attributes of NCCs are widespread features of invertebrate embryonic ectoderm. In addition, they suggest ancient origins for the neural border domain and chondroid skeletal tissue in the first bilaterian, and show that NCCs must have evolved in a chordate with an unduplicated invertebrate-type genome. On the basis of these observations, a stepwise model for the evolution of NCCs involving heterotopic and heterochronic activation of ancient ectodermal gene programs and new responsiveness to preexisting inducing signals is proposed. In light of the phylogenetic distribution of neural crest-like cells, the deep homology of developmental gene networks, and the central role of evolutionary loss in deuterostome evolution, this article concludes with suggestions for future studies in a broad range of bilaterians to test key aspects of this model. WIREs Dev Biol 2013, 2:1-15. doi: 10.1002/wdev.85 For further resources related to this article, please visit the WIREs website. PMID- 23799624 TI - Stress and stem cells. AB - The unique properties and functions of stem cells make them particularly susceptible to stresses and also lead to their regulation by stress. Stem cell division must respond to the demand to replenish cells during normal tissue turnover as well as in response to damage. Oxidative stress, mechanical stress, growth factors, and cytokines signal stem cell division and differentiation. Many of the conserved pathways regulating stem cell self-renewal and differentiation are also stress-response pathways. The long life span and division potential of stem cells create a propensity for transformation (cancer) and specific stress responses such as apoptosis and senescence act as antitumor mechanisms. Quiescence regulated by CDK inhibitors and a hypoxic niche regulated by FOXO transcription factor function to reduce stress for several types of stem cells to facilitate long-term maintenance. Aging is a particularly relevant stress for stem cells, because repeated demands on stem cell function over the life span can have cumulative cell-autonomous effects including epigenetic dysregulation, mutations, and telomere erosion. In addition, aging of the organism impairs function of the stem cell niche and systemic signals, including chronic inflammation and oxidative stress. PMID- 23799628 TI - Organogenesis of the vertebrate heart. AB - Organogenesis of the vertebrate heart involves a complex sequence of events initiating with specification and differentiation of myocardial and endocardial cells in anterior lateral mesoderm shortly after gastrulation, followed by formation and rightward looping of the early heart tube. During looping, the heart tube elongates by addition of second heart field progenitor cells from adjacent pharyngeal mesoderm at the arterial and venous poles. Progressive differentiation is controlled by intercellular signaling events between pharyngeal mesoderm, foregut endoderm, and neural crest-derived mesenchyme. Regulated patterns of myocardial gene expression and proliferation within the embryonic heart drive morphogenesis of atrial and ventricular chambers, while cardiac cushions, precursors of the definitive valves, form in the atrioventricular and outflow regions. In amniotes, separate systemic and pulmonary circulatory systems arise by septation and remodeling events that divide the atria and ventricles into left and right chambers. Cardiac neural crest cells play a key role in dividing the arterial pole of the heart into the ascending aorta and pulmonary trunk. During the remodeling phase the definitive cardiac conduction system, that coordinates the heartbeat, is established. In addition, the epicardium, critical for regulated ventricular growth and development of the coronary vasculature, spreads over the surface of the heart as an epithelium from which cells invade the myocardium to give rise to diverse cell types including fibroblasts and smooth muscle cells. Cardiogenesis thus involves highly coordinated development of multiple cell types and insight into the different lineage contributions and molecular regulation of each of these steps is expanding rapidly. WIREs Dev Biol 2013, 2:17-29. doi: 10.1002/wdev.68 For further resources related to this article, please visit the WIREs website. PMID- 23799629 TI - Evolution of homeobox genes. AB - Many homeobox genes encode transcription factors with regulatory roles in animal and plant development. Homeobox genes are found in almost all eukaryotes, and have diversified into 11 gene classes and over 100 gene families in animal evolution, and 10 to 14 gene classes in plants. The largest group in animals is the ANTP class which includes the well-known Hox genes, plus other genes implicated in development including ParaHox (Cdx, Xlox, Gsx), Evx, Dlx, En, NK4, NK3, Msx, and Nanog. Genomic data suggest that the ANTP class diversified by extensive tandem duplication to generate a large array of genes, including an NK gene cluster and a hypothetical ProtoHox gene cluster that duplicated to generate Hox and ParaHox genes. Expression and functional data suggest that NK, Hox, and ParaHox gene clusters acquired distinct roles in patterning the mesoderm, nervous system, and gut. The PRD class is also diverse and includes Pax2/5/8, Pax3/7, Pax4/6, Gsc, Hesx, Otx, Otp, and Pitx genes. PRD genes are not generally arranged in ancient genomic clusters, although the Dux, Obox, and Rhox gene clusters arose in mammalian evolution as did several non-clustered PRD genes. Tandem duplication and genome duplication expanded the number of homeobox genes, possibly contributing to the evolution of developmental complexity, but homeobox gene loss must not be ignored. Evolutionary changes to homeobox gene expression have also been documented, including Hox gene expression patterns shifting in concert with segmental diversification in vertebrates and crustaceans, and deletion of a Pitx1 gene enhancer in pelvic-reduced sticklebacks. WIREs Dev Biol 2013, 2:31-45. doi: 10.1002/wdev.78 For further resources related to this article, please visit the WIREs website. CONFLICT OF INTEREST: The author declares that he has no conflicts of interest. PMID- 23799630 TI - The TGFbeta superfamily signaling pathway. AB - The transforming growth factor (TGF)beta superfamily of secreted factors is comprised of over 30 members including Activins, Nodals, Bone Morphogenetic Proteins (BMPs), and Growth and Differentiation Factors (GDFs). Members of the family, which are found in both vertebrates and invertebrates, are ubiquitously expressed in diverse tissues and function during the earliest stages of development and throughout the lifetime of animals. Indeed, key roles in embryonic stem cell self-renewal, gastrulation, differentiation, organ morphogenesis, and adult tissue homeostasis have been delineated. Consistent with this ubiquitous activity, aberrant TGFbeta superfamily signaling is associated with a wide range of human pathologies including autoimmune, cardiovascular and fibrotic diseases, as well as cancer. TGFbeta superfamily ligands signal through cell-surface serine/threonine kinase receptors to the intracellular Smad proteins, which in turn accumulate in the nucleus to regulate gene expression. In addition to this universal cascade, Smad-independent pathways are also employed in a cell-specific manner to transduce TGFbeta signals. Ligand access to the signaling receptors is regulated by numerous secreted agonists and antagonists and by membrane-associated coreceptors that act in a context-dependent manner. Given the fundamental role of the TGFbeta superfamily in metazoans and the diversity of biological responses, it is not surprising that the signaling pathway is subject to tight and complex regulation at levels both outside and inside the cell. WIREs Dev Biol 2013, 2:47-63. doi: 10.1002/wdev.86 For further resources related to this article, please visit the WIREs website. PMID- 23799631 TI - Patterns of root growth acclimation: constant processes, changing boundaries. AB - Plasticity, the hallmark of plant morphogenesis, extends to kinetics. To enhance acclimation, growing plant organs adeptly adjust their growth rate, up or down. In roots, rates of division and elemental expansion as well as the length of division and elongation zones are readily characterized because of their linear organization, radial symmetry, and indeterminate growth, and can be measured accurately with kinematic methods. Here, for roots, I describe key concepts from kinematics and review patterns of growth and division during acclimation. The growth rate of a root reflects the integral of elemental expansion activity over the span of the growth zone; therefore, an acclimating plant can change the rate of root growth by changing either or both the span of the growth zone or the rate of elemental expansion. The analogous dichotomy exists for cell division where the rate at which cells are produced reflects the integral of cell division rate over the span of the division zone. Surprisingly, expansion responses nearly always involve changes in the length of the growth zone. Similarly, although based on fewer data, changes in cell division rate are rare, whereas changes in meristem length are common. These patterns imply that setting the boundaries for meristem and elongation zone is the key regulatory act for root growth rate acclimation. WIREs Dev Biol 2013, 2:65-73. doi: 10.1002/wdev.94 For further resources related to this article, please visit the WIREs website. PMID- 23799632 TI - Hirschsprung disease: a developmental disorder of the enteric nervous system. AB - Hirschsprung disease (HSCR), which is also called congenital megacolon or intestinal aganglionosis, is characterized by an absence of enteric (intrinsic) neurons from variable lengths of the most distal bowel. Because enteric neurons are essential for propulsive intestinal motility, infants with HSCR suffer from severe constipation and have a distended abdomen. Currently the only treatment is surgical removal of the affected bowel. HSCR has an incidence of around 1:5,000 live births, with a 4:1 male:female gender bias. Most enteric neurons arise from neural crest cells that emigrate from the caudal hindbrain and then migrate caudally along the entire gut. The absence of enteric neurons from variable lengths of the bowel in HSCR results from a failure of neural crest-derived cells to colonize the affected gut regions. HSCR is therefore regarded as a neurocristopathy. HSCR is a multigenic disorder and has become a paradigm for understanding complex factorial disorders. The major HSCR susceptibility gene is RET. The penetrance of several mutations in HSCR susceptibility genes is sex dependent. HSCR can occur as an isolated disorder or as part of syndromes; for example, Type IV Waardenburg syndrome is characterized by deafness and pigmentation defects as well as intestinal aganglionosis. Studies using animal models have shown that HSCR genes regulate multiple processes including survival, proliferation, differentiation, and migration. Research into HSCR and the development of enteric neurons is an excellent example of the cross fertilization of ideas that can occur between human molecular geneticists and researchers using animal models. WIREs Dev Biol 2013, 2:113-129. doi: 10.1002/wdev.57 For further resources related to this article, please visit the WIREs website. PMID- 23799633 TI - Stem cells of the adult lung: their development and role in homeostasis, regeneration, and disease. AB - The lung has vital functions in gas exchange and immune defense. To fulfill these functions the cellular composition and complex three-dimensional organization of the organ must be maintained for a lifetime. Cell turnover in the adult lung is normally low. However, in response to cellular injury by agents such as infection, toxic compounds, and irradiation there is rapid proliferation and differentiation of endogenous stem and progenitor cells to repair and regenerate the damaged tissue. In the mouse, different populations of epithelial progenitor cells have been identified in different regions of the respiratory system: basal cells in the proximal tracheobronchial region and submucosal glands, and secretory cells in the conducting airways and bronchioalveolar duct junction. The identification of the long-term stem cells in the alveolar region is still under debate, and little is known about resident stem and progenitor cells for the many mesodermal populations. Within this framework information is provided about the origin of lung progenitor cells during development, the microenvironment in which they reside, the experimental injury and repair systems used to promote their regenerative response, and some of the mechanisms regulating their behavior. WIREs Dev Biol 2013, 2:131-148. doi: 10.1002/wdev.58 For further resources related to this article, please visit the WIREs website. PMID- 23799634 TI - Development of the cerebellum: from gene expression patterns to circuit maps. AB - The internal structure of the cerebellum reflects an intriguing paradox; its cytoarchitecture is relatively simple and repeated throughout, yet the connections between its neurons are wired into a complex array of gene expression domains and functional circuits. The developmental mechanisms that coordinate the establishment of cerebellar structure and circuitry provide a powerful model for understanding how functional brain networks are formed. Two primary germinal zones generate the cells that make up the cerebellum. Each zone expresses a specific set of genes that establish the cell lineages within the cerebellar anlage. Then, cohorts of differentiated projection neurons and interneuron progenitors migrate into the developing cerebellum. Thereafter, a number of remarkable patterning events occur including transformation of the smooth cerebellar surface into an intricately patterned series of folds, formation of three distinct cellular layers, and the demarcation of parasagittal gene expression domains. Together, these structural and molecular organizations are thought to support the proper connectivity between incoming afferent projections and their target cells. After birth, genetic programs and neural activity repattern synaptic connections into topographic neural networks called modules, which are organized around a longitudinal zone plan and are defined by their molecular, anatomic, and functional properties. WIREs Dev Biol 2013, 2:149-164. doi: 10.1002/wdev.65 For further resources related to this article, please visit the WIREs website. PMID- 23799635 TI - Cilia-mimetic hairy surfaces based on end-immobilized nanocellulose colloidal rods. AB - We show a simple method toward nanoscale cilia-like structures, i.e., functional hairy surfaces, upon topochemically functionalizing nanorods of cellulose nanocrystals (CNCs) with thiol end groups (CNC-SHs), which leads to their immobilization onto a gold surface from one end, still allowing their orientational mobility. CNCs having a lateral dimension of 3-5 nm and length of 50-500 nm incorporate the native crystalline structure with hydrogen-bonded cellulose chains in the parallel configuration. This facilitates asymmetric, selective chemical modification of the reducing ends through reductive amination. Successful thiol functionalization is demonstrated using cryo transmission electron microscopy based on selective attachment of silver nanoparticles to the CNC-SH ends to form Janus-like colloidal rod-sphere adducts. The extent of thiol modification of CNC-SHs is quantified using X-ray photoelectron spectroscopy. The promoted binding of CNC-SHs on gold surfaces is shown by atomic force microscopy and quartz crystal microbalance, where the high dissipation suggests pronounced orientational mobility due to flexible joints at one rod end onto the surfaces. That the joints are flexible is also shown by the bending and realignment of the CNC-SH rods using a receding triple-phase evaporation front of a drying drop of water. The ability of the hairy surface to size-selectively resist particle binding was also investigated. As the CNCs are piezoelectric and allow magnetic functionalization by nanoparticles, we foresee a general platform for nanosized artificial cilia for fluid manipulation and controlled adsorption/desorption. PMID- 23799636 TI - Singlet oxygen formation from wastewater organic matter. AB - Singlet oxygen ((1)O2) plays an important role in the inactivation of pathogens and the degradation of organic contaminants. The present study looks at the surface steady-state concentration of (1)O2 and quantum yields (PhiSO) for organic matter present in or derived from wastewater (WWOM), including those that are partially treated and after undergoing oxidation. The surface steady state concentrations of (1)O2 ranged from 1.23 to 1.43 * 10(-13) M for bulk wastewaters under simulated sunlight. The PhiSO values for these samples varied from 2.8% to 4.7% which was higher than the values observed for the natural organic matter isolates evaluated (1.6-2.1%). Size fractionation of WWOM resulted in PhiSO increases, with a value of up to 8.6% for one of the <1 kDa fractions. Furthermore, oxidation of WWOM by hypochlorous acid (HOCl) and molecular ozone also resulted in an increase in PhiSO, with the highest measured value being 9.3%. This research further explores the correlations between the photosensitizing properties of WWOM and optical characteristics (e.g., absorbance, E2:E3 ratio). Making use of easily measurable absorbance values, a model for the prediction of (1)O2 steady-state concentrations is proposed. PMID- 23799637 TI - Catalytic epoxidation activity of keplerate polyoxomolybdate nanoball toward aqueous suspension of olefins under mild aerobic conditions. AB - Catalytic efficiency of a sphere-shaped nanosized polyoxomolybdate {Mo132} in the aerobic epoxidation of olefins in water at ambient temperature and pressure in the absence of reducing agent is exploited which resulted good-to-high yields and desired selectivity. PMID- 23799638 TI - MoSe2 and WSe2 nanofilms with vertically aligned molecular layers on curved and rough surfaces. AB - Two-dimensional (2D) layered materials exhibit high anisotropy in materials properties due to the large difference of intra- and interlayer bonding. This presents opportunities to engineer materials whose properties strongly depend on the orientation of the layers relative to the substrate. Here, using a similar growth process reported in our previous study of MoS2 and MoSe2 films whose layers were oriented vertically on flat substrates, we demonstrate that the vertical layer orientation can be realized on curved and rough surfaces such as nanowires (NWs) and microfibers. Such structures can increase the surface area while maintaining the perpendicular orientation of the layers, which may be useful in enhancing various catalytic activities. We show vertically aligned MoSe2 and WSe2 nanofilms on Si NWs and carbon fiber paper. We find that MoSe2 and WSe2 nanofilms on carbon fiber paper are highly efficient electrocatalysts for hydrogen evolution reaction (HER) compared to flat substrates. Both materials exhibit extremely high stability in acidic solution as the HER catalytic activity shows no degradation after 15 000 continuous potential cycles. The HER activity of MoSe2 is further improved by Ni doping. PMID- 23799639 TI - Universal multilayer assemblies of graphene in chemically resistant microtubes for microextraction. AB - Graphene is a new kind of two-dimensional carbon nanomaterial with excellent properties and is promising for solid-phase microextraction (SPME). Plastic microtubes such as poly(tetrafluoroethylene) (PTFE) and poly(ether ether ketone) are ideal substrates for in-tube SPME. However, immobilization of graphene layers onto these materials is still a problem due to their nature of chemical resistance. In order to solve the problem, we proposed a novel method based on universal mussel-inspired polydopamine (PD) and layer-by-layer assembly of graphene in this work. To make a graphene assembly layer inside PTFE, the strategy includes two major steps. First, a PD layer is made on the PTFE surface by noncovalent interaction. Second, multilayer graphene is assembled on the PD layer by covalent interaction. By repeating these two steps, a functional graphene oxide (FGO)-modified PTFE tube with a controllable number of layers can be obtained. Morphology of the multilayer structure of graphene has been confirmed by scanning electronic microscopy. Formation of the covalent layer has also been characterized by Foourier transform infrared and X-ray photoelectron spectroscopy. It is very interesting that (FGO-PD)3-PTFE shows exceptional efficiency for SPME. Enrichment from 1082- to 2331-fold was achieved for six polyaromatic hydrocarbons (PAHs). An online SPME-HPLC-fluorescent detection method has been developed on the basis of (FGO-PD)3-PTFE. For qualitative analysis of PAHs, the method has low limits of detection of 0.05-0.1 pg/mL, which is significantly lower (up to 1000 times) than that reported in literature. The method shows wide linear range (0.3-200 pg/mL), good linearity (R(2) >= 0.9968), and good reproducibility (relative standard deviation < 3.4%). The method has been applied to determine PAHs in environmental samples. Good recoveries were obtained, ranging from 85.1% to 96.7%. PMID- 23799641 TI - Indium triiodide catalyzed reductive functionalization of amides via the single stage treatment of hydrosilanes and organosilicon nucleophiles. AB - The indium triiodide catalyzed single-stage cascade reaction of N-sulfonyl amides with hydrosilanes and two types of organosilicon nucleophiles such as silyl cyanide and silyl enolates selectively promoted deoxygenative functionalization to give alpha-cyanoamines and beta-aminocarbonyl compounds, respectively. PMID- 23799640 TI - Non-specificity and synergy at the binding site of the carboplatin-induced DNA adduct via molecular dynamics simulations of the MutSalpha-DNA recognition complex. AB - MutSalpha is the most abundant mismatch-binding factor of human DNA mismatch repair (MMR) proteins. MMR maintains genetic stability by recognizing and repairing DNA defects. Failure to accomplish their function may lead to cancer. In addition, MutSalpha recognizes at least some types of DNA damage making it a target for anticancer agents. Here, complementing scarce experimental data, we report unique hydrogen-bonding motifs associated with the recognition of the carboplatin induced DNA damage by MutSalpha. These data predict that carboplatin and cisplatin induced damaging DNA adducts are recognized by MutSalpha in a similar manner. Our simulations also indicate that loss of base pairing at the damage site results in (1) non-specific binding and (2) changes in the atomic flexibility at the lesion site and beyond. To further quantify alterations at MutSalpha-DNA interface in response to damage recognition, non-bonding interactions and salt bridges were investigated. These data indicate (1) possible different packing and (2) disruption of the salt bridges at the MutSalpha-DNA interface in the damaged complex. These findings (1) underscore the general observation of disruptions at the MutSalpha-DNA interface and (2) highlight the nature of the anticancer effect of the carboplatin agent. The analysis was carried out from atomistic simulations. PMID- 23799642 TI - Analytical and sensory studies on the release of sodium from wheat bread crumb. AB - As a basis for sodium reduction, interactions between sodium and wheat bread ingredients and their impact on salt perception in bread crumb were examined. The theoretical sodium binding capacities of wheat proteins revealed that a maximum amount of 0.24% NaCl (based on flour) could be bound in bread crumb by ionic interactions between sodium ions and acidic amino acid side chains. However, the sodium binding capacities of wheat proteins, determined by a magnetic beads assay and a sodium-selective electrode, were only about 0.002% NaCl. They were negligible concerning the sensory perception of saltiness, as 0.075 and 0.3% NaCl were the lowest noticeable differences using bread containing 0 and 1% NaCl as a reference, respectively. Extracting bread crumb in a mastication simulator with ultrapure water, buffer solutions, and artificial and human saliva revealed that interactions between sodium and wheat bread ingredients were sufficiently weak to enable complete sodium extraction during simulated mastication. PMID- 23799643 TI - Design, synthesis, and evaluation of multitarget-directed resveratrol derivatives for the treatment of Alzheimer's disease. AB - A series of multitarget-directed resveratrol derivatives was designed and synthesized for the treatment of Alzheimer's disease (AD). In vitro studies indicated that most of the target compounds exhibit significant inhibition of self-induced beta-amyloid (Abeta) aggregation and Cu(II)-induced Abeta1-42 aggregation and acted as potential antioxidants and biometal chelators. In particular, compounds 5d and 10d are potential lead compounds for AD therapy (5d, IC50 = 7.56 MUM and 10d, IC50 = 6.51 MUM for self-induced Abeta aggregation; the oxygen radical absorbance capacity assay using fluorescein (ORAC-FL) values are 4.72 and 4.70, respectively). Moreover, these compounds are capable of disassembling the highly structured Abeta fibrils generated by self- and Cu(II) induced Abeta aggregation. Furthermore, 5d crossed the blood-brain barrier (BBB) in vitro and did not exhibit any acute toxicity in mice at doses of up to 2000 mg/kg. Taken together, the data indicate that 5d is a very promising lead compound for AD. PMID- 23799644 TI - Toxicity assessment of cerium oxide nanoparticles in cilantro (Coriandrum sativum L.) plants grown in organic soil. AB - Studies have shown that CeO2 nanoparticles (NPs) can be accumulated in plants without modification, which could pose a threat for human health. In this research, cilantro (Coriandrum sativum L.) plants were germinated and grown for 30 days in soil amended with 0 to 500 mg kg-1 CeO2 NPs and analyzed by spectroscopic techniques and biochemical assays. At 125 mg kg-1, plants produced longer roots (p <= 0.05), and at 500 mg kg-1, there was higher Ce accumulation in tissues (p <= 0.05). At 125 mg, catalase activity significantly increased in shoots and ascorbate peroxidase in roots (p <= 0.05). The FTIR analyses revealed that at 125 mg kg-1 the CeO2 NPs changed the chemical environment of carbohydrates in cilantro shoots, for which changes in the area of the stretching frequencies were observed. This suggests that the CeO2 NPs could change the nutritional properties of cilantro. PMID- 23799645 TI - Isolation and identification of a sibutramine analogue adulterated in slimming dietary supplements. AB - A suspected sibutramine analogue was detected in a slimming functional food by an ultra performance liquid chromatography-electrospray ionisation-time of flight mass spectrometry (UPLC-ESI-TOF/MS) method. The ultraviolet (UV) spectrum of this suspected compound showed close similarity to that of sibutramine. The sample was extracted with 70% MeOH and isolated by semi-preparative column chromatography. The structure of this compound was identified by spectroscopic analyses (nuclear magnetic resonance [NMR] technique, mass and tandem mass etc.). The structure of the unknown compound was demonstrated to be [(+/-)-dimethyl-1-[1-(3,4 dichlorophenyl)cyclobutyl]-N,N,3-trimethylbutan-1-amine (molecular formula C17H25NCl2) and named as chloro-sibutramine. Compared with sibutramine, it has one more chlorine atom than the 3-cholorophenyl group so was switched to 3,4 dichlorophenyl. Until now, chloro-sibutramine was isolated for the first time from the undeclared ingredient included in dietary supplements. Although the safety of chloro-sibutramine is unknown, there is a potential health risk to consumers because of a similar skeleton to sibutramine. For public health, this sibutramine analogue has been included in the inspection list of illegal adulterants in Korea. PMID- 23799646 TI - Behavior of engineered nanoparticles in landfill leachate. AB - This research sought to understand the behavior of engineered nanoparticles in landfill leachate by examining the interactions between nanoparticles and leachate components. The primary foci of this paper are the effects of ZnO, TiO2, and Ag nanoparticles on biological landfill processes and the form of Zn, Ti, and Ag in leachate following the addition of nanoparticles. Insight into the behavior of nanoparticles in landfill leachate was gained from the observed increase in the aqueous concentrations over background for Zn, Ti, and Ag in some tested leachates attributed to leachate components interacting with the nanoparticle coatings resulting in dispersion, dissolution/dissociation, and/or agglomeration. Coated nanoparticles did not affect biological processes when added to leachate; five-day biochemical oxygen demand and biochemical methane potential results were not statistically different when exposed to nanoparticles, presumably due to the low concentration of dissolved free ionic forms of the associated metals resulting from the interaction with leachate components. Chemical speciation modeling predicted that dissolved Zn in leachate was primarily associated with dissolved organic matter, Ti with hydroxide, and Ag with hydrogen sulfide and ammonia; less than 1% of dissolved Zn and Ag was in the free ionic form, and free ionic Ti and Ag concentrations were negligible. PMID- 23799647 TI - Spontaneous freezing of supercooled water under isochoric and adiabatic conditions. AB - The return of a supercooled liquid to equilibrium usually begins with a fast heating up of the sample which ends when the system reaches the equilibrium freezing temperature. At this stage, the system is still a microsegregated mixture of solid and liquid. Only later is solidification completed through the exchange of energy with the surroundings. Using the IAPWS-95 formulation, we investigate the adiabatic freezing of supercooled water in a closed and rigid vessel, i.e., under thermally and mechanically isolated conditions, which captures the initial stage of the decay of metastable water to equilibrium. To improve realism further, we also account for a fixed amount of foreign gas in the vessel. Under the simplifying assumption that the system is at equilibrium immediately after the nominal freezing temperature has been attained, we determine-as a function of undercooling and gas mole number-the final temperature and pressure of the system, the fraction of ice at equilibrium, and the entropy increase. Assuming a nonzero energy cost for the ice-water interface, we also show that, unless sufficiently undercooled, perfectly isolated pure-water droplets cannot start freezing in the bulk. PMID- 23799648 TI - Nutraceutically inspired pectin-Mg(OH)2 nanocomposites for bioactive packaging applications. AB - This paper reports on the development of bioactive edible films based on pectin as a dietary matrix and magnesium hydroxide (Mg(OH)2) nanoplates as a reinforcing filler. Nanocomposites of high-methoxyl (HM) and low-methoxyl (LM) pectins were prepared using the casting method at concentrations of Mg(OH)2 ranging from 0.5 to 5 wt %. Atomic force microscopy and FTIR spectroscopy were employed to characterize the nanocomposite structure. The tensile properties and thermal stability of the nanocomposites were also examined to ascertain the effect of Mg(OH)2 inclusion and degree of methoxylation. The results provided evidence that the Mg(OH)2 nanoplates were uniformly dispersed and interacted strongly with the film matrix. The mechanical and thermal properties were significantly improved in the nanocomposite films compared to the control. Mg(OH)2 nanoplates were more effective in improving properties of LM pectin. Preliminary migration studies using arugula leaves confirmed that pectin-Mg(OH)2 nanocomposites can release magnesium hydroxide by contact, demonstrating their potential for magnesium supplementation in bioactive packaging. PMID- 23799649 TI - Dendritic cell targeted liposomes-protamine-DNA complexes mediated by synthetic mannosylated cholesterol as a potential carrier for DNA vaccine. AB - To construct mannosylated liposomes/protamine/DNA (LPD) carriers for DNA vaccine targeting to dendritic cells (DCs), a mannosylated cholesterol derivative (Man-C6 Chol) was synthesized via simple ester linkage and amide bonds. Then, the Man-C6 Chol was applied to LPD formulation as a synthetic ligand. The physicochemical properties of mannosylated LPD (Man-LPD) were first evaluated, including the size and zeta potential, morphology and the ability to protect DNA against DNase I degradation. Man-LPD showed a small size with a stable viral-like structure. In comparison to non-mannose liposomes/LPD (Man-free liposomes/LPD), mannosylated liposomes/LPD (Man-liposomes/Man-LPD) exhibited higher efficiency in both intracellular uptake (2.3-fold) and transfection (4.5-fold) in vitro. Subsequent MTT assays indicated that the LPD carriers had low toxicity on the tested cells. Afterwards, the investigation into the maturation activation on primary bone marrow-derived DCs (BMDCs) showed that both Man-LPD and Man-free LPD induced remarkable up-regulation of CD80, CD86 and CD40 on BMDCs. Inspired by these studies, we can conclude that the synthetic mannosylated LPD targeting to DCs was a potential carrier for DNA vaccine. PMID- 23799650 TI - Phthalate exposure and allergy in the U.S. population: results from NHANES 2005 2006. AB - BACKGROUND: Environmental exposures to phthalates, particularly high-molecular weight (HMW) phthalates, are suspected to contribute to allergy. OBJECTIVE: We assessed whether phthalate metabolites are associated with allergic symptoms and sensitization in a large nationally representative sample. METHODS: We used data on urinary phthalate metabolites and allergic symptoms (hay fever, rhinitis, allergy, wheeze, asthma) and sensitization from participants >= 6 years of age in the National Health and Nutrition Examination Survey (NHANES) 2005-2006. Allergen sensitization was defined as a positive response to at least one of 19 specific IgE antigens (>= 0.35 kU/L). Odds ratios (ORs) per one log10 unit change in phthalate concentration were estimated using logistic regression adjusting for age, race, body mass index, gender, creatinine, and cotinine. Separate analyses were conducted for children (6-17 years of age) and adults. RESULTS: The HMW phthalate metabolite monobenzyl phthalate (MBzP) was the only metabolite positively associated with current allergic symptoms in adults (wheeze, asthma, hay fever, and rhinitis). Mono-(3-carboxypropyl) phthalate and the sum of diethylhexyl phthalate metabolites (both representing HMW phthalate exposures) were positively associated with allergic sensitization in adults. Conversely, in children, HMW phthalate metabolites were inversely associated with asthma and hay fever. Of the low-molecular-weight phthalate metabolites, monoethyl phthalate was inversely associated with allergic sensitization in adults (OR = 0.79; 95% CI: 0.70, 0.90). CONCLUSION: In this cross-sectional analysis of a nationally representative sample, HMW phthalate metabolites, particularly MBzP, were positively associated with allergic symptoms and sensitization in adults, but there was no strong evidence for associations between phthalates and allergy in children 6-17 years of age. PMID- 23799651 TI - Gold nanorod vaccine for respiratory syncytial virus. AB - Respiratory syncytial virus (RSV) is a major cause of pneumonia and wheezing in infants and the elderly, but to date there is no licensed vaccine. We developed a gold nanorod construct that displayed the major protective antigen of the virus, the fusion protein (F). Nanorods conjugated to RSV F were formulated as a candidate vaccine preparation by covalent attachment of viral protein using a layer-by-layer approach. In vitro studies using ELISA, electron microscopy and circular dichroism revealed that conformation-dependent epitopes were maintained during conjugation, and transmission electron microscopy studies showed that a dispersed population of particles could be achieved. Human dendritic cells treated with the vaccine induced immune responses in primary human T cells. These results suggest that this vaccine approach may be a potent method for immunizing against viruses such as RSV with surface glycoproteins that are targets for the human immune response. PMID- 23799652 TI - Prenatal exposure to persistent organochlorines and childhood obesity in the US collaborative perinatal project. AB - BACKGROUND: In some previous studies, prenatal exposure to persistent organochlorines such as 1,1,-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE), polychlorinated biphenyls (PCBs), and hexachlorobenzene (HCB) has been associated with higher body mass index (BMI) in children. OBJECTIVE: Our goal was to evaluate the association of maternal serum levels of beta-hexachlorocyclohexane (beta-HCH), p,p'-DDE, dichlorodiphenyltrichloroethane (p,p'-DDT), dieldrin, heptachlor epoxide, HCB, trans-nonachlor, oxychlordane, and PCBs with offspring obesity during childhood. METHODS: The analysis was based on a subsample of 1,915 children followed until 7 years of age as part of the U.S. Collaborative Perinatal Project (CPP). The CPP enrolled pregnant women in 1959-1965; exposure levels were measured in third-trimester maternal serum that was collected before these organochlorines were banned in the United States. Childhood overweight and obesity were defined using age- and sex-specific cut points for BMI as recommended by the International Obesity Task Force. RESULTS: Adjusted results did not show clear evidence for an association between organochlorine exposure and obesity; however, a suggestive finding emerged for dieldrin. Compared with those in the lowest quintile (dieldrin, < 0.57 MUg/L), odds of obesity were 3.6 (95% CI: 1.3, 10.5) for the fourth and 2.3 (95% CI: 0.8, 7.1) for the highest quintile. Overweight and BMI were unrelated to organochlorine exposure. CONCLUSIONS: In this population with relatively high levels of exposure to organochlorines, no clear associations with obesity or BMI emerged. PMID- 23799653 TI - Coaxial PCL/PVA electrospun nanofibers: osseointegration enhancer and controlled drug release device. AB - The failure of prosthesis after total joint replacement is mainly due to dysfunctional osseointegration and implant infection. There is a critical need for orthopedic implants that promote rapid osseointegration and prevent bacterial colonization, particularly when placed in bone compromised by disease or physiology of the patients. The aim of this study was to fabricate a novel coaxial electrospun polycaprolactone (PCL)/polyvinyl alcohol (PVA) core-sheath nanofiber (NF) blended with both hydroxyapatite nanorods (HA) and type I collagen (Col) (PCL(Col)/PVA(HA)). Doxycycline (Doxy) and dexamethasone (Dex) were successfully incorporated into the PCL(Col)/PVA(HA) NFs for controlled release. The morphology, surface hydrophilicity and mechanical properties of the PCL/PVA NF mats were analyzed by scanning electron microscopy, water contact angle and atomic force microscopy. The PCL(Col)/PVA(HA) NFs are biocompatible and enhance the adhesion and proliferation of murine pre-osteoblastic MC3T3 cells. The release of Doxy and Dex from coaxial PCL(Col)/PVA(HA) NFs showed more controlled release compared with the blended NFs. Using an ex vivo porcine bone implantation model we found that the PCL(Col)/PVA(HA) NFs bind firmly on the titanium rod surface and the NFs coating remained intact on the surface of titanium rods after pullout. No disruption or delamination was observed after the pullout test. These findings indicate that PCL(Col)/PVA(HA) NFs encapsulating drugs have great potential in enhancing implant osseointegration and preventing implant infection. PMID- 23799654 TI - Organ size increases with weight gain in power-trained athletes. AB - The purpose of this study was to determine whether overfeeding and high-intensity physical training increase organ mass. We examined this question using cross sectional and longitudinal studies in which we measured collegiate male American football players. Freshman (n = 10) and senior players in their second and third years of college (n = 17) participated in the cross-sectional study. The same measurements of the same freshman players (n = 10) were assessed after the one year weight gain period in the longitudinal study. Fat-free mass (FFM), skeletal muscle, and adipose tissue mass were obtained using dual-energy X-ray absorptiometry. Liver, kidney, brain, and heart volumes were calculated using magnetic resonance imaging or echocardiography. Compared with the freshman players, the senior players had 10.8 kg more FFM, and 0.29 kg, 0.08 kg, and 0.09 kg greater liver, heart, and kidney mass, respectively. In the longitudinal study, FFM, liver, heart, and kidney mass of the freshman players increased by 5.2 kg, 0.2 kg, 0.04 kg, and 0.04 kg, respectively, after one year of overfeeding and physical training. On the other hand, the organ-tissue mass to FFM ratio did not change, except for the brain, in either the cross-sectional or longitudinal studies. Our results indicated that the organ-tissue masses increased with overfeeding and physical training in male collegiate American football players. PMID- 23799655 TI - Proteomic analysis of nuclei dissected from fixed rat brain tissue using expression microdissection. AB - Expression microdissection (xMD) is a high-throughput, operator-independent technology that enables the procurement of specific cell populations from tissue specimens. In this method, histological sections are first stained for cellular markers via either chemical or immuno-guided methods, placed in close contact with an ethylene vinyl acetate (EVA) film, and exposed to a light source. The focal, transient heating of the stained cells or subcellular structures melts the EVA film selectively to the targets for procurement. In this report, we introduce a custom-designed flashcube system that permits consistent and reproducible microdissection of nuclei across an FFPE rat brain tissue section in milliseconds. In addition, we present a method to efficiently recover and combine captured proteins from multiple xMD films. Both light and scanning electron microscopy demonstrated captured nuclear structures. Shotgun proteomic analysis of the samples showed a significant enrichment in nuclear localized proteins, with an average 25% of recovered proteins localized to the nucleus, versus 15% for whole tissue controls (p < 0.001). Targeted mass spectrometry using multiple reaction monitoring (MRM) showed more impressive data, with a 3-fold enrichment in histones, and a concurrent depletion of proteins localized to the cytoplasm, cytoskeleton, and mitochondria. These data demonstrate that the flashcube-xMD technology is applicable to the proteomic study of a broad range of targets in molecular pathology. PMID- 23799656 TI - Examining the impact of obesity on individuals with chronic fatigue syndrome. AB - Chronic fatigue syndrome (CFS) is a complex disorder affecting multiple body systems. The most commonly used definition of CFS is 6 or more months of fatigue and the presence of at least four of eight minor symptoms. In addition, many health and psychological conditions, including severe obesity-body mass index (BMI) of 40 kg/m(2) or greater-exclude individuals from a diagnosis of CFS. Obesity has been correlated with fatigue, sleep problems, and less satisfaction with general health, functioning, and vitality. The current study investigated weight trends over time in a community-based sample of individuals with CFS and healthy controls. The study further investigated the impact of comorbid weight issues on several health and disability outcomes in a subset of overweight individuals. Overweight and obese individuals with CFS demonstrated poorer functioning than controls who were similarly weighted. One participant was excluded because she had gained weight at a monitoring visit and her BMI was greater than 40 kg/m(2). The implications of these findings for health care workers are discussed. PMID- 23799658 TI - Promoting universal vaccination among workers. AB - A discussion of vaccines often focuses on protecting children from vaccine preventable diseases. However, 10 vaccines are available for adults, and occupational health nurses should consider these vaccines when providing health care to adult workers. This article discusses the 10 adult vaccines, indications for using each vaccine, barriers preventing adults from being vaccinated and occupational health nurses from increasing vaccination rates, and strategies nurses can use to promote adult vaccination. Promoting universal vaccination among adults, especially employees, accomplishes two goals. First, universal vaccination promotes a healthy work force, enabling employees to report to work regularly and be more productive while working. Second, vaccinating adults protects the most vulnerable members of the community, young children, those with immunodeficiencies, and those who cannot be vaccinated, via herd immunity. PMID- 23799657 TI - Female farmworkers' health during pregnancy: health care providers' perspectives. AB - Pregnant farmworkers and their fetuses are at increased risk of negative health outcomes due to environmental and occupational factors at their workplaces. Health care providers who serve farm communities can positively affect workers' health through the informed care they deliver. Yet, interviews with rural health care providers reveal limited knowledge about agricultural work or occupational and environmental health risks during pregnancy. Professional associations, government organizations, academic institutions, and practice settings must renew their efforts to ensure that environmental and occupational health education, especially as it relates to women and their children, is incorporated into academic and practice environments. PMID- 23799659 TI - The graphene/Au/Ni interface and its application in the construction of a graphene spin filter. AB - A modification of the contact of graphene with ferromagnetic electrodes in a model of the graphene spin filter allowing restoration of the graphene electronic structure is proposed. It is suggested for this aim to intercalate into the interface between the graphene and the ferromagnetic (Ni or Co) electrode a Au monolayer to block the strong interaction between the graphene and Ni (Co) and, thus, prevent destruction of the graphene electronic structure which evolves in direct contact of graphene with Ni (Co). It is also suggested to insert an additional buffer graphene monolayer with the size limited by that of the electrode between the main graphene sheet providing spin current transport and the Au/Ni electrode injecting the spin current. This will prevent the spin transport properties of graphene from influencing contact phenomena and eliminate pinning of the graphene electronic structure relative to the Fermi level of the metal, thus ensuring efficient outflow of injected electrons into the graphene. The role of the spin structure of the graphene/Au/Ni interface with enhanced spin orbit splitting of graphene pi states is also discussed, and its use is proposed for additional spin selection in the process of the electron excitation. PMID- 23799660 TI - In situ control of oxygen vacancies in TiO2 by atomic layer deposition for resistive switching devices. AB - Oxygen vacancies (V(O)) have profound effects on the physical and chemical performance of devices based on oxide materials. This is particularly true in the case of oxide-based resistive random access memories, in which memory switching operation under an external electrical stimulus is closely associated with the migration and ordering of the oxygen vacancies in the oxide material. In this paper, we report on a reliable approach to in situ control of the oxygen vacancies in TiOx films. Our strategy for tight control of the oxygen vacancy is based on the utilization of plasma-enhanced atomic layer deposition of titanium oxide under precisely regulated decomposition of the precursor molecules (titanium (IV) tetraisopropoxide, Ti[OCH(CH3)2]4) by plasma-activated reactant mixture (N2+O2). From the various spectroscopic and microstructural analyses by using Rutherford backscattering spectrometry, x-ray photoelectron spectroscopy, high-resolution transmission electron microscopy, confocal Raman spectroscopy, and spectroscopic ellipsometry, we found that the precursor decomposition power (R(F)) of plasma-activated reactant mixture determines not only the oxygen vacancy concentration but also the crystallinity of the resulting TiO(x) film: nanocrystalline anatase TiO(x) with fewer oxygen vacancies under high R(F), while amorphous TiOx with more oxygen vacancies under low RF. Enabled by our controlling capability over the oxygen vacancy concentration, we were able to thoroughly elucidate the effect of oxygen vacancies on the resistive switching behavior of TiO(x)-based memory capacitors (Pt/TiO(x)/Pt). The electrical conduction behavior at the high resistance state could be explained within the framework of the trap-controlled space-charge-limited conduction with two characteristic transition voltages. One is the voltage (V(SCL)) for the transition from Ohmic conduction to space-charge-limited conduction, and the other is the voltage (V(TFL)) for transition from space-charge-limited conduction to trap-filled-limited conduction. In this work, we have disclosed for the first time the dependence of these two characteristic transition voltages (i.e., V(SCL) and V(TFL)) on the oxygen vacancy concentration. PMID- 23799661 TI - An electrochemical aptasensor based on the amplification of two kinds of gold nanocrystals for the assay of L-histidine with picomolar detection limit. AB - Au nanocrystals (NCs) enclosed by higher-index facets have high surface chemical activity. They attract much attention because of their excellent biocompatibility. In this work, well-defined elongated tetrahexahedral (ETHH) Au NCs and end-truncated ETHH with high-index facets are successfully prepared by using a single surfactant system of didodecyldimethylammonium bromide (DDAB) and a binary system of cetyltrimethylammoniumbromide and DDAB in two-step seed mediated growth. The characteristics of high-index facet Au NC modified electronic aptamer-based sensors are presented and they are applicable to a wide range of aptamers. Herein, we only take L-histidine as the representative sensing target. With modification of the Au NCs, a very low detection limit (sub picomolar) is obtained. In particular, a detailed sensitivity comparison between the modification of end-truncated ETHH and ETHH Au NCs is presented to demonstrate the slight difference in the chemical activities of Au NCs with different high-index facets. Our work sheds light on the large scale fabrication of Au/metallic NCs with high-index facets and also provides a new eye-opening example of engineering ultra-sensitive DNA sensors based on Au NCs. PMID- 23799662 TI - An ultraviolet photodetector fabricated from WO3 nanodiscs/reduced graphene oxide composite material. AB - A high sensitivity, fast ultraviolet (UV) photodetector was fabricated from WO3 nanodiscs (NDs)/reduced graphene oxide (RGO) composite material. The WO3 NDs/reduced GO composite material was synthesized using a facile three-step synthesis procedure. First, the Na2WO4/GO precursor was synthesized by homogeneous precipitation. Second, the Na2WO4/GO precursor was transformed into Na2WO4/GO composites by acidification. Finally, the Na2WO4/GO composites were reduced to WO3 NDs/RGO via a hydrothermal reduction process. The UV photodetector showed a fast transient response and high responsivity, which are attributed to the improved carrier transport and collection efficiency through graphene. The excellent material properties of the WO3 NDs/RGO composite demonstrated in this work may open up new possibilities for using WO3 NDs/RGO for future optoelectronic applications. PMID- 23799664 TI - Developing Galleria mellonella as a model host for human pathogens. PMID- 23799663 TI - Targeting the bacteria-host interface: strategies in anti-adhesion therapy. AB - Bacterial infections are a major cause of morbidity and mortality worldwide and are increasingly problematic to treat due to the rise in antibiotic-resistant strains. It becomes more and more challenging to develop new antimicrobials that are able to withstand the ever-increasing repertoire of bacterial resistance mechanisms. This necessitates the development of alternative approaches to prevent and treat bacterial infections. One of the first steps during bacterial infection is adhesion of the pathogen to host cells. A pathogen's ability to colonize and invade host tissues strictly depends on this process. Thus, interference with adhesion (anti-adhesion therapy) is an efficient way to prevent or treat bacterial infections. As a basis to present different strategies to interfere with pathogen adhesion, this review briefly introduces general concepts of bacterial attachment to host cells. We further discuss advantages and disadvantages of anti-adhesion treatments and issues that are in need of improvement so as to make anti-adhesion compounds a more broadly applicable alternative to conventional antimicrobials. PMID- 23799666 TI - Virulence profile: Dimitrios P Kontoyiannis. PMID- 23799665 TI - Two quorum sensing systems control biofilm formation and virulence in members of the Burkholderia cepacia complex. AB - The Burkholderia cepacia complex (Bcc) consists of 17 closely related species that are problematic opportunistic bacterial pathogens for cystic fibrosis patients and immunocompromised individuals. These bacteria are capable of utilizing two different chemical languages: N-acyl homoserine lactones (AHLs) and cis-2-unsaturated fatty acids. Here we summarize the current knowledge of the underlying molecular architectures of these communication systems, showing how they are interlinked and discussing how they regulate overlapping as well as specific sets of genes. A particular focus is laid on the role of these signaling systems in the formation of biofilms, which are believed to be highly important for chronic infections. We review genes that have been implicated in the sessile lifestyle of this group of bacteria. The new emerging role of the intracellular second messenger cyclic dimeric guanosine monophosphate (c-di-GMP) as a downstream regulator of the fatty acid signaling cascade and as a key factor in biofilm formation is also discussed. PMID- 23799668 TI - The diabetes healthy outcomes program: results of free health care for uninsured at a federally qualified community health center. AB - BACKGROUND: Uninsured patients with diabetes are at increased risk for poor outcomes and often have limited access to health and prescription services necessary to manage diabetes. Hamilton Health Center, a federally qualified community health center, with support from the Highmark Foundation, implemented a Diabetes Healthy Outcomes Program (DHOP) for uninsured patients. PURPOSE: To evaluate the effectiveness of DHOP that is designed to provide health care and supportive services for uninsured diabetic patients at a federally qualified community health center. METHODS: Mixed quantitative and qualitative analyses of participant outcomes and satisfaction were used to assess program effectiveness. RESULTS: A total of 189 participants enrolled in DHOP over 2 years. Thirty-four (18%) participants had adequate glycemic control with hemoglobin A1c (HbA1c) <= 7%. Overall, 105 participants received prescription drugs, 101 participants received eye care services, 23 participants received dental services, 45 received podiatry services, 37 received nutrition services, and 28 patients engaged in an exercise program. More participants (38%, 34) had controlled diabetes mellitus at study start than at the end (28%, 25). However, 30% versus 17% of participants with 2 HbA1c measurements achieved or maintained HbA1c <= 7% by the end of the program compared with the start. Participants who accessed more services were more likely to achieve glycemic control as measured by HbA1c (P > .01). CONCLUSION: Although 30% of participants improved or maintained glycemic control over 2 years, more were uncontrolled at the end than at study start. Participants who accessed more primary and specialty care services were more likely to achieve glycemic control. Multidisciplinary care may improve diabetes control in low income patients. PMID- 23799667 TI - Outcomes of bereavement care among widowed older adults with complicated grief and depression. AB - Bereavement is common among older adults and may result in major depression or complicated grief (CG). Little is known about the effectiveness of physician care for these conditions. We examined whether, among older adults with CG and/or major depression, using physician support was associated with reductions in grief, depression, or anxiety severity. Outcomes were compared to group and religious support. We analyzed data from the Changing Lives of Older Couples (CLOC) Study, a prospective cohort study of married couples in the Detroit area. Spousal death was tracked over 5 years, and follow-up interviews conducted with widowed participants at 6 months (wave 1) and 18 months (wave 2) post loss. Analyses were limited to those with CG or depression with support-seeking data (weighted n = 89). Yes/no items asked whether participants had seen each provider for help with grief up until wave 1. A 19-item grief severity measure was developed by CLOC researchers. The 20-item Center for Epidemiologic Studies Depression scale measured depression severity. The Symptom Checklist 90-Revised assessed anxiety severity. Regressions indicated that seeking support from a family doctor at wave 1 was not associated with changes in anxiety, depression, or grief severity at wave 2 (P > .05). However, support group use was associated with reductions in grief severity (beta = -8.46, P < .05), and religious leader support-seeking associated with reductions in depression severity (beta = -10.12, P < .01). Findings imply that physician care for grief may not be effective, and support group referral may be helpful. Physicians may benefit from training in recognizing and appropriate referring for bereavement-related distress. PMID- 23799669 TI - Sunbed use, attitudes, and knowledge after the under-18s ban: a school-based survey of adolescents aged 15 to 17 years in Sandwell, United Kingdom. AB - BACKGROUND: Sunbed use in childhood increases risk of melanoma. The under-18s sunbed ban was introduced in England, April 2011. Impact on use has not been investigated since. This cross-sectional study estimates the prevalence of under 18s' use in Sandwell after the commercial ban and identifies factors associated with use/intention. METHODS: Adolescents aged 15 to 17 years in schools were surveyed using self-completed anonymous questionnaires. Data collected include demographics, sunbed use, tanning attitudes, knowledge of risks and ban awareness. All Sandwell schools were approached; adolescents available on the survey days were included. RESULTS: Five out of 22 schools participated, 407 adolescents responded (95.1%). Twenty participants (5.3%; 95% confidence interval [CI] = 3.4-8.0) had used sunbeds, of who 16 reported use in commercial settings. After exclusion of one school cohort with atypical use (possibly associated with beauty vocational course and European migrants), the prevalence of use was 1.7% (95% CI = 0.7-3.9, n = 5). Less than half of all were aware of the ban (48.2%; 95% CI = 43.2-53.3). Users/potential users were less aware of associated risks. Being female, having family/friends who use sunbeds increased use/intention 2- to 4-fold. CONCLUSION: Strategies targeting parents, stricter enforcement, and greater publicity of the ban are needed. Further research exploring the possible association between certain vocational courses, migrants, and sunbed use is required. PMID- 23799670 TI - Practice-based interventions addressing concomitant depression and chronic medical conditions in the primary care setting: a systematic review and meta analysis. AB - BACKGROUND: Depression concomitant with chronic medical conditions is common and burdensome in primary care. OBJECTIVE: To assess the effectiveness of practice based interventions for improving depression and chronic medical outcomes. DATA SOURCES: MEDLINE, Embase, the Cochrane Library, CINAHL, and PsycINFO from inception to June 11, 2012. STUDY SELECTION, APPRAISAL, AND SYNTHESIS: Two reviewers independently selected, extracted data from, and rated the quality of trials and systematic reviews. Strength of evidence (SOE) was graded using established criteria. RESULTS: Twenty-four published articles reported data from 12 studies, all at least 6 months long. All studies compared a form of collaborative care with usual or enhanced usual care. Studies evaluated adults with arthritis, cancer, diabetes, heart disease, HIV, or multiple medical conditions. Meta-analyses found that intervention recipients achieved greater improvement than controls in depression symptoms, response, remission, and depression-free days (moderate SOE); satisfaction with care (moderate SOE); and quality of life (moderate SOE). Few data were available on outcomes for chronic medical conditions. Meta-analyses revealed that patients with diabetes receiving collaborative care exhibited no difference in diabetes control compared with control groups (change in HbA1c: weighted mean difference 0.13, 95% confidence interval = -0.22 to 0.48 at 6 months; 0.24, 95% confidence interval = -0.14 to 0.62 at 12 months; low SOE). The only study to use HbA1c as a predefined outcome measure and a "treat-to-target" intervention for diabetes as well as depression, TEAMcare, reported significant reductions in HbA1c (7.42 vs 7.87 at 6 months; 7.33 vs 7.81 at 12 months; overall P < .001). LIMITATIONS: Few relevant trials reported on medical outcomes. CONCLUSIONS: Collaborative care interventions improved outcomes for depression and quality of life in primary care patients with varying medical conditions. Few data were available on medical outcomes. Future studies of concomitant depression and chronic medical conditions should consider measures of medical outcomes as primary outcomes. PMID- 23799671 TI - Impact of implementing mental health screening by mail with a primary care management model. AB - BACKGROUND: Early recognition and treatment of social and emotional disorders in children is significant for school preparation. These disorders are frequently underdetected without the use of standardized screening instruments. The purpose of our study is to describe the implementation of the Ages and Stages Questionnaire: Social-Emotional (ASQ:SE) in primary care practice by mail when children are 30 months old. METHODS: In this 4-month study, parents of all 30 month-old children who receive primary care at our study site were mailed the ASQ:SE. In children who did not pass screening or received a call from a registered nurse for parental concerns documented on the questionnaire, short term clinical outcomes were obtained from the electronic medical record. During the last month of the study, the demographics variables of race and insurance type were analyzed for an association with questionnaire completion by mail. RESULTS: Of the 870 families mailed 30-month ASQ:SE screens, 507 (58.3%) were returned by mail. Out of the children with returned screens, 38 (7.5%) of parents were contacted for either elevated scores or concerning comments and 6 (1.2%) were referred to Early Intervention. Parents of children with government insurance returned the ASQ:SE questionnaire 34.2% (13/38) of the time compared with 65.5% (76/116) of those with private insurance (P < .001). CONCLUSION: Our results indicate that mental health screening can be effectively managed in primary care practice by a registered nurse using a follow-up protocol. Mailing the ASQ:SE is likely not an effective way to comprehensively screen most primary care populations. PMID- 23799672 TI - Sync and swim: the impact of medication consolidation on adherence in Medicaid patients. AB - BACKGROUND: Medication nonadherence is associated with higher cost of care and poor outcomes. Medication refill consolidation (synchronization of refill dates for patients on multiple drugs) is an important component of regimen complexity. We presumed that Medicaid patients with a 30-day medication supply limit would have significant difficulty with refill consolidation. We evaluated regimen complexity and refill consolidation in relation to medication adherence in the Medicaid population. METHODS: A survey was administered to 50 Medicaid patients taking 2 or more daily medications in the outpatient setting. The survey included demographics, 13 items related to medication and pharmacy history, and 10 items related to medication regimen complexity and refill consolidation. Chi-square analysis was used to assess the relationship between adherence and missed medication doses due to regimen complexity. Wilcoxon rank sum test was used to determine association between total number of prescribing providers and number of daily medications with various aspects of regimen complexity. RESULTS: 52% were required to go to the pharmacy more than once per month to keep all of their medications filled and 46% missed a day or more of medication because their medications must be refilled on different dates. Those who missed a day or more of medication because of need to refill prescriptions on different days had higher number of prescriptions (P = .03) and higher number of prescribers (P = .03). CONCLUSION: Medicaid patients had low medication adherence in the context of high regimen complexity and poor refill consolidation. This population would benefit from interventions focused on improving synchronization of medication refills. PMID- 23799673 TI - Describing adolescent breastfeeding environments through focus groups in an urban community. AB - PURPOSE: Breastfeeding is a potential solution to improve health outcomes for adolescent mothers and infants. Adolescence is a risk factor for low breastfeeding rates and is associated with a higher risk for perinatal complication. This study investigated facilitators and barriers to adolescent breastfeeding initiation and duration in an urban setting. METHODS: Four, 1-hour focus groups were conducted. Twenty-nine (N = 29) adolescent mothers and pregnant adolescents participated and described attitudes toward breastfeeding, attitudes among family and friends, current knowledge, and barriers and facilitators for breastfeeding. RESULTS: Four themes emerged, including the following: behavioral histories of breastfeeding, community assets, social support, and barriers. Participants identified positive histories and community resources such as local hospitals and social services as facilitators. Lifestyle, independence, lack of support from family and primary care providers, social stigma/embarrassment, and difficulty with breastfeeding techniques were described as barriers. CONCLUSION: A comprehensive and integrated primary care and public health community effort is needed to support and improve adolescent breastfeeding. Further examination of integrated interventions focused on adolescent breastfeeding behaviors through an environmental approach is needed. PMID- 23799674 TI - Evaluation of fecal immunochemical tests for colorectal cancer screening. AB - BACKGROUND: Colorectal cancer (CRC) screening reduces the mortality due to CRC. It is important for health care providers to be aware of the variation in the products available for CRC screening. PURPOSE: The purpose of this study was to summarize the accuracy of results of individual fecal immunochemical test (FIT) products across pathology proficiency testing programs. METHODS: Secondary data analysis of proficiency testing programs' FIT results. RESULTS: Four of 7 proficiency testing program's FIT evaluations were obtained for a 2-year period. Fourteen unique FIT brands were evaluated by at least 1 of the 4 proficiency testing programs. Five of the products performed similarly with sensitivities ranging from 98.1% to 98.8% and specificities from 98.1% to 99.6%. Ninety-three percent of the FIT tests completed were manual Clinical Laboratory Improvement Amendments-waived FITs. CONCLUSIONS: About two thirds of the commonly used FIT products performed acceptably on spiked samples of human hemoglobin. However, some had low sensitivity and specificity and probably should not be used for population-based or other screening. Further investigation to determine appropriate, reliable products for fecal occult blood testing is warranted. PMID- 23799675 TI - Clinical supervision among family physicians: prevalence, needs, and attitudes. AB - BACKGROUND: Clinical supervision (CS) is not an established support system among physicians. Family physicians (FPs) have used Balint groups as a form of clinical supervision. In all, not much is known about the prevalence of physicians' attendance to or needs for CS. OBJECTIVE: We studied what proportion of FPs compared with other physicians have attended or report they would need CS and whether having patients who request certain tests or medicines is associated with FPs' attendance to or need for CS. DESIGN: A postal survey for all working-aged Finnish physicians was performed in 2008. Special questions concerning CS (eg, Balint) and patients' requests were included. RESULTS: Response rate for the survey was 74% (N = 13 708). Special questions were responded by 10 559 physicians of whom 1252 were FPs. FPs had attended CS more often than other physicians (42% vs 29%, P < .001). Of FPs, 25% reported a need for CS with no availability of it. FPs experienced with or needing for CS were more often than other FPs females, had participated in continuing medical education, and reported that patients with requests have increased in recent years. CONCLUSION: Both experience of CS and a need for CS with no availability are common among Finnish FPs. Experiences of patients with requests may reflect a need for CS among FPs. Studies on the content, significance and effectiveness CS among FPs are needed. PMID- 23799676 TI - Assessing long-term health and cost outcomes of patient-centered medical homes serving adults with poor diabetes control. AB - The patient-centered medical home (PCMH) is an integrated primary care delivery model particularly suited for patients with poor diabetes control. Although PCMH models targeting adults with diabetes have shown some early success, little is known about the long-term benefits of medical homes in terms of health and cost outcomes. The performance of a PCMH model in adults with poor diabetes control was assessed using simulated controlled trial data obtained from the Archimedes model of disease progression and health care utilization. Using the Cardio Metabolic Risk data set, we compared health and cost outcomes over a 20-year period between adults with poor diabetes control (HbA1c >9%) receiving standard care and these same adults receiving care under a PCMH model with a 49% HbA1c intervention improvement rate at a per-beneficiary per-month care management cost of $20 per month. The results suggest that the PCMH model has the potential to not only reduce the proportion of the population with bilateral blindness, foot amputations, and myocardial infarctions-and the mortality rate-but it can also do so in a cost-effective manner ($7898 per quality-adjusted life year). The PCMH model is cost saving for the population 50 to 64 years old and it is particularly cost-effective for men ($883 per quality-adjusted life year). Moreover, these effects are relatively large for adults 30 to 49 years old (lower bilateral blindness and death rates), women (lower foot amputation and death rates), and men (lower bilateral blindness and myocardial infarction rates). The PCMH model has potential long-term benefits to both patients with poor diabetes control as well as health care systems and providers willing to invest in this health care delivery approach. PMID- 23799677 TI - Examining health care costs among MANNA clients and a comparison group. AB - Chronically ill populations have a strong need for quality public health nutrition services to aid in disease management and improve health outcomes. Evidence suggests that neglecting the importance of adequate nutrition in chronically ill patients has far-reaching implications on the health status of the individual and the health care costs. Research is currently lacking a focus on this topic. This pilot study done through the nonprofit organization MANNA (Metropolitan Area Neighborhood Nutrition Alliance), which serves the greater Philadelphia area, explored the health care expenditures of 65 MANNA clients over time in comparison with a similar group of Medicaid patients who did not receive MANNA services. Health care expenditures were examined before and after clients began receiving services. The study found that the mean monthly health care costs decreased for three consecutive months after initiation of MANNA services. Other health care cost-related factors, such as inpatient costs, length of stay, and number of hospital admissions also displayed a downward trend. These results help show the significance of medical nutrition therapy and home-delivered meal services on overall health care. PMID- 23799678 TI - Integration of depression and primary care: barriers to adoption. AB - OBJECTIVE: Despite the prevailing consensus as to its value, the adoption of integrated care models is not widespread. Thus, the objective of this article it to examine the barriers to the adoption of depression and primary care models in the United States. METHODS: A literature search focused on peer-reviewed journal literature in Medline and PsycInfo. The search strategy focused on barriers to integrated mental health care services in primary care, and was based on previously existing searches. The search included: MeSH terms combined with targeted keywords; iterative citation searches in Scopus; searches for grey literature (literature not traditionally indexed by commercial publishers) in Google and organization websites, examination of reference lists, and discussions with researchers. FINDINGS: Integration of depression care and primary care faces multiple barriers. Patients and families face numerous barriers, linked inextricably to create challenges not easily remedied by any one party, including the following: vulnerable populations with special needs, patient and family factors, medical and mental health comorbidities, provider supply and culture, financing and costs, and organizational issues. CONCLUSIONS: An analysis of barriers impeding integration of depression and primary care presents information for future implementation of services. PMID- 23799679 TI - A hybrid BCI system combining P300 and SSVEP and its application to wheelchair control. AB - In this paper, a hybrid brain-computer interface (BCI) system combining P300 and steady-state visual evoked potential (SSVEP) is proposed to improve the performance of asynchronous control. The four groups of flickering buttons were set in the graphical user interface. Each group contained one large button in the center and eight small buttons around it, all of which flashed at a fixed frequency (e.g., 7.5 Hz) to evoke SSVEP. At the same time, the four large buttons of the four groups were intensified through shape and color changes in a random order to produce P300 potential. During the control state, the user focused on a desired group of buttons (target buttons) to evoke P300 potential and SSVEP, simultaneously. Discrimination between the control and idle states was based on the detection of both P300 and SSVEP on the same group of buttons. As an application, this method was used to produce a "go/stop" command in real-time wheelchair control. Several experiments were conducted, and data analysis results showed that combining P300 potential and SSVEP significantly improved the performance of the BCI system in terms of detection accuracy and response time. PMID- 23799680 TI - Exposure system and dosimetry for in vitro studies of biocompatibility of pulse modulated RF signals of ultrahigh field MRI. AB - A new setup for exposure of human cells in vitro at 37 degrees C to pulse modulated 300 and 500 MHz signals of future magnetic resonance imaging (MRI) systems is designed, built up, and characterized. Two dipole antennas, specifically designed for ultrahigh field MRI, are used as radiating structures. The electromagnetic (EM) field distribution inside the incubator containing the cells is computed, and it is shown to be in a good agreement with measurements. The electric field at the cell level is quantified numerically. Local, 1-g average, and averaged over the culture medium volume SAR are provided along with the standard deviation values for each well. Temperature increments are measured inside the culture medium during the exposure using an optical fiber thermometer. Then, we identify the pulse parameters corresponding to the thermal threshold of 1 degrees C, usually considered as a threshold for thermally induced biological effects. For these parameters, the induction of heat shock proteins is assessed to biologically verify a potential thermal response of cells. The data demonstrate that, under the considered experimental conditions, exposure to pulse modulated radiations emulating typical ultrahigh field MRI signals, corresponding to temperature increments below 1 degrees C, does not trigger any heat shock response in human brain cells. PMID- 23799681 TI - Validation of the inverse pulse wave transit time series as surrogate of systolic blood pressure in MVAR modeling. AB - Short-term cardiovascular regulation mediated by the sympathetic and parasympathetic branches of the autonomic nervous system has been investigated by multivariate autoregressive (MVAR) modeling, providing insightful analysis. MVAR models employ, as inputs, heart rate (HR), systolic blood pressure (SBP) and respiratory waveforms. ECG (from which HR series is obtained) and respiratory flow waveform (RFW) can be easily sampled from the patients. Nevertheless, the available methods for acquisition of beat-to-beat SBP measurements during exams hamper the wider use of MVAR models in clinical research. Recent studies show an inverse correlation between pulse wave transit time (PWTT) series and SBP fluctuations. PWTT is the time interval between the ECG R-wave peak and photoplethysmography waveform (PPG) base point within the same cardiac cycle. This study investigates the feasibility of using inverse PWTT (IPWTT) series as an alternative input to SBP for MVAR modeling of the cardiovascular regulation. For that, HR, RFW, and IPWTT series acquired from volunteers during postural changes and autonomic blockade were used as input of MVAR models. Obtained results show that IPWTT series can be used as input of MVAR models, replacing SBP measurements in order to overcome practical difficulties related to the continuous sampling of the SBP during clinical exams. PMID- 23799682 TI - Evaluation and real-time monitoring of data quality in electrical impedance tomography. AB - Electrical impedance tomography (EIT) is a noninvasive method to image conductivity distributions within a body. One promising application of EIT is to monitor ventilation in patients as a real-time bedside tool. Thus, it is essential that an EIT system reliably provide meaningful information, or alert clinicians when this is impossible. Because the reconstructed images are very sensitive to system instabilities (primarily from electrode connection variability and movement), EIT systems should continuously monitor and, if possible, correct for such errors. Motivated by this requirement, we describe a novel approach to quantitatively measure EIT data quality. Our goals are to define the requirements of a data quality metric, develop a metric q which meets these requirements, and an efficient way to calculate it. The developed metric q was validated using data from saline tank experiments and a retrospective clinical study. Additionally, we show that q may be used to compare the performance of EIT systems using phantom measurements. Results suggest that the calculated metric reflects well the quality of reconstructed EIT images for both phantom and clinical data. The proposed measure can thus be used for real-time assessment of EIT data quality and, hence, to indicate the reliability of any derived physiological information. PMID- 23799683 TI - Testing of a web-based program to facilitate parental smoking cessation readiness in primary care. AB - OBJECTIVE: To test the efficacy of a self-administered web-based computer intervention designed to facilitate readiness to alter tobacco use or secondhand smoke exposure among parents of children visiting a pediatric primary care clinic. The computer program included an assessment of the participant's smoking behavior and personalized feedback. METHODS: Self-identified smoking parents of children presenting to a general pediatric outpatient clinic completed measures of motivation and readiness to cease smoking. Participants were then randomly assigned to complete the computer program or receive treatment as usual. One month after completing the intervention, participants were contacted either in person or by phone to complete measures of motivational readiness to engage in smoking cessation. RESULTS: Compared to treatment-as-usual parents, intervention parents reported increased readiness to change their smoking at follow-up. This effect appeared to strengthen, favoring the intervention condition, when analyses included only those participants who identified at baseline that they were contemplating quitting smoking in the next 6 months. CONCLUSIONS: Results of this small study supported the integration of a brief computerized tobacco intervention in the pediatric primary care setting and provided some evidence for efficacy. Brief, self-administered, and computer-based interventions such as this can be disseminated and deployed at relatively little cost or burden to existing practices, which makes small effects more meaningful and justifiable. Future investigations should investigate this intervention with larger samples and with expanded measures of parent smoking behavior. PMID- 23799684 TI - Evaluation of a standardized all-terrain vehicle safety education intervention for youth in rural Central Illinois. AB - BACKGROUND: Although research investigating all-terrain vehicle (ATV) riders and ATV injury patterns has led to support for legislative and educational efforts to decrease injuries in users younger than 16 years, there is little published data regarding the utility of ATV safety education programs. This study investigates the effectiveness of a standardized adolescent ATV safety program in changing the safety knowledge and safe ATV riding practices reported by rural Central Illinois youths. METHODS: A convenience sample of 260 rural Central Illinois middle and high school students received an ATV safety presentation with both didactic and interactive features during the 2009-2010 school year. Preintervention and postintervention surveys were distributed and collected by teachers. Survey questions consisted of multiple-choice questions pertaining to demographics, ATV safety knowledge, and ATV riding practices. More than 200 surveys were collected prior to the intervention and 165 surveys were collected 12 to 24 weeks after the intervention. Percentages are reported, with differences in nominal variables tested by chi(2) test and interval variables by t test. RESULTS: Following the intervention, there was a significant increase in the correct response rate for ATV safety knowledge questions (45.2% vs 56.2%, P < .001). For adolescents who reported riding ATVs, both safety gear use (11.8% to 21.2%, P = .05) and helmet use (25.4% to 29.0%, P = .56) increased; changes were not significant. Adolescent ATV riders reporting 2 or more accidents showed a slight nonsignificant decrease (25.2% vs 23.4%, P = .77) between the time of the pretest and posttest. CONCLUSION: This safety program was effective at increasing ATV safety knowledge but demonstrates limited effect on safe riding practices. PMID- 23799685 TI - Older adult opinions of "advance driving directives". AB - BACKGROUND: Discussions about driving cessation are difficult. "Advance driving directives" (ADDs), like advance directives for end-of-life care, would allow drivers to designate someone to help make driving decisions for them in the future. It is not known if older drivers support the concept of ADDs. DESIGN AND METHODS: Cross-sectional study of a convenience sample of English-speaking drivers (55+ years) at 2 independent living facilities and 2 community centers who completed anonymous surveys. RESULTS: Of 168 participants, 80% were female; the median age was 76.5 years (range = 56-93 years). Most (74%) drove daily or almost daily, and 7% reported a crash in the past year. Few had spoken with someone about driving safety (5%) or their wishes when driving skills decline (21%). Of the few who had discussed this topic, 83% had spoken with a family member; only 17% had spoken with a health care provider. However, participants were open to driving discussions, and 54% said they would be willing to complete an ADD if recommended. Of these, 79% said it was "likely" or "very likely" they would comply with the directive in the future. Most (73%) supported mandatory, age-based retesting; the median recommended testing age suggested was 80 years. More participants thought the driver (71%), a family member (61%), or a physician (59%) should determine license revocation for an unsafe driver, rather than the department of motor vehicles (32%). CONCLUSIONS: Many older drivers may be open to discussing their driving plans with physicians and family members. ADDs may facilitate these discussions in the present and help define driving-related wishes in the future. PMID- 23799686 TI - HIV screening of patients presenting for routine medical care in a primary care setting. AB - BACKGROUND: HIV screening is recommended for all patients between the ages of 13 and 64 years. OBJECTIVE: To increase the rate of HIV screening in a primary care setting by routinely offering HIV screening to all patients. METHODS: All patients seen over a 3-month period in the authors' clinic were offered HIV screening by a medical assistant. RESULTS: During the 3-month study period, 17% of patients offered HIV testing accepted screening, a large increase from the less than 1% rate of an earlier time period. CONCLUSION: HIV screening can be increased by routinely offering the test to all patients in the office. Use of trained health care professionals other than physicians may increase the number of patients screened. PMID- 23799687 TI - Living Smart, Living Fit: a patient-centered program to improve perinatal outcomes in a community health center population. AB - BACKGROUND: Depression and obesity/overweight during pregnancy are important public health concerns, as they are frequently associated with poor birth outcomes. The Living Smart, Living Fit(r) (LSLF) program was an intervention program initiated in 2008 to provide comprehensive care to low-income pregnant and postpartum women with elevated body mass index (BMI) and depressive symptoms. It linked patients to clinical care coordinators trained in motivational interviewing who promoted participation in a portfolio of mental and physical wellness activities. OBJECTIVE: The objective of this study was to evaluate the effectiveness of LSLF in improving depression, BMI, birth weight, and smoking status among low-income perinatal patients. METHODS: Women with Patient Health Questionnaire (PHQ-9) depression scores >=10 and/or BMI >25 kg/m(2) at their prenatal intake visit were eligible for enrollment into the LSLF program. Enrolled participants met with clinical care coordinators who encouraged engagement in a portfolio of LSLF activities that included pregnancy/family, physical health, and mental health interventions. Outcomes were measured at the 6 week postpartum visit and included change in PHQ-9 scores, change in BMI, birth weight, and change in smoking status. RESULTS: Of the 107 enrollees, 86% participated in some LSLF activity. Participation in pregnancy/family related activities was significantly associated with decreased PHQ-9 scores. Participation in mental health services was significantly associated with increased birth weight. No changes in BMI or smoking status were associated with LSLF involvement. CONCLUSIONS: The findings of this pilot study indicate that pregnant women with depression or obesity/overweight can benefit from care coordination and a portfolio of activities for mental and physical wellness. The LSLF program provides a model for delivering this patient-centered comprehensive support. Further research should include more controlled trials to better evaluate the effectiveness of LSLF intervention. PMID- 23799688 TI - Postpartum doula and peer telephone support for postpartum depression: a pilot randomized controlled trial. AB - OBJECTIVES: This research provides the first test of feasibility of recruiting postpartum doulas and depressed mothers for a peer support intervention study and begins to evaluate the benefit of postpartum doula support and peer telephone support for at-risk mothers. METHODS: The authors recruited postpartum doulas from national doula organizations, peer telephone supporters from nursing referrals, and mothers with depressive symptoms from 3 local hospitals, local medical practices, Web sites, and community organizations. Participating mothers were randomized to 3 groups--postpartum doula, peer telephone support, and control group. Surveys were completed at 0, 3, and 6 months postenrollment. RESULTS: Thirty-nine mothers with depressive symptoms, 6 postpartum doulas, and 6 peer telephone supporters participated. The postpartum doula group, compared with the other 2 groups, had a higher proportion of women with a previous history of depression, and similarly, a higher proportion of women who were depressed and receiving depression treatment at the 6-month follow-up. Satisfaction with study sponsored support was greater in the postpartum doula group than in the telephone support group. CONCLUSIONS: It is feasible to recruit postpartum doulas, peer telephone supporters, and mothers with depressive symptoms for a peer support intervention trial. Mothers were more satisfied with postpartum doulas than peer telephone support. The authors recommend further research to assess the benefit of postpartum doula support for postpartum depression as adjunctive or alternative therapy. PMID- 23799689 TI - Pilot study of a new model for managing hypertension in an uninsured population. AB - For millions of uninsured Americans who have hypertension, quality medical care is too expensive to access with any regularity. The Community-based Chronic Disease Management (CCDM) Clinic was created to deliver clinical care for medically uninsured patients in a setting of low resources and high need. CCDM's model melds nurse-led teams with the chronic disease model and uses evidence based clinical decision protocols. This new model of care differs from traditional models. CCDM conducted a nonrandomized prospective trial of the effectiveness of this new model of care. The intervention included free education, medications, and laboratory investigations. For hypertensives treated for 6 months and 1 year, national benchmark goals were reached for 45% (50/110, P < .00005) and 56% (43/77, P < .00005) of patients, respectively, compared with 18% and 22% being at goal at initial presentation. The CCDM model may have implications for health service delivery in insured populations as well. Further study is warranted. PMID- 23799690 TI - Alcohol outlet availability and excessive alcohol consumption in breast cancer survivors. AB - BACKGROUND: Breast cancer survivors who consume alcohol excessively are at increased risk of recurrence and have worse prognosis. Because the environments in which people live shape many health behaviors, there has been increased attention to how neighborhood environments (eg, alcohol outlet availability) may influence alcohol consumption. The authors hypothesized that proximity to alcohol outlets increases the likelihood of excessive consumption (ie, more than 1 drink/day) among breast cancer survivors independent of their personal or neighborhood characteristics. METHODS: With the Missouri Cancer Registry, the authors conducted a cross-sectional study of 1047 female breast cancer survivors (aged 27-96 years) 1 year after diagnosis. Using telephone interviews, the authors obtained data regarding survivors' alcohol consumption during the past 30 days and several covariates of alcohol use. They also obtained street addresses of all licensed alcohol outlets in Missouri and calculated the road network distance between a participant's address of residence and the nearest alcohol outlet, using a geographic information system. Logistic regression was used to determine if distance was independently associated with excessive alcohol consumption. RESULTS: Eighteen percent of participants reported consuming more than 1 drink on average per day. Women who lived within 3 miles of the nearest outlet were more likely to report excessive alcohol consumption (odds ratio: 2.09; 95% confidence interval: 1.08, 4.05) than women who lived at least 3 miles from the nearest outlet in adjusted analysis. DISCUSSION: Opportunities exist to reduce excessive alcohol use among breast cancer survivors through policy (eg, restricting number of alcohol outlets) and behavioral (eg, counseling) interventions. PMID- 23799691 TI - Predictors of success of a lifestyle intervention in relation to weight loss and improvement in glucose tolerance among individuals at high risk for type 2 diabetes: the FIN-D2D project. AB - AIM: The authors assessed the predictors of success of a lifestyle intervention (weight loss >= 5% and improved glucose tolerance) in individuals at high risk for type 2 diabetes in a 1-year follow-up in a primary health care setting. METHODS: High-risk individuals for type 2 diabetes were identified by opportunistic screening in the implementation of the Finnish National Diabetes Prevention Program (FIN-D2D). All together, 3880 individuals participated in the 1-year follow-up. Sociodemographic characteristics, health status and behavior, family history of diabetes, clinical factors, and health care provider were considered possible predictors of lifestyle intervention success. RESULTS: In sum, 19.3% of individuals lost at least 5% of weight, and 32.6% with abnormal glucose tolerance at baseline showed improvement in glucose tolerance. Abnormal glucose tolerance was the strongest predictor of weight loss and improvement in glucose tolerance. High attendance at lifestyle intervention visits, being outside of labor force, and high body mass index at baseline were also related to weight loss, and high education was related to improvement in glucose tolerance. CONCLUSIONS: In "real-life settings," glucose tolerance status, number of intervention visits, employment status, education, and body mass index explained the success of lifestyle intervention. These factors may help in targeting interventions, although they may not be generalized to other cultural settings. PMID- 23799692 TI - Shared decision making in prostate-specific antigen testing: the effect of a mailed patient flyer prior to an annual exam. AB - INTRODUCTION AND AIMS: Professional societies recommend that the decision to screen for prostate cancer involves a shared discussion between patient and provider. Many men are tested without this discussion. Prostate cancer screening decision aids increase patient knowledge and participation in prostate-specific antigen (PSA) testing decisions under ideal circumstances but are often resource intensive and elaborate. There is a need for evaluation of interventions that are low cost, low literacy, and practical for widespread distribution. The authors evaluated the effect of a mailed low-literacy informational patient flyer about the PSA test on measures of shared decision making. METHODS: A pragmatic randomized controlled trial comparing the mailed flyer versus usual care was conducted among 303 men aged 50 to 74 years who were scheduled for annual health maintenance exams in 2 general internal medicine clinics (University of Colorado and University of Colorado Hospital). Charts were reviewed after the visits for documentation of PSA screening discussions and PSA testing rates. Follow-up patient surveys assessed include perceived participation in PSA screening decisions, knowledge of the PSA test, and flyer acceptability. RESULTS: Rates of chart-documented PSA discussions were low with no difference between the flyer and control groups (17.7% and 13.6%, respectively; P = .28). Rates of PSA testing were also similar in both groups (62.5% vs 58.5%; P = .48). Rates of patient reported PSA discussions were higher than the documented rates but also without differences between the groups (71.8% vs 62.3%; P = .22). The intervention had no effect in the PSA knowledge scores (3.5/5 vs 3.3/5, P = .60). Patients found the flyer to be highly acceptable. CONCLUSIONS: A mailed low-literacy informational flyer was well received by patients but had no effect on rates of PSA discussions, PSA testing, or patient knowledge of prostate cancer screening. PMID- 23799693 TI - Early identification of exacerbations in patients with chronic obstructive pulmonary disease. AB - Frequent exacerbations of chronic obstructive pulmonary disease (COPD) place a considerable burden on the health care system and are a major cause of decreased health-related quality of life, accelerated pulmonary decline, and mortality in individual patients. Primary care physicians are usually the first point of contact for patients experiencing an exacerbation and are therefore best placed to prevent, identify, and treat these events in a timely manner. This review addresses the triggers and risk factors for COPD exacerbations, including the exacerbation-prone phenotype. The prevention, prompt diagnosis, and early appropriate pharmacological/nonpharmacological treatment of COPD exacerbations is important, as early recognition of symptoms (as supported by tools for measuring the illness/wellness experience of COPD patients in primary care) and treatment lead to optimal recovery in these patients. The review also highlights the importance of the urgency in identifying exacerbations and the important role played by primary care physicians in the prevention and postexacerbation management of patients with COPD. PMID- 23799694 TI - On the method of logarithmic cumulants for parametric probability density function estimation. AB - Parameter estimation of probability density functions is one of the major steps in the area of statistical image and signal processing. In this paper we explore several properties and limitations of the recently proposed method of logarithmic cumulants (MoLC) parameter estimation approach which is an alternative to the classical maximum likelihood (ML) and method of moments (MoM) approaches. We derive the general sufficient condition for a strong consistency of the MoLC estimates which represents an important asymptotic property of any statistical estimator. This result enables the demonstration of the strong consistency of MoLC estimates for a selection of widely used distribution families originating from (but not restricted to) synthetic aperture radar image processing. We then derive the analytical conditions of applicability of MoLC to samples for the distribution families in our selection. Finally, we conduct various synthetic and real data experiments to assess the comparative properties, applicability and small sample performance of MoLC notably for the generalized gamma and K families of distributions. Supervised image classification experiments are considered for medical ultrasound and remote-sensing SAR imagery. The obtained results suggest that MoLC is a feasible and computationally fast yet not universally applicable alternative to MoM. MoLC becomes especially useful when the direct ML approach turns out to be unfeasible. PMID- 23799695 TI - Sparse texture active contour. AB - In image segmentation, we are often interested in using certain quantities to characterize the object, and perform the classification based on criteria such as mean intensity, gradient magnitude, and responses to certain predefined filters. Unfortunately, in many cases such quantities are not adequate to model complex textured objects. Along a different line of research, the sparse characteristic of natural signals has been recognized and studied in recent years. Therefore, how such sparsity can be utilized, in a non-parametric way, to model the object texture and assist the textural image segmentation process is studied in this paper, and a segmentation scheme based on the sparse representation of the texture information is proposed. More explicitly, the texture is encoded by the dictionaries constructed from the user initialization. Then, an active contour is evolved to optimize the fidelity of the representation provided by the dictionary of the target. In doing so, not only a non-parametric texture modeling technique is provided, but also the sparsity of the representation guarantees the computation efficiency. The experiments are carried out on the publicly available image data sets which contain a large variety of texture images, to analyze the user interaction, performance statistics, and to highlight the algorithm's capability of robustly extracting textured regions from an image. PMID- 23799696 TI - A decoupled approach to illumination-robust optical flow estimation. AB - Despite continuous improvements in optical flow in the last three decades, the ability for optical flow algorithms to handle illumination variation is still an unsolved challenge. To improve the ability to interpret apparent object motion in video containing illumination variation, an illumination-robust optical flow method is designed. This method decouples brightness into reflectance and illumination components using a stochastic technique; reflectance is given higher weight to ensure robustness against illumination, which is suppressed. Illumination experiments using the Middlebury and University of Oulu databases demonstrate the decoupled method's improvement when compared with state-of-the art. In addition, a novel technique is implemented to visualize optical flow output, which is especially useful to compare different optical flow methods in the absence of the ground truth. PMID- 23799697 TI - Learning-based, automatic 2D-to-3D image and video conversion. AB - Despite a significant growth in the last few years, the availability of 3D content is still dwarfed by that of its 2D counterpart. To close this gap, many 2D-to-3D image and video conversion methods have been proposed. Methods involving human operators have been most successful but also time-consuming and costly. Automatic methods, which typically make use of a deterministic 3D scene model, have not yet achieved the same level of quality for they rely on assumptions that are often violated in practice. In this paper, we propose a new class of methods that are based on the radically different approach of learning the 2D-to-3D conversion from examples. We develop two types of methods. The first is based on learning a point mapping from local image/video attributes, such as color, spatial position, and, in the case of video, motion at each pixel, to scene-depth at that pixel using a regression type idea. The second method is based on globally estimating the entire depth map of a query image directly from a repository of 3D images ( image+depth pairs or stereopairs) using a nearest neighbor regression type idea. We demonstrate both the efficacy and the computational efficiency of our methods on numerous 2D images and discuss their drawbacks and benefits. Although far from perfect, our results demonstrate that repositories of 3D content can be used for effective 2D-to-3D image conversion. An extension to video is immediate by enforcing temporal continuity of computed depth maps. PMID- 23799698 TI - Stiffness Feedback for Myoelectric Forearm Prostheses Using Vibrotactile Stimulation. AB - The ability to distinguish object stiffness is a very important aspect in object handling, but completely lacking in current myoelectric prostheses. In human hands both tactile and proprioceptive sensory information are required for stiffness determination. Therefore, it was investigated whether it is possible to distinguish object stiffness with vibrotactile feedback of hand opening and grasping force. Three configurations consisting of an array of coin motors and a single miniature vibrotactile transducer were investigated. Ten healthy subjects and seven subjects with upper limb loss due to amputation or congenital defects performed virtual grasping tasks, in which they controlled hand opening and grasping force. They were asked to determine the stiffness of a grasped virtual object from four options. With hand opening feedback alone or in combination with grasping force feedback, correct stiffness determination was achieved in around 60% of the cases and significantly higher than the 25% achieved without feedback or grasping force feedback alone. Despite the equal performance results, the combination of hand opening and grasping force feedback was preferred by the subjects over the hand opening feedback alone. No differences between feedback configurations and between subjects with upper limb loss and healthy subjects were found. PMID- 23799699 TI - Stimulation selectivity of the "thin-film longitudinal intrafascicular electrode" (tfLIFE) and the "transverse intrafascicular multi-channel electrode" (TIME) in the large nerve animal model. AB - Neural prostheses are limited by the availability of peripheral neural electrodes to record the user's intention or provide sensory feedback through functional electrical stimulation. Our objective was to compare the ability of the novel "transverse intrafascicular multi-channel electrode" (TIME) and an earlier generation "thin-film longitudinal intrafascicular electrode" (tfLIFE) to selectively stimulate nerve fascicles and activate forelimb muscles in pigs. TIME was designed to access a larger subpopulation of fascicles than tfLIFE and should therefore be able to selectively activate a larger number of muscles. Electrodes were implanted in the median nerve, and sequential electric stimulation was applied to individual contacts. The compound muscle action potentials of seven muscles were recorded to quantify muscle recruitment. As expected, TIME was able to recruit more muscles with higher selectivity than tfLIFE (significant difference when comparing the performance of an entire electrode); a similar activation current was used (no significant difference). Histological analysis revealed that electrodes were located between fascicles, which influenced the selectivity and activation current level. In conclusion, TIME is a viable neural interface for selective activation of multiple fascicles in human-sized nerves that may assist to pave the way for future neuroprosthesis applications. PMID- 23799700 TI - Using an outbreak investigations model for quality improvement studies. PMID- 23799701 TI - Views, barriers, and suggestions for colorectal cancer screening among american Indian women older than 50 years in the midwest. AB - OBJECTIVE: Although colorectal cancer (CRC) mortality rates in the US population have shown a decline, American Indian (AI) CRC mortality rates appear to be increasing. CRC screening rates of AIs remain low when compared with other ethnic groups. The research team explored women's perceptions toward CRC screening, existing barriers, and suggestions to promote education and screening among AI women in Kansas and Missouri. METHODS: Using a community-based participatory research approach, the authors conducted 7 focus groups with AI women older than 50 years (N = 52) to better understand their perceptions of and attitudes toward CRC screening. RESULTS: Women recognized barriers to screening, such as embarrassment, privacy issues, fear, insurance, and cost. They countered perceived barriers through inventive suggestions for education and awareness via social support systems and intergenerational relationships. DISCUSSION: CRC screening interventions for AI must be culturally tailored. PMID- 23799702 TI - Evaluating the effectiveness of a physical activity referral scheme among women. AB - Evidence supports the effectiveness of interventions delivered in primary care to promote physical activity (PA). Specifically, approaches where physician counseling is coupled with other strategies (eg, referrals to community resources) have been recognized as the most promising. The purpose of this study was to compare the effectiveness of a PA prescription plus referral intervention versus a prescription only intervention delivered in primary care. Ten family physicians and their female patients (N = 35, mean age = 36 years) were randomly assigned to 1 of 3 conditions: prescription plus (n = 12), prescription only (n = 12), and usual care (n = 11). The prescription plus group received a PA prescription plus a referral to a community program, the prescription only group received only the PA prescription, and the usual care group received usual health care. The Godin Leisure-Time Exercise Questionnaire was used to measure PA. A significant increase on the PA score (P < .05, partial eta(2) = .178) and on total weekly PA minutes (P < .05, partial eta(2) = .179) was observed in both prescription groups after the intervention. There were no significant group differences (P > .05). No PA changes were observed in the usual care group. Findings from this pilot study suggest that brief PA counseling and a prescription delivered in primary care can be effective for promoting PA among women. Referring patients did not seem to enhance the effect on PA. PMID- 23799703 TI - Subutilization of COPD guidelines in primary care: a pilot study. AB - SUMMARY: Despite the popularity of chronic obstructive pulmonary disease (COPD) guidelines, studies have reported important deficits among primary care physicians (PCPs) with respect to diagnosis and treatment of COPD; as a consequence, COPD remains underrecognized and undertreated. METHODS: This was a multicenter pilot study to assess prescribing practices for COPD by PCPs according to COPD guidelines. This was a 2-phase study: In phase 1, PCPs from 27 Mexican cities, referred patients for evaluation, including spirometry and in phase 2, PCPs from 10 of those same cities were asked to answer a questionnaire on COPD practice guidelines. RESULTS: A total of 2293 subjects were included in phase 1; 472 (20.6%) had a FEV1/FVC <70%. Only 39% of patients with 30% <= FEV1 < 50% and 22% with FEV1 <30% were receiving combination therapy (long-acting bronchodilator + inhaled steroid). In phase 2, we recruited 999 PCPs; 72.5% of them said that they had read a COPD guideline and 59.4% answered that they used one in their practice. When asked which guideline(s) they used, we had 86 different responses with GOLD (Global Initiative for Chronic Obstructive Lung Disease; 34.1%) being the most common, followed by GINA (Global Initiative for Asthma; 12.8%). When asked why they did not used a guideline, we got 33 different answers; "never read them" was the most frequent answer (41.8%) followed by "lack of access to them" (18.2%) and "not enough time to read them" (6.0%). CONCLUSION: Despite the existence and availability of evidence-based guidelines, only a minority of primary health care COPD patients in Mexico are receiving state-of the-art treatment at the primary care level. PMID- 23799704 TI - Reliability of a telemedicine system designed for rural Kenya. AB - OBJECTIVE: Access to health care in rural areas of developing nations is hindered by both the lack of physicians and the preference of many physicians to practice in urban settings. As a result, rural patients often choose not to sacrifice wages or time to visit distant health care providers. A telemedicine system, Mashavu: Networked Health Solutions, designed to increase access to preprimary health care in rural areas, was field-tested in rural Kenya. This study aims to examine the reliability of the system compared to the traditional face-to-face method of health care delivery. METHOD: Reliability of the telemedicine system was tested using a modified intraobserver concordance study. Community health workers operated the system in various remote locations. Patient health information including chief complaint, medical history, and vital statistics were sent via Internet to a consulting nurse. After patients completed the telemedicine consultation, they also met in-person with the same nurse. Subsequently, the nurse's advice during the in-person session was compared with his feedback provided through the telemedicine consultation. RESULTS: When comparing the nurse's advice given through the telemedicine system with the advice given through more traditional face-to-face, in-person consultation, the nurse provided consistent medical feedback in 78.4% of the cases (n = 102). The nurse's advice regarding patient action (eg, clinical referrals or no further care necessary) was the same in 89.2% of the cases (n = 91). CONCLUSION: The study found that this telemedicine system was able to provide patients with approximately the same quality of care and advice as if the patient had physically travelled to a clinic to see a nurse. In rural areas of developing nations where there are high logistical and economical barriers to accessing health care, this telemedicine system successfully increased the ease and lowered the cost of connecting rural patients with nurses to provide preprimary care. PMID- 23799705 TI - Physician-targeted financial incentives and primary care physicians' self reported ability to provide high-quality primary care. AB - OBJECTIVE: High-quality primary care is envisaged as the centerpiece of the emerging health care delivery system under the Affordable Care Act. Reengineering the US health care system into a primary care-driven model will require widespread, rapid changes in the management and organization of primary care physicians (PCPs). Financial incentives to influence physician behavior have been attempted with various approaches, without empirical evidence of their effectiveness in improving care quality. This study examines the above research question adjusting for the patient-centeredness of the practice climate, a major contextual factor affecting PCPs' ability to provide high-quality care. METHODS: Secondary data on a sample of salaried PCPs (n = 1733) from the nation-wide Community Tracking Study Physician Survey 2004-2005 were subject to generalized multinomial logit modeling to examine associations between financial incentives and PCPs' self-reported ability to provide quality care. RESULTS: After adjusting for patient-centered medical home (PCMH)-consistent practice environment, financial incentive aligned with care quality/care content is positively associated with PCPs' ability to provide high-quality care. An encouraging finding was that financial incentives aligned with clinic productivity/profitability do not to impede high-quality care in a PCMH practice environment. CONCLUSION: Financial incentives targeted to care quality or content indicators may facilitate rapid transformation of the health system to a primary care-driven system. The study provides empirical evidence of the utility of practically deployable financial incentives to facilitate high-quality primary care. PMID- 23799706 TI - The impact of an online social network with wireless monitoring devices on physical activity and weight loss. AB - BACKGROUND: Online social networks (OSNs) are a new, promising approach for catalyzing health-related behavior change. To date, the empirical evidence on their impact has been limited. PURPOSE: Using a randomized trial, we assessed the impact of a health-oriented OSN with accelerometer and scales on participant's physical activity, weight, and clinical indicators. METHODS: A sample of 349 PeaceHealth Oregon employees and family members were randomized to the iWell OSN or a control group and followed for 6 months in 2010-2011. The iWell OSN enabled participants to connect with "friends," make public postings, view contacts' postings, set goals, download the number of their steps from an accelerometer and their weight from a scale, view trends in physical activity and weight, and compete against others in physical activity. Both control and intervention participants received traditional education material on diet and physical activity. Laboratory data on weight and clinical indicators (triglycerides, high density lipoprotein, or low-density lipoprotein), and self-reported data on physical activity, were collected at baseline, 3 months, and 6 months. RESULTS: At 6 months, the intervention group increased leisure walking minutes by 164% compared with 47% in the control group. The intervention group also lost more weight than the controls (5.2 pounds compared with 1.5 pounds). There were no observed significant differences in vigorous exercise or clinical indicators between the 2 groups. Among intervention participants, greater OSN use, as measured by number of private messages sent, was associated with a greater increase in leisure walking and greater weight reduction over the study period. CONCLUSIONS: The study provides evidence that interventions using OSNs can successfully promote increases in physical activity and weight loss. PMID- 23799707 TI - Cost-effectiveness of a hypertension control intervention in three community health centers in China. AB - BACKGROUND: Hypertension and associated chronic diseases impose enormous and growing health and economic burdens worldwide. The objective of this study was to investigate the cost-effectiveness (CE) of a hypertension control program in China. METHODS: We collected information on program costs and health outcomes in three community health centers over a 1-year period. The participants were 4902 people with hypertension (systolic blood pressure [SBP] >=140 mm Hg and/or diastolic blood pressure [DBP] >=90 mm Hg, or on hypertension medication) aged 18 years and older. The SBP and DBP changes in the populations were estimated from a random sample of 818 participants by conducting face-to-face interviews and physical examinations. We derived CE measures based on the costs and effects on health outcomes. FINDINGS: The total cost of implementing the intervention was Renminbi (RMB) 240 772 yuan (US$35 252), or 49 yuan (US$7.17) per participant in 2009. On average, SBP decreased from 143 to 131 mm Hg (P < .001) and DBP decreased from 84 to 78 mm Hg (P < .001), the SBP decreases ranged from 7.6 to 17.8 mm Hg and DBP decreases ranged from 3.9 to 8.3 mm Hg. CE ratios ranged from RMB 3.6 to 5.0 yuan (US$0.53-US$0.73) per person per mm Hg SBP decrease, and from RMB 6.3 to 9.7 yuan (US$0.92-US$1.42) per person per mm Hg DBP decrease. INTERPRETATION: Per capita costs varied widely across the communities, as did changes in SBP and DBP, but CE was similar. The findings suggest (a) a positive correlation between per capita costs and program effectiveness, (b) differences in intervention levels, and (c) differences in health status. CE results could be helpful to policy makers in making resource allocation decisions. PMID- 23799708 TI - Consumer governance may harm health center financial performance. AB - INTRODUCTION: Federally qualified health centers (FQHCs), which must be governed by a patient majority, have historically struggled to remain financially viable while caring for a disproportionately low-income and uninsured population. Consumer governance is credited with making FQHCs responsive to community needs, but to the extent that patient trustees resemble the typical low-income FQHC patient, patient trustees might lack the capacity to govern, harming financial performance as a result. Thus, this study sought to empirically evaluate the relationship between FQHC board composition and financial performance. METHODS: Using data from years 2002-2007 of the Uniform Data System and the Area Resource File, and years 2003-2006 of FQHC grant applications, FQHC operating margin was modeled as a function of board and executive committee composition, the interaction between them, general time trends, other FQHC and county-level factors, and FQHC-level fixed effects. Trustees were classified as representative (ie, low-income) consumers, nonrepresentative (ie, high-income) consumers, and nonconsumers on the basis of their self-reported patient status and occupation. RESULTS: Each 10 percentage point increase in the proportion of representative consumers on the board is associated with a 1.7 percentage point decrease in operating margin. This effect becomes insignificant if any consumers serve on the executive committee. There is no significant relationship between the proportion of nonrepresentative consumers and operating margin. CONCLUSIONS: If consumers are given leadership roles on the board, consumer governance does not harm financial performance and may be beneficial enough in other respects to justify its being required as a condition of federal FQHC funding. Without such strengthening of the provision, consumer governance appears to harm financial performance and it is unclear from this study whether it offers other benefits that are significant enough to justify this financial risk. PMID- 23799709 TI - Cervical cancer screening practice and knowledge among Hispanic migrant and seasonal farmworkers of Michigan. AB - BACKGROUND: High incidence of cervical cancer among Hispanics and low utilization of cervical screening among farmworkers led us to examine Pap test use and knowledge among Hispanic farmworkers in Michigan. METHODS: Patients and potential patients of Northwest Michigan Health Services, Inc were surveyed in 2 communities (A and B) about their screening knowledge, attitudes, and practice. RESULTS: In all, 324 farmworkers participated, including 184 seasonal and 125 migrant farmworkers. Among the entire study population, 87.7% women reported receiving a Pap test recently, with no difference between migrant and seasonal farmworkers (88.0% and 87.4%, respectively, P = .088). More women from community B reported a recent Pap (93%) compared with those from community A (83%, P = .01). Only 35% of the participants had knowledge of any cervical cancer risk factors. DISCUSSION: Migrant farmworkers may not experience more difficulty in accessing Pap tests than seasonal farmworkers in Michigan. Knowledge about cervical cancer risk factors is low and needs to be addressed in future educational interventions. PMID- 23799710 TI - Primary care physicians' concerns may affect adolescents' access to intrauterine contraception. AB - PURPOSE: Although the intrauterine device (IUD) may be safely used in adolescents, few US adolescents use IUDs. Increasing IUD use in adolescents can decrease pregnancy rates. Primary care providers' clinical practices many be one of the many barriers to increasing adolescents access to IUDs. We explored primary care physicians' (PCPs) approaches to contraception counseling with adolescents, focusing on their views about who would be appropriate IUD candidates. METHODS: Phone interviews were conducted with 28 urban family physicians, pediatricians, and obstetrician-gynecologists. Using standard qualitative techniques, we developed coding template and applied codes. RESULTS: Most respondents have a patient-centered general contraceptive counseling approach. However, when considering IUDs many PCPs describe more paternalistic counseling. For example, although many respondents believe adolescents' primary concern is pregnancy prevention, many PCPs prioritize sexually transmitted infection (STI) prevention and thus would not offer an IUD. Attributes PCPs associate with an appropriate IUD candidate include responsibility, reliability, maturity, and monogamy. CONCLUSION: Our findings suggest that when considering IUDs for adolescents some PCPs' subjective assessment of adolescent sexual behavior, attitudes about STI risk factors and use of overly restrictive IUD eligibility criteria impede adolescent's IUD access. Education around best practices may be insufficient to counterbalance attitudes concerning adolescent sexuality and STI risk; there is also a need to identify and discuss PCPs potential biases or assumptions affecting contraception counseling. PMID- 23799711 TI - An epidemiologic analysis of low back pain in primary care: a hot humid country and global comparison. AB - BACKGROUND: Low back pain is one of the most common conditions for which patients seek medical care. AIM: The aim of the study was to study the epidemiology of low back pain in primary care setting with emphasis on frequency, sociodemographic factors, and impact of low back pain on lifestyle habits. SUBJECTS AND METHODS: This is a cross-sectional study. A representative sample of 2742 patients was approached and 2180 subjects agreed to participate in this study (79.5%). The survey was conducted among primary health care visitors during the period from March to October 2012. The questionnaire collected the sociodemographic characteristics, lifestyle habits, and type of treatment taken for relief from recruited subjects. RESULTS: Of the subjects studied, 52.9% were males and 47.1% were females. The prevalence of low back pain in the study sample was 59.2%. Low back pain was more prevalent among women (67.7%) than among men (51.6%). The proportion of low back pain was highest in the age-group 45 to 55 years in both the genders (37.6% and 36.4%, respectively). Nearly half of the men (45.7%) and women (45.2%) with low back pain were overweight with a significant difference (P < .001). More than half of the women with low back pain were housewives (50.4%), whereas most of the men had clerical jobs (36.8%). There was a significant difference observed between men and women in terms of nationality (P < .001), body mass index (P < .001), and occupation (P < .001). Prolonged standing (41.2% vs 29.5%; P < .001) and use of sponge mattress (50.9% vs 45.8%; P .041) was significantly higher among male patients with low back pain compared with females. Coughing/sneezing/straining (9.7% vs 5.9%; P = .01) were more frequent triggering factors in male patients with low back pain as compared with females. CONCLUSION: The study findings revealed that the prevalence of low back pain was higher among women than among men. Low back pain was observed more frequently among older people and among those who were overweight. PMID- 23799712 TI - Lessons learned from a colocation model using psychiatrists in urban primary care settings. AB - OBJECTIVES: Comorbid psychiatric illness has been identified as a major driver of health care costs. The colocation of psychiatrists in primary care practices has been proposed as a model to improve mental health and medical care as well as a model to reduce health care costs. METHODS: Financial models were developed to determine the sustainability of colocation. RESULTS: We found that the population studied had substantial psychiatric and medical burdens, and multiple practice logistical issues were identified. CONCLUSION: The providers found the experience highly rewarding and colocation was financially sustainable under certain conditions. The colocation model was effective in identifying and treating psychiatric comorbidities. PMID- 23799713 TI - Managerial epidemiology. PMID- 23799714 TI - Patients whose physicians recommend colonoscopy and those who follow through. AB - BACKGROUND: More than half of eligible individuals are not up-to-date with colon cancer screening. PURPOSE: To assess the characteristics of those who received a colonoscopy screening recommendation and those who followed the physician recommendation. METHODS: Patient self-administered questionnaire and medical record review in 16 private family physician practices. RESULTS: From 8372 patients invited to participate, 685 were enrolled and had a medical record review; 219 (32%) had a colonoscopy recommendation and 86 (39%) received a colonoscopy. Independent factors associated with having a recommendation for colonoscopy were significantly younger in age (odds ratios [OR] = 1.6), higher incomes (annual income >=$40 000 vs <$40 000; OR = 1.8), physician or nurse discussion about colon cancer tests (OR = 1.6), physical visit in the preceding 26 months (OR = 1.7), distant relative with colon cancer (OR = 2.4), and a medical diagnosis of hyperlipidemia (OR = 2.1). Independent factors associated with following through on colonoscopy after a recommendation were age >=65 years (OR = 0.3), male patient (OR = 0.4), and feeling that colon cancer screening is very important (OR = 3.2). CONCLUSIONS: Socioeconomic factors are associated with receipt of a colonoscopy recommendation. Fewer than one third of patients had documentation of a physician colonoscopy recommendation and of those, less than half followed through. PMID- 23799715 TI - Predictors of tetanus-diphtheria- acellular pertussis vaccination among adults receiving tetanus vaccine in the United States: data from the 2008 national health interview survey. AB - BACKGROUND . The incidence of pertussis in the United States has been increasing. Adult vaccination is important to reduce disease burden and prevent transmission to infants at high risk of complications. The tetanus-diphtheria-acellular pertussis (Tdap) vaccine has been available in the United States since 2005 and is indicated as a one-time replacement for the routine tetanus-diphtheria (Td) booster. However, among adults receiving tetanus vaccination, only about half receive Tdap. PURPOSE . To identify predictors of adult Tdap vaccination among individuals who receive tetanus vaccine. METHODS . National Health Interview Survey data from 2008 were analyzed in 2011. Respondents were 18 to 64 years old, received tetanus vaccination during 2005-2008, and were aware if it contained pertussis. Predictors of Tdap vaccination were identified with multivariate logistic regression using procedures for complex survey methods. RESULTS . Overall, 51.1% of respondents received Tdap. Vaccination was less likely for those 50 to 64 years old compared with those 18 to 24 years old (odds ratio [OR] = 0.61, 95% confidence interval [CI] = 0.38-0.96). Some college education was associated with higher odds of vaccination compared with lower education levels (OR = 1.55, 95% CI = 1.16-2.07). Having 2 to 3 office visits (OR = 2.01, 95% CI = 1.32-3.06) or 4 to 9 office visits (OR = 1.60, 95% CI = 1.06-2.42) in the previous year increased the odds of vaccination compared with no visits. Individuals with functional limitation due to illness had lower odds compared with no limitation (OR = 0.70, 95% CI = 0.54-0.91). CONCLUSIONS . In 2008, 51.1% of adult Td vaccinations included pertussis, suggesting continued efforts to remove barriers are needed. Interventions should target older, functionally impaired, and educationally disadvantaged populations. PMID- 23799716 TI - Epidemiology of polypharmacy among family medicine patients at hospital discharge. AB - BACKGROUND: Polypharmacy has been identified as a quality indicator, but no studies have been reported about the epidemiology of polypharmacy among hospital patients at discharge. METHODS: Records of 142 family medicine patients aged >=65 years who were discharged from the hospital during the period November 2008 to October 2009 were extracted. Forty-six of these patients were readmitted within 30 days and the remaining 96 not readmitted within 30 days. Polypharmacy was measured as >16 medications at dismissal. Independent variables related to person (use of medical care in the 12 months prior to hospitalization, number of high risk diagnoses, and demographic characteristics), place (living situation at admission and disposition location), and time (month of admission). Chronic obstructive pulmonary disease, cancer, diabetes mellitus, congestive heart failure, and coronary artery disease were diagnoses determined to be high-risk. RESULTS: Mean number of medications at dismissal was 13.5 and 23.2% of patients were prescribed more than 16 medications. No interactions were found between readmission status and any of the independent variables. Use of medical services in the previous year was not related to polypharmacy and no seasonal pattern was detected. Two or more high-risk diagnoses were independently related to polypharmacy (odds ratio [OR] = 4.75, confidence interval [CI] = 1.0-11.2, P = .00). Being discharged to a location with personal health services such as home care or a skilled nursing facility was also related to polypharmacy (OR = 3.07, CI = 1.3-7.2, P = .01). CONCLUSION: Drug reviews intended to reduce the rate of polypharmacy among discharged persons aged >=65 years can be targeted at patients who have 2 or more high-risk diagnoses and at those discharged to receive personal health services either at home or in a convalescence facility. PMID- 23799717 TI - Colorectal cancer screening disparities for rural minorities in the United States. AB - BACKGROUND: Despite the existence of effective screening, colorectal cancer remains the second leading cause of cancer death in the United States. Adults living in rural areas and members of minority populations both experience disparities in colorectal cancer screening. METHODS: Cross-sectional prevalence study of Behavioral Risk Factor Surveillance System from the Centers for Disease Control from 1998 to 2005. PRIMARY OUTCOME: Predicted probability of reporting timely colorectal cancer screening. INDEPENDENT VARIABLES: rural residence, race/ethnicity. We adjusted for demographic and socioeconomic characteristics of respondents. RESULTS: After adjustment rural non-Hispanic whites (44.3%), rural African American/blacks (44.8%), urban and rural Hispanic/Latinos (43.7% and 40.8%, respectively), urban and rural American Indian/Alaska Natives (45.8% and 46.8%), and urban and rural Asians (35.4% and 39.6%) had lower compared with urban non-Hispanic whites (49.5%; P < .05% for all comparisons). Urban Asians were least likely to report use of fecal occult blood testing (8.6%, 95% confidence interval = 6.3% to 10.9%) and rural Asians were least likely to report use of endoscopy screening (21.2%, 95% confidence interval = 16.2% to 26.2%). DISCUSSION: Rural minorities may face different barriers to colorectal cancer screening than urban minorities or rural non-Hispanic whites. Further research to develop interventions to improve screening in these populations is warranted. PMID- 23799718 TI - Incentives for healthy behaviors: experience from Florida Medicaid's Enhanced Benefit Rewards program. AB - OBJECTIVE: Engaging individuals in their own health care proves challenging for policy makers, health plans, and providers. Florida Medicaid introduced the Enhanced Benefits Rewards (EBR) program in 2006, providing financial incentives as rewards to beneficiaries who engage in health care seeking and healthy behaviors. METHODS: This study analyzed beneficiary survey data from 2009 to determine predictors associated with awareness of and participation in the EBR program. RESULTS: Non-English speakers, those in a racial and ethnic minority group, those with less than a high school education, and those with limited or no connection to a health care provider were associated with lower awareness of the program. Among those aware of the program, these factors were also associated with reduced likelihood of engaging in the program. Individuals in fair or poor health were also less likely to engage in an approved behavior. Individuals who speak Spanish at home and those without a high school diploma were more likely than other groups to spend their earned program credits. CONCLUSIONS: Findings underscore the fact that initial engagement in such a program can prove challenging as different groups are not equally likely to be aware of or participate in an approved activity or redeem a credit. Physicians may play important roles in encouraging participation in programs to incentivize healthy behaviors. PMID- 23799719 TI - Patient body mass index does not predict six-month clinical outcome of depression managed under collaborative care. AB - Obesity and depression are often comorbid conditions. There appears to be a bidirectional relationship between these. Obesity at baseline has been shown to increase the risk of onset of depression and depression at baseline increased the odds for developing obesity. Less is understood about the impact of obesity on depression treatment outcomes. The authors' hypothesis was that obesity (body mass index [BMI] >= 30 kg/m2) and morbid obesity (BMI >= 40 kg/m2) would each have negative effects on depression remission rates after 6 months of enrollment into collaborative care management for depression. In a retrospective analysis of 1111 depressed patients with a PHQ-9 (Patient Health Questionnaire) score of 10 or greater, multivariate analysis for the odds ratio of achieving remission at 6 months demonstrated that the patient's BMI at baseline was not an independent risk factor for depression outcome at 6 months. Collaborative care management for depression has been shown to be effective for improving depression outcomes, yet minimal prior research has focused on other clinical comorbidities that might affect outcomes. Although obesity was common in the study population, it was reassuring, based on this study that 6-month depression treatment outcomes do not appear to be significantly affected by the patient's baseline BMI. PMID- 23799720 TI - Comparison of waiting and consultation times in convenient care clinics and physician offices: a cross-sectional study. AB - This study measures waiting times and consultation times at convenient care clinics (CCCs), and compares them with equivalent times in traditional, family practice, physician offices. The analysis was limited to conditions most commonly treated at CCCs. It was found that patients using CCCs had significantly shorter waiting times from check-in to seeing a clinician than the equivalent waiting times reported by patients at family practice physicians' offices and that CCC patients had significantly longer consultation times with the clinician than those reported by family practice patients. Applying a correction factor to adjust for potential differences between real waiting times and perceived waiting times did not substantially alter the conclusions. Shorter waiting times may increase satisfaction and thereby encourage patients to seek care; and spending additional time with the clinician may help ensure that all of a patient's concerns or questions are addressed. This study provides objective evidence from a large database that CCCs provide prompt, satisfying care. PMID- 23799721 TI - Prolonged care management for depression: a case-controlled study of those enrolled for more than one year. AB - INTRODUCTION: Collaborative care management (CCM) for the treatment of depression has been shown to be an effective therapy. CCM can be seen as a resource intensive treatment. Early identification of patients who would not be effectively treated with CCM could allow for alteration of therapy or change in modality. METHODS: A retrospective case-controlled study used 132 patients with prolonged enrollment (>1 year) in CCM (cases) and 396 randomized CCM patients who achieved remission within 6 months (controls). The hypothesis was that by studying the epidemiology of patients in prolonged care management (PCM), characteristics could be determined to help define this group. RESULTS: With regression modeling, the odds of a patient having PCM at 1 year was highly significant for those unmarried patients (odds ratio [OR] = 1.736, confidence interval [CI] = 1.115-2.703, P = .015) with dysthymia (OR = 2.362, CI = 1.104 5.052, P = .027) and severe depression (OR = 2.856, CI = 1.551-5.260, P = .001). The adjusted baseline Patient Health Questionnaire-9 (PHQ-9) score showed a difference of 16.0 for the cases versus 14.8 for the controls (P < .001). By 10 weeks, the difference is much larger at (10.7 vs 4.9, P < .001). At 26 weeks, the control group had an adjusted average PHQ-9 score of 2.0, whereas the case group was still elevated at 10.2 (P < .001). CONCLUSIONS: Case-controlled analysis of PCM patients demonstrated independent predictors (such as unmarried status, diagnosis of dysthymia or severe depression), however, no baseline data was of sufficient clarity to suggest changes in clinical practice. The trend of the patient's PHQ-9 over time was strongly suggestive of allowing differentiation between the groups. PMID- 23799723 TI - Does access to comprehensive outpatient care alter patterns of emergency department utilization among uninsured patients in East Baltimore? AB - BACKGROUND: The annual number of emergency department (ED) visits in the United States increased 23% between 1997 and 2007. The uninsured and those with chronic medical conditions are high users of emergency care. OBJECTIVE: We sought to determine whether access to comprehensive outpatient primary and specialty care and care coordination provided by The Access Partnership (TAP) reduced ED utilization among uninsured patients relative to patients who chose not to enroll. METHODS: Multiple time series analysis was performed to examine rates of ED utilization and inpatient admission among TAP patients and a comparison group of eligible patients who did not join (non-TAP patients). Monthly ED utilization and inpatient admission rates for both groups were examined prior to and subsequent to referral to TAP, within a study period 2007-2011. RESULTS: During the study period, 623 patients were eligible to enroll, and 374 joined the program. Rates of ED visits per month increased in both groups. Compared with non TAP patients, TAP patients had 2.0 fewer ED visits not leading to admission per 100 patient-months post-TAP (P = .03, 95% confidence interval = 0.2-3.9). TAP status was a moderate predictor of ED visits not leading to admission, after controlling for age, gender, and zip code (P = .04, 95% confidence interval = 0.1 3.9). CONCLUSIONS: Although overall ED utilization did not change significantly between program participants and nonparticipants, TAP patients had a lower rate of ED visits not resulting in inpatient admission relative to the comparison group. PMID- 23799724 TI - Managerial epidemiology: it's about time! PMID- 23799722 TI - Does providing care for uninsured patients decrease emergency room visits and hospitalizations? AB - BACKGROUND: Access to primary care could reduce use of more costly health care by uninsured individuals through prevention and early treatment. We analyzed data from a program providing free primary care to test this hypothesis. METHODS: We compared emergency room (ER) visits and hospitalizations among uninsured, low income adults who received immediate versus delayed access to a program providing free primary care, including labs, X-rays, and specialty consultation. We used surveys to identify ER visits and hospitalizations during the 12 months preceding and following program enrollment or wait list entry. RESULTS: Hospitalizations decreased from the year before entry to the year following entry in participants with immediate and delayed (6.0% vs 8.8% decrease) access. ER use also decreased in both groups (11.2% vs 15.4%). CONCLUSIONS: Free primary care services and specialty consultation did not reduce use of more costly health care services during its first year. More prolonged availability of primary care might have greater impact. PMID- 23799725 TI - Family medicine patients who use retail clinics have lower continuity of care. AB - PURPOSE: The purpose of this study was to compare continuity of care for family medicine patients using retail medicine clinics to continuity for patients not using retail clinics. Retail medicine clinics have become popular in some markets. However, their impact on continuity of care has not been studied. METHODS: Electronic medical records of adult primary care patients seen in a large group practice in Minnesota in 2011 were analyzed for this study. Two randomly chosen groups of patients were selected (N = 400): those using 1 of 3 retail walk-in clinics staffed by nurse practitioners in addition to standard office care and a comparison group that only used standard office care. Continuity was measured as the percentage of visits that involved the primary care provider. We also compared patients who made zero visits to their primary care providers with those who made some visits to their primary care providers. RESULTS: Continuity of care was lower for patients who used retail clinics than for patients who did not use retail clinics (0.17 vs 0.44, mean difference 0.27). The percentage of patients who made zero visits to their primary care providers was 54.5 for users of retail clinics versus 31.0 for those who did not use retail clinics. CONCLUSIONS: Continuity of care should be monitored as retail medicine continues to expand. PMID- 23799726 TI - The role of databases in improving the quality of care for congenital heart disease. PMID- 23799727 TI - Anomalous coronary arteries: cardiovascular computed tomographic angiography for surgical decisions and planning. AB - Cardiovascular computed tomographic angiography (CCTA) provides an understanding of the three-dimensional (3D) coronary artery anatomy in relation to cardiovascular thoracic structures important to the surgical management of anomalous coronary arteries (ACAs). Although some ACA variants are not clinically significant, others can lead to ischemia/infarction, related acute ventricular dysfunction, ventricular arrhythmias, and sudden cardiac death. The CCTA is important to surgical decision making, as it provides noninvasive visualization of the coronary arteries with (1) assessment of origin, course, and termination of coronary artery anomalies in the context of 3D thoracic anatomy, (2) characterization of anatomy helpful for differentiation of benign versus hemodynamically significant variants, (3) identification of other cardiothoracic anomalies, and (4) detection of coronary artery disease. High-risk ACA anatomy in the appropriate clinical setting can require surgical intervention with decisions including minimally invasive versus open sternotomy approach, correction via reimplantation of a coronary artery, alteration of the ACA course without reimplantation, or bypass of an ACA. Given the rarity of ACA, there is limited data in the literature, and significant controversy related to the management issues. The management of ACA requires comprehensive clinical history, thorough assessment of cardiac function, and detailed anatomic imaging. Future studies will need to address the long-term outcome based on detailed assessment of original anatomy and surgical approach. PMID- 23799728 TI - Improved long-term survival for rheumatic mitral valve repair compared to replacement in the young. AB - BACKGROUND: Mitral valve (MV) repair offers potential advantages over replacement in patients with rheumatic heart disease (RHD). We present the first long-term study that compares MV repair with replacement in children with RHD. METHODS AND RESULTS: Single institute retrospective review of patients with RHD under 20 years of age, who underwent their first isolated MV surgery between 1990 and 2006. Of the 81 patients, 98% were Maori or Pacific Islander. The median age was 12.7 (3-19) years. The MV was repaired in 59%, a mechanical valve replacement (MVR) took place in 35% and bioprosthetic valve replacement in 6% of the patients. Follow-up data were available for 91.4% of the patients with mean follow-up of 7.6 years (range 0-19.4 years), a total of 620 patient years. Actuarial survival at 10 and 14 years for patients with MVR was 79% and 44%, compared to 90% and 90% for patients who underwent repair (P = .06). Actuarial freedom from late reoperation at 10 and 14 years for patients with MVR was 88% and 73%, compared to 76% and 76% for patients with repair (P = .52). Actuarial freedom from thrombotic, embolic, and hemorrhagic events at 10 and 14 years for patients with MVR was 63% and 45%, compared to 100% and 100% for patients with repair P < .01). CONCLUSION: This study shows that MV repair is superior to replacement for RHD in the young with follow-up to 19 years. Repair offers a survival advantage, greater freedom from valve-related morbidity, and long-term durability that equals that of MVR. PMID- 23799729 TI - Congenital heart disease in Mexico: advances of the regionalization project. AB - Consistent with the mission of the World Society for Pediatric and Congenital Heart Surgery to promote health care for children with congenital heart disease all around the world, a Mexican Association of Specialists in Congenital Heart Disease (abbreviated in Spanish as AMECC) was created in Mexico in 2008. Our efforts were coordinated with those of the National Health Secretary with the objective being implementation of a national plan for regionalization of care for patients with congenital heart disease. To improve our knowledge related to technologic and human resources for management of congenital heart disease, we developed a national survey. Finally, a national database was created for collecting all Mexican centers' information related to congenital heart disease care in order to quantify the advances related to the proposed plans. The database utilized international consensus nomenclature. The aim of this article is to show the sequence of our actions in relation to direct accomplishments and the current status of congenital heart disease care in Mexico. This article emphasizes the main aspects of these actions: regionalization project implementation, national survey results, and cardiovascular pediatric surgical database creation. Knowledge of outcomes related to successful actions would be useful for those countries that face similar challenges and may lead them to consider adoption of similar measures with the respective adjustments to their own reality. PMID- 23799730 TI - Congenital heart disease in Nigerian children: a multicenter echocardiographic study. AB - BACKGROUND: Congenital heart disease (CHD) is among the leading causes of morbidity and mortality in childhood. We report on the spectrum of echocardiographically diagnosed CHD from three different centers across Nigeria. METHODS: Over a period of 42 months, children who were referred for echocardiographic evaluation in the centers located in three large metropolitan cities were consecutively recruited if they were confirmed to have identifiable CHD. Data were collected on age, gender, and types of CHD and analyzed using SPSS 16 (Chicago, Illinois,). RESULTS: A total of 605 children were recruited, their mean age was 2.1 +/- 3.5 (range 0-17) years, and 296 (48.9%) were males. Nearly half (42.5%) had echocardiographic diagnosis of their CHD within the first year of life. Only 17% of the diagnoses were made in the neonatal age group. Acyanotic CHDs were more common than the cyanotic heart diseases (82.8% vs 17.2%). The most common CHD was ventricular septal defect (VSD; 46.6%) followed by patent ductus arteriosus (12.1%), atrial septal defect (8.7%), atrioventricular septal defect (8.2%), and tetralogy of Fallot (7.8%). More than half of the VSDs were perimembranous (55.1%) followed by outlet VSD (23.8%), muscular (10.7%), and inlet VSD (9.6%). Only 42 (6.9%) of the entire study population had definitive intervention. CONCLUSION: The VSD is the most prevalent CHD in Nigerian children. There is increasing awareness, availability, and use of diagnostic facilities as mirrored in the age distribution of the children. However, access to definitive surgery is poor and draws attention to the urgent need for affordable surgical facilities in the country. PMID- 23799731 TI - Fetal complete common atrioventricular canal defect: spontaneous closure of the ventricular septal defect--in utero anatomic evolution and postnatal outcomes. AB - BACKGROUND: We describe in utero anatomic evolution and postnatal outcome of complete common atrioventricular canal defect (CCAVCD). METHODS: Retrospective data on 31 fetuses with CCAVCD were analyzed. We reviewed prenatal and postnatal echocardiograms, karyotype, and postnatal outcomes. RESULTS: A total of 20 fetuses had complete data, 18 with serial fetal echocardiograms and postnatal data and 2 terminations. At initial examination, isolated CCAVCD was seen in 12 (67%) fetuses while 6 (33%) were associated with heterotaxy syndrome. On follow up, 4 fetuses (22%) had spontaneous closure of the inlet ventricular septal defect (VSD) component of the CCAVCD, seen both at 30 to 35 weeks of gestation and on postnatal echocardiograms. These 4 fetuses had previously demonstrated CCAVCD between 18 and 25 weeks of gestation. A total of 15 (83%) patients underwent operative correction, 10 with isolated complete atrioventricular septal defect and 5 with heterotaxy had surgical repair. Four infants in whom spontaneous intrauterine closure of the VSD component was observed had no VSD noted at surgery and underwent closure of primum atrial septal defect and repair of the left atrioventricular (AV) valve cleft. CONCLUSIONS: Our data demonstrate that CCAVCD diagnosed during fetal life is not a static anomaly. In our series, an inlet VSD less than 4 mm and Rastelli type A anatomy (AV valve attachment to septal crest) during second trimester may evolve during third trimester by formation of AV sulcus pouch and spontaneous closure of the VSD. To the best of our knowledge, this is the first study to report such anatomic evolution of CCAVCD in the fetus. This information is vital for appropriate counseling for expectant parents. PMID- 23799732 TI - The paediatric cardiac centre for Africa--proceedings of the March 2012 symposium. AB - The Pediatric Cardiac Centre for Africa (PCCA) was opened by national patron Mr Nelson Mandela on November 7, 2003. In 2008, the Centre's international pediatric cardiac symposium was introduced as a learning forum for pediatric cardiac surgeons and cardiologists in the continent. The symposium has consistently grown in attendance and attracted distinguished leaders in the field. The 2012 symposium featured Dr. Thomas Spray of Children's Hospital of Philadelphia, Dr. David Barron of Birmingham Children's Hospital, and Dr. John Brown of Indiana University School of Medicine as guest speakers. Experience of the Fontan procedure, the small aortic root, hypoplastic left heart syndrome, right ventricular outflow tract reconstruction, transposition of the great arteries, and interrupted aortic arch were the highlights of the symposium. In the "African Corner," centers in South Africa, Ghana, and Angola presented work done from across the African continent. PMID- 23799733 TI - Tetralogy of Fallot: controversies in early management. AB - Management of the cyanotic neonate with tetralogy of Fallot (ToF) remains a challenging condition. Outcomes for single-stage repair of ToF have steadily improved over the past 30 years and the best results have been achieved with repair between 3 and 9 months of age. The traditional management of cyanotic neonates and small infants has been palliation with a Blalock-Taussig shunt, but this continues to carry a significant mortality that has remained relatively constant even in the contemporary series. This has led to the promotion of neonatal complete repair, but analysis of published outcomes would suggest that this also carries significant risk compared to repair at an older age. Low birth weight and small pulmonary arteries (PAs) remain the greatest independent risk factors. Right ventricular outflow tract (RVOT) stenting may offer an alternative approach to neonatal repair in high-risk neonates and allow for PA growth and delay of repair until the child reaches a safer age. A stratified approach to early management utilizing RVOT stenting in high-risk cases may lead to better overall outcomes. PMID- 23799734 TI - European Congenital Heart Surgeons Association presidential address 2012. PMID- 23799735 TI - Severe hyperkalemia during cardiopulmonary bypass: etiology and effective therapy. AB - Hyperkalemia is considered a medical emergency as it can result in severe disturbances in cardiac rhythm and death. Although many causes of hyperkalemia exist, exogenous red blood cell transfusions are being recognized as the primary perioperative etiology. The authors report a case of severe intraoperative hyperkalemia associated with the use of allogeneic blood products (packed red blood cells), during a surgical mission to a developing country. The patient was undergoing repeat mitral valve replacement with cardiopulmonary bypass (CPB) and developed significant hyperkalemia with a serum potassium value of 9.9 mEq/L. Successful intraoperative therapies were instituted with a gradual reduction in the serum potassium value to 4.8 mEq, which allowed the patient to be weaned from CPB. The authors review the etiology of hyperkalemia in children including its relationship with allogeneic red blood cell transfusions and treatment modalities including specific therapies which can be instituted during CPB. PMID- 23799736 TI - Isolated anomalous origin of the right coronary artery from the pulmonary artery in an asymptomatic 12-year-old girl: role of MRI in depicting the anatomy, detecting the ischemic burden, and quantifying the amount of left-to-right shunt. AB - Asymptomatic 12-year-old girl with a heart murmur underwent echocardiogram and suspicious continuous flow was detected in her interventricular septum. She underwent cardiac magnetic resonance (CMR) for further investigation. The CMR images demonstrated anomalous origin of the right coronary artery from the pulmonary artery. Adenosine stress perfusion scan showed an inducible perfusion defect in the right coronary artery and left circumflex artery territories. Flow quantification showed a left-to-right shunt with pulmonary to systemic blood flow ratio (Qp/Qs) of 1.25. PMID- 23799737 TI - Tetralogy of Fallot with absent pulmonary valve syndrome, right aortic arch, and disconnected left pulmonary artery. AB - We present a rare case of a two-week-old infant with tetralogy of Fallot , absent pulmonary valve syndrome , right aortic arch, and disconnected left pulmonary artery (LPA) whose origin was from ductal ligament adjacent to the left subclavian artery. One-stage surgical correction, including closure of ventricular septal defect (VSD), LPA reconstruction and reconnection to the pulmonary trunk, reduction in size of the right pulmonary artery (RPA), and right ventricular outflow tract reconstruction with valved conduit, was successfully performed with good clinical mid-term outcome. PMID- 23799738 TI - Cardiac myxoma with prenatal diagnosis. AB - The presentation of myxoma in the neonatal period is quite rare. We report the case of a female patient in whom two cardiac tumors were diagnosed prenatally. Surgery was performed at eight days of age, using cardiopulmonary bypass and circulatory arrest to facilitate excision of two polypoid tumors from within the right atrium. Pathology studies were consistent with myxoma. The postoperative course was satisfactory and the patient was discharged 14 days after surgery, at 22 days old. PMID- 23799739 TI - Death by late-presenting Bochdalek hernia in infant soon after congenital cardiac repair. AB - Congenital diaphragmatic hernia (CDH) presenting beyond the neonatal period is commonly perceived to be rare. With reported frequencies of 2.6% to 20% of all CDH, it may be an overlooked cause of mortality. Variable symptomatology makes its diagnosis challenging. We report the sudden death of a 3-month-old patient shortly after hospital discharge following congenital heart surgery. Autopsy findings associated the patient's demise with migrated abdominal contents in the chest through a Bochdalek hernia defect. No indications of CDH existed before hospital discharge. Relevant issues pertaining to congenital heart disease, CDH, and importance of autopsy in this context are discussed. PMID- 23799740 TI - Anatomically corrected malposition of the great arteries {S, D, L} with left juxtaposition of the atrial appendages in DORV: influence on surgical approach. AB - The case of an infant with double outlet right ventricle with anatomically corrected malposition of the great arteries, bilateral infundibulum, and an echocardiographically routable ventricular septal defect (VSD) is presented. After numerous efforts to visualize the margins of the VSD, the best surgical exposure of the VSD was through the aorta. We believe this to be the first report of this phenomenon, which results from the left-sided position of the aorta and the presence of left juxtaposition of the atrial appendages. PMID- 23799741 TI - Left atrial myxoma in a child: a challenging diagnosis of a rare lesion. AB - An eight-year-old child presented with congestive heart failure, blurred vision, and unexplained constitutional symptoms. An echocardiogram demonstrated a giant left atrial mass that obstructed the mitral valve inflow. After excision of the myxoma, the patient had an uneventful recovery. PMID- 23799742 TI - Congenital division of the left atrium (cor triatriatum) in the setting of congenitally corrected transposition of the great arteries. AB - Congenital division of the left atrium (cor triatriatum) and congenitally corrected transposition of the great arteries are both rare congenital cardiac malformations; their coexistence is exceedingly rare with only two previous reports identified in the literature. This combination of lesions is characterized by a pressure-loaded morphologically left ventricle and a propensity for pulmonary edema dependent on the degree of pulmonary venous obstruction caused by the dividing left atrial shelf. The probable impact of this on the natural history and surgical decision making is discussed. PMID- 23799743 TI - Bilateral branch pulmonary artery banding as a bridge to decision/preoperative optimization of high-risk neonates with hypoplastic left heart syndrome. AB - We present our experience with bilateral branch pulmonary artery banding as a bridge to decision/optimization of hemodynamics, followed by standard Norwood stage I palliation in very high-risk infants with hypoplastic left heart syndrome. PMID- 23799744 TI - Isolated left common carotid artery connected to the pulmonary artery: where was the arterial duct? AB - A three-year-old boy was referred for persistent arterial duct. Transthoracic echocardiography showed a right aortic arch and an unusual Doppler flow in the arch vessels and the pulmonary artery. The tomodensitometry showed a right-sided aortic arch, with successive origin of the right common carotid, the right subclavian artery, and an aberrant (lusoria) left subclavian artery. The left common carotid took origin from the pulmonary trunk. During surgery, a fibrous cord independent from the anomaly was identified. An end-to-side anastomosis between the left carotid and the ascending aorta was done and the fibrous cord was divided. Was this fibrous cord a ductal ligament? PMID- 23799745 TI - A slight modification of the intra-atrial conduit Fontan procedure. PMID- 23799746 TI - Reply to "A slight modification of the intra-atrial conduit Fontan procedure" by Dr. F. Fantini. PMID- 23799747 TI - Why should we care about ethical and policy challenges in congenital heart disease? AB - Congenital heart disease (CHD) affects 1% of infants worldwide, and approximately 90% of children with serious CHD who have access to surgery survive to adulthood. Particularly as this population ages, there are unique ethical and policy challenges pertaining to this diverse population of children and adults, which also serve as a paradigm for other chronic diseases. A unique forum to discuss these issues occurred at the University of Pennsylvania in Philadelphia on March 16 to 17, 2012, and was entitled "Ethics of the Heart: Ethical and Policy Challenges in Adult and Pediatric Congenital Heart Disease." The conference convened a multidisciplinary panel of nationally known experts in the fields of Pediatric Congenital Heart Disease, Adult Congenital Heart Disease, and Bioethics to identify and discuss the most important ethical issues in CHD through talks, panel discussions, and one-on-one interviews in six topic areas: genetic testing, transitions of care from pediatric to adult CHD, transplantation and mechanical circulatory support, research and development in CHD, the social and personal costs of success in treating CHD, and end-of-life considerations. This article is an introduction to the topics discussed. PMID- 23799748 TI - Report from the Society of Thoracic Surgeons National Database Workforce: clarifying the definition of operative mortality. AB - Several distinct definitions of postoperative death have been used in various quality reporting programs. Some have defined postoperative mortality as the occurrence of death after a surgical procedure when the patient dies while still in the hospital, while others have considered all deaths occurring within a predetermined, standardized time interval after surgery to be postoperative mortality. While mortality data are still collected and reported using both these individual definitions, the Society of Thoracic Surgeons (STS) believes that either approach alone may be inadequate. Accordingly, the STS prefers a more encompassing metric, Operative Mortality. Operative Mortality is defined in all STS databases as (1) all deaths, regardless of cause, occurring during the hospitalization in which the operation was performed, even if after 30 days (including patients transferred to other acute care facilities); and (2) all deaths, regardless of cause, occurring after discharge from the hospital, but before the end of the 30th postoperative day. This article provides clarification for some uncommon but important scenarios in which the correct application of this definition may be challenging. PMID- 23799749 TI - Long-term results of the subclavian flap repair for coarctation of the aorta in infants. AB - BACKGROUND: Coarctation is a congenital narrowing of the aorta that often requires repair during infancy. The subclavian flap aortoplasty was once widely favored for its avoidance of a circumferential suture line and low incidence of recoarctation. The aim of this study is to report the long-term results of the subclavian flap repair for coarctation of the aorta in infants. METHODS: Our operative database was queried for infants with coarctation who underwent subclavian flap aortoplasty from 1966 to 1991. Medical records were reviewed for patient characteristics and outcomes. Survivors were identified for additional phone interview. RESULTS: Fifty-five patients met the inclusion criteria. There were 7 early deaths (in hospital), 11 late deaths, 5 patients lost to follow-up, and 32 known long-term survivors with a mean follow-up of 22.0 years (range 2.4 34.9). Hospital mortality was not associated with patient characteristics but was associated with earlier year of surgery (P = .015). A trend toward decreased overall survival was seen in patients with coarctation with associated cardiac defects (P = .072). Reintervention for recoarctation was required in 3 (6.6%) patients and was not related to the patient characteristics. There were no apparent complications related to subclavian artery sacrifice. CONCLUSIONS: Subclavian flap aortoplasty provides excellent long-term results for the repair of coarctation in infants. The incidence of recoarctation requiring reintervention is low and compares favorably with other techniques. Compromise of growth or function of the left arm was not appreciated. The subclavian flap technique remains a viable surgical option for the repair of coarctation in infants. PMID- 23799750 TI - Diaphragmatic nerve palsy after cardiac surgery in children in Egypt: outcome and debate in management. AB - INTRODUCTION: Diaphragmatic paralysis (DP) due to phrenic nerve injury is a complication which occurs in association with congenital cardiac surgery and may be a life-threatening event in infants and young children. Information about this complication is still scarce from the developing countries. METHODS: Retrospective study evaluated the incidence of DP among 414 patients who underwent congenital cardiac surgery in Abo Elriesh Children's Specialized Hospital, Cairo University, Egypt, in the duration from April 2009 to December 2011. RESULTS: Incidence of DP was 3.6% (15 of 414 cases). Median age of affected patients was 10 months (ranged from 1 month to 13 years). Diagnosis of DP was observed after ventricular septal defect repair (3.9%), Glenn anastomosis (8.6%), Tetralogy of Fallot repair (4.3%), Senning operation (10%), arterial switch operation (3.2%), Fontan procedure (33%), coarctation of the aorta repair (7%), and pulmonary artery banding (6.4%). Diaphragmatic plication was performed in 4 of 15 cases. Patients with DP had significantly prolonged mechanical ventilation duration as compared to unaffected patients (median 120, range 48-600 vs 4, range 0-48 hours, P < .000). They also had a higher incidence of nosocomial pneumonia in 8 of 15 (53%) cases, longer duration of intensive care unit stay (median 15, range 4-62 days, P < .006), and significant mortality in 7 of 15 (46%; P < .004). Mortality among patients who underwent diaphragm plication was 1 of 4 (25%). CONCLUSION: Diaphragmatic paralysis is a relatively rare complication of congenital cardiac surgery in children. Its occurrence is associated with increased morbidity and mortality. A high index of clinical suspicion, utilization of bedside diagnostic tools, and a policy of early plication for certain patients may lead to improved outcomes. PMID- 23799751 TI - Comparison of cardioprotective effects of volatile anesthetics in children undergoing ventricular septal defect closure. AB - BACKGROUND: Volatile anesthetic agents may precondition the myocardium and protect against ischemia and infarction. Preconditioning by volatile anesthetic agents is well documented in adults but is underinvestigated in children. The present study compares the effect of preconditioning in children by three volatile anesthetic agents along with several other variables associated with cardioprotection. METHOD: Eighty children scheduled for ventricular septal defect closure under cardioplegic arrest were assigned to preconditioning for five minutes after commencement of cardiopulmonary bypass (CPB) with one minimum alveolar concentration (MAC) of one of the following agents: isoflurane, sevoflurane, desflurane, or placebo (oxygen-air mixture). The plasma concentration of creatine kinase MB (CK-MB) was determined after initiation of CPB, and again 6 and 24 hours after admission to the intensive care unit (ICU) after surgery. Duration of inotropic support, mechanical ventilation, and length of ICU stay in all the groups were also recorded. RESULTS: Preconditioning with isoflurane, sevoflurane, and desflurane was associated with significantly decreased postoperative release of CK-MB as compared to placebo group at 6 (group 1: 237.2 +/- 189, group 2: 69.8 +/- 15.8, group 3: 64.7 +/- 37.8, and group 4: 70.4 +/- 26.7) and 24 hours (group 1: 192.4 +/- 158.2, group 2: 67.7 +/- 25.0, group 3: 85.7 +/- 66.8, and group 4: 50.4 +/- 31.6) after admission to ICU. No significant differences were observed in the CK-MB levels among the three volatile anesthetic agents. Duration of inotropic support, mechanical ventilation, and length of ICU stay were greater in placebo group as compared to other groups without reaching statistical significance. CONCLUSION: Volatile anesthetic appear to provide definite cardioprotection to pediatric myocardium. No conclusion can be drawn regarding the best preconditioning agent among isoflurane, sevoflurane, and desflurane. PMID- 23799752 TI - Anomalous pulmonary venous connections and related anomalies: nomenclature, embryology, anatomy, and morphology. AB - This article combines material from three complementary overviews presented in the Symposium on Pulmonary Venous Anomalies during the Joint Meeting of the World Society for Pediatric and Congenital Heart Surgery and Sociedad Latina de Cardiologia y Cirugia Cardiovascular Pediatrica in Lima, Peru. We discuss the embryologic basis for nomenclature, the hierarchical diagnostic categories, and the important anatomic and morphologic characteristics of anomalous pulmonary venous connections. The anatomic descriptions help to guide an understandable and sensible approach to the diagnosis and surgical management of these various disorders. PMID- 23799753 TI - Partial anomalous pulmonary venous connections: surgical management. AB - Partial anomalous pulmonary venous connections (PAPVCs) are a heterogeneous group of congenital heart lesions in which at least one pulmonary vein will drain into the systemic venous system. The consequences are a variable left-to-right hemodynamic shunt and more rarely pulmonary artery hypertension. Often, PAPVC occurs in association with other congenital cardiac malformations. Surgical correction is most often advisable and is generally straightforward and simple to achieve. Historically, some repairs have included incision across the junction of the superior vena cava with the right atrium, which can lead to late arrhythmias. The Warden technique avoids incision across the atriocaval junction. Neonates and infants with Scimitar syndrome represent the most challenging subset of patients with PAPVC. PMID- 23799754 TI - Ethics and clinical trials in congenital heart disease. AB - There is a strong need for well-designed clinical trials in congenital heart disease. Research in children, including children with congenital heart disease, must adhere to the highest ethical standards at all times. PMID- 23799755 TI - Genetic testing in congenital heart disease: ethical considerations. AB - On March 16, 2012, the Ethics of the Heart 2012: Ethical and Policy Challenges in Pediatric and Adult Congenital Heart Disease Conference took place in Philadelphia, Pennsylvania. The first session focused on the ethics surrounding genetic testing in patients with congenital heart disease. Summarized here is the introductory presentation given by Dr Elizabeth Goldmuntz entitled "The Role of Genetic Testing in Congenital Heart Disease," followed by a case presentation given by Dr Lisa D'Alessandro. The case and the panel discussion that ensued highlight several ethical principles and challenges in this unique patient population. PMID- 23799757 TI - Advance care planning and end-of-life management of adult patients with congenital heart disease. AB - As a result of advances in the diagnosis and treatment of congenital heart disease (CHD), it is now adult care providers, rather than pediatric providers, who are faced with the majority of patient deaths. Effective advance care planning and end-of-life (EOL) care require open communication and collaboration in order to benefit patients, family members, and clinicians. Published guidelines recommend early completion of advance directives and addressing EOL issues in routine care. This article reviews the pattern of shifting CHD mortality, current knowledge regarding advanced care planning and EOL discussions with adults with CHD (ACHD), and guidelines to facilitate and optimize these important discussions. PMID- 23799756 TI - Ethical challenges of the use of whole exome sequencing in the clinic. AB - Genetic testing has been utilized to determine the etiology of some pediatric cardiac conditions for decades. However, new techniques, such as clinical whole exome sequencing, raise ethical challenges that must be addressed for the successful integration of these techniques into routine clinical care. One major ethical concern is the ability of patients to provide meaningful informed consent for this type of complex testing. A case of familial dilated cardiomyopathy with pediatric onset of unknown genetic etiology was utilized to facilitate the discussion of these issues by a panel including cardiologists, a geneticist, and a genetic counselor. Cardiologists and their medical genetics colleagues need to continue to discuss and investigate how to ethically integrate rapidly advancing genetic testing technologies into patient care to optimize potential benefits and minimize potential harms. PMID- 23799758 TI - Ethical considerations related to the use of mechanical support in congenital heart disease. AB - Heart failure frequently complicates congenital heart disease (CHD) in children and adults. In patients with end-stage disease, mechanical circulatory support may improve survival, quality of life, and serve as bridge to cardiac transplantation. There are many ethical issues surrounding the use of mechanical circulatory support in patients with CHD including the use of prospective and randomized trials, proper oversight of new therapies, and transparency in reporting. Additionally, there are ethical considerations relevant to the greater society as these therapies are highly resource intensive in a resource-limited society. This article will review the burden of disease of heart failure in patients with CHD, the challenges of mechanical circulatory support and heart transplantation, and the ethical considerations and problems that arise for this population. PMID- 23799759 TI - Adult and pediatric perspectives on heart retransplant. AB - At the Ethics of the Heart II: Ethical and Policy Challenges in Congenital Heart Disease Conference, March 16-17, 2012 in Philadelphia, Pennsylvania, one of the sessions focused on the issues related to end-stage heart failure in patients with congenital heart disease including utilizing the therapy of heart transplantation. This article will summarize the session related to repeat heart transplant that was based on discussion of actual patient cases, two adults and one pediatric, presented, respectively, by an adult and a pediatric heart transplant specialist. Outcome data related to retransplant for both adult and pediatric heart transplant populations are reviewed. The complicated ethical issues related to considerations of beneficence versus nonmalfeasance by a medical care team for an individual patient, patient autonomy related to adherence, and obligations to society to fairly allocate the scarce precious resource of donor organs are discussed. PMID- 23799760 TI - What does palliative care mean in prenatal diagnosis of congenital heart disease? AB - Palliative care in congenital heart disease is relatively uncommon. A condition in which discussion of palliative care may occasionally arise is in the case of prenatal diagnosis of hypoplastic left heart syndrome. Prenatal diagnosis allows families to be counseled and educated about the anomaly and provides the opportunity for a conscious, deliberate choice between the options of pregnancy termination, interventional management after birth, or nonintervention with palliative care. Multiple factors contribute to the decision making. Despite the improved outcomes, palliative care is still considered a viable option by the congenital heart care provider community. In a large series of consecutive fetuses presenting with hypoplastic left heart syndrome, approximately 11% chose termination of pregnancy and 7% chose postnatal palliative care. As outcomes steadily improve, the threshold for discontinuing the viability of palliative care as an option will be reached. PMID- 23799761 TI - Operative techniques in association with arrhythmia surgery in patients with congenital heart disease. AB - Arrhythmia surgery in patients with congenital disease is challenged by the range of anatomic variants, arrhythmia types, and intramyocardial scar location. Experimental and clinical studies have elucidated the mechanisms of arrhythmias for accessory connections, atrial fibrillation, atrial reentry tachycardia, nodal reentry tachycardia, focal or automatic atrial tachycardia, and ventricular tachycardia. The surgical and transcatheter possibilities are numerous, and the congenital heart surgeon should have a comprehensive understanding of all arrhythmia types and potential methods of ablation. The purpose of this article is to introduce resternotomy techniques for safe mediastinal reentry and to review operative techniques of arrhythmia surgery in association with congenital heart disease. PMID- 23799762 TI - Double root switch: a complete anatomical correction for transposition of the great arteries. AB - We report the cases of two neonates with transposition of the great arteries, whose surgical correction consisted of translocation of the aortic root with the aortic valve and coronary arteries to the left ventricle and translocation of the pulmonary root with the pulmonary valve to the right ventricle. We believe that the aortic translocation may reduce the likelihood of dilatation of the neoaorta, aortic regurgitation, and changes in the endothelium of coronary arteries which have occasionally been seen following arterial switch operations. PMID- 23799763 TI - A unique case of two sources of right ventricle enlargement in tetralogy of Fallot. AB - The most common long-term sequelae of tetralogy of Fallot (TOF) are related to acquired late postsurgical pulmonary valve pathology. This is often in the form of pulmonic insufficiency (PI) ultimately leading to right ventricular (RV) enlargement and failure, which may necessitate pulmonary valve replacement. We present a case of severe PI in TOF with an incidental large circumflex to RV fistula and single-vessel coronary artery stenosis in a patient with an enlarged RV. The diagnostic dilemma was to determine whether the RV enlargement was caused by severe PI, shunting from the coronary fistula, or a combination of both. PMID- 23799764 TI - Unidirectional valved patch closure of ventricular septal defect along with total repair in a 12-year-old patient with truncus arteriosus. AB - We report the case of a 12-year-old patient with truncus arteriosus (common arterial trunk) who underwent successful surgical repair. The ventricular septal defect was closed using a unidirectional valved patch to act as a safeguard in the event of postoperative pulmonary hypertension and right ventricular decompensation. PMID- 23799765 TI - Magnetic resonance imaging of a restrictive atrial septal defect in a univentricular connection. AB - Magnetic resonance imaging (MRI) provides accurate and valuable information regarding cardiac shunts including their location, size, and flow. We describe the MRI findings of a restrictive atrial septal defect within a complex case of congenital heart disease: univentricular atrioventricular connection of left ventricular type with right-sided discordant atrioventricular connection (single), absent left atrioventricular connection, and ventriculoarterial discordance. Few similar cases are reported in the literature. Magnetic resonance imaging may add valuable information regarding restrictive atrial shunts in univentricular hearts. PMID- 23799766 TI - Pseudoaneurysm of surgically reconstructed right ventricular outflow tract. AB - Surgical reconstruction of the right ventricular outflow tract (RVOT) for congenital heart disease can rarely result in the serious complication of pseudoaneurysm development, with or without symptoms. We report on a case of clinically apparent pseudoaneurysm of the RVOT after homograft replacement for a patient with a history of tetralogy of Fallot. PMID- 23799767 TI - Single-stage correction of interrupted aortic arch in an adolescent patient. AB - Interrupted aortic arch (IAA) is a rare condition that generally requires surgical correction in the newborn. We report a case of delayed presentation of type A interrupted aortic arch with ventricular septal defect in a 13-year-old female. Single-stage correction without circulatory arrest was accomplished via midline sternotomy approach. Tissue-to-tissue anastomosis was performed without the use of prosthetic material in order to optimize chances for future growth. This simplified technique avoids additional procedures, reduces ischemic time, and prevents problems related to circulatory arrest. PMID- 23799768 TI - Cardiopulmonary bypass in an infant with a recent history of malaria. AB - Severe malarial infection is associated with impaired cardiac function. We report a child who underwent repair of tetralogy of Fallot two weeks after being treated for malaria. The postoperative course was complicated by impaired left ventricular function. The pathogenesis of malaria is discussed as well as the potential complications of cardiopulmonary bypass (CPB). PMID- 23799769 TI - Ventricular septal defect and bidirectional shunting? Things are not what they seem. AB - This report describes the case of a 19-year-old woman with a diagnosis of muscular ventricular septal defect. Bidirectional shunting was observed during a transthorathic echocardiography evaluation which also suggested normal pulmonary arterial pressure. Moreover, anomalous and hypertrophic right ventricular muscular bands were observed. After having ruled out other possibilities, the plausible explanation is one, which is not described in the literature. The findings may be explained as a sequestrated portion of the cavity of the right ventricle that remains isolated from the rest of the right ventricle (RV) by anomalous and hypertrophic right ventricular muscular bands, with communication only between the left ventricle and the sequestrated part of the RV. This is an unusual variant of two-chambered RV simulating two-chambered left ventricle. PMID- 23799770 TI - Intercostal artery aneurysm with coarctation of the aorta. PMID- 23799771 TI - Common arterial trunk with restrictive ventricular septal defect. PMID- 23799772 TI - Differences between young and older adults' spoken language production in descriptions of negative versus neutral pictures. AB - Young and older participants produced oral picture descriptions that were analyzed to determine the impact of negative emotional content on spoken language production. An interaction was found for speech disfluencies: young adults' disfluencies did not vary, whereas older adults' disfluencies increased, for negative compared to neutral pictures. Young adults adopted a faster speech rate while describing negative compared to neutral pictures, but older adults did not. Reference errors were uncommon for both age groups, but occurred more during descriptions of negative than neutral pictures. Our findings indicate that negative content can be differentially disruptive to older adults' spoken language production, and add to the literature on aging, emotion, and cognition by exploring effects within the domain of language production. PMID- 23799773 TI - Group critical incident stress debriefing with emergency services personnel: a randomized controlled trial. AB - Although single-session individual debriefing is contraindicated, the efficacy of group psychological debriefing remains unresolved. We conducted the first randomized controlled trial of critical incident stress debriefing (CISD) with emergency workers (67 volunteer fire-fighters) following shared exposure to an occupational potentially traumatic event (PTE). The goals of group CISD are to prevent post-traumatic stress and promote return to normal functioning following a PTE. To assess both goals we measured four outcomes, before and after the intervention: post-traumatic stress, psychological distress, quality of life, and alcohol use. Fire brigades were randomly assigned to one of three treatment conditions: (1) CISD, (2) Screening (i.e., no-treatment), or (3) stress management Education. Controlling for pre-intervention scores, CISD was associated with significantly less alcohol use post-intervention relative to Screening, and significantly greater post-intervention quality of life relative to Education. There were no significant effects on post-traumatic stress or psychological distress. Overall, CISD may benefit broader functioning following exposure to work-related PTEs. Future research should focus on individual, group, and organizational factors and processes that can promote recovery from operational stressors. Ultimately, an occupational health (rather than victim based) approach will provide the best framework for understanding and combating potential threats to the health and well-being of workers at high risk for PTE exposure. PMID- 23799774 TI - scAAV9 intracisternal delivery results in efficient gene transfer to the central nervous system of a feline model of motor neuron disease. AB - On the basis of previous studies suggesting that vascular endothelial growth factor (VEGF) could protect motor neurons from degeneration, adeno-associated virus vectors (serotypes 1 and 9) encoding VEGF (AAV.vegf) were administered in a limb-expression 1 (LIX1)-deficient cat-a large animal model of lower motor neuron disease-using three different delivery routes to the central nervous system. AAV.vegf vectors were injected into the motor cortex via intracerebral administration, into the cisterna magna, or intravenously in young adult cats. Intracerebral injections resulted in detectable transgene DNA and transcripts throughout the spinal cord, confirming anterograde transport of AAV via the corticospinal pathway. However, such strategy led to low levels of VEGF expression in the spinal cord. Similar AAV doses injected intravenously resulted also in poor spinal cord transduction. In contrast, intracisternal delivery of AAV exhibited long-term transduction and high levels of VEGF expression in the entire spinal cord, yet with no detectable therapeutic clinical benefit in LIX1 deficient animals. Altogether, we demonstrate (i) that intracisternal delivery is an effective AAV delivery route resulting in high transduction of the entire spinal cord, associated with little to no off-target gene expression, and (ii) that in a LIX1-deficient cat model, however, VEGF expressed at high levels in the spinal cord has no beneficial impact on the disease course. PMID- 23799775 TI - Discovery of bufadienolides as a novel class of ClC-3 chloride channel activators with antitumor activities. AB - ClC-3 chloride (Cl(-)) channel has been shown to be involved in cell proliferation, cell cycle, and cell migration processes. Herein, we found that a series of bufadienolides isolated from toad venom were a novel class of ClC-3 Cl( ) channel activators with antitumor activities. Bufalin, which has the most potent antitumor activity, and 15beta-acetyloxybufalin, which has no antitumor activity, were chosen as representative compounds to investigate the role of the ClC-3 Cl(-) channel. It was found that bufalin rapidly elicited activation of the ClC-3 Cl(-) channel and subsequently induced apoptosis through inhibition of the PI3K/Akt/mTOR pathway. The PI3K/Akt/mTOR pathway was attenuated by pretreatment with Cl(-) channel blockers [tamoxifen and 5-nitro-2-(3-phenylpropylamino)benzoic acid, NPPB] or ClC-3 small interfereing RNA. In summary, we discovered that activation of the ClC-3 Cl(-) channel, which subsequently induced inhibition of the PI3K/Akt/mTOR signaling pathway, was involved in the antitumor activities of bufadienolides. PMID- 23799776 TI - Optimized anion exchange membranes for vanadium redox flow batteries. AB - In order to understand the properties of low vanadium permeability anion exchange membranes for vanadium redox flow batteries (VRFBs), quaternary ammonium functionalized Radel (QA-Radel) membranes with three ion exchange capacities (IECs) from 1.7 to 2.4 mequiv g(-1) were synthesized and 55-60 MUm thick membrane samples were evaluated for their transport properties and in-cell battery performance. The ionic conductivity and vanadium permeability of the membranes were investigated and correlated to the battery performance through measurements of Coulombic efficiency, voltage efficiency and energy efficiency in single cell tests, and capacity fade during cycling. Increasing the IEC of the QA-Radel membranes increased both the ionic conductivity and VO(2+) permeability. The 1.7 mequiv g(-1) IEC QA-Radel had the highest Coulombic efficiency and best cycling capacity maintenance in the VRFB, while the cell's voltage efficiency was limited by the membrane's low ionic conductivity. Increasing the IEC resulted in higher voltage efficiency for the 2.0 and 2.4 mequiv g(-1) samples, but the cells with these membranes displayed reduced Coulombic efficiency and faster capacity fade. The QA-Radel with an IEC of 2.0 mequiv g(-1) had the best balance of ionic conductivity and VO(2+) permeability, achieving a maximum power density of 218 mW cm(-2) which was higher than the maximum power density of a VRFB assembled with a Nafion N212 membrane in our system. While anion exchange membranes are under study for a variety of VRFB applications, this work demonstrates that the material parameters must be optimized to obtain the maximum cell performance. PMID- 23799777 TI - Elucidation of carbohydrate molecular interaction mechanism of recombinant and native ArtinM. AB - The quartz crystal microbalance (QCM) technique has been applied for monitoring the biorecognition of ArtinM lectins at low horseradish peroxidase glycoprotein (HRP) concentrations, using a simple kinetic model based on Langmuir isotherm in previous work.18 The latter approach was consistent with the data at dilute conditions but it fails to explain the small differences existing in the jArtinM and rArtinM due to ligand binding concentration limit. Here we extend this analysis to differentiate sugar-binding event of recombinant (rArtinM) and native (jArtinM) ArtinM lectins beyond dilute conditions. Equivalently, functionalized quartz crystal microbalance with dissipation monitoring (QCM-D) was used as real time label-free technique but structural-dependent kinetic features of the interaction were detailed by using combined analysis of mass and dissipation factor variation. The stated kinetic model not only was able to predict the diluted conditions but also allowed to differentiate ArtinM avidities. For instance, it was found that rArtinM avidity is higher than jArtinM avidity whereas their conformational flexibility is lower. Additionally, it was possible to monitor the hydration shell of the binding complex with ArtinM lectins under dynamic conditions. Such information is key in understanding and differentiating protein binding avidity, biological functionality, and kinetics. PMID- 23799778 TI - New insight into adsorption mechanism of ionizable compounds on carbon nanotubes. AB - We studied the pH-dependent adsorption of benzoic acid (BA), phthalic acid (PA), and 2,6-dichloro-4-nitrophenol (DCNP) by hydroxylated, carboxylated, and graphitized carbon nanotubes (CNTs). Adsorption is contributed by formation of a negative charge-assisted H-bond (-)CAHB between a carboxyl group on the solute and a phenolate or carboxylate group on the surface having a comparable pKa. This exceptionally strong H-bond is depicted as (RCO2...H...O-CNTs)(-). Over a limited pH range the free anion undergoes proton exchange with water concurrent with adsorption, releasing hydroxide ion in a stoichiometry of up to 1.0 for BA, 1.7 for PA, and 0.5 for DCNP. Little hydroxide is released upon adsorption by the O sparse graphitized CNTs. Anion exchange and ligand exchange reactions as a source of hydroxide release were ruled out. The higher stoichiometry for PA indicates involvement of both carboxyl groups with adjacent surface oxyl groups. The lower stoichiometry for DCNP is consistent with steric inhibition of H-bonding by the ortho chlorines. Formation of (-)CAHB helps overcome the unfavorable free energy of proton exchange with water, and results in an upward shift in the pKa in the adsorbed state compared to the dissolved state from 0.9 to 3.1 units. The proposed mechanism is further supported by additional structure-activity considerations. The findings provide new understanding of the interactions between ionizable organic compounds and carbonaceous surfaces, which has implications for noncovalent derivatization of CNTs, fate of ionizable pollutants, and associations of natural organic matter with CNTs and other carbonaceous materials in the environment. PMID- 23799779 TI - Photoelectrochemical properties of (In,Ga)N nanowires for water splitting investigated by in situ electrochemical mass spectroscopy. AB - We investigated the photoelectrochemical properties of both n- and p-type (In,Ga)N nanowires (NWs) for water splitting by in situ electrochemical mass spectroscopy (EMS). All NWs were prepared by plasma-assisted molecular beam epitaxy. Under illumination, the n-(In,Ga)N NWs exhibited an anodic photocurrent, however, no O2 but only N2 evolution was detected by EMS, indicating that the photocurrent was related to photocorrosion rather than water oxidation. In contrast, the p-(In,Ga)N NWs showed a cathodic photocurrent under illumination which was correlated with the evolution of H2. After photodeposition of Pt on such NWs, the photocurrent density was significantly enhanced to 5 mA/cm(2) at a potential of -0.5 V/NHE under visible light irradiation of ~40 mW/cm(2). Also, incident photon-to-current conversion efficiencies of around 40% were obtained at -0.45 V/NHE across the entire visible spectral region. The stability of the NW photocathodes for at least 60 min was verified by EMS. These results suggest that p-(In,Ga)N NWs are a promising basis for solar hydrogen production. PMID- 23799780 TI - Self-assembled supramolecular clusters based on phosphines and coinage metals: tetrahedra, helicates, and mesocates. AB - An array of coordination-driven supramolecular metal-ligand clusters has been synthesized using polytopic phosphine ligands and coinage metals (Cu(+), Ag(+), Au(+)). Rigid 3-fold or 2-fold symmetric phosphine ligands have been prepared: 1,3,5-tris((4-(diphenylphosphino)ethynyl)phenyl)benzene) (tppepb, L(1)), 1,4 bis((diphenylphosphino)ethynyl)benzene (1,4-dppeb, L(2)), 1,3 bis((diphenylphosphino)ethynyl)benzene (1,3-dppeb, L(3)), 2,6 bis((diphenylphosphino)ethynyl)pyridine (2,6-dppep, L(4)), and 1,5 bis((diphenylphosphino)ethynyl)naphthalene (1,5-dppen, L(5)). Self-assembly of these ligands with coinage metals produces four different types of metal-ligand clusters, or in some cases coordination polymers, depending on number and relative geometry of the phosphine donor atoms. Supramolecular tetrahedral clusters of the formula M4(L(1))4I4 (M = Cu(+), Ag(+), Au(+)) were obtained with the tppepb ligand, encapsulating solvent molecules (either CH2Cl2 or DMF) as guests within the central cavity of the clusters. The ligands 1,3-dppeb (L(3)) and 2,6-dppep (L(4)) give achiral, triple-stranded, dinuclear mesocates with the formula M2(L)3I2 (M = Cu(+) or Au(+)). In contrast, the ligand 1,4-dppeb (L(2)) generates a triple-stranded, dinuclear helicate with Cu(+), but a coordination polymer with Au(+) (both with the empirical formula M2(L(2))3I2). Finally, coordination polymers were obtained from 1,5-dppen (L(5)) with Cu(+). The clusters have been fully characterized by single crystal X-ray crystallography, high-resolution mass spectrometry, (1)H NMR, and (31)P NMR. PMID- 23799781 TI - Heteroarylcarbenes. PMID- 23799783 TI - Molecular secondary ion mass spectrometry. PMID- 23799784 TI - Microstructure and performance of multiwalled carbon nanotube/m-aramid composite films as electric heating elements. AB - We report microstructure of thermomechanically stable multiwalled carbon nanotube (MWCNT)/poly(m-phenylene isophthalamide) (m-aramid) composite films containing 0.0-10.0 wt % MWCNTs and their performance as electric heating elements. FE-SEM images show that the MWCNTs are well dispersed in the composite films and are wrapped with m-aramid chains and that the interfacial thickness of m-aramid wrapped MWCNTs decreases with the MWCNT content. The electrical resistivity of films varies from ~10(13) Omega cm for the neat m-aramid to ~10(0) Omega cm of the film with 10.0 wt % MWCNT owing to the formation of a conductive three dimensional network of MWCNTs. Accordingly, the performance of MWCNT/m-aramid films as electric heating elements is strongly dependent on MWCNT content as well as applied voltage. For the composite film with 10.0 wt % MWCNT, a maximum temperature of ~176 degrees C is attained even at a low applied voltage of 10 V. The excellent performance such as rapid temperature response and high electric power efficiency at given applied voltages is found to be related with the microstructural features of the MWCNT/m-aramid films. PMID- 23799782 TI - Effect of chelators on the pharmacokinetics of (99m)Tc-labeled imaging agents for the prostate-specific membrane antigen (PSMA). AB - Technetium-99m, the most commonly used radionuclide in nuclear medicine, can be attached to biologically important molecules through a variety of chelating agents, the choice of which depends upon the imaging application. The prostate specific membrane antigen (PSMA) is increasingly recognized as an important target for imaging and therapy of prostate cancer (PCa). Three different (99m)Tc labeling methods were employed to investigate the effect of the chelator on the biodistribution and PCa tumor uptake profiles of 12 new urea-based PSMA-targeted radiotracers. This series includes hydrophilic ligands for radiolabeling with the [(99m)Tc(CO)3](+) core (L8-L10), traditional NxSy-based chelating agents with varying charge and polarity for the (99m)Tc-oxo core (L11-L18), and a (99m)Tc organohydrazine-labeled radioligand (L19). (99m)Tc(I)-Tricarbonyl-labeled [(99m)Tc]L8 produced the highest PSMA+ PC3 PIP to PSMA- PC3 flu tumor ratios and demonstrated the lowest retention in normal tissues including kidney after 2 h. These results suggest that choice of chelator is an important pharmacokinetic consideration in the development of (99m)Tc-labeled radiopharmaceuticals targeting PSMA. PMID- 23799785 TI - Applicability of anaerobic nitrate-dependent Fe(II) oxidation to microbial enhanced oil recovery (MEOR). AB - Microbial processes that produce solid-phase minerals could be judiciously applied to modify rock porosity with subsequent alteration and improvement of floodwater sweep in petroleum reservoirs. However, there has been little investigation of the application of this to enhanced oil recovery (EOR). Here, we investigate a unique approach of altering reservoir petrology through the biogenesis of authigenic rock minerals. This process is mediated by anaerobic chemolithotrophic nitrate-dependent Fe(II)-oxidizing microorganisms that precipitate iron minerals from the metabolism of soluble ferrous iron (Fe(2+)) coupled to the reduction of nitrate. This mineral biogenesis can result in pore restriction and reduced pore throat diameter. Advantageously and unlike biomass plugs, these biominerals are not susceptible to pressure or thermal degradation. Furthermore, they do not require continual substrate addition for maintenance. Our studies demonstrate that the biogenesis of insoluble iron minerals in packed bed columns results in effective hydrology alteration and homogenization of heterogeneous flowpaths upon stimulated microbial Fe(2+) biooxidation. We also demonstrate almost 100% improvement in oil recovery from hydrocarbon-saturated packed-bed columns as a result of this metabolism. These studies represent a novel departure from traditional microbial EOR approaches and indicate the potential for nitrate-dependent Fe(2+) biooxidation to improve volumetric sweep efficiency and enhance both the quality and quantity of oil recovered. PMID- 23799786 TI - Upgrading light hydrocarbons via tandem catalysis: a dual homogeneous Ta/Ir system for alkane/alkene coupling. AB - Light alkanes and alkenes are abundant but are underutilized as energy carriers because of their high volatility and low energy density. A tandem catalytic approach for the coupling of alkanes and alkenes has been developed in order to upgrade these light hydrocarbons into heavier fuel molecules. This process involves alkane dehydrogenation by a pincer-ligated iridium complex and alkene dimerization by a Cp*TaCl2(alkene) catalyst. These two homogeneous catalysts operate with up to 60/30 cooperative turnovers (Ir/Ta) in the dimerization of 1 hexene/n-heptane, giving C13/C14 products in 40% yield. This dual system can also effect the catalytic dimerization of n-heptane (neohexene as the H2 acceptor) with cooperative turnover numbers of 22/3 (Ir/Ta). PMID- 23799787 TI - Fe-TPP coordination network with metalloporphyrinic neutral radicals and face-to face and edge-to-face pi-pi stacking. AB - Compound ([FeTPPbipy](*))n (TPP = meso-tetraphenylporphyrin and bipy = 4,4' bipyridine) is the first example of a Fe-TPP-bipy coordination network, and it consists of 1D polymers packed through face-to-face and edge-to-face pi-pi interactions. The compound has been investigated by means of X-ray diffraction, IR, Mossbauer, UV-visible, and EPR spectroscopies, thermogravimetry, magnetic susceptibility measurements, and quantum-mechanical density functional theory (DFT) and time-dependent DFT calculations. The chemical formula for this compound can be confusing because it is compatible with Fe(II) and TPP(2-) anions. However, the spectroscopic and magnetic properties of this compound are consistent with the presence of low-spin Fe(III) ions and [FeTPPbipy](*) neutral radicals. These radicals are proposed to be formed by the reduction of metalloporphyrin, and the quantum-mechanical calculations are consistent with the fact that the acquired electrons are located on the phenyl groups of TPP. PMID- 23799788 TI - Patterns and problems associated with transitions after hip fracture in older adults. AB - This qualitative, descriptive, longitudinal, multiple case study describes the number and type of care transitions and problems experienced by 21 older urban and rural hip fracture patients in the year following hip fracture repair. Three patterns of transitions emerged: home to hospital to inpatient rehabilitation facility (n = 8); home to hospital to skilled nursing facility (SNF, n = 11); and intermediate nursing home to hospital to SNF (n = 2). Hip fracture patients experienced a median of 4 (range = 4 to 8) transitions in the year following repair. Problems common to all patterns were weight loss, delirium, depression, pressure ulcers, falls, and urinary incontinence. Patients newly admitted to SNFs experienced more problems and order discrepancies than those discharged to an inpatient rehabilitation facility. Families often identified problems first. Strategies to improve transitional care to older hip fracture patients should include improved patient and family involvement at the time of transition, irrespective of initial discharge location. PMID- 23799789 TI - Competency of new graduate nurses: a review of their weaknesses and strategies for success. AB - Because of the ongoing nursing shortage and the increasing acuity of patients, new graduate nurses must master both psychomotor and critical thinking skills rapidly. Inadequate orientation leads to high turnover rates for new graduates. Health care leaders must examine the competencies needed for new graduate nurses to succeed in this environment. A critical review of studies (n = 26) was conducted to identify crucial competencies that are needed for new graduate nurses to be successful. Six areas were identified in which new graduates lacked competence: communication, leadership, organization, critical thinking, specific situations, and stress management. Strategies were identified to improve the transition of new graduates. Hospitals should consider implementing nurse residency programs that include strategies for clear communication and conflict management, prioritization skills, and leadership development. Schools of nursing should add communication strategies to their current focus on critical thinking, clinical reasoning, and simulation scenarios and include situation-specific skills such as end-of-life scenarios. Further research should focus on stress management, leadership, clinical reasoning, and evaluation of measurement tools for new graduates. PMID- 23799790 TI - Development of an online orientation course for preceptors in a dedicated education unit program. AB - The dedicated education unit (DEU) is an emerging model of nursing education. Instead of an instructor-led clinical group, students are partnered with a unit staff nurse for precepted learning. These experiences in learning typically begin with early clinical courses. Precepting nursing students in a DEU is different from precepting newly hired staff nurses and traditional clinical students. This article describes the DEU model implemented at one university, the challenges associated with preparing staff nurses to precept nursing students, the development of a face-to-face DEU preceptor orientation, and progression to an innovative online orientation course. PMID- 23799791 TI - Fundus findings in chronic granulomatous disease. AB - Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disease that has been reported to present with various chorioretinal findings, predominantly in men. We report a case of a 17-year-old girl with a known diagnosis of CGD referred to the ophthalmology clinic for evaluation of an inflamed pingueculum. Upon clinical examination and ophthalmic imaging, high quality montage fundus photographs demonstrated a wide array of bilaterally asymmetric chorioretinal findings known to be characteristic of the ophthalmic manifestations of CGD, including chorioretinitis and focal subretinal granuloma. This report also adds to the body of evidence that the chorioretinal findings associated with this disease have the potential to worsen over time. PMID- 23799792 TI - Accuracy and reproducibility of seven brands of small-volume syringes used for intraocular drug delivery. AB - BACKGROUND AND OBJECTIVE: Little is known about the accuracy and precision of syringes used to deliver small-volume intravitreal injection of medication. The authors investigated the accuracy and reproducibility of seven brands of small volume syringes used for intravitreal injection. MATERIALS AND METHODS: This experimental laboratory investigation compared EXELint 1 cc TB, BD Luer-lok, BD 1 cc TB, Kendall Monoject TB, Nipro TB, Terumo 1 cc, and Terumo 0.5 cc syringes. A calibrated Pipetman served as a control. One hundred syringes of each brand delivered 0.05 mL and 0.10 mL distilled water onto a balance. One-sample t-test (P < .01) compared delivered and intended volumes. RESULTS: The Nipro TB was the most accurate syringe at 0.05 mL. All other brands over-delivered the target volume. At 0.10 mL, the BD Luer-lok and Nipro TB were the most accurate. BD Luer lok over-delivered while Nipro TB under-delivered, but these deviations were not statistically significant. The Pipetman control was the most accurate and reproducible device at both volumes. CONCLUSION: Nipro TB was the most accurate syringe at both volumes. Terumo 0.5 cc gave the most reproducible results but lacked accuracy. These findings may affect treatment efficacy and explain variability in treatment responses. Industry-standardized delivery devices may increase the accuracy and reproducibility of medication delivery. PMID- 23799793 TI - The association between residual astigmatism and refractive errors in a population-based study. AB - PURPOSE: To examine the relationship of spherical equivalent (SE) with refractive, corneal, and residual astigmatism. METHODS: Using stratified cluster sampling, 6,311 individuals were invited and 82.2% participated in this study. Examinations including uncorrected and corrected distance visual acuity tests, refraction, slit-lamp examination, and funduscopy were performed for all participants. Refraction and keratometry were used to calculate refractive and corneal astigmatism, respectively, and their difference was regarded as residual astigmatism. RESULTS: Refractive astigmatism showed a U-shaped relationship with SE; with every diopter (D) increase in astigmatism, the SE increased by 0.230 D in hyperopes and 0.664 D in myopes (P < .001). With every 1.0 D increase in residual astigmatism, the SE showed 0.376 D myopic shift in myopes (P = .004) and 0.077 D hyperopic shift in hyperopes (P = .224). Mean SE was highest among cases of with-the-rule (WTR) astigmatism (P < .001). Cases of high myopia and high hyperopia mostly had WTR and most emmetropes had against-the-rule (ATR) refractive astigmatism. Residual astigmatism was mostly WTR in emmetropic cases; at higher levels of SE error in myopes and hyperopes, WTR residual astigmatism decreased, whereas ATR and oblique residual astigmatism increased. CONCLUSIONS: Increases in SE are associated with higher levels of refractive and residual astigmatism among myopic and hyperopic cases. Unlike refractive astigmatism, WTR residual astigmatism was mostly seen in near emmetropic individuals. PMID- 23799794 TI - Keratectasia after treating presbyopia with INTRACOR followed by SUPRACOR enhancement. AB - PURPOSE: To report a case of unilateral keratectasia after INTRACOR, which was followed by an additional excimer LASIK enhancement with a new presbyopia correcting ablation profile. METHODS: The non-dominant eye of a 49-year-old man with emmetropia was treated with the INTRACOR procedure using the Technolas femtosecond laser (Technolas Perfect Vision GmbH, Munich, Germany) for presbyopia. Neither eye had risk factors for keratectasia. Two years later, a presbyopia-correcting LASIK (SUPRACOR LASIK; Technolas Perfect Vision GmbH) enhancement was performed in the same eye because of deteriorated distance and near visual acuity. RESULTS: The eye treated with INTRACOR followed by SUPRACOR LASIK developed marked keratectasia topographically limited to the area altered by INTRACOR, whereas the fellow eye remained stable and still has no signs of keratoconus. CONCLUSIONS: This case emphasizes the incomplete knowledge of the risk factors for keratectasia following INTRACOR alone and in combination with a SUPRACOR LASIK enhancement. It also suggests that the combined weakening effect of both procedures on corneal mechanical stability may be too strong even in the absence of established risk factors for LASIK surgery. PMID- 23799795 TI - Complications of femtosecond laser-assisted re-treatment for residual refractive errors after LASIK. AB - PURPOSE: To report complications of femtosecond laser-assisted re-treatment by the creation of side cuts within the old flaps for residual refractive error after primary LASIK in two patients. METHODS: Case report. RESULTS: Three eyes of two patients had complications with a circumferential sliver of stromal tissue displaced during surgery due to overlap of old and new side cuts. The displaced tissue was repositioned and corneal anatomy was restored. Two of three eyes demonstrated improvement in the uncorrected visual acuity, whereas one eye lost two lines of corrected visual acuity due to loss of tissue at side cut resulting from flap manipulation, which was done at 1 week. CONCLUSIONS: These cases demonstrate a complication of femtosecond laser-enabled side-cut for LASIK enhancement and factors that may lead to this complication and precautions to avoid it. PMID- 23799796 TI - Quantification of steady-state ion transport through single conical nanopores and a nonuniform distribution of surface charges. AB - Electrostatic interactions of mobile charges in solution with the fixed surface charges are known to strongly affect stochastic sensing and electrochemical energy conversion processes at nanodevices or devices with nanostructured interfaces. The key parameter to describe this interaction, surface charge density (SCD), is not directly accessible at nanometer scale and often extrapolated from ensemble values. In this report, the steady-state current voltage (i-V) curves measured using single conical glass nanopores in different electrolyte solutions are fitted by solving Poisson and Nernst-Planck equations through finite element approach. Both high and low conductivity state currents of the rectified i-V curve are quantitatively fitted in simulation at less than 5% error. The overestimation of low conductivity state current using existing models is overcome by the introduction of an exponential SCD distribution inside the conical nanopore. A maximum SCD value at the pore orifice is determined from the fitting of the high conductivity state current, while the distribution length of the exponential SCD gradient is determined by fitting the low conductivity state current. Quantitative fitting of the rectified i-V responses and the efficacy of the proposed model are further validated by the comparison of electrolytes with different types of cations (K(+) and Li(+)). The gradient distribution of surface charges is proposed to be dependent on the local electric field distribution inside the conical nanopore. PMID- 23799797 TI - Thermoreversible physical gels of poly(dimethylsiloxane) without cross-links or functionalization. AB - The preparation of gels of poly(dimethylsiloxane) (PDMS) reported in the literature so far involves catalysts and chemical cross-links (chemical gels) or functionalization with organogelators. We report that thermoreversible physical gels of PDMS, without cross-links or functionalization, can be made with propylamine or hexylamine as a solvent. The gels consist of spherical domains as small as 20 nm. We show that these spherical domains are part of a network. Differential scanning calorimetry (DSC), optical microscopy, and rheology show that the gel is thermoreversible. With the DSC experiments, we have devised a procedure to achieve thermoreversibility with very similar gel-sol transition endotherms in the first and second heating cycles. PMID- 23799798 TI - Controllable preparation of monodisperse microspheres using geometrically mediated droplet formation in a single mold. AB - We present a surfactant-free fabrication method for simultaneous generation of monodisperse microspheres with controllable size manner. Droplets that become microspheres by solidification processes are made in a two-step process: capillary rising-induced fluid division and wetting of immiscible fluid in a micromold. Design of the mold geometry and the monomer concentration primarily determines the microsphere size and the size distribution. Furthermore, the synergistic effect of two parameters is able to efficiently manipulate the microsphere sizes from submicrometers to a few hundred micrometers. PMID- 23799799 TI - Force interactions of nonagglomerating polylactide particles obtained through covalent surface grafting with hydrophilic polymers. AB - Nonagglomerating polylactide (PLA) particles with various interaction forces were designed by covalent photografting. PLA particles were surface grafted with hydrophilic poly(acrylic acid) (PAA) or poly(acrylamide) (PAAm), and force interactions were determined using colloidal probe atomic force microscopy. Long range repulsive interactions were detected in the hydrophilic/hydrophilic systems and in the hydrophobic/hydrophilic PLA/PLA-g-PAAm system. In contrast, attractive interactions were observed in the hydrophobic PLA/PLA and in the hydrophobic/hydrophilic PLA/PLA-g-PAA systems. AFM was also used in the tapping mode to determine the surface roughness of both neat and surface-grafted PLA film substrates. The imaging was performed in the dry state as well as in salt solutions of different concentrations. Differences in surface roughness were identified as conformational changes induced by the altered Debye screening length. To understand the origin of the repulsive force, the AFM force profiles were compared to the Derjaguin, Landau, Verwey, and Overbeek (DLVO) theory and the Alexander de Gennes (AdG) model. The steric repulsion provided by the different grafted hydrophilic polymers is a useful tool to inhibit agglomeration of polymeric particles. This is a key aspect in many applications of polymer particles, for example in drug delivery. PMID- 23799800 TI - Intrinsic line shape of the Raman 2D-mode in freestanding graphene monolayers. AB - We report a comprehensive study of the two-phonon intervalley (2D) Raman mode in graphene monolayers, motivated by recent reports of asymmetric 2D-mode line shapes in freestanding graphene. For photon energies in the range 1.53-2.71 eV, the 2D-mode Raman response of freestanding samples appears as bimodal, in stark contrast with the Lorentzian approximation that is commonly used for supported monolayers. The transition between the freestanding and supported cases is mimicked by electrostatically doping freestanding graphene at carrier densities above 2 * 10(11) cm(-2). This result quantitatively demonstrates that low levels of charging can obscure the intrinsically bimodal 2D-mode line shape of monolayer graphene. In pristine freestanding graphene, we observe a broadening of the 2D mode feature with decreasing photon energy that cannot be rationalized using a simple one-dimensional model based on resonant inner and outer processes. This indicates that phonon wavevectors away from the high-symmetry lines of the Brillouin zone must contribute to the 2D-mode, so that a full two-dimensional calculation is required to properly describe multiphonon-resonant Raman processes. PMID- 23799801 TI - Interrupted Fischer-indole intermediates via oxyarylation of alkenyl boronic acids. AB - The oxyarylation of alkenyl boronic acids with N-arylbenzhydroxamic acids has been achieved under both copper-mediated and copper-catalyzed conditions to provide access to interrupted Fischer-indole intermediates. This transformation is believed to proceed through a copper-promoted C-O bond forming event followed by a [3,3] rearrangement. The scope of the method is described and mechanistic experiments are discussed. PMID- 23799802 TI - Ortho- and para-selective ruthenium-catalyzed C(sp2)-H oxygenations of phenol derivatives. AB - Versatile ruthenium catalysts allowed for efficient direct oxygenations of aryl carbamates under remarkably mild reaction conditions. In addition to chelation assisted C-H activation, the optimized ruthenium catalyst proved amenable to para selective hydroxylations of anisoles without Lewis basic directing groups. PMID- 23799803 TI - In vitro randomized comparison of a standard and novel echogenic needle for ultrasonography-guided renal targeting. AB - BACKGROUND AND PURPOSE: Urologists are becoming increasingly aware of the importance of pretreatment percutaneous renal biopsy of small renal cortical neoplasms. A barrier to the routine performance of ultrasonography-guided percutaneous renal biopsy has been the technical challenges associated with the procedure. We evaluated a new modified needle, which incorporates an echogenic needle tip designed to improve the needle tip's visibility under ultrasonographic visualization. We evaluated and compared the ultrasonographic imaging quality of the echogenic needle (EN) and a standard needle (SN). METHODS: Forty-eight participants were recruited to perform ultrasonography-guided needle targeting and drainage of a simulated cyst within a phantom model. The simulated cysts were embedded in an opaque gel mold. Each participant was blinded to the type of needle being deployed and was asked to identify and aspirate the simulated cyst with each needle under ultrasonography guidance. Each needle was tested at three ultrasound-aiming angles, (0, 15, and 30 degrees). The quality of needle visibility under ultrasonographic imaging was assessed via a questionnaire, including needle preference and a visibility score (1-10) at each aiming angle. Participants were stratified by level of ultrasound experience. RESULTS: For each angle tested, the EN received higher visibility ratings. The mean visibility scores for the EN vs the SN were 6.44 vs 5.52 at 0 degrees (P=0.001), 7.77 vs 6.96 at 15 degrees (P=0.0004) and 8.33 vs 7.54 at 30 degrees (P=0.0001). Participants reported significantly greater comfort using the EN needle compared with the SN (P=0.001). These results held true regardless of the sequence of needle tested first. Also, there was a significant difference in visibility scores by angle (P=0.0001). Larger angles (30>15>0) resulted in higher scores. CONCLUSIONS: In this in vitro trial, the application of the EN improved needle visibility for users of all levels of experience. Clinical correlation is pending. PMID- 23799804 TI - Communicating in complex situations: a normative approach to HIV-related talk among parents who are HIV+. AB - Parents with HIV/AIDS are confronted with unique challenges when discussing HIV related information with their children. Strategies for navigating these challenges effectively have not been systematically examined. In this study, we conducted in-depth interviews with 76 parents with HIV/AIDS who had children ages 10-18 years. Guided by O'Keefe and Delia's definition of a complex communication situation and Goldsmith's normative approach to interpersonal communication, we examined parents' goals for discussing HIV-related information, factors that made conversations challenging, and instances where these conversational purposes conflicted with one another. Our data reveal the following parent-adolescent communication predicaments: relaying safety information about HIV while minimizing child anxiety, modeling open family communication without damaging one's parental identity, and balancing parent-child relational needs amid living with an unpredictable health condition. Parents also described a variety of strategies for mitigating challenges when discussing HIV-related topics. Strategies parents perceived as effective included reframing HIV as a chronic, manageable illness; keeping talk educational; and embedding HIV-related topics within more general conversations. The theoretical and practical applications of these findings are discussed with regard to their relevance to health communication scholars and HIV care professionals. PMID- 23799805 TI - HIV/AIDS prevention and media campaigns: limited information? AB - This piece begins with a brief literature review that focuses upon how media attempt to make sense of news events and construct meaning about HIV/AIDS. We then focus specifically on a linguistic process identified in French dailies in articles about the prevalence and incidence of HIV/AIDS, namely, the presence of certain adverbs. The impact of this linguistic process is also investigated in an experimental study. The results indicated that participants who were exposed to a message within which epidemiological data were marked by such adverbs compared to those who processed a message without such an adverbial marking expressed a higher level of perceived risk and declared a stronger intention to use a condom and to practice a screening test. They also judged the epidemiological situation as more serious and were more supportive of a coercive management of the epidemic. These effects also appeared when the message referred to a sexually transmitted infection with which the subjects were not familiar. PMID- 23799806 TI - EPPM and willingness to respond: the role of risk and efficacy communication in strengthening public health emergency response systems. AB - This study examines the attitudinal impact of an Extended Parallel Process Model (EPPM)-based training curriculum on local public health department (LHD) workers' willingness to respond to representative public health emergency scenarios. Data are from 71 U.S. LHDs in urban and rural settings across nine states. The study explores changes in response willingness and EPPM threat and efficacy appraisals between randomly assigned control versus intervention health departments, at baseline and 1 week post curriculum, through an EPPM-based survey/resurvey design. Levels of response willingness and emergency response-related attitudes/beliefs are measured. Analyses focus on two scenario categories that have appeared on a U.S. government list of scenarios of significant concern: a weather-related emergency and a radiological "dirty" bomb event (U.S. Department of Homeland Security, 2007). The greatest impact from the training intervention on response willingness was observed among LHD workers who had low levels of EPPM related threat and efficacy perceptions at baseline. Self-efficacy and response efficacy and response willingness increased in intervention LHDs for both scenarios, with greater response willingness increases observed for the radiological "dirty" bomb terrorism scenario. Findings indicate the importance of building efficacy versus enhancing threat perceptions as a path toward greater response willingness, and suggest the potential applicability of such curricular interventions for boosting emergency response willingness among other cadres of health providers. PMID- 23799807 TI - What are Americans seeing? Examining the message frames of local television health news stories. AB - While local television news is the number-one source among Americans for health information, little attention has been given to what viewers are actually watching in these newscasts. Toward this end, a content analysis of local television health news stories (n = 416) was conducted, to examine how local health news stories utilize gain and loss message frames, and whether there are differences in story topics, location, length, presence of self-efficacy methods, and conflict, according to the message frames. Results showed that health news stories that dealt with advancements in treatment or philanthropic events were mainly reported using gain frames, while loss frame health news stories most frequently reported on statistics and trends. The majority of the health news stories were less than 30 seconds among all frames, and conflict appeared more often for the loss frames than gain frames. Furthermore, while efficacy information was mostly absent across all types of frames, gain frames were more likely than loss frames to present efficacy methods. Finally, efficacy information appeared most frequently in health-related statistical reports and prevention messages, while discrimination and health-policy stories had the least efficacy information in them. PMID- 23799808 TI - Instructional messages during health-related crises: essential content for self protection. AB - Mediated instructional messages have the potential to enhance individuals' knowledge and self-efficacy to take self-protective actions during a food-related health crisis. This two-phased study used content analysis to examine the presence of instructions during an actual egg recall crisis (n = 566 television broadcasts). Next, these messages were used in a pretest-posttest experiment to explore changes in participants' (n = 651) foodborne illness knowledge and self efficacy after watching a standard media message or a high instruction media message. In general, actual broadcasts only provided self-protective instructions between 3% and 17% of the time. Standard messages slightly increased viewer knowledge, but decreased viewer efficacy. Conversely, the high instructional message significantly increased both knowledge and efficacy. PMID- 23799810 TI - Three-arm noninferiority trials with a prespecified margin for inference of the difference in the proportions of binary endpoints. AB - The design of a three-arm trial including the experimental treatment, an active reference treatment, and a placebo is recommended as a useful approach to the assessment of noninferiority of the experimental treatment. The inclusion of the placebo arm enables the assessment of assay sensitivity and internal validation, in addition to testing the noninferiority of the experimental treatment to the reference. Generally, the acceptable noninferiority margin Delta has been defined as the maximum clinically irrelevant difference between treatments in many two arm noninferiority trials. However, many articles have considered a design in which the noninferiority margin Delta is relatively defined as a prespecified fraction f of the unknown effect size of the reference treatment. Therefore, these methods cannot be applied to cases where the margin is defined as a prespecified difference between treatments. In this article, we propose score based statistical procedures for a three-arm noninferiority trial with a prespecified margin Delta for inference of the difference in the proportions of binary endpoints. In addition, we derive the approximate sample size and optimal allocation to minimize the total sample size and that of the placebo arm. A randomized controlled trial on major depressive disorder based on the difference in the proportions of remission is used to demonstrate our proposed method. PMID- 23799811 TI - Establishment of an equivalence acceptance criterion for accelerated stability studies. AB - In this article, the use of statistical equivalence testing for providing evidence of process comparability in an accelerated stability study is advocated over the use of a test of differences. The objective of such a study is to demonstrate comparability by showing that the stability profiles under nonrecommended storage conditions of two processes are equivalent. Because it is difficult at accelerated conditions to find a direct link to product specifications, and hence product safety and efficacy, an equivalence acceptance criterion is proposed that is based on the statistical concept of effect size. As with all statistical tests of equivalence, it is important to collect input from appropriate subject-matter experts when defining the acceptance criterion. PMID- 23799814 TI - It takes a village: ecological and fitness impacts of multipartite mutualism. AB - Microbial symbioses, in which microbes have either positive (mutualistic) or negative (parasitic) impacts on host fitness, are integral to all aspects of biology, from ecology to human health. In many well-studied cases, microbial symbiosis is characterized by a specialized association between a host and a specific microbe that provides it with one or more beneficial functions, such as novel metabolic pathways or defense against pathogens. Even in relatively simple associations, symbiont-derived benefits can be context dependent and influenced by other host-associated or environmental microbes. Furthermore, naturally occurring symbioses are typically complex, in which multiple symbionts exhibit coordinated, competing, or independent influences on host physiology, or in which individual symbionts affect multiple interacting hosts. Here we describe research on the mechanisms and consequences of multipartite symbioses, including consortia in which multiple organisms interact with the host and one another, and on conditional mutualists whose impact on the host depends on additional interacting organisms. PMID- 23799815 TI - The biology of the PmrA/PmrB two-component system: the major regulator of lipopolysaccharide modifications. AB - The ability of gram-negative bacteria to resist killing by antimicrobial agents and to avoid detection by host immune systems often entails modification to the lipopolysaccharide (LPS) in their outer membrane. In this review, we examine the biology of the PmrA/PmrB two-component system, the major regulator of LPS modifications in the enteric pathogen Salmonella enterica. We examine the signals that activate the sensor PmrB and the targets controlled by the transcriptional regulator PmrA. We discuss the PmrA/PmrB-dependent chemical decorations of the LPS and their role in resistance to antibacterial agents. We analyze the feedback mechanisms that modulate the activity and thus output of the PmrA/PmrB system, dictating when, where, and to what extent bacteria modify their LPS. Finally, we explore the qualitative and quantitative differences in gene expression outputs resulting from the distinct PmrA/PmrB circuit architectures in closely related bacteria, which may account for their differential survival in various ecological niches. PMID- 23799816 TI - Microbial contributions to phosphorus cycling in eutrophic lakes and wastewater. AB - Phosphorus is a key element controlling the productivity of freshwater ecosystems, and microbes drive most of its relevant biogeochemistry. Eutrophic lakes are generally dominated by cyanobacteria that compete fiercely with algae and heterotrophs for the element. In wastewater treatment, engineers select for specialized bacteria capable of sequestering phosphorus from the water, to protect surface waters from further loading. The intracellular storage molecule polyphosphate plays an important role in both systems, allowing key taxa to control phosphorus availability. The importance of dissolved organic phosphorus in eutrophic lakes and mineralization mechanisms is still underappreciated and understudied. The need for functional redundancy through biological diversity in wastewater treatment plants is also clear. In both systems, a holistic ecosystems biology approach is needed to understand the molecular mechanisms controlling phosphorus metabolism and the ecological interactions and factors controlling ecosystem-level process rates. PMID- 23799817 TI - Clinical trial registration. PMID- 23799819 TI - Clinician of the Year Award 2012. PMID- 23799820 TI - Perceived stress and depression in left and right hemisphere post-stroke patients. AB - Although it is well accepted that depression and stress are closely related in the general adult population, this link is less understood in post-stroke patients. Due to the high occurrence of depression in post-stroke patients it is important to look closely at this possible association. The current study explores perceived stress and depression in post-stroke patients. Nineteen left hemisphere (LH) stroke patients and 12 right hemisphere (RH) post-stroke patients were assessed for depression, perceived stress, and neurological functioning with the Stroke Aphasia Depression Questionnaire, the Perceived Stress Scale, and the Scandinavian Stroke Scale once per month for three months. Perceived stress and depressive symptoms were significantly correlated for both stroke groups. Neurological functioning was not correlated with either depressive symptoms or perceived stress in either stroke group. The perception of stress may be a more critical variable in developing post-stroke depression than neurological functioning is in stroke patients. Routine screening of perception of stress may need to occur in post-stroke patients to avoid development of depression. PMID- 23799821 TI - Treatment with SiMiaoFang, an anti-arthritis chinese herbal formula, inhibits cartilage matrix degradation in osteoarthritis rat model. AB - A Chinese herbal preparation, SiMiaoFang (SMF), has been used clinically for treating arthralgia by virtue of its anti-inflammatory and pain-relieving activities. However, no evidence base links SMF to anti-osteoarthritis (OA), particularly its link to inhibiting cartilage matrix degradation. In this study, we undertook a characterization of anti-OA activity of SMF using an in vivo rat model induced by anterior cruciate ligament transection and medial meniscus resection (ACLT+MMx) together with in vitro studies with chondrocytes for further molecular characterization. ACLT+MMx rats were treated with SMF at doses of 0.63, 1.25, and 2.5 grams/kg per day for 6 weeks. SMF treatments significantly inhibited cartilage matrix degradation, as indicated by increasing proteoglycan and collagen content, particularly type II collagen expression in articular cartilage, decreasing CTX-II (collagen type II degradation marker), and increasing CPII (collagen type II synthesis marker) in circulation. Moreover, SMF suppressed synovial inflammation and inhibited release of interleukin-1beta (IL 1beta) and tumor necrosis factor-alpha in serum. The levels of serum prostaglandin E2 and nitric oxide productions were decreased via suppression of the production of cyclooxygenase-2 and inducible nitric oxide synthase, respectively. Importantly, SMF interfered with OA-augmented expression of matrix metalloproteinases (MMPs) -3 and -13 and aggrecanases (ADAMTS) -4 and -5, which are considered to be key enzymes in cartilage matrix degradation, and simultaneously augmented OA-reduced tissue inhibitors of metalloproteinases (TIMPs) -1 and -3 expression in the joints. The largest changes in these parameters were found at the highest dose. Meanwhile, SMF significantly decreased MMP-3 and -13 and increased TIMP-1 and -3 at mRNA and protein levels in IL-1beta induced chondrocytes. These findings provide the first evidence that SMF effectively treats OA by inhibiting cartilage matrix degradation. PMID- 23799823 TI - The Smoking Cessation and Reduction in Pregnancy Treatment (SCRIPT) Adoption Scale: evaluating the diffusion of a tobacco treatment innovation to a statewide prenatal care program and providers. AB - When a new patient education program is being considered for adoption by a public health agency, it is essential to determine provider perceptions of its acceptability for routine use. In 2007, the West Virginia Bureau of Public Health Perinatal Program, Right From The Start (RFTS), decided to adopt the Smoking Cessation and Reduction in Pregnancy Treatment (SCRIPT) Program. RFTS is a statewide perinatal home visitation initiative delivered by designated care coordinators (DCCs). The authors developed the SCRIPT Adoption Scale (SAS) in the absence of a valid instrument to assess the perceived attributes of a tobacco treatment innovation among the RFTS DCC population. They evaluated the validity of the five constructs of the Rogers' Diffusion of Innovations model in an organization (relative advantage, compatibility, complexity, observability, and trialability) to predict SCRIPT use. After reviewing the literature and developing draft SAS forms, 2 expert panel reviews established the face and content validity of a 43-item SAS. It was administered to 90% (85/90) of the RFTS DCC population. Psychometric analyses confirmed the validity and reliability of a 28-item scale. All 28 items had factor loadings greater than 0.40 (range = 0.43 0.81). All SAS subscales were strongly correlated, r = 0.51 to 0.97, supporting the convergent validity of a 5-factor SAS. There was a significant association between the DCC SAS score and DCC SCRIPT Program Implementation Index supporting the SAS convergent (construct) validity (r = 0.38). The SAS internal consistencyr = 0.93 and stabilityr = 0.76. Although 2 specific subscales need to be improved, the SAS can be adapted by prenatal care programs to measure the attributes of adoption of new, evidence-based patient education and counseling methods. PMID- 23799822 TI - Non-neuronal release of gamma-aminobutyric Acid by embryonic pluripotent stem cells. AB - gamma-Aminobutyric acid (GABA), the principle inhibitory transmitter in the mature central nervous system, is also involved in activities outside the nervous system. Recent studies have shown that functional GABA receptors are expressed in embryonic stem (ES) cells and these receptors control ES cell proliferation. However, it is not clear whether ES cells have their own GABAergic transmission output machinery that can fulfill GABA release or whether the cells merely process the GABA receptors by receiving and responding to the diffused GABA released elsewhere. To get further insight into this unresolved problem, we detected the repertoire of components for GABA synthesis, storage, reaction, and termination in ES and embryonal carcinoma stem cells by biological assays, and then directly quantified released GABA in the intercellular milieu from these pluripotent stem (PS) cells by an analytical chemical assay based on high performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). We found that embryonic PS cells processed a GABAergic circuit machinery and spontaneously released GABA, which suggests the potential that embryonic PS cells could autonomously establish a GABA niche via release of the transmitter. PMID- 23799824 TI - Accelerometer load as a measure of activity profile in different standards of netball match play. AB - PURPOSE: To determine differences in load/min (AU) between standards of netball match play. METHODS: Load/ min (AU) representing accumulated accelerations measured by triaxial accelerometers was recorded during matches of 2 higher- and 2 lower-standard teams (N = 32 players). Differences in load/min (AU) were compared within and between standards for playing position and periods of play. Differences were considered meaningful if there was >75% likelihood of exceeding a small (0.2) effect size. RESULTS: Mean (+/- SD) full-match load/min (AU) for the higher and lower standards were 9.96 +/- 2.50 and 6.88 +/- 1.88, respectively (100% likely lower). The higher standard had greater (mean 97% likely) load/min (AU) values in each position. The difference between 1st and 2nd halves' load/min (AU) was unclear at the higher standard, while lower-grade centers had a lower ( 7.7% +/- 10.8%, 81% likely) load/min (AU) in the 2nd half and in all quarters compared with the 1st. There was little intrastandard variation in individual vector contributions to load/min (AU); however, higher-standard players accumulated a greater proportion of the total in the vertical plane (mean 93% likely). CONCLUSIONS: Higher-standard players produced greater load/min (AU) than their lower-standard counterparts in all positions. Playing standard influenced the pattern of load/min (AU) accumulation across a match, and individual vector analysis suggests that different-standard players have dissimilar movement characteristics. Load/min (AU) appears to be a useful method for assessing activity profile in netball. PMID- 23799825 TI - Recovery from repeated on-court tennis sessions: combining cold-water immersion, compression, and sleep recovery interventions. AB - PURPOSE: To investigate the effects of combining cold-water immersion (CWI), full body compression garments (CG), and sleep-hygiene recommendations on physical, physiological, and perceptual recovery after 2-a-day on-court training and match play sessions. METHODS: In a crossover design, 8 highly trained tennis players completed 2 sessions of on-court tennis-drill training and match play, followed by a recovery or control condition. Recovery interventions included a mixture of 15 min CWI, 3 h of wearing full-body CG, and following sleep-hygiene recommendations that night, while the control condition involved postsession stretching and no regulation of sleeping patterns. Technical performance (stroke and error rates), physical performance (accelerometry, countermovement jump [CMJ]), physiological (heart rate, blood lactate), and perceptual (mood, exertion, and soreness) measures were recorded from each on-court session, along with sleep quantity each night. RESULTS: While stroke and error rates did not differ in the drill session (P > .05, d < 0.20), large effects were evident for increased time in play and stroke rate in match play after the recovery interventions (P > .05, d > 0.90). Although accelerometry values did not differ between conditions (P > .05, d < 0.20), CMJ tended to be improved before match play with recovery (P > .05, d = 0.90). Furthermore, CWI and CG resulted in faster postsession reductions in heart rate and lactate and reduced perceived soreness (P > .05, d > 1.00). In addition, sleep-hygiene recommendations increased sleep quantity (P > .05, d > 2.00) and maintained lower perceived soreness and fatigue (P < .05, d > 2.00). CONCLUSIONS: Mixed-method recovery interventions (CWI and CG) used after tennis sessions increased ensuing time in play and lower-body power and reduced perceived soreness. Furthermore, sleep hygiene recommendations helped reduce perceived soreness. PMID- 23799826 TI - Variability and predictability of performance times of elite cross-country skiers. AB - Analyses of elite competitive performance provide useful information for research and practical applications. PURPOSE: Here the authors analyze performance times of cross-country skiers at international competitions (World Cup, World Championship, and Olympics) in classical and free styles of women's and men's distance and sprint events, each with a total of 410-569 athletes competing in 1 44 races at 15-25 venues from seasons 2002 to 2011. METHODS: A linear mixed model of race times for each event provided estimates of within-athlete race-to-race variability expressed as a coefficient of variation (CV) after adjustment for fixed or random effects of snow conditions, altitude, race length, and competition terrain. RESULTS: Within-athlete variability was similar for men and women over various events for all athletes (CV of 1.5-1.8%) and for the annual top-10 athletes (1.1-1.4%). Observed effects of snow conditions and altitude on mean time were substantial (~2%) but mostly unclear, owing to large effects of terrain (CV of 4-10% in top-10 analyses). Predictability of performance was extremely high for all athletes (intraclass correlations of .90-.96) but only trivial to poor for top-10 athletes (men .00-.03, women .03-.35). CONCLUSION: The race-to-race variability of top-ranked skiers is similar to that of other elite endurance athletes. Estimates of the smallest worthwhile performance enhancement (0.3* within-athlete variability) will help researchers and practitioners evaluate strategies affecting performance of elite skiers. PMID- 23799827 TI - High-intensity intermittent exercise: methodological and physiological aspects. AB - High-intensity intermittent exercise (HIIE) has been applied in competitive sports for more than 100 years. In the last decades, interval studies revealed a multitude of beneficial effects in various subjects despite a large variety of exercise prescriptions. Therefore, one could assume that an accurate prescription of HIIE is not relevant. However, the manipulation of HIIE variables (peak workload and peak-workload duration, mean workload, intensity and duration of recovery, number of intervals) directly affects the acute physiological responses during exercise leading to specific medium- and long-term training adaptations. The diversity of intermittent-exercise regimens applied in different studies may suggest that the acute physiological mechanisms during HIIE forced by particular exercise prescriptions are not clear in detail or not taken into consideration. A standardized and consistent approach to the prescription and classification of HIIE is still missing. An optimal and individual setting of the HIIE variables requires the consideration of the physiological responses elicited by the HIIE regimen. In this regard, particularly the intensities and durations of the peak workload phases are highly relevant since these variables are primarily responsible for the metabolic processes during HIIE in the working muscle (eg, lactate metabolism). In addition, the way of prescribing exercise intensity also markedly influences acute metabolic and cardiorespiratory responses. Turn-point or threshold models are suggested to be more appropriate and accurate to prescribe HIIE intensity than using percentages of maximal heart rate or maximal oxygen uptake. PMID- 23799828 TI - Stride rate and walking intensity in healthy older adults. AB - PURPOSE: The study investigated (a) walking intensity (stride rate and energy expenditure) under three speed instructions; (b) associations between stride rate, age, height, and walking intensity; and (c) synchronization between stride rate and music tempo during overground walking in a population of healthy older adults. METHODS: Twenty-nine participants completed 3 treadmill-walking trials and 3 overground-walking trials at 3 self-selected speeds. Treadmill VO2 was measured using indirect calorimetry. Stride rate and music tempo were recorded during overground-walking trials. RESULTS: Mean stride rate exceeded minimum thresholds for moderate to vigorous physical activity (MVPA) under slow (111.41 +/- 11.93), medium (118.17 +/- 11.43), and fast (123.79 +/- 11.61) instructions. A multilevel model showed that stride rate, age, and height have a significant effect (p < .01) on walking intensity. CONCLUSIONS: Healthy older adults achieve MVPA with stride rates that fall below published minima for MVPA. Stride rate, age, and height are significant predictors of energy expenditure in this population. Music can be a useful way to guide walking cadence. PMID- 23799829 TI - Greater effect of adiposity than physical activity or lean mass on physical function in community-dwelling older adults. AB - Adiposity, lean mass, and physical activity (PA) are known to influence physical function in older adults, although the independent influences are not completely characterized. Older adults (N = 156, M age = 68.9 +/- 6.7 yr, 85 men) were assessed for body composition via dual-energy X-ray absorptiometry, PA by accelerometer, and physical function via timed up-and-go (UP&GO), 30-s chair stand, 6-min walk (6-min WALK), and Star-Excursion Balance Test. In the absence of percentage-body-fat by PA interactions (p > .05), main effects existed such that a higher percentage body fat was associated with poorer performance in UP&GO, 30-s chair stand, and 6-min WALK (p < .05). No significant main effects were found for PA and functional performance. Adiposity explains 4.6-11.4% in physical functional variance (p < .05). Preventing increases in adiposity with age may help older adults maintain functional independence. PMID- 23799830 TI - Relationship between knee walking kinematics and muscle flexibility in runners. AB - CONTEXT: Decreased flexibility in muscles and joints of lower extremities is commonly observed in runners. Understanding the effect of decreased flexibility on knee walking kinematics in runners is important because, over time, altered gait patterns can make runners vulnerable to overuse injuries or degenerative pathologies. OBJECTIVES: To compare hamstring and iliotibial-band (ITB) flexibility and knee kinematics in runners and nonrunners. DESIGN: A descriptive, comparative laboratory study. SETTING: Hamstring and ITB flexibility were measured with the active knee-extension test and the modified Ober test, respectively, in both groups of participants. Three-dimensional (3D) walking kinematic data were then recorded at the knee using a motiontracking system. PARTICIPANTS: 18 runners and 16 nonrunners. MAIN OUTCOME MEASURES: Knee-extension angle (hamstring flexibility) and hip-adduction angle (ITB flexibility). Knee kinematic parameters of interest included knee angle at initial contact, peak knee angles, and knee-angle range in all planes of movement. RESULTS: The runners had a significantly less flexible ITB than the nonrunners (hip adduction [-] and adduction [+] angles, 3.1 degrees +/- 5.6 degrees vs -.4 degrees +/- 4.5 degrees ; P < .001). The runners demonstrated a greater mean tibial external rotation angle at initial contact (7.3 degrees +/- 5.8 degrees vs 2.0 degrees +/- 4.0 degrees ; P = .01) and a smaller mean peak tibial internal-rotation angle (-1.6 degrees +/- 3.0 degrees vs -4.2 degrees +/- 3.2 degrees ; P = .04) than the nonrunners. CONCLUSION: This study provides new insight into the relationship between muscle flexibility and 3D knee kinematics in runners. This supports the premise that there is an association between muscle flexibility and transverse plane knee kinematics in this population. PMID- 23799831 TI - The effectiveness of shoulder stretching and joint mobilizations on posterior shoulder tightness. AB - CLINICAL SCENARIO: It has been suggested that posterior shoulder tightness is a common contributor to shoulder impingement in overhead-throwing athletes. The incidence of shoulder pain in the general population has been reported to be as high as 27%, and as many as 74% of the patients who were seen for shoulder issues had signs of impingement. Particularly regarding physically active adults, shoulder impingement is frequent among overhead-throwing athletes and may lead to lost participation in sport, as well as other injuries including labral pathologies. Therefore, finding an effective mechanism to reduce posterior shoulder tightness in overhead athletes is important and may help prevent impingement-type injuries. Typically, posterior shoulder tightness is identified by measuring horizontal humeral adduction; although another clinical measure that is commonly used is the bilateral measurement of glenohumeral internal-rotation (IR) range of motion (ROM). It is important to note, however, that the measurement of glenohumeral IR ROM specifically aims to identify glenohumeral IR ROM deficits (GIRD). Although GIRD is believed to be a leading contributor to posterior shoulder tightness, this measure alone may not capture the full spectrum of posterior shoulder tightness. While treatment interventions to correct any ROM deficits typically include a stretching protocol to help increase IR, joint mobilizations have been found to produce greater mobility of soft tissue and capsular joints. However, it is unclear whether the combination of both joint mobilizations and a stretching protocol will produce even larger gains of ROM that will have greater longevity for the patient suffering from posterior shoulder tightness. FOCUSED CLINICAL QUESTION: Does the use of joint mobilizations combined with a stretching protocol more effectively increase glenohumeral IR ROM in adult physically active individuals who participate in overhead sports and are suffering from posterior shoulder tightness, compared with a stretching protocol alone? PMID- 23799832 TI - Difference in ratio of evertor to invertor activity between the dominant and nondominant legs during simulated lateral ankle sprain. AB - CONTEXT: The dominant and nondominant legs respond asymmetrically during landing tasks, and this difference may occur during an inversion perturbation and provide insight into the role of ankle-evertor and -invertor muscle activity. OBJECTIVE: To determine if there is a difference in the ratio of evertor to invertor activity between the dominant and nondominant legs and outer-sole conditions when the ankle is forced into inversion. DESIGN: Repeated-measures single-group design. SETTING: University laboratory. PARTICIPANTS: 15 physically active healthy volunteers with no previous history of an ankle sprain or lower extremity surgery or fracture. INTERVENTIONS: An outer sole with fulcrum was used to cause 25 degrees of inversion at the subtalar joint after landing from a 27-cm step down task. Participants performed 10 fulcrum trials on both the dominant and nondominant leg. MAIN OUTCOME MEASURES: The ratio of evertor to invertor muscle activity 200 ms before and 200 ms after the inversion perturbation was measured using electromyography. This ratio was the dependent variable. Independent variables included outer-sole condition (fulcrum, flat), leg (dominant, nondominant), and time (prelanding, postlanding). The data were analyzed with separate 2-way repeated-measures ANOVA, 1 for the prelanding ratios and 1 for the postlanding ratios. RESULTS: For the postlanding ratios, the fulcrum outer sole had a significantly greater (P < .05) ratio than the flat outer sole, and the nondominant leg had a significantly greater (P < .05) ratio than the dominant leg. CONCLUSIONS: These results indicate that a greater evertor response is produced when the ankle is forced into inversion, and a greater response is produced for the nondominant leg, which may function better during a postural stabilizing task than the dominant leg. PMID- 23799833 TI - Leatherback turtles are capital breeders: morphometric and physiological evidence from longitudinal monitoring. AB - Organisms compensate for reproduction costs through two major strategies: capital breeders store body reserves before reproduction and do not feed during the breeding season, whereas income breeders adjust their food intake depending on concurrent reproductive needs. Sea turtles are commonly considered capital breeders. Yet recent biometric and behavioral studies have suggested that sea turtles may in fact feed during reproduction. We tested this hypothesis in the leatherback turtle Dermochelys coriacea, nesting in French Guiana. Our study is based on the innovative use of longitudinal monitoring for morphological (body size, body mass, and body condition) and physiological (plasma glucose, triacylglycerides, urea, calcium, and hematocrit) measurements in 35 females throughout the 2006 nesting season. During their 71-d nesting period, leatherbacks lost a mean (+/-SE) of [Formula: see text] kg (i.e., ~11% of their initial body mass of [Formula: see text] kg). Simultaneously, a significant decrease in plasma concentrations of glucose, triacylglycerides, and urea was observed throughout the nesting season, following typical patterns reported in other long-fasting animals that rely on lipid body stores. At the end of the nesting season, the interindividual variability in plasma concentrations was very low, which may characterize some minimum thresholds associated with the end of reproduction. We also identified a minimum necessary threshold for female body condition at the onset of reproduction; the body condition of any females beginning the nesting period below this threshold decreased dramatically. This study makes a compelling case that, in French Guiana, gravid leatherback females are anorexic during the nesting season (i.e., leatherback turtles are capital breeders). We further highlight the mechanisms that prevent this multiparous reptile from jeopardizing its own body condition while not feeding during reproduction. PMID- 23799834 TI - Morphological and physiological changes during reproduction and their relationships to reproductive performance in a capital breeder. AB - Current reproductive effort typically comes at a cost to future reproductive value by altering somatic function (e.g., growth or self-maintenance). Furthermore, effects of reproduction often depend on both fecundity and stage of reproduction, wherein allocation of resources into additional offspring and/or stages of reproduction results in increased costs. Despite these widely accepted generalities, interindividual variation in the effects of reproduction is common yet the proximate basis that allows some individuals to mitigate these detrimental effects is unclear. We serially measured several variables of morphology (e.g., musculature) and physiology (e.g., antioxidant defenses) in female Children's pythons (Antaresia childreni) throughout reproduction to examine how these traits change over the course of reproduction and whether certain physiological traits are associated with reduced effects of reproduction in some individuals. Reproduction in this capital breeder was associated with changes in both morphology and physiology, but only morphological changes varied with fecundity and among specific reproductive stages. During reproduction, we detected negative relationships between morphology and self-maintenance (e.g., increased muscle allocation to reproduction was related to reduced immune function). Additionally, females that allocated resources more heavily into current reproduction also did so during future reproduction, and these females assimilated resources more efficiently, experienced reduced detriments to self maintenance (e.g., lower levels of oxidative damage and glucocorticoids) during reproduction, and produced clutches with greater hatching success. Our results suggest that interindividual variation in specific aspects of physiology (assimilation efficiency and oxidative status) may drive variation in reproductive performance. PMID- 23799835 TI - Incubation conditions are more important in determining early thermoregulatory ability than posthatch resource conditions in a precocial bird. AB - Recent research in birds suggests that investing in incubation is one mechanism by which parents can enhance the phenotype of their offspring. Posthatch environmental conditions can also shape an individual's phenotype, and it is thus possible for pre- and posthatch conditions to have interactive effects on an individual's phenotype. In this study, we examined the individual and interactive effects of prehatch incubation temperature and posthatch food availability on growth, food consumption, and thermoregulatory ability in wood duck (Aix sponsa) ducklings. Eggs were incubated at one of three temperatures (35.0 degrees , 35.9 degrees , or 37.0 degrees C), and then ducklings were reared on an either ad lib. or time-restricted diet for 12 d after hatching. We found that food availability influenced duckling growth, with the slowest growth occurring in ducklings fed the restricted diet. Incubation temperature also interacted with food conditions to influence duckling growth: ducklings fed ad lib. from the lowest incubation temperature grew slower than ducklings fed ad lib. from the higher incubation temperatures. Most importantly, we found that the improvement in a duckling's ability to maintain body temperature in the face of a thermal challenge was influenced by embryonic incubation temperature but not feeding conditions. Ducklings from the highest incubation temperature experienced the greatest improvement in thermoregulatory performance with age. Our findings suggest that the prehatch environment is more important than posthatch resource conditions in determining some physiological functions and underscores the important role that incubation temperature plays in determining offspring phenotype in birds. PMID- 23799836 TI - Individual variation in thermogenic capacity is correlated with flight muscle size but not cellular metabolic capacity in American goldfinches (Spinus tristis). AB - Abstract Cold tolerance and overwinter survival are positively correlated with organismal thermogenic capacity (=summit metabolic rate [Msum]) in endotherms. Msum varies seasonally in small-bird populations and may be mechanistically associated with variation in flight muscle size or cellular metabolic capacity, but the relative roles of these traits as drivers of individual variation in thermogenic performance are poorly known. We measured flight muscle size by ultrasonography, pectoralis and supracoracoideus muscle masses, and muscular activities of key aerobic enzymes (citrate synthase, carnitine palmitoyl transferase, and beta-hydroxyacyl-CoA dehydrogenase) and correlated these measurements with Msum for individual American goldfinches (Spinus tristis) to test the hypotheses that muscle size and/or cellular metabolic capacity serve as prominent drivers of individual variation in organismal metabolic capacity. Ultrasonographic flight muscle size was weakly positively correlated with Msum ([Formula: see text]). Both log10-transformed Msum and flight muscle mass were significantly correlated with log10 body mass, so we calculated allometric residuals for log Msum and for log flight muscle mass to test their correlation independent of body mass. Flight muscle mass residuals were significantly positively correlated with Msum residuals, and this correlation was primarily driven by variation in pectoralis muscle mass. In contrast, none of the mass specific activities of any enzyme in any muscle were significantly correlated with Msum. These data suggest that flight muscle size, not cellular metabolic capacity, is the primary driver of individual variation in thermogenic performance in goldfinches. This is consistent with the idea that phenotypic flexibility of flight muscle mass is a general mechanism mediating variation in metabolic performance in response to changing energy demands in birds. PMID- 23799837 TI - Effects of temperature variation on male behavior and mating success in a montane beetle. AB - Locomotion and mating ability are crucial for male reproductive success yet are energetically costly and susceptible to physiological stress. In the Sierra willow beetle Chrysomela aeneicollis, male mating success depends on locating and mating with as many females as possible. Variation at the glycolytic enzyme locus phosphoglucose isomerase (Pgi) is concordant with a latitudinal temperature gradient in these populations, with Pgi-1 frequent in the cooler north, Pgi-4 in the warmer south, and alleles 1 and 4 in relatively equal frequency in areas intermediate in geography and climate. Beetles experience elevated air temperatures during a mating season that causes differential physiological stress among Pgi genotypes, and running speeds of individuals homozygous for Pgi-4 are more tolerant of repeated thermal stress than individuals possessing Pgi-1. Here the importance of running behavior for male mating activity was examined, and differential effects of thermal stress among Pgi genotypes on male mating activity were measured. In nature, males run more than females, and nearly half of males mate or fight for a mate after running. In the laboratory, mating activity was positively correlated with running speed, and repeated mating did not reduce running speed or subsequent mating activity. Males homozygous for Pgi 4 mated longer and more frequently after heat treatment than 1-1 and 1-4 males. All heat-treated males had lower mating frequencies and higher heat shock protein expression than control males; however, mating frequency of recovering 4-4 males increased throughout mating trials, while treated 1-1 and 1-4 males remained low. These results suggest that effects of stress on mating activity differ between Pgi genotypes, implying a critical role for energy metabolism in organisms' response to stressful temperatures. PMID- 23799838 TI - Selective blubber fatty acid mobilization in lactating gray seals (Halichoerus grypus). AB - During negative energy balance periods, fatty acids (FAs) are mobilized to cover the metabolic demands of the body. FAs from adipose tissue are selectively mobilized according to their carbon length (CL) and number of double bonds (DBs); however, studies in vivo have focused only on fasting and nonlactating animals. During lactation, UK gray seals fast for 18 d, mobilizing a large amount of lipid from blubber to sustain their own metabolic demands and the nutritional requirements of pups. We investigated FA mobilization in individual gray seal mothers from two UK colonies sampled in 2005 and 2006. Linear mixed-effects models were used to examine to what extent the mobilization observed from FAs in blubber can be explained as a function of FAs' CL and number of DBs. FAs were mobilized according to their structure, such that for a given CL, mobilization increased with the number of DBs, and for a given number of DBs, mobilization decreased as CL increased. This pattern of selective mobilization was very similar between colonies, although the relative amounts of component FAs in blubber at early lactation were different between them. FAs, which are considered crucial to pup development, were mobilized more than predicted by the model. This suggests that selective mobilization of FAs is not related solely to the physicochemical characteristics of the FAs but also to the needs of a growing pup. PMID- 23799839 TI - Dehydration hardly slows hopping toads (Rhinella granulosa) from xeric and mesic environments. AB - The locomotor capacity of amphibians depends strongly on temperature and hydration. Understanding the potential interactions between these variables remains an important challenge because temperature and water availability covary strongly in natural environments. We explored the effects of temperature and hydration on the hopping speeds of Rhinella granulosa, a small toad from the semiarid Caatinga and the Atlantic Rain Forest in Brazil. We asked whether thermal and hydric states interact to determine performance and whether toads from the Caatinga differ from their conspecifics from the Atlantic Forest. Both dehydration and cooling impaired hopping speed, but effects were independent of one another. In comparison to performances of other anurans, the performance of R. granulosa was far less sensitive to dehydration. Consequently, dehydrated members of this species may be able to sustain performance through high body temperatures, which agrees with the exceptional heat tolerance of this species. Surprisingly, toads from both the Caatinga and the Atlantic Forest were relatively insensitive to dehydration. This observation suggests that migration or gene flow between toads from the forest and those from a drier region occurred or that toads from a dry region colonized the forest secondarily. PMID- 23799840 TI - Interindividual variation in thermal sensitivity of maximal sprint speed, thermal behavior, and resting metabolic rate in a lizard. AB - Studies of the relationship of performance and behavioral traits with environmental factors have tended to neglect interindividual variation even though quantification of this variation is fundamental to understanding how phenotypic traits can evolve. In ectotherms, functional integration of locomotor performance, thermal behavior, and energy metabolism is of special interest because of the potential for coadaptation among these traits. For this reason, we analyzed interindividual variation, covariation, and repeatability of the thermal sensitivity of maximal sprint speed, preferred body temperature, thermal precision, and resting metabolic rate measured in ca. 200 common lizards (Zootoca vivipara) that varied by sex, age, and body size. We found significant interindividual variation in selected body temperatures and in the thermal performance curve of maximal sprint speed for both the intercept (expected trait value at the average temperature) and the slope (measure of thermal sensitivity). Interindividual differences in maximal sprint speed across temperatures, preferred body temperature, and thermal precision were significantly repeatable. A positive relationship existed between preferred body temperature and thermal precision, implying that individuals selecting higher temperatures were more precise. The resting metabolic rate was highly variable but was not related to thermal sensitivity of maximal sprint speed or thermal behavior. Thus, locomotor performance, thermal behavior, and energy metabolism were not directly functionally linked in the common lizard. PMID- 23799841 TI - Effect of thermal acclimation on organ mass, tissue respiration, and allometry in Leichhardtian river prawns Macrobrachium tolmerum (Riek, 1951). AB - Changes to an animal's abiotic environment-and consequent changes in the allometry of metabolic rate in the whole animal and its constituent parts-has considerable potential to reveal important patterns in both intraspecific and interindividual variation of metabolic rates. This study demonstrates that, after 6 wk of thermal acclimation at replicate treatments of 16 degrees , 21 degrees , and 25 degrees C, standard metabolic rate (SMR) scales allometrically in Leichhardtian river prawns Macrobrachium tolmerum ([Formula: see text]) and that the scaling exponent and normalization constant of the relationship between SMR and body mass is not significantly different among acclimation treatments when measured at 21 degrees C. There is, however, significant variation among individuals in whole-animal metabolic rate. We hypothesized that these observations may arise because of changes in the metabolic rate and allometry of metabolic rate or mass of organ tissues within the animal. To investigate this hypothesis, rates of oxygen consumption in a range of tissues (gills, gonads, hepatopancreas, chelae muscle, tail muscle) were measured at 21 degrees C and related to the body mass (M) and whole-animal SMR of individual prawns. We demonstrate that thermal acclimation had no effect on organ and tissue mass, that most organ and tissue (gills, gonads, hepatopancreas) respiration rates do not change with acclimation temperature, and that residual variation in the allometry of M. tolmerum SMR is not explained by differences in organ and tissue mass and respiration rates. These results suggest that body size and ambient temperature may independently affect metabolic rate in this species. Both chelae and tail muscle, however, exhibited a reduction in respiration rate in animals acclimated to 25 degrees relative to those acclimated to 16 degrees and 21 degrees C. This reduction in respiration rates of muscle at higher temperatures is evidence of a tissue-specific acclimation response that was not detectable at the whole-animal level. PMID- 23799842 TI - Diagnostic SOX10 gene signatures in salivary adenoid cystic and breast basal-like carcinomas. AB - BACKGROUND: Salivary adenoid cystic carcinoma (ACC) is an insidious slow-growing cancer with the propensity to recur and metastasise to distant sites. Basal-like breast carcinoma (BBC) is a molecular subtype that constitutes 15-20% of breast cancers, shares histological similarities and basal cell markers with ACC, lacks expression of ER (oestrogen receptor), PR (progesterone receptor), and HER2 (human epidermal growth factor receptor 2), and, similar to ACC, metastasises predominantly to the lung and brain. Both cancers lack targeted therapies owing to poor understanding of their molecular drivers. METHODS: Gene expression profiling, immunohistochemical staining, western blot, RT-PCR, and in silico analysis of massive cancer data sets were used to identify novel markers and potential therapeutic targets for ACC and BBC. For the detection and comparison of gene signatures, we performed co-expression analysis using a recently developed web-based multi-experiment matrix tool for visualisation and rank aggregation. RESULTS: In ACC and BBC we identified characteristic and overlapping SOX10 gene signatures that contained a large set of novel potential molecular markers. SOX10 was validated as a sensitive diagnostic marker for both cancers and its expression was linked to normal and malignant myoepithelial/basal cells. In ACC, BBC, and melanoma (MEL), SOX10 expression strongly co-segregated with the expression of ROPN1B, GPM6B, COL9A3, and MIA. In ACC and breast cancers, SOX10 expression negatively correlated with FOXA1, a cell identity marker and major regulator of the luminal breast subtype. Diagnostic significance of several conserved elements of the SOX10 signature (MIA, TRIM2, ROPN1, and ROPN1B) was validated on BBC cell lines. CONCLUSION: SOX10 expression in ACC and BBC appears to be a part of a highly coordinated transcriptional programme characteristic for cancers with basal/myoepithelial features. Comparison between ACC/BBC and other cancers, such as neuroblastomaand MEL, reveals potential molecular markers specific for these cancers that are likely linked to their cell identity. SOX10 as a novel diagnostic marker for ACC and BBC provides important molecular insight into their molecular aetiology and cell origin. Given that SOX10 was recently described as a principal driver of MEL, identification of conserved elements of the SOX10 signatures may help in better understanding of SOX10-related signalling and development of novel diagnostic and therapeutic tools. PMID- 23799843 TI - Polypeptide N-acetylgalactosaminyl transferase 3 independently predicts high grade tumours and poor prognosis in patients with renal cell carcinomas. AB - BACKGROUND: The polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts) family of enzymes regulates the initial steps of mucin-type O-glycosylation. N acetylgalactosaminyltransferases might show novel patterns of GalNAc-T glycosylation on tumour-derived proteins, which could influence cancer biology, but its mechanisms are unclear. We investigated the association of GalNAc-T3 and T6 expressions with clinicopathological features and prognoses of patients with renal cell carcinomas (RCCs). METHODS: Expressions of GalNAc-T3/6 and cell adhesion molecules were analysed immunohistochemically in 254 paraffin-embedded tumour samples of patients with RCC. RESULTS: Of 138 GalNAc-T3+ cases, 46 revealed significant co-expression with GalNAc-T6. N acetylgalactosaminyltransferases-3+ expression showed a close relationship to poor clinical performance and large tumour size, or pathologically high Fuhrman's grading, and presence of vascular invasion and necrosis. The GalNAc-T3-positivity potentially suppressed adhesive effects with a significantly low beta-catenin expression. Univariate and multivariate analyses showed the GalNAc-T3+ group, but not the GalNAc-T6+ group, to have significantly worse survival rates. CONCLUSION: N-acetylgalactosaminyltransferases-3 expression independently predicts high-grade tumour and poor prognosis in patients with RCC, and may offer a therapeutic target against RCC. PMID- 23799844 TI - TERT promoter mutations in ocular melanoma distinguish between conjunctival and uveal tumours. AB - BACKGROUND: Recently, activating mutations in the TERT promoter were identified in cutaneous melanoma. We tested a cohort of ocular melanoma samples for similar mutations. METHODS: The TERT promoter region was analysed by Sanger sequencing in 47 uveal (ciliary body or choroidal) melanomas and 38 conjunctival melanomas. RESULTS: Mutations of the TERT promoter were not identified in uveal melanomas, but were detected in 12 (32%) conjunctival melanomas. Mutations had a UV signature and were identical to those found in cutaneous melanoma. CONCLUSION: Mutations of TERT promoter with UV signatures are frequent in conjunctival melanomas and favour a pathogenetic kinship with cutaneous melanomas. Absence of these mutations in uveal melanomas emphasises their genetic distinction from cutaneous and conjunctival melanomas. PMID- 23799845 TI - BCR-ABL1 kinase domain mutations may persist at very low levels for many years and lead to subsequent TKI resistance. AB - BACKGROUND: BCR-ABL1 mutation analysis is recommended for chronic myeloid leukaemia patients. However, mutations may become undetectable after changing therapy, and it is unknown whether they have been eradicated. METHODS: We examined longitudinal data of patients with imatinib-resistant mutations, which became undetectable by Sanger sequencing to determine whether mutations could reappear, and the related circumstances. RESULTS: Identical imatinib- and nilotinib-resistant mutations reappeared following further therapy changes in five patients, and was associated with subsequent nilotinib resistance in four. CONCLUSION: The data suggest that some BCR-ABL1 mutations may persist at undetectable levels for many years after changing therapy, and can be reselected and confer resistance to subsequent inhibitors. PMID- 23799846 TI - Comparison of the prognostic value of longitudinal measurements of systemic inflammation in patients undergoing curative resection of colorectal cancer. AB - BACKGROUND: The systemic inflammation-based prognostic scores, modified Glasgow Prognostic Score (mGPS) and the neutrophil-lymphocyte ratio (NLR) are now recognised to be useful in predicting survival in a variety of solid organ malignancies, including colorectal cancer (CRC) before treatment. However, there would appear to have been no direct comparison of these longitudinal measurements of systemic inflammation. Therefore, the aim of the present study was to compare the prognostic value of longitudinal measures of systemic inflammation, the mGPS and NLR in patients undergoing potentially curative resection for CRC. METHODS: Three hundred and twenty-six patients underwent potentially curative resection for CRC between 2006 and 2010. Full biochemical and haematological data both pre- and post-operatively (3-6 months) were available for 206 patients. RESULTS: In 206 patients, there was no significant overall change in either the mGPS or the NLR, from pre- to post-operatively. On univariate survival analysis, T-stage (P<0.001), tumour, node, metastasis stage (P<0.005), pre-operative mGPS (P<0.05), pre-operative NLR (<0.05), post-operative mGPS (P<0.001) and post-operative NLR (P<0.005) were associated with cancer-specific survival. On multivariate survival analysis, comparing pre-operative mGPS and NLR, both pre-operative mGPS and NLR were independently associated with reduced cancer-specific survival (mGPS hazard ratio (HR) 1.97, CI 1.16-3.34, P<0.05, and NLR HR 3.07, CI 1.23-7.63, P<0.05). When the same multivariate comparison was carried out on post-operative data, only the post-operative mGPS was independently associated with cancer-specific survival (HR 4.81, CI 2.13-10.83, P<0.001). CONCLUSION: The results of the present study support the longitudinal assessment of the systemic inflammatory response, in particular the mGPS, in patients undergoing potentially curative resection for CRC. PMID- 23799847 TI - Increased neutrophil-lymphocyte ratio is a poor prognostic factor in patients with primary operable and inoperable pancreatic cancer. AB - BACKGROUND: The neutrophil-lymphocyte ratio (NLR) has been proposed as an indicator of systemic inflammatory response. Previous findings from small-scale studies revealed conflicting results about its independent prognostic significance with regard to different clinical end points in pancreatic cancer (PC) patients. Therefore, the aim of our study was the external validation of the prognostic significance of NLR in a large cohort of PC patients. METHODS: Data from 371 consecutive PC patients, treated between 2004 and 2010 at a single centre, were evaluated retrospectively. The whole cohort was stratified into two groups according to the treatment modality. Group 1 comprised 261 patients with inoperable PC at diagnosis and group 2 comprised 110 patients with surgically resected PC. Cancer-specific survival (CSS) was assessed using the Kaplan-Meier method. To evaluate the independent prognostic significance of the NLR, the modified Glasgow prognostic score (mGPS) and the platelet-lymphocyte ratio univariate and multivariate Cox regression models were applied. RESULTS: Multivariate analysis identified increased NLR as an independent prognostic factor for inoperable PC patients (hazard ratio (HR)=2.53, confidence interval (CI)=1.64-3.91, P<0.001) and surgically resected PC patients (HR=1.61, CI=1.02 2.53, P=0.039). In inoperable PC patients, the mGPS was associated with poor CSS only in univariate analysis (HR=1.44, CI=1.04-1.98). CONCLUSION: Risk prediction for cancer-related end points using NLR does add independent prognostic information to other well-established prognostic factors in patients with PC, regardless of the undergoing therapeutic modality. Thus, the NLR should be considered for future individual risk assessment in patients with PC. PMID- 23799848 TI - Ron tyrosine kinase receptor synergises with EGFR to confer adverse features in head and neck squamous cell carcinoma. AB - BACKGROUND: Although EGFR inhibitors have shown some success in the treatment of head and neck squamous cell carcinomas (HNSCCs), the results are not dramatic. Additional molecular targets are urgently needed. We previously showed that the loss of Ron receptor activity significantly slowed squamous tumour growth and progression in a murine model. Based on these data, we hypothesised that Ron expression confers an aggressive phenotype in HNSCCs. We prospectively collected and evaluated 154 snap-frozen, primary HNSCCs for Ron and EGFR expression/phosphorylation. Biomarker correlation with clinical, pathological and outcome data was performed. The biological responses of HNSCC cell lines to Ron knockdown, its activation and the biochemical interaction between Ron and EGFR were examined. RESULTS: We discovered that 64.3% (99 out of 154) HNSCCs expressed Ron. The carcinomas expressed exclusively mature functional Ron, whereas the adjacent nonmalignant epithelium expressed predominantly nonfunctional Ron precursor. There was no significant association between Ron and sex, tumour differentiation, perineural/vascular invasion or staging. However, patients with Ron+HNSCC were significantly older and more likely to have oropharyngeal tumours. Ron+HNSCC also had significantly higher EGFR expression and correlated strongly with phosphorylated EGFR (pEGFR). Newly diagnosed HNSCC with either Ron/pEGFR or both had lower disease-free survival than those without Ron and pEGFR. Knocking down Ron in SCC9 cells significantly blunted their migratory response to not only the Ron ligand, MSP, but also EGF. Stimulation of Ron in SCC9 cells significantly augmented the growth effect of EGF; the synergistic effect of both growth factors in SCC9 cells was dependent on Ron expression. Activated Ron also interacted with and transactivated EGFR. CONCLUSION: Ron synergises with EGFR to confer certain adverse features in HNSCCs. PMID- 23799849 TI - MicroRNA profiles classify papillary renal cell carcinoma subtypes. AB - BACKGROUND: Besides the conventional clear-cell renal cell carcinoma (ccRCC), papillary RCC (pRCC) is the second most common renal malignancy. Papillary RCCs can further be subdivided into two distinct subtypes. Although a clinical relevance of pRCC subtyping has been shown, little is known about the molecular characteristics of both pRCC subtypes. METHODS: We performed microarray-based microRNA (miRNA) expression profiling of primary ccRCC and pRCC cases. A subset of miRNAs was identified and used to establish a classification model for ccRCC, pRCC types 1 and 2 and normal tissue. Furthermore, we performed gene set enrichment analysis with the predicted miRNA target genes. RESULTS: Only five miRNAs (miR-145, -200c, -210, -502-3p and let-7c) were sufficient to identify the samples with high accuracy. In a collection of 111 tissue samples, 73.9% were classified correctly. An enrichment of miRNA target genes in the family of multidrug-resistance proteins was noted in all tumours. Several components of the Jak-STAT signalling pathway might be targets for miRNAs that define pRCC tumour subtypes. CONCLUSION: MicroRNAs are able to accurately classify RCC samples. Deregulated miRNAs might contribute to the high chemotherapy resistance of RCC. Furthermore, our results indicate that pRCC type 2 tumours could be dependent on oncogenic MYC signalling. PMID- 23799850 TI - miR-320c regulates gemcitabine-resistance in pancreatic cancer via SMARCC1. AB - BACKGROUND: Gemcitabine-based chemotherapy is the standard treatment for pancreatic cancer. However, the issue of resistance remains unresolved. The aim of this study was to identify microRNAs (miRNAs) that govern the resistance to gemcitabine in pancreatic cancer. METHODS: miRNA microarray analysis using gemcitabine-resistant clones of MiaPaCa2 (MiaPaCa2-RGs), PSN1 (PSN1-RGs), and their parental cells (MiaPaCa2-P, PSN1-P) was conducted. Changes in the anti cancer effects of gemcitabine were studied after gain/loss-of-function analysis of the candidate miRNA. Further assessment of the putative target gene was performed in vitro and in 66 pancreatic cancer clinical samples. RESULTS: miR 320c expression was significantly higher in MiaPaCa2-RGs and PSN1-RGs than in their parental cells. miR-320c induced resistance to gemcitabine in MiaPaCa2. Further experiments showed that miR-320c-related resistance to gemcitabine was mediated through SMARCC1, a core subunit of the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex. In addition, clinical examination revealed that only SMARCC1-positive patients benefited from gemcitabine therapy with regard to survival after recurrence (P=0.0463). CONCLUSION: The results indicate that miR-320c regulates the resistance of pancreatic cancer cells to gemcitabine through SMARCC1, suggesting that miR-320c/SMARCC1 could be suitable for prediction of the clinical response and potential therapeutic target in pancreatic cancer patients on gemcitabine-based therapy. PMID- 23799851 TI - The association of waiting times from diagnosis to surgery with survival in women with localised breast cancer in England. AB - BACKGROUND: Survival from breast cancer in the United Kingdom is lower than in other developed countries. It is unclear to what extent waiting times for curative surgery affect survival. METHODS: Using national databases for England (cancer registries, Hospital Episode Statistics and Office of National Statistics), we identified 53 689 women with localised breast cancer, aged >= 15 years, diagnosed between 1996 and 2009, who had surgical resection with curative intent within 62 days of diagnosis. We used relative survival and excess risk modelling to determine associations between waiting times and 5-year survival. RESULTS: The median diagnosis to curative surgery waiting time among breast cancer patients was 22 days (interquartile range (IQR): 15-30). Relative survival was similar among women waiting between 25 and 38 days (RS: 93.5%; 95% CI: 92.8 94.2%), <25 days (RS: 93.0%; 95% CI: 92.5-93.4%) and between 39 and 62 days (RS: 92.1%; 95% CI: 90.8-93.4%). There was little evidence of an increase in excess mortality with longer waiting times (excess hazard ratio (EHR): 1.06; 95% CI: 0.88-1.27 comparing waiting times 39-62 with 25-38 days). Excess mortality was associated with age (EHR 65-74 vs 15-44 year olds: 1.23; 95% CI: 1.07-1.41) and deprivation (EHR most vs least deprived: 1.28; 95% CI: 1.09-1.49), but waiting times did not explain these differences. CONCLUSION: Within 62 days of diagnosis, decreasing waiting times from diagnosis to surgery had little impact on survival from localised breast cancer. PMID- 23799852 TI - Autophagy inhibition induces enhanced proapoptotic effects of ZD6474 in glioblastoma. AB - BACKGROUND: Autophagy is a lysosomal degradation pathway that can provide energy through its recycling mechanism to act as a cytoprotective adaptive response mediating treatment resistance in cancer cells. We investigated the autophagy inducing effects of ZD6474, a small-molecule inhibitor that blocks activities of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), and RET tyrosine kinases. METHODS: We investigated the effects of ZD6474 on autophagy in glioblastomas cells. The ZD6474 mechanism of action was determined by western blot. We then examined the impacts of the inhibition of autophagy in combination with ZD6474 on cell apoptosis in vitro. Furthermore, we evaluated the synergistic anticancer activity of combination treatment with an autophagy inhibitor (chloroquine) and ZD6474 in U251 glioblastoma cells xenograft model. RESULTS: ZD6474-induced autophagy was dependent on signalling through the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway. ZD6474-induced autophagy was inhibited by both knockdown of the ATG7 and Beclin 1 gene, essential autophagy genes, and pharmacologic agents (chloroquine and 3-methyalanine) treatment. Both treatments also dramatically sensitised glioblastoma cells to ZD6474-induced apoptosis, decreasing cell viability in vitro. Furthermore, in a xenograft mouse model, combined treatment with ZD6474 and chloroquine significantly inhibited U251 tumour growth, and increased the numbers of apoptotic cells compared with treatment with either agent alone. CONCLUSION: Autophagy protects glioblastoma cells from the proapoptotic effects of ZD6474, which might contribute to tumour resistance against ZD6474 treatment. PMID- 23799853 TI - Membrane expression of MRP-1, but not MRP-1 splicing or Pgp expression, predicts survival in patients with ESFT. AB - BACKGROUND: Primary Ewing's sarcoma family of tumours (ESFTs) may respond to chemotherapy, although many patients experience subsequent disease recurrence and relapse. The survival of ESFT cells following chemotherapy has been attributed to the development of resistant disease, possibly through the expression of ABC transporter proteins. METHODS: MRP-1 and Pgp mRNA and protein expression in primary ESFTs was determined by quantitative reverse-transcriptase PCR (RT-qPCR) and immunohistochemistry, respectively, and alternative splicing of MRP-1 by RT PCR. RESULTS: We observed MRP-1 protein expression in 92% (43 out of 47) of primary ESFTs, and cell membrane MRP-1 was highly predictive of both overall survival (P<0.0001) and event-free survival (P<0.0001). Alternative splicing of MRP-1 was detected in primary ESFTs, although the pattern of splicing variants was not predictive of patient outcome, with the exception of loss of exon 9 in six patients, which predicted relapse (P=0.041). Pgp protein was detected in 6% (38 out of 44) of primary ESFTs and was not associated with patient survival. CONCLUSION: For the first time we have established that cell membrane expression of MRP-1 or loss of exon 9 is predictive of outcome but not the number of splicing events or expression of Pgp, and both may be valuable factors for the stratification of patients for more intensive therapy. PMID- 23799854 TI - A leukotriene B4 receptor-2 is associated with paclitaxel resistance in MCF-7/DOX breast cancer cells. AB - BACKGROUND: Breast cancer is the most common malignancy in women. Although chemotherapeutic agents, such as paclitaxel, are effective treatments for the majority of breast cancer patients, recurrence is frequent and often leads to death. Thus, there is an urgent need to identify novel therapeutic targets that sensitise tumour cells to existing chemotherapy agents. METHODS: The levels of leukotriene B4 receptor-2 (BLT2) in multidrug-resistant MCF-7/DOX cells were determined using quantitative PCR and FACS analysis. The potential role of BLT2 in the paclitaxel resistance of MCF-7/DOX cells was assessed using a pharmacological inhibitor and small interfering RNA knockdown, and the BLT2 associated resistance mechanism was assessed. RESULTS: The expression levels of BLT2 were markedly upregulated in MCF-7/DOX cells. The inhibition of BLT2 by pre treatment with LY255283 or siBLT2 knockdown significantly sensitised MCF-7/DOX cells to paclitaxel and induced significant levels of apoptotic death, suggesting that BLT2 mediates paclitaxel resistance. We also demonstrated that BLT2-induced paclitaxel resistance was associated with the upregulation of P-glycoprotein. Finally, co-treatment with a BLT2 inhibitor and paclitaxel markedly reduced tumour growth in an MCF-7/DOX in vivo model. CONCLUSION: Together, our results demonstrate that BLT2 is a novel therapeutic target that sensitises drug resistant breast cancer cells to paclitaxel. PMID- 23799855 TI - Biochemical markers of bone turnover and clinical outcome in patients with renal cell and bladder carcinoma with bone metastases following treatment with zoledronic acid: The TUGAMO study. AB - BACKGROUND: Levels of bone turnover markers (BTM) might be correlated with outcome in terms of skeletal-related events (SRE), disease progression, and death in patients with bladder cancer (BC) and renal cell carcinoma (RCC) with bone metastases (BM). We try to evaluate this possible correlation in patients who receive treatment with zoledronic acid (ZOL). METHODS: This observational, prospective, and multicenter study analysed BTM and clinical outcome in these patients. Serum levels of bone alkaline phosphatase (BALP), procollagen type I amino-terminal propeptide (PINP), and beta-isomer of carboxy-terminal telopeptide of type I collagen (beta-CTX) were analysed. RESULTS: Patients with RCC who died or progressed had higher baseline beta-CTX levels and those who experienced SRE during follow-up showed high baseline BALP levels. In BC, a poor rate of survival was related with high baseline beta-CTX and BALP levels, and new SRE with increased PINP levels. Cox univariate analysis showed that beta-CTX levels were associated with higher mortality and disease progression in RCC and higher mortality in BC. Bone alkaline phosphatase was associated with increased risk of premature SRE appearance in RCC and death in BC. CONCLUSION: Beta-isomer of carboxy-terminal telopeptide of type I collagen and BALP can be considered a complementary tool for prediction of clinical outcomes in patients with BC and RCC with BM treated with ZOL. PMID- 23799856 TI - Cancer prevalence in United States, Nordic Countries, Italy, Australia, and France: an analysis of geographic variability. AB - BACKGROUND: The objectives of this study were to quantitatively assess the geographic heterogeneity of cancer prevalence in selected Western Countries and to explore the associations between its determinants. METHODS: For 20 cancer sites, 5-year cancer prevalence, incidence, and survival were observed and age standardised for the mid 2000s in the United States, Nordic European Countries, Italy, Australia, and France. RESULTS: In Italy, 5-year crude prevalence for all cancers was 1.9% in men and 1.7% in women, while it was ~1.5% in all other countries and sexes. After adjustment for the different age distribution of the populations, cancer prevalence in the United States was higher (20% in men and 10% in women) than elsewhere. For all cancers combined, the geographic heterogeneities were limited, though relevant for specific cancers (e.g., prostate, showing >30% higher prevalence in the United States, or lung, showing >50% higher prevalence in USA women than in other countries). For all countries, the correlations between differences of prevalence and differences of incidence were >0.9, while prevalence and survival were less consistently correlated. CONCLUSION: Geographic differences and magnitude of crude cancer prevalence were more strongly associated with incidence rates, influenced by population ageing, than with survival rates. These estimates will be helpful in allocating appropriate resources. PMID- 23799858 TI - Size-dependent subnanometer Pd cluster (Pd4, Pd6, and Pd17) water oxidation electrocatalysis. AB - Water oxidation is a key catalytic step for electrical fuel generation. Recently, significant progress has been made in synthesizing electrocatalytic materials with reduced overpotentials and increased turnover rates, both key parameters enabling commercial use in electrolysis or solar to fuels applications. The complexity of both the catalytic materials and the water oxidation reaction makes understanding the catalytic site critical to improving the process. Here we study water oxidation in alkaline conditions using size-selected clusters of Pd to probe the relationship between cluster size and the water oxidation reaction. We find that Pd4 shows no reaction, while Pd6 and Pd17 deposited clusters are among the most active (in terms of turnover rate per Pd atom) catalysts known. Theoretical calculations suggest that this striking difference may be a demonstration that bridging Pd-Pd sites (which are only present in three dimensional clusters) are active for the oxygen evolution reaction in Pd6O6. The ability to experimentally synthesize size-specific clusters allows direct comparison to this theory. The support electrode for these investigations is ultrananocrystalline diamond (UNCD). This material is thin enough to be electrically conducting and is chemically/electrochemically very stable. Even under the harsh experimental conditions (basic, high potential) typically employed for water oxidation catalysts, UNCD demonstrates a very wide potential electrochemical working window and shows only minor evidence of reaction. The system (soft-landed Pd4, Pd6, or Pd17 clusters on a UNCD Si-coated electrode) shows stable electrochemical potentials over several cycles, and synchrotron studies of the electrodes show no evidence for evolution or dissolution of either the electrode material or the clusters. PMID- 23799857 TI - Alginate dressings for healing diabetic foot ulcers. AB - BACKGROUND: Foot ulcers in people with diabetes mellitus are a common and serious global health issue. Dressings form a key part of ulcer treatment, with clinicians and patients having many different types to choose from including alginate dressings. A clear and current overview of current evidence is required to facilitate decision-making regarding dressing use. OBJECTIVES: To compare the effects of alginate wound dressings with no wound dressing or alternative dressings on the healing of foot ulcers in people with diabetes mellitus. SEARCH METHODS: For this first update, in April 2013, we searched the following databases the Cochrane Wounds Group Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE; and EBSCO CINAHL. There were no restrictions based on language or date of publication. SELECTION CRITERIA: Published or unpublished randomised controlled trials (RCTs) that have compared the effects on ulcer healing of alginate dressings with alternative wound dressings or no dressing in the treatment of foot ulcers in people with diabetes. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, risk of bias assessment and data extraction. MAIN RESULTS: We included six studies (375 participants) in this review; these compared alginate dressings with basic wound contact dressings, foam dressings and a silver-containing, fibrous-hydrocolloid dressing. Meta analysis of two studies found no statistically significant difference between alginate dressings and basic wound contact dressings: risk ratio (RR) 1.09 (95% CI 0.66 to 1.80). Pooled data from two studies comparing alginate dressings with foam dressings found no statistically significant difference in ulcer healing (RR 0.67, 95% CI 0.41 to 1.08). There was no statistically significant difference in the number of diabetic foot ulcers healed when an anti-microbial (silver) hydrocolloid dressing was compared with a standard alginate dressing (RR 1.40, 95% CI 0.79 to 2.47). All studies had short follow-up times (six to 12 weeks), and small sample sizes. AUTHORS' CONCLUSIONS: Currently there is no research evidence to suggest that alginate wound dressings are more effective in healing foot ulcers in people with diabetes than other types of dressing however many trials in this field are very small. Decision makers may wish to consider aspects such as dressing cost and the wound management properties offered by each dressing type e.g. exudate management. PMID- 23799859 TI - Ultralight three-dimensional boron nitride foam with ultralow permittivity and superelasticity. AB - Dielectrics with ultralow permittivity within 2 times that of air, excellent mechanical performance, and high thermal stability are highly attractive to many applications. However, since the finding of silica aerogels in the 1930s, no alternative ultralight porous dielectric with density below 10 mg/cm(3) has been developed. Here we present three-dimensional hierarchical boron nitride foam with permittivity of 1.03 times that of air, density of 1.6 mg/cm(3), and thermal stability up to 1200 degrees C obtained by chemical vapor deposition on a nickel foam template. This BN foam exhibits complete recovery after cyclic compression exceeding 70% with permittivity within 1.12 times that of air. Gathering all these exceptional characters, the BN foam should create a breakthrough development of flexible ultralow-permittivity dielectrics and ultralight materials. PMID- 23799860 TI - Enhanced retention and cellular uptake of nanoparticles in tumors by controlling their aggregation behavior. AB - Effective accumulation of nanoparticles (NPs) in tumors is crucial for NP assisted cancer diagnosis and treatment. With the hypothesis that aggregation of NPs stimulated by tumor microenvironment can be utilized to enhance retention and cellular uptake of NPs in tumors, we designed a smart NP system to evaluate the effect of aggregation on NPs' accumulation in tumor tissue. Gold nanoparticles (AuNPs, ~16 nm) were facilely prepared by surface modification with mixed-charge zwitterionic self-assembled monolayers, which can be stable at the pH of blood and normal tissues but aggregate instantly in response to the acidic extracellular pH of solid tumors. The zwitterionic AuNPs exhibited fast, ultrasensitive, and reversible response to the pH change from pH 7.4 to pH 6.5, which enabled the AuNPs to be well dispersed at pH 7.4 with excellent stealth ability to resist uptake by macrophages, while quickly aggregating at pH 6.5, leading to greatly enhanced uptake by cancer cells. An in vivo study demonstrated that the zwitterionic AuNPs had a considerable blood half-life with much higher tumor accumulation, retention, and cellular internalization than nonsensitive PEGylated AuNPs. A preliminary photothermal tumor ablation evaluation suggested the aggregation of AuNPs can be applied to cancer NIR photothermal therapy. These results suggest that controlled aggregation of NPs sensitive to tumor microenvironment can serve as a universal strategy to enhance the retention and cellular uptake of inorganic NPs in tumors, and modifying NPs with a mixed-charge zwitterionic surface can provide an easy way to obtain stealth properties and pH sensitivity at the same time. PMID- 23799861 TI - Comparative evaluation of three impactor samplers for measuring airborne bacteria and fungi concentrations. AB - Portable microbial samplers are useful for detecting microorganisms in the air. However, limited data are available on their performance when sampling airborne biological agents in a routine practice. We compared bacterial and fungal concentrations obtained in field conditions using three impactor samplers with different designs (AES Chemunex Sampl'Air, bioMerieux Air Ideal, and Sartorius AirPort MD8/BACTair). The linearity of mold collection was tested in the range of 100 L to 1000 L, and all the devices had a correlation coefficient higher than 0.95. For optimal comparison of the samplers, we performed experiments in different hospital rooms with varying levels of air biocontamination. Each sampling procedure was repeated to assess reproducibility. No significant difference between the samplers was observed for the mold concentrations on Sabouraud agar, whereas Sampl'Air collected significantly more bacteria on tryptic soy agar than Air Ideal or BACTair at one of the sites. Impactor location in the room was nevertheless associated with the variability observed with the three samplers at the highest microbial concentration levels. On the basis of their performance, autonomy and simplicity of use, these three impactors are suitable for routine indoor evaluation of microbial air contamination. PMID- 23799862 TI - Protecting nanotechnology workers while waiting for godot. PMID- 23799863 TI - Comparison effects and dielectric properties of different dose methylene-blue doped hydrogels. AB - The dielectric properties of methylene blue (MB)-doped hydrogels were investigated by impedance spectroscopy. The real part (epsilon') and the imaginary part (epsilon") of the complex dielectric constant and the energy loss tangent/dissipation factor (tan delta) were measured in the frequency range of 10 Hz to 100 MHz at room temperature for pH 5.5 value. Frequency variations of the resistance, the reactance, and the impedance of the samples have also been investigated. The dielectric permittivity of the MB-doped hydrogels is sensitive to ionic conduction and electrode polarization in low frequency. Furthermore, the dielectric behavior in high-frequency parts was attributed to the Brownian motion of the hydrogen bonds. The ionic conduction for MB-doped samples was prevented for Cole-Cole plots, while the Cole-Cole plots for pure sample show equivalent electrical circuit. The alternative current (ac) conductivity increases with the increasing MB concentration and the frequency. PMID- 23799866 TI - Sediment trapping by dams creates methane emission hot spots. AB - Inland waters transport and transform substantial amounts of carbon and account for ~18% of global methane emissions. Large reservoirs with higher areal methane release rates than natural waters contribute significantly to freshwater emissions. However, there are millions of small dams worldwide that receive and trap high loads of organic carbon and can therefore potentially emit significant amounts of methane to the atmosphere. We evaluated the effect of damming on methane emissions in a central European impounded river. Direct comparison of riverine and reservoir reaches, where sedimentation in the latter is increased due to trapping by dams, revealed that the reservoir reaches are the major source of methane emissions (~0.23 mmol CH4 m(-2) d(-1) vs ~19.7 mmol CH4 m(-2) d(-1), respectively) and that areal emission rates far exceed previous estimates for temperate reservoirs or rivers. We show that sediment accumulation correlates with methane production and subsequent ebullitive release rates and may therefore be an excellent proxy for estimating methane emissions from small reservoirs. Our results suggest that sedimentation-driven methane emissions from dammed river hot spot sites can potentially increase global freshwater emissions by up to 7%. PMID- 23799864 TI - Oxytocin, social support, and sleep quality in low-income minority women living with HIV. AB - Sleep disturbances are highly prevalent in women with HIV, and few studies examine potential protective factors that may reduce risk for sleep disturbances in this high-risk population. This study predicted that HIV-specific social support from various sources (i.e., friends, family members, and spouses), as well as oxytocin (OT), would explain sleep quality in 71 low-income minority women living with HIV. Social support from family members was associated with better sleep quality in women. For women with high OT, support from friends was associated with better sleep quality, whereas for women with low OT, support from friends was associated with poorer sleep quality. Women with low OT may not effectively interpret and utilize available support resources, which may be associated with sleep disturbances. PMID- 23799867 TI - Antibiotic and other lock treatments for tunnelled central venous catheter related infections in children with cancer. AB - BACKGROUND: The risk of developing a tunnelled central venous catheter (CVC) related infection ranges between 0.1 and 2.3 per 1000 catheter days for children with cancer. These infections are difficult to treat with systemic antibiotics (salvage rate 24% - 66%) due to biofilm formation in the CVC. Lock treatments can achieve 100 - 1000 times higher concentrations locally without exposure to high systemic concentrations. OBJECTIVES: Our objective was to investigate the efficacy of antibiotic and other lock treatments in the treatment of CVC-related infections in children with cancer compared to a control intervention. We also assessed adverse events of lock treatments. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, issue 3, 2011), MEDLINE/PubMed (1945 to August 2011) and EMBASE/Ovid (1980 to August 2011). In addition we searched reference lists from relevant articles and the conference proceedings of the International Society for Paediatric Oncology (SIOP) (from 2006 to 2010), American Society of Clinical Oncology (ASCO) (from 2006 to 2010), the Multinational Association of Supportive Care in Cancer (MASCC) (from 2006 to 2011), the American Society of Hematology (ASH) (from 2006 to 2010) and the International Society of Thrombosis and Haematology (ISTH) (from 2006 to 2011). We scanned the ISRCTN Register and the National Institute of Health Register for ongoing trials (www.controlled-trials.com) (August 2011). SELECTION CRITERIA: Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) comparing an antibiotic lock or other lock treatment (with or without concomitant systemic antibiotics) with a control intervention (other lock treatment with or without concomitant systemic antibiotics or systemic antibiotics alone) for the treatment of CVC-related infections in children with cancer. For the description of adverse events, cohort studies were also eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies, extracted data and performed 'Risk of bias' assessments of included studies. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: Two RCTs evaluated urokinase lock treatment with concomitant systemic antibiotics (n = 56) versus systemic antibiotics alone (n = 48), and one CCT evaluated ethanol lock treatment with concomitant systemic antibiotics (n = 15) versus systemic antibiotics alone (n = 13). No RCTs or CCTs evaluating antibiotic lock treatments were identified. All studies had methodological limitations and clinical heterogeneity between studies was present. We found no evidence of significant difference between ethanol or urokinase lock treatments with concomitant systemic antibiotics and systemic antibiotics alone regarding the number of participants cured, the number of recurrent CVC-related infections, the number of days until the first negative blood culture, the number of CVCs prematurely removed, ICU admission and sepsis. Not all studies were included in all analyses. No adverse events occurred in the five publications of cohort studies (one cohort was included in two publications) assessing this outcome; CVC malfunctioning occurred in three out of five publications of cohort studies assessing this outcome. AUTHORS' CONCLUSIONS: No significant effect of urokinase or ethanol lock in addition to systemic antibiotics was found. However, this could be due to low power or a too-short follow-up. The cohort studies identified no adverse events; some cohort studies reported CVC malfunctioning. No RCTs or CCTs were published on antibiotic lock treatment alone. More well-designed RCTs are needed to further explore the effect of antibiotic or other lock treatments in the treatment of CVC related infections in children with cancer. PMID- 23799868 TI - Improvement in dynamic balance and core endurance after a 6-week core-stability training program in high school track and field athletes. AB - CONTEXT: Core training specifically for track and field athletes is vague, and it is not clear how it affects dynamic balance and core-endurance measures. OBJECTIVE: To determine the effects of a 6-week core-stabilization-training program for high school track and field athletes on dynamic balance and core endurance. DESIGN: Test-retest. SETTING: High school in north central West Virginia. PARTICIPANTS: Thirteen healthy high school student athletes from 1 track and field team volunteered for the study. INTERVENTIONS: Subjects completed pretesting 1 wk before data collection. They completed a 6-wk core-stabilization program designed specifically for track and field athletes. The program consisted of 3 levels with 6 exercises per level and lasted for 30 min each session 3 times per week. Subjects progressed to the next level at 2-wk intervals. After 6 wk, posttesting was conducted MAIN OUTCOME MEASURES: The subjects were evaluated using the Star Excursion Balance Test (SEBT) for posteromedial (PM), medial (M), and anteromedial (AM) directions; abdominal-fatigue test (AFT); back-extensor test (BET); and side-bridge test (SBT) for the right and left sides. RESULTS: Posttest results significantly improved for all 3 directions of the SEBT (PM, M, and AM), AFT, BET, right SBT, and left SBT. Effect size was large for all variables except for PM and AM, where a moderate effect was noted. Minimal detectable-change scores exceeded the error of the measurements for all dependent variables. CONCLUSION: After the 6-wk core-stabilization-training program, measures of the SEBT, AFT, BET, and SBT improved, thus advocating the use of this core-stabilization-training program for track and field athletes. PMID- 23799869 TI - Photothermal analysis of individual nanoparticulate samples using micromechanical resonators. AB - The ability to detect and analyze single sample entities such as single nanoparticles, viruses, spores, or molecules is of fundamental interest. This can provide insight into the individual specific properties which may differ from the statistical sample average. Here we introduce resonant photothermal spectroscopy, a novel method that enables the analysis of individual nanoparticulate samples. Absorption of light by an individual sample placed on a microstring resonator results in local heating of the string, which is reflected in its resonance frequency. The working principle of the spectrometer is demonstrated by analyzing the optical absorption of different micro- and nanoparticles on a microstring. We present the measurement of a simple absorption spectrum of multiple polystyrene microparticles illuminated with an unfocused LED light source. Using a diode laser, single 170 nm polystyrene nanoparticles are detected. With the current setup, nanoparticulate samples with a mass of ~40 ag are detectable. By using nanostrings, visible and infrared photothermal spectroscopy in the subattogram mass regime is possible and single molecule detection is within reach. PMID- 23799870 TI - mazEF-mediated programmed cell death in bacteria: "what is this?". AB - Toxin-antitoxin (TA) systems consist of a bicistronic operon, encoding a toxin and an antitoxin. They are widely distributed in the prokaryotic kingdom, often in multiple numbers. TAs are implicated in contradicting phenomena of persistence and programmed cell death (PCD) in bacteria. mazEF TA system, one of the widely distributed type II toxin-antitoxin systems, is particularly implicated in PCD of Escherichia coli. Nutrient starvation, antibiotic stress, heat shock, DNA damage and other kinds of stresses are shown to elicit mazEF-mediated-PCD. ppGpp and extracellular death factor play a central role in regulating mazEF-mediated PCD. The activation of mazEF system is achieved through inhibition of transcription or translation of mazEF loci. Upon activation, MazF cleaves RNA in a ribosome independent fashion and subsequent processes result in cell death. It is hypothesized that PCD aids in perseverance of the population during stress; the surviving minority of the cells can scavenge the nutrients released by the dead cells, a kind of "nutritional-altruism." Issues regarding the strains, reproducibility of experimental results and ecological plausibility necessitate speculation. We review the molecular mechanisms of the activation of mazEF TA system, the consequences leading to cell death and the pros and cons of the altruism hypothesis from an ecological perspective. PMID- 23799871 TI - Utility of bronchoalveolar lavage fluid galactomannan alone or in combination with PCR for the diagnosis of invasive aspergillosis in adult hematology patients: a systematic review and meta-analysis. AB - BACKGROUND: The clinical utility of bronchoalveolar lavage (BAL) fluid galactomannan (GM) for the early diagnosis of invasive aspergillosis (IA) varies widely across studies mainly due to heterogeneity of the studied populations. METHODS: We conducted a systematic review and meta-analysis of 16 studies involving 783 adults with hematological malignancies to derive summary estimates of the overall accuracy of BAL-GM for diagnosing IA. FINDINGS: Summary estimates of BAL-GM using an optical density (OD) index cutoff value of 1.5 for proven and probable IA were: sensitivity 0.92 (95% CI = 0.48-0.99), specificity 0.98 (95% CI = 0.78-1.00), positive likelihood ratio 53.7 (95% CI = 3.7-771.8), and negative likelihood ratio 0.08 (95% CI = 0.01-0.83). Comparing serum GM and Aspergillus PCR testing on BAL fluid, BAL-GM conferred greater sensitivity, but lower specificity than the serum GM test, and similar specificity as the PCR assay. The use of BAL-GM with serum GM or BAL-PCR tests increased the sensitivity moderately when a positive result was defined by either assay. INTERPRETATION: GM quantification in BAL fluid at an OD index cutoff value of 1.5 has excellent sensitivity and specificity to assist clinical decision-making in confirming or excluding a diagnosis of IA when results are interpreted with clinical findings. Additional research investigating the effects of antifungal agents, optimal timing and processing of BAL sampling are needed to improve the diagnostic accuracy of BAL-GM testing. PMID- 23799872 TI - Harnessing plant-microbe interactions for enhancing farm productivity. AB - Declining soil fertility and farm productivity is a major global concern in order to achieve food security for a burgeoning world population. It is reported that improving soil health alone can increase productivity by 10-15% and in combination with efficient plant traits, farm productivity can be increased up to 50-60%. In this article we explore the emerging microbial and bioengineering technologies, which can be employed to achieve the transformational increase in farm productivity and can simultaneously enhance environmental outcomes i.e., low green house gas (GHG) emissions. We argue that metagenomics, meta-transcriptomics and metabolomics have potential to provide fundamental knowledge on plant microbes interactions necessary for new innovations to increase farm productivity. Further, these approaches provide tools to identify and select novel microbial/gene resources which can be harnessed in transgenic and designer plant technologies for enhanced resource use efficiencies. PMID- 23799873 TI - A phase I/II trial to evaluate the safety, feasibility and activity of salvage therapy consisting of the mTOR inhibitor Temsirolimus added to standard therapy of Rituximab and DHAP for the treatment of patients with relapsed or refractory diffuse large cell B-Cell lymphoma - the STORM trial. AB - BACKGROUND: The current standard treatment of patients with relapsed or refractory diffuse large cell B-Cell lymphoma (DLBCL) primarily consists of intensified salvage therapy and, if the disease is chemo-sensitive, high dose therapy followed with autologous stem cell transplantation. In the rituximab era however, this treatment approach has shown only limited benefit. In particular, patients relapsing after rituximab-containing primary treatment have an adverse prognosis, especially if this occurs within the first year after therapy or if the disease is primarily refractory. Therefore there is an ultimate need for improved salvage treatment approaches. METHODS/DESIGN: The STORM study is a prospective, multicentre phase I/II study to evaluate the safety, feasibility and activity of salvage therapy consisting of the mTOR inhibitor temsirolimus added to the standard therapy rituximab and DHAP for the treatment of patients with relapsed or refractory DLBCL. The primary objective of the phase I of the trial is to establish the maximum tolerated dose (MTD) of temsirolimus in combination with rituximab and DHAP. The secondary objective is to demonstrate that stem cells can be mobilized during this regimen in patients scheduled to proceed to high dose therapy. In phase II, the previously established maximum tolerated dose of temsirolimus will be used. The primary objective is to evaluate the overall response rate (ORR) in patients with relapsed DLBCL. The secondary objective is to evaluate progression free survival (PFS), overall survival (OS) and toxicity. The study will be accompanied by an analysis of lymphoma subtypes determined by gene expression analysis (GEP). DISCUSSION: The STORM trial evaluates the safety, feasibility and activity of salvage therapy consisting of the mTOR inhibitor temsirolimus added to standard therapy of rituximab and DHAP for the treatment of patients with relapsed or refractory DLBCL. It also might identify predictive markers for this treatment modality. TRIAL REGISTRATION: ClinicalTrials.gov NCT01653067. PMID- 23799874 TI - Aging with HIV and disability: the role of uncertainty. AB - Due to advances in treatment, people with HIV are living longer and developing disabilities related to the virus, adverse side effects of medications, and aging. Illness-related uncertainty has been shown to contribute to disablement; however, there is little understanding of the uncertainties related to aging with HIV. The purpose of this research was to describe the contribution of uncertainty to the disability experienced by older adults living with HIV. Forty-nine men and women living with HIV and 50 years or older participated in in-depth qualitative interviews exploring various aspects of social participation and disability. Transcriptions of the interviews were analyzed using a grounded theory approach. Age-related uncertainties were described in the following themes: source of health challenge; health providers' age-related knowledge and skills; financial uncertainty; transition to retirement; appropriate long-term housing, and uncertainty over who would care for them. While not directly attributable to aging, the episodic nature of HIV left many with uncertainties related to when their next episode of illness would occur and often resulted in an inability to plan in advance. Results highlight the need to focus on the notion of successful and positive aging with the view to identifying effective interventions that reduce disability and enhance the overall health of older adults with HIV. This work builds on previous studies highlighting the role of uncertainty in the disability experience by identifying age-related components specific to older adults aging with HIV. PMID- 23799875 TI - Measuring psychotic depression. AB - OBJECTIVE: Psychotic depression (PD) is a highly debilitating condition, which needs intensive monitoring. However, there is no established rating scale for evaluating the severity of PD. The aim of this analysis was to assess the psychometric properties of established depression rating scales and a number of new composite rating scales, covering both depressive and psychotic symptoms, in relation to PD. METHOD: The psychometric properties of the rating scales were evaluated based on data from the Study of Pharmacotherapy of Psychotic Depression. RESULTS: A rating scale consisting of the 6-item Hamilton melancholia subscale (HAM-D6 ) plus five items from the Brief Psychiatric Rating Scale (BPRS), named the HAMD-BPRS11 , displayed clinical validity (Spearman's correlation coefficient between HAMD-BPRS11 and Clinical Global Impression - Severity (CGI-S) scores = 0.79-0.84), responsiveness (Spearman's correlation coefficient between change in HAMD-BPRS11 and Clinical Global Impression - Improvement (CGI-I) scores = -0.74--0.78) and unidimensionality (Loevinger's coefficient of homogeneity = 0.41) in the evaluation of PD. The HAM-D6 fulfilled the same criteria, whereas the full 17-item Hamilton Depression Scale failed to meet criteria for unidimensionality. CONCLUSION: Our results suggest that the HAMD-BPRS11 is a more valid measure than pure depression scales for evaluating the severity of PD. PMID- 23799876 TI - Updated national multicenter registry on procedural safety of catheter ablation for atrial fibrillation. AB - INTRODUCTION: Despite catheter ablation (CA) becoming an accepted treatment option for symptomatic, drug-resistant atrial fibrillation (AF), safety of this procedure continues to be cause for concern. Aim of the present multicenter registry was to assess the incidence of early CA complications and detect their predictors in a contemporary, unselected AF population METHODS AND RESULTS: From January 1, 2011 to December 31, 2011, data from 2,323 consecutive patients who underwent CA (median age 60 [52-67]; 72.3% male) for AF in 29 Italian centers were collected. All major complications occurring to the patient from admission to 30th postprocedural day were recorded. No procedure-related death was observed. Major complications occurred in 94 patients (4.0%): 50 patients (2.2%) suffered vascular access complications; 12 patients (0.5%) developed cardiac tamponade; 14 patients (0.6%) presented with pericarditis; 5 patients (0.2%) had transient ischemic attack; 4 patients had stroke; 3 patients (0.1%) had phrenic nerve paralysis; 3 patients (0.1%) had hemothorax. Other isolated but serious adverse events were documented in 3 patients (0.1%). Female gender (OR 2.643; 95% CI 1.686-4.143; P < 0.0001) and longer procedural duration (OR 2.195; 95% CI 1.388-3.473; P < 0.001) independently predicted a higher risk of complications. CONCLUSION: Major complications occurred in 4.0% of the CA procedures for AF, with vascular access complications being the most frequent events. PMID- 23799877 TI - Global transcriptome profiles of Camellia sinensis during cold acclimation. AB - BACKGROUND: Tea is the most popular non-alcoholic health beverage in the world. The tea plant (Camellia sinensis (L.) O. Kuntze) needs to undergo a cold acclimation process to enhance its freezing tolerance in winter. Changes that occur at the molecular level in response to low temperatures are poorly understood in tea plants. To elucidate the molecular mechanisms of cold acclimation, we employed RNA-Seq and digital gene expression (DGE) technologies to the study of genome-wide expression profiles during cold acclimation in tea plants. RESULTS: Using the Illumina sequencing platform, we obtained approximately 57.35 million RNA-Seq reads. These reads were assembled into 216,831 transcripts, with an average length of 356 bp and an N50 of 529 bp. In total, 1,770 differentially expressed transcripts were identified, of which 1,168 were up-regulated and 602 down-regulated. These include a group of cold sensor or signal transduction genes, cold-responsive transcription factor genes, plasma membrane stabilization related genes, osmosensing-responsive genes, and detoxification enzyme genes. DGE and quantitative RT-PCR analysis further confirmed the results from RNA-Seq analysis. Pathway analysis indicated that the "carbohydrate metabolism pathway" and the "calcium signaling pathway" might play a vital role in tea plants' responses to cold stress. CONCLUSIONS: Our study presents a global survey of transcriptome profiles of tea plants in response to low, non-freezing temperatures and yields insights into the molecular mechanisms of tea plants during the cold acclimation process. It could also serve as a valuable resource for relevant research on cold-tolerance and help to explore the cold-related genes in improving the understanding of low-temperature tolerance and plant-environment interactions. PMID- 23799879 TI - Association of subclinical myocardial injury with arterial stiffness in patients with type 2 diabetes mellitus. AB - OBJECTIVE: Type 2 diabetes mellitus (T2DM) is associated with subclinical myocardial injury although the underlying mechanism is uncertain. We postulated that arterial stiffness, endothelial dysfunction and subclinical atherosclerosis may contribute to subclinical myocardial injury in patients with T2DM. METHODS: Serum high-sensitivity troponin I (hs-TNI) an indicator of myocardial injury, was measured in 100 patients with T2DM without clinical evidence of macrovascular disease and 150 age and gender-matched controls. Elevated hs-TnI was defined as follow (derived from the 99th percentile from controls): Male >11.1 ng/L; female >7.6 ng/L. Measures that may contribute to myocardial damage in patients with T2DM, including brachial-ankle pulse wave velocity (ba-PWV), brachial flow mediated dilatation (FMD) and carotid intima media thickness (IMT), were also assessed. RESULTS: The serum level of hs-TNI (5.7 +/- 9.2 MUg/L vs. 3.2 +/- 1.9 MUg/L, P< 0.01) and the prevalence of elevated hs-TNI (12% vs. 4%, P = 0.02) were significantly higher in patients with T2DM than controls. Patients with T2DM also had significantly worse ba-PWV (17.98 +/- 3.91ms-1 vs. 15.70 +/- 2.96 ms-1), brachial FMD (2.6 +/- 3.5% vs. 5.5 +/- 4.2%, P< 0.01) and carotid IMT (0.96 +/- 0.20 mm vs. 0.86 +/- 0.14 mm, P< 0.01). In patients with T2DM, hs-TNI was positively correlated with systolic blood pressure (r = 0.31, P<0.01), serum creatinine (r = 0.26, P = 0.01) and ba-PWV (r = 0.34, P< 0.01). Importantly, multiple regression revealed that only ba-PWV was independently associated with hs-TNI (beta = 0.25, P = 0.04). CONCLUSION: The results demonstrated an independent association between ba-PWV and hs-TNI in patients with T2DM with no clinical evidence of macrovascular disease. These findings suggest that increased arterial stiffness is closely related to subclinical myocardial injury in patients with T2DM. PMID- 23799878 TI - The epidemiology of hepatitis C virus in Egypt: a systematic review and data synthesis. AB - BACKGROUND: Egypt has the highest prevalence of hepatitis C virus (HCV) in the world, estimated nationally at 14.7%. Our study's objective was to delineate the evidence on the epidemiology of HCV infection among the different population groups in Egypt, and to draw analytical inferences about the nature of HCV transmission in this country. METHODS: We conducted a systematic review of all data on HCV prevalence and incidence in Egypt following PRISMA guidelines. The main sources of data included PubMed and Embase databases. We also used a multivariate regression model to infer the temporal trend of HCV prevalence among the general population and high risk population in Egypt. RESULTS: We identified 150 relevant records, four of which were incidence studies. HCV incidence ranged from 0.8 to 6.8 per 1,000 person-years. Overall, HCV prevalence among pregnant women ranged between 5-15%, among blood donors between 5-25%, and among other general population groups between 0-40%. HCV prevalence among multi-transfused patients ranged between 10-55%, among dialysis patients between 50-90%, and among other high risk populations between 10% and 85%. HCV prevalence varied widely among other clinical populations and populations at intermediate risk. Risk factors appear to be parenteral anti-schistosomal therapy, injections, transfusions, and surgical procedures, among others. Results of our time trend analysis suggest that there is no evidence of a statistically significant decline in HCV prevalence over time in both the general population (p-value: 0.215) and high risk population (p-value: 0.426). CONCLUSIONS: Egypt is confronted with an HCV disease burden of historical proportions that distinguishes this nation from others. A massive HCV epidemic at the national level must have occurred with substantial transmission still ongoing today. HCV prevention in Egypt must become a national priority. Policymakers, and public health and medical care stakeholders need to introduce and implement further prevention measures targeting the routes of HCV transmission. PMID- 23799880 TI - Gold nanoarray deposited using alternating current for emission rate-manipulating nanoantenna. AB - We have proposed an easy and controllable method to prepare highly ordered Au nanoarray by pulse alternating current deposition in anodic aluminum oxide template. Using the ultraviolet-visible-near-infrared region spectrophotometer, finite difference time domain, and Green function method, we experimentally and theoretically investigated the surface plasmon resonance, electric field distribution, and local density of states enhancement of the uniform Au nanoarray system. The time-resolved photoluminescence spectra of quantum dots show that the emission rate increased from 0.0429 to 0.5 ns-1 (10.7 times larger) by the existence of the Au nanoarray. Our findings not only suggest a convenient method for ordered nanoarray growth but also prove the utilization of the Au nanoarray for light emission-manipulating antennas, which can help build various functional plasmonic nanodevices. PMID- 23799881 TI - INI1/hSNF5-interaction defective HIV-1 IN mutants exhibit impaired particle morphology, reverse transcription and integration in vivo. AB - BACKGROUND: Retroviral integrase catalyzes integration of viral DNA into the host genome. Integrase interactor (INI)1/hSNF5 is a host factor that binds to HIV-1 IN within the context of Gag-Pol and is specifically incorporated into HIV-1 virions during assembly. Previous studies have indicated that INI1/hSNF5 is required for late events in vivo and for integration in vitro. To determine the effects of disrupting the IN-INI1 interaction on the assembly and infectivity of HIV-1 particles, we isolated mutants of IN that are defective for binding to INI1/hSNF5 and tested their effects on HIV-1 replication. RESULTS: A reverse yeast two hybrid system was used to identify INI1-interaction defective IN mutants (IID IN). Since protein-protein interactions depend on the surface residues, the IID IN mutants that showed high surface accessibility on IN crystal structures (K71R, K111E, Q137R, D202G, and S147G) were selected for further study. In vitro interaction studies demonstrated that IID-IN mutants exhibit variable degrees of interaction with INI1. The mutations were engineered into HIV-1(NL4-3) and HIV Luc viruses and tested for their effects on virus replication. HIV-1 harboring IID-IN mutations were defective for replication in both multi- and single-round infection assays. The infectivity defects were correlated to the degree of INI1 interaction of the IID-IN mutants. Highly defective IID-IN mutants were blocked at early and late reverse transcription, whereas partially defective IID-IN mutants proceeded through reverse transcription and nuclear localization, but were partially impaired for integration. Electron microscopic analysis of mutant particles indicated that highly interaction-defective IID-IN mutants produced morphologically aberrant virions, whereas the partially defective mutants produced normal virions. All of the IID-IN mutant particles exhibited normal capsid stability and reverse transcriptase activity in vitro. CONCLUSIONS: Our results demonstrate that a severe defect in IN-INI1 interaction is associated with production of defective particles and a subsequent defect in post-entry events. A partial defect in IN-INI1 interaction leads to production of normal virions that are partially impaired for early events including integration. Our studies suggest that proper interaction of INI1 with IN within Gag-Pol is necessary for proper HIV-1 morphogenesis and integration. PMID- 23799882 TI - Grass pollen allergy in children and adolescents-symptoms, health related quality of life and the value of pollen prognosis. AB - INTRODUCTION: An association between pollen count (Poaceae) and symptoms is well known, but to a lesser degree the importance of priming and lag effects. Also, threshold levels for changes in symptom severity need to be validated. The present study aims to investigate the relationship between pollen counts, symptoms and health related quality of life (HRQL), and to validate thresholds levels, useful in public pollen warnings. MATERIAL AND METHODS: Children aged 7 18 with grass pollen allergy filled out a symptom diary during the pollen season for nose, eyes and lung symptoms, as well as a HRQL questionnaire every week. Pollen counts were monitored using a volumetric spore trap. RESULTS: 89 (91%) of the included 98 children completed the study. There was a clear association between pollen count, symptom severity and HRQL during the whole pollen season, but no difference in this respect between early and late pollen season. There was a lag effect of 1-3 days after pollen exposure except for lung symptoms. We found only two threshold levels, at 30 and 80 pollen grains/m(3) for the total symptom score, not three as is used today. The nose and eyes reacted to low doses, but for the lung symptoms, symptom strength did hardly change until 50 pollen grains/m(3). CONCLUSION: Grass pollen has an effect on symptoms and HRQL, lasting up to 5 days after exposure. Symptoms from the lungs appear to have higher threshold levels than the eyes and the nose. Overall symptom severity does not appear to change during the course of season. Threshold levels need to be revised. We suggest a traffic light model for public pollen warnings directed to children, where green signifies "no problem", yellow signifies "can be problems, especially if you are highly sensitive" and red signifies "alert - take action". PMID- 23799883 TI - The development of a patient-reported outcome measure for assessing nighttime symptoms of chronic obstructive pulmonary disease. AB - BACKGROUND: The assessment of symptoms of chronic obstructive pulmonary disease (COPD) is important for monitoring and managing the disease and for evaluating outcomes of interventions. COPD patients experience symptoms during the day and night, and symptoms experienced at night often disturb sleep. The aim of this paper is to describe methods used to develop a patient-reported outcome (PRO) instrument for evaluating nighttime symptoms of COPD, and to document evidence for the content validity of the instrument. METHODS: Literature review and clinician interviews were conducted to inform discussion guides to explore patients' nighttime COPD symptom experience. Data from focus groups with COPD patients was used to develop a conceptual framework and the content of a new PRO instrument. Patient understanding of the new instrument was assessed via cognitive interviews with COPD patients. RESULTS: The literature review confirmed that there is no instrument with evidence of content validity currently available to assess nighttime symptoms of COPD. Additionally, the literature review and clinician interviews suggested the need to understand patients' experience of specific symptoms in order to evaluate nighttime symptoms of COPD. Analyses of patient focus group data (N = 27) supported saturation of concepts and aided in development of a conceptual framework. Items were generated using patients' terminology to collect data on concepts in the framework including the occurrence and severity of COPD symptoms, use of rescue medication at night, and nocturnal awakening. Response options were chosen to reflect concepts that were salient to patients. Subsequent cognitive interviewing with ten COPD patients demonstrated that the items, response options, recall period, and instructions were understandable, relevant, and interpreted as intended. CONCLUSIONS: A new PRO instrument, the Nighttime Symptoms of COPD Instrument (NiSCI), was developed with documented evidence of content validity. The NiSCI is ready for empirical testing, including item reduction and evaluation of psychometric properties. PMID- 23799884 TI - Three-dimensional echocardiographic assessment of patent foramen ovale in platypnea-orthodeoxia. AB - Platypnea-orthodeoxia is an uncommon syndrome characterized by positional dyspnea and hypoxia when upright that improves with lying down. We present a 75-year-old man with platypnea-orthodeoxia in the setting of a patent foramen ovale (PFO) and a 2.1 cm highly mobile atrial septal aneurysm with 2 cm bowing. Prior reports have established the use of three-dimensional echocardiography to facilitate percutaneous closure of PFO and atrial septal defect, but its use in patients with platypnea-orthodeoxia is unclear. We document three-dimensional echocardiographic images that accurately estimated PFO defect size and confirmed placement of the occluder device. PMID- 23799885 TI - Genetic variation in four maturity genes affects photoperiod insensitivity and PHYA-regulated post-flowering responses of soybean. AB - BACKGROUND: Absence of or low sensitivity to photoperiod is necessary for short day crops, such as rice and soybean, to adapt to high latitudes. Photoperiod insensitivity in soybeans is controlled by two genetic systems and involves three important maturity genes: E1, a repressor for two soybean orthologs of Arabidopsis FLOWERING LOCUS T (GmFT2a and GmFT5a), and E3 and E4, which are phytochrome A genes. To elucidate the diverse mechanisms underlying photoperiod insensitivity in soybean, we assessed the genotypes of four maturity genes (E1 through E4) in early-flowering photoperiod-insensitive cultivars and their association with post-flowering responses. RESULTS: We found two novel dysfunctional alleles in accessions originally considered to have a dominant E3 allele according to known DNA markers. The E3 locus, together with E1 and E4, contained multiple dysfunctional alleles. We identified 15 multi-locus genotypes, which we subdivided into 6 genotypic groups by classifying their alleles by function. Of these, the e1-as/e3/E4 genotypic group required an additional novel gene (different from E1, E3, and E4) to condition photoperiod insensitivity. Despite their common pre-flowering photoperiod insensitivity, accessions with different multi-locus genotypes responded differently to the post-flowering photoperiod. Cultivars carrying E3 or E4 were sensitive to photoperiod for post flowering characteristics, such as reproductive period and stem growth after flowering. The phytochrome A-regulated expression of the determinate growth habit gene Dt1, an ortholog of Arabidopsis TERMINAL FLOWER1, was involved in the persistence of the vegetative activity at the stem apical meristem of flower induced plants under long-day conditions. CONCLUSIONS: Diverse genetic mechanisms underlie photoperiod insensitivity in soybean. At least three multi-locus genotypes consisting of various allelic combinations at E1, E3, and E4 conferred pre-flowering photoperiod insensitivity to soybean cultivars but led to different responses to photoperiod during post-flowering vegetative and reproductive development. The phyA genes E3 and E4 are major controllers underlying not only pre-flowering but also post-flowering photoperiod responses. The current findings improve our understanding of genetic diversity in pre-flowering photoperiod insensitivity and mechanisms of post-flowering photoperiod responses in soybean. PMID- 23799886 TI - Telehealth system (e-CUIDATE) to improve quality of life in breast cancer survivors: rationale and study protocol for a randomized clinical trial. AB - BACKGROUND: Breast cancer survivors suffer physical impairment after oncology treatment. This impairment reduces quality of life (QoL) and increase the prevalence of handicaps associated to unhealthy lifestyle (for example, decreased aerobic capacity and strength, weight gain, and fatigue). Recent work has shown that exercise adapted to individual characteristics of patients is related to improved overall and disease-free survival. Nowadays, technological support using telerehabilitation systems is a promising strategy with great advantage of a quick and efficient contact with the health professional. It is not known the role of telerehabilitation through therapeutic exercise as a support tool to implement an active lifestyle which has been shown as an effective resource to improve fitness and reduce musculoskeletal disorders of these women. METHODS / DESIGN: This study will use a two-arm, assessor blinded, parallel randomized controlled trial design. People will be eligible if: their diagnosis is of stages I, II, or IIIA breast cancer; they are without chronic disease or orthopedic issues that would interfere with ability to participate in a physical activity program; they had access to the Internet and basic knowledge of computer use or living with a relative who has this knowledge; they had completed adjuvant therapy except for hormone therapy and not have a history of cancer recurrence; and they have an interest in improving lifestyle. Participants will be randomized into e-CUIDATE or usual care groups. E-CUIDATE give participants access to a range of contents: planning exercise arranged in series with breathing exercises, mobility, strength, and stretching. All of these exercises will be assigned to women in the telerehabilitation group according to perceived needs. The control group will be asked to maintain their usual routine. Study endpoints will be assessed after 8 weeks (immediate effects) and after 6 months. The primary outcome will be QoL measured by The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 version 3.0 and breast module called The European Organization for Research and Treatment of Cancer Breast Cancer-Specific Quality of Life questionnaire. The secondary outcomes: pain (algometry, Visual Analogue Scale, Brief Pain Inventory short form); body composition; physical measurement (abdominal test, handgrip strength, back muscle strength, and multiple sit-to-stand test); cardiorespiratory fitness (International Fitness Scale, 6-minute walk test, International Physical Activity Questionnaire-Short Form); fatigue (Piper Fatigue Scale and Borg Fatigue Scale); anxiety and depression (Hospital Anxiety and Depression Scale); cognitive function (Trail Making Test and Auditory Consonant Trigram); accelerometry; lymphedema; and anthropometric perimeters. DISCUSSION: This study investigates the feasibility and effectiveness of a telerehabilitation system during adjuvant treatment of patients with breast cancer. If this treatment option is effective, telehealth systems could offer a choice of supportive care to cancer patients during the survivorship phase. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01801527. PMID- 23799887 TI - Assessing awareness of colorectal cancer symptoms and screening in a peripheral colorectal surgical unit: a survey based study. AB - BACKGROUND: The National Screening Program for colorectal cancer is scheduled to commence in the near future. Previous studies on the topic of colorectal cancer and screening have highlighted paucity in public awareness of epidemiology, symptoms and signs of colorectal cancer. The aim of this study was to assess understanding of colorectal cancer and screening in a representative sample of the local catchment population of Mayo General Hospital. METHODS: A prospective cohort study was instituted utilising an anonymous survey, which was distributed at consecutive general surgical out-patient clinics over a one month period prior to initiation of the screening program. Data collected included demographics, presenting complaint type and duration, and general knowledge of colorectal cancer facts. Attitudes towards screening were also evaluated. RESULTS: Eighty eight of the one hundred and thirty six patients sampled were female (65%). Thirty-six per cent of the sample was within the screening target age-group (55 74), with mean age 53 years (+/-18). Most respondents recognised bleeding per rectum as a possible symptom of colorectal cancer. A significant proportion, however, incorrectly selected less sinister symptoms as concerning, while only fifty per cent correctly cited weight loss. Family history was acknowledged as a risk factor by fifty-seven per cent with age and gender cited less often (29%, 4%), while forty-seven per cent incorrectly cited stress as a risk. Screening was defined as testing of symptomatic patients or those with a positive family history by eighty-one per cent of respondents, with only nineteen per cent associating screening with an asymptomatic cohort. Strikingly, twenty-five per cent of patients would decline screening. CONCLUSIONS: There remains poverty of awareness regarding colorectal cancer. More public health initiatives are required to help improve understanding of the disease process, and to improve public compliance with the screening initiative. PMID- 23799888 TI - Surgical embolus excision in retinal artery occlusion - two case reports. PMID- 23799889 TI - Polyol-mediated synthesis of mesoporous alpha-Ni(OH)2 with enhanced supercapacitance. AB - Flower-like alpha-Ni(OH)2 microspheres composed of nanowires are prepared by a solvothermal method using triethylene glycol and water as the mixed solvent. The formation of this unique structure is attributed to the synergetic effect of dissolution-recrystallization procedure, Ostwald ripening, and aggregative lateral attachment. Experimental results indicate that the dielectric constant, viscosity, and the chain lengths of the alcohols in the solvent may greatly affect the morphology and size of the as-obtained alpha-Ni(OH)2 samples. Because of the high Brunauer, Emmett, and Teller (BET) nitrogen sorption surface area of 318 m(2) g(-1) and large pore volume, this sample displays a maximum discharge specific capacity of 1788.9 F g(-1) at a discharge current density of 0.5 A g( 1). Besides, rate performance of this sample is also excellent, indicating that this sample is promising in electrochemical supercapacitors. PMID- 23799890 TI - Increased frequency of circulating IL-21 producing Th-cells in patients with granulomatosis with polyangiitis (GPA). AB - INTRODUCTION: The present study aimed to explore a possible role for IL-21 producing Th-cells in the immunopathogenesis of granulomatosis with polyangiitis (GPA). METHODS: Peripheral blood from 42 GPA patients in remission and 29 age matched healthy controls (HCs) were stimulated in vitro, and the frequencies of IL-21 producing Th-cells were determined by flow cytometry. Since Th17-cells produce a low level of IL-21, IL-17 was also included in the analysis. Given that IL-21 is a hallmark cytokine for T follicular helper cells (T(FH)), we next evaluated the expression of their key transcription factor BCL-6 by RT-PCR and flow cytometry. To investigate the effect of IL-21 on autoantibody-production, PBMCs from GPA patients were stimulated in vitro with BAFF/IL-21 and total IgG and ANCA levels were measured in supernatants. In addition, the expression of IL 21-receptor on B-cells was analyzed. RESULTS: Percentages of IL-21 producing Th cells were significantly elevated in GPA-patients compared to HCs, and were restricted to ANCA-positive patients. The expression of BCL-6 was significantly higher in ANCA-positive GPA-patients, as compared with ANCA-negative patients and HCs. IL-21 enhanced the production of IgG and ANCA in vitro in stimulated PBMCs from GPA patients. No difference was found in the expression of the IL-21 receptor on B-cells between ANCA-negative patients, ANCA-positive patients, and HCs. CONCLUSION: The increased frequency of circulating IL-21 producing Th-cells in ANCA-positive GPA patients and the stimulating capacity of IL-21 on ANCA production suggest a role for these cells in the immunopathogenesis of GPA. Blockade of IL-21 could constitute a new therapeutic strategy for GPA. PMID- 23799891 TI - Prospective study of prevalence of overactive bladder symptoms and child-bearing in women of reproductive age. AB - AIM: The aim of the study was to verify the presence of overactive bladder syndrome (OAB) symptoms in premenopausal women and relate them with child-bearing data. MATERIAL AND METHODS: We interviewed 1050 women aged 20-45 years in the area of Campinas, Brazil, to investigate the prevalence of OAB symptoms. In this study we used the International Consultation on Incontinence Questionnaire - Overactive Bladder (ICIQ-OAB) questionnaire (International Continence Society standard), in its validated Portuguese version and a specific questionnaire for the demographics. RESULTS: Overall, multiparous and primiparous women showed significantly higher scores in the ICIQ-OAB questionnaire than nulliparous women. Multiparous women also presented more frequency than nulliparous women (P < 0.0001). Nulliparous women presented less nocturia than primiparous or multiparous women (P < 0.0001). No significant differences were found in urgency (P = 0.0682), and multiparous women presented more urgency incontinence than nulliparous ones (P = 0.0313). CONCLUSIONS: Nulliparous women presented fewer OAB symptoms than primiparous women. Multiparous women presented more symptoms than the other two groups. There were no significant differences between cesarean and vaginal delivery, but the scores of women who had vaginal delivery were higher than those who had cesareans. Both types of delivery were related to higher ICIQ OAB scores (more severe symptoms) than those of nulliparous women. PMID- 23799892 TI - Voluntary exercise protects against methamphetamine-induced oxidative stress in brain microvasculature and disruption of the blood-brain barrier. AB - BACKGROUND: There is no effective therapeutic intervention developed targeting cerebrovascular toxicity of drugs of abuse, including methamphetamine (METH). We hypothesize that exercise protects against METH-induced disruption of the blood brain barrier (BBB) by enhancing the antioxidant capacity of cerebral microvessels and modulating caveolae-associated signaling. Mice were subjected to voluntary wheel running for 5 weeks resembling the voluntary pattern of human exercise, followed by injection with METH (10 mg/kg). The frequency, duration, and intensity of each running session were monitored for each mouse via a direct data link to a computer and the running data are analyzed by Clock labTM Analysis software. Controls included mice sedentary that did not have access to running wheels and/or injections with saline. RESULTS: METH induced oxidative stress in brain microvessels, resulting in up regulation of caveolae-associated NAD(P)H oxidase subunits, and phosphorylation of mitochondrial protein 66Shc. Treatment with METH disrupted also the expression and colocalization of tight junction proteins. Importantly, exercise markedly attenuated these effects and protected against METH-induced disruption of the BBB integrity. CONCLUSIONS: The obtained results indicate that exercise is an important modifiable behavioral factor that can protect against METH-induced cerebrovascular toxicity. These findings may provide new strategies in preventing the toxicity of drug of abuse. PMID- 23799893 TI - Long-term treatment of somatostatin analog-refractory growth hormone-secreting pituitary tumors with pegvisomant alone or combined with long-acting somatostatin analogs: a retrospective analysis of clinical practice and outcomes. AB - BACKGROUND: Pegvisomant (PEGV) is widely used, alone or with somatostatin analogs (SSA), for GH-secreting pituitary tumors poorly controlled by SSAs alone. No information is available on specific indications for or relative efficacies of PEGV+SSA versus PEGV monotherapy. Aim of our study was to characterize real-life clinical use of PEGV vs. PEGV+SSA for SSA-resistant acromegaly (patient selection, long-term outcomes, adverse event rates, doses required to achieve control). METHODS: A retrospective analysis of data collected in 2005-2010 in five hospital-based endocrinology centers in Rome was performed. Sixty-two adult acromegaly patients treated >=6 months with PEGV (Group 1, n=35) or PEGV+SSA (Group 2, n=27) after unsuccessful maximal-dose SSA monotherapy (>=12 months) were enroled. Groups were compared in terms of clinical/biochemical characteristics at diagnosis and before PEGV or PEGV+SSA was started (baseline) and end-of-follow-up outcomes (IGF-I levels, adverse event rates, final PEGV doses). RESULTS: Group 2 showed higher IGF-I and GH levels and sleep apnea rates, higher rates residual tumor tissue at baseline, more substantial responses to SSA monotherapy and worse outcomes (IGF-I normalization rates, final IGF-I levels). Tumor growth and hepatotoxicity events were rare in both groups. Final daily PEGV doses were similar and significantly increased with treatment duration in both groups. CONCLUSIONS: PEGV and PEGV+SSA are safe, effective solutions for managing SSA-refractory acromegaly. PEGV+SSA tends to be used for more aggressive disease associated with detectable tumor tissue. With both regimens, ongoing monitoring of responses is important since PEGV doses needed to maintain IGF-I control are likely to increase over time. PMID- 23799894 TI - Correctional nursing: a study protocol to develop an educational intervention to optimize nursing practice in a unique context. AB - BACKGROUND: Nurses are the primary healthcare providers in correctional facilities. A solid knowledge and expertise that includes the use of research evidence in clinical decision making is needed to optimize nursing practice and promote positive health outcomes within these settings. The institutional emphasis on custodial care within a heavily secured, regulated, and punitive environment presents unique contextual challenges for nursing practice. Subsequently, correctional nurses are not always able to obtain training or ongoing education that is required for broad scopes of practice. The purpose of the proposed study is to develop an educational intervention for correctional nurses to support the provision of evidence-informed care. METHODS: A two-phase mixed methods research design will be used. The setting will be three provincial correctional facilities. Phase one will focus on identifying nurses' scope of practice and practice needs, describing work environment characteristics that support evidence-informed practice and developing the intervention. Semi structured interviews will be completed with nurses and nurse managers. To facilitate priorities for the intervention, a Delphi process will be used to rank the learning needs identified by participants. Based on findings, an online intervention will be developed. Phase two will involve evaluating the acceptability and feasibility of the intervention to inform a future experimental design. DISCUSSION: The context of provincial correctional facilities presents unique challenges for nurses' provision of care. This study will generate information to address practice and learning needs specific to correctional nurses. Interventions tailored to barriers and supports within specific contexts are important to enable nurses to provide evidence-informed care. PMID- 23799895 TI - Peripartum anesthetic management of renal transplant patients--a multicenter cohort study. AB - As the number and success of renal transplantation has grown, there has been an increase in the number of renal transplant patients giving birth. To date, there has been no data on obstetric anesthesia management of these patients. The purpose of this study was to build an Israeli national database on parturients after renal transplant. A sixteen-year (calendar years 1996-2011) retrospective study was conducted at three major tertiary centers with a combined current birth rate of approximately 25,000 deliveries annually. We found 83 labors in 64 women. Forty-two percent of this population suffered from hypertension while 12.5% had diabetes. Forty-seven percent of women had a vaginal delivery while 53% of women had a cesarean section. The rate of epidural analgesia for labor was 59%, and rate of regional anesthesia during cesarean section was 75%. There were no anesthetic complications in any cases. Standard ASA monitoring was used in all cases except for one woman with severe hypertension who required an arterial line during her cesarean section. Forty-seven percent of newborn were under 37 weeks with average gestational week 36 +/- 3 days and birth weight 2.5 +/- 0.7 kg. Average Apgar was 8.4 +/- 1.3 at one minute and 9.3 +/- 0.7 at five minutes. There was one neonatal death in the CS group due to placental abruption. Patients after renal transplant can safely undergo birth and obstetric analgesia. PMID- 23799897 TI - A facile approach to a silver conductive ink with high performance for macroelectronics. AB - An unusual kind of transparent and high-efficiency organic silver conductive ink (OSC ink) was synthesized with silver acetate as silver carrier, ethanolamine as additive, and different kinds of aldehyde-based materials as reduction agents and was characterized by using a thermogravimetric analyzer, X-ray diffraction, a scanning electron microscope, and a four-point probe. The results show that different reduction agents all have an important influence on the conductive properties of the ink through a series of complex chemical reactions, and especially when formic acid or dimethylformamide was used as the reduction agent and sintered at 120 degrees C for 30 s, the resistivity can be lowered to 6 to 9 MUOmega.cm. Furthermore, formula mechanism, conductive properties, temperature, and dynamic fatigue properties were investigated systematically, and the feasibility of the OSC ink was also verified through the preparation of an antenna pattern. PMID- 23799896 TI - Intraclonal genome diversity of Pseudomonas aeruginosa clones CHA and TB. AB - BACKGROUND: Adaptation of Pseudomonas aeruginosa to different living conditions is accompanied by microevolution resulting in genomic diversity between strains of the same clonal lineage. In order to detect the impact of colonized habitats on P. aeruginosa microevolution we determined the genomic diversity between the highly virulent cystic fibrosis (CF) isolate CHA and two temporally and geographically unrelated clonal variants. The outcome was compared with the intraclonal genome diversity between three more closely related isolates of another clonal complex. RESULTS: The three clone CHA isolates differed in their core genome in several dozen strain specific nucleotide exchanges and small deletions from each other. Loss of function mutations and non-conservative amino acid replacements affected several habitat- and lifestyle-associated traits, for example, the key regulator GacS of the switch between acute and chronic disease phenotypes was disrupted in strain CHA. Intraclonal genome diversity manifested in an individual composition of the respective accessory genome whereby the highest number of accessory DNA elements was observed for isolate PT22 from a polluted aquatic habitat. Little intraclonal diversity was observed between three spatiotemporally related outbreak isolates of clone TB. Although phenotypically different, only a few individual SNPs and deletions were detected in the clone TB isolates. Their accessory genome mainly differed in prophage-like DNA elements taken up by one of the strains. CONCLUSIONS: The higher geographical and temporal distance of the clone CHA isolates was associated with an increased intraclonal genome diversity compared to the more closely related clone TB isolates derived from a common source demonstrating the impact of habitat adaptation on the microevolution of P. aeruginosa. However, even short-term habitat differentiation can cause major phenotypic diversification driven by single genomic variation events and uptake of phage DNA. PMID- 23799898 TI - Tolerance to alternative cyclooxygenase-2 inhibitors in nonsteroidal anti inflammatory drug hypersensitive patients. AB - BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) frequently cause adverse drug reactions. Many studies have shown that drugs which selectively inhibit the cyclooxygenase-2 enzyme (COX-2) are safe alternatives in the majority of patients. However, hypersensitivity reactions to COX-2 inhibitors have been published. Hardly any data are available regarding the safety of alternatives in case of COX-2 inhibitor hypersensitivity. We aimed to investigate the tolerance to COX-2 inhibitors in patients with non-selective NSAID hypersensitivity. Furthermore, in COX-2 hypersensitive patients tolerance of a second COX-2 inhibitor was investigated. METHODS: We retrospectively analyzed 91 patients with proven non-selective NSAID hypersensitivity that underwent oral challenges with a COX-2 inhibitor. Patients with intolerance to the first challenged COX-2 inhibitor received a second challenge with a different COX-2 inhibitor. RESULTS: 19 out of 91 (21%) patients had a positive reaction to the first oral challenge with a COX-2 inhibitor. 14 of them underwent a second challenge with a different COX-2 inhibitor and 12 (86%) did not react. CONCLUSIONS: A relatively high percentage (21%) of the non-selective NSAID hypersensitive patients did not tolerate a COX-2 inhibitor and oral challenge is advised prior to prescription of a COX-2 inhibitor. For the majority of patients reacting to a COX-2 inhibitor an alternative can be found. PMID- 23799900 TI - The attachment system and physiology in adulthood: normative processes, individual differences, and implications for health. AB - Attachment theory provides a conceptual framework for understanding intersections between personality and close relationships in adulthood. Moreover, attachment has implications for stress-related physiology and physical health. We review work on normative processes and individual differences in the attachment behavioral system, as well as their associations with biological mechanisms related to health outcomes. We highlight the need for more basic research on normative processes and physiology and discuss our own research on individual differences in attachment and links with physiology. We then describe a novel perspective on attachment and physiology, wherein stress-related physiological changes may also be viewed as supporting the social-cognitive and emotion regulatory functions of the attachment system through providing additional energy to the brain, which has implications for eating behavior and health. We close by discussing our work on individual differences in attachment and restorative processes, including sleep and skin repair, and by stressing the importance of developing biologically plausible models for describing how attachment may impact chronic illness. PMID- 23799899 TI - Impact of HDL genetic risk scores on coronary artery calcified plaque and mortality in individuals with type 2 diabetes from the Diabetes Heart Study. AB - BACKGROUND: Patients with type 2 diabetes (T2D) are at elevated risk for cardiovascular disease (CVD) events and mortality. Recent studies have assessed the impact of genetic variants affecting high-density lipoprotein cholesterol (HDL) concentrations on CVD risk in the general population. This study examined the utility of HDL-associated single nucleotide polymorphisms (SNPs) for CVD risk prediction in European Americans with T2D enrolled in the Diabetes Heart Study (DHS). METHODS: Genetic risk scores (GRS) of HDL-associated SNPs were constructed and evaluated for potential associations with mortality and with coronary artery calcified atherosclerotic plaque (CAC), a measure of subclinical CVD strongly associated with CVD events and mortality. Two sets of SNPs were used to construct GRS; while all SNPs were selected primarily for their impacts on HDL, one set of SNPs had pleiotropic effects on other lipid parameters, while the other set lacked effects on low-density lipoprotein cholesterol (LDL) or triglyceride concentrations. RESULTS: The GRS were specifically associated with HDL concentrations (4.90 * 10(-7) < p < 0.02) in models adjusted for age, sex, and body mass index (BMI), but were not associated with LDL or triglycerides. Cox proportional hazards regression analysis suggested the HDL-associated GRS had no impact on risk of CVD-mortality (0.48 < p < 0.99) in models adjusted for other known CVD risk factors. However, associations between several of the GRS and CAC were observed (3.85 * 10(-4) < p < 0.03) in models adjusted for other known CVD risk factors. CONCLUSIONS: The GRS analyzed in this study provide a tool for assessment of HDL-associated SNPs and their impact on CVD risk in T2D. The observed associations between several of the GRS and CAC suggest a potential role for HDL-associated SNPs on subclinical CVD risk in patients with T2D. PMID- 23799901 TI - Targeted delivery of siRNA against hepatitis B virus by preS1 peptide molecular ligand. AB - AIM: For chronic hepatitis B virus (HBV) infection, the effects of current therapies are limited. RNA interference of virus-specific genes has emerged as a potential antiviral mechanism. However, a suitable delivery vector is still to be developed. We studied a novel vector transferring siRNA targeting hepatic cells in vivo and in vitro in order to find a new way to cure HBV-related live diseases. METHODS: The preS1-9Arg ligand was used to deliver siRNA to HepG2 and to HepG2 2.2.15 cells. To validate the antiviral efficacy in vivo, a HBV viremic animal model was established by s.c. inoculation of HepG2 2.2.15 tumor cells in nude mice. The minimal retardation effect on the migration of siRNA was detected by gel electrophoresis to confirm the combination and the optimal ratio. Hepatitis B surface antigen (HBsAg) levels were detected by semiquantitatively enzyme-linked immunosorbent assay RNA levels were quantified with quantitative real-time polymerase chain reaction and protein levels were determined with immunoblots and immunohistochemistry. RESULTS: PreS1-9Arg peptide strongly combined and transferred siRNA into HepG2 cells. PreS1-9Arg-siRNA molecular conjugate effectively reduced the production of HBsAg and HBV DNA without liver toxicity in vitro and in vivo. CONCLUSION: The results indicated that preS1-9Arg may be a potential novel vector to deliver siRNA targeting liver cells. PMID- 23799903 TI - Outcomes of buttonhole and rope-ladder cannulation techniques in a tropical renal service. AB - BACKGROUND: Buttonhole cannulation was introduced into this Queensland Renal Service in 2005. Contrary to published literature, a local review of cannulation outcomes found no greater likelihood of infections with the buttonhole technique. OBJECTIVES: To compare the outcomes of buttonhole and rope-ladder cannulation techniques. DESIGN: Prospective cohort. PARTICIPANTS: Consenting patients attending for haemodialysis via an existing arteriovenous fistula (n = 104). MEASUREMENTS: Cannulation sites were assessed at every dialysis session for 12 weeks; fear and pain were scored by participants weekly. RESULTS: No statistically significant differences in infection, haematoma formation, pain or fear between the techniques. Occurrence of aneurysm was higher (p < 0.05) in the rope-ladder group. More patients in buttonhole group required multiple cannulation attempts (p < 0.05). More of the rope-ladder group failed to attend their scheduled dialysis sessions (p < 0.05). CONCLUSIONS AND APPLICATIONS TO PRACTICE: This study confirms that in this setting there are few negative outcomes of either technique of fistula cannulation. Specifically, buttonhole cannulation appears to be a safe alternative means of fistula access to the gold standard cannulation technique. The Service is examining strategies to improve attendance. PMID- 23799902 TI - Benzodiazepine-site pharmacology on GABAA receptors in histaminergic neurons. AB - BACKGROUND AND PURPOSE: The histaminergic tuberomamillary nucleus (TMN) of the posterior hypothalamus controls the cognitive aspects of vigilance which is reduced by common sedatives and anxiolytics. The receptors targeted by these drugs in histaminergic neurons are unknown. TMN neurons express nine different subunits of the GABAA receptor (GABAA R) with three alpha- (alpha1, alpha2 and alpha5) and two gamma- (gamma1, gamma 2) subunits, which confer different pharmacologies of the benzodiazepine-binding site. EXPERIMENTAL APPROACH: We investigated the actions of zolpidem, midazolam, diazepam, chlordiazepoxide, flumazenil (Ro15-1788) and methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3 carboxylate (DMCM) in TMN neurons using mouse genetics, electrophysiological and molecular biological methods. KEY RESULTS: We find the sensitivity of GABAA R to zolpidem, midazolam and DMCM significantly reduced in TMN neurons from gamma2F77I mice, but modulatory activities of diazepam, chlordiazepoxide and flumazenil not affected. Potencies and efficacies of these compounds are in line with the dominance of alpha2- and alpha1-subunit containing receptors associated with gamma2- or gamma1-subunits. Functional expression of the gamma1-subunit is supported by siRNA-based knock-down experiments in gamma2F77I mice. CONCLUSIONS AND IMPLICATIONS: GABAA R of TMN neurons respond to a variety of common sedatives with a high affinity binding site (gamma2F77I) involved. The gamma1-subunit likely contributes to the action of common sedatives in TMN neurons. This study is relevant for understanding the role of neuronal histamine and benzodiazepines in disorders of sleep and metabolism. PMID- 23799904 TI - Methylome reorganization during in vitro dedifferentiation and regeneration of Populus trichocarpa. AB - BACKGROUND: Cytosine DNA methylation (5mC) is an epigenetic modification that is important to genome stability and regulation of gene expression. Perturbations of 5mC have been implicated as a cause of phenotypic variation among plants regenerated through in vitro culture systems. However, the pattern of change in 5mC and its functional role with respect to gene expression, are poorly understood at the genome scale. A fuller understanding of how 5mC changes during in vitro manipulation may aid the development of methods for reducing or amplifying the mutagenic and epigenetic effects of in vitro culture and plant transformation. RESULTS: We investigated the in vitro methylome of the model tree species Populus trichocarpa in a system that mimics routine methods for regeneration and plant transformation in the genus Populus (poplar). Using methylated DNA immunoprecipitation followed by high-throughput sequencing (MeDIP seq), we compared the methylomes of internode stem segments from micropropagated explants, dedifferentiated calli, and internodes from regenerated plants. We found that more than half (56%) of the methylated portion of the genome appeared to be differentially methylated among the three tissue types. Surprisingly, gene promoter methylation varied little among tissues, however, the percentage of body methylated genes increased from 9% to 14% between explants and callus tissue, then decreased to 8% in regenerated internodes. Forty-five percent of differentially-methylated genes underwent transient methylation, becoming methylated in calli, and demethylated in regenerants. These genes were more frequent in chromosomal regions with higher gene density. Comparisons with an expression microarray dataset showed that genes methylated at both promoters and gene bodies had lower expression than genes that were unmethylated or only promoter-methylated in all three tissues. Four types of abundant transposable elements showed their highest levels of 5mC in regenerated internodes. CONCLUSIONS: DNA methylation varies in a highly gene- and chromosome-differential manner during in vitro differentiation and regeneration. 5mC in redifferentiated tissues was not reset to that in original explants during the study period. Hypermethylation of gene bodies in dedifferentiated cells did not interfere with transcription, and may serve a protective role against activation of abundant transposable elements. PMID- 23799905 TI - Survival benefit of helicopter emergency medical services compared to ground emergency medical services in traumatized patients. AB - INTRODUCTION: Physician-staffed helicopter emergency medical services (HEMS) are a well-established component of prehospital trauma care in Germany. Reduced rescue times and increased catchment area represent presumable specific advantages of HEMS. In contrast, the availability of HEMS is connected to a high financial burden and depends on the weather, day time and controlled visual flight rules. To date, clear evidence regarding the beneficial effects of HEMS in terms of improved clinical outcome has remained elusive. METHODS: Traumatized patients (Injury Severity Score; ISS>=9) primarily treated by HEMS or ground emergency medical services (GEMS) between 2007 and 2009 were analyzed using the TraumaRegister DGU(r) of the German Society for Trauma Surgery. Only patients treated in German level I and II trauma centers with complete data referring to the transportation mode were included. Complications during hospital treatment included sepsis and organ failure according to the criteria of the American College of Chest Physicians/Society of Critical Care Medicine (ACCP/SCCM) consensus conference committee and the Sequential Organ Failure Assessment (SOFA) score. RESULTS: A total of 13,220 patients with traumatic injuries were included in the present study. Of these, 62.3% (n=8,231) were transported by GEMS and 37.7% (n=4,989) by HEMS. Patients treated by HEMS were more seriously injured compared to GEMS (ISS 26.0 vs. 23.7, P<0.001) with more severe chest and abdominal injuries. The extent of medical treatment on-scene, which involved intubation, chest and treatment with vasopressors, was more extensive in HEMS (P<0.001) resulting in prolonged on-scene time (39.5 vs. 28.9 minutes, P<0.001). During their clinical course, HEMS patients more frequently developed multiple organ dysfunction syndrome (MODS) (HEMS: 33.4% vs. GEMS: 25.0%; P<0.001) and sepsis (HEMS: 8.9% vs. GEMS: 6.6%, P<0.001) resulting in an increased length of ICU treatment and in-hospital time (P<0.001). Multivariate logistic regression analysis found that after adjustment by 11 other variables the odds ratio for mortality in HEMS was 0.75 (95% CI: 0.636 to 862). CONCLUSIONS: Although HEMS patients were more seriously injured and had a significantly higher incidence of MODS and sepsis, these patients demonstrated a survival benefit compared to GEMS. PMID- 23799907 TI - Inherited KIF21A and PAX6 gene mutations in a boy with congenital fibrosis of extraocular muscles and aniridia. AB - BACKGROUND: Mutations in the KIF21A gene are detected in the patients with congenital fibrosis of the extraocular muscles. Mutations in the PAX6 gene are detected in the patients with congenital aniridia. CASE PRESENTATION: Herein we report a boy with both congenital fibrosis of extraocular muscles and aniridia. Sequence analysis of his KIF21A and PAX6 genes reveals a 1-bp deletion (c.745delC) in the PAX6 gene and a missense mutation of c.2860C > T (p.Arg954Trp) in KIF21A. CONCLUSIONS: This study demonstrates that the occurrence of independent mutations in more than a single gene in a patient may lead to a complex phenotype. PMID- 23799906 TI - An ethnographic exploration of influences on prescribing in general practice: why is there variation in prescribing practices? AB - BACKGROUND: Prescribing is a core activity for general practitioners, yet significant variation in the quality of prescribing has been reported. This suggests there may be room for improvement in the application of the current best research evidence. There has been substantial investment in technologies and interventions to address this issue, but effect sizes so far have been small to moderate. This suggests that prescribing is a decision-making process that is not sufficiently understood. By understanding more about prescribing processes and the implementation of research evidence, variation may more easily be understood and more effective interventions proposed. METHODS: An ethnographic study in three Scottish general practices with diverse organizational characteristics. Practices were ranked by their performance against Audit Scotland prescribing quality indicators, incorporating established best research evidence. Two practices of high prescribing quality and one practice of low prescribing quality were recruited. Participant observation, formal and informal interviews, and a review of practice documentation were employed. RESULTS: Practices ranked as high prescribing quality consistently made and applied macro and micro prescribing decisions, whereas the low-ranking practice only made micro prescribing decisions. Macro prescribing decisions were collective, policy decisions made considering research evidence in light of the average patient, one disease, condition, or drug. Micro prescribing decisions were made in consultation with the patient considering their views, preferences, circumstances and other conditions (if necessary).Although micro prescribing can operate independently, the implementation of evidence-based, quality prescribing was attributable to an interdependent relationship. Macro prescribing policy enabled prescribing decisions to be based on scientific evidence and applied consistently where possible. Ultimately, this influenced prescribing decisions that occur at the micro level in consultation with patients. CONCLUSION: General practitioners in the higher prescribing quality practices made two different 'types' of prescribing decision; macro and micro. Macro prescribing informs micro prescribing and without a macro basis to draw upon the low-ranked practice had no effective mechanism to engage with, reflect on and implement relevant evidence. Practices that recognize these two levels of decision making about prescribing are more likely to be able to implement higher quality evidence. PMID- 23799909 TI - There is no relationship between Paraoxonase serum level activity in women with endometriosis and the stage of the disease: an observational study. AB - BACKGROUND: Endometriosis is a chronic condition whose pathophysiology is unknown, but there is evidence suggesting a link with oxidative stress. Paraoxonase is a serum enzyme which circulates associated with high-density lipoprotein (HDL). It acts protecting HDL and LDL of lipid peroxidation. We aimed to compare the serum levels of PON-1 activity in women with endometriosis in different stages of the disease (minimal/mild and moderate/severe). METHODS: 80 infertile women with endometriosis diagnosed by laparoscopy/laparotomy with histologic confirmation of the disease were divided according to the American Society for Reproductive Medicine classification in minimal/mild (n = 33) and moderate/severe (n = 47) cases. Paraoxonase activity and arilesterase activity were measured by spectrophotometry. Body mass index and fasting glucose levels were also determined. RESULTS: The paraoxonase activity were 191.29 +/- 22.41 U/l in women with minimal/mild endometriosis and 224.85 +/- 21.50 U/l in women with moderate/severe disease (P = 0.274). Considering arilesterase level, the results showed 89.82 +/- 4.61 U/l in women with minimal/mild endometriosis and 90.78 +/- 3.43 U/l in moderate/severe disease (P = 0.888). CONCLUSIONS: Evidence of lower paraoxonase activity in women with endometriosis was not found in this study. Besides, no difference was found considering minimal/mild or moderate/severe endometriosis. PMID- 23799908 TI - ULTIMATE-SHF trial (UdenafiL Therapy to Improve symptoMAtology, exercise Tolerance and hEmodynamics in patients with chronic systolic heart failure): study protocol for a randomized, placebo-controlled, double-blind trial. AB - BACKGROUND: Over the last few years, the use of phosphodiesterase type 5 (PDE5) inhibitors has been expanded to management of various cardiovascular disorders beyond pulmonary arterial hypertension. This study is designed to investigate the ability of udenafil, a newly developed long-acting PDE5 inhibitor, to improve functional capacity and hemodynamic status in a cohort of chronic systolic heart failure (SHF) patients. METHODS/DESIGN: Stable, chronic SHF patients will be randomly assigned to placebo (26 patients) or udenafil at a dose of 50 mg twice per day (26 patients) for the first 4 weeks followed by 100 mg twice daily for the next 8 weeks. Eligibility criteria will be age >= 18 years, clinical diagnosis of chronic SHF with current New York Heart Association class II to IV symptoms, left ventricular ejection fraction <= 40%, and experience of at least one of following during the 12 months prior to study entry: hospitalization for decompensated heart failure, acute treatment with intravenous loop diuretics or hemofiltration, or pulmonary artery systolic pressure >= 40 mmHg on transthoracic echocardiography. Pharmacological therapy for SHF will be optimized in all patients at least 30 days before study entry. The primary outcome will be the change of maximal oxygen uptake, assessed by cardiopulmonary exercise testing. Secondary outcomes will include changes in ventilatory efficiency (minute ventilation/carbon dioxide production slope), left ventricular systolic and diastolic parameters, pulmonary artery systolic pressure, plasma concentration of brain natriuretic peptide, occurrence of mortality or hospitalization for heart failure, and the occurrence of any adverse event. CLINICAL TRIAL REGISTRATION: Unique identifier: NCT01646515. PMID- 23799910 TI - Macroglossia as the only presenting feature of amyloidosis due to MGUS. PMID- 23799911 TI - Crowdsourcing the corpasome. AB - The suffix -ome conveys "comprehensiveness" in some way. The idea of the Corpasome started half-jokingly, acknowledging the efforts to sequence five members of my family. After the unexpected response from many scientists from around the world, it has become clear how useful this approach could be for understanding the genomic information contained in our personal genomics tests. PMID- 23799912 TI - Soluble Neural-cadherin as a novel biomarker for malignant bone and soft tissue tumors. AB - BACKGROUND: Neural-cadherin (N-cadherin) is one of the most important molecules involved in tissue morphogenesis, wound healing, and the maintenance of tissue integrity. Recently, the cleavage of N-cadherin has become a focus of attention in the field of cancer biology. Cadherin and their ectodomain proteolytic shedding play important roles during cancer progression. The aims of this study are to investigate the serum soluble N-cadherin (sN-CAD) levels in patients with malignant bone and soft tissue tumors, and to evaluate the prognostic significance of the sN-CAD levels. METHODS: We examined the level of serum sN-CAD using an ELISA in 80 malignant bone and soft tissue tumors (bone sarcoma, n = 23; soft tissue sarcoma, n = 50; metastatic cancer, n = 7) and 87 normal controls. The mean age of the patients was 51 years (range, 10-85 years) and the mean follow-up period was 43 months (range, 1-115 months). RESULTS: The median serum sN-CAD level was 1,267 ng/ml (range, 135-2,860 ng/ml) in all patients. The mean serum sN-CAD level was 1,269 ng/ml (range, 360-2,860 ng/ml) in sarcoma patients, otherwise 1,246 ng/ml (range, 135-2,140 ng/ml) in cancer patients. The sN-CAD levels in patient were higher than those found in the controls, who had a median serum level of 108 ng/ml (range, 0-540 ng/ml). The patients with tumors larger than 5 cm had higher serum sN-CAD levels than the patients with tumors smaller than 5 cm. The histological grade in the patients with higher serum sN-CAD levels was higher than that in the patients with lower serum sN-CAD levels. A univariate analysis demonstrated that the patients with higher serum sN-CAD levels showed a worse disease-free survival rate, local recurrence-free survival rate, metastasis free survival rate, and overall survival rate compared to those with lower serum sN-CAD levels. In the multivariate analysis, sN-CAD was an independent factor predicting disease-free survival. CONCLUSIONS: sN-CAD is a biomarker for malignant bone and soft tissue tumors, and a potentially valuable pre-therapeutic prognostic factor in patients with bone and soft tissue sarcoma. PMID- 23799913 TI - Estimation of the effect of dalfampridine-ER on health utility by mapping the MSWS-12 to the EQ-5D in multiple sclerosis patients. AB - BACKGROUND: Trials have not assessed the effect of dalfampridine-extended release (dalfampridine-ER) on health utility. We sought to evaluate the effect of dalfampridine-ER tablets (prolonged-release fampridine in Europe) on health utility in patients with multiple sclerosis (MS) by mapping subjects' individual item scores from the 12-Item Multiple Sclerosis Walking Scale (MSWS-12) onto the Euroqol 5-Dimension (EQ-5D) health utility index. METHODS: Data from study MS F203, a randomized trial of dalfampridine-ER tablets, 10 mg twice daily, in patients with MS, were used to calculate the health utility scores with two MSWS 12 to EQ-5D mapping equations (one derived in a North American [NA] registry, the other a United Kingdom [UK] registry). MS-F203 participants were categorized as dalfampridine-ER 20%-responders (achieving >=20% improvement on the Timed 25-Foot Walk), dalfampridine-ER 20%-nonresponders (<20% improvement), or placebo patients. Mean change in health utility scores from baseline to each double-blind treatment evaluation (visits 3-6 occurring at post-randomization weeks 2, 6, 10, and 14) and each off-drug follow-up evaluation (visits 7-8 occurring at weeks 16 and 18) were calculated and reported as effect sizes (ESs). RESULTS: Using the NA derived equation, dalfampridine-ER 20%-responders demonstrated improvement in health utility vs. placebo; starting at week 6 (mean difference in ES = 0.44, p = 0.002) and maintained at weeks 10 (ES = 0.41, p = 0.01) and 14 (ES = 0.71, p < 0.001). These improvements were no longer evident after dalfampridine-ER was discontinued (p > 0.05 at weeks 16 and 18). Dalfampridine-ER 20%-nonresponders did not show improvement vs. placebo at any visit (p > 0.05 for all). When using the UK-derived equation, improvement was seen in dalfampridine-ER 20%-responders vs. placebo at weeks 2, 6, 10, and 14 (ESs = 0.49, 0.55, 0.59, and 0.99; p < 0.03 for all), but not when dalfampridine-ER was discontinued (weeks 16 and 18; p > 0.05 for both). Dalfampridine-ER 20%-nonresponders showed no improvement at any visit (p > 0.05 for all). CONCLUSION: Regardless of the equation used, dalfampridine-ER response was associated with an improvement in health utility. PMID- 23799914 TI - Sulforaphane induced cell cycle arrest in the G2/M phase via the blockade of cyclin B1/CDC2 in human ovarian cancer cells. AB - BACKGROUND: Malignant tumors are the single most common cause of death and the mortality rate of ovarian cancer is the highest among gynecological disorders. The excision of benign tumors is generally followed by complete recovery; however, the activity of cancer cells often results in rapid proliferation even after the tumor has been excised completely. Thus, clinical treatment must be supplemented by auxiliary chemotherapy or radiotherapy. Sulforaphane (SFN) is an extract from the mustard family recognized for its anti-oxidation abilities, phase 2 enzyme induction, and anti-tumor activity. METHODS: This study investigated the cell cycle arrest in G2/M by SFN and the expression of cyclin B1, Cdc2, and the cyclin B1/CDC2 complex in PA-1 cells using western blotting and co-IP western blotting. RESULTS: This study investigated the anticancer effects of dietary isothiocyanate SFN on ovarian cancer, using cancer cells line PA-1. SFN-treated cells accumulated in metaphase by CDC2 down-regulation and dissociation of the cyclin B1/CDC2 complex. CONCLUSION: Our findings suggest that, in addition to the known effects on cancer prevention, SFN may also provide antitumor activity in established ovarian cancer. PMID- 23799915 TI - Ventral root re-implantation is better than peripheral nerve transplantation for motoneuron survival and regeneration after spinal root avulsion injury. AB - BACKGROUND: Peripheral nerve (PN) transplantation and ventral root implantation are the two common types of recovery operations to restore the connection between motoneurons and their target muscles after brachial plexus injury. Despite experience accumulated over the past decade, fundamental knowledge is still lacking concerning the efficacy of the two microsurgical interventions. METHODS: Thirty-eight adult female Sprague-Dawley rats were divided into 5 groups. Immediately following root avulsion, animals in the first group (n = 8) and the second group (n = 8) received PN graft and ventral root implantation respectively. The third group (n = 8) and the fourth group (n = 8) received PN graft and ventral root implantation respectively at one week after root avulsion. The fifth group received root avulsion only as control (n = 6). The survival and axonal regeneration of severed motoneurons were investigated at 6 weeks post implantation. RESULTS: Re-implantation of ventral roots, both immediately after root avulsion and in delay, significantly increased the survival and regeneration of motoneurons in the avulsed segment of the spinal cord as compared with PN graft transplantation. CONCLUSIONS: The ventral root re-implantation is a better surgical repairing procedure than PN graft transplantation for brachial plexus injury because of its easier manipulation for re-implanting avulsed ventral roots to the preferred site, less possibility of causing additional damage and better effects on motoneuron survival and axonal regeneration. PMID- 23799916 TI - Current status of HTLV-1 carrier in Japanese pregnant women. AB - We examined the current status of human T-cell leukemia virus type 1 (HTLV-1) carrier in Japanese pregnant women, according to the results of HTLV-1 screening and confirmation tests of women who gave birth in Japan in 2011. We requested 2642 obstetrical facilities to provide information of HTLV-1 tests and 71.3% of them responded. Considering the response rate and the rate of implementation of confirmation tests, the number of HTLV-1 carrier in Japanese pregnant women was estimated to be 1620 (0.16%) per year. PMID- 23799917 TI - Narcissism and discrepancy between self and friends' perceptions of personality. AB - Most research on narcissism and person perception has used strangers as perceivers. However, research has demonstrated that strangers' ratings are influenced by narcissists' stylish appearance (Back, Schmukle, & Egloff, 2010). In the present study, we recruited participants and their close friends, individuals whose close relationship should immunize them to participants' superficial appearance cues. We investigated the relation between narcissism and personality ratings by self and friends. Participants (N = 66; 38 women; Mage = 20.83 years) completed the Narcissistic Personality Inventory (Raskin & Terry, 1988) and described their personality on the 100-item California Adult Q-Sort (CAQ; Block, 2008). Participants' personality was also described on the CAQ by close friends. The "optimally adjusted individual" prototype was used to summarize participant and friend personality ratings (Block, 2008). Participants with high narcissism scores were ascribed higher optimal adjustment by self than by friends. Narcissistic individuals' self-ratings were extremely positive and more favorable than friends' ratings of them. PMID- 23799918 TI - Implementation and evaluation of a low health literacy and culturally sensitive diabetes education program. AB - Low health literacy is more prevalent in persons with limited education, members of ethnic minorities, and those who speak English as a second language, and is associated with multiple adverse diabetes-related health outcomes. This study examined the effectiveness of a low health literacy and culturally sensitive diabetes education program for economically and socially disadvantaged adult patients with type 2 diabetes. A pre-post prospective study design was used to examine outcomes over 12 months. Outcome measures included diabetes knowledge, self-efficacy, and self-care, measured using reliable and valid survey tools, and A1C. Over this period of time 277 patients were enrolled in the program, with 106 participants completing survey data. At the completion of the program patients had significant improvements in diabetes knowledge (p < .001), self-efficacy (p < .001), and three domains of self-care including diet (p < .001), foot care (p < .001), and exercise (p < .001). There were no significant improvements in the frequency of blood glucose testing (p = .345). Additionally, A1C values significantly improved 3 months after completing the program (p = .007). In conclusion, a diabetes education program designed to be culturally sensitive and meet the needs of individuals with low health literacy improves short-term outcomes. PMID- 23799919 TI - Does postoperative pain predict the outcome of endometrial ablation? AB - AIM: In this article, we hypothesized that significant pain in the immediate postoperative period is due to a deeper degree of thermal ablation, down to the myometrial layer, and consequently an increased likelihood of successful outcome. MATERIAL AND METHODS: We retrospectively reviewed the medical records of 87 subjects who underwent thermal balloon endometrial ablation as the sole procedure under general anesthesia, administered by the same anesthetist using a standard protocol over a 10-year period from 2000 to 2010 at Thornbury Hospital, Sheffield, UK. All the cases were performed by the same surgeon in one hospital. RESULTS: Twenty-eight (32.2%) subjects experienced severe or intractable pain within 1 h after the thermal balloon endometrial ablation procedure, while 26 (29.9%) subjects required morphine injection in the postoperative period. Overall, more than 70% of women experienced significant reduction in their menstrual flow. There was no difference in the clinical outcome between those who did or did not experience severe pain or between those who did or did not require morphine injection in the postoperative period. CONCLUSION: The amount of postoperative pain did not predict the outcome of thermal balloon endometrial ablation. PMID- 23799920 TI - Relationship between serum uric acid levels and metabolic syndrome in Chinese postmenopausal women. AB - OBJECTIVE: Serum uric acid levels have been reported to be associated with metabolic syndrome (MetS). However, few studies specifically examining the relationship between serum uric acid (SUA) levels and MetS in postmenopausal women have been reported in China. Thus, we conducted this study in order to assess the relationship between SUA levels and MetS in Chinese postmenopausal women. METHODS: A cross-sectional study of 1022 Chinese postmenopausal women (aged 42-80 years) who participated in annual health check-ups was employed. MetS was defined by National Cholesterol Education Program/Adult Treatment Panel III criteria (NCEP-ATP III). Of all the participants, 385 women were diagnosed with MetS (MetS group) and the others were without MetS (non-MetS group). SUA quartiles were defined as follows: Q1, < 3.9 mg/dl; Q2, 3.9-4.5 mg/dl; Q3, 4.6 5.1 mg/dl; Q4, 5.2-6.0 mg/dl. The association between SUA quartiles and MetS was assessed using binary logistic regression. RESULTS: The adjusted odds ratio (95% confidence interval) for the presence of metabolic syndrome in the highest SUA quartile vs. the lowest quartile was 3.768 (2.386-5.950) for all women (p < 0.01) after adjusting for age, body mass index, blood urea nitrogen, serum creatinine, total cholesterol, low density lipoprotein cholesterol and C-reactive protein. The presence of MetS significantly increased in the second, third and fourth quartiles of SUA. The prevalence of MetS increased gradually with an increasing serum uric acid quartile (p for trend < 0.001). CONCLUSION: Higher SUA levels are positively and independently associated with the presence of MetS in Chinese postmenopausal women. PMID- 23799921 TI - Safety of intravenous administration of hydrogen-enriched fluid in patients with acute cerebral ischemia: initial clinical studies. AB - BACKGROUND: Most of the results regarding hydrogen (H2) therapy for acute cerebral ischemia are derived from in vitro studies and animal experiments, with only a few obtained from human trials with a limited number of subjects. Thus, there is a paucity of information regarding both the beneficial therapeutic effects as well as the side effects of H2 on acute cerebral ischemia in humans. We designed a pilot study to investigate single dose intravenous H2 administration in combination with edaravone, aiming to provide an initial estimate of the possible risks and benefits in select patients presenting with acute ischemic stroke. METHODS: An open-label, prospective, non-randomized study of intravenous H2-administration was performed in 38 patients hospitalized for acute ischemic stroke. All patients received an H2-enriched intravenous solution in addition to edaravone immediately after the diagnosis of acute ischemic stroke. Acute stroke patients within 3 h of onset received intravenous tissue plasminogen activator (t-PA) (0.6 mg/kg) treatment, and patients receiving t-PA had to commence the administration of the H2-enriched intravenous solution and edaravone before or at the same time as the t-PA was infused. RESULTS: Complications were observed in 2 patients (5.3%), which consisted of diarrhea in 1 patient (2.6%) and cardiac failure in 1 patient (2.6%). No deterioration in laboratory tests, urinary tests, ECG, or chest X-ray radiograms occurred in any patient in this study. In all patients, the mean National Institutes of Health Stroke Scale (NIHSS) scores at baseline, and 7, 30, and 90 d after admission were 8.2 +/- 7.5, 5.6 +/- 7.1, 4.9 +/- 6.5, and 4.5 +/- 6.3, respectively. The early recanalization was identified in 4 of 11 patients (36.4%) who received intravenous t-PA administration. Hemorrhagic transformation was observed in 2 patients (18.2%). None of the patients in this study that were treated with t-PA developed symptomatic intracranial hemorrhage. CONCLUSIONS: Data from the current study indicate that an H2-enriched intravenous solution is safe for patients with acute cerebral infarction, including patients treated with t-PA. PMID- 23799922 TI - Safety and efficacy of different lanreotide doses in the treatment of polycystic liver disease: pooled analysis of individual patient data. AB - BACKGROUND: Long-acting lanreotide (LAN) 120 mg every 4 weeks reduces liver volume (LV) in patients with polycystic liver diseases (PCLD). Animal studies demonstrated that the inhibition of hepatic and renal cystogenesis is dose dependent. AIM: To investigate the safety and efficacy of two different LAN doses in PCLD patients. METHODS: The 6-month results of the LOCKCYST I trial, its extension study and the LOCKCYST II trial were pooled. LV at baseline and month 6 was measured by CT-scan and blindly re-analysed by two independent radiologists. RESULTS: The study population [132 treatment periods, age 49 years (IQR: 45-55), 114 women] consisted of three groups. Each received treatment every 4 weeks during 6 months: placebo (n = 26); LAN 90 mg (n = 55) or LAN 120 mg (n = 51). The inter-observer variability and agreement in the calculation of LV were excellent. Severe side effects occurred with placebo, LAN 90 mg and LAN 120 mg in respectively 0%, 7% and 16%. Change in LV's after 6 months in these three groups were respectively: increase of +36 mL [(-45)-(+138)]; decrease of -82 mL [(-285) (+92)] and decrease of -123 mL [(-312)-(+4)] (Kruskal-Wallis One Way anova on Ranks; P = 0.002). Based on ROC analysis, a reduction of >=120 mL in LV has a positive predictive value of 64% for improving symptoms (ROC analysis AUC: 0.729; sensitivity 73%, specificity 69%, P < 0.0001). CONCLUSIONS: Both LAN 90 mg and LAN 120 mg reduce liver volume. LAN 90 mg has less side effects. This suggests that in case of intolerance to LAN 120 mg, a dose reduction to LAN 90 mg is meaningful. PMID- 23799923 TI - Structural and nanomechanical properties of BiFeO3 thin films deposited by radio frequency magnetron sputtering. AB - The nanomechanical properties of BiFeO3 (BFO) thin films are subjected to nanoindentation evaluation. BFO thin films are grown on the Pt/Ti/SiO2/Si substrates by using radio frequency magnetron sputtering with various deposition temperatures. The structure was analyzed by X-ray diffraction, and the results confirmed the presence of BFO phases. Atomic force microscopy revealed that the average film surface roughness increased with increasing of the deposition temperature. A Berkovich nanoindenter operated with the continuous contact stiffness measurement option indicated that the hardness decreases from 10.6 to 6.8 GPa for films deposited at 350 degrees C and 450 degrees C, respectively. In contrast, Young's modulus for the former is 170.8 GPa as compared to a value of 131.4 GPa for the latter. The relationship between the hardness and film grain size appears to follow closely with the Hall-Petch equation. PMID- 23799925 TI - Improving detection and genetic counseling in carriers of spinal muscular atrophy with two copies of the SMN1 gene. AB - Spinal muscular atrophy (SMA) is an autosomal recessive disease caused by mutations in the survival motor neuron1 gene (SMN1). Global carrier frequency is around 1 in 50 and carrier detection is crucial to define couples at risk to have SMA offspring. Most SMA carriers have one SMN1 copy and are currently detected using quantitative methods. A few, however, have two SMN1 genes in cis (2/0 carriers), complicating carrier diagnosis in SMA. We analyzed our experience in detecting 2/0 carriers from a cohort of 1562 individuals, including SMA parents, SMA relatives, and unrelated individuals of the general population. Interestingly, in three couples who had an SMA child, both the parents had two SMN1 copies. Families of this type have not been previously reported. Our results emphasize the importance of performing a detailed carrier study in SMA parents with two SMN1 copies. Expanding the analysis to other key family members might confirm potential 2/0 carriers. Finally, when a partner of a known carrier presents two SMN1 copies, the study of both parents will provide a more accurate diagnosis, thus optimizing genetic counseling. PMID- 23799924 TI - The complete mitochondrial genomes of two rice planthoppers, Nilaparvata lugens and Laodelphax striatellus: conserved genome rearrangement in Delphacidae and discovery of new characteristics of atp8 and tRNA genes. AB - BACKGROUND: Nilaparvata lugens (the brown planthopper, BPH) and Laodelphax striatellus (the small brown planthopper, SBPH) are two of the most important pests of rice. Up to now, there was only one mitochondrial genome of rice planthopper has been sequenced and very few dependable information of mitochondria could be used for research on population genetics, phylogeographics and phylogenetic evolution of these pests. To get more valuable information from the mitochondria, we sequenced the complete mitochondrial genomes of BPH and SBPH. These two planthoppers were infected with two different functional Wolbachia (intracellular endosymbiont) strains (wLug and wStri). Since both mitochondria and Wolbachia are transmitted by cytoplasmic inheritance and it was difficult to separate them when purified the Wolbachia particles, concomitantly sequencing the genome of Wolbachia using next generation sequencing method, we also got nearly complete mitochondrial genome sequences of these two rice planthoppers. After gap closing, we present high quality and reliable complete mitochondrial genomes of these two planthoppers. RESULTS: The mitogenomes of N. lugens (BPH) and L. striatellus (SBPH) are 17, 619 bp and 16, 431 bp long with A + T contents of 76.95% and 77.17%, respectively. Both species have typical circular mitochondrial genomes that encode the complete set of 37 genes which are usually found in metazoans. However, the BPH mitogenome also possesses two additional copies of the trnC gene. In both mitochondrial genomes, the lengths of the atp8 gene were conspicuously shorter than that of all other known insect mitochondrial genomes (99 bp for BPH, 102 bp for SBPH). That two rearrangement regions (trnC-trnW and nad6-trnP-trnT) of mitochondrial genomes differing from other known insect were found in these two distantly related planthoppers revealed that the gene order of mitochondria might be conservative in Delphacidae. The large non-coding fragment (the A+T-rich region) putatively corresponding responsible for the control of replication and transcription of mitochondria contained a variable number of tandem repeats (VNTRs) block in different natural individuals of these two planthoppers. Comparison with a previously sequenced individual of SBPH revealed that the mitochondrial genetic variation within a species exists not only in the sequence and secondary structure of genes, but also in the gene order (the different location of trnH gene). CONCLUSION: The mitochondrial genome arrangement pattern found in planthoppers was involved in rearrangements of both tRNA genes and protein-coding genes (PCGs). Different species from different genera of Delphacidae possessing the same mitochondrial gene rearrangement suggests that gene rearrangements of mitochondrial genome probably occurred before the differentiation of this family. After comparatively analyzing the gene order of different species of Hemiptera, we propose that except for some specific taxonomical group (e.g. the whiteflies) the gene order might have diversified in family level of this order. The VNTRs detected in the control region might provide additional genetic markers for studying population genetics, individual difference and phylogeographics of planthoppers. PMID- 23799926 TI - Cylindrical rotating triboelectric nanogenerator. AB - We demonstrate a cylindrical rotating triboelectric nanogenerator (TENG) based on sliding electrification for harvesting mechanical energy from rotational motion. The rotating TENG is based on a core-shell structure that is made of distinctly different triboelectric materials with alternative strip structures on the surface. The charge transfer is strengthened with the formation of polymer nanoparticles on surfaces. During coaxial rotation, a contact-induced electrification and the relative sliding between the contact surfaces of the core and the shell result in an "in-plane" lateral polarization, which drives the flow of electrons in the external load. A power density of 36.9 W/m(2) (short-circuit current of 90 MUA and open-circuit voltage of 410 V) has been achieved by a rotating TENG with 8 strip units at a linear rotational velocity of 1.33 m/s (a rotation rate of 1000 r/min). The output can be further enhanced by integrating more strip units and/or applying larger linear rotational velocity. This rotating TENG can be used as a direct power source to drive small electronics, such as LED bulbs. This study proves the possibility to harvest mechanical energy by TENGs from rotational motion, demonstrating its potential for harvesting the flow energy of air or water for applications such as self-powered environmental sensors and wildlife tracking devices. PMID- 23799927 TI - Family issues and family functioning of Japanese outpatients with type 2 diabetes: a cross-sectional study. AB - BACKGROUND: Previous studies confirmed that the control of diabetes is related to family functioning, but the validity of the tools used to assess family functioning in these studies is questionable. Few studies have focused on family issues. In this study, we used a new assessment tool to evaluate family functioning and family issues of patients with type 2 diabetes. METHODS: A cross sectional questionnaire was given to outpatients with type 2 diabetes at a community hospital in Aichi, Japan, between August 2001 and March 2002. First, the patients were asked to answer FACESKGIV-16, which measures cohesion and adaptability, questions regarding family issues, daily lifestyle, and HAD. Physical and serological data were measured. Family functioning, family issues, and relationships between each parameter and family functioning or family issues were analyzed. RESULTS: Of the 133 participants, 121 (33.3%) had some sort of family issue. Family issues included "Health problems of family members" (40.9%), "Family life cycle issues" (22.7%), and others.The best fit multiple regression model (Adjusted R2: 0.494, p = 0.020) included Plasma Glucose as an independent variable, and the squared value of cohesion score, depression score of HAD, Total calorie intake, Exercise time, Housekeeping time, and BMI were dependent variables. The results show that extremes of family cohesion with either too many or too few issues related to family functioning are correlated with the plasma glucose level. CONCLUSIONS: Family issues were common among patients with type 2 diabetes, and the extremes of family cohesion were associated with the glucose level, in contrast to the common wisdom that a well balanced family leads to good control of diabetes. PMID- 23799928 TI - Comparisons between intragastric and small intestinal delivery of enteral nutrition in the critically ill: a systematic review and meta-analysis. AB - INTRODUCTION: The largest cohort of critically ill patients evaluating intragastric and small intestinal delivery of nutrients was recently reported. This systematic review included recent data to compare the effects of small bowel and intragastric delivery of enteral nutrients in adult critically ill patients. METHODS: This is a systematic review of all randomised controlled studies published between 1990 and March 2013 that reported the effects of the route of enteral feeding in the critically ill on clinically important outcomes. RESULTS: Data from 15 level-2 studies were included. Small bowel feeding was associated with a reduced risk of pneumonia (Relative Risk, RR, small intestinal vs. intragastric: 0.75 (95% confidence interval 0.60 to 0.93); P=0.01; I2=11%). The point estimate was similar when only studies using microbiological data were included. Duration of ventilation (weighted mean difference: -0.36 days (-2.02 to 1.30); P=0.65; I2=42%), length of ICU stay (WMD: 0.49 days, (-1.36 to 2.33); P=0.60; I2=81%) and mortality (RR 1.01 (0.83 to 1.24); P=0.92; I2=0%) were unaffected by the route of feeding. While data were limited, and there was substantial statistical heterogeneity, there was significantly improved nutrient intake via the small intestinal route (% goal rate received: 11% (5 to 16%); P=0.0004; I2=88%). CONCLUSIONS: Use of small intestinal feeding may improve nutritional intake and reduce the incidence of ICU-acquired pneumonia. In unselected critically ill patients other clinically important outcomes were unaffected by the site of the feeding tube. PMID- 23799930 TI - Medication utilization patterns among type 2 diabetes patients initiating Exenatide BID or insulin glargine: a retrospective database study. AB - BACKGROUND: Type 2 diabetes is a common and costly illness, associated with significant morbidity and mortality. Despite this, there is relatively little information on the 'real-world' medication utilization patterns for patients with type 2 diabetes initiating exenatide BID or glargine. The objective of this study was to evaluate the 'real-world' medication utilization patterns in patients with type 2 diabetes treated with exenatide BID (exenatide) versus insulin glargine (glargine). METHODS: Adult patients( >=18 years of age) with type 2 diabetes who were new initiators of exenatide or glargine from October 1, 2006 through March 31, 2008 with continuous enrollment for the 12 months pre- and 18 months post index period were selected from the MarketScan(r) Commercial and Medicare Databases. To control for selection bias, propensity score matching was used to complete a 1:1 match of glargine to exenatide patients. Key study outcomes (including the likelihood of overall treatment modification, discontinuation, switching, or intensification) were analyzed using survival analysis. RESULTS: A total of 9,197 exenatide- and 4,499 glargine-treated patients were selected. Propensity score matching resulted in 3,774 matched pairs with a mean age of 57 years and a mean Deyo Charlson Comorbidity Index score of 1.6; 54% of patients were males. The 18-month treatment intensification rates were 15.9% and 26.0% (p < 0.0001) and the discontinuation rates were 38.3% and 40.0% (p = 0.14) for exenatide and glargine, respectively. Alternatively, 14.9% of exenatide-treated patients switched therapies, compared to 10.0% of glargine-treated patients (p < 0.0001). Overall, glargine-treated patients were more likely to modify their treatment [hazard ratio (HR) = 1.33, p < 0.0001] with shorter mean time on treatment until modification (123 vs. 159 days, p < 0.0001). Compared to exenatide-treated patients, glargine-treated patients were more likely to discontinue [hazard ratio (HR) = 1.25, p < 0.0001] or intensify therapy (HR = 1.72, p < 0.0001) but less likely to switch (HR = 0.71, p < 0.0001) the index therapy. CONCLUSIONS: Patients treated for type 2 diabetes with exenatide BID or insulin glargine differ in their adherence to therapy. Exenatide-treated patients were less likely to discontinue or modify treatment but more likely to switch therapy compared to glargine-treated patients. PMID- 23799929 TI - Assessing the effectiveness and cost effectiveness of subcutaneous nerve stimulation in patients with predominant back pain due to failed back surgery syndrome (SubQStim study): study protocol for a multicenter randomized controlled trial. AB - BACKGROUND: Chronic radicular pain can be effectively treated with spinal cord stimulation, but this therapy is not always sufficient for chronic back pain. Subcutaneous nerve stimulation (SQS) refers to the placement of percutaneous leads in the subcutaneous tissue within the area of pain. Case series data show that failed back surgery syndrome (FBSS) patients experience clinically important levels of pain relief following SQS and may also reduce their levels of analgesic therapy and experience functional well-being. However, to date, there is no randomized controlled trial evidence to support the use of SQS in FBSS. METHODS/DESIGN: The SubQStim study is a multicenter randomized controlled trial comparing SQS plus optimized medical management ('SQS arm') versus optimized medical management alone ('OMM arm') in patients with predominant back pain due to FBSS. Up to 400 patients will be recruited from approximately 33 centers in Europe and Australia and will be randomized 1:1 to the SQS or OMM arms. After 9 months, patients who fail to reach the primary outcome will be allowed to switch treatments. Patients will be evaluated at baseline (prior to randomization) and at 1, 3, 6, 9, 12, 18, 24, and 36 months after randomization. The primary outcome is the proportion of patients at 9 months with a >=50% reduction in back pain intensity compared to baseline. The secondary outcomes are: back and leg pain intensity score, functional disability, health-related quality of life, patient satisfaction, patient global impression of change, healthcare resource utilization/costs, cost-effectiveness analysis and adverse events. Outcomes arms will be compared between SQS and OMM arms at all evaluation points up to and including 9 months. After the 9-month assessment visit, the main analytic focus will be to compare within patient changes in outcomes relative to baseline. DISCUSSION: The SubQStim trial began patient recruitment in November 2012. Recruitment is expected to close in late 2014. TRIAL REGISTRATION: ClinicalTrials.gov NCT01711619. PMID- 23799931 TI - Simplification of risk stratification for splenic marginal zone lymphoma: a point based score for practical use. PMID- 23799932 TI - Cataract surgery combined with excimer laser trabeculotomy to lower intraocular pressure: effectiveness dependent on preoperative IOP. AB - BACKGROUND: Cataract surgery combined with excimer laser trabeculotomy (phaco ELT) can reduce intraocular pressure (IOP). The aim of this study was to evaluate the effect of phaco-ELT on IOP in patients as a function of preoperative IOP. METHODS: Patients with open-angle glacuoma or ocular hypertension who received phaco-ELT between 01/2008 and 10/2009 were included. Patients were assigned based on preoperative IOP either to the study group (<=21 mmHg) or control group (>21 mmHg) in this IRB-approved, prospective, consecutive case series. Visual Acuity, IOP, and number of anti-glaucoma drugs (AGD) were recorded at baseline and 12 months after phaco-ELT. Any postoperative complications were also recorded. RESULTS: 64 eyes of 64 patients (76.5 +/- 9.4 years) were included. Baseline IOP was 19.8 +/- 5.3 mmHg (AGD 2.4 +/- 1.1) for all eyes, 16.5 +/- 2.9 mmHg (AGD 2.5 +/- 1.0) for the study group, and 25.8 +/- 2.9 mmHg (AGD 2.2 +/- 1.4) for the control group. Across the two groups, IOP was reduced by 4.5 +/- 5.9 mmHg ( 23.0%, p < 0.001) and AGD by 0.9 +/- 1.5 (-38.9%, p < 0.001). For the study group IOP was reduced by 1.9 +/- 4.4 mmHg (-11. 5 %, p = 0.012) and AGD by 1.1 +/- 1.4 (-42.9%, p < 0.001), and for the control group by 9.5 +/- 5.4 mmHg (-36.6%, p < 0.001) and AGD by 0.7 +/- 1.6 (-29.5%, p = 0.085). There were no serious postoperative complications such as endophthalmitis, significant hyphema, or a severe fibrinous reaction of the anterior chamber. CONCLUSIONS: IOP remained significantly reduced from baseline 12 months after phaco-ELT regardless of preoperative IOP levels, with no major complications. The IOP reduction remained constant over the entire follow-up. Hence, phaco-ELT can be considered in glaucoma and ocular hypertensive patients whenever cataract surgery is performed, in order to further reduce IOP or to reduce the requirement for IOP-reducing medications. PMID- 23799934 TI - Ethics, privacy and the legal framework governing medical data: opportunities or threats for biomedical and public health research? AB - Privacy is an important concern in any research programme that deals with personal medical data. In recent years, ethics and privacy have become key considerations when conducting any form of scientific research that involves personal data. These issues are now addressed in healthcare professional training programmes. Indeed, ethics, legal frameworks and privacy are often the subject of much confusion in discussions among healthcare professionals. They tend to group these different concepts under the same heading and delegate responsibility for "ethical" approval of their research programmes to ethics committees. Public health researchers therefore need to ask questions about how changes to legal frameworks and ethical codes governing privacy in the use of personal medical data are to be applied in practice. What types of data do these laws and codes cover? Who is involved? What restrictions and requirements apply to any research programme that involves medical data? PMID- 23799933 TI - Global end-diastolic volume increases to maintain fluid responsiveness in sepsis induced systolic dysfunction. AB - BACKGROUND: Sepsis-induced cardiac dysfunction may limit fluid responsiveness and the mechanism thereof remains unclear. Since cardiac function may affect the relative value of cardiac filling pressures, such as the recommended central venous pressure (CVP), versus filling volumes in guiding fluid loading, we studied these parameters as determinants of fluid responsiveness, according to cardiac function. METHODS: A delta CVP-guided, 90 min colloid fluid loading protocol was performed in 16 mechanically ventilated patients with sepsis-induced hypotension and three 30 min consecutive fluid loading steps of about 450 mL per patient were evaluated. Global end-diastolic volume index (GEDVI), cardiac index (CI) and global ejection fraction (GEF) were assessed from transpulmonary dilution. Baseline and changes in CVP and GEDVI were compared among responding (CI increase >=10% and >=15%) and non-responding fluid loading steps, in patient with low (<20%, n = 9) and near-normal (>=20%) GEF (n = 7) at baseline. RESULTS: A low GEF was in line with other indices of impaired cardiac (left ventricular) function, prior to and after fluid loading. Of 48 fluid loading steps, 9 (of 27) were responding when GEF <20% and 6 (of 21) when GEF >=20. Prior to fluid loading, CVP did not differ between responding and non-responding steps and levels attained were 23 higher in the latter, regardless of GEF (P = 0.004). Prior to fluid loading, GEDVI (and CI) was higher in responding (1007 +/- 306 mL/m(2)) than non-responding steps (870 +/- 236 mL/m(2)) when GEF was low (P = 0.002), but did not differ when GEF was near-normal. Increases in GEDVI were associated with increases in CI and fluid responsiveness, regardless of GEF (P < 0.001). CONCLUSIONS: As estimated from transpulmonary dilution, about half of patients with sepsis-induced hypotension have systolic cardiac dysfunction. During dysfunction, cardiac dilation with a relatively high baseline GEDVI maintains fluid responsiveness by further dilatation (increase in GEDVI rather than of CVP) as in patients without dysfunction. Absence of fluid responsiveness during systolic cardiac dysfunction may be caused by diastolic dysfunction and/or right ventricular dysfunction. PMID- 23799935 TI - Transient impact of omalizumab in pollen allergic patients undergoing specific immunotherapy. AB - BACKGROUND: Recently, we showed that combination of omalizumab with specific immunotherapy (SIT) for treatment of patients with seasonal allergic rhinitis (SAR) and comorbid seasonal allergic asthma (SAA) is safe and reduced the symptom load in a statistically significant and clinically meaningful manner during the first pollen season. OBJECTIVE: The aim of this study was to investigate long lasting effects of an initial combination treatment with SIT+omalizumab, a monoclonal anti-IgE antibody, in a follow-up period with SIT treatment only in patients with SAR and comorbid SAA incompletely controlled by conventional pharmacotherapy. METHODS: A randomized, double-blind, placebo-controlled, multicenter trial was performed to assess the efficacy and safety of omalizumab (Xolair((r))) vs. placebo in combination with SIT (depigmented allergoid vaccine, Depigoid((r))) during the first grass pollen season. Omalizumab or placebo therapy was started 2 wk before SIT; the whole treatment lasted 18 wk. After the first pollen season, SIT was given for two subsequent years without omalizumab. Primary end-point was daily 'symptom load', the sum of daily scores for symptom severity and rescue medication use in the second and third year. RESULTS: A total of 140 patients (age 11-46 yr) were randomized; 130, 128, and 114 patients finished the study after 1, 2, and 3 yr, respectively. The main efficacy variable was the mean daily symptom load as assessed in the patients' diary. No systematic differences between both analysis groups were detected in the findings from symptom load, symptom severity score, or rescue medication score. Further subjective data did not show differences between both groups in the quality-of life data as assessed with the ACQ, AQLQ, and the RQLQ. Investigators' assessment of treatment effectiveness in the first and second year of study extension showed more patients with favorable long-term treatment outcome ('excellent' and 'good') in the SIT plus omalizumab group than in the SIT plus placebo group. In line with these findings, FEV1 improved at the end of both years in the group which was treated with the combination therapy in the double-blind study compared with the Depigoid plus placebo group. CONCLUSION: Eighteen weeks' treatment of omalizumab in combination with SIT in patients with SAR and comorbid SAA reduced the symptom load during the treatment period but showed no prolonged effect during treatment with SIT only. A slight increase in lung function (FEV1) in patients formerly treated with the omalizumab/SIT combination therapy should encourage further evaluation of long-term effects of omalizumab. PMID- 23799936 TI - Reactivation of immune responses against Mycobacterium tuberculosis by boosting with the CpG oligomer in aged mice primarily vaccinated with Mycobacterium bovis BCG. AB - BACKGROUND: Mycobacterium bovis bacillus Calmette Guerin (BCG) vaccine, which has been inoculated to more than one billion people world-wide, has significant effect in preventing tuberculous meningitis and miliary tuberculosis (TB) in neonate and early childhood. However, BCG fails to adequately protect against pulmonary TB and reactivation of latent infections in adults. To overcome this problem, adequate booster is urgently desired in adult who received prior BCG vaccination, and appropriate animal models that substitute human cases would be highly valuable for further experimentation. FINDINGS: The booster effect of the synthesized CpG oligomer (Oligo-B) on aged mice which had been primarily vaccinated with BCG at the age of 4-week old. The specific Th1 type reaction, production of interferon-gamma, in response to TB antigens, purified protein derivatives (PPD) and protection against challenge with Mycobacterium tuberculosis (MTB) H37Rv decreased with increasing age and were not observed in 89-week old mice. In order to rejuvenate the Th1 type response against PPD and protection activity against MTB infection, Oligo-B, which is known to augment Th1 responses, was administered as a booster to 81-90-week old mice (late 50's in human equivalent) vaccinated with BCG at 4-week old. The boosting with Oligo-B increased the number of CD4+ CD44high CD62Lhigh, central memory type T cell. Furthermore, the Oligo-B boosting rejuvenated the ability of mice to protect against infection with MTB H37Rv. CONCLUSIONS: Th1-adjuvant CpG oligo DNA, such as Oligo-B, may be a promising booster when coupled with BCG priming. PMID- 23799937 TI - Metabolic engineering of Kluyveromyces lactis for L-ascorbic acid (vitamin C) biosynthesis. AB - BACKGROUND: L-ascorbic acid (L-AA) is naturally synthesized in plants from D glucose by 10 steps pathway. The pathway branch to synthesize L-galactose, the key intermediate for L-ascorbic acid biosynthesis, has been recently elucidated. Budding yeast produces an 5-carbon ascorbic acid analogue Dehydro-D-arabinono 1,4 lactone (D-DAL), which is synthesized from D-arabinose. Yeast is able to synthesize L-ascorbic acid only if it is cultivated in the presence of one of its precursors: L-galactose, L-galactono 1,4-lactone, or L-gulono 1,4-lactone extracted from plants or animals. To avoid feeding the yeast culture with this "L" enantiomer, we engineered Kluyveromyces lactis with L-galactose biosynthesis pathway genes: GDP-mannose 3,5-epimerase (GME), GDP-L-galactose phosphorylase (VTC2) and L-galactose-1-phosphate phosphatase (VTC4) isolated from Arabidopsis thaliana. RESULTS: Plasmids were constructed and modified such that the cloned plant genes were targeted to the K. lactis LAC4 Locus by homologous recombination and that the expression was associated to the growth on D-galactose or lactose. Upon K. lactis transformation, GME was under the control of the native LAC4 promoter whereas VTC2 and VTC4 were expressed from the S. cerevisiae promoters GPD1 and ADH1 respectively. The expression in K. lactis, of the L-galactose biosynthesis genes was determined by Reverse Transcriptase-PCR and western blotting. The recombinant yeasts were capable to produce about 30 mg.L(-1) of L ascorbic acid in 48 hours of cultivation when cultured on rich medium with 2% (w/v) D-galactose. We also evaluated the L-AA production culturing recombinant recombinant strains in cheese whey, a waste product during cheese production, as an alternative source of lactose. CONCLUSIONS: This work is the first attempt to engineer K. lactis cells for L-ascorbic acid biosynthesis by a fermentation process without any trace of "L" isomers precursors in the culture medium. We have engineered K. lactis strains capable of converting lactose and D-galactose into L-galactose, by the integration of the genes from the A. thaliana L galactose pathway. L-galactose is a rare sugar, which is one of the main precursors for L-AA production. PMID- 23799938 TI - Secreted Listeria adhesion protein (Lap) influences Lap-mediated Listeria monocytogenes paracellular translocation through epithelial barrier. AB - BACKGROUND: Listeria adhesion protein (Lap), an alcohol acetaldehyde dehydrogenase (lmo1634) promotes bacterial paracellular translocation through epithelial cell junctions during gastrointestinal phase of infection. Secreted Lap is critical for pathogenesis and is mediated by SecA2 system; however, if strain dependent variation in Lap secretion would affect L. monocytogenes paracellular translocation through epithelial barrier is unknown. METHODS: Amounts of Lap secretion were examined in clinical isolates of L. monocytogenes by cell fractionation analysis using Western blot. Quantitative reverse transcriptase PCR (qRT-PCR) was used to verify protein expression profiles. Adhesion and invasion of isolates were analyzed by in vitro Caco-2 cell culture model and paracellular translocation was determined using a trans-well model pre seeded with Caco-2 cells. RESULTS: Western blot revealed that expression of Lap in whole cell preparation of isolates was very similar; however, cell fractionation analysis indicated variable Lap secretion among isolates. The strains showing high Lap secretion in supernatant exhibited significantly higher adhesion (3.4 - 4.8% vs 1.5 - 2.3%, P < 0.05), invasion and paracellular translocation in Caco-2 cells than the low secreting isolates. In cell wall fraction, Lap level was mostly uniform for both groups, while Lap accumulated in cytosol in low secreting strains indicating that Lap distribution in cellular compartments is a strain-dependent phenomenon, which may be controlled by the protein transport system, SecA2. DeltasecA2 mutants showed significantly reduced paracellular translocation through epithelial barrier (0.48 +/- 0.01 vs 0.24 +/- 0.02, P < 0.05). qRT-PCR did not show any discernible variation in lap transcript levels in either high or low secreting isolates. CONCLUSION: This study revealed that secreted Lap is an important determinant in Lap-mediated L. monocytogenes translocation through paracellular route and may serve as an indicator for pathogenic potential of an isolate. PMID- 23799939 TI - A genetic variant of the atrial natriuretic peptide gene is associated with left ventricular hypertrophy in a non-diabetic population--the Malmo preventive project study. AB - BACKGROUND: Epidemiological studies have shown considerable heritability of blood pressure, thus suggesting a role for genetic factors. Previous studies have shown an association of a single nucleotide polymorphism rs5068 in the NPPA locus gene with higher levels of circulating atrial natriuretic peptide as well as with lower intra individual blood pressure, but up to date, no association between rs5068 and cardiac organ damage, i.e. left ventricular hypertrophy, has been accounted for in humans. We sought to explore if rs5068 is associated with left ventricular hypertrophy as measured by echocardiographic examination in a non diabetic population. METHODS: 968 non-diabetic individuals from the Malmo Preventive Project (mean age 67 years; 31% women) were genotyped and examined with echocardiography. Logistic regression was used to adjust for covariates. RESULTS: The minor allele of rs5068 was associated with decreased prevalence of left ventricular hypertrophy (p = 0.021) after adjustment for sex and age. In the multivariate logistic analysis including; age, sex, systolic blood pressure, antihypertensive and/or cardioprotective treatment, body mass index and fasting plasma glucose, the association of rs5068 with left ventricular hypertrophy was, as expected, attenuated (p = 0.061). CONCLUSION: In a non-diabetic population, the minor allele of rs5068 was associated with lower left ventricular mass. These findings suggest that rs5068, or genetic variants in linkage disequilibrium, might affect susceptibility to left ventricular hypertrophy and support the possible protective role of natriuretic peptides. PMID- 23799940 TI - Controlled ingestion of kaolinite (5%) modulates enteric nitrergic innervation in rats. AB - We have previously shown that kaolinite slowed down gastric emptying and intestinal transit and induced changes in enteric mechanical activities. As gastric emptying and intestinal transit have been shown to be regulated by nitric oxide (NO), the effect of an imposed ingestion of kaolinite on enteric nitrergic innervation was determined. Kaolinite has also been shown to increase plasmatic levels of leptin. Therefore, the responses of enteric neurons in the presence of leptin after kaolinite ingestion were determined, and a possible role of nitrergic neurons was evaluated in rats using organ bath technique. Our results showed that kaolinite modulates activities of enteric nerves at 14 days of ingestion. Exogenous l-NNA produced a decrease in nerve stimulation (NS)-induced relaxation in both jejunum and colon of control groups. At 14 days of kaolinite ingestion, this effect of l-NNA was significantly reduced only in the jejunum. Although l-NNA did not affect NS-induced contraction in jejunum and colon of control animals, it increased the amplitude of the NS-induced contraction in the colon of rats at 14 days of kaolinite ingestion. Leptin inhibitory effects on ENS in the jejunum were also altered at 14 days of ingestion. These differences were masked in the presence of l-NNA. Our data give evidence that changes in mechanical activities induced by kaolinite might be due to alterations in inhibitory (nitrergic and/or other) innervation at 14 days of kaolinite ingestion and to modifications of leptin effects on the responses to intramural nerve stimulation. PMID- 23799941 TI - Examining primacy as an identifier of salience. AB - This article examines whether the first things people report in narrative accounts represent themes of particular importance to them. In two studies, college students recounted autobiographical memories in an interview setting (Study 1: N = 56; Mage = 19.4; 29 male, 27 female; 48.2% Caucasian, 17.9% Asian, 14.3% African American, 10.7% Hispanic/Latino; Study 2: N = 40; Mage = 18.7; 27 female, 13 male; 57.5% Caucasian, 15% Asian, 12.5% Hispanic/Latino, 7.5% African American). Participants reported happy and sad memories (Study 1) or memories of any emotional type (Study 2), and narrative themes were identified from these memories using standard categories of emotion-eliciting events. Study 2 included a follow-up task one month later in which participants rated the importance of these themes. The themes from the first memories recurred in subsequent memories significantly more often than would be expected by chance, and this recurrence was not a function of the order of memories, the participant's gender, or the type of theme. Furthermore, the themes from the first memories were rated as significantly more important than other themes in the follow-up task. These findings provide strong empirical evidence that primacy identifies important material in the context of narrative analysis. PMID- 23799942 TI - An in-vitro animal experiment on metal implants' thermal effect on radiofrequency ablation. AB - BACKGROUND: To explore metal implants' thermal effect on radiofrequency ablation (RFA) and ascertain distance-thermal relationship between the metal implants and radiofrequency (RF) electrode. METHODS: Metal implants models were established in seven in-vitro porcine livers using silver clips or 125I seeds. RFA were conducted centering the RF electrode axis1 cm away from them, with one side containing a metal implants model the test group and the other side the control group. The thermometric needles were used to measure multi-point temperatures in order to compare the time-distance-temperature difference between the two groups. The gross scopes of the ablation of the two groups were measured and the tissues were analyzed for microscopic histology. RESULTS: At the ablation times of 8, 12, and 15 min, the average multi-point temperatures of the test group and the control group were 48.2+/-18.07 degrees C, 51.5+/-19.57 degrees C, 54.6+/-19.75 degrees C, and 48.6+/-17.69 degrees C, 52.2+/-19.73 degrees C, 54.9+/-19.24 degrees C, respectively, and the differences were not statistically significant (n=126, P>0.05). At the ablation times of 12 and 15 min, the ablation scopes of the test group and the control group were (horizontal/longitudinal diameter) 1.55/3.48 cm, 1.89/3.72 cm, and 1.56/3.48 cm, 1.89/3.72 cm, respectively, and the differences were not statistically significant (n=14, P>0.05). The two groups had the same manifestations in microscopy. CONCLUSIONS: Metal implants do not cause significant thermal effect on RFA. PMID- 23799943 TI - Designing a valid randomized pragmatic primary care implementation trial: the my own health report (MOHR) project. AB - BACKGROUND: There is a pressing need for greater attention to patient-centered health behavior and psychosocial issues in primary care, and for practical tools, study designs and results of clinical and policy relevance. Our goal is to design a scientifically rigorous and valid pragmatic trial to test whether primary care practices can systematically implement the collection of patient-reported information and provide patients needed advice, goal setting, and counseling in response. METHODS: This manuscript reports on the iterative design of the My Own Health Report (MOHR) study, a cluster randomized delayed intervention trial. Nine pairs of diverse primary care practices will be randomized to early or delayed intervention four months later. The intervention consists of fielding the MOHR assessment--addresses 10 domains of health behaviors and psychosocial issues--and subsequent provision of needed counseling and support for patients presenting for wellness or chronic care. As a pragmatic participatory trial, stakeholder groups including practice partners and patients have been engaged throughout the study design to account for local resources and characteristics. Participatory tasks include identifying MOHR assessment content, refining the study design, providing input on outcomes measures, and designing the implementation workflow. Study outcomes include the intervention reach (percent of patients offered and completing the MOHR assessment), effectiveness (patients reporting being asked about topics, setting change goals, and receiving assistance in early versus delayed intervention practices), contextual factors influencing outcomes, and intervention costs. DISCUSSION: The MOHR study shows how a participatory design can be used to promote the consistent collection and use of patient-reported health behavior and psychosocial assessments in a broad range of primary care settings. While pragmatic in nature, the study design will allow valid comparisons to answer the posed research question, and findings will be broadly generalizable to a range of primary care settings. Per the pragmatic explanatory continuum indicator summary (PRECIS) framework, the study design is substantially more pragmatic than other published trials. The methods and findings should be of interest to researchers, practitioners, and policy makers attempting to make healthcare more patient-centered and relevant. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01825746. PMID- 23799944 TI - Exclusion of context knowledge in the development of prehospital guidelines: results produced by realistic evaluation. AB - BACKGROUND: Prehospital work is accomplished using guidelines and protocols, but there is evidence suggesting that compliance with guidelines is sometimes low in the prehospital setting. The reason for the poor compliance is not known. The objective of this study was to describe how guidelines and protocols are used in the prehospital context. METHODS: This was a single-case study with realistic evaluation as a methodological framework. The study took place in an ambulance organization in Sweden. The data collection was divided into four phases, where phase one consisted of a literature screening and selection of a theoretical framework. In phase two, semi-structured interviews with the ambulance organization's stakeholders, responsible for the development and implementation of guidelines, were performed. The third phase, observations, comprised 30 participants from both a rural and an urban ambulance station. In the last phase, two focus group interviews were performed. A template analysis style of documents, interviews and observation protocols was used. RESULTS: The development of guidelines took place using an informal consensus approach, where no party from the end users was represented. The development process resulted in guidelines with an insufficiently adapted format for the prehospital context. At local level, there was a conscious implementation strategy with lectures and manikin simulation. The physical format of the guidelines was the main obstacle to explicit use. Due to the format, the ambulance personnel feel they have to learn the content of the guidelines by heart. Explicit use of the guidelines in the assessment of patients was uncommon. Many ambulance personnel developed homemade guidelines in both electronic and paper format. The ambulance personnel in the study generally took a positive view of working with guidelines and protocols and they regarded them as indispensable in prehospital care, but an improved format was requested by both representatives of the organization and the ambulance personnel. CONCLUSIONS: The personnel take a positive view of the use of guidelines and protocols in prehospital work. The main obstacle to the use of guidelines and protocols in this organization is the format, due to the exclusion of context knowledge in the development process. PMID- 23799945 TI - The 24-month course of manic symptoms in children. AB - OBJECTIVES: The Longitudinal Assessment of Manic Symptoms (LAMS) study was designed to investigate phenomenology and establish predictors of functional outcomes in children with elevated manic symptoms. The purpose of this series of analyses was to determine whether the participants demonstrated different trajectories of parent-reported manic and biphasic symptoms over the first 24 months of follow-up and to describe the clinical characteristics of the trajectories. METHODS: The 707 participants were initially aged 6-12 years and ascertained from outpatient clinics associated with the four university affiliated LAMS sites. There were 621 children whose parents/guardians' ratings scored >= 12 on the Parent General Behavior Inventory-10-item Mania Form (PGBI 10M) and a matched random sample of 86 children whose parents/guardians' ratings scored <= 11 on the PGBI-10M. Participants were seen every six months after the baseline and their parents completed the PGBI-10M at each visit. RESULTS: For the whole sample, manic symptoms decreased over 24 months (linear effect B = -1.15, standard error = 0.32, t = -3.66, p < 0.001). Growth mixture modeling revealed four unique trajectories of manic symptoms. Approximately 85% of the cohort belonged to two classes in which manic symptoms decreased. The remaining ~15% formed two classes (high and rising and unstable) characterized by the highest rates of diagnostic conversion to a bipolar disorder (all p-values < 0.001). CONCLUSIONS: Outcomes are not uniform among children with symptoms of mania or at high risk for mania. A substantial minority of clinically referred children shows unstable or steadily increasing manic symptoms, and these patterns have distinct clinical correlates. PMID- 23799946 TI - In-plane optical anisotropy of InAs/GaSb superlattices with alternate interfaces. AB - The in-plane optical anisotropy (IPOA) in InAs/GaSb superlattices has been studied by reflectance difference spectroscopy (RDS) at different temperatures ranging from 80 to 300 K. We introduce alternate GaAs- and InSb-like interfaces (IFs), which cause the symmetry reduced from D 2d to C 2v . IPOA has been observed in the (001) plane along [110] and [1[Formula: see text]0] axes. RDS measurement results show strong anisotropy resonance near critical point (CP) energies of InAs and GaSb. The energy positions show red shift and RDS intensity decreases with the increasing temperature. For the superlattice sample with the thicker InSb-like IFs, energy positions show red shift, and the spectra exhibit stronger IPOA. The excitonic effect is clearly observed by RDS at low temperatures. It demonstrates that biaxial strain results in the shift of the CP energies and IPOA is enhanced by the further localization of the carriers in InSb like IFs. PMID- 23799947 TI - Pathologic fracture does not influence prognosis in stage IIB osteosarcoma: a case-control study. AB - OBJECTIVE: This study tested the implication of pathologic fractures on the prognosis in stage IIb osteosarcoma. METHODS: A single center retrospective evaluation of clinical management and oncologic outcome was conducted with 15 pathological fracture patients (M:F = 10:5; age: mean 23.2, range 12-42) and 50 non-fracture patients between April 2002 and December 2010. These stage IIB osteosarcoma patients were matched for age, tumor site (femur, tibia, and humerus), and osteosarcoma subtype (i.e., control patients with osteosarcoma in the same sites as the fracture patients). All osteosarcoma patients with pathological fractures underwent brace or cast immobilization, adjuvant chemotherapy, and limb salvage surgery or amputation. Musculoskeletal Tumor Society (MSTS) functional scores were assessed. The mean follow-up time was 34.7 months (range, 8-47 months). RESULTS: Following limb salvage surgery, no statistical differences were observed in major complications (fracture = 20.0%, control = 12.0%, P = 0.43) or local recurrence complications (fracture = 26.7%, control = 14.0%, P = 0.25). Overall 3-year survival rates of the fracture and control groups (66.7% and 75.3%, respectively) were not statistically different (P = 0.5190). Three-year disease-free survival rates of the fracture and control groups were 53.3% and 66.5%, respectively (P = 0.25). CONCLUSIONS: Pathologic fracture was not a prognostic indicator of recurrence or overall survival in localized osteosarcoma patients. Limb salvage can be achieved by and maintaining adequate surgical margins and applying adjuvant chemotherapy. PMID- 23799948 TI - Infliximab as rescue therapy in hospitalised patients with steroid-refractory acute ulcerative colitis: a long-term follow-up of 211 Swedish patients. AB - BACKGROUND: Rescue therapy with infliximab (IFX) has been proven effective in a steroid-refractory attack of ulcerative colitis (UC). The long-term efficacy is not well described. AIM: To present a retrospective study of IFX as rescue therapy in UC. Primary end points were colectomy-free survival at 3 and 12 months. METHODS: In this multicentre study, 211 adult patients hospitalised between 1999 and 2010 received IFX 5 mg/kg as rescue therapy due to a steroid refractory, moderate-to-severe attack of UC. Exclusion criteria were duration of current flare for >12 weeks, corticosteroid treatment for >8 weeks before hospitalisation, previous IFX therapy or Crohn's disease. RESULTS: Probability of colectomy-free survival at 3 months was 0.71 (95% CI, 0.64-0.77), at 12 months 0.64 (95% CI, 0.57-0.70), at 3 years 0.59 (95% CI, 0.52-0.66) and at 5 years 0.53 (95% CI, 0.44-0.61). Steroid-free, clinical remission was achieved in 105/211 (50%) and 112/209 (54%) patients at 3 and 12 months respectively. Of 75 colectomies during the first year, 48 (64%) were carried out during the first 14 days, 13 (17%) on days 15-90 and 14 (19%) between 3 and 12 months. There were three (1.4%) deaths during the first 3 months. CONCLUSIONS: Infliximab is an effective rescue treatment, both short- and long-term, in a steroid-refractory attack of UC. Most IFX failures underwent surgery during the first 14 days, which calls for studies on how to optimise induction treatment with IFX. Serious complications, including mortality, were rare. PMID- 23799949 TI - Ambushing the Ambush Hypothesis: predicting and evaluating off-frame codon frequencies in prokaryotic genomes. AB - BACKGROUND: In this paper, we address the evidence for the Ambush Hypothesis. Proposed by Seligmann and Pollock, this hypothesis posits that there exists a selection for off-frame stop codons (OSCs) to counteract the possible deleterious effects of translational frameshifts, including the waste of resources and potential cytotoxicity. Two main types of study have been used to support the hypothesis. Some studies analyzed codon usage and showed that codons with more potential to create OSCs seem to be favored over codons with lower potential; they used this finding to support the Ambush Hypothesis. Another study used 342 bacterial genomes to evaluate the hypothesis directly, finding significant excesses of OSCs in these genomes. RESULTS: We repeated both analyses with newer datasets and searched for other factors that could explain the observed trends. In the first case, the relative frequency of codons with the potential to create OSCs is directly correlated with the GC content of organisms, as stop codons are GC-poor. When evaluating the frequency of OSCs directly in 1,976 bacterial genomes we also detected a significant excess. However, when comparing the excess of OSCs with similarly obtained results for the frequency of out-of-frame sense codons, some sense codons have a more significant excess than stop codons. CONCLUSIONS: Two avenues of study have been used to support the Ambush Hypothesis. Using the same methods as these previous studies, we demonstrate that the evidence in support of the Ambush Hypothesis does not hold up against more rigorous testing. PMID- 23799950 TI - Solving a methodological challenge in work stress evaluation with the Stress Assessment and Research Toolkit (StART): a study protocol. AB - BACKGROUND: Stress evaluation is a field of strong interest and challenging due to several methodological aspects in the evaluation process. The aim of this study is to propose a study protocol to test a new method (i.e., the Stress Assessment and Research Toolkit) to assess psychosocial risk factors at work. DESIGN: This method addresses several methodological issues (e.g., subjective vs. objective, qualitative vs quantitative data) by assessing work-related stressors using different kinds of data: i) organisational archival data (organisational indicators sheet); ii) qualitative data (focus group); iii) worker perception (questionnaire); and iv) observational data (observational checklist) using mixed methods research. In addition, it allows positive and negative aspects of work to be considered conjointly, using an approach that considers at the same time job demands and job resources. DISCUSSION: The integration of these sources of data can reduce the theoretical and methodological bias related to stress research in the work setting, allows researchers and professionals to obtain a reliable description of workers' stress, providing a more articulate vision of psychosocial risks, and allows a large amount of data to be collected. Finally, the implementation of the method ensures in the long term a primary prevention for psychosocial risk management in that it aims to reduce or modify the intensity, frequency or duration of organisational demands. PMID- 23799951 TI - A descriptive analysis of a novel intervention to help residents become evidence users. AB - BACKGROUND AND OBJECTIVES: To evaluate the educational and clinical effectiveness of the 'Brief Evidence-Based Assessment of Research' (BEAR), a template to assist residents in searching, evaluating and integrating relevant medical literature into daily practice. METHODS: We completed a descriptive analysis of BEARs submitted by first year residents between 2005 and 2007 at the University of Alberta Family Medicine Residency program. RESULTS: 317 BEARs were analyzed. The most common type of question for which information was searched was therapy (59%). Residents searched Pubmed most often (38%) followed by Summary (i.e. Clinical Evidence) (22%) and Filtered sites (i.e. ACP Journal Club) (19%). Original research articles were the largest resource category used to answer questions (41%). Secondary peer-reviewed resources (filtered articles, summary sites, reviews/meta-analysis and guidelines) accounted for 48% of all resources used. 19% of residents reported a large change in practice with completion of the BEAR, 50% reported a small change, 12% stated they were reassured and 8% reported that the intervention was of no help to them. CONCLUSIONS: The BEAR facilitates the use of a variety of resources in answering clinical questions. 69% of users reported at least a small change in clinical practice, suggesting that the BEAR may be a useful tool in evidence-based resident education. PMID- 23799952 TI - The CD47-binding peptide of thrombospondin-1 induces defenestration of liver sinusoidal endothelial cells. AB - BACKGROUND & AIMS: A fenestrated phenotype is characteristic of liver sinusoidal endothelial cells (LSECs), but liver sinusoids become defenestrated during fibrosis and other liver diseases. Thrombospondin-1 (TSP1) is a matrix glycoprotein with pro-fibrotic effects, and the CD47-binding fragment of TSP1 also has anti-angiogenic effects in endothelial cells. We hypothesized that the CD47-binding fragment of TSP1 could induce defenestration in LSECs through the Rho-Rho kinase (ROCK)-myosin pathway. METHODS: Freshly isolated rat LSECs were treated with TSP1 or CD47-binding peptides of TSP1. LSEC fenestration was assessed with scanning electron microscopy, and myosin phosphorylation was assessed with immuno-fluorescence. RESULTS: Treating LSECs with TSP1 caused a dose-dependent loss of fenestrae, and this effect could not be blocked by SB 431542, the TGF-beta1 receptor inhibitor. A CD47-binding fragment of TSP1, p4N1, was able to induce defenestration, and a CD47-blocking antibody, B6H12, was able to suppress p4N1-induced defenestration. The p4N1 fragment also caused contraction of fenestra size, correlated with an increase in myosin activation. Pretreatment with Y-237642 (a ROCK inhibitor) prevented p4N1-induced myosin activation and fenestrae decrease. Simvastatin has also been shown to antagonize Rho-ROCK signalling, and we found that simvastatin pretreatment protected LSECs from p4N1-induced myosin activation and defenestration. CONCLUSIONS: We conclude that CD47 signals through the Rho-ROCK-myosin pathway to induce defenestration in LSECs. In addition, our results show that simvastatin and Y-237642 have a beneficial impact on fenestration in vitro, providing an additional explanation for the efficacy of these compounds for regression of liver fibrosis. PMID- 23799953 TI - Cortical speech sound differentiation in the neonatal intensive care unit predicts cognitive and language development in the first 2 years of life. AB - AIM: Neurodevelopmental delay in childhood is common in infants born preterm, but is difficult to predict before infants leave the neonatal intensive care unit (NICU). We hypothesized that event-related potential (ERP) methodology characterizing the cortical differentiation of speech sounds in hospitalized infants would predict cognitive and language outcomes during early childhood. METHODS: We conducted a prospective study of 57 infants in NICU (34 male, gestational age at birth 24-40wks), quantifying the amplitude of ERP responses to speech sounds before discharge (median gestational age 37.1wks), followed by standardized neurodevelopmental assessments at 12 months and 24 months. Analyses were performed using ordinary least squares linear regression. RESULTS: Overall validity of constructs using all ERP variables, as well as sex, maternal education, gestational age, and age at ERP, was good and allowed significant prediction of cognitive and communication outcomes at 12 months and 24 months (R(2) =22-42%; p<0.05). Quantitative models incorporating specific ERPs, gestational age, and age at ERP explained a large proportion of the variance in cognition and receptive language on the Bayley Scales of Infant Development at 24 months (R(2) >50%; p<0.05). INTERPRETATION: This study establishes ERP methodology as a valuable research tool to quantitatively assess cortical function in the NICU and to predict meaningful outcomes in early childhood. PMID- 23799954 TI - Body mass index, smoking, age and cancer mortality among women: a classification tree analysis. AB - AIM: Although obesity is an established risk factor for cancer mortality among women, little is known about how body mass index (BMI) is interacting with certain lifestyle behaviors and sociodemographic characteristics to increase the risk of cancer mortality. The purpose of this study was to use classification trees to examine possible interactions between BMI, smoking, age, poverty level and marital status in identifying high-risk subgroups for all-cause cancer mortality in women. MATERIAL AND METHODS: Data from the US National Health Interview Survey linked with the National Death Index from 1990-2004 were used in this study. The data were restricted to women with complete information on all risk factors considered in the analyses. The data were analyzed using descriptive statistics and classification trees. RESULTS: Findings revealed that younger women (41-50 years old) who smoked had higher cancer mortality if they were underweight. Even among 51-60-year-old never smokers, we observed an inverse relationship between BMI and mortality. High BMI, however, was not a protective factor in 51-60-year-old women who were not married and did not smoke. CONCLUSION: Classification tree analysis confirms and extends current knowledge about the role of BMI and smoking on cancer mortality by providing preliminary risk profiles. The findings indicate that it is imperative for cancer-related studies to examine BMI and smoking within age-specific groups and in the context of several sociodemographic factors that are known to independently affect cancer mortality. PMID- 23799956 TI - Response to Letter: lithium poisoning: the value of early digestive tract decontamination. PMID- 23799957 TI - Discrete subpulmonic membrane in association with isolated severe pulmonary valvar stenosis. AB - BACKGROUND: Subpulmonic membrane as a cause of right ventricular outflow tract obstruction in patients with concordant ventriculoarterial connection and intact ventricular septum is considered to be rare. CASE PRESENTATION: A 7-year-old boy was referred to a tertiary care hospital with complaints of dyspnea on moderate exertion and palpitations of about 2 years duration. Physical examination revealed parasternal lift, systolic thrill and a 4/6 ejection systolic murmur, best heard over the left 2nd intercostal space. His oxygen saturation was 88% on room air. Two-dimensional echocardiography showed a thickened pulmonary valve with fused leaflets that show severe systolic doming. There was a discrete subpulmonic membrane about 1.3 cm below the pulmonary valve annulus. Continuous wave Doppler interrogation showed peak systolic pressure gradient of 185 mmHg across the pulmonary valve. Balloon dilation of the pulmonary valve was performed and the pressure gradient came down to 50 mmHg. Follow-up transthoracic echocardiography showed residual pressure gradient of about 50-60 mmHg across the pulmonary valve. The residual pressure gradient appeared to be mainly subvalvar, as seen on the continuous wave Doppler tracing. The patient reported marked improvement in terms of exercise tolerance and subjective symptoms. CONCLUSIONS: Association of subpulmonic membrane with severe pulmonary valvar stenosis, concordant ventriculoarterial connection and intact ventricular septum is rare. When it occurs, the result of percutaneous valve dilation may be suboptimal. PMID- 23799955 TI - Knock-in/Knock-out (KIKO) vectors for rapid integration of large DNA sequences, including whole metabolic pathways, onto the Escherichia coli chromosome at well characterised loci. AB - BACKGROUND: Metabolic engineering projects often require integration of multiple genes in order to control the desired phenotype. However, this often requires iterative rounds of engineering because many current insertion approaches are limited by the size of the DNA that can be transferred onto the chromosome. Consequently, construction of highly engineered strains is very time-consuming. A lack of well-characterised insertion loci is also problematic. RESULTS: A series of knock-in/knock-out (KIKO) vectors was constructed for integration of large DNA sequences onto the E. coli chromosome at well-defined loci. The KIKO plasmids target three nonessential genes/operons as insertion sites: arsB (an arsenite transporter); lacZ (beta-galactosidase); and rbsA-rbsR (a ribose metabolism operon). Two homologous 'arms' target each insertion locus; insertion is mediated by lambda Red recombinase through these arms. Between the arms is a multiple cloning site for the introduction of exogenous sequences and an antibiotic resistance marker (either chloramphenicol or kanamycin) for selection of positive recombinants. The resistance marker can subsequently be removed by flippase mediated recombination. The insertion cassette is flanked by hairpin loops to isolate it from the effects of external transcription at the integration locus. To characterize each target locus, a xylanase reporter gene (xynA) was integrated onto the chromosomes of E. coli strains W and K-12 using the KIKO vectors. Expression levels varied between loci, with the arsB locus consistently showing the highest level of expression. To demonstrate the simultaneous use of all three loci in one strain, xynA, green fluorescent protein (gfp) and a sucrose catabolic operon (cscAKB) were introduced into lacZ, arsB and rbsAR respectively, and shown to be functional. CONCLUSIONS: The KIKO plasmids are a useful tool for efficient integration of large DNA fragments (including multiple genes and pathways) into E. coli. Chromosomal insertion provides stable expression without the need for continuous antibiotic selection. Three non-essential loci have been characterised as insertion loci; combinatorial insertion at all three loci can be performed in one strain. The largest insertion at a single site described here was 5.4 kb; we have used this method in other studies to insert a total of 7.3 kb at one locus and 11.3 kb across two loci. These vectors are particularly useful for integration of multigene cassettes for metabolic engineering applications. PMID- 23799958 TI - Association between somatic amplification, anxiety, depression, stress and migraine. AB - BACKGROUND: The aim of this study is to investigate the associations between migraine related disability and somatosensory amplification, depression, anxiety, and stress. METHOD: Fifty-five migraine patients who applied to the outpatient unit of the Neurology Department of Acibadem University School of Medicine, Maslak Hospital in Istanbul, Turkey, and twenty-eight subjects without migraine were recruited for the study. The participants were asked to complete a sociodemographic form, Migraine Disability Assessment Scale (MIDAS), Depression Anxiety Stress Scale, Somatosensory Amplification Scale (SSAS). RESULTS: Somatosensory amplification scores were significantly higher in the migraineurs than in the control group (29.85+/-6.63 vs 26.07+/-7.1; p=0.027). Somatosensory amplification scores and depression scores were significantly higher in migraineurs with moderate and severe disability than in patients with minimal and mild disability (31.7+/-6.4 vs 27.71+/-5.49; p=0.01, 11.27+/-8.7 vs 7.38+/-8.11; p=0.04, respectively). A significant positive correlation was found between the frequency of migraine attacks for at least three consecutive months (MIDAS A scores) and the SSAS scores (r=0.363, p=0.007) in migraineurs. The MIDAS total scores were also significantly correlated with the DASS depression subcale scores (r=0.267, p=0.04), and the DASS stress subscale scores (r=0.268, p=0.05). CONCLUSION: Psychological factors, and vulnerability to bodily sensations may incease the burden of migraine. We point out that the timely assessing of somatic amplification and the evaluation of mental status would help improve the quality of life of in migraineurs. PMID- 23799959 TI - Sharpening of expression domains induced by transcription and microRNA regulation within a spatio-temporal model of mid-hindbrain boundary formation. AB - BACKGROUND: The establishment of the mid-hindbrain region in vertebrates is mediated by the isthmic organizer, an embryonic secondary organizer characterized by a well-defined pattern of locally restricted gene expression domains with sharply delimited boundaries. While the function of the isthmic organizer at the mid-hindbrain boundary has been subject to extensive experimental studies, it remains unclear how this well-defined spatial gene expression pattern, which is essential for proper isthmic organizer function, is established during vertebrate development. Because the secreted Wnt1 protein plays a prominent role in isthmic organizer function, we focused in particular on the refinement of Wnt1 gene expression in this context. RESULTS: We analyzed the dynamics of the corresponding murine gene regulatory network and the related, diffusive signaling proteins using a macroscopic model for the biological two-scale signaling process. Despite the discontinuity arising from the sharp gene expression domain boundaries, we proved the existence of unique, positive solutions for the partial differential equation system. This enabled the numerically and analytically analysis of the formation and stability of the expression pattern. Notably, the calculated expression domain of Wnt1 has no sharp boundary in contrast to experimental evidence. We subsequently propose a post-transcriptional regulatory mechanism for Wnt1 miRNAs which yields the observed sharp expression domain boundaries. We established a list of candidate miRNAs and confirmed their expression pattern by radioactive in situ hybridization. The miRNA miR-709 was identified as a potential regulator of Wnt1 mRNA, which was validated by luciferase sensor assays. CONCLUSION: In summary, our theoretical analysis of the gene expression pattern induction at the mid-hindbrain boundary revealed the need to extend the model by an additional Wnt1 regulation. The developed macroscopic model of a two-scale process facilitate the stringent analysis of other morphogen based patterning processes. PMID- 23799960 TI - Reiki and related therapies in the dialysis ward: an evidence-based and ethical discussion to debate if these complementary and alternative medicines are welcomed or banned. AB - BACKGROUND: Complementary and Alternative Medicines (CAMs) are increasingly practiced in the general population; it is estimated that over 30% of patients with chronic diseases use CAMs on a regular basis. CAMs are also used in hospital settings, suggesting a growing interest in individualized therapies. One potential field of interest is pain, frequently reported by dialysis patients, and seldom sufficiently relieved by mainstream therapies. Gentle-touch therapies and Reiki (an energy based touch therapy) are widely used in the western population as pain relievers.By integrating evidence based approaches and providing ethical discussion, this debate discusses the pros and cons of CAMs in the dialysis ward, and whether such approaches should be welcomed or banned. DISCUSSION: In spite of the wide use of CAMs in the general population, few studies deal with the pros and cons of an integration of mainstream medicine and CAMs in dialysis patients; one paper only regarded the use of Reiki and related practices. Widening the search to chronic pain, Reiki and related practices, 419 articles were found on Medline and 6 were selected (1 Cochrane review and 5 RCTs updating the Cochrane review). According to the EBM approach, Reiki allows a statistically significant but very low-grade pain reduction without specific side effects. Gentle-touch therapy and Reiki are thus good examples of approaches in which controversial efficacy has to be balanced against no known side effect, frequent free availability (volunteer non-profit associations) and easy integration with any other pharmacological or non pharmacological therapy. While a classical evidence-based approach, showing low-grade efficacy, is likely to lead to a negative attitude towards the use of Reiki in the dialysis ward, the ethical discussion, analyzing beneficium (efficacy) together with non maleficium (side effects), justice (cost, availability and integration with mainstream therapies) and autonomy (patients' choice) is likely to lead to a permissive positive attitude. SUMMARY: This paper debates the current evidence on Reiki and related techniques as pain-relievers in an ethical framework, and suggests that physicians may wish to consider efficacy but also side effects, contextualization (availability and costs) and patient's requests, according also to the suggestions of the Society for Integrative Oncology (tolerate, control efficacy and side effects). PMID- 23799961 TI - Food allergy knowledge of parents - is ignorance bliss? AB - BACKGROUND: Food allergic children are at least partially dependent on their parents to care for their food allergy. In addition, parents are often responsible for the education of others regarding food allergy, including the family, school, neighbors, and friends. The aim of this study was to investigate food allergy knowledge, attitudes, and beliefs of parents with food allergic children in the Netherlands. In addition, a cross-cultural comparison was made between parents from the USA and parents from the Netherlands. METHODS: The original Chicago Food Allergy Research Survey for Parents of Children with Food Allergy (CFARS-PRNT) was translated into Dutch. Parents of children with at least one doctor-diagnosed food allergy were included. Knowledge scores and attitude/beliefs scores were determined and compared with the data from 2945 parents from the USA. Predictors of overall knowledge scores were investigated. RESULTS: Dutch parents of children completed the translated CFARS-PRNT (n = 299). The mean overall knowledge score in the Netherlands was 9.9 after adjusting for guessing, compared with 12.7 in the USA (p < 0.001). Attitudes and beliefs regarding food allergy among parents from the Netherlands were generally more optimistic. The overall knowledge scores could be predicted by country of origin, educational degree, being member of a patient organization, visiting an allergist, and a history of anaphylaxis. CONCLUSIONS: Food allergy knowledge among parents of food allergic children from the Netherlands is suboptimal when compared with their counterparts from the USA, although these parents tend to be more optimistic toward food allergy than parents from the USA. PMID- 23799962 TI - UK population norms for the modified dental anxiety scale with percentile calculator: adult dental health survey 2009 results. AB - BACKGROUND: A recent UK population survey of oral health included questions to assess dental anxiety to provide mean and prevalence estimates of this important psychological construct. METHODS: A two-stage cluster sample was used for the survey across England, Wales, and Northern Ireland. The survey took place between October-December 2009, and January-April 2010. All interviewers were trained on survey procedures. Within the 7,233 households sampled there were 13,509 adults who were asked to participate in the survey and 11,382 participated (84%). RESULTS: The scale was reliable and showed some evidence of unidimensionality. Estimated proportion of participants with high dental anxiety (cut-off score = 19) was 11.6%. Percentiles and confidence intervals were presented and can be estimated for individual patients across various age ranges and gender using an on-line tool. CONCLUSIONS: The largest reported data set on the MDAS from a representative UK sample was presented. The scale's psychometrics is supportive for the routine assessment of patient dental anxiety to compare against a number of major demographic groups categorised by age and sex. Practitioners within the UK have a resource to estimate the rarity of a particular patient's level of dental anxiety, with confidence intervals, when using the on-line percentile calculator. PMID- 23799963 TI - New pre-arrival instructions can avoid abdominal hand placement for chest compressions. AB - OBJECTIVE: To investigate if modified pre-arrival instructions using patient's arm and nipple line as landmarks could avoid abdominal hand placements for chest compressions. METHOD: Volunteers were randomized to one of two telephone instructions: "Kneel down beside the chest. Place one hand in the centre of the victim's chest and the other on top" (control) or "Lay the patient's arm which is closest to you, straight out from the body. Kneel down by the patient and place one knee on each side of the arm. Find the midpoint between the nipples and place your hands on top of each other" (intervention). Hand placement was conducted on an adult male and documented by laser measurements. Hand placement, quantified as the centre of the compressing hands in the mid-sagittal plane, was compared to the inter-nipple line (INL) for reference and classified as above or below. Fisher's exact test was used for comparison of proportions. RESULTS: Thirty-six lay people, age range 16-60, were included. None in the intervention group placed their hands in the abdominal region, compared to 5/18 in the control group (p = 0.045). Using INL as a reference, the new instructions resulted in less caudal hand placement, and the difference in mean hand position was 47 mm [95% CI 21,73], p = 0.001. CONCLUSION: New pre-arrival instructions where the patient's arm and nipple line were used as landmarks resulted in less caudal hand placements and none in the abdominal region. PMID- 23799964 TI - Health equity: evidence synthesis and knowledge translation methods. AB - BACKGROUND: At the Rio Summit in 2011 on Social Determinants of Health, the global community recognized a pressing need to take action on reducing health inequities. This requires an improved evidence base on the effects of national and international policies on health inequities. Although systematic reviews are recognized as an important source for evidence-informed policy, they have been criticized for failing to assess effects on health equity. METHODS: This article summarizes guidance on both conducting systematic reviews with a focus on health equity and on methods to translate their findings to different audiences. This guidance was developed based on a series of methodology meetings, previous guidance, a recently developed reporting guideline for equity-focused systematic reviews (PRISMA-Equity 2012) and a systematic review of methods to assess health equity in systematic reviews. RESULTS: We make ten recommendations for conducting equity-focused systematic reviews; and five considerations for knowledge translation. Illustrative examples of equity-focused reviews are provided where these methods have been used. CONCLUSIONS: Implementation of the recommendations in this article is one step toward monitoring the impact of national and international policies and programs on health equity, as recommended by the 2011 World Conference on Social Determinants of Health. PMID- 23799965 TI - Mechanical ventilation worsens abdominal edema and inflammation in porcine endotoxemia. AB - INTRODUCTION: We hypothesized that mechanical ventilation per se increases abdominal edema and inflammation in sepsis and tested this in experimental endotoxemia. METHODS: Thirty anesthetized piglets were allocated to one of five groups: healthy control pigs breathing spontaneously with continuous positive pressure of 5 cm H2O or mechanically ventilated with positive end-expiratory pressure of 5 cm H2O, and endotoxemic piglets during mechanical ventilation for 2.5 hours and then continued on mechanical ventilation with positive end expiratory pressure of either 5 or 15 cm H2O or switched to spontaneous breathing with continuous positive pressure of 5 cm H2O for another 2.5 hours. Abdominal edema formation was estimated by isotope technique, and inflammatory markers were measured in liver, intestine, lung, and plasma. RESULTS: Healthy controls: 5 hours of spontaneous breathing did not increase abdominal fluid, whereas mechanical ventilation did (Normalized Index increased from 1.0 to 1.6; 1 to 3.3 (median and range, P<0.05)). Endotoxemic animals: Normalized Index increased almost sixfold after 5 hours of mechanical ventilation (5.9; 4.9 to 6.9; P<0.05) with twofold increase from 2.5 to 5 hours whether positive end-expiratory pressure was 5 or 15, but only by 40% with spontaneous breathing (P<0.05 versus positive end-expiratory pressure of 5 or 15 cm H2O). Tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6 in intestine and liver were 2 to 3 times higher with mechanical ventilation than during spontaneous breathing (P<0.05) but similar in plasma and lung. Abdominal edema formation and TNF-alpha in intestine correlated inversely with abdominal perfusion pressure. CONCLUSIONS: Mechanical ventilation with positive end-expiratory pressure increases abdominal edema and inflammation in intestine and liver in experimental endotoxemia by increasing systemic capillary leakage and impeding abdominal lymph drainage. PMID- 23799966 TI - Performance of the pediatric index of mortality 2 (PIM-2) in cardiac and mixed intensive care units in a tertiary children's referral hospital in Italy. AB - BACKGROUND: Mortality rate of patients admitted to Intensive Care Units is a widely adopted outcome indicator. Because of large case-mix variability, comparisons of mortality rates must be adjusted for the severity of patient illness at admission. The Pediatric Index of Mortality 2 (PIM-2) has been widely adopted as a tool for adjusting mortality rate by patients' case mix. The objective of this study was to assess the performance of PIM-2 in children admitted to intensive care units after cardiac surgery, other surgery, or for other reasons. METHODS: This was a prospective cohort study, conducted in a 607 inpatient-bed tertiary-care pediatric hospital in Italy, with three pediatric intensive care Units (PICUs) and one cardiac Unit (CICU). In 2009-11, all consecutive admissions to PICUs/CICU of children aged 0-16 years were included in the study. Discrimination and calibration measures were computed to assess PIM-2 performance. Multivariable logistic regression analysis was used to assess the association of patients' main reason for intensive care admission (cardiac surgical, other-surgical, medical), age, Unit and year with observed mortality, adjusting for PIM-2 score. RESULTS: PIM-2 data collection was completed for 91.2% of total PICUs/CICU patient admissions (2912), and for 94.8% of patients who died in PICUs/CICU (129). Overall observed mortality was 4.4% (95% CI, 3.7-5.2), compared to 6.4% (95% CI, 5.5-7.3) expected mortality. Standardised mortality ratio was 0.7 (95% CI: 0.6-0.8). PIM-2 discrimination was fair (area under the curve, 0.79; 95% CI: 0.75-0.83). Calibration was less satisfactory, mainly because of the over two-fold overprediction of deaths in the highest risk group (114.7 vs 53; p < 0.001), and particularly in cardiac-surgical patients. Multivariable logistic analysis showed that risk of death was significantly reduced in cardiac-surgical patients and in those aged 1 month to 12 years, independently from PIM-2. CONCLUSIONS: The children age distribution and the proportion of cardiac-surgical patients should be taken into account when interpreting SMRs estimated using the PIM-2 prediction model in different Units. A new calibration study of PIM-2 score might be needed, and more appropriate cardiac-focused risk-adjustment models should be developed. The role of age on risk of death needs to be further explored. PMID- 23799967 TI - HeLa cell response proteome alterations induced by mammalian reovirus T3D infection. AB - BACKGROUND: Cells are exposed to multiple stressors that induce significant alterations in signaling pathways and in the cellular state. As obligate parasites, all viruses require host cell material and machinery for replication. Virus infection is a major stressor leading to numerous induced modifications. Previous gene array studies have measured infected cellular transcriptomes. More recently, mass spectrometry-based quantitative and comparative assays have been used to complement such studies by examining virus-induced alterations in the cellular proteome. METHODS: We used SILAC (stable isotope labeling with amino acids in cell culture), a non-biased quantitative proteomic labeling technique, combined with 2-D HPLC/mass spectrometry and reciprocal labeling to identify and measure relative quantitative differences in HeLa cell proteins in purified cytosolic and nuclear fractions after reovirus serotype 3 Dearing infection. Protein regulation was determined by z-score analysis of each protein's label distribution. RESULTS: A total of 2856 cellular proteins were identified in cytosolic fractions by 2 or more peptides at >99% confidence and 884 proteins were identified in nuclear fractions. Gene ontology analyses indicated up regulated host proteins were associated with defense responses, immune responses, macromolecular binding, regulation of immune effector processes, and responses to virus, whereas down-regulated proteins were involved in cell death, macromolecular catabolic processes, and tissue development. CONCLUSIONS: These analyses identified numerous host proteins significantly affected by reovirus T3D infection. These proteins map to numerous inflammatory and innate immune pathways, and provide the starting point for more detailed kinetic studies and delineation of virus-modulated host signaling pathways. PMID- 23799968 TI - Effects of genes and environment on the fetoplacental arterial microcirculation in mice revealed by micro-computed tomography imaging. AB - The fetoplacental arterial tree is critical for efficient distribution of arterial blood to capillaries throughout the placental exchange region; yet, little is known about the factors and mechanisms that control its development. Advances in micro-CT imaging and analysis, and available mutant mouse strains, are facilitating rapid progress. Indeed, micro-CT studies show that genetic differences between the CD1 and C57Bl/6 mouse strains, and between Gcm1 heterozygotes and wild-type littermates alter the developmental trajectory of the fetoplacental arterial tree as do environmental factors including maternal exposure to toxins in cigarette smoke and malarial infection. Relative to other vascular beds, the fetoplacental arterial tree is particularly tractable because veins can more easily be excluded when infusing the contrast agent and because of the placenta's small size, which means that the whole organ can be imaged (maintaining connectivity) and that the tree is simpler (fewer branching generations). Despite these differences, measured parameters were found to be similar to arterial trees in other adult rodent organs. Thus, micro-CT analysis provides a means for advancing of our understanding of the mechanisms controlling development of the fetoplacental arterial tree. Results will likely have relevance to other arterial vasculatures as well. PMID- 23799969 TI - Common heritable effects underpin concerns over norm maintenance and in-group favoritism: evidence from genetic analyses of right-wing authoritarianism and traditionalism. AB - Research has shown that in-group favoritism is associated with concerns over the maintenance of social norms. Here we present two studies examining whether genetic factors underpin this association. A classical twin design was used to decompose phenotypic variance into genetic and environmental components in two studies. Study 1 used 812 pairs of adult U.S. twins from the nationally representative MIDUS II sample. Study 2 used 707 pairs of middle-age twins from the Minnesota Twin Registry. In-group favoritism was measured with scales tapping preferences for in-group (vs. out-group) individuals; norm concerns were measured with the Multidimensional Personality Questionnaire-Traditionalism (Study 1) and Right-Wing Authoritarianism (RWA; Study 2) scales. In Study 1, heritable effects underlying traditionalism were moderately (c. 35%) overlapping with the genetic variance underpinning in-group favoritism. In Study 2, heritable influences on RWA were entirely shared with the heritable effects on in-group favoritism. Moreover, we observed that Big Five Openness shared common genetic links to both RWA and in-group favoritism. These results suggest that, at the genetic level, in group favoritism is linked with a system related to concern over normative social practices, which is, in turn, partially associated with trait Openness. PMID- 23799970 TI - Blue-emitting self-assembled polymer electrolytes for fast, sensitive, label-free detection of Cu(II) ions in aqueous media. AB - We have developed a light-emitting material based on nonconjugated block copolymers that contain polystyrene sulfonate (PSS) chains. The confinement of the PSS chains within nanosized domains appeared to be a powerful means of achieving enhanced fluorescence signals. High fluorescence quantum yield, with a maximum value of 37%, was obtained by adjusting the types of self-assembled morphologies of PSS-containing block copolymers; in contrast, the fluorescence quantum yield was merely 5% for the PSS homopolymer lacking organization. The wavelength of fluorescence emission was tunable by rational molecular design. In addition, significant self-quenching behavior was not noticed in diverse forms of this material such as solutions, thin films, and free-standing membranes. Notably, the light-emitting self-assembled block copolymer electrolytes exhibited high sensitivity toward Cu(2+) ions, with a detection limit of parts per billion levels, rapid response time of <=1 min, and insignificant interference of other competitive metal ions. PMID- 23799971 TI - Body mass index in relation to truncal asymmetry of healthy adolescents, a physiopathogenetic concept in common with idiopathic scoliosis: summary of an electronic focus group debate of the IBSE. AB - There is no generally accepted scientific theory for the cause of adolescent idiopathic scoliosis (AIS). As part of its mission to widen understanding of scoliosis etiology, the International Federated Body on Scoliosis Etiology (IBSE).introduced the electronic focus group (EFG) as a means of increasing debate on knowledge of important topics. This has been designated as an on-line Delphi discussion. The text for this debate was written by Dr TB Grivas. It is based on published research from Athens, Greece evaluating schoolchildren age 11 17 years for the relation of body mass index (BMI) to each of truncal asymmetry (TA) and menarcheal status. Girls with relatively lower BMI were found to have a significant excess of severe TAs and significantly later menarche confirming the well-known relation of BMI to menarche. Together with other evidence linking nutritional status to skeletal growth, the observations suggest energy balance via the hypothalamus is related to trunk asymmetry. As with a recent speculative hypothesis for the pathogenesis of AIS in girls, Grivas et al. suggest that the severe TAs involve a genetically-determined selectively increased sensitivity (up regulation) of the hypothalamus to circulating leptin with asymmetry as an adverse response to stress (hormesis). The TA is expressed bilaterally via the sympathetic nervous system to produce left-right asymmetry in ribs and/or vertebrae leading to severe TAs when beyond the capacity of postural mechanisms of the somatic nervous system to control the shape distortion in the trunk. This EFG discusses the findings and interpretations of the paper by Grivas and colleagues as research at the borderland between the genesis of TA (physiogenesis) and AIS (pathogenesis). It is suggested that TAs, here regarded in common with AIS, result from the combination of secondary sexual development affecting body composition, adolescent skeletal growth velocity, and an asymmetry process. The possible involvement of epigenetic factors is not considered. PMID- 23799972 TI - The role of tobacco use on dental care and oral disease severity within community dental clinics in Japan. AB - BACKGROUND: To examine facilitators of dental smoking intervention practices in Japan, where smokeless tobacco is rarely used, we evaluated the characteristics of dental care for smokers. METHODS: Community dentists volunteered to record the treated disease or encounter with patients that was principally responsible for their dental care on the survey day. Patients were classified into groups receiving gingival/periodontal treatment (GPT), caries/endodontic treatment (CET), prosthetic treatment (PRT), periodical check-up/orthodontic treatment (POT), or other encounters/treatments. Potential effect of dentist clustering was adjusted by incorporating the complex survey design into the analysis. RESULTS: Data of 2835 current smokers (CS) and 6850 non-smokers (NS) from 753 clinics were analysed. Distribution of treatments significantly differed between CS and NS (P = 0.001). In ad hoc multiple comparisons for each treatment, CS were significantly higher than NS for CET (47.1% vs. 43.6%, P = 0.002), and lower for POT (1.6% vs. 2.7%, P = 0.001), whereas GPT and PRT proportions were equivalent by smoking. When stage of disease progression was compared in the GPT subpopulation, CS were more likely received treatment for advanced stage disease than NS in the age groups of 40-59 years (24.9% vs. 15.3%, P = 0.001) and more than 60 years (40.8% vs. 22.1%, P < 0.001). However, the difference was less apparent in the entire population (9.7% vs. 6.0%), and CS were not predominant among patients receiving GPT for advanced stage disease (37.6%). CONCLUSIONS: The association of smoking with type of dental care of CET and GPT severity would warrant the need for dental professionals to engage their patients smoking within clinical practice. The detrimental effects of smoking in dental care for smokers, as evidenced by the distribution of treatment and encounter and stage of treated disease, may not be clearly realized by dental professionals, unless the smoking status of all patients is identified. PMID- 23799973 TI - Beyond classification: gene-family phylogenies from shotgun metagenomic reads enable accurate community analysis. AB - BACKGROUND: Sequence-based phylogenetic trees are a well-established tool for characterizing diversity of both macroorganisms and microorganisms. Phylogenetic methods have recently been applied to shotgun metagenomic data from microbial communities, particularly with the aim of classifying reads. But the accuracy of gene-family phylogenies that characterize evolutionary relationships among short, non-overlapping sequencing reads has not been thoroughly evaluated. RESULTS: To quantify errors in metagenomic read trees, we developed MetaPASSAGE, a software pipeline to generate in silico bacterial communities, simulate a sample of shotgun reads from a gene family represented in the community, orient or translate reads, and produce a profile-based alignment of the reads from which a gene-family phylogenetic tree can be built. We applied MetaPASSAGE to a variety of RNA and protein-coding gene families, built trees using a range of different phylogenetic methods, and compared the resulting trees using topological and branch-length error metrics. We identified read length as one of the major sources of error. Because phylogenetic methods use a reference database of full length sequences from the gene family to guide construction of alignments and trees, we found that error can also be substantially reduced through increasing the size and diversity of the reference database. Finally, UniFrac analysis, which compares metagenomic samples based on a summary statistic computed over all branches in a read tree, is very robust to the level of error we observe. CONCLUSIONS: Bacterial community diversity can be quantified using phylogenetic approaches applied to shotgun metagenomic data. As sequencing reads get longer and more genomes across the bacterial tree of life are sequenced, the accuracy of this approach will continue to improve, opening the door to more applications. PMID- 23799974 TI - Granulocyte-macrophage colony stimulating factor (GM-CSF) enhances cumulus cell expansion in bovine oocytes. AB - BACKGROUND: The objectives of the study were to characterize the expression of the alpha- and beta-subunits of granulocyte-macrophage colony stimulating factor (GM-CSF) receptor in bovine cumulus cells and oocytes and to determine the effect of exogenous GM-CSF on cumulus cells expansion, oocyte maturation, IGF-2 transcript expression and subsequent competence for embryonic development. METHODS: Cumulus-oocyte complexes (COC) were obtained by aspirating follicles 3- to 8-mm in diameter with an 18 G needle connected to a vacuum pump at -50 mmHg. Samples of cumulus cells and oocytes were used to detect GM- CSF receptor by immunofluorescence. A dose-response experiment was performed to estimate the effect of GM-CSF on cumulus cell expansion and nuclear/cytoplasmic maturation. Also, the effect of GM-CSF on IGF-2 expression was evaluated in oocytes and cumulus cells after in vitro maturation by Q-PCR. Finally, a batch of COC was randomly assigned to in vitro maturation media consisting of: 1) synthetic oviductal fluid (SOF, n = 212); 2) synthetic oviductal fluid supplemented with 100 ng/ml of GM-CSF (SOF + GM-CSF, n = 224) or 3) tissue culture medium (TCM 199, n = 216) and then subsequently in vitro fertilized and cultured for 9 days. RESULTS: Immunoreactivity for both alpha and beta GM-CSF receptors was localized in the cytoplasm of both cumulus cells and oocytes. Oocytes in vitro matured either with 10 or 100 ng/ml of GM-CSF presented a higher (P < 0.05) cumulus cells expansion than that of the control group (0 ng/ml of GM-CSF). GM-CSF did not affect the proportion of oocytes in metaphase II, cortical granules dispersion and IGF-2 expression. COC exposed to 100 ng/ml of GM-CSF during maturation did not display significant differences in terms of embryo cleavage rate (50.4% vs. 57.5%), blastocyst development at day 7 (31.9% vs. 28.7%) and at day 9 (17.4% vs. 17.9%) compared to untreated control (SOF alone, P = 0.2). CONCLUSIONS: GM-CSF enhanced cumulus cell expansion of in vitro matured bovine COC. However, GM-CSF did not increase oocyte nuclear or cytoplasmic maturation rates, IGF-2 expression or subsequent embryonic development. PMID- 23799975 TI - The association between low-dose aspirin use and the incidence of colorectal cancer: a nationwide cohort study. AB - BACKGROUND: Considerable evidence suggests that aspirin has a chemopreventive effect on colorectal cancer (CRC). However, optimal dose and treatment duration have not been defined, and data on the effects of low-dose aspirin are contradictory. AIM: To determine if the incidence of CRC in patients with low dose aspirin use was lower than in those without aspirin use. METHOD: From Taiwan's National Health Insurance research database, aspirin users (n = 1985) were defined as adults (age >=20 years) with at least 3.5 years of regular low dose aspirin use (50-150 mg per day) between 1998 and 2002. Non-users (n = 7940) were those who did not use aspirin and were matched 4:1 with the user group by age, gender, date of ambulatory care (index date), and presence of known risk factors for cardiovascular disease (including hypertension, diabetes mellitus and hyperlipidaemia). Follow-up of the two study groups was made until the end of 2010, and incidences and hazard ratios of colorectal cancer were determined. RESULTS: During a median follow-up period of 8.9 years, 129 non-users and 14 users developed CRC, corresponding to incidence rates of 180.43 and 79.42 per 100,000 person-years respectively. Duration of aspirin use among users ranged from 3.5 to 12.6 years (mean 8.7 years). The multivariate-adjusted hazard ratio for CRC was 0.5 (95% confidence interval 0.28-0.87) among users as compared with non-users. CONCLUSIONS: Long-term use of low-dose aspirin appears to be associated with a lower incidence of CRC in patients with high cardiovascular risk. Further randomised clinical trials are necessary to confirm these findings. PMID- 23799976 TI - Neonatal blood pressure monitoring: visual assessment is an unreliable method for selecting cuff sizes. AB - AIM: To compare current practice of cuff size selection for noninvasive blood pressure measurement in a single-centre, tertiary-level neonatal intensive care unit (visual assessment of bladder width/limb length closest to 2/3) with common recommendations for appropriate cuff selection. METHODS: Visual assessment of the appropriate cuff size ('2/3 rule') for upper arm, forearm and calf in 103 neonates (309 cuff selections) was compared with the following recommendations: (i) Method A - guidelines of the cuff manufacturer, (ii) Method B - cuff width/limb circumference ratio 0.44-0.60 and (iii) Method C - cuff width/limb length ratio closest to 0.66. RESULTS: The upper arm cuff size was correctly chosen in 84% of cases (Method A), 43% (Method B) and 56% (Method C). The forearm cuff size was correctly chosen in 94% of cases (Method A), 68% (Method B) and 54% (Method C). The calf cuff size was correctly chosen in 96% of cases (Method A), 72% (Method B) and 63% (Method C). CONCLUSION: The accuracy of selecting cuff size by visual assessment is low. Further research on accurate cuff selection for neonates, including at the forearm and calf, is warranted. PMID- 23799977 TI - Non-radiological method for three-dimensional implant position evaluation using an intraoral scan method. AB - INTRODUCTION: This technical innovation presents a method that reproduces the position of a dental implant after insertion without the reuse of X-ray radiation. MATERIAL AND METHODS: An implant was inserted into the natural gap between the canines and premolars of three domestic pigs. A Straumann Scanbody was then screwed to the implant, and a digital impression of the jaw segment was made. The scanbody was scanned using a hand-held scanner. This was followed by the radiological detection of implant position on a CBCT. On the computer, the position of the implant was calculated and compared with the radiologically detected position. RESULTS: The calculated and determined position of the dental implant by the scanner is in good agreement with the radiologically controlled position. DISCUSSION: Evaluating the position of implants using intraoral scans is an easy and radiation-free method of three-dimensional site assessment after superimposition over a three-dimensional data set. PMID- 23799979 TI - Cough in chronic obstructive pulmonary disease: is it important and what are the effects of treatment? AB - Over the last 40 years the assessment and treatment of chronic obstructive pulmonary disease has focused primarily on airflow obstruction with little significance given to the problem of cough. The reasons for this include a view that cough arises simply from the direct irritant and inflammatory effect of cigarette smoke or the presence of excess mucus in the airways. Doubt that cough is of any consequence to patients or responsive to current therapies has reinforced this opinion. At odds with this is the emerging evidence that cough impacts adversely on patients' health status and forms an important component of recently validated quality of life instruments. This article presents the arguments why the assessment and treatment of cough should have a more prominent place in the clinical management of COPD. PMID- 23799978 TI - Flt-1 in colorectal cancer cells is required for the tumor invasive effect of placental growth factor through a p38-MMP9 pathway. AB - BACKGROUND: Placenta growth factor (PlGF), a dimeric glycoprotein with 53% homology to VEGF, binds to VEGF receptor-1 (Flt-1), but not to VEGF receptor-2 (Flk-1), and may function by modulating VEGF activity. We previously have showed that PlGF displays prognostic value in colorectal cancer (CRC) but the mechanism remains elucidated. RESULTS: Overexpression of PlGF increased the invasive/migration ability and decreased apoptosis in CRC cells showing Flt-1 expression. Increased migration was associated with increasing MMP9 via p38 MAPK activation. Tumors grew faster, larger; with higher vascularity from PlGF over expression cells in xenograft assay. In two independent human CRC tissue cohorts, PlGF, MMP9, and Flt-1 expressions were higher in the advanced than the localized disease group. PlGF expression correlated with MMP9, and Flt-1 expression. CRC patients with high PlGF and high Flt-1 expression in tissue had poor prognosis. CONCLUSION: PlGF/Flt-1 signaling plays an important role in CRC progression, blocking PlGF/Flt-1 signaling maybe an alternative therapy for CRC. PMID- 23799980 TI - Neutrophil gelatinase-associated lipocalin in prediction of mortality in patients with hepatorenal syndrome: a prospective observational study. AB - BACKGROUND & AIMS: Hepatorenal syndrome (HRS) is a severe complication of cirrhosis which is characterized by renal dysfunction and associated with poor survival. Neutrophil gelatinase-associated lipocalin (NGAL) is a troponin-like biomarker for human acute kidney injury. We aimed to investigate levels of plasma and urine NGAL in HRS and predictive ability of these markers for all-cause mortality, in HRS, stable cirrhosis and control subjects. METHODS: A total of 64 patients with cirrhosis (8 patients with type 1 HRS, 22 with type 2 HRS, and 34 without HRS) and 23 control subjects were included in the study. Blood and urine samples were measured with Human NGAL sandwich ELISA. Patients were followed up prospectively. RESULTS: Patients with type 1 and type 2 HRS had significantly higher plasma and urine NGAL levels compared with stable cirrhosis and control subjects. Cox regression analysis showed that plasma NGAL and MELD-Na scores were independent predictors of mortality. ROC-curve analysis showed that the plot of the plasma NGAL, urine NGAL, MELD-Na and Child-Turcot-Pugh score could predict all-cause mortality in cirrhotic patients' area under the curve (AUC 0.819, 0.686, 0.807 and 0.795 respectively). CONCLUSIONS: NGAL could predict mortality in patients with HRS independent of other commonly used risk factors. PMID- 23799981 TI - The relationship between training status, blood pressure and uric acid in adults and elderly. AB - BACKGROUND: Hypertension can be generated by a great number of mechanisms including elevated uric acid (UA) that contribute to the anion superoxide production. However, physical exercise is recommended to prevent and/or control high blood pressure (BP). The purpose of this study was to investigate the relationship between BP and UA and whether this relationship may be mediated by the functional fitness index. METHODS: All participants (n = 123) performed the following tests: indirect maximal oxygen uptake (VO2max), AAHPERD Functional Fitness Battery Test to determine the general fitness functional index (GFFI), systolic and diastolic blood pressure (SBP and DBP), body mass index (BMI) and blood sample collection to evaluate the total-cholesterol (CHOL), LDL-cholesterol (LDL-c), HDL-cholesterol (HDL-c), triglycerides (TG), uric acid (UA), nitrite (NO2) and thiobarbituric acid reactive substances (T-BARS). After the physical, hemodynamic and metabolic evaluations, all participants were allocated into three groups according to their GFFI: G1 (regular), G2 (good) and G3 (very good). RESULTS: Baseline blood pressure was higher in G1 when compared to G3 (+12% and +11%, for SBP and DBP, respectively, p<0.05) and the subjects who had higher values of BP also presented higher values of UA. Although UA was not different among GFFI groups, it presented a significant correlation with GFFI and VO2max. Also, nitrite concentration was elevated in G3 compared to G1 (140+/-29 MUM vs 111+/-29 MUM, for G3 and G1, respectively, p<0.0001). As far as the lipid profile, participants in G3 presented better values of CHOL and TG when compared to those in G1. CONCLUSIONS: Taking together the findings that subjects with higher BP had elevated values of UA and lower values of nitrite, it can be suggested that the relationship between blood pressure and the oxidative stress produced by uric acid may be mediated by training status. PMID- 23799983 TI - Measurement of physical activity in children and adolescents with cerebral palsy: the way forward. PMID- 23799982 TI - Mining breast cancer genes with a network based noise-tolerant approach. AB - BACKGROUND: Mining novel breast cancer genes is an important task in breast cancer research. Many approaches prioritize candidate genes based on their similarity to known cancer genes, usually by integrating multiple data sources. However, different types of data often contain varying degrees of noise. For effective data integration, it's important to design methods that work robustly with respect to noise. RESULTS: Gene Ontology (GO) annotations were often utilized in cancer gene mining works. However, the vast majority of GO annotations were computationally derived, thus not completely accurate. A set of genes annotated with breast cancer enriched GO terms was adopted here as a set of source data with realistic noise. A novel noise tolerant approach was proposed to rank candidate breast cancer genes using noisy source data within the framework of a comprehensive human Protein-Protein Interaction (PPI) network. Performance of the proposed method was quantitatively evaluated by comparing it with the more established random walk approach. Results showed that the proposed method exhibited better performance in ranking known breast cancer genes and higher robustness against data noise than the random walk approach. When noise started to increase, the proposed method was able to maintained relatively stable performance, while the random walk approach showed drastic performance decline; when noise increased to a large extent, the proposed method was still able to achieve better performance than random walk did. CONCLUSIONS: A novel noise tolerant method was proposed to mine breast cancer genes. Compared to the well established random walk approach, it showed better performance in correctly ranking cancer genes and worked robustly with respect to noise within source data. To the best of our knowledge, it's the first such effort to quantitatively analyze noise tolerance between different breast cancer gene mining methods. The sorted gene list can be valuable for breast cancer research. The proposed quantitative noise analysis method may also prove useful for other data integration efforts. It is hoped that the current work can lead to more discussions about influence of data noise on different computational methods for mining disease genes. PMID- 23799985 TI - Biodegradable poly([D,L]-lactide-co-glycolide) nanofibers for the sustainable delivery of lidocaine into the epidural space after laminectomy. AB - AIM: We developed biodegradable, lidocaine-embedded poly([D,L]-lactide-co glycolide) nanofibers for epidural analgesia to reduce the severe pain in rats after laminectomies. MATERIALS & METHODS: Nanofibers were prepared by an electrospinning process and were introduced into the epidural space of rats after laminectomy. The lidocaine concentration, postoperative bodyweight change and amount of food/water intake were monitored to evaluate the analgesic effectiveness of the drug-eluting nanofibers. RESULTS: It was demonstrated that the nanofibers provided a sustained release of lidocaine for more than 2 weeks, and the local pharmaceutical concentration was much higher than the concentration in plasma. Rats that received laminectomies without nanofibers exhibited the greatest bodyweight reduction. The food/water intake and activity performance were significantly higher in rats receiving laminectomies with nanofibers than in rats without nanofibers. CONCLUSION: The results of this study suggest that the lidocaine-loaded nanofibers can provide an easy, practical and safe means of achieving effective postlaminectomy analgesia. PMID- 23799984 TI - Heterogeneity in nanoparticles influences biodistribution and targeting. AB - AIM: A large fraction of the administered dose of nanoparticles (NPs) localizes into nontarget tissue, which could be due to the heterogeneous population of NPs. MATERIALS & METHODS: To investigate the impact of the above issue, we simultaneously tracked the biodistribution using optical imaging of two different sized poly(d,l-lactide co-glycolide) NPs, which also varied in their surface charge and texture, in a prostate tumor xenograft mouse model. RESULTS: Although formulated using the same polymer and emulsifier concentration, small NPs were neutral (S-neutral-NPs), whereas large NPs were anionic (L-anionic-NPs). Simultaneous injection of these NPs, representing heterogeneity, shows significantly different biodistribution. S-neutral-NPs demonstrated longer circulation time than L-anionic-NPs (t1/2 = 96 vs 13 min); accounted for 75% of total NPs accumulated in the tumor; and showed 13-fold greater tumor to liver signal intensity ratio than L-anionic-NPs. CONCLUSION: The data underscore the importance of formulating nanocarriers of specific properties to enhance their targeting efficacy. PMID- 23799986 TI - Maternal tumor necrosis factor receptor 2 gene variants associated with pre eclampsia in Tunisian women. AB - AIM: The tumor necrosis factor receptor 2 (TNFR2) is expressed in placental tissue and it is involved in immune responses, inflammation, angiogenesis and blood pressure regulation; which makes it an attractive pre-eclampsia (PE) candidate gene. Furthermore, TNFR2 expression is altered in the first trimester in placentas of women who are destined to develop PE. Therefore, we examined the association between maternal and fetal genetic variants of TNFR2 and PE. MATERIAL AND METHODS: Women with PE (n = 157) and their offspring with PE (n = 60) were compared to a control group of women (n = 97) and their offspring (n = 52) in the same Tunisian hospital-based population. We genotyped by polymerase chain reaction and restriction fragment length polymorphism the T/G polymorphism at position 676 in exon 6 (rs1061622) of the TNFR2 gene and examined its association with PE. RESULTS: The frequencies of TNFR2 (G/G) genotype and G allele were higher in the mothers with PE (n = 154) compared to the control group (15.3% vs 4.1% and 37% vs 26.3%, respectively); furthermore, the difference reached statistical significance (P = 0.002, odds ratio = 4.9; 95% confidence interval: 1.69-17.4 and P = 0.03, odds ratio = 1.69; 95% confidence interval: 1.03-2.8, respectively). In contrast, the fetal genotype and allele frequencies of this polymorphism had no effect on the risk of PE. CONCLUSIONS: The exon 6 polymorphism in TNFR2 (rs1061622) or a gene at proximity is associated specifically with PE at least in the Tunisian population and could increase the risk for PE for mothers carrying the homozygote minor allele. Nevertheless, these results need to be confirmed in other populations. PMID- 23799987 TI - Impact of dye-protein interaction and silver nanoparticles on rose bengal photophysical behavior and protein photocrosslinking. AB - The role of recombinant Type-I human collagen in the free form or forming AgNP@collagen on the photophysical and photochemical behavior of rose Bengal was analyzed. The formation of dye aggregates on the protein surface was experimentally observed and corroborated by docking calculations. The formation of such aggregates is believed to change the main oxidative mechanism from Type II (singlet oxygen) to Type-I (free radical) photosensitization. Remarkably, the presence of AgNP in the form of AgNP@collagen altered the dynamics of dye triplet deactivation, effectively preventing the dye degradation and reducing the extent of protein crosslinked. Both crosslinked rHC and AgNP@collagen were able to support fibroblasts proliferation, but only the material containing silver was resistant to S. epidermidis infection. PMID- 23799988 TI - Critically ill patients in emergency department may be characterized by low amplitude and high variability of amplitude of pulse photoplethysmography. AB - BACKGROUND: The aim of the present pilot study was to determine if pulse photoplethysmography amplitude (PPGA) could be used as an indicator of critical illness and as a predictor of higher need of care in emergency department patients. METHODS: This was a prospective observational study. We collected vital signs and one minute of pulse photoplethysmograph signal from 251 consecutive patients admitted to a university hospital emergency department. The patients were divided in two groups regarding to the modified Early Warning Score (mEWS): > 3 (critically ill) and <= 3 (non-critically ill). Photoplethysmography characteristics were compared between the groups. RESULTS: Sufficient data for analysis was acquired from 212 patients (84.5%). Patients in critically ill group more frequently required intubation and invasive hemodynamic monitoring in the ED and received more intravenous fluids. Mean pulse photoplethysmography amplitude (PPGA) was significantly lower in critically ill patients (median 1.105 [95% CI of mean 0.9946-2.302] vs. 2.476 [95% CI of mean 2.239-2.714], P = 0.0257). Higher variability of PPGA significantly correlated with higher amount of fluids received in the ED (r = 0.1501, p = 0.0296). CONCLUSIONS: This pilot study revealed differences in PPGA characteristics between critically ill and non critically ill patients. Further studies are needed to determine if these easily available parameters could help increase accuracy in triage when used in addition to routine monitoring of vital signs. PMID- 23799989 TI - Protective effect of erythropoietin on renal injury induced in rats by four weeks of exhaustive exercise. AB - BACKGROUND: The protective effect of Erythropoietin (EPO) analogue rHuEPO on acute renal injury induced by exhaustive exercise had been reported. The purpose of this study is to probe into the protective effect of EPO on chronic renal injury induced by repeated exhaustive exercise for four weeks. METHODS: Eighty adult male Sprague-Dawley rats were used in this experiment. The animals were randomly allocated to one of four groups: control (C), exhaustive exercise test (ET), ET plus EPO pre-treatement (ET+EPO) and ET+EPO plus LY294002 pretreatment (ET+EPO+LY). RESULTS: Compared with the rats in control group, there was considerable damage in kidney cells in rats of ET group as revealed by histological and ultrastructural examinations. However, treatment with EPO during the training, the exhaustive running distance was significant increased (P < 0.01), and the pathological changes of kidney cell were much less compared with those of rats without EPO intervention. When LY294002, a specific inhibitor of phospholipids phthalocyanine inositol 3-kinase, was added to the EPO treated rats, the injury changes of renal cell were becoming more pronounced. CONCLUSIONS: The protective effect of EPO on chronic renal injury induced by repeated exhaustive exercise was demonstrated in the present study. We proposed that the effect could be due to inhibiting the cell apoptosis and blocking the formation of interstitial fibrosis via activation of the PI3K/Akt pathway, thus plays role in the endogenous protection of the kidney injury. PMID- 23799990 TI - Phytophthora capsici-tomato interaction features dramatic shifts in gene expression associated with a hemi-biotrophic lifestyle. AB - BACKGROUND: Plant-microbe interactions feature complex signal interplay between pathogens and their hosts. Phytophthora species comprise a destructive group of fungus-like plant pathogens, collectively affecting a wide range of plants important to agriculture and natural ecosystems. Despite the availability of genome sequences of both hosts and microbes, little is known about the signal interplay between them during infection. In particular, accurate descriptions of coordinate relationships between host and microbe transcriptional programs are lacking. RESULTS: Here, we explore the molecular interaction between the hemi biotrophic broad host range pathogen Phytophthora capsici and tomato. Infection assays and use of a composite microarray allowed us to unveil distinct changes in both P. capsici and tomato transcriptomes, associated with biotrophy and the subsequent switch to necrotrophy. These included two distinct transcriptional changes associated with early infection and the biotrophy to necrotrophy transition that may contribute to infection and completion of the P. capsici lifecycle CONCLUSIONS: Our results suggest dynamic but highly regulated transcriptional programming in both host and pathogen that underpin P. capsici disease and hemi-biotrophy. Dynamic expression changes of both effector-coding genes and host factors involved in immunity, suggests modulation of host immune signaling by both host and pathogen. With new unprecedented detail on transcriptional reprogramming, we can now explore the coordinate relationships that drive host-microbe interactions and the basic processes that underpin pathogen lifestyles. Deliberate alteration of lifestyle-associated transcriptional changes may allow prevention or perhaps disruption of hemi biotrophic disease cycles and limit damage caused by epidemics. PMID- 23799991 TI - Correlations among adiposity measures in school-aged children. AB - BACKGROUND: Given that it is not feasible to use dual x-ray absorptiometry (DXA) or other reference methods to measure adiposity in all pediatric clinical and research settings, it is important to identify reasonable alternatives. Therefore, we sought to determine the extent to which other adiposity measures were correlated with DXA fat mass in school-aged children. METHODS: In 1110 children aged 6.5-10.9 years in the pre-birth cohort Project Viva, we calculated Spearman correlation coefficients between DXA (n=875) and other adiposity measures including body mass index (BMI), skinfold thickness, circumferences, and bioimpedance. We also computed correlations between lean body mass measures. RESULTS: 50.0% of the children were female and 36.5% were non-white. Mean (SD) BMI was 17.2 (3.1) and total fat mass by DXA was 7.5 (3.9) kg. DXA total fat mass was highly correlated with BMI (r(s)=0.83), bioimpedance total fat (r(s)=0.87), and sum of skinfolds (r(s)=0.90), and DXA trunk fat was highly correlated with waist circumference (r(s)=0.79). Correlations of BMI with other adiposity indices were high, e.g., with waist circumference (r(s)=0.86) and sum of subscapular plus triceps skinfolds (r(s)=0.79). DXA fat-free mass and bioimpedance fat-free mass were highly correlated (r(s)=0.94). CONCLUSIONS: In school-aged children, BMI, sum of skinfolds, and other adiposity measures were strongly correlated with DXA fat mass. Although these measurement methods have limitations, BMI and skinfolds are adequate surrogate measures of relative adiposity in children when DXA is not practical. PMID- 23799992 TI - Intimate partner violence and mental health in Bolivia. AB - BACKGROUND: Latin America has among the highest rates of intimate partner violence. While there is increasing evidence that intimate partner violence is associated with mental health problems, there is little such research for developing countries. The purpose of this paper is to examine the relationship between Bolivian women's experiences with physical, psychological, and sexual intimate partner violence and mental health outcomes. METHODS: This study analyzes data from the 2008 Bolivia Demographic and Health Survey. 10,119 married or cohabiting women ages 15-49 are included in the analysis. Probit regression models are used to assess the association between intimate partner violence and mental health, after controlling for other demographic factors and partner characteristics. The questionnaire uses selected questions from the SRQ-20 to measure symptoms of mental health problems. RESULTS: Intimate partner violence is common in Bolivia, with 47% of women experiencing some type of spousal abuse in the 12 months before the survey. Women exposed to physical spousal violence in the past year are more likely to experience symptoms of depression, anxiety, psychogenic non-epileptic seizures, and psychotic disorders, after controlling for other demographic and partner characteristics. Women who experienced sexual abuse by a partner are most likely to suffer from all mental health issues. Psychological abuse is also associated with an increased risk of experiencing symptoms of depression, anxiety, and psychogenic seizures. Women who experienced only psychological abuse report mental health problems similar to those who were physically abused. CONCLUSION: This study demonstrates an urgent need for research on the prevalence and health consequences of psychological abuse in developing countries. Our findings highlight the need for mental health services for victims of intimate partner violence. Because physical and psychological violence are often experienced concurrently, it is recommended that health providers who are treating victims of physical intimate partner violence also screen them for symptoms of potential mental health problems and refer them to appropriate mental health services. PMID- 23799993 TI - Induction with interleukin-2 antagonist for transplantation of kidneys from older deceased donors: an observational study. AB - BACKGROUND: The most important limiting factor in kidney transplantation is the scarcity of donor organs. Consequently, there is an increased use worldwide of kidneys from older deceased donors. High donor age is a known risk factor for acute cellular rejection and premature graft failure, and the optimal immunosuppressive regimen in these circumstances remains to be established. METHODS: We investigated whether induction treatment with an interleukin 2 (IL-2) receptor antagonist improves graft survival and reduces rejection episodes in recipients of kidneys from deceased donors aged >= 60 years. Data were retrieved for all recipients transplanted at our center from 2004 to 2009 with a kidney from a deceased donor aged > 60 years. The outcome was compared between recipients treated with (IL-2 plus) or without (IL-2 minus) an IL-2 receptor antagonist. All recipients received a calcineurin inhibitor, steroids and mycophenolate. RESULTS: A total of 232 first-transplant recipients were included (IL-2 plus = 149, IL-2 minus = 83). IL-2 minus was associated with increased risk of early acute rejection (OR 2.42; 95% CI 1.25 to 4.68, P = 0.009) and steroid resistant rejection (OR 8.04; 2.77 to 23.25, P< 0.001). IL-2 plus patients had superior two-year estimated uncensored (87% versus 70%, P = 0.001) and death censored (95% versus 79%, P< 0.001) graft survival. CONCLUSIONS: Induction treatment with IL-2 receptor antagonist was associated with a reduction in acute rejection episodes and improved two-year graft survival in patients transplanted with kidneys from older deceased donors. PMID- 23799994 TI - Increased invasion and tumorigenicity capacity of CD44+/CD24- breast cancer MCF7 cells in vitro and in nude mice. AB - BACKGROUND: Identification of cancer stem cells (CSCs) and their behaviors will provide insightful information for the future control of human cancers. This study investigated CD44 and CD24 cell surface markers as breast cancer CSC markers in vitro and in vivo. METHODS: Flow cytometry with CD44 and CD24 markers was used to sort breast cancer MCF7 cells for scanning electron microscopy (SEM), tumor cell invasion assay, and nude mouse xenograft assay. RESULTS: Flow cytometry assay using CD44 and CD24 markers sorted MCF7 cells into four subsets, i.e., CD44+/CD24-/low, CD44-/CD24+, CD44+/CD24+, and CD44-/CD24-. The SEM data showed that there were many protrusions on the surface of CD44+/CD24-/low cells. CD44+/CD24-/low cells had many microvilli and pseudopodia. The CD44+/CD24-/low cells had a higher migration and invasion abilities than that of the other three subsets of the cells. The in vivo tumor formation assay revealed that CD44+/CD24- cells had the highest tumorigenic capacity compared to the other three subsets. CONCLUSION: CD44 and CD24 could be useful markers for identification of breast CSCs because CD44+/CD24-/low cells had unique surface ultrastructures and the highest tumorigenicity and invasive abilities. PMID- 23799995 TI - Graphene quantum dots as universal fluorophores and their use in revealing regulated trafficking of insulin receptors in adipocytes. AB - Graphene quantum dots (GQDs) hold great promise as a new class of fluorophores for bioimaging, owing to their remarkable physicochemical properties including tunable photoluminescence, excellent photostability, and biocompatibility. Despite their highly anticipated potentials, GQDs have yet to be used to specifically label and track molecular targets involved in dynamic cellular processes in live cells. Here, we demonstrate that GQDs can serve as universal fluorophores for bioimaging because they can be readily conjugated with a wide range of biomolecules while preserving their functionalities. As a proof-of concept demonstration, insulin-conjugated GQDs have been synthesized and utilized for specific labeling and dynamic tracking of insulin receptors in 3T3-L1 adipocytes. Our experiments reveal, for the first time, that the internalization and recycling of insulin receptors in adipocytes are oppositely regulated by apelin and TNFalpha, which may contribute to the regulations of these two cytokines in insulin sensitivity. PMID- 23799996 TI - SBRT in unresectable advanced pancreatic cancer: preliminary results of a mono institutional experience. AB - BACKGROUND: To assess the efficacy and safety of stereotactic body radiotherapy (SBRT) in patients with either unresectable locally advanced pancreatic adenocarcinoma or by locally recurrent disease after surgery. METHODS: Between January 2010 and October 2011, 30 patients with unresectable or recurrent pancreatic adenocarcinoma underwent exclusive SBRT. Twenty-one patients (70%) presented with unresectable locally advanced disease and 9 patients (30%) showed local recurrence after surgery. No patients had metastatic disease. Gemcitabine based chemotherapy was administered to all patients before SBRT. Prescription dose was 45Gy in 6 daily fractions of 7.5Gy. SBRT was delivered using the volumetric modulated arc therapy (VMAT) by RapidArc. Primary end-point of this study was freedom from local progression (FFLP), secondary end-points were overall survival (OS), progression free survival (PFS) and toxicity. RESULTS: Median Clinical Target Volume (CTV) was 25.6 cm3 (3.2-78.8 cm3) and median Planning Target Volume (PTV) was 70.9 cm3 (20.4- 205.2 cm3). The prescription dose was delivered in 25 patients (83%), in 5 patients (17%) it was reduced to 36Gy in 6 fractions not to exceed the dose constraints of organs at risk (OARs). Median follow-up was 11 months (2-28 months). FFLP was 91% at 6 months, 85% at median follow-up and 77% at 1 and 2 years. For the group with prescription dose of 45Gy, FFLP was 96% at 1 and 2 years. The median PFS was 8 months. The OS was 47% at 1 year and median OS was 11 months. At the end of the follow-up, 9 patients (32%) were alive and 4 (14%) were free from progression. No patients experienced G >= 3 acute toxicity. CONCLUSIONS: Our preliminary results show that SBRT can obtain a satisfactory local control rate for unresectable locally advanced and recurrent pancreatic adenocarcinoma. This fractionation schedule is feasible, and no G >= 3 toxicity was observed. SBRT is an effective emerging technique in the multi-modality treatment of locally advanced pancreatic tumors. PMID- 23799997 TI - Morphogenesis of peri-implant mucosa revisited: an experimental study in humans. AB - AIM: To apply a novel human model to evaluate the morphogenesis of the mucosal attachment to implants. MATERIAL AND METHODS: Twenty one patients receiving implant-supported single-tooth replacement were enrolled in this study. After implant installation, a custom-designed experimental abutment was connected to the implant. Soft tissue biopsies representing 2, 4, 8 or 12 weeks of healing were collected by the use of a circular cutting device and prepared for histological analysis. RESULTS: The soft tissue biopsies were retrieved, preserved and processed with a technique that was safe and reproducible. The results from the histological analysis in regards to dimensional and qualitative changes in the mucosa over time were consistent with those reported from animal experiments. At 8 weeks, the soft tissue dimension was about 3.6 mm and included a barrier epithelium of 1.9 mm and a connective tissue portion of 1.7 mm. Similar dimensions were found at 12 weeks. CONCLUSION: It is suggested that the new human model provides advantages in terms of cost-effectiveness in research as well as from ethical aspects and should be considered as an alternative to pre-clinical in vivo studies in animals. PMID- 23799998 TI - To transform renal patient care. PMID- 23799999 TI - Surveillance on A/H5N1 virus in domestic poultry and wild birds in Egypt. AB - BACKGROUND: The endemic H5N1 high pathogenicity avian influenza virus (A/H5N1) in poultry in Egypt continues to cause heavy losses in poultry and poses a significant threat to human health. METHODS: Here we describe results of A/H5N1 surveillance in domestic poultry in 2009 and wild birds in 2009-2010. Tracheal and cloacal swabs were collected from domestic poultry from 22024 commercial farms, 1435 backyards and 944 live bird markets (LBMs) as well as from 1297 wild birds representing 28 different types of migratory birds. Viral RNA was extracted from a mix of tracheal and cloacal swabs media. Matrix gene of avian influenza type A virus was detected using specific real-time reverse-transcription polymerase chain reaction (RT-qPCR) and positive samples were tested by RT-qPCR for simultaneous detection of the H5 and N1 genes. RESULTS: In this surveillance, A/H5N1 was detected from 0.1% (n = 23/) of examined commercial poultry farms, 10.5% (n = 151) of backyard birds and 11.4% (n = 108) of LBMs but no wild bird tested positive for A/H5N1. The virus was detected from domestic poultry year round with higher incidence in the warmer months of summer and spring particularly in backyard birds. Outbreaks were recorded mostly in Lower Egypt where 95.7% (n = 22), 68.9% (n = 104) and 52.8% (n = 57) of positive commercial farms, backyards and LBMs were detected, respectively. Higher prevalence (56%, n = 85) was reported in backyards that had mixed chickens and waterfowl together in the same vicinity and LBMs that had waterfowl (76%, n = 82). CONCLUSION: Our findings indicated broad circulation of the endemic A/H5N1 among poultry in 2009 in Egypt. In addition, the epidemiology of A/H5N1 has changed over time with outbreaks occurring in the warmer months of the year. Backyard waterfowl may play a role as a reservoir and/or source of A/H5N1 particularly in LBMs. The virus has been established in poultry in the Nile Delta where major metropolitan areas, dense human population and poultry stocks are concentrated. Continuous surveillance, tracing the source of live birds in the markets and integration of multifaceted strategies and global collaboration are needed to control the spread of the virus in Egypt. PMID- 23800000 TI - Cataract surgery: the 'race' to lower intraocular pressure. PMID- 23800002 TI - Obstetric complications in women with polycystic ovary syndrome: a systematic review and meta-analysis. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of childbearing age. The risk of pregnancy and neonatal complications in women with PCOS is debatable. In order to determine the risk of pregnancy and neonatal complications, evidence regarding these risks was examined. METHODS: Literature searches were performed in the electronic databases MEDLINE, EMBASE, and CENTRAL based on the established strategy and eligible tries were included according to inclusion and exclusion criteria. A systematic literature review looking at rates of gestational diabetes mellitus (GDM), pregnancy-induced hypertension (PIH), preeclampsia, premature delivery, neonatal birth weight, caesarean section and admission to a neonatal intensive care unit (NICU) was conducted in women with PCOS. Pregnancy outcomes between women with PCOS versus controls were included. Sensitivity analyses were performed to determine the reliability of the available evidence and to validate the results. The study was performed with the approval of the ethics committee of the First Affiliated Hospital of Guangxi Medical University. RESULTS: A total of 27studies, involving 4982 women with PCOS and 119692 controls were eligible for the meta-analysis. Women with PCOS demonstrated a significantly higher risk of developing GDM (OR3.43; 95% CI: 2.49-4.74), PIH (OR3.43; 95% CI: 2.49-4.74), preeclampsia (OR2.17; 95% CI: 1.91-2.46), preterm birth (OR1.93; 95%CI: 1.45-2.57), caesarean section (OR 1.74; 95% CI: 1.38-2.11) compared to controls. Their babies had a marginally significant lower birth weight (WMD -0.11g; 95%CI: -0.19 - -0.03), and higher risk of admission to NICU (OR 2.32; 95% CI: 1.40-3.85) compared to controls. CONCLUSIONS: Women with PCOS have increased risk of adverse pregnancy and neonatal complications. It is necessary to establish guidelines for supervision during pregnancy and parturition to prevent these complications. PMID- 23800003 TI - Can unknown predisposition in familial breast cancer be family-specific? AB - Genetic predisposition plays a key role in the development of familial breast cancer. In spite of strong familial clustering of the disease and extensive efforts made during the past decade; however, progress has been slow in identifying genetic predisposition for the majority of familial breast cancer families. The question arises therefore as to whether current approaches are adequate in identifying the unknown genetic predisposition. We analyzed eight members of a BRCA1-, BRCA2-, p53-, and PTEN-negative breast cancer family, of which five had breast cancer, one is an obligate gene carrier, and two were unaffected. We sequenced the entire coding region of the genome for each member using exome sequencing to identify nonsynonymous variants. We identified 55 nonsynonymous germline variants affecting 49 genes in multiple members of the family, of which 22 are predicted to have damaging effects. We validated 20 of the 22 selected variants in the family by Sanger sequencing. Two variants in KAT6B, an acetal transferase gene, were identified in six family members of which five were affected with breast cancer and one is the unaffected obligate carrier. We further examined the presence of the identified variants in a cohort of 40 additional breast cancer cases from 22 familial breast cancer families, but none of the 22 variants was detected in these cases. Sequencing the entire coding exons in KAT6B detects no variants in these cases. Our results show that genetic predisposition for familial breast cancer can be rich in an affected family, but the predisposition can be family-specific. As such, it will be difficult to detect them by applying population-based approach. Our study supports the concept that focusing on each affected family will be required to determine the genetic predisposition for many familial breast cancer families whose genetic dispositions remain unknown. PMID- 23800004 TI - Comparison of heart rate and oxygen saturation measurements from Masimo and Nellcor pulse oximeters in newly born term infants. AB - AIM: To compare heart rate (HR) measurements from Masimo and Nellcor pulse oximeters (POs) against HR measured via a three lead electrocardiograph (ECG) (HRECG ). We also compared peripheral oxygen saturation (SpO2 ) measurements between Nellcor and Masimo oximeters. METHOD: Term infants born via elective caesarean section were studied. ECG leads were placed on the infant's chest and abdomen. Masimo and Nellcor PO sensors were randomly allocated to either foot. The monitors were placed on a trolley, and data from each monitor screen captured by a video camera. HR, SpO2 measurements and signal quality were extracted. Bland Altman analysis was used to determine agreement between HR from the ECG and each oximeter, and between SpO2 from the oximeters. RESULTS: We studied 44 infants of whom 4 were resuscitated. More than 8000 pairs of observations were used for each comparison of HR and SpO2. The mean difference (+/-2SD) between HRECG and HRN ellcor was -0.8 (+/-11) beats per minute (bpm); between HRECG and HRM asimo was 0.2 (+/-9) bpm. The mean (+/-2SD) difference between SpO2Masimo and SpO2Nellcor was -3 (+/-15)%. The Nellcor PO measured 20% higher than the Masimo PO at SpO2 <70%. CONCLUSION: Both oximeters accurately measure HR. There was good agreement between SpO2 measurements when SpO2 >=70%. At lower SpO2 , agreement was poorer. PMID- 23800005 TI - Benign pericardial schwannoma in a Chinese woman: a case report. AB - BACKGROUND: Intrathoracic schwannomas are most frequently located in the posterior mediastinum. A Chinese woman presented with a benign pericardial schwannoma in the pretracheal space and aortopulmonary window, a location which has not been described previously in the literature. CASE PRESENTATION: A 50-year old Chinese woman initially reported a cough associated with a small amount of sputum. Contrast-enhanced computed tomography (CT) subsequently revealed a 9 * 11 cm2 lobulated mass with sharp margins that presented as a capsule with heterogeneous enhancement and punctate calcification. Complete surgical resection was performed using a thoracotomy approach. The resected intrapericardial tumor was a firm, large mass with lobulation. Capsulation prevented infiltration of the mass into adjacent organs. Pathological examination verified that the tumor was a benign pericardial schwannoma. CONCLUSION: This is the first reported case of a benign pericardial schwannoma located in the pretracheal space and aortopulmonary window. While a contrast-enhanced CT scan was able to differentiate this pericardial schwannoma from other middle mediastinal tumors, the exact diagnosis and plan for treatment depended on a pathological examination. For similar cases involving pericardial schwannomas, complete surgical resection is recommended, particularly for the prevention of life-threatening cardiopulmonary complications. PMID- 23800006 TI - A study on the distribution of 37 well conserved families of C2H2 zinc finger genes in eukaryotes. AB - BACKGROUND: The C2H2 zinc-finger (ZNF) containing gene family is one of the largest and most complex gene families in metazoan genomes. These genes are known to exist in almost all eukaryotes, and they constitute a major subset of eukaryotic transcription factors. The genes of this family usually occur as clusters in genomes and are thought to have undergone a massive expansion in vertebrates by multiple tandem duplication events (BMC Evol Biol 8:176, 2008). RESULTS: In this study, we combined two popular approaches for homolog detection, Reciprocal Best Hit (RBH) (Proc Natl Acad Sci USA 95:6239-6244, 1998) and Hidden Markov model (HMM) profiles search (Bioinformatics 14:755-763, 1998), on a diverse set of complete genomes of 124 eukaryotic species ranging from excavates to humans to identify all detectable members of 37 C2H2 ZNF gene families. We succeeded in identifying 3,890 genes as distinct members of 37 C2H2 gene families. These 37 families are distributed among the eukaryotes as progressive additions of gene blocks with increasing complexity of the organisms. The first block featuring the protists had 7 families, the second block featuring plants had 2 families, the third block featuring the fungi had 2 families (one of which was also present in plants) and the final block consisted of metazoans with 25 families. Among the metazoans, the simpler unicellular metazoans had just 15 of the 25 families while most of the bilaterians had all 25 families making up a total of 37 families. Multiple potential examples of lineage-specific gene duplications and gene losses were also observed. CONCLUSIONS: Our hybrid approach combines features of the both RBH and HMM methods for homolog detection. This largely automated technique is much faster than manual methods and is able to detect homologs accurately and efficiently among a diverse set of organisms. Our analysis of the 37 evolutionarily conserved C2H2 ZNF gene families revealed a stepwise appearance of ZNF families, agreeing well with the phylogenetic relationship of the organisms compared and their presumed stepwise increase in complexity (Science 300:1694, 2003). PMID- 23800007 TI - 'Roll-your-own' cigarette smoking in South Africa between 2007 and 2010. AB - BACKGROUND: The prevalence of smoking and consumption of cigarettes have decreased in South Africa over the last 20 years. This decrease is a result of comprehensive tobacco control legislation, particularly large cigarette tax increases. However, little attention has been given to the potential use of 'roll your-own' cigarettes as cheaper alternatives, especially among the socio economically disadvantaged population. This study therefore sought to determine socio-demographic correlates of 'roll-your-own' cigarette use among South African adults (2007-2010). METHODS: This secondary data analysis used a merged dataset from two nationally representative samples of 2 907 and 3 112 South African adults (aged >=16 years) who participated in the 2007 and 2010 annual South African Social Attitude Surveys respectively. The surveys used a face-to-face interviewer-administered questionnaire. The overall response rates were 83.1% for 2007 and 88.9% for 2010. Data elicited included socio-demographic data, current smoking status, type of tobacco products used, past quit attempts and self efficacy in quitting. Data analysis included chi-square statistics and multi variable adjusted logistic regression analysis. RESULTS: Of the 1 296 current smokers in this study, 24.1% (n = 306) reported using roll-your-own cigarettes. Some of whom also smoked factory-made cigarettes. Roll-your-own cigarette smoking was most common among black Africans and was more common among male smokers than among female smokers (27% vs 15.8%; p < 0.01). Compared to smokers who exclusively used factory-made cigarettes, roll-your-own cigarette smokers were less confident that they could quit, more likely to be less educated, and more likely to reside in rural areas. The odds of use of roll-your-own cigarette were significantly higher in 2010 than in 2007 (OR = 1.24; 95% CI: 1.07-1.44). CONCLUSIONS: Despite an aggregate decline in smoking prevalence, roll-your-own cigarette smoking has increased and is particularly common among smokers in the lower socio-economic group. The findings also suggest the need for a more intensive treatment intervention to increase self-efficacy to quit among roll your-own cigarette smokers. PMID- 23800008 TI - Drug safety evaluation of vemurafenib in the treatment of melanoma. AB - INTRODUCTION: Nearly 50% of melanomas harbor a BRAF mutation, and vemurafenib has shown a clinical response rate of approximately 50% and a median progression-free survival duration of ~ 6 - 7 months in patients with V600 BRAF-mutant advanced melanoma. Based on a Phase III study demonstrating a survival advantage over dacarbazine, vemurafenib was approved by the regulatory agencies for the treatment of V600 BRAF-mutant advanced melanoma in 2011. Although vemurafenib does not induce life-threatening toxicity frequently associated with conventional chemotherapy. It is associated with other adverse events, particularly skin toxicities. AREAS COVERED: We discuss the mechanism of action, pharmacokinetics and pharmacodynamics, clinical efficacy, and safety profile of vemurafenib in patients with metastatic melanoma harboring a BRAF mutation. In particular, we describe in detail the skin toxicity of vemurafenib, including the development of keratoacanthoma and squamous cell carcinoma of the skin. EXPERT OPINION: Both preclinical and clinical investigations have shed light on our understanding of the skin toxicities associated with vemurafenib and have led to potential strategies for reducing the frequency of these adverse events. Further understanding of other associated toxicities could significantly improve the quality of life for patients undergoing treatment with vemurafenib or another BRAF inhibitor. PMID- 23800009 TI - Macromolecular juggling by ubiquitylation enzymes. AB - The posttranslational modification of target proteins with ubiquitin and ubiquitin-like proteins is accomplished by the sequential action of E1, E2, and E3 enzymes. Members of the E1 and E3 enzyme families can undergo particularly large conformational changes during their catalytic cycles, involving the remodeling of domain interfaces. This enables the efficient, directed and regulated handover of ubiquitin from one carrier to the next one. We review some of these conformational transformations, as revealed by crystallographic studies. PMID- 23800010 TI - Drug repositioning: a machine-learning approach through data integration. AB - : Existing computational methods for drug repositioning either rely only on the gene expression response of cell lines after treatment, or on drug-to-disease relationships, merging several information levels. However, the noisy nature of the gene expression and the scarcity of genomic data for many diseases are important limitations to such approaches. Here we focused on a drug-centered approach by predicting the therapeutic class of FDA-approved compounds, not considering data concerning the diseases. We propose a novel computational approach to predict drug repositioning based on state-of-the-art machine-learning algorithms. We have integrated multiple layers of information: i) on the distances of the drugs based on how similar are their chemical structures, ii) on how close are their targets within the protein-protein interaction network, and iii) on how correlated are the gene expression patterns after treatment. Our classifier reaches high accuracy levels (78%), allowing us to re-interpret the top misclassifications as re-classifications, after rigorous statistical evaluation. Efficient drug repurposing has the potential to significantly impact the whole field of drug development. The results presented here can significantly accelerate the translation into the clinics of known compounds for novel therapeutic uses. PMID- 23800012 TI - Visualizing carbene equilibria. AB - Reviewed herein are equilibria between halocarbenes and halocarbanions, carbenes and carbene complexes and carbenes and O-ylides. The transient species were visualized by laser flash photolysis coupled with UV-Visible spectroscopy. This methodology enabled the determination of equilibrium constants and the extraction of associated thermodynamic parameters. Parallel computational studies provided anticipated structures and energies for the transient species, as well as electronic absorption wavelengths and oscillator strengths. PMID- 23800011 TI - A high density physical map of chromosome 1BL supports evolutionary studies, map based cloning and sequencing in wheat. AB - BACKGROUND: As for other major crops, achieving a complete wheat genome sequence is essential for the application of genomics to breeding new and improved varieties. To overcome the complexities of the large, highly repetitive and hexaploid wheat genome, the International Wheat Genome Sequencing Consortium established a chromosome-based strategy that was validated by the construction of the physical map of chromosome 3B. Here, we present improved strategies for the construction of highly integrated and ordered wheat physical maps, using chromosome 1BL as a template, and illustrate their potential for evolutionary studies and map-based cloning. RESULTS: Using a combination of novel high throughput marker assays and an assembly program, we developed a high quality physical map representing 93% of wheat chromosome 1BL, anchored and ordered with 5,489 markers including 1,161 genes. Analysis of the gene space organization and evolution revealed that gene distribution and conservation along the chromosome results from the superimposition of the ancestral grass and recent wheat evolutionary patterns, leading to a peak of synteny in the central part of the chromosome arm and an increased density of non-collinear genes towards the telomere. With a density of about 11 markers per Mb, the 1BL physical map provides 916 markers, including 193 genes, for fine mapping the 40 QTLs mapped on this chromosome. CONCLUSIONS: Here, we demonstrate that high marker density physical maps can be developed in complex genomes such as wheat to accelerate map based cloning, gain new insights into genome evolution, and provide a foundation for reference sequencing. PMID- 23800013 TI - What is your diagnosis? Renal mass in a dog. PMID- 23800015 TI - Mediastinal epithelioid hemangioendothelioma with abundant spindle cells and osteoclast-like giant cells mimicking malignant fibrous histiocytoma. AB - Epithelioid hemangioendothelioma is a relatively uncommon lesion usually presenting in soft tissues. The occurrence in the mediastinum is exceptional rare. Histologically, this tumor is characterized by epithelioid cells with intracytoplasmic vacuoles in a hyalinized or mucinous stroma. Occasionally, spindle cells or osteoclast-like giant cells can be observed. Herein, we present a case of epithelioid hemangioendothelioma in a 38 year-old Chinese male. The tumor was predominantly composed of abundant spindle cells with marked atypia and scattered osteoclast-like giant cells reminiscent of malignant fibrous histiocytoma. The unusual histological appearance can pose a great diagnostic challenge. It may be easily misdiagnosed, especially if the specimen is limited or from fine-needle aspiration. PMID- 23800016 TI - New findings and concepts about the G-spot in normal and absent vagina: precautions possibly needed for preservation of the G-spot and sexuality during surgery. AB - AIM: The aim of this study was to extend the clinicohistological study to involve the whole normal and absent vagina for confirming the presence of the G-spot and its relation to the surrounding organs and sexuality and to identify certain precautions for its preservation during surgery. MATERIAL AND METHODS: This study was a descriptive randomized prospective study conducted at Kasr El Aini School of Medicine, Cairo University, Egypt. The G-spot was examined in 1500 women, 500 of them having vaginal and vulval surgery done for gynecological reasons. The G spot was examined for its clinical and histological features and for determining the effect of surgery on its state and function. RESULTS: The G-spot was found to be present in all women. It was a localized spot in 58% and diffuse in 42% of cases. Associated ejaculation was reported in all cases of the localized type and in 24.5% of the diffuse types. Clinical examination was found to be associated with certain local response in 52.7% of the local types. The G-spot was also found to be connected to the hymen in 100%, the urethra in 52.7%, the vulva in 82.2% and the cervix in 10.8% of cases. The mean of the sex scores and sexuality were significantly decreased in surgery involving the G-spot area. Recorded figures were 93.6 +/- 3.4 and 88.2 +/- 3.3 before and after surgery, respectively. The corresponding figures in the cases having a general spot were 86.4 +/- 4.4 and 84.5 +/- 2.4, respectively. The G-spot was found in cases of absent vagina to be localized in 59%, generalized in 28.2% and absent in 12.8% of cases. CONCLUSIONS: The G-spot is actually present in all women. It is originally related to the lower urinary tract and it is connected to different parts of the genital tract. It may be localized or generalized. Its integrity is essential for obtaining normal physiological sexuality. Surgery may affect the integrity of the G-spot, so surgical precautions must be carried out to maintain the integrity of this spot and the patient's sexuality. PMID- 23800014 TI - An emerging role for the anti-inflammatory cytokine interleukin-10 in dengue virus infection. AB - Infection with dengue virus (DENV) causes both mild dengue fever and severe dengue diseases, such as dengue hemorrhagic fever and dengue shock syndrome. The pathogenic mechanisms for DENV are complicated, involving viral cytotoxicity, immunopathogenesis, autoimmunity, and underlying host diseases. Viral load correlates with disease severity, while the antibody-dependent enhancement of infection largely determines the secondary effects of DENV infection. Epidemiological and experimental studies have revealed an association between the plasma levels of interleukin (IL)-10, which is the master anti-inflammatory cytokine, and disease severity in patients with DENV infection. Based on current knowledge of IL-10-mediated immune regulation during infection, researchers speculate an emerging role for IL-10 in clinical disease prognosis and dengue pathogenesis. However, the regulation of dengue pathogenesis has not been fully elucidated. This review article discusses the regulation and implications of IL 10 in DENV infection. For future strategies against DENV infection, manipulating IL-10 may be an effective antiviral treatment in addition to the development of a safe dengue vaccine. PMID- 23800017 TI - Plan-provider integration, premiums, and quality in the Medicare Advantage market. AB - OBJECTIVE: To investigate how integration between Medicare Advantage plans and health care providers is related to plan premiums and quality ratings. DATA SOURCE: We used public data from the Centers for Medicare and Medicaid Services (CMS) and the Area Resource File and private data from one large insurer. Premiums and quality ratings are from 2009 CMS administrative files and some control variables are historical. STUDY DESIGN: We estimated ordinary least squares models for premiums and plan quality ratings, with state fixed effects and firm random effects. The key independent variable was an indicator of plan provider integration. DATA COLLECTION: With the exception of Medigap premium data, all data were publicly available. We ascertained plan-provider integration through examination of plans' websites and governance documents. PRINCIPAL FINDINGS: We found that integrated plan-providers charge higher premiums, controlling for quality. Such plans also have higher quality ratings. We found no evidence that integration is associated with more generous benefits. CONCLUSIONS: Current policy encourages plan-provider integration, although potential effects on health insurance products and markets are uncertain. Policy makers and regulators may want to closely monitor changes in premiums and quality after integration and consider whether quality improvement (if any) justifies premium increases (if they occur). PMID- 23800018 TI - Quality assessment on Polygoni Multiflori Caulis using HPLC/UV/MS combined with principle component analysis. AB - BACKGROUND: Polygoni Multiflori Caulis, the dried caulis of Polygonum multiflorum Thunb., is one of the commonly used traditional Chinese medicines having antioxidant, anti-obesity, anti-inflammatory and antibacterial effects. Polygoni Multiflori Caulis used clinically or circulated on market have great differences in their diameters. However, to the best of our knowledge, no study has been reported on the qualities of Polygoni Multiflori Caulis with different diameters. RESULTS: Systematic HPLC/UV/MS chromatographic fingerprinting and quantitative analytical methods combined with principal component analysis were developed and applied to analyze different Polygoni Multiflori Caulis samples. The contents of 2,3,5,4'-tetrahydroxystilbene-2-O-beta-D-glucoside, the chemical marker for quality control on Polygoni Multiflori Caulis specified in Chinese Pharmacopoeia (2010 edition), were found to have surprising relevance with the samples' diameters for the first time. CONCLUSION: The finding provides a scientific basis for collecting Polygoni Multiflori Caulis in the best time. Moreover, the diameter can be used as the criterion for quality control on Polygoni Multiflori Caulis as a preliminary step in the future. In addition, scores plot obtained from principal component analysis shows the obvious differences between unqualified Polygoni Multiflori Caulis samples and qualified ones visually, which can be used to single out the unqualified ones with qualified ones efficiently and immediately. PMID- 23800019 TI - Relation between the diffusivity, viscosity, and ionic radius of LiCl in water, methanol, and ethylene glycol: a molecular dynamics simulation. AB - A molecular dynamics (MD) investigation of LiCl in water, methanol, and ethylene glycol (EG) at 298 K is reported. Several structural and dynamical properties of the ions as well as the solvent such as self-diffusivity, radial distribution functions, void and neck distributions, velocity autocorrelation functions, and mean residence times of solvent in the first solvation shell have been computed. The results show that the reciprocal relationship between the self-diffusivity of the ions and the viscosity is valid in almost all solvents with the exception of water. From an analysis of radial distribution functions and coordination numbers the nature of hydrogen bonding within the solvent and its influence on the void and neck distribution becomes evident. It is seen that the solvent-solvent interaction is important in EG while solute-solvent interactions dominate in water and methanol. From Voronoi tessellation, it is seen that the voids and necks within methanol are larger as compared to those within water or EG. On the basis of the void and neck distributions obtained from MD simulations and literature experimental data of limiting ion conductivity for various ions of different sizes, we show that there is a relation between the void and neck radius on the one hand and dependence of conductivity on the ionic radius on the other. It is shown that the presence of large diameter voids and necks in methanol is responsible for maximum in limiting ion conductivity (lambda0) of TMA+, while in water and EG, the maximum is seen for Rb+. In the case of monovalent anions, maximum in lambda0 as a function ionic radius is seen for Br- in water and EG but for the larger ClO4 - ion in methanol. The relation between the void and neck distribution and the variation in lambda0 with ionic radius arises via the Levitation effect which is discussed. These studies show the importance of the solvent structure and the associated void structure. PMID- 23800020 TI - Lessons learned from implementing a national infrastructure in Sweden for storage and analysis of next-generation sequencing data. AB - : Analyzing and storing data and results from next-generation sequencing (NGS) experiments is a challenging task, hampered by ever-increasing data volumes and frequent updates of analysis methods and tools. Storage and computation have grown beyond the capacity of personal computers and there is a need for suitable e-infrastructures for processing. Here we describe UPPNEX, an implementation of such an infrastructure, tailored to the needs of data storage and analysis of NGS data in Sweden serving various labs and multiple instruments from the major sequencing technology platforms. UPPNEX comprises resources for high-performance computing, large-scale and high-availability storage, an extensive bioinformatics software suite, up-to-date reference genomes and annotations, a support function with system and application experts as well as a web portal and support ticket system. UPPNEX applications are numerous and diverse, and include whole genome-, de novo- and exome sequencing, targeted resequencing, SNP discovery, RNASeq, and methylation analysis. There are over 300 projects that utilize UPPNEX and include large undertakings such as the sequencing of the flycatcher and Norwegian spruce. We describe the strategic decisions made when investing in hardware, setting up maintenance and support, allocating resources, and illustrate major challenges such as managing data growth. We conclude with summarizing our experiences and observations with UPPNEX to date, providing insights into the successful and less successful decisions made. PMID- 23800021 TI - Evaluation of antioxidant and anticancer properties of the seed extracts of Syzygium fruticosum Roxb. growing in Rajshahi, Bangladesh. AB - BACKGROUND: The use of plants and their derived substances increases day by day for the discovery of therapeutic agents owing to their versatile applications. Current research is directed towards finding naturally-occurring antioxidants having anticancer properties from plant origin since oxidants play a crucial role in developing various human diseases. The present study was designed to investigate the antioxidant and anticancer properties of Sygygium fruticosum (Roxb.) (abbreviated as SF). METHODS: The dried coarse powder of seeds of SF was exhaustively extracted with methanol and the resulting crude methanolic extract (CME) was successively fractionated with petroleum ether, chloroform and ethyl acetate to get petroleum ether (PEF), chloroform (CHF), ethyl acetate (EAF) and lastly aqueous (AQF) fraction. The antioxidant activities were determined by several assays: total antioxidant capacity assay, DPPH free radical scavenging assay, hydroxyl radical scavenging assay, ferrous reducing antioxidant capacity and lipid peroxidation inhibition assay. The in vivo anticancer activity of SF was determined on Ehrlich's Ascite cell (EAC) induced Swiss albino mice. RESULTS: All the extractives showed strong antioxidant activities related to the standard. The total antioxidant capacity (TAC) of the fractions was in the following order: EAF>AQF>CME>PEF>CHF. The TAC of EAF at 320 MUg/mL was 2.60+/-0.005 which was significantly higher (p < 0.01) than that of standard catechin (1.37 +/- 0.005). The ferrous reducing antioxidant capacity of the extracts was in the following order: EAF>AQF>CME>AA>CHF>PEF. In DPPH free radical scavenging assay, the IC50 value of EAF was 4.85 MUg/mL, whereas that of BHT was 9.85 MUg/mL. In hydroxyl radical scavenging assay and lipid peroxidation inhibition assay, the EAF showed the most potent inhibitory activity with IC50 of 43.3 and 68.11 MUg/mL, respectively. The lipid peroxidation inhibition assay was positively correlated (p < 0 .001) with both DPPH free radical scavenging and hydroxyl radical scavenging assay. The total phenolic contents of SF were also positively correlated (p < 0 .001) with DPPH free radical scavenging, hydroxyl radical scavenging and lipid peroxidation inhibition assay. Based on antioxidant activity, EAF was selected for cytotoxic assay and it was found that EAF inhibited 67.36% (p < 0.01) cell growth at a dose of 50 mg/kg (ip) on day six of EAC cell incubation. CONCLUSIONS: Our results suggest that EAF of seeds of SF possess significant antioxidant and moderate anticancer properties. Seeds of SF may therefore be a good source for natural antioxidants and a possible pharmaceutical supplement. PMID- 23800022 TI - Genistein promotes cell death of ethanol-stressed HeLa cells through the continuation of apoptosis or secondary necrosis. AB - BACKGROUND: Apoptosis is a major target and treatment effect of multiple chemotherapeutical agents in cancer. A soybean isoflavone, genistein, is a well studied chemopreventive agent and has been reported to potentiate the anticancer effect of some chemotherapeutics. However, its mechanistic basis of chemo enhancement effect remains to be fully elucidated. METHODS: Apoptotic features of low concentration stressed cancer cells were studied by microscopic method, western blot, immunostaining and annexin V/PI assay. Genistein's effects on unstressed cells and recovering cells were investigated using MTT cell viability assay and LDH cytotoxicity assay. Quantitative real-time PCR was employed to analyze the possible gene targets involved in the recovery and genistein's effect. RESULTS: Low-concentration ethanol stressed cancer cells showed apoptotic features and could recover after stress removal. In stressed cells, genistein at sub-toxic dosage promoted the cell death. Quantitative real-time PCR revealed the up-regulation of anti-apoptotic genes MDM2 and XIAP during the recovery process in HeLa cells, and genistein treatment suppressed their expression. The application of genistein, MDM2 inhibitor and XIAP inhibitor to the recovering HeLa cells caused persistent caspase activity and enhanced cell death. Flow cytometry study indicated that genistein treatment could lead to persistent phosphatidylserine (PS) externalization and necrotic events in the recovering HeLa cells. Caspase activity inhibition shifted the major effect of genistein to necrosis. CONCLUSIONS: These results suggested two possible mechanisms through which genistein promoted cell death in stressed cancer cells. Genistein could maintain the existing apoptotic signal to enhance apoptotic cell death. It could also disrupt the recovering process in caspase-independent manner, which lead to necrotic events. These effects may be related to the enhanced antitumor effect of chemotherapeutic drugs when they were combined with genistein. PMID- 23800023 TI - The clinical status and survival in elderly dialysis: example of the oldest region of France. AB - BACKGROUND: The number of elderly (>=75 years) patients with end-stage renal disease (ESRD) has increased markedly, including in the Limousin region, which has the oldest population in France. We retrospectively compared outcomes in elderly and non-elderly ESRD patients who started dialysis during two time periods. METHODS: Baseline clinical characteristics, care, and survival rates were assessed in 557 ESRD patients aged >=75 and <75 years who started dialysis in 2002-2004 and 2005-2007. Survival curves and Cox proportional hazards model were used to assess survival and factors associated with survival. RESULTS: Of the 557 patients, 343 and 214 were <75 years and >=75 years, respectively. Dialysis was started in 2002-2004 and 2005-2007 by 197 and 146 patients <75 years, respectively, and by 96 and 118 patients >=75 years, respectively. Median age (73.4 years [interquartile range [IQR] 61.7-79.5 years] vs 69.5 years [IQR 57.4-77.4 years] p = 0.001) and the proportion aged >=75 years (44.7% vs 32.8%, p = 0.004) were significantly higher in 2005-2007 than in 2002-2004. Improved initial status during 2005-2007 was observed only in patients >=75 years, with a decrease in some co-morbidities, improved walking and better preparation for dialysis. Mortality rates were significantly lower in 2005-2007 than in 2002-2004 (hazard ratio 0.81, 95% confidence interval 0.69-0.95; p = 0.008), with the difference due to factors associated with clinical status and care. CONCLUSIONS: Improved initial clinical status and better preparation for dialysis, accompanied by increased survival, were observed for patients >=75 years who started dialysis more recently, perhaps because of early referral to a nephrologist. PMID- 23800024 TI - Dosimetric accuracy and clinical quality of Acuros XB and AAA dose calculation algorithm for stereotactic and conventional lung volumetric modulated arc therapy plans. AB - INTRODUCTION: The main aim of the current study was to assess the dosimetric accuracy and clinical quality of volumetric modulated arc therapy (VMAT) plans for stereotactic (stage I) and conventional (stage III) lung cancer treatments planned with Eclipse version 10.0 Anisotropic Analytical Algorithm (AAA) and Acuros XB (AXB) algorithm. METHODS: The dosimetric impact of using AAA instead of AXB, and grid size 2.5 mm instead of 1.0 mm for VMAT treatment plans was evaluated. The clinical plan quality of AXB VMAT was assessed using 45 stage I and 73 stage III patients, and was compared with published results, planned with VMAT and hybrid-VMAT techniques. RESULTS: The dosimetric impact on near-minimum PTV dose (D98%) using AAA instead of AXB was large (underdose up to 12.3%) for stage I and very small (underdose up to 0.8%) for stage III lung treatments. There were no significant differences for dose volume histogram (DVH) values between grid sizes. The calculation time was significantly higher for AXB grid size 1.0 than 2.5 mm (p < 0.01). The clinical quality of the VMAT plans was at least comparable with clinical qualities given in literature of lung treatment plans with VMAT and hybrid-VMAT techniques. The average mean lung dose (MLD), lung V(20Gy) and V(5Gy) in this study were respectively 3.6 Gy, 4.1% and 15.7% for 45 stage I patients and 12.4 Gy, 19.3% and 46.6% for 73 stage III lung patients. The average contra-lateral lung dose V(5Gy-cont) was 35.6% for stage III patients. CONCLUSIONS: For stereotactic and conventional lung treatments, VMAT calculated with AXB grid size 2.5 mm resulted in accurate dose calculations. No hybrid technique was needed to obtain the dose constraints. AXB is recommended instead of AAA for avoiding serious overestimation of the minimum target doses compared to the actual delivered dose. PMID- 23800025 TI - The perturbation of tryptophan fluorescence by phenylalanine to alanine mutations identifies the hydrophobic core in a subset of bacterial Ig-like domains. AB - Many host-parasite interactions are mediated via surface-exposed proteins containing bacterial immunoglobulin-like (Big) domains. Here, we utilize the spectral properties of a conserved Trp to provide evidence that, along with a Phe, these residues are positioned within the hydrophobic core of a subset of Big_2 domains. The mutation of the Phe to Ala decreases Big_2 domain stability and impairs the ability of LigBCen2 to bind to the host protein, fibronectin. PMID- 23800026 TI - Moderate acoustic changes can disrupt the sleep of very preterm infants in their incubators. AB - AIM: To evaluate the impact of moderate noise on the sleep of very early preterm infants (VPI). METHODS: Observational study of 26 VPI of 26-31 weeks' gestation, with prospective measurements of sound pressure level and concomitant video records. Sound peaks were identified and classified according to their signal-to noise ratio (SNR) above background noise. Prechtl's arousal states during sound peaks were assessed by two observers blinded to the purpose of the study. Changes in sleep/arousal states following sound peaks were compared with spontaneous changes during randomly selected periods without sound peaks. RESULTS: We identified 598 isolated sound peaks (5 <= SNR < 10 decibel slow response A (dBA), n = 518; 10 <= SNR < 15 dBA, n = 80) during sleep. Awakenings were observed during 33.8% (95% CI, 24-43.7%) of exposures to sound peaks of 5-10 dBA SNR and 39.7% (95% CI, 26-53.3%) of exposures to sound peaks of SNR 10-15 dBA, but only 11.7% (95% CI, 6.2-17.1%) of control periods. The proportions of awakenings following sound peaks were higher than the proportions of arousals during control periods (p < 0.005). CONCLUSIONS: Moderate acoustic changes can disrupt the sleep of VPI, and efficient sound abatement measures are needed. PMID- 23800027 TI - The relative benefits of tamoxifen in older women with T1 early-stage breast cancer treated with breast-conserving surgery and radiation therapy. AB - Small, hormone receptor-positive breast carcinomas in older women are associated with low local recurrence rates. The relative benefits of adjuvant hormonal therapy remain unclear in elderly women with small, node-negative breast cancer after breast-conserving surgery and adjuvant radiation therapy. From our institutional data base, 224 patients >=65 years of age with T1N0M0 breast cancer treated with BCS+RT were identified. Of these, 102 patients (45.5%) received tamoxifen (TAM) and 122 patients (54.5%) did not (no-TAM). The median follow-up time was 62.6 months. The 10-year local relapse-free survival (LRFS) was 98% in both the TAM and no-TAM cohorts (p = 0.58); the 10-year DMFS was 83% TAM vs. 89% no-TAM (p = 0.91). There was no difference in 10-year contralateral breast relapse or overall survival (OS) between the two cohorts. In univariate and multivariate analysis, use of TAM was not associated with LRFS, distant metastases-free survival (DMFS), OS, or a reduction in contralateral breast cancers when compared with the no-TAM cohort. In this large cohort of T1N0 elderly breast cancer patients treated with CS+RT, the use of TAM did not appear to decrease ipsilateral breast relapse, contralateral breast relapse, distant metastasis, or OS. PMID- 23800028 TI - Gender-based distributional skewness of the United Republic of Tanzania's health workforce cadres: a cross-sectional health facility survey. AB - BACKGROUND: While severe shortages, inadequate skills and a geographical imbalance of health personnel have been consistently documented over the years as long term critical challenges in the health sector of the United Republic of Tanzania, there is limited evidence on the gender-based distribution of the health workforce and its likely implications. Extant evidence shows that some people may not seek healthcare unless they have access to a provider of their gender. This paper, therefore, assesses the gender-based distribution of the United Republic of Tanzania's health workforce cadres. METHODS: This is a secondary analysis of data collected in a cross-sectional health facility survey on health system strengthening in the United Republic of Tanzania in 2008. During the survey, 88 health facilities, selected randomly from 8 regions, yielded 815 health workers (HWs) eligible for the current analysis. While Chi-square was used for testing associations in the bivariate analysis, multivariate analysis was conducted using logistic regression to assess the relationship between gender and each of the cadres involved in the analysis. RESULTS: The mean age of the HWs was 39.7, ranging from 15 to 63 years. Overall, 75% of the HWs were women. The proportion of women among maternal and child health aides or medical attendants (MCHA/MA), nurses and midwives was 86%, 86% and 91%, respectively, while their proportion among clinical officers (COs) and medical doctors (MDs) was 28% and 21%, respectively. Multivariate analysis revealed that the odds ratio (OR) and 95% confidence interval (CI) that a HW was a female (baseline category is "male") for each cadre was: MCHA/MA, OR = 3.70, 95% CI 2.16-6.33; nurse, OR = 5.61, 95% CI 3.22-9.78; midwife, OR = 2.74, 95% CI 1.44-5.20; CO, OR = 0.08, 95% CI 0.04 0.17 and MD, OR = 0.04, 95% CI 0.02-0.09. CONCLUSION: The distribution of the United Republic of Tanzania's health cadres is dramatically gender-skewed, a reflection of gender inequality in health career choices. MCHA/MA, nursing and midwifery cadres are large and female-dominant, whereas COs and MDs are fewer in absolute numbers and male-dominant. While a need for more staff is necessary for an effective delivery of quality health services, adequate representation of women in highly trained cadres is imperative to enhance responses to some gender specific roles and needs. PMID- 23800029 TI - Laser microdissection coupled with RNA-seq analysis of porcine enterocytes infected with an obligate intracellular pathogen (Lawsonia intracellularis). AB - BACKGROUND: Lawsonia intracellularis is an obligate intracellular bacterium and the etiologic agent of proliferative enteropathy. The disease is endemic in pigs, emerging in horses and has been described in various other species including nonhuman primates. Cell proliferation is associated with bacterial replication in enterocyte cytoplasm, but the molecular basis of the host-pathogen interaction is unknown. We used laser capture microdissection coupled with RNA-seq technology to characterize the transcriptional responses of infected enterocytes and the host pathogen interaction. RESULTS: Proliferative enterocytes was associated with activation of transcription, protein biosynthesis and genes acting on the G1 phase of the host cell cycle (Rho family). The lack of differentiation in infected enterocytes was demonstrated by the repression of membrane transporters related to nutrient acquisition. The activation of the copper uptake transporter by infected enterocytes was associated with high expression of the Zn/Cu superoxide dismutase by L. intracellularis. This suggests that the intracellular bacteria incorporate intracytoplasmic copper and express a sophisticated mechanism to cope with oxidative stress. CONCLUSIONS: The feasibility of coupling microdissection and RNA-seq was demonstrated by characterizing the host-bacterial interactions from a specific cell type in a heterogeneous tissue. High expression of L. intracellularis genes encoding hypothetical proteins and activation of host Rho genes infers the role of unrecognized bacterial cyclomodulins in the pathogenesis of proliferative enteropathy. PMID- 23800031 TI - Overuse and traumatic extremity injuries in schoolchildren surveyed with weekly text messages over 2.5 years. AB - The objectives of this prospective cohort study were to report the incidence, prevalence, and duration of traumatic and overuse injuries during a period of 2.5 years and to estimate the odds of injury types. In all, 1259 schoolchildren, aged 6-12, were surveyed each week with an automated mobile phone text message asking questions on the presence of any musculo-skeletal problems and participation in leisure-time sport. Children were examined and injuries classified as overuse or traumatic. The overall injury incidence and prevalence were 1.2% and 4.6% per week, with 2.5 times more overuse than traumatic injuries in lower extremities, and mean injury duration of 5.3 and 4.8 weeks, respectively. A reverse pattern was found for upper extremities, with 3.1 times more traumatic than overuse injuries and mean durations of 3.3 and 5.2 weeks, respectively. Grade level, school type, leisure-time sport, and seasonal variation were associated with the risk of sustaining lower extremity injuries. Only grade level was associated with upper extremity injuries. The magnitude of overuse and traumatic limb injuries emphasizes the need for health professionals, coaches, and parents to pay special attention in relation to the growing and physically active child. PMID- 23800032 TI - Airborne spread and infection of a novel swine-origin influenza A (H1N1) virus. AB - BACKGROUND: The novel swine-origin influenza A (H1N1) virus (S-O 2009 IV) can cause respiratory infectious diseases in humans and pigs, but there are few studies investigating the airborne spread of the virus. In January 2011, a swine origin H1N1 epidemic emerged in eastern China that rapidly spread to neighboring farms, likely by aerosols carried by the wind. METHODS: In this study, quantitative reverse transcription polymerase chain reaction (RT-PCR) was used to detect viruses in air samples from pig farms. Based on two aerosol infection models (Pig and guinea pig), we evaluated aerosol transmission and infection of the novel S-O 2009 IV isolate. RESULTS: Three novel S-O 2009 IV were isolated from the diseased pig. The positive rate and viral loads of air samples were 26.1% and 3.14-5.72 log10copies/m3 air, respectively. In both pig and guinea pig infection models, the isolate (A/swine/Shandong/07/2011) was capable of forming aerosols and infected experimental animals at a range of 2.0-4.2 m by aerosols, but aerosol route was less efficient than direct contact. CONCLUSIONS: The results indicated that S-O 2009 IV is able to be aerosolized by infected animals and to be transmitted to susceptible animals by airborne routes. PMID- 23800033 TI - CYP450 phenotyping and metabolite identification of quinine by accurate mass UPLC MS analysis: a possible metabolic link to blackwater fever. AB - BACKGROUND: The naturally occurring alkaloid drug, quinine is commonly used for the treatment of severe malaria. Despite centuries of use, its metabolism is still not fully understood, and may play a role in the haemolytic disorders associated with the drug. METHODS: Incubations of quinine with CYPs 1A2, 2C9, 2C19, 2D6, and 3A4 were conducted, and the metabolites were characterized by accurate mass UPLC-MS(E) analysis. Reactive oxygen species generation was also measured in human erythrocytes incubated in the presence of quinine with and without microsomes. RESULTS: The metabolites 3-hydroxyquinine, 2'-oxoquininone, and O-desmethylquinine were observed after incubation with CYPs 3A4 (3 hydroxyquinine and 2'-oxoquininone) and 2D6 (O-desmethylquinine). In addition, multiple hydroxylations were observed both on the quinoline core and the quinuclidine ring system. Of the five primary abundance CYPs tested, 3A4, 2D6, 2C9, and 2C19 all demonstrated activity toward quinine, while 1A2 did not. Further, quinine produced robust dose-dependent oxidative stress in human erythrocytes in the presence of microsomes. CONCLUSIONS: Taken in context, these data suggest a CYP-mediated link between quinine metabolism and the poorly understood haemolytic condition known as blackwater fever, often associated with quinine ingestion. PMID- 23800034 TI - Molecular characterization of canine BCR-ABL-positive chronic myelomonocytic leukemia before and after chemotherapy. AB - Genetic aberrations linked to tumorigenesis have been identified in both canine and human hematopoietic malignancies. While the response of human patients to cancer treatments is often evaluated using cytogenetic techniques, this approach has not been used for dogs with comparable neoplasias. The aim of this study was to demonstrate the applicability of cytogenetic techniques to evaluate the cytogenetic response of canine leukemia to chemotherapy. Cytology and flow cytometric techniques were used to diagnose chronic myelomonocytic leukemia in a dog. High-resolution oligonucleotide array comparative genomic hybridization (oaCGH) and multicolor fluorescence in situ hybridization (FISH) were performed to identify and characterize DNA copy number aberrations (CNAs) and targeted structural chromosome aberrations in peripheral blood WBC at the time of diagnosis and following one week of chemotherapy. At the time of diagnosis, oaCGH indicated the presence of 22 distinct CNAs, of which trisomy of dog chromosome 7 (CFA 7) was the most evident. FISH analysis revealed that this CNA was present in 42% of leukemic cells; in addition, a breakpoint cluster region-Abelson murine leukemia viral oncogene homolog (BCR-ABL) translocation was evident in 17.3% of cells. After one week of treatment, the percentage of cells affected by trisomy of CFA7 and BCR-ABL translocation was reduced to 2% and 3.3%, respectively. Chromosome aberrations in canine leukemic cells may be monitored by molecular cytogenetic techniques to demonstrate cytogenetic remission following treatment. Further understanding of the genetic aberrations involved in canine leukemia may be crucial to improve treatment protocols. PMID- 23800035 TI - Investment case for improving maternal and child health: results from four countries. AB - BACKGROUND: Without addressing the constraints specific to disadvantaged populations, national health policies such as universal health coverage risk increasing equity gaps. Health system constraints often have the greatest impact on disadvantaged populations, resulting in poor access to quality health services among vulnerable groups. METHODS: The Investment Cases in Indonesia, Nepal, Philippines, and the state of Orissa in India were implemented to support evidence-based sub-national planning and budgeting for equitable scale-up of quality MNCH services. The Investment Case framework combines the basic setup of strategic problem solving with a decision-support model. The analysis and identification of strategies to scale-up priority MNCH interventions is conducted by in-country planners and policymakers with facilitation from local and international research partners. RESULTS: Significant variation in scaling-up constraints, strategies, and associated costs were identified between countries and across urban and rural typologies. Community-based strategies have been considered for rural populations served predominantly by public providers, but this analysis suggests that the scaling-up of maternal, newborn, and child health services requires health system interventions focused on 'getting the basics right'. These include upgrading or building facilities, training and redistribution of staff, better supervision, and strengthening the procurement of essential commodities. Some of these strategies involve substantial early capital expenditure in remote and sparsely populated districts. These supply-side strategies are not only the 'best buys', but also the 'required buys' to ensure the quality of health services as coverage increases. By contrast, such public supply strategies may not be the 'best buys' in densely populated urbanised settings, served by a mix of public and private providers. Instead, robust regulatory and supervisory mechanisms are required to improve the accessibility and quality of services delivered by the private sector. They can lead to important maternal mortality reductions at relatively low costs. CONCLUSIONS: National strategies that do not take into consideration the special circumstances of disadvantaged areas risk disempowering local managers and may lead to a "business-as-usual" acceptance of unreachable goals. To effectively guide health service delivery at a local level, national plans should adopt typologies that reflect the different problems and strategies to scale up key MNCH interventions. PMID- 23800036 TI - Peptidergic regulation of plasminogen activator inhibitor-1 gene expression in vivo. AB - BACKGROUND: The mechanisms by which PAI-1 biosynthesis is altered during stress have not been fully elucidated. Studies suggest a major role for neuro peptidergic modulation of the stress response by PACAP (pituitary adenylate cyclase-activating polypeptide), a member of the VIP/secretin/glucagon family. OBJECTIVE: We tested the hypothesis that PACAP regulates PAI-1 biosynthesis during stress in vivo. METHODS: PAI-1 gene expression was monitored by RT-PCR in adrenal glands harvested from C57BL/6J mice that were unstressed, or subjected to restraint stress for 2 h, or treated with PACAP. RESULTS: PAI-1 mRNA expression was markedly increased in adrenals from stressed mice. Restraint stress resulted in much smaller increments in adrenal tPA mRNA, suggesting that local adrenal tPA/PAI-1 biosynthetic balance is markedly altered by stress. The observed increases in PAI-1mRNA during stress were substantially blunted (55 +/- 4%, P < 0.001) by pretreatment with the specific PACAP receptor antagonist, PACAP6-38, compared with pretreatment with vehicle. Administration of the agonist PACAP1-38 alone resulted in a dose-dependent increase in tissue PAI-1 mRNA. PACAP1-38 administration also resulted in substantial increases in plasma PAI-1 antigen and active PAI-1 concentrations that were significantly greater in male mice than in female mice. CONCLUSIONS: We conclude that adrenal PAI-1 mRNA expression is markedly increased by stress, and that the PACAP peptidergic signaling pathway plays a major role in mediating the stress-induced increase in PAI-1 biosynthesis. PMID- 23800037 TI - Cardiovascular effects of antimuscarinic agents in overactive bladder. AB - INTRODUCTION: The potential impact of antimuscarinics (AMs) on cardiac function is a major concern in the treatment of overactive bladder (OAB) patients, especially in older ones who are likely to present cardiovascular (CV) comorbidities and other risk factors that may predispose them to the adverse cardiac effects of this therapy. AREAS COVERED: This article aims to review the literature on the impact on the CV system of AMs used in the treatment of OAB, giving a comprehensive explanation of the pathogenetic mechanisms of AMs' effects on CV system and the impact of each AM drug on cardiac function. EXPERT OPINION: Although the CV safety of AM drugs seems to be good, evidence provided in this manuscript does not allow to exclude an increase in HR, QT prolongation or an increase in the CV risk due to drug-drug interactions in OAB patients who are usually elderly and have comorbidities. Clinical and electrocardiographic monitoring may be necessary throughout the administration period in selected populations such as patients aged > 80 years, those with coronary heart disease or congestive heart failure. Further studies are needed to understand whether the most recently developed AM drugs, such as imidafenacin, are safer than the old ones. PMID- 23800038 TI - Using imputed pre-treatment cholesterol in a propensity score model to reduce confounding by indication: results from the multi-ethnic study of atherosclerosis. AB - BACKGROUND: Studying the effects of medications on endpoints in an observational setting is an important yet challenging problem due to confounding by indication. The purpose of this study is to describe methodology for estimating such effects while including prevalent medication users. These techniques are illustrated in models relating statin use to cardiovascular disease (CVD) in a large multi ethnic cohort study. METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) includes 6814 participants aged 45-84 years free of CVD. Confounding by indication was mitigated using a two step approach: First, the untreated values of cholesterol were treated as missing data and the values imputed as a function of the observed treated value, dose and type of medication, and participant characteristics. Second, we construct a propensity-score modeling the probability of medication initiation as a function of measured covariates and estimated pre treatment cholesterol value. The effect of statins on CVD endpoints were assessed using weighted Cox proportional hazard models using inverse probability weights based on the propensity score. RESULTS: Based on a meta-analysis of randomized controlled trials (RCT) statins are associated with a reduced risk of CVD (relative risk ratio = 0.73, 95% CI: 0.70, 0.77). In an unweighted Cox model adjusting for traditional risk factors we observed little association of statins with CVD (hazard ratio (HR) = 0.97, 95% CI: 0.60, 1.59). Using weights based on a propensity model for statins that did not include the estimated pre-treatment cholesterol we observed a slight protective association (HR = 0.92, 95% CI: 0.54 1.57). Results were similar using a new-user design where prevalent users of statins are excluded (HR = 0.91, 95% CI: 0.45-1.80). Using weights based on a propensity model with estimated pre-treatment cholesterol the effects of statins (HR = 0.74, 95% CI: 0.38, 1.42) were consistent with the RCT literature. CONCLUSIONS: The imputation of pre-treated cholesterol levels for participants on medication at baseline in conjunction with a propensity score yielded estimates that were consistent with the RCT literature. These techniques could be useful in any example where inclusion of participants exposed at baseline in the analysis is desirable, and reasonable estimates of pre-exposure biomarker values can be estimated. PMID- 23800039 TI - Thermal stress effects on grain yield in Brachypodium distachyon occur via H2A.Z nucleosomes. AB - BACKGROUND: Crop plants are highly sensitive to ambient temperature, with a 1 oC difference in temperature sufficient to affect development and yield. Monocot crop plants are particularly vulnerable to higher temperatures during the reproductive and grain-filling phases. The molecular mechanisms by which temperature influences grain development are, however, unknown. In Arabidopsis thaliana, H2A.Z-nucleosomes coordinate transcriptional responses to higher temperature. We therefore investigated whether the effects of high temperature on grain development are mediated by H2A.Z-nucleosomes. RESULTS: We have analyzed the thermal responses of the Pooid grass, Brachypodium distachyon, a model system for crops. We find that H2A.Z-nucleosome occupancy is more responsive to increases in ambient temperature in the reproductive tissue of developing grains compared withvegetative seedlings. This difference correlates with strong phenotypic responses of developing grain to increased temperature, including early maturity and reduced yield. Conversely, temperature has limited impact on the timing of transition from the vegetative to generative stage, with increased temperature unable to substitute for long photoperiod induction of flowering. RNAi silencing of components necessary for H2A.Z-nucleosome deposition is sufficient to phenocopythe effects of warmer temperature on grain development. CONCLUSIONS: H2A.Z-nucleosomes are important in coordinating the sensitivity of temperate grasses to increased temperature during grain development. Perturbing H2A.Z occupancy, through higher temperature or genetically, strongly reduces yield. Thus, we provide a molecular understanding of the pathways through which high temperature impacts on yield. These findings may be useful for breeding crops resilient to thermal stress. PMID- 23800040 TI - Predicting the protein targets for athletic performance-enhancing substances. AB - BACKGROUND: The World Anti-Doping Agency (WADA) publishes the Prohibited List, a manually compiled international standard of substances and methods prohibited in competition, out-of-competition and in particular sports. It would be ideal to be able to identify all substances that have one or more performance-enhancing pharmacological actions in an automated, fast and cost effective way. Here, we use experimental data derived from the ChEMBL database (~7,000,000 activity records for 1,300,000 compounds) to build a database model that takes into account both structure and experimental information, and use this database to predict both on-target and off-target interactions between these molecules and targets relevant to doping in sport. RESULTS: The ChEMBL database was screened and eight well populated categories of activities (Ki, Kd, EC50, ED50, activity, potency, inhibition and IC50) were used for a rule-based filtering process to define the labels "active" or "inactive". The "active" compounds for each of the ChEMBL families were thereby defined and these populated our bioactivity-based filtered families. A structure-based clustering step was subsequently performed in order to split families with more than one distinct chemical scaffold. This produced refined families, whose members share both a common chemical scaffold and bioactivity against a common target in ChEMBL. CONCLUSIONS: We have used the Parzen-Rosenblatt machine learning approach to test whether compounds in ChEMBL can be correctly predicted to belong to their appropriate refined families. Validation tests using the refined families gave a significant increase in predictivity compared with the filtered or with the original families. Out of 61,660 queries in our Monte Carlo cross-validation, belonging to 19,639 refined families, 41,300 (66.98%) had the parent family as the top prediction and 53,797 (87.25%) had the parent family in the top four hits. Having thus validated our approach, we used it to identify the protein targets associated with the WADA prohibited classes. For compounds where we do not have experimental data, we use their computed patterns of interaction with protein targets to make predictions of bioactivity. We hope that other groups will test these predictions experimentally in the future. PMID- 23800041 TI - Structures in solid state and solution of dimethoxy curcuminoids: regioselective bromination and chlorination. AB - BACKGROUND: Several papers described the structure of curcumin and some other derivatives in solid and in solution. In the crystal structure of curcumin, the enol H atom is located symmetrically between both oxygen atoms of the enolone fragment with an O...O distance of 2.455 A, which is characteristic for symmetrical H-bonds. In the solution, the geometry of the enolone fragment is attributed to the inherent disorder of the local environment, which solvates one of the basic sites better than the other, stabilizing one tautomer over the other. In this paper, how the position of methoxy groups in dimethoxy curcuminoids influence the conformation of molecules and how the halogen atoms change it when they are bonded at alpha-position in keto-enol part of molecules is described. RESULTS: Six isomers of dimethoxy curcuminoids were prepared. Conformations in solid state, which were determined by X-ray single crystallography and 1H MAS and 13C CPMAS NMR measurements, depend on the position of methoxy groups in curcuminoid molecules. In solution, a fast equilibrium between both keto-enol forms exists. A theoretical calculation finding shows that the position of methoxy groups changes the energy of HOMO and LUMO. An efficient protocol for the highly regioselective bromination and chlorination leading to alpha-halogenated product has been developed. All alpha-halogenated compounds are present mainly in cis keto-enol form. CONCLUSIONS: The structures in solid state of dimethoxy curcuminoids depend on the position of methoxy groups. The NMR data of crystalline solid samples of 3,4-diOCH3 derivative, XRD measurements and X-ray structures lead us to the conclusion that polymorphism exists in solids. The same conclusion can be done for 3,5-diOCH3 derivative. In solution, dimethoxy curcuminoids are present in the forms that can be described as the coexistence of two equivalent tautomers being in fast equilibrium. The position of methoxy groups has a small influence on the enolic hydrogen bond. Theoretical calculations show that the energy gap between HOMO and LUMO depend on the position of methoxy groups and are lower in solution. Chlorination and bromination on alpha-position of 1,3-diketone moiety do not change the preferential form being cis keto-enol as in parent compounds. PMID- 23800042 TI - RNAi targeting CXCR4 inhibits proliferation and invasion of esophageal carcinoma cells. AB - CXC chemokine receptor 4 was found to be expressed by many different types of human cancers and its expression has been correlated with tumor aggressiveness, poor prognosis and resistance to chemotherapy. However the effect of CXCR4 on the esophageal carcinoma cells remains unclear, the present study explored the effects of CXCR4 siRNA on proliferation and invasion of esophageal carcinoma KYSE 150 and TE-13 cells. Two siRNA sequence targeting CXCR4 gene were constructed and then were transfected into KYSE-150 and TE-13 cells by LipofectamineTM2000. Changes of CXCR4 mRNA and protein were analyzed by qRT-PCR and Western blot. Effect of CXCR4 siRNA on KYSE-150 and TE-13 cells proliferation was determined by MTT. Transwell invasion assay was used to evaluate the invasion and metastasis of KYSE-150 and TE-13 cells. Tumor growth was assessed by subcutaneous inoculation of cells into BALB/c nude mice. qRT-PCR and Western blot demonstrate that the expression level of CXCR4 gene were obviously decreased in KYSE-150 and TE-13 cells transfected with CXCR4 targeting siRNA expression vectors. The average amount of cells transfected with CXCR4 siRNA penetrating Matrigel was significantly decreased (p<0.05). Injection of CXCR4 siRNA transfected cells inhibited tumor growth in a xenograft model compared with blank and negative control groups (p <0.05). CXCR4 silenced by siRNA could suppress the proliferation, invasion and metastasis of esophageal carcinoma cell lines KYSE 150 and TE-13 in vitro and in vivo. The results provide a theoretical and experimental basis for the gene therapy of ESCC using RNAi technology based on CXCR4 target site. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3502376691001138. PMID- 23800043 TI - Assessment of phytochemicals, antioxidant, anti-lipid peroxidation and anti hemolytic activity of extract and various fractions of Maytenus royleanus leaves. AB - BACKGROUND: Maytenus royleanus is traditionally used in gastro-intestinal disorders. The aim of this study was to evaluate the methanol extract of leaves and its derived fractions for various antioxidant assays and for its potential against lipid peroxidation and hemolytic activity. METHODS: Various parameters including scavenging of free-radicals (DPPH, ABTS, hydroxyl and superoxide radical), hydrogen peroxide scavenging, Fe3+ to Fe2+ reducing capacity, total antioxidant capacity, anti-lipid peroxidation and anti-hemolytic activity were investigated. Methanol extract and its derived fractions were also subjected for chemical constituents. LC-MS was also performed on the methanol extract. RESULTS: Qualitative analysis of methanol extract exhibited the presence of alkaloids, anthraquinones, cardiac glycosides, coumarins, flavonoids, saponins, phlobatannins, tannins and terpenoids. LC-MS chromatogram indicated the composition of diverse compounds including flavonoids, phenolics and phytoestrogens. Methanol extract, its ethyl acetate and n-butanol fractions constituted the highest amount of total phenolic and flavonoid contents and showed a strong correlation coefficient with the IC50 values for the scavenging of DPPH, hydrogen peroxide radicals, superoxide radicals, anti-lipid peroxidation and anti-hemolytic efficacy. Moreover, n-butanol fraction showed the highest scavenging activity for ABTS radicals and for reduction of Fe3+ to Fe2+. CONCLUSIONS: Present results suggested the therapeutic potential of Maytenus royleanus leaves, in particular, methanol extract, ethyl acetate and n-butanol fraction as therapeutic agent against free-radical associated damages. The protective potential of the extract and or fraction may be attributed due to the high concentration of phenolic, flavonoid, tannins and terpenoids. PMID- 23800044 TI - Racial and ethnic differences in childhood asthma treatment in the United States. AB - OBJECTIVE: To examine racial-ethnic differences in asthma controller medication use among insured U.S. children. DATA SOURCES: Linked nationally representative data from the Medical Expenditure Panel Survey (2005-2008), the 2000 Decennial Census, and the National Health Interview Survey (2004-2007). STUDY DESIGN: The study quantifies the portion of racial-ethnic differences in children's controller use that are attributable to differences in need, enabling and predisposing characteristics. PRINCIPAL FINDINGS: Non-Hispanic black and Hispanic children were less likely to use controllers than non-Hispanic white children. Blinder-Oaxaca decomposition results indicated that observable characteristics explain less than 40 percent of the overall differential in controller use between non-Hispanic whites and non-Hispanic blacks. In contrast, observable characteristics explain more than two-thirds (71.3 percent) of the overall non Hispanic white-Hispanic differential in controller use. For non-Hispanic blacks, a majority of the explained differential in controller use were attributed to enabling characteristics. For Hispanics, a significant portion of the explained differential in controller use was attributed to predisposing characteristics. In addition, a larger portion of the differential in controller use was explained by observable characteristics for publicly insured non-Hispanic black and Hispanic children. CONCLUSIONS: The large observed differences in controller use highlight the continuing challenges of ensuring that all U.S. children have access to quality asthma care. PMID- 23800046 TI - Pairing mechanism among ionic liquid ions in aqueous solutions: a molecular dynamics study. AB - In this study, we carried out molecular dynamics simulations to examine the molecular mechanism for ionic liquid pair association in aqueous solutions. We chose the commonly studied imidazolium-based ionic liquid pairs. We computed potentials of mean force (PMF) for four systems: 1,3 dimethlylimidazoliumchloride, 1,3-dimethlylimidazolium iodide, 1-methly-3 octylimidazolium chloride, and 1-methly-3-octylimidazolium iodide. Our PMF studies show a stronger interaction for the ion pairs of systems involving dimethlylimidazolium as the cation species compared with that of the systems containing octylimidazolium. This result indicates a decrease in ion-pair association as the cation alkyl tail length increases. We also studied the kinetics of ion-pair dissociation using different rate theories such as the Grote Hynes and Kramer's theories. As expected, the computed rate results significantly deviated from results obtained from transition state theory because it does not account for dynamical solvent effects. Dissociative barrier curvatures are found to be very small for the systems investigated because the transmission coefficients computed using Grote-Hynes theory and Kramer's theory are approximately equal. Our analysis of the rotational dynamics of cations revealed that the time scales for molecular reorientation are longer for cations with longer alkyl tails. PMID- 23800045 TI - Improved in vitro and in vivo cutaneous delivery of protoporphyrin IX from PLGA based nanoparticles. AB - We report the development of D, L lactic co-glycolic acid) (PLGA)-based nanoparticles (NPs) for topical delivery of protoporphyrin IX (PpIX), a photosensitizer (PS), in treatments like photodynamic therapy (PDT) of skin cancers. PpIX-NPs were obtained in ~75.0% yield, encapsulation efficiency of 67.7%, drug content of 50.3 MUg mg(-1), average diameter of 290 nm maintained up to 30 days and a zeta potential of 32.3 mV. Sustained in vitro release of PpIX through artificial membranes following Higuchi kinetics was kept up to 10 days. In vitro retentions of PpIX both in stratum corneum (SC) and epidermis + dermis ([EP + D]) were higher from NPs (23.0 and 10.0 times, respectively) compared to control solutions at all times. Quantification of PpIX by extraction, after in vivo skin application of NPs-PpIX on hairless mice, showed higher retention of the PS both in SC and in [EP + D] (3.0 and 2.0 times, respectively) compared to control solutions. Taken together, the results indicate that NPs are suitable for PpIX encapsulation showing minimal permeation through the skin and a localized effect, characteristics of a potential and promising delivery system for PDT associated treatments of skin cancers, photodiagnosis and their off-label uses. PMID- 23800047 TI - Involvement of STIM1 and Orai1 in EGF-mediated cell growth in retinal pigment epithelial cells. AB - BACKGROUND: In non-excitable cells, one major route for calcium entry is through store-operated calcium (SOC) channels in the plasma membrane. These channels are activated by the emptying of intracellular Ca2+ store. STIM1 and Orai1 are major regulators of SOC channels. In this study, we explored the functions of STIM1 and Orai1 in epidermal growth factor (EGF)-induced cell proliferation and migration in retinal pigment epithelial cells (ARPE-19 cell line). RESULTS: EGF triggers cell proliferation and migration in ARPE-19 cells. Cell proliferation and migration involve STIM1 and Orai1, as well as phosphorylation of extracellular signal-regulated protein kinase (ERK) 1/2, and Akt. Pharmacological inhibitors of SOC channels and siRNA of Orai1 and STIM1 suppress cell proliferation and migration. Pre-treatment of mitogen-activated protein kinase kinase (MEK) inhibitors and a phosphatidylinositol 3 kinases (PI3K) inhibitor attenuated cell proliferation and migration. However, inhibition of the SOC channels failed to prevent EGF-mediated ERK 1/2 and Akt phosphorylation. CONCLUSIONS: Our results showed that STIM1, Orai1, ERK 1/2, and Akt are key determinants of EGF-mediated cell growth in ARPE-19 cells. EGF is a potent growth molecule that has been linked to the development of PVR, and therefore, STIM1, Orai1, as well as the MEK/ERK 1/2 and PI3K/Akt pathways, might be potential therapeutic targets for drugs aimed at treating such disorders. PMID- 23800048 TI - High serum HTATIP2/TIP30 level in serous ovarian cancer as prognostic or diagnostic marker. AB - BACKGROUND: Human HIV-1 TAT interactive protein 2 (HTATIP2/TIP30) is an evolutionarily conserved gene that is expressed ubiquitously in human tissues and some tumor tissues. This protein has been found to be associated with some gynecological cancers; as such, this study aimed to investigate blood HTATIP2/TIP30 levels in patients with ovarian cancer. METHODS: Twenty-three women with ovarian cancer and 18 patients with various non-cancerous gynecological complaints (for example, dysfunctional uterine bleeding, fibroids, and urinary incontinence) were included in the study. The pathological diagnosis of ovarian cancer was adenocarcinoma. HTATIP2/TIP30 concentration in the patients' blood samples was determined using ELISA kits. RESULTS: The HTATIP2/TIP30 level was significantly higher in the cancer group than in the control group (1.84 +/- 0.82 versus 0.57 +/- 0.13 ng/ml, mean +/- SD). CONCLUSIONS: We demonstrated the potential role of HTATIP2/TIP30 in ovarian cancer for the first time, thereby enlightening future studies targeting HTATIP2/TIP30 in ovarian cancer treatment, diagnosis, and prevention. PMID- 23800049 TI - Potential predictors of disease progression for main-duct intraductal papillary mucinous neoplasms of the pancreas. AB - BACKGROUND AND AIM: The evidence for main pancreatic duct intraductal papillary mucinous neoplasms (MPD-IPMN) malignancy is based predominantly on investigation of resected cases, and the natural history is still unclear. The aim of the present study is to investigate the natural history of MPD-IPMN and examine potential predictors of disease progression in MPD-IPMN patients who conformed to "high-risk stigmata" criteria. METHODS: This study included consecutive 20 follow up patients and 19 surgical patients with "high-risk stigmata" MPD-IPMN, in whom the diameter of the MPD was > 10 mm, branch duct was < 5 mm, and who underwent clinical follow up for >= 2 years. RESULTS: Among surgical patients, mural nodules and MPD diameter of invasive patients were significantly different compared with non-invasive patients. On the other hand, among follow-up patients, univariate analysis revealed the following potential predictors for disease progression: diameter of MPD >= 15 mm (hazard ratio [HR], 20.9; 95% confidence interval [CI], 2.59-173.4; P < 0.01); and diffuse lesions of MPD-IPMN (HR, 4.46; 95% CI, 1.10-18.0; P = 0.04). On the other hand, multivariate analysis identified only diameter of MPD >= 15 mm (HR, 19.2; 95% CI, 1.87-198.5; P = 0.01) as a potential predictor of disease progression. CONCLUSION: If MPD-IPMN patients have other severe complications or reasons for not undergoing surgical treatment, MPD diameter < 15 mm, negative cytology, and no mural nodules, conservative clinical follow up for several years may be an option. PMID- 23800050 TI - Long-term treatment with intravenous bisphosphonates in metastatic breast cancer: a retrospective study. AB - Bisphosphonates are important therapies used to reduce the risk of skeletal related events in patients with bone metastases from breast cancer (BC). This retrospective cohort study evaluated the incidence of osteonecrosis of the jaw (ONJ) and renal impairment in women (n = 221) with bone metastases from BC treated with intravenous bisphosphonates from January 1999 to June 2008. In the long-term cohort, 159 patients received pamidronate (n = 9), zoledronic acid (n = 110), or both (n = 40) for >=24 months. The comparator group consisted of patients treated with intravenous bisphosphonates for 12-23 months (n = 62). After 39 months' median follow-up, six of 159 patients developed ONJ (3.8%; median 38.5 treatment cycles and 44 months' exposure) in the long-term cohort. Of patients who developed ONJ, 50% resumed intravenous bisphosphonates after a 12 month treatment holiday. Renal impairment developed in 19 patients in the long term cohort (11.9%; median 26 treatment cycles and 26 months' exposure). Of these 19 patients, 11 (57.9%) recovered baseline renal function and seven (36.7%) showed partial recovery. After modification of the intravenous bisphosphonate regimen, 17 of 19 patients (89.4%) resumed therapy. Of the 62 patients in the comparator cohort, one patient developed ONJ (1.6%) and six developed renal impairment (9.7%). Similar incidence rates of ONJ and renal impairment were observed for the long-term and comparator cohorts. Times to ONJ or renal impairment also were similar across intravenous bisphosphonate type. Long-term (>=24 months) intravenous bisphosphonate use in metastatic BC is well tolerated, with low incidences of ONJ and renal impairment. PMID- 23800051 TI - Baculum morphology predicts reproductive success of male house mice under sexual selection. AB - BACKGROUND: Diversity in penile morphology is characterised by extraordinary variation in the size and shape of the baculum (penis bone) found in many mammals. Although functionally enigmatic, diversity in baculum form is hypothesised to result from sexual selection. According to this hypothesis, the baculum should influence the outcome of reproductive competition among males within promiscuous mating systems. However, a test of this key prediction is currently lacking. RESULTS: Here we show that baculum size explains significant variation in the reproductive success of male house mice under competitive conditions. After controlling for body size and other reproductive traits, the width (but not length) of the house mouse baculum predicts both the mean number of offspring sired per litter and total number of offspring sired. CONCLUSIONS: By providing the first evidence linking baculum morphology to male reproductive success, our results support the hypothesis that evolutionary diversity in baculum form is driven by sexual selection. PMID- 23800052 TI - Circulating CLA+ T lymphocytes as peripheral cell biomarkers in T-cell-mediated skin diseases. AB - T lymphocytes expressing the CLA antigen constitute a subset of effector memory lymphocytes that are functionally involved in T-cell-mediated cutaneous diseases. Skin-seeking lymphocytes recirculate between inflamed skin and blood during cutaneous inflammation. Many studies in different T-cell-mediated inflammatory cutaneous diseases have clearly related their pathologic mechanisms to CLA+ T cells. Based on common features of these cells in different cutaneous disorders mediated by T cells, we propose that circulating CLA+T cells could constitute very useful peripheral cellular biomarkers for T-cell-mediated skin diseases. PMID- 23800053 TI - Bacterial landscape of human skin: seeing the forest for the trees. AB - Skin harbours large communities of colonizing bacteria. The same bacterial species can exist in different physiological states: viable, dormant, non-viable. Each physiological state can have a different impact on skin health and disease. Various analytical methodologies target different physiological states of bacteria, and this must be borne in mind while interpreting microbiological tests and drawing conclusions about possible cause-effect relationships. PMID- 23800054 TI - TRPV3: a 'more than skinny' channel. AB - The skin is our largest organ serving different tasks from barrier formation through somatosensing to hair development. Recently, members of the large trp (Transient Receptor Potential, TRP) gene family encoding proteins that form cation selective ion channel have been identified to play a crucial role in skin functions. Within the 28 different mammalian TRP channels, TRPV3 might be the most important member in the skin. This review gives an overview on functional properties of TRPV3 in skin physiology and in certain skin diseases. PMID- 23800056 TI - Computational characterization of reflectance confocal microscopy features reveals potential for automated photoageing assessment. AB - Skin photoageing results from a combination of factors including ultraviolet (sun) exposure, leading to significant changes in skin morphology and composition. Conventional methods assessing the degree of photoageing, in particular histopathological assessment involve an invasive multistep process. Advances in microscopy have enabled a shift towards non-invasive in vivo microscopy techniques such as reflectance confocal microscopy (RCM) in this context. Computational image analysis of RCM images has the potential to be of use in the non-invasive assessment of photoageing. In this report, we computationally characterized a clinical RCM data set from younger and older Caucasians with varying levels of photoageing. We identified several mathematical relationships that related to the degree of photoageing as assessed by conventional scoring approaches (clinical photography, SCINEXA and RCM). Furthermore, by combining the mathematical features into a single computational assessment score, we observed significant correlations with conventional RCM (P < 0.0001) and the other clinical assessment techniques. PMID- 23800055 TI - Paeoniflorin suppresses vascular damage and the expression of E-selectin and ICAM 1 in a mouse model of cutaneous Arthus reaction. AB - Paeoniflorin (PF) extracted from the root of Paeonia lactiflora pall, displays anti-inflammation properties in several animal models. Adhesion molecules are important for the recruitment of leucocyte to the vessel wall and involved in the pathogenesis of various autoimmune and inflammatory diseases. Herein, we investigate the effects of PF on adhesion molecule expression in a mouse model of cutaneous Arthus reaction and cultured human dermal microvascular endothelial cells (HDMECs). We showed that PF significantly ameliorated the immune complex (IC) induced vascular damage, leucocyte infiltrates and adhesion molecules expression. Furthermore, PF markedly blocked tumor necrosis factor-alpha (TNF alpha)-induced E-selectin and intercellular adhesion molecule-1 (ICAM-1) expression in HDMECs at both mRNA and protein levels. PF also suppressed TNF alpha-induced adhesion of polymorphonuclear leucocytes (PMNs) to HDMECs. Finally, western blot data revealed that PF can inhibit the phosphorylation of p38, JNK in TNF-alpha-treated HDMECs. These data suggest that PF, as an anti-inflammatory agent, can downregulate adhesion molecules expression. PF may be a candidate medicine for the treatment of IC-induced inflammatory response. PMID- 23800057 TI - Black tattoo inks induce reactive oxygen species production correlating with aggregation of pigment nanoparticles and product brand but not with the polycyclic aromatic hydrocarbon content. AB - Black tattoo inks are composed of carbon nanoparticles, additives and water and may contain polycyclic aromatic hydrocarbons (PAHs). We aimed to clarify whether reactive oxygen species (ROS) induced by black inks in vitro is related to pigment chemistry, physico-chemical properties of the ink particles and the content of chemical additives and contaminants including PAHs. The study included nine brands of tattoo inks of six colours each (black, red, yellow, blue, green and white) and two additional black inks of different brands (n = 56). The ROS formation potential was determined by the dichlorofluorescein (DCFH) assay. A semiquantitative method was developed for screening extractable organic compounds in tattoo ink based on gas chromatography-mass spectrometry (GC-MS) and matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Two black inks produced high amounts of ROS. Peroxyl radicals accounted for up to 72% of the free radicals generated, whereas hydroxyl radicals and H2O2 accounted for <14% and 16%, respectively. The same two inks aggregated strongly in water in contrast to the other black inks. They did not exhibit any shared pattern in PAHs and other organic substances. Aggregation was exclusively shared by all ink colours belonging to the same two brands. Ten of 11 black inks had PAH concentrations exceeding the European Council's recommended level, and all 11 exceeded the recommended level for benzo(a)pyrene. It is a new finding that aggregation of tattoo pigment particles correlates with ROS production and brand, independently of chemical composition including PAHs. ROS is hypothesized to be implicated in minor clinical symptoms. PMID- 23800058 TI - Fisetin inhibits growth, induces G2 /M arrest and apoptosis of human epidermoid carcinoma A431 cells: role of mitochondrial membrane potential disruption and consequent caspases activation. AB - Non-melanoma skin cancers (NMSCs), one of the most common neoplasms, cause serious morbidity and mortality. Therefore, identification of non-toxic phytochemicals for prevention/treatment of NMSCs is highly desirable. Fisetin (3,3',4',7-tetrahydroxyflavone), a dietary flavonoid, present in fruits and vegetables possesses anti-oxidant and antiproliferative properties. The aim of this study was to investigate the chemotherapeutic potential of fisetin in cultured human epidermoid carcinoma A431 cells. Treatment of A431 cells with fisetin (5-80 MUm) resulted in a significant decrease in cell viability in a dose and time-dependent manner. Employing clonogenic assay, we found that fisetin treatment significantly reduced colony formation in A431 cells. Fisetin treatment of A431 cells resulted in G2 /M arrest and induction of apoptosis. Furthermore, treatment of A431 cells with fisetin resulted in (i) decreased expression of anti apoptotic proteins (Bcl2; Bcl-xL and Mcl-1); (ii) increased expression of pro apoptotic proteins (Bax, Bak and Bad); (iii) disruption of mitochondrial potential; (iv) release of cytochrome c and Smac/DIABLO from mitochondria; (v) activation of caspases; and (vi) cleavage of Poly(ADP-ribose) polymerase (PARP) protein. Pretreatment of A431 cells with the pan-caspase inhibitor (Z-VAD-FMK) blocked fisetin-induced cleavage of caspases and PARP. Taken together, these data provide evidence that fisetin possesses chemotherapeutic potential against human epidermoid carcinoma A431 cells. Overall, these results suggest that fisetin could be developed as a novel therapeutic agent for the management of NMSCs. PMID- 23800059 TI - TNFalpha- and IL-17A-mediated S100A8 expression is regulated by p38 MAPK. AB - The antimicrobial peptide S100A8 is known to be upregulated in lesional psoriatic skin compared with non-lesional psoriatic skin and is believed to play a role in the pathogenesis of psoriasis. However, little is known about the signalling pathways involved in the regulation of S100A8 expression. Using quantitative real time RT-PCR analysis, we demonstrated that stimulation with TNFalpha and IL-17A in combination resulted in a significant and synergistic induction of S100A8 mRNA in human keratinocytes. TNFalpha and IL-17A also induced the S100A8 promoter activity synergistically. This was demonstrated by a gene reporter assay in cells transfected with a luciferase plasmid construct, consisting of 3502 base pairs of the human S100A8 promoter. The TNFalpha- and IL-17A-mediated induction of S100A8 mRNA and protein was mediated by a p38 MAPK-dependent mechanism, as demonstrated by the use of a p38 MAPK inhibitor. Finally, adalimumab treatment for patients with psoriasis significantly decreased S100A8 mRNA at day fourteen after start of treatment, but not at day four. Taken together, this study demonstrates that the p38 MAPK signalling pathway plays a key role in the TNFalpha- and IL-17A-induced expression of S100A8 in cultured human keratinocytes. PMID- 23800060 TI - Methods of hair loss evaluation: a comparison of TrichoScan((r)) with the modified wash test. AB - The reliability of the methods currently used for diagnosing hair loss is ill defined. We studied 41 subjects complaining of hair loss, including androgenetic alopecia and telogen effluvium, and compared the results obtained with the modified wash test (MWT) and TrichoScan((r)) . Data were analysed statistically with the t-test and the Cohen kappa statistic. The concordance between the clinical diagnosis and that of MWT (5% cut-off) was fair (kappa = 0.32) and that between clinical diagnosis and TrichoScan((r)) was still fair though less satisfactory (kappa = 0.22). Only in 17 patients (41%) were the MWT and TrichoScan((r)) diagnoses concordant. MWT was better in general and especially at detecting telogen effluvium (TE) (29% vs 19%). In conclusion, the clinical observation should be assisted by MWT and dermoscopy, leaving the biopsy for very difficult cases. TrichoScan((r)) is less useful and may be even misleading in TE. PMID- 23800061 TI - Caspase-14 overexpression in hairless mice is not involved in utricle formation. AB - Loss of functional hairless (HR) transcriptional repressor leads to utricle formation and congenital hair loss both in mice and men. Studies in mice have shown that this is preceded by overexpression of caspase-14 at the infundibulum in the hair follicle before conversion to utricle occurs. In this report, we show that HR regulates caspase-14 expression dependent on its interaction with histone deacetylases, implicating chromatin remodelling in the transcriptional regulation of caspase-14. However, crossing hairless mutant mice with caspase-14-deficient mice revealed that caspase-14 overexpression is not the cause of utricle formation. PMID- 23800062 TI - Functional and molecular genetic analyses of nine newly identified XPD-deficient patients reveal a novel mutation resulting in TTD as well as in XP/CS complex phenotypes. AB - The xeroderma pigmentosum (XP) group D protein is involved in nucleotide excision repair (NER) as well as in basal transcription. Determined by the type of XPD mutation, six different clinical entities have been distinguished: XP, XP with neurological symptoms, trichothiodystrophy (TTD), XP/TTD complex, XP/Cockayne syndrome (CS) complex or the cerebro-oculo-facio-skeletal syndrome (COFS). We identified nine new XPD-deficient patients. Their fibroblasts showed reduced post UV cell survival, reduced NER capacity, normal XPD mRNA expression and partly reduced XPD protein expression. Six patients exhibited a XP phenotype in accordance with established XP-causing mutations (c.2079G>A, p.R683Q; c.2078G>T, p.R683W; c.1833G>T, p.R601L; c.1878G>C, p.R616P; c.1878G>A, p.R616Q). One TTD patient was homozygous for the known TTD-causing mutation p.R722W (c.2195C>T). Two patients were compound heterozygous for a TTD-causing mutation (c.366G>A, p.R112H) and a novel p.D681H (c.2072G>C) amino acid exchange, but exhibited different TTD and XP/CS complex phenotypes, respectively. Interestingly, the XP/CS patient's cells exhibited a reduced but well detectable XPD protein expression compared with hardly detectable XPD expression of the TTD patient's cells. Same mutations with different clinical outcomes in NER-defective patients demonstrate the complexity of phenotype-genotype correlations, for example relating to additional genetic variations (parental consanguinity), different allelic expression due to SNPs or differences in the methylation status. PMID- 23800063 TI - Expression analysis of multiple microRNAs in each patient with scleroderma. AB - In this study, we compared expression pattern of multiple microRNAs in individual patient with scleroderma with that in normal subject. Serum levels of six microRNAs (miR-7 g, miR-21, miR-29b, miR-125, miR-145 and miR-206) were evaluated using real-time PCR in 15 patients with scleroderma and 15 normal subjects. While levels of the six microRNAs were similar between the two groups, we found significant difference in the ranks between miRNAs in patients with scleroderma. Additionally, levels of let-7 g and miR-125b showed strong and significant correlation in normal subjects, but not in patients with scleroderma. Thus, miRNA expression pattern may be different in patients with scleroderma. We also found the combination of serum levels of miR-206 and miR-21 was more useful in distinguishing patients with scleroderma from normal subjects than either miR-206 or miR-21 alone. Our study is the first to demonstrate different expression profiles of multiple microRNAs in each patient with scleroderma and examine its clinical significance. PMID- 23800064 TI - Resveratrol induces autophagy through death-associated protein kinase 1 (DAPK1) in human dermal fibroblasts under normal culture conditions. AB - Autophagy is an essential process degrading damaged components. Although resveratrol has various beneficial activities for health, little is known about the effects of resveratrol on autophagy in skin. We investigated whether resveratrol affects autophagy in human dermal fibroblasts grown in complete medium. We found that after the resveratrol treatment, LC3-II reached a maximum level at 8 h and then gradually decreased. By PCR array analysis, we identified death-associated protein kinase 1 (DAPK1) as a new target of resveratrol, and we confirmed that the expression level of DAPK1 was enhanced by resveratrol. We also demonstrated that DAPK1 knock-down by siRNA was sufficient to reduce resveratrol induced autophagy but did not affect the phosphorylation level of AMP-activated kinase (AMPK), a well-known target of resveratrol. These data indicate that resveratrol-induced autophagy can be mediated by DAPK1, raising the possibility that some of the beneficial effects of resveratrol may be due to its regulation of DAPK1. PMID- 23800065 TI - Role of CPI-17 in restoring skin homoeostasis in cutaneous field of cancerization: effects of topical application of a film-forming medical device containing photolyase and UV filters. AB - Cutaneous field of cancerization (CFC) is caused in part by the carcinogenic effect of the cyclobutane pyrimidine dimers CPD and 6-4 photoproducts (6-4PPs). Photoreactivation is carried out by photolyases which specifically recognize and repair both photoproducts. The study evaluates the molecular effects of topical application of a film-forming medical device containing photolyase and UV filters on the precancerous field in AK from seven patients. Skin improvement after treatment was confirmed in all patients by histopathological and molecular assessment. A gene set analysis showed that skin recovery was associated with biological processes involved in tissue homoeostasis and cell maintenance. The CFC response was associated with over-expression of the CPI-17 gene, and a dependence on the initial expression level was observed (P = 0.001). Low CPI-17 levels were directly associated with pro-inflammatory genes such as TNF (P = 0.012) and IL-1B (P = 0.07). Our results suggest a role for CPI-17 in restoring skin homoeostasis in CFC lesions. PMID- 23800066 TI - Pretreatment of epidermal growth factor promotes primary hair recovery via the dystrophic anagen pathway after chemotherapy-induced alopecia. AB - Epidermal growth factor (EGF) is not only a cell growth stimulant but also has a catagen-inducing effect. Because chemotherapeutic agents primarily damage anagen hair follicles, it would be important to investigate whether catagen inducers have beneficial effects in chemotherapy-induced alopecia (CIA). We pretreated hair follicles with topical EGF-liposomal solution in the C57BL/6 mouse model of cyclophosphamide-induced alopecia and observed the catagen-inducing property and damage response pathway after CIA. We confirmed that topical EGF application induced a catagen-like stage and found that these catagen-like hairs were protected from chemotherapy-mediated damage. Moreover, our results showed that EGF treatment favoured primary hair recovery via the dystrophic anagen pathway after CIA. Given that hair follicles subjected to less severe chemotherapeutic insult enter the dystrophic anagen pathway followed by primary recovery, the results of this study suggest that catagen inducers could be useful as a new alopecia-protection strategy, especially in the context of CIA. PMID- 23800067 TI - A mouse model of vitiligo induced by monobenzone. AB - The paucity of vitiligo animal models limits the understanding of vitiligo pathogenesis and the development of therapies for the skin disorder. In this study, we developed a new mouse model of vitiligo by topically applying the skin depigmenting agent monobenzone on mice. We demonstrated that monobenzone-induced skin depigmentation on the non-exposed sites and that the severity of lesions depended on drug dosage. The result of the histological examination of the depigmented skin indicated loss of epidermal melanocytes and perilesional accumulation of CD8+ T cells. Furthermore, the monobenzone-induced depigmentation of the Rag1 gene knockout did not appear on the non-exposed sites, supporting the involvement of infiltrating CD8+ T cells in melanocyte destruction. Resemblance in histological characteristics and pathogenesis between monobenzone-induced depigmentation and active human vitiligo suggests good potential of our mouse model for use in vitiligo research. PMID- 23800068 TI - Are therapeutic effects of antiacne agents mediated by activation of FoxO1 and inhibition of mTORC1? AB - Acne pathogenesis has recently been linked to decreased nuclear FoxO1 levels and increased mTORC1 activity. This hypothesis postulates that antiacne agents either enhance nuclear FoxO activity or inhibit mTORC1. Benzoyl peroxide (BPO), by activation of oxidative stress-inducible kinases, increases nuclear FoxO levels promoting Sestrin3-mediated AMPK activation. Furthermore, BPO-derived ROS may activate AMPK via ataxia-telangiectasia mutated. Isotretinoin and all-trans retinoic acid may stimulate FoxO gene expression. Doxycycline may enhance FoxOs nuclear retention by inhibiting the expression of exportin 1. Suppression of TNFalpha signalling by tetracyclines, erythromycin and other macrolides may attenuate IKKbeta-TSC1-mediated mTORC1 activation. Erythromycin attenuates ERK1/2 activity and thereby increases TSC2. Azelaic acid may decrease mTORC1 by inhibiting mitochondrial respiration, increasing cellular ROS and nuclear FoxO levels. Antiandrogens may attenuate mTORC1 by suppressing mTORC2-mediated Akt/TSC2 signalling. This hypothesis unmasks a common mode of action of antiacne agents as either FoxO enhancers or mTORC1 inhibitors and thus provides a rational approach for the development of new antiacne agents. PMID- 23800069 TI - Turning acne on/off via mTORC1. AB - Over the past 10 years, the increase in comprehension of the mechanisms behind acne has been truly exponential. Starting with the ethnological work of Cordain, accelerated by the epidemiological work of Adebamowo, supported by the clinical trials of Smith and Mann, Kwon, DiLandro and others, the interface of diet and acne is coming into focus. Melnik now presents an exceptional pair of papers that illustrate for dermatologists what translational research is all about. The Western diet, the role of dairy, FoxO1 and mTORC1, the interplay of agonists and antagonists, therapeutics present and future - the jigsaw puzzle is coming together. PMID- 23800071 TI - Shedding light on junior doctors' work practices after hours. AB - BACKGROUND: It is imperative to understand the current work practices of hospital personnel to inform efforts and secure resources towards the improvement of hospital systems. Research examining doctors' work during night-shifts is limited. AIM: To describe and quantify the night-shift work practices of junior doctors. METHODS: An observational time and motion study was conducted. Eight resident doctors in four general wards were observed for 96 h during night shifts (Monday-Friday, 2200-0800). RESULTS: Doctors spent the highest proportion (28%; 95% CI 21-35) of their time performing social/personal tasks (e.g. sleeping, eating) and indirect care (24%; 95% CI 22-25) (e.g. reviewing notes, ordering tests). Work-related discussion comprised 15% (95% CI 13-17), and most took place at the beginning of the night. Medication-related tasks consumed a small proportion of time (4%; 95% CI 3-4) but attracted a higher level of multitasking and interruptions than most other tasks. On average, 2 h of every shift were spent at a computer and 1.3 h with patient notes. Doctors spent 72% of the night shift alone, multitasked 6.4% of the time and were interrupted, on average, once every 46 min. CONCLUSIONS: This study provides new data about junior doctors' work at night. Relative to doctors during the day, greater proportions of time were devoted to social/personal tasks (including sleep) and indirect care, but a similar proportion to direct care. Multitasking and interruptions were minimal. Computer activities were an integral part of work. Handovers were observed at the beginning but not the completion of the night shift, which may have implications for patient safety. PMID- 23800072 TI - The diagnostic value of ultrasonography in carpal tunnel syndrome: a comparison between diabetic and non-diabetic patients. AB - BACKGROUND: To compare the value of ultrasonography for diagnosing carpal tunnel syndrome (CTS) in patients with and without diabetes mellitus (DM). METHODS: Eighty non-DM and 40 DM patients with electromyography-confirmed CTS were assessed and underwent high-resolution ultrasonography of the wrists. Cross sectional area (CSA) and flattening ratio (FR) of the median nerve were measured at the carpal tunnel outlet (D) and wrist crease (W). RESULTS: The 80 non-DM and 40 DM patients had 81 and 59 CTS-hands, respectively. The CSA_D and CSA_W were significantly larger in the CTS-hands and DM-CTS-hands compared to the normal control (p < 0.001). However, there is no difference of CSA_D and CSA_W between DM and non-DM CTS patients. Receiver operating characteristics [ROC] curve analysis revealed that CSA_W >=13 mm2 was the most powerful predictor of CTS in DM (area under curve [AUC] = 0.72; sensitivity 72.9%, specificity 61.9%) and non DM (AUC = 0.72; sensitivity 78.5%, specificity 53.2%) patients. The CSA positively correlated with the distal motor latency of the median compound motor action potential (CMAP), distal sensory latency of the median sensory nerve action potential (SNAP), and latency of the median F wave, but negatively correlated with the amplitude of the median CMAP, amplitude of the median SNAP, and sensory NCV of the median nerve. Stepwise logistic regression revealed that CSA_W (OR 1.21, 95% CI 1.07-1.38; p = 0.003) was independently associated with CTS in DM patients and any 1 mm2 increase in CSA_W increased the rate of CTS by 28%. CONCLUSIONS: The CSA of the median nerve at the outlet and wrist crease are significantly larger in CTS hands in both DM and non-DM patients compared to normal hands. The CSA of the median nerve by ultrasonography may be a diagnostic tool for evaluating CTS in DM and non-DM patients. PMID- 23800073 TI - Temporary organ displacement coupled with image-guided, intensity-modulated radiotherapy for paraspinal tumors. AB - BACKGROUND: To investigate the feasibility and dosimetric improvements of a novel technique to temporarily displace critical structures in the pelvis and abdomen from tumor during high-dose radiotherapy. METHODS: Between 2010 and 2012, 11 patients received high-dose image-guided intensity-modulated radiotherapy with temporary organ displacement (TOD) at our institution. In all cases, imaging revealed tumor abutting critical structures. An all-purpose drainage catheter was introduced between the gross tumor volume (GTV) and critical organs at risk (OAR) and infused with normal saline (NS) containing 5-10% iohexol. Radiation planning was performed with the displaced OARs and positional reproducibility was confirmed with cone-beam CT (CBCT). Patients were treated within 36 hours of catheter placement. Radiation plans were re-optimized using pre-TOD OARs to the same prescription and dosimetrically compared with post-TOD plans. A two-tailed permutation test was performed on each dosimetric measure. RESULTS: The bowel/rectum was displaced in six patients and kidney in four patients. One patient was excluded due to poor visualization of the OAR; thus 10 patients were analyzed. A mean of 229 ml (range, 80-1000) of NS 5-10% iohexol infusion resulted in OAR mean displacement of 17.5 mm (range, 7-32). The median dose prescribed was 2400 cGy in one fraction (range, 2100-3000 in 3 fractions). The mean GTV Dmin and PTV Dmin pre- and post-bowel TOD IG-IMRT dosimetry significantly increased from 1473 cGy to 2086 cGy (p=0.015) and 714 cGy to 1214 cGy (p=0.021), respectively. TOD increased mean PTV D95 by 27.14% of prescription (p=0.014) while the PTV D05 decreased by 9.2% (p=0.011). TOD of the bowel resulted in a 39% decrease in mean bowel Dmax (p=0.008) confirmed by CBCT. TOD of the kidney significantly decreased mean kidney dose and Dmax by 25% (0.022). CONCLUSIONS: TOD was well tolerated, reproducible, and facilitated dose escalation to previously radioresistant tumors abutting critical structures while minimizing dose to OARs. PMID- 23800074 TI - Factors influencing the fertility choices of child immigrants in Canada. AB - We analysed the fertility of women who migrated to Canada before reaching age 19, using the 20 per cent sample of the Canadian censuses from 1991 to 2006. Fertility increases with age at immigration, and is particularly high for those immigrating in late adolescence. This pattern prevails regardless of the country of origin, and of whether the mother tongue of the migrants was an official language in Canada. The fertility of those for whom it was an official language is always lower on average than of those for whom it was not, but there does not seem to be a critical age at which the fertility of the former and the latter starts to diverge. Formal education has an effect: the fertility of immigrants who arrived in Canada at any age before adulthood and who were or became college graduates is similar to that of their native peers. An appendix to this paper is available at http://dx.doi.org/10.1080/00324728.2013.802007. PMID- 23800075 TI - Nonsustained hypercalcaemia and primary hyperparathyroidism in the PEARS cohort. PMID- 23800076 TI - The eukaryotic translation initiation factor 3 subunit L protein interacts with Flavivirus NS5 and may modulate yellow fever virus replication. AB - BACKGROUND: Yellow fever virus (YFV) belongs to the Flavivirus genus and causes an important disease. An alarming resurgence of viral circulation and the expansion of YFV-endemic zones have been detected in Africa and South America in recent years. NS5 is a viral protein that contains methyltransferase and RNA dependent RNA polymerase (RdRp) domains, which are essential for viral replication, and the interactions between NS5 and cellular proteins have been studied to better understand viral replication. The aim of this study was to characterize the interaction of the NS5 protein with eukaryotic translation initiation factor 3 subunit L (eIF3L) and to evaluate the role of eIF3L in yellow fever replication. METHODS: To identify interactions of YFV NS5 with cellular proteins, we performed a two-hybrid screen using the YFV NS5 RdRp domain as bait with a human cDNA library, and RNApol deletion mutants were generated and analyzed using the two-hybrid system for mapping the interactions. The RNApol region involved was segmented into three fragments and analyzed using an eIF3L expressing yeast strain. To map the NS5 residues that are critical for the interactions, we performed site-direct mutagenesis in segment 3 of the interaction domain (ID) and confirmed the interaction using in vitro assays and in vivo coimmunoprecipitation. The significance of eIF3L for YFV replication was investigated using eIF3L overexpression and RNA interference. RESULTS: In this work, we describe and characterize the interaction of NS5 with the translation factor eIF3L. The interaction between NS5 and eIF3L was confirmed using in vitro binding and in vivo coimmunoprecipitation assays. This interaction occurs at a region (the interaction domain of the RNApol domain) that is conserved in several flaviviruses and that is, therefore, likely to be relevant to the genus. eIF3L overexpression and plaque reduction assays showed a slight effect on YFV replication, indicating that the interaction of eIF3L with YFV NS5 may play a role in YFV replication. CONCLUSIONS: Although the precise function of eIF3L on interactions with viral proteins is not entirely understood, these results indicate an interaction of eIF3L with YF NS5 and that eIF3L overexpression facilitates translation, which has potential implications for virus replication. PMID- 23800077 TI - Current status of renin-aldosterone angiotensin system-targeting anti hypertensive drugs as therapeutic options for Alzheimer's disease. AB - INTRODUCTION: Hypertension is a modifiable risk factor for Alzheimer's disease (AD) and other dementias. Yet, despite this well-documented association, few of the current strategies to treat AD are directed at this possible target. The renin-aldosterone angiotensin system (RAAS) is a centrally active modifiable pathway that is involved in cerebral blood flow regulation. Currently, three classes of RAAS-targeting drugs are licensed for treatment of peripheral hypertension--angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin II receptor blockers (ARBs) and direct renin inhibitors (DRIs). All of these are generally well tolerated and have been shown to offer varying degrees of protection on aspects of cognition and dementia, thus making them an attractive therapeutic option for AD. AREAS COVERED: This review summarises existing evidence regarding the plausibility of using RAAS-targeting drugs as a strategy to treat AD and highlights unresolved aspects to such approaches, namely the potential impact of altering angiotensin II-mediated processes in the central nervous system. EXPERT OPINION: Continued biochemical research of the RAAS pathway in combination with formal investigation of current RAAS-modifying drugs in randomised clinical trials is now necessary to determine their therapeutic value in AD. PMID- 23800078 TI - Proton pump inhibitors and the risk of pneumonia: a comparison of cohort and self controlled case series designs. AB - BACKGROUND: To compare the results of a new-user cohort study design and the self controlled case series (SCCS) design using the risk of hospitalisation for pneumonia in those dispensed proton pump inhibitors compared to those unexposed as a case study. METHODS: The Australian Government Department of Veterans' Affairs administrative claims database was used. Exposure to proton pump inhibitors and hospitalisations for pneumonia were identified over a 4 year study period 01 Jul 2007 -30 Jun 2011. The same inclusion and exclusion criteria were applied to both studies, however, the SCCS study included subjects with a least one hospitalisation for pneumonia. RESULTS: There were 105,467 subjects included in the cohort study and 6775 in the SCCS. Both studies showed an increased risk of hospitalisations for pneumonia in the three defined risk periods following initiation of proton pump inhibitors compared to baseline. With the highest risk in the first 1 to 7 days (Cohort RR, 3.24; 95% CI (2.50, 4.19): SCCS: RR, 3.07; 95% CI (2.69, 3.50)). CONCLUSIONS: This study has shown that the self-controlled case series method produces similar risk estimates to a new-users cohort study design when applied to the association of proton pump inhibitors and pneumonia. Exposure to a proton pump inhibitor increases the likelihood of being admitted to hospital for pneumonia, with the risk highest in the first week of treatment. PMID- 23800079 TI - Nursing and midwifery regulatory reform in east, central, and southern Africa: a survey of key stakeholders. AB - BACKGROUND: In sub-Saharan Africa, nurses and midwives provide expanded HIV services previously seen as the sole purview of physicians. Delegation of these functions often occurs informally by shifting or sharing of tasks and responsibilities. Normalizing these arrangements through regulatory and educational reform is crucial for the attainment of global health goals and the protection of practitioners and those whom they serve. Enacting appropriate changes in both regulation and education requires engagement of national regulatory bodies, but also key stakeholders such as government chief nursing officers (CNO), professional associations, and educators. The purpose of this research is to describe the perspectives and engagement of these stakeholders in advancing critical regulatory and educational reform in east, central, and southern Africa (ECSA). METHODS: We surveyed individuals from these three stakeholder groups with regard to task shifting and the challenges related to practice and education regulation reform. The survey used a convenience sample of nursing and midwifery leaders from countries in ECSA who convened on 28 February 2011, for a meeting of the African Health Profession Regulatory Collaborative. RESULTS: A total of 32 stakeholders from 13 ECSA countries participated in the survey. The majority (72%) reported task shifting is practiced in their countries; however only 57% reported their national regulations had been revised to incorporate additional professional roles and responsibilities. Stakeholders also reported different roles and levels of involvement with regard to nursing and midwifery regulation. The most frequently cited challenge impacting nursing and midwifery regulatory reform was the absence of capacity and resources needed to implement change. DISCUSSION: While guidelines on task shifting and recommendations on transforming health professional education exist, this study provides new evidence that countries in the ECSA region face obstacles to adapting their practice and education regulations accordingly. Stakeholders such as CNOs, nursing associations, and academicians have varied and complementary roles with regard to reforming professional practice and education regulation. CONCLUSION: This study provides information for effectively engaging leaders in regulatory reform by clarifying their roles, responsibilities, and activities regarding regulation overall as well as their specific perspectives on task shifting and pre-service reform. PMID- 23800080 TI - Evaluation of purity with its uncertainty value in high purity lead stick by conventional and electro-gravimetric methods. AB - BACKGROUND: A conventional gravimetry and electro-gravimetry study has been carried out for the precise and accurate purity determination of lead (Pb) in high purity lead stick and for preparation of reference standard. Reference materials are standards containing a known amount of an analyte and provide a reference value to determine unknown concentrations or to calibrate analytical instruments. A stock solution of approximate 2 kg has been prepared after dissolving approximate 2 g of Pb stick in 5% ultra pure nitric acid. From the stock solution five replicates of approximate 50 g have been taken for determination of purity by each method. The Pb has been determined as PbSO4 by conventional gravimetry, as PbO2 by electro gravimetry. The percentage purity of the metallic Pb was calculated accordingly from PbSO4 and PbO2. RESULTS: On the basis of experimental observations it has been concluded that by conventional gravimetry and electro-gravimetry the purity of Pb was found to be 99.98 +/- 0.24 and 99.97 +/- 0.27 g/100 g and on the basis of Pb purity the concentration of reference standard solutions were found to be 1000.88 +/- 2.44 and 1000.81 +/- 2.68 mg kg-1 respectively with 95% confidence level (k = 2). The uncertainty evaluation has also been carried out in Pb determination following EURACHEM/GUM guidelines. The final analytical results quantifying uncertainty fulfills this requirement and gives a measure of the confidence level of the concerned laboratory. CONCLUSIONS: Gravimetry is the most reliable technique in comparison to titremetry and instrumental method and the results of gravimetry are directly traceable to SI unit. Gravimetric analysis, if methods are followed carefully, provides for exceedingly precise analysis. In classical gravimetry the major uncertainties are due to repeatability but in electro-gravimetry several other factors also affect the final results. PMID- 23800081 TI - ATF2 knockdown reinforces oxidative stress-induced apoptosis in TE7 cancer cells. AB - Cancer cells showing low apoptotic effects following oxidative stress-induced DNA damage are mainly affected by growth arrest. Thus, recent studies focus on improving anti-cancer therapies by increasing apoptosis sensitivity. We aimed at identifying a universal molecule as potential target to enhance oxidative stress based anti-cancer therapy through a switch from cell cycle arrest to apoptosis. A cDNA microarray was performed with hydrogen peroxide-treated oesophageal squamous epithelial cancer cells TE7. This cell line showed checkpoint activation via p21(WAF1) , but low apoptotic response following DNA damage. The potential target molecule was chosen depended on the following demands: it should regulate DNA damage response, cell cycle and apoptosis. As the transcription factor ATF2 is implicated in all these processes, we focused on this protein. We investigated checkpoint activation via ATF2. Indeed, ATF2 knockdown revealed ATF2-triggered p21(WAF1) protein expression, suggesting p21(WAF1) transactivation through ATF2. Using chromatin immunoprecipitation (ChIP), we identified a hitherto unknown ATF2 binding sequence in the p21(WAF1) promoter. p-ATF2 was found to interact with p-c Jun, creating the AP-1 complex. Moreover, ATF2 knockdown led to c-Jun downregulation. This suggests ATF2-driven induction of c-Jun expression, thereby enhancing ATF2 transcriptional activity via c-Jun-ATF2 heterodimerization. Notably, downregulation of ATF2 caused a switch from cell cycle arrest to reinforced apoptosis, presumably via p21(WAF1) downregulation, confirming the importance of ATF2 in the establishment of cell cycle arrest. 1-Chloro-2,4 dinitrobenzene also led to ATF2-dependent G2/M arrest, suggesting that this is a general feature induced by oxidative stress. As ATF2 knockdown also increased apoptosis, we propose ATF2 as a target for combined oxidative stress-based anti cancer therapies. PMID- 23800082 TI - Glycemic control among patients in China with type 2 diabetes mellitus receiving oral drugs or injectables. AB - BACKGROUND: The prevalence of type 2 diabetes mellitus (T2DM) is increasing rapidly among Chinese adults, and limited data are available on T2DM management and the status of glycemic control in China. We assessed the efficacy of oral antidiabetes drugs (OADs), glucagon-like peptide-1 (GLP-1) receptor agonists, and insulin for treatment of T2DM across multiple regions in China. METHODS: This was a multicenter, cross-sectional survey of outpatients conducted in 606 hospitals across China. Data from all the patients were collected between April and June, 2011. RESULTS: A total of 238,639 patients were included in the survey. Eligible patients were treated with either OADs alone (n=157,212 [65.88%]), OADs plus insulin (n=80,973 [33.93%]), or OADs plus GLP-1 receptor agonists (n=454 [0.19%]). The OAD monotherapy, OAD + insulin, and OAD + GLP-1 receptor agonist groups had mean glycosylated hemoglobin (HbA1c) levels (+/-SD) of 7.67% (+/ 1.58%), 8.21% (+/-1.91%), and 7.80% (+/-1.76%), respectively. Among those three groups, 34.63%, 26.21%, and 36.12% met the goal of HbA1c <7.0%, respectively. Mean HbA1c and achievement of A1c <7.0% was related to the duration of T2DM. CONCLUSIONS: Less than one third of the patients had achieved the goal of HbA1c <7.0%. Glycemic control decreased and insulin use increased with the duration of diabetes. PMID- 23800083 TI - Mapping IS6110 in high-copy number Mycobacterium tuberculosis strains shows specific insertion points in the Beijing genotype. AB - BACKGROUND: Mycobacterium tuberculosis Beijing strains are characterized by a large number of IS6110 copies, suggesting the potential implication of this element in the virulence and capacity for rapid dissemination characteristic of this family. This work studies the insetion points of IS6110 in high-copy clinical isolates specifically focusing on the Beijing genotype. RESULTS: In the present work we mapped the insertion points of IS6110 in all the Beijing strains available in the literature and in the DNA sequence databases. We generated a representative primer collection of the IS6110 locations, which was used to analyse 61 high-copy clinical isolates. A total of 440 points of insertion were identified and analysis of their flanking regions determined the exact location, the direct repeats (DRs), the orientation and the distance to neighboring genes of each copy of IS6110. We identified specific points of insertion in Beijing strains that enabled us to obtain a dendrogram that groups the Beijing genotype. CONCLUSIONS: This work presents a detailed analysis of locations of IS6110 in high-copy clinical isolates, showing points of insertion present with high frequency in the Beijing family and absent in other strains. PMID- 23800084 TI - A case of adenocarcinoma of the rete testis accompanied by focal adenomatous hyperplasia. AB - Adenocarcinoma of the rete testis is very rare. There is still little knowledge about its etiology and pathogenesis. Herein, we present a case of rete testis adenocarcinoma in a 36-year-old Chinese male. The tumor was predominantly composed of irregular small tubules and papillary structures with cuboidal or polygonal cells. In peripheral area of the tumor, the remaining normal rete testis and adenomatous hyperplasia of the rete testis could also be seen, indicating the possible relationship between adenomatous hyperplasia and adenocarcinoma. In addition, the patient underwent a left hydrocelectomy because of the existence of hydrocele 3 years ago. But, it is unclear whether hydrocele and hydrocelectomy is its cause or just the early clinical presentation of the adenocarcinoma. PMID- 23800085 TI - Separating homeologs by phasing in the tetraploid wheat transcriptome. AB - BACKGROUND: The high level of identity among duplicated homoeologous genomes in tetraploid pasta wheat presents substantial challenges for de novo transcriptome assembly. To solve this problem, we develop a specialized bioinformatics workflow that optimizes transcriptome assembly and separation of merged homoeologs. To evaluate our strategy, we sequence and assemble the transcriptome of one of the diploid ancestors of pasta wheat, and compare both assemblies with a benchmark set of 13,472 full-length, non-redundant bread wheat cDNAs. RESULTS: A total of 489 million 100 bp paired-end reads from tetraploid wheat assemble in 140,118 contigs, including 96% of the benchmark cDNAs. We used a comparative genomics approach to annotate 66,633 open reading frames. The multiple k-mer assembly strategy increases the proportion of cDNAs assembled full-length in a single contig by 22% relative to the best single k-mer size. Homoeologs are separated using a post-assembly pipeline that includes polymorphism identification, phasing of SNPs, read sorting, and re-assembly of phased reads. Using a reference set of genes, we determine that 98.7% of SNPs analyzed are correctly separated by phasing. CONCLUSIONS: Our study shows that de novo transcriptome assembly of tetraploid wheat benefit from multiple k-mer assembly strategies more than diploid wheat. Our results also demonstrate that phasing approaches originally designed for heterozygous diploid organisms can be used to separate the close homoeologous genomes of tetraploid wheat. The predicted tetraploid wheat proteome and gene models provide a valuable tool for the wheat research community and for those interested in comparative genomic studies. PMID- 23800086 TI - The association and predictive value analysis of metabolic syndrome on diastolic heart failure in patients at high risk for coronary artery disease. AB - BACKGROUND: The purpose of the present study was to evaluate the effect and predictive value of metabolic syndrome (MetS) and its components on diastolic heart failure (DHF) in patients at high risk for coronary artery disease (CAD). MATERIALS AND METHODS: We enrolled 261 patients with normal left ventricular ejection fraction (>=50%) who were scheduled to undergo coronary angiography for suspected myocardial ischemia. They were categorized into three groups (non-MetS, pre-MetS and MetS) based on the number of MetS criteria. Echocardiography was used to assess left ventricular (LV) diastolic function. The association between MetS and DHF was assessed by multivariate logistic regression (MLR) analysis (non DHF patients as reference group) after controlling for confounders. The predictive performance of the MetS severity score (MSS) was evaluated using the area under the receiver-operating characteristic curve (AUC). RESULTS: A tendency toward increased DHF prevalence with increasing MSS was found (p < 0.001). MLR analysis showed that in patients with an MSS of 1, the odds ratio (OR) of DHF was 1.60 (95% confidence interval-CI, 1.19-2.16; p = 0.02) compared to non-DHF patients; in patients with MSS >=4, the OR was 6.61 (95% CI, 4.90-8.90; p < 0.001) compared to non-DHF patients. MSSs strongly predicted DHF (AUC = 0.73, 95% CI, 0.66-0.78, p < 0.001). MLR with MetS components as binary variables showed that blood pressure (BP) and triglycerides (TGs) were significantly associated with DHF (P = 0.001 and 0.043, respectively). CONCLUSION: Our findings signify that MetS and its components of BP or TG were associated with DHF in high-risk CAD patients. DHF prevalence tends to increase with increasing MSS that has a high value in predicting DHF in high-risk CAD patients. PMID- 23800087 TI - Geographic variation in ambulatory electronic health record adoption: implications for underserved communities. AB - OBJECTIVE: To describe small area variation in ambulatory electronic health record (EHR) adoption and assess evidence of a "digital divide" in whether adoption is lagging in traditionally underserved communities. DATA SOURCES: Survey data on U.S. ambulatory health care sites (261,973 sites representing 716,160 providers) collected by SK&A Information Services in 2011. STUDY DESIGN: We examined cross-sectional variation in two measures of local area EHR adoption: share of providers at sites using an EHR with e-prescribing functionality; and predicted probability of EHR adoption for the average site. Local areas were defined as Public Use Microdata Areas (n = 2,068). Using multivariate regression, we examined the association between adoption and three area characteristics: high concentration of minority population; high concentration of low-income population; and metropolitan status. PRINCIPAL FINDINGS: EHR adoption varied significantly across local areas, ranging from 8 to 88 percent with a median of 41 percent. Adoption was lower in large metropolitan areas; areas with high concentration of minority population in the Northeast and West; and areas with high concentration of low-income population in the Midwest. CONCLUSIONS: Our 2011 estimates suggest there was substantial room for increased EHR adoption across the United States, including some underserved areas with relatively low EHR adoption rates. Further research should monitor policy initiatives in these areas and examine sources of heterogeneity in low- and high-adoption communities. PMID- 23800088 TI - Use of insecticide treated net and malaria preventive education: effect on malaria parasitemia among people living with AIDS in Nigeria, a cross-sectional study. AB - BACKGROUND: Malaria and HIV are major causes of morbidity and mortality in sub Saharan Africa with both diseases highly endemic in Nigeria. This study was conducted to assess the effect of long lasting insecticide treated net (ITN) use and malaria preventive education on burden of malaria parasite among people living with AIDS (PLWHA) at Osogbo southwestern Nigeria. METHOD: A descriptive cross-sectional study of newly recruited consenting PLWHA that were screened consecutively for malaria, those positive were treated with artemisinin combination therapy. All PLWHA were educated about malaria infection, given ITN and followed up monthly for three months when they were rescreened for malaria infection. Data collected was analyzed using descriptive and inferential statistics. RESULT: A total of 392 (92%) PLWHA completed the study. Mean age of the respondents was 33 +/- 11.6 years. They were 120 (31%) males and 272 (69%) females. Majority (80%) were married, over 33% completed secondary education while 21% had tertiary education. Most were traders (40%) and artisans (25%). About 60% had Plasmodium falciparum malaria parasitemia at baseline which drastically reduced to 5% at three months with ITN use and malaria prevention education. CONCLUSION: Malaria is a major preventable condition among PLWHA. Preventive education and ITN use reduced malaria parasite burden among this population. PMID- 23800090 TI - The choice of alternatives to acute hospitalization: a descriptive study from Hallingdal, Norway. AB - BACKGROUND: Hallingdal is a rural region in southern Norway. General practitioners (GPs) refer acutely somatically ill patients to any of three levels of care: municipal nursing homes, the regional community hospital or the local general hospital. The objective of this paper is to describe the patterns of referrals to the three different somatic emergency service levels in Hallingdal and to elucidate possible explanations for the differences in referrals. METHODS: Quantitative methods were used to analyse local patient statistics and qualitative methods including focus group interviews were used to explore differences in referral rates between GPs. The acute somatic admissions from the six municipalities of Hallingdal were analysed for the two-year period 2010-11 (n = 1777). A focus group interview was held with the chief municipal medical officers of the six municipalities. The main outcome measure was the numbers of admissions to the three different levels of acute care in 2010-11. Reflections of the focus group members about the differences in admission patterns were also analysed. RESULTS: Acute admissions at a level lower than the local general hospital ranged from 9% to 29% between the municipalities. Foremost among the local factors affecting the individual doctor's admission practice were the geographical distance to the different places of care and the GP's working experience in the local community. CONCLUSION: The experience from Hallingdal demonstrates that GPs use available alternatives to hospitalization but to varying degrees. This can be explained by socio-demographic factors and factors related to the medical reasons for admission. However, there are also important local factors related to the individual GP and the structural preparedness for alternatives in the community. PMID- 23800089 TI - When does trimethylamine N-oxide fold a polymer chain and urea unfold it? AB - Longstanding mechanistic questions about the role of protecting osmolyte trimethylamine N-oxide (TMAO) that favors protein folding and the denaturing osmolyte urea are addressed by studying their effects on the folding of uncharged polymer chains. Using atomistic molecular dynamics simulations, we show that 1 M TMAO and 7 M urea solutions act dramatically differently on these model polymer chains. Their behaviors are sensitive to the strength of the attractive dispersion interactions of the chain with its environment: when these dispersion interactions are sufficiently strong, TMAO suppresses the formation of extended conformations of the hydrophobic polymer as compared to water while urea promotes the formation of extended conformations. Similar trends are observed experimentally for real protein systems. Quite surprisingly, we find that both protecting and denaturing osmolytes strongly interact with the polymer, seemingly in contrast with existing explanations of the osmolyte effect on proteins. We show that what really matters for a protective osmolyte is its effective depletion as the polymer conformation changes, which leads to a negative change in the preferential binding coefficient. For TMAO, there is a much more favorable free energy of insertion of a single osmolyte near collapsed conformations of the polymer than near extended conformations. By contrast, urea is preferentially stabilized next to the extended conformation and thus has a denaturing effect. PMID- 23800092 TI - "Polyanalgesic Consensus Conference 2012: Recommendations for the management of pain by intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel" by Timothy R. Deer, MD et al., that was published in your prestigious journal under the following reference: Neuromodulation 2012;15:436 466. PMID- 23800093 TI - Remobilization of hematopoietic stem cells with high-dose methotrexate and cytarabine in patients with non-Hodgkin's lymphoma and multiple myeloma after failure to mobilize with chemotherapy and cytokines. AB - BACKGROUND: High-dose chemotherapy supported by autologous stem cell transplantation is an effective treatment for patients with relapsed or refractory non-Hodgkin's lymphomas (NHLs) and fit patients with multiple myeloma (MM). However, failure rates of hematopoietic stem cell mobilization are estimated to be between 5 and 30%, respectively. Thus, we investigated the efficacy of the combination chemotherapy of high-dose methotrexate (MTX) and cytarabine with granulocyte-colony-stimulating factor (G-CSF) as a remobilization method in those who failed a prior mobilization and collection with chemotherapy and G-CSF. STUDY DESIGN AND METHODS: Mobilization failure was defined as a collection of fewer than 5 * 10(6) CD34+ cells after three to five apheresis procedures. MTX (3500 mg/m(2) in a 120-min infusion) on Day 1 and cytarabine (3000 mg/m(2) infusion for 120 min) on Day 4 and Day 5 were followed by G-CSF (10 MUg/kg daily). RESULTS: A total of eight patients (six NHL and two MM; median age, 55 years) who had failed in prior mobilization with conventional chemotherapy and G-CSF underwent the second mobilization as described in the method. Successful collection of CD34+ cells (> 5 * 10(6) /kg) was achieved in six patients (75%) with three to five apheresis procedures. The total yield of CD34+ cells/kg body weight was 6.28 * 10(6) /kg (median; range, 1.53 * 10(6) 10.09 * 10(6) /kg). CONCLUSIONS: This preliminary result warrants further investigation of high-dose MTX and cytarabine plus G-CSF as a means to remobilize stem cells in those with prior failure to mobilize stem cells with chemotherapy and G-CSF. PMID- 23800091 TI - Spica prunellae promotes cancer cell apoptosis, inhibits cell proliferation and tumor angiogenesis in a mouse model of colorectal cancer via suppression of stat3 pathway. AB - BACKGROUND: Constitutive activation of STAT3 is one of the major oncogenic pathways involved in the development of various types of malignancies including colorectal cancer (CRC); and thus becomes a promising therapeutic target. Spica Prunellae has long been used as an important component in many traditional Chinese medicine formulas to clinically treat CRC. Previously, we found that Spica Prunellae inhibits CRC cell growth through mitochondrion-mediated apoptosis. Furthermore, we demonstrated its anti-angiogenic activities in vivo and in vitro. To further elucidate the precise mechanism of the potential tumoricidal activity of Spica Prunellae, using a CRC mouse xenograft model, in this study we evaluated its therapeutic efficacy against CRC and investigated the underlying molecular mechanisms. METHODS: CRC mouse xenograft model was generated by subcutaneous injection of human colon carcinoma HT-29 cells into nude mice. Animals were given intra-gastric administration with 6 g/kg of the ethanol extract of Spica Prunellae (EESP) daily, 5 days a week for 16 days. Body weight and tumor growth were measured every two days. Tumor growth in vivo was determined by measuring the tumor volume and weight. HT-29 cell viability was examined by MTT assay. Cell apoptosis and proliferation in tumors from CRC xenograft mice was evaluated via immunohistochemical staining (IHS) for TUNEL and PCNA, and the intratumoral microvessel density (MVD) was examined by using IHS for the endothelial cell-specific marker CD31. The activation of STAT3 was evaluated by determining its phosphorylation level using IHS. The mRNA and protein expression of Bcl-2, Bax, Cyclin D1, VEGF-A and VEGFR2 was measured by RT PCR and IHS, respectively. RESULTS: EESP treatment reduced tumor volume and tumor weight but had no effect on body weight change in CRC mice; decreased HT-29 cell viability in a dose-dependent manner, suggesting that EESP displays therapeutic efficacy against colon cancer growth in vivo and in vitro, without apparent toxicity. In addition, EESP significantly inhibited the phosphorylation of STAT3 in tumor tissues, indicating its suppressive action on the activation of STAT3 signaling. Consequently, the inhibitory effect of EESP on STAT3 activation resulted in an increase in the pro-apoptotic Bax/Bcl-2 ratio, decrease in the expression of the pro-proliferative Cyclin D1 and CDK4, as well as down regulation of pro-angiogenic VEGF-A and VEGFR-2 expression. Finally, these molecular effects led to the induction of apoptosis, the inhibition of cell proliferation and tumor angiogenesis. CONCLUSIONS: Spica Prunellae possesses a broad range of anti-cancer activities due to its ability to affect STAT3 pathway, suggesting that Spica Prunellae could be a novel potent therapeutic agent for the treatment of CRC. PMID- 23800094 TI - Novel single-step multiplex real-time polymerase chain reaction assay for simultaneous quantification of hepatitis virus A, B, C, and E in serum. AB - BACKGROUND AND AIM: Viral hepatitis needs an earliest diagnosis for its proper and timely treatment. Although serodiagnosis of viral hepatitis is in regular practice, however, it has certain limitations and points to alternate procedures of diagnosis. Present study was designed to develop a single-step multiplex real time polymerase chain reaction (PCR) assay for detection of hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis E virus (HEV) related nucleic acids in sera from infected patients. METHODS: The PCR was standardized to detect HAV, HBV, HCV and HEV in serum using variables including annealing temperature, extension temperature, MgCl2 , and primer concentrations. The conserved regions of all viral genomes were used as targets for amplification. RESULTS: This novel assay was found to be a fast, sensitive, specific, and reproducible system for detection of HAV, HBV, HCV, and HEV in serum. The detection limit for different viral genomes at 100% level was found to be 280 copies/mL for HAV, 290 copies/mL for HBV, 30 copies/mL for HCV, and 300 copies/mL for HEV in a single-tube assay system. CONCLUSION: Present multiplex real-time PCR is the first report on single-step nucleic acid detection of HAV, HBV, HCV, and HEV in sera samples. It is an alternate diagnostic assay for common use in laboratories analyzing viral hepatitis cases. PMID- 23800095 TI - GDF-15 protects from macrophage accumulation in a mousemodel of advanced atherosclerosis. AB - BACKGROUND: The cytokine growth differentiation factor-15 (GDF-15), a member of the TGF beta superfamily, has recently been discovered to play an important role in cardiovascular diseases. It is mostly expressed in macrophages of atherosclerotic lesions, but its impact on advanced atherosclerosis is still unknown. This study was performed to evaluate the effects of GDF-15 in an established mouse model of advanced atherosclerosis. METHODS: Thirty-eight LDL receptor deficient mice received a lethal body radiation. Half of the group was transplanted with bone marrow of GDF-15 deficient mice. Nineteen mice were transplanted with bone marrow from wild-type controls. After 24 weeks on an atherogenic diet, animals were euthanized and sections of the aortic sinus were prepared. Lesion size and lesion composition, as well as macrophage content,were evaluated. RESULTS: While demonstrating no difference in lesion size, LDL receptor knockout mice transplanted with bone marrow from GDF-15 deficient mice showed enhanced macrophage accumulation and features of atherosclerotic plaque destabilization, such as thinning of fibrous caps. Immunostaining against intercellular adhesion molecule-1 further revealed an increased expression in mice receiving GDF-15-deficient bone marrow. CONCLUSIONS: This is the first study that demonstrates a protective role of GDF-15 in advanced atherosclerosis and macrophage accumulation, possibly due to the reduced expression of adhesion molecules. PMID- 23800096 TI - Pilot study of the effects of bariatric surgery and continuous positive airway pressure treatment on vascular function in obese subjects with obstructive sleep apnoea. AB - BACKGROUND: The mechanisms by which obesity and obstructive sleep apnoea (OSA) may contribute to endothelial dysfunction are unclear. AIMS: We sought to follow up a sample of obese subjects undergoing either bariatric surgery or continuous positive airway pressure (CPAP) therapy to treat OSA. We hypothesised improved vascular function with both therapeutic approaches, consistent with a reversible OSA effect on the circulation. METHODS: Twenty-seven obese (BMI >=30 kg/m(2)) subjects with OSA underwent either bariatric surgery without CPAP (n = 12, median BMI 43.7 kg/m(2) IQR 9.4) or CPAP (n = 15, median BMI 33.8 kg/m(2) IQR 6.6). Polysomnography and vascular testing (flow-mediated dilation of the brachial artery measured with high-resolution ultrasound, endothelium-dependent change in skin blood flow measured with laser Doppler flowmetry, and arterial stiffness measured with applanation tonometry) took place at baseline and after 6 months. RESULTS: Both groups showed significant improvements in the apnoea-hypopnea index and overnight oxygen saturation. Endothelium-dependent microvascular reactivity was 45.6% (IQR 37.5) at baseline in the CPAP group, which increased to 69.1% (IQR 62.3) post-treatment (P < 0.05). No significant changes were observed in the surgery group, despite significant weight loss (post-surgery BMI 32.7 kg/m2 IQR 8.6 (P < 0.01); no change in BMI was observed in the CPAP group. There were no significant changes in brachial artery flow-mediated dilation in either group. CONCLUSIONS: This pilot study demonstrates that 6 months of CPAP may be sufficient to improve endothelium-dependent microvascular reactivity, while substantial surgically induced weight loss did not result in improvements. Further research should be directed towards comparative effectiveness trials using these novel surrogate outcomes, as well as hard cardiovascular outcomes. PMID- 23800097 TI - Three-dimensional characterization of tissue-engineered constructs by contrast enhanced nanofocus computed tomography. AB - To successfully implement tissue-engineered (TE) constructs as part of a clinical therapy, it is necessary to develop quality control tools that will ensure accurate and consistent TE construct release specifications. Hence, advanced methods to monitor TE construct properties need to be further developed. In this study, we showed proof of concept for contrast-enhanced nanofocus computed tomography (CE-nano-CT) as a whole-construct imaging technique with a noninvasive potential that enables three-dimensional (3D) visualization and quantification of in vitro engineered extracellular matrix (ECM) in TE constructs. In particular, we performed a 3D qualitative and quantitative structural and spatial assessment of the in vitro engineered ECM, formed during static and perfusion bioreactor cell culture in 3D TE scaffolds, using two contrast agents, namely, Hexabrix(r) and phosphotungstic acid (PTA). To evaluate the potential of CE-nano-CT, a comparison was made to standardly used techniques such as Live/Dead viability/cytotoxicity, Picrosirius Red staining, and to net dry weight measurements of the TE constructs. When using Hexabrix as the contrast agent, the ECM volume fitted linearly with the net dry ECM weight independent from the flow rate used, thus suggesting that it stains most of the ECM. When using PTA as the contrast agent, comparing to net weight measurements showed that PTA only stains a part of the ECM. This was attributed to the binding specificity of this contrast agent. In addition, the PTA-stained CE-nano-CT data showed pronounced distinction between flow conditions when compared to Hexabrix, indicating culture specific structural ECM differences. This novel type of information can contribute to optimize bioreactor culture conditions and potentially critical quality characteristics of TE constructs such as ECM quantity and homogeneity, facilitating the gradual transformation of TE constructs in well-characterized TE products. PMID- 23800098 TI - Mercury export to the Arctic Ocean from the Mackenzie River, Canada. AB - Circumpolar rivers, including the Mackenzie River in Canada, are sources of the contaminant mercury (Hg) to the Arctic Ocean, but few Hg export studies exist for these rivers. During the 2007-2010 freshet and open water seasons, we collected river water upstream and downstream of the Mackenzie River delta to quantify total mercury (THg) and methylmercury (MeHg) concentrations and export. Upstream of the delta, flow-weighted mean concentrations of bulk THg and MeHg were 14.6 +/ 6.2 ng L(-1) and 0.081 +/- 0.045 ng L(-1), respectively. Only 11-13% and 44-51% of bulk THg and MeHg export was in the dissolved form. Using concentration discharge relationships, we calculated bulk THg and MeHg export into the delta of 2300-4200 kg yr(-1) and 15-23 kg yr(-1) over the course of the study. Discharge is not presently known in channels exiting the delta, so we assessed differences in river Hg concentrations upstream and downstream of the delta to estimate its influence on Hg export to the ocean. Bulk THg and MeHg concentrations decreased 19% and 11% through the delta, likely because of particle settling and other processes in the floodplain. These results suggest that northern deltas may be important accumulators of river Hg in their floodplains before export to the Arctic Ocean. PMID- 23800099 TI - Double-blind cluster randomised controlled trial of wheat flour chapatti fortified with micronutrients on the status of vitamin A and iron in school-aged children in rural Bangladesh. AB - Food fortification is a cost-effective and sustainable strategy to prevent or correct micronutrient deficiencies. A double-blind cluster (bari) randomised controlled trial was conducted in a rural community in Bangladesh to evaluate the impact of consumption of chapatti made of micronutrient-fortified wheat flour for 6 months by school-aged children on their vitamin A, haemoglobin and iron status. A total of 43 baris (group of households) were randomly selected. The baris were randomly assigned to either intervention or control group. The intervention group received wheat flour fortified with added micronutrients (including 66 mg hydrogen-reduced elemental iron and 3030 MUg retinol equivalent as retinyl palmitate per kilogram of flour), while the control group received wheat flour without added micronutrients. A total of 352 children were enrolled in the trial, 203 in the intervention group and 149 in the control group. Analyses were carried out on children who completed the study (191 in the intervention group and 143 in the control group). Micronutrient-fortified wheat flour chapatti significantly increased serum retinol concentration at 6 months by 0.12 MUmol L(-1) [95% confidence interval (CI): 0.06, 0.19; P < 0.01]. The odds of vitamin A deficiency was significantly lower for children in the intervention group at 3 months [odds ratio (OR) = 0.26; 95% confidence interval (CI): 0.07, 0.89; P < 0.05] and 6 months (OR = 0.21; 95% CI: 0.06, 0.68; P < 0.01). No demonstrable effect of fortified chapatti consumption on iron status, haemoglobin levels or anaemia was observed. Consumption of fortified chapattis demonstrated a significant improvement in the vitamin A status, but not in iron, haemoglobin or anaemia status. PMID- 23800100 TI - Vaccination induced antibodies to recombinant avian influenza A virus M2 protein or synthetic M2e peptide do not bind to the M2 protein on the virus or virus infected cells. AB - BACKGROUND: Influenza viruses are characterized by their highly variable surface proteins HA and NA. The third surface protein M2 is a nearly invariant protein in all Influenza A strains. Despite extensive studies in other animal models, this study is the first to describe the use of recombinant M2 protein and a peptide coding for the extracellular part of the M2 protein (M2e) to vaccinate poultry. METHODS: Four groups of layer chickens received a prime-boost vaccination with recombinant M2 protein, M2e, a tetrameric construct from M2e peptide bound to streptavidin and a control tetrameric construct formulated with Stimune adjuvant. RESULTS: We determined the M2-specific antibody (Ab) responses in the serum before vaccination, three weeks after vaccination and two weeks after booster, at days 21, 42 and 56 of age. The group vaccinated with the M2 protein in combination with Stimune adjuvant showed a significant Ab response to the complete M2 protein as compared to the other groups. In addition an increased Ab response to M2e peptide was found in the group vaccinated with the M2e tetrameric construct. None of the vaccinated animals showed seroconversion to AI in a commercial ELISA. Finally no Ab's were found that bound to M2 expressed on in vitro AI infected MDCK cells. CONCLUSION: Although Ab's are formed against the M2 protein and to Streptavidin bound M2e peptide in a tetrameric conformation these Ab's do not recognize of M2 on the virus or on infected cells. PMID- 23800101 TI - Evidence of systematic and proportional error in a widely used glucose oxidase analyser: impact for clinical research? PMID- 23800103 TI - Implementing a court diversion and liaison scheme in a remand prison by systematic screening of new receptions: a 6 year participatory action research study of 20,084 consecutive male remands. AB - BACKGROUND: A mental health needs assessment in the Irish prison population confirmed findings from other jurisdictions showing high prevalence of severe mental illness, including psychosis amongst those newly committed. We implemented a participatory action research approach in order to provide an integrated mental health prison in-reach and court liaison service for this population. RESULTS: Following extensive consultation, a two stage screening process was developed which was supplemented by an inter-agency referral management system. During the six years 2006-2011, all 20,084 new remands to the main remand prison serving 58% of the national population were screened. Following the first stage screen, 3,195 received a comprehensive psychiatric assessment. Of these 561 (2.8%) had symptoms of psychosis - corresponding to the prior research finding - and 572 were diverted from the criminal justice system to mental health services (89 to a secure forensic hospital, 164 to community mental health hospitals and 319 to other community mental health services). CONCLUSIONS: We have shown that it is possible to match research findings in clinical practice by systematic screening, to sustain this over a long period and to achieve consistent levels of diversion from the criminal justice system to appropriate mental health services. The sustained and consistent performance of the model used is likely to reflect the use of participatory action research both to find the most effective model and to achieve wide ownership and cooperation with the model of care. PMID- 23800104 TI - Changes in villus-like projections of corneocytes from the facial skin in normal infants with or without infantile eczema; useful parameter to assess barrier function. AB - BACKGROUND/PURPOSE: Skin barrier function changes rapidly during the first year of life in infants. Measuring skin barrier function in infants is difficult because of the burden on patients and their parents or guardians. A simple method for assessing barrier function in infants that can be performed quickly and would enable swift treatment and skin care management. METHODS: We used laser microscopy to investigate villus-like projections (VPs) observed on the lower surface of corneocytes obtained on tape strips from 18 normal Japanese infants at the ages of 1, 3, and 6 months. We also performed transepidermal water loss and corneocyte size measurements. A dermatologist clinically assessed the cutaneous findings. We rapidly measured skin barrier function changes during the first 6 months of life in infants. RESULTS: During the study period, very slight erythema and pityriasis were the primary reasons for skin rash, which were generally most severe at 3 months. The results showed that barrier function declined at approximately 3 months of age in nearly all subjects. Therefore, we found that normal barrier function of infantile skin becomes temporarily impaired after birth. CONCLUSION: We conclude that even in patients with very mild skin rashes, multiple objective indices of skin barrier function deteriorate simultaneously. Observation of VPs on the surface of corneocytes using laser microscopy is a rapid, painless, and effective method of monitoring skin barrier function in infants, and VP score offers a useful index for assessing barrier function. PMID- 23800105 TI - Pharmacologic management of diabetic peripheral neuropathic pain. AB - INTRODUCTION: Diabetic peripheral neuropathic pain (DPNP) is a debilitating and distressing complication that occurs in patients with diabetes mellitus. This article provides an overview of diabetic peripheral neuropathy focusing on DPNP. AREAS COVERED: This article reviews the diagnosis, pathogenesis, prevention and treatment of diabetic neuropathy and neuropathic pain. A comprehensive and systematic Medline search of the published literature for treatment of diabetic peripheral neuropathy was done from 1965 to December 2012. Studies not in English language were excluded. EXPERT OPINION: Neuropathic pain is difficult to treat, and patients rarely experience complete pain relief. Despite several pharmacological agents being used in the treatment of DPNP, only duloxetine and pregabalin have evidence-based support for controlling DPNP. PMID- 23800102 TI - The beneficial role of vitamin D in obesity: possible genetic and cell signaling mechanisms. AB - The prevalence rates of overweight and obesity are considered an important public issue in the United States, and both of these conditions are increasing among both children and adults. There is evidence of aberrations in the vitamin D endocrine system in obese subjects. Vitamin D deficiency is highly prevalent in patients with obesity, and many studies have demonstrated the significant effect of calcitriol on adipocytes. Genetic studies have provided an opportunity to determine which proteins link vitamin D to obesity pathology, including the vitamin D receptor, toll-like receptors, the renin-angiotensin system, apolipoprotein E, vascular endothelial growth factor, and poly (ADP-ribose) polymerase-1. Vitamin D also exerts its effect on obesity through cell-signaling mechanisms, including matrix metalloproteinases, mitogen-activated protein kinase pathways, the reduced form of nicotinamide adenine dinucleotide phosphate, prostaglandins, reactive oxygen species, and nitric oxide synthase.In conclusion, vitamin D may have a role in obesity. The best form of vitamin D for use in the obese individuals is calcitriol because it is the active form of the vitamin D3 metabolite, its receptors are present in adipocytes, and modulates inflammatory cytokine expression. PMID- 23800106 TI - Gothenburg very early supported discharge study (GOTVED) NCT01622205: a block randomized trial with superiority design of very early supported discharge for patients with stroke. AB - BACKGROUND: Stroke is the disease with the highest costs for hospital care and also after discharge. Early supported discharge (ESD) has shown to be efficient and safe and the best results with well-organised discharge teams and patients with less severe strokes. The aim is to investigate if very early supported discharge (VESD) for stroke patients in need for on-going individualised rehabilitation at home is useful for the patient and cost effective. METHODS/DESIGN: A randomized controlled trial comparing VESD with ordinary discharge. INCLUSION CRITERIA: confirmed stroke, >18 years of age, living within 30 min from the stroke unit, on day 2 0-16 points on the National institute of health stroke scale (NIHSS) and 50-100 points on the Barthel Index (BI), with BI 100 then the patient can be included if the Montreal Cognitive Assessment is < 26. Exclusion criteria are: NIHSS >16, BI < 50, life expectancy < 1 year, inability to speak or to communicate in Swedish. The inclusion occurs on day 4 and in block randomization of 20 and with blinded assessor. PRIMARY OUTCOME: levels of anxiety and depression. SECONDARY OUTCOMES: independence, security, level of function, quality of health, needs of support in activities of daily living and caregiver burden. Power calculation is based on the level of anxiety and with a power of 80%, p-value 0.05 (2 sided test) 44 persons per group are needed. Data is gathered on co-morbidity, re-entry to hospital, mortality and a health economic analysis. Interviews will be accomplished with a strategic sample of 15 patients in the intervention group before discharge, within two weeks after homecoming and 3 months later. Interviews are also planned with 15 relatives in the intervention group 3 months after discharge. DISCUSSION: The ESD studies in the Cochrane review present hospital stays of a length that no longer exist in Sweden. There is not yet, to our knowledge, any study of early supported discharge with present length of hospital stay. Thus it is not clear if home rehabilitation nowadays without risks, is cost effective, or with the same patient usefulness as earlier studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT01622205. PMID- 23800107 TI - Triple A (Allgrove) syndrome: an unusual association with syringomyelia. AB - Triple A (Allgrove) syndrome was first described by Allgrove in 1978 in two pairs of siblings. Since then, about 100 cases have been reported, all of them displaying an autosomal recessive pattern of inheritance. Clinical picture is characterized by achalasia, alacrimia and ACTH-resistant adrenal failure. A progressive neurological syndrome including central, peripheral and autonomic nervous system impairment, and mild mental retardation is often associated. The triple A syndrome gene, designated AAAS, is localized on chromosome 12q13. It consists of 16 exons, encoding for a 546 aminoacid protein called ALADIN (Alacrimia-Achalasia-aDrenal Insufficiency Neurologic disorder). PMID- 23800108 TI - Establishing a national influenza sentinel surveillance system in a limited resource setting, experience of Sierra Leone. AB - BACKGROUND: Acute respiratory infections remain a leading cause of morbidity and mortality in Sierra Leone; however, similar to other African countries, little is known regarding the contribution of influenza. Routine influenza surveillance is thus a key element to improve understanding of the burden of acute respiratory infections in Africa. In 2011, the World Health Organization (WHO) funded the Strengthening Influenza Sentinel Surveillance in Africa (SISA) project with the goal of developing and strengthening influenza surveillance in eight countries in sub-Saharan Africa, including Sierra Leone. This paper describes the process of establishing a functional Influenza Sentinel Surveillance (ISS) system in Sierra Leone, a post-conflict resource-poor country previously lacking an influenza monitoring system. METHODS: Sierra Leone utilized a systematic approach, including situational assessment, selection of sentinel sites, preparation of implementation plan, adaptation of the standard operating procedures, supervision and training of staff, and monitoring of influenza surveillance activities. The methods used in Sierra Leone were adapted to its specific context, using the Integrated Disease Surveillance and Response (IDSR) strategy as a platform for establishing ISS. RESULTS: The ISS system started functioning in August 2011 with subsequent capacity to contribute surveillance activity data to global influenza databases, FluID and FluNet, demonstrating a functional influenza surveillance system in Sierra Leone within the period of the WHO SISA project support. Several factors were necessary for successful implementation, including a systematic approach, national ownership, appropriate timing and external support. CONCLUSIONS: The WHO SISA project demonstrated the feasibility of building a functional influenza surveillance system in Sierra Leone, integrated into existing national IDSR system. The ISS system, if sustained long-term, would provide valuable data to determine epidemiological and virological patterns and seasonal trends to assess the influenza disease burden that will ultimately guide national control strategies. PMID- 23800109 TI - Whole breast radiotherapy in prone and supine position: is there a place for multi-beam IMRT? AB - BACKGROUND: Early stage breast cancer patients are long-term survivors and finding techniques that may lower acute and late radiotherapy-induced toxicity is crucial. We compared dosimetry of wedged tangential fields (W-TF), tangential field intensity-modulated radiotherapy (TF-IMRT) and multi-beam IMRT (MB-IMRT) in prone and supine positions for whole-breast irradiation (WBI). METHODS: MB-IMRT, TF-IMRT and W-TF treatment plans in prone and supine positions were generated for 18 unselected breast cancer patients. The median prescription dose to the optimized planning target volume (PTVoptim) was 50 Gy in 25 fractions. Dose volume parameters and indices of conformity were calculated for the PTVoptim and organs-at-risk. RESULTS: Prone MB-IMRT achieved (p<0.01) the best dose homogeneity compared to WTF in the prone position and WTF and MB-IMRT in the supine position. Prone IMRT scored better for all dose indices. MB-IMRT lowered lung and heart dose (p<0.05) in supine position, however the lowest ipsilateral lung doses (p<0.001) were in prone position. In left-sided breast cancer patients population averages for heart sparing by radiation dose was better in prone position; though non-significant. For patients with a PTVoptim volume >=600 cc heart dose was consistently lower in prone position; while for patients with smaller breasts heart dose metrics were comparable or worse compared to supine MB IMRT. Doses to the contralateral breast were similar regardless of position or technique. Dosimetry of prone MB-IMRT and prone TF-IMRT differed slightly. CONCLUSIONS: MB-IMRT is the treatment of choice in supine position. Prone IMRT is superior to any supine treatment for right-sided breast cancer patients and left sided breast cancer patients with larger breasts by obtaining better conformity indices, target dose distribution and sparing of the organs-at-risk. The influence of treatment techniques in prone position is less pronounced; moreover dosimetric differences between TF-IMRT and MB-IMRT are rather small. PMID- 23800111 TI - Heightened clinical suspicion of pulmonary embolism and disregard of the D-dimer assay: a contemporary trend in an era of increased access to computed tomography pulmonary angiogram? AB - BACKGROUND: Prospective studies have shown that utilising qualitative D-dimers in those with a low Wells pre-test probability (PTP) of pulmonary embolism (PE) have significantly reduced the number of computed tomography pulmonary angiograms (CTPA) being performed. These studies have been based on a PE prevalence of approximately 6% in the low PTP group. AIM: This study compares the diagnostic approach to PE in the study institution to well-established guidelines. The study also re-examines the cost-benefit analyses of qualitative d-dimers and CTPA in the low PTP group. METHODS: A retrospective study of 169 consecutive CTPA requested in the emergency department of a major teaching hospital during a 12 month period. RESULTS: The prevalence of PE was 0% (0/65), 11.7% (9/77) and 0% (0/2) in the low, moderate and high Wells PTP groups respectively, and 6.3% (9/144) overall. PTP was documented in 10 (6.9%) cases, and the qualitative Clearview Simplify D-dimer was only ordered in 33.8% (22/65) of low PTP subjects. The false positive D-dimer rate was 90.2% (37/41). Cost-benefit analysis and assay performance defines a narrow range of low PTP PE prevalence between 1% and 5% for the utilisation of the qualitative D-dimer assay. CONCLUSIONS: The overall prevalence of PE in subjects undergoing CTPA was significantly lower compared with data in the literature. The authors recommend warranted clinical suspicion of PE should be confirmed by a senior physician prior to placing a patient in the PE work-up pathway. In such patients, the qualitative D-dimer assay should be utilised if PTP is low, and the exclusionary efficiency of the D-dimer will be improved in the setting of higher PE prevalence in this subgroup. Hospitals should audit local PE prevalence, as cost-benefit analyses raises questions about the effectiveness of D-dimers when PE prevalence is very low in the low PTP subgroup. PMID- 23800112 TI - The Managing Emergencies in Paediatric Anaesthesia global rating scale is a reliable tool for simulation-based assessment in pediatric anesthesia crisis management. AB - INTRODUCTION: The use of simulation-based assessments for high-stakes physician examinations remains controversial. The Managing Emergencies in Paediatric Anaesthesia course uses simulation to teach evidence-based management of anesthesia crises to trainee anesthetists in the United Kingdom (UK) and Canada. In this study, we investigated the feasibility and reliability of custom-designed scenario-specific performance checklists and a global rating scale (GRS) assessing readiness for independent practice. METHODS: After research ethics board approval, subjects were videoed managing simulated pediatric anesthesia crises in a single Canadian teaching hospital. Each subject was randomized to two of six different scenarios. All 60 scenarios were subsequently rated by four blinded raters (two in the UK, two in Canada) using the checklists and GRS. The actual and predicted reliability of the tools was calculated for different numbers of raters using the intraclass correlation coefficient (ICC) and the Spearman-Brown prophecy formula. RESULTS: Average measures ICCs ranged from 'substantial' to 'near perfect' (P <= 0.001). The reliability of the checklists and the GRS was similar. Single measures ICCs showed more variability than average measures ICC. At least two raters would be required to achieve acceptable reliability. CONCLUSIONS: We have established the reliability of a GRS to assess the management of simulated crisis scenarios in pediatric anesthesia, and this tool is feasible within the setting of a research study. The global rating scale allows raters to make a judgement regarding a participant's readiness for independent practice. These tools may be used in the future research examining simulation-based assessment. PMID- 23800113 TI - Alberta family physicians' willingness to work during an influenza pandemic: a cross-sectional study. AB - OBJECTIVE: Effective pandemic responses rely on frontline healthcare workers continuing to work despite increased risk to themselves. Our objective was to investigate Alberta family physicians willingness to work during an influenza pandemic. DESIGN: Cross-sectional survey. SETTING: Alberta prior to the fall wave of the H1N1 epidemic. PARTICIPANTS: 192 participants from a random sample of 1000 Alberta family physicians stratified by region. MAIN OUTCOME MEASURES: Willingness to work through difficult scenarios created by an influenza epidemic. RESULTS: The corrected response rate was 22%. The most physicians who responded were willing to continue working through some scenarios caused by a pandemic, but in other circumstances less than 50% would continue. Men were more willing to continue working than women. In some situations South African and British trained physicians were more willing to continue working than other groups. CONCLUSIONS: Although many physicians intend to maintain their practices in the event of a pandemic, in some circumstances fewer are willing to work. Pandemic preparation requires ensuring a workforce is available. Healthcare systems must provide frontline healthcare workers with the support and resources they need to enable them to continue providing care. PMID- 23800114 TI - Clinicopathological correlates and prognostic significance of KRAS mutation status in a pooled prospective cohort of epithelial ovarian cancer. AB - BACKGROUND: Activating KRAS mutations are common in ovarian carcinomas of low histological grade, less advanced clinical stage and mucinous histological subtype, and form part of the distinct molecular alterations associated with type I tumors in the dualistic model of ovarian carcinogenesis. Here, we investigated the occurrence, clinicopathological correlates and prognostic significance of specific KRAS mutations in tumours from 153 epithelial ovarian cancer (EOC) cases from a pooled, prospective cohort. METHODS: KRAS codon 12,13 and 61 mutations were analysed by pyrosequencing in tumours from 163 incident EOC cases in the Malmo Diet and Cancer Study and Malmo Preventive Project. Associations of mutational status with clinicopathological and molecular characteristics were assessed by Pearson Chi Square test. Ovarian cancer-specific survival (OCSS) according to mutational status was explored by Kaplan-Meier analysis and Cox proportional hazards modelling. KRAS-mutation status was also analysed in 28 concomitantly sampled benign-appearing fallopian tubes. RESULTS: Seventeen (11.1%) EOC cases harboured mutations in the KRAS gene, all but one in codon 12, and one in codon 13. No KRAS mutations were found in codon 61 and all examined fallopian tubes were KRAS wild-type. KRAS mutation was significantly associated with lower grade (p = 0.001), mucinous histological subtype (p = < 0.001) and progesterone receptor expression (p = 0.035). Kaplan-Meier analysis revealed a significantly improved OCSS for patients with KRAS-mutated compared to KRAS wild type tumours (p = 0.015). These associations were confirmed in unadjusted Cox regression analysis (HR = 2.51; 95% CI 1.17-5.42) but did not remain significant after adjustment for age, grade and clinical stage. The beneficial prognostic impact of KRAS mutation was ony evident in tumours of low-intermediate differentiation grade (p = 0.023), and in a less advanced clinical stage (p = 0.014). Moreover, KRAS mutation was associated with a significantly improved OCSS in the subgroup of endometroid carcinomas (p = 0.012). CONCLUSIONS: The results from this study confirm previously demonstrated associations of KRAS mutations with well-differentiated and mucinous ovarian carcinomas. Moreover, KRAS-mutated tumours had a significantly improved survival in unadjusted, but not adjusted, analysis. A finding that merits further study is the significant prognostic impact of KRAS mutation in endometroid carcinomas, potentially indicating that response to Ras/Raf/MEK/ERK-targeting therapies may differ by histological subtype. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1788330379100147. PMID- 23800115 TI - Molecular dynamics study of oxidized lipid bilayers in NaCl solution. AB - Polyunsaturated lipids are major targets of free radicals forming oxidized lipids through the lipid peroxidation process. Thus, oxidized lipids play a significant role in cell membrane damage. Using atomistic molecular dynamics (MD) simulations to investigate the dynamics of oxidized lipid bilayers, we examined the effects of NaCl on them. Lipid bilayer systems of 1-palmitoyl-2-linoleoyl-sn-glycero-3 phosphatidylcholine (PLPC) and 4 oxidation products, namely, 9-tc-hydroperoxide linoleic acid, 13-tc-hydroperoxide linoleic acid, 9-oxononanoic acid, and 12-oxo 9-didecadienoic acid in 0, 0.06, and 1 M NaCl solution were studied. These 51 systems, combined over 15 MUs of total simulation time, show Cl(-) anions remaining in the water phase and Na(+) cations permeating into the headgroup region of the bilayer leading to membrane packing. The effects of NaCl on thickness and area per molecule were found to be independent of the concentration of oxidized lipids. NaCl disturbed the bilayers with aldehyde lipids more than those with peroxide lipids. The key finding is that oxidized lipids bend their polar tails toward the water interface. This behavior was monitored by following the time evolution of hydrogen bonds between the oxidized functional groups of different lipids, and the concomitant increase of hydrogen bonds between oxidized functional groups and water molecules. Our results also show that the number of hydrogen bonds should be considered as an equilibration parameter: Very long simulations are needed to equilibrate systems with high NaCl concentrations. PMID- 23800116 TI - Overexpression of PRMT6 does not suppress HIV-1 Tat transactivation in cells naturally lacking PRMT6. AB - BACKGROUND: Protein arginine methyltransferase 6 (PRMT6) can methylate the HIV-1 Tat, Rev and nucleocapsid proteins in a manner that diminishes each of their functions in in vitro assays, and increases the stability of Tat in human cells. In this study, we explored the relationship between PRMT6 and HIV-1 Tat by determining the domains in each protein required for interaction. METHODS: Through domain mapping and immunoprecipitation experiments, we determined that both the amino and carboxyl termini of PRMT6, and the activation domain within Tat are essential for interaction. Mutation of the basic domain of Tat did not affect the ability of PRMT6 to interact with Tat. RESULTS: We next used the A549 human alveolar adenocarcinoma cell line, which naturally expresses undetectable levels of PRMT6, as a model for testing the effects of PRMT6 on Tat stability, transactivation, and HIV-1 replication. As previously observed, steady state levels and the protein half-life of Tat were increased by the ectopic expression of PRMT6. However, no down regulation of Tat transactivation function was observed, even with over 300-fold molar excess of PRMT6 plasmid. We also observed no negative effect on HIV-1 infectivity when A549 producer cells overexpressed PRMT6. CONCLUSIONS: We show that PRMT6 requires the activation domain, but surprisingly not the basic domain, of Tat for protein interaction. This interaction between Tat and PRMT6 may impact upon pathogenic effects attributed to Tat during HIV-1 infection other than its function during transactivation. PMID- 23800117 TI - Suboptimal blood pressure control in chronic kidney disease stage 3: baseline data from a cohort study in primary care. AB - BACKGROUND: Poorly controlled hypertension is independently associated with mortality, cardiovascular risk and disease progression in chronic kidney disease (CKD). In the UK, CKD stage 3 is principally managed in primary care, including blood pressure (BP) management. Controlling BP is key to improving outcomes in CKD. This study aimed to investigate associations of BP control in people with CKD stage 3. METHODS: 1,741 patients with CKD 3 recruited from 32 general practices for the Renal Risk in Derby Study underwent medical history, clinical assessment and biochemistry testing. BP control was assessed by three standards: National Institute for Health and Clinical Excellence (NICE), National Kidney Foundation Kidney Disease Outcome Quality Initiative (KDOQI) and Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. Descriptive statistics were used to compare characteristics of people achieving and not achieving BP control. Univariate and multivariate logistic regression was used to identify factors associated with BP control. RESULTS: The prevalence of hypertension was 88%. Among people with hypertension, 829/1426 (58.1%) achieved NICE BP targets, 512/1426 (35.9%) KDOQI targets and 859/1426 (60.2%) KDIGO targets. Smaller proportions of people with diabetes and/or albuminuria achieved hypertension targets. 615/1426 (43.1%) were only taking one antihypertensive agent. On multivariable analysis, BP control (NICE and KDIGO) was negatively associated with age (NICE odds ratio (OR) 0.27; 95% confidence interval (95% CI) 0.17-0.43) 70-79 compared to <60), diabetes (OR 0.32; 95% CI 0.25-0.43)), and albuminuria (OR 0.56; 95% CI 0.42-0.74)). For the KDOQI target, there was also association with males (OR 0.76; 95% CI 0.60-0.96)) but not diabetes (target not diabetes specific). Older people were less likely to achieve systolic targets (NICE target OR 0.17 (95% CI 0.09,0.32) p < 0.001) and more likely to achieve diastolic targets (OR 2.35 (95% CI 1.11,4.96) p < 0.001) for people >80 compared to < 60). CONCLUSIONS: Suboptimal BP control was common in CKD patients with hypertension in this study, particularly those at highest risk of adverse outcomes due to diabetes and or albuminuria. This study suggests there is scope for improving BP control in people with CKD by using more antihypertensive agents in combination while considering issues of adherence and potential side effects. PMID- 23800118 TI - Is the double-guidewire technique superior to the pancreatic duct guidewire technique in cases of pancreatic duct opacification? AB - BACKGROUND AND AIMS: Pancreatic duct guidewire placement (P-GW) techniques include both the injection cannulation technique with a contrast medium and wire guided cannulation without contrast injection for selective biliary cannulation; the latter is the so-called "double-guidewire technique" (D-GW). The aim of this study was to compare the outcomes between P-GW and D-GW for biliary cannulation. METHODS: The procedures for biliary cannulation with a naive papilla were performed in a total of 363 cases. We divided the patients chronologically, according to the time period during which the procedures were performed, into two groups: group A, P-GW performed from March 2008 to June 2009; and group B, D-GW performed from July 2009 to December 2010. The success rates and complication rates were evaluated in each group. RESULTS: Biliary cannulation was successful in 31 (81.6%) patients in the P-GW group and 34 patients (82.9%) in the D-GW group. The onsets of postendoscopic retrograde cholangiopancreatography pancreatitis (PEP) occurred in the P-GW and D-GW groups were four (10.5%) and three (7.3%) patients, respectively, and all were mild cases (P = 0.616). The frequency of hyperamylasemia and the serum amylase level tended to be lower in the D-GW group than in the P-GW group (P = 0.213). There was a statistically significant difference on the onsets of PEP in the GW and non-GW groups (P = 0.04, 8.9% and 1.1%, respectively). CONCLUSIONS: Both the D-GW and P-GW techniques were equally effective for difficult biliary cannulation. Furthermore, the complication rates, including PEP, were similar in both techniques. A prospective randomized trial is warranted. PMID- 23800119 TI - Mobilization of lipids and fortification of cell wall and cuticle are important in host defense against Hessian fly. AB - BACKGROUND: Wheat - Hessian fly interaction follows a typical gene-for-gene model. Hessian fly larvae die in wheat plants carrying an effective resistance gene, or thrive in susceptible plants that carry no effective resistance gene. RESULTS: Gene sets affected by Hessian fly attack in resistant plants were found to be very different from those in susceptible plants. Differential expression of gene sets was associated with differential accumulation of intermediates in defense pathways. Our results indicated that resources were rapidly mobilized in resistant plants for defense, including extensive membrane remodeling and release of lipids, sugar catabolism, and amino acid transport and degradation. These resources were likely rapidly converted into defense molecules such as oxylipins; toxic proteins including cysteine proteases, inhibitors of digestive enzymes, and lectins; phenolics; and cell wall components. However, toxicity alone does not cause immediate lethality to Hessian fly larvae. Toxic defenses might slow down Hessian fly development and therefore give plants more time for other types of defense to become effective. CONCLUSION: Our gene expression and metabolic profiling results suggested that remodeling and fortification of cell wall and cuticle by increased deposition of phenolics and enhanced cross-linking were likely to be crucial for insect mortality by depriving Hessian fly larvae of nutrients from host cells. The identification of a large number of genes that were differentially expressed at different time points during compatible and incompatible interactions also provided a foundation for further research on the molecular pathways that lead to wheat resistance and susceptibility to Hessian fly infestation. PMID- 23800120 TI - Pregnancy recognition signaling mechanisms in ruminants and pigs. AB - Maternal recognition of pregnancy refers to the requirement for the conceptus (embryo and its associated extra-embryonic membranes) to produce a hormone that acts on the uterus and/or corpus luteum (CL) to ensure maintenance of a functional CL for production of progesterone; the hormone required for pregnancy in most mammals. The pregnancy recognition signal in primates is chorionic gonadotrophin which acts directly on the CL via luteinizing hormone receptors to ensure maintenance of functional CL during pregnancy. In ruminants, interferon tau (IFNT) is the pregnancy recognition signal. IFNT is secreted during the peri implantation period of pregnancy and acts on uterine epithelia to silence expression of estrogen receptor alpha and oxytocin receptor which abrogates the oxytocin-dependent release of luteolytic pulses of prostaglandin F2-alpha (PGF) by uterine epithelia; therefore, the CL continues to produce progesterone required for pregnancy. Pig conceptuses secrete interferon delta and interferon gamma during the peri-implantation period of pregnancy, but there is no evidence that they are involved in pregnancy recognition signaling. Rather, pig conceptuses secrete abundant amounts of estrogens between Days 11 to 15 of pregnancy required for maternal recognition of pregnancy. Estrogen, likely in concert with prolactin, prevents secretion of PGF into the uterine venous drainage (endocrine secretion), but maintains secretion of PGF into the uterine lumen (exocrine secretion) where it is metabolized to a form that is not luteolytic. Since PGF is sequestered within the uterine lumen and unavailable to induce luteolysis, functional CL are maintained for production of progesterone. In addition to effects of chorionic gonadotrophin, IFNT and estrogens to signal pregnancy recognition, these hormones act on uterine epithelia to enhance expression of genes critical for growth and development of the conceptus. PMID- 23800121 TI - Impact of health beliefs, social support and self-efficacy on physical activity and dietary habits during the post-partum period after gestational diabetes mellitus: study protocol. AB - BACKGROUND: Gestational diabetes mellitus (GDM) is defined as a glucose intolerance of variable severity occurring or diagnosed for the first time during pregnancy. Numerous epidemiological studies show that this disorder affects between 1 and 18% of pregnancies, depending on the ethnicity of the populations studied, the diagnostic criteria, or the body mass index (BMI). Its incidence is constantly rising worldwide. Patients with GDM have a high risk of developing type 2 diabetes in the months after delivery. For this reason, GDM patients are encouraged to practice specific health behaviors (dietary habits, physical activity) during the postpartum period. It is important to identify the factors that may impact adherence to these behaviors. METHODS/DESIGN: A targeted sample size of 200 eligible pregnant women with a diagnosis of GDM will be enrolled in this prospective, cohort study. They will be recruited from 30-36 weeks of gestation as part of their diabetes consultation in Geneva University Hospital (GUH) maternity unit. Psychosocial variables that could impact adherence to health behaviors in the postpartum period (behavioral intentions, risk perceptions, general knowledge about diabetes, health beliefs, social support, self-efficacy) will be evaluated using specific tools at the end of pregnancy, at 6 weeks postpartum and at 6 months postpartum. Multiple regression analyses will be performed on SPSS. DISCUSSION: For the first time in Europe, the objective of this research is to study in women with very recent GDM the link between dietary habits, physical activity levels, and psychosocial and cognitive factors possibly involved in the adoption of health behaviors in the postpartum period. These factors have been identified in the literature, but to date have never been combined in a single study. The study will allow a predictive theoretical model of health behavior to be established and used as a basis for reflection to optimize interventions carried out on women who have had GDM. PMID- 23800123 TI - Nursing home quality and financial performance: does the racial composition of residents matter? AB - OBJECTIVE: To examine the effects of the racial composition of residents on nursing homes' financial and quality performance. The study examined Medicare and Medicaid-certified nursing homes across the United States that submitted Medicare cost reports between the years 1999 and 2004 (11,472 average per year). DATA SOURCE: Data were obtained from the Minimum Data Set, the On-Line Survey Certification and Reporting, Medicare Cost Reports, and the Area Resource File. STUDY DESIGN: Panel data regression with random intercepts and negative binomial regression were conducted with state and year fixed effects. PRINCIPAL FINDINGS: Financial and quality performance differed between nursing homes with high proportions of black residents and nursing homes with no or medium proportions of black residents. Nursing homes with no black residents had higher revenues and higher operating margins and total profit margins and they exhibited better processes and outcomes than nursing homes with high proportions of black residents. CONCLUSION: Nursing homes' financial viability and quality of care are influenced by the racial composition of residents. Policy makers should consider initiatives to improve both the financial and quality performance of nursing homes serving predominantly black residents. PMID- 23800122 TI - Hidden hysteresis - population dynamics can obscure gene network dynamics. AB - BACKGROUND: Positive feedback is a common motif in gene regulatory networks. It can be used in synthetic networks as an amplifier to increase the level of gene expression, as well as a nonlinear module to create bistable gene networks that display hysteresis in response to a given stimulus. Using a synthetic positive feedback-based tetracycline sensor in E. coli, we show that the population dynamics of a cell culture has a profound effect on the observed hysteretic response of a population of cells with this synthetic gene circuit. RESULTS: The amount of observable hysteresis in a cell culture harboring the gene circuit depended on the initial concentration of cells within the culture. The magnitude of the hysteresis observed was inversely related to the dilution procedure used to inoculate the subcultures; the higher the dilution of the cell culture, lower was the observed hysteresis of that culture at steady state. Although the behavior of the gene circuit in individual cells did not change significantly in the different subcultures, the proportion of cells exhibiting high levels of steady-state gene expression did change.Although the interrelated kinetics of gene expression and cell growth are unpredictable at first sight, we were able to resolve the surprising dilution-dependent hysteresis as a result of two interrelated phenomena - the stochastic switching between the ON and OFF phenotypes that led to the cumulative failure of the gene circuit over time, and the nonlinear, logistic growth of the cell in the batch culture. CONCLUSIONS: These findings reinforce the fact that population dynamics cannot be ignored in analyzing the dynamics of gene networks. Indeed population dynamics may play a significant role in the manifestation of bistability and hysteresis, and is an important consideration when designing synthetic gene circuits intended for long term application. PMID- 23800124 TI - Rhaphidophora korthalsii modulates peripheral blood natural killer cell proliferation, cytokine secretion and cytotoxicity. AB - BACKGROUND: Rhaphidophora korthalsii (Araceae) is a root-climber plant which has been widely used in Chinese traditional medicine for cancer and skin disease treatment. Previous reports have recorded its immunomodulatory effects on mice splenocyte and human peripheral blood. This study investigated the potential immunostimulatory effect of Rhaphidophora korthalsii on human PBMC enriched NK cell. METHODS: PBMC was exposed to various concentrations of R. korthalsii extract and the T and NK cell population in the control and extract treated PBMC were identified by immunophenotyping. Intracellular perforin and granzyme B expressions were detected by flow cytometry and extra-cellular Granzyme B, IFN gamma and TNF-alpha production in the isolated NK cells were determined by ELISA. The cytotoxicity of effector NK cell towards target K562 cell was assessed by CytoTox 96 assay. RESULTS: Rhaphidophora korthalsii methanol extract significantly increased PBMC NK cell population and intracellular perforin and granzyme B expressions. Moreover, the extract also enhanced the secretion of IFN gamma and TNF-alpha which subsequently enhanced the cytotoxicity of NK cell against the NK sensitive target K562 cell line. NK cell enriched with extract treated PBMC showed better activation than NK cell directly treated with the extract. CONCLUSION: Our findings indicated a potential IL-2 free immunotherapy through direct and indirect R. korthalsii stimulation on NK cell activation. PMID- 23800125 TI - Frosted branch angiitis as a result of immune recovery uveitis in a patient with cytomegalovirus retinitis. AB - BACKGROUND: Since the introduction of Highly Active Antiretroviral Therapy (HAART), AIDs related morbidity and mortality have declined. However, the advent of HAART brought the new problem of immune recovery inflammatory syndrome. Cytomegalovirus retinitis remains the most common cause of visual loss in AIDs patients. Some patients with cytomegalovirus retinitis who experienced immune recovery as a consequence of HAART develop worsening of visual symptoms from immune recovery uveitis (IRU). FINDINGS: We report a case of cytomegalovirus retinitis and AIDs who developed an unusual presentation of IRU after the initiation of HAART. A 40-year-old woman presented with a history of blurry vision in the right eye. She was diagnosed with human immunodeficiency virus infection and cytomegalovirus retinitis, treated with intravitreal injections of ganciclovir. The retinitis improved. One week after HAART initiation, she developed IRU, characterized by increased intraocular inflammation, extensive frosted branch angiitis and cystoid macular edema. The CD4+ T lymphocyte count increased from 53 to 107 cells/mm3. Systemic prednisolone with continuation of HAART and intravitreal injections of ganciclovir were given with significant improvement. CONCLUSION: Atypical presentation of IRU, characterized by extensive frosted branch angiitis and increased intraocular inflammation may occur in immunocompromised patients with cytomegalovirus retinitis who experienced immune recovery. The time from HAART initiation to develop IRU may vary from days to months. This case demonstrated a very rapidly developed IRU which should be recognized and appropriately managed to avoid permanent damage of the eye. PMID- 23800126 TI - Mapping gene activity of Arabidopsis root hairs. AB - BACKGROUND: Quantitative information on gene activity at single cell-type resolution is essential for the understanding of how cells work and interact. Root hairs, or trichoblasts, tubular-shaped outgrowths of specialized cells in the epidermis, represent an ideal model for cell fate acquisition and differentiation in plants. RESULTS: Here, we provide an atlas of gene and protein expression in Arabidopsis root hair cells, generated by paired-end RNA sequencing and LC/MS-MS analysis of protoplasts from plants containing a pEXP7-GFP reporter construct. In total, transcripts of 23,034 genes were detected in root hairs. High-resolution proteome analysis led to the reliable identification of 2,447 proteins, 129 of which were differentially expressed between root hairs and non root hair tissue. Dissection of pre-mRNA splicing patterns showed that all types of alternative splicing were cell type-dependent, and less complex in EXP7 expressing cells when compared to non-root hair cells. Intron retention was repressed in several transcripts functionally related to root hair morphogenesis, indicative of a cell type-specific control of gene expression by alternative splicing of pre-mRNA. Concordance between mRNA and protein expression was generally high, but in many cases mRNA expression was not predictive for protein abundance. CONCLUSIONS: The integrated analysis shows that gene activity in root hairs is dictated by orchestrated, multilayered regulatory mechanisms that allow for a cell type-specific composition of functional components. PMID- 23800127 TI - Influence of skin extension upon the epidermal morphometry, an in vivo study. AB - BACKGROUND: The Dermal-Epidermal Junction (DEJ) is characterized by undulations whose apices are called papillae. With aging, epidermis becomes thinner, together with a flattening of the DEJ, leading to a decreased density of papillae. The causes of these modifications are likely as multiple as uncertain. The present paper deals with in vivo morphometric characterization of the DEJ and its changes following a skin surface deformation. METHODS: Living epidermis of human adults was examined by means of in vivo Reflectance Confocal Microscopy. Distances between skin surface and papillae apex and pegs of the DEJ were, respectively, recorded in both relaxed and stretched skin situation. The number of papillae present within a single image (field of view, 500 * 500 MUm) was also measured. RESULTS: Skin extension has no effect upon the distance between skin surface and the apex of papillae. In contrast, the distance between skin surface and the pegs of papillae decreases. On the other hand, skin extension leads to a significant decrease in the number of papillae within a single image. CONCLUSION: Epidermal atrophy and structural changes observed in the DEJ with aging may be, by some extent, related to daily and repetitive skin deformations all along the life span. PMID- 23800129 TI - GLA mutation as a risk factor for later life small vessel ischaemic disease. PMID- 23800128 TI - Correlation between metabolic syndrome and knee osteoarthritis: data from the Korean National Health and Nutrition Examination Survey (KNHANES). AB - BACKGROUND: This study was designed to investigate the correlations of knee osteoarthritis (OA) with metabolic syndrome (MetS) and MetS parameters in Korean subjects. METHODS: This study included data from 270 subjects with knee OA and 1964 control subjects with a mean age of 54.56 (SD 11.53) years taken from the Korean National Health and Nutritional Examination Survey (KNHANES) 2008. Multivariate logistic regression analysis was conducted to examine possible associations for knee OA with MetS and MetS parameters. RESULTS: MetS was shown to be associated with an increased risk of knee OA in female subjects in unadjusted analysis (OR 1.798, 95% CI 1.392, 2.322), but this significance disappeared when adjusted for confounding factors (OR 1.117, 95% CI 0.805, 1.550). No significant association between MetS and knee OA was found in male subjects. Among parameters of MetS, only high waist circumference (WC) in female subjects was significantly associated with an increased prevalence of knee OA, even after adjusting for confounding factors, while no other significant associations were found in both male and female subjects. CONCLUSION: We found that WC was associated with knee OA in female subjects, but neither MetS nor any parameters thereof were shown to be associated with knee OA in the Korean subjects of this study. Although we found no relationship between a pre inflammatory state of MetS and knee OA, we believe further investigation of this relationship in various aspects is warranted, as MetS may also be a risk factor for complications in knee OA related procedures. PMID- 23800130 TI - Dapagliflozin for the treatment of type 2 diabetes. AB - INTRODUCTION: Despite the availability of many antihypreglycemic agents, many patients with type 2 diabetes (T2DM) fail to achieve the glycemic treatment goal, primarily due to progressive beta-cell dysfunction, and increased risk of hypoglycemia. AREAS COVERED: The aim of the present article is to review the efficacy and safety of dapagliflozin , a novel antihyperglycemic drug that lowers the plasma glucose concentration by the inhibition of renal sodium-glucose cotransport, in lowering the plasma glucose concentration and the HbA1c in T2DM patents. This review summarizes the published data about the mechanism of action and clinical efficacy of dapagliflozin in lowering the HbA1c in patients with T2DM. It also discusses additional non-glycemic benefits of dapagliflozin and the safety profile of the drug. EXPERT OPINION: Dapagliflozin is effective in lowering the plasma glucose concentration in patients with T2DM with a good safety profile. Because of its unique mechanism of action, dapagliflozin can be utilized in combination with all other antihyperglycemic agents and at all stages of the disease. PMID- 23800131 TI - What is on your mind? Using the perceptual cycle model and critical decision method to understand the decision-making process in the cockpit. AB - Aeronautical decision-making is complex as there is not always a clear coupling between the decision made and decision outcome. As such, there is a call for process-orientated decision research in order to understand why a decision made sense at the time it was made. Schema theory explains how we interact with the world using stored mental representations and forms an integral part of the perceptual cycle model (PCM); proposed here as a way to understand the decision making process. This paper qualitatively analyses data from the critical decision method (CDM) based on the principles of the PCM. It is demonstrated that the approach can be used to understand a decision-making process and highlights how influential schemata can be at informing decision-making. The reliability of this approach is established, the general applicability is discussed and directions for future work are considered. PRACTITIONER SUMMARY: This paper introduces the PCM, and the associated schema theory, as a framework to structure and explain data collected from the CDM. The reliability of both the method and coding scheme is addressed. PMID- 23800132 TI - Endonasal endoscopic transsphenoidal pituitary surgery: early experience and outcome in paediatric Cushing's disease. AB - BACKGROUND: Selective adenomectomy remains the first-line treatment for Cushing's disease (CD), until recently by microscopic transsphenoidal pituitary surgery. Endonasal transsphenoidal endoscopic surgery (ETES) is emerging as a novel, less invasive treatment for pituitary adenomas and has become the optimal surgical approach. OBJECTIVE: There are no published series for the treatment of paediatric CD by ETES, and we report our centre's preliminary results. DESIGN: Retrospective analysis. PATIENTS: Six paediatric patients (median age 15.8 years; range 11.7-17.0 years) fulfilled standard diagnostic criteria for CD. Preoperatively, no abnormality was identified on pituitary MR scanning in 3 (50%) patients, one had a macroadenoma. Bilateral petrosal sinus sampling demonstrated central ACTH secretion (IPS/P ACTH ratio >=3.0, post-CRH) in 3/6 (50%) patients. The same neurosurgeon and endoscopic nasal surgeon undertook all the operations. OUTCOME MEASURES: Therapeutic outcome and rate of complications. RESULTS: Clinical recovery and biochemical 'cure' were achieved in 5 (83%) patients, and a corticotroph adenoma was confirmed histologically in all cured cases. One case developed post-operative CSF leak requiring lumbar drain insertion and patching. At a mean interval of 4.7 years (0.1-10.8 years) post-operatively, cured patients have shown no recurrence. One patient, with a large diffuse adenoma requiring more extensive surgery, has panhypopituitarism, and another patient has GH and gonadotrophin deficiencies. CONCLUSIONS: Our experience shows that ETES for removing corticotroph adenomas in children, in most cases not visualized on MRI, is minimally invasive and gave excellent post-operative recovery/results. In skilled hands, this technique provides an alternative to conventional transsphenoidal microscopic surgery in managing paediatric CD. PMID- 23800133 TI - The relationship between cell phone use, physical and sedentary activity, and cardiorespiratory fitness in a sample of U.S. college students. AB - BACKGROUND: Today's cell phones increase opportunities for activities traditionally defined as sedentary behaviors (e.g., surfing the internet, playing video games). People who participate in large amounts of sedentary behaviors, relative to those who do not, tend to be less physically active, less physically fit, and at greater risk for health problems. However, cell phone use does not have to be a sedentary behavior as these devices are portable. It can occur while standing or during mild-to-moderate intensity physical activity. Thus, the relationship between cell phone use, physical and sedentary activity, and physical fitness is unclear. The purpose of this study was to investigate these relationships among a sample of healthy college students. METHODS: Participants were first interviewed about their physical activity behavior and cell phone use. Then body composition was assessed and the validated self-efficacy survey for exercise behaviors completed. This was followed by a progressive exercise test on a treadmill to exhaustion. Peak oxygen consumption (VO2 peak) during exercise was used to measure cardiorespiratory fitness. Hierarchical regression was used to assess the relationship between cell phone use and cardiorespiratory fitness after controlling for sex, self-efficacy, and percent body fat. Interview data was transcribed, coded, and Chi-square analysis was used to compare the responses of low and high frequency cell phone users. RESULTS: Cell phone use was significantly (p = 0.047) and negatively (beta = -0.25) related to cardio respiratory fitness independent of sex, self-efficacy, and percent fat which were also significant predictors (p < 0.05). Interview data offered several possible explanations for this relationship. First, high frequency users were more likely than low frequency users to report forgoing opportunities for physical activity in order to use their cell phones for sedentary behaviors. Second, low frequency users were more likely to report being connected to active peer groups through their cell phones and to cite this as a motivation for physical activity. Third, high levels of cell phone use indicated a broader pattern of sedentary behaviors apart from cell phone use, such as watching television. CONCLUSION: Cell phone use, like traditional sedentary behaviors, may disrupt physical activity and reduce cardiorespiratory fitness. PMID- 23800134 TI - Primary renal teratoma: a rare entity. AB - Teratomas are neoplasms that arise from pluripotent cells and can differentiate along one or more embryonic germ lines. Renal teratoma is an exceedingly rare condition. Teratomas commonly arise in the gonads, sacrococcygeal region, pineal gland, and retroperitoneum. They present mainly as an abdominal mass with few other symptoms. Majority of the tumors are benign, situated on the left side and para renal, occasional lesions are bilateral. If diagnosed early, they are amenable to curative excision.Renal teratomas are rare and most have been dismissed as cases of teratoid nephroblastomas or retroperitoneal teratomas secondarily invading the kidney. The differentiation between these two neoplasms in the kidney is often problematic.We present a case of intrarenal immature teratoma in a six-month-old baby girl. VIRTUAL SLIDES: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1746249869599954. PMID- 23800135 TI - Effect of static seeding methods on the distribution of fibroblasts within human acellular dermis. AB - INTRODUCTION: When developing tissue engineered solutions for existing clinical problems, cell seeding strategies should be optimized for desired cell distribution within matrices. The purpose of this investigation was to compare the effects of different static cell seeding methods and subsequent static cell culture for up to 12 days with regard to seeding efficiency and resulting cellular distribution in acellular dermis. MATERIALS AND METHODS: The seeding methods tested were surface seeding of both unmodified and mechanically incised dermis, syringe injection of cell suspension, application of low-pressure and use of an ultrasonic bath to remove trapped air. The effect of "platelet derived growth factor" (PDGF) on surface seeding and low pressure seeding was also investigated. Scaffolds were incubated for up to 12 days and were histologically examined at days 0, 4, 8 and 12 for cell distribution and infiltration depth. The metabolic activity of the cells was quantified with the MTT assay at the same time points. RESULTS: The 50 ml syringe degassing procedure produced the best results in terms of seeding efficiency, cell distribution, penetration depth and metabolic activity within the measured time frame. The injection and ultrasonic bath methods produced the lowest seeding efficiency. The incision method and the 20 ml syringe degassing procedure produced results that were not significantly different to those obtained with a standard static seeding method. CONCLUSION: We postulate that air in the pores of the human acellular dermis (hAD) hinders cell seeding and subsequent infiltration. We achieved the highest seeding efficiency, homogeneity, infiltration depth and cell growth within the 12 day static culturing period by degassing the dermis using low- pressure created by a 50 ml syringe. We conclude that this method to eliminate trapped air provides the most effective method to seed cells and to allow cell proliferation in a natural scaffold. PMID- 23800136 TI - MetaPathways: a modular pipeline for constructing pathway/genome databases from environmental sequence information. AB - BACKGROUND: A central challenge to understanding the ecological and biogeochemical roles of microorganisms in natural and human engineered ecosystems is the reconstruction of metabolic interaction networks from environmental sequence information. The dominant paradigm in metabolic reconstruction is to assign functional annotations using BLAST. Functional annotations are then projected onto symbolic representations of metabolism in the form of KEGG pathways or SEED subsystems. RESULTS: Here we present MetaPathways, an open source pipeline for pathway inference that uses the PathoLogic algorithm to map functional annotations onto the MetaCyc collection of reactions and pathways, and construct environmental Pathway/Genome Databases (ePGDBs) compatible with the editing and navigation features of Pathway Tools. The pipeline accepts assembled or unassembled nucleotide sequences, performs quality assessment and control, predicts and annotates noncoding genes and open reading frames, and produces inputs to PathoLogic. In addition to constructing ePGDBs, MetaPathways uses MLTreeMap to build phylogenetic trees for selected taxonomic anchor and functional gene markers, converts General Feature Format (GFF) files into concatenated GenBank files for ePGDB construction based on third-party annotations, and generates useful file formats including Sequin files for direct GenBank submission and gene feature tables summarizing annotations, MLTreeMap trees, and ePGDB pathway coverage summaries for statistical comparisons. CONCLUSIONS: MetaPathways provides users with a modular annotation and analysis pipeline for predicting metabolic interaction networks from environmental sequence information using an alternative to KEGG pathways and SEED subsystems mapping. It is extensible to genomic and transcriptomic datasets from a wide range of sequencing platforms, and generates useful data products for microbial community structure and function analysis. The MetaPathways software package, installation instructions, and example data can be obtained from http://hallam.microbiology.ubc.ca/MetaPathways. PMID- 23800137 TI - Imipenem versus piperacillin/tazobactam for empiric treatment of neutropenic fever in adults. AB - Australian guidelines for neutropenic fever recommend piperacillin/tazobactam (PIP-TAZ) or cefepime for first-line empiric treatment of neutropenic fever. We compared outcomes among haematology patients before and after changing our first line neutropenic fever treatment from imipenem to PIP-TAZ. Forty-five patients received imipenem and 60 PIP-TAZ. Despite a higher rate of antibiotic modification in the PIP-TAZ cohort, treatment success and time to defervescence were similar, with a trend towards fewer Clostridium difficile infections in the PIP-TAZ cohort. PMID- 23800138 TI - Changing practice as a quality indicator for primary care: analysis of data on voluntary disenrollment from the English GP Patient Survey. AB - BACKGROUND: Changing family practice (voluntary disenrollment) without changing address may indicate dissatisfaction with care. We investigate the potential to use voluntary disenrollment as a quality indicator for primary care. METHODS: Data from the English national GP Patient Survey (2,169,718 respondents), the number of voluntary disenrollments without change of address, data relating to practice characteristics (ethnicity, deprivation, gender of patients, practice size and practice density) and doctor characteristics were obtained for all family practices in England (n = 8450). Poisson regression analyses examined associations between rates of voluntary disenrollment, patient experience, and practice and doctor characteristics. RESULTS: Mean and median rates of annual voluntary disenrollment were 11.2 and 7.3 per 1000 patients respectively. Strongest associations with high rates of disenrollment were low practice scores for doctor-patient communication and confidence and trust in the doctor (rate ratios 4.63 and 4.85). In a fully adjusted model, overall satisfaction encompassed other measures of patient experience (rate ratio 3.46). Patients were more likely to move from small practices (single-handed doctors had 2.75 times the disenrollment rate of practices with 6-9 doctors) and where there were other local practices. After allowing for these, substantial unexplained variation remained in practice rates of voluntary disenrollment. CONCLUSION: Family practices with low levels of patient satisfaction, especially for doctor patient communication, are more likely to experience high rates of disenrollment. However substantial variation in disenrollment rates remains among practices with similar levels of patient satisfaction, limiting the utility of voluntary disenrollment as a performance indicator for primary care in England. PMID- 23800140 TI - Serum hepatitis B surface antigen quantification as a useful assessment for significant fibrosis in hepatitis B e antigen-positive hepatitis B virus carriers. AB - BACKGROUND AND AIMS: The role of serum quantitative hepatitis B surface antigen (qHBsAg) in identifying hepatitis B virus (HBV) carriers with significant fibrosis is unknown. This study aims to evaluate the diagnostic value of qHBsAg for hepatic fibrosis in hepatitis B e antigen (HBeAg)-positive HBV carriers. METHODS: Consecutive biopsy-proven HBeAg-positive HBV carriers were prospectively recruited in our center from 2009 to 2011 and were randomly divided into training and validation set. Area under receiver-operator curve (AUC) was used to determine the diagnostic accuracy of simple tests for significant fibrosis (Scheuer stage, F >= 2). RESULTS: Overall, a total of 197 eligible patients (median age 31 years; 149 males) were enrolled. The median qHBsAg was 4.20 (log10 IU/mL). Significant fibrosis was confirmed in 112 (56.9%) patients. By logistical regression analysis, qHBsAg and gamma-glutamyl transpeptidase were identified as predictors for significant fibrosis in training set (n = 124). Thus, qHBsAg index and gamma-glutamyl transpeptidase to qHBsAg ratio (GqHBsR) were selected for the subsequent analysis. In the training set, an AUC of 0.762, 0.826, 0.749, and 0.771 was observed for qHBsAg index, GqHBsR, FIB-4, and aspartate aminotransferase to platelet ratio index, respectively (all P < 0.05). GqHBsR yielded a higher AUC than aspartate aminotransferase to platelet ratio index and FIB-4 (both P < 0.05). Using the optimal cut-off of 7.78, GqHBsR showed a sensitivity of 78.9% and a specificity of 73.6%. About 80% of liver biopsy could be avoided in the entire cohort. CONCLUSIONS: Serum qHBsAg-based simple tests, especially GqHBsR, can accurately and specifically identify significant fibrosis in treatment-naive HBeAg-positive HBV carriers. PMID- 23800139 TI - Perspectives of men on antenatal and delivery care service utilisation in rural western Kenya: a qualitative study. AB - BACKGROUND: Poor utilisation of facility-based antenatal and delivery care services in Kenya hampers reduction of maternal mortality. Studies suggest that the participation of men in antenatal and delivery care is associated with better health care seeking behaviour, yet many reproductive health programs do not facilitate their involvement. This qualitative study conducted in rural Western Kenya, explored men's perceptions of antenatal and delivery care services and identified factors that facilitated or constrained their involvement. METHODS: Eight focus group discussions were conducted with 68 married men between 20-65 years of age in May 2011. Participants were of the Luo ethnic group residing in Asembo, western Kenya. The area has a high HIV-prevalence and polygamy is common. A topic guide was used to guide the discussions and a thematic framework approach for data analysis. RESULTS: Overall, men were positive in their views of antenatal and delivery care, as decision makers they often encouraged, some even 'forced', their wives to attend for antenatal or delivery care. Many reasons why it was beneficial to accompany their wives were provided, yet few did this in practice unless there was a clinical complication. The three main barriers relating to cultural norms identified were: 1) pregnancy support was considered a female role; and the male role that of provider; 2) negative health care worker attitudes towards men's participation, and 3) couple unfriendly antenatal and delivery unit infrastructure. CONCLUSION: Although men reported to facilitate their wives' utilisation of antenatal and delivery care services, this does not translate to practice as adherence to antenatal-care schedules and facility based delivery is generally poor. Equally, reasons proffered why they should accompany their wives are not carried through into practice, with barriers outweighing facilitators. Recommendations to improve men involvement and potentially increase services utilisation include awareness campaigns targeting men, exploring promotion of joint HIV testing and counselling, staff training, and design of couple friendly antenatal and delivery units. PMID- 23800141 TI - Mitochondrial network morphology: building an integrative, geometrical view. AB - The morphology of mitochondrial networks is complex and highly varied, yet vital to cell function. The first step toward an integrative understanding of how mitochondrial morphology is generated and regulated is to define the interdependent geometrical features and their dynamics that together generate the morphology of a mitochondrial network within a cell. Distinct aspects of the size, shape, position, and dynamics of mitochondrial networks are described and examples of how these features depend on one another discussed. PMID- 23800142 TI - Maintaining the structural integrity of the Bamboo mosaic virus 3' untranslated region is necessary for retaining the catalytic constant for minus-strand RNA synthesis. AB - BACKGROUND: Bamboo mosaic virus (BaMV) and the Potato virus X (PVX) are members of the genus Potexvirus and have a single-stranded positive-sense RNA genome. The 3'-untranslated region (UTR) of the BaMV RNA genome was mapped structurally into ABC (a cloverleaf-like), D (a stem-loop), and E (pseudoknot) domains. The BaMV replicase complex that was isolated from the infected plants was able to recognize the 3' UTR of PVX RNA to initiate minus-strand RNA synthesis in vitro. RESULTS: To investigate whether the 3' UTR of PVX RNA is also compatible with BaMV replicase in vivo, we constructed chimera mutants using a BaMV backbone containing the PVX 3' UTR, which was inserted in or used to replace the various domains in the 3' UTR of BaMV. None of the mutants, except for the mutant with the PVX 3' UTR inserted upstream of the BaMV 3' UTR, exhibited a detectable accumulation of viral RNA in Nicotiana benthamiana plants. The in vitro BaMV RdRp replication assay demonstrated that the RNA products were generated by the short RNA transcripts, which were derived from the chimera mutants to various extents. Furthermore, the Vmax/KM of the BaMV 3' UTR (rABCDE) was approximately three fold higher than rABCP, rP, and rDE in minus-strand RNA synthesis. These mutants failed to accumulate viral products in protoplasts and plants, but were adequately replicated in vitro. CONCLUSIONS: Among the various studied BaMV/PVX chimera mutants, the BaMV-S/PABCDE that contained non-interrupted BaMV 3' UTR was the only mutant that exhibited a wild-type level of viral product accumulation in protoplasts and plants. These results indicate that the continuity of the domains in the 3' UTR of BaMV RNA was not interrupted and the domains were not replaced with the 3' UTR of PVX RNA in vivo. PMID- 23800143 TI - From kitchen table to operating room. PMID- 23800144 TI - The BraveNet prospective observational study on integrative medicine treatment approaches for pain. AB - BACKGROUND: Chronic pain affects nearly 116 million American adults at an estimated cost of up to $635 billion annually and is the No. 1 condition for which patients seek care at integrative medicine clinics. In our Study on Integrative Medicine Treatment Approaches for Pain (SIMTAP), we observed the impact of an integrative approach on chronic pain and a number of other related patient-reported outcome measures. METHODS: Our prospective, non-randomized, open label observational evaluation was conducted over six months, at nine clinical sites. Participants received a non-standardized, personalized, multimodal approach to chronic pain. Validated instruments for pain (severity and interference levels), quality of life, mood, stress, sleep, fatigue, sense of control, overall well-being, and work productivity were completed at baseline and at six, 12, and 24 weeks. Blood was collected at baseline and week 12 for analysis of high-sensitivity C-reactive protein and 25-hydroxyvitamin D levels. Repeated-measures analysis was performed on data to assess change from baseline at 24 weeks. RESULTS: Of 409 participants initially enrolled, 252 completed all follow-up visits during the 6 month evaluation. Participants were predominantly white (81%) and female (73%), with a mean age of 49.1 years (15.44) and an average of 8.0 (9.26) years of chronic pain. At baseline, 52% of patients reported symptoms consistent with depression. At 24 weeks, significantly decreased pain severity (-23%) and interference (-28%) were seen. Significant improvements in mood, stress, quality of life, fatigue, sleep and well-being were also observed. Mean 25-hydroxyvitamin D levels increased from 33.4 (17.05) ng/mL at baseline to 39.6 (16.68) ng/mL at week 12. CONCLUSIONS: Among participants completing an integrative medicine program for chronic pain, significant improvements were seen in pain as well as other relevant patient-reported outcome measures. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01186341. PMID- 23800145 TI - All-trans retinoic acid attenuates airway inflammation by inhibiting Th2 and Th17 response in experimental allergic asthma. AB - BACKGROUND: Airway inflammation is mainly mediated by T helper 2 cells (Th2) that characteristically produce interleukin (IL)-4, IL-5, and IL-13. Epidemiological studies have revealed an inverse association between the dietary intake of vitamin A and the occurrence of asthma. Serum vitamin A concentrations are significantly lower in asthmatic subjects than in healthy control subjects. It has been reported that all-trans retinoic acid (ATRA), a potent derivative of vitamin A, regulates immune responses. However, its role in Th2-mediated airway inflammation remains unclear. We investigated the effects of ATRA in a mouse model of allergic airway inflammation. RESULTS: We found that ATRA treatment attenuated airway inflammation and decreased mRNA levels of Th2- and Th17-related transcription factors. The data showed that airway inflammation coincided with levels of Th2- and Th17-related cytokines. We also showed that ATRA inhibited Th17 and promoted inducible regulatory T-cell differentiation, whereas it did not induce an obvious effect on Th2 differentiation in vitro. Our data suggest that ATRA may interfere with the in vivo Th2 responses via T-cell extrinsic mechanisms. CONCLUSIONS: Administration of ATRA dramatically attenuated airway inflammation by inhibiting Th2 and Th17 differentiation and/or functions. ATRA may have potential therapeutic effects for airway inflammation in asthmatic patients. PMID- 23800146 TI - Polyvinylferrocene for noncovalent dispersion and redox-controlled precipitation of carbon nanotubes in nonaqueous media. AB - We report noncovalent dispersion of carbon nanotubes (CNTs) in organic liquids with extremely high loading (~2 mg mL(-1)) using polyvinylferrocene (PVF). In contrast to common dispersants, PVF does not contain any conjugated structures or ionic moieties. PVF is also shown to be effective in controlling nanotube dispersion and reprecipitation because it exhibits redox-switchable affinity for solvents, while maintaining stable physical attachment to CNTs during redox transformation. This switchability provides a novel approach to creating CNT functionalized surfaces. The material systems described here offer new opportunities for applications of CNTs in nonaqueous media, such as nanotube polymer composites and organic liquid-based optical limiters, and expand the means of tailoring nanotube dispersion behavior via external stimuli, with potential applications in switching devices. The PVF/CNT hybrid system with enhanced redox response of ferrocene may also find applications in high performance biosensors and pseudocapacitors. PMID- 23800147 TI - Development of a D-xylose fermenting and inhibitor tolerant industrial Saccharomyces cerevisiae strain with high performance in lignocellulose hydrolysates using metabolic and evolutionary engineering. AB - BACKGROUND: The production of bioethanol from lignocellulose hydrolysates requires a robust, D-xylose-fermenting and inhibitor-tolerant microorganism as catalyst. The purpose of the present work was to develop such a strain from a prime industrial yeast strain, Ethanol Red, used for bioethanol production. RESULTS: An expression cassette containing 13 genes including Clostridium phytofermentans XylA, encoding D-xylose isomerase (XI), and enzymes of the pentose phosphate pathway was inserted in two copies in the genome of Ethanol Red. Subsequent EMS mutagenesis, genome shuffling and selection in D-xylose enriched lignocellulose hydrolysate, followed by multiple rounds of evolutionary engineering in complex medium with D-xylose, gradually established efficient D xylose fermentation. The best-performing strain, GS1.11-26, showed a maximum specific D-xylose consumption rate of 1.1 g/g DW/h in synthetic medium, with complete attenuation of 35 g/L D-xylose in about 17 h. In separate hydrolysis and fermentation of lignocellulose hydrolysates of Arundo donax (giant reed), spruce and a wheat straw/hay mixture, the maximum specific D-xylose consumption rate was 0.36, 0.23 and 1.1 g/g DW inoculum/h, and the final ethanol titer was 4.2, 3.9 and 5.8% (v/v), respectively. In simultaneous saccharification and fermentation of Arundo hydrolysate, GS1.11-26 produced 32% more ethanol than the parent strain Ethanol Red, due to efficient D-xylose utilization. The high D-xylose fermentation capacity was stable after extended growth in glucose. Cell extracts of strain GS1.11-26 displayed 17-fold higher XI activity compared to the parent strain, but overexpression of XI alone was not enough to establish D-xylose fermentation. The high D-xylose consumption rate was due to synergistic interaction between the high XI activity and one or more mutations in the genome. The GS1.11-26 had a partial respiratory defect causing a reduced aerobic growth rate. CONCLUSIONS: An industrial yeast strain for bioethanol production with lignocellulose hydrolysates has been developed in the genetic background of a strain widely used for commercial bioethanol production. The strain uses glucose and D-xylose with high consumption rates and partial cofermentation in various lignocellulose hydrolysates with very high ethanol yield. The GS1.11-26 strain shows highly promising potential for further development of an all-round robust yeast strain for efficient fermentation of various lignocellulose hydrolysates. PMID- 23800149 TI - Intensity-modulated radiotherapy versus three-dimensional conformal radiotherapy for stage I-II natural killer/T-cell lymphoma nasal type: dosimetric and clinical results. AB - BACKGROUND: This study was to compare radiotherapy treatment planning and treatment outcomes following three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT) in stage I-II natural killer (NK)/T-cell lymphoma. METHODS: The cases of 94 patients with stage I-II NK/T-cell lymphoma, nasal type in the upper aerodigestive tract who treated between May 2005 and Dec 2008 were reviewed. These patients received radiotherapy with or without induction chemotherapy. Definitive radiotherapy was conducted using 3DCRT in 47 patients and IMRT in the other 47 patients with a regional field and a total dose of 50 Gy. Dosimetric pmeters of radiation treatment plans, local control probability (LCP), overall survival (OS), and toxicities were analyzed and compared between 3DCRT and IMRT. RESULTS: From the dosimetric analysis, IMRT demonstrated significantly better dose coverage and homogeneity than 3DCRT. However, after a median follow-up of 46 months, IMRT was not associated with improvements in 4y-OS (80.9% for 3DCRT vs. 82.7% for IMRT, p=0.87) or 4y-LCP (86.3% for 3DCRT vs. 88.9% for IMR p=0.85). Of the 18 patients who received cervical lymph node irradiation, those in the IMRT group received a lower mean parotid dose. Furthermore, at-risk organs were strictly kept within the safe dose range in both groups, and no severe late toxicity was observed. CONCLUSIONS: IMRT provided better dose coverage than 3DCRT, although it failed to provide LCP and OS benefits. Definitive radiotherapy with a regional field and a total dose of 50 Gy is efficient and safe for NK/T-cell lymphoma using either IMRT or 3DCRT. However, IMRT may have the potential to reduce parotid gland hypofunction following cervical irradiation. PMID- 23800148 TI - Incentivizing primary care providers to innovate: building medical homes in the post-Katrina New Orleans safety net. AB - OBJECTIVE: To evaluate safety-net clinics' responses to a novel community-wide Patient-Centered Medical Home (PCMH) financial incentive program in post-Katrina New Orleans. DATA SOURCES/STUDY SETTING: Between June 2008 and June 2010, we studied 50 primary care clinics in New Orleans receiving federal funds to expand services and improve care delivery. STUDY DESIGN: Multiwave, longitudinal, observational study of a local safety-net primary care system. DATA COLLECTION: Clinic-level data from a semiannual survey of clinic leaders (89.3 percent response rate), augmented by administrative records. PRINCIPAL FINDINGS: Overall, 62 percent of the clinics responded to financial incentives by achieving PCMH recognition from the National Committee on Quality Assurance (NCQA). Higher patient volume, higher baseline PCMH scores, and type of ownership were significant predictors of achieving NCQA recognition. The steepest increase in adoption of PCMH processes occurred among clinics achieving the highest, Level 3, NCQA recognition. Following NCQA recognition, 88.9 percent stabilized or increased their use of PCMH processes, although several specific PCMH processes had very low rates of adoption overall. CONCLUSIONS: Findings demonstrate that widespread PCMH implementation is possible in a safety-net environment when external financial incentives are aligned with the goal of practice innovation. PMID- 23800150 TI - Controlling conformations of conjugated polymers and small molecules: the role of nonbonding interactions. AB - The chemical variety present in the organic electronics literature has motivated us to investigate potential nonbonding interactions often incorporated into conformational "locking" schemes. We examine a variety of potential interactions, including oxygen-sulfur, nitrogen-sulfur, and fluorine-sulfur, using accurate quantum-chemical wave function methods and noncovalent interaction (NCI) analysis on a selection of high-performing conjugated polymers and small molecules found in the literature. In addition, we evaluate a set of nonbonding interactions occurring between various heterocyclic and pendant atoms taken from a group of representative pi-conjugated molecules. Together with our survey and set of interactions, it is determined that while many nonbonding interactions possess weak binding capabilities, nontraditional hydrogen-bonding interactions, oxygen hydrogen (CH...O) and nitrogen-hydrogen (CH...N), are alone in inducing conformational control and enhanced planarity along a polymer or small molecule backbone at room temperature. PMID- 23800151 TI - Altered molecular repertoire of immune system by renal dysfunction in the elderly: is prediction and targeted prevention in the horizon? AB - BACKGROUND: Patients on chronic hemodialysis (HD) have impaired cellular and humoral immunity. The percentage of elderly people among the total population in Taiwan is increasing dramatically, and HD is the primary alternative for renal replacement therapy when renal function declines. Activated vitamin D is widely used in HD patients with secondary hyperparathyroidism (SHPT) and is a well-known immunomodulatory agent. Personalized medicine and integrative medical approach has been a trend in current clinical practice. Can we improve their immune function using vitamin D in spite of the mineral aspect? Here, we investigated the relationship between serum 25-hydroxyvitamin D (25(OH)D) level and T cell differentiation in chronic HD patients. METHODS: Forty patients with chronic HD were enrolled. HD patients with SHPT had been treated with activated vitamin D for 3 months. Peripheral blood mononuclear cells obtained from the patients were cultured and stimulated by mitogens, and T cells were analyzed by flow cytometry. Serum 25(OH)D levels were detected by enzyme-linked immunosorbent assay. RESULTS: The incidence of T cell differentiation to the T helper cell (Th)2 subtype was more prevalent in the elderly group than in the controls (p = 0.001). Th2 differentiation was also correlated with age (p = 0.004) and serum 25(OH)D levels (p < 0.05). After treated with activated vitamin D, the level of Th1 cytokines decreased while the Th2 cytokine level increased in the sera (p < 0.05). The T cell differentiation tended toward the Th2 subtype (p = 0.027) after treatment of activated vitamin D in SHPT patients. CONCLUSIONS: These results demonstrated that Th2 differentiation is correlated with age and the serum 25(OH)D level of patients. Treatment with activated vitamin D influenced T cell differentiation and cytokine expression in SHPT patients. Taking vitamin D is the possible prediction and targeted treatment in the immune dysfunction in chronic HD patients. PMID- 23800152 TI - Immunity, resistance and tolerance in bird-parasite interactions. AB - Interacting pathogens and hosts have evolved reciprocal adaptations whose function is to allow host exploitation (from the pathogen stand point) or minimize the cost of infection (from the host stand point). Once infected, two strategies are offered to the host: parasite clearing (resistance) and withstanding the infection while paying a low fitness cost (tolerance). In both cases, the immune system plays a central role. Interestingly, whatever the defence strategy adopted by the host, this is likely to have an effect on parasite evolution. Given their short generation time and large population size, parasites are expected to rapidly adapt to the environmental conditions provided by their hosts. The immune system can therefore represent a powerful engine of parasite evolution, with the direction of such evolutionary trajectory depending on, among other factors, (i) the type of mechanism involved (resistance or tolerance) and (ii) the damage induced by overreacting immune defences. In this article, I will discuss these different issues focusing on selected examples of recent work conducted on two bird pathogens, the protozoa responsible for avian malaria (Plasmodium sp.) and the bacterium Mycoplasma gallisepticum. PMID- 23800153 TI - Could a brief assessment of negative emotions and self-esteem identify adolescents at current and future risk of self-harm in the community? A prospective cohort analysis. AB - BACKGROUND: Self-harm is common in adolescents, but it is often unreported and undetected. Available screening tools typically ask directly about self-harm and suicidal ideation. Although in an ideal world, direct enquiry and open discussion around self-harm would be advocated, non-psychiatric professionals in community settings are often reluctant to ask about this directly and disclosure can be met with feeling of intense anxiety. Training non-specialist staff to directly ask about self-harm has limited effects suggesting that alternative approaches are required. This study investigated whether a targeted analysis of negative emotions and self-esteem could identify young adolescents at risk of self-harm in community settings. METHODS: Data were collected as part of a clinical trial from young people in school years 8-11 (aged 12-16) at eight UK secondary schools (N = 4503 at baseline, N = 3263 in prospective analysis). The Short Mood and Feelings Questionnaire, Revised Child Anxiety and Depression Scale, Rosenberg Self-Esteem Scale, personal failure (Children's Automatic Thoughts Scale), and two items on self-harm were completed at baseline, 6 and 12 months. RESULTS: Following a process of Principal Components Analysis, item reduction, and logistic regression analysis, three internally reliable factors were identified from the original measures that were independently associated with current and future self-harm; personal failure (3 items), physical symptoms of depression/anxiety (6 items), positive self-esteem (5 items). The summed score of these 14 items had good accuracy in identifying current self-harm (AUC 0.87 girls, 0.81 boys) and at six months for girls (0.81), and fair accuracy at six months for boys (AUC 0.74) and 12 months for girls (AUC 0.77). CONCLUSIONS: A brief and targeted assessment of negative emotions and self-esteem, focusing on factors that are strongly associated with current and future self-harm, could potentially be used to help identify adolescents who are at risk in community settings. Further research should assess the psychometric properties of the items identified and test this approach in more diverse community contexts. PMID- 23800155 TI - A novel SACS mutation results in non-ataxic spastic paraplegia and peripheral neuropathy. AB - BACKGROUND AND PURPOSE: Mutations in the SACS gene are commonly associated with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a complex neurodegenerative disorder characterized by progressive degeneration of the cerebellum and spinal cord tracts. The aim of this study was to identify the genetic cause of the disease in an Italian family with spastic paraplegia and peripheral neuropathy. METHODS: Affected subjects were subjected to a comprehensive neurological examination including electromyography and brain magnetic resonance imaging. Genetic studies included exclusion of known disease genes, genome-wide linkage analysis using high density single nucleotide polymorphism genotyping and candidate gene sequencing. RESULTS: Molecular analyses revealed a novel missense mutation in the SACS gene (c.11,104A>G) occurring in a homozygous state in patients and absent in 700 Italian control chromosomes. The mutation led to the amino acid substitution p.Thr3702Ala in the sacsin protein, in a possible protein-protein interaction site of UBE3A binding domain. CONCLUSION: This study broadens the genetic spectrum of SACS mutations and expands the clinical ARSACS phenotype suggesting that the SACS gene can be considered in patients with non-canonical ARSACS clinical presentations. PMID- 23800156 TI - Do patient and practice characteristics confound age-group differences in preferences for general practice care? A quantitative study. AB - BACKGROUND: Previous research showed inconsistent results regarding the relationship between the age of patients and preference statements regarding GP care. This study investigates whether elderly patients have different preference scores and ranking orders concerning 58 preference statements for GP care than younger patients. Moreover, this study examines whether patient characteristics and practice location may confound the relationship between age and the categorisation of a preference score as very important. METHODS: Data of the Consumer Quality Index GP Care were used, which were collected in 32 general practices in The Netherlands. The rank order and preference score were calculated for 58 preference statements for four age groups (0-30, 31-50, 51-74, 75 years and older). Using chi-square tests and logistic regression analyses, it was investigated whether a significant relationship between age and preference score was confounded by patient characteristics and practice location. RESULTS: Elderly patients did not have a significant different ranking order for the preference statements than the other three age groups (r = 0.0193; p = 0.41). However, in 53% of the statements significant differences were found in preference score between the four age groups. Elderly patients categorized significantly less preference statements as 'very important'. In most cases, the significant relationships were not confounded by gender, education, perceived health, the number of GP contacts and location of the GP practice. CONCLUSION: The preferences of elderly patients for GP care concern the same items as younger patients. However, their preferences are less strong, which cannot be ascribed to gender, education, perceived health, the number of GP contacts and practice location. PMID- 23800154 TI - Effects of nutraceutical diet integration, with coenzyme Q10 (Q-Ter multicomposite) and creatine, on dyspnea, exercise tolerance, and quality of life in COPD patients with chronic respiratory failure. AB - BACKGROUND: The protein-calorie malnutrition, resulting in muscle mass loss, frequently occurs in severe COPD patients with chronic respiratory failure (CRF), causing dyspnea, reduced exercise tolerance and impaired quality of life.The cause of this occurrence is an intake-output energy imbalance. A documented deficit of phosphocreatine and reduced mithocondrial energy production can contribute to this imbalance.Aim of this study is to verify whether a dietary supplementation with creatine and coenzyme Q10, important mitochondrial function factors, is able to influence this mechanism leading to a dyspnea reduction and improving exercise tolerance and quality of life. METHODS: 55 COPD patients with chronic respiratory failure (in long term O2 therapy), in stable phase of the disease and without severe comorbidities were assigned (double-blind, randomized) to: group A (30 patients) with daily dietary supplementation with Creatine 340 mg + 320 mg Coenzyme Q-Ter (Eufortyn(r), Scharper Therapeutics Srl) for 2 months whereas Group B (25 patients) received placebo.All patients continued the same diet, rehabilitation and therapy during the study. At recruitment (T0) and after 2 months (T1), patients were submitted to medical history, anthropometry (BMI), bioelectrical impedance, arterial blood gas analysis, evaluation of dyspnea (VAS, Borg, BDI, MRC) and functional independence (ADL), 6-minute walk test (6MWT) and quality of life questionnaire (SGRQ). At 6 months and 1 year, a telephone follow up was conducted on exacerbations number. RESULTS: No significant difference was detected at baseline (T0) in the 2 groups. After 2 months of therapy (T1) the FFMI increased in the daily dietary supplementation group (+ 3.7 %) and decreased in the placebo group (- 0.6 %), resulting in a statistically significant (p < 0.001) treatment difference. Statistically significant treatment differences, favouring daily dietary supplementation group, were also seen for the 6MWT comparison. Group A patients also showed significant: 1) improvement in the degree of dyspnea (VAS: p < 0.05; Borg: p < 0.05; MRC: p < 0.001; BDI1: p < 0.05; BDI3: p < 0.03), and independence level in activities of daily living (p < 0.03); 2) improvement in quality of life in activity section (- 6.63 pt) and in total score (- 5.43 pt); 3) exacerbation number decrease (p < 0.02). No significant differences were found (end of study vs baseline) in group B. CONCLUSIONS: The nutraceutical diet integration with Q-Ter and creatine, in COPD patients with CRF in O2TLT induced an increasing lean body mass and exercise tolerance, reducing dyspnea, quality of life and exacerbations. These results provide a first demonstration that acting on protein synthesis and muscular efficiency can significantly modify the systemic consequences of the disease. PMID- 23800158 TI - Performance of the Emotiv Epoc headset for P300-based applications. AB - BACKGROUND: For two decades, EEG-based Brain-Computer Interface (BCI) systems have been widely studied in research labs. Now, researchers want to consider out of-the-lab applications and make this technology available to everybody. However, medical-grade EEG recording devices are still much too expensive for end-users, especially disabled people. Therefore, several low-cost alternatives have appeared on the market. The Emotiv Epoc headset is one of them. Although some previous work showed this device could suit the customer's needs in terms of performance, no quantitative classification-based assessments compared to a medical system are available. METHODS: This paper aims at statistically comparing a medical-grade system, the ANT device, and the Emotiv Epoc headset by determining their respective performances in a P300 BCI using the same electrodes. On top of that, a review of previous Emotiv studies and a discussion on practical considerations regarding both systems are proposed. Nine healthy subjects participated in this experiment during which the ANT and the Emotiv systems are used in two different conditions: sitting on a chair and walking on a treadmill at constant speed. RESULTS: The Emotiv headset performs significantly worse than the medical device; observed effect sizes vary from medium to large. The Emotiv headset has higher relative operational and maintenance costs than its medical-grade competitor. CONCLUSIONS: Although this low-cost headset is able to record EEG data in a satisfying manner, it should only be chosen for non critical applications such as games, communication systems, etc. For rehabilitation or prosthesis control, this lack of reliability may lead to serious consequences. For research purposes, the medical system should be chosen except if a lot of trials are available or when the Signal-to-Noise Ratio is high. This also suggests that the design of a specific low-cost EEG recording system for critical applications and research is still required. PMID- 23800157 TI - Prediction of gene-phenotype associations in humans, mice, and plants using phenologs. AB - BACKGROUND: Phenotypes and diseases may be related to seemingly dissimilar phenotypes in other species by means of the orthology of underlying genes. Such "orthologous phenotypes," or "phenologs," are examples of deep homology, and may be used to predict additional candidate disease genes. RESULTS: In this work, we develop an unsupervised algorithm for ranking phenolog-based candidate disease genes through the integration of predictions from the k nearest neighbor phenologs, comparing classifiers and weighting functions by cross-validation. We also improve upon the original method by extending the theory to paralogous phenotypes. Our algorithm makes use of additional phenotype data--from chicken, zebrafish, and E. coli, as well as new datasets for C. elegans--establishing that several types of annotations may be treated as phenotypes. We demonstrate the use of our algorithm to predict novel candidate genes for human atrial fibrillation (such as HRH2, ATP4A, ATP4B, and HOPX) and epilepsy (e.g., PAX6 and NKX2-1). We suggest gene candidates for pharmacologically-induced seizures in mouse, solely based on orthologous phenotypes from E. coli. We also explore the prediction of plant gene-phenotype associations, as for the Arabidopsis response to vernalization phenotype. CONCLUSIONS: We are able to rank gene predictions for a significant portion of the diseases in the Online Mendelian Inheritance in Man database. Additionally, our method suggests candidate genes for mammalian seizures based only on bacterial phenotypes and gene orthology. We demonstrate that phenotype information may come from diverse sources, including drug sensitivities, gene ontology biological processes, and in situ hybridization annotations. Finally, we offer testable candidates for a variety of human diseases, plant traits, and other classes of phenotypes across a wide array of species. PMID- 23800159 TI - Molecular cloning, sequencing and structural studies of granulocyte-macrophage colony-stimulating factor (GM-CSF) from Indian water buffalo (Bubalus bubalis). AB - Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine that is essential for growth and development of progenitors of granulocytes and monocytes/macrophages. In this study, we report molecular cloning, sequencing and characterization of GM-CSF from Indian water buffalo, Bubalus bubalis. In addition, we performed sequence and structural analysis for buffalo GM-CSF. Buffalo GM-CSF has been compared with 17 mammalian GM-CSFs using multiple sequence alignment and phylogenetic tree. Three-dimensional model for buffalo GM CSF and human receptor complex was built using homology modelling to study cross reactivity between two species. Detailed analysis was performed to study GM-CSF interface and various interactions at the interface. PMID- 23800160 TI - The association of unwanted pregnancy and social support with depressive symptoms in pregnancy: evidence from rural Southwestern Ethiopia. AB - BACKGROUND: Depression in pregnancy has adverse health outcomes for mothers and children. The magnitude and risk factors of maternal depression during pregnancy is less known in developing countries. This study examines the association between pregnancy intention, social support and depressive symptoms in pregnancy in Ethiopia. METHODS: Data for this study comes from a baseline survey conducted as part of a community- based cohort study that involved 627 pregnant women from a Demographic Surveillance Site (DSS) in Southwestern Ethiopia. The Edinburgh Postnatal Depression Scale (EPDS) was used to measure depressive symptoms during pregnancy. Data on depressive symptoms, pregnancy intention, social support and other explanatory variables were gathered using an interviewer-administered structured questionnaire. The association between independent variables and depressive symptom during pregnancy was assessed using multivariable logistic regression. RESULTS: The prevalence of depressive symptoms during pregnancy was 19.9% (95% CI, 16.8-23.1), using EPDS cut off point of 13 and above. The mean score on the EPDS was 8, ranging from 0 to 25 (SD +/-5.4). Women reporting that the pregnancy was unwanted were almost twice as likely to experience depressive symptoms compared with women with a wanted pregnancy. (Adjusted Odds Ratio (AOR) = 1.96, 95% Confidence Interval (CI) 1.04-3.69) Women who reported moderate (AOR = 0.27; 95% CI 0.14-0.53) and high (AOR = 0.23, 95% CI 0.11-0.47) social support during pregnancy were significantly less likely to report depressive symptoms. Women who experienced household food insecurity and intimate partner physical violence during pregnancy were also more likely to report depressive symptoms. CONCLUSION: About one in five pregnant women in the study area reported symptoms of depression. While unwanted pregnancy increases women's risk of depression, increased social support plays a buffering role from depression. Thus, identifying women's pregnancy intention and the extent of social support they receive during antenatal care visits is needed to provide appropriate counseling and improve women's mental health during pregnancy. PMID- 23800161 TI - Pharmacokinetics, pharmacodynamics, and safety of esomeprazole injection/infusion in healthy Chinese volunteers: a five-way crossover study. AB - BACKGROUND: Esomeprazole provides effective and long lasting inhibition of gastric acid secretion. However, the pharmacokinetics and pharmacodynamics of intravenous esomeprazole in the Chinese population remain unclear. AIM: To compare the pharmacokinetics and pharmacodynamics of intravenous esomeprazole (injection and infusion) and their clinical safety and tolerability in healthy Chinese subjects. METHODS: A randomized, single-center, open-label, five-way crossover study was conducted in 20 healthy volunteers. CYP2C19 metabolizer genotype and Helicobacter pylori status were examined. Five dosing regimens were used: single 40 mg injection, 40 mg infusion every 12 h, 40 mg infusion followed by continuous infusion at 8 mg/h, 80 mg infusion followed by continuous infusion at 4 or 8 mg/h. Intragastric pH was recorded within 24 h. Plasma concentration time curve, maximum plasma concentration (Cmax ), steady state concentration, and total plasma clearance were determined. Adverse events were also recorded. RESULTS: Continuous infusion resulted in a higher mean area under the curve and Cmax than injection. There were no significant differences among the four infusion groups in terms of percentages of time at pH > 4, > 5, > 6, > 7 within 24 h and pH > 6 within the first 3 h. There were no significant differences in pharmacokinetic or pH values among variants of CYP2C19 genotype. The pH value within 24 h was unaffected by H. pylori infection in subjects with continuous infusion. CONCLUSIONS: Esomeprazole administrated by infusion produces better pharmacokinetic and intragastric pH profiles compared with those by injection. The optimal administration schedule for esomeprazole in Chinese subjects is infusion with 40 mg/12 h. PMID- 23800162 TI - Malignant ossifying fibromyxoid tumor of the tongue: case report and review of the literature. AB - Ossifying fibromyxoid tumor (OFMT) is a rare mesenchymal neoplasm that arises in subcutaneous tissue, with that in the oral cavity extremely rare. We present a case of malignant OFMT in the tongue. A 26-year-old male noticed a painless mass in the tongue, which was extracted at a general hospital. Four years later, the tumor recurred and was resected at our department. Histologically, the recurrent tumor was composed of the closely packed cells positive for vimentin and S-100 proliferating in a nodular fashion. It showed high cellularity and mitotic activity. In the primary tumor, some tumor cells were arranged in a diffuse or cord-like manner within an abundant fibromyxoid matrix, along with a small amount of metaplastic ossification, corresponding with the histopathological characteristic of OFMT. Accordingly, a diagnosis of malignant OFMT arising in typical OFMT was established. This is the first reported case of malignant OFMT in the tongue. Long-term follow-up is needed for confirmation of prognosis and biological behavior. PMID- 23800163 TI - Atypical hand-foot-mouth disease in children: a hospital-based prospective cohort study. AB - BACKGROUND: In 2010, we observed children with atypical presentations of hand foot-mouth disease (HFMD), such as rashes on earlobes and faces, or bullae on trunks and bilateral limbs. Hyperpigmentation later developed as the bullous lesions crusted. Thus, we intended to study the etiology of the illness and the phylogeny of the pathogens. METHOD: Patients were prospectively enrolled in a tertiary medical center in Taipei, Taiwan. The definition of atypical HFMD includes symptoms of acute viral infection with either of the following presentations: (1) maculopapular rashes presenting on the trunks, buttocks or facial areas, or (2) large vesicles or bullae on any sites of the body. Patients were classified into two groups according to vesicle sizes by two pediatricians at different points in time. The large vesicle group was defined as having vesciculobullous lesions >= 1 cm in diameter; the small rashes group had maculopapular rashes < 1cm in diameter. Two throat swabs were collected from each patient for virus isolation and reverse transcription polymerase chain reactions. RESULTS: We enrolled 101 patients between March and December 2010. The mean age of the participants was 3.3 +/- 3.0 years (median age: 2.5 years, range: 21 days 13.5 years). The ratio of males to females was 1.8 to 1. All samples were enterovirus-positive, including coxsackievirus A6 (80%), coxsackievirus A16 (6%), enterovirus 71 (1%), coxsackievirus A5 (1%) and 12 non-typable enterovirus (12%). Bullous fluid aspirated from 2 patients also grew coxsackievirus A6. Among the patients infected with coxsackievirus A6, 54% (45/81) had bullae, compared to 25% (5/20) of those having non-coxsackievirus A6 infections (P=0.02). Fourteen cases had myoclonic jerks and one boy was diagnosed with febrile convulsions. None had complications or sequelae. Phylogenetic analysis showed the strains in Taiwan in 2010 shared more commonality with strains from Finland in 2009 (GenBank: FJ870502 FJ870508), and were close to those circulating in Japan in 2011 (GenBank: AB649286-AB649291). CONCLUSIONS: Coxsackievirus A6 infections may cause atypical manifestations of HFMD, including vesicles or papules on faces or bullae on trunks. These features could provide valuable information to distinguish this versatile enterovirus infection from other virus-induced vesiculobullous diseases. PMID- 23800164 TI - Reducing the length of stay for acute hospital patients needing admission into inpatient rehabilitation: a multicentre study of process barriers. AB - BACKGROUND: Patient flow is a major problem in hospitals. Delays in accessing inpatient rehabilitation have not been well studied. AIMS: Measure the time taken for key processes in the patient journey from acute hospital admission through to inpatient rehabilitation admission in order to identify opportunities for improvement. METHODS: Retrospective open cohort study. All patients admitted over 8- and 10-month periods during 2008 into two inpatient rehabilitation units in Melbourne, Australia. Main outcome measures were the duration of the following key processes: acute hospital admission until referral for rehabilitation, referral until assessment by the rehabilitation service, assessment until deemed ready for transfer to rehabilitation, ready for transfer until rehabilitation admission. RESULTS: Three hundred and sixty patients were in the study sample (females = 186; 51.7%); mean age = 58.4 (standard deviation = 15.0) years. There was a median of 7 (interquartile range [IQR] 4-13) days from acute hospital admission till referral for rehabilitation, a median of 1 (IQR 0-1) day from referral till assessment, a median of 0 (IQR 0-2) days from assessment till deemed ready for transfer and a median of 1 (IQR 0-3) day from ready till admission into rehabilitation. Overall, patients spent 12.0% (804/6682) of their acute hospital admission waiting for a rehabilitation bed. CONCLUSIONS: There are opportunities to improve the efficiency of key processes in the acute hospital journey for patients subsequently admitted to inpatient rehabilitation; in particular, reducing the time from acute hospital admission till referral for rehabilitation and from being deemed ready for transfer to rehabilitation till admission. PMID- 23800165 TI - Increasing paternal age at childbirth is associated with taller stature and less favourable lipid profiles in their children. AB - BACKGROUND: Paternal age at childbirth has been increasing worldwide, and we assessed whether this increase affects growth, body composition and metabolism in their children. METHODS: We studied 277 children (aged 3-12 years) born to fathers aged 19.8-51.8 years. Clinical assessments were height and weight adjusted for parental measurements, DEXA-derived body composition, fasting lipids, glucose homoeostasis and hormonal profiles. RESULTS: Children born to fathers aged 31-35 (P = 0.009) and >35 years (P = 0.021) were 2 cm taller than those of fathers aged <=30 years. Children of fathers aged >35 years at childbirth had a lower body mass index (BMI) (-0.32 SDS) than offspring of fathers aged 31-35 (-0.01 SDS; P = 0.043) and <=30 (0.22 SDS; P = 0.019). There were marked effects of paternal age at childbirth on childhood blood lipids. LDL C concentrations in children born to fathers aged >35 years were 11% and 21% higher than in children of fathers aged 31-35 and <=30 years, respectively (P < 0.01). Total cholesterol to HDL-C ratio was also higher among the children of fathers aged 31-35 (12%; P = 0.014) and >35 (16%; P = 0.004) years at childbirth compared with the <=30 group. In addition, HOMA-IR in girls (but not boys) born of fathers aged 31-35 (0.99) and >35 years (1.11) indicated better insulin sensitivity compared with offspring in the <=30 group (1.63; P < 0.05). CONCLUSIONS: Increasing paternal age at childbirth is associated with a more favourable phenotype in their children (taller and slimmer, with better insulin sensitivity in girls) but with a less favourable lipid profile. PMID- 23800166 TI - A comparison of sex-specific immune signatures in Gulf War illness and chronic fatigue syndrome. AB - BACKGROUND: Though potentially linked to the basic physiology of stress response we still have no clear understanding of Gulf War Illness (GWI), a debilitating condition presenting complex immune, endocrine and neurological symptoms. Here we compared male (n = 20) and female (n = 10) veterans with GWI separately against their healthy counterparts (n = 21 male, n = 9 female) as well as subjects with chronic fatigue syndrome/ myalgic encephalomyelitis (CFS/ME) (n = 12 male, n = 10 female). METHODS: Subjects were assessed using a Graded eXercise Test (GXT) with blood drawn prior to exercise, at peak effort (VO2 max) and 4-hours post exercise. Using chemiluminescent imaging we measured the concentrations of IL-1a, 1b, 2, 4, 5, 6, 8, 10, 12 (p70), 13, 15, 17 and 23, IFNgamma, TNFalpha and TNFbeta in plasma samples from each phase of exercise. Linear classification models were constructed using stepwise variable selection to identify cytokine co expression patterns characteristic of each subject group. RESULTS: Classification accuracies in excess of 80% were obtained using between 2 and 5 cytokine markers. Common to both GWI and CFS, IL-10 and IL-23 expression contributed in an illness and time-dependent manner, accompanied in male subjects by NK and Th1 markers IL 12, IL-15, IL-2 and IFNgamma. In female GWI and CFS subjects IL-10 was again identified as a delineator but this time in the context of IL-17 and Th2 markers IL-4 and IL-5. Exercise response also differed between sexes: male GWI subjects presented characteristic cytokine signatures at rest but not at peak effort whereas the opposite was true for female subjects. CONCLUSIONS: Though individual markers varied, results collectively supported involvement of the IL-23/Th17/IL 17 axis in the delineation of GWI and CFS in a sex-specific way. PMID- 23800167 TI - Pre-exposure prophylaxis for HIV infection: how antiretroviral pharmacology helps to monitor and improve adherence. AB - INTRODUCTION: Pre-exposure prophylaxis (PrEP) with antiretroviral drugs is a novel biomedical intervention that can prevent HIV transmission among high-risk populations. As findings from multiple PrEP studies have suggested that adherence is vital to achieve the full prevention benefits of PrEP, it is important to understand the clinical pharmacology and pharmacokinetic (PK) properties of PrEP antiretrovirals, the association of PK and PrEP efficacy, and the potential for drug concentration measurement to be used as a tool to monitor PrEP adherence. AREAS COVERED: This review examines studies related to PrEP adherence with attention to the clinical pharmacology and PK of current and novel PrEP agents. Studies of animal models, PK, and clinical trials related to PrEP and adherence were reviewed. EXPERT OPINION: In summary, when combined as part of a comprehensive prevention strategy that includes use of condoms and risk-reduction counseling, PrEP has tremendous promise as an adjunctive biomedical HIV prevention intervention, providing that adherence is maintained. PMID- 23800168 TI - Multi-residue method for the analysis of pesticides in Arabica coffee using liquid chromatography/tandem mass spectrometry. AB - Coffee is a major tropical agricultural commodity and represents a significant fraction of the economy of many countries. However, certain plant and animal species can damage coffee crops, affecting trade. A solution to this issue is the use of pesticides, some of which are harmful to human health and the environment. This work consisted of the development of a multi-residue method for the analysis of pesticides in coffee by using LC-MS/MS. The QuEChERS extraction procedure was used. The following analytical parameters were optimised: selectivity, analytical range, linearity, LOD, LOQ, precision (RSD%) and recovery of the method. The results showed that the method is selective, as they were linear in the range of 10.0-100.0 ug kg(-1). The sensitivity, recovery and precision were adequate for the multi-residue analysis of pesticides in coffee. The method was applied to the analyses of 15 Brazilian coffee samples. PMID- 23800169 TI - Large IncHI2-plasmids encode extended-spectrum beta-lactamases (ESBLs) in Enterobacter spp. bloodstream isolates, and support ESBL-transfer to Escherichia coli. AB - We investigated the prevalence of extended-spectrum beta-lactamases (ESBLs) in Enterobacter spp. bloodstream isolates from 19 hospital laboratories in Norway during 2011. A total of 62/230 (27%) isolates were resistant to third-generation cephalosporins and four (1.7%) were ESBL-positive; blaCTX -M-15 (n = 3) and blaSHV -12 (n = 1). This is comparable to the prevalence of ESBLs in clinical isolates of Escherichia coli and Klebsiella pneumoniae in Norway during the same period. All ESBL-positive isolates were multidrug resistant (MDR) and harboured plasmid-mediated quinolone resistance. Three isolates supported transfer of large IncHI2-plasmids harbouring ESBL- and MDR-encoding genes to E. coli recipients by in vitro conjugation. PMID- 23800171 TI - Extramammary Paget's disease of the scalp: examination by in vivo and ex vivo reflectance confocal microscopy. PMID- 23800170 TI - Parental education associations with children's body composition: mediation effects of energy balance-related behaviors within the ENERGY-project. AB - BACKGROUND: It is well known that the prevalence of overweight and obesity is considerably higher among youth from lower socio-economic families, but there is little information about the role of some energy balance-related behaviors in the association between socio-economic status and childhood overweight and obesity. The objective of this paper was to assess the possible mediation role of energy balance-related behaviors in the association between parental education and children's body composition. METHODS: Data were obtained from the cross sectional study of the "EuropeaN Energy balance Research to prevent excessive weight Gain among Youth" (ENERGY) project. 2121 boys and 2516 girls aged 10 to 12 from Belgium, Greece, Hungary, the Netherlands, Norway, Slovenia and Spain were included in the analyses. Data were obtained via questionnaires assessing obesity related dietary, physical activity and sedentary behaviors and basic anthropometric objectively measured indicators (weight, height, waist circumference). The possible mediating effect of sugared drinks intake, breakfast consumption, active transportation to school, sports participation, TV viewing, computer use and sleep duration in the association between parental education and children's body composition was explored via MacKinnon's product-of-coefficients test in single and multiple mediation models. Two different body composition indicators were included in the models, namely Body Mass Index and waist circumference. RESULTS: The association between parental education and children's body composition was partially mediated by breakfast consumption, sports participation, TV viewing and computer use. Additionally, a suppression effect was found for sugared drinks intake. No mediation effect was found for active transportation and sleep duration. The significant mediators explained a higher proportion of the association between parental education and waist circumference compared to the association between parental education and BMI. CONCLUSIONS: Tailored overweight and obesity prevention strategies in low SES preadolescent populations should incorporate specific messages focusing on the importance of encouraging daily breakfast consumption, increasing sports participation and decreasing TV viewing and computer use. However, longitudinal research to support these findings is needed. PMID- 23800172 TI - Frameless fractionated stereotactic radiation therapy of intracranial lesions: impact of cone beam CT based setup correction on dose distribution. AB - BACKGROUND: The purpose of this study was to evaluate the impact of Cone Beam CT (CBCT) based setup correction on total dose distributions in fractionated frameless stereotactic radiation therapy of intracranial lesions. METHODS: Ten patients with intracranial lesions treated with 30 Gy in 6 fractions were included in this study. Treatment planning was performed with Oncentra(r) for a SynergyS(r) (Elekta Ltd, Crawley, UK) linear accelerator with XVI(r) Cone Beam CT, and HexaPODTM couch top. Patients were immobilized by thermoplastic masks (BrainLab, Reuther). After initial patient setup with respect to lasers, a CBCT study was acquired and registered to the planning CT (PL-CT) study. Patient positioning was corrected according to the correction values (translational, rotational) calculated by the XVI(r) system. Afterwards a second CBCT study was acquired and registered to the PL-CT to confirm the accuracy of the corrections. An in-house developed software was used for rigid transformation of the PL-CT to the CBCT geometry, and dose calculations for each fraction were performed on the transformed CT. The total dose distribution was achieved by back-transformation and summation of the dose distributions of each fraction. Dose distributions based on PL-CT, CBCT (laser set-up), and final CBCT were compared to assess the influence of setup inaccuracies. RESULTS: The mean displacement vector, calculated over all treatments, was reduced from (4.3 +/- 1.3) mm for laser based setup to (0.5 +/- 0.2) mm if CBCT corrections were applied. The mean rotational errors around the medial-lateral, superior-inferior, anterior-posterior axis were reduced from (-0.1 +/- 1.4) degrees , (0.1 +/- 1.2) degrees and (-0.2 +/- 1.0) degrees , to (0.04 +/- 0.4) degrees , (0.01 +/- 0.4) degrees and (0.02 +/- 0.3) degrees . As a consequence the mean deviation between planned and delivered dose in the planning target volume (PTV) could be reduced from 12.3% to 0.4% for D95 and from 5.9% to 0.1% for D(av). Maximum deviation was reduced from 31.8% to 0.8% for D95, and from 20.4% to 0.1% for D(av). CONCLUSION: Real dose distributions differ substantially from planned dose distributions, if setup is performed according to lasers only. Thermoplasic masks combined with a daily CBCT enabled a sufficient accuracy in dose distribution. PMID- 23800173 TI - DNA damage strength modulates a bimodal switch of p53 dynamics for cell-fate control. AB - BACKGROUND: The p53 pathway is differentially activated in response to distinct DNA damage, leading to alternative phenotypic outcomes in mammalian cells. Recent evidence suggests that p53 expression dynamics play an important role in the differential regulation of cell fate, but questions remain as to how p53 dynamics and the subsequent cellular response are modulated by variable DNA damage. RESULTS: We identified a novel, bimodal switch of p53 dynamics modulated by DNA damage strength that is crucial for cell-fate control. After low DNA damage, p53 underwent periodic pulsing and cells entered cell-cycle arrest. After high DNA damage, p53 underwent a strong monotonic increase and cells activated apoptosis. We found that the damage dose-dependent bimodal switch was due to differential Mdm2 upregulation, which controlled the alternative cell fates mainly by modulating the induction level and pro-apoptotic activities of p53. CONCLUSIONS: Our findings not only uncover a new mode of regulation for p53 dynamics and cell fate, but also suggest that p53 oscillation may function as a suppressor, maintaining a low level of p53 induction and pro-apoptotic activities so as to render cell-cycle arrest that allows damage repair. PMID- 23800174 TI - Gold nanoparticles - the theranostic challenge for PPPM: nanocardiology application. AB - The article overviews the potential biomedical applications of nanoscale gold particles for predictive, preventive and personalised nanomedicine in cardiology. The review demonstrates the wide opportunities for gold nanoparticles due to their unique biological properties. The use of gold nanoparticles in cardiology is promising to develop fundamentally new methods of diagnosis and treatment. The nanotheranostics in cardiovascular diseases allows the non-invasive imaging associated with simultaneous therapeutic intervention and predicting treatment outcomes. Imaging may reflect the effectiveness of treatment and has become a fundamental optimisation setting for therapeutic protocol. Combining the application of biomolecular and cellular therapies with nanotechnologies foresees the development of complex integrated nanodevices. Nanocardiology may challenge existing healthcare system and economic benefits as cardiovascular diseases are the leading cause of morbidity and mortality at present. PMID- 23800175 TI - How effective are traditional methods of compositional analysis in providing an accurate material balance for a range of softwood derived residues? AB - BACKGROUND: Forest residues represent an abundant and sustainable source of biomass which could be used as a biorefinery feedstock. Due to the heterogeneity of forest residues, such as hog fuel and bark, one of the expected challenges is to obtain an accurate material balance of these feedstocks. Current compositional analytical methods have been standardised for more homogenous feedstocks such as white wood and agricultural residues. The described work assessed the accuracy of existing and modified methods on a variety of forest residues both before and after a typical pretreatment process. RESULTS: When "traditional" pulp and paper methods were used, the total amount of material that could be quantified in each of the six softwood-derived residues ranged from 88% to 96%. It was apparent that the extractives present in the substrate were most influential in limiting the accuracy of a more representative material balance. This was particularly evident when trying to determine the lignin content, due to the incomplete removal of the extractives, even after a two stage water-ethanol extraction. Residual extractives likely precipitated with the acid insoluble lignin during analysis, contributing to an overestimation of the lignin content. Despite the minor dissolution of hemicellulosic sugars, extraction with mild alkali removed most of the extractives from the bark and improved the raw material mass closure to 95% in comparison to the 88% value obtained after water-ethanol extraction. After pretreatment, the extent of extractive removal and their reaction/precipitation with lignin was heavily dependent on the pretreatment conditions used. The selective removal of extractives and their quantification after a pretreatment proved to be even more challenging. Regardless of the amount of extractives that were originally present, the analytical methods could be refined to provide reproducible quantification of the carbohydrates present in both the starting material and after pretreatment. CONCLUSION: Despite the challenges resulting from the heterogeneity of the initial biomass substrates a reasonable summative mass closure could be obtained before and after steam pretreatment. However, method revision and optimisation was required, particularly the effective removal of extractives, to ensure that representative and reproducible values for the major lignin and carbohydrate components. PMID- 23800176 TI - MD-2 is involved in the stimulation of matrix metalloproteinase-1 expression by interferon-gamma and high glucose in mononuclear cells - a potential role of MD-2 in Toll-like receptor 4-independent signalling. AB - We reported recently that treatment of diabetic apolipoprotein E-deficient mice with the Toll-like receptor 4 (TLR4) antagonist Rs-LPS, a lipopolysaccharide isolated from Rhodobacter sphaeroides, inhibited atherosclerosis. Since it is known that Rs-LPS antagonizes TLR4 by targeting TLR4 co-receptor MD-2, this finding indicates that MD-2 is a potential target for the treatment of atherosclerosis. In this study, we determined if MD-2 is involved in the gene expression regulated by signalling pathways independent of TLR4. Given that interferon-gamma (IFNgamma) and hyperglycaemia play key roles in atherosclerosis, we determined if MD-2 is involved in IFN-gamma and high-glucose-regulated gene expression in mononuclear cells. Results showed that IFN-gamma and high glucose synergistically stimulated matrix metalloproteinase 1 (MMP-1), a proteinase essential for vascular tissue remodelling and atherosclerosis, in U937 mononuclear cells, but Rs-LPS inhibited the MMP-1 stimulation. To provide more evidence for a role of MD-2 in IFN-gamma-stimulated MMP-1, studies using antibodies and small interfering RNA demonstrated that MD-2 blockade or knockdown attenuated the effect of IFN-gamma on MMP-1. Furthermore, studies using PCR arrays showed that MD-2 blockade had a similar effect as IFN-gamma receptor blockade on the inhibition of IFN-gamma-stimulated pro-inflammatory molecules. Although these findings indicate the involvement of MD-2 in IFN-gamma signalling, we also observed that MD-2 was up-regulated by IFN-gamma and high glucose. We found that MD-2 up-regulation by IFN-gamma played an essential role in the synergistic effect of IFN-gamma and LPS on MMP-1 expression. Taken together, these findings indicate that MD-2 is involved in IFN-gamma signalling and IFN gamma-augmented MMP-1 up-regulation by LPS. PMID- 23800177 TI - Recruiting equal numbers of indigenous and non-indigenous participants to a 'polypill' randomized trial. AB - INTRODUCTION: Maori are disproportionately affected by cardiovascular disease (CVD), which is the main reason for the eight year difference in life expectancy between Maori and non-Maori. The primary care-based IMPACT (IMProving Adherence using Combination Therapy) trial evaluates whether fixed dose combination therapy (a "polypill") improves adherence to guideline-based therapy compared with current care among people at high risk of CVD. Interventions shown in trials to be effective do not necessarily reduce ethnic disparities, and may in fact widen them. Indigenous populations with poorer health outcomes are often under represented in trials so the effect of interventions cannot be assessed for them, specifically. Therefore, the IMPACT trial aimed to recruit as many Maori as non Maori to assess the consistency of the effect of the polypill. This paper describes the methods and results of the recruitment strategy used to achieve this. METHODS: Experienced Maori researchers were involved in trial governance throughout trial development and conduct. The trial Steering Committee included leading Maori researchers and was committed to equal recruitment of Maori and non Maori. Additional funding and Maori research nurses were sought to allow home based assessment, establishment of the relationship between research nurse and participant, more family involvement prior to enrollment, continuity of the research nurse-participant relationship, and acknowledgement of other Maori culturally important procedures, interactions, language and manners. Primary care practices with high enrollment of Maori were targeted, with over-sampling of potentially eligible Maori patients, lower thresholds for screening of Maori and 6 months continued Maori recruitment after non-Maori recruitment had finished. RESULTS: A total of 257 Maori and 256 non-Maori participants were randomized. Four Maori and eight non-Maori participants were randomized per research nurse per month. Potentially eligible Maori were more likely than non-Maori to proceed to subsequent stages of recruitment. Differences between randomized Maori and non Maori were evident (e.g. Maori were less likely to have established coronary artery disease). CONCLUSIONS: Recruitment of equal numbers of indigenous and non indigenous participants is possible if it is prioritised, adequately resourced and self-determination is supported. TRIAL REGISTRATION: The trial is registered with the Australian New Zealand Clinical Trial Registry ACTRN12606000067572. PMID- 23800178 TI - The utility of single-balloon enteroscopy for the diagnosis and management of small bowel disorders according to their clinical manifestations: a retrospective review. AB - BACKGROUND: The advent of double-balloon enteroscopy has enabled more accurate diagnosis and treatment of small bowel disorders. Single-balloon enteroscopy permits visualization of the entire small intestine less often than does double balloon enteroscopy. However, the relative clinical advantages of the 2 methods remain controversial. This study therefore aimed to identify the indications for and therapeutic impact of performing single-balloon enteroscopy. METHODS: We retrospectively reviewed prospectively collected data from adults who underwent single-balloon enteroscopy from January 2007 through November 2011 and analyzed their baseline characteristics, endoscopic findings, pathological diagnoses, and clinical outcomes. RESULTS: A total of 145 procedures were performed in 116 patients with a mean age of 58.1 +/- 17.7 years (range, 18-89 years). The most common indications for performing single-balloon enteroscopy were overt gastrointestinal (GI) bleeding, chronic diarrhea, and occult GI bleeding, accounting for 57.9%, 12.4%, and 9.7% of the patients, respectively. The area of interest was achieved in 80.7% of the cases, with a 5.5% rate of technical failure. An overall positive finding was detected in 65.5% of the cases, of which 33.8% were ulcers and erosions; 8.3%, masses; and 3.4%, angiodysplasia. The diagnostic yields were 42.9%, 52.4%, 78.6%, 50.0%, and 25.0% for patients with overt GI bleeding, occult GI bleeding, abdominal pain, chronic diarrhea, and abnormal imaging results, respectively. Therapeutic procedures were performed in 11% of patients with GI bleeding and achieved a therapeutic yield of 14.6% with a minor complication rate of 11.7%. CONCLUSIONS: Single-balloon enteroscopy was effective for the diagnosis and treatment of small bowel disorders, especially in patients who presented with abdominal pain, GI bleeding, or focal abnormalities on imaging scans. PMID- 23800179 TI - Assessment of primary health care received by the elderly and health related quality of life: a cross-sectional study. AB - BACKGROUND: Population aging leads to increased burden of chronic diseases and demand in public health. This study aimed to assess whether the score of Primary Health Care (PHC) is associated with a) the model of care - Family Health Strategy (FHS) vs. traditional care model (the Basic Health Units; BHU); b) morbid conditions such as - hypertension, diabetes mellitus, mental disorders, chronic pain, obesity and central obesity; c) quality of life in elderly individuals who received care in those units. METHODS: A survey was conducted among the elderly between August 2010 and August 2011, in Ilheus, Bahia. We interviewed elderly patients - 60 years or older - who consulted at BHU or FHS units in that day or participated in a group activity, and those who were visited at home by the staff of PHC, selected through a random sample. Demographic and socioeconomic characteristics, services' attainment of primary care attributes, health problems and quality of life were investigated. The Short Form Health Survey (SF-12) was used to assess quality of life and PCATool to generate PHC scores. In addition, weight, height and waist circumference were measured. Trained research assistants, under supervision performed the data collection. RESULTS: A total of 511 elderly individuals were identified, two declined to participate, resulting in 509 individuals interviewed. The health care provided by the FHS has higher attainment of PHC attributes, in comparison to the BHU, resulting in lower prevalence of score below six. Except for hypertension and cardiovascular disease, other chronic problems were not independently associated with low scores in PHC. It was observed an independent and positive association between PHC score and the mental component of quality of life and an inverse association with the physical component. CONCLUSIONS: This study showed higher PHC attributes attainment in units with FHS, regardless of the health problem. The degree of orientation to PHC increased the mental component score of quality of life. PMID- 23800180 TI - N-terminal pro-brain natriuretic peptide level determined at different times identifies transient ischaemic attack patients with atrial fibrillation. AB - BACKGROUND AND PURPOSE: The etiological classification of patients with transient ischaemic attack (TIA) is a difficult endeavor and the use of serum biomarkers could improve the diagnostic accuracy. The aim of this study was to correlate atrial fibrillation, the main cardioembolic etiology (CE), with different serum biomarkers measured in consecutive TIA patients. METHODS: The concentrations of interleukin-6 (IL-6), tumor necrosis factor-alpha, neuron-specific enolase, high sensitivity C-reactive protein, IL-1-alpha and the N-terminal pro-B type natriuretic peptide (NT-proBNP) were quantified in the serum of 140 patients with TIA and 44 non-stroke subjects. Measurements were performed at different times throughout evolution: within 24 h of symptoms onset and at days 7 and 90. RESULTS: With the exception of IL-6, all biomarkers were higher in TIA patients than in controls. NT-proBNP was significantly related to the presence or new diagnosis of AF at all time points analyzed. Furthermore, the baseline NT-proBNP level was significantly higher than values at the 7-day and 90-day follow-up. For this reason, different cut-off values were obtained at different times: 313 pg/ml at baseline [odds ratio (OR) = 18.99, P < 0.001], 181 pg/ml at 7 days (OR = 11.4, P = 0.001) and 174 pg/ml (OR = 8.46, P < 0.001) at 90 days. CONCLUSION: High levels of NT-proBNP determined during the first 3 months after a TIA were associated with AF. Consequently, this biomarker may be useful to reclassify undetermined TIA patients as having disease of CE. PMID- 23800181 TI - Ethnobotany of Heracleum persicum Desf. ex Fisch., an invasive species in Norway, or how plant names, uses, and other traditions evolve. AB - BACKGROUND: Heracleum persicum was introduced to Norway as an ornamental in the 1830's. Towards the end of the 19th century, it started spreading outside gardens, later to become a frequent sight in the major towns and settlements of North Norway - and a veritable pest plant. During the last 100 years or so, a substantial ethnobotanical tradition related to the species has evolved, demonstrating that folk knowledge is not only forgotten and lost, but also charting new terrain. METHODS: This survey is based on data extracted from all relevant publications, including botanical literature, travel accounts, newspaper notes, etc., as far as they have come to my attention. In addition, information on vernacular names and various uses of the H. persicum in Norway has been extracted from my own, substantial archive of interviews, questionnaires, and correspondence related to the ethnobotany of Norway. RESULTS: Where extant, H. persicum tends to be known to everyone, even by city dwellers who otherwise generally neglect plants. People tend to love or hate it, and in Tromso, the largest town of northern Norway, the species has become more or less emblematic of the city. Both here and in other areas of northern Norway, it is referred to by a variety of vernacular names, partly borrowed from other species, partly derived from the Latin genus name, and partly coined for this species only. In the latter group, tromsopalme ('the palm of Tromso') has proved by far the most popular invention. It was seemingly first used (and coined) by German soldiers during the World War II occupation of Norway, but now largely replaces other vernacular names. The plant is still popular with children, who frequently play in and with it, whereas adults have been more prone to speculate on its origins - and how to get rid of it. Salt is the most popular "herbicide" for this purpose. CONCLUSIONS: Over the years, H. persicum has accumulated at least twenty different vernacular names in Norway, and a variety of other traditions. By necessity, all these traditions are less than 180 years old, showing that even modern and urban societies may produce a substantial body of plant lore, which certainly merits ethnobotanical attention. PMID- 23800182 TI - Effect of probiotic bacteria on the intestinal microbiota in irritable bowel syndrome. AB - BACKGROUND AND AIM: In irritable bowel syndrome (IBS), the gut microbiota may be altered. Probiotic bacteria appear to be therapeutically effective. We characterized the mucosa-associated microbiota, and determined the clinical and microbiological effects of orally administered probiotic bacteria, in patients with IBS. METHODS: Mucosal microbiota from rectal biopsies of IBS patients and controls were assessed on the V1 and V2 variable regions of the 16S ribosomal RNA gene amplified using 454 pyrosequencing. Clinical symptoms and changes in mucosal microbiota were assessed in IBS patients before and after 4 weeks of treatment with probiotic mix VSL#3. RESULTS: Ten IBS subjects (eight female; mean age 46 years) were included. At week 4 of probiotic therapy, six patients showed symptom improvement on global symptom assessment compared with baseline (P = 0.031). Before therapy, intestinal microbiota of IBS subjects differed significantly from that of healthy controls, with less diversity and evenness than controls (n = 9; P < 0.05), increased abundance of Bacteroidetes (P = 0.014) and Synegitestes (P = 0.017), and reduced abundance of Actinobacteria (P = 0.004). The classes Flavobacteria (P = 0.028) and Epsilonproteobacteria (P = 0.017) were less enriched in IBS. Abundance differences were largely consistent from the phylum to genus level. Probiotic treatment in IBS patients was associated with a significant reduction of the genus Bacteroides (all taxonomy levels; P < 0.05) to levels similar to that of controls. CONCLUSION: In this pilot study, global and deep molecular analysis demonstrates an altered mucosal microbiota composition in IBS. Probiotic leads to detectable changes in the microbiota. These effects of probiotic bacteria may contribute to their therapeutic benefit. PMID- 23800183 TI - Predictive research methods of enamel and dentine for initial caries detection. AB - Currently, various research methods of enamel and dentine for precautionary diagnostics of initial caries forms are developed; however, the vast majority of these do not provide objective criteria of caries diagnostics or are very difficult to perform. Therefore, the search of diagnostics and enamel research methods, which will allow predicting caries emergence and to carry out personalised prevention of this pathology, is necessary. In this review, modern diagnostic methods that allow understanding the main aspects of caries process, assess the risk of its development, and also suggest the possibility of emergency prevention of caries progression in the nearest future are presented. PMID- 23800184 TI - Uncontrolled variability in the extinction spectra of C60 nanoparticle suspensions. AB - To properly investigate the environmental transport, fate, and impact of fullerene C60 nanoparticles (nC60), it is necessary to reproducibly obtain nC60 suspensions and to accurately determine their concentration ([C60]). The results in the present study, however, clearly illustrate that the production of nC60 via extended mixing and via sonication are highly stochastic top-down processes subject to widely divergent end points. nC60 suspensions exhibit variable characteristics (e.g., [C60], average particle size, size distribution, etc.) that make it challenging, if not impossible, to acquire reproducible UV-vis extinction spectra. The mass extinction coefficient, which is the absorptivity of a suspension with [C60] = 1 mM obtained by normalizing UV-vis spectra by the mass concentration of C60 in the suspension, decreases with a given suspension's hydrodynamic diameter, whereas the particle extinction coefficient, which is the absorptivity of a suspension containing one mole of nC60 nanoparticles with the same size distribution as the target suspension and calculated based upon the suspension nanoparticle size distribution, increases with its number weighted average diameter. Other spectroscopic properties of nC60 (e.g., absorbance bandwidth, position of absorption maximum, and relative extinction intensity) also change with average particle size. As a result of the extant variability between samples, when UV-vis spectra are employed to calculate or represent [C60] for fullerene nanoparticle suspensions, extreme care must be taken and other colloidal properties of this suspension must be measured to obtain an accurate result. PMID- 23800185 TI - An objective assessment of melanin in vitiligo skin treated with Balneo PUVA therapy. AB - BACKGROUND: Visual clinical methods of skin color evaluation for diagnostic purposes are so far mostly subjective and thus inaccurate. We present a modified method of melanin amount measurement based on diffuse reflectance spectroscopy (DRS). This method is non-invasive and objective, and allows easy quantification and comparison of melanin levels. MATERIAL AND METHODS: Skin pigmentation was measured by DRS method in 0-18 year old patients at the Department of Pediatric Dermatovenerology, School of Medicine Comenius University Bratislava. Patients were treated for their vitiligo by Balneo PUVA treatment twice weekly. Each patient had measured his remittance spectra from the treated vitiliginous skin before the treatment was started, after 10 irradiations of Balneo PUVA and at the end of the treatment after 25 irradiations of Balneo PUVA. In our study as a reference skin for spectroscopic assessment of melanin in vivo was used the averaged remittance spectra (measured on the inner arm) from the sample of 10 albino patients. The remittance spectra obtained from the vitiligo patients were ratioed against the newly described remittance reference albino skin. We exploited the linear behavior of the spectral curve in the 620-720 nm interval (significant for melanin absorption) and used the slope of the regression line to compute the quantification index alpha. RESULTS: By clinical examination before the Balneo PUVA therapy, after the 10th dose of Balneo PUVA therapy as well as at the end of the complete course of Balneo PUVA therapy (after 25 irradiations) we recorded a marked increase of pigmentation in all treated patients for their vitiligo. In each patient the values of melanin quantification angle alpha were calculated. Statistically we found a significant difference between the melanin quantification angle alpha in vitiliginous skin before, during the 10th dose of treatment and after the treatment. Similar significant difference was also observed between treated and non-involved skin. We could confirm a clear association between clinical visual examination of treated vitiligo lesions, objective data collected by DRS and melanin quantification angle alpha. CONCLUSIONS: By using a new standard for the reference skin (albino skin) we could more exactly compare melanin levels in different subjects. Our proposed melanin quantification angle alpha expresses the extent of the difference in melanin levels between the examined skin lesions. We successfully used this index to quantify the variations of melanin (progress of repigmentation) throughout different stages of treatment of the same lesion and also to objectively evaluate the final effect of the therapy. In the present study, we showed that the diffuse reflectance spectroscopy (DRS) may be suitable method to measure skin colour and the content of human skin melanin in vivo. PMID- 23800186 TI - Cinema in the training of psychiatry residents: focus on helping relationships. AB - BACKGROUND: Medical schools are currently charged with a lack of education as far as empathic/relational skills and the meaning of being a health-care provider are concerned, thus leading to increased interest in medical humanities. DISCUSSION: Medical humanities can offer an insight into human illness and in a broader outlook into human condition, understanding of one self, responsibility. An empathic relation to patients might be fostered by a matching approach to humanities and sciences, which should be considered as subjects of equal relevance, complementary to one another. Recently, movies have been used in medical--psychiatric--trainees education, but mainly within the limits of teaching a variety of disorders. A different approach dealing with the use of cinema in the training of psychiatry residents is proposed, based on Jung and Hillman's considerations about the relation between images and archetypes, archetypal experience and learning. SUMMARY: Selected full-length movies or clips can offer a priceless opportunity to face with the meaning of being involved in a care-providing, helping profession. PMID- 23800188 TI - An empirical assessment of tree branching networks and implications for plant allometric scaling models. AB - Several theories predict whole-tree function on the basis of allometric scaling relationships assumed to emerge from traits of branching networks. To test this key assumption, and more generally, to explore patterns of external architecture within and across trees, we measure branch traits (radii/lengths) and calculate scaling exponents from five functionally divergent species. Consistent with leading theories, including metabolic scaling theory, branching is area preserving and statistically self-similar within trees. However, differences among scaling exponents calculated at node- and whole-tree levels challenge the assumption of an optimised, symmetrically branching tree. Furthermore, scaling exponents estimated for branch length change across branching orders, and exponents for scaling metabolic rate with plant size (or number of terminal tips) significantly differ from theoretical predictions. These findings, along with variability in the scaling of branch radii being less than for branch lengths, suggest extending current scaling theories to include asymmetrical branching and differential selective pressures in plant architectures. PMID- 23800187 TI - Role of SIRT3 in the regulation of redox balance during oral carcinogenesis. AB - BACKGROUND: Sirtuins (SIRT1-7) are a family of NAD-dependent deacetylases, which play an important role in regulating cancer tumorigenesis; however, their role in oral cancer has been controversial. SIRT3 is localized in the mitochondria, where it deacetylates and activates several enzymes involved in cellular redox balance and defense against oxidative damage. RESULTS: We found that compared with normal human oral keratinocytes (HOK), SIRT3 is highly expressed in oral squamous cell carcinoma (OSCC) cell lines, but the enzymatic deacetylation is significantly reduced. We also sequenced the entire coding region of SIRT3 and found the same mutation in 2 different OSCC cell lines. This point mutation is located in close proximity to the active site of deacetylase in the SIRT3 protein, and reduces the overall enzymatic efficiency of deacetylation. Furthermore, up-regulation of SIRT3 inhibited the cell growth of OSCCs and decreased the levels of basal reactive oxygen species (ROS) in both OSCC lines. To verify that the SIRT3 sequence variation was associated with oral carcinogenesis, we sequenced the SIRT3 gene from 21 OSCC patients, and 5 of the 21 patients (23.8%) carried the heterozygous missense mutation, p.Val208Ile. The heterozygous missense mutation in these patients was present in gremlin DNA isolated from both normal and tumor tissues. CONCLUSIONS: Our findings provide a valuable insight into the potential role of SIRT3 in the development of oral squamous cell carcinoma, by showing that a non-synonymous point mutation in SIRT3 contributes to reduced catalytic activity of the protein and affects redox balance in OSCCs. PMID- 23800189 TI - Sodium iodide symporter in the fight against thyroid cancer. PMID- 23800190 TI - Video Q&A: molecular profiling of breast cancer. AB - In this video Q&A, we talk to Professor Carlos Caldas about the identification of breast cancer subtypes through molecular profiling, and the clinical implications for diagnosis and treatment. PMID- 23800191 TI - Delayed cardiac tamponade after open heart surgery - is supplemental CT imaging reasonable? AB - BACKGROUND: Cardiac tamponade is a severe complication after open heart surgery. Diagnostic imaging is challenging in postoperative patients, especially if tamponade develops with subacute symptoms. Hypothesizing that delayed tamponade after open heart surgery is not sufficiently detected by transthoracic echocardiography, in this study CT scans were used as standard reference and were compared with transthoracic echocardiography imaging in patients with suspected cardiac tamponade. METHOD: Twenty-five patients after open heart surgery were enrolled in this analysis. In case of suspected cardiac tamponade patients underwent both echocardiography and CT imaging. Using CT as standard of reference sensitivity, specificity, positive and negative predictive values of ultrasound imaging in detecting pericardial effusion/hematoma were analyzed. Clinical appearance of tamponade, need for re-intervention as well as patient outcome were monitored. RESULTS: In 12 cases (44%) tamponade necessitated surgical re intervention. Most common symptoms were deterioration of hemodynamic status and dyspnea. Sensitivity, specificity, positive and negative predictive values of echocardiography were 75%, 64%, 75%, and 64% for detecting pericardial effusion, and 33%, 83%, 50, and 71% for pericardial hematoma, respectively. In-hospital mortality of the re-intervention group was 50%. CONCLUSION: Diagnostic accuracy of transthoracic echocardiography is limited in patients after open heart surgery. Suplemental CT imaging provides rapid diagnostic reliability in patients with delayed cardiac tamponade. PMID- 23800192 TI - Functional characterisation of the non-essential protein kinases and phosphatases regulating Aspergillus nidulans hydrolytic enzyme production. AB - BACKGROUND: Despite recent advances in the understanding of lignocellulolytic enzyme regulation, less is known about how different carbon sources are sensed and the signaling cascades that result in the adaptation of cellular metabolism and hydrolase secretion. Therefore, the role played by non-essential protein kinases (NPK) and phosphatases (NPP) in the sensing of carbon and/or energetic status was investigated in the model filamentous fungus Aspergillus nidulans. RESULTS: Eleven NPKs and seven NPPs were identified as being involved in cellulase, and in some cases also hemicellulase, production in A. nidulans. The regulation of CreA-mediated carbon catabolite repression (CCR) in the parental strain was determined by fluorescence microscopy, utilising a CreA::GFP fusion protein. The sensing of phosphorylated glucose, via the RAS signalling pathway induced CreA repression, while carbon starvation resulted in derepression. Growth on cellulose represented carbon starvation and derepressing conditions. The involvement of the identified NPKs in the regulation of cellulose-induced responses and CreA derepression was assessed by genome-wide transcriptomics (GEO accession 47810). CreA::GFP localisation and the restoration of endocellulase activity via the introduction of the ?creA mutation, was assessed in the NPK deficient backgrounds. The absence of either the schA or snfA kinase dramatically reduced cellulose-induced transcriptional responses, including the expression of hydrolytic enzymes and transporters. The mechanism by which these two NPKs controlled gene transcription was identified, as the NPK-deficient mutants were not able to unlock CreA-mediated carbon catabolite repression under derepressing conditions, such as carbon starvation or growth on cellulose. CONCLUSIONS: Collectively, this study identified multiple kinases and phosphatases involved in the sensing of carbon and/or energetic status, while demonstrating the overlapping, synergistic roles of schA and snfA in the regulation of CreA derepression and hydrolytic enzyme production in A. nidulans. The importance of a carbon starvation-induced signal for CreA derepression, permitting transcriptional activator binding, appeared paramount for hydrolase secretion. PMID- 23800193 TI - A bacterial tyrosine aminomutase proceeds through retention or inversion of stereochemistry to catalyze its isomerization reaction. AB - beta-Amino acids are biologically active compounds of interest in medicinal chemistry. A class I lyase-like family of aminomutases isomerizes (S)-alpha arylalanines to the corresponding beta-amino acids by exchange of the NH2/H pair. This family uses a 3,5-dihydro-5-methylidene-4H-imidazol-4-one (MIO) group within the active site to initiate the reaction. The absolute stereochemistry of the product is known for an MIO-dependent tyrosine aminomutase from Chondromyces crocatus (CcTAM) that isomerizes (S)-alpha-tyrosine to (R)-beta-tyrosine. To evaluate the cryptic stereochemistry of the CcTAM mechanism, (2S,3S)-[2,3-(2)H2]- and (2S,3R)-[3-(2)H]-alpha-tyrosine were stereoselectively synthesized from unlabeled (or [(2)H]-labeled) (4'-hydroxyphenyl)acrylic acids by reduction with D2 (or H2) gas and a chiral Rh-Prophos catalyst. GC/EIMS analysis of the [(2)H] beta-tyrosine biosynthesized by CcTAM revealed that the alpha-amino group was transferred to Cbeta of the phenylpropanoid skeleton with retention of configuration. These labeled substrates also showed that the pro-(3S) proton exchanges with protons from the bulk media during its migration to Calpha during catalysis. (1)H- and (2)H NMR analyses of the [(2)H]-beta-tyrosine derived from (2S)-[3,3-(2)H2]-alpha-tyrosine by CcTAM catalysis showed that the migratory proton attached to Calpha of the product also with retention of configuration. CcTAM is stereoselective for (R)-beta-tyrosine (85%) yet also forms the (S)-beta tyrosine enantiomer (15%) through inversion of configuration at both migration termini, as described herein. The proportion of the (S)-beta-isomer made by CcTAM during steady state interestingly increased with solvent pH, and this effect on the proposed reaction mechanism is also discussed. PMID- 23800194 TI - Improved accessibility of emergency obstetrics and newborn care (EmONC) services for maternal and newborn health: a community based project. AB - BACKGROUND: Every year an estimated three million neonates die globally and two hundred thousand of these deaths occur in Pakistan. Majority of these neonates die in rural areas of underdeveloped countries from preventable causes (infections, complications related to low birth weight and prematurity). Similarly about three hundred thousand mother died in 2010 and Pakistan is among ten countries where sixty percent burden of these deaths is concentrated. Maternal and neonatal mortality remain to be unacceptably high in Pakistan especially in rural areas where more than half of births occur. METHOD/DESIGN: This community based cluster randomized controlled trial will evaluate the impact of an Emergency Obstetric and Newborn Care (EmONC) package in the intervention arm compared to standard of care in control arm. Perinatal and neonatal mortality are primary outcome measure for this trial. The trial will be implemented in 20 clusters (Union councils) of District Rahimyar Khan, Pakistan. The EmONC package consists of provision of maternal and neonatal health pack (clean delivery kit, emollient, chlorhexidine) for safe motherhood and newborn wellbeing and training of community level and facility based health care providers with emphasis on referral of complicated cases to nearest public health facilities and community mobilization. DISCUSSION: Even though there is substantial evidence in support of effectiveness of various health interventions for improving maternal, neonatal and child health. Reduction in perinatal and neonatal mortality remains a big challenge in resource constrained and diverse countries like Pakistan and achieving MDG 4 and 5 appears to be a distant reality. A comprehensive package of community based low cost interventions along the continuum of care tailored according to the socio cultural environment coupled with existing health force capacity building may result in improving the maternal and neonatal outcomes. The findings of this proposed community based trial will provide sufficient evidence on feasibility, acceptability and effectiveness to the policy makers for replicating and scaling up the interventions within the health system. PMID- 23800195 TI - What are the key endodontic factors associated with oral health-related quality of life? AB - AIM: To determine the associations between endodontic factors and oral health related quality of life (OHQoL), controlling for socio-demographics, pain and other oral health clinical factors. METHODOLOGY: OHQoL assessments were conducted amongst a consecutive sample of 412 Chinese patients requiring endodontic treatment employing the short-form Oral Heath Impact Profile (OHIP-14). Information on (i) number of teeth requiring endodontic treatment, (ii) tooth type, (iii) retreatment requirements, (iv) periapical radiolucency assessment and (v) diagnostic classification was obtained. In addition, socio-demographic information (age, gender, educational attainment and family income), pain ratings on a visual analogue scale (VAS) and other clinical oral health status information were collected. RESULTS: Bivariate analyses identified association between number of teeth requiring endodontic treatment and summary OHIP-14 score (P < 0.01) and four of its seven domain scores (P < 0.05). Need for endodontic retreatment was associated with summary OHIP-14 score (P < 0.05) and two of its seven domain scores (P < 0.05). In regression analyses having controlled for socio-demographics, other clinical factors and pain rating amongst 15 confounding variables, patients requiring endodontic treatment for multiple teeth were more than twice as likely to have poor OHQoL (upper quintile OHIP-14 scores) compared with those requiring endodontic treatment for a single tooth (OR = 2.16, 95% CI 1.17, 3.98, P < 0.05). Pain VAS rating and age also emerged as significant factors associated with poor OHQoL in the regression analysis. CONCLUSION: OHQoL is compromised amongst patients requiring endodontic treatment. Number of teeth requiring endodontic treatment is associated with poor OHQoL, controlling for socio-demographic and other oral health clinical and pain factors. PMID- 23800196 TI - Cost-effectiveness of personalized plaque control for managing the gingival manifestations of oral lichen planus: a randomized controlled study. AB - AIM: To undertake cost-effectiveness and cost-benefit analyses of an intervention to improve oral health in patients presenting with the gingival manifestations of oral lichen planus (OLP). MATERIALS & METHODS: Eighty-two patients were recruited to a 20-week randomized controlled trial. The intervention was personalized plaque control comprising powered tooth brushing and inter-dental cleaning advice. The primary outcome measure was the oral health impact profile (OHIP) with secondary outcomes of pain, plaque index, mucosal disease score and cost effectiveness. Private cost data and stated willingness-to-pay (WTP) values for treatment were obtained from intervention patients at 20 weeks. RESULTS: Overall, 81% of intervention patients showed improvement in both plaque index and mucosal disease score at 20 weeks compared to 30% of controls that continued with their usual plaque control regimen. All intervention group patients stated a positive WTP value. The mean net value of the treatment was L172 compared to the incremental cost of the treatment estimated at L122.75. The cost-effectiveness analysis resulted in an incremental cost-effectiveness ratio of L13 per OHIP point. CONCLUSIONS: The tailored plaque control programme was more effective than control in treating the gingival manifestations of oral lichen planus. The programme is cost effective for modest values placed on a point on the OHIP scale and patients generally valued the treatment in excess of the cost. PMID- 23800197 TI - Chromosomal integration of the novel plasmid pUR3912 from methicillin-susceptible Staphylococcus aureus ST398 of human origin. AB - The novel erm(T)-cadDX-carrying plasmid pUR3912 has recently been described in the methicillin-susceptible Staphylococcus aureus ST398-t571 strain C3912 from a healthy human in Spain. Structural analysis revealed that pUR3912 belongs to the pC194 replicon family, replicates via a rolling circle mechanism and harbours putative double-strand (dso) and single-strand (sso) origins of replication. Besides its plasmid location, a copy of pUR3912 was also found in the chromosomal DNA of strain C3912. Two IS431 copies, which flank the plasmid, most probably mediated its chromosomal integration. Its ability to not only exist extrachromosomally, but also to integrate into the chromosomal DNA ensures persistence and dissemination of pUR3912. PMID- 23800199 TI - Does body shaping influence brain shape? Habitual physical activity is linked to brain morphology independent of age. AB - OBJECTIVES: Physical activity (PA) was found to influence human brain morphology. However, the impact of PA on brain morphology was mainly demonstrated in seniors. We investigated healthy individuals across a broad age range for the relation between habitual PA and brain morphology. METHODS: Ninety-five participants (19 82 years) were assessed for self-reported habitual PA with the "Baecke habitual physical activity questionnaire", and T1-weighted magnetic resonance images were evaluated with whole brain voxel based morphometry for gray and white matter volumes and densities. RESULTS: Regression analyses revealed a positive relation between the extent of physical activity and gray matter volume bilaterally in the anterior hippocampal and parahippocampal gyrus independent of age and gender. Age as well as leisure and locomotion activities were linked to enhanced white matter volumes in the posterior cingulate gyrus and precuneus, suggesting a positive interaction especially in seniors. CONCLUSIONS: Habitual physical activity is associated with regional volumetric gray and white matter alterations. The positive relation of hippocampal volume and physical activity seems not to be restricted to seniors. Thus, habitual physical activity should be generally considered as an influencing factor in studies investigating medial temporal lobe volume and associated cognitive functions (memory), especially in psychiatric research. PMID- 23800198 TI - Intracellular fate of carbon nanotubes inside murine macrophages: pH-dependent detachment of iron catalyst nanoparticles. AB - BACKGROUND: Carbon nanotubes (CNT) are a family of materials featuring a large range of length, diameter, numbers of walls and, quite often metallic impurities coming from the catalyst used for their synthesis. They exhibit unique physical properties, which have already led to an extensive development of CNT for numerous applications. Because of this development and the resulting potential increase of human exposure, an important body of literature has been published with the aim to evaluate the health impact of CNT. However, despite evidences of uptake and long-term persistence of CNT within macrophages and the central role of those cells in the CNT-induced pulmonary inflammatory response, a limited amount of data is available so far on the CNT fate inside macrophages. Therefore, the overall aim of our study was to investigate the fate of pristine single walled CNT (SWCNT) after their internalization by macrophages. METHODS: To achieve our aim, we used a broad range of techniques that aimed at getting a comprehensive characterization of the SWCNT and their catalyst residues before and after exposure of murine macrophages: X-ray diffraction (XRD), High Resolution (HR) Transmission Electron Microscopy (TEM), High Angle Annular Dark Field-Scanning TEM (HAADF-STEM) coupled to Electron Energy Loss Spectroscopy (EELS), as well as micro-X-ray fluorescence mapping (MUXRF), using synchrotron radiation. RESULTS: We showed 1) the rapid detachment of part of the iron nanoparticles initially attached to SWCNT which appeared as free iron nanoparticles in the cytoplasm and nucleus of CNT-exposed murine macrophages, and 2) that blockade of intracellular lysosomal acidification prevented iron nanoparticles detachment from CNT bundles and protected cells from CNT downstream toxicity. CONCLUSIONS: The present results, while obtained with pristine SWCNT, could likely be extended to other catalyst-containing nanomaterials and surely open new ways in the interpretation and understanding of CNT toxicity. PMID- 23800200 TI - Deconvolution of gene expression from cell populations across the C. elegans lineage. AB - BACKGROUND: Knowledge of when and in which cells each gene is expressed across multicellular organisms is critical in understanding both gene function and regulation of cell type diversity. However, methods for measuring expression typically involve a trade-off between imaging-based methods, which give the precise location of a limited number of genes, and higher throughput methods such as RNA-seq, which include all genes, but are more limited in their resolution to apply to many tissues. We propose an intermediate method, which estimates expression in individual cells, based on high-throughput measurements of expression from multiple overlapping groups of cells. This approach has particular benefits in organisms such as C. elegans where invariant developmental patterns make it possible to define these overlapping populations of cells at single-cell resolution. RESULT: We implement several methods to deconvolve the gene expression in individual cells from population-level data and determine the accuracy of these estimates on simulated data from the C. elegans embryo. CONCLUSION: These simulations suggest that a high-resolution map of expression in the C. elegans embryo may be possible with expression data from as few as 30 cell populations. PMID- 23800202 TI - Estimating animal resource selection from telemetry data using point process models. AB - 1. Analyses of animal resource selection functions (RSF) using data collected from relocations of individuals via remote telemetry devices have become commonplace. Increasing technological advances, however, have produced statistical challenges in analysing such highly autocorrelated data. Weighted distribution methods have been proposed for analysing RSFs with telemetry data. However, they can be computationally challenging due to an intractable normalizing constant and cannot be aggregated (i.e. collapsed) over time to make space-only inference. 2. In this study, we take a conceptually different approach to modelling animal telemetry data for making RSF inference. We consider the telemetry data to be a realization of a space-time point process. Under the point process paradigm, the times of the relocations are also considered to be random rather than fixed. 3. We show the point process models we propose are a generalization of the weighted distribution telemetry models. By generalizing the weighted model, we can access several numerical techniques for evaluating point process likelihoods that make use of common statistical software. Thus, the analysis methods can be readily implemented by animal ecologists. 4. In addition to ease of computation, the point process models can be aggregated over time by marginalizing over the temporal component of the model. This allows a full range of models to be constructed for RSF analysis at the individual movement level up to the study area level. 5. To demonstrate the analysis of telemetry data with the point process approach, we analysed a data set of telemetry locations from northern fur seals (Callorhinus ursinus) in the Pribilof Islands, Alaska. Both a space-time and an aggregated space-only model were fitted. At the individual level, the space-time analysis showed little selection relative to the habitat covariates. However, at the study area level, the space-only model showed strong selection relative to the covariates. PMID- 23800201 TI - Prevalence and risk factors of Helicobacter pylori infection in Korea: nationwide multicenter study over 13 years. AB - BACKGROUND: The aim of this study was to evaluate the time trend of seropositivity of Helicobacter pylori (H. pylori) over the period of 13 years in an asymptomatic Korean population, and investigate associated risk factors. METHODS: This cross-sectional nationwide multicentre study surveyed anti-H. pylori IgG antibodies in 19,272 health check-up subjects (aged [greater than and equal to]16 years) in 2011. Risk factors for H. pylori infection were investigated using logistic regression. Seropositivity in asymptomatic subjects without H. pylori eradication was compared between the years 1998 and 2005. Birth cohort effects were also evaluated. RESULTS: After exclusion of subjects with a history of H. pylori eradication therapy (n = 3,712, 19.3%) and gastric symptoms (n = 4,764, 24.7%), the seroprevalence of H. pylori infection was 54.4% in 10,796 subjects. This was significantly lower than the seroprevalence of 59.6% in 2005 and that of 66.9% in 1998, and this decrease of seropositivity of H. pylori became widespread across all ages and in most areas of the country. This decreasing trend could be explained by cohort analysis. All younger birth cohorts had a lower seroprevalence of H. pylori than older birth cohorts at the same age. Decreased seroprevalence within the same birth cohorts also accounted for this phenomenon. Clinical risk factors of H. pylori infection were higher cholesterol level ([greater than and equal to] 240 mg/dl) (OR = 1.33; 95% CI = 1.14-1.54), male gender, older age, low income, and residence in a rural area. CONCLUSIONS: A decreasing trend of H. pylori seroprevalence due to a birth cohort effect requires further studies on its related human host factors as well as socio economic and hygienic factors. In addition, the relationship between H. pylori infection and high cholesterol level needs more investigation regarding underlying pathogenesis. PMID- 23800203 TI - Tracheal pseudo-tumor caused by herpes simplex virus. AB - BACKGROUND: Herpes simplex virus (HSV) has been shown to cause respiratory tract infections mostly in severely immunocompromised patients. Endobronchial tumor like lesions have been described very rarely as HSV pulmonary manifestations in critically ill patients or in immunosuppressed individuals. CASE PRESENTATION: This case study describes a 75-yr-old male who presented with persistent hoarseness. Fiberoptic bronchoscopy showed marked mucosal thickening protruding in mid and distal trachea causing stenosis. Biopsy specimens demonstrated cytopathological changes consistent with HSV type 1 and 2 infection. CONCLUSIONS: To the best of the authors' knowledge, this is the first reported case of HSV presenting as an endotracheal tumor in an immunocompetent person. PMID- 23800204 TI - Sleep, physical activity and BMI in six to ten-year-old children measured by accelerometry: a cross-sectional study. AB - BACKGROUND: The aim of this study is to describe the relationship between objective measures of sleep, physical activity and BMI in Swedish pre adolescents. The day-to-day association between physical activity and sleep quality as well as week-day and weekend pattern of sleep is also described. METHOD: We conducted a cross sectional study consisted of a cohort of 1.231 children aged six to ten years within the Stockholm county area. Sleep and physical activity were measured by accelerometry during seven consecutive days. Outcome measures are total sleep time, sleep efficiency, sleep start and sleep end; physical activity intensity divided into: sedentary (<1.5 METS), light (1.5 to 3 METS) and moderate-to-vigorous (> 3 METS); and Body Mass Index standard deviations score, BMIsds. RESULTS: Total sleep time decreased with increasing age, and was shorter in boys than girls on both weekdays and weekends. Late bedtime but consistent wake-up time during weekends made total sleep time shorter on weekends than on weekdays. Day-to-day within-subject analysis revealed that moderate-to-vigorous intense physical activity promoted an increased sleep efficiency the following night (CI < 0.001 to 0.047), while total sleep time was not affected (CI -0.003 to 0.043). Neither sleep duration (CI -0.024 to 0.022) nor sleep efficiency (CI -0.019 to 0.028) affected mean physical activity level the subsequent day. The between-subject analysis indicates that the sleep of children characterized by high moderate-to-vigorous physical activity during the day was frequently interrupted (SE = -.23, P < .01). A negative association between BMIsds and sleep duration was found (-.10, p < .01). CONCLUSIONS: Short sleep duration was associated with high BMI in six to ten year old children. This study underscores the importance of consistent bedtimes throughout the week for promoting sleep duration in preadolescents. Furthermore, this study suggests that a large proportion of intensive physical activity during the day might promote good sleep quality. PMID- 23800205 TI - Diversity and biofilm-production ability among isolates of Escherichia coli phylogroup D belonging to ST69, ST393 and ST405 clonal groups. AB - BACKGROUND: Phylogenetic group D Escherichia coli clones (ST69, ST393, ST405) are increasingly reported as multidrug resistant strains causing extra-intestinal infections. We aim to characterize inter- and intraclonal diversity of a broad sample (isolates from different geographic locations and origins with variable antibiotic resistance profiles, 1980-2010) and their ability to adhere and form biofilm by both a modified quantitative biofilm producing assay and Field Emission Scanning Electron Microscopy (FESEM). RESULTS: High virulence scores were observed among ST69 (median 14/range 9-15) and ST393 (median 14/range 8-15) clones, particularly enriched in pap alleles, iha, kpsMTII-K5 and ompT, in contrast with ST405 (median 6/range 2-14) isolates, exhibiting frequently fyuA, malX and traT. All ST69 and ST393 and only two ST405 isolates were classified as ExPEC. Biofilm production was detected in two non-clinical ST69 and three ST393 isolates from different origins showing variable virulence profiles. Within each clonal group, and despite the high diversity of PFGE-types observed, isolates from different countries and recovered over large periods of time were clustered in a few groups sharing common virulence gene profiles among ST69 (n = 10 isolates) and ST393 (n = 9 isolates) (fimH-iha-iutA-kpsMTII-K5-(traT)-sat-(ompT) papA-papEF-papGII-papC) or ST405 (n = 6 isolates) (fimH-traT-fyuA-malX). CONCLUSIONS: This study highlights the circulation of highly transmissible ST69, ST393 and ST405 variants among different settings. Biofilm production seems not to be directly correlated with their epidemiological success. PMID- 23800206 TI - Screen more or screen more often? Using mathematical models to inform syphilis control strategies. AB - BACKGROUND: Syphilis incidence among men who have sex with men (MSM) continues to rise despite attempts to increase screening and treatment uptake. We examined the marginal effect of increased frequency versus increased coverage of screening on syphilis incidence in Toronto, Canada. METHODS: We developed an agent-based, network model of syphilis transmission, representing a core population of 2,000 high-risk MSM. Epidemiological and biological parameters were drawn from regional surveillance data and literature-derived estimates. The pre-intervention period of the model was calibrated using surveillance data to identify 1000 credible simulations per strategy. Evaluated strategies included: annual syphilis screening at baseline coverage, increased screening frequency at baseline coverage, and increased coverage of annual screening. Intervention impact was measured as annual prevalence of detected infectious cases and syphilis incidence per year over 10 years. RESULTS: Of the strategies evaluated, increasing the frequency of syphilis screening to every three months was most effective in reducing reported and incident syphilis infections. Increasing the fraction of individuals tested, without increasing test frequency, resulted a smaller decline in incidence, because reductions in infectious syphilis via treatment were counterbalanced by increased incident syphilis among individuals with prior latent syphilis. For an equivalent number of additional tests performed annually, increased test frequency was consistently more effective than improved coverage. CONCLUSIONS: Strategies that focus on higher frequency of testing in smaller fractions of the population were more effective in reducing syphilis incidence in a simulated MSM population. The findings highlight how treatment-induced loss of immunity can create unexpected results in screening-based control strategies. PMID- 23800207 TI - Clinicopathologic features of hyperplastic/serrated polyposis syndrome in Japan. AB - BACKGROUND AND AIM: Hyperplastic/serrated polyposis syndrome (HPS) is a condition characterized by multiple hyperplastic/serrated colorectal polyps. The risk of colorectal cancer (CRC) is increased in HPS. The clinicopathologic characteristics of HPS in Japanese patients are unknown. The aim of this study is to clarify the clinicopathologic features of HPS in Japanese patients. METHODS: We retrieved records of patients diagnosed with HPS between April 2008 and March 2011 from the endoscopy database of Hiroshima University Hospital. In addition, we mailed a questionnaire to the hospital's 13 affiliated hospitals in July 2012. Data collected from the database and questionnaires included patient age, sex, number of hyperplastic/serrated polyps and tubular adenomas, size of the largest polyp, polyp location, resection for polyps, coexistence of HPS with CRC, and the diagnostic criterion met. RESULTS: Of the 73,608 patients who underwent colonoscopy, 10 (0.014%) met the criteria for HPS. The mean age of these patients was 58.3 years, and 6 (60%) were men. No subjects had a first-degree relative with HPS. Four (40%) HPS patients had more than 30 hyperplastic/serrated polyps, and average size of the largest polyp was 19 mm. Three (30%) HPS patients had coexistence of HPS with CRC. In these 3 patients, polyps were observed throughout the colorectum. CONCLUSIONS: Although HPS was a rare condition in the overall study population, patients with the disease may have high risk of CRC. HPS should be diagnosed correctly and followed up carefully. PMID- 23800208 TI - Dysanaptic growth of lung and airway in children with post-infectious bronchiolitis obliterans. AB - RATIONALE: Post-infectious bronchiolitis obliterans (PBO) is a rare form of chronic obstructive lung disease associated with small airway fibrosis following a severe insult to the lower respiratory tract. It has been suggested that PBO is a non-progressive disease. However, evidence supporting this statement is limited. In this case series, we sought to determine the changes of pulmonary function tests (PFT) over time in children with PBO. METHODS: Seven children with PBO, ages 6-15 years old, were retrospectively studied between 1994 and 2012. Spirometry and lung volumes tests were performed in accordance with American Thoracic Society (ATS) guidelines and were monitored over time. The average rate of change was calculated using generalized linear mixed models. RESULTS: The median baseline values for forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), the FEV1/FVC ratio and forced expiratory flow 25%-75% (FEF25%-75%) were 57%, 50%, 87% and 29%, respectively. FVC increased at a rate of 1.8% per year (P = 0.008). There was no significant change in FEV1 over time (P = 0.112). However, the FEV1/FVC ratio decreased by 2.6% per year (P < 0.001). CONCLUSION: PFT in childhood PBO was characterized by significant airway obstruction. Over time, FVC (lung parenchyma) increased and FEV1 (airway) remained stable, but FEV1/FVC ratio declined more than expected, suggesting a mismatch in the growth of the airway and lung parenchyma (dysanaptic growth). Further studies in larger populations are needed to validate these observations. PMID- 23800209 TI - Exploratory benchtop study evaluating the use of surgical design and simulation in fibula free flap mandibular reconstruction. AB - BACKGROUND: Surgical design and simulation (SDS) is a useful tool to help surgeons visualize the anatomy of the patient and perform operative maneuvers on the computer before implementation in the operating room. While these technologies have many advantages, further evidence of their potential to improve outcomes is required. The present benchtop study was intended to identify if there is a difference in surgical outcome between free-hand surgery completed without virtual surgical planning (VSP) software and preoperatively planned surgery completed with the use of VSP software. METHODS: Five surgeons participated in the study. In Session A, participants were asked to do a free hand reconstruction of a 3d printed mandible with a defect using a 3d printed fibula. Four weeks later, in Session B, the participants were asked to do the same reconstruction, but in this case using a preoperatively digitally designed surgical plan. Digital registration computer software, hard tissue measures and duration of the task were used to compare the outcome of the benchtop reconstructions. RESULTS: The study revealed that: (1) superimposed images produced in a computer aided design (CAD) software were effective in comparing pre and post-surgical outcomes, (2) there was a difference, based on hard tissue measures, in surgical outcome between the two scenarios and (3) there was no difference in the time it took to complete the sessions. CONCLUSION: The study revealed that the participants were more consistent in the preoperatively digitally planned surgery than they were in the free hand surgery. PMID- 23800210 TI - Increased serum triglycerides and reduced HDL cholesterol in male rats after intake of ammonium chloride for 3 weeks. AB - BACKGROUND: Previous data suggested that intake of sodas and other acid beverages might be associated with increased levels of serum triglycerides, lowered HDL cholesterol, and increased formation of mono unsaturated fatty acids, which are the preferred ones for triglyceride synthesis. The present work is an extension of these studies. METHODS: Thirty male rats were divided into 3 groups. All groups were given the same food, but various beverages: water (W), ammonium chloride, 200 mmol/L (AC), or sodium bicarbonate, 200 mmol/L (SB). Serum triglycerides, HDL cholesterol, and the fatty acid distribution in total serum lipids were determined. Delta9-desaturase in serum lipids was estimated by the ratio of palmitoleic to palmitic acid, and by the oleic/stearic acid ratio. Correlation and ANOVA were used to study associations and group differences. RESULTS: After 3 weeks, the AC group had higher triglyceride concentration and higher Delta9 desaturase indexes, but lower serum HDL and body weight as compared with the SB and W groups. In each of the groups, the oleic acid/stearic acid ratio correlated positively with serum triglycerides; in the pooled group the correlation coefficient was r = 0.963, p<0.01. CONCLUSIONS: Rats ingesting ammonium chloride as compared with sodium bicarbonate responded with increased desaturase indexes, increased serum triglycerides, and lowered HDL cholesterol concentration, thereby possibly contributing to explain the increased triglyceride concentration previously observed in subjects with a frequent intake of acid beverages, such as sodas containing carbonic acid, citric acid, and phosphoric acid. PMID- 23800211 TI - Lessons learned from implementation of computerized provider order entry in 5 community hospitals: a qualitative study. AB - BACKGROUND: Computerized Provider Order Entry (CPOE) can improve patient safety, quality and efficiency, but hospitals face a host of barriers to adopting CPOE, ranging from resistance among physicians to the cost of the systems. In response to the incentives for meaningful use of health information technology and other market forces, hospitals in the United States are increasingly moving toward the adoption of CPOE. The purpose of this study was to characterize the experiences of hospitals that have successfully implemented CPOE. METHODS: We used a qualitative approach to observe clinical activities and capture the experiences of physicians, nurses, pharmacists and administrators at five community hospitals in Massachusetts (USA) that adopted CPOE in the past few years. We conducted formal, structured observations of care processes in diverse inpatient settings within each of the hospitals and completed in-depth, semi-structured interviews with clinicians and staff by telephone. After transcribing the audiorecorded interviews, we analyzed the content of the transcripts iteratively, guided by principles of the Immersion and Crystallization analytic approach. Our objective was to identify attitudes, behaviors and experiences that would constitute useful lessons for other hospitals embarking on CPOE implementation. RESULTS: Analysis of observations and interviews resulted in findings about the CPOE implementation process in five domains: governance, preparation, support, perceptions and consequences. Successful institutions implemented clear organizational decision making mechanisms that involved clinicians (governance). They anticipated the need for education and training of a wide range of users (preparation). These hospitals deployed ample human resources for live, in-person training and support during implementation. Successful implementation hinged on the ability of clinical leaders to address and manage perceptions and the fear of change. Implementation proceeded smoothly when institutions identified and anticipated the consequences of the change. CONCLUSIONS: The lessons learned in the five domains identified in this study may be useful for other community hospitals embarking on CPOE adoption. PMID- 23800212 TI - Comparative study of hair follicle morphology in eight mammalian species and humans. AB - BACKGROUND: The objective of the present study was the investigation of hair follicle morphology in eight mammalian species in order to evaluate the species specific contribution of hair follicles to skin penetration particularly with regard to the utilization of the different animal species as skin models for human skin. METHODS: Cyanoacrylate skin surface biopsy method (CSSB), light microscopy and also digital photography were used for the measurements of hair follicle morphology. RESULTS: The results revealed species-specific differences regarding the pattern of hair follicle distribution and also differences with regard to hair follicle parameters and characteristics. The results also showed that hair follicles generally possess enormous reservoir capacities, regarding the follicular volume. In all examined species, hair follicles reached at least one-fifth of stratum corneum storage capacity. The results were compared with human data obtained in a previous study. CONCLUSION: With regard to hair follicle morphology and skin structure, the porcine skin seems to be the most appropriate skin model for human skin analog to previous investigations, whereas the skin of dog, cat, and rabbit showed the most significant differences. PMID- 23800213 TI - Measurement of active site ionization equilibria in the 670 kDa proteasome core particle using methyl-TROSY NMR. AB - The 20S proteasome core particle is a molecular machine that plays a central role in the regulation of cellular function through proteolysis, and it has emerged as a valuable drug target for certain classes of cancers. Central to the development of new and potent pharmaceuticals is an understanding of the mechanism by which the proteasome cleaves substrates. A number of high-resolution structures of the 20S proteasome with and without inhibitors have emerged that provide insight into the chemistry of peptide bond cleavage and establish the role of Thr1 Ogamma1 as the catalytic nucleophile. The source of the base that accepts the Thr1 Hgamma1 is less clear. Using a highly deuterated sample of the proteasome labeled with (13)CH3 at the Thr-gamma positions, the pKA of the Thr1 amino group has been measured to be 6.3 and hence deprotonated in the range of maximal enzyme activity. This provides strong evidence that the terminal amino group of Thr1 serves as the base in the first step of the peptide bond cleavage reaction. PMID- 23800214 TI - Role of oxidative stress in the pathogenesis of alcohol-induced liver disease. AB - Chronic alcohol consumption is a well-known risk factor for liver disease, which represents a major cause of morbidity and mortality worldwide. The pathological process of alcohol-induced liver disease is characterized by a broad spectrum of morphological changes ranging from steatosis with minimal injury to more advanced liver damage, including steato-hepatitis and fibrosis/cirrhosis. Experimental and clinical studies increasingly show that the oxidative damage induced by ethanol contribute in many ways to the pathogenesis of alcohol hepatotoxicity. This article describes the contribution of oxidative mechanisms to liver damage by alcohol. PMID- 23800216 TI - Where do features come from? AB - It is possible to learn multiple layers of non-linear features by backpropagating error derivatives through a feedforward neural network. This is a very effective learning procedure when there is a huge amount of labeled training data, but for many learning tasks very few labeled examples are available. In an effort to overcome the need for labeled data, several different generative models were developed that learned interesting features by modeling the higher order statistical structure of a set of input vectors. One of these generative models, the restricted Boltzmann machine (RBM), has no connections between its hidden units and this makes perceptual inference and learning much simpler. More significantly, after a layer of hidden features has been learned, the activities of these features can be used as training data for another RBM. By applying this idea recursively, it is possible to learn a deep hierarchy of progressively more complicated features without requiring any labeled data. This deep hierarchy can then be treated as a feedforward neural network which can be discriminatively fine-tuned using backpropagation. Using a stack of RBMs to initialize the weights of a feedforward neural network allows backpropagation to work effectively in much deeper networks and it leads to much better generalization. A stack of RBMs can also be used to initialize a deep Boltzmann machine that has many hidden layers. Combining this initialization method with a new method for fine-tuning the weights finally leads to the first efficient way of training Boltzmann machines with many hidden layers and millions of weights. PMID- 23800215 TI - Traditional medicinal plants used for the treatment of diabetes in rural and urban areas of Dhaka, Bangladesh--an ethnobotanical survey. AB - BACKGROUND: The usage of medicinal plants is traditionally rooted in Bangladesh and still an essential part of public healthcare. Recently, a dramatically increasing prevalence brought diabetes mellitus and its therapy to the focus of public health interests in Bangladesh. We conducted an ethnobotanical survey to identify the traditional medicinal plants being used to treat diabetes in Bangladesh and to critically assess their anti-diabetic potentials with focus on evidence-based criteria. METHODS: In an ethnobotanical survey in defined rural and urban areas 63 randomly chosen individuals (health professionals, diabetic patients), identified to use traditional medicinal plants to treat diabetes, were interviewed in a structured manner about their administration or use of plants for treating diabetes. RESULTS: In total 37 medicinal plants belonging to 25 families were reported as being used for the treatment of diabetes in Bangladesh. The most frequently mentioned plants were Coccinia indica, Azadirachta indica, Trigonella foenum-graecum, Syzygium cumini, Terminalia chebula, Ficus racemosa, Momordica charantia, Swietenia mahagoni. CONCLUSION: Traditional medicinal plants are commonly used in Bangladesh to treat diabetes. The available data regarding the anti-diabetic activity of the detected plants is not sufficient to adequately evaluate or recommend their use. Clinical intervention studies are required to provide evidence for a safe and effective use of the identified plants in the treatment of diabetes. PMID- 23800217 TI - Predicting novel trophic interactions in a non-native world. AB - Humans are altering the global distributional ranges of plants, while their co evolved herbivores are frequently left behind. Native herbivores often colonise non-native plants, potentially reducing invasion success or causing economic loss to introduced agricultural crops. We developed a predictive model to forecast novel interactions and verified it with a data set containing hundreds of observed novel plant-insect interactions. Using a food network of 900 native European butterfly and moth species and 1944 native plants, we built an herbivore host-use model. By extrapolating host use from the native herbivore-plant food network, we accurately forecasted the observed novel use of 459 non-native plant species by native herbivores. Patterns that governed herbivore host breadth on co evolved native plants were equally important in determining non-native hosts. Our results make the forecasting of novel herbivore communities feasible in order to better understand the fate and impact of introduced plants. PMID- 23800218 TI - Impaired emotional empathy and related social network deficits in cocaine users. AB - Chronic cocaine users consistently display neurochemical and functional alterations in brain areas involved in social cognition (e.g. medial and orbitofrontal cortex). Although social functioning plays a crucial role in the development and treatment of drug dependence, studies investigating social cognition in cocaine users are lacking. Therefore, we investigated mental perspective taking ('theory of mind') and emotional and cognitive empathy in recreational (RCU) and dependent (DCU) cocaine users. Furthermore, we related these measures to real-life indicators of social functioning. One-hundred cocaine users (69 RCU, 31 DCU) and 68 stimulant-naive healthy controls were tested with the Multifaceted Empathy Test (MET), Movie for the Assessment of Social Cognition (MASC) and Reading the Mind in the Eyes Test (RMET). The Social Network Questionnaire was conducted to assess social network size. Furthermore, participants provided information on committed criminal offenses. RCU and DCU showed less emotional empathy compared to controls (MET), whereas cognitive empathy was not impaired (MET, RMET). Additionally, DCU made more errors in mental perspective taking (MASC). Notably, cocaine users committed more criminal offenses and displayed a smaller social network and higher cocaine use was correlated with less social contacts. Diminished mental perspective taking was tentatively correlated with more intense cocaine use as well. Finally, younger age of onset of cocaine use was associated with more pronounced empathy impairment. In conclusion, social cognition impairments in cocaine users were related to real-life social functioning and should therefore be considered in therapy and prevention strategies. PMID- 23800219 TI - Influence of risk behavior aggregation in different categories of physical activity on the occurrence of cardiovascular risk factors. AB - BACKGROUND: We aimed to verify the association of risk behavior aggregation in different categories of physical activity (PA) with the presence of cardiovascular risk factors (RF) employees at a public university. METHOD: We analyzed data of 376 employees, which were visited in their workplace for measurement of weight, height and questionnaires to identify the risk behaviors and risk factors. Chi-square test was used to analyze the association between the dependent and independent variables and binary logistic regression was used to construct a multivariate model for the observed associations. RESULTS: Associations were found between the aggregation of following risk behaviors: smoking, alcohol consumption and physical inactivity, considered in different categories of PA, and the increase in RF, except for the presence of hypertriglyceridemia. Individuals with two or more risk behaviors in occupational PA category are more likely to be hypertensive (3.04 times) and diabetes (3.44 times). For the free time PA category, these individuals were 3.18 times more likely to have hypercholesterolemia and for locomotion PA, more likely to be hypertensive (2.42 times) and obese (2.51 times). CONCLUSION: There are association between the aggregation of two or more risk behaviors and the presence of cardiovascular RF. PMID- 23800220 TI - Modelling during an emergency: the 2009 H1N1 influenza pandemic. AB - During the 2009 H1N1 pandemic, decision-makers had access to mathematical and computational models that were not available in previous pandemics in 1918, 1957, and 1968. How did models contribute to policy and action during the 2009 H1N1 pandemic? Modelling encountered six primary challenges: (i) expectations of modelling were not clearly defined; (ii) appropriate real-time data were not readily available; (iii) modelling results were not generated, shared, or disseminated in time; (iv) decision-makers could not always decipher the structure and assumptions of the models; (v) modelling studies varied in intervention representations and reported results; and (vi) modelling studies did not always present the results or outcomes that are useful to decision-makers. However, there were also seven general successes: (i) modelling characterized the role of social distancing measures such as school closure; (ii) modelling helped to guide data collection; (iii) modelling helped to justify the value of the vaccination programme; (iv) modelling helped to prioritize target populations for vaccination; (v) modelling addressed the use of antiviral medications; (vi) modelling helped with health system preparedness planning; and (vii) modellers and decision-makers gained a better understanding of how to work with each other. In many ways, the 2009 pandemic served as practice and a learning opportunity for both modellers and decision-makers. Modellers can continue working with decision makers and other stakeholders to help overcome these challenges, to be better prepared when the next emergency inevitably arrives. PMID- 23800221 TI - Genetic heterogeneity in breast cancer: the road to personalized medicine? AB - More women die from breast cancer across the world today than from any other type of malignancy. The clinical course of breast cancer varies tremendously between patients. While some of this variability is explained by traditional clinico pathological factors (including patient age, tumor stage, histological grade and estrogen receptor status), molecular profiling studies have defined breast cancer subtypes with distinct clinical outcomes. This mini-review considers recent studies which have used genomics technologies in an attempt to identify new biomarkers of prognosis and treatment response. These studies highlight the genetic heterogeneity that exists within breast cancers in space and time. PMID- 23800222 TI - Pretreatment alcohol drinking goals are associated with treatment outcomes. AB - BACKGROUND: A large subset of patients who enter treatment for alcohol dependence report nonabstinent drinking goals (e.g., reduction in drinking) rather than abstinence, and this pretreatment goal choice may be associated with drinking outcomes and alcohol-related problems. METHODS: An analysis of the 16-week Combined Pharmacotherapies and Behavioral Interventions (COMBINE) study was conducted to determine the association between self-reported pretreatment drinking goal and drinking outcomes and alcohol-related problems. Participants who reported a nonabstinent drinking goal (n = 340) were matched with participants who reported an abstinent drinking goal (n = 340) on 3 variables believed to contribute to treatment outcomes: COMBINE experimental group, gender, and number of prebaseline heavy drinking days. RESULTS: Analyses revealed no interaction between the COMBINE experimental group and drinking goal on outcome measures, so results were collapsed and examined as a function of drinking goal group. Participants who chose an abstinent drinking goal had significantly more weeks with no drinking or no heavy drinking, reported fewer heavy drinking days, reported fewer days with >1 drink, and were more likely to have a >=50% decrease in drinks per day between baseline and week 16 of the intervention. However, both groups reported reductions over time in percent drinking days, mean drinks per day, number of heavy drinking days, and number of drinking days per week, and participants in both groups experienced significant reductions in alcohol-related problems and improvements in psychosocial functioning. CONCLUSIONS: Results replicate and expand upon previous studies examining the association between drinking goal and treatment outcome. These data also provide support for the standard inclusion of drinking treatment goal as a stratification variable in study interventions or as a covariate in outcome analyses and highlight several areas that warrant additional research regarding patients who enter alcohol treatment with a nonabstinent drinking goal. PMID- 23800223 TI - Rates of projected climate change dramatically exceed past rates of climatic niche evolution among vertebrate species. AB - A key question in predicting responses to anthropogenic climate change is: how quickly can species adapt to different climatic conditions? Here, we take a phylogenetic approach to this question. We use 17 time-calibrated phylogenies representing the major tetrapod clades (amphibians, birds, crocodilians, mammals, squamates, turtles) and climatic data from distributions of > 500 extant species. We estimate rates of change based on differences in climatic variables between sister species and estimated times of their splitting. We compare these rates to predicted rates of climate change from 2000 to 2100. Our results are striking: matching projected changes for 2100 would require rates of niche evolution that are > 10,000 times faster than rates typically observed among species, for most variables and clades. Despite many caveats, our results suggest that adaptation to projected changes in the next 100 years would require rates that are largely unprecedented based on observed rates among vertebrate species. PMID- 23800224 TI - Growth of human bronchial epithelial cells at an air-liquid interface alters the response to particle exposure. AB - BACKGROUND: We tested the hypothesis that normal human bronchial epithelial (NHBE) cells 1) grown submerged in media and 2) allowed to differentiate at air liquid interface (ALI) demonstrate disparities in the response to particle exposure. RESULTS: Following exposure of submerged NHBE cells to ambient air pollution particle collected in Chapel Hill, NC, RNA for IL-8, IL-6, heme oxygenase 1 (HOX1) and cyclooxygenase 2 (COX2) increased. The same cells allowed to differentiate over 3, 10, and 21 days at ALI demonstrated no such changes following particle exposure. Similarly, BEAS-2B cells grown submerged in media demonstrated a significant increase in IL-8 and HOX1 RNA after exposure to NIST 1648 particle relative to the same cells exposed after growth at ALI. Subsequently, it was not possible to attribute the observed decreases in the response of NHBE cells to differentiation alone since BEAS-2B cells, which do not differentiate, showed similar changes when grown at ALI. With no exposure to particles, differentiation of NHBE cells at ALI over 3 to 21 days demonstrated significant decrements in baseline levels of RNA for the same proteins (i.e. IL 8, IL-6, HOX1, and COX2). With no exposure to particles, BEAS-2B cells grown at ALI showed comparable changes in RNA for IL-8 and HOX1. After the same particle exposure, NHBE cells grown at ALI on a transwell in 95% N2-5% CO2 and exposed to NIST 1648 particle demonstrated significantly greater changes in IL-8 and HOX1 relative to cells grown in 95% air-5% CO2. CONCLUSIONS: We conclude that growth of NHBE cells at ALI is associated with a diminished biological effect following particle exposure relative to cells submerged in media. This decreased response showed an association with increased oxygen availability. PMID- 23800226 TI - Trophic cascades: linking ungulates to shrub-dependent birds and butterflies. AB - 1. Studies demonstrating trophic cascades through the loss of top-down regulatory processes in productive and biologically diverse terrestrial ecosystems are limited. 2. Elk Island National Park, Alberta and surrounding protected areas have a wide range of ungulate density due to the functional loss of top predators, management for high ungulate numbers and variable hunting pressure. This provides an ideal setting for studying the effects of hyper-abundant ungulates on vegetation and shrub-dependent bird and butterfly species. 3. To examine the cascading effects of high ungulate density, we quantified vegetation characteristics and abundances of yellow warbler Dendroica petechia and Canadian tiger swallowtail Papilio canadensis under different ungulate density in and around Elk Island National Park. 4. Using Structural Equation Models we found that ungulate density was inversely related to shrub cover, whereas shrub cover was positively related to yellow warbler abundance. In addition, chokecherry Prunus virginiana abundance was inversely related to browse impact but positively related to P. canadensis abundance. 5. These results demonstrate a cascade resulting from hyper-abundant ungulates on yellow warblers and Canadian tiger swallowtails through reductions in shrub cover and larval host plant density. The combined effect of the functional loss of top predators and management strategies that maintain high ungulate numbers can decouple top-down regulation of productive temperate ecosystems. PMID- 23800225 TI - Automatic workflow for the classification of local DNA conformations. AB - BACKGROUND: A growing number of crystal and NMR structures reveals a considerable structural polymorphism of DNA architecture going well beyond the usual image of a double helical molecule. DNA is highly variable with dinucleotide steps exhibiting a substantial flexibility in a sequence-dependent manner. An analysis of the conformational space of the DNA backbone and the enhancement of our understanding of the conformational dependencies in DNA are therefore important for full comprehension of DNA structural polymorphism. RESULTS: A detailed classification of local DNA conformations based on the technique of Fourier averaging was published in our previous work. However, this procedure requires a considerable amount of manual work. To overcome this limitation we developed an automatic classification method consisting of the combination of supervised and unsupervised approaches. A proposed workflow is composed of k-NN method followed by a non-hierarchical single-pass clustering algorithm. We applied this workflow to analyze 816 X-ray and 664 NMR DNA structures released till February 2013. We identified and annotated six new conformers, and we assigned four of these conformers to two structurally important DNA families: guanine quadruplexes and Holliday (four-way) junctions. We also compared populations of the assigned conformers in the dataset of X-ray and NMR structures. CONCLUSIONS: In the present work we developed a machine learning workflow for the automatic classification of dinucleotide conformations. Dinucleotides with unassigned conformations can be either classified into one of already known 24 classes or they can be flagged as unclassifiable. The proposed machine learning workflow permits identification of new classes among so far unclassifiable data, and we identified and annotated six new conformations in the X-ray structures released since our previous analysis. The results illustrate the utility of machine learning approaches in the classification of local DNA conformations. PMID- 23800227 TI - Correlates of preferences for home or hospital confinement in Pakistan: evidence from a national survey. AB - BACKGROUND: Despite the pregnancy complications related to home births, homes remain yet major place of delivery in Pakistan and 65 percent of totals births take place at home. This work analyses the determinants of place of delivery in Pakistan. METHODS: Multivariate Logistic regression is used for analysis. Data are extracted from Pakistan Demographic and Health Survey (2006-07). Based on information on last birth preceding 5 years of survey, we construct dichotomous dependent variable i.e. whether women deliver at home (Coded=1) or at health facility (coded=2). RESULTS: Bivariate analysis shows that 72% (p<=0.000) women from rural area and 81% women residing in Baluchistan delivered babies at home. Furthermore 75% women with no formal education, 81% (p<=0.000) women working in agricultural sector, 75% (p<=0.000) of Women who have 5 and more children and almost 77% (p<=0.000) who do not discussed pregnancy related issues with their husbands are found delivering babies at home. Multivariate analysis documents that mothers having lower levels of education, economic status and empowerment, belonging to rural area, residing in provinces other than Punjab, working in agriculture sector and mothers who are young are more likely to give births at home. CONCLUSION: A trend for home births, among Pakistani women, can be traced in lower levels of education, lower autonomy, poverty driven working in agriculture sector, higher costs of using health facilities and regional backwardness. PMID- 23800228 TI - Enhanced second harmonic generation by photonic-plasmonic Fano-type coupling in nanoplasmonic arrays. AB - In this communication, we systematically investigate the effects of Fano-type coupling between long-range photonic resonances and localized surface plasmons on the second harmonic generation from periodic arrays of Au nanoparticles arranged in monomer and dimer geometries. Specifically, by scanning the wavelength of an ultrafast tunable pump laser over a large range, we measure the second harmonic excitation spectra of these arrays and demonstrate their tunability with particle size and separation. Moreover, through a comparison with linear optical transmission spectra, which feature asymmetric Fano-type lineshapes, we demonstrate that the second harmonic generation is enhanced when coupled photonic plasmonic resonances of the arrays are excited at the fundamental pump wavelength, thus boosting the intensity of the electromagnetic near-fields. Our experimental results, which are supported by numerical simulations of linear optical transmission and near-field enhancement spectra based on the Finite Difference Time Domain method, demonstrate a direct correlation between the onset of Fano-type coupling and the enhancement of second harmonic generation in arrays of Au nanoparticles. Our findings enable the engineering of the nonlinear optical response of Fano-type coupled nanoparticle arrays that are relevant to a number of device applications in nonlinear nano-optics and plasmonics, such as on-chip frequency generators, modulators, switchers, and sensors. PMID- 23800229 TI - The mitochondrial carrier Rim2 co-imports pyrimidine nucleotides and iron. AB - Mitochondrial iron uptake is of key importance both for organelle function and cellular iron homoeostasis. The mitochondrial carrier family members Mrs3 and Mrs4 (homologues of vertebrate mitoferrin) function in organellar iron supply, yet other low efficiency transporters may exist. In Saccharomyces cerevisiae, overexpression of RIM2 (MRS12) encoding a mitochondrial pyrimidine nucleotide transporter can overcome the iron-related phenotypes of strains lacking both MRS3 and MRS4. In the present study we show by in vitro transport studies that Rim2 mediates the transport of iron and other divalent metal ions across the mitochondrial inner membrane in a pyrimidine nucleotide-dependent fashion. Mutations in the proposed substrate-binding site of Rim2 prevent both pyrimidine nucleotide and divalent ion transport. These results document that Rim2 catalyses the co-import of pyrimidine nucleotides and divalent metal ions including ferrous iron. The deletion of RIM2 alone has no significant effect on mitochondrial iron supply, Fe-S protein maturation and haem synthesis. However, RIM2 deletion in mrs3/4Delta cells aggravates their Fe-S protein maturation defect. We conclude that under normal physiological conditions Rim2 does not play a significant role in mitochondrial iron acquisition, yet, in the absence of the main iron transporters Mrs3 and Mrs4, this carrier can supply the mitochondrial matrix with iron in a pyrimidine-nucleotide-dependent fashion. PMID- 23800230 TI - Quantitation of small intestinal permeability during normal human drug absorption. AB - BACKGROUND: Understanding the quantitative relationship between a drug's physical chemical properties and its rate of intestinal absorption (QSAR) is critical for selecting candidate drugs. Because of limited experimental human small intestinal permeability data, approximate surrogates such as the fraction absorbed or Caco-2 permeability are used, both of which have limitations. METHODS: Given the blood concentration following an oral and intravenous dose, the time course of intestinal absorption in humans was determined by deconvolution and related to the intestinal permeability by the use of a new 3 parameter model function ("Averaged Model" (AM)). The theoretical validity of this AM model was evaluated by comparing it to the standard diffusion-convection model (DC). This analysis was applied to 90 drugs using previously published data. Only drugs that were administered in oral solution form to fasting subjects were considered so that the rate of gastric emptying was approximately known. All the calculations are carried out using the freely available routine PKQuest Java (http://www.pkquest.com) which has an easy to use, simple interface. RESULTS: Theoretically, the AM permeability provides an accurate estimate of the intestinal DC permeability for solutes whose absorption ranges from 1% to 99%. The experimental human AM permeabilities determined by deconvolution are similar to those determined by direct human jejunal perfusion. The small intestinal pH varies with position and the results are interpreted in terms of the pH dependent octanol partition. The permeability versus partition relations are presented separately for the uncharged, basic, acidic and charged solutes. The small uncharged solutes caffeine, acetaminophen and antipyrine have very high permeabilities (about 20 x 10-4 cm/sec) corresponding to an unstirred layer of only 45 MUm. The weak acid aspirin also has a large AM permeability despite its low octanol partition at pH 7.4, suggesting that it is nearly completely absorbed in the first part of the intestine where the pH is about 5.4. CONCLUSIONS: The AM deconvolution method provides an accurate estimate of the human intestinal permeability. The results for these 90 drugs should provide a useful benchmark for evaluating QSAR models. PMID- 23800231 TI - Accuracy of the Masimo Pronto-7(r) system in patients with left ventricular assist device. AB - BACKGROUND: The Masimo Pronto-7(r) calculates hemoglobin (Hb) values using the pulsoximetry technique and a variety of mathematical algorithms analyzing the pulse waveform. Although this system has demonstrated a high level of accuracy in average patients, the performance might be altered in special patient populations. Regarding patients with left ventricular cardiac failure, a rotary blood pump generates a constant, continuous, non-pulsatile flow to improve effective cardiac output. Due to this alteration in both, blood flow and arterial blood pressure we hypothesized a reduced accuracy of the Masimo Pronto-7(r) to detect Hb in patients with left ventricular cardiac failure. To test our hypothesis, we evaluated the Pronto-7(r)SpHb system in outpatients after continuous-flow-left ventricular assist device (cf-LVAD) implantation (HeartMate II, Thoratec). METHODS: 21 cf-LVAD outpatients from the Clinic for Cardiac, Thoracic and Vascular Surgery were investigated during routine follow up examinations. After venous blood samples were drawn, the Pronto-7(r) sensor was attached to one randomly selected finger of one hand. The collected SpHb data were compared with Hb values measured by our central laboratory. The difference between the methods was determined using Bland - Altman analysis. The study was registered in the DRKS (DRKS00004415). RESULTS: In all cf-LVAD patients evaluated, the Pronto-7(r) successfully detected SpHb values. Using Bland - Altman analysis, a bias of 0.14 g/dl (95% upper and lower limits of agreement +/- 2.76 g/dl) was calculated. CONCLUSION: The Pronto-7(r) overestimated the actual Hb value in cf-LVAD outpatients with the HeartMate II. Due to this, we conclude that the system is suitable for screening in routine examinations and further analysis can be performed if needed. However, its use as an emergency tool is questionable because of the increased inaccuracy when Hb values are critically low. PMID- 23800233 TI - Hepatocellular carcinoma associated with Budd-Chiari syndrome: imaging features and transcatheter arterial chemoembolization. AB - BACKGROUND: Budd-Chiari syndrome (BCS) often leads to hepatocellular carcinoma (HCC). Transcatheter arterial chemoembolization (TACE) has been increasingly used to treat BCS patients with HCC. The purposes of this study were to illustrate imaging features in BCS patients with HCC, and to analyze the effects of TACE on BCS patients with HCC. METHODS: 246 consecutive patients with primary BCS were retrospectively studied. 14 BCS patients with HCC were included in this study. BCS were treated with angioplasty and/or stenting, and HCC were managed with TACE. Imaging features on ultrasonography, CT, MRI, and angiography and the serum AFP level were analyzed. RESULTS: Inferior vena cava block and stricture of hepatic venous outflow tract more frequently occurred. Portal vein invasion was found in only 2 patients (14.2%). Imaging studies showed that most nodules of HCC were near the edge of liver, irregular, more than 3 cm in diameter, heterogeneous mass and solitary (<=3 nodules). HCC in patients associated with BCS was isointense or hypointense in nonenhanced CT images, and exhibited heterogeneous enhancement during the arterial phase and washout during the portal venous phase on enhanced CT and MRI. The serum AFP level significantly declined after TACE treatment. CONCLUSIONS: BCS patients with inferior vena cava block and stricture of hepatic venous outflow tract seems to be associated with HCC. A single, large, irregular nodule with a peripheral location appears to be HCC. TACE can effectively treat HCC in BCS patients. PMID- 23800234 TI - Novel marine actinobacteria from emerald Andaman & Nicobar Islands: a prospective source for industrial and pharmaceutical byproducts. AB - BACKGROUND: Andaman and Nicobar Islands situated in the eastern part of Bay of Bengal are one of the distinguished biodiversity hotspot. Even though number of studies carried out on the marine flora and fauna, the studies on actinobacteria from Andaman and Nicobar Islands are meager. The aim of the present study was to screen the actinobacteria for their characterization and identify the potential sources for industrial and pharmaceutical byproducts. RESULTS: A total of 26 actinobacterial strains were isolated from the marine sediments collected from various sites of Port Blair Bay where no collection has been characterized previously. Isolates were categorized under the genera: Saccharopolyspora, Streptomyces, Nocardiopsis, Streptoverticillium, Microtetraspora, Actinopolyspora, Actinokineospora and Dactylosporangium. Majority of the isolates were found to produce industrially important enzymes such as amylase, protease, gelatinase, lipase, DNase, cellulase, urease and phosphatase, and also exhibited substantial antibacterial activity against human pathogens. 77% of isolates exhibited significant hemolytic activity. Among 26 isolates, three strains (NIOT VKKMA02, NIOT-VKKMA22 and NIOT-VKKMA26) were found to generate appreciable extent of surfactant, amylase, cellulase and protease enzyme. NIOT-VKKMA02 produced surfactant using kerosene as carbon source and emulsified upto E(24)-63.6%. Moreover, NIOT-VKKMA02, NIOT-VKKMA22 and NIOT-VKKMA26 synthesized 13.27 U/ml, 9.85 U/ml and 8.03 U/ml amylase; 7.75 U/ml, 5.01 U/ml and 2.08 U/ml of cellulase and 11.34 U/ml, 6.89 U/ml and 3.51 U/ml of protease enzyme, respectively. CONCLUSIONS: High diversity of marine actinobacteria was isolated and characterized in this work including undescribed species and species not previously reported from emerald Andaman and Nicobar Islands, including Streptomyces griseus, Streptomyces venezuelae and Saccharopolyspora salina. The enhanced salt, pH and temperature tolerance of the actinobacterial isolates along with their capacity to secrete commercially valuable primary and secondary metabolites emerges as an attractive feature of these organisms. These results are reported for the first time from these emerald Islands and expand the scope to functionally characterize novel marine actinobacteria and their metabolites for the potential novel molecules of commercial interest. PMID- 23800235 TI - Culture, perception, and artistic visualization: a comparative study of children's drawings in three Siberian cultural groups. AB - In a study of three indigenous and non-indigenous cultural groups in northwestern and northeastern Siberia, framed line tests and a landscape drawing task were used to examine the hypotheses that test-based assessments of context sensitivity and independence are correlated with the amount of contextual information contained in drawings, and with the order in which the focal and background objects are drawn. The results supported these hypotheses, and inspection of the regression relationships suggested that the intergroup variations in test performance were likely to result from differences in the attention accorded to contextual information, as revealed by the drawings. Social and environmental explanations for the group differences in context sensitivity are also discussed. The conclusions support the argument that cultural differences in artistic styles and perceptual tests reflect the same underlying perceptual tendencies, and they are consistent with the argument that these tendencies reflect corresponding differences in patterns of social and environmental interaction. PMID- 23800232 TI - Functionally important amino acid residues in the transient receptor potential vanilloid 1 (TRPV1) ion channel--an overview of the current mutational data. AB - This review aims to create an overview of the currently available results of site directed mutagenesis studies on transient receptor potential vanilloid type 1 (TRPV1) receptor. Systematization of the vast number of data on the functionally important amino acid mutations of TRPV1 may provide a clearer picture of this field, and may promote a better understanding of the relationship between the structure and function of TRPV1. The review summarizes information on 112 unique mutated sites along the TRPV1, exchanged to multiple different residues in many cases. These mutations influence the effect or binding of different agonists, antagonists, and channel blockers, alter the responsiveness to heat, acid, and voltage dependence, affect the channel pore characteristics, and influence the regulation of the receptor function by phosphorylation, glycosylation, calmodulin, PIP2, ATP, and lipid binding. The main goal of this paper is to publish the above mentioned data in a form that facilitates in silico molecular modelling of the receptor by promoting easier establishment of boundary conditions. The better understanding of the structure-function relationship of TRPV1 may promote discovery of new, promising, more effective and safe drugs for treatment of neurogenic inflammation and pain-related diseases and may offer new opportunities for therapeutic interventions. PMID- 23800237 TI - Elevated serum dopamine increases while coffee consumption decreases the occurrence of reddish streaks in the intact stomach. AB - BACKGROUND AND AIM: Reddish streaks in an intact stomach are an endoscopic feature of duodenogastric reflux. This study aimed to identify which factors are associated with gastric reddish streaks and thus help prevent mucosal damage from duodenogastric reflux. METHODS: Demographic data, personal habits, stressful life events, and psychological distress were compared between subjects with only gastric reddish streaks and those with normal mucosa who underwent upper gastrointestinal endoscopy as part of a self-paid physical checkup. Stress hormones dopamine and cortisol were also checked by high-performance liquid chromatography and radioimmunoassay methods respectively. RESULTS: There were 95 subjects with gastric reddish streaks and 52 subjects with normal mucosa. No significant differences in age, gender, blood groups, education levels, marital status, religion, aspirin or nonsteroidal anti-inflammatory drug (NSAID) use, smoking habit, alcohol consumption, and intake of tea was found between the two groups, but intake of coffee was borderline more common in subjects with normal mucosa (38.5% vs 22.1%, P = 0.055). Subjects with gastric reddish streaks had lower Helicobacter pylori infection rate (37.8% vs 19.3%, P < 0.05). There were no significant differences in psychological distress and stressful life events between the two groups. Multivariate analysis shows that serum dopamine concentrations (odds ratio = 11.31, 95% confidence interval = 2.11-60.48, P = 0.005) and being without the consumption of coffee (odds ratio = 2.97, 95% confidence interval = 1.27-6.94, P = 0.012) were associated with gastric reddish streaks. CONCLUSIONS: Elevated serum dopamine and less coffee consumption are associated with gastric reddish streaks. These findings implicate that increased dopamine level plays a role for abnormal duodenogastric reflux. PMID- 23800236 TI - The altered expression profile of microRNAs in cardiopulmonary bypass canine models and the effects of mir-499 on myocardial ischemic reperfusion injury. AB - BACKGROUND: MicroRNAs were enrolled in various cardiovascular disease especially ischemic heart diseases, but the microRNA changes during myocardial ischemia reperfusion injury underwent cardiopulmonary bypass are still unknown. This study screens the microRNA differences in CPB canines and evaluates the relationship of microRNAs with myocardial ischemia reperfusion injury. METHODS: 13 healthy canines received CPB with 60 minutes of aortic clamping and cardioplegic arrest, followed by 90 minutes reperfusion. Left ventricular myocardial samples, blood samples and hemodynamic data were taken at different time points. We performed microRNAs microarray experiments upon the left ventricle myocardium tissue of canines before CPB and after reperfusion for 90 minutes by pooling 3 tissue samples together and used qRT-PCR for confirmation. RESULTS: Statistically significant difference was found in mir-499 level before CPB and after reperfusion (T1 vs. T4, p=0.041). We further examined the mir-499 levels by using qRT-PCR in all 13 canines at 4 different time points (T1 vs. T4, p=0.029). Mir 499 expression was negatively correlated with cardiac troponin T (cTnT) and creatine kinase- MB (CK-MB) levels of canines in all time points samples (r=0.469, p<0.001 and r=0.273, p=0.050 respectively). Moreover, higher mir-499 expression level was associated with higher dP/dtmax at 25 minutes and 90 minutes after reperfusion. CONCLUSION: Myocardial ischemic reperfusion injury with cardiopulmonary bypass results in declining level of mir-499 expression in left ventricle myocardium of canines, suggesting mir-499 would be a potential therapeutic target in cardiac protection during open heart surgery. PMID- 23800238 TI - The effects of Cosmos caudatus (ulam raja) on dynamic and cellular bone histomorphometry in ovariectomized rats. AB - BACKGROUND: Cosmos caudatus is a local plant which has antioxidant properties and contains high calcium. It is also reported to be able to strengthen the bone. This report is an extension to previously published article in Evidence Based Complementary and Alternative Medicine (doi:10.1155/2012/817814). In this study, we determined the effectiveness of C. caudatus as an alternative treatment for osteoporosis due to post-menopause by looking at the dynamic and cellular paramaters of bone histomorphometry. METHODS: Forty female Wistar rats were divided into four groups i.e. sham operated, ovariectomized, ovariectomized treated with calcium 1% ad libitum and ovariectomized force-fed with 500 mg/kg C. caudatus extract. Treatment was given six days a week for eight weeks. RESULTS: Dynamic and cellular histomorphometry parameters were measured. C. caudatus increased double-labeled surface (dLS/BS), mineral appositional rate (MAR), osteoid volume (OV/BV) and osteoblast surface (Ob.S/BS). C. caudatus also gave better results compared to calcium 1% in the osteoid volume (OV/BV) parameter. CONCLUSIONS: C. caudatus at the 500 mg/kg dose may be an alternative treatment in restoring bone damage that may occur in post-menopausal women. PMID- 23800239 TI - Lipid composition analysis of milk fats from different mammalian species: potential for use as human milk fat substitutes. AB - The lipid compositions of commercial milks from cow, buffalo, donkey, sheep, and camel were compared with that of human milk fat (HMF) based on total and sn-2 fatty acid, triacylglycerol (TAG), phospholipid, and phospholipid fatty acid compositions and melting and crystallization profiles, and their degrees of similarity were digitized and differentiated by an evaluation model. The results showed that these milk fats had high degrees of similarity to HMF in total fatty acid composition. However, the degrees of similarity in other chemical aspects were low, indicating that these milk fats did not meet the requirements of human milk fat substitutes (HMFSs). However, an economically feasible solution to make these milks useful as raw materials for infant formula production could be to modify these fats, and a possible method is blending of polyunsaturated fatty acids (PUFA) and 1,3-dioleoyl-2-palmitoylglycerol (OPO) enriched fats and minor lipids based on the corresponding chemical compositions of HMF. PMID- 23800240 TI - Spirometric reference values for healthy nonsmoking Saudi adults. AB - OBJECTIVES: To derive prediction equations of spirometric values of healthy Saudi adults and to compare the derived equations with equations reported in selected population. METHODS: Cross-sectional study of healthy nonsmoking men and women Saudi adults. The measured spirometric values were the forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1 ), peak expiratory flow (PEF) and forced mid-expiratory flow (FEF 25%-75%). RESULTS: A total of 621 spirometric tests were done. The prediction equations were derived using the following formula: Predicted spirometric value = constant + (b1 * age) + (b2 * height (cm)), where b1 and b2 represent the regression coefficients for age and height, respectively. Variable Constant Age (years) Height (cm) Variable Constant Age (years) Height (cm) Males (n = 292) Females (n = 175) FVC -2.933 -0.018 0.046 FVC -3.470 -0.016 0.045 FEV1 -1.886 -0.019 0.036 FEV1 -2.482 -0.018 0.036 FEV1 /FVC (%) 98.41 -0.095 -0.068 FEV1 /FVC (%) 100.67 -0.142 -0.072 PEF 17.274 -1.243 3.471 PEF -226.648 -0.499 4.076 FEF25%-75% 0.100 -0.024 0.027 FEF25%-75% -1.337 0.021 0.031 The means of the measured FVC and FEV1 were significantly lower than the predicted values derived by the American equations of -7.2% and -4.6% among males, respectively (P value < 0.00001), and -4.7%, and -5.26% among females, respectively (P value < 0.00001). CONCLUSION: The reference spirometric values derived in our study were significantly lower than the predicted values derived by the American equations. PMID- 23800241 TI - Celiac disease and other autoimmune diseases in patients with collagenous colitis. AB - BACKGROUND AND AIMS: Collagenous colitis (CC) is associated with autoimmune disorders. The aim of the present study was to investigate the relationship between CC and autoimmune disorders in a Swedish multicenter study. METHODS: Patients with CC answered questionnaires about demographic data and disease activity. The patient's files were scrutinized for information about autoimmune diseases. RESULTS: A total number of 116 CC patients were included; 92 women, 24 men, median age 62 years (IQR 55-73). In total, 30.2% had one or more autoimmune disorder. Most common were celiac disease (CeD; 12.9%) and autoimmune thyroid disease (ATD, 10.3%), but they also had Sjogren's syndrome (3.4%), diabetes mellitus (1.7%) and conditions in skin and joints (6.0%). Patients with associated autoimmune disease had more often nocturnal stools. The majority of the patients with associated CeD or ATD got these diagnoses before the colitis diagnosis. CONCLUSION: Autoimmune disorders occurred in one-third of these patients, especially CeD. In classic inflammatory bowel disease (IBD), liver disease is described in contrast to CC where no cases occurred. Instead, CeD was prevalent, a condition not reported in classic IBD. Patients with an associated autoimmune disease had more symptoms. Patients with CC and CeD had an earlier onset of their colitis. The majority of the patients with both CC and CeD were smokers. Associated autoimmune disease should be contemplated in the follow-up of these patients. PMID- 23800242 TI - The differential role of androgens in early human sex development. AB - Sexual development in humans is only partly understood at the molecular level. It is dependent on genetic control primarily induced by the sex chromosomal differences between males and females. This leads to the development of the gonads, whereby afterwards the differentiation of the apparent phenotype is controlled by hormone action. Sex steroids may exert permanent and temporary effects. Their organizational features of inducing permanent changes in phenotype occur through genetic control of downstream genes. In this, androgens are the key elements for the differentiation of male internal and external genitalia as well as other sexual organs and general body composition, acting through a single androgen receptor. The androgen receptor is a nuclear transcription factor modulating DNA transcription of respective target genes and thereby driving development and growth in a stringent manner. The specificity of androgen action seems to be a strictly time-controlled process with the androgen receptor acting in concert with different metabolites and an array of cofactors modulating the cellular response and thereby permanently altering the phenotype of any given individual. For every cell programmed by androgens, a specific 'androgen response index' must be proposed. PMID- 23800244 TI - Infection status outcome, machine learning method and virus type interact to affect the optimised prediction of hepatitis virus immunoassay results from routine pathology laboratory assays in unbalanced data. AB - BACKGROUND: Advanced data mining techniques such as decision trees have been successfully used to predict a variety of outcomes in complex medical environments. Furthermore, previous research has shown that combining the results of a set of individually trained trees into an ensemble-based classifier can improve overall classification accuracy. This paper investigates the effect of data pre-processing, the use of ensembles constructed by bagging, and a simple majority vote to combine classification predictions from routine pathology laboratory data, particularly to overcome a large imbalance of negative Hepatitis B virus (HBV) and Hepatitis C virus (HCV) cases versus HBV or HCV immunoassay positive cases. These methods were illustrated using a never before analysed data set from ACT Pathology (Canberra, Australia) relating to HBV and HCV patients. RESULTS: It was easier to predict immunoassay positive cases than negative cases of HBV or HCV. While applying an ensemble-based approach rather than a single classifier had a small positive effect on the accuracy rate, this also varied depending on the virus under analysis. Finally, scaling data before prediction also has a small positive effect on the accuracy rate for this dataset. A graphical analysis of the distribution of accuracy rates across ensembles supports these findings. CONCLUSIONS: Laboratories looking to include machine learning as part of their decision support processes need to be aware that the infection outcome, the machine learning method used and the virus type interact to affect the enhanced laboratory diagnosis of hepatitis virus infection, as determined by primary immunoassay data in concert with multiple routine pathology laboratory variables. This awareness will lead to the informed use of existing machine learning methods, thus improving the quality of laboratory diagnosis via informatics analyses. PMID- 23800243 TI - Sharing experiences: towards an evidence based model of dengue surveillance and outbreak response in Latin America and Asia. AB - BACKGROUND: The increasing frequency and intensity of dengue outbreaks in endemic and non-endemic countries requires a rational, evidence based response. To this end, we aimed to collate the experiences of a number of affected countries, identify strengths and limitations in dengue surveillance, outbreak preparedness, detection and response and contribute towards the development of a model contingency plan adaptable to country needs. METHODS: The study was undertaken in five Latin American (Brazil, Colombia, Dominican Republic, Mexico, Peru) and five in Asian countries (Indonesia, Malaysia, Maldives, Sri Lanka, Vietnam). A mixed methods approach was used which included document analysis, key informant interviews, focus-group discussions, secondary data analysis and consensus building by an international dengue expert meeting organised by the World Health Organization, Special Program for Research and Training in Tropical Diseases (WHO TDR). RESULTS: Country information on dengue is based on compulsory notification and reporting ("passive surveillance"), with laboratory confirmation (in all participating Latin American countries and some Asian countries) or by using a clinical syndromic definition. Seven countries additionally had sentinel sites with active dengue reporting, some also had virological surveillance. Six had agreed a formal definition of a dengue outbreak separate to seasonal variation in case numbers. Countries collected data on a range of warning signs that may identify outbreaks early, but none had developed a systematic approach to identifying and responding to the early stages of an outbreak. Outbreak response plans varied in quality, particularly regarding the early response. The surge capacity of hospitals with recent dengue outbreaks varied; those that could mobilise additional staff, beds, laboratory support and resources coped best in comparison to those improvising a coping strategy during the outbreak. Hospital outbreak management plans were present in 9/22 participating hospitals in Latin America and 8/20 participating hospitals in Asia. CONCLUSIONS: Considerable variation between countries was observed with regard to surveillance, outbreak detection, and response. Through discussion at the expert meeting, suggestions were made for the development of a more standardised approach in the form of a model contingency plan, with agreed outbreak definitions and country-specific risk assessment schemes to initiate early response activities according to the outbreak phase. This would also allow greater cross-country sharing of ideas. PMID- 23800245 TI - Validation of a stoma-specific quality of life questionnaire in a sample of patients with colostomy or ileostomy. AB - AIM: The aim of this study was to determine how socio-demographic and clinical variables affect quality of life (QoL) and to assess the validity of a 20-item scale in a sample of Italian subjects with colostomy, ileostomy and multiple stomata. METHOD: A cross-sectional multicentre survey was carried out in Italy between 2009 and 2010 in 73 stoma centres coordinated by the University of Padova. Patients aged 18 years old and above with a history of nontemporary stoma were included in the study. The Stoma Care QoL scale was measured and validated using a Rasch model. Socio-demographic and clinical characteristics were considered in the analyses. RESULTS: Two hundred and fifty-one patients were recruited for the study; the mean age was 62 years, 58% were men, 72% had colostomy and 25% ileostomy; approximately 70% of patients had intestinal cancer requiring a stoma, 13% a complication and 10% an inflammatory disease. No significant differences were observed throughout strata in the Stoma Care QoL scale index, except for geographical area, where subjects from south Italy showed a significantly lower index than subjects living in other parts of Italy (P < 0.01). Colostomy and ileostomy patients reported very similar QoL. Cronbach's alpha for the Stoma Care QoL scale was 0.90 (95% CI 0.88-0.92). Rasch analysis supported the viability of the Stoma Care QoL scale questionnaire and showed acceptable goodness-of-fit. Three under-fitted items were observed. CONCLUSION: The study confirms the validity of the 20-item Stoma Care QoL scale questionnaire as a research tool for stoma patients but the number of items could be reduced. PMID- 23800247 TI - Ultrasonic spectrum analysis for in vivo characterization of tumor microstructural changes in the evaluation of tumor response to chemotherapy using diagnostic ultrasound. AB - BACKGROUND: There is a strong need for early assessment of tumor response to chemotherapy in order to avoid the adverse effects of unnecessary chemotherapy and to allow early transition to second-line therapy. The purpose of this study was to determine the feasibility of ultrasonic spectral analysis for the in vivo characterization of changes in tumor microstructure in the evaluation of tumor response to chemotherapy using diagnostic ultrasound. METHODS: Experiments were approved by the regional animal care committee. Twenty-four MCF-7 breast cancer bearing nude mice were treated with adriamycin or sterile saline administered by intraperitoneal injection. Ultrasonic radio-frequency (RF) data was collected using a clinically available ultrasound scanner (6-MHz linear transducer). Linear regression parameters (spectral slope and midband-fit) regarding the calibrated power spectra from the RF signals were tested to monitor tumor response to treatment. The section equivalent to the ultrasound imaging plane was stained with hematoxylin and eosin to allow for assessment of the density of tumor cell nuclei. RESULTS: Treatment with adriamycin significantly reduced tumor growth in comparison with the control group (p = 0.003). Significant changes were observed in the ultrasonic parameters of the treated relative to the untreated tumors (p < 0.05). The spectral slope increased by 48.5%, from -10.66 +/- 2.96 to -5.49 +/- 2.69; the midband-fit increased by 12.8%, from -57.10 +/- 7.68 to -49.81 +/- 5.40. Treated tumors were associated with a significant decrease in the density of tumor cell nuclei as compared with control tumors (p < 0.001). CONCLUSIONS: Ultrasonic spectral analysis can detect changes in tumor microstructure after chemotherapy, and this will be helpful in the early evaluation tumor response to chemotherapy. PMID- 23800248 TI - A new objective histological scale for studying human photoaged skin. AB - BACKGROUND: A quantitative understanding of the histological alteration of the skin is important for assessing the severity of photoaging. METHODS: We performed Elastica-van Gieson staining and immunohistochemistry for decorin on 34 facial skin sections. We evaluated the alteration of collagen fibers and decorin (a modulator for collagen fibrillogenesis), according to the 5 grades of morphological change in elastic fibers that was established by Kligman (1969). The objectivity of a stage (Stages I-VI), which was established in this study, was evaluated using weighted kappa statistical analysis based on the degree of agreement in stage determination by 11 observers using a blind procedure. Correlation between the crow's-feet-area wrinkles grades of another 26 women and stages was also analyzed. RESULTS: The initial alteration of elastic fibers was observed in the deep dermis. Decorin was not detected in very severely altered skin. Based on the combination of changes in the elastic fibers, collagenic fibers, and decorin, skin tissues were categorized into 6 stages according to severity. The statistical analysis showed almost perfect agreement between observers. Significant positive correlation between stages and wrinkle scores was found. CONCLUSIONS: We propose a new objective histological scale that is useful for assessing the severity of photoaging. PMID- 23800249 TI - Insights into population ecology from long-term studies of red grouse Lagopus lagopus scoticus. AB - Long-term studies have been the backbone of population ecology. The red grouse Lagopus lagopus scoticus is one species that has contributed widely to this field since the 1950s. This paper reviews the trajectory and profound impact that these studies have had. Red grouse research has combined long-term studies of marked individuals with demographic studies over wide geographical areas and replicated individual- and population-level manipulations. A main focus has been on understanding the causes of population cycles in red grouse, and in particular the relative importance of intrinsic (behaviour) and extrinsic (climate, food limitation and parasite) mechanisms. Separate studies conducted in different regions initially proposed either the nematode parasite Trichostrongylus tenuis or changes in male aggressiveness in autumn as drivers of population cycles. More recent experiments suggest that parasites are not a necessary cause for cycles and have highlighted that behavioural and parasite-mediated mechanisms are interrelated. Long-term experiments show that parasites and aggressiveness interact. Two outstanding questions remain to be tested experimentally. First, what intrinsic mechanism causes temporal variation in patterns of male aggressiveness? The current favoured mechanism is related to patterns of kin structuring although there are alternative hypotheses. Second, how do the dual, interacting mechanisms, affect population dynamics? Red grouse studies have had an important impact on the field of population ecology, in particular through highlighting: (1) the impact of parasites on populations; (2) the role of intrinsic mechanisms in cyclic dynamics and (3) the need to consider multiple, interacting mechanisms. PMID- 23800250 TI - Cost-effectiveness of different interferon beta products for relapsing-remitting and secondary progressive multiple sclerosis: Decision analysis based on long term clinical data and switchable treatments. AB - BACKGROUND: Multiple sclerosis (MS) is a highly debilitating immune mediated disorder and the second most common cause of neurological disability in young and middle-aged adults. Iran is amongst high MS prevalence countries (50/100,000). Economic burden of MS is a topic of important deliberation in economic evaluations study. Therefore determining of cost-effectiveness interferon beta (INF beta) and their copied biopharmaceuticals (CBPs) and biosimilars products is significant issue for assessment of affordability in Lower-middle-income countries (LMICs). METHODS: A literature-based Markov model was developed to assess the cost-effectiveness of three INF betas products compared with placebo for managing a hypothetical cohort of patients diagnosed with relapsing remitting MS (RRMS) in Iran from a societal perspective. Health states were based on the Kurtzke Expanded Disability Status Scale (EDSS). Disease progression transition probabilities for symptom management and INF beta therapies were obtained from natural history studies and multicenter randomized controlled trials and their long term follow up for RRMS and secondary progressive MS (SPMS). A cross sectional study has been developed to evaluate cost and utility. Transitions among health states occurred in 2-years cycles for fifteen cycles and switching to other therapies was allowed. Calculations of costs and utilities were established by attachment of decision trees to the overall model. The incremental cost effectiveness ratio (ICER) of cost/quality adjusted life year (QALY) for all available INF beta products (brands, biosimilars and CBPs) were considered. Both costs and utilities were discounted. Sensitivity analyses were done to assess robustness of model. RESULTS: ICER for Avonex, Rebif and Betaferon was 18712, 11832, 15768 US Dollars ($) respectively when utility attained from literature review has been considered. ICER for available CBPs and biosimilars in Iran was $847, $6964 and $11913. CONCLUSIONS: The Markov pharmacoeconomics model determined that according to suggested threshold for developing countries by world health organization, all brand INF beta products are cost effective in Iran except Avonex. The best strategy among INF beta therapies is CBP intramuscular INF beta-1a (Cinnovex). Results showed that a policy of encouraging accessibility to CBPs and biosimilars could make even high technology products cost-effective in LMICs. PMID- 23800251 TI - Characteristics of chemokine signatures elicited by EGF and TNF in ovarian cancer cells. AB - BACKGROUND: Ovarian cancer, an inflammation-associated cancer, is the fifth leading cause of cancer deaths in women. The malignancy produces a large amount of tumor necrosis factor (TNF) which promotes a proinflammatory tumor microenvironment. In addition, the epidermal growth factor receptor (EGFR) is frequently overexpressed in high-grade ovarian cancer, which likely aggravates cancer progression. Since ovarian cancer progression is closely associated with chemokine networks driven by inflammation or EGFR activation, we investigated the chemokine signatures elicited by EGF and TNF in ovarian cancer cells to determine their individual profiles and if there was in fact some kind of synergy between their actions on the chemokine network. METHODS: We used a PCR array for the chemokine network to examine the signature of chemokines and their receptors elicited by EGF and TNF in four ovarian cancer cell lines (OVCAR-3, SKOV-3, CaOV 3 and TOV-21G). RESULTS: The chemokine network revealed that ovarian cancer cells commonly expressed high levels of proinflammatory chemokines such as CCL20, CXCL1 3 and CXCL8 in response to EGF or TNF. However, the responsiveness to EGF or TNF displayed a cell line specific pattern. Although OVCAR-3 and SKOV-3 cells were responsive to either EGF or TNF, their TNF responsiveness was dominant. On the other hand, CaOV-3 and TOV-21G cells were responsive to EGF but less to TNF, probably due to the high levels of non-canonical nuclear factor (NF)-kappaB components such as IKKalpha and p52 in these cell lines compared to OVCAR-3 and SKOV-3 cells. Among chemokine receptors, only CXCR5 was responsive to EGF or TNF in CaOV-3 cells. Finally, CCL20 and CXCL8 responded synergistically in response to EGF and TNF in OVCAR-3 and SKOV-3 cells. CONCLUSION: Our results indicate that CCL20, CXCL1-3 and CXCL8 are the primary chemokines induced by EGF or TNF and are elicited in these ovarian cancer cells via NF-kappaB, Akt and Erk signaling pathways. Of interest, there was a syngergistic response in terms of CCL20 and CXCL8 levels, when OVCAR-3 and SKOV-3 cells were exposed to EGF plus TNF. Targeting these proinflammatory chemokines may be a promising therapeutic strategy for ovarian cancer with abundant TNF and EGFR activation patterns. PMID- 23800252 TI - Functional microbial diversity explains groundwater chemistry in a pristine aquifer. AB - BACKGROUND: The diverse microbial populations that inhabit pristine aquifers are known to catalyze critical in situ biogeochemical reactions, yet little is known about how the structure and diversity of this subsurface community correlates with and impacts upon groundwater chemistry. Herein we examine 8,786 bacterial and 8,166 archaeal 16S rRNA gene sequences from an array of monitoring wells in the Mahomet aquifer of east-central Illinois. Using multivariate statistical analyses we provide a comparative analysis of the relationship between groundwater chemistry and the microbial communities attached to aquifer sediment along with those suspended in groundwater. RESULTS: Statistical analyses of 16S rRNA gene sequences showed a clear distinction between attached and suspended communities; with iron-reducing bacteria far more abundant in attached samples than suspended, while archaeal clones related to groups associated with anaerobic methane oxidation and deep subsurface gold mines (ANME-2D and SAGMEG-1, respectively) distinguished the suspended community from the attached. Within the attached bacterial community, cloned sequences most closely related to the sulfate-reducing Desulfobacter and Desulfobulbus genera represented 20% of the bacterial community in wells where the concentration of sulfate in groundwater was high (> 0.2 mM), compared to only 3% in wells with less sulfate. Sequences related to the genus Geobacter, a genus containing ferric-iron reducers, were of nearly equal abundance (15%) to the sulfate reducers under high sulfate conditions, however their relative abundance increased to 34% when sulfate concentrations were < 0.03 mM. Also, in areas where sulfate concentrations were <0.03 mM, archaeal 16S rRNA gene sequences similar to those found in methanogens such as Methanosarcina and Methanosaeta comprised 73-80% of the community, and dissolved CH4 ranged between 220 and 1240 MUM in these groundwaters. In contrast, methanogens (and their product, CH4) were nearly absent in samples collected from groundwater samples with > 0.2 mM sulfate. In the suspended fraction of wells where the concentration of sulfate was between 0.03 and 0.2 mM, the archaeal community was dominated by sequences most closely related to the ANME-2D, a group of archaea known for anaerobically oxidizing methane. Based on available energy (?GA) estimations, results varied little for both sulfate reduction and methanogenesis throughout all wells studied, but could favor anaerobic oxidation of methane (AOM) in wells containing minimal sulfate and dihydrogen, suggesting AOM coupled with H2-oxidizing organisms such as sulfate or iron reducers could be an important pathway occurring in the Mahomet aquifer. CONCLUSIONS: Overall, the results show several distinct factors control the composition of microbial communities in the Mahomet aquifer. Bacteria that respire insoluble substrates such as iron oxides, i.e. Geobacter, comprise a greater abundance of the attached community than the suspended regardless of groundwater chemistry. Differences in community structure driven by the concentration of sulfate point to a clear link between the availability of substrate and the abundance of certain functional groups, particularly iron reducers, sulfate reducers, methanogens, and methanotrophs. Integrating both geochemical and microbiological observations suggest that the relationships between these functional groups could be driven in part by mutualism, especially between ferric-iron and sulfate reducers. PMID- 23800253 TI - Effects of auditing patient safety in hospital care: design of a mixed-method evaluation. AB - BACKGROUND: Auditing of patient safety aims at early detection of risks of adverse events and is intended to encourage the continuous improvement of patient safety. The auditing should be an independent, objective assurance and consulting system. Auditing helps an organisation accomplish its objectives by bringing a systematic, disciplined approach to evaluating and improving the effectiveness of risk management, control, and governance. Audits are broadly conducted in hospitals, but little is known about their effects on the behaviour of healthcare professionals and patient safety outcomes. This study was initiated to evaluate the effects of patient safety auditing in hospital care and to explore the processes and mechanisms underlying these effects. METHODS AND DESIGN: Our study aims to evaluate an audit system to monitor and improve patient safety in a hospital setting. We are using a mixed-method evaluation with a before-and-after study design in eight departments of one university hospital in the period October 2011-July 2014. We measure several outcomes 3 months before the audit and 15 months after the audit. The primary outcomes are adverse events and complications. The secondary outcomes are experiences of patients, the standardised mortality ratio, prolonged hospital stay, patient safety culture, and team climate. We use medical record reviews, questionnaires, hospital administrative data, and observations to assess the outcomes. A process evaluation will be used to find out which components of internal auditing determine the effects. DISCUSSION: We report a study protocol of an effect and process evaluation to determine whether auditing improves patient safety in hospital care. Because auditing is a complex intervention targeted on several levels, we are using a combination of methods to collect qualitative and quantitative data about patient safety at the patient, professional, and department levels. This study is relevant for hospitals that want to early detect unsafe care and improve patient safety continuously. TRIAL REGISTRATION: Netherlands Trial Register (NTR): NTR3343. PMID- 23800255 TI - Medicinal plants from swidden fallows and sacred forest of the Karen and the Lawa in Thailand. AB - BACKGROUND: Many ecosystem services provided by forests are important for the livelihoods of indigenous people. Sacred forests are used for traditional practices by the ethnic minorities in northern Thailand and they protect these forests that are important for their culture and daily life. Swidden fallow fields are a dominant feature of the agricultural farming landscapes in the region. In this study we evaluate and compare the importance of swidden fallow fields and sacred forests as providers of medicinal plants among the Karen and Lawa ethnic minorities in northern Thailand. METHODS: We made plant inventories in swidden fallow fields of three different ages (1-2, 3-4, 5-6 years old) and in sacred forests around two villages using a replicated stratified design of vegetation plots. Subsequently we interviewed the villagers, using semi structured questionnaires, to assess the medicinal use of the species encountered in the vegetation survey. RESULTS: We registered a total of 365 species in 244 genera and 82 families. Of these 72(19%) species in 60(24%) genera and 32(39%) families had medicinal uses. Although the sacred forest overall housed more species than the swidden fallow fields, about equal numbers of medicinal plants were derived from the forest and the fallows. This in turn means that a higher proportion (48% and 34%) of the species in the relatively species poor fallows were used for medicinal purposes than the proportion of medicinal plants from the sacred forest which accounted for 17-22%. Of the 32 medicinal plant families Euphorbiaceae and Lauraceae had most used species in the Karen and Lawa villages respectively. CONCLUSION: Sacred forest are important for providing medicinal plant species to the Karen and Lawa communities in northern Thailand, but the swidden fallows around the villages are equally important in terms of absolute numbers of medicinal plant species, and more important if counted as proportion of the total number of species in a habitat. This points to the importance of secondary vegetation as provider of medicinal plants around rural villages as seen elsewhere in the tropics. PMID- 23800254 TI - Suppression and epigenetic regulation of MiR-9 contributes to ethanol teratology: evidence from zebrafish and murine fetal neural stem cell models. AB - BACKGROUND: Fetal alcohol exposure produces multiorgan defects, making it difficult to identify underlying etiological mechanisms. However, recent evidence for ethanol (EtOH) sensitivity of the miRNA miR-9 suggests one mechanism, whereby EtOH broadly influences development. We hypothesized that loss of miR-9 function recapitulates aspects of EtOH teratology. METHODS: Zebrafish embryos were exposed to EtOH during gastrulation, or injected with anti-miR-9 or nonsense control morpholinos during the 2-cell stage of development and collected between 24 and 72 hours postfertilization (hpf). We also assessed the expression of developmentally important, and known miR-9 targets, FGFR-1, FOXP2, and the nontargeted transcript, MECP2. Methylation at CpG islands of mammalian miR-9 genes was assessed in fetal murine neural stem cells (mNSCs) by methylation specific PCR, and miRNA processing assessed by qRT-PCR for pre-miR-9 transcripts. RESULTS: EtOH treatment and miR-9 knockdown resulted in similar cranial defects including microcephaly. Additionally, EtOH transiently suppressed miR-9, as well as FGFR-1 and FOXP2, and alterations in miR-9 expression were correlated with severity of EtOH-induced teratology. In mNSCs, EtOH increased CpG dinucleotide methylation at the miR-9-2 locus and accumulation of pre-miR-9-3. CONCLUSIONS: EtOH exerts regulatory control at multiple levels of miR-9 biogenesis. Moreover, early embryonic loss of miR-9 function recapitulated the severe range of teratology associated with developmental EtOH exposure. EtOH also disrupts the relationship between miR-9 and target gene expression, suggesting a nuanced relationship between EtOH and miRNA regulatory networks in the developing embryo. The implications of these data for the expression and function of mature miR-9 warrant further investigation. PMID- 23800256 TI - Ambulatory consolidation chemotherapy for acute myeloid leukemia with antibacterial prophylaxis is associated with frequent bacteremia and the emergence of fluoroquinolone resistant E. Coli. AB - BACKGROUND: Ambulatory consolidation chemotherapy for acute myeloid leukemia (AML) is frequently associated with bloodstream infections but the spectrum of bacterial pathogens in this setting has not been well-described. METHODS: We evaluated the emergence of bacteremias and their respective antibiotic susceptibility patterns in AML patients receiving ambulatory-based consolidation therapy. Following achievement of complete remission, 207 patients received the first cycle (C1), and 195 the second cycle (C2), of consolidation on an ambulatory basis. Antimicrobial prophylaxis consisted of ciprofloxacin, amoxicillin and fluconazole. RESULTS: There were significantly more positive blood cultures for E. coli in C2 as compared to C1 (10 vs. 1, p=0.0045); all E. coli strains for which susceptibility testing was performed demonstrated resistance to ciprofloxacin. In patients under age 60 there was a significantly higher rate of Streptococccus spp. bacteremia in C2 vs. C1; despite amoxicillin prophylaxis all Streptococcus isolates in C2 were sensitive to penicillin. Patients with Staphylococcus bacteremia in C1 had significantly higher rates of Staphylococcus bacteremia in C2 (p=0.009, OR=8.6). CONCLUSIONS: For AML patients undergoing outpatient-based intensive consolidation chemotherapy with antibiotic prophylaxis, the second cycle is associated with higher rates of ciprofloxacin resistant E. coli, penicillin-sensitive Streptococcus bacteremias and recurrent Staphylococcus infections. PMID- 23800257 TI - Graft-versus-tumor effect after allogeneic stem cell transplantation in HIV positive patients with high-risk hematologic malignancies. AB - Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is a well established therapeutic option for hematological malignancies. Combination antiretroviral therapy (cART) has enabled the treatment of medical conditions in patients infected with the human immunodeficiency virus (HIV) in the same way as in the general population. Moreover, improvements in supportive care have allowed HIV-infected patients with life-threatening hematological disorders to be treated with Allo-HSCT. We report on four HIV-infected patients with hematological malignancies receiving an Allo-HSCT in our institution, and on the use of donor lymphocyte infusions to successfully treat post-Allo-HSCT relapse. Of note, one of them is the first HIV(+) patient to receive a "dual transplant" (unrelated umbilical cord blood stem cells combined with mobilized T cell-depleted CD34(+) stem cells from a mismatched third party donor). cART drugs interactions were satisfactorily managed. This approach provided long-term control of the hematological disease. Nevertheless, despite adequate immune reconstitution, infections were the main cause of morbidity and mortality after Allo-HSCT. PMID- 23800258 TI - Vaccinia virus expressing bone morphogenetic protein-4 in novel glioblastoma orthotopic models facilitates enhanced tumor regression and long-term survival. AB - BACKGROUND: Glioblastoma multiforme (GBM) is one of the most aggressive forms of cancer with a high rate of recurrence. We propose a novel oncolytic vaccinia virus (VACV)-based therapy using expression of the bone morphogenetic protein (BMP)-4 for treating GBM and preventing recurrence. METHODS: We have utilized clinically relevant, orthotopic xenograft models of GBM based on tumor-biopsy derived, primary cancer stem cell (CSC) lines. One of the cell lines, after being transduced with a cDNA encoding firefly luciferase, could be used for real time tumor imaging. A VACV that expresses BMP-4 was constructed and utilized for infecting several primary glioma cultures besides conventional serum-grown glioma cell lines. This virus was also delivered intracranially upon implantation of the GBM CSCs in mice to determine effects on tumor growth. RESULTS: We found that the VACV that overexpresses BMP-4 demonstrated heightened replication and cytotoxic activity in GBM CSC cultures with a broad spectrum of activity across several different patient-biopsy cultures. Intracranial inoculation of mice with this virus resulted in a tumor size equal to or below that at the time of injection. This resulted in survival of 100% of the treated mice up to 84 days post inoculation, significantly superior to that of a VACV lacking BMP-4 expression. When mice with a higher tumor burden were injected with the VACV lacking BMP-4, 80% of the mice showed tumor recurrence. In contrast, no recurrence was seen when mice were injected with the VACV expressing BMP-4, possibly due to induction of differentiation in the CSC population and subsequently serving as a better host for VACV infection and oncolysis. This lack of recurrence resulted in superior survival in the BMP-4 VACV treated group. CONCLUSIONS: Based on these findings we propose a novel VACV therapy for treating GBM, which would allow tumor specific production of drugs in the future in combination with BMPs which would simultaneously control tumor maintenance and facilitate CSC differentiation, respectively, thereby causing sustained tumor regression without recurrence. PMID- 23800260 TI - An interview with Nicola Maffulli, section editor for the musculoskeletal regenerative medicine section of BMC Sports Science, Medicine and Rehabilitation. PMID- 23800259 TI - IgG4-related lung disease showing high standardized uptake values on FDG-PET: report of two cases. AB - Immunoglobulin G4 (IgG4)-related lung disease is a disease in which IgG4-positive plasma cells and lymphocytes infiltrate lung tissues along with immunohistochemically evident fibrous interstitial proliferation in the background, in addition to hyper-IgG4 disease. The diagnosis of this disease can be difficult. Here, we report 2 cases with IgG4-related lung disease that was difficult to differentiate from malignant tumors because both cases had pulmonary lesions showing high standardized uptake values (SUV) on positron emission tomography (PET). Case 1: A 75-year-old man under treatment for autoimmune pancreatitis and diabetes mellitus was noted to have multiple nodular opacities in both lungs and a mass density in the right paravertebral region on computed tomography (CT). As high SUVmax was noted for both lesions on exploration by fluorodeoxyglucose (FDG)-PET/CT, an advanced malignant tumor was diagnosed and a video-assisted thoracoscopic (VATS) biopsy was performed and diagnosed IgG4 related lung disease. Case 2: A 48-year-old woman consulted our clinic with a chief complaint of bloody sputum. Chest CT revealed a mass density with 12-, 13-, and 16-mm spiculations in the S2 segment of the right upper lobe and irregular thickening of the pleura including the paravertebral region. The lesion was a mass showing high SUV in the S2 segment on FDG-PET. Malignancy was suspected from the imaging findings, and a VATS biopsy was performed and diagnosed IgG4-related lung disease. Actively undertaking VATS biopsy in cases with this disease is valuable for making the differential diagnosis between malignant tumors and IgG4 related lung disease, since the diagnosis can be difficult in some patients showing high SUV. PMID- 23800262 TI - Synovial sarcoma presenting with huge mediastinal mass: a case report and review of literature. AB - BACKGROUND: Synovial sarcoma presenting in the mediastinum is exceedingly rare. Furthermore, data addressing optimal therapy is limited. Herein we present a case where an attempt to downsize the tumor to a resectable state with chemotherapy was employed. CASE PRESENTATION: A 32 year female presented with massive pericardial effusion and unresectable huge mediastinal mass. Computed axial tomography scan - guided biopsy with adjunctive immunostains and molecular studies confirmed a diagnosis of synovial sarcoma. Following three cycles of combination Ifosfamide and doxorubicin chemotherapy, no response was demonstrated. The patient refused further therapy and had progression of her disease 4 months following the last cycle. CONCLUSION: Synovial sarcoma presenting with unresectable mediastinal mass carry a poor prognosis. Up to the best of our knowledge there are only four previous reports where primary chemotherapy was employed, unfortunately; none of these cases had subsequent complete surgical resection. Identification of the best treatment strategy for patients with unresectable disease is warranted. Our case can be of benefit to medical oncologists and thoracic surgeons who might be faced with this unique and exceedingly rare clinical scenario. PMID- 23800261 TI - Complex between alpha-bungarotoxin and an alpha7 nicotinic receptor ligand binding domain chimaera. AB - To identify high-affinity interactions between long-chain alpha-neurotoxins and nicotinic receptors, we determined the crystal structure of the complex between alpha-btx (alpha-bungarotoxin) and a pentameric ligand-binding domain constructed from the human alpha7 AChR (acetylcholine receptor) and AChBP (acetylcholine binding protein). The complex buries ~2000 A2 (1 A=0.1 nm) of surface area, within which Arg36 and Phe32 from finger II of alpha-btx form a pi-cation stack that aligns edge-to-face with the conserved Tyr184 from loop-C of alpha7, while Asp30 of alpha-btx forms a hydrogen bond with the hydroxy group of Tyr184. These inter-residue interactions diverge from those in a 4.2 A structure of alpha-ctx (alpha-cobratoxin) bound to AChBP, but are similar to those in a 1.94 A structure of alpha-btx bound to the monomeric alpha1 extracellular domain, although compared with the monomer-bound complex, the alpha-btx backbone exhibits a large shift relative to the protein surface. Mutational analyses show that replacing Tyr184 with a threonine residue abolishes high-affinity alpha-btx binding, whereas replacing with a phenylalanine residue maintains high affinity. Comparison of the alpha-btx complex with that coupled to the agonist epibatidine reveals structural rearrangements within the binding pocket and throughout each subunit. The overall findings highlight structural principles by which alpha neurotoxins interact with nicotinic receptors. PMID- 23800263 TI - Effect of acute auditory stress on gastric motor responses to a meal in healthy volunteers. AB - BACKGROUND AND AIM: Stress is believed to play a role in the pathogenesis of functional gastrointestinal disorders. The aim of the present study was to investigate the effect of acute auditory stress on gastric motor responses to a meal in healthy subjects. METHODS: A total of eight healthy volunteers (seven men and one woman; median age, 33.4 years [30-35 years]) who had no recurrent gastrointestinal symptoms participated in the prospective, randomized, crossover study. Gastric half-emptying time and meal-induced proximal gastric accommodation were measured using gastric scintigraphy under the auditory stress and control conditions in a randomized crossover design. RESULTS: The gastric half-emptying time under the stress condition was significantly longer than that under the control condition (130.8 +/- 16.6 vs. 105.0 +/- 13.1 min; P = 0.005 by paired t test). Under the stress and control conditions, the proximal gastric volume significantly increased after a meal (P < 0.001 by repeated measures analysis of variance). The degree of the postprandial increase in proximal gastric volume did not significantly differ between both conditions (P = 0.598 by tests of between subjects effects using repeated measures analysis of variance). The severity scores of postprandial epigastric discomfort and fullness were significantly higher under the stress condition than under the control condition (P = 0.001 and P = 0.039, respectively, by paired t-test). CONCLUSIONS: Acute auditory stress delays gastric emptying and increases the severity of postprandial symptoms in the healthy subjects, suggesting the relevance of psychological stress to the pathophysiological mechanism of functional dyspepsia. PMID- 23800264 TI - Comparison of the antimicrobial effects of semipurified cyclotides from Iranian Viola odorata against some of plant and human pathogenic bacteria. AB - AIMS: Cyclotides are mini-proteins that are synthesized via the ribosomal pathway. They have a variety of biological activities such as antimicrobial, antitumour, anti-HIV activities. Because of their various bioactivities and unique stability, they are suitable candidate in drug design applications. The main aim of this study was to determine new antimicrobial agents, which can be used instead of chemical antibiotics. For this reason, we compared the antimicrobial effects of semipurified cyclotides against human and plant pathogenic bacteria. METHODS AND RESULTS: The cyclotides were isolated from the Iranian plant Viola odorata by fractionation methods and semipurified on a SPE C18 column chromatography. Antimicrobial activities of extracted cyclotides were studied by radial diffusion assays (RDAs), minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC). Data analysis showed that MIC of semipurified cyclotides was 1.6 mg ml(-1) against Staphylococcus aureus, gram positive bacteria. It was also revealed they are the most susceptible among human pathogenic bacteria used in this research. On the other hand, plant pathogenic bacteria are more susceptible than human pathogenic bacteria. CONCLUSION: The results of the study show that cyclotides from Iranian V. odorata have potent antimicrobial activity against gram-negative, plant pathogenic bacteria. SIGNIFICANCE AND IMPACT OF THE STUDY: This study is a part of our extended researches on finding new pharmaceutical potentials of plants and on developing new peptides for special purposes in a way that does not have harmful side effects or have the least side effects. PMID- 23800265 TI - Comparing influenza vaccine efficacy against mismatched and matched strains: a systematic review and meta-analysis. AB - BACKGROUND: Influenza vaccines are most effective when the antigens in the vaccine match those of circulating strains. However, antigens contained in the vaccines do not always match circulating strains. In the present work we aimed to examine the vaccine efficacy (VE) afforded by influenza vaccines when they are not well matched to circulating strains. METHODS: We identified randomized clinical trials (RCTs) through MEDLINE, EMBASE, the Cochrane Library, and references of included RCTs. RCTs reporting laboratory-confirmed influenza among healthy participants vaccinated with antigens of matching and non-matching influenza strains were included. Two independent reviewers screened citations/full-text articles, abstracted data, and appraised risk of bias. Conflicts were resolved by discussion. A random effects meta-analysis was conducted. VE was calculated using the following formula: (1 - relative risk * 100%). RESULTS: We included 34 RCTs, providing data on 47 influenza seasons and 94,821 participants. The live-attenuated influenza vaccine (LAIV) showed significant protection against mismatched (six RCTs, VE 54%, 95% confidence interval (CI) 28% to 71%) and matched (seven RCTs, VE 83%, 95% CI 75% to 88%) influenza strains among children aged 6 to 36 months. Differences were observed between the point estimates for mismatched influenza A (five RCTs, VE 75%, 95% CI 41% to 90%) and mismatched influenza B (five RCTs, VE 42%, 95% CI 22% to 56%) estimates among children aged 6 to 36 months. The trivalent inactivated vaccine (TIV) also afforded significant protection against mismatched (nine RCTs, VE 52%, 95% CI 37% to 63%) and matched (eight RCTs, VE 65%, 95% CI 54% to 73%) influenza strains among adults. Numerical differences were observed between the point estimates for mismatched influenza A (five RCTs, VE 64%, 95% CI 23% to 82%) and mismatched influenza B (eight RCTs, VE 52%, 95% CI 19% to 72%) estimates among adults. Statistical heterogeneity was low (I2 <50%) across all meta-analyses, except for the LAIV meta-analyses among children (I2 = 79%). CONCLUSIONS: The TIV and LAIV vaccines can provide cross protection against non-matching circulating strains. The point estimates for VE were different for matching versus non matching strains, with overlapping CIs. PMID- 23800267 TI - Improved docking of polypeptides with Glide. AB - Predicting the binding mode of flexible polypeptides to proteins is an important task that falls outside the domain of applicability of most small molecule and protein-protein docking tools. Here, we test the small molecule flexible ligand docking program Glide on a set of 19 non-alpha-helical peptides and systematically improve pose prediction accuracy by enhancing Glide sampling for flexible polypeptides. In addition, scoring of the poses was improved by post processing with physics-based implicit solvent MM-GBSA calculations. Using the best RMSD among the top 10 scoring poses as a metric, the success rate (RMSD <= 2.0 A for the interface backbone atoms) increased from 21% with default Glide SP settings to 58% with the enhanced peptide sampling and scoring protocol in the case of redocking to the native protein structure. This approaches the accuracy of the recently developed Rosetta FlexPepDock method (63% success for these 19 peptides) while being over 100 times faster. Cross-docking was performed for a subset of cases where an unbound receptor structure was available, and in that case, 40% of peptides were docked successfully. We analyze the results and find that the optimized polypeptide protocol is most accurate for extended peptides of limited size and number of formal charges, defining a domain of applicability for this approach. PMID- 23800266 TI - Impaired proteasomal degradation enhances autophagy via hypoxia signaling in Drosophila. AB - BACKGROUND: Two pathways are responsible for the majority of regulated protein catabolism in eukaryotic cells: the ubiquitin-proteasome system (UPS) and lysosomal self-degradation through autophagy. Both processes are necessary for cellular homeostasis by ensuring continuous turnover and quality control of most intracellular proteins. Recent studies established that both UPS and autophagy are capable of selectively eliminating ubiquitinated proteins and that autophagy may partially compensate for the lack of proteasomal degradation, but the molecular links between these pathways are poorly characterized. RESULTS: Here we show that autophagy is enhanced by the silencing of genes encoding various proteasome subunits (alpha, beta or regulatory) in larval fat body cells. Proteasome inactivation induces canonical autophagy, as it depends on core autophagy genes Atg1, Vps34, Atg9, Atg4 and Atg12. Large-scale accumulation of aggregates containing p62 and ubiquitinated proteins is observed in proteasome RNAi cells. Importantly, overexpressed Atg8a reporters are captured into the cytoplasmic aggregates, but these do not represent autophagosomes. Loss of p62 does not block autophagy upregulation upon proteasome impairment, suggesting that compensatory autophagy is not simply due to the buildup of excess cargo. One of the best characterized substrates of UPS is the alpha subunit of hypoxia inducible transcription factor 1 (HIF-1alpha), which is continuously degraded by the proteasome during normoxic conditions. Hypoxia is a known trigger of autophagy in mammalian cells, and we show that genetic activation of hypoxia signaling also induces autophagy in Drosophila. Moreover, we find that proteasome inactivation-induced autophagy requires sima, the Drosophila ortholog of HIF 1alpha. CONCLUSIONS: We have characterized proteasome inactivation- and hypoxia signaling-induced autophagy in the commonly used larval Drosophila fat body model. Activation of both autophagy and hypoxia signaling was implicated in various cancers, and mutations affecting genes encoding UPS enzymes have recently been suggested to cause renal cancer. Our studies identify a novel genetic link that may play an important role in that context, as HIF-1alpha/sima may contribute to upregulation of autophagy by impaired proteasomal activity. PMID- 23800268 TI - Cardiac surgery: a rare and often overlooked cause of Budd-Chiari syndrome. PMID- 23800269 TI - Mesotherapy for local fat reduction. AB - Mesotherapy, which is the injection of substances locally into mesodermally derived subcutaneous tissue, developed from empirical observations of a French physician in the 1950s. Although popular in Europe for many medical purposes, it is used for local cosmetic fat reduction in the United States. This paper reviews manuscripts indexed in PubMed/MEDLINE under 'mesotherapy', which pertains to local fat reduction. The history of lipolytic mesotherapy, the physiology of body fat distribution, the mechanism of action of different lipolytic stimulators and their increased efficacy in combination are reviewed. Mesotherapy falls into two categories. Lipolytic mesotherapy using lipolytic stimulators requires more frequent treatments as the fat cells are not destroyed and can refill over time. Ablative mesotherapy destroys fat cells with a detergent, causes inflammation and scarring from the fat necrosis, but requires fewer treatments. The historic and empiric mixing of sodium channel blocking local anaesthetics in mesotherapy solutions inhibits the intended lipolysis. Major mesotherapy safety concerns include injection site infections from poor sterile technique. Cosmetic mesotherapy directs the area from which fat is lost to improve self-image. Studies were of relatively small number, many with limited sample sizes. Future research should be directed towards achieving a Food and Drug Administration indication rather than continuing expansion of off-label use. PMID- 23800270 TI - Aboriginal birth cohort (ABC): a prospective cohort study of early life determinants of adiposity and associated risk factors among Aboriginal people in Canada. AB - BACKGROUND: Aboriginal people living in Canada have a high prevalence of obesity, type 2 diabetes, and cardiovascular disease (CVD). To better understand the pre and postnatal influences on the development of adiposity and related cardio metabolic factors in adult Aboriginal people, we will recruit and follow prospectively Aboriginal pregnant mothers and their children - the Aboriginal Birth Cohort (ABC) study. METHODS/DESIGN: We aim to recruit 300 Aboriginal pregnant mothers and their newborns from the Six Nations Reserve, and follow them prospectively to age 3 years. Key details of environment and health including maternal nutrition, glucose tolerance, physical activity, and weight gain will be collected. At birth, cord blood and placenta samples will be collected, as well as newborn anthropometric measurements. Mothers and offspring will be followed annually with serial measurements of diet and physical activity, growth trajectory, and adiposity. DISCUSSION: There is an urgent need to understand maternal and child factors that underlie the early development of adiposity and type 2 diabetes in Aboriginal people. The information generated from this cohort will assist the Six Nations community in developing interventions to prevent early adiposity in Aboriginal children. PMID- 23800271 TI - Burkitt lymphoma of the ovary: a case report and literature review. AB - We report an extremely rare case of primary ovarian Burkitt lymphoma. A 15-year old girl was referred to our department because of persistent constipation and abdominal distension. Abdominal computed tomography and magnetic resonance imaging revealed a 10-cm-diameter solid tumor located on the right side of the uterus. Serum lactate dehydrogenase and carbohydrate antigen-125 levels were elevated at 3250 IU/L and 235.7 U/mL, respectively. Initially, ovarian dysgerminoma was suspected, but poor performance and progressive disease were suggestive of malignant lymphoma. However, bone marrow aspiration and ascitic fluid cytology findings were not indicative of lymphoma. Laparotomy was performed to confirm pathology. On laparotomy, the right ovary was firm and enlarged, but the uterus and left ovary were normal. Diffuse thickness of retroperitoneal space was observed. Right salpingo-oophorectomy was performed, and the tumor was diagnosed as Burkitt lymphoma. Although intensive chemotherapy was administered, the patient died 171 days after the initial operation. PMID- 23800272 TI - The immune system in pigment cell biology: villain or hero? PMID- 23800273 TI - Episodic memory retrieval for story characters in high-functioning autism. AB - BACKGROUND: The objective of this study was to examine differences in episodic memory retrieval between individuals with autism spectrum disorder (ASD) and typically developing (TD) individuals. Previous studies have shown that personality similarities between readers and characters facilitated reading comprehension. Highly extraverted participants read stories featuring extraverted protagonists more easily and judged the outcomes of such stories more rapidly than did less extraverted participants. Similarly, highly neurotic participants judged the outcomes of stories with neurotic protagonists more rapidly than did participants with low levels of neuroticism. However, the impact of the similarity effect on memory retrieval remains unclear. This study tested our 'similarity hypothesis', namely that memory retrieval is enhanced when readers with ASD and TD readers read stories featuring protagonists with ASD and with characteristics associated with TD individuals, respectively. METHODS: Eighteen Japanese individuals (one female) with high-functioning ASD (aged 17 to 40 years) and 17 age- and intelligence quotient (IQ)-matched Japanese (one female) TD participants (aged 22 to 40 years) read 24 stories; 12 stories featured protagonists with ASD characteristics, and the other 12 featured TD protagonists. Participants read a single sentence at a time and pressed a spacebar to advance to the next sentence. After reading all 24 stories, they were asked to complete a recognition task about the target sentence in each story. RESULTS: To investigate episodic memory in ASD, we analyzed encoding based on the reading times for and readability of the stories and retrieval processes based on the accuracy of and response times for sentence recognition. Although the results showed no differences between ASD and TD groups in encoding processes, they did reveal inter-group differences in memory retrieval. Although individuals with ASD demonstrated the same level of accuracy as did TD individuals, their patterns of memory retrieval differed with respect to response times. CONCLUSIONS: Individuals with ASD more effectively retrieved ASD-congruent than ASD incongruent sentences, and TD individuals retrieved stories with TD more effectively than stories with ASD protagonists. Thus, similarity between reader and story character had different effects on memory retrieval in the ASD and TD groups. PMID- 23800274 TI - Cognitive function and number of teeth in a community-dwelling population in Japan. AB - BACKGROUND: It has been reported that oral health is poor in elderly populations and is associated with poor cognition and dementia. The objective of this study was to examine the association between tooth loss and cognitive function in a community-dwelling population in Japan. METHODS: We examined the association between tooth loss and cognitive function in 462 Japanese community-dwelling individuals. The Mini-Mental State Examination (MMSE) was employed to measure global cognitive status. A multiple logistic regression analysis, with both crude and adjusted conditions for confounding factors, was used to assess the relationship between poor cognition and the number of remaining teeth. RESULTS: The overall prevalence of poor cognition (MMSE <= 23) in this study population was 5.6%. Subjects with poor cognition were significantly older, less educated, scored lower in intellectual activity, and had fewer remaining teeth than those with normal cognition. According to the multiple logistic regression analysis, a lower number of teeth (0-10) was found to be a significant independent risk factor (OR = 20.21, 95% confidence interval = 2.20 to 185.47) of cognitive impairment. CONCLUSIONS: This cross-sectional study on a Japanese community dwelling population revealed relationships between tooth loss and cognitive function. However, the interpretation of our results was hampered by a lack of data, including socioeconomic status and longitudinal observations. Future research exploring tooth loss and cognitive function is warranted. PMID- 23800275 TI - Low expression of the X-linked ribosomal protein S4 in human serous epithelial ovarian cancer is associated with a poor prognosis. AB - BACKGROUND: The X-linked ribosomal protein S4 (RPS4X), which is involved in cellular translation and proliferation, has previously been identified as a partner of the overexpressed multifunctional protein YB-1 in several breast cancer cells. Depletion of RPS4X results in consistent resistance to cisplatin in such cell lines. METHODS: As platinum-based chemotherapy is a standard first line therapy used to treat patients with ovarian cancer, we evaluated the prognostic value of RPS4X and YB-1 at the protein level in specimen from 192 high-grade serous epithelial ovarian cancer patients. RESULTS: Immunohistochemistry studies indicated that high expression of RPS4X was associated with a lower risk of death and later disease progression (HR = 0.713, P = 0.001 and HR = 0.761, P = 0.001, respectively) as compared to low expression of RPS4X. In contrast, YB-1 was not significantly associated with either recurrence or survival time in this cohort. Finally, the depletion of RPS4X with different siRNAs in two different ovarian cancer cell lines reduced their proliferative growth rate but more importantly increased their resistance to cisplatin. CONCLUSION: Altogether, these results suggest that the levels of RPS4X could be a good indicator for resistance to platinum-based therapy and a prognostic marker for ovarian cancer. Our study also showed that RPS4X is an independent prognostic factor in patients with serous epithelial ovarian cancer. PMID- 23800276 TI - T1 and extracellular volume mapping in the heart: estimation of error maps and the influence of noise on precision. AB - BACKGROUND: Quantitative measurements in the myocardium may be used to detect both focal and diffuse disease processes that result in an elevation of T1 and/or extracellular volume (ECV) fraction. Detection of abnormal myocardial tissue by these methods is affected by both the accuracy and precision. The sensitivity for detecting abnormal elevation of T1 and ECV is limited by the precision of T1 estimates which is a function of the number and timing of measurements along the T1-inversion recovery curve, the signal-to-noise ratio (SNR), the tissue T1, and the method of fitting. METHODS: The standard deviation (SD) of T1 and ECV estimates are formulated and SD maps are calculated on a pixel-wise basis using the Modified Look-Locker Inversion recovery (MOLLI) method. SD estimates are validated by numerical simulation using Monte-Carlo analysis and with phantoms using repeated trials. SD estimates are provided for pre- and post-contrast optimized protocols for a range of T1s and SNRs. In-vivo examples are provide for normal, myocarditis, and HCM in human subjects. The formulation of SD maps was extended to R1 and ECV. RESULTS: The measured myocardial SNR ranged from 23 to 43 across the heart using the specific T1-mapping protocol in this study. In this range of SNRs, the estimated SD for T1 was approximately 20-45 ms for pre contrast myocardial T1 around 1000 ms, and was approximately 10-20 ms for post contrast T1 around 400 ms. The proposed estimate of SD was an unbiased estimate of the standard deviation of T1 validated by numerical simulation and had > 99% correlation with phantom measurements. The measured SD maps exhibited variation across the heart due to drop off in surface coil sensitivity as expected for the variation in SNR. Focal elevation in T1 and ECV was shown to have statistical significance on a pixel-wise basis for in-vivo examples. CONCLUSIONS: Pixel-wise estimates of T1 mapping errors have been formulated and validated, and the formulation has been extended to ECV. The ability to quantify the measurement error has potential to determine the statistical significance of subtle abnormalities that arise due to diffuse disease processes involving fibrosis and/or edema and is useful both as a confidence metric for overall quality, and in optimization and comparison of imaging protocols. PMID- 23800277 TI - Molecular epidemiology of extended-spectrum beta-lactamase-producing Escherichia coli in Tunisia and characterization of their virulence factors and plasmid addiction systems. AB - BACKGROUND: Extended-spectrum beta-lactamases (ESBLs), particularly CTX-M- type ESBLs, are among the most important resistance determinants spreading worldwide in Enterobacteriaceae. The aim of this study was to characterize a collection of 163 ESBL-producing Escherichia coli collected in Tunisia, their ESBL-encoding plasmids and plasmid associated addiction systems. RESULTS: The collection comprised 163 ESBL producers collected from two university hospitals of Sfax between 1989 and 2009. 118 isolates harbored blaCTX-M gene (101 blaCTX-M-15 gene and 17 blaCTX-M-14 gene). 49 isolates carried blaSHV-12 gene, 9 blaSHV-2a gene and only 3 blaTEM-26 gene. 16 isolates produced both CTX-M and SHV-12. The 101 CTX-M-15-producing isolates were significantly associated to phylogroup B2 and exhibiting a high number of virulence factors. 24 (23.7%) of the group B2 isolates belonged to clonal complex ST131. Pulsed-field gel electrophoresis (PFGE) typing revealed a genetic diversity of the isolates. 144 ESBL determinants were transferable mostly by conjugation. The majority of plasmid carrying blaCTX M-15 genes (72/88) were assigned to various single replicon or multireplicon IncF types and had significantly a higher frequency of addiction systems, notably the VagCD module. CONCLUSION: This study demonstrates that the dissemination of CTX-M 15 producing E. coli in our setting was due to the spread of various IncF-type plasmids harboring multiple addiction systems, into related clones with high frequency of virulence determinants. PMID- 23800278 TI - Worse outcome of sorafenib therapy associated with ascites and Child-Pugh score in advanced hepatocellular carcinoma. AB - BACKGROUND AND AIM: The outcomes of sorafenib therapy in patients with advanced hepatocellular carcinoma (HCC) and impaired liver function remain unresolved. Although Child-Pugh (CP) classification is widely used for patient categorization, heterogeneity within a given CP class makes outcomes less predictable. The aim was to investigate the prognostic significance of CP score elements on the outcome of sorafenib in patients with advanced HCC and impaired liver function. METHODS: Of 1385 consecutive patients with advanced HCC in our center between January 2007 and December 2010, we reviewed the medical records of 325 patients who received sorafenib monotherapy. RESULTS: Median duration of sorafenib was 2.0 months (range 0.4-24.2) and median follow-up was 4.9 months (range 0.5-43.4). Disease control rates were significantly higher in CP class A (CPA) than in CP class B (CPB) patients. Median overall survival (OS) was 5.8 months. Subgroups with different CP scores showed significantly different OS (months): CPA5, 8.4; CPA6, 5.1; CPB7, 3.5; CPB8-9, 2.6 (P < 0.001). The presence of ascites was a significant prognostic factor in CPB7 patients (hazard ratio 2.262; P = 0.016). OS of CPB7 patients without ascites was similar to that of CPA6 patients (4.6 months) and was significantly longer than that of CPB7 patients with ascites (2.5 months; P = 0.027). OS of CPB7 patients with ascites was similar to that of CPB8-9 patients. CONCLUSIONS: CP score was more important than CP class in predicting the outcome of sorafenib therapy in patients with advanced HCC. Among the CP score components, presence of ascites was a significant prognostic factor, especially in CPB7 patients. PMID- 23800280 TI - Adverse events among Ontario home care clients associated with emergency room visit or hospitalization: a retrospective cohort study. AB - BACKGROUND: Home care (HC) is a critical component of the ongoing restructuring of healthcare in Canada. It impacts three dimensions of healthcare delivery: primary healthcare, chronic disease management, and aging at home strategies. The purpose of our study is to investigate a significant safety dimension of HC, the occurrence of adverse events and their related outcomes. The study reports on the incidence of HC adverse events, the magnitude of the events, the types of events that occur, and the consequences experienced by HC clients in the province of Ontario. METHODS: A retrospective cohort design was used, utilizing comprehensive secondary databases available for Ontario HC clients from the years 2008 and 2009. The data were derived from the Canadian Home Care Reporting System, the Hospital Discharge Abstract Database, the National Ambulatory Care Reporting System, the Ontario Mental Health Reporting System, and the Continuing Care Reporting System. Descriptive analysis was used to identify the type and frequency of the adverse events recorded and the consequences of the events. Logistic regression analysis was used to examine the association between the events and their consequences. RESULTS: The study found that the incident rate for adverse events for the HC clients included in the cohort was 13%. The most frequent adverse events identified in the databases were injurious falls, injuries from other than a fall, and medication-related incidents. With respect to outcomes, we determined that an injurious fall was associated with a significant increase in the odds of a client requiring long-term-care facility admission and of client death. We further determined that three types of events, delirium, sepsis, and medication-related incidents were associated directly with an increase in the odds of client death. CONCLUSIONS: Our study concludes that 13% of clients in homecare experience an adverse event annually. We also determined that an injurious fall was the most frequent of the adverse events and was associated with increased admission to long-term care or death. We recommend the use of tools that are presently available in Canada, such as the Resident Assessment Instrument and its Clinical Assessment Protocols, for assessing and mitigating the risk of an adverse event occurring. PMID- 23800281 TI - Phylogeny determines the role of helminth parasites in intertidal food webs. AB - 1. Parasites affect interactions among species in food webs and should be considered in any analysis of the structure, dynamics or resilience of trophic networks. 2. However, the roles of individual parasite species, such as their importance as connectors within the network, and what factors determine these roles, are yet to be investigated. Here, we test the hypotheses that the species roles of trematode, cestode and nematode parasites in aquatic food webs are influenced by the type of definitive host they use, and also determined by their phylogenetic affiliations. 3. We quantified the network role of 189 helminth species from six highly resolved intertidal food webs. We focused on four measures of centrality (node degree, closeness centrality, betweenness centrality and eigenvalue centrality), which characterize each parasite's position within the web, and on relative connectedness of a parasite species to taxa in its own module vs. other modules of the web (within-module degree and participation coefficient). 4. All six food webs displayed a significant modular structure, that is, they consisted of subsets of species interacting mostly with each other and less with species from other subsets. We demonstrated that the parasites themselves are not generating this modularity, though they contribute to intermodule connectivity. 5. Mixed-effects models revealed only a modest influence of the type of definitive host used (bird or fish) and of the web of origin on the different measures of parasite species roles. In contrast, the taxonomic affiliations of the parasites, included in the models as nested random factors, accounted for 37-93% of the total variance, depending on the measure of species role. 6. Our findings indicate that parasites are important intermodule connectors and thus contribute to web cohesion. We also uncover a very strong phylogenetic signal in parasite species roles, suggesting that the role of any parasite species in a food web, including new invasive species, is to some extent predictable based solely on its taxonomic affiliations. PMID- 23800279 TI - Multiparametric and semiquantitative scoring systems for the evaluation of mouse model histopathology--a systematic review. AB - BACKGROUND: Histopathology has initially been and is still used to diagnose infectious, degenerative or neoplastic diseases in humans or animals. In addition to qualitative diagnoses semiquantitative scoring of a lesion's magnitude on an ordinal scale is a commonly demanded task for histopathologists. Multiparametric, semiquantitative scoring systems for mouse models histopathology are a common approach to handle these questions and to include histopathologic information in biomedical research. RESULTS: Inclusion criteria for scoring systems were a first description of a multiparametric, semiquantiative scoring systems which comprehensibly describe an approach to evaluate morphologic lesion. A comprehensive literature search using these criteria identified 153 originally designed semiquantitative scoring systems for the analysis of morphologic changes in mouse models covering almost all organs systems and a wide variety of disease models. Of these, colitis, experimental autoimmune encephalitis, lupus nephritis and collagen induced osteoarthritis colitis were the disease models with the largest number of different scoring systems. Closer analysis of the identified scoring systems revealed a lack of a rationale for the selection of the scoring parameters or a correlation between scoring parameter value and the magnitude of the clinical symptoms in most studies. CONCLUSION: Although a decision for a particular scoring system is clearly dependent on the respective scientific question this review gives an overview on currently available systems and may therefore allow for a better choice for the respective project. PMID- 23800282 TI - Compartmentalized, functional role of angiogenin during spotted fever group rickettsia-induced endothelial barrier dysfunction: evidence of possible mediation by host tRNA-derived small noncoding RNAs. AB - BACKGROUND: Microvascular endothelial barrier dysfunction is the central enigma in spotted fever group (SFG) rickettsioses. Angiogenin (ANG) is one of the earliest identified angiogenic factors, of which some are relevant to the phosphorylation of VE-cadherins that serve as endothelial adherens proteins. Although exogenous ANG is known to translocate into the nucleus of growing endothelial cells (ECs) where it plays a functional role, nuclear ANG is not detected in quiescent ECs. Besides its nuclear role, ANG is thought to play a cytoplasmic role, owing to its RNase activity that cleaves tRNA to produce small RNAs. Recently, such tRNA-derived RNA fragments (tRFs) have been shown to be induced under stress conditions. All these observations raise an intriguing hypothesis about a novel cytoplasmic role of ANG, which is induced upon infection with Rickettsia and generates tRFs that may play roles in SFG rickettsioses. METHODS: C3H/HeN mice were infected intravenously with a sublethal dose of R. conorii. At days 1, 3, and 5 post infection (p.i.), liver, lung and brain were collected for immunofluorescence (IF) studies of R. conorii and angiogenin (ANG). Human umbilical vein endothelial cells (HUVECs) were infected with R. conorii for 24, 48, and 72 hrs before incubation with 1MUg/ml recombinant human ANG (rANG) in normal medium for 2 hrs. HUVEC samples were subjected to IF, exogenous ANG translocation, endothelial permeability, and immunoprecipitation phosphorylation assays. To identify small non-coding RNAs (sncRNAs) upon rickettsial infection, RNAs from pulverized mouse lung tissues and HUVECs were subjected to library preparation and deep sequencing analysis using an Illumina 2000 instrument. Identified sncRNAs were confirmed by Northern hybridization, and their target mRNAs were predicted in silico using BLAST and RNA hybrid programs. RESULTS: In the present study, we have demonstrated endothelial up-regulation of ANG, co localized with SFG rickettsial infection in vivo. We also have provided direct evidence that rickettsial infection sensitizes human ECs to the translocation of exogenous ANG in a compartmentalized pattern at different times post-infection. Typically, exogenous ANG translocates into the nucleus at 24 hrs and to the cytoplasm at 72 hrs post-infection. The ANG cytoplasmic translocation enhances phosphorylation and destabilization of VE-cadherin and attenuates endothelial barrier function. Of note, deep sequencing analysis detected tRFs, mostly derived from the 5'-halves of host tRNAs, that are induced by ANG. Northern hybridization validates the two most abundantly cloned tRFs derived from tRNA-ValGTG and tRNA GlyGCC, in both mouse tissues and human cells. Bioinformatics analysis predicted that these tRFs may interact with transcripts associated with the endothelial barrier, the host cell inflammatory response, and autophagy. CONCLUSIONS: Our data provide new insight into the role of compartmentalized ANG during SFG rickettsioses, and highlight its possible mediation through tRFs. PMID- 23800283 TI - Spatial disaggregation of tick occurrence and ecology at a local scale as a preliminary step for spatial surveillance of tick-borne diseases: general framework and health implications in Belgium. AB - BACKGROUND: The incidence of tick-borne diseases is increasing in Europe. Sub national information on tick distribution, ecology and vector status is often lacking. However, precise location of infection risk can lead to better targeted prevention measures, surveillance and control. METHODS: In this context, the current paper compiled geolocated tick occurrences in Belgium, a country where tick-borne disease has received little attention, in order to highlight the potential value of spatial approaches and draw some recommendations for future research priorities. RESULTS: Mapping of 89,289 ticks over 654 sites revealed that ticks such as Ixodes ricinus and Ixodes hexagonus are largely present while Dermacentor reticulatus has a patchy distribution. Suspected hot spots of tick diversity might favor pathogen exchanges and suspected hot spots of I. ricinus abundance might increase human-vector contact locally. This underlines the necessity to map pathogens and ticks in detail. While I. ricinus is the main vector, I. hexagonus is a vector and reservoir of Borrelia burgdorferi s.l., which is active the whole year and is also found in urban settings. This and other nidiculous species bite humans less frequently, but seem to harbour pathogens. Their role in maintaining a pathogenic cycle within the wildlife merits investigation as they might facilitate transmission to humans if co occurring with I. ricinus. Many micro-organisms are found abroad in tick species present in Belgium. Most have not been recorded locally but have not been searched for. Some are transmitted directly at the time of the bite, suggesting promotion of tick avoidance additionally to tick removal. CONCLUSION: This countrywide approach to tick-borne diseases has helped delineate recommendations for future research priorities necessary to design public health policies aimed at spatially integrating the major components of the ecological cycle of tick borne diseases. A systematic survey of tick species and associated pathogens is called for in Europe, as well as better characterisation of species interaction in the ecology of tick-borne diseases, those being all tick species, pathogens, hosts and other species which might play a role in tick-borne diseases complex ecosystems. PMID- 23800284 TI - Body mass index and risk of pneumonia: a systematic review and meta-analysis. AB - The aims of our meta-analysis were to examine the pattern and gender's influence on body mass index (BMI) - pneumonia relationship. Published studies were searched from PubMed, Web of Science, Cochrane Library databases using keywords of pneumonia, BMI and epidemiologic studies. Random-effects analysis was applied to estimate pooled effect sizes from individual studies. The Cochrane Q-test and index of heterogeneity (I(2) ) were used to evaluate heterogeneity, and Egger's test was used to evaluate publication bias. Random-effects meta-regression was applied to examine the pattern and gender's influence on BMI-pneumonia relationship. A total of 1,531 studies were initially identified, and 25 studies finally were included. The pooled relative risk (RR) and meta-regression model revealed a J-shaped relationship between BMI and risk of community-acquired pneumonia (underweight, RR 1.8, 95% confidence interval [CI], 1.4-2.2, P < 0.01; overweight, 0.89, 95%CI, 0.8-1.03, P, 0.1; obesity, 1.03, 95% CI, 0.8-1.3, p. 8) and U-shaped relationship between BMI and risk of influenza-related pneumonia (underweight, RR 1.9, 95% CI, 1.2-3, P < 0.01; overweight, 0.89, 95% CI, 0.79 0.99, P, 0.03; obesity, 1.3, 95% CI, 1.05-1.63, p. 2; morbidity obesity, 4.6, 95% CI, 2.2-9.8, P < 0.01); whereas, no difference in risk of nosocomial pneumonia was found across the BMI groups. Gender difference did not make significant contribution in modifying BMI-pneumonia risk relationship. PMID- 23800285 TI - Proteome adaptations in Ethe1-deficient mice indicate a role in lipid catabolism and cytoskeleton organization via post-translational protein modifications. AB - Hydrogen sulfide is a physiologically relevant signalling molecule. However, circulating levels of this highly biologically active substance have to be maintained within tightly controlled limits in order to avoid toxic side effects. In patients suffering from EE (ethylmalonic encephalopathy), a block in sulfide oxidation at the level of the SDO (sulfur dioxygenase) ETHE1 leads to severe dysfunctions in microcirculation and cellular energy metabolism. We used an Ethe1 deficient mouse model to investigate the effect of increased sulfide and persulfide concentrations on liver, kidney, muscle and brain proteomes. Major disturbances in post-translational protein modifications indicate that the mitochondrial sulfide oxidation pathway could have a crucial function during sulfide signalling most probably via the regulation of cysteine S-modifications. Our results confirm the involvement of sulfide in redox regulation and cytoskeleton dynamics. In addition, they suggest that sulfide signalling specifically regulates mitochondrial catabolism of FAs (fatty acids) and BCAAs (branched-chain amino acids). These findings are particularly relevant in the context of EE since they may explain major symptoms of the disease. PMID- 23800286 TI - Self-assembled nanoparticles based on modified cationic dipeptides and DNA: novel systems for gene delivery. AB - BACKGROUND: Gene therapy is most effective when delivery is both efficient and safe. However, it has often proven difficult to find a balance between efficiency and safety in case of viral or polymeric vectors for gene therapy. Peptide based delivery systems may be attractive alternatives but their relative instability to proteolysis is a major concern in realizing their potential application in biomedical sciences. In this work we report gene delivery potential of nanoparticles (Nps) synthesized from cationic dipeptides containing a non-protein amino acid alpha, beta-dehydrophenylalanine (?Phe) residue. METHODS: Dipeptides were synthesized using solution phase peptide synthesis method. Nps were formed using self-assembly. Nps were characterized using light scattering, electron microscopy. Transfection efficiency was tested in hepatocellular carcinoma (HuH 7) cells. RESULTS: The cationic dipeptides condensed plasmid DNA into discrete vesicular nanostructures. Dipeptide Nps are non-cytotoxic, protected the condensed DNAs from enzymatic degradation and ferried them successfully inside different types of cells. GFP encoding plasmid DNA loaded dipeptide Nps showed positive transfection and gene expression in HuH 7 cells. CONCLUSIONS: The cationic dipeptide Nps can successfully deliver DNA without exerting any cytotoxic effect. Owing to their simple dipeptide origin, ease of synthesis, enhanced enzymatic stability as well unmatched biocompatibility, these could be successfully developed as vehicles for effective gene therapy. PMID- 23800287 TI - The acute effects of alcohol on sleep architecture in late adolescence. AB - BACKGROUND: Alcohol consumption is prevalent in late adolescence; however, little is known about its effect on sleep in this group. In mature adults, alcohol decreases sleep onset latency (SOL) and sleep efficiency (SE) and increases wake after sleep onset (WASO). It also increases slow wave sleep (SWS) and decreases rapid eye movement (REM) sleep in the first half of the night, with the inverse occurring in the second half. Alcohol's effect on sleep during late adolescence is of interest given that this age group shows both dramatic increases in alcohol consumption and significant developmental changes in the central nervous system. This study examined the effect of alcohol on sleep architecture in women and men aged 18 to 21 years and whether previously reported sleep architecture effects may have been as an artificial result of changes to sleep cycle length. METHODS: Twenty-four (12 women) healthy 18- to 21-year-old light social drinkers (19.1 +/- 1.0 years) underwent 2 conditions: presleep alcohol (target breath alcohol concentration [BAC] 0.10%) and placebo-administered under controlled conditions, followed by standard polysomnography. RESULTS: In the alcohol condition, mean BAC at lights out was 0.084 +/- 0.016%. Time in bed, total sleep time, and SOL (all p > 0.05) did not differ between conditions. However, there was less REM (p = 0.011) and more stage-2 sleep (p = 0.035) in the alcohol condition. Further, alcohol increased SWS (p = 0.02) and decreased REM sleep (p < 0.001) in the first half of the night and disrupted sleep in the second half, with increased WASO (interaction: p = 0.034), and decreased SE (p = 0.04) and SWS (p = 0.01) and no REM sleep rebound in the second half of the night (p = 0.262). Additionally, alcohol had no effect on sleep cycle length (p = 0.598). CONCLUSIONS: The results were broadly consistent with the adult literature with the novel extension that half night sleep architecture effects could not be attributed to changes in sleep cycle length. However, alcohol did not reduce SOL, or result in a REM rebound following reduced REM in the first half of the night. The results suggest that the effects of alcohol on sleep are modified by sleep's prevailing developmental stage. PMID- 23800288 TI - Molecular study of HBZ and gp21 human T cell leukemia virus type 1 proteins isolated from different clinical profile infected individuals. AB - Human T cell leukemia virus type 1 (HTLV-1) is associated with a neurological syndrome named tropical spastic paraparesis/HTLV-associated myelopathy (TSP/HAM) and the disease progression involves viral factors. The gp21 glycoprotein is involved in envelope trafficking and membrane targeting while the bZIP protein is indispensable for cell growth and proliferation. This study aimed to assess the molecular diversity of gp21 and HBZ proteins in TSP/HAM and healthy carriers. DNA samples from HTLV-1-infected individuals were submitted to PCR and sequencing, and the molecular analyses were performed using bioinformatics tools. From eight gp21-analyzed sequences one amino acid change (Y477H) was associated with the switch of a helix to coil structure at secondary structure prediction. From 10 HBZ analyzed sequences, two amino acid changes were identified (S9P and T95I) at the activation domain. One mutation (R112C) located at the nuclear localization signal was present in 66.7% and 25% of healthy carriers (HC) and TSP/HAM groups, respectively. This is the first report of mutations in the HBZ region. These polymorphisms might be important for viral fitness. PMID- 23800289 TI - Digenic mutational inheritance of the integrin alpha 7 and the myosin heavy chain 7B genes causes congenital myopathy with left ventricular non-compact cardiomyopathy. AB - BACKGROUND: We report an Italian family in which the proband showed a severe phenotype characterized by the association of congenital fiber type disproportion (CFTD) with a left ventricular non-compaction cardiomyopathy (LVNC). This study was focused on the identification of the responsible gene/s. METHODS AND RESULTS: Using the whole-exome sequencing approach, we identified the proband homozygous missense mutations in two genes, the myosin heavy chain 7B (MYH7B) and the integrin alpha 7 (ITGA7). Both genes are expressed in heart and muscle tissues, and both mutations were predicted to be deleterious and were not found in the healthy population.The R890C mutation in the MYH7B gene segregated with the LVNC phenotype in the examined family. It was also found in one unrelated patient affected by LVNC, confirming a causative role in cardiomyopathy.The E882K mutation in the ITGA7 gene, a key component of the basal lamina of muscle fibers, was found only in the proband, suggesting a role in CFTD. CONCLUSIONS: This study identifies two novel disease genes. Mutation in MYH7B causes a classical LVNC phenotype, whereas mutation in ITGA7 causes CFTD. Both phenotypes represent alterations of skeletal and cardiac muscle maturation and are usually not severe. The severe phenotype of the proband is most likely due to a synergic effect of these two mutations.This study provides new insights into the genetics underlying Mendelian traits and demonstrates a role for digenic inheritance in complex phenotypes. PMID- 23800290 TI - Outcomes of pregnancy in women who had rescue cerclage for cervical insufficiency: a single-center retrospective study. AB - AIM: The aim of this study was to evaluate outcome of pregnancies in women with rescue cerclage for cervical insufficiency. MATERIAL AND METHODS: A retrospective study of all women who underwent rescue cerclage between 2002 and 2011 at an advanced tertiary care perinatal institute in India was conducted. Data retrieved from medical records was used to explore potential associations with prolongation of pregnancy beyond 28 weeks. RESULTS: The mean (standard deviation) gestational age at cerclage was 21.9 (2.7) weeks for the 74 women in the study. The McDonald technique was the preferred method for rescue cerclage (91.9%). All women received antibiotics; tocolytics were used in 35.1% and progesterones in 62.2% of women. The mean prolongation of pregnancy was 7.4 weeks with 42.0% women delivering after 28 weeks and 30.4% after 34 weeks. The take-home-baby rate was 50.7% (95% confidence interval: 38.7-62.6%). Postoperative vaginal infection was present in 16.2% of women, preterm premature rupture of membranes in 31.1% of women and neonatal sepsis in 5.8% of neonates. Cerclage placement after 20 weeks and negative pathogenic organisms in vaginal swab culture were significantly associated with delivery beyond 28 weeks. CONCLUSIONS: Although half of the women had successful pregnancy outcomes after rescue cerclage, pregnancy extended from previability to prematurity in most of them. PMID- 23800291 TI - The impact of coating hardness on the anti-barnacle efficacy of an embedded antifouling biocide. AB - The efficacy of antifouling coatings designed to minimise the release of biocide, either by embedded (non-covalent) or tethered (covalently bonded) biocides, relies on sufficient bioavailability of the active compound upon contact between the organism and the coating. This investigation is focused on whether coating hardness affects the efficacy of embedded coating systems. Two experimental, non eroding and waterborne latex paint formulations composed mainly of polystyrene (PS) or polyvinyl versatate (PV) were chosen for their difference in mechanical properties measured in terms of Buchholz indentation resistance. Ivermectin was added to both formulations to a final concentration of 0.1% (w/v) and the steady state release rate was measured according to ISO 15181 at between 34 and 70 ng cm(-2) day(-1) for both formulations. Field trials conducted over 3 months showed significant differences in anti-barnacle efficacy between the formulations despite their similar release profiles. The softer PV coating showed complete anti-barnacle efficacy, ie no barnacles were detected, while the harder PS coating showed no efficacy against barnacle colonisation during the same time period. The results indicate a new antifouling strategy whereby a route of intoxication is triggered by the organism itself upon interaction with the coating and its embedded biocide. This finding opens new possibilities in controlling macrofouling by low emission antifouling coatings. PMID- 23800292 TI - A qualitative exploration of young adult smokers' responses to novel tobacco warnings. AB - BACKGROUND: Despite reduced smoking among adolescents, smoking prevalence peaks among young adults aged 18-30, many of whom believe themselves exempt from the health risks of smoking shown in warning labels. We explored how young adult smokers perceived warnings featuring proximal risks, and whether these encouraged cessation more effectively than traditional health messages. METHODS: We conducted in-depth interviews with 17 young adult smokers and explored their perceptions of current warnings as well as novel warnings representing short-term health consequences; immediate social risks, and tobacco's toxicity (denormalizing tobacco as an everyday product). We used a thematic analysis approach to explore how participants rationalized existing warnings and interpreted the novel messages. RESULTS: Participants considered the immediate social and physiological benefits they gained from smoking outweighed the distal risks shown in health warnings, which they regarded as improbable and irrelevant. Of the novel warnings, those presenting immediate social risks altered the balance of gains and losses young adults associated with smoking; however, those presenting short-term health risks or depicting tobacco as a toxin were less effective. CONCLUSIONS: Participants regarded warnings featuring proximal social risks as more salient and they were less likely to rationalise these as irrelevant. Social risk messages merit further investigation to examine their potential as a complement to traditional health warnings. PMID- 23800294 TI - Efficient direct ethanol production from cellulose by cellulase- and cellodextrin transporter-co-expressing Saccharomyces cerevisiae. AB - Efficient degradation of cellulosic biomass requires the synergistic action of the cellulolytic enzymes endoglucanase, cellobiohydrolase, and beta-glucosidase. Although there are many reports describing consolidation of hydrolysis and fermentation steps using recombinant Saccharomyces cerevisiae that express cellulolytic enzymes, the efficiency of cellulose degradation has not been sufficiently improved. Although the yeast S. cerevisiae cannot take up cellooligosaccharide, some fungi can take up and assimilate cellooligosaccharide through a cellodextrin transporter. In this study, a S. cerevisiae strain co expressing genes for several cell surface display cellulases and the cellodextrin transporter was constructed for the purpose of improving the efficiency of direct ethanol fermentation from phosphoric acid swollen cellulose (PASC). The cellulase/cellodextrin transporter-coexpressing strain produced 1.7-fold more ethanol (4.3 g/L) from PASC during a 72-h fermentation than did a strain expressing cellulase only (2.5 g/L). Direct ethanol production from PASC by the recombinant S. cerevisiae strain was improved by co-expression of cellulase display and cellodextrin transporter genes. These results suggest that cellulase- and cellodextrin transporter-co-expressing S. cerevisiae could be a promising technology for efficient direct ethanol production from cellulose. PMID- 23800293 TI - Multi-scale agent-based modeling on melanoma and its related angiogenesis analysis. AB - BACKGROUND: Recently, melanoma has become the most malignant and commonly occurring skin cancer. Melanoma is not only the major source (75%) of deaths related to skin cancer, but also it is hard to be treated by the conventional drugs. Recent research indicated that angiogenesis is an important factor for tumor initiation, expansion, and response to therapy. Thus, we proposed a novel multi-scale agent-based computational model that integrates the angiogenesis into tumor growth to study the response of melanoma cancer under combined drug treatment. RESULTS: Our multi-scale agent-based model can simulate the melanoma tumor growth with angiogenesis under combined drug treatment. The significant synergistic effects between drug Dox and drug Sunitinib demonstrated the clinical potential to interrupt the communication between melanoma cells and its related vasculatures. Also, the sensitivity analysis of the model revealed that diffusivity related to the micro-vasculatures around tumor tissues closely correlated with the spread, oscillation and destruction of the tumor. CONCLUSIONS: Simulation results showed that the 3D model can represent key features of melanoma growth, angiogenesis, and its related micro-environment. The model can help cancer researchers understand the melanoma developmental mechanism. Drug synergism analysis suggested that interrupting the communications between melanoma cells and the related vasculatures can significantly increase the drug efficacy against tumor cells. PMID- 23800295 TI - Consumption and acceptability of whole grain staples for lowering markers of diabetes risk among overweight and obese Tanzanian adults. AB - BACKGROUND: Dietary changes characterized by a reduction in carbohydrate quality are occurring in developing countries and may be associated with a higher prevalence of obesity and chronic diseases such as type 2 diabetes mellitus. We assessed the preferences and acceptability of unrefined whole grain carbohydrate staples (i.e., brown rice, unrefined maize and unrefined sorghum ugali) as substitutes for commonly consumed refined carbohydrates in Tanzania. METHODS: A questionnaire was used to collect sociodemographic information and dietary habits, and pre-and post-tasting questionnaires were administered for test foods. A 10-point LIKERT scale was used to rate attributes of the three test foods. RESULTS: White rice and refined maize ugali were the most commonly consumed carbohydrate staples in this population; 98% and 91%, respectively. Occasional consumption of unrefined maize and sorghum ugali was reported by 32% and 23% of the participants, respectively. All of the test foods were highly rated for smell, taste, color, appearance and texture. Taste was rated highest for unrefined maize ugali. Almost all of the participants were willing to participate in a future dietary intervention involving regular consumption of these unrefined carbohydrates for at least six months duration. CONCLUSIONS: These findings suggest that whole grain carbohydrates are highly acceptable, and that there is a promising potential for their use in future dietary intervention studies in Tanzania. PMID- 23800296 TI - Low-dose acetylsalicylic acid and gastrointestinal ulcers or bleeding--a cohort study of the effects of proton pump inhibitor use patterns. AB - OBJECTIVE: The aim of this study was to investigate the associations between proton pump inhibitor (PPI) usage patterns and risk of severe gastrointestinal events in patients treated with low-dose acetylsalicylic acid (LDA). DESIGN AND SETTING: A nationwide cohort study in Sweden. PATIENTS: All Swedish residents >= 40 years of age, without cancer and receiving LDA treatment (>= 80% adherence for 365 days between 2005 and 2009) were identified in the Swedish Prescription Register. Continuous PPI use was defined as > 60 of 90 days covered by daily PPI doses and further divided into high (>= 80%) or moderate (< 80) adherence. All other PPI use was defined as intermittent use. MAIN OUTCOME MEASURES: The risk of a combined end-point of gastrointestinal ulcer or bleeding was analysed using Cox proportional hazard models. We also investigated risk of > 45 days of LDA treatment interruption. RESULTS: During a median follow-up of 2.5 years, 7880 of 648,807 (1.2%) LDA-treated patients experienced gastrointestinal events. In multivariable-adjusted models, both intermittent-PPI and no-PPI use were associated with increased risk of gastrointestinal ulcers or bleeding compared with continuous PPI use with a high level of adherence [hazard ratio (HR) 1.83 (95% CI 1.66-2.02) and 1.14 (95% CI 1.05-1.23), respectively]. Amongst continuous PPI users, moderate adherence also increased the risk of gastrointestinal ulcers or bleeding [HR 1.22 (95% CI 1.07-1.40)]. The risk of LDA treatment interruption was higher with intermittent PPI use [HR 1.16 (95% CI 1.14-1.19)] than continuous PPI use with high adherence. CONCLUSIONS: In this large cohort of LDA users, intermittent PPI use was associated with higher risk of gastrointestinal ulcers or bleeding and interrupted LDA treatment, compared with continuous PPI use. PMID- 23800297 TI - Genetic structure and demographic history of Colletotrichum gloeosporioides sensu lato and C. truncatum isolates from Trinidad and Mexico. AB - BACKGROUND: C. gloeosporioides sensu lato is one of the most economically important post-harvest diseases affecting papaya production worldwide. There is currently no information concerning the genetic structure or demographic history of this pathogen in any of the affected countries. Knowledge of molecular demographic parameters for different populations will improve our understanding of the biogeographic history as well as the evolutionary and adaptive potential of these pathogens. In this study, sequence data for ACT, GPDH, beta-TUB and ITS gene regions were analyzed for C. gloeosporioides sensu lato and C. truncatum isolates infecting papaya in Trinidad and Mexico in order to determine the genetic structure and demographic history of these populations. RESULTS: The data indicated that Mexico is the ancestral C. gloeosporioides sensu lato population with asymmetrical migration to Trinidad. Mexico also had the larger effective population size but, both Mexico and Trinidad populations exhibited population expansion. Mexico also had greater nucleotide diversity and high levels of diversity for each gene. There was significant sub-division of the Trinidad and Mexico populations and low levels of genetic divergence among populations for three of the four gene regions; beta-TUB was shown to be under positive selection. There were also dissimilar haplotype characteristics for both populations. Mutation may play a role in shaping the population structure of C. gloeosporioides sensu lato isolates from Trinidad and from Mexico, especially with respect to the ACT and GPDH gene regions. There was no evidence of gene flow between the C. truncatum populations and it is possible that the Mexico and Trinidad populations emerged independently of each other. CONCLUSIONS: The study revealed relevant information based on the genetic structure as well as the demographic history of two fungal pathogens infecting papaya, C. gloeosporioides sensu lato and C. truncatum, in Trinidad and Mexico. Understanding the genetic structure of pathogen populations will assist in determining the evolutionary potential of the pathogen and in identifying which evolutionary forces may have the greatest impact on durability of resistance. Intervention strategies that target these evolutionary forces would prove to be the most practical. PMID- 23800298 TI - A link between maternal malnutrition and depletion of glutathione in the developing lens: a possible explanation for idiopathic childhood cataract? AB - Lens cataract is the leading cause of blindness in developing countries. While cataract is primarily a disease of old age and is relatively rare in children, accounting for only four per cent of global blindness, childhood cataract is responsible for a third of the economic cost of blindness. While many of the causes of cataract in children are known, over half of childhood cataracts are idiopathic with no known cause. The incidence of idiopathic cataract is highest in developing countries and studies have discovered that low birth weight is a risk factor in the development of idiopathic childhood cataract. As low birth weight is a reflection of poor foetal growth, it is possible that maternal malnutrition, which is endemic in some developing countries, results in the altered physiology of the foetal lens. We have conducted a review of the literature that provides evidence for a link between maternal malnutrition, low birth weight and the development of childhood cataract. Using our accumulated knowledge on the pathways that deliver nutrients to the adult lens, we propose a cellular mechanism, by which oxidative stress caused by maternal malnutrition affects the development of antioxidant defence pathways in the embryonic lens, leading to an accelerated onset of nuclear cataract in childhood. PMID- 23800299 TI - Early microvascular dysfunction in cerebral small vessel disease is not detectable on 3.0 Tesla magnetic resonance imaging: a longitudinal study in spontaneously hypertensive stroke-prone rats. AB - BACKGROUND: Human cerebral small vessel disease (CSVD) has distinct histopathologic and imaging findings in its advanced stages. In spontaneously hypertensive stroke-prone rats (SHRSP), a well-established animal model of CSVD, we recently demonstrated that cerebral microangiopathy is initiated by early microvascular dysfunction leading to the breakdown of the blood-brain barrier and an activated coagulatory state resulting in capillary and arteriolar erythrocyte accumulations (stases). In the present study, we investigated whether initial microvascular dysfunction and other stages of the pathologic CSVD cascade can be detected by serial magnetic resonance imaging (MRI). FINDINGS: Fourteen SHRSP and three control (Wistar) rats (aged 26-44 weeks) were investigated biweekly by 3.0 Tesla (3 T) MRI. After perfusion, brains were stained with hematoxylin-eosin and histology was correlated with MRI data. Three SHRSP developed terminal CSVD stages including cortical, hippocampal, and striatal infarcts and macrohemorrhages, which could be detected consistently by MRI. Corresponding histology showed small vessel thromboses and increased numbers of small perivascular bleeds in the infarcted areas. However, 3 T MRI failed to visualize intravascular erythrocyte accumulations, even in those brain regions with the highest densities of affected vessels and the largest vessels affected by stases, as well as failing to detect small perivascular bleeds. CONCLUSION: Serial MRI at a field strength of 3 T failed to detect the initial microvascular dysfunction and subsequent small perivascular bleeds in SHRSP; only terminal stages of cerebral microangiopathy were reliably detected. Further investigations at higher magnetic field strengths (7 T) using blood- and flow-sensitive sequences are currently underway. PMID- 23800300 TI - Gene polymorphisms of the MMP1, MMP9, MMP12, IL-1beta and TIMP1 and the risk of primary open-angle glaucoma. AB - BACKGROUND: Primary open-angle glaucoma (POAG) is the main cause of irreversible blindness worldwide. Matrix metalloproteinases (MMPs) and their regulators (TIMPs and ILs) have been extensively studied as POAG risk factors. Recent reports have showed several single-nucleotide polymorphisms (SNPs) for MMPs, TIMPs and ILs encoding genes in patients with POAG. The aim of this study was to investigate association of the -1607 1G/2G MMP1, -the 1562 C/T MMP9, the -82 A/G MMP12, the 511 C/T IL-1beta and the 372 T/C TIMP1 gene polymorphisms with POAG occurrence and to investigate their impact on main clinical features. MATERIAL AND METHODS: In the present case-control study, we examined group of 511 unrelated Caucasian subjects consist of 255 patients with POAG (mean age 70 +/- 15) and 256 controls (mean age 67 +/- 16). Determination of genes polymorphic variants was made using polymerase chain reaction-restriction fragment length polymorphism technique (PCR RFLP). The odds ratios (ORs) and 95% confidence intervals (CIs) for each genotype and allele were calculated. RESULTS: Presented study showed statistically significant increase in the POAG development risk of the -1607 2G/2G MMP1 genotype (OR 1.75; 95% CI, 1.11-2.75; p = 0.014) and for the -1607 2G MMP1 allele (OR 1.35; 95% CI, 1.05-1.73; p = 0.017), as well as for the -1562 C/T MMP9 genotype (OR 1.74; 95% CI, 1.17-2.59; p = 0.006) and the -1562 T MMP9 allele (OR 1.55; 95% CI, 1.10-2.17; p = 0.012) in patients with POAG in comparison with healthy control group. We also observed positive association of the -511 T/T IL 1beta genotype (OR 2.60; 95% CI, 1.41-4.80; p = 0.002) as well as the -511 T IL 1beta allele occurrence with an increased POAG development risk (OR 1.47; 95% CI, 1.13-1.90; p = 0.003). Furthermore, we found an association of the -1607 1G/2G MMP1, -1562 C/T MMP9 (anova, p < 0.001) and the -511 C/T IL-1beta gene polymorphism (anova, p < 0.05) with decreased retinal nerve fibre layer (RNFL) thickness in patients with POAG group. Results displayed also an association of the 372 T/C TIMP1 gene polymorphism with normal range RNFL (anova, p < 0.001). We observed an association of decreased RA value (rim area) with the -82 A/G MMP12 (anova, p < 0.001). Normal RA value was observed in patients with POAG group connected with the 372 T/C TIMP1 (anova, p < 0.05) and the -511 C/T IL-1beta (anova, p < 0.05) genes polymorphisms occurrence. Finally, results showed an association of the -1562 C/T MMP9 (anova, p < 0.001) gene polymorphism with decreased cup/disc index in patients with POAG group. CONCLUSION: In conclusion, we suggest that the -1607 1G/2G MMP1, -1562 C/T MMP9, -511 C/T IL-1beta gene polymorphisms can be considered as an important risk factors associated with POAG. PMID- 23800301 TI - Normal sonographic anatomy of the abdomen of coatis (Nasua nasua Linnaeus 1766). AB - BACKGROUND: The use of ultrasound in veterinary medicine is widespread as a diagnostic supplement in the clinical routine of small animals, but there are few reports in wild animals. The objective of this study was to describe the anatomy, topography and abdominal sonographic features of coatis. RESULTS: The urinary bladder wall measured 0.11 +/- 0.03 cm. The symmetrical kidneys were in the left and right cranial quadrant of the abdomen and the cortical, medullary and renal pelvis regions were recognized and in all sections. The medullary rim sign was visualized in the left kidney of two coatis. The liver had homogeneous texture and was in the cranial abdomen under the rib cage. The gallbladder, rounded and filled with anechoic content was visualized in all coatis, to the right of the midline. The spleen was identified in the left cranial abdomen following the greater curvature of the stomach. The parenchyma was homogeneous and hyperechogenic compared to the liver and kidney cortex. The stomach was in the cranial abdomen, limited cranially by the liver and caudo-laterally by the spleen. The left adrenal glands of five coatis were seen in the cranial pole of the left kidney showing hypoechogenic parenchyma without distinction of cortex and medulla. The pancreas was visualized in only two coatis. The left ovary (0.92 cm x 0.56 cm) was visualized on a single coati in the caudal pole of the kidney. The uterus, right adrenal, right ovary and intestines were not visualized. CONCLUSIONS: Ultrasound examination of the abdomen of coatis may be accomplished by following the recommendations for dogs and cats. It is possible to evaluate the anatomical and topographical relationships of the abdominal organs together with the knowledge of the peculiarities of parenchymal echogenicity and echotexture of the viscera. PMID- 23800302 TI - Seroprevalence and risk factors of toxoplasmosis in cattle from extensive and semi-intensive rearing systems at Zona da Mata, Minas Gerais state, Southern Brazil. AB - BACKGROUND: Concerning the infection of humans by T. gondii, limited efforts have been directed to the elucidation of the role of horizontal transmission between hosts. One of the main routes of transmission from animals to humans occurs through the ingestion of raw or insufficiently cooked meat. However, even though the detection of T. gondii in meat constitutes an important short-term measure, control strategies can only be accomplished by a deeper understanding of the epidemiology of toxoplasmosis. The present study aimed to investigate the seroprevalence of toxoplasmosis in cattle from Zona da Mata, Minas Gerais, Brazil, and to identify associated risk factors, through an epidemiological investigation. METHODS: The animals studied (Bos indicus, breed Nelore or Gir) were reared in the Zona da Mata micro-region and killed at a commercial slaughterhouse at Juiz de Fora, Minas Gerais state. The animals came from 53 cattle farms with extensive (predominantly pasture feeding management) or semi intensive (food management based on grazing, salt mineral and feed supplementation) rearing systems. Blood samples were collected from 1200 animals, and assigned to Indirect Fluorescent Antibody Test. RESULTS: When analyzing IgG anti-T.gondii we found an overall seroprevalence of 2.68%. In Brazil prevalences vary from 1.03% to 60%. Although in the present study, the seroprevalence per animal is considered low compared to those observed in other studies, we found out that of the 53 farms analyzed, 17 (34.69%) had one or more positive cattle. It is a considerable percentage, suggesting that the infection is well distributed through the Zona da Mata region. The results of the epidemiological investigation showed that the main risk factors of Toxoplasma gondii infection are related to animal management and to the definive host. There was a relationship between the number of seropositive cattle and the presence and number of resident cats, presence and number of stray cats, presence of cats walking freely, rat control by using cats and feed storage. CONCLUSION: These results may contribute to the development of preventive strategies in Brazil and other developing countries were extensive and semi-intensive cattle rearing systems are very widespread and the efforts to control this important zoonotic disease have attained little success. PMID- 23800304 TI - Separate goals, converging priorities: on the ethics of treatment as prevention. AB - Recent evidence confirming that the administration of antiretroviral drugs (ARVs) to HIV-infected persons may effectively reduce their risk of transmission has revived the discussion about priority setting in the fight against HIV/AIDS. The fact that the very same drugs can be used both for treatment purposes and for preventive purposes (Treatment as Prevention) has been seen as paradigm-shifting and taken to spark a new controversy: In a context of scarce resources, should the allocation of ARVs be prioritized based on the goal of providing treatment, or on the goal of preventing the spread of the HIV epidemic? Contributions to this discussion tend to assume that treatment and prevention constitute two divergent goals that entail conflicting priorities. We challenge that assumption on the basis of both conceptual and empirical examination. We argue that, as far as the provision of ARVs to HIV-infected persons is concerned, the goals of treatment and prevention do not entail conflicting priorities; to the contrary, they dictate converging strategies for the optimal allocation of ARVs. In light of the current evidence, the concept of Treatment as Prevention can indeed be seen as paradigm-shifting, yet in a novel way: Rather than extending the tension between the goals of treatment and prevention to the level of drug-allocation, it dissolves this tension by providing a rationale for a unified strategy for allocating ARVs. PMID- 23800303 TI - How to perform RT-qPCR accurately in plant species? A case study on flower colour gene expression in an azalea (Rhododendron simsii hybrids) mapping population. AB - BACKGROUND: Flower colour variation is one of the most crucial selection criteria in the breeding of a flowering pot plant, as is also the case for azalea (Rhododendron simsii hybrids). Flavonoid biosynthesis was studied intensively in several species. In azalea, flower colour can be described by means of a 3-gene model. However, this model does not clarify pink-coloration. The last decade gene expression studies have been implemented widely for studying flower colour. However, the methods used were often only semi-quantitative or quantification was not done according to the MIQE-guidelines. We aimed to develop an accurate protocol for RT-qPCR and to validate the protocol to study flower colour in an azalea mapping population. RESULTS: An accurate RT-qPCR protocol had to be established. RNA quality was evaluated in a combined approach by means of different techniques e.g. SPUD-assay and Experion-analysis. We demonstrated the importance of testing noRT-samples for all genes under study to detect contaminating DNA. In spite of the limited sequence information available, we prepared a set of 11 reference genes which was validated in flower petals; a combination of three reference genes was most optimal. Finally we also used plasmids for the construction of standard curves. This allowed us to calculate gene-specific PCR efficiencies for every gene to assure an accurate quantification. The validity of the protocol was demonstrated by means of the study of six genes of the flavonoid biosynthesis pathway. No correlations were found between flower colour and the individual expression profiles. However, the combination of early pathway genes (CHS, F3H, F3'H and FLS) is clearly related to co-pigmentation with flavonols. The late pathway genes DFR and ANS are to a minor extent involved in differentiating between coloured and white flowers. Concerning pink coloration, we could demonstrate that the lower intensity in this type of flowers is correlated to the expression of F3'H. CONCLUSIONS: Currently in plant research, validated and qualitative RT-qPCR protocols are still rare. The protocol in this study can be implemented on all plant species to assure accurate quantification of gene expression. We have been able to correlate flower colour to the combined regulation of structural genes, both in the early and late branch of the pathway. This allowed us to differentiate between flower colours in a broader genetic background as was done so far in flower colour studies. These data will now be used for eQTL mapping to comprehend even more the regulation of this pathway. PMID- 23800305 TI - Functional variants of ERAP1 gene are associated with HLA-B27 positive spondyloarthritis. AB - We investigated two nonsynonymous variants (rs30187 and rs27044) of ERAP1 gene in HLA-B27 positive individuals (150 spondyloarthritis and 108 controls) and in general ankylosing spondylitis (AS) patients (n = 137) vs random controls (n = 139). Both single nucleotide polymorphisms (SNPs) were associated with the risk of spondyloarthritis [odds ratio (OR) 1.80, 95% confidence interval (CI) 1.24 2.62, P = 0.001 for rs30187, OR 1.58, 95% CI 1.07-2.34, P = 0.02 for rs27044]. The CC haplotype was a protective factor (P = 0.002), while the TG haplotype was a risk factor (P = 0.01) for spondyloarthritis. The SNP rs30187 was also associated with the risk of HLA-B27+ AS. For the general group of AS, the carriers of minor alleles showed an increased risk for the disease (OR 1.92, 95% CI 1.17-3.13 for rs30187, OR 1.74, 95% CI 1.08-2.80 for rs27044). This is the first study that shows the association of ERAP1 gene variants and haplotypes with HLA-B27 positive spondyloarthritis. PMID- 23800306 TI - Conditional survival for longer-term survivors from 2000-2004 using population based cancer registry data in Osaka, Japan. AB - BACKGROUND: We usually report five-year survival from population-based cancer registries in Japan; however these survival estimates may be pessimistic for cancer survivors, because many patients with unfavourable prognosis die shortly after diagnosis. Conditional survival can provide relevant information for cancer survivors, their family and oncologists. METHODS: We used the period approach to estimate the latest 10-year survival of 38,439 patients with stomach, colorectal, lung, breast and prostate cancer diagnosed between 1990 and 2004 and followed-up from 2000-04 in Osaka, Japan. Conditional survival is an estimate, with the pre condition of having already survived a certain length of time. Conditional five year relative survival of one to five years after diagnosis was calculated by site, age and stage for survivors under the age of 70. RESULTS: Five-year relative survival for stomach cancer was 60%. Conditional five-year relative survival was 77% one year after diagnosis and 97% five years after diagnosis. This means that 97% of patients who survive five years after diagnosis can survive a further five years. Conditional five-year relative survival improved successively with each additional year that patients lived after diagnosis for stomach, colorectal and lung cancer. These figures for breast and prostate cancer were stable at high survival. Liver cancer did not show an increase in conditional five-year survival. CONCLUSION: Conditional five-year survival is a relevant figure for long-term cancer survivors in Japan. It is important for population-based cancer registries to provide figures which cancer patients and oncologists really need. PMID- 23800307 TI - Hospital survey on patient safety culture in China. AB - BACKGROUND: Patient safety culture is an important measure in assessing the quality of health care. There is a growing recognition of the need to establish a culture of hospital focused on patient safety. This study explores the attitudes and perceptions of patient safety culture for health care workers in China by using a Hospital Survey on Patient Safety Culture (HSPSC) questionnaire and comparing it with the psychometric properties of an adapted translation of the HSPSC in Chinese hospitals with that of the US. METHOD: We used the modified HSPSC questionnaire to measure 10 dimensions of patient safety culture from 32 hospitals in 15 cities all across China. The questionnaire included 1160 Chinese health-care workers who consisted of predominately internal physicians and nurses. We used SPSS 17.0 and Microsoft Excel 2007 to conduct the statistical analysis on survey data including descriptive statistics and validity and reliability of survey. All data was input and checked by two investigators independently. RESULT: A total of 1500 questionnaires were distributed of which 1160 were responded validly (response rate 77%). The positive response rate for each item ranged from 36% to 89%. The positive response rate on 5 dimensions (Teamwork Within Units, Organization Learning-Continuous Improvement, Communication Openness, Non-punitive Response and Teamwork Across Units) was higher than that of AHRQ data (P < 0.05). There was a statistical difference on the perception of patient safety culture in groups of different work units, positions and qualification levels. The internal consistency of the total survey was comparatively satisfied (Cronbach's alpha = 0.84). CONCLUSION: The results show that amongst the health care workers surveyed in China there was a positive attitude towards the patient safety culture within their organizations. The differences between China and the US in patient safety culture suggests that cultural uniqueness should be taken into consideration whenever safety culture measurement tools are applied in different culture settings. PMID- 23800308 TI - Combining a photocatalyst with microtopography to develop effective antifouling materials. AB - Polydimethylsiloxane surfaces textured with a square-wave linear grating profile (0, 20, 200, 300 and 600 MUm), and embedded with a range of photocatalytic titanium dioxide (TiO2) nanoparticle loadings (3.75, 7.5, 11.25 and 15 wt.%), were used to test the combined efficacy of these technologies as antifouling materials. Settlement of the fouling bryozoan species Bugula neritina was quantified in the laboratory under two intensities of UV light. The lowest settlement rates were observed on 20 MUm surfaces. However, texture effects were not as critical to larval settlement as the presence of TiO2. In conjunction with UV light, TiO2 completely inhibited larval metamorphosis even at the lowest loading (3.75 wt.%) and the lowest intensity of UV light (24 W m(-2)). Recruitment of B. neritina was also quantified in field trials and showed similar results to laboratory assays. The lowest recruitment was observed on 20 and 200 MUm surfaces, with recruitment being significantly lower on all surfaces containing TiO2. Therefore for B. neritina, although all TiO2 loadings were effective, 3.75 wt.% can be used as a minimum inhibitory concentration to deter larval settlement and the addition of a 20 MUm texture further increases the deterrent effect. PMID- 23800309 TI - Chronic alcohol consumption increases the expression of uncoupling protein-2 and 4 in the brain. AB - BACKGROUND: Chronic alcohol consumption leads to oxidative stress in a variety of cells, especially in brain cells because they have a reduced oxidative metabolism of alcohol. Uncoupling proteins (UCPs) are anion channels of the inner mitochondrial membrane, which can decouple internal respiration. "Mild uncoupling" of the mitochondrial respiratory chain leads to a reduced production of free radicals (reactive oxygen species) and a reduction in oxidative cell stress. The extent to which chronic alcohol consumption regulates UCP-2 and -4 in the brain is still unknown. METHODS: We examined the effects of a 12-week 5% alcohol diet in the brain of male Wistar rats (n = 34). Cerebral gene and protein expression of UCP-2, -4, as well as Bcl-2, and the release of cytochrome c out of the mitochondria were detected by real-time polymerase chain reaction and Western blot analysis. The percentage of degenerated cells was determined by Fluoro-Jade B staining of brain slices. RESULTS: Brains of rats with a chronic alcohol diet showed an increased gene and protein expression of UCP-2 and -4. The expression of the antiapoptotic protein Bcl-2 in the brain of the alcohol-treated animals was decreased significantly, whereas cytochrome c release from mitochondria was increased. In addition increased neurodegeneration could be demonstrated in the alcohol-treated animals. CONCLUSIONS: Chronic alcohol consumption leads to a cerebral induction of UCP-2 and -4 with a simultaneous decrease in the antiapoptotic protein Bcl-2, cytochrome c release from mitochondria and increased neurodegeneration. This study reveals a compensatory effect of UCP-2 and -4 in the brain during chronic alcohol consumption. PMID- 23800310 TI - Cross-sectional study of hepatitis B virus infection in rural communities, Central African Republic. AB - BACKGROUND: As most data on hepatitis in resource-poor countries relate to urban communities, surveys in the rural environment are necessary to determine the 'true' prevalence of these viral infections. We undertook a survey to determine the prevalence of hepatitis B virus (HBV) infection in an apparently healthy rural population in the Central African Republic (CAR). METHODS: The cross sectional study was based on dried blood spots (DBS) from 273 people recruited in four prefectures (Lobaye, Nana-Mambere, Ouham and Ouaka). Eluates from DBS were tested with commercial ELISA kits to detect markers of HBV infection. DBS were directly used for DNA extraction, followed by PCR and genotyping based on preS/S gene sequences. RESULTS: The overall prevalence of HBc antibodies was 27.1% (Lobaye 29%, Nana-Mambere 28%, Ouaka 29% and Ouham 23%) and that of HBsAg was 10.6% (Lobaye 9%, Nana-Mambere 9%, Ouaka 19% and Ouham 8%), with no statistically significant difference among the surveyed communities. Nineteen sequences obtained from 74 anti-HBc-positive patients all belonged to genotype E. Risk factor analysis of HBV infection pointed to sexual transmission of the virus. CONCLUSION: The prevalence of HBV is high in rural communities in the CAR and comparable to that observed in urban areas. In addition, genotype E is prevalent in these areas. These findings underline the importance of instituting a programme of active HBV surveillance and vaccination of the population. PMID- 23800311 TI - Quality of antiretroviral therapy in public health facilities in Nigeria and perceptions of end users. AB - AIM: This paper describes perceptions of the end users on quality of antiretroviral therapy (ART) in public health facilities in Nigeria. BACKGROUND: Health care services in Nigeria face challenges of meeting end users' requirements and expectations for quality ART service provision. METHOD: A qualitative design was followed. Unstructured focus group discussions were conducted with end users (n = 64) in six locations across the six geopolitical zones of Nigeria. RESULTS: The findings indicate that end users were satisfied with uninterrupted antiretroviral drug supplies, courtesy treatment, volunteerism of support group members and quality counselling services. CONCLUSION: End users expect effective collaboration between healthcare providers and support group members, to enhance the quality of life of people living with HIV. IMPLICATIONS FOR NURSING MANAGEMENT: A best practice guideline for the provision of end user focused ART service provision was developed for nurse managers. PMID- 23800312 TI - Quinolone prophylaxis for the prevention of BK virus infection in kidney transplantation: study protocol for a randomized controlled trial. AB - BACKGROUND: BK virus infection has emerged as a major complication in kidney transplantation leading to a significant reduction in graft survival. There are currently no proven strategies to prevent or treat BK virus infection. Quinolone antibiotics, such as levofloxacin, have demonstrated activity against BK virus. We hypothesize that administration of a quinolone antibiotic, when given early post-transplantation, will prevent the establishment of BK viral replication in the urine and thus prevent systemic BK virus infection. METHODS/DESIGN: The aim of this pilot trial is to assess the efficacy, safety and feasibility of a 3 month course of levofloxacin in the kidney transplant population. This is a multicenter, randomized, double-blind, placebo-controlled trial with two parallel arms conducted in 11 Canadian kidney transplant centers. A total of 154 patients with end-stage renal disease undergoing kidney transplantation will be randomized to receive a 3-month course of levofloxacin or placebo starting in the early post transplant period. Levofloxacin will be administered at 500 mg po daily with dose adjustments based on kidney function. The primary outcome will be the time to occurrence of BK viruria within the first year post-transplantation. Secondary outcomes include BK viremia, measures of safety (adverse events, resistant infections,Clostridium difficile-associated diarrhea), measures of feasibility (proportion of transplanted patients recruited into the trial), proportion of patients adherent to the protocol, patient drop-out and loss to follow-up,and use of quinolone antibiotics outside of the trial protocol. DISCUSSION: Results from this pilot study will provide vital information to design and conduct a large, multicenter trial to determine if quinolone therapy decreases clinically meaningful outcomes in kidney transplantation. If levofloxacin significantly reduces BK viruria and urine viral loads in kidney transplantation, it will provide important justification to progress to the larger trial. If the full trial shows that levofloxacin significantly reduces BK infection and improves outcomes, its use in kidney transplantation will be strongly endorsed given the lack of proven therapies for this condition. TRIAL REGISTRATION: This trial was funded by the Canadian Institutes of Health Research (grant number:222493) and is registered at ClinicalTrials.gov (NCT01353339). PMID- 23800313 TI - Targeting cancer cell-specific RNA interference by siRNA delivery using a complex carrier of affibody-displaying bio-nanocapsules and liposomes. AB - BACKGROUND: Small interfering RNA (siRNA) has attracted attention in the field of nucleic acid medicine as a RNA interference (RNAi) application that leads to gene silencing due to specific messenger RNA (mRNA) destruction. However, since siRNA is unstable in blood and unable to cross the cell membrane, encapsulation of siRNA into a carrier is required. RESULTS: In this study, we used a carrier that combined ZHER2-displaying bio-nanocapsule (derived from hepatitis B virus surface antigen) and liposomes in a complex in order to investigate the feasibility of effective and target-cell-specific RNAi applications. As a result, by observing RNAi only in HER2-expressing breast cancer cells, using our proposed methodology, we successfully demonstrated target-cell-specific delivery and effective function expression of siRNA. CONCLUSIONS: These findings show that, in the field of nucleic acid medicine, ZHER2-BNC/LP can be a useful carrier for siRNA delivery, and could also become a useful tool for gene silencing and to accomplish protein knock-down. PMID- 23800314 TI - Near full-length genome identification of a novel HIV type 1 B'/C recombinant isolate JL100091 in Jilin, China. AB - We report here a novel HIV-1 B'/C recombinant isolate JL100091, identified from an HIV-positive female subject infected through heterosexual transmission in Jilin in 2006. The near full-length genome analyses of the novel recombinant (JL10091) showed that one subtype B' region (3,085 bp) was inserted into the subtype C backbone, with two breakpoints observed in gag and pol genes. To our knowledge, this is the first detection of a novel HIV-1 B'/C recombinant in Jilin, which indicates ongoing transmission of networks among the heterosexual population in the region. The novel HIV-1 B'/C recombinant (JL10091) in Jilin originated from India subtype C and China subtype B' may suggest potential transmission routes of HIV-1 in China. Further monitoring of the molecular epidemiology of the HIV-1 epidemic in Jilin will provide critical information for designing effective control and prevention measures against HIV transmission in the region. PMID- 23800315 TI - Tumor inhibitory T cell immunity may be largely a transplantation artifact not necessarily dependent upon a lack of Tregs. AB - There exists a very large literature suggesting that T cells come in a variety of species and that without the action of Tregs tumors would seldom survive inhibition by T cell effectors. We believe that much of the evidence supporting the role of Tregs in cancer is compatible with a perhaps simpler hypothesis based upon the demonstration that that small quantities of effector T cells tend to stimulate tumors while larger quantities of seemingly the same cells are inhibitory (an hormesis-like effect). This possibility seems to destroy much of the need to postulate a role for T cell suppressors (Tregs) in cancer, but the exposure of effector T cells to antigen may convert them into Tregs (Tregs do exist). Furthermore, many other data suggest the possibility that immune inhibition of cancer could be a laboratory artifact seldom if ever seen in unmodified nature. PMID- 23800316 TI - Achievement of 10-year survival: a case of pubic bone recurrence as the primary failure site of chemo-refractory ovarian clear cell carcinoma. AB - Clear cell carcinoma of the ovary tends to have a poor response to conventional platinum-based chemotherapy. Bone recurrence from ovarian cancer is rare and prognosis of patients with such a condition is poor. We report a patient with chemo-refractory ovarian clear cell carcinoma who developed pubic bone recurrence and subsequent para-aortic node recurrence. The patient achieved long-term survival after salvage surgery twice in spite of these inauspicious conditions. Surgical treatment should be taken into consideration for skeletal recurrence from ovarian clear cell carcinoma. PMID- 23800318 TI - EvoDevo meets ecology: the Ninth Okazaki Biology Conference on Marine Biology. AB - The "9th Okazaki Biology Conference: Marine Biology II" held at the National Institute for Basic Biology (NIBB) in Okazaki, Japan and at the Okinawa Institute of Science and Technology (OIST) in Okinawa, Japan (14-19 October 2012) bridged the fields of EvoDevo, symbiosis and coral reef ecology. PMID- 23800317 TI - Effect of plate working length on plate stiffness and cyclic fatigue life in a cadaveric femoral fracture gap model stabilized with a 12-hole 2.4 mm locking compression plate. AB - BACKGROUND: There are several factors that can affect the fatigue life of a bone plate, including the mechanical properties of the plate and the complexity of the fracture. The position of the screws can influence construct stiffness, plate strain and cyclic fatigue of the implants. Studies have not investigated these variables in implants utilized for long bone fracture fixation in dogs and cats. The purpose of the present study was to evaluate the effect of plate working length on construct stiffness, gap motion and resistance to cyclic fatigue of dog femora with a simulated fracture gap stabilized using a 12-hole 2.4 mm locking compression plates (LCP). Femora were plated with 12-hole 2.4 mm LCP using 2 screws per fracture segment (long working length group) or with 12-hole 2.4 mm LCP using 5 screws per fracture segment (a short working length group). RESULTS: Construct stiffness did not differ significantly between stabilization techniques. Implant failure did not occur in any of the plated femora during cycling. Mean +/- SD yield load at failure in the short plate working length group was significantly higher than in the long plate working length group. CONCLUSION: In a femoral fracture gap model stabilized with a 2.4 mm LCP applied in contact with the bone, plate working length had no effect on stiffness, gap motion and resistance to fatigue. The short plate working length constructs failed at higher loads; however, yield loads for both the short and long plate working length constructs were within physiologic range. PMID- 23800321 TI - Specific heat capacity of molten salt-based alumina nanofluid. AB - There is no consensus on the effect of nanoparticle (NP) addition on the specific heat capacity (SHC) of fluids. In addition, the predictions from the existing model have a large discrepancy from the measured SHCs in nanofluids. We show that the SHC of the molten salt-based alumina nanofluid decreases with reducing particle size and increasing particle concentration. The NP size-dependent SHC is resulted from an augmentation of the nanolayer effect as particle size reduces. A model considering the nanolayer effect which supports the experimental results was proposed. PMID- 23800320 TI - Clinical manifestations in female carriers of mucopolysaccharidosis type II: a Spanish cross-sectional study. AB - BACKGROUND: Mucopolysaccharidosis type II (MPS II) is an inherited X-linked disease associated with a deficiency in the enzyme iduronate 2-sulfatase due to iduronate 2-sulfatase gene (IDS) mutations. Recent studies in MPS II carriers did not find clinical involvement, but these were mainly performed by anamnesis and patients' self-reported description of signs and symptoms. So although it is rare in heterozygous carriers, investigations in other types of inherited X-linked disorders suggest that some clinical manifestations may be a possibility. The aim of this study was to evaluate the clinical pattern in female carriers of MPS II and to determine whether clinical symptoms were associated with the X-chromosome inactivation (XCI) pattern and age. METHODS: Female carriers of MPS II were genetically identified by molecular analysis of IDS. The clinical evaluation protocol included pedigree analysis, a comprehensive anamnesis, complete physical examination, ophthalmological evaluation, brain-evoked auditory response, electrocardiogram, echocardiogram, pulmonary function tests, abdominal sonogram, skeletal survey, neurophysiological studies, blood cell counts and biochemistry, urine glycosaminoglycan (GAGs) quantification, karyotype and pattern of XCI. RESULTS: Ten women were included in the study. The mean age of the participants was 40.2 +/- 13.1 years. Six carriers presented a skewed XCI pattern, 3 of whom (aged 38, 42 and 52 years) had increased levels of GAGs in the urine and showed typical MPS II clinical manifestations, such as skeletal anomalies, liver abnormalities, carpal tunnel syndrome, recurrent ear infection, hypoacusia and more frequent severe odontological problems without coarse facial features. CONCLUSIONS: This is the first study performing a comprehensive evaluation of heterozygous MPS II carriers. Our results provide evidence of possible progressive, age-dependent, mild clinical manifestations in MPS II female carriers with a skewed XCI pattern, most likely affecting the normal allele. Further comparative studies with systematized clinical examinations in larger age stratified populations of MPS II female carriers are required. PMID- 23800319 TI - Role of platelet chemokines, PF-4 and CTAP-III, in cancer biology. AB - With the recent addition of anti-angiogenic agents to cancer treatment, the angiogenesis regulators in platelets are gaining importance. Platelet factor 4 (PF-4/CXCL4) and Connective tissue activating peptide III (CTAP-III) are two platelet-associated chemokines that modulate tumor angiogenesis, inflammation within the tumor microenvironment, and in turn tumor growth. Here, we review the role of PF-4 and CTAP-III in the regulation of tumor angiogenesis; the results of clinical trial using recombinant PF-4 (rPF-4); and the use of PF-4 and CTAP-III as cancer biomarkers. PMID- 23800322 TI - CSF levels of the neuronal injury biomarker visinin-like protein-1 in Alzheimer's disease and dementia with Lewy bodies. AB - The overlapping clinical features of Alzheimer's disease (AD) and Dementia with Lewy bodies (DLB) make differentiation difficult in the clinical environment. Evaluating the CSF levels of biomarkers in AD and DLB patients could facilitate clinical diagnosis. CSF Visinin-like protein-1 (VILIP-1), a calcium-mediated neuronal injury biomarker, has been described as a novel biomarker for AD. The aim of this study was to investigate the diagnostic utility of CSF VILIP-1 and VILIP-1/Abeta1-42 ratio to distinguish AD from DLB. Levels of CSF VILIP-1, t-tau, p-tau181P , Abeta1-42 , and alpha-synuclein were measured in 61 AD patients, 32 DLB patients, and 40 normal controls using commercial ELISA kits. The results showed that the CSF VILIP-1 level had significantly increased in AD patients compared with both normal controls and DLB patients. The CSF VILIP-1 and VILIP 1/Abeta1-42 levels had enough diagnostic accuracy to allow the detection and differential diagnosis of AD. Additionally, CSF VILIP-1 levels were positively correlated with t-tau and p-tau181P within each group and with alpha-synuclein in the AD and control groups. We conclude that CSF VILIP-1 could be a diagnostic marker for AD, differentiating it from DLB. The analysis of biomarkers, representing different neuropathologies, is an important approach reflecting the heterogeneous features of AD and DLB. Neuronal Ca(2+) -sensor protein VILIP-1 has been implicated in the calcium-mediated neuronal injury and pathological change of AD. The CSF VILIP-1 and VILIP-1/Abeta1-42 levels had enough diagnostic accuracy to allow the detection and differential diagnosis of AD. CSF VILIP-1 is a useful biomarker for AD. Evaluating the CSF levels of VILIP-1 in AD and DLB patients could facilitate clinical diagnosis. PMID- 23800323 TI - Parallel re-modeling of EF-1alpha function: divergent EF-1alpha genes co-occur with EFL genes in diverse distantly related eukaryotes. AB - BACKGROUND: Elongation factor-1alpha (EF-1alpha) and elongation factor-like (EFL) proteins are functionally homologous to one another, and are core components of the eukaryotic translation machinery. The patchy distribution of the two elongation factor types across global eukaryotic phylogeny is suggestive of a 'differential loss' hypothesis that assumes that EF-1alpha and EFL were present in the most recent common ancestor of eukaryotes followed by independent differential losses of one of the two factors in the descendant lineages. To date, however, just one diatom and one fungus have been found to have both EF 1alpha and EFL (dual-EF-containing species). RESULTS: In this study, we characterized 35 new EF-1alpha/EFL sequences from phylogenetically diverse eukaryotes. In so doing we identified 11 previously unreported dual-EF-containing species from diverse eukaryote groups including the Stramenopiles, Apusomonadida, Goniomonadida, and Fungi. Phylogenetic analyses suggested vertical inheritance of both genes in each of the dual-EF lineages. In the dual-EF-containing species we identified, the EF-1alpha genes appeared to be highly divergent in sequence and suppressed at the transcriptional level compared to the co-occurring EFL genes. CONCLUSIONS: According to the known EF-1alpha/EFL distribution, the differential loss process should have occurred independently in diverse eukaryotic lineages, and more dual-EF-containing species remain unidentified. We predict that dual-EF containing species retain the divergent EF-1alpha homologues only for a sub-set of the original functions. As the dual-EF-containing species are distantly related to each other, we propose that independent re-modelling of EF-1alpha function took place in multiple branches in the tree of eukaryotes. PMID- 23800324 TI - What should be done about policy on alcohol pricing and promotions? Australian experts' views of policy priorities: a qualitative interview study. AB - BACKGROUND: Alcohol policy priorities in Australia have been set by the National Preventative Health Task Force, yet significant reform has not occurred. News media coverage of these priorities has not reported public health experts as in agreement and Government has not acted upon the legislative recommendations made. We investigate policy experts' views on alcohol policy priorities with a view to establishing levels of accord and providing suggestions for future advocates. METHODS: We conducted semi-structured in depth interviews with alcohol policy experts and advocates around Australia. Open-ended questions examined participants' thoughts on existing policy recommendations, obvious policy priorities and specifically, the future of national reforms to price and promotions policies. All transcripts were analysed for major themes and points of agreement or disagreement. RESULTS: Twenty one alcohol policy experts agreed that pricing policies are a top national priority and most agreed that "something should be done" about alcohol advertising. Volumetric taxation and minimum pricing were regarded as the most important price policies, yet differences emerged in defining the exact form of a proposed volumetric tax. Important differences in perspective emerged regarding alcohol promotions, with lack of agreement about the preferred form regulations should take, where to start and who the policy should be directed at. Very few discussed online advertising and social networks. CONCLUSIONS: Despite existing policy collaborations, a clear 'cut through' message is yet to be endorsed by all alcohol control advocates. There is a need to articulate and promote in greater detail the specifics of policy reforms to minimum pricing, volumetric taxation and restrictions on alcohol advertising, particularly regarding sporting sponsorships and new media. PMID- 23800325 TI - Retinal arterial macroaneurysms. AB - Retinal arterial macroaneurysms are acquired saccular or fusiform dilatations of the large arterioles of the retina, usually within the first three orders of bifurcation. They are associated with systemic vascular conditions such as hypertension and arteriosclerotic disease occurring most commonly in elderly women. The primary reported symptom is a sudden loss of vision due to haemorrhage or oedema affecting the macula. Most of macroaneurysms regress without treatment and without causing decreased visual acuity. Poor visual outcome may occur secondary to foveal exudates and subfoveal haemorrhage. PMID- 23800326 TI - From modeling to morals: imagining the future of HIV PREP in Lesotho. AB - Amidst growing global endorsements of new biomedical HIV prevention strategies, ARV-based pre-exposure prophylaxis (ARV PrEP) has garnered considerable attention as a potentially promising prevention strategy. Though it may offer more effective protection for certain at-risk groups than conventional prevention strategies (such as sexual partner reduction, condom use, and prevention of mother-to-child transmission), PrEP is more costly. PrEP requires more ongoing contact between individuals and providers, and a level of surveillance from the health system that is not necessary with other preventive measures. In this sense, it represents a new bio-technology for HIV prevention that poses particular challenges for worldwide implementation, given developing countries' struggling health systems and incomplete HIV treatment programs. Since the emergence of PrEP has stimulated ethical discussions premised on incomplete knowledge of efficacy and implementation, this paper explores the ethical parameters of a likely scenario for PrEP usage in a single, resource-poor country. We first develop a plausible model for PrEP deployment and utilization based on current PrEP research, while carefully considering the reigning institutional values of feasibility and effectiveness in global health approaches. Drawing on ethnographic research of HIV treatment and prevention approaches in Lesotho, we address ethical questions arising from this scenario of PrEP delivery. Lesotho presents a compelling and emblematic case study of PrEP's potential successes and pitfalls in a developing country, given the country's high HIV prevalence, struggles to achieve universal access to HIV treatment regimes, continued existence of stigma around the epidemic, and difficulties in addressing persistent social inequalities that fuel infections. PMID- 23800327 TI - Families and health-care professionals' perspectives and expectations of family centred care: hidden expectations and unclear roles. AB - BACKGROUND AND OBJECTIVE: Family-centred care (FCC) is viewed as a pivotal concept in the provision of high-quality nursing care for children and their families, yet implementation continues to be problematic worldwide. This research investigated how FCC was enacted from families and nurses' perspectives. DESIGN: Descriptive qualitative approach using elements of analysis from grounded theory method. Data were collected though individual interviews with 18 children aged 7 16 years, their parents (n = 18) and 18 nurses from two children's hospital and one children's unit in a large general hospital in Ireland. RESULTS: Four key themes were identified: expectations; relying on parents' help; working out roles; and barriers to FCC. Nurses wholeheartedly endorsed FCC because of the benefits for families and their reliance on parents' contribution to the workload. There was minimal evidence of collaboration or negotiation of roles which resulted in parents feeling stressed or abandoned. Nurses cited busy workload, under-staffing and inappropriate documentation as key factors which resulted in over-reliance on parents and hindered their efforts to negotiate and work alongside parents. CONCLUSIONS: Families are willing to help in their child's care but they require clear guidance, information and support from nurses. Hidden expectations and unclear roles are stressful for families. Nurses need skills training, adequate resources and managerial support to meet families' needs appropriately, to establish true collaboration and to deliver optimal family-centred care. PMID- 23800328 TI - Loss of control of alcohol use and severity of alcohol dependence in non treatment-seeking heavy drinkers are related to lower glutamate in frontal white matter. AB - BACKGROUND: The development and maintenance of alcohol use disorders (AUD) have been hypothesized to be associated with an imbalance of glutamate (GLU) homeostasis. White matter (WM) loss, especially in anterior brain regions, has been reported in alcohol dependence, which may involve disturbances in both myelin and axonal integrity. Frontal lobe dysfunction plays an important role in addiction, because it is suggested to be associated with the loss of control over substance use. This study investigated magnetic resonance spectroscopy (MRS) detectable Glu levels in frontal WM of non-treatment-seeking heavy drinkers and its associations with AUD symptoms. METHODS: Single-voxel MR spectra optimized for Glu assessment (TE 80 ms) were acquired at 3T from a frontal WM voxel in a group of heavy drinking, non-treatment-seeking subjects in comparison with a group of subjects with only light alcohol consumption. RESULTS: The results corroborate previous findings of increased total choline in heavy drinking subjects. A negative association of Glu levels with severity of alcohol dependence and especially loss of control over time and amount of alcohol intake was observed. CONCLUSIONS: In contrast to the rather unspecific rise in choline containing compounds, low Glu in frontal WM may be specific for the shift from nondependent heavy drinking to dependence and does not reflect a simple effect of the amount of alcohol consumption alone. PMID- 23800329 TI - Immune mediators of sea-cucumber Holothuria tubulosa (Echinodermata) as source of novel antimicrobial and anti-staphylococcal biofilm agents. AB - The present study aims to investigate coelomocytes, immune mediators cells in the echinoderm Holothuria tubulosa, as an unusual source of antimicrobial and antibiofilm agents. The activity of the 5kDa peptide fraction of the cytosol from H. tubulosa coelomocytes (5-HCC) was tested against a reference group of Gram negative and Gram-positive human pathogens. Minimal inhibitory concentrations (MICs) ranging from 125 to 500 mg/ml were determined against tested strains. The observed biological activity of 5-HCC could be due to two novel peptides, identified by capillary RP-HPLC/nESI-MS/MS, which present the common chemical physical characteristics of antimicrobial peptides. Such peptides were chemically synthesized and their antimicrobial activity was tested. The synthetic peptides showed broad-spectrum activity at 12.5 mg/ml against the majority of the tested Gram-positive and Gram-negative strains, and they were also able to inhibit biofilm formation in a significant percentage at a concentration of 3.1 mg/ml against staphylococcal and Pseudomonas aeruginosa strains.The immune mediators in H. tubulosa are a source of novel antimicrobial peptides for the development of new agents against biofilm bacterial communities that are often intrinsically resistant to conventional antibiotics. PMID- 23800330 TI - Fetal brain genomic reprogramming following asphyctic preconditioning. AB - BACKGROUND: Fetal asphyctic (FA) preconditioning is effective in attenuating brain damage incurred by a subsequent perinatal asphyctic insult. Unraveling mechanisms of this endogenous neuroprotection, activated by FA preconditioning, is an important step towards new clinical strategies for asphyctic neonates. Genomic reprogramming is thought to be, at least in part, responsible for the protective effect of preconditioning. Therefore we investigated whole genome differential gene expression in the preconditioned rat brain. FA preconditioning was induced on embryonic day 17 by reversibly clamping uterine circulation. Male control and FA offspring were sacrificed 96 h after FA preconditioning. Whole genome transcription was investigated with Affymetrix Gene1.0ST chip. RESULTS: Data were analyzed with the Bioconductor Limma package, which showed 53 down regulated and 35 up-regulated transcripts in the FA-group. We validated these findings with RT-qPCR for adh1, edn1, leptin, rdh2, and smad6. Moreover, we investigated differences in gene expression across different brain regions. In addition, we performed Gene Set Enrichment Analysis (GSEA) which revealed 19 significantly down-regulated gene sets, mainly involved in neurotransmission and ion transport. 10 Gene sets were significantly up-regulated, these are mainly involved in nucleosomal structure and transcription, including genes such as mecp2. CONCLUSIONS: Here we identify for the first time differential gene expression after asphyctic preconditioning in fetal brain tissue, with the majority of differentially expressed transcripts being down-regulated. The observed down-regulation of cellular processes such as neurotransmission and ion transport could represent a restriction in energy turnover which could prevent energy failure and subsequent neuronal damage in an asphyctic event. Up-regulated transcripts seem to exert their function mainly within the cell nucleus, and subsequent Gene Set Enrichment Analysis suggests that epigenetic mechanisms play an important role in preconditioning induced neuroprotection. PMID- 23800331 TI - Gender differences in health-related quality of life of Australian chronically ill adults: patient and physician characteristics do matter. AB - BACKGROUND: The aims of this study were to explore the health-related quality of life (HRQoL) in a large sample of Australian chronically-ill patients (type 2 diabetes and/or hypertension/ischaemic heart disease), to investigate the impact of characteristics of patients and their general practitioners on their HRQoL and to examine clinically significant differences in HRQoL among males and females. METHODS: This was a cross-sectional study with 193 general practitioners and 2181 of their chronically-ill patients aged 18 years or more using the standard Short Form Health Survey (SF-12) version 2. SF-12 physical component score (PCS-12) and mental component score (MCS-12) were derived using the standard US algorithm. Multilevel regression analysis (patients at level 1 and general practitioners at level 2) was applied to relate PCS-12 and MCS-12 to patient and general practitioner (GP) characteristics. RESULTS: Employment was likely to have a clinically significant larger positive effect on HRQoL of males (regression coefficient (B) (PCS-12) = 7.29, P < 0.001, effect size = 1.23 and B (MCS-12) = 3.40, P < 0.01, effect size = 0.55) than that of females (B(PCS-12) = 4.05, P < 0.001, effect size = 0.78 and B (MCS-12) = 1.16, P > 0.05, effect size = 0.16). There was a clinically significant difference in HRQoL among age groups. Younger men (< 39 years) were likely to have better physical health than older men (> 59 years, B = -5.82, P < 0.05, effect size = 0.66); older women tended to have better mental health (B = 5.62, P < 0.001, effect size = 0.77) than younger women. Chronically-ill women smokers reported clinically significant (B = -3.99, P < 0.001, effect size = 0.66) poorer mental health than women who were non smokers. Female GPs were more likely to examine female patients than male patients (33% vs. 15%, P < 0.001) and female patients attending female GPs reported better physical health (B = 1.59, P < 0.05, effect size = 0.30). CONCLUSIONS: Some of the associations between patient characteristics and SF-12 physical and/or mental component scores were different for men and women. This finding underlines the importance of considering these factors in the management of chronically-ill patients in general practice. The results suggest that chronically ill women attempting to quit smoking may need more psychological support. More quantitative studies are needed to determine the association between GP gender and patient gender in relation to HRQoL. PMID- 23800332 TI - Topical ophthalmic use of cyclosporin A for Splendore-Hoeppli phenomenon. AB - The Splendore-Hoeppli reaction is a rare phenomenon characterised by the formation of eosinophilic material around infectious or non-infectious agents. A 33-year-old patient with persistent Splendore-Hoeppli phenomenon was previously treated with topical steroids but this resulted in a rise in intraocular pressure. The patient was treated with topical cyclosporin A one per cent twice daily as an alternative immunosuppression. After three weeks of treatment the patient had complete resolution of her conjunctival granuloma. This case report introduces cyclosporin A as a treatment option for the Splendore-Hoeppli phenomenon. This is a safe drug for long-term topical use in this condition. PMID- 23800334 TI - Do governance choices matter in health care networks?: an exploratory configuration study of health care networks. AB - BACKGROUND: Health care networks are widely used and accepted as an organizational form that enables integrated care as well as dealing with complex matters in health care. However, research on the governance of health care networks lags behind. The research aim of our study is to explore the type and importance of governance structure and governance mechanisms for network effectiveness. METHODS: The study has a multiple case study design and covers 22 health care networks. Using a configuration view, combinations of network governance and other network characteristics were studied on the level of the network. Based on interview and questionnaire data, network characteristics were identified and patterns in the data looked for. RESULTS: Neither a dominant (or optimal) governance structure or mechanism nor a perfect fit among governance and other characteristics were revealed, but a number of characteristics that need further study might be related to effective networks such as the role of governmental agencies, legitimacy, and relational, hierarchical, and contractual governance mechanisms as complementary factors. CONCLUSIONS: Although the results emphasize the situational character of network governance and effectiveness, they give practitioners in the health care sector indications of which factors might be more or less crucial for network effectiveness. PMID- 23800333 TI - Feasibility, acceptability and preliminary effectiveness of patient advocates for improving asthma outcomes in adults. AB - BACKGROUND: Asthmatic adults from low-income urban neighborhoods have inferior health outcomes which in part may be due to barriers accessing care and with patient-provider communication. We adapted a patient advocate (PA) intervention to overcome these barriers. OBJECTIVE: To conduct a pilot study to assess feasibility, acceptability and preliminary evidence of effectiveness. METHODS: A prospective randomized design was employed with mixed methods evaluation. Adults with moderate or severe asthma were randomized to 16 weeks of PA or a minimal intervention (MI) comparison condition. The PA, a non-professional, modeled preparations for a medical visit, attended the visit and confirmed understanding. The PA facilitated scheduling, obtaining insurance coverage and overcoming barriers to implementing medical advice. Outcomes included electronically monitored inhaled corticosteroid (ICS) adherence, asthma control, quality of life, FEV1, emergency department (ED) visits and hospitalizations. Mixed-effects models guided an intention-to-treat analysis. RESULTS: 100 adults participated: age 47 +/- 14 years, 75% female, 71% African-American, 16% white, baseline FEV1 69% +/- 18%, 36% experiencing hospitalizations and 56% ED visits for asthma in the prior year. Ninety-three subjects completed all visits; 36 of 53 PA-assigned had a PA visit. Adherence declined significantly in the control (p = 0.001) but not significantly in the PA group (p = 0.30). Both PA and MI groups demonstrated improved asthma control (p = 0.01 in both) and quality of life (p = 0.001, p = 0.004). Hospitalizations and ED visits for asthma did not differ between groups. The observed changes over time tended to favor the PA group, but this study was underpowered to detect differences between groups. CONCLUSION: The PA intervention was feasible and acceptable and demonstrated potential for improving asthma control and quality of life. PMID- 23800335 TI - Low expression of N-myc downstream-regulated gene 2 in oesophageal squamous cell carcinoma correlates with a poor prognosis. AB - BACKGROUND: It is currently unclear whether a correlation exists between N-myc downstream-regulated gene 2 (NDRG2) expression and oesophageal squamous cell carcinoma (ESCC). The aim of this study was to examine the underlying clinical significance of NDRG2 expression in ESCC patients and to investigate the effects of NDRG2 up-regulation on ESCC cell growth in vitro and in vivo. METHODS: Immunohistochemistry was used to determine the level of NDRG2 expressions in ESCC tissue, which was then compared to specific clinicopathological features in the patient and tissue specimens. Factors associated with patient survival were analysed. Moreover, the effects of up-regulating NDRG2 expression on the growth of an ESCC cell line were examined by MTT, colony formation, DNA replication activity and nude mouse model assays. RESULTS: Notably low expression of NDRG2 in ESCC patients was inversely associated with clinical stage, NM classification, histological differentiation and patients' vital status (all P < 0.05). ESCC patients expressing high levels of NDRG2 exhibited a substantially higher 5-year overall survival rate than NDRG2-negative patients. Furthermore, NDRG2 over expression reduced the proliferation, colony formation and DNA replication activity in ESCC cells, as well as inhibiting the growth of ESCC cells in vivo. CONCLUSION: The present experiments demonstrated that NDRG2 may be a diagnostic and prognostic marker in patients with ESCC, and up-regulation of NDRG2 might act as a promising therapeutic strategy for aggressive ESCC. PMID- 23800336 TI - Impact of engaging middle management in practice interventions on staff support and learning culture: a quasi-experimental design. AB - AIM: This study evaluated the impact of different levels of engaging middle management in ward based strategies implemented by a project educator. BACKGROUND: The challenge for learning in practice is to develop effective teams where experienced staff engage and foster learning with students and other novice staff. DESIGN: A quasi-experimental pre- and post- intervention four group design was conducted from November 2009 to May 2010 across four general surgical and four general medical inpatient matched units in two settings in South East Queensland, Australia. METHOD: Staff survey data was used to compare control and intervention groups (one actively engaging nurse managers) before and after 'practice learning' interventions. The survey comprised demographic data and data from two validated scales (support instrument for nurses facilitating learning and clinical learning organisational culture). RESULTS: Number of surveys returned pre- and post-intervention was 336 from 713 (47%). There were significant differences across many subscales pertaining to staff perception of support in the intervention groups, with only one change in the control group. The number of significant different subscales in the learning culture was also greater when middle management supported the intervention. IMPLICATIONS FOR NURSING MANAGEMENT: Middle management should work closely with facilitators to assist embedding practice interventions. PMID- 23800337 TI - Frequency of MEFV mutation and genotype-phenotype correlation in cases with dysmenorrhea. AB - AIM: We aimed to investigate the relation between mutations and polymorphisms playing roles in the onset of clinical findings of Familial Mediterranean Fever (FMF) and clinical phenotypic reflections manifesting with painful episodes, such as dysmenorrhea. MATERIAL AND METHODS: A total of 1000 female patients who had not responded well to non-steroidal anti-inflammatory drugs in the menstrual period, and who had presented to the emergency room with the complaint of recurrent pain episodes were included in the study. All the patients were Turkish women living in Istanbul. In this study, the mutations most frequently seen in the Mediterranean Fever Gene (MEFV), namely M694V, E148Q, M680I(G/C), V726A, P369S, R761H, A744S, M694I, K695R, F479L, M680I(G/A), and I692del were examined using the DNA sequence analysis following DNA isolation. RESULTS: The number of individuals who had a mutation in at least one allele for FMF was 511 out of 1000 patients. Of these 511 patients, homozygous mutations were found in 21% (n = 109), compound heterozygous mutations were found in 27% (n = 136), and heterozygous mutations were found in 52% (n = 266). The most frequent homozygous genotype seen in our study population was M694V/M694V. The most common compound heterozygote genotypes were M694V/M680I, M694V/V726A, M694V/E148Q, and M680I/V726A; and 11.7% (n = 60) of the families in whom mutations were found had consanguinity. CONCLUSION: Women who present to the emergency room with the complaint of dysmenorrhea that is irresponsive to non-steroidal anti-inflammatory drugs may have several types of MEFV mutations that are responsible for FMF. PMID- 23800338 TI - Relatively high prevalence of drug resistance among antiretroviral-naive patients from Henan, Central China. AB - To elucidate the prevalence of HIV-1 subtypes and transmitted drug resistance in Henan, central China, HIV-1-positive blood samples from 187 antiretroviral-naive patients were collected in our study from August 2009 to November 2010. Subtype B' (92.0%, 172 of 187) remains the predominant HIV-1 subtype in Henan province and was prevalent in all risk populations and geographic regions. Of 98 pol sequences 67 (68.4%) harbored drug resistance mutations, and only 14 (14.3%, 14 of 98) sequences have mutations associated with significantly reduced phenotypic susceptibility to antiretroviral drugs. The unexpectedly high percentage of drug resistance in Henan province is mainly due to the prevalence of minor mutations in the protease and integrase regions, especially A71T/V and L68V/I/IM/LV. In all, we detected a relatively high prevalence of drug resistance with unique mutation distributions among antiretroviral-naive patients from Henan province. PMID- 23800339 TI - Live-virus exposure of vaccine-protected macaques alters the anti-HIV-1 antibody repertoire in the absence of viremia. AB - BACKGROUND: We addressed the question whether live-virus challenges could alter vaccine-induced antibody (Ab) responses in vaccinated rhesus macaques (RMs) that completely resisted repeated exposures to R5-tropic simian-human immunodeficiency viruses encoding heterologous HIV clade C envelopes (SHIV-Cs). RESULTS: We examined the Ab responses in aviremic RMs that had been immunized with a multi component protein vaccine (multimeric HIV-1 gp160, HIV-1 Tat and SIV Gag-Pol particles) and compared anti-Env plasma Ab titers before and after repeated live virus exposures. Although no viremia was ever detected in these animals, they showed significant increases in anti-gp140 Ab titers after they had encountered live SHIVs. When we investigated the dynamics of anti-Env Ab titers during the immunization and challenge phases further, we detected the expected, vaccine induced increases of Ab responses about two weeks after the last protein immunization. Remarkably, these titers kept rising during the repeated virus challenges, although no viremia resulted. In contrast, in vaccinated RMs that were not exposed to virus, anti-gp140 Ab titers declined after the peak seen two weeks after the last immunization. These data suggest boosting of pre-existing, vaccine-induced Ab responses as a consequence of repeated live-virus exposures. Next, we screened polyclonal plasma samples from two of the completely protected vaccinees by peptide phage display and designed a strategy that selects for recombinant phages recognized only by Abs present after - but not before - any SHIV challenge. With this "subtractive biopanning" approach, we isolated V3 mimotopes that were only recognized after the animals had been exposed to live virus. By detailed epitope mapping of such anti-V3 Ab responses, we showed that the challenges not only boosted pre-existing binding and neutralizing Ab titers, but also induced Abs targeting neo-antigens presented by the heterologous challenge virus. CONCLUSIONS: Anti-Env Ab responses induced by recombinant protein vaccination were altered by the multiple, live SHIV challenges in vaccinees that had no detectable viral loads. These data may have implications for the interpretation of "vaccine only" responses in clinical vaccine trials. PMID- 23800340 TI - Integrated pharmacokinetics/pharmacodynamics parameters-based dosing guidelines of enrofloxacin in grass carp Ctenopharyngodon idella to minimize selection of drug resistance. AB - BACKGROUND: Antibiotic resistance has become a serious global problem and is steadily increasing worldwide in almost every bacterial species treated with antibiotics. In aquaculture, the therapeutic options for the treatment of A. hydrophila infection were only limited to several antibiotics, which contributed for the fast-speed emergence of drug tolerance. Accordingly, the aim of this study was to establish a medication regimen to prevent drug resistant bacteria. To determine a rational therapeutic guideline, integrated pharmacodynamics and pharmacokinetics parameters were based to predict dose and dosage interval of enrofloxacin in grass carp Ctenopharyngodon idella infected by a field-isolated A. hydrophila strain. RESULTS: The pathogenic A. hydrophila strain (AH10) in grass carp was identified and found to be sensitive to enrofloxacin. The mutant selection window (MSW) of enrofloxacin on isolate AH10 was determined to be 0.5-3 MUg/mL based on the mutant prevention concentration (MPC) and minimum inhibitory concentration (MIC) value. By using high-performance liquid chromatography (HPLC) system, the Pharmacokinetic (PK) parameters of enrofloxacin and its metabolite ciprofloxacin in grass carp were monitored after a single oral gavage of 10, 20, 30 MUg enrofloxacin per g body weight. Dosing of 30 MUg/g resulted in serum maximum concentration (Cmax) of 7.151 MUg/mL, and concentration in serum was above MPC till 24 h post the single dose. Once-daily dosing of 30 MUg/g was determined to be the rational choice for controlling AH10 infection and preventing mutant selection in grass carp. Data of mean residue time (MRT) and body clearance (CLz) indicated that both enrofloxacin and its metabolite ciprofloxacin present similar eliminating rate and pattern in serum, muscle and liver. A withdraw time of more than 32 d was suggested based on the drug eliminating rate and pharmacokinetic model described by a polyexponential equation. CONCLUSIONS: Based on integrated PK/PD parameters (AUC/MIC, Cmax/MIC, and T>MPC), the results of this study established a principle, for the first time, on drawing accurate dosing guideline for pharmacotherapy against A. hydrophila strain (AH10) for prevention of drug-resistant mutants. Our approach in combining PK data with PD parameters (including MPC and MSW) was the new effort in aquaculture to face the challenge of drug resistance by drawing a specific dosage guideline of antibiotics. PMID- 23800341 TI - Metabolite analysis distinguishes between mice with epidermolysis bullosa acquisita and healthy mice. AB - BACKGROUND: Epidermolysis bullosa acquisita (EBA) is a rare skin blistering disease with a prevalence of 0.2/ million people. EBA is characterized by autoantibodies against type VII collagen. Type VII collagen builds anchoring fibrils that are essential for the dermal-epidermal junction. The pathogenic relevance of antibodies against type VII collagen subdomains has been demonstrated both in vitro and in vivo. Despite the multitude of clinical and immunological data, no information on metabolic changes exists. METHODS: We used an animal model of EBA to obtain insights into metabolomic changes during EBA. Sera from mice with immunization-induced EBA and control mice were obtained and metabolites were isolated by filtration. Proton nuclear magnetic resonance (NMR) spectra were recorded and analyzed by principal component analysis (PCA), partial least squares discrimination analysis (PLS-DA) and random forest. RESULTS: The metabolic pattern of immunized mice and control mice could be clearly distinguished with PCA and PLS-DA. Metabolites that contribute to the discrimination could be identified via random forest. The observed changes in the metabolic pattern of EBA sera, i.e. increased levels of amino acid, point toward an increased energy demand in EBA. CONCLUSIONS: Knowledge about metabolic changes due to EBA could help in future to assess the disease status during treatment. Confirming the metabolic changes in patients needs probably large cohorts. PMID- 23800342 TI - Effectiveness of acupuncture intervention for neck pain caused by cervical spondylosis: study protocol for a randomized controlled trial. AB - BACKGROUND: Neck pain caused by cervical spondylosis has become a common health problem worldwide among >40-year-old adults. Acupuncture intervention is one of the most popular treatment measures for this disorder. However, evidence for its efficacy in relieving neck pain and recovering neck physiological function has not been established in randomized, placebo-controlled trials. The primary aim of this trial is to assess the efficacy and safety of active acupuncture compared with sham acupuncture intervention for neck pain caused by cervical spondylosis. METHODS/DESIGN: We will conduct a randomized, double-blind, parallel-group, placebo-controlled trial comparing active acupuncture with placebo (sham acupuncture). A total of 456 patients with neck pain caused by cervical spondylosis who meet the eligibility criteria from outpatient clinics of the Second People's Hospital of Fujian Province and the Affiliated Rehabilitation Hospital, Fujian University of Traditional Chinese Medicine will be recruited and randomized into an active acupuncture or sham acupuncture group. The participants will undergo treatment sessions with either active or sham acupuncture intervention five times a week for 2 weeks. Evaluation by blinded assessors at baseline and at intervention for 1 and 2 weeks will include demographic characteristics, validated questionnaires (Northwick Park Neck Pain Questionnaire (NPQ) scale, Short-Form 36 (SF-36) scale, and McGill pain scale), examination of neck physiological function, and adverse events. All included patients will be followed up and investigated for relapse of neck pain at 4, 8, and 12 weeks after intervention. DISCUSSION: This paper describes the rationale and design of a randomized double-blind, placebo-controlled trial that aims to determine the efficacy and safety of acupuncture intervention for neck pain caused by cervical spondylosis. The primary outcomes are changes in the NPQ score and neck physiological function. Secondary outcome measures include quality of life, adverse events, and relapse of neck pain. If successful, this project will provide evidence of the efficacy and safety of acupuncture for neck pain caused by cervical spondylosis. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR-TRC-12002206. Registration date: 11 May 2012. PMID- 23800343 TI - Hypothalamic and amygdalar cell lines differ markedly in mitochondrial rather than nuclear encoded gene expression. AB - BACKGROUND: Corticotropin-releasing hormone (CRH) plays an important role in regulating the mammalian stress response. Two of the most extensively studied neuronal populations that express CRH are in the hypothalamus and amygdala. Both regions are involved in the stress response, but the amygdala is also involved in mediating response to fear and anxiety. Given that both hypothalamus and amygdala have overlapping functions, but their CRH-expressing neurons may respond differently to a given perturbation, we sought to identify differentially expressed genes between two neuronal cell types, amygdalar AR-5 and hypothalamic IVB cells. Thus, we performed a microarray analysis. Our hypothesis was that we would identify differentially expressed transcription factors, coregulators and chromatin-modifying enzymes. RESULTS: A total of 31,042 genes were analyzed, 10,572 of which were consistently expressed in both cell lines at a 95% confidence level. Of the 10,572 genes, 2,320 genes in AR-5 were expressed at >= 2 fold relative to IVBs, 1,104 genes were expressed at >=2-fold in IVB relative to AR-5 and 7,148 genes were expressed at similar levels between the two cell lines. The greatest difference was in six mitochondrial DNA-encoded genes, which were highly abundant in AR-5 relative to IVB cells. The relative abundance of these genes ranged from 413 to 885-fold according to the microarray results. Differential expression of these genes was verified by RTqPCR. The differentially expressed mitochondrial genes were cytochrome b (MT-CYB), cytochrome c oxidase subunit 1 and 2 (MT-CO1 and MT-CO2) and NADH-ubiquinone oxidoreductase chain 1, 2, and 3 (MT-ND1, MT-ND2, MT-ND3). CONCLUSION: As expected, the array revealed differential expression of transcription factors and coregulators; however the greatest difference between the two cell lines was in genes encoded by the mitochondrial genome. These genes were abundant in AR-5 relative to IVBs. At present, the reason for the marked difference is unclear. The cells may differ in mtDNA copy number, number of mitochondria, or regulation of the mitochondrial genome. The specific functions served by having such different levels of mitochondrial expression have not been determined. It is possible that the greater expression of the mitochondrial genes in the amygdalar cells reflects higher energy requirements than in the hypothalamic cell line. PMID- 23800345 TI - Binge drinking-induced subtle myocardial injury. AB - BACKGROUND: Most of the clinical, histopathological, and biochemical studies consider the effect of chronic alcohol intoxication on myocardial injury. Much less attention has been paid to acute alcohol (binge drinking)-induced cardiotoxicity, even though alcohol binging is much more common than alcohol dependence. METHODS: We briefly present some of the binge drinking-induced "holiday heart" effects. The literature was searched to find effects of alcohol on heart. RESULTS: In binge drinking, the literature has demonstrated transient myocardial subtle changes in cardiac magnetic resonance, increased serological markers of myocardial injury and inflammation, abnormal cardiac rhythm, changes in other biochemical and ultrastructural indices of myocardial dysfunction, as well as changes in metabolism, blood pressure, heart rate, thrombosis/fibrinolysis processes, and coronary vasoconstriction. CONCLUSIONS: Although acute low alcohol exposure has widely proven positive effect on myocardial function, heavy acute drinking frequent events are related to adverse cardiovascular effects. PMID- 23800344 TI - Identification and real-time expression analysis of selected Toxoplasma gondii in vivo induced antigens recognized by IgG and IgM in sera of acute toxoplasmosis patients. AB - BACKGROUND: Toxoplasma gondii is an obligate intracellular zoonotic parasite of the phylum Apicomplexa which infects a wide range of warm-blooded animals, including humans. In this study in-vivo induced antigens of this parasite was investigated using in-vivo induced antigen technology (IVIAT) and pooled sera from patients with serological evidence of acute infection. METHODS: The pooled sera was first pre-absorbed against three different preparations of antigens from in-vitro-grown cells of each T. gondii and E. coli XL1-Blue MRF', subsequently it was used to screen T. gondii cDNA phage expression library. Positive clones from each group were subjected to quantitative real-time PCR expression analysis on mRNA of in-vivo and in-vitro grown parasites. RESULTS: A total of 29 reactive clones from each IgM and IgG immunoscreenings were found to have high homology to T. gondii genes. Quantitative real-time PCR expression analysis showed that 20 IgM-detected genes and 11 IgG-detected genes were up-regulated in-vivo relative to their expression levels in-vitro. These included genes encoding micronemes, sterol-regulatory element binding protein site, SRS34A, MIC2-associated protein M2AP, nucleoredoxin, protein phosphatase 2C and several hypothetical proteins. A hypothetical protein (GenBank accession no. 7899266) detected by IgG had the highest in-vivo over in-vitro fold change of 499.86; while another up-regulated hypothetical protein (GenBank accession no. 7898829) recognized by IgM showed high sensitivity (90%) and moderate specificity (70%) in detecting T. gondii antibodies when tested with 20 individual serum samples. CONCLUSION: The highly up-regulated genes and the corresponding proteins, in particular the hypothetical proteins, may be useful in further studies on understanding the disease pathogenesis and as potential vaccine candidates. PMID- 23800346 TI - Age and hemispheric differences in transcallosal inhibition between motor cortices: an ispsilateral silent period study. AB - BACKGROUND: In this study, we investigated age and hemispheric differences in transcallosal inhibition (TCI) in the context of active contraction using the ipsilateral silent period (iSP). We also examined whether age-related changes in TCI would be related to corresponding changes in manual performance with age. Participants consisted of right-handed individuals from two age groups (young adults, n=13; seniors, n=17). The iSP was measured for each hemisphere using suprathreshold TMS pulses delivered over the primary motor cortex ipsilateral to the maximally contracting hand while the homologue muscles of the opposite hand were lightly contracting (~15% of the maximum). Manual performance was assessed bilaterally for both grip strength and fine dexterity. RESULTS: Our results yielded two main findings. First, TCI measures derived from iSP were strongly influenced by age, whereas differences between hemispheres were only minor. Second, correlation analyses revealed that age-related variations in TCI measures were related to changes in manual performance, so that left-to-right TCI correlated with right hand performance and vice-versa for the opposite hand/hemisphere. CONCLUSION: Overall, these results concur with other recent reports indicating that mutual inhibition between motor cortices tends to decline with age. In this respect, our observations are in line with the notion that the balance of normally predominantly inhibitory interactions between motor cortices is shifted toward excitatory processes with age. PMID- 23800347 TI - Neuronal complications of intravitreal silicone oil: an updated review. AB - Silicone oil (SiO) has a well-established role as a long-term endotamponade agent in the management of complicated retinal detachments. Complications of intraocular SiO include keratopathy, glaucoma, cataract and subretinal migration of the oil droplets. SiO tamponade can also lead to a severe optic neuropathy caused by retrolaminar migration. Nevertheless, intracranial migration of the SiO through the optic nerve posterior to the lamina cribrosa to the optic chiasm and brain is uncommon. The mechanism is still under debate, but it has been suggested elevated intraocular pressure, macrophages or optic nerve head anatomical predispositions as potential explanations. Moreover, central scotoma may develop in eyes with SiO not only at the time of oil removal, but also during the period of tamponade. We performed a PubMed search of neuronal complications of silicone oil over a period of 25 years. This review summarizes our current understanding of the specific pathogenic mechanisms of intraocular SiO neuronal side effects, concluding that pre-existing glaucoma and optic nerve abnormalities are the main risk factors associated with this damage. In their absence, the risk of extraocular SiO penetration is so low that the use of SiO endotamponade in complex retinal detachment patients does not need to be modified. MRI images to assess extraocular SiO migration are only necessary in very few and special cases, such as patients with optic nerve abnormalities and glaucoma. PMID- 23800348 TI - Carer quality of life and experiences of health services: a cross-sectional survey across three neurological conditions. AB - BACKGROUND: Neurological conditions have a substantial impact on carers, with carer well-being having been shown to be influenced by a number of demographic, patient and caregiving factors. Support given to carers can lead to better coping. This study investigated the relationship between carer well-being and experiences with health and social services. METHODS: A cross-sectional survey was conducted of 1910 (37.4%) of carers of 5109 people with motor neuron disease (MND) (n=434, 54.9%), multiple sclerosis (MS) (n=721, 30.7%) and Parkinson's disease (PD) (n=755, 38.2%). Carers completed a generic health status measure (SF 12), a carer strain measure (Carer Strain Index- CSI) and a newly developed questionnaire on health and social care experiences. Data were analysed by analysis of variance with p set at <0.05. RESULTS: Carer well-being was found to be compromised and differed significantly between the three conditions. Furthermore, a considerable number of carers experienced problems with aspects of health and social care, although there was no clear pattern according to the condition that was cared for. The total number of problems reported did not differ significantly between conditions but was significantly (all p<0.001) associated with carer quality of life (both physical and mental health) and strain, even when other influencing factors (demographic and caregiving variables) were corrected for. The association was particularly strong for carer strain, and less strong (but still significant) for quality of life. CONCLUSIONS: The results show that carer well-being is compromised, in line with previous studies. Furthermore, the link of carer well-being to the number of problems reported suggests that minimizing problems experienced could improve carer well being. This stresses the importance of health and social services appropriately supporting carers. PMID- 23800349 TI - Analysis of polyhydroxyalkanoate (PHA) synthase gene and PHA-producing bacteria in activated sludge that produces PHA containing 3-hydroxydodecanoate. AB - Activated sludge is an alternative to pure cultures for polyhydroxyalkanoate (PHA) production due to the presence of many PHA-producing bacteria in activated sludge community. In this study, activated sludge was submitted to aerobic dynamic feeding in a sequencing batch reactor. During domestication, the changes of bacterial community structure were observed by terminal restriction fragment length polymorphism analysis. Furthermore, some potential PHA-producing bacteria, such as Thauera, Acinetobacter and Pseudomonas, were identified by denaturing gradient gel electrophoresis analysis. The constructed PHA synthase gene library was analyzed by DNA sequencing. Of the 80 phaC genes obtained, 76 belonged to the Class I PHA synthase, and four to the Class II PHA synthase. Gas chromatography mass spectrometry analysis showed that PHA produced by activated sludge was composed of three types of monomers: 3-hydroxybutyrate, 3-hydroxyvalerate and 3 hydroxydodecanoate (3HDD). This is the first report of production of medium-chain length PHAs (PHAMCL ) containing 3HDD by activated sludge. Further studies suggested that a Pseudomonas strain may play an important role in the production of PHAMCL containing 3HDD. Moreover, a Class II PHA synthase was found to have a correlation with the production of 3HDD-containing PHAMCL . PMID- 23800350 TI - Binding of the repressor complex REST-mSIN3b by small molecules restores neuronal gene transcription in Huntington's disease models. AB - Transcriptional dysregulation is a hallmark of Huntington's disease (HD) and one cause of this dysregulation is enhanced activity of the REST-mSIN3a-mSIN3b-CoREST HDAC repressor complex, which silences transcription through REST binding to the RE1/NRSE silencer. Normally, huntingtin (HTT) prevents this binding, allowing expressing of REST target genes. Here, we aimed to identify HTT mimetics that disrupt REST complex formation in HD. From a structure-based virtual screening of 7 million molecules, we selected 94 compounds predicted to interfere with REST complex formation by targeting the PAH1 domain of mSIN3b. Primary screening using DiaNRSELuc8 cells revealed two classes of compounds causing a greater than two fold increase in luciferase. In particular, quinolone-like compound 91 (C91) at a non-toxic nanomolar concentration reduced mSIN3b nuclear entry and occupancy at the RE1/NRSE within the Bdnf locus, and restored brain-derived neurotrophic factor (BDNF) protein levels in HD cells. The mRNA levels of other RE1/NRSE regulated genes were similarly increased while non-REST-regulated genes were unaffected. C91 stimulated REST-regulated gene expression in HTT-knockdown Zebrafish and increased BDNF mRNA in the presence of mutant HTT. Thus, a combination of virtual screening and biological approaches can lead to compounds reducing REST complex formation, which may be useful in HD and in other pathological conditions. PMID- 23800351 TI - Patient centered care in Islam: distinguishing between religious and sociocultural factors. AB - The use of patient centered care is promoted by Islam. Many of the countries with the highest percentage of diabetics are Muslim majority countries. The use of patient centered care in these areas is likely to reduce the burden of diabetes in these countries. However there are several challenges faced by the physicians working in these countries. Most of these challenges are sociocultural in origin and a thorough knowledge of the Islamic principles can help overcome these challenges. PMID- 23800352 TI - Predicting response to physiotherapy treatment for musculoskeletal shoulder pain: protocol for a longitudinal cohort study. AB - BACKGROUND: Shoulder pain affects all ages, with a lifetime prevalence of one in three. The most effective treatment is not known. Physiotherapy is often recommended as the first choice of treatment. At present, it is not possible to identify, from the initial physiotherapy assessment, which factors predict the outcome of physiotherapy for patients with shoulder pain. The primary objective of this study is to identify which patient characteristics and baseline measures, typically assessed at the first physiotherapy appointment, are related to the functional outcome of shoulder pain 6 weeks and 6 months after starting physiotherapy treatment. METHODS/DESIGN: Participants with musculoskeletal shoulder pain of any duration will be recruited from participating physiotherapy departments. For this longitudinal cohort study, the participants care pathway, including physiotherapy treatment will be therapist determined. DISCUSSION: This study may offer service users and providers with guidance to help identify whether or not physiotherapy is likely to be of benefit. Clinicians may have some direction as to what key factors indicate a patient's likely response to physiotherapy. PMID- 23800353 TI - Microstructure and dielectric properties of biocarbon nanofiber composites. AB - A kind of web-like carbon with interconnected nanoribbons was fabricated using bacterial cellulose pyrolyzed at various temperatures, and the microwave dielectric properties were investigated. Bacterial cellulose was converted into carbonized bacterial cellulose (CBC) with a novel three-dimensional web built of entangled and interconnected cellulose ribbons when the carbonization temperature was below 1,200 degrees C; the web-like structure was destroyed at a temperature of 1,400 degrees C. Composites of CBC impregnated with paraffin wax exhibited high complex permittivity over a frequency range of 2 to 18 GHz, depending on the carbonization temperature. Both real and imaginary parts were the highest for CBC pyrolyzed at 1,200 degrees C. The complex permittivity also strongly depended on CBC loadings. For 7.5 wt.% loading, the real and imaginary permittivities were about 12 and 4.3, respectively, and the minimum reflection loss was -39 dB at 10.9 GHz. For 30 wt.% loading, the real and imaginary permittivities were about 45 and 80, respectively, and the shielding efficiency was more than 24 dB in the measured frequency range and could be up to 39 dB at 18 GHz. The electromagnetic properties were assumed to correlate with both the dielectric relaxation and the novel web-like structure. PMID- 23800355 TI - Rationale and design of the Multicenter Medication Reconciliation Quality Improvement Study (MARQUIS). AB - BACKGROUND: Unresolved medication discrepancies during hospitalization can contribute to adverse drug events, resulting in patient harm. Discrepancies can be reduced by performing medication reconciliation; however, effective implementation of medication reconciliation has proven to be challenging. The goals of the Multi-Center Medication Reconciliation Quality Improvement Study (MARQUIS) are to operationalize best practices for inpatient medication reconciliation, test their effect on potentially harmful unintentional medication discrepancies, and understand barriers and facilitators of successful implementation. METHODS: Six U.S. hospitals are participating in this quality improvement mentored implementation study. Each hospital has collected baseline data on the primary outcome: the number of potentially harmful unintentional medication discrepancies per patient, as determined by a trained on-site pharmacist taking a "gold standard" medication history. With the guidance of their mentors, each site has also begun to implement one or more of 11 best practices to improve medication reconciliation. To understand the effect of the implemented interventions on hospital staff and culture, we are performing mixed methods program evaluation including surveys, interviews, and focus groups of front line staff and hospital leaders. DISCUSSION: At baseline the number of unintentional medication discrepancies in admission and discharge orders per patient varies by site from 2.35 to 4.67 (mean=3.35). Most discrepancies are due to history errors (mean 2.12 per patient) as opposed to reconciliation errors (mean 1.23 per patient). Potentially harmful medication discrepancies averages 0.45 per patient and varies by site from 0.13 to 0.82 per patient. We discuss several barriers to implementation encountered thus far. In the end, we anticipate that MARQUIS tools and lessons learned have the potential to decrease medication discrepancies and improve patient outcomes. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT01337063. PMID- 23800356 TI - Recurrent cervical cancer in a patient who was compound heterozygous for UGT1A1*6 and UGT1A1*28 presenting with serious adverse events during irinotecan hydrochloride/nedaplatin therapy. AB - There have been no case reports of the risk of serious adverse events associated with the administration of irinotecan hydrochloride (CPT-11) in patients with gynecologic cancer who are compound heterozygous for UGT1A1*6 and UGT1A1*28. A 71 year-old patient presented with recurrent stage IIIb cervical cancer. Combined chemotherapy was initiated with CPT-11 (60 mg/m2 on days 1 and 8) plus nedaplatin (NDP; 80 mg/m2 on day 1), with each cycle lasting for 28 days. The patient was a compound heterozygote for UGT1A1*6 and UGT1A1*28. Hematotoxic adverse events observed during the chemotherapy were grade 4 neutropenia, grade 3 anemia, and grade 4 thrombocytopenia, and the non-hematotoxic adverse events were grade 3 diarrhea and grade 3 fatigue. The findings in this patient indicate that CPT-11 should be administered with great care, even at a dose of 60 mg/m2, in patients receiving combined therapy with CPT-11 and NDP who are compound heterozygous for UGT1A1*6 and UGT1A1*28. PMID- 23800357 TI - Connexin-43 can delay early recurrence and metastasis in patients with hepatitis B-related hepatocellular carcinoma and low serum alpha-fetoprotein after radical hepatectomy. AB - BACKGROUND: We studied the relationships among Cx43, CD105, and VEGF in specimens of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) with different serum AFP levels with respect to recurrence and metastasis. METHODS: Expressions of Cx43, CD105, and VEGF in 234 HCC tissue specimens were examined using tissue microarray and immunohistochemistry. Cx43 mRNA expression was examined in 38 frozen HCC specimens using RT-PCR. Correlations between these expressions and tumor recurrence, metastasis, and prognosis were analyzed using Kaplan-Meier and Cox regression analyses. RESULTS: Cx43 expression correlated with early tumor recurrence (P = 0.001), disease-free survival (P = 0.026), and overall survival (P = 0.000) in patients with serum AFP < 400 ng/ml, but not in those with serum AFP >= 400 MUg/L. Cx43 expression is an independent predictor of later recurrence and longer overall survival and is inversely correlated with expression of CD105 and VEGF (P = 0.018 and 0.023, respectively), histological differentiation (P = 0.002), vessel tumor embolism (P = 0.029), and focal number (P = 0.017). Immunohistochemistry showed that Cx43 expression in patients with low AFP was lower in patients with distant metastases than in those with no metastasis or those with liver metastasis. Patients with early recurrence expressed less Cx43 mRNA than did those with no recurrence (chi2 = 9.827, P = 0.002). CONCLUSIONS: Cx43 expression can delay early HCC recurrence, metastasis, and poor prognosis after radical hepatectomy in patients with HBV-related HCC and low AFP. PMID- 23800359 TI - Comparison of balloon catheter ablation technologies for pulmonary vein isolation: the laser versus cryo study. AB - INTRODUCTION: Balloon catheters have been developed to facilitate pulmonary vein isolation (PVI) in patients with paroxysmal atrial fibrillation (PAF). We sought to compare the safety and efficacy of the cryoballoon (CB) and the laserballoon (LB) in a pilot study. METHODS AND RESULTS: One hundred and forty patients with drug-refractory PAF were prospectively allocated in a 1:1 fashion to undergo a PVI procedure with the 28 mm CB or the LB and were followed for 12 months using 3 day Holter ECG recording. The primary efficacy endpoint was a documented AF recurrence >= 30 seconds between 90 and 365 days after the index ablation. In total, 269 of 270 PVs (99.6%) and 270 of 273 PVs (98.9%) were acutely isolated in the CB and LB group, respectively. Mean procedural time was 136 +/- 30 minutes for the CB group and 144 +/- 33 minutes for the LB group (P = 0.13). Mean fluoroscopy time was longer in the CB group (21 +/- 9 minutes vs 15 +/- 6 minutes; P < 0.001). During 12 months follow-up, 37% of patients in the CB group and 27% in the LB group experienced an AF recurrence (P = 0.18). Phrenic nerve palsies occurred in 5.7% (CB) and 4.2% (LB) of patients, respectively. CONCLUSION: Balloon catheters are a viable option to safely perform a PVI procedure in patients with drug-refractory PAF. Ninety-nine percent of PVs may be acutely isolated with a single balloon catheter. The AF free survival rate after a single ablation procedure was not statistically different between groups. PMID- 23800358 TI - Biophysical characterization and crystal structure of the Feline Immunodeficiency Virus p15 matrix protein. AB - BACKGROUND: Feline Immunodeficiency Virus (FIV) is a viral pathogen that infects domestic cats and wild felids. During the viral replication cycle, the FIV p15 matrix protein oligomerizes to form a closed matrix that underlies the lipidic envelope of the virion. Because of its crucial role in the early and late stages of viral morphogenesis, especially in viral assembly, FIV p15 is an interesting target in the development of potential new therapeutic strategies. RESULTS: Our biochemical study of FIV p15 revealed that it forms a stable dimer in solution under acidic conditions and at high concentration, unlike other retroviral matrix proteins. We determined the crystal structure of full-length FIV p15 to 2 A resolution and observed a helical organization of the protein, typical for retroviral matrix proteins. A hydrophobic pocket that could accommodate a myristoyl group was identified, and the C-terminal end of FIV p15, which is mainly unstructured, was visible in electron density maps. As FIV p15 crystallizes in acidic conditions but with one monomer in the asymmetric unit, we searched for the presence of a biological dimer in the crystal. No biological assembly was detected by the PISA server, but the three most buried crystallographic interfaces have interesting features: the first one displays a highly conserved tryptophan acting as a binding platform, the second one is located along a 2-fold symmetry axis and the third one resembles the dimeric interface of EIAV p15. Because the C-terminal end of p15 is involved in two of these three interfaces, we investigated the structure and assembly of a C terminal-truncated form of p15 lacking 14 residues. The truncated FIV p15 dimerizes in solution at a lower concentration and crystallizes with two molecules in the asymmetric unit. The EIAV-like dimeric interface is the only one to be retained in the new crystal form. CONCLUSION: The dimeric form of FIV p15 in solution and its extended C-terminal end are characteristic among lentiviral matrix proteins. Crystallographic interfaces revealed several interactions that might be involved in FIV replication. Further studies are needed to better understand their biological relevance in the function of FIV Gag during viral replication. PMID- 23800360 TI - Relationship between viral load and self-report measures of medication adherence among youth with perinatal HIV infection. AB - Poor adherence to antiretroviral therapy (ART) contributes to disease progression and emergence of drug-resistant HIV in youth with perinatally acquired HIV infection (PHIV +), necessitating reliable measures of adherence. Although electronic monitoring devices have often been considered the gold-standard assessment in HIV research, they are costly, can overestimate nonadherence and are not practical for routine care. Thus, the development of valid, easily administered self-report adherence measures is crucial for adherence monitoring. PHIV+youth aged 7-16 (n = 289) and their caregivers, enrolled in a multisite cohort study, were interviewed to assess several reported indicators of adherence. HIV-1 RNA viral load (VL) was dichotomized into >/<= 400 copies/mL. Lower adherence was significantly associated with VL >400 copies/mL across most indicators, including >= 1 missed dose in past seven days [youth report: OR = 2.78 (95% CI, 1.46-5.27)]. Caregiver and combined youth/caregiver reports yielded similar results. Within-rater agreement between various adherence indicators was high for both youth and caregivers. Inter-rater agreement on adherence was moderate across most indicators. Age >= 13 years and living with biological mother or relative were associated with VL >400 copies/mL. Findings support the validity of caregiver and youth adherence reports and identify youth at risk of poor adherence. PMID- 23800361 TI - TREM2 in neurodegeneration: evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson's disease. AB - BACKGROUND: A rare variant in the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene has been reported to be a genetic risk factor for Alzheimer's disease by two independent groups (Odds ratio between 2.9-4.5). Given the key role of TREM2 in the effective phagocytosis of apoptotic neuronal cells by microglia, we hypothesized that dysfunction of TREM2 may play a more generalized role in neurodegeneration. With this in mind we set out to assess the genetic association of the Alzheimer's disease-related risk variant in TREM2 (rs75932628, p.R47H) with other related neurodegenerative disorders. RESULTS: The study included 609 patients with frontotemporal dementia, 765 with amyotrophic lateral sclerosis, 1493 with Parkinson's disease, 772 with progressive supranuclear palsy, 448 with ischemic stroke and 1957 controls subjects free of neurodegenerative disease. A significant association was observed for the TREM2 p.R47H substitution in susceptibility to frontotemporal dementia (OR = 5.06; p value = 0.001) and Parkinson's disease (OR = 2.67; p-value = 0.026), while no evidence of association with risk of amyotrophic lateral sclerosis, progressive supranuclear palsy or ischemic stroke was observed. CONCLUSIONS: Our results suggest that the TREM2 p.R47H substitution is a risk factor for frontotemporal dementia and Parkinson's disease in addition to Alzheimer's disease. These findings suggest a more general role for TREM2 dysfunction in neurodegeneration, which could be related to its role in the immune response. PMID- 23800362 TI - First report on circulation of Echinococcus ortleppi in the one humped camel (Camelus dromedaries), Sudan. AB - BACKGROUND: Echinococcus granulosus (EG) complex, the cause of cystic echinococcosis (CE), infects humans and several other animal species worldwide and hence the disease is of public health importance. Ten genetic variants, or genotypes designated as (G1-G10), are distributed worldwide based on genetic diversity. The objective of this study was to provide some sequence data and phylogeny of EG isolates recovered from the Sudanese one-humped camel (Camelus dromedaries). Fifty samples of hydatid cysts were collected from the one- humped camels (Camelus dromedaries) at Taboul slaughter house, central Sudan. DNAs were extracted from protoscolices and/or associated germinal layers of hydatid cysts using a commercial kit. The mitochondrial NADH dehydrogenase subunit 1 (NADH1) gene and the cytochrome C oxidase subunit 1 (cox1) gene were used as targets for polymerase chain reaction (PCR) amplification. The PCR products were purified and partial sequences were generated. Sequences were further examined by sequence analysis and subsequent phylogeny to compare these sequences to those from known strains of EG circulating globally. RESULTS: The identity of the PCR products were confirmed as NADH1 and cox1 nucleotide sequences using the Basic Local Alignment Search Tool (BLAST) of NCBI (National Center for Biotechnology Information, Bethesda, MD). The phylogenetic analysis showed that 98% (n = 49) of the isolates clustered with Echinococcus canadensis genotype 6 (G6), whereas only one isolate (2%) clustered with Echinococcus ortleppi (G5). CONCLUSIONS: This investigation expands on the existing sequence data generated from EG isolates recovered from camel in the Sudan. The circulation of the cattle genotype (G5) in the one-humped camel is reported here for the first time. PMID- 23800363 TI - The complete mitochondrial genomes of three parasitic nematodes of birds: a unique gene order and insights into nematode phylogeny. AB - BACKGROUND: Analyses of mitochondrial (mt) genome sequences in recent years challenge the current working hypothesis of Nematoda phylogeny proposed from morphology, ecology and nuclear small subunit rRNA gene sequences, and raise the need to sequence additional mt genomes for a broad range of nematode lineages. RESULTS: We sequenced the complete mt genomes of three Ascaridia species (family Ascaridiidae) that infest chickens, pigeons and parrots, respectively. These three Ascaridia species have an identical arrangement of mt genes to each other but differ substantially from other nematodes. Phylogenetic analyses of the mt genome sequences of the Ascaridia species, together with 62 other nematode species, support the monophylies of seven high-level taxa of the phylum Nematoda: 1) the subclass Dorylaimia; 2) the orders Rhabditida, Trichinellida and Mermithida; 3) the suborder Rhabditina; and 4) the infraorders Spiruromorpha and Oxyuridomorpha. Analyses of mt genome sequences, however, reject the monophylies of the suborders Spirurina and Tylenchina, and the infraorders Rhabditomorpha, Panagrolaimomorpha and Tylenchomorpha. Monophyly of the infraorder Ascaridomorpha varies depending on the methods of phylogenetic analysis. The Ascaridomorpha was more closely related to the infraorders Rhabditomorpha and Diplogasteromorpha (suborder Rhabditina) than they were to the other two infraorders of the Spirurina: Oxyuridorpha and Spiruromorpha. The closer relationship among Ascaridomorpha, Rhabditomorpha and Diplogasteromorpha was also supported by a shared common pattern of mitochondrial gene arrangement. CONCLUSIONS: Analyses of mitochondrial genome sequences and gene arrangement has provided novel insights into the phylogenetic relationships among several major lineages of nematodes. Many lineages of nematodes, however, are underrepresented or not represented in these analyses. Expanding taxon sampling is necessary for future phylogenetic studies of nematodes with mt genome sequences. PMID- 23800364 TI - Speckle tracking echocardiographic analysis of left ventricular systolic and diastolic functions of young elite athletes with eccentric and concentric type of cardiac remodeling. AB - AIMS: In individuals who exercise regularly and for extended periods of time, some structural alterations in the heart, called the athlete's heart, develop in time. These alterations vary in type, can be eccentric or concentric, depending on the nature of exercise. Speckle tracking echocardiography (STE) is a novel, angle-independent method that accurately and reliably measures systolic and diastolic functions of the left ventricle (LV) with considerably lower inter operator variability. METHODS AND RESULTS: Twenty-two marathon runners, 24 wrestlers, and 20 healthy sedentary individuals were included in the study. The average age of subjects is 17.5 +/- 2.2 in marathon runners, 16.8 +/- 1.9 in wrestlers, and 16.4 +/- 1.8 in control group. The parameters of LV longitudinal strain (S), LV longitudinal strain rate systolic (SRS), LV longitudinal strain rate diastolic early filling (SRE), and longitudinal strain rate diastolic late filling (SRA) were evaluated by apical two-, three-, and four-chamber grayscale imaging using the global longitudinal strain (GLS) and GLS rate (GLSR). Conventional echocardiographic parameters demonstrated increased LV diameters and wall thickness in the marathon runners and increased wall thickness without increased LV diameters in the wrestlers. Systolic and diastolic functions were comparable between the marathon runners and wrestlers with conventional echocardiography. Analysis with STE, however, yielded higher systolic strain and strain rates in the athletes. Normalized GLS parameters and end-diastolic volume (EDV) were shown to be correlated. CONCLUSION: Overall, conventional echocardiography can detect some differences between young athletes with eccentric and concentric type of athlete's heart but it is incapable of revealing differences in intrinsic myocardial functions. However, analysis using STE demonstrated increased systolic functions in athletes commensurate with increased load, with unaltered diastolic functions. PMID- 23800365 TI - Formaldehyde in brain: an overlooked player in neurodegeneration? AB - Formaldehyde is an environmental pollutant that is also generated in substantial amounts in the human body during normal metabolism. This aldehyde is a well established neurotoxin that affects memory, learning, and behavior. In addition, in several pathological conditions, including Alzheimer's disease, an increase in the expression of formaldehyde-generating enzymes and elevated levels of formaldehyde in brain have been reported. This article gives an overview on the current knowledge on the generation and metabolism of formaldehyde in brain cells as well as on formaldehyde-induced alterations in metabolic processes. Brain cells have the potential to generate and to dispose formaldehyde. In culture, both astrocytes and neurons efficiently oxidize formaldehyde to formate which can be exported or further oxidized. Although moderate concentrations of formaldehyde are not acutely toxic for brain cells, exposure to formaldehyde severely affects their metabolism as demonstrated by the formaldehyde-induced acceleration of glycolytic flux and by the rapid multidrug resistance protein 1-mediated export of glutathione from both astrocytes and neurons. These formaldehyde-induced alterations in the metabolism of brain cells may contribute to the impaired cognitive performance observed after formaldehyde exposure and to the neurodegeneration in diseases that are associated with increased formaldehyde levels in brain. PMID- 23800366 TI - Patient preference for involvement, experienced involvement, decisional conflict, and satisfaction with physician: a structural equation model test. AB - BACKGROUND: A comprehensive model of the relationships among different shared decision-making related constructs and their effects on patient-relevant outcomes is largely missing. Objective of our study was the development of a model linking decision-making in medical encounters to an intermediate and a long-term endpoint. The following hypotheses were tested: physicians are more likely to involve patients who have a preference for participation and are willing to take responsibility in the medical decision-making process, increased patient involvement decreases decisional conflict, and lower decisional conflict favourably influences patient satisfaction with the physician. METHODS: This model was tested in a German primary care sample (N = 1,913). Psychometrically tested instruments were administered to assess the following: patients' preference for being involved in medical decision-making, patients' experienced involvement in medical decision-making, decisional conflict, and satisfaction with the primary care provider. Structural equation modelling was used to explore multiple associations. The model was tested and adjusted in a development sub sample and cross-validated in a confirmatory sample. Demographic and clinical characteristics were accounted for as possible confounders. RESULTS: Local and global indexes suggested an acceptable fit between the theoretical model and the data. Increased patient involvement was strongly associated with decreased decisional conflict (standardised regression coefficient Beta = -.73). Both high experienced involvement (Beta = .34) and low decisional conflict (B = -.28) predicted higher satisfaction with the physician. Patients' preference for involvement was negatively associated with the experienced involvement (B = .24). CONCLUSION: Altogether, our model could be largely corroborated by the collected empirical data except the unexpected negative association between preference for involvement and experienced involvement. Future research on the associations among different SDM-related constructs should incorporate longitudinal studies in order to strengthen the hypothesis of causal associations. PMID- 23800367 TI - Peripheral regulatory cells immunophenotyping in primary Sjogren's syndrome: a cross-sectional study. AB - INTRODUCTION: IL-10-producing B cells, Foxp3-expressing T cells (Tregs) and the IDO-expressing dendritic cells (pDC) are able to modulate inflammatory processes, to induce immunological tolerance and, in turn, to inhibit the pathogenesis of autoimmune disease. The aim of the study was to characterize and to enumerate peripheral IL-10--producing B cells, Tregs and pDCregs in primary Sjogren's Syndrome (pSS) patients in regard of their clinical and serologic activity. METHODS: Fifty pSS patients and 25 healthy individuals were included in the study. CD19+-expressing peripheral B lymphocytes were purified by positive selection. CD19+/CD24(hi)/CD38(hi)/IL-10-producing B cells, CD4+/CD25(hi)/Foxp3+ and CD8+/CD28+/Foxp3+ Tregs, as well as CCR6+/CD123+/IDO+ DCs, were quantitated by flow cytometry. RESULTS: Immature/transitional circulating IgA+ IL-10 producing B cells had higher levels in pSS patients versus control group, whereas CD19+/CD38(hi)/IgG+/IL-10+ cells had lower percentage versus control. Indeed CD19+/CD24(hi)/CD38(hi)/CD5+/IL-10+, CD19+/CD24(hi)/CD38(hi)/CD10+/IL-10+, CD19+/CD24(hi)/CD38(hi)/CD20+/IL-10+, CD19+/CD24(hi)/CD38(hi)/CD27-/IL-10+, and CD19+/CD24(hi)/CD38(hi)/CXCR7+/IL-10+ cells had higher frequency in clinical inactive pSS patients when compared with control group. Remarkably, only percentages of CD19+/CD24(hi)/CD38(hi)/CD10+/IL-10+ and CD19+/CD24(hi)/CD38(hi)/CD27-/IL-10+ subsets were increased in pSS serologic inactive versus control group (P < 0.05). The percentage of IDO-expressing pDC cells was higher in pSS patients regardless of their clinical or serologic activity. There were no statistically significant differences in the percentage of CD4+/CD25(hi)/Foxp3+ Tregs between patient groups versus controls. Nonetheless, a decrease in the frequency of CD8+/CD28-/Foxp3+ Tregs was found in inactive pSS patients versus controls (P < 0.05). CONCLUSIONS: The findings of this exploratory study show that clinical inactive pSS patients have an increased frequency of IL-10--producing B cells and IDO-expressing pDC cells. PMID- 23800369 TI - Synthesis of CdTe quantum dot-conjugated CC49 and their application for in vitro imaging of gastric adenocarcinoma cells. AB - The purpose of this experiment was to investigate the visible imaging of gastric adenocarcinoma cells in vitro by targeting tumor-associated glycoprotein 72 (TAG 72) with near-infrared quantum dots (QDs). QDs with an emission wavelength of about 550 to 780 nm were conjugated to CC49 monoclonal antibodies against TAG-72, resulting in a probe named as CC49-QDs. A gastric adenocarcinoma cell line (MGC80 3) expressing high levels of TAG-72 was cultured for fluorescence imaging, and a gastric epithelial cell line (GES-1) was used for the negative control group. Transmission electron microscopy indicated that the average diameter of CC49-QDs was 0.2 nm higher compared with that of the primary QDs. Also, fluorescence spectrum analysis indicated that the CC49-QDs did not have different optical properties compared to the primary QDs. Immunohistochemical examination and in vitro fluorescence imaging of the tumors showed that the CC49-QDs probe could bind TAG-72 expressed on MGC80-3 cells. PMID- 23800370 TI - Ceria and titania incorporated silica based catalyst prepared from rice husk: adsorption and photocatalytic studies of methylene blue. AB - Titania and ceria incorporated rice husk silica based catalyst was synthesized via sol-gel method using CTAB and glycerol as surface directing agents at room temperature and labeled as RHS-50Ti10Ce. The catalyst was used to study the adsorption and photodegradation of methylene blue (MB) under UV irradiation. The powder XRD pattern of RHS-50Ti10Ce was much broader (2theta=25-30 degrees ) than that of the parent RHS (2theta=22 degrees ). The catalyst exhibited type IV isotherm with H3 hysteresis loop, and the TEM images showed partially ordered pore arrangements. The TGA-DTG thermograms confirmed the complete removal of the templates after calcination at 500 degrees C. RHS-50Ti10Ce exhibited excellent adsorption capability with more than 99% removal of MB from a 40 mg L(-1) solution in just 15 min. It also decolorized an 80 mg L(-1) MB solution under UV irradiation in 210 min, which was comparable with the commercialized pure anatase TiO2. PMID- 23800368 TI - Fluid biomarkers in Alzheimer's disease - current concepts. AB - The diagnostic guidelines of Alzheimer's disease (AD) have recently been updated to include brain imaging and cerebrospinal fluid (CSF) biomarkers, with the aim of increasing the certainty of whether a patient has an ongoing AD neuropathologic process or not. The CSF biomarkers total tau (T-tau), hyperphosphorylated tau (P-tau) and the 42 amino acid isoform of amyloid beta (Abeta42) reflect the core pathologic features of AD, which are neuronal loss, intracellular neurofibrillary tangles and extracellular senile plaques. Since the pathologic processes of AD start decades before the first symptoms, these biomarkers may provide means of early disease detection. The updated guidelines identify three different stages of AD: preclinical AD, mild cognitive impairment (MCI) due to AD and AD with dementia. In this review, we aim to summarize the CSF biomarker data available for each of these stages. We also review results from blood biomarker studies. In summary, the core AD CSF biomarkers have high diagnostic accuracy both for AD with dementia and to predict incipient AD (MCI due to AD). Longitudinal studies on healthy elderly and recent cross-sectional studies on patients with dominantly inherited AD mutations have also found biomarker changes in cognitively normal at-risk individuals. This will be important if disease-modifying treatment becomes available, given that treatment will probably be most effective early in the disease. An important prerequisite for this is trustworthy analyses. Since measurements vary between studies and laboratories, standardization of analytical as well as pre-analytical procedures will be essential. This process is already initiated. Apart from filling diagnostic roles, biomarkers may also be utilized for prognosis, disease progression, development of new treatments, monitoring treatment effects and for increasing the knowledge about pathologic processes coupled to the disease. Hence, the search for new biomarkers continues. Several candidate biomarkers have been found in CSF, and although biomarkers in blood have been harder to find, some recent studies have presented encouraging results. But before drawing any major conclusions, these results need to be verified in independent studies. PMID- 23800371 TI - Nano-photocatalysts for the destruction of chloro-organic compounds and bacteria in water. AB - The article deals with a novel electrochemical method of preparing nano photocatalysts suspended in aqueous solution and their application for water treatment from chloro-organic compounds and bacteria. The nano-photocatalysts have been electrolytically synthesized in the cell with titanium and graphite electrodes. The synthesized nano-photocatalysts based on nanocarbon-titanium composition have the active functional groups including carbonyl (>C=O), hydroxyl (-OH), carboxyl (-COOH), and photocatalytic -Ti(OH)-O-Ti(OH)- formed on the surface of carbon nanoparticles. Here, we report that the synthesized nano photocatalysts can destroy chloro-organic compounds including dichloro-diphenyl trichloroethane (DDT), aldrin (C12H8Cl6), lindane (C6H6Cl6), and polychlorinated biphenyls (PCBs) and bacteria Escherichia coli in water under UV and sunlight. In addition, the method of nano-photocatalysts detection in water has been described. PMID- 23800372 TI - Colloid mobilization by fluid displacement fronts in channels. AB - Understanding colloid mobilization during transient flow in soil is important for addressing colloid and contaminant transport issues. While theoretical descriptions of colloid detachment exist for saturated systems, corresponding mechanisms of colloid mobilization during drainage and imbibition have not been considered in detail. In this work, theoretical force and torque analyses were performed to examine the interactive effects of adhesion, drag, friction, and surface tension forces on colloid mobilization and to outline conditions corresponding to the mobilization mechanisms such as lifting, sliding, and rolling. Colloid and substrate contact angles were used as variables to determine theoretical criteria for colloid mobilization mechanisms during drainage and imbibition. Experimental mobilization of hydrophilic and hydrophobic microspheres with drainage and imbibition fronts was investigated in hydrophilic and hydrophobic channels using a confocal microscope. Colloid mobilization differed between drainage and imbibition due to different dynamic contact angles and interfacial geometries on the contact line. Experimental results did not fully follow the theoretical criteria in all cases, which was explained with additional factors not included in the theory such as presence of aggregates and trailing films. Theoretical force and torque analyses resulted in similar mobilization predictions and suggested that all mobilization mechanisms contributed to the observed colloid mobilization. PMID- 23800373 TI - Biofunctionalized nanofibrous membranes as super separators of protein and enzyme from water. AB - Here, we report development of a novel biofunctionalized nanofibrous membrane which, despite its macroporous structure, is able to separate even trace amounts (as low as 2mg/L) of biomolecules such as protein and enzyme from water with an optimum efficiency of ~90%. Such an extraordinary protein selectivity at this level of pollutant concentration for a nanofibrous membrane has never been reported. In the current study, poly(acrylonitrile-co-glycidyl methacrylate) (PANGMA) electrospun nanofibers are functionalized by a bovine serum albumin (BSA) protein. This membrane is extraordinarily successful in removal of BSA protein and Candida antarctica Lipase B (Cal-B) enzyme from a water based solution. Despite a negligible non-specific adsorption of both BSA and Cal-B to the PANGMA nanofibrous membrane (8%), the separation efficiency of the biofunctionalized membrane for BSA and Cal-B reaches to 88% and 81%, respectively. The optimum separation efficiency at a trace amount of protein models is due to the water-induced conformational change of the biofunctional agent. The conformational change not only exposes more functional groups available to catch the biomolecules but also leads to swelling of the nanofibers thereby a higher steric hindrance for the solutes. Besides the optimum selectivity, the biofunctionalized membranes are highly wettable thereby highly water permeable. PMID- 23800374 TI - Concentrating materials covered by molecular imprinted nanofiltration layer with reconfigurability prepared by a surface sol-gel process for gas-selective detection. AB - Sensors that recognize molecules are acquired for the comprehensive detection of great many kinds of gases. Adsorbents with high molecular recognition and condensation ability were developed for selective gas sensing with a molecular imprinting technique. Developed adsorbents have multilayer structures consisted of a chemically modified polymer layer on the surface of a substrate covered by a TiO2 gel monolayer by the surface sol-gel process. Ellipsometry measurements showed that the 6-nm-thick layers deposited on the substrate. Cavities of molecular templates were imprinted on these layers, and thus, the film acts as a molecular gas filter without concentrating ability, which could form specific binding sites for various molecules that confirmed using solid-phase microextraction and gas chromatography-mass spectrometry. Gases were selectively absorbed into an accumulating adsorption layer and other gas molecules were blocked by the nanofiltration. These developed adsorbents enabled effective concentration ability and the filtration of gases or odors. In addition, these filters possess the flexibility to be easily configured with specific surface properties to interact with volatile molecules under appropriate conditions. A successful multiplex filter, imprinted simultaneously on an adsorbent with different sites, was demonstrated. PMID- 23800375 TI - Mechanism and kinetics of nanostructure evolution during early stages of resorcinol-formaldehyde polymerisation. AB - Resorcinol and formaldehyde react in aqueous solutions to form nanoporous organic gels well suited for a wide range of applications from supercapacitors and batteries to adsorbents and catalyst supports. In this work, we investigated the mechanism and kinetics of formation of primary clusters in the early stages of formation of resorcinol-formaldehyde gels in the presence of dissolved sodium carbonate. Dynamic Light Scattering measurements showed that size of freely diffusing primary clusters was independent of both reactant and carbonate concentrations at a given temperature, reaching the mean hydrodynamic radius of several nanometres before further changes were observed. However, more primary clusters formed at higher carbonate concentrations, and cluster numbers were steadily increasing over time. Our results indicate that the size of primary clusters appears to be thermodynamically controlled, where a solubility/miscibility limit is reached due to formation of certain reaction intermediates resulting in approximately monodisperse primary clusters, most likely liquid-like, similar to formation of micelles or spontaneous nanoemulsions. Primary clusters eventually form a particulate network through subsequent aggregation and/or coalescence and further polymerisation, leading to nanoscale morphologies of resulting wet gels. Analogous formation mechanisms have been previously proposed for several polymerisation and sol-gel systems, including monodisperse silica, organosilicates and zeolites. PMID- 23800376 TI - Diabetes care in Switzerland: good, but perfectible: a population-based cross sectional survey. AB - BACKGROUND: While Switzerland invests a lot of money in its healthcare system, little is known about the quality of care delivered. The objective of this study was to assess the quality of care provided to patients with diabetes in the Canton of Vaud, Switzerland. METHODS: Cross-sectional study of 406 non institutionalized adults with type 1 or 2 diabetes. Patients' characteristics, diabetes and process of care indicators were collected using a self-administered questionnaire. Process indicators (past 12 months) included HbA1C check among HbA1C-aware patients, eye assessment by ophtalmologist, microalbuminuria check, feet examination, lipid test, blood pressure and weight measurement, influenza immunization, physical activity recommendations, and dietary recommendations. Item-by-item (each process of care indicator: percentage of patients having received it), composite (mean percentage of recommended care: sum of received processes of care / sum of possible recommended care), and all-or-none (percentage of patients receiving all specified recommended care) measures were computed. RESULTS: Mean age was 64.4 years; 59% were men. Type 1 and type 2 diabetes were reported by 18.2% and 68.5% of patients, respectively, but diabetes type remained undetermined for almost 20% of patients. Patients were treated with oral anti-diabetic drugs (50%), insulin (23%) or both (27%). Of 219 HbA1C-aware patients, 98% reported >= one HbA1C check during the last year. Also, >=94% reported >= one blood pressure measurement, >= one weight measurement or lipid test, and 68%, 64% and 56% had feet examination, microalbuminuria check and eye assessment, respectively. Influenza immunization was reported by 62% of the patients.The percentage of patients receiving all processes of care ranged between 14.2%-16.9%, and 46.6%-50.7%, when considering ten and four indicators, respectively. Ambulatory care utilization showed little use of multidisciplinary care, and low levels of participation in diabetes-education classes. CONCLUSIONS: While routine processes-of-care were performed annually in most patients, diabetes-specific risk screenings, influenza immunization, physical activity and dietary recommendations were less often reported; this was also the case for multidisciplinary care and participation in education classes. There is room for diabetes care improvement in Switzerland. These results should help define priorities and further develop country-specific chronic disease management initiatives for diabetes. PMID- 23800378 TI - Dynamical electron backscatter diffraction patterns. Part I: pattern simulations. AB - A new approach for the simulation of dynamic electron backscatter diffraction (EBSD) patterns is introduced. The computational approach merges deterministic dynamic electron-scattering computations based on Bloch waves with a stochastic Monte Carlo (MC) simulation of the energy, depth, and directional distributions of the backscattered electrons (BSEs). An efficient numerical scheme is introduced, based on a modified Lambert projection, for the computation of the scintillator electron count as a function of the position and orientation of the EBSD detector; the approach allows for the rapid computation of an individual EBSD pattern by bi-linear interpolation of a master EBSD pattern. The master pattern stores the BSE yield as a function of the electron exit direction and exit energy and is used along with weight factors extracted from the MC simulation to obtain energy-weighted simulated EBSD patterns. Example simulations for nickel yield realistic patterns and energy-dependent trends in pattern blurring versus filter window energies are in agreement with experimental energy filtered EBSD observations reported in the literature. PMID- 23800377 TI - Hypersusceptibility mechanism of Tenofovir-resistant HIV to EFdA. AB - BACKGROUND: The K65R substitution in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is the major resistance mutation selected in patients treated with first-line antiretroviral tenofovir disoproxil fumarate (TDF). 4' ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), is the most potent nucleoside analog RT inhibitor (NRTI) that unlike all approved NRTIs retains a 3'-hydroxyl group and has remarkable potency against wild-type (WT) and drug-resistant HIVs. EFdA acts primarily as a chain terminator by blocking translocation following its incorporation into the nascent DNA chain. EFdA is in preclinical development and its effect on clinically relevant drug resistant HIV strains is critically important for the design of optimal regimens prior to initiation of clinical trials. RESULTS: Here we report that the K65R RT mutation causes hypersusceptibility to EFdA. Specifically, in single replication cycle experiments we found that EFdA blocks WT HIV ten times more efficiently than TDF. Under the same conditions K65R HIV was inhibited over 70 times more efficiently by EFdA than TDF. We determined the molecular mechanism of this hypersensitivity using enzymatic studies with WT and K65R RT. This substitution causes minor changes in the efficiency of EFdA incorporation with respect to the natural dATP substrate and also in the efficiency of RT translocation following incorporation of the inhibitor into the nascent DNA. However, a significant decrease in the excision efficiency of EFdA-MP from the 3' primer terminus appears to be the primary cause of increased susceptibility to the inhibitor. Notably, the effects of the mutation are DNA-sequence dependent. CONCLUSION: We have elucidated the mechanism of K65R HIV hypersusceptibility to EFdA. Our findings highlight the potential of EFdA to improve combination strategies against TDF-resistant HIV-1 strains. PMID- 23800379 TI - High serum sCD163/sTWEAK ratio is associated with lower risk of digital ulcers but more severe skin disease in patients with systemic sclerosis. AB - INTRODUCTION: Systemic sclerosis (SSc) is an autoimmune disease characterized by chronic inflammation, vascular injury and excessive fibrosis. CD163 is a scavenger receptor which affects inflammatory response and may contribute to connective tissue remodelling. It has recently been demonstrated that CD163 can bind and neutralize the TNF-like weak inducer of apoptosis (TWEAK), a multifunctional cytokine which regulates inflammation, angiogenesis and tissue remodelling. We aimed to investigate the relationships between serum levels of soluble CD163 (sCD163) and soluble TWEAK (sTWEAK) in relation to disease manifestations in SSc patients. METHODS: This study included 89 patients with SSc who had not received immunosuppressive drugs or steroids for at least 6 months and 48 age- and sex-matched healthy controls (HC) from four European centres. Serum concentrations of sTWEAK and sCD163 were measured using commercially available ELISA kits. RESULTS: The mean serum concentrations of sTWEAK were comparable between SSc patients (mean +/- SD: 270 +/- 171 pg/mL) and HC (294 +/- 147pg/mL, P >0.05). Concentration of sCD163 and sCD163/sTWEAK ratio were significantly greater in SSc patients (984 +/- 420 ng/mL and 4837 +/- 3103, respectively) as compared to HC (823 +/- 331 ng/mL and 3115 +/- 1346 respectively, P <0.05 for both). High sCD163 levels and a high sCD163/sTWEAK ratio (defined as > mean +2SD of HC) were both associated with a lower risk of digital ulcers in SSc patients (OR, 95%CI: 0.09; 0.01, 0.71, and 0.17; 0.06, 0.51, respectively). Accordingly, patients without digital ulcers had a significantly higher sCD163 concentration and sCD163/sTWEAK ratio as compared to SSc patients with digital ulcers (P <0.01 for both) and HC (P <0.05 for both). A high sCD163/sTWEAK ratio, but not high sCD163 levels, was associated with greater skin involvement. CONCLUSIONS: The results of our study indicate that CD163-TWEAK interactions might play a role in the pathogenesis of SSc and that CD163 may protect against the development of digital ulcers in SSc. Further studies are required to reveal whether targeting of the CD163-TWEAK pathway might be a potential strategy for treating vascular disease and/or skin fibrosis in SSc. PMID- 23800380 TI - A link between premenopausal iron deficiency and breast cancer malignancy. AB - BACKGROUND: Young breast cancer (BC) patients less than 45 years old are at higher risk of dying from the disease when compared to their older counterparts. However, specific risk factors leading to this poorer outcome have not been identified. METHODS: One candidate is iron deficiency, as this is common in young women and a clinical feature of young age. In the present study, we used immuno competent and immuno-deficient mouse xenograft models as well as hemoglobin as a marker of iron status in young BC patients to demonstrate whether host iron deficiency plays a pro-metastatic role. RESULTS: We showed that mice fed an iron deficient diet had significantly higher tumor volumes and lung metastasis compared to those fed normal iron diets. Iron deficiency mainly altered Notch but not TGF-beta and Wnt signaling in the primary tumor, leading to the activation of epithelial mesenchymal transition (EMT). This was revealed by increased expression of Snai1 and decreased expression of E-cadherin. Importantly, correcting iron deficiency by iron therapy reduced primary tumor volume, lung metastasis, and reversed EMT markers in mice. Furthermore, we found that mild iron deficiency was significantly associated with lymph node invasion in young BC patients (p<0.002). CONCLUSIONS: Together, our finding indicates that host iron deficiency could be a contributor of poor prognosis in young BC patients. PMID- 23800381 TI - Inhibitory effects of forced swim stress and corticosterone on the acquisition but not expression of morphine-induced conditioned place preference: involvement of glucocorticoid receptor in the basolateral amygdala. AB - Addiction is a common chronic psychiatric disease which represents a global problem and stress has an important role to increase drug addiction and relapse. In the present study, we investigated the effects of physical stress and exogenous corticosterone on the acquisition and expression of morphine-induced conditioned place preference (CPP). Also, we tried to find out the role of glucocorticoid receptors (GRs) of basolateral amygdala (BLA) in this regard. In the CPP paradigm, conditioning score and locomotion activity were recorded by Ethovision software. Male adult rats received forced swim stress (FSS) as a physical stress or corticosterone (10 mg/kg; ip) as a dominant stress hormone in rodents, 10min before morphine injection (5 mg/kg; sc) during three conditioning days (acquisition) or just prior to CPP test in the post-conditioning day (expression). In FSS procedure, animals were forced to swim for 6 min in cylinder filled with water (24-27 degrees C). To evaluate the role of glucocorticoid receptors in the BLA, different doses of mifepristone (RU38486) as a GR antagonist were injected into the BLA (0.3, 3 and 30 ng/side) during 3-day conditioning phase before FSS or injection of corticosterone in morphine-CPP paradigm. The results showed that FSS and corticosterone reduce the acquisition but not expression of morphine-induced CPP. Moreover, blockade of GRs in the BLA could diminish the inhibitory effects of FSS or corticosterone on the acquisition of morphine-induced CPP. It seems that stress exerts its effect on reward pathway via glucocorticoid receptors in the BLA. PMID- 23800382 TI - The effect of oxysterols on the interaction of Alzheimer's amyloid beta with model membranes. AB - The interaction of amyloid beta (Abeta) peptide with cell membranes has been shown to be influenced by Abeta conformation, membrane physicochemical properties and lipid composition. However, the effect of cholesterol and its oxidized derivatives, oxysterols, on Abeta-induced neurotoxicity to membranes is not fully understood. We employed here model membranes to investigate the localization of Abeta in membranes and the peptide-induced membrane dynamics in the presence of cholesterol and 7-ketocholesterol (7keto) or 25-hydroxycholesterol (25OH). Our results have indicated that oxysterols rendered membranes more sensitive to Abeta, in contrast to role of cholesterol in inhibiting Abeta/membrane interaction. We have demonstrated that two oxysterols had different impacts owing to distinct positions of the additional oxygen group in their structures. 7keto containing cell-sized liposomes exhibited a high propensity toward association with Abeta, while 25OH systems were more capable of morphological changes in response to the peptide. Furthermore, we have shown that 42-amino acid Abeta (Abeta-42) pre-fibril species had higher association with membranes, and caused membrane fluctuation faster than 40-residue isoform (Abeta-40). These findings suggest the enhancing effect of oxysterols on interaction of Abeta with membranes and contribute to clarify the harmful impact of cholesterol on Abeta-induced neurotoxicity by means of its oxidation. PMID- 23800383 TI - Progressive morphological changes and impaired retinal function associated with temporal regulation of gene expression after retinal ischemia/reperfusion injury in mice. AB - Retinal ischemia/reperfusion (I/R) injury is an important cause of visual impairment. However, questions remain on the overall I/R mechanisms responsible for progressive damage to the retina. In this study, we used a mouse model of I/R and characterized the pathogenesis by analyzing temporal changes of retinal morphology and function associated with changes in retinal gene expression. Transient ischemia was induced in one eye of C57BL/6 mice by raising intraocular pressure to 120 mmHg for 60 min followed by retinal reperfusion by restoring normal pressure. At various time points post I/R, retinal changes were monitored by histological assessment with H&E staining and by SD-OCT scanning. Retinal function was also measured by scotopic ERG. Temporal changes in retinal gene expression were analyzed using cDNA microarrays and real-time RT-PCR. In addition, retinal ganglion cells and gliosis were observed by immunohistochemistry. H&E staining and SD-OCT scanning showed an initial increase followed by a significant reduction of retinal thickness in I/R eyes accompanied with cell loss compared to contralateral control eyes. The greatest reduction in thickness was in the inner plexiform layer (IPL) and inner nuclear layer (INL). Retinal detachment was observed at days 3 and 7 post- I/R injury. Scotopic ERG a- and b-wave amplitudes and implicit times were significantly impaired in I/R eyes compared to contralateral control eyes. Microarray data showed temporal changes in gene expression involving various gene clusters such as molecular chaperones and inflammation. Furthermore, immunohistochemical staining confirmed Muller cell gliosis in the damaged retinas. The time-dependent changes in retinal morphology were significantly associated with functional impairment and altered retinal gene expression. We demonstrated that I/R-mediated morphological changes the retina closely associated with functional impairment as well as temporal changes in retinal gene expression. Our findings will provide further understanding of molecular pathogenesis associated with ischemic injury to the retina. PMID- 23800385 TI - [Long-term proton pump inhibitor therapy and osteoporosis. Is there a real danger?]. AB - Proton pump inhibitors are widely used in the treatment of acid-related diseases because they are considered to be effective and safe. In the past 10 years the use of proton pump inhibitors increased by over three folds, which is not associated with the increased prevalence of acid-related diseases obviously. However, like any other drugs, they have potential side effects. In recent years many studies have been published about the correlation between long-term proton pump inhibitor therapy and the increase of bone fractures. Most studies showed that long-term proton pump inhibitor therapy moderately increased fracture risk. The underlying mechanisms of increased number of bone fractures are not clarified yet. However, chronic acid suppression caused by long-term proton pump inhibitor therapy may play a crucial role in decreased absorption of calcium and vitamin B12 and, therefore, indirectly affecting the bones resulting in a decrease of bone mineral density. The available data suggest that proton pump inhibitors should be used with caution in patients with increased risk of osteoporosis. PMID- 23800384 TI - Disuse-induced muscle wasting. AB - Loss of skeletal muscle mass occurs frequently in clinical settings in response to joint immobilization and bed rest, and is induced by a combination of unloading and inactivity. Disuse-induced atrophy will likely affect every person in his or her lifetime, and can be debilitating especially in the elderly. Currently there are no good therapies to treat disuse-induced muscle atrophy, in part, due to a lack of understanding of the cellular and molecular mechanisms responsible for the induction and maintenance of muscle atrophy. Our current understanding of disuse atrophy comes from the investigation of a variety of models (joint immobilization, hindlimb unloading, bed rest, spinal cord injury) in both animals and humans. Under conditions of unloading, it is widely accepted that there is a decrease in protein synthesis, however, the role of protein degradation, especially in humans, is debated. This review will examine the current understanding of the molecular and cellular mechanisms regulating muscle loss under disuse conditions, discussing the similarities and areas of dispute between the animal and human literature. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. PMID- 23800386 TI - [Over- or underestimated? Bibliographic survey of the biomedical periodicals published in Hungary]. AB - INTRODUCTION: This publication - based on an article published in 2006 - emphasises the qualities of the current biomedical periodicals of Hungarian editions. AIM: The aim of this study was to analyse how Hungarian journals meet the requirements of the scientific aspect and international visibility. METHOD: Authors evaluated 93 Hungarian biomedical periodicals by 4 viewpoints of the two criteria mentioned above. RESULTS: 35% of the analysed journals complete the attributes of scientific aspect, 5% the international visibility, 6% fulfill all examined criteria, and 25% are indexed in international databases. CONCLUSIONS: 6 biomedical Hungarian periodicals covered by each of the three main bibliographic databases (Medline, Scopus, Web of Science) have the best qualities. Authors recommend to improve viewpoints of the scientific aspect and international visibility. The basis of qualitative adequacy are the accurate authors' guidelines, title, abstract, keywords of the articles in English, and the ability to publish on time. PMID- 23800387 TI - [Kidney function and liver transplantation]. AB - INTRODUCTION: In liver cirrhosis renal function decreases as well. Hepatorenal syndrome is the most frequent cause of the decrease, but primary kidney failure, diabetes mellitus and some diseases underlying endstage liver failure (such as hepatitis C virus infection) can also play an important role. In liver transplantation several further factors (total cross-clamping of vena cava inferior, polytransfusion, immunosuppression) impair the renal function, too. AIM: The aim of this study was to analyse the changes in kidney function during the first postoperative year after liver transplantation. METHOD: Retrospective data analysis was performed after primary liver transplantations (n = 319). RESULTS: impaired preoperative renal function increased the devepolment of postoperative complications and the first year cumulative patient survival was significantly worse (91,7% vs 69,9%; p<0,001) in this group. If renal function of the patients increased above 60 ml/min/1,73 m2 after the first year, patient survival was better. Independently of the preoperative kidney function, 76% of the patients had impaired kidney function at the first postoperative year. In this group, de novo diabetes mellitus was more frequently diagnosed (22,5% vs 9,5%; p = 0,023). CONCLUSIONS: Selection of personalized immunosuppressive medication has a positive effect on renal function. PMID- 23800388 TI - [Screening of trisomy 21 nowadays. Is maternal age so important?]. AB - INTRODUCTION: Trisomy 21 is the most common chromosomal abnormality, therefore, screening and diagnosis of this disorder is in the centre of attention worldwide. An efficient screening method is the combined test based on maternal age, ultrasound signs, biochemical markers, and a risk ratio can be calculated based on these data. AIM: The aim of the authors was to determine the causes of missed prenatal diagnosis of Down's syndrome at the 2nd Department of Obstetrics and Gynecology, Semmelweis University. METHOD: A retrospective study was carried out by collecting data from medical records of mothers who had delivered a newborn with Down's syndrome in the Department between 2008 and 2012. Each medical record was analyzed individually. RESULTS: In most cases the missed diagnosis of Down's syndrome occurred when the expectant mother failed to attend the first trimester screening or did not take the risk of invasive diagnostic procedures needed for fetal kariotyping. CONCLUSIONS: Analysis of fetal DNA circulating in maternal plasma can be a solution for those who refuse invasive fetal diagnostics. This test has high sensitivity and very low false positive rate. It has become available since the end of 2011 in the United States and, since the autumn of 2012, in Hungary, too. The test, however, is not reimbursed by national health insurance. PMID- 23800389 TI - [We've come far, but we've lost something on the way?]. PMID- 23800390 TI - Phase classification by mean shift clustering of multispectral materials images. AB - A mean-shift clustering (MSC) algorithm is introduced as a valuable alternative to perform materials phase classification from multispectral images. As opposed to other multivariate statistical techniques, such as factor analysis or principal component analysis (PCA), clustering techniques directly assign a class label to each pixel, so that their outputs are phase segmented images, i.e., there is no need for an additional segmentation algorithm. On the other hand, as compared to other clustering procedures and classification methods, such as segmentation by thresholding of multiple spectral components, MSC has the advantages of not requiring previous knowledge of the number of data clusters and not assuming any shape for these clusters, i.e., neither the number nor the composition of the phases must be previously known. This makes MSC a particularly useful tool for exploratory research, assisting phase identification of unknown samples. Visualization and interpretation of the results are also simplified, since the information content of the output image does not depend on the particular choice of the content of the color channels.We applied MSC to the analysis of two sets of X-ray maps acquired in scanning electron microscopes equipped with energy-dispersive detection systems. Our results indicate that MSC is capable of detecting additional phases, not clearly identified through PCA or multiple thresholding, with a very low empirical reject rate. PMID- 23800391 TI - Selective cytotoxic effects on human breast carcinoma of new methoxylated flavonoids from Euryops arabicus grown in Saudi Arabia. AB - The chloroform-methanol extract of Euryops arabicus, collected from Saudi provenance, yielded a new kaurane diterpene (1) and seven methoxylated flavones (2-8), two of which are new (2 and 3). Structures of the compounds were elucidated through interpretation of spectral data of NMR, MS and comparison with literature values. All compounds were evaluated for their anti-tumor activities, employing four different cancer cell lines (WI-38, VERO, HepG2 and MCF-7), ABTS free radical scavenging and immunemodulatory effects. All metabolites had considerable antioxidant and immunestimulatory effects. All compounds showed anticancer activity with IC50 in range 10-125 MUM, whilst 2 and 6 showed significant anti-proliferative activity against HepG2 (IC50 = 20 and 15 MUM) and MCF-7 (IC50 = 15 and 10 MUM), respectively. This effect was attributed to significant S-phase cell cycle arrest. PMID- 23800392 TI - Study of surgical indication for knee arthroplasty by cartilage analysis in three compartments using data from Osteoarthritis Initiative (OAI). AB - BACKGROUND: Bicompartmental or unicompartmental knee arthroplasty (BKA, UKA) is currently advocated as an alternative solution to conventional total knee arthroplasty (TKA) in order to preserve bone stock and ligaments for limited osteoarthritis (OA) with intact anterior and posterior cruciate ligaments (ACL, PCL). However, the actual rate of UKA or BKA compared to TKA procedures in OA patients has not been reported. In this study, we retrospectively analyzed preoperative MRI of the knee in subjects who underwent knee arthroplasty and assessed the potential for UKA or BKA as an alternative treatment. METHODS: Data were extracted from the Osteoarthritis Initiative (OAI) public use data set, which included 4,796 subjects, ages 45-79. 3.0 Tesla MRI scanners were dedicated to imaging the knees of OAI participants annually from February 2004 to March 2010. Extensive quantitative measurements of the knee MRI were performed on 87 patients who underwent knee arthroplasty during follow-up visits. We assessed the cartilage thickness and defect size in the medial femorotibial joint (FTJ), lateral FTJ, and patellofemoral joint (PFJ) as well as ligamentous injury, bone marrow edema, and subchondral cyst size from 2D coronal turbo spin echo (TSE), 2D sagittal TSE, 3D coronal T1-weighted water-excitation fast low angle shot (FLASH), and 3D sagittal water-excitation double echo steady-state (DESS) with axial and coronal reformat images. RESULTS: Eighty-five subjects (97.7%) were subjected to TKA, while only 2 subjects (2.3%) received UKA from the OAI database. Based on the preoperative MRI findings criteria, 51 of 87 subjects (58.6%) met the indication for TKA including the 2 UKA subjects above. This rate was significantly lower (p<0.001) than the actual TKA rate received. Among 85 subjects who actually underwent TKA, 31 subjects (36.5%) and 5 subjects (5.9%) met the indication for BKA and UKA, respectively. CONCLUSIONS: Many medial or lateral compartmental OA subjects, with or without patellar compartment defects have undergone TKA. The results of this study suggest the indication for partial arthroplasty, such as UKA or BKA, may increase when cartilage in each compartment, as well as ligaments and subchondral bone status are comprehensively evaluated. PMID- 23800393 TI - Predictive value of the amplitude integrated EEG in infants with hypoxic ischaemic encephalopathy: data from a randomised trial of therapeutic hypothermia. AB - The amplitude integrated EEG (aEEG) is reputed to be one of the best predictors of neurological outcome following hypoxic ischaemic encephalopathy in term newborns and was used to select infants into trials of neuroprotection with hypothermia, but its predictive value and the effect of moderate hypothermia on the aEEG have not previously been examined in a randomised study. The positive predictive value (PPV) of the aEEG recorded within 6 h of birth for death or disability at 18 months of age was determined in 314 infants born after 35 weeks gestation who were randomised to receive standard care with or without cooling for 72 h. The aEEG was classified according to voltage and by pattern. The PPV of a severely abnormal aEEG assessed by the voltage and pattern methods was 0.63 and 0.59 respectively in non-cooled infants and 0.55 and 0.51 in cooled infants (p>0.05). Although the differences in PPV between cooled and non-cooled groups were not significant, they are consistent with observational studies showing a lower PPV in infants treated with hypothermia, probably due to a neuroprotective effect of cooling. PMID- 23800394 TI - Do depressed and anxious men do groups? What works and what are the barriers to help seeking? AB - AIM: To map the availability and types of depression and anxiety groups, to examine men's experiences and perception of this support as well as the role of health professionals in accessing support. BACKGROUND: The best ways to support men with depression and anxiety in primary care are not well understood. Group based interventions are sometimes offered but it is unknown whether this type of support is acceptable to men. METHODS: Interviews with 17 men experiencing depression or anxiety. A further 12 interviews were conducted with staff who worked with depressed men (half of whom also experienced depression or anxiety themselves). There were detailed observations of four mental health groups and a mapping exercise of groups in a single English city (Bristol). FINDINGS: Some men attend groups for support with depression and anxiety. There was a strong theme of isolated men, some reluctant to discuss problems with their close family and friends but attending groups. Peer support, reduced stigma and opportunities for leadership were some of the identified benefits of groups. The different types of groups may relate to different potential member audiences. For example, unemployed men with greater mental health and support needs attended a professionally led group whereas men with milder mental health problems attended peer-led groups. Barriers to help seeking were commonly reported, many of which related to cultural norms about how men should behave. General practitioners played a key role in helping men to acknowledge their experiences of depression and anxiety, listening and providing information on the range of support options, including groups. Men with depression and anxiety do go to groups and appear to be well supported by them. Groups may potentially be low cost and offer additional advantages for some men. Health professionals could do more to identify and promote local groups. PMID- 23800395 TI - The expression and regulation of microRNA-125b in cancers. AB - Cancer is one of the leading causes of death worldwide. There is a definite need for novel approaches to improve the diagnostics and treatment of cancers. The pathological processes leading to carcinoma are associated with the altered expression of a specific gene relevant to malignancy. MicroRNA-125b (miR-125b) is a small non-coding, multipurpose miRNA that plays a key role in several different biological processes. Increasing amounts of evidence indicates that miR-125b may serve as a diagnostic biomarker of certain kinds of cancers. miR-125b may be suitable to be used as a therapeutical target in several human diseases including neoplastic disease. Here, we review the latest progress in the identification and validation of the relationship between cancer-related miR-125b and cancers, and discuss the functions of miR-125b that regulates many processes of diseases, including cell proliferation, differentiation, and apoptosis. PMID- 23800396 TI - Candida albicans CUG mistranslation is a mechanism to create cell surface variation. AB - In the human fungal pathogen Candida albicans, the CUG codon is translated 97% of the time as serine and 3% of the time as leucine, which potentially originates an array of proteins resulting from the translation of a single gene. Genes encoding cell surface proteins are enriched in CUG codons; thus, CUG mistranslation may influence the interactions of the organism with the host. To investigate this, we compared a C. albicans strain that misincorporates 28% of leucine at CUGs with a wild-type parental strain. The first strain displayed increased adherence to inert and host molecules. In addition, it was less susceptible to phagocytosis by murine macrophages, probably due to reduced exposure of cell surface beta glucans. To prove that these phenotypes occurred due to serine/leucine exchange, the C. albicans adhesin and invasin ALS3 was expressed in Saccharomyces cerevisiae in its two natural isoforms (Als3p-Leu and Als3p-Ser). The cells with heterologous expression of Als3p-Leu showed increased adherence to host substrates and flocculation. We propose that CUG mistranslation has been maintained during the evolution of C. albicans due to its potential to generate cell surface variability, which significantly alters fungus-host interactions. IMPORTANCE: The translation of genetic information into proteins is a highly accurate cellular process. In the human fungal pathogen Candida albicans, a unique mistranslation event involving the CUG codon occurs. The CUG codon is mainly translated as serine but can also be translated as leucine. Leucine and serine are two biochemically distinct amino acids, hydrophobic and hydrophilic, respectively. The increased rate of leucine incorporation at CUG decoding triggers C. albicans virulence attributes, such as morphogenesis, phenotypic switching, and adhesion. Here, we show that CUG mistranslation masks the fungal cell wall molecule beta-glucan that is normally recognized by the host immune system, delaying its response. Furthermore, we demonstrate that two different proteins of the adhesin Als3 generated by CUG mistranslation confer increased hydrophobicity and adhesion ability on yeast cells. Thus, CUG mistranslation functions as a mechanism to create protein diversity with differential activities, constituting an advantage for a mainly asexual microorganism. This could explain its preservation during evolution. PMID- 23800397 TI - High-throughput nano-biofilm microarray for antifungal drug discovery. AB - Micro- and nanoscale technologies have radically transformed biological research from genomics to tissue engineering, with the relative exception of microbial cell culture, which is still largely performed in microtiter plates and petri dishes. Here, we present nanoscale culture of the opportunistic fungal pathogen Candida albicans on a microarray platform. The microarray consists of 1,200 individual cultures of 30 nl of C. albicans biofilms ("nano-biofilms") encapsulated in an inert alginate matrix. We demonstrate that these nano-biofilms are similar to conventional macroscopic biofilms in their morphological, architectural, growth, and phenotypic characteristics. We also demonstrate that the nano-biofilm microarray is a robust and efficient tool for accelerating the drug discovery process: (i) combinatorial screening against a collection of 28 antifungal compounds in the presence of immunosuppressant FK506 (tacrolimus) identified six drugs that showed synergistic antifungal activity, and (ii) screening against the NCI challenge set small-molecule library identified three heretofore-unknown hits. This cell-based microarray platform allows for miniaturization of microbial cell culture and is fully compatible with other high throughput screening technologies. IMPORTANCE: Microorganisms are typically still grown in petri dishes, test tubes, and Erlenmeyer flasks in spite of the latest advances in miniaturization that have benefitted other allied research fields, including genomics and proteomics. Culturing microorganisms in small scale can be particularly valuable in cutting down time, cost, and reagent usage. This paper describes the development, characterization, and application of nanoscale culture of an opportunistic fungal pathogen, Candida albicans. Despite a more than 2,000 fold reduction in volume, the growth characteristics and drug response profiles obtained from the nanoscale cultures were comparable to the industry standards. The platform also enabled rapid identification of new drug candidates that were effective against C. albicans biofilms, which are a major cause of mortality in hospital-acquired infections. PMID- 23800398 TI - Is the nickel-dependent urease complex of Cryptococcus the pathogen's Achilles' heel? AB - The nitrogen-scavenging enzyme urease has been coopted in a variety of pathogenic organisms as a virulence factor, most notoriously to neutralize stomach acid and establish infection by the gastric pathogen Helicobacter pylori. The opportunistic fungal pathogen Cryptococcus neoformans also utilizes urease as a virulence factor, only in this case to invade the central nervous system (CNS) via the blood-brain barrier and cause life-threatening meningoencephalitis. A recent study [A. Singh, R. Panting, A. Varma, T. Saijo, K. Waldron, A. Jong, P. Ngamskulrungroj, Y. Chan, J. Rutherford, K. Kwon-Chung, mBio 4(3):e00220-13] genetically and biochemically characterizes the accessory proteins required for successful activation of the urease protein complex, including the essential nickel cofactor. The accessory proteins Ure4, Ure6, and Ure7 are all essential for urease function. Ure7 appears to combine the roles of two bacterial accessory proteins: it incorporates both the GTPase activity and nickel chaperone properties of UreE, a bacterial protein whose homolog is missing in the fungi. An accompanying nickel transporter, Nic1, is responsible for most, but not all, nickel uptake into the fungal cell. Mutants of the core urease protein Ure1, accessory protein Ure7, and transporter Nic1 are all attenuated for invasion of the CNS of mice, and urease activity may directly affect integrity of the tight junction of the endothelial cells of the blood-brain barrier, the network of proteins that limits paracellular permeability. This work highlights the potential of urease, its accessory proteins, and nickel transport as potential chemotherapeutic targets. PMID- 23800400 TI - High- and low-purity glycerine supplementation to dairy cows in early lactation: effects on silage intake, milk production and metabolism. AB - This study evaluated the effects of supplemental low- and high-purity glycerine on silage intake, milk yield and composition, plasma metabolites and body condition score (BCS) in dairy cows. A total of 42 cows of the Swedish Red Breed, housed in individual tie stalls, were fed 0.25 kg of low- or high-purity glycerine on top of concentrate, twice daily, during the first 4 weeks of lactation. One-third of the cows acted as controls, receiving no glycerine. Silage was fed for ad libitum intake and concentrate was fed at restricted level of intake, about 6 kg/day for primiparous cows and 7 kg/day for multiparous cows. Feed refusals were weighed daily. Cows were milked twice daily, milk yield was recorded on four occasions per week and milk samples were collected simultaneously. Blood samples were drawn from the coccygeal vessel once a week. Low- and high-purity glycerine had no effect on silage or total dry matter intake (P = 0.38 and P = 0.75, respectively) or on BCS (P = 0.45). Cows fed high-purity glycerine tended to have higher milk yield than control cows (P = 0.06). Milk composition tended to differ among treatments. No main effects of treatment on concentration of glycerine (P = 0.44), glucose (P = 0.78), insulin (P = 0.33), non-esterified fatty acids (P = 0.33) and beta-hydroxybutyrate (P = 0.15) in plasma. These data indicate that high-purity glycerine has the potential to increase milk yield, as well as enhance the milk protein concentration and milk fat + protein yield. PMID- 23800399 TI - Reproductive function of the male obese Zucker rats: alteration in sperm production and sperm DNA damage. AB - Obesity has been considered a public health issue in many countries and is of increasing concern for authorities over the past 6 years. The Zucker rat is a good experimental model for obesity and diabetes studies due to its metabolic characteristics that are similar to those developed by humans. A total of 12 obese Zucker rats and their lean littermates were killed in pubertal and young adult phases for assessing organ weights (testis and epididymis), testicular histomorphometric and stereological analyses, daily sperm production, and transit time in the epididymis. Sperm integrity was also investigated in the adult animals using the Comet assay. Alterations in organ weights, seminiferous epithelium architecture, sperm production, and transit time were noticed in the pubertal fatty rats. The volume density of the lymphatic space was decreased in both the ages. Adult animals had a significant increase in the extent of damage found in sperm DNA. Our results show for the first time that leptin receptor deficiency compromises sperm production during puberty and that genetic obese Zucker rats have increased sperm DNA fragmentation. PMID- 23800401 TI - Quality of life and somatic symptoms in children with constipation: a school based study. AB - OBJECTIVE: To assess the health related quality of life (HRQoL) and somatization in school children with constipation. STUDY DESIGN: This cross-sectional survey was conducted in children aged 13-18 years, in 4 schools in Gampaha district of Sri Lanka. Data were collected using a pretested, self-administered questionnaire with questions on bowel habits, somatization, and HRQoL. Constipation was diagnosed using Rome III criteria. RESULTS: A total of 1792 children were included in the analysis (males 975 [54.4%], mean age 14.4 and SD 1.3 years). One hundred thirty-eight (7.7%) fulfilled Rome criteria for constipation. Children with constipation had lower HRQoL scores for physical (83.6 vs 91.4 in controls, P < .0001), social (85.0 vs 92.7, P = .0001), emotional (73.6 vs 82.7, P =.0001), school functioning (75.0 vs 82.5, P < .0001), and lower overall scores (79.6 vs 88.0, P = .0001). HRQoL scores were lower in those with fecal incontinence and constipation compared with constipation alone (70.0 vs 81.1, P = .004). Patient perceived severity of abdominal pain (r = -0.22, P = .01) and severity of bowel symptoms (r = -0.22, P = .01) showed significant negative correlation with total HRQoL scores. Total somatization score also found to be negatively correlated (r = -0.47, P < .0001) with HRQoL. CONCLUSIONS: Children with constipation have lower HRQoL scores than controls in physical, social, emotional, and school functioning. They also have a wide range of somatic symptoms. These issues need to be addressed during clinical evaluation of children with constipation to understand the impact of the disease on the life of affected children and to provide optimal care. PMID- 23800402 TI - Thoracoscopic imaging of Swyer-James-MacLeod syndrome in an adolescent patient. PMID- 23800403 TI - Efficacy and safety of once-daily esomeprazole for the treatment of gastroesophageal reflux disease in neonatal patients. AB - OBJECTIVE: To evaluate the efficacy and safety of proton pump inhibitors in infants aged <1 year with gastroesophageal reflux disease (GERD). STUDY DESIGN: In this randomized, double-blind, placebo-controlled multicenter study, neonates (premature to 1 month corrected age; n = 52) with signs and symptoms of GERD received esomeprazole 0.5 mg/kg or placebo once daily for up to 14 days. Change from baseline in the total number of GERD symptoms (from video monitoring) and GERD-related signs (from cardiorespiratory monitoring) was assessed with simultaneous esophageal pH, impedance, cardiorespiratory, and 8-hour video monitoring. RESULTS: There were no significant differences between the esomeprazole and placebo groups in the percentage change from baseline in the total number of GERD-related signs and symptoms (-14.7% vs -14.1%, respectively). Mean change from baseline in total number of reflux episodes was not significantly different between esomeprazole and placebo (-7.43 vs -0.2, respectively); however, the percentage of time pH was <4.0 and the number of acidic reflux episodes >5 minutes in duration was significantly decreased with esomeprazole vs placebo (-10.7 vs 2.2 and -5.5 vs 1.0, respectively; P <= .0017). The number of patients with adverse events was similar between treatment groups. CONCLUSIONS: Signs and symptoms of GERD traditionally attributed to acidic reflux in neonates were not significantly altered by esomeprazole treatment. Esomeprazole was well tolerated and reduced esophageal acid exposure and the number of acidic reflux events in neonates. PMID- 23800404 TI - Quality of life of young adults and adolescents with chronic kidney disease. AB - OBJECTIVE: To elicit utility-based quality of life (QOL) in adolescents and young adults with chronic kidney disease (CKD). STUDY DESIGN: A cross-sectional study was conducted among patients aged 12-25 years with CKD stage 3-5 and 5D from 6 centers in Australia. QOL was measured using a visual analogue scale, and 3 utility-based QOL measures: Health Utilities Index Mark 2 and 3 (HUI2/3), Kidney Disease Quality of Life, incorporating the short form (SF)-12 transformed to SF 6D, and time trade-off (TTO). Multiple linear regression was used to define predictors for TTO QOL weights, SF-6D, and visual analogue scale scores. RESULTS: On a utility scale, with extremes of 0 (death) to 1 (full health), the 27 participants had a mean TTO QOL weight of 0.59 (SD = 0.40), HUI2 of 0.73 (SD = 0.28), HUI3 of 0.74 (SD = 0.26), and SF-6D of 0.70 (SD = 0.14). QOL weights were consistently low across the 4 utility-based instruments with widest variability in TTO responses. Mean QOL weights were higher among predialysis participants. The HUI2 indicated variability in the domain of emotion. From the Kidney Disease Quality of Life measures, decrements were observed in all QOL domains though dialysis patients reported a significantly higher burden attributed to kidney disease. CONCLUSIONS: Adolescent and young adults with CKD report low QOL values. Their utility-based QOL scores imply they are willing to trade considerable life expectancy for perfect health. Holistic care to improve QOL and minimize disease burden are imperative for optimizing health outcomes in young people with CKD, particularly those on dialysis. PMID- 23800405 TI - Amino acid substitutions in sigma1 and MU1 outer capsid proteins are selected during mammalian reovirus adaptation to Vero cells. AB - Establishment of viral persistence in cell culture has previously led to the selection of mammalian reovirus mutants, although very few of those have been characterized in details. In the present study, reovirus was adapted to Vero cells that, in contrast to classically-used L929 cells, are inefficient in supporting the early steps of reovirus uncoating and are also unable to produce interferon as an antiviral response once infection occurs. The Vero cell-adapted reovirus exhibits amino acids substitutions in both the sigma1 and MU1 proteins. This contrasts with uncoating mutants from persistently infected L929 cells, and various other cell types, that generally harbor amino acids substitutions in the sigma3 outer capsid protein. The Vero cell-adapted virus remained sensitive to an inhibitor of lysosomal proteases; furthermore, in the absence of selective pressure for its maintenance, the virus has partially lost its ability to resist interferon. The positions of the amino acids substitutions on the known protein structures suggest an effect on binding of the viral sigma1 protein to the cell surface and on MU1 disassembly from the outer capsid. PMID- 23800406 TI - The Cre/loxP recombination system for production of infectious mouse polyomavirus. AB - Murine polyomavirus mutants are frequently produced for experimental as well as therapy purposes. Commonly used methods for preparation of mutant viral genomes from recombinant vectors are laborious and give variable yields and quality. We describe an efficient and reproducible Cre/loxP-mediated recombination system that generates polyomavirus genomes from recombinant plasmid in vivo. We designed and constructed two variants of recombinant vectors containing the wild-type polyomavirus genome flanked by loxP homologous sites. The loxP sites were introduced either into the intronic region of early genes or between the two poly(A) signal sites of convergent transcriptional units. After cotransfection of the recombinant plasmids with the Cre-expressing vector into mouse 3T6 cells, we obtained infectious virus from the genome variant containing loxP site in the intronic region, but we failed to isolate any infectious virus from the viral genome containing loxP site between poly(A) signals. We show that the Cre/loxP based method of polyomavirus production is simple, expedient, and reproducible and works with satisfactory efficiency. PMID- 23800407 TI - Participation after multidisciplinary rehabilitation for moderate to severe traumatic brain injury in adults. AB - The article by Brasure et al represents a systematic review of the literature on effectiveness of multidisciplinary rehabilitation for traumatic brain injury using rigorous methodology and focusing on participation as an outcome. The review assumes that rehabilitation "seeks to restore an individual's functioning and participation to preinjury levels" and that participation is a preferentially valued outcome. Each of these assumptions can be challenged on clinical and/or methodologic grounds. For example, holistic neuropsychologic rehabilitation seeks to promote changes in a patient's social identity as much as their social participation. Participation may not be directly related to changes in patients' activity limitations or well-being, and will not be the appropriate outcome for all studies of treatment effectiveness. The emphasis on methodologic rigor needs to be balanced by the search for relevance and reliance on the best available evidence to guide clinical practice. PMID- 23800408 TI - Adjusting for multiple-misclassified variables in a study using birth certificates. AB - PURPOSE: Birth certificates are a convenient source of population data for epidemiologic studies. It is well documented, however, that birth certificate data can be highly inaccurate. Nonetheless, studies based on birth certificates are routinely analyzed without accounting for sources of data errors. We focused on the association between maternal cigarette smoking and cleft lip and palate based on birth certificate data. METHODS: We adjusted odds ratio estimates simultaneously for exposure and outcome misclassification. We also calculated odds ratios adjusted for exposure misclassification only and outcome misclassification only. RESULTS: Adjustment for both maternal smoking during pregnancy and clefting resulted in adjusted odds ratios that ranged from less than 1.0 to much greater than the unadjusted estimate of 1.16, with most adjusted estimates outside of the 95% confidence limits (1.01, 1.33). CONCLUSIONS: Because of the potentially large impact of birth certificate classification errors, we suggest that inferences from these or similar records employ quantitative methods for incorporating uncertainties caused by data errors. PMID- 23800409 TI - Neurotransmitter transporters in schistosomes: structure, function and prospects for drug discovery. AB - Neurotransmitter transporters (NTTs) play a fundamental role in the control of neurotransmitter signaling and homeostasis. Sodium symporters of the plasma membrane mediate the cellular uptake of neurotransmitter from the synaptic cleft, whereas proton-driven vesicular transporters sequester the neurotransmitter into synaptic vesicles for subsequent release. Together these transporters control how much transmitter is released and how long it remains in the synaptic cleft, thereby regulating the intensity and duration of signaling. NTTs have been the subject of much research in mammals and there is growing interest in their activities among invertebrates as well. In this review we will focus our attention on NTTs of the parasitic flatworm Schistosoma mansoni. Bloodflukes of the genus Schistosoma are the causative agents of human schistosomiasis, a devastating disease that afflicts over 200 million people worldwide. Schistosomes have a well-developed nervous system and a rich diversity of neurotransmitters, including many of the small-molecule ("classical") neurotransmitters that normally employ NTTs in their mechanism of signaling. Recent advances in schistosome genomics have unveiled numerous NTTs in this parasite, some of which have now been cloned and characterized in vitro. Moreover new genetic and pharmacological evidence suggests that NTTs are required for proper control of neuromuscular signaling and movement of the worm. Among these carriers are proteins that have been successfully targeted for drug discovery in other organisms, in particular sodium symporters for biogenic amine neurotransmitters such as serotonin and dopamine. Our goal in this chapter is to review the current status of research on schistosome NTTs, with emphasis on biogenic amine sodium symporters, and to evaluate their potential for anti-schistosomal drug targeting. Through this discussion we hope to draw attention to this important superfamily of parasite proteins and to identify new directions for future research. PMID- 23800410 TI - Evaluation of cerebral circulation and oxygen metabolism in infants using near infrared light. AB - Bedside monitoring of cerebral circulation or oxygen metabolism in infants to appropriately manage circulation and establish the oxygen dose, aiming at improving the neurological prognosis, is needed in general clinical practice. Near-infrared spectroscopy is used for measurements of neonatal cerebral Hb oxygen saturation, cerebral blood volume, cerebral blood flow and cerebral metabolic rate of oxygen. Near-infrared time-resolved spectroscopy is particularly useful for bedside evaluation of cerebral circulation and oxygen metabolism because of its simple measurement procedure. Combined evaluation of cerebral blood volume and cerebral Hb oxygen saturation is expected to contribute to treatment centering on the brain in neonatal medical care. PMID- 23800411 TI - The major function of a metallothionein from the aquatic fungus Heliscus lugdunensis is cadmium detoxification. AB - A spring from a former copper shale mine in the area of Mansfelder Land, Germany, shows extremely high transition metal ion concentrations, i.e. 40mM Zn(II), 208MUM Cu(II), 61MUM As(V), and 25MUM Cd(II). This makes it a challenging habitat for living organisms as they have to cope with metal ion concentrations that by far exceed the values usually observed in spring water. One of the surviving species found is the aquatic fungus Heliscus lugdunensis (teleomorph: Nectria lugdunensis). Investigation of its redox related heavy metal tolerance revealed the presence of small thiol containing compounds as well as a small metallothionein, Neclu_MT1 (MT1_NECLU: P84865). While Cd(II)-induction of metallothioneins is observed in many species, the fact that exclusively Cd(II), but not Zn(II), Cu(I), As(III) or oxidative stress can induce Neclu_MT1 protein synthesis is unparalleled. To complement the physiological studies performed in the fungus H. lugdunensis, the Cd(II) and Zn(II) binding characteristics of the recombinantly expressed protein were spectroscopically analysed in vitro aiming to demonstrate the observed Cd(II) specificity also on the protein level. Stoichiometric analyses of the recombinant protein in combination with photospectrometric metal ion titrations and (113)Cd-NMR experiments reveal that metal ion binding capacities and consequently the structures formed at physiological Neclu_MT1 concentrations differ from each other. Concluding, we describe the first solely Cd(II)-inducible metallothionein, Neclu_MT1, from H. lugdunensis, featuring a difference in the structure of the Cd(II)versus the Zn(II) metalated protein in a physiologically relevant concentration range. PMID- 23800412 TI - Effects of the gout-causing Q141K polymorphism and a CFTR DeltaF508 mimicking mutation on the processing and stability of the ABCG2 protein. AB - ABCG2 is an important multidrug transporter involved also in urate transport, thus its mutations can lead to the development of gout and may also alter general drug absorption, distribution and excretion. The frequent ABCG2 polymorphism, Q141K, is associated with an elevated risk of gout and has been controversially reported to reduce the plasma membrane expression and/or the transport function of the protein. In the present work we examined the stability and cellular processing of the Q141K ABCG2 variant, as well as that of the DeltaF142 ABCG2, corresponding to the DeltaF508 mutation in the CFTR (ABCC7) protein, causing cystic fibrosis. The processing and localization of full length ABCG2 variants were investigated in mammalian cells, followed by Western blotting and confocal microscopy, respectively. Folding and stability were examined by limited proteolysis of Sf9 insect cell membranes expressing these ABCG2 constructs. Stability of isolated nucleotide binding domains, expressed in and purified from bacteria, was studied by CD spectroscopy. We find that the Q141K variant has a mild processing defect which can be rescued by low temperature, a slightly reduced activity, and a mild folding defect, especially affecting the NBD. In contrast, the DeltaF142 mutant has major processing and folding defects, and no ATPase function. We suggest that although these mutations are both localized within the NBD, based on molecular modeling their contribution to the ABCG2 structure and function is different, thus rescue strategies may be devised accordingly. PMID- 23800413 TI - Transglutaminase 6 interacts with polyQ proteins and promotes the formation of polyQ aggregates. AB - A common feature of polyglutamine (polyQ) diseases is the presence of aggregates in neuronal cells caused by expanded polyglutamine tracts. PolyQ proteins are the substrates of transglutaminase 2, and the increased activity of transglutaminase in polyQ diseases suggests that transglutaminase may be directly involved in the formation of the aggregates. We previously identified the transglutaminase 6 gene to be causative of spinocerebellar ataxia type 35 (SCA35), and we found that SCA35-associated mutants exhibited reduced transglutaminase activity. Here we report that transglutaminase 6 interacts and co-localizes with both normal and expanded polyQ proteins in HEK293 cells. Moreover, the overexpression of transglutaminase 6 promotes the formation of polyQ aggregates and the conversion of soluble polyQ into insoluble polyQ aggregates. However, SCA35-associated mutants do not affect their interactions with polyQ proteins. These data suggest that transglutaminase 6 could be involved in polyQ diseases and there may exist a common pathological link between polyQ associated SCA and SCA35. PMID- 23800414 TI - Germline traits of human hepatoblastoma cells associated with growth and metastasis. AB - Genes that are specific to germline and embryonic development can be activated in many tumors. Here, we show that germline traits that are present in human hepatoblastoma cells might be associated with the malignant behaviors of these tumor cells. In culture, single human hepatoblastoma cells differentiated into germ cell-like cells, which further developed into oocyte-like cells and formed parthenogenetic blastocyst-like structures. The germ cell-like cells and their embryonic derivatives from hepatoblastoma cells may favorably give rise to xenograft tumors with embryonal/germline traits and intrahepatic metastasis. These findings suggest that germline potential can be spontaneously activated in human hepatoblastoma cells and it might be important for tumor formation and metastasis. PMID- 23800416 TI - Prenatal methylmercury exposure through maternal rice ingestion: insights from a feasibility pilot in Guizhou Province, China. AB - Maternal hair and blood were investigated as biomarkers for prenatal methylmercury (MeHg) exposure among seventeen mothers recruited at parturition in Wanshan, Guizhou Province, China, where rice ingestion was the primary MeHg exposure pathway and atmospheric mercury (Hg) levels were elevated. For all three trimesters (n = 51), hair total Hg (THg) and MeHg concentrations ranged from 0.27 to 4.9 MUg/g (median: 0.96 MUg/g) and 0.077 to 2.3 MUg/g (median: 0.43 MUg/g), respectively, while blood THg levels ranged from 1.7 to 11 MUg/L (median: 3.0 MUg/L, n = 17). Despite adequate hair washing procedures, median %MeHg (of THg) was 37% (range: 14-89%, n = 51), indicating exogenous inorganic Hg(II) contamination or incorporation of elemental Hg (Hg(o)) into the hair shaft were important. Rice MeHg levels (n = 17) were highly correlated with blood THg (r(2) = 0.66) compared to hair MeHg (r(2) = 0.31) (when variables were log10 transformed), suggesting blood THg was a more preferable biomarker for prenatal MeHg exposure within this population. PMID- 23800415 TI - Promoter identification and transcriptional regulation of the metastasis gene MACC1 in colorectal cancer. AB - MACC1, Metastasis associated in colon cancer 1, is a newly identified prognostic biomarker for colorectal cancer metastasis and patient survival, when determined in the primary tumor or patient blood. MACC1 induces cell motility and proliferation in cell culture and metastasis in mouse models. MACC1 acts as a transcriptional regulator of the receptor tyrosine kinase gene Met via binding to its promoter. However, no information about the promoter of the MACC1 gene and its transcriptional regulation has been reported so far. Here we report the identification of the MACC1 promoter using a promoter luciferase construct that directs transcription of MACC1. To gain insights into the essential domains within this promoter region, we constructed 5' truncated deletion constructs. Our results show that the region from -426 to -18 constitutes the core promoter and harbors functional motifs for the binding of AP-1, Sp1, and C/EBP transcription factors as validated by site directed mutagenesis study. Using electrophoretic mobility shift assay and chromatin immunoprecipitation assay, we demonstrated the physical interaction of these transcription factors to a minimal essential MACC1 core promoter sequence. Knock down of these transcription factors using RNAi strategy reduced MACC1 expression (P < 0.001), and resulted in decrease of cell migration (P < 0.01) which could be specifically rescued by ectopic overexpression of MACC1. In human colorectal tumors, expression levels of c-Jun and Sp1 correlated significantly to MACC1 (P = 0.0007 and P = 0.02, respectively). Importantly, levels of c-Jun and Sp1 also showed significant correlation to development of metachronous metastases (P = 0.01 and P = 0.001, respectively). This is the first study identifying the MACC1 promoter and its transcriptional regulation by AP-1 and Sp1. Knowledge of the transcriptional regulation of the MACC1 gene will implicate in enhanced understanding of its role in cancer progression and metastasis. PMID- 23800417 TI - Effects of forage intake level on nitrogen net flux by portal-drained viscera of mature sheep with abomasal infusion of an amino acid mixture. AB - This study aimed to investigate the pattern of nitrogen (N) metabolites flux across the portal-drained viscera (PDV) of mature sheep over a wide range of forage intake, and to determine the effect of dry matter intake (DMI) on the PDV recovery of an abomasally infused amino acids (AA) mixture. Four Suffolk mature sheep (61.4 +/- 3.6 kg BW) surgically fitted with abomasal cannulae and multi catheters were fed four levels of DMI of lucerne hay cubes ranging from 0.4 to 1.6 fold the metabolizable energy requirements for maintenance. Each period lasted for 17 days: 7 days for diet adaptation, 5 days for measurement of N balance and N metabolites flux under basal pre-infusion conditions (basal phase) and 5 days for determining the recovery of the infused AA (584 mmol/day) across the PDV (infusion phase). Six sets of blood samples were collected on the last day of both basal and infusion phases. Increasing DMI increased portal release of AA and enhanced N retention. At 0.4 M and as a proportion of digested N, there was a marked drop in total AA-N release accompanied by greater ammonia-N release and urea-N uptake across the PDV. The incremental recovery ratio of infused AA across the PDV was altered with increasing DMI accounting for 0.88, 1.12, 1.23 and 1.31 at 0.4, 0.8, 1.2 and 1.6 M, respectively. In addition, across the individual AA, the net portal recovery ratio of infused methionine and valine increased linearly (P < 0.05) while that of phenylalanine, branched-chain AA and total essential AA tended to increase linearly (P < 0.10) with increasing DMI. These results indicated that DMI affects the net portal recovery of AA available in the small intestine of mature sheep. PMID- 23800418 TI - Clinical features and drug induced side effects in early versus late antidepressant responders. AB - Early antidepressant response (2nd week) has been reported as the result of a true antidepressant effect and a predictor of subsequent stable response. With the purpose to study the clinical profile of early response/remission (2nd week) compared to late response/remission (4th-6th weeks), two independent major depressive disorder (MDD) samples (the Sequenced Treatment Alternatives to Relieve Depression or STAR*D n=1922 and an Italian sample n=171) were investigated. Patients were treated with citalopram in the STAR*D while in a naturalistic setting in the Italian sample. Depressive symptomatology was assessed by the Hamilton Depressive Rating Scale weekly in the Italian sample and biweekly by the Quick Inventory of Depressive Symptomatology Clinician Rated in the STAR*D. Logistic regression was used to investigate possible predictors of early response and the Bonferroni correction was applied. In the STAR*D, higher levels of baseline core depressive symptoms (Bech subscale) were associated with early response (p=0.00017), as well as lower baseline insomnia (p=0.003) and higher work and social functioning (p=0.001). In the Italian sample none of these variables were associated with the phenotype, but a non significant trend of lower baseline quality of life (p=0.078) was observed in late remitters. In the STAR*D late responders reported higher levels of antidepressant induced side effects, especially difficulty in sleeping (p=5.68e-13), with a non significant trend in the same direction in the Italian sample (p=0.09). The identification of late versus early antidepressant responders at the beginning of the treatment may be useful to guide therapeutic choices in clinical settings. PMID- 23800419 TI - A double-blind randomized study comparing plasma level-targeted dose imipramine and high-dose venlafaxine in depressed inpatients. AB - OBJECTIVE: To compare the efficacy of plasma level-targeted dose imipramine and high-dose venlafaxine in depressed inpatients in a randomized double-blind study. METHODS: The study included 85 patients with a diagnosis of major depressive episode according to the DSM IV criteria and a 17-item Hamilton Rating Scale for Depression (HAM-D) score >= 17. Patients were randomized to imipramine or venlafaxine. The dose of imipramine was adjusted for each patient to a predefined blood level of 200-300 ng/ml. The dose of venlafaxine was increased gradually to 300-375 mg/day. Efficacy was evaluated after 7 weeks of treatment. RESULTS: The mean age of the study group was 54.5 (range 29-82) years. There was no significant difference according to the primary outcome criterion of a >=50% reduction on the HAM-D score: 17 of 43 (39.5%) patients on imipramine were responders compared to 21 of 42 (50%) patients on venlafaxine. When considering remission as outcome criterion (HAM-D score <= 7), 10 of 43 (23.3%) patients on imipramine were remitters compared to 15 of 42 (35.7%) patients on venlafaxine; again, no significant difference. When analysing a subpopulation of patients without psychotic features, with remission as outcome criterion, a significant difference was found: 5 of 34 (14.7%) patients on imipramine were remitters compared to 12 of 31 (38.7%) patients on venlafaxine. CONCLUSIONS: The present study used optimal doses in depressed inpatients and showed that venlafaxine is at least equal in efficacy to imipramine. The results in the subgroup without psychotic features indicate a possible superiority of venlafaxine. PMID- 23800420 TI - PK modulation of haptenylated peptides via non-covalent antibody complexation. AB - We applied noncovalent complexes of digoxigenin (Dig) binding antibodies with digoxigeninylated peptide derivatives to modulate their pharmacokinetic properties. A peptide derivative which activates the Y2R receptor was selectively mono-digoxigeninylated by reacting a NHS-Dig derivative with an epsilon-amino group of lysine 2. This position tolerates modifications without destroying receptor binding and functionality of the peptide. Dig-peptide derivatives can be loaded onto Dig-binding IgGs in a simple and robust reaction, thereby generating peptide-IgG complexes in a defined two to one molar ratio. This indicates that each antibody arm becomes occupied by one haptenylated peptide. In vitro receptor binding and signaling assays showed that Dig-peptides as well as the peptide antibody complexes retain better potency than the corresponding pegylated peptides. In vivo analyses revealed prolonged serum half-life of antibody complexed peptides compared to unmodified peptides. Thus, complexes are of sufficient stability for PK modulation. We observed more prolonged weight reduction in a murine diet-induced obesity (DIO) model with antibody-complexed peptides compared to unmodified peptides. We conclude that antibody-hapten complexation can be applied to modulate the PK of haptenylated peptides and in consequence improve the therapeutic efficacy of therapeutic peptides. PMID- 23800421 TI - Prevalence of hepatitis C and B virus among patients infected with HIV: a cross sectional analysis of a large HIV care programme in Myanmar. AB - Co-infection with the hepatitis C virus (HCV) and/or hepatitis B virus (HBV) influences the morbidity and mortality of patients with HIV. A cross sectional analysis was of 11,032 HIV-infected patients enrolled in the Integrated HIV Care Program from May 2005 to April 2012 and Epi-info 3.5 was used to determine the serological prevalence of chronic hepatitis B and hepatitis C. The mean +/- standard deviation age of patients was 36 +/- 8.4 years (adult cohort) and 7 +/- 3 years (paediatric cohort). The sero prevalence of hepatitis B surface antigen, hepatitis C (anti HCV antibodies) and triple infection are 8.7%, 5.3% and 0.35%, respectively. Men who have sex with men are at the highest risk of being co infected with hepatitis B while intravenous drug users are at the highest risk of being co-infected with hepatitis C. It is important to screen for hepatitis B and C in HIV infected people in order to provide quality care for HIV patients with co-infection. PMID- 23800422 TI - An interleukin-10 gene polymorphism associated with the development of cervical lesions in women infected with Human Papillomavirus and using oral contraceptives. AB - Human Papillomavirus (HPV) infection plays a crucial role in the development of cervical lesions and tumors, however most lesions containing high-risk HPVs do not progress to cervical tumors. Some studies suggest that the use of oral contraceptives may increase the risk of cervical carcinogenesis, but this has not been confirmed by all the studies. Cytokines are important molecules that act in the defense of an organism against viral infections. Several genetic studies have attempted to correlate cytokine polymorphisms with human diseases, including cancer. The significance of IL10 polymorphisms for cancer is that they have both immunosuppressive and antiangiogenic properties. We aimed to investigate the role of promoter polymorphisms in the IL10 gene in women with cervical lesions associated with HPV infection, in the presence of the use of oral contraceptives. Using High Resolution Melt analysis (HRM), we analyzed an SNP -1082A/G and 819C/T in interleukin-10 promoter region in 364 Brazilian women: 171 with cervical lesions and HPV infection, and 193 with normal cytological results and HPV-negative. We observed no significant differences in genotype and allele frequencies in the two loci between patients and healthy controls. Furthermore, in the haplotype analysis of IL10, we found that CA haplotype was significantly more frequent in patients infected with HPV than in the control group (p = 0.0188). We did not find any genotype and allelic association of the IL10 gene polymorphisms between cases and controls. However, in this study, when the HPV positive patients were stratified according to their use of contraceptives, we found a significant association between the -1082G allele (p = 0.0162) and 1082GG genotype (p = 0.0332) among HPV-infected patients who used oral contraceptives. Our findings suggest that -1082A/G gene polymorphism represents a greater susceptibility to progressive cervical lesions in HPV- infected women who use oral contraceptives. PMID- 23800423 TI - Hexabromocyclododecane in alpine fish from the Tibetan Plateau, China. AB - Hexabromocyclododecanes (HBCDs) has just been listed into Stockholm Convention as a persistent organic pollutant recently. This paper studied the HBCDs in 79 wild fish from high mountain lakes and rivers of the Tibetan Plateau. The ?HBCDs in fish muscles ranged from non detectable levels to 13.7 ng/g lipid weight (lw) (mean value of 2.12 ng/g lw) with a high detection frequency of 65.8%. alpha-HBCD dominated among the isomers and accounted for 78.2% of the total burden. Concentrations of ?HBCDs in the fish were significantly correlated with the lipid content. A decreasing trend was observed between alpha-HBCD and trophic level. Positive correlation was also noted between the HBCD levels in fish from lakes and the annual precipitation, and this implied the long-range atmospheric transport of HBCDs to the Tibet Plateau. This was the first work to widely explore HBCDs contamination in the aquatic ecosystems of the Tibetan Plateau. PMID- 23800424 TI - Seasonal and spatial variation of trace elements and metals in quasi-ultrafine (PM0.25) particles in the Los Angeles metropolitan area and characterization of their sources. AB - Year-long sampling campaign of quasi-ultrafine particles (PM0.25) was conducted at 10 distinct locations across the Los Angeles south coast air basin and concentrations of trace elements and metals were quantified at each site using high-resolution inductively coupled plasma sector field mass spectrometry. In order to characterize sources of trace elements and metals, principal component analysis (PCA) was applied to the dataset. The major sources were identified as road dust (influenced by vehicular emissions as well as re-suspended soil), vehicular abrasion, residual oil combustion, cadmium sources and metal plating. These sources altogether accounted for approximately 85% of the total variance of quasi-ultrafine elemental content. The concentrations of elements originating from source and urban locations generally displayed a decline as we proceeded from the coast to the inland. Occasional concentration peaks in the rural receptor sites were also observed, driven by the dominant westerly/southwesterly wind transporting the particles to the receptor areas. PMID- 23800425 TI - Chronic exposure to volcanogenic air pollution as cause of lung injury. AB - Few studies were made regarding the pulmonary effects of exposure to volcanogenic air pollution, representing an unrecognized health risk for humans inhabiting non eruptive volcanically active areas (10% of world human population). We tested the hypothesis whether chronic exposure to air pollution of volcanogenic origin causes lung injury, using wild mice (Mus musculus) as model. Lung injury was determined using histological morphometric parameters, inflammatory status (InfS) and the amount of black silver deposits (BSD). Mice exposed to volcanogenic air pollution have decreased percentage of alveolar space, alveolar perimeter and lung structural functionality (LSF) ratio and, increased alveolar septal thickness, amount of BSD and InfS. For the first time it is evidenced that non eruptive active volcanism has a high potential to cause lung injury. This study also highlights the usefulness of M. musculus as bioindicator species, and of the developed biomarker of effect LSF ratio, for future animal and/or human biomonitoring programs. PMID- 23800428 TI - Recent improvements for Animal Health Research Reviews: Thomson Reuters indexation, online-only format and an open-access option. PMID- 23800427 TI - Multi-wavelength spectrophotometric analysis for detection of xanthochromia in cerebrospinal fluid and accuracy for the diagnosis of subarachnoid hemorrhage. AB - BACKGROUND: Cerebrospinal fluid (CSF) was examined for bilirubin, an important indicator for diagnosis of subarachnoid hemorrhage (SAH). METHODS: A multi wavelength (340, 415, and 460 nm) spectrophotometric assay was developed for the quantitative measurement of bilirubin in CSF, enabling the mathematical correction for absorbance of hemoglobin and proteins. Bilirubin and hemoglobin results were correlated to HPLC and a standard colorimetric assay, respectively. A subset of samples was sent for an absorbance reading at 450 nm following baseline correction. The multi-wavelength bilirubin assay was validated on 70 patients with confirmed SAH and 70 patients with neurologic symptoms who ruled out for SAH. RESULTS: The multi-wavelength spectrophometric assay demonstrated no interferences due to proteins (albumin) up to 30 g/l or oxyhemoglobin up to 260 mg/l. The assay limit of detection was 0.2 mg/l, linear to 20 mg/l, and CVs ranged from 1 to 6% at bilirubin concentrations of 0.84 and 2.1mg/l. The spectrophotometric assay correlated to HPLC and the colorimetric assay for bilirubin and hemoglobin, respectively. Results also correlated to the absorbance method (with removal of samples with high hemoglobin and proteins). The area under the ROC curve for diagnosis of SAH was 0.971 and 0.954 for the HPLC and spectrophotometric assay, respectively. At a cutoff of 0.2mg/l, the clinical specificity was 100% for both assays, and the clinical sensitivity was 94.3% and 88.6% for SAH for the HPLC and spectrophotometric asays, respectively. CONCLUSIONS: The multi-wavelength spectrophotometric assay is an objective alternative to visual inspection, HPLC, and absorbance for CSF bilirubin. PMID- 23800426 TI - Novel Burkholderia mallei virulence factors linked to specific host-pathogen protein interactions. AB - Burkholderia mallei is an infectious intracellular pathogen whose virulence and resistance to antibiotics makes it a potential bioterrorism agent. Given its genetic origin as a commensal soil organism, it is equipped with an extensive and varied set of adapted mechanisms to cope with and modulate host-cell environments. One essential virulence mechanism constitutes the specialized secretion systems that are designed to penetrate host-cell membranes and insert pathogen proteins directly into the host cell's cytosol. However, the secretion systems' proteins and, in particular, their host targets are largely uncharacterized. Here, we used a combined in silico, in vitro, and in vivo approach to identify B. mallei proteins required for pathogenicity. We used bioinformatics tools, including orthology detection and ab initio predictions of secretion system proteins, as well as published experimental Burkholderia data to initially select a small number of proteins as putative virulence factors. We then used yeast two-hybrid assays against normalized whole human and whole murine proteome libraries to detect and identify interactions among each of these bacterial proteins and host proteins. Analysis of such interactions provided both verification of known virulence factors and identification of three new putative virulence proteins. We successfully created insertion mutants for each of these three proteins using the virulent B. mallei ATCC 23344 strain. We exposed BALB/c mice to mutant strains and the wild-type strain in an aerosol challenge model using lethal B. mallei doses. In each set of experiments, mice exposed to mutant strains survived for the 21-day duration of the experiment, whereas mice exposed to the wild-type strain rapidly died. Given their in vivo role in pathogenicity, and based on the yeast two-hybrid interaction data, these results point to the importance of these pathogen proteins in modulating host ubiquitination pathways, phagosomal escape, and actin-cytoskeleton rearrangement processes. PMID- 23800429 TI - Immunity to bovine herpesvirus 1: I. Viral lifecycle and innate immunity. AB - Bovine herpesvirus 1 (BHV-1) causes a variety of diseases and is globally distributed. It infects via mucosal epithelium, leading to rapid lytic replication and latent infection, primarily in sensory ganglia. Large amounts of virus can be excreted by the host on primary infection or upon recrudescence of latent infection, resulting in disease spread. The bovine immune response to BHV 1 is rapid, robust, balanced, and long-lasting. The innate immune system is the first to respond to the infection, with type I interferons (IFNs), inflammatory cytokines, killing of infected host cells, and priming of a balanced adaptive immune response. The virus possesses a variety of immune evasion strategies, including inhibition of type I IFN production, chemokine and complement binding, infection of macrophages and neutrophils, and latency. BHV-1 immune suppression contributes to the severity of its disease manifestations and to the bovine respiratory disease complex, the leading cause of cattle death loss in the USA. PMID- 23800430 TI - Immunity to bovine herpesvirus 1: II. Adaptive immunity and vaccinology. AB - Bovine herpesvirus 1 (BHV-1) infection is widespread and causes a variety of diseases. Although similar in many respects to the human immune response to human herpesvirus 1, the differences in the bovine virus proteins, immune system components and strategies, physiology, and lifestyle mean the bovine immune response to BHV-1 is unique. The innate immune system initially responds to infection, and primes a balanced adaptive immune response. Cell-mediated immunity, including cytotoxic T lymphocyte killing of infected cells, is critical to recovery from infection. Humoral immunity, including neutralizing antibody and antibody-dependent cell-mediated cytotoxicity, is important to prevention or control of (re-)infection. BHV-1 immune evasion strategies include suppression of major histocompatibility complex presentation of viral antigen, helper T-cell killing, and latency. Immune suppression caused by the virus potentiates secondary infections and contributes to the costly bovine respiratory disease complex. Vaccination against BHV-1 is widely practiced. The many vaccines reported include replicating and non-replicating, conventional and genetically engineered, as well as marker and non-marker preparations. Current development focuses on delivery of major BHV-1 glycoproteins to elicit a balanced, protective immune response, while excluding serologic markers and virulence or other undesirable factors. In North America, vaccines are used to prevent or reduce clinical signs, whereas in some European Union countries marker vaccines have been employed in the eradication of BHV-1 disease. PMID- 23800432 TI - Estimated costs of malingered disability. AB - The feigning of disabling illness for the purpose of disability compensation, or "malingering," is common in Social Security Disability examinations, occurring in 45.8%-59.7% of adult cases. In this study, we estimated the costs of malingering based on mental disorder data published by the Social Security Administration. At the most widely accepted base rate of malingering in medicolegal cases involving external incentive, costs were high, totaling $20.02 billion in 2011 for adult mental disorder claimants. Moreover, these figures clearly underestimate the costs of the larger problem with feigned disability in both adults and children. We urge a change in Social Security policies to allow the use of validity testing in the examination for disability claims. PMID- 23800433 TI - IL-33 in rheumatoid arthritis: potential role in pathogenesis and therapy. AB - Rheumatoid arthritis (RA) is characterized by chronic inflammatory disease, including synovial proliferation and excessive pro-inflammatory cytokines production, leading to cartilage and bone destruction. Cytokine-mediated immunity plays an important role in the pathogenesis of various autoimmune diseases such as RA. Recently, the IL-1 family member IL-33, was recognized to perform as an inflammatory cytokine, exerted profound effects in human RA and experimental inflammatory arthritis. Furthermore, inhibition of IL-33 signaling proposed a potential therapeutic approach. In this review, we summarize recent advances on the pathological roles of IL-33 in RA and discuss the therapeutic significance of these new findings. PMID- 23800431 TI - Parental communication and psychosis: a meta-analysis. AB - BACKGROUND: Parental communication deviance (CD) has long been suggested as a potential risk factor for the development of psychosis and thought disorder in genetically sensitive offspring. However, the findings of the studies on the prevalence of CD in parents of psychotic patients have never been submitted to quantitative synthesis. METHOD: PsycINFO was searched from January 1959 to January 2012 for studies on the prevalence of CD in parents of psychotic patients. This search was supplemented with the results from a much larger systematic search (PsycINFO, PubMed, EMBASE, and Web of Science) on childhood trauma and psychosis. RESULTS: A total of 20 retrieved studies (n = 1753 parents) yielded a pooled g of large magnitude (0.97; 95% CI [0.76; 1.18]) with a significant amount of heterogeneity (Q = 33.63; P = .014; I (2) = 46.47). Subgroup and sensitivity analysis of methodological features (study's design, comparison group, diagnostic criteria, CD rating method, inter-rater reliability not reported, year of publication, and verbosity) and demographic characteristics (level of education or offspring's age) revealed that pooled effect size was stable and unlikely to have been affected by these features. CONCLUSION: CD is highly prevalent in parents of psychotic offspring. This is discussed in the broader context of adoption and longitudinal studies that have reported a G * E interaction in the development of psychosis and thought disorder. A potential developmental mechanism is suggested to explain how CD may affect the developing offspring. The importance of further studies on CD and its potential value as a clinical concept are discussed. PMID- 23800434 TI - No association between IL-1RN VNTR and the risk of duodenal ulcer: a meta analysis. AB - The aim of this study was to perform a meta-analysis to investigate a more authentic association between interleukin-1 RN variable number of tandem repeats (IL-1RN VNTR) and duodenal ulcer (DU). Systematic searches of electronic databases Embase, PubMed and Web of Science were performed. Statistical analyses were conducted using software Stata 11.0. The pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were applied. Publication bias was tested by Begg's funnel plot and Egger's regression test. A total of 16 studies including 2115 cases and 3622 controls were included in our final meta-analysis. There was no evidence of significant association between IL-1RN VNTR and DU (allelic model: OR = 1.04, 95% CI = 0.87-1.26; additive model: OR = 0.85, 95% CI = 0.62-1.16; dominant model: OR = 1.06, 95% CI = 0.92-1.23; and recessive model: OR = 0.83, 95% CI = 0.61-1.12). Significant protective associations were found in additive model (OR = 0.51, 95% CI = 0.31-0.83) and recessive model (OR = 0.45, 95% CI = 0.28-0.73) in Caucasian subgroup. In conclusion, our meta-analysis suggests that there is no evidence of significant association between IL-1RN VNTR and DU with or without Helicobacter pylori infection in overall population, whereas significant association is found by subgroup analyses which showed protective effect of IL-1RN allele 2 against DU risk in Caucasian population. PMID- 23800435 TI - Low levels of vasoactive intestinal peptide are associated with Chagas disease cardiomyopathy. AB - The interconnection between immune and neuroendocrine systems influences regulation of inflammatory responses. The possible relevance that this integrative response may have during the course of Chagas disease remains poorly characterized. In this context, our study was designed to determine the expression of vasoactive intestinal peptide (VIP), a neuropeptide with anti inflammatory properties, in blood from the indeterminate and cardiac polarized forms of Chagas disease. Moreover, we determined whether the differential expression of VIP is associated with the development of cardiomyopathy in individuals infected with Trypanosoma cruzi. Finally, we analyzed gene polymorphisms of VIP receptors, VPAC1 and VPAC2, and performed correlation analysis of these polymorphisms with the different clinical forms of Chagas disease. Our results demonstrated that low plasma levels of VIP were associated with the cardiac morbidity in Chagas disease. Accordingly, correlation analysis showed that low plasma levels of VIP were associated with worse cardiac function, as determined by left ventricular ejection fraction and left ventricular diastolic diameter values. Polymorphism analysis showed a significant association between VPAC1 and the indeterminate form of Chagas disease development. Our data indicate that VIP expression and its receptors' polymorphism may be important in determining susceptibility to progression from mild to severe forms of Chagas disease. PMID- 23800437 TI - A comparison of EMG-based muscle fatigue assessments during dynamic contractions. AB - Several EMG-based approaches to muscle fatigue assessment have recently been proposed in the literature. In this work, two multivariate fatigue indices developed by the authors: a generalized mapping index (GMI) and the first component of principal component analysis (PCA) were compared to three univariate indices: Dimitrov's normalized spectral moments (NSM), Gonzalez-Izal's waveletbased indices (WI), and Talebinejad's fractal-based Hurst Exponent (HE). Nine healthy participants completed two repetitions of fatigue tests during isometric, cyclic and random fatiguing contractions of the biceps brachii. The fatigue assessments were evaluated in terms of a modified sensitivity to variability ratio yielding the following scores (mean+/-std.dev.): PCA: (12.6+/ 5.6), GMI: (11.5+/-5.4), NSM: (10.3+/-5.4), WI: (8.9+/-4.6), HE: (8.0+/-3.3). It was shown that PCA statistically outperformed WI and HE (p<0.01) and that GMI outperformed HE (p<0.02). There was no statistical difference among NSM, WI and HE (p>0.2). It was found that taking the natural logarithm of NSM and WI, although reducing the parameters' sensitivity to fatigue, increased SVR scores by reducing variability. PMID- 23800436 TI - Characterization of corneal stromal stem cells with the potential for epithelial transdifferentiation. AB - INTRODUCTION: The corneal stroma is being increasingly recognized as a repository for stem cells. Like the limbal and endothelial niches, stromal stem cells often reside in the peripheral cornea and limbus. These peripheral and limbal corneal stromal cells (PLCSCs) are known to produce mesenchymal stem cells in vitro. Recently, a common corneal stromal and epithelial progenitor was hinted at. This study aims to examine the stem cell potential of corneal stromal cells and to investigate their epithelial transdifferentiation ability. METHODS: PLCSCs were grown in traditional Dulbecco modified Eagle medium (DMEM)-based keratocyte culture medium and an M199-based medium and analyzed for a profile of cell surface markers by using flow cytometry and differentiated into mesenchymal phenotypes analyzed with quantitative polymerase chain reaction (qPCR) and histologic staining. PLCSCs in M199 were subsequently divided into subpopulations based on CD34 and CD105 expression by using fluorescence- activated cell sorting (FACS). Subpopulations were characterized by marker profile and mesenchymal differentiation ability. Both whole PLCSCs and subpopulations were also cultured for epithelial transdifferentiation. RESULTS: Cells cultured in M199 demonstrated a more stem-like cell-surface marker profile, and the keratocyte marker CD34 was retained for several passages but absent in cells cultured in DMEM. Cells cultured in M199 also exhibited a greater mesenchymal differentiation potential, compared with DMEM. PLCSCs could be divided into CD34(+)CD105(+), CD34-CD105(+), and CD34-CD105- subpopulations, of which CD34(+)CD105(+) cells were the most stemlike with regard to marker expression and mesenchymal differentiation potential. Subpopulations of PLCSCs exhibited differing abilities to transdifferentiate into epithelial phenotypes. Cells that were initially CD34(+)CD105(+) showed the greatest differentiation potential, producing CK3(+) and CK19(+) cells, and expressed a range of both epithelial progenitor (HES1, FRZB1, DCT, SOD2, ABCG2, CDH1, KRT19) and terminally differentiated (DSG3, KRT3, KRT12, KRT24) genes. CONCLUSIONS: Culture medium has a significant effect on the phenotype and differentiation capacity of PLCSCs. The stroma contains a heterogeneous cell population in which we have identified CD34(+) cells as a stem cell population with a capacity for mesenchymal and epithelial differentiation. PMID- 23800438 TI - Differential effects of mental concentration and acute psychosocial stress on cervical muscle activity and posture. AB - Physical and psychosocial stressors in the workplace have been independently associated with the development of neck pain, yet interactions among these risk factors remain unclear. The purpose of this study was to compare the effects of mentally challenging computer work performed with and without exposure to a psychosocial stressor on cervical muscle activity and posture. Changes in cervical posture and electromyography of upper trapezius, cervical extensor, and sternocleidomastoid muscles were compared between a resting seated posture at baseline, a low stress condition with mental concentration, and a high stress condition with mental concentration and psychosocial stress in sixty healthy office workers. Forward head posture significantly increased with mental concentration compared to baseline, but did not change with further introduction of the stressor. Muscle activity significantly increased from the low stress to high stress condition for both the dominant and non-dominant upper trapezius, with no corresponding change in activity of the cervical extensors or flexors between stress conditions. These findings suggest that upper trapezius muscles are selectively activated by psychosocial stress independent of changes in concentration or posture, which may have implications for the prevention of stress-related trapezius myalgia in the workplace. PMID- 23800439 TI - Assessment of surgical residents in a vascular anastomosis laboratory. AB - BACKGROUND: We designed a simple, low-cost workshop to teach surgical residents the basic skills of vascular anastomosis. We studied our ability to identify objective procedural and end-product metrics that could be used to measure improvement in vascular anastomotic skill before and after training. MATERIALS AND METHODS: Ten postgraduate year 2 residents without previous vascular surgery experience and four attending surgeons (expert) performed end-to-side anastomosis using a synthetic graft. The residents were taught the basic skills of vascular anastomosis during three didactic workshops. The objective metrics included volume leakage after saline perfusion (leak) and the time needed to complete the anastomosis. Penalty points were assigned for broken sutures, air knots, locking sutures, and failure to maintain an outside-in to inside-out technique. The leak, time, and penalties before and after training were compared. RESULTS: The mean leak was 70.4 +/- 13.7 mL and the mean completion time was 18.7 +/- 3 min for the pretraining group versus 45.3 +/- 10.6 mL (P < 0.01) and 8.5 +/- 1 min (P < 0.001), respectively, for the attending group. After training, significant improvement was seen in resident leak (46.7 +/- 6.8 mL; P < 0.001) and completion time (14.4 +/- 3 min; P < 0.01). Leak was similar between the post-training and expert groups (46.7 +/- 6.8 mL and 45.3 +/- 10.6 mL, respectively; P = 0.77); however, a significant difference for the completion time remained (14.4 +/- 3.0 min and 8.5 +/- 1 min, respectively; P < 0.01). The mean number of technical errors improved from 2.7 in the pretraining group to zero for the post-training group after completing the workshop. CONCLUSIONS: We have reported an easy to implement workshop for teaching surgical residents the basic skills of performing vascular anastomosis. PMID- 23800440 TI - Outer membrane vesicles from pathogenic bacteria initiate an inflammatory response in human endothelial cells. AB - INTRODUCTION: Gram-negative bacteria release outer membrane vesicles (OMVs) during growth that contain various membrane components involved in eliciting an inflammatory response, including lipopolysaccharide and virulence factors. However, little is known about the role of OMVs in sepsis. The objective of this study was to determine how OMVs, derived from Escherichia (E.) coli, elicit the cellular responses involved in activating the inflammatory cascade, and to determine whether additional virulence factors in pathogenic OMVs augment the inflammatory response. METHODS: Human umbilical endothelial cells were inoculated with OMVs from non-pathogenic E. coli (npOMV) or pathogenic E. coli (pOMV) and analyzed for adhesion protein synthesis, cytokine production, and necrosis factor (NF)-kappaB translocation. RESULTS: Flow cytometry demonstrated that human umbilical vein endothelial cells exposed to npOMV or pOMV significantly increased expression of E-selectin and intercellular adhesion molecule, with a large population of cells demonstrating increased expression of both proteins. Interleukin-6 levels were significantly elevated by 4 h after exposure to npOMV and pOMVs. NF-kappaB translocation to the nucleus was shown to be induced by npOMV and pOMVs. However, the role of additional virulence factors associated with pOMVs remains undefined. CONCLUSIONS: Both npOMVs and pOMVs are capable of initiating the inflammatory cascade in endothelial cells. OMVs trigger NF-kappaB translocation to the nucleus, resulting in up-regulation of adhesion molecules and cytokines, presumably for the recruitment of leukocytes. By eliciting an inflammatory response, OMVs could facilitate the transition from a localized infection to a systemic response, and ultimately sepsis. PMID- 23800441 TI - National cost of trauma care by payer status. AB - BACKGROUND: Several studies have described the burden of trauma care, but few have explored the economic burden of trauma inpatient costs from a payer's perspective or highlighted the differences in the average costs per person by payer status. The present study provides a conservative inpatient national trauma cost estimate and describes the variation in average inpatient trauma cost by payer status. METHODS: A retrospective analysis of patients who had received trauma care at hospitals in the Nationwide Inpatient Sample from 2005-2010 was conducted. Our sample patients were selected using the appropriate "International Classification of Diseases, Ninth Revision, Clinical Modification" codes to identify admissions due to traumatic injury. The data were weighted to provide national population estimates, and all cost and charges were converted to 2010 US dollar equivalents. Generalized linear models were used to describe the costs by payer status, adjusting for patient characteristics, such as age, gender, and race, and hospital characteristics, such as location, teaching status, and patient case mix. RESULTS: A total of 2,542,551 patients were eligible for the present study, with the payer status as follows: 672,960 patients (26.47%) with private insurance, 1,244,817 (48.96%) with Medicare, 262,256 (10.31%) with Medicaid, 195,056 (7.67%) with self-pay, 18,506 (0.73%) with no charge, and 150,956 (5.94%) with other types of insurance. The estimated yearly trauma inpatient cost burden was highest for Medicare at $17,551,393,082 (46.79%), followed by private insurance ($10,772,025,421 [28.72%]), Medicaid ($3,711,686,012 [9.89%], self-pay ($2,831,438,460 [7.55%]), and other payer types ($2,370,187,494 [6.32%]. The estimated yearly trauma inpatient cost burden was $274,598,190 (0.73%) for patients who were not charged for their inpatient trauma treatment. Our adjusted national inpatient trauma yearly costs were estimated at $37,511,328,659 US dollars. Privately insured patients had a significantly higher mean cost per person than did the Medicare, Medicaid, self-pay, or no charge patients. CONCLUSIONS: The results of the present study have demonstrated that the distribution of trauma burden across payers is significantly different from that of the overall healthcare system and suggest that although the burden of trauma is high, the burden of self-pay or nonreimbursed inpatient services is actually lower than that of overall medical care. PMID- 23800442 TI - Leachate risk and identification of accumulated heavy metals in Pangasius sutchi. AB - Pollutants put great stress on the environment, especially the aquatic ecosystem; therefore, the ease with which pollutants migrate in water is a subject of global concern. In this study, leachate from landfill that was analyzed with the objective of understanding the potential impact to the environment was tested on Pangasius sutchi. Heavy metals available at various concentrations in raw leachate samples of both closed and active landfills necessitated the determination of their degree of bioaccumulation in this fish species in order to enrich the risk data on toxicity of effluents. Zinc (3.2 ug g(-1)), iron (2.1 ug g(-1)) and chromium (0.24 ug g(-1)) detected in the fish within 96 h of acute exposure is of concern. A histopathology test on excised liver of P. sutchi indicated cellular disruption from normal stain. Heterogeneous effluents like leachate may affect not only groundwater but can endanger aquatic ecosystems, especially in some regions where improper waste disposal and treatment allow the flow of leachate into surface water courses. Though metals might be beneficial to organisms, the extent at which they can accumulate in leachate-exposed fish is a risk and can initiate metal toxicity in aquatic life. PMID- 23800443 TI - Six-months outcomes of a randomised trial of supportive text messaging for depression and comorbid alcohol use disorder. AB - BACKGROUND AND OBJECTIVES: We have previously reported that supportive text messages delivered twice daily for three months have the potential to provide personalised support for patients with depression and co-morbid Alcohol Use Disorder (AUD). In this study we report the six months outcomes. METHODS: Participants (n=54) with a DSM IV diagnosis of unipolar depression and AUD who completed an in-patient dual diagnosis treatment programme were randomised to receive daily twice supportive text messages (n=26) or a fortnightly thank you text message (n=28) for three months. Primary outcome measures at six months were Beck's Depression Inventory (BDI-II) scores and Cumulative Abstinence Duration (CAD). TRIAL REGISTRATION: NCT0137868. RESULTS: Unlike at three months, there was no statistically significant difference in six months BDI-II scores between the intervention (n=24) and control (n=24) groups; 13.28 (SD=8.7) vs. 15.08 (SD=11.37) respectively after adjusting for the baseline scores, F (1, 45)=0.192, p=0.66. There was also no significant difference in CAD between the text message group and the control group: 84.14 days (9.20) vs. 74.73 days (28.97), t=1.422, df=41, p=0.16. However, patients in the intervention group had significantly higher days to first drink compared to those in the control group: 119.9 (47.7) vs. 62.4 (44.9), t=2.99, df=22, p=0.01. LIMITATIONS: Limitations of the study include the small sample size and the potential for loss of rater blinding. CONCLUSION: The effects of supportive text message intervention were not sustained beyond the period that the patients were receiving the intervention. PMID- 23800444 TI - Hippocampal multimodal structural changes and subclinical depression in healthy individuals. AB - BACKGROUND: Several neuroimaging studies report reduced hippocampal volume in depressed patients. However, it is still unclear if hippocampal changes in healthy individuals can be considered a risk factor for progression to clinical depression. Here, we investigated subclinical depression and its hippocampal correlates in a non-clinical sample of healthy individuals, with particular regard to gender differences. METHODS: One-hundred-two participants underwent a comprehensive clinical assessment, a high-resolution T1-weighted magnetic resonance imaging and diffusion tensor imaging protocol using a 3T MRI scanner. Data of macro-(volume) and micro-(mean diffusivity, MD) structural changes of the hippocampus were analyzed with reference to the Beck Depression Inventory score. RESULTS: Results of multivariate regression analyses revealed reduced bilateral volume, along with increased bilateral MD in hippocampal formation predicting subclinical depressive phenomenology only in healthy males. Conversely, subclinical depressive phenomenology in healthy female was accounted for by only lower educational level, in the absence of any hippocampal structure variations. LIMITATIONS: To date, this is the only evidence reporting a relationship between subclinical depressive phenomenology and changes in hippocampal formation in healthy individuals. CONCLUSIONS: Our findings demonstrated that reduced volume, along with increased MD in hippocampal formation, is significantly associated with subclinical depressive phenomenology in healthy males. This encourages to study the hypothesis that early macro- and microstructural changes in hippocampi associated with subclinical depression may constitute a risk factor of developing depressive disorders in males. PMID- 23800445 TI - Age and belongingness moderate the effects of combat exposure on suicidal ideation among active duty Air Force personnel. AB - OBJECTIVE: To determine if intensity of combat exposure relates to suicidal ideation among active duty Air Force personnel according to age and perceived belonging. METHOD: Self-report measures of suicidal ideation, combat exposure (e.g., firing weapons, being fired upon), aftermath exposure (e.g., seeing dead bodies and devastation), emotional distress, belongingness, and perceived burdensomeness were completed by 273 (81.7% male; 67.8% Caucasian, 20.5% African American, 2.2% Native American,.7% Asian,.4% Pacific Islander, and 8.4% "other"; age M=25.99, SD=5.90) active duty Air Force Security Forces personnel. Multiple regression modeling was utilized to test the associations of combat exposure and aftermath exposure with recent suicidal ideation. RESULTS: A significant age-by combat exposure interaction was found (B=0.014, SE=0.006, p=0.019), suggesting combat exposure and suicidal ideation was strongest among military personnel above the age of 34. The age-by-aftermath exposure interaction was not significant (B=-0.003, SE=0.004, p=0.460). A significant three-way interaction of age, combat exposure, and belongingness was also found (B=0.011, SE=0.005, p=0.042). The Johnson-Neyman test indicated that suicidal ideation was most severe among Airmen above the age of 29 years with high combat exposure and low levels of belongingness. LIMITATIONS: Cross-sectional, self-report design limited to two Air Force units. CONCLUSIONS: A strong sense of belonging protects against suicidal ideation among Airmen above the age of 29 years who have been exposed to higher levels of combat. PMID- 23800446 TI - Personal history of major depression may put women at risk for premenstrual dysphoric symptomatology. AB - BACKGROUND: Premenstrual dysphoric disorder (PMDD) is a chronic condition that significantly affects a woman's well-being on a monthly basis. Although co occurrence of PMDD and major depressive disorder (MDD) is common, most studies examine whether women with PMDD are at risk for depression and investigations of PMDD in depressed women are scant. Therefore, the present study examined rates of PMDD in young depressed women. METHODS: PMDD was assessed using a structured clinical interview (SCID-PMDD) in a sample of 164 young women with (n=85) and without (n=79) any history of depression. RESULTS: Rates of PMDD were elevated among women with MDD in this sample. This result held true regardless of participants' MDD status (current, lifetime or past history-only symptoms of MDD) and regardless of whether all or most DSM-IV-TR PMDD criteria were met. LIMITATIONS: Sample size in the present study was relatively small, and daily diary data were not available to confirm a PMDD diagnosis. CONCLUSIONS: The current study highlights the need for clinicians to assess for PMDD in young female patients with major depression. Depressed women experiencing the added physical and psychological burden of PMDD may have a more severe disease course, and future studies will need to identify appropriate treatments for this subset of depressed women. PMID- 23800447 TI - Performance evaluation of three assays for the detection of PR3-ANCA in granulomatosis with polyangiitis in daily practice. AB - BACKGROUND: Anti-neutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 (PR3-ANCA) are a serological hallmark of small vessel vasculitis, particularly granulomatosis with polyangiitis (GPA). To increase their sensitivity, some ELISA employ the human native PR3 combined with a recombinant protein. Their specificity in daily practice is still to be defined. Our objective was to compare the performance for GPA diagnosis of three PR3-ANCA assays in daily practice. PATIENTS AND METHODS: Seventy-eight consecutive patients' sera with suggestive IIF were included. All sera were tested with a routine Enzyme Linked Immuno adsorbant Assay (ELISA) employing a mixture of human native and human recombinant (hn+hr) PR3 (EUROIMMUNTM) compared to two assays using immobilized purified human PR3 (QUANTA Lite((r)) ELISA and QUANTA Flash((r)) Chemiluminescence assay (CIA), INOVA Diagnostics). Clinical data including BVAS score were collected retrospectively. RESULTS: Nineteen out of the 78 patients had GPA. The hn+hr PR3 ELISA had a good sensitivity (100%) but a lower specificity for the diagnosis of GPA (61.0%) than the assays using the sole native protein (hn ELISA: 81.4%, hn CIA: 69.5%). False positive results mainly consisted of patients with inflammatory bowel disease, who had a specific PR3 ANCA positivity assembly when coupling the assays. The antibody titers by human native PR3 assays, but not hn+hr assay, positively correlated with BVAS score. CONCLUSION: These results highlight the need of a close collaboration between physicians and immunologists. Combining assays including last generation CIA employing human native antigens should improve the performance of GPA's diagnosis. PMID- 23800448 TI - Long-term safety of abatacept in patients with rheumatoid arthritis. AB - Abatacept is a selective T cell co-stimulation modulator that was first approved by the Italian Medicines Agency and reimbursed by the Italian National Health Service when used to treat active rheumatoid arthritis "not sufficiently responsive to other disease-modifying anti-rheumatic drugs (DMARDs) including at least one TNF inhibitor", and is now also approved as a first line biological agent. The aim of this review is to summarise the safety data collected in clinical trials and observational studies. PMID- 23800449 TI - A novel systematic approach to the evaluation of the fetal venous system. AB - Sonographic evaluation of the fetal venous system in normal and abnormal conditions has drawn increasing interest in recent years. Whereas the assessment of the fetal heart and the related arteries is standardized using well-defined planes, the fetal venous system is still lacking a systematic approach. In this article we present a novel sonographic algorithm for a systematic examination of the fetal venous system using six planes of transverse and oblique views of the fetal abdomen and chest. These planes, using two-dimensional and color Doppler, enable a targeted demonstration of the typical veins to include the umbilical vein, ductus venosus, portal veins, hepatic veins, inferior vena cava, azygos vein, pulmonary veins, coronary sinus, superior vena cava and brachiocephalic vein. We postulate that integrating such a sequential stepwise algorithm for the evaluation of the venous system into targeted fetal cardiac imaging may improve the detection of isolated and combined anomalies of the fetal systemic and pulmonary veins. PMID- 23800450 TI - Size-dependent regulation of dorsal-ventral patterning in the early Drosophila embryo. AB - How natural variation in embryo size affects patterning of the Drosophila embryo dorsal-ventral (DV) axis is not known. Here we examined quantitatively the relationship between nuclear distribution of the Dorsal transcription factor, boundary positions for several target genes, and DV axis length. Data were obtained from embryos of a wild-type background as well as from mutant lines inbred to size select embryos of smaller or larger sizes. Our data show that the width of the nuclear Dorsal gradient correlates with DV axis length. In turn, for some genes expressed along the DV axis, the boundary positions correlate closely with nuclear Dorsal levels and with DV axis length; while the expression pattern of others is relatively constant and independent of the width of the Dorsal gradient. In particular, the patterns of snail (sna) and ventral nervous system defective (vnd) correlate with nuclear Dorsal levels and exhibit scaling to DV length; while the pattern of intermediate neuroblasts defective (ind) remains relatively constant with respect to changes in Dorsal and DV length. However, in mutants that exhibit an abnormal expansion of the Dorsal gradient which fails to scale to DV length, only sna follows the Dorsal distribution and exhibits overexpansion; in contrast, vnd and ind do not overexpand suggesting some additional mechanism acts to refine the dorsal boundaries of these two genes. Thus, our results argue against the idea that the Dorsal gradient works as a global system of relative coordinates along the DV axis and suggest that individual targets respond to changes in embryo size in a gene-specific manner. PMID- 23800451 TI - Ethical considerations of clinical photography in an area of emerging technology and smartphones. AB - Recent advances in digital technology including internet, email and smartphones has revolutionised clinical photography and medical record data storage. The use of smartphones is becoming ubiquitous among medical professionals and the use of clinical photography has become an integral component of the management of patients in a variety of visually orientated specialties. Although clinical photography has its benefits, with this evolving technology also emerge new ethical, legal and social issues, which clinicians must be aware of. PMID- 23800452 TI - The million mutation project: a new approach to genetics in Caenorhabditis elegans. AB - We have created a library of 2007 mutagenized Caenorhabditis elegans strains, each sequenced to a target depth of 15-fold coverage, to provide the research community with mutant alleles for each of the worm's more than 20,000 genes. The library contains over 800,000 unique single nucleotide variants (SNVs) with an average of eight nonsynonymous changes per gene and more than 16,000 insertion/deletion (indel) and copy number changes, providing an unprecedented genetic resource for this multicellular organism. To supplement this collection, we also sequenced 40 wild isolates, identifying more than 630,000 unique SNVs and 220,000 indels. Comparison of the two sets demonstrates that the mutant collection has a much richer array of both nonsense and missense mutations than the wild isolate set. We also find a wide range of rDNA and telomere repeat copy number in both sets. Scanning the mutant collection for molecular phenotypes reveals a nonsense suppressor as well as strains with higher levels of indels that harbor mutations in DNA repair genes and strains with abundant males associated with him mutations. All the strains are available through the Caenorhabditis Genetics Center and all the sequence changes have been deposited in WormBase and are available through an interactive website. PMID- 23800454 TI - Six-month outcomes following an emergency hospital admission for older adults with co-morbid mental health problems indicate complexity of care needs. AB - BACKGROUND: two-thirds of older patients admitted as an emergency to a general hospital have co-existing mental health problems including delirium, dementia and depression. This study describes the outcomes of older adults with co-morbid mental health problems after an acute hospital admission. METHODS: a follow-up study of 250 patients aged over 70 admitted to 1 of 12 wards (geriatric, medical or orthopaedic) of an English acute general hospital with a co-morbid mental health problem and followed up at 180 days. RESULTS: twenty-seven per cent did not return to their original place of residence after the hospital admission. After 180 days 31% had died, 42% had been readmitted and 24% of community residents had moved to a care home. Only 31% survived without being readmitted or moving to a care home. However, 16% spent >170 of the 180 days at home. Significant predictors for poor outcomes were co-morbidity, nutrition, cognitive function, reduction in activities of daily living ability prior to admission, behavioural and psychiatric problems and depression. Only 42% of survivors recovered to their pre-acute illness level of function. Clinically significant behavioural and psychiatric symptoms were present at follow-up in 71% of survivors with baseline cognitive impairment, and new symptoms developed frequently in this group. CONCLUSIONS: the variable, but often adverse, outcomes in this group implies a wide range of health and social care needs. Community and acute services to meet these needs should be anticipated and provided for. PMID- 23800453 TI - The Y chromosome as a regulatory element shaping immune cell transcriptomes and susceptibility to autoimmune disease. AB - Understanding the DNA elements that constitute and control the regulatory genome is critical for the appropriate therapeutic management of complex diseases. Here, using chromosome Y (ChrY) consomic mouse strains on the C57BL/6J (B6) background, we show that susceptibility to two diverse animal models of autoimmune disease, experimental allergic encephalomyelitis (EAE) and experimental myocarditis, correlates with the natural variation in copy number of Sly and Rbmy multicopy ChrY genes. On the B6 background, ChrY possesses gene regulatory properties that impact genome-wide gene expression in pathogenic CD4(+) T cells. Using a ChrY consomic strain on the SJL background, we discovered a preference for ChrY mediated gene regulation in macrophages, the immune cell subset underlying the EAE sexual dimorphism in SJL mice, rather than CD4(+) T cells. Importantly, in both genetic backgrounds, an inverse correlation exists between the number of Sly and Rbmy ChrY gene copies and the number of significantly up-regulated genes in immune cells, thereby supporting a link between copy number variation of Sly and Rbmy with the ChrY genetic element exerting regulatory properties. Additionally, we show that ChrY polymorphism can determine the sexual dimorphism in EAE and myocarditis. In humans, an analysis of the CD4(+) T cell transcriptome from male multiple sclerosis patients versus healthy controls provides further evidence for an evolutionarily conserved mechanism of gene regulation by ChrY. Thus, as in Drosophila, these data establish the mammalian ChrY as a member of the regulatory genome due to its ability to epigenetically regulate genome-wide gene expression in immune cells. PMID- 23800455 TI - Fenestrated and branched endovascular aortic repair for chronic type B aortic dissection with thoracoabdominal aneurysms. AB - OBJECTIVE: The treatment of patients with arch and thoracoabdominal aortic aneurysms (TAAAs) and chronic dissections is challenging. We report the results of fenestrated and branched endovascular aortic repair (FEVAR) of such aneurysms. METHODS: A single-center prospective FEVAR trial enrolled 356 patients (2006 to 2011), of whom 30 had chronic dissections with arch aneurysm or TAAAs, or both. Patients were divided into group A, 15 patients (mean age, 58 years) with extensive dissections extending from the arch through the visceral segment, and group B, 15 patients (mean age, 74 years old) with focal dissections and no extension into the thoracic aorta. Inclusion criterion was aneurysm size >5.5 cm in diameter. Customized grafts were implanted into the true lumen, and branches were extended into the true lumen of the supra-aortic trunk (arch branch devices) and visceral vessels. Patients were monitored annually with clinical, imaging, and laboratory studies. Outcome analyses included survival, rupture, spinal cord ischemia, endoleak, morbidity (cardiac, renal or pulmonary), reinterventions, dissection, and aneurysm growth. RESULTS: The mean time from the onset of dissection to the FEVAR performed in group A was 10.4 years. The mean maximum aneurysm diameter was 60 mm. Follow-up averaged 1.7 years. There were no perioperative deaths. One aortic-related death occurred at 87 days due to progression of a pre-existing untreated arch dissection. No ruptures, cardiac, renal, pulmonary, or spinal cord ischemia complications occurred. Despite the initially narrow true lumen dimensions, stent grafts expanded to their nominal diameters after implantation without any blood flow disturbance of branched visceral vessels and distal aorta. No graft compression occurred. Post-FEVAR growth was noted in two patients, related to type II endoleaks. Sac regression was similar (-6.8 vs -11.4 mm; P = .43), but early endovascular reinterventions were more common in group A (8 patients). Patients with extensive dissection were younger, and the dissection more likely to be associated with a defined connective tissue disease (Marfan syndrome or Loeys-Dietz mutations, 40% vs 0%; P = .006). CONCLUSIONS: FEVAR is feasible for patients with chronic dissections and TAAA. Concerns regarding visceral vessel access and graft compression resulting from narrow true lumen diameters were not relevant in our experience. Favorable sac and lumen morphologic changes, coupled with a low mortality and complication risk, makes this an attractive means of handling this clinical problem. PMID- 23800456 TI - Perinatal undernutrition programmes thyroid function in the adult rat offspring. AB - Increasing evidence suggests that alterations in early nutrition programme physiological changes in adulthood. In the present study, we determined the effects of undernutrition during gestation and lactation on the programming of thyroid function in adult rat offspring. Perinatal undernutrition was achieved by a 40% food restriction in female Wistar rats from the mating day to weaning. On postpartum day 21, the offspring of the control and food-restricted dams were weaned and given free access to a commercial diet until adulthood. The results showed that undernourished rats exhibited decreased 3,5,3'-triiodothyronine (T3) levels but had normal thyroxine (T4) and thyrotropin (TSH) levels at weaning; on day 90, these rats displayed a significant flip, exhibiting normalised T3 (total and free) and total T4 levels, but low free T4 and persistently higher TSH levels, which were maintained even on postnatal day 140. This profile was accompanied by a scarce fat depot, a lower RMR and an exacerbated sympathetic brown adipose tissue (BAT) tone (deiodinase type 2 expression) in basal conditions. Moreover, when a functional challenge (cold exposure) was applied, the restricted group exhibited partial changes in TSH (29 v. 100%) and T4 (non response v. 17%) levels, a significant decrease in leptin levels (75 v. 32%) and the maintenance of a sympathetic BAT over-response (higher noradrenaline levels) in comparison with the control group. The findings of the present study suggest that undernutrition during the perinatal period produces permanent changes in the hypothalamus-pituitary-thyroid axis with consequent low body weight and decreased RMR and facultative thermogenesis. We hypothesise that these changes predispose individuals to exhibiting adult subclinical hypothyroidism. PMID- 23800457 TI - Modulation of multiple sclerosis by sunlight exposure: role of cis-urocanic acid. AB - The role of cis-urocanic acid (UCA) as a UV-mediated immunomodulator in MS patients was investigated. Plasma levels of cis-UCA were significantly lower in MS patients compared to controls. Stimulation of MBP- and MOG-specific T cells in the presence of cis-UCA, significantly increased IL-10, and inhibited IFN-gamma production. PBMCs cultured in the presence of cis-UCA increased CD4(+)CD25(+)FoxP3(+) regulatory T cell percentages. Dendritic cells cultured in the presence of cis-UCA significantly reduced Ag presentation capacity. Finally, cis-UCA activated the 5-HT2A receptor, inducing the increase in phosphorylated forms of ERK 1/2 and JNK2. Thus, in addition to vitamin D, cis-UCA also appears to be an additional UV-mediated immunomodulator. PMID- 23800458 TI - Cerebrospinal fluid and serum JC virus antibody detection in multiple sclerosis patients treated with natalizumab. AB - Progressive multifocal leukoencephalopathy (PML) is a complication of natalizumab treatment. In order to identify natalizumab-treated patients at risk of developing PML, we assayed for anti-JC virus (JCV) antibody levels in cerebrospinal fluid (CSF). Serial CSF antibody levels were obtained, with 4 patients showing increases in anti-JCV levels indicating possibly viral activation. In patients with both CSF and serum antibody levels, a comparison showed only a moderate Spearman Rank Correlation Coefficient of 0.38. Our data suggests that serum anti-JCV antibody testing alone may not suffice in identifying at-risk patients because of the lack of uniform correlation with CSF titers. PMID- 23800459 TI - Distribution and accumulation of heavy metals in carbonate and reducible fractions of marine sediment from offshore mid-western Taiwan. AB - Two marine sediment cores from offshore mid-western Taiwan were subsampled and pre-treated using a sequential extraction procedure to separate carbonate and reducible fractions. Aliquots of these extracts were analyzed to determine their chemical composition to evaluate the geochemical processes responsible for heavy metal distribution and accumulation in the coastal environment. Our data demonstrate that sedimentation rates derived from excess (210)Pb associated with metal fluxes show large increases circa A.D. 1990. A well-synchronized increase in metal flux in both geochemical fractions was found and validated by Pearson's correlation. Principal component analysis revealed the heavy metal fluxes to be highly correlated with the sediment deposition rate, with metal contamination potentially driven by a sole contributor. This study emphasizes the changes in sedimentation rate is potentially caused by activities associated with the inland economic development during this time, rather than by raising heavy metal pollution dominated the accumulation offshore mid-western Taiwan. PMID- 23800460 TI - Seagrass meadows globally as a coupled social-ecological system: implications for human wellbeing. AB - Seagrass ecosystems are diminishing worldwide and repeated studies confirm a lack of appreciation for the value of these systems. In order to highlight their value we provide the first discussion of seagrass meadows as a coupled social ecological system on a global scale. We consider the impact of a declining resource on people, including those for whom seagrass meadows are utilised for income generation and a source of food security through fisheries support. Case studies from across the globe are used to demonstrate the intricate relationship between seagrass meadows and people that highlight the multi-functional role of seagrasses in human wellbeing. While each case underscores unique issues, these examples simultaneously reveal social-ecological coupling that transcends cultural and geographical boundaries. We conclude that understanding seagrass meadows as a coupled social-ecological system is crucial in carving pathways for social and ecological resilience in light of current patterns of local to global environmental change. PMID- 23800461 TI - Correlates of exercise capacity in pediatric patients on chronic hemodialysis. AB - OBJECTIVE: Pediatric patients on chronic hemodialysis (HD) are at high risk of inactivity and poor physical fitness. The aim of this study was to assess the main correlates of exercise capacity in a cohort of children and young adults on chronic HD. METHODS: Twelve patients on chronic HD (median age 15.6 years; range 9.1-24.2) underwent a 6-minute walking test (WT), spirometry, a 1-minute chair stand test, and the measurement of lower extremity strength. Demographic data, anthropometry (dry weight, height, body mass index, and skinfold thickness, all expressed as standard deviation scores [SDS]), biochemistry (serum albumin, hemoglobin, creatinine, C-reactive protein, bicarbonate), bioimpedance analysis, HD adequacy indices (spKt/V and eKt/V), left ventricular mass index, and medications were also recorded. RESULTS: There was a significant correlation among the distance covered during the WT (median 552 m, range 186-670), forced vital capacity (87.8% of predicted, range 49.7-136), forced expiratory volume in 1 second (86.7%, range 54.7-126.7), and peak expiratory flow (75.5%, 49.7-105.1). All of these indices positively correlated with the weight SDS (r 0.69-0.85), pre HD serum creatinine (0.57-0.77), and serum albumin (0.60-0.77) and negatively correlated with weekly erythropoietin dose per kilogram of body weight (from 0.64 to -0.83), with P values ranging from <.05 to <.0005. Lower extremity strength (median 11.5 kg, range 3-15) positively correlated with the number of stands at the chair stand test (median 33, range 18-47; r 0.73, P < .05) and serum albumin (r 0.83, P < .01). Distance at the WT, forced vital capacity, lower extremity strength, and the number of stands at the chair stand test all negatively correlated with C-reactive protein levels (r from -0.81 to -0.67, P < .05). CONCLUSION: Our findings show that protein-energy wasting and chronic inflammation are strongly correlated with the exercise capacity of children and young adults on chronic HD. PMID- 23800462 TI - Change in body composition in accordance with residual renal function in patients on peritoneal dialysis. AB - OBJECTIVES: The aim of this study is to evaluate changes in body composition in accordance with residual renal function (RRF). SUBJECTS AND METHODS: Two hundred forty-four patients with more than 1 year of follow-up were enrolled. The mean value of RRF at peritoneal dialysis (PD) initiation and 1 year after PD initiation was used as an indicator of the time-averaged RRF (TA-RRF). The patients were divided into 3 groups with respect to the tertile of the TA-RRF level: low tertile (n = 81), middle tertile (n = 82), and high tertile (n = 81). Body composition measurement was determined from dual-energy X-ray absorptiometry and bioimpedance analysis. This analysis was performed at PD initiation and 1 year after PD initiation. RESULTS: Multivariate analysis showed that the high TA RRF tertile was associated with an increase in lean mass index. Fat mass index in all tertiles and bone mineral content index in the middle and high TA-RRF tertiles were increased, but no significant difference were observed in these changes among the 3 tertiles. The edema index decreased over the 1-year PD period. The high TA-RRF tertile was associated with a lower edema index. Although there was no statistical significance, the increase in fat mass/lean mass ratio (FM/LM) attenuated as the grade of TA-RRF tertile increased. The increase in fat mass index was similar to the trend in FM/LM. CONCLUSION: TA-RRF was associated with an increase in total lean mass and a decrease in edema index. PMID- 23800463 TI - Perforator-based chimaeric thoracodorsal flap for foot reconstruction. AB - The reconstruction of severe defects of the ankle and foot is a challenge. The ideal solution should combine a thin skin flap on the dorsum to allow shoe fitting and a muscle flap with a split-thickness skin graft on the weight-bearing area. Perforator-based thoracodorsal chimaeric flaps allow us to achieve these two goals with minimal donor-site morbidity. We present a reconstruction of an extended circumferential defect of the ankle with an exposed heel using a chimaeric thoracodorsal perforator flap with a serratus muscle flap. The skin flap was transferred on the dorsal foot, whereas the serratus anterior muscle was transferred on the exposed heel. Postoperative recovery was uneventful and the patient began full weight bearing after 3 months. Twelve months after reconstruction, natural shape and walking function were successfully achieved. PMID- 23800464 TI - Is there a cerebellar compensatory effort in first-episode, treatment-naive major depressive disorder at rest? AB - BACKGROUND: This study was undertaken to explore whether there is a cerebellar compensatory response in patients with first-episode, treatment-naive major depressive disorder (MDD). The cerebellar compensatory response is defined as a cerebellar hyperactivity which would be inversely correlated with both the activation of the functionally connected cerebral regions and the depression severity. METHODS: Resting-state functional magnetic resonance imaging (fMRI) data of 24 patients with MDD and 24 healthy subjects were analyzed with the fractional amplitude of low-frequency fluctuations (fALFF) and functional connectivity (FC) methods. The structural images were processed with the voxel based morphometry (VBM) method. RESULTS: Compared to healthy controls, depressed patients had significantly increased fALFF in the left Crus I and the left cerebellar lobule VI. FC analysis of these two seeded regions found that depressed patients had increased FC between the left Crus I and the right hippocampus, but had decreased FC between the left Crus I and the left inferior parietal lobule (IPL), and between the left cerebellar lobule VI and bilateral inferior temporal gyrus. No correlation was observed between the abnormal fALFF of the seeds and their connected regions and the depression severity or the executive function. The VBM results did not show significant reduction in gray or white matter volume in any above-mentioned region. CONCLUSIONS: Our findings suggest that increased cerebellar activity at resting state may be a disease state phenomenon but not a compensatory response to the dysfunction of the default mode network (DMN) in MDD. PMID- 23800465 TI - Different effects of the NMDA receptor antagonists ketamine, MK-801, and memantine on postsynaptic density transcripts and their topography: role of Homer signaling, and implications for novel antipsychotic and pro-cognitive targets in psychosis. AB - Administration of NMDA receptor antagonists, such as ketamine and MK-801, may induce psychotic-like behaviors in preclinical models of schizophrenia. Ketamine has also been observed to exacerbate psychotic symptoms in schizophrenia patients. However, memantine, a non-competitive NMDA receptor antagonist approved for Alzheimer's disease and proposed for antipsychotic augmentation, may challenge this view. To date, the molecular mechanisms by which these NMDA receptor antagonists cause different neurochemical, behavioral, and clinical effects are still a matter of debate. Here, we investigated by molecular imaging whether these agents could differently modulate gene expression and topographical distribution of glutamatergic postsynaptic density (PSD) proteins. We focused on Homer1a/Homer1b/PSD-95 signaling network, which may be implicated in glutamate dependent synaptic plasticity, as well as in psychosis pathophysiology and treatment. Ketamine (25 and 50mg/kg) and MK-801 (0.8mg/kg) significantly induced the transcripts of immediate-early genes (Arc, c-fos, and Homer1a) in cortical regions compared to vehicle, whereas they reduced Homer1b and PSD-95 expression in cortical and striatal regions. Differently, memantine (5mg/kg) did not increase Homer1a signal compared to vehicle, whereas it induced c-fos in the somatosensory and in the medial agranular cortices. Moreover, memantine did not affect Homer1b and PSD-95 expression. When compared to ketamine and MK-801, memantine significantly increased the expression of c-fos, Homer1b and PSD-95. Overall, ketamine and MK-801 prominently increased Homer1a/Homer1b expression ratio, whereas memantine elicited the opposite effect. These data may support the view that ketamine, MK-801 and memantine exert divergent effects on PSD transcripts, which may contribute to their partially different behavioral and clinical effects. PMID- 23800467 TI - A role for platelet TRPC channels in the Ca2+ response that induces procoagulant activity. AB - After vascular injury, platelets are rapidly activated by collagen and other agonists, causing them to adhere and aggregate to prevent blood loss. In addition, phosphatidylserine (PS) exposure on the platelet surface accelerates thrombin formation by the coagulation pathway. Thrombin is a potent platelet agonist and converts fibrinogen to fibrin, thereby stabilizing the platelet plug. PS exposure during hemostasis and thrombosis results from a sustained cytosolic Ca(2+) increase; however, the underlying Ca(2+) mobilization pathways have remained unclear. Store-operated Orai1 channels provide substantial, prolonged Ca(2+) influx after inositol trisphosphate-dependent release, and anoctamin 6 (TMEM16F) may operate as a Ca(2+)-activated, Ca(2+)-permeable channel in addition to its scramblase activity that exteriorizes PS. A new study shows that Na(+) entry, resulting from coactivation of the transient receptor potential (TRP) nonselective cation channels TRPC3 and TRPC6, followed by reverse-mode operation of Na(+)/Ca(2+) exchangers, is an important mechanism for the increase in cytosolic Ca(2+) that triggers PS exposure, particularly during combined thrombin and collagen stimulation. PMID- 23800466 TI - In vitro models of angiogenesis and vasculogenesis in fibrin gel. AB - In vitro models of endothelial assembly into microvessels are useful for the study of angiogenesis and vasculogenesis. In addition, such models may be used to provide the microvasculature required to sustain engineered tissues. A large range of in vitro models of both angiogenesis and vasculogenesis have utilized fibrin gel as a scaffold. Although fibrin gel is conducive to endothelial assembly, its ultrastructure varies substantially based on the gel formulation and gelation conditions, making it challenging to compare between models. This work reviews existing models of endothelial assembly in fibrin gel and posits that differerences between models are partially caused by microstructural differences in fibrin gel. PMID- 23800468 TI - Transient receptor potential channels function as a coincidence signal detector mediating phosphatidylserine exposure. AB - Blood platelet aggregation must be tightly controlled to promote clotting at injury sites but avoid inappropriate occlusion of blood vessels. Thrombin, which cleaves and activates Gq-coupled protease-activated receptors, and collagen related peptide, which activates the receptor glycoprotein VI, stimulate platelets to aggregate and form thrombi. Coincident activation by these two agonists synergizes, causing the exposure of phosphatidylserine on the cell surface, which is a marker of cell death in many cell types. Phosphatidylserine exposure is also essential to produce additional thrombin on platelet surfaces, which contributes to thrombosis. We found that activation of either thrombin receptors or glycoprotein VI alone produced a calcium signal that was largely dependent only on store-operated Ca(2+) entry. In contrast, experiments with platelets from knockout mice showed that the presence of both ligands activated nonselective cation channels of the transient receptor potential C (TRPC) family, TRPC3 and TRPC6. These channels principally allowed entry of Na(+), which coupled to reverse-mode Na(+)/Ca(2+) exchange to allow calcium influx and thereby contribute to Ca(2+) signaling and phosphatidylserine exposure. Thus, TRPC channels act as coincidence detectors to coordinate responses to multiple signals in cells, thereby indirectly mediating in platelets an increase in intracellular calcium concentrations and exposure of prothrombotic phosphatidylserine. PMID- 23800469 TI - Rapgef2 connects GPCR-mediated cAMP signals to ERK activation in neuronal and endocrine cells. AB - G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR)-mediated increases in the second messenger cyclic adenosine monophosphate (cAMP) activate the mitogen-activated protein kinase (MAPK) extracellular signal regulated kinase (ERK), and in neuroendocrine cells, this pathway leads to cAMP dependent neuritogenesis mediated through Rap1 and B-Raf. We found that the Rap guanine nucleotide exchange factor Rapgef2 was enriched from primary bovine neuroendocrine cells by cAMP-agarose affinity chromatography and that it was specifically eluted by cAMP. With loss-of-function experiments in the rat neuronal cell line Neuroscreen-1 (NS-1) and gain-of-function experiments in human embryonic kidney 293T cells, we demonstrated that Rapgef2 connected GPCR dependent activation of adenylate cyclase and increased cAMP concentration with the activation of ERK in neurons and endocrine cells. Furthermore, knockdown of Rapgef2 blocked cAMP- and ERK-dependent neuritogenesis. Our data are consistent with a pathway involving the cAMP-mediated activation of Rapgef2, which then stimulates Rap1, leading to increases in B-Raf, MEK, and ERK activity. PMID- 23800470 TI - A novel arsenate reductase from the bacterium Thermus thermophilus HB27: its role in arsenic detoxification. AB - Microorganisms living in arsenic-rich geothermal environments act on arsenic with different biochemical strategies, but the molecular mechanisms responsible for the resistance to the harmful effects of the metalloid have only partially been examined. In this study, we investigated the mechanisms of arsenic resistance in the thermophilic bacterium Thermus thermophilus HB27. This strain, originally isolated from a Japanese hot spring, exhibited tolerance to concentrations of arsenate and arsenite up to 20mM and 15mM, respectively; it owns in its genome a putative chromosomal arsenate reductase (TtarsC) gene encoding a protein homologous to the one well characterized from the plasmid pI258 of the Gram+bacterium Staphylococcus aureus. Differently from the majority of microorganisms, TtarsC is part of an operon including genes not related to arsenic resistance; qRT-PCR showed that its expression was four-fold increased when arsenate was added to the growth medium. The gene cloning and expression in Escherichia coli, followed by purification of the recombinant protein, proved that TtArsC was indeed a thioredoxin-coupled arsenate reductase with a kcat/KM value of 1.2*10(4)M(-1)s(-1). It also exhibited weak phosphatase activity with a kcat/KM value of 2.7*10(-4)M(-1)s(-1). The catalytic role of the first cysteine (Cys7) was ascertained by site-directed mutagenesis. These results identify TtArsC as an important component in the arsenic resistance in T. thermophilus giving the first structural-functional characterization of a thermophilic arsenate reductase. PMID- 23800471 TI - Medication exposure may confound the association between dietary intake and frailty. PMID- 23800472 TI - Being an adolescent with a cochlear implant in the world of hearing people: coping in school, in society and with self identity. AB - OBJECTIVE: The cochlear implant has revolutionized functioning with severe-to profound sensori-neural loss. A deaf child implanted at an early age with good habilitation may have good language abilities and function well in daily life. As the implanted child grows up, managing in the world of hearing people may become more complex. During adolescence, the teenager copes with many issues, including identity, socialization with the peer group, and managing in the school setting. These issues may be even more challenging for the adolescents using a cochlear implant. This study was designed to shed light on how adolescents with cochlear implants experience coping with the issues mentioned. METHOD: Twelve teenagers (14-18 years old), fairly similar to the entire adolescent implanted population at the center at which the study was conducted, participated in the study. They had been unilaterally or bilaterally implanted at differing ages. The participants filled out a questionnaire dealing with their functioning in the educational setting, their social preferences and functioning, and their identity as hearing or deaf. The results were analyzed using the principles of thematic analysis. RESULTS: At school, some reported better achievements than others but they all expressed some difficulty functioning in class mainly in situations involving several speakers. From a social point of view, some reported a preference for association with normal hearing peers, whereas others favored hard of-hearing friends, and one had no preference. Of those who touched on the topic of self-identity, one referred to herself as deaf, eight defined themselves as hard-of-hearing, and two consider themselves hearing. CONCLUSIONS: From the responses of these teenagers, it is clear that adolescents with cochlear implants are a heterogeneous group. Parents and teachers should be aware that adolescents with implants, even when successful academically, may experience difficulties in the classroom setting. Most of the participants in this study learning in a mainstream setting, preferred social relationships with hearing peers (to hard of hearing/deaf). The responses of these adolescents with cochlear implants support the conjecture that they have both a hearing identity and a deaf identity, which may be expressed at varying intensities depending on the situation at the time. PMID- 23800473 TI - Suppression of TIM-1 predicates clinical efficacy of sublingual immunotherapy for allergic rhinitis in children. AB - OBJECTIVE: To evaluate the clinical efficacy of sublingual immunotherapy (SLIT) with house-dust mite (HDM) extract and to examine the change of biomarkers (TIM 1, IL-5 and IL-10) after 6-month SLIT in children with allergic rhinitis (AR). METHODS: One hundred and sixteen HDM-sensitized children with persistent AR were enrolled to assess the clinical efficacy of SLIT by determining the individual nasal symptom score (INSS) and total nasal symptom scores (TNSS) after 6-month SLIT. Moreover, the mRNA expression of TIM-1, IL-5 and IL-10 in peripheral blood mononuclear cells (PBMCs) was examined in 16 well-controlled and 12 uncontrolled AR patients using quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: After 6-month SLIT, both TNSS and INSS scores were significantly decreased compared with the baseline value (p < 0.01). The rates for well-controlled, partly controlled and uncontrolled children were 43.1%, 32.8% and 24.1%, respectively. Accordingly, the mRNA levels of TIM-1 and IL-5 decreased significantly and IL-10 mRNA level increased significantly compared with the baseline value in well-controlled children (p < 0.05). CONCLUSION: Our findings suggest SLIT with HDM extract is effective and safe for AR children and TIM-1 may be considered as an indicator for evaluating the clinical efficacy of SLIT. PMID- 23800474 TI - Pediatric maxillofacial injuries - if a new look is required? AB - OBJECTIVE: Maxillofacial injuries in children always present a challenge in respect of their diagnosis and management. The phenomenal increase in automotives on the road has led to a tremendous rise in the number of road traffic accidents leading to facial injuries, of which children are the most unfortunate victims. The purpose of this retrospective study was to evaluate the epidemiology, etiology and pattern of facial injuries and also to access the most feasible method for the management of facial injuries in children without hampering the facial growth. METHODS: The records and radiographs of 110 patients within the age range of 0-16 years were retrospectively reviewed who have presented with maxillofacial injuries to our department from October 2008 to June 2012. The information extracted from patient's case records included patient's gender (male/female), age, etiology, fracture type (single fractures and multiple fractures), occlusal status, fracture site and treatment performed. RESULTS: Patient's age at the time of accident ranged from 0 to 16 years, with a mean of 6.1 years. 54.54% (n = 60) of the patients were under 6 years (infants and preschool), 31.82% (n = 35) were between 6 and 11 (school age), and 13.64% (n = 15) were between 12 and 16 years (adolescents). Road side accident was the most frequent cause of injury. Most fractures occurred in the mandible (54.54%; n = 60). The fractures with minimal or no occlusal disturbance were managed by liquid diet alone. CONCLUSION: We believe that even after so much advancement in surgical techniques and armamentarium, conservative treatment is still the most reliable approach in managing maxillofacial injuries in children. PMID- 23800475 TI - Neurocognitive functioning in bipolar depression: a component structure analysis. AB - BACKGROUND: Previous studies of neurocognitive performance in bipolar disorder (BD) have focused predominantly on euthymia. In this study we aimed to compare the neurocognitive profile of BD patients when depressed with healthy controls and explore the component structure of neurocognitive processes in these populations. METHOD: Cognitive tests of attention and executive function, immediate memory, verbal and visuospatial learning and memory and psychomotor speed were administered to 53 patients with a SCID-verified diagnosis of BD depression and 47 healthy controls. Test performance was assessed in terms of statistical significance, effect size and percentile standing. Principal component analysis (PCA) was used to explore underlying cognitive factor structure. RESULTS: Multivariate analysis revealed an overall group effect, depressed BD patients performing significantly worse than controls. Patients performed significantly worse on 18/26 measures examined, with large effect sizes (d > 0.8) on tests of speed of processing, verbal learning and specific executive/working memory processes. Almost all tests produced at least one outcome measure on which ~25-50% of the BD sample performed at more than 1 standard deviation (s.d.) below the control mean. Between 20% and 34% of patients performed at or below the fifth percentile of the control group in working memory, verbal learning and memory, and psychomotor/processing speed. PCA highlighted overall differences between groups, with fewer extracted components and less specificity in patients. CONCLUSIONS: Overall, neurocognitive test performance is significantly reduced in BD patients when depressed. The use of different methods of analysing cognitive performance is highlighted, along with the relationship between processes, indicating important directions for future research. PMID- 23800476 TI - Here/in this issue and there/abstract thinking: from pixels to voxels: television, brain, and behavior. PMID- 23800477 TI - iCAP: harnessing the power of technology. PMID- 23800478 TI - Landmark legislative trends in juvenile justice: an update and primer for child and adolescent psychiatrists. PMID- 23800479 TI - How are our children? A dialogue. PMID- 23800480 TI - Should I stay or should I go now: when should clinicians try a different antipsychotic? PMID- 23800481 TI - The role of emotion regulation in autism spectrum disorder. AB - OBJECTIVE: Autism spectrum disorder (ASD) is associated with amplified emotional responses and poor emotional control, but little is known about the underlying mechanisms. This article provides a conceptual and methodologic framework for understanding compromised emotion regulation (ER) in ASD. METHOD: After defining ER and related constructs, methods to study ER were reviewed with special consideration on how to apply these approaches to ASD. Against the backdrop of cognitive characteristics in ASD and existing ER theories, available research was examined to identify likely contributors to emotional dysregulation in ASD. RESULTS: Little is currently known about ER in youth with ASD. Some mechanisms that contribute to poor ER in ASD may be shared with other clinical populations (e.g., physiologic arousal, degree of negative and positive affect, alterations in the amygdala and prefrontal cortex), whereas other mechanisms may be more unique to ASD (e.g., differences in information processing/perception, cognitive factors [e.g., rigidity], less goal-directed behavior and more disorganized emotion in ASD). CONCLUSIONS: Although assignment of concomitant psychiatric diagnoses is warranted in some cases, poor ER may be inherent in ASD and may provide a more parsimonious conceptualization for the many associated socioemotional and behavioral problems in this population. Further study of ER in youth with ASD may identify meaningful subgroups of patients and lead to more effective individualized treatments. PMID- 23800482 TI - Early antipsychotic response to aripiprazole in adolescents with schizophrenia: predictive value for clinical outcomes. AB - OBJECTIVE: In adults with chronic schizophrenia, most symptom decreases occur in the first few weeks of antipsychotic treatment, and nonresponse at week 2 predicts a later nonresponse. The trajectory of antipsychotic response and the predictive value of early antipsychotic effects were investigated for ultimate outcome in adolescent schizophrenia, where such data are still lacking. METHOD: This post hoc analysis of a 6-week, randomized, double-blinded trial of aripiprazole (n = 196) versus placebo (n = 98) evaluated if adolescents 13 to 17 years old with schizophrenia exhibited substantial symptomatic improvement to aripiprazole in the first few treatment weeks and whether early response (ER) versus early nonresponse (ENR) predicted clinically relevant outcomes. ER decreased at least 20% and ENR decreased less than 20% in Positive and Negative Syndrome Scale (PANSS) total score at week 2 (ER2/ENR2) or 3 (ER3/ENR3). Ultimate response decreased at least 40% in PANSS score. RESULTS: Nearly 50% of the PANSS decrease was achieved by week 2 and up to 75% by week 3. ER2/ER3 subjects showed significantly greater improvement than ENR subjects in PANSS total score, PANSS positive and negative subscale scores, and functionally relevant outcomes. In general, ER3 had better sensitivity, specificity, and positive and negative predictive values than ER2 for predicting ultimate response. ER2 subjects were 8.8 times (95% confidence interval 4.0-19.4) and ER3 subjects were 8.6 times (95% confidence interval 4.5-16.6) more likely to achieve remission at week 6 (p < .0001) than ENR2 and ENR3 subjects, respectively, although adverse events were similar. CONCLUSIONS: Like adults with chronic schizophrenia, adolescents with early-phase schizophrenia exhibited most symptomatic improvement early during aripiprazole treatment, with week 3 improvements having the best predictive power. Although requiring extension, these results may inform clinical decision making. Clinical trial registration information-Aripiprazole in Adolescents with Schizophrenia, http://clinicaltrials.gov/, NCT00102063. PMID- 23800483 TI - Examination of disruptive behavior outcomes and moderation in a randomized psychotherapy trial for mood disorders. AB - OBJECTIVE: Multifamily psychoeducational psychotherapy (MF-PEP) is an efficacious treatment for children with mood disorders. Given the comorbidity between disruptive behaviors and mood disorders, this study examined associations between disruptive behaviors and impairment, impact of MF-PEP on disruptive behaviors, and whether disruptive behaviors affected treatment response of mood symptoms. METHOD: Secondary analyses examined a randomized controlled trial of MF-PEP versus waitlist control (N = 165 children 8-11 years old with mood disorders and their parents). Comorbid behavioral diagnoses occurred in 97% of children. All participants continued treatment as usual. RESULTS: Greater degree of disruptive behaviors was associated with worse mood symptoms and impairment. Between-group analyses examining outcome of disruptive behaviors were nonsignificant. Within group analyses and between-group effect sizes suggested that MF-PEP was associated with decreases in attention-deficit/hyperactivity disorder (d = 0.39), oppositional defiant disorder (d = 0.30), and overall disruptive behavior symptoms (d = 0.30), but not conduct disorder symptoms. Baseline severity of disruptive behaviors did not affect treatment response of mood symptoms to MF PEP. CONCLUSIONS: MF-PEP is an effective intervention for children with mood disorders and provides some benefit for disruptive behaviors. Given that disruptive behavior severity does not affect children's ability to experience improved mood symptoms, MF-PEP may be an important early intervention for children with comorbid mood and disruptive behavior disorders. Subsequent intervention targeting behavioral symptoms after improvement in mood may be beneficial. Studies examining treatment sequencing for children with comorbid mood and disruptive behavior disorders are needed. Clinical trial registration information-Family psychoeducation for children with mood disorders; http://clinicaltrials.gov; NCT00050557. PMID- 23800484 TI - Childhood self-control and adult outcomes: results from a 30-year longitudinal study. AB - OBJECTIVE: A study by Moffitt et al. reported pervasive associations between childhood self-control and adult outcomes. The current study attempts to replicate the findings reported by Moffitt et al., adjusting these results for the confounding influence of childhood conduct problems. METHOD: Data were gathered from the Christchurch Health and Development Study, a longitudinal birth cohort studied to age 30 years. Self-control during ages 6 to 12 years was measured analogously to that in Moffitt et al., using parent-, teacher-, and self report methods. Outcome measures to age 30 included criminal offending, substance use, education/employment, sexual behavior, and mental health. Associations between self-control and outcomes were adjusted for possible confounding by gender, socioeconomic status (SES), IQ, and childhood conduct problems (ages 6 10). RESULTS: In confirmation of the findings of Moffitt et al., all outcomes except major depression were significantly (p < .05) associated with childhood self-control. Adjustment for gender, SES, and IQ reduced to some extent the magnitude of the associations. However, adjustment for childhood conduct disorder further reduced the magnitude of many of these associations, with only 4 of the 14 outcomes remaining statistically significantly (p < .05) associated with self control. After adjustment for gender, SES, IQ, and conduct problems, those individuals who scored higher in self-control had lower odds of violent offending and welfare dependence, were more likely to have obtained a university degree, and had higher income levels. CONCLUSIONS: The findings from this study suggest that observed linkages between a measure of childhood self-control and outcomes in adulthood were largely explained by the correlated effects of childhood conduct problems, SES, IQ, and gender. PMID- 23800485 TI - Oppositionality and socioemotional competence: interacting risk factors in the development of childhood conduct disorder symptoms. AB - OBJECTIVES: Oppositional behavior in childhood is a probabilistic risk factor for the subsequent development of more serious conduct problems characteristic of conduct disorder (CD). The capacity to understand the subjective states of others (socioemotional competence) helps regulate antisocial behavior in typical development. We hypothesized that socioemotional competence moderates the developmental relationship between oppositionality and CD symptoms, such that oppositional defiant disorder (ODD) symptoms pose the greatest risk for subsequent CD symptoms in children with poor socioemotional competence. METHOD: Parent-report data were collected for 6,218 children at 7 and 10 years of age. Bootstrap multiple regression predicting CD symptoms at age 10 was used to test for an interaction between socioemotional competence and ODD symptoms, while also accounting for direct effects and controlling for sex, maternal education, attention-deficit/hyperactivity disorder symptoms, and CD symptoms at 7 years. We further tested whether the interaction applied to both males and females, and to both aggressive and rule-breaking CD symptoms. RESULTS: A significant interaction was found between ODD and socioemotional competence: the association between oppositionality at 7 years and CD traits at 10 years was strongest for children with poor socioemotional capacities. As predicted, this moderation effect was significant in a model predicting aggression, but it was not significant for rule breaking CD symptoms. CONCLUSION: Socioemotional competence moderates the developmental relationship between mid-childhood oppositionality and more serious conduct problems in later childhood. A capacity to understand the subjective states of others may buffer the risk posed by oppositionality for later CD symptoms, including aggression. PMID- 23800486 TI - Detecting psychiatric disorders in preschoolers: screening with the strengths and difficulties questionnaire. AB - OBJECTIVE: To examine screening efficiency for preschool psychopathology by comparing the Strengths and Difficulties Questionnaire findings against diagnostic information, and to determine the added value of impact scores and teacher information. METHOD: Using a 2-phase sampling design, a population-based sample of 845 children 4 years of age was recruited from community health check ups in Trondheim, Norway, screen score stratified and oversampled for high screening scores. Blinded to screen ratings, DSM-IV diagnoses were assigned using the Preschool Age Psychiatric Assessment interview, against which the Strengths and Difficulties Questionnaire scores were compared through receiver operating characteristic analysis. RESULTS: Emotional and behavioral disorders were identified through parent ratings with a specificity of 88.8% (range, 87.0% 90.6%) and a sensitivity of 65.1% (range, 51.6-78.6%). The negative predictive value was 97.9% (range, 96.8%-98.9%), whereas the positive predictive value was 24.2% (range, 18.0%-30.3%) at a prevalence of 5.2%. Parental ratings identified more behavioral disorders (79.3%) than emotional disorders (59.2%). Screening for any disorder was somewhat less efficient: specificity, 88.9% (range, 87.0% 90.7%); sensitivity, 54.2% (range, 41.8%-66.6%); negative predictive value, 96.4% (range, 95.0%-97.8%); and positive predictive value, 25.9% (range, 19.6%-32.2%) at a prevalence of 6.7%. The area under the curve (AUC) value was 0.83 (range, 0.76-0.90) for emotional and behavioral disorders and 0.76 (range, 0.68-0.83) for any disorder. The prediction accuracy was not improved by impact scores or teacher information. CONCLUSIONS: The results indicate that preschoolers' emotional and behavioral disorders can be screened with the same efficiency as those of older children and adults. Other disorders were identified to a lesser extent. Further research should explore the potential of preschool screening to improve early detection and subsequent intervention. PMID- 23800487 TI - Disrupted amygdala reactivity in depressed 4- to 6-year-old children. AB - OBJECTIVE: Disrupted amygdala activity in depressed adolescents and adults while viewing facial expressions of emotion has been reported. However, few data are available to inform the developmental nature of this phenomenon, an issue that studies of the earliest known forms of depression might elucidate. The current study addressed this question by examining functional brain activity and its relationships to emotion regulation in depressed 4- to 6-year-old children and their healthy peers. METHOD: A total of 54 medication-naive 4- to 6-year-olds (23 depressed and 31 healthy) participated in a case-control study using functional magnetic resonance imaging (fMRI). Imaging data were used to compare functional brain activity in children with and without depression during emotion face processing. RESULTS: A right-lateralized pattern of elevated amygdala, thalamus, inferior frontal gyrus, and angular gyrus activity during face processing was found in depressed 4- to 6-year-olds. In addition, relationships between increased amygdala activity during face processing and disruptions in parent reported emotion regulation and negative affect were found. No between-group differences specific to emotion face type were identified. CONCLUSION: To our knowledge, this is the earliest evidence of alterations in functional brain activity in depression using fMRI. Results suggest that, similar to findings in older depressed groups, depression at this age is associated with disrupted amygdala functioning during face processing. The findings also raise the intriguing possibility that disrupted amygdala function is a depression-related biomarker that spans development. Additional studies will be needed to clarify whether the current findings are a precursor to or a consequence of very early childhood depression. PMID- 23800489 TI - Role of pulvinar-cortical functional brain pathways in attention deficit/hyperactivity disorder. PMID- 23800488 TI - Neuroeconomics and adolescent substance abuse: individual differences in neural networks and delay discounting. AB - OBJECTIVE: Many adolescents with substance use problems show poor response to evidence-based treatments. Treatment outcome has been associated with individual differences in impulsive decision making as reflected by delay discounting (DD) rates (preference for immediate rewards). Adolescents with higher rates of DD were expected to show greater neural activation in brain regions mediating impulsive/habitual behavioral choices and less activation in regions mediating reflective/executive behavioral choices. METHOD: Thirty adolescents being treated for substance abuse completed a DD task optimized to balance choices of immediate versus delayed rewards, and a control condition accounted for activation during magnitude valuation. A group independent component analysis on functional magnetic resonance imaging time courses identified neural networks engaged during DD. Network activity was correlated with individual differences in discounting rate. RESULTS: Higher discounting rates were associated with diminished engagement of an executive attention control network involving the dorsolateral prefrontal cortex, dorsomedial prefrontal cortex, inferior parietal cortex, cingulate cortex, and precuneus. Higher discounting rates also were associated with less deactivation in a "bottom-up" reward valuation network involving the amygdala, hippocampus, insula, and ventromedial prefrontal cortex. These 2 networks were significantly negatively correlated. CONCLUSIONS: Results support relations between competing executive and reward valuation neural networks and temporal decision making, an important, potentially modifiable risk factor relevant for the prevention and treatment of adolescent substance abuse. Clinical trial registration information-The Neuroeconomics of Behavioral Therapies for Adolescent Substance Abuse, http://clinicaltrials.gov/, NCT01093898. PMID- 23800491 TI - Understanding the role of the microenvironment during definitive hemopoietic development. AB - Hemopoietic stem cells (HSCs) are sustained in a specific microenvironment known as the stem cell niche. Recent studies in adult bone marrow have identified osteoblasts and endothelial cells as two important supportive cell types within the niche and demonstrated that interactions between HSCs and cellular and extracellular components within the endosteal and perivascular regions are critical for HSC regulation. However, the understanding of the role of the microenvironment in definitive HSC establishment, expansion, and maintenance during embryonic development is extremely limited. This review focuses on what is known about the components of each HSC microenvironment at various developmental stages and their known functional roles. PMID- 23800492 TI - Nascent lobar microbleeds and stroke recurrences. AB - BACKGROUND: Lobar microbleeds (MBs) are occasionally visible on gradient-echo T2* weighted (T2*-w) magnetic resonance imagings (MRIs) in patients with deep intracerebral hemorrhages (ICHs). This study investigated the contribution of nascent lobar MBs to occurrences of deep ICHs. METHODS: We prospectively analyzed nascent lobar MBs in patients admitted to our hospital who were treated with index strokes between April 2004 and November 2009. Numbers of nascent lobar MBs were counted on T2*-w MRI scans around 1 year after index strokes and compared with previous MRIs on admission. Deep ICH occurrence-free rate curves were generated by the Kaplan-Meier method using the log-rank test. The odds ratio (OR) for deep ICH occurrence was derived from a multivariate logistic regression model using nascent lobar MBs and risk factors. RESULTS: We investigated MRIs (interscan interval: 14.6 +/- 5.9 months) of 508 patients (207 women, 68.9 +/- 11.5 years), with a follow-up period of 44.1 +/- 15.4 months. Repeated T2*-w MRIs demonstrated 157 nascent lobar MBs in 62 of 508 patients. The occurrence rate of deep ICHs (1.9% per year) was significantly higher in patients with nascent lobar MBs than in those without (.5% per year, P = .012). Multivariate analyses revealed that the rate of nascent lobar MBs was significantly elevated in patients with deep ICH-type stroke recurrences (OR: 3.85, P = .020), adjusted by the presence of hypertension, diabetes mellitus, use of antithrombotic drugs, severity of white matter lesions, age, and gender. CONCLUSIONS: Though a cohort study limited the power of analyses, our findings suggested that lobar MBs might be associated with deep ICH. PMID- 23800493 TI - Blood pressure control among stroke patients in Thailand--the i-STROKE study. AB - BACKGROUND: Direct correlation between stroke mortality and hypertension calls for a tight blood pressure (BP) control. Our study determined the prevalence of the BP control and evaluated current clinical practices on hypertension management in stroke patients in Thailand. METHODS: This multicenter, cross sectional, retrospective, observational study was carried out between February 2010 and January 2011 and enrolled stroke patients aged 45 years or older with ictus incidence 12,030 days before the enrollment. The events were confirmed by either computerized tomography scan or magnetic resonance imaging. Patient data including demographics, medical, and clinical history were collected. RESULTS: At enrollment, 274 of 558 (49.1%) patients had controlled arterial BP with an average pressure of 134.220.4/78.812.8 mm Hg; 412 (73.8%) patients received antihypertensive medications and the most common use was angiotensin-converting enzyme inhibitors (ACEIs), reported in 200 (35.8%) patients. With questionnaire, insufficient antihypertensive use and lack of patients' awareness were the 2 most common reasons given by physicians for the patients' uncontrolled BP. Factors identified to have adverse association with the controlled BP at enrollment were diabetes at baseline, stage II hypertension, stage I hypertension, and the use of ACEIs at discharge (odds ratio of .18, .24, .30 [P < .001], and .53 [P = .009], respectively). CONCLUSIONS: Despite clinical evidence of the benefits of the BP control in reduction of secondary stroke events, a substantial number of stroke patients in Thailand do not achieve their BP targets, and this could possibly be a result of inadequate use of antihypertensive therapies and lack of compliance to BP management guidelines. PMID- 23800494 TI - Atrial fibrillation detected after acute ischemic stroke: evidence supporting the neurogenic hypothesis. AB - BACKGROUND: It is unknown whether atrial fibrillation (AF) detected after acute ischemic stroke is caused by neurogenic or cardiogenic mechanisms. Based on the potential damage to the autonomic nervous system, neurogenic mechanisms could be implicated in the pathophysiology of newly diagnosed AF. To test this hypothesis, we developed a mechanistic approach by comparing a prespecified set of indicators in acute ischemic stroke patients with newly diagnosed AF, known AF, and sinus rhythm. METHODS: We prospectively assessed every acute ischemic stroke patient undergoing continuous electrocardiographic monitoring from 2008 through 2011. We compared newly diagnosed AF, known AF, and sinus rhythm patients by using 20 indicators grouped in 4 domains: vascular risk factors, underlying cardiac disease, burden of neurological injury, and in-hospital outcome. RESULTS: We studied 275 acute ischemic stroke patients, 23 with newly diagnosed AF, 64 with known AF, and 188 with sinus rhythm. Patients with newly diagnosed AF had a lower proportion of left atrial enlargement (60.9% versus 91.2%, P=.001), a smaller left atrial area (22.0 versus 26.0 cm2, P=.021), and a higher frequency of insular involvement (30.4% versus 9.5%, P=.017) than participants with known AF. Compared with patients in sinus rhythm, those with newly diagnosed AF had a higher proportion of brain infarcts of 15 mm or more (60.9% versus 37.2%, P=.029) and a higher frequency of insular involvement (30.4% versus 7.3%, P<.001). CONCLUSIONS: The low frequency of underlying cardiac disease and the strikingly high proportion of concurrent strategic insular infarctions in patients with newly diagnosed AF provide additional evidence supporting the role of neurogenic mechanisms in a subset of AF detected after acute ischemic stroke. PMID- 23800495 TI - Acute kidney injury and edaravone in acute ischemic stroke: the Fukuoka Stroke Registry. AB - BACKGROUND: A free radical scavenger, edaravone, which has been used for the treatment of ischemic stroke, was reported to cause acute kidney injury (AKI) as a fatal adverse event. The aim of the present study was to clarify whether edaravone is associated with AKI in patients with acute ischemic stroke. METHODS: From the Fukuoka Stroke Registry database, 5689 consecutive patients with acute ischemic stroke who were hospitalized within 24 hours of the onset of symptoms were included in this study. A logistic regression analysis for the Fukuoka Stroke Registry cohort was done to identify the predictors for AKI. A propensity score-matched nested case-control study was also performed to elucidate any association between AKI and edaravone. RESULTS: Acute kidney injury occurred in 128 of 5689 patients (2.2%) with acute ischemic stroke. A multivariate analysis revealed that the stroke subtype, the basal serum creatinine level, and the presence of infectious complications on admission were each predictors of developing AKI. In contrast, a free radical scavenger, edaravone, reduced the risk of developing AKI (multivariate-adjusted odds ratio [OR] .45, 95% confidence interval [CI] .30-.67). Propensity score-matched case-control study confirmed that edaravone use was negatively associated with AKI (propensity score-adjusted OR .46, 95% CI .29-.74). CONCLUSIONS: Although AKI has a significant impact on the clinical outcome of hospital inpatients, edaravone has a protective effect against the development of AKI in patients with acute ischemic stroke. PMID- 23800496 TI - Indecision in the clinical practice of anticoagulation for brief atrial arrhythmias after cryptogenic stroke. AB - INTRODUCTION: Long-term cardiac monitoring has a substantial yield for paroxysmal atrial fibrillation (PAF) detection in cryptogenic stroke or transient ischemic attack (TIA) patients; however, many of these episodes were brief. We analyzed treatment decisions taken by the clinicians regarding anticoagulation in these short-duration PAF patients. METHODS: We performed a retrospective analysis on all mobile cardiac outpatient telemetry records between June 2009 and January 2012, initiated by neurologists from a large tertiary care institution stroke center. RESULTS: In all, 39 patients were found to have atrial fibrillation (AF), and their records were reviewed. AF episodes were categorized as less than 30 seconds in 24 (62%) patients and 30 seconds or more in 15 (38%) patients. Among the 16 patients without a cardiology evaluation, the rate of anticoagulation was high and did not differ for patients with short AF (90%, 9 of 10) and long AF (83%, 5 of 6) (P>.99). However, among the 23 patients with a cardiology evaluation, the difference in rates of anticoagulation was significant between patients with short AF (43%, 6 of 14) and long AF (89%, 8 of 9) (P=.039). CONCLUSION: Our study demonstrates the differences in anticoagulant prescribing practices between neurologists and cardiologists and the inherent indecision these findings have produced. Further study is needed to better define the risks and benefits associated with anticoagulation of brief episodes of atrial arrhythmias lasting less than 30 seconds in patients with cryptogenic stroke or TIA. PMID- 23800497 TI - The impact of intracranial carotid artery calcification on the development of thrombolysis-induced intracerebral hemorrhage. AB - BACKGROUND: We aimed to assess whether intracranial carotid artery calcification (ICAC) evident on head computed tomography is a risk factor for symptomatic intracerebral hemorrhage (sICH) following tissue plasminogen activator (tPA) treatment for acute stroke. METHODS: We classified 297 consecutive patients into 2 groups (no to mild ICAC and moderate to severe ICAC) according to ICAC severity. Outcome measures included detection of intracerebral hemorrhage and assessment using a modified Rankin scale (mRS) at 1 month and 1 year after stroke. RESULTS: ICH (any type) was significantly more common in patients with moderate to severe ICAC than in patients with no to mild ICAC (22.5% versus 12%; relative risk [RR], 1.67; 95% confidence interval [CI], 1.1-2.5; P<.05). The moderate to severe ICAC group tended to have a higher percentage of sICH, but this association was not statistically significant (RR, 1.57; 95% CI, .75-3.3, P>.05). Multivariate adjusted regression analysis revealed that moderate to severe ICAC was an independent risk factor for ICH following tPA treatment (odds ratio, 2.52; 95% CI, 1.07-5.94; P=.04). Dependent functional outcome (mRS score 3 6) at 1-month and 1-year follow-up was significantly associated with moderate to severe ICAC (RR, 1.56; 95% CI, 1.06-2.27; and RR, 1.56; 95% CI, 1.06-2.33; P<.05). However, ICAC was not an independent factor of functional dependency at 1 month and 1-year follow-up in the final multivariate regression model. CONCLUSION: A significantly higher percentage of patients with moderate to severe ICAC developed ICH following tPA administration for stroke. ICAC severity is an independent risk factor for ICH events. ICAC severity can help predict short-term and long-term functional dependency in tPA-treated patients, although this can be confounded by other cardiovascular risk factors and stroke severity. PMID- 23800498 TI - Subjective cognitive complaints after stroke: a systematic review. AB - BACKGROUND: Most studies to date have assessed poststroke cognitive impairment objectively, whereas less attention is paid to subjective cognitive complaints (SCC). We, therefore, systematically searched the literature to summarize and evaluate the current knowledge about poststroke SCC. METHODS: Articles were included in this review if the study evaluated SCC in adult stroke survivors, and the publication was an original empirical article from which the full text was available. There were no year or language restrictions. RESULTS: Twenty-six studies were found on poststroke SCC. There is a huge heterogeneity among these studies with respect to stroke sample, SCC definitions, and instruments used, but they all showed that SCC are very common after stroke. Other main findings are that SCC tend to increase over time and that there is moderate agreement between patients and their proxies on prevalence and severity of patients' SCC. Furthermore, SCC are inconsistently associated with current depressive symptoms and objective cognitive performances, whereas they may predict future emotional and cognitive functioning. CONCLUSIONS: This review highlights that poststroke SCC are highly prevalent and that clinicians should take such complaints seriously. More research is, however, needed to gain further insight into poststroke SCC, to be able to accurately inform patients and relatives, and to develop adequate treatment programs. Based on the limitations of the studies to date, suggestions are made on how both future research and ultimately patient centered care may be improved in stroke survivors. PMID- 23800499 TI - Nascent deep microbleeds and stroke recurrences. AB - BACKGROUND: Cerebral microbleeds (MBs) on gradient echo T2*-weighted magnetic resonance imaging (MRI) scans are associated with the severity of cerebral microangiopathies. This study investigated the contributions of nascent deep MBs to stroke recurrence. METHODS: We prospectively analyzed nascent deep MBs in patients admitted to our hospital who were treated for index strokes between April 2004 and November 2009. The number of nascent deep MBs was counted on T2* weighted MRI scans around 1 year after the index strokes, and compared to previous MRIs on admission. Stroke recurrence-free rate curves were generated using the Kaplan-Meier method using the log-rank test. The odds ratio for nascent deep MBs was derived using a multivariate logistic regression model that was based on recurrent strokes and other risk factors. RESULTS: We evaluated the MRIs (interval between MRIs 14.6 +/- 5.9 months) of 508 patients (207 women; 68.9 +/- 11.5 years), with a follow-up period of 44.1 +/- 15.4 months. Repeated T2* weighted MRI scans revealed 256 nascent deep MBs in 116 of 508 patients. The incidence of deep intracerebral hemorrhage was significantly greater in patients with nascent deep MBs than those without (2.0% vs 0.4% per year, respectively; P < .0001). Multivariate analyses revealed that the rate of nascent deep MBs was significantly elevated in patients whose stroke recurrences took the form of deep intracerebral hemorrhages (odds ratio 5.41; P = .007), when adjusted for hypertension, preexisting MBs, and other risk factors. CONCLUSIONS: Our findings suggested that nascent deep MBs might be associated with stroke recurrence, in particular with deep intracerebral hemorrhage. PMID- 23800500 TI - Critical role of matrix metalloproteinase-9 in acute cold exposure-induced stroke in renovascular hypertensive rats. AB - Our objectives are to investigate the role of MMP-9 in cold exposure-induced stroke and assess the preventive effect of doxycycline, a total of 200 rats were assigned to a control group, sham group, 2-kidney, 2-clip (2K-2C) group, and doxycycline-received 2K-2C group (2K-2C+doxy) (N=50, each), and subsequently, each group were randomly assigned to 2 groups: acute cold exposure (ACE) and nonacute cold exposure (NACE) (N=25, each). After the blood pressure was stabilized, rats were maintained on a 12-h light (22 degrees C)/dark (4 degrees C) cycle (ACE group) or a 12-h light (22 degrees C)/dark (22 degrees C) cycle (NACE group) for 3 cycles. The results showed that ACE upregulated Ang II and MMP 9 protein levels in brains and aortas and considerably enhanced stroke incidence in 2K-2C rats. In contrast, doxycycline treatment prevented upregulation of MMP-9 protein expression and activity in brains and aortas in response to ACE and significantly decreased stroke incidence. These findings suggest that cold exposure-induced MMP-9 via activation of RAS might play a critical role in the initiation of cold exposure-induced stroke during chronic hypertension and doxycycline shows protective effects against cold exposure-induced stroke. PMID- 23800501 TI - The iScore predicts clinical response to tissue plasminogen activator in Korean stroke patients. AB - BACKGROUND: Despite substantial differences in clinical features between Asian and Western stroke patients, there are no published prognostic tools validated in an Asiatic population for thrombolytic therapy. We assessed the ability of the iScore to predict the clinical response after intravenous thrombolysis with tissue plasminogen activator (tPA) in a Korean stroke population. METHODS: We applied the iScore to eligible participants in the nationwide multicenter stroke registry in Korea. Main outcome measures were poor functional outcome defined as having a modified Rankin Scale score 3-6 and death at 3 months. Symptomatic intracranial hemorrhage (sICH) was evaluated as a safety outcome. C statistic was calculated to assess performance of iScore. RESULTS: Among 4760 patients with an acute ischemic stroke, 622 (13.1%) received tPA, 548 patients had complete information for the analysis. C statistics for poor functional outcome and death at 3 months were .813 (95% confidence interval [CI]: .778-.848) and .820 (95% CI: .769-.872), respectively. Overall, there was a high correlation between observed and expected outcome for poor functional outcome (Pearson correlation coefficient, r = .982) and for death at 3 months (r = .950) at the risk score level. An iScore of 180 or more was associated with a more than 2 times risk of poor functional outcome and about 6 times risk of death at 3 months. There was an interaction between the iScore and tPA for a poor functional outcome (P value for the interaction < .001). We found a gradient effect in the incident risk of sICH with the iScore. CONCLUSION: The iScore reliably predicts stroke outcomes after tPA in Asiatic population. PMID- 23800502 TI - Reversible dropped head syndrome after hemispheric striatal infarction. AB - We report a rare case of transient "dropped head syndrome" (DHS) after acute ischemic stroke. A 64-year-old man noticed a sudden onset of mild weakness in his left hand and also difficulty in preventing his head from dropping onto his chest without weakness of the neck extensor muscles. Magnetic resonance images showed acute ischemic changes at the right putamen and caudate nucleus. Surface electromyography (EMG) performed 3 days after the stroke showed that both trapeziuses were hypertonic at rest, whereas the activity of the sternocleidomastoids was gradually increased on passive head lifting, indicating dystonia of the neck muscles. His dropped head fully improved by 9 days after the stroke. Re-examination by surface EMG 30 days after the stroke showed no hypertonic activity in the neck muscles. DHS is characterized by an abnormal ante fixed posture of the neck, usually observed in patients with neurodegenerative disorders such as multiple system atrophy and Parkinson disease. This is the first case of reversible DHS after acute ischemic stroke, and the accumulation of similar cases will be important to elucidate the mechanisms underlying the development of DHS and stroke-associated movement disorders. PMID- 23800504 TI - Unexpected arterial recanalization after decompressive hemicraniectomy. AB - We report a 43-year-old patient with malignant embolic ischemic stroke in the right middle cerebral artery (MCA), treated by decompressive hemicraniectomy. Cerebrovascular ultrasound detected a subtotally occluding thrombus in the right internal carotid artery and a partial occlusion of the ipsilateral MCA. After the surgery, complete recanalization of the affected vessels was observed. PMID- 23800503 TI - Predictors of stroke recurrence in patients with recent lacunar stroke and response to interventions according to risk status: secondary prevention of small subcortical strokes trial. AB - BACKGROUND: Among participants in the Secondary Prevention of Small Subcortical Strokes randomized trial, we sought to identify patients with high versus low rates of recurrent ischemic stroke and to assess effects of aggressive blood pressure control and dual antiplatelet therapy according to risk status. METHODS: Multivariable analyses of 3020 participants with recent magnetic resonance imaging-defined lacunar strokes followed for a mean of 3.7 years with 243 recurrent ischemic strokes. RESULTS: Prior symptomatic lacunar stroke or transient ischemic attack (TIA) (hazard ratio [HR] 2.2, 95% confidence interval [CI] 1.6, 2.9), diabetes (HR 2.0, 95% CI 1.5, 2.5), black race (HR 1.7, 95% CI 1.3, 2.3), and male sex (HR 1.5, 95% CI 1.1, 1.9) were each independently predictive of recurrent ischemic stroke. Recurrent ischemic stroke occurred at a rate of 4.3% per year (95% CI 3.4, 5.5) in patients with prior symptomatic lacunar stroke or TIA (15% of the cohort), 3.1% per year (95% CI 2.6, 3.9) in those with more than 1 of the other 3 risk factors (27% of the cohort), and 1.3% per year (95% CI 1.0, 1.7) in those with 0-1 risk factors (58% of the cohort). There were no significant interactions between treatment effects and stroke risk status. CONCLUSIONS: In this large, carefully followed cohort of patients with recent lacunar stroke and aggressive blood pressure management, prior symptomatic lacunar ischemia, diabetes, black race, and male sex independently predicted ischemic stroke recurrence. The effects of blood pressure targets and dual antiplatelet therapy were similar across the spectrum of independent risk factors and recurrence risk. PMID- 23800505 TI - Associations of collagen type I alpha2 polymorphisms with the presence of intracranial aneurysms in patients from Germany. AB - OBJECTIVE: Subarachnoid hemorrhage from ruptured intracranial aneurysms is associated with a severe prognosis. Preventive treatment of unruptured intracranial aneurysms is possible and recommended. However, the identification of risk patients by genetic analyses is not possible because of lack of candidate genes. Collagen type I alpha2 (COL1A2) has been associated with the presence of aneurysms in patients from Japan, China, and Korea. In this study, we investigate whether COL1A2 is a possible aneurysm candidate gene in the German population. METHODS: Patients admitted with intracranial aneurysms to our department and collaborating departments were enrolled. Three single-nucleotide polymorphisms (SNPs) of the COL1A2 gene, namely rs42524 in exon 28, rs1800238 in exon 32, and rs2621215 in intron 46 were investigated using restriction enzymes and sequencing. HapMap data were used for comparison of allelic frequencies with the normal population by chi2 test to identify significant associations between genotypes and the presence of aneurysms. RESULTS: Two hundred sixty-nine patients were enrolled into the study. There was a significant correlation with the presence of aneurysms for the GC allele of the SNP rs42524 in exon 28 (P = .02). The other polymorphisms did not show significant correlations. CONCLUSIONS: The COL1A2 gene is associated with intracranial aneurysms in a subset of the German population. However, it is not responsible for the majority of aneurysms, and further candidate genes need to be identified to develop sensitive genetic screening for patients at risk. PMID- 23800506 TI - Gravity-dependent nystagmus and inner-ear dysfunction suggest anterior and posterior inferior cerebellar artery infarct. AB - Cerebellar lesions may present with gravity-dependent nystagmus, where the direction and velocity of the drifts change with alterations in head position. Two patients had acute onset of hearing loss, vertigo, oscillopsia, nausea, and vomiting. Examination revealed gravity-dependent nystagmus, unilateral hypoactive vestibulo-ocular reflex (VOR), and hearing loss ipsilateral to the VOR hypofunction. Traditionally, the hypoactive VOR and hearing loss suggest inner ear dysfunction. Vertigo, nausea, vomiting, and nystagmus may suggest peripheral or central vestibulopathy. The gravity-dependent modulation of nystagmus, however, localizes to the posterior cerebellar vermis. Magnetic resonance imaging in our patients revealed acute cerebellar infarct affecting posterior cerebellar vermis, in the vascular distribution of the posterior inferior cerebellar artery (PICA). This lesion explains the gravity-dependent nystagmus, nausea, and vomiting. Acute onset of unilateral hearing loss and VOR hypofunction could be the manifestation of inner-ear ischemic injury secondary to the anterior inferior cerebellar artery (AICA) compromise. In cases of combined AICA and PICA infarction, the symptoms of peripheral vestibulopathy might masquerade the central vestibular syndrome and harbor a cerebellar stroke. However, the gravity dependent nystagmus allows prompt identification of acute cerebellar infarct. PMID- 23800507 TI - Myocardial mechanical remodeling after septal myectomy for severe obstructive hypertrophic cardiomyopathy. AB - BACKGROUND: Septal myectomy for symptomatic patients with hypertrophic obstructive cardiomyopathy (HOCM) is a well-established procedure for symptomatic relief. Myocardial mechanics are abnormal in patients with HOCM, demonstrating low longitudinal strain, high circumferential strain, and high apical rotation compared with healthy subjects. The aim of this study was to determine whether functional improvement after myectomy is associated with improved myocardial mechanics. METHODS: Clinical data and paired echocardiographic studies before and after myectomy (6-18 months) were retrospectively analyzed and compared in 66 patients (mean age, 54 +/- 13 years; 64% men) with HOCM. Myocardial mechanics including longitudinal and circumferential strain and rotation were assessed using two-dimensional strain software (Velocity Vector Imaging). RESULTS: Patients had significant symptomatic alleviation (mean New York Heart Association class, 2.8 +/- 0.4 at baseline and 1.3 +/- 0.5 after myectomy; P < .05). Left ventricular outflow gradient decreased dramatically (from 93 +/- 26 to 17 +/- 12 mm Hg; P < .05), and left atrial volume index decreased (from 48 +/- 16 to 37 +/- 13 cm(3)/m(2); P < .05). Low longitudinal strain decreased at the myectomy site, increased in the lateral segments, and remained unchanged globally (-16 +/- 4). High circumferential strain decreased (from -31 +/- 5 to -25 +/- 6, P < .05). High left ventricular twist normalized (from -15.5 +/- 6.2 degrees to 12.8 +/- 4.2 degrees , P < .05). Independent predictors of symptomatic response included younger age before myectomy, thinner posterior wall, and higher lateral early diastolic velocity (e'). CONCLUSION: In patients with HOCM, surgical myectomy alleviated symptoms, relieved obstruction, and decreased left atrial volume index. Longitudinal strain remained unchanged, but circumferential strain and rotation decreased, demonstrating different mechanical adaptations to chronic elevated afterload seen in patients with severe aortic stenosis undergoing valve replacement. Disease extent (age, posterior wall involvement) and the presence of diastolic dysfunction seem to be related to partial symptomatic response to myectomy. PMID- 23800508 TI - Derivation of mean pulmonary artery pressure from systolic pressure: implications for the diagnosis of pulmonary hypertension. PMID- 23800509 TI - Echo-Doppler assessment of arterial stiffness in pediatric patients with Kawasaki disease. AB - BACKGROUND: There is growing evidence to suggest increased arterial stiffness in patients with a history of Kawasaki disease (KD). Pulse-wave velocity (PWV) is the most validated measure of arterial stiffness. The aim of this study was to determine if aortic PWV is increased in children with KD. METHODS: This was a retrospective cohort study. The study cohort was composed of 42 patients with KD (mean age, 9.7 +/- 2.0 years) and 44 age-matched control subjects. The primary measure was aortic PWV. Secondary measures included characteristic impedance (Zc), input impedance (Zi), elastic pressure-strain modulus (Ep), and beta stiffness index and the following measures of left ventricular size and function: end-diastolic and end-systolic dimensions, wall thickness in diastole and systole, mass, shortening and ejection fractions, mean velocity of circumferential fiber shortening, and stress at peak systole. The appropriate measures were indexed to body surface area. The aortic stiffness and impedance indexes were derived using an echocardiography-Doppler method. RESULTS: Height, weight, body mass index, and body surface area were similar between the groups. PWV was higher in patients with KD compared with controls (495 vs 370 cm/sec, P = .0008). Zc, Ep, and beta stiffness index were higher in patients with KD, but the difference was not statistically significant. Left ventricular dimensions were all within normal limits, with no differences between the groups. Patients with KD had lower stress at peak systole compared with controls (55 vs 64 g/cm(2), P = .01). There was a significant association between the length of time between the initial diagnosis and testing with PWV (r = 0.32, P = .04) and Zi (r = -0.38, P = .01) in patients with KD. There was no significant association between the arterial stiffness indexes (PWV, Zi, Zc, Ep, and beta stiffness index) and length of fever, age at KD diagnosis, or heart rate. Logistic regression analysis revealed no association between coronary artery lesion classification and length of fever, day of illness at first treatment, age at KD diagnosis, or any of the arterial stiffness indexes. In the control group, there were significant associations between age and heart rate (r = -0.48, P = .001), Zi (r = -0.55, P < .0001), Zc (r = -0.66, P < .0001), and beta stiffness index (r = -0.31, P = .04). There was an association between heart rate and Zc (r = 0.44, P = .003) but no association between heart rate and PWV, Zi, Ep, or beta stiffness index. CONCLUSIONS: Arterial stiffness was increased in children with KD. There was no association between acute-phase KD coronary involvement and PWV. This implies that patients with KD may be at increased cardiovascular risk in the future. PMID- 23800510 TI - Cathepsin proteases promote angiogenic sprouting and laser-induced choroidal neovascularisation in mice. AB - Cysteine cathepsins are a family of proteases involved in intracellular protein turnover and extracellular matrix degradation. Cathepsin B (Ctsb) and cathepsin Z (Ctsz) promote tumorigenesis and Ctsb is a known modulator of tumor angiogenesis. We therefore investigated the angiomodulatory function of these cathepsins in vitro as well as in a mouse model of laser-induced choroidal neovascularization (laser-CNV). Ctsb(-/-), Ctsz(-/-), Ctsb/Ctsz double-knockout (Ctsb/z DKO), and wild type (WT) mice underwent argon laser treatment to induce choroidal neovascularization (CNV). The neovascularized area was quantified individually for each lesion at 14 days after laser coagulation. In vitro the effects of cathepsin inhibitors on angiogenesis were analysed by endothelial cell (EC) spheroid sprouting and EC invadosome assays. Retinas from cathepsin KO mice did not show gross morphological abnormalities. In the laser CNV model, however, Ctsb/z DKO mice displayed a significantly reduced neovascularized area compared to WT (0.027 mm(2) vs. 0.052 mm(2); p = 0.012), while single knockouts did not differ significantly from WT. In line, VEGF-induced EC spheroid sprouting and invadosome formation were not significantly altered by a specific cathepsin B inhibitor alone, but significantly suppressed when more than one cathepsin was inhibited. Our results demonstrate that laser-CNV formation is significantly reduced in Ctsb/z DKO mice. In line, EC sprouting and invadosome formation are blunted when more than one cathepsin is inhibited in vitro. These results reveal an angiomodulatory potential of cathepsins with partial functional redundancies between different cathepsin family members. PMID- 23800511 TI - Anterior and posterior corneal stroma elasticity assessed using nanoindentation. AB - Corneal biomechanics is an essential parameter for developing diagnostic and treatment methods of corneal-related diseases. It is widely accepted that corneal mechanical strength stems from the stroma's collagenous composition. However, more comprehensive insight into the mechanical properties within the stroma is needed to improve current corneal diagnostic and treatment techniques. The purpose of this study was to perform elasticity characterization of anterior and posterior stromal regions of human corneas using atomic force microscopy (AFM). Nine pairs of human whole globes were placed in 20% Dextran solution, cornea side down, to restore the corneal thickness to physiological levels (400-600 MUm). The epithelium and Bowman's membrane were removed from all eyes. Anterior stromal AFM elasticity testing was then performed on left (OS) eyes. Additional stroma was removed from right (OD) eyes to allow posterior stromal measurements at a depth of 50% of the original thickness. All experiments were performed with corneas submerged in 15% Dextran to maintain corneal hydration. The results of the study showed that the Young's modulus of elasticity of the anterior stroma (average: 281 +/- 214 kPa; range: 59-764 kPa) was significantly higher than that of the posterior stroma (average: 89.5 +/- 46.1 kPa; range: 29-179 kPa) (p = 0.014). In addition, a linear relationship was found between the posterior stromal elasticity and anterior stromal elasticity (p = 0.0428). On average, the elasticity of the posterior stroma is 39.3% of the anterior stroma. In summary, there appears to be an elasticity gradient within the corneal stroma, which should be considered in the design and development of corneal diagnostic and treatment methods to enhance efficacy. PMID- 23800512 TI - Is octreotide beneficial in patients undergoing pancreaticoduodenectomy? Best evidence topic (BET). AB - A best evidence topic was written according to a structured protocol. The question addressed was whether the prophylactic administration of somatostatin or somatostatin analogues in patients undergoing pancreaticoduodenectomy (Whipple's procedure) is beneficial in terms of improved surgical outcomes, reduced morbidity or reduced mortality. A total of 118 papers were found using the reported searches of which 5 represented the best evidence (1 meta-analysis, 1 systematic review and 3 randomized control trials). The authors, date, journal, study type, population, main outcome measures and results were tabulated. There is evidence that the perioperative administration of somatostatin or somatostatin analogues reduces biochemical incidence of pancreatic fistula but, it is still unclear if there is a beneficial effect in the incidence of clinically significant pancreatic fistula. Further adequately powered trials with low risk of bias are necessary. From the available data, somatostatin or somatostatin analogues have no effect on mortality post Whipple's. Interestingly, there are only limited data available on the cost-benefit and financial constraints imposed by this treatment, an issue that has only been addressed in a few studies. PMID- 23800513 TI - Ailing bones and failing kidneys: a case of chronic cadmium toxicity. AB - Heavy metal toxicity is often caused by occupational exposure. Chronic cadmium toxicity is a significant health concern among workers engaged in zinc smelting, battery production and silver jewellery industries, particularly in developing countries. We report the case of a 48-year-old man who presented with severe osteoporosis, impaired renal function and acquired Fanconi syndrome. He was finally diagnosed with chronic cadmium toxicity resulting from long-term occupational exposure. Cadmium has a long biological half-life and there is no effective treatment for people who are exposed to it. Therefore, an early diagnosis and prevention of further exposure are important. PMID- 23800514 TI - Modelling interventions during a dengue outbreak. AB - We present a stochastic dynamical model for the transmission of dengue that considers the co-evolution of the spatial dynamics of the vectors (Aedes aegypti) and hosts (human population), allowing the simulation of control strategies adapted to the actual evolution of an epidemic outbreak. We observed that imposing restrictions on the movement of infected humans is not a highly effective strategy. In contrast, isolating infected individuals with high levels of compliance by the human population is efficient even when implemented with delays during an ongoing outbreak. We also studied insecticide-spraying strategies assuming different (hypothetical) efficiencies. We observed that highly efficient fumigation strategies seem to be effective during an outbreak. Nevertheless, taking into account the controversial results on the use of spraying as a single control strategy, we suggest that carrying out combined strategies of fumigation and isolation during an epidemic outbreak should account for a suitable strategy for the attenuation of epidemic outbreaks. PMID- 23800515 TI - Bone micro-architecture, estimated bone strength, and the muscle-bone interaction in elite athletes: an HR-pQCT study. AB - Athletes participating in sports characterized by specific loading modalities have exhibited different levels of augmentation of bone properties; however, the extent to which these loading environments affect bone micro-architecture and estimated bone strength (i.e., bone quality) remains unclear. Furthermore, the relative role of impact loading versus loading due to muscle forces in determining bone properties is confounded. The objectives of this study were 1) to examine the role of impact loading on bone quality of the distal radius and distal tibia in elite athletes, as determined by high resolution peripheral quantitative computed tomography (HR-pQCT) and finite element analysis (FEA), and 2) to investigate the relationship between bone quality and muscle strength in elite athletes. Ninety-five females (n=59) and males (n=36) between the ages of 16-30 years participated in the study. Participants included alpine skiers (high impact), soccer players (moderate impact), swimmers (low-impact), and non athletic controls. All group comparisons were made after accounting for age, height, and body mass. As expected, minimal differences in HR-pQCT parameters across groups were observed at the non weight-bearing distal radius. At the weight-bearing distal tibia, female alpine skiers and soccer players had significantly higher bone density, cortical thickness, and failure load (i.e., bone strength (N) in compression estimated by FEA) than swimmers (p<0.05). Female alpine skiers also had lower trabecular separation than swimmers and controls. Male alpine skiers had 20% higher trabecular bone mineral density than swimmers, and male soccer players exhibited 22% higher trabecular number than swimmers at the distal tibia (p<0.05). Male alpine skiers and soccer players had 28-38% higher failure load at the distal tibia than swimmers. No differences in bone parameters were observed between swimmers and controls for either sex at either site. Both muscle strength and sporting activity were predictors of failure load at the distal tibia in the female cohort. Sporting activity, but not muscle strength, was a significant predictor of failure load in the male cohort at both the radius and tibia. This data suggests that impact loading in sporting activity is highly associated with bone quality. Longitudinal and interventional studies are required to further clarify the muscle-bone interaction. PMID- 23800516 TI - Five-year fracture risk estimation in patients with Parkinson's disease. AB - BACKGROUND: Previous studies have shown that patients with Parkinson's disease (PD) are at increased risk of fractures. However, no specific prediction model for fracture estimation among PD patients is currently available. Therefore, the aim of this study was to develop a simple score for estimating the 5-year osteoporotic and hip fracture risks among patients with PD. METHODS: The U.K. Clinical Practice Research Datalink (1987-2011) was used to identify incident PD patients. Cox proportional-hazards models were used to calculate the 5-year risks of osteoporotic and hip fracture among PD patients. The regression model was fitted with various risk factors for fracture and the final Cox model was converted into integer risk scores. RESULTS: We identified 4411 incident PD patients without a history of osteoporotic treatment. The 5-year risks of osteoporotic and hip fracture were plotted in relation to the risk score. Risk scores increased with age, female gender, history of renal disease and history of dementia. The C-statistic, which is a parameter to test the internal validity of the model, was reasonable for the prediction of osteoporotic fracture (0.69) and hip fracture (0.73). CONCLUSION: In this study, we developed a simple model to estimate 5-year fracture risk among incident PD patients. It may be useful in daily practice after external validation. PMID- 23800517 TI - Determinants of bone marrow adiposity: the modulation of peroxisome proliferator activated receptor-gamma2 activity as a central mechanism. AB - Although the presence of adipocytes in the bone marrow is a normal physiological phenomenon, the role of these cells in bone homeostasis and during pathological states has not yet been fully delineated. As osteoblasts and adipocytes originate from a common progenitor, with an inverse relationship existing between osteoblastogenesis and adipogenesis, bone marrow adiposity often negatively correlates with osteoblast number and bone mineral density. Bone adiposity can be affected by several physiological and pathophysiological factors, with abnormal, elevated marrow fat resulting in a pathological state. This review focuses on the regulation of bone adiposity by physiological factors, including aging, mechanical loading and growth factor expression, as well as the pathophysiological factors, including diseases such as anorexia nervosa and dyslipidemia, and pharmacological agents such as thiazolidinediones and statins. Although these factors regulate bone marrow adiposity via a plethora of different intracellular signaling pathways, these diverse pathways often converge on the modulation of the expression and/or activity of the pro-adipogenic transcription factor peroxisome proliferator-activated receptor (PPAR)-gamma2, suggesting that any factor that affects PPAR-gamma2 may have an impact on the fat content of bone. PMID- 23800518 TI - Cold weather threats to health: how does Europe prepare? PMID- 23800519 TI - Early-onset drinking in Ireland: negative outcomes and behaviours. PMID- 23800521 TI - Welcome to the new seminars. PMID- 23800520 TI - Fallout from the Chernobyl accident and overall cancer incidence in Finland. AB - AIM: We studied whether incidence of all cancer sites combined was associated with the radiation exposure due to fallout from the Chernobyl accident in Finland. An emphasis was on the first decade after the accident to assess the suggested "promotion effect". METHODS: The segment of Finnish population with a stable residence in the first post-Chernobyl year (2 million people) was studied. The analyses were based on a 250m * 250m grid squares covering all of Finland and all cancer cases except cancers of the breast, prostate and lung. Cancer incidence in four exposure areas (based on first-year dose due to external exposure <0.1 mSv, 0.1-1.3, 0.3-0.5, or >= 0.5 mSv) was compared before the Chernobyl accident (1981-1985) and after it (1988-2007) taking into account cancer incidence trends for a longer period prior to the accident (since 1966). RESULTS: There were no systematic differences in the cancer incidence in relation to radiation exposure in any calendar period, or any subgroup by sex or age at accident. CONCLUSION: The current large and comprehensive cohort analysis of the relatively low levels of the Chernobyl fallout in Finland did not observe a cancer promotion effect. PMID- 23800522 TI - Racial disparities and lung cancer care: why the unequal playing field? AB - The existence of disparities within our healthcare system is receiving considerable national attention, as we seek to understand the magnitude of these disparities with the goal of eliminating them altogether. Herein, we review recent important work that captures the current progress in this important area that has direct implications for the thoracic surgeon's daily practice management. PMID- 23800523 TI - Molecular prognostication of non-small cell lung cancer. PMID- 23800524 TI - A radiation oncologist's and thoracic surgeon's view on the role of stereotactic ablative radiotherapy for operable lung cancer. AB - Stereotactic ablative radiotherapy, also known as stereotactic body radiation therapy, has been developed as an innovative therapy for stage I non-small cell lung cancer and has now emerged as a standard treatment option for medically inoperable patients through careful analysis using prospective multi institutional trials. We review and update the evidence for use of stereotactic ablative radiotherapy in medically inoperable patients with stage I lung cancer, and its possible extension of use to operable patients, from the perspectives of an experienced radiation oncologist and a thoracic surgeon. PMID- 23800525 TI - Current readings: pathology, prognosis, and lung cancer. AB - The 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma introduced the new categories of adenocarcinoma in situ, minimally invasive adenocarcinoma, and invasive mucinous adenocarcinoma, and replaced the category of mixed subtype adenocarcinoma with lepidic, acinar, papillary, micropapillary, and solid predominant adenocarcinoma. The aim of this manuscript is to evaluate whether the new classification can be applied successfully in determining prognosis of surgically resected patients. Six consecutive clinicopathologic studies using the new classification that were published between spring 2011 and fall 2012 were reviewed. Overall, they demonstrated excellent outcome for adenocarcinoma in situ and minimally invasive adenocarcinoma; intermediate outcome for lepidic, acinar, and papillary predominant adenocarcinoma; and poor outcome for solid and micropapillary predominant adenocarcinoma and invasive mucinous adenocarcinoma. As the new classification remains a proposal at this time, it is hoped that thoracic surgeons will play a leading role in its worldwide dissemination for clinical care and research. PMID- 23800526 TI - Current readings: sublobar resection for non-small-cell lung cancer. AB - The Lung Cancer Study Group consensus recommending lobectomy for stage I non small-cell lung cancer (NSCLC) to reduce local recurrence associated with sublobar resections has directed NSCLC care since its 1995 publication. However, enhancements in imaging technology and in our understanding of the molecular biology of NSCLC over the past 2 decades have produced large cohorts of patients with smaller, better staged, and more indolent tumors than evaluated by the Lung Cancer Study Group. Numerous single-institution trials have demonstrated that in well-selected patients, sublobar resection can afford comparable survival and recurrence rates with lobectomy with a more favorable risk profile. This review of recent literature will focus on 2 separate issues with regard to the use of sublobar resections for stage I NSCLC: (1) a comparison to nonoperative ablative therapies in medically unfit patients, and (2) identifying in which subset of the noncompromised standard-risk population, sublobar resections provide equivalent outcome to lobectomy. PMID- 23800527 TI - Current readings: status of tricuspid valve repair. AB - The surgical management of mitral and aortic valvular heart disease has changed significantly over the last decade. Meanwhile, tricuspid valve (TV) surgery has remained less commonly performed than left-sided valve surgeries, and there is a relative paucity of reports in the literature. There are ongoing controversies as to the optimal surgical management of TV disease, including repair versus replacement, the type of prosthesis preferred, optimal repair techniques, appropriate management of functional tricuspid regurgitation (TR) with concomitant left heart valve surgery, and others. In this article, we review what we believe are five important and contemporary papers that cover important aspects of TV surgery and provide recommendations for the surgical management of TV disease. PMID- 23800528 TI - Inaugural discussions in cardiothoracic treatment and care: surgery for esophageal cancer, November 16, 2012, Boston, MA. PMID- 23800529 TI - Current status of left ventricular assist device technology. AB - The use of long-term left ventricular assist devices (LVADs) has revolutionized the treatment of end-stage heart failure. The most significant advance in this field has been the longer durability of devices secondary to a simpler pump design with fewer or no mechanical bearings and valves. Continuous-flow LVADs have recently been shown to provide safe and effective circulatory support and have replaced the first-generation fill-to-empty devices. The Thoratec HeartMate II and the HeartWare HVAD are currently the 2 most commonly implanted LVADs worldwide. As LVAD technology moves forward and new miniaturized, more durable, and reliable pumps are being developed, the number of recipients who will benefit from this technology continues to grow. Elimination of the driveline with fully implantable pumps, implantation of miniature pumps with minimally invasive surgical techniques, wireless data transmission, and improved patient selection will further transform this field in the next few years. PMID- 23800530 TI - The state of the art in heart transplantation. AB - Cardiac transplantation is in its fourth decade as a treatment for end-stage cardiomyopathy and heart failure. It has reached a mature stage in its development as an effective treatment and many issues are settled with respect to best practices. However, there are many areas of ongoing research and significant advances that are continually being recognized. What constitutes 'State of the Art' in heart transplantation? This review focuses on developments in the pretransplant, peritransplant, and posttransplant phases of the care of the potential heart transplant recipient. PMID- 23800531 TI - Artificial lung and novel devices for respiratory support. AB - There is a growing demand for new technology that can take over the function of the human lung, whether it is to assist an injured or recently transplanted lung or to completely replace the native lung. The use of extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation was reported for the first time more than 3 decades ago; nevertheless, its use in lung transplantation was largely abandoned owing to poor patient survival and frequent complications. ECMO as a bridge to lung transplantation has significantly increased during the past 10 years. This increase in utilization is reflected in the growing success reported with the use of different ECMO modalities in patients awaiting lung transplantation. The use of ECMO is now being considered in awake and nonintubated patients so as to improve oxygenation, facilitate ambulation, and improve physical conditioning before transplant. Several programs have developed ambulatory capability of most forms of ECMO, and ambulatory ECMO is now often referred to as the "artificial lung." We present a brief description of the evolution of the use of ECMO in lung transplantation and summarize the available technology and current approaches to provide ECMO support. PMID- 23800532 TI - How to teach robotic pulmonary resection. PMID- 23800533 TI - Within-center matching performed better when using propensity score matching to analyze multicenter survival data: empirical and Monte Carlo studies. AB - OBJECTIVE: Propensity score (PS) methods are applied frequently to multicenter data. To date, methods for handling cluster effect when analyzing PS-matched data have not been assessed for survival data. Accordingly, the objective of the present study was to determine the optimal PS-model to account for a potential cluster effect when analysing multicenter observational data. STUDY DESIGN AND SETTING: In the current study, five strategies were compared. One analyzed the original sample and four used global or within-cluster matching using a global or a cluster-specific PS. All were applied to simulated data sets and to two cohorts. RESULTS: Failing to account for clustering in the PS model led to a biased estimate of the treatment effect and to an inflated test size. Within cluster matching using either a global or a cluster-specific PS led to the lowest mean squared error and to a test size close to its nominal value. However, the cluster-specific approach led to a drastic reduction of sample size compared with the global PS one. Analyses of the cohorts confirmed that the latter model led to the smallest sample size, but also necessitated the discard of a high number of clusters from the matched sample. CONCLUSION: In the considered simulation scenarios, within-cluster matching using a global PS presented the best balance between sample size and bias reduction, and it should be used when applying PS methods to clustered observational survival data. PMID- 23800534 TI - Drug exposure: inclusion of dispensed drugs before pregnancy may lead to underestimation of risk associations. AB - OBJECTIVES: To assess the impact of exposure misclassification on risk associations when using prescription databases as the source for drug exposure in pregnancy by applying results from a validation analysis of exposure classification. STUDY DESIGN AND SETTING: Linkage of data on 27,656 participants in the Norwegian Mother and Child Cohort Study (MoBa) with the Norwegian Prescription Database (NorPD). Exposure to selective serotonin reuptake inhibitors (SSRIs) was defined by dispensed drugs during pregnancy including different time windows before pregnancy. The validity of NorPD data was estimated using self-reported use in MoBa as the reference standard. We applied the results from the validation analysis on data from a Nordic study on SSRI use in pregnancy and risk of persistent pulmonary hypertension in the newborn. RESULTS: Sensitivity increased and specificity decreased when the time window in NorPD was expanded before pregnancy. Using the same time window as in the Nordic study (+90 days before pregnancy), for use in early pregnancy, the odds ratio (OR) corrected for misclassification was 2.6 compared with the OR of 1.6 in the Nordic study. CONCLUSION: Expansion of the time window to include intervals before pregnancy can lead to lower specificity and underestimation of risk associations. PMID- 23800535 TI - Identification of calcium-transporting ATPases of Entamoeba histolytica and cellular localization of the putative SERCA. AB - Calcium has an important role on signaling of different cellular processes in the protozoa parasite Entamoeba histolytica, including development and pathogenesis. However, the systems that control calcium responses in this parasite are incompletely understood. Calcium-ATPases (Ca(2+)-ATPases) are proteins that play an important role in calcium homeostasis by catalyzing the active efflux of this ion from cytoplasm and are essential to the correct functioning of the cell machinery. Here, we reported the identification of five E. histolytica genes encoding putative Ca(2+)-ATPases, three related to PMCA, and two related to organellar ATPases. RT-PCR assays showed that all those genes are expressed in trophozoites and specific antibodies against the SERCA-like member located this protein in a continuous cytoplasmic network, supporting the hypothesis that it corresponds to the Ca(2+)-ATPase responsible to sequester calcium in the endoplasmic reticulum of this parasite. PMID- 23800536 TI - 2DPCA with L1-norm for simultaneously robust and sparse modelling. AB - Robust dimensionality reduction is an important issue in processing multivariate data. Two-dimensional principal component analysis based on L1-norm (2DPCA-L1) is a recently developed technique for robust dimensionality reduction in the image domain. The basis vectors of 2DPCA-L1, however, are still dense. It is beneficial to perform a sparse modelling for the image analysis. In this paper, we propose a new dimensionality reduction method, referred to as 2DPCA-L1 with sparsity (2DPCAL1-S), which effectively combines the robustness of 2DPCA-L1 and the sparsity-inducing lasso regularization. It is a sparse variant of 2DPCA-L1 for unsupervised learning. We elaborately design an iterative algorithm to compute the basis vectors of 2DPCAL1-S. The experiments on image data sets confirm the effectiveness of the proposed approach. PMID- 23800537 TI - Prevalence and predictors of persistent versus remitting mood, anxiety, and substance disorders in a national sample of older adults. AB - OBJECTIVES: Relatively little is known about whether mental disorders other than depression remit versus persist in later life, especially within nationally representative samples. Our objectives were to examine the prevalence of persistent mood, anxiety, and substance disorders in older adults and to explore a range of physical and mental health predictors of disorder chronicity. METHODS: This study involved a 3-year follow-up design using Wave 1 (2001-2002) and Wave 2 (2004-2005) of the National Epidemiologic Survey on Alcohol and Related Conditions. Participants included 1,994 adults aged 55 years and older who had a past-year mental disorder at Wave 1 and who completed Wave 2. The primary outcome was the prevalence of persistent mood, anxiety, and substance disorders at Wave 2. Potential predictors of persistence included sociodemographic variables, physical health (chronic health conditions and physical health-related quality of life), and mental health (childhood adversity, suicide attempts, mental health related quality of life, comorbid mental disorders, personality disorders, and lifetime treatment-seeking). RESULTS: With the exception of nicotine dependence, the prevalence of persistent mood, anxiety, and substance disorders ranged from 13% to 33%. Only younger age predicted substance disorder chronicity. Significant predictors of persistent mood and anxiety disorders included physical and mental health comorbidity, physical health- and mental health-related quality of life, suicide attempts, comorbid personality disorders, and treatment-seeking. CONCLUSIONS: At least two-thirds of mental disorders in these older adults were not persistent. Sociodemographic variables had little influence on chronicity, whereas a number of markers of mental disorder severity and complexity predicted persistent mood and anxiety disorders. The findings have important treatment and prevention implications. PMID- 23800538 TI - Sex hormone binding globulin and verbal memory in older men. AB - OBJECTIVE: Cognitive function in older adults may be affected by multiple factors, such as sex hormone levels, metabolic disturbances, and neuropsychiatric illness. However, relatively few studies have tested the associations between these factors and cognitive function in a single sample. A cross-sectional analysis was conducted to examine the association between sex hormones, metabolic parameters, and psychiatric diagnoses with verbal memory in nondemented older men. METHODS: Participants were 112 men (mean age: 61.3 years) from the Baltimore Epidemiologic Catchment Area Follow-Up Study who completed measures of blood sex hormone levels, metabolic parameters (e.g., lipid profiles), and verbal memory. RESULTS: Higher levels of serum sex hormone binding globulin (SHBG) were associated with lower delayed verbal memory scores (standardized coefficients [beta]=-0.19, t=-2.07, df=1, 105, p=0.04), and higher body mass index (BMI) was associated with better immediate (beta=0.21, t=2.41, df=1,105, p=0.02) and delayed (beta=0.22, t=2.46, df=1,105, p=0.02) verbal memory performance after adjustment for age, education, and psychiatric disorders. There was an inverse correlation between SHBG levels and BMI (Pearson's r=-0.37, N=112, p<0.001). Estimated free testosterone levels revealed curvilinear associations with verbal memory performance. CONCLUSION: Our data suggest that higher SHBG levels are associated with worse verbal memory, whereas a higher BMI is associated with better verbal memory in older men. Higher SHBG levels due to lower adiposity may be a risk factor for cognitive dysfunction. The mechanisms linking SHBG to cognitive function have yet to be elucidated. PMID- 23800539 TI - A threshold concentration of anti-merozoite antibodies is required for protection from clinical episodes of malaria. AB - Antibodies to selected Plasmodium falciparum merozoite antigens are often reported to be associated with protection from malaria in one epidemiological cohort, but not in another. Here, we sought to understand this paradox by exploring the hypothesis that a threshold concentration of antibodies is necessary for protection. We analyzed data from two independent cohorts along the Kenyan coast, one in which antibodies to AMA1, MSP-2 and MSP-3 were associated with protection from malaria (Chonyi) and another in which this association was not observed (Junju). We used a malaria reference reagent to standardize antibody measurements across both cohorts, and applied statistical methods to derive the threshold concentration of antibodies against each antigen that best correlated with a reduced risk of malaria (the protective threshold), in the Chonyi cohort. We then tested whether antibodies in Junju reached the protective threshold concentrations observed in the Chonyi cohort. Except for children under 3 years, the age-matched proportions of children achieving protective threshold concentrations of antibodies against AMA1 and MSP-2 were significantly lower in Junju compared to Chonyi (Fishers exact test, P<0.01). For MSP-3, this difference was significant only among 4-5 year olds. We conclude that although antibodies are commonly detected in malaria endemic populations, they may be present in concentrations that are insufficient for protection. Our results have implications for the analysis and interpretation of similar data from immuno epidemiological studies. PMID- 23800541 TI - Enhancing access to immunization services and exploiting the benefits of recent innovations in the African region. AB - The African Regional Office of the World Health Organization (WHO AFRO) organized the annual regional conference on immunization (ARCI) from 10 to 12 December 2012 in Dar es Salaam, Tanzania, under the theme, "Innovations, access and the right of all to vaccines". The meeting reviewed the status of immunization in the region and identified all innovations, strategies and technologies available and how these could be fully utilized to enhance the access and the rights of all to vaccines. Over 50 oral presentations were made in plenary and parallel sessions of the conference which was attended by over 200 participants drawn from national immunization programs, academia, public health experts and immunization partners. In addition there were 40 poster presentations. This manuscript summarizes of the meeting, highlighting the innovations in immunization being piloted or scaled-up, their impact and suggesting ways to further improve immunization service delivery for the eradication, elimination and control of vaccine-preventable diseases in the region. PMID- 23800540 TI - Feline immunodeficiency virus (FIV) vaccine efficacy and FIV neutralizing antibodies. AB - A HIV-1 tier system has been developed to categorize the various subtype viruses based on their sensitivity to vaccine-induced neutralizing antibodies (NAbs): tier 1 with greatest sensitivity, tier 2 being moderately sensitive, and tier 3 being the least sensitive to NAbs (Mascola et al., J Virol 2005; 79:10103-7). Here, we define an FIV tier system using two related FIV dual-subtype (A+D) vaccines: the commercially available inactivated infected-cell vaccine (Fel-O Vax((r)) FIV) and its prototype vaccine solely composed of inactivated whole viruses. Both vaccines afforded combined protection rates of 100% against subtype A tier-1 FIVPet, 89% against subtype-B tier-3 FIVFC1, 61% against recombinant subtype-A/B tier-2 FIVBang, 62% against recombinant subtype-F'/C tier-3 FIVNZ1, and 40% against subtype-A tier-2 FIVUK8 in short-duration (37-41 weeks) studies. In long-duration (76-80 weeks) studies, the commercial vaccine afforded a combined protection rate of at least 46% against the tier-2 and tier-3 viruses. Notably, protection rates observed here are far better than recently reported HIV 1 vaccine trials (Sanou et al., The Open AIDS J 2012; 6:246-60). Prototype vaccine protection against two tier-3 and one tier-2 viruses was more effective than commercial vaccine. Such protection did not correlate with the presence of vaccine-induced NAbs to challenge viruses. This is the first large-scale (228 laboratory cats) study characterizing short- and long-duration efficacies of dual subtype FIV vaccines against heterologous subtype and recombinant viruses, as well as FIV tiers based on in vitro NAb analysis and in vivo passive-transfer studies. These studies demonstrate that not all vaccine protection is mediated by vaccine-induced NAbs. PMID- 23800542 TI - Reduction of cerebral Abeta burden and improvement in cognitive function in Tg APPswe/PSEN1dE9 mice following vaccination with a multivalent Abeta3-10 DNA vaccine. AB - To develop a safe and efficient Abeta vaccine for Alzheimer's disease, we constructed a plasmid DNA vaccine encoding ten repeats of Abeta3-10 and three copies of C3d-p28 as a molecular adjuvant and administered it intramuscularly in 12-month-old female Tg-APPswe/PSEN1dE9 mice. Therapeutic immunization with p(Abeta3-10)10-C3d-p28.3 stimulated a Th2 immune response that elicited therapeutic levels of anti-Abeta antibodies and improved cognitive function. In addition, the vaccine reduced the cerebral Abeta burden and astrocytosis without increasing the incidence of microhemorrhage. Our results indicate that the p(Abeta3-10)10-C3d-p28.3 vaccine is a promising immunotherapeutic option for Abeta vaccination in Alzheimer's disease. PMID- 23800543 TI - Effects of transcranial direct current stimulation on language improvement and cortical activation in nonfluent variant primary progressive aphasia. AB - We investigate the effects of transcranial direct current stimulation (tDCS) on language improvement and cortical activation in nonfluent variant primary progressive aphasia (nfvPPA). A 67-year-old woman diagnosed as nfvPPA received sham-tDCS for 5 days over the left posterior perisylvian region (PPR) in the morning and over left Broca's area in the afternoon in Phases A1 and A2, and tDCS for 5 days with an anodal electrode over the left PPR in the morning and over left Broca's area in the afternoon in Phases B1 and B2. Auditory word comprehension, picture naming, oral word reading and word repetition subtests of the Psycholinguistic Assessment in Chinese Aphasia (PACA) were administered before and after each phase. The EEG nonlinear index of approximate entropy (ApEn) was calculated before Phase A1, and after Phases B1 and B2. Our findings revealed that the patient improved greatly in the four subtests after A-tDCS and ApEn indices increased in stimulated areas and non-stimulated areas. We demonstrated that anodal tDCS over the left PPR and Broca's area can improve language performance of nfvPPA. tDCS may be used as an alternative therapeutic tool for PPA. PMID- 23800544 TI - External validation and updating of a prediction model for nosocomial pneumonia after coronary artery bypass graft surgery. AB - The generalizability of a prediction model from North America for incident nosocomial pneumonia following coronary artery bypass graft surgery was assessed for 23247 patients on the Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) registry. The performance of the North American model was evaluated using measures of calibration and discrimination. The model had reasonable discrimination (area under the receiver-operating characteristic curve, AUC=0.69), but unsatisfactory calibration (Hosmer-Lemeshow test, P<0.001) in the ANZSCTS patients. An update of the model coefficients yielded a model with AUC=0.71 and good calibration (P=0.46). PMID- 23800546 TI - The role of animacy in Chinese relative clause processing. AB - Two experiments investigated Chinese relative clause processing by manipulating the animacy of the head noun phrases in the matrix clause (hereafter called head NPs) and in the embedded clause (hereafter called relative-clause-internal NPs) in a self-paced reading paradigm. Experiment 1 showed that subject-modifying object relative clauses (S-ORCs) were easier to process than subject-modifying subject relative clauses (S-SRCs) under animate-inanimate configuration (animate relative-clause-internal NPs and inanimate head NPs), but S-SRCs were easier to process than S-ORCs under inanimate-animate configuration (inanimate relative clause-internal NPs and animate head NPs). Experiment 2 showed that object modifying object relative clauses (O-ORCs) were easier to process than object modifying subject relative clauses (O-SRCs) under both animacy configurations. These results suggest that animacy configuration of the relative-clause-internal NPs and the head NPs plays an important role in Chinese relative clause processing. These results can be explained by thematic fit accounts. PMID- 23800545 TI - The papillomavirus major capsid protein L1. AB - The elegant icosahedral surface of the papillomavirus virion is formed by a single protein called L1. Recombinant L1 proteins can spontaneously self-assemble into a highly immunogenic structure that closely mimics the natural surface of native papillomavirus virions. This has served as the basis for two highly successful vaccines against cancer-causing human papillomaviruses (HPVs). During the viral life cycle, the capsid must undergo a variety of conformational changes, allowing key functions including the encapsidation of the ~8 kb viral genomic DNA, maturation into a more stable state to survive transit between hosts, mediating attachment to new host cells, and finally releasing the viral DNA into the newly infected host cell. This brief review focuses on conserved sequence and structural features that underlie the functions of this remarkable protein. PMID- 23800547 TI - Prevalence of troponin elevations in patients with cardiac arrest and implications for assessing quality of care in hypothermia centers. AB - The prevalence of troponin elevations in patients with cardiac arrest (CA) using newer generation troponin assays when the ninety-ninth percentile is used has not been well described. We studied patients admitted with CA without ST elevation myocardial infarction (MI). Treatment included a multidisciplinary protocol that included routine use of hypothermia for appropriate patients. Serial assessment of cardiac biomarkers, including troponin I was obtained over the initial 24 to 36 hours. Patients were classified into 1 of 5 groups on the basis of multiples of the ninety-ninth percentile (upper reference limit [URL]), using the peak troponin I value: <1*, 1 to 3*, 3 to 5*, 5 to 10*, and >10*. Serial changes between the initial and second troponin I values were also assessed. A total of 165 patients with CA (mean age 58 +/- 16, 67% men) were included. Troponin I was detectable in all but 2 patients (99%); all others had peak troponin I values that were greater than or equal to the URL. Most patients had peak troponin I values >10* URL, including patients with ventricular fibrillation or ventricular tachycardia (85%), asystole (50%), and pulseless electrical activity (59%). Serial changes in troponin I were present in almost all patients: >=20% change in 162 (98%), >=30% change in 159 (96%), and an absolute increase of >=0.02 ng/ml in 85% of patients. In conclusion, almost all patients with CA who survived to admission had detectable troponin I, most of whom met biomarker guideline criteria for MI. Given the high mortality of these patients, these data have important implications for MI mortality reporting at CA treatment centers. PMID- 23800548 TI - Cardiac steatosis and left ventricular hypertrophy in patients with generalized lipodystrophy as determined by magnetic resonance spectroscopy and imaging. AB - Generalized lipodystrophy is a rare disorder characterized by marked loss of adipose tissue with reduced triglyceride storage capacity, leading to a severe form of metabolic syndrome including hypertriglyceridemia, insulin resistance, type 2 diabetes mellitus, and hepatic steatosis. Recent echocardiographic studies suggest that concentric left ventricular (LV) hypertrophy is another characteristic feature of this syndrome, but the mechanism remains unknown. It has recently been hypothesized that the LV hypertrophy could be an extreme clinical example of "lipotoxic cardiomyopathy": excessive myocyte accumulation of triglyceride leading to adverse hypertrophic signaling. To test this hypothesis, the first cardiac magnetic resonance study of patients with generalized lipodystrophy was performed, using magnetic resonance imaging and localized proton spectroscopy to detect excessive triglyceride content in the hypertrophied myocytes. Six patients with generalized lipodystrophy and 6 healthy controls matched for age, gender, and body mass index were studied. As hypothesized, myocardial triglyceride content was threefold higher in patients than controls: 0.6 +/- 0.2% versus 0.2 +/- 0.1% (p = 0.004). The presence of pericardial fat was also found, representing a previously undescribed adipose depot in generalized lipodystrophy. Patients with generalized lipodystrophy, compared with controls, also had a striking degree of concentric LV hypertrophy, independent of blood pressure: LV mass index 101.0 +/- 18.3 versus 69.0 +/- 17.7 g/m(2), respectively (p = 0.02), and LV concentricity 1.3 +/- 0.3 versus 0.99 +/- 0.1 g/ml, respectively (p = 0.04). In conclusion, these findings advance the lipotoxicity hypothesis as a putative underlying mechanism for the dramatic concentric LV hypertrophy found in generalized lipodystrophy. PMID- 23800549 TI - Real-time three-dimensional transesophageal echocardiography in the assessment of mechanical prosthetic mitral valve ring thrombosis. AB - Although 2-dimensional (2D) transesophageal echocardiography (TEE) is the gold standard for the diagnosis of prosthetic valve thrombosis, nonobstructive clots located on mitral valve rings can be missed. Real-time 3-dimensional (3D) TEE has incremental value in the visualization of mitral prosthesis. The aim of this study was to investigate the utility of real-time 3D TEE in the diagnosis of mitral prosthetic ring thrombosis. The clinical outcomes of these patients in relation to real-time 3D transesophageal echocardiographic findings were analyzed. Of 1,263 patients who underwent echocardiographic studies, 174 patients (37 men, 137 women) with mitral ring thrombosis detected by real-time 3D TEE constituted the main study population. Patients were followed prospectively on oral anticoagulation for 25 +/- 7 months. Eighty-nine patients (51%) had thrombi that were missed on 2D TEE and depicted only on real-time 3D TEE. The remaining cases were partially visualized with 2D TEE but completely visualized with real time 3D TEE. Thirty-seven patients (21%) had thromboembolism. The mean thickness of the ring thrombosis in patients with thromboembolism was greater than that in patients without thromboembolism (3.8 +/- 0.9 vs 2.8 +/- 0.7 mm, p <0.001). One hundred fifty-five patients (89%) underwent real-time 3D TEE during follow-up. There were no thrombi in 39 patients (25%); 45 (29%) had regression of thrombi, and there was no change in thrombus size in 68 patients (44%). Thrombus size increased in 3 patients (2%). Thrombosis was confirmed surgically and histopathologically in 12 patients (7%). In conclusion, real-time 3D TEE can detect prosthetic mitral ring thrombosis that could be missed on 2D TEE and cause thromboembolic events. PMID- 23800550 TI - Myocardial deformation and rotational profiles in mitral valve prolapse. AB - We studied whether evaluation of overall left ventricular (LV) and left atrial (LA) mechanics would be useful to detect subclinical dysfunction in patients with mitral valve prolapse (MVP), mitral regurgitation (MR), and normal LV ejection fraction (EF). Fifty consecutive patients (27 men, mean age 61 +/- 19 years) with MVP, MR, and normal systolic function (LVEF >=60%) were prospectively enrolled and compared with 40 age- and gender-matched healthy subjects (22 men, mean age: 59 +/- 16 years). At baseline, 2-dimensional and color-flow Doppler transthoracic echocardiography were performed for MR quantification and analysis of left chambers mechanics. Patients were divided into groups by severity of MR: mild (n = 14), moderate (n = 19), and severe (n = 17). Left ventricular dimensions, volume and mass, and LA area and volume indices were significantly increased in patients with moderate and severe MR compared with control subjects. Circumferential strain, basal/apical rotations, and twist were significantly enhanced in patients with moderate MR compared with controls; with the exception of basal rotation, they decreased in those with severe MR. Furthermore, LA strain and untwisting rate were progressively and significantly reduced from normal subjects to patients with severe MR. Effective regurgitant orifice area and MR vena contracta were significantly related to most systolic and diastolic function parameters and LA volume as well as LA strain and LV untwisting rate in all patients. In conclusion, cardiac mechanics indices, particularly LA deformation and LV rotational parameters, could help unmask incipient myocardial dysfunction in patients with MVP, especially in those with severe MR and yet normal LVEF. PMID- 23800551 TI - Prognostic value of coronary flow reserve on long-term cardiovascular outcomes in patients with chronic kidney disease. AB - Cardiovascular (CV) diseases and chronic kidney disease (CKD) have common predisposing factors that subsequently cause microvascular dysfunction. In the absence of obstructive coronary artery disease, coronary flow reserve (CFR) represents the status of coronary microcirculation. This study aimed to investigate the prognostic importance of impaired CFR, as a marker of microvascular dysfunction, on long-term CV outcomes in patients with CKD. This study consisted of 139 patients with an estimated glomerular filtration rate of <60 ml/min/1.73 m(2) who had no obstructive narrowing of the left anterior descending artery. Transthoracic Doppler echocardiography was used to measure CFR in the left anterior descending artery. During the follow-up period (3.3 +/- 1.6 years), CV events occurred in 26 patients (18.7%). Multivariate analysis that included CFR as a continuous value identified a serum level of C-reactive protein (hazard ratio 1.41, p = 0.03) and a value of CFR (hazard ratio 0.21, p = 0.009) as determinants for CV events, independent of traditional CV risk factors. Patients with a CFR of <2.0 had worse CV outcomes compared with those with a CFR of >=2.0 (p <0.001). In conclusion, transthoracic Doppler echocardiographically derived CFR was useful for the risk stratification of CV outcomes in patients with CKD. The presence of microvascular dysfunction may play an important role in the association between CKD and future CV events. PMID- 23800552 TI - Impact of co-morbidities and patient characteristics on international normalized ratio control over time in patients with nonvalvular atrial fibrillation. AB - This study determined the association between co-morbidities, including heart failure (HF) and time in therapeutic range (TTR), in patients with nonvalvular atrial fibrillation. Longitudinal patient-level anticoagulation management records collected from 2006 to 2010 were analyzed. Adult patients with nonvalvular atrial fibrillation who used warfarin for a 12-month period with no gap of >60 days between visits were identified. TTR <55% was defined as "lower" TTR. CHADS2 score of >=2 was defined as "higher" CHADS2. Logistic regression analyses were conducted to determine the association between co-morbidities and TTR. A total of 23,425 patients met the study criteria. The mean age +/- SD was 74.8 +/- 9.7 years, with 84.8% aged >=65 years. The most common co-morbidities were hypertension (41.7%), diabetes (24.1%), HF (11.7%), and previous stroke (11.1%). The mean TTR +/- SD was 67.3 +/- 14.4%, with 18.6% of patients in the lower TTR range. In multivariate analyses using age, gender, hypertension, diabetes, stroke, and region as covariates, HF (adjusted odds ratio [OR] 1.41, 95% confidence interval [CI] 1.28 to 1.56; p <0.001), diabetes (OR 1.28, 95% CI 1.19 to 1.38; p <0.001), and previous stroke (OR 1.15, 95% CI 1.04 to 1.27; p <0.001) were associated with lower TTR. In a second set of multivariate analyses using gender and region as covariates, a higher CHADS2 score was associated with lower TTR (OR 1.11, 95% CI 1.04 to 1.18; p <0.001). In conclusion, HF was associated with the greatest likelihood of a lower TTR, followed by diabetes, then stroke. Anticoagulation control may be more challenging for patients with these conditions. PMID- 23800553 TI - Differential lexical and semantic spreading activation in Alzheimer's disease. AB - Alzheimer's disease (AD) is known to be associated with disruption in semantic networks. Previous studies examining changes in spreading activation in AD have used a lexical decision task paradigm. We have used a paradigm based on average word frequencies obtained from the words generated on the Controlled Oral Word Association Test (COWAT) and the Animal Naming (AN) test. The COWAT and AN tests were administered to a group of 25 patients with AD and 20 control participants. We predicted that the patients with AD would have higher average word frequencies on the COWAT and AN tests than the control participants. The results indicated that the AD group generated words with a higher average word frequency on the AN test but a lower average word frequency on the COWAT. The reasons for the discrepancy in average word frequencies on the AN test and COWAT are discussed. PMID- 23800554 TI - Letter by Serebruany and DiNicolantonio regarding article, "Ticagrelor in patients with acute coronary syndromes and stroke: interpretation of subgroups in clinical trials". PMID- 23800555 TI - Response to letter regarding article, "Low plasma arginine:asymmetric dimethyl arginine ratios predict mortality after intracranial aneurysm rupture". PMID- 23800556 TI - Response to letter regarding article, "Ticagrelor in patients with acute coronary syndromes and stroke: interpretation of subgroups in clinical trials". PMID- 23800557 TI - Letter by Tsuda regarding article, "Low plasma arginine:asymmetric dimethyl arginine ratios predict mortality after intracranial aneurysm rupture". PMID- 23800558 TI - Factors associated with 28-day hospital readmission after stroke in Australia. AB - BACKGROUND AND PURPOSE: Understanding the factors that contribute to early readmission after discharge following stroke is limited. We aimed to describe the factors associated with 28-day readmission after hospitalization for stroke. METHODS: Factors associated with readmission were classified from the medical record standardized audits of 50 to 100 consecutively admitted patients with stroke from 35 Australian hospitals during multiple time periods (2000-2010). Factors were compared between patients readmitted and not readmitted after stroke hospitalization (n=43) grouped using 5 categories: patient characteristics (n=16; eg, age), clinical processes of care (n=13; eg, admitted into a stroke unit), social circumstances (n=3; eg, living home alone prior), health system (n=6; eg, location of hospital), and health outcome (n=5; eg, length of stay). Multilevel logistic regression modeling was used to examine the association with these independent factors selected if statistical significance P<0.15 or if considered clinically important and readmission status. RESULTS: Among 3328 patients, 6.5% were readmitted within 28 days (mean age, 75; 48% female; 92% ischemic). After bivariate analyses 14/43 factors from 4/5 categories were associated with readmission after hospitalization for stroke. Two factors from patient and health outcome categories remained independently associated with readmission after multivariable analyses. These were dependent premorbid functional status (adjusted odds ratio, 1.87; 95% confidence interval, 1.25-2.81) and having a severe adverse event during the initial hospitalization for stroke (adjusted odds ratio, 2.81; 95% confidence interval, 1.55-5.12). CONCLUSIONS: This is the first study to comprehensively evaluate factors associated with 28-day readmission after stroke. The factors associated with 28-day readmission are diverse and include potentially modifiable and nonmodifiable factors. PMID- 23800559 TI - Temperature induced-masculinisation in the Nile tilapia causes rapid up regulation of both dmrt1 and amh expressions. AB - Nile tilapia has primarily a XX/XY sex determining system but minor genetic factors as well as temperature can override the major factors. Female XX progenies can be sex-reversed into functional males by rearing at high temperatures (>34 degrees C) from 10dpf onwards. Temperature effects on the molecular pathways during sex differentiation in teleosts need to be deciphered. The temporal expression profiles of cyp19a1a and foxl2, two ovarian-developmental genes and dmrt1 and amh, two testes-developmental genes were analysed during key stages of the sex differentiation of genetic all-females, all-males and temperature-masculinised XX females (TM) tilapia. Overall QPCR analysis was similar between gonads and trunks. Both amh and dmrt1 expressions were up regulated simultaneously in TM already at 13-15dpf. Dmrt1 expression became markedly elevated ~3-fold higher than XY male levels at 20-26dpf whereas amh had similar levels to XY males. Foxl2 and cyp19a1a expression profiles were similar. Both were up-regulated at early stages in TM but repressed after 17-19dpf, whilest levels continued to increase in XX-females. Our results show that temperature action on tilapia testis development induces the rapid increase of both dmrt1 and amh expressions followed by the down-regulation of foxl2 and cyp19a1a. This suggests that dmrt1 and/or amh may be the modulator(s) of the down regulation of foxl2 and/or cyp19a1a. PMID- 23800560 TI - Rapid modulation of gene expression profiles in the telencephalon of male goldfish following exposure to waterborne sex pheromones. AB - Sex pheromones rapidly affect endocrine physiology and behaviour, but little is known about their effects on gene expression in the neural tissues that mediate olfactory processing. In this study, we exposed male goldfish for 6h to waterborne 17,20betaP (4.3 nM) and PGF2alpha (3 nM), the main pre-ovulatory and post-ovulatory pheromones, respectively. Both treatments elevated milt volume (P=0.001). Microarray analysis of male telencephalon following PGF2alpha treatment identified 71 unique transcripts that were differentially expressed (q<5%; 67 up, 4 down). Functional annotation of these regulated genes indicates that PGF2alpha pheromone exposure affects diverse biological processes including nervous system functions, energy metabolism, cholesterol/lipoprotein transport, translational regulation, transcription and chromatin remodelling, protein processing, cytoskeletal organization, and signalling. By using real-time RT-PCR, we further validated three candidate genes, ependymin-II, calmodulin-A and aldolase C, which exhibited 3-5-fold increase in expression following PGF2alpha exposure. Expression levels of some other genes that are thought to be important for reproduction were also determined using real-time RT-PCR. Expression of sGnRH was increased by PGF2alpha, but not 17,20betaP, whereas cGnRH expression was increased by 17,20betaP but not PGF2alpha. In contrast, both pheromones increase the expression of glutamate (GluR2a, NR2A) and gamma-aminobutyric acid (GABAA gamma2) receptor subunit mRNAs. Milt release and rapid modulation of neuronal transcription are part of the response of males to female sex pheromones. PMID- 23800561 TI - Influence of diet and stress on reproductive hormones in Nigerian olive baboons. AB - A female mammal's reproductive function and output are limited by the energy she is able to extract from her environment. Previous studies of the interrelationships between energetic circumstances and reproductive function in a variety of mammal species have produced varied results, which do not all support the common assumption that higher female reproductive hormone levels, specifically progesterone, indicate better ovarian function and greater reproductive potential, and are associated with lower energetic stress. In the present study faecal progesterone and glucocorticoid levels were assessed in two troops of olive baboons (Papio anubis) in the same population. They face similar ecological challenges, except that one troop crop-raids, potentially affecting its energetic intake and stress levels. The energy intake of individual females was assessed by combining detailed feeding observations with nutritional analysis of food samples. The crop-raiding troop experienced 50% higher energy intake rates and 50% lower glucocorticoid levels compared to the non-crop-raiding troop alongside substantially lower progesterone levels. This suggests that energetic stress is associated with elevated progesterone levels and may be the cause of the non-crop-raiding troop's lower reproductive output. By comparing groups which differ little, except in terms of food access, and also by directly assessing energy intake, our study addresses some of the design limitations of previous research investigating variation in progesterone levels and energetic stress. It therefore has the potential to contribute to greater understanding of the factors affecting differences in reproductive and stress hormone levels and reproductive function in mammals experiencing different energetic circumstances. PMID- 23800562 TI - Impact of nutrition on serum levels of docosahexaenoic acid among Omani children with autism. AB - OBJECTIVES: Autism is a lifelong neurodevelopmental disorder of early childhood. Dietary supplementation of the omega-3 fatty acid (docosahexaenoic acid [DHA]) during prenatal and postnatal life is considered a protective dietary intervention strategy to minimize the risk for autism spectrum disorder (ASD). To our knowledge, no relevant studies have been conducted in the Middle East investigating the status of DHA among children with autism during early childhood. The aim of this study was to investigate the serum levels and dietary intake status of DHA among Omani children recently diagnosed with ASD. METHODS: The present case-control study involved 80 Omani children (<5 y), 40 cases and 40 controls matched for age and sex. A semi-quantitative food frequency questionnaire was used to assess dietary intake of all the participants, while serum levels of DHA were measured using high-performance liquid chromatography. RESULTS: Our results showed that children with ASD had lower dietary consumption of foodstuff containing DHA, as well as lower serum levels of DHA than controls. CONCLUSION: The present finding from Oman supports the view of other studies that there are low serum levels of DHA among children with ASD. PMID- 23800563 TI - Serum vitamin B6, folate, and homocysteine concentrations and oxidative DNA damage in Japanese men and women. AB - OBJECTIVE: Higher vitamin B status has been linked to a lower risk for cancer, but the underlying mechanism remains elusive. The aim of the present study was to examine the association of pyridoxal, folate, and homocysteine (Hcy) with urinary 8-hydroxydeoxyguanosine (8-OHdG), a marker of oxidative DNA damage. METHODS: The participants were 500 employees (293 men and 207 women), ages 21 to 66 y, of two municipal offices in Japan. Serum pyridoxal and Hcy concentrations were measured using high-performance liquid chromatography (HPLC) method, and serum folate concentrations were measured using chemiluminescent immunoassay. Urinary 8-OHdG concentrations were measured using HPLC method. Multiple regression was used to estimate means of 8-OHdG for each tertile of pyridoxal, folate, and Hcy with adjustment for potential confounders. RESULTS: In multivariate analysis, 8-OHdG concentration was inversely associated with pyridoxal concentration in men (P for trend = 0.045) but not in women. The association in men was confined to non smokers (P for trend = 0.033) or those who consumed no or < 20 g/d of ethanol (P for trend = 0.048). 8-OHdG concentrations were not appreciably associated with folate and Hcy concentrations. CONCLUSION: The results suggest that vitamin B6, but not folate and homocysteine, plays a role against oxidative DNA damage in Japanese men. PMID- 23800564 TI - Presentation and interpretation of food intake data: factors affecting comparability across studies. AB - Non-uniform, unclear, or incomplete presentation of food intake data limits interpretation, usefulness, and comparisons across studies. In this contribution, we discuss factors affecting uniform reporting of food intake across studies. The amount of food eaten can be reported as mean portion size, number of servings or total amount of food consumed per day; the absolute intake value for the specific study depends on the denominator used because food intake data can be presented as per capita intake or for consumers only. To identify the foods mostly consumed, foods are reported and ranked according to total number of times consumed, number of consumers, total intake, or nutrient contribution by individual foods or food groups. Presentation of food intake data primarily depends on a study's aim; reported data thus often are not comparable across studies. Food intake data further depend on the dietary assessment methodology used and foods in the database consulted; and are influenced by the inherent limitations of all dietary assessments. Intake data can be presented as either single foods or as clearly defined food groups. Mixed dishes, reported as such or in terms of ingredients and items added during food preparation remain challenging. Comparable presentation of food consumption data is not always possible; presenting sufficient information will assist valid interpretation and optimal use of the presented data. A checklist was developed to strengthen the reporting of food intake data in science communication. PMID- 23800565 TI - Effects of creatine supplementation on oxidative stress and inflammatory markers after repeated-sprint exercise in humans. AB - OBJECTIVE: The goal of this study was to evaluate the effects of creatine (Cr) supplementation on oxidative stress and inflammation markers after acute repeated sprint exercise in humans. METHODS: Twenty-five players under age 20 y were randomly assigned to two groups: Cr supplemented and placebo. Double-blind controlled supplementation was performed using Cr (0.3 g/kg) or placebo tablets for 7 d. Before and after 7 d of supplementation, the athletes performed two consecutive Running-based Anaerobic Sprint Tests (RAST). RAST consisted of six 35 m sprint runs at maximum speed with 10 sec rest between them. Blood samples were collected just prior to start of test (pre), just after the completion (0 h), and 1 h after completion. RESULTS: Average, maximum, and minimum power values were greater in the Cr-supplemented group compared with placebo (P < 0.05). There were significant increases (P < 0.05) in plasma tumor necrosis factor alpha (TNF alpha) and C-reactive protein (CRP) up to 1 h after acute sprint exercise in the placebo-supplemented group. Malondialdehyde, lactate dehydrogenase (LDH), catalase, and superoxide dismutase enzymes also were increased after exercise in both groups. Red blood cell glutathione was lower after exercise in both groups. Cr supplementation reversed the increase in TNF-alpha and CRP as well as LDH induced by acute exercise. Controversially, Cr supplementation did not inhibit the rise in oxidative stress markers. Also, antioxidant enzyme activity was not different between placebo and Cr-supplemented groups. CONCLUSION: Cr supplementation inhibited the increase of inflammation markers TNF-alpha and CRP, but not oxidative stress markers, due to acute exercise. PMID- 23800566 TI - Re: Association between monosodium glutamate intake and sleep-disordered breathing among Chinese adults with normal body weight. PMID- 23800567 TI - Vitamin D status and body fat measured by dual-energy X-ray absorptiometry in a general population of Japanese children. AB - OBJECTIVE: For a general population of children, data on the relationship between vitamin D status and adiposity are limited. The aim of this study was to assess the relationships between the serum concentration of 25-hydroxyvitamin D (25-OH D) and body fat variables measured by dual-energy X-ray absorptiometry (DXA) in a general population of Japanese children, including underweight, normal, and overweight children. METHODS: The source population comprised 521 fifth-grade children who attended either of the two public schools in Hamamatsu, Japan. Total and regional body fat mass (FM) measured by DXA were evaluated along with the serum concentration of 25-OH-D. RESULTS: We were able to analyze the FM and 25-OH D data of 400 of the 521 children. Among boys, significant inverse relationships were observed between serum vitamin D levels and body fat variables (total FM, r = -0.201; trunk FM, r = -0.216; appendicular FM, r = -0.187; P < 0.05 for all values). Mean values of total FM and trunk FM in the vitamin D-deficient group (25-OH-D <50 nmol/L) were larger than those in the vitamin D-sufficient group (25 OH-D >=75 nmol/L) after adjusting for confounding factors, such as sedentary behavior (P < 0.05). No relationship was observed between vitamin D status and FM among girls. CONCLUSIONS: Vitamin D deficiency was associated with higher total and trunk adiposities in a general population of Japanese children, particularly boys. PMID- 23800568 TI - Eating behavior influences diet, weight, and central obesity in women after pregnancy. AB - OBJECTIVE: The aim of this study was to explore whether type of eating behavior is related to diet and overweight in women after childbirth. METHODS: In a prospective mother-infant study, women's (N = 189) eating behavior, dietary intake from food diaries, weight, and waist circumference (WC) were measured at 6, 12, 24, and 48 mo after giving birth. Three aspects of eating behavior were measured by the validated Three Factor Eating Questionnaire-18: cognitive restraint (CR; restricting of eating without associated hunger or fullness), emotional eating (EE; overeating due to negative feelings), and uncontrolled eating (UE; overeating irrespective of physiologic need). RESULTS: High scores in CR associated with the lowest tertile of fat intake (% of energy [E%], P = 0.045). High UE scores associated with the highest tertiles of intakes of energy (kcal; P < 0.001), fiber (g; P < 0.001) and sucrose (E%; P < 0.001). High EE scores (P = 0.003) linked with overweight (body mass index >= 25 kg/m(2)), whereas UE (P < 0.001) linked with central obesity (WC >= 80 cm). CONCLUSIONS: We demonstrated that certain types of eating behavior related to both energy-dense diet and weight and central adiposity. We propose that measuring eating behavior by the simple questionnaire could be a helpful tool in dietary counseling that aids in identifying women who are likely at risk for unhealthy dietary patterns and for developing overweight. PMID- 23800569 TI - Re. Association between monosodium glutamate intake and sleep-disordered breathing among Chinese adults with normal body weight: emerging opportunities for research on monosodium glutamate intake and health at a population level. PMID- 23800570 TI - Effects of low-dose thiazide diuretics on fasting plasma glucose and serum potassium-a meta-analysis. AB - This study is a meta-analysis of the metabolic profile (fasting plasma glucose and serum potassium) of low-dose thiazide and thiazide-like diuretics. The meta analysis involved 10 randomized controlled clinical trials with a total sample size of 17,636 and 17,947 for the potassium and glucose arms respectively. The random effect model was used to calculate the odds ratio with 95 percent confidence interval. The cumulative mean change of fasting plasma glucose was +0.20 mmol/L (+3.6 mg/dL) for the diuretic arm versus +0.12 mmol/L (+2.2 mg/dL) for the comparator arm. The cumulative mean change of serum potassium was -0.22 mmol/L (-0.22 mEq/L) for the diuretic arm versus +0.05 mmol/L (+0.05 mEq/L) for the comparator arm. The aggregate odds ratio for having higher fasting plasma glucose in subjects on low-dose thiazide versus non-thiazide antihypertensive was 1.22 (1.11 to 1.33; P < .01). The odds ratio for having a lower serum potassium in subjects on low-dose thiazide versus non-thiazide antihypertensive was 0.36 (0.27 to 0.49; P < .01). The magnitude of the observed change in fasting plasma glucose associated with low-dose thiazide diuretic use, while statistically significant, does not appear to place patients at clinically significant risk. On the other hand, the observed change in serum potassium was also statistically significant, and may be clinically significant in patients whose baseline potassium concentration is low or low-normal, and could predispose at-risk patients, such as those with ischemic heart disease, to ventricular arrhythmias. PMID- 23800571 TI - Clinical outcomes after zotarolimus and everolimus drug eluting stent implantation in coronary artery bifurcation lesions: insights from the RESOLUTE All Comers Trial. AB - OBJECTIVE: We investigated clinical outcomes after treatment of coronary bifurcation lesions with second generation drug eluting stents (DES). DESIGN: Post hoc analysis of a randomised, multicentre, non-inferiority trial. SETTING: Multicentre study. PATIENTS: All comers study with minimal exclusion criteria. INTERVENTIONS: Patients were treated with either zotarolimus or everolimus eluting stents. The patient population was divided according to treatment of bifurcation or non-bifurcation lesions and clinical outcomes were compared between groups. MAIN OUTCOMES MEASURES: Clinical outcomes within 2-year follow up. RESULTS: A total of 2265 patients were included in the present analysis. Two year follow-up data were available in 2223 patients: 1838 patients in the non bifurcation group and 385 patients in the bifurcation group. At 2-year follow-up the bifurcation and the non-bifurcation lesion groups showed no significant differences in terms of cardiac death (2.3 vs 2.1, p=0.273), target lesion failure (9.7% vs 13.8%, p=0.255), major adverse cardiac events (11.5% vs 15.1%, p=0.305), target lesion revascularisation (4.7% vs 6.0%, p=0.569), and definite or probable stent thrombosis (1.6% vs 1.8%, p=0.419). CONCLUSIONS: The use of second generation DES for the treatment of coronary bifurcation lesions was associated with similar long term mortality and clinical outcomes compared with non-bifurcation lesions. PMID- 23800572 TI - Glucose abnormalities associated with impaired nocturnal fall in blood pressure in normotensive severely obese patients. AB - BACKGROUND: The purpose of this study was to identify factors affecting the nocturnal decline in blood pressure (BP) in severe obesity. METHODS: Clinical, biochemical, polysomnographic data, glucose tolerance status, and body fat composition were obtained in 82 candidates for bariatric surgery (mean age: 40 (11) years; BMI: 46 (4)kg/m(2)). To determine the nocturnal BP fall we used 24-h ambulatory BP monitoring to measure the magnitude (Delta) of nocturnal decline, the % day-night systolic BP (SBP) and diastolic BP (DBP), dipper status and nocturnal hypertension (HT). RESULTS: Twenty-three percent of patients had nocturnal HT. Sixty percent had non dipper status, of which 95% had nocturnal HT. No specific factors were associated with the average 24-h SBP and DBP. Having glucose abnormalities was of primary importance for all variables evaluating nocturnal BP decline independent of daytime BP levels and severity of obesity. In comparing patients with or without glucose tolerance abnormalities, the night time SBP and DBP were significantly higher and the Delta nocturnal decline and % day-night in both SBP and DBP were significantly lower in those with glucose tolerance abnormalities. In an adjusted multivariate model, having both glucose abnormalities and nocturnal HT remained associated with non dipper status with an OR of 3.13 (95% CI 1.11-8.87, p=0.03) and 14.93 (95% CI 1.77-125.62, p=0.001), respectively. CONCLUSION: In normotensive severely obese patients, non dipper status and nocturnal HT are common, and the presence of glucose abnormalities was the primary variable associated with impaired nocturnal fall in BP. PMID- 23800573 TI - Treatment of depression in type 2 diabetic patients: effects on depressive symptoms, quality of life and metabolic control. AB - BACKGROUND AND OBJECTIVES: Type 2 diabetes (T2DM) almost doubles the risk of comorbid depression, with lifetime prevalence up to 29%. Recognition and treatment of depression in T2DM are important because of its association with hyperglycemia, diabetic complications and poor quality of life (QoL). However, although currently available medical therapy for depression is effective in reducing depressive symptoms, it does not consistently improve HbA1c levels. The aim of this study was to determine the effects of antidepressant therapy on depressive symptoms, health-related QoL and metabolic control in T2DM. METHODS: 48 T2DM (47.8% males, age 59.8 +/- 11.1, T2DM duration 9.5 +/- 6.5 years) who had a major depressive disorder diagnosed with a Beck Depression Inventory (BDI) test score greater than 16 and confirmed with a structured interview, were prescribed citalopram 20mg once daily. 10 out of 48 refused the prescription and were used as controls. BDI score, BMI, HbA1c and the Spanish version of the SF-36 Health Survey were recorded baseline and after 6 months of treatment. Sociodemographic characteristics, complications related to T2DM and comorbidities were also recorded. RESULTS: No differences in baseline characteristics were observed between the two groups. When compared with the untreated group (n=10), patients treated with citalopram (n=38) showed significant improvements in BDI score and in almost all areas of quality of life, except in general health and bodily pain. No differences in HbA1c, waist circumference or BMI were found. CONCLUSIONS: Treating depressive symptoms with medical therapy in T2DM is associated with improvements in QoL and depression, but with no improvement in metabolic control or weight. PMID- 23800574 TI - Effectiveness of a locking plate in preserving midcalcaneal length and positional outcome after Evans calcaneal osteotomy: a retrospective pilot study. AB - When using the Evans calcaneal osteotomy for repair of a calcaneovalgus deformity, lengthening of the lateral column of the foot is the method by which the procedure acts to correct the deformity. Therefore, maintaining the length is a priority. In our experience, substantial length is lost soon after surgery using the traditional nonfixated procedure. To test this hypothesis, a retrospective study was undertaken in which we compared the calcaneal length before and after the Evans procedures in 22 patients treated without fixation and 13 patients in whom the graft was fixated with a small locking plate to bridge the osteotomy and reduce the compressive forces on the graft. Within the first 10 days after surgery, the increase in calcaneal length from the preoperative length was 6.3 mm in the nonfixated group and 6.8 mm in the fixated group (p = .54 for the 0.5-mm difference). At 12 weeks after surgery, the mean amount of shortening from the value observed at 1 week was 2.45 (range 0 to 6) mm in the nonfixated group and 1.0 (range 0 to 3) mm in the internal fixation group (p = .48). Also, at 12 weeks, distal calcaneal migration or dorsal anterior calcaneal displacement of more than 3 mm occurred in 5 patients (23%) in the nonfixated group and 1 patient (8%) in the fixated group (p = .04). Our results suggest that locking plates do preserve the correction obtained with the Evans calcaneal osteotomy. PMID- 23800575 TI - Detection and species identification of malaria parasites by isothermal tHDA amplification directly from human blood without sample preparation. AB - We report the clinical and analytical performance of an isothermal thermophilic helicase-dependent amplification assay for blood Plasmodium parasite detection and species-level identification. The assay amplifies the 18S rRNA gene fragment of all Plasmodium species and uses a species-specific probe and a pan-malarial probe to definitively identify Plasmodium falciparum from other infectious Plasmodium species. Amplicon-probe hybridization products are detected with a disposable dipstick enclosed in a cassette. With a pan-malarial-positive and P. falciparum-negative result, an additional test is performed to detect if the pan malarial-positive band was the result of the presence of Plasmodium vivax. The assay uses only 2 MUL of human whole blood directly for a 50-MUL amplification reaction, without any pre-amplification processing. The clinical performance of the assay was validated using 88 samples from New York patients suspected of malaria or babesiosis. The overall sensitivity of the assay was 96.6% (95% CI, 87.3% to 99.4%), and the specificity was 100% (95% CI, 85.4% to 100%), compared with gold standard microscopy and a laboratory-developed molecular assay, respectively. The analytical sensitivity was 50 copies of DNA per assay or 200 parasites per microliter of blood, and the assay can detect samples with parasitemia levels <1%. This novel molecular diagnostic assay requires minimal laboratory instrumentation and uses un-processed blood as input; it can be readily performed in the field. PMID- 23800576 TI - A genome-wide high-resolution array-CGH analysis of cutaneous melanoma and comparison of array-CGH to FISH in diagnostic evaluation. AB - Benign melanocytic nevi and cutaneous melanomas can be difficult to differentiate by means of routine microscopic analysis. Recent evidence has suggested that cytogenomic analysis may be a useful diagnostic method for evaluation of melanocytic proliferations. We investigated the array-based comparative genomic hybridization (aCGH) platform for DNA copy number analysis of formalin-fixed, paraffin-embedded (FFPE) tissues in melanocytic tumors and compared aCGH analysis with fluorescence in situ hybridization (FISH) assays in diagnosis of melanoma. aCGH findings and FISH results were interpreted independently in a blinded fashion. Positive findings were not noted in any benign nevi at aCGH analysis, whereas substantial unbalanced genomic aberrations were revealed in 92% of melanomas. Positive results were obtained in 72% of melanomas via the four-probe FISH assay (RREB1/MYB/CEP6/CCND1). A few additional FISH studies were performed to verify some aCGH findings of focal amplification of oncogenes and homozygous deletion of tumor suppressor genes. The overall concordance in aberrations detected using the two methods was 90%. Most discrepancies were due to a minor abnormal clone identified via FISH that was below analytical sensitivity of the FFPE aCGH test. Our study demonstrated that copy number analysis of FFPE tumor samples via aCGH is a robust and reliable method in diagnosis of melanoma and that aCGH and FISH tests should be used as complementary methods to improve the accuracy of genetic evaluation of melanocytic tumors. PMID- 23800577 TI - Calorie restriction in overweight males ameliorates obesity-related metabolic alterations and cellular adaptations through anti-aging effects, possibly including AMPK and SIRT1 activation. AB - BACKGROUND: Calorie restriction (CR) is accepted as an experimental anti-aging paradigm. Several important signal transduction pathways including AMPK and SIRT1 are implicated in the regulation of physiological processes of CR. However, the mechanisms responsible for adaptations remain unclear in humans. SCOPE OF REVIEW: Four overweight male participants were enrolled and treated with 25% CR of their baseline energy requirements for 7weeks. Characteristics, including body weight (BW), body mass index (BMI), %fat, visceral fat area (VFA), mean blood pressure (MBP) and VO2 max, as well as metabolic parameters, such as insulin, lipid profiles and inflammatory makers and the expression of phosphorylated AMPK and SIRT1 in peripheral blood mononuclear cells (PBMNCs), were determined at baseline and then after 7weeks. In addition, we assessed the effects of the serum collected from the participants on AMPK and SIRT1 activation and mitochondrial biogenesis in cultured human skeletal muscle cells. MAJOR CONCLUSIONS: After CR, BW, BMI, %fat, VFA and MBP all significantly decreased, while VO2 max increased, compared to those at baseline. The levels of fasting insulin, free fatty acid, and inflammatory makers, such as interleukin-6 and visfatin, were significantly reduced, whereas the expression of phosphorylated AMPK and SIRT1 was significantly increased in PBMNCs collected after CR, compared to those at baseline. The skeletal muscle cells that were cultured in serum collected after CR showed an increase in AMPK and SIRT1 activity as well as mitochondrial biogenesis. GENERAL SIGNIFICANCE: CR is beneficial for obesity-related metabolic alterations and induces cellular adaptations against aging, possibly through AMPK and SIRT1 activation via circulating factors. PMID- 23800578 TI - PEGylation of lysine residues reduces the pro-migratory activity of IGF-I. AB - BACKGROUND: The insulin-like growth factor (IGF) system is composed of ligands and receptors which regulate cell proliferation, survival, differentiation and migration. Some of these functions involve regulation by the extracellular milieu, including binding proteins and other extracellular matrix proteins. However, the functions and exact nature of these interactions remain incomplete. METHODS: IGF-I variants PEGylated at lysines K27, K65 and K68, were assessed for binding to IGFBPs using BIAcore, and for phosphorylation of the IGF-IR. Furthermore, functional consequences of PEGylation were investigated using cell viability and migration assays. In addition, downstream signaling pathways were analyzed using phospho-AKT and phospho-ERK1/2 assays. RESULTS: IGF-I PEGylated at lysines 27 (PEG-K27), 65 (PEG-K65) or 68 (PEG-K68) was employed. Receptor phosphorylation was similarly reduced 2-fold with PEG-K65 and PEG-K68 in 3T3 fibroblasts and MCF-7 breast cancer cells, whereas PEG-K27 showed a more than 10- and 3-fold lower activation for 3T3 and MCF-7 cells, respectively. In addition, all PEG-IGF-I variants had a 10-fold reduced association rate to IGF binding proteins (IGFBPs). Functionally, all PEG variants lost their ability to induce cell migration in the presence of IGFBP-3/vitronectin (VN) complexes, whereas cell viability was fully preserved. Analysis of downstream signaling revealed that AKT was preferentially affected upon treatment with PEG-IGF-I variants whereas MAPK signaling was unaffected by PEGylation. CONCLUSION: PEGylation of IGF-I has an impact on cell migration but not on cell viability. GENERAL SIGNIFICANCE: PEG-IGF-I may differentially modulate IGF-I mediated functions that are dependent on receptor interaction as well as key extracellular proteins such as VN and IGFBPs. PMID- 23800580 TI - Isolation and genetic characterization of naturally NS-truncated H3N8 equine influenza virus in South Korea. AB - Equine influenza virus (EIV) causes a highly contagious respiratory disease in equids, with confirmed outbreaks in Europe, America, North Africa, and Asia. Although China, Mongolia, and Japan have reported equine influenza outbreaks, Korea has not. Since 2011, we have conducted a routine surveillance programme to detect EIV at domestic stud farms, and isolated H3N8 EIV from horses showing respiratory disease symptoms. Here, we characterized the genetic and biological properties of this novel Korean H3N8 EIV isolate. This H3N8 EIV isolate belongs to the Florida sublineage clade 1 of the American H3N8 EIV lineage, and surprisingly, possessed a non-structural protein (NS) gene segment, where 23 bases of the NS1-encoding region were naturally truncated. Our preliminary biological data indicated that this truncation did not affect virus replication; its effect on biological and immunological properties of the virus will require further study. PMID- 23800579 TI - Double-tailed lipid modification as a promising candidate for oligonucleotide delivery in mammalian cells. AB - BACKGROUND: The potential use of nucleic acids as therapeutic drugs has triggered the quest for oligonucleotide conjugates with enhanced cellular permeability. To this end, the biophysical aspects of previously reported potential lipid oligodeoxyribonucleotide conjugates were studied including its membrane-binding properties and cellular uptake. METHODS: These conjugates were fully characterized by MALDI-TOF mass spectrometry and HPLC chromatography. Their ability to insert into lipid model membrane systems was evaluated by Langmuir balance and confocal microscopy followed by the study of the internalization of a lipid oligodeoxyribonucleotide conjugate bearing a double-tail lipid modification (C28) into different cell lines by confocal microscopy and flow cytometry. This compound was also compared with other lipid containing conjugates and with the classical lipoplex formulation using Transfectin as transfection reagent. RESULTS: This double-tail lipid modification showed better incorporation into both lipid model membranes and cell systems. Indeed, this lipid conjugation was capable of inserting the oligodeoxyribonucleotide into both liquid-disordered and liquid-ordered domains of model lipid bilayer systems and produced an enhancement of oligodeoxyribonucleotide uptake in cells, even better than the effect caused by lipoplexes. In addition, in beta2 integrin (CR3) expressing cells this receptor was directly involved in the enhanced internalization of this compound. CONCLUSIONS: All these features confirm that the dual lipid modification (C28) is an excellent modification for enhancing nucleic acid delivery without altering their binding properties. GENERAL SIGNIFICANCE: Compared to the commercial lipoplex approach, oligodeoxyribonucleotide conjugation with C28 dual lipid modification seems to be promising to improve oligonucleotide delivery in mammalian cells. PMID- 23800581 TI - Aortopathies: etiologies, genetics, differential diagnosis, prognosis and management. AB - Aortic root and ascending aortic dilatation are indicators associated with risk of aortic dissection, which varies according to underlying etiologic associations, indexed aortic root size, and rate of progression. Typical aortic involvement is most commonly seen in syndromic cases for which there is increasing evidence that aortic aneurysm represents a spectrum of familial inheritance associated with variable genetic penetrance and phenotypic expression. Aortic root and ascending aortic dimensions should be measured routinely with echocardiography. Pharmacologic therapy may reduce the rate of progression. Timing of surgical intervention is guided by indexed aortic size and rate of change of aortic root and ascending aorta dimensions. Lifelong surveillance is recommended. PMID- 23800582 TI - Plasma dabigatran activity one week after discontinuation despite normal renal function. PMID- 23800583 TI - Adherence to secondary prevention medications and four-year outcomes in outpatients with atherosclerosis. AB - BACKGROUND: Although nonadherence with evidence-based secondary prevention medications is common in patients with established atherothrombotic disease, long term outcomes studies are scant. We assessed the prevalence and long-term outcomes of nonadherence to secondary prevention (antiplatelet agents, statins, and antihypertensive agents) medications in stable outpatients with established atherothrombosis (coronary, cerebrovascular, or peripheral artery disease) enrolled in the international REduction of Atherothrombosis for Continued Health registry. METHODS: Adherence with these medications in eligible patients at baseline and 1-year follow-up was assessed. The primary outcome was a composite of cardiovascular death, myocardial infarction, or stroke at 4 years. RESULTS: A total of 37,154 patients with established atherothrombotic disease were included. Adherence rates with all evidence-based medications at baseline and 1 year were 46.7% and 48.2%, respectively. Nonadherence with any medication at baseline (hazard ratio, 1.18; 95% confidence interval, 1.11-1.25) and at 1 year (hazard ratio, 1.19; 95% confidence interval, 1.11-1.28) were both significantly associated with an increased risk of the primary end point. The risk of all-cause mortality was similarly elevated. Corresponding numbers needed to treat were 31 and 25 patients for the composite end point and total mortality, respectively. This also was true for each disease-specific subgroup. Patients who were fully adherent at both time points had the lowest incidence of adverse outcomes, whereas patients who were nonadherent at both time points had the worst outcomes (P < .01). CONCLUSIONS: Our analysis of a large international registry demonstrates that nonadherence with evidence-based secondary prevention therapies in patients with established atherothrombosis is associated with a significant increase in long-term adverse events, including mortality. PMID- 23800584 TI - Dynamic changes of rhizosphere properties and antioxidant enzyme responses of wheat plants (Triticum aestivum L.) grown in mercury-contaminated soils. AB - A pot experiment was conducted to investigate the dynamic changes in the rhizosphere properties and antioxidant enzyme responses of wheat plants (Triticum aestivum L.) grown in three levels of Hg-contaminated soils. The concentrations of soluble Hg and dissolved organic carbon (DOC) in the rhizosphere soil solutions of the wheat plants were characterised by the sequence before sowing>trefoil stage>stooling stage, whereas the soil solution pH was found to follow an opposite distribution pattern. The activities of antioxidant enzymes in wheat plants under Hg stress were substantially altered. Greater superoxide dismutase (SOD), catalase (CAT) and ascorbate peroxidase (APX) activities were observed in the wheat plants grown in a highly polluted soil than in a slightly polluted soil (with increases of 11-27% at the trefoil stage and 26-70% at the stooling stage); however, increasing concentrations of Hg up to seriously polluted level led to reduced enzyme activities. The present results suggest that wheat plants could positively adapt to environmental Hg stress, with rhizosphere acidification, the enhancement of DOC production and greater antioxidant enzyme activities perhaps being three important mechanisms involved in the metal uptake/tolerance in the rhizospheres of wheat plants grown in Hg-contaminated soils. PMID- 23800585 TI - Residues of cyantraniliprole and its metabolite J9Z38 in rice field ecosystem. AB - A simple and reliable analytical method was developed to detect cyantraniliprole (HGW86) and its metabolite J9Z38 in rice straw, paddy water, brown rice, and paddy soil. The fate of cyantraniliprole and its metabolite J9Z38 in rice field ecosystem was also studied. The target compounds were extracted using acetonitrile, cleaned up on silicagel or strong anion exchange column, and analyzed by ultra-performance liquid chromatography-tandem mass spectrometry. The average recoveries of cyantraniliprole and J9Z38 in rice straw, paddy water, brown rice, and paddy soil ranged from 79.0% to 108.6%, with relative standard deviations of 1.1-10.6%. The limits of quantification of cyantraniliprole and J9Z38 were 18 and 39MUgkg(-1) for rice straw, 2.8 and 5.0MUgkg(-1) for paddy water, 4.3 and 6.3MUgkg(-1) for brown rice, and 3.9 and 5.3MUgkg(-1) for paddy soil. The trial results showed that the half-lives of cyantraniliprole were 3.2, 4.4, and 6.3d in rice straw and 4.9, 2.0, and 6.2d in paddy water in Zhejiang, Hunan, and Shandong, respectively. The respective final residues of cyantraniliprole and J9Z38 in brown rice were lower than 0.05 and 0.02mgkg(-1) after 14d of pre-harvest interval. The maximum residue limit of cyantraniliprole at 0.1mgkg(-1) and dosage of 100g a.i.hm(-2), which could be considered safe to human beings and animals, were recommended. PMID- 23800586 TI - Dissolved heavy metal concentrations of the Kralkizi, Dicle and Batman dam reservoirs in the Tigris River basin, Turkey. AB - Water samples were collected at monthly intervals during 1 year of monitoring from Kralkizi, Dicle and Batman dam reservoirs in the Tigris River basin to assess the concentrations of dissolved heavy metals and to determine their spatial and seasonal variations. The results indicated that dissolved heavy metal concentrations in the reservoirs were very low, reflecting the natural background levels. The lowest total metal concentrations in the three dam reservoirs were detected at sampling sites close to the dam wall. However, the highest total concentrations were observed at sites, which are located at the entrance of the streams to the reservoirs. Fe, Cr and Ni were the most abundant elements in the reservoirs, whereas Cd and As were the less abundant. The mean concentrations of dissolved metals in the dam reservoirs never exceeded the maximum permitted concentrations established by EC (European Community), WHO and USEPA drinking water quality guidelines. All heavy metals showed significant seasonal variations. As, Cd, Cr, Cu, Fe, Ni and Pb displayed higher values in the dry season, while higher values for Zn in the wet season. Cluster analysis grouped all ten sampling sites into three clusters. Clusters 1 and 2, and cluster 3 corresponded to relatively low polluted and moderate polluted regions, respectively. PCA/FA demonstrated the dissolved metals in the dam reservoirs controlled by natural sources. PMID- 23800587 TI - Antifungal efficacy of some natural phenolic compounds against significant pathogenic and toxinogenic filamentous fungi. AB - In terms of food safety, species of the Fusarium, Aspergillus and Penicillium genera are considered the most significant because they produce the great majority of known mycotoxins. Developing resistance against commonly used fungicides have become a critical problem in area such as agriculture, the storage and production of food and even in human medicines. The need for research and development of new alternative antifungal treatment based on natural antifungal substances is obvious. Here, the antifungal efficacy of 21 phenolic components of essential oils and plant substances were tested against these filamentous fungi with respect to their different molecular structures. Minimum inhibitory concentration values MIC50 and MIC100 were successfully estimated for 15 substances by means of probit analysis. Thymol and carvacrol were evaluated as the most effective. The MIC50 values for thymol ranged from 30 to 52 MUg mL(-1). The MIC100 values for thymol ranged from 76 to 255 MUg mL(-1), respectively. For carvacrol, the MIC50 values ranged from 37 to 76 MUg mL(-1), and the MIC100 ranged from 131 to 262 MUg mL(-1). The results also revealed differences in the efficacy of phenols depending on molecular structures and different inter-species sensitivity. PMID- 23800588 TI - Microtubule integrity and cell viability under metal (Cu, Ni and Cr) stress in the seagrass Cymodocea nodosa. AB - The effects of increasing Cu, Ni and Cr concentrations (0.5, 5, 10, 20 and 40 mg L(-1)) on microtubule organization and the viability of leaf cells of the seagrass Cymodocea nodosa for 13 consecutive days were investigated under laboratory conditions. Increased oblique microtubule orientation, microtubule depolymerization at the 5-40 mg L(-1) Ni treatments after 3 d of exposure, and a complete microtubule depolymerization at all Ni treatments after 5 d were observed. Cu depolymerised microtubules after three to 7 d of exposure, while Cr caused an extensive microtubule bundling after 9 or 11 d of exposure, depending on metal dosage. Fluorescence intensity measurements further consolidated the above phenomena. Cell death, occurring at later time than microtubule disturbance, was also observed at all Cu and Ni treatments and at the 10-40 mg L( 1) Cr treatments and adding to the above quantification of the number of dead cells clearly showed that only a portion of the cell population studied died. The data presented, being the first assessment of microtubule disturbance in seagrasses, indicate that microtubules in seagrass leaf cells could be used as a valuable and early marker of metal-induced stress in biomonitoring programmes. PMID- 23800589 TI - Water quality parameters controlling the photodegradation of two herbicides in surface waters of the Columbia Basin, Washington. AB - The water quality parameters nitrate-nitrogen, dissolved organic carbon, and suspended solids were correlated with photodegradation rates of the herbicides atrazine and 2,4-D in samples collected from four sites in the Columbia River Basin, Washington, USA. Surface water samples were collected in May, July, and October 2010 and analyzed for the water quality parameters. Photolysis rates for the two herbicides in the surface water samples were then evaluated under a xenon arc lamp. Photolysis rates of atrazine and 2,4-D were similar with rate constants averaging 0.025 h(-1) for atrazine and 0.039 h(-1) for 2,4-D. Based on multiple regression analysis, nitrate-nitrogen was the primary predictor of photolysis for both atrazine and 2,4-D, with dissolved organic carbon also a predictor for some sites. However, at sites where suspended solids concentrations were elevated, photolysis rates of the two herbicides were controlled by the suspended solids concentration. The results of this research provide a basis for evaluating and predicting herbicide photolysis rates in shallow surface waters. PMID- 23800590 TI - Differential survival and reproductive performance across three mitochondrial lineages in Melita plumulosa following naphthalene exposure. AB - Populations subject to anthropogenic contaminants often display altered patterns of genetic variation, including decreased genetic variability. Selective pressures of contaminant exposure are also reflected in differential tolerance between genotypes. An industrial chemical spill in a major eastern Australian waterway in July 2006 resulted in altered patterns of genetic variability in a nearby population of the amphipod, Melita plumulosa for up to one year post spill, despite the site being declared clean after 48 h. Here, we investigate the toxicant response of three mitochondrial lines naturally occurring at the impacted site by comparing survivorship and life-history trait variables following naphthalene exposure. Overall, M. plumulosa demonstrated differential survivorship between mitochondrial lines under exposure to high concentrations of naphthalene. In addition, we identified differential fecundity and frequencies of gravidity in female amphipods between the mitochondrial haplotypes examined. These findings suggest that the patterns of genetic variability previously identified may be linked with differential tolerance and/or reproductive performance between mitochondrial lineages. PMID- 23800591 TI - Sublethal effects of copper on some biological traits of the amphipod Gammarus aequicauda reared under laboratory conditions. AB - The common and widespread copper contamination in marine coastal environments make toxicity data necessary to assess the aquatic hazard and risk of this metal. In the present study, the sublethal effects of copper on survival, growth and reproduction of Gammarus aequicauda were investigated. Amphipods were exposed for 77d to 2 nominal copper concentrations (50, 100 MUg L(-1)). Survival was the most sensitive measure of effect and was significantly reduced, especially during early life stage (juveniles). Growth of amphipods was also negatively affected by copper and the growth impairment in G. aequicauda increases with increasing metal concentration. The reproductive traits were impaired by each of the copper concentrations, even if there were not any significant differences between control and copper treatments. The size at maturity increased with increasing copper, so the smallest ovigerous females in the control and copper treatments were 0.83 mm and 1.35 mm head length, respectively. There was a positive correlation between the brood size and the body size of the female in all treatments, whilst the fecundity (n degrees juveniles/female) decreased in the order control, 50 and 100 MUg Cu L(-1). Copper demonstrates chronic toxicity to G. aequicauda at realistic environmental concentrations. The results of this study entail that the understanding of chronic toxicity of a substance, especially on population level effects, is crucial to assess the long-term effect of the substance in the ecosystem. PMID- 23800592 TI - Chronic exposure to environmental stressors induces fluctuating asymmetry in shrews inhabiting protected Mediterranean sites. AB - Many ecotoxicological studies have addressed the effects of contaminant exposure at various levels of biological organization. However, little information exists on the effects of toxicants on wildlife populations. Here we examined exposure of populations of the greater white-toothed shrew Crocidura russula (Soricomorpha, Soricidae) occupying two protected Mediterranean sites (a polluted area, the Ebro Delta, and a control site, Garraf Massif). Bioaccumulation of selected elements (Pb, Hg, Cd, Zn, Cu, Fe, Mn, Cr, Mo, Sr, Ba, and B), a body condition index (BCI) and fluctuating asymmetry (FA) were used to assess the chronic exposure to environmental pollution. BCI was correlated neither to metal concentrations nor to FA, suggesting that this fitness measure only reflects environmental disturbances at a local level. However, shrews from the polluted area showed higher concentrations of metals and metalloids (Pb, Hg, B, and Sr) and greater shape FA than specimens from the reference area. A correlation between FA was found for both first and second principal component vectors suggesting that developmental instability increases as a result of exposure to multiple pollutants. Our results corroborate the suitability of C. russula as a bioindicator of environmental quality and show that FA is an appropriate index to examine impact of developmental stressors in populations inhabiting disturbed areas. PMID- 23800593 TI - The impact of sewage sludge compost on tree peony growth and soil microbiological, and biochemical properties. AB - In order to assess the suitability of sludge compost application for tree peony (Paeonia suffruticosa)-soil ecosystems, we determined soil microbial biomass C (Cmic), basal respiration (Rmic), enzyme activities, and tree peony growth parameters at 0-75% sludge compost amendment dosage. Soil Cmic, Rmic, Cmic as a percent of soil organic C, enzyme (invertase, urease, proteinase, phosphatase, polyphenoloxidase) activities, and plant height, flower diameter, and flower numbers per plant of tree peony significantly increased after sludge compost amendment; however, with the increasing sludge compost amendment dosage, a decreasing trend above 45% sludge compost amendment became apparent although soil organic C, total Kjeldahl N, and total P always increased with the sludge compost amendment. Soil metabolic quotient first showed a decreasing trend with the increasing sludge compost application in the range of 15-45%, and then an increasing trend from compost application of 45-75%, with the minimum found at compost application of 45%. As for the diseased plants, 50% of tree peony under the treatment without sludge compost amendment suffered from yellow leaf disease of tree peony, while no any disease was observed under the treatments with sludge compost application of 30-75%, which showed sludge compost application had significant suppressive effect on the yellow leaf disease of tree peony. This result convincingly demonstrated that <=45% sludge compost application dosage can take advantage of beneficial effect on tree peony growth and tree peony-soil ecosystems. PMID- 23800594 TI - Simulation of a Hazardous and Noxious Substances (HNS) spill in the marine environment: lethal and sublethal effects of acrylonitrile to the European seabass. AB - Despite the extensive maritime transportation of Hazardous and Noxious Substances (HNS), there is a current lack of knowledge on the effects posed by HNS spills on the marine biota. Among the HNS identified as priority, acrylonitrile was selected to conduct ecotoxicological assays. We assessed the acute and subletal effects of acrylonitrile in seabass, followed by a recovery phase to simulate the conditions of a spill incident. The work aimed at testing a broad range of biological responses induced by acrylonitrile. Sublethal exposure to the highest two doses increased the fish mortality rate (8.3% and 25% mortality in 0.75 and 2 mg L(-1) acrylonitrile concentrations), whereas no mortality were observed in control and 0.15 mg L(-1) treatments. Additionally, important alterations at sub individual level were observed. Acrylonitrile significantly induced the activities of Catalase- CAT and Glutathione S-Transferase - GST; and the levels of DNA damage were significantly increased. Conversely, Superoxide Dismutase- SOD - activity was found to be significantly inhibited and no effects were found on Lipid Peroxidation- LPO and ethoxyresorufin O-deethylase - EROD - activity. Following a 7d recovery period, the levels of CAT, GST and EROD fell to levels at or below those in the control. In the 2 mg L(-1) group, SOD remained at the levels found during exposure phase. This study has gathered essential information on the acute and subletal toxicity of acrylonitrile to seabass. It also demonstrated that 7d recovery allowed a return of most endpoints to background levels. These data will be useful to assist relevant bodies in preparedness and response to HNS spills. PMID- 23800595 TI - Comparison of CaO's effect on the fate of heavy metals during thermal treatment of two typical types of MSWI fly ashes in China. AB - Both grate and fluidized bed incinerators are widely used for MSW incineration in China. CaO addition for removing hazardous emissions from MSWI flue gas changes the characteristics of fly ash and affects the thermal behavior of heavy metals when the ash is reheated. In the present work, two types of MSWI fly ashes, sampled from both grate and fluidized bed incinerators respectively, were thermal treated at 1023-1323 K and the fate of heavy metals was observed. The results show that both of the fly ashes were rich in Ca and Ca-compounds were the main alkaline matter which strongly affected the leaching behavior of heavy metals. Ca was mostly in the forms of Ca(OH)2 and CaCO3 in the fly ash from grate incinerator in which nascent fly ash particles were covered by Ca-compounds. In contrast, the content of Ca was lower in the fly ash from fluidized bed incinerator and Ca was mostly in the form of CaSO4. Chemical reactions among Ca compounds caused particle agglomeration in thermal treated fly ash from grate incinerator, restraining the heavy metals volatilization. In thermal treated fly ash from fluidized bed incinerator, Ca was converted into aluminosilicates especially at 1323 K which enhanced heavy metals immobilization, decreasing their volatile fractions as well as leaching concentrations. Particle agglomeration hardly affected the leaching behavior of heavy metals. However, it suppressed the leachable-CaCrO4 formation and lowered Cr leaching concentration. PMID- 23800596 TI - Correlation between virulence gene expression and proton pump inhibitors and ambient pH in Clostridium difficile: results of an in vitro study. AB - Proton pump inhibitors (PPIs) are associated with the development of Clostridium difficile infection in humans. Though it is assumed that PPIs mediate this effect through gastric acid suppression, there has been little investigation into whether PPIs, or ambient pH, might directly affect the expression of C. difficile toxin genes. In the present study, C. difficile ribotypes 001, 027 and 078 obtained from human subjects were grown under anaerobic conditions prepared at pHs of 5, 7.3 and 9. Matched trios were exposed to 100 uM and 200 uM of omeprazole along with PPI untreated controls. Custom designed reverse transcription quantitative PCR hydrolysis probes were used to assess C. difficile gene expression for toxins A (tcdA), B (tcdB) and binary toxin (cdtB), as well as their positive regulators (tcdR and cdtR), using rrsA, which encodes 16S rRNA, as a constitutively expressed reference gene. tcdC and codY, negative regulators of toxin expression, were also assessed. Basic pH resulted in greater expression of tcdA, and with PPI exposure a 120-fold higher expression was noted with ribotype 001. tcdB and cdtB expressions were much less responsive to pH or PPIs, though a clear response to acidic pH and PPI exposure was observed in ribotype 027. tcdC and codY expressions were largely unaffected, except with ribotype 027; low pH and PPIs resulted in their greater expression, though to a lesser degree than with toxin genes and their positive regulators. Non-neutral pH and PPI exposure appear to have an effect on C. difficile, one that has a net effect towards toxin gene expression. PMID- 23800597 TI - Antimicrobial resistance and genetic characteristics of integron-carrier shigellae isolated in Hungary (1998-2008). AB - Antimicrobial susceptibility, integron carriage, genetic relationship and presence of some important virulence genes of the integron-carrier strains of Shigella sonnei (n = 230) and Shigella flexneri (n = 22) isolated from stool samples of patients in Hungary between 1998 and 2008 were investigated. Sixty seven per cent (168/252) of the strains were resistant to sulfamethoxazole/trimethoprim (SxT) followed by streptomycin (S, 47%), ampicillin (A, 32%) and tetracycline (Tc, 28%). Thirty-six per cent (90/252) exhibited multidrug resistance, mostly showing SSxTTc or ASSxTc, ASSxTTc resistance patterns. An S. sonnei strain of imported origin was resistant to cefotaxime and harboured a blaCTX-M-55-type extended-spectrum beta-lactamase gene. Altogether 33% of the S. sonnei (n = 75) and 14% of the S. flexneri (n = 3) strains had either class 1 or class 2 integrons or both. The variable regions encoded aadA1 or dfrA1-aadA1 genes for the class 1 and dfrA1-sat2-aadA1 or dfrA1-sat2 genes for the class 2 integrons. Pulsed-field gel electrophoresis analysis revealed that those strains that have different integron types represented different genetic clusters. The Shiga toxin (stx1) gene was identified in one S. sonnei strain and the cdtB gene was detected in an S. flexneri strain. The results reveal the high incidence of antibiotic resistance among Shigella isolates and the presence of the stx1 gene in S. sonnei and the cdtB gene in S. flexneri. The genetic diversity of Shigella spp. isolated recently in Hungary was also demonstrated. PMID- 23800598 TI - Quantitative detection of Staphylococcus aureus, Enterococcus faecalis and Pseudomonas aeruginosa in human oral epithelial cells from subjects with periodontitis and periodontal health. AB - Epithelial cells in oral cavities can be considered reservoirs for a variety of bacterial species. A polymicrobial intracellular flora associated with periodontal disease has been demonstrated in buccal cells. Important aetiological agents of systemic and nosocomial infections have been detected in the microbiota of subgingival biofilm, especially in individuals with periodontal disease. However, non-oral pathogens internalized in oral epithelial cells and their relationship with periodontal status are poorly understood. The purpose of this study was to detect opportunistic species within buccal and gingival crevice epithelial cells collected from subjects with periodontitis or individuals with good periodontal health, and to associate their prevalence with periodontal clinical status. Quantitative detection of total bacteria and Staphylococcus aureus, Pseudomonas aeruginosa and Enterococcus faecalis in oral epithelial cells was determined by quantitative real-time PCR using universal and species-specific primer sets. Intracellular bacteria were visualized by confocal microscopy and fluorescence in situ hybridization. Overall, 33% of cell samples from patients with periodontitis contained at least one opportunistic species, compared with 15% of samples from healthy individuals. E. faecalis was the most prevalent species found in oral epithelial cells (detected in 20.6% of patients with periodontitis, P = 0.03 versus healthy individuals) and was detected only in cells from patients with periodontitis. Quantitative real-time PCR showed that high levels of P. aeruginosa and S. aureus were present in both the periodontitis and healthy groups. However, the proportion of these species was significantly higher in epithelial cells of subjects with periodontitis compared with healthy individuals (P = 0.016 for P. aeruginosa and P = 0.047 for S. aureus). Although E. faecalis and P. aeruginosa were detected in 57% and 50% of patients, respectively, with probing depth and clinical attachment level >=6 mm, no correlation was found with age, sex, bleeding on probing or the presence of supragingival biofilm. The prevalence of these pathogens in epithelial cells is correlated with the state of periodontal disease. PMID- 23800599 TI - Evaluation of LAMP assay using phenotypic tests and conventional PCR for detection of blaNDM-1 and blaKPC genes among carbapenem-resistant clinical Gram negative isolates. AB - Carbapenem-resistant pathogens cause infections associated with significant morbidity and mortality. This study evaluates the use of the loop-mediated isothermal amplification (LAMP) assay for rapid and cost-effective detection of bla(NDM-1) and bla(KPC) genes among carbapenem-resistant Gram-negative bacteria in comparison with conventional PCR and existing phenotypic methods. A total of 60 carbapenem-resistant clinical isolates [Escherichia coli (15), Klebsiella pneumoniae (22), Acinetobacter baumannii (23)] were screened for the presence of carbapenemases (bla(KPC) and bla(NDM-1)) using phenotypic methods such as the modified Hodge test (MHT) and combined disc test (CDT) and molecular methods such as conventional PCR and LAMP assay. In all, 47/60 isolates (78.3%) were MHT positive while 48 isolates were positive by CDT [46.6% positive with EDTA, 30% with 3' aminophenylboronic acid (APB) plus EDTA and 1.6% with APB alone]. Isolates showing CDT positivity with EDTA or APB contained bla(NDM-1) and bla(KPC) genes, respectively. bla(NDM-1) was present as a lone gene in 28 isolates (46.7%) and present together with the bla(KPC) gene in 19 isolates (31.7%). Only one E. coli isolate had a lone bla(KPC) gene. The LAMP assay detected either or both bla(NDM-1) and bla(KPC) genes in four isolates that were missed by conventional PCR. Neither gene could be detected in 12 (20%) isolates. The LAMP assay has greater sensitivity, specificity and rapidity compared to the phenotypic methods and PCR for the detection of bla(NDM-1) and bla(KPC). With a turnaround time of only 2-3 h, the LAMP assay can be considered a point-of-care assay. PMID- 23800600 TI - Epidemiology of qnrVC alleles and emergence out of the Vibrionaceae family. PMID- 23800601 TI - Metastatic splenic angiosarcoma presenting with thrombocytopenia and bone marrow fibrosis mimicking idiopathic thrombocytopenic purpura and primary myelofibrosis: a diagnostic challenge. PMID- 23800602 TI - CD4(-)/CD8(-) variant of T-cell large granular lymphocytic leukemia or hepatosplenic T-cell lymphoma: a clinicopathologic dilemma. PMID- 23800603 TI - Moving into a new neighborhood: NOS goes nuclear. PMID- 23800604 TI - Effect of in-feed paromomycin supplementation on antimicrobial resistance of enteric bacteria in turkeys. AB - Histomoniasis in turkeys can be prevented by administering paromomycin sulfate, an aminoglycoside antimicrobial agent, in feed. The aim of this study was to evaluate the impact of in-feed paromomycin sulfate supplementation on the antimicrobial resistance of intestinal bacteria in turkeys. Twelve flocks of breeder turkeys were administered 100 ppm paromomycin sulfate from hatching to day 120; 12 flocks not supplemented with paromomycin were used as controls. Faecal samples were collected monthly from days 0 to 180. The resistance of Escherichia coli, Enterococcus faecium and Staphylococcus aureus to paramomycin and other antimicrobial agents was compared in paromomycin supplemented (PS) and unsupplemented (PNS) flocks. E. coli from PS birds had a significantly higher frequency of resistance to paromomycin, neomycin and kanamycin until 1 month after the end of supplementation compared to PNS birds. Resistance to amoxicillin or trimethoprim-sulfamethoxazole was also more frequent in PS turkeys. Resistance was mainly due to the presence of aph genes, which could be transmitted by conjugation, sometimes with streptomycin, tetracycline, amoxicillin, trimethoprim or sulfonamide resistance genes. Resistance to kanamycin and streptomycin in E. faecium was significantly different in PS and PNS breeders on days 60 and 90. Significantly higher frequencies of resistance to paromomycin, kanamycin, neomycin and tobramycin were observed in S. aureus isolates from PS birds. Paromomycin supplementation resulted in resistance to aminoglycosides in bacteria of PS turkeys. Co-selection for resistance to other antimicrobial agents was observed in E. coli isolates. PMID- 23800605 TI - Group versus single handed primary care: a performance evaluation of the care delivered to chronic patients by Italian GPs. AB - OBJECTIVES: In family medicine contrasting evidence exists on the effectiveness of team practice compared with solo practice on chronic disease management. In Italy, several experiences of team practice have been introduced since the late 1990s but few studies detail their impact on the quality of care. The aim of this paper is to evaluate the impact of team practice in family medicine in six Italian regions using chronic disease management process indicators as a measure of outcome. METHODS: Cross-sectional studies were performed to assess impact on quality of care for diabetes, congestive heart failure and ischaemic heart disease. The impact of team vs. solo practice was approximated through performance comparison of general practitioners (GPs) adhering to a team with respect to GPs working in a solo practice. Among the 2082 practitioners working in the 6 regions those assisting 300+ patients were selected. Quality of care towards 164,267 patients having at least one of three chronic conditions was estimated for the year 2008 using administrative databases. Quality indicators (% of patients receiving appropriate care) were selected (4 for diabetes, 4 for congestive heart failure, 3 for ischaemic heart disease) and a total score was computed for each patient. For each disease the response variable associated to each physician was the average score of the patients on his/her list. A multilevel model was estimated assessing the impact of team vs. solo practice. RESULTS: No impact was found for diabetes and heart failure. For ischaemic heart disease a slightly significant impact was observed (0.040; 95% CI: 0.015, 0.065). CONCLUSIONS: No significant difference was found between team practice and solo practice on chronic disease management in six Italian regions. PMID- 23800606 TI - Health professionals moving to... and from Portugal. AB - The mobility of health professionals in the European Union is a phenomenon which policy-makers must take into account to provide the conditions to adjust for demand and supply of health services. This paper presents the case of Portugal, a country which at the same time imports and exports health workers. Since the early 1990s Portugal became a destination country receiving foreign health care professionals. This situation is now changing with the current economic situation as fewer immigrants come and more Portuguese emigrate. Foreigners coming to Portugal do so in part for similar reasons that bring Portuguese to want to emigrate, mainly the search for better work conditions and professional development opportunities. The emigration of Portuguese health professionals is also stimulated by the difficulty for recently graduated nurses, dentists and diagnostic and therapeutic technicians to find employment, low salaries in the public and private sectors, heavy workloads, remuneration not related to performance and poor career prospects. The paradoxes described in this study illustrate the consequences of the absence of a policy for the health professions. Strategies based on evidence, and on an integrated information system that captures the dynamic evolution of the workforce in health are not only necessary but also a good investment. PMID- 23800607 TI - Quality of care and in-hospital resource use in acute myocardial infarction: evidence from Japan. AB - OBJECTIVES: To determine the association between quality of care in process and outcome measures and in-hospital resource use among patients admitted for acute myocardial infarction (AMI) in Japan. METHODS: We analyzed 23,512 AMI patients across 150 hospitals in Japan between April 2008 and March 2011. The exposure measure was inpatient hospital resource use, which was calculated from the sum of all hospital fees for healthcare services provided to AMI patients. Hospitals were then categorized into quartiles based on a risk-adjusted in-hospital resource use index. Quality of care was assessed using three process measures (in hospital prescription of aspirin, beta-blockers, and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers) and two outcome measures (7-day and 30-day in-hospital mortality). Process and outcome measures were analyzed with multilevel logistic regression models that adjusted for patient and hospital characteristics. RESULTS: No significant differences in process measures were observed across the quartiles of in-hospital resource use. In contrast, hospitals with the lowest resource use were significantly associated with poorer outcomes (7-day in-hospital mortality OR: 1.851 [95% CI 1.327-2.582]; 30-day in-hospital mortality OR: 1.706 [95% CI 1.259-2.312]) than hospitals with higher resource use. CONCLUSION: Poorer quality of care in outcome measures was significantly associated with lower resource utilization among AMI patients in Japanese hospitals, but process measures did not show similar associations. PMID- 23800608 TI - Confirmatory factor analysis of the Frontal Systems Behavior Scale (FrSBe). AB - The Frontal Systems Behavior Scale (FrSBe) is a 46-item questionnaire that measures behaviors associated with frontal subcortical deficits (apathy, disinhibition, and executive dysfunction) in adult neurologic populations. Based on findings from a previous exploratory factor analysis on the scale, the current study used confirmatory factor analysis to explore and potentially improve on the measurement model fit of current FrSBe scores. Model fit indices and reliabilities (measured using internal consistency reliability) were compared in the original and in several alternative models. The original scale demonstrated a generally good fitting model, although the best fitting model (referred to as the reduced model) removed eight items from the original measure and modestly improved model fit over the original FrSBe. Strong reliability was found in both versions. Results from the current study provide a critical first step in a potential FrSBe scale revision. PMID- 23800609 TI - High sensitivity point-of-care device for direct virus diagnostics. AB - Influenza infections are associated with high morbidity and mortality, carry the risk of pandemics, and pose a considerable economic burden worldwide. To improve the management of the illness, it is essential with accurate and fast point-of care diagnostic tools for use in the field or at the patient's bedside. Conventional diagnostic methods are time consuming, expensive and require specialized laboratory facilities. We present a highly sensitive, highly specific, and low cost platform to test for acute virus infections in less than 15 min, employing influenza A virus (H1N1) as an example of its usability. An all polymer microfluidic system with a functionalized conductive polymer (PEDOT OH:TsO) microelectrode array was developed and exploited for label free and real time electrochemical detection of intact influenza A virus (H1N1) particles. DNA aptamers with affinity for influenza A virus (H1N1) were linked covalently to the conductive polymer microelectrodes in the microfluidic channel. Based on changes in the impedance when virions were captured by immobilized probes, we could detect clinically relevant concentrations of influenza A virus (H1N1) in saliva. This is a new, stable and very sensitive point-of-care platform for detection and diagnostics of intact virus particles. PMID- 23800610 TI - Oriented antibody immobilization by site-specific UV photocrosslinking of biotin at the conserved nucleotide binding site for enhanced antigen detection. AB - The nucleotide binding site (NBS) is an under-utilized, highly conserved binding site found within the variable region of nearly all antibody Fab arms. Here, we describe an NBS specific UV photocrosslinking biotinylation method (UV NBS(Biotin)) for the oriented immobilization of antibodies to streptavidin-coated surfaces, such that the antigen binding activity remains unaffected. An optimal UV exposure of 1J/cm(2) yielded an average conjugation efficiency of ~ 1 biotin per antibody resulting in significant immobilization efficiency while maintaining maximal antigen binding activity. With the continued push for miniaturization of medical diagnostics to reduce cost and increase patient accessibility the ever shrinking on chip detection areas necessitate the highest level of immobilized antibody activity to maximize assay detection capabilities. The UV-NBS(Biotin) method yielded surfaces with significantly enhanced antigen detection capabilities, improved antigen detection sensitivity and the highest amount of active surface immobilized antibody when compared to other common immobilization methods including: epsilon-NH3(+) surface conjugation, NHS-Biotin, and direct physical adsorption. Taken together, the UV-NBS(Biotin) method provides a universal, site-specific immobilization method that is amenable to any available assay detection modality with potential significant implications in the development of miniaturized medical diagnostics and lab on a chip technologies. PMID- 23800611 TI - Simultaneous quantification of the fluorescent responses of an ensemble of bacterial sensors. AB - Bacterial bioreporters are genetically engineered microbial strains capable of detecting specific chemicals, groups of chemicals or global biological effects such as toxicity or genotoxicity. A scheme for simultaneous selective detection of the fluorescent signals emitted by a bacterial biosensor array, able to detect four different types of toxicants, using a single photodetector (photomultiplier) is presented. The underlying principle of the scheme is to convert the spatially distributed signals from all the elements in the array to temporally distributed frequency multiplexed signals at the output of the photodetector. Experimental proof of this concept is demonstrated in a four-channel system, in which low power (a few tens of picowatts) fluorescent signals produced by the bacterial sensors are measured, while maintaining a wide dynamic range of detection (more than 3 orders of magnitude). Simultaneous monitoring of concentrations down to a few mg/l of different chemicals in a liquid sample is demonstrated. PMID- 23800612 TI - A novel fluorescence-quenching immunochromatographic sensor for detection of the heavy metal chromium. AB - A novel fluorescence quenching immunochromatographic sensor (ICS) was developed for detecting chromium (Cr(3+)) within 15 min utilizing the fluorescence quenching function of gold nanoparticles (Au-NPs). The sensor performed with a positive readout. When the low concentrations of Cr(3+) samples were applied, detection signals of the test line (T line) were quenched, whereas when higher concentration Cr(3+) samples (1.56 ng/mL) were applied, the detection signal of the T line appeared. The detection signal intensity of the T line increased with increasing concentrations of Cr(3+). The low detection limit of developed fluorescence quenching ICS was 1.56 ng/mL. The fluorescence quenching ICS has a linear range of detection of Cr(3+) comprising between 6.25 ng/mL to 800 ng/mL. The recoveries of the fluorescence quenching ICS to detect Cr(3+) in tap water ranged from 94.7% to 101.7%. This result indicated that the developed sensor gave higher sensitivity and reliable reproducibility. It could provide a general detection method for small analyte in water samples. PMID- 23800613 TI - Definition and description of schizophrenia in the DSM-5. AB - Although dementia praecox or schizophrenia has been considered a unique disease for over a century, its definitions and boundaries have changed over this period and its etiology and pathophysiology remain elusive. Despite changing definitions, DSM-IV schizophrenia is reliably diagnosed, has fair validity and conveys useful clinical information. Therefore, the essence of the broad DSM-IV definition of schizophrenia is retained in DSM-5. The clinical manifestations are extremely diverse, however, with this heterogeneity being poorly explained by the DSM-IV clinical subtypes and course specifiers. Additionally, the boundaries of schizophrenia are imprecisely demarcated from schizoaffective disorder and other diagnostic categories and its special emphasis on Schneiderian "first-rank" symptoms appears misplaced. Changes in the definition of schizophrenia in DSM-5 seek to address these shortcomings and incorporate the new information about the nature of the disorder accumulated over the past two decades. Specific changes in its definition include elimination of the classic subtypes, addition of unique psychopathological dimensions, clarification of cross-sectional and longitudinal course specifiers, elimination of special treatment of Schneiderian 'first-rank symptoms', better delineation of schizophrenia from schizoaffective disorder, and clarification of the relationship of schizophrenia to catatonia. These changes should improve diagnosis and characterization of individuals with schizophrenia and facilitate measurement-based treatment and concurrently provide a more useful platform for research that will elucidate its nature and permit a more precise future delineation of the 'schizophrenias'. PMID- 23800614 TI - Quantification of endocannabinoids in postmortem brain of schizophrenic subjects. AB - Numerous studies have implicated the endocannabinoid system in the pathophysiology of schizophrenia. Endocannabinoids have been measured in blood and cerebrospinal fluid in schizophrenic patients but, to the date, there are no published reports dealing with measurements of endocannabinoid levels in schizophrenics' brain tissue. In the present study, postmortem brain samples from 19 subjects diagnosed with schizophrenia (DSM-IV) and 19 matched controls were studied. In specific brain regions, levels of four endocannabinoids (2 arachidonoylglycerol (2-AG), arachidonoylethanolamine (anandamide, AEA), dihomo gamma-linolenoylethanolamine (LEA), and docosahexaenoylethanolamine (DHEA)) and two cannabimimetic compounds (palmitoyl-ethanolamine (PEA) and oleoyl ethanolamine (OEA)) were measured using quantitative liquid chromatography with triple quadrupole mass spectrometric detection. Suffering from schizophrenia significantly affects the brain levels of 2-AG (p<0.001), AEA (p<0.0001), DHEA (p<0.0001), LEA (p<0.01) and PEA (p<0.05). In schizophrenic subjects, the three studied brain regions (cerebellum: 130+/-18%; p=0.16; hippocampus: 168+/-28%, p<0.01; prefrontal cortex: 237+/-45%, p<0.05) showed higher 2-AG levels when compared to matched controls. Conversely, AEA levels were lower in all brain regions of schizophrenic subjects (cerebellum: 66+/-7%, p<0.01; hippocampus: 66+/ 7%, p<0.01; prefrontal cortex: 75+/-10%, p=0.07). Statistically significant lower levels of DHEA were also found in cerebellum (60+/-6%, p<0.001) and hippocampus (68+/-7%, p<0.05) of schizophrenic subjects. PEA (71+/-6%, p<0.05) and LEA (72+/ 6%, p<0.05) levels were also found to be lower in cerebellum. No significant differences were found in OEA levels. Our results evidence specific alterations in the levels of some endocannabinoids in different brain regions of schizophrenic subjects. Furthermore, these data evidence the involvement of the endocannabinoid system in the pathophysiology of schizophrenia. PMID- 23800615 TI - Neurophysiological responses to schizophrenia-associated communication abnormalities. AB - BACKGROUND: Individuals with schizophrenia experience difficulty with interpersonal interactions, in part resulting from communication abnormalities that are common in the disorder, and to the expectancy effects from knowledge of the person's diagnosis. The auditory N400 event-related potential provides an objective measure of recognition of incongruent speech and thus is a potential tool to understand how listeners respond to disordered speech as a function of awareness of diagnosis. METHODS: In this study, participants listened to segments of conversation between two people in which the sentence final word was a normal ending, a word approximation, or a neologism while EEG was recorded. Participants were randomized to two groups: told that the speaker had a diagnosis of schizophrenia or not told about a diagnosis. RESULTS: Participants who were not told that the speaker had schizophrenia displayed a significant N400 during both word approximations and neologisms. However, no significant N400 was observed for participants who were told that the speaker had schizophrenia. CONCLUSIONS: Differential neurological responses to the same abnormal speech depending on whether the diagnosis of the speaker was known, indicate an early processing expectancy effect for abnormal communication to come from someone with schizophrenia. Such responses to abnormal speech in schizophrenia indicate an expectation of abnormality from individuals with schizophrenia, which has implications for understanding social exclusion of individuals with the disorder. PMID- 23800618 TI - Spatiotemporal profiles of neurons receptive fields in the cat posteromedial lateral suprasylvian cortex. AB - The cortical area located in the lateral portion of the posteromedial suprasylvian sulcus (PMLS) is considered a key area for motion processing. It receives major projections from areas 17 and 18 but also from the lateral posterior-pulvinar complex where neurons exhibit, for the most part, complex receptive fields (RF). Based on these inputs, complex-like RFs would be expected for PMLS neurons and results from hand-plot mapping support this idea. However, PMLS neurons' first-order spatiotemporal RF profiles and their role in shaping neuronal response characteristics is currently unknown. In this study, the first order spatiotemporal characteristics of PMLS cells were revealed using reverse correlation analysis, based on responses elicited by coarse white noise stimuli. Experiments were carried out in adult anesthetized cats. Detailed RF profiles were obtained by analyzing bright and dark subfields separately. Results indicate that the average maximal spike probability is higher for dark subfields than for their paired bright subfields. Spatial RF analysis shows that neurons exhibit oval RF subfields and that their size is larger for dark subfields. The majority of cells have complex-like profiles, with spatially overlapping RF subfields. Temporal analysis showed that for the majority of cells, subfields are coincidentally activated; however, a subset of neurons exhibit time-dissociated subfield peak activity windows. Correlation analysis between spatial and temporal parameters of RF subfields and their neuron's response characteristics to gratings was also performed. The data show that the direction index is positively correlated with subfield size difference and negatively correlated with spatial subfield overlap. Modulation index is negatively correlated with the degree of temporal subfield activity overlap. We conclude that first-order RF structures are important functional factors that shape PMLS neurons response characteristics. PMID- 23800617 TI - Decreased axial diffusivity within language connections: a possible biomarker of schizophrenia risk. AB - Siblings of patients diagnosed with schizophrenia are at elevated risk for developing this disorder. The nature of such risk associated with brain abnormalities, and whether such abnormalities are similar to those observed in schizophrenia, remain unclear. Deficits in language processing are frequently reported in increased risk populations. Interestingly, white matter pathology involving fronto-temporal language pathways, including arcuate fasciculus (AF), uncinate fasciculus (UF), and inferior occipitofrontal fasciculus (IOFF), are frequently reported in schizophrenia. In this study, high spatial and directional resolution diffusion MRI data was obtained on a 3T magnet from 33 subjects with increased familial risk for developing schizophrenia, and 28 control subjects. Diffusion tractography was performed to measure white matter integrity within AF, UF, and IOFF. To understand these abnormalities, Fractional Anisotropy (FA, a measure of tract integrity) and Trace (a measure of overall diffusion), were combined with more specific measures of axial diffusivity (AX, a putative measure of axonal integrity) and radial diffusivity (RD, a putative measure of myelin integrity). Results revealed a significant decrease in Trace within IOFF, and a significant decrease in AX in all tracts. FA and RD anomalies, frequently reported in schizophrenia, were not observed. Moreover, AX group effect was modulated by age, with increased risk subjects demonstrating a deviation from normal maturation trajectory. Findings suggest that familial risk for schizophrenia may be associated with abnormalities in axonal rather than myelin integrity, and possibly associated with disruptions in normal brain maturation. AX should be considered a possible biomarker of risk for developing schizophrenia. PMID- 23800619 TI - Outbreak of leptospirosis after white-water rafting: sign of a shift from rural to recreational leptospirosis in Sri Lanka? AB - This paper reports the first recreation-related leptospirosis outbreak in Sri Lanka in 20 office workers who were involved in white-water rafting during a staff outing. Two weeks after the rafting event on 7 September 2012, six participants developed fever, of which four had classical clinical features of leptospirosis. Four weeks after the exposure, an outbreak investigation was conducted for 19 of the 20 participants. Of the six fever patients, four were confirmed as having acute leptospirosis using either single sample MAT titre >= 1/400 (n = 2) or positive IgM ELISA (n = 2). An afebrile patient with headache and myalgia also had a MAT titre >= 1/400. Seventeen of the 19 participants investigated showed anti-leptospiral antibodies. None of the participants had a history of leptospirosis or recent outdoor exposures other than the rafting event. This outbreak provides evidence of the changing epidemiology of leptospirosis and suggests a wider range of risk exposures including those related to recreational activities of more affluent urban populations in addition to the well recognized occupational hazards of rural farming. PMID- 23800620 TI - Spatial variability of climate change impacts on yield of rice and wheat in the Indian Ganga Basin. AB - Indian Ganga Basin (IGB), one of the most densely populated areas in the world, is facing a significant threat to food grain production, besides increased yield gap between actual and potential production, due to climate change. We have analyzed the spatial variability of climate change impacts on rice and wheat yields at three different locations representing the upper, middle and lower IGB. The DSSAT model is used to simulate the effects of climate variability and climate change on rice and wheat yields by analyzing: (i) spatial crop yield response to current climate, and (ii) impact of a changing climate as projected by two regional climate models, REMO and HadRM3, based on SRES A1B emission scenarios for the period 2011-2040. Results for current climate demonstrate a significant gap between actual and potential yield for upper, middle and lower IGB stations. The analysis based on RCM projections shows that during 2011-2040, the largest reduction in rice and wheat yields will occur in the upper IGB (reduction of potential rice and wheat yield respectively by 43.2% and 20.9% by REMO, and 24.8% and 17.2% by HadRM3). In the lower IGB, however, contrasting results are obtained, with HadRM3 based projections showing an increase in the potential rice and wheat yields, whereas, REMO based projections show decreased potential yields. We discuss the influence of agro-climatic factors; variation in temperature, length of maturity period and leaf area index which are responsible for modeled spatial variability in crop yield response within the IGB. PMID- 23800621 TI - Effective management of combined renewable energy resources in Tajikistan. AB - Water is needed mostly in summer time for irrigation and in winter time for generation of electric power. This results in conflicts between downstream countries that utilize water mostly for irrigation and those upstream countries, which use water for generation of electric power. At present Uzbekistan is blocking railway connection that is going to Tajikistan to interfere to transportation of the equipment and materials for construction of Rogun hydropower plant. In order to avoid conflicts between Tajikistan and Uzbekistan a number of measures for the utilization of water resources of the trans-boundary Rivers Amu-Darya and Sir-Darya are discussed. In addition, utilization of water with the supplement of wind and solar energy projects for proper and efficient management of water resources in Central Asia; export-import exchanges of electric energy in summer and winter time between neighboring countries; development of small hydropower project, modern irrigation system in main water consuming countries and large water reservoir hydropower projects for control of water resources for hydropower and irrigation are also discussed. It is also concluded that an effective management of water resources can be achieved by signing Water treaty between upstream and downstream countries, first of all between Tajikistan and Uzbekistan. In this paper management of water as renewable energy resource in Tajikistan and Central Asian Republics are presented. PMID- 23800622 TI - Heparanase procoagulant activity is elevated in women using oral contraceptives. AB - STUDY QUESTION: What is the effect of estrogen on heparanase procogulant activity? SUMMARY ANSWER: Estrogen increases heparanase procoagulant activity. WHAT IS KNOWN ALREADY: Estrogen therapy increases the risk of thrombosis and was previously found to up-regulate heparanase expression. Heparanase is involved in angiogenesis and metastasis, and has been shown to form a complex with tissue factor (TF) and also shown to enhance the generation of factor Xa. STUDY DESIGN, SIZE, DURATION: A case-control study. Thirty-four healthy women using oral contraceptives (OC) and 41 women not using hormonal therapy and not pregnant per history were enrolled, over a 5-month period, at the Rambam Medical Center, Haifa, Israel. In vitro, estrogen receptor-positive (MCF-7) and -negative (MDA 231) cell lines were incubated with estrogen, tamoxifen and ICI-182.780 a pure estrogen receptor antagonist. The cell medium was evaluated for TF/heparanase complex activity, TF activity and heparanase procoagulant activity by chromogenic substrate. PARTICIPANTS/MATERIALS, SETTING, METHODS: Exclusion criteria included age <18 years, post-menopausal women, concomitant medications other than supplement minerals and vitamins, acute or chronic illness. MAIN RESULTS AND THE ROLE OF CHANCE: The study demonstrates increased risk of high heparanase procoagulant activity in OC users. When a cutoff level of 0.25 (absorbance 405 490 nm) was set, the odds ratio was 131 (P < 0.0001). When all results were studied by quartiles, in quartiles 3 and 4 the results were almost exclusively of the OC users (P < 0.0001). In cell cultures, estrogen and tamoxifen increased heparanase procoagulant activity in the medium of estrogen receptor-positive (MCF 7) cells. LIMITATIONS, REASONS FOR CAUTION: The main limitation of the current study is that the two estrogens given to the women and cell cultures, ethinyl estradiol (EE) and 17-beta-estradiol (E2), respectively, may have different effects on the coagulation system, although an increase in heparanase procoagulant activity was demonstrated in both of them. Although the sample size of the study group was limited, significant differences in the activation of the extrinsic coagulation pathway were demonstrated. WIDER IMPLICATIONS OF THE FINDINGS: The clinical relevance of the heparanase procoagulant activity assay as a screening tool in thrombophilia work-up should further be elucidated. PMID- 23800623 TI - Evolution of substrate specificity in a recipient's enzyme following horizontal gene transfer. AB - Despite the prominent role of horizontal gene transfer (HGT) in shaping bacterial metabolism, little is known about the impact of HGT on the evolution of enzyme function. Specifically, what is the influence of a recently acquired gene on the function of an existing gene? For example, certain members of the genus Corynebacterium have horizontally acquired a whole l-tryptophan biosynthetic operon, whereas in certain closely related actinobacteria, for example, Mycobacterium, the trpF gene is missing. In Mycobacterium, the function of the trpF gene is performed by a dual-substrate (betaalpha)8 phosphoribosyl isomerase (priA gene) also involved in l-histidine (hisA gene) biosynthesis. We investigated the effect of a HGT-acquired TrpF enzyme upon PriA's substrate specificity in Corynebacterium through comparative genomics and phylogenetic reconstructions. After comprehensive in vivo and enzyme kinetic analyses of selected PriA homologs, a novel (betaalpha)8 isomerase subfamily with a specialized function in l-histidine biosynthesis, termed subHisA, was confirmed. X-ray crystallography was used to reveal active-site mutations in subHisA important for narrowing of substrate specificity, which when mutated to the naturally occurring amino acid in PriA led to gain of function. Moreover, in silico molecular dynamic analyses demonstrated that the narrowing of substrate specificity of subHisA is concomitant with loss of ancestral protein conformational states. Our results show the importance of HGT in shaping enzyme evolution and metabolism. PMID- 23800624 TI - Log-transformation is useful for examining proportional relationships in allometric scaling. PMID- 23800625 TI - Fungal airsacculitis associated with serratospiculiasis in captive falcons of the United Arab Emirates. PMID- 23800626 TI - Alfalfa dodder (Cuscuta campestris) toxicity in horses: clinical, haematological and serum biochemical findings. AB - The objective of this observational study is to describe clinical, haematological and serum biochemical findings of horses affected with alfalfa dodder (Cuscuta campestris) toxicity. Twenty horses naturally exposed to alfalfa dodder toxicity were examined and information was collected on history and clinical signs. Physical examination was done on horses in the premises (n=20), and venous blood samples of 12 horses were submitted for haematology and serum biochemical examination for each horse. Abnormal clinical signs started around 36 hours after horses were fed the contaminated alfalfa. Abnormal signs were seen in 11 horses and those included diarrhoea (n=8), decreased appetite (n=7), neurological signs (n=4) and abdominal pain (n=1). Some horses had multiple clinical signs of the above. The results of complete blood cell count revealed leukocytopenia, neutropenia and thrombocytopenia. Serum biochemical analysis revealed decreased ALP, AST and CPK levels and increased direct bilirubin level. The used alfalfa was stopped immediately and a different alfalfa from a new container that did not contain any weeds was fed. Horses on the premises were observed closely, and the abnormal clinical signs resolved within three days. No treatment was implemented. Knowledge about toxicity of horses by Cuscuta species is scarce in the English veterinary literature and very limited. PMID- 23800628 TI - Masters, marionettes and modulators: intersection of pathogen virulence factors and mammalian death receptor signaling. AB - TNF and its receptor, TNFR1, are members of the TNF superfamily and play important roles during infection by orchestrating an inflammatory response. The key role that TNFR1 signaling plays in host defense singles it out as a frequent target of pathogen manipulation. This review describes how the TNFR1 signaling pathway is attacked by pathogen virulence factors and how the different TNFR1 signaling pathways, in particular the death signaling response, have evolved to counteract these pathogen manipulations. We examine recent data showing that other 'Death Receptors' in the TNF superfamily, namely TRAIL-R and Fas, also participate in the immune response to pathogens. Finally we explore how knowledge of the inhibition of these pathways is being translated for clinical applications. PMID- 23800629 TI - Effects of CO2 enrichment and nutrients supply intermittency on batch cultures of Isochrysis galbana. AB - Aiming at enhanced performance to increase economic feasibility of microalgae based processes, Isochrysis galbana was grown in three modes of cultivation: batch, intermittent fed batch and semi-continuous. The batch mode was conducted under two regimes of aeration: conventional aeration and CO2 enriched aeration (5% v/v in air). Increased biomass productivity without significant impact on lipid accumulation was observed for CO2 enriched aeration relatively to cultivation aerated with air only. The intermittent fed batch cultivation policy was proven to be useful for lipid accumulation, increasing the lipid content by 19.8%. However, the semi-continuous mode resulted in higher productivity due to increased biomass concentration; the biomass productivity reached 0.51 g/(Ld). Fluorescence measurements were performed; the calculated low electron transport rate showed the need to increase the irradiance. The results showed that I. galbana can be grown in semi-continuous condition at high levels of biomass productivity. PMID- 23800627 TI - Associations of IGF-1 gene variants and milk protein intake with IGF-I concentrations in infants at age 6 months - results from a randomized clinical trial. AB - OBJECTIVE: The interplay of genetic and nutritional regulation of the insulin like growth factor-I axis in children is unclear. Therefore, potential gene nutrient effects on serum levels of the IGF-I axis in a formula feeding trial were studied. DESIGN: European multicenter randomized clinical trial of 1090 term, formula-fed infants assigned to receive cow's milk-based infant and follow on formulae with lower (LP: 1.25 and 1.6 g/100 mL) or higher (HP: 2.05 and 3.2 g/100 mL) protein contents for the first 12 months of life; a comparison group of 588 breastfed infants (BF) was included. Eight single nucleotide polymorphisms (SNPs) of the IGF-1-(rs6214, rs1520220, rs978458, rs7136446, rs10735380, rs2195239, rs35767, and rs35766) and two of the IGFBP-3-(rs1496495, rs6670) gene were analyzed. Serum levels of total and free IGF-I, IGFBP-3 and the molar ratio IGF-1/IGFBP-3 at age 6 months were regressed on determined SNPs and feeding groups in 501 infants. RESULTS: IGF-1-SNPs rs1520220, rs978458, and rs2195239 significantly increased total-IGF-I and molar-ratio IGF-I/IGFBP-3 by ~1.3 ng/mL and ~1.3 per allele, respectively; compared to LP infants concentration and molar ratio were increased in HP by ~1.3 ng/mL and ~1.3 and decreased in BF infants by ~0.6 ng/mL and ~0.6, respectively. IGFBP-3 was only affected by the BF group with ~450 ng/mL lower levels than the LP group. No gene-feeding-group interaction was detected for any SNP, even without correction for multiple testing. CONCLUSIONS: Variants of the IGF-1-gene play an important role in regulating serum levels of the IGF-I axis but there is no gene-protein-interaction. The predominant nutritional regulation of IGF-I and IGFBP-3 gives further evidence that higher protein intake contributes to metabolic programming of growth. PMID- 23800630 TI - Influence of thermal pretreatment on the biochemical methane potential of wheat straw. AB - The biochemical methane potential of steam exploded wheat straw was evaluated in a pilot plant under different temperature-time combinations. The optimum was obtained for 1 min and 220 degrees C thermal pretreatment (3.5 severity factor), resulting in a 20% increase in methane production respect non-treated straw. For more severe treatments the biodegradability decreased due to a possible formation of inhibitory compounds. The results of the tests were modeled with a first order equation to estimate the hydrolysis constant and biodegradability extent, and the influence of temperature and time on the kinetic parameters was obtained with a response surface study. The data processing confirmed the accuracy of the model and the optimum operation conditions, and demonstrated that the biomethanization of raw and pretreated wheat straw is limited by the hydrolysis, being the individual influence of temperature and time much more important than the interaction between them. PMID- 23800631 TI - Voice discrimination in four primates. AB - One accepted function of vocalisations is to convey information about the signaller, such as its age-sex class, motivation, or relationship with the recipient. Yet, in natural habitats individuals not only interact with conspecifics but also with members of other species. This is well documented for African forest monkeys, which form semi-permanent mixed-species groups that can persist for decades. Although members of such groups interact with each other on a daily basis, both physically and vocally, it is currently unknown whether they can discriminate familiar and unfamiliar voices of heterospecific group members. We addressed this question with playbacks on monkey species known to form polyspecific associations in the wild: red-capped mangabeys, Campbell's monkeys and Guereza colobus monkeys. We tested subjects' discrimination abilities of contact calls of familiar and unfamiliar female De Brazza monkeys. When pooling all species, subjects looked more often towards the speaker when hearing contact calls of unfamiliar than familiar callers. When testing De Brazza monkeys with their own calls, we found the same effect with the longest gaze durations after hearing unfamiliar voices. This suggests that primates can discriminate, not only between familiar and unfamiliar voices of conspecifics, but also between familiar and unfamiliar voices of heterospecifics living within a close proximity. PMID- 23800632 TI - Outbreak of enterotoxigenic Escherichia coli O169 enteritis in schoolchildren associated with consumption of kimchi, Republic of Korea, 2012. AB - Enterotoxigenic Escherichia coli (ETEC) is now recognized as a common cause of foodborne outbreaks. This study aimed to describe the first ETEC O169 outbreak identified in Korea. In this outbreak, we identified 1642 cases from seven schools. Retrospective cohort studies were performed in two schools; and case control studies were conducted in five schools. In two schools, radish kimchi was associated with illness; and in five other schools, radish or cabbage kimchi was found to have a higher risk among food items. Adjusted relative risk of kimchi was 5.87-7.21 in schools that underwent cohort studies; and adjusted odds ratio was 4.52-12.37 in schools that underwent case-control studies. ETEC O169 was isolated from 230 affected students, and was indistinguishable from the isolates detected from the kimchi product distributed by company X, a food company that produced and distributed kimchi to all seven schools. In this outbreak, we found that the risk of a kimchi-borne outbreak of ETEC O169 infection is present in Korea. We recommend continued monitoring regarding food safety in Korea, and strengthening surveillance regarding ETEC O169 infection through implementation of active laboratory surveillance to confirm its infection. PMID- 23800633 TI - Time trends in pulmonary embolism: a matter of age and gender. PMID- 23800634 TI - The Owren INR in liver disease: a way towards standardisation? PMID- 23800635 TI - Nonadherence with INR monitoring and anticoagulant complications. AB - INTRODUCTION: This study tests the hypothesis that nonadherence with INR monitoring is associated with an increased risk for warfarin-related bleeding and thrombosis and describes patient characteristics associated with INR monitoring nonadherence. MATERIALS AND METHODS: This was a retrospective, longitudinal, matched cohort study wherein patients were categorized into adherent and nonadherent cohorts; adherent patients were matched 2:1 to nonadherent patients. The primary study endpoint was the first occurrence of bleeding or thromboembolism. Multivariate logistic regression modeling identified patient characteristics associated with INR monitoring adherence or nonadherence. RESULTS: A total of 4995 and 2544 patients contributed 10729 and 5385 patient years of warfarin therapy in the adherent and nonadherent groups, respectively. The rate of thromboembolic events during follow up was higher in the nonadherent group than in the adherent group (0.95% vs. 0.62% per patient-year, respectively; p=0.019) and nonadherence to INR monitoring was associated with a moderately higher risk of thromboembolism (adjusted Hazard Ratio=1.51; 95% confidence interval=1.04 - 2.20). The difference in bleeding between the two groups was not statistically significant. CONCLUSIONS: Repeatedly missing INR tests is an easily identified clinical parameter that is associated with moderately increased risk for thromboembolism in patients taking chronic warfarin therapy. Clinicians should carefully consider the underlying thromboembolic risk and extent of nonadherence when weighing the benefits of continued warfarin therapy for a given patient. PMID- 23800636 TI - Lipopolysaccharide-induced plasma PAI-1 increase does not correlate with PAI-1 synthesised de novo in the liver. PMID- 23800637 TI - Self-reported family history in estimating the risk of hormone, surgery and cast related VTE in women. AB - BACKGROUND: Combined hormonal contraceptives, menopause hormone treatment and surgery/cast in orthopedic patients are important risk factors for venous thromboembolism (VTE) in women. OBJECTIVES: To evaluate whether self-reported family history can be used for risk assessment concerning hormone and surgery /cast related VTE in women. PATIENTS/METHODS: 1288 women 18-64 years with a first event of VTE and 1327 age-matched controls were included in a nation-wide population-based case-control study in Sweden. Odds ratios were calculated by comparing occurrence of VTE in women with and without a positive family history in combination with hormones or surgery/cast. RESULTS: The risk of hormone associated VTE was doubled in women with a family history of VTE as compared to women with hormones and negative family history. The risk was more than tripled in women with surgery/cast and a positive family history, as compared to surgery/cast patients with negative family history. Women with a positive family history and combined hormonal contraceptive or menopause hormone treatment had an OR of 15.3 (95% CI 6.1-38) and 5.9 (95% CI 3.3-11) respectively compared to women without hormones or family history. The corresponding OR in women with surgery/cast and a positive family history was 67 (95% CI 21-213) compared to women without surgery/cast treatment and a negative family history. CONCLUSION: Self-reported family history is associated with increased odds of developing VTE on combined hormonal contraceptives, menopause hormone treatment and in connection with surgery or plaster. We believe that assessing family history of VTE can be helpful in identifying high risk patients. PMID- 23800638 TI - A qualitative study on the perceptions of preventing falls as a health priority among older people in Northern India. AB - BACKGROUND: In India, fall-related injury morbidity and mortality is an emerging public health problem in older people. Despite awareness of a growing burden, there is a scarcity of literature on effective and acceptable interventions. This study was undertaken to explore the perceptions of older people regarding the risk of falls and understanding of fall prevention programmes. METHODS: We conducted six focus group discussions (FGDs), comprising single gender for three socio-demographic groups in a north Indian city, Chandigarh, in 2011. FGDs were conducted in local language (Punjabi), recorded, transcribed and translated in English. Two researchers independently conducted thematic analysis. RESULTS: Focus group participants were aware of the devastating consequences of fall related injuries. The predominant reasons for explaining an increased risk of falling was age, uneven surfaces, physical weakness and mental health. There were several other competing health priorities in this population. Preventive measures ranging from individual to government level initiatives were suggested. The experience, knowledge, perceptions and health priorities were diverse among the three socio-demographic groups. However, the feasibility, acceptability and effectiveness for improving balance and strength using yoga in this population needs to be evaluated. CONCLUSIONS: Careful consideration of health priorities is required for development of falls prevention, particularly among the urban poor. Further, initiatives that foster community engagement, such as participatory action may increase acceptability of initiatives to prevent fall-related injury among older people in India. PMID- 23800639 TI - An association between preterm delivery and long-term maternal cardiovascular morbidity. AB - OBJECTIVE: The purpose of this study was to investigate whether a history of preterm delivery (PTD) poses a risk for subsequent maternal long-term cardiovascular morbidity. STUDY DESIGN: A population-based study compared the incidence of cardiovascular morbidity in a cohort of women who delivered preterm (<37 weeks' gestation) and those who gave birth at term at the same period. Deliveries occurred during the years 1988-1999 with follow up until 2010. Kaplan Meier survival curves were used to estimate cumulative incidence of cardiovascular hospitalizations. Cox proportional hazards models were used to estimate the adjusted hazard ratios for cardiovascular hospitalizations. RESULTS: During the study period 47,908 women met the inclusion criteria; 12.5% of the patients (n = 5992) delivered preterm. During a follow-up period of >10 years, patients with PTD had higher rates of simple and complex cardiovascular events and higher rates of total cardiovascular-related hospitalizations. A linear association was found between the number of previous PTD and future risk for cardiovascular hospitalizations (5.5% for >=2 PTDs; 5.0% for 1 PTD vs 3.5% in the comparison group; P < .001). The association remained significant for spontaneous vs induced PTD and for early (<34 weeks) and late (34 weeks to 36 weeks 6 days' gestation) PTD. In a Cox proportional hazards model that adjusted for pregnancy confounders such as labor induction, diabetes mellitus, preeclampsia, and obesity, PTD was associated independently with cardiovascular hospitalizations (adjusted hazard ratio, 1.4; 95% confidence interval, 1.2-1.6). CONCLUSION: PTD is an independent risk factor for long-term cardiovascular morbidity in a follow up period of more than a decade. PMID- 23800640 TI - [Methylprednisolone- acute spinal cord injury, benefits or risks?]. AB - Methylprednisolone is a synthetic glucocorticoid with a potent and long-acting anti-inflammatory, antiallergic and immunosuppressant. Its mechanism of action of methylprednisolone is the result of many cellular changes. Methylprednisolone is used in many diseases, such as rheumatic diseases, autoimmune diseases, allergic, anaphylactic shock, asthma. Methylprednisolone was also used in patients with spinal cord injury, in order to minimize neurological damage. While in the above mentioned fields of medicine is undeniable role of methylprednisolone, whereas its use in the treatment of traumatic spinal cord injury within the last few years raises a lot of controversy, and in most cases, the side effects of its use outweigh the potential benefits. PMID- 23800641 TI - Adipose transplant for inborn errors of branched chain amino acid metabolism in mice. AB - Liver transplantation appears to be quite beneficial for treatment of maple syrup urine disease (MSUD, an inherited disorder of branched chain amino acid metabolism); however, there is a limited availability of donor livers worldwide and the first year costs of liver transplants are quite high. Recent studies have suggested that intact adipose tissue, already widely used in reconstructive surgery, may have an underappreciated high capacity for branched chain amino acid (BCAA) metabolism. Here we examined the potential for adipose tissue transplant to lower circulating BCAAs in two models of defective BCAA metabolism, BCATm and PP2Cm [branched chain keto acid dehydrogenase complex (BCKDC) phosphatase] knockout (KO) mice. After 1-2g fat transplant, BCATm and PP2Cm KO mice gained or maintained body weight 3weeks after surgery and consumed similar or more food/BCAAs the week before phlebotomy. Transplant of fat into the abdominal cavity led to a sterile inflammatory response and nonviable transplanted tissue. However when 1-2g of fat was transplanted subcutaneously into the back, either as small (0.1-0.3g) or finely minced pieces introduced with an 18-ga. needle, plasma BCAAs decreased compared to Sham operated mice. In two studies on BCATm KO mice and one study on PP2Cm KO mice, fat transplant led to 52-81% reductions in plasma BCAAs compared to baseline plasma BCAA concentrations of untreated WT type siblings. In PP2Cm KO mice, individual BCAAs in plasma were also significantly reduced by fat transplant, as were the alloisoleucine/Phe ratios. Therefore, subcutaneous fat transplantation may have merit as an adjunct to dietary treatment of MSUD. Additional studies are needed to further refine this approach. PMID- 23800642 TI - Severe obesity and diabetes insipidus in a patient with PCSK1 deficiency. AB - Non-synonymous mutations affecting both alleles of PCSK1 (proprotein convertase 1/3) are associated with obesity and impaired prohormone processing. We report a proband who was compound heterozygous for a maternally inherited frameshift mutation and a paternally inherited 474kb deletion that encompasses PCSK1, representing a novel genetic mechanism underlying this phenotype. Although pro vasopressin is not a known physiological substrate of PCSK1, the development of central diabetes insipidus in this proband suggests that PCSK1 deficiency can be associated with impaired osmoregulation. PMID- 23800644 TI - Superoxide constitutes a major signal of mitochondrial superoxide flash. AB - AIMS: Mitochondrial flashes detected with an N- and C-terminal circularly permuted yellow fluorescent protein (cpYFP) have been thought to represent transient and quantal bursts of superoxide production under physiological, stressful and pathophysiological conditions. However, the superoxide nature of the cpYFP-flash has been challenged, considering the pH-sensitivity of cpYFP and the distinctive regulation of the flash versus the basal production of mitochondrial reactive oxygen species (ROS). Thus, the aim of the study is to further determine the origin of mitochondrial flashes. MAIN METHODS: We investigated the origin of the flashes using the widely-used pH-insensitive ROS indicators, mitoSOX, an indicator for superoxide, and 2, 7 dichlorodihydrofluorescein diacetate (DCF), an indicator for H2O2 and other oxidants. KEY FINDINGS: Robust, quantal, and stochastic mitochondrial flashes were detected with either mitoSOX or DCF in several cell-types and in mitochondria isolated from the heart. Both mitoSOX-flashes and DCF-flashes showed similar incidence and kinetics to those of cpYFP-flashes, and were equally sensitive to mitochondria-targeted antioxidants. Furthermore, they were markedly decreased by inhibitors or an uncoupler of the mitochondrial electron transport chain, as is the case with cpYFP-flashes. The involvement of the mitochondrial permeability transition pore in DCF-flashes was evidenced by the coincidental loss of mitochondrial membrane potential and matrix-enriched rhod-2, as well as by their sensitivity to cyclosporine A. SIGNIFICANCE: These data indicate that all the three types of mitochondrial flashes stem from the common physiological process of bursting superoxide and ensuing H2O2 production in the matrix of single mitochondrion. PMID- 23800643 TI - Associations between structural and functional changes to the kidney in diabetic humans and mice. AB - Type 1 and Type 2 diabetic patients are at high risk of developing diabetic nephropathy (DN). Renal functional decline is gradual and there is high variability between patients, though the reason for the variability is unknown. Enough diabetic patients progress to end stage renal disease to make diabetes the leading cause of renal failure. The first symptoms of DN do not appear for years or decades after the onset of diabetes. During and after the asymptomatic period structural changes develop in the diabetic kidney. Typically, but not always, the first symptom of DN is albuminuria. Loss of renal filtration rate develops later. This review examines the structural abnormalities of diabetic kidneys that are associated with and possibly the basis for advancing albuminuria and declining GFR. Mouse models of diabetes and genetic manipulations of these models have become central to research into mechanisms underlying DN. This article also looks at the value of these mouse models to understanding human DN as well as potential pitfalls in translating the mouse results to humans. PMID- 23800645 TI - Diacylglycerol promotes GLUT4 translocation to the cell surface in a PKCepsilon dependent and PKClambda/iota and -zeta-independent manner. AB - AIM: Emerging evidence has pointed to the participation of protein kinase C (PKC) in insulin-regulated trafficking of the glucose transporter GLUT4. The present study investigated the effect of the PKC activator diacylglycerol (DAG) on GLUT4 trafficking and glucose uptake. MAIN METHODS: 3T3L1-GLUT4myc fibroblast cells expressing GLUT4myc were differentiated into adipocytes. Western blotting, glucose assay, and real-time RT-PCR were carried out in 3T3L1-GLUT4myc adipocytes. PKClambda/iota, -zeta, -epsilon, and -gamma were knocked-down by transfecting each siRNA. Activity of PKC isozymes was assayed under the cell-free conditions. KEY FINDINGS: Insulin increased cell surface localization of GLUT4 in 3T3L1-GLUT4myc adipocytes, and a similar effect was obtained with 1,2-dioleoyl-sn glycerol (DO-DAG), 1-oleoyl-2-acetyl-sn-glycerol (OA-DAG), or 1,2-dipalmitoyl-sn glycerol (DP-DAG). Like insulin, DO-DAG stimulated glucose uptake into adipocytes, but no significant synergistic increase in the glucose uptake was found with co-treatment with insulin and DO-DAG. Insulin activated Akt in adipocytes, but no Akt activation was induced by any investigated DAG. In the cell-free PKC assay, DAGs examined here activated PKCalpha, -betaI, -betaII, gamma, -delta, and -epsilon, but the atypical PKC isozymes PKClambda/iota and zeta were not activated. Insulin-induced GLUT4 translocation to the cell surface was inhibited by knocking-down PKClambda/iota and -zeta, but not PKCgamma or epsilon. In contrast, DO-DAG-induced GLUT4 translocation to the cell surface was clearly prevented by knocking-down PKCepsilon. SIGNIFICANCE: The results of the present study indicate that DAG stimulates GLUT4 translocation to the cell surface by activating PKCepsilon, regardless of PKClambda/-iota and -zeta. PMID- 23800646 TI - Prolonged postsurgical recovery period and adverse effects of a leptin application in endotoxemic obese rodents. AB - AIMS: Increasing evidence suggests that the adipokine leptin plays a role in modulating immune responses and mediating the link between metabolism and immune system. Obese patients are more susceptible to infections than normal weight individuals. To define the pathophysiological role of leptin during endotoxemia, we examined the effects of leptin on energy metabolism, hemodynamics and quality of life in normal weight and diet-induced obese rats by means of radio-telemetry. MAIN METHODS: Telemetric-transmitter and a central venous catheter were implanted in male Lewis rats. All animals performed two experiments. First, an intravenous injection of 500MUlkg(-1) leptin or vehicle (isotonic saline) was performed. After an infusion time of 30min an i.v. bolus of 0.2ml saline over 1min was injected. In the second phase, infusion of placebo or 500MUlkg(-1) leptin and an i.v. bolus injection of 100MUlkg(-1)Escherichia coli endotoxin were performed. Mean arterial blood pressure (MAP), locomotor activity and electromyogram were recorded via radio-telemetry. Food and water consumption were assessed daily. Quality of life tests were performed at specific times. KEY FINDINGS: Obese animals displayed a prolonged postsurgical recovery period. No benefit could be observed by exogenous leptin in endotoxemic lean or obese animals regarding nutrition balance and locomotor activity. However, leptin treatment even destabilized MAP in obese endotoxemic animals. SIGNIFICANCE: These data demonstrate the necessity to differentiate between normal weight and obese individuals when targeting novel therapeutic strategies for endotoxemia and point out the body weight dependent postsurgical recovery period. PMID- 23800647 TI - Liquid balance monitoring inside conventional, Retrofit, and bio-reactor landfill cells. AB - The Outer Loop landfill bioreactor (OLLB) in Louisville, KY, USA has been the site of a study to evaluate long-term bioreactor performance at a full-scale operational landfill. Three types of landfill units were studied including a conventional landfill (Control cell), a new landfill area that had an air addition and recirculation piping network installed as waste was being placed (As Built cell), and a conventional landfill that was modified to allow for liquids recirculation (Retrofit cell). During the monitoring period, the Retrofit, Control, and As-Built cells received 48, 14, and 213LMg(-1) (liters of liquids per metric ton of waste), respectively. The leachate collection system yielded 60, 57 and 198LMg(-1) from the Retrofit, Control, and As-Built cells, respectively. The head on liner in all cells was below regulatory limits. In the Control and As-Built cells, leachate head on liner decreased once waste placement stopped. The measured moisture content of the waste samples was consistent with that calculated from the estimate of accumulated liquid by the liquid balance. Additionally, measurements on excavated solid waste samples revealed large spatial variability in waste moisture content. The degree of saturation in the Control cells decreased from 85% to 75%. The degree of saturation increased from 82% to 83% due to liquids addition in the Retrofit cells and decreased back to 80% once liquid addition stopped. In the As-Built cells, the degree of saturation increased from 87% to 97% during filling activities and then started to decrease soon after filling activities stopped to reach 92% at the end of the monitoring period. The measured leachate generation rates were used to estimate an in-place saturated hydraulic conductivity of the MSW in the range of 10(-8) to 10(-7)ms( 1) which is lower than previous reports. In the Control and Retrofit cells, the net loss in liquids, 43 and 12LMg(-1), respectively, was similar to the measured settlement of 15% and 5-8% strain, respectively (Abichou et al., 2013). The increase in net liquid volume in the As-Built cells indicates that the 37% (average) measured settlement strain in these cells cannot be due to consolidation as the waste mass did not lose any moisture but rather suggests that settlement was attributable to lubrication of waste particle contacts, softening of flexible porous materials, and additional biological degradation. PMID- 23800648 TI - Estimating water content in an active landfill with the aid of GPR. AB - Landfill gas (LFG) receives a great deal of attention due to both negative and positive environmental impacts, global warming and a green energy source, respectively. However, predicting the quantity of LFG generated at a given landfill, whether active or closed is difficult due to the heterogeneities present in waste, and the lack of accurate in situ waste parameters like water content. Accordingly, ground penetrating radar (GPR) was evaluated as a tool for estimating in situ water content. Due to the large degree of subsurface heterogeneity and the electrically conductive clay cap covering landfills, both of which affect the transmission of the electromagnetic pulses, there is much scepticism concerning the use of GPR to quantify in situ water content within a municipal landfill. Two landfills were studied. The first landfill was used to develop the measurement protocols, while the second landfill provided a means of confirming these protocols. GPR measurements were initially completed using the surface GPR approach, but the lack of success led to the use of borehole (BH) GPR. Both zero offset profiling (ZOP) and multiple offset gathers (MOG) modes were tried, with the results indicating that BH GPR using the ZOP mode is the most simple and efficient method to measure in situ water content. The best results were obtained at a separation distance of 2m, where higher the water content, smaller the effective separation distance. However, an increase in water content did appear to increase the accuracy of the GPR measurements. For the effective separation distance of 2m at both landfills, the difference between GPR and lab measured water contents were reasonable at 33.9% for the drier landfill and 18.1% for the wetter landfill. Infiltration experiments also showed the potential to measure small increases in water content. PMID- 23800650 TI - Design and simulation of GaN based Schottky betavoltaic nuclear micro-battery. AB - The current paper presents a theoretical analysis of Ni-63 nuclear micro-battery based on a wide-band gap semiconductor GaN thin-film covered with thin Ni/Au films to form Schottky barrier for carrier separation. The total energy deposition in GaN was calculated using Monte Carlo methods by taking into account the full beta spectral energy, which provided an optimal design on Schottky barrier width. The calculated results show that an 8 MUm thick Schottky barrier can collect about 95% of the incident beta particle energy. Considering the actual limitations of current GaN growth technique, a Fe-doped compensation technique by MOCVD method can be used to realize the n-type GaN with a carrier concentration of 1*10(15) cm(-3), by which a GaN based Schottky betavoltaic micro battery can achieve an energy conversion efficiency of 2.25% based on the theoretical calculations of semiconductor device physics. PMID- 23800651 TI - Acute kidney injury secondary to exposure to insecticides used for bedbug (Cimex lectularis) control. AB - Bedbug (Cimex lectularis) infestation is becoming a worldwide epidemic due to the emergence of insecticide-resistant strains. Pyrethroids are approved by the US Environmental Protection Agency for use against bedbugs and are considered minimally toxic to humans, with known respiratory, neurologic, and gastrointestinal effects. We present the first reported case of pyrethroid induced toxic acute tubular necrosis (ATN). A 66-year-old healthy woman receiving no prior nephrotoxic medications presented with extreme weakness, decreased urine output, and acute kidney injury. She had administered multiple applications of a bedbug spray (permethrin) and a fogger (pyrethrin), exceeding the manufacturer's recommended amounts. She was found to have severe nonoliguric acute kidney injury associated with profound hypokalemia. Kidney biopsy revealed toxic ATN with extensive tubular degenerative changes and cytoplasmic vacuolization. With conservative management, serum creatinine level decreased from 13.0 mg/dL (estimated glomerular filtration rate, 3 mL/min/1.73 m(2)) to 1.67 mg/dL (estimated glomerular filtration rate, 37 mL/min/1.73 m(2)) within 6 weeks. Literature review uncovered no prior report of pyrethroid insecticide-induced ATN in humans, although there are reports of ATN with similar tubular vacuolization in rats exposed to this agent. Bedbug insecticides containing pyrethroids should be used with caution due to the potential development of toxic ATN after prolonged exposure. PMID- 23800652 TI - Predictors of agreement between general practitioner detection of dementia and the revised Cambridge Cognitive Assessment (CAMCOG-R). AB - BACKGROUND: Dementia is a complex and variable condition which makes recognition of it particularly difficult in a low prevalence primary care setting. This study examined the factors associated with agreement between an objective measure of cognitive function (the revised Cambridge Cognitive Assessment, CAMCOG-R) and general practitioner (GP) clinical judgment of dementia. METHODS: This was a cross-sectional study involving 165 GPs and 2,024 community-dwelling patients aged 75 years or older. GPs provided their clinical judgment in relation to each of their patient's dementia status. Each patient's cognitive function and depression status was measured by a research nurse using the CAMCOG-R and the 15 item Geriatric Depression Scale (GDS), respectively. RESULTS: GPs correctly identified 44.5% of patients with CAMCOG-R dementia and 90% of patients without CAMCOG-R dementia. In those patients with CAMCOG-R dementia, two patient dependent factors were most important for predicting agreement between the CAMCOG R and GP judgment: the CAMCOG-R score (p = 0.006) and patient's mention of subjective memory complaints (SMC) to the GP (p = 0.040). A higher CAMCOG-R (p < 0.001) score, female gender (p = 0.005), and larger practice size (p < 0.001) were positively associated with GP agreement that the patient did not have dementia. Subjective memory complaints (p < 0.001) were more likely to result in a false-positive diagnosis of dementia. CONCLUSIONS: Timely recognition of dementia is advocated for optimal dementia management, but early recognition of a possible dementia syndrome needs to be balanced with awareness of the likelihood of false positives in detection. Although GPs correctly agree with dimensions measured by the CAMCOG-R, improvements in sensitivity are required for earlier detection of dementia. PMID- 23800653 TI - Clinical and pathological features of primary neuroectodermal tumor/Ewing sarcoma of the kidney. AB - OBJECTIVE: To collect and analyze clinical and pathological features of primitive neuroectodermal tumor (PNET)/Ewing sarcoma (EWS), a rare tumor occurring most commonly in bone and soft tissues of young people, which rarely occurs as a primary renal neoplasm and exhibits highly aggressive biological behavior. METHODS: All cases of PNET/EWS published from 1975 to February 2012 were collected. When available, clinical and pathological data were extracted for each case. Survivals were estimated with the Kaplan-Meier method and compared with the log-rank test with 95% confidence interval (CI). RESULTS: A total of 116 cases were found. All patients had clinical symptoms as first presentation of disease such as pain (54%), hematuria (29%), and bulky renal mass (28%). Sixty-six percent of patients had stage IV disease at diagnosis. Median disease-free survival (DFS) was 5.0 months (95% CI 2.4-7.6). The probability to be alive at 18 months was 60% and 85% for patients with metastatic disease (M1) or not (M0) at diagnosis, respectively. Median overall survival (OS) was 24 months (95% CI 4.5 15.1) in patients with M1 disease, whereas it was not reached in patients with M0 disease (P <.001). In patients with M0 disease, 50% received neoadjuvant chemotherapy and the 12-month OS was 93% compared to 75% of untreated patients (P = .092). In patients with M1 disease who underwent treatment, the median progression-free survival (PFS) was 22.0 months (95% CI 17.9-26.1) with a clinical benefit in 74% of cases. CONCLUSION: Our findings suggest that PNET/EWS is a rare aggressive tumor affecting principally young people, with a poor prognosis for patients with M1 disease; chemotherapy is an effective strategy in M1 disease and probably also in M0 disease. PMID- 23800655 TI - Growth factors in preeclampsia: a vascular disease model. A failed vasodilation and angiogenic challenge from pregnancy onwards? AB - Preeclampsia is the major cause of maternofetal and neonatal morbi-mortality including intrauterine growth retardation, miscarriages and stillbirths. Inadequate vascular dilation and angiogenesis represent the crucial underlying defect of gravidic hypertension, denoting a failed response to the vasodilatory and pro-angiogenic challenge imposed by pregnancy, especially if multifetal. A similar pathogenesis appears involved in gestational diabetes. In this review we aimed to provide a hint on understanding the deeply involved angiogenic disorders which eventually culminate in utero-placental failure. The key players in these complex processes may be found in an intricate network of growth factors (GFs) and GF inhibitors, controlled by several vascular risk factors modulated by environment and genes, which eventually impact on early and late cardiovascular outcomes of mother and fetus. PMID- 23800654 TI - Fine tuning a well-oiled machine: Influence of NK1.1 and NKG2D on NKT cell development and function. AB - Natural killer T cells (NKT) represent a group of CD1d-restricted T-lineage cells that provide a functional interface between innate and adaptive immune responses in infectious disease, cancer, allergy and autoimmunity. There have been remarkable advances in understanding the molecular events that underpin NKT development in the thymus and in the complex array of functions in the periphery. Most functional studies have focused on activation of T cell antigen receptors expressed by NKT cells and their responses to CD1d presentation of glycolipid and related antigens. Receiving less attention has been several molecules that are hallmarks of Natural Killer (NK) cells, but nonetheless expressed by NKT cells. These include several activating and inhibitory receptors that may fine-tune NKT development and survival, as well as activation via antigen receptors. Herein, we review the possible roles of the NK1.1 and NKG2D receptors in regulating development and function of NKT cells in health and disease. We suggest that pharmacological alteration of NKT activity should consider the potential complexities commensurate with NK1.1 and NKG2D expression. PMID- 23800656 TI - Biological characterization of the antiproliferative potential of Co(II) and Sn(IV) coordination compounds in human cancer cell lines: a comparative proteomic approach. AB - BACKGROUND: The discovery of cisplatin's antitumor activity led to a great interest in the potential application of coordination compounds as chemotherapeutic agents. It is essential to identify new compounds that selectively inhibit tumor proliferation, evading secondary effects and resistance associated with chemotherapeutics. METHODS: The in vitro antiproliferative potential of an organotin(IV) compound was evaluated using colorectal and hepatocellular carcinoma, mammary gland adenocarcinoma cell lines, and human fibroblasts. Tumor cell death was evaluated by fluorescence microscopy and flow cytometry for the Sn(IV) compound and also for a Co(II) compound bearing 1,10 phenanthroline-5,6-dione as ligand. Comparative proteomic analysis for both compounds was assessed in the colorectal cancer cell line. RESULTS: The Sn(IV) compound presented a high cytotoxic effect in colorectal and hepatocellular carcinoma cell lines (IC50 of 0.238 +/- 0.011 MUM, 0.199 +/- 0.003 MUM, respectively), and a lower cytotoxicity in human fibroblasts. Both compounds induced cell apoptosis and promoted the overexpression of oxidative stress related enzyme superoxide dismutase [Cu-Zn] (SODC). The Co(II) compound induced a decreased expression of anti-apoptotic proteins (translationally-controlled tumor protein and endoplasmin), and the Sn(IV) compound decreased expression of proteins involved in microtubule stabilization, TCTP, and cofilin-1. CONCLUSIONS: Our data reveals a high in vitro antiproliferative potential against cancer cell lines and a moderate selectivity promoted by the Sn(IV) compound. Proteomic analysis of Sn(IV) and Co(II) compounds in the colorectal cancer cell line allowed an insight to their mechanisms of action, particularly by affecting the expression of proteins typically deregulated in cancer, and also suggesting a promising therapeutic potential for both compounds. PMID- 23800657 TI - Performance characteristics of consensus approaches for small and minor paroxysmal nocturnal hemoglobinuria clone determination by flow cytometry. AB - BACKGROUND: Evaluation of paroxysmal nocturnal hemoglobinuria (PNH) clones by flow cytometry (FCM) is not standardized and is associated with consistent inter laboratory variability. METHODS: In order to rule out the influence of particular approach in generating final results, we analyzed the performance characteristics of individual consensus strategies for small to intermediate (1%-20%) and minor (<1%) PNH clones within the white blood cell (WBC) and red blood cell (RBC) compartments with sensitivity up to 0.1%. RESULTS: Coefficient of variation (CV) for precision/reproducibility analysis ranged from 0.67%/1.49% to 2.56%/3.09% for granulocytes, from 0.93%/3.09% to 7.76%/12.06% for monocytes and from 0.41%/4.73% to 6.53%/5.1% for RBCs. Coefficient of determination (r2) for linear regression analysis ranged from 0.95 to 0.99, Wilcoxon ranks test showed no statistically significant differences (p>0.05), Bland-Altman analysis demonstrated performance agreement with mean bias ranging from -0.18 to 1.24. CONCLUSIONS: Our results confirmed very good performance characteristics for precision and reproducibility analysis, excellent correlation and favorable agreement between strategies, suggesting that reported inter-laboratory variability is related mainly to incorrect performance and/or insufficient experience with PNH testing by flow cytometry, rather than to relevant limitations of any particular approach. PMID- 23800658 TI - Measurement of immature platelets with Abbott CD-Sapphire and Sysmex XE-5000 in haematology and oncology patients. AB - BACKGROUND: Measurement of immature platelets was introduced into routine diagnostics by Sysmex as immature platelet fraction (IPF) some years ago and recently by Abbott as reticulated platelet fraction (rPT). Here, we compare both methods. METHODS: We evaluated the precision and agreement of these parameters between Sysmex XE-5000 and Abbott CD-Sapphire in three distinct thrombocytopaenic cohorts: 30 patients with beginning thrombocytopaenia and 64 patients with recovering platelets (PLT) after chemotherapy, 16 patients with immune thrombocytopaenia (ITP) or heparin-induced thrombocytopaenia type 2 (HIT) and 110 additional normal controls. Furthermore, we analysed, how IPF/rPT differed between these thrombocytopaenic cohorts and controls. RESULTS: Both analysers demonstrated acceptable overall precision (repeatability) of IPF/rPT with lower precision at low PLT counts. IPF/rPT artificially increased during storage of blood samples overnight. Inter-instrument comparison showed a moderate correlation (Pearson r2=0.38) and a systematic bias of 1.04 towards higher IPF values with the XE-5000. IPF/rPT was highest in recovering thrombopoesis after chemotherapy and moderately increased in ITP/HIT. The normal range deduced from control samples was much narrower with CD-Sapphire (1.0%-3.8%, established here for the first time) in comparison to XE-5000 (0.8%-7.9%) leading to a smaller overlap of samples with increased PLT turnover and normal controls. CONCLUSIONS: IPF and rPT both give useful information on PLT turnover, although the two analysers only show a moderate inter-instrument correlation and have different reference ranges. A better separation of patient groups with high PLT turnover like ITP/HIT from normal controls is obtained by CD-Sapphire. PMID- 23800659 TI - Red cell indices: differentiation between beta-thalassemia trait and iron deficiency anemia and application to sickle-cell disease and sickle-cell thalassemia. AB - BACKGROUND: In Tunisia, thalassemia and sickle cell disease represent the most prevalent monogenic hemoglobin disorders with 2.21% and 1.89% of carriers, respectively. This study aims to evaluate the diagnosis reliability of a series of red blood cell indices and parameters in differentiation of beta-thalassemia trait (beta-TT) from iron deficiency anemia (IDA) and between homozygous sickle cell disease (SS) and sickle cell-thalassemia (ST). METHODS: The study covered 384 patients divided into three groups. The first one is composed of 145 control group, the second consists of 57 beta-TT and 52 IDA subjects and the last one with 88 SS and 42 ST patients. We calculated sensitivity, specificity, positive predictive values, negative-predictive values, percentage of correctly identified patients and Youden's index for each indice. We also established new cut-off values by receiver operating characteristic curves for each indice. An evaluation study was performed on another population composed of 106 beta-TT, 125 IDA, 31 SS and 17 ST patients. RESULTS: Srivastava Index, mean corpuscular hemoglobin, red blood cell, Mentzer Index (MI) and mean corpuscular hemoglobin concentration show the highest reliability in discriminating beta-TT from IDA with new cut-offs slightly different from those described in literature. Ehsani Index, mean corpuscular volume, MI, Shine and Lal Index and Sirdah Index are the most powerful in the differentiation between SS and ST. CONCLUSIONS: The effectiveness and the simplicity of calculation of these indices make them acceptable and easy to use for differential diagnosis. PMID- 23800660 TI - Overexpression of sheepgrass R1-MYB transcription factor LcMYB1 confers salt tolerance in transgenic Arabidopsis. AB - Sheepgrass [Leymus chinensis (Trin.) Tzvel.] is a dominant, rhizomatous grass that has extensive plasticity in adapting to various harsh environments. Based on data from 454 high-throughput sequencing (GS FLX) exposure to salt stress, an unknown functional MYB-related gene LcMYB1 was identified from sheepgrass. Tissue specific expression profiles showed that the LcMYB1 gene was expressed ubiquitously in different tissues, with higher expression levels observed in the rhizome and panicle. The expression of LcMYB1 was induced obviously by high salt, drought and abscisic acid and was induced slightly by cold. A fusion protein of LcMYB1 with green fluorescent protein (GFP) was localized to the nucleus, and yeast one-hybrid analysis indicated that LcMYB1 was an activator of transcriptional activity. LcMYB1-overexpressing plants were more tolerant to salt stress than WT plants. The amounts of proline and soluble sugars were higher in transgenic Arabidopsis than in WT plants under salt stress conditions. The overexpression of LcMYB1 enhanced the expression levels of P5CS1 and inhibited other salt stress response gene markers. These findings demonstrate that LcMYB1 influences the intricate salt stress response signaling networks by promoting different pathways than the classical DREB1A- and MYB2-mediated signaling pathway. Additionally, LcMYB1 is a promising gene resource for improving salinity tolerance in crops. PMID- 23800661 TI - The Solanum chacoense ovary receptor kinase 11 (ScORK11) undergoes tissue dependent transcriptional, translational and post-translational regulation. AB - Using a subtraction screen to isolate weakly expressed transcripts from ovule and ovary libraries, we uncovered 30 receptor-like kinases that were predominantly expressed in ovary and fruit tissues following fertilization [1]. Here we describe the analysis of Solanum chacoense ovule receptor kinase 11 (ScORK11), a member of the large LRR III receptor kinase subfamily that localizes to the plasma membrane. In situ analyses demonstrated that ScORK11 gene expression was mainly restricted to the ovule integument, the embryo sac and the pericarp of the fruit. Tight regulation of ScORK11 expression at the mRNA level was also accompanied by both translational and post-translational regulation of protein levels. PMID- 23800662 TI - Expression profiling of genes involved in ascorbate biosynthesis and recycling during fleshy root development in radish. AB - Ascorbate is a primary antioxidant and an essential enzyme cofactor in plants, which has an important effect on the development of plant root system. To investigate the molecular mechanisms of ascorbate accumulation during root development and reveal the key genes of the ascorbate biosynthesis and recycling pathways, the expression of 16 related genes together with ascorbate abundance were analyzed in the flesh and skin of radish (Raphanus sativus L.) fleshy root. The content of ascorbate decreased with root growth in both the flesh and skin. Expression of GDP-d-mannose pyrophosphorylase, GDP-d-mannose-3',5'-epimerase and d-galacturonate reductase were also decreased and correlated with ascorbate levels in the flesh. In the skin, the expression of GDP-d-mannose pyrophosphorylase and l-galactose dehydrogenase was correlated with ascorbate levels. These results suggested that ascorbate accumulation is affected mainly by biosynthesis rather than recycling in radish root, and the l-galactose pathway may be the major biosynthetic route of ascorbate, and moreover, the salvage pathway may also contribute to ascorbate accumulation. The data suggested that GDP-d-mannose pyrophosphorylase could play an important role in the regulation of ascorbate accumulation during radish fleshy taproot development. PMID- 23800663 TI - Hydrogen sulfide alleviates hypoxia-induced root tip death in Pisum sativum. AB - Flooding of soils often results in hypoxic conditions surrounding plant roots, which is a harmful abiotic stress to crops. Hydrogen sulfide (H2S) is a highly diffusible, gaseous molecule that modulates cell signaling and is involved in hypoxia signaling in animal cells. However, there have been no previous studies of H2S in plant cells in response to hypoxia. The effects of H2S on hypoxia induced root tip death were studied in pea (Pisum sativum) via analysis of endogenous H2S and reactive oxygen species (ROS) levels. The activities of key enzymes involved in antioxidative and H2S metabolic pathways were determined using spectrophotometric assays. Ethylene was measured by gas chromatography. We found that exogenous H2S pretreatment dramatically alleviated hypoxia-induced root tip death by protecting root tip cell membranes from ROS damage induced by hypoxia and by stimulating a quiescence strategy through inhibiting ethylene production. Conversely, root tip death induced by hypoxia was strongly enhanced by inhibition of the key enzymes responsible for endogenous H2S biosynthesis. Our results demonstrated that exogenous H2S pretreatment significantly alleviates hypoxia-induced root tip death in pea seedlings and, therefore, enhances the tolerance of the plant to hypoxic stress. PMID- 23800664 TI - Interplay between ABA and phospholipases A(2) and D in the response of citrus fruit to postharvest dehydration. AB - The interplay between abscisic acid (ABA) and phospholipases A2 and D (PLA2 and PLD) in the response of citrus fruit to water stress was investigated during postharvest by using an ABA-deficient mutant from 'Navelate' orange named 'Pinalate'. Fruit from both varieties harvested at two different maturation stages (mature-green and full-mature) were subjected to prolonged water loss inducing stem-end rind breakdown (SERB) in full-mature fruit. Treatment with PLA2 inhibitor aristolochic acid (AT) and PLD inhibitor lysophosphatidylethanolamine (LPE) reduced the disorder in both varieties, suggesting that phospholipid metabolism is involved in citrus peel quality. Expression of CsPLDalpha and CsPLDbeta, and CssPLA2alpha and CssPLA2beta was studied by real-time RT-PCR during water stress and in response to ABA. CsPLDalpha expression increased in mature-green fruit from 'Navelate' but not in 'Pinalate' and ABA did not counteract this effect. ABA enhanced repression of CsPLDalpha in full-mature fruit. CsPLDbeta gene expression decreased in mature-green 'Pinalate', remained unchanged in 'Navelate' and was induced in full-mature fruit from both varieties. CssPLA2alpha expression increased in mature-green fruit from both varieties whereas in full-mature fruit only increased in 'Navelate'. CssPLA2beta expression increased in mature-green flavedo from both varieties, but in full-mature fruit remained steady in 'Navelate' and barely increased in 'Pinalate' fruit. ABA reduced expression in both after prolonged storage. Responsiveness to ABA increased with maturation. Our results show interplay between PLA2 and PLD and suggest that ABA action is upstream phospholipase activation. Response to ABA during water stress in citrus is regulated during fruit maturation and involves membrane phospholipid degradation. PMID- 23800665 TI - Protection of dopaminergic neurons by 5-lipoxygenase inhibitor. AB - Neuroinflammation and oxidative stress are important factors that induce neurodegeneration in age-related neurological disorders. 5-Lipoxygenase (5-LOX) is the enzyme responsible for catalysing the synthesis of leukotriene or 5-HETE from arachidonic acid. 5-LOX is expressed in the central nervous system and may cause neurodegenerative disease. In this study, we investigated the effect of the pharmacological inhibition of 5-lipoxygenase on 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)/MPP(+)-induced dopaminergic neuronal death in midbrain neuron-glia co-cultures and in mice. It was found that 5-LOX was over-expressed in astrocytes after the injection of MPTP into C57BL6 mice. MK-886, a specific inhibitor of 5-LOX activating protein (FLAP), significantly increased [(3)H] dopamine uptake, a functional indicator of the integrity of dopaminergic neurons, in midbrain cultures or the SH-SY5Y human dopaminergic cell line following MPP(+) treatment. In addition, LTB4, one of 5-LOX's downstream products, was increased in the striatum and substantia nigra following MPTP injection in mice. LTB4 but not LTD4 and 5-HETE enhanced MPP(+)-induced neurotoxicity in primary midbrain cultures. MK-886 administration increased the number of tyrosine hydroxylase positive neurons in the substantia nigra and the dopamine content in the striatum in MPTP-induced parkinsonian mice. Furthermore, the MPTP-induced upregulation of LTB4 in the striatum and substantia nigra was antagonised by MK-886. These results suggest that 5-LOX inhibitors may be developed as novel neuroprotective agents and LTB4 may play an important pathological role in Parkinson's disease. PMID- 23800666 TI - Aberrant and alternative splicing in skeletal system disease. AB - The main function of skeletal system is to support the body and help movement. A variety of factors can lead to skeletal system disease, including age, exercise, and of course genetic makeup and expression. Pre-mRNA splicing plays a crucial role in gene expression, by creating multiple protein variants with different biological functions. The recent studies show that several skeletal system diseases are related to pre-mRNA splicing. This review focuses on the relationship between pre-mRNA splicing and skeletal system disease. On the one hand, splice site mutation that leads to aberrant splicing often causes genetic skeletal system disease, like COL1A1, SEDL and LRP5. On the other hand, alternative splicing without genomic mutation may generate some marker protein isoforms, for example, FN, VEGF and CD44. Therefore, understanding the relationship between pre-mRNA splicing and skeletal system disease will aid in uncovering the mechanism of disease and contribute to the future development of gene therapy. PMID- 23800667 TI - A functional (E)-4-hydroxy-3-methylbut-2-enyl diphosphate reductase exhibits diurnal regulation of expression in Stevia rebaudiana (Bertoni). AB - The leaves of stevia [Stevia rebaudiana (Bertoni)] are a rich source of steviol glycosides that are used as non-calorific sweetener in many countries around the world. Steviol moiety of steviol glycosides is synthesized via plastidial 2C methyl-D-erythritol 4-phosphate pathway, where (E)-4-hydroxy-3-methylbut-2-enyl diphosphate reductase (HDR) is the key enzyme. HDR catalyzes the simultaneous conversion of (E)-4-hydroxy-3-methylbut-2-enyl diphosphate into five carbon isoprenoid units, isopentenyl diphosphate and dimethylallyl diphosphate. Stevia HDR (SrHDR) successfully rescued HDR lethal mutant strain MG1655 ara<>ispH upon genetic complementation, suggesting SrHDR to encode a functional protein. The gene exhibited diurnal variation in expression. To identify the possible regulatory elements, upstream region of the gene was cloned and putative cis acting elements were detected by in silico analysis. Electrophoretic mobility shift assay, using a putative light responsive element GATA showed the binding of nuclear proteins (NP) isolated from leaves during light period of the day, but not with the NP from leaves during the dark period. Data suggested the involvement of GATA box in light mediated gene regulation of SrHDR in stevia. PMID- 23800668 TI - Molecular characterization of major and minor rDNA repeats and genetic variability assessment in different species of mahseer found in North India. AB - Relationship among the mahseer species (Family: Cyprinidae) has long been debated in fish systematics. Present study concentrates on the nature of the phylogenetic relationship among the five mahseer species using the sequence of major ribosomal DNA (45S rDNA). We have covered rDNA sequence of approximately 5.2 kb per individual, 26.0 kb per species and 130.0 kb as a whole. We also characterized the 45S and 5S rDNA regions with respect to their nucleotide composition. For phylogenetic analyses, nucleotide sequences were divided into four datasets. First and second datasets contained 18S rDNA and ITS1 sequence, whereas third and fourth datasets consisted of ITS2 and complete 18S-ITS1-5.8S-ITS2-28S, respectively. The NJ tree was constructed for all the datasets. The mahseer species under study formed a monophyletic group well separated from the outgroup species. Similarly, the individuals of Neolissochilus hexagonolepis form monophyletic group with Tor species, indicating Neolissochilus as a sister genus of Tor. The findings from the present study provide greater insights into taxonomic status of mahseer, and set the stage for future investigations dealing with phylo-geography, taxonomy, conservation and co-evolution within this interesting and important group of fish. PMID- 23800669 TI - Impact of the interval between short-course radiotherapy and surgery on outcomes of rectal cancer patients. AB - AIMS: Pre-operative radiotherapy has proven to reduce local recurrences after curative surgery for rectal cancer. Radiotherapy is generally well tolerated, although postoperative morbidity and mortality was increased in some patients. Current study was undertaken to analyse whether the interval between preoperative radiotherapy and surgery influences post-operative mortality and recurrence for two cohorts. METHODS: All Dutch patients included in the total mesorectal excision (TME)-trial receiving radiotherapy for resectable rectal cancer were included in this study (n=642). The verification set consisted of all patients receiving short-course radiotherapy for resectable rectal cancer in two radiotherapy clinics in The Netherlands (n=600). Univariate and multivariable survival analyses for overall survival, disease-free survival, local recurrence free survival and non-cancer related survival were calculated. RESULTS: Patients aged 75 years and older treated during the TME-trial showed a worse overall and non-cancer-related survival when surgically treated 4-7 days after the last fraction of radiotherapy. No differences in survival between the interval groups were found in the verification set. CONCLUSION: Present study found that elderly patients aged 75 years and older operated 4-7 days after the last fraction of radiotherapy had a higher chance of dying due to non-cancer-related causes during the TME-trial as compared to patients with an interval of 0-3 days. In the verification set similar differences could not be confirmed, which could be due to awareness of the clinicians who avoided delayed surgery after radiotherapy since the results have been presented during congresses. A longer than recommended interval between radiotherapy and surgery should be avoided. Besides, the verification set suggests that radiotherapy duration of 7 days is acceptable. PMID- 23800670 TI - Hormone replacement therapy increases the risk of cranial meningioma. AB - AIM: We investigated the influence of hormone replacement therapy (HRT) use on the risk of meningioma in a population-based setting. METHODS: We conducted a nationwide case-control study in Denmark based on population-based administrative and health registries. The study included all female patients aged 55-84 years with a first time diagnosis of meningioma during 2000-2009. The cases were matched on birth year with female population controls. Ever use of HRT since 1995 was defined as >=2 HRT prescriptions and categorised according to HRT type (oestrogen only, combined oestrogen-progestagen, and progestagen only) and cumulated duration of use (<1, >=1 to <5, >=5 to <10, >=10 years). We used conditional logistic regression to compute odds ratios (ORs), with 95% confidence intervals (CIs), for meningioma associated with HRT use, and adjusting for potential confounders. RESULTS: We identified 924 cases and 6122 controls. Ever use of HRT was associated with an increased risk of meningioma (OR, 1.3; 95%CI, 1.1-1.5) compared with non-use (0-1 prescriptions). The risk increased with increasing duration of HRT use, reaching an OR of 1.7 (95% CI, 1.2-2.3) after more than 10 years of use. The risk of meningioma associated with long-term (>=10 years) HRT use was most pronounced for combined oestrogen-progestagen therapy (OR, 2.2; 95% CI, 1.4-3.3), especially when this regimen constituted the sole HRT therapy (OR, 2.7; 95% CI, 0.9-7.5), although the latter estimate was based on small numbers. CONCLUSIONS: Long-term HRT use, particularly of combined oestrogen progestagen therapy, may increase the risk of meningioma. PMID- 23800671 TI - Preoperative chemo(radio)therapy versus primary surgery for gastroesophageal adenocarcinoma: systematic review with meta-analysis combining individual patient and aggregate data. AB - BACKGROUND: The prognosis of patients with gastroesophageal adenocarcinoma is poor. There is conflicting evidence regarding effects of preoperative chemotherapy on survival and other outcomes. METHODS: We conducted a meta analysis with aggregate and individual patient data (IPD) to assess the effect of preoperative chemotherapy for gastroesophageal adenocarcinoma on survival and other outcomes. Two independent reviewers identified eligible randomised controlled trials (RCTs) comparing chemotherapy+/-radiotherapy followed by surgery with surgery alone for gastroesophageal adenocarcinoma. IPD was solicited from all trials. Meta-analyses were performed using the two stage method. RESULTS: We identified 14 RCTs (2422 patients). For eight RCTs (1049 patients; 43.3%) we obtained IPD. Preoperative chemotherapy was associated with longer overall survival (hazard ratio [HR] 0.81; 95% confidence interval [CI] 0.73-0.89; p<0.0001). There were larger treatment effects in tumours of the gastroesophageal junction and for chemoradiotherapy compared to chemotherapy, but the tests for subgroup differences were not statistically significant. Preoperative chemotherapy was associated with longer disease-free survival, higher likelihood of R0 resection and more favourable post-treatment tumour stage, but not perioperative complications. CONCLUSION: Preoperative chemotherapy for locoregional gastroesophageal adenocarcinoma increases survival compared to surgery alone. It should be offered to all eligible patients. There appear to be larger survival advantages in tumours of the gastroesophageal junction and for chemoradiotherapy, but these findings require prospective confirmation. PMID- 23800672 TI - Local recurrence following breast-conserving treatment in women aged 40 years or younger: trends in risk and the impact on prognosis in a population-based cohort of 1143 patients. AB - AIM: To evaluate trends in the risk of local recurrences after breast-conserving treatment (BCT) and to examine the impact of local recurrence (LR) on distant relapse-free survival in a large, population-based cohort of women aged <=40 years with early-stage breast cancer. METHODS: All women (n=1143) aged <=40 years with early-stage (pT1-2/cT1-2, N0-2, M0) breast cancer who underwent BCT in the south of the Netherlands between 1988 and 2010 were included. BCT consisted of local excision of the tumour followed by irradiation of the breast. RESULTS: After a median follow-up of 8.5 (0.1-24.6)years, 176 patients had developed an isolated LR. The 5-year LR-rate for the subgroups treated in the periods 1988 1998, 1999-2005 and 2006-2010 were 9.8% (95% confidence interval (CI) 7.1-12.5), 5.9% (95% CI 3.2-8.6) and 3.3% (95% CI 0.6-6.0), respectively (p=0.006). In a multivariate analysis, adjuvant systemic treatment was associated with a reduced risk of LR of almost 60% (hazard ratio (HR) 0.42; 95%CI 0.28-0.60; p<0.0001). Patients who experienced an early isolated LR (<=5 years after BCT) had a worse distant relapse-free survival compared to patients without an early LR (HR 1.83; 95% CI 1.27-2.64; p=0.001). Late local recurrences did not negatively affect distant relapse-free survival (HR 1.24; 95% CI 0.74-2.08; p=0.407). CONCLUSION: Local control after BCT improved significantly over time and appeared to be closely related to the increased use and effectiveness of systemic therapy. These recent results underline the safety of BCT for young women with early-stage breast cancer. PMID- 23800673 TI - Tumors metastasizing to the oral cavity: a study of 16 cases. AB - PURPOSE: An analysis was performed of the clinical and epidemiologic characteristics of a group of patients diagnosed with oral metastases of distant primary tumors or unknown primary malignancies. MATERIAL AND METHODS: The study series consisted of 16 patients with oral metastatic lesions seen in the Department of Stomatology and Maxillofacial Surgery, Valencia University General Hospital (Valencia, Spain) that had been diagnosed in the previous 15 years. A retrospective analysis was made of patient age and gender, clinical characteristics of metastatic lesions, location of the primary tumor, and time elapsed from diagnosis to the death of a patient. RESULTS: There were 13 male and 3 female patients (mean age, 58.8 years). Ten patients had been diagnosed previously and were being treated for a primary tumor; 2 patients were diagnosed with a primary malignancy in the department; and 4 patients presented with an unidentified primary tumor (metastatic disease diagnosed from biopsy study). The predominant clinical presentation was mixed soft tissue and bone metastases followed by solely soft tissue lesions and solely bone lesions. Some patients showed no apparent oral lesions. Primary malignancies originated mainly from the lung followed by the prostate, gastrointestinal tract, thyroid gland, breast, and liver. Mean survival from diagnosis of oral metastases was 8.25 months. CONCLUSION: Oral metastatic lesions are infrequent, can affect male and female patients equally, can manifest at any age, and may constitute the first manifestation of a still unidentified primary malignancy. According to the literature, bone metastases are more common than soft tissue metastases. Nevertheless, in the present series, there was a clear male predominance, and the oral metastases showed a predominance of mixed presentations followed by solely soft tissue lesions and solely bone metastases. PMID- 23800674 TI - Does skeletal surgery for asymmetric mandibular prognathism influence the soft tissue contour and thickness? AB - PURPOSE: The purpose of the present study was to investigate whether asymmetric mandibular prognathism accompanies a fundamental difference in soft tissue thickness and whether asymmetric mandibular setback surgery would influence the contour and thickness of the soft tissue of the chin. MATERIALS AND METHODS: The present retrospective study included skeletal class III patients with significant mandibular chin deviation greater than 6 mm at the pogonion, who had undergone cone-beam computed tomography before and 6 months after surgery during a 2-year period. The predictor variables were timing (pre- and postoperatively) and side (asymmetric vs contralateral). The outcome measures were the hard and soft tissue contours and soft tissue thickness of the chin at the infradentale, B-point, and pogonion level evaluated with reformatted computed tomography images. The study variables were statistically compared using regression model and correlation analysis. RESULTS: The present study consisted of 20 patients (10 males and 10 females; average age 20.2 years; range, 18 to 25). Preoperatively, the chin deviation side showed a more prominent hard and soft tissue outline but had a thinner soft tissue thickness, which camouflaged the hard tissue asymmetry. After surgery, the hard and soft tissue outline was greatly improved, and the soft tissue thickness had become nearly symmetric. Most of the soft tissue thickness changes correlated negatively with the hard tissue changes. CONCLUSIONS: Asymmetric mandibular prognathism accompanied the 3-dimensional soft tissue contour and thickness asymmetry. Because the soft tissue responds favorably after skeletal surgery, the correction of 3-dimensional asymmetry of bone should be emphasized in patients with asymmetric mandibular prognathism. PMID- 23800675 TI - Validation of an FFQ to assess antioxidant intake in overweight postmenopausal women. AB - OBJECTIVE: To validate an FFQ to assess antioxidant intake in overweight postmenopausal women. DESIGN: A seventy-four-item antioxidant 1-month FFQ was developed based on major antioxidant sources in the American diet. Forty overweight postmenopausal women participated in a 9-month observational study and completed four sets of FFQ and 7 d food record (7dFR) every 3 months. Twelve-hour fasting blood was collected for plasma antioxidant measurement at the first visit. SETTING: Connecticut, USA. SUBJECTS: Forty overweight postmenopausal women. RESULTS: Spearman correlation coefficients of 1-month antioxidant intake estimated from the first set of FFQ and 7dFR ranged from 0.34 to 0.87, except for gamma-tocopherol. The proportion of participants categorized into the extremely opposite tertiles averaged 7 %. Significant correlations were observed for diet plasma vitamin C, alpha-tocopherol and carotenoids (P < 0.05). No time effect was observed on the dietary antioxidant intakes estimated from four 7dFR and four FFQ. Dietary antioxidants estimated from averaged four 7dFR showed moderate to high correlation with those estimated from averaged four FFQ and from each FFQ collected every 3 months. Bland-Altman plots did not show any systematic bias. Averaged misclassifications were below 10 % between these two instruments. CONCLUSIONS: These findings attested a reasonable validity and a good acceptance of this 1-month FFQ in assessing both short-term and long-term diverse antioxidant intakes in these overweight postmenopausal women. The use of this FFQ in associating antioxidant intake with disease risk needs further investigation. PMID- 23800676 TI - Arsenic exposure and cancer mortality in a US-based prospective cohort: the strong heart study. AB - BACKGROUND: Inorganic arsenic, a carcinogen at high exposure levels, is a major global health problem. Prospective studies on carcinogenic effects at low moderate arsenic levels are lacking. METHODS: We evaluated the association between baseline arsenic exposure and cancer mortality in 3,932 American Indians, 45 to 74 years of age, from Arizona, Oklahoma, and North/South Dakota who participated in the Strong Heart Study from 1989 to 1991 and were followed through 2008. We estimated inorganic arsenic exposure as the sum of inorganic and methylated species in urine. Cancer deaths (386 overall, 78 lung, 34 liver, 18 prostate, 26 kidney, 24 esophagus/stomach, 25 pancreas, 32 colon/rectal, 26 breast, and 40 lymphatic/hematopoietic) were assessed by mortality surveillance reviews. We hypothesized an association with lung, liver, prostate, and kidney cancers. RESULTS: Median (interquartile range) urine concentration for inorganic plus methylated arsenic species was 9.7 (5.8-15.6) MUg/g creatinine. The adjusted HRs [95% confidence interval (CI)] comparing the 80th versus 20th percentiles of arsenic were 1.14 (0.92-1.41) for overall cancer, 1.56 (1.02-2.39) for lung cancer, 1.34 (0.66, 2.72) for liver cancer, 3.30 (1.28-8.48) for prostate cancer, and 0.44 (0.14, 1.14) for kidney cancer. The corresponding hazard ratios were 2.46 (1.09-5.58) for pancreatic cancer, and 0.46 (0.22-0.96) for lymphatic and hematopoietic cancers. Arsenic was not associated with cancers of the esophagus and stomach, colon and rectum, and breast. CONCLUSIONS: Low to moderate exposure to inorganic arsenic was prospectively associated with increased mortality for cancers of the lung, prostate, and pancreas. IMPACT: These findings support the role of low-moderate arsenic exposure in development of lung, prostate, and pancreas cancer and can inform arsenic risk assessment. PMID- 23800677 TI - A practical scoring system to determine whether to proceed with surgical resection in recurrent glioblastoma. AB - BACKGROUND: To determine the benefit of surgical management in recurrent glioblastoma, we analyzed a series of patients with recurrent glioblastoma who had undergone surgery, and we devised a new scale to predict their survival. METHODS: Clinical data from 55 consecutive patients with recurrent glioblastoma were evaluated after surgical management. Kaplan-Meier survival analysis and Cox proportional hazards regression modeling were used to identify prognostic variables for the development of a predictive scale. After the multivariate analysis, performance status (P = .078) and ependymal involvement (P = .025) were selected for inclusion in the new prognostic scale. The devised scale was validated with a separate set of 96 patients from 3 different institutes. RESULTS: A 3-tier scale (scoring range, 0-2 points) composed of additive scores for the Karnofsky performance status (KPS) (0 for KPS >= 70 and 1 for KPS < 70) and ependymal involvement (0 for no enhancement and 1 for enhancement of the ventricle wall in the magnetic resonance imaging) significantly distinguished groups with good (0 points; median survival, 18.0 months), intermediate (1 point; median survival, 10.0 months), and poor prognoses (2 points; median survival, 4.0 months). The new scale was successfully applied to the validation cohort of patients showing distinct prognosis among the groups (median survivals of 11.0, 9.0, and 4.0 months for the 0-, 1-, and 2-point groups, respectively). CONCLUSIONS: We developed a practical scale to facilitate deciding whether to proceed with surgical management in patients with recurrent glioblastoma. This scale was useful for the diagnosis of prognostic groups and can be used to develop guidelines for patient treatment. PMID- 23800678 TI - Overcoming challenges integrating patient-generated data into the clinical EHR: lessons from the CONtrolling Disease Using Inexpensive IT--Hypertension in Diabetes (CONDUIT-HID) Project. AB - INTRODUCTION: The CONDUIT-HID intervention integrates patients' electronic blood pressure measurements directly into the clinical EHR using Microsoft HealthVault as an intermediary data store. The goal of this paper is to describe generalizable categories of patient and technical challenges encountered in the development and implementation of this inexpensive, commercial off-the-shelf consumer health informatics intervention, examples of challenges within each category, and how the example challenges were resolved prior to conducting an RCT of the intervention. METHODS: The research team logged all challenges and mediation strategies during the technical development of the intervention, conducted home visits to observe patients using the intervention, and conducted telephone calls with patients to understand challenges they encountered. We then used these data to iteratively refine the intervention. RESULTS: The research team identified a variety of generalizable categories of challenges associated with patients uploading data from their homes, patients uploading data from clinics because they did not have or were not comfortable using home computers, and patients establishing the connection between HealthVault and the clinical EHR. Specific challenges within these categories arose because: (1) the research team had little control over the device and application design, (2) multiple vendors needed to coordinate their actions and design changes, (3) the intervention use cases were not anticipated by the device and application designers, (4) PHI accessed on clinic computers needed to be kept secure, (5) the research team wanted the data in the clinical EHR to be valid and reliable, (6) patients needed the ability to share only the data they wanted, and (7) the development of some EHR functionalities were new to the organization. While these challenges were varied and complex, the research team was able to successfully resolve each one prior to the start of the RCT. CONCLUSIONS: By identifying these generalizable categories of challenges, we aim to help others proactively search for and remedy potential challenges associated with their interventions, rather than reactively responding to problems as they arise. We posit that this approach will significantly increase the likelihood that these types of interventions will be successful. PMID- 23800679 TI - Two and a half-year-old children are prosocial even when their partners are not. AB - A total of 33 2.5-year-old toddlers were tested for proactive and selective prosocial responding in an iterated Prosocial Game with unfamiliar adult partners who were communicatively neutral and alternated their roles as actors and recipients every other trial. When children were actors, they were required to choose, at no cost to themselves, between a selfish option that delivered a reward to them only (1/0) and a prosocial option that delivered identical rewards to both themselves and their partners (1/1). When adult partners were actors, they consistently behaved prosocially (1/1) or selfishly (1/0) over 10 alternating trials, depending on test condition. An additional 17 children were used as a recipient-absent control group to test for self-oriented versus other oriented prosocial preferences. This study shows that by 2.5 years of age, and in the particular context of the task administered, toddlers can display proactive, other-oriented prosocial behavior, but their prosocial responding is indiscriminate in that they fail to respond contingently to their partners' prosocial or selfish behavior in the previous trials. These findings lend further support to the view that human prosociality is in place early in development as a basic tendency to be nice to others. This inclination may be so strong that not even partners who are communicatively neutral or repeatedly selfish toward children can erode it. They also suggest that this precocious proactive prosociality may be independent of reciprocity in terms of both its developmental schedule and psychological scaffolding. PMID- 23800681 TI - The two sides of spatial representation in neglect patients: the same spatial distortion for different patterns of performance. AB - Patients with neglect show disorders in horizontal space perception. It has been argued that these disorders may depend on a distortion of space that takes the form of a left-right relaxation of the representational medium that becomes progressively "relaxed" toward the contralesional space and progressively "compressed" toward the ipsilesional space (the space anisometry hypothesis). In the present paper we tested this hypothesis by using the Oppel-Kundt illusion that consists of the perception of a filled space as larger than an empty space of the same size. Two experiments were carried out with 14 brain-damaged patients with neglect, 9 brain-damaged patients without neglect and 12 healthy subjects. In the first experiment participants were requested to bisect and read words with different letter spacing simulating the way space is thought to be distorted in neglect. In the second experiment we asked the participants to physically and numerically bisect numerical intervals. The results of the two experiments are in line with the predictions of the space anisometry hypothesis. Specifically, with a background resembling the space distortion proposed by the space anisometry hypothesis, neglect signs are ameliorated in reading words and in numerically bisect numerical intervals, while they are worsened in bisecting words and physically bisect numerical intervals. These results support the idea that the abnormalities observed in typical neglect tests are due to a distorted internal representation of the outside world that takes the form of a mental continuum logarithmically distorted along the horizontal dimension. PMID- 23800680 TI - Germline PTPRD mutations in Ewing sarcoma: biologic and clinical implications. AB - Ewing sarcoma occurs in children, adolescents and young adults. High STAT3 levels have been reported in approximately 50% of patients with Ewing sarcoma, and may be important in tumorigenesis. Protein tyrosine phosphatase delta (PTPRD) is a tumor suppressor that inhibits STAT3 activation. To date, while somatic mutations in PTPRD have been reported in diverse tumors, germline mutations of PTPRD have not been investigated in Ewing sarcoma or other cancers. We identified a novel germline mutation in the PTPRD gene in three of eight patients (37.5%) with metastatic Ewing sarcoma. Although the functional impact in two of the patients is unclear, in one of them the aberration was annotated as a W775stop germline mutation, and would be expected to lead to gene truncation and, hence, loss of the STAT3 dephosphorylation function of PTPRD. Since STAT3 is phosphorylated after being recruited to the insulin growth factor receptor (IGF-1R), suppression of IGF-1R could attenuate the enhanced STAT3 activation expected in the presence of PTPRD mutations. Of interest, two of three patients with germline PTPRD mutations achieved durable complete responses following treatment with IGF-1R monoclonal antibody-based therapies. Our pilot data suggest that PTPRD germline mutations may play a role in the development of Ewing sarcoma, a disease of young people, and their presence may have implications for therapy. PMID- 23800682 TI - Testicular phosphoproteome in perfluorododecanoic acid-exposed rats. AB - Perfluorododecanoic acid (PFDoA) is a common environmental pollutant, which has been detected in human sera and has adverse effects on testicular function in animal models. Exploring phosphorylation events in testes helps elucidate the specific phosphorylation signals involved in testicular toxicity of PFDoA. Combining efficient prefractionation of tryptic peptide mixtures using self packed reversed phase C18 columns with TiO2 and IMAC phosphopeptide enrichment techniques followed by 2D-LC-MS/MS, we identified 4077 unique phosphopeptides from 1777 proteins with a false discovery rate below 1.0% in the testes of rats exposed to PFDoA for 110 days. In addition, 937 novel phosphorylation sites were discovered in testicular proteins. Hundreds of phosphorylated proteins identified might be involved in spermatogenesis and sperm function. With increasing PFDoA dosage, the number of casein kinase 2 kinase-modified peptides significantly increased. Pathway analysis suggested that the mitogen-activated protein kinase pathway and cell division cycle protein 2 (CDC2) may have contributed to sperm activity and testicular function. By in vitro experiments, CDC2 phosphorylation activity was found to be likely involved in PFDoA-induced toxicity in Leydig cells. This study provides the first examination of the whole proteins' phosphorylation profile in rat testis and suggests that the MAPK pathway and CDC2 protein phosphorylation are critical for PFDoA testicular toxicity. PMID- 23800683 TI - Enhancement of anaerobic ammonium oxidation in lake sediment by applying drinking water treatment residuals. AB - In this study, the effect of drinking water treatment residuals (WTRs), non hazardous byproducts from drinking water treatment plants, on anaerobic ammonium oxidation (anammox) in lake sediments were investigated, qualitatively and quantitatively based on enrichment tests. The results suggested that after the enrichment, anammox were strengthened significantly in enriched sediments with no WTRs (ESNW) and with WTRs (ESW). Comparatively, anammox bacteria in ESW were more aggregated than ESNW. The activity (9.2 nmol g(-1)h(-1)) and abundance (9.8*10(7)copies g(-1)) of anammox bacteria in ESW were also higher than ESNW (6.1 nmol g(-1)h(-1)and 8.9*10(7) copies g(-1)). Further analysis suggested that after enrichment, anammox bacteria in sediments were phylogenetically more distant from Candidatus Kuenenia; anammox bacteria in ESW were closely related to Candidatus Brocadia. Overall, WTRs promoted aggregation, strengthened activity and increased abundance of anammox bacteria in lake sediments. Therefore, WTRs can enhance anammox in lake sediments. PMID- 23800684 TI - A chemoenzymatic route to synthesize unnatural sugar nucleotides using a novel N acetylglucosamine-1-phosphate pyrophosphorylase from Camphylobacter jejuni NCTC 11168. AB - A novel N-acetylglucosamine-1-phosphate pyrophosphorylase was identified from Campylobacter jejuni NCTC 11168. An unprecedented degree of substrate promiscuity has been revealed by systematic studies on its substrate specificities towards sugar-1-P and NTP. The yields of the synthetic reaction of seven kinds of sugar nucleotides catalyzed by the enzyme were up to 60%. In addition, the yields of the other nine were around 20%. With this enzyme, three novel sugar nucleotide analogs were synthesized on a preparative scale and well characterized. PMID- 23800685 TI - Synthesis and cytotoxic activities of novel hybrid 2-phenyl-3-alkylbenzofuran and imidazole/triazole compounds. AB - A series of novel hybrid compounds of 2-phenyl-3-alkylbenzofuran and imidazole or triazole were prepared and evaluated in vitro against a panel of human tumor cell lines. The results suggest that the 2-ethyl-imidazole ring, and substitution of the imidazolyl-3-position with a 2-bromobenzyl or naphthylacyl group, were vital for modulating inhibitory activity. In particular, hybrid compound 31 was found to be the most potent derivative with IC50 values of 0.08-0.55 MUM against five strains human tumor cell lines and was found to be more selective against breast carcinoma (MCF-7) and colon carcinoma (SW480) (IC50 values 40.8-fold and 40.1 fold lower than cisplatin (DDP)). PMID- 23800686 TI - Mono-carbonyl curcumin analogues as 11beta-hydroxysteroid dehydrogenase 1 inhibitors. AB - A series of structurally novel mono-carbonyl curcumin analogues have been synthesized and biologically evaluated to test their inhibitory potencies and the structure-activity relationship (SAR) on human and rat 11beta-hydroxysteroid dehydrogenase isoform (11beta-HSD1) activities. 11beta-HSD1 selective inhibitors have been discovered and compound A10 is discovered as a very potent with an IC50 value of 97 nM without inhibiting 11beta-HSD2. PMID- 23800687 TI - Treating chronic arsenic toxicity with high selenium lentil diets. AB - Arsenic (As) toxicity causes serious health problems in humans, especially in the Indo-Gangetic plains and mountainous areas of China. Selenium (Se), an essential micronutrient is a potential mitigator of As toxicity due to its antioxidant and antagonistic properties. Selenium is seriously deficient in soils world-wide but is present at high, yet non-toxic levels in the great plains of North America. We evaluate the potential of dietary Se in counteracting chronic As toxicity in rats through serum biochemistry, blood glutathione levels, immunotoxicity (antibody response), liver peroxidative stress, thyroid response and As levels in tissues and excreta. To achieve this, we compare diets based on high-Se Saskatchewan (SK) lentils versus low-Se lentils from United States. Rats drank control (0ppm As) or As (40ppm As) water while consuming SK lentils (0.3ppm Se) or northwestern USA lentils (<0.01ppm Se) diets for 14weeks. Rats on high Se diets had higher glutathione levels regardless of As exposure, recovered antibody responses in As exposed group, higher fecal and urinary As excretion and lower renal As residues. Selenium deficiency caused greater hepatic peroxidative damage in the As exposed animals. Thyroid hormones, triiodothyronine (T3) and thyroxine (T4), were not different. After 14weeks of As exposure, health indicators in rats improved in response to the high Se lentil diets. Our results indicate that high Se lentils have a potential to mitigate As toxicity in laboratory mammals, which we hope will translate into benefits for As exposed humans. PMID- 23800688 TI - Silver nanoparticles induce endoplasmatic reticulum stress response in zebrafish. AB - Silver nanoparticles (AgNPs) find increasing applications, and therefore humans and the environment are increasingly exposed to them. However, potential toxicological implications are not sufficiently known. Here we investigate effects of AgNPs (average size 120 nm) on zebrafish in vitro and in vivo, and compare them to human hepatoma cells (Huh7). AgNPs are incorporated in zebrafish liver cells (ZFL) and Huh7, and in zebrafish embryos. In ZFL cells AgNPs lead to induction of reactive oxygen species (ROS), endoplasmatic reticulum (ER) stress response, and TNF-alpha. Transcriptional alterations also occur in pro-apoptotic genes p53 and Bax. The transcriptional profile differed in ZFL and Huh7 cells. In ZFL cells, the ER stress marker BiP is induced, concomitant with the ER stress marker ATF-6 and spliced XBP-1 after 6h and 24h exposure to 0.5 g/L and 0.05 g/L AgNPs, respectively. This indicates the induction of different pathways of the ER stress response. Moreover, AgNPs induce TNF-alpha. In zebrafish embryos exposed to 0.01, 0.1, 1 and 5mg/L AgNPs hatching was affected and morphological defects occurred at high concentrations. ER stress related gene transcripts BiP and Synv are significantly up-regulated after 24h at 0.1 and 5mg/L AgNPs. Furthermore, transcriptional alterations occurred in the pro-apoptotic genes Noxa and p21. The ER stress response was strong in ZFL cells and occurred in zebrafish embryos as well. Our data demonstrate for the first time that AgNPs lead to induction of ER stress in zebrafish. The induction of ER stress can have several consequences including the activation of apoptotic and inflammatory pathways. PMID- 23800690 TI - Different strategies to overcome multidrug resistance in cancer. AB - The risk of acquisition of resistance to chemotherapy remains a major hurdle in the management of various types of cancer patients. Several cellular and noncellular mechanisms are involved in developing both intrinsic and acquired resistance in cancer cells toward chemotherapy. This review covers the various multidrug resistance (MDR) mechanisms observed in cancer cells as well as the various strategies developed to overcome these MDR mechanisms. Extensive studies have been conducted during the last several decades to enhance the efficacy of chemotherapy by suppressing or evading these MDR mechanisms including the use of new anticancer drugs that could escape from the efflux reaction, MDR modulators or chemosensitizers, multifunctional nanocarriers, and RNA interference (RNAi) therapy. PMID- 23800689 TI - Inhibition of chlorine-induced pulmonary inflammation and edema by mometasone and budesonide. AB - Chlorine gas is a widely used industrial compound that is highly toxic by inhalation and is considered a chemical threat agent. Inhalation of high levels of chlorine results in acute lung injury characterized by pneumonitis, pulmonary edema, and decrements in lung function. Because inflammatory processes can promote damage in the injured lung, anti-inflammatory therapy may be of potential benefit for treating chemical-induced acute lung injury. We previously developed a chlorine inhalation model in which mice develop epithelial injury, neutrophilic inflammation, pulmonary edema, and impaired pulmonary function. This model was used to evaluate nine corticosteroids for the ability to inhibit chlorine-induced neutrophilic inflammation. Two of the most potent corticosteroids in this assay, mometasone and budesonide, were investigated further. Mometasone or budesonide administered intraperitoneally 1h after chlorine inhalation caused a dose dependent inhibition of neutrophil influx in lung tissue sections and in the number of neutrophils in lung lavage fluid. Budesonide, but not mometasone, reduced the levels of the neutrophil attractant CXCL1 in lavage fluid 6h after exposure. Mometasone or budesonide also significantly inhibited pulmonary edema assessed 1 day after chlorine exposure. Chlorine inhalation resulted in airway hyperreactivity to inhaled methacholine, but neither mometasone nor budesonide significantly affected this parameter. The results suggest that mometasone and budesonide may represent potential treatments for chemical-induced lung injury. PMID- 23800691 TI - Multiple endocrine neoplasia syndromes associated with mutation of p27. AB - Multiple endocrine neoplasias (MEN) are autosomal dominant disorders characterized by the occurrence of tumors in at least two endocrine glands. Until recently, two MEN syndromes were known, i.e. the MEN type 1 (MEN1) and type 2 (MEN2), which are caused by germline mutations in the MEN1 and RET genes, respectively. These two syndromes are characterized by a different tumor spectrum. A few years ago we described a variant of the MEN syndromes, which spontaneously developed in a rat colony and was named MENX. Affected animals consistently develop multiple endocrine tumors, with a spectrum that shares features with both MEN1 and MEN2 human syndromes. Genetic studies identified a germline mutation in the Cdkn1b gene, encoding the p27 cell cycle inhibitor, as the causative mutation for MENX. Capitalizing on these findings, germline mutations in the human homologue, CDKN1B, were searched for and identified in patients with multiple endocrine tumors. As a consequence of this discovery, a novel human MEN syndrome, named MEN4, was recognized, which is caused by heterozygous mutations in p27. These studies identified Cdkn1b/CDKN1B as a novel tumor susceptibility gene for multiple endocrine tumors in both rats and humans. Here we review the characteristics of the MENX and MEN4 syndromes and we briefly address the main function of p27 and how it is affected by MENX- or MEN4 associated mutations. PMID- 23800692 TI - Intrinsically fluorescent silica nanocontainers: a promising theranostic platform. AB - In this paper we describe the preparation of fluorescent mesoporous silica nanoparticles (MSNs) for traceable drug delivery systems. The nanoparticles were prepared following a sol-gel procedure, incorporating a modified perylenediimide dye in the silica structure. Transmission electron microscopy and scanning electron microscopy show that the nanoparticles are monodispersed, with a spheroid shape and a raspberry-type surface morphology. The hybrid MSNs are robust, maintaining the mesoporous structure after template removal, with a pore diameter above 2 nm. A polymer shell was synthesized from the external surface of the hybrid nanoparticles by atom transfer radical polymerization, showing temperature-switchable collapsed/expanded conformation control. The fluorescent properties of the perylenediimide dye incorporated in the MSN pore walls are intact, and internalization in HEK293 cells shows that the nanoparticles are efficiently dispersed in the cytosol. These results show that the mesoporous fluorescent hybrid nanoparticles are an excellent platform for development of a traceable drug delivery system. PMID- 23800693 TI - Human parechovirus-3 infection in children, South Korea. AB - BACKGROUND: Human parechoviruses (HPeVs) have recently been recognized as important viral pathogens causing sepsis-like illness and meningitis in children, but the data on these infections in Korea is limited. Klassevirus is emerging as a novel etiologic agent of acute gastroenteritis, but its role in meningitis remains unclear. OBJECTIVES: To understand the epidemiology of HPeVs and klassevirus in sepsis-like illness and meningitis through the detection and typing of the virus in cerebrospinal fluid (CSF) samples. STUDY DESIGN: One hundred and eighty-three CSF samples collected from 183 patients ranging in the age group 1 day to 15 years were tested by using a RT-PCR assay for HPeV, EV and klassevirus. Amplification products of the VP3/VP1 and 3D region of the HPeV, and VP1 region of the EV were sequenced to identify the type. RESULTS: A total of 12 HPeV positive samples (6.5%) were detected from 183 CSF samples and all the samples were typed as HPeV-3. EVs were detected in 39 patients (21.3%) in which echovirus 25 and CVA6 were frequently detected, but mixed infection of HPeV-3 and EV was not observed. Klassevirus was not detected in the study population. Most of the HPeV-3 positive patients were under 3 months of age. HPeV-3 infection was detected mostly in the summer season. The VP3/VP1 gene of the 12 Korean strains clustered most closely to the Japan strain (AB759192) and the 3D gene of the Korean strains also clustered to the Japan strain, which showed no evidence of recombination. CONCLUSIONS: To our knowledge, this is the first report on the detection of HPeV-3 from CSF samples in Korea, which suggests the necessity of routine screening for this virus in young infants with sepsis-like illness and meningitis. PMID- 23800694 TI - Prostaglandin E1 or E2 (PGE1, PGE2) prevents premature luteolysis induced by progesterone given early in the estrous cycle in ewes. AB - The objective of this study was to determine whether prostaglandin E1 (PGE1) or prostaglandin E2 (PGE2) prevents premature luteolysis in ewes when progesterone is given during the first 6 days of the estrous cycle. Progesterone (3 mg in oil, im) given twice daily from Days 1 to 6 (estrus = Day 0) in ewes decreased (P < 0.05) luteal weights on Day 10 postestrus. Plasma progesterone concentrations differed (P < 0.05) among the treatment groups; toward the end of the experimental period, concentrations in jugular venous blood decreased (P < 0.05) compared with the other treatment groups. Plasma progesterone concentrations in ewes receiving PGE1 or PGE1 + progesterone were greater (P < 0.05) than in vehicle controls or in ewes receiving PGE2 or PGE2 or PGE2 + progesterone. Chronic intrauterine treatment with PGE1 or PGE2 prevented (P < 0.05) decreases in plasma progesterone concentrations, luteal weights, and the proportion of luteal unoccupied and occupied LH receptors on Day 10 postestrus in ewes given exogenous progesterone, but did not affect (P > 0.05) concentrations of PGF2alpha in inferior vena cava blood. Progesterone given on Days 1 to 6 in ewes advanced (P < 0.05) increases in PGF2alpha in inferior vena cava blood. We concluded that PGE1 or PGE2 prevented progesterone-induced premature luteolysis by suppressing loss of luteal LH receptors (both unoccupied and occupied). PMID- 23800695 TI - Fecal estradiol-17beta and testosterone in prepubertal domestic cats. AB - The aim of this article was to describe the time course of prepubertal sexual steroids in domestic cats. Fourteen newborn kittens were followed up until puberty (physical, behavioral, and hormonal changes). Fecal testosterone [T; males] and E estradiol 17-beta [E2; females] concentrations were analyzed by repeated measures ANOVA and two consecutive time windows (TWs) were used to compare changes in both male (postnatal weeks 1-4 vs. 5-14) and females (postnatal weeks 1-5 vs. 6-13). Puberty was achieved 14.3 +/- 0.3 and 13.3 +/- 0.4 weeks after birth in male and female cats, respectively. In both genders, during TW-1 fecal steroids concentrations were similar (males) or even higher (females) to that previously described for mature cats. Fecal T (P < 0.01) and E2 (P < 0.01) varied throughout the weeks. Differences were found when hormonal concentrations of TW-1 were compared with those of TW-2 both for male (61.4 +/- 7.9 vs. 16.9 +/- 2.2 ng/g; P < 0.01) and female (78.2 +/- 12.5 vs. 11.2 +/- 4.0 ng/g; P < 0.01) cats. It is concluded that in domestic cats there is a sexual steroid surge during the first 4 and 5 postnatal weeks in male and female animals, respectively. PMID- 23800696 TI - Postoperative external beam radiation therapy and concurrent cisplatin followed by carboplatin/paclitaxel for stage III (FIGO 2009) endometrial cancer. AB - OBJECTIVE: The optimal adjuvant therapy in advanced endometrial cancer is controversial. One regimen is concurrent external beam pelvic irradiation (RT) and cisplatin, then carboplatin/paclitaxel. This study reports an institutional experience using this approach in stage III (FIGO 2009) endometrial cancer. METHODS: Patients with stage III (FIGO 2009) endometrial cancer who underwent total hysterectomy and bilateral salpingo-oophorectomy at a single institution from 01/2004 to 12/2009 were identified retrospectively. Those treated with adjuvant RT/cisplatin, followed by carboplatin/paclitaxel comprised the study population. RESULTS: Of the 40 eligible patients, 7 (18%) were stage IIIA and 33 (82%) IIIC. Nineteen patients (48%) were >= 60 years of age. Twenty-three (58%) had >= 50% myometrial invasion, 30 (75%) lymphovascular invasion, 11 (28%) cervical stromal invasion, and 5 (12%) positive peritoneal cytology. Histology was endometrioid in 32 (80%), serous in 6 (15%), and clear cell in 2 (5%). At a median follow-up of 49 months, the 5-year freedom from relapse was 79% and overall survival 85%. The 5-year rate of vaginal recurrence was 3%, non-vaginal pelvic recurrence 3%, para-aortic recurrence 11%, peritoneal recurrence 5%, and other distant recurrence 11%. Thirty-one patients (78%) were able to complete the planned RT/cisplatin and 4 cycles of carboplatin/paclitaxel. Acute grade 3 toxicity occurred in 10 patients (4 neutropenia, 2 anemia, 1 fatigue, 2 diarrhea). No late toxicity was grade >= 3. CONCLUSION: These favorable outcomes corroborate those of RTOG 9708. Until prospective data that compare adjuvant therapy regimens mature, concurrent chemoradiation should be strongly considered in stage III endometrial cancer. PMID- 23800697 TI - Therapeutic vaccines for ovarian cancer. AB - While therapeutic vaccines for ovarian cancer represent only a small fraction of active clinical trials, growing interest in this area and the accumulated data supporting the use of vaccines in cancer treatment portend further expansion of trials incorporating these strategies. This review explores the rationale for the use of vaccines for the treatment of ovarian cancer. It examines vaccine platforms that have been investigated and reviews the data from these studies. We also highlight recently reported phase 2 and 3 clinical trials with clinical outcomes as endpoints. Finally, we consider directions for the next generation of vaccines in light of these findings and our emerging understanding of agents that may augment vaccine responses by targeting the immunosuppressive impact of the tumor microenvironment. PMID- 23800699 TI - How much is another randomized trial of lymph node dissection in endometrial cancer worth? A value of information analysis. AB - OBJECTIVE: This study aimed to assess the value of a randomized controlled trial (RCT) of lymph node dissection (LND) at the time of hysterectomy for high-risk subsets of women with endometrial cancer. METHODS: A modified Markov decision model compared routine LND to no LND for women with grade 3 or grades 2-3 endometrial cancer. Inputs were modeled as distributions for Monte Carlo probabilistic sensitivity and value of information (VOI) analyses. Survival without LND was modeled from Surveillance, Epidemiology and End Results program data. A hazard ratio (HR) describing survival in the high-risk group undergoing LND (estimate 0.9, 95% CI 0.6-1.1), adverse event rates, probability and type of adjuvant therapy were modeled from published RCTs. Costs were obtained from national reimbursement data. VOI estimated the value of reducing uncertainty regarding the survival benefit of LND. RESULTS: For grade 3, LND had an incremental cost-effectiveness ratio of $40,183/quality-adjusted life year (QALY) compared to no LND. Acceptability curves revealed considerable uncertainty, with an expected value of perfect information of $4,195 per patient at societal willingness to pay of $50,000/QALY. The estimated value of partial perfect information regarding the HR was $3,702 per patient. Assuming 8,000 individuals annually with grade 3 endometrial cancer in the US, the upper limit of VOI for the HR was $29.6 million annually. For grades 2 and 3 combined, analysis revealed a much lower likelihood of finding LND cost-effective. CONCLUSION: A clinical trial defining the survival effect of LND in women with grade 3 endometrial cancer is a worthwhile use of resources. PMID- 23800698 TI - Poor survival with wild-type TP53 ovarian cancer? AB - OBJECTIVE: The objective of this study is to investigate whether wild-type TP53 status in high-grade serous ovarian carcinoma is associated with poorer survival. METHODS: Clinical and genomic data of 316 sequenced samples from The Cancer Genome Atlas (TCGA) ovarian high-grade serous carcinoma study were downloaded from TCGA data portal. Association between wild-type TP53 and survival was analyzed with Kaplan Meier method and Cox regression. The diagnosis of high-grade serous carcinomas was evaluated by reviewing pathological reports and high resolution hematoxylin and eosin (H&E) images from frozen sections. The authenticity of wild-type TP53 in these tumor samples was assessed by analyzing SNP array data with ASCAT algorithm, reverse phase protein array (RPPA) data and RNAseq data. RESULTS: Fifteen patients with high grade serous ovarian carcinomas were identified to have wild-type TP53, which had significantly shorter survival and higher chemoresistance than those with mutated TP53. The authenticity of wild type TP53 status in these fifteen patients was supported by SNP array, RPPA, and RNAseq data. Except four cases with mixed histology, the classification as high grade serous carcinomas was supported by pathological reports and H&E images. Using RNAseq data, it was found that EDA2R gene, a direct target of wild-type TP53, was highly up-regulated in samples with wild-type TP53 in comparison to samples with either nonsense or missense TP53 mutations. CONCLUSION: Although patients with wild-type TP53 ovarian cancer were rare in the TCGA high grade ovarian serous carcinomas cohort, these patients appeared to have a poorer survival and were more chemoresistant than those with mutated TP53. Differentially expressed genes in these TP53 wild-type tumors may provide insight in the molecular mechanism in chemotherapy resistance. PMID- 23800700 TI - Clinical utility of EUS before cholangioscopy in the evaluation of difficult biliary strictures. AB - BACKGROUND: Biliary tract malignancies can be assessed with either EUS or SpyGlass cholangioscopy (SGC). OBJECTIVE: To evaluate the impact of EUS and guided biopsy before considering SGC in patients who had biliary strictures with negative ductal brushing. DESIGN: Prospective, observational study. SETTING: Tertiary level referral hospital. PATIENTS: Forty consecutive patients with biliary strictures. INTERVENTION: EUS evaluation and biopsy, where possible, were performed in all patients. If EUS examination failed to provide a definitive diagnosis, SGC and ductal biopsy was performed. Results were compared with surgical specimens or positive histocytology. MAIN OUTCOME MEASUREMENTS: Tissue diagnosis, technical success, adverse events, and clinical outcomes. RESULTS: On EUS, abnormalities responsible for the biliary strictures were identified in 39 patients (98%), with FNA achievable in 30 patients (75%). EUS-FNA provided positive histocytology in 23 patients (58%). SGC-guided biopsy was performed to evaluate nondiagnostic EUS-FNA (17 patients) and to clarify autoimmune pancreatitis on FNA (2 patients). The procedure was successful in 18 patients (95%) and provided tissue diagnosis in 16 patients (88%), with 2 false-negative results from extrinsic pathologies. When EUS was used before the SGC approach, the need for SGC was avoided in 24 patients (60%), cholangitis was minimized in 2.5%, and a cost saving of U.S.$110,000 was realized. Tissue diagnosis was achieved in 38 patients (94%) with this approach. LIMITATIONS: Relatively small sample size. CONCLUSIONS: EUS evaluation in patients with difficult biliary stricture prevents the need, cost, and adverse events of SGC in 60% of patients. Together, EUS followed by the SGC approach provides correct clinical diagnosis in 94% of patients with minimal adverse events. PMID- 23800701 TI - Corrosive esophageal injury by button battery. PMID- 23800702 TI - Limb-girdle muscular dystrophy type 2I is not rare in Taiwan. AB - Alpha-dystroglycanopathy is caused by the glycosylation defects of alpha dystroglycan (alpha-DG). The clinical spectrum ranges from severe congenital muscular dystrophy (CMD) to later-onset limb girdle muscular dystrophy (LGMD). Among all alpha-dystroglycanopathies, LGMD type 2I caused by FKRP mutations is most commonly seen in Europe but appears to be rare in Asia. We screened uncategorized 40 LGMD and 10 CMD patients by immunohistochemistry for alpha-DG and found 7 with reduced alpha-DG immunostaining. Immunoblotting with laminin overlay assay confirmed the impaired glycosylation of alpha-DG. Among them, five LGMD patients harbored FKRP mutations leading to the diagnosis of LGMD2I. One common mutation, c.948delC, was identified and cardiomyopathy was found to be very common in our cohort. Muscle images showed severe involvement of gluteal muscles and posterior compartment at both thigh and calf levels, which is helpful for the differential diagnosis. Due to the higher frequency of LGMD2I with cardiomyopathy in our series, the early introduction of mutation analysis of FKRP in undiagnosed Taiwanese LGMD patients is highly recommended. PMID- 23800703 TI - Inhibiting autophagy by shRNA knockdown: cautions and recommendations. AB - A glance through Autophagy or any other journal in this field shows that it is very common to block autophagy by RNA interference-based knockdown of ATG mRNAs in mammalian cell lines. Our lab's experience is that this approach can easily make for failed experiments because good knockdown of even essential autophagy regulators does not necessarily mean you will get good inhibition of autophagy, and, over time, cells can find ways to circumvent the inhibitory effects of the knockdown. PMID- 23800704 TI - Orally disintegrating tablet of novel salt of antiepileptic drug: formulation strategy and evaluation. AB - The aim of present research was to design and evaluate orally disintegrating tablet (ODT) of novel lamotrigine-cyclamate salt. Box-Behnken response surface methodology was selected to design the optimized formulation. The independent factors selected were tablet hardness (X1), disintegrant (X2) and lubricant (X3) levels, and responses chosen were disintegration time (DT, Y1), friability (Y2), T50 (Y3), and T90 (Y4). The tablets were also characterized for drug uniformity by near infrared chemical imaging (NIR-CI) and taste masking evaluation by electronic tongue. All the selected independent variables were statistically (p<0.05) effect the Y1 while Y2, Y3, and Y4 affected only by X2. The optimized ODT was found to meet the regulatory requirement of DT and friability specification. The NIR-CI images indicated uniform distribution of active and inactive ingredients within the tablets. The electronic tongue results were analyzed by principle component analysis (PCA). It indicated that novel salt of lamotrigine and its ODT formulation have a taste similar to cyclamic acid which is indicated by close proximity on PCA score plot, lower Euclidean distance, and high discrimination index values. Furthermore, these parameters were very close to ODT placebo formulation. On the other hand, lamotrigine, its ODT, and placebo formulation were far from each other. In summary, lamotrigine salt provides another avenue for pediatric friendly formulation for children and will enhance patience compliance. PMID- 23800705 TI - Altered neural circuits related to sustained attention and executive control in children with ADHD: an event-related fMRI study. AB - OBJECTIVE: The aim of this study was to investigate the neural basis of sustained attention, executive processing, and cognitive control in children with attention deficit hyperactivity disorder (ADHD). METHODS: Event-related functional magnetic resonance imaging (fMRI) was used to compare brain activation of 28 medication naive children with ADHD aged 7-12 years and 31 healthy controls during a cued continuous performance task (AX-CPT) in three stimulus context conditions (Go, NoGo, Lure). RESULTS: The children with ADHD showed increased activation in the left middle frontal gyrus, bilateral middle temporal gyrus, left precuneus and right cerebellum posterior lobe under the Lure condition compared to the controls. In the Lure condition, in contrast to the NoGo condition, an increased activation in the left inferior frontal gyrus, right medial frontal gyrus and right inferior parietal gyrus was observed in ADHD children. CONCLUSIONS: The results demonstrate that medication-naive ADHD children show spatial and temporal abnormalities in neural activities involved in sustained attention and executive control. SIGNIFICANCE: These findings show that there are distinct alternations in neural circuits related to sustained attention and executive control in children with ADHD, and further improve our understanding of the neural substrates of cognitive impairment in children with ADHD. PMID- 23800706 TI - Vestibular evoked myogenic potentials and habituation to seasickness. AB - OBJECTIVE: Seasickness may impose severe limitations on the performance of ships' crew. Cervical vestibular evoked myogenic potentials (cVEMP) assess the function of the saccule, the organ responsible for monitoring vertical linear acceleration, which has been found to be the most provocative motion stimulus in the evolution of motion sickness. We used the cVEMP test in a prospective evaluation of susceptibility and habituation to seasickness. METHODS: Forty-six naval recruits underwent the cVEMP test before exposure to sea conditions. After 6 months' sailing experience, participants completed a questionnaire evaluating their initial and current seasickness severity. Based on their most recent experience, subjects were divided into three groups: non-vomiting non-habituating (NV-NH), vomiting (V), and non-vomiting habituating (NV-H). RESULTS: Statistically significant lower thresholds for cVEMP were found in subjects who habituated to sea conditions (NV-H), compared with those remaining severely susceptible (V) (77.0 dB HL vs. 84.9 dB HL; p<0.01). CONCLUSIONS: The ability to produce the cVEMP at lower thresholds represents a broader dynamic range, in which the reflex can respond to a wider array of stimuli amplitudes. SIGNIFICANCE: The present study demonstrates the potential of the cVEMP test for predicting future habituation to seasickness. PMID- 23800707 TI - Multifocus optical microscopy applied to the study of archaeological metals. AB - Studies on cultural metal artifacts can benefit greatly from microscopy techniques. The examination of microstructural features can provide relevant information about ancient manufacturing techniques, as well as about corrosion/degradation processes. In the present work, advantages of the use of multifocus imaging techniques in optical microscopy for the study of archaeological metals are presented. An archaeometallurgical study of a large collection of bronzes demonstrates the possibility of a microstructural study with no need for sample removal, which is a great advantage in the study of cultural objects. In addition, the study of mounted samples illustrates the advantages of the multifocus technique in the examination of particular corrosion features, with the possibility of three-dimensional reconstructions. PMID- 23800708 TI - Coherent topological transport on the surface of Bi2Se3. AB - The two-dimensional surface of the three-dimensional topological insulator is in the symplectic universality class and should exhibit perfect weak antilocalization reflected in positive weak-field magneto-resistance. Previous studies in topological insulator thin films suffer from high level of bulk n-type doping making quantitative analysis of weak antilocalization difficult. Here we measure the magneto-resistance of bulk-insulating Bi2Se3 thin films as a function of film thickness and gate-tuned carrier density. For thick samples, the magnitude of weak antilocalization indicates two decoupled (top and bottom) symplectic surfaces. On reducing thickness, we observe first a crossover to a single symplectic channel, indicating coherent coupling of top and bottom surfaces via interlayer tunnelling, and second, a complete suppression of weak antilocalization. The first crossover is governed by the ratio of phase coherence time to the inter-surface tunnelling time, and the second crossover occurs when the hybridization gap becomes comparable to the disorder strength. PMID- 23800709 TI - Influence of inclination angles on intra- and inter-limb load-sharing during uphill walking. AB - Uphill walking is an inevitable part of daily living, placing more challenges on the locomotor system with greater risk of falls than level walking does. The current study aimed to investigate the effects of inclination angles on the inter joint and inter-limb load-sharing during uphill walking in terms of total support moment and contributions of individual joint moments to the total support moment. Fifteen young adults walked up walkways with 0 degrees , 5 degrees , 10 degrees and 15 degrees of slope while kinematic and kinetic data were collected and analyzed. With increasing inclination angles, the first peak of the total support moment was increased with unaltered individual joint contributions, suggesting an unaltered inter-joint control pattern in the leading limb to meet the increased demands. The second peak of the total support moment remained unchanged with increasing inclination angles primarily through a compensatory redistribution of the hip and knee moments. During DLS, the leading limb shared the majority of the whole body support moments. The current results reveal basic intra- and inter limb load-sharing patterns of uphill walking, which will be helpful for a better understanding of the control strategies adopted and for subsequent clinical applications. PMID- 23800710 TI - Language-specific cortical activation patterns for verbal fluency tasks in Japanese as assessed by multichannel functional near-infrared spectroscopy. AB - In Japan, verbal fluency tasks are commonly utilized as a standard paradigm for neuropsychological testing of cognitive and linguistic abilities. The Japanese "letter fluency task" is a mora/letter fluency task based on the phonological and orthographical characteristics of the Japanese language. Whether there are similar activation patterns across languages or a Japanese-specific mora/letter fluency pattern is not certain. We investigated the neural correlates of overt mora/letter and category fluency tasks in healthy Japanese. The category fluency task activated the bilateral fronto-temporal language-related regions with left superior lateralization, while the mora/letter fluency task led to wider activation including the inferior parietal regions (left and right supramarginal gyrus). Specific bilateral supramarginal activation during the mora/letter fluency task in Japanese was distinct from that of similar letter fluency tasks in syllable-alphabet-based languages: this might be due to the requirement of additional phonological processing and working memory, or due to increased cognitive load in general. PMID- 23800711 TI - Multiple routes for compound word processing in the brain: evidence from EEG. AB - Are compound words represented as unitary lexical units, or as individual constituents that are processed combinatorially? We investigated the neuro cognitive processing of compounds using EEG and a passive-listening oddball design in which lexical access and combinatorial processing elicit dissociating Mismatch Negativity (MMN) brain-response patterns. MMN amplitude varied with compound frequency and semantic transparency (the clarity of the relationship between compound and constituent meanings). Opaque compounds elicited an enhanced 'lexical' MMN, reflecting stronger lexical representations, to high- vs. low frequency compounds. Transparent compounds showed no frequency effect, nor differed to pseudo-compounds, reflecting the combination of a reduced 'syntactic' MMN indexing combinatorial links, and an enhanced 'lexical' MMN for real-word compounds compared to pseudo-compounds. We argue that transparent compounds are processed combinatorially alongside parallel lexical access of the whole-form representation, but whole-form access is the dominant mechanism for opaque compounds, particularly those of high-frequency. Results support a flexible dual route account of compound processing. PMID- 23800713 TI - Offshore wind farms as productive sites or ecological traps for gadoid fishes?- impact on growth, condition index and diet composition. AB - With the construction of wind farms all across the North Sea, numerous artificial reefs are created. These windmill artificial reefs (WARs) harbour high abundances of fish species which can be attracted from elsewhere or can be the result of extra production induced by these wind farms. To resolve the attraction production debate in suddenly altered ecosystems (cf. wind farms), the possible consequences of attraction should be assessed; thereby bearing in mind that ecological traps may arise. In this paper we investigated whether the wind farms in the Belgian part of the North Sea act as ecological traps for pouting and Atlantic cod. Length-at-age, condition and diet composition of fish present at the windmill artificial reefs was compared to local and regional sandy areas. Fish data from the period 2009-2012 were evaluated. Mainly I- and II-group Atlantic cod were present around the WARs; while the 0- and I-group dominated for pouting. For Atlantic cod, no differences in length were observed between sites, indicating that fitness was comparable at the WARs and in sandy areas. No significant differences in condition index were observed for pouting. At the WARs, they were slightly larger and stomach fullness was enhanced compared to the surrounding sandy areas. Also diet differed considerably among the sites. The outcome of the proxies indicate that fitness of pouting was slightly enhanced compared to the surrounding sandy areas. No evidence was obtained supporting the hypothesis that the WARs act as an ecological trap for Atlantic cod and pouting. PMID- 23800712 TI - Revisiting clinical trials using EGFR inhibitor-based regimens in patients with advanced non-small cell lung cancer: a retrospective analysis of an MD Anderson Cancer Center phase I population. AB - PURPOSE: Single-agent EGFR inhibitor therapy is effective mainly in patients with lung cancer and EGFR mutations. Treating patients who develop resistance, or who are insensitive from the outset, often because of resistant mutations, other aberrations or the lack of an EGFR mutation, probably requires rational combinations. We therefore investigated the outcome of EGFR inhibitor-based combination regimens in patients with heavily-pretreated non-small cell lung cancer (NSCLC) referred to a Phase I Clinic. METHODS: We reviewed the electronic records of patients with NSCLC treated with an EGFR inhibitor-based combination regimen: erlotinib and cetuximab; erlotinib, cetuximab and bevacizumab; erlotinib and dasatinib; erlotinib and bortezomib; or cetuximab and sirolimus. RESULTS: EGFR mutations were detected in 16% of patients (21/131). EGFR inhibitor-based combination regimens were administered to 15 patients with EGFR-mutant NSCLC and 24 with EGFR wild-type disease. Stable disease (SD) >=6 months/partial remission (PR) was attained in 20% of EGFR-mutant patients (3/15; two with sensitive mutations and secondary resistance to prior erlotinib, and one with a resistant mutation), as well as 26% of evaluable patients (5/19) with wild-type disease. One of three evaluable patients with squamous cell histology achieved SD for 26.5 months (EGFR wild-type, TP53-mutant, regimen=erlotinib, cetuximab and bevacizumab). CONCLUSIONS: Eight of 34 evaluable patients (24%) with advanced, refractory NSCLC evaluable for response achieved SD >=6 months/PR (PR=3; SD >=6 months=5) on EGFR inhibitor-based combination regimens (erlotinib, cetuximab; erlotinib, cetuximab and bevacizumab; and, erlotinib, bortezomib), including patients with secondary resistance to single-agent EGFR inhibitors, resistant mutations, wild-type disease, and, squamous histology. PMID- 23800714 TI - Regional experiences of tissue donation and forensic medicine in hamburg - results of a 5-year period. AB - OBJECTIVE: We present the operational organization and daily workflow of our Hamburg model and the results of the years 2007-2011 concerning donation of corneas, musculoskeletal and, since 2010, cardiovascular tissues. METHODS: Each of the about 3,600 deceased every year undergoes an evaluation process by two coordinators on duty, the tissue coordinator and the family coordinator. All donation connected issues are carried out within the standardized protocols of a quality management system and documented in a special data base. Two catamnestic surveys evaluated the satisfaction of donor families retrospectively. The inclusion rate for cornea donation was 23% and for musculoskeletal donation 10%, with a decrease after the 75 years age restriction of musculoskeletal donors in 2011 defined by the contracting tissue bank German Institute for Cell and Tissue Replacement gGmbH (DIZG), Berlin. RESULTS: Since 2007 1,268 corneas were explanted altogether, reflecting an increasing explantation rate from 156 (University Medical Center Hamburg-Eppendorf (UMC: 9) in 2007 up to 304 (UMC: 52) in 2011. Overall 173 musculoskeletal donors (5 years) and 11 cardiovascular donors (2 years) spent tissues. The consent rate was much higher. The evaluation of the families reflected a positive feedback for the guiding of the donation process. CONCLUSION: Forensic institutes can act as an interface between donors and recipients without neglecting forensic investigations. They are uniquely positioned to recognize potential donors. In addition, the contact with a physician of the forensic institute may help families during the mourning phase. PMID- 23800715 TI - Dopamine release regulation by astrocytes during cerebral ischemia. AB - Brain ischemia triggers excessive release of neurotransmitters that mediate neuronal damage following ischemic injury. The striatum is one of the areas most sensitive to ischemia. Release of dopamine (DA) from ischemic neurons is neurotoxic and directly contributes to the cell death in affected areas. Astrocytes are known to be critically involved in the physiopathology of cerebrovascular disease. However, their response to ischemia and their role in neuroprotection in striatum are not completely understood. In this study, we used an in vitro model to evaluate the mechanisms of ischemia-induced DA release, and to study whether astrocytes modulate the release of DA in response to short-term ischemic conditions. Using slices of adult mouse brain exposed to oxygen and glucose deprivation (OGD), we measured the OGD-evoked DA efflux using fast cyclic voltammetry and also assessed metabolic impairment by 2,3,5-triphenyltetrazolium chloride (TTC) and tissue viability by propidium iodide (PI) staining. Our data indicate that ischemia induces massive release of DA by dual mechanisms: one which operates via vesicular exocytosis and is action potential dependent and another involving reverse transport by the dopamine transporter (DAT). Simultaneous blockade of astrocyte glutamate transporters and DAT prevented the massive release of dopamine and reduced the brain tissue damage. The present results provide the first experimental evidence that astrocytes function as a key cellular element of ischemia-induced DA release in striatum, constituting a novel and promising therapeutic target in ischemia. PMID- 23800716 TI - Understanding the relationship between access to care and facility-based delivery through analysis of the 2008 Ghana Demographic Health Survey. AB - OBJECTIVE: To determine the types of access to care most strongly associated with facility-based delivery among women in Ghana. METHODS: Data relating to the "5 As of Access" framework were extracted from the 2008 Ghana Demographic Health Survey and analyzed using multivariate logistic regression. RESULTS: In all, 55.5% of a weighted sample of 1102 women delivered in a healthcare facility, whereas 45.5% delivered at home. Affordability was the strongest access factor associated with delivery location, with health insurance coverage tripling the odds of facility delivery. Availability, accessibility (except urban residence), acceptability, and social access variables were not significant factors in the final models. Social access variables, including needing permission to seek healthcare and not being involved in decisions regarding healthcare, were associated with a reduced likelihood of facility-based delivery when examined individually. Multivariate analysis suggested that these variables reflected maternal literacy, health insurance coverage, and household wealth, all of which attenuated the effects of social access. CONCLUSION: Affordability was an important determinant of facility delivery in Ghana-even among women with health insurance-but social access variables had a mediating role. PMID- 23800717 TI - Effect of a single preoperative dose of sublingual misoprostol on intraoperative blood loss during total abdominal hysterectomy. AB - OBJECTIVE: To investigate whether use of preoperative misoprostol can reduce blood loss during total abdominal hysterectomy (TAH). METHODS: In a randomized double-blind placebo-controlled trial at a tertiary care hospital in Kolkata, India, between March 2011 and April 2012, women (n=132) undergoing TAH with or without bilateral salpingo-oophorectomy for symptomatic myomas were randomly allocated to receive either 400 MUg of misoprostol or placebo 30 minutes before surgery. The primary outcome measure was intraoperative blood loss was. The secondary outcomes were postoperative drop in hemoglobin, need for blood transfusion, and incidence of adverse effects. RESULTS: The 2 groups were similar with regard to demographic and clinical characteristics. There was a significant reduction of blood loss during TAH after sublingual administration of misoprostol compared with placebo before surgery (356 mL vs 435 mL; P=0.049). The mean postoperative hemoglobin concentration was higher (10.5 g/dL vs 9.5 g/dL; P<0.001) and the postoperative drop in hemoglobin was smaller (1.1g/dL vs 1.9 g/dL; P=0.004) in the misoprostol group than in the placebo group. No significant adverse effects occurred in either group. CONCLUSION: The results showed that a single dose of misoprostol administered before abdominal hysterectomy resulted in a significant reduction of blood loss with minimal adverse effects. Clinical Trial Registry India (www.ctri.nic.in): CTRI/2011/091/000216. PMID- 23800718 TI - Vaginal cuff dehiscence after hysterectomy. AB - OBJECTIVE: To determine the incidence of vaginal cuff dehiscence (VCD) among women undergoing hysterectomy according to clinico-surgical factors including surgical route, and to describe patient characteristics associated with VCD. METHODS: In a retrospective study, the medical records of all women who underwent hysterectomy between January 2005 and March 2011 at a university teaching hospital in Seoul, Republic of Korea, were reviewed. The incidence of VCD was determined in relation to the following factors: patient age, hysterectomy route, indication for hysterectomy, and extent of resection (either simple or radical hysterectomy). RESULTS: Among 9973 hysterectomies, 37 (0.37%) cases of VCD were identified. The incidence of VCD was significantly higher after abdominal hysterectomy (0.6%) than after laparoscopic (0.2%) or vaginal (0.4%) hysterectomy (P=0.016). Compared with laparoscopic approaches, abdominal hysterectomy was associated with a higher risk of VCD (odds ratio, 2.735; 95% confidence interval, 1.380-5.420). However, there was no significant difference in the incidence of VCD according to surgical indication or extent of resection. CONCLUSION: Laparoscopic hysterectomy was found to be associated with a lower risk of VCD compared with abdominal hysterectomy. The lower risk is probably related to the different techniques used for colpotomy and cuff closure. PMID- 23800719 TI - The cell-mediated immunity of Drosophila melanogaster: hemocyte lineages, immune compartments, microanatomy and regulation. AB - In the animal kingdom, innate immunity is the first line of defense against invading pathogens. The dangers of microbial and parasitic attacks are countered by similar mechanisms, involving the prototypes of the cell-mediated immune responses, the phagocytosis and encapsulation. Work on Drosophila has played an important role in promoting an understanding of the basic mechanisms of phylogenetically conserved modules of innate immunity. The aim of this review is to survey the developments in the identification and functional definition of immune cell types and the immunological compartments of Drosophila melanogaster. We focus on the molecular and developmental aspects of the blood cell types and compartments, as well as the dynamics of blood cell development and the immune response. Further advances in the characterization of the innate immune mechanisms in Drosophila will provide basic clues to the understanding of the importance of the evolutionary conserved mechanisms of innate immune defenses in the animal kingdom. PMID- 23800720 TI - Cytoprotective and nonprotective autophagy in cancer therapy. AB - Two primary forms of autophagy have been identified in the field of cancer therapy based on their apparent functions in the tumor cell; these are the cytoprotective form that could, in theory, be inhibited for the purpose of sensitization to radiation and chemotherapeutic drugs and the "cytotoxic" form that either mediates or contributes to the actions of these treatment modalities. Surprisingly, to date, no clear-cut biochemical or molecular characteristics have been identified that might serve to distinguish between these two forms. In this commentary, we develop the concept of an additional form of autophagy that is nonprotective in that its inhibition neither sensitizes the tumor cell to exogenous stress (again, chemotherapy or radiation) nor protects the cell from the impact of these treatments. This form of autophagy also fails to exhibit any characteristics that might distinguish it from the cytoprotective and/or cytotoxic forms of autophagy. However, the existence of nonprotective autophagy is of potential significance in that it contributes to the challenge of predicting when the strategy of autophagy suppression might prove to have therapeutic benefit in the clinical treatment of cancer. PMID- 23800721 TI - A homogeneous single-label quenching resonance energy transfer assay for a delta opioid receptor-ligand using intact cells. AB - This study, a homogeneous assay system for delta opioid receptor binding ligands has been developed using Quenching Resonance Energy Transfer (QRET). The QRET system allows receptor-ligand binding assays on intact cells using a single-label approach and a nonspecific quenching mechanism. Binding of antagonists or agonists to the receptor can be defined using a europium(III) labeled ligand. In the presence of the unlabeled ligand the labeled ligand is displaced and remains in solution. The non-bound labeled ligand is not protected by the target receptor, and the luminescence signal is quenched. For this objective, a Eu(III) labeled peptide molecule with three different linkers (AX0, AX1 and AX2) was designed. Peptides were evaluated using the homogeneous QRET technique, radioligand binding assays and the heterogeneous time-resolved luminescence (TRL) technique. Using the Eu-AX0 peptide and the QRET method, a panel of opioid compounds (naltrexone, naltrindole, SCN-80, DPDPE and DAMGO) was tested to prove the assay performance. The signal-to-background ratio for the tested opioid ligand ranged from 3.3 to 12.0. The QRET method showed prominent performance also in high DMSO concentrations. QRET is a homogenous and a non-radioactive detection system for screening and this is the first attempt to utilize peptide ligands in the QRET concept. PMID- 23800722 TI - Structural development of the hippocampus and episodic memory: developmental differences along the anterior/posterior axis. AB - The hippocampus is critically involved in episodic memory, yet relatively little is known about how the development of this structure contributes to the development of episodic memory during middle to late childhood. Previous research has inconsistently reported associations between hippocampal volume and episodic memory performance during this period. We argue that this inconsistency may be due to assessing the hippocampus as a whole, and propose to examine associations separately for subregions along the longitudinal axis of the hippocampus. In the present study, we examined age-related differences in volumes of the hippocampal head, body, and tail, and collected episodic memory measures in children ages 8 11 years and young adults (N = 62). We found that adults had a smaller right hippocampal head, larger hippocampal body bilaterally, and smaller right hippocampal tail compared with children. In adults, but not in children, better episodic memory performance was associated with smaller right hippocampal head and larger hippocampal body. In children, but not in adults, better episodic memory was associated with larger left hippocampal tail. Overall, the results suggest that protracted development of hippocampal subregions contribute to age related differences in episodic memory. PMID- 23800723 TI - Multimerized CHR-derived peptides as HIV-1 fusion inhibitors. AB - To date, several HIV-1 fusion inhibitors based on the carboxy-terminal leucine/isoleucine heptad repeat (CHR) region of an HIV-1 envelope protein gp41 have been discovered. We have shown that a synthetic peptide mimetic of a trimer form of the CHR-derived peptide C34 has potent inhibitory activity against the HIV-1 fusion mechanism, compared to a monomer C34 peptide. The present study revealed that a dimeric form of C34 is evidently structurally critical for fusion inhibitors, and that the activity of multimerized CHR-derived peptides in fusion inhibition is affected by the properties of the unit peptides C34, SC34EK, and T20. The fluorescence-based study suggested that the N36-interactive sites of the C34 trimer, including hydrophobic residues, are exposed outside the trimer and that trimerization of C34 caused a remarkable increase in fusion inhibitory activity. The present results could be useful in the design of fusion inhibitors against viral infections which proceed via membrane fusion with host cells. PMID- 23800724 TI - Novel 3,4-disubstituted-Neu5Ac2en derivatives as probes to investigate flexibility of the influenza virus sialidase 150-loop. AB - Novel 3,4-disubstituted-Neu5Ac2en derivatives have been synthesised to probe the open 150-loop conformation of influenza virus sialidases. Both equatorially and axially (epi) substituted C4 amino and guanidino 3-(p-tolyl)allyl-Neu5Ac2en derivatives were prepared, via the 4-epi-hydroxy derivative. The equatorially substituted 4-amino derivative showed low micromolar inhibition of both group-1 (pdm09 H1N1) and group-2 (pdm57 H2N2) sialidases, and provides the first in vitro evidence that a group-2 sialidase may exhibit 150-loop flexibility. PMID- 23800725 TI - Fundamental limitations for quantum and nanoscale thermodynamics. AB - The relationship between thermodynamics and statistical physics is valid in the thermodynamic limit-when the number of particles becomes very large. Here we study thermodynamics in the opposite regime-at both the nanoscale and when quantum effects become important. Applying results from quantum information theory, we construct a theory of thermodynamics in these limits. We derive general criteria for thermodynamical state transitions, and, as special cases, find two free energies: one that quantifies the deterministically extractable work from a small system in contact with a heat bath, and the other that quantifies the reverse process. We find that there are fundamental limitations on work extraction from non-equilibrium states, owing to finite size effects and quantum coherences. This implies that thermodynamical transitions are generically irreversible at this scale. As one application of these methods, we analyse the efficiency of small heat engines and find that they are irreversible during the adiabatic stages of the cycle. PMID- 23800726 TI - Aromatic interactions in asymmetric catalysis: control of enantioselectivity in Diels-Alder reactions catalysed by camphor-derived hydrazides. AB - Density functional theory calculations (M06-2X//B3LYP) have been performed to determine the factors responsible for enantioselectivity in Diels-Alder reactions catalysed by two series of camphor-derived amines. Hydrazides 2 and sulfonylhydrazides 3 catalyze the reaction of cyclopentadiene with cinnamaldehyde to give the same enantiomer of cycloadduct. The calculations reveal that the two classes of catalysts control enantioselectivity by opposite mechanisms. Hydrazides 2 favour addition to the bottom face of a trans iminium cation, while sulfonylhydrazides 3 favour addition to the top face of a cis iminium ion. In the transition state for cycloadditions catalysed by 2, a stabilising CH-pi interaction between the diene and a benzyl substituent alpha to the iminium nitrogen accelerates the reaction and enhances the enantioselectivity. The facial selectivity can be reinforced by appending onto the benzyl side-arm an alpha methyl group that sterically hinders addition to the top face. PMID- 23800727 TI - A comparison of population air pollution exposure estimation techniques with personal exposure estimates in a pregnant cohort. AB - There is increasing evidence of the harmful effects for mother and fetus of maternal exposure to air pollutants. Most studies use large retrospective birth outcome datasets and make a best estimate of personal exposure (PE) during pregnancy periods. We compared estimates of personal NOx and NO2 exposure of pregnant women in the North West of England with exposure estimates derived using different modelling techniques. A cohort of 85 pregnant women was recruited from Manchester and Blackpool. Participants completed a time-activity log and questionnaire at 13-22 weeks gestation and were provided with personal Ogawa samplers to measure their NOx/NO2 exposure. PE was compared to monthly averages, the nearest stationary monitor to the participants' home, weighted average of the closest monitor to home and work location, proximity to major roads, as well as to background modelled concentrations (DEFRA), inverse distance weighting (IDW), ordinary kriging (OK), and a land use regression model with and without temporal adjustment. PE was most strongly correlated with monthly adjusted DEFRA (NO2r = 0.61, NOxr = 0.60), OK and IDW (NO2r = 0.60; NOxr = 0.62) concentrations. Correlations were stronger in Blackpool than in Manchester. Where there is evidence for high temporal variability in exposure, methods of exposure estimation which focus solely on spatial methods should be adjusted temporally, with an improvement in estimation expected to be better with increased temporal variability. PMID- 23800728 TI - Orchids and dandelions: how some children are more susceptible to environmental influences for better or worse and the implications for child development. PMID- 23800729 TI - Alternative FIB TEM sample preparation method for cross-sections of thin metal films deposited on polymer substrates. AB - Transmission electron microscopy (TEM) and focused ion beam (FIB) are proven tools to produce site-specific samples in which to study devices from initial processing to causes for failure, as well as investigating the quality, defects, interface layers, etc. However, the use of polymer substrates presents new challenges, in the preparation of suitable site-specific TEM samples, which include sample warping, heating, charging, and melting. In addition to current options that address some of these problems such as cryo FIB, we add an alternative method and FIB sample geometry that address these challenges and produce viable samples suitable for TEM elemental analysis. The key feature to this approach is a larger than usual lift-out block into which small viewing windows are thinned. Significant largely unthinned regions of the block are left between and at the base of the thinned windows. These large unthinned regions supply structural support and thermal reservoirs during the thinning process. As proof-of-concept of this sample preparation method, we also present TEM elemental analysis of various thin metallic films deposited on patterned polycarbonate, lacquer, and poly-di-methyl-siloxane substrates where the pattern (from low- to high-aspect ratio) is preserved. PMID- 23800730 TI - Yield and proliferation rate of adipose-derived stromal cells as a function of age, body mass index and harvest site-increasing the yield by use of adherent and supernatant fractions? AB - BACKGROUND AIMS: Adipose-derived stem cells are easily accessed and have a relatively high density compared with other mesenchymal stromal cells. Isolation protocols of adipose-derived stem cells (ASC) rely on the cell's ability to adhere to tissue culture plastic overnight. It was evaluated whether the floating ASC fractions are also of interest for cell-based therapies. In addition, the impact of age, body mass index (BMI) and harvest site was assessed. METHODS: The surface protein profile with the use of flow cytometry, the cell yield and the doubling time of passages 4, 5 and 6 of ASC from 30 donors were determined. Adherent and supernatant fractions were compared. The impact of age, BMI and harvest site on cell yield and doubling times was determined. RESULTS: Both adherent and supernatant fractions showed high mean fluorescence intensities for CD13, CD29, CD44, CD73, CD90 and CD105 and comparatively low mean fluorescence intensities for CD11b, CD62L, intracellular adhesion molecule-1 and CD34. Doubling times of adherent and supernatant fractions did not differ significantly. Whereas the old age group had a significantly lower cell yield compared with the middle aged group, BMI and harvest site had no impact on cell yield. Finally, doubling times for passages 4, 5 and 6 were not influenced by the age and BMI of the donors, nor the tissue-harvesting site. CONCLUSIONS: The floating ASC fraction is an equivalent second cell source just like the adherent ASC fraction. Donor age, BMI and harvest site do not influence cell yield and proliferation rate. PMID- 23800731 TI - Remodeling epigenetic modifications at tumor suppressor gene promoters with bovine oocyte extract. AB - BACKGROUND AIMS: Epigenetic silencing of tumor suppressor genes by aberrant DNA methylation and histone modifications at their promoter regions plays an important role in the initiation and progression of cancer. The therapeutic effect of the widely used epigenetic drugs, including DNA methyltransferase inhibitors and histone deacetylase inhibitors, remains unsatisfactory. One important underlying factor in the ineffectiveness of these drugs is that their actions lack specificity. METHODS: To investigate whether oocyte extract can be used for epigenetic re-programming of cancer cells, H460 human lung cancer cells were reversibly permeabilized and incubated with bovine oocyte extract. RESULTS: Bisulfite sequencing showed that bovine oocyte extract induced significant demethylation at hypermethylated promoter CpG islands of the tumor suppressor genes RUNX3 and CDH1; however, the DNA methylation levels of repetitive sequences were not affected. Chromatin immunoprecipitation showed that bovine oocyte extract significantly reduced transcriptionally repressive histone modifications and increased transcriptionally activating histone modifications at the promoter regions of RUNX3 and CDH1. Bovine oocyte extract reactivated the expression of RUNX3 and CDH1 at both the messenger RNA and the protein levels without up regulating the transcription of pluripotency-associated genes. At the functional level, anchorage-independent proliferation, migration and invasion of H460 cells was strongly inhibited. CONCLUSIONS: These results demonstrate that bovine oocyte extract reactivates epigenetically silenced tumor suppressor genes by remodeling the epigenetic modifications at their promoter regions. Bovine oocyte extract may provide a useful tool for investigating epigenetic mechanisms in cancer and a valuable source for developing novel safe therapeutic approaches that target epigenetic alterations. PMID- 23800732 TI - Age-dependent decrease in the chondrogenic potential of human bone marrow mesenchymal stromal cells expanded with fibroblast growth factor-2. AB - BACKGROUND AIMS: Human bone marrow mesenchymal stromal cells are useful in regenerative medicine for various diseases, but it remains unclear whether the aging of donors alters the multipotency of these cells. In this study, we examined age-related changes in the chondrogenic, osteogenic and adipogenic potential of mesenchymal stromal cells from 17 donors (25-81 years old), including patients with or without systemic vascular diseases. METHODS: All stem cell lines were expanded with fibroblast growth factor-2 and then exposed to differentiation induction media. The chondrogenic potential was determined from the glycosaminoglycan content and the SOX9, collagen type 2 alpha 1 (COL2A1) and aggrecan (AGG) messenger RNA levels. The osteogenic potential was determined by monitoring the alkaline phosphatase activity and calcium content, and the adipogenic potential was determined from the glycerol-3-phosphate dehydrogenase activity and oil red O staining. RESULTS: Systemic vascular diseases, including arteriosclerosis obliterans and Buerger disease, did not significantly affect the trilineage differentiation potential of the cells. Under these conditions, all chondrocyte markers examined, including the SOX9 messenger RNA level, showed age related decline, whereas none of the osteoblast or adipocyte markers showed age dependent changes. CONCLUSIONS: The aging of donors from young adult to elderly selectively decreased the chondrogenic potential of mesenchymal stromal cells. This information will be useful in stromal cell-based therapy for cartilage related diseases. PMID- 23800733 TI - Inclusivity, exclusivity and limit of detection of commercially available real time PCR assays for the detection of Salmonella. AB - The traditional cultural detection of Salmonella spp. is both time- and labour intensive. Salmonella is often a release criterion for the food industry and time to result is therefore an important factor. Storage of finished products and raw materials can be costly and may adversely impact available shelf-life. The application of real-time PCR for the detection of Salmonella spp. in food samples enables a potential time-saving of up to four days. The advancement of real-time PCR coupled with the development of commercially available systems in different formats has made this technology accessible for laboratories in an industrial environment. Ideally these systems are reliable and rapid as well as easy to use. The current study represents a comparative evaluation of seven commercial real time PCR systems for the detection of Salmonella. Forty-nine target and twenty nine non-target strains were included in the study to assess inclusivity and exclusivity. The limit of detection for each of the method was determined in four different food products. All systems evaluated were able to correctly identify the 49 Salmonella strains. Nevertheless, false positive results (Citrobacter spp.) were obtained with four of the seven systems. In milk powder and bouillon powder, the limit of detection was similar for all systems, suggesting a minimal matrix effect with these samples. Conversely, for black tea and cocoa powder some systems were prone to inhibition from matrix components. Up to 100% of the samples were inhibited using the proprietary extracts but inhibition could be reduced considerably by application of a DNA clean-up kit. PMID- 23800734 TI - egc characterization of enterotoxigenic Staphylococcus aureus isolates obtained from raw milk and cheese. AB - Genes encoding staphylococcal enterotoxins (SEs) are carried by mobile genetic elements, and enterotoxin gene clusters (egc) are pathogenicity island-borne structures comprising several SE genes, which are frequently found among clinical Staphylococcus aureus isolates. In the present study, we investigated the distribution and the genetic variability of egc loci in S. aureus strains isolated from raw milk and soft cheese in Minas Gerais, Brazil. Ninety-two isolates were submitted to PCR detection of individual egc-borne SE genes (seg, sei, sem, sen, seo, seu), and egc loci were typed using PCR-RFLP. PCR products of egc positive isolates were sequenced. Ninety-one isolates harbored at least one SE gene, which generated 14 different genotypes. The sei gene was the most widely distributed (97.8%), and was found in combination with seg in 49 isolates (53.3%). Altogether, a complete set of individual egc genes was detected in 37 isolates (40%). However, egc loci were detected by PCR-RFLP in only 4 isolates, and classified as egc1 (n=2), egc3 (n=1), and egc4 (n=1). This investigation demonstrated the low occurrence of the egc in S. aureus isolated from dairy products. However, the frequency of complete sets of individual egc-borne genes reflects either the presence of these SE genes outside egc or the existence of new egc types in these strains. PMID- 23800735 TI - Improvement of fermentation ability under baking-associated stress conditions by altering the POG1 gene expression in baker's yeast. AB - During the bread-making process, yeast cells are exposed to many types of baking associated stress. There is thus a demand within the baking industry for yeast strains with high fermentation abilities under these stress conditions. The POG1 gene, encoding a putative transcription factor involved in cell cycle regulation, is a multicopy suppressor of the yeast Saccharomyces cerevisiae E3 ubiquitin ligase Rsp5 mutant. The pog1 mutant is sensitive to various stresses. Our results suggested that the POG1 gene is involved in stress tolerance in yeast cells. In this study, we showed that overexpression of the POG1 gene in baker's yeast conferred increased fermentation ability in high-sucrose-containing dough, which is used for sweet dough baking. Furthermore, deletion of the POG1 gene drastically increased the fermentation ability in bread dough after freeze-thaw stress, which would be a useful characteristic for frozen dough baking. Thus, the engineering of yeast strains to control the POG1 gene expression level would be a novel method for molecular breeding of baker's yeast. PMID- 23800736 TI - Intraspecific variability of HOG1 phosphorylation in Penicillium verrucosum reflects different adaptation levels to salt rich habitats. AB - Mycotoxin biosynthesis in Penicillium verrucosum is modulated by different molecular regulation mechanisms. One important mechanism is the HOG1 (high osmolarity glycerol) MAP kinase signaling pathway. In a comparative analysis three different P. verrucosum strains were selected from six strains with different ability to produce the mycotoxins ochratoxin and citrinin. The fungal strains were grown on laboratory medium supplemented with different concentrations of NaCl. It could be shown that there exists an interrelationship between the growth rate, the level of HOG phosphorylation and the mycotoxin biosynthesis under the respective growth condition. The weak to non ochratoxin producing P. verrucosum strain, BFE875, showed only a poor growth rate but the strongest HOG1 phosphorylation; the strong ochratoxin and citrinin producing strain BFE575 showed a reasonable HOG1 phosphorylation with an average growth rate; and the strong ochratoxin and weak citrinin producing strain BFE495 showed only a poor phosphorylation but the highest growth rate in 7days of incubation at 25 degrees C. The magnitude of phosphorylation of the HOG1 protein seems to be inversely correlated with the degree of adaption of the fungus to hyperosmotic growth conditions. PMID- 23800737 TI - Potential effects of environmental conditions on the efficiency of the antifungal tebuconazole controlling Fusarium verticillioides and Fusarium proliferatum growth rate and fumonisin biosynthesis. AB - Fusarium verticillioides and Fusarium proliferatum are important phytopathogens which contaminate cereals in the Mediterranean climatic region with fumonisins. In this study we examined the interaction between the fungicide efficacy of tebuconazole and water potential (Psiw) (-0.7-7.0MPa)*temperature (20-35 degrees C) on growth and FUM1 gene expression by real time RT-PCR (an indicator of fumonisin biosynthesis) in strains of both Fusarium species. Concentrations of tebuconazole required to reduce growth by 50 and 90% (ED50 and ED90 values) were determined. Growth of strains of both species was largely reduced by tebuconazole, with similar efficacy profiles in the interacting water potential*temperature conditions. In contrast, FUM1 expression was not generally reduced by tebuconazole. Moreover, sub-lethal doses in combination with mild water stress and temperatures less than 35 degrees C significantly induced FUM1 expression with slight differences in both species. These results suggest that the efficacy of antifungal compounds to reduce mycotoxin risk would be more effective if consideration is given to both growth rate and toxin biosynthesis in relation to interacting environmental conditions. This is the first study linking fungicide efficacy of tebuconazole with environmental factor effects on control of growth and FUM1 gene expression of F. verticillioides and F. proliferatum. PMID- 23800738 TI - Diversity assessment of Listeria monocytogenes biofilm formation: impact of growth condition, serotype and strain origin. AB - The foodborne pathogen Listeria monocytogenes has the ability to produce biofilms in food-processing environments and then contaminate food products, which is a major concern for food safety. The biofilm forming behavior of 143 L. monocytogenes strains was determined in four different media that were rich, moderate or poor in nutrients at 12 degrees C, 20 degrees C, 30 degrees C and 37 degrees C. The biofilm formation was mostly influenced by temperature, resulting in decreased biofilm formation with decreasing temperature. Biofilm formation was enhanced in nutrient-poor medium rather than in nutrient-rich medium, and especially in nutrient-poor medium significantly enhanced biofilm production was observed early in biofilm maturation underlining the effect of medium on biofilm formation rate. Also serotype had a significant effect on biofilm formation and was influenced by medium used because strains from both serotype 1/2b and 1/2a formed more biofilm than serotype 4b strains in nutrient-rich medium at 20 degrees C, 30 degrees C and 37 degrees C, whereas in nutrient-poor medium the biofilm production levels of serotype 1/2a and 4b strains were rather similar and lower than serotype 1/2b strains. The strains used originated from various origins, including dairy, meat, industrial environment, human and animal, and the level of biofilm formation was not significantly affected by the origin of isolation, irrespective of medium used and temperature tested. A linear model was used to correlate crystal violet staining of biofilm production to the number of viable cells within the biofilm. This showed that crystal violet staining was poorly correlated to the number of viable cells in nutrient-poor medium, and LIVE/DEAD staining and DNase I treatment revealed that this could be attributed to the presence of non-viable cells and extracellular DNA in the biofilm matrix. The significant impact of intrinsic and extrinsic factors on biofilm production of L. monocytogenes underlined that niche-specific features determine the levels of biofilm produced, and insights in biofilm formation characteristics will allow us to further optimize strategies to control the biofilm formation of L. monocytogenes. PMID- 23800739 TI - Salmonella and Campylobacter reduction and quality characteristics of poultry carcasses treated with various antimicrobials in a post-chill immersion tank. AB - Innovations in poultry processing include implementation of antimicrobials in post-chill decontamination tanks. In this study, a total of 160 broiler carcasses were analyzed to evaluate the efficacy of five post-chill water treatments consisting of 0.004% (40ppm) total chlorine, 0.04% (400ppm) or 0.1% (1000ppm) peracetic acid (PAA), and 0.1% (1000ppm) or 0.5% (5000ppm) lysozyme against Salmonella and Campylobacter spp. In addition, sensory analysis was performed to evaluate any associated effects of the antimicrobials on quality attributes of chicken breast meat. Treatment with 0.04% and 0.1% PAA was most effective (P<=0.05) in reducing populations of Salmonella and Campylobacter as compared to the chlorine treatment at 0.004% and lysozyme treatments at 0.1% and 0.5%, as well as the water treatment and the positive control. Treatment with the various antimicrobials was not found to have negative (P<=0.05) impacts on sensory attributes. Results from this study suggest that utilizing PAA as an antimicrobial in a post-chill immersion tank is an effective application for reducing Salmonella and Campylobacter on carcasses while maintaining product quality. PMID- 23800740 TI - Effect of phenylpyrrole-resistance on fitness parameters and ochratoxin production in Aspergillus carbonarius. AB - The risk of resistance development to fludioxonil and the potential implications of resistance mutations to ochratoxin production in Aspergillus carbonarius were investigated. Mutants of A. carbonarius highly resistant to phenylpyrroles were isolated at a high mutation frequency after N-MNTG-mutagenesis and selection on media containing fludioxonil. A highly reduced sensitivity to fungicides belonging to the same cross-resistance group (AHDs and phenylpyrroles) such as the aromatic hydrocarbon tolclofos-methyl and the dicarboximide fungicides iprodione and vinclozolin was also observed. No cross-resistance relationships were found between fludioxonil and the triazole epoxiconazole, the anilinopyrimidine cyprodinil and the chloronitrile chlorothalonil. Interestingly, fludioxonil-resistant isolates were highly sensitive to the QoI fungicide pyraclostrobin compared to the wild-type parental strain. Fitness studies revealed that resistance mutation(s) had a negative effect on mycelial growth, resistance to osmotic stress and pathogenicity of the fludioxonil-resistant strains. Mycotoxin analysis showed that most fludioxonil-resistant strains produce less quantities of ochratoxin A (OTA) than the wild-type strain both when grown on artificial medium and on grapes. Increased osmotic sensitivity and reduced pathogenicity of the mutant strains were significantly correlated with reduced ochratoxin production in vivo but not in vitro. The above-mentioned data indicate that fludioxonil is an excellent fungicide for the control of A. carbonarius in grapes and a valuable asset for farmers in terms of resistance management and ochratoxin contamination of grapes, vine products and wines. PMID- 23800741 TI - Covalent incorporation of non-chemically modified gelatin into degradable PVA tyramine hydrogels. AB - Development of tissue engineering solutions for biomedical applications has driven the need for integration of biological signals into synthetic materials. Approaches to achieve this typically require chemical modification of the biological molecules. Examples include chemical grafting of synthetic polymers onto protein backbones and covalent modification of proteins using crosslinkable functional groups. However, such chemical modification processes can cause protein degradation, denaturation or loss of biological activity due to side chain disruption. This study exploited the observation that native tyrosine rich proteins could be crosslinked via radical initiated bi-phenol bond formation without any chemical modification of the protein. A new, tyramine functionalised poly(vinyl alcohol) (PVA) polymer was synthesised and characterised. The tyramine modified PVA (PVA-Tyr) was fabricated into hydrogels using a visible light initiated crosslinking system. Mass loss studies showed that PVA-Tyr hydrogels were completely degraded within 19 days most likely via degradation of ester linkages in the network. Protein incorporation to form a biosynthetic hydrogel was achieved using unmodified gelatin, a protein derived from collagen and results showed that 75% of gelatin was retained in the gel post-polymerisation. Incorporation of gelatin did not alter the sol fraction, swelling ratio and degradation profile of the hydrogels, but did significantly improve the cellular interactions. Moreover, incorporation of as little as 0.01 wt% gelatin was sufficient to facilitate fibroblast adhesion onto PVA-Tyr/gelatin hydrogels. Overall, this study details the synthesis of a new functionalised PVA macromer and demonstrates that tyrosine containing proteins can be covalently incorporated into synthetic hydrogels using this innovative PVA-Tyr system. The resultant degradable biosynthetic hydrogels hold great promise as matrices for tissue engineering applications. PMID- 23800742 TI - EGRF conjugated PEGylated nanographene oxide for targeted chemotherapy and photothermal therapy. AB - Low accumulation of chemotherapeutic agent in tumor tissue and multidrug resistance (MDR) present a major obstacle to curing cancer treatment. Therefore, how to combine several therapeutics in one system is a key issue to overcome the problem. Here, we demonstrate epidermal growth factor receptor (EGFR) antibody conjugated PEGylated nanographene oxide (PEG-NGO) to carry epirubicin (EPI) for tumor targeting and triple-therapeutics (growth signal blocking, chemotherapy, photothermal therapy) in tumor treatment. This synergistic targeted treatment simultaneously enhances the local drug concentration (6.3-fold) and performs the ultra-efficient tumor suppression to significantly prolong the mice survival (over the course of 50 days). PMID- 23800743 TI - Selective cellular uptake and induction of apoptosis of cancer-targeted selenium nanoparticles. AB - Selenium nanoparticles (SeNPs) have garnered a great deal of attention as potential cancer therapeutic payloads. However, the in vivo targeting drug delivery has been challenging. Herein, we describe the synthesis of tansferrin (Tf)-conjugated SeNPs and its use as a cancer-targeted drug delivery system to achieve enhanced cellular uptake and anticancer efficacy. Tf as targeting ligand significantly enhances the cellular uptake of doxorubicin (DOX)-loaded SeNPs through clathrin-mediated and caveolae/lipid raft-mediated endocytosis in cancer cells overexpressing transferrin receptor, and increases their selectivity between cancer and normal cells. DOX-loaded and Tf-conjugated SeNPs (Tf-SeNPs) exhibits unprecedented enhanced cytotoxicity toward cancer cells through induction of apoptosis with the involvement of intrinsic and extrinsic pathways. Internalized Tf-SeNPs triggers intracellular ROS overproduction, thus activates p53 and MAPKs pathways to promote cell apoptosis. In the nude mice xenograft experiment, Tf-SeNPs significantly inhibits the tumor growth via induction of p53 mediated apoptosis. This cancer-targeted design of SeNPs opens a new path for synergistic treating of cancer with higher efficacy and decreased side effects. PMID- 23800744 TI - In vitro biomechanical comparison of load to failure testing of a canine unconstrained medial compartment elbow arthroplasty system and normal canine thoracic limbs. AB - Elbow dysplasia, primarily affecting the medial compartment, is the most common cause of lameness in the thoracic limb. Elbow arthroplasty is an option for end stage or severely affected patients. The purpose of this study was to compare ex vivo axial load to failure of an implanted novel elbow arthroplasty system to control limbs. The partial arthroplasty is a medial compartmental, unconstrained system, intended to allow conversion to total arthroplasty. We hypothesized that there would not be any significant difference between implanted and controlled limbs when loaded to failure. Six pairs of medium mixed breed canine cadaveric thoracic limbs were prepared for comparison of failure loading of control and implanted limbs. Axial compression was performed using a mechanical testing system. Failure loads were normalized to bodyweight. The mean normalized failure load (N/kg) for the implanted limbs and control limbs were 2.47 (range: 1.62 3.38) and 2.68 (range: 2.25-3.25), respectively. An implanted to control ratio of 0.93 +/- 0.19 was calculated. The difference between paired control and implanted limbs in normalized failure loading was not significant (p = 0.38). There were not any differences noted in the yield load (p = 0.30), stiffness (p = 0.62), or energy (0.58). Failure modes were recorded. We concluded that the differences between implanted and control limbs in supra-physiologic axial load to failure were not significant. PMID- 23800745 TI - Platelet activating factors in depression and coronary artery disease: a potential biomarker related to inflammatory mechanisms and neurodegeneration. AB - The persistence of a depressive episode in coronary artery disease (CAD) patients not only heightens the risk of acute ischemic events, but it is also associated with accelerated cognitive decline. Antidepressant interventions for depression in CAD have only modest effects and novel approaches are limited by a poor understanding of etiological mechanisms. This review proposes that the platelet activating factor (PAF) family of lipids might be associated with the persistence of a depressive episode and related neurodegenerative pathology in CAD due to their association with leading etiological mechanisms for depression in CAD such as inflammation, oxidative and nitrosative stress, vascular endothelial dysfunction, and platelet reactivity. The evidence implicating PAFs in CAD, vascular pathology, and neurodegenerative processes is also presented. We also propose future directions for the investigation of PAFs as mediators of persistent depression. In summary, PAFs are implicated in leading mechanisms associated with depression in CAD. PAFs may therefore be associated with the persistence of depression in CAD and related to neurodegenerative and cognitive sequelae. PMID- 23800746 TI - Reference values of bone mineral density and prevalence of osteoporosis in Chinese adults. AB - We pooled bone mineral density (BMD) data published in 91 articles including 139,912 Chinese adults and then established a national-wide BMD reference database at the lumbar spine and femur neck for Chinese adults. The prevalence of osteoporosis in the middle-aged and elderly Chinese population was also estimated. INTRODUCTION: Well-accepted reference value of BMD is lacking in Chinese. We established the reference database and assessed osteoporosis prevalence based on published literature conducted in the Mainland China, Taiwan, and Hong Kong Chinese. METHODS: We searched for all published articles indexed in MEDLINE, PubMed, CNKI, and SinoMed up to January 2013. We included cross sectional studies that examined BMD using a dual-energy X-ray absorptiometry at the femur neck (FN) and/or lumbar spine (LS) in healthy adults. Overall age specific mean (SD) BMD were pooled after standardization. RESULTS: Ninety-one studies including 51,906 males and 88,006 females (>= 20 years) in 38 cities in China were included in this pooling study. Gender- and age-specific reference curves of standardized BMD (sBMD) at the LS and FN were constructed. The sBMD cutoffs for osteoporosis classification were 0.746 and 0.549 in women, and 0.680 and 0.568 g/cm(2) in men; age-standardized prevalence of osteoporosis was 23.9 % and 12.5 % in women and 3.2 % and 5.3 % in men aged >= 50 years at the LS and FN, respectively. Meta-regression analysis showed that greater age and altitude, lower latitude, smaller city size, earlier detection time, and random sample were correlated to lower sBMD in at least one gender-specific bone sites; the Hologic DXA produced a higher value of FN sBMD than the other two devices (Lunar and Norland). CONCLUSION: We have established a national-wide BMD reference database at the LS and FN for Chinese adults and estimated the prevalence of osteoporosis in the middle-aged and elderly Chinese population. PMID- 23800747 TI - A case report of disabling bone pain after long-term kidney transplantation. AB - A 77-year-old man, who received a renal transplant 13 years before for IgA glomerulonephritis, was referred after he developed bilateral mid-tibial aching pain that did not improve with simple analgesia. He had recently been changed from low-dose cyclosporine to tacrolimus, but the pain did not improve when this was reversed. He had a history of focal prostatic adenocarcinoma, cryptococcal lung infection, osteoporosis treated with alendronate for 2 years and multiple squamous cell carcinomas, including one requiring left neck dissection and radiotherapy. Upon physical examination, he had gouty tophi and marked bilateral tibial tenderness but had no other clinical findings. Laboratory investigations included an elevated intact parathyroid hormone value of 7.9 pmol/L (1.6 to 6.9), bone specific alkaline phosphatase of 22 ug/L (3.7 to 20.9), urinary deoxypyridinoline/creatinine ratio of 7.2 nmol/mmol (2.5 to 5.4) and C-reactive protein. Chest X-ray and tibial X-rays were normal, but there was marrow oedema and a prominent periosteal reaction on magnetic resonance imaging. A radionuclide bone scan showed increased symmetrical, linear uptake in both tibiae and the left femur, and uptake was also noted in both clinically asymptomatic humeri. Tibial bone biopsy disclosed small deposits of poorly differentiated metastatic cancer and a follow-up chest CT revealed a lung lesion. It was concluded that the bone pain and periostitis was caused by primary lung cancer with metastatic disease to bone, and an associated hypertrophic osteoarthropathy. PMID- 23800748 TI - Operational definitions of sarcopenia and their associations with 5-year changes in falls risk in community-dwelling middle-aged and older adults. AB - Sarcopenia may be diagnosed in the clinic using operational definitions based on low muscle mass or function. This prospective, population-based study revealed that sex-specific associations may exist between operational definitions of sarcopenia and falls in community-dwelling middle-aged and older adults. INTRODUCTION: The objective of this study is to verify associations between sarcopenia and falls risk and to determine changes in sarcopenia prevalence over 5 years in middle-aged and older men and women according to different anthropometric and performance-based operational definitions. METHODS: N = 681 volunteers (48% female; mean +/- SD age 61.4 +/- 7.0 years) participated in baseline and follow-up assessments (mean 5.1 +/- 0.5 years later). Appendicular lean mass (ALM) was assessed by dual-energy X-ray absorptiometry, hand grip (HGS) and lower-limb (LLS) strength were assessed by dynamometry, and falls risk was determined using the physiological profile assessment. Anthropometric definitions (ALM/height squared [ALM-H], ALM/weight * 100 and a residuals method [ALM-R]) and performance-based definitions (HGS, LLS and upper- and lower-limb muscle quality [LMQ]) of sarcopenia were examined. The lowest 20% of the sex-specific distribution for each definition at baseline was classified as sarcopenia. RESULTS: Sarcopenia prevalence increased after 5 years for all operational definitions except ALM-H (men: -4.0%; women: -5.5%). Men classified with sarcopenia according to anthropometric definitions, and women classified with sarcopenia according to performance-based definitions, had significant increases in falls risk over 5 years (all P < 0.05) compared to individuals without sarcopenia. Significant sex interactions were observed for ALM-R, LLS and LMQ (all P < 0.05) definitions. CONCLUSIONS: Sarcopenia prevalence generally increases at a higher rate when assessed using performance-based definitions. Sarcopenia is associated with increases in falls risk over 5 years in community dwelling middle-aged and older adults, but sex-specific differences may exist according to different anthropometric or performance-based definitions. PMID- 23800749 TI - ROS-induced autophagy in cancer cells assists in evasion from determinants of immunogenic cell death. AB - Calreticulin surface exposure (ecto-CALR), ATP secretion, maturation of dendritic cells (DCs) and stimulation of T cells are prerequisites for anticancer therapy induced immunogenic cell death (ICD). Recent evidence suggests that chemotherapy induced autophagy may positively regulate ICD by favoring ATP secretion. We have recently shown that reactive oxygen species (ROS)-based endoplasmic reticulum (ER) stress triggered by hypericin-mediated photodynamic therapy (Hyp-PDT) induces bona fide ICD. However, whether Hyp-PDT-induced autophagy regulates ICD was not explored. Here we showed that, in contrast to expectations, reducing autophagy (by ATG5 knockdown) in cancer cells did not alter ATP secretion after Hyp-PDT. Autophagy-attenuated cancer cells displayed enhanced ecto-CALR induction following Hyp-PDT, which strongly correlated with their inability to clear oxidatively damaged proteins. Furthermore, autophagy-attenuation in Hyp-PDT treated cancer cells increased their ability to induce DC maturation, IL6 production and proliferation of CD4(+) or CD8(+) T cells, which was accompanied by IFNG production. Thus, our study unravels a role for ROS-induced autophagy in weakening functional interaction between dying cancer cells and the immune system thereby helping in evasion from ICD prerequisites or determinants. PMID- 23800750 TI - New obesity agents: lorcaserin and phentermine/topiramate. AB - OBJECTIVE: To evaluate the evidence for lorcaserin and phentermine/topiramate in the treatment of obesity. DATA SOURCES: Literature was accessed through PubMed (June 1975-March 2013) using the search terms lorcaserin, phentermine, topiramate, or phenter mine/topiramate. Additionally, reference citations from publications identified were reviewed. Additional information was obtained from the Food and Drug Administration (FDA)-approved prescribing information and FDA briefing documents. STUDY SELECTION AND DATA EXTRACTION: English-language articles focusing on Phase 3 clinical trials for obesity were critiqued. Data from preclinical and Phase 1 and/or 2 trials are reported when appropriate. Six prospective Phase 3 trials were reviewed. DATA SYNTHESIS: Obesity has reached epidemic proportions, affecting more than one third of adults in the US. Two medication products, lorcaserin and phenter mine/topiramate, have recently received FDA approval as adjuncts to a reduced-calorie diet and increased physical activity among individuals with a body mass index greater than or equal to 30 kg/m(2) or greater than or equal to 27 kg/m(2) with an obesity-related comorbidity, such as hypertension, dyslipidemia, or diabetes. Lorcaserin is a selective serotonin 5-HT2C agonist that regulates food intake, while the combination of phentermine/topiramate causes appetite suppression and enhanced satiety. Three Phase 3 randomized, placebo-controlled trials reported approximately 75% and 45% of patients achieved greater than or equal to 5% weight loss with phentermine/topiramate and lorcaserin, respectively. CONCLUSIONS: With lifestyle modification, phentermine/topiramate appears most effective in terms of weight loss. Lorcaserin demonstrates moderate efficacy. Long-term cardiovascular outcomes studies are needed to confirm the safety and benefit of these new obesity agents. PMID- 23800751 TI - Time to finger point or fix? An invitation to join ongoing efforts to promote ethical authorship and other good publication practices. AB - In this commentary, we present evidence that unethical authorship (eg, guest and ghost authoring) and other publication practices are not restricted to the pharmaceutical industry; they also occur in academia. Such practices are not an industry problem--they are a research problem. To enhance trust in industry sponsored research, companies have made rapid and far-reaching changes to their publication guidelines, policies, and procedures. Professional medical writers have adopted, and continue to implement, these changes. Although evidence indicates that industry practices are improving, there is certainly more to do, both in industry and academia. We invite readers to join ongoing efforts to promote ethical publication practices. PMID- 23800752 TI - A versatile ionic strength sensitive tag from a human GM-CSF-derived linear epitope. AB - A 7-mer hGM-CSF-derived linear epitope (APARSPS) is herein described as a novel and small tag taking into account its particular binding affinity in native conditions that could be easily modified by increasing or lowering the ionic strength. Thus, a 3.4 or 3.8-fold binding increment was observed in high NaCl concentration when the tag was fused to IFN-alpha2b or when the peptide was in its native environment, respectively. The high salt concentration increased the affinity of the binding interaction and improved the APARSPS epitope binding to the paratope allowing one to design an immunoaffinity chromatography purification step in which the high ionic strength was useful to adsorb the fusion protein to the immunoaffinity matrix and the low ionic strength at pH 9 was valuable to desorb it (a 470-fold purification with a 94%-purity was attained in only one step). Also, this short tag did not affect the functionality of the fusion protein and it was able to be detected both in the natural molecule (hGM-CSF) as in the tagged one with the same high detection limit: 273pg of each protein. PMID- 23800754 TI - Aneurysmal bone cyst of the ascending ramus mandible. A case report. AB - We report the clinical course of a 28-year old male patient with a large aneurysmal bone cyst of the ascending ramus of the left mandible. Surgical treatment was performed as radical resection of the ascending ramus of the mandible including the condyle with one-stage reconstruction with a free fibula flap. Aggressive growth, clinical symptoms and a high recurrence rate of aneurysmatic bone cysts were the reason for this surgical treatment. The free fibula flap offers a good quality of cortical bone, which is supposed to be the best choice for reconstruction of the condyle. PMID- 23800753 TI - Comparison of general anaesthesia versus regional anaesthesia with sedation in selected maxillofacial surgery: a randomized controlled trial. AB - BACKGROUND: The airway is the foremost challenge in maxillofacial surgery. The major concerns are difficulty in managing the patient's airway and sharing it between the anaesthetist and surgeons. General anaesthesia, with endotracheal intubation, is the commonly used technique for maxillofacial procedures. We assessed the efficacy and safety of a regional block with sedation technique in certain maxillofacial operations, specifically temporomandibular joint (TMJ) ankylosis and mandibular fracture cases, and compared it with conventional general anaesthesia. We compared the time to discharge from the post anaesthesia care unit (PACU) and the occurrence of side effects, as well as surgeon and patient satisfaction with the anaesthetic technique, between the two groups. MATERIALS & METHODS: We enrolled 50 patients of ASA grade 1 or 2, aged 15-50 years, scheduled for maxillofacial surgery (mandibular fracture or TMJ ankylosis). The patients were divided into two groups of 25 each, to receive sedation with a regional block with the use of a peripheral nerve stimulator in group I and general anaesthesia in group II. We observed haemodynamic parameters, intraoperative and postoperative complications and the amount of surgical bleeding in the two groups. Total anaesthesia time, patient and surgeon satisfaction, time to rescue analgesia, the number of rescue doses required, and the time to discharge from the PACU were compared. RESULTS: The groups were comparable with respect to demographic profile, intraoperative haemodynamic parameters, surgical time, and amount of blood loss. Postoperative pain was assessed using the visual analogue score (VAS). Patients in group I had lower VAS scores after surgery and remained pain-free for longer than those in group II. The mean pain-free interval in group I was 159.12 +/- 43.95 min and in group II was 60.36 +/- 19.77 min (p < 0.005). Patients in group I required lower doses of rescue analgesia than those undergoing the surgery under general anaesthesia (p < 0.005). Patients receiving regional blocks also had fewer episodes of postoperative nausea and vomiting (p = 0.005). These results led to earlier discharge of patients in group I from the PACU. CONCLUSIONS: Regional block with sedation is a safe alternative technique for patients undergoing surgery for mandible fracture or TMJ ankylosis, with clear advantages over general anaesthesia. PMID- 23800755 TI - The relationship between scaphocephaly at the skull vault and skull base in sagittal synostosis. AB - HYPOTHESIS: The skull vault is scaphocephalic in sagittal synostosis but little is known about the deformity at the skull base. If differential progressive deformity occurs between the vault and base, this might affect decision making regarding the timing of surgical intervention. We used 3-dimensional CT (3DCT) scans to compare deformity at the vault, base and posterior fossa in sagittal synostosis. Cephalic index (CI) was measured in 34 consecutive cases of isolated sagittal synostosis and 16 controls using predefined landmarks on the 3DCT volume data set. Planes were generated by a VitreaTM workstation. Data were analysed by Student's t-test and Pearson coefficient. RESULTS: Ratios of CI between the vault and base, and the vault and posterior fossa were significantly reduced in sagittal synostosis (p < 0.0001 and p = 0.0031) demonstrating a milder deformity at the base and posterior fossa. However there was strong positive correlation between CI at the vault and base (r = 0.77, p < 0.0001). We have therefore shown for the first time that the deformity at the base is less severe, but is still closely correlated with the vault in unoperated sagittal synostosis. This study provides a basis for future work analysing the progression of these deformities before and after surgery. PMID- 23800756 TI - Association of osteonecrosis of the jaws and POEMS syndrome in a patient assuming rituximab. AB - POEMS syndrome, is a rare condition characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal proteinaemia, and skin lesions. We report a rare case of a patient affected by Waldenstrom macroglobulinemia, who developed POEMS syndrome and who presented at the time of diagnosis with oral manifestations of the lymphoma and an osteonecrosis of the jaw (ONJ) after rituximab treatment. Although the etiology of ONJ is not known, it is likely that several factors are at play, including endothelial cell damage, decreased angiogenesis, and microvascular compromise. Our patient was treated with rituximab for a long period, and recent studies have demonstrated the possibility that rituximab, a monoclonal antibody directed against the CD20 can exert part of its anti-tumor action, through its action on angiogenesis. Although our report does not allow identification of rituximab as a new risk factor for the onset of the ONJ, further studies seem necessary to exclude a role of the antibody in the alterations of angiogenesis that could lead to the development of the syndrome after rituximab treatment. PMID- 23800757 TI - Molybdenum metabolism in plants. AB - The viability of plants relies on molybdenum, which after binding to the organic moiety of molybdopterin forms the molybdenum cofactor (Moco) and acquires remarkable redox properties. Moco is in the active site of critical molybdoenzymes, which use to work as small electron transport chains and participate in N and S metabolism, hormone biosynthesis, toxic compound transformations and other important processes not only in plants but also in all the other kingdoms of life. Molybdate metabolism in plants is reviewed here, with special attention to two main aspects, the different molybdate transporters that with a very high affinity participate in molybdenum acquisition and the recently discovered Moco enzyme amidoxime-reducing component. Their functionality is starting to be understood. PMID- 23800759 TI - Magnetoelectric control of frozen state in a toroidal glass. AB - The glass state of matter represents a frozen state of an atomically disordered system with local order only. Instead of atoms, systems with glassy states of magnetic and electric dipole moments in solids are known as spin and dipole glasses, respectively. In these conventional glasses, slow dynamics, such as relaxation and memory phenomena, are characteristics of their magnetic/dielectric properties. Here we propose a new glassy state in solids, a 'toroidal glass', in which toroidal moments-vector-like electromagnetic multipole moments breaking both space inversion and time reversal symmetries, and producing a linear magnetoelectric coupling-are randomly oriented and frozen. We investigate the dynamics of a linear magnetoelectric effect in Ni0.4Mn0.6TiO3 and find that the magnetoelectric responses strongly depend on the magnetoelectric cooling history and show striking memory effects. These unusual magnetoelectric dynamical features can be explained in the framework of a toroidal glass in which the toroidal frozen state can be controlled magnetoelectrically. PMID- 23800758 TI - Comparison of methods used to measure the thickness of soft tissues and their influence on the evaluation of tensile stress. AB - Measuring the physical dimensions of soft tissue is difficult due to its deformable nature. Such measurements are used to evaluate the tissue's mechanical properties. Imprecise measurements of the tissue's thickness can alter the assessment of tensile stress which may have significant clinical relevance when used as a diagnostic tool. The performance of routinely used measurement methods including a (i) vernier calipers, (ii) micrometer, (iii) thickness gauge, (iv) glass slide technique coupled with (i) and (ii) and a (v) laser displacement sensor were assessed by comparing them to a photogrammetric technique which was considered to be the measurement standard. All measurements were performed on two tissue types: porcine aorta and human intraluminal thrombus from an abdominal aortic aneurysm (AAA) and results were compared against predetermined criteria whose limits represented a 10% change in experimentally derived tensile stress. The inter-rater and retest reliability of the vernier calipers, micrometer and thickness gauge were also investigated. The thickness gauge was shown to be the most reliable and could accurately measure the thickness of aortic tissue. The conditions of the criteria were not met by any instrument used to measure the thickness of the AAA intraluminal thrombus, however, the micrometer, which proved highly reliable, was considered the most suitable (effects on tensile stress: +14.7%). For both tissues the glass slide and laser techniques significantly over estimated the thickness measurement altering the tensile stress by up to -29.6%. This study highlights the effects of inaccurate measurements on the assessment of tensile stress and recommends a thickness gauge be used to measure structured tissue (aorta) and a micrometer for unstructured tissue (AAA intraluminal thrombus). PMID- 23800760 TI - Identification of ferrous-ferric Fe3O4 nanoparticles in recombinant human ferritin cages. AB - Recombinant ferritin is an excellent template for the synthesis of magnetic nanoparticles. This paper describes carefully performed experiments both to identify ironoxides within nanoparticles and to measure the number of iron atoms in the cores of recombinant human H-chain ferritin (HFn), based on spectroscopy techniques. Using electron energy-loss spectroscopy (EELS) analysis, magnetite (Fe3O4) has been unequivocally identified as the ironoxide formed within HFn cores under special preparation conditions. Atom counting analysis by EELS and high-angle annular dark-field imaging further allowed the correlation of the particle sizes to the real Fe atom numbers in a quantitative manner. These results help clarify some structural confusion between magnetite and maghemite (gamma-Fe2O3), and also provide standard data for the number of Fe atoms within Fe3O4 particles of a given size, whose use is not limited to cases of magnetite synthesized in the cores of recombinant human ferritin. PMID- 23800761 TI - Mobility on the reconstructed Pt(100)-hex surface in ethylene and in its mixture with hydrogen and carbon monoxide. AB - By using high-pressure scanning tunneling microscopy and ambient-pressure X-ray photoelectron spectroscopy, we studied the mobility along with composition, structure and reactivity on the Pt(100)-hex surface. Adsorbates are mobile under 1 Torr of C2H4 and C2H4-H2 mixtures, but adding 3 mTorr of CO quenches the mobility. Ethylene-related adsorbates can also weaken Pt-Pt bonds and thus facilitate displacements in the hexagonal layer. PMID- 23800762 TI - A novel homology model of TRPC3 reveals allosteric coupling between gate and selectivity filter. AB - Utilizing a novel molecular model of TRPC3, based on the voltage-gated sodium channel from Arcobacter butzleri (Na(V)AB) as template, we performed structure guided mutagenesis experiments to identify amino acid residues involved in divalent permeation and gating. Substituted cysteine accessibility screening within the predicted selectivity filter uncovered amino acids 629-631 as the narrowest part of the permeation pathway with an estimated pore diameter of < 5.8A. E630 was found to govern not only divalent permeability but also sensitivity of the channel to block by ruthenium red. Mutations in a hydrophobic cluster at the cytosolic termini of transmembrane segment 6, corresponding to the S6 bundle crossing structure in Na(V)AB, distorted channel gating. Removal of a large hydrophobic residue (I667A or I667E) generated channels with approximately 60% constitutive activity, suggesting I667 as part of the dynamic structure occluding the permeation path. Destabilization of the gate was associated with reduced Ca2+ permeability, altered cysteine cross-linking in the selectivity filter and promoted channel block by ruthenium red. Collectively, we present a structural model of the TRPC3 permeation pathway and localize the channel's selectivity filter and the occluding gate. Moreover, we provide evidence for allosteric coupling between the gate and the selectivity filter in TRPC3. PMID- 23800763 TI - In vivo analysis of aquaporin 0 function in zebrafish: permeability regulation is required for lens transparency. AB - PURPOSE: The zebrafish lens is well suited for studies of physiology and development due to its rapid formation in the embryo and genetic accessibility. Aquaporin 0 (AQP0), a lens-specific membrane protein, is required for lens clarity. Zebrafish have two copies of AQP0 (Aqp0a and b), whereas mammals have a single, multifunctional protein. Here we demonstrate a reliable knockdown/rescue system in zebrafish and use it to provide evidence for subfunctionalization of Aqp0a and b, as well as to show that calcium-mediated regulation of Aqp0a in zebrafish lenses is necessary for transparency. METHODS: Coinjection of antisense oligonucleotides and DNA rescue constructs into zebrafish embryos, followed by evaluation of the developing fish for cataracts, was used to analyze the functions of Aqp0a and b. The water permeability and regulation characteristics of each rescue protein were tested in a Xenopus oocyte swelling assay. RESULTS: Both copies of AQP0 are necessary for lens clarity in the zebrafish, and neither is sufficient. Water permeability is necessary but also insufficient. Phosphorylation and regulation of Aqp0a are required for its function. CONCLUSIONS: In the zebrafish lens, the two closely related AQP0s have acquired distinct functions that are both necessary for lens development and clarity. Regulation of AQP0 water permeability, a well-studied phenomenon in vitro, may be physiologically relevant in the living lens. PMID- 23800765 TI - Vision and Quality of Life Index: validation of the Indian version using Rasch analysis. AB - PURPOSE: A multi-attribute utility instrument (MAUI) consists of a descriptive system in which the items and responses seek information about a concept of the universe of health-related quality of life (QoL), and responses to these items then are weighted and combined to produce the index. To our knowledge, the 6-item Vision and Quality of Life Index (VisQoL) is the only available vision-related MAUI, developed and validated in Australia, specifically for visually impaired (VI) populations. To our knowledge, the psychometric properties of the VisQoL have not yet been investigated in an Indian VI sample; this was the aim of our study. METHODS: The Indian VisQoL was administered to 349 VI adults face-to-face by a trained interviewer at the Vision Rehabilitation Centres of a tertiary eye care facility, South India. Rasch analysis was used to assess the psychometric properties. RESULTS: Rescoring was necessary for all except one item before ordered thresholds were obtained. All items fit the Rasch model and unidimensionality was confirmed. Person separation was acceptable (2.01), indicating that the instrument can discriminate among three strata of participants" vision-related QoL (VRQoL). The VisQoL items were targeted substantially to the participants" VRQoL (-0.69 logits). One item ("ability to have friendships") demonstrated large differential item functioning by work status; working participants reported the item to be more difficult (-1.13 logits) relative to other items when compared to the nonworking participants. CONCLUSIONS: The 6-item Indian VisQoL satisfies unidimensional Rasch model expectations in VI patients. Disordering of response categories was evident; replication is required before a common rescoring option should be considered. PMID- 23800764 TI - Reduction in direction discrimination with age and slow speed is due to both increased internal noise and reduced sampling efficiency. AB - PURPOSE: Sensitivity to moving structure decreases with age and slow speeds may be selectively impaired. This loss could be caused by elevated internal noise in the responses of motion sensors or a reduction in the efficiency with which motion responses are integrated. We adapt an equivalent noise paradigm to analyze the perception of slow and fast speed motion as a function of normal aging. METHODS: A total of 70 observers (20 to 89 years) identified the direction of global motion in a two-alternative forced choice task. In a central 8 degrees aperture, 100 dots of 10% Michelson contrast were moving at 1.6 or 5.5 degrees /s. The direction of each dot was drawn from a Gaussian distribution whose mean and SD were adaptively changed. Internal noise and sampling efficiency were estimated from direction discrimination thresholds as a function of external direction noise, speed, and age. RESULTS: Direction sensitivity was significantly worse for slow speeds at all ages (paired t-test, P < 0.05) and decreased approximately 2% per year (linear regressions, P < 0.01). This aging deficit was due to significant changes in internal noise (5.5 degrees /s) and sampling efficiency (1.6 degrees /s) (linear regression, P < 0.05). CONCLUSIONS: There is motion sensitivity loss with age that arises from an increase in internal noise in the responses of directional sensors and a decrease in responses that contribute to the global decision. Differences in the rates of progression at each speed indicate that motion is processed by independent systems tuned to different speeds, and that the channel for slow speed may be more vulnerable to normal age-related changes. PMID- 23800766 TI - The long-term course of functional and anatomical recovery after macular hole surgery. AB - PURPOSE: To investigate the long-term effect of macular hole surgery, foveal structure and the thickness of retinal layers were analyzed with spectral-domain optical coherence tomography (SD-OCT). The long-term postoperative course of macular thickness and best-corrected visual acuity (BCVA) were followed. METHODS: In a retrospective cohort study, SD-OCT scans were obtained from the horizontal midline in 51 eyes 54+/-20 months postoperatively and from 30 control eyes. Retinal layer thickness was measured with a manual segmentation procedure aided by a customized computer program. BCVA was followed and macular thickness was quantified over time with the time-domain (TD) OCT Fast Macular Thickness program for up to 91 months. RESULTS: Median foveal thickness between the outer plexiform and ganglion cell layers was greater than normal while that of the other retinal layers was normal. The median foveal shape remained slightly distorted. The postoperative decrease of central macular thickness toward normal values was delayed to 28 months postoperatively. Nasal macular thickness was decreased to normal at 6 months while superior, temporal, and inferior macular thickness was decreased to normal at 1 to 2 months postoperatively. Preoperative mean BCVA was 20/100+/-3 lines. Postoperatively, mean BCVA was 20/44+/-2 lines at 3 to 6 months, 20/40+/-2 lines at 1 year, 20/32+/-2 lines at 2 years, and 20/28+/-1 line after a mean follow-up period of 54+/-20 months. CONCLUSIONS: Long-term postoperatively, the median thickness of retinal layers remains slightly thickened between the outer plexiform and the ganglion cell layer. The process of gradual recovery may continue for several years after macular hole surgery. PMID- 23800767 TI - Otago Glaucoma Surgery Outcome Study: cytology and immunohistochemistry of trabeculectomy blebs. AB - PURPOSE: To describe findings of light microscopic examination of trabeculectomy blebs. METHODS: Histologic and immunohistochemical features of blebs including cell types, and distribution of apoptotic cells and proapoptotic death messengers were examined in six eyes 6.0 to 25.9 years after trabeculectomy. RESULTS: All specimens showed a channel opening into a rectangular cleft in the middle layer of sclera. The channels showed degenerative changes with disintegration and loss of collagen fibers and few pyknotic cells. Changes were extensive on the upper surface of the cleft forming irregular channels extending through and around the edges of the superficial scleral flap into moderately cellular and vascular oedematous conjunctiva covered by intact epithelium. Immunohistochemical staining demonstrated migration of histiocytes from superficial blood vessels into the deeper layers where they apoptosed and disintegrated. Fas ligand+ proapoptotic death messengers were concentrated in the superficial conjunctival regions of blebs. CONCLUSIONS: These results indicated that the normal cell processes in functioning trabeculectomy blebs were similar to that of Molteno implant capsules. These processes involved migration of cells from superficial blood vessels into perivascular spaces and the deeper tissues where apoptosis occurred. Apoptosis was associated with breakdown of tissue matrix and release of proapoptotic death messengers that were transported by aqueous to the superficial layers where they suppressed collagen synthesis by inducing apoptosis in metabolically active cells. PMID- 23800768 TI - The progression of haze formation in rabbit corneas following phototherapeutic keratectomy. AB - PURPOSE: To determine the topographical location and time course of development of corneal haze in a phototherapeutic keratectomy model using slit lamp examination, macrophotography, quantitative image analysis, and immunofluorescence staining of corneal sections. METHODS: Rabbit corneas were ablated with an excimer laser and were observed and graded for haze via slit lamp, imaged, and graded by macrophotography. Corneal sections were stained for alpha-smooth muscle actin (alpha-SMA) and tenascin-C (TNC). The distribution of haze imaged in the macrophotographs and density of alpha-SMA and TNC staining were compared. A daily image time course of haze formation was generated using macrophotography. RESULTS: The first signs of corneal haze were apparent shortly after reepithelialization. The haze was distributed as a ring at the wound margin in all cases, while nearly all corneas also had some central islands of haze initiation. With time, the haze spread within the ablated zone and intensified. The pattern of immunofluorescent staining for alpha-SMA and TNC at the wound margin mirrored the haze distribution, spread, and intensification with time. CONCLUSIONS: The initiation and spread of subepithelial haze begins shortly after reepithelialization. The haze then spreads from the loci of initiation and becomes more dense with time, maturing as early as 14 days after wounding. The improved temporal and spatial resolution provided by these data improve the current model of light-scattering haze formation in wounded corneas, which will improve the design of studies aimed at maintaining corneal clarity following acute injury or surgery. PMID- 23800769 TI - The PLGA implant as an antimitotic delivery system after experimental trabeculectomy. AB - PURPOSE: To investigate the effect of poly (lactic-co-glycolic acid) (PLGA) implants loaded with mitomycin C (MMC) and with different adjuvant treatments after glaucoma filtration surgery (GFS), in comparison to standard treatments. METHODS: Forty-two New Zealand White rabbits underwent bilateral GFS and received different treatments: topical MMC (group 1); topical 5-fluorouracil (5-FU; group 2); PLGA implant (group 3); MMC-loaded and -coated PLGA implant (group 4); MMC loaded and 5-FU-coated PLGA implant (group 5); subconjunctival bevacizumab (group 6); MMC-loaded PLGA implant and subconjunctival bevacizumab (group 7); and no treatment (right eye of all animals; control group). Intraocular pressure (IOP) and filtering bleb were evaluated on different days after GFS. Histology was performed to examine the conjunctiva, sclerotomy, filtering bleb, and persistence of the implant. RESULTS: The best hypotensive results were achieved in the MMC loaded and -coated PLGA implant group, which presented the lowest IOP values on days 1, 5, 7, 14, and 28 after GFS. Excluding the implant groups, in which the bleb could not be properly measured, bleb survival was superior to controls in groups 1, 2 and lower in group 6. Group 7 presented greater extension, height, and vascularization of the bleb. Epithelial thinning and lymphoplasmacytic infiltrate were observed in groups 1, 2, 4, 5, and 7. The rates of closure of the sclerotomy and bleb were 100% and 76%, respectively, and implant persistence was 95%. CONCLUSIONS: MMC-loaded and -coated implants have optimal surgical results, followed by topical MMC application. In this experimental model, bevacizumab could interact with MMC. PMID- 23800770 TI - Survey of common eye diseases in laboratory mouse strains. AB - PURPOSE: As in human populations, in which founder mutations have been identified in groups of families, a number of founder mutations have been observed across strains in mice. In this report, we provide a phenotype and genotype survey of three common eye diseases in the collection of JAX mice strains at The Jackson Laboratory (JAX). These eye diseases are retinal degeneration 1 (Pde6b(rd1)), retinal degeneration 8 (Crb1(rd8)), and cone photoreceptor function loss 3 (Gnat2(cpfl3)). METHODS: Ocular lesions for rd1 and rd8 were evaluated by fundus examination and fundus photography, and the abnormal retinal function observed in mice homozygous for cpfl3 was assessed by ERG. Genotyping protocols for rd1, rd8, and cpfl3 mutations were performed by PCR with appropriate primers. RESULTS: We have actively screened retired breeders for surface dysmorphologies, and for intraocular defects by indirect ophthalmoscopy, slit-lamp biomicroscopy, and ERG to discover new spontaneous mutations in strains from the Genetic Resource Science (GRS) production colony. Through this process, we have found that of the strains screened, 99 strains carried the rd1 mutation, 85 strains carried the rd8 mutation, and 20 strains carried the cpfl3 mutation. CONCLUSIONS: Of the 1000 of strains screened during this study, 204 carried one of three founder mutations in Pde6b, Crb1, or Gnat2. Since these three retinal mutations occur commonly in various mouse strains, genotyping for these mutations, and/or avoiding mouse strains or stocks carrying these mutant alleles when studying new retinal disorders is recommended. The robust PCR genotyping protocols to test for these common alleles are described herein. PMID- 23800772 TI - Simple and reliable HPLC method for the monitoring of methotrexate in osteosarcoma patients. AB - Methotrexate (MTX) is a dihydrofolate reductase inhibitor that is used for the treatment of tumors and autoimmune diseases. Several automated binding assays are used in clinical practice and numerous chromatographic methods have been developed toward higher specificity and sensitivity. In the present study, phenyl cartridges were used for the solid-phase extraction (SPE) of MTX from human serum samples; subsequently, extracts were analyzed by reversed-phase high-performance liquid chromatography. Isocratic separation was implemented on a Kromasil-C18 column with a mobile phase consisting of 50 mM sodium acetate buffer (pH 3.6) acetonitrile (89:11, v/v) and ultraviolet detection at 307 nm. MTX eluted in less than 12 min with no interference from impurities or 24 examined drugs. Detector response was linear in the range of 0.025-5.00 uMU (coefficient of correlation > 0.99). Recovery from the serum was 93.1-98.2% and bias was < 8.3%. Intra-day and inter-day precision were <7.8 and 12.6%, respectively (n = 6). The limit of quantitation was 0.01 uM and the limit of detection was 0.003 uMU. The method was validated by using serum samples from osteosarcoma patients treated with high dose MTX (8-12 g/m(2)). In conclusion, the combined use of a phenyl functionalized sorbent for SPE and a Kromasil-C18 column, and specific detection at 307 nm, assured a selective, fast, robust and cost-effective method for the monitoring of MTX in osteosarcoma patients under high-dose MTX treatment, thus contributing to more efficient treatment. PMID- 23800771 TI - Effect of nitric oxide on anterior segment physiology in monkeys. AB - PURPOSE: To determine the effect of the nitric oxide donor, sodium nitroprusside (SNP), and the nitric oxide synthase (NOS) inhibitor, L-nitro-arginine methylester (L-NAME), on IOP, mean arterial pressure (MAP), pupil diameter (PD), refraction (Rfx), aqueous humor formation (AHF), and outflow facility (OF) in monkeys. METHODS: Monkeys were treated with single or multiple topical treatments of 500 MUg SNP or L-NAME to one eye. IOP was determined by Goldmann applanation tonometry, PD with vernier calipers in room light, Rfx by Hartinger coincidence refractometry, AHF by fluorophotometry, and MAP with a blood pressure monitor. OF was determined by two-level constant pressure perfusion following anterior chamber exchange. RESULTS: Following four topical treatments with 500 MUg SNP, 30 minutes apart, IOP was significantly decreased from 2 to 6 hours compared with the contralateral control with the maximum IOP reduction of 20% at 3 hours (P < 0.001). PD, Rfx, and AHF were unchanged. Effects on MAP were variable. OF after SNP exchange was significantly increased by 77% (P < 0.05) at 10(-3) M. Topical L NAME had no effect on IOP, PD, Rfx, or MAP. CONCLUSIONS: Enhancement of nitric oxide concentration at targeted tissues in the anterior segment may be a useful approach for IOP reduction for glaucoma therapy. Additional studies are warranted before conclusions can be made regarding the effect of NOS inhibition on ocular physiology in nonhuman primates. PMID- 23800773 TI - Experimental and computational studies on 4-[(3,5-dimethyl-1H-pyrazol-1 yl)methoxy]phthalonitrile and synthesis and spectroscopic characterization of its novel phthalocyanine magnesium(II) and tin(II) metal complexes. AB - The molecular structure of the substituted phthalonitrile was analyzed crystallographically and compared with optimized geometric structure. The structural properties of the compound such as energy, vibrational frequency, ground state transitions, (1)H and (13)C NMR chemical shifts, NBO analysis and hyperpolarizability were computed by DFT (Density Functional Theory) method and compared with experimental results. The novel Mg(II) and Sn(II) phthalocyanines synthesized from the substituted phthalonitrile and their aggregation behaviors were investigated in different solvents and at different concentrations in DMSO. PMID- 23800774 TI - The peculiarities of spectral manifestations of high-voltage electric discharge in different phase states of ion systems. AB - The effects of high-voltage pulsed discharge (HVPD activation) on vibrational spectra of ion salt systems have been studied. The peculiarities of spectral display of HVPD in ion melts and aqueous solutions of electrolytes, in ion conducting phases of crystalline and glassy salt systems have been investigated. After HVPD a salt system is in non-equilibrium activated state. In the activated state of a salt system, the relaxation time of the vibrational excited states of molecular ions is shorter than in the equilibrium state if the vibrational relaxation rate increases with temperature in the system. For those systems for which the relaxation rate decreases at elevated temperatures, the relaxation time of the vibrational excited states of molecular ions is longer than in the equilibrium state. HVPD activation of a salt system can change the configuration of the electron shell of molecular ions. Therefore, the lifetime values of activated state of salt systems are abnormally large. PMID- 23800775 TI - Defect formation of gamma irradiated MoO3-doped borophosphate glasses. AB - Borophosphate glasses of the basic composition (50P2O5, 30B2O3, 20Na2O mol%) containing different doping molybdenum oxide percents (0.16-0.98) were prepared by melting and annealing method. Infrared and UV-visible absorption spectroscopic measurements before and after gamma irradiation were carried out. The base undoped borophosphate glass reveals strong UV absorption bands but with no visible bands and these UV bands are related to unavoidable trace iron impurities contaminated within the raw materials used for the preparation of this glass. The introduction of MoO3 (in doping ratio) into this glass produces an additional UV band and a broad visible band and their intensities increase with the MoO3 content. These additional bands are related to both Mo(6+) and Mo(5+) ions. The base undoped borophosphate glass shows retardation effect towards gamma irradiation. Gamma irradiation produces marked changes in the UV-visible spectra of Mo-O3-doped glasses. Such changes can be related to the production of induced defects from photochemical reactions and the generation of positive holes. Infrared absorption spectrum of the undoped borophosphate glass reveals complex vibrational bands due to the presence of both phosphate groups beside borate groups with triangular and tetrahedrally coordinated units. The introduction of MoO3 causes some limited variations in the FTIR spectra. Gamma irradiation produces minor changes in the intensities of some IR bands. Such changes are related to the changes in the bond angles and/or bond lengths of few structural groups upon irradiation while the main structural groups remain unchanged in their number and position. PMID- 23800776 TI - Surface enhanced Raman spectroscopic studies on magnetic Fe3O4@AuAg alloy core shell nanoparticles. AB - A facile approach has been developed to fabricate multifunctional Fe3O4@AuAg alloy core-shell nanoparticles, owning the magnetism of the core and the surface enhanced Raman spectroscopy (SERS) activities of the alloy shell. By changing the amount of HAuCl4 and AgNO3, Fe3O4@AuAg alloy nanoparticles with different component ratios of Au and Ag were successfully prepared. The surface plasmon resonance of the composition was linearly tuned in a wide range by varying the molar fraction of Ag and Au, suggesting the formation of AuAg alloy shell. SERS and magnetic enrichment effects were investigated by using thiophenol (TP) as the probe molecule. The SERS intensity was strongly dependent on the molar ratios of Au and Ag and the excitation line. Enrichment for the molecules with low concentration and on line SERS monitoring experiments were performed through combining the magnetism of the core and the SERS effect of the alloy shell. The results revealed that the magnetic enrichment efficiency was dramatically increased due to the strong magnetism of Fe3O4 core. In addition, the Fe3O4@AuAg nanoparticles were also used in the microfluidic chip to continuously detect different flowing solution in the channel. The detection time and amount of analyte were successfully decreased. PMID- 23800777 TI - Structural elucidation and spectral characterizations of Co3O4 nanoflakes. AB - A facile solvothermal process is successfully developed to prepare F-center cubic Co3O4 nanoflakes in ethylene-glycol-water solvent. Cobalt acetate [Co(Ac)2.4H2O] is directly used as precursor and ethylene glycol performs a reducer and modifying agent in the system. The as obtained products were characterized by XRD, FT-IR, UV-Vis-DRS, SEM, EDAX, XPS and HR-TEM. XRD studies indicate that the nanoflakes have the same crystal structure found in cubic form of Co3O4. The lattice parameter, X-ray density and the specific area of nanoflakes were also estimated from XRD pattern. The various functional groups present in Co3O4 nanoflakes were identified by FTIR analysis. The band gap energy of Co3O4 nanoflakes was calculated from UV-Vis-DRS spectral studies. SEM analyses ascertain that Co3O4 nanocrystals are nanoflakes in nature and the particle size in SEM is exactly consistent with XRD results. The elemental composition was determined using the energy dispersive X-ray spectroscopy was performed at several points in the region and averaged to obtain the representative results. The atomic composition of the Co3O4 was detected by X-ray photoelectron spectroscopy (XPS). The nanoscale structures were observed using high-resolution transmission electron microscopy. PMID- 23800778 TI - Fighting fires and fat: an intervention to address obesity in the fire service. PMID- 23800779 TI - A qualitative investigation of teachers' information, motivation, and behavioral skills for increasing fruit and vegetable consumption in preschoolers. AB - OBJECTIVE: Using the Information-Motivation-Behavioral Skills model as a framework, researchers qualitatively assessed preschool teachers' perceived motivation, facilitators, and barriers related to getting preschool children to eat fruits and vegetables (FV). METHODS: Individual, semi-structured interviews with 28 Head Start teachers in central North Carolina. RESULTS: Participants reported the need for FV-related information (Information) to improve FV consumption in children, perceived themselves to be parents at school (Motivation), and reported using conditional rewards and punishment statements to get preschoolers to eat FV (Behavioral Skills). CONCLUSIONS AND IMPLICATIONS: Nutrition educators may use the Information-Motivation-Behavioral Skills model to develop education materials targeting increases in preschoolers' FV consumption. To motivate preschool teachers who see themselves as parents at school (Motivation), nutrition educators can provide teachers with FV-related information that was reported as their needs (Information), and supportive feeding practices (Behavioral Skills) to get preschoolers to consume FV. PMID- 23800780 TI - Child Care Mealtime and Active Play Partnerships (Child Care MAPP): evaluation of a training resource Web site for enhancing nutrition education communication. AB - The communication component of the Child Care MAPP Web site was designed according to an established theoretical base, and was critically reviewed. The communication materials were targeted for use by trainers who educate child care providers, and may be incorporated into higher education curricula to guide nutrition educators who will be working in child nutrition and child feeding programs. Evaluation of the impact of the communication materials on a group of trainers demonstrated a significant increase in participant confidence to communicate about nutrition. In particular, the child- and adult-centered phrases developed as a novel and developmentally appropriate approach to nutrition education were evaluated by respondents as useful, and were found to increase confidence to communicate with children. Future research should further examine the use of child-centered and adult-centered nutrition phrases in nutrition education and higher education, to determine whether the way in which adults talk with children improves children's knowledge about nutrition, and whether use of the phrases can positively affect children's nutrition behaviors. PMID- 23800781 TI - First insights into the cattle serological response to tsetse salivary antigens: a promising direct biomarker of exposure to tsetse bites. AB - In the context of the Pan African Tsetse and Trypanosomiasis Eradication Campaign, the value of tsetse saliva antibodies as a biomarker of cattle exposure to tsetse flies was evaluated, as this could provide an alternative and complementary tool to conventional entomological methods. Serum immune reactivity to Glossina (G.) palpalis (p.) gambiensis, G. tachinoides and G. morsitans (m.) submorsitans whole saliva extracts (WSE) were monitored in cattle from both tsetse free and tsetse infested areas, and in cows experimentally exposed to tsetse flies and other hematophagous arthropods. In the tsetse infested area, cattle IgG responses to Glossina WSE were significantly higher during the dry season (p<0.0001) when herds are most exposed to tsetse flies and in infected animals (p=0.01) as expected in the case of a biomarker of exposure. Experimental studies further confirmed this as a quick rise of specific IgGs was observed in animals exposed to tsetse flies (within weeks), followed by a rapid clearance after exposure was stopped. In contrast to the two other tsetse species, G. m. submorsitans WSE enabled to detect exposure to all tsetse species and were associated with low level of cross-reactivity to other blood sucking arthropods. Finally, IgG responses to G. m. submorsitans salivary antigens enabled to distinguish different groups of cows according to exposure levels, thus indicating that tsetse saliva antibodies are not only indicators of tsetse exposure but also are correlated to the intensity of tsetse contacts (p=0.0031). Implementation of this new sero-epidemiological marker of cattle exposure to tsetse flies in the framework of tsetse elimination campaigns is discussed. PMID- 23800782 TI - Evaluation of surgical treatment of medial patellar luxation in Pomeranian dogs. AB - In a prospective study, the outcome of surgical correction of medial patellar luxation of 70 stifle joints in 55 Pomeranian dogs was evaluated. Trochlear block recession alone was performed in 46 stifle joints, or in combination with tibial tuberosity transposition in 24 stifle joints in cases with grade II, III or IV medial patellar luxation. Additional procedures were performed to restore lateral and medial retinacular function. The recurrence of patellar luxation and the degree of lameness were evaluated up to at least 16 weeks after surgery. The overall recurrence rate was 10%. The outcome of surgery was considered good for grade II luxation with a 100% success rate. Recurrent medial patellar luxation was diagnosed in approximately 11% of dogs with grade III and in 36% of dogs with grade IV luxation. The postoperative lameness score decreased significantly in comparison with the preoperative score at four weeks and thereafter until the end of the study. PMID- 23800783 TI - Identifying sources of groundwater nitrate contamination in a large alluvial groundwater basin with highly diversified intensive agricultural production. AB - Groundwater quality is a concern in alluvial aquifers underlying agricultural areas worldwide. Nitrate from land applied fertilizers or from animal waste can leach to groundwater and contaminate drinking water resources. The San Joaquin Valley, California, is an example of an agricultural landscape with a large diversity of field, vegetable, tree, nut, and citrus crops, but also confined animal feeding operations (CAFOs, here mostly dairies) that generate, store, and land apply large amounts of liquid manure. As in other such regions around the world, the rural population in the San Joaquin Valley relies almost exclusively on shallow domestic wells (<=150 m deep), of which many have been affected by nitrate. Variability in crops, soil type, and depth to groundwater contribute to large variability in nitrate occurrence across the underlying aquifer system. The role of these factors in controlling groundwater nitrate contamination levels is examined. Two hundred domestic wells were sampled in two sub-regions of the San Joaquin Valley, Stanislaus and Merced (Stan/Mer) and Tulare and Kings (Tul/Kings) Counties. Forty six percent of well water samples in Tul/Kings and 42% of well water samples in Stan/Mer exceeded the MCL for nitrate (10mg/L NO3-N). For statistical analysis of nitrate contamination, 78 crop and landuse types were considered by grouping them into ten categories (CAFO, citrus, deciduous fruits and nuts, field crops, forage, native, pasture, truck crops, urban, and vineyards). Vadose zone thickness, soil type, well construction information, well proximity to dairies, and dominant landuse near the well were considered. In the Stan/Mer area, elevated nitrate levels in domestic wells most strongly correlate with the combination of very shallow (<=21 m) water table and the presence of either CAFO derived animal waste applications or deciduous fruit and nut crops (synthetic fertilizer applications). In Tulare County, statistical data indicate that elevated nitrate levels in domestic well water are most strongly associated with citrus orchards when located in areas with a very shallow (<=21 m) water table. Kings County had relatively few nitrate MCL exceedances in domestic wells, probably due to the deeper water table in Kings County. PMID- 23800784 TI - The effects of a maintenance therapy with peg-interferon alpha-2a on liver fibrosis in HIV/HCV co-infected patients: a randomized controlled trial. AB - OBJECTIVE: We hypothesized that, in Human Immunodeficiency Virus and Hepatitis C Virus (HIV/HCV) co-infected patients who did not respond to peg-interferon and ribavirin, a maintenance therapy with peg-interferon could induce fibrosis regression. METHODS: This was a randomized study with two parallel groups. HIV/HCV co-infected patients received peg-interferon alpha-2a at 180 MUg/week or remained on observation for 96 weeks. The primary endpoint was the percentage of patients who experienced a decrease of at least one point in their Metavir fibrosis score between initial and final liver biopsies. Secondary endpoints included plasma fibrosis markers at week 96, occurrence of HCV-related complications, and survival. RESULTS: A total of 52 patients were randomized (peg interferon: 25; control: 27) including 18 with cirrhosis. The median (interquartile range) age was 44 (40-46) years, and 69% were male. A total of 64% had ALT levels >1.5 normal values, and the CD4 cell count was 391 (296-537) cells/mm(3); 67% of patients had HIV RNA <200 copies/mL at entry. The main endpoint was assessed in 41 patients. Response rates were 3/20 (15%) and 4/21 (19%) in the peg-interferon and control groups, respectively (p = 0.99). There was no significant difference between peg-interferon and control groups on plasma fibrosis markers at the final visit. Severe liver-related complications were observed in 2 and 5 patients in peg-interferon and control groups, respectively. Three deaths were observed, all in the control group. CONCLUSIONS: A maintenance therapy with peg-interferon alpha-2a over 96 weeks in HIV/HCV co-infected patients, who were non-responders to HCV treatment, did not change liver fibrosis. ClinicalTrials.gov Identifier: NCT00122616. PMID- 23800785 TI - Reaching un-drugable intracellular targets with the long arm of antibodies. PMID- 23800786 TI - Clinical characteristics, morbidity, and prognostic value of concomitant coronary artery disease in idiopathic dilated cardiomyopathy. AB - BACKGROUND: Patients with idiopathic dilated cardiomyopathy (dCMP) might present coronary artery disease (CAD) concomitant to dCMP and prognostic differences between ischemic heart disease and non-ischemic cardiomyopathy have been described. Clinical characteristics and prognostic implications of concomitant CAD in patients with dCMP are largely unknown. METHODS: A total of 1,263 patients with chronic systolic dysfunction from dCMP-of these 67.1 % (n = 847; 72.3 % men) without and 32.9 % (n = 416; 80.8 % men) with concomitant CAD were included and baseline clinical characteristics noted. They were followed prospectively for 36.3 (20.8-65.0) months, representing 5,168 patient-years. All-cause mortality was the primary endpoint; and decompensation requiring hospitalisation as well as the combined endpoint thereof were secondary endpoints. RESULTS: Independent significant predictors of CAD were smoking status (current smoker: OR 2.68, 95 % CI 1.61-4.46; p < 0.001; past smoker: OR 2.52, 95 % CI 1.40-4.52; p < 0.005; each vs. non-smoker), presence of dyslipidemia (OR 3.46, 95 % CI 2.23-5.35; p < 0.001), age (OR 1.06, 95 % CI 1.04-1.08; p < 0.001), and female sex (OR 0.49, 95 % CI 0.29-0.81; p = 0.005). The presence of CAD was not a significant predictor of all-cause mortality (adjusted HR 0.74, 95 % CI 0.36-1.54; p = 0.42), morbidity (adjusted HR 1.48, 95 % CI 0.55-3.99; p = 0.44), or the combined endpoint (HR 0.65, 95 % CI 0.24-1.78; p = 0.40). CONCLUSION: Concomitant CAD is common in patients with dCMP. Clinical predictors of its presence are largely coincident with classic risk factors in the general population. The presence of concomitant CAD appears not to be associated with adverse prognosis (morbidity or mortality) in patients with dCMP. PMID- 23800787 TI - Intralaminar stimulation of the inferior colliculus facilitates frequency specific activation in the auditory cortex. AB - OBJECTIVE: Auditory midbrain implants (AMI) provide inadequate frequency discrimination for open set speech perception. AMIs that can take advantage of the tonotopic laminar of the midbrain may be able to better deliver frequency specific perception and lead to enhanced performance. Stimulation strategies that best elicit frequency specific activity need to be identified. This research examined the characteristic frequency (CF) relationship between regions of the auditory cortex (AC), in response to stimulated regions of the inferior colliculus (IC), comparing monopolar, and intralaminar bipolar electrical stimulation. APPROACH: Electrical stimulation using multi-channel micro-electrode arrays in the IC was used to elicit AC responses in anaesthetized male hooded Wistar rats. The rate of activity in AC regions with CFs within 3 kHz (CF aligned) and unaligned CFs was used to assess the frequency specificity of responses. MAIN RESULTS: Both monopolar and bipolar IC stimulation led to CF aligned neural activity in the AC. Altering the distance between the stimulation and reference electrodes in the IC led to changes in both threshold and dynamic range, with bipolar stimulation with 400 um spacing evoking the lowest AC threshold and widest dynamic range. At saturation, bipolar stimulation elicited a significantly higher mean spike count in the AC at CF-aligned areas than at CF unaligned areas when electrode spacing was 400 um or less. Bipolar stimulation using electrode spacing of 400 um or less also elicited a higher rate of elicited activity in the AC in both CF-aligned and CF-unaligned regions than monopolar stimulation. When electrodes were spaced 600 um apart no benefit over monopolar stimulation was observed. Furthermore, monopolar stimulation of the external cortex of the IC resulted in more localized frequency responses than bipolar stimulation when stimulation and reference sites were 200 um apart. SIGNIFICANCE: These findings have implications for the future development of AMI, as a bipolar stimulation strategy may improve the ability of implant users to discriminate between frequencies. PMID- 23800788 TI - Novel paradigms of innate immune sensing of viral infections. AB - According to the existing paradigm, cellular recognition of viral infection is mediated by molecular patterns within the virus particle or produced during virus replication. However, there are various physical cellular changes indicative of infection that could also trigger innate antiviral responses. The type-I interferon response is rapidly engaged to limit viral infection and a number of studies have shown that the interferon response, or components of it, are induced by general perturbations to cellular processes. Virus entry requires membrane and cytoskeletal perturbation, and both membrane fusion or actin depolymerising agents alone are able to activate antiviral genes. Viruses cause cellular stress and change the cellular environment, and oxidative stress or endoplasmic reticulum stress will amplify antiviral signaling. Many of these responses converge on interferon regulatory factor 3, suggesting that it plays a crucial role in determining the degree to which the cell responds. This review highlights novel paradigms of viral recognition and speculates that viral infection is sensed as a danger signal. PMID- 23800789 TI - The IL17A and IL17F loci have divergent histone modifications and are differentially regulated by prostaglandin E2 in Th17 cells. AB - Prostaglandin E2 (PGE2), IL-23 and IL-1beta are implicated in inflammatory bowel disease susceptibility, likely in part by modulating IL-17 producing CD4(+) T helper (Th17) cells. To better understand how these three mediators affect Th17 cell memory responses, we characterized the gene expression profiles of activated human peripheral CD4(+) effector memory T cells and sorted Th17 memory cells from healthy donors concurrent with IL17A mRNA induction mediated by PGE2 and/or IL-23 plus IL-1beta. We discovered that PGE2 and IL-23 plus IL-1beta differentially regulate Th17 cytokine expression and synergize to induce IL-17A, but not IL-17F. IL-23 plus IL-1beta preferentially induce IL-17F expression. The addition of PGE2 to IL-23 plus IL-1beta only enhances IL-17A expression as mediated by the PGE2 EP4 receptor, and promotes a switch from an IL-17F to an IL-17A predominant immune response. The human Th17 HuT-102 cell line was also found to constitutively express IL-17A, but not IL-17F. We went on to show that the IL17A and IL17F loci have divergent epigenetic architectures in unstimulated HuT-102 and primary Th17 cells and are poised for preferential expression of IL17A. We conclude that the chromatin for IL17A and IL17F are distinctly regulated, which may play an important role in mucosal health and disease. PMID- 23800791 TI - Interoceptive and multimodal functions of the operculo-insular cortex: tactile, nociceptive and vestibular representations. AB - The operculo-insular cortex has been termed the 'homeostatic control center' or 'general magnitude estimator' of the human mind. In this study, somatosensory, nociceptive and caloric vestibular stimuli were applied to reveal, whether there are mainly common, or possibly specific regions activated by one modality alone and whether lateralization effects, time pattern differences or influences of the aversive nature of the stimuli could be observed. Activation of the dorsal posterior insula was caused by all stimuli alike thus terming this area multimodal. Early phases of the noxious heat and caloric vestibular stimulation led to responses in the anterior insula. Using conjunction analyses we found that left- and right-sided tactile stimulation, but not nociceptive stimulation, caused a joint activation of the cytoarchitectonic area OP1 and nociceptive but not tactile stimulation of the anterior insula bilaterally. Tactile activation in the parietal operculum (SII, OP1) was distinct from nociceptive activation (OP3 and frontal operculum). The joint activation by all three stimuli located in the dorsal posterior insula argues for the presence of multisensory structures. The distinct activation of the anterior insula by aversive stimuli and the posterior insula by multisensory signals supports the concept of a partitioned insular cortex recently introduced based on connectivity studies and meta-analyses. PMID- 23800790 TI - The EEG correlates of the TMS-induced EMG silent period in humans. AB - Application of magnetic or electrical stimulation to the motor cortex can result in a period of electromyography (EMG) silence in a tonically active peripheral muscle. This period of EMG silence is referred to as the silent period (SP). The duration of SP shows intersubject variability and reflects the integrity of cortical and corticospinal pathways. A non-invasive technique for assessing the duration of SP is the combination of Transcranial Magnetic Stimulation (TMS) with EMG. Utilizing TMS-EMG, several studies have reported on the shortening or lengthening of SP in neuropsychiatric disorders such as schizophrenia, bipolar disorder, depression, obsessive compulsive disorder, epilepsy, Parkinson's disease, and stroke. However, cortical, corticospinal and peripheral components are difficult to disentangle from EMG alone. Here, we use the multimodal neuroimaging technique of TMS-EMG combined with concurrent electroencephalography (EEG) recording to further examine the cortical origin of SP and the cortical oscillatory activity that underlies SP genesis. We demonstrate that the duration of SP is related to the temporal characteristics of the cortical reactivity and the power of delta to alpha oscillations in both local and remote areas ipsilateral and contralateral to the stimulation site, and beta oscillations locally. We illustrate that, compared to EMG, the EEG indices of the SP provide additional information about the brain dynamics and propose that the EEG measures of SP may be used in future clinical and research investigations to more precisely delineate the mechanisms underlying inhibitory impairments. PMID- 23800792 TI - Limited relationships between two-year changes in sulcal morphology and other common neuroimaging indices in the elderly. AB - Measuring the geometry or morphology of sulcal folds has recently become an important approach to investigating neuroanatomy. However, relationships between cortical sulci and other brain structures are poorly understood. The present study investigates how age-related changes in sulcal width are associated with age-related changes in traditional indices of brain structure such as cortical thickness, and cortical gray matter (GM), white matter (WM), subcortical, and white matter hyperintensity (WMH) volumes. These indices and sulcal width were measured at baseline and at two-year follow up in 185 community-dwelling individuals (91 men) aged 70-89 years. There were significant increases in sulcal width and WMH volume, and significant decreases in all other indices between baseline and follow-up. Sulcal widening was associated with decreases in cortical GM, subcortical and WM volumes. A further association between sulcal width and cortical thickness became non-significant when cortical GM volume was controlled for. Our findings give insights into the mechanisms responsible for cortical sulcal morphology. The relationships between sulcal morphology and other common measures suggest that it could be a more comprehensive measure for clinical classifications than traditional neuroimaging metrics, such as cortical thickness. PMID- 23800793 TI - Magnetoencephalographic evidence for the modulation of cortical swallowing processing by transcranial direct current stimulation. AB - Swallowing is a complex neuromuscular task that is processed within multiple regions of the human brain. Rehabilitative treatment options for dysphagia due to neurological diseases are limited. Because the potential for adaptive cortical changes in compensation of disturbed swallowing is recognized, neuromodulation techniques like transcranial direct current stimulation (tDCS) are currently considered as a treatment option. Here we evaluate the effect of tDCS on cortical swallowing network activity and behavior. In a double-blind crossover study, anodal tDCS (20 min, 1 mA) or sham stimulation was administered over the left or right swallowing motor cortex in 21 healthy subjects in separate sessions. Cortical activation was measured using magnetoencephalography (MEG) before and after tDCS during cued "simple", "fast" and "challenged" swallow tasks with increasing levels of difficulty. Swallowing response times and accuracy were measured. Significant bilateral enhancement of cortical swallowing network activation was found in the theta frequency range after left tDCS in the fast swallow task (p=0.006) and following right tDCS in the challenged swallow task (p=0.007), but not after sham stimulation. No relevant behavioral effects were observed on swallow response time, but swallow precision improved after left tDCS (p<0.05). Anodal tDCS applied over the swallowing motor cortex of either hemisphere was able to increase bilateral swallow-related cortical network activation in a frequency specific manner. These neuroplastic effects were associated with subtle behavioral gains during complex swallow tasks in healthy individuals suggesting that tDCS deserves further evaluation as a treatment tool for dysphagia. PMID- 23800794 TI - Reduced linewidth multipolar plasmon resonances in metal nanorods and related applications. AB - Using dark-field scattering spectroscopy, we study the multipolar plasmon resonances in single crystallized silver nanorods. The lineshapes and homogenous linewidths of the surface plasmon resonances (SPRs) of different orders are analyzed and compared. The high-order resonances are found to sustain asymmetric Fano lineshapes and their linewidths are narrower than the dipolar resonance. A quantitative comparison using the finite element method reveals more than a three times reduction in the linewidth for the third order resonance, as compared with the dipolar one. These narrow linewidths result from the smaller radiative damping of the multipolar SPRs. Benefiting from the reduced damping, multipolar SPRs in nanorods are better candidates for many plasmonic applications, including increased-sensitivity single particle SPR sensors and reduced-threshold nanolasers. PMID- 23800795 TI - Cerebral ischemia-reperfusion-induced autophagy protects against neuronal injury by mitochondrial clearance. AB - Cerebral ischemia-reperfusion (I-R) is a complex pathological process. Although autophagy can be evoked by ischemia, its involvement in the reperfusion phase after ischemia and its contribution to the fate of neurons remains largely unknown. In the present investigation, we found that autophagy was activated in the reperfusion phase, as revealed in both mice with middle cerebral artery occlusion and oxygen-glucose deprived cortical neurons in culture. Interestingly, in contrast to that in permanent ischemia, inhibition of autophagy (by 3 methyladenine, bafilomycin A 1, Atg7 knockdown or in atg5(-/-) MEF cells) in the reperfusion phase reinforced, rather than reduced, the brain and cell injury induced by I-R. Inhibition of autophagy either with 3-methyladenine or Atg7 knockdown enhanced the I-R-induced release of cytochrome c and the downstream activation of apoptosis. Moreover, MitoTracker Red-labeled neuronal mitochondria increasingly overlapped with GFP-LC3-labeled autophagosomes during reperfusion, suggesting the presence of mitophagy. The mitochondrial clearance in I-R was reversed by 3-methyladenine and Atg7 silencing, further suggesting that mitophagy underlies the neuroprotection by autophagy. In support, administration of the mitophagy inhibitor mdivi-1 in the reperfusion phase aggravated the ischemia induced neuronal injury both in vivo and in vitro. PARK2 translocated to mitochondria during reperfusion and Park2 knockdown aggravated ischemia-induced neuronal cell death. In conclusion, the results indicated that autophagy plays different roles in cerebral ischemia and subsequent reperfusion. The protective role of autophagy during reperfusion may be attributable to mitophagy-related mitochondrial clearance and inhibition of downstream apoptosis. PARK2 may be involved in the mitophagy process. PMID- 23800796 TI - Clinical and laboratory studies of 17 patients with acute myeloid leukemia harboring t(7;11)(p15;p15) translocation. AB - The cellular and molecular genetic aberrations of hematopoietic and lymphoid tissues are increasingly important in leukemia classification and are prognostically significant. Although some recurrent molecular cytogenetic abnormalities in AML have been extensively studied, others including t(7;11)(p15;p15) have not been well characterized. In this paper, seventeen AML patients with t(7;11)(p15;p15) were retrospectively reviewed for cell morphology, immuno-phenotype, cytogenetics as well as clinical features and prognosis. Among them, thirteen were female; nine were AML-M2. Six patients who were newly diagnosed were alive, one was lost for followed up and ten died. The median survival was 8 months. Taking together, AML with t(7;11)(p15;p15) is a rare and distinct disease. Most patients with this translocation are female at younger age and have special clinical and hematological characteristics such as M2-subtype of AML, easy to relapse and poor prognosis. PMID- 23800797 TI - The role of intracellular pathways in the proliferation of human K562 cells mediated by muscarinic receptors. AB - Muscarinic acetylcholine receptors (mAChRs) are members of the superfamily of G protein coupled receptors (GPCRs). Muscarinic receptors are relatively abundant in the central nervous system and in the peripheral parasympathetic nervous system. Several studies have suggested that muscarinic receptors also mediate some cellular events in hematopoietic cells. K562 erythroleukemia cells contain muscarinic receptors M2, M3 and M4, and activation of muscarinic receptors changes cell proliferation. We examined the effects of several compounds on cell proliferation in K562 erythroleukemia cells. These included a muscarinic receptor agonist carbachol (CCh), a protein kinase inhibitor staurosporine; the phospholipase C inhibitor U73122, the MEK 1-2 inhibitor UO126, the PI3-kinase inhibitor wortmannin, the Ca(2+) chelators BAPTA/AM and 2-aminoethoxy diphenylborate (2APB). In addition, we also investigated muscarinic receptor mediated protein kinase C (PKC) expression in K562 cells. CCh caused a decrease in DNA synthesis in K562 cells supplemented with 1% fetal bovine serum after starvation. Pre-treatment of K562 cells with U73122 and BAPTA/AM antagonized the inhibitory effect of CCh, suggesting that phospholipase C and intracellular calcium are involved in CCh-mediated inhibition of proliferation in K562 cells. Our data also suggest that the regulatory roles of protein kinase C and the MAPK/ERK pathways in K562 cell proliferation are independent of cholinergic activation. PMID- 23800800 TI - Seroprotection for hepatitis B in children with nephrotic syndrome. AB - BACKGROUND: Children with nephrotic syndrome have been shown to have lower seroconversion to various vaccines due to immune dysregulation, prolonged immunosuppressive treatment and recurrent prolonged proteinuria.The primary aim of this study was to determine hepatitis B surface antibody (anti-HBs) titers in children with nephrotic syndrome who had been previously vaccinated against hepatitis B. The secondary aim was to study the association of anti-HBs titers with type of disease, schedule and dose of vaccination, and type of immunosuppressive therapy. METHODS: This cross-sectional study was conducted in the Department of Pediatrics in a tertiary care hospital between January 2011 and January 2012). All children (aged 1-18 years) with nephrotic syndrome who tested negative for hepatitis B surface antigen and who had previously been vaccinated against hepatitis B, with the last dose being at least 1 month prior to being included in the study. A form consisting of history and clinical details was filled in, and the schedule and dose of vaccination(s) received was noted. A blood sample was taken from all patients for biochemical assessment and determination of anti-HBs titer. RESULTS: The patient cohort comprised 75 children (51 males; 24 females) of whom 42 (56%) had steroid-resistant nephrotic syndrome (SRNS) and 33 (44%) had steroid-sensitive nephrotic syndrome (SSNS). Most patients enrolled in the study (96%) were in remission at the time of the biochemical and serological assessment. Twenty-one (28%) patients had received only steroids, while 72 % also received other immunosuppressants. Forty-six (61.3%) patients had received a double dose of vaccine. Of the 75 children enrolled, 36 (48%) and 39 (52%) had an anti-HBs titer of >=10 mIU/mL (seroprotected) and <10 mIU/mL (unprotected), respectively. The mean titer among all patients was 143.58 mIU/mL. The seroprotection rates were 63.6% in SSNS patients and 35.7% in SRNS subjects (P = 0.016). CONCLUSIONS: Based on our results, we conclude that children with SRNS are less likely to seroconvert with vaccination. A higher dose (double) of hepatitis B vaccine should be used for vaccinating such patients. Anti-HBs titers should be monitored in SRNS patients post-vaccination, and a booster should be given if titers fall to <10 mIU/mL. PMID- 23800801 TI - Hemolytic uremic syndrome complicating Mycoplasma pneumoniae infection. AB - BACKGROUND: Mycoplasma pneumoniae can cause various extrapulmonary manifestations but, to our knowledge, no case of Mycoplasma pneumoniae associated with hemolytic uremic syndrome (HUS) has been reported. CASE-DIAGNOSIS/TREATMENT: We describe a 1-year-old boy with M. pneumoniae respiratory tract infection and associated microangiopathic hemolytic anemia, slightly decreased platelet count and mild renal impairment, suggesting a diagnosis of HUS. Assuming M. pneumoniae infection was the cause of HUS in this case, the different possible mechanisms, including an atypical HUS due to preexisting complement dysregulation, an alternative complement pathway activation induced by M. pneumoniae infection at the acute phase, an autoimmune disorder, and a direct role of the bacteria in inducing endothelial injury, are discussed. The signs of HUS resolved with treatment of the M. pneumoniae infection. CONCLUSIONS: Hemolytic uremic syndrome may be an unusual complication of M. pneumoniae infection. PMID- 23800802 TI - NPHS2 homozygous p.R229Q variant: potential modifier instead of causal effect in focal segmental glomerulosclerosis. AB - BACKGROUND: The pathogenicity of the NPHS2 homozygous p.R229Q variant in steroid resistant nephrotic syndrome (SRNS) is doubtful. While it has been reported in unaffected controls, it is enriched in patients with SRNS, suggesting pathogenicity. CASE-DIAGNOSIS/TREATMENT: A family with three members homozygous for the NPHS2 p.R229Q variant is presented: a 37-year-old patient who was diagnosed with proteinuria at age 7 months, focal segmental glomerulosclerosis (FSGS) at age 20 years, and end-stage renal disease (ESRD) at age 33 years, his 59 year-old father and his 40 year-old brother, both unaffected with no proteinuria. The affected son also harbors a heterozygous de novo, truncating PAX2 mutation (c.76dupG, p.V26Gfs*28), which can explain his chronic renal failure but which is rarely associated with FSGS. CONCLUSIONS: This family provides further evidence that homozygous p.R229Q in itself may not cause FSGS. Nevertheless, the rare association of FSGS to a PAX2 mutation may reflect the modifier effect of p.R229Q in the homozygous state. Such a modifier effect can also explain its enrichment in SRNS patients. Patients with homozygous p.R229Q should be screened for the causative mutation in a second gene. PMID- 23800803 TI - Characterization of the impact to PET quantification and image quality of an anterior array surface coil for PET/MR imaging. AB - OBJECT: The aim of this study was to determine the impact to PET quantification, image quality and possible diagnostic impact of an anterior surface array used in a combined PET/MR imaging system. MATERIALS AND METHODS: An extended oval phantom and 15 whole-body FDG PET/CT subjects were re-imaged for one bed position following placement of an anterior array coil at a clinically realistic position. The CT scan, used for PET attenuation correction, did not include the coil. Comparison, including liver SUV(mean), was performed between the coil present and absent images using two methods of PET reconstruction. Due to the time delay between PET scans, a model was used to account for average physiologic time change of SUV. RESULTS: On phantom data, neglecting the coil caused a mean bias of -8.2% for non-TOF/PSF reconstruction, and -7.3% with TOF/PSF. On clinical data, the liver SUV neglecting the coil presence fell by -6.1% (+/- 6.5%) for non TOF/PSF reconstruction; respectively -5.2% (+/- 5.3%) with TOF/PSF. All FDG-avid features seen with TOF/PSF were also seen with non-TOF/PSF reconstruction. CONCLUSION: Neglecting coil attenuation for this anterior array coil results in a small but significant reduction in liver SUV(mean) but was not found to change the clinical interpretation of the PET images. PMID- 23800804 TI - Hydrophilic interaction ultra-high performance liquid chromatography coupled with triple quadrupole mass spectrometry for determination of nucleotides, nucleosides and nucleobases in Ziziphus plants. AB - In this study, a rapid and sensitive analytical method was developed for the determination of 20 nucleobases, nucleosides and nucleotides in Ziziphus plants at trace levels by using hydrophilic interaction ultra-high performance liquid chromatography coupled with triple-quadrupole tandem mass spectrometry (HILIC UHPLC-TQ-MS/MS) in multiple-reaction monitoring (MRM) mode. Under the optimized chromatographic conditions, good separation for 20 target compounds were obtained on a UHPLC Amide column with sub-2MUm particles within 10min. The overall LODs and LOQs were between 0.11-3.12ngmL(-1) and 0.29-12.48ngmL(-1) for the 20 analytes, respectively. It is the first report about simultaneous analysis of nucleobases, nucleosides and nucleotides in medicinal plants using HILIC-UHPLC-TQ MS/MS method, which affords good linearity, precision, repeatability and accuracy. The developed method was successfully applied to Ziziphus plant (Z. jujuba, Z. jujuba var. spinosa and Z. mauritiana) samples. The analysis showed that the fruits and leaves of Ziziphus plants are rich in nucleosides and nucleobases as well as nucleotides, and could be selected as the healthy food resources. Our results in present study suggest that HILIC-UHPLC-TQ-MS/MS method could be employed as a useful tool for quality assessment of the samples from the Ziziphus plants as well as other medicinal plants or food samples using nucleotides, nucleosides and nucleobases as markers. PMID- 23800805 TI - Research forums: enhancing access to emerging research. PMID- 23800806 TI - Hearing conservation program for marching band members: a risk for noise-induced hearing loss? AB - PURPOSE: To examine the risk for noise-induced hearing loss (NIHL) in university marching band members and to provide an overview of a hearing conservation program for a marching band. METHOD: Sound levels during band rehearsals were recorded and audiometric hearing thresholds and transient otoacoustic emission were measured over a 3-year period. Musician's earplugs and information about hearing loss were provided to the students. The hearing thresholds of other college students were tested as a partial control. RESULTS: There were no significant differences in hearing thresholds between the two groups. During initial testing, more marching band members showed apparent high-frequency notches than control students. Follow-up hearing tests in a subsequent year for the marching band members showed that almost all notches disappeared. Persistent standard threshold shift (STS) across tests was not observed in the band members. CONCLUSION: Band members showed no evidence of STS or persistent notched audiograms. Because accepted procedures for measuring hearing showed a lack of precision in reliably detecting early NIHL in marching band members, it is recommended that signs of NIHL be sought in repeated measurements compared to baseline audiograms rather than in a single measure (a single notch). A hearing conservation program for this population is still recommended because of lengthy rehearsal times with high sound-level exposure during rehearsals. PMID- 23800807 TI - Autoimmune inner ear disease preliminary case report: audiometric findings following steroid treatments. AB - PURPOSE: This study examined the audiometric findings following steroid treatment for autoimmune inner ear disease (AIED), which is characterized by bilateral subacute hearing loss, using oral and intratympanic treatment. METHOD: The charts of 9 patients with AIED who had been seen in the Saint Louis University School of Medicine's clinic between 2004 and 2011 were reviewed, with special focus on audiometric results. RESULTS: The majority of patients benefited from treatment for AIED. Four patients (6 ears) received intratympanic therapy as part of their treatment. CONCLUSION: Patients with AIED appeared to benefit from a clinical pathway using a prolonged course of oral steroids, followed by a trial of intratympanic steroids and/or immunosuppresants for refractory cases. PMID- 23800808 TI - Effect of tinnitus on distortion product otoacoustic emissions varies with hearing loss. AB - PURPOSE: The aim of this study was to measure the effect of tinnitus, while accounting for the effect of hearing loss and aging, on distortion product otoacoustic emissions (DPOAEs). METHOD: DPOAEs were measured twice in both ears in 5 groups of participants: young adults with normal hearing, middle-age adults with normal hearing, adults with high-frequency sensorineural hearing loss, age matched adults with similar hearing loss and tinnitus, and adults with normal hearing and chronic tinnitus. RESULTS: Multivariate analysis revealed a main effect of hearing loss and age, but no effect of tinnitus, across all 5 groups. Separate tests revealed significant effects of age and tinnitus in the normal hearing groups and hearing loss in adults with or without tinnitus, but no effect of tinnitus in those with hearing loss. CONCLUSION: DPOAE levels in the group of adults with hearing loss and tinnitus were diminished, but those in the group with normal hearing and tinnitus were enhanced, relative to DPOAE levels in the controls. Outer hair cell function, as indexed by DPOAEs, exhibits a complex association with tinnitus, and this has implications in the use of DPOAEs as a tool both for testing for tinnitus presence and for creating a model of neural mechanisms underlying tinnitus. PMID- 23800809 TI - Masking release and modulation interference in cochlear implant and simulation listeners. AB - PURPOSE: To examine the effects of temporal and spectral interference of masking noise on sentence recognition for listeners with cochlear implants (CI) and normal-hearing persons listening to vocoded signals that simulate signals processed through a CI (NH-Sim). METHOD: NH-Sim and CI listeners participated in the experiments using speech and noise that were processed by bandpass filters. Depending on the experimental condition, the spectra of the maskers relative to that of speech were set to be completely embedded with, partially overlapping, or completely separate from, the speech. The maskers were either steady or amplitude modulated and were presented at +10 dB signal-to-noise ratio. RESULTS: NH-Sim listeners experienced progressively more masking as the masker became more spectrally overlapping with speech, whereas CI listeners experienced masking even when the masker was spectrally remote from the speech signal. Both the NH-Sim and CI listeners experienced significant modulation interference when noise was modulated at a syllabic rate (4 Hz), suggesting that listeners may experience both modulation interference and masking release. Thus, modulated noise has mixed and counteracting effects on speech perception. CONCLUSION: When the NH-Sim and CI listeners with poor spectral resolution were tested using syllabic-like rates of modulated noise, they tended to integrate or confuse the noise with the speech, causing an increase in speech errors. Optional training programs might be useful for CI listeners who show more difficulty understanding speech in noise. PMID- 23800810 TI - Performance-intensity functions of Mandarin word recognition tests in noise: test dialect and listener language effects. AB - PURPOSE: This study established the performance-intensity function for Beijing and Taiwan Mandarin bisyllabic word recognition tests in noise in native speakers of Wu Chinese. Effects of the test dialect and listeners' first language on psychometric variables (i.e., slope and 50%-correct threshold) were analyzed. METHOD: Thirty-two normal-hearing Wu-speaking adults who used Mandarin since early childhood were compared to 16 native Mandarin-speaking adults. Both Beijing and Taiwan bisyllabic word recognition tests were presented at 8 signal-to-noise ratios (SNRs) in 4-dB steps (-12 dB to +16 dB). At each SNR, a half list (25 words) was presented in speech-spectrum noise to listeners' right ear. The order of the test, SNR, and half list was randomized across listeners. Listeners responded orally and in writing. RESULTS: Overall, the Wu-speaking listeners performed comparably to the Mandarin-speaking listeners on both tests. Compared to the Taiwan test, the Beijing test yielded a significantly lower threshold for both the Mandarin- and Wu-speaking listeners, as well as a significantly steeper slope for the Wu-speaking listeners. CONCLUSION: Both Mandarin tests can be used to evaluate Wu-speaking listeners. Of the 2, the Taiwan Mandarin test results in more comparable functions across listener groups. Differences in the performance intensity function between listener groups and between tests indicate a first language and dialectal effect, respectively. PMID- 23800812 TI - Introduction to the AJA research forum on hearing screening in adults and older adults. AB - PURPOSE: To illustrate the overall project that led to the development of a series of research forums highlighting several key contributions to AHS 2012, the 2nd International Conference on Adult Hearing Screening, in Cernobbio (Lake Como), Italy, and, in particular, to provide an overview of the first research forum, "Hearing Screening in Adults and Older Adults," which contains a set of brief papers that tackle prominent issues related to adult hearing screening: guiding principles for adult screening, development of methods and technologies, program implementation and evaluation, possible future scenarios, and health policy issues. PMID- 23800811 TI - Masking release due to linguistic and phonetic dissimilarity between the target and masker speech. AB - PURPOSE: To investigate masking release for speech maskers for linguistically and phonetically close (English and Dutch) and distant (English and Mandarin) language pairs. METHOD: Thirty-two monolingual speakers of English with normal audiometric thresholds participated in the study. Data are reported for an English sentence recognition task in English and for Dutch and Mandarin competing speech maskers (Experiment 1) and noise maskers (Experiment 2) that were matched either to the long-term average speech spectra or to the temporal modulations of the speech maskers from Experiment 1. RESULTS: Listener performance increased as the target-to-masker linguistic distance increased (English-in-English < English in-Dutch < English-in-Mandarin). CONCLUSION: Spectral differences between maskers can account for some, but not all, of the variation in performance between maskers; however, temporal differences did not seem to play a significant role. PMID- 23800813 TI - Using the speech understanding in noise (SUN) test for adult hearing screening1. AB - PURPOSE: To develop a novel speech-in-noise test for adult hearing screening-the Speech Understanding in Noise (SUN) test. The goal was to design a fast, automated, easy-to-use test to identify difficulties in speech communication. METHOD: The SUN test consists of a short list of intervocalic consonants in noise presented in a forced-choice paradigm by means of a touch screen. The SUN test was developed and evaluated in an overall population of >6,000 participants. The test is available in various languages (i.e., English, French, German, and Italian) and continues to be developed in others (e.g., Spanish, Portuguese, and Mandarin). RESULTS: Test time was <1 min/ear. Test-retest reliability was very good. The test showed good agreement with conventional clinical measures (e.g., pure-tone testing, speech-in-noise testing, and self-reported hearing handicap). The test's sensitivity and specificity to identify disabling hearing impairment were 84% and 75%, respectively. The same results were obtained in low and high ambient noise. CONCLUSION: The SUN test is fast, repeatable, easy to use, self explanatory, specific to the impairment, and robust to ambient noise. It may be a viable approach for adult hearing screening in clinical as well as nonclinical settings. PMID- 23800814 TI - Speech-in-noise tests for multilingual hearing screening and diagnostics1. AB - PURPOSE: New complementary multilingual speech-in-noise tests in Russian, Turkish, and Spanish for hearing self-screening purposes and follow-up hearing diagnostics are compared to the speech tests of the European project, HearCom (Hearing in the Communication Society). METHOD: The tests consist of spoken numbers (Digit Triplet Test; Smits, Kapteyn, & Houtgast, 2004) or sentences (Matrix Test; e.g., Hagerman, 1982) presented in a background noise and estimate the speech reception threshold, which is the signal-to-noise ratio that yields 50% speech intelligibility. All tests were developed according to the HearCom minimum quality standards for speech intelligibility tests. This report presents a cross-language comparison of reference speech intelligibility functions for monaural headphone measurements with normal-hearing listeners. The same model function was employed to describe the speech intelligibility functions for all of the tests. RESULTS: Reference speech intelligibility functions of the new versions of the Digit Triplet Test and Matrix Test show high comparability to the HearCom tests. In order to achieve the highest possible comparability across languages, language- and speaker-dependent factors in speech intelligibility should be compensated for. CONCLUSION: To date, several complementary tests for screening and diagnostics have been developed in several languages. Adhering to the HearCom standards, the tests are highly comparable across languages. For the Matrix Test, equal syntax and linguistic complexity were maintained across languages due to common methodological standards. PMID- 23800815 TI - Tool kit for screening otologic function of older adults1. AB - PURPOSE: To propose a hearing health care tool kit, for use in primary care, that includes a new, comprehensive, and easy-to-administer self-report tool, namely, the Screening for Otologic Functional Impairments (SOFI). The target population for the proposed tool kit includes older adults with multimorbidity who are (a) at risk for hearing-related functional deficits and/or (b) likely to benefit from targeted audiologic interventions designed to optimize function, support independence, maximize safety, and cultivate self-sufficiency and social connectedness (American Academy of Nursing's Expert Panel on Acute and Critical Care, 2012). METHOD: Twenty-nine older adults with varying levels of hearing impairment drawn from 2 ear, nose, and throat clinics and 1 university clinic underwent hearing testing and completed a series of self-report tools designed to assess otologic function and depression. All of the participants completed the SOFI on 2 occasions. RESULTS: The SOFI has high reliability and validity and the potential for identifying older adults requiring audiologic intervention. CONCLUSION: The proposed tool kit, for use in primary care, includes several components that are integral to help-seeking behavior. The goal is to identify older adults with multimorbidity who are at risk for otologic conditions, that, once identified and treated, may help promote older adults' quality of care and life. PMID- 23800816 TI - Adult hearing screening: follow-up and outcomes1. AB - PURPOSE: To screen hearing and evaluate outcomes in community-dwelling older adults. METHOD: Three thousand and twenty-five adults responded to an invitation to be screened by questionnaire, otoscopy, and pure-tone audiometry. Pure-tone average (PTA) >35 dB HL in the worse ear, unilateral hearing loss, or otoscopic findings were the criteria for referral for services. A questionnaire related to compliance with referral recommendations was completed by telephone interview for 160 randomly selected participants after 1-2 years from referral. RESULTS: The referral rate for audiologic/hearing aid evaluation was 46%, and referral for cerumen removal/medical evaluation was 17%. Of the people referred for audiologic/hearing aid evaluation, 18% tried a hearing aid; 2 years later, 11% were using a hearing aid. Screening recommendations affected participants' decision to seek help. Study participants stated that the screening was helpful, it should be offered to everybody, and they would participate in future screenings. CONCLUSION: Although adult hearing screening offered timely identification of hearing loss for adults seeking help, follow-up with hearing aid treatment was low. PMID- 23800817 TI - The effects and costs of a hearing screening and rehabilitation program in residential care homes for the elderly in the Netherlands1. AB - PURPOSE: This study describes the effects and costs of hearing screening and rehabilitation in residential care homes for the elderly. It was hypothesized that offering an in-house hearing screening and rehabilitation program would be an effective strategy to increase hearing aid ownership among the residents. METHOD: All 705 residents of 8 residential care homes in the Netherlands were invited to participate in a hearing screening (pure-tone audiometry) and rehabilitation (hearing aids) program. Resident participation was analyzed, and the costs were calculated. RESULTS: A total of 243 residents (34%) participated in the screening, 222 (91%) of whom had hearing loss. Ninety-one (41%) of the screening participants with hearing loss started rehabilitation, which was successful for 50 (55%) of them. Hearing aid ownership among the residents with hearing loss increased from 28% at the start of the program to 33% at the end. The costs were ?1,896 (US $2,480) per successfully rehabilitated resident. Hearing aid trials and hearing aids together accounted for 83% of the total costs. CONCLUSION: The effectiveness of the program was limited, as hearing aid ownership increased only slightly. Cost reduction measures should focus on decreasing the number of unsuccessful hearing aid trials. PMID- 23800818 TI - Effects of tubing length and coupling method on hearing threshold and real-ear to coupler difference measures. AB - PURPOSE: This tutorial demonstrates the effects of tubing length and coupling type (i.e., foam tip or personal earmold) on hearing threshold and real-ear-to coupler difference (RECD) measures. METHOD: Hearing thresholds from 0.25 kHz through 8 kHz are reported at various tubing lengths for 28 normal-hearing adults between the ages of 22 and 31 years. RECD values are reported for 14 of the adults. All measures were made with an insert earphone coupled to a standard foam tip and with an insert earphone coupled to each participant's personal earmold. RESULTS: Threshold and RECD measures obtained with a personal earmold were significantly different from those obtained with a foam tip on repeated measures analyses of variance. One-sample t tests showed these differences to vary systematically with increasing tubing length, with the largest average differences (7-8 dB) occurring at 4 kHz. CONCLUSIONS: This systematic examination demonstrates the equal and opposite effects of tubing length on threshold and acoustic measures. Specifically, as tubing length increased, sound pressure level in the ear canal decreased, affecting both hearing thresholds and the real-ear portion of the RECDs. This demonstration shows that when the same coupling method is used to obtain the hearing thresholds and RECD, equal and accurate estimates of real-ear sound pressure level are obtained. PMID- 23800819 TI - The crystal structure of multidrug-resistance regulator RamR with multiple drugs. AB - RamR is a transcriptional repressor of the gene-encoding RamA protein, which controls the expression of the multidrug efflux system genes acrAB-tolC. RamR is an important multidrug-resistance factor, however, its structure and the identity of the molecules to which it responds have been unknown. Here, we report the crystal structure of RamR in complex with multiple drugs, including berberine, crystal violet, dequalinium, ethidium bromide and rhodamine 6G. All compounds are found to interact with Phe155 of RamR, and each compound is surrounded by different amino acid residues. Binding of these compounds to RamR reduces its DNA binding affinity, which results in the increased expression of ramA. Our results reveal significant flexibility in the substrate-recognition region of RamR, which regulates the bacterial efflux participating in multidrug resistance. PMID- 23800820 TI - Differential phenotypic behaviors of human degenerative nucleus pulposus cells under normoxic and hypoxic conditions: influence of oxygen concentration during isolation, expansion, and cultivation. AB - BACKGROUND CONTEXT: Intervertebral discs (IVDs) are the largest avascular structures in the body; therefore, cells within these discs might be adapted to low-oxygen conditions. Although it has been demonstrated that a low oxygen concentration could promote synthesis of the extracellular matrix by IVD cells in the in vitro culture, isolation, expansion, and cultivation of IVD cells under classical tissue culture O2 saturation could still be detrimental. PURPOSE: To investigate the phenotypic differences between human degenerative nucleus pulposus (NP) cells during isolation and expansion under normoxic (Nx: 21% O2) or hypoxic (Hx: 3.5% O2) conditions. STUDY DESIGN: We investigated in vitro isolation, expansion, and cultivation of human NP cells. METHODS: Human NP tissue samples were obtained from patients who underwent lumbar disc surgeries. Nucleus pulposus cells were then isolated, expanded, and cultivated under normoxic or hypoxic conditions. To determine whether the effects of normoxic expansion are reversible, another group of cells was isolated and expanded in normoxic conditions and then cultivated under hypoxic conditions (Nx->Hx group). Cellular proliferation, RNA expression of selected genes, and immunohistochemical staining were performed to evaluate the phenotypic behaviors of human NP cells under different conditions. RESULTS: Expressions of Type II collagen and aggrecan in the Nx->Hx group were significantly higher than those in the normoxic group but were significantly lower than those in the hypoxic group. The normoxic group showed higher expression of matrix metalloproteinase (MMP)-2 and MMP-13 than did the other groups. Expression levels of hypoxia-inducible factors (HIFs) were significantly higher in the normoxic groups; however, a greater degree of HIF 1alpha staining was found in the hypoxic group, whereas a greater degree of HIF 2alpha staining was found in the normoxic group. CONCLUSIONS: Human degenerative NP cells isolated, expanded, and cultivated in hypoxic conditions could better preserve the cells' regenerative potential. Compromised properties that were observed during isolation and expansion under normoxic conditions could only be partially rescued by later hypoxic cultivation. The superior phenotypic behaviors of human NP cells under hypoxia may be related to higher HIF-1alpha production and lower HIF-2alpha production. Cells that are isolated, expanded, and cultivated under hypoxic conditions may show better regenerative results when transplanted; therefore, the isolation and expansion processes of human degenerative NP cells should be managed in a hypoxic environment. PMID- 23800821 TI - Effects of misalignment on static torsional strength of anterior cervical plate systems. AB - BACKGROUND CONTEXT: There is little understanding of cervical plate misalignment as a risk factor for plate failure at the plate-screw-bone interface. PURPOSE: To assess the torsional strength and mode of failure of cervical plates misaligned relative to the midsagittal vertical axis. STUDY DESIGN: Plastic and foam model spine segments were tested using static compression and torsion to assess effects of misaligned and various lengths anterior cervical plate (ACPs). METHODS: Different length ACPs and cancellous fixed angle screws underwent axial torsional testing on a servo-hydraulic test frame at a rate of 0.5 degrees /s. A construct consisted of one ACP, four screws, one ultrahigh-molecular weight polyethylene inferior block, and one polyurethane foam superior block. Group 1 had ACPs aligned in the midsagittal vertical axis, group 2 plates were positioned 20 degrees offset from the midline, and group 3 had the ACP shifted 5 mm away and 20 degrees offset from midline. Torques versus angle data were recorded. The failure criterion was the first sign of pullout determined visually and graphically. RESULTS: Group 1 had a more direct screw pullout during failure. For the misaligned plates, failure was a combination of the screws elongating the holes and shear forces acting between the plate and block. The misaligned plates needed more torque to failure. The failure torque was 50% reduced for the longer versus the shorter plates in the neutral position. Graphically shown initial screw slippage inside the block preceded visual identification of slippage in some cases. CONCLUSIONS: We observed different failure mechanisms for neutral versus misaligned plates. Clinically, misalignment may have the benefit of needing more torque to fail. Misalignment was a risk factor for failure of the screw-bone interface, especially in longer plate constructs. These comparisons of angulations may be a solid platform for expansion toward a more applicable in vivo model. PMID- 23800822 TI - Acute epidural lipedema: a novel entity and potential complication of bone morphogenetic protein use in lumbar spine fusion. AB - BACKGROUND CONTEXT: Bone morphogenetic proteins (BMPs) induce osteogenesis, making them useful for decreasing time to union and increasing union rates. Although the advantages of BMP-2 as a substitute for iliac crest graft have been elucidated, less is known about the safety profile and adverse events linked to their use in spinal fusion. An accumulation of reactive edema in the epidural fat may lead to neural compression and significant morbidity after lumbar spinal fusion. Bone morphogenetic protein has never been implicated as a cause of spinal epidural lipedema. PURPOSE: We report on a case of rapid accumulation of edematous adipose tissue in the epidural space after lumbar spine decompression and fusion with bone morphogenic protein. STUDY DESIGN: Case report. METHODS: The patient was a 45-year-old woman with chronic back pain, worsening bilateral L5 radiculopathy, and degenerative disc disease. Surgery consisting of a one-level transpedicular decompression, transforaminal lumbar interbody fusion, and posterolateral fusion was performed using BMP-2 as an adjunct for arthrodesis. RESULTS: Two days postoperatively, the patient developed progressive cauda equina syndrome. Lumbar magnetic resonance imaging revealed edematous epidural fat extending above the initial laminectomy, compromising the spinal canal, and compressing the thecal sac. Emergent laminectomies at L3, L4, and L5 were performed, and intraoperative pathology revealed edematous epidural adipose tissue. The patient's cauda equina syndrome resolved after spinal decompression and the removal of epidural fat. Final cultures were negative for infection, and histology report yielded an accumulation of edematous fibroadipose tissue. CONCLUSIONS: We present a case of rapid accumulation of edematous adipose tissue causing cauda equina syndrome after a lumbar decompression and fusion surgery. The acute nature and extensive development of the lipedema presented in this case indicate an intense inflammatory reaction. We hypothesize that there may be a link between the use of BMP-2 and the accumulation of this edematous tissue. A thorough understanding of the mechanisms of BMP-2 and specific guidelines for their role in spinal surgery may improve functional outcomes and reduce the number of preventable complications. To the best of our knowledge and after a thorough literature search, this is the only reported case of epidural lipedema causing cauda equina syndrome. PMID- 23800823 TI - Effectiveness of cross-linking posterior segmental instrumentation in adolescent idiopathic scoliosis: a 2-year follow-up comparative study. AB - BACKGROUND CONTEXT: Surgeons continue to debate the need for a cross-link (CL) in posterior spinal instrumentation constructs with segmental pedicle screws in adolescent idiopathic scoliosis (AIS). Advantage of CLs is increased stiffness of the construct, and disadvantages include added expense and risk of late operative site pain and pseudarthrosis. PURPOSE: To compare the effectiveness of using CLs versus using no cross-links (NCLs) in posterior segmental instrumentation in AIS. STUDY DESIGN: Retrospective comparative study, level of evidence 3. PATIENT SAMPLE: Seventy-five AIS patients less than 21 years of age, who underwent posterior spinal instrumentation with segmental pedicle screws (25 with CLs and 50 with NCLs) at a single institution with 2-year follow-up, are described. OUTCOME MEASURES: Physiologic measures include imaging: thoracic and lumbar Cobb angles, correction rate, apical vertebral translation (AVT), and apical vertebral rotation (AVR); self-report measures include Scoliosis Research Society (SRS) domain outcome scores. METHODS: Preoperative (pre-op) and postoperative first erect, 1-year, and 2-year follow-up radiographs were measured. Instrumentation related complications and normalized SRS scores were recorded. Independent sample t test, chi(2) test, and repeated-measures analysis of variance were used for analyses. RESULTS: The average age at surgery was 14 years, the mean pre-op Cobb angle was 57 degrees , and the mean number of levels fused was 10.9. The groups were similar preoperatively with respect to age, sex, Lenke curve, Cobb angle, AVT, and Risser grade and were similar intraoperatively for levels fused and anchor density. There was no difference in AVR, Cobb angle, correction rate, or AVT between the groups (p>.05). Complications included one wound infection in the CL group and one painful scar in the NCL group. There were no differences in SRS domain scores. CONCLUSION: We observed no differences in maintenance of correction, SRS scores, and complications with or without cross-linking posterior segmental instrumentation in AIS patients over 2-year follow-up. Further follow up is necessary. PMID- 23800824 TI - Catalytic oxidative cleavage of catechol by a non-heme iron(III) complex as a green route to dimethyl adipate. AB - The catalyst system prepared in situ from iron(III) salts, tris(2 pyridylmethyl)amine and a base readily catalyses the intradiol dioxygenation of pyrocatechol in methanol, to primarily afford the half-methyl ester of muconic acid. Dimethyl adipate is obtained by the subsequent, one-step catalytic hydrogenation/esterification, thus providing a green route to this important nylon precursor. PMID- 23800825 TI - Cross-sectional area and mean echogenicity of shoulder and elbow tendons in adult German Shepherd dogs. AB - The aim of this study was to describe the cross-sectional area and mean echogenicity of the main tendons of the shoulder and elbow joints in adult German Shepherd dogs and to determine the effects of sex, weight, and age on these parameters. No previous publications in the veterinary literature have reported information regarding quantitative ultrasonographic tendon measurements in dogs. Thirty German Shepherd dogs were examined: 13 males and 17 females. The cross sectional area was significantly higher in males than in females (p <0.05) for the distal tendon of the triceps brachii muscle and the tendons of the flexor carpi ulnaris and common digital extensor muscles. The influence of sex on mean echogenicity was not significant. According to age, mean echogenicity was higher in older dogs, while the cross-sectional areas were similar in the two groups. Cross-sectional area and mean echogenicity of the tendons showed a direct increase with an increase in body weight. The data gained from this study can help support the clinician to discriminate between normal and pathological conditions. PMID- 23800826 TI - Occipital nerve entrapment within the semispinalis capitis muscle diagnosed with ultrasound. PMID- 23800827 TI - SUNCT/SUNA and neurovascular compression: new cases and critical literature review. AB - BACKGROUND: Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache with cranial autonomic symptoms (SUNA) are primary headache syndromes. A growing body of literature has focused on brain magnetic resonance imaging (MRI) evidence of neurovascular compression in these syndromes. OBJECTIVE: The objective of this article is to assess whether SUNCT is a subset of SUNA or whether the two are separate syndromes and clarify the role of neurovascular compression. METHOD: We describe three new SUNCT cases with MRI findings of neurovascular compression and critically review published SUNCT/SUNA cases. RESULTS: We identified 222 published SUNCT/SUNA cases. Our three patients with neurovascular compression added to the 34 cases previously described (16.9%). SUNCT and SUNA share the same clinical features and therapeutic options. At present, there is no available abortive treatment for attacks. Lamotrigine was effective in 64% of patients; topiramate and gabapentin in about one-third of cases. Of the 34 cases with neurovascular compression, seven responded to drug therapies, 16 patients underwent microvascular decompression of the trigeminal nerve (MVD) with effectiveness in 75%. CONCLUSIONS: We suggest that SUNCT and SUNA should be considered clinical phenotypes of the same syndrome. Brain MRI should always be performed with a dedicated view to exclude neurovascular compression. The high percentage of remission after MVD supports the pathogenetic role of neurovascular compression. PMID- 23800828 TI - Primary red ear syndrome associated with cochleo-vestibular symptomatology: a paediatric case report. AB - BACKGROUND: Red ear syndrome (RES), first described by Lance in 1996 in an adult series, may be primary or associated with headache syndromes, upper cervical disorders or vascular anomalies. Clinically the disease is characterised by recurrent episodes of reddening and burning pain in the auricle, usually elicited by different triggers. The prevalence of RES in the paediatric age group remains poorly understood. Several therapeutic approaches have been tried with heterogeneous clinical response. CASE RESULTS: We report a paediatric patient suffering from primary RES associated with debilitating cochleo-vestibular symptomatology causing severe discomfort. Three years after the disease onset, the patient also developed headache, with clinical features of migraine. DISCUSSION: The temporal and spatial association could suggest shared pathogenetic features between neurological (cochleo-vestibular) and vascular (red and burning ear) symptomatology, likely related to trigeminal autonomic reflex activation, although further studies are required for full comprehension of RES pathogenesis. PMID- 23800830 TI - Separation of long RNA by agarose-formaldehyde gel electrophoresis. AB - We describe a method to facilitate electrophoretic separation of high-molecular weight RNA species, such as ribosomal RNAs and their precursors, on agarose formaldehyde gels. Two alternative "pK-matched" buffer systems were substituted for the traditionally used Mops-based conductive medium. The key advantages include shortened run times, a 5-fold reduction in formaldehyde concentration, a significantly improved resolution of long RNAs, and consistency in separation. The new procedure has a streamlined work flow that helps to minimize errors and is broadly applicable to agarose gel electrophoresis of RNA samples and their subsequent analysis by Northern blotting. PMID- 23800829 TI - Validation of a latent construct for dementia case-finding in Mexican-Americans. AB - We have constructed a latent dementia proxy, "delta", and validated it in several datasets, including well characterized subjects participating in the Texas Alzheimer's Research and Care Consortium (TARCC) study. It may be possible to construct delta homologs from almost any ad hoc combination of cognitive and functional status measures. delta homologs may also be relatively immune to measurement error, including cultural, linguistic, or educational biases. These properties make factor scores derived from latent variables a potentially attractive solution for dementia case-finding in rural or minority populations. Here we have explored an alternative and briefer assessment by which to construct a delta homolog and validate the resulting latent variable (dMA) in Mexican American (MA) TARCC subjects. dMA, composed of simple "bedside" dementia screening instruments, achieves Areas Under the Receiver Operative Curve that rival those of delta itself. Ethnicity has a small effect on dMA's performance. These results suggest that it may be possible to validly export dMA into other MA populations, or to export delta homolog factor scores from one population to another. PMID- 23800831 TI - Hypogonadism as a new comorbidity in male patient's selection for bariatric surgery: towards an extended concept of metabolic surgery? AB - Hypogonadism and subfertility can be frequently associated to obesity. These endocrine alterations may have consequences in the health and quality of life of obese men since they may result in impaired fertility and poor sexual life. As many clinical reports suggest, weight loss can ameliorate hypogonadism and, more generally, alterations in sex hormones. This effect is evident even when weight loss is induced by bariatric surgery. The evidence that hypogonadism in morbidly obese patients can regress after bariatric surgery should lead us to consider it as a modifiable comorbidity associated to obesity. This would have as a consequence that obese male patients with symptomatic hypogonadism could be candidates for bariatric surgery even with a BMI < 40 kg/m(2). Controlled clinical trials, involving obese hypogonadal males, should be encouraged. PMID- 23800832 TI - Dipyridamole-related enhancement of gap junction coupling in the GM-7373 aortic endothelial cells correlates with an increase in the amount of connexin 43 mRNA and protein as well as gap junction plaques. AB - Previous data showed that dipyridamole enhanced gap junction coupling in vascular endothelial and smooth muscle cell lines by a cAMP-dependent mechanism. The present study investigates the level at which dipyridamole affects gap junction coupling. In the GM-7373 endothelial cell line, scrape loading/dye transfer experiments revealed a rapid increase in gap junction coupling induced during the first 6 h of dipyridamole treatment, followed by a slow increase induced by further incubation. Immunostaining analyses showed that the rapid enhancement of gap junction coupling correlated with an increased amount of Cx43 gap junction plaques and a reduced amount of Cx43 containing vesicles, while the amount of Cx43 mRNA or protein was not changed during this period, as found by semiquantitative RT-PCR and Western blot. Additionally, brefeldin A did not block this short-term-induced enhancement of gap junction coupling. Along with the dipyridamole-induced long-term enhancement of gap junction coupling, the amount of Cx43 mRNA and protein additionally to the amount of Cx43 gap junction plaques were increased. Furthermore, the anti-Cx43 antibody detected only two bands at 42 kDa and 44 kDa in control cells and cells treated with dipyridamole for 6 h, while long-term dipyridamole-treated cells showed a third band at 46 kDa. We propose that a dipyridamole-induced cAMP synthesis increased gap junction coupling in the GM-7373 endothelial cell line at different levels: the short-term effect is related to already oligomerised connexins beyond the Golgi apparatus and the long-term effect involves new expression and synthesis as well as posttranslational modification of Cx43. PMID- 23800834 TI - Silica colloidal crystals as emerging materials for high-throughput protein electrophoresis. AB - Silica colloidal crystals are a new type of media for protein electrophoresis, and they are assessed for their promise in rapidly measuring aggregation of monoclonal antibodies. The nature of silica colloidal crystals is described in the context of the need for a high-throughput separation tool for optimizing the formulations of protein drugs for minimal aggregation. The fundamental relations between molecular weight and mobility in electrophoresis are used to make a theoretical comparison of selectivity between gels and colloidal crystals. The results show that the selectivity is similar for these media, but slightly higher, 10%, for gels, and the velocity is inherently lower than that for gels due to the smaller free volume fraction. These factors are more than compensated for by lower broadening in colloidal crystals. These new media give plate heights of only 0.15 MUm for the antibody monomer and 0.42 MUm for the antibody dimer. The monoclonal antibody is separated from its dimer in 72 s over a distance of only 6.5 mm. This is five times faster than size-exclusion chromatography, with more than tenfold miniaturization, and amenable to parallel separations, all of which are promising for the design of high-throughput devices for optimizing protein drug formulations. PMID- 23800833 TI - Phytochemicals from cruciferous vegetables, epigenetics, and prostate cancer prevention. AB - Epidemiological evidence has demonstrated a reduced risk of prostate cancer associated with cruciferous vegetable intake. Follow-up studies have attributed this protective activity to the metabolic products of glucosinolates, a class of secondary metabolites produced by crucifers. The metabolic products of glucoraphanin and glucobrassicin, sulforaphane, and indole-3-carbinol respectively, have been the subject of intense investigation by cancer researchers. Sulforaphane and indole-3-carbinol inhibit prostate cancer by both blocking initiation and suppressing prostate cancer progression in vitro and in vivo. Research has largely focused on the anti-initiation and cytoprotective effects of sulforaphane and indole-3-carbinol through induction of phases I and II detoxification pathways. With regards to suppressive activity, research has focused on the ability of sulforaphane and indole-3-carbinol to antagonize cell signaling pathways known to be dysregulated in prostate cancer. Recent investigations have characterized the ability of sulforaphane and indole-3 carbinol derivatives to modulate the activity of enzymes controlling the epigenetic status of prostate cancer cells. In this review, we will summarize the well-established, "classic" non-epigenetic targets of sulforaphane and indole-3 carbinol, and highlight more recent evidence supporting these phytochemicals as epigenetic modulators for prostate cancer chemoprevention. PMID- 23800835 TI - Integrating phylogenetics, phylogeography and population genetics through genomes and evolutionary theory. AB - Evolutionary theory is primed to synthesize microevolutionary processes with macroevolutionary divergence by taking advantage of multilocus multispecies genomic data in the molecular evolutionary analysis of biodiversity. While coalescent theory bridges across timescales to facilitate this integration, it is important to appreciate the assumptions, caveats, and recent theoretical advances so as to most effectively exploit genomic analysis. Here I outline the connections between population processes and phylogeny, with special attention to how genomic features play into underlying predictions. I discuss empirical and theoretical complications, and solutions, relating to recombination and multifurcating genealogical processes, predictions about how genome structure affects gene tree heterogeneity, and practical choices in genome sequencing and analysis. I illustrate the conceptual implications and practical benefits of how genomic features generate predictable patterns of discordance of gene trees and species trees along genomes, for example, as a consequence of how regions of low recombination and sex linkage interact with natural selection and with the accumulation of reproductive incompatibilities in speciation. Moreover, treating population genetic parameters as characters to be mapped onto phylogenies offers a new way to understand the evolutionary drivers of diversity within and differentiation between populations. Despite a number of challenges conferred by genomic information, the melding of phylogenetics, phylogeography and population genetics into integrative molecular evolution is poised to improve our understanding of biodiversity at all levels. PMID- 23800836 TI - Climate change and biometeorology, the International Society of Biometeorology and its journal: a perspective on the past and a framework for the future. AB - Anthropogenic climate change is inherently a biometeorological issue. As such, it would be reasonably expected that the International Society of Biometeorology (ISB) and its journal, International Journal of Biometeorology (IJB), would have had climate change feature prominently in their activities, articles etc., and to therefore have made a substantial and valuable contribution to the science of the issue. This article presents an analysis of climate change science in ISB and IJB. The analysis focusses on climate-change-related publications by ISB Presidents found through searches of Thomson Reuters Web of Science; contributions to the Intergovernmental Panel on Climate Change's (IPCC's) Working Group II (WGII) by ISB Presidents; and climate change-related publications in IJB found through searches of Thomson Reuters Web of Science. The results demonstrate that the ISB, as represented by its recent, current, and future Presidents, is actively engaged in climate change research and the production of scholarly climate change publications. For example, ISB Presidents have contributed as authors to all four IPCC WGII Assessment Reports, with some Presidents having contributed to more than one Assessment Report or several chapters of the one report. Similarly, it is evident that the IJB is increasingly attracting and publishing climate-change-related articles, with such articles generally having greater impact (as indicated by citations) than other IJB articles. Opportunities for the ISB to provide an internal framework for, and showcase, its climate change work are described. Such opportunities, if enacted, would complement the recent creation of two IJB climate change Field Editor positions. PMID- 23800837 TI - Sublinear binocular integration preserves orientation selectivity in mouse visual cortex. AB - Inputs from the two eyes are first combined in simple cells in the primary visual cortex. Consequently, visual cortical neurons need to have the flexibility to encode visual features under both monocular and binocular situations. Here we show that binocular orientation selectivity of mouse simple cells is nearly identical to monocular orientation selectivity in both anaesthetized and awake conditions. In vivo whole-cell recordings reveal that the binocular integration of membrane potential responses is sublinear. The sublinear integration keeps binocularly evoked depolarizations below threshold at non-preferred orientations, thus preserving orientation selectivity. Computational simulations based on measured synaptic conductances indicate that inhibition promotes sublinear binocular integration, which are further confirmed by experiments using genetic and pharmacological manipulations. Our findings therefore reveal a cellular mechanism for how visual system can switch effortlessly between monocular and binocular conditions. The same mechanism may apply to other sensory systems that also integrate multiple channels of inputs. PMID- 23800839 TI - Chemical control of superhydrophobicity of carbon nanotube surfaces: droplet pinning and electrowetting behavior. AB - We report the remarkable transformation of a superhydrophobic surface of multiwalled carbon nanotubes after chemical manipulation (functionalization, especially by ozonolysis), which leads to a pinning action and eventually hydrophilic behavior, upon the application of an electric field. The effect of droplet pinning on a hydrophobic surface is an indication of the Wenzel formalism, where it is assumed that the liquid fills up the space between the protrusions on the surface. Also, the ozonized bucky surfaces show fascinating electrowetting behavior in the presence of an electrolyte, which follows a transition from a superhydrophobic, Cassie-Baxter state to a hydrophilic, Wenzel state as a function of the electric field, this has been modelled using a simple approach and the corresponding interfacial capacitance has been determined. PMID- 23800838 TI - Role of the viral hemagglutinin in the anti-influenza virus activity of newly synthesized polycyclic amine compounds. AB - We here report on the synthesis of new series of polycyclic amines initially designed as ring-rearranged analogs of amantadine and featuring pentacyclo, hexacyclo, and octacyclo rings. A secondary amine, 3 azahexacyclo[7.6.0.01,5.05,12.06,10.011,15]pentadeca-7,13-diene, 3, effectively inhibited A/M2 proton channel function, and, moreover, possessed dual activity against an A/H3N2 virus carrying a wild-type A/M2 proton channel, as well as an amantadine-resistant A/H1N1 virus. Among the polycyclic amines that did not inhibit influenza A/M2 proton channel function, several showed low-micromolar activity against tested A/H1N1 strains (in particular, the A/PR/8/34 strain), but not A/H3N2 influenza viruses. A/PR/8/34 mutants selected for resistance to these compounds possessed mutations in the viral hemagglutinin that markedly increased the hemolysis pH. Our data suggest that A/H1N1 viruses such as the A/PR/8/34 strain are particularly sensitive to a subtle increase in the endosomal pH, as caused by the polycyclic amine compounds. PMID- 23800840 TI - Fast screening of stabilizers in polymeric materials by flow injection-tandem mass spectrometry. AB - In the present study, the applicability of rapid flow injection-triple quadrupole mass spectrometry for simultaneous qualitative screening of different classes of stabilizers in polymeric materials is demonstrated. Electrospray ionization and atmospherical pressure chemical ionization were compared, whereby the latter yielded generally poorer detection limits and only single charged ions that were for some analytes beyond the mass range of the quadrupole mass spectrometry. Positive electrospray ionization allowed the interference-free monitoring of multiple reaction monitoring transitions selective for 36 commonly used stabilizers without chromatographic separation. Real polymer samples were extracted by toluene and the method allowed the detection of analytes down to 0.00001-0.025 wt% depending on the stabilizer. PMID- 23800841 TI - FK506 reduces abnormal prion protein through the activation of autolysosomal degradation and prolongs survival in prion-infected mice. AB - Prion diseases are fatal neurodegenerative disorders and no effective treatment has been established to date. In this study, we evaluated the effect of FK506 (tacrolimus), a macrolide that is known to be a mild immunosuppressant, on prion infection, using cell culture and animal models. We found that FK506 markedly reduced the abnormal form of prion protein (PRNP(Sc)) in the cell cultures (N2a58 and MG20) infected with Fukuoka-1 prion. The levels of autophagy-related molecules such as LC3-II, ATG12-ATG5 and ATG7 were significantly increased in the FK506-treated cells, and resulted in the increased formation of autolysosomes. Upregulation of the autophagy-related molecules was also seen in the brains of FK506-treated mice and the accumulation of PRNP(Sc) was delayed. The survival periods in mice inoculated with Fukuoka-1 were significantly increased when FK506 was administered from day 20 post-inoculation. These findings provide evidence that FK506 could constitute a novel antiprion drug, capable of enhancing the degradation of PRNP(Sc) in addition to attenuation of microgliosis and neuroprotection. PMID- 23800842 TI - Handling of the tibial muscle envelope in tibial plateau levelling osteotomy - to elevate or not? A clinical study of 40 dogs. AB - OBJECTIVE: To compare the outcome of the tibial plateau levelling osteotomy (TPLO) procedure, using a 6-hole 3.5 mm locking TPLO plate and performed with the muscle elevation technique (ET) and placement of sponges, to the TPLO without performing these steps (non-elevation-technique [NET]). MATERIAL AND METHODS: Medical records and radiographs of dogs with ET (n = 21) or NET (n = 19) were retrospectively reviewed. Signalment, TPLO procedure side, meniscal treatment, surgery time, haemorrhage, pre- and postoperative tibial plateau angle, assistant, amount of rehabilitation, bone healing (cortical, osteotomy, combined healing scores), complications, limb function, recovery time and follow-up were recorded and analysed using multivariate analysis. A value of p <0.05 was considered significant. RESULTS: Surgery time was significantly shorter with the NET (68.5 min +/- 3.4) than with the ET (87.8 min +/- 3.4) (p <0.01). No significant differences were detected for all other evaluated factors. Soft tissue trauma was minimal and none of the dogs suffered severe haemorrhage. The bone healing scores with the NET and the ET were not significantly different (p = 0.1, p = 0.2, p = 0.1). Complications were rare, minor and not significantly different between groups (p = 0.73). CLINICAL RELEVANCE: The results of this in vivo study indicate that NET is a feasible technique that can be considered for the clinical setting. PMID- 23800843 TI - Material characterization of liver parenchyma using specimen-specific finite element models. AB - The liver is one of the most frequently injured abdominal organs during motor vehicle crashes. Realistic car crash simulations require incorporating strain rate dependent mechanical properties of soft tissue in finite element (FE) material models. This study presents a total of 30 tension tests performed on fresh bovine liver parenchyma at various loading rates in order to characterize the biomechanical and failure properties of liver parenchyma. Each specimen, cut in a standard dog-bone shape, was tested until failure at one of three loading rates (0.01 s(-1), 0.1s(-1), 1 s(-1)) using a tensile testing setup. Load and acceleration recorded from each specimen grip were employed to calculate the time history of force at specimen ends. The shapes of all specimens were reconstructed from laser scans recorded prior to each test and then used to develop specimen specific FE models. A first-order Ogden material model and the time histories of specimen end displacement were assigned to each specimen FE model. The failure Green-Lagrangian strain showed averages around 50% and no significant dependence on loading rates, but the failure 2nd Piola-Kirchhoff stress showed rate dependence with average values ranging from 33 kPa to 94 kPa. The FE models with material model parameters identified using a simulation-based optimization replicated well the time history of load recorded during the test. The FE simulations with model parameters identified using an analytical approach or based on the displacement of optical markers showed a significantly stiffer response and lower failure stress/strain than the FE specimen-specific models. This study provides novel biomechanical and failure data which can be easily implemented in FE models and used to assess injury risk in automobile collisions. PMID- 23800844 TI - Effect of components and surface treatments of fiber-reinforced composite posts on bond strength to composite resin. AB - The aim of this study was to clarify the effect of the components and surface treatments of fiber-reinforced composite (FRC) posts on the durable bonding to core build-up resin evaluated using the pull-out and microtensile tests. Four types of experimental FRC posts, combinations of two types of matrix resins (polymethyl methacrylate and urethane dimethacrylate) and two types of fiberglass (E-glass and zirconia-containing glass) were examined. The FRC posts were subjected to one of three surface treatments (cleaned with ethanol, dichloromethane, or sandblasting). The bond strength between the FRC posts and core build-up resin were measured using the pull-out and microtensile tests before and after thermal cycling. The bond strengths obtained by each test before and after thermal cycling were statistically analyzed by three-way ANOVA and Tukey's multiple comparisons test (p<0.05). The bond strengths except for UDMA by the pull-out test decreased after thermal cycling. Regardless the test method and thermal cycling, matrix resins, the surface treatment and their interaction were statistically significant, but fiberglass did not. Dichloromethane treatment was effective for the PMMA-based FRC posts by the pull-out test, but not by the microtensile test. Sandblasting was effective for both PMMA- and UDMA-based FRC posts, regardless of the test method. The bond strengths were influenced by the matrix resin of the FRC post and the surface treatment. The bond strengths of the pull-out test showed a similar tendency of those of the microtensile test, but the value obtained by these test were different. PMID- 23800845 TI - A microporous metal-organic open framework containing uncoordinated carbonyl groups as postsynthetic modification sites for cation exchange and Tb3+ sensing. AB - A novel 3D microporous compound [Zn3(Httca)2(4,4'-bpy)(H2O)2]n (MOF-COOH) containing uncoordinated carbonyl groups pointing to the pores was prepared. The uncoordinated carbonyl groups in the channels can act as postsynthetic modification sites for cation exchange. The MOF-COOH compound can effectively and selectively serve as an antenna for sensitizing the visible-emitting Tb(3+) cation. PMID- 23800846 TI - Secondary Mullerian system: an atypical case of tumor originating from vestigial Mullerian cells embedded in the peritoneum. PMID- 23800847 TI - Impact of response to prior chemotherapy in patients with advanced urothelial carcinoma receiving second-line therapy: implications for trial design. AB - BACKGROUND: The prognostic impact of response to prior chemotherapy independent of performance status (PS), hemoglobin (Hb), liver metastasis (LM), and time from prior chemotherapy (TFPC) in the context of second-line therapy for advanced urothelial carcinoma (UC) is unknown. METHODS: Six phase II trials evaluating second-line therapy (n = 504) were pooled. Patients who received prior therapy for metastatic disease were eligible for analysis if Hb, LM, PS, and TFPC were available. Response by Response Evaluation Criteria in Solid Tumors 1.0 to first line therapy was recorded. Progression-free survival (PFS) and overall survival (OS) were calculated from the date of registration using the Kaplan-Meier method. RESULTS: A total of 275 patients were evaluable for analysis. Patients received gemcitabine-paclitaxel, cyclophosphamide-paclitaxel, pazopanib, docetaxel plus vandetanib/placebo, or vinflunine (2 trials). Those with prior response (n = 111) had a median OS of 8.0 months (95% confidence interval [CI], 6.8-9.4), compared with 5.9 months (95% CI, 5.0-6.6) for those without prior response (n = 164). Those with prior response had a median PFS of 3.0 months (95% CI, 2.6-4.0) compared with 2.6 months (95% CI, 2.0-2.8) in patients without response. Multivariable analysis did not reveal a significant independent impact of prior response on PFS and OS. CONCLUSIONS: Best prior response in patients receiving prior chemotherapy for metastatic disease did not confer an independent prognostic impact with second-line therapy for advanced UC. Given that the setting of prior chemotherapy (metastatic or perioperative) has not appeared significant in a prior study, patients who received prior chemotherapy in perioperative or metastatic settings may be enrolled in the same second-line trial stratified for PS, Hb, LM, and TFPC. PMID- 23800848 TI - Microarray analysis of active cardiac remodeling genes in a familial hypertrophic cardiomyopathy mouse model rescued by a phospholamban knockout. AB - Familial hypertrophic cardiomyopathy (FHC) is a disease characterized by ventricular hypertrophy, fibrosis, and aberrant systolic and/or diastolic function. Our laboratories have previously developed two mouse models that affect cardiac performance. One mouse model encodes an FHC-associated mutation in alpha tropomyosin: Glu -> Gly at amino acid 180, designated as Tm180. These mice display a phenotype that is characteristic of FHC, including severe cardiac hypertrophy with fibrosis and impaired physiological performance. The other model was a gene knockout of phospholamban (PLN KO), a regulator of calcium uptake in the sarcoplasmic reticulum of cardiomyocytes; these hearts exhibit hypercontractility with no pathological abnormalities. Previous work in our laboratories shows that when mice were genetically crossed between the PLN KO and Tm180, the progeny (PLN KO/Tm180) display a rescued hypertrophic phenotype with improved morphology and cardiac function. To understand the changes in gene expression that occur in these models undergoing cardiac remodeling (Tm180, PLN KO, PLN KO/Tm180, and nontransgenic control mice), we conducted microarray analyses of left ventricular tissue at 4 and 12 mo of age. Expression profiling reveals that 1,187 genes changed expression in direct response to the three genetic models. With these 1,187 genes, 11 clusters emerged showing normalization of transcript expression in the PLN KO/Tm180 hearts. In addition, 62 transcripts are highly involved in suppression of the hypertrophic phenotype. Confirmation of the microarray analysis was conducted by quantitative RT-PCR. These results provide insight into genes that alter expression during cardiac remodeling and are active during modulation of the cardiomyopathic phenotype. PMID- 23800849 TI - Generation of leptin-deficient Lepmkyo/Lepmkyo rats and identification of leptin responsive genes in the liver. AB - Leptin is one of the key molecules in maintaining energy homeostasis. Although genetically leptin-deficient Lep(ob)/Lep(ob) mice have greatly contributed to elucidating leptin physiology, the use of more than one species can improve the accuracy of analysis results. Using the N-ethyl-N-nitrosourea mutagenesis method, we generated a leptin-deficient Lep(mkyo)/Lep(mkyo) rat that had a nonsense mutation (Q92X) in leptin gene. Lep(mkyo)/Lep(mkyo) rats showed obese phenotypes including severe fatty liver, which were comparable to Lep(ob)/Lep(ob) mice. To identify genes that respond to leptin in the liver, we performed microarray analysis with Lep(mkyo)/Lep(mkyo) rats and Lep(ob)/Lep(ob) mice. We sorted out genes whose expression levels in the liver of Lep(mkyo)/Lep(mkyo) rats were changed from wild-type (WT) rats and were reversed toward WT rats by leptin administration. In this analysis, livers were sampled for 6 h, a relatively short time after leptin administration to avoid the secondary effect of metabolic changes such as improvement of fatty liver. We did the same procedure in Lep(ob)/Lep(ob) mice and selected genes whose expression patterns were common in rat and mouse. We verified their gene expressions by real-time quantitative PCR. Finally, we identified eight genes that primarily respond to leptin in the liver commonly in rat and mouse. These genes might be important for the effect of leptin in the liver. PMID- 23800850 TI - A novel genetic locus modulates infarct volume independently of the extent of collateral circulation. AB - In the mouse model of permanent, middle cerebral artery occlusion, infarct volume varies widely across inbred strains but generally is inversely correlated with collateral vessel number. However, we also observed certain mouse strains that share similar collateral vessel anatomy but exhibit significantly different infarct volume. To identify genetic factors determining infarct volume in a collateral vessel-independent manner, we performed quantitative trait locus analysis on a F2 cross between C57BL/6J and C3H/HeJ strains. We mapped four novel loci (Civq4 through Civq7) that modulate infarct volume. Civq4, on chromosome 8, is the strongest locus (logarithm of the odds 9.8) that contributes 21% of the phenotypic variance of infarct volume in the cross. The Civq4 and Civq6 loci represent transgressive B6 alleles that render animals susceptible to larger infarcts. Based on genomic sequence and microarray analyses, we propose candidate genes for the Civq4 locus. By selecting inbred strains with similar collateral vessel anatomy but that vary significantly in infarct volume, we have mapped four loci determining infarct volume in a mouse model of ischemic stroke. Two of the loci appear to modulate infarct volume through a collateral vessel-independent mechanism. Based on strain-specific sequence variants and differences in transcript levels, Msr1 and Mtmr7 appear to be strong candidate genes for Civq4. Identifying the underlying genetic factors of these loci will elucidate the genetic architecture response to cerebral ischemia, shed new light on disease mechanisms of ischemic stroke, and identify potential therapeutic targets for clinical applications. PMID- 23800851 TI - Cetuximab for treatment of advanced squamous cell carcinoma in solid organ transplant recipients. AB - Survival of solid organ transplant patients has been prolonged, leading to increased incidence of non-melanoma skin cancers. Metastatic squamous cell carcinoma is an increasing problem in these patients. This paper reviews the evidence available for the treatment of advanced squamous cell carcinoma with the epidermal growth factor receptor inhibitor, cetuximab. PMID- 23800852 TI - Immunolocalization of vascular endothelial growth factor, its receptors (flt1/fms, flk1/KDR, flt4) and vascular endothelial growth inhibitor in the bitch uterus during the sexual cycle. AB - Angiogenesis is regulated by proangiogenic and antiangiogenic factors. Vascular endothelial growth factor (VEGF) is a prime proangiogenic regulator, whereas vascular endothelial growth inhibitor (VEGI) is a specific antiangiogenic cytokine. To clarify temporal changes in the localization of pro-angiogenic and anti-angiogenic factors in the uterus of normal bitches during the proestrus, estrus, diestrus and anestrus phases of the estrous cycle, the expressions of VEGF and its receptors (flt1/fms, flk1/KDR and flt4) and their correlation with VEGI were analyzed using immunohistochemistry. Uteruses were collected after ovariohysterectomy. Immunohistochemical staining was evaluated semi quantitatively by an immunohistochemical total score consisting of the sum of the intensity and proportional scores. The results in the bitch uterus demonstrated that positive immunohistochemical staining was found exclusively in the cytoplasm and apical membrane of luminal and glandular epithelial, stromal and smooth muscle cells and nuclear staining was observed in the flt1/fms, flk4 and VEGI during proestrous and estrous. Semi-quantitative analyses revealed that the total score for VEGF in the glandular epithelial cells was significantly higher than that of luminal, endometrial stromal and myometrial smooth muscle cells during proestrous (p<0.05). The total score for flk1/KDR and flt4 in the glandular epithelium was also significantly higher than that of endometrial stromal cells during proestrous, whilst the total score for flt1/fms in the glandular epithelium was significantly higher than that of endometrial stromal cells during anestrus (p<0.05). We conclude that, in the bitch uterus, cyclic changes may be precisely regulated by the combined functions of VEGF family members, angiogenic VEGF and VEGF receptors, and the angiogenesis inhibitor VEGI. PMID- 23800853 TI - Comment on "association of anorexia with sarcopenia in a community-dwelling elderly population: results from the ilSIRENTE study". PMID- 23800854 TI - Glycosides from the aerial parts of Patrinia villosa. AB - An investigation of the Korean medicinal plant Patrinia villosa (THUNB.) JUSS. (Valerianaceae) led to the isolation of two new flavonoid glycosides, patrivilosides 1 (1) and 2 (2), a new iridoid glycoside, patrinovalerosidate (3), and two new saponins, patrinovilosides A (4) and B (5), along with six known compounds including three flavonoid glycosides and three iridoid glycosides. The structures of the new compounds were elucidated based on analysis of their one dimensional (1D)- and 2D-NMR spectra along with their mass spectrometric data and the results of acid hydrolysis. PMID- 23800855 TI - Differential regulation of ABCA1 and macrophage cholesterol efflux by elaidic and oleic acids. AB - Trans fatty acid consumption is associated with an increased risk of coronary heart disease. This increased risk has been attributed to decreased levels of HDL cholesterol and increased levels of LDL cholesterol. However, the mechanism by which trans fatty acid modulates cholesterol transit remains poorly defined. ATP binding cassette transporter A1 (ABCA1)-mediated macrophage cholesterol efflux is the rate-limiting step initiating apolipoprotein A-I lipidation. In this study, elaidic acid, the most abundant trans fatty acid in partially hydrogenated vegetable oil, was shown to stabilize macrophage ABCA1 protein levels in comparison to that of its cis fatty acid isomer, oleic acid. The mechanism responsible for the disparate effects of oleic and elaidic acid on ABCA1 levels was through accelerated ABCA1 protein degradation in cells treated with oleic acid. In contrast, no apparent differences were observed in ABCA1 mRNA levels, and only minor changes were observed in Liver X receptor/Retinoic X receptor promoter activity in cells treated with elaidic and oleic acid. Efflux of both tracers and cholesterol mass revealed that elaidic acid slightly increased ABCA1 mediated cholesterol efflux, while oleic acid led to decreased ABCA1-mediated efflux. In conclusion, these studies show that cis and trans structural differences in 18 carbon n-9 monoenoic fatty acids variably impact cholesterol efflux through disparate effects on ABCA1 protein degradation. PMID- 23800856 TI - CT Lesion Model-Based Structural Allografts: Custom Fabrication and Clinical Experience. AB - BACKGROUND: Patients requiring knee and hip revision arthroplasty often present with difficult anatomical situations that limit options for surgery. Customised mega-implants may be one of few remaining treatment options. However, extensive damage to residual bone stock may also be present, and in such cases even customised prosthetics may be difficult to implant. Small quantities of lost bone can be replaced with standard allografts or autologous bone. Larger defects may require structural macro-allografts, sometimes in combination with implants (allograft-prosthesis composites). METHODS: Herein, we describe a process for manufacturing lesion-specific large structural allografts according to a 3D, full scale, lithographically generated defect model. These macro-allografts deliver the volume and the mechanical stability necessary for certain complex revisions. They are patient-and implant-matched, negate some requirements for additional implants and biomaterials and save time in the operating theatre by eliminating the requirement for intra-operative sizing and shaping of standard allografts. CONCLUSION: While a robust data set from long-term follow-up of patients receiving customised macro-allografts is not yet available, initial clinical experience and results suggest that lesion-matched macro-allografts can be an important component of revision joint surgery. PMID- 23800857 TI - The gallic acid-phospholipid complex improved the antioxidant potential of gallic acid by enhancing its bioavailability. AB - Gallic acid (GA) is well known for its antioxidant and hepatoprotective activity, though its effectiveness is restricted due to rapid metabolism and elimination. To overcome these problems, gallic acid-phospholipid complex was prepared and the effect of phospholipid complexation was investigated on carbon tetrachloride (CCl4)-induced oxidative damage in rat liver. The complex significantly reduced the hepatic marker enzymes in rat serum and restored the antioxidant enzyme levels with respect to CCl4-induced group (P < 0.05 and P < 0.01). Also, the complex improved the pharmacokinetics of GA by increasing the relative bioavailability and elimination half-life. The study therefore suggests that phospholipid complexation has enhanced the therapeutic efficacy of GA which may be due to its improved absorption and increased bioavailability in rat serum. PMID- 23800858 TI - Design and formulation technique of a novel drug delivery system for azithromycin and its anti-bacterial activity against Staphylococcus aureus. AB - Azithromycin, an important member of the azalide subclass is effective against both Gram-positive and Gram-negative organisms. Certain physicochemical properties of the drug like poor water solubility and relatively low bioavailability of 37% due to incomplete absorption after ingestion, aroused the need for the development of a novel drug delivery system to enhance the solubilization potential and antibacterial activity against Staphylococcus aureus at a very low concentration. Cinnamon oil (Cinnamonum zeylanicum)-based microemulsion system formulated using non-ionic surfactant, Tween 20, and water was characterized. The drug-incorporated system F4 (oil to surfactant ratio of 1:4 (v/v)) showed enhanced solubilization of the drug, droplet diameter of 5-8 nm, and a good thermodynamic stability. The effect of surfactant concentration exhibited a negative correlation with droplet size diameter and turbidity and a positive correlation with stability and viscosity. The system was investigated for its antibacterial activity that demonstrated a significantly higher activity at a minimum concentration (4 MUg/ml) of the novel drug-loaded system in comparison with the conventional formulation (128 MUg/ml). Examination through scanning electron microscopy analysis further confirmed a considerable morphologic variation due to alteration in the membrane permeability of the microemulsion-treated system. The small droplet size of the microemulsion system and the antibacterial property of cinnamon oil, together, accounts clearly for the enhanced efficacy of the new formulated system F4 and not just azithromycin alone. Staining with acridine orange/ethidium bromide dyes as examined through fluorescence microscopy also substantiated with the results of membrane permeability of bacteria. Thus, our study discloses a potential oral drug delivery system of azithromycin with improved biocompatibility. PMID- 23800859 TI - Deciphering and engineering of the final step halogenase for improved chlortetracycline biosynthesis in industrial Streptomyces aureofaciens. AB - Chlortetracycline (CTC) is an important member from antibiotics tetracycline (TC) family, which inhibits protein synthesis in bacteria and is widely involved in clinical therapy, animal feeds and aquaculture. Previous works have reported intricately the biosynthesis of CTC from the intermediates in random mutants of Streptomyces aureofaciens and the crucial chlorination remained unclear. We have developed the genetic manipulation in an industrial producer, in which about 15.0g/l CTC predominated along with 1.2g/l TC, and discovered that chlorination by ctcP (an FADH2-dependent halogenase gene) is the last inefficient step during CTC biosynthesis. Firstly, the DeltactcP strain accumulated about 18.9g/l "clean" TC without KBr addition and abolished the production of CTC. Subsequently, CtcP was identified to exhibit a substrate stereo-specificity to absolute TC (4S) rather than TC (4R), with low kcat of 0.51+/-0.01min(-1), while it could halogenate several TC analogs. Accordingly, we devised a strategy for overexpression of ctcP in S. aureofaciens and improved CTC production to a final titer of 25.9g/l. We anticipate that our work will provide a biotechnological potential of enzymatic evolution and strain engineering towards new TC derivatives in microorganisms. PMID- 23800861 TI - EconOmics. PMID- 23800860 TI - B-cell lymphoma in a patient with complete interferon gamma receptor 1 deficiency. AB - Immunosuppression-associated lymphoproliferative disorders can be related to primary as well as acquired immune disorders. Interferon gamma receptor (IFN gammaR) deficiency is a rare primary immune disorder, characterized by increased susceptibility to mycobacterial infections. Here we report the first case of an Epstein Barr Virus (EBV) related B-cell lymphoma in a patient with complete IFN gammaR1 deficiency. The patient was a 20-year-old man with homozygous 22Cdel in IFNGR1 resulting in complete absence of IFN-gammaR1 surface expression and complete lack of responsiveness to IFN-gamma in vitro. He had disseminated refractory Mycobacterium avium complex and Mycobacterium abscessus infections. At age 18 he presented with new spiking fever and weight loss that was due to an EBV positive B-cell non-Hodgkin lymphoma. Two years later he died of progressive lymphoma. IFN-gamma plays an important role in tumor protection and rejection. Patients with IFN-gammaR deficiencies and other immune deficits predisposing to mycobacterial disease seem to have an increased risk of malignancies, especially those related to viral infections. As more of these patients survive their early infections, cancer awareness and tumor surveillance may need to become a more routine part of management. PMID- 23800862 TI - David R. Cox 1946-2013. PMID- 23800863 TI - Hypomethylation marks enhancers within transposable elements. AB - Transposable elements (TEs) make up 50% of the human genome and are usually considered a mutational burden. A new study uses signatures of DNA hypomethylation to identify tissue-specific enhancers within TEs, providing fresh evidence that mobile DNA has a non-negligible role in genome regulation and evolution. PMID- 23800864 TI - Leveraging the species barrier to advance cancer therapy. AB - The discovery of new therapeutic targets and the personalization of treatments are two active areas of cancer research. New studies suggest that a 'co-clinical' approach may expedite both therapeutic target validation and risk stratification in patients with advanced prostate cancer. PMID- 23800865 TI - Biological variability and the emergence of multidrug-resistant tuberculosis. AB - A new study demonstrates that bacterial mutation rates associated with the Mycobacterium tuberculosis lineage most commonly linked to multidrug-resistant tuberculosis are multifold higher than shown in previous studies. This discovery, when considered together with recent findings on pharmacokinetic variability in patients, leads to new models of how multidrug-resistant tuberculosis arises, with direct therapeutic implications. PMID- 23800871 TI - Use of a revision cup for treatment of Zurich cementless acetabular cup loosening. Surgical technique and clinical application in 31 cases. AB - Loosening of the acetabular cup is one of the most common complications following total hip replacement and has an incidence rate of 1.8% to 36.8%. The objective of this study was to describe the surgical technique for the application of a cementless acetabular component specifically designed for treatment of cup loosening and preliminary clinical experience. The Kyon revision cup is composed of two components; the first is a perforated titanium outer shell with holes for 2.4 mm titanium screws, which is impacted into the acetabulum after removal of the loose cup and reaming of the acetabulum. It is secured with a variable number of screws. The second component is an inner plain titanium cup with an ultra-high molecular-weight polyethylene insert, which is impacted into the outer shell to obtain press-fit stability. This revision cup was used in 31 dogs with cup loosening and a minimum follow-up period of six months. There were four intra operative complications and two postoperative complications. The main intra operative complication was difficulty inserting the inner cup into the outer shell. Postoperative complications included craniodorsal hip luxation in one dog, which was successfully managed, and cup loosening in another dog, which required explantation of the prosthesis. The main advantage of the revision cup appears to be increased implant stability afforded by screw fixation. Our initial clinical results in 31 dogs were promising; all but one dog had a successful clinical outcome. PMID- 23800873 TI - Intrinsic region length scaling of heavily doped carbon nanotube p-i-n junctions. AB - We investigated the dependence of the transport properties of heavily doped intratube single-walled carbon nanotube (SWCNT) p-i-n junctions on the length of the intrinsic region by using empirical self-consistent quantum transport simulations. When the length of the intrinsic region is scaled from a few angstroms to over 10 nanometers, the SWCNT p-i-n junction evolves from a tunneling diode with a large negative rectification and large negative differential resistance to one with a large positive rectification (like a conventional positive rectifying diode). The critical length of the intrinsic length is about 8.0 nm. Therefore, one can obtain nanoscale diodes of different performance types by changing the intrinsic region length. PMID- 23800872 TI - Venous angioarchitectural features of intracranial dural arteriovenous shunt and its relation to the clinical course. AB - INTRODUCTION: The aim of this study is to assess the relationship between the venous angioarchitectural features and the clinical course of intracranial dural arteriovenous shunt (DAVS) with cortical venous reflux (CVR). METHODS: With institutional review board approval, 41 patients (M:F = 24:17; median age, 52 years (range, 1-72 years), median follow-up; 1.5 years; partial treatment, n = 36) with persistent CVR were included. We evaluated the initial presentation and the incidence of annual morbidity (hemorrhage or new/worsened nonhemorrhagic neurological deficit (NHND)) according to the venous angiographic patterns isolated venous sinus, occlusion of the draining sinus, direct pial venous drainage, pseudophlebitic pattern, venous ectasia, brisk venous drainage, and length of pial vein reflux-on digital subtraction angiography. Cox regression was performed to identify independent factors for clinical course. RESULTS: During 111.9 patient-years of follow-up, the overall annual morbidity rate was 11.6 % (mortality; n = 3, rate; 2.6 %/year). Hemorrhage occurred in five patients (12.2 %, rate; 4.5 %/year) and new/worsened NHND occurred in eight patients (19.5 %, rate; 7.2 %/year). Patients with isolated venous sinus, direct pial venous drainage, and pseudophlebitic pattern were associated with initial aggressive presentation. Venous ectasia was associated with initial hemorrhagic presentation. Brisk venous drainage was associated with initial benign presentation. Patients with isolated venous sinus showed a poor clinical course with a higher annual incidence of hemorrhage or new/worsened NHND (91.2 %/year vs 9.2 %/year; hazard ratio, 6.681; p = 0.027). CONCLUSIONS: Venous angioarchitectural features may be predictive of the clinical course of DAVSs. DAVS patients with isolated venous sinus may be especially at high risk for future aggressive clinical course. PMID- 23800874 TI - Decreased mitochondrial DNA copy number in the hippocampus and peripheral blood during opiate addiction is mediated by autophagy and can be salvaged by melatonin. AB - Drug addiction is a chronic brain disease that is a serious social problem and causes enormous financial burden. Because mitochondrial abnormalities have been associated with opiate addiction, we examined the effect of morphine on mtDNA levels in rat and mouse models of addiction and in cultured cells. We found that mtDNA copy number was significantly reduced in the hippocampus and peripheral blood of morphine-addicted rats and mice compared with control animals. Concordantly, decreased mtDNA copy number and elevated mtDNA damage were observed in the peripheral blood from opiate-addicted patients, indicating detrimental effects of drug abuse and stress. In cultured rat pheochromocytoma (PC12) cells and mouse neurons, morphine treatment caused many mitochondrial defects, including a reduction in mtDNA copy number that was mediated by autophagy. Knockdown of the Atg7 gene was able to counteract the loss of mtDNA copy number induced by morphine. The mitochondria-targeted antioxidant melatonin restored mtDNA content and neuronal outgrowth and prevented the increase in autophagy upon morphine treatment. In mice, coadministration of melatonin with morphine ameliorated morphine-induced behavioral sensitization, analgesic tolerance and mtDNA content reduction. During drug withdrawal in opiate-addicted patients and improvement of protracted abstinence syndrome, we observed an increase of serum melatonin level. Taken together, our study indicates that opioid addiction is associated with mtDNA copy number reduction and neurostructural remodeling. These effects appear to be mediated by autophagy and can be salvaged by melatonin. PMID- 23800875 TI - Myeloid calcifying cells promote atherosclerotic calcification via paracrine activity and allograft inflammatory factor-1 overexpression. AB - Several cell types contribute to atherosclerotic calcification. Myeloid calcifying cells (MCCs) are monocytes expressing osteocalcin (OC) and bone alkaline phosphatase (BAP). Herein, we tested whether MCCs promote atherosclerotic calcification in vivo. We show that the murine spleen contains OC(+)BAP(+) cells with a phenotype similar to human MCCs, a high expression of adhesion molecules and CD11b, and capacity to calcify in vitro and in vivo. Injection of GFP(+) OC(+)BAP(+) cells into 8- or 40-week ApoE(-/-) mice led to more extensive calcifications in atherosclerotic areas after 24 or 4 weeks, respectively, compared to control OC(-)BAP(-) cells. Despite that OC(+)BAP(+) cells had a selective transendothelial migration capacity, tracking of the GFP signal revealed that presence of injected cells within atherosclerotic areas was an extremely rare event and so GFP mRNA was undetectable by qPCR of lesion extracts. By converse, injected OC(+)BAP(+) cells persisted in the bloodstream and bone marrow up to 24 weeks, suggesting a paracrine effect. Indeed, OC(+)BAP(+) cell-conditioned medium (CM) promoted calcification by cultured vascular smooth muscle cells (VSMC) more than CM from OC(-)BAP(-) cells. A genomic and proteomic investigation of MCCs identified allograft inflammatory factor (AIF)-1 as a potential candidate of this paracrine activity. AIF-1 stimulated VSMC calcification in vitro and monocyte-specific (CD11b-driven) AIF-1 overexpression in ApoE(-/-) mice increased calcium content in atherosclerotic areas. In conclusion, we show that murine OC(+)BAP(+) cells correspond to human MCCs and promote atherosclerotic calcification in ApoE(-/-) mice, through paracrine activity and modulation of resident cells by AIF-1 overexpression. PMID- 23800876 TI - The aryl hydrocarbon receptor interacts with nuclear factor erythroid 2-related factor 2 to mediate induction of NAD(P)H:quinoneoxidoreductase 1 by 2,3,7,8 tetrachlorodibenzo-p-dioxin. AB - NAD(P)H:quinoneoxidoreductase 1 (NQO1) belongs to a group of the aryl hydrocarbon receptor (AhR) battery of drug-metabolizing enzymes that are characteristically induced by both AhR agonists and nuclear factor erythroid 2-related factor 2 (Nrf2) activators. We have previously reported that induction of Nqo1 by the AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in hepa1c1c7 cells involves Nrf2 (Ma et al., Biochem J 377, 205-213, 2004). Here we analyzed the molecular mechanism of induction. Induction required AhR and its DNA-binding partner Arnt because induction was not observed in AhR or Arnt-defective cells, but induction was restored upon reconstitution of the variant cells with functional AhR or Arnt. Induction also required Nrf2, as induction by benzo[a]pyrene was lost in the liver of Nrf2 knockout mice similarly to induction by butyl hydroxyanisol, demonstrating a cross-interaction between the AhR and Nrf2 pathways for induction in vivo. TCDD increased the protein level and induced the nuclear accumulation of Nrf2 with a delayed kinetics compared with activation of AhR. Chromatin immunoprecipitation revealed that TCDD recruited both AhR and Nrf2 to the Nqo1 promoter enhancer region containing a DRE and an ARE in time-dependent manners. Co-immunoprecipitation experiments revealed that, in addition to AhR-Arnt binding, TCDD induced an interaction between AhR and Nrf2 as well as Keap1. The findings reveal that TCDD induces multi protein complexes to mediate cross interaction between the AhR and Nrf2 pathways, uncovering a novel mechanistic aspect of gene regulation by environmental chemicals through AhR and Nrf2. PMID- 23800877 TI - Folate polyglutamylation eliminates dependence of activity on enzyme concentration in mitochondrial serine hydroxymethyltransferases from Arabidopsis thaliana. AB - The reversible reaction catalyzed by serine hydroxymethyltransferase (SHMT) is the major one-carbon unit source for essential metabolic processes. The Arabidopsis thaliana genome encodes seven SHMT isozymes localized in mitochondria, plastids, nuclei, and the cytosol. Knowledge of the biochemical properties of each isozyme is central to understanding and manipulating one carbon metabolism in plants. We heterologously expressed and purified three recombinant SHMTs from A. thaliana (AtSHMTs) putatively localized in mitochondria (two) and the cytosol (one). Their biochemical properties were characterized with respect to the impact of folate polyglutamylation on substrate saturation kinetics. The two mitochondrial AtSHMTs, but not the cytosolic one, had increased turnover rates at higher (>0.4ng/MUL) enzyme concentrations in the presence of monoglutamylated folate substrates, but not in the presence of pentaglutamylated folate substrates. We found no experimental support for a change in oligomerization state over the range of enzyme concentration studied. Modeling of the enzyme structures presented features that may explain the activity differences between the mitochondrial and cytosolic isozymes. PMID- 23800878 TI - Hybridization chain reaction-based branched rolling circle amplification for chemiluminescence detection of DNA methylation. AB - A novel hybridization chain reaction-based branched rolling circle amplification combining the fabrication of multi-HRP-capped MNPs is developed for chemiluminescence detection of DNA methyltransferase activities and inhibitors with high sensitivity in a well-controlled manner. PMID- 23800879 TI - Temporal and spatial pattern of dref expression during Drosophila bristle development. AB - The DNA replication-related element-binding factor (DREF) is a BED finger-type transcription factor that has important roles in cell cycle progression. In an earlier study, we showed that DREF is required for endoreplication during posterior scutellar macrochaete development. However, dynamic change in the dref expression in the cell lineage is unclear. In this study, we focused on the spatio-temporal pattern of expression of the dref gene during bristle development. Gene expression analysis using GAL4 enhancer trap lines of dref and the upstream activation sequence-green fluorescent protein with nuclear localization signals (UAS-GFPnls) in combination with immunostaining revealed the half-life of GFPnls in vivo (<6 hours) is short enough to monitor the dref gene expression. The analysis revealed that the dref expression occurs in clusters that include cells consisting of a bristle as well as surrounding epidermal cells. The intensity of GFP signals was almost the same in those cells, suggesting expression of the dref gene in bristle cell lineages occurs simultaneously in clusters. Further analysis showed that GFP signals increased twice during sensory organ precursor development as well as in bristle development at 9 hours and 15 hours after pupal formation, respectively. However, its expression was barely detectable in the cell lineages in and around asymmetric cell division or at other stages of development. For the first time, we clarified a spatio-temporal pattern of expression of the dref gene in vivo and revealed that expression of the dref gene occurs in clusters and is temporally regulated at specific times during bristle development. PMID- 23800880 TI - Exercise training favors increased insulin-stimulated glucose uptake in skeletal muscle in contrast to adipose tissue: a randomized study using FDG PET imaging. AB - Physical exercise increases peripheral insulin sensitivity, but regional differences are poorly elucidated in humans. We investigated the effect of aerobic exercise training on insulin-stimulated glucose uptake in five individual femoral muscle groups and four different adipose tissue regions, using dynamic (femoral region) and static (abdominal region) 2-deoxy-2-[18F]fluoro-d-glucose (FDG) PET/CT methodology during steady-state insulin infusion (40 mU.m-2.min-1). Body composition was measured by dual X-ray absorptiometry and MRI. Sixty-one healthy, sedentary [V(O2max) 36(5) ml.kg-1.min-1; mean(SD)], moderately overweight [BMI 28.1(1.8) kg/m2], young [age: 30(6) yr] men were randomized to sedentary living (CON; n = 17 completers) or moderate (MOD; 300 kcal/day, n = 18) or high (HIGH; 600 kcal/day, n = 18) dose physical exercise for 11 wk. At baseline, insulin-stimulated glucose uptake was highest in femoral skeletal muscle followed by intraperitoneal visceral adipose tissue (VAT), retroperitoneal VAT, abdominal (anterior + posterior) subcutaneous adipose tissue (SAT), and femoral SAT (P < 0.0001 between tissues). Metabolic rate of glucose increased similarly (~30%) in the two exercise groups in femoral skeletal muscle (MOD 24[9, 39] MUmol.kg-1.min-1, P = 0.004; HIGH 22[9, 35] MUmol.kg-1.min-1, P = 0.003) (mean[95% CI]) and in five individual femoral muscle groups but not in femoral SAT. Standardized uptake value of FDG decreased ~24% in anterior abdominal SAT and ~20% in posterior abdominal SAT compared with CON but not in either intra- or retroperitoneal VAT. Total adipose tissue mass decreased in both exercise groups, and the decrease was distributed equally among subcutaneous and intra-abdominal depots. In conclusion, aerobic exercise training increases insulin-stimulated glucose uptake in skeletal muscle but not in adipose tissue, which demonstrates some interregional differences. PMID- 23800881 TI - Effects of sleeve gastrectomy and ileal transposition, alone and in combination, on food intake, body weight, gut hormones, and glucose metabolism in rats. AB - Bariatric surgeries are hypothesized to produce weight loss and improve diabetes control by multiple mechanisms including gastric restriction and lower gut stimulation; the relative importance of these mechanisms remains poorly understood. We compared the effects of a typical foregut procedure, sleeve gastrectomy, (SG) with a primarily hindgut surgery, ileal transposition (IT), alone and together (SGIT), or sham manipulations, on food intake, body weight, gut hormones, glucose tolerance, and key markers of glucose homeostasis in peripheral tissues of adult male Sprague-Dawley rats (450-550 g, n = 7-9/group). SG, IT, and SGIT surgeries produced transient reduction in food intake and weight gain; the effects of SG and IT on intake and body weight were nonadditive. SG, IT, and SGIT surgeries resulted in increased tissue expression and plasma concentrations of the lower gut hormones glucagon-like peptide-1 and peptide YY and decreased plasma glucose-dependent insulinotropic peptide, insulin, and leptin concentrations. Despite transient effects on intake and weight gain, the SG, IT, and SGIT surgeries produced a significant improvement in glucose tolerance. In support of glycemic improvements, the protein abundance of key markers of glucose metabolism (e.g., GLUT4, PKA, IRS-1) in muscle and adipose tissue were increased, whereas the expression of key gluconeogenic enzyme in liver (G-6-Pase) were decreased following the surgeries. Therefore, our data suggest that enhanced lower gut stimulation following SG, IT, and SGIT surgeries leads to transient reduction in food intake and weight gain together with enhanced secretion of lower gut hormones and improved glucose clearance by peripheral tissues. PMID- 23800882 TI - Ceacam1 deletion causes vascular alterations in large vessels. AB - Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) promotes hepatic insulin clearance and endothelial survival. However, its role in the morphology of macrovessels remains unknown. Mice lacking Ceacam1 (Cc1-/-) exhibit hyperinsulinemia, which causes insulin resistance and fatty liver. With increasing evidence of an association among hyperinsulinemia, fatty liver disease, and atherosclerosis, we investigated whether Cc1-/- exhibited vascular lesions in atherogenic-prone aortae. Histological analysis revealed impaired endothelial integrity with restricted fat deposition and aortic plaque-like lesions in Cc1-/- aortae, likely owing to their limited lipidemia. Immunohistochemical analysis indicated macrophage deposition, and in vitro studies showed increased leukocyte adhesion to aortic wall, mediated in part by elevation in vascular cell adhesion molecule 1 levels. Basal aortic eNOS protein and NO content were reduced, in parallel with reduced Akt/eNOS and Akt/Foxo1 phosphorylation. Ligand-induced vasorelaxation was compromised in aortic rings. Increased NADPH oxidase activity and plasma 8-isoprostane levels revealed oxidative stress and lipid peroxidation in Cc1-/- aortae. siRNA-mediated CEACAM1 knockdown in bovine aortic endothelial cells adversely affected insulin's stimulation of IRS-1/PI 3-kinase/Akt/eNOS activation by increasing IRS-1 binding to SHP2 phosphatase. This demonstrates that CEACAM1 regulates both endothelial cell autonomous and nonautonomous mechanisms involved in vascular morphology and NO production in aortae. Systemic factors such as hyperinsulinemia could contribute to the pathogenesis of these vascular abnormalities. Cc1-/- mice provide a first in vivo demonstration of distinct CEACAM1-dependent hepatic insulin clearance linking hepatic to macrovascular abnormalities. PMID- 23800889 TI - Thoracoscopic pericardial fenestration for effective long-term management of non tuberculous mycobacterium pericarditis. AB - The long-term consequences of non-tuberculous mycobacterium pericarditis with pericardial effusion after fenestration have not been described. We encountered a case of non-tuberculous mycobacterium pericarditis in a 59-year-old woman with an underlying collagenosis. Repeated drainage was required because of rapid reaccumulation of the effusion. To definitively control the effusion, pericardial fenestration was performed by video-assisted thoracoscopic surgery. Chest radiography performed 6 years postoperatively showed no accumulation of pericardial or pleural fluid. The patient required careful follow-up and, to date, the pulmonary non-tuberculous mycobacterium (NTM) infection has been successfully suppressed by continuous antibiotic therapy. Pericardial fenestration with antibiotic therapy was an appropriate treatment for recurrent effusion in this case of NTM pericarditis. PMID- 23800883 TI - Autophagy is involved in adipogenic differentiation by repressesing proteasome dependent PPARgamma2 degradation. AB - Animal studies have shown that autophagy is essential in the process of obesity. Here, we performed daily injection of the autophagy inhibitor chloroquine (CQ) in mice and found that systemic administration of CQ blocks high-fat diet-induced obesity. To investigate the potential underlying molecular mechanism, we employed genetic and pharmacological interventions in cultured preadipocytes to investigate the role of autophagy in the control of the expression of the adipogenic regulator peroxisome proliferatior-activated receptor-gamma (PPARgamma). We show that adipogenic differentiation of 3T3-L1 preadipocytes is associated with activation of autophagy and increased PPARgamma2 protein level. Treatment with CQ, shRNA-mediated knockdown, or genetic engineering-induced deletion of autophagy-related gene 5 (Atg5) promoted proteasome-dependent PPARgamma2 degradation and attenuated adipogenic differentiation. Therefore, activated autophagy increases PPARgamma2 stability and promotes adipogenic differentiation, and inhibition of autophagy may prevent high-fat diet-induced obesity and the consequential type 2 diabetes. PMID- 23800890 TI - Animal-assisted intervention in dementia: effects on quality of life. AB - There is a need to develop nonpharmacological treatments and methods which can serve as alternatives or complements to medications in dementia care. Previous research indicates that animal-assisted intervention (AAI) can be beneficial. The purpose of the present pilot project was to evaluate effects of AAI on quality of life (QoL) in people with dementia in four Swedish nursing homes. A pretest/posttest research design was used. Twenty people (12 women, 8 men; aged 58 to 88) were included. Nine people completed the intervention which comprised 10 training sessions with a certified therapy dog team. QoL improved in the expected direction after the intervention (p = .035). Even though the effects of AAI may not be discernible over longer periods of time, there are still immediate effects which can promote better QoL for people living with dementia diseases. PMID- 23800891 TI - HER2 in gastric cancer: an immunohistochemical study on tissue microarrays and the corresponding whole-tissue sections with a supplemental fish study. AB - Since focal HER2 expression is an issue in GC, TMA construction from the paraffin embedded surgically-obtained tissue may not reflect its real status. The aim of this study was to assess the HER2 status in tissue microarrays (TMAs) and the corresponding whole sections using HercepTest immunohistochemistry (IHC), and to correlate it and to assess the concordance of HER2 IHC and fluorescence in situ hybridization (FISH) in TMAs. Concordance of the HER2 expression status for 302 cases of gastric cancer using 9 paired TMAs was evaluated using a 2-mm core size and 305 corresponding whole sections. Concordance of the IHC and FISH HER2 status was compared. In addition,, the HER2 status was compared to clinicopathological characteristics and patients' survival. Using the whole-section approach, HER2 over-expression was found in 25.2 % (HER2 3+ 6.6 %, HER2 2+ 18.7 %) of tumours. The overall concordance of IHC between the cores and the whole section was 84.9 %; 15.1 % of the tumours showed HER2 amplification. The overall concordance of IHC and FISH on cores was 75.7 %. The level of amplification correlated with the IHC score. Relationship between the intestinal and papillary types and tumour grade was observed for tumours with over-expression and amplification, whereas tumour location was related only to over-expression. There was a statistically significant difference in the overall survival of the patients, which was related to HER2 amplification. In conclusion, good concordance of the IHC HER2 results between tissue cores in TMA and whole sections, and excellent concordance of the IHC and FISH results on tissue cores was found. At least a part of the observed IHC HER2 heterogeneity could very likely be explained by fixation artifacts. With adequate fixation, a higher concordance of IHC HER2 between the cores and the whole sections can be expected. The TMA approach could enable an easier analysis of more than one representative tumour block. PMID- 23800892 TI - A new on-fluorescent probe for manganese (II) ion. AB - A new fluorescent probe for Mn(2+) ion, (6E)-N-((E)-1,2-diphenyl-2-(pyridin-2 ylimino)ethylidene)pyridin-2-amine (L), has been synthesized from benzil and 2 amino pyridine and characterized. In 1:1 (v/v) CH3CN:H2O (pH 4.0, universal buffer) L exhibits fluorescent intensity with emission peak at lambdamax 360 nm on excitation with photons of 310 nm. Fluorescent intensity of L increases distinguishingly on interaction with Mn(2+) ion compared to metal ions--Na(+), K(+), Ca(2+), Mg(2+), Ba(2+), Fe(2+), Co(2+), Ni(2+), Cu(2+), Zn(2+), Cd(2+), Hg(2+), Pb(2+) and Ag(+) individually or all together. The enhancement in fluorescent intensity is due to snapping of photoinduced electron transfer (PET) prevailed in free L. Fluorescence and UV/visible spectral data analysis shows that binding stoichiometry between Mn(2+) and L is 1:1 with log beta ~ 3.0. Both L and its Mn(2+) complex were optimised using density functional theory (DFT) and vibrational frequency calculations confirm that both are at local minima on the potential energy surfaces. PMID- 23800894 TI - Clinical research in surgical oncology: an analysis of ClinicalTrials.gov. AB - BACKGROUND: The objective of this study was to provide a descriptive analysis of registered clinical trials in surgical oncology at ClinicalTrials.gov. METHODS: Data was extracted from ClinicalTrials.gov using the following search engine criteria: "Cancer" as Condition, "Surgery OR Operation OR Resection" as Intervention, and Non-Industry sponsored. The search was limited to Canada and the United States and included trials registered from January 1, 2001 to January 1, 2011. RESULTS: Of 9,961 oncology trials, 1,049 (10.5%) included any type of surgical intervention. Of these trials, 125 (11.9%, 1.3% of all oncology trials) assessed a surgical variable, 773 (73.7%) assessed adjuvant/neoadjuvant therapies, and 151 (14.4%) were observational studies. Of the trials assessing adjuvant therapies, systemic treatment (362 trials, 46.8%) and multimodal therapy (129 trials, 16.7%) comprised a large focus. Of the 125 trials where surgery was the intervention, 59 trials (47.2%) focused on surgical techniques or devices, 45 trials (36.0%) studied invasive diagnostic methods, and 21 trials (16.8%) evaluated surgery versus no surgery. The majority of the 125 trials were nonrandomized (72, 57.6%). CONCLUSIONS: The number of registered surgical oncology trials is small in comparison to oncology trials as a whole. Clinical trials specifically designed to assess surgical interventions are vastly outnumbered by trials focusing on adjuvant therapies. Randomized surgical oncology trials account for <1% of all registered cancer trials. Barriers to the design and implementation of randomized trials in surgical oncology need to be clarified in order to facilitate higher-level evidence in surgical decision making. PMID- 23800893 TI - Stressful life events and depression symptoms: the effect of childhood emotional abuse on stress reactivity. AB - OBJECTIVE: Stressful life events are associated with an increase in depressive symptoms and the onset of major depression. Importantly, research has shown that the role of stress changes over the course of depression. The present study extends the current literature by examining the effects of early life stress on emotional reactivity to current stressors. METHOD: In a multiwave study (N = 281, mean age = 18.76; 68% female), we investigated the proximal changes that occur in depressive symptoms when individuals are faced with life stress and whether a history of childhood emotional abuse moderates this relationship. RESULTS: Results support the stress sensitivity hypothesis for early emotional abuse history. Individuals with greater childhood emotional abuse severity experienced greater increases in depressive symptoms when confronted with current dependent stressors, controlling for childhood physical and sexual abuse. CONCLUSIONS: This study highlights the importance of emotional abuse as an indicator for reactivity to stressful life events. PMID- 23800895 TI - Associations between genetic polymorphisms of epidermal growth factor receptor (EGFR) and survival of colorectal cancer (CRC) patients treated with 5 fluorouracil-based chemotherapy. AB - PURPOSE: This retrospective cohort study investigated the association between epidermal growth factor receptor (EGFR) polymorphisms and clinical outcomes in colorectal cancer (CRC) patients treated with 5-fluorouracil (5-FU)-based chemotherapy. METHODS: We genotyped 3 EGFR polymorphisms including R497K, G-216T, and the (CA)n repeat, among 499 histologically confirmed CRC patients who had received 5-FU-based chemotherapy after surgery between 1995 and 2001. Survival analyses of EGFR polymorphisms were performed by the log rank test and Kaplan Meier curves. We used the Cox proportional hazard model to evaluate the association between EGFR genotypes and clinical outcomes. Stratification analysis by gender, tumor stage, and subsite were also carried out. RESULTS: CRC patients with the EGFR (CA)n L/L genotype compared to those with the S/S+S/L genotype had a significantly better overall survival (L, >= 20 repeats; S, <20 repeats) (hazard ratio (HR) 0.74; 95 % confidence interval (CI) 0.57-0.95), particularly for patients who were male (HR 0.63; 95 % CI 0.44-0.90), who had stage IV disease (HR 0.70; 95 % CI 0.49-0.99), and who had rectal cancer (HR 0.62; 95 % CI 0.42 0.92). Better survival was prominent among patients with the combined genotypes of EGFR (CA)n L/L, G-216T G/G, and R497K K/K (HR 0.51; 95 % CI 0.30-0.87), compared to those with the most common genotypes of the EGFR (CA)n S allele, G 216T G/G, and R497K R allele. CONCLUSIONS: EGFR polymorphisms can serve as prognostic predictors for CRC patients receiving 5-FU-based chemotherapy. PMID- 23800896 TI - Prediction of disease-free survival in hepatocellular carcinoma by gene expression profiling. AB - BACKGROUND: Progression of hepatocellular carcinoma (HCC) often leads to vascular invasion and intrahepatic metastasis, which correlate with recurrence after surgical treatment and poor prognosis. The molecular prognostic model that could be applied to the HCC patient population in general is needed for effectively predicting disease-free survival (DFS). METHODS: A cohort of 286 HCC patients from South Korea and a second cohort of 83 patients from Hong Kong, China, were used as training and validation sets, respectively. RNA extracted from both tumor and adjacent nontumor liver tissues was subjected to microarray gene expression profiling. DFS was the primary clinical end point. Gradient lasso algorithm was used to build prognostic signatures. RESULTS: High-quality gene expression profiles were obtained from 240 tumors and 193 adjacent nontumor liver tissues from the training set. Sets of 30 and 23 gene-based DFS signatures were developed from gene expression profiles of tumor and adjacent nontumor liver, respectively. DFS gene signature of tumor was significantly associated with DFS in an independent validation set of 83 tumors (P = 0.002). DFS gene signature of nontumor liver was not significantly associated with DFS in the validation set (P = 0.827). Multivariate analysis in the validation set showed that DFS gene signature of tumor was an independent predictor of shorter DFS (P = 0.018). CONCLUSIONS: We developed and validated survival gene signatures of tumor to successfully predict the length of DFS in HCC patients after surgical resection. PMID- 23800897 TI - Chemoradiotherapy before and after surgery for locally advanced esophageal cancer: a SEER-Medicare analysis. AB - PURPOSE: The optimal combination and timing of therapy for esophageal cancer remains controversial. The Surveillance, Epidemiology, and End Results (SEER) Medicare registry was used to assess neoadjuvant and adjuvant therapy. METHODS: Patients diagnosed with nonmetastatic T3+ or N1+ esophageal adenocarcinoma (ACA) or squamous cell carcinoma (SCC) from 1995 to 2002 who underwent surgical resection within 6 months of diagnosis were studied. Medicare data defined preoperative chemoradiotherapy (preCRT), preoperative radiotherapy (preRT), postoperative CRT (postCRT), chemotherapy and surgery (CT + S), and surgery alone. RESULTS: Of 419 eligible patients, 126 received preCRT, 55 preRT, 40 postCRT, 29 CT + S, and 169 surgery alone. PreCRT yielded median overall survival (OS) of 37 months, greater than surgery alone (17 months, p = 0.002) and postCRT (17 months, p = 0.06). PreRT (20 months, p = 0.20), postCRT (p = 0.88), and CT + S (20 months, p = 0.42) were not associated with OS benefit versus surgery alone. For SCC, preCRT improved survival versus surgery alone (p = 0.01), with a trend for ACA (p = 0.07). ACA (22 months) had greater OS than SCC (17 months) (p = 0.03). ACA, younger age, and married status were associated with increased OS. Adjusting for these, preCRT had longer OS versus surgery alone (p = 0.02) and postCRT (p = 0.03). Chemotherapy agents and surgical approach did not affect OS. CONCLUSIONS: In the SEER-Medicare cohort, preCRT significantly improved survival versus surgery alone and postCRT for locally advanced esophageal cancer, particularly for SCC. PreRT, postCRT, and CT + S were not associated with longer survival. PMID- 23800898 TI - Malignant peritoneal mesothelioma treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: is GLUT1 expression a major prognostic factor? A preliminary study. AB - PURPOSE: Diffuse malignant peritoneal mesothelioma (DMPM) is a rare primary peritoneal malignancy. Its prognosis has been improved by an aggressive locoregional treatment combining extensive cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Prognostic factors are currently poorly defined for this disease but are essential if treatment is to be standardized. METHODS: Twenty-eight patients with DMPM, who were considered preoperatively to be candidates for CRS and HIPEC between June 1998 and August 2010 at our institution, were selected for this study. Medical records and histopathological features were retrospectively reviewed and 24 clinical, histological, and immunohistochemical parameters were assessed for their association with overall survival by univariate and multivariate analyses. RESULTS: The following factors were significantly associated with overall survival by univariate analysis: predominant histological growth pattern in the epithelioid areas, nuclear grooves in the epithelioid areas, atypical mitoses, and calretinin and GLUT1 expression by immunohistochemistry in the epithelioid areas. Expression of the facilitative glucose transporter protein GLUT1 in the epithelioid areas was the only factor independently associated with overall survival by multivariate analysis. CONCLUSIONS: GLUT1 expression appears to be an indicator of poor prognosis in DMPM. Standard histological classification of DMPM may not be adequate to select patients for aggressive locoregional treatments, such as CRS and HIPEC. Multicenter validation of the prognostic factors identified in this preliminary study is needed to refine patient selection for potential cure. PMID- 23800899 TI - Obesity and peritoneal surface disease: outcomes after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for appendiceal and colon primary tumors. AB - BACKGROUND: It is estimated that 37% of the U.S. population is obese. It is unknown how obesity influences the operative and survival outcomes of cytoreductive surgery (CRS)/hyperthermic intraperitoneal chemotherapy (HIPEC) procedures. METHODS: A retrospective analysis of a prospective database of 1,000 procedures was performed. Type of malignancy, performance status, resection status, hospital and intensive care unit stay, comorbidities, morbidity, mortality, and survival were reviewed. RESULTS: A total of 246 patients with body mass index (BMI) of >30 kg/m(2) underwent 272 CRS/HIPEC procedures. Ninety-five (38.6%) were severely obese (BMI > 35 kg/m(2)). A total of 135 (49.6%) procedures were performed for appendiceal and 60 (22.1%) for colon cancer. Median follow-up was 52 months. Both major and minor morbidity were similar for obese and non obese patients. The 30-day mortality rates for obese and non-obese patients were 1.5 and 2.5%, respectively. Median intensive care unit and hospital stay were 1 and 9 days, regardless of BMI. The 30-day readmission rate was similar between obese and non-obese patients (24.8 vs. 19.4%, p = 0.11). Median survival for low grade appendiceal cancer (LGA) was 76 months for obese patients and 107 months for non-obese patients (p = 0.32). Survival was worse for severely obese patients (median survival 54 months) versus non-obese patients with LGA (p = 0.04). Survival was similar for obese and non-obese patients with peritoneal surface disease (PSD) from colon cancer or high-grade appendiceal cancer. CONCLUSIONS: Obesity does not influence postoperative morbidity or mortality of patients with PSD, regardless of primary tumor. Severe obesity is associated with decreased long-term survival only in patients with LGA primary disease; however, application of CRS/HIPEC still offers meaningful prolongation of life. Obesity should not be considered a contraindication for CRS/HIPEC procedures. PMID- 23800900 TI - The blaCTX-M-1 IncI1/ST3 plasmid is dominant in chickens and pets in Tunisia. PMID- 23800901 TI - Population pharmacokinetics and dosing simulations of amoxicillin/clavulanic acid in critically ill patients. AB - OBJECTIVES: The objective of this study was to investigate the population pharmacokinetics and pharmacodynamics of amoxicillin and clavulanic acid in critically ill patients. METHODS: In this observational pharmacokinetic study, multiple blood samples were taken over one dosing interval of intravenous amoxicillin/clavulanic acid (1000/200 mg). Blood samples were analysed using a validated ultra HPLC-tandem mass spectrometry technique. Population pharmacokinetic analysis and dosing simulations were performed using non-linear mixed-effects modelling. RESULTS: One-hundred-and-four blood samples were collected from 13 patients. For both amoxicillin and clavulanic acid, a two compartment model with between-subject variability for both the clearance and the volume of distribution of the central compartment described the data adequately. For both compounds, 24 h urinary creatinine clearance was supported as a descriptor of drug clearance. The mean clearance of amoxicillin was 10.0 L/h and the mean volume of distribution was 27.4 L. For clavulanic acid, the mean clearance was 6.8 L/h and the mean volume of distribution was 19.2 L. Dosing simulations for amoxicillin supported the use of standard dosing regimens (30 min infusion of 1 g four-times daily or 2 g three-times daily) for most patients when using a target MIC of 8 mg/L and a pharmacodynamic target of 50% fT>MIC, except for those with a creatinine clearance >190 mL/min. Dosing simulations for clavulanic acid showed little accumulation when high doses were administered to patients with high creatinine clearance. CONCLUSIONS: Although vast pharmacokinetic variability exists for both amoxicillin and clavulanic acid in intensive care unit patients, current dosing regiments are appropriate for most patients, except those with very high creatinine clearance. PMID- 23800902 TI - MRSA decolonization of cotton rat nares by a combination treatment comprising lysostaphin and the antimicrobial peptide ranalexin. AB - OBJECTIVES: To evaluate the in vivo effectiveness of a combination treatment containing ranalexin (a natural antimicrobial peptide) and lysostaphin (an antistaphylococcal endopeptidase) for reducing nasal burden of methicillin resistant Staphylococcus aureus (MRSA). METHODS: The community-acquired MRSA strain S. aureus NRS384 (USA300-0114) was used in the present study because it is commonly isolated from human nares and it established consistent and reproducible colonization of cotton rat nares. This model was used to evaluate the efficacy of ranalexin/lysostaphin gels (0.1%-1% w/v; administered intranasally once or once per day for 3 consecutive days) for reducing nasal MRSA burden. Control animals were administered vehicle gel only (0.5% hydroxypropyl methylcellulose) or 2% mupirocin, which is used clinically for nasal decolonization of MRSA. Nasal MRSA burden was assessed at 192 h post-inoculation, which was at least 72 h after the final treatment had been administered. An additional study assessed the efficacy of 0.1% ranalexin/lysostaphin against a mupirocin-resistant MRSA strain (MUP20), which had been selected by serial passage of S. aureus NRS384 through subinhibitory concentrations of mupirocin. RESULTS: Gels containing 0.1% ranalexin/lysostaphin consistently reduced median nasal burden of MRSA to an extent similar to or greater than 2% mupirocin. Treatment with 0.1% ranalexin/lysostaphin was also effective against the MUP20 strain. There was evidence for only minimal irritancy in cotton rat nares administered three doses of 0.1% ranalexin/lysostaphin, suggesting that this agent is suitable for short course therapy such as is employed currently for nasal decolonization with mupirocin. CONCLUSIONS: Ranalexin/lysostaphin could serve as an alternative to mupirocin for nasal decolonization of MRSA. PMID- 23800903 TI - A systematic review of antibiotic utilization in China. AB - OBJECTIVES: Reliable data about antibiotic utilization in the large pharmaceutical market of the world's most populous country, the People's Republic of China, are in short supply. Although many primary studies have investigated the use of antibiotics in China, most of the relevant studies were published in the Chinese language. This systematic review aims to summarize reported percentages of outpatient encounters resulting in the prescription of antibiotics in China. METHODS: We systematically searched and reviewed studies of antibiotic prescribing patterns in China, published in Chinese or English between 2000 and August 2012. The study quality was assessed and the overall percentage of outpatient encounters resulting in the prescription of antibiotics was calculated using random-effects meta-analysis. Subgroup analyses were conducted to investigate heterogeneity across studies. RESULTS: We included 57 eligible studies (with a total of 556 ,435 outpatient encounters). The overall percentage of outpatients prescribed antibiotics was 50.3% (95% CI: 47.4%-53.1%). Of the outpatients prescribed antibiotics, 74.0% (95% CI: 71.3%-76.6%) were prescribed one antibiotic, 23.3% (95% CI: 21.1%-25.7%) were prescribed two antibiotics and 2.0% (95% CI: 1.3%-2.8%) were prescribed three or more antibiotics. The proportion of antibiotic utilization differed greatly across hospital levels and geographical regions and fluctuated over time. CONCLUSIONS: The percentage use of antibiotics is high in China. The excessive use of antibiotics is particularly more problematic in lower-level hospitals and in less developed western China. The implementation and impact of the national efforts to control the excessive use of antibiotics should be appropriately evaluated. PMID- 23800905 TI - A new regimen for continuous infusion of vancomycin during continuous renal replacement therapy. AB - INTRODUCTION: Continuous infusion (CI) of high-dose vancomycin is often used to treat life-threatening infections caused by less-susceptible Gram-positive bacteria. However, this approach has not been well studied in patients on continuous renal replacement therapy (CRRT). The aim of this study was to evaluate the adequacy of a new CI vancomycin regimen in septic patients undergoing CRRT. METHODS: In this prospective study we measured vancomycin concentrations obtained with a new CI regimen for CRRT, which included a loading dose of 35 mg/kg given over a 4 h period followed by a daily dose of 14 mg/kg. Vancomycin concentrations were measured: at the end of the loading dose (T1); 12 h after the onset of therapy (T2); and 24 h after the onset of therapy (T3). Drug concentrations (at T2 and T3) were considered adequate if between 20 and 30 mg/L. CRRT intensity was calculated as: dialysate rate (mL/kg/h) + ultrafiltration rate (mL/kg/h). Vancomycin population pharmacokinetics were calculated using non linear mixed-effects modelling. RESULTS: We studied 32 patients who received median (IQR) loading and daily vancomycin doses of 2750 mg (2250-3150) and 1100 mg (975-1270), respectively. Drug concentrations were: T1, 44 mg/L (38-58); T2, 27 mg/L (24-31); and T3, 23 mg/L (19-31). Vancomycin concentrations were adequate in 22/32 patients (69%) at T2 and in 20/32 (63%) at T3. The two relevant covariates that significantly affected drug concentrations were body weight and CRRT intensity. CONCLUSIONS: This new vancomycin regimen allowed the rapid achievement of target drug concentrations in the majority of patients. CRRT intensity had an influence on vancomycin clearance. PMID- 23800904 TI - A high-throughput microfluidic dental plaque biofilm system to visualize and quantify the effect of antimicrobials. AB - OBJECTIVES: Few model systems are amenable to developing multi-species biofilms in parallel under environmentally germane conditions. This is a problem when evaluating the potential real-world effectiveness of antimicrobials in the laboratory. One such antimicrobial is cetylpyridinium chloride (CPC), which is used in numerous over-the-counter oral healthcare products. The aim of this work was to develop a high-throughput microfluidic system that is combined with a confocal laser scanning microscope (CLSM) to quantitatively evaluate the effectiveness of CPC against oral multi-species biofilms grown in human saliva. METHODS: Twenty-four-channel BioFlux microfluidic plates were inoculated with pooled human saliva and fed filter-sterilized saliva for 20 h at 37 degrees C. The bacterial diversity of the biofilms was evaluated by bacterial tag-encoded FLX amplicon pyrosequencing (bTEFAP). The antimicrobial/anti-biofilm effect of CPC (0.5%-0.001% w/v) was examined using Live/Dead stain, CLSM and 3D imaging software. RESULTS: The analysis of biofilms by bTEFAP demonstrated that they contained genera typically found in human dental plaque. These included Aggregatibacter, Fusobacterium, Neisseria, Porphyromonas, Streptococcus and Veillonella. Using Live/Dead stain, clear gradations in killing were observed when the biofilms were treated with CPC between 0.5% and 0.001% w/v. At 0.5% (w/v) CPC, 90% of the total signal was from dead/damaged cells. Below this concentration range, less killing was observed. In the 0.5%-0.05% (w/v) range CPC penetration/killing was greatest and biofilm thickness was significantly reduced. CONCLUSIONS: This work demonstrates the utility of a high-throughput microfluidic CLSM system to grow multi-species oral biofilms, which are compositionally similar to naturally occurring biofilms, to assess the effectiveness of antimicrobials. PMID- 23800906 TI - Reversion to susceptibility of a carbapenem-resistant clinical isolate of Klebsiella pneumoniae producing KPC-3. AB - OBJECTIVES: We report the case of a kidney-transplant patient, suffering an intra abdominal abscess at the surgical site caused by a carbapenem-resistant ST258 Klebsiella pneumoniae clone, producing the KPC-3 carbapenemase. Under tigecycline treatment, the patient developed a sepsis caused by a carbapenem-susceptible ST258 K. pneumoniae strain. Complete DNA sequences of the plasmids carried by the resistant and susceptible strains from this patient were determined. METHODS: The complete DNA sequences of plasmids were obtained by applying the 454 Genome Sequencer FLX-PLUS procedure on a library constructed of total plasmid DNA purified from the carbapenem-resistant and -susceptible strains. RESULTS: In the carbapenem-resistant strain, four plasmids encoding 24 resistance genes, including blaKPC-3, and two putative virulence clusters were detected. In the susceptible strain, large rearrangements occurred in the KPC-carrying plasmid, causing the deletion of the entire Tn4401::blaKPC-3 transposon, with the consequent reversion of the strain to carbapenem susceptibility. The patient was successfully treated with carbapenems and fully recovered. CONCLUSIONS: The description of the plasmid content in these two strains gives interesting insights into the plasticity of KPC-carrying plasmids in K. pneumoniae. PMID- 23800909 TI - The cover. The dance. PMID- 23800911 TI - Behring's new method of inoculation against diphtheria. PMID- 23800912 TI - IOM report: Evidence fails to support guidelines for dietary salt reduction. PMID- 23800913 TI - Avoiding hypoglycemia at all costs is crucial for some with diabetes. PMID- 23800914 TI - Continuing antithrombotics advised for stroke survivors during certain procedures. PMID- 23800915 TI - CDC probes new outbreak associated with compounded steroids. PMID- 23800925 TI - Fibrosis and mortality in patients with dilated cardiomyopathy. PMID- 23800926 TI - Fibrosis and mortality in patients with dilated cardiomyopathy. PMID- 23800927 TI - Fibrosis and mortality in patients with dilated cardiomyopathy--reply. PMID- 23800928 TI - Overuse of emergency departments. PMID- 23800929 TI - Overuse of emergency departments--reply. PMID- 23800930 TI - Prevalence and correlates of traumatic brain injuries among adolescents. PMID- 23800933 TI - A piece of my mind. Cocktail party nephrology. PMID- 23800934 TI - Aspirin use and risk of colorectal cancer according to BRAF mutation status. AB - IMPORTANCE: Aspirin use reduces the risk of colorectal carcinoma. Experimental evidence implicates a role of RAF kinases in up-regulation of prostaglandin endoperoxide synthase 2 (PTGS2, cyclooxygenase 2), suggesting that BRAF-mutant colonic cells might be less sensitive to the antitumor effects of aspirin than BRAF-wild-type neoplastic cells. OBJECTIVE: To examine whether the association of aspirin intake with colorectal cancer risk differs according to status of tumor BRAF oncogene mutation. DESIGN AND SETTING: We collected biennial questionnaire data on aspirin use and followed up participants in the Nurses' Health Study (from 1980) and the Health Professionals Follow-up Study (from 1986) until July 1, 2006, for cancer incidence and until January 1, 2012, for cancer mortality. Duplication-method Cox proportional cause-specific hazards regression for competing risks data was used to compute hazard ratios (HRs) for colorectal carcinoma incidence according to BRAF mutation status. MAIN OUTCOMES AND MEASURES: Incidence of colorectal cancer cases according to tumor BRAF mutation status. RESULTS: Among 127,865 individuals, with 3,165,985 person-years of follow up, we identified 1226 incident rectal and colon cancers with available molecular data. Compared with nonuse, regular aspirin use was associated with lower BRAF wild-type cancer risk (multivariable HR, 0.73; 95% CI, 0.64 to 0.83; age-adjusted incidence rate difference [RD], -9.7; 95% CI, -12.6 to -6.7 per 100,000 person years). This association was observed irrespective of status of tumor PTGS2 expression or PIK3CA or KRAS mutation. In contrast, regular aspirin use was not associated with a lower risk of BRAF-mutated cancer (multivariable HR, 1.03; 95% CI, 0.76 to 1.38; age-adjusted, incidence RD, 0.7; 95% CI, -0.3 to 1.7 per 100,000 person-years: P for heterogeneity = .037, between BRAF-wild-type vs BRAF mutated cancer risks). Compared with no aspirin use, aspirin use of more than 14 tablets per week was associated with a lower risk of BRAF-wild-type cancer (multivariable HR, 0.43; 95% CI, 0.25 to 0.75; age-adjusted incidence RD, -19.8; 95% CI, -26.3 to -13.3 per 100,000 person-years). The relationship between the number of aspirin tablets per week and colorectal cancer risk differed significantly by BRAF mutation status (P for heterogeneity = .005). CONCLUSIONS AND RELEVANCE: Regular aspirin use was associated with lower risk of BRAF-wild type colorectal cancer but not with BRAF-mutated cancer risk. These findings suggest that BRAF-mutant colon tumor cells may be less sensitive to the effect of aspirin. Given the modest absolute risk difference, further investigations are necessary to determine clinical implications of our findings. PMID- 23800935 TI - Use of advanced treatment technologies among men at low risk of dying from prostate cancer. AB - IMPORTANCE: The use of advanced treatment technologies (ie, intensity-modulated radiotherapy [IMRT] and robotic prostatectomy) for prostate cancer is increasing. The extent to which these advanced treatment technologies have disseminated among patients at low risk of dying from prostate cancer is uncertain. OBJECTIVE: To assess the use of advanced treatment technologies, compared with prior standards (ie, traditional external beam radiation treatment [EBRT] and open radical prostatectomy) and observation, among men with a low risk of dying from prostate cancer. DESIGN, SETTING, AND PATIENTS: Using Surveillance, Epidemiology, and End Results (SEER)-Medicare data, we identified a retrospective cohort of men diagnosed with prostate cancer between 2004 and 2009 who underwent IMRT (n = 23,633), EBRT (n = 3926), robotic prostatectomy (n = 5881), open radical prostatectomy (n = 6123), or observation (n = 16,384). Follow-up data were available through December 31, 2010. MAIN OUTCOMES AND MEASURES: The use of advanced treatment technologies among men unlikely to die from prostate cancer, as assessed by low-risk disease (clinical stage <=T2a, biopsy Gleason score <=6, and prostate-specific antigen level <=10 ng/mL), high risk of noncancer mortality (based on the predicted probability of death within 10 years in the absence of a cancer diagnosis), or both. RESULTS: In our cohort, the use of advanced treatment technologies increased from 32% (95% CI, 30%-33%) to 44% (95% CI, 43%-46%) among men with low-risk disease (P < .001) and from 36% (95% CI, 35%-38%) to 57% (95% CI, 55%-59%) among men with high risk of noncancer mortality (P < .001). The use of these advanced treatment technologies among men with both low-risk disease and high risk of noncancer mortality increased from 25% (95% CI, 23%-28%) to 34% (95% CI, 31%-37%) (P < .001). Among all patients diagnosed in SEER, the use of advanced treatment technologies for men unlikely to die from prostate cancer increased from 13% (95% CI, 12%-14%), or 129.2 per 1000 patients diagnosed with prostate cancer, to 24% (95% CI, 24%-25%), or 244.2 per 1000 patients diagnosed with prostate cancer (P < .001). CONCLUSION AND RELEVANCE: Among men diagnosed with prostate cancer between 2004 and 2009 who had low-risk disease, high risk of noncancer mortality, or both, the use of advanced treatment technologies has increased. PMID- 23800936 TI - Vulvar swelling, plaques, and nodules in a young adult woman. PMID- 23800937 TI - Differential effects of aspirin before and after diagnosis of colorectal cancer. PMID- 23800938 TI - JAMA patient page. Ciguatera fish poisoning. PMID- 23800939 TI - Spray deposition of water-soluble multiwall carbon nanotube and Cu2ZnSnSe4 nanoparticle composites as highly efficient counter electrodes in a quantum dot sensitized solar cell system. AB - In this paper, low-cost counter electrodes (CEs) based on water-soluble multiwall carbon nanotube (MWCNT) and Cu2ZnSnSe4 nanoparticle (CZTSe NP) composites have been successfully introduced into a quantum dot-sensitized solar cell (QDSC) system. Suitable surface modification allows the MWCNTs and CZTSe NPs to be homogeneously dispersed in water, facilitating the subsequent low-temperature spray deposition of high quality composite films with different composite ratios. The electrochemical catalytic activity of the composite CEs has been critically compared by electrochemical impedance spectroscopy and Tafel-polarization analysis. It is found that the composite CE at the MWCNT : CZTSe ratio of 0.1 offers the best performance, leading to an optimal solar cell efficiency of 4.60%, which is 50.8% higher than that of the Pt reference CE. The as demonstrated higher catalytic activity of the composite CEs compared to their single components could be ascribed to the combination of the fast electron transport of the MWCNTs and the high catalytic activity of CZTSe NPs. PMID- 23800940 TI - Exchange transfusion for severe malaria: evidence base and literature review. AB - BACKGROUND: Exchange transfusion (ET) has biologic plausibility as an adjunct to antimalarial drugs in treating severe malaria and has been used for decades despite limited evidence of its efficacy in improving survival. We examined the efficacy of ET as an adjunct treatment for severe malaria using US surveillance data and reviewed the literature to update recommendations. METHODS: Patients with severe malaria reported to the US national malaria surveillance system during 1985-2010 were matched, and survival outcomes were compared between patients receiving and not receiving ET. The literature review used search terms "severe malaria" and "exchange transfusion." Case reports and series, observational and case-control studies, and meta-analysis were included. RESULTS: One hundred one patients receiving ET were matched to 314 patients not receiving ET. There was no statistically significant association between ET and survival outcome (odds ratio, 0.84; 95% confidence interval, .44-1.60). We found 87 articles, mostly case reports or series, showing successful use of ET, likely reporting bias. There were 12 comparative studies, most of which were retrospective cohort studies, underpowered with no significant differences in survival. A previously published meta-analysis of 8 comparative studies found no significant survival differences. Adverse events were rarely reported but included acute respiratory distress syndrome, ventricular fibrillation, and hypotension. CONCLUSIONS: Despite rapid parasite clearance times resulting from ET, there is no evidence for efficacy of ET as adjunctive therapy in severe malaria. Adjunct ET cannot be recommended. When rapidly acting antimalarials, specifically artemisinins, become more widely available, the biologic plausibility argument for ET will become less relevant. PMID- 23800941 TI - Identification of a major locus, TNF1, that controls BCG-triggered tumor necrosis factor production by leukocytes in an area hyperendemic for tuberculosis. AB - BACKGROUND: Tumor necrosis factor (TNF) is a key immune regulator of tuberculosis resistance, as exemplified by the highly increased risk of tuberculosis disease among individuals receiving TNF-blocker therapy. METHODS: We determined the extent of TNF production after stimulation with BCG or BCG plus interferon gamma (IFN-gamma) using a whole blood assay in 392 children belonging to 135 nuclear families from an area hyperendemic for tuberculosis in South Africa. We conducted classical univariate and bivariate genome-wide linkage analysis of TNF production using the data from both stimulation protocols by means of an extension of the maximum-likelihood-binomial method for quantitative trait loci to multivariate analysis. RESULTS: Stimulation of whole blood by either BCG or BCG plus IFN-gamma resulted in a range of TNF release across subjects. Extent of TNF production following both stimulation protocols was highly correlated (r = 0.81). We failed to identify genetic linkage of TNF release when considering each stimulus separately. However, using a multivariate approach, we detected a major pleiotropic locus (P < 10(-5)) on chromosome region 11p15, termed TNF locus 1 (TNF1), that controlled TNF production after stimulation by both BCG alone and BCG plus IFN-gamma. CONCLUSIONS: The TNF1 locus was mapped in the vicinity of the TST1 locus, previously identified in the same family sample, that controls tuberculin skin test (TST) negativity per se, that is, T-cell-independent resistance to Mycobacterium tuberculosis infection. This suggested that there is a connection between TST negativity per se and TNF production. PMID- 23800942 TI - HIV incidence among men with and those without sexually transmitted rectal infections: estimates from matching against an HIV case registry. AB - BACKGROUND: Sexually transmitted bacterial rectal infections are objective markers of HIV risk behavior. Quantifying HIV risk among men who have sex with men (MSM) who have had these infections can inform prevention efforts. We measured HIV risk among MSM who have and those who have not been diagnosed with rectal Chlamydia trachomatis (CT) and/or rectal Neisseria gonorrhoeae (GC). METHODS: HIV incidence among a cohort of 276 HIV-negative MSM diagnosed with rectal CT and/or GC in New York City sexually transmitted disease (STD) clinics was compared to HIV incidence among HIV-negative MSM without these infections. Matches against the citywide HIV/AIDS registry identified HIV diagnoses from STD clinics, and by other providers. Cox proportional hazards models were used to explore factors associated with HIV acquisition among MSM with rectal infections. RESULTS: HIV-negative MSM with rectal infections (>70% of which were asymptomatic) contributed 464.7 person-years of follow-up. Among them, 31 (11.2%) were diagnosed with HIV, of whom 14 (45%) were diagnosed by non-STD clinic providers. The annual HIV incidence was significantly higher among MSM with rectal infections (6.67%; 95% confidence interval [CI], 4.61%-9.35%) than among MSM without rectal infections (2.53%; 95% CI, 1.31%-4.42%). Black race (hazard ratio, 4.98; 95% CI, 1.75-14.17) was associated with incident HIV among MSM with rectal CT/GC. CONCLUSIONS: One in 15 MSM with rectal infections was diagnosed with HIV within a year, a higher risk than for MSM without rectal infections. Such data have implications for screening for rectal STD, and may be useful for targeting populations for risk-reduction counseling and other HIV prevention strategies, such as preexposure prophylaxis. PMID- 23800943 TI - Association of glucokinase regulatory gene polymorphisms with risk and severity of non-alcoholic fatty liver disease: an interaction study with adiponutrin gene. AB - BACKGROUND: Recent genome-wide association studies demonstrated an association between single nucleotide polymorphisms (SNPs) on the glucokinase regulatory gene (GCKR) with hepatic steatosis. This study attempted to investigate the association of GCKR rs780094 and rs1260326 with susceptibility to non-alcoholic fatty liver disease (NAFLD) and its severity. METHODS: The genotypes were assessed on 144 histologically confirmed NAFLD patients and 198 controls using a Sequenom MassARRAY platform. RESULTS: The GCKR rs1260326 and rs780094 allele T were associated with susceptibility to NAFLD (OR 1.49, 95 % CI 1.09-2.05, p = 0.012; and OR 1.51, 95 % CI 1.09-2.09, p = 0.013, respectively), non-alcoholic steatohepatitis (NASH) (OR 1.55, 95 % CI 1.10-2.17, p = 0.013; and OR 1.56, 95 % CI 1.10-2.20, p = 0.012, respectively) and NASH with significant fibrosis (OR 1.50, 95 % CI 1.01-2.21, p = 0.044; and OR 1.52, 95 % CI 1.03-2.26, p = 0.038, respectively). Following stratification by ethnicity, significant association was seen in Indian patients between the two SNPs and susceptibility to NAFLD (OR 2.64, 95 % CI 1.28-5.43, p = 0.009; and OR 4.35, 95 % CI 1.93-9.81, p < 0.0001, respectively). The joint effect of GCKR with adiponutrin rs738409 indicated greatly increased the risk of NAFLD (OR 4.14, 95 % CI 1.41-12.18, p = 0.010). Histological data showed significant association of GCKR rs1260326 with high steatosis grade (OR 1.76, 95 % CI 1.08-2.85, p = 0.04). CONCLUSION: This study suggests that risk allele T of the GCKR rs780094 and rs1260326 is associated with predisposition to NAFLD and NASH with significant fibrosis. The GCKR and PNPLA3 genes interact to result in increased susceptibility to NAFLD. PMID- 23800944 TI - miR-874 Inhibits cell proliferation, migration and invasion through targeting aquaporin-3 in gastric cancer. AB - BACKGROUND: Aquaporin-3 (AQP3) is a water transporting protein which plays an oncogenic role in several malignant tumors. However, its regulatory mechanism remains elusive to date. In this study, we investigated the microRNA-mediated gene repression mechanism involved in AQP3's role. METHODS: The potential microRNAs targeting AQP3 were searched via bioinformatic methods and identified by luciferase reporter assays, microRNA RT-PCR and western blotting. The expression patterns of miR-874 and AQP3 in human gastric cancer (GC) specimens and cell lines were determined by microRNA RT-PCR and western blotting. 5-ethynyl 2'-deoxyuridine, cell migration and invasion assays and tumorigenicity in vivo were adopted to observe the effects of miR-874 depletion or ectopic miR-874 expression on GC cell phenotypes. Cell apoptosis was evaluated by FACS and TUNEL in vitro and in vivo respectively. RESULTS: miR-874 suppressed AQP3 expression by binding to the 3'UTR of AQP3 mRNA in GC cells. miR-874 was significantly down regulated and reversely correlated with AQP3 protein levels in clinical samples. Analysis of the clinicopathological significance showed that miR-874 and AQP3 were closely correlated with GC characteristics. Functional analyses indicated that ectopic miR-874 expression suppressed the growth, migration, invasion and tumorigenicity of GC cells, whereas miR-874 knockdown promoted these phenotypes. Down-regulation of Bcl-2, MT1-MMP, MMP-2 and MMP-9 and upregulation of caspase-3 activity and Bax were involved in miR-874 inducing cell apoptosis, and inhibiting migration and invasion. CONCLUSIONS: These results provide a mechanism by which AQP3 is upregulated, as well as highlight the importance of miR-874 in gastric cancer development and progression. PMID- 23800945 TI - Bofutsushosan, a Japanese herbal (Kampo) medicine, attenuates progression of nonalcoholic steatohepatitis in mice. AB - BACKGROUND: Obesity-induced liver disease (nonalcoholic fatty liver disease, NAFLD) is now the commonest cause of chronic liver disease in affluent nations. There are presently no proven treatments for NAFLD or its more severe stage, nonalcoholic steatohepatitis (NASH). Bofutsushosan (BTS), a Japanese herbal (Kampo) medicine, long used as an anti-obesity medicine in Japan and other Asian countries, has been shown to reduce body weight and improve insulin resistance (IR) and hepatic steatosis. The precise mechanism of action of BTS, however, remains unclear. To evaluate the ability of BTS to prevent the development of NASH, and determine the mediators and pathways involved. METHODS: C57BL/6 mice were injected intra-peritoneally with gold-thioglucose and fed a high-fat diet (HF) or HF diet admixed with either 2 or 5 % BTS for 12 weeks. The effectiveness of BTS in attenuating features of NASH and the mechanisms through which BTS attenuated NASH were then assayed through an assessment of the anthropometric, radiological, biochemical and histological parameters. RESULTS: BTS attenuated the progression of NASH through induction of adiponectin and its receptors along with an induction of PPAR-alpha and PPAR-gamma, decreased expression of SREBP-1c, increased hepatic fatty acid oxidation and increased hepatic export of triglycerides. BTS moreover, reduced IR through phosphorylation of the protein kinase, Akt. CONCLUSIONS: BTS through induction of adiponectin signaling and Akt attenuated development of NASH. Identification of the active entity in BTS should allow development of novel treatments for NASH. PMID- 23800946 TI - Efficacy of spraying l-menthol solution during endoscopic treatment of early gastric cancer: a phase III, multicenter, randomized, double-blind, placebo controlled study. AB - BACKGROUND: The topical antispasmodic agent l-menthol is useful for inhibiting gastric peristalsis during diagnostic upper gastrointestinal endoscopy. However, it remains unclear whether l-menthol is similarly effective during therapeutic endoscopy, thereby improving treatment outcomes in a clinical setting. METHODS: A total of 83 patients scheduled to undergo endoscopic treatment at 8 Japanese referral centers were randomly assigned to receive l-menthol or placebo. The degree of gastric peristalsis (peristaltic score: grade 1-5) was assessed by an independent committee. The primary outcome was the proportion of subjects in whom no or mild peristalsis (grade 1 or 2) was maintained throughout endoscopic treatment. Secondary outcomes were the duration of sustained response and the incidence of adverse drug reactions. RESULTS: The proportion of patients with no or mild peristalsis was significantly higher in the l-menthol group (85.4 %, 95 % confidence intervals 70.8-94.4: 35/41 subjects) than in the placebo group (39.0 %, 24.2-55: 16/41; P < 0.001). The sustained response rates in the l-menthol and the placebo were, respectively, 90.0 and 39.6 % 30 min post-dose, and 79.9 and 35.7 % at the completion of the resection. The sustained response rates were significantly higher in the l-menthol group than in the placebo group (P < 0.001, log-rank test). The incidence of adverse drug reactions did not differ significantly between the two groups (P = 1.000). CONCLUSIONS: During gastric endoscopic submucosal dissection, spraying l-menthol on the gastric mucosa significantly suppressed peristalsis, with minimal adverse drug reactions as compared with placebo. l-menthol solution might be useful for therapeutic endoscopy. PMID- 23800947 TI - [Early repolarisation. A dilemma of risk stratification]. AB - Early repolarization, involving infero-lateral ST segment elevation and prominent J waves at the QRS-ST junction has been considered a normal ECG variant for more than 80 years. More recent studies suggest that this phenomenon is not as benign as earlier believed and may represent a risk for subsequent ventricular fibrillation in patients with and without structural heart disease. However, based on current data it seems unjustified to consider these often accidental ECG findings a marker for high risk of sudden cardiac death. The concept of a reduced repolarization reserve developed for the Long QT syndrome can be transformed to early repolarization syndrome. In general a "fibrillation reserve" is relatively high but if triggers such as a genetic background, age, gender, influences of the autonomous nervous system, changes in body temperature, or an acute coronary syndrome act together ventricular fibrillation may occur. A combination of an "early repolarization ECG" with syncope and/or a positive family history of sudden cardiac death may justify defibrillator therapy just on an individual basis. This review intends to summarize actual aspects of early repolarizations syndrome and focuses on the dilemma of risk stratification. PMID- 23800948 TI - Life-threatening subcapsular renal hematoma after flexible ureteroscopic laser lithotripsy: treatment with superselective renal arterial embolization. PMID- 23800949 TI - Characteristics and requirements of basal autophagy in HEK 293 cells. AB - Basal autophagy-here defined as macroautophagic activity during cellular growth in normal medium containing amino acids and serum-appears to be highly active in many cell types and in animal tissues. Here we characterized this pathway in mammalian HEK 293 cells. First, we examined, side by side, three compounds that are widely used to reveal basal autophagy by blocking maturation of autophagosomes: bafilomycin A 1 (BafA1), chloroquine and vinblastine. Only BafA1 appeared to be without complicating side effects. Chloroquine partially inhibited mechanistic target of rapamycin (MTOR) activity, which would induce autophagy induction as well as block autophagosome maturation. Vinblastine caused the distribution of early omegasome components into punctate phagophore assembly sites, and therefore it would also induce autophagy, complicating interpretation. Basal autophagy was significantly sensitive to inhibition by wortmannin, and therefore required formation of phosphatidylinositol 3-phosphate (PtdIns3P), but it was twice as resistant to wortmannin as starvation-induced autophagy. We also determined that basal autophagy was significantly suppressed by MTOR activation brought about by overexpression of RHEB or activated RAGs. Finally we investigated the spatial relationship of nascent autophagosomes to the endoplasmic reticulum (ER) or to mitochondria by live imaging experiments under conditions that reveal basal autophagy (with BafA1 treatment), or upon MTOR inactivation (which would result in autophagy induction). Side-by-side comparison showed that under both basal and induced autophagy, 100% of autophagosomes first appeared in close proximity to ER strands. In parallel measurements, 40% were in close proximity to mitochondria under both conditions. We concluded that in HEK 293 cells, basal autophagy is mechanistically similar to that induced by MTOR inactivation in all aspects examined. PMID- 23800950 TI - Morphological and genetic characteristics of newly crossbred cauliflower mushroom (Sparassis latifolia). AB - Cauliflower mushroom (Sparassis latifolia or S. crispa) is popular for food and medicine. Importance of new varieties of Sparassis was raised and studied widely by protection system of UPOV. In this study, 10 crossbred strains of Sparassis latifolia that specifically expressed distinctive features during basidiocarp formation and mycelium growth were applied to sawdust medium inoculated with S. latifolia mycelia. The 10 crossbred strains were divided into 3 groups on the basis of morphological (size of marginal wave and basidiocarp color) and genetic characteristics. Each phenotype of the parent and crossbred strains represented 3 marginal wave-sizes (large, medium, and small) and 3 color notations (NN155D, 163C, and 8D). Our result suggests that morphological characteristics of cauliflower mushroom can be affected by various environmental and genetic stimuli under artificial conditions such as crossbreed. Also this research showed genetic differences among breeding isolates and their morphological characteristics were correlated with the molecular data within parent and crossed strain. PMID- 23800951 TI - Involvement of phosphatidylinositol 3-Kinase/Akt signaling pathway in beta1 integrin-mediated internalization of Staphylococcus aureus by alveolar epithelial cells. AB - The invasion of Staphylococcus aureus into alveolar epithelial cells is regarded as the key step for S. aureus lung infection. However, the mechanism of internalization of S. aureus by alveolar epithelial cells is not clear, and was the aim of this investigation Human lung adenocarcinomic epithelial cells and A549 cells were used. Human beta1 integrin and rat beta1 integrin were detected by real-time reverse transcription (RT)-PCR. The expressions of beta1 integrin, Akt and p-Akt were detected by Western blot analysis. To further investigate the role of beta1 integrin in S. aureus internalization by alveolar epithelial cells, we next performed siRNA-mediated knockdown of beta1 integrin expression. In this study, we found that S. aureus invades human alveolar epithelial cells and rat primary alveolar epithelial cells. The beta1 integrin ligand competitive inhibitor, GRGDS-peptide, blocked the internalization of S. aureus by A549 cells. Knockdown of beta1 integrin also inhibited the internalization of S. aureus. In addition, the PI3K/Akt signaling pathway in alveolar epithelial cells was activated by the infection with S. aureus. Furthermore, Akt phosphorylation was abolished by transient transfection with beta1 integrin siRNA in A549 cells challenged with S. aureus. Our results suggest that the phosphatidylinositol 3 kinase/Akt signaling pathway plays an important role in beta1 integrin-mediated internalization of S. aureus by alveolar epithelial cells. PMID- 23800952 TI - Detection of inhibitors of phenotypically drug-tolerant Mycobacterium tuberculosis using an in vitro bactericidal screen. AB - Many whole cell screens of chemical libraries currently in use are based on inhibition of bacterial growth. The goal of this study was to develop a chemical library screening model that enabled detection of compounds that are active against drug-tolerant non-growing cultures of Mycobacterium tuberculosis. An in vitro model of low metabolically active mycobacteria was established with 8 and 30 day old cultures of M. smegmatis and M. tuberculosis, respectively. Reduction of resazurin was used as a measure of viability and the assay was applied in screens of chemical libraries for bactericidal compounds. The model provided cells that were phenotypically-resilient to killing by first and second-line clinical drugs including rifampicin. Screening against chemical libraries identified proteasome inhibitors, NSC310551 and NSC321206, and a structurally related series of thiosemicarbazones, as having potent killing activity towards aged cultures. The inhibitors were confirmed as active against virulent M. tuberculosis strains including multi- and extensively-drug resistant clinical isolates. Our library screen enabled detection of compounds with a potent level of bactericidal activity towards phenotypically drug-tolerant cultures of M. tuberculosis. PMID- 23800954 TI - One-dimensional self-assembly of a water soluble perylene diimide molecule by pH triggered hydrogelation. AB - A water soluble perylene diimide molecule has been fabricated into nanofibers via a pH triggered hydrogelation route. The one-dimensional self-assembly is dominated by the intermolecular pi-pi stacking interactions in concert with the hydrogen bonding between the carboxylic acid side chains. The anisotropic electronic and optical properties observed for the nanofibers are consistent with the one-dimensional intermolecular pi-pi arrangement. PMID- 23800953 TI - Mechanism of DNA damage responses induced by exposure to an oligonucleotide homologous to the telomere overhang in melanoma. AB - T-oligo, an 11-base oligonucleotide homologous to the 3'-telomeric overhang, is a novel, potent therapeutic modality in melanoma and multiple other tumor types. T oligo is proposed to function in a manner similar to experimental disruption of the telomere overhang and induces DNA damage responses including apoptosis, differentiation and senescence. However, important components involved in T-oligo induced responses are not defined, particularly the role of p53, TRF1 and TRF2 in mediating the T-oligo induced responses. In MU, PM-WK, and MM-MC melanoma cells, exposure to T-oligo upregulates p53 expression and phosphorylation, resulting in cellular differentiation and activation of a caspase-mediated apoptotic cascade. However, siRNA-mediated knockdown of p53 completely blocks T-oligo induced differentiation and significantly decreases apoptosis, suggesting that p53 is an important mediator of T-oligo induced responses. In addition, we characterized the roles of telomere binding proteins, TRF1, TRF2, and tankyrase-1, in T-oligo induced damage responses. We demonstrate that tankyrase-1 activity is required for initiation of T-oligo induced damage responses including p53 phosphorylation and reduction of cellular proliferation. These results highlight TRF1, TRF2, tankyrase-1 and p53 as important elements in T-oligo mediated responses and suggest new avenues for research into T-oligo's mechanism of action. PMID- 23800955 TI - Using GIS to evaluate a fire safety program in North Carolina. AB - Evaluating program impact is a critical aspect of public health. Utilizing Geographic Information Systems (GIS) is a novel way to evaluate programs which try to reduce residential fire injuries and deaths. The purpose of this study is to demonstrate the application of GIS within the evaluation of a smoke alarm installation program in North Carolina. This approach incorporates national fire incident data which, when linked with program data, provides a clear depiction of the 10 years impact of the Get Alarmed, NC! program and estimates the number of potential lives saved. We overlapped Get Alarmed, NC! program installation data with national information on fires using GIS to identify homes that experienced a fire after an alarm was installed and calculated potential lives saved based on program documentation and average housing occupancy. We found that using GIS was an efficient and quick way to match addresses from two distinct sources. From this approach we estimated that between 221 and 384 residents were potentially saved due to alarms installed in their homes by Get Alarmed, NC!. Compared with other program evaluations that require intensive and costly participant telephone surveys and/or in-person interviews, the GIS approach is inexpensive, quick, and can easily analyze large disparate datasets. In addition, it can be used to help target the areas most at risk from the onset. These benefits suggest that by incorporating previously unutilized data, the GIS approach has the potential for broader applications within public health program evaluation. PMID- 23800956 TI - Analyzing exposure, use, and policies related to tobacco use on campus for the development of comprehensive tobacco policies at Canadian post-secondary institutions. AB - Canadians in their early twenties represent the highest prevalence of reported tobacco use among all age groups. With the majority of Canadian young adults accessing post-secondary education, post-secondary institutions can facilitate targeting of health promotion efforts to curb tobacco use among young adults. Effective targeting requires clear comprehensive campus tobacco policies. However, the development and implementation of comprehensive campus tobacco policies has been lacking among Canadian post-secondary institutions. As the first step towards the development of a comprehensive campus tobacco policy at the University of Guelph, an on-line survey of students, faculty and staff was conducted in November 2012. The objectives of this survey were two-fold: (1) Determine the current level of exposure to second-hand smoke on campus, the type and frequency of tobacco use, opinions on seven different tobacco policy options, and the level of awareness of current tobacco policies and programs and; (2) Determine if any associations between opinions on tobacco policy options and exposure to second-hand smoke and tobacco use existed. The results of this survey demonstrate that tobacco use is associated with opinions on tobacco policy options and that the level of awareness of tobacco policies and programs is relatively low and is not associated with tobacco use. This study represents one of the first studies to examine the association between tobacco use and support of policy options and awareness of tobacco policies and programs. As other post secondary institutions develop comprehensive tobacco policies, these findings will serve as a comparison for other similar institutions. PMID- 23800957 TI - A comparison of self-reported physical health and health conditions of American Indian/Alaskan Natives to other college students. AB - American Indian/Alaska Natives comprise a small portion of the general college student population, but often have the poorest health and wellness, as well as the highest dropout rates compared to any other race or ethnicity. Despite the well-documented issues this group faces in higher education, they are often ignored in studies due to their status as the minority within the minority, comprising only 0.8% of all college students in the US. This study examines the differences in college students' overall ratings of health across racial and ethnic groups, focusing specifically on the health and wellness of AI/AN students compared to their counterparts. This paper also investigates the physical health issues students experienced in the past 12 months and the health issues' impact on their academic achievement. Results showed that AI/AN students reported the lowest overall health ratings and the most health issues in the past year. PMID- 23800959 TI - Prognostic factors of work disability in sick-listed cancer survivors. AB - PURPOSE: Sick-listed cancer survivors may face lasting side-effects, even after a successful completion of treatment. As a consequence, they are at risk of work disability, which may lead to job loss. Knowledge of prognostic factors of work disability may support cancer survivors in their trajectory of vocational rehabilitation. The purpose of this study was to identify prognostic factors of work disability in sick-listed cancer survivors. METHODS: From the first day of sick leave, a cohort of 131 cancer survivors was followed for 24 months. Included participants were aged between 20 and 63 years. Data were collected, using questionnaires, at 10 months after reporting sick. The level of work disability, i.e., entitlement for disability compensation, was assessed by an insurance physician and a labour expert at 24 months. Univariate and multiple logistic regression analyses were performed. RESULTS: In the univariate analysis, 14 variables were found to be associated with the level of work disability at 24 months. These factors were related to socio-demographics, health characteristics, work-related characteristics, and return to work (RTW) expectations. Multiple logistic regression showed that at 10-month sick leave, perception of health care providers on cancer survivors' work ability and experienced influence on RTW, both reported by workers, were significantly associated with the level of work disability at 24 months. CONCLUSION: It seems in the interest of cancer survivors to take an active role in planning their RTW trajectory and to discuss RTW with their health care providers. IMPLICATIONS FOR CANCER SURVIVORS: The potential role healthcare providers may play in counselling cancer survivors on RTW must not be underestimated. Cancer survivors may benefit in having control on their RTW trajectory. PMID- 23800958 TI - Regulation of innate immune function in bovine oviduct epithelial cells in culture: the homeostatic role of epithelial cells in balancing Th1/Th2 response. AB - This study aimed to investigate the role of epithelial cells in regulating innate immunity in bovine oviduct epithelial cell (BOEC) culture. We studied the effect of Escherichia coli lipopolysaccharide (LPS) and its interaction with ovarian steroids, estradiol (E2) and progesterone (P4), and luteinizing hormone (LH) at concentrations observed during the preovulatory period on immune responses in BOEC culture. Immunohistochemistry of oviduct tissue showed intensive expression of Toll-like receptor-4 (TLR-4) and TLR-2 in epithelial cells. A dose of 10 ng/ml LPS stimulated TLR-4, cyclooxygenase-2 (COX-2), nuclear factor kappa B inhibitor A (NFKBIA), interleukin 1beta (IL-1beta) and tumor necrosis factor alpha (TNF alpha) expression, indicating an early pro-inflammatory response. A dose of 100 ng/ml LPS did not induce expression of these genes but stimulated TLR-2, IL-10,IL 4 and microsomal prostaglandin E synthase-1 (mPGES-1) expression and PGE2 secretion, indicating an anti-inflammatory response. Ovarian steroids and LH completely block LPS (10 ng/ml)-induced TLR-4, IL-1beta and TNF-alpha expression as well as LPS (100 ng/ml)-induced TLR-2 expression. Taken together, this study suggests the existence of an early signaling system to respond to infection in the BOEC. In addition, ovarian steroids and LH may play a critical role in inducing homeostasis and in controlling hyperactive pro-inflammatory responses detrimental to epithelial cells, sperm and the embryo. PMID- 23800960 TI - Healthcare information technology's relativity problems: a typology of how patients' physical reality, clinicians' mental models, and healthcare information technology differ. AB - OBJECTIVE: To model inconsistencies or distortions among three realities: patients' physical reality; clinicians' mental models of patients' conditions, laboratories, etc; representation of that reality in electronic health records (EHR). To serve as a potential tool for quality improvement of EHRs. METHODS: Using observations, literature, information technology (IT) logs, vendor and US Food and Drug Administration reports, we constructed scenarios/models of how patients' realities, clinicians' mental models, and EHRs can misalign to produce distortions in comprehension and treatment. We then categorized them according to an emergent typology derived from the cases themselves and refined the categories based on insights gained from the literature of interactive sociotechnical systems analysis, decision support science, and human computer interaction. Typical of grounded theory methods, the categories underwent repeated modifications. RESULTS: We constructed 45 scenarios of misalignment between patients' physical realities, clinicians' mental models, and EHRs. We then identified five general types of misrepresentation in these cases: IT data too narrowly focused; IT data too broadly focused; EHRs miss critical reality; data multiplicities-perhaps contradictory or confusing; distortions from data reflected back and forth across users, sensors, and others. The 45 scenarios are presented, organized by the five types. CONCLUSIONS: With humans, there is a physical reality and actors' mental models of that reality. In healthcare, there is another player: the EHR/healthcare IT, which implicitly and explicitly reflects many mental models, facets of reality, and measures thereof that vary in reliability and consistency. EHRs are both microcosms and shapers of medical care. Our typology and scenarios are intended to be useful to healthcare IT designers and implementers in improving EHR systems and reducing the unintended negative consequences of their use. PMID- 23800961 TI - Directional molecular sliding at room temperature on a silicon runway. AB - The design of working nanovehicles is a key challenge for the development of new devices. In this context, 1D controlled sliding of molecules on a silicon-based surface is successfully achieved by using an optimized molecule-substrate pair. Even though the molecule and surface are compatible, the molecule-substrate interaction provides a 1D template effect to guide molecular sliding along a preferential surface orientation. Molecular motion is monitored by STM experiments under ultra-high vacuum at room temperature. Molecule-surface interactions are elucidated by semi-empirical calculations. PMID- 23800962 TI - The deubiquitinating enzyme AMSH1 and the ESCRT-III subunit VPS2.1 are required for autophagic degradation in Arabidopsis. AB - In eukaryotes, posttranslational modification by ubiquitin regulates the activity and stability of many proteins and thus influences a variety of developmental processes as well as environmental responses. Ubiquitination also plays a critical role in intracellular trafficking by serving as a signal for endocytosis. We have previously shown that the Arabidopsis thaliana associated molecule with the SH3 domain of STAM3 (AMSH3) is a deubiquitinating enzyme (DUB) that interacts with endosomal complex required for transport-III (ESCRT-III) and is essential for intracellular transport and vacuole biogenesis. However, physiological functions of AMSH3 in the context of its ESCRT-III interaction are not well understood due to the severe seedling lethal phenotype of its null mutant. In this article, we show that Arabidopsis AMSH1, an AMSH3-related DUB, interacts with the ESCRT-III subunit vacuolar protein sorting2.1 (VPS2.1) and that impairment of both AMSH1 and VPS2.1 causes early senescence and hypersensitivity to artificial carbon starvation in the dark similar to previously reported autophagy mutants. Consistent with this, both mutants accumulate autophagosome markers and accumulate less autophagic bodies in the vacuole. Taken together, our results demonstrate that AMSH1 and the ESCRT-III subunit VPS2.1 are important for autophagic degradation and autophagy-mediated physiological processes. PMID- 23800964 TI - Whole-genome analysis of the journey from phytopathogen to biocontrol agent. PMID- 23800963 TI - Salt-responsive ERF1 regulates reactive oxygen species-dependent signaling during the initial response to salt stress in rice. AB - Early detection of salt stress is vital for plant survival and growth. Still, the molecular processes controlling early salt stress perception and signaling are not fully understood. Here, we identified salt-responsive ERF1 (SERF1), a rice (Oryza sativa) transcription factor (TF) gene that shows a root-specific induction upon salt and hydrogen peroxide (H2O2) treatment. Loss of SERF1 impairs the salt-inducible expression of genes encoding members of a mitogen-activated protein kinase (MAPK) cascade and salt tolerance-mediating TFs. Furthermore, we show that SERF1-dependent genes are H2O2 responsive and demonstrate that SERF1 binds to the promoters of MAPK kinase kinase6 (MAP3K6), MAPK5, dehydration responsive element bindinG2A (DREB2A), and zinc finger protein179 (ZFP179) in vitro and in vivo. SERF1 also directly induces its own gene expression. In addition, SERF1 is a phosphorylation target of MAPK5, resulting in enhanced transcriptional activity of SERF1 toward its direct target genes. In agreement, plants deficient for SERF1 are more sensitive to salt stress compared with the wild type, while constitutive overexpression of SERF1 improves salinity tolerance. We propose that SERF1 amplifies the reactive oxygen species-activated MAPK cascade signal during the initial phase of salt stress and translates the salt-induced signal into an appropriate expressional response resulting in salt tolerance. PMID- 23800965 TI - The transition from a phytopathogenic smut ancestor to an anamorphic biocontrol agent deciphered by comparative whole-genome analysis. AB - Pseudozyma flocculosa is related to the model plant pathogen Ustilago maydis yet is not a phytopathogen but rather a biocontrol agent of powdery mildews; this relationship makes it unique for the study of the evolution of plant pathogenicity factors. The P. flocculosa genome of ~23 Mb includes 6877 predicted protein coding genes. Genome features, including hallmarks of pathogenicity, are very similar in P. flocculosa and U. maydis, Sporisorium reilianum, and Ustilago hordei. Furthermore, P. flocculosa, a strict anamorph, revealed conserved and seemingly intact mating-type and meiosis loci typical of Ustilaginales. By contrast, we observed the loss of a specific subset of candidate secreted effector proteins reported to influence virulence in U. maydis as the singular divergence that could explain its nonpathogenic nature. These results suggest that P. flocculosa could have once been a virulent smut fungus that lost the specific effectors necessary for host compatibility. Interestingly, the biocontrol agent appears to have acquired genes encoding secreted proteins not found in the compared Ustilaginales, including necrosis-inducing-Phytophthora protein- and Lysin-motif- containing proteins believed to have direct relevance to its lifestyle. The genome sequence should contribute to new insights into the subtle genetic differences that can lead to drastic changes in fungal pathogen lifestyles. PMID- 23800966 TI - Q-site inhibitor induced ROS production of mitochondrial complex II is attenuated by TCA cycle dicarboxylates. AB - The impact of complex II (succinate:ubiquinone oxidoreductase) on the mitochondrial production of reactive oxygen species (ROS) has been underestimated for a long time. However, recent studies with intact mitochondria revealed that complex II can be a significant source of ROS. Using submitochondrial particles from bovine heart mitochondria as a system that allows the precise setting of substrate concentrations we could show that mammalian complex II produces ROS at subsaturating succinate concentrations in the presence of Q-site inhibitors like atpenin A5 or when a further downstream block of the respiratory chain occurred. Upon inhibition of the ubiquinone reductase activity, complex II produced about 75% hydrogen peroxide and 25% superoxide. ROS generation was attenuated by all dicarboxylates that are known to bind competitively to the substrate binding site of complex II, suggesting that the oxygen radicals are mainly generated by the unoccupied flavin site. Importantly, the ROS production induced by the Q-site inhibitor atpenin A5 was largely unaffected by the redox state of the Q pool and the activity of other respiratory chain complexes. Hence, complex II has to be considered as an independent source of mitochondrial ROS in physiology and pathophysiology. PMID- 23800967 TI - beta-endorphin via the delta opioid receptor is a major factor in the incubation of cocaine craving. AB - Cue-induced cocaine craving intensifies, or 'incubates', during the first few weeks of abstinence and persists over extended periods of time. One important factor implicated in cocaine addiction is the endogenous opioid beta-endorphin. In the present study, we examined the possible involvement of beta-endorphin in the incubation of cocaine craving. Rats were trained to self-administer cocaine (0.75 mg/kg, 10 days, 6 h/day), followed by either a 1-day or a 30-day period of forced abstinence. Subsequent testing for cue-induced cocaine-seeking behavior (without cocaine reinforcement) was performed. Rats exposed to the drug associated cue on day 1 of forced abstinence demonstrated minimal cue-induced cocaine-seeking behavior concurrently with a significant increase in beta endorphin release in the nucleus accumbens (NAc). Conversely, exposure to the cue on day 30 increased cocaine seeking, while beta-endorphin levels remained unchanged. Intra-NAc infusion of an anti-beta-endorphin antibody (4 MUg) on day 1 increased cue-induced cocaine seeking, whereas infusion of a synthetic beta endorphin peptide (100 ng) on day 30 significantly decreased cue response. Both intra-NAc infusions of the delta opioid receptor antagonist naltrindole (1 MUg) on day 1 and naltrindole together with beta-endorphin on day 30 increased cue induced cocaine-seeking behavior. Intra-NAc infusion of the MU opioid receptor antagonist CTAP (30 ng and 3 MUg) had no behavioral effect. Altogether, these results demonstrate a novel role for beta-endorphin and the delta opioid receptor in the development of the incubation of cocaine craving. PMID- 23800969 TI - Treatment of palmar hyperhidrosis with botulinum toxin type A: results of a pilot study based on a novel injective approach. AB - Botulinum toxin type A (BoNT/A) improves symptoms of palmar hyperhidrosis, but some drawbacks related to its injection in the hands still persist (e.g., muscle weakness caused by drug diffusion, pain during injections, or delayed functional recovery of the hand when using wrist block). In this open, controlled, non randomized, intra-individual clinical trial, 50 patients with severe palmar hyperhidrosis received in the same session intradermal injections of BoNT/A through a new injection technique (NA/BoNT/A) based on the use of a specific adapter for needles (PCT/IT2011/000299) in one hand, and BoNT/A injection following the anaesthetic block of the wrist (WB/BoNT/A) in the other. Several measures of efficacy and safety were evaluated both before (T0) and four weeks after the treatment (T4): disease severity improvement, sweat reduction, handgrip strength decrease, pain/discomfort during the treatment, and patient's global satisfaction. All patients were also re-evaluated through the gravimetric assessment of sweat production in both hands at T12 and T24 to compare the long term efficacy of the two treatments. All patients were responsive to the treatments, and disease severity was significantly decreased at T4 compared to baseline (p < 0.0001). Both procedures were equally effective in reducing sweat production in the short term (p = 0.08 at T4), but WB/BoNT/A caused a higher decrease of handgrip strength compared with WB/BoNT/A at T4 (p < 0.0001). Finally, patients reported that NA/BoNT/A and WB/BoNT/A procedures were comparable for pain/discomfort (p = 0.204); however, they were globally more satisfied with the NA/BoNT/A rather than WB/BoNT/A method (p < 0.0001). No significant difference in percentage of clinical relapse at T12 and T24 was detected between hands treated via WB/BoNT/A or NA/BoNT/A (p = 0.70). The use of the described adapter to inject BoNT/A in the hands seems to lead the clinicians to obtain same therapeutic results of conventional method based on the use of anaesthetic block of the wrist. Moreover, this new injective approach seems to increase the safety of the treatment by reducing the extent of muscle weakness and is preferred by patients mostly because it makes the functional recovery of the hand faster. PMID- 23800970 TI - Molecular and cellular mechanisms of bone morphogenetic proteins and activins in the skin: potential benefits for wound healing. AB - Bone morphogenetic proteins (BMPs) and activins are phylogenetically conserved proteins, belonging to the transforming growth factor-beta superfamily, that signal through the phosphorylation of receptor-regulated Smad proteins, activating different cell responses. They are involved in various steps of skin morphogenesis and wound repair, as can be evidenced by the fact that their expression is increased in skin injuries. BMPs play not only a role in bone regeneration but are also involved in cartilage, tendon-like tissue and epithelial regeneration, maintain vascular integrity, capillary sprouting, proliferation/migration of endothelial cells and angiogenesis, promote neuron and dendrite formation, alter neuropeptide levels and are involved in immune response modulation, at least in animal models. On the other hand, activins are involved in wound repair through the regulation of skin and immune cell migration and differentiation, re-epithelialization and granulation tissue formation, and also promote the expression of collagens by fibroblasts and modulate scar formation. This review aims at enunciating the effects of BMPs and activins in the skin, namely in skin development, as well as in crucial phases of skin wound healing, such as inflammation, angiogenesis and repair, and will focus on the effects of these proteins on skin cells and their signaling pathways, exploring the potential therapeutic approach of the application of BMP-2, BMP-6 and activin A in chronic wounds, particularly diabetic foot ulcerations. PMID- 23800968 TI - Integrative biological analysis for neuropsychopharmacology. AB - Although advances in psychotherapy have been made in recent years, drug discovery for brain diseases such as schizophrenia and mood disorders has stagnated. The need for new biomarkers and validated therapeutic targets in the field of neuropsychopharmacology is widely unmet. The brain is the most complex part of human anatomy from the standpoint of number and types of cells, their interconnections, and circuitry. To better meet patient needs, improved methods to approach brain studies by understanding functional networks that interact with the genome are being developed. The integrated biological approaches--proteomics, transcriptomics, metabolomics, and glycomics--have a strong record in several areas of biomedicine, including neurochemistry and neuro-oncology. Published applications of an integrated approach to projects of neurological, psychiatric, and pharmacological natures are still few but show promise to provide deep biological knowledge derived from cells, animal models, and clinical materials. Future studies that yield insights based on integrated analyses promise to deliver new therapeutic targets and biomarkers for personalized medicine. PMID- 23800972 TI - A large-scale outbreak of bovine ephemeral fever in Turkey, 2012. AB - Regional cases of bovine ephemeral fever (BEF) were documented previously in Turkey. Previous cases were confirmed in South-East Turkey with low cow mortality. Recent BEF-suspected outbreaks with high mortality were documented in many regions of Turkey in 2012. The aim of study was the epidemiological examination of the outbreak and molecular characterization of the viruses detected from the outbreak. For this reason, blood samples were collected from BEF-suspected outbreak regions. From the results of RT-PCR, high rate of BEF suspected samples (48/60 or 80%) was found positive for BEF virus (BEFV) RNA. The nucleotide sequences of the G1 region of G gene of BEFV in the current study during the 2012 outbreak were grouped into cluster II of BEFV. It was suggested that BEFV may be spread out to other neighbor countries in the future years. PMID- 23800973 TI - Combined hepatocellular-cholangiocarcinoma in a Yellow-headed Amazon (Amazona oratrix). AB - A 9-year-old male Yellow-headed Amazon (Amazona oratrix) with a history of anorexia and vomiting died of a liver tumor. The tumor consisted of neoplastic cells with hepatocellular and cholangiocellular differentiations and their intermingled areas. Neoplastic hepatocytes showed islands or trabecular growth with vacuolated eosinophilic cytoplasm. Cells showing biliary differentiation formed ducts or tubules lined by cytokeratin AE1/AE3-positive epithelia, accompanied by desmoplasia consisting of myofibroblasts reacting to alpha-smooth muscle actin and desmin. The tumor was diagnosed as a combined hepatocellular cholangiocarcinoma, which is very rare in the avian. PMID- 23800974 TI - MiR-205 is downregulated in hereditary hemorrhagic telangiectasia and impairs TGF beta signaling pathways in endothelial cells. AB - Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by arteriovenous malformations and hemorrhages. This vascular disease results mainly from mutations in 2 genes involved in the TGF-beta pathway (ENG and ALK1) that are exclusively expressed by endothelial cells. The present study identified miR-27a and miR-205 as two circulating miRNAs differentially expressed in HHT patients. The plasma levels of miR-27a are elevated while those of miR-205 are reduced in both HHT1 and HHT2 patients compared to healthy controls. The role of miR-205 in endothelial cells was further investigated. Our data indicates that miR-205 expression displaces the TGF-beta balance towards the anti-angiogenic side by targeting Smad1 and Smad4. In line, overexpression of miR 205 in endothelial cells reduces proliferation, migration and tube formation while its inhibition shows opposite effects. This study not only suggests that detection of circulating miRNA (miR-27a and miR-205) could help for the screening of HHT patients but also provides a functional link between the deregulated expression of miR-205 and the HHT phenotype. PMID- 23800975 TI - Towards a rational combination therapy of cystic fibrosis: How cystamine restores the stability of mutant CFTR. AB - Cystic fibrosis (CF) is most frequently due to homozygous DeltaF508-CFTR mutation. The DeltaF508-CFTR protein is unstable in the plasma membrane (PM), even if it is rescued by pharmacological agents that prevent its intracellular retention and degradation. Restoring defective autophagy in CF airways by proteostasis regulators (such as cystamine and its reduced form, cysteamine) can rescue and stabilize DeltaF508-CFTR at the PM, thus enabling the action of CFTR potentiators, which are pharmacological agents that stimulate the function of CFTR as an ion channel. The effects of cystamine extend for days (in vitro) and weeks (in vivo) beyond washout, suggesting that once peripheral proteostasis has been re-established, PM-resident DeltaF508-CFTR sustains its own stability. We demonstrated that the pharmacological inhibition of wild-type CFTR [cystic fibrosis transmembrane conductance regulator (ATP-binding cassette subfamily C, member 7)], in bronchial epithelial cells decreases the stability of the CFTR protein by inhibiting autophagy, elevating the abundance of SQSTM1/p62 and its interaction with CFTR at the PM, increasing the ubiqutination of CFTR, stimulating the lysosomal degradation of CFTR and avoiding its recycling. All these effects could be inhibited by cystamine. Moreover, CFTR-sufficient epithelia generate permissive conditions for incorporating DeltaF508-CFTR into the PM and stabilizing it at this location. These results provide the rationale for a combination therapy of CF in which pretreatment with cystamine or cysteamine enables the later action of CFTR potentiators. PMID- 23800976 TI - Verapamil in infants: an exaggerated fear? AB - The use of intravenous verapamil for tachyarrhythmia in infants is widely considered contraindicated due to the perceived risk of hemodynamic collapse after administration. This article reviews the relatively limited evidence that led to this well-known contraindication and highlights the interesting process by which medical practice may evolve in the absence of persuasive science. PMID- 23800977 TI - Randomized trial of perindopril, enalapril, losartan and telmisartan in overweight or obese patients with hypertension. AB - BACKGROUND AND OBJECTIVES: Obesity exacerbates hypertension and stimulates the renin-angiotensin-aldosterone system (RAAS). Full-dose RAAS inhibition could be a therapeutic option in overweight or obese patients with hypertension. This study compared four RAAS inhibitors at full therapeutic doses to determine their effect on blood pressure (BP) and cardiovascular risk factors in these patients. METHODS: We conducted a 24-week, single-blind, randomized, parallel-group study in 120 overweight or obese patients (body mass index >=27 kg/m(2)) with hypertension, aged 18-60 years. The primary endpoint was the change in mean 24-h systolic BP and diastolic BP from baseline to study end. Central BP, arterial stiffness, and metabolic and cardiac indices were also investigated. Patients were randomly allocated to perindopril 10 mg/day, enalapril 20 mg/day, losartan 100 mg/day or telmisartan 80 mg/day. Nonpharmacological interventions were also recommended. RESULTS: Reductions in mean 24-h systolic BP (and diastolic BP) were all significant (p < 0.05 versus baseline) for perindopril, enalapril, losartan and telmisartan: systolic BP -22, -11, -12 and -15 mmHg, respectively; (and diastolic BP -13, -6, -13 and -12 mmHg, respectively). Aortic elasticity improved with perindopril and telmisartan. Perindopril was associated with the greatest reductions in central aortic BP and leptin levels [30 % versus 2 %, 7 % and 14 % with enalapril, losartan and telmisartan, respectively (all p < 0.05 versus perindopril)]. Reductions in other BP, echocardiographic, metabolic and anthropometric parameters occurred with all treatments. CONCLUSION: Full-dose RAAS inhibition, particularly with perindopril, effectively reduces BP, improves arterial structure and regulates cardiovascular risk factors in overweight or obese patients with hypertension. PMID- 23800978 TI - A national survey examining obstetrician perspectives on use of 17-alpha hydroxyprogesterone caproate post-US FDA approval. AB - BACKGROUND: A randomized study published in 2003 by the National Institute of Child Health and Human Development Maternal Fetal Medicine Units network showed efficacy of 17-alpha hydroxyprogesterone caproate (17P) for the prevention of recurrent preterm delivery. Between 2003 and 2011 the drug was often provided by compounding pharmacies. In 2011, the US Food and Drug Administration (FDA) approved the drug for this indication. OBJECTIVE: The objective of this study was to evaluate the impact of FDA approval on physician attitudes and perceptions regarding use of 17P as a drug for preventing recurrent preterm delivery. METHODS: A 10-min online survey using a structure closed-ended questionnaire format was designed and administered from 17 June 2011 to 7 July 2011 among 401 obstetricians distributed evenly throughout the USA. RESULTS: There is nearly universal awareness of 17P for the prevention of preterm birth (93 %), with a large majority (80 %) of obstetricians having reported prescribing the medication. However, surveyed physicians reported that the average proportion of eligible patients seen in their practice but not prescribed 17P in 2009-2010 was 41 %. Financial and logistical barriers carried the most weight (approximately 75 %) in the decision not to prescribe 17P to an eligible patient. Forty-one percent of respondents cited lack of FDA approval of 17P as a deterrent to prescribing the medication. Thirty-nine percent of respondents had professional liability concerns regarding prescribing compounded 17P. Assuming the same out-of-pocket expense for patients, two-thirds of obstetricians would choose to prescribe Makena((r)). CONCLUSION: Awareness of 17P for the prevention of preterm birth among obstetricians is high. FDA-approved medications seem to have physician preference due to enhanced assurance for product efficacy and safety. PMID- 23800979 TI - Investigation of the origin and synthetic application of the pseudodilution effect for Pd-catalyzed macrocyclisations in concentrated solutions with immobilized catalysts. AB - Immobilized Pd-complexes allowed macrocyclisations via the Tsuji-Trost-reaction in concentrated solutions. Systematic studies suggest that the origin of this pseudodilution effect is neither film diffusion nor gel diffusion, but the reduction in conformational freedom of intermediates and intramolecular prenucleophile activation. In contrast a pseudodilution effect could not be observed for Sonogashira- and Suzuki-macrocyclisations. PMID- 23800981 TI - A peptide based two component white light emitting system. AB - A peptide based two component white light emitting system has been designed and developed on the basis of a co-assembly of a PDI containing peptide system as an acceptor and a stilbene containing peptide system as a donor in organic solvents. PMID- 23800980 TI - Factors affecting warfarin dose requirements and quality of anticoagulation in adult Egyptian patients: role of gene polymorphism. AB - BACKGROUND: Warfarin is the mainstay of anticoagulation therapy worldwide. CYP2C9 and VKORC1 are two major genetic factors associated with inter-individual and inter-ethnic variability in the warfarin dose. AIM: This study aims to assess the impact of VKORC1-1639G>A polymorphism and the most common CYP2C9 variant alleles (*2 and *3) on warfarin response in Egyptian patients. METHODS: Genetic analysis of VKORC1-1639G>A and CYP2C9*2, CYP2C9*3 was performed using real-time PCR system. Patients maintained on a constant dose targeting an international normalized ratio range of 2-3.5 for at least three consecutive times were considered as good candidates. A stepwise linear regression analysis was used to determine the independent effects of genetic and non-genetic factors on daily warfarin dose requirements. RESULTS: Patients carrying VKORC1 and CYP2C9 variant genotypes needed a 44.8 % lower mean daily warfarin dose as compared to wild types. Patients with G allele for VKORC1-1639G>A had a significantly higher number of thromboembolic complications per month during therapy. On the first 30 days of therapy, presence of a variant allele either in VKORC1 or in CYP2C9 was associated with increased time required to achieve stable dosing. Multiple regression analysis showed that, VKORC1-1639G>A, age, CYP2C9*3, and smoking status explained 43.4 % of the overall variability in the warfarin dose. CONCLUSION: VKORC1-1639G>A and CYP2C9 polymorphisms contribute to the difference in warfarin dose requirements and quality of anticoagulation amongst Egyptian patients. Study results support using personalized warfarin treatment in Egyptian patients. PMID- 23800982 TI - An approach to medical knowledge sharing in a hospital information system using MCLink. AB - Clinicians often need access to electronic information resources that answer questions that occur in daily clinical practice. This information generally comes from publicly available resources. However, clinicians also need knowledge on institution-specific information (e.g., institution-specific guidelines, choice of drug, choice of laboratory test, information on adverse events, and advice from professional colleagues). This information needs to be available in real time. This study characterizes these needs in order to build a prototype hospital information system (HIS) that can help clinicians get timely answers to questions. We previously designed medical knowledge units called Medical Cells (MCs). We developed a portal server of MCs that can create and store medical information such as institution-specific information. We then developed a prototype HIS that embeds MCs as links (MCLink); these links are based on specific terms (e.g., drug, laboratory test, and disease). This prototype HIS presents clinicians with institution-specific information. The HIS clients (e.g., clinicians, nurses, pharmacists, and laboratory technicians) can also create an MCLink in the HIS using the portal server in the hospital. The prototype HIS allowed efficient sharing and use of institution-specific information to clinicians at the point of care. This study included institution-specific information resources and advice from professional colleagues, both of which might have an important role in supporting good clinical decision making. PMID- 23800983 TI - Lower incidence of emergence agitation in children after propofol anesthesia compared with sevoflurane: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Emergence agitation (EA) from general anesthesia has been reported as an adverse effect of sevoflurane in children. We describe a meta-analysis of randomized controlled trials that compared the incidence of EA between children who underwent sevoflurane anesthesia and those who underwent propofol anesthesia. METHODS: A literature search was conducted to identify clinical trials that met our inclusion criteria. Prospective randomized trials comparing sevoflurane and propofol anesthesia in children less than 15 years of age were included in the meta-analysis. Data from each trial were combined using the random effects model to calculate pooled odds ratios (ORs) and their corresponding 95 % confidence intervals (CIs). The heterogeneity of data was assessed by Cochran's Q and I (2) tests. Sensitivity analysis was conducted for study quality, patient age, and type of surgical procedure. RESULTS: The meta-analysis included 14 studies, in which 560 patients received sevoflurane and 548 received propofol. The pooled OR for EA was 0.25 with a 95 % CI of 0.16-0.39 (P = 0.000), which indicates that propofol anesthesia resulted in a lower incidence of EA. The heterogeneity of data was not statistically supported (P = 0.191). All sensitivity analyses strengthened the evidence for the lower incidence of EA with propofol. CONCLUSIONS: Our meta-analysis demonstrated that EA in children is less likely to occur after propofol anesthesia compared with sevoflurane anesthesia. PMID- 23800984 TI - Comparison between intranasal dexmedetomidine and intranasal ketamine as premedication for procedural sedation in children undergoing MRI: a double-blind, randomized, placebo-controlled trial. AB - INTRODUCTION: Providing anesthesia to children undergoing MRI is challenging. Adequate premedication, administered noninvasively, would make the process smoother. In this study, we compare the efficacy of intranasal dexmedetomidine (DXM) with the intranasal administration of ketamine for procedural sedation in children undergoing MRI. METHODS: We studied 150 children, between 1 and 10 years of age, divided randomly into three groups (DXM, K, and S). For blinding, every child received the intranasal drugs twice; syringe S1, 60 min before, and syringe S2, 30 min before intravenous (IV) cannulation. For children in group DXM, S1 contained DXM (1 MUg/kg) and S2 was plain saline. Children in group K received saline in S1 and ketamine (5 mg/kg) in S2 whereas children in group S received saline in both S1 and S2. The child's response to drug administration, ease of IV cannulation, the satisfaction of the anesthesiologist and child's parents with the premedication, and the total propofol dose required for the satisfactory conduct of the procedure were compared. We also compared the time to awakening and discharge of the child as well as the occurrence of any side effects with these drugs. RESULTS: Both DXM and ketamine were equally effective as premedication in these patients. Most of the children accepted the intranasal drugs with minimal discomfort; 90.4 % of the anesthesiologists in the DXM group and 82.7 % in the ketamine group were satisfied with the conditions for IV cannulation whereas only 21.3 % were satisfied in the saline group. The total dose of propofol used was less in the study groups. Furthermore, children in group DXM and group K had earlier awakening and discharge than those in group S. CONCLUSION: DXM and ketamine were equally effective, by the intranasal route, as premedication in children undergoing MRI. PMID- 23800985 TI - Optimal in-hospital and discharge medical therapy in acute coronary syndromes in Kerala: results from the Kerala acute coronary syndrome registry. AB - BACKGROUND: In-hospital and postdischarge treatment rates for acute coronary syndrome (ACS) remain low in India. However, little is known about the prevalence and associations of the package of optimal ACS medical care in India. Our objective was to define the prevalence, associations, and impact of optimal in hospital and discharge medical therapy in the Kerala ACS Registry of 25,718 admissions. METHODS AND RESULTS: We defined optimal in-hospital ACS medical therapy as receiving the following 5 medications: aspirin, clopidogrel, heparin, beta-blocker, and statin. We defined optimal discharge ACS medical therapy as receiving all of the above therapies except heparin. Comparisons by optimal versus nonoptimal ACS care were made via Student t test for continuous variables and chi(2) test for categorical variables. We created random effects logistic regression models to evaluate the association between Global Registry of Acute Coronary Events risk score variables and optimal in-hospital or discharge medical therapy. Optimal in-hospital and discharge medical care were delivered in 40% and 46% of admissions, respectively. Wide variability in both in-hospital and discharge medical care was present, with few hospitals reaching consistently high (>90%) levels. Patients receiving optimal in-hospital medical therapy had an adjusted odds ratio (95% confidence interval)=0.93 (0.71, 1.22) for in-hospital death and an adjusted odds ratio (95% confidence interval)=0.79 (0.63, 0.99) for major adverse cardiovascular event rates. Patients who received optimal in hospital medical care were far more likely to receive optimal discharge care (adjusted odds ratio [95% confidence interval] = 10.48 [9.37, 11.72]). CONCLUSIONS: Strategies to improve in-hospital and discharge medical therapy are needed to improve local process-of-care measures and ACS outcomes in Kerala. PMID- 23800986 TI - CD44variant exon 9 plays an important role in colon cancer initiating cells. AB - Cancer stem cells(cancer initiating cells) have become increasingly important in the treatment of malignant tumors. CD44 in particular has been identified as a marker for stem cells in colon cancer, which is a high-morbidity tumor. However, many details remain unknown, including identification of the relevant exon. The elucidation of these details could lead to the development of new therapies and improvements in prognosis. We report our findings on the importance of CD44 variant exon 9(v9) of stem cells in colon cancer. Using the anti-CD44 standard form(s) antibody, as well as antibodies for each of the CD44 variant exons, we studied colon cancer cell lines by examining stained images of stem cells in the crypt of normal colon mucosa. Using the anti-CD44v9 antibody that fits the normal colon mucosa stem cells, we screened cells using flow cytometry to examine colony formation, resistance to anticancer drugs, and tumor mass formation after subcutaneous implantation in mice. The stem cell-containing region in the crypt of normal colon mucosa was negative for anti-Ki67 antibody staining; only the anti-CD44 v9 antibody stain was expressed. As for colony formation, resistance to anticancer drugs, and tumor mass formation, cells positive both for anti-CD44s and anti-CD44v9 antibody stains was significantly more frequent than those positive for anti-CD44s antibody stain and negative for anti-CD44v9 antibody stain and those negative both for anti-CD44s and anti-CD44v9 antibody stains. CD44 variant exon 9 plays an important role in colon cancer stem cells. PMID- 23800987 TI - Single-nucleotide evolution quantifies the importance of each site along the structure of mitochondrial carriers. AB - Mitochondrial carriers are membrane-embedded proteins consisting of a tripartite structure, a three-fold pseudo-symmetry, related sequences, and similar folding whose main function is to catalyze the transport of various metabolites, nucleotides, and coenzymes across the inner mitochondrial membrane. In this study, the evolutionary rate in vertebrates was screened at each of the approximately 50,000 nucleotides corresponding to the amino acids of the 53 human mitochondrial carriers. Using this information as a starting point, a scoring system was developed to quantify the evolutionary pressure acting on each site of the common mitochondrial carrier structure and estimate its functional or structural relevance. The degree of evolutionary selection varied greatly among all sites, but it was highly similar among the three symmetric positions in the tripartite structure, known as symmetry-related sites or triplets, suggesting that each triplet constitutes an evolutionary unit. Based on evolutionary selection, 111 structural sites (37 triplets) were found to be important. These sites play a key role in structure/function of mitochondrial carriers and are involved in either conformational changes (sites of the gates, proline-glycine levels, and aromatic belts) or in binding and specificity of the transported substrates (sites of the substrate-binding area in between the two gates). Furthermore, the evolutionary pressure analysis revealed that the matrix short helix sites underwent different degrees of selection with high inter-paralog variability. Evidence is presented that these sites form a new sequence motif in a subset of mitochondrial carriers, including the ADP/ATP translocator, and play a regulatory function by interacting with ligands and/or proteins of the mitochondrial matrix. PMID- 23800988 TI - Emerging mechanisms and consequences of calcium regulation of alternative splicing in neurons and endocrine cells. AB - Alternative splicing contributes greatly to proteomic complexity. How it is regulated by external stimuli to sculpt cellular properties, particularly the highly diverse and malleable neuronal properties, is an underdeveloped area of emerging interest. A number of recent studies in neurons and endocrine cells have begun to shed light on its regulation by calcium signals. Some mechanisms include changes in the trans-acting splicing factors by phosphorylation, protein level, alternative pre-mRNA splicing, and nucleocytoplasmic redistribution of proteins to alter protein-RNA or protein-protein interactions, as well as modulation of chromatin states. Importantly, functional analyses of the control of specific exons/splicing factors in the brain point to a crucial role of this regulation in synaptic maturation, maintenance, and transmission. Furthermore, its deregulation has been implicated in the pathogenesis of neurological disorders, particularly epilepsy/seizure. Together, these studies have not only provided mechanistic insights into the regulation of alternative splicing by calcium signaling but also demonstrated its impact on neuron differentiation, function, and disease. This may also help our understanding of similar regulations in other types of cells. PMID- 23800990 TI - Health-related dysfunctional beliefs and health anxiety: further evidence of cognitive specificity. AB - OBJECTIVE: The specificity of Salkovskis and Warwick's (2001) 4 health-related dysfunctional beliefs to health anxiety was examined. METHOD: Specificity was examined using a medically healthy sample of community members recruited through the Internet (N = 410, mean age = 32.9 years, 55.4% female). Structural equation modeling was used to compare the equivalence of latent correlations and partial path coefficients that controlled for the overlap among the targeted dysfunctional beliefs. RESULTS: Health-related dysfunctional beliefs were significantly more strongly related to health anxiety than obsessive-compulsive symptoms. Further, health-related dysfunctional beliefs continued to share robust relations with health anxiety after controlling for related dysfunctional beliefs, although anxiety sensitivity appeared particularly relevant to health anxiety as well. CONCLUSIONS: These results support the specificity of Salkovskis and Warwick's health-related dysfunctional beliefs to health anxiety, as well as the importance given to dysfunctional beliefs within cognitive-behavioral models and treatments of health anxiety. PMID- 23800989 TI - Nrf2 and Nrf1 signaling and ER stress crosstalk: implication for proteasomal degradation and autophagy. AB - The endoplasmic reticulum (ER) lumen is chemically complex and crowded with polypeptides in different stages of assembly. ER quality control monitors chaperone-assisted protein folding, stochastic errors and off-pathway intermediates. In acute conditions, potentially toxic polypeptides overflow the capacity of the chaperone system and lead to ER stress. Activation of the unfolded protein response (UPR) following ER stress buys time for non-native polypeptides to refold or be eliminated; otherwise cell death occurs. The clearance routes for deleterious proteins are endoplasmic reticulum-associated degradation (ERAD) and ER stress-activated autophagy. The ERAD pathway is a chaperone and proteasome-mediated polypeptide degradation, while autophagy applies to wider range of substances. ER stress signal transduction recruits diverse molecules and pathways upon UPR induction to compensate stress condition. NF-E2-related factor 1 (Nrf1) and Nrf2 are two transcription factors mostly known by their induction through an antioxidant response; they can also be activated by UPR machinery. Discovery of diverse molecules downstream of Nrf1 and Nrf2 has expanded our understanding of the biological impacts of these transcription factors beyond classic antioxidant activation. In this review, we summarize our current understanding of mutual relationships between Nrf1, Nrf2, and ER stress clearance mechanisms and highlight the crosstalk of specific molecules mediating these correlations. PMID- 23800991 TI - Identification of genes involved in the response of Arabidopsis to simultaneous biotic and abiotic stresses. AB - In field conditions, plants may experience numerous environmental stresses at any one time. Research suggests that the plant response to multiple stresses is different from that for individual stresses, producing nonadditive effects. In particular, the molecular signaling pathways controlling biotic and abiotic stress responses may interact and antagonize one another. The transcriptome response of Arabidopsis (Arabidopsis thaliana) to concurrent water deficit (abiotic stress) and infection with the plant-parasitic nematode Heterodera schachtii (biotic stress) was analyzed by microarray. A unique program of gene expression was activated in response to a combination of water deficit and nematode stress, with 50 specifically multiple-stress-regulated genes. Candidate genes with potential roles in controlling the response to multiple stresses were selected and functionally characterized. RAPID ALKALINIZATION FACTOR-LIKE8 (AtRALFL8) was induced in roots by joint stresses but conferred susceptibility to drought stress and nematode infection when overexpressed. Constitutively expressing plants had stunted root systems and extended root hairs. Plants may produce signal peptides such as AtRALFL8 to induce cell wall remodeling in response to multiple stresses. The methionine homeostasis gene METHIONINE GAMMA LYASE (AtMGL) was up-regulated by dual stress in leaves, conferring resistance to nematodes when overexpressed. It may regulate methionine metabolism under conditions of multiple stresses. AZELAIC ACID INDUCED1 (AZI1), involved in defense priming in systemic plant immunity, was down-regulated in leaves by joint stress and conferred drought susceptibility when overexpressed, potentially as part of abscisic acid-induced repression of pathogen response genes. The results highlight the complex nature of multiple stress responses and confirm the importance of studying plant stress factors in combination. PMID- 23800992 TI - An improved simplified high-sensitivity quantification method for determining brassinosteroids in different tissues of rice and Arabidopsis. AB - Quantification of brassinosteroids is essential and extremely important to study the molecular mechanisms of their physiological roles in plant growth and development. Herein, we present a simple, material and cost-saving high performance method for determining endogenous brassinosteroids (BRs) in model plants. This new method enables simultaneous enrichment of a wide range of bioactive BRs such as brassinolide, castasterone, teasterone, and typhasterol with ion exchange solid-phase extraction and high-sensitivity quantitation of these BRs based on isotope dilution combined with internal standard approach. For routine analysis, the consumption of plant materials was reduced to one-twentieth of previously reported and the overall process could be completed within 1 day compared with previous 3 to 4 days. The strategy was validated by profiling BRs in different ecotypes and mutants of rice (Oryza sativa) and Arabidopsis (Arabidopsis thaliana), and the BR distributions in different model plants tissues were determined with the new method. The method allows plant physiologists to monitor the dynamics and distributions of BRs with 1 gram fresh weight of model plant tissues, which will speed up the process for the molecular mechanism research of BRs with these model plants in future work. PMID- 23800993 TI - Roles of Na+/H+ exchanger type 1 and intracellular pH in angiotensin II-induced reactive oxygen species generation and podocyte apoptosis. AB - A growing body of evidence suggests that podocyte apoptosis is a major cause of decreased podocyte number, which leads to albuminuria and glomerular injury. The aim of this study was to clarify the molecular mechanisms of angiotensin II (Ang II)-induced apoptosis in cultured mouse podocytes. We examined the effects of Ang II (100 nmol/L) on apoptosis, superoxide anions, and cytosol pH in podocytes. For intracellular pH measurements, image analysis was conducted using confocal laser microscopy after incubation with carboxy-seminaphthorhodafluor-1. Superoxide anions and intracellular pH were elevated with Ang II treatment. Apoptotic cell numbers, as measured by TUNEL staining and caspase 3 activity, were also augmented in the Ang II-treated group. Pre-treatment with olmesartan (100 nmol/L, an Ang II type 1-receptor blocker), apocynin (50 MUmol/L, NADPH oxidase inhibitor), or 5-N,N hexamethylene amiloride [30 MUmol/L, Na+/H+ exchanger type 1 (NHE-1) inhibitor] abolished Ang II-induced podocyte apoptosis, whereas NHE-1 mRNA and protein expression was not affected by Ang II treatment. Moreover, Ang II increased NHE-1 phosphorylation. These results suggest that superoxide production, NHE-1 activation, and intracellular alkalization were early features prior to apoptosis in Ang II-treated mouse podocytes, and may offer new insights into the mechanisms responsible for Ang II-induced podocyte injury. PMID- 23800995 TI - Chromatin: Limiting the DDR. PMID- 23800996 TI - Ambulatory blood pressure monitoring can unmask hypertension in patients with psoriasis vulgaris. AB - BACKGROUND: Psoriasis vulgaris is one of the most prevalent chronic, inflammatory skin disorders. Patients with psoriasis have excess risk of essential hypertension. Masked hypertension (MH), defined as normal office blood pressure (BP) with elevated ambulatory BP (ABPM), has been drawing attention recently due to its association with increased risk of developing sustained hypertension, cardiovascular morbidity, and mortality. The aim of this study was to investigate the prevalence of MH in psoriatic patients. MATERIAL AND METHODS: On hundred and ten middle-aged, normotensive, non-obese patients with psoriasis vulgaris and 110 age- and sex-matched normotensive controls were included in the study. ABPM was performed in all participants over a 24-h period. The clinical severity of the disease was determined according to current indexes. RESULTS: The prevalence of MH among subjects with psoriasis vulgaris was 31.8% and increased compared to control subjects (p<0.01). Predictors of MH in patients with psoriasis vulgaris were detected as male sex, smoking, obesity-related anthropometric measures, and disease activity. Male sex, waist circumference, and diffuse psoriatic involvement were detected as independent predictors of MH. CONCLUSIONS: MH is prevalent in patients with psoriasis vulgaris. Assessment with ABPM and close follow-up for development of hypertension is reasonable. PMID- 23800997 TI - The toxic chemistry of methyl bromide. AB - Methyl bromide (MeBr) is a chemically reactive compound that has found use as a fire retardant and fumigant used for wood, soil, fruits and grains. Its use is banned in many countries because of its ozone-depleting properties. Despite this ban, the use of MeBr persists in some parts of the world (e.g. New Zealand) due to its important role in maintaining strict biosecurity of exported and imported products. Its high chemical reactivity leads to a broad toxicological profile ranging from acute respiratory toxicity following inhalation exposure, through carcinogenicity to neurotoxicty. In this article, we discuss the chemistry of MeBr in the context of its mechanisms of toxicity. The chemical reactivity of MeBr clearly underlies its toxicity. Bromine (Br) is electronegative and a good leaving group; the delta+ carbon thus facilitates electrophilic methylation of biological molecules including glutathione (GSH) via its delta- sulphur atom, leading to downstream effects due to GSH depletion. DNA alkylation, either directly by MeBr or indirectly due to reduction in GSH-mediated detoxification of reactive alkylating chemical species, might explain the carcinogenicity of MeBr. The neurotoxicity of MeBr is much more difficult to understand, but we speculate that methyl phosphates formed in cells might contribute to its neurone-specific toxicity via cholinesterase inhibition. Finally, evidence reviewed shows that it is unlikely for Br- liberated by the metabolism of MeBr to have any toxicological effect because the Br- dose is very low. PMID- 23800998 TI - Historical use of x-rays: treatment of inner ear infections and prevention of deafness. AB - PURPOSE: This article provides an historical assessment of the role of radiotherapy in the treatment of inner ear infections. MATERIALS AND METHODS: The research utilized a literature-based evaluation of the use of x-rays during the first half of the 20th century on the treatment of otitis media (OM), mastoiditis, and cervical adenitis and their impact on the occurrence of deafness. RESULTS: X-Rays were consistently found to be effective as a treatment modality at relatively low doses, in the range of 10-20% of the skin erythema dose, rapidly reducing inflammation, and accelerating the healing process. The mechanistic basis of the clinical successes, while addressed by contemporary researchers, is evaluated in the present article in light of current molecular biology advances, which indicate that clinically effective low doses of ionizing radiation act via the creation of an anti-inflammatory phenotype in highly inflamed tissue. CONCLUSIONS: X-Ray treatment of OM, mastoiditis, and cervical adenitis was widely accepted in the first half of the 20th century by clinicians as an effective treatment when administered within an appropriate dosage range. PMID- 23800994 TI - Diversifying microRNA sequence and function. AB - MicroRNAs (miRNAs) regulate the expression of most genes in animals, but we are only now beginning to understand how they are generated, assembled into functional complexes and destroyed. Various mechanisms have now been identified that regulate miRNA stability and that diversify miRNA sequences to create distinct isoforms. The production of different isoforms of individual miRNAs in specific cells and tissues may have broader implications for miRNA-mediated gene expression control. Rigorously testing the many discrepant models for how miRNAs function using quantitative biochemical measurements made in vivo and in vitro remains a major challenge for the future. PMID- 23800999 TI - Biochemical and biological analysis of Philodryas baroni (Baron's green racer; Dipsadidae) venom: relevance to the findings of human risk assessment. AB - Philodryas baroni--an attractively colored snake--has become readily available through the exotic pet trade. Most people consider this species harmless; however, it has already caused human envenomation. As little is known about the venom from this South American opisthoglyphous "colubrid" snake, herein, we studied its protein composition by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), as well as its effects on the hemostatic system. Both reducing and nonreducing SDS-PAGE analysis demonstrated that the venom exhibits greatest complexity in the range of 50-80 kDa. The venom displayed proteolytic activity toward azocollagen, with a specific activity of 75.5 U mg-1, and rapidly hydrolyzed the Aalpha-chain of fibrinogen, exhibiting lower activity toward the Bbeta- and gamma-chains. The venom from P. baroni showed no platelet proaggregating activity per se, but it inhibited collagen- and thrombin-induced platelet aggregation. Prominent hemorrhage developed in mouse skin after intradermal injection of the crude venom, and its minimum hemorrhagic dose was 13.9 MUg. When injected intramuscularly into the gastrocnemius of mice, the venom induced local effects such as hemorrhage, myonecrosis, edema, and leucocyte infiltration. Due to its venom toxicity shown herein, P. baroni should be considered dangerous to humans and any medically significant bite should be promptly reviewed by a qualified health professional. PMID- 23801000 TI - Understanding mild acid pretreatment of sugarcane bagasse through particle scale modeling. AB - Sugarcane bagasse is an abundant and sustainable resource, generated as a by product of sugarcane milling. The cellulosic material within bagasse can be broken down into glucose molecules and fermented to produce ethanol, making it a promising feedstock for biofuel production. Mild acid pretreatment hydrolyses the hemicellulosic component of biomass, thus allowing enzymes greater access to the cellulosic substrate during saccharification. A particle-scale mathematical model describing the mild acid pretreatment of sugarcane bagasse has been developed, using a volume averaged framework. Discrete population-balance equations are used to characterise the polymer degradation kinetics, and diffusive effects account for mass transport within the cell wall of the bagasse. As the fibrous material hydrolyses over time, variations in the porosity of the cell wall and the downstream effects on the reaction kinetics are accounted for using conservation of volume arguments. Non-dimensionalization of the model equations reduces the number of parameters in the system to a set of four dimensionless ratios that compare the timescales of different reaction and diffusion events. Theoretical yield curves are compared to macroscopic experimental observations from the literature and inferences are made as to constraints on these "unknown" parameters. These results enable connections to be made between experimental data and the underlying thermodynamics of acid pretreatment. Consequently, the results suggest that data-fitting techniques used to obtain kinetic parameters should be carefully applied, with prudent consideration given to the chemical and physiological processes being modeled. PMID- 23801001 TI - Anatomical education and surgical simulation based on the Chinese Visible Human: a three-dimensional virtual model of the larynx region. AB - Anatomical knowledge of the larynx region is critical for understanding laryngeal disease and performing required interventions. Virtual reality is a useful method for surgical education and simulation. Here, we assembled segmented cross-section slices of the larynx region from the Chinese Visible Human dataset. The laryngeal structures were precisely segmented manually as 2D images, then reconstructed and displayed as 3D images in the virtual reality Dextrobeam system. Using visualization and interaction with the virtual reality modeling language model, a digital laryngeal anatomy instruction was constructed using HTML and JavaScript languages. The volume larynx models can thus display an arbitrary section of the model and provide a virtual dissection function. This networked teaching system of the digital laryngeal anatomy can be read remotely, displayed locally, and manipulated interactively. PMID- 23801002 TI - Physiologic effects of dry needling. AB - During the past decades, worldwide clinical and scientific interest in dry needling (DN) therapy has grown exponentially. Various clinical effects have been credited to dry needling, but rigorous evidence about its potential physiological mechanisms of actions and effects is still lacking. Research identifying these exact mechanisms of dry needling action is sparse and studies performed in an acupuncture setting do not necessarily apply to DN. The studies of potential effects of DN are reviewed in reference to the different aspects involved in the pathophysiology of myofascial triggerpoints: the taut band, local ischemia and hypoxia, peripheral and central sensitization. This article aims to provide the physiotherapist with a greater understanding of the contemporary data available: what effects could be attributed to dry needling and what are their potential underlying mechanisms of action, and also indicate some directions at which future research could be aimed to fill current voids. PMID- 23801003 TI - Borderline personality disorder and chronic pain: a practical approach to evaluation and treatment. AB - Patients with chronic pain present a spectrum of complexity that can be overwhelming for the individual practitioner. These patients require thoughtful care and a comprehensive treatment plan. This complexity should be acknowledged, not avoided, and the patient should be engaged, not shunned. A practical approach will assist in developing expertise and proceeding empathically. The presence of a superimposed personality disorder significantly increases the difficulty of caring for these patients. Studies investigating the prevalence of borderline personality disorder in patients with chronic pain averaged 30 %, highlighting the importance of being able to effectively treat this patient population. Appropriate management of these patients should focus on a collaboration to practice productive behaviors despite intense emotional distress. Longitudinal research provides a foundation for an optimistic prognosis that can be enhanced with this rehabilitative approach. PMID- 23801004 TI - Headache and epilepsy. AB - Headache and epilepsy often co-occur. Epidemiologic studies conducted in the past few years reinforce the notion of a bi-directional association between migraine and epilepsy. Data on an association between headache (in general) and epilepsy, however, are less clear. Peri-ictal headache often presents with migraine-like symptoms and can be severe. A correct diagnosis and management are paramount. It was demonstrated that cortical hyperexcitability may underlie both epilepsy and migraine. A recent study linked spreading depolarisation, the supposed underlying pathophysiological mechanism of migraine with aura, to epilepsy. Although this study was carried out in patients who had suffered a subarachnoid haemorrhage, the finding may shed light on pathophysiological mechanisms common to epilepsy and migraine. PMID- 23801005 TI - Fascial components of the myofascial pain syndrome. AB - Myofascial pain syndrome (MPS) is described as the muscle, sensory, motor, and autonomic nervous system symptoms caused by stimulation of myofascial trigger points (MTP). The participation of fascia in this syndrome has often been neglected. Several manual and physical approaches have been proposed to improve myofascial function after traumatic injuries, but the processes that induce pathological modifications of myofascial tissue after trauma remain unclear. Alterations in collagen fiber composition, in fibroblasts or in extracellular matrix composition have been postulated. We summarize here recent developments in the biology of fascia, and in particular, its associated hyaluronan (HA)-rich matrix that address the issue of MPS. PMID- 23801006 TI - Clinical implication of latent myofascial trigger point. AB - Myofascial trigger points (MTrPs) are hyperirritable points located within a taut band of skeletal muscle or fascia, which cause referred pain, local tenderness and autonomic changes when compressed. There are fundamental differences between the effects produced by the two basic types of MTrPs (active and latent). Active trigger points (ATrPs) usually produce referred pain and tenderness. In contrast, latent trigger points (LTrPs) are foci of hyperirritability in a taut band of muscle, which are clinically associated with a local twitch response, tenderness and/or referred pain upon manual examination. LTrPs may be found in many pain free skeletal muscles and may be "activated" and converted to ATrPs by continuous detrimental stimuli. ATrPs can be inactivated by different treatment strategies; however, they never fully disappear but rather convert to the latent form. Therefore, the diagnosis and treatment of LTrPs is important. This review highlights the clinical implication of LTrPs. PMID- 23801007 TI - Complementary therapies for fibromyalgia syndrome -- a rational approach. AB - Fibromyalgia syndrome (FMS) is a complex chronic condition, the treatment of which still poses many challenges. Complementary therapies (CT) have gained increasing popularity among FMS patients. Past reviews evaluating effectiveness of CT for treatment of FMS revealed some potential benefits arising from certain modalities. However, with the data available, it becomes difficult to formulate a unique opinion about this matter. In the present paper, the authors propose some guidelines to conciliate the expectations of patients with the lack of solid evidence, in a practicable yet responsible way. Many items should be considered before prescribing, proscribing, or tolerating a CT, besides results from randomized controlled trials, such as efficacy (mechanisms of action); effectiveness (effect in practice); efficiency (cost-benefit ratio); safety; risk benefit ratio; legislation; healthcare service involvement; practitioner characteristics; objective (purpose); and the potential of combination with conventional treatment. PMID- 23801008 TI - The role of vitamin D in pathophysiology and treatment of fibromyalgia. AB - Recent studies showed that most cells have receptors and enzymes responsible for metabolism of vitamin D. Several diseases have been linked to vitamin D deficiency, such as hypertension, diabetes, depression, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and chronic pain syndromes such as fibromyalgia. The association between fibromyalgia and vitamin D deficiency is very controversial in the literature with conflicting studies and methodological problems, which leads to more questions than answers. The purpose of this article is to raise questions about the association of hypovitaminosis D with fibromyalgia considering causal relationships, treatment, and pathophysiological explanations. PMID- 23801010 TI - A 4 + 4 strategy for synthesis of zeolitic metal-organic frameworks: an indium MOF with SOD topology as a light-harvesting antenna. AB - A zeolitic metal-organic framework with a SOD topology, (Et2NH2)[In(BCBAIP)].4DEF.4EtOH (H4BCBAIP: 5-(bis(4 carboxybenzyl)amino)isophthalic acid) (1), has been constructed by a 4 + 4 synthetic strategy from tetrahedral organic building units and In(3+) ions. Compound 1 could adsorb organic dyes and be used as a light-harvesting antenna. PMID- 23801009 TI - Worldwide epidemiology of fibromyalgia. AB - Studying the epidemiology of fibromyalgia (FM) is very important to understand the impact of this disorder on persons, families and society. The recent modified 2010 classification criteria of the American College of Rheumatology (ACR), without the need of tender points palpation, allows that larger and nationwide surveys may be done, worldwide. This article reviews the prevalence and incidence studies done in the general population, in several countries/continents, the prevalence of FM in special groups/settings, the association of FM with some sociodemographic characteristics of the population, and the comorbidity of FM with others disorders, especially with headaches. PMID- 23801011 TI - Effect of ovarian stimulation with recombinant follicle-stimulating hormone, gonadotropin-releasing hormone agonist and antagonists, on follicular fluid stem cell factor and serum urocortin 1 levels on the day of oocyte retrieval. AB - PURPOSE: To compare the serum and follicular fluid (FF) concentrations of stem cell factor (SCF) as well as the serum urocortin 1 (UCN1) concentration in gonadotropin-releasing hormone antagonist (GnRH-ant) and gonadotropin-releasing hormone agonist (GnRH-a) protocols for controlled ovarian hyperstimulation (COH) in IVF patients. METHODS: Follicular fluids and blood samples of 42 infertile women undergoing COH for IVF-embryo transfer with either GnRH agonist (n = 22) or GnRH antagonist (n = 20) protocols from 2010 to 2011 were collected during oocyte retrieval. SCF concentrations of serum and FF were assessed by sandwich enzyme immunoassay using ELISA Kit for SCF kid. Serum UCN1 concentration were measured using commercially available enzyme-linked immunosorbent assay. RESULTS: Concentrations of serum UCN1, serum and FF SCF were similar in the two groups. The serum SCF levels correlated strongly with the follicular SCF levels (r = 0.770, p < 0.001). The mean implantation rate, biochemical and clinical pregnancy rate and live birth rate per cycle were also similar in the groups. CONCLUSIONS: These observations suggest that there is no significant difference in follicular microenvironment in terms of SCF and UCN1 between agonist and antagonist protocols. PMID- 23801012 TI - Associations between change in sleep duration and inflammation: findings on C reactive protein and interleukin 6 in the Whitehall II Study. AB - Cross-sectional evidence suggests associations between sleep duration and levels of the inflammatory markers, C-reactive protein and interleukin-6. This longitudinal study uses data from the London-based Whitehall II study to examine whether changes in sleep duration are associated with average levels of inflammation from 2 measures 5 years apart. Sleep duration (<=5, 6, 7, 8, >=9 hours on an average week night) was assessed in 5,003 middle-aged women and men in 1991/1994 and 1997/1999. Fasting levels of C-reactive protein and interleukin 6 were measured in 1997/1999 and 2002/2004. Cross-sectional analyses indicated that shorter sleep is associated with higher levels of inflammatory markers. Longitudinal analyses showed that each hour per night decrease in sleep duration between 1991/1994 and 1997/1999 was associated with higher levels of C-reactive protein (8.1%) and interleukin-6 (4.5%) averaged across measures in 1997/1999 and 2002/2004. Adjustment for longstanding illness and major cardiometabolic risk factors indicated that disease processes may partially underlie these associations. An increase in sleep duration was not associated with average levels of inflammatory markers. These results suggest that both short sleep and reductions in sleep are associated with average levels of inflammation over a 5 year period. PMID- 23801013 TI - Serial monogamy and biologic concurrency: measurement of the gaps between sexual partners to inform targeted strategies. AB - Having multiple sexual partners concurrently increases the risk of transmission of a sexually transmitted infection. Even if partnerships do not overlap, transmission potential exists when the gap between partnerships is shorter than the remaining infectious period. In the present article, we quantify the gap between partners to assess transmission potential using data collected by a cross sectional survey of 2,203 genitourinary medicine clinic patients in England in 2009. Questionnaires asked about patients' 3 most recent partnerships. Gaps were calculated as time (days) between the last sexual encounter with a former partner and the first sexual encounter with the next partner. Among 1,875 patients who reported 1 or more partners in the previous 3 months, 47.6% of men and 27.7% of women reported 2 or more partners. Forty-two percent of the gaps were negative (i.e., partnerships that were concurrent); the median gaps were -7 and -17 days for men and women, respectively (i.e., overlaps were 7 and 17 days for men and women, respectively). Although half of the gaps were positive (serially monogamous partnerships), many were of short duration; the median gaps were 14 and 24 days for men and women, respectively. In over half of the gaps, condoms were used inconsistently with one or both partners, and in one-quarter, condoms were never used with either partner. There is thus a high potential for sexually transmitted infections, as even if partnerships are not behaviorally concurrent, they may be biologically concurrent. These data have important implications for designing and targeting effective health promotion messages. PMID- 23801014 TI - Beyond surveillance: a role for respondent-driven sampling in implementation science. AB - We are now in the fourth decade of the human immunodeficiency virus (HIV) pandemic. Several novel prevention tools have been identified, and prevalence and incidence have declined in many settings. A remaining challenge is the delivery of preventive interventions to hard-to-reach populations, including men who have sex with men and injection drug users. Leaders in the field of HIV have called for a new focus on implementation science, which requires a shift in thinking from individual randomized controlled trials to cluster-randomized trials. Multiple challenges need to be addressed in the conduct of cluster-randomized trials, including: 1) generalizability of the study population to the target population, 2) potential contamination through overlap/exchange of members of control and intervention clusters, and 3) evaluation of effectiveness at multiple levels of influence. To address these key challenges, we propose a novel application of respondent-driven sampling-a chain-referral strategy commonly used for surveillance-in the recruitment of participants for the evaluation of a cluster-randomized trial of a community intervention. We illustrate this application with an empirical example of a cluster-randomized trial that is currently under way to assess the effectiveness of men's wellness centers in improving utilization of HIV counseling and testing among men who have sex with men in India. PMID- 23801015 TI - Family history and its association to curve size and treatment in 1,463 patients with idiopathic scoliosis. AB - PURPOSE: To study family history in relation to curve severity, gender, age at diagnosis and treatment in idiopathic scoliosis. METHODS: A self-assessment questionnaire on family history of scoliosis was administered to 1,463 untreated, brace or surgically treated idiopathic scoliosis patients. RESULTS: Out of the 1,463 patients, 51 % had one or more relatives with scoliosis. There was no significant difference between females and males, nor between juvenile and adolescent study participants in this respect (p = 0.939 and 0.110, respectively). There was a significant difference in maximum curve size between patients with one or more relatives with scoliosis (median 35 degrees , interquartile range 25) and patients without any relative with scoliosis (median 32 degrees , interquartile range 23) (p = 0.022). When stratifying patients according to treatment (observation, brace treatment or surgery), we found that it was more common to have a relative with scoliosis among the treated patients (p = 0.011). The OR for being treated was 1.32 (95% CI 1.06-1.64) when the patient had a relative with scoliosis, compared to not having. CONCLUSIONS: Larger curve sizes were found in patients with a family history of scoliosis than in the ones without. No relation between family history and gender or between family history and age at onset of idiopathic scoliosis was found. Although the presence of a family history of scoliosis may not be a strong prognostic risk factor, it indicates that these patients are at higher risk of developing a more severe curve. PMID- 23801016 TI - Surgical outcomes of posterior thoracic interbody fusion for thoracic disc herniations. AB - INTRODUCTION: Surgical strategy for thoracic disc herniation (TDH) remains controversial. We have performed posterior thoracic interbody fusion (PTIF) by bilateral total facetectomies with pedicle screw fixation. The objectives of this retrospective study are to demonstrate the surgical outcomes of PTIF for TDH. MATERIALS AND METHODS: We enrolled 11 patients who underwent PTIF for myelopathy due to TDH and were followed for at least 1 year. The mean age at surgery was 55.2 years and the average period of follow-up was 4.3 years. The levels of operation were T10-T11 in three cases, T12-L1 in three, and T2-T3, T3-T4, T9-T10, T11-T12, and T10-T12 in one case, respectively. The pre- and postoperative clinical status was evaluated according to the modified Frankel grade and the Japanese Orthopaedic Association (JOA) score modified for thoracic myelopathy. Additionally, postoperative complications were assessed. Local kyphosis at the operated segment and status of fusion were evaluated using plain radiographs and computed tomography. RESULTS: Improvement of at least one modified Frankel grade was observed in all but one patient. Average pre- and postoperative JOA scores were 4.9 and 8.8 points, respectively. The average recovery rate was 61%. Bony union was observed in ten cases. One patient's postsurgical outcome resulted in pseudoarthrosis, which required revision surgery due to kyphosis deterioration. Cerebrospinal fluid leakage was observed in one patient postoperatively with neither neurological deficit nor evidence of infection. CONCLUSION: PTIF has produced satisfactory outcomes for myelopathy due to TDH. Therefore, PTIF is one of the surgical treatments of choice for patients with TDH causing myelopathy. PMID- 23801017 TI - Robot-assisted and fluoroscopy-guided pedicle screw placement: a systematic review. AB - PURPOSE: At present, most spinal surgeons undertake pedicle screw implantation using either anatomical landmarks or C-arm fluoroscopy. Reported rates of screw malposition using these techniques vary considerably, though the evidence generally favors the use of image-guidance systems. A miniature spine-mounted robot has recently been developed to further improve the accuracy of pedicle screw placement. In this systematic review, we critically appraise the perceived benefits of robot-assisted pedicle screw placement compared to conventional fluoroscopy-guided technique. METHODS: The Cochrane Central Register of Controlled Trials, PubMed, and EMBASE databases were searched between January 2006 and January 2013 to identify relevant publications that (1) featured placement of pedicle screws, (2) compared robot-assisted and fluoroscopy-guided surgery, (3) assessed outcome in terms of pedicle screw position, and (4) present sufficient data in each arm to enable meaningful comparison (>10 pedicle screws in each study group). RESULTS: A total of 246 articles were retrieved, of which 5 articles met inclusion criteria, collectively reporting placement of 1,308 pedicle screws (729 robot-assisted, 579 fluoroscopy-guided). The findings of these studies are mixed, with limited higher level of evidence data favoring fluoroscopy-guided procedures, and remaining comparative studies supporting robot assisted pedicle screw placement. CONCLUSIONS: There is insufficient evidence to unequivocally recommend one surgical technique over the other. Given the high cost of robotic systems, and the high risk of spinal surgery, further high quality studies are required to address unresolved clinical equipoise in this field. PMID- 23801019 TI - March of the living, a holocaust educational tour: effect on adolescent Jewish identity. AB - March of the Living (MOTL) is a worldwide two-week trip for high school seniors to learn about the Holocaust by traveling to sites of concentration/death camps and Jewish historical sites in Poland and Israel. The mission statement of MOTL International states that participants will be able to "bolster their Jewish identity by acquainting them with the rich Jewish heritage in pre-war Eastern Europe." However, this claim has never been studied quantitatively. Therefore, 152 adolescents who participated in MOTL voluntarily completed an initial background questionnaire, a Jewish Identity Survey and a Global Domains Survey pre-MOTL, end-Poland and end-Israel. Results suggest that Jewish identity did not substantially increase overall or from one time period to the next. PMID- 23801018 TI - Summary measures of adherence using pill counts in two HIV prevention trials: the need for standardisation in reporting. AB - For trials of user-dependent HIV prevention products, accurate adherence measurements are essential to interpret and compare results across trials. We used pill count data from two recent HIV prevention trials of herpes simplex virus type 2 (HSV-2) suppression, to show that estimates of adherence vary substantially depending on assumptions that are made in analysing pill count data. We associate calculated adherence with biological markers of anti-HSV-2 activity. In both trials, calculated adherence varied considerably, depending on the summary measure used, and the handling of intervals with apparent 'over adherence' (fewer pills returned than expected), and unreturned pills. Intervals of apparent over-adherence were associated with reduced antiviral effects on biological markers of herpes reactivation, indicating these are likely to represent periods of non-adherence. Our results demonstrate the clear need for standardisation in reporting of adherence data that are based on pill counts. PMID- 23801020 TI - Brain natriuretic peptide and cardiac resynchronization therapy in patients with mildly symptomatic heart failure. AB - BACKGROUND: There are limited data on the prognostic implications of brain natriuretic peptide (BNP) assessment in patients with mildly symptomatic heart failure (HF) who receive cardiac resynchronization therapy with a defibrillator (CRT-D). METHODS AND RESULTS: The effect of elevated baseline and 1-year BNP levels (dichotomized at the upper tertile BNP of 120 pg/mL) on the risk of HF or death was assessed among the cohort of 1197 patients with baseline BNP data enrolled in MADIT (Multicenter Automated Defibrillator Implantation Trial)-CRT. Elevated baseline BNP was associated with a significant 68% (P=0.007) and 58% (P=0.02) increase in the risk of HF or death among MADIT-CRT patients allocated to CRT-D and implantable cardioverter defibrillator-only therapy, respectively. At 1 year of follow-up, patients allocated to CRT-D displayed significantly greater reductions in BNP (26% reduction) levels compared with implantable cardioverter defibrillator-only patients (8% increase; P=0.005). Patients with CRT-D in whom 1-year BNP levels were reduced or remained low experienced a significantly lower risk of subsequent HF or death as compared with patients in whom 1-year BNP levels were high. Similarly, the echocardiographic response to CRT-D was highest among those who maintained low BNP levels or in whom BNP level at 1-year was reduced. CONCLUSIONS: Our findings suggest that assessment of baseline and follow-up BNP provides important prognostic implications in patients with mildly symptomatic HF who receive CRT. PMID- 23801021 TI - Co-occurring eating and psychiatric symptoms in Taiwanese college students: effects of gender and parental factors. AB - OBJECTIVE: To test whether gender and parental factors moderate the relationships between symptoms of eating disorder (ED) and other psychiatric symptoms. METHODS: A total of 5,015 new entrants completed several questionnaires and 541 individuals with ED symptoms were identified by the Adult Self-Report Inventory-4 that assessed a wide range of Diagnostic and Statistical Manual of Mental Disorders Fourth Edition psychopathology. The participants also reported on their parents' attitude toward them before their ages of 16. RESULTS: ED symptoms, female gender, less parental care, and more parental protection were associated with more severe co-occurring psychiatric symptoms. Gender and parental factors also demonstrated differential moderating effects on the relationships between ED and co-occurring psychiatric symptoms. CONCLUSIONS: Parenting counseling may be individualized to young adults with ED symptoms and different co-occurring psychiatric symptoms. PMID- 23801023 TI - Strain, negative emotions, and juvenile delinquency: the United States versus taiwan. AB - General strain theory (GST) is an established criminological theory. Although the theory has been examined by many and enjoys empirical support, some limitations of previous studies need to be addressed. Many previous studies rely heavily on samples from Western countries, mostly the United States; thus, possible cultural influences are ignored. Although a few studies have moved forward by using subjects from Asia (e.g., China, Korea), these studies only provide empirical results regarding whether GST is applicable in other cultures. However, these studies do not directly compare Western and Eastern countries. The present study used two samples from the United States and Taiwan to directly compare and contrast central GST propositions. Although most of the GST propositions are found to be similar between the U.S. and Taiwanese juveniles, some differences were also discovered. Explanation of these similarities and differences from their cultural perspectives are offered in this study. PMID- 23801022 TI - Brain tumor stem cell multipotency correlates with nanog expression and extent of passaging in human glioblastoma xenografts. AB - Glioblastoma multiforme (GBM) is the most common primary brain tumor, with a median survival of only 15 months. A subpopulation of cells, the brain tumor stem cells (BTSCs), may be responsible for the malignancy of this disease. Xenografts have proven to be a robust model of human BTSCs, but the effects of long-term passaging have yet to be determined. Here we present a study detailing changes in BTSC multipotency, invasive migration, and proliferation after serial passaging of human GBM xenografts. Immunocytochemistry and tumorsphere formation assays demonstrated the presence of BTSCs in both early generation (EG-BTSCs; less than 15 passages) and late generation (LG-BTSCs; more than 24 passages) xenografts. The EG-BTSCs upregulated expression of lineage markers for neurons and oligodendrocytes upon differentiation, indicating multipotency. In contrast, the LG-BTSCs were restricted to an astrocytic differentiation. Quantitative migration and proliferation assays showed that EG-BTSCs are more migratory and proliferative than LG-BTSCs. However, both populations respond similarly to the chemokine SDF-1 by increasing invasive migration. These differences between the EG- and LG-BTSCs were correlated with a significant decrease in nanog expression as determined by qRT-PCR. Mice implanted intracranially with EG-BTSCs showed shorter survival when compared to LG-BTSCs. Moreover, differentiation prior to implantation of EG-BTSCs, but not LG-BTSCs, led to increased survival. Thus, nanog may identify multipotent BTSCs. Furthermore, limited passaging of xenografts preserves these multipotent BTSCs, which may be an essential underlying feature of GBM lethality. PMID- 23801024 TI - Normal metabolic flexibility despite insulin resistance women with polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is a common heterogeneous disorder, where insulin resistance might be involved in the development of endocrine and metabolic abnormalities. Insulin resistance (IR) is connected with disturbances in switching between lipid and carbohydrate oxidation in response to insulin, called "metabolic inflexibility". The aim of the present study was to estimate the whole-body insulin sensitivity, lipid and carbohydrate oxidation, metabolic flexibility in lean and obese PCOS women. The study group consisted of 92 women with PCOS, 40 lean (BMI<25 kg/m2) and 52 overweight or obesity (BMI>25 kg/m2), and 30 healthy normally menstruating women (14 lean and 16 overweight/obese) with normal glucose tolerance. Hyperinsulinemic euglycemic clamp and indirect calorimetry were performed. An increase in respiratory exchange ratio in response to insulin was used as a measure of metabolic flexibility. Both the presence of PCOS (P<0.001) and obesity (P=0.005) were independently characterized by lower insulin sensitivity. PCOS (P=0.002) and obesity (P=0.001) independently predisposed to the lower non-oxidative glucose metabolism. Obese women had lower glucose oxidation (P=0.005) and higher lipid oxidation (P<0.001) in insulin stimulated conditions in comparison to lean subject whereas PCOS had no effect on these parameters (P=0.29 and P=0.43; respectively). Metabolic flexibility was impaired in the obese (P=0.001) but it was not influenced by the presence of PCOS (P=0.78). Our data indicate that PCOS women have normal metabolic flexibility, which could suggest a distinct pathophysiological mechanism for insulin resistance in this group. PMID- 23801025 TI - Catheter-over-needle method facilitates effective continuous infraclavicular block. PMID- 23801026 TI - One-pot direct C-H arylation of arenes in water catalysed by RuCl3.nH2O-NaOAc in the presence of Zn. AB - The inexpensive and commercially available catalytic system RuCl3.nH2O-NaOAc-Zn is active in water for the direct C-H arylation of arenes with aryl/heteroaryl chlorides. The reaction can be accelerated by the use of microwave irradiation and can also be scaled up to a multi-gram scale with excellent isolated yields. PMID- 23801027 TI - Supplemented alphaMEM/F12-based medium enables the survival and growth of primary ovarian follicles encapsulated in alginate hydrogels. AB - Hydrogel-encapsulating culture systems for ovarian follicles support the in vitro growth of secondary follicles from various species including mouse, non-primate human, and human; however, the growth of early stage follicles (primary and primordial) has been limited. While encapsulation maintains the structure of early stage follicles, feeder cell populations, such as mouse embryonic fibroblasts (MEFs), are required to stimulate growth and development. Hence, in this report, we investigated feeder-free culture environments for early stage follicle development. Mouse ovarian follicles were encapsulated within alginate hydrogels and cultured in various growth medium formulations. Initial studies employed embryonic stem cell medium formulations as a tool to identify factors that influence the survival, growth, and meiotic competence of early stage follicles. The medium formulation that maximized survival and growth was identified as alphaMEM/F12 supplemented with fetuin, insulin, transferrin, selenium, and follicle stimulating hormone (FSH). This medium stimulated the growth of late primary (average initial diameter of 80 um) and early secondary (average initial diameter of 90 um) follicles, which developed antral cavities and increased to terminal diameters exceeding 300 um in 14 days. Survival ranged from 18% for 80 um follicles to 36% for 90 um follicles. Furthermore, 80% of the oocytes from surviving follicles with an initial diameter of 90-100 um underwent germinal vesicle breakdown (GVBD), and the percentage of metaphase II (MII) eggs was 50%. Follicle/oocyte growth and GVBD/MII rates were not significantly different from MEF co-culture. Survival was reduced relative to MEF co-culture, yet substantially increased relative to the control medium that had been previously used for secondary follicles. Continued development of culture medium could enable mechanistic studies of early stage folliculogenesis and emerging strategies for fertility preservation. PMID- 23801029 TI - Study protocol: trial of inflation osteoplasty in the management of tibial plateau fractures. AB - INTRODUCTION: Restoration of articular congruency is a key factor in preventing post-traumatic osteoarthritis following tibial plateau fractures. Current surgical techniques using a bone tamp carry the risk of joint perforation and comminution of the depressed fragments which affect patient outcome. Successful use of inflation osteoplasty has been reported in both in vitro studies (Broome et al. in J Orthopaed Traumatol 13(2):89-95, 2012; Mauffrey et al. in Patient Saf Surg 6:6, 2012) and case reports in the management of fractures of the calcaneus, cuboid, distal radius, tibial plateau and acetabulum (Gupta et al. in Foot Ankle Int 32(2):205-210, 2011; Heim et al. in Foot Ankle Int 29(11):1154-1157, 2008; Konig et al. in Case Rep Unfallchirurg 109(4):328-331, 2006; Reiley in J Orthop Trauma 17:141-163, 2006). The aim of our study is to assess whether the use of the balloon osteoplasty improves the quality of reduction of a depressed tibial plateau fracture when compared to traditional methods of fracture reduction. METHOD: This is a single-centred randomised trial. We will recruit 24 adult patients admitted with either a depressed or split depressed tibial plateau fracture (medial or lateral) requiring surgical intervention. Consenting patients will be randomly allocated to the two treatment groups. Patients with concomitant injuries influencing the management of the tibial plateau fracture will be excluded from our study. The primary outcome measure is the quality of reduction based on the post-operative CT scan. Secondary outcome measures will be any surgical complication and patient satisfaction, measured using the Oxford Knee score and SF12 questionnaire at 3, 6 and 12 months. Principal analysis will be for the success of fracture reduction from the two techniques and the effect the operative technique had on patient satisfaction and the prevalence of surgical complications. PMID- 23801028 TI - Genome reduction as the dominant mode of evolution. AB - A common belief is that evolution generally proceeds towards greater complexity at both the organismal and the genomic level, numerous examples of reductive evolution of parasites and symbionts notwithstanding. However, recent evolutionary reconstructions challenge this notion. Two notable examples are the reconstruction of the complex archaeal ancestor and the intron-rich ancestor of eukaryotes. In both cases, evolution in most of the lineages was apparently dominated by extensive loss of genes and introns, respectively. These and many other cases of reductive evolution are consistent with a general model composed of two distinct evolutionary phases: the short, explosive, innovation phase that leads to an abrupt increase in genome complexity, followed by a much longer reductive phase, which encompasses either a neutral ratchet of genetic material loss or adaptive genome streamlining. Quantitatively, the evolution of genomes appears to be dominated by reduction and simplification, punctuated by episodes of complexification. PMID- 23801030 TI - Laboratory evaluation of thermal protective clothing performance upon hot liquid splash. AB - This study provides an understanding of heat and mass transfer through materials exposed to hot liquid splash, a relatively unexplored hazard in the safety clothing industry. Selected fabrics and layered systems were exposed to three hot liquids to study the effects of hot liquids and configuration. To explore the energy transfer mechanisms, a modified apparatus (based on ASTM F 2701-08) was developed to assess the protection performance provided by a fabric when exposed to a hot liquid. The modified test method allows measurement of the energy absorbed by the sensor, and with the use of a skin model, the time required to produce a second-degree burn injury was predicted. The preliminary testing demonstrated that mass transfer of the hot liquid through the fabric is the main factor contributing to burn injury. Key factors that determine the level of protection that a fabric system provides are summarized. PMID- 23801031 TI - Liver resection following FOLFOXIRI plus bevacizumab: a detailed pathological review. PMID- 23801032 TI - Primary breast cancer stem-like cells metastasise to bone, switch phenotype and acquire a bone tropism signature. AB - BACKGROUND: Bone metastases represent a common and severe complication in breast cancer, and the involvement of cancer stem cells (CSCs) in the promotion of bone metastasis is currently under discussion. Here, we used a human-in-mice model to study bone metastasis formation due to primary breast CSCs-like colonisation. METHODS: Primary CD44+CD24- breast CSCs-like were transduced by a luciferase lentiviral vector and injected through subcutaneous and intracardiac (IC) routes in non-obese/severe-combined immunodeficient (NOD/SCID) mice carrying subcutaneous human bone implants. The CSCs-like localisation was monitored by in vivo luciferase imaging. Bone metastatic CSCs-like were analysed through immunohistochemistry and flow cytometry, and gene expression analyses were performed by microarray techniques. RESULTS: Breast CSCs-like colonised the human implanted bone, resulting in bone remodelling. Bone metastatic lesions were histologically apparent by tumour cell expression of epithelial markers and vimentin. The bone-isolated CSCs-like were CD44-CD24+ and showed tumorigenic abilities after injection in secondary mice. CD44-CD24+ CSCs-like displayed a distinct bone tropism signature that was enriched in genes that discriminate bone metastases of breast cancer from metastases at other organs. CONCLUSION: Breast CSCs-like promote bone metastasis and display a CSCs-like bone tropism signature. This signature has clinical prognostic relevance, because it efficiently discriminates osteotropic breast cancers from tumour metastases at other sites. PMID- 23801036 TI - Bacterial meningitis in older adults. AB - OPINION STATEMENT: The burden of disease due to bacterial meningitis is shifting toward older adults. Clinicians should maintain a high level of suspicion of meningitis in older adults, since they may present without classic signs and symptoms. Clinicians should remember that more older patients are at risk of healthcare-associated meningitis and may be at risk of more resistant organisms. A lumbar puncture should be performed as quickly as possible. If a CT scan is required before the lumbar puncture, blood cultures should be drawn and appropriate empiric antibiotics should be started before sending the patient to the CT scanner. Empiric antibiotics should be chosen based on patient history, review of patient's known illnesses and risk factors, results of CSF Gram stain, and local institution antibiotic resistance patterns. Clinicians should remember that Streptococcus pneumoniae may be resistant to penicillin and cephalosporins, so vancomycin is usually also administered until the bacterial resistance pattern is known. Adjunctive dexamethasone may be started before or at the time of antibiotic therapy based on risk versus benefit analysis, and may be discontinued if patient is found to not have Streptococcus pneumoniae meningitis. PMID- 23801037 TI - Cuticular fatty acid profile analysis of three Rhipicephalus tick species (Acari: Ixodidae). AB - Cuticular fatty acids (CFA) are important constituents of the arthropod exoskeleton, serving as structural and defense components, and participating in intra-species communication. Here we describe for the first time a comparative analysis of the CFA profiles of three tick species of the genus Rhipicephalus: R. annulatus, R. bursa and R. sanguineus. CFA profiles were determined for R. bursa and R. sanguineus grown both on rabbit or calf, and for R. annulatus grown on calf. CFA composition was compared for each species before and after ethanol treatment, for different hosts of each species, and between the different species. Our data suggest that adsorption of the host's fatty acids changes the apparent CFA composition. Ethanol treatment efficiently removed the unbound fatty acids from the ticks and revealed the actual composition. Comparison between ticks grown on rabbit versus calf showed significant difference in the relative abundance of fatty acids C14 and 9,12-C18:2 for R. bursa, and a difference in the relative abundance of C14 for R. sanguineus. Comparison of the CFA between the three species revealed significant differences in the abundance of fatty acids C16, 9,12-C18:2, 9-C18:1, C18 and C20. Our results show that while the host had a minor effect on CFA composition within each species, significant differences were observed in the CFA profiles of different species. We suggest that CFA profiles may be used to distinguish between related species. CFA analysis can also be used in studies of communication and defense mechanisms in ticks and other arthropods. PMID- 23801038 TI - Temperature-dependent life history of Oligonychus mangiferus (Acari: Tetranychidae) on Mangifera indica. AB - The mango red spider mite, Oligonychus mangiferus (Rhaman and Sapra), is a major mango pest in Taiwan. This mite damages the leaves of the mango tree and affects the quality of the fruit. This study investigates the life history of the mango red spider mite on Mangifera indica L. cv. Irwin at five constant temperatures (17, 21, 25, 29, and 33 degrees C), under 80 +/- 5 % RH and L12:D12 photoperiod conditions. An increase in temperature significantly decreased the developmental times for each stage and the overall immature period in females and males. The lower developmental thresholds of the immature stage were 12.5 and 12.4 degrees C for females and males, respectively. The thermal summations for the development of the immature stage were 185.9 and 175.7 degree-days for females and males, respectively. Based on the annual field temperature, an estimated 26 generations can reproduce in a mango orchard annually. The longevity of adults of both sexes decreased as temperature increased, and adult males lived longer than females. The preoviposition periods were shorter than 1 day when the temperature exceeded 25 degrees C. The development period and the oviposition period were shortest at 29 degrees C. At this point, daily fecundity was highest, and fecundity was second highest, resulting in the highest intrinsic rate of increase (r m ), 0.182 day(-1). These life history traits are applied to improve the management of O. mangiferus. PMID- 23801039 TI - [Unicompartimental joint (Oxford III) with mobile bearing : Minimally invasive implantation of a in the medial compartiment]. AB - OBJECTIVE: Replacement of the joint surfaces in the medial compartment by an endoprothesis with a mobile bearing. INDICATIONS: Unicompartimental anteromedial gonarthrosis with an intact anterior cruciate ligament. Avascular necrosis at the medial femoral condyle. CONTRAINDICATIONS: Third to fourth degree cartilage damage in the lateral compartment. Lateral menisectomy. Symptomatic osteoarthritis in the femoropatellar joint. Chronic polyarthritis. More than 15 degrees varus. Varus passive not redressable. Medial or lateral subluxation. More than 15 degrees extension deficit. Passive flexion less than 110 degrees . Cruciate ligament lesions with instability. Poor soft tissue conditions. SURGICAL TECHNIQUE: The leg is mounted on an electric leg holder that allows flexion up to 120 degrees . The joint is opened via an anteromedial arthrotomy starting at the medial border of the patella and ending 3 cm below the tibia plateau. The osteophytes are resected and the tibial resection is performed with an oscillating saw under guidance of a jig which is positioned according to the physiological tibial slope. The medial collateral ligament must be protected with a Hohmann retractor. The vertical cut is performed first; then the horizontal cut is performed. The size of the resected plateau should allow space for a tibial component and a meniscus implant of 4 mm. The resected plateau seves to determine the size of the plateau. The jig for the femoral preparation is adjusted according to the axis of femur and tibia. After the posterior resection the 0 mm spigot is inserted into the central drill hole and the distal part of the condyle is milled. The depth of milling is determined by equalizing the flexion and extension gap. Extension and flexion gap balancing is controlled with test inlays. Posterior osteophytes at the medial femur condyle are cut with a special chisel. In the anterior aspect bone resection is needed to prevent impingement of the meniscus implant. Then the tibia plateau is finally prepared. After inserting the test implants the femoral and tibial components are cemented in one or two stages. POSTOPERATIVE MANAGEMENT: The patient is mobilised under full weight bearing with two crutches. RESULTS: A total of 50 Oxford III hemiarthroplasties were implanted using the minimal invasive technique. Indication was an anteromedial gonarthrosis with intakt anterior cruciate ligament. Age varied between 59 and 79 years with a mean of 71 years. Follow-up was 5 years. There were three revisions till final follow-up. Cause was an inlay luxation in one case and in two cases with lateral arthrosis. The average KOOS score was 92.3 points (+/- 6 points). PMID- 23801040 TI - Minimally invasive periprosthetic plate osteosynthesis using the locking attachment plate. AB - OBJECTIVE: Stable fixation of periprosthetic or periimplant fractures with an angular stable plate and early weight bearing as tolerated. INDICATIONS: Periprosthetic femur fractures around the hip, Vancouver type B1 or C. Periprosthetic femur and tibia fractures around the knee. Periprosthetic fractures of the humerus. Periimplant fractures after intramedullary nailing. CONTRAINDICATIONS: Loosening of prosthesis. Local infection. Osteitis. SURGICAL TECHNIQUE: Preoperative planning is recommended. After minimally invasive fracture reduction and preliminary fixation, submuscular insertion of a large fragment femoral titanium plate or a distal femur plate. The plate is fixed with locking head screws and/or regular cortical screws where possible. If stability is insufficient, one or two locking attachment plates (LAP) are mounted to the femoral plate around the stem of the prosthesis. After fixing the LAP to one of the locking holes of the femoral plate, 3.5 mm screws are used to connect the LAP to the cortical bone and/or cement mantle of the prosthesis. POSTOPERATIVE MANAGEMENT: Weight bearing as tolerated starting on postoperative day 1 is suggested under supervision of a physiotherapist. RESULTS: In 6 patients with periprosthetic fractures and 2 patients with periimplant fractures, no surgical complications (e.g., wound infection or bleeding) were observed. The mean time to bony union was 14 weeks. No implant loosening of the locking attachment plate was observed. At the follow-up examination, all patients had reached their prefracture mobility level. PMID- 23801041 TI - [Correction of posttraumatic lower leg deformities using the Taylor Spatial Frame]. AB - OBJECTIVE: Correction of posttraumatic lower leg deformities using percutaneous osteotomy, external fixation with a ring fixator, and computer-assisted gradual correction with the Taylor Spatial Frame (TSF). INDICATIONS: Posttraumatic lower leg deformities not suitable for acute correction and internal fixation or deformities that are suitable but have a significantly increased risk for complications: deformities with poor soft tissue coverage, rigid deformities that require gradual correction, complex mulitplanar deformities, deformities with shortening, and periarticular juvenile deformities. CONTRAINDICATIONS: Posttraumatic lower leg deformities which are suitable for acute correction and internal fixation are also suitable for deformity correction using the TSF. In these cases, however, we recommend acute correction and internal fixation in order to improve the patient comfort. Lack of patient compliance for self contained correction and pin care. SURGICAL TECHNIQUE: Percutaneous fixation of the TSF rings to the main fragments using transosseous K-wires and half pins (hybrid fixation). Percutaneous osteotomy of the tibia either by drilling across both cortices and completion of the osteotomy using an osteotome (DeBastiani method) or by using the Gigli saw with preservation of the periostal envelope. Connection of both rings with six oblique telescopic struts via universal joints (hexapod platform). Computer-assisted planning of the correction. POSTOPERATIVE MANAGEMENT: Gradual postoperative correction of the deformity by changing the strut lengths according to the correction plan. Strut changes, if required. Osseous consolidation of the osteotomy site with the TSF or revision to internal fixation. RESULTS: The correction of posttraumatic lower leg deformities using the TSF was performed in 6 cases. The mean deformity was 15 degrees (12-22 degrees ) in the frontal plane and 6 degrees (4-8 degrees ) in the sagittal plane. The correction time was 19 days (14-22 days). The deviation between planned and achieved correction was 0-3 degrees in the frontal plane and 0-2 degrees in the sagittal plane. The osseous consolidation of the osteotomy site was carried out in the TSF in 5 cases with a mean external fixation time of 112 days (94-134 days). In one case, the TSF was removed after the correction and the osteotomy site was fixed using an intramedullary nail. Pin site infections were observed in 3 cases. There were no further complications. The treatment goal was achieved in all cases. The examination at final follow-up was performed after 1 year. All patients were able to walk without walking aids and with no pain at that time. They were able to perform all of their activities of the daily life and their leisure activities without limitations. PMID- 23801043 TI - Diagnosis and treatment complications of chronic otitis media. PMID- 23801044 TI - Optimized extraction and characterization of antimicrobial phenolic compounds from mangosteen (Garcinia mangostana L.) cultivation and processing waste. AB - BACKGROUND: Applications for antimicrobials derived from the mangosteen (Garcinia mangostana L.) plant are presently restricted by high production costs. Extraction from cultivation or processing waste streams using a solvent-free approach could lessen to permit commercial applications in food processing and preservation. RESULTS: Phenolics were extracted from mangosteen bark, leaf and fruit pericarp in methanol and in water using response surface methodology to optimize recovery. Initial examination of antimicrobial effects revealed a lack of antimicrobial activity against fungi and weak activity against the Gram negative bacteria Escherichia coli and Salmonella typhimurium. In contrast, extracts prepared from bark or fruit pericarp exhibited strong pH-dependent bacteriostatic and bactericidal effects against Listeria monocytogenes and Staphylococcus aureus. Activity was slightly weaker in aqueous extracts due to lower concentrations of tartaric acid esters and flavonols than in methanolic extracts. Measurement of propidium iodide uptake and ATP leakage indicated that the extracts induced damage to the membrane of Gram-positive bacteria. CONCLUSION: Extracts of mangosteen bark and fruit pericarp contain mixtures of phenolic compounds with activity against Gram-positive bacteria, notably Listeria monocytogenes. Extraction of phenolics from mangosteen waste could yield fractions for potential applications in the formulation of low-cost processing aids or sanitizers for the food industry. PMID- 23801045 TI - Psychiatric disorders: repetitive circuits. PMID- 23801046 TI - Neurogenesis: a bombshell of a finding. PMID- 23801047 TI - Metagenomic technology and genome mining: emerging areas for exploring novel nitrilases. AB - Nitrilase is one of the most important members in the nitrilase superfamily and it is widely used for bioproduction of commodity chemicals and pharmaceutical intermediates as well as bioremediation of nitrile-contaminated wastes. However, its application was hindered by several limitations. Searching for new nitrilases and improving their application performances are the driving force for researchers. Genetic data resources in various databases are quite rich in post genomic era. Besides, more than 99 % of microbes in the environment are unculturable. Metagenomic technology and genome mining are thus becoming burgeoning areas and provide unprecedented opportunities for searching more useful novel nitrilases due to the abundance of already existing but unexplored gene resources, namely uncharacterized genome information in the database and unculturable microbes in the natural environment. These techniques seem to be innovative and highly efficient. This study reviews the current status and future directions of metagenomics and genome mining in nitrilase exploration. Moreover, it discussed their utilization in coping with the challenges for nitrilase application. In the next several years, with the rapid development of nitrile biocatalysis, these two techniques would be bound to attract increasing attentions and even become a dominant trend for finding more novel nitrilases. Also, this review would provide guidance for exploitation of other commercially important enzymes. PMID- 23801048 TI - beta-galactosyl-pyrrolidinyl diazeniumdiolate: an efficient tool to investigate nitric oxide functions on promoting cell death. AB - Nitric oxide (NO) is an active free radical gas that plays crucial roles in a broad range of biological processes. Extremely short half-life makes it difficult to use NO directly in research. It has been suggested that different concentrations of NO may lead to quite opposite results on cytotoxicity. However, the net effect of intracellular NO on tumor cell death has been controversial, partly because it is hard to precisely control the amount of NO generated exclusively within the target cells. Therefore, we have developed a cell-specific NO donor, beta-galactosyl-pyrrolidinyl diazeniumdiolate (beta-Gal-NONOate), in hopes of simulating the actual effects of intracellularly derived NO on the patterns of cell death as well as investigating its underlying mechanisms. In this study, by using three different tumor cell models, we showed that beta-Gal NONOate could steadily transport NO into the target cells with similar delivery efficiencies and exerted a determinative effect on cell death. In addition, beta Gal-NONOate-derived intracellular NO could provoke both apoptosis and necrosis in a concentration-dependent manner. While lower NO concentration primarily induced apoptosis, higher NO concentration mainly triggered necrosis. Moreover, the intrinsic apoptotic pathway, characterized by rapid Ca2+ overload and subsequent mitochondrial damage, was the collective mechanism responsible for the apoptotic death in all the three tumor cell lines. Taken together, since this cell specifically derived NO is cheap to use and easy to quantify, beta-Gal-NONOate might be used as a novel and ideal tool to standardize intracellular NO generation and evaluate its net effects in different cellular and experimental settings in the coming future. PMID- 23801049 TI - Loss of microRNA-132 predicts poor prognosis in patients with primary osteosarcoma. AB - MicroRNA-132 (miR-132), an angiogenic growth factor inducible microRNA in the endothelium, facilitates pathological angiogenesis. Previous study showed that miR-132 was downregulated in human osteosarcoma. However, its functional attributes associated with tumor progression of osteosarcoma have not been fully elucidated. The aim of this study was to investigate the clinical significance of miR-132 expression in human osteosarcoma. miR-132 expression was detected by quantitative reverse transcription polymerase chain reaction using 166 pairs of osteosarcoma and noncancerous bone tissues. Then, the association of miR-132 expression with clinicopathological factors or survival of osteosarcoma patients was also evaluated. miR-132 expression was significantly lower in osteosarcoma tissues than that in corresponding noncancerous bone tissues (P < 0.001). In addition, miR-132 expression was decreased in the osteosarcoma specimens with advanced clinical stage (P = 0.009), positive distant metastasis (P = 0.006), and poor response to chemotherapy (P = 0.009). Moreover, both the univariate and multivariate analyses showed that osteosarcoma patients with low miR-132 expression had poorer overall and disease-free survival (both P < 0.001), and low miR-132 expression was an independent prognostic factor for both overall (P = 0.001) and disease-free survival (P = 0.006). These findings offer the convinced evidence for the first time that miR-132 may participate in tumor progression of osteosarcoma and loss of miR-132 expression may be a predictor for unfavorable outcome of osteosarcoma patients. PMID- 23801050 TI - NOX1 abet mesangial fibrogenesis via iNOS induction in diabetes. AB - Both NADPH oxidase (NOX) and inducible nitric oxide synthase (iNOS) are the main sources of reactive oxygen species in kidney. However, their interactions in oxidative stress and contributions to kidney fibrosis during diabetic nephropathy have not been studied. Human mesangial cells were treated with normal glucose (5.6 mmol/L), high glucose (30 mmol/L) in the presence or absence of AGE (200 mg/L). Protein expressions of NOX1, NOX2, NOX4, and iNOS were examined by immunoblotting. NOX was genetically silenced with specific RNAi to study the interactions between NOX and iNOS in diabetic milieu. Superoxide (O(.-)) and peroxynitrite (ONOO(.-)) productions were assessed by dihydroethidium and hydroxyphenyl fluorescein, respectively. Fibrotic factors were determined by biochemistry assay. Superoxide, peroxynitrite, TGF-beta, and fibronectin productions as well as the protein expressions of NOX1, NOX2, NOX4, and iNOS were increased in the diabetic milieu (high glucose 30 mmol/L plus AGE 200 mg/L). However, abolishment of iNOS induction with 1400W or iNOS RNAi would restore peroxynitrite, TGF-beta, and fibronectin productions completely to basal level and attenuate superoxide production. Moreover, NOX1 inhibition not only prevented iNOS induction but also abrogated changes consequent to iNOS induction such as mesangial fibrogenesis. PMID- 23801051 TI - Isolated juvenile xanthogranuloma in the larynx of a three-year-old child. AB - Juvenile xanthogranuloma (JXG) is a benign manifestation of non-Langerhans cell histiocytosis characterized by yellowish cutaneous nodules. Its occurrence in the larynx is very rare, but laryngeal JXG may cause severe respiratory distress. We report a patient with isolated laryngeal JXG treated by laryngomicrosurgery, and this is the first report of JXG extending to vocal fold. A 3-year-old girl presented with hoarseness and inspiration stridor. A bulky tumor was found in right glottic to subglottic region. Subtotal resection of the tumor was carried out by laryngomicrosurgery, and airway distress was diminished after the operation. In pathological examination, the resected specimen showed proliferation of histiocytic cells and spindle cells with Touton giant cells that are characterized by polynuclei or wreath nuclei and are known to appear in JXG but not in LCH. Immunohistochemistry of histiocytic cell markers demonstrated positivity for CD68, lysozyme, alpha1-anti-chymotrypsin, factor XIIIa and vimentin, and negativity for CD1a and S-100, leading to diagnosis of JXG, but not LCH. The patient was thus expected with benign prognosis, and additional resection of the tumor including vocal fold was not indicated in the initial treatment. Six weeks later, the JXG recurred and a second procedure using CO2 laser was needed. The tumor did not re-grow thereafter, and there was no residual voice handicap. Because of its favorable prognosis and tendency for spontaneous regression, JXG in the larynx needs to be considered carefully with regard to whether reduction surgery and/or tracheotomy are necessary, and thus precise diagnosis is required. PMID- 23801052 TI - A C(3)-symmetric chiroptical molecular propeller based on hexakis(phenylethynyl)benzene with a threefold terephthalamide: stereospecific propeller generation through the cooperative transmission of point chiralities on the host and guest upon complexation. AB - Propeller-shaped dynamic helicity was generated in a hexakis(phenylethynyl)benzene framework that preferred a particular sense to afford a strong CD signal, which was realized by the cooperative transmission of point chiralities upon complexation with a chiral guest through a threefold binding site presented by a syn-formed terephthalamide. PMID- 23801053 TI - Assessing the effectiveness of a Grand Rounds CME activity for health-care professionals. AB - The Lymphoma Research Foundation offers Grand Rounds continuing medical education (CME) activities on specific issues related to advances in the management of patients with lymphoma. The 2012 activity comprised interactive case studies presented by local lymphoma experts. A case-based survey was designed to assess whether the management choices of program participants are consistent with the evidence-based content of the CME activity. This survey was administered to participants 1 month after completion of the CME activity and also to a control group who did not participate in the educational program. Participants were more aware of the epidemiology of CD20-positive tumors than were controls and were more likely to appropriately diagnose primary mediastinal large B cell lymphoma (PMBCL), use evidence-based second-line therapy for PMBCL, and properly manage a patient with classic Hodgkin lymphoma that did not respond to standard therapy. Participants were also more confident than controls in their ability to interpret histology and cytogenetic testing for selecting an optimal treatment. PMID- 23801054 TI - Single versus double stapling anastomotic technique in rectal cancer surgery. AB - PURPOSE: The present study was designed to investigate whether there is a difference in the anastomotic leakage rate (AL) between the single stapling (CSA) and double stapling (DSA) anastomosis techniques. METHODS: One hundred consecutive rectal cancer patients who underwent rectal resection with primary anastomosis were enrolled in this study. RESULTS: The overall rate of clinical anastomotic leakage in both groups was 7 % (7/100); 6 % (3/50) in the CSA group and 8 % (4/50) in the DSA group. The anastomotic technique did not have any significant influence on the rate of AL. All AL were seen in low anastomoses (7 cm and below). The rate of AL in patients with a diverting stoma (13 %, 3/23) was not significantly different from that of the patients without (5.2 %, 4/77) (p = 0.195). The mean length of the operation was significantly shorter in the DSA group compared to the CSA group, at 127 and 141 min, respectively (p = 0.005). There were significantly higher rates of AL in patients receiving preoperative long course radiotherapy (15.4 %, 6/39) compared with those who did not receive radiotherapy (1.63 %, 1/61) (p = 0.014). CONCLUSIONS: The CSA and DSA techniques are equally safe for the creation of a rectal anastomosis, without any significant difference in the AL rate. However, we recommend using the DSA technique because it has other definite advantages. In cases of neoadjuvant treatment and a low anastomosis, proximal diversion is recommended. PMID- 23801055 TI - Liver resection with concomitant inferior vena cava resection: experiences without veno-venous bypass. AB - PURPOSE: Liver resection offers the chance of a cure for liver cancer. However, when extended hepatectomies were performed in combination with resection of the inferior vena cava (IVC), the procedures were reported to have a surgical mortality rate in excess of 5 %. While most of these operations were performed with the use of veno-venous bypass, this study presents our experience performing the procedure without the bypass. METHODS: Data were collected from a prospectively maintained database. A retrospective evaluation of a consecutive series of concomitant IVC and liver resections was performed. RESULTS: Five hundred and seventy-five liver resections were performed between June 2008 and November 2011. Eleven patients (1.9 %) underwent concomitant IVC and liver resections. One patient required segmental IVC replacement, and four IVC defects were closed using a bovine pericardial patch without bypass. Only one patient had histologically confirmed IVC invasion. There was no postoperative mortality. Nine postoperative complications occurred in five patients. No complications in terms of IVC patency were seen. Five patients had disease recurrence, one of whom died within 12 months of surgery. CONCLUSION: Concomitant liver and IVC resection is safe without using a bypass procedure, with acceptable short-term results. Meticulous technique, careful patient selection and a specialized anesthetic team are key to obtaining low postoperative morbidity and mortality rates and an acceptable oncological outcome. PMID- 23801056 TI - Incisional bladder hernia following appendectomy: report of a case. AB - We herein report the case of a 68-year-old male who presented with a few years' history of swelling at the scar of an appendectomy, which he had undergone nearly 40 years earlier, and which was associated with radiating pain towards the penis when he pushed on the swelling. The scar was located in the right lower quadrant of the abdomen. Abdominal sonography and a computed tomography (CT) scan demonstrated the presence of an incisional bladder hernia, and surgery was performed. The herniated bladder was successfully replaced into the preperitoneal space, and the orifice was covered with a polypropylene mesh. Most bladder hernias develop in the inguinal and/or femoral region, and an incisional bladder hernia is extremely rare, especially after abdominal surgery. To our knowledge, this is the fourth report of an incisional bladder hernia following abdominal surgery. PMID- 23801057 TI - Detection of a metastatic lesion and tiny yolk sac tumors in two teenage patients by FDG-PET: report of two cases. AB - We herein report the efficacy of FDG-PET for detecting yolk sac tumors in two teenage patients. One patient had a rare bone metastasis and the other had tiny recurrent lesions at the mediastinum. Both lesions were difficult to detect by conventional diagnostic modalities. In contrast, FDG-PET was very effective for detecting these lesions. Furthermore, the SUVmax of the lesion reflected the tumor activity, which was also suggested by the fluctuating values of serum alpha fetoprotein (AFP), an established marker of yolk sac tumors. FDG-PET may be a useful procedure to detect tiny and metastatic, pediatric yolk sac tumors. PMID- 23801058 TI - Disruption of Myc-Max heterodimerization with improved cell-penetrating analogs of the small molecule 10074-G5. AB - The c-Myc (Myc) oncoprotein is a high-value therapeutic target given that it is deregulated in multiple types of cancer. However, potent small molecule inhibitors of Myc have been difficult to identify, particularly those whose mechanism relies on blocking the association between Myc and its obligate heterodimerization partner, Max. We have recently reported a structure-activity relationship study of one such small molecule, 10074-G5, and generated an analog, JY-3-094, with significantly improved ability to prevent or disrupt the association between recombinant Myc and Max proteins. However, JY-3094 penetrates cells poorly. Here, we show that esterification of a critical para-carboxylic acid function of JY-3-094 by various blocking groups significantly improves cellular uptake although it impairs the ability to disrupt Myc-Max association in vitro. These pro-drugs are highly concentrated within cells where JY-3-094 is then generated by the action of esterases. However, the pro-drugs are also variably susceptible to extracellular esterases, which can deplete extracellular reservoirs. Furthermore, while JY-3-094 is retained by cells for long periods of time, much of it is compartmentalized within the cytoplasm in a form that appears to be less available to interact with Myc. Our results suggest that persistently high extracellular levels of pro-drug, without excessive susceptibility to extracellular esterases, are critical to establishing and maintaining intracellular levels of JY-3-094 that are sufficient to provide for long-term inhibition of Myc-Max association. Analogs of JY-3-094 appear to represent promising small molecule Myc inhibitors that warrant further optimization. PMID- 23801059 TI - Labral injuries of the hip in rowers. AB - BACKGROUND: Injuries of the hip in the adolescent and young adult athlete are receiving more attention with advances in the understanding of femoroacetabular impingement (FAI), labral pathology, and hip arthroscopy. Labral tears have not been well characterized in rowers. QUESTIONS/PURPOSES: The purposes of this study were (1) to describe the clinical presentation of labral pathology in rowers; (2) to describe the MRI and radiographic findings of labral pathology in rowers; and (3) to determine the likelihood that a rower with labral injury, treated arthroscopically, will return to sport. METHODS: We conducted a review from August 2003 to August 2010 to identify all rowers with MRI-confirmed intraarticular pathology of the hip presenting to our institution. Baseline demographics, symptoms and physical findings, and location of the labral tear with associated pathology, management, and early followup were recorded. The review yielded a total of 21 hips (18 rowers, three with bilateral labral pathology) with a mean patient age of 18.5 years (range, 14-23 years). Most of the rowers (85%) were female and the series included prep school (44%) and collegiate rowers (56%). Eighteen of the 21 hips (85%) eventually underwent arthroscopic surgery at our institution. RESULTS: A large majority of patients had isolated groin pain (71%) and physical findings consistent with impingement (81%). There was no single, dominant location for the labral tears on MRI. Among the 18 patients who had surgery, 10 (56%) returned to rowing, six (33%) never returned, and return data were not available for two (11%) at a mean of 8 months (range, 3-25 months) after surgery. CONCLUSIONS: The repetitive motions of the hip required for rowing may be a factor leading to intraarticular labral injuries in the athletes. Underlying anatomic abnormalities of the hip such as FAI may predispose certain patients to these injuries. However, many patients treated arthroscopically did not return to sport at a mean of 8 months after surgery. PMID- 23801060 TI - Taper design affects failure of large-head metal-on-metal total hip replacements. AB - BACKGROUND: Large-head metal-on-metal (MoM) hip arthroplasties have demonstrated poor survival. Damage at the taper-trunnion junction is a contributing factor; however, the influence of junction design is not well understood. QUESTIONS/PURPOSES: (1) Does taper type affect fretting, corrosion, and volumetric wear at the junction? (2) Do taper types have different wear patterns? (3) Does larger offset or head diameter increase fretting, corrosion, and wear? (4) Is the extent of fretting and corrosion associated with earlier failure? METHODS: Taper damage in 40 retrieved heads was subjectively graded for fretting and corrosion, and wear was determined with high-resolution confocal measurement. Taper types (11/13, 12/14, and Type 1) differed by angle, distal diameter, and contact length; Type 1 were thinnest and 11/13 had longer contact lengths. RESULTS: Fretting scores were higher in 11/13 than in Type 1 tapers. Volumetric wear and wear rates did not differ among types. Uniform, circumferential, and longitudinal wear patterns were observed in all types, but fretting, corrosion, and wear did not differ among the patterns. Head diameter and lateral offset did not correlate with fretting, corrosion, or wear. No correlation was found between fretting, corrosion, or wear and length of implantation. CONCLUSIONS: In general, thicker tapers with longer contact lengths were associated with greater fretting scores, whereas no relationship was found among the three designs for corrosion scores or volumetric wear. This finding suggests that trunnion diameter and engagement length are important factors to consider when improving taper-trunnion junction design. PMID- 23801061 TI - Causes and frequency of unplanned hospital readmission after total hip arthroplasty. AB - BACKGROUND: Total hip arthroplasty (THA) is a beneficial and cost-effective procedure for patients with osteoarthritis. Recent initiatives to improve hospital quality of care include assessing unplanned hospital readmission rates. Patients presenting for THA have different indications and medical comorbidities that may impact rates of readmission. QUESTIONS/PURPOSES: This study measured (1) the unplanned hospital readmission rate in primary THA, revision THA, and antibiotic-spacer staged revision THA to treat infection. Additionally, we determined (2) the medical and surgical causes of readmission; and (3) the risk factors associated with unplanned readmission. METHODS: A total of 1415 patients (988 primary THA, 344 revision THA, 82 antibiotic-spacer staged revision THA to treat infection) from a single institution were included. All hospital readmissions within 90 days of discharge were reviewed. Patient demographics and medical comorbidities were included in a Cox proportional hazards model to assess risk of readmission. RESULTS: The overall unplanned readmission rate was 4% at 30 days and 7% at 90 days. At 90 days, primary THA (5%) had a lower unplanned readmission rate than revision THA (10%, p < 0.001) and antibiotic-spacer staged revision THA (18%, p < 0.001). Medical diagnoses were responsible for almost one fourth of unplanned readmissions, whereas over half of surgical readmissions were the result of dislocation, surgical site infection, and postoperative hematoma. Type of procedure, hospital stay greater than 5 days, cardiac valvular disease, diabetes with end-organ complications, and substance abuse were each associated with increased risk of unplanned readmission. CONCLUSIONS: Higher rates of unplanned hospital readmissions in revision THA rather than primary THA suggest that healthcare quality measures that incorporate readmission rates as a proxy for quality of care should distinguish between primary and revision procedures. Failure to do so may negatively impact tertiary referral hospitals that often care for patients requiring complex revision procedures. PMID- 23801062 TI - Factors associated with survey response in hand surgery research. AB - BACKGROUND: A low response rate is believed to decrease the validity of survey studies. Factors associated with nonresponse to surveys are poorly characterized in orthopaedic research. QUESTIONS/PURPOSES: This study addressed whether (1) psychologic factors; (2) demographics; (3) illness-related factors; and (4) pain are predictors of a lower likelihood of a patient returning a mailed survey. METHODS: One hundred four adult, new or return patients completed questionnaires including the Pain Catastrophizing Scale, Patient Health Questionnaire-9 depression scale, Short Health Anxiety Index, demographics, and a pain scale (0 10) during a routine visit to a hand and upper extremity surgeon. Of these patients, 38% had undergone surgery and the remainder was seen for various other conditions. Six months after their visit, patients were mailed the DASH questionnaire and a scale to rate their satisfaction with the visit (0-10). Bivariate analysis and logistic regression were used to determine risk factors for being a nonresponder to the followup of this study. The cohort consisted of 57 women and 47 men with a mean age of 51 years with various diagnoses. Thirty five patients (34%) returned the questionnaire. Responders were satisfied with their visit (mean satisfaction, 8.7) and had a DASH score of 9.6. RESULTS: Compared with patients who returned the questionnaires, nonresponders had higher pain catastrophizing scores, were younger, more frequently male, and had more pain at enrollment. In logistic regression, male sex (odds ratio [OR], 2.6), pain (OR, 1.3), and younger age (OR, 1.03) were associated with not returning the questionnaire. CONCLUSIONS: Survey studies should be interpreted in light of the fact that patients who do not return questionnaires in a hand surgery practice differ from patients who do return them. Hand surgery studies that rely on questionnaire evaluation remote from study enrollment should include tactics to improve the response of younger, male patients with more pain. LEVEL OF EVIDENCE: Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 23801063 TI - Longitudinal urban-rural discrepancies in the US orthopaedic surgeon workforce. AB - BACKGROUND: It is unclear whether the supply of orthopaedic surgeons can meet the needs of a growing and aging population. This may be especially concerning in rural areas where there are known disparities in overall healthcare provision. QUESTIONS/PURPOSES: We therefore (1) determined urban-rural trends in the US physician and orthopaedic workforce (including the age of that workforce) from 1995 to 2010; (2) geographically mapped the physician and orthopaedic distribution; and (3) examined urban-rural changes in select nonorthopaedic musculoskeletal provider (chiropractor and podiatrist) workforces from 2000 to 2010. METHODS: County-level provider data from 1995 to 2010 were obtained from the Department of Health and Human Services. This was aggregated to Hospital Referral Regions and ranked by Rural-Urban Continuum Code. Hospital Referral Region-level data were mapped to identify geographic trends. Total physician and orthopaedic surgeon workforce data were averaged across the most urban and rural regions for the study period. RESULTS: There were urban-rural discrepancies in the physician and orthopaedic workforce from 1995 to 2010 with fewer orthopaedic surgeons in rural areas than urban areas (6.52 versus 8.73 per 100,000 in 2010; p=0.001). Furthermore, orthopaedic surgeons in rural areas were older than their urban counterparts, with a workforce age ratio (age>55: age<55 years) of 0.92 versus 0.65 in 2010 (p=0.024). From 2000 to 2010, the rural chiropractor and podiatrist workforces showed tremendous growth of 229.6% and 279.9%, respectively. CONCLUSIONS: There were significant urban-rural orthopaedic surgeon workforce discrepancies from 1995 to 2010. Concurrent growth in chiropractor and podiatrist numbers shows significant trends in the musculoskeletal provider workforce that warrant continuing observation and analysis. LEVEL OF EVIDENCE: Level IV, economic and decision analyses. See Guidelines for Authors for a complete description of levels of evidence. PMID- 23801064 TI - The role of insulin-like growth factor 1 and its receptor in the formation and development of colorectal carcinoma. AB - OBJECTIVE: To investigate the role of insulin-like growth factor (IGF)-1 and its receptor (IGF1R) in the formation and development of colorectal carcinoma. METHODS: Colorectal tissue and matching serum samples were collected from patients with adenomatous polyps or carcinoma and healthy control subjects. IGF1R mRNA levels were determined via quantitative real-time reverse transcription polymerase chain reaction. Serum IGF1 was quantified using enzyme-linked immunosorbent assay. RESULTS: Serum IGF1 concentrations and mucosal IGF1R mRNA levels were significantly higher in patients with adenomatous polyps (n = 24) or carcinoma (n = 13) compared with healthy control subjects (n = 13). There was a significant positive correlation between serum IGF1 and mucosal IGF1R mRNA in patients with adenomatous polyps. CONCLUSIONS: High circulating IGF1 concentrations and mucosal IGF1R expression may play important roles in both the formation and development of colorectal carcinoma. IGF1 and its receptor may be activated before carcinogenesis, and may promote the growth and malignant transformation of adenomatous polyps. IGF1 and IGF1R may be useful biomarkers for evaluating the stage and risk of carcinogenesis. PMID- 23801065 TI - Inhibitory effect of geraniol in combination with gemcitabine on proliferation of BXPC-3 human pancreatic cancer cells. AB - OBJECTIVE: To investigate the inhibitory effect of geraniol alone, or in combination with gemcitabine, on the proliferation of BXPC-3 pancreatic cancer cells. METHODS: BXPC-3 cells were treated under different conditions: with geraniol at 10, 20, 40, 80 and 160 umol/l each for 24 h, 48 h or 72 h; with 20 umol/l geraniol for 24 h or 0 h before 20 umol/l gemcitabine for 24 h; with 20 umol/l geraniol for 24 h, 48 h and 72 h following 20 umol/l gemcitabine for 24 h; or with 20 umol/l gemcitabine alone as a control. Cell proliferation was assessed and changes in cell morphology were assessed by light and fluorescence microscopy. Apoptosis was detected using flow cytometry. RESULTS: Geraniol inhibited BXPC-3 cell proliferation in a time- and dosa-dependent manner. Geraniol alone or combined with gemcitabine induced BXPC-3 cell apoptosis. BXPC-3 inhibition rates with combined treatment were 55.24%, 50.69%, 49.83%, 41.85% and 45.27% following treatment with 20 umol/l geraniol for 24 h or 0 h before 20 umol/l gemcitabine for 24 h, or 20 umol/l geraniol for 24 h, 48 h and 72 h, following 20 umol/l gemcitabine for 24 h, respectively. CONCLUSION: Geraniol inhibited the proliferation of BXPC-3 cells. Geraniol significantly increased the antiproliferative and apoptosis-inducing effects of gemcitabine on BXPC-3 cells. Maximum inhibition of BXPC-3 cells was achieved with geraniol treatment for 24 h before gemcitabine treatment. PMID- 23801067 TI - Transgenic mice for cGMP imaging. AB - RATIONALE: Cyclic GMP (cGMP) is an important intracellular signaling molecule in the cardiovascular system, but its spatiotemporal dynamics in vivo is largely unknown. OBJECTIVE: To generate and characterize transgenic mice expressing the fluorescence resonance energy transfer-based ratiometric cGMP sensor, cGMP indicator with an EC50 of 500 nmol/L (cGi500), in cardiovascular tissues. METHODS AND RESULTS: Mouse lines with smooth muscle-specific or ubiquitous expression of cGi500 were generated by random transgenesis using an SM22alpha promoter fragment or by targeted integration of a Cre recombinase-activatable expression cassette driven by the cytomegalovirus early enhancer/chicken beta-actin/beta-globin promoter into the Rosa26 locus, respectively. Primary smooth muscle cells isolated from aorta, bladder, and colon of cGi500 mice showed strong sensor fluorescence. Basal cGMP concentrations were < 100 nmol/L, whereas stimulation with cGMP-elevating agents such as 2-(N,N-diethylamino)-diazenolate-2-oxide diethylammonium salt (DEA/NO) or the natriuretic peptides, atrial natriuretic peptide, and C-type natriuretic peptide evoked fluorescence resonance energy transfer changes corresponding to cGMP peak concentrations of ~ 3 umol/L. However, different types of smooth muscle cells had different sensitivities of their cGMP responses to DEA/NO, atrial natriuretic peptide, and C-type natriuretic peptide. Robust nitric oxide-induced cGMP transients with peak concentrations of ~ 1 to > 3 umol/L could also be monitored in blood vessels of the isolated retina and in the cremaster microcirculation of anesthetized mice. Moreover, with the use of a dorsal skinfold chamber model and multiphoton fluorescence resonance energy transfer microscopy, nitric oxide-stimulated vascular cGMP signals associated with vasodilation were detected in vivo in an acutely untouched preparation. CONCLUSIONS: These cGi500 transgenic mice permit the visualization of cardiovascular cGMP signals in live cells, tissues, and mice under normal and pathological conditions or during pharmacotherapy with cGMP elevating drugs. PMID- 23801066 TI - Bone-derived stem cells repair the heart after myocardial infarction through transdifferentiation and paracrine signaling mechanisms. AB - RATIONALE: Autologous bone marrow-derived or cardiac-derived stem cell therapy for heart disease has demonstrated safety and efficacy in clinical trials, but functional improvements have been limited. Finding the optimal stem cell type best suited for cardiac regeneration is the key toward improving clinical outcomes. OBJECTIVE: To determine the mechanism by which novel bone-derived stem cells support the injured heart. METHODS AND RESULTS: Cortical bone-derived stem cells (CBSCs) and cardiac-derived stem cells were isolated from enhanced green fluorescent protein (EGFP+) transgenic mice and were shown to express c-kit and Sca-1 as well as 8 paracrine factors involved in cardioprotection, angiogenesis, and stem cell function. Wild-type C57BL/6 mice underwent sham operation (n=21) or myocardial infarction with injection of CBSCs (n=67), cardiac-derived stem cells (n=36), or saline (n=60). Cardiac function was monitored using echocardiography. Only 2/8 paracrine factors were detected in EGFP+ CBSCs in vivo (basic fibroblast growth factor and vascular endothelial growth factor), and this expression was associated with increased neovascularization of the infarct border zone. CBSC therapy improved survival, cardiac function, regional strain, attenuated remodeling, and decreased infarct size relative to cardiac-derived stem cells- or saline-treated myocardial infarction controls. By 6 weeks, EGFP+ cardiomyocytes, vascular smooth muscle, and endothelial cells could be identified in CBSC treated, but not in cardiac-derived stem cells-treated, animals. EGFP+ CBSC derived isolated myocytes were smaller and more frequently mononucleated, but were functionally indistinguishable from EGFP- myocytes. CONCLUSIONS: CBSCs improve survival, cardiac function, and attenuate remodeling through the following 2 mechanisms: (1) secretion of proangiogenic factors that stimulate endogenous neovascularization, and (2) differentiation into functional adult myocytes and vascular cells. PMID- 23801068 TI - Radiosensitization by histone deacetylase inhibition in an osteosarcoma mouse model. AB - BACKGROUND: Osteosarcomas (OS) are highly malignant and radioresistant tumors. Histone deacetylase inhibitors (HDACi) constitute a novel class of anticancer agents. We sought to investigate the effect of combined treatment with suberoylanilide hydroxamic acid (SAHA) and radiotherapy in OS in vivo. METHODS: Clonogenic survival of human OS cell lines as well as tumor growth delay of OS xenografts were tested after treatment with either vehicle, radiotherapy (XRT), SAHA, or XRT and SAHA. Tumor proliferation, necrosis, microvascular density, apoptosis, and p53/p21 were monitored by immunohistochemistry. The CD95 pathway was performed by flow cytometry, caspase (3/7/8) activity measurements, and functional inhibition of CD95 death signaling. RESULTS: Combined treatment with SAHA and XRT markedly reduced the surviving fraction of OS cells as compared to XRT alone. Likewise, dual therapy significantly inhibited OS tumor growth in vivo as compared to XRT alone, reflected by reduced tumor proliferation, impaired angiogenesis, and increased apoptosis. Addition of HDACi to XRT led to elevated p53, p21, CD95, and CD95L expression. Inhibition of CD95 signaling reduced HDACi- and XRT-induced apoptosis. CONCLUSION: Our data show that HDACi increases the radiosensitivity of osteosarcoma cells at least in part via ligand-induced apoptosis. HDACi thus emerge as potentially useful treatment components of OS. PMID- 23801069 TI - Caffeic acid production enhancement by engineering a phenylalanine over-producing Escherichia coli strain. AB - Caffeic acid is a plant-specific phenylpropanoic acid with multiple health improving effects reported, and its therapeutic derivatives have also been studied throughout the last decade. To meet its market need and achieve high level production, microbial production of caffeic acid approaches have been developed in metabolically engineered Escherichia coli. In our previous work, we have established the first artificial pathway that realized de novo production of caffeic acid using E. coli endogenous 4-hydroxyphenylacetate 3-hydroxylase (4HP3H). In this work, we exploited the catalytic potential of 4HPA3H in the whole-cell bioconversion study and produced 3.82 g/L (461.12 mg/L/OD) caffeic acid from p-coumaric acid, a direct precursor. We further engineered a phenylalanine over-producer into a tyrosine over-producer and then introduced the artificial pathway. After adjusting the expression strategy and optimizing the inoculants timing, de novo production of caffeic acid reached 766.68 mg/L. Both results from the direct precursor and simple carbon sources represent the highest titers of caffeic acid from microbial production so far. PMID- 23801070 TI - On the near-wall accumulation of injectable particles in the microcirculation: smaller is not better. AB - Although most nanofabrication techniques can control nano/micro particle (NMP) size over a wide range, the majority of NMPs for biomedical applications exhibits a diameter of ~100 nm. Here, the vascular distribution of spherical particles, from 10 to 1,000 nm in diameter, is studied using intravital microscopy and computational modeling. Small NMPs (<=100 nm) are observed to move with Red Blood Cells (RBCs), presenting an uniform radial distribution and limited near-wall accumulation. Larger NMPs tend to preferentially accumulate next to the vessel walls, in a size-dependent manner (~70% for 1,000 nm NMPs). RBC-NMP geometrical interference only is responsible for this behavior. In a capillary flow, the effective radial dispersion coefficient of 1,000 nm particles is ~3-fold larger than Brownian diffusion. This suggests that sub-micron particles could deposit within diseased vascular districts more efficiently than conventional nanoparticles. PMID- 23801071 TI - A liquid chromatography/electrospray ionisation tandem mass spectrometry method for the simultaneous quantification of salicylic, jasmonic and abscisic acids in Coffea arabica leaves. AB - BACKGROUND: Plants have developed an efficient system of recognition that induces a complex network of signalling molecules such as salicylic acid (SA), jasmonic acid (JA) and abscisic acid (ABA) in case of a pathogenic infection. The use of specific and sensitive methods is mandatory for the analysis of compounds in these complex samples. RESULTS: In this study a liquid chromatography/electrospray ionisation tandem mass spectrometry method was developed and validated for the simultaneous quantification of SA, JA and ABA in Coffea arabica (L.) leaves in order to understand the role of these phytohormones in the signalling network involved in the coffee defence response against Hemileia vastatrix. The results showed that the method was specific, linear (r >= 0.99) in the range 0.125-1.00 ug mL-1 for JA and ABA and 0.125-5.00 ug mL-1 for SA, and precise (relative standard deviation <=11%), and the limit of detection (0.010 ug g-1 fresh weight) was adequate for quantifying these phytohormones in this type of matrix. CONCLUSION: In comparison with healthy leaves, those infected with H. vastatrix (resistance reaction) displayed an increase in SA level 24 h after inoculation, suggesting the involvement of an SA-dependent pathway in coffee resistance. PMID- 23801072 TI - "They increase in beauty and elegance": transforming cadavers and the epistemology of dissection in early nineteenth-century American medical education. AB - This paper investigates the origins of the practice of dissection in American medical education in order to both understand the function of dissection in medical education and challenge conventional wisdom about that function. In the late eighteenth and early nineteenth centuries, American medical schools increasingly made human dissection a crucial part of their curricula, privileging use of the human cadaver over any other anatomical model. In this paper, I break apart the claims that American physicians made at that time regarding the unique pedagogic usefulness of the cadaver, and I juxtapose those claims against the realities of the dissection process. In doing so, I show how the realities of dissection differed sharply from the depictions given by physicians. In the conclusion, I argue that the cadaver still remained epistemologically and ontologically useful to the medical profession, although not necessarily for the reasons physicians explicitly stated. PMID- 23801077 TI - In vitro anti-caries effect of fluoridated hydroxyapatite-coated preformed metal crowns. AB - AIM: To synthesise fluoridated hydroxyapatite (FA) crystals directly on preformed metal crowns (PMCs) and evaluate the anti-cariogenic properties in an in vitro model. METHODS: FA crystals were grown on etched PMCs and stainless steel discs and characterised by SEM. FA-coated discs allowed fluoride release to be assessed from a known surface area of FA crystals. Discs were divided into four groups (n = 6/group) and exposed to solutions at pH 4-7. Fluoride levels in solution were measured after each exposure. Twelve FA-coated and 12 non-coated PMCs were cemented onto human molars using glass ionomer (GI) or unfilled resin, making four groups of six teeth; FA-coated + GI, FA-coated + resin; non-coated + GI and non-coated + resin. Teeth were exposed to acidified gelatin (pH = 4.3) for 9 weeks. RESULTS: SEM showed FA crystal growth on interior and exterior of the crowns. Average fluoride release from FA-coated discs was 0.16 mg/L/cm2 at pH < 5.0. Teeth were sectioned through the lesion. Polarised microscopic examination revealed significantly smaller lesions in FA-coated crown groups compared to non coated crown groups. CONCLUSION: FA-coated PMCs demonstrated carious lesion preventing effects, i.e. fluoride release and reduction of demineralisation at crown/tooth interface. FA-coated crowns could be an aesthetic, inexpensive and caries preventive alternative in clinical dentistry. PMID- 23801078 TI - A foreign body in disguise. AB - BACKGROUND: Young children habitually place objects in their mouths to discover and learn about the world and it is considered a normal stage of early childhood development. Ingestion and aspiration of foreign objects predominantly occurs in preschool toddlers with a peak incidence at age three years, and can have serious consequences. CASE REPORT: A 2-year-old boy presented to the Dublin Dental University Hospital with a tooth-coloured mass tightly adherent to a lower primary incisor. The lesion surrounded the cervical third of the crown on the lower right primary central incisor and extended subgingivally. The tooth was mobile but with minimal inflammation. TREATMENT: The tooth was subsequently extracted under general anaesthesia to reveal that the mass was in fact a foreign body, although this was originally thought unlikely as a cause. FOLLOW-UP: The patient underwent an unremarkable recovery. CONCLUSION: The case of a foreign body disguised as a tooth-like abnormality was only identified under general anaesthesia, and even then it was impossible to prise the object from the tooth in situ. Misdiagnosis of impacted foreign bodies in young children presents complicated diagnostic problems. PMID- 23801079 TI - Recombinant GnRH-p53 protein sensitizes breast cancer cells to 5-fluorouracil induced apoptosis in vitro and in vivo. AB - An ideal approach to treat cancers with dysfunctional p53 tumor suppressor gene is to reinstate p53 functionality by directly using p53 protein as a therapeutic agent. However, this has not been possible because the cells cannot readily internalize the protein. We constructed a fusion protein consisting of gonadotropin-releasing hormone (GnRH-p53) and p53 moieties. The recombinant protein was directly used to treat human breast cancer cells and athymic nude mice bearing breast cancer xenografts, with or without DNA synthesis-arresting agent 5-fluorouracil (5-FU). Treatments of cells from breast cancer cell-lines MDA-MB-231, T47D, or SKBR-3 with GnRH-p53 in combination with 5-FU significantly enhanced p53-activated apoptosis signals, including PUMA expression, BAX translocation to mitochondria, and activated caspase-3. Intratumoral injection of the GnRH-p53 protein inhibited MDA-MB-231 xenograft growth and induced p53 mediated apoptosis in the tumors. Systemic treatment of the tumor-bearing mice via tail vein injection of GnRH-p53 markedly augmented the anticancer efficacy of 5-FU. Substitution of GnRH-p53 with wild type p53 protein had no effect. Recombinant GnRH-p53 is able to function as a surrogate of p53 with regard to its apoptosis-inducing activity. Combination of GnRH-p53 with DNA-damaging drugs may be of important therapeutic value for cancer treatment. PMID- 23801080 TI - Anti-MS4a4B treatment abrogates MS4a4B-mediated protection in T cells and ameliorates experimental autoimmune encephalomyelitis. AB - Recent data show that anti-CD20 therapy is effective for some autoimmune diseases, including multiple sclerosis (MS). However, the efficacy of anti-CD20 therapy for MS is largely limited because anti-CD20 antibodies target only B cells. In previous studies, we have investigated the function of MS4a4B, a novel CD20 homologue, in T cell proliferation. Here, we found that MS4a4B regulates not only T cell proliferation but also T cell apoptosis. Knockdown of MS4a4B by MS4a4B-siRNA or MS4a4B-shRNA-expressing vector promoted apoptosis in primary T cells and T32 cell line. In contrast, vector-driven over-expression of MS4a4B reduced apoptosis in EL-4 cells. Machinery analysis showed that MS4a4B-mediated T cell survival was associated with decreased activity of caspases 3, 8 and 9. Interestingly, binding of anti-MS4a4B antibodies to T cells induced activated T cells to undergo apoptosis. To test whether anti-MS4a4B antibody interferes with MS4a4B-mediated protection of T cells, we injected anti-MS4a4B antibodies into mice with experimental autoimmune encephalomyelitis (EAE). The results show that anti-MS4a4B treatment ameliorated the severity of EAE, accompanied by decreased Th1 and Th17 cell responses and reduced levels of pro-inflammatory cytokines in the central nervous system, suggesting that MS4a4B may serve as a target of antibody-based therapy for T cell-mediated diseases. PMID- 23801082 TI - Live long and prosper: germline stem cell maintenance revisited (retrospective on DOI: 10.1002/bies.201000085). PMID- 23801081 TI - Isocitrate dehydrogenase 1 mutant R132H sensitizes glioma cells to BCNU-induced oxidative stress and cell death. AB - Isocitrate dehydrogenase 1 (IDH1) decarboxylates isocitrate to alpha ketoglutarate (alpha-KG) leading to generation of NADPH, which is required to regenerate reduced glutathione (GSH), the major cellular ROS scavenger. Mutation of R132 of IDH1 abrogates generation of alpha-KG and leads to conversion of alpha KG to 2-hydroxyglutarate. We hypothesized that glioma cells expressing mutant IDH1 have a diminished antioxidative capacity and therefore may encounter an ensuing loss of cytoprotection under conditions of oxidative stress. Our study was performed with LN229 cells stably overexpressing IDH1 R132H and wild type IDH1 or with a lentiviral IDH1 knockdown. Quantification of GSH under basal conditions and following treatment with the glutathione reductase inhibitor BCNU revealed significantly lower GSH levels in IDH1 R132H expressing cells and IDH1 KD cells compared to their respective controls. FACS analysis of cell death and ROS production also demonstrated an increased sensitivity of IDH1-R132H expressing cells and IDH1 KD cells to BCNU, but not to temozolomide. The sensitivity of IDH1-R132H-expressing cells and IDH1 KD cells to ROS induction and cell death was further enhanced with the transaminase inhibitor aminooxyacetic acid and under glutamine free conditions, indicating that these cells were more addicted to glutaminolysis. Increased sensitivity to BCNU-induced ROS production and cell death was confirmed in HEK293 cells inducibly expressing the IDH1 mutants R132H, R132C and R132L. Based on these findings we propose that in addition to its established pro-tumorigenic effects, mutant IDH1 may also limit the resistance of gliomas to specific death stimuli, therefore opening new perspectives for therapy. PMID- 23801083 TI - Direct reprogramming into desired cell types by defined factors. AB - In the field of developmental biology, the concept that cells, once terminally differentiated, are fixed in their cell fate was long believed to be true. However, Dr. Gurdon and colleagues challenged this fundamental doctrine and demonstrated that cellular reprogramming and cell fate conversion are possible by somatic nuclear transfer and cell fusion. The Weintraub laboratory discovered in the 1980s that a single transcription factor, MyoD, can convert fibroblasts into skeletal muscle cells, and subsequent studies also demonstrated that several transcription factors are lineage converting factors within the blood cell lineage. In 2006, Takahashi and Yamanaka discovered that transduction of the four stem cell-specific transcription factors Oct4, Sox2, Klf4, and c-Myc can reprogram mouse fibroblast cells into a pluripotent state. In 2007, they demonstrated that the same four factors similarly reprogram human somatic cells into pluripotent stem cells. These discoveries by Dr. Yamanaka and colleagues fundamentally changed research in the fields of disease modeling and regenerative medicine and also inspired the next stage of cellular reprogramming, i.e., the generation of desired cell types without reverting to stem cells by overexpression of lineage-specific transcription factors. Recent studies demonstrated that a diverse range of cell types, such as pancreatic beta cells, neurons, neural progenitors, cardiomyocytes, and hepatocytes, can be directly induced from somatic cells by combinations of specific factors. In this article, I review the pioneering works of cellular reprogramming and discuss the recent progress and future perspectives of direct reprogramming technology. PMID- 23801085 TI - Model-based approach to describe G-CSF effects in carboplatin-treated cancer patients. AB - PURPOSE: Granulocyte colony-stimulating factor (G-CSF) is often used in cancer patients receiving cytotoxic drugs to prevent or reduce high grade neutropenia. We propose a pharmacokinetic/pharmacodynamic model to describe myelotoxicity in both G-CSF treated and non-treated patients that shall increase our understanding of G-CSF effects. METHODS: The model was built from absolute neutrophil counts (ANC) obtained in 375 carboplatin-treated patients, 47 of whom received G-CSF. It includes some prior information on G-CSF taken from the literature. Simulations were performed to understand differences in G-CSF effects and explore the impact of G-CSF formulation. RESULTS: Our model well described the data in all patients. Model simulations showed that G-CSF was not as beneficial as expected in some patients. Furthermore, a longer and stronger effect was observed for the pegylated formulation in comparison with the daily standard formulation even if the latter was given for 11 consecutive days. CONCLUSIONS: The proposed model allows a mechanistic interpretation of G-CSF effects on ANC and raises the question of a systematic beneficial effect of G-CSF treatment. Other studies are needed to confirm these findings and help identifying patients for whom G-CSF is beneficial. PMID- 23801088 TI - Robust switching characteristics of CdSe/ZnS quantum dot non-volatile memory devices. AB - In this paper we report Al/CdSe-ZnS core-shell quantum dot/AlOx/CdSe-ZnS core shell quantum dot/ITO based non-volatile resistive memory devices with an ON/OFF ratio of ~1000. The facile solution processed device exhibited excellent endurance characteristics for 200,000 switching cycles. Retention tests showed good stability for over 20,000 s and the devices are reproducible. A memory operating mechanism is proposed based on charge trapping-detrapping in core-shell quantum dots with AlOx acting as a barrier leading to Coulomb blockade. I-V characteristics of a three terminal device fabricated with the additional terminal wired-out from the middle AlOx layer supports the proposed charge trapping mechanism. PMID- 23801087 TI - The use of condensational growth methods for efficient drug delivery to the lungs during noninvasive ventilation high flow therapy. AB - PURPOSE: The objective of this study was to evaluate the delivery of nasally administered aerosols to the lungs during noninvasive ventilation using controlled condensational growth techniques. METHODS: An optimized mixer, combined with a mesh nebulizer, was used to generate submicrometer aerosol particles using drug alone (albuterol sulfate) and with mannitol or sodium chloride added as hygroscopic excipients. The deposition and growth of these particles were evaluated in an adult nose-mouth-throat (NMT) model using in vitro experimental methods and computational fluid dynamics simulations. RESULTS: Significant improvement in the lung dose (3-4* increase) was observed using excipient enhanced growth (EEG) and enhanced condensational growth (ECG) delivery modes compared to control studies performed with a conventional size aerosol (~5 MUm). This was due to reduced device retention and minimal deposition in the NMT airways. Increased condensational growth of the initially submicrometer particles was observed using the ECG mode and in the presence of hygroscopic excipients. CFD predictions for regional drug deposition and aerosol size increase were in good agreement with the observed experimental results. CONCLUSIONS: These controlled condensational growth techniques for the delivery of submicrometer aerosols were found to be highly efficient methods for delivering nasally administered drugs to the lungs. PMID- 23801089 TI - Surgical management and outcomes of petroclival meningiomas: a single-center case series of 259 patients. AB - BACKGROUND: Surgical management of petroclival meningiomas is challenging. Various and inconsistent outcome and prognostic factors of the lesions have been evaluated previously. In the present study, the surgical outcome, philosophy, and experience of petroclival meningiomas are detailed based on a large patient series. METHODS: A series of 259 patients with petroclival meningiomas (70 males and 189 females) were surgically treated. Clinical charts and radiographs were reviewed. Follow-up results were evaluated. RESULTS: The preoperative Karnofsky Performance Scale (KPS) score was 74.2 +/- 10.5. The mean tumor size was 4.3 +/- 1.0 cm. The gross total resection (GTR) rate was 52.5%. During a mean follow-up period of 55.3 months, recurrence/progression (R/P) occurred in 11 patients. The recent KPS score was 78.4 +/- 22.7, it improved in 139 (57.2%) patients and stabilized in 53 (21.8%) patients, and 201 (82.7%) patients lived independently. The risk factors affecting the KPS score included (but were not limited to) age >= 60, preoperative KPS <= 60, and brainstem edema. The adverse factors contributing to R/P-free survival included (but were not limited to) non-total resection and the absence of the subarachnoid space. The R/P-free survival rate was 94.5% at 5 years and 91.2% at 9 years. The overall survival rate was 94.7% at 5 years and 94.7% at 9 years. CONCLUSIONS: Favorable outcomes from petroclival meningiomas could be achieved by microsurgery. Neurological function and quality of life were prioritized, and GTR was attempted. Risk factors should be considered in surgical schemes, and tumor recurrence should be aggressively monitored and treated. PMID- 23801090 TI - Osteology of the prowfish, Zaprora silenus (Cottiformes: Zoarcoidei: Zaproridae). AB - The prowfish, Zaprora silenus, is the sole member of the family Zaproridae. It is a large, relatively elongate species with a robust head and body, and it feeds primarily on jellyfishes. Although the larvae and juveniles are pelagic, the adults are demersal, and the species is widely distributed from Southern California around the Pacific Rim to Hokkaido, Japan. The stichaeid affinities of this species have long been recognized, and the family is currently placed, along with the Stichaeidae, in the Zoarcoidei. Previous anatomical studies of Zaprora have been based on relatively few specimens from a limited geographic range and have not included cleared and stained (c&s) specimens. Here, we provide a complete description of the osteology of the prowfish, based on a large series of specimens representing a broad ontogenetic range, including a series of c&s specimens. Our results contradict the findings of previous authors in the structure of the pharyngeal teeth, presence of the pelvic girdle, and the placement of the first dorsal pterygiophore. However, we concur with the findings of previous morphological and molecular phylogenetic studies, which indicate that the prowfish is probably most closely related to at least some members of the Stichaeidae. PMID- 23801086 TI - Methodologies to assess drug permeation through the blood-brain barrier for pharmaceutical research. AB - The drug discovery process for drugs that target the central nervous system suffers from a very high rate of failure due to the presence of the blood-brain barrier, which limits the entry of xenobiotics into the brain. To minimise drug failure at different stages of the drug development process, new methodologies have been developed to understand the absorption, distribution, metabolism, excretion and toxicity (ADMET) profile of drug candidates at early stages of drug development. Additionally, understanding the permeation of drug candidates is also important, particularly for drugs that target the central nervous system. During the first stages of the drug discovery process, in vitro methods that allow for the determination of permeability using high-throughput screening methods are advantageous. For example, performing the parallel artificial membrane permeability assay followed by cell-based models with interesting hits is a useful technique for identifying potential drugs. In silico models also provide interesting information but must be confirmed by in vitro models. Finally, in vivo models, such as in situ brain perfusion, should be studied to reduce a large number of drug candidates to a few lead compounds. This article reviews the different methodologies used in the drug discovery and drug development processes to determine the permeation of drug candidates through the blood-brain barrier. PMID- 23801091 TI - A case of instantaneous rigor? AB - The question of whether instantaneous rigor mortis (IR), the hypothetic sudden occurrence of stiffening of the muscles upon death, actually exists has been controversially debated over the last 150 years. While modern German forensic literature rejects this concept, the contemporary British literature is more willing to embrace it. We present the case of a young woman who suffered from diabetes and who was found dead in an upright standing position with back and shoulders leaned against a punchbag and a cupboard. Rigor mortis was fully established, livor mortis was strong and according to the position the body was found in. After autopsy and toxicological analysis, it was stated that death most probably occurred due to a ketoacidotic coma with markedly increased values of glucose and lactate in the cerebrospinal fluid as well as acetone in blood and urine. Whereas the position of the body is most unusual, a detailed analysis revealed that it is a stable position even without rigor mortis. Therefore, this case does not further support the controversial concept of IR. PMID- 23801092 TI - Dosimetric accuracy of Gafchromic EBT2 and EBT3 film for in vivo dosimetry. AB - Radiochromic film has the potential to provide accurate in vivo dosimetry measurements. However, it is not known whether small film pieces can still provide accurate dosimetric results. The use of small film pieces is of particular interest in regions of interest (ROIs) such as the eye, or where the patient's contour changes rapidly. This study examines the dosimetric accuracy of Gafchromic EBT2 and EBT3 models of radiochromic film and its dependence on film size, ROI size, and height above the scan bed for 6 MV photons and 9 MeV electrons. Films cut to sizes of 5.0 * 5.0, 10.0 * 10.0, 20.0 * 20.0, and 40.0 * 40.0 mm2 were tested and it was found that there was no increase in uncertainty of dose when even the smallest film sizes were used. For a film 5.0 * 5.0 mm2, ROIs of 1.4 * 1.4, 2.1 * 2.1 and 3.5 * 3.5 mm2 were tested and it was found that the ROI size of 2.1 * 2.1 mm2 was the most accurate. The standard deviation of the EBT3 placed on the glass (2.1%) was larger than the standard deviation of the EBT3 film raised above the glass (1.2%), therefore it is recommended that film is scanned raised above the scan bed. The general dosimetric performance of EBT3 was comparable to EBT2. We conclude that film pieces as small as 5.0 * 5.0 mm2 could be used for the purpose of in vivo dosimetry of radiotherapy treatments. PMID- 23801093 TI - Preoperative immunonutrition and its effect on postoperative outcomes in well nourished and malnourished gastrointestinal surgery patients: a randomised controlled trial. AB - BACKGROUND/OBJECTIVES: Invasive procedures such as surgery cause immunosuppression, leading to increased risk of complications, infections and extended hospital stay. Emerging research around immune-enhancing nutrition supplements and their ability to reduce postoperative complications and reduce treatment costs is promising. This randomised controlled trial aims to examine the effect of preoperative immunonutrition supplementation on length of hospital stay (LOS), complications and treatment costs in both well-nourished and malnourished gastrointestinal surgery patients. SUBJECTS/METHODS: Ninety-five patients undergoing elective upper and lower gastrointestinal surgery were recruited. The treatment group (n=46) received a commercial immuno-enhancing supplement 5 days preoperatively. The control group (n=49) received no supplements. The primary outcome measure was LOS, and secondary outcome measures included complications and cost. RESULTS: A nonsignificant trend towards a shorter LOS within the treatment group was observed (7.1 +/- 4.1 compared with 8.8 +/- 6.5 days; P=0.11). For malnourished patients, this trend was greater with hospital stay reduced by 4 days (8.3 +/- 3.5 vs 12.3 +/- 9.5 days; P=0.21). Complications and unplanned intensive care admission rates were very low in both the groups. The average admission cost was reduced by AUD1576 in the treatment group compared with the control group (P=0.37). CONCLUSIONS: Preoperative immunonutrition therapy in gastrointestinal surgery has the potential to reduce the LOS and cost, with greater treatment benefit seen in malnourished patients; however, there is a need for additional research with greater patient numbers. PMID- 23801094 TI - Serum pyridoxal concentrations and depressive symptoms among Japanese adults: results from a prospective study. AB - BACKGROUND/OBJECTIVES: Vitamin B6 is suggested to have a protective role against depression. However, the association between vitamin B6 intake and depression remains inconclusive, and few studies have examined the relationship between circulating vitamin B6 concentrations and depressive symptoms. Here, we investigated the cross-sectional and prospective associations between serum pyridoxal concentrations and depressive symptoms among Japanese workers. SUBJECTS/METHODS: Participants were 422 municipal employees (aged 21-67 years) who participated in a baseline survey in 2006 for cross-sectional analysis, and 210 subjects without depressive symptoms at baseline (2006) who completed both baseline and follow-up (2009) surveys for prospective analysis. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES D) scale. Logistic regression analysis was used to estimate the odds ratio of depressive symptoms (CES-D scale of >= 19) according to tertile of serum pyridoxal with adjustment for potential confounding variables. RESULTS: In the cross-sectional analysis, serum pyridoxal concentrations were significantly associated with a decreased prevalence of depressive symptoms (P for trend=0.03); the multivariable-adjusted odds ratio of depressive symptoms for the highest tertile of pyridoxal was 0.54 (95% confidence interval 0.30-0.96) compared with the lowest tertile. In longitudinal analyses, higher serum pyridoxal concentrations at baseline were associated with a trend toward reduced depressive symptoms after 3 years; the multivariable-adjusted odds ratio of depressive symptoms for the highest versus the lowest tertile of pyridoxal concentration was 0.55 (95% confidence interval 0.13-2.32). CONCLUSIONS: A higher vitamin B6 status may be associated with a decreased risk of depressive symptoms in Japanese. PMID- 23801095 TI - How important is the choice of the nutrient profile model used to regulate broadcast advertising of foods to children? A comparison using a targeted data set. AB - BACKGROUND/OBJECTIVE: The World Health Assembly recommends that children's exposure to marketing of unhealthy foods should be reduced. Nutrient profile models have been developed that define 'unhealthy' to support regulation of broadcast advertising of foods to children. The level of agreement between these models is not clear. The objective of this study was to measure the agreement between eight nutrient profile models that have been proposed for the regulation of marketing to children over (a) how many and (b) what kind of foods should be permitted to be advertised during television viewed by children. SUBJECTS/METHODS: A representative data set of commercials for foods broadcast during television viewed by children in the UK was collected in 2008. The data set consisted of 11,763 commercials for 336 different products or brands. This data set was supplemented with nutrition data from company web sites, food packaging and a food composition table, and the nutrient profile models were applied. RESULTS: The percentage of commercials that would be permitted by the different nutrient profile models ranged from 2.1% (0.4%, 3.7%) to 47.4% (42.1%, 52.6%). Half of the pairwise comparisons between models yielded kappa statistics less than 0.2, indicating that there was little agreement between models. CONCLUSIONS: Policy makers considering the regulation of broadcast advertising to children should carefully consider the choice of nutrient profile model to support the regulation, as this choice will have considerable influence on the outcome of the regulation. PMID- 23801096 TI - Attitudes toward healthy eating: a mediator of the educational level-diet relationship. AB - BACKGROUND/OBJECTIVES: A higher educational level is associated with a healthier diet. The goal of this study was to establish whether this association is mediated by attitudes toward healthy eating. SUBJECTS/METHODS: The cross sectional MONA LISA-NUT study was performed in 2005-2007 on adults aged 35-64 years from northern and north-eastern France. Diet quality was assessed on the basis of a 3-day food record and a validated score based on French national dietary guidelines. Specific questions investigated attitudes toward healthy eating. Multivariate analyses were used to quantify the proportion of the educational level-diet relationship that was mediated by attitudes toward healthy eating. RESULTS: Among the 1631 subjects, favourable attitudes toward healthy eating were associated with both higher educational level and diet quality. In the mediation analysis, 'organic food consumption' explained 14% (95% confidence interval (8;24)) of the educational level-diet relationship and 'attention paid to health when buying food' explained 9% (3;16). In contrast, 'attention to food choice', 'searching for information about food' and 'perceived role of eating' were not mediators of the association between educational level and diet. In a multivariate model, the attitude items together accounted for 25% (10;45) of the relationship. The mediation was more pronounced in women than in men (37% (15;54) vs 16% (1;27), respectively) and was significant for consumption of fruits and vegetables (23% (13;37)), whole-grain food (32% (15;58)) and seafood (22% (9;55)). CONCLUSIONS: Our results suggest that poor attitudes toward healthy eating in groups with low socioeconomic status constitute an additional factor (along with cost constraints) in the choice of unhealthy foods. PMID- 23801098 TI - Enantioselective hydrolysis of dl-menthyl benzoate by cell-free extract of newly isolated Acinetobacter sp. ECU2040. AB - Production of l-menthol by bioprocesses attracts increasing attention nowadays. Herein, we attempted to develop a bioresolution process for production of l menthol through enantioselective hydrolysis of dl-menthyl benzoate using a newly isolated bacterium from soil samples. Among 129 active soil isolates screened rapidly by thin-layer chromatography, an outstanding bacterial strain numbered ECU2040, which was subsequently identified as Acinetobacter species, was finally selected as our target enzyme producer due to its highest activity and the best enantioselectivity toward l-substrate as confirmed by chiral gas chromatography. The catalytic performance of the cell-free extract from Acinetobacter sp. ECU2040 was preliminarily examined, indicating that its optimal pH and temperature for the reaction were 7.5 and 37 degrees C, respectively. Under the optimal conditions, the enzymatic reaction was performed on a 1-L scale, affording l menthol in 48 % yield and 71 % ee. PMID- 23801097 TI - Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets. AB - Very-low-carbohydrate diets or ketogenic diets have been in use since the 1920s as a therapy for epilepsy and can, in some cases, completely remove the need for medication. From the 1960s onwards they have become widely known as one of the most common methods for obesity treatment. Recent work over the last decade or so has provided evidence of the therapeutic potential of ketogenic diets in many pathological conditions, such as diabetes, polycystic ovary syndrome, acne, neurological diseases, cancer and the amelioration of respiratory and cardiovascular disease risk factors. The possibility that modifying food intake can be useful for reducing or eliminating pharmaceutical methods of treatment, which are often lifelong with significant side effects, calls for serious investigation. This review revisits the meaning of physiological ketosis in the light of this evidence and considers possible mechanisms for the therapeutic actions of the ketogenic diet on different diseases. The present review also questions whether there are still some preconceived ideas about ketogenic diets, which may be presenting unnecessary barriers to their use as therapeutic tools in the physician's hand. PMID- 23801099 TI - Association of trochlear dysplasia with degenerative abnormalities in the knee: data from the Osteoarthritis Initiative. AB - OBJECTIVE: To evaluate trochlear morphology as a potential risk factor for patellofemoral osteoarthritis, determined by morphological and quantitative measurements of cartilage degeneration using 3-T magnetic resonance imaging (MRI) of the knee. MATERIALS AND METHODS: MRI of the right knees of 304 randomly selected subjects, aged 45-60 years, from the Osteoarthritis Initiative (OAI) progression cohort were screened for trochlear dysplasia, defined by an abnormal trochlear depth. Out of 304 subjects, n = 85 demonstrated a shallow trochlea (depth <=3 mm; 28 %). In these, and also in a random sample of controls with normal trochlear depth (n = 50), the facet ratio and the sulcus angle were calculated and knee structural abnormalities were assessed by using a modified Whole Organ MR Imaging Score (WORMS). Cartilage segmentation was performed and T2 relaxation times and patellar cartilage volume were determined. ANOVA and multivariate regression models were used for statistical analysis of the association of MRI structural measures and trochlear morphology. RESULTS: Knees with a shallow trochlea showed higher patellofemoral degeneration (WORMS mean +/- standard deviation, 11.2 +/- 0.5 versus 5.7 +/- 0.6; multivariate regression, P < 0.001) and lower patellar cartilage volume than controls (900 +/- 664 mm(3) versus 1,671 +/- 671 mm(3); P < 0.001). Knees with an abnormal medial-to-lateral facet ratio (<0.4) showed increased patellofemoral WORMS scores (12.3 +/- 0.9 versus 8.3 +/- 0.5; P < 0.001). Knees with an abnormal sulcus angle (>170 degrees ) also showed increased WORMS scores (12.2 +/- 1.1 versus 8.6 +/- 0.6; P = 0.003). T2 values at the patella were significantly lower in the dysplasia group with a shallow trochlea. However, significance was lost after adjustment for cartilage volume (P = 0.673). CONCLUSION: Trochlear dysplasia, defined by a shallow trochlea, was associated with higher WORMS scores and lower cartilage volume, indicating more advanced osteoarthritis at the patellofemoral joint. PMID- 23801102 TI - Mental health of Latin Americans in Canada: a literature review. AB - BACKGROUND: Latin Americans represent one of the fastest-growing immigrant populations in Canada. But very little is known about their mental health. AIMS: This paper reviews the literature on the mental health of Latin American immigrants to Canada. The paper also identifies potential areas to expand the research agenda. METHOD: Twenty-five papers were identified by a comprehensive electronic search undertaken in medical- and humanities-related databases. RESULTS RESULT: s are reported in three sections: (1) the rates of mental illness; (2) the risk factors that affect mental health; and (3) the access and barriers to care and services. Findings indicate that despite the diversity of immigration from Latin America to Canada, much of the information on mental health focuses on Central American refugees. The most frequently examined risk factor is displacement as a consequence of political persecution and torture in the home country. Access to mental health services in this population seems to be limited by cultural differences and language barriers. CONCLUSION: New research on this topic should reflect the growing diversity and heterogeneity of the Latin American population in Canada. PMID- 23801100 TI - Lipomatosis of the sciatic nerve secondary to compression by a desmoid tumor. AB - Lipomatosis of nerve is a rare benign tumor-like process characterized by infiltration of the epineurium by adipose and fibrous tissue leading to nerve enlargement. We describe a case of lipomatosis of the sciatic nerve compressed by an adjacent desmoid tumor. This case supports the hypothesis that lipomatosis of nerve may form as a result of irritation or compression by adjacent structures. PMID- 23801103 TI - [Lymphedema. Diagnostics and therapy]. AB - Swellings of the extremities are often observed in routine practice and are initially seen as a symptom; therefore, it is extremely important to find the cause and often produces differential diagnostic problems. As the diagnosis of lymphedema is mostly a clinical one it is especially necessary to thoroughly investigate an exact anamnesis and clinical examination which should be combined with as little technical equipment as possible. Implementation of the correct and consistent therapy of this chronic disease and continuous surveillance represents a special challenge for physicians and therapists. Operative solutions represent the last resort and often end in unsure results. PMID- 23801104 TI - [Indications, technique and complications of port implantation]. AB - Implanted central venous access devices are becoming increasingly more important in oncology as an important tool for therapists and patients. As an intracorporeal system with reduced risk of infection compared to percutaneous tunnelled catheters they ensure a permanent and safe access to the central venous system. However, they can be associated with risks and sometimes severe complications which should not be underestimated so that planning and performance of the implantation require a high level of care and attention. Postoperative care and the correct allocation of all groups of persons involved in the therapy can reduce complication rates and are thus of prognostic relevance. PMID- 23801105 TI - Cardiopulmonary resuscitation quality: [corrected] improving cardiac resuscitation outcomes both inside and outside the hospital: a consensus statement from the American Heart Association. AB - The "2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care" increased the focus on methods to ensure that high-quality cardiopulmonary resuscitation (CPR) is performed in all resuscitation attempts. There are 5 critical components of high-quality CPR: minimize interruptions in chest compressions, provide compressions of adequate rate and depth, avoid leaning between compressions, and avoid excessive ventilation. Although it is clear that high-quality CPR is the primary component in influencing survival from cardiac arrest, there is considerable variation in monitoring, implementation, and quality improvement. As such, CPR quality varies widely between systems and locations. Victims often do not receive high-quality CPR because of provider ambiguity in prioritization of resuscitative efforts during an arrest. This ambiguity also impedes the development of optimal systems of care to increase survival from cardiac arrest. This consensus statement addresses the following key areas of CPR quality for the trained rescuer: metrics of CPR performance; monitoring, feedback, and integration of the patient's response to CPR; team-level logistics to ensure performance of high-quality CPR; and continuous quality improvement on provider, team, and systems levels. Clear definitions of metrics and methods to consistently deliver and improve the quality of CPR will narrow the gap between resuscitation science and the victims, both in and out of the hospital, and lay the foundation for further improvements in the future. PMID- 23801106 TI - Salbutamol extraction from urine and its stability in different solutions: identification of methylation products and validation of a quantitative analytical method. AB - Salbutamol is commonly used in asthma treatment, being considered a short-effect bronchodilator. This drug poses special interest in certain fields of chemical analysis, such as food, clinical and doping analyses, in which it needs to be analyzed with quantitative precision and accuracy. Salbutamol, however, is known to degrade under certain conditions and this is critical if quantitative results must be generated. The present work aimed to investigate salbutamol extraction from urine samples, to determine whether salbutamol is unstable in other solvents as well as in urine samples, to elucidate the structures of the possible degradation products and to validate an analytical method using the extraction procedure evaluated. Stability investigations were performed in urine at different pH values, in methanol and acetone at different temperatures. Semi preparative liquid chromatography was performed for the isolation of degradation products, and gas chromatography coupled to mass spectrometry as well as nuclear magnetic resonance were used for identification. Three unreported methylation products were detected in methanolic solutions and had their structures elucidated. Urine samples showed a reduction in salbutamol concentration of up to 25.8% after 5 weeks. These results show that special care must be taken regarding salbutamol quantitative analyses, since degradation either in standard solutions or in urine could lead to incorrect values. PMID- 23801107 TI - Tobacco-related cancer mortality: projections for different geographical regions in Switzerland. AB - PRINCIPLES: Switzerland is divided into 26 cantons of variable population size and cultural characteristics. Although a federal law to protect against passive smoking and a national tobacco control programme exist, details of tobacco related policies are canton-specific. This study aimed to project gender-specific tobacco-related cancer mortality in Switzerland at different geographical levels for the periods 2009-2013 and 2014-2018. METHODS: In this analysis, data on Swiss tobacco-related cancer mortality from 1984 until 2008 were used. Bayesian age period-cohort models were formulated to assess past trends of gender-specific tobacco-related cancer mortality and to project them up to 2018 at cantonal and language region levels. Furthermore, estimates are provided on a national scale by age categories of 50-69 and >=70 years. RESULTS: Model-based estimates at cantonal level identified regions with low and high tobacco-related cancer mortality rates for the observed and projected periods. Our analysis based on language regions showed the lowest mortality in the German-speaking part. Projections at national level, between younger (age 50-69) and older (age >=70) males, indicated an ongoing decreasing trend for males but an upward trend for females. The gap in tobacco-related cancer mortality rates between younger and older males seems to be shrinking. In females, a stronger rise was obtained for the younger age group. CONCLUSION: Our findings indicate region-, sex- and age related differences in tobacco-related cancer mortality in Switzerland and this could be useful for healthcare planning and for evaluating the impact of canton specific tobacco-related policies and interventions. PMID- 23801108 TI - Highly efficient visible light-induced O2 generation by self-assembled nanohybrids of inorganic nanosheets and polyoxometalate nanoclusters. AB - Unusually high photocatalytic activity of visible light-induced O2 generation can be achieved by electrostatically-derived self-assembly between exfoliated Zn-Cr LDH 2D nanosheets and POM 0D nanoclusters (W7O246- and V10O286-) acting as an electron acceptor. This self-assembly can provide a high flexibility in the control of the chemical composition and pore structure of the resulting LDH-based nanohybrids. The hybridization with POM nanoclusters remarkably enhances the photocatalytic activity of the pristine Zn-Cr-LDH, which is attributable to the formation of porous structure and depression of charge recombination. Of prime interest is that the excellent photocatalytic activity of the as-prepared Zn-Cr LDH-POM nanohybrid for visible light-induced O2 generation can be further enhanced by calcination at 200 degrees C, leading to the very high apparent quantum yield of ~75.2% at 420 nm. The present findings clearly demonstrate that the self-assembly of LDH-POM is fairly powerful in synthesizing novel LDH-based porous nanohybrid photocatalyst for visible light-induced O2 generation. PMID- 23801109 TI - Skeletal muscle density predicts prognosis in patients with metastatic renal cell carcinoma treated with targeted therapies. AB - BACKGROUND: Studies have shown that skeletal muscle and adipose tissue are linked to overall survival (OS) and progression-free survival (PFS). Because targeted therapies have improved the outcome in patients with metastatic renal cell carcinoma (mRCC), new prognostic parameters are required. The objective of the current study was to analyze whether body composition parameters play a prognostic role in patients with mRCC. METHODS: Adipose tissue, skeletal muscle, and skeletal muscle density (SMD) were assessed with computed tomography imaging by measuring cross-sectional areas of the tissues and mean muscle Hounsfield units (HU). A high level of mean HU indicates a high SMD and high quality of muscle. OS and PFS were estimated using the Kaplan-Meier method and compared with the log-rank test. The multivariable Cox proportional hazards model was adjusted for Heng risk score and treatment. RESULTS: In the 149 patients studied, the median OS was 21.4 months and was strongly associated with SMD; the median OS in patients with low SMD was approximately one-half that of patients with high SMD (14 months vs 29 months; P = .001). After adjustment for Heng risk score and treatment, high SMD was associated with longer OS (hazards ratio, 1.85; P = .004) and longer PFS (hazards ratio, 1.81; P = .002). Adding SMD will separate the intermediate-risk and favorable-risk groups into 3 groups, with different median OS periods ranging from 8 months (95% confidence interval [95% CI], 6 months-12 months) for an intermediate-risk Heng score/low SMD to 22 months (95% CI, 14 months-27 months) for an intermediate-risk Heng score/high SMD and a favorable risk Heng score/low SMD to 35 months (95% CI, 24 months-43 months) for a favorable-risk Heng score/high SMD. CONCLUSIONS: High muscle density appears to be independently associated with improved outcome and could be integrated into the prognostic scores thereby enhancing the management of patients with mRCC. PMID- 23801110 TI - Heterologous expression and characterization of a malathion-hydrolyzing carboxylesterase from a thermophilic bacterium, Alicyclobacillus tengchongensis. AB - A carboxylesterase gene from thermophilic bacterium, Alicyclobacillus tengchongensis, was cloned and expressed in Escherichia coli BL21 (DE3). The gene coded for a 513 amino acid protein with a calculated molecular mass of 57.82 kDa. The deduced amino acid sequence had structural features highly conserved among serine hydrolases, including Ser204, Glu325, and His415 as a catalytic triad, as well as type-B carboxylesterase serine active site (FGGDPENITIGGQSAG) and type-B carboxylesterase signature 2 (EDCLYLNIWTP). The purified enzyme exhibited optimum activity with beta-naphthyl acetate at 60 degrees C and pH 7 as well as stability at 25 degrees C and pH 7. One unit of the enzyme hydrolyzed 5 mg malathion l(-1) by 50 % within 25 min and 89 % within 100 min. The enzyme strongly degraded malathion and has a potential use for the detoxification of malathion residues. PMID- 23801111 TI - Long-chain ethers as solvents can amplify the enantioselectivity of the Carica papaya lipase-catalyzed transesterification of 2-(substituted phenoxy)propanoic acid esters. AB - The enantioselectivity of the transesterification of the 2,2,2-trifluoroethyl esters of 2-(substituted phenoxy)propanoic acids, as catalyzed by the lipase from Carica papaya, was greatly improved by using long-chain ethers, such as di-n hexyl ether, as solvents instead of the conventional diisopropyl ether. Thus, for example, the E value was enhanced from 21 [in diisopropyl ether (0.8 ml)] to 57 [in di-n-hexyl ether (0.8 ml)] in the reaction of 2,2,2-trifluoroethyl(RS)-2 phenoxypropanoate (0.1 mmol) with methanol (0.4 mmol) in the presence of the plant lipase preparation (10 mg); it was also improved from 13 (in diisopropyl ether) to 44 (in di-n-hexyl ether) in the reaction of 2,2,2-trifluoroethyl(RS)-2 (2-chlorophenoxy)propanoate with methanol under the same reaction conditions. PMID- 23801112 TI - A two-dimensional mass transfer model for an annular bioreactor using immobilized photosynthetic bacteria for hydrogen production. AB - A two-dimensional model for substrate transfer and biodegradation in a novel, annular fiber-illuminating bioreactor (AFIBR) is proposed in which photosynthetic bacteria are immobilized on the surface of a side-glowing optical fiber to form a stable biofilm. When excited by light, the desired intensity and uniform light distribution can be obtained within the biofilm zone in bioreactor and then realize continuous hydrogen production. Substrate transfer and biodegradation within the biofilm zone, as well as substrate diffusion and convection within bulk fluid regions are considered simultaneously in this model. The validity of the model is verified experimentally. Based on the model analysis, influences of flow rate and light intensity on the substrate consumption rate and substrate degradation efficiency were investigated. The simulation results show that the optimum operational conditions for the substrate degradation within the AFIBR are: flow rate 100 ml h(-1) and light intensity 14.6 MUmol photons m(-2 )s(-1). PMID- 23801113 TI - Apoptosis-antagonizing transcription factor (AATF) gene silencing: role in induction of apoptosis and down-regulation of estrogen receptor in breast cancer cells. AB - Apoptosis-antagonizing transcription factor (AATF) is involved in transcriptional regulation, cell cycle control, DNA damage responses and in the execution of cell death programs. It also interacts directly with nuclear hormone receptors to enhance their transactivation. This study highlights the RNomics of AATF gene in the pathogenesis of breast cancer: RNA interference gave 64% reduction in AATF mRNA and 47% decline in AATF protein expression in MCF-7 breast cancer cells. Cell proliferation decreased by 41% after transfection and was accompanied by apoptosis induction in 30% MCF-7 cells. Pro-apoptotic genes (Bax, Bag4, Fas, Faslg, Fadd, Casp5, Casp6, Abl 1, Apaf1, Bcl2l 11, Card4, -6, -8, Bnip2 and Bnip3l) were up-regulated and anti-apoptotic genes (Bcl2, Mcl1dc, TNF, Pycard, Tradd, Bcl2A1 and Birc1) were down-regulated as were estrogen receptor mRNA (42%) and protein expression (30 %). In normal non-malignant mammary epithelial cells (MCF-10A) apoptosis induction was only 18% with a 9% fall in ER protein expression. Thus, AATF-silencing can be used to induce apoptosis and regulate ER expression in breast cancer cells for therapeutic interventions. PMID- 23801114 TI - Preparation of submicrometer monodispersed magnetic silica particles using a novel water in oil microemulsion: properties and application for enzyme immobilization. AB - The synthesis of monodispersed magnetic silica nanoparticles (MSN) is described using a water-in-oil reverse microemulsion system that does not require the use of co-surfactants. Sodium silicate, Tween 20 as a neutral surfactant and 1 butanol as the organic phase were used. There are several advantages of the proposed method including a saturation magnetization value of 10 emu/g for the particles obtained, uniformity of size and that they are easily functionalized to bind urease covalently. Moreover, the intra-day, inter-day and long-term stability results confirm that the procedure was successful and the enzyme-linked MSNs were stable over repeated uses and storage retaining more than 75% activity after 4 months. PMID- 23801115 TI - Production of ramoplanin analogues by genetic engineering of Actinoplanes sp. AB - Ramoplanins are lipopeptides effective against a wide range of Gram-positive pathogens. Ramoplanin A2 is in Phase III clinical trials. The structure-activity relationship of the unique 2Z,4E-fatty acid side-chain of ramoplanins indicates a significant contribution to the antimicrobial activities but ramoplanin derivatives with longer 2Z,4E-fatty acid side-chains are not easy to obtain by semi-synthetic approaches. To construct a strain that produces such analogues, an acyl-CoA ligase gene in a ramoplanin-producing Actinoplanes was inactivated and a heterologous gene from an enduracidin producer (Streptomyces fungicidicus) was introduced into the mutant. The resulting strain produced three ramoplanin analogues with longer alkyl chains, in which X1 was purified. The MIC value of X1 was ~0.12 MUg/ml against Entrococcus sp. and was also active against vancomycin resistant Staphylococcus aureus (MIC = 2 MUg/ml). PMID- 23801116 TI - Residue Phe42 is critical for the catalytic activity of Escherichia coli major nitroreductase NfsA. AB - The major O2-insensitive nitroreductase (NfsA) of Escherichia coli shares low sequence homology but similar biochemical and structural features with NfsB, the E. coli minor O2-insensitive nitroreductase. A structural comparison revealed Phe42 was present in the active site of NfsA but not NfsB. F42Y, F42N and F42A were generated and had decreased activity toward nitrofurazone by 52, 96, and 99%, respectively. The kinetic parameters for other nitroaromatic substrates were also determined. Compared to wild type, the mutants did not have significantly altered K(m)s, but had dramatically decreased k(cat) and k(cat)/K(m) values. Far UV CD spectral analysis of the mutants suggested that there were no significant conformational changes however F42A and F42N had changes from 208 to 222 nm, which was attributed to loss of helix content. These findings revealed that Phe42 is important for maintaining NfsA activity and structure. PMID- 23801117 TI - MiR-424 regulates monocytic differentiation of human leukemia U937 cells by directly targeting CDX2. AB - MiR-424 plays an important role via promoting the monocytic differentiation in many human leukemia cell lines. Here, we report that miR-424 decreased miR-125b expression to 36 % by directly targeting caudal type homeobox 2. However, miR-424 also decreased expression of Fes, PU.1 and colony-stimulating factor receptor (MCSFR). As Fes, PU.1 and MCSFR were down-regulated by over-expression of miR 125b (unpublished work), a similar effect of miR-424 and Fes siRNA on CD64, Egr 1, Egr-2 and CEBPA indicates that Fes may be an important downstream target of miR-424. We hypothesize that miR-424 promotes monocytic differentiation by regulating other critical factors and miR-424 has high affinity for these factors. For the first time, the molecular mechanism of miR-424 during monocytic differentiation of U937 cells has been elucidated in this study. PMID- 23801118 TI - Identification and characterization of P GCW14 : a novel, strong constitutive promoter of Pichia pastoris. AB - The available promoters in the Pichia pastoris expression platform are still limited. We selected and identified a novel strong constitutive promoter, P GCW14 , and tested its promoter activity using enhanced green fluorescent protein (EGFP) as a reporter. Potential promoter regions of P GCW14 were cloned upstream of the EGFP gene and promoter activity was analyzed by measuring fluorescence intensity. P GCW14 exhibited significantly stronger promoter activity than the classic strong constitutive promoters P TEF1 and P GAP under various carbon sources, suggesting that P GCW14 is a strong and constitutive promoter. Hence, P GCW14 can be used as a promoter for high-level expression of heterologous proteins. PMID- 23801119 TI - 3-O-Acetyloleanolic acid exhibits anti-angiogenic effects and induces apoptosis in human umbilical vein endothelial cells. AB - 3-O-Acetyloleanolic acid, a pentacyclic triterpenoid isolated from cowpea seeds, inhibited proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner. HUVECs. The induced apoptosis was characterized by detection of cell surface annexin V and sub-G1 populations. The number of cells immunostained with annexin V-fluorescein isothiocyanate increased after treatment with 3-O-acetyloleanolic acid. The sub G1 cell populations were also increased in treated HUVECs. 3-O-Acetyloleanolic acid induced activation of caspase 3, a critical mediator of apoptosis signaling. It also significantly inhibited angiogenesis in an in vivo Matrigel plug assay. 3 O-Acetyloleanolic acid thus exhibits anti-angiogenic effects and induces apoptosis in HUVECs and the results suggest that it has a potential use for suppression of the tumor growth stimulated by angiogenesis. PMID- 23801120 TI - Characterization of a recombinant mannobiose 2-epimerase from Spirochaeta thermophila that is suggested to be a cellobiose 2-epimerase. AB - A purified recombinant enzyme from Spirochaeta thermophila, that is suggested to be a cellobiose 2-epimerase, was a 47 kDa monomer with a specific activity of 29.2 U min(-1) for mannobiose. The epimerization activity of the recombinant enzyme for mannobiose was maximal at pH 7.0 and 60 degrees C with a half-life of 124 h. The enzyme exhibited a higher epimerization activity for mannose or the mannose moiety at the reducing end of beta- and alpha-1,4-glycosyl-mannose than for glucose or the glucose moiety of beta- and alpha-1,4-glycosyl-glucose. The enzyme was identified as a mannobiose 2-epimerase by evaluating its substrate specificity with not only glucose-containing sugars but also mannose-containing sugars. The activities of the reported cellobiose 2-epimerases from Caldicellulosiruptor saccharolyticus, Dictyoglomus turgidum and Ruminococcus marinus for mannobiose were higher than those for cellobiose, strongly suggesting that these enzymes are not cellobiose 2-epimerases but are mannobiose 2 epimerases. PMID- 23801121 TI - Lipase production by diverse phylogenetic clades of Aureobasidium pullulans. AB - Thirty-nine strains representing 12 diverse phylogenetic clades of Aureobasidium pullulans were surveyed for lipase production using a quantitative assay. Strains in clades 4 and 10 produced 0.2-0.3 U lipase/ml, while color variant strain NRRL Y-2311-1 in clade 8 produced 0.54 U lipase/ml. Strains in clade 9, which exhibit a dark olivaceous pigment, produced the highest levels of lipase, with strain NRRL 62034 yielding 0.57 U lipase/ml. By comparison, Candida cylindracea strain NRRL Y-17506 produced 0.05 U lipase/ml under identical conditions. A. pullulans strain NRRL 62034 reached maximal lipase levels in 5 days on lipase induction medium, while A. pullulans strain NRRL Y-2311-1 and strains in clades 4 and 10 were highest after 6 days. A. pullulans strain NRRL Y-2311-1 and strains in clade 9 produced two extracellular proteins in common, at >50 and <37 kDa. PMID- 23801122 TI - Increasing ethanol titer and yield in a gpd1Delta gpd2Delta strain by simultaneous overexpression of GLT1 and STL1 in Saccharomyces cerevisiae. AB - We have investigated whether simultaneous modification of cofactor metabolism and glycerol in a strain of Saccharomyces cerevisiae can eliminate glycerol synthesis during ethanol production. Two strains, S812 (gpd1Delta gpd2Delta PGK1p-GLT1) and LE17 (gpd1Delta gpd2Delta PGK1p-GLT1 PGKp-STL1) were generated that showed a 8 and 8.2 % increase in the ethanol yield, respectively, compared to the wild type KAM-2 strain. The ethanol titer was improved from 90.4 g/l for KAM-2 to 97.6 g/l for S812 and 97.8 g/l for LE17, respectively. These results provide a new insight into rationalization of metabolic engineering strategies for improvement of ethanol yield through elimination of glycerol production. PMID- 23801123 TI - Recent advances in glycotechnology for glycoconjugate synthesis using microbial endoglycosidases. AB - Biotechnology associated with synthesis of glycopeptides and glycoproteins has recently advanced as glycotechnology. Studies toward glycotechonology include the artificial modification of sugar chains in glycoconjugates to improve their function because the physiological importance of sugar chains in living organisms is well recognized. Methods involving addition of oligosaccharides to peptides and proteins have attracted attention as efficient techniques in glycotechnology, especially those involving the transglycosylation activities of microbial endoglycosidases. The exploration of oligosaccharide oxazolines as donor substrates for the transglycosylation of endoglycosidases has significantly enhanced the efficiency of these processes. Moreover, discovery of novel endoglycosidase mutants with glycosynthase-like activity has made it possible to effectively synthesize large quantities of glycopeptides, as well as homogeneous glycoprotein. The use of mutant enzymes and oligosaccharide oxazolines has led to development of practical applications for the synthesis of bioactive glycopeptides and therapeutic glycoproteins as bio-medicines. PMID- 23801124 TI - A comparative study of the adjuvanticity of Hansenula polymorpha, Saccharomyces cerevsiae and Yarrowia lipolytica in oral and nasal immunization with virus capsid antigens. AB - The adjuvanticity of Hansenula polymorpha, Saccharomyces cerevsiae and Yarrowia lipolytica were compared for oral and nasal immunization with virus capsid antigens. Mice were immunized orally with human papillomavirus type 16 L1 virus like particles (HPV16 L1 VLPs), or intra-nasally with formalin-inactivated influenza A virus (FIV), in combination with one or other yeast. Mice receiving HPV16 L1 VLPs combined with H. polymorpha had a significantly higher titer for serum anti-HPV16 L1 IgG and neutralizing activity than those receiving HPV16 L1 VLPs combined with either of the other two yeasts. Also, mice receiving FIV combined with H. polymorpha had not only a markedly higher anti-influenza A virus IgG titer but also a higher survival rate after a potentially lethal influenza A virus challenge. We suggest that H. polymorpha thus will be useful for enhancing immune responses in mucosal immunizations. PMID- 23801125 TI - High-CO2 tolerance in microalgae: possible mechanisms and implications for biotechnology and bioremediation. AB - Recent developments in the field of microalgal biotechnology, including CO2 biomitigation and the discovery of new species of microalgae that are tolerant to extremely high CO2 levels (40-100 vol%), have renewed interest in the physiological effects and mechanisms of high-CO2 tolerance in photoautotrophs. Photosynthetic apparatus state transitions that increase ATP generation, upregulation of H(+)-ATPases pumping protons out of the cell, rapid shutdown of CO2-concentrating mechanisms, and adjustment of membranes' fatty acid composition are currently believed to be the key mechanisms governing cellular pH homeostasis and hence microalgae's tolerance to high CO2 levels, which is especially characteristic of extremophile and symbiotic species. The mechanisms governing acclimation to high CO2 comprise the subject of this review and are discussed in view of the use of CO2 enrichment to increase the productivity of microalgal cultures, as well as the practice of carbon capture from flue gases. PMID- 23801126 TI - Identification of a second cytotoxic protein produced by Bacillus thuringiensis A1470. AB - Bacillus thuringiensis A1470 produces multiple proteins with similar molecular masses (~30 kDa) with cytotoxicity against human cell lines. One that was previously identified, parasporin-4, is a beta-pore-forming toxin. The N-terminal sequence of a second cytotoxic protein was identical to a partial sequence of parasporin-2 produced by B. thuringiensis A1547. PCR was performed on total plasmid DNA from A1470 by using primers for parasporin-2 to amplify a gene which was then cloned. The cloned gene differed from A1547 parasporin-2 by 8 bp and the predicted protein differed by four amino acids. The gene was expressed in Escherichia coli, and the cytotoxic activities of the recombinant protein against four human cell lines (MOLT-4, Jurkat, HeLa, and HepG2) were similar to those of A1547 parasporin-2. We then confirmed that the A1470 strain simultaneously produces parasporin-2 and parasporin-4. PMID- 23801127 TI - Delayed recovery from ertapenem induced encephalopathy: case-report and a possible mechanism. AB - CASE: The objective of this case report is to report a patient with moderate renal impairment who developed ertapenem-induced encephalopathy with delayed recovery of up to 2 weeks despite receiving and appropriately adjusted dosage of ertapenem. The patient was managed conservatively with full recovery. Carbapenem related neurotoxicity most commonly manifests as seizure with an estimated incidence of 3 %. There are increasing reports of encephalopathy being related to ertapenem and most commonly subsides within days and extended recovery of up to 2 weeks have only been reported in patients with end-stage renal failure. CONCLUSIONS: Prolonged ertapenem induced encephalopathy can occur in patients with moderate renal impairment. These patients can be managed conservatively and they should make a complete recovery. PMID- 23801128 TI - Histiocytic sarcoma : an updated literature review based on the 2008 WHO classification. AB - Histiocytic sarcoma (HS) is an extremely rare malignant neoplasm showing morphologic and immunophenotypic evidence of histiocytic differentiation. The vast majority of previously reported HSs are now generally recognized to be misdiagnosed examples of non-Hodgkin lymphomas, predominantly diffuse large B cell lymphoma or anaplastic large cell lymphoma. The recognition of such tumors parallels the development and widespread use of immunohistochemical techniques, along with the development of molecular genetic methods to detect immunoglobulin (IG) or T-cell receptor (TCR) gene rearrangement. The 2001 World Health Organization (WHO) definition of HS requires the absence of clonal B/T-cell receptor gene rearrangements. However, the 2008 WHO classification no longer strictly requires the absence of clonal immunoglobulin heavy chain (IGH) or TCR gene rearrangement for the diagnosis of HS. Recent studies demonstrated that HSs that occur subsequent to or concurrent with B- or T-lymphoblastic lymphoma/leukemia or mature B-cell neoplasms generally show clonal IgH and/or TCR gene rearrangement. These findings suggest the possibility of transdifferentiation of the two otherwise morphologically and immunohistochemically distinctive neoplasms. In addition, a recent study suggested clonal IG gene rearrangements may be detected at a high frequency in sporadic HS, indicating that a large subset of sporadic HSs may inherit the B lymphocyte genotype. These findings provide new insights into the pathogenesis of HS, although the etiology of HS is still unknown. HS is a diagnosis of exclusion. It is necessary to rule out other diseases that could be misdiagnosed as HS with extensive immunophenotypical analysis before diagnosing HS. PMID- 23801129 TI - The evaluation of immunohistochemical markers and thymic cortical microenvironmental cells in distinguishing thymic carcinoma from type b3 thymoma or lung squamous cell carcinoma. AB - Thymic carcinoma (TC) is often very difficult to distinguish from type B3 thymoma and lung squamous cell carcinoma (L-SCC) involving the anterior mediastinum. The present study evaluated the usefulness of immunohistochemical markers including c Kit, CD5, glucose transporter-1 (GLUT-1), claudin-1 (CLDN-1), thymoproteasome beta5t, p53 and Ki-67 (MIB-1) and thymic cortical environmental marker cells, cortical thymocytes (c-Thy) and thymic cortical dendritic macrophages (TCDMs) in distinguishing thymic carcinoma (TC) from type B3 thymoma or lung squamous cell carcinoma (L-SCC) using 17 cases of type B3 thymoma, 18 cases of TC and 12 cases of L-SCC. The results indicated that c-Kit and CD5 are very useful markers for TC, while GLUT-1, CLDN-1, p53 and Ki-67 are not. Thymic cortical microenvironmental marker cells, especially TCDMs, and thymic cortical epithelial cell-marker beta5t are also useful for distinguishing TC from type B3 thymoma. Although none of these markers are adequate for making a distinction when used alone, the plural use of c-Kit, CD5, beta5t thymic cortical environmental marker cells, c-Thys and TCDMs may therefore lead to a correct distinction between TC and type B3 thymoma or L-SCC. [J Clin Exp Hematop 53(1) : 9-19, 2013]. PMID- 23801130 TI - A case of extramedullary plasmablastic plasmacytoma successfully treated using a combination of thalidomide and dexamethasone and a review of the medical literature. AB - A 56-year-old man developed epistaxis, hoarseness, and swelling of a finger in March 2010. On the basis of biopsies of the masses in the pharynx and finger, he was diagnosed with extramedullary plasmablastic plasmacytoma, with somewhat immature CD45(+), MPC-1(-), and CD49e(-). CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) and VCAP (vincristine, cyclophosphamide, doxorubicin, and prednisolone) therapy was ineffective, but combination therapy with thalidomide and dexamethasone was highly effective. Thalidomide monotherapy successfully maintained partial remission for approximately 7 months. A mass appeared in the right neck in February 2011, and a biopsy confirmed recurrence. Changes to CD45 negativity and MPC-1 partial positivity were seen, while CD49e negativity persisted, suggesting that the plasmablastic plasmacytoma had reverted to a more immature state. Bortezomib therapy was started in March 2011 and was effective. However, during the second round of treatment, the patient developed acute lung injury, which was improved by steroid pulse therapy. After the discontinuation of bortezomib, the extramedullary mass increased rapidly, and the patient died of multiple organ failure. An autopsy showed that plasmablastic plasmacytomas had infiltrated into multiple organs. Extramedullary plasmacytomas and those that revert to an immature state are associated with a poor prognosis, so further treatment improvements are needed in the future. PMID- 23801131 TI - Simultaneous presentation of Waldenstrom macroglobulinemia and multiple myeloma: multidisciplinary diagnosis, treatment and 30-month follow-up. AB - Waldenstrom macroglobulinemia and multiple myeloma are mature B-cell neoplasms deriving from post-germinal cells at different stages of differentiation. The simultaneous presentation of Waldenstrom macroglobulinemia and multiple myeloma in the same patient is a very rare phenomenon and, so far, only two cases have been described. We report the case of a 75-year Caucasian female patient, with a silent clinical history, who presented with anemia and two different monoclonal proteins (IgMkappa and IgGkappa). The trephine biopsy showed the presence of a dual population, represented by small lymphoplasmacytoid cells and by plasma cells, which infiltrated the bone marrow with a clearly different pattern. Both immunohistochemistry and flow cytometry demonstrated the biclonal origin such neoplastic cells, since lymphoplasmacytoid cells resulted IgMkappa while plasma cells were IgGkappa. This biclonal pattern was further confirmed by the demonstration of a different IgH gene rearrangement of the two neoplasms. The patient was treated with bortezomib, dexamethasone and rituximab, achieving partial remission of both Waldenstrom macroglobulinemia and multiple myeloma. After a 30-month follow-up, she is in stable disease. Multiple myeloma has been described in association with other indolent B-cell neoplasms, mostly chronic lymphocytic leukemia, while Waldenstrom macroglobulinemia can be followed by diffuse large B-cell lymphoma in some instances, after chemotherapy. The association of Waldenstrom macroglobulinemia and multiple myeloma seems to be very rare. Our study shows that an integrated diagnostic work-up is very useful in such cases, with an interesting role for flow cytometry. [J Clin Exp Hematop 53(1): 29-36, 2013]. PMID- 23801132 TI - CD56+ angioimmunoblastic T-cell lymphoma with evans syndrome : a case report and review of the literature. AB - A 67-year-old man was diagnosed with CD56(+) angioimmunoblastic T cell lymphoma (AITL), which was associated with autoimmune thrombocytopenic purpura (ATP) and autoimmune hemolytic anemia (AIHA) (Evans syndrome). The ATP was refractory to Helicobacter pylori eradication therapy and steroid. Complete remission (CR) of both AITL and AIHA was achieved with THP-COP chemotherapy (pirarubicin, cyclophosphamide, vincristine, and prednisolone), but ATP was not improved promptly. AITL associated with ATP has been reported in only 14 cases. The present case was not related to the serum interleukin-6 levels, suggesting the possibility of an association with other factors. This case is the first report of Evans syndrome associated with AITL. The AITL relapsed 2 months after CR. The AITL tumor were CD56-positive at initial diagnosis and CD56-negative at relapse, and showed complex additional chromosomal abnormalities, and the morphological characteristics of blast cells. CD56(+) AITL are rare, although CD56 expression has not been investigated in many cases ; our observations suggest that CD56 expression and its significance in AITL should be investigated in the future. There has been only one other case of CD56(+) AITL, the patient died 4 months after the diagnosis. Our patient reported showed early relapse, central nervous system infiltration and was refractory to treatment, suggesting that CD56 positivity may be a poor prognostic marker in patients with AITL. [J Clin Exp Hematop 53(1): 37-47, 2013]. PMID- 23801133 TI - A case of conjunctival follicular lymphoma mimicking mucosa-associated lymphoid tissue lymphoma. AB - Ocular adnexal lymphoma may involve the eyelids, conjunctiva, orbital tissue, or lacrimal structures. The majority are non-Hodgkin's B-cell lymphomas of mucosa associated lymphoid tissue (MALT) lymphoma type. Follicular lymphomas represent a small percentage of ocular adnexa lymphomas, particularly in Japan. We report a 68-year-old female patient who presented with a salmon pink patch-like lesion of the left conjunctiva, suspected of being (MALT) lymphoma. However, histologic and immunohistologic examinations were consistent with follicular lymphoma. This case demonstrates the importance of considering such rare lymphomas when making a diagnosis of ocular adnexal lymphoid neoplasms. [J Clin Exp Hematop 53(1): 49-52, 2013]. PMID- 23801134 TI - A case of IgG4-related dacryoadenitis that regressed without systemic steroid administration. AB - There are no reports on the effect of anti-allergic agents against IgG4-related disease. We herein report a case of IgG4-related dacryoadenitis that is believed to have regressed due to the administration of anti-allergic agents. A 57-year old woman consulted us because of bilateral temporal upper eyelid swelling and induration. She had also been suffering from allergic rhinitis and allergic conjunctivitis for 20 years. We performed an incisional biopsy of the lesion. With respect to the pathology, extranodal marginal zone lymphoma of mucosa associated lymphoid tissue type was strongly suspected. On obtaining consent from the patient, follow-up alone was to be continued without radiation therapy. In addition to the observation of lacrimal gland lesions, the administration of epinastine hydrochloride at a dosage of 20 mg/day and 0.01% betamethasone eye drops twice a day to both eyes was commenced in order to treat both allergic rhinitis and allergic conjunctivitis. The lacrimal gland lesion decreased in size over time, becoming predominantly normal 7 years after the commencement of agent administration. We therefore re-examined the blood and pathology specimens. As a result, the serum IgG4 level was found to have increased to 540 mg/dl, while IgG4/IgG was 36.2%. The pathological diagnosis was revised to IgG4-related dacryoadenitis. The hypotheses of spontaneous remission and/or the effect of epinastine hydrochloride administration can be proposed regarding the mechanism by which the lacrimal gland lesion decreased in size. [J Clin Exp Hematop 53(1): 53-56, 2013]. PMID- 23801135 TI - Castleman-Kojima disease (TAFRO syndrome) : a novel systemic inflammatory disease characterized by a constellation of symptoms, namely, thrombocytopenia, ascites (anasarca), microcytic anemia, myelofibrosis, renal dysfunction, and organomegaly : a status report and summary of Fukushima (6 June, 2012) and Nagoya meetings (22 September, 2012). AB - Recently, a unique clinicopathologic variant of multicentric Castleman's disease (MCD) has been identified in Japan. This disease is characterized by a constellation of symptoms, as listed in the title, and multiple lymphadenopathy of mild degree with a pathologic diagnosis of atypical CD, often posing diagnostic and therapeutic problems for pathologists and hematologists, respectively. These findings suggest that this disease represents a novel clinical entity belonging to systemic inflammatory disorders with a background of immunological abnormality beyond the ordinal spectrum of MCD. To define this disorder more clearly, Japanese participants presented clinicopathologic data at the Fukushima and Nagoya meetings. Many of the patients presented by the participants were significantly accompanied by a combination of thrombocytopenia, ascites (anasarca), pleural effusions, microcytic anemia, fever, myelofibrosis, renal dysfunction, and organomegaly (TAFRO). Multiple lymphadenopathies were generally of mild degree, less than 1.5 cm in diameter, and consistently featured the histopathology of mixed- or less hyaline vascular-type CD. Autoantibodies were often detected. However, this disease did not fulfill the diagnostic criteria for well-known autoimmune diseases including systemic lupus erythematosus. Castleman-Kojima disease and TAFRO syndrome (the favored clinical term) were proposed for this disease. The patients were sensitive to steroid and anti-interleukin-6 receptor antibody (tocilizumab), but some exhibited a deteriorated clinical course despite the treatment. The participants proposed a future nationwide survey and a Japanese consortium to facilitate further clinical and therapeutic studies of this novel disease. [J Clin Exp Hematop 53(1): 57-61, 2013]. PMID- 23801136 TI - Thrombocytopenia with reticulin fibrosis accompanied by fever, anasarca and hepatosplenomegaly : a clinical report of five cases. AB - We report five cases that presented with high fever, anasarca, hepatosplenomegaly and severe thrombocytopenia with reticulin fibrosis of the bone marrow. The constellation of symptoms is not compatible with any known disease, and we had difficulty in diagnosis and treatment. The age distribution was from 47 to 56 years, and two men and three women were affected. Two patients needed hemodialysis because of renal dysfunction and oliguria with massive pleural effusion. Laboratory examinations showed normal immunoglobulin levels and no monoclonal protein. None of them showed diagnostic autoantibodies for any autoimmune diseases. Histological examination of the liver in three patients and spleen in two showed non-specific findings. Lymphadenopathy was tiny and lymph node biopsy was carried out in only one case. Histologically, paracortical hyperplasia with vascular proliferation and atrophic germinal centers resembling hyaline-vascular-type Castleman's disease or POEMS syndrome were detected. Without a definitive diagnosis, treatment was started with cyclophosphamide, hydroxydaunorubicin, vincristine and prednisolone (CHOP) regimen in one patient, semi-pulse therapy with methyl-predonisolone in three and cyclosporin A in three. Two patients achieved complete remission, two were steroid-dependent and the remaining one died of multiple organ failure. These findings suggest that this disease may be a novel clinical entity belonging to systemic inflammatory disorder with a background of immunological abnormality or a unique variant of multicentric Castleman's disease. [J Clin Exp Hematop 53(1): 63-68, 2013]. PMID- 23801137 TI - Clinical features and treatment of multicentric castleman's disease : a retrospective study of 21 Japanese patients at a single institute. AB - Multicentric Castleman's disease (MCD) is a rare polyclonal lymphoproliferative disorder that manifests with lymphadenopathy and inflammatory symptoms. In order to clarify the clinical features and actual management of MCD in Japan, we analyzed 21 patients diagnosed with MCD and treated in Kyoto University Hospital between 2005 and 2012. There were 12 men and 9 women. The median age at disease onset was 46 years, and the median follow-up period was 98 months. Common symptoms included splenomegaly (13/20), renal dysfunction (11/21), interstitial pneumonia (7/21), pleural effusion and/or ascites (7/21), and thrombocytopenia (6/21). The results of the anti-human immunodeficiency virus antibody and human herpes virus-8 DNA tests in the blood were available in 13 and 5 cases, respectively, and no patient was positive for either. Among 12 patients treated with tocilizumab, an anti-interleukin-6 receptor antibody, 11 exhibited an improvement in MCD-related symptoms and 3 achieved complete resolution of all these symptoms. In 8 patients treated with tocilizumab for over 1 year, the mean Hb level increased from 7.4 to 12.2 g/dL while the mean serum C-reactive protein level decreased from 13.2 to 0.4 mg/dL. Three patients died during the observation period due to sepsis, secondary leukemia, or pancreatic cancer. The clinical courses of most cases were indolent; however, in some cases with pleural effusion, ascites, renal dysfunction, and/or thrombocytopenia, the disease manifestation was serious. A nationwide survey is required to further clarify the epidemiology, clinical features, and optimal treatment strategies of MCD in Japan. PMID- 23801138 TI - Japanese variant of multicentric castleman's disease associated with serositis and thrombocytopenia--a report of two cases: is TAFRO syndrome (Castleman- Kojima disease) a distinct clinicopathological entity? AB - Multicentric Castleman's disease (MCD) is a polyclonal lymphoproliferative disorder that manifests as marked hyper-gamma-globulinemia, severe inflammation, anemia, and thrombocytosis. Recently, Takai et al. reported a new disease concept, TAFRO syndrome, named from thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly. Furthermore, Kojima et al. reported Japanese MCD cases with effusion and thrombocytopenia (Castleman-Kojima disease). Here, we report two cases of MCD associated with marked pleural effusion, ascites, and thrombocytopenia, and discuss the independence of the TAFRO syndrome (Castleman Kojima disease). Case 1: A 57-year-old woman had fever, anemia, anasarca, and some small cervical lymphadenopathy. Although she had been administered steroid therapy, and full-coverage antibiotics, her general condition, including fever, systemic inflammation, and anasarca, deteriorated steadily. We administered chemotherapy [CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisolone) regimen], but despite a transient improvement, she died due to septic shock. Case 2: A 73-year-old man with a history of aplastic anemia and remission presented with fever, severe inflammation, and anasarca. Prednisolone was administered (15 mg daily), and his hyperinflammation once improved. Nevertheless, his general condition, including pleural effusion and ascites, worsened, and C-reactive protein and interleukin-6 levels showed marked increases. The patient died due to multiorgan failure. Cases of TAFRO syndrome (Castleman-Kojima disease) are still rare. Therefore, it is necessary to conduct multicenter clinical surveys including similar cases, such as ours, to reach a consensus regarding diagnostic criteria, therapeutic strategy, and pathophysiological etiology for this syndrome. PMID- 23801139 TI - Atypical hyaline vascular-type castleman's disease with thrombocytopenia, anasarca, fever, and systemic lymphadenopathy. AB - Recently, atypical Castleman's disease (CD) was reported in Japan. This disease is considered as TAFRO syndrome or non-idiopathic plasmacytic lymphadenopathy (IPL), a constellation of clinical symptoms, namely, thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly without hyper-gamma-globulinemia. Histopathologically, this disease is similar to hyaline vascular (HV)-type CD. Here, we present a 43-year-old Japanese woman meeting the clinical criteria of TAFRO syndrome who was successfully treated with combined corticosteroid therapy. She showed a rapidly progressive course of thrombocytopenia, systemic lymphadenopathy, fever, anasarca, and increase in acute inflammatory proteins without hyper-gamma-globulinemia. Lymph node biopsy was performed and revealed HV type CD without human herpes virus 8 infection, which was clinicopathologically compatible with non-IPL. The association of these atypical features with well known multicentric Castleman's disease (MCD), namely, HV-type histology with systemic lymphadenopathy, marked thrombocytopenia even with a high level of interleukin-6, and increased acute inflammatory proteins without hyper-gamma globulinemia, suggests that TAFRO syndrome as presented in our case is a novel entity, which may have been diagnosed as MCD in the past. To define this novel entity more clearly and to demonstrate its etiology, further nationwide surveys of this syndrome and MCD are needed. PMID- 23801140 TI - Complete resolution of TAFRO syndrome (thrombocytopenia, anasarca, fever, reticulin fibrosis and organomegaly) after immunosuppressive therapies using corticosteroids and cyclosporin A : a case report. AB - A 49-year-old woman with severe thrombocytopenia was admitted after an episode of syncope. She also had anemia, fever, pleural effusion and ascites, and multiple lymphadenopathies subsequently appeared. Her bone marrow showed increased megakaryocytes with mild fibrosis, whereas her lymph nodes lacked histologically specific findings. Her presentation was not consistent with multicentric Castleman's disease, angioimmunoblastic T-cell lymphoma, systemic lupus erhythematosus or any other well-recognized entities. Her clinical features were, however, thought to be compatible with TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly) syndrome. Corticosteroid therapy induced a partial remission of fever and systemic fluid retention, but thrombocytopenia persisted. After additional immunosuppressive therapy with cyclosporin A, her symptoms showed full resolution. [J Clin Exp Hematop 53(1) : 95-99, 2013]. PMID- 23801141 TI - A case of multicentric castleman's disease of mixed-type, which showed constellation of symptoms, i.e., thrombocytopenia, anasarca, anemia, fever, myelofibrosis, and lymphadenopathy. PMID- 23801143 TI - Shape-changing polymer assemblies. AB - A panoply of stimuli-sensitive polymorphic polymer assemblies has been constructed through the intentional synthesis of amphiphilic block copolymers comprising hydrophilic, stimulus-responsive, and hydrophobic blocks. Transformations among canonical micellar forms of polymer assemblies-spherical micelles, wormlike micelles, and vesicles (polymersomes)-have been demonstrated with a number of synthetic systems. This review discusses recent progress in the development and understanding of these systems with a focus on open questions about kinetics of shape change, effects of block copolymer architecture on the rate and nature of the transformation, and potential applications. PMID- 23801144 TI - The hindlimb myology of Milvago chimango (Polyborinae, Falconidae). AB - We describe the hindlimb myology of Milvago chimango. This member of the Falconidae: Polyborinae is a generalist and opportunist that can jump and run down prey on the ground, unlike Falconinae that hunt birds in flight and kill them by striking with its talons. Due to differences in the locomotion habits between the subfamilies, we hypothesized differences in their hindlimb myology. Gross dissections showed that the myology of M. chimango is concordant with that described of other falconids, except for the following differences: the m. flexor cruris medialis has one belly with a longitudinal division; the m. iliotibialis lateralis does not have a connection with the m. iliofibularis; the m. fibularis longus is strongly aponeurotic; the m. tibialis cranialis lacks an accessory tendons and the m. flexor hallucis longus has one place of origin, instead of two. The presence of the m. flexor cruris lateralis can be distinguished as it has been described absent for the Falconidae. We associated its presence with the predominant terrestrial habit of the M. chimango. Each muscle dissected was weighed and the relationship between flexors and extensors at each joint was assessed. The extensor muscles predominated in all joints in M. chimango. Among the flexors, the m. flexor hallucis longus was the heaviest, which could be related to the importance of the use of its talons to obtain food. PMID- 23801145 TI - Changes of body balance before and after total knee arthroplasty in patients who suffered from bilateral knee osteoarthritis. AB - PURPOSE: It is still controversial whether simultaneous or staged total knee arthroplasty (TKA) is most desirable for patients with bilateral knee osteoarthritis. We retrospectively evaluated changes in balance among patients with bilateral osteoarthritis who underwent staged TKA using a gravicorder. METHODS: Patients were stratified into two groups: the unilateral group (UG) (22 patients) consisted of patients who did not undergo a second TKA within 24 months of the first TKA, and the bilateral group (BG) (20 patients) were those who had a second TKA within 12 months after initial TKA. RESULTS: The mean gravity center position (GCP), which indicates the translation of GCP in the mediolateral direction between pre- and post-TKA shifted to the operative side in both groups after initial surgery. While the GCP was maintained on the same side in UG over 2 years follow-up, in BG it moved to the opposite side and approached a central position after the second TKA. Locus length of GCP (LG), which indicates postural control function by proprioceptive reflex showed significant improvement after initial TKA in UG, while BG showed significant improvement after the second TKA. CONCLUSIONS: The degree of LG improvement after initial TKA may indicate the necessity of a second TKA for patients with bilateral osteoarthritis. The current study suggests that simultaneous bilateral TKA is not always necessary for patients with bilateral knee arthritis, and that properly performed rehabilitation such as improving postural sway after initial TKA might attenuate the timing for the second TKA. PMID- 23801146 TI - Tibial plateau fracture after single bundle anterior cruciate ligament reconstruction using post-tie washer-screw fixation. PMID- 23801147 TI - Adaptations of leptin, ghrelin or insulin during weight loss as predictors of weight regain: a review of current literature. AB - Numerous laboratory studies involving both animal and human models indicate that weight loss induces changes in leptin, ghrelin and insulin sensitivity, which work to promote weight regain. It is unclear, however, whether these biological changes serve as a biomarker for predicting weight regain in free-living humans in which biological, behavioral and environmental factors are likely at play. We identified 12 studies published between January 1995 and December 2011 that reported changes in leptin, ghrelin or insulin during intentional weight loss with a follow-up period to assess regain. Two of the nine studies examining leptin suggested that larger decreases were associated with greater regain, three studies found the opposite (smaller decreases were associated with greater regain), whereas four studies found no significant relationship; none of the studies supported the hypothesis that increases in ghrelin during weight loss were associated with regain. One study suggested that improvements in insulin resistance were associated with weight gain, but five subsequent studies reported no association. Changes in leptin, ghrelin or insulin sensitivity, taken alone, are not sufficient to predict weight regain following weight loss in free-living humans. In future studies, it is important to include a combination of physiological, behavioral and environmental variables in order to identify subgroups at greatest risk of weight regain. PMID- 23801148 TI - Depression in peri- and postmenopausal women: prevalence, pathophysiology and pharmacological management. AB - Epidemiologic and clinic data have unequivocally supported the notion that women experience more psychiatric problems at some point in their lives compared with men, particularly mood and anxiety symptoms and sleep problems. It is also known that, for some women, such increased risk might be associated with reproductive cycle events such as the postpartum period or the menopausal transition. These periods are not only marked by substantial hormone variations but also quite often accompanied by stressful events and changes in personal, family and professional responsibilities. The complexity of these reproductive-related 'windows of vulnerability' poses a challenge to physicians and other professionals dedicated to women's health across the lifespan. The menopausal transition and early postmenopausal years constitute a characteristic example; during this period in life, dynamic changes in sex hormones and reproductive function co-occur with modifications in metabolism, sexuality, lifestyle behaviours and overall health, sometimes affecting a woman's quality of life and overall functioning. For most women, however, this transition has little or no significant impact on their mental wellness. A prior depressive episode- particularly if related to reproductive events--is the strongest predictor of mood symptoms or depression during menopausal years. Also, the presence and severity of vasomotor symptoms and other health-related issues appear to modulate the risk for depression in midlife women. Mechanistically, estrogen plays an important modulatory role in mood and cognitive regulation, hence the effects noted when midlife women are exposed to significant estrogen fluctuations or to estrogen-based therapies (use or withdrawal). Transdermal estradiol, as well as serotonergic and noradrenergic antidepressants, have shown efficacy in the management of depression in this population. Other evidence-based treatment options (hormonal, pharmacological, behavioural) are available to clinicians and health professionals who care for this population. PMID- 23801149 TI - Occurrence and molecular detection of toxigenic Aspergillus species in food grain samples from India. AB - BACKGROUND: The aim of this study was to detect the presence of different mycotoxigenic Aspergillus species in major food grains from southern states of India, namely maize, paddy, groundnut and sorghum. A total of 200 isolates recovered from 320 grain samples from four southern states were tested for their toxin chemotypes using high-performance liquid chromatography (HPLC), high performance thin layer chromatography (HPTLC) and polymerase chain reaction (PCR) methods. The diversity and distribution of the isolates were recorded in terms of their frequency, density, importance value index and diversity indices. RESULTS: Among the different grain samples tested, 83% of groundnut, 69% of maize, 57% of sorghum and 29% of paddy samples had aflatoxin B1 (AFB1) levels above the allowed limit, while 82% of maize, 70% of sorghum, 42% of paddy and 17% of groundnut samples had ochratoxin A (OTA) concentrations higher than the permitted threshold (5 ug kg-1). CONCLUSION: Since the southern states of India are temperate regions, environmental factors, especially temperature and relative humidity, may be responsible for the high levels of mycotoxins present in the grains studied. Therefore there is a need to generate awareness among farmers and consumers about the possible adverse health effects of high levels of mycotoxins present in different food grains. PMID- 23801150 TI - Uric acid is associated with the prevalence but not disease progression of multiple system atrophy in Chinese population. AB - Oxidative stress is involved in the pathogenesis of multiple system atrophy (MSA). Uric acid has an antioxidative effect. Our aim is to clarify the correlations between serum uric acid and MSA in Chinese population. A total of 234 patients with probable MSA and 240 age- and gender- matched healthy controls were included in the study. The serum uric acid levels of all the patients and controls were evaluated. The Unified MSA Rating Scale (UMSARS) was used to assess the severity and the mean rate of annualized changes of UMSARS to assess the progression of MSA. The mean age of MSA patients was 58.90 +/- 9.00 years and the mean disease duration was 2.60 +/- 1.75 years. The serum uric acid levels of MSA patients were significantly lower than that of controls in males (p = 0.0001). The occurrence of MSA was increased in the lowest uric acid quartiles compared with the highest uric acid quartiles (p = 0.005). In a gender-specific analysis, increased occurrence was found in the lowest quartiles and second quartiles compared with the highest quartiles in males (p = 0.001 and p = 0.0001 respectively), but not in females. No correlation was found between the mean rate of annualized changes and serum levels of uric acid, as well as other independent factors, such as age, BMI, gender, subtype (C-type or P-type) and disease duration at the initial visit in 107 followed-up patients. MSA patients have lower levels of serum uric acid than controls. High levels of serum uric acid may be associated with a lower prevalence of MSA in the Chinese population, especially in males. However, serum uric acid does not deteriorate or ameliorate the progression of MSA. PMID- 23801151 TI - Glutathione S-transferase M1 null genotype is associated with increased risk of oral cancer in East Asians: a meta-analysis. AB - The association between glutathione S-transferase M1 (GSTM1) null genotype and risk of oral cancer in East Asians is uncertain owing to the inconclusive results from published studies. In the present study, we performed a meta-analysis of 12 studies from three East Asian countries (China, Japan, and Korea). Those 12 studies consisted of 1,718 cases and 2,236 controls. The pooled odds ratio (OR) and corresponding 95 % confidence interval (95 %CI) were calculated to assess the relationship. Overall, the meta-analysis showed that GSTM1 null genotype was associated with increased risk of oral cancer in East Asians (OR = 1.48, 95 %CI = 1.09-2.00, P = 0.011). The results of the cumulative meta-analysis further identified the significant association above. Subgroup analysis by countries showed that the association was still significant in Japan (OR = 1.56, 95 %CI = 1.10-2.22, P = 0.012), but not in China (OR = 1.35, 95 %CI = 0.68-2.68, P = 0.393) and Korea (OR = 1.35, 95 %CI = 0.79-2.32, P = 0.271). In conclusion, the meta-analysis suggests that GSTM1 null genotype is associated with increased risk of oral cancer in East Asians. Further studies are needed to provide new and comprehensive assessments on the association in China and Korea. PMID- 23801152 TI - Effects of ARHI on breast cancer cell biological behavior regulated by microRNA 221. AB - The aplysia ras homolog member I (ARHI) is a tumor suppressor gene and is downregulated in various cancers. The downregulation of ARHI was regulated by miR 221 in prostate cancer cell lines. However, it has not been reported whether ARHI is regulated by miR-221 in breast cancer. Here, we reported that the ARHI protein level was downregulated in breast cancer tissues and breast cancer cell lines. The overexpression of ARHI could inhibit cell proliferation and invasion and induce cell apoptosis. To address whether ARHI is regulated by miR-221 in breast cancer cell lines, the results in this study showed that a significant inverse correlation existed between ARHI and miR-221. MiR-221 displayed an upregulation in breast cancer tissues and breast cancer cell lines. The inhibition of miR-221 induced a significant upregulation of ARHI in MCF-7 cells. To prove a direct interaction between miR-221 and ARHI mRNA, ARHI 3'UTR, which includes the potential target site for miR-221, was cloned downstream of the luciferase reporter gene of the pMIR-REPORT vector to generate the pMIR-ARHI-3'UTR vector. The results confirmed a direct interaction of miR-221 with a target site on the 3'UTR of ARHI. In conclusion, ARHI is a tumor suppressor gene that is downregulated in breast cancer. The overexpression of ARHI could inhibit breast cancer cell proliferation and invasion and induce cell apoptosis. This study demonstrated for the first time that the downregulation of ARHI in breast cancer cells could be regulated by miR-221. PMID- 23801153 TI - Determination of the stress biomarker corticosterone in serum of tumor-bearing mice by surrogate-based liquid chromatography-tandem mass spectrometry. AB - A simple, robust and specific liquid chromatography tandem mass spectrometry (LC MS/MS) method was developed and validated to determine the concentration of corticosterone (Cort) which is usually regarded as a stress biomarker in mouse serum. Since Cort is an endogenous hormone, a 'surrogate analyte' strategy was adopted using the stable isotope-deuterated corticosterone as a surrogate of the authentic analyte to generate the calibration curve. With telmisartan as the internal standard, the analytes were extracted with methanol, ethanol and acetone (1:1:1, v/v/v) and separated on a XTerra C18 (2.1 * 50 mm, 3.5 um) column using a mobile phase consisting of 0.2% formic acid in water-methanol (30:70, v/v). Detection was performed in multiple reaction monitoring mode with an electrospray ionization source operated in positive ion mode. The standard curves were linear (r(2) > 0.999) over the dynamic range of 8.60-430 ng/mL, with a lower limit of quantification of 8.60 ng/mL. The intra- and inter-assay precisions were less than 15.0% of the relative standard deviation. This method was further used for analysis of serum samples from C57B/L tumor-bearing mice before and after the treatment of fluoxetine. Validation of the assay and its application to the analysis demonstrated that the method was applicable to determine meaningful changes in Cort concentrations in serum samples of the tumor-bearing mice for the stress status evaluation. PMID- 23801154 TI - Frailty and health-related quality of life among residents of long-term care facilities. AB - OBJECTIVE: To determine the prevalence and relationship of frailty and health related quality of life (HRQOL) among residents of long-term care [nursing homes (NH) and assisted living (AL)] facilities. METHODS: Residents of NH and AL facilities in La Crosse County, Wisconsin, were recruited 1/2009-6/2010 and assessed for frailty (gait speed, unintended weight loss, grip strength), comorbidity (Charlson index), and HRQOL [Short Form (SF)-36]. RESULTS: Among 137 participants, 85% were frail. Frail residents were older, had more comorbidities (2.0 vs. 0, p < .001) and lower mean SF-36 Physical Component Score (PCS, 32 vs. 48, p < .001). Following adjustments for age, sex, and comorbidities, compared to nonfrail residents, frail residents had lower SF-36 PCS (mean difference -14.7, 95% CI. -19.3,-10.1, p < .001). Frailty, comorbidity, and HRQOL did not differ between NH and AL facilities. DISCUSSION: Frail residents had lower HRQOL, suggesting that preventing frailty may lead to better HRQOL among residents of long-term care facilities. PMID- 23801155 TI - Clinical investigation of fasudil for the prevention of cerebral vasospasm in extracranial carotid artery stenting. AB - To evaluate fasudil hydrochloride for the prevention of cerebral vasospasm (CVS) in extra-cranial carotid angioplasty and stenting (CAS). We retrospectively analyzed 178 patients with unilateral CAS who were given intravenous fasudil hydrochloride during the perioperative period. CVS, hypotension, stroke, and mortality incidence rates were recorded. Of the cohort studied, 80.9 % patients exhibited no local CVS, asymptomatic vasospasm was observed in 17.4 % patients and symptomatic vasospasm in 1.7 % patients via DSA imaging. All CVS was relieved and symptoms disappeared after intra-arterial infusion of papaverine hydrochloride. Intracerebral hemorrhage occurred in two cases during the perioperative period, one of which resulted in death. CVS is a severe complication of CAS. Fasudil hydrochloride can rapidly relieve cerebral vasospasm, has no selective effect on cerebral vasculature, and little influence on blood pressure. It is suitable for the prevention of CVS during interventional treatment of ischemic cerebrovascular disease. PMID- 23801156 TI - Mechanistic insights into interaction of humic acid with silver nanoparticles. AB - Humic acid (HA) is one of the major components of the natural organic matter present in the environment that alters the fate and behavior of silver nanoparticles (Ag NPs). Transformation of Ag NPs happens upon interaction with HA, thereby, changing both physical and chemical properties. Fluorescence spectroscopy and scanning electron microscopy (SEM) were used to analyze the interaction of Ag NPs with HA. In pH and time-dependent studies, the near field electro dynamical environment of Ag NPs influenced the fluorescence of HA, indicated by fluorescence enhancement. SEM revealed not only morphological changes, but also significant reduction in size of Ag NPs after interaction with HA. Based on these studies, a probable mechanism was proposed for the interaction of HA with Ag NPs, suggesting the possible transformation that these nanoparticles can undergo in the environment. PMID- 23801157 TI - MiR-335, an adipogenesis-related microRNA, is involved in adipose tissue inflammation. AB - During the development of obesity, adipose tissue releases a host of different adipokines and inflammatory cytokines, such as leptin, resistin, tumor necrosis factor alpha (TNF-alpha), Interleukin-6 (IL-6), and adiponectin, which mediate insulin resistance. Recently, some microRNAs (miRNAs) regulated by adiponectin were identified as novel targets for controlling adipose tissue inflammation. Therefore, the relationship between adipokines and miRNA is worth studying. MiR 335 is an adipogenesis-related miRNA and implicated in both fatty acid metabolism and lipogenesis. In this study, we focused on the association of miR-335 and adipokines, and examined the expression trend of miR-335 during human adipocyte differentiation. Our results showed that miR-335 is significantly upregulated with treatment of leptin, resistin, TNF-alpha, and IL-6 in human mature adipocytes, and its expression elevated in the process of adipocyte differentiation. Interestingly, the transcriptional regulation of miR-335 by these adipokines seems independent of its host gene (mesoderm-specific transcript homolog, MEST). Thus, we cloned and identified potential promoter of miR-335 within the intron of MEST. As a result, a fragment about 600-bp length upstream sequences of miR-335 had apparent transcription activity. These findings indicated a novel role for miR-335 in adipose tissue inflammation, and miR-335 might play an important role in the process of obesity complications via its own transcription mechanism. PMID- 23801158 TI - The impact of the 21-gene Recurrence Score assay on clinical decision-making in node-positive (up to 3 positive nodes) estrogen receptor-positive breast cancer patients. AB - Oncotype DX testing is reimbursed in Israel for node-negative and node-positive (N1+; up to 3 positive nodes including micrometastases), estrogen receptor positive (ER+), breast cancer patients. This retrospective study evaluated the impact of Oncotype DX testing on treatment decisions in N1+/ER+ breast cancer patients. To this end, we compared treatments for all N+ patients for whom testing had been ordered with treatments for patients with similar characteristics where the test had not been available. The retrospective analysis included 951 patients (282 Oncotype DX, 669 controls), all of whom received endocrine therapy with or without chemotherapy. In Oncotype DX patients, 7.1, 37.0, and 100 % of those with low, intermediate, and high Recurrence Score results (Oncotype DX summary score) received chemotherapy, respectively (P < 0.0001, all comparisons). Chemotherapy use was lower in Oncotype DX patients versus controls (24.5 vs. 70.1 %). In a multivariate logistic regression analysis in which the probability of receiving chemotherapy was modeled as a function of Oncotype DX testing, age, tumor size, tumor grade, nodal status, and the interactions between Oncotype DX testing and the other covariates, Oncotype DX testing was associated with significantly lower odds of receiving chemotherapy (odds ratio 0.16; 95 % CI 0.11-0.24; P < 0.0001). In summary, our findings suggest that Oncotype DX testing has a significant impact on reducing chemotherapy use in N1+/ER+ breast cancer patients in Israel. PMID- 23801159 TI - Breast cancer characteristics and HIV among 1,092 women in Soweto, South Africa. AB - In the low-income HIV-endemic regions of sub-Saharan Africa, malignancies related to HIV have long been recognized as a major public health problem. However, epithelial malignancies associated with older age, such as breast cancer, are also rising dramatically in those regions. We compared consecutive HIV-positive and -negative black women diagnosed with breast cancer at a large public hospital in Soweto, South Africa, on age, year of diagnosis, stage, grade, and receptor status, and grouped HIV-positive patients by CD4 cell counts. We computed prevalence ratios of the associations of HIV status and CD4 category with stage, grade, receptor status, and among the HIV-positive patients, receipt of ART, controlling for age and year of diagnosis. Of 1,092 patients, 765 were tested for HIV; 151 (19.7 %) tested positive, a prevalence similar to that in the source population. Although, HIV-positive patients were younger than HIV-negative patients (p < 0.001), HIV status was not associated with the tumor characteristics. Thirty-seven women (25.9 %) had CD4 cell counts <200 cells/MUl. Patients in that severely immunocompromised group were older than those in the other groups (p = 0.01). This study is the first to analyze the association of HIV with breast cancer in a large sample. Based on similar HIV prevalence in our sample and the population of the hospital's catchment area, clinicians serving HIV-endemic communities should promote routine HIV testing of younger breast cancer patients and immediate treatment of those who test positive, prior to the initiation of chemotherapy. Research is needed on treatment and outcomes given HIV and low CD4 cell count. PMID- 23801160 TI - [Histopathology of renal cell carcinoma]. AB - By integrating genetic data into the traditional histology and immunohistochemistry-based classification system, the revised WHO classification of malignant tumors (2004) defined additional renal cell carcinoma subtypes, thereby enabling the application of additional diagnostic procedures. PMID- 23801161 TI - [Non-invasive and invasive urothelial tumours: special challenges in uropathological diagnostics]. AB - The current 2004 WHO classification of bladder tumors categorizes non-invasive and invasive urothelial neoplasms into prognostically relevant groups according to the histopathological cell morphology and underlying genetic changes. Although many parts of the classification have not been changed dramatically, even small changes have caused uncertainty and scepticism among urologists and pathologists in recent years. The following review article is structured into various challenges for urologists and pathologists and provides an overview of rare but clinically relevant subgroups and diagnostics, interpretation of diagnoses and pathological findings with respect to consequences for the daily clinical routine (extended diagnosis, therapy and prognosis). PMID- 23801162 TI - [Uropathology - requirements for standards and quality]. AB - The variety of therapeutic approaches to urological diseases, particularly in urological oncology increases the need for detailed and standardized uropathological diagnostic procedures. A standardized diagnostic approach helps to achieve a high quality of diagnoses in uropathology. It is now expected that certain features in biopsies and resected tumors will be evaluated and described in pathology reports. German pathology offers guidelines for handling specimens and in addition there are some sophisticated clinical/pathological guidelines (e.g. European guidelines) with specific standards relating to diagnostic requirements which will be discussed in this article. There are German pathology guidelines for tumors of the prostate, testis, kidneys, renal pelvis, urethra and urinary bladder. PMID- 23801163 TI - [Personalized urooncology based on molecular uropathology: part 1: what is diagnostic routine?]. AB - The approval of new therapeutic procedures for the three main malignancies of the urogenital tract in recent years has generated a need for personalization of urooncology. As a consequence the diagnostic procedures are no longer limited to histology and immunohistochemistry but also include the analysis of genetic alterations (mutations and chromosomal aberrations). PMID- 23801164 TI - [Uropathology for urologist]. PMID- 23801165 TI - Career after successful medical board examination in general practice--a cross sectional survey. AB - QUESTION UNDER STUDY: Switzerland is facing a shortage of general practitioners (GPs). Knowledge of the factors influencing career choice is crucial for increasing the attractiveness of general practice. The aim of our study was to report the working conditions of recently certified GPs and the effect of vocational training in general practice on GP skills and knowledge, and economic skills. Furthermore, we recorded when GPs chose general practice as a career, as well as potential barriers to and facilitators of their decision. METHODS: STUDY DESIGN: Cross-sectional survey with an online-based questionnaire. STUDY GROUP: 1,133 physicians certified in general practice between the years 2000 and 2010. RESULTS: The response rate was 40.6% (456); 426 (44.1% females) were included in further analysis. A total of 341 (80.0%) were currently working in general practice. Female GPs were significantly more often employed (rather than working independently), working part-time and in group practices. Fifty-two (12.2%) of the participants did not work in general practice although they had intended to earlier. The majority (54.3%) of the participants working as GPs decided to become a GP during their residency. Overall, 60.6% of all participants completed vocational training in a general practice, which significantly improved self perceived general practice skills compared with their colleagues without such training. CONCLUSIONS: Residency is a more important time-period than medical school for career decisions to become a GP. Attractive residency programmes must be developed to engage physicians in this vulnerable phase. The workplace settings of female GPs were significantly different from those of male GPs. Vocational training in general practice had a positive effect on self-perceived GP skills. PMID- 23801166 TI - First FDA approval of dual anti-HER2 regimen: pertuzumab in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer. AB - On June 8, 2012, the U.S. Food and Drug Administration (FDA) approved pertuzumab (Perjeta, Genentech) for use in combination with trastuzumab (Herceptin, Genentech) and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. Approval was based on the results of a randomized, double-blind, placebo-controlled trial conducted in 808 patients with HER2-positive MBC. Patients were randomized (1:1) to receive pertuzumab (n = 402) or placebo (n = 406) in combination with trastuzumab and docetaxel. The primary endpoint was progression-free survival (PFS) and a key secondary endpoint was overall survival (OS). A statistically significant improvement in PFS (difference in medians of 6.1 months) was observed in patients receiving pertuzumab [HR, 0.62; 95% confidence interval (CI), 0.51-0.75; P < 0.0001]. A planned interim analysis suggested an improvement in OS (HR, 0.64; 95% CI, 0.47-0.88; P = 0.0053) but the HR and P value did not cross the stopping boundary. Common adverse reactions (>30%) observed in patients on the pertuzumab arm included diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. No additive cardiac toxicity was observed. Significant manufacturing issues were identified during the review. On the basis of substantial evidence of efficacy for pertuzumab in MBC and the compelling public health need, FDA did not delay availability to patients pending final resolution of all manufacturing concerns. Therefore, FDA approved pertuzumab but limited its approval to lots not affected by manufacturing problems. The applicant agreed to multiple manufacturing and testing postmarketing commitments under third-party oversight to resolve manufacturing issues. PMID- 23801167 TI - Diagnostic usefulness of 18F-FAMT PET and L-type amino acid transporter 1 (LAT1) expression in oral squamous cell carcinoma. AB - PURPOSE: L-[3-(18)F]-alpha-Methyltyrosine ((18)F-FAMT) was developed as an amino acid tracer for PET imaging to provide better specificity than 2-[(18)F]fluoro-2 deoxy-D-glucose ((18)F-FDG) PET for cancer diagnosis. We investigated the diagnostic usefulness of (18)F-FAMT in oral squamous cell carcinoma (OSCC). The correlation between tumour uptake of (18)F-FAMT and L-type amino acid transporter 1 (LAT1) expression was determined. METHODS: The study group comprised 68 OSCC patients who underwent both (18)F-FAMT and (18)F-FDG PET. Resected tumour sections were stained by immunohistochemistry for LAT1, CD98 and Ki-67, and microvessel density was determined in terms of CD34 and p53 expression. RESULTS: The sensitivity of primary tumour detection by (18)F-FAMT and (18)F-FDG PET was 98 % and 100 %, respectively. The sensitivity, specificity and accuracy of (18)F FAMT PET for detecting malignant lymph nodes were 68 %, 99 % and 97 %, respectively, and equivalent values for (18)F-FDG PET were 84 %, 94 % and 94 %, respectively. The specificity and accuracy of (18)F-FAMT were significantly higher than those of (18)F-FDG. The uptake of (18)F-FAMT was significantly correlated with LAT1 expression, cell proliferation and advanced stage. The expression of LAT1 in OSCC cells was closely correlated with CD98 levels, cell proliferation and angiogenesis. CONCLUSION: (18)F-FAMT PET showed higher specificity for detecting malignant lesions than (18)F-FDG PET. The uptake of (18)F-FAMT by OSCC cells can be determined by the presence of LAT1 expression and tumour cell proliferation. PMID- 23801168 TI - [11C]PIB, [18F]FDG and MR imaging in patients with mild cognitive impairment. AB - PURPOSE: Cortical glucose metabolism, brain amyloid beta accumulation and hippocampal atrophy imaging have all been suggested as potential biomarkers in predicting which patients with mild cognitive impairment (MCI) will convert to Alzheimer's disease (AD). The aim of this study was to compare the prognostic ability of [(11)C]PIB PET, [(18)F]FDG PET and quantitative hippocampal volumes measured with MR imaging in predicting conversion to AD in patients with MCI. METHODS: The study group comprised 29 patients with MCI who underwent [(11)C]PIB PET and MR imaging. Of these, 22 also underwent [(18)F]FDG PET. All subjects were invited back for clinical evaluation after 2 years. RESULTS: During the follow-up time 17 patients had converted to AD while 12 continued to meet the criteria for MCI. The two groups did not differ in age, gender or education level, but the converter group tended to have lower MMSE and Word List learning than the nonconverter group. High [(11)C]PIB retention in the frontotemporal regions and anterior and posterior cingulate (p < 0.05) predicted conversion to AD. Also reduced [(18)F]FDG uptake in the left lateral temporal cortex (LTC) predicted conversion (p < 0.05), but quantitative hippocampal volumes did not (p > 0.1). In receiver operating characteristic (ROC) analysis the measurements that best predicted the conversion were [(11)C]PIB retention in the lateral frontal cortex and [(18)F]FDG uptake in the left LTC. Both PET methods resulted in good sensitivity and specificity and neither was significantly superior to the other. CONCLUSION: The findings indicate that [(11)C]PIB and [(18)F]FDG are superior to hippocampal volumes in predicting conversion to AD in patients with MCI. PMID- 23801169 TI - Clinical significance of VEGFR-2 and 18F-FDG PET/CT SUVmax pretreatment score in predicting the long-term outcome of patients with locally advanced rectal cancer treated with neoadjuvant therapy. AB - PURPOSE: Vascular endothelial growth factor receptor-2 (VEGFR-2), epidermal growth factor receptor-1 (EGFR), and cyclooxygenase-2 (COX-2) stimulate key processes involved in tumor progression and are important targets for cancer drugs. (18)F-FDG maximum standardized uptake value (SUVmax) is a marker of tumor metabolic activity. The purpose of this study was to measure SUVmax combined with VEGFR-2, EGFR and COX-2 proteins in pretreatment tumor biopsies from patients with locally advanced rectal cancer receiving intensive neoadjuvant treatment and to correlate the findings with clinical outcome. METHODS: VEGFR-2, EGFR and COX-2 were measured using the immunoreactive score (IRS). SUVmax (median 8.4) was quantified in tumors with molecular overexpression (IRS >=3 + SUVmax >= 8.4 indicating active tumors; SUVmax <8.4 indicating inactive tumors). The Cox proportional hazards model was used to explore associations between tumor markers, disease-free survival (DFS) and overall survival (OS). RESULTS: The study group comprised 38 patients with a median follow-up of 69.3 months (range 4.5 - 92 months). Multivariate analysis showed that active tumors (overexpressing VEGFR-2, high SUVmax) were associated with worse DFS (HR 4.73, 95 % CI 1.18 - 22.17; p = 0.04) and OS (HR 4.28, 95 % CI 1.04 - 20.12; p = 0.05). CONCLUSION: Active tumors overexpressing VEGFR-2 are associated with a worse overall outcome in patients with rectal cancer treated with induction chemotherapy followed by pelvic chemoradiation and surgery. The optimal diagnostic cut-off level for this novel biomarker association should be investigated. Evaluation in a clinical trial is required to determine whether selected patients could benefit from a VEGFR-targeting drug. PMID- 23801170 TI - SUVmax of 2.5 should not be embraced as a magic threshold for separating benign from malignant lesions. PMID- 23801173 TI - A very elderly lung cancer patient: case report of a long disease free survival. AB - Despite the fact that non-small-cell lung cancer (NSCLC) is very common in the older population, these patients are frequently underrepresented in clinical and surgical trials and thus it is difficult to reach evidence-based recommendations for this special population. We present a case of a surgical treatment of asymptomatic lung cancer in a very elderly patient. The patient had no recurrence for 4 years after a complete resection. PMID- 23801171 TI - Temperature response of photosynthesis in C3, C4, and CAM plants: temperature acclimation and temperature adaptation. AB - Most plants show considerable capacity to adjust their photosynthetic characteristics to their growth temperatures (temperature acclimation). The most typical case is a shift in the optimum temperature for photosynthesis, which can maximize the photosynthetic rate at the growth temperature. These plastic adjustments can allow plants to photosynthesize more efficiently at their new growth temperatures. In this review article, we summarize the basic differences in photosynthetic reactions in C3, C4, and CAM plants. We review the current understanding of the temperature responses of C3, C4, and CAM photosynthesis, and then discuss the underlying physiological and biochemical mechanisms for temperature acclimation of photosynthesis in each photosynthetic type. Finally, we use the published data to evaluate the extent of photosynthetic temperature acclimation in higher plants, and analyze which plant groups (i.e., photosynthetic types and functional types) have a greater inherent ability for photosynthetic acclimation to temperature than others, since there have been reported interspecific variations in this ability. We found that the inherent ability for temperature acclimation of photosynthesis was different: (1) among C3, C4, and CAM species; and (2) among functional types within C3 plants. C3 plants generally had a greater ability for temperature acclimation of photosynthesis across a broad temperature range, CAM plants acclimated day and night photosynthetic process differentially to temperature, and C4 plants was adapted to warm environments. Moreover, within C3 species, evergreen woody plants and perennial herbaceous plants showed greater temperature homeostasis of photosynthesis (i.e., the photosynthetic rate at high-growth temperature divided by that at low-growth temperature was close to 1.0) than deciduous woody plants and annual herbaceous plants, indicating that photosynthetic acclimation would be particularly important in perennial, long-lived species that would experience a rise in growing season temperatures over their lifespan. Interestingly, across growth temperatures, the extent of temperature homeostasis of photosynthesis was maintained irrespective of the extent of the change in the optimum temperature for photosynthesis (T opt), indicating that some plants achieve greater photosynthesis at the growth temperature by shifting T opt, whereas others can also achieve greater photosynthesis at the growth temperature by changing the shape of the photosynthesis-temperature curve without shifting T opt. It is considered that these differences in the inherent stability of temperature acclimation of photosynthesis would be reflected by differences in the limiting steps of photosynthetic rate. PMID- 23801174 TI - Sutureless surgical techniques for arch aneurysm repair in a patient with Behcet's disease. AB - In patients with vasculo-Behcet's disease, endovascular stent graft is a reasonable treatment from the viewpoint of prevention of an anastomotic pseudo aneurysm. We report a case of total arch replacement combined with open stent grafting technique to the downstream aorta and graft inclusion into sino-tubular junction as sutureless surgical techniques for an arch aneurysm in a 42-year-old woman with Behcet's disease. Postoperative computed tomography (CT) showed that the aortic aneurysm had completely disappeared in 11 months after the operation. Open stent grafting technique was effective to prevent anastomotic pseudo aneurysm formation. PMID- 23801175 TI - Surgical resection of a massive primary mediastinal liposarcoma using clamshell incision combined with lower median sternotomy: report of a case. AB - We experienced a case of massive mediastinal liposarcoma expanding to the bilateral pleural cavities. Preoperative positron emission tomography-computed tomography scan showed that the uptake of (18)F-fluorodeoxyglucose (FDG) into the tumor was slight for its size. Clamshell incision together with lower median sternotomy provided the excellent visualization and the complete resection of the tumor. The surgical resection should be performed even for a massive liposarcoma, especially if the uptake of F-FDG into the tumor is low, as complete surgical resection is the only definitive treatment for liposarcoma. PMID- 23801176 TI - Simultaneous surgery for patent ductus arteriosus associated with papillary fibroelastoma. AB - We describe a case of patent ductus arteriosus (PDA) in a 76-year-old woman with a history of stroke, atrial fibrillation, and chronic obstructive pulmonary disease. Cranial diffusion-weighted imaging (DWI) performed for preoperative assessment showed a hyperintense lesion in the left cerebellum. Preoperative transesophageal echocardiography (TEE) demonstrated two highly mobile masses approximately 5 mm in diameter adherent to the left and non-coronary cusps of the aortic valve. We performed transpulmonary patch closure of PDA under hypothermic circulatory arrest. Subsequently, two frond-like masses were completely shaved off the cusps, preserving the native aortic leaflets. Pathological examination confirmed the diagnosis of papillary fibroelastoma (PFE). To our knowledge, this is the first report of PDA associated with PFE. Perioperative use of TEE is an effective tool for management of cardiovascular patients with suspected cardiogenic embolism. PMID- 23801177 TI - A stepwise aortic clamp procedure to treat porcelain aorta associated with aortic valve stenosis and hemodialysis. AB - A 62-year-old man was referred for an aortic-valve surgery because of severe aortic stenosis. Thirty years ago, he had undergone a mitral valve commissurotomy and after 9 years, the valve had been replaced by a mechanical valve. He had been undergoing hemodialysis for the past 8 years. A computed tomographic (CT) scan of the chest and abdomen showed a dense circumferential calcification in the wall of the entire thoracic and abdominal aorta, pulmonary artery, and left and right atrium. A conventional aortic-valve replacement was performed. To avoid an embolic event, a "stepwise aortic clamp" procedure was attempted and involved the following: (1) brief circulatory arrest and aortotomy during moderate hypothermia; (2) balloon occlusion at the ascending aorta during low-flow cardiopulmonary bypass (CPB); (3) endoarterectomy by using an ultrasonic surgical aspirator to enable aortic cross-clamping; and (4) a cross-clamp reinforced with felt and full-flow CPB. The patient recovered without any thromboembolic events. Using this procedure to treat a porcelain aorta seemed to reduce the time limit and reduced the risk of brain injury during cardiac surgery. PMID- 23801178 TI - Risk factors in the treatment of abdominal aortic aneurysms in the endovascular ERA. AB - PURPOSE: Endovascular aneurysm repair (EVAR) is a minimally invasive treatment that is becoming standard in abdominal aortic aneurysm treatment. We examine the risk factors of death by comparing the short-term results of abdominal aortic aneurysm by open surgical repair with EVAR. METHODS: We performed elective abdominal aortic aneurysm treatment on 122 cases during the period from January 2008 to December 2009. Seventy one cases were treated with open surgical repair while 51 cases were treated with EVAR. RESULTS: Compared to the open surgical repair group, the EVAR group was significantly older and had a higher complication rate and past laparotomy rates. No significant difference in hospital deaths was observed between the two groups. Two deaths with thromboembolism due to shaggy aorta were observed in the EVAR group. Two cases in the open surgical repair group developed postoperative myocardial infarction and one death was observed. Both patients underwent coronary artery treatment using drug eluting stents (DES) prior to surgery. CONCLUSION: Shaggy aorta has a high possibility of causing thromboembolism and EVAR should not be performed unless there is a considerable reason. In cases in which coronary artery treatment is performed with DES in recent days, EVAR is more preferable. PMID- 23801179 TI - Surgical outcomes after superior vena cava reconstruction with expanded polytetrafluoroethylene grafts. AB - OBJECTIVES: Graft occlusion is a problem after superior vena cava (SVC) reconstruction for thoracic malignancy. Expanded polytetrafluoroethylene (ePTFE) is considered to be an optimal material for venous reconstruction. METHODS: We reviewed the hospital records of 13 patients who underwent complete resection of thoracic malignancy invading the SVC, including SVC reconstruction with ePTFE grafts. Single bypass grafting was performed in two patients (one right-sided, one left-sided) and double bypasses grafting was performed in the other patients. All patients received antithrombotic therapy after surgery. Eight patients died of recurrence or other disease during the follow-up period (range 5-41 months). RESULTS: Of the 24 grafts in 13 patients, graft patency was confirmed in 20 grafts in 9 patients at a mean time follow-up time of 47.8 +/- 50.0 months after surgery. In the remaining four grafts in four patients, occlusion was diagnosed at a mean time of 1.25 +/- 0.50 months after surgery. All obstructed grafts were left-sided bypass grafts in patients who underwent double bypass grafting, and did not result in SVC syndrome. CONCLUSIONS: SVC reconstruction with ringed ePTFE grafts was safe and had good outcomes. In patients who underwent double bypasses grafting, the left-sided bypass grafts were susceptible to occlusion. PMID- 23801180 TI - Treatment of prosthetic graft infection after thoracic aorta replacement. AB - PURPOSE: Prosthetic graft infection is a fatal complication after thoracic aorta replacement, and it is sometimes difficult to perform a prompt re-operation when the patient carries the infectious source of the graft. We evaluated the early and mid-term outcomes of aortic graft infection after thoracic aorta replacement, focusing on the timing of the surgery. METHODS: This study included eight consecutive patients with thoracic graft infection from 1997 to 2011 among 513 patients of graft replacement during this period. We performed re-graft replacement in six patients. Of these six patients, emergency surgery was performed in two and scheduled surgery was performed in two. An unscheduled emergency surgery was required in two patients during the medical treatment of the infection source. Solo medical treatment was performed in two patients. RESULTS: In-hospital mortality occurred in two of the eight patients (25%). Re graft infection was not observed in the six patients who underwent re-graft replacement or the one patient who underwent medical treatment during the 1.5- to 14-year observation period. CONCLUSIONS: Prompt re-replacement of the infected graft should be performed even when an orthotopic infection source led to the graft infection. Medical treatment might be applicable when neither an abscess nor pseudoaneurysm is observed. PMID- 23801181 TI - Gastrointestinal complications after mitral valve surgery. AB - INTRODUCTION: Gastrointestinal (GI) complications are well-recognized risks of open heart surgery. However, open heart surgery comes in different shapes and sizes with widely varying pre-operative, intra-operative and post-operative pathologies. The aim of this study was to examine the etiology and risk factors for GI complications after mitral valve surgery. METHODS: A retrospective analysis of 565 patients who underwent mitral valve surgery from 2003-2005 was performed. Prospectively collected data included preoperative risk factors, cardiac status, intra-operative data, postoperative GI complications and mortality. Survival was analyzed using log-rank analysis. RESULTS: In this study population, 13 patients (2.3%) had 16 GI complications after mitral valve surgery resulting in an overall mortality of 0.7%. Complications included GI bleed (n = 9), cholecystitis (n = 3), perforated diverticulitis (n = 1) and ischemic bowel (n = 3). By univariate analysis, a history of hypertension, chronic renal insufficiency (CRI), hypercholesterolemia, myocardial infarction, congestive heart failure, cardiogenic shock, emergency valve surgery, coronary artery bypass surgery and preoperative vasopressor use were each associated with an increased incidence of GI complications (p <0.05). No increased incidence was seen in patients with atrial fibrillation. On multivariate analysis adjusted for age, cardiogenic shock (OR 8.1; 95% CI, 1.9-34.8), CRI (OR 8.1; 95% CI, 2.2-30.0) and vasopressor use (OR 6.5; 95% CI, 1.3-31.0) remained significant (p <0.02). Mean survival (3.2 vs. 5.4 years) was significantly lower (p <0.05) in those with GI complications. CONCLUSIONS: GI complications after mitral valve surgery are infrequent, with a higher incidence in those with cardiogenic shock, CRI or requiring vasopressors. Pre-operative hemodynamic instability may be a bellwether for potential GI complications and should be of more prominent concern in this cohort of patients. PMID- 23801182 TI - Lung re-expansion following one-lung ventilation induces neutrophil cytoskeletal rearrangements in rats. AB - PURPOSE: To investigate the morphological and functional behavior of neutrophils during and after one-lung ventilation (OLV). METHODS: We utilized an OLV rat model system and performed 3 hours of OLV followed by either re-expansion (RE) and 30 minutes of two-lung ventilation (TLV) (RE group), only two-lung ventilation (TLV group), or only OLV (OLV group). Cytoskeletal rearrangements of circulating neutrophils were assessed by determining the localization of filamentous actin (F-actin). In addition, the number of sequestered neutrophils in the lung capillary and the cytokine-induced neutrophil chemoattractant 1 (CINC 1) levels in the plasma were determined. RESULTS: The F-actin rimmed neutrophils in the RE group increased after RE, but did not increase in the other groups. In the RE group, the sequestered neutrophils in the ventilated lung were significantly more numerous, and the plasma CINC-1 levels were significantly higher than in the other groups. CONCLUSIONS: Lung RE following OLV induces cytoskeletal rearrangements in circulating neutrophils and would thereby promote their sequestration in the lung capillaries. The plasma CINC-1 elevation after RE can be involved in neutrophil recruitment. PMID- 23801183 TI - Primary mediastinal hydatid cysts. AB - PURPOSE: Hydatid disease is endemic in many parts of the world. Mediastinal hydatidosis is seen less than 0.1% of all hydatid diseases. We want to report our primary mediastinal hydatid cysts. MATERIALS AND METHODS: In this retrospective study, from January 2010 to December 2012, 158 patients with intrathoracic hydatid cysts were operated in our thoracic surgery clinic. Nine of 158 (5.69%) patients had mediastinal hydatid cyst. Chest X-ray and computed tomography (CT) were used as diagnostic tools. RESULTS: Hydatid cyst was confirmed surgically and pathologically in all the patients. Anterior mediastinal hydatid cysts and one cardiac involvement were determined in our study. While total cyst excision was performed in seven patients, partial pericystectomy could be done in two patients. In one patient, left ventricle invasion was seen and it was totally excised. Postoperative albendazole was applied to patients and there was no recurrence of disease till now. CONCLUSIONS: Mediastinal hydatid cysts are uncommon and should be kept in mind in differential diagnosis of mediastinal cystic lesions especially in endemic regions. Surgical resection must be done and then medical therapy is needed to prevent recurrence. PMID- 23801184 TI - Candida urinary tract infection and Candida species susceptibilities to antifungal agents. AB - The purpose of this study is to review Candida isolation from urine of urinary tract infection (UTI) patients over the recent 3 years at the Kobe University Hospital. We recorded the type of strain, the department where the patient was treated such as the intensive care unit (ICU), and combined isolation of Candida with other microorganisms. We investigated Candida isolation and susceptibilities to antifungal agents and analyzed the risk factors for combined isolation with other microorganisms. The most frequently isolated Candida was Candida albicans, which showed good (100%) susceptibilities to 5-fluorocytosine (5-FC) and fluconazole (FLCZ) but not to voriconazole (VRCZ), followed by C. glabrata. ICU was the greatest source of Candida-positive samples, and the most relevant underlying diseases of ICU patients were pneumonia followed by renal failure and post liver transplantation status. Combined isolation with other bacteria was seen in 27 cases (42.9%) in 2009, 25 (33.3%) in 2010 and 31 (31.3%) in 2011 and comparatively often seen in non-ICU patients. Other candidas than C. albicans showed significantly decreased susceptibility to FLCZ over these 3 years (P=0.004). One hundred (97.1%) of 103 ICU cases were given antibiotics at the time of Candida isolation, and the most often used antibiotics were cefazolin or meropenem. In conclusion, C. albicans was representatively isolated in Candida UTI and showed good susceptibilities to 5-FC, FLCZ and VRCZ, but other candidas than C. albicans showed significantly decreased susceptibility to FLCZ in the change of these 3 years. PMID- 23801185 TI - Effects of ceftazidime and ciprofloxacin on biofilm formation in Proteus mirabilis rods. AB - Proteus mirabilis rods are one of the most commonly isolated species of the Proteus genus from human infections, mainly those from the urinary tract and wounds. They are often related to biofilm structure formation. The bacterial cells of the biofilm are less susceptible to routinely used antimicrobials, making the treatment more difficult. The aim of this study was to evaluate quantitatively the influence of ceftazidime and ciprofloxacin on biofilm formation on the polyvinyl chloride surface by 42 P. mirabilis strains isolated from urine, purulence, wound swab and bedsore samples. It has been shown that ceftazidime and ciprofloxacin at concentrations equal to 1/4, 1/2 and 1 times their MIC values for particular Proteus spp. strains decrease their ability to form biofilms. Moreover, ciprofloxacin at concentrations equal to 1/4, 1/2 and 1 times their MIC values for particular P. mirabilis strains reduces biofilm formation more efficiently than ceftazidime at the corresponding concentration values. PMID- 23801186 TI - Biosynthesis of ebelactone A: isotopic tracer, advanced precursor and genetic studies reveal a thioesterase-independent cyclization to give a polyketide beta lactone. AB - Macrocyclization of polyketides generates arrays of molecular architectures that are directly linked to biological activities. The four-membered ring in oxetanones (beta-lactones) is found in a variety of bioactive polyketides (for example, lipstatin, hymeglusin and ebelactone), yet details of its molecular assembly have not been extensively elucidated. Using ebelactone as a model system, and its producer Streptomyces aburaviensis ATCC 31860, labeling with sodium [1-(13)C,(18)O2]propionate afforded ebelactone A that contains (18)O at all oxygen sites. The pattern of (13)C-(18)O bond retention defines the steps for ebelactone biosynthesis, and demonstrates that beta-lactone ring formation occurs by attack of a beta-hydroxy group onto the carbonyl moiety of an acyclic precursor. Reaction of ebelactone A with N-acetylcysteamine (NAC) gives the beta hydroxyacyl thioester, which cyclizes quantitatively to give ebelactone A in aqueous ethanol. The putative gene cluster encoding the polyketide synthase (PKS) for biosynthesis of 1 was also identified; notably the ebelactone PKS lacks a terminal thioesterase (TE) domain and no stand alone TE was found. Thus the formation of ebelactone is not TE dependent, supporting the hypothesis that cyclization occurs on the PKS surface in a process that is modeled by the chemical cyclization of the NAC thioester. PMID- 23801188 TI - Photocatalytic activity of semiconductor sulfide heterostructures. AB - This paper reports a theoretical and experimental study of the heterostructure photocatalytic activity in a CdS or ZnS and CdS@ZnS decorated system prepared by a microwave assisted solvothermal (MAS) method. A theoretical model of the decorated system was created in order to analyze the electronic transition mainly in their interface. The results show that CdS and ZnS interfaces produce an electron charge transfer from the CdS electron-populated clusters to the ZnS hole populated clusters which helps to enhance the photocatalytic activity of the CdS@ZnS decorated system. PMID- 23801187 TI - Occurrence, distribution, dereplication and efficient discovery of thiazolyl peptides by sensitive-resistant pair screening. AB - Natural products have been major sources of antibacterial agents and remain very promising. Frequent rediscoveries of known compounds hampers progress of new discoveries and demands development and utilization of new methods for rapid biological and chemical dereplication. This paper describes an efficient approach for discovery of new thiazolyl peptides by sensitive-resistant pair screening and dereplication in a time and cost-effective manner at industrial scale. A highly effective library-based dereplication of thiazolyl peptides by high resolution fourier transform liquid chromatography mass spectrometry (HRFTLCMS) has been developed, which can detect and dereplicate very low levels of thiazolyl peptides particularly when combined with miniaturized high-throughput 96-well solid-phase extraction separation, and as well can be automated. Combination of sensitive (susceptible)-resistant pair screening, diversified screening collection and miniaturized high-throughput SPE and HRFTLCMS techniques were applied for discovery of new thiazolyl peptides. The combined approach allowed for identification of over 24 thiazolyl peptides represented by three of the five structural subgroups, including three novel compounds. In addition, it is possible for the first time to mechanistically group three structural subgroups of over 24 thiazolyl peptides. Furthermore, these studies helped to understand natural frequency of distribution of these compounds and helped in discovery of new producing strains of many thiazolyl compounds. PMID- 23801189 TI - Quantification of the level of fat-soluble vitamins in feed based on the novel microemulsion electrokinetic chromatography (MEEKC) method. AB - BACKGROUND: Simultaneous quantification of liposoluble vitamins is not a new area of interest, since these compounds co-determine the nutritional quality of food and feed, a field widely explored in the human and animal diet. However, the development of appropriate methods is still a matter of concern, especially when the vitamin composition is highly complex, as is the case with feed designated for laboratory animals, representing a higher health and microbiological status. RESULTS: A method combining microemulsion electrokinetic chromatography (MEEKC) with liquid-liquid extraction was developed for the determination of four fat soluble vitamins in animal feed. A separation medium consisting of 25 mmol L-1 phosphate buffer (pH 2.5), 2-propanol, 1-butanol, sodium dodecyl sulfate and octane allowed the simultaneous determination of vitamins A, D, E and K within a reasonable time of 25 min. The polarity of the separation voltage was reversed in view of the strongly suppressed electro-osmotic flow, and the applied voltage was set at 12 kV. The fat-soluble vitamins were separated in the order of decreasing hydrophobicity. CONCLUSION: It was proved that the proposed MEEKC method was sufficiently specific and sensitive for screening fat-soluble vitamins in animal feed samples after their sterilization. PMID- 23801190 TI - Synthesis and antioxidant activities of acetamidomethylsulfonyl bis heterocycles oxazolyl/thiazolyl/imidazolyl-1,3,4-oxadiazoles. AB - A new class of acetamidomethylsulfonyl bis heterocycles-oxazolyl-1,3,4 oxadiazoles, -thiazolyl-1,3,4-oxadiazoles, and -imidazolyl-1,3,4-oxadiazoles were synthesized from the synthetic intermediates, methyl 2-((4-aryloxazol-2 ylcarbamoyl)methylsulfonyl)acetate, methyl 2-((4-arylthiazol-2 ylcarbamoyl)methylsulfonyl)acetate, and methyl 2-((4-aryl-1H-imidazol-2 ylcarbamoyl)methylsulfonyl)acetate. All the title compounds were tested for their antioxidant activity. The oxadiazolylmethylsulfonyloxazolylacetamide displayed excellent radical-scavenging activity when compared with the standard ascorbic acid. PMID- 23801191 TI - Resolution of diabetic papillopathy with a single intravitreal injection of bevacizumab combined with triamcinolone acetonide. PMID- 23801192 TI - Effects of agomelatine on oxidative stress in the brain of mice after chemically induced seizures. AB - Agomelatine is a novel antidepressant drug with melatonin receptor agonist and 5 HT(2C) receptor antagonist properties. We analyzed whether agomelatine has antioxidant properties. Antioxidant activity of agomelatine (25, 50, or 75 mg/kg, i.p.) or melatonin (50 mg/kg) was investigated by measuring lipid peroxidation levels, nitrite content, and catalase activities in the prefrontal cortex, striatum, and hippocampus of Swiss mice pentylenetetrazole (PTZ) (85 mg/kg, i.p.), pilocarpine (400 mg/kg, i.p.), picrotoxin (PTX) (7 mg/kg, i.p.), or strychnine (75 mg/kg, i.p.) induced seizure models. In the pilocarpine-induced seizure model, all dosages of agomelatine or melatonin showed a significant decrease in TBARS levels and nitrite content in all brain areas when compared to controls. In the strychnine-induced seizure model, all dosages of agomelatine and melatonin decreased TBARS levels in all brain areas, and agomelatine at low doses (25 or 50 mg/kg) and melatonin decreased nitrite contents, but only agomelatine at 25 or 50 mg/kg showed a significant increase in catalase activity in three brain areas when compared to controls. Neither melatonin nor agomelatine at any dose have shown no antioxidant effects on parameters of oxidative stress produced by PTX- or PTZ-induced seizure models when compared to controls. Our results suggest that agomelatine has antioxidant activity as shown in strychnine- or pilocarpine-induced seizure models. PMID- 23801193 TI - Expression of pituitary adenylate cyclase-activating peptide (PACAP) and PAC1 in the periodontal ligament after tooth luxation. AB - Pituitary adenylate cyclase-activating peptide (PACAP) is widely distributed throughout the nervous system. PACAP not only acts as a neurotransmitter but also elicits a broad spectrum of biological action via the PACAP-specific receptor, PAC1. However, no studies have investigated PACAP and PAC1 in the periodontal ligament (PDL), so we aimed to perform this investigation in rats after tooth luxation. In the PDL of an intact first molar, there are few osteoclasts and osteoblasts. However, at days 3 and 5 after luxation, large PAC1-positive cells, thought to be osteoclasts because of their expression of the osteoclast marker, tartrate-resistant acid phosphatase, were detected in appreciable numbers. Osteoblast numbers increased dramatically on day 7 after luxation, and PAC1 positive mononuclear small cells were increased at day 14, many of which expressed the osteoblast marker, alkaline phosphatase. PACAP-positive nerve fibers were rarely detected in the PDL of intact first molars, but were increasingly evident at this site on days 5 and 7 after luxation. Double immunofluorescence analysis demonstrated the relationship between PACAP-positive nerve fibers and PAC1-positive osteoclasts/-blasts in the PDL. At 5 days after luxation, PACAP-positive nerve fibers appeared in close proximity to PAC1 positive osteoclasts. At 7 days after luxation, PACAP-positive nerve fibers appeared in close proximity to PAC1-positive osteoblasts. These results suggest that PACAP may have effects on osteoclasts and osteoblasts in the PDL after tooth luxation and thus regulate bone remodeling after these types of injury. PMID- 23801195 TI - Lack of association between OSAS and hypothyroidism. PMID- 23801194 TI - Lymphocytes and immunoglobulin patterns across the threshold of severe obesity. AB - The proinflammatory state of metabolic disorders encompasses the alterations in leukocyte counts and acute-phase reactants, and thus, predisposes to acute and chronic cardiovascular events linked to fat accumulation. Leptin is a marker of adiposity and also yields regulatory effects on innate and adaptive immunity; however, its role on the immune function of obese subjects remains to be elucidated. The aim of this study is to determine the influence of obesity and the role of leptin concentrations on lymphocyte counts and immunoglobulin levels as broad markers of immune function. Cross-sectional analysis in 147 obese (64 M, BMI 43 +/- 8.1 kg/m(2)) and 111 age- and sex-matched controls (36 M, BMI 22.5 +/- 2.6 kg/m(2)) by assessment of peripheral leukocyte counts, immunoglobulin (Ig) A, G, M levels, leptin, glucose and lipid homeostasis, and acute-phase reactants. Compared to controls, all the leukocyte components were significantly increased in obesity (p < 0.0001 for all) except for basophils and eosinophils. While IgA and IgG levels were similar between groups, IgM levels were lower (p < 0.001) in obese individuals. A significant relationship was evident between leptin and leukocyte counts (p < 0.001), with this latter being correlated to insulin resistance, adiposity, and lipid profile. At the stepwise multiple regression analysis, leukocytes were best predicted by leptin (beta = 0.43, p < 0.0001) and male gender (beta = 0.15, p < 0.05), yet when obesity entered the equation, it acted as an independent predictor of leukocytes (beta = 0.51, p < 0.0001). Leptin also acted as a predictor of IgA levels (beta = 0.20, p < 0.01). Current results show that IgM levels are significantly decreased in patients with obesity in association to significant increments in leukocyte counts. These latter are markedly correlated to leptin levels, insulin resistance, lipid profile, and adiposity. This circumstance, and the significant correlation seen between leptin and IgA levels, may suggest an indirect intervention of leptin in the immunologic alterations consequent to obesity and related to its cardiovascular risk. PMID- 23801196 TI - Supramolecular photocyclodimerization of 2-hydroxyanthracene with a chiral hydrogen-bonding template, cyclodextrin and serum albumin. AB - 2-Hydroxyanthracene (HA) in its neutral form smoothly photocyclodimerized to four stereoisomeric [4 + 4]-cyclodimers, which were isolated and characterized for the first time, whereas the anionic form of HA turned out to be photochemically inert. Enantiodifferentiating photocyclodimerization of HA in the presence of a chiral hydrogen-bonding template (TKS159), gamma-cyclodextrin (gamma-CDx) and bovine serum albumin (BSA) was examined to afford chiral syn-head-to-tail and anti-head-to-head cyclodimers in modest enantiomeric excesses with TKS159 and gamma-CDx, but practically no photocyclodimerization proceeded in the presence of BSA probably due to the ionization of HA in the binding sites. PMID- 23801197 TI - [Application of precise radiotherapy in the combined modality therapy of gastrointestinal tract tumors]. AB - Single modality treatment of advanced gastrointestinal cancer has been associated with unfavorable outcomes. Radiotherapy as an important component of the combined modality therapy of gastrointestinal tract tumors may achieve down-staging, increase resection rate while preserving sphincter function, decrease local recurrence rate, and improve survival rate. Precision radiotherapy has better conformity, accuracy, and lower toxicity. Precision radiotherapy will become more and more important in the combined modality therapy of gastrointestinal tract cancer. PMID- 23801198 TI - [Improvement of standardization and accuracy of medical imaging and pathological diagnosis for better diagnosis and treatment of rectal cancer]. AB - Rectal cancer is one of the most common malignancies in human. Because rectal cancer locates in the narrow pelvis and is close to many complicated anatomic structures, seeking R0 resection and decreasing the positive rate of circumferential resection margin become the focus of concern for surgeons. The authors review the diagnosis standard of rectal cancer in AJCC TNM cancer staging (seventh edition) and guideline of College of American Pathologists, and propose the concept of "diagnosis priority using the standardized methods". Selecting the correct medical imaging and pathology diagnosis methods is the key to improve the standardized and individualized comprehensive therapy. PMID- 23801199 TI - [Timing of surgery after neoadjuvant chemotherapy for advanced gastric cancer]. AB - Several studies have demonstrated the benefit of perioperative chemotherapy in the treatment of advanced gastric cancers, especially the neoadjuvant chemotherapy (NAC). Many NAC trials in the United States, UK and Japan have proved that NAC can shrink the tumor and metastatic lymph nodes, downstage the T and N staging, achieve more curative (R0) resection for the unresectable cases, and even improve survival. Various neoadjuvant chemotherapy regimens have different effects on the body, therefore the timing selection of surgery, surgical programs and goals are different accordingly. Optimal surgery after neoadjuvant chemotherapy should be based on full comprehension of the pharmacology and pharmacokinetics. Strict surgical quality control is necessary. PMID- 23801200 TI - [Surgical treatment strategies for locally advanced rectal cancer after neoadjuvant radiation]. AB - For locally advanced rectal cancer after neoadjuvant radiation, it is difficult to make a choice between close observation, local resection, and radical resection. The decision should be made after carefully weighing postoperative complications, anal function, local recurrence and long-term survival. There is a high consistency of the radiosensitivity between primary tumor and mesenteric lymph node, which may be used to guide the treatment decisions. If the primary tumor shrinks significantly after neoadjuvant radiation, local resection is recommended, and the next treatment plan should be made based on the pathological examination of resected specimen. Transabdominal radical resection is recommended for unfavorable tumors. Distal resection margin should be at least 1 cm, and marking the inferior margin of tumor is also recommended before neoadjuvant radiation since it would shrink significantly after radiation. PMID- 23801201 TI - [Standardized treatment of mid-low rectal cancer]. AB - In recent years, the treatment strategy of mid-low rectal cancer has changed from surgical resection alone to multidisciplinary treatment. In order to offer the greatest benefits to the mid-low rectal cancer patients, it is necessary to carry out the preoperative TNM staging for appropriate therapeutic strategies. Total mesorectal excision (TME), preoperative TNM staging and neoadjuvant chemoradiotherapy together may achieve a breakthrough in the therapeutic outcome of mid-low rectal cancer. PMID- 23801202 TI - [Current status of clinical research on gastric cancer in China]. AB - Gastric cancer remains the most lethal disease in China. Although great progress has been made in the treatment, intractable problems in clinical practice are yet to be answered by clinical research. After development during decades, clinical research on gastric cancer in China has stepped from simple following to independent initiation. In this paper, we will review the development history of clinical research in China, and compare with that of developed countries in order to elucidate the advantage and future prospect. PMID- 23801203 TI - [Correlation of MDR1 and ABCG2 genetic polymorphisms with the efficacy and adverse events of irinotecan chemotherapy in patients with colorectal cancer]. AB - OBJECTIVE: To investigate the correlation of MDR1 and ABCG2 genetic polymorphisms with the efficacy and adverse events of irinotecan chemotherapy in patients with colorectal cancer (CRC). METHODS: Clinical data of CRC patients treated with irinotecan-based chemotherapy in the Peking University Cancer Hospital between January 1996 and December 2011 were collected, and their blood samples were collected accordingly. Genomic DNA was extracted from blood samples. The following SNP detection of MDR1 and ABCG2 genes was conducted by direct sequencing method. The correlation of genetic SNPs with efficacy and toxicity of irinotecan treatment was further analyzed. RESULTS: Allele frequencies of MDR1 2677 G>T/A, ABCG2 421 C>A, 34 G>A, 376 C>T were comparable with previous studies. Genetic SNPs results from peripheral blood samples and tumor tissues were highly consistent. Patients carrying MDR1 2677 wild type had higher clinical benefit than those carrying mutant genotype, while the differences were not significant. The progression-free survival (PFS) was longer in wild-type patients as compared to mutant-type patients in second-line chemotherapy (P=0.012). There were no significant correlations between ABCG2 421 C>A, 34 G>A, 376 C>T and chemotherapy efficacy. No significant correlations were observed between MDR1 2677 G>T/A, ABCG2 421 C>A, ABCG2 34 G>A, ABCG2 376 C>T and irinotecan-related grade 3 and 4 neutropenia or diarrhea. CONCLUSION: MDR1 2677 G>T/A may be served as a biomarker in predicting the efficacy of irinotecan chemotherapy in patients with colorectal cancer. PMID- 23801204 TI - [Association of nutrition with treatment compliance and toxicities in patients undergoing chemoradiation after gastrectomy]. AB - OBJECTIVE: To investigate the association of nutritional status with treatment compliance and toxicities in patients undergoing chemoradiation therapy (CRT) after gastrectomy. METHODS: From September 2010 to May 2012, 40 patients with gastric cancer received adjuvant CRT in the Department of Radiation, Shanghai Cancer Center. Data including clinical data, weight loss of perioperative period, dynamic changes of weight, NRS 2002 score, PG-SGA score, lymph cell count and serum albumin during CRT, toxic effects and nutritional interventions were collected. Treatment compliance of CRT and adjuvant chemotherapy was recorded. Associations among nutrition, toxicities and treatment compliance were statistically studied. RESULTS: Weight loss percentage from pre-operation to pre CRT(T1-T2) was 10.0%, which was significantly higher than that of 4.3% during CRT(T3) (P<0.05). Adverse reaction incidence of digestive tract during T3 was 95.0% (38/40). Patients with weight loss >5% during T3 had higher ratio of >II degree digestive tract adverse reaction [91.3% (21/23) vs. 76.5% (13/17), P<0.01] and higher ratio of >3 symptoms of digestive tract[82.4% (14/17) vs. 39.1% (9/23), P<0.05] as compared to those with weight loss <=5% during T3. Fourteen patients (35.0%) did not complete the synchronous CRT. Factors related to incompletion of CRT were weight loss >7% after surgery (T1) or >10% during T1-T2, malnourishment before CRT, dependence on nutritional support during CRT. Factors related to incompletion of adjuvant chemotherapy were weight loss >5% during CRT(T3), requirement for nutritional support and NRS 2002 score >=5 at the end of radiation (all P<0.05). CONCLUSIONS: Nutritional deterioration before CRT may aggravate the toxicities and reduce compliance of CRT in patients with radical resection of gastric cancer. Malnutrition during CRT may impair compliance to adjuvant chemotherapy. Therefore, early and persistent nutritional interventions are crucial considerations of strategies of multidisciplinary treatment for patients with gastric cancer. PMID- 23801205 TI - [Indirect comparison of different adjuvant chemotherapies for stage II-III gastric cancer after D2 gastrectomy in Asian patients]. AB - OBJECTIVE: To compare efficacy of different adjuvant chemotherapy regimens for stage II-III gastric cancer after D2 gastrectomy in Asian patients. METHODS: Associated literatures were searched through electronic databases and hand searching. Prospective randomized clinical trials (RCTs) comparing adjuvant chemotherapy after D2 gastrectomy with surgery alone were included in the study. Overall survival and disease-free survival were chosen as the endpoints. Relative hazard was analyzed by Bucher adjusted indirect comparison. RESULTS: Two RCTs were selected, including comparison between S-1 versus surgery alone and comparison between XELOX versus surgery alone. There was no statistical difference in overall survival between the two regimens (HR=0.94, 95%CI:0.62 1.44, P=0.79). The recurrence risk of S-1 was slightly higher as compared to XELOX, but no statistical difference was found (HR=1.11, 95%CI:0.80-1.53, P=0.54). CONCLUSION: The adjuvant chemotherapy with S-1 is similar to XELOX for stage II-III gastric cancer after D2 gastrectomy in Asian patients. PMID- 23801206 TI - [Role of BH3-only gene in the oxaliplatin-induced apoptosis of colon cancer cells]. AB - OBJECTIVE: To study the role of BH3-only gene in oxaliplatin-induced apoptosis of human colon cancer cell line, and to explore the associated mechanisms. METHODS: Two strains of human colon cancer cell line SW480 and HT29 were selected, and treated respectively with different concentrations of oxaliplatin (0.3, 0.6, 1.25, 2.5, 5, 10 and 20 mg/L). Cell growth and inhibition were detected by MTT method. Apoptosis was measured by flow cytometry. Bim and PUMA expressions were examined by fluorescence quantitative PCR. RESULTS: After treatment of different oxaliplatin concentrations in human colon carcinoma cells SW480 line, the cell growth was inhibited in a dose-dependent manner, while Bim and PUMA expressions were significantly up-regulated. While HT29 cell lines received the same treatment, no obvious inhibition of cell growth and up-regulation of Bim and PUMA expression were found. When SW480 cells were exposed to 5 mg/L and 10 mg/L of oxaliplatin for 24 h, the early apoptotic rates were (4.87+/-0.55)% and (12.10+/ 1.04)%; for 48 h, the early apoptotic rates were (11.47+/-0.85)% and (30.07+/ 2.01)%; for 72 h, the early apoptotic rates were (28.99+/-2.12)% and (38.32+/ 3.15)% respectively, which were all significantly higher than those in control group [(0.30+/-0.10)%, (0.40+/-0.10)% and (0.50+/-0.20)%, all P<0.01]. In HT29 cells, the differences of apoptotic rates between oxaliplatin treatment group and control group were not statistically significant (all P>0.05). CONCLUSIONS: Oxaliplatin can inhibit colon cancer cell line SW480 growth and induce apoptosis. Induction of apoptosis of colon cancer cells by oxaliplatin may be associated with the up-regulation of BH3-only proteins, Bim and PUMA. PMID- 23801207 TI - [Prognosis analysis of 310 patients with pathological stage pN3 gastric cancer]. AB - OBJECTIVE: To investigate the clinicopathological characteristics and prognostic factors of patients with pathological stage pN3 gastric cancer. METHODS: A retrospective study of 310 patients with histologically confirmed pN3 stage gastric cancer undergoing radical gastrectomy from January 2000 to December 2006 in our department was performed. The Kaplan-Meier method was used to analyze the survival. Log-rank test and Cox regression model were carried out for univariate and multivariate analyses. RESULTS: All the patients were followed up for 2 to 103 (mean 35.7) months. The overall 5-year survival rate was 14.6%. There were 201 cases with stage pN3a and 109 cases with stage pN3b, and the 5-year survival rates were 16.8% and 10.3% respectively (P=0.013). Univariate analysis showed that tumor location, Borrmann type, depth of tumor invasion, surgical method, metastatic lymph node ratio, and pN stage were associated with postoperative survival (all P<0.05). The multivariate analysis revealed that depth of tumor invasion, surgical method and metastatic lymph node ratio were independent prognostic factors, while the pN stage was not. The difference of 5-year survival rate between pN3a and pN3b subgroups was significant in pT4a patients (16.1% vs. 12.8%, P=0.001), while such difference was not significant in pT4b patients (8.6% vs. 3.1%, P=0.137). CONCLUSIONS: Prognosis of patients with pN3 stage gastric cancer after radical resection is poor. Depth of tumor invasion and surgical method are independent prognostic factors for pN3 stage gastric cancer. Metastatic lymph node ratio is valuable to predict the prognosis of pN3 stage patients. The pN3 staging of the 7th UICC provides a more accurate prediction of prognosis. PMID- 23801208 TI - [Comparison of local immune microenvironment between liver-metastasis colorectal cancer and non-liver-metastasis colorectal cancer]. AB - OBJECTIVE: To investigate the difference of local immune microenvironment in primary tumors between liver-metastasis and non-liver-metastasis cohort in stage III to IIII colorectal cancer patients. METHODS: Tumor samples from 167 patients of colorectal cancer were harvested, who received tumor resection for the first time in The First Affiliated Hospital of Sun Yat-sen University from 2000 to 2005. Patients were divided into two groups according to liver metastasis or not. Expressions of 18 immune markers, including CD3, CD4 and CD8 were examined and quantified by immunohistochemistry staining. RESULTS: No significant differences of gender, age, BMI, tumor differentiation, pathology type and preoperative CEA level were found between the two groups. The expressions of CD8, CD45RO, IL-17, tryptase and FAS were lower in liver-metastasis group as compared to non-liver metastasis group (all P<0.05). CONCLUSIONS: Decrease of the number of T lymphocyte and mast cell may play an important role in local infiltration of immune microenvironment of stage III to IIII colorectal cancer with liver metastasis. PMID- 23801209 TI - [Association between the score of preoperative nutritional risk screening and anastomotic leakage following anterior resection for the rectal cancer]. AB - OBJECTIVE: To explore the association between the score of preoperative Nutritional Risk Screening 2002 (NRS 2002) and anastomotic leakage following anterior resection for the rectal cancer. METHODS: Clinical data of 641 patients with rectal cancer undergoing anterior resection in Nanfang Hospital, Southern Medical University between January 2003 and July 2012 were analyzed retrospectively. Preoperative nutritional status was evaluated using NRS 2002. Association of clinicopathologic characteristics with postoperative anastomotic leakage was examined using univariate chi(2) and Logistic regression model. RESULTS: Among the 641 patients, postoperative anastomotic leakage occurred in 26 (4.1%) cases. The proportion of anastomotic leakage in patients with the NRS 2002 score >=3 was significantly higher than that in patients with the score <3 (6.9% vs. 2.1%, P=0.002). After the adjustment of factors as age, distance of anastomosis above the anal margin, and pathological staging, NRS 2002 score >=3 was identified as an independent risk factor for anastomotic leakage following anterior resection for rectal cancer (OR=3.198, 95%CI:1.324-7.722, P=0.010). CONCLUSION: The use of the NRS 2002 for preoperative evaluation on patient's nutritional status may help to predict the occurrence of anastomotic leakage following anterior resection for rectal cancer, which may be involved in the indication of protecting ileostomy in clinical practice. PMID- 23801210 TI - [Clinical diagnostic value of (18)F-FDG PET-CT in incidental finding of focal hypermetabolism focus in the colon and rectum]. AB - OBJECTIVE: To investigate the value of incidental focal (18)F-FDG uptake in the colon and rectum and characteristics of functional anatomic form for differential diagnosis of colorectal benign or malignant diseases. METHODS: Clinical data and images of incidental focal hypermetabolism focus in colon and rectum of 37 individuals undergoing (18)F-FDG PET-CT were analyzed retrospectively. According to the eventual outcomes of pathological examination and clinical follow-up, these cases were divided into four subgroups: malignant disease, benign tumor (including precancerous change), inflammation and physiological uptake. Radioactive uptake level (SUVmax) and change of delayed imaging (RI) of focal hypermetabolism focus were compared between groups. The data analysis was performed using variance analysis. RESULTS: The average SUVmax was 6.3+/-3.7, 8.8+/-6.5, 5.2+/-1.4, and 3.8+/-0.9 in malignant disease (n=11), benign (precancerous) tumor (n=9), inflammation (n=9) and physiological uptaking (n=8) respectively. The average SUVmax was 7.6+/-5.6 in benign and malignant tumor, and 4.7+/-1.5 in inflammation and physiological uptake. The distinction of average SUVmax was not statistically significant between benign and malignant tumor or inflammation and physiological uptake. But it was higher in tumors as compared to inflammation or physiological uptake with a statistically difference (P<0.05). The RI was 0.3+/-0.2, 0.4+/-0.1, 0.3+/-0.2, 0.4+/-0.2 in above 4 groups respectively, and the differences were not statistically significant. CONCLUSIONS: The incidental focal hypermetabolism focus in the colon the rectum during (18)F-FDG PET-CT may indicate potential colorectal malignant diseases and precancerous lesions. SUVmax value in focal hypermetabolism focus in the colon and rectum can help to distinguish tumor from inflammation or physiological uptake. But there is no diagnostic value for distinguishing malignant disease from benign tumor. PMID- 23801211 TI - [Application of Onodera prognostic nutrition index in prognostic evaluation of elderly patients with colorectal cancer]. AB - OBJECTIVE: To study the applied valuation of Onodera prognostic nutrition index (Onodera index) in elderly patients with colorectal cancer. METHODS: Onodera indexes of 163 elderly patients with colorectal cancer were calculated and these patients were divided into better-nourished group (Onodera index >=45) and under nourished group (Onodera index <45). Correlations of Onodera index with general data, operation type, postoperative complication, recovery of gastrointestinal function, clinicopathological feature and prognosis were analyzed. Cox proportional hazards model was also established to identify the independent prognostic factors for prognosis of elderly patients with colorectal cancer. RESULTS: Patients in better-nourished group had significantly higher radical resection rate [90.9% (70/77) vs. 62.8% (54/86), P<0.01], lower postoperative complication rate [17.1% (12/70) vs. 53.7% (29/54), P<0.01] and earlier postoperative defecation [(3.09+/-1.14) d vs. (3.43+/-1.98) d, P<0.05] than those in under-nourished group. Onodera index was found to be related to age, tumor location, tumor size, and operation type (all P<0.05). Better-nourished group had significantly better survival than worse-nourished group (5-year survival rate: 64% vs. 24%, P<0.01). Onodera index was identified as an independent prognostic factor for elderly patients with colorectal cancer (RR=0.888, 95%CI:0.800-0.985, P=0.025). CONCLUSION: Onodera index is a valuable clinical marker in preoperative estimation as well as prognosis prediction for elderly patients with colorectal cancer. PMID- 23801212 TI - [Laparoscopic versus open intersphincteric resection for low rectal cancer: a clinical comparative study]. AB - OBJECTIVE: To compare the clinical and oncological outcomes between laparoscopic and open intersphincteric resection in patients with low rectal cancer. METHODS: From January 2007 to January 2010, patients with low rectal cancer treated by laparoscopic or open intersphincteric resection were included in a retrospective comparative study. Patients were classified into laparoscopy group (n=27) and open group (n=41). The operative procedures, postoperative complications, anal function and clinicopathological data were compared. RESULTS: Compared to the open group, the laparoscopic group had longer operative time [(242.2+/-42.5) min vs. (199.1+/-44.3) min, P=0.000], less blood loss [(150.5+/-102.2) ml vs. (258.4+/-149.2) ml, P=0.002], faster recovery of bowel function [(2.9+/-1.1) d vs. (3.6+/-1.5) d, P=0.032] and resumption of regular diet [(6.6+/-1.2) d vs. [(7.5+/-1.7) d, P=0.012], and shorter postoperative hospital stay [(7.7+/-1.4) d vs. (9.1+/-2.4) d, P=0.006]. The postoperative complication rate between the laparoscopic and open groups was not significantly different [18.5% (5/27) vs. 19.5% (8/41), P=0.464]. Oncological parameters were comparable between the two groups including lymph node harvested [(14.1+/-4.1) vs. (16.4+/-6.8), P=0.113], distal resection margin [(1.4+/-0.7) cm vs. (1.6+/-0.8) cm, P=0.311], and circumferential margin [7.4% (2/27) vs. 2.4% (1/41), P=0.709]. Local recurrence rates in laparoscopic and open groups were 7.4% (2/27) and 2.4% (1/41), and distant metastasis rates were 0 and 4.9% (2/41) respectively, and the differences were not significant (both P>0.05). CONCLUSIONS: Laparoscopic intersphincteric resection possesses same efficacy of open intersphincteric resection with less blood loss, shorter recovery time and hospital stay, and similar oncological outcomes, and no increased postoperative morbidity and mortality. PMID- 23801213 TI - [Prognostic analysis of 42 patients with gastric neuroendocrine carcinoma]. AB - OBJECTIVE: To investigate the clinicopathological characteristics and prognosis of gastric neuroendocrine carcinoma (NEC). METHODS: Clinical data of 42 patients with gastric neuroendocrine carcinoma admitted in the Cancer Hospital of Zhengzhou University between May 2006 and July 2011 were analyzed retrospectively. The prognostic factors were determined by Log-rank test. RESULTS: Gastric NEC was found in 42 (0.83%) of 5046 patients with gastric cancer during the same period, including 37 males and 5 females. The average age of the patients was 63 years old at the diagnosis. Forty patients underwent R0 resection and 2 patients R1 resection. Forty patients received routine adjuvant chemotherapy with fluorouracil plus oxaliplatin. The median follow-up duration was 26.0 months (range 4-70 months). The median survival was 25.0 months, and the overall 1-, 3-, 5-year survival rates were 71.4%, 26.2% and 11.9%, respectively. Univariate analysis revealed that maximum tumor diameter, tumor invasion depth, lymph node metastasis, lymphatic invasion, stage, and curability were associated with survival (all P<0.05). CONCLUSIONS: Gastric NEC is rare. Curative operation is essential for improving the prognosis, while the choice of comprehensive treatment after surgery should be optimized. PMID- 23801214 TI - [Application of titrated target-controlled infusion anesthesia in laparoscopic colorectal surgery]. AB - OBJECTIVE: To evaluate the effect of titrated target-controlled infusion with propofol and remifentanil on anesthetics consumption and anesthesia depth in patients undergoing elective laparoscopic colorectal surgery. METHODS: Sixty ASA I-III patients for elective laparoscopic colorectal surgery were enrolled. Titrated target-controlled infusion (TCI) with propofol and remifentanil was performed. Plasma concentration of the drugs was administered by titrated method to maintain bispectral index (BIS) in the range of 40-60 with systolic blood pressure (SBP) fluctuation within 20% of the basic value. BIS, SBP, plasma concentration of propofol and remifentanil were recorded at different time points. Awareness during operation was inquired postoperatively. RESULTS: During the entire anesthesia period, the blood pressure was stable and BIS was maintained less than 60. There was no awareness during operation. The plasma concentrations (95% confidence interval) for TCI of propofol and remifentanil were 2.55-2.65 mg/L and 4.09-4.26 MUg/L respectively when existing surgical stimulation during anesthesia, and the plasma target concentration of propofol was lower than the recommended dosages. CONCLUSION: Titrated target-controlled infusions with propofol and remifentanil for elective laparoscopic colorectal surgery can maintain proper anesthesia depth and reduce the drug consumption. PMID- 23801215 TI - [NF-kappab inhibitor PDTC enhances tumor necrosis factor alpha-induced apoptosis of gastric cancer cell SGC-7901]. AB - OBJECTIVE: To investigate the effect of PDTC (inhibitor of NF-kappab) on apoptosis of human gastric cancer cell line SGC-7901 induced by tumor necrosis factor alpha (TNF-alpha) and explore the related mechanisms. METHODS: After the treatment with different concentrations of PDTC, TNF-alpha or PDTC combined with TNF-alpha on gastric cancer cell line SGC-7901, the growth inhibition of SGC-7901 was measured by MTT assay. Hoechst was used to assess SGC-7901 cell apoptosis. The protein expressions of survivin and caspase-3 were detected by Western blot assay. RESULTS: The growth inhibition rate of SGC-7901 induced by PDTC (15, 30, 60, 100 MUmol/L) was (12.14+/-0.91)%, (20.00+/-1.11)%, (37.63+/-1.01)% and (41.46+/-1.07)%. Different concentrations of PDTC all inhibited the growth of SGC 7901 significantly (all P<0.01), The growth inhibition rate of SGC-7901 induced by 25 mg/L TNF-alpha was (2.38+/-0.67)%, which could not significantly inhibit the growth of SGC-7901 [control (1.50+/-0.81)%], while TNF-alpha of 50, 100, 150 mg/L could inhibit the growth of SGC-7901 significantly [(4.53+/-0.85)%, (4.43+/ 0.70)% and (4.74+/-1.07)%, all P<0.05]. PDTC (15 MUmol/L) combined with TNF-alpha (25, 50, 100, 150 mg/L) significantly increased the cell growth inhibition rate compared with TNF-alpha alone or PDTC 15 MUmol/L alone (all P<0.01). Hoechst assay showed that 100 mg/L TNF-alpha, 15 MUmol/L PDTC and combination of above two all induced cell apoptosis (P<0.01), and the combination group had significantly higher percentage of cell apoptosis (P<0.01). Survivin protein was significantly down-regulated in combination group as compared with single TNF alpha (100 mg/L) group, but was not significant down-regulated as compared with single PDTC (15 MUmol/L) group. Caspase-3 protein expression was significantly increased in combination group as compared with other two groups. CONCLUSION: PDTC can enhance the cell apoptosis induced by TNF-alpha, which may be associated with the blocking of TNF-alpha-activated NF-kappaB signaling pathway by PDTC, the down-regulation of survivin expression, and up-regulation of caspase-3 expression. PMID- 23801216 TI - [Experimental study of the impact of hyperlipidemia on the chemotherapy in colorectal cancer model]. AB - OBJECTIVE: To study the effect of hyperlipidemia on the prognosis and therapeutic response for colorectal cancer and to explore the associated mechanism. METHODS: The hyperlipidemic subcutaneous heterotopic colorectal cancer orthotopic transplant model of nude mice was established by feeding high fat diet and performing transplantation. Seventy mice were divided into 7 groups with 10 mice in each group. Two groups were used as pre-experiment. The remaining 5 groups included 4 high-fat groups (G1 to G4), and 1 normal-diet control group (G5). G1, G2, G3, G4, and G5 received normal saline, capecitabine, simvastatin, capecitabine plus simvastatin and capecitabine respectively for 3 weeks. Changes of tumor volume, tumor weight, tumor growth rate and blood lipid parameters (TC, TG, HDL, LDL, Lpa, apoA and apoB) were observed. RESULTS: In G1 to G4, TC, HDL, apoA, TG, LDL, Lpa, apoB increased, but only TC, HDL, apoA were significantly different as compared with G5 (P=0.020, P=0.001, P=0.001, P=0.911, P=0.249, P=0.681, P=0.053). The tumor in G1 grew fastest, and its growth rate was significantly different as compared with G2, G4, G5 except G3 (P=0.001, P=0.806, P=0.001, P=0.010). The tumor growth rate of G3 was lower than group G1, but higher than G2, G4, G5 with significant difference (P=0.001, P=0.002, P=0.016). The tumor of G5 grew faster than G2 and G4, but without significant differences (P=0.051, P=0.070). The tumor of G4 grew slowest without significant difference as compared to G2 (P=0.438). Compared with pre-administration, at the third week, the TC of G1 was increased [(3.8+/-0.4) mmol/L], while the other 4 groups decreased [G2 (2.8+/-1.8) mmol/L, G3 (2.9+/-0.7) mmol/L, G4 (1.4+/-0.9) mmol/L, G5 (2.1+/-0.2) mmol/L]. G4 decreased significantly (P=0.004). At the fifth week, the TC of all the 5 groups decreased, while the lipids of G4 were higher as compared to those at the third week. The TG, Lpa, ApoA were significantly decreased at the third week (all P<0.05), while no significant differences were found in HDL and apoB. CONCLUSIONS: A hyperlipidemia colon tumor model involving subcutaneous colon translocation and orthotopic transplantation of nude mice is successfully established. This model is an ideal research model for hyperlipidemia and colorectal cancer. The effect of capecitabine on tumors in hyperlipidemia groups is better as compared to normal diet group. The proliferation of tumor cells can increase serum total serum cholesterol. PMID- 23801217 TI - [Research progress on pathologic complete response after neoadjuvant chemoradiotherapy for locally advanced rectal cancer]. AB - Neoadjuvant chemoradiotherapy followed by surgery is the standard treatment for patients with locally advanced rectal cancer. Controversy on whether patients should receive radical surgery after pathological complete response (pCR) after neoadjuvant chemoradiotherapy has remained since pCR patients have shown favorable long-term outcome. Progress in multidisciplinary modalities has been made, including MRI, PET/CT imaging studies, genetic expression profiling, etc. The methods of predicting pCR response are inspiring. In this article, we review the methods for prediction and prognostic effect of pCR response when patients with locally advanced rectal cancer are treated with neoadjuvant chemoradiotherapy. PMID- 23801218 TI - [Progress of surgical managements in patients with local recurrent rectal cancer]. AB - Local recurrent rectal cancer (LRRC) is located in the pelvis with or without distant metastasis. It is life-threatening for patients with rectal cancer. Despite the addition of imaging technology, preoperative neoadjuvant therapy and total mesorectal excision, loco-regional relapse still occurs with an incidence as high as 10% in recent reports. Non-operative approaches to management such as radiotherapy and chemotherapy can only prolong survival time by 1 year. Improvements in surgical techniques, reconstruction methods and management of preoperative complications have helped increase the cure rate of patients with recurrent rectal cancer. Multimodality therapy based on surgery is the key of treating LRRC. This review article highlights the progress in surgical managements for local recurrent rectal cancer. PMID- 23801219 TI - Vildagliptin is Effective for Glycemic Control in Diabetic Patients Undergoing either Hemodialysis or Peritoneal Dialysis. AB - INTRODUCTION: Vildagliptin can be used in patients with type 2 diabetes mellitus and renal impairment. However, there have been few reports investigating the clinical effectiveness of vildagliptin in diabetic patients undergoing hemodialysis. No previous studies have evaluated the use of vildagliptin in patients undergoing peritoneal dialysis. The authors determined the usefulness of vildagliptin for treating type 2 diabetic patients receiving chronic dialysis, including peritoneal dialysis. METHODS: A retrospective study of ten diabetic patients undergoing peritoneal dialysis and five diabetic patients undergoing hemodialysis who were treated with 50 mg/day of vildagliptin was performed. Clinical parameters were investigated for a period of 6 months starting from the vildagliptin therapy. RESULTS: The hemoglobin A1c (HbA1c) levels were significantly reduced after baseline in both the peritoneal dialysis and hemodialysis groups, whereas the hemoglobin levels did not change during the follow-up period. The mean change in the HbA1c level (DeltaHbA1c) was -0.6 +/- 0.9% and -0.5 +/- 0.7% among the patients undergoing peritoneal dialysis and hemodialysis, respectively. The glycated albumin (GA) levels were also significantly reduced compared with baseline in the peritoneal dialysis group, although the serum albumin levels did not change. The mean change in the GA level (DeltaGA) was -3.4 +/- 3.1% and -2.1 +/- 2.5% among the patients undergoing peritoneal dialysis and hemodialysis, respectively. Stepwise multivariate analyses demonstrated the level of HbA1c at baseline to be significantly associated with the DeltaHbA1c and that the level of GA at baseline was significantly associated with the DeltaGA. CONCLUSION: Vildagliptin exhibits effectiveness in patients with type 2 diabetes mellitus undergoing peritoneal dialysis or hemodialysis. The degree of improvement in the HbA1c and GA levels was dependent on these levels at baseline, similar to the findings of previous reports of subjects without end-stage kidney disease. PMID- 23801220 TI - Morphological characterization of sprouting and intussusceptive angiogenesis by SEM in oral squamous cell carcinoma. AB - The word angiogenesis indicates the formation of new vascular segments from existing vessels such as capillaries and venules. Blood vessel formation in tumors is the result of rapid, disorganized vascular growth through two distinct mechanisms: sprouting and intussusceptive angiogenesis. The objective of this study was to elucidate the morphological aspects of these two vascular growth mechanisms in oral squamous cell carcinoma induced in hamster buccal pouch. Eight Syrian golden hamsters had their right buccal pouch treated with DMBA 0.5% and 10% carbamide peroxide for 90 days in order to produce squamous cell carcinoma in this site. Next, buccal pouches of the animals were submitted to the vascular corrosion technique and then analyzed by scanning electron microscopy. The vascular figures of sprouts were observed in the entire vascular network of the buccal pouches, as opposed to the intussusceptive angiogenesis that was predominantly observed in the sub-epithelial network. It was possible to differentiate the figures of sprouts from artifacts by the analysis of the blind ending of these structures. Intussusceptive angiogenesis was identified by the presence of holes trespassing the lumen of the capillaries. Vascular expansion occurred through intussusceptive angiogenesis in two ways: by the fusion of the pillars to form a new capillary and, by increasing the girth of the pillar to form meshes. The method of corrosion associated with scanning electron microscopy proved to be an excellent tool to study the two types of angiogenesis in oral squamous cell carcinoma in the hamster buccal pouch. PMID- 23801222 TI - Indium(III)-dicarboxylic microporous frameworks with high adsorption selectivity for CO2 over N2. AB - Two microporous metal-organic frameworks formulated as H2In3O(OH)3(1,3-bdc)3 (1) and HIn(1,4-bdc)2 (2) (bdc = benzenedicarboxylic) were designed and synthesized. Compound 2 shows a high adsorption selectivity for CO2 over N2 as well as a high stability. PMID- 23801221 TI - Plasticity of Schwann cells and pericytes in response to islet injury in mice. AB - AIMS/HYPOTHESIS: Islet Schwann (glial) cells and pericytes are the microorgan's accessory cells positioned at the external and internal boundaries facing the exocrine pancreas and endothelium, respectively, adjacent to the endocrine cells. Plasticity of glial cells and pericytes is shown in the glial scar formation after injury to the central nervous system. It remains unclear whether similar reactive cellular responses occur in insulitis. We applied three-dimensional (3D) histology to perform qualitative and quantitative analyses of the islet Schwann cell network and pericytes in normal, streptozotocin-injected (positive control of gliosis) and NOD mouse models. METHODS: Vessel painting paired with immunostaining of mouse pancreatic tissue was used to reveal the islet Schwann cells and pericytes and their association with vasculature. Transparent islet specimens were prepared by optical clearing to facilitate 3D confocal microscopy for panoramic visualisation of the tissue networks. RESULTS: In-depth microscopy showed that the islet Schwann cell network extends from the peri-islet domain into the core. One week after streptozotocin injection, we observed intra-islet perivascular gliosis and an increase in pericyte density. In early/moderate insulitis in the NOD mice, perilesional gliosis occurred at the front of the lymphocytic infiltration with atypical islet Schwann cell morphologies, including excessive branching and perivascular gliosis. Meanwhile, pericytes aggregated on the walls of the feeding arteriole at the peri- and intralesional domains with a marked increase in surface marker density. CONCLUSIONS/INTERPRETATION: The reactive cellular responses demonstrate plasticity and suggest a stop-gap mechanism consisting of the Schwann cells and pericytes in association with the islet lesion and vasculature when injury occurs. PMID- 23801223 TI - [Pre-registration experimentation: provisional knowledge?]. PMID- 23801224 TI - [The role of drug registries in the post-marketing surveillance]. AB - The aim of this article is to provide an introduction to issue of Recenti Progressi in Medicina, devoted to the role of drug registries in the post marketing surveillance. We first motivate the need to implement registries as a tool in promoting the appropriateness of drug use and acquiring additional information on the risk-benefit profile of drugs. Then, the different role that can be played by registries in comparison with prescription monitoring systems and observational studies is clarified. The presentation of some of the most relevant registries established in Italy since the end of the '90s, with the analysis of their strengths and weaknesses, helps to understand some of the crucial issues that should be taken into account before a new registry is adopted. Specifically, we deal with the relationship between objectives - of appropriateness, effectiveness and safety - and methods; the overlapping between drug-based registries and disease-based ones; the duration and extension of data collection, which may be either exhaustive or based on a sampling frame; the importance of ensuring the quality of the data and to minimize the number of subjects who are lost to follow-up; the importance of infrastructures, and of ad hoc funding, for the functioning of a registry; the independence in data analysis and publication of findings. PMID- 23801225 TI - [From the "note limitative" to the "registri AIFA"]. AB - In Italy, over the past 10 years, we have had a proliferation of registers associated with the reimbursement of drugs by the National Health Service. The regulatory path that made them grow comes from the so-called "note limitative" and treatment plans associated with the use of certain drugs. From these experiences different types of registries have been created that collect, at the time of prescription, information about the safety and appropriateness of use of medication where a benefit-risk profile in the general population is still not well defined. The critical analysis of some of these experiences can present positive and negative aspects associated with a regulatory reality now used in clinical practice nationwide. PMID- 23801226 TI - [Dermatology: experience with the disease registry for the treatment of psoriasis]. AB - INTRODUCTION: The Psocare project started in August 2005, integrating several activities: a survey of the management of psoriasis in Italy, the institution of a network of reference centres for psoriasis in Italy, the activation of a registry and outcome research project of moderate-to-severe psoriasis involving the centres. METHODS: Data collection is through a web-based data collection form. As of December 31, 2010, a total of 167 centres participated and provided data about a total of 20,170 patients. RESULTS: Etanercept and cyclosporine were the drugs most frequently prescribed at entry. Among the others, the outcome research study documented that drug survival was better for biologicals than for conventional treatment, that hospitalization rates were reduced in patients receiving biologicals as compared with patients on conventional treatment, and that body mass index influenced response to treatment irrespective of the treatment considered. DISCUSSION: The Psocare programme had a role in improving clinical management of psoriasis in Italy by establishing reference centres and by promoting long-term structured care for the disease. PMID- 23801227 TI - [ProMoFIA_Oncologic: monitoring project of the innovative oncology drugs in Abruzzo]. AB - INTRODUCTION: The unmet therapeutic needs lead to accelerated registration of new oncology drugs, even with incomplete information of the benefit-risk ratio. METHODS: In Italy the Onco-AIFA Register was established to monitor oncology drugs when used according to authorized indications and to assure their appropriate use in clinical practice. In the Abruzzo region, an observational longitudinal study (ProMoFIA_Oncologici) was performed to evaluate in standard clinical practice all patients treated with these new oncology drugs for any indication. RESULTS: During the period 2008-2011, 3435 patients were observed: in 62.2% of patients, the use of these drugs was eligible also for the Onco-AIFA Register; in 22.7% it was in-label but not monitored in the Onco-AIFA; in 15.1% the use was off-label. DISCUSSION: The study findings showed a widespread use of the new oncology drugs beyond the Onco-AIFA indications, as well as their off label use. PMID- 23801228 TI - [The register GiViTI about the use of the drug Xigris(r) in the Italian intensive care units]. AB - INTRODUCTION: The Register was aimed at monitoring the use, possible side effects, and clinical effectiveness of Xigris(r) - drotrecogin alfa (activated) - for the treatment of severe sepsis in Italian intensive care units (ICUs). METHODS: Data collection was performed using an online web form or a specific electronic module of the software Margherita, available only for the ICUs adhering to the GiViTI. Drug purchase information available for each center was used to identify and stimulate collaboration of non-compliant centers. Several countermeasures were taken to have the largest participation. RESULTS: We analyzed data from 1001 patients treated in 161 ICUs between July 2003 and September 2007, corresponding to 70% of all the patients who received the drug in that period. The off-label use of the drug was frequent: 15.6% of cases before and 27.3% after the label change with the introduction of timing restrictions. Treatment was temporarily interrupted in 10%, and definitely stopped in 25% of cases, after the occurrence of adverse events, the most frequent being bleeding. Severe bleeding occurred in 3.8% of patients. Multivariable analysis, which allowed an adjusted comparison with a control group, showed that treatment increased mortality among elective-surgery patients (OR 2.79, 95%CI 1.31-5.97). DISCUSSION: The results of this study and other evidences led the European Medicines Agency (EMA) to require a confirmatory trial in 2007. In October 2011 Ely-Lilly, the producer of the drug, announced the worldwide withdrawal from the market of Xigris(r), on the basis of the negative results of the confirmatory trial. CONCLUSIONS: The availability of purchase information is essential to carry out post-marketing drug surveillance studies, since it allows to identify and contact non-compliant centers. Actually, a representative sample of treated patients provides reliable information on the use, efficacy, and safety of the drug in daily clinical practice that could positively influence healthcare policies. PMID- 23801229 TI - [ADHD register: post-marketing evaluation of the benefit-risk profile of drugs and promotion of the appropriateness]. AB - INTRODUCTION: The Register was aimed at assessing the benefit-risk profile of the treatment of attention deficit hyperactivity disorder (ADHD) with atomoxetine and methylphenidate. METHODS: Post-marketing observational study, phase IV. Prescription medication to children and adolescents with ADHD aged between 6 and 18 years in the centres of reference for ADHD accredited by the Italian regions. RESULTS: In the period from September 2007 to October 2011, 1098 children and adolescents were treated with methylphenidate and 951 with atomoxetine. 411 (21.5%) patients are released from the register: 274 treated with atomoxetine and 167 with methylphenidate, with a greater risk of discontinuation for atomoxetine: RR 1.4 (1.3-1.6) p<0.001. The length of treatment at the time of removal from the register is 4.1 months for atomoxetine and 2 months for methylphenidate. Patients treated with atomoxetine are more likely to experience an adverse event compared to those treated with methylphenidate (RR 2.8; 1.9-4.2). The total number of serious adverse events observed was 110: 82 (75%) patients treated with atomoxetine and 28 (25%) individuals treated with methylphenidate. For 98 patients with serious adverse events, the adverse event led to the interruption of treatment with exit from the registry. The chance of a serious adverse event among those treated with atomoxetine compared to those with methylphenidate is RR 2.8 (1.8-4.2). There have been 14 cardiovascular events, all grown positively. 69 were found with a ECG alterations, with an increased risk for methylphenidate (RR 2.4; 1.4-4.2). The incidence of suicidal ideation was 4.5/1000 patients treated with atomoxetine. Hepatic alterations occurred with an incidence of 1/1000 subjects treated with methylphenidate and 4/1000 of those who received atomoxetine. DISCUSSION: The survey was carried out on a population which represents appropriately the paediatric population. The observed prevalence of ADHD corresponds to the expectation based on data from previous epidemiological investigations in Italy but considerably lower than what is reported in the international scientific literature. The rate of exposure to pharmacological treatments is similar to that of other European countries. PMID- 23801230 TI - [Human papillomavirus vaccine register]. AB - INTRODUCTION: We carried out an active surveillance of common adverse events occurring among women (9 to 26 years old) receiving human papillomavirus vaccine (Gardasil(r) and Cervarix(r)) in 9 Italian Regions. METHODS: Common adverse events occurring in the two weeks following each dose administration were collected using a structured diary. RESULTS: From August 2008 to September 2011, 12,066 immunised women (9,084 receiving Cervarix(r) and 2,982 Gardasil(r)) were included in the surveillance for a total of 29,494 administered doses. 53% of women concluded the vaccination cycle (74% with Gardasil(r) and 47% with Cervarix(r)). 61% of women experienced an adverse event after the administration of the first dose. The high proportion of adverse events reported is mainly due to the design of the study, since women were requested to report all events occurring after the vaccination; however the majority of events were mild and transient. DISCUSSION: As for all vaccines, and in particular for newly marketed ones, the surveillance of adverse events represents an essential step in the evaluation of a vaccination programme. PMID- 23801231 TI - [Registries for neurological drugs landscape]. AB - In Italy we can mention two experiences related to the use of registries for neurological drugs. The first one involved the use of cholinesterase inhibitors (donepezil, rivastigmine, galantamine) in the treatment of probable Alzheimer's dementia of mild-moderate level; the second, currently in progress, concerned the use of natalizumab for the treatment of multiple sclerosis. The registry of the use of cholinesterase inhibitors in Alzheimer's dementia produced an observational study, whereas the registry on the use of natalizumab in multiple sclerosis, a rare experience in the international, can be regarded as an opportunity not fully appreciated in terms of public health. Natalizumab is prescribed in current clinical practice in patients other than those included in registration studies. In this paper the two Italian experiences will be presented with the understanding that registries cannot make up for the lack of proper registration studies, but can provide, especially when they are conducted and planned as observational studies, new scientific evidence on the risk/benefit profile of the drugs in the real world. PMID- 23801232 TI - [Drug registries: post-marketing evaluation of the benefit-risk profile and promotion of appropriateness. The regional point of view]. AB - Italian Regions and the Italian regulatory agency share a common interest in promoting the appropriateness of drug use, containing drug expenditure and acquiring additional evidence on the effectiveness and safety of drugs. Drug registries can help attaining these objectives. Specifically, the registries implemented in Italy were able to cover the first two objectives, whereas some critical issues were raised on the third one. For instance, the data recorded in the registries are not available at regional level to conduct safety and effectiveness investigations. This is a paradox, when considering that drugs included in the registries have a risk-benefit profile that is only partially defined at the moment of marketing. Currently, researchers and regions can conduct epidemiological research (cohort and case control studies), on the basis of record-linkage procedures, on all drugs prescribed in general practice (which are older drugs with a better defined risk-benefit profile). The expected outcomes of registries should be more clearly defined: when the main aim is to promote appropriateness, the recording of only a very limited amount of data should be required (to avoid a bureaucratic burden on clinicians).The Italian centers of the ENCePP network might play an important role in planning and conducting drug registries: through the presence in the steering committees of the registries, and in conducting epidemiological studies that make the most of this powerful instrument. PMID- 23801233 TI - [Post-authorization research, registries, and drug development]. AB - In the last decade regulators, payers and health care providers tried to react to three major problems in drug development and drug use in clinical practice: the pharmaceutical R&D productivity crisis, the immaturity of benefit-risk profile for several newly approved drugs and the overall impact on economic sustainability of reimbursing new high cost drugs in their systems. The potentiality of create a continuum between the evidence requirements relevant for registration, for reimbursement and for post authorization research is clear. All different parties involved, like regulators, HTA agencies, scientific communities and manufacturers, are working to improve the knowledge profile of new drugs in order to anticipate the patient access to innovation, limiting or preventing the clinical and economical risks deriving from an incomplete safety and effectiveness profile. The Italian example of "New Drugs AIFA Registries", with or without the application of risk sharing schemes (cost sharing, pay for performance, etc.), introduced a new process and increased the sensitivity on this topic. However this might probably represents only a partial answer to the problem of how to set up the governance of coverage with evidence, drug utilization monitoring, comparative effectiveness research, outcome research programs and may be how to link them to access, pricing and reimbursement. The step change in post authorization research could be to "integrate" different sources and stakeholders in a wider and continuous approach, in a well designed and inclusive "second generation" HTA approach, where all resources (competencies, data, funding) will concur to increase the evidence profile and reduce the risks, and where any "evidence generation approach" is really compliant with the standard and rules of best research practices. PMID- 23801234 TI - [A perspective for the role of drug registries in the post-marketing surveillance]. AB - Drug registries are implemented after the authorization of new products and represent a tool for systematic collection of data aimed at obtaining additional knowledge on appropriateness, effectiveness and safety. The design of registries needs to be coherent with the main objective and a study protocol is required before the implementation. A registry aimed at the appropriateness of drug use should be primarily considered for high cost drugs when there is a risk, either for the patients' safety or for public expenditure, in using the drug outside the approved indications. Since the registry is a condition for the access to drugs, and all users are included, an extremely simplified data collection is required. However, the data should be available at regional level to allow record linkage procedures with other databases for conducting outcome studies. When registries are aimed at acquiring new information on the risk profile, the duration and the regional extension of data collection should be coherent with the expected incidence of events of interest. A great attention should be devoted in preventing that patients are lost to follow-up, since the reasons for being lost are frequently associated with harmful outcomes, such as adverse drug reactions. In a registry focused on effectiveness, the main aim consists in ascertaining the reasons (the prognostic factors), for possible discrepancies between premarketing studies and clinical practice. Taking into account the greater incidence of the expected events, there are fewer reasons for extending data collection to all users, whereas the main attention should focus on quality controls and the ascertainment of confounding factors. Given the relevance of the validity issues, in the set out of a registry it is important to think about ad hoc resources and the adequacy of infrastructures. As for any epidemiological study, an adequate qualification of the researcher/clinician in charge of conducting a registry should be guaranteed, together with independence in data analysis and freedom to publish all findings. PMID- 23801236 TI - Size measurement and flexion gap balancing in total knee arthroplasty--new benefits of the AttuneTM system? PMID- 23801237 TI - Using mixed methods effectively in prevention science: designs, procedures, and examples. AB - There is growing interest in using a combination of quantitative and qualitative methods to generate evidence about the effectiveness of health prevention, services, and intervention programs. With the emerging importance of mixed methods research across the social and health sciences, there has been an increased recognition of the value of using mixed methods for addressing research questions in different disciplines. We illustrate the mixed methods approach in prevention research, showing design procedures used in several published research articles. In this paper, we focused on two commonly used mixed methods designs: concurrent and sequential mixed methods designs. We discuss the types of mixed methods designs, the reasons for, and advantages of using a particular type of design, and the procedures of qualitative and quantitative data collection and integration. The studies reviewed in this paper show that the essence of qualitative research is to explore complex dynamic phenomena in prevention science, and the advantage of using mixed methods is that quantitative data can yield generalizable results and qualitative data can provide extensive insights. However, the emphasis of methodological rigor in a mixed methods application also requires considerable expertise in both qualitative and quantitative methods. Besides the necessary skills and effective interdisciplinary collaboration, this combined approach also requires an open-mindedness and reflection from the involved researchers. PMID- 23801238 TI - Association between lifestyle and physical activity level in the elderly: a study using doubly labeled water and simplified physical activity record. AB - PURPOSE: Physical activity level (PAL) is associated with all-cause mortality in the elderly. However, few studies have attempted to clarify the relationship between lifestyle and PAL in the elderly. This study aimed to examine the determinants of PAL in the elderly in terms of behavioral patterns and exercise intensity, and to validate the simplified physical activity record (sPAR). METHODS: Thirty healthy, elderly individuals, aged 64-87 years, participated in the study. Total energy expenditure (TEEDLW), physical activity energy expenditure (PAEEDLW), and PAL (PALDLW) were calculated based on doubly labeled water (DLW) and measured basal metabolic rate. Physical activity was recorded using the sPAR. RESULTS: PALDLW was significantly correlated with PAL estimated by sPAR (r = 0.588, P < 0.001). Good agreement was observed between TEEDLW (1,860 +/- 373 kcal/day) and TEE estimated by sPAR (1,854 +/- 377 kcal/day) (r = 0.825, P < 0.001). Good agreement was also observed between PAEEDLW (552 +/- 242 kcal/day) and PAEE estimated by sPAR (562 +/- 240 kcal/day) (r = 0.666, P < 0.001). The high PALDLW group had significantly shorter durations of 'sleeping time and rest periods' and 'daily life sedentary activities', and significantly longer durations of 'bicycling with moderate speed', 'housekeeping with standing', 'gymnastics, tai chi, stretching' and "swimming, hill climbing, fast jogging" than the low PAL group (P < 0.05). CONCLUSIONS: The sPAR provides valid estimates of TEE and PAEE in the healthy elderly. The results suggest that engaging in housekeeping or sports activities for longer and being less sedentary may increase PALDLW in healthy elderly individuals. PMID- 23801239 TI - Small intestinal lymphoma in a post-renal transplant patient: a rare case with late presentation. PMID- 23801240 TI - Effects of histidine-rich glycoprotein on cerebral blood vessels. AB - Delayed cerebral vasospasm is thought to be caused by factors released from a subarachnoid blood clot. Because vasospasm occurs several days after hemorrhage, we hypothesized that clotted blood releases vasoactive factors as it ages. Targeted proteomics identified histidine-rich glycoprotein (HRG) as a potentially vasoactive factor released within the first 72 hours of clot formation. In vitro studies revealed that HRG caused moderate (~30%) dilation of cannulated cerebral arterioles and proliferation of cerebrovascular endothelial cells. We conclude that HRG released from clotted blood, while unlikely to contribute to cerebral vasospasm, might provide important vasodilatory or angiogenic stimuli after hemorrhagic stroke. PMID- 23801241 TI - Polynitroxylated-pegylated hemoglobin attenuates fluid requirements and brain edema in combined traumatic brain injury plus hemorrhagic shock in mice. AB - Polynitroxylated-pegylated hemoglobin (PNPH), a bovine hemoglobin decorated with nitroxide and polyethylene glycol moieties, showed neuroprotection vs. lactated Ringer's (LR) in experimental traumatic brain injury plus hemorrhagic shock (TBI+HS). HYPOTHESIS: Resuscitation with PNPH will reduce intracranial pressure (ICP) and brain edema and improve cerebral perfusion pressure (CPP) vs. LR in experimental TBI+HS. C57/BL6 mice (n=20) underwent controlled cortical impact followed by severe HS to mean arterial pressure (MAP) of 25 to 27 mm Hg for 35 minutes. Mice (n=10/group) were then resuscitated with a 20 mL/kg bolus of 4% PNPH or LR followed by 10 mL/kg boluses targeting MAP>70 mm Hg for 90 minutes. Shed blood was then reinfused. Intracranial pressure was monitored. Mice were killed and %brain water (%BW) was measured (wet/dry weight). Mice resuscitated with PNPH vs. LR required less fluid (26.0+/-0.0 vs. 167.0+/-10.7 mL/kg, P<0.001) and had a higher MAP (79.4+/-0.40 vs. 59.7+/-0.83 mm Hg, P<0.001). The PNPH treated mice required only 20 mL/kg while LR-resuscitated mice required multiple boluses. The PNPH-treated mice had a lower peak ICP (14.5+/-0.97 vs. 19.7+/-1.12 mm Hg, P=0.002), higher CPP during resuscitation (69.2+/-0.46 vs. 45.5+/-0.68 mm Hg, P<0.001), and lower %BW vs. LR (80.3+/-0.12 vs. 80.9+/-0.12%, P=0.003). After TBI+HS, resuscitation with PNPH lowers fluid requirements, improves ICP and CPP, and reduces brain edema vs. LR, supporting its development. PMID- 23801242 TI - BOLD consistently matches electrophysiology in human sensorimotor cortex at increasing movement rates: a combined 7T fMRI and ECoG study on neurovascular coupling. AB - Blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) is widely used to measure human brain function and relies on the assumption that hemodynamic changes mirror the underlying neuronal activity. However, an often reported saturation of the BOLD response at high movement rates has led to the notion of a mismatch in neurovascular coupling. We combined BOLD fMRI at 7T and intracranial electrocorticography (ECoG) to assess the relationship between BOLD and neuronal population activity in human sensorimotor cortex using a motor task with increasing movement rates. Though linear models failed to predict BOLD responses from the task, the measured BOLD and ECoG responses from the same tissue were in good agreement. Electrocorticography explained almost 80% of the mismatch between measured- and model-predicted BOLD responses, indicating that in human sensorimotor cortex, a large portion of the BOLD nonlinearity with respect to behavior (movement rate) is well predicted by electrophysiology. The results further suggest that other reported examples of BOLD mismatch may be related to neuronal processes, rather than to neurovascular uncoupling. PMID- 23801243 TI - Perfluorocarbons enhance a T2*-based MRI technique for identifying the penumbra in a rat model of acute ischemic stroke. AB - Accurate imaging of ischemic penumbra is crucial for improving the management of acute stroke patients. T2* magnetic resonance imaging (MRI) combined with a T2*oxygen challenge (T2*OC) is being developed to detect penumbra based on changes in blood deoxyhemoglobin. Using 100% O2, T2*OC-defined penumbra exhibits ongoing glucose metabolism and tissue recovery on reperfusion. However, potential limitations in translating this technique include a sinus artefact in human scans with delivery of 100% OC and relatively small signal changes. Here we investigate whether an oxygen-carrying perfluorocarbon (PFC) emulsion can enhance the sensitivity of the technique, enabling penumbra detection with lower levels of inspired oxygen. Stroke was induced in male Sprague-Dawley rats (n=17) with ischemic injury and perfusion deficit determined by diffusion and perfusion MRI, respectively. T2* signal change was measured in regions of interest (ROIs) located within ischemic core, T2*OC-defined penumbra and equivalent contralateral areas during 40% O2+/-prior PFC injection. Region of interest analyses between groups showed that PFC significantly enhanced the T2* response to 40% O2 in T2* defined penumbra (mean increase of 10.6+/-2.3% compared to 5.6+/-1.5% with 40% O2, P<0.001). This enhancement was specific to the penumbra ROI. Perfluorocarbon emulsions therefore enhances the translational potential of the T2*OC technique for identifying penumbra in acute stroke patients. PMID- 23801244 TI - Omega-3 polyunsaturated fatty acid supplementation improves neurologic recovery and attenuates white matter injury after experimental traumatic brain injury. AB - Dietary supplementation with omega-3 (omega-3) fatty acids is a safe, economical mean of preventive medicine that has shown protection against several neurologic disorders. The present study tested the hypothesis that this method is protective against controlled cortical impact (CCI). Indeed, mice fed with omega-3 polyunsaturated fatty acid (PUFA)-enriched diet for 2 months exhibited attenuated short and long-term behavioral deficits due to CCI. Although omega-3 PUFAs did not decrease cortical lesion volume, these fatty acids did protect against hippocampal neuronal loss after CCI and reduced pro-inflammatory response. Interestingly, omega-3 PUFAs prevented the loss of myelin basic protein (MPB), preserved the integrity of the myelin sheath, and maintained the nerve fiber conductivity in the CCI model. omega-3 PUFAs also directly protected oligodendrocyte cultures from excitotoxicity and blunted the microglial activation-induced death of oligodendrocytes in microglia/oligodendrocyte cocultures. In sum, omega-3 PUFAs elicit multifaceted protection against behavioral dysfunction, hippocampal neuronal loss, inflammation, and loss of myelination and impulse conductivity. The present report is the first demonstration that omega-3 PUFAs protect against white matter injury in vivo and in vitro. The protective impact of omega-3 PUFAs supports the clinical use of this dietary supplement as a prophylaxis against traumatic brain injury and other nervous system disorders. PMID- 23801245 TI - Androgen and PARP-1 regulation of TRPM2 channels after ischemic injury. AB - The calcium-permeable transient receptor potential M2 (TRPM2) ion channel was recently demonstrated to have a sexually dimorphic contribution to ischemic brain injury, with inhibition or knockdown of the channel protecting male brain preferentially. We tested the hypothesis that androgen signaling is required for this male-specific cell-death pathway. Additionally, we tested the hypothesis that differential activation of the enzyme poly (ADP-ribose) polymerase-1 (PARP 1) is responsible for male-specific TRPM2 channel activation and neuronal injury. We observed that administration of the TRPM2 inhibitor clotrimazole (CTZ) 2 hours after onset of ischemia reduced infarct volume in male mice and that protection from ischemic damage by CTZ was abolished by removal of testicular androgens (castration; CAST) and rescued by androgen replacement. Male PARP-1 knockout mice had reduced ischemic damage compared with WT mice and inhibition of TRPM2 with CTZ failed to reduce infarct size. Lastly, we observed that ischemia increased PARP activity in the peri-infarct region of male mice to a greater extent than female mice and the difference was abolished in CAST male mice. Data presented in the current study indicate that TRPM2-mediated neuronal death in the male brain requires intact androgen signaling and PARP-1 activity. PMID- 23801247 TI - Photocycloadditions of substituted oxazoles with isoquinoline-1,3,4-trione--chemo , regio-, diastereoselectivities and transformation of the photocycloadducts. AB - Photoreactions of isoquinoline-1,3,4-triones and oxazoles with different substituents were found to give different chemo-, regio- and diastereoselectivities. The substituent at the C5 on the oxazole ring showed great influence on the chemoselectivity of the photoreaction as well as on the transformation of the photocycloadducts. The 2-methyl-5-methoxyoxazoles reacted with isoquinoline-1,3,4-triones rapidly and gave spirooxetanes with high regio- and diastereo-selectivity. Diastereoselectivity in the reaction of 2-phenyl-5 methoxyoxazoles with isoquinoline-1,3,4-triones was relevant to the substituent on the 4-position on the oxazole ring. Replacement of the 5-methoxy group with 5 methyl or 5-phenyl resulted in significant decrease on the reactivity of the oxazole as well as change on the diastereoselectivity in photocycloaddition with isoquinoline-1,3,4-triones. Acid-mediated transformations of the photocycloadduct spirooxetanes was found to give different type of products including beta-hydroxy alpha-aminocarbonyl compounds and spiroisoquinolineoxazolines under different reaction conditions. Substituents on the spirooxetanes as well as the type and amount of acid used in the reaction played important roles in determining the type and diastereoselectivity of the products in the transformations. PMID- 23801246 TI - Chronic rapamycin restores brain vascular integrity and function through NO synthase activation and improves memory in symptomatic mice modeling Alzheimer's disease. AB - Vascular pathology is a major feature of Alzheimer's disease (AD) and other dementias. We recently showed that chronic administration of the target-of rapamycin (TOR) inhibitor rapamycin, which extends lifespan and delays aging, halts the progression of AD-like disease in transgenic human (h)APP mice modeling AD when administered before disease onset. Here we demonstrate that chronic reduction of TOR activity by rapamycin treatment started after disease onset restored cerebral blood flow (CBF) and brain vascular density, reduced cerebral amyloid angiopathy and microhemorrhages, decreased amyloid burden, and improved cognitive function in symptomatic hAPP (AD) mice. Like acetylcholine (ACh), a potent vasodilator, acute rapamycin treatment induced the phosphorylation of endothelial nitric oxide (NO) synthase (eNOS) and NO release in brain endothelium. Administration of the NOS inhibitor L-NG-Nitroarginine methyl ester reversed vasodilation as well as the protective effects of rapamycin on CBF and vasculature integrity, indicating that rapamycin preserves vascular density and CBF in AD mouse brains through NOS activation. Taken together, our data suggest that chronic reduction of TOR activity by rapamycin blocked the progression of AD like cognitive and histopathological deficits by preserving brain vascular integrity and function. Drugs that inhibit the TOR pathway may have promise as a therapy for AD and possibly for vascular dementias. PMID- 23801248 TI - Polysomnographic evaluation of propofol-induced sleep in patients with respiratory sleep disorders and controls. AB - OBJECTIVES/HYPOTHESIS: The treatment for obstructive sleep apnea syndrome (OSAS) depends on correct localization of upper airway obstruction, exception made for continuous positive airway pressure (CPAP). Drug-induced sleep endoscopy (DISE) with propofol allows this evaluation, but the drug effects on sleep parameters are not yet well established. Our objective was to study by polysomnography (PSG) whether propofol would change sleep parameters by means of a prospective cross sectional clinical study in a tertiary hospital. STUDY DESIGN: Thirty non-obese subjects (6 controls and 24 OSAS patients) underwent two daytime PSGs, one with DISE and the other without DISE. METHODS: During DISE exam, propofol was administered intravenously in continuous infusion using a target-controlled infusion pump. The parameters evaluated were: presence of snoring, apnea-hypopnea index (AHI), oxyhemoglobin saturation (SaO2), and sleep macroarchitecture. RESULTS: Snoring was absent in all healthy subjects during DISE sleep with propofol, and present in all OSAS patients (100%). AHI and mean SaO2 showed no statistical difference between the two tests, with and without propofol. However, minimum SaO2 was significantly lower during propofol infusion (88.64 for without vs. 85.04 for with propofol; P < 0.01). Regarding sleep macroarchitecture, the tests with propofol significantly increased N3 sleep and totally extinguished REM sleep (P < 0.005). CONCLUSIONS: The results demonstrate that propofol significantly changes sleep macroarchitecture. However, the main respiratory parameters, AHI and mean SaO2 , remained unaffected. Thus, in order to determine the sites of obstruction, propofol DISE used with target-controlled infusion proved to be an effective drug for endoscopic evaluation of patients with OSAS. PMID- 23801249 TI - Antimicrobial activity of the synthetic peptide scolopendrasin ii from the centipede Scolopendra subspinipes mutilans. AB - The centipede Scolopendra subpinipes mutilans is a medicinally important arthropod species. However, its transcriptome is not currently available and transcriptome analysis would be useful in providing insight into a molecular level approach. Hence, we performed de novo RNA sequencing of S. subpinipes mutilans using next-generation sequencing. We generated a novel peptide (scolopendrasin II) based on a SVM algorithm, and biochemically evaluated the in vitro antimicrobial activity of scolopendrasin II against various microbes. Scolopendrasin II showed antibacterial activities against gram-positive and negative bacterial strains, including the yeast Candida albicans and antibiotic resistant gram-negative bacteria, as determined by a radial diffusion assay and colony count assay without hemolytic activity. In addition, we confirmed that scolopendrasin II bound to the surface of bacteria through a specific interaction with lipoteichoic acid and a lipopolysaccharide, which was one of the bacterial cell-wall components. In conclusion, our results suggest that scolopendrasin II may be useful for developing peptide antibiotics. PMID- 23801250 TI - Taxol production by an endophytic fungus, Fusarium redolens, isolated from Himalayan yew. AB - Different endophytic fungi isolated from Himalayan Yew plants were tested for their ability to produce taxol. The BAPT gene (C-13 phenylpropanoid side chain CoA acetyl transferase) involved in the taxol biosynthetic pathway was used as a molecular marker to screen taxol-producing endophytic fungi. Taxol extracted from fungal strain TBPJ-B was identified by HPLC and MS analysis. Strain TBPJ-B was identified as Fusarium redolens based on the morphology and internal transcribed spacer region of nrDNA analysis. HPLC quantification of fungal taxol showed that F. redolens was capable of producing 66 MUg/l of taxol in fermentation broth. The antitumour activity of the fungal taxol was tested by potato disc tumor induction assay using Agrobacterium tumefaciens as the tumor induction agent. The present study results showed that PCR amplification of genes involved in taxol biosynthesis is an efficient and reliable method for prescreening taxol-producing fungi. We are reporting for the first time the production of taxol by F. redolens from Taxus baccata L. subsp. wallichiana (Zucc.) Pilger. This study offers important information and a new source for the production of the important anticancer drug taxol by endophytic fungus fermentation. PMID- 23801251 TI - Cloning and mRNA expression analysis of the gene encoding phenylalanine ammonia lyase of the ectomycorrhizal fungus Tricholoma matsutake. AB - The ectomycorrhizal fungus Tricholoma matsutake grows symbiotically with Pinus densiflora. Phenylalanine ammonia-lyase (E.C. 4.3.1.24) catalyzes the conversion of L-phenylalanine to trans-cinnamic acid. The role of fungal phenylalanine ammonia-lyase, however, has not been clear until now. In this study, the gene encoding phenylalanine ammonia-lyase (PAL), which was isolated from T. matsutake, was cloned and characterized. The PAL gene (tmpal) consists of 2,160 nucleotides, coding for a polypeptide containing 719 amino acid residues. The deduced amino acid sequence of tmpal from T. matsutake shows high identity (70%) with that from Laccaria bicolor. Comparative analysis of the PAL genes among T. matsutake and other species of the class Agaricomycetes showed that both active sites and binding sites were significantly conserved among these genes. The transcriptional analysis of the PAL gene revealed a differential gene expression pattern depending on the developmental stages (mycelium, primordium, stipe, pileus, and gills) of T. matsutake. These results suggest that the PAL gene in T. matsutake plays an important role in multiple physiological functions. PMID- 23801252 TI - Enhanced biofuel production from high-concentration bioethanol wastewater by a newly isolated heterotrophic microalga, Chlorella vulgaris LAM-Q. AB - Microalgal biofuel production from wastewater has economic and environmental advantages. This article investigates the lipid production from high chemical oxygen demand (COD) bioethanol wastewater without dilution or additional nutrients, using a newly isolated heterotrophic microalga, Chlorella vulgaris LAM Q. To enhance lipid accumulation, the combined effects of important operational parameters were studied via response surface methodology. The optimal conditions were found to be temperature of 22.8C, initial pH of 6.7, and inoculum density of 1.2 * 10(8) cells/ml. Under these conditions, the lipid productivity reached 195.96 mg/l/d, which was markedly higher than previously reported values in similar systems. According to the fatty acid composition, the obtained lipids were suitable feedstock for biodiesel production. Meanwhile, 61.40% of COD, 51.24% of total nitrogen, and 58.76% of total phosphorus were removed from the bioethanol wastewater during microalgal growth. In addition, 19.17% of the energy contained in the wastewater was transferred to the microalgal biomass in the fermentation process. These findings suggest that C. vulgaris LAMQ can efficiently produce lipids from high-concentration bioethanol wastewater, and simultaneously performs wastewater treatment. PMID- 23801253 TI - Therapeutic effects of bacteriophages against Salmonella gallinarum infection in chickens. AB - In this study the isolation and characterization of three bacteriophages (ST4, L13, and SG3) infecting Salmonella gallinarum were carried out. They were further tested for their in vivo efficacy in phage therapy. All three phages belong to the Siphoviridae family with isometric heads and non-contractile tails. They have a broad host range among serovars of Salmonella enterica. The burst sizes were observed to be 1670, 80, and 28 for ST4, L13, and SG3, respectively. The in vivo efficacy of the phages was tested in chickens. Layer chickens were challenged with S. gallinarum, whereas contact chickens were cohabited without direct challenge. Each bacteriophage was orally inoculated in the form of feed additives. Mortality was observed and S. gallinarum was periodically re-isolated from the livers, spleens, and cecums of the chickens. Bacterial re-isolation from the organs and mortality decreased significantly in both challenged and contact chickens treated with the bacteriophages compared with untreated chickens serving as the control. The three bacteriophages may be effective alternatives to antibiotics for the control of fowl typhoid disease in chickens. PMID- 23801255 TI - A DFT study on the sensing behavior of a BC2N nanotube toward formaldehyde. AB - We investigated the viability of using a BC2N nanotube to detect formaldehyde (H2CO) molecule by means of B3LYP and M06 density functionals. The results indicate that the molecule is weakly adsorbed on the intrinsic BC2N nanotube releasing energy of 0.8 kcal mol(-1) (at B3LYP/6-31G(d)) without significant effect on the HOMO-LUMO energy gap and electrical conductivity of the tube. Thus, H2CO cannot be detected using this intrinsic nanotube. To overcome this problem, a carbon atom of the tube wall was substituted by a Si atom. It was demonstrated that the Si-doped tube cannot only strongly adsorb the H2CO molecule, but also may effectively detect its presence because of the increase in the electric conductivity of the tube. PMID- 23801254 TI - Theoretical study on the antioxidant properties of 2'-hydroxychalcones: H-atom vs. electron transfer mechanism. AB - The free radical scavenging activity of six 2'-hydroxychalcones has been studied in gas phase and solvents using the density functional theory (DFT) method. The three main working mechanisms, hydrogen atom transfer (HAT), stepwise electron transfer-proton-transfer (ET-PT) and sequential-proton-loss-electron-transfer (SPLET) have been considered. The O-H bond dissociation enthalpy (BDE), ionization potential (IP), proton affinity (PA) and electron transfer energy (ETE) parameters have been computed in gas phase and solvents. The theoretical results confirmed the important role of the B ring in the antioxidant properties of hydroxychalcones. In addition, the calculated results matched well with experimental values. The results suggested that HAT would be the most favorable mechanism for explaining the radical-scavenging activity of hydroxychalcone in gas phase, whereas SPLET mechanism is thermodynamically preferred pathway in aqueous solution. PMID- 23801256 TI - A head-to-head comparison of aripiprazole and risperidone for safety and treating autistic disorders, a randomized double blind clinical trial. AB - Aripiprazole and risperidone are the only FDA approved medications for treating irritability in autistic disorder, however there are no head-to-head data comparing these agents. This is the first prospective randomized clinical trial comparing the safety and efficacy of these two medications in patients with autism spectrum disorders. Fifty nine children and adolescents with autism spectrum disorders were randomized to receive either aripiprazole or risperidone for 2 months. The primary outcome measure was change in Aberrant Behavior Checklist (ABC) scores. Adverse events were assessed. Aripiprazole as well as risperidone lowered ABC scores during 2 months. The rates of adverse effects were not significantly different between the two groups. The safety and efficacy of aripiprazole (mean dose 5.5 mg/day) and risperidone (mean dose 1.12 mg/day) were comparable. The choice between these two medications should be on the basis of clinical equipoise considering the patient's preference and clinical profile. PMID- 23801257 TI - Sibling characteristics and early onset psychoses among the young adolescent patient population. AB - We investigated the relationship between sibling characteristics (birth order, number of siblings and birth interval) and early onset psychosis among adolescent psychiatric inpatients and their mentally healthy controls. A short birth interval of 1-2 years to the nearest sibling was more common among adolescents with schizophrenia and schizophrenia spectrum psychoses and differed significantly from healthy controls (p = 0.037). A large family (at least 6 children in family) was more common among adolescents with psychosis NOS than among healthy controls (p = 0.035). The birth order among young adolescents with any subtype of psychosis did not differ from healthy controls. Sibling characteristics may be contributing factors in the multifactorial aetiology of schizophrenia and other psychotic disorders. Further studies are required to determine whether sibling characteristics reflect other unknown environmental factors. PMID- 23801259 TI - [Antibiotics: are continuous infusions more effective?]. PMID- 23801260 TI - [CT-colonography for primary diagnostics of symptoms suggestive of colorectal cancer?--Endoscopic diagnostics remain no. 1]. PMID- 23801258 TI - Prion-like propagation of protein aggregation and related therapeutic strategies. AB - Many neurodegenerative diseases are characterized by the progressive accumulation of aggregated protein. Recent evidence suggests the prion-like propagation of protein misfolding underlies the spread of pathology observed in these diseases. This review traces our understanding of the mechanisms that underlie this phenomenon and discusses related therapeutic strategies that derive from it. PMID- 23801261 TI - [Characterization and economic impact of medical patients presenting at the emergency department of an university hospital]. AB - BACKGROUND: The number of patients in German emergency departments has been rising for years. This means additional need of staff and infrastructure for hospitals. METHODS: In this monocentric retrospective analysis the patient population of the central emergency department (ZNA) at the university hospital Frankfurt was investigated. Major symptoms, diagnoses with respect to diagnose related groups and modes of admission to the emergency department have been analyzed. RESULTS: During 3 months, a total of 7376 patients presented to the ZNA. Analysis focused on 2186 patients referred to the department of internal medicine: most patients presented spontaneously (50.6%), 38.2% were admitted by ambulance services, only 9.7% were admitted by a primary physician. 44.9% of these patients were hospitalized, mainly with cardiological, pneumological and gastroenterological disorders. The predominant major symptoms were acute chest pain (15.4%), abdominal pain (7.1%) and syncope or collapse (6.1%). Patients hospitalized via ZNA contributed 31.9% of the total revenues of internal medicine departments. 31.7% of all hospitalized patients were admitted to the hospital by the ZNA. CONCLUSION: Emergency departments become more and more a regular part of ambulatory patients health care and contribute efficiently to the economic revenue of hospitals. PMID- 23801262 TI - [Successful closure of a postoperative esophagobronchial fistula following esophageal resection using fibrin glue]. AB - HISTORY AND INTERVENTION: A 52-year-old female patient underwent open abdominothoracic cardia and esophageal resection with gastric transposition because of histologically diagnosed Barrett metaplasia with "high-grade" intraepithelial neoplasia (HGIEN) and parts of an invasive adenocarcinoma. The anastomotic insufficiency on the 10th postoperative day including an esophagobronchial fistula prompted to a subsequent surgical re-intervention with suture of the fistula, lavage and additional drainage, an endoscopic stenting of the fistula from esophageal site, as well as repeated (n = 22) bronchoscopic applications of fibrin glue (1-3 ml each) into the lumen of the fistula after each bronchoscopic lavage of the fistula until the complete closure was achieved. The changeful clinical course of 77 days on the surgical ICU was characterized by secondary complications such as pneumonia, mediastinitis and respiratory insufficiency with long-term artificial respiration and creation of a percutaneous dilatation tracheotomy. CONCLUSION: The application of fibrin glue can be considered a promising, minimally invasive therapeutic option in the management of postoperative fistula after esophageal resection, which requires expertise in decision-making and the finding-specific approach, in particular, if indicated inital steps of the sequential complication management such as surgical re-intervention and conventional endoscopic measures (stenting, Endo-VAC[ sponge]) do not provide great therapeutic potential any more due to the prolonged postoperative time course and the unfavorable local findings. In the presented case, modes of an assisted artificial respiration with low pressure and short phases of apnoe after fibrin glue application were the crucial predictions for an initial and favorable adhesion of this glue and finally for a successful sealing resulting in a sufficient closure of the fistula. PMID- 23801263 TI - [Renal failure and recurrent episodes of flash pulmonary edema in a 70-year-old patient]. AB - HISTORY AND ADMISSION FINDINGS: We report on a patient presenting with renal failure who developed mutliple episodes of flash pulmonary edema. INVESTIGATIONS: Volume retention due to ischemic nephropathy was found to be the cause. DIAGNOSIS, TREATMENT AND COURSE: She was diagnosed to have a high grade renal artery stenosis in a functional solitary kidney and underwent percutaneous angioplasty. After being anuric and dialysis-dependent, she regained her kidney function leading to resolution of the volume retention and could be weaned from dialysis. CONCLUSIONS: Ischemic nephropathy is often accompanied by recurrent episodes of flash pulmonary edema and responds well to an interventional treatment. PMID- 23801264 TI - [Thyroid hormone treatment]. AB - The autoimmune thyroiditis with overt or subclinical primary hypothyroidism is the most common endocrine disease. Although the diagnosis of hypothyroidism is not difficult, the question when a replacement therapy in subclinical hypothyroidism should be initiated is still under discussion. In patients with overt hypothyroidism defined as low FT4 and elevated TSH or TSH > 10 mU/L a replacement with levothyroxine is clearly indicated. In patients with subclinical hypothyroidism defined as a TSH between 4 and 10 mU/L and normal FT4, the treatment with Levothyroxine depends on the underlying disease and symptoms. Levothyroxine is a prohormone with is activated by deiodination in the organs to triiodothyronine. Therefore, levothyroxine for replacement therapy is mainly used. Some patients, however, do not feel well with this treatment and therefore studies with a combination therapy of levothyroxine and triiodothyronine had been performed and it could be shown that this might be related to a polymorphism in type 2 deiodinase in some patients, with the consequence of lower intracellular triodothyronine formation. In women on levothyroxine replacement therapy getting pregnant, the demand of levothyroxine increases up to 25-50 ug, especially in the early weeks of pregnancy. It also has to be considered that the resorption of levothyroxine depends on normal stomach acid and therefore patients on acid blockers or atrophic gastritis require higher dosages of levothyroxine. Only patients after thyroidectomy because of differentiated thyroid carcinoma with higher grad of malignancy need a TSH suppressive therapy, those with occult papillary thyroid carcinoma the TSH should be within the low normal range. PMID- 23801265 TI - [Current therapy of hepatocellular carcinoma with special consideration of new and multimodal treatment concepts]. AB - The incidence of hepatocellular carcinoma (HCC) is increasing worldwide due to the growing number of hepatitis C related HCCs. In more than 80% of the patients, HCC arises in a cirrhotic liver. Furthermore, more than half of the patients have an advanced Child-Pugh score or an inoperable tumor stage at the initial diagnosis. Recommendations for the treatment of HCC by national and international guidelines rely on the BCLC ("Barcelona Clinic for Liver Cancer") algorithm. Depending on the stage of liver function and tumor disease it recommends resection, liver transplantation, radiofrequency thermal ablation (RFA), transarterial chemoembolisation (TACE), systemic therapy with sorafenib or best supportive care, but does neither take into consideration combination of therapies nor new therapy modalities. However, there is increasing evidence that combinations i. e. sorafenib with TACE or combination of locoregional techniques enhance effectivity and tumor control compared to monotherapies. TACE with drug eluting beads, selective internal radiotherapy (SIRT) and new locoregional therapy procedures like microwave ablation (MWA) are further promising therapeutic approaches. Patients with HCC should be discussed in a local tumor board in order to provide the optimal and most individual way of treatment. PMID- 23801266 TI - Thrombocytopenia in very low birth weight infants. PMID- 23801267 TI - Accumulation of the cyclobutane thymine dimer in defined sequences of free and nucleosomal DNA. AB - Photochemical cyclobutane dimerization of adjacent thymines generates the major lesion in DNA caused by exposure to sunlight. Not all nucleotide sequences and structures are equally susceptible to this reaction or its potential to create mutations. Photostationary levels of the cyclobutane thymine dimer have now been quantified in homogenous samples of DNA reconstituted into nucleosome core particles to examine the basis for previous observations that such structures could induce a periodicity in dimer yield when libraries of heterogeneous sequences were used. Initial rate studies did not reveal a similar periodicity when a homogenous core particle was analyzed, but this approach examined only formation of this photochemically reversible cyclobutane dimer. Photostationary levels result from competition between dimerization and reversion and, as described in this study, still express none of the periodicity within two alternative core particles that was evident in heterogeneous samples. Such periodicity likely arises from only a limited set of sequences and structural environments that are not present in the homogeneous and well-characterized assemblies available to date. PMID- 23801268 TI - Symmetric bursting behaviors in the generalized FitzHugh-Nagumo model. AB - In the current paper, we have investigated the generalized FitzHugh-Nagumo model. We have shown that symmetric bursting behaviors of different types could be observed in this model with an appropriate recovery term. A modified version of this system is used to construct bursting activities. Furthermore, we have shown some numerical examples of delayed Hopf bifurcation and canard phenomenon in the symmetric bursting of super-Hopf/homoclinic type near its super-Hopf and homoclinic bifurcations, respectively. PMID- 23801269 TI - Racial/Ethnic disparities in depression and its theoretical perspectives. AB - The purpose of this review is to look at racial/ethnic disparities in the diagnosis of depression and its treatment and to explain the dynamics and causes of these racial/ethnic disparities in depression by looking at several theories, such as perceived racism, cultural competency, and other theories. Perceived racism is that the perceptions of an environmental stimulus as being racist affects the coping responses of ethnic/racial minorities, which alters psychological and physiological stress responses, and finally affects health outcomes negatively. A lower level of cultural competence can lead to health disparities. In addition, lower socioeconomic status and health care providers' beliefs and behaviors about patients' race/ethnicity and class can affect depressive symptoms as well as diagnosis and treatment. In order to reduce these racial/ethnic disparities in depression, diverse interventions should be developed to improve depression outcomes for ethnic minority populations based on these theoretical perspectives. PMID- 23801270 TI - Anticancer effect of Tamarix gallica extracts on human colon cancer cells involves Erk1/2 and p38 action on G2/M cell cycle arrest. AB - Taking into account that oxidative stress is among the factors causing cancer related death; chemoprevention which consists in using antioxidant substances such as phenolics could prevent cancer formation and progression. In the present study, phenolic contents and antioxidant activities of methanolic extracts from the halophyte Tamarix gallica shoots were determined. Moreover, the anticancer effect of this species on human colon cancer cells and the likely underlying mechanisms were also investigated. Shoot extracts showed an appreciable total phenolic content (85 mg GAE/g DW) and a high antioxidant activity (IC50 = 3.3 MUg/ml for DPPH test). At 50 and 100 MUg/ml, shoot, leaf, and flower extracts significantly inhibited Caco-2 cell growth. For instance, almost all plant part extracts inhibited cell growth by 62 % at the concentration 100 MUg/ml. DAPI staining results revealed that these extracts decrease DNA synthesis and confirm their effect on Caco-2 cells proliferation, principally at 100 MUg/ml. More importantly, cell mitosis was arrested at G2/M phase. The changes in the cell cycle-associated proteins (cyclin B1, p38, Erk1/2, Chk1, and Chk2) are correlated with the changes in cell cycle distribution. Taken together, our data suggest that T. gallica is a promising candidate species to be used as a source of anticancer biomolecules. PMID- 23801272 TI - Facile fabrication and photoluminescence properties of rare-earth-doped Gd2O3 hollow spheres via a sacrificial template method. AB - Rare-earth-doped gadolinium oxide (Gd2O3) hollow spheres were successfully fabricated on a large scale by using PS spheres as sacrificed templates and urea as a precipitating agent, which involved the deposition of an inorganic coating Gd(OH)CO3 on the surface of PS spheres and subsequent calcination in the air. Various approaches including X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared (FT-IR), thermogravimetric and differential thermal analysis (TG-DTA), as well as photoluminescence spectroscopies were used to characterize the samples. The results indicate that the sample is composed of uniform hollow Gd2O3 spheres with a mean particle size of about 2.3 MUm and these hollow spheres have the mesoporous shell that are composed of a large amount of nanoparticles. The possible mechanism of evolution from PS spheres to the amorphous precursor and to the final hollow Gd2O3 spheres have been proposed. The as-obtained samples show strong light emission with different colors corresponding to different Ln3+ ions under ultraviolet-visible light and electron-beam excitation. Under 980 nm NIR irradiation, Gd2O3:Ln3+ (Ln3+ = Yb3+/Er3+, Yb3+/Tm3+ and Yb3+/Ho3+) exhibit characteristic up-conversion (UC) emissions of red (Er3+, 2H11/2, 4S3/2, 4F9/2 -> 4I15/2), blue (Tm3+, 1G4 -> 3H6) and green (Ho3+, 5F4, 5S2 -> 5I8), respectively. These merits of multicolor emissions in the visible region endow these kinds of materials with potential applications in the field of light display systems, lasers, optoelectronic devices, and MRI contrast agents. PMID- 23801271 TI - Circulating endothelial progenitor cells in acromegaly. AB - BACKGROUND: Endothelial progenitor cells (EPCs), involved in the repairing mechanisms of vascular damage, are positively correlated to insulin-like growth factor I (IGF-I) concentrations in healthy adults. However, the levels of EPCs and their role in acromegalic patients have never been investigated. AIM: We conducted a cross-sectional study in order to assess the levels of the different phenotypes of circulating EPC in acromegalic patients. SUBJECTS AND METHODS: The study was performed at the Endocrinology Unit of Federico II University and at the Unit of Metabolic Diseases and Endocrinology of the Second University of Naples. Fifty-five acromegalic patients and 65 healthy controls were studied. EPCs were assessed by flow cytometry and IGF-I by immunoradiometric assay. RESULTS: Compared with subjects of the control group, acromegalic patients showed significantly higher levels of EPCs phenotypes expressing KDR antigen [KDR+, cells per 106 events, median and interquartile range, 44 (28-67) vs 23 (13-40), p=0.006; CD34+KDR+ 25 (18-38) vs 12 (8-17), p<0.001; CD133+KDR+ 17 (13-30) vs 8 (6-12), p<0.001; CD34+KDR+CD133+ 16 (12-25) vs 8 (6-10), p<0.001]. There was a positive correlations between CD34+KDR+CD133+ cells count and IGF-I in acromegaly group (r=0.79, p<0.001). CONCLUSIONS: Acromegalic patients show higher circulating EPCs levels expressing KDR, positively correlated with IGF-I, suggesting a role for IGF-I in regulating the expression of this surface marker in the early phase of EPCs differentiation. PMID- 23801273 TI - Short-term digestible energy intake in captive moose (Alces alces) on different diets. AB - Moose (Alces alces) are regularly described as problematic animals in captivity, mainly because of their particular digestive physiology and resulting feeding demands. According to the literature, moose regularly reject non-browse forages offered in captivity, which may indirectly lead to an overproportional ingestion of easily digestible feeds and thus chronic acidosis, which may in turn be the cause of their low life expectancy in captivity. By feeding experiments in four animals, this study aimed at testing whether maintaining moose on roughage-only diets appears feasible. The diets used consisted of the typical zoo ration with mixed feeds (including alfalfa hay), and exclusive diets of alfalfa hay, combinations of alfalfa hay and grass hay, alfalfa hay and grass hay and dried browse leaves, and dried browse leaves only. Whereas results confirmed that moose do not ingest grass hay in relevant amounts, digestible energy (DE) intake on alfalfa hay was, at 0.67 +/- 0.15 DE MJ kg(-0.75) day(-1), above the estimated maintenance requirement of 0.6, and higher on the browse diets. At least for short-time periods, results contradict previous reports in the literature that alfalfa hay only is not a suitable maintenance diet for moose. At the same time the results promote feeding moose in captivity forage-based diets. PMID- 23801274 TI - Round window membrane permeability to golimumab in guinea pigs: a pilot study. AB - OBJECTIVES/HYPOTHESIS: Autoimmune inner ear disorder is one of a few types of sensorineural hearing loss that is treatable and potentially reversible. Treatment involves oral steroids and methotrexate. Other treatment modalities have been tried with variable success. All such treatments are systemic, with inherent side effects limiting their effectiveness. Recently, tumor necrosis factor (TNF)-alpha blockers have been suggested as a modality of treatment. The objective of this study was to assess the round window membrane permeability to golimumab, a TNF-alpha blocker. This study is the first to look at the feasibility of local golimumab delivery into the inner ear, which may allow for targeted immune modulation of autoimmune inner ear disorders without the consequences of systemic treatment. STUDY DESIGN: This is a single-blinded, placebo-controlled, pilot study using guinea pigs to assess round window membrane permeability to golimumab. METHODS: Golimumab was instilled into the guinea pigs' middle ear. Inner ear fluid was sampled through the round window membrane after approximately 30 minutes of drug exposure. Golimumab presence in the inner ear was assessed by enzyme-linked immunosorbent assay in both drug-treated and control ears. RESULTS: Higher concentrations of golimumab were detected in the inner ear fluid samples of golimumab-exposed ears than in the control ears. The difference was statistically significant (P < .001). CONCLUSIONS: Golimumab crosses the round window membrane and is detected in measurable concentrations in the inner ear fluid after 30 minutes of exposure to the membrane. Further studies are needed to learn its pharmacokinetics and the time needed to reach optimal concentration in the inner ear. LEVEL OF EVIDENCE: NA. Laryngoscope, 123:2840 2844, 2013. PMID- 23801275 TI - Rapid microwave synthesis of high aspect-ratio ZnO nanotetrapods for swift bisphenol A detection. AB - Highly crystalline and high aspect-ratio ZnO nanotetrapods were grown by a novel and swift microwave synthesis. FESEM analysis revealed that each tetrapod has four thin arms and are derived from the midst of the crystal. The diameter of each arm is larger at the base and smaller at the tip. Structural analysis revealed that these nanotetrapods are single crystalline and have a wurtzite hexagonal crystal structure. These ZnO nanotetrapods were used for the detection of BPA. The electrochemical sensor based on the ZnO nanotetrapods modified electrode showed electrocatalytic activity in terms of significant improvement of the anodic current of BPA and lowering of the detection limit. Under optimized conditions, the squarewave oxidation peak current of BPA was linear over the concentration range of 12.4 nM to 1.2 MUM with the detection limit of 1.7 nM and sensitivity of 5.0 MUA nM(-1) cm(-2). This sensor showed high sensitivity and response compared with other electrochemical sensors reported for the detection of BPA. PMID- 23801276 TI - Aggregate exposure approaches for parabens in personal care products: a case assessment for children between 0 and 3 years old. AB - In the risk assessment of chemical substances, aggregation of exposure to a substance from different sources via different pathways is not common practice. Focusing the exposure assessment on a substance from a single source can lead to a significant underestimation of the risk. To gain more insight on how to perform an aggregate exposure assessment, we applied a deterministic (tier 1) and a person-oriented probabilistic approach (tier 2) for exposure to the four most common parabens through personal care products in children between 0 and 3 years old. Following a deterministic approach, a worst-case exposure estimate is calculated for methyl-, ethyl-, propyl- and butylparaben. As an illustration for risk assessment, Margins of Exposure (MoE) are calculated. These are 991 and 4966 for methyl- and ethylparaben, and 8 and 10 for propyl- and butylparaben, respectively. In tier 2, more detailed information on product use has been obtained from a small survey on product use of consumers. A probabilistic exposure assessment is performed to estimate the variability and uncertainty of exposure in a population. Results show that the internal exposure for each paraben is below the level determined in tier 1. However, for propyl- and butylparaben, the percentile of the population with an exposure probability above the assumed "safe" MoE of 100, is 13% and 7%, respectively. In conclusion, a tier 1 approach can be performed using simple equations and default point estimates, and serves as a starting point for exposure and risk assessment. If refinement is warranted, the more data demanding person-oriented probabilistic approach should be used. This probabilistic approach results in a more realistic exposure estimate, including the uncertainty, and allows determining the main drivers of exposure. Furthermore, it allows to estimate the percentage of the population for which the exposure is likely to be above a specific value. PMID- 23801277 TI - Contemporary hernia smartphone applications (apps). AB - AIMS: Smartphone technology and downloadable applications (apps) have created an unprecedented opportunity for access to medical information and healthcare related tools by clinicians and their patients. Here, we review the current smartphone apps in relation to hernias, one of the most common operations worldwide. This article presents an overview of apps relating to hernias and discusses content, the presence of medical professional involvement and commercial interests. METHODS: The most widely used smartphone app online stores (Google Play, Apple, Nokia, Blackberry, Samsung and Windows) were searched for the following hernia-related terms: hernia, inguinal, femoral, umbilical, incisional and totally extraperitoneal. Those with no reference to hernia or hernia surgery were excluded. RESULTS: 26 smartphone apps were identified. Only 9 (35 %) had named medical professional involvement in their design/content and only 10 (38 %) were reviewed by consumers. Commercial interests/links were evident in 96 % of the apps. One app used a validated mathematical algorithm to help counsel patients about post-operative pain. CONCLUSIONS AND OPPORTUNITIES: There were a relatively small number of apps related to hernias in view of the worldwide frequency of hernia repair. This search identified many opportunities for the development of informative and validated evidence-based patient apps which can be recommended to patients by physicians. Greater regulation, transparency of commercial interests and involvement of medical professionals in the content and peer-review of healthcare-related apps is required. PMID- 23801278 TI - Association between single genetic polymorphisms of MDR1 gene and gastric cancer susceptibility in Chinese. AB - Gastric cancer is a common cancer worldwide. The multidrug resistance 1 gene (MDR1) is one of the most important candidate genes for influencing gastric cancer susceptibility. This study aimed to analyze the association between genetic variants of MDR1 gene and the susceptibility to gastric cancer in Chinese Han population. A total of 365 gastric cancer patients and 367 cancer-free controls were enrolled in this study. The single genetic polymorphisms (SNPs) of MDR1 gene were genotyped by the created restriction site-polymerase chain reaction method. Our data suggested that the allele and genotype frequencies of c.159G > T and c.1564A > T were statistically different between gastric cancer patients and cancer-free controls. Association analyses indicated that these two SNPs were statistically associated with the increased risk of gastric cancer (for c.159G > T, TT versus (vs.) GG: OR 2.34, 95 % CI 1.31-4.19; TT vs. GT/GG: OR 2.32, 95 % CI 1.32-4.08; T vs. G: OR 1.27, 95 % CI 1.01-1.59; for c.1564A > T, TT vs. AA: OR 2.27, 95 % CI 1.31-3.93; TT vs. AT/AA: OR 2.21, 95 % CI 1.30-3.75; T vs. A: OR 1.30, 95 % CI 1.04-1.62). The allele-T of both these two SNPs may contribute to the susceptibility to gastric cancer in Chinese Han population. The c.159G > T and c.1564A > T genetic variants might be used as molecular markers for detecting gastric cancer susceptibility. PMID- 23801280 TI - Enhanced SOX10 and KIT expression in cutaneous melanoma. PMID- 23801279 TI - Evidence for angiogenesis-independent contribution of VEGFR1 (FLT1) in gastric cancer recurrence. AB - Angiogenesis plays an important role in cancer progression and involves activation of multiple signaling cascades. This study investigated the relationships between microvessel density, expression of VEGF and VEGFR1 (FLT1), and gastric cancer (GC) recurrence. Twenty-nine surgically treated GC cases with similar initial clinical presentation were selected for the study; 11 of these cases recurred within 3 years, while the remaining 18 did not. Microvessel density correlated with VEGF mRNA content, but neither of these parameters was associated with the disease outcome. When tumors were ranked according to the level of expression of angiogenic molecules, 9 out of 10 cases with the highest VEGFR1 expression belonged to the recurrence group, while none of the 10 GC with the lowest content of VEGFR1 mRNA had the disease relapse (p = 0.000). VEGFR1 expression did not show even a trend to correlation with the level of cancer tissue vascularization. Immunofluorescent staining by anti-VEGFR1 antibody revealed VEGFR1 expression in tumor cells but not in other cell types. Our data provide indirect support to the evidence for a non-angiogenic contribution of VEGFR1 in cancer pathogenesis. PMID- 23801281 TI - Laser-induced azomethine ylide formation and its covalent entrapment by fulleropyrrolidine derivatives during MALDI analysis. AB - Two novel monofunctionalized fulleropyrrolidine derivatives (Prato adducts) were prepared and characterized by matrix-assisted laser desorption/ionization (MALDI) and electrospray ionization (ESI). MALDI experiments conducted in the positive ion mode on pure and mixed samples of both monofunctionalized fullerene derivatives revealed the efficient formation of bisadducts (in the case of the pure samples) and mixed bisadducts (in the case of a mixed sample). Bisadducts were not observed in the ESI experiments and thus not present in the sample. A mechanism for the MALDI formation of these bisadduct ions is proposed in which an azomethine ylide fragment is formed in situ from the monofunctionalized fulleropyrrolidine species upon laser irradiation. This fragment, which can survive as an intact moiety in the gas phase in the special environment provided by the MALDI experiment, is then able to attach to a fulleropyrrolidine monoadduct which acts as a dipolarophile, thus leading to the formation of a bisadduct fullerene derivative. The unprecedented re-attachment of the azomethine ylide implies that the establishment of the ligand attainment of Prato adducts based on MALDI analysis alone can lead to wrong assignments. PMID- 23801282 TI - A high serum level of M65 is associated with tumour aggressiveness and an unfavourable prognosis for epithelial ovarian cancer. AB - PURPOSE: This study was conducted to determine the clinical significance of serum M30 and M65 in epithelial ovarian cancer (EOC). METHODS: A total of 56 patients with EOC and 56 healthy women were included in the study. All of the patients received platinum-based chemotherapy. Pretreatment levels of M30 and M65 were measured using the quantitative ELISA method. RESULTS: The median M30 and M65 serum levels were significantly elevated in the EOC patients compared with the healthy controls (96.7 vs. 69.5, p = 0.028 and 436.4 versus 166.3, p < 0.001, respectively). The cut-off value of 423.4 U/L for M65 determined with ROC analysis, predicted progression with 75.1 % sensitivity and 65.6 % specificity (AUC = 0.708, p = 0.008). Patients with higher M65 levels had shorter progression free survival (PFS) (p = 0.021). Both M30 and M65 serum levels were significantly higher for serous-type histology (p = 0.001 and p < 0.001, respectively). Increased M65 serum levels were associated with advanced disease (p = 0.005) and higher grade (p = 0.005). Moreover, M65 levels were higher for chemotherapy resistant patients (p = 0.04). Multivariate analysis revealed that an elevated serum M65 level was the only significant independent prognostic factor (p = 0.039, HR 3.792). CONCLUSIONS: These results indicated that serum M30 and M65 levels were significantly elevated in patients with EOC compared with healthy women. Particularly, high serum M65 levels were associated with poor prognosis and resistance to platinum-based chemotherapy. PMID- 23801283 TI - Phase II study of single agent oral vinorelbine as first-line treatment in patients with HER-2 negative metastatic breast cancer. AB - PURPOSE: Previous studies indicated that oral chemotherapy is convenient and preferred by many patients. We hereby report the efficacy and safety of oral vinorelbine as first-line chemotherapy for metastatic breast cancer (MBC). METHODS: Thirty-one patients with HER-2 negative MBC were enrolled between January 2007 and December 2010 in a prospective phase II trial. Patients were treated every 3 weeks with oral vinorelbine 60 mg/m2 Days 1 and 8 for the 1st cycle and thereafter 80 mg/m2 Days 1 and 8 every 3 weeks. Treatment was administered until disease progression or unexpected adverse event or patient refusal to continue. Primary endpoint was objective response rate (ORR); secondary endpoints were time-to-progression (TTP), overall survival (OS) and safety. Follow-up results until October 2012 are reported. RESULTS: Median age was 42 years (range 33-75). 26 (84 %) patients had 2 or more metastatic sites. A median of 6 cycles were administered (range 2-20). ORR was achieved in 9 (29 %) patients including 1 complete and 8 partial responses. 12 (39 %) patients had stable disease, resulting in a disease control rate of 68 %. Median TTP was 5.2 months [95 % CI 2.8-7.5]. Median OS was 16 months [95 % CI 11.3-20.7]. 3 (10 %) patients developed Grade 3-4 neutropenia. No events of febrile neutropenia, cardiac, renal toxicities or alopecia were recorded. Grade 3 thrombocytopenia and nausea-vomiting were reported in 2 (6 %) and 5 (16 %) patients, respectively. CONCLUSION: Results show a good efficacy and tolerance profile of oral vinorelbine as first-line chemotherapy for HER-2 negative MBC patients. PMID- 23801284 TI - Endoluminal transgastric endoscopic anastomosis of the gallbladder using an anchoring self-expanding metal stent. PMID- 23801285 TI - Full-thickness laparoendoscopic stapled excision of colonic lesion in a porcine ex vivo model. PMID- 23801286 TI - Disappearance of a large pedunculated polyp after diagnostic colonoscopy. PMID- 23801287 TI - The 'clip-band closure' technique: a new endoscopic traction method for closure of a large ulcer. PMID- 23801288 TI - Endoscopic drainage of a post-cholecystectomy biloma with biloma-gastric stenting. PMID- 23801289 TI - Use of artificial tissue to practice endoscopic submucosal dissection. PMID- 23801290 TI - Acute stroke due to air embolism complicating ERCP. PMID- 23801291 TI - Small-intestinal hemorrhage caused by treatment with sorafenib for hepatocellular carcinoma and diagnosed by capsule endoscopy. PMID- 23801292 TI - A rare presentation of esophageal actinomycosis in an immunocompetent patient. PMID- 23801293 TI - Two techniques for guide wire advancement along a tortuous pancreatic duct: the through-the-stent and flipped "U-wire" techniques. PMID- 23801294 TI - Colonic findings in Churg-Strauss syndrome. PMID- 23801295 TI - A review of patient-reported outcomes for children and adolescents with obesity. AB - INTRODUCTION: Obesity is a chronic condition that can impact the physical, emotional, mental and social elements that encompass a child's life. The objectives of this study were to identify which generic and obesity-specific patient-reported outcome (PRO) instruments are used in obesity literature, as well as review their conceptual approach, health and health-related content, ethical content and psychometric properties. METHOD: PubMed, CINAHL, EMBASE and PsycINFO were searched from the inception of each database to May 2012 to identify all studies using multi-dimensional PRO instruments with children who are overweight or obese. The most common generic and all obesity-specific instruments were analyzed according to the study objectives. RESULTS: From 4,226 articles identified by our search, 70 articles used 6 generic and 4 obesity specific PRO instruments. While the most commonly used PRO instrument was the generic PedsQL 4.0 (used in 53 studies), many health domains were found in the obesity-specific instruments that are not measured by the PedsQL 4.0. Summary of the development and psychometric properties of the generic and obesity PROs identified that no one instrument meets all the guideline criteria for instrument development and validation, e.g., only one instrument included qualitative input from children with obesity in the content development phase. DISCUSSION: This comprehensive review provides information to aid in selecting multi-dimensional PRO instruments in children with obesity according to various aspects of content as well as psychometric properties. The conceptual analysis shows that the reviewed PRO instruments contain inconsistencies in their conceptual approaches. Also, certain relevant health domains to children and youth with obesity were not included in the most commonly used generic instrument. The obesity-specific instruments require further validation before they can be used in intervention studies. PMID- 23801296 TI - Peace of mind for patients with differentiated thyroid cancer? AB - Differentiated thyroid carcinomas (DTC) have an excellent prognosis, with 10-year overall survival rates over 90%. In addition, DTC patients benefit from their lifelong medical surveillance. The AIM of the study was to compare the patients' overall survival with that of a matched general population. PATIENTS AND METHODS: We have analyzed 1497 consecutive patients with DTC, who underwent radioiodine therapy in Munster, Germany, according to international standards. We classified our patients according to the current 7th edition of the UICC (Union Internationale Contre le Cancer) classification and we compared the overall survival of the patients with the expected survival based on age and sex of the general population as provided by the Federal Statistical Office, Germany. RESULTS: There were no significant differences in overall survival rates between DTC patients of the cohort in stages I to IVa compared to the expected survival based on age and sex of the general population. However, patients in stage IVc showed a significantly worse overall survival rate using the log-rank test (p < 0.0001). CONCLUSION: Patients with DTC showed excellent overall survival rates in stages I, II, III and IVa. All patients, except for those in stage IVc (M1 >= 45 years), had overall survival rates similar to the general population. PMID- 23801297 TI - Strigolactones fine-tune the root system. AB - Strigolactones were originally discovered to be involved in parasitic weed germination, in mycorrhizal association and in the control of shoot architecture. Despite their clear role in rhizosphere signaling, comparatively less attention has been given to the belowground function of strigolactones on plant development. However, research has revealed that strigolactones play a key role in the regulation of the root system including adventitious roots, primary root length, lateral roots, root hairs and nodulation. Here, we review the recent progress regarding strigolactone regulation of the root system and the antagonism and interplay with other hormones. PMID- 23801298 TI - Genome-wide expression analysis of rice aquaporin genes and development of a functional gene network mediated by aquaporin expression in roots. AB - The world population continually faces challenges of water scarcity for agriculture. A common strategy called water-balance control has evolved to adapt plant growth to these challenges. Aquaporins are a family of integral membrane proteins that play a central role in water-balance control. In this study, we identified 34 members of the rice aquaporin gene family, adding a novel member to the previous list. A combination of phylogenetic tree and anatomical meta expression profiling data consisting of 983 Affymetrix arrays and 209 Agilent 44 K arrays was used to identify tissue-preferred aquaporin genes and evaluate functional redundancy among aquaporin family members. Eight aquaporins showed root-preferred expression in the vegetative growth stage, while 4 showed leaf/shoot-preferred expression. Integrating stress-induced expression patterns into phylogenetic tree and semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) analyses revealed that 3 rice aquaporin genes were markedly downregulated and 4 were upregulated by water deficiency in the root, suggesting that these candidate genes are key regulators of water uptake from the soil. Finally, we constructed a functional network of genes mediated by water stress and refined the network by confirming the differential expression using RT PCR and real-time PCR. Our data will be useful to elucidate the molecular mechanism of water-balance control in rice root. PMID- 23801300 TI - Engineering flavonoid glycosyltransferases for enhanced catalytic efficiency and extended sugar-donor selectivity. AB - Flavonoids are predominantly found as glycosides in plants. The glycosylation of flavonoids is mediated by uridine diphosphate-dependent glycosyltransferases (UGT). UGTs attach various sugars, including arabinose, glucose, galactose, xylose, and glucuronic acid, to flavonoid aglycones. Two UGTs isolated from Arabidopsis thaliana, AtUGT78D2 and AtUGT78D3, showed 89 % amino acid sequence similarity (75 % amino acid sequence identity) and both attached a sugar to the 3 hydroxyl group of flavonols using a UDP-sugar. The two enzymes used UDP-glucose and UDP-arabinose, respectively, and AtUGT78D2 was approximately 90-fold more efficient than AtUGT78D3 when judged by the k(cat)/K(m) value. Domain exchanges between AtUGT78D2 and AtUGT78D3 were carried out to find UGTs with better catalytic efficiency for UDP-arabinose and exhibiting dual sugar selectivity. Among 19 fusion proteins examined, three showed dual sugar selectivity, and one fusion protein had better catalytic efficiency for UDP-arabinose compared with AtUGT78D3. Using molecular modeling, the changes in enzymatic properties in the chimeric proteins were elucidated. To the best of our knowledge, this is the first report on the construction of fusion proteins with expanded sugar-donor range and enhanced catalytic efficiencies for sugar donors. PMID- 23801299 TI - Hemicellulose biosynthesis. AB - One major component of plant cell walls is a diverse group of polysaccharides, the hemicelluloses. Hemicelluloses constitute roughly one-third of the wall biomass and encompass the heteromannans, xyloglucan, heteroxylans, and mixed linkage glucan. The fine structure of these polysaccharides, particularly their substitution, varies depending on the plant species and tissue type. The hemicelluloses are used in numerous industrial applications such as food additives as well as in medicinal applications. Their abundance in lignocellulosic feedstocks should not be overlooked, if the utilization of this renewable resource for fuels and other commodity chemicals becomes a reality. Fortunately, our understanding of the biosynthesis of the various hemicelluloses in the plant has increased enormously in recent years mainly through genetic approaches. Taking advantage of this knowledge has led to plant mutants with altered hemicellulosic structures demonstrating the importance of the hemicelluloses in plant growth and development. However, while we are on a solid trajectory in identifying all necessary genes/proteins involved in hemicellulose biosynthesis, future research is required to combine these single components and assemble them to gain a holistic mechanistic understanding of the biosynthesis of this important class of plant cell wall polysaccharides. PMID- 23801301 TI - Phase I trial of sorafenib in combination with ifosfamide in patients with advanced sarcoma: a Spanish group for research on sarcomas (GEIS) study. AB - BACKGROUND: This phase I trial assessed safety, pharmacokinetics (PK), dose limiting toxicity (DLT), maximum tolerated dose and recommended dose (RD) of the combination of sorafenib plus ifosfamide in patients with advanced sarcoma. METHODS: Twelve sarcoma patients (9 soft-tissue, 3 bone sarcoma) were treated with sorafenib plus ifosfamide (starting doses 200 mg bid and 6 g/m(2) respectively). A 3 + 3 dose escalation design with cohorts of 3-6 patients was used. A study to assess the in vitro efficacy of the combination was also conducted. RESULTS: Three DLTs were observed: fatigue grade 4 with sorafenib 400 mg bid plus ifosfamide 6 g/m(2) and encephalopathy and emesis grade 3 with sorafenib 400 mg bid plus ifosfamide 7.5 g/m(2). Other toxicities included diarrhea, hand-foot syndrome, mucositis, neutropenia, skin rash and thrombocytopenia. There were no relevant effects on PK of sorafenib but an increase in ifosfamide active metabolite 4-hydroxy-ifosfamide was observed. Eight patients achieved stable disease lasting more than 12 weeks. An additive effect was observed in vitro. CONCLUSIONS: RD was sorafenib 400 mg bid plus ifosfamide 6 g/m(2), allowing administration of active doses of both agents. Limited preliminary antitumor activity was also observed. A phase II study is currently ongoing. PMID- 23801302 TI - Patupilone in patients with pretreated metastatic/locally recurrent colorectal cancer: results of the Phase II CINATRA trial. AB - BACKGROUND: Phase I trials of the microtubule stabilising agent patupilone showed encouraging tumour control and response rates in patients with metastatic colorectal cancer. METHODS: Patients with metastatic or locally recurrent colorectal cancer who had progressed following treatment with oxaliplatin, irinotecan and fluoropyrimidines were treated with patupilone (8 mg/m(2) IV every 3 weeks) in combination with dexamethasone or prednisolone. RESULTS: The trial was closed early after 29 patients had been enrolled due to concerns about toxicity. 20 patients (71.4 %) experienced at least one grade 3-5 toxicity, most commonly diarrhoea (14 patients), dehydration (7 patients) and lethargy (6 patients). The 12 week progression-free survival rate was 16.7 % (95 % CI 6.1 % 36.5 %) in the 24 patients with a 12 week scan available or who had died prior to the 12 week scan. No complete or partial responses were seen by 12 weeks. The median progression-free survival was 2.6 months (95 % CI 2.3-2.9) and median overall survival was 6.1 months (95 % CI 3.7-8.4). CONCLUSION: Patupilone given at a dose of 8 mg/m(2) IV over 20 min every 3 weeks was associated with high levels of toxicity and no significant evidence of efficacy in patients with pre treated colorectal cancer. PMID- 23801304 TI - A subset of two adherence systems, acute pro-inflammatory pap genes and invasion coding dra, fim, or sfa, increases the risk of Escherichia coli translocation to the bloodstream. AB - An analysis of the phylogenetic distribution and virulence genes of Escherichia coli isolates which predispose this bacteria to translocate from the urinary tract to the bloodstream is presented. One-dimensional analysis indicated that the occurrence of P fimbriae and alpha-hemolysin coding genes is more frequent among the E. coli which cause bacteremia. However, a two-dimensional analysis revealed that a combination of genes coding two adherence factors, namely, P + Dr, P + S, S + Dr, S + fim, and hemolysin + one adherence factor, were associated with bacteremia and, therefore, with the risk of translocation to the vascular system. The frequent and previously unrecognized co-existence of pro-inflammatory P fimbriae with the invasion promoting Dr adhesin in the same E. coli isolate may represent high-risk and potentially lethal pathogens. PMID- 23801303 TI - Cediranib in combination with fulvestrant in hormone-sensitive metastatic breast cancer: a randomized Phase II study. AB - Hormone receptor-positive breast cancer is treated with estrogen inhibitors. Fulvestrant (FASLODEXTM), an estrogen receptor (ER) antagonist with no known agonist effects, competitively binds, blocks and degrades the ER. Vascular endothelial growth factor (VEGF) may mediate resistance to ER antagonists. Cediranib is a highly potent VEGF signaling inhibitor with activity against all three VEGF receptors. This randomized Phase II study evaluated cediranib plus fulvestrant. Postmenopausal women with hormone-sensitive metastatic breast cancer were eligible. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), duration of response, clinical benefit rate (CBR), safety/tolerability and pharmacokinetics (PK). Patients received cediranib 45 mg/day (n=31) or placebo (n=31) both plus fulvestrant. Demographic/baseline characteristics were well balanced. Patients treated with cediranib had a numerical advantage in PFS (hazard ratio=0.867, P=0.669; median 223 vs. 112 days, respectively) and ORR (22 vs. 8 %, respectively) vs. placebo, although not statistically significant. CBR was 42 % in both arms. The most common adverse events (AEs) in the cediranib arm were diarrhea (68 %), fatigue (61 %) and hypertension (55 %). The incidence of grade >= 3 AEs (68 % vs. 32 %), serious AEs (48 % vs. 13 %), discontinuation AEs (39 % vs. 10 %), and cediranib dose reductions/interruptions (74 % vs. 32 %) were higher in the cediranib arm. There was no evidence of a clinically relevant effect of cediranib on fulvestrant PK. Cediranib plus fulvestrant may demonstrate clinical activity in this population, but cediranib 45 mg was not sufficiently well tolerated. Investigation of lower doses of cediranib plus hormonal/chemotherapy could be considered. PMID- 23801305 TI - Antigen-bearing dendritic cells from the sublingual mucosa recirculate to distant systemic lymphoid organs to prime mucosal CD8 T cells. AB - Effector T cells are described to be primed in the lymph nodes draining the site of immunization and to recirculate to effector sites. Sublingual immunization generates effector T cells able to disseminate to the genital tract. Herein, we report an alternative mechanism that involves the recirculation of antigen bearing dendritic cells (DCs) in remote lymphoid organs to prime T cells. Sublingual immunization with a muco-adhesive model antigen unable to diffuse through lymphatic or blood vessels induced genital CD8 T cells. The sublingual draining lymph nodes were not mandatory to generate these lymphocytes, and antigen-bearing DCs from distant lymph nodes and spleen were able to prime specific CD8 T cells in a time- and dose-dependent manner. This study demonstrates, for the first time, that antigen-bearing DCs originating from the site of immunization recirculate to distant lymphoid organs and provides insights into the mechanism of distant CD8 T-cell generation by sublingual immunization. PMID- 23801307 TI - Comprehensive assessment of tibial plateau morphology in total knee arthroplasty: Influence of shape and size on anthropometric variability. AB - Better understanding of proximal tibia morphology can lead to improvements in total knee arthroplasty (TKA) through development of tibial tray families that adequately reflect the diversity of global anatomy using an appropriate number of components. We quantified variations in proximal tibial morphology at the TKA level and characterized differences attributable to gender and ethnicity. Virtual TKA was performed on digital models of 347 tibiae, spanning both genders and multiple ethnicities. The geometry of the resection profile was quantified using both a comprehensive set of morphological measurements (reflecting size and shape) and principal component analysis (PCA). The dominant statistical modes of variation were associated primarily with size (plateau dimensions, radii, and area), with lesser contributions associated with asymmetry and aspect ratios. Medial and lateral AP dimensions were strongly correlated with plateau ML width, with minimal differences in correlations due to gender or ethnicity. In conclusion, clinically relevant differences in proximal tibia morphology at the level of TKA resections across genders and multiple ethnicities can be attributed largely to variations in overall proximal tibial size, not gender- or ethnic specific shape variations. PMID- 23801306 TI - Acting locally: innate mucosal immunity in resistance to HIV-1 infection in Kenyan commercial sex workers. AB - Cohort studies of female commercial sex workers (CSWs) in Kenya were among the first to identify highly HIV-1-exposed seronegative (HESN) individuals. As natural resistance is usually mediated by innate immune mechanisms, we focused on determining whether expression and function of innate signaling pathways were altered locally in the genital mucosa of HESN CSWs. Our results demonstrated that selected pattern-recognition receptors (PRRs) were significantly reduced in expression in cervical mononuclear cells (CMCs) from HESN compared with the new HIV-negative (HIV-N) and HIV-positive (HIV-P) groups. Although baseline levels of secreted cytokines were reduced in CMCs of HESN, they were highly stimulated following exposure to ssRNA40 in vitro. Importantly, cervical epithelial cells from HESN also expressed reduced levels of PRRs, but Toll-like receptor 3 (TLR3) and TLR7 as well as nuclear factor-kappaB and activator protein 1 were highly expressed and activated. Lastly, inflammatory cytokines interleukin (IL)-1beta, IL-8, and RANTES (regulated and normal T cell expressed and secreted) were detected at lower levels in cervicovaginal lavage of HESN compared with the HIV-N and HIV-P groups. Overall, our study reveals a local microenvironment of HIV resistance in the genital mucosa consisting of a finely controlled balance of basal immune quiescence with a focused and potent innate anti-viral response critical to resistance to sexual transmission of HIV-1. PMID- 23801308 TI - Primary and concomitant flexor enthesopathy of the canine elbow. AB - OBJECTIVES: To report the characteristics of two types of flexor enthesopathy, primary and concomitant, based on different diagnostic techniques. MATERIALS AND METHODS: Over a period of three years a prospective study was performed on dogs admitted for the complaint of elbow lameness. Based on the radiographic findings a selection of dogs underwent a complete series of different imaging modalities. With each technique, pathology of the medial epicondyle and the presence of other elbow disorders were recorded. All joints with signs of flexor pathology apparent with at least three techniques were selected. A distinction was made between primary and concomitant flexor enthesopathy based on the absence or presence of other elbow disorders. RESULTS: Primary flexor enthesopathy was diagnosed in 23 joints and concomitant flexor enthesopathy in 20 joints. In 43% of the joints with primary and in 75% of the joints with concomitant flexor enthesopathy, pathology at the medial epicondyle was demonstrated by all techniques. All joints with concomitant flexor enthesopathy had a diagnosis of medial coronoid disease, osteochondritis dissecans, or both. CLINICAL SIGNIFICANCE: Pathology at the medial epicondyle is a sign of flexor enthesopathy. It may be present as the only sign in a joint with primary flexor enthesopathy or concomitant with other elbow pathology. In both groups flexor lesions can be demonstrated with different imaging techniques. The distinction between the primary and concomitant form is based on the presence or absence of other elbow pathology, mainly medial coronoid disease. Recognizing both types is important for a correct treatment decision. PMID- 23801309 TI - Synthesis and structural characterization of bis and tris(2-mercapto-1 methylbenzimidazolyl)hydroborato complexes: benzannulation promotes kappa3 coordination. AB - The benzannulated bis and tris(mercaptoimidazolyl)borohydride compounds, [BmMeBenz]Na and [TmMeBenz]Na, have been synthesized via the reactions of NaBH4 with two and three equivalents of 1-methyl-1,3-dihydro-2H-benzimidazole-2-thione, respectively. X-ray diffraction studies on the THF adducts, {MU [BmMeBenz]Na(THF)2}2 and {[TmMeBenz]Na}2(MU-THF)3, indicate that both compounds are dinuclear but differ according to the nature of the bridging ligand. Specifically, {MU-[BmMeBenz]Na(THF)2}2 possesses bridging [BmMeBenz] ligands and terminal THF ligands, while {[TmMeBenz]Na}2(MU-THF)3 possesses terminal [TmMeBenz] ligands and bridging THF ligands. The tris(mercaptoimidazolyl)borohydride ligand of {[TmMeBenz]Na}2(MU-THF)3 coordinates in a kappa3-manner, which is in marked contrast to the kappa2-, kappa1- and kappa0-modes that have been reported for various [TmMe]Na derivatives. Density functional theory (DFT) geometry optimization calculations of the anions [TmMeBenz]- and [TmMe]- in the gas phase indicate that the conformation required for kappa3-S3 coordination, i.e. one in which the three sulfur donors point away from the B-H group, is relatively more stable for [TmMeBenz]- than for [TmMe]-, and thus provides a rationalization for the observation that benzannulation enables kappa3-coordination of tris(mercaptoimidazolyl)borohydride ligand in {[TmMeBenz]Na}2(MU-THF)3. Furthermore, comparison of the molecular structure and IR spectroscopic properties of [TmMeBenz]Re(CO)3 with those of [TmMe]Re(CO)3 indicates that benzannulation reduces the electron donating properties of the ligand, but has little effect on its steric properties. {MU-[BmMeBenz]Na(THF)2}2 and {[TmMeBenz]Na}2(MU-THF)3 react with [Me3PCuCl]4 to give [BmMeBenz]CuPMe3 and [TmMeBenz]CuPMe3, the first pair of structurally related bis and tris(mercaptoimidazolyl)hydroborato copper(I) compounds. PMID- 23801311 TI - Surveillance after colonic neoplasia: to die of success. PMID- 23801310 TI - Anti-neuroinflammatory effect of a novel caffeamide derivative, KS370G, in microglial cells. AB - Accumulating evidence suggests that inflammatory processes in the central nervous system that are mediated by microglial activation play important roles in several neurodegenerative disorders. Therefore, development of methods for microglial inhibition is considered an important strategy in the search for neuroprotective agents. Caffeic acid phenethyl ester (CAPE) is distributed wildly in nature, but rapid decomposition by esterase leads to its low bioavailability. In this study, we investigated the effects of KS370G, a novel caffeic acid phenylethyl amide, on microglial activation. KS370G significantly inhibited the release of nitric oxide (NO) and the expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Treatment with KS370G also induced heme oxygenase (HO) 1 and suppressors of cytokine signaling (SOCS)-3 expression in the microglia. Furthermore, the anti-inflammatory effects of KS370G were found to be regulated by phosphorylated adenosine monophosphate-activated protein kinase-alpha (AMPK alpha) translocated to the nucleus. Moreover, KS370G showed significant anti neuroinflammatory effects on microglial activation in vivo and on motor behavior as well. The protective effect of KS370G was weakened by an AMPK inhibitor Compound C. This study focuses on the importance of key molecular determinants of inflammatory homeostasis, AMPK, HO-1, and SOCS-3, and their possible involvement in anti-neuroinflammatory responses. PMID- 23801312 TI - Can high resolution microendoscopy improve the resect and discard strategy? PMID- 23801313 TI - Evaluation of an endoscopic suturing device for transoral outlet reduction in patients with weight regain following Roux-en-Y gastric bypass. AB - BACKGROUND AND STUDY AIMS: A dilated gastrojejunal anastomosis (GJA) is thought to be associated with weight regain in patients with Roux-en-Y gastric bypass (RYGB). Due to a high rate of perioperative morbidity, surgical revision is not generally performed. The aim of this study was to assess the technical feasibility, safety, and early outcomes of a procedure using a commercially available endoscopic suturing device to reduce the diameter of the GJA. PATIENTS AND METHODS: This was a retrospective analysis of 25 consecutive patients who underwent transoral outlet reduction (TORe) for dilated GJA and weight regain. An endoscopic suturing device was used to place sutures at the margin of the GJA in order to reduce its aperture. On chart review, clinical data were available at 3, 6, and 12 months. RESULTS: Patients had regained a mean of 24 kg from their weight loss nadir and had a mean body mass index of 43 kg/m2 at the time of endoscopic revision. Average anastomosis diameter was 26.4 mm. Technical success was achieved in all patients (100 %) with a mean reduction in anastomosis diameter to 6 mm (range 3 - 10 mm), representing a 77.3 % reduction. The mean weight loss in successful cases was 11.5 kg, 11.7 kg, and 10.8 kg at 3, 6, and 12 months, respectively. There were no major complications. CONCLUSION: This case series demonstrated the technical feasibility, safety, and efficacy of performing gastrojejunostomy reduction using a commercially available endoscopic suturing device. This technique may represent an effective and minimally invasive option for the management of weight regain in patients with RYGB. PMID- 23801314 TI - Performance of additional colonoscopies and yield of neoplasms within 3 years after screening colonoscopy: a historical cohort study. AB - BACKGROUND AND STUDY AIMS: After screening colonoscopy, additional colonoscopies may be required for adenoma surveillance or diagnostic reasons. The aim of the present study was to explore their utilization and findings in routine practice. PATIENTS AND METHODS: The study comprised an historical cohort of individuals participating in colonoscopy screening in 2006. Utilization and yield of neoplasms of additional colonoscopies performed in these individuals by the same physician ( < 6 months and 6 - 36 months after screening) between 2006 and 2009 were assessed using data of a colonoscopy quality assurance program in Bavaria, Germany. Screening including polypectomy, and short-term follow-up colonoscopy was assumed to have been completed within <= 6 months. Multivariate logistic regression was used to identify predictors of additional colonoscopy and advanced neoplasms (high risk adenoma or colorectal cancer [CRC]) among those with additional colonoscopy during the period of 6 - 36 months after screening. RESULTS: A total of 51 301 individuals undergoing screening colonoscopy were included. Of these, 10.1 % (95 % confidence interval [CI] 9.8 % - 10.3 %) had an additional colonoscopy performed by the same physician between 6 and 36 months after screening. The percentages of those with additional colonoscopy were 5.7 % (95 %CI 5.5 % - 5.9 %), 18.6 % (95 %CI 17.8 % - 19.4 %), and 33.7 % (95 %CI 32.2 % - 35.2 %) after negative screening, low risk adenoma at screening, and high risk adenoma at screening, respectively. The overall findings were negative colonoscopy, low risk adenoma, high risk adenoma, and CRC in 68.6 % (95 %CI 67.3 % - 69.8 %), 24.1 % (95 %CI 23.0 % - 25.3 %), 6.7 % (95 %CI 6.0 % - 7.4 %), and 0.6 % (95 %CI 0.4 % - 0.8 %), respectively. Younger age, male sex, screen detected adenomas, inflammatory bowel disease, and early repeat colonoscopy within 6 months were predictors of additional colonoscopy. Older age, male sex, screen-detected adenomas, and surveillance indications were associated with increased risk of advanced neoplasms at post-screening colonoscopy. CONCLUSION: The results indicate frequent utilization of additional colonoscopies along with substantial adenoma yield in the first 3 years after screening colonoscopy. PMID- 23801315 TI - Feasibility and efficacy of argon plasma coagulation for early esophageal squamous cell neoplasia. AB - We present 19 cases in which argon plasma coagulation (APC) was used as curative initial treatment for 5 low-grade esophageal squamous intraepithelial neoplasias (ESINs), 12 high-grade ESINs, and 2 early esophageal squamous cell carcinomas (ESCCs). Complete response was defined as the absence of tumor from any biopsy taken from the ablated lesion. At follow-up endoscopy 2 - 4 months after APC, 94.7 % of patients had achieved complete response in a single treatment session. Only one patient with high-grade ESIN showed local recurrence. This patient underwent additional APC and showed complete response at 12 months after initial APC. At the 12-month follow-up endoscopy, again 94.7 % had a complete response. The exception was one patient with local recurrence, who underwent additional APC. After the 12-month follow-up endoscopy, no patient showed local recurrence during a median follow-up of 22 months. No stricture requiring endoscopic dilation occurred after the procedure. This study suggests that APC is a feasible and effective treatment modality for ESIN and early ESCC. PMID- 23801316 TI - Microvascular caliber changes in intramucosal and submucosally invasive esophageal cancer. AB - BACKGROUND AND STUDY AIM: Intrapapillary capillary loops (IPCLs) show distinct pattern changes corresponding to tumor progression and depth of invasion, important for in vivo characterization of superficial squamous cell carcinoma (SCC). We examined the relation between invasion depth and histopathologic IPCL diameter. PATIENTS AND METHODS: Prospectively, before lesion resection, magnification endoscopy and narrow band imaging were used to identify IPCL patterns of type V1 (corresponding to tumors limited to the mucosa; 10 patients) and type Vn (submucosally invading tumors; 10 patients). Post-resection, IPCL samples (type I [normal mucosa], n = 103; V1, n = 113; Vn, n = 100) were stained with hematoxylin & eosin, CD34, and desmin, and vessel diameter measured using light microscopy. RESULTS: Mean (standard deviation [SD]) histopathologic calibers of IPCLs of types I, V1, and Vn were significantly different, being 7.7 (2.8) um, 21.9 (7.4) um, and 65.2 (22.9) um; type 1 vs. V1, P < 0.001; V1 vs. Vn, P < 0.001. CONCLUSIONS: Magnification endoscopy observation of IPCLs allows in vivo discrimination between intramucosal and submucosally invasive cancer. PMID- 23801317 TI - The EndoResect study: endoscopic full-thickness resection of gastric subepithelial tumors. PMID- 23801318 TI - Reply to Qin and Linghu. PMID- 23801320 TI - Molecular characterization of 2-chlorobiphenyl degrading Stenotrophomonas maltophilia GS-103. AB - The catabolic potential of transformer oil contaminated soil bacteria in aerobic degradation of polychlorinated biphenyls (PCB) were assessed. Transformer oil contaminated soil sample was subjected to microcosm enrichment experiments (PAS medium/biphenyl as sole carbon source). PCB-degrading activity of the enrichment cultures in PAS medium with the addition of 2-chlorobiphenyl were analysed by GC MS indicated that, although the isolates differed in PCB-degrading capabilities, all of the enrichment cultures expressed activity toward at least some of the lower chlorinated congeners. Biphenyl-utilizing bacteria isolated from the most active PCB-degrading mixed cultures showed little taxonomic diversity and identified as Stenotrophomonas maltophilia GS-103. PMID- 23801321 TI - Information underpinning anticipation of goal-directed throwing. AB - We identified the information used to anticipate throw direction in handball. In two experiments, we examined how anticipation performance is affected when the information from one of five body areas (right arm, shoulders, hips, trunk, or total throw side) was either neutralized or decoupled from the motion of other body segments. In the first experiment, performance was significantly reduced when information from the throwing arm was neutralized, irrespective of skill levels. Skilled participants were negatively affected when the shoulders, hips, and trunk were neutralized, whereas less-skilled participants showed trends toward improvement under identical conditions. In the second experiment, partially disrupting relative motion via decoupling was not enough to reduce the anticipation performance among skilled participants to chance levels, whereas less-skilled participants lost their ability to anticipate in three conditions. Our findings suggest that skilled and less-skilled participants employ different information extraction strategies, yet information from the throwing arm is critical to anticipation for both groups. The two experiments suggest that relative motion mediated by both the absolute displacement trajectories of individual marker locations and their relative timings are important in informing anticipation, irrespective of skill level. PMID- 23801322 TI - Effects of pitch distance and likelihood on the perceived duration of deviant auditory events. AB - When a deviant (oddball) stimulus is presented within a series of otherwise identical (standard) stimuli, the duration of the oddball tends to be overestimated. Two experiments investigated factors affecting systematic distortions in the perceived duration of oddball stimuli. Both experiments used an auditory oddball paradigm where oddball tones varied in both their pitch distance from the pitch of a standard tone and their likelihood of occurrence. Experiment 1 revealed that (1) far-pitch oddballs were perceived to be longer than near-pitch oddballs, (2) effects of pitch distance were greater in low likelihood conditions, and (3) oddballs in later serial positions were perceived to be longer than oddballs in earlier serial positions. The above effects held regardless of whether oddballs were higher or lower in pitch than the standard. Experiment 2 revealed a pattern of response times in an oddball detection task that generally paralleled the pattern of data observed in Experiment 1; across conditions, there was a negative correlation between detection times and perceived duration. Taken together, the results suggest that the observed effects of oddball pitch, likelihood, and position on perceived duration are at least partly driven by how quickly individuals are able to initiate timing the oddball following its onset. Implications for different theoretical accounts of the oddball effect are discussed. PMID- 23801323 TI - The prolonged influence of subsequent context on spoken word recognition. AB - Connine, Blasko, and Hall (Journal of Memory and Language 30:234-250, 1991) suggested that within a 1-second temporal window, subsequent biasing information can influence the identification of a previously spoken word. Four experiments further explored this hypothesis. Our participants heard sentences in which an ambiguous target word was followed less than or more than a second later by a word biased in favor of either the target word or another word. Overall, the effects of the contextual biases on responding, measured using phonemic restoration and phoneme identification, were almost as large after 1 second as before 1 second. The implications of these results for defining the window of contextual effects are discussed. PMID- 23801324 TI - The association between race and gender, treatment attitudes, and antidepressant treatment adherence. AB - OBJECTIVES: We examined the associations between treatment attitudes and beliefs with race-gender differences in antidepressant adherence. METHODS: Subjects (n = 186) were African-American and White subjects aged >=60 years, diagnosed with clinically significant depression, and had a new outpatient primary care recommendation for antidepressant treatment. Antidepressant adherence was assessed using the Brief Medication Questionnaire. Attitudes and beliefs were assessed using the Patients Attitudes Toward and Ratings of Care for Depression, two items rating perceived medication importance, and a modified version of the Stigma Scale for Receiving Psychological Help. RESULTS: African-American men and women had significantly greater concerns about antidepressants and significantly less understanding about treatment than White women. African-American men had significantly more negative attitudes toward healthcare providers than African American and White women. African-American women were more likely than White men and women to endorse a medication other than their antidepressant as most important. Whereas some race-gender differences were found in personal spirituality, no group differences were found in perceived stigma. In a logistic regression model adjusted for key baseline variables, White women were significantly more adherent to antidepressants than African-American women (OR = 3.05, 95% CI = 1.06-8.81). Fewer concerns about antidepressants and indicating the antidepressant as the most important medication were both significantly associated with adherence. After including either of these two variables, the adherence difference between White women and African-American women was no longer significant (OR = 2.56, 95% CI = 0.84-7.80). CONCLUSIONS: Concerns about antidepressants and the importance of antidepressant medication are associated with adherence and are potentially modifiable through improved patient-provider communication, psycho-education, and therapeutic interventions. PMID- 23801325 TI - Real time monitoring of population dynamics in concurrent bacterial growth using SIFT-MS quantification of volatile metabolites. AB - Population dynamics of three different bacterial species, Serratia rubidaea (R), Serratia marcescens (F) and Escherichia coli (Ec), growing in single or mixed populations in liquid media, was monitored by real time headspace quantification of volatile compounds using selected ion flow tube mass spectrometry, SIFT-MS. The three bacterial species interact with each other in a competitive fashion in a way similar to the game "rock-paper-scissors" (R-Ec-F). The concentrations of volatile metabolites (ammonia, ethanol, acetaldehyde, propanol, acetoin, acetone and acetic acid) were measured in the headspace of the individual species and of their mixtures continuously for 24 hour periods. The results demonstrate that dynamics in bacterial cultures can be monitored using SIFT-MS in real time. PMID- 23801326 TI - Application of random mutagenesis to enhance the production of polyhydroxyalkanoates by Cupriavidus necator H16 on waste frying oil. AB - Using random chemical mutagenesis we obtained the mutant of Cupriavidus necator H16 which was capable of improved (about 35 %) production of poly(3 hydroxybuytrate) (PHB) compared to the wild-type strain. The mutant exhibited significantly enhanced specific activities of enzymes involved in oxidative stress response such as malic enzyme, NADP-dependent isocitrate dehydrogenase, glucose-6-phosphate dehydrogenase and glutamate dehydrogenase. Probably, due to the activation of these enzymes, we also observed an increase of NADPH/NADP+ ratio. It is likely that as a side effect of the increase of NADPH/NADP+ ratio the activity of PHB biosynthetic pathway was enhanced, which supported the accumulation of PHB. Furthermore, the mutant was also able to incorporate propionate into copolymer poly(3-hydroxybuytyrate-co-3-hydroxyvalerate) [P(3HB-co 3HV)] more efficiently than the wild-type strain (Y3HV/prec = 0.17 and 0.29 for the wild-type strain and the mutant, respectively)). We assume that it may be caused by lower availability of oxaloacetate for the utilization of propionyl-CoA in 2-methylcitrate cycle due to increased action of malic enzyme. Therefore, propionyl-CoA was incorporated into copolymer rather than transformed to pyruvate via 2-methylcitrate cycle. Thus, the mutant was capable of the utilization of waste frying oils and the production of P(3HB-co-3HV) with better yields and improved content of 3HV resulting in better mechanical properties of copolymer than the wild-type strain. The results of this work may be used for the development of innovative fermentation strategies for the production of PHA and also it might help to define novel targets for the genetic manipulations of PHA producing bacteria. PMID- 23801327 TI - Decoupling the role of ubiquitination for the dislocation versus degradation of major histocompatibility complex (MHC) class I proteins during endoplasmic reticulum-associated degradation (ERAD). AB - Aberrantly or excessively expressed proteins in the endoplasmic reticulum are identified by quality control mechanisms and dislocated to the cytosol for proteasome-mediated, ubiquitin-dependent degradation by a process termed endoplasmic reticulum-associated degradation (ERAD). In addition to its role in degradation, ubiquitination has also been implicated in substrate dislocation, although whether direct ubiquitin conjugation of ERAD substrates is required for dislocation has been difficult to ascertain. An obstacle in probing the mechanism of quality control-induced ERAD is the paucity of ERAD substrates being dislocated and detected at any given time. To obviate this problem, we report here the use of a sensitive biotinylation system to probe the dislocation of major histocompatibility complex I (MHCI) heavy chain substrates in the absence of immune evasion proteins. Using this assay system the dislocation of MHCI heavy chains was found not to require potential ubiquitin conjugation sites in the cytoplasmic tail or Lys residues in the ectodomain. By contrast, dislocation of MHCI heavy chains did require deubiquitinating enzyme activity and rapid proteasome-mediated degradation required Lys residues in MHCI heavy chain ectodomain. These combined findings support the model that the endoplasmic reticulum quality control-induced dislocation of MHCI heavy chains may not require direct ubiquitination/deubiquitination as is required for proteasome mediated degradation post dislocation. PMID- 23801328 TI - Anandamide-derived prostamide F2alpha negatively regulates adipogenesis. AB - Lipid mediators variedly affect adipocyte differentiation. Anandamide stimulates adipogenesis via CB1 receptors and peroxisome proliferator-activated receptor gamma. Anandamide may be converted by PTGS2 (COX2) and prostaglandin F synthases, such as prostamide/prostaglandin F synthase, to prostaglandin F2alpha ethanolamide (PGF2alphaEA), of which bimatoprost is a potent synthetic analog. PGF2alphaEA/bimatoprost act via prostaglandin F2alphaFP receptor/FP alt4 splicing variant heterodimers. We investigated whether prostamide signaling occurs in preadipocytes and controls adipogenesis. Exposure of mouse 3T3-L1 or human preadipocytes to PGF2alphaEA/bimatoprost during early differentiation inhibits adipogenesis. PGF2alphaEA is produced from anandamide in preadipocytes and much less so in differentiating adipocytes, which express much less PTGS2, FP, and its alt4 splicing variant. Selective antagonism of PGF2alphaEA receptors counteracts prostamide effects on adipogenesis, as does inhibition of ERK1/2 phosphorylation. Selective inhibition of PGF2alphaEA versus prostaglandin F2alpha biosynthesis accelerates adipogenesis. PGF2alphaEA levels are reduced in the white adipose tissue of high fat diet-fed mice where there is a high requirement for new adipocytes. Prostamides also inhibit zebrafish larval adipogenesis in vivo. We propose that prostamide signaling in preadipocytes is a novel anandamide-derived antiadipogenic mechanism. PMID- 23801329 TI - Lactosylceramide interacts with and activates cytosolic phospholipase A2alpha. AB - Lactosylceramide (LacCer) is a member of the glycosphingolipid family and is known to be a bioactive lipid in various cell physiological processes. However, the direct targets of LacCer and cellular events mediated by LacCer are largely unknown. In this study, we examined the effect of LacCer on the release of arachidonic acid (AA) and the activity of cytosolic phospholipase A2alpha (cPLA2alpha). In CHO-W11A cells, treatment with 1-phenyl-2-palmitoylamino-3 morpholino-1-propanol (PPMP), an inhibitor of glucosylceramide synthase, reduced the glycosphingolipid level, and the release of AA induced by A23187 or platelet activating factor was inhibited. The addition of LacCer reversed the PPMP effect on the stimulus-induced AA release. Exogenous LacCer stimulated the release of AA, which was decreased by treatment with an inhibitor of cPLA2alpha or silencing of the enzyme. Treatment of CHO-W11A cells with LacCer induced the translocation of full-length cPLA2alpha and its C2 domain from the cytosol to the Golgi apparatus. LacCer also induced the translocation of the D43N mutant of cPLA2alpha. Treatment of L929 cells with TNF-alpha induced LacCer generation and mediated the translocation of cPLA2alpha and AA release, which was attenuated by treatment with PPMP. In vitro studies were then conducted to test whether LacCer interacts directly with cPLA2alpha. Phosphatidylcholine vesicles containing LacCer increased cPLA2alpha activity. LacCer bound to cPLA2alpha and its C2 domain in a Ca(2+)-independent manner. Thus, we propose that LacCer is a direct activator of cPLA2alpha. PMID- 23801330 TI - Calcium-dependent activator protein for secretion 1 (CAPS1) binds to syntaxin-1 in a distinct mode from Munc13-1. AB - Calcium-dependent activator protein for secretion 1 (CAPS1) is a multidomain protein containing a Munc13 homology domain 1 (MHD1). Although CAPS1 and Munc13-1 play crucial roles in the priming stage of secretion, their functions are non redundant. Similar to Munc13-1, CAPS1 binds to syntaxin-1, a key t-SNARE protein in neurosecretion. However, whether CAPS1 interacts with syntaxin-1 in a similar mode to Munc13-1 remains unclear. Here, using yeast two-hybrid assays followed by biochemical binding experiments, we show that the region in CAPS1 consisting of the C-terminal half of the MHD1 with the corresponding C-terminal region can bind to syntaxin-1. Importantly, the binding mode of CAPS1 to syntaxin-1 is distinct from that of Munc13-1; CAPS1 binds to the full-length of cytoplasmic syntaxin-1 with preference to its "open" conformation, whereas Munc13-1 binds to the first 80 N-terminal residues of syntaxin-1. Unexpectedly, the majority of the MHD1 of CAPS1 is dispensable, whereas the C-terminal 69 residues are crucial for the binding to syntaxin-1. Functionally, a C-terminal truncation of 69 or 134 residues in CAPS1 abolishes its ability to reconstitute secretion in permeabilized PC12 cells. Our results reveal a novel mode of binding between CAPS1 and syntaxin-1, which play a crucial role in neurosecretion. We suggest that the distinct binding modes between CAPS1 and Munc13-1 can account for their non-redundant functions in neurosecretion. We also propose that the preferential binding of CAPS1 to open syntaxin-1 can contribute to the stabilization of the open state of syntaxin-1 during its transition from "closed" state to the SNARE complex formation. PMID- 23801331 TI - Polysialic acid on neuropilin-2 is exclusively synthesized by the polysialyltransferase ST8SiaIV and attached to mucin-type o-glycans located between the b2 and c domain. AB - Neuropilin-2 (NRP2) is well known as a co-receptor for class 3 semaphorins and vascular endothelial growth factors, involved in axon guidance and angiogenesis. Moreover, NRP2 was shown to promote chemotactic migration of human monocyte derived dendritic cells (DCs) toward the chemokine CCL21, a function that relies on the presence of polysialic acid (polySia). In vertebrates, this posttranslational modification is predominantly found on the neural cell adhesion molecule (NCAM), where it is synthesized on N-glycans by either of the two polysialyltransferases, ST8SiaII or ST8SiaIV. In contrast to NCAM, little is known on the biosynthesis of polySia on NRP2. Here we identified the polySia attachment sites and demonstrate that NRP2 is recognized only by ST8SiaIV. Although polySia-NRP2 was found on bone marrow-derived DCs from wild-type and St8sia2(-/-) mice, polySia was completely lost in DCs from St8sia4(-/-) mice despite normal NRP2 expression. In COS-7 cells, co-expression of NRP2 with ST8SiaIV but not ST8SiaII resulted in the formation of polySia-NRP2, highlighting distinct acceptor specificities of the two polysialyltransferases. Notably, ST8SiaIV synthesized polySia selectively on a NRP2 glycoform that was characterized by the presence of sialylated core 1 and core 2 O-glycans. Based on a comprehensive site-directed mutagenesis study, we localized the polySia attachment sites to an O-glycan cluster located in the linker region between b2 and c domain. Combined alanine exchange of Thr-607, -613, -614, -615, -619, and 624 efficiently blocked polysialylation. Restoration of single sites only partially rescued polysialylation, suggesting that within this cluster, polySia is attached to more than one site. PMID- 23801332 TI - Sea anemone peptide with uncommon beta-hairpin structure inhibits acid-sensing ion channel 3 (ASIC3) and reveals analgesic activity. AB - Three novel peptides were isolated from the venom of the sea anemone Urticina grebelnyi. All of them are 29 amino acid peptides cross-linked by two disulfide bridges, with a primary structure similar to other sea anemone peptides belonging to structural group 9a. The structure of the gene encoding the shared precursor protein of the identified peptides was determined. One peptide, pi-AnmTX Ugr 9a-1 (short name Ugr 9-1), produced a reversible inhibition effect on both the transient and the sustained current of human ASIC3 channels expressed in Xenopus laevis oocytes. It completely blocked the transient component (IC50 10 +/- 0.6 MUM) and partially (48 +/- 2%) inhibited the amplitude of the sustained component (IC50 1.44 +/- 0.19 MUM). Using in vivo tests in mice, Ugr 9-1 significantly reversed inflammatory and acid-induced pain. The other two novel peptides, AnmTX Ugr 9a-2 (Ugr 9-2) and AnmTX Ugr 9a-3 (Ugr 9-3), did not inhibit the ASIC3 current. NMR spectroscopy revealed that Ugr 9-1 has an uncommon spatial structure, stabilized by two S-S bridges, with three classical beta-turns and twisted beta-hairpin without interstrand disulfide bonds. This is a novel peptide spatial structure that we propose to name boundless beta-hairpin. PMID- 23801333 TI - Sulfation of the bikunin chondroitin sulfate chain determines heavy chain.hyaluronan complex formation. AB - Inter-alpha-trypsin inhibitor (IalphaI) is a complex comprising two heavy chains (HCs) that are covalently bound by an ester bond to chondroitin sulfate (CS), which itself is attached to Ser-10 of bikunin. IalphaI is essential for the trans esterification of HCs onto hyaluronan (HA). This process is important for the stabilization of HA-rich matrices during ovulation and some inflammatory processes. Bikunin has been isolated previously by anion exchange chromatography with a salt gradient up to 0.5 M NaCl and found to contain unsulfated and 4 sulfated CS disaccharides. In this study, bikunin-containing fractions in plasma and urine were separated by anion exchange chromatography with a salt gradient of 0.1-1.0 M NaCl, and fractions were analyzed for their reactivity with the 4 sulfated CS linkage region antibody (2B6). The fractions that reacted with the 2B6 antibody (0.5-0.8 M NaCl) were found to predominantly contain sulfated CS disaccharides, including disulfated disaccharides, whereas the fractions that did not react with this antibody (0.1-0.5 M NaCl) contained unsulfated and 4-sulfated CS disaccharides. IalphaI in the 0.5-0.8 M NaCl plasma fraction was able to promote the trans-esterification of HCs to HA in the presence of TSG-6, whereas the 0.1-0.5 M NaCl fraction had a much reduced ability to transfer HC proteins to HA, suggesting that the CS containing 4-sulfated linkage region structures and disulfated disaccharides are involved in the HC transfer. Furthermore, these data highlight that the structure of the CS attached to bikunin is important for the transfer of HC onto HA and emphasize a specific role of CS chain sulfation. PMID- 23801334 TI - The Keap1/Nrf2 protein axis plays a role in osteoclast differentiation by regulating intracellular reactive oxygen species signaling. AB - Reactive oxygen species (ROS) act as intracellular signaling molecules in the regulation of receptor activator of nuclear factor-kappaB ligand (RANKL) dependent osteoclast differentiation, but they also have cytotoxic effects that include peroxidation of lipids and oxidative damage to proteins and DNA. Cellular protective mechanisms against oxidative stress include transcriptional control of cytoprotective enzymes by the transcription factor, nuclear factor E2-related factor 2 (Nrf2). This study investigated the relationship between Nrf2 and osteoclastogenesis. Stimulation of osteoclast precursors (mouse primary peritoneal macrophages and RAW 264.7 cells) with RANKL resulted in the up regulation of kelch-like ECH-associated protein 1 (Keap1), a negative regulator of Nrf2. It also decreased the Nrf2/Keap1 ratio, and it down-regulated cytoprotective enzymes (heme oxygenase-1, gamma-glutamylcysteine synthetase, and glucose-6-phosphate dehydrogenase). Nrf2 overexpression up-regulated the expression of cytoprotective enzymes, decreased ROS levels, decreased the number of tartrate-resistant acid phosphatase-positive multinucleated cells, reduced marker genes for osteoclast differentiation, and attenuated bone destruction in both in vitro and in vivo models. Overexpression of Keap1 or RNAi knockdown of Nrf2 exerted the opposite actions. In addition, in vivo local Nrf2 overexpression attenuated lipopolysaccharide-mediated RANKL-dependent cranial bone destruction in vivo. This is the first study to show that the Keap1/Nrf2 axis regulates RANKL dependent osteoclastogenesis through modulation of intracellular ROS signaling via expression of cytoprotective enzymes. This raises the exciting possibility that the Keap1-Nrf2 axis may be a therapeutic target for the treatment of bone destructive disease. PMID- 23801335 TI - The Pneumocystis Ace2 transcription factor regulates cell wall-remodeling genes and organism virulence. AB - Pneumocystis carinii (Pc) beta-glucans are major components of the organism cell wall; yet, the regulation of Pc cell wall genesis and remodeling is not well understood. Ace2 transcription factors, which are present in many fungi, regulate glucanases and other enzymes needed for cell wall remodeling. The cloning and heterologous expression of PcAce2 in ace2Delta Saccharomyces cerevisiae demonstrated that PcAce2 can restore the defective glucanase and endochitinase gene expression of the mutant as well as regulate cell wall beta-glucan biosynthetic genes. Furthermore, when a reconstructed yeast system was used, PcAce2 activated the transcription of the Pneumocystis gsc1 beta-glucan synthetase, confirming the activity of a Pc transcription factor on a native Pneumocystis promoter and gene for the first time. We further observed that Pneumocystis binding to host extracellular matrix proteins and lung epithelial cells induced the phosphorylation (activation) of the PcAce2 transcription factor. Finally, we present a novel method that confirms the role of PcAce2 in modulating organism virulence using ace2Delta Candida glabrata infection in neutropenic mice. Together, these results indicate that the adherence of Pc to lung matrix proteins and epithelial cells leads to the activation of the Ace2 transcription factor, which regulates cell wall degradation and biosynthesis genes that are required for cell wall remodeling. PMID- 23801336 TI - Virus NAT for HIV, HBV, and HCV in Post-Mortal Blood Specimens over 48 h after Death of Infected Patients - First Results. AB - OBJECTIVE: According to EU regulations (EU directive 2006/17/EC), blood specimens for virologic testing in the context of post-mortal tissue donation must be taken not later than 24 h post mortem. METHODS: To verify validity of NAT in blood specimens collected later, viral nucleic acid concentrations were monitored in blood samples of deceased persons infected with HIV (n = 7), HBV (n = 5), and HCV (n = 17) taken upon admission and at 12 h, 24 h, 36 h and 48 h post mortem. HIV and HCV RNA were quantified using Cobas TaqMan (Roche), HBV DNA was measured by in-house PCR. RESULTS: A more than 10-fold decrease of viral load in samples taken 36 h or 48 h post mortem was seen in one HIV-infected patient only. For all other patients tested the decrease of viral load in 36-hour or 48-hour post mortal samples was less pronounced. Specimens of 3 HIV- and 2 HBV-infected patients taken 24 h post mortem or later were even found to have increased concentrations (>10-fold), possibly due to post-mortem liberation of virus from particular cells or tissues. CONCLUSION: Our preliminary data indicate that the time point of blood collection for HIV, HBV and HCV testing by PCR may be extended to 36 h or even 48 h post mortem and thus improve availability of tissue donations. PMID- 23801337 TI - Lymph node ratio is a critical prognostic predictor in gastric cancer treated with S-1 chemotherapy. AB - BACKGROUND: S-1 is an oral anticancer drug widely used in postoperative adjuvant therapy for patients in Japan with stage II/III gastric cancer. Candidates for more intense adjuvant treatments need to be identified, particularly among patients with stage III cancer. METHODS: Univariate and multivariate analyses were conducted for patients with stage II/III gastric cancer who underwent surgery and received S-1 postoperatively between 2000 and 2010. RESULTS: Factors indicating poor prognosis identified by univariate analysis include male sex (P = 0.022), age >=67 years (P = 0.021), intestinal-type histology (P = 0.049), lymph node ratio >=16.7 % (P < 0.0001), open surgery (P = 0.039), as well as the 13th JGCA stage (P < 0.0001) and the 14th JGCA/7th International Union Against Cancer (UICC) stage (P < 0.0001). Multivariate analysis revealed that lymph node ratio >=16.7 % and intestinal-type histology were significant as predictors of prognosis, independent from the pathological stages. Based on these and other findings, stage IIIC cancer on the 14th JGCA/7th UICC stage system in combination with the lymph node ratio could identify patients with extremely high risk for recurrence CONCLUSIONS: Our current findings suggest that lymph node ratio >=16.7 % in combination with the new staging system could be a useful prognostic indicator in advanced gastric cancer. Because these high-risk patients cannot be identified preoperatively by any diagnostic tool, further improvement in postoperative adjuvant therapy is warranted. PMID- 23801338 TI - Time trend of medical economic outcomes of endoscopic submucosal dissection for gastric cancer in Japan: a national database analysis. AB - BACKGROUND: Little information is available on the analysis of chronological changes in medical economic outcomes of endoscopic submucosal dissection (ESD) for gastric cancer. This study aimed to investigate the recent time trend of medical economic outcomes of ESD for gastric cancer based on the Japanese administrative database. METHODS: A total of 32,943 patients treated with ESD for gastric cancer were referred to 907 hospitals from 2009 to 2011 in Japan. We collected patients' data from the administrative database to compare ESD-related complications, risk-adjusted length of stay (LOS), and medical costs during hospitalization. The study periods were categorized into three groups: 2009 (n = 9,727), 2010 (n = 11,052), and 2011 (n = 12,164). RESULTS: No significant difference was observed in ESD-related complications between three study periods (p = 0.496). However, mean LOS and medical costs during hospitalization of patients with ESD were significantly lower in 2011 than in 2009 and 2010 (p < 0.001). Multiple linear regression analysis showed that patients who received ESD in 2011 had a significantly shorter LOS and lower medical costs during hospitalization compared with those in 2009. The unstandardized coefficient of patients with ESD in 2011 for LOS was -0.78 days [95 % confidence interval (CI), 0.89 to -0.65; p <= 0.001], while that of those for medical costs during hospitalization was -290.5 US dollars (95 % CI, -392.3 to -188.8; p <= 0.001). CONCLUSIONS: This study showed that the complication rate of ESD was stable, whereas the LOS and medical costs of patients were significantly reduced from 2009 to 2011. PMID- 23801339 TI - Spatial distribution of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans in soil around a municipal solid waste incinerator. AB - Municipal solid waste incinerators (MSWIs) are usually considered to be important sources of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs). To examine the influence of PCDD/Fs emissions from a MSWI on the surrounding environment, 21 soil samples were collected from various sampling sites distributed at distances of 300-1,700 m away from the stack of a MSWI. International Toxic Equivalent (I-TEQ) concentrations ranged from 0.47 to 2.07 pg I-TEQ g(-1), with average and median concentrations of 1.08 and 1.05 pg I-TEQ g( 1), respectively. Comparison of the results presented herein with other worldwide studies suggested that the concentrations of PCDD/Fs in the ambient soil were relatively low, indicating a limited impact on the surrounding environment. The emission concentrations from the incinerator were the critical factor in generating an environmental impact on the surrounding environment. An exponential function was developed, indicating a slight decline in TEQs of PCDD/Fs with increasing distance from the MSWI stack. The ordinary kriging interpolation technique was selected to create a contour map, which intuitively showed that a limited surrounding area (<=1,000 m from the stack) was obviously influenced by the MSWI. PMID- 23801340 TI - Levels and profiles of Dechlorane Plus in a major E-waste dismantling area in China. AB - Dechlorane Plus (DP) is a high-production volume, chlorinated flame retardant comprising two major isomers, syn- and anti-DP. In this study, levels of DP were measured in soil and earthworm samples in farmland from a typical E-waste dismantling area in China. The concentrations of total DP ranged from 0.17 to 1,990 ng g(-1) dw in soil samples and 3.43 to 89.2 ng g(-1) lw in earthworm samples. Higher DP levels were found in some main E-waste dismantling sites than those in other sites. The ratios of anti-DP to total DP (f anti) ranged from 0.57 to 0.80 in soil samples and 0.47 to 0.81 in earthworm samples, respectively. The f anti in most samples in this study was in the range of the reported technical DP values. These results showed that improper E-waste dismantling activities could result in the emission of DP. Most earthworm samples showed very low BSAFs (biota-to-soil accumulation factors) for total DP. The values of BSAF were in the range of 0.0007-1.85, with an average value of 0.23. This study presents the first report of the DP in earthworms, which would be useful for ecological risk assessment of DP in terrestrial ecosystem. PMID- 23801341 TI - The nitrate time bomb: a numerical way to investigate nitrate storage and lag time in the unsaturated zone. AB - Nitrate pollution in groundwater, which is mainly from agricultural activities, remains an international problem. It threatens the environment, economics and human health. There is a rising trend in nitrate concentrations in many UK groundwater bodies. Research has shown it can take decades for leached nitrate from the soil to discharge into groundwater and surface water due to the 'store' of nitrate and its potentially long travel time in the unsaturated and saturated zones. However, this time lag is rarely considered in current water nitrate management and policy development. The aim of this study was to develop a catchment-scale integrated numerical method to investigate the nitrate lag time in the groundwater system, and the Eden Valley, UK, was selected as a case study area. The method involves three models, namely the nitrate time bomb-a process based model to simulate the nitrate transport in the unsaturated zone (USZ), GISGroundwater--a GISGroundwater flow model, and N-FM--a model to simulate the nitrate transport in the saturated zone. This study answers the scientific questions of when the nitrate currently in the groundwater was loaded into the unsaturated zones and eventually reached the water table; is the rising groundwater nitrate concentration in the study area caused by historic nitrate load; what caused the uneven distribution of groundwater nitrate concentration in the study area; and whether the historic peak nitrate loading has reached the water table in the area. The groundwater nitrate in the area was mainly from the 1980s to 2000s, whilst the groundwater nitrate in most of the source protection zones leached into the system during 1940s-1970s; the large and spatially variable thickness of the USZ is one of the major reasons for unevenly distributed groundwater nitrate concentrations in the study area; the peak nitrate loading around 1983 has affected most of the study area. For areas around the Bowscar, Beacon Edge, Low Plains, Nord Vue, Dale Springs, Gamblesby, Bankwood Springs, and Cliburn, the peak nitrate loading will arrive at the water table in the next 34 years; statistical analysis shows that 8.7 % of the Penrith Sandstone and 7.3 % of the St Bees Sandstone have not been affected by peak nitrate. This research can improve the scientific understanding of nitrate processes in the groundwater system and support the effective management of groundwater nitrate pollution for the study area. With a limited number of parameters, the method and models developed in this study are readily transferable to other areas. PMID- 23801342 TI - Stereoisomeric profiling of pharmaceuticals ibuprofen and iopromide in wastewater and river water, China. AB - Stereoisomeric compositions can provide insights into sources, fate, and ecological risks of contaminants in the environment. In this study, stereoisomeric profiles of ibuprofen and iopromide were investigated in wastewater and receiving surface water of the Pearl River Delta, south China. The enantiomeric fraction (EF) of ibuprofen was 0.108-0.188 and 0.480, whereas the isomer ratio (IR) of iopromide was 1.426-1.673 and 1.737-1.898 in the influent and final effluent, respectively, suggesting stereoselective degradation occurred for both pharmaceuticals during wastewater treatment. Ibuprofen showed enantioselective degradation in the anaerobic, anoxic, and aerobic conditions, whereas iopromide displayed isomer-selective degradation only under the aerobic condition. In the river waters, the EF of ibuprofen was 0.130-0.327 and the IR of iopromide was 1.500-2.531. The results suggested that pharmaceuticals in the mainstream Pearl River were mainly from discharge of treated wastewater, whereas in the tributary rivers and urban canals, direct discharge of untreated wastewater represented a significant contribution. The IR of iopromide can be an applicable and efficient tracer for wastewater discharge in the environment. PMID- 23801343 TI - Carpal joint injuries in cats - an epidemiological study. AB - OBJECTIVE: Injuries of the carpal joint are rare in cats. The most common cause is a fall from a height, known as 'high-rise syndrome'. So far, only limited data about carpal joint injuries (CJI) in cats are available. The aim of this study was to investigate the epidemiology, aetiology, location, and type of CJI in cats. METHODS: Case records of cats diagnosed with CJI between 1998 and 2010 were retrospectively analysed. Data concerning signalment, history and type of CJI, accompanying systemic injuries and further orthopaedic injuries were collected. RESULTS: During the study period, 73 cats were diagnosed with CJI (87 injured carpal joints) and the prevalence in our hospital population was 0.26% (73 out of 28,482). Cats with CJI were more likely to be presented in the period from April October (85%, p = 0.003) compared with the rest of the year. Carpal joint injuries were caused by a fall from a height in 72.6% of the cases. Of all carpal joints, the antebrachiocarpal joint was predominantly injured (50.6%, p = 0.001) and this was commonly caused by a fall from the fourth floor or higher (p = 0.002). The carpometacarpal joint was predominantly affected by a fall from heights up to the third floor (p = 0.004). CLINICAL SIGNIFICANCE: The data of this study confirm previous data with respect to time of occurrence and cause of injury. Of note, the height of the fall appears to influence the location of the injury within the carpus of cats. PMID- 23801344 TI - Mapping of amide, amine, and aliphatic peaks in the CEST spectra of murine xenografts at 7 T. AB - PURPOSE: To evaluate the performance of endogenous chemical exchange saturation transfer (CEST) spectra and derived maps in a longitudinal study of tumor xenografts to ascertain the role of CEST parameters in describing tumor progression and in distinguishing between tumor, muscle, and necrosis. METHODS: CEST spectra of 24 mice with tumor xenografts (20 LLC and 4 MDA) were acquired at three time-points. We employed a novel method of decomposing the CEST spectrum into a sum of four Lorentzian shapes, each with a corresponding measured amplitude, width and frequency offset. This semi-quantitative method is an improvement over techniques which simply assess the asymmetry in the spectrum for the presence of CEST, due to the fact that it is not confounded by CEST peaks on opposing sides of the direct effect. The CEST images were compared to several other commonly employed contrast mechanisms: T1 relaxation, T2 relaxation, diffusion (ADC), and magnetization transfer (MT). RESULTS: Tumor spectra had distinct CEST peaks corresponding to the presence of hydrogen exchange between free water and amide, amine, and aliphatic groups. All three CEST peaks (amide, amine, and aliphatic) were larger in the tumor tissue as compared with the adjacent healthy muscle. CONCLUSIONS: CEST contrast (particularly the amine peak amplitude) performed especially well in distinguishing areas of apoptosis and/or necrosis from actively progressing tumor, as validated by histology. PMID- 23801345 TI - Prevalence of dental fluorosis among primary school children in rural areas of Karera Block, Madhya Pradesh. AB - OBJECTIVE: To determine prevalence and severity of dental fluorosis in school going children of ten villages of Karera block of Shivpuri District, Madhya Pradesh. METHODS: Fluoride ion concentration was measured in ten hand pump and two wells waters with a fluoride meter (ORION model 720). For the study total 750 school children were selected from ten government primary schools of ten rural villages. The survey was conducted during the period of November 2007 through December 2009. The dental and oral examination was done by two trained dentists. The occurrence and severity of dental fluorosis was recorded using Dean's index. RESULTS: Drinking water sources considered for study were hand pumps, and wells. Out of 750 children surveyed, 341 were found affected with dental fluorosis. The boys had greater prevalence (46.75%) as compared to girls (42.18%). Dental fluorosis, as assessed by Dean's Index shows that 20.8% children had grade I, 19.47% grade II, 5.2% grade III. Overall, 45.46% of the sample showed some grades of dental fluorosis. CONCLUSIONS: In all the 144 water samples from ten villages fluoride level was higher than permissible limits. The boys had greater prevalence of dental fluorosis over the girls. PMID- 23801346 TI - Evaluation of synovial inflammation in juvenile idiopathic arthritis by power color Doppler and Spectral Doppler ultrasonography. AB - OBJECTIVES: To compare Power Color Doppler and Spectral Doppler ultrasonography indices (Resistive index and color fraction) in cases of Juvenile Idiopathic Arthritis (JIA) with healthy controls and evaluate their correlation with clinical and laboratory parameters. METHODS: A cross sectional study was done over a period of 16 mo. Thirty patients of JIA and 30 age and sex matched healthy children were enrolled. Swelling and tenderness scores were evaluated and hemoglobin, total leukocyte count, erythrocyte sedimentation rate and C-reactive protein were done. A total of 112 diseased joints and 135 healthy joints were evaluated by USG by the same radiologist, and color fraction and RI were recorded. RESULTS: Statistically significant higher color fraction and lower RI (Resistive Index) were found in diseased joints as compared to healthy joints. Also the value of color fraction increased significantly with increasing grade of tenderness and RI decreased significantly with increasing grade of swelling. CONCLUSIONS: Power Color Doppler and Spectral Doppler ultrasonography (USG) indices (RI and color fraction) are significantly different in JIA patients. These might find a place in early diagnosis, monitoring of disease activity and response to therapy in JIA patients. PMID- 23801347 TI - Nutritional status of tribal children and adolescents in rural south India: the effect of an NGO delivered nutritional programme. AB - OBJECTIVES: To investigate the prevalence of malnutrition using anthropometric measures in a cohort of tribal students attending a school in rural south India. Children attending the school were offered three meals a day during attendance. Analysis of anthropometric data obtained aimed to determine the nutritional effect of the food provided. METHODS: The nutritional status of 409 students were assessed by comparing anthropometric measurements to reference values according to WHO/NCHS guidelines. Height for age <3rd percentile was defined as stunting. BMI for age <5th percentile was defined as thinness. 'New' students were defined as attending the school for <1 y. 'Old' students were defined as being in attendance for >= 1 y. Comparison of thinness and stunting prevalence in these groups enabled evaluation of the meals provided by the organisation. RESULTS: Four hundred and nine students were included for analysis in the study. The prevalence of thinness was 39.4 %. 59.5 % of 'new' and 52.9 % of 'old' students at the school demonstrated thinness. 59.4 % of students were classified as stunted. 73.8 % of 'new' students and 52.9 % of 'old' students demonstrated stunting (p 0.091). Significantly (p 0.010) more 'new' female students had stunted growth. CONCLUSIONS: Acute and chronic measures of malnutrition were high amongst adolescent students attending the school. Comparison of 'new' and 'old' adolescent pupils at the school hints that the 'old' students were less malnourished than their 'new' counterparts. This study demonstrates the importance for NGOs to develop their nutritional programmes with a special focus on adolescents. PMID- 23801348 TI - Dental fluorosis and its extended effects. PMID- 23801349 TI - Unilateral phrenic nerve palsy: a rare manifestation of vincristine neurotoxicity. PMID- 23801350 TI - Truly work-like work extraction via a single-shot analysis. AB - The work content of non-equilibrium systems in relation to a heat bath is often analysed in terms of expectation values of an underlying random work variable. However, when optimizing the expectation value of the extracted work, the resulting extraction process is subject to intrinsic fluctuations, uniquely determined by the Hamiltonian and the initial distribution of the system. These fluctuations can be of the same order as the expected work content per se, in which case the extracted energy is unpredictable, thus intuitively more heat-like than work-like. This raises the question of the 'truly' work-like energy that can be extracted. Here we consider an alternative that corresponds to an essentially fluctuation-free extraction. We show that this quantity can be expressed in terms of a one-shot relative entropy measure introduced in information theory. This suggests that the relations between information theory and statistical mechanics, as illustrated by concepts like Maxwell's demon, Szilard engines and Landauer's principle, extends to the single-shot regime. PMID- 23801351 TI - Anion-dependent host-guest properties of porous assemblies of coordination complexes (PACs), [Cu(A)2(py)4] (A = PF6, BF4, CF3SO3, and CH3SO3; py = pyridine), based on Werner-type copper(II) complexes in the solid state. AB - We report the syntheses and crystal structures of novel porous assemblies of coordination complexes (PACs) with/without guest molecules, alpha-[Cu(A)2(py)4] (alpha-PAC-2-A (A = PF6, BF4, CF3SO3, and CH3SO3); py = pyridine), gamma {[Cu(PF6)2(py)4].2guest} (gamma-PAC-2-PF6 ? 2guest (guest = acetone and py)), gamma-{[Cu(BF4)2(py)4].2acetone} (gamma-PAC-2-BF4 ? 2acetone), and beta {[Cu(CH3SO3)2(py)4].2.67H2O} (beta-PAC-2-CH3SO3 ? 2.67H2O). The single-crystal X ray diffraction analyses of alpha-PAC-2-A show that alpha-PAC-2-A have dense packing structures, in which anions of the discrete coordination complexes form weak hydrogen-bonding and anion-pi interactions. In contrast, gamma-PAC-2-PF6 ? 2guest, gamma-PAC-2-BF4 ? 2acetone, and beta-PAC-2-CH3SO3 ? 2.67H2O form guest including structures with coordination environments around the Cu(II) atoms similar to the alpha-forms. The vapour adsorption measurements for MeCN and acetone in alpha-PAC-2-A suggest that the adsorption associated with structural transformations is induced by weak Lewis-base PF6- and BF4- anions covered only with fluorine atoms, which weaken the host-host interactions. PMID- 23801352 TI - Peritoneal morphological changes due to pneumoperitoneum: the effect of intra abdominal pressure. AB - INTRODUCTION: Carbon dioxide (CO2) used in laparoscopy evokes local and systemic effects. This study was designed to evaluate the histopathologic morphologic changes due to CO2 and air insufflation, at different pressure levels, on visceral and parietal peritoneum in rats. MATERIALS AND METHODS: A total of 56 rats were object of the study, randomly divided into five groups. Pneumoperitoneum (PN) was maintained for 30 minutes, at a flow rate of 0.5 L/min and at a pressure of 10 and 6 mm Hg with CO2 (group S1-S2, n = 32) and filtered air (group A1-A2, n = 16). Only anesthesia was performed in the fifth group (group C, n = 8). Peritoneal samples were obtained 24 hours later for blinded histological evaluation. A grading system was adopted to evaluate histological peritoneal changes (0, no change; 1, mild; 2, moderate; and 3, severe) such as mesothelial aspect, inflammatory response, edema, and hemorrhage. The score reflected the severity of damage and was calculated by the sum of the degree evaluated separately. Values were compared with the analysis of variance analysis. RESULTS: CO2 and air insufflation caused reactive mesothelial cells and peritoneal inflammation of different degrees depending on the level of intra abdominal pressure (IAP) and type of gas. These modifications were absent in group C and were less evident in low pressure S2 group with respect to S1 and A1 A2 groups. The average values of histopathologic peritoneal score showed significant differences between S2 (11.5) versus S1 groups (16.83) with respect to A groups (A1 = 27.83; A2 = 20.5) and compared with the controls (C = 2.5). CONCLUSIONS: Our data confirm that PN affects the peritoneal integrity. The grades of morphological peritoneal changes are related to the level of IAP. Low CO2 pressure causes minor peritoneal changes with respect to high pressure and air insufflation. PMID- 23801353 TI - A case with bladder exstrophy and unbalanced X chromosome rearrangement. AB - INTRODUCTION: Bladder exstrophy is a rare congenital malformation of the bladder and is believed to be a complex disorder with genetic and environmental background. We describe a young adult female with an isolated bladder exstrophy and with an X chromosome aberration. Patients and METHODS: Karyotyping identified an X chromosome rearrangement that was further characterized with array comparative genomic hybridization (CGH) and confirmed by multiplex ligation dependent probe amplification and fluorescence in situ hybridization (FISH) analysis. RESULTS: The identified X chromosome rearrangement in our index patient consists of a gain of chromosomal material in region Xq26.3- > qter and loss in region Xp22.12- > pter. This aberration was also carried by her mother and sister, none with bladder exstrophy. All three have a disproportionate short stature, as expected due to the deletion of one of the copies of the SHOX gene on Xp22.3. X-inactivation studies revealed a complete skewed inactivation pattern in carriers. Crossover events in the maternal germline furthermore resulted in different genetic material on the rearranged X chromosome between the index patient and her sister. CONCLUSION: Our findings suggest an X-linked genetic risk factor for bladder exstrophy. PMID- 23801354 TI - Duration of postoperative intravenous antibiotics in childhood complicated appendicitis: a propensity score-matched comparison study. AB - INTRODUCTION: Postoperative antibiotics complement surgery in managing childhood complicated appendicitis. However, there is limited evidence to guide clinicians on appropriate duration of therapy. A comparison cohort study was performed to determine whether tailoring duration of inpatient intravenous (IV) antibiotic therapy to patient response, assessed using a set of clinical criteria, leads to shortened hospital length of stay (LOS) without compromising patient outcomes. PATIENTS AND METHODS: Over a 6-month period, 47 children (aged 5-14 years) with complicated appendicitis were treated with postoperative IV antibiotics until each satisfied a set of bedside clinical parameters suggesting resolved intraperitoneal infection (core temperature < 38 degrees C for 24 hours, tolerated two consecutive meals, mobilizing independently, requiring only oral analgesia). Complicated appendicitis was defined as the presence of generalized peritonitis, appendiceal perforation or gangrene, and/or abscess. Postoperative recovery parameters were prospectively recorded and compared with those of 47 historical control patients, matched by propensity scores, who received 5 days minimum of postoperative IV antibiotics. Sample size was determined by a priori power calculation based on reduction in LOS. Severity of postoperative complications was graded using the Clavien-Dindo system. RESULTS: Study group variables were comparable including patient demographics, duration of presenting symptoms, severity of presenting disease, preoperative antibiotics received, length of operation, seniority of primary surgeon, surgical approach taken, and intraoperative findings. The prospective cohort had a significantly shorter median LOS compared with the historical control cohort (5 vs. 6 nights, p = 0.010) while readmission rates and the incidence and severity of complications were similar, including incidence of postoperative intra-abdominal infections (6 vs. 8 cases, p = 0.562). CONCLUSION: Using bedside clinical parameters indicative of resolved intraperitoneal infection to tailor duration of postoperative IV antibiotics for children with complicated appendicitis shortens LOS without apparent compromise to patient outcomes. PMID- 23801355 TI - Mixed method approaches in open-ended, qualitative, exploratory research involving people with intellectual disabilities: a comparative methods study. AB - People with intellectual disabilities and their families are increasingly being asked to provide input into the services they receive. Under the aegis of the United Nation Convention of the Rights of Persons with Disabilities, support plans crucially depend on a participant's articulation of his or her preferences and life goals. Yet, research highlighting the strengths and weaknesses of different methodological approaches has not been published. This study compared the results of a suite of qualitative methods (questionnaire, focus group, semi structured interview, "case in point" ethnographic observation, photographic images, and carer proxy response) by identifying the advantages and disadvantages of each method employed. It also foregrounds an effective mix of methods that is likely to produce an adequate representation of the views of people with disabilities within the context of open-ended exploratory questions. PMID- 23801356 TI - Monitoring metabolic side effects of atypical antipsychotics in people with an intellectual disability. AB - This audit was undertaken prospectively to examine the compliance of a group of psychiatrists against guidelines they developed for monitoring the onset of metabolic syndrome, a potential side effect of antipsychotic medication, especially second generation or atypical ones. Phase 1 of the audit was to set standards by a questionnaire survey of participating psychiatrists against Consensus Guidelines on monitoring (American Diabetic Association, 2004), which they favoured. The results led to modifying these guidelines to develop minimum acceptable standards against which their practice was audited in Phase 2. Although in Phase 1, 77% of the psychiatrists felt that they did some baseline recording, Phase 2 finding did not corroborate this--only 53.8% of the notes recorded the assessment of risk factors in personal history; 37.5% risk factors in family history; 31.7% baseline weight and 26.4% baseline blood sugar/lipid levels. In Phase 1, 85% of the psychiatrists thought that they carried out some of the recommended monitoring; our audit found the records of weight monitoring in 69.7% of the notes and blood sugar and lipids monitoring in 44.2%. People with intellectual disability have a shorter life expectancy and increased risk of early death when compared with the general population. Obesity is already a health issue for people with intellectual disability. We discuss the challenges faced by psychiatrists in implementing their own minimum acceptable standards and suggest measures to reduce the metabolic risk associated with antipsychotic medication through increasing awareness--use of information leaflets in accessible format, health promotion and use of side effect checklists and improving access--by working collaboratively with general practitioners utilising the forum of annual health checks. PMID- 23801357 TI - Effects of ketoconazole on the pharmacokinetics of ponatinib in healthy subjects. AB - Ponatinib is a BCR-ABL tyrosine kinase inhibitor (TKI) approved for the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia in patients resistant or intolerant to prior TKIs. In vitro studies suggested that metabolism of ponatinib is partially mediated by CYP3A4. The effects of CYP3A4 inhibition on the pharmacokinetics of ponatinib and its CYP3A4-mediated metabolite, AP24567, were evaluated in a single-center, randomized, two-period, two-sequence crossover study in healthy volunteers. Subjects (N = 22) received two single doses (orally) of ponatinib 15 mg, once given alone and once coadministered with daily (5 days) ketoconazole 400 mg, a CYP3A4 inhibitor. Ponatinib plus ketoconazole increased ponatinib maximum plasma concentration (C(max)) and area under the concentration-time curve (AUC) compared with ponatinib alone. The estimated mean ratios for AUC0-infinity, AUC0-t, and C(max) indicated increased exposures to ponatinib of 78%, 70%, and 47%, respectively; exposure to AP24567 decreased by 71%. Exposure to AP24567 was marginal after ponatinib alone (no more than 4% of the exposure to ponatinib). These results suggest that caution should be exercised with the concurrent use of ponatinib and strong CYP3A4 inhibitors and that a ponatinib dose decrease to 30 mg daily, from the 45 mg daily starting dose, could be considered. PMID- 23801359 TI - [Injection therapy of cervical spine syndromes]. AB - In cervical spine syndromes, specific injections can reach the pain focus or diminish the nerve root irritation, thus overcoming the vicious circle. Indications, contra-indications, complications, the exact procedure of placing the needle, and the combined use with conservative treatment must be taken into consideration. PMID- 23801358 TI - Antipsychotics for delirium in the general hospital setting in consecutive 2453 inpatients: a prospective observational study. AB - OBJECTIVE: Attention to risk of antipsychotics for older patients with delirium has been paid. A clinical question was whether risk of antipsychotics for older patients with delirium would exceed efficacy of those even in the general hospital setting. METHODS: A prospective observational study proceeded over a 1 year period at 33 general hospitals, where at least one psychiatrist worked full time. Subjects were patients who developed delirium during their admission due to acute somatic diseases or surgery, and who received antipsychotics for delirium. The primary outcome was rates and kinds of serious adverse events. RESULTS: Among 2834 patients who developed delirium, 2453 patients received antipsychotics, such as risperidone (34%), quetiapine (32%), and parenteral haloperidol (20%), for delirium. Out of 2453 patients, 22 serious adverse events (0.9%) were reported. Aspiration pneumonia was the most frequent (17 patients, 0.7%), followed by cardiovascular events (4 patients, 0.2%) and venous thromboembolism (1 patient, 0.0%). There was no patient with a fracture or intracranial injury due to a fall. No one died because of antipsychotic side effects. The mean Clinical Global Impressions-Improvement Scale score was 2.02 (SD 1.09). Delirium was resolved within 1 week in more than half of the patients (54%). CONCLUSIONS: In the general hospital setting under management including fine dosage adjustment and early detection of side effects, risk of antipsychotics for older patients with delirium might be low, in contrast to antipsychotics for dementia in the nursing home or outpatient settings. A point may be not how to avoid using antipsychotics but how to monitor their risk. PMID- 23801361 TI - Non-contact halogen lamp heating assisted LTP ionization miniature rectilinear ion trap: a platform for rapid, on-site explosives analysis. AB - A platform consisting of a halogen lamp, a low temperature plasma (LTP) probe, and a miniature rectilinear ion trap mass spectrometer (RIT-MS) has been constructed and evaluated to detect organic and inorganic explosives on solid surfaces. This platform features two attractive characteristics: high sensitivity for the explosives with low volatility, and rapid analysis speed for the explosives on large surface areas. With non-contact heating by the halogen lamp, the signal intensities for the explosives with relatively high volatility were improved by over an order of magnitude, compared to those obtained at room temperature; and even more, the explosives with low volatility, which could hardly be detected at room temperature, were able to be readily identified. The limits of detection (LODs) of the selected explosives were all at the picogram level (e.g., 10 pg and 20 pg for TNT and RDX, respectively) with a heating time of 3 s. Using manual surface swabbing, the analysis of explosives on a large surface area (7.5 cm * 2.5 cm) was accomplished within 10 s, and an acceptable sensitivity could be acquired; additionally, inorganic explosives (black powder and firecracker) were successfully detected. Without any sample pretreatment, the platform was used to analyze the wastewater from an explosives factory, confirming the existence of 2,4,6-trinitrotoluene (TNT), 2,4-dinitrotoluene (2,4 DNT), and 2,6-dinitrotoluene (2,6-DNT), and the concentration of TNT was determined to be 5 ng mL(-1). All these results indicated that the proposed platform was a promising technique for security monitoring and environmental analysis. PMID- 23801360 TI - Characterization and localization of mitochondrial DNA-encoded tRNAs and nuclear DNA-encoded tRNAs in the sea anemone Metridium senile. AB - The mitochondrial (mt) genome of the sea anemone Metridium senile contains genes for only two transfer RNAs (tRNAs), tRNAf-Met and tRNATrp. Experiments were conducted to seek evidence for the occurrence of functional tRNAs corresponding to these genes and for the participation of nuclear DNA-encoded tRNAs in mt protein synthesis. RNA sequences corresponding to the two mt-tRNA genes were located in mitochondria and it was shown that 3'-CC (and possibly A, but no other nucleotide) is added post-transcriptionally to the 3' end of at least 50 % of mt tRNAf-Met molecules and to a small fraction of the mt-tRNATrp molecules. Using specific oligonucleotide primers based on expected nuclear DNA-encoded tRNAs in a series of RACE experiments, we located the nuclear genes for tRNAGln, tRNAIle, tRNAi-Met, tRNAVal and tRNAThr. Data from Northern blot analyses indicated that mtDNA-encoded tRNAf-Met is limited to mitochondria but that nuclear DNA-encoded tRNAVal and tRNAi-Met are present in the cytoplasm and in mitochondria. These data provide direct evidence that in M. senile, mature, functional tRNAs are transcribed from the mtDNA-encoded tRNAf-Met and tRNATrp genes, and are consistent with the interpretation that both nuclear DNA-encoded tRNAVal and tRNAi-Met are utilized in mitochondrial and cytosolic protein synthesis. PMID- 23801362 TI - Changes of the GPR17 receptor, a new target for neurorepair, in neurons and glial cells in patients with traumatic brain injury. AB - Unveiling the mechanisms participating in the damage and repair of traumatic brain injury (TBI) is fundamental to develop new therapies. The P2Y-like GPR17 receptor has recently emerged as a sensor of damage and a key actor in lesion remodeling/repair in the rodent brain, but its role in humans is totally unknown. Here, we characterized GPR17 expression in brain specimens from seven intensive care unit TBI patients undergoing neurosurgery for contusion removal and from 28 autoptic TBI cases (and 10 control subjects of matched age and gender) of two university hospitals. In both neurosurgery and autoptic samples, GPR17 expression was strong inside the contused core and progressively declined distally according to a spatio-temporal gradient. Inside and around the core, GPR17 labeled dying neurons, reactive astrocytes, and activated microglia/macrophages. In peri contused parenchyma, GPR17 decorated oligodendrocyte precursor cells (OPCs) some of which had proliferated, indicating re-myelination attempts. In autoptic cases, GPR17 expression positively correlated with death for intracranial complications and negatively correlated with patients' post-traumatic survival. Data indicate lesion-specific sequential involvement of GPR17 in the (a) death of irreversibly damaged neurons, (b) activation of microglia/macrophages remodeling the lesion, and (c) activation/proliferation of multipotent parenchymal progenitors (both reactive astrocytes and OPCs) starting repair processes. Data validate GPR17 as a target for neurorepair and are particularly relevant to setting up new therapies for TBI patients. PMID- 23801363 TI - In vivo antimalarial activity of Trichilia megalantha harms extracts and fractions in animal models. AB - The crude methanol extracts of leaf, stem bark, root bark and stem bark fractions of Trichilia megalantha (Meliaceae) were screened for in vivo antimalarial activities in mice against a chloroquine resistant Plasmodium berghei berghei ANKA clone using the 4-day suppressive test procedure. Chloroquine diphosphate was used as the positive control. The extracts demonstrated intrinsic antimalarial property. Of all the seven extracts studied, the stem bark gave the highest activity. At 200 mg/kg of mouse, the stem bark extract had complete suppression of parasite growth (100%). Least activity was observed for the leaf extract, while the root bark had a parasite suppression of 98.4% at 800 mg/kg comparable to that of Chloroquine. Percentage suppression of parasite growth on day 4 post-infection ranged from 3.1 to 96.1% in mice infected with P. berghei and treated with extracts and fractions of T. megalantha when compared with chloroquine diphosphate, the standard reference drug which had a chemosuppression of 96.2%. At 400 mg/kg, the stem bark chloroform fraction was the most active fraction with 89.1% parasite growth suppression followed by the ethyl acetate fraction (76.4%), hexane soluble fraction (54.8%) and methanol fraction (20.5%). The mean survival time of mice that received extract ranged from 8.75 +/- 0.65 to 26.0 +/- 1.2 days (increased as the dose increases to 800 mg/kg), which was statistically significant, except the lowest dose (100 mg/kg) compared to the negative control group mice (9.45 +/- 0.6 days). The animals that were treated with Chloroquine had mean survival time of 23.5 +/- 1.2 days. PMID- 23801364 TI - Stress in African catfish (Clarias gariepinus) following overland transportation. AB - Of the many stressors in aquaculture, transportation of fish has remained poorly studied. The objective of this study was therefore to assess the effects of a (simulated) commercial transportation on stress physiology of market-size African catfish (Clarias gariepinus). Catfish weighing approximately 1.25 kg were returned to the farm after 3 h of truck-transportation, and stress-related parameters were measured for up to 72 h following return. Recovery from transportation was assessed through blood samples measuring plasma cortisol, glucose and non-esterified fatty acids (NEFA) and gill histology. Also, the number of skin lesions was compared before and after transport. Pre-transport handling and sorting elevated plasma cortisol levels compared to unhandled animals (before fasting). Plasma cortisol levels were further increased due to transportation. In control fish, plasma cortisol levels returned to baseline values within 6 h, whereas it took 48 h to reach baseline values in transported catfish. Plasma glucose and NEFA levels remained stable and were similar across all groups. Transported catfish did not, on average, have more skin lesions than the handling group, but the number of skin lesions had increased compared to unhandled animals. The macroscopic condition of the gills was similar in control, transported and unhandled catfish; however, light microscopy and immunohistochemistry revealed atypical morphology and chloride cell migration normally associated with adverse water conditions. From our data, we conclude that transportation may be considered a strong stressor to catfish that may add to other stressors and thus inflict upon the welfare of the fish. PMID- 23801365 TI - Prostanoids-induced dispersion in the melanophores of a carp Labeo rohita (Ham.). AB - Effects of three prostaglandins (i.e., prostanoids) and one of its precursors, arachidonic acid, were examined on the melanophores of the fish Labeo rohita (Ham.). PGE1, PGE2, PGF(2alpha) and arachidonic acid elicit a concentration related dispersion in the fish melanophores. In vitro analysis of melanophores was performed through incubation of the isolated fish scales in different agonists and antagonists solutions. Dispersal effect of prostanoids may be mediated directly through the typical receptors or indirectly through release of neurotransmitter substance(s) from the melanophore nerve endings. Denervation of fish melanophores rendered them insensitive to prostanoid (PGF(2alpha)). Propranolol and verapamil completely inhibited the dispersal effects of PGF(2alpha); theophylline and indomethacine blocked the effects of higher concentrations of PGF(2alpha). During dispersing influence of PGF(2alpha), a free flux of Ca2+ ions was required and the indirectly released substance(s) from melanophore nerve endings would be the catecholamines of adrenergic and purinergic in nature. PMID- 23801367 TI - The Endocrine Society Clinical Practice Guidelines: a self-assessment. PMID- 23801366 TI - Robotic-assisted transanal surgery for total mesorectal excision (RATS-TME): a description of a novel surgical approach with video demonstration. AB - A new era has emerged in rectal cancer surgery--transanal total mesorectal excision (TME). Various platforms have been used to facilitate this novel approach, including transanal minimally invasive surgery (TAMIS) and transanal endoscopic microsurgery. We have previously reported the use of TAMIS-TME. This is a report of the first human case of robotic-assisted transanal surgery for TME. PMID- 23801368 TI - The use of planar bone scintigraphy and HiSPECT for diagnosis of primary and concomitant flexor enthesopathy in the canine elbow. AB - OBJECTIVE: To investigate the possibilities and limitations of planar bone scintigraphy and high resolution single photon emission computed tomography (HiSPECT) to diagnose flexor enthesopathy and to distinguish primary flexor enthesopathy from the concomitant form. MATERIALS AND METHODS: A prospective study of 46 dogs with primary flexor enthesopathy, concomitant flexor enthesopathy, medial coronoid disease, and normal elbows was performed. All dogs underwent planar bone scintigraphy and HiSPECT imaging. The obtained images were visually scored for increased radiopharmaceutical uptake in the medial humeral epicondylar and medial coronoid process region using a score from 1-3. RESULTS: Planar bone scintigraphy demonstrated increased radiopharmaceutical uptake in all diseased elbow joints, except for one. HiSPECT demonstrated increased radiopharmaceutical uptake of the medial humeral epicondyle in nearly all clinically affected joints with primary and concomitant flexor enthesopathy. Additional uptake of the medial coronoid process was recorded in all clinically affected joints with concomitant flexor enthesopathy and in six out of 18 with primary flexor enthesopathy. No difference in intensity of the uptake was noticed. CLINICAL SIGNIFICANCE: Planar bone scintigraphy allows the attribution of lameness to the elbow joint in cases of primary flexor enthesopathy with minimal or even absent radiographic changes. The more detailed HiSPECT enables the localization of pathology within the elbow joint and is a sensitive technique to detect flexor enthesopathy. However HiSPECT is insufficient to distinguish primary from concomitant flexor enthesopathy. PMID- 23801369 TI - Microstructure of microemulsion modified with ionic liquids in microemulsion electrokinetic chromatography and analysis of seven corticosteroids. AB - In this work, the influences of ionic liquid (IL) as a modifier on microemulsion microstructure and separation performance in MEEKC were investigated. Experimental results showed that synergetic effect between IL 1-butyl-3 methylimidazolium tetrafluoro-borate (BmimBF4 ) and surfactant SDS gave a decreased CMC. With increment of IL in microemulsion, negative zeta potential of the microdroplets reduced gradually. The influence of IL on the dimensions of microdroplet was complicated. At BmimBF4 less than 8 mM, IL made microemulsion droplet smaller in size. While at BmimBF4 more than 10 mM, the size increased and reached to a maximum value at 12 mM, where the microdroplets were larger than that without IL. After that, the micreodroplet size decreased again. Relative fluorescence intensity of the first vibration band of pyrene to the third one (I1 /I3 ) enhanced as IL was added to microemulsion, which indicated that this addition increased environmental polarity in the inner core of microdroplets. Prednisone, hydrocortisone, prednisolone, hydrocortisone acetate, cortisone acetate, prednisolone acetate, and triamcinolone acetonide were analyzed with MEEKC modified with IL to evaluate the separation performance. Cortisone acetate and prednisolone acetate could not be separated at all in typical microemulsion. The seven analytes could be separated by the addition of 10 mM BmimBF4 into the microemulsion system. The method has been used for analysis of corticosteroids in cosmetic samples with simple extraction; the recoveries for seven analytes were between 86 and 114%. This method provides accuracy, reproducibility, pretreatment simplicity, and could be applied to the quality control of cosmetics. PMID- 23801370 TI - Stripping the boss: the powerful role of humor in the Egyptian Revolution 2011. AB - The Egyptian Revolution 2011 has shaken the Arab world and stirred up Middle-East politics. Moreover, it caused a rush in political science and the neighboring disciplines, which had not predicted an event like this and now have troubles explaining it. While many things can be learned from the popular uprising, and from the limitations of previous scholarship, our focus will be on a moral resource, which has occasionally been noticed, but not sufficiently explored: the role of humor in keeping up the spirit of the Revolution. For 18 days, protestors persevered at Liberation Square in Central Cairo, the epicenter of resistance; at times a few dozens, at times hundreds of thousands. What they did was to fight the terror of the regime, which reached absurd peaks during those days, with humor-successfully. We offer a social-functionalist account of the uprising, which includes behavioral as well as cultural levels of analysis, and illuminates how humorous means helped to achieve deadly serious goals. By reconstructing how Egyptians laughed themselves into democracy, we outline a social psychology of resistance, which uses humor both as a sword and a shield. PMID- 23801371 TI - Prediagnostic plasma testosterone, sex hormone-binding globulin, IGF-I and hepatocellular carcinoma: etiological factors or risk markers? AB - Elevated prediagnostic testosterone and insulin-like growth factor I (IGF-I) concentrations have been proposed to increase risk of hepatocellular carcinoma (HCC). However, the metabolism of these hormones is altered as a consequence of liver damage and they may have clinical utility as HCC risk markers. A case control study was nested within the European Prospective Investigation into Cancer and Nutrition cohort and included 125 incident HCC cases and 247 individually matched controls. Testosterone, sex hormone-binding globulin (SHBG) and IGF-I were analyzed by immunoassays. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by conditional logistic regression. The area under the receiver operating curves (AUC) was calculated to assess HCC predictive ability of the tested models. After adjustments for epidemiological variables (body mass index, smoking, ethanol intake, hepatitis and diabetes) and liver damage (a score based on albumin, bilirubin, aspartate aminotransaminase, alanine aminotransaminase, gamma-glutamyltransferase and alkaline phosphatase concentrations), only SHBG remained significantly associated with risk [OR for top versus bottom tertile of 3.86 (1.32-11.3), p(trend) = 0.009]. As a single factor SHBG had an AUC of 0.81 (0.75-0.86). A small, but significant increase in AUC was observed when SHBG was added to a model including the liver damage score and epidemiological variables (from 0.89 to 0.91, p = 0.02) and a net reclassification of 0.47% (0.45-0.48). The observed associations of HCC with prediagnostic SHBG, free testosterone and IGF-I concentrations are in directions opposite to that expected under the etiological hypotheses. SHBG has a potential to be tested as prediagnostic risk marker for HCC. PMID- 23801373 TI - Direct anion effects on coordination polymerizations: construction and physicochemical properties of 1D, 2D, and 3D copper(II) coordination polymers containing 1,3,5-tris(isonicotinoyloxyethyl)cyanurate. AB - Investigations into the anion effects on the molecular construction of a series of CuX2 (X- = BF4-, ClO4-, and NO3-) complexes with 1,3,5 tris(isonicotinoyloxyethyl)cyanurate (L) were carried out. Suitable combinations of tridentate N-donor ligands and a variety of coordination geometries of copper(II) ions produce unique 1D, 2D, and 3D coordination polymers containing open cavities suitable for small chemical species, according to the nature of the polyatomic anions. Indeed, the anion exchangeability and catalytic effects of these polymers are strongly dependent on subtle anion differences, including solubility. Calcination of [Cu(ClO4)(L)(Me2SO)2](ClO4).2CH2Cl2 crystals preserves its crystallinity at 200 degrees C, and at 600 degrees C finally produces stick shaped microcrystalline copper(ii) oxide. PMID- 23801372 TI - MR elastography derived shear stiffness--a new imaging biomarker for the assessment of early tumor response to chemotherapy. AB - PURPOSE: The overall goal is to develop magnetic resonance elastography derived shear stiffness as a biomarker for the early identification of chemotherapy response, allowing dose, agent type and treatment regimen to be tailored on a per patient basis, improving therapeutic outcome and minimizing normal tissue toxicity. The specific purpose of this study is to test the feasibility of this novel biomarker to measure the treatment response in a well-known chemotherapy model. METHODS: Tumors were grown in the right flank of genetically modified mice by subcutaneous injection of DoHH2 (non-Hodgkin's lymphoma) cells. Magnetic resonance elastography was used to quantify tumor stiffness before and after injection of a chemotherapeutic agent or saline. Histological tests were also performed on the tumors. RESULTS: A significant decrease (P < 0.0001) in magnetic resonance elastography-derived tumor shear stiffness was observed within 4 days of chemotherapy treatment, while no appreciable change was observed in saline treated tumors. No significant change in volume occurred at this early stage, but there were decreased levels of cellular proliferation in chemotherapy-treated tumors. CONCLUSION: These results demonstrate that magnetic resonance elastography-derived estimates of shear stiffness reflect an initial response to cytotoxic therapy and suggest that this metric could be an early and sensitive biomarker of tumor response to chemotherapy. PMID- 23801374 TI - Photoelectrochemical lab-on-paper device based on molecularly imprinted polymer and porous Au-paper electrode. AB - In this work, microfluidic paper-based analytical device (MU-PAD) was applied in a photoelectrochemical (PEC) method and thus a truly low-cost, simple, portable, and disposable microfluidic PEC origami device (MU-PECOD) was demonstrated. The molecular imprinting technique was introduced into microfluidic paper-based analytical devices (MU-PADs) through electropolymerization of molecular imprinted polyaniline (MPANI) in a novel Au nanoparticle (AuNP)-modified paper working electrode (Au-PWE). This is fabricated through the growth of an AuNP layer on the surfaces of cellulose fibers in the PWE. Under visible light irradiation, MPANI can generate the photoelectric transition from the highest occupied molecular orbital (HOMO) to the lowest unoccupied molecular orbital (LUMO), delivering the excited electrons to the AuNPs, and then to the carbon working electrode. Simultaneously, it is believed that a positively charged hole of MPANI that took part in the oxidation process was consumed by ascorbic acid (AA) to promote the amplifying photocurrent response. On the basis of this novel MPANI-Au-PWE and the principle of origami, a microfluidic molecular imprinted polymer (MIP)-based photoelectrochemical analytical origami device (MU-MPECOD), comprised of an auxiliary tab and a sample tab, is developed for the detection of heptachlor in the linear range from 0.03 nmol L(-1) to 10.0 nmol L(-1) with a low detection limit of 8.0 pmol L(-1). The selectivity, reproducibility, and stability of this MU-MPECOD are investigated. This MU-MPECOD would provide a new platform for high throughput, sensitive, specific, and multiplex assay in public health, environmental monitoring, and the developing world. PMID- 23801376 TI - Investigation of the performance of digital mammographic X-ray equipment: determination of noise equivalent quanta (NEQQC) and detective quantum efficiency (DQEQC) compared with the automated analysis of CDMAM test images with CDCOM and CDIC programs. AB - PURPOSE: The purpose of this study was to determine the values for noise equivalent quanta, detective quantum efficiency, modulation transfer function, noise power spectrum, and the values for the parameters for automated CDMAM test phantom analyses required to achieve satisfactory quality of digital mammograms. MATERIALS AND METHODS: During the course of tests according to PAS 1054 (8 CR and 12 DR systems), test images were made with a test phantom insertion plate containing two lead edges in nearly horizontal and vertical directions. Only original data were processed with a program that was developed at the Cologne University of Applied Sciences (FH-Koln). All equipment systems complied with the requirements regarding visual recognition of gold-plated mammo detail test objects. CDMAM test images were also evaluated using the CDIC (CUAS) and CDCOM (EUREF) programs. RESULTS: CDMAM test images show comparable values for the parameters, precision, sensitivity and specificity. DR systems require about half the dose used for CR systems for similar results. The NEQ values achieved with the dose used for the CDMAM test images show larger scatter ranges. The MTF of the different equipment system types differ significantly from each other. CONCLUSION: Visual evaluation of CDMAM test images can be replaced by automated evaluation. Limiting values were determined for each parameter. Automated evaluation of CDMAM test phantom images should be used to determine the physical parameter NEQQC. This method is much more sensitive to noise and sharpness influences and has a higher validity than diagnostic methods. Automated evaluation objectivizes testing. PMID- 23801377 TI - Contrast-enhanced ultrasound reveals renal artery aneurysm after detection of 'parapelvic lithiasis'. PMID- 23801378 TI - Pan1 is an intrinsically disordered protein with homotypic interactions. AB - The yeast scaffold protein Pan1 contains two EH domains at its N-terminus, a predicted coiled-coil central region, and a C-terminal proline-rich domain. Pan1 is also predicted to contain regions of intrinsic disorder, characteristic of proteins that have many binding partners. In vitro biochemical data suggest that Pan1 exists as a dimer, and we have identified amino acids 705 to 848 as critical for this homotypic interaction. Tryptophan fluorescence was used to further characterize Pan1 conformational states. Pan1 contains four endogenous tryptophans, each in a distinct region of the protein: Trp(312) and Trp(642) are each in an EH domain, Trp(957) is in the central region, and Trp(1280) is a critical residue in the Arp2/3 activation domain. To examine the local environment of each of these tryptophans, three of the four tryptophans were mutagenized to phenylalanine to create four proteins, each with only one tryptophan residue. When quenched with acrylamide, these single tryptophan mutants appeared to undergo collisional quenching exclusively and were moderately accessible to the acrylamide molecule. Quenching with iodide or cesium, however, revealed different Stern-Volmer constants due to unique electrostatic environments of the tryptophan residues. Time-resolved fluorescence anisotropy data confirmed structural and disorder predictions of Pan1. Further experimentation to fully develop a model of Pan1 conformational dynamics will assist in a deeper understanding of the mechanisms of endocytosis. PMID- 23801379 TI - Responding to discriminatory requests for a different healthcare provider. AB - Patient requests for a healthcare provider of a particular race or sexual orientation create a conflict of obligations. On the one hand, providers have a duty to deliver clinically indicated care consistent with patient preferences. On the other hand, providers have legal, professional, and organizational assurances that they should not suffer workplace discrimination. Protecting healthcare providers from harm while maintaining obligations to patients requires unambiguous messaging to both parties. Providers need to be clear that their organization will not be complicit in discrimination against them, instead supporting their needs and preferences for management of the situation. In a context of patient-centered care, harm principle-based boundaries of respect for autonomy must be defined. A Caregiver preference guideline developed and used at University Health Network, Toronto provides a standardized way for the organization to decide when it will honor patient requests for providers of a particular background. This process stresses dialogue, assessment of clinical feasibility, and empowerment and support for affected care providers. PMID- 23801380 TI - Association of the IRF5 rs2004640 polymorphism with rheumatoid arthritis: a meta analysis. AB - Several molecular epidemiological studies have been conducted in recent years to evaluate a possible association between the interferon regulatory factor 5 (IRF5) rs2004640 polymorphism and rheumatoid arthritis risk in diverse populations. However, the results remain conflicting rather than conclusive. Our aim was to assess associations of IRF5 gene polymorphisms with rheumatoid arthritis risk. Meta-analysis was performed on six published case-control studies (from eight countries) that included 4,818 cases of rheumatoid arthritis and 4,316 controls. The rs2004640-T allele was associated with a significantly increased risk of rheumatoid arthritis when the dominant genetic model was applied (T/T + T/G versus G/G: P = 0.003, OR = 1.14, 95% CI 1.05-1.25). Upon stratified analysis by ethnicity, the rs2004640 polymorphism was associated with an increased rheumatoid arthritis risk in Caucasians when the homozygotic contrast model was employed(T/T versus G/G: P = 0.03, OR = 1.25, 95% CI 1.02-1.53) and this was also the case when the dominant genetic model was used (T/T + T/G versus G/G: P = 0.04, OR = 1.20, 95% CI 1.01-1.42), whereas, in Asian populations, only the dominant genetic model was associated with an increased rheumatoid arthritis risk (T/T + T/G versus G/G: P = 0.02, OR = 1.14, 95% CI 1.02-1.26). The results suggest that the IRF5 rs2004640 polymorphism is associated with rheumatoid arthritis especially when the dominant genetic model is applied. PMID- 23801381 TI - Comparison of in situ Corneoscleral Disc Excision versus Whole Globe Enucleation in Cornea Donors Regarding Microbial Contamination in Organ Culture Medium - a Prospective Monocentric Study over 9 Years. AB - BACKGROUND: CORNEAS NEEDED FOR KERATOPLASTY CAN BE HARVESTED USING TWO TECHNIQUES: whole globe enucleation and in situ excision of the corneoscleral disc. This study evaluates the rate of microbial contamination of the donor cornea organ culture medium according to the method of retrieval. METHODS: All donor corneas of our cornea bank received between January 1, 2001 and December 31, 2009 put into organ culture and microbio-logically tested were prospectively analyzed for microbial contamination of the organ culture medium. RESULTS: 2,805 donor corneas could be included in this study in total. 975 of them were retrieved by whole globe enucleation (group 1) and 1,830 by in situ corneoscleral disc excision (group 2). 15 corneas of group 1 (1.5%) and 46 corneas of group 2 (2.5%) showed a contamination of the organ culture medium. The difference was shown not to be statistically significant (p = 0.082). CONCLUSION: The rate of microbial contamination in organ-cultured donor corneas does not seem to be dependent on the method of their retrieval. PMID- 23801382 TI - Diagnostic value of high-resolution sonography in common fibular neuropathy at the fibular head. AB - INTRODUCTION: In 30% of patients with common fibular (CF) neuropathy at the fibular head, reliable localization of the site of the lesion by means of electrodiagnostic testing is challenging. METHODS: We prospectively assessed proximal CF nerve cross-sectional area (CSA) measurements and at the fibular head in 87 patients with CF neuropathy and 16 with a different condition. Reference values were obtained in 64 healthy volunteers. RESULTS: Patients with CF neuropathy had a significantly larger CF nerve CSA than controls and patient controls (P < 0.0001). Sonography localized the lesion at the fibular head in 55% and just above it in 71% of patients. Assessment of the most thickened part of the CF nerve resulted in a cut-off value of >8 mm2 with a sensitivity of 90% (CI 81-95%) and a specificity of 69% (CI 58-78%). CONCLUSION: High-resolution sonography in addition to electrodiagnostic testing improves diagnostic reliability in CF neuropathy. PMID- 23801383 TI - Passive leg raising: influence of blood pressure transducer site. PMID- 23801384 TI - Prognostication of neurologic outcome in cardiac arrest patients after mild therapeutic hypothermia: a meta-analysis of the current literature. AB - PURPOSE: To assess the sensitivity and false positive rate (FPR) of neurological examination and somatosensory evoked potentials (SSEPs) to predict poor outcome in adult patients treated with therapeutic hypothermia after cardiopulmonary resuscitation (CPR). METHODS: MEDLINE and EMBASE were searched for cohort studies describing the association of clinical neurological examination or SSEPs after return of spontaneous circulation with neurological outcome. Poor outcome was defined as severe disability, vegetative state and death. Sensitivity and FPR were determined. RESULTS: A total of 1,153 patients from ten studies were included. The FPR of a bilaterally absent cortical N20 response of the SSEP could be calculated from nine studies including 492 patients. The SSEP had an FPR of 0.007 (confidence interval, CI, 0.001-0.047) to predict poor outcome. The Glasgow coma score (GCS) motor response was assessed in 811 patients from nine studies. A GCS motor score of 1-2 at 72 h had a high FPR of 0.21 (CI 0.08-0.43). Corneal reflex and pupillary reactivity at 72 h after the arrest were available in 429 and 566 patients, respectively. Bilaterally absent corneal reflexes had an FPR of 0.02 (CI 0.002-0.13). Bilaterally absent pupillary reflexes had an FPR of 0.004 (CI 0.001-0.03). CONCLUSIONS: At 72 h after the arrest the motor response to painful stimuli and the corneal reflexes are not a reliable tool for the early prediction of poor outcome in patients treated with hypothermia. The reliability of the pupillary response to light and the SSEP is comparable to that in patients not treated with hypothermia. PMID- 23801385 TI - Decay uncovered in nonverbal short-term memory. AB - Decay theory posits that memory traces gradually fade away over the passage of time unless they are actively rehearsed. Much recent work exploring verbal short term memory has challenged this theory, but there does appear to be evidence for trace decay in nonverbal auditory short-term memory. Numerous discrimination studies have reported a performance decline as the interval separating two tones is increased, consistent with a decay process. However, most of this tone comparison research can be explained in other ways, without reference to decay, and these alternative accounts were tested in the present study. In Experiment 1, signals were employed toward the end of extended retention intervals to ensure that listeners were alert to the presence and frequency content of the memoranda. In Experiment 2, a mask stimulus was employed in an attempt to distinguish between a highly detailed sensory trace and a longer-lasting short-term memory, and the distinctiveness of the stimuli was varied. Despite these precautions, slow-acting trace decay was observed. It therefore appears that the mere passage of time can lead to forgetting in some forms of short-term memory. PMID- 23801386 TI - Minimally invasive treatment of gastric leak after sleeve gastrectomy. AB - PURPOSE: Obesity is a leading problem in Western countries, and laparoscopic sleeve gastrectomy (SG) is the most commonly used procedure for the surgical management of morbid obesity. SG is recognised as one of the safest and most effective bariatric procedures but it is limited by a rate of gastric leaks (GL) ranging from 1.4% to 20%. No international consensus exists about the treatment of GL. This paper reports our experience with the noninvasive management of GL. MATERIALS AND METHODS: From July 2004 to December 2010, 16 patients with GL after SG were referred to our unit. All patients underwent contrast radiography (Gastrografin) and computed tomography (CT) examination. On the basis of the radiographic findings, patients were divided into those eligible for drainage and those not eligible. RESULTS: Twelve patients (75%) were eligible for percutaneous drainage. Of these, seven patients (44%) were successfully treated with percutaneous drainage alone, whereas five patients (31%) required placement of a covered stent due to incomplete resolution of the collection. After 1009.8+/ 456.7 days of follow-up, one patient died from a cardiovascular event and two patients required a bilio-pancreatic-digestive bypass (BPD-BP). Twelve patients (75%) were in an excellent state of health with significant reduction of their body mass index (BMI). CONCLUSIONS: Our experience confirms the value of an algorithm based on patient eligibility for percutaneous drainage in the treatment of GL. The patient's general condition and in particular the presence of sepsis supports the value of this approach in preference to the conventional surgical approach. PMID- 23801387 TI - Short-course preoperative radiotherapy combined with chemotherapy in resectable locally advanced rectal cancer: local control and quality of life. AB - PURPOSE: The authors sought to evaluate the clinical outcome after preoperative short-course radiotherapy (SC-RT) for locally advanced resectable rectal cancer in terms of local control (LC) and quality of life (QoL). MATERIALS AND METHODS: Patients with locally advanced rectal cancer enrolled between 1997 and 2008 in an observational study of preoperative SC-RT were analysed. The treatment algorithm was neo-adjuvant chemotherapy (CT) administered for four cycles, followed by preoperative SC-RT administered 1 week after chemotherapy completion, delivering 20 Gy in five fractions over 1 week. Immediately in the following week surgery was performed. The adjuvant 5-FU-based CT was planned for pathological stage UICC>=II. LC, overall survival (OS), disease-free survival (DFS), early and late complications (RTOG scale) were analysed. All patients completed the EORTC QoL (C 30 and C-38), Faecal Incontinence QoL, and International Index of Erectile Function questionnaires (IIEF). RESULTS: A total of 67 patients were analysed. Chemotherapy and radiotherapy were well tolerated. At the pathological analysis, stable disease was obtained in 24 patients (36%), reduction of disease stage in 34 patients (50.7%), and progression in nine cases (13.3%). Adjuvant chemotherapy was indicated in 21 patients. Two locoregional recurrences, both within the radiotherapy volume, were observed, resulting in a 5-year LC of 97%. The 5-year DFS was 84%, with mean time to systemic progression of 24 months. After a mean follow-up of 114 months, the 5-year OS rate was 67%. Late toxicity >grade II was observed in 9% of patients. High anterior resection (AR) patients had significantly better scores than low AR or abdomino-perineal resection (APR). A total of 89% of the patients treated with conservative surgery had regular anal sphincter function. In male patients undergoing AR or APR, erectile dysfunction was found in 47% and 75% of the cases, respectively. CONCLUSIONS: Preoperative SC RT combined with chemotherapy for locally advanced resectable rectal cancers was well tolerated. This treatment resulted in favourable LC, OS, low rates of toxicity and satisfying QoL. PMID- 23801388 TI - Ultrasound evaluation of liver fibrosis: preliminary experience with acoustic structure quantification (ASQ) software. AB - PURPOSE: The aim of our study was to assess the diagnostic accuracy of acoustic structure quantification (ASQ) ultrasound software in estimating the degree of hepatic fibrosis compared to Fibroscan and liver biopsy. MATERIALS AND METHODS: Seventy-seven patients with chronic viral hepatitis B and C underwent standard ultrasound examination, ASQ, Fibroscan and liver biopsy. ASQ analysis was conducted by placing a single region of interest (ROI) on each image captured, and calculating mode, average and standard deviation. The sonographic technique was developed through a preliminary evaluation of 20 healthy volunteers. RESULTS: The area under the receiver operating characteristic (AUROC) curve for the diagnosis of cirrhosis (F>=4) with ASQ was 0.77, whereas for the diagnosis of any degree of fibrosis (F>=1) it was 0.71. The AUROC for the diagnosis of cirrhosis (F>=4) with Fibroscan was 0.98, while for the diagnosis of any degree of fibrosis (F>=1) it was 0.94. The difference between the AUROC was statistically significant (p<0.05). CONCLUSIONS: ASQ is a promising new ultrasound software programme which offers encouraging results in the diagnosis of both liver cirrhosis (F=4) and fibrosis (F>=1). However, to date it has not attained the same level of diagnostic performance as Fibroscan. PMID- 23801389 TI - Accuracy of tumour size assessment in the preoperative staging of breast cancer: comparison of digital mammography, tomosynthesis, ultrasound and MRI. AB - PURPOSE: Accurate measurement of breast tumour size is fundamental for treatment planning. We compared the accuracy of digital mammography (DM), digital breast tomosynthesis (DBT), ultrasound (US) and magnetic resonance imaging (MRI) for the preoperative evaluation of breast cancer size. MATERIALS AND METHODS: We retrospectively reviewed 149 breast cancers in 110 patients who underwent DM, DBT, US and MRI between January 2010 and December 2011, before definitive surgery. The lesions were measured by two radiologists, without knowledge of the final histological examination, considered the gold standard. For each imaging modality, the maximum tumour size was measured to the nearest millimetre; the measurements were considered concordant if they were within +/- 5 mm. Pearson's correlation coefficient was calculated for each imaging modality. RESULTS: The median pathological tumour size was 22.3 mm. MRI and DBT had a level of concordance with pathology of 70% and 66%, respectively, which was higher than that of DM (54%). DBT and MRI measurements had a better correlation with pathological tumour size (R:0.89 and R:0.92, respectively) compared to DM (R:0.83) and US (R:0.77). CONCLUSIONS: DBT and MRI are superior to DM and US in the preoperative assessment of breast tumour size. DBT seems to improve the accuracy of DM, although MRI remains the most accurate imaging modality for breast cancer extension. PMID- 23801390 TI - MR-arthrography in superior instability of the shoulder: correlation with arthroscopy. AB - PURPOSE: This study was undertaken to evaluate magnetic resonance (MR) arthrography in the detection and classification of lesions that may cause superior instability. MATERIALS AND METHODS: Forty-two consecutive patients with clinical signs of chronic superior instability of the shoulder underwent MR arthrography followed by arthroscopic surgery. For each patient we retrospectively reviewed the MR arthrography and surgical findings. RESULTS: We detected 31 superior labral anterior posterior (SLAP) lesions, all confirmed on arthroscopy with three cases of underestimation: in the detection of SLAP lesions, the sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of MR arthrography were 100%; in the evaluation of the type of SLAP lesion, sensitivity was 100%, specificity was 78.5%, accuracy was 92.8%, PPV was 71.7% and NPV was 100%. All cases of capsular laxity (13/42) and biceps tendon lesions (3/42) were confirmed on arthroscopy with sensitivity, specificity, accuracy, PPV and NPV of 100%. Eleven cuff lesions were detected on MR arthrography, 10 of which confirmed at arthroscopy: sensitivity was 100%, specificity was 96.8%, accuracy was 97.6%, PPV was 90.9% and NPV was 100%. Associated lesions were found in 38/42 patients. CONCLUSIONS: Superior instability is frequently associated with different anatomical variants or pathological conditions, such as SLAP lesions. The role of MR arthrography is to describe the key features of lesions affecting the superior portion of the shoulder, including location, morphology, extent, and associated injuries and leanatomical variants and to correlate these features with clinical symptoms. PMID- 23801391 TI - Pulmonary artery intimal sarcoma. Problems in the differential diagnosis. AB - PURPOSE: Pulmonary artery sarcomas (PAS) are rare malignant tumours that originate from the intimal layer of the pulmonary artery, occur in middle age and have a poor prognosis. In planning appropriate treatment, malignant disease should be suspected whenever there are specific clinical and radiological manifestations, in order to establish the differential diagnosis with acute pulmonary embolism or chronic thromboembolic pulmonary hypertension, with which this malignancy is most commonly confused. MATERIALS AND METHODS: Between 2008 and 2012, we managed four adult patients with a nonspecific clinical presentation who, at the conclusion of the diagnostic process, were found to be affected by PAS. Because of the initial suspicion of pulmonary embolism, all patients underwent chest radiograph, lung perfusion scintigraphy, trans-oesophageal echocardiography, and computed tomography (CT) angiography of the chest. Then, because of the peculiar CT findings and lack of response to anticoagulation therapy, a clinical suspicion of PAS was considered and all patients underwent positron-emission tomography (PET)-CT, and one patient also magnetic resonance imaging (MRI) of the chest. Subsequently, all patients underwent thromboendoarterectomy with histological investigation of the surgical specimen, which confirmed the clinical and radiological suspicion of PAS. RESULTS: CT is the technique that enabled the first step in the differential diagnosis between PAS and pulmonary embolism. The CT characteristics suggestive of PAS included the particular filling defect occupying the entire lumen of the pulmonary trunk with increase in diameter of the involved vessel and patchy and delayed contrast enhancement at CT angiography, more evident in the venous phase. PET-CT was used to differentiate between PAS and pulmonary embolism on the basis of the intensity of increased radiopharmaceutical uptake. MRI was used in one case of equivocal results on PET-CT, to improve tissue characterisation of the lesions and differentiation between the thrombotic and neoplastic components. CONCLUSIONS: The radiologist is usually the first to raise a suspicion of PAS in patients with severe dyspnoea and filling defect in the pulmonary artery, unresponsive to anticoagulation therapy. Combining CT and PET-CT proved to be extremely useful in assessing patients with suspected PAS. Early diagnosis with the help of integrated imaging remains today the main direction to pursue in order to obtain improvements in prognosis. PMID- 23801392 TI - Endovascular treatment of intracranial aneurysms with flow-diverter stents: preliminary single-centre experience. AB - PURPOSE: This paper reports our preliminary experience with the endovascular treatment of intracranial aneurysms using flow-diverter stents (FDs) and compares it with the literature data. MATERIALS AND METHODS: From May 2009 to April 2012, 28 patients (6 men and 22 women; mean age, 54 years) with a total of 35 aneurysms were treated with FDs. We evaluated postprocedural technical success and long term efficacy, with follow-up examinations performed at 3-7 days [computed tomography (CT)/magnetic resonance (MR) angiography] and at 3, 6 and 12 months (digital subtraction angiography, DSA). A total of 43 FDs were placed, 36 Pipeline and 7 Silk. RESULTS: A total of 30 procedures were performed (two patients were treated twice). Technical success was 96.6%, with one case of postprocedural death; the aneurysm exclusion rate at 3, 6 and 12 months was 60%, 73% and 89%, respectively. There was no case of acute stent thrombosis, and only two cases of nonsignificant stenosis. All covered side branches were patent, except one case of steno-occlusion of the ophthalmic artery. CONCLUSIONS: Our results are consistent with the literature and demonstrate the effectiveness and safety of FDs in selected cases of cerebral aneurysm (wide neck, fusiform, blister-like). PMID- 23801393 TI - Multifocal branch-duct intraductal papillary mucinous neoplasms (IPMNs) of the pancreas: magnetic resonance (MR) imaging pattern and evolution over time. AB - PURPOSE: The aim of our study was to follow the evolution over time of multifocal intraductal papillary mucinous neoplasms (IPMN) of the pancreatic duct side branches by means of magnetic resonance imaging (MRI). MATERIALS AND METHODS: A total of 155 patients with multifocal IPMN of the side branches were examined with MRI and MR cholangiopancreatography (MRI/MRCP). Inclusion criteria were patients with >=2 dilated side branches involving any site of the parenchyma; presence of communication with the main pancreatic duct and previous investigations by MRI/MRCP within at least six months. Median follow-up was 25.8 months (range, 12-217). Patients with a follow-up period shorter than 12 months (n=33) and those with a diagnosis of multifocal IPMN of the side branches without any follow-up (n=14) were excluded from the study. The final study population thus comprised 108 patients. A double, quantitative and qualitative, analysis was carried out. The quantitative image analysis included: number of dilated side branches in the head-uncinate process and body-tail; maximum diameter of lesions in the head-uncinate process; maximum diameter in the body-tail; maximum diameter of the main pancreatic duct in the head and body-tail. The qualitative image analysis included: presence of malformations or anatomical variants of the pancreatic ductal system; site of the lesions (head-uncinate process, body-tail, ubiquitous, bridge morphology); presence of gravity-dependent intraluminal filling defects; presence of enhancing mural nodules. RESULTS: At diagnosis, the mean number of cystic lesions of the side branches was 7.09. The mean diameter of the cystic lesions was 13.7 mm. The mean diameter of the main pancreatic duct was 3.6 mm. At follow-up, the mean number of cystic lesions was 7.76. The mean diameter of the cystic lesions was 13.9 mm. The mean diameter of the main pancreatic duct was 3.7 mm. Intraluminal filling defects in the side branches were seen in 18/108 patients (16.6%); enhancing mural nodules were seen in 3/108 patients (2.7%). CONCLUSIONS: Multifocal IPMN of the branch ducts shows a very slow growth and evolution over time. In our study, only 3/108 patients showed mural nodules which, however, did not require any surgical procedure, indicating that careful nonoperative management may be safe and effective in asymptomatic patients. PMID- 23801394 TI - Whole-body MRI and PET/CT in multiple myeloma patients during staging and after treatment: personal experience in a longitudinal study. AB - PURPOSE: Diagnostic imaging plays a pivotal role in staging and prognostic assessment of multiple myeloma (MM) as well as planning and monitoring treatment. The aim of our study was to estimate the diagnostic accuracy of wholebody magnetic resonance imaging (WB-MRI) and positron emission tomography/computed tomography (PET/CT) in MM patients studied before and after treatment. MATERIALS AND METHODS: We considered 22 consecutive patients (10 males, 12 females; age range, 48-83 years) with newly diagnosed MM (NDMM group), and the same 22 patients underwent at least one re-assessment after treatment (previously treated MM, PTMM group). WBMRI and PET/CT were performed within days from each other in both the NDMM (22 studies) and PTMM (29 studies) group. The imaging findings were compared to the results of bone marrow aspiration. RESULTS: PET/CT was positive in 18/22 NDMM patients, whereas WB-MRI correctly identified 100% of patients. Of 20 responder patients in the PTMM group, 16 were negative at PET/CT and 12/20 at MRI. By contrast, of the nine nonresponder patients, MRI correctly detected active disease in all cases, and PET only in seven. CONCLUSIONS: WB-MRI proved superior to PET/CT in detecting MM, especially in diffuse disease. PET/CT appears to be more sensitive in the assessment of MM after treatment. PMID- 23801395 TI - Radiation therapy after breast reconstruction: outcomes, complications, and patient satisfaction. AB - PURPOSE: The aim of this study was to evaluate treatment-related complications, outcomes, and patient satisfaction in women with locally advanced breast cancer who received post-mastectomy radiation therapy (PMRT) after breast reconstruction (BR). MATERIALS AND METHODS: Between October 2007 and November 2010, 46 patients with locally advanced breast cancer who underwent mastectomy followed by BR received PMRT at our Department. Radiotherapy was delivered to the chest wall with a dose of 50 Gy in 25 fractions over 5 weeks. RESULTS: The median follow-up was 19 months. Skin erythema grade 1 and 2 was seen in 44 (96%) and two (4%) patients, respectively. Major complications, requiring additional corrective surgical procedure, occurred in three (7%) patients (one patient with prosthesis, one patient with tissue expander and one patient with deep inferior epigastric perforator flap). At univariate analysis, smoking, chemotherapy, hormone therapy with tamoxifen and reconstruction with implant were associated with overall complications (capsular contracture and reconstruction failure). Forty (86%) patients were very satisfied or satisfied with the cosmetic outcome of reconstruction. CONCLUSIONS: Radiotherapy can be safely delivered after BR, with a low complication rate and good patient satisfaction. Further randomised studies are needed to better define the optimal timing of breast reconstruction and post mastectomy radiation therapy. PMID- 23801396 TI - Inappropriateness of breast imaging: cost analysis. AB - PURPOSE: The aim of this study was to assess how an incorrect indication for an examination may affect the diagnostic workup and diagnosis as well as healthcare expenditure. MATERIALS AND METHODS: We considered all the requests for breast imaging (mammography, ultrasound and magnetic resonance imaging) received by our radiology department between October 2010 and December 2010, and assessed their appropriateness based on the patient's age and the clinical question, if present. We then analysed the unnecessary costs resulting from inappropriate requests. RESULTS: Out of a total of 1500 requests for ultrasound examination, the request was appropriate in 855 (57%) cases; out of a total of 2350 requests for mammography, the request was appropriate in 493 (21%) cases; out of a total of 100 requests for magnetic resonance imaging, the request was appropriate in 83 (83%) cases. The cost deriving from inappropriate requests was 51,235.04 Euros. CONCLUSIONS: Improving the timeliness of diagnosis is an important goal to be pursued by enhancing the available health services, improving communication and coordination of the different professionals involved and optimising diagnostic pathways in order to reduce healthcare spending. PMID- 23801397 TI - The role of MDCT arthrography in the follow-up of scapholunate stabilisation. AB - PURPOSE: The aim of this study was to assess outcomes in a group of patients with scapholunate dissociation treated with stabilisation surgery (Brunelli-Stanley) and to compare arthrography with multidetector computed tomography (MDCT) with conventional radiography, the gold standard in the follow-up of wrist surgery. MATERIALS AND METHODS: Twelve patients (13 wrists) underwent surgery for scapholunate dissociation and were followed up with clinical (visual analogue scale, Mayo Wrist Score, Patient-Rated Wrist Evaluation, and Disabilities of the Arm, Shoulder, and Hand) and radiological assessment (conventional radiography and CT arthrography). Conventional radiography was assessed for: the scapholunate gap, scapholunate angle, radiolunate angle, capitate-lunate angle, and carpal height index; the CT arthrography images were also evaluated for: the distance between the dorsal exit hole of the bone tunnel and the proximal scaphoid pole, the thickness and tension of the flexor carpi radialis (FCR) strip, and any signs of joint degeneration. RESULTS: Analysis of the data from conventional radiography and MDCT arthrography demonstrated a significant statistical correlation among the measurements obtained on the radiograms and multiplanar CT reconstructions and the patients' clinical outcome. CONCLUSIONS: Our results show that MDCT arthrography has the same value as conventional radiography in the evaluation of standard parameters (scapholunate gap, scapholunate angle, radiolunate angle, capitolunate angle, carpal height index), but in addition provides an accurate delineation of the FCR tendon graft, allowing differentiation of its thickness, direction and degree of tension. PMID- 23801398 TI - Bone stress injuries of the leg in athletes. AB - Bone stress injuries, whose incidence is increasing among competitive and recreational athletes, represent a pathophysiological continuum along which a bone responds to a changing mechanical environment. Frank stress fracture is the endpoint of this process, resulting from the accumulation of microinjuries due to repeated abnormal stresses. The legs are largely the most frequently affected bone district. The aim of this paper is to review the imaging findings of the whole spectrum of stress-induced bone lesions of the leg in athletes. We emphasise the role of computed tomography and magnetic resonance imaging, which allow recognition of early alterations. PMID- 23801399 TI - Evolution of ventriculomegaly: comparison between foetal MR imaging and postnatal diagnostic imaging. AB - PURPOSE: We evaluated the evolution of ventriculomegaly (VM) by comparing foetal magnetic resonance imaging (MRI) with postnatal transcranial ultrasonography (US) and/or encephalic MRI. MATERIALS AND METHODS: Between January 2006 and April 2011, 70 foetuses with a mean gestational age of 28 weeks and 4 days (range, 18 36) weeks with VM on foetal MRI were assessed in this prospective study. Half Fourier rapid acquisition with relaxation enhancement (RARE) T2-weighted, T1 weighted and diffusion-weighted (DWI) images along the three orthogonal planes according to the longitudinal axis of the mother, and subsequently of the foetal brain, were acquired. Quantitative image analysis included the transverse diameter of lateral ventricles in axial and coronal planes. Qualitative image analysis included searching for associated structural anomalies. RESULTS: Thirty four of 70 patients with a diagnosis of VM on foetal MRI underwent postnatal imaging. Twenty-five of those 34 (73%) had mild, four (12%) had moderate and five (15%) had severe VM on MRI. Normalisation of the diameter of lateral ventricles was observed in 16 of the 34 (47%) newborns. Among these 16, 13 (81%) had mild and three (19%) had moderate VM (two isolated and one associated VM). VM stabilisation was observed in 16 of the 34 (47%) babies. Among them, 11 (69%) had mild (eight isolated and three associated), one (6%) had moderate associated and four (25%) had severe associated VM. Progression from mild to severe (associated) VM was observed in two of the 34 (6%) babies. CONCLUSIONS: The absence of associated anomalies and a mild VM are favourable prognostic factors in the evolution of VM. PMID- 23801400 TI - Malpractice claims related to musculoskeletal imaging. Incidence and anatomical location of lesions. AB - PURPOSE: Failure to detect lesions of the musculoskeletal system is a frequent cause of malpractice claims against radiologists. MATERIALS AND METHODS: We examined all the malpractice claims related to alleged errors in musculoskeletal imaging filed against Italian radiologists over a period of 14 years (1993-2006). RESULTS: During the period considered, a total of 416 claims for alleged diagnostic errors relating to the musculoskeletal system were filed against radiologists; of these, 389 (93.5%) concerned failure to report fractures, and 15 (3.6%) failure to diagnose a tumour. CONCLUSIONS: Incorrect interpretation of bone pathology is among the most common causes of litigation against radiologists; alone, it accounts for 36.4% of all malpractice claims filed during the observation period. Awareness of this risk should encourage extreme caution and diligence. PMID- 23801401 TI - MR-guided stereotactic breast biopsy using a mixed ferromagnetic-nonmagnetic coaxial system with 12- to 18-gauge needles: clinical experience and long-term outcome. AB - PURPOSE: This study investigated the clinical application of a magnetic-resonance (MR)-guided breast biopsy (MRBB) system consisting of a nonmagnetic coaxial needle and a ferromagnetic core biopsy needle. MATERIALS AND METHODS: MRBB was performed on 70 breast lesions. The biopsy device consisted of a nonmagnetic 14- to 16-gauge coaxial needle and a ferromagnetic 16- to 18-gauge biopsy needle. RESULTS: Of the 70 lesions, 29 were malignant and 41 nonmalignant. All 29 malignant lesions underwent surgery and were confirmed as malignant at final histology. Of the 41 nonmalignant lesions, 35 underwent follow-up breast MR imaging (mean, 26 +/- 19 months), which demonstrated no lesions changes; six lesions underwent surgery because of poor radiological-pathological correlation; of these 6 lesions, 3 were nonmalignant, one was borderline (lobular carcinoma in situ) and two were malignant (well-differentiated tubular carcinoma and infiltrating ductal carcinoma). Sensitivity, specificity, positive and negative predictive values and diagnostic accuracy were, respectively, 93.5%, 100%, 100%, 95.1% and 97.1% if the lobular carcinoma in situ was considered a nonmalignant histological result, and 90.6%, 100%, 100%, 92.7% and 95.7% if the lobular carcinoma in situ was considered malignant. CONCLUSIONS: MRBB with a ferromagnetic-nonmagnetic coaxial system represented an easy way to perform a biopsy procedure and was easily applicable in the routine clinical setting. PMID- 23801402 TI - Magnetic resonance urography vs computed tomography urography in the evaluation of patients with haematuria. AB - PURPOSE: This study was done to evaluate by direct comparison the image quality of magnetic resonance urography (MRU) and computed tomography urography (CTU) and to assess the diagnostic confidence of the two techniques in detecting urothelial malignancy in patients with haematuria MATERIALS AND METHODS: Thirty-five patients with haematuria underwent both CTU and MRU. Two different investigators evaluated calyceal, renal pelvis, ureteral and bladder visibility. Their diagnostic confidence in detecting urothelial malignancy with the two procedures was assessed. A Wilcoxon matched-pairs test was performed to compare results. Inter-reader agreement was calculated by weighted kappa (WK) statistic. Patient history (further examinations, cystoscopy and histological specimens) was considered as reference standard to calculate receiver operating characteristic (ROC) curves of diagnostic confidence. RESULTS: CTU provided better visibility of urothelial structures (p<0.01) and allowed for greater diagnostic confidence (ROC area 0.994 vs. 0.938) than MRU, with a good inter-reader agreement (WK=0.62). Nevertheless, in obstructive patients with impaired excretory function, MRU, thanks to the static-fluid technique, offered better visualisation than CTU. CONCLUSIONS: There is a potential role for MRU in urinary tract imaging, but as diagnostic confidence in detecting urothelial malignancy is poorer than in CTU, it might be stareserved for patients at low risk for malignancy and for evaluating obstructed patients. PMID- 23801403 TI - Preoperative assessment of nonfunctioning pancreatic endocrine tumours: role of MDCT and MRI. AB - PURPOSE: This study was done to compare the diagnostic accuracy of multidetector computed tomography (MDCT) and magnetic resonance imaging (MRI) in the preoperative assessment of nonfunctioning pancreatic endocrine tumours (NFPET). MATERIALS AND METHODS: Fifty-one patients (25 men, 26 women; mean age, 52 years), preoperatively investigated by both MDCT and MRI and subsequently operated on with a histological diagnosis of NFPET, were included in this study. MDCT and MRI accuracy in evaluating location, size, margins, baseline density/signal intensity, structure, pattern of enhancement, peak enhancement phase, involvement of main pancreatic duct, involvement of adjacent organs, infiltration of peritumoural vessels, involvement of locoregional lymph nodes, and liver metastases was compared using Pearson correlation, Mann-Whitney and chi-square tests. A value of p<0.05 was considered statistically significant. RESULTS: MDCT and MRI had similar accuracy in assessing size, margins, baseline density/signal intensity, structure, pattern of enhancement, peak enhancement phase, involvement of main pancreatic duct, involvement of adjacent organs, involvement of locoregional lymph nodes, and liver metastases (p>0.05). MDCT was superior to MRI in evaluating the infiltration of peritumoural vessels (p=0.025). CONCLUSIONS: MDCT performed better than MRI in assessing vascular involvement and should be considered the best imaging tool for preoperative evaluation of NFPET. PMID- 23801405 TI - Diagnostic utility of PETCT in thyroid malignancies: an update. AB - The primary clinical application of (18)F FDG PET/CT ((18)Fluorine labeled flurodeoxyglucose positron emission tomography/computed tomography) in differentiated thyroid carcinoma is in the identification of active disease in thyroglobulin (Tg) positive (>10 ng/ml), whole body iodine scan negative patients. The impact of FDG PET/CT in diagnosis, surveillance, cure, and progression-free survival of differentiated thyroid carcinoma patients remains to be seen. Five main indications of FDG PET/CT in thyroid cancer have been recommended by revised American thyroid association guidelines 2009. This review aims to provide a complete picture of PET imaging in thyroid malignancies and enumerates each indication with literature review. This review also highlights recent advances in targeted molecular imaging. Currently differentiated thyroid cancer is best imaged using conventional single photon emission computed tomography-based radioiodine tracers ((123)I/(131)I). Although the utility of FDG PET in well differentiated thyroid cancer patients who are iodine negative but with raised Tg is well established, evidence is emerging on the advantages of FDG PET/CT in other histological types of thyroid malignancy, such as Hurthle cell, medullary, and the anaplastic malignancies. Novel PET radiotracers, such as (124)Iodine ((124)I), (18)F-DOPA (3,4-dihydroxy-L-phenylalanine), and (68)Ga-DOTA peptides are revolutionizing the way thyroid malignancies are imaged. Newer concepts on targeted molecular imaging and theranostics are ushering in new possibilities for imaging and treating thyroid cancer. PMID- 23801404 TI - The density of macrophages in colorectal cancer is inversely correlated to TGF beta1 expression and patients' survival. AB - The role of macrophages in colorectal cancer tumorogenesis is complex because they can both prevent and promote tumor development. We investigated CD68 positive cell infiltration in tumor tissue and its correlations with proteins of TGF-beta1 signaling pathway and survival of the patients after surgical therapy. A non-selected panel of 210 primary tumors of colorectal origin was investigated immunohistochemically with antibodies against CD68, TGF-beta1, TGFbetaRII and Smad4. Lower CD68 infiltration in tumor stroma was associated with expression of TGF-beta1 (p = 0.002) and SMAD4 (p = 0.090) in tumor cell cytoplasm and with TGFbetaRII expression (p = 0.017) in tumor cells membranes. The absence of SMAD4 immune deposits in tumor cell nuclei was more often seen in biopsies with low number of CD68 in the invasive front (p = 0.044). The low number of CD68-positive cells was significantly associated with several adverse clinical and histological tumor characteristics as the presence of metastases in local lymph nodes (p = 0.047), distant metastases (p = 0.0003), advanced tumor stage (p = 0.006), tumor cell invasion of blood, lymph vessels or perineural invasion (p = 0.004), higher histological types (p = 0.0002) and lower grade of inflammatory infiltration in the invasive front (p = 0.002). Moreover, the low grade of CD68 appeared to be significant unfavorable factors of prognosis of the patients with colorectal cancer. The results of our study confirm the prognostic significance of low level of tumor-associated macrophage infiltration in colorectal cancer as unfavorable marker for survival of the patients. PMID- 23801406 TI - Analysis of progression and recurrence of meningioma using (11)C-methionine PET. AB - OBJECTIVE: The recurrence rate of meningioma after surgery is high, and progression is often observed. The risk factors for recurrence and progression are not clear. We evaluated the risk factors for recurrence and progression in meningioma using (11)C-methionine (MET) positron emission tomography (PET). METHODS: Thirty-seven patients (mean follow-up, 80 months) with an intracranial meningioma were enrolled. MET PET was performed before treatment between 1995 and 2010, and patients were followed up in an out-patient clinic. Surgery was performed in 33 patients, and a wait-and-see approach was taken in four patients. We evaluated the extent of tumor resection, location, WHO grade, Ki-67 labeling index, and lesion to normal ratio (LN ratio) of MET uptake. RESULTS: Six of the surgical cases had a recurrence, and two of the observation-only patients had tumor progression. A high LN ratio of MET uptake was a significant risk factor for recurrence and progression with univariate analysis. The area under the curve of receiver operating characteristic curve for the LN ratio of MET uptake was 0.754, and the optimal cutoff value was 3.18 (sensitivity 63 %, specificity 79 %). With multivariate analysis, a high LN ratio of MET uptake, non-gross total resection, and a high WHO grade were significant risk factors for progression and recurrence. CONCLUSION: A high LN ratio of MET uptake was a risk factor for tumor progression and recurrence. The advantage of MET PET is that it is not invasive and can easily be used to evaluate the whole tumor. PMID- 23801407 TI - Random mutagenesis identifies factors involved in formate-dependent growth of the methanogenic archaeon Methanococcus maripaludis. AB - Methane is a key intermediate in the carbon cycle and biologically produced by methanogenic archaea. Most methanogens are able to conserve energy by reducing CO2 to methane using molecular hydrogen as electron donor (hydrogenotrophic methanogenesis), but several hydrogenotrophic methanogens can also use formate as electron donor for methanogenesis. Formate dehydrogenase (Fdh) oxidizes formate to CO2 and is involved in funneling reducing equivalents into the methanogenic pathway, but details on other factors relevant for formate-dependent physiology of methanogens are not available. To learn more about the factors involved in formate-dependent growth of Methanococcus maripaludis strain JJ, we used a recently developed system for random in vitro mutagenesis, which is based on a modified insect transposable element to create 2,865 chromosomal transposon mutants and screened them for impaired growth on formate. Of 12 M. maripaludis transposon-induced mutants exhibiting this phenotype, the transposon insertion sites in the chromosome were mapped. Among the genes, apparently affecting formate-dependent growth were those encoding archaeal transcription factor S, a regulator of ion transport, and carbon monoxide dehydrogenase/acetyl-CoA synthase. Interestingly, in seven of the mutants, transposons were localized in a 10.2 kb region where Fdh1, one of two Fdh isoforms in the organism, is encoded. Two transcription start sites within the 10.2 kb region could be mapped, and quantification of transcripts revealed that transposon insertion in this region diminished fdhA1 expression due to polar effects. PMID- 23801408 TI - A genome-wide analysis of multidrug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis Beijing genotype. AB - The Beijing genotype of Mycobacterium tuberculosis (MTB) is one of the most successful MTB lineages that has disseminated in the world. In China, the rate of multidrug-resistant (MDR) tuberculosis is significantly higher than the global average rate, and the Beijing genotype strains take the largest share of MDR strains. To study the genetic basis of the epidemiological findings that Beijing genotype has often been associated with tuberculosis outbreaks and drug resistance, we determined the genome sequences of four clinical isolates: two extensively drug resistant (XDR1219, XDR1221) and two multidrug resistant (WX1, WX3), using whole-genome sequencing. A large number of individual and shared SNPs of the four Beijing strains were identified. Our isolates harbored almost all classic drug resistance-associated mutations. The mutations responsible for drug resistance in the two XDR strains were consistent with the clinical quantitative drug resistance levels. COG analysis revealed that Beijing strains have significantly higher abundances of the mutations responsible for cell wall/membrane/envelope biogenesis (COG M), secondary metabolites biosynthesis, transport and catabolism (COG Q), lipid transport and metabolism (COG I) and defense mechanisms (COG V). The shared mutated genes of the four studied Beijing strains were significantly overrepresented in three DNA repair pathways. Our analyses promote the understanding of the genome polymorphism of the Beijing family strains and provide the molecular genetic basis for their wide dissemination capacity and drug resistance. PMID- 23801409 TI - Residual recombination in Neurospora crassa spo11 deletion homozygotes occurs during meiosis. AB - Spo11 is considered responsible for initiation of meiotic recombination in higher organisms, but previous analysis using spo11 (RIP) mutants suggests that the his 3 region of Neurospora crassa experiences spo11-independent recombination. However, despite possessing several stop codons, it is conceivable that the mutants are not completely null. Also, since lack of spo11 interferes with chromosomal pairing and proper segregation at Meiosis I, spores can be partially diploid for a period after meiosis. Thus, it is possible that the recombination observed could be an abnormal event, occurring during the period of aneuploidy rather than during meiosis. To test the former hypothesis, we generated spo11 deletion homozygotes. Using crosses heteroallelic for his-3 mutations, we showed that His(+) progeny are generated in spo11 deletion homozygotes at a frequency at least as high as in wild type and, as in the spo11 (RIP) mutants, local crossing over is not reduced. To test the latter hypothesis, we utilised mutations in either end of a histone H1-GFP fusion gene, inserted between the recombination hotspot cog and his-3, in which GFP(+) spores arise as a result of recombination in a cross between the two GFP alleles. In a control cross homozygous for spo11 (+), the frequency at which GFP(+) spores arise is comparable to the frequency of His(+) spores and glowing nuclei first appear during prophase, prior to metaphase I, as expected for a product of meiotic recombination. Similarly in spo11 deletion homozygotes, GFP(+) spores arise at high frequency and glowing nuclei are first seen before metaphase, indicating that allelic recombination occurs during meiosis in the absence of spo11. We have therefore shown that spo11 is not essential for either his-3 allelic recombination or crossing over in the vicinity of his-3, and that spo11-independent allelic recombination is meiotic, indicating that there is a spo11-independent mechanism for initiation of recombination in Neurospora. PMID- 23801411 TI - Multidimensional GC using planar microfluidic devices for the characterization of phenolic antioxidants in fuels. AB - A multidimensional gas chromatographic approach using planar microfluidic devices for Deans switching has been developed and implemented for the characterization of sterically hindered phenolic compounds used as antioxidants in fuels. Detection and quantitation was conducted with MS in selected ion monitoring mode. A complete analysis is conducted in less than 15 min with precision greater than 5.5% at 1 and 25 ppm w/w (ppm(w)). LODs of 50 ppb w/w (ppb(w)) or better in selected ion monitoring mode and a linear range of 100 ppb(w) to 100 ppm(w) with a correlation coefficient greater than 0.998 were attained for all analytes. Unique to this analytical configuration is the use of a mass spectrometer capable of monitoring the column effluent from either dimension by incorporating a high temperature rotary valve and a three-port planar microfluidic device. High molecular-weight (C25-C40) fuel contaminants eluting from the first column can be selectively sent to the mass spectrometer for profile characterization in scan mode. These compounds would otherwise be retained substantially by the low-phase ratio analytical column employed in the second dimension. PMID- 23801410 TI - Simultaneous multislice multiband parallel radiofrequency excitation with independent slice-specific transmit B1 homogenization. AB - PURPOSE: To develop a new parallel transmit (pTx) pulse design for simultaneous multiband (MB) excitation in order to tackle simultaneously the problems of transmit B1 (B1+) inhomogeneity and total radiofrequency (RF) power, so as to allow for optimal RF excitation when using MB pulses for slice acceleration for high and ultrahigh field MRI. METHODS: With the proposed approach, each of the bands that are simultaneously excited is subject to a band-specific set of B1 complex shim weights. The method was validated in the human brain at 7T using a 16-channel pTx system and was compared to conventional MB pulses operating in the circularly polarized (CP) mode. Further numerical simulations based on measured B1 maps were conducted. RESULTS: The new method improved B1+ homogeneity by 60% when keeping the total RF power constant and reduced total RF power by 72% when keeping the excitation fidelity constant, as compared to the conventional CP mode. CONCLUSION: A new pTx pulse design formalism is introduced targeting slice specific B1+ homogenization in MB excitation while constraining total RF power. These pulses lead to significantly improved slice-wise B1+ uniformity and/or largely reduced total RF power, as compared to the conventionally employed MB pulses applied in the CP mode. PMID- 23801412 TI - Layer-by-layer aqueous rapid synthesis of ZIF-8 films on a reactive surface. AB - The synthesis of zeolitic imidazolate framework-8 (ZIF-8) films in an aqueous system was achieved. ZIF-8 films with controllable thickness were successfully grown on a modified substrate at room temperature. The 3-(2-imidazolin-1 yl)propyltriethoxysilane (IPTES) was used to first form a pseudo-surface of ZIF-8 on a glass substrate, followed by layer-by-layer growth. The film thickness of ZIF-8 was controlled within the range from 220 to 640 nm per growth cycle by changing the reactivity of the zinc source. Notably, the use of a preorganized zinc source led to drastic changes in the formation rate of ZIF-8. The use of a low-reactivity growth solution containing zinc acetate thus allowed the preparation of dense ZIF-8 films. PMID- 23801413 TI - Planar chiral iridium complexes with the Delta-TRISPHAT anion: toward the first enantiopure o-quinone methide pi-complex. AB - We describe the resolution of a planar chiral cationic iridium complex [Cp*Ir(eta5-2-methyl-oxodienyl)][OT f] (2) following the counterion strategy, where anion metathesis by Delta-TRISPHAT generates the two diastereomers (pR, pS) [Cp*Ir(eta5-2-methyl-oxodienyl)][Delta-TRISPHAT] (3a, 3a'). Upon fractional crystallization both compounds were separated as confirmed by 1H nuclear magnetic resonance (NMR) and circular dichroism studies recorded in solution. The latter represents the key-complex precursors for the enantioselective synthesis of metallated o-quinone methide complexes (4a, 4a'). PMID- 23801414 TI - Design and evaluation of capillary coupled with optical fiber light-emitting diode induced fluorescence detection for capillary electrophoresis. AB - A new detector, capillary coupled with optical fiber LED-induced fluorescence detector (CCOF-LED-IFD, using CCOF for short), is introduced for CE. The strategy of the present work was that the optical fiber and separation capillary were, in the parallel direction, fastened in a fixation capillary with larger inner diameter. By employing larger inner diameter, the fixation capillary allowed the large diameter of the optical fiber to be inserted into it. By transmitting an enhanced excitation light through the optical fiber, the detection sensitivity was improved. The advantages of the CCOF-CE system were validated by the detection of riboflavin, and the results were compared to those obtained by the in-capillary common optical fiber LED-induced fluorescence detector (IC-COF-LED IFD, using COF for short). The LODs of CCOF-CE and COF-CE were 0.29 nM and 11.0 nM (S/N = 3), respectively. The intraday (n = 6) repeatability and interday (n = 6) reproducibility of migration time and corresponding peak area for both types of CE were all less than 1.10 and 3.30%, respectively. The accuracy of the proposed method was judged by employing standard addition method, and recoveries obtained were in the range of 98.0-102.4%. The results indicated that the sensitivity of the proposed system was largely improved, and that its reproducibility and accuracy were satisfactory. The proposed system was successfully applied to separate and determine riboflavin in real sample. PMID- 23801415 TI - An atomic force microscopy statistical analysis of laser-induced azo-polyimide periodic tridimensional nanogrooves. AB - The surface morphology of azo-polyimide films was investigated after 355 nm Nd: YAG laser irradiation with two different incident fluencies. Atomic force microscopy (AFM) was employed to correlate the laser-induced tridimensional nanogrooved surface relief with the incident fluence and the number of irradiation pulses. The height images revealed that the grooves depth increased even tens of times by increasing the incident fluence, using the same numbers of irradiation pulses. For low incident fluence, the films were uniformly patterned till 100 pulses of irradiation. Instead, when using higher fluence, after 15 pulses of irradiation the accuracy of the surface relief definition was reduced. This behavior could be explained by means of two different mechanisms, one that suppose the film photo-fluidization due to the cis-trans isomerization processes of the azo-groups and the second one responsible for the directional mass displacement. The dominant surface direction and parameters like isotropy, periodicity, and period were evaluated from the polar representation for texture analysis, revealing the appearance of ordered and directionated nanostructures for most of the experimental conditions. Also, the graphical studies of the functional volume parameters have evidenced the improvement of the relief structuration during surface nanostructuration. The correlation of these statistical texture parameters with the irradiation characteristics is important in controlling the alignment of either the liquid crystals or the cells/tissues on patterned azo-polyimide surfaces for optoelectronic devices and implantable biomaterials, respectively. PMID- 23801416 TI - Decreased Muc5AC expression is associated with poor prognosis in gastric cancer. AB - Mucins reportedly play numerous key roles in carcinogenesis, including in tumor invasion, regulation of differentiation and tumor cell proliferation. We investigated the effect of Muc5AC, a secreted mucin, on the invasiveness/migratory capability of gastric cancer cells and the prognostic significance of Muc5AC in gastric cancer patients. The clinicopathological and prognostic significance of Muc5AC expression was validated using immunohistochemical analysis in 412 gastric cancer patients. Differential gene expression was investigated using complementary DNA microarray analysis of 48 fresh tumor tissue samples. Silencing of Muc5AC by using a small hairpin RNA containing lentivirus increased the invasion and migration of SNU216 and AGS cells as well as Akt phosphorylation and the expression of vascular endothelial growth factor and matrix metalloproteinase-7, which were blocked by inhibitors of the phosphatidylinositol 3-kinase/Akt pathway. Loss of Muc5AC expression was significantly associated with tumor progression (advanced T stage; p = 0.004), lymph node metastases (p = 0.001), lymphovascular invasion (p < 0.0001), and increased tumor size (p = 0.027). Lower MUC5AC expression was identified as an independent poor prognostic factor in diffuse-type gastric cancer by using the Cox regression proportional hazard model (hazard ratio, 2.39; p = 0.043). Complementary DNA microarray analysis revealed 86 differentially expressed genes, including genes related to metastasis and invasion, in gastric cancer tissues with high (>=25%) and low (<25%) Muc5AC expression levels. Low Muc5AC expression increased the invasion and migration of gastric cancer cells and could be a useful biomarker of poor prognosis in gastric cancer. PMID- 23801417 TI - Inherited neuropathies: clinical overview and update. AB - Inherited neuropathy is a group of common neurologic disorders with heterogeneous clinical presentations and genetic causes. Detailed neuromuscular evaluations, including nerve conduction studies, laboratory testing, and histopathologic examination, can assist in identification of the inherited component beyond family history. Genetic testing increasingly enables definitive diagnosis of specific inherited neuropathies. Diagnosis, however, is often complex, and neurologic disability may have both genetic and acquired components in individual patients. The decision of which genetic test to order or whether to order genetic tests is often complicated, and the strategies to maximize the value of testing are evolving. Apart from rare inherited metabolic neuropathies, treatment approaches remain largely supportive. We provide a clinical update of the various types of inherited neuropathies, their differential diagnoses, and distinguishing clinical features (where available). A framework is provided for clinical evaluations, including the inheritance assessment, electrophysiologic examinations, and specific genetic tests. PMID- 23801418 TI - Ceftaroline fosamil: a review of its use in the treatment of complicated skin and soft tissue infections and community-acquired pneumonia. AB - Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil (Zinforo, Teflaro), is an advanced-generation, parenteral cephalosporin with broad-spectrum antibacterial activity in vitro against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug resistant Streptococcus pneumoniae and Gram-negative bacteria, including Haemophilus influenzae and Moraxella catarrhalis, but not Pseudomonas aeruginosa. Ceftaroline has demonstrated a low potential for the selection of resistance in vitro for drug-resistant Gram-positive organisms, including MRSA, as well as for Gram negative respiratory pathogens. In pivotal phase III studies, intravenous ceftaroline fosamil demonstrated noninferiority to intravenous vancomycin plus aztreonam in patients hospitalized with complicated skin and soft tissue infections (cSSTIs) and intravenous ceftriaxone in patients hospitalized with community-acquired pneumonia (CAP) [Pneumonia Outcomes Research Team (PORT) risk class III or IV]; however, patients with CAP admitted to the intensive care unit were not evaluated. Ceftaroline fosamil was generally well tolerated in these trials, with an adverse event profile similar to that of other cephalosporins. Diarrhoea was the most commonly reported adverse event; however, the risk of Clostridium difficile-associated diarrhoea with ceftaroline fosamil appeared to be low. Potential limitations of the drug include the lack of an oral formulation and the requirement for twice-daily administration. Nonetheless, ceftaroline fosamil represents an attractive option (either alone or in combination with other agents) for the initial empirical treatment of patients hospitalized with cSSTIs (including those with suspected MRSA infection) or CAP (PORT risk class III or IV) who require intravenous antimicrobial therapy. As with all antibacterial agents, ceftaroline fosamil should be used in accordance with good antimicrobial stewardship. PMID- 23801419 TI - Efficacy of intra-tendinous injection of platelet-rich plasma in treating tendinosis: comprehensive assessment of a rat model. AB - OBJECTIVES: To assess the potential of intra-tendinous injection of platelet rich plasma (PRP) to treat tendinosis (T+) in a rat model of patellar and Achilles T+, and evaluate its local toxicity. METHODS: Thirty rats (120 patellar and Achilles tendons) were used. We induced T+ into 80 tendons (patellar = 40, Achilles = 40) by injecting collagenase at day 0 under ultrasound (US) guidance. Clinical examination and US at day 3, followed by US-guided intra-tendinous injection of either PRP (PRPT+, n = 40) or physiological serum (ST+, n = 40, control). Follow up was at days 6, 13, 18 and 25 using clinical, US and histological evaluation. To study PRP toxicity, we injected PRP into 40 normal tendons (PRPT-) and compared with 40 untreated normal tendons (T-). RESULTS: All PRPT+ showed better joint mobilisation compared with ST+ at day 6 (P = 0.005), day 13 (P = 0.02), day 18 (P = 0.003) and day 25 (P = 0.01). Similar results were found regarding US and histology, with smaller collagen fibre diameters (day 6, P = 0.003, day 25, P <= 0.004), less disorganisation and fewer neovessels (day 6, P = 0.003, day 25, P = 0.0003) in PRPT+ compared with ST+. Comparison between PRPT- and T- showed no PRP toxicity (P = 0.18). CONCLUSIONS: Our study suggests that mono-injection of PRP in T+ improves tendon healing, with no local toxicity. KEY POINTS: * We assessed the potential of platelet rich plasma (PRP) to treat tendinosis. * We treated patellar and Achilles tendinosis in a rat model. * We evaluated clinical, imaging and histological data. * Intra-tendinous PRP injection could be useful in the treatment of tendinosis. PMID- 23801420 TI - The efficiency of acoustic radiation force impulse imaging for the staging of liver fibrosis: a meta-analysis. AB - OBJECTIVES: Acoustic radiation force impulse (ARFI) imaging is an ultrasound based elastography method that is integrated into a conventional ultrasound machine. A meta-analysis based on original and abstract publications was performed to evaluate the overall performance of ARFI for the diagnosis of liver fibrosis. METHODS: Literature databases and conference abstracts were searched from 2007 up to February 2012. A random effects meta-analysis of the area under the receiver operating characteristic (ROC) curve (AUROC) and the diagnostic odds ratio (DOR) was performed as well as summary ROC curve techniques. Quality analyses were conducted to assess sources of heterogeneity. RESULTS: The systematic literature search revealed 36 studies, with 3,951 patients overall. The mean diagnostic accuracy of ARFI expressed as the AUROC was 0.84 (DOR, 11.54) for the diagnosis of significant fibrosis (F >= 2), 0.89 (DOR, 33.54) for the diagnosis of severe fibrosis (F >= 3) and 0.91 (DOR, 45.35) for the diagnosis of liver cirrhosis (F = 4). Subgroup analyses showed sources of heterogeneity between the different underlying liver diseases for F >= 3 and F = 4. The mean body mass index had a significant influence for F >= 2. CONCLUSIONS: The meta analysis revealed good diagnostic accuracy of the ARFI imaging for the staging of F >= 2 and F >= 3, and excellent diagnostic accuracy for F = 4. KEY POINTS: * Acoustic radiation force impulse (ARFI) imaging adds important information over conventional ultrasound. * ARFI imaging provides good diagnostic performance for assessing significant/severe hepatic fibrosis. * ARFI imaging shows excellent diagnostic accuracy and odds ratio for cirrhosis staging. * Body mass index significantly influences the assessment of significant fibrosis. PMID- 23801421 TI - Diagnostic performance of computed tomography angiography and contrast-enhanced magnetic resonance angiography in patients with critical limb ischaemia and intermittent claudication: systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the diagnostic performance of computed tomography angiography (CTA) and contrast-enhanced magnetic resonance angiography (CE-MRA) in detecting haemodynamically significant arterial stenosis or occlusion in patients with critical limb ischaemia (CLI) or intermittent claudication (IC). METHODS: Medline and Embase were searched for studies comparing CTA or CE-MRA with digital subtraction angiography as a reference standard, including patients with CLI or IC. Outcome measures were aortotibial arterial stenosis of more than 50 % or occlusion. Methodological quality of studies was assessed using QUADAS. RESULTS: Out of 5,693 articles, 12 CTA and 30 CE-MRA studies were included, respectively evaluating 673 and 1,404 participants. Summary estimates of sensitivity and specificity were respectively 96 % (95 % CI, 93-98 %) and 95 % (95 % CI, 92-97 %) for CTA, and 93 % (95 % CI, 91-95 %) and 94 % (95 % CI, 93-96 %) for CE-MRA. Regression analysis showed that the prevalence of CLI in individual studies was not an independent predictor of sensitivity and specificity for either technique. Methodological quality of studies was moderate to good. CONCLUSION: CTA and CE-MRA are accurate techniques for evaluating disease severity of aortotibial arteries in patients with CLI or IC. No significant differences in the diagnostic performance of the two techniques between patients with CLI and IC were found. KEY POINTS: * Computed tomography and contrast-enhanced magnetic resonance angiography can both demonstrate arterial disease. * CTA and CE-MRA can both accurately evaluate arteries in peripheral arterial disease. * Diagnostic performances of critical limb ischaemia and intermittent claudication are not different. * Separate imaging technique of tibial arteries by CE-MRA is preferred. * CTA and CE-MRA can distinguish confidently between high-grade stenoses and occlusions. PMID- 23801422 TI - Statin therapy in patients with atypical chest pain and mild-to-moderate coronary stenosis on 64-slice multidetector coronary computed tomography; a retrospective propensity score matching analysis. AB - BACKGROUND: The effect of computed tomography (CT)-guided statin therapy on patients with atypical chest pain and mild-to-moderate coronary artery disease has not been elucidated yet. METHODS: A total of 1,952 patients who had 1-69 % stenosis on CT were reviewed retrospectively. After propensity score matching, 643 patients who were prescribed statins after CT (statin users) and 643 patients without statin therapy (statin non-users) were compared. Major cardiovascular events included all-cause death, acute coronary syndrome and stroke. RESULTS: During a median of 42 months' follow-up, all-cause death was reported in 17 patients (1.3 %), of whom 6 (0.9 %) were statin users and 11 (1.7 %) statin nonusers. Major cardiovascular events developed in 6.1 % in the statin user group and 5.6 % in the statin non-users (P = 0.812). When evaluated according to plaque subtypes, statins showed significant benefit in patients who had non-calcified or mixed plaque (HR 0.47, 95 % CI 0.22-1.01, P = 0.047). However, in patients with calcified plaques, statins had no benefit in reducing adverse events (P = 0.620). CONCLUSION: In most patients with mild-to-moderate coronary artery stenosis on CT, statin therapy has no beneficial effect on reducing adverse events. However, in patients with non-calcified or mixed plaques, statin therapy showed a significant benefit. KEY POINTS: * Multidetector CT now identifies numerous subjects with mild-to-moderate coronary stenosis. * Statin therapy has little beneficial effect on patients with calcified plaques. * However, statins reduce adverse events in those with non-calcified or mixed plaques. PMID- 23801423 TI - Optimizing contrast agent concentration and spoiled gradient echo pulse sequence parameters for catheter visualization in MR-guided interventional procedures: an analytic solution. AB - PURPOSE: A critical requirement of MR-guided interventions is the visualization of an instrument (e.g., catheter, needle) during the procedure. One approach is to fill the instrument with a contrast agent. Previously, the optimization of contrast agent visualization was performed only empirically. In the present study, an analytic optimization of contrast agent SNR efficiency was performed for a spoiled gradient echo pulse sequence. METHODS: Optimal flip angle, repetition time, echo time, and contrast agent concentration were derived analytically. The solution is valid for any contrast agent, provided the relationship between T1 , T2 , and doping concentration is known. RESULTS: Phantom experiments validated the analytic optimization for Gd- and MnCl2 -based contrast agents. Results showed excellent agreement between experimentally predicted and theoretically observed magnetization behavior. In vivo experiments demonstrated optimized contrast agent visualization in brain, heart, and prostate applications. The results demonstrated the large SNR that can be achieved with analytic optimization. As a practical guideline, an 11% dilution of 500 mMol/L Gd DTPA solution, repetition time ~ 4 ms, echo time ~ 1 ms, and theta ~ 65 degrees was found to provide a large SNR. CONCLUSION: This study derived and validated a method for analytically optimizing contrast agent SNR efficiency. This information may be useful for visualizing instruments during MR-guided interventions. PMID- 23801424 TI - Development of a model of a multi-lymphangion lymphatic vessel incorporating realistic and measured parameter values. AB - Our published model of a lymphatic vessel consisting of multiple actively contracting segments between non-return valves has been further developed by the incorporation of properties derived from observations and measurements of rat mesenteric vessels. These included (1) a refractory period between contractions, (2) a highly nonlinear form for the passive part of the pressure-diameter relationship, (3) hysteretic and transmural-pressure-dependent valve opening and closing pressure thresholds and (4) dependence of active tension on muscle length as reflected in local diameter. Experimentally, lymphatic valves are known to be biased to stay open. In consequence, in the improved model, vessel pumping of fluid suffers losses by regurgitation, and valve closure is dependent on backflow first causing an adverse valve pressure drop sufficient to reach the closure threshold. The assumed resistance of an open valve therefore becomes a critical parameter, and experiments to measure this quantity are reported here. However, incorporating this parameter value, along with other parameter values based on existing measurements, led to ineffective pumping. It is argued that the published measurements of valve-closing pressure threshold overestimate this quantity owing to neglect of micro-pipette resistance. An estimate is made of the extent of the possible resulting error. Correcting by this amount, the pumping performance is improved, but still very inefficient unless the open-valve resistance is also increased beyond the measured level. Arguments are given as to why this is justified, and other areas where experimental data are lacking are identified. The model is capable of future adaptation as new experimental data appear. PMID- 23801425 TI - A direct stereoselective preparation of a fish pheromone and application of the zinc porphyrin tweezer chiroptical protocol in its stereochemical assignment. AB - A two-step stereoselective preparation of a goldfish pheromone, 17alpha,20beta dihydroxy-4-pregnen-3-one, is reported from the readily available cortexolone in 64% overall yield. The (20S)-epimer was also synthesized in three steps from cortexolone with an overall yield of 47%. A microscale chiroptical technique based on a host/guest complexation mechanism between the substrate and a dimeric metalloporphyrin host (tweezer) was used to confirm the stereochemical assignment, while Density Functional Theory (DFT) calculations were employed to explain the high stereoselectivity induced by the 17alpha-hydroxyl and C18-methyl groups. PMID- 23801426 TI - Validation of the Microbiological Testing of Tissue Preparations Using the BACTECTM Blood Culture System. AB - BACKGROUND: Since blood culture bottles are validated by the manufacturer for blood only, an additional validation for the use with fluids of tissue preparations is necessary. METHODS: Two 10-ml samples of cornea culture medium, histidine-tryptophan-ketoglutarate (HTK) solution, or Ringer solution at the end of femur head thermo-disinfection were given into blood culture bottles (BD BACTECTM Plus Aerobic/F, Anaerobic/F for cornea culture medium and BD BACTECTM Standard Aerobic/Anaerobic for HTK and Ringer solution) and subsequently spiked with 10-100 colony forming units (CFU) of bacteria or fungi (aerobic bacteria: Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa; anaerobic bacteria: Clostridium sporogenes; fungi: Candida albicans, Aspergillus brasiliensis) according to the European Pharmacopoeia Chapter 2.6.1. RESULTS: All tested bacteria and fungi could be detected in all solutions. All positive and negative controls were tested correctly. Compared to the positive controls, the microbial growth was delayed in the antibiotic-containing cornea culture medium, and negative in two cases of B. subtilis spiking. CONCLUSION: The use of BACTECTM blood culture bottles seems to be a suitable method for microbiological testing of HTK solution, Ringer solution, and, with limitations, also for testing of the antibiotic-containing cornea culture medium. PMID- 23801427 TI - Successful treatment of a patient with adult T cell leukemia/lymphoma using anti CC chemokine receptor 4 monoclonal antibody mogamulizumab followed by allogeneic hematopoietic stem cell transplantation. AB - Adult T cell leukemia/lymphoma (ATLL) is an aggressive peripheral T cell neoplasm caused by human T cell lymphotropic/leukemia virus type-1 and has a poor prognosis. A new anti-CC chemokine receptor 4 monoclonal antibody (mogamulizumab) has been shown to be effective for ATLL. Although mogamulizumab is now available in Japan for patients with ATLL, the influence on allogeneic hematopoietic stem cell transplantation (HSCT) remains unclear. Here we report a woman with ATLL resistant to combination chemotherapy, who achieved complete remission following treatment with mogamulizumab and subsequently received allogeneic HSCT. The patient has remained in complete remission with controlled graft-versus-host disease. To our knowledge, this is the first report of an ATLL patient who received mogamulizumab treatment followed by allogeneic HSCT. We suggest that administration of mogamulizumab to chemotherapy-resistant patients with ATLL may improve their disease status before allogeneic HSCT and result in better survival. PMID- 23801428 TI - Comparative core fucosylation analysis of some major therapeutic antibody N glycans by direct infusion ESI-MS and CE-LIF detection. AB - The analysis of carbohydrate moieties of glycoprotein biopharmaceuticals is of high importance, especially because glycosylation changes can impact the biological effect of the drugs. In the case of monoclonal antibody therapeutics, the degree of core fucosylation significantly influences its effector function, thus should be closely monitored during the clone selection, development and manufacturing processes. MS analysis of labile sugar residues such as core fucosylation and terminal silylation may be misleading as such residues can break off during the ionization process or alter the ionization efficiency, both of which affect the results. In the case of monoclonal antibody therapeutics tailored for antibody-dependent cellular cytotoxicity function, core fucosylation should be kept minimal; therefore, close attention should be paid to the prevalence of this particular sugar residue. This paper reports on the core fucosylation analysis of some major immunoglobulin G N-glycans by direct infusion ESI-MS and CE-LIF. In comparison to the industry standard of CE-LIF, a lower degree of core fucosylated structures was found by ESI-MS analysis, emphasizing the need to use orthogonal quantitative separation methods in addition to MS. PMID- 23801429 TI - Mesenchymal stem cells and cartilage lesions. PMID- 23801430 TI - Hypercholesterolemia as one of the risk factors of intracerebral hemorrhage. AB - Stroke is still a major cause of morbidity and mortality throughout the world, although better stratification and treatment modalities are being developed. As compared to ischemic stroke, intracerebral hemorrhage (ICH) possesses many unknown data and lacks guidelines for better prophylaxis. In this study, we aimed to investigate patients with ICH hospitalized in our neurology department within 5 years in terms of risk stratification. A total of 4,449 patients were hospitalized; 1,378 of patients (31%) were diagnosed as having cerebrovascular disease and of these 165 patients (3.7%) had ICH. The risk factors of patients with ICH were investigated and compared with age- and gender matched 75 healthy subjects. We observed that hypercholesterolemia (p = 0.002) was one of the most common risk factors in patients with ICH as compared to controls, together with hypertension (p = 0.010). On the other hand, hypolipidemia (LDL-cholesterol level < 50 mg/dl) was not present in any of the patients. As our purpose as neurologists is to reduce the occurrence and fatal outcome of cerebrovascular events, we aimed to emphasize the importance of risk factors to be well defined, for which every effort should be exhibited for both primary and secondary prevention. PMID- 23801431 TI - Possible effect of perampanel on focal status epilepticus after generalized tonic clonic status epilepticus. PMID- 23801432 TI - Peer bystanders to bullying: who wants to play with the victim? AB - Given widespread concern associated with school-based bullying, researchers have looked beyond a dyadic perspective (i.e., bullies and victims only), and now consider the broader social ecology of the peer group. In this research, we examined how the behaviors of peer bystanders influence subsequent reactions to bullies and their victims. Two hundred and six 10- to 15-year-old boys (Mage = 12.46) were invited to play a computer game with three other boys allegedly located at another school. Before the start of the game, participants "met the other players" apparently sitting in a waiting room. These child actors depicted an escalating bullying episode in which the behavior of the bystander was manipulated: aide to the bully, defender of the victim, or passive outsider. Immediately after exposure to the bullying, each participant played a ball toss game (Cyberball) with the three other boys in the video. Individual differences among participants were examined as moderators of the effect of bystander behavior on participants' willingness to include the "victim" in the game. Results indicated that, when exposed to a passive bystander, boys' normative beliefs about aggression, as well as their tendency to morally disengage from observed egregious acts, decreased their willingness to include the victim in the game. PMID- 23801433 TI - Chronic mild stress for modeling anhedonia. AB - Major depressive disorder is a complex disease implicating many brain circuitries. The clinical symptomatology is inconsistent and heterogenous and the pathogenesis is a complicated interplay of genetic and environmental factors. The episodic and recurrent nature of the disease, as well as the fact that several symptoms are only verbally expressed, make it challenging to establish valid and legitimate animal models of this disease. The purpose of this review is to provide some background knowledge and overview of valid rodent models of depression with an emphasis on our own experience with a chronic mild stress model in modeling of anhedonia and cognitive impairments associated with depression. In a final concluding remark, a 'dying-forward' hypothesis, for development of depression, is suggested on the basis of mainly our own data on a hippocampal pathology. PMID- 23801434 TI - Early development of cephalochordates (amphioxus). AB - The Phylum Chordata includes three groups--Vertebrata, Tunicata, and Cephalochordata. In cephalochordates, commonly called amphioxus or lancelets, which are basal in the Chordata, the eggs are small and relatively non-yolky. As in vertebrates, cleavage is indeterminate with cell fates determined gradually as development proceeds. The oocytes are attached to the ovarian follicle at the animal pole, where the oocyte nucleus is located. The cytoplasm at the opposite side of the egg, the vegetal pole, contains the future germ plasm or pole plasm, which includes determinants of the germline. After fertilization, additional asymmetries are established by movements of the egg and sperm nuclei, resulting in a concentration of mitochondria at one side of the animal hemisphere. This may be related to establishment of the dorsal/ventral axis. Patterning along the embryonic axes is mediated by secreted signaling proteins. Dorsal identity is specified by Nodal/Vg1 signaling, while during the gastrula stage, opposition between Nodal/Vg1 and BMP signaling establishes dorsal/anterior (i.e., head) and ventral/posterior (i.e., trunk/tail) identities, respectively. Wnt/beta-catenin signaling specifies posterior identity while retinoic acid signaling specifies positions along the anterior/posterior axis. These signals are further modulated by a number of secreted antagonists. This fundamental patterning mechanism is conserved, with some modifications, in vertebrates. PMID- 23801435 TI - Compartmentalization of the foregut tube: developmental origins of the trachea and esophagus. AB - The mammalian trachea and esophagus share a common embryonic origin. They arise by compartmentalization of a single foregut tube, composed of foregut endoderm (FGE) and surrounding mesenchyme, around midgestation. Aberrant compartmentalization is thought to lead to relatively common human birth defects, such as esophageal atresia (EA) and tracheoesophageal fistula (EA/TEF), which can prevent or disrupt a newborn infant's ability to feed and breathe. Despite its relevance to human health, morphogenesis of the anterior foregut is still poorly understood. In this article, we provide a comprehensive review of trachea and esophagus formation from a common precursor, including the embryonic origin of the FGE, current models for foregut morphogenesis, relevant human birth defects, insights from rodent models, and the emerging picture of the mechanisms underlying normal and abnormal foregut compartmentalization. Recent research suggests that a number of intercellular signaling pathways and several intracellular effectors are essential for correct formation of the trachea and esophagus. Different types of defects in the formation of either ventral or dorsal foregut tissues can disrupt compartmentalization in rodent models. This implies that EA/TEF defects in humans may also arise by multiple mechanisms. Although our understanding of foregut compartmentalization is growing rapidly, it is still incomplete. Future research should focus on synthesizing detailed information gleaned from both human patients and rodent models to further our understanding of this enigmatic process. PMID- 23801437 TI - Spindle positioning in the stem cell niche. AB - Stem cells are the source of differentiated cells that constitute tissues and organs. Two fundamental characteristics of stem cells are their abilities to self renew stem cell identity and to produce differentiated cells, the balance of which can be achieved by asymmetric stem cell division. Many stem cells have been shown to reside in a stem cell niche, the home of stem cells that regulates the stem cell behavior. Recent studies have revealed the critical contribution of cytoskeletons in achieving asymmetric stem cell division: mitotic spindles in dividing stem cells are often oriented with respect to the stem cell niche, which is supported by concerted actions of microtubule networks and components at the cell membrane such as adherens junctions, the actin cytoskeleton, and the extracellular matrix. In this article, we review the mechanism of stem cell spindle orientation, with emphasis on its relationship with the stem cell niche, and discuss how it contributes to tissue development and homeostasis. PMID- 23801436 TI - Somatic muscle specification during embryonic and post-embryonic development in the nematode C. elegans. AB - Myogenesis has proved to be a powerful paradigm for understanding cell fate specification and differentiation in many model organisms. Studies of somatic bodywall muscle (BWM) development in Caenorhabditis elegans allow us to define, with single cell resolution, the distinct hierarchies of transcriptional regulators needed for myogenesis throughout development. Although all 95 BWM cells appear uniform after differentiation, there are several different regulatory cascades employed embryonically and post-embryonically. These, in turn, are integrated into multiple extrinsic cell signaling events. The convergence of these different pathways on the key nodal point, that is the activation of the core muscle module, commits individual cells to myogenesis. Comparisons of myogenesis between C. elegans and other model systems provide insights into the evolution of contractile cell types, demonstrating the conservation of regulatory schemes for muscles throughout the animal kingdom. PMID- 23801438 TI - Morphogenesis in sea urchin embryos: linking cellular events to gene regulatory network states. AB - Gastrulation in the sea urchin begins with ingression of the primary mesenchyme cells (PMCs) at the vegetal pole of the embryo. After entering the blastocoel the PMCs migrate, form a syncitium, and synthesize the skeleton of the embryo. Several hours after the PMCs ingress the vegetal plate buckles to initiate invagination of the archenteron. That morphogenetic process occurs in several steps. The nonskeletogenic cells produce the initial inbending of the vegetal plate. Endoderm cells then rearrange and extend the length of the gut across the blastocoel to a target near the animal pole. Finally, cells that will form part of the midgut and hindgut are added to complete gastrulation. Later, the stomodeum invaginates from the oral ectoderm and fuses with the foregut to complete the archenteron. In advance of, and during these morphogenetic events, an increasingly complex input of transcription factors controls the specification and the cell biological events that conduct the gastrulation movements. PMID- 23801440 TI - Self-incompatibility in Petunia: a self/nonself-recognition mechanism employing S locus F-box proteins and S-RNase to prevent inbreeding. AB - Many flowering plants producing bisexual flowers have adopted self incompatibility (SI), a reproductive strategy which allows pistils to distinguish between self and nonself pollen, and to only permit nonself pollen to effect fertilization. To date, three different SI mechanisms have been identified, and this article focuses on the S-RNase-based mechanism using Petunia (Solanaceae) as a model. The genetic basis of this type of SI was established nearly a century ago; the polymorphic S-locus specifies the genetic identity of pollen and the pistil. Molecular genetic studies carried out since the late 1980s have led to the identification of the polymorphic genes at the S-locus that control self/nonself-recognition between pollen and the pistil. The S-RNase gene, which controls pistil specificity, was identified first, and subsequent sequencing of the S-locus region containing S-RNase led to the identification of the S-locus F box (SLF) gene (now named SLF1). A transgenic approach was used to show that S2 SLF1 (SLF1 of S2-halotype) of Petunia inflata controls pollen specificity. The S locus contains additional pollen-expressed F-box genes that show sequence similarity with SLF1, and initially they were thought not to be involved in pollen specificity. However, further studies of SLF1 suggested that it is not the only pollen specificity gene. Indeed, it has recently been shown that two previously identified SLF-like genes in P. inflata (now named SLF2 and SLF3) and a yet unknown number of additional SLF-like genes (named SLF4, SLF5, etc.) collaboratively function to control pollen specificity. The significance and implications of this new finding are discussed. PMID- 23801439 TI - Anterior-posterior patterning in early development: three strategies. AB - The anterior-posterior (AP) axis is the most ancient of the embryonic axes and exists in most metazoans. Different animals use a wide variety of mechanisms to create this axis in the early embryo. In this study, we focus on three animals, including two insects (Drosophila and Tribolium) and a vertebrate (zebrafish) to examine different strategies used to form the AP axis. While Drosophila forms the entire axis within a syncytial blastoderm using transcription factors as morphogens, zebrafish uses signaling factors in a cellularized embryo, progressively forming the AP axis over the course of a day. Tribolium uses an intermediate strategy that has commonalities with both Drosophila and zebrafish. We discuss the specific molecular mechanisms used to create the AP axis and identify conserved features. PMID- 23801441 TI - Molecular mechanisms of root gravity sensing and signal transduction. AB - Plants use gravity as a guide to direct their roots down into the soil to anchor themselves and to find resources needed for growth and development. In higher plants, the columella cells of the root tip form the primary site of gravity sensing, and in these cells the sedimentation of dense, starch-filled plastids (amyloplasts) triggers gravity signal transduction. This generates an auxin gradient across the root cap that is transmitted to the elongation zone where it promotes differential cell elongation, allowing the root to direct itself downward. It is still not well understood how amyloplast sedimentation leads to auxin redistribution. Models have been proposed to explain how mechanosensitive ion channels or ligand-receptor interactions could connect these events. Although their roles are still unclear, possible second messengers in this process include protons, Ca(2+), and inositol 1,4,5-triphosphate. Upon gravistimulation, the auxin efflux facilitators PIN3 and PIN7 relocalize to the lower side of the columella cells and mediate auxin redistribution. However, evidence for an auxin independent secondary mechanism of gravity sensing and signal transduction suggests that this physiological process is quite complex. Furthermore, plants must integrate a variety of environmental cues, resulting in multifaceted relationships between gravitropism and other directional growth responses such as hydro-, photo-, and thigmotropism. PMID- 23801443 TI - Brachet's cleft: a model for the analysis of tissue separation in Xenopus. AB - Tissue border formation is an important process that prevents mixing of cells during embryonic development. The establishment of tissue borders is not a trivial problem, particularly in early embryos when cells and tissues are not fully differentiated. An example of an early tissue separation process is the formation of Brachet's cleft in Xenopus. During early gastrulation, this morphologically visible cleft separates mesendoderm and ectoderm. Over the last decade, it was recognized that morphogenetic processes, including tissue separation, can be experimentally uncoupled from embryonic patterning events. In this study, we summarize the data explaining the regulation of Brachet's cleft and introduce the experimental arsenal that was used for this analysis. The formation of Brachet's cleft involves the activity of transcription factors, cell adhesion molecules, and signaling modules, which act in a complex regulatory network. According to the current state of knowledge, Rho signaling seems to be the central player during this process. The mechanisms that regulate Rho during tissue separation and the experimental approaches to monitor Rho activity are discussed. PMID- 23801442 TI - Uncorking gastrulation: the morphogenetic movement of bottle cells. AB - Bottle cell-driven blastopore lip formation externally marks the initiation of gastrulation in amphibian embryos. The blastopore groove is formed when bottle cells undergo apical constriction and transform from cuboidal to flask-shaped. Apical constriction is sufficient to cause invagination and is a highly conserved mechanism for sheet bending and folding during morphogenesis; therefore, studying apical constriction in Xenopus bottle cells could provide valuable insight into this fundamental shape change. Initially described over a century ago, the dramatic shape change that occurs in bottle cells has long captured the imaginations of embryologists. However, only recently have investigators begun to examine the cellular and molecular mechanisms underlying bottle cell apical constriction. Bottle cell apical constriction is driven by actomyosin contractility as well as by endocytosis of the apical membrane. The Nodal signaling pathway, Wnt5a, and Lgl1 are all required for bottle cell formation, but how they induce subcellular changes resulting in apical constriction remains to be elucidated. Xenopus bottle cells now represent an excellent vertebrate system for the dissection of how molecular inputs can drive cellular outputs, specifically the cell shape change of apical constriction. PMID- 23801444 TI - Internalizing the vegetal cell mass before and during amphibian gastrulation: vegetal rotation and related movements. AB - The movement of the prospective mesoderm and endoderm to the interior of the amphibian embryo starts in the vegetal cell mass well before the onset of overt gastrulation. By an animally directed movement of cells, the vegetal mass constricts its outer part and expands its inner region including the blastocoel floor, in a process of pregastrulation emboly. Further internalization of the vegetal region has been studied in the Xenopus embryo. At the onset of gastrulation, vegetal rotation sets in at the periphery of the vegetal cell mass, first dorsally and then spreading laterally and ventrally. It consists of an intense inward surging of cells due to active cell rearrangements that can be observed in explants of the vegetal cell mass. In its course, the blastocoel floor expands further and becomes apposed to the blastocoel roof. The boundary between apposed floor and roof forms Brachet's cleft. Another effect of vegetal rotation is the downward and inward movement of the mesodermal marginal zone, constituting the first phase of involution. Together, the upward and outward movement of the peripheral vegetal mass and the downward and inward translocation of the marginal zone lead to an apparent rotation of the whole peripheral region of the gastrula. Vegetal rotation continues to contribute to endoderm internalization to near the end of gastrulation. PMID- 23801445 TI - A niche for Drosophila neuroblasts? AB - Stem cells, which can self-renew and give rise to differentiated daughters, are responsible for the generation of diverse cell types during development and the maintenance of tissue/organ homeostasis in adulthood. Thus, the precise regulation of stem-cell self-renewal and proliferative potential is a key aspect of development. The stem-cell niche confers such control by concentrating localized factors including signaling molecules which favor stem-cell self-renew and regulate stem-cell proliferation in line with developmental programs. In contrast, Drosophila neuroblasts (NBs), often referred to as neural stem cells/progenitors, can undergo asymmetric cell division to self-renew and produce differentiated daughters even in isolation (or in culture). Furthermore, these isolated NBs can also progress through an intrinsically regulated temporal series (of transcription factor expression) to generate diverse cell types in vitro. These data argue that NBs may depend only to a limited extent, if at all, on local environment (a niche) for their maintenance. On the other hand, there is increasing evidence which indicate that the interaction between NBs and their surrounding glia is critical for the control of NB proliferative potential and these glia, in conjunction with systemic regulation, perform the niche function to regulate NB behavior. Thus, these observations emphasize the importance of coordinated local microenvironment (niche activity) and systemic environment (global activity) on the regulation of NB behavior in vivo, and suggest NBs may conform to an alternative stem-cell/progenitor maintenance model. PMID- 23801446 TI - [Rectal GIST as an incidental finding on CT colonography]. PMID- 23801447 TI - [A rare case of an intraventricular meningioma WHO grade II]. PMID- 23801448 TI - Magnetic resonance imaging-based diagnosis of congenital ureterocele. PMID- 23801449 TI - First experience using navigation-guided radiofrequency kyphoplasty for sacroplasty in sacral insufficiency fractures. AB - PURPOSE: To evaluate the efficacy and safety of navigation-guided radiofrequency kyphoplasty for sacroplasty in patients with sacral insufficiency fractures. METHODS: In this single-center retrospective observational study, four consecutive patients with sacral insufficiency fractures were treated with navigation-guided radiofrequency kyphoplasty for sacroplasty between April 2010 and May 2012. Symptom characteristics, pain duration and pain intensity were recorded for each patient. Cement extravasation was evaluated in thin-sliced and triplanar reconstructed CT scans of the sacrum. RESULTS: Four female patients with painful sacral insufficiency fractures and extensive osteopenic areas significantly improved from an average pre-treatment VAS score of 8.3 +/- 0.5 to 2.3 +/- 1.0 (p < 0.001) on the first postoperative day and to 1.3 +/- 1.9 (p < 0.004) at follow-up (mean, 20.1 weeks). Slight cement extravasations were observed without evidence of being symptomatic. No major complications or procedure-related morbidity were noted. CONCLUSION: From the limited experience in four patients, navigation-guided radiofrequency kyphoplasty appears to be a safe and effective treatment option for sacral insufficiency fractures even though asymptomatic cement extravasation was noted. The use of navigation based on intraoperative 3 D images simplifies the positioning of the navigated bone needles via the long axis approach. The radiofrequency kyphoplasty system provides the possibility to administer a sufficient amount of bone cement with a well-defined viscosity over the entire period of the procedure leading to high security and low cement extravasation. Sacroplasty provides rapid and enduring pain relief and facilitates prompt mobilization. PMID- 23801450 TI - A preregistered STAMP method for image-guided temporal bone surgery. AB - OBJECTIVES: Image-guided otological surgeries require minimal invasiveness and high accuracy, and these two factors usually compete with each other. Our recently developed registration method, called the STAMP method, showed minimal invasiveness with accuracy comparable to that of the current more invasive registration methods used in image-guided temporal bone surgery. However, surgeons perceived the STAMP method as complex and time-consuming. METHODS: We modified our STAMP method to further simplify the surgeon's tasks in the operating room. We attached an optical tracking target on the STAMP plate and registered the plate in an IGS system before surgery, outside the operating room. The registration was completed in the operating room by finishing the final simple task, which was to hold the preregistered STAMP plate still on the patient's temporal bone. We tested this modified preregistered STAMP method in simulation surgery and actual surgeries. The registration times and errors of the STAMP method and preregistered STAMP method were compared. RESULTS: The proposed new preregistered STAMP method significantly reduced the registration time in the operating room without compromising the registration accuracy. CONCLUSIONS: The preregistered STAMP method significantly improved the original STAMP method in terms of time and convenience. It is now considered to be one of the easiest and quickest registrations for image-guided temporal bone surgery. Because most of the critical processes of registration can be completed in the laboratory, the registration task in the operating room is therefore greatly simplified, thus allowing surgeons to concentrate more on the surgery itself. PMID- 23801452 TI - A compact CCD-monitored atomic force microscope with optical vision and improved performances. AB - A novel CCD-monitored atomic force microscope (AFM) with optical vision and improved performances has been developed. Compact optical paths are specifically devised for both tip-sample microscopic monitoring and cantilever's deflection detecting with minimized volume and optimal light-amplifying ratio. The ingeniously designed AFM probe with such optical paths enables quick and safe tip sample approaching, convenient and effective tip-sample positioning, and high quality image scanning. An image stitching method is also developed to build a wider-range AFM image under monitoring. Experiments show that this AFM system can offer real-time optical vision for tip-sample monitoring with wide visual field and/or high lateral optical resolution by simply switching the objective; meanwhile, it has the elegant performances of nanometer resolution, high stability, and high scan speed. Furthermore, it is capable of conducting wider range image measurement while keeping nanometer resolution. PMID- 23801451 TI - Design and synthesis of a novel fluorescent protein probe for easy and rapid electrophoretic gel staining by using a commonly available UV-based fluorescent imaging system. AB - A new fluorescent molecular probe, methyl 3-(3,5-bis((bis(pyridin-2 ylmethyl)amino)-methyl)-4-hydroxyphenyl)-2-(5-(dimethylamino)naphthalene-1 sulfonamido) propanoate, dizinc(II) chloride salt (Dansyl-1-Zn(II)), which possesses Zn(II) complexes and a dansyl group, was designed and synthesized to enable the detection of proteins in solution and in high-throughput electrophoresis by using a UV-based detection system. Dansyl-1-Zn(II) exhibited weak fluorescence in the absence of proteins and strong green fluorescence at approximately 510 nm in the presence of BSA upon irradiation with light at a wavelength of 345 nm. Compared with conventional protocols for in-gel SDS-PAGE protein staining (e.g. silver staining, SYPRO Ruby, and Oriole), the operating times of which range from 90 min to overnight, Dansyl-1-Zn(II) allowed 1-step protein staining (SDS-PAGE ->Staining ->Detection) and shortened the operating time (35 min) with high sensitivity (LOD: 1 ng or less) under 312-nm or 365-nm light excitation with orange or red emission filters, respectively. Moreover, Dansyl-1-Zn(II) was successfully applied to protein identification by MS via in gel tryptic digestion, Western blotting, and Native-PAGE. Accordingly, Dansyl-1 Zn(II) may facilitate highly sensitive and high-throughput protein detection, and it may be widely applicable as a convenient tool in various scientific and medical fields. PMID- 23801453 TI - An improved bioassay facilitates the screening of repellents against cat flea, Ctenocephalides felis (Siphonaptera: Pulicidae). AB - BACKGROUND: Repellents are a common method for preventing flea bites, making an effective system for flea repellent screening advantageous. We describe an improved technique to facilitate repellent activity screening of numerous plant based Ctenocephalides felis (cat flea) repellents. RESULTS: Two long strips of filter paper were impregnated with test compounds (dissolved in ethanol) and ethanol only, respectively. After drying, the two filter papers were glued together along the long side and inserted into a glass tube containing non-fed cat fleas. The distribution of cat fleas in each half of the filter paper was recorded after 30 min to calculate repellency. Results showed that the essential oil of Cinnamomum osmophloeum (from leaf), Taiwania cryptomerioides (from heartwood) and Plectranthus amboinicus (from leaf) exhibits repellent activity against cat fleas in a dose dependent manner. Moreover, the repellent activities against cat fleas of 2% trans-cinnamaldehyde (the main constituent of Ci. osmophloeum essential oil) and 0.5% thymol (the main constituent of P. amboinicus essential oil) are 97.6% and 90.6%, and can persist for up to 4 and 8 h, respectively. These results are comparable to those of 15% DEET. CONCLUSION: The proposed screening technique can facilitate the pre-screening of numerous flea repellents for further evaluation on animal or human subjects. PMID- 23801454 TI - Generating color-coded anatomic muscle maps for correlation of quantitative magnetic resonance imaging analysis with clinical examination in neuromuscular disorders. AB - INTRODUCTION: Fatty infiltration of muscles may be seen in many neuromuscular disorders, including glycogen storage disease (GSD), muscular dystrophy, and amyotrophic lateral sclerosis. Recording pathologic involvement of musculature in these patients is cumbersome, given marked disease heterogeneity within each individual. We describe a novel method for simplifying this process and present its application in a patient with GSD type IIIa. METHODS: A color-coded visual mapping tool was developed based on a commonly used spreadsheet platform. RESULTS: This tool depicts individual muscle groups as shapes linked to data cells corresponding to quantitative MRI-based measures of fatty infiltration and weakness assessed by physical examination. It allows for rapid evaluation and chronological comparison of all mapped muscle groups on a single graphical sheet, as well as assessment of response to therapy. CONCLUSION: This approach can be applied in any neuromuscular disorder where muscle function is assessed by clinical or imaging scores. PMID- 23801455 TI - Quality of coping skills predicts depressive symptom reactivity over repeated stressors. AB - OBJECTIVE: The purpose of this study was to examine the quality of coping skills as a predictor of change in depressive symptoms surrounding a series of naturally occurring stressors. METHOD: A total of 213 undergraduate students completed study measures surrounding 3 stressors (involving 6 assessments per participant). Primary analyses focused on occasions of disappointing exam performance. RESULTS: Consistent with expectations, coping skill quality was predictive of more adaptive responses (i.e., less depressive symptom reactivity), with this relation being particularly strong among participants with high initial levels of depressive symptoms and on occasions when participants had a marked worsening of mood. The quality of skills used in coping with specific stressors continued to predict depressive symptom reactivity after controlling for a one-time measure of coping skill quality. CONCLUSIONS: Our results support the importance of both stressor-specific coping skill quality and consideration of key contextual factors in understanding depressive symptom reactivity surrounding stressors. PMID- 23801456 TI - High spatial and temporal resolution dynamic contrast-enhanced magnetic resonance angiography using compressed sensing with magnitude image subtraction. AB - PURPOSE: We propose a compressed-sensing (CS) technique based on magnitude image subtraction for high spatial and temporal resolution dynamic contrast-enhanced MR angiography (CE-MRA). METHODS: Our technique integrates the magnitude difference image into the CS reconstruction to promote subtraction sparsity. Fully sampled Cartesian 3D CE-MRA datasets from 6 volunteers were retrospectively under-sampled and three reconstruction strategies were evaluated: k-space subtraction CS, independent CS, and magnitude subtraction CS. The techniques were compared in image quality (vessel delineation, image artifacts, and noise) and image reconstruction error. Our CS technique was further tested on seven volunteers using a prospectively under-sampled CE-MRA sequence. RESULTS: Compared with k space subtraction and independent CS, our magnitude subtraction CS provides significantly better vessel delineation and less noise at 4* acceleration, and significantly less reconstruction error at 4* and 8* (P < 0.05 for all). On a 1-4 point image quality scale in vessel delineation, our technique scored 3.8 +/- 0.4 at 4*, 2.8 +/- 0.4 at 8*, and 2.3 +/- 0.6 at 12* acceleration. Using our CS sequence at 12* acceleration, we were able to acquire dynamic CE-MRA with higher spatial and temporal resolution than current clinical TWIST protocol while maintaining comparable image quality (2.8 +/- 0.5 vs. 3.0 +/- 0.4, P = NS). CONCLUSION: Our technique is promising for dynamic CE-MRA. PMID- 23801457 TI - Chiral discrimination of ammonium neurotransmitters by C3-symmetric enantiopure hemicryptophane hosts. AB - Enantiopure hemicryptophanes efficiently discriminate chiral ammonium neurotransmitters. The ephedrine and norephedrine molecules associate with hemicryptophane hosts to form 1:1 and 1:2 host-guest complexes. Binding constants are determined by fitting the 1H nuclear magnetic resonance (NMR) titration curves to give beta1 and beta2 values, which are used to characterize the diastereomeric and enantiomeric discriminating potentials of the hosts. PMID- 23801458 TI - Novel links among peroxiredoxins, endothelial dysfunction, and severity of atherosclerosis in type 2 diabetic patients with peripheral atherosclerotic disease. AB - Peroxiredoxins, a group of antioxidant protein enzymes (PRDX1 to 6), are reported as antiatherogenic factors in animals; however, human studies are lacking. The present work aims to provide baseline data regarding the phenotype of PRDX1, 2, 4, and 6 in diabetic patients with peripheral atherosclerosis disease (PAD) and their relation to endothelial dysfunction (ED) and disease severity. Plasma levels of PRDX1, 2, 4, and 6 and markers of endothelial dysfunction (ICAM-1 and VCAM-1) were measured using ELISA in 55 type 2 diabetic patients having PAD and 25 healthy subjects. Ankle-brachial index (ABI), body mass index (BMI), triglycerides (TG), total cholesterol, HbA1c, and insulin resistance (HOMA IR) were measured. PRDX1, 2, 4, and 6 levels were significantly higher in patients compared to controls (PRDX1 21.9 +/- 5.71 vs 16.8 +/- 3.9 ng/ml, P < 0.001, PRDX2 36.5 +/- 14.83 vs 20.4 +/- 8.61 ng/ml, P < 0.001, PRDX4 3,840 +/- 1,440 vs 2,696 +/- 1,972 pg/ml, P < 0.005, PRDX6 311 +/- 110 vs 287.9 +/- 114 pg/ml, P < 0.05). PRDX1 and PRDX4 correlated negatively with ABI (r = -0.273, P < 0.05 and r = 0.28, P < 0.05, respectively), while PRDX1 and PRDX2 correlated positively with HOMA/IR and TG (r = 0.276, P < 0.01 and r = 0.295, P < 0.01, respectively). ICAM 1 was associated with PRDX2 and log PRDX6 (r = 0.345, P = 0.0037 and r = 0.344, P = 0.0038). Our results provide strong links among PRDXs, ED, and severity of PAD in diabetic patients which warrants further evaluation to clarify whether high circulating levels of PRDXs are a consequence of chronic atherosclerotic disease or a predisposing factor for later cardiovascular events. PMID- 23801459 TI - Novel use of the ultra-short-acting intravenous beta1-selective blocker landiolol for supraventricular tachyarrhythmias in patients with congestive heart failure. AB - The purpose of this study was to find a safe dosing regimen for landiolol, an ultra-short-acting beta-adrenergic blocking agent, to rapidly control supraventricular tachyarrhythmias (SVTs) in patients with heart failure (HF). Landiolol is reported to have good effects in the treatment of SVTs after cardiac surgery. We evaluated 52 patients with SVT and symptoms of HF (NYHA class III/IV, 10/42; EF 32 +/- 12 %) on admission because of ischaemic disease (n = 10), non ischaemic cardiomyopathy (n = 32), or valvular disease (n = 10). Paroxysmal/persistent atrial fibrillation and atrial tachycardia were present in 16 (30 %), 23 (45 %), and 13 (25 %) patients, respectively. The patients first underwent conventional therapy with carperitide, dobutamine, or milrinone. Intravenous landiolol was administered at an infusion rate of 1 MUg/kg/min and, if no adverse effects developed, the maintenance dose, titrated to HR and blood pressure response, was increased. At an average dose of 10.8 +/- 9.4 MUg/kg/min, mean HR significantly decreased significantly from 133 +/- 27 to 82 +/- 15 beats/min (P < 0.01), whereas systolic blood pressure did not differ from baseline to attainment of an effective dose level (105 +/- 21 vs. 101 +/- 19 mmHg, P = ns). Within 60 min after initiation of therapy, all patients had achieved a 20 % reduction in HR at the maintenance dose. Transient asymptomatic hypotension requiring cessation of landiolol therapy occurred in three patients. Intravenous administration of landiolol was both effective in rapidly controlling HR for up to 24 h and useful as bridging treatment to additional therapy of oral beta blockade, pulmonary vein catheter ablation, or cardiac resynchronisation therapy in patients with HF. PMID- 23801460 TI - Relation of omega-3 fatty acid and C-reactive protein to peripheral artery disease in patients with coronary artery disease. AB - Eicosapentaenoic acid (EPA), a member of the omega-3 polyunsaturated fatty acid family, prevents cardiovascular disease. C-reactive protein (CRP) is a marker of inflammation, which promotes atherosclerosis. The aim of this study was to investigate the relationship among EPA, CRP, and the prevalence of peripheral artery disease (PAD), which is a manifestation of systemic atherosclerosis. A cross-sectional study was performed on 238 patients with coronary artery disease (CAD). Blood EPA and CRP levels and ankle-brachial pressure indices were measured. Cut-off values for plasma EPA levels and serum CRP levels were determined using receiver operating characteristic (ROC) analysis. Patients with ABIs <=0.9 were defined as having PAD. EPA levels were significantly lower and CRP levels were significantly higher in patients with PAD than in those without [48 (26-77) vs. 58 (41-83) MUg/ml, p = 0.026 and 3.3 (0.64-14.0) vs. 0.70 (0.32, 2.4) mg/l, p = 0.004]. Multivariate analysis for PAD revealed that high CRP levels and low EPA levels were significant and independent predictors of PAD [odds ratio 3.1 (95 % CI 1.4-6.9), p = 0.006 and odds ratio 4.9 (95 % CI 1.5 9.7), p = 0.004]. Furthermore, to predict PAD, adding high CRP levels and low EPA levels to the established risk factors significantly improved the area under the ROC curves, from 0.66 to 0.78, of the PAD prediction model (p = 0.004). A significant relationship among EPA, CRP, and PAD was confirmed in patients with CAD. PMID- 23801461 TI - Intranasal sodium hyaluronate on the nasal cytology of patients with allergic and nonallergic rhinitis. AB - BACKGROUND: Rhinitis is an extremely common medical problem characterized by nasal congestion, clear rhinorrhea, sneezing, and itching. Hyaluronate is an endogenous compound that has an important role in mucociliary clearance by the epithelial surface of the nasal passages and in mucosal surface healing and repair. The objective of this work was to determine the effects of intranasal administration of sodium hyaluronate on nasal cytology in patients with allergic and nonallergic rhinitis. METHODS: In a single-center, randomized, blinded trial, 78 patients received intranasal mometasone and oral desloratadine plus either intranasal sodium hyaluronate or saline for 1 month. Nasal cytology was performed and the change from baseline in the numbers of neutrophils, eosinophils, mast cells, lymphocytes, and infective species was determined. Other outcomes included changes in symptoms and the endoscopic appearance of the nasal mucosa, and tolerability. RESULTS: Patients receiving sodium hyaluronate experienced a significant decrease in the median neutrophil count seen on nasal cytology compared with controls (p = 0.001). Sodium hyaluronate was associated with significant improvements in sneezing, rhinorrhea, and nasal congestion, and on exudate seen on endoscopy at 1 month compared with baseline. Intranasal sodium hyaluronate received better tolerability scores than saline over the 1-month treatment period. CONCLUSION: The addition of sodium hyaluronate to intranasal corticosteroid and systemic antihistamine reduced the neutrophil count seen on nasal cytology in patients with allergic and nonallergic rhinitis and improved several clinical and endoscopic parameters while being well tolerated. These data provide encouraging evidence of the efficacy of sodium hyaluronate in the treatment of this common disease. PMID- 23801462 TI - Barriers and facilitators to care for the terminally ill: a cross-country case comparison study of Canada, England, Germany, and the United States. AB - BACKGROUND: Why do many patients not die at their preferred location? AIM: Analyze system-level characteristics influencing the ability to implement best practices in delivering care for terminally ill adults (barriers and facilitators). DESIGN: Cross-country comparison study from a "most similar-most different" perspective, triangulating evidence from a scoping review of the literature, document analyses, and semi-structured key informant interviews. SETTING: Case study of Canada, England, Germany, and the United States. RESULTS: While similar with regard to leading causes of death, patient needs, and potential avenues to care, different models of service provision were employed in the four countries studied. Although hospice and palliative care services were generally offered with standard care along the disease continuum and in various settings, and featured common elements such as physical, psycho-social, and spiritual care, outcomes (access, utilization, etc.) varied across jurisdictions. Barriers to best practice service provision included legislative (including jurisdictional), regulatory (e.g. education and training), and financial issues as well as public knowledge and perception ("giving up hope") challenges. Advance care planning, dedicated and stable funding toward hospice and palliative care, including caregiver benefits, population aging, and standards of practice and guidelines to hospice and palliative care, were identified as facilitators. CONCLUSION: Successful implementation of effective and efficient best practice approaches to care for the terminally ill, such as shared care, requires concerted action to align these system-level characteristics; many factors were identified as being essential but not sufficient. Policy implementation needs to be tailored to the respective health-care system(s), monitored, and fine-tuned. PMID- 23801463 TI - Implementing patient-reported outcome measures in palliative care clinical practice: a systematic review of facilitators and barriers. AB - BACKGROUND: Many patient-reported outcome measures have been developed in the past two decades, playing an increasingly important role in palliative care. However, their routine use in practice has been slow and difficult to implement. AIM: To systematically identify facilitators and barriers to the implementation of patient-reported outcome measures in different palliative care settings for routine practice, and to generate evidence-based recommendations, to inform the implementation process in clinical practice. DESIGN: Systematic literature review and narrative synthesis. DATA SOURCES: Medline, PsycInfo, Cumulative Index to Nursing and Allied Health Literature, Embase and British Nursing Index were systematically searched from 1985. Hand searching of reference lists for all included articles and relevant review articles was performed. RESULTS: A total of 3863 articles were screened. Of these, 31 articles met the inclusion criteria. First, data were integrated in the main themes: facilitators, barriers and lessons learned. Second, each main theme was grouped into either five or six categories. Finally, recommendations for implementation on outcome measures at management, health-care professional and patient levels were generated for three different points in time: preparation, implementation and assessment/improvement. CONCLUSIONS: Successful implementation of patient-reported outcome measures should be tailored by identifying and addressing potential barriers according to setting. Having a coordinator throughout the implementation process seems to be key. Ongoing cognitive and emotional processes of each individual should be taken into consideration during changes. The educational component prior to the implementation is crucial. This could promote ownership and correct use of the measure by clinicians, potentially improving practice and the quality of care provided through patient-reported outcome measure data use in clinical decision making. PMID- 23801464 TI - Acute and chronic pathological effects of sulfur mustard on genitourinary system and male fertility. AB - PURPOSE: To review the acute and chronic pathological effects of sulfur mustard on the genitourinary system and male fertility. MATERIALS AND METHODS: We searched PubMed and Google Scholar to find studies related to the sulfur mustard induced genitourinary effects and male infertility. Information in the abstracts of non-English related papers as well as those in the proceedings of congresses on sulfur mustard were reviewed as well. RESULTS: In acute phase after sulfur mustard exposure, evidences are in favor of microscopic and macroscopic renal lesions, very low androgen levels, and impaired spermatogenesis. Several years following sulfur mustard exposure, the long-term pathological effects vary from the renal function impairment to the gonadal damage, in particular the spermatogenesis. Nevertheless, carcinogenic effect of sulfur mustard on the genitourinary system as well as the prevalence of male infertility among sulfur mustard-exposed veterans in the chronic post-exposure phase is still unclear. CONCLUSION: Sulfur mustard causes both acute and chronic injuries to different parts of the genitourinary system. PMID- 23801465 TI - Delayed ureteral obstruction following gunshot pellet migration. PMID- 23801466 TI - Problems and prospects of neglected renal calculi in Pakistan: can this tragedy be averted? AB - PURPOSE: To report our recent experience of treating patients with stones associated with renal failure, some of the factors underlying this problem, and few suggestions to avert this tragedy. MATERIALS AND METHODS: From January 2010 to December 2010, a total of 2838 new patients with stone disease were treated at a tertiary care center. The medical files of 278 patients presenting with stone disease and renal failure were reviewed and compared with a cohort of 878 patients with normal renal functions. Their demographic and clinicopathological parameters were noted and analyzed. RESULTS: Of 2838 patients, 278 (9.7%) presented with acute and chronic renal failure, 40 (1.4%) with unilateral non functioning kidneys, and 25 (0.8%) with pyonephrosis and perinephric abscess. Management in 278 subjects was divided into initial relief of obstruction by percutaneous nephrolithotomy and double-J stents followed by definitive management in the form of open surgery, percutaneous nephrolithotomy, extracorporeal shockwave lithotripsy, and ureterorenoscopy to make these patients stone-free. Results of treatment showed that 72% of patients either recovered their renal functions or became dialysis-free at the end of the follow-up period. CONCLUSION: Complications of renal calculi in the era of modern treatment can be prevented by public education and organizing courses for family physicians as well as opening new stone clinics in the rural areas of the country equipped with modern treatment facilities and strategies for prevention of renal calculi. PMID- 23801467 TI - Percutaneous nephrolithotomy in horseshoe kidney: our 5-year experience. AB - PURPOSE: To review our 5-year experience in percutaneous nephrolithotomy (PCNL) for horseshoe kidney with large stone burden or failed shockwave lithotripsy (SWL). MATERIALS AND METHODS: During 5 years (2006 to 2011), PCNL was performed on 21 patients with horseshoe kidney stone. We evaluated patients (age and gender), stones characteristics (size, number, side, and site), surgical technique, and outcomes. RESULTS: Sixteen (76.16%) subjects were men and 5 (23.80%) were women, with the mean age of 35 +/- 12 years. Mean stone size was 37.2 +/- 16.6 mm. Percutaneous nephrolithotomy was performed because of the stone size (over 20 mm) in 18 (85.68%) and failed SWL in 3 (14.28%) subjects. Stone numbers were more than one in 18 (85.68%) subjects, and were in the pelvis and at least one calyx. The most common access site was superior posterior calyx (66.64%). Stone-free rate with single session and rigid nephroscope was 71.40%. No major complication occurred during the surgery or in post surgical period. Postoperative minor complications occurred in 3 (14.28%) patients, including transfusion in one (4.76%), fever in one (4.76%), and ileus in one (4.76%) subject. CONCLUSION: Percutaneous nephrolithotomy has acceptable results in horseshoe kidney stone and is feasible with rigid nephroscope. Safety and efficacy of PCNL resembled the normal anatomy kidney in our study. PMID- 23801468 TI - Complications of entry using Direct Trocar and/or Veress Needle compared with modified open approach entry in laparoscopy: six-year experience. AB - PURPOSE: To compare the results obtained from three routine laparoscopic entry techniques, including Direct Trocar (DT), Veress Needle (VN), and Open Approach (OA). MATERIALS AND METHODS: Safety and efficacy of three main laparoscopic entry techniques were evaluated prospectively in 453 consecutive patients who had undergone laparoscopy either with DT, VN, or modified OA technique in recent six years. RESULTS: Of 453 patients, 105 (23.2%) were operated on with the DT, 168 (37.1%) with the VN, and 180 (39.7%) with the modified OA technique. Statistical differences were seen among the groups in terms of mean age (P = .003), male-to female ratio (P < .001), indications for the operation (P < .001), and mean trocar insertion time (P < .001). Three major complications (1 colon perforation and 2 iliac artery injuries) occurred in DT and one (iliac artery injury) in VN group, and modified OA group had no major complication (P = .04). Four major complications required laparotomy. Minor complications were seen in 6 (5.8%), 9 (5.4%), and 17 (9.4%) patients (P = .274) and gas leakage in 4 (3.8%), 16 (9.5%), and 27 (15%) patients (P = .01) in DT, VN, and modified OA groups, respectively. CONCLUSION: Although DT and VN are rapid and relatively safe, they can be associated with major complications. Therefore, modified OA seems to be safe, feasible, and most acceptable due to less major complications. PMID- 23801469 TI - Value of MRI in local staging of bladder cancer. AB - PURPOSE: To evaluate the accuracy of magnetic resonance imaging (MRI) in bladder cancer staging as well as differentiating superficial from invasive tumors and organ-confined from non-organ-confined tumors. MATERIALS AND METHODS: A total number of 108 bladder tumors in 86 patients (86% men and 14% women) were evaluated by 1.5 Tesla MRI machine. The tumor stages that were determined by MRI study were compared with pathology results after resection of the tumor. RESULTS: The most common stage determined by both MRI and pathology was T2a. Considering stages in details, the kappa agreement coefficient between MRI and pathology was 0.8 (P < .0001). Combining groups a and b in each stage, the kappa agreement coefficient between MRI and pathology was 0.87 (P < .0001). Considering stages in details, we had 22 (20.3%) mismatches in staging between MRI and pathology; 10 (45.5%) were underestimation and 12 (54.5%) were overestimation. Combining groups a and b in each stage, we had 14 (13%) mismatch cases; 6 (46.2%) were underestimation and 8 (53.8%) were overestimation. The detection rate of MRI was 0% in stage Ta, 80% in stage T1, 88.1% in stage T2, 81.2% in stage T3, and 100% in stage T4. The sensitivity and specificity of MRI in differentiating superficial from deep tumors were 0.98 and 0.82, respectively. The sensitivity and specificity of MRI in differentiating organ-confined from non-organ-confined tumors were 0.93 and 0.94, respectively. CONCLUSION: Magnetic resonance imaging is a reliable modality for determining the stage of bladder tumors with high accuracy, and could show the depth of invasion and extension of tumor that is useful for treatment planning. PMID- 23801470 TI - Is modified retroperitoneal lymph node dissection alive for clinical stage I non seminomatous germ cell testicular tumor? AB - PURPOSE: To evaluate efficacy of modified retroperitoneal lymph node dissection (RPLND) in the management of patients with pathological stage (PS) I non seminomatous germ cell testicular tumor (NSGCT) in a retrospective study. MATERIALS AND METHODS: Between April 2002 and April 2012, 55 patients with clinical stage (CS) I NSGCT had undergone modified RPLND according to Sloan Kettering modified RPLND template. Clinicopathological parameters, retroperitoneal relapse, and antegrade ejaculation rate were evaluated in patients with PS I. RESULTS: Of 55 patients, 41 (74.5%) and 14 (25.5%) subjects were in PS I and II, respectively. In PS I group, the mean patients' age was 32.8 years (range, 19 to 51 years) at the end of the follow-up period. Three patients missed the follow-up; hence, were excluded from the study. Mean follow-up duration was 56 months (range, 6 to 120 months). Tumor recurrence was identified in no subjects at the end of the follow-up period. Overall peri and postoperative complication rate was 18% (7 patients). Out of 38 patients, 23 (61%) had post RPLND antegrade ejaculation at the end of the study. CONCLUSION: Modified template RPLND is a safe, effective, and sufficient treatment for patients with no retroperitoneal micrometastasis after the procedure. Furthermore, this strategy may obviate the need for close, expensive, and potentially harmful follow-up protocol in patients with PS I NSGCT. PMID- 23801471 TI - Validation of psychometric properties of the Persian version of the Female Sexual Function Index. AB - PURPOSE: To examine the psychometric properties of a Persian language version of the Female Sexual Function Index (P-FSFI) amongst a sample of healthy Iranian women. MATERIALS AND METHODS: All participants (562) completed a battery of questionnaires, including the P-FSFI, Depression Anxiety Stress Scales (DASS), Positive and Negative Affect Scales (PANAS), and Locke-Wallace Marital Adjustment Test (LWMAT). The dimensions of the P-FSFI and its convergent and divergent validity were examined, using principal component analysis and Pearson correlations, respectively. To examine the predictive validity of the P-FSFI, data collected from 562 healthy participants were compared with 108 women with sexual problems who completed the P-FSFI measure. The P-FSFI reliability was determined in two ways: calculating Cronbach alpha and measuring test-retest coefficients (with a 4-week interval). RESULTS: The results indicated that the P FSFI is conceptualized within a-four factor model. These factors were named as: Sexual Response, Sexual Desire, Sexual-related Pain, and Sexual Satisfaction. Results also indicated that the P-FSFI and its 4 subscales had good internal consistency and test-retest reliability. Significant correlations in the predicted directions between the scores of the P-FSFI and its 4 subscales with the scores of DASS, PANAS, and LWMAT supported both the convergent and divergent validity for the P-FSFI. The results also indicated that the scores of the P-FSFI and its 4 subscales significantly differentiated women with and without sexual problems. CONCLUSION: In general, these findings support the reliability and the validity of the P-FSFI amongst Iranian healthy females. PMID- 23801472 TI - Effects of intensive cell phone (Philips Genic 900) use on the rat kidney tissue. AB - PURPOSE: To investigate effects of electromagnetic radiation (EMR) emitted by cell phones on the rat kidney tissue. MATERIALS AND METHODS: Twenty-one male Albino rats were divided into 3 groups, each comprising 7 rats. Group 1 was exposed to a cell phone in speech mode for 8 hours/day for 20 days and their kidneys were removed. Group 2 was exposed to EMR for 20 days and then their kidneys were removed after an interval of 20 days. Cell phone used in the present study was Philips Genie 900, which has the highest specific absorption rate on the market. RESULTS: Light microscopic examination of the kidney tissues obtained from the first group of rats revealed glomerular damage, dilatation of Bowman's capsule, formation of large spaces between the tubules, tubular damage, perivascular edema, and inflammatory cell infiltration. The mean severity score was 4.64 +/- 1.7 in group 1, 4.50 +/- 0.8 in group 2, and 0 in group 3. While there was no significant difference between group 1 and group 2 (P > .05), the mean severity scores of groups 1 and 2 were significantly higher than that of the control group (P = .001 for each). CONCLUSION: Considering the damage in rat kidney tissue caused by EMR-emitting cell phones, high-risk individuals should take protective measures. PMID- 23801473 TI - Editorial comment. PMID- 23801474 TI - Evaluation of patency of arteriovenous fistula and its relative complications in diabetic patients. AB - PURPOSE: To study the arteriovenous fistula patency, duration of its maintenance, and its relative complications. MATERIALS AND METHODS: One hundred and thirty patients who had undergone hemodialysis during five years (1996 to 2001) were included in this study. The patency rate and complications, including paresthesia, pain induced by ischemia, venous hypertension, infection, erythema, and edema, were assessed. Data were recorded in the pre-designed questionnaire and statistically analyzed using t test. RESULTS: Mean +/- standard deviation age of the patients was 58.08 +/- 11.73 years (range, 18 to 80 years). Most of the fistulas were created at the left bracheocephalic (58 subjects). Side-to-side technique was the mostly applied technique (99.2%). The fistula patency was 100%, 92.64%, 89.48%, 84.38%, and 83.61% at year 1 to 5, respectively. There was a significant negative correlation between the subjects' age and maintained patency (P = .02). However, no significant difference was observed between the maintained patency and other variables, including gender, location of the fistula, and the type of the technique applied for creation of the fistula (P > .05). CONCLUSION: Diabetes does not have a negative impact on the rate of patency and its duration in arteriovenous fistula. However, further investigations on a larger population are recommended. PMID- 23801475 TI - Tight swimming trunks to prevent post scrotal surgery: an experimental justification. AB - PURPOSE: To conduct a study to measure the pressure effects of the different scrotal supports applied on a simulated expanding scrotal hematoma. MATERIALS AND METHODS: We created a model of an expanding hematoma with simultaneous pressure recording using a urodynamics system. Pressures were recorded independently first without application of any support. Then, three types of scrotal supports were tested, including Euron Net Knickers, scrotal suspensory bandage, and tight swimming trunks brand Speedo(r) brief and shorts. Subsequent pressures were recorded using the model created, which was applied inside the supports worn by two male volunteers A and B. RESULTS: Without any external compression, the pressure inside the simulated expanding hematoma "balloon" reached a maximum of 15 cmH2O. The pressures measured whilst wearing "Netelast knickers" in both subjects A and B reached a maximum of 15 cmH2O suggesting that this garment exerted no measurable compression. The suspensory scrotal support was then tested in both subjects. As the balloon started to fill with saline, the simulated hematoma pushed the scrotal support forward resulting in falling of the balloon outside the scrotal support. Subsequently, Speedo(r) briefs and shorts were tested. With Speedo(r) briefs, maximum filling pressures of 49 cmH2O and 40 cmH2O were reached in subjects A and B, respectively. When using Speedo(r) shorts, however, maximum pressures of 55 cmH2O in subject A and 54 cmH2O in subject B were reached at the end of the balloon filling to 300 mL of saline. CONCLUSION: The use of tight swimming trunks (Speedo(r)) has led to satisfactory results in the prevention of hematoma post scrotal surgery. PMID- 23801476 TI - A novel irrigation system in percutaneous renal surgery. PMID- 23801477 TI - Renal replacement lipomatosis with coexistent papillary renal cell carcinoma, renal tubulopapillary adenomatosis, and xanthogranulomatous pyelonephritis: an extremely rare association and possible pathogenetic correlation. PMID- 23801478 TI - Persistent Mullerian duct syndrome with transverse testicular ectopia: rare presentation of inguinal hernia. PMID- 23801479 TI - Bladder calcification secondary to ketamine. PMID- 23801480 TI - Hair-thread tourniquet syndrome in an adult penis: case report and review of literature. PMID- 23801481 TI - Bridging therapy: a challenging area in the management of patients with atrial fibrillation. PMID- 23801482 TI - Ultrafiltration versus intravenous diuretic therapy to treat acute heart failure: a systematic review. AB - BACKGROUND: Patients with decompensated heart failure frequently present with volume overload, which is conventionally treated with diuretics. These drugs have been associated with several adverse effects, including increased mortality, leading some clinicians to propose ultrafiltration as a safe alternative to remove sodium and water. OBJECTIVE: The objective of our study was to compare the safety and efficacy of ultrafiltration and conventional intravenous diuretic therapy for patients with acute heart failure and volume overload. DATA SOURCES: We searched the following databases through November 2012: Cochrane Library (1993 ), PubMed (1988-), OVID (1984-), EBSCO (1984-), CBM (1978-), VIP (1989-), and CNKI (1979-). In addition, we manually searched relevant references and review articles. STUDY SELECTION: Randomized controlled trials comparing the efficacy of ultrafiltration and intravenous diuretics in patients diagnosed with hypervolemic acute heart failure were included. Five trials were found to satisfy all the inclusion criteria. STUDY APPRAISAL AND SYNTHESIS METHODS: Two reviewers independently determined study eligibility, assessed methodological quality and extracted the data. We analyzed the data and pooled them, when appropriate, using Revman 5.0. We assessed the risk of bias in the included studies using guidelines in the Cochrane Handbook 5.0 for Systematic Reviews of Interventions, taking into account sequence generation, allocation concealment, blinding, incomplete outcome data, and selective outcome reporting. RESULTS: Data from the initial phase of five trials involving 477 participants were included. Meta-analysis of the pooled data showed that ultrafiltration was significantly better than diuretic drugs based on 48-h weight loss (Z = 3.72; P < 0.001, weighted mean difference [WMD] = 1.25 kg, 95 % CI 0.59-1.91) and based on 48-h fluid removal (Z = 4.23; P < 0.001, WMD = 1.06 L, 95 % CI 0.57-1.56). Adverse events did not differ significantly between the ultrafiltration and intravenous diuretic treatment groups. LIMITATIONS: There are several limitations to our review, including publication bias and selection bias. Our review included only a few studies involving relatively few participants. CONCLUSIONS: The available evidence suggests that early ultrafiltration is safe and effective for patients with hypervolemic acute heart failure. It allows greater fluid removal and weight loss by 48 h than do intravenous diuretics, with no significant increase in adverse effects. PMID- 23801483 TI - Delayed vesicovaginal fistula after ring pessary usage. AB - Vaginal pessaries are commonly used in the conservative management of pelvic organ prolapse, and are generally viewed as safe alternatives to surgery. Serious complications are rare, but can and do arise, typically as a result of the pessary not being fitted and maintained correctly. This case describes delayed development of a vesicovaginal fistula (VVF) 8 months after vaginal ulceration was noted and the ring pessary removed. The 82-year-old patient was managed with a urinary diversion via ileal conduit. This case highlights the importance of meticulous follow-up when a pessary is removed in the setting of ulceration. It is the third documented case of a genitourinary fistula resulting from a vaginal ring pessary, and is the first reported case of this surgical technique being successfully used in this setting. PMID- 23801484 TI - Pelvic organ prolapse surgery in Western Australia: a population-based analysis of trends and peri-operative complications. AB - INTRODUCTION AND HYPOTHESIS: We previously described a declining rate of surgery in the treatment of pelvic organ prolapse (POP) in Western Australia. This paper builds on previous work by examining temporal trends and the post-operative risk of in-hospital complications, following first time incident prolapse surgery in a population-based cohort of women. METHODS: We investigated rates of prolapse surgery between 1988 and 2005 according to age group and concomitant procedure type for 34,509 women whose data were extracted from the WA Data Linkage System. We investigated changes over time in the demographic characteristics of women undergoing surgery and whether the presence of selected concomitant procedures increased the risk of in-hospital complications. RESULTS: During the study period, 34,509 women underwent an incident surgery for POP. Concomitant hysterectomy was performed in more than half of all surgeries (52.4 %) and a concomitant urinary incontinence (UI) surgery was noted in 25.8 %. 10.9 % of patients experienced a complication of interest, with the highest percentage of complications recorded in women who underwent multi-concomitant surgery. After controlling for age, comorbidity and time period we found that concomitant UI surgery increases in-hospital complications (OR 1.61 95 % CI 1.42-1.83) only in women who have a repair procedure (colporrhaphy and/or enterocele repair). There was no significant effect of concomitant procedures in women who underwent a combined repair and apical prolapse procedure. CONCLUSIONS: Surgery to treat prolapse is common, has low mortality and concomitant surgery only increases complications when combined with simpler prolapse surgery. PMID- 23801485 TI - Overflow urinary incontinence due to bladder stones. AB - Overflow urinary incontinence is rare in women. We report a case of overflow incontinence due to bladder stones in a 40-year-old widow (para 2) who presented with a 5-month history of involuntary loss of urine aggravated by postural change, and associated with recurrent painful ineffectual urge to urinate. Her intravenous urogram revealed multiple bladder stones, for which she underwent cystolithotomy. However, following catheter removal on the fifth postoperative day, she developed urge incontinence due to urinary tract infection. She responded well to the choice of antibiotics dictated by the sensitivity result of her postoperative urinary culture, and she was discharged home on the ninth postoperative day. This case highlights the uncommon occurrence of bladder stones as a cause of urinary incontinence, as well as the potential value of intravenous urography in incontinence evaluation. PMID- 23801486 TI - Comparison of nonaqueous hydrophilic interaction chromatography with aqueous normal-phase chromatography on hydrosilated silica-based stationary phases. AB - We investigated the retention behavior of phenolic acids in nonaqueous normal phase (NP) LC with buffered methanol/acetonitrile mobile phases on hydrosilated silica-based stationary phases. The silica hydride, Diamond hydride, Bidentate C18, and Cholesterol columns showed a higher retention of phenolic acids in the nonaqueous mobile phases than in aqueous NP mobile phases. There are some selectivity differences between the aqueous and nonaqueous mobile phases, but generally the resolution and selectivity are better in the aqueous systems. The retention of the phenolic acids tested decreased with increasing concentration of methanol in the mobile phase, up to 20% v/v methanol. At increased temperatures, the retention factors and peak widths decrease in both NP modes, showing linear ln k versus 1/T plots, due to a single retention mechanism over the temperature range from 25 degrees C up to the column stability limit, however, the best separations are achieved at low temperatures. The enthalpic and entropic contributions to the retention were determined, and the differences between the aqueous and nonaqueous modes are possibly due to the adsorbed water layer. PMID- 23801487 TI - Root branching: mechanisms, robustness, and plasticity. AB - Plants are sessile organisms that must efficiently exploit their habitat for water and nutrients. The degree of root branching impacts the efficiency of water uptake, acquisition of nutrients, and anchorage. The root system of plants is a dynamic structure whose architecture is determined by modulation of primary root growth and root branching. This plasticity relies on the continuous integration of environmental inputs and endogenous developmental programs controlling root branching. This review focuses on the cellular and molecular mechanisms involved in the regulation of lateral root distribution, initiation, and organogenesis with the main focus on the root system of Arabidopsis thaliana. We also examine the mechanisms linking environmental changes to the developmental pathways controlling root branching. Recent progress that emphasizes the parallels to the formation of root branches in other species is discussed. PMID- 23801488 TI - Cortical rotation and messenger RNA localization in Xenopus axis formation. AB - In Xenopus eggs, fertilization initiates a rotational movement of the cortex relative to the cytoplasm, resulting in the transport of critical determinants to the future dorsal side of the embryo. Cortical rotation is mediated by microtubules, resulting in activation of the Wnt/beta-catenin signaling pathway and expression of organizer genes on the dorsal side of the blastula. Similar cytoplasmic localizations resulting in beta-catenin activation occur in many chordate embryos, suggesting a deeply conserved mechanism for patterning early embryos. This review summarizes the experimental evidence for the molecular basis of this model, focusing on recent maternal loss-of-function studies that shed light on two main unanswered questions: (1) what regulates microtubule assembly during cortical rotation and (2) how is Wnt/beta-catenin signaling activated dorsally? In addition, as these processes depend on vegetally localized molecules in the oocyte, the mechanisms of RNA localization and novel roles for localized RNAs in axis formation are discussed. The work reviewed here provides a beginning framework for understanding the coupling of asymmetry in oogenesis with the establishment of asymmetry in the embryo. PMID- 23801489 TI - Nematode model systems in evolution and development. AB - The free-living nematode Caenorhabditis elegans is one of the most important model organisms in all areas of modern biology. Using the knowledge about C. elegans as a baseline, nematodes are now intensively studied in evolution and development. Evolutionary developmental biology or for short, 'evo-devo' has been developed as a new research discipline during the last two decades to investigate how changes in developmental processes and mechanisms result in the modification of morphological structures and phenotypic novelty. In this article, we review the concepts that make nematode evo-devo a successful approach to evolutionary biology. We introduce selected model systems for nematode evo-devo and provide a detailed discussion of four selected case studies. The most striking finding of nematode evo-devo is the magnitude of developmental variation in the context of a conserved body plan. Detailed investigation of early embryogenesis, gonad formation, vulva development, and sex determination revealed that molecular mechanisms evolve rapidly, often in the context of a conserved body plan. These studies highlight the importance of developmental systems drift and neutrality in evolution. PMID- 23801490 TI - Scoliosis and segmentation defects of the vertebrae. AB - The vertebral column derives from somites, which are transient paired segments of mesoderm that surround the neural tube in the early embryo. Somites are formed by a genetic mechanism that is regulated by cyclical expression of genes in the Notch, Wnt, and fibroblast growth factor (FGF) signaling pathways. These oscillators together with signaling gradients within the presomitic mesoderm help to set somitic boundaries and rostral-caudal polarity that are essential for the precise patterning of the vertebral column. Disruption of this mechanism has been identified as the cause of severe segmentation defects of the vertebrae in humans. These segmentation defects are part of a spectrum of spinal disorders affecting the skeletal elements and musculature of the spine, resulting in curvatures such as scoliosis, kyphosis, and lordosis. While the etiology of most disorders with spinal curvatures is still unknown, genetic and developmental studies of somitogenesis and patterning of the axial skeleton and musculature are yielding insights into the causes of these diseases. PMID- 23801491 TI - The maternal muscle determinant in the ascidian egg. AB - Muscle formation in ascidian embryos has been investigated for more than a century as a representative example of cell fate specification by localized maternal factors within the egg cytoplasm. Observations of colored cytoplasm in combination with micromanipulation techniques have suggested the presence of a muscle-forming factor. The molecular basis has been elucidated with the discovery of macho-1. macho-1 mRNA is already present in the unfertilized egg, and translocates to the posterior region of the egg during ooplasmic movements. It encodes a zinc-finger transcription factor that positively regulates the expression of target genes. macho-1-binding cis-elements have been identified in muscle-specific zygotic genes. Maternally localized macho-1 appears to have originated in the ascidian lineage, but it activates a muscle-forming developmental program that is shared by the vertebrates. macho-1 is also involved in establishment of the anterior-posterior axis as a competence factor in mesenchyme induction in the posterior region. It is suggested that translation of the macho-1 protein is initiated at the eight-cell stage, and that the protein is inherited by all descendant blastomeres of the posterior-vegetal region. The macho-1 activities in nonmuscle descendants are suppressed or modified by cell interactions during the cleavage stages. In addition to the primary muscle specified by maternal macho-1, ascidian embryos develop secondary muscle, whose fate is determined by cell interactions. Dozens of maternal mRNAs show similar localization to macho-1, and these are known as postplasmic/PEM RNAs, being also involved in various posterior-specific developmental events. Evolutionary aspects relevant to macho-1 and tail muscle formation are also discussed in this article. PMID- 23801492 TI - Neural crest migration: interplay between chemorepellents, chemoattractants, contact inhibition, epithelial-mesenchymal transition, and collective cell migration. AB - Neural crest (NC) cells are induced at the border of the neural plate and subsequently leave the neuroepithelium during a delamination phase. This delamination involves either a complete or partial epithelium-to-mesenchyme transition, which is directly followed by an extensive cell migration. During migration, NC cells are exposed to a wide variety of signals controlling their polarity and directionality, allowing them to colonize specific areas or preventing them from invading forbidden zones. For instance, NC cells are restricted to very precise pathways by the presence of inhibitory signals at the borders of each route, such as Semaphorins, Ephrins, and Slit/Robo. Although specific NC chemoattractants have been recently identified, there is evidence that repulsive interactions between the cells, in a process called contact inhibition of locomotion, is one of the major driving forces behind directional migration. Interestingly, in cellular and molecular terms, the invasive behavior of NC is similar to the invasion of cancer cells during metastasis. NC cells eventually settle in various places and make an immense contribution to the vertebrate body. They form the major constituents of the skull, the peripheral nervous system, and the pigment cells among others, which show the remarkable diversity and importance of this embryonic-stem cell like cell population. Consequently, several birth defects and craniofacial disorders, such as Treacher Collins syndrome, are due to improper NC cell migration. PMID- 23801493 TI - Drosophila models of epithelial stem cells and their niches. AB - Epithelial stem cells are regulated through a complex interplay of signals from diffusible ligands, cellular interactions, and attachment to the extracellular matrix. The development of Drosophila models of epithelial stem cells and their associated niche has made it possible to dissect the contribution of each of these factors in vivo, during both basal homeostasis and in response to acute damage such as infection. Studies of Drosophila epithelial stem cells have also provided insight into the mechanisms by which a healthy population of stem cells are maintained throughout adulthood by demonstrating, for example, that stem cells have a finite lifespan and may be displaced by replacement cells competing for niche occupancy. Here, we summarize the literature on each of the known Drosophila epithelial stem cells, with a focus on the two most well-characterized types, the follicle stem cells (FSCs) in the ovary and the intestinal stem cells (ISCs) in the posterior midgut. Several themes have emerged from these studies, which suggest that there may be a common set of features among niches in a variety of epithelia. For example, unlike the simpler Drosophila germline stem cell niches, both the FSC and ISC niches produce multiple, partially redundant, niche signals, some of which activate pathways such as Wnt/Wingless, Hedgehog, and epidermal growth factor (EGF) that also regulate mammalian epithelial tissue renewal. Further study into these relatively new stem cell models will be of use in understanding both the specifics of epithelial regeneration and the diversity of mechanisms that regulate adult stem cells in general. PMID- 23801494 TI - Small molecule screening in zebrafish: swimming in potential drug therapies. AB - Phenotype-driven chemical genetic screens in zebrafish have become a proven approach for both dissection of developmental mechanisms and discovery of potential therapeutics. A library of small molecules can be arrayed into multiwell plates containing zebrafish embryos. The embryo becomes a whole organism in vivo bioassay that can produce a phenotype upon treatment. Screens have been performed that are based simply on the morphology of the embryo. Other screens have scored complex phenotypes using whole mount in situ hybridization, fluorescent transgenic reporters, and even tracking of embryo movement. The availability of many well-characterized zebrafish mutants has also enabled the discovery of chemical suppressors of genetic phenotypes. Importantly, the application of chemical libraries that already contain FDA-approved drugs has allowed the rapid translation of hits from zebrafish chemical screens to clinical trials. PMID- 23801495 TI - Molecular genetic testing for lung adenocarcinomas: a practical approach to clinically relevant mutations and translocations. AB - There is a consensus that molecular testing of the lung carcinoma should be the standard of care in the clinical management of patients with lung carcinoma. Recent practice guidelines in oncology and pathology recommend that all advanced and metastatic non-small-cell lung carcinoma with adenocarcinoma histology undergo biomarker testing for epidermal growth factor receptor gene (EGFR) mutations and anaplastic lymphoma kinase gene (ALK) rearrangements. Other types of non-small-cell carcinoma may be considered for such testing if they occur in never-smokers. The landscape of targetable biomarkers in non-small-cell carcinoma is changing rapidly, and demand for clinical testing beyond EGFR mutations and ALK gene rearrangements is increasing. Many patients may test positive for other 'drivers'. As a result, they may be treated with approved biomarker-driven therapies or may be eligible to receive investigational agents in clinical trials. This creates challenges for treating physicians and pathologists such as obtaining sufficient tissue for molecular testing and standardisation of molecular testing in clinical laboratories. This review will focus on the most important lung carcinoma biomarkers predictive of response and will discuss proposed routine molecular testing in clinical practice. PMID- 23801496 TI - Virus-associated apoptosis of blood neutrophils as a risk factor for invasive meningococcal disease. AB - AIMS: To quantify a range of haematological indicators of viral infection (leucocyte apoptosis, cytopenia of normal lymphocytes, reactive lymphocyte increase, neutropenia) in patients with recent onset invasive meningococcal disease (IMD), with a view to test the association of viral infection with IMD and identify possible haematological risk factors for its development. SUBJECTS AND METHODS: 88 patients with recent onset IMD, classified on clinical severity as fatal (n=14), septic shock survived (n=26) and no shock (n=48), and 50 healthy controls were studied. Blood film microscopy and leucocyte counts were used to quantify the virus-associated indicators. Cocci-containing neutrophils were also quantified. RESULTS: All viral parameters were significantly more frequent or higher in patients than controls, with leucocyte apoptosis found only in the patients. A significant gradient in accord with clinical severity was found for neutrophil and lymphocyte apoptosis, neutropenia and cocci-containing neutrophils. Crucially, apoptotic neutrophils did not contain cocci, and cocci containing neutrophils were not apoptotic. CONCLUSIONS: The correlation between magnitude of neutrophil apoptosis and severity of IMD suggests a cause-effect relationship. We propose that neutrophil apoptosis is more likely a facilitator rather than an effect of IMD for these reasons: (1) apoptotic neutrophils did not contain cocci and cocci-containing neutrophils were not apoptotic, (2) leucocyte apoptosis is a recognised viral effect and (3) Neisseria meningitidis is incapable of producing a Panton-Valentine type leucocidin. The lymphocyte apoptosis which accompanies neutrophil death may contribute to risk by impairing the generation of microbicidal antibody. Leucocyte apoptosis is a morphological expression of viral immunosuppression and, we suggest, is a likely contributor to a range of viral effects. PMID- 23801497 TI - Identification of MET genomic amplification, protein expression and alternative splice isoforms in neuroblastomas. AB - BACKGROUND: Crizotinib, a dual anaplastic lymphoma kinase (ALK) and mesenchymal epithelial transition (MET) tyrosine kinase inhibitor, is currently being evaluated for the treatment of neuroblastoma. Its effects are thought to be mediated mainly via its activity against ALK. Although MET genomic/protein expression status might conceivably affect crizotinib efficacy, this issue has hitherto not received attention in neuroblastomas. AIMS/METHODS: MET genomic and protein expression status was characterised by silver in situ hybridisation and immunohistochemistry (IHC) respectively, in a cohort of 54 neuroblastoma samples. MET splice isoforms were characterised in 15 of these samples by quantitative PCR. RESULTS: One case (1/54; prevalence 1.85%) displayed MET genomic amplification, while another case (1/54; prevalence 1.85%) displayed strong membranous MET protein expression (IHC score 3+). Alternative exon 10-deleted and exon 14-deleted MET splice isoforms were identified. CONCLUSIONS: MET amplification and protein expression, although low in prevalence, are present in neuroblastomas. This has implications when crizotinib is employed as a therapeutic agent in neuroblastomas. Additionally, the existence of alternatively spliced MET isoforms may have clinical and biological implications in neuroblastomas. PMID- 23801498 TI - Verification of serum reference intervals for free light chains in a local South African population. AB - Monoclonal serum free light chain measurements are used to follow up and manage patients with monoclonal gammopathies, and abnormal serum free light chain ratios are associated with risk of progression in certain diseases. We aimed to validate the reference intervals in our population. Reference intervals for kappa and lambda free light chains were established on 120 healthy adults. Creatinine levels were measured to exclude renal dysfunction and serum protein electrophoresis was performed. All creatinine values were within normal limits. After exclusion of subjects with abnormal serum protein electrophoreses, 113 subjects were available for analysis. The 95% reference interval was 6.3-20.6 mg/L for kappa free light chains, 8.7-25.9 mg/L for lambda free light chains and 0.46-1.23 for free light chain ratio. Most of the values fell within the manufacturer's recommended limits and therefore could be used for our population. PMID- 23801499 TI - Application of dielectric spectroscopy for monitoring high cell density in monoclonal antibody producing CHO cell cultivations. AB - The application of dielectric spectroscopy was frequently investigated as an on line cell culture monitoring tool; however, it still requires supportive data and experience in order to become a robust technique. In this study, dielectric spectroscopy was used to predict viable cell density (VCD) at industrially relevant high levels in concentrated fed-batch culture of Chinese hamster ovary cells producing a monoclonal antibody for pharmaceutical purposes. For on-line dielectric spectroscopy measurements, capacitance was scanned within a wide range of frequency values (100-19,490 kHz) in six parallel cell cultivation batches. Prior to detailed mathematical analysis of the collected data, principal component analysis (PCA) was applied to compare dielectric behavior of the cultivations. PCA analysis resulted in detecting measurement disturbances. By using the measured spectroscopic data, partial least squares regression (PLS), Cole-Cole, and linear modeling were applied and compared in order to predict VCD. The Cole-Cole and the PLS model provided reliable prediction over the entire cultivation including both the early and decline phases of cell growth, while the linear model failed to estimate VCD in the later, declining cultivation phase. In regards to the measurement error sensitivity, remarkable differences were shown among PLS, Cole-Cole, and linear modeling. VCD prediction accuracy could be improved in the runs with measurement disturbances by first derivative pre treatment in PLS and by parameter optimization of the Cole-Cole modeling. PMID- 23801500 TI - Ultrathin sP(EO-stat-PO) hydrogel coatings are biocompatible and preserve functionality of surface bound growth factors in vivo. AB - Hydrogel coatings prepared from reactive star shaped polyethylene oxide based prepolymers (NCO-sP(EO-stat-PO)) minimize unspecific protein adsorption in vitro, while proteins immobilized on NCO-sP(EO-stat-PO) coatings retain their structure and biological function. The aim of the present study was to assess biocompatibility and the effect on early osseointegrative properties of a NCO sP(EO-stat-PO) coating with additional RGD-peptides and augmentation with bone morphogenetic protein-4 (BMP) used on a medical grade high-density polyethylene (HDPE) base under in vivo circumstances. For testing of biocompatibility dishes with large amounts of bulk NCO-sP(EO-stat-PO) were implanted subcutaneously into 14 Wistar rats. In a second set-up functionalization of implants with ultrathin surface layers by coating ammonia-plasma treated HDPE with NCO-sP(EO-stat-PO), functionalization with linear RGD-peptides, and augmentation with RGD and BMP-4 was analyzed. Therefore, implants were placed subcutaneously in the paravertebral tissue and transcortically in the distal femur of another 14 Wistar rats. Both tests revealed no signs of enhanced inflammation of the surrounding tissue analyzed by CD68, IL-1beta-/TNF-alpha-antibody staining, nor systemic toxic reactions according to histological analysis of various organs. The mean thickness of the fibrous tissue surrounding the femoral implants was highest in native HDPE-implants and tended to be lower in all NCO-sP(EO-stat-PO) modified implants. Micro-CT analysis revealed a significant increase of peri-implant bone volume in RGD/BMP-4 coated samples. These results demonstrate that even very low amounts of surface bound growth factors do have significant effects when immobilized in an environment that retains their biological function. Hence, NCO sP(EO-stat-PO)-coatings could offer an attractive platform to improve integration of orthopedic implants. PMID- 23801501 TI - Effect of chitosan-gluconic acid conjugate/poly(vinyl alcohol) cryogels as wound dressing on partial-thickness wounds in diabetic rats. AB - We previously developed chitosan cryogels from chitosan-gluconic acid conjugate without using toxic additives for wound care. In this study, we improved physiological characteristics of the previous cryogels by incorporating poly(vinyl alcohol) that also form cryogels. Mechanical strength of the cryogels was more than two times higher than that of the previous cryogels. Furthermore, the incorporation of poly(vinyl alcohol) enhanced water retention and resistance to degradation of the gels by lysozyme. The cryogels retained the favorable biological properties of the previous cryogels that they accelerate infiltration of inflammatory cells into wound sites. Time period for repairing 50 % of initial area of partial-thickness skin wound treated with the cryogels (4.0 +/- 1.1 days) was shorter than those with gauze (6.5 +/- 0.3 days) or a commercial hydrogel dressing (5.7 +/- 0.3 days). Finally, we confirmed that incorporation of basic fibroblast growth factor into the cryogels was effective to further accelerate wound healing (2.7 +/- 1.0 days). These results demonstrate that the cryogels in this study are promising for wound care. PMID- 23801502 TI - Central brain herniation in Dandy-Walker syndrome. PMID- 23801503 TI - A high-accuracy theoretical study of the CH(n)P systems n = 1-3. AB - We have performed high-level electronic structure computations on the most important species of the CH(n)P systems n = 1-3 to characterize them and provide reliable information about the equilibrium and vibrationally averaged molecular structures, rotational constants, vibrational frequencies (harmonic and anharmonic), formation enthalpies, and vertical excitation energies. Those chemical systems are intermediates for several important reactions and also prototypical phosphorus-carbon compounds; however, they are often elusive to experimental detection. The present results significantly complement their knowledge and can be used as an assessment of the experimental information when available. The explicitly correlated coupled-cluster RCCSD(T)-F12 method has been used for geometry optimizations and vibrational frequency calculations. Vibrational configuration interaction theory has been used to account for anharmonicity effects. Basis-set limit extrapolations have been carried out to determine accurate thermochemical quantities. Electronic excited states have been calculated with coupled-cluster approaches and also by means of the multireference configuration interaction method. PMID- 23801504 TI - Stress hormone response to various anaesthetic techniques during thyroidectomy. AB - BACKGROUND: Thyroidectomy is among the most frequently performed procedures in endocrine surgery. The hormonal response to surgery and anaesthesia depends in part on the anaesthetic techniques used; therefore, we measured serum concentrations of TSH, fT4, and fT3 in patients scheduled for elective thyroidectomy under TIVA or VIMA. METHODS: Seventy-eight adult patients, of both sexes, with non-toxic or hyperthyroid nodular goitre, were divided into groups with regard to the goitre type and the technique of anaesthesia used during thyroid surgery. Serum concentrations of TSH, fT4, and fT3, were measured and the surgical stress was estimated using the E-PASS scale. RESULTS: In the groups examined, the mean serum concentrations of TSH remained unchanged during the period of observation. The initially high fT4 and fT3 concentrations gradually decreased, reaching their lowest level on the fourth day after surgery. CONCLUSIONS: [corrected] Both VIMA and TIVA can be regarded as safe techniques of anaesthesia for thyroidectomy. PMID- 23801505 TI - Analysis of intraoperative transfusions of red blood cell concentrates in adults. AB - BACKGROUND: Transfusion of red blood cell (RBC) concentrates is the most common allogeneic transplantation. The aim of the study was to analyse the indications for RBC transfusions, compared to the estimated intraoperative blood loss and the actual requirements for blood transfusion. METHODS: We retrospectively analysed the files of 250 adult patients who were transfused over the year 2006, during various general, oncologic, trauma, vascular, plastic and thoracic surgical procedures. Preoperative screening was done in a hospital laboratory, whereas postoperative haemoglobin concentration and haematocrit were assessed at the bedside using a co-oximeter. RESULTS: The majority of RBC transfusions were started at relatively high haemoglobin concentrations (mean 5.6 mmol L-1), contrary to the current guidelines. A high correlation coefficient (r=0.82) was found between the estimated blood loss and the volume of RBCs transfused; therefore we concluded that the observed blood loss was the main factor in transfusion decisions. CONCLUSIONS: Despite enormous progress in transfusion science, the current practice in our institution is still far from ideal; RBCs are frequently transfused too early and without a real indication. PMID- 23801506 TI - Analysis of nutrition mixtures in ITU patients. AB - BACKGROUND: The aim of this study was to analyse the composition of parenteral nutrition (PN) mixtures used in the ITU. METHODS: Restrospective analysis involved 2124 prescriptions for individual PN bags. They were administered over an 18-month period, to 160 ITU patients with the mean APACHE II score of 26 points (range: 5-61), calculated on admission. The mortality rate was 40%. Nutrition programs were prepared individually following the 2009 ESPEN guidelines. The prescription was modified according to the individual patient's clinical condition. One hundred and sixty prescriptions were analysed on the first day of PN (T1), 139 - on the second day (T2) and 1825 on the third and subsequent days (T3). RESULTS: The mean energy supplies were: 1381 kcal/day (range: 456-2612) on T1, 1467 kcal/day (range: 524-2860) on T2, and 1654 kcal/day (range: 390-2969) on T3. The mean supplies of amino acids, glucose and lipids were as follows: amino acids 68.3 g/day (range:20-120) on T1; 71.6 g/ day (range:27.5-125) on T2; 88.0 g/day (range:11-196) on T3; glucose 210.25 g/day (range: 120- 400) on T1; 218.34 g/day (range: 65-480) on T2; 278.5 g/day (range: 18-520) on T3; lipids 34.9 g/ day (range: 0-100) on T1; 38.7 g/day (range: 0-100) on T2; 52.66 g/day (range: 0-117) on T3. The percentages of non-protein energy from lipids were: 29.25 (0-73) on T1; 31.58 (range: 0-60) on T2; 33.5 (0-60) on T3. The following statistically significant differences were found: T2-T3- (p<0.05). CONCLUSIONS: The compositions of nutrition bags prepared for ITU patients were consistent with the ESPEN guidelines. The composition varied on different days of nutrition. The differences in the supply of nutrition components indirectly confirm the need for individual prescriptions for ITU patients. PMID- 23801507 TI - Factors influencing the occurence of nosocomial bloodstream infections observed in thoracic and cardiosurgical postoperative care units. AB - BACKGROUND: The aim of this study was to analyse the epidemiology and aetiology of laboratoryconfirmed bloodstream infections (LC-BSI) and central line associated bloodstream infections (CLABSI) after pulmonary and coronary surgery, in postoperative intensive care units in 2009. METHODS: Sources of infections were identified by the hospital Infection Control Team in cooperation with ITU personnel using the CDC definitions. RESULTS: A total of 37 LC-BSI and 21 CLA-BSI cases in 3.096 patients were detected. Central line device utilization ratio was 0.50. The total cumulative LC-BSI incidence rate was 1.2% and CLA-BSI rate 8.7 per 1,000 central line days. The most common causes of LC-BSI were Gram-positive cocci (Staphylococcus aureus - 5.9%, CNS - 50.0%, Enterococcus faecium - 5.9%). CONCLUSIONS: We found that in those units in which surveillance of CLA-BSI had been conducted since 2002, BSI incidence rates were higher than those reported in the NHSN programme. PMID- 23801508 TI - Coronary air embolism during removal of a central venous catheter. AB - BACKGROUND: Acute air embolism has been described during central venous cannulation, but it may also occur during catheter removal in a spontaneously breathing patient. We describe an episode of acute coronary ischaemia that occurred during CV catheter removal. CASE REPORT: A 23-year-old male, multiple trauma patient was treated over 27 days in an ITU. He required a tracheostomy, two weeks of mechanical ventilation, and several surgical interventions. On the 27th day, he was scheduled to be transferred to a low-dependency area and his CVC was removed from the left subclavian vein. After five minutes, the pressure pad was released from the site of cannulation; the patient started coughing and became dyspnoeic. He developed tachyarrhythmia with ST depression in the 2nd, 3rd and aVF leads, followed by marked ST elevation, and subsequently, ventricular fibrillation. The patient was placed in the Trendelenburg position and CPR was started. Normal sinus rhythm returned after three defibrillations. Echocardiography revealed the presence of a large amount of air bubbles within the left ventricle, which disappeared spontaneously within one minute. The patient quickly regained consciousness and his condition returned to normal within 12 h, with transient elevation of heart enzymes. Five days later, he was decannulated and transferred to the orthopaedic ward in a satisfactory condition. DISCUSSION: Air embolism during CV catheter removal is a rare event, but it may occur when a persistent tunnel remains after prolonged cannulation, associated with negative intrathoracic pressure created by a spontaneously breathing or coughing patient. In the case described, acute myocardial ischaemia occurred in the region supplied by the right coronary artery, which is located higher than the left one and is therefore more exposed to air bubbles. We could not demonstrate, however, the presence of a persistent foramen ovale, however some connection had to exist between the right and left sides of the heart in our patient. CONCLUSION: Special caution should be exercised during CV catheter removal, and the procedure should be always done with the patient placed in the Trendelenburg position. PMID- 23801509 TI - Traumatic air in spinal canal (pneumorrhachis). AB - BACKGROUND: Pneumorrhachis (PR) means the presence of air in the spinal canal; it is an exceptional, but important radiographic finding, which may be associated with different aetiologies and pathways of air entry into the spinal canal. CASE REPORT: An 18-year-old male was admitted to hospital after a road traffic accident. He was conscious, with several abrasions and subcutaneous haematoma and emphysema on the left side, but no pneumothorax. Ultrasound of the abdomen showed a grade 2 splenic rupture with minimal bleeding. CT revealed no fractures but the presence of air in the spinal canal. The patient was placed on conservative treatment and discharged home without any complications or sequelae. DISCUSSION AND CONCLUSION: PR can be epidural or subdural, iatrogenic or traumatic. It is usually asymptomatic, but can be also associated with marked morbidity, especially when it is subdural in the cervical region. It can be regarded as a predictor of the severity of head injury. Pneumorrhachis does not usually require surgical intervention. PMID- 23801510 TI - Neuromuscular block reversal with sugammadex in a morbidly obese patient with myasthenia gravis. AB - BACKGRAOUND: Myasthenia gravis is a rare immunological illness that impairs neuromuscular transmission. Myasthenic patients are usually hypersensitive to non depolarising muscle relaxants, and reversal with neostigmine is rarely effective. We report the successful reversal of rocuroniuminduced neuromuscular block in a morbidly obese myasthenic patient. CASE REPORT: A 38-year-old morbidly obese (body weight 160 kg, BMI 48.8 kg m-2) woman was scheduled for elective laparoscopic gastric banding. She was anaesthetised with propofol-based TIVA; intubation was facilitated by 24 mg of rocuronium. After spontaneous recovery of T1, she received 200 mg of sugammadex, which completely restored the NMT ratio (TOF=100%) within 2 min and 48 sec., and she was extubated. No postoperative complications were observed. CONCLUSION: Sugammadex can be successfully used in myasthenic patients, allowing for the safe use of muscle relaxants in these patients. PMID- 23801511 TI - Tapia's syndrome after arthroscopic shoulder stabilisation under general anaesthesia and LMA. AB - BACKGROUND: Anaesthetic complications, albeit rare, still occur and may be severe and unanticipated, with significant morbidity. Extracranial ipsilateral palsy of the recurrent laryngeal and the hypoglossal nerves is known as the Tapia's syndrome. Damage to these nerves may result from displacement of the head during mask ventilation, endotracheal intubation, bronchoscopy or the use of a laryngeal mask airway (LMA). We describe unilateral paralysis of the muscles of the tongue and ipsilateral vocal cord due to a lesion of cranial nerves X and XII that occurred following LMA anaesthesia combined with plexus block. CASE REPORT: A 57 year-old man with a rupture of the right shoulder underwent arthroscopic shoulder stabilisation and internal fixation. General anaesthesia with aLMA was combined with an interscalene plexus block. After induction with propofol and fentanyl, a LMA was inserted with some difficulty without muscle relaxation. The cuff was inflated with 30 mL of air and further volumes of air until a "just-seal" pressure was obtained. The anaesthesia was maintained with sevoflurane in oxygen/air. The procedure was carried out in a semi-supine position with the head inclined slightly forward, and the upper body slightly elevated. Surgery lasted 55 min and anaesthesia 70 min. After surgery, the patient quickly regained consciousness and the LMA was removed when he was responding to commands and was able to fully open his mouth. During the immediate postoperative period, the patient's voice was hoarse but he breathed without difficulty. The following day, he developed dysphagia and slurred speech; on examination, paralysis of the left side of the tongue was found. The diagnosis of an acute injury to the hypoglossal and laryngeal recurrent nerves was made and the patient was transferred to the neurology clinic for further treatment. CONCLUSIONS: This rare complication reminds us not only of the importance of positioning during anaesthesia and surgery, but also of the need for careful and correct airway management. It could be probably prevented by careful insertion of an appropriate size LMA, and the use of low intracuff pressures and/or volumes. PMID- 23801512 TI - Sufentanil in anaesthesiology and intensive therapy. AB - Sufentanil, a potent alpha-1 agonistic opioid, was synthesized in mid-1970s. It was introduced into clinical practice ten years later, gaining some popularity over the last twenty years. A piperidine derivative, sufentanil has been reported to be 6-10 times more potent than fentanyl, depending on the route of administration; it has been registered for intravenous, epidural and subarachnoid administration. Its reported off-label use has included intra-articular and intranasal administration; moreover, it has been applied as an adjunct in peripheral blocks. In the review, contemporary uses of sufentanil, together with detailed pharmacokinetics and pharmacodynamics are presented. The author concludes that the limited side effects of sufentanil, together with its attractive pharmacokinetic profile, should promote its wider use in clinical practice. PMID- 23801513 TI - The use of opioid adjuvants in perioperative multimodal analgesia. AB - Postoperative analgesia plays a crucial role in day-case surgery. Patients expect effective pain relief after surgery, without side effects, and this may not always be possible when more complicated procedures are performed in ambulatory settings. Moreover, both surgeons and patients expect anaesthesiologists to provide an effective pain treatment service especially after ambulatory surgery, even in private practice settings. The protocols based on intravenous opioids or central neuraxial blockade are no longer appropriate, when a short, uncomplicated postoperative course is anticipated. Multimodal analgesia, combining different groups of analgesics, both opioid and non-opioid, with different mechanisms of action, and targets in central and peripheral nervous systems with minimal side effects may be an answer. In this review, we present and discuss the current status of knowledge, with special reference to the role of adjuvants to opioids in acute postoperative pain. PMID- 23801514 TI - Mortality scoring in ITU. AB - Chronic shortage of ITU beds makes decisions on admission difficult and responsible. The use of computer-based mortality scoring should help in decision making and for this purpose, a number of different scoring systems have been created; in principle, they should be easy to use, adaptable to all populations of patients and suitable for predicting the risk of mortality during both ITU and hospital stay. Most of existing scales and scoring systems were included in this review. They are frequently used in ITUs and become a necessary tool to describe ITU populations and to explain differences in mortality. As there are several pitfalls related to the interpretation of the numbers supplied by the systems, they should be used with the knowledge on the severity scoring science. Moreover, the cost and significant workload limit the use of scoring systems; in many cases an extra person has to be employed for collection and analysis of data only. PMID- 23801515 TI - Resuscitation and hospital ethics committees. PMID- 23801516 TI - Reply to comments on 'The ethics of resuscitation'. PMID- 23801517 TI - Enhancing information pertaining to client characteristics to facilitate evidence based practice. AB - OBJECTIVE: Evidence-based practice (EBP) includes utilization of empirically supported treatments, application of clinical expertise, and consideration of client characteristics. The following brief report aims to elucidate barriers in the study and dissemination of research regarding these client characteristics. DESIGN: Authors examined empirical papers cited on psychologicaltreatments.org (N = 338) and categorized each according to efficacy evidence available pertaining to gender, race/ethnicity, and socioeconomic status (SES). RESULTS: Gender was most commonly considered (7% of studies), with less than 2% of studies analyzing efficacy in relation to race/ethnicity or SES. CONCLUSIONS: Available findings are summarized according to disorder. Researchers are encouraged to attend to client variables in efficacy studies and suggestions are offered for training students to include client variables in EBP. PMID- 23801518 TI - Hydrogen bonding or stacking interactions in differentiating duplex stability in oligonucleotides containing synthetic nucleoside probes for alkylated DNA. AB - Oligonucleotides that hybridize to modified DNA are useful chemical tools to probe the noncovalent interactions that stabilize DNA duplexes. In an effort to better understand the interactions that influence the specificity of hybridization probes for O(6)-alkylguanine lesions, we examined a series of synthetic nucleoside analogues (BIM, Benzi, and Peri) with respect to their ability to stabilize duplex DNA comprised of native or damaged DNA oligonucleotides. The base-modified nucleoside analogues contained systematically varied hydrogen-bonding and pi-stacking properties. The nucleoside probes were incorporated into DNA and paired opposite canonical bases (A, T, C, or G), O(6) methylguanine (O(6)-MeG), O(6)-benzylguanine (O(6)-BnG), or a stable abasic site analogue (tetrahydrofuran, THF). On the basis of the free energy of duplex formation, the highest degree of stabilization was observed when Peri was paired opposite O(6)-MeG. The thermodynamic data suggest that the smaller probes stabilize DNA duplexes more through hydrogen bonding, whereas the larger probes, with a greater capacity to pi stack, contribute to duplex stabilization more on the basis of base stacking. These results demonstrate that increased helix stability could be achieved when BIM, Benzi, or Peri were paired opposite damage containing DNA rather than unmodified DNA (that is, O(6)-MeG rather than G). This knowledge is expected to be useful in the design and development of nucleoside analogues for uses in DNA-based technologies. PMID- 23801519 TI - Gastroparesis: what is the current state-of-the-art for evaluation and medical management? What are the results? AB - Gastroparesis is a chronic motility disorder that leads to delayed gastric emptying and negatively impacts morbidity, mortality, and quality of life. This paper provides an overview of the pathophysiology leading to symptoms in gastroparesis, discusses tests for diagnosis, and examines the evidence behind different treatment options for gastroparesis. Although delayed gastric emptying is the cardinal finding in gastroparesis, other physiologic abnormalities may contribute to the pathogenesis of symptoms. Gastric emptying scintigraphy is considered the gold standard for the diagnosis of gastroparesis but novel tests are currently available. Although metoclopramide is the only FDA approved medication to treat gastroparesis, alternative therapeutic options are available and should be tailored according to symptoms as well as physiologic abnormalities. PMID- 23801520 TI - Current Concepts and Controversies in Foregut Motility: the 2012 Kelly and Carlos Pellegrini SSAT/SAGES Joint Symposium. AB - The 2012 Kelley and Carlos Pellegrini SSAT/SAGES Joint Symposium covered the topic "Current Concepts and Controversies in Foregut Motility". This article summarizes the high points of this session, which included the diagnosis and management of achalasia, gastroparesis, and biliary dyskinesia. PMID- 23801521 TI - Role of the mannose receptor in phagocytosis of Enterococcus faecalis strain EC 12 by antigen-presenting cells. AB - The aim of this study was to clarify the phagocytic mechanisms of a heat-killed cell preparation of Enterococcus faecalis strain EC-12 (EC-12) by antigen presenting cells (APCs). Fluorescein isothiocyanate (FITC)-labeled EC-12 was cocultured with peritoneal macrophage and the amount of EC-12 phagocytosed by peritoneal macrophages was measured using a microplate fluorometer. Peritoneal macrophages from toll-like receptor (TLR)2-, TLR7-, and MyD88-deficient knockout (KO) mice exhibited similar levels of EC-12 phagocytosis to those from wild-type mice. Similarly, dectin-1 neutralization of peritoneal macrophages had no effect on EC-12 phagocytosis. However, blockade of the mannose receptor (MR) significantly decreased the amount of EC-12 phagocytosed by peritoneal macrophages; the same effect was observed in bone marrow-derived macrophages and dendritic cells. Our findings suggest that MR plays a major role in EC-12 phagocytosis by the APCs. PMID- 23801522 TI - Mapping water exchange rates in rat tumor xenografts using the late-stage uptake following bolus injections of contrast agent. AB - PURPOSE: To map the intra-to-extracellular water exchange rate constant in rat xenografts using a two-compartment model of relaxation with water exchange and a range of contrast agent concentrations and compare with histology. METHODS: MDA MB-231 cells were xenografted into six nude rats. Three bolus injections of gadodiamide were administered. When uptake in the tumor demonstrated a steady state, T1 data were acquired by spoiled gradient recalled acquisitions at four flip angles. A global fit of data to a two-compartment model incorporating exchange was performed, assuming a distribution volume of 20% of the rat. RESULTS: Voxels that did not reach steady-state and were excluded from parametric maps tended to be in large necrotic areas. TUNEL-negative (nonapoptotic) regions tended to have well-defined error bounds, with an average intra-to-extracellular exchange rate constant of 0.6 s(-1) . Apoptotic regions had higher exchange, but poorly determined upper bounds, with goodness of fit similar to that for a model assuming infinitely fast exchange. A lower bound of >3 s(-1) was used to establish voxels where the exchange rate constant was fast despite a large upper bound. CONCLUSION: Water exchange rates were higher in apoptotic regions, but examination of statistical errors was an important step in the mapping process. PMID- 23801523 TI - Interpersonal factors associated with depression in adolescents: are these consistent with theories underpinning interpersonal psychotherapy? AB - The aim of this study was to investigate whether depressed adolescents differed from non-depressed adolescents in terms of constructs consistent with those that are proposed to underpin interpersonal psychotherapy. In particular, it was hypothesized that compared with non-depressed adolescents, depressed adolescents would demonstrate a greater number of negative life events associated with interpersonal loss and major life transitions, a more insecure attachment style and poorer communication skills, interpersonal relationships and social support. Thirty-one clinically diagnosed depressed adolescents were matched with 31 non depressed adolescents on age, gender and socio-economic status. The 62 participants were aged between 12 and 19 years and comprised 18 male and 44 female adolescents. On a self-report questionnaire, depressed adolescents reported a greater number of negative interpersonal life events, a less secure attachment style and scored higher on all insecure attachment styles compared with the non-depressed adolescents. In addition, depressed adolescents demonstrated lower levels of social skill (on both adolescent and parent report), a poorer quality of relationship with parents (on both adolescent and parent report) and lower social competence (adolescent report only). Parents of depressed adolescents also reported more negative parental attitudes and behaviours towards their adolescent compared with parents of non-depressed adolescents. Thus, the results of this study are consistent with the constructs underlying interpersonal psychotherapy and suggest their usefulness in the assessment, conceptualization and treatment of adolescent depression. Clinical implications are discussed. PMID- 23801524 TI - Obligate exudativory characterizes the diet of the pygmy slow loris Nycticebus pygmaeus. AB - Few primate species are known to excavate plant sources to procure exudates and other foods via active gouging. It is now apparent that slow lorises belong to this rare guild of obligate exudativorous primates. We investigate the diet of the pygmy loris (Nycticebus pygmaeus) in a mixed deciduous forest in the Seima Protection Forest, Eastern Cambodia, and attempted to determine the importance of this resource in their diet. Feeding behaviors of six females and seven males were observed using radio-tracking to facilitate follows, and nine fecal samples were collected in February-May and January-March in 2008 and 2009 respectively. We observed 168 feeding bouts, during which the animals ate exudates (76); fruits (33); arthropods (27); flower parts (21); fungi (3); parts of bamboo culms (7); and reptiles (1). We filmed 19 bouts of exudativory, and observed animals consuming exudates in an orthograde posture, or standing quadrupedally over the exudate source. Pygmy lorises also gouged bamboo to collect lichen and fungi, or broke open dead culms to access invertebrates. Feeding occurred on terminal tree branches (24), tree trunks (21), bamboo (13), the middle of branches (7), and the undergrowth (1). The fecal samples contained plant parts, small-sized arthropods (primarily Coleoptera and Lepidoptera), reptile scales, animal bones, and animal hairs. Pygmy slow lorises are morphologically specialized for processing and digesting exudates, displaying small body sizes, specialized dentitions, elongated, and narrow tongues, large caecums, short duodenums, expanded volar pads, and modified hindlimbs. These features, combined with the prevalence of exudates in their diet across seasons, and ill health when exudates are missing from their diet in captivity, points to this species being an obligate exudativore. PMID- 23801525 TI - Validation of Virus NAT for HIV, HCV, HBV and HAV Using Post-Mortal Blood Samples. AB - OBJECTIVE: Commercial available NAT systems are usually not validated for screening of post-mortem blood samples. NAT testing might be challenging due to inhibitory substances in the cadaveric blood sample that cause false-negative test results. Validation studies have to be performed to show the performance characteristics of the NAT assays for testing cadaveric blood. METHODS: A set of 32 post-mortem serum and plasma samples from cornea donors and 40 control samples from blood donors, serologically and NAT negative for all investigated parameters, were spiked with defined concentrations of WHO reference material and tested for HIV-1, HCV, HBV, and HAV by NAT using DRK Baden-Wurttemberg-Hesse CE PCR kits. Analytical sensitivity, analytical specificity and reproducibility/precision were validated and compared with each other in both groups of samples. RESULTS: The analytical sensitivity was 100% for control and post-mortem specimens when spiked with virus standards at concentrations of 3 * level of detection (LOD). Invalid results did not occur. The analytical specificity rate for all assays was 100%. Intra-assay variation was analyzed as a function of sample material and sampling time post mortem. Values of % coefficient of variation (%CV) were comparable for serum and plasma but slightly higher for post-mortem samples especially for those samples collected more than 24 h post mortem. CONCLUSION: Based on the presented validation, postmortem donor samples can be tested with the automated DRK Baden-Wurtemberg-Hesse NAT system. PMID- 23801527 TI - A patient with mutation in the SCN4A p.M1592v presenting with fixed weakness, rhabdomyolysis, and episodic worsening of weakness. PMID- 23801526 TI - Effects of exercise and lifestyle modification on fitness, insulin resistance, skeletal muscle oxidative phosphorylation and intramyocellular lipid content in obese children and adolescents. AB - BACKGROUND: Obesity is associated with poor fitness and adverse metabolic consequences in children. OBJECTIVE: To investigate how exercise and lifestyle modification may improve fitness and insulin sensitivity in this population. DESIGN AND SUBJECTS: Randomized controlled trial, 21 obese (body mass index >= 95% percentile) subjects, ages 10 to 17 years. METHODS: Subjects were given standardized healthful lifestyle advice for 8 weeks. In addition, they were randomized to an in-home supervised exercise intervention (n = 10) or control group (n = 11). MEASUREMENTS: Fasting laboratory studies (insulin, glucose, lipid profile) and assessments of fitness, body composition, skeletal muscle oxidative phosphorylation and intramyocellular lipid content (IMCL), were performed at baseline and study completion. RESULTS: Subjects were 13.0 +/- 1.9 (standard deviation) years old, 72% female and 44% non-white. Exercise improved fitness (P = 0.03) and power (P = 0.01), and increased IMCL (P = 0.02). HOMA-IR decreased among all subjects in response to lifestyle modification advice (P = 0.01), regardless of exercise training assignment. In univariate analysis in all subjects, change in cardiovascular fitness was associated with change in HOMA-IR. In exploratory analyses, increased IMCL was associated with greater resting energy expenditure (r = 0.78, P = 0.005) and a decrease in fasting respiratory quotient (r = -0.70, P = 0.02) (n = 11). CONCLUSIONS: Change in fitness was found to be related to change in insulin resistance in response to lifestyle modification and exercise in obese children. IMCL increased with exercise in these obese children, which may reflect greater muscle lipid oxidative capacity. PMID- 23801528 TI - Safety, tolerability, and efficacy of oral therapies for relapsing-remitting multiple sclerosis. AB - Treatment options for relapsing-remitting multiple sclerosis (RRMS) have been continuously expanding in recent years, and the emergence of a number of oral disease-modifying agents (DMAs) has significantly changed the landscape of therapeutic options for MS patients. Many of these oral DMAs have demonstrated satisfactory safety and tolerability profiles in clinical trial settings, but the long-term safety of these agents is an important concern. This review discusses salient points on the safety and clinical efficacy of the approved and emerging novel oral therapies in RRMS, including fingolimod, teriflunomide, dimethyl fumarate, laquinimod, and cladribine. PMID- 23801529 TI - A post hoc comparison of the effects of lisdexamfetamine dimesylate and osmotic release oral system methylphenidate on symptoms of attention-deficit hyperactivity disorder in children and adolescents. AB - INTRODUCTION: There are limited head-to-head data comparing the efficacy of long acting amfetamine- and methylphenidate-based psychostimulants as treatments for individuals with attention-deficit hyperactivity disorder (ADHD). This post hoc analysis provides the first parallel-group comparison of the effect of lisdexamfetamine dimesylate (lisdexamfetamine) and osmotic-release oral system methylphenidate (OROS-MPH) on symptoms of ADHD in children and adolescents. STUDY DESIGN: This was a post hoc analysis of a randomized, double-blind, parallel group, dose-optimized, placebo-controlled, phase III study. SETTING: The phase III study was carried out in 48 centres across ten European countries. PATIENTS: The phase III study enrolled children and adolescents (aged 6-17 years) who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for a primary diagnosis of ADHD and who had a baseline ADHD Rating Scale IV (ADHD-RS-IV) total score of 28 or higher. INTERVENTION: Eligible patients were randomized (1:1:1) to receive a once-daily, optimized dose of lisdexamfetamine (30, 50 or 70 mg/day), placebo or OROS-MPH (18, 36 or 54 mg/day) for 7 weeks. MAIN OUTCOME MEASURES: In this post hoc analysis, efficacy was assessed using the ADHD-RS-IV and Clinical Global Impressions-Improvement (CGI-I) scale. Responders were defined as those achieving at least a 30% reduction from baseline in ADHD-RS-IV total score and a CGI-I score of 1 (very much improved) or 2 (much improved). The proportion of patients achieving an ADHD-RS-IV total score less than or equal to the mean for their age (based on normative data) was also determined. Endpoint was the last on-treatment visit with a valid assessment. Safety assessments included treatment-emergent adverse events (TEAEs) and vital signs. RESULTS: Of the 336 patients randomized, 332 were included in the safety population, 317 were included in the full analysis set and 196 completed the study. The mean (standard deviation) ADHD-RS-IV total score at baseline was 40.7 (7.31) for lisdexamfetamine, 41.0 (7.14) for placebo and 40.5 (6.72) for OROS MPH. The least-squares (LS) mean change (standard error) in ADHD-RS-IV total score from baseline to endpoint was -24.3 (1.16) for lisdexamfetamine, -5.7 (1.13) for placebo and -18.7 (1.14) for OROS-MPH. The difference between lisdexamfetamine and OROS-MPH in LS mean change (95% confidence interval [CI]) in ADHD-RS-IV total score from baseline to endpoint was statistically significant in favour of lisdexamfetamine (-5.6 [-8.4 to -2.7]; p < 0.001). The difference between lisdexamfetamine and OROS-MPH in the percentage of patients (95% CI) with a CGI-I score of 1 or 2 at endpoint was 17.4 (5.0-29.8; p < 0.05; number needed to treat [NNT] 6), and the difference in the percentage of patients (95% CI) achieving at least a 30% reduction in ADHD-RS-IV total score and a CGI-I score of 1 or 2 was 18.3 (5.4-31.3; p < 0.05; NNT 6). The difference between lisdexamfetamine and OROS-MPH in the percentage of patients (95% CI) with an ADHD RS-IV total score less than or equal to the mean for their age at endpoint was 14.0 (0.6-27.4; p = 0.050). The overall frequency of TEAEs and the frequencies of decreased appetite, insomnia, decreased weight, nausea and anorexia TEAEs were greater in patients treated with lisdexamfetamine than in those treated with OROS MPH, whereas headache and nasopharyngitis were more frequently reported in patients receiving OROS-MPH. CONCLUSIONS: This post hoc analysis showed that, at the doses tested, patients treated with lisdexamfetamine showed statistically significantly greater improvement in symptoms of ADHD than those receiving OROS MPH, as assessed using the ADHD-RS-IV and CGI-I. The safety profiles of lisdexamfetamine and OROS-MPH were consistent with the known effects of stimulant medications. PMID- 23801531 TI - Enhancers. AB - Transcription of eukaryotic genes is an exceedingly sophisticated and complicated process, orchestrated by layers of control mechanisms involving a myriad of transcription factors and DNA control sequences, with both groups subject to multiple modifications. The availability of various recent genomic approaches has provided previously unforeseen opportunities to examine the cis-regulatory landscape of the entire genome, resulting in the identification of a potentially overwhelming number of enhancers and novel enhancer functions. In this review, we focus on the activities of enhancers in metazoans and discuss how they serve to regulate gene expression during early development. PMID- 23801532 TI - Cytoplasmic localization and reorganization in ascidian eggs: role of postplasmic/PEM RNAs in axis formation and fate determination. AB - Localization of maternal molecules in eggs and embryos and cytoplasmic movements to relocalize them are fundamental for the orderly cellular and genetic processes during early embryogenesis. Ascidian embryos have been known as 'mosaic eggs' because of their autonomous differentiation abilities based on localized cell fate determinants. This review gives a historical overview of the concept of cytoplasmic localization, and then explains the key features such as ooplasmic movements and cell lineages that are essential to grasp the process of ascidian development mediated by localized determinant activities. These activities are partly executed by localized molecules named postplasmic/PEM RNAs, originating from approximately 50 genes, of which the muscle determinant, macho-1, is an example. The cortical domain containing these RNAs is relocalized to the posterior-vegetal region of the egg by cytoskeletal movements after fertilization, and plays crucial roles in axis formation and cell fate determination. The cortical domain contains endoplasmic reticulum and characteristic granules, and gives rise to a subcellular structure called the centrosome-attracting body (CAB), in which postplasmic/PEM RNAs are highly concentrated. The CAB is responsible for a series of unequal partitionings of the posterior-vegetal cytoplasmic domain and the postplasmic/PEM RNAs at the posterior pole during cleavage. Some components of this domain, which is rich in granules, are eventually inherited by prospective germline cells with particular postplasmic/PEM RNAs such as vasa. The postplasmic/PEM RNAs are classified into two groups according to their final cellular destinations and localization pathways. Localization of these RNAs is regulated by specific nucleotide sequences in the 3' untranslated regions (3'UTRs). PMID- 23801534 TI - Endosperm development: dynamic processes and cellular innovations underlying sibling altruism. AB - The endosperm is a product of fertilization that evolved to support and nourish its genetic twin sibling embryo. Cereal endosperm accumulates starch and protein stores, which later support the germinating seedling. These nutritional stores prompted the domestication of cereals and are the focus of ongoing efforts for crop improvement and biotechnological innovations. Endosperm development entails several novel modifications to basic cellular and developmental processes. Cereals display nuclear endosperm development, which begins with a period of free nuclear division to generate a coenocyte. Cytoskeletal arrays distribute nuclei around the periphery of the cytoplasm and direct the subsequent deposition of cell wall material during cellularization. Positional cues and signaling systems function dynamically in the specification of the four major cell types: transfer cells, embryo-surrounding cells, starchy endosperm (SE), and aleurone. Genome balance, epigenetic gene regulation, and parent-of-origin effects are essential for directing these processes. Transfer cells transport solutes, including sugars and amino acids, from the maternal plant tissues into the developing grain where they are partitioned between embryo and SE cells. Cells of the embryo-surrounding region appear to coordinate development of the embryo and endosperm. As the seed matures, SE cells assimilate starch and protein stores, undergo DNA endoreduplication, and finally undergo programmed cell death. In contrast, aleurone cells follow a maturation program similar to the embryo, allowing them to survive desiccation. At germination, the aleurone cells secrete amylases and proteases that hydrolyze the storage products of the SE to nourish the germinating seedling. PMID- 23801535 TI - Annual fish: developmental adaptations for an extreme environment. AB - Annual fish are freshwater teleosts found in South America and Africa that are exposed to an extremely variable environment. They develop and reproduce in seasonal ponds that dry during the summer eliminating the entire adult population. Remarkably, desiccation-resistant embryos survive in these dry ponds that hatch during the next rainy season when the ponds are recreated. Among vertebrates, they represent one of the most remarkable extremophiles. They share several features with other fish models; however, they exhibit unique traits related to their peculiar life cycle. Epiboly is temporally and spatially uncoupled from organogenesis, and the embryos can undergo reversible developmental arrests (diapauses). These attributes make them a useful model to study diverse topics in developmental biology using a comparative and evolutionary approach. In this article, different aspects related to annual fish biology, taxonomy and phylogenetic considerations, reproductive strategy, and developmental characteristics with special focus on arrests, are summarized. The current challenge is to document and determine the factors that generate such high diversity and unique adaptations of annual fish. To understand this complexity, interdisciplinary approaches are being employed taking into consideration evolutionary biology, ethology, reproductive strategies, regulation of developmental mechanisms, and senescence. PMID- 23801533 TI - The molecular and cellular basis of gonadal sex reversal in mice and humans. AB - The mammalian gonad is adapted for the production of germ cells and is an endocrine gland that controls sexual maturation and fertility. Gonadal sex reversal, namely, the development of ovaries in an XY individual or testes in an XX, has fascinated biologists for decades. The phenomenon suggests the existence of genetic suppressors of the male and female developmental pathways and molecular genetic studies, particularly in the mouse, have revealed controlled antagonism at the core of mammalian sex determination. Both testis and ovary determination represent design solutions to a number of problems: how to generate cells with the right properties to populate the organ primordium; how to produce distinct organs from an initially bipotential primordium; how to pattern an organ when the expression of key cell fate determinants is initiated only in a discrete region of the primordium and extends to other regions asynchronously; how to coordinate the interaction between distinct cell types in time and space and stabilize the resulting morphology; and how to maintain the differentiated state of the organ throughout the adult period. Some of these, and related problems, are common to organogenesis in general; some are distinctive to gonad development. In this review, we discuss recent studies of the molecular and cellular events underlying testis and ovary development, with an emphasis on the phenomenon of gonadal sex reversal and its causes in mice and humans. Finally, we discuss sex-determining loci and disorders of sex development in humans and the future of research in this important area. PMID- 23801536 TI - Hemangioblast: an in vitro phantom. AB - The hemangioblast, a bipotent progenitor that generates both endothelial cells (EC) and blood cells (BC) in the blood islands (BI) of the yolk sac (YS) has been a core notion of developmental hematology since the early 20th century. However, its actual presence has not been directly addressed for long. At the very end of the 20th century, the hemangioblast was revisited as a result of the development of new technologies that enable detection of such bipotent precursors in vitro. Such studies provided evidence for the presence of bipotent precursors for EC and BC. On the other hand, subsequent studies analyzing the processes occurring within BI strongly argued against the notion of hemanigioblasts and suggest that the hemangioblast is an in vitro artefact. In this article, I overview the history of the study of the hemangioblast and try to explain why hemangioblast that can be defined in vitro cannot be detected in BI. PMID- 23801537 TI - GC-MS study of compounds isolated from Coffea arabica flowers by different extraction techniques. AB - Headspace (HS), extractive, and distillative methods were employed to isolate volatile and semivolatile compounds from fresh Coffea arabica flowers. Static HS solid-phase microextraction (HS-SPME), microwave-assisted HS-SPME (MW-HS-SPME) with simultaneous hydrodistillation, and extraction with hexane or supercritical CO2 -isolated mixtures in which around 150 different chemical substances were identified or tentatively identified by GC-MS analysis. n-Pentadecane (20-37% relative peak area, RPA) was the most abundant compound in the HS fractions from fresh flowers, followed by 8-heptadecene (8-20% RPA) and geraniol (6-14% RPA). Hydrocarbons (mostly C13 -C30 paraffins) were the predominant compound class in all the sorptive extractions (HS-SPME, MW-HS-SPME, distillate), followed by terpenoids or oxygenated compounds (which varied with the isolation technique). Caffeine, a distinctive component of coffee fruits and beans, was also found in relatively high amounts in the supercritical CO2 extract of C. arabica flowers. PMID- 23801538 TI - SAGES clinical spotlight review: endoluminal treatments for gastroesophageal reflux disease (GERD). PMID- 23801539 TI - Late onset eating disorders in Spain: clinical characteristics and therapeutic implications. AB - OBJECTIVE: The literature on later age of onset (LAO) in women with eating disorders is scarce. We compared the severity of eating disorders, eating disorder subtype, and personality profiles in a clinical sample of consecutively assessed women with eating disorders with later age of onset (LAO, > = 25 years) to women with typical age of onset (TAO, <25 years). METHOD: All eating disorder patients met the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) criteria and were admitted to the Eating Disorder Unit of the University Hospital of Bellvitge in Barcelona, Spain. Ninety-six patients were classified as LAO and 759 as TAO. ASSESSMENT: Measures included the Eating Attitude Test-40 (EAT-40), Eating Disorders Inventory-2 (EDI-2), Bulimic Investigatory Test Edinburgh (BITE), Symptom Checklist Revised (SCL-90-R), and the Temperament and Character Inventory-Revised (TCI-R), as well as other clinical and psychopathological indices. RESULTS: LAO individuals reported significantly fewer weekly vomiting episodes, fewer self-harming behaviours, less drug abuse, and lower scores on the BITE symptoms, the EDI-2 drive for thinness, and the TCI-R harm avoidance scales than TAO individuals. Conversely, the LAO group reported more current and premorbid obesity than the TAO group. CONCLUSION: LAO eating disorder patients in this sample presented with milder symptomatology and less extreme personality traits. Premorbid obesity may be more relevant to LAO than TAO eating disorders and should be routinely assessed and considered when planning treatment. PMID- 23801541 TI - Embedding sulfur in MOF-derived microporous carbon polyhedrons for lithium-sulfur batteries. PMID- 23801540 TI - Magnetic susceptibility as a B0 field strength independent MRI biomarker of liver iron overload. AB - PURPOSE: MR-based quantification of liver magnetic susceptibility may enable field strength-independent measurement of liver iron concentration (LIC). However, susceptibility quantification is challenging, due to nonlocal effects of susceptibility on the B0 field. The purpose of this work is to demonstrate feasibility of susceptibility-based LIC quantification using a fat-referenced approach. METHODS: Phantoms consisting of vials with increasing iron concentrations immersed between oil/water layers, and 27 subjects (9 controls/18 subjects with liver iron overload) were scanned. Ferriscan (1.5 T) provided R2 based reference LIC. Multiecho three-dimensional-SPGR (1.5 T/3 T) enabled fat water, B0- and R2*-mapping. Phantom iron concentration (mg Fe L(-1)) was estimated from B0 differences (DeltaB0) between vials and neighboring oil. Liver susceptibility and LIC (mg Fe g(-1) dry tissue) was estimated from DeltaB0 between the lateral right lobe of the liver and adjacent subcutaneous adipose tissue. RESULTS: Estimated phantom iron concentrations had good correlation with true iron concentrations (1.5 T:slope = 0.86, intercept = 0.72, r(2) = 0.98; 3 T:slope = 0.85, intercept = 1.73, r(2) = 0.98). In liver, DeltaB0 correlated strongly with R2* (1.5 T:r(2) = 0.86; 3 T:r(2) = 0.93) and B0-LIC had good agreement with Ferriscan-LIC (slopes/intercepts nearly 1.0/0.0, 1.5 T:r(2) = 0.67, slope = 0.93 +/- 0.13, P ~ 0.50, intercept = 1.93 +/- 0.78, P ~ 0.02; 3 T:r(2) = 0.84, slope = 1.01 +/- 0.09, P ~ 0.90, intercept = 0.23 +/- 0.52, P ~ 0.68). DISCUSSION: Fat-referenced, susceptibility-based LIC estimation is feasible at both field strengths. This approach may enable improved susceptibility mapping in the abdomen. PMID- 23801542 TI - Behavioral and physiological responses to subgroup size and number of people in howler monkeys inhabiting a forest fragment used for nature-based tourism. AB - Animals' responses to potentially threatening factors can provide important information for their conservation. Group size and human presence are potentially threatening factors to primates inhabiting small reserves used for recreation. We tested these hypotheses by evaluating behavioral and physiological responses in two groups of mantled howler monkeys (Alouatta palliata mexicana) at the "Centro Ecologico y Recreativo El Zapotal", a recreational forest reserve and zoo located in the Mexican state of Chiapas. Both groups presented fission-fusion dynamics, splitting into foraging subgroups which varied in size among, but not within days. Neither subgroup size nor number of people had an effect on fecal cortisol. Out of 16 behavioral response variables tested, the studied factors had effects on six: four were affected by subgroup size and two were affected by number of people. With increasing subgroup size, monkeys increased daily path lengths, rested less, increased foraging effort, and used more plant individuals for feeding. As the number of people increased, monkeys spent more time in lower quality habitat, and less time engaged in social interactions. Although fecal cortisol levels were not affected by the factors studied, one of the monkey groups had almost twice the level of cortisol compared to the other group. The group with higher cortisol levels also spent significantly more time in the lower quality habitat, compared to the other group. Our results suggest that particular behavioral adjustments might allow howler monkeys at El Zapotal to avoid physiological stress due to subgroup size and number of people. However, the fact that one of the monkey groups is showing increased cortisol levels may be interpreted as a warning sign, indicating that an adjustment threshold is being reached, at least for part of the howler monkey population in this forest fragment. PMID- 23801544 TI - Analysis of free amino acids in flue-cured tobacco leaves using ultra-high performance liquid chromatography with single quadrupole mass spectrometry. AB - Amino acids are one of the most important metabolites of organisms. They play an important role in plant growth, development, and product quality. A method based on RP ultra-performance LC with single quadrupole MS and 6-aminoquinolyl-N hydroxysuccinimidyl carbamate precolumn derivatization was developed for the analysis of free amino acids in flue-cured tobacco leaves. Unlike the corresponding UV detection method, this method avoids matrix interference of complicated tobacco components, and the quantitative accuracy and resolution were improved. Twenty free amino acids were detected in flue-cured tobacco leaves. The method showed a good linearity with correlation coefficients of 0.9966-0.9998. The LODs for derivatized amino acids were 0.2-9.7 fmol/MUL. Good repeatability with an RSD of 2.5-8.6% and satisfactory intra- and interday precisions were obtained. The developed method was used to investigate free amino acids in flue cured tobacco leaves in China. The effects of aroma type, variety, and growing regions on free amino acids were investigated. The results showed that free amino acids in tobacco were affected by growing regions and varieties. PMID- 23801545 TI - Mindfulness training in a heterogeneous psychiatric sample: outcome evaluation and comparison of different diagnostic groups. AB - OBJECTIVES: To examine outcome after mindfulness training in a heterogeneous psychiatric outpatient population and to compare outcome in different diagnostic groups. METHOD: One hundred and forty-three patients in 5 diagnostic categories completed questionnaires about psychological symptoms, quality of life, and mindfulness skills prior to and immediately after treatment. RESULTS: The mixed patient group as a whole improved significantly on all outcome measures. Differential improvement was found for different diagnostic categories with respect to psychological symptoms and quality of life: Bipolar patients did not improve significantly on these measures. This finding could be explained by longer illness duration and lower baseline severity in the bipolar category. CONCLUSION: Mindfulness training is associated with overall improvement in a heterogeneous outpatient population. Differences in outcome between diagnostic categories may be ascribed to differences in illness duration and baseline severity. PMID- 23801546 TI - Distinct solid and solution state self-assembly pathways of RADA16-I designer peptide. AB - Solid state NMR measurements on selectively (13) C-labeled RADA16-I peptide (COCH3 -RADARADARADARADA-NH2 ) were used to obtain new molecular level information on the conversion of alpha-helices to beta-sheets through self assembly in the solid state with increasing temperature. Isotopic labeling at the A4 Cbeta site enabled rapid detection of (13) C NMR signals. Heating to 344-363 K with simultaneous NMR detection allowed production of samples with systematic variation of alpha-helix and beta-strand content. These samples were then probed at room temperature for intermolecular (13) C-(13) C nuclear dipolar couplings with the PITHIRDS-CT NMR experiment. The structural transition was also characterized by Fourier transform infrared spectroscopy and wide angle X-ray diffraction. Independence of PITHIRDS-CT decay shapes on overall alpha-helical and beta-strand content infers that beta-strands are not observed without association with beta-sheets, indicating that beta-sheets are formed at elevated temperatures on a timescale that is fast relative to the NMR experiment. PITHIRDS CT NMR data were compared with results of similar measurements on RADA16-I nanofibers produced by self-assembly in aqueous salt solution. We report that beta-sheets formed through self-assembly in the solid state have a structure that differs from those formed through self-assembly in the solution state. Specifically, solid state RADA16-I self-assembly produces in-register parallel beta-sheets, whereas nanofibers are composed of stacked parallel beta-sheets with registry shifts between adjacent beta-strands in each beta-sheet. These results provide evidence for environment-dependent self-assembly mechanisms for RADA16-I beta-sheets as well as new constraints on solid state self-assembled structures, which must be avoided to maximize solution solubility and nanofiber yields. PMID- 23801547 TI - Total synthesis and absolute configuration of epicoccamide D, a naturally occurring mannosylated 3-acyltetramic acid. AB - The endofungal metabolite epicoccamide D was synthesised in eighteen steps and 17 % yield as the first member of the family of natural glycotetramic acids. The modular character of the synthesis opens access also to analogues featuring different sugars and spacers. It comprises several high-yielding key steps. The beta-D-mannosyl group was introduced by using an alpha-D-glucosyl imidate donor with subsequent oxidative-reductive epimerisation at C-2'. The pyrrolidine ring was closed quantitatively by a Lacey-Dieckmann condensation of an N-(beta ketoacyl)-N-methyl alaninate. The resulting 3-[omega-(beta-D-mannosyl)octadec-2 enoyl]tetramic acid was hydrogenated in the presence of the rhodium catalyst (R,R)-[Rh(Et-DUPHOS)][BF4 ] to establish the (7S)-stereocentre. This was possible only after blocking the acyltetramic acid as a BF2 -chelate to prevent capture of the metal catalyst. We also assigned the hitherto unknown configuration of the natural product as being 5S,7S by comparison of its (13) C NMR spectroscopic and optical rotation data with those of our two synthetic 5S,7R/S-diasteromers. PMID- 23801548 TI - Stents for the prevention of pancreatic fistula following pancreaticoduodenectomy. AB - BACKGROUND: Several studies have demonstrated that the use of pancreatic duct stents following pancreaticoduodenectomy is associated with a lower risk of pancreatic fistula. However, to date, there is a lack of accord in the literature on whether the use of stents is beneficial and, if so, whether internal or external stenting is preferable. OBJECTIVES: To determine the efficacy of pancreatic stents in preventing pancreatic fistula after pancreaticoduodenectomy. SEARCH METHODS: The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, ISI Web of Science and four major Chinese biomedical databases were searched up to February 2011. We also searched four major trials registers. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing the use of stents (either internal or external) versus no stents, and comparing internal stents versus external stents following pancreaticoduodenectomy. DATA COLLECTION AND ANALYSIS: Two authors extracted the data independently. The outcomes studied were incidence of pancreatic fistula, need for reoperation, length of hospital stay, overall complications, and in-hospital mortality. The results were shown as relative risk (RR) with 95% confidence interval (CI). MAIN RESULTS: A total of 656 patients were included in the systematic review. Overall, the use of stents (both external and internal) was not associated with a statistically significant change in any of the studied outcomes. In a subgroup analysis, it was found that the use of external, but not internal, stents is associated with a significant reduction in the incidence of pancreatic fistulae (RR 0.33; 95% CI 0.11 to 0.98, P = 0.04), the incidence of complications (RR 0.48; 95% CI 0.25 to 0.92, P = 0.03) and length of hospital stay (RR -0.57; 95% CI -0.94 to -0.21, P = 0.002). In RCTs on the use of internal versus external stents, no statistically significant difference was found in terms of any of the studied outcomes. AUTHORS' CONCLUSIONS: This systematic review suggests that the use of external stents following pancreaticoduodenectomy may be beneficial. However, only a limited number of RCTs with rather small sample sizes were available. Further RCTs on the use of stents after pancreaticoduodenectomy are warranted. PMID- 23801549 TI - Single dose oral ibuprofen plus oxycodone for acute postoperative pain in adults. AB - BACKGROUND: Combining two different analgesics in fixed doses in a single tablet can provide better pain relief than either drug alone in acute pain. This appears to be broadly true across a range of different drug combinations, in postoperative pain and migraine headache. Fixed-dose combinations of ibuprofen and oxycodone are available, and the drugs may be separately used in combination in some acute pain situations. OBJECTIVES: To assess the analgesic efficacy and adverse effects of a single oral dose of ibuprofen plus oxycodone for moderate to severe postoperative pain. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, (CENTRAL), on The Cochrane Library, (Issue 4 of 12, 2013), MEDLINE (1950 to 21st May 2013), EMBASE (1974 to 21st May 2013), the Oxford Pain Database, ClinicalTrials.gov, and reference lists of articles. SELECTION CRITERIA: Randomised, double-blind clinical trials of single dose, oral ibuprofen plus oxycodone compared with placebo or the same dose of ibuprofen alone for acute postoperative pain in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently considered trials for inclusion in the review, assessed quality, and extracted data. We used the area under the pain relief versus time curve to derive the proportion of participants prescribed ibuprofen plus oxycodone, ibuprofen alone, oxycodone alone, or placebo with at least 50% pain relief over six hours, using validated equations. We calculated relative risk (RR) and number needed to treat to benefit (NNT). We used information on use of rescue medication to calculate the proportion of participants requiring rescue medication and the weighted mean of the median time to use. We also collected information on adverse events. MAIN RESULTS: Searches identified three studies involving 1202 participants. All examined the same dose combination. Included studies provided data from 603 participants for the comparison of ibuprofen 400 mg + oxycodone 5 mg with placebo, 717 participants for the comparison of ibuprofen 400 mg + oxycodone 5 mg with ibuprofen 400 mg alone, and 471 participants for the comparison of ibuprofen 400 mg + oxycodone 5 mg with oxycodone 5 mg alone.The proportion of participants achieving at least 50% pain relief over 6 hours was 60% with ibuprofen 400 mg + oxycodone 5 mg and 17% with placebo, giving an NNT of 2.3 (2.0 to 2.8). For ibuprofen 400 mg alone the proportion was 50%, producing no significant difference between ibuprofen 400 mg + oxycodone 5 mg and ibuprofen 400 mg alone. For oxycodone 5 mg alone the proportion was 23%, giving an NNT for ibuprofen 400 mg + oxycodone 5 mg compared with oxycodone alone of 2.9 (2.3 to 4.0).Ibuprofen + oxycodone resulted in longer times to remedication than with placebo. The median time to use of rescue medication was more than 5 hours for ibuprofen 400 mg + oxycodone 5 mg, and 2.3 hours or less with placebo. Fewer participants needed rescue medication with ibuprofen + oxycodone combination than with placebo or ibuprofen alone. The proportion was 40% with ibuprofen 400 mg + oxycodone 5 mg, 83% with placebo, 53% with ibuprofen alone, and 83% with oxycodone alone, giving NNT to prevent one patient needing rescue medication of 2.4 (2.0 to 2.9), 11 (6.1 to 56), and 2.6 (2.1 to 3.4) for comparisons of ibuprofen 400 mg + oxycodone 5 mg with placebo, ibuprofen alone, and oxycodone alone, respectively.The proportion of participants experiencing one or more adverse events was 25% with ibuprofen 400 mg + oxycodone 5 mg, 25% with placebo, 26% with ibuprofen alone, and 35% with oxycodone alone; they were not significantly different. Serious adverse events were reported only after abdominal surgery 6/169 with the combination, 1/175 with ibuprofen alone, 3/52 with oxycodone alone, and 1/60 with placebo. Withdrawals for reasons other than lack of efficacy were fewer than 5% and balanced across treatment arms. AUTHORS' CONCLUSIONS: The combination of ibuprofen 400mg + oxycodone 5mg provided analgesia for longer than oxycodone alone, but not ibuprofen alone (at the same dose). There was also a smaller chance of needing additional analgesia over about eight hours, and with no greater chance of experiencing an adverse event. PMID- 23801550 TI - An adaptive model switching approach for phase I dose-finding trials. AB - Model-based phase I dose-finding designs rely on a single model throughout the study for estimating the maximum tolerated dose (MTD). Thus, one major concern is about the choice of the most suitable model to be used. This is important because the dose allocation process and the MTD estimation depend on whether or not the model is reliable, or whether or not it gives a better fit to toxicity data. The aim of our work was to propose a method that would remove the need for a model choice prior to the trial onset and then allow it sequentially at each patient's inclusion. In this paper, we described model checking approach based on the posterior predictive check and model comparison approach based on the deviance information criterion, in order to identify a more reliable or better model during the course of a trial and to support clinical decision making. Further, we presented two model switching designs for a phase I cancer trial that were based on the aforementioned approaches, and performed a comparison between designs with or without model switching, through a simulation study. The results showed that the proposed designs had the advantage of decreasing certain risks, such as those of poor dose allocation and failure to find the MTD, which could occur if the model is misspecified. PMID- 23801551 TI - Estimation in AB/BA crossover trials with application to bioequivalence studies with incomplete and complete data designs. AB - Crossover studies are frequently used in clinical research as they allow within subject comparisons instead of the between-subject evaluation of parallel group designs. Estimation of interesting parameters from such designs is, however, not trivial. We provide three methods for estimating treatment effects and associated standard errors from an AB/BA crossover trial. Assuming at least asymptotic normality, we can obtain the confidence intervals for single parameters as well as for differences or ratios of treatment effects. The latter is particularly useful in a pharmacokinetic context to establish bioequivalence using area under the concentration versus time curves (AUCs). In this work, we will illustrate how Fieller-type confidence intervals can be constructed for the ratio of AUCs estimated using a noncompartmental approach in a sparse sampling setting from a two-treatment, two-period, two-sequence crossover trial. In particular, we will discuss a flexible batch design, which includes traditional serial sampling and complete data designs as special cases. Via simulation, we show that the proposed intervals have nominal coverage and keep the type I error even for small sample sizes. Moreover, we illustrate the methodology in a real data example. PMID- 23801552 TI - Reforms and emerging noncommunicable disease: some challenges facing a conflict ridden country--the case of the Syrian Arab Republic. AB - The past year witnessed considerable turbulence in the Arab world-in this case, Syria, a lower middle-income country with a record of a strong public health infrastructure. This paper explores the current challenges facing its health system from reforms, civil strife and international sanctions all of which we argue have serious implications for population health. The health sector in Syria was little known, and until recently, it was well integrated to provide preventive and specialized care when needed. Regionally, it was one of the few countries ready and capable of addressing the challenges of demographic and epidemiologic transition with a long-standing emphasis on primary care and prevention, unlike most countries of the region. This context has changed dramatically through the recent implementation of reforms and the current civil war. Changes to financing, management and the delivery of health service placed access to services in jeopardy, but now, these are compounded by the destruction from an intractable and violent conflict and international sanctions. This paper explores some of the combined effects of reforms, conflict and sanctions on population health. PMID- 23801553 TI - The organization of irrational beliefs in posttraumatic stress symptomology: testing the predictions of REBT theory using structural equation modelling. AB - OBJECTIVE: This study directly tests a central prediction of rational emotive behaviour therapy (REBT) that has received little empirical attention regarding the core and intermediate beliefs in the development of posttraumatic stress symptoms. METHOD: A theoretically consistent REBT model of posttraumatic stress disorder (PTSD) was examined using structural equation modelling techniques among a sample of 313 trauma-exposed military and law enforcement personnel. RESULTS: The REBT model of PTSD provided a good fit of the data, chi(2) = 599.173, df = 356, p < .001; standardized root mean square residual = .05 (confidence interval = .04-.05); standardized root mean square residual = .04; comparative fit index = .95; Tucker Lewis index = .95. Results demonstrated that demandingness beliefs indirectly affected the various symptom groups of PTSD through a set of secondary irrational beliefs that include catastrophizing, low frustration tolerance, and depreciation beliefs. CONCLUSIONS: Results were consistent with the predictions of REBT theory and provides strong empirical support that the cognitive variables described by REBT theory are critical cognitive constructs in the prediction of PTSD symptomology. PMID- 23801554 TI - Morphological processing in reading disabled and skilled Spanish children. AB - This article presents the results of a lexical decision experiment in which the base frequency (BF) effect is explored in reading disabled children and skilled readers. Three groups of participants were created. The first group was composed of children with reading disorders, the second group of skilled readers matched with the first group for chronological age and the third group of skilled readers matched for vocabulary size. The results of the experiment showed strong effects for Group, BF and also for the Group by BF interaction. Children matched for chronological age with children with reading disorders were significantly faster and more accurate than children of the other groups, who did not show any difference from each other. The effect of BF showed that children responded faster to stimuli composed of frequent bases than to stimuli with less frequent bases. However, the analysis of the interaction between Group and BF showed that only the skilled readers matched to children with reading disorders for chronological age benefited from the BF effect. The results of the experiment are discussed in the framework of theoretical accounts of morphological processing in children as well as considering the role played by the experimental task. PMID- 23801556 TI - In vivo MRI analysis of depth-dependent ultrastructure in human knee cartilage at 7 T. AB - Signal intensities of T2-weighted magnetic resonance images depend on the local fiber arrangement in hyaline cartilage. The aims of this study were to determine whether angle-sensitive MRI at 7 T can be used to quantify the cartilage ultrastructure of the knee in vivo and to assess potential differences with age. Ten younger (21-30) and ten older (55-76 years old) healthy volunteers were imaged with a T2-weighted spin-echo sequence in a 7 T whole-body MRI. A "fascicle" model was assumed to describe the depth-dependent fiber arrangement of cartilage. The R/T boundary positions between radial and transitional zones were assessed from intensity profiles in small regions of interest in the femur and tibia, and normalized to cartilage thickness using logistic curve fits. The quality of our highly resolved (0.3 * 0.3 * 1.0 mm(3)) MR cartilage images were high enough for quantitative analysis (goodness of fit R(2) = 0.91 +/- 0.09). Between younger and older subjects, normalized positions of the R/T boundary, with value 0 at the bone-cartilage interface and 1 at the cartilage surface, were significantly (p < 0.05) different in femoral (0.51 +/- 0.12 versus 0.41 +/- 0.10), but not in tibial cartilage (0.65 +/- 0.11 versus 0.57 +/- 0.09, p = 0.119). Within both age groups, differences between femoral and tibial R/T boundaries were significant. Using a fascicle model and angle-sensitive MRI, the depth-dependent anisotropic fiber arrangement of knee cartilage could be assessed in vivo from a single 7 T MR image. The derived quantitative parameter, thickness of the radial zone, may serve as an indicator of the structural integrity of cartilage. This method may potentially be suitable to detect and monitor early osteoarthritis because the progressive disintegration of the anisotropic network is also indicative of arthritic changes in cartilage. PMID- 23801557 TI - Emerging antiviral strategies to interfere with influenza virus entry. AB - Influenza A and B viruses are highly contagious respiratory pathogens with a considerable medical and socioeconomical burden and known pandemic potential. Current influenza vaccines require annual updating and provide only partial protection in some risk groups. Due to the global spread of viruses with resistance to the M2 proton channel inhibitor amantadine or the neuraminidase inhibitor oseltamivir, novel antiviral agents with an original mode of action are urgently needed. We here focus on emerging options to interfere with the influenza virus entry process, which consists of the following steps: attachment of the viral hemagglutinin to the sialylated host cell receptors, endocytosis, M2 mediated uncoating, low pH-induced membrane fusion, and, finally, import of the viral ribonucleoprotein into the nucleus. We review the current functional and structural insights in the viral and cellular components of this entry process, and the diverse antiviral strategies that are being explored. This encompasses small molecule inhibitors as well as macromolecules such as therapeutic antibodies. There is optimism that at least some of these innovative concepts to block influenza virus entry will proceed from the proof of concept to a more advanced stage. Special attention is therefore given to the challenging issues of influenza virus (sub)type-dependent activity or potential drug resistance. PMID- 23801558 TI - Improving biotechnology communication. AB - Successful dialog between science and the public is vital for the development and introduction of new technologies. The National Academy of Science and Engineering in Germany has analysed experiences gained from controversies and communication strategies surrounding green genetic engineering and other fields of biotechnology, from a communications and social science viewpoint, as well as a historical perspective. From this, recommendations on how to communicate biotechnology in the future, with objectivity and balance, have been derived. PMID- 23801559 TI - Reopening the case for anti-basal ganglia antibodies (ABGAs): identification of dopamine-2 receptor antibodies associated with movement disorders. PMID- 23801560 TI - Progressive dystonia in Mohr-Tranebjaerg syndrome with cochlear implant and deep brain stimulation. PMID- 23801561 TI - Commentary. PMID- 23801562 TI - Dopamine dysregulation syndrome in Parkinson's disease patients on duodenal levodopa infusion. PMID- 23801563 TI - Chemical synthesis of hydrocarbon-stapled peptides for protein interaction research and therapeutic targeting. AB - The peptide alpha-helix represents one of nature's most featured protein shapes and is employed in a diversity of protein architectures, from the cytoskeletal infrastructure to the most intimate contact points between crucial signaling proteins. By installing an all-hydrocarbon crosslink into native sequences, the shape and biological activity of natural peptide alpha-helices can be recapitulated, yielding a chemical toolbox that can be used both to interrogate the protein interactome and to modulate interaction networks for potential therapeutic benefit. Here, current methodology for synthesizing stabilized alpha helices (SAH) corresponding to key protein interaction domains is described. A stepwise approach is taken for the production of crosslinking non-natural amino acids, incorporation of the residues into peptide templates, and application of ruthenium-catalyzed ring-closing metathesis to generate hydrocarbon-stapled peptides. Through facile derivatization and functionalization steps, SAHs can be tailored for a broad range of applications in biochemical, structural, proteomic, cellular, and in vivo studies. Curr. Protoc. Chem. Biol. 3:99-117 (c) 2011 by John Wiley & Sons, Inc. PMID- 23801564 TI - Triple-addition assay protocols for detecting and characterizing modulators of seven-transmembrane receptors. AB - The detection and characterization of seven-transmembrane-receptor modulators (orthosteric binding site agonists, antagonists, and more recently allosteric modulators) is an area of intense interest for both drug discovery and basic research. Traditionally, assays used to detect and characterize these different modes of modulation have been executed as separate, discrete protocols focused on a particular mode of action (e.g., agonism). In recent years, investigators have begun to combine aspects of these separate protocols to produce methods that detect multiple modes of modulation simultaneously. The power of such approaches is revealed not only in conservation of time and resources, but more importantly in a superior ability to discover and characterize novel modulators of the targets of interest. The protocols in this article describe a general procedure for developing, validating, and utilizing triple-addition assays to enable the simultaneous detection and characterization of multiple modes of seven transmembrane-receptor modulation. Curr. Protoc. Chem. Biol. 3:119-140 (c) 2011 by John Wiley & Sons, Inc. PMID- 23801565 TI - Compound management: guidelines for compound storage, provision, and quality control. AB - The scientific discipline of compound management has developed significantly over the last decade, as witnessed by the large number of conferences dedicated to this topic. The key elements of compound management include (1) the management, storage, and processing of both solids and liquids; (2) compound delivery and interface with key customers; (3) performance of instruments and automation that support these operations; (4) analytical techniques used for quality assurance; and (5) sample informatics, including registration, routing, and compound quality data. This article incorporates guidelines, best practices, and experimental protocols for these key aspects of compound management. Curr. Protoc. Chem. Biol. 3:141-152 (c) 2011 by John Wiley & Sons, Inc. PMID- 23801567 TI - From bedside back to bench? A commentary on: "The future of cognitive behavioral therapy for insomnia: what important research remains to be done?". AB - In this month's issue of the Journal of Clinical Psychology, Vitiello and colleagues articulate an important research agenda that will help advance cognitive-behavioral therapy for insomnia (CBT-I) research and clinical practice. In addition to this ambitious agenda, we also propose that pursuing a parallel research program, focusing on treatment mechanisms and process will help move the CBT-I field forward and optimize therapeutic dissemination and uptake. PMID- 23801566 TI - Sex differences in MU-opioid receptor expression in trigeminal ganglia under a myositis condition in rats. AB - BACKGROUND: Peripheral opioid receptor expression is up-regulated under inflammatory conditions, which leads to the increased efficacy of peripherally administered opioids. Sex differences in the effects of inflammation, cytokines and gonadal hormones on MU-opioid receptor (MOR) expression in trigeminal ganglia (TG) are not well understood. METHODS: MOR mRNA and protein levels in TG from male and female Sprague Dawley rats following complete Freund's adjuvant (CFA) induced muscle inflammation were assessed. Cytokine-induced changes in MOR mRNA expression from TG cultures prepared from intact and gonadectomized male and female, and gonadectomized male rats with testosterone replacement were examined. Behavioural experiments were then performed to examine the efficacy of a peripherally administered MOR agonist in male, female and gonadectomized male rats under a myositis condition. RESULTS: CFA and cytokine treatments induced significant up-regulation of MOR expression in TG from male, but not from female, rats. The cytokine-induced up-regulation of MOR mRNA expression was prevented in TG from orchidectomized (GDX) male rats, which was restored with testosterone replacement. Peripherally administered DAMGO, a specific MOR agonist, significantly attenuated CFA-induced masseter mechanical hypersensitivity only in intact male rats. CONCLUSIONS: Collectively, these data indicate that testosterone plays a key role in the regulation of MOR in TG under inflammatory conditions, and that sex differences in the anti-hyperalgesic effects of peripherally administered opioids are, in part, mediated by peripheral opioid receptor expression levels. PMID- 23801568 TI - Diagnosis and management of thrombotic microangiopathy: the role of registries. PMID- 23801569 TI - High-resolution imaging of magnetisation transfer and nuclear Overhauser effect in the human visual cortex at 7 T. AB - The aim of this study was to optimise a pulse sequence for high-resolution imaging sensitive to the effects of conventional macromolecular magnetisation transfer (MT(m)) and nuclear Overhauser enhancement (NOE), and to use it to investigate variations in these parameters across the cerebral cortex. A high spatial-resolution magnetisation transfer-prepared turbo field echo (MT-TFE) sequence was designed to have high sensitivity to MT(m) and NOE effects, whilst being robust to B0 and B1 inhomogeneities, and producing a good point spread function across the cortex. This was achieved by optimising the saturation and imaging components of the sequence using simulations based on the Bloch equations, including exchange and an image simulator. This was used to study variations in these parameters across the cortex. Using the sequence designed to be sensitive to NOE and MT(m), a variation in signals corresponding to a variation in MT(m) and NOE across the cortex, consistent with a reduction in myelination from the white matter surface to the pial surface of the cortex, was observed. In regions in which the stria was visible on T2*-weighted images, it could also be detected in signals sensitive to MT(m) and NOE. There was greater variation in signals sensitive to NOE, suggesting that the NOE signal is more sensitive to myelination. A sequence has been designed to image variations in MT(m) and NOE at high spatial resolution and has been used to investigate variations in contrast in these parameters across the cortex. PMID- 23801570 TI - Microbial production of the aromatic building-blocks (S)-styrene oxide and (R) 1,2-phenylethanediol from renewable resources. AB - (S)-Styrene oxide and (R)-1,2-phenylethanediol are chiral aromatic molecular building blocks used commonly as precursors to pharmaceuticals and other specialty chemicals. Two pathways have been engineered in Escherichia coli for their individual biosynthesis directly from glucose. The novel pathways each constitute extensions of the previously engineered styrene pathway, developed by co-expressing either styrene monooxygenase (SMO) or styrene dioxygenase (SDO) to convert styrene to (S)-styrene oxide and (R)-1,2-phenylethanediol, respectively. StyAB from Pseudomonas putida S12 was determined to be the most effective SMO. SDO activity was achieved using NahAaAbAcAd of Pseudomonas sp. NCIB 9816-4, a naphthalene dioxygenase with known broad substrate specificity. Production of phenylalanine, the precursor to both pathways, was systematically enhanced through a number of mutations, most notably via deletion of tyrA and over expression of tktA. As a result, (R)-1,2-phenylethanediol reached titers as high as 1.23 g/L, and at 1.32 g/L (S)-styrene oxide titers already approach their toxicity limit. As with other aromatics, product toxicity was strongly correlated with a model of membrane accumulation and disruption. This study additionally demonstrates that greater flux through the styrene pathway can be achieved if its toxicity is addressed, as achieved in this case by reacting styrene to less toxic products. PMID- 23801571 TI - Utility of the Dimensions of Anger Reactions-5 (DAR-5) scale as a brief anger measure. AB - BACKGROUND: Anger is a common emotional sequel in the aftermath of traumatic experience. As it is associated with significant distress and influences recovery, anger requires routine screening and assessment. Most validated measures of anger are too lengthy for inclusion in self-report batteries or as screening tools. This study examines the psychometric properties of a shortened 5 item version of the Dimensions of Anger Reactions (DAR), an existing screening tool. METHODS: Responses to the DAR-5 were analysed from a sample of 486 college students with and without a history of trauma exposure. RESULTS: The DAR-5 demonstrated strong internal reliability and concurrent validity with the State Trait Anger Expression Inventory-2 (STAXI-2). Confirmatory factor analysis supported a single factor model of the DAR-5 for the trauma-exposed and nontrauma subsamples. A screening cut-off point of 12 on the DAR-5 successfully differentiated high and low scorers on STAXI-2 Trait Anger and PCL posttraumatic stress scores. Further discriminant validity was found with depression symptom scores. CONCLUSIONS: The results support use of the DAR-5 for screening for anger when a short scale is required. PMID- 23801572 TI - The morphology of the cephalic lobes and anterior pectoral fins in six species of batoids. AB - Many benthic batoids utilize their pectoral fins for both undulatory locomotion and feeding. Certain derived, pelagic species of batoids possess cephalic lobes, which evolved from the anterior pectoral fins. These species utilize the pectoral fins for oscillatory locomotion while the cephalic lobes are used for feeding. The goal of this article was to compare the morphology of the cephalic lobes and anterior pectoral fins in species that possess and lack cephalic lobes. The skeletal elements (radials) of the cephalic lobes more closely resembled the radials in the pectoral fin of undulatory species. Second moment of area (I), calculated from cephalic lobe radial cross sections, and the number of joints revealed greater flexibility and resistance to bending in multiple directions as compared to pectoral fin radials of oscillatory species. The cephalic lobe musculature was more complex than the anterior pectoral fin musculature, with an additional muscle on the dorsal side, with fiber angles running obliquely to the radials. In Rhinoptera bonasus, a muscle presumably used to help elevate the cephalic lobes is described. Electrosensory pores were found on the cephalic lobes (except Mobula japonica) and anterior pectoral fins of undulatory swimmers, but absent from the anterior pectoral fins of oscillatory swimmers. Pore distributions were fairly uniform except in R. bonasus, which had higher pore numbers at the edges of the cephalic lobes. Overall, the cephalic lobes are unique in their anatomy but are more similar to the anterior pectoral fins of undulatory swimmers, having more flexibility and maneuverability compared to pectoral fins of oscillatory swimmers. The maneuverable cephalic lobes taking on the role of feeding may have allowed the switch to oscillatory locomotion and hence, a more pelagic lifestyle. PMID- 23801573 TI - Movement disorders in GLUT1 deficiency syndrome respond to the modified Atkins diet. AB - BACKGROUND: Movement disorders are a prominent feature of glucose transporter-1 (GLUT1) deficiency syndrome (GLUT1DS). First-choice treatment is a ketogenic diet, but compliance is poor. We have investigated the effect of the modified Atkins diet as an alternative treatment for movement disorders in GLUT1DS. METHODS: Four patients with GLUT1DS ages 15 to 30 years who had movement disorders as the most prominent feature were prospectively evaluated after initiation of the modified Atkins diet. Movement disorders included dystonia, ataxia, myoclonus, and spasticity, either continuous or paroxysmal, triggered by action or exercise. Duration of treatment ranged from 3 months to 16 months. RESULTS: All patients reached mild to moderate ketosis and experienced remarkable improvement in the frequency and severity of paroxysmal movement disorders. Cognitive function also improved subjectively. CONCLUSIONS: The modified Atkins diet is an effective and feasible alternative to the ketogenic diet for the treatment of GLUT1DS-related paroxysmal movement disorders in adolescence and adulthood. PMID- 23801574 TI - HLA class II genotyping of African American type 1 diabetic patients reveals associations unique to African haplotypes. AB - HLA genotyping was performed in African American type 1 diabetic patients (n = 772) and controls (n = 1,641) in the largest study of African Americans and type 1 diabetes reported to date. Cases were from Children's Hospital and Research Center Oakland and from existing collections (Type 1 Diabetes Genetics Consortium [T1DGC], Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications [DCCT/EDIC], and Genetics of Kidneys in Diabetes [GoKinD]). Controls were from the T1DGC and from newborn bloodspot cards. The diversity of HLA DRB1-DQA1-DQB1 haplotypes and genotypes is far greater than that found in Europeans and European Americans. Association analyses replicated many type 1 diabetes risk effects of European-derived haplotypes but also revealed novel effects for African-derived haplotypes. Notably, the African-specific "DR3" haplotype DRB1*03:02-DQA1*04:01-DQB1*04:02 is protective for type 1 diabetes, in contrast to the common and highly-susceptible DR3 DRB1*03:01-DQA1*05:01 DQB1*02:01. Both DRB1*07:01 and DRB1*13:03 haplotypes are predisposing when they include DQA1*03:01-DQB1*02:01g but are protective with DQA1*02:01-DQB1*02:01g. The heterozygous DR4/DR9 genotype, containing the African-derived "DR9" haplotype DRB1*09:01-DQA1*03:01-DQB1*02:01g, exhibits extremely high risk (odds ratio = 30.88), approaching that for DR3/DR4 in European populations. Disease risk assessment for African Americans differs greatly from risk assessment in European populations. This has profound implications on risk screening programs and underscores the need for high-resolution genotyping of multiple populations for the rational design of screening programs with tests that will fairly represent the population being screened. PMID- 23801575 TI - Impaired tethering and fusion of GLUT4 vesicles in insulin-resistant human adipose cells. AB - Systemic glucose homeostasis is profoundly influenced by adipose cell function. Here we investigated GLUT4 dynamics in living adipose cells from human subjects with varying BMI and insulin sensitivity index (Si) values. Cells were transfected with hemagglutinin (HA)-GLUT4-green fluorescent protein (GFP)/mCherry (red fluorescence), and were imaged live using total internal reflection fluorescence and confocal microscopy. HA-GLUT4-GFP redistribution to the plasma membrane (PM) was quantified by surface-exposed HA epitope. In the basal state, GLUT4 storage vesicle (GSV) trafficking to and fusion with the PM were invariant with donor subject Si, as was total cell-surface GLUT4. In cells from insulin sensitive subjects, insulin augmented GSV tethering and fusion approximately threefold, resulting in a corresponding increase in total PM GLUT4. However, with decreasing Si, these effects diminished progressively. All insulin-induced effects on GLUT4 redistribution and trafficking correlated strongly with Si and only weakly with BMI. Thus, while basal GLUT4 dynamics and total cell-surface GLUT4 are intact in human adipose cells, independent of donor Si, cells from insulin-resistant donors show markedly impaired GSV tethering and fusion responses to insulin, even after overnight culture. This altered insulin responsiveness is consistent with the hypothesis that adipose cellular dysfunction is a primary contributor to systemic metabolic dysfunction. PMID- 23801576 TI - Relaxin treatment reverses insulin resistance in mice fed a high-fat diet. AB - The endogenous hormone relaxin increases vascular reactivity and angiogenesis. We demonstrate that acute relaxin infusion in lean C57BL/6J mice enhances skeletal muscle perfusion and augments muscle glucose uptake during a hyperinsulinemic euglycemic clamp. However, an acute effect was absent in mice fed a high-fat (HF) diet for 13 weeks. In contrast, mice fed an HF diet for 13 weeks and continuously treated with relaxin for the final 3 weeks of the diet exhibited decreased fasting blood glucose. Insulin-stimulated whole-body glucose disappearance and percent suppression of hepatic glucose production are corrected by chronic relaxin. The increase in peripheral glucose utilization is a result of augmented in vivo skeletal muscle glucose uptake. Relaxin intervention improves endothelial dependent vascular reactivity and induces a two-fold proliferation in skeletal muscle capillarity. The metabolic effects of the treatment are not attributed to changes in myocellular insulin signaling. Relaxin intervention reverses the accumulation of collagen III in the liver and collagen III and collagen IV in the heart; this is induced by HF feeding. These studies show the potential of relaxin in the treatment of diet-induced insulin resistance and vascular dysfunction. Relaxin provides a novel therapeutic approach targeting the extramyocellular barriers to insulin action, which are critical to the pathogenesis of insulin resistance. PMID- 23801577 TI - Glucokinase activation ameliorates ER stress-induced apoptosis in pancreatic beta cells. AB - The derangement of endoplasmic reticulum (ER) homeostasis triggers beta-cell apoptosis, leading to diabetes. Glucokinase upregulates insulin receptor substrate 2 (IRS-2) expression in beta-cells, but the role of glucokinase and IRS 2 in ER stress has been unclear. In this study, we investigated the impact of glucokinase activation by glucokinase activator (GKA) on ER stress in beta-cells. GKA administration improved beta-cell apoptosis in Akita mice, a model of ER stress-mediated diabetes. GKA increased the expression of IRS-2 in beta-cells, even under ER stress. Both glucokinase-deficient Akita mice and IRS-2-deficient Akita mice exhibited an increase in beta-cell apoptosis, compared with Akita mice. beta-cell-specific IRS-2-overexpressing (betaIRS-2-Tg) Akita mice showed less beta-cell apoptosis than Akita mice. IRS-2-deficient islets were vulnerable, but betaIRS-2-Tg islets were resistant to ER stress-induced apoptosis. Meanwhile, GKA regulated the expressions of C/EBP homologous protein (CHOP) and other ER stress-related genes in an IRS-2-independent fashion in islets. GKA suppressed the expressions of CHOP and Bcl2-associated X protein (Bax) and protected against beta-cell apoptosis under ER stress in an ERK1/2-dependent, IRS-2-independent manner. Taken together, GKA ameliorated ER stress-mediated apoptosis by harmonizing IRS-2 upregulation and the IRS-2-independent control of apoptosis in beta-cells. PMID- 23801578 TI - Impairments in site-specific AS160 phosphorylation and effects of exercise training. AB - The purpose of this study was to determine if site-specific phosphorylation at the level of Akt substrate of 160 kDa (AS160) is altered in skeletal muscle from sedentary humans across a wide range of the adult life span (18-84 years of age) and if endurance- and/or strength-oriented exercise training could rescue decrements in insulin action and skeletal muscle AS160 phosphorylation. A euglycemic-hyperinsulinemic clamp and skeletal muscle biopsies were performed in 73 individuals encompassing a wide age range (18-84 years of age), and insulin stimulated AS160 phosphorylation was determined. Decrements in whole-body insulin action were associated with impairments in insulin-induced phosphorylation of skeletal muscle AS160 on sites Ser-588, Thr-642, Ser-666, and phospho-Akt substrate, but not Ser-318 or Ser-751. Twelve weeks of endurance- or strength oriented exercise training increased whole-body insulin action and reversed impairments in AS160 phosphorylation evident in insulin-resistant aged individuals. These findings suggest that a dampening of insulin-induced phosphorylation of AS160 on specific sites in skeletal muscle contributes to the insulin resistance evident in a sedentary aging population and that exercise training is an effective intervention for treating these impairments. PMID- 23801579 TI - Teplizumab preserves C-peptide in recent-onset type 1 diabetes: two-year results from the randomized, placebo-controlled Protege trial. AB - Protege was a phase 3, randomized, double-blind, parallel, placebo-controlled 2 year study of three intravenous teplizumab dosing regimens, administered daily for 14 days at baseline and again after 26 weeks, in new-onset type 1 diabetes. We sought to determine efficacy and safety of teplizumab immunotherapy at 2 years and to identify characteristics associated with therapeutic response. Of 516 randomized patients, 513 were treated, and 462 completed 2 years of follow-up. Teplizumab (14-day full-dose) reduced the loss of C-peptide mean area under the curve (AUC), a prespecified secondary end point, at 2 years versus placebo. In analyses of prespecified and post hoc subsets at entry, U.S. residents, patients with C-peptide mean AUC >0.2 nmol/L, those randomized <=6 weeks after diagnosis, HbA1c <7.5% (58 mmol/mol), insulin use <0.4 units/kg/day, and 8-17 years of age each had greater teplizumab-associated C-peptide preservation than their counterparts. Exogenous insulin needs tended to be reduced versus placebo. Antidrug antibodies developed in some patients, without apparent change in drug efficacy. No new safety or tolerability issues were observed during year 2. In summary, anti-CD3 therapy reduced C-peptide loss 2 years after diagnosis using a tolerable dose. PMID- 23801580 TI - Ebselen treatment prevents islet apoptosis, maintains intranuclear Pdx-1 and MafA levels, and preserves beta-cell mass and function in ZDF rats. AB - We reported earlier that beta-cell-specific overexpression of glutathione peroxidase (GPx)-1 significantly ameliorated hyperglycemia in diabetic db/db mice and prevented glucotoxicity-induced deterioration of beta-cell mass and function. We have now ascertained whether early treatment of Zucker diabetic fatty (ZDF) rats with ebselen, an oral GPx mimetic, will prevent beta-cell deterioration. No other antihyperglycemic treatment was given. Ebselen ameliorated fasting hyperglycemia, sustained nonfasting insulin levels, lowered nonfasting glucose levels, and lowered HbA1c levels with no effects on body weight. Ebselen doubled beta-cell mass, prevented apoptosis, prevented expression of oxidative stress markers, and enhanced intranuclear localization of pancreatic and duodenal homeobox (Pdx)-1 and v-maf musculoaponeurotic fibrosarcoma oncogene family, protein A (MafA), two critical insulin transcription factors. Minimal beta-cell replication was observed in both groups. These findings indicate that prevention of oxidative stress is the mechanism whereby ebselen prevents apoptosis and preserves intranuclear Pdx-1 and MafA, which, in turn, is a likely explanation for the beneficial effects of ebselen on beta-cell mass and function. Since ebselen is an oral antioxidant currently used in clinical trials, it is a novel therapeutic candidate to ameliorate fasting hyperglycemia and further deterioration of beta-cell mass and function in humans undergoing the onset of type 2 diabetes. PMID- 23801583 TI - Agenesis of the corpus callosum with interhemispheric cyst, associated with aberrant cortical sulci and without underlying cortical dysplasia. PMID- 23801581 TI - Remodeling the integration of lipid metabolism between liver and adipose tissue by dietary methionine restriction in rats. AB - Dietary methionine restriction (MR) produces an integrated series of biochemical and physiological responses that improve biomarkers of metabolic health, limit fat accretion, and enhance insulin sensitivity. Using transcriptional profiling to guide tissue-specific evaluations of molecular responses to MR, we report that liver and adipose tissue are the primary targets of a transcriptional program that remodeled lipid metabolism in each tissue. The MR diet produced a coordinated downregulation of lipogenic genes in the liver, resulting in a corresponding reduction in the capacity of the liver to synthesize and export lipid. In contrast, the transcriptional response in white adipose tissue (WAT) involved a depot-specific induction of lipogenic and oxidative genes and a commensurate increase in capacity to synthesize and oxidize fatty acids. These responses were accompanied by a significant change in adipocyte morphology, with the MR diet reducing cell size and increasing mitochondrial density across all depots. The coordinated transcriptional remodeling of lipid metabolism between liver and WAT by dietary MR produced an overall reduction in circulating and tissue lipids and provides a potential mechanism for the increase in metabolic flexibility and enhanced insulin sensitivity produced by the diet. PMID- 23801584 TI - Cartilage, bone, and intermandibular connective tissue in the Australian lungfish, Neoceratodus forsteri (Osteichthyes: Dipnoi). AB - The connective tissue that links the bones of the mandible in the Australian lungfish, Neoceratodus forsteri, has been described as an intermandibular cartilage, and as such has been considered important for phylogenetic analyses among lower vertebrates. However, light and electron microscopy of developing lungfish jaws demonstrates that the intermandibular tissue, like the connective tissue that links the bones of the upper jaw, contains fibroblasts and numerous bundles of collagen fibrils, extending from the trabeculae of the bones supporting the tooth plates. It differs significantly in structure and in staining reactions from the cartilage and the bone found in this species. In common with the cladistian Polypterus and with actinopterygians and some amphibians, lungfish have no intermandibular cartilage. The connective tissue linking the mandibular bones has no phylogenetic significance for systematic grouping of lungfish, as it is present in a range of different groups among lower vertebrates. PMID- 23801585 TI - Transdermal rotigotine in early stage Parkinson's disease: a randomized, double blind, placebo-controlled trial. AB - BACKGROUND: We conducted a randomized, double-blind, placebo-controlled trial to determine the safety and efficacy of transdermal rotigotine at doses up to 16 mg/24 hours in patients with early stage Parkinson's disease (PD) in Japan. METHODS: Patients received once-daily rotigotine 2 to 16 mg/24 hours (mean dose, 12.8 mg/24 hours; n = 82) or placebo (n = 90) for 12 weeks. The primary endpoint was the change in Unified Parkinson's Disease Rating Scale (UPDRS) part II (activities of daily living) and part III (motor function) scores from baseline to the end of treatment. RESULTS: The mean (+/- standard deviation) changes in UPDRS part II and III scores were -8.4 +/- 9.7 in the rotigotine group and -4.1 +/- 8.2 in the placebo group and were significantly different (P = 0.002). More patients in the rotigotine group than in the placebo group had a >= 20% score reduction. No serious drug-related adverse events were reported. CONCLUSIONS: Rotigotine at doses up to 16 mg/24 hours was well tolerated and improved function in patients with early stage PD. PMID- 23801586 TI - Engineering a recyclable elastin-like polypeptide capturing scaffold for non chromatographic protein purification. AB - Previously, we reported a non-chromatographic protein purification method exploiting the highly specific interaction between the dockerin and cohesin domains from Clostridium thermocellum and the reversible aggregation property of elastin-like polypeptide (ELP) to provide fast and cost-effective protein purification. However, the bound dockerin-intein tag cannot be completely dissociated from the ELP-cohesin capturing scaffold due to the high binding affinity, resulting in a single-use approach. In order to further reduce the purification cost by recycling the ELP capturing scaffold, a truncated dockerin domain with the calcium-coordinating function partially impaired was employed. We demonstrated that the truncated dockerin domain was sufficient to function as an effective affinity tag, and the target protein was purified directly from cell extracts in a single binding step followed by intein cleavage. The efficient EDTA mediated dissociation of the bound dockerin-intein tag from the ELP-cohesin capturing scaffold was realized, and the regenerated ELP capturing scaffold was reused in another purification cycle without any decrease in the purification efficiency. This recyclable non-chromatographic based affinity method provides an attractive approach for efficient and cost-effective protein purification. PMID- 23801587 TI - Zirconia-based aerogels via hydrolysis of salts and alkoxides: the influence of the synthesis procedures on the properties of the aerogels. AB - This contribution aims at evaluating different synthesis procedures leading to zirconia-based aerogels. A series of undoped and yttrium-doped zirconia aerogels have been prepared via hydrolysis and condensation reaction of different alkoxy- and different inorganic salt-based precursors followed by supercritical drying. Well-established but deleterious zirconium n-propoxide (TPOZ) or zirconium n butoxide (TBOZ) were used as metal precursors in combination with acids like nitric acid and acetic acid as auxiliary agent for the generation of non-yttrium stabilized zirconia aerogels. Yttrium-stabilized zirconia aerogels as well as pure zirconia aerogels were obtained by the salt route starting from ZrCl4 and crosslinking agents like propylene oxide or acetylacetone. The characteristics of the products were analyzed by nitrogen adsorption measurements, electron microscopy, and X-ray scattering. It turned out that with respect to all relevant properties of the aerogels as well as the practicability of the synthesis procedures, approaches based on inexpensive non-toxic salt precursors are the methods of choice. The salt-based approaches allow not only for low-cost, easy-to handle synthesis procedures with realizable gelation times of less than 60 seconds, but also delivered the products with the highest surface area (449 m(2) g(-1) for ZrCl4) within this series of syntheses. PMID- 23801588 TI - Collagen plug sealing of iatrogenic fetal membrane defects after fetoscopic surgery for congenital diaphragmatic hernia. AB - OBJECTIVES: To investigate the efficacy of collagen plugs at reducing the risk of preterm premature rupture of membranes (PPROM) after fetoscopic surgery for congenital diaphragmatic hernia (CDH). METHODS: This was a single-center cohort study on all consecutive cases undergoing fetoscopic endoluminal tracheal occlusion (FETO) for severe or moderate CDH, between April 2002 and May 2011 (n = 141). Cases either received a collagen plug for sealing the fetal membrane defect after FETO or did not, depending on the operating surgeon. The principal outcome measure was the time from fetal surgery to PPROM, further referred to as 'latency'. A multivariable Cox regression model was used to investigate the association between collagen plug and latency while adjusting for risk factors for PPROM. RESULTS: Of the 141 cases, 54 (38%) received a collagen plug and 87 (62%) did not. Sixty cases experienced PPROM, 26 among cases with and 34 among cases without a plug (48 vs 39%). The hazard ratio of plug use was 1.29 (95% CI, 0.76-2.19), which does not exclude a potentially increased risk for PPROM when a collagen plug is used. For cases with a plug, 24% had PPROM before balloon removal and 24% had PPROM after elective balloon removal. For cases without a plug, these rates were 30 and 9%, respectively. Perinatal outcomes were similar in both groups. CONCLUSIONS: No evidence was found that collagen plugs reduce the risk of PPROM after FETO for CDH. PMID- 23801589 TI - Trajectories of change in anxiety severity and impairment during and after treatment with evidence-based treatment for multiple anxiety disorders in primary care. AB - BACKGROUND: Coordinated Anxiety Learning and Management (CALM) is a model for delivering evidence-based treatment for anxiety disorders in primary care. Compared to usual care, CALM produced greater improvement in anxiety symptoms. However, mean estimates can obscure heterogeneity in treatment response. This study aimed to identify (1) clusters of participants with similar patterns of change in anxiety severity and impairment (trajectory groups); and (2) characteristics that predict trajectory group membership. METHODS: The CALM randomized controlled effectiveness trial was conducted in 17 primary care clinics in four US cities in 2006-2009. 1,004 English- or Spanish-speaking patients age 18-75 with panic, generalized anxiety, social anxiety, and/or posttraumatic stress disorder participated. The Overall Anxiety Severity and Impairment Scale was administered repeatedly to 482 participants randomized to CALM treatment. Group-based trajectory modeling was applied to identify trajectory groups and multinomial logit to predict trajectory group membership. RESULTS: Two predicted trajectories, representing about two-thirds of participants, were below the cut-off for clinically significant anxiety a couple of months after treatment initiation. The predicted trajectory for the majority of remaining participants was below the cut-off by 9 months. A small group of participants did not show consistent improvement. Being sicker at baseline, not working, and reporting less social support were associated with less favorable trajectories. CONCLUSIONS: There is heterogeneity in patient response to anxiety treatment. Adverse circumstances appear to hamper treatment response. To what extent anxiety symptoms improve insufficiently because adverse patient circumstances contribute to suboptimal treatment delivery, suboptimal treatment adherence, or suboptimal treatment response requires further investigation. PMID- 23801590 TI - Mild cognitive impairment in patients with Parkinson's disease is associated with increased cortical degeneration. AB - Mild cognitive impairment (MCI) can occur early in the course of Parkinson's disease (PD), and its presence increases the risk of developing dementia. Determining the cortical changes associated with MCI in PD, thus, may be useful in predicting the future development of dementia. To address this objective, 37 patients with PD, divided into 2 groups according to the presence or absence MCI (18 with and 19 without) and 16 matched controls, underwent anatomic magnetic resonance imaging. Corticometry analyses were performed to measure the changes in cortical thickness and surface area as well as their correlation with disease duration. Compared with healthy controls, the PD-MCI group exhibited increased atrophy and changes of local surface area in the bilateral occipital, left temporal, and frontal cortices; whereas the PD non-MCI group exhibited only unilateral thinning and decreased surface area in the occipital lobe and in the frontal cortex. In addition, a comparison between the PD-MCI and PD non-MCI groups revealed increased local surface area in the occipital lobe, temporal lobe, and postcentral gyrus for the cognitively impaired patients. It is noteworthy that, in the PD-MCI group, cortical thickness had a significant negative correlation with disease duration in the precentral, supramarginal, occipital, and superior temporal cortices; whereas, in the PD non-MCI group, such a correlation was absent. The findings from this study reveal that, at the same stage of PD evolution, the presence of MCI is associated with a higher level of cortical changes, suggesting that cortical degeneration is increased in patients with PD because of the presence of MCI. PMID- 23801591 TI - Mandibular and hyoid muscles of Galeomorph sharks (Chondrichthyes: Elasmobranchii), with remarks on their phylogenetic intrarelationships. AB - The superorder Galeomorph comprises the orders Heterodontiformes, Orectolobiformes, Lamniformes, and Carcharhiniformes. Recent morphological and molecular support that it is a monophyletic taxon. The phyletic relationship within the Galeomorphi are also well resolved. However, only few morphological characters of the mandibular and hyoid muscles have been employed, and a detailed description of these muscles and their variations may contribute new interpretations of homology and to the discussion of different hypothesis of intrarelationships. This paper provides a detailed description of mandibular and hyoid arch muscles in galeomorph sharks, within a comparative elasmobranch framework, with the objective to discuss putative homologies that may elucidate our understanding of galeomorph evolution. Twenty-eight galeomorph species were dissected, described, illustrated and compared with other elasmobranchs and with data from the literature. The Galeomorphi are supported as monophyletic by presenting the m. levator labii superioris attached directly to the neurocranium, different from the attachment through a tendon in basal squalomorphs. Heterodontiformes and Orectolobiformes share particular variations in the position and insertion of the m. levator labii superioris and the presence of a well-defined m. levator hyomandibulae. Lamniformes and Carcharhiniformes show similar patterns in the position and attachment of the m. levator labii superioris, subdivision of the m. adductor mandibulae, and the presence of an almost indivisible m. levator hyomandibulae and m. constrictor hyoideus dorsalis, similar to the condition, albeit independently, in basal squalomorphs. No specific mandibular or hyoid arch muscle character was found to support the clade composed of Orectolobiformes, Lamniformes, and Carcharhiniformes, as advocated by recent phylogenetic analyses. PMID- 23801592 TI - Overcoming bottlenecks of enzymatic biofuel cell cathodes: crude fungal culture supernatant can help to extend lifetime and reduce cost. AB - Enzymatic biofuel cells (BFCs) show great potential for the direct conversion of biochemically stored energy from renewable biomass resources into electricity. However, enzyme purification is time-consuming and expensive. Furthermore, the long-term use of enzymatic BFCs is hindered by enzyme degradation, which limits their lifetime to only a few weeks. We show, for the first time, that crude culture supernatant from enzyme-secreting microorganisms (Trametes versicolor) can be used without further treatment to supply the enzyme laccase to the cathode of a mediatorless BFC. Polarization curves show that there is no significant difference in the cathode performance when using crude supernatant that contains laccase compared to purified laccase in culture medium or buffer solution. Furthermore, we demonstrate that the oxygen reduction activity of this enzymatic cathode can be sustained over a period of at least 120 days by periodic resupply of crude culture supernatant. This is more than five times longer than control cathodes without the resupply of culture supernatant. During the operation period of 120 days, no progressive loss of potential is observed, which suggests that significantly longer lifetimes than shown in this work may be possible. Our results demonstrate the possibility to establish simple, cost efficient, and mediatorless enzymatic BFC cathodes that do not require expensive enzyme purification procedures. Furthermore, they show the feasibility of an enzymatic BFC with an extended lifetime, in which self-replicating microorganisms provide the electrode with catalytically active enzymes in a continuous or periodic manner. PMID- 23801593 TI - Use of spatiotemporal image correlation at 11-14 weeks' gestation. AB - OBJECTIVE: To assess prospectively the use of four-dimensional (4D) spatiotemporal image correlation (STIC) in the evaluation of the fetal heart at 11-14 weeks' gestation. METHODS: The study involved offline analysis of 4D-STIC volumes of the fetal heart acquired at 11-14 weeks' gestation in a population at high risk for congenital heart disease (CHD). Regression analysis was used to investigate the effect of gestational age, maternal body mass index, quality of the 4D-STIC volume, use of a transvaginal vs transabdominal probe and use of color Doppler ultrasonography on the ability to visualize separately different heart structures. The accuracy in diagnosing CHD based on early fetal echocardiography (EFE) using 4D-STIC vs conventional two-dimensional (2D) ultrasound was also evaluated. RESULTS: One hundred and thirty-nine fetuses with a total of 243 STIC volumes were included in this study. Regression analysis showed that the ability to visualize different heart structures was correlated with the quality of the acquired 4D-STIC volumes. Independently, the use of a transvaginal approach improved visualization of the four-chamber view, and the use of Doppler improved visualization of the outflow tracts, aortic arch and interventricular septum. Follow-up was available in 121 of the 139 fetuses, of which 27 had a confirmed CHD. A diagnosis based on EFE using 4D-STIC was possible in 130 (93.5%) of the 139 fetuses. Accuracy in diagnosing CHD using 4D-STIC was 88.7%, and the results of 45% of the cases were fully concordant with those of 2D ultrasound or the final follow-up diagnosis. EFE using 2D ultrasound was possible in all fetuses, and accuracy in diagnosing CHD was 94.2%. Five of the seven false positive or false-negative cases were minor CHD. CONCLUSIONS: In fetuses at 11-14 weeks' gestation, the heart can be evaluated offline using 4D-STIC in a large number of cases, and this evaluation is more successful the higher the quality of the acquired volume. 2D ultrasound remains superior to 4D-STIC at 11-14 weeks, unless volumes of good to high quality can be obtained. PMID- 23801594 TI - Role of sulfur dioxide in acute lung injury following limb ischemia/reperfusion in rats. AB - Sulfur dioxide (SO2) is naturally synthesized by glutamate-oxaloacetate transaminase (GOT) from L-cysteine in mammalian cells. We aim to investigate the role of SO2 in inflammation in acute lung injury (ALI) following limb ischemia/reperfusion (I/R). Male Wistar rats were subjected to limb I/R and were injected with saline, GOT inhibitor hydroxamate (HDX, 0.47 mmol/kg), or the SO2 donor Na2 SO3 /NaHSO3 (0.54 mmol/kg/0.18 mmol/kg). Compared with the sham operation, the plasma SO2 levels were significantly decreased by limb I/R treatment. In addition, SO2 concentration and GOT activity in the lung tissue were also reduced in ALI. The occurrence of ALI following limb I/R can be prevented by Na2 SO3 /NaHSO3 treatment, whereas it can be significantly aggravated by HDX. The plasma IL-1beta, IL-6, and IL-10 levels were consistent with myeloperoxidase activity and inflammation in lung tissue. In conclusion, our data suggest that downregulation of endogenous SO2 production might be involved in pathogenesis of ALI following limb I/R in rats. PMID- 23801595 TI - Impulse control disorders and related behaviors in Indian patients with Parkinson's disease. PMID- 23801597 TI - Getting into the mind of a worm--a personal view. PMID- 23801598 TI - Ceria-catalyzed conversion of carbon dioxide into dimethyl carbonate with 2 cyanopyridine. PMID- 23801599 TI - EPCAM germline and somatic rearrangements in Lynch syndrome: identification of a novel 3'EPCAM deletion. AB - 3'EPCAM (Epithelial Cell Adhesion Molecule) genomic rearrangements can be a cause of mismatch repair deficiency in rare Lynch syndrome families. 3'EPCAM deletions include the polyadenylation signal and might result in promoter hypermethylation of the centromeric MSH2 gene in cis. A somatic rearrangement in trans affecting MSH2 is responsible for the final mismatch repair deficiency in the corresponding tumors but the mechanisms are not well documented. In this report two germline 3'EPCAM deletions are described together with the corresponding somatic mutations in the patient's colorectal tumors. Mutation and breakpoint analysis resulted in the identification of one novel (c.556-531_*872del) and one known EPCAM deletion (c.859-689_*14697del). Both deletions resulted from Alu mediated homologous recombination causing aberrant EPCAM-MSH2 fusion transcripts. The colorectal tumors of the deletion carriers were MSI-high. Strong hypermethylation of the MSH2 promoter was measured. Analysis of somatic genomic rearrangements showed a 4 Mb deletion including the EPCAM, MSH2 and MSH6 genes in one tumor and copy neutral loss of heterozygosity in the EPCAM-MSH2 region in the other tumor. This indicates that hemi- and homozygous hypermethylation of the MSH2 promoter and hence complete silencing of MSH2 expression was responsible for the mismatch repair deficiency in both colorectal tumors. PMID- 23801596 TI - Transcriptional regulation of gene expression in C. elegans. AB - Protein coding gene sequences are converted to mRNA by the highly regulated process of transcription. The precise temporal and spatial control of transcription for many genes is an essential part of development in metazoans. Thus, understanding the molecular mechanisms underlying transcriptional control is essential to understanding cell fate determination during embryogenesis, post embryonic development, many environmental interactions, and disease-related processes. Studies of transcriptional regulation in C. elegans exploit its genomic simplicity and physical characteristics to define regulatory events with single-cell and minute-time-scale resolution. When combined with the genetics of the system, C. elegans offers a unique and powerful vantage point from which to study how chromatin-associated proteins and their modifications interact with transcription factors and their binding sites to yield precise control of gene expression through transcriptional regulation. PMID- 23801600 TI - Effectiveness of intermittent preventive treatment with sulfadoxine-pyrimethamine during pregnancy on maternal and birth outcomes in Machinga district, Malawi. AB - BACKGROUND: Malaria during pregnancy is associated with low birth weight and increased perinatal mortality, especially among primigravidae. Despite increasing prevalence of malarial parasite resistance to sulfadoxine-pyrimethamine (SP), SP continues to be recommended for intermittent preventive treatment in pregnancy (IPTp). METHODS: Women without human immunodeficiency virus infection were enrolled upon delivery. Data on the number of SP doses received during pregnancy were recorded. The primary outcome was placental infection demonstrated by histologic analysis. Secondary outcomes included malaria parasitemia (in peripheral, placental, cord blood specimens) at delivery and composite birth outcome (small for gestational age, preterm delivery, or low birth weight). RESULTS.: Of 703 women enrolled, 22% received <2 SP doses. Receipt of >= 2 SP doses had no impact on histologically confirmed placental infection. IPTp-SP was associated with a dose-dependent protective effect on composite birth outcome in primigravidae, with an adjusted prevalence ratio of 0.50 (95% confidence interval [CI], .30-.82), 0.30 (95% CI, .19-.48), and 0.18 (95% CI, .05-.61) for 1, 2, and >= 3 doses, respectively, compared with 0 doses. CONCLUSIONS: IPTp-SP did not reduce the frequency of placental infection but was associated with improved birth outcomes. Few women received no SP, so the true effect of IPTp-SP may be underestimated. Malawian pregnant women should continue to receive IPTp-SP, but alternative strategies and antimalarials for preventing malaria during pregnancy should be investigated. PMID- 23801601 TI - Anopheles gambiae circumsporozoite protein-binding protein facilitates plasmodium infection of mosquito salivary glands. AB - Malaria, a mosquito-borne disease caused by Plasmodium species, causes substantial morbidity and mortality throughout the world. Plasmodium sporozoites mature in oocysts formed in the mosquito gut wall and then invade the salivary glands, where they remain until transmitted to the vertebrate host during a mosquito bite. The Plasmodium circumsporozoite protein (CSP) binds to salivary glands and plays a role in the invasion of this organ by sporozoites. We identified an Anopheles salivary gland protein, named CSP-binding protein (CSPBP), that interacts with CSP. Downregulation of CSPBP in mosquito salivary glands inhibited invasion by Plasmodium organisms. In vivo bioassays showed that mosquitoes that were fed blood with CSPBP antibody displayed a 25% and 90% reduction in the parasite load in infected salivary glands 14 and 18 days after the blood meal, respectively. These results suggest that CSPBP is important for the infection of the mosquito salivary gland by Plasmodium organisms and that blocking CSPBP can interfere with the Plasmodium life cycle. PMID- 23801602 TI - Telaprevir activity in treatment-naive patients infected hepatitis C virus genotype 4: a randomized trial. AB - BACKGROUND: This partially blinded, randomized, phase 2a C210 study evaluated the antiviral activity of telaprevir-based regimens in treatment-naive patients with chronic hepatitis C virus (HCV) genotype 4 infection. METHODS: Twenty-four patients received telaprevir 750 mg every 8 hours for 15 days (T; n = 8), telaprevir in combination with pegylated interferon alfa-2a and ribavirin (Peg IFN/RBV) for 15 days (TPR; n = 8), or Peg-IFN/RBV plus placebo for 15 days (PR; n = 8), followed by Peg-IFN/RBV for 46 or 48 weeks. The primary objective was to assess the effect of telaprevir on HCV RNA levels. RESULTS: HCV RNA levels decreased slightly with T and PR; TPR produced substantial, rapid declines. On day 15, median reductions in the HCV RNA load from baseline were -0.77, -4.32, and -1.58 log10 IU/mL for T, TPR, and PR, respectively, and 0 patients in the T group, 1 in the TPR group, and 0 in the PR group had undetectable HCV RNA. Five of 8 patients who received telaprevir monotherapy had viral breakthrough within 15 days of treatment. Adverse event incidence was similar across treatments and comparable with the incidences from previous clinical trials. One patient (in T group) had a serious adverse event (considered unrelated to telaprevir) that led to treatment discontinuation. CONCLUSIONS: Telaprevir with Peg-IFN/RBV had greater activity than Peg-IFN/RBV treatment or telaprevir monotherapy against HCV genotype 4. Telaprevir was generally safe and well tolerated. Further investigation of telaprevir combination therapy in patients with HCV genotype 4 infection is warranted. PMID- 23801603 TI - Monocyte responses in the context of Q fever: from a static polarized model to a kinetic model of activation. AB - BACKGROUND: Q fever is caused by Coxiella burnetii, a bacterium that persists in M2-polarized macrophages. We wondered whether the concept of M1/M2 polarization is applicable to Q fever patients. METHODS: Monocytes from healthy controls were cultured with IFN-gamma and IL-4, agonists of M1 and M2 macrophages, respectively, and their gene expression was assessed using whole-genome microarrays. Selected biomarkers were assessed in blood from Q fever patients by real-time reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Monocytes exhibited early (6-hour) patterns of activation specific to IFN-gamma or IL-4 and a late (18-hour) pattern of common activation. Because these responses were not reducible to M1/M2 polarization, we selected biomarkers and tested their relevance in Q fever patients. The early genes NLRC5, RTP4, and RHOH, which were modulated in response to IFN-gamma, were up-regulated in patients with acute Q fever, and the expression levels of the late genes ALOX15, CLECSF1, CCL13, and CCL23 were specifically increased in patients with Q fever endocarditis. The RHOH and ALOX15 genes were associated with the activity of acute Q fever and Q fever endocarditis, respectively. CONCLUSIONS: Our results show that the kinetic model of monocyte activation enables a dynamic approach for the evaluation of Q fever patients. PMID- 23801604 TI - Staphylokinase promotes the establishment of Staphylococcus aureus skin infections while decreasing disease severity. AB - Skin infections are frequently caused by Staphylococcus aureus and can lead to a fatal sepsis. The microbial mechanisms controlling the initiation and progression from mild skin infection to a severe disseminated infection remain poorly understood. Using a combination of clinical data and in vitro and ex vivo assays, we show that staphylokinase, secreted by S. aureus, promoted the establishment of skin infections in humans and increased bacterial penetration through skin barriers by activating plasminogen. However, when infection was established, the interaction between staphylokinase and plasminogen did not promote systemic dissemination but induced the opening and draining of abscesses and decreased disease severity in neutropenic mice. Also, increased staphylokinase production was associated with noninvasive S. aureus infections in patients. Our results point out the dual roles of staphylokinase in S. aureus skin infections as promoting the establishment of infections while decreasing disease severity. PMID- 23801605 TI - Dysregulation of angiopoietin 1 and 2 in Escherichia coli O157:H7 infection and the hemolytic-uremic syndrome. AB - Escherichia coli O157:H7-associated hemolytic-uremic syndrome (HUS) is characterized by profound prothrombotic abnormalities. Endothelial dysfunction, manifested as dysregulation of angiopoietins 1 and 2 (Ang-1/2), could underlie HUS pathophysiology. We measured Ang-1/2 in 77 children with E. coli O157:H7 infection. Ang-1, Ang-2, and the Ang-2/Ang-1 ratio were significantly different in HUS vs the pre-HUS phase of illness or uncomplicated infection. Angiopoietin dysregulation preceded HUS and worsened as HUS developed. In vitro exposure of human microvascular endothelial cells to Shiga toxin recapitulated the in vivo observations. Angiopoietin regulation is profoundly affected before and during HUS, reflecting that subclinical endothelial dysfunction precedes overt microangiopathy. PMID- 23801607 TI - Eradication of Helicobacter pylori according to 23S ribosomal RNA point mutations associated with clarithromycin resistance. AB - BACKGROUND: Clarithromycin-resistant Helicobacter pylori is associated with point mutations in the 23S ribosomal RNA (rRNA) gene. METHODS: A total of 1232 patients participated and were divided into 2 control groups and 1 case group. Patients in the APC control group, which consisted of 308 randomly assigned participants, were treated with standard triple therapy, consisting of amoxicillin, rabeprazole, and clarithromycin; 308 participants in the APM control group were treated with amoxicillin, rabeprazole, and metronidazole. For the 616 participants in the case group, a test for point mutations in the 23S rRNA gene of H. pylori was conducted. A total of 218 individuals in the case group received a new tailored therapy regimen, in which amoxicillin, rabeprazole, and clarithromycin were given in the absence of a mutation, whereas clarithromycin was replaced by metronidazole if the mutation was detected. RESULTS: The rate of eradication of H. pylori in the tailored group was 91.2% (176/193), which was significantly higher than that in the APC (75.9% [214/282]; P < .001) and APM (79.1% [219/277]; P < .001) control groups. CONCLUSION: The rate of H. pylori eradication among patients who received tailored therapy on the basis of detection of a clarithromycin resistance mutation by polymerase chain reaction was much higher than the rate among patients who received a standard triple therapy regimen. CLINICAL TRIALS REGISTRATION: NCT0145303. PMID- 23801608 TI - Occupational exposure to hepatitis C virus: early T-cell responses in the absence of seroconversion in a longitudinal cohort study. AB - BACKGROUND: T-cell responses have been described in seronegative patients who test negative for hepatitis C virus (HCV) RNA despite frequent HCV exposure. However, the cross-sectional design of those studies did not clarify whether T cells were indeed induced by low-level HCV exposure without seroconversion or whether they resulted from regular acute infection with subsequent antibody loss. METHODS: Over a 10-year period, our longitudinal study recruited 72 healthcare workers with documented HCV exposure. We studied viremia and antibody and T-cell responses longitudinally for 6 months. RESULTS: All healthcare workers remained negative for HCV RNA and antibodies. However, 48% developed proliferative T-cell response and 42% developed responses in interferon-gamma enzyme-linked immunosorbent spot assays, with 29 healthy HCV-unexposed controls used to define assay cutoffs. The response prevalence was associated with the transmission risk score. T-cell responses peaked at week 4 and returned to baseline by week 12 after exposure. They predominantly targeted nonstructural HCV proteins, which are not part of the HCV particle and thus must have been synthesized in infected cells. CONCLUSIONS: Subclinical transmission of HCV occurs frequently, resulting in infection and synthesis of nonstructural proteins despite undetectable systemic viremia. T-cell responses are more sensitive indicators of this low level HCV exposure than antibodies. PMID- 23801610 TI - Thiobencarb herbicide reduces growth, photosynthetic activity, and amount of Rieske iron-sulfur protein in the diatom Thalassiosira pseudonana. AB - We investigated the effects of the herbicide thiobencarb on the growth, photosynthetic activity, and expression profile of photosynthesis-related proteins in the marine diatom Thalassiosira pseudonana. Growth rate was suppressed by 50% at a thiobencarb concentration of 1.26 mg/L. Growth and photosystem II activity (Fv /Fm ratio) were drastically decreased at 5 mg/L, at which the expression levels of 13 proteins increased significantly and those of 11 proteins decreased significantly. Among these proteins, the level of the Rieske iron-sulfur protein was decreased to less than half of the control level. This protein is an essential component of the cytochrome b6 f complex in the photosynthetic electron transport chain. Although the mechanism by which thiobencarb decreased the Rieske iron-sulfur protein level is not clear, these results suggest that growth was inhibited by interruption of the photosynthetic electron transport chain by thiobencarb. PMID- 23801606 TI - Decreases in inflammatory and coagulation biomarkers levels in HIV-infected patients switching from enfuvirtide to raltegravir: ANRS 138 substudy. AB - Stored plasma specimens from 164 participants in the ANRS 138 trial were analyzed to determine interleukin 6 (IL-6), high-sensitivity C-reactive protein (hsCRP), and D-dimer levels at baseline and weeks 24 and 48. These virologically suppressed, treatment-experienced patients were randomly assigned to undergo an immediate switch (IS) or a deferred switch (DS; at week 24) from an enfuvirtide based antiretroviral therapy (ART) regimen to a raltegravir-based regimen. At week 24, a significant decrease from baseline was observed in the IS arm, compared with the DS arm, for IL-6 level (-30% vs +10%; P < .002), hsCRP level ( 46% vs +15%; P < .0001), and D-dimer level (-40% vs +6%; P < .0001). At week 48, there was a reproducible decrease in levels of all biomarkers in the DS arm. PMID- 23801611 TI - [Role of astrocyte in pathogenesis of epilepsy]. PMID- 23801609 TI - Three distinct phases of HIV-1 RNA decay in treatment-naive patients receiving raltegravir-based antiretroviral therapy: ACTG A5248. AB - OBJECTIVE: The goal of this study was to define viral kinetics after initiation of raltegravir (RAL)-based antiretroviral therapy (ART). METHODS: ART-naive patients received RAL, tenofovir disoproxil fumarate, and emtricitabine for 72 weeks. Human immunodeficiency virus type 1 (HIV-1) RNA were measured by ultrasensitive and single-copy assays, and first (d1)-, second (d2)-, and, third (d3)-phase decay rates were estimated by mixed-effects models. Decay data were compared to historical estimates for efavirenz (EFV)- and ritonavir/lopinavir (LPV/r)-based regimens. RESULTS: Bi- and tri-exponential models for ultrasensitive assay (n = 38) and single-copy assay (n = 8) data, respectively, provided the best fits over 8 and 72 weeks. The median d1 with ultrasensitive data was 0.563/day (interquartile range [IQR], 0.501-0.610/day), significantly slower than d1 for EFV-based regimens [P < .001]). The median duration of d1 was 15.1 days, transitioning to d2 at an HIV-1 RNA of 91 copies/mL, indicating a longer duration of d1 and a d2 transition at lower viremia levels than with EFV. Median patient-specific decay estimates with the single-copy assay were 0.607/day (IQR, 0.582-0.653) for d1, 0.070/day (IQR, 0.042-0.079) for d2, and 0.0016/day (IQR, 0.0005-0.0022) for d3; the median d1 duration was 16.1 days, transitioning to d2 at 69 copies/mL. d3 transition occurred at 110 days, at 2.6 copies/mL, similar to values for LPV/r-based regimens. CONCLUSIONS: Models using single-copy assay data revealed 3 phases of decay with RAL-containing ART, with a longer duration of first-phase decay consistent with RAL-mediated blockade of productive infection from preintegration complexes. PMID- 23801612 TI - [Leukotriene D4 activates BV2 microglia in vitro]. AB - OBJECTIVE: To investigate the effects of CysLT receptor agonist leukotriene D4(LTD4) and antagonists on activation of microglia BV2 cells. METHODS: The expression of CysLT1 and CysLT2 protein was determined by Western blotting and immunostaining in microglia BV2 cells. BV2 cells were pretreated with or without CysLT1 receptor selective antagonist montelukast, CysLT2 receptor selective antagonist HAMI 3379, or CysLT1/CysLT2 receptor dual antagonist BAY u9773 for 30 min, then the cells were treated with LTD4 for 24 h. Cell viability was detected by MTT reduction assay. Phagocytosis and mRNA expression of IL-6 were determined by fluorescent bead tracking and RT-PCR, respectively. RESULTS: In BV2 cells, LTD4 did not affect proliferation but significantly enhanced phagocytosis and increased IL-6 mRNA expression in a concentration-dependent manner. LTD4 at 100 nmol/L induced a 1.4-fold increase of phagocytic index and a 2-fold up-regulation of IL-6 mRNA expression (P<0.01). HAMI 3379 and BAY u9773 (100 nmol/L) further increased LTD4-induced phagocytosis; BAY u9773 and montelukast decreased LTD4 induced IL-6 mRNA expression, while HAMI 3379 had no effect on that. CONCLUSION: LTD4 activates BV2 cells in vitro and enhances IL-6 mRNA expression mediated by CysLT1 receptor, LTD4 induces phagocytosis which might be negatively regulated by CysLT2 receptor in BV2 cells. PMID- 23801613 TI - [Aminoguanidine suppresses methylglyoxal-mediated oxygen-glucose deprivation injury in human brain microvascular endothelial cells]. AB - OBJECTIVE: To evaluate the effects of aminoguanidine on methylglyoxal-mediated oxygen-glucose deprivation (OGD) injury in the cultured human brain microvascular endothelial cells (HBMEC). METHODS: Cultured HBMEC cells were pretreated with methylglyoxal before oxygen-glucose deprivation injury. Cell vitality was determined by MTT method, cell mortality was assessed by LDH release method, cell apoptosis was examined by Annexin V/PI formation method, and the advanced glycation end products (AGEs) were detected by Western-blot. RESULTS: Methylglyoxal induced HBMEC injury in a dose-dependent manner. At 2 mmol/L of methylglyoxal, the cell viability was 56.1% when methylglyoxal-pretreated cells exposed to oxygen-glucose deprivation, the cell inhibition rate was 90.0%. Aminoguanidine (1 mmol/L) inhibited methylglyoxal and OGD induced LDH release and Annexin V/PI formation. Furthermore, aminoguanidine (1 mmol/L) also decreased advanced glycation end products (AGEs) formation induced by methylglyoxal and oxygen-glucose deprivation. CONCLUSION: Aminoguanidine protected methylglyoxal mediated-oxygen-glucose deprivation injury in the cultured HBMEC, which may be associated with anti-glycation activity. PMID- 23801614 TI - [Effects of aquaporin-4 gene knockout on behavior changes and cerebral morphology during aging in mice]. AB - OBJECTIVE: To investigate the effects of aquaporin-4 (AQP4) gene knockout on the behavior changes and cerebral morphology during aging in mice,and to compare that of young and aged mice between AQP4 knockout mice (AQP4(-/-)) and wild type mice (AQP4(+/+)). METHODS: Fifty-eight CD-1 mice were divided into four groups: young (2-3 months old) AQP4(-/-), aged (17-19 months old) AQP4(-/-), young AQP4(+/+) and aged AQP4(+/+). The activity levels and exploring behavior of mice were tested in open field. The neurons were stained with toluidine blue and NeuN, the astrocytes and microglia were stained with GFAP and Iba-1, respectively. The morphological changes of neuron, astrocyte and microglia were then analyzed. RESULTS: Compared with young mice, the total walking distance in open field of aged AQP4(+/+) mice and aged AQP4(-/-) mice decreased 41.2% and 44.1%, respectively (P<0.05); while there was no difference in the ratio of distance and retention time in the central area of open field. The density of neuron in cortex of aged AQP4(+/+) mice and aged AQP4(-/-) mice decreased 19.6% and 15.8%, respectively (P<0.05), while there was no difference in the thickness of neuron cell body in hippocampus CA1 region. The density of astrocyte in hippocampus CA3 region of aged AQP4(+/+) mice and aged AQP4(-/-) mice increased 57.7% and 64.3%, respectively (P<0.001), while there was no difference in the area of astrocyte. The area of microglia in hippocampus CA3 region of aged AQP4(+/+) mice and aged AQP4(-/-) mice increased 46.9% and 52.0%, respectively (P<0.01), while there was no difference in the density of microglia. Compared with AQP4(+/+) mice, the young and aged AQP4(-/-) mice showed smaller area of astrocyte in hippocampus CA3 region, reduced 18.0% in young mice and 23.6% in aged mice. There was no difference between AQP4(+/+) mice and AQP4(-/-) mice for other observed indexes. CONCLUSION: AQP4 may be involved in change of astrocyte and astrocyte-related behaviors during aging. AQP4 gene knockout may have limited effects on the change of neuron, microglia and most neuronal behaviors in aging process. PMID- 23801615 TI - [Identification of a HEK-293 cell line containing stably-transfected H3R gene and screening for novel non-imidazole histamine H3 receptor antagonists]. AB - OBJECTIVE: To identify a HEK293 cell line containing stably-transfected H3R gene, and to screen the novel non-imidazole compounds with H3R antagonist activity. METHODS: The expression of rat H3 receptor in cell line was detected by RT-PCR and Western blot. An elevation of intercellular cAMP concentration induced by forskolin was measured as the index for screening compounds with H3R antagonist activity. RESULTS: The H3R-transfected HEK-293 cells stably expressed high level of rat H3 receptor mRNA and protein. Forskolin significantly increased intercellular cAMP concentration in the H3R-transfected HEK-293 cells. H3R agonist (R)-alpha-methylhistamine inhibited the forskolin-induced production of intercellular cAMP. H3R antagonist thioperamide and newly synthesized non imidazole compounds XHA23 and XHA25 blocked (R)-alpha- methylhistamine reversal of forskolin-induced cAMP formation in a concentration-dependent manner, and the IC50 values were 3.62 MUmol/L, 0.49 MUmol/L, 0.14 MUmol/L, respectively. CONCLUSION: The H3R-transfected HEK293 cells stably express high level of rat H3 receptor, and can be used for screening compounds with H3R antagonist activity. The non-imidazole compounds XHA23 and XHA25 may have H3R antagonist activity. PMID- 23801616 TI - [Roles of protease-activated receptor-1 in thrombin-induced brain injury and neurogenesis in rats]. AB - OBJECTIVE: To investigate the roles of protease-activated receptors (PARs) in thrombin-induced brain injury and neurogenesis in rats. METHODS: Ninety male SD rats were randomly assigned to receive intra-hippocampus injection of NS, thrombin or specific agonists of 3 protease-activated receptors (PAR-1, PAR-3 and PAR-4), respectively. At 1,3 and 7 d after injection, the area of the hippocampus was determined with HE staining, the density and morphology of astrocyte were detected with GFAP staining, degenerated neurons were detected with Fluoro-Jade C staining, and the neurogenesis was examined with DCX staining. RESULTS: Compared to NS injection, the area of the hippocampus significantly increased at 1-3 d and decreased at 7 d after the injection of thrombin and PAR-1 agonist (P<0.05). In addition, injection of thrombin and PAR-1 agonist significantly increased the density of astrocyte and Fluoro-Jade C positive cells at 1-7 d after injection (P<0.05), and significantly increased the density of DCX positive cells at 3-7 d after injection(P<0.05). The injection of PAR-3 agonist and PAR-4 agonist had no affect on the area of the hippocampus, the density of astrocyte, Fluoro-Jade C positive cells and DCX positive cells. CONCLUSION: The activation of protease activated receptor-1 may be related to the thrombin-induced brain injury and neurogenesis in rat hippocampus. PMID- 23801617 TI - [Protective effects of carnosine against closed head injury in mice]. AB - OBJECTIVE: To investigate the protective effects of carnosine against experimental closed head injury (CHI) in mice. METHODS: The CHI model was established by free-falling weight-drop. Carnosine (250 mg/kg or 500 mg/kg) was administered intraperitoneally 30 min before brain trauma, then q.d for 7 d; while normal saline was administrated for control group. The neurological defect was evaluated by neurological severity score (NSS) within 7 d; the survival rate and the histological alternations were observed. RESULTS: Carnosine prevented the body weight loss of mice at dose of 500 mg/kg; significantly increased the survival rate, and reduced the neurological defect and histological damage at dose of 250 and 500 mg/kg. CONCLUSION: Carnosine can attenuate closed head injury in mice. PMID- 23801618 TI - [Quantitative EEG and event-related potentials (P300) in partial epilepsy]. AB - OBJECTIVE: Quantitative EEG and event-related potential P300 were used to evaluate impairment of cerebral function in patient with partial epilepsy. METHODS: W value was calculated (power of EEG delta and theta rhythm divided by power of alpha and beta rhythm ) for the extent of focal cortical dysfunction. The W values in left partial epilepsy group, right partial epilepsy group and control group during interictal period compared. The latency, amplitude and reaction time of P300 potential change were observed in each groups. RESULTS: The W values in F(8), T(4) and T(6) regions in patients with left partial epilepsy (P <0.05). The W values in T(3). O(1) regions of patients with left partial epilepsy were higher than those in patients with right partial epilepsy (P < 0.05). Furthermore, the W value in T(6) regions of patients with a disease course longer than 5y was significantly higher than that of patients with a disease course 1-5 y or less than 1y; the W value in O(2) regions of patients with a disease course longer than 5y was significantly higher than that of patients with a disease course between 1-5y (P < 0.05). In patients with right or left partial epilepsy, the total abnormal rate of P300 was 54. 76%, the latency, amplitude and reaction team were significantly different to the control group. The abnormal rate of P300 in left and right partial epilepsy groups were 77. 78% and 37.50%, respectively, and the former is significantly higher than the latter. The amplitudes of P300 in C(z) and P(z) of left partial epilepsy were significantly lower than those of right partial epilepsy and control group (P < 0.05). The latency and reaction time of P300 in C(z) and P(z) of all partial epilepsy were significantly longer than those of control group (P < 0.05), however, no difference was found between left and right partial epilepsy. CONCLUSION: In partial epilepsy the cortical dysfunction occurs ipsilaterally to the epileptogenic zone, and extent of cortical dysfunction is positively correlated with duration of disease course. Cerebral dysfunction in left partial epilepsy is more severe than that in right partial epilepsy. PMID- 23801619 TI - [Effects of recombinant human NAMPT on physiological/biochemical indexes and brain structure in mice]. AB - OBJECTIVE: To observe the effect of recombinant human nicotinamide phosphoribosyl transferase (NAMPT) on physiological/biochemical indexes and brain structure in mice. METHODS: Wild type human recombinant NAMPT (10, 30 and 100 MUg/kg) or H247A mutant NAMPT (with very weak enzymatic activity) were administrated by intravenous injection in mice once every 3 d for 32 d. The changes of body weight, blood pressure, heart rate, serum glucose, serum total cholesterol and triglyceride were determined, and the morphology of neuron, astrocyte and microglia in hippocampus were observed. RESULTS: The injection of wild and mutated type NAMPT had no significant effect on body weight, blood pressure,heart rate, blood glucose, total cholesterol and triglyceride, and did not affect the morphology of neuron, astrocyte and microglia in hippocampus of mice. CONCLUSION: Elevation of plasma NAMPT may not induce metabolic and neuronal dysfunction in normal individual. PMID- 23801620 TI - [Isolation and identification of human endometrial stromal stem cells]. AB - OBJECTIVE: To isolate, culture and identify of human endometrial stromal stem cells. METHODS: Endometrial tissue was obtained from 10 women undergoing hysterectomy. Purified stromal stem cell suspensions were then obtained by selecting cells with magnetic bead sorting and colony-forming. The surface markers of stromal cell were identified by flow cytometry. Proliferation of stromal stem cell was observed by MTT methods. The osteogenic potential was evaluated by alizarin red staining, the adipogenic potential by oil red O staining. Then the adipogenic and osteogenic specific markers of differentiated cells assayed by RT-PCR method. Expression of cell surface antigen OCT-4 was detected with immunocytochemical staining. RESULTS: Endometrial stem cells were successfully isolated from human endometrial tissue. They were stably proliferated and subcultured in vitro. Most of the passage cells expressed mesenchymal stem cell markers CD90, CD105 but not hemopoietic markers CD34, CD45. The analysis of cell cycle indicated that the percentage of G2-M phase and S phase cells increased. The growth curves of the third passage presented in "S" shape. After cultured in differentiation medium, the cells differentiated toward adipoblasts and osteoblasts as verified by positive staining with Oil Red O and alizarin red staining. Under induction,cells expressed osteogenic and adipogenic marker genes. The immunocytochemical staining of OCT-4 was positive. CONCLUSION: Human endometrium contains endometrial stromal stem cells, which present characteristics of mesenchymal stem cells and may be used as seed cells for tissue engineering. PMID- 23801621 TI - [Seasonal changes and response to stress of total flavonoids content of Farfugium japonicum]. AB - OBJECTIVE: To investigate the seasonal variation of total flavonoid content of Farfugium japonicum and its response to stress. METHODS: The total flavonoids of Farfugium japonicum were determined by spectrophotometry in different seasons and under various stressful factors. RESULTS: The total flavonoid content in Farfugium japonicum leaves was the highest, followed by the petiole, and rhizomes (P<0.05). The total flavonoid content in the leaves in December was higher than that in other months; that in the petiole and rhizome fluctuated in different seasons (P<0.05). As the light intensity enhanced, the total flavonoids in Farfugium japonicum leaves, petioles, rhizomes showed a downward trend. With the increase of water stress, the total flavonoid content in Farfugium japonicum leaves gradually increased, that in petiole first increased and then decreased,while that in rhizomes decreased (P<0.05). With the salt stress, the total flavonoid content in leaves, petioles and rhizomes of Farfugium japonicum showed a decreasing trend (P<0.05). With the increasing of temperature, the total flavonoid content in the leaves showed a gradually increasing trend; that in petiole first decreased and then increased,while that in the rhizomes first increased and then decreased (P<0.05). CONCLUSION: The total flavonoids of Farfugium japonicum fluctuate with the change of seasons and that in different parts of the plant has different responses to ecological stressful factors. PMID- 23801622 TI - [Dexmedetomidine preconditioning protects isolated rat hearts against ischemia/reperfusion injuries and its mechanism]. AB - OBJECTIVE: To investigate the protective effect of dexmedetomidine (Dex) preconditioning against ischemia/reperfusion (I/R) injuries in isolated rat hearts and its relation to mitochondrial permeability transition pore (mPTP) and mitochondrial ATP-sensitive K(+) channel (mitoKATP). METHODS: The hearts of male SD rats were isolated to mount on the Langendorff apparatus and subjected to 30 min global ischemia followed by 120 min reperfusion. The isolated hearts were treated with Dex (10 nmol/L) before ischemia for 15 min. The left ventricular hemodynamic parameters,coronary flow (CF) and the lactate dehydrogenase (LDH) release in the coronary effluent at 5 min reperfusion were measured. The formazan content was assayed to determine the myocardial viability at the end of reperfusion. RESULTS: Compared with normal controls, I/R markedly decreased the left ventricular developed pressure and CF during the whole reperfusion period and the formazan content; while the left ventricular end diastolic pressure and LDH release were significantly increased. Dex preconditioning markedly improved the myocardial viability and cardiac function (P<0.01), which were reversed by the treatment with both atractyloside (20 MUmol/L before ischemia), an opener of mPTP, and 5-hydroxydecanoate (100 MUmol/L at the beginning of reperfusion), an inhibitor of mitoKATP, for 20 min. CONCLUSION: Dex has protective effect against I/R injuries in isolated rat hearts, which may be related to inhibiting the opening of mPTP at the beginning of reperfusion and activating mitoKATP before ischemia. PMID- 23801623 TI - [Biological characteristics of phage SM1 for Stenotrophomonas maltophilia and its effect in animal infection model]. AB - OBJECTIVE: To investigate the biological characteristics of phage SM1 for stenotrophomonas maltophilia (Sm) and its effect in animal infection model. METHODS: Phage SM1 isolated from raw sewage of hospital was identified by the plaque method. The morphology of phage SM1 was observed by electron micrographics with negative staining. The extraction and electrophoresis of phage SM1 DNA were performed. Optimal multiplicity of infection, resistant mutation rate, one step growth curve and the effectiveness in animal models of phage SM1 were determined. RESULTS: One Sm specific phage of myoviridae double-stranded DNA was identified, and named SM1. Electrophoresis of DNA demonstrated that the size of phage SM1 genome was about 50 kb. The growth curve of phage SM1 showed that the durations of incubation and burst period were 15 min and 50 min, respectively; and the burst size was 187. The resistant mutation rate of phage SM1 was 6 x 10(-10). All mice treated with phage SM1 survived after 7 d of infection with stenotrophomonas maltophilia. CONCLUSION: The phage SM1 has a relatively broad host range, a shorter incubation period,an apparent burst size and a lower resistant mutation rate. The therapy of phage SM1 for Sm infection in mice is effective. PMID- 23801624 TI - [Microbubbles enhanced HIFU ablation on rabbit hepatic VX2 tumors: detecting residual tumor with contrast-enhanced ultrasound and spiral CT]. AB - OBJECTIVE: To assess the application of gray-scale contrast-enhanced ultrasound (CEUS) and contrast-enhanced spiral computed tomography (CECT) in detection of residual tumor after high intensity focused ultrasound (HIFU) ablation with microbubbles on rabbit hepatic VX2 tumors. METHODS: Forty rabbits with hepatic VX2 tumors were randomly divided into three groups before ablation. Group I (n=10) served as sham ablation controls, rabbits in group II (n=15) and group III (n=15) were ablated using HIFU under the manipulation of computer. A bolus of 0.2 ml SonoVue solution was injected via ear marginal vein of rabbits in group III before ablation. Tumors were examined with CEUS and CECT before and within 3h after HIFU ablation. Necropsy and histopathological assessment were performed immediately after the completion of images evaluation. RESULTS: Before ablation, intense arterial feeding vessels was detected in the tumors (77.5%,31/40 Compared with 52.5%,21/40) or the periphery of the tumors (22.5%,9/40 Compared with 47.5%,19/40) by CEUS and CECT, respectively. The tumors were characterized by quick wash-in and wash-out (high and rapid peak of enhancement in the arterial phase,followed by a fast decrease in enhancement level). The dose parameters used to achieve therapeutic effect in group III were significantly lower than those in group II(P<0.01). There were local residual viable tumor tissues due to incomplete ablation in 60.0% (9/15) of group II and 13.3% (2/15) of group III revealed by histopathology(P<0.05). The concordance rate of CECT and CEUS with histopathology on residual tumor detection was 27.3% and 81.8% (P<0.05), respectively. CONCLUSION: The administration of microbubble agent enhances the efficacy of HIFU on rabbit hepatic VX2 tumors. CEUS is more sensitive than CECT in detection of residual viable rabbit VX2 tumor after HIFU. PMID- 23801625 TI - [Association of hepatitis C virus genotype with glycolipid iron metabolism in Gansu Han population]. AB - OBJECTIVE: To investigate the association of hepatitis C virus (HCV) genotype with glycolipids iron metabolism in Gansu Han population. METHODS: The genotypes of HCV 1b type and 2a type were detected in Gansu Han HCV carriers. The Glu, Insulin, CHOL, TG, UIBC, TRF, TIBC, SF, Serum Iron, AST, ALT, TBil, IBil, DBil, ALP, GGT were measured and compared between patients with different HCV genotypes. RESULTS: There were 84 cases with HCV1b type and 136 cases with 2a type. There were significant differences in TG, ALT, TRF, TIBC between 1b type and 2a type genotype HCV carriers. CONCLUSION: The 2a type HCV carriers may be more inclined to develop hyperlipidemia and liver damage, and 1b type HCV carriers are likely to have iron metabolism defect. PMID- 23801626 TI - [Evaluation of methods for collection of peripheral blood stem cells in children]. AB - OBJECTIVE: To evaluate the methods for collection of peripheral blood stem cells (PBSC) in children. METHODS: Peripheral blood stem cells were collected from 20 child patients and 11 donors. The patients treated with chemotherapy, received G CSF or GM-CSF and the donors received G-CSF for mobilization. When the peripheral blood (PB) leukocyte count reached to 5 X10(9)/L,the hematopoietic stem cells were collected with CS-3000 Plus, COM TEC or COBE Spectra blood cell separators from patients and donors. For children whose weight <20 kg,HCT <24% or TBV <1 100 1 650 ml,blood cell separators were pre-injected with the same type RBCs irradiated by 25 Gy of gamma-ray and with low flow rate (10-30 ml/min). The number of CD34(+) cell was detected by flow cytometry. The relationship of number of CD34(+) cell with mononuclear cell (MNC) and processed blood volume was analyzed. RESULTS: Successful collection of the PBSCs with the CS- 3000 Plus (n=10), the COM TEC (n=3) and the COBE Spectra (n=18) was achieved in all the 31 cases with 1-5 aphereses used. Number of CD34(+) cells was (7.9 +/-2.9) X 10(6)/kg and that of MNCs was (7.4 +/-3.1) X 10(8)/kg. The total CD34(+) cell count was correlated with MNCs before aphaeresis and processed blood volume. CONCLUSION: For collection of high quality PBSCs, the appropriate methods should be chosen according to the body weight, TBV, mobilization of child patients/donors. PMID- 23801627 TI - [Role of G protein-coupled receptor 17 in central nervous system injury]. AB - G-protein-coupled receptor 17 (GPR17), an originally orphan receptor, was identified as a new uracil nucleotides/cysteinyl leukotriene receptor. However, whether GPR17 is really classified as a leukotriene receptor is a matter deserving further investigation. GPR17 is involved in many physiological and pathological processes including brain injury, spinal cord injury, and oligodendrocyte differentiation. GPR17 may become a new therapeutic target in these diseases. In this article, the research progress on the pharmacology and pathophysiological roles of GPR17 is reviewed. PMID- 23801628 TI - [Research progress on genome-wide association studies of colorectal cancer]. AB - Colorectal cancer (CRC), one of the most common malignant tumors, is caused both by environmental and genetic factors. Genetic factor plays an important role in the pathogenesis of CRC. Genome-wide association study (GWAS) is a new tool of genetic research. A series of susceptibility genes and loci of the complex diseases has been identified with GWAS strategy. In this article, the research progress on GWAS of CRC is reviewed, and the advantages and limitations of GWAS study as well as the prospective of its application are discussed. PMID- 23801629 TI - Alloantibodies to a paternally derived RBC KEL antigen lead to hemolytic disease of the fetus/newborn in a murine model. AB - Exposure to nonself red blood cell (RBC) antigens, either from transfusion or pregnancy, may result in alloimmunization and incompatible RBC clearance. First described as a pregnancy complication 80 years ago, hemolytic disease of the fetus and newborn (HDFN) is caused by alloimmunization to paternally derived RBC antigens. Despite the morbidity/mortality of HDFN, women at risk for RBC alloimmunization have few therapeutic options. Given that alloantibodies to antigens in the KEL family are among the most clinically significant, we developed a murine model with RBC-specific expression of the human KEL antigen to evaluate the impact of maternal/fetal KEL incompatibility. After exposure to fetal KEL RBCs during successive pregnancies with KEL-positive males, 21 of 21 wild-type female mice developed anti-KEL alloantibodies; intrauterine fetal anemia and/or demise occurred in a subset of KEL-positive pups born to wild type, but not agammaglobulinemic mothers. Similar to previous observations in humans, pregnancy-associated alloantibodies were detrimental in a transfusion setting, and transfusion-associated alloantibodies were detrimental in a pregnancy setting. This is the first pregnancy-associated HDFN model described to date, which will serve as a platform to develop targeted therapies to prevent and/or mitigate the dangers of RBC alloantibodies to fetuses and newborns. PMID- 23801630 TI - MicroRNA expression profiling identifies molecular signatures associated with anaplastic large cell lymphoma. AB - Anaplastic large-cell lymphomas (ALCLs) encompass at least 2 systemic diseases distinguished by the presence or absence of anaplastic lymphoma kinase (ALK) expression. We performed genome-wide microRNA (miRNA) profiling on 33 ALK positive (ALK[+]) ALCLs, 25 ALK-negative (ALK[-]) ALCLs, 9 angioimmunoblastic T cell lymphomas, 11 peripheral T-cell lymphomas not otherwise specified (PTCLNOS), and normal T cells, and demonstrated that ALCLs express many of the miRNAs that are highly expressed in normal T cells with the prominent exception of miR-146a. Unsupervised hierarchical clustering demonstrated distinct clustering of ALCL, PTCL-NOS, and the AITL subtype of PTCL. Cases of ALK(+) ALCL and ALK(-) ALCL were interspersed in unsupervised analysis, suggesting a close relationship at the molecular level. We identified an miRNA signature of 7 miRNAs (5 upregulated: miR 512-3p, miR-886-5p, miR-886-3p, miR-708, miR-135b; 2 downregulated: miR-146a, miR 155) significantly associated with ALK(+) ALCL cases. In addition, we derived an 11-miRNA signature (4 upregulated: miR-210, miR-197, miR-191, miR-512-3p; 7 downregulated: miR-451, miR-146a, miR-22, miR-455-3p, miR-455-5p, miR-143, miR 494) that differentiates ALK(-) ALCL from other PTCLs. Our in vitro studies identified a set of 32 miRNAs associated with ALK expression. Of these, the miR 17~92 cluster and its paralogues were also highly expressed in ALK(+) ALCL and may represent important downstream effectors of the ALK oncogenic pathway. PMID- 23801631 TI - Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. AB - Rearrangements of the MLL gene define a genetically distinct subset of acute leukemias with poor prognosis. Current treatment options are of limited effectiveness; thus, there is a pressing need for new therapies for this disease. Genetic and small molecule inhibitor studies have demonstrated that the histone methyltransferase DOT1L is required for the development and maintenance of MLL rearranged leukemia in model systems. Here we describe the characterization of EPZ-5676, a potent and selective aminonucleoside inhibitor of DOT1L histone methyltransferase activity. The compound has an inhibition constant value of 80 pM, and demonstrates 37 000-fold selectivity over all other methyltransferases tested. In cellular studies, EPZ-5676 inhibited H3K79 methylation and MLL-fusion target gene expression and demonstrated potent cell killing that was selective for acute leukemia lines bearing MLL translocations. Continuous IV infusion of EPZ-5676 in a rat xenograft model of MLL-rearranged leukemia caused complete tumor regressions that were sustained well beyond the compound infusion period with no significant weight loss or signs of toxicity. EPZ-5676 is therefore a potential treatment of MLL-rearranged leukemia and is under clinical investigation. PMID- 23801632 TI - beta-Catenin activation synergizes with Pten loss and Myc overexpression in Notch independent T-ALL. AB - Wnt signaling is important for T-cell differentiation at the early CD4(-)CD8(-) stage and is subsequently downregulated with maturation. To assess the importance of this downregulation, we generated a mouse line (R26-betacat) in which high levels of active beta-catenin are maintained throughout T-cell development. Young R26-betacat mice show a differentiation block at the CD4(+)CD8(+) double-positive (DP) stage. These DP cells exhibit impaired apoptosis upon irradiation or dexamethasone treatment. All R26-betacat mice develop T-cell leukemias at 5 to 6 months of age. R26-betacat leukemias remain dependent on beta-catenin function but lack Notch pathway activation. They exhibit recurrent secondary genomic rearrangements that lead to Myc overexpression and loss of Pten activity. Because beta-catenin activation and Myc translocations were previously found in murine T cell acute lymphoblastic leukemias (T-ALLs) deficient for Pten, our results suggest that activation of the canonical Wnt pathway is associated with a subtype of Notch-independent T-ALLs that bear Myc gene rearrangements and Pten mutations. PMID- 23801633 TI - Lenalidomide induces long-lasting responses in elderly patients with chronic lymphocytic leukemia. AB - We evaluated long-term outcomes of 60 patients with chronic lymphocytic leukemia treated with an initial therapy of lenalidomide. At a median follow-up of 4 years, time-to-treatment failure has not been reached and overall survival is 82%. Thirty-five (58%) patients had a response lasting >36 months (long-term responders [LTRs]). Best LTR responses consisted of 25 (71%) complete remissions and 10 (29%) partial remissions. In addition to clinical responses, an increase in IgA, IgG, and IgM levels of >50% from baseline was reported in 61%, 45%, and 42% of LTRs. Normalization in the percentage of CD4+ and CD8+ cells and T-cell numbers was observed in 48%, 71% and 99% of LTRs. Compared with other patients in the study, LTRs had lower baseline plasma levels of beta-2-microglobulin, were more likely to have trisomy 12, and less likely to have deletion 17p. PMID- 23801634 TI - Elucidating the role of interleukin-17F in cutaneous T-cell lymphoma. AB - Inappropriately regulated expression of interleukin (IL)-17A is associated with the development of inflammatory diseases and cancer. However, little is known about the role of other IL-17 family members in carcinogenesis. Here, we show that a set of malignant T-cell lines established from patients with cutaneous T cell lymphoma (CTCL) spontaneously secrete IL-17F and that inhibitors of Janus kinases and Signal transducer and activator of transcription 3 are able to block that secretion. Other malignant T-cell lines produce IL-17A but not IL-17F. Upon activation, however, some of the malignant T-cell lines are able to coexpress IL 17A and IL-17F, leading to formation of IL-17A/F heterodimers. Clinically, we demonstrate that IL-17F messenger RNA expression is significantly increased in CTCL skin lesions compared with healthy donors and patients with chronic dermatitis. IL-17A expression is also increased and a significant number of patients express high levels of both IL-17A and IL-17F. Concomitantly, we observed that the expression of the IL-17 receptor is significantly increased in CTCL skin lesions compared with control subjects. Importantly, analysis of a historic cohort of 60 CTCL patients indicates that IL-17F expression is associated with progressive disease. These findings implicate IL-17F in the pathogenesis of CTCL and suggest that IL-17 cytokines and their receptors may serve as therapeutic targets. PMID- 23801635 TI - Downregulation of the activating NKp30 ligand B7-H6 by HDAC inhibitors impairs tumor cell recognition by NK cells. AB - Natural killer (NK) cells are central effector cells during innate immune responses against cancer. Natural cytotoxicity receptors expressed by NK cells such as NKp30 are involved in the recognition of transformed cells. Recently, the novel B7 family member B7-H6, which is expressed on the cell surface of various tumor cells including hematological malignancies, was identified as an activating ligand for NKp30. To investigate expression and regulation of B7-H6, we generated monoclonal antibodies. Our study reveals that B7-H6 surface protein and messenger RNA (mRNA) expression in various tumor cell lines was downregulated upon treatment with pan- or class I histone deacetylase inhibitors (HDACi) as well as after small interfering RNA-mediated knockdown of the class I histone deacetylases (HDAC) 2 or 3. B7-H6 downregulation was associated with decreased B7 H6 reporter activity and reduced histone acetylation at the B7-H6 promoter. In certain primary lymphoma and hepatocellular carcinoma samples, B7-H6 mRNA levels were elevated and correlated with HDAC3 expression. Finally, downregulation of B7 H6 on tumor cells by HDACi reduced NKp30-dependent effector functions of NK cells. Thus, we identified a novel mechanism that governs B7-H6 expression in tumor cells that has implications for potential cancer treatments combining immunotherapy with HDACi. PMID- 23801636 TI - Dietary alpha-linolenic acid increases the platelet count in ApoE-/- mice by reducing clearance. AB - Previously we reported that dietary intake of alpha-linolenic acid (ALA) reduces atherogenesis and inhibits arterial thrombosis. Here, we analyze the substantial increase in platelet count induced by ALA and the mechanisms of reduced platelet clearance. Eight-week-old male apolipoprotein E knockout (ApoE(-/-)) mice were fed a 0.21g% cholesterol diet complemented by either a high- (7.3g%) or low-ALA (0.03g%) content. Platelet counts doubled after 16 weeks of ALA feeding, whereas the bleeding time remained similar. Plasma glycocalicin and glycocalicin index were reduced, while reticulated platelets, thrombopoietin, and bone marrow megakaryocyte colony-forming units remained unchanged. Platelet contents of liver and spleen were substantially reduced, without affecting macrophage function and number. Glycoprotein Ib (GPIb) shedding, exposure of P-selectin, and activated integrin alphaIIbbeta3 upon activation with thrombin were reduced. Dietary ALA increased the platelet count by reducing platelet clearance in the reticulo endothelial system. The latter appears to be mediated by reduced cleavage of GPIb by tumor necrosis factor-alpha-converting enzyme and reduced platelet activation/expression of procoagulant signaling. Ex vivo, there was less adhesion of human platelets to von Willebrand factor under high shear conditions after ALA treatment. Thus, ALA may be a promising tool in transfusion medicine and in high turnover/high activation platelet disorders. PMID- 23801637 TI - Electrochemical properties of yolk-shell, hollow, and dense WO3 particles prepared by using spray pyrolysis. PMID- 23801638 TI - Validity of diagnostic codes to identify cases of severe acute liver injury in the US Food and Drug Administration's Mini-Sentinel Distributed Database. AB - PURPOSE: The validity of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes to identify diagnoses of severe acute liver injury (SALI) is not well known. We examined the positive predictive values (PPVs) of hospital ICD-9-CM diagnoses in identifying SALI among health plan members in the Mini-Sentinel Distributed Database (MSDD) for patients without liver/biliary disease and for those with chronic liver disease (CLD). METHODS: We selected random samples of members (149 without liver/biliary disease; 75 with CLD) with a principal hospital diagnosis suggestive of SALI (ICD 9-CM 570, 572.2, 572.4, 572.8, 573.3, 573.8, or V42.7) in the MSDD (2009-2010). Medical records were reviewed by hepatologists to confirm SALI events. PPVs of codes and code combinations for confirmed SALI were determined by CLD status. RESULTS: Among 105 members with available records and no liver/biliary disease, SALI was confirmed in 26 (PPV, 24.7%; 95%CI, 16.9-34.1%). Combined hospital diagnoses of acute hepatic necrosis (570) and liver disease sequelae (572.8) had high PPV (100%; 95%CI, 59.0-100%) and identified 7/26 (26.9%) events. Among 46 CLD members with available records, SALI was confirmed in 19 (PPV, 41.3%; 95%CI, 27.0-56.8%). Acute hepatic necrosis (570) or hepatorenal syndrome (572.4) plus any other SALI code had a PPV of 83.3% (95%CI, 51.6-97.9%) and identified 10/19 (52.6%) events. CONCLUSIONS: Most individual hospital ICD-9-CM diagnoses had low PPV for confirmed SALI events. Select code combinations had high PPV but did not capture all events. PMID- 23801639 TI - Impact of derived global weather data on simulated crop yields. AB - Crop simulation models can be used to estimate impact of current and future climates on crop yields and food security, but require long-term historical daily weather data to obtain robust simulations. In many regions where crops are grown, daily weather data are not available. Alternatively, gridded weather databases (GWD) with complete terrestrial coverage are available, typically derived from: (i) global circulation computer models; (ii) interpolated weather station data; or (iii) remotely sensed surface data from satellites. The present study's objective is to evaluate capacity of GWDs to simulate crop yield potential (Yp) or water-limited yield potential (Yw), which can serve as benchmarks to assess impact of climate change scenarios on crop productivity and land use change. Three GWDs (CRU, NCEP/DOE, and NASA POWER data) were evaluated for their ability to simulate Yp and Yw of rice in China, USA maize, and wheat in Germany. Simulations of Yp and Yw based on recorded daily data from well-maintained weather stations were taken as the control weather data (CWD). Agreement between simulations of Yp or Yw based on CWD and those based on GWD was poor with the latter having strong bias and large root mean square errors (RMSEs) that were 26 72% of absolute mean yield across locations and years. In contrast, simulated Yp or Yw using observed daily weather data from stations in the NOAA database combined with solar radiation from the NASA-POWER database were in much better agreement with Yp and Yw simulated with CWD (i.e. little bias and an RMSE of 12 19% of the absolute mean). We conclude that results from studies that rely on GWD to simulate agricultural productivity in current and future climates are highly uncertain. An alternative approach would impose a climate scenario on location specific observed daily weather databases combined with an appropriate upscaling method. PMID- 23801640 TI - A qualitative study of women's experiences of familial ovarian cancer screening. AB - OBJECTIVE: One risk management strategy that women at increased familial risk of ovarian cancer may use is screening. Until recently, this has been available as part of the UK Familial Ovarian Cancer Screening Study (UKFOCSS), using ultrasound scans of the ovaries and tumour marker blood tests. The present study aimed to gain an in-depth understanding of women's experiences of participating in ovarian cancer screening. METHODS: Semi-structured interviews were conducted with 48 UKFOCSS participants. Interviews were recorded, transcribed and relevant sections analysed using a framework approach. RESULTS: Screening provided women with reassurance which they found beneficial. A sense of privilege, as well as feeling proactive in potentially detecting ovarian cancer at an early stage was described. The wider benefit to research and the potential impact this could have on others was also important to women. Negative experiences of screening included worry about the screening tests and results, false reassurance by test results and disappointment with ineffective screening. Aspects of the screening study, such as the logistics, organisation and communication, were described as both good and problematic. When weighed up by the women, most described an overall positive experience of screening. CONCLUSIONS: Women reported both positive and negative experiences of screening. Overall, screening seemed to be an acceptable risk management strategy to most women who participated in this interview study. Improvements could be made particularly in helping women to understand the limitations of familial ovarian cancer screening in order to avoid false reassurance. PMID- 23801641 TI - Gimme shelter--the relative sensitivity of parasitic nematodes with direct and indirect life cycles to climate change. AB - Climate change is expected to alter the dynamics of host-parasite systems globally. One key element in developing predictive models for these impacts is the life cycle of the parasite. It is, for example, commonly assumed that parasites with an indirect life cycle would be more sensitive to changing environmental conditions than parasites with a direct life cycle due to the greater chance that at least one of their obligate host species will go extinct. Here, we challenge this notion by contrasting parasitic nematodes with a direct life cycle against those with an indirect life cycle. Specifically, we suggest that behavioral thermoregulation by the intermediate host may buffer the larvae of indirectly transmitted parasites against temperature extremes, and hence climate warming. We term this the 'shelter effect'. Formalizing each life cycle in a comprehensive model reveals a fitness advantage for the direct life cycle over the indirect life cycle at low temperatures, but the shelter effect reverses this advantage at high temperatures. When examined for seasonal environments, the models suggest that climate warming may in some regions create a temporal niche in mid-summer that excludes parasites with a direct life cycle, but allows parasites with an indirect life cycle to persist. These patterns are amplified if parasite larvae are able to manipulate their intermediate host to increase ingestion probability by definite hosts. Furthermore, our results suggest that exploiting the benefits of host sheltering may have aided the evolution of indirect life cycles. Our modeling framework utilizes the Metabolic Theory of Ecology to synthesize the complexities of host behavioral thermoregulation and its impacts on various temperature-dependent parasite life history components in a single measure of fitness, R0 . It allows quantitative predictions of climate change impacts, and is easily generalized to many host-parasite systems. PMID- 23801642 TI - Reply to comparative study of epidermal growth factor receptor mutation analysis on cytology smears and surgical pathology specimens from primary and metastatic lung carcinomas. PMID- 23801643 TI - Do we get it right? Radiation oncology outpatients' perceptions of the patient centredness of life expectancy disclosure. AB - OBJECTIVE: A patient-centred approach to discussing life expectancy with cancer patients is recommended in Western countries. However, this approach to eliciting and meeting patient preferences can be challenging for clinicians. The aims of this study were the following: (i) to examine cancer patients' preferences for life expectancy disclosure; and (ii) to explore agreement between cancer patients' preferences for, and perceived experiences of, life expectancy disclosure. METHODS: Cancer patients undergoing radiotherapy treatment in metropolitan Australia completed a cross-sectional touchscreen computer survey including optional questions about their life expectancy disclosure preferences and experiences. RESULTS: Of the 208 respondents, 178 (86%) indicated that they would prefer their clinician to ask them before discussing life expectancy, and 30 (14%) indicated that they would prefer others (i.e. clinicians, family) to decide whether they were given life expectancy information. Of the 175 respondents who were classified as having a self- determined or other-determined disclosure experience, 105 (60%) reported an experience of life expectancy disclosure that was in accordance with their preferences. Cohen's kappa was -0.04 (95% CI, -0.17, 0.08), indicating very poor agreement between patients' preferences for and perceived experiences of life expectancy disclosure (p = 0.74). CONCLUSIONS: In light of patient-centred prognosis disclosure guidelines, our findings of a majority preference for, and experience of, a self-determined approach to life expectancy disclosure amongst radiation oncology patients are encouraging. However, poor agreement between preferences and experiences highlights that additional effort from clinicians is required in order to achieve a truly patient-centred approach to life expectancy disclosure. PMID- 23801644 TI - The dynamics of lysozyme from bacteriophage lambda in solution probed by NMR and MD simulations. AB - (15) N NMR relaxation studies, analyses of NMR data to include chemical shifts, residual dipolar couplings (RDC), NOEs and H(N) -H(alpha) coupling constants, and molecular dynamics (MD) simulations have been used to characterise the behaviour of lysozyme from bacteriophage lambda (lambda lysozyme) in solution. The lower and upper lip regions in lambda lysozyme (residues 51-60 and 128-141, respectively) show reduced (1) H-(15) N order parameters indicating mobility on a picosecond timescale. In addition, residues in the lower and upper lips also show exchange contributions to T2 indicative of slower timescale motions. The chemical shift, RDC, coupling constant and NOE data for lambda lysozyme indicate that two fluctuating beta-strands (beta3 and beta4) are populated in the lower lip region while the N terminus of helix alpha6 (residues 136-139) forms dynamic helical turns in the upper lip region. This behaviour is confirmed by MD simulations that show hydrogen bonds, indicative of the beta-sheet and helical secondary structure in the lip regions, with populations of 40-60 %. Thus in solution lambda lysozyme adopts a conformational ensemble that will contain both the open and closed forms observed in the crystal structures of the protein. PMID- 23801645 TI - Minimizing delays in DNA retrieval: The "freezer method" for glass coverslip removal. Letter to the editor regarding comparative study of epidermal growth factor receptor mutation analysis on cytology smears and surgical pathology specimens from primary and metastatic lung carcinomas. PMID- 23801646 TI - Carbon footprint of Breton pate production: a case study. AB - This study targeted 9 different pork pates, produced with pork from different meat production systems (conventional, organic, and other quality certifications). Besides greenhouse gas (GHG) emissions, the study also included a detailed analysis of product nutrition. Results show that the GHG emissions range from 200 g CO2 e per 100 g of product for conventional pork pates and 330 g CO2 e per 100 g for organic pork pates. Results for organic pates are an indirect consequence of the lower productivity of swine feed ingredients. However, if the reference flow unit is nutritional indicator (e.g., calories, protein) instead of 100 g of product, results can be inverted. This fact highlights the difficulty of choosing a functional unit for studies on food products. The function of a food product is to provide quality nutrition, but because there are many different nutritional indicators, life cycle assessment practitioners normally use simple comparisons between amounts. This issue together with the choice of emissions allocation method between pork parts are the main sources of uncertainty. Also, the life cycle of pork production is the main hotspot in the C footprint, accounting for more than 80% of the total emissions. Energy spent for processing and packaging, the only life cycle step that the producer controls directly, accounts for less than 10% of the impact. PMID- 23801647 TI - Development and properties of surfactant-free water-dispersible Cu2ZnSnS4 nanocrystals: a material for low-cost photovoltaics. AB - A simple, yet novel hydrothermal method has been developed to synthesize surfactant-free Cu2ZnSnS4 nanocrystal ink in water. The environmentally friendly, 2-4 nm ultrafine particles are stable in water for several weeks. Detailed X-ray diffraction (XRD) and high-resolution transmission electron microscopy revealed the formation of single-crystalline-kesterite-phase Cu2ZnSnS4. Elemental mapping by scanning electron microscopy/energy dispersive spectrometry corroborated the presence of all four elements in a stoichiometric ratio with minor sulfur deficiency. Finally, Raman spectroscopy ruled out the possible presence of impurities of ZnS, Cu2SnS3, SnS, SnS2, Cu(2-x)S, or Sn2S3, which often interfere with the XRD and optical spectra of Cu2ZnSnS4. X-ray photoelectron spectroscopic studies of the as-synthesized samples confirmed that the oxidation states of the four elements match those of the bulk sample. Optical absorption analyses of thin film and solution samples showed high absorption efficiency (>10(4) cm(-1)) across the visible and near-infrared spectral regions and a band gap E(g) of 1.75 eV for the as-synthesized sample. A non-ohmic asymmetric rectifying response was observed in the I-V measurement at room temperature. The nonlinearity was more pronounced for this p-type semiconductor when the resistance was measured against temperature in the range 180-400 K, which was detected in the hot-point probe measurement. PMID- 23801648 TI - Assessment of riverine load of contaminants to European seas under policy implementation scenarios: an example with 3 pilot substances. AB - An evaluation of conventional emission scenarios is carried out targeting a possible impact of European Union (EU) policies on riverine loads to the European seas for 3 pilot pollutants: lindane, trifluralin, and perfluorooctane sulfonate (PFOS). The policy scenarios are investigated to the time horizon of year 2020 starting from chemical-specific reference conditions and considering different types of regulatory measures including business as usual (BAU), current trend (CT), partial implementation (PI), or complete ban (PI ban) of emissions. The scenario analyses show that the model-estimated lindane load of 745 t to European seas in 1995, based on the official emission data, would be reduced by 98.3% to approximately 12.5 t in 2005 (BAU scenario), 10 years after the start of the EU regulation of this chemical. The CT and PI ban scenarios indicate a reduction of sea loads of lindane in 2020 by 74% and 95%, respectively, when compared to the BAU estimate. For trifluralin, an annual load of approximately 61.7 t is estimated for the baseline year 2003 (BAU scenario), although the applied conservative assumptions related to pesticide use data availability in Europe. Under the PI (ban) scenario, assuming only small residual emissions of trifluralin, we estimate a sea loading of approximately 0.07 t/y. For PFOS, the total sea load from all European countries is estimated at approximately 5.8 t/y referred to 2007 (BAU scenario). Reducing the total load of PFOS below 1 t/y requires emissions to be reduced by 84%. The analysis of conventional scenarios or scenario typologies for emissions of contaminants using simple spatially explicit GIS-based models is suggested as a viable, affordable exercise that may support the assessment of implementation of policies and the identification or negotiation of emission reduction targets. PMID- 23801649 TI - Clinical efficacy and cost-effectiveness of bespoke and prefabricated foot orthoses for plantar heel pain: a prospective cohort study. AB - BACKGROUND: Plantar heel pain is a common reason for referral to podiatric practice, and one of the key interventions is the use of orthoses. The aim of the present study was to compare the clinical efficacy of bespoke, casted foot orthoses and prefabricated foot orthoses for plantar heel pain. METHODS: People with plantar heel pain were included if, following initial assessment, foot orthoses were indicated and participants received either bespoke, casted foot orthoses or prefabricated semi-rigid orthoses (PowerstepTM). Clinical efficacy was assessed at eight weeks using the Manchester Foot Pain and Disability Questionnaire (MFPDQ). RESULTS: A total of 67 patients completed the trial and at baseline there were no appreciable differences in the two groups of patients in terms of the MFPDQ score; however, at eight weeks post-treatment both had significantly reduced foot pain and disability (both p < 0.0001). There was no significant difference in effectiveness between the bespoke or prefabricated orthoses. However, prefabricated devices were 38% cheaper per patient compared with the average costs of casted devices. CONCLUSION: For most patients with plantar heel pain, prefabricated semi-rigid insoles such as the PowerstepTM devices used in the present trial provide short-term benefit equivalent to that of bespoke, casted foot orthoses, but at considerably reduced costs. PMID- 23801650 TI - Evaluation of urovysion and cytology for bladder cancer detection: a study of 1835 paired urine samples with clinical and histologic correlation. AB - BACKGROUND: Urine cytology has been used for screening of bladder cancer but has been limited by its low sensitivity. UroVysion is a multiprobe fluorescence in situ hybridization (FISH) assay that detects common chromosome abnormalities in bladder cancers. For this study, the authors evaluated the effectiveness of multiprobe FISH and urine cytology in detecting urothelial cell carcinoma (UCC) in the same urine sample. METHODS: In total, 1835 cases with the following criteria were selected: valid results from both the multiprobe FISH assay and urine cytology in the same urine sample, histologic and/or cystoscopic follow-up within 4 months of the original tests, or at least 3 years of clinical follow-up information. The results of FISH and cytology were correlated with clinical outcomes derived from a combination of histologic, cystoscopic, and clinical follow-up information. RESULTS: Of 1835 cases, 1045 cases were from patients undergoing surveillance of recurrent UCC, and 790 were for hematuria. The overall sensitivity, specificity, positive predictive value, and negative predictive value in detecting UCC were 61.9%, 89.7%, 53.9%, and 92.4%, respectively, for FISH and 29.1%, 96.9%, 64.4%, and 87.5%, respectively, for cytology. The performance of both FISH and cytology generally was better in the surveillance population and in samples with high-grade UCC. In 95 of 296 cases with atypical cytology that were proven to have UCC, 61 cases, mostly high-grade UCC, were positive using the multiprobe FISH assay. CONCLUSIONS: The UroVysion multiprobe FISH assay was more sensitive than urine cytology in detecting UCC, but it produced more false-positive results. The current data suggest that the use of FISH as a reflex test after an equivocal cytologic diagnosis may play an effective role in detecting UCC. PMID- 23801651 TI - 1,4-Dihydroxy-2-naphthoic acid from Propionibacterium freudenreichii reduces inflammation in interleukin-10-deficient mice with colitis by suppressing macrophage-derived proinflammatory cytokines. AB - The anti-inflammatory mechanism of prebiotics has recently been shown to have an impact on the host immune system. DHNA from Propionibacterium freudenreichii is known to promote the proliferation of Bifidobacterium and can ameliorate colitis, although its mode of action remains unknown. In this study, we investigated whether DHNA attenuates inflammation in piroxicam-treated IL-10(-/-) mice, particularly focusing on the changes of the host immune mechanism. DHNA was administered to IL-10(-/-) mice with colitis, and the expression of adhesion molecules and mRNA levels of proinflammatory cytokines were determined. DHNA pretreatment attenuated the piroxicam-induced histological changes. The increased F4/80-positive cell infiltration and VCAM-1 expression were decreased by DHNA administration. The increased mRNA levels of proinflammatory cytokines were also suppressed by DHNA. In in vitro experiments, increased mRNA levels of proinflammatory cytokines after endotoxin exposure were decreased significantly by DHNA pretreatment in RAW264.7, a macrophage cell line, and IL-10(-/-) mice BMMs, whereas the expression of VCAM-1 in bEnd.3 cells, a endothelial cell line, was not affected. Taken together, these findings suggest that administration of DHNA is useful for the treatment of colitis in piroxicam-treated IL-10(-/-) mice and that attenuation of colitis by DHNA may partly be a result of its direct action on intestinal macrophages to inhibit proinflammatory cytokine production. PMID- 23801652 TI - Functional consequences of platelet binding to T lymphocytes in inflammation. AB - Expression of the scavenger receptor CD36 on lymphocytes is intriguing. We observed that a minor subpopulation of lymphocytes expressed CD36 on the cell surface. We investigated the source of CD36 and also the proliferation and cytokine production of these CD36(+) CD4(+) lymphocytes. Flow cytometry analysis and immunofluorescence microscopy showed that CD36(+) platelets were responsible for CD36 detection on lymphocytes. CD36 was then used as a tool to characterize lymphocytes with bound platelets. Activation-induced proliferation was lower in CD4(+) lymphocytes with bound platelets than lymphocytes without bound platelets. IL-17 and IFN-gamma production was also reduced in lymphocytes with bound platelets. We then studied the presence of CD36(+) CD4(+) lymphocytes in RA patients. We observed that the percentage of CD4(+) lymphocytes with bound platelets was higher on RA patients than in healthy donors. RA patients with higher titers of anti-CCP, RF levels, and cardiovascular risk index presented a lower percentage of CD4(+) lymphocytes with bound platelets. These patients also had higher IL-17 and IFN-gamma production. These results suggest that platelet binding modifies lymphocyte function. This binding could be a regulatory mechanism in RA that confers a less severe phenotype. PMID- 23801653 TI - FMNL1 promotes proliferation and migration of leukemia cells. AB - The human FMNL1 is expressed predominantly in hematopoietic cells and has been described previously as overexpressed in hematopoietic malignancies. However, it is not known whether FMNL1 contributes to leukemogenesis. Here, we investigate the FMNL1 function using two different human leukemia models: Namalwa and K562 cell lines. FMNL1 depletion reduced cell proliferation and colony formation in both leukemic cell types, as well as a decrease in the tumor growth of FMNL1 depleted Namalwa cell xenografts. In addition, there was a decrease in migration and in TEM in FMNL1-depleted Namalwa cells. FMNL1 endogenously associates with Rac1, and FMNL1 silencing resulted in an increased Rac1 activity. The reduced migration observed in FMNL1-depleted cells was restored by inhibiting Rac activity. Our results indicate that FMNL1 stimulates leukemia cell proliferation as well as migration. This suggests that FMNL1 contributes to leukemogenesis and could act in part through Rac1 regulation. PMID- 23801654 TI - The role of type 2 innate lymphoid cells in asthma. AB - Asthma is a complex and heterogeneous disease with several phenotypes, including an allergic asthma phenotype, characterized by Th2 cytokine production and associated with allergen sensitization and adaptive immunity. Asthma also includes nonallergic asthma phenotypes that require innate rather than adaptive immunity. These innate pathways to asthma involve macrophages, neutrophils, as well as ILCs, newly described cell types that produce a variety of cytokines, including IL-5 and IL-13. We review the recent data regarding ILCs and their role in asthma. PMID- 23801656 TI - A literature review of the outcomes after robot-assisted laparoscopic and conventional laparoscopic Nissen fundoplication for gastro-esophageal reflux disease in children. AB - BACKGROUND: Robot-assisted surgery is a promising technical innovation. Given the similarities between laparoscopic and robot-assisted surgery it is unlikely that randomized controlled trials would be conducted to disclose any differences between these two technical instruments. Thus, skepticism remains due to lack of any definitive conclusions in the literature. AIMS: The aim of the study was to disclose any difference in outcome after robot-assisted (RNF) versus conventional laparoscopic (LNF) Nissen fundoplication for gastro-esophageal reflux disease in children. MATERIALS AND METHODS: A literature review was carried out. Only studies comparing the two modalities were included. Operative time, duration of hospital stay, 30 days morbidity, mortality, conversion, recurrence and complication rates were analyzed. Review Manager 5.1.6 software, from the Cochrane library, was used for statistical analysis. RESULTS: Three case series fulfilled the criteria for inclusion in this review. Data on 174 children were identified; 89 were operated on using the computer-assisted technology and 85 controls were operated on using the conventional laparoscopic technique. Data showed no significant difference between these two modalities. DISCUSSION: This literature review demonstrates no significant difference between patients operated on with robot-assisted surgery and those undergoing conventional laparoscopic surgery regarding the parameters studied. CONCLUSION: The robot assisted Nissen fundoplication in children is a safe alternative to conventional laparoscopic surgery. No data support the need for case selection to one of these two minimally invasive procedures. PMID- 23801657 TI - Stem cells as a good tool to investigate dysregulated biological systems in autism spectrum disorders. AB - Identification of the causes of autism spectrum disorders (ASDs) is hampered by their genetic heterogeneity; however, the different genetic alterations leading to ASD seem to be implicated in the disturbance of common molecular pathways or biological processes. In this scenario, the search for differentially expressed genes (DEGs) between ASD patients and controls is a good alternative to identify the molecular etiology of such disorders. Here, we employed genome-wide expression analysis to compare the transcriptome of stem cells of human exfoliated deciduous teeth (SHEDs) of idiopathic autistic patients (n = 7) and control samples (n = 6). Nearly half of the 683 identified DEGs are expressed in the brain (P = 0.003), and a significant number of them are involved in mechanisms previously associated with ASD such as protein synthesis, cytoskeleton regulation, cellular adhesion and alternative splicing, which validate the use of SHEDs to disentangle the causes of autism. Autistic patients also presented overexpression of genes regulated by androgen receptor (AR), and AR itself, which in turn interacts with CHD8 (chromodomain helicase DNA binding protein 8), a gene recently shown to be associated with the cause of autism and found to be upregulated in some patients tested here. These data provide a rationale for the mechanisms through which CHD8 leads to these diseases. In summary, our results suggest that ASD share deregulated pathways and revealed that SHEDs represent an alternative cell source to be used in the understanding of the biological mechanisms involved in the etiology of ASD. PMID- 23801658 TI - Click chemistry immobilization strategies in the development of strong cation exchanger chiral stationary phases for HPLC. AB - Enantioseparation of chiral amines with HPLC has developed into a widely used analytical and preparative tool. Chiral basic molecules, which act as cationic species upon protonation, are suited for an enantioselective cation exchange process. Novel strong cation exchangers (SCX) based on different 3,5 disubstituted benzoic acids functionalized with trans-(R,R)- and trans-(S,S)-2 aminocyclohexanesulfonic acid as the chiral selector (SO) and ion exchange unit were synthesized. Employing 1,3-dipolar cycloaddition (azide-yne click chemistry), the SOs were immobilized onto azidopropyl-modified silica gel. This immobilization strategy enables controlled loading of the SO, and especially, high SO density on the silica surface compared to the thiol-ene click immobilization. The performance of the novel SCX chiral stationary phases was evaluated under polar organic mode conditions with different ratios of methanol and acetonitrile, thereby changing the polarity of the bulk mobile phase. The type of co- and counterion additives employed in the mobile phase was varied as well. The influence of the formed 1,2,3-triazol spacer as well as different substitution patterns in the benzene unit on the chiral recognition properties of the SOs is discussed. PMID- 23801655 TI - Microbial characterization of probiotics--advisory report of the Working Group "8651 Probiotics" of the Belgian Superior Health Council (SHC). AB - When ingested in sufficient numbers, probiotics are expected to confer one or more proven health benefits on the consumer. Theoretically, the effectiveness of a probiotic food product is the sum of its microbial quality and its functional potential. Whereas the latter may vary much with the body (target) site, delivery mode, human target population, and health benefit envisaged microbial assessment of the probiotic product quality is more straightforward. The range of stakeholders that need to be informed on probiotic quality assessments is extremely broad, including academics, food and biotherapeutic industries, healthcare professionals, competent authorities, consumers, and professional press. In view of the rapidly expanding knowledge on this subject, the Belgian Superior Health Council installed Working Group "8651 Probiotics" to review the state of knowledge regarding the methodologies that make it possible to characterize strains and products with purported probiotic activity. This advisory report covers three main steps in the microbial quality assessment process, i.e. (i) correct species identification and strain-specific typing of bacterial and yeast strains used in probiotic applications, (ii) safety assessment of probiotic strains used for human consumption, and (iii) quality of the final probiotic product in terms of its microbial composition, concentration, stability, authenticity, and labeling. PMID- 23801659 TI - In this edition of the International Forum of Allergy and Rhinology. PMID- 23801660 TI - Bacteria in the nose of young adults during wellness and rhinovirus colds: detection by culture and microarray methods in 100 nasal lavage specimens. AB - BACKGROUND: Patients with viral respiratory infections/viral rhinitis/common colds are often treated with antibiotic; however, there is little information on whether or how bacterial microbiota in the nose and nasopharynx might influence the course of viral illnesses. METHODS: To initiate investigation of possible interaction between viral respiratory illness and microbiota of the nose/nasopharynx, we used microarray technology to examine 100 nasal lavage fluid (NLF) samples for bacterial species and recorded the bacterial titer of culturable bacteria. Rhinovirus illnesses were induced by self-inoculation using the "finger to nose or eye natural transmission route" in 10 otherwise healthy young adults. NLF samples were collected during wellness and at specific time points following experimental rhinovirus inoculation. RESULTS: The rhinovirus infection rate was 70%. There were no consistent changes in the prevalence of different bacterial species determined by microarray and bacterial titer by culture methods during rhinovirus infection. The bacterial profile in NLF samples showed high variability between volunteers but low variability in multiple NLFs obtained before and following infection from the same volunteer. Streptococcus epidermidis/coagulase-negative staphylococcus (CNS) were identified in all 10 subjects. One or more bacterial sinus/otitis pathogens were identified by microarray in 6 of the 10 volunteers. The microarray identified a few bacteria not included in traditional bacterial cultures. CONCLUSION: Our pilot study showed that each of the 10 volunteers had a unique bacterial profile in the nose by microarray analysis and that bacterial load did not change during experimental rhinovirus colds. Larger scale studies are warranted. PMID- 23801661 TI - Antisense oligonucleotide inhibition of cholesteryl ester transfer protein enhances RCT in hyperlipidemic, CETP transgenic, LDLr-/- mice. AB - Due to their ability to promote positive effects across all of the lipoprotein classes, cholesteryl ester transfer protein (CETP) inhibitors are currently being developed as therapeutic agents for cardiovascular disease. In these studies, we compared an antisense oligonucleotide (ASO) inhibitor of CETP to the CETP small molecule inhibitor anacetrapib. In hyperlipidemic CETP transgenic (tg) mice, both drugs provided comparable reductions in total plasma cholesterol, decreases in CETP activity, and increases in HDL cholesterol. However, only mice treated with the antisense inhibitor showed an enhanced effect on macrophage reverse cholesterol transport, presumably due to differences in HDL apolipoprotein composition and decreases in plasma triglyceride. Additionally, the ASO-mediated reductions in CETP mRNA were associated with less accumulation of aortic cholesterol. These preliminary findings suggest that CETP ASOs may represent an alternative means to inhibit that target and to support their continued development as a treatment for cardiovascular disease in man. PMID- 23801662 TI - Relationship between diet and plasma long-chain n-3 PUFAs in older people: impact of apolipoprotein E genotype. AB - The main risk factors for Alzheimer's disease, age and the epsilon4 allele of the APOE gene (APOE4), might modify the metabolism of n-3 PUFAs and in turn, their impact on cognition. The aim of this study was to investigate the association between dietary fat and plasma concentrations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in elderly persons, taking the APOE4 genotype into account. The sample was composed of 1,135 participants from the Three-City study aged 65 years and over, of whom 19% were APOE4 carriers. Mean plasma proportions of EPA [1.01%, standard deviation (SD) 0.60] and DHA (2.41%, SD 0.81) did not differ according to APOE4. In multivariate models, plasma EPA increased with frequency of fish consumption (P < 0.0001), alcohol intake (P = 0.0006), and female gender (P = 0.02), and decreased with intensive consumption of n-6 oils (P = 0.02). The positive association between fish consumption and plasma DHA was highly significant whatever the APOE genotype (P < 0.0001) but stronger in APOE4 noncarriers than in carriers (P = 0.06 for interaction). Plasma DHA increased significantly with age (P = 0.009) in APOE4 noncarriers only. These findings suggest that dietary habits, gender, and APOE4 genotype should be considered when designing interventions to increase n-3 PUFA blood levels in older people. PMID- 23801663 TI - Introducing WIREs Developmental Biology. PMID- 23801664 TI - Morphogen gradients in development: from form to function. AB - Morphogens are substances that establish a graded distribution and elicit distinct cellular responses in a dose-dependent manner. They function to provide individual cells within a field with positional information, which is interpreted to give rise to spatial patterns. Morphogens can consist of intracellular factors that set up a concentration gradient by diffusion in the cytoplasm. More commonly, morphogens comprise secreted proteins that form an extracellular gradient across a field of cells. Experimental studies and computational analyses have provided support for a number of diverse strategies by which extracellular morphogen gradients are formed. These include free diffusion in the extracellular space, restricted diffusion aided by interactions with heparan sulfate proteoglycans, transport on lipid-containing carriers or transport aided by soluble binding partners. More specialized modes of transport have also been postulated such as transcytosis, in which repeated rounds of secretion, endocytosis, and intracellular trafficking move morphogens through cells rather than around them, or cytonemes, which consist of filopodial extensions from signal-receiving cells that are hypothesized to reach out to morphogen-sending cells. Once the gradient has formed, cells must distinguish small differences in morphogen concentration and store this information even after the gradient has dissipated. This is often achieved by translating ligand concentration into a proportional increase in numbers of activated cell surface receptors that are internalized and continue to signal from endosomal compartments. Ultimately, this leads to activation of one or a few transcription factors that transduce this information into qualitatively distinct gene responses inside the nucleus. PMID- 23801667 TI - Neural crest specification: tissues, signals, and transcription factors. AB - The neural crest is a transient population of multipotent and migratory cells unique to vertebrate embryos. Initially derived from the borders of the neural plate, these cells undergo an epithelial to mesenchymal transition to leave the central nervous system, migrate extensively in the periphery, and differentiate into numerous diverse derivatives. These include but are not limited to craniofacial cartilage, pigment cells, and peripheral neurons and glia. Attractive for their similarities to stem cells and metastatic cancer cells, neural crest cells are a popular model system for studying cell/tissue interactions and signaling factors that influence cell fate decisions and lineage transitions. In this review, we discuss the mechanisms required for neural crest formation in various vertebrate species, focusing on the importance of signaling factors from adjacent tissues and conserved gene regulatory interactions, which are required for induction and specification of the ectodermal tissue that will become neural crest. PMID- 23801666 TI - Perspectives on the RNA polymerase II core promoter. AB - The RNA polymerase II core promoter is sometimes referred to as the gateway to transcription. The core promoter is generally defined to be the stretch of DNA that directs the initiation of transcription. This simple description belies a complex multidimensional regulatory element, as there is considerable diversity in core promoter structure and function. Core promoters can be viewed at the levels of DNA sequences, transcription factors, and biological networks. Key DNA sequences are known as core promoter elements, which include the TATA box, initiator (Inr), polypyrimidine initiator (TCT), TFIIB recognition element (BRE), motif ten element (MTE), and downstream core promoter element (DPE) motifs. There are no universal core promoter elements that are present in all promoters. Different types of core promoters are transcribed by different sets of transcription factors and exhibit distinct properties, such as specific interactions with transcriptional enhancers, that are determined by the presence or absence of particular core promoter motifs. Moreover, some core promoter elements have been found to be associated with specific biological networks. For instance, the TCT motif is dedicated to the transcription of ribosomal protein genes in Drosophila and humans. In addition, nearly all of the Drosophila Hox genes have a DPE motif in their core promoters. The complexity of the core promoter is further seen in the relation among transcription initiation patterns, the stability or lability of transcriptional states, and the organization of the chromatin structure in the promoter region. Hence, the current data indicate that the core promoter is a critical component in the regulation of gene activity. PMID- 23801665 TI - Comparisons of the embryonic development of Drosophila, Nasonia, and Tribolium. AB - Studying the embryogenesis of diverse insect species is crucial to understanding insect evolution. Here, we review current advances in understanding the development of two emerging model organisms: the wasp Nasonia vitripennis and the beetle Tribolium castaneum in comparison with the well-studied fruit fly Drosophila melanogaster. Although Nasonia represents the most basally branching order of holometabolous insects, it employs a derived long germband mode of embryogenesis, more like that of Drosophila, whereas Tribolium undergoes an intermediate germband mode of embryogenesis, which is more similar to the ancestral mechanism. Comparing the embryonic development and genetic regulation of early patterning events in these three insects has given invaluable insights into insect evolution. The similar mode of embryogenesis of Drosophila and Nasonia is reflected in their reliance on maternal morphogenetic gradients. However, they employ different genes as maternal factors, reflecting the evolutionary distance separating them. Tribolium, on the other hand, relies heavily on self-regulatory mechanisms other than maternal cues, reflecting its sequential nature of segmentation and the need for reiterated patterning. PMID- 23801668 TI - Salivary gland organogenesis. AB - Our understanding of vertebrate salivary gland organogenesis has been largely informed by the study of the developing mouse submandibular gland (SMG), which will be the major focus of this review. The mouse SMG has been historically used as a model system to study epithelial-mesenchymal interactions, growth factor extracellular matrix (ECM) interactions, and branching morphogenesis. SMG organogenesis involves interactions between a variety of cell types and their stem/progenitor cells, including the epithelial, neuronal, and mesenchymal cells, and their ECM microenvironment, or niche. Here, we will review recent literature that provides conceptual advances in understanding the molecular mechanisms of salivary gland development. We will describe SMG organogenesis, introduce the model systems used to study development, and outline the key signaling pathways and cellular processes involved. We will also review recent research focusing on the identification of stem/progenitor cells in the SMG and how they are directed along a series of cell fate decisions to form a functional gland. The mechanisms that drive SMG organogenesis provide a template to regenerate functional salivary glands in patients who suffer from salivary hypofunction due to irreversible glandular damage after irradiation or removal of tumors. Additionally, these mechanisms may also control growth and development of other organ systems. PMID- 23801669 TI - The microRNA regulation of stem cells. AB - The microRNA (miRNA) pathway, as a fundamental mechanism of gene regulation, plays a key role in controlling the establishment, self-renewal, and differentiation of stem cells. Such regulation is manifested as fine tuning the temporal- and tissue-specificity of gene expression. This fine-tuning function is achieved by (1) miRNAs form positive and negative feedback loops with transcription factors and epigenetic factors to exert concerted control of given biological processes and/or (2) different miRNAs converge to control one or more mRNA targets in a signaling pathway. These regulatory mechanisms are found in embryonic stem cells, iPS cells, and adult tissue stem cells. The distinct expression profiles of miRNAs and their regulatory roles in various types of stem cells render these RNAs potentially effective tools for clinical diagnosis and therapy. PMID- 23801670 TI - Pathfinding in angiosperm reproduction: pollen tube guidance by pistils ensures successful double fertilization. AB - Sexual reproduction in flowering plants is unique in multiple ways. Distinct multicellular gametophytes contain either a pair of immotile, haploid male gametes (sperm cells) or a pair of female gametes (haploid egg cell and homodiploid central cell). After pollination, the pollen tube, a cellular extension of the male gametophyte, transports both male gametes at its growing tip and delivers them to the female gametes to affect double fertilization. The pollen tube travels a long path and sustains its growth over a considerable amount of time in the female reproductive organ (pistil) before it reaches the ovule, which houses the female gametophyte. The pistil facilitates the pollen tube's journey by providing multiple, stage-specific, nutritional, and guidance cues along its path. The pollen tube interacts with seven different pistil cell types prior to completing its journey. Consequently, the pollen tube has a dynamic gene expression program allowing it to continuously reset and be receptive to multiple pistil signals as it migrates through the pistil. Here, we review the studies, including several significant recent advances, that led to a better understanding of the multitude of cues generated by the pistil tissues to assist the pollen tube in delivering the sperm cells to the female gametophyte. We also highlight the outstanding questions, draw attention to opportunities created by recent advances and point to approaches that could be undertaken to unravel the molecular mechanisms underlying pollen tube-pistil interactions. PMID- 23801672 TI - Direct cellular reprogramming in Caenorhabditis elegans: facts, models, and promises for regenerative medicine. AB - In vitro systems of cellular reprogramming [induced pluripotent stem (iPS) cells and direct reprogramming or transdifferentiation] are rapidly improving our repertoire of molecular techniques that can force cells in culture to change into a desired identity. However, the new frontier for regenerative medicine is in vivo cellular reprogramming, which in light of concerns about the safety of in vitro cell manipulations, is an increasingly attractive approach for regenerative medicine. Powerful in vivo approaches are currently being undertaken in the genetic model Caenorhabditis elegans. Several very distinct cell types have been induced to change or have been discovered to transform naturally, into altogether different cell types. These examples have improved our understanding of the fundamental molecular and cellular mechanisms that permit cell identity changes in live animals. In addition, the combination of a stereotyped lineage with single cell analyses allows dissection of the early and intermediate mechanisms of reprogramming, as well as their kinetics. As a result, several important concepts on in vivo cellular reprogramming have been recently developed. PMID- 23801673 TI - Frontier of life science. PMID- 23801671 TI - From genes to function: the C. elegans genetic toolbox. AB - This review aims to provide an overview of the technologies which make the nematode Caenorhabditis elegans an attractive genetic model system. We describe transgenesis techniques and forward and reverse genetic approaches to isolate mutants and clone genes. In addition, we discuss the new possibilities offered by genome engineering strategies and next-generation genome analysis tools. PMID- 23801674 TI - Characterization of different osteosarcoma phenotypes by PET imaging in preclinical animal models. AB - The aim of this study was to characterize the different phenotypes of osteosarcoma by PET, comparing the uptake of 3 tracers ((18)F-FDG, (18)F fluoromisonidazole [(18)F-FMISO], and (18)F-fluoride) in preclinical mouse models that reflect the heterogeneity of the human disease. METHODS: Mouse LM8 osteosarcoma, human 143B, and Caprin-1 stably overexpressing SaOS-2 cells were injected intratibially in C3H and severe-combined immunodeficient mice. PET imaging with (18)F-FDG, (18)F-FMISO, and (18)F-fluoride was performed in these mouse models, and a ratio between the standardized uptake value of the primary tumor and a control area of bone was calculated and compared among the models. Histology and immunohistochemistry were performed to confirm the PET findings. RESULTS: The pattern of tracer uptake differed among the primary tumors of the 3 models in accordance with the histology and immunohistochemistry on primary tumor sections. The osteolytic tumors in the 143B model showed the highest uptake of (18)F-FDG, an indicator of glucose metabolism, which was significantly higher (P < 0.05) than in the SaOS-2/Caprin-1 model and correlated with the percentage of Ki67-positive cells in the primary tumors. Hypoxia, indicated by (18)F-FMISO accumulation, was higher in the SaOS-2/Caprin-1 and 143B cell line-derived tumors (P < 0.01). Finally (18)F-fluoride, a marker of bone remodeling, correlated with the osteoblastic phenotype. The SaOS-2/Caprin-1 cell-derived tumors showed a significantly higher uptake than the moderately osteoblastic LM8 (P < 0.05) and the osteolytic 143B (P < 0.01) cell line-derived tumors. CONCLUSION: Differential PET imaging with tracers indicating metabolic activity, hypoxia, or bone remodeling will be helpful for the characterization of different osteosarcoma phenotypes and subsequent evaluation of more specific treatment modalities targeting the processes that are predominant in each specific tumor type or subtype. PMID- 23801675 TI - Exploratory evaluation of MR permeability with 18F-FDG PET mapping in pediatric brain tumors: a report from the Pediatric Brain Tumor Consortium. AB - The purpose of this study was to develop a method of registering (18)F-FDG PET with MR permeability images for investigating the correlation of (18)F-FDG uptake, permeability, and cerebral blood volume (CBV) in children with pediatric brain tumors and their relationship with outcome. METHODS: Twenty-four children with brain tumors in a phase II study of bevacizumab and irinotecan underwent brain MR and (18)F-FDG PET within 2 wk. Tumor types included supratentorial high grade astrocytoma (n = 7), low-grade glioma (n = 9), brain stem glioma (n = 4), medulloblastoma (n = 2), and ependymoma (n = 2). There were 33 cases (pretreatment only [n = 12], posttreatment only [n = 3], and both pretreatment [n = 9] and posttreatment [n = 9]). (18)F-FDG PET images were registered to MR images from the last time point of the T1 perfusion time series using mutual information. Three-dimensional regions of interest (ROIs) drawn on permeability images were automatically transferred to registered PET images. The quality of ROI registration was graded (1, excellent; 2, very good; 3, good; 4, fair; and 5, poor) by 3 independent experts. Spearman rank correlations were used to assess correlation of maximum tumor permeability (Kps(max)), maximum CBV (CBV(max)), and maximum (18)F-FDG uptake normalized to white matter (T/W(max)). Cox proportional hazards models were used to investigate associations of these parameters with progression-free survival (PFS). RESULTS: The quality of ROI registration between PET and MR was good to excellent in 31 of 33 cases. There was no correlation of baseline Kps(max) with CBV(max) (Spearman rank correlation = 0.018 [P = 0.94]) or T/W(max) (Spearman rank correlation = 0.07 [P = 0.76]). Baseline CBV(max) was correlated with T/W(max) (Spearman rank correlation = 0.47 [P = 0.036]). Baseline Kps(max), CBV(max), and T/W(max) were not significantly associated with PFS (P = 0.42, hazard ratio [HR] = 0.97, 95% confidence interval [CI] = 0.90-1.045, and number of events [n(events)] = 15 for Kps(max); P = 0.41, HR = 0.989, 95% CI = 0.963-1.015, and n(events) = 14 for CBV(max); and P = 0.17, HR = 1.49, 95% CI = 0.856-2.378, and n(events) = 15 for T/W(max)). CONCLUSION: (18)F-FDG PET and MR permeability images were successfully registered and compared across a spectrum of pediatric brain tumors. The lack of correlation between metabolism and permeability may be expected because these parameters characterize different molecular processes. The correlation of CBV and tumor metabolism may be related to an association with tumor grade. More patients are needed for a covariate analysis of these parameters and PFS by tumor histology. PMID- 23801676 TI - PET imaging of high-affinity alpha4beta2 nicotinic acetylcholine receptors in humans with 18F-AZAN, a radioligand with optimal brain kinetics. AB - We evaluated (-)-2-(6-[(18)F]fluoro-2,3'-bipyridin-5'-yl)-7-methyl-7-aza bicyclo[2.2.1]heptane ((18)F-AZAN), a novel radiotracer that binds to alpha4beta2 nicotinic acetylcholine receptors (alpha4beta2-nAChRs) and shows high specific binding and rapid and reversible kinetics in the baboon and human brain. METHODS: We tested safety tolerability and test-retest reliability (n = 5) and proposed initial quantification of (18)F-AZAN receptors in 3 healthy human subjects who had nicotine exposure and 9 who did not. We also present a receptor blocking study in a nicotine subject dosed with the alpha4beta2-nAChR-selective partial agonist varenicline. RESULTS: Radiation dosimetry PET/CT experiments indicated that most human organs received doses between 0.008 and 0.015 mSv/MBq, with an effective dose of approximately 0.014 mSv/MBq. The tracer rapidly entered the brain, and the peak was reached before 20 min, even for thalamus. Ninety-minute scans were sufficient for (18)F-AZAN to obtain the ratio at equilibrium of specifically bound radioligand to nondisplaceable radioligand in tissue (BPND) using plasma reference graphical analysis, which showed excellent reproducibility of BPND (test-retest variability < 10%) in the nAChR-rich brain regions. Regional plasma reference graphical analysis BP(ND) values exceeded 2 in the midbrain tegmental nuclei, lateral geniculate body, and thalamus for nonsmokers (n = 9) but were less than 1 in the nAChR-poor brain regions. There was a dramatic reduction of (18)F-AZAN brain uptake in smokers and varenicline-treated subjects. CONCLUSION: (18)F-AZAN is a highly specific, safe, and effective PET radioligand for human subjects that requires only 90 min of PET scanning to estimate high affinity alpha4beta2-nAChR in the living human brain. PMID- 23801677 TI - Dihydrotestosterone alters urocortin levels in human umbilical vein endothelial cells. AB - Urocortin (UCN1) is a member of corticotrophin-releasing factor (CRF) family, which has been proven to participate in inflammation. Previous work showed that dihydrotestosterone (DHT) could promote the inflammatory process. Little is known about the effect of DHT on UCN1 expression. The aim of our study is to investigate the effects and underlying mechanisms of DHT on endothelial UCN1 expression in the absence and presence of induced inflammation. Therefore, we tested the alterations of endothelial UCN1 expression treated with DHT in the presence or absence of lipopolysaccharide (LPS). Our data showed that DHT alone decreased UCN1 levels, which were attenuated in the presence of the androgen receptor (AR) antagonist flutamide. Conversely, in the presence of LPS, DHT augmented the LPS-induced increase in UCN1 expression, which was, interestingly, not affected by flutamide. When cells were treated with DHT alone, AR was upregulated and translocated into the nuclei, which might repress UCN1 expression via a potential androgen-responsive element found in human CRF family promoter. In the presence of LPS, DHT did not influence AR expression and location while it increased toll-like receptor 4 expression and activation, which was not altered by flutamide. DHT enhanced LPS-induced p38MAPK, ERK1/2, and nuclear factor kappaB pathway activation, which may contribute to the elevated expression of UCN1. These data suggest that DHT differentially influences UCN1 levels under normal and inflammatory conditions in human umbilical vein endothelial cells, which involves AR-dependent and -independent mechanisms respectively. PMID- 23801679 TI - Brutal pragmatism on food. PMID- 23801678 TI - Differential drug-drug interactions of the synthetic Cannabinoids JWH-018 and JWH 073: implications for drug abuse liability and pain therapy. AB - Marijuana substitutes often contain blends of multiple psychoactive synthetic cannabinoids (SCBs), including the prevalent SCBs (1-pentyl-1H-indole-3-yl)-1 naphthalenyl-methanone (JWH-018) and (1-butyl-1H-indole-3-yl)-1-naphthalenyl methanone (JWH-073). Because SCBs are frequently used in combinations, we hypothesized that coadministering multiple SCBs induces synergistic drug-drug interactions. Drug-drug interactions between JWH-018 and JWH-073 were investigated in vivo for Delta(9)-tetrahydrocannabinol (Delta(9)-THC)-like discriminative stimulus effects, analgesia, task disruption, and hypothermia. Combinations (JWH-018:JWH-073) of these drugs were administered to mice in assays of Delta(9)-THC discrimination, tail-immersion, and food-maintained responding, and rectal temperatures were measured. Synergism occurred in the Delta(9)-THC discrimination assay for two constant dose ratio combinations (1:3 and 1:1). A 1:1 and 2:3 dose ratio induced additivity and synergy, respectively, in the tail immersion assay. Both 1:1 and 2:3 dose ratios were additive for hypothermia, whereas a 1:3 dose ratio induced subadditive suppression of food-maintained responding. In vitro drug-drug interactions were assessed using competition receptor-binding assays employing mouse brain homogenates and cannabinoid 1 receptor (CB1R)-mediated inhibition of adenylyl cyclase activity in Neuro2A wild type cells. Interestingly, synergy occurred in the competition receptor-binding assay for two dose ratios (1:5 and 1:10), but not in the adenylyl cyclase activity assay (1:5). Altogether, these data indicate that drug-drug interactions between JWH-018 and JWH-073 are effect- and ratio-dependent and may increase the relative potency of marijuana substitutes for subjective Delta(9)-THC-like effects. Combinations may improve the therapeutic profile of cannabinoids, considering that analgesia but not hypothermia or task disruption was potentiated. Importantly, synergy in the competition receptor-binding assay suggests multiple CB1R-SCB binding sites. PMID- 23801680 TI - Familial breast cancer: summary of updated NICE guidance. PMID- 23801681 TI - Abortion in bipolar disorder case. Who will take responsibility and sign the abortion form in the case of the woman with bipolar disorder? PMID- 23801682 TI - Patients are mismanaged when they are well investigated but not well examined. PMID- 23801683 TI - Clinical examination enables diagnosis of silent syndromes in diabetes. PMID- 23801684 TI - Clinical examination is the stuff of general practice. PMID- 23801685 TI - We need to evaluate each component of clinical examination like any other diagnostic test. PMID- 23801686 TI - Is clinical examination dead? Author's reply to Armour, Coll, Thomas, and Witham. PMID- 23801687 TI - Day of the week and surgical mortality. Media wrongly jump to blame junior doctors for increased surgical mortality at weekends. PMID- 23801688 TI - Day of the week and surgical mortality. Hospital set up over the week explains difference in mortality for elective surgery. PMID- 23801689 TI - Diabetes UK replies to Dr Aseem Malhotra. PMID- 23801690 TI - Workforce planning. Why is India short of nurses and what can we do about it? PMID- 23801691 TI - Don't forget children with imported malaria in non-endemic countries. PMID- 23801692 TI - Dying in hospital is not always a bad thing. PMID- 23801693 TI - Importance of eye care in meeting the needs of patients with learning disabilities. PMID- 23801694 TI - Statins are not bad medicine but their misuse is. PMID- 23801695 TI - Meeting needs in learning disability.Human rights should be taught in medical school to ensure proper care for people with learning disabilities. PMID- 23801696 TI - Hearing loss in adults requires a holistic tailored approach. PMID- 23801697 TI - Coronavirus will spread as long as natural host is unknown, say scientists. PMID- 23801698 TI - More doctors have no legal representation at GMC hearings. PMID- 23801699 TI - BMA meeting: BMA passes vote of no confidence in health secretary. PMID- 23801700 TI - Former CQC executive denies any "cover up" of internal report. PMID- 23801701 TI - NICE recommends preventive drugs for breast cancer. PMID- 23801702 TI - Health insurance is "very important" to young US adults, poll finds. PMID- 23801703 TI - Excess mortality associated with diabetes is falling, study shows. PMID- 23801704 TI - JAMA relaxes requirements on industry sponsored studies. PMID- 23801705 TI - Former chief of Care Quality Commission hits back at allegations of a cover up. PMID- 23801706 TI - BMA meeting: doctors call for professional regulation of managers to hold them to account. PMID- 23801707 TI - Experts call for greater regulation of deep brain stimulation. PMID- 23801708 TI - Problem of pressure on emergency services won't be solved overnight, government warns. PMID- 23801709 TI - Platelet-rich therapy in the treatment of patients with hip fractures: a single centre, parallel group, participant-blinded, randomised controlled trial. AB - OBJECTIVE: To quantify and draw inferences on the clinical effectiveness of platelet-rich therapy in the management of patients with a typical osteoporotic fracture of the hip. DESIGN: Single centre, parallel group, participant-blinded, randomised controlled trial. SETTING: UK Major Trauma Centre. PARTICIPANTS: 200 of 315 eligible patients aged 65 years and over with any type of intracapsular fracture of the proximal femur. Patients were excluded if their fracture precluded internal fixation. INTERVENTIONS: Participants underwent internal fixation of the fracture with cannulated screws and were randomly allocated to receive an injection of platelet-rich plasma into the fracture site or not. MAIN OUTCOME MEASURES: Failure of fixation within 12 months, defined as any revision surgery. RESULTS: Primary outcome data were available for 82 of 101 and 78 of 99 participants allocated to test and control groups, respectively; the remainder died prior to final follow-up. There was an absolute risk reduction of 5.6% (95% CI -10.6% to 21.8%) favouring treatment with platelet-rich therapy (chi(2) test, p=0.569). An adjusted effect estimate from a logistic regression model was similar (OR=0.71, 95% CI 0.36 to 1.40, z test; p=0.325). There were no significant differences in any of the secondary outcome measures excepting length of stay favouring treatment with platelet-rich therapy (median difference 8 days, Mann-Whitney U test; p=0.03). The number and distribution of adverse events were similar. Estimated cumulative incidence functions for the competing events of death and revision demonstrated no evidence of a significant treatment effect (HR 0.895, 95% CI 0.533 to 1.504; p=0.680 in favour of platelet-rich therapy). CONCLUSIONS: No evidence of a difference in the risk of revision surgery within 1 year in participants treated with platelet-rich therapy compared with those not treated. However, we cannot definitively exclude a clinically meaningful difference. TRIAL REGISTRATION: Current Controlled Trials, ISRCTN49197425, http://www.controlled-trials.com/ISRCTN49197425. PMID- 23801710 TI - Investigating community ownership of a text message programme to improve adherence to antiretroviral therapy and provider-client communication: a mixed methods research protocol. AB - INTRODUCTION: Mobile phone ownership and use are growing fastest in sub-Saharan Africa, and there is evidence that mobile phone text messages can be used successfully to significantly improve adherence to antiretroviral therapy and reduce treatment interruptions. However, the effects of many mobile health interventions are often reduced by human resource shortages within health facilities. Also, research projects generating evidence for health interventions in developing countries are most often conducted using external funding sources, with limited sustainability and adoption by local governments following completion of the projects. Strong community participation driven by active outreach programmes and mobilisation of community resources are the key to successful adoption and long-term sustainability of effective interventions. Our aim was to develop a framework for community ownership of a text messaging programme to improve adherence to antiretroviral therapy; improve communication between patients and doctors and act as a reminder for appointments. METHODS AND ANALYSIS: We will use the exploratory sequential mixed methods approach. The first qualitative phase will entail focus group discussions with people living with HIV at the Yaounde Central Hospital in Yaounde, Cameroon (6-10 participants/group). The second quantitative phase will involve a cross-sectional survey (n=402). In this study, binary logistic regression techniques will be used to determine the factors associated with community readiness and acceptability of ownership. Data from both phases will be merged. ETHICS AND DISSEMINATION: This study has been approved by the Yaounde Central Hospital Institutional Review Board. The results of this paper will be disseminated as peer-reviewed publications at conferences and as part of a doctoral thesis. PMID- 23801712 TI - Can nutrition be promoted through agriculture-led food price policies? A systematic review. AB - OBJECTIVE: To systematically review the available evidence on whether national or international agricultural policies that directly affect the price of food influence the prevalence rates of undernutrition or nutrition-related chronic disease in children and adults. DESIGN: Systematic review. SETTING: Global. SEARCH STRATEGY: We systematically searched five databases for published literature (MEDLINE, EconLit, Agricola, AgEcon Search, Scopus) and systematically browsed other databases and relevant organisational websites for unpublished literature. Reference lists of included publications were hand-searched for additional relevant studies. We included studies that evaluated or simulated the effects of national or international food-price-related agricultural policies on nutrition outcomes reporting data collected after 1990 and published in English. PRIMARY AND SECONDARY OUTCOMES: Prevalence rates of undernutrition (measured with anthropometry or clinical deficiencies) and overnutrition (obesity and nutrition related chronic diseases including cancer, heart disease and diabetes). RESULTS: We identified a total of four relevant reports; two ex post evaluations and two ex ante simulations. A study from India reported on the undernutrition rates in children, and the other three studies from Egypt, the Netherlands and the USA reported on the nutrition-related chronic disease outcomes in adults. Two of the studies assessed the impact of policies that subsidised the price of agricultural outputs and two focused on public food distribution policies. The limited evidence base provided some support for the notion that agricultural policies that change the prices of foods at a national level can have an effect on population-level nutrition and health outcomes. CONCLUSIONS: A systematic review of the available literature suggests that there is a paucity of robust direct evidence on the impact of agricultural price policies on nutrition and health. PMID- 23801711 TI - Health risk factors and the incidence of hypertension: 4-year prospective findings from a national cohort of 60 569 Thai Open University students. AB - OBJECTIVE: This study evaluates the impact of a number of demographic, biological, behavioural and lifestyle health risk factors on the incidence of hypertension in Thailand over a 4-year period. DESIGN: A 4-year prospective study of health risk factors and their effects on the incidence of hypertension in a national Thai Cohort Study from 2005 to 2009. SETTING: As Thailand is transitioning from a developing to a middle-income developed country, chronic diseases (particularly cardiovascular disease) have emerged as major health issues. Hypertension is a major risk factor for heart attack and stroke and cross sectional studies have indicated that the prevalence is increasing. STUDY PARTICIPANTS: A total of 57 558 Sukhothai Thammathirat Open University students who participated in both the 2005 and 2009 questionnaire surveys and who were normotensive in 2005 were included in the analysis. MEASURES: Adjusted relative risks associating each risk factor and incidence of hypertension by sex, after controlling for confounders such as age, socioeconomic status, body mass index (BMI) and underlying diseases. RESULTS: The overall 4-year incidence of hypertension was 3.5%, with the rate in men being remarkably higher than that in women (5.2% vs 2.1%). In both sexes, hypertension was associated with age, higher BMI and comorbidities but not with income and education. In men, hypertension was associated with physical inactivity, smoking, alcohol and fast food intake. In women, hypertension was related to having a partner. CONCLUSIONS: In both men and women, hypertension was strongly associated with age, obesity and comorbidities while it had no association with socioeconomic factors. The cohort patterns of socioeconomy and hypertension reflect that the health risk transition in Thais is likely to be at the middle stage. Diet and lifestyle factors associate with incidence of hypertension in Thais and may be amenable targets for hypertension control programmes. PMID- 23801714 TI - Direct autocrine action of insulin on beta-cells: does it make physiological sense? AB - In recent years there has been a growing interest in the possibility of a direct autocrine effect of insulin on the pancreatic beta-cell. Indeed, there have been numerous intriguing articles and several eloquent reviews written on the subject (1-3); however, the concept is still controversial. Although many in vitro experiments, a few transgenic mouse studies, and some human investigations would be supportive of the notion, there exist different insights, other studies, and circumstantial evidence that question the concept. Therefore, the idea of autocrine action of insulin remains a conundrum. Here we outline a series of thoughts, insights, and alternative interpretations of the available experimental evidence. We ask, how convincing are these, and what are the confusing issues? We agree that there is a clear contribution of certain downstream elements in the insulin signaling pathway for beta-cell function and survival, but the question of whether insulin itself is actually the physiologically relevant ligand that triggers this signal transduction remains unsettled. PMID- 23801715 TI - AMPK: a target for drugs and natural products with effects on both diabetes and cancer. AB - The AMP-activated protein kinase (AMPK) is a highly conserved sensor of cellular energy that appears to have arisen at an early stage during eukaryotic evolution. In 2001 it was shown to be activated by metformin, currently the major drug for treatment for type 2 diabetes. Although the known metabolic effects of AMPK activation are consistent with the idea that it mediates some of the therapeutic benefits of metformin, as discussed below it now appears unlikely that AMPK is the sole target of the drug. AMPK is also activated by several natural plant products derived from traditional medicines, and the mechanisms by which they activate AMPK are discussed. One of these is salicylate, probably the oldest medicinal agent known to humankind. The salicylate prodrug salsalate has been shown to improve metabolic parameters in subjects with insulin resistance and prediabetes, and whether this might be mediated in part by AMPK is discussed. Interestingly, there is evidence that both metformin and aspirin provide some protection against development of cancer in humans, and whether AMPK might be involved in these effects is also discussed. PMID- 23801716 TI - What's the Time? Does the Artificial Pancreas Need to Know? PMID- 23801717 TI - A novel link between circadian clocks and adipose tissue energy metabolism. PMID- 23801718 TI - Happy birthday, Claude Bernard. PMID- 23801721 TI - Response to comment on: Takeda et al. Loss of ACE2 exaggerates high-calorie diet induced insulin resistance by reduction of GLUT4 in mice. Diabetes 2013;62:223 233. PMID- 23801722 TI - Comment on: Takeda et al. Loss of ACE2 exaggerates high-calorie diet-induced insulin resistance by reduction of GLUT4 in mice. Diabetes 2013;62:223-233. PMID- 23801723 TI - Clinical and economic benefits associated with the achievement of both HbA1c and LDL cholesterol goals in veterans with type 2 diabetes. AB - OBJECTIVE: This study compared the clinical and economic benefits associated with dual-goal achievement, glycated hemoglobin (HbA1c)<7% (53 mmol/mol) and LDL cholesterol (LDL-C)<100 mg/dL, with achievement of only the LDL-C goal or only the HbA1c goal in veterans with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: This retrospective cohort analysis evaluated electronic medical records (Veterans Integrated Service Network 16) in adult T2DM patients with two or more measurements of LDL-C and HbA1c between 1 January 2004 and 30 June 2010 (N=75,646). Cox proportional hazards models were used to compare microvascular and cardiovascular outcomes by goal achievement status; generalized linear regression models were used to assess diabetes-related resource utilization (hospitalization days and number of outpatient visits) and medical service costs. RESULTS: Relative to achievement of only the LDL-C goal, dual-goal achievement was associated with lower risk of microvascular complications (adjusted hazard ratio [aHR] 0.79), acute coronary syndrome (0.88), percutaneous coronary intervention (0.78), and coronary artery bypass graft (CABG) (0.74); it was also associated with fewer hospitalization days (adjusted incidence rate ratio [aIRR] 0.93) and outpatient visits (0.88), as well as lower diabetes-related annual medical costs (-$130.89). Compared with achievement of only the HbA1c goal, dual goal achievement was associated with lower risk of the composite cardiovascular related end point (aHR 0.87) and CABG (aHR 0.62), as well as fewer outpatient visits (aIRR 0.98). CONCLUSIONS: Achieving both HbA1c and LDL-C goals in diabetes care is associated with additional clinical and economic benefits, as compared with the achievement of either goal alone. PMID- 23801724 TI - Genetically elevated fetuin-A levels, fasting glucose levels, and risk of type 2 diabetes: the cardiovascular health study. AB - OBJECTIVE: Fetuin-A levels are associated with higher risk of type 2 diabetes, but it is unknown if the association is causal. We investigated common (>5%) genetic variants in the fetuin-A gene (AHSG) fetuin-A levels, fasting glucose, and risk of type 2 diabetes. RESEARCH DESIGN AND METHODS: Genetic variation, fetuin-A levels, and fasting glucose were assessed in 2,893 Caucasian and 542 African American community-living individuals 65 years of age or older in 1992 1993. RESULTS: Common AHSG variants (rs4917 and rs2248690) were strongly associated with fetuin-A concentrations (P<0.0001). In analyses of 259 incident cases of type 2 diabetes, the single nucleotide polymorphisms (SNPs) were not associated with diabetes risk during follow-up and similar null associations were observed when 579 prevalent cases were included. As expected, higher fetuin-A levels were associated with higher fasting glucose concentrations (1.9 mg/dL [95% CI, 1.2-2.7] higher per SD in Caucasians), but Mendelian randomization analyses using both SNPs as unbiased proxies for measured fetuin-A did not support an association between genetically predicted fetuin-A levels and fasting glucose ( 0.3 mg/dL [95% CI, -1.9 to 1.3] lower per SD in Caucasians). The difference between the associations of fasting glucose with actual and genetically predicted fetuin-A level was statistically significant (P=0.001). Results among the smaller sample of African Americans trended in similar directions but were statistically insignificant. CONCLUSIONS: Common variants in the AHSG gene are strongly associated with plasma fetuin-A concentrations, but not with risk of type 2 diabetes or glucose concentrations, raising the possibility that the association between fetuin-A and type 2 diabetes may not be causal. PMID- 23801725 TI - Infancy-onset dietary counseling of low-saturated-fat diet improves insulin sensitivity in healthy adolescents 15-20 years of age: the Special Turku Coronary Risk Factor Intervention Project (STRIP) study. AB - OBJECTIVE: We reported previously that low-saturated-fat dietary counseling started in infancy improves insulin sensitivity in healthy children 9 years of age. The aim of this study was to evaluate the effect of lifelong dietary counseling on insulin sensitivity in healthy adolescents between 15 and 20 years of age. In addition, we examined dietary fiber intake and the polyunsaturated fatty acid (PUFA)+monounsaturated (MUFA)-to-saturated fatty acid (SFA) ratio in the intervention and control adolescents and the association of these dietary factors with homeostasis model of insulin resistance (HOMA-IR). RESEARCH DESIGN AND METHODS: The study comprised adolescents participating in the randomized, controlled Special Turku Coronary Risk Factor Intervention Project (STRIP) study, which aims to guide the study participants toward a diet beneficial for cardiovascular health. HOMA-IR was assessed annually between 15 and 20 years of age (n=518; intervention, n=245; control, n=273), along with diet, BMI, pubertal status, serum cotinine concentrations, and physical activity. Dietary counseling was given biannually during the follow-up. RESULTS: HOMA-IR was lower (7.5% on average) in the intervention group than in the control group between 15 and 20 years of age (P=0.0051). The intervention effect was similar in girls and boys. The PUFA+MUFA-to-SFA ratio was higher (P<0.0001) and the dietary fiber (g/MJ) intake was higher (P=0.0058) in the intervention group compared with the control group. There was no association between the PUFA+MUFA-to-/SFA ratio and HOMA-IR, whereas dietary fiber intake (g/MJ) was associated with HOMA-IR in girls (P<0.0001). CONCLUSIONS: Dietary counseling initiated in infancy and maintained until 20 years of age was associated with improved insulin sensitivity in adolescents. PMID- 23801726 TI - Derivation and validation of a renal risk score for people with type 2 diabetes. AB - OBJECTIVE: Diabetes has become the leading cause of end-stage renal disease (ESRD). Renal risk stratification could assist in earlier identification and targeted prevention. This study aimed to derive risk models to predict ESRD events in type 2 diabetes in primary care. RESEARCH DESIGN AND METHODS: The nationwide derivation cohort included adults with type 2 diabetes from the New Zealand Diabetes Cohort Study initially assessed during 2000-2006 and followed until December 2010, excluding those with pre-existing ESRD. The outcome was fatal or nonfatal ESRD event (peritoneal dialysis or hemodialysis for ESRD, renal transplantation, or death from ESRD). Risk models were developed using Cox proportional hazards models, and their performance was assessed in a separate validation cohort. RESULTS: The derivation cohort included 25,736 individuals followed for up to 11 years (180,497 person-years; 86% followed for >=5 years). At baseline, mean age was 62 years, median diabetes duration 5 years, and median HbA1c 7.2% (55 mmol/mol); 37% had albuminuria; and median estimated glomerular filtration rate (eGFR) was 77 mL/min/1.73 m2. There were 637 ESRD events (2.5%) during follow-up. Models that included sex, ethnicity, age, diabetes duration, albuminuria, serum creatinine, systolic blood pressure, HbA1c, smoking status, and previous cardiovascular disease status performed well with good discrimination and calibration in the derivation cohort and the validation cohort (n=5,877) (C-statistics 0.89-0.92), improving predictive performance compared with previous models. CONCLUSIONS: These 5-year renal risk models performed very well in two large primary care populations with type 2 diabetes. More accurate risk stratification could facilitate earlier intervention than using eGFR and/or albuminuria alone. PMID- 23801728 TI - Math dance. PMID- 23801729 TI - Early human diets. Interview by Charles Choi. PMID- 23801727 TI - Total mortality by elevated transferrin saturation in patients with diabetes. AB - OBJECTIVE: It is not known to what extent iron overload predicts prognosis in patients with diabetes after diagnosis or whether iron overload is a risk factor independent of the HFE genotype. We investigated total and cause-specific mortality according to increased transferrin saturation (>= 50 vs. <50%), whether mortality is driven by the HFE genotype, and whether early measurement of transferrin saturation helps to predict mortality outcome. RESEARCH DESIGN AND METHODS: Cohort 1 included patients with late-onset type 1 diabetes (n = 716) with a cross-sectional measurement of transferrin saturation and HFE genotype. Cohort 2 included consecutively recruited patients with any diabetes (n = 6,120), transferrin saturation measurement at referral, and HFE genotype if transferrin saturation was above 50%. RESULTS: In cohort 1, the hazard ratio for total mortality was 2.3 (95% CI 1.3-3.9; P = 0.002) and for cause-specific mortality by neoplasms was 5.8 (2.4-14; P = 0.00007) in patients with transferrin saturation >= 50 vs. <50%. Excluding genotypes C282Y/C282Y and C282Y/H63D gave similar results. The hazard ratio for total mortality was 4.0 (1.2-13; P = 0.01) and for cause-specific mortality by neoplasms was 13 (3.6-49; P = 0.0001) in patients with C282Y/C282Y versus wild type. In cohort 2, total mortality was not different in patients with transferrin saturation >= 50 vs. <50%. In patients with late onset type 1 diabetes and transferrin saturation >= 50%, the hazard ratio for total mortality was 0.4 (0.2-0.9; P = 0.03) in cohort 2 versus cohort 1. CONCLUSIONS: Increased transferrin saturation and HFE genotype C282Y/C282Y predict total mortality in patients with late-onset type 1 diabetes, and increased transferrin saturation after diagnosis is an independent risk factor. Early measurement of transferrin saturation in these patients leading to early intervention improves life expectancy. PMID- 23801733 TI - Brain. Editorial. PMID- 23801735 TI - Relation of lead trajectory and electrode position to neuropsychological outcomes of subthalamic neurostimulation in Parkinson's disease: results from a randomized trial. AB - Deep brain stimulation of the subthalamic nucleus improves motor functions in patients suffering from advanced Parkinson's disease but in some patients, it is also associated with a mild decline in cognitive functioning about one standard deviation from the preoperative state. We assessed the impact of the cortical lead entry point, the subcortical electrode path and the position of the active electrode contacts on neuropsychological changes after subthalamic nucleus-deep brain stimulation compared to a control group of patients receiving best medical treatment. Sixty-eight patients with advanced Parkinson's disease were randomly assigned to have subthalamic nucleus-deep brain stimulation or best medical treatment for Parkinson's disease. All patients had a blinded standardized neuropsychological exam (Mattis Dementia Rating scale, backward digit span, verbal fluency and Stroop task performance) at baseline and after 6 months of treatment. Patients with subthalamic nucleus-deep brain stimulation were defined as impaired according to a mild decline of one or more standard deviations compared to patients in the best medical treatment group. The cortical entry point of the electrodes, the electrode trajectories and the position of the active electrode contact were transferred into a normalized brain volume by an automated, non-linear registration algorithm to allow accurate statistical group analysis using pre- and postoperative magnetic resonance imaging data. Data of 31 patients of the subthalamic nucleus-deep brain stimulation group and 31 patients of the best medical treatment group were analysed. The subthalamic nucleus-deep brain stimulation group showed impaired semantic fluency compared with the best medical treatment group 6 months after surgery (P = 0.02). Electrode trajectories intersecting with caudate nuclei increased the risk of a decline in global cognition and working memory performance. Statistically, for every 0.1 ml overlap with a caudate nucleus, the odds for a decline >1 standard deviation increased by a factor of 37.4 (odds ratio, confidence interval 2.1-371.8) for the Mattis Dementia Rating Scale and by a factor of 8.8 (odds ratio, confidence interval 1.0 70.9) for the backward digit span task. Patients with subthalamic nucleus-deep brain stimulation who declined in semantic verbal fluency, Stroop task and the backward digit span task performance showed a position of the active electrode outside the volume built by the active electrodes of stable performers. Passage of the chronic stimulation lead through the head of the caudate increases the risk of global cognitive decline and working memory performance after subthalamic nucleus-deep brain stimulation in Parkinson's disease. Therefore the electrode path should be planned outside the caudate nuclei, whenever possible. This study also stresses the importance of precise positioning of the active stimulating contact within the subthalamic volume to avoid adverse effects on semantic verbal fluency and response inhibition. PMID- 23801734 TI - Defective cerebellar control of cortical plasticity in writer's cramp. AB - A large body of evidence points to a role of basal ganglia dysfunction in the pathophysiology of dystonia, but recent studies indicate that cerebellar dysfunction may also be involved. The cerebellum influences sensorimotor adaptation by modulating sensorimotor plasticity of the primary motor cortex. Motor cortex sensorimotor plasticity is maladaptive in patients with writer's cramp. Here we examined whether putative cerebellar dysfunction in dystonia is linked to these patients' maladaptive plasticity. To that end we compared the performances of patients and healthy control subjects in a reaching task involving a visuomotor conflict generated by imposing a random deviation (-40 degrees to 40 degrees ) on the direction of movement of the mouse/cursor. Such a task is known to involve the cerebellum. We also compared, between patients and healthy control subjects, how the cerebellum modulates the extent and duration of an ongoing sensorimotor plasticity in the motor cortex. The cerebellar cortex was excited or inhibited by means of repeated transcranial magnetic stimulation before artificial sensorimotor plasticity was induced in the motor cortex by paired associative stimulation. Patients with writer's cramp were slower than the healthy control subjects to reach the target and, after having repeatedly adapted their trajectories to the deviations, they were less efficient than the healthy control subjects to perform reaching movement without imposed deviation. It was interpreted as impaired washing-out abilities. In healthy subjects, cerebellar cortex excitation prevented the paired associative stimulation to induce a sensorimotor plasticity in the primary motor cortex, whereas cerebellar cortex inhibition led the paired associative stimulation to be more efficient in inducing the plasticity. In patients with writer's cramp, cerebellar cortex excitation and inhibition were both ineffective in modulating sensorimotor plasticity. In patients with writer's cramp, but not in healthy subjects, behavioural parameters reflecting their capacity for adapting to the rotation and for washing-out of an earlier adaptation predicted the efficacy of inhibitory cerebellar conditioning to influence sensorimotor plasticity: the better the online adaptation, the smaller the influence of cerebellar inhibitory stimulation on motor cortex plasticity. Altered cerebellar encoding of incoming afferent volleys may result in decoupling the motor component from the afferent information flow, and also in maladjusted sensorimotor calibration. The loss of cerebellar control over sensorimotor plasticity might also lead to building up an incorrect motor program to specific adaptation tasks such as writing. PMID- 23801736 TI - The coeruleus/subcoeruleus complex in rapid eye movement sleep behaviour disorders in Parkinson's disease. AB - In Parkinson's disease, rapid eye movement sleep behaviour disorder is an early non-dopaminergic syndrome with nocturnal violence and increased muscle tone during rapid eye movement sleep that can precede Parkinsonism by several years. The neuronal origin of rapid eye movement sleep behaviour disorder in Parkinson's disease is not precisely known; however, the locus subcoeruleus in the brainstem has been implicated as this structure blocks muscle tone during normal rapid eye movement sleep in animal models and can be damaged in Parkinson's disease. Here, we studied the integrity of the locus coeruleus/subcoeruleus complex in patients with Parkinson's disease using combined neuromelanin-sensitive, structural and diffusion magnetic resonance imaging approaches. We compared 24 patients with Parkinson's disease and rapid eye movement sleep behaviour disorder, 12 patients without rapid eye movement sleep behaviour disorder and 19 age- and gender matched healthy volunteers. All subjects underwent clinical examination and characterization of rapid eye movement sleep using video-polysomnography and multimodal imaging at 3 T. Using neuromelanin-sensitive imaging, reduced signal intensity was evident in the locus coeruleus/subcoeruleus area in patients with Parkinson's disease that was more marked in patients with than those without rapid eye movement sleep behaviour disorder. Reduced signal intensity correlated with the percentage of abnormally increased muscle tone during rapid eye movement sleep. The results confirmed that this complex is affected in Parkinson's disease and showed a gradual relationship between damage to this structure, presumably the locus subcoeruleus, and abnormal muscle tone during rapid eye movement sleep, which is the cardinal marker of rapid eye movement sleep behaviour disorder. In longitudinal studies, the technique may also provide early markers of non dopaminergic Parkinson's disease pathology to predict the occurrence of Parkinson's disease. PMID- 23801737 TI - Progressive sleep and electroencephalogram changes in mice carrying the Huntington's disease mutation. AB - Sleep disturbances in Huntington's disease may be deleterious to the cognitive performance, affective behaviour, and general well-being of patients, but a comprehensive description of the progression of changes in sleep and electroencephalogram in Huntington's disease has never been conducted. Here we studied sleep and electroencephalogram disturbances in a transgenic mouse model of Huntington's disease (R6/2 mice). We implanted 10 R6/2 mice and five wild-type littermates with electromyography electrodes, frontofrontal and frontoparietal electroencephalogram electrodes and then recorded sleep/wake behaviour at presymptomatic, symptomatic and late stages of the disease. In addition to sleep wake scoring, we performed a spectral analysis of the sleep electroencephalogram. We found that sleep and electroencephalogram were already significantly disrupted in R6/2 mice at 9 weeks of age (presymptomatic stage). By the time they were symptomatic, R6/2 mice were unable to maintain long periods of wakefulness and had an increased propensity for rapid eye movement sleep. In addition, the peak frequency of theta rhythm was shifted progressively from 7 Hz to 6 Hz during rapid eye movement sleep, whereas slow wave activity decreased gradually during non-rapid eye movement sleep. Finally, as the disease progressed, an abnormal electroencephalogram gamma activity (30-40 Hz) emerged in R6/2 mice irrespective of sleep states. This is reminiscent of the increased gamma power described in schizophrenic patients during sleep and events of psychosis. Gaining a better understanding of sleep and electroencephalogram changes in patients with Huntington's disease should be a priority, since it will enable clinicians to initiate appropriate investigations and to instigate treatments that could dramatically improve patients' quality of life. PMID- 23801738 TI - Longitudinal analysis of the electroencephalogram and sleep phenotype in the R6/2 mouse model of Huntington's disease. AB - Deficits in sleep and circadian organization have been identified as common early features in patients with Huntington's disease that correlate with symptom severity and may be instrumental in disease progression. Studies in Huntington's disease gene carriers suggest that alterations in the electroencephalogram may reflect underlying neuronal dysfunction that is present in the premanifest stage. We conducted a longitudinal characterization of sleep/wake and electroencephalographic activity in the R6/2 mouse model of Huntington's disease to determine whether analogous electroencephalographic 'signatures' could be identified early in disease progression. R6/2 and wild-type mice were implanted for electroencephalographic recordings along with telemetry for the continuous recording of activity and body temperature. Diurnal patterns of activity and core body temperature were progressively disrupted in R6/2 mice, with a large reduction in the amplitude of these rhythms apparent by 13 weeks of age. The diurnal variation in sleep/wake states was gradually attenuated as sleep became more fragmented and total sleep time was reduced relative to wild-type mice. These genotypic differences were augmented at 17 weeks and evident across the entire 24-h period. Quantitative electroencephalogram analysis revealed anomalous increases in high beta and gamma activity (25-60 Hz) in all sleep/wake states in R6/2 mice, along with increases in theta activity during both non-rapid eye movement and rapid eye movement sleep and a reduction of delta power in non-rapid eye movement sleep. These dramatic alterations in quantitative electroencephalographic measures were apparent from our earliest recording (9 weeks), before any major differences in diurnal physiology or sleep/wake behaviour occurred. In addition, the homeostatic response to sleep deprivation was greatly attenuated with disease progression. These findings demonstrate the sensitivity of quantitative electroencephalographic analysis to identify early pathophysiological alterations in the R6/2 model of Huntington's disease and suggest longitudinal studies in other preclinical Huntington's disease models are needed to determine the generality of these observations as a potential adjunct in therapeutic development. PMID- 23801739 TI - Beclin 1 mitigates motor and neuropathological deficits in genetic mouse models of Machado-Joseph disease. AB - Machado-Joseph disease or spinocerebellar ataxia type 3, the most common dominantly-inherited spinocerebellar ataxia, results from translation of the polyglutamine-expanded and aggregation prone ataxin 3 protein. Clinical manifestations include cerebellar ataxia and pyramidal signs and there is no therapy to delay disease progression. Beclin 1, an autophagy-related protein and essential gene for cell survival, is decreased in several neurodegenerative disorders. This study aimed at evaluating if lentiviral-mediated beclin 1 overexpression would rescue motor and neuropathological impairments when administered to pre- and post-symptomatic lentiviral-based and transgenic mouse models of Machado-Joseph disease. Beclin 1-mediated significant improvements in motor coordination, balance and gait with beclin 1-treated mice equilibrating longer periods in the Rotarod and presenting longer and narrower footprints. Furthermore, in agreement with the improvements observed in motor function beclin 1 overexpression prevented neuronal dysfunction and neurodegeneration, decreasing formation of polyglutamine-expanded aggregates, preserving Purkinje cell arborization and immunoreactivity for neuronal markers. These data show that overexpression of beclin 1 in the mouse cerebellum is able to rescue and hinder the progression of motor deficits when administered to pre- and post-symptomatic stages of the disease. PMID- 23801740 TI - In vivo characterization of the early states of the amyloid-beta network. AB - Alzheimer's disease is a neurodegenerative disease that is associated with the abnormal accumulation of amyloid-beta. Much is known about regional brain atrophy in Alzheimer's disease, yet our knowledge about the network nature of Alzheimer's disease-associated amyloid-beta accumulation is limited. We use stepwise connectivity analysis of Pittsburgh Compound B positron emission tomography images to reveal the network properties of amyloid-beta deposits in normal elderly subjects and clinical patients with Alzheimer's disease. We found that amyloid-beta accumulation in the medial temporal lobe is associated with accumulation in cortical regions such as orbitofrontal, lateral temporal and precuneus/posterior cingulate cortices in Alzheimer's disease. In normal subjects, there was a predominant association between amyloid-beta deposits in the hippocampus and the midline prefrontal/orbitofrontal regions, even in those with very low amyloid-beta burden. Moreover, the orbitofrontal cortex, amygdala nucleus and hippocampus exhibit hub properties in the amyloid-beta network that may be critical to understanding the putative spreading mechanisms of Alzheimer's disease pathology in early stages. PMID- 23801742 TI - Sodium accumulation is associated with disability and a progressive course in multiple sclerosis. AB - Neuroaxonal loss is a major substrate of irreversible disability in multiple sclerosis, however, its cause is not understood. In multiple sclerosis there may be intracellular sodium accumulation due to neuroaxonal metabolic dysfunction, and increased extracellular sodium due to expansion of the extracellular space secondary to neuroaxonal loss. Sodium magnetic resonance imaging measures total sodium concentration in the brain, and could investigate this neuroaxonal dysfunction and loss in vivo. Sodium magnetic resonance imaging has been examined in small cohorts with relapsing-remitting multiple sclerosis, but has not been investigated in patients with a progressive course and high levels of disability. We performed sodium magnetic resonance imaging in 27 healthy control subjects, 27 patients with relapsing-remitting, 23 with secondary-progressive and 20 with primary-progressive multiple sclerosis. Cortical sodium concentrations were significantly higher in all subgroups of multiple sclerosis compared with controls, and deep grey and normal appearing white matter sodium concentrations were higher in primary and secondary-progressive multiple sclerosis. Sodium concentrations were higher in secondary-progressive compared with relapsing remitting multiple sclerosis in cortical grey matter (41.3 +/- 4.2 mM versus 38.5 +/- 2.8 mM, P = 0.008), normal appearing white matter (36.1 +/- 3.5 mM versus 33.6 +/- 2.5 mM, P = 0.018) and deep grey matter (38.1 +/- 3.1 mM versus 35.7 +/- 2.4 mM, P = 0.02). Higher sodium concentrations were seen in T1 isointense (44.6 +/- 7.2 mM) and T1 hypointense lesions (46.8 +/- 8.3 mM) compared with normal appearing white matter (34.9 +/- 3.3 mM, P < 0.001 for both comparisons). Higher sodium concentration was observed in T1 hypointense lesions in secondary progressive (49.0 +/- 7.0 mM) and primary-progressive (49.3 +/- 8.0 mM) compared with relapsing-remitting multiple sclerosis (43.0 +/- 8.5 mM, P = 0.029 for both comparisons). Independent association was seen of deep grey matter sodium concentration with expanded disability status score (coefficient = 0.24, P = 0.003) and timed 25 ft walk speed (coefficient = -0.24, P = 0.01), and of T1 lesion sodium concentration with the z-scores of the nine hole peg test (coefficient = -0.12, P < 0.001) and paced auditory serial addition test (coefficient = -0.081, P < 0.001). Sodium concentration is increased within lesions, normal appearing white matter and cortical and deep grey matter in multiple sclerosis, with higher concentrations seen in secondary-progressive multiple sclerosis and in patients with greater disability. Increased total sodium concentration is likely to reflect neuroaxonal pathophysiology leading to clinical progression and increased disability. PMID- 23801743 TI - Nitrous oxide: are we still in equipoise? A qualitative review of current controversies. AB - This review considers the current position of nitrous oxide in anaesthetic practice and balances potential beneficial and disadvantageous effects. The classic adverse characteristics of nitrous oxide, such as diffusion hypoxia, expansion of gas-filled spaces, and postoperative nausea and vomiting, are often cited as reasons to avoid this old drug. Recent concerns regarding neurotoxicity, adverse cardiovascular outcomes, and wound complications have further hardened many practitioners against nitrous oxide. New evidence and underpinning mechanistic data, however, suggest potential beneficial effects on the central nervous system, cardiovascular system, and acute and chronic pain. While we await the outcome of large studies including ENIGMA-II, many clinicians have already decided against this agent. The authors argue that this abandonment may be premature. Clinical Trial Registration None required. PMID- 23801741 TI - Axonal neuregulin 1 is a rate limiting but not essential factor for nerve remyelination. AB - Neuregulin 1 acts as an axonal signal that regulates multiple aspects of Schwann cell development including the survival and migration of Schwann cell precursors, the ensheathment of axons and subsequent elaboration of the myelin sheath. To examine the role of this factor in remyelination and repair following nerve injury, we ablated neuregulin 1 in the adult nervous system using a tamoxifen inducible Cre recombinase transgenic mouse system. The loss of neuregulin 1 impaired remyelination after nerve crush, but did not affect Schwann cell proliferation associated with Wallerian degeneration or axon regeneration or the clearance of myelin debris by macrophages. Myelination changes were most marked at 10 days after injury but still apparent at 2 months post-crush. Transcriptional analysis demonstrated reduced expression of myelin-related genes during nerve repair in animals lacking neuregulin 1. We also studied repair over a prolonged time course in a more severe injury model, sciatic nerve transection and reanastamosis. In the neuregulin 1 mutant mice, remyelination was again impaired 2 months after nerve transection and reanastamosis. However, by 3 months post-injury axons lacking neuregulin 1 were effectively remyelinated and virtually indistinguishable from control. Neuregulin 1 signalling is therefore an important factor in nerve repair regulating the rate of remyelination and functional recovery at early phases following injury. In contrast to development, however, the determination of myelination fate following nerve injury is not dependent on axonal neuregulin 1 expression. In the early phase following injury, axonal neuregulin 1 therefore promotes nerve repair, but at late stages other signalling pathways appear to compensate. PMID- 23801744 TI - Temporal and spatial dispersion of human body temperature during deep hypothermia. AB - BACKGROUND: Clinical temperature management remains challenging. Choosing the right sensor location to determine the core body temperature is a particular matter of academic and clinical debate. This study aimed to investigate the relationship of measured temperatures at different sites during surgery in deep hypothermic patients. METHODS: In this prospective single-centre study, we studied 24 patients undergoing cardiothoracic surgery: 12 in normothermia, 3 in mild, and 9 in deep hypothermia. Temperature recordings of a non-invasive heat flux sensor at the forehead were compared with the arterial outlet temperature of a heart-lung machine, with the temperature on a conventional vesical bladder thermistor and, for patients undergoing deep hypothermia, with oesophageal temperature. RESULTS: Using a linear model for sensor comparison, the arterial outlet sensor showed a difference among the other sensor positions between -0.54 and -1.12 degrees C. The 95% confidence interval ranged between 7.06 and 8.82 degrees C for the upper limit and -8.14 and -10.62 degrees C for the lower limit. Because of the hysteretic shape, the curves were divided into phases and fitted into a non-linear model according to time and placement of the sensors. During cooling and warming phases, a quadratic relationship could be observed among arterial, oesophageal, vesical, and cranial temperature recordings, with coefficients of determination ranging between 0.95 and 0.98 (standard errors of the estimate 0.69-1.12 degrees C). CONCLUSION: We suggest that measured surrogate temperatures as indices of the cerebral temperature (e.g. vesical bladder temperature) should be interpreted with respect to the temporal and spatial dispersion during cooling and rewarming phases. PMID- 23801745 TI - Efficacy comparison of the novel water-soluble propofol prodrug HX0969w and fospropofol in mice and rats. AB - BACKGROUND: HX0969w is a novel water-soluble prodrug designed to release propofol and gamma-hydroxybutyrate (GHB) and has a sedative-hypnotic effect. This study was performed to compare the efficacy of HX0969w with fospropofol in mice and rats. METHODS: We performed hydrolysis studies in the plasma from mice and rats. The half-maximal effective doses (ED50) and half-maximal lethal doses (LD50) of fospropofol and HX0969w were determined. A pharmacodynamics comparison of these two compounds was also performed. Time to loss of righting reflex, time to return of righting reflex, recovery time, and adverse effects were recorded. RESULTS: The hydrolysis studies demonstrated that HX0969w released propofol as expected. HX0969w ED50 values in mice and rats were 133.03 and 53.79 mg kg(-1), respectively, and LD50 values were 607.11 and 283.79 mg kg(-1), respectively. The calculated therapeutic index (TI), safety index (SI), and certain safety factor (CSF) of HX0969w were 4.56, 3.33, and 2.92 for mice, and 5.28, 3.94, and 3.49 for rats, respectively. The pharmacodynamic comparison studies suggest that HX0969w has a longer onset time and shorter duration than fospropofol. CONCLUSIONS: Similar to fospropofol, HX0969w is an effective, water-soluble prodrug that is capable of inducing a sedative-hypnotic effect in mice and rats. Unlike fospropofol, HX0969w releases GHB instead of formaldehyde. Further studies regarding the efficacy and safety of HX0969w are necessary. PMID- 23801746 TI - Confocal laser endomicroscopy reliably detects sepsis-related and treatment associated changes in intestinal mucosal microcirculation. AB - BACKGROUND: Microcirculatory alterations play a central role in the pathophysiology of sepsis. We investigated probe-based confocal laser endomicroscopy (pCLE) to assess alterations in mucosal microcirculatory perfusion in vivo in a porcine model of septic shock and in patients fulfilling consensus criteria for severe sepsis. METHODS: Septic shock was induced using a faecal peritonitis model in anaesthetized, mechanically ventilated pigs. Mucosal microcirculation was assessed using pCLE in the stomach, duodenum, terminal ileum, and rectum. Duodenal microcirculation was further evaluated in 10 patients with severe sepsis and in 8 healthy controls to quantify capillary diameter, capillary length, and functional capillary density (FCD). RESULTS: In the animal model, FCD was markedly decreased in duodenal (P<0.001), ileal (P<0.001), gastric (P<0.001), and rectal mucosa (P<0.005) 4 h after induction of sepsis. After volume therapy, FCD partially recovered to 90.0% (duodenum), 94.4% (ileum), 95.4% (gastric), and 97% (rectum) of baseline values, indicating decoupling of microvascular and macrovascular flow. In septic patients, the mean capillary diameter (P<0.01) and FCD (P<0.05) in duodenal mucosa were decreased compared with healthy controls. CONCLUSIONS: pCLE reliably detected and quantified microcirculatory alterations in the gastrointestinal mucosa in a porcine model of sepsis and in patients with severe sepsis. Our data suggest that pCLE is a promising tool to assess the efficacy of therapeutic interventions on mucosal microcirculation in real-time, even in the clinical context. PMID- 23801747 TI - Regulation of the transcriptional coactivator FHL2 licenses activation of the androgen receptor in castrate-resistant prostate cancer. AB - It is now clear that progression from localized prostate cancer to incurable castrate-resistant prostate cancer (CRPC) is driven by continued androgen receptor (AR), signaling independently of androgen. Thus, there remains a strong rationale to suppress AR activity as the single most important therapeutic goal in CRPC treatment. Although the expression of ligand-independent AR splice variants confers resistance to AR-targeted therapy and progression to lethal castrate-resistant cancer, the molecular regulators of AR activity in CRPC remain unclear, in particular those pathways that potentiate the function of mutant AR in CRPC. Here, we identify FHL2 as a novel coactivator of ligand-independent AR variants that are important in CRPC. We show that the nuclear localization of FHL2 and coactivation of the AR is driven by calpain cleavage of the cytoskeletal protein filamin, a pathway that shows differential activation in prostate epithelial versus prostate cancer cell lines. We further identify a novel FHL2-AR filamin transcription complex, revealing how deregulation of this axis promotes the constitutive, ligand-independent activation of AR variants, which are present in CRPC. Critically, the calpain-cleaved filamin fragment and FHL2 are present in the nucleus only in CRPC and not benign prostate tissue or localized prostate cancer. Thus, our work provides mechanistic insight into the enhanced AR activation, most notably of the recently identified AR variants, including AR-V7 that drives CRPC progression. Furthermore, our results identify the first disease specific mechanism for deregulation of FHL2 nuclear localization during cancer progression. These results offer general import beyond prostate cancer, given that nuclear FHL2 is characteristic of other human cancers where oncogenic transcription factors that drive disease are activated like the AR in prostate cancer. PMID- 23801749 TI - The CpG island methylator phenotype: what's in a name? AB - Although the CpG island methylator phenotype (CIMP) was first identified and has been most extensively studied in colorectal cancer, the term "CIMP" has been repeatedly used over the past decade to describe CpG island promoter methylation in other tumor types, including bladder, breast, endometrial, gastric, glioblastoma (gliomas), hepatocellular, lung, ovarian, pancreatic, renal cell, and prostate cancers, as well as for leukemia, melanoma, duodenal adenocarninomas, adrenocortical carcinomas, and neuroblastomas. CIMP has been reported to be useful for predicting prognosis and response to treatment in a variety of tumor types, but it remains unclear whether or not CIMP is a universal phenomenon across human neoplasia or if there should be cancer-specific definitions of the phenotype. Recently, it was shown that somatic isocitrate dehydrogenase-1 (IDH1) mutations, frequently observed in gliomas, establish CIMP in primary human astrocytes by remodeling the methylome. Interestingly, somatic IDH1 and IDH2 mutations, and loss-of-function mutations in ten-eleven translocation (TET) methylcytosine dioxygenase-2 (TET2) associated with a hypermethylation phenotype, are also found in multiple enchondromas of patients with Ollier disease and Mafucci syndrome, and leukemia, respectively. These data provide the first clues for the elucidation of a molecular basis for CIMP. Although CIMP appears as a phenomenon that occurs in various cancer types, the definition is poorly defined and differs for each tumor. The current perspective discusses the use of the term CIMP in cancer, its significance in clinical practice, and future directions that may aid in identifying the true cause and definition of CIMP in different forms of human neoplasia. PMID- 23801748 TI - FOXL1, a novel candidate tumor suppressor, inhibits tumor aggressiveness and predicts outcome in human pancreatic cancer. AB - The forkhead box L1 (FOXL1) transcription factor regulates epithelial proliferation and development of gastrointestinal tract and has been implicated in gastrointestinal tumorigenesis in mouse models. However, the role of FOXL1 in pancreatic cancer development and progression remains to be elucidated. Here, we report that higher expression of FOXL1 is significantly associated with better clinical outcome in human pancreatic ductal adenocarcinoma (PDAC). A lower FOXL1 expression is correlated with metastasis and advanced pathologic stage of pancreatic cancer. Mechanistic analyses showed that overexpression of FOXL1 induces apoptosis and inhibits proliferation and invasion in pancreatic cancer cells, whereas silencing of FOXL1 by siRNA inhibits apoptosis and enhances tumor cell growth and invasion. Furthermore, FOXL1 overexpression significantly suppressed the growth of tumor xenografts in nude mice. FOXL1 promoted apoptosis partly through the induction of TNF-related apoptosis-inducing ligand (TRAIL) in pancreatic cancer cells. In addition, FOXL1 suppressed the transcription of zinc finger E-box-binding homeobox 1 (ZEB1), an activator of epithelial-mesenchymal transition, and the negative regulation of ZEB1 contributed to the inhibitory effect of FOXL1 on tumor cell invasion. Taken together, our findings suggest that FOXL1 expression is a candidate predictor of clinical outcome in patients with resected PDAC and it plays an inhibitory role in pancreatic tumor progression. PMID- 23801750 TI - Fate of the replisome following arrest by UV-induced DNA damage in Escherichia coli. AB - Accurate replication in the presence of DNA damage is essential to genome stability and viability in all cells. In Escherichia coli, DNA replication forks blocked by UV-induced damage undergo a partial resection and RecF-catalyzed regression before synthesis resumes. These processing events generate distinct structural intermediates on the DNA that can be visualized in vivo using 2D agarose gels. However, the fate and behavior of the stalled replisome remains a central uncharacterized question. Here, we use thermosensitive mutants to show that the replisome's polymerases uncouple and transiently dissociate from the DNA in vivo. Inactivation of alpha, beta, or tau subunits within the replisome is sufficient to signal and induce the RecF-mediated processing events observed following UV damage. By contrast, the helicase-primase complex (DnaB and DnaG) remains critically associated with the fork, leading to a loss of fork integrity, degradation, and aberrant intermediates when disrupted. The results reveal a dynamic replisome, capable of partial disassembly to allow access to the obstruction, while retaining subunits that maintain fork licensing and direct reassembly to the appropriate location after processing has occurred. PMID- 23801751 TI - Discovery of a glycerol 3-phosphate phosphatase reveals glycerophospholipid polar head recycling in Mycobacterium tuberculosis. AB - Functional assignment of enzymes encoded by the Mycobacterium tuberculosis genome is largely incomplete despite recent advances in genomics and bioinformatics. Here, we applied an activity-based metabolomic profiling method to assign function to a unique phosphatase, Rv1692. In contrast to its annotation as a nucleotide phosphatase, metabolomic profiling and kinetic characterization indicate that Rv1692 is a D,L-glycerol 3-phosphate phosphatase. Crystal structures of Rv1692 reveal a unique architecture, a fusion of a predicted haloacid dehalogenase fold with a previously unidentified GCN5-related N acetyltransferase region. Although not directly involved in acetyl transfer, or regulation of enzymatic activity in vitro, this GCN5-related N-acetyltransferase region is critical for the solubility of the phosphatase. Structural and biochemical analysis shows that the active site features are adapted for recognition of small polyol phosphates, and not nucleotide substrates. Functional assignment and metabolomic studies of M. tuberculosis lacking rv1692 demonstrate that Rv1692 is the final enzyme involved in glycerophospholipid recycling/catabolism, a pathway not previously described in M. tuberculosis. PMID- 23801752 TI - Histone deacetylase 10 promotes autophagy-mediated cell survival. AB - Tumor cells activate autophagy in response to chemotherapy-induced DNA damage as a survival program to cope with metabolic stress. Here, we provide in vitro and in vivo evidence that histone deacetylase (HDAC)10 promotes autophagy-mediated survival in neuroblastoma cells. We show that both knockdown and inhibition of HDAC10 effectively disrupted autophagy associated with sensitization to cytotoxic drug treatment in a panel of highly malignant V-MYC myelocytomatosis viral related oncogene, neuroblastoma derived-amplified neuroblastoma cell lines, in contrast to nontransformed cells. HDAC10 depletion in neuroblastoma cells interrupted autophagic flux and induced accumulation of autophagosomes, lysosomes, and a prominent substrate of the autophagic degradation pathway, p62/sequestosome 1. Enforced HDAC10 expression protected neuroblastoma cells against doxorubicin treatment through interaction with heat shock protein 70 family proteins, causing their deacetylation. Conversely, heat shock protein 70/heat shock cognate 70 was acetylated in HDAC10-depleted cells. HDAC10 expression levels in high-risk neuroblastomas correlated with autophagy in gene set analysis and predicted treatment success in patients with advanced stage 4 neuroblastomas. Our results demonstrate that HDAC10 protects cancer cells from cytotoxic agents by mediating autophagy and identify this HDAC isozyme as a druggable regulator of advanced-stage tumor cell survival. Moreover, these results propose a promising way to considerably improve treatment response in the neuroblastoma patient subgroup with the poorest outcome. PMID- 23801755 TI - Defining a length scale for millisecond-timescale protein conformational exchange. AB - Although atomic resolution 3D structures of protein native states and some folding intermediates are available, the mechanism of interconversion between such states remains poorly understood. Here we study the four-helix bundle FF module, which folds via a transiently formed and sparsely populated compact on pathway intermediate, I. Relaxation dispersion NMR spectroscopy has previously been used to elucidate the 3D structure of this intermediate and to establish that the conformational exchange between the I and the native, N, states of the FF domain is driven predominantly by water dynamics. In the present study we use NMR methods to define a length scale for the FF I-N transition, namely the effective hydrodynamic radius (EHR) that provides an average measure of the size of the structural units participating in the transition at any given time. Our experiments establish that the EHR is less than 4 A, on the order of the size of one to two amino acid side chains, much smaller than the FF domain hydrodynamic radius (13 A). The small magnitude of the EHR provides strong evidence that the I N interconversion does not proceed via the synchronous motion of large clusters of amino acid residues, but rather by the exposure/burial of one or two side chains from solvent at any given time. Because the hydration of small hydrophobic solutes (< 4 A) does not involve considerable dewetting or disruption of the water-hydrogen bonding network, the FF domain I-N transition does not require appreciable changes to the structure of the surrounding water. PMID- 23801756 TI - Water diffusion in brain cortex closely tracks underlying neuronal activity. AB - Neuronal activity results in a local increase in blood flow. This concept serves as the basis for functional MRI. Still, this approach remains indirect and may fail in situations interfering with the neurovascular coupling mechanisms (drugs, anesthesia). Here we establish that water molecular diffusion is directly modulated by underlying neuronal activity using a rat forepaw stimulation model under different conditions of neuronal stimulation and neurovascular coupling. Under nitroprusside infusion, a neurovascular-coupling inhibitor, the diffusion response and local field potentials were maintained, whereas the hemodynamic response was abolished. As diffusion MRI reflects interactions of water molecules with obstacles (e.g., cell membranes), the observed changes point to a dynamic modulation of the neural tissue structure upon activation, which remains to be investigated. These findings represent a significant shift in concept from the current electrochemical and neurovascular coupling principles used for brain imaging, and open unique avenues to investigate mechanisms underlying brain function. PMID- 23801757 TI - Conformational dynamics control ubiquitin-deubiquitinase interactions and influence in vivo signaling. AB - Ubiquitin is a highly conserved eukaryotic protein that interacts with a diverse set of partners to act as a cellular signaling hub. Ubiquitin's conformational flexibility has been postulated to underlie its multifaceted recognition. Here we use computational and library-based means to interrogate core mutations that modulate the conformational dynamics of human ubiquitin. These ubiquitin variants exhibit increased affinity for the USP14 deubiquitinase, with concomitantly reduced affinity for other deubiquitinases. Strikingly, the kinetics of conformational motion are dramatically slowed in these variants without a detectable change in either the ground state fold or excited state population. These variants can be ligated into substrate-linked chains in vitro and in vivo but cannot solely support growth in eukaryotic cells. Proteomic analyses reveal nearly identical interaction profiles between WT ubiquitin and the variants but identify a small subset of altered interactions. Taken together, these results show that conformational dynamics are critical for ubiquitin-deubiquitinase interactions and imply that the fine tuning of motion has played a key role in the evolution of ubiquitin as a signaling hub. PMID- 23801758 TI - Targeted therapy of spontaneous murine pancreatic tumors by polymeric micelles prolongs survival and prevents peritoneal metastasis. AB - Nanoscaled drug-loaded carriers are of particular interest for efficient tumor therapy as numerous studies have shown improved targeting and efficacy. Nevertheless, most of these studies have been performed against allograft and xenograft tumor models, which have altered microenvironment features affecting the accumulation and penetration of nanocarriers. Conversely, the evaluation of nanocarriers on genetically engineered mice, which can gradually develop clinically relevant tumors, permits the validation of their design under normal processes of immunity, angiogenesis, and inflammation. Therefore, considering the poor prognosis of pancreatic cancer, we used the elastase 1-promoted luciferase and Simian virus 40 T and t antigens transgenic mice, which develop spontaneous bioluminescent pancreatic carcinoma, and showed that long circulating micellar nanocarriers, incorporating the parent complex of oxaliplatin, inhibited the tumor growth as a result of their efficient accumulation and penetration in the tumors. The reduction of the photon flux from the endogenous tumor by the micelles correlated with the decrease of serum carbohydrate-associated antigen 19 9 marker. Micelles also reduced the incidence of metastasis and ascites, extending the survival of the transgenic mice. PMID- 23801759 TI - Structure of the C-terminal region of an ERG channel and functional implications. AB - The human ether-a-go-go-related gene (hERG) encodes a K(+) channel crucial for repolarization of the cardiac action potential. EAG-related gene (ERG) channels contain a C-terminal cyclic nucleotide-binding homology domain coupled to the pore of the channel by a C-linker. Here, we report the structure of the C linker/cyclic nucleotide-binding homology domain of a mosquito ERG channel at 2.5 A resolution. The structure reveals that the region expected to form the cyclic nucleotide-binding pocket is negatively charged and is occupied by a short beta strand, referred to as the intrinsic ligand, explaining the lack of direct regulation of ERG channels by cyclic nucleotides. In hERG channels, the intrinsic ligand harbors hereditary mutations associated with long-QT syndrome (LQTS), a potentially lethal cardiac arrhythmia. Mutations in the intrinsic ligand affected hERG channel gating and LQTS mutations abolished hERG currents and altered trafficking of hERG channels, which explains the LQT phenotype. The structure also reveals a dramatically different conformation of the C-linker compared with the structures of the related ether-a-go-go-like K(+) and hyperpolarization activated cyclic nucleotide-modulated channels, suggesting that the C-linker region may be highly dynamic in the KCNH, hyperpolarization-activated cyclic nucleotide-modulated, and cyclic nucleotide-gated channels. PMID- 23801760 TI - Alternatively spliced tissue factor promotes breast cancer growth in a beta1 integrin-dependent manner. AB - Full-length tissue factor (flTF), the coagulation initiator, is overexpressed in breast cancer (BrCa), but associations between flTF expression and clinical outcome remain controversial. It is currently not known whether the soluble alternatively spliced TF form (asTF) is expressed in BrCa or impacts BrCa progression. We are unique in reporting that asTF, but not flTF, strongly associates with both tumor size and grade, and induces BrCa cell proliferation by binding to beta1 integrins. asTF promotes oncogenic gene expression, anchorage independent growth, and strongly up-regulates tumor expansion in a luminal BrCa model. In basal BrCa cells that constitutively express both TF isoforms, asTF blockade reduces tumor growth and proliferation in vivo. We propose that asTF plays a major role in BrCa progression acting as an autocrine factor that promotes tumor progression. Targeting asTF may comprise a previously unexplored therapeutic strategy in BrCa that stems tumor growth, yet does not impair normal hemostasis. PMID- 23801761 TI - Prevalent genome streamlining and latitudinal divergence of planktonic bacteria in the surface ocean. AB - Planktonic bacteria dominate surface ocean biomass and influence global biogeochemical processes, but remain poorly characterized owing to difficulties in cultivation. Using large-scale single cell genomics, we obtained insight into the genome content and biogeography of many bacterial lineages inhabiting the surface ocean. We found that, compared with existing cultures, natural bacterioplankton have smaller genomes, fewer gene duplications, and are depleted in guanine and cytosine, noncoding nucleotides, and genes encoding transcription, signal transduction, and noncytoplasmic proteins. These findings provide strong evidence that genome streamlining and oligotrophy are prevalent features among diverse, free-living bacterioplankton, whereas existing laboratory cultures consist primarily of copiotrophs. The apparent ubiquity of metabolic specialization and mixotrophy, as predicted from single cell genomes, also may contribute to the difficulty in bacterioplankton cultivation. Using metagenome fragment recruitment against single cell genomes, we show that the global distribution of surface ocean bacterioplankton correlates with temperature and latitude and is not limited by dispersal at the time scales required for nucleotide substitution to exceed the current operational definition of bacterial species. Single cell genomes with highly similar small subunit rRNA gene sequences exhibited significant genomic and biogeographic variability, highlighting challenges in the interpretation of individual gene surveys and metagenome assemblies in environmental microbiology. Our study demonstrates the utility of single cell genomics for gaining an improved understanding of the composition and dynamics of natural microbial assemblages. PMID- 23801762 TI - Distinct patterns of functional brain connectivity correlate with objective performance and subjective beliefs. AB - The degree of correspondence between objective performance and subjective beliefs varies widely across individuals. Here we demonstrate that functional brain network connectivity measured before exposure to a perceptual decision task covaries with individual objective (type-I performance) and subjective (type-II performance) accuracy. Increases in connectivity with type-II performance were observed in networks measured while participants directed attention inward (focus on respiration), but not in networks measured during states of neutral (resting state) or exogenous attention. Measures of type-I performance were less sensitive to the subjects' specific attentional states from which the networks were derived. These results suggest the existence of functional brain networks indexing objective performance and accuracy of subjective beliefs distinctively expressed in a set of stable mental states. PMID- 23801763 TI - Orally fed seeds producing designer IgAs protect weaned piglets against enterotoxigenic Escherichia coli infection. AB - Oral feed-based passive immunization can be a promising strategy to prolong maternal lactogenic immunity against postweaning infections. Enterotoxigenic Escherichia coli (ETEC)-caused postweaning diarrhea in piglets is one such infection that may be prevented by oral passive immunization and might avert recurrent economic losses to the pig farming industry. As a proof of principle, we designed anti-ETEC antibodies by fusing variable domains of llama heavy chain only antibodies (VHHs) against ETEC to the Fc part of a porcine immunoglobulin (IgG or IgA) and expressed them in Arabidopsis thaliana seeds. In this way, four VHH-IgG and four VHH-IgA antibodies were produced to levels of about 3% and 0.2% of seed weight, respectively. Cotransformation of VHH-IgA with the porcine joining chain and secretory component led to the production of light-chain devoid, assembled multivalent dimeric, and secretory IgA-like antibodies. In vitro analysis of all of the antibody-producing seed extracts showed inhibition of bacterial binding to porcine gut villous enterocytes. However, in the piglet feed-challenge experiment, only the piglets receiving feed containing the VHH-IgA based antibodies (dose 20 mg/d per pig) were protected. Piglets receiving the VHH IgA-based antibodies in the feed showed a progressive decline in shedding of bacteria, significantly lower immune responses corroborating reduced exposure to the ETEC pathogen, and a significantly higher weight gain compared with the piglets receiving VHH-IgG producing (dose 80 mg/d per pig) or wild-type seeds. These results stress the importance of the antibody format in oral passive immunization and encourage future expression of these antibodies in crop seeds. PMID- 23801764 TI - Diversification through multitrait evolution in a coevolving interaction. AB - Mutualisms between species are interactions in which reciprocal exploitation results in outcomes that are mutually beneficial. This reciprocal exploitation is evident in the more than a thousand plant species that are pollinated exclusively by insects specialized to lay their eggs in the flowers they pollinate. By pollinating each flower in which she lays eggs, an insect guarantees that her larval offspring have developing seeds on which to feed, whereas the plant gains a specialized pollinator at the cost of some seeds. These mutualisms are often reciprocally obligate, potentially driving not only ongoing coadaptation but also diversification. The lack of known intermediate stages in most of these mutualisms, however, makes it difficult to understand whether these interactions could have begun to diversify even before they became reciprocally obligate. Experimental studies of the incompletely obligate interactions between woodland star (Lithophragma; Saxifragaceae) plants and their pollinating floral parasites in the moth genus Greya (Prodoxidae) show that, as these lineages have diversified, the moths and plants have evolved in ways that maintain effective oviposition and pollination. Experimental assessment of pollination in divergent species and quantitative evaluation of time-lapse photographic sequences of pollination viewed on surgically manipulated flowers show that various combinations of traits are possible for maintaining the mutualism. The results suggest that at least some forms of mutualism can persist and even diversify when the interaction is not reciprocally obligate. PMID- 23801765 TI - iRhom2 controls the substrate selectivity of stimulated ADAM17-dependent ectodomain shedding. AB - Protein ectodomain shedding by ADAM17 (a disintegrin and metalloprotease 17), a principal regulator of EGF-receptor signaling and TNFalpha release, is rapidly and posttranslationally activated by a variety of signaling pathways, and yet little is known about the underlying mechanism. Here, we report that inactive rhomboid protein 2 (iRhom2), recently identified as essential for the maturation of ADAM17 in hematopoietic cells, is crucial for the rapid activation of the shedding of some, but not all substrates of ADAM17. Mature ADAM17 is present in mouse embryonic fibroblasts (mEFs) lacking iRhom2, and yet ADAM17 is unable to support stimulated shedding of several of its substrates, including heparin binding EGF and Kit ligand 2 in this context. Stimulated shedding of other ADAM17 substrates, such as TGFalpha, is not affected in iRhom2(-/-) mEFs but can be strongly reduced by treating iRhom2(-/-) mEFs with siRNA against iRhom1. Activation of heparin-binding EGF or Kit ligand 2 shedding by ADAM17 in iRhom2(-/ ) mEFs can be rescued by wild-type iRhom2 but not by iRhom2 lacking its N terminal cytoplasmic domain. The requirement for the cytoplasmic domain of iRhom2 for stimulated shedding by ADAM17 may help explain why the cytoplasmic domain of ADAM17 is not required for stimulated shedding. The functional relevance of iRhom2 in regulating shedding of EGF receptor (EGFR) ligands is established by a lack of lysophasphatidic acid/ADAM17/EGFR-dependent crosstalk with ERK1/2 in iRhom2(-/-) mEFs, and a significant reduction of FGF7/ADAM17/EGFR-stimulated migration of iRhom2(-/-) keratinocytes. Taken together, these findings uncover functions for iRhom2 in the regulation of EGFR signaling and in controlling the activation and substrate selectivity of ADAM17-dependent shedding events. PMID- 23801766 TI - Combined optical and topographic imaging reveals different arrangements of human RAD54 with presynaptic and postsynaptic RAD51-DNA filaments. AB - Essential genome transactions, such as homologous recombination, are achieved by concerted and dynamic interactions of multiple protein components with DNA. Which proteins do what and how, will be reflected in their relative arrangements. However, obtaining high-resolution structural information on the variable arrangements of these complex assemblies is a challenge. Here we demonstrate the versatility of a combined total internal reflection fluorescence and scanning force microscope (TIRF-SFM) to pinpoint fluorescently labeled human homologous recombination protein RAD54 interacting with presynaptic (ssDNA) and postsynaptic (dsDNA) human recombinase RAD51 nucleoprotein filaments. Labeled proteins were localized by superresolution imaging on complex structures in the SFM image with high spatial accuracy. We observed some RAD54 at RAD51 filament ends, as expected. More commonly, RAD54 interspersed along RAD51-DNA filaments. RAD54 promotes RAD51-mediated DNA strand exchange and has been described to both stabilize and destabilize RAD51-DNA filaments. The different architectural arrangements we observe for RAD54 with RAD51-DNA filaments may reflect the diverse roles of this protein in homologous recombination. PMID- 23801767 TI - GAPDH is critical for superior efficacy of female bone marrow-derived mesenchymal stem cells on pulmonary hypertension. AB - AIMS: Pulmonary arterial hypertension, a chronic lung disease, remains an unacceptable prognosis despite significant advances in conventional therapies. Stem cell therapy represents a novel and effective modality. This study was aimed to add new insight in gender differences of bone marrow-derived mesenchymal stem cells on therapy against pulmonary arterial hypertension and the underlying mechanism. METHODS AND RESULTS: By in vivo experiments, we showed for the first time female bone marrow-derived mesenchymal stem cells possessed a better therapeutic potential against monocrotaline-induced pulmonary arterial hypertension in C57BL/6J mice compared with male counterparts. In vitro experiments demonstrated superior function of female bone marrow-derived mesenchymal stem cells in cell proliferation, migration and [Ca(2+)]i kinetics. Moreover, we unexpectedly found that, compared with male ones, female bone marrow derived mesenchymal stem cells had a higher expression level of glyceraldehyde-3 phosphate dehydrogenase and manipulations of its expression in female or male bone marrow-derived mesenchymal stem cells profoundly affected their cellular behaviours and therapeutic efficacies against pulmonary arterial hypertension. CONCLUSION: Our results suggest that glyceraldehyde-3-phosphate dehydrogenase plays a critical role in determining the superior functions of female bone marrow derived mesenchymal stem cells in cell therapy against pulmonary arterial hypertension by regulating [Ca(2+)]i signal-associated cellular behaviours. PMID- 23801768 TI - Exercise and type 2 diabetes mellitus: changes in tissue-specific fat distribution and cardiac function. AB - PURPOSE: To prospectively assess the effects of an exercise intervention on organ specific fat accumulation and cardiac function in type 2 diabetes mellitus. MATERIALS AND METHODS: Written informed consent was obtained from all participants, and the study protocol was approved by the medical ethics committee. The study followed 12 patients with type 2 diabetes mellitus (seven men; mean age, 46 years +/- 2 [standard error]) before and after 6 months of moderate-intensity exercise, followed by a high-altitude trekking expedition with exercise of long duration. Abdominal, epicardial, and paracardial fat volume were measured by using magnetic resonance (MR) imaging. Cardiac function was quantified with cardiac MR, and images were analyzed by a researcher who was supervised by a senior researcher (4 and 21 years of respective experience in cardiac MR). Hepatic, myocardial, and intramyocellular triglyceride (TG) content relative to water were measured with proton MR spectroscopy at 1.5 and 7 T. Two tailed paired t tests were used for statistical analysis. RESULTS: Exercise reduced visceral abdominal fat volume from 348 mL +/- 57 to 219 mL +/- 33 (P < .01), and subcutaneous abdominal fat volume remained unchanged (P = .9). Exercise decreased hepatic TG content from 6.8% +/- 2.3 to 4.6% +/- 1.6 (P < .01) and paracardial fat volume from 4.6 mL +/- 0.9 to 3.7 mL +/- 0.8 (P = .02). Exercise did not change epicardial fat volume (P = .9), myocardial TG content (P = .9), intramyocellular lipid content (P = .3), or cardiac function (P = .5). CONCLUSION: A 6-month exercise intervention in type 2 diabetes mellitus decreased hepatic TG content and visceral abdominal and paracardial fat volume, which are associated with increased cardiovascular risk, but cardiac function was unaffected. Tissue-specific exercise-induced changes in body fat distribution in type 2 diabetes mellitus were demonstrated in this study. PMID- 23801769 TI - Use of imaging in the emergency department: physicians have limited effect on variation. AB - PURPOSE: To quantify interphysician variation in imaging use during emergency department (ED) visits and examine the contribution of factors to this variation at the patient, visit, and physician level. MATERIALS AND METHODS: This study was HIPAA compliant and approved by the institutional review board of Partners Healthcare System (Boston, Mass), with waiver of informed consent. In this retrospective study of 88 851 consecutive ED visits during 2011 at a large urban teaching hospital, a hierarchical logistic regression model was used to identify multiple predictors for the probability that low- or high-cost imaging would be ordered during a given visit. Physician-specific random effects were estimated to articulate (by odds ratio) and quantify (by intraclass correlation coefficient [ICC]) interphysician variation. RESULTS: Patient- and visit-level factors found to be statistically significant predictors of imaging use included measures of ED busyness, prior ED visit, referral source to the ED, and ED arrival mode. Physician-level factors (eg, sex, years since graduation, annual workload, and residency training) did not correlate with imaging use. The remaining amount of interphysician variation was very low (ICC, 0.97% for low-cost imaging; ICC, 1.07% for high-cost imaging). These physician-specific odds ratios of imaging estimates were moderately reliable at 0.78 (95% confidence interval [CI]: 0.77, 0.79) for low-cost imaging and 0.76 (95% CI: 0.74, 0.78) for high-cost imaging. CONCLUSION: After careful and comprehensive case-mix adjustment by using hierarchical logistic regression, only about 1% of the variability in ED imaging utilization was attributable to physicians. PMID- 23801770 TI - Global small bowel motility: assessment with dynamic MR imaging. AB - PURPOSE: To assess the repeatability in human volunteers of software-quantified small bowel motility captured with magnetic resonance (MR) imaging and to test the ability to detect changes in motility induced by pharmacologic agents. MATERIALS AND METHODS: The study was approved by the Royal Free Research Ethics Committee, and all subjects gave full written informed consent. Twenty-one healthy volunteers (14 men, seven women; mean age, 28 years) underwent cine MR imaging with a three-dimensional balanced turbo field-echo sequence to capture small bowel motility. Volume blocks (15 cm thick) were acquired every second during a 20-second breath hold. A randomized, blinded, placebo-controlled crossover study of either 0.5 mg neostigmine or saline (n = 11) or 20 mg intravenous butylscopolamine or saline (n = 10) was performed with motility MR imaging at baseline and repeated at a mean of 4 weeks (range, 2-7 weeks). Two readers independently drew regions of interest around the small bowel, and motility was quantified by using a registration algorithm that provided a global motility metric in arbitrary units. Repeatability of the motility measurements at baseline was assessed by using Bland-Altman and within-subject coefficient of variation measures. Changes in mean motility measurements after drug administration were compared with those after placebo administration by using paired t testing. RESULTS: The repeatability between baseline measurements of motility was high; the Bland-Altman mean difference was -0.0025 (range, 0.28 0.4), the 95% limit of agreement was +/-0.044 arbitrary units (au), and the within-subject coefficient of variation was 4.9%. Measured motility with neostigmine (mean, 0.39 au) was significantly higher than that with placebo (mean, 0.34 au; P < .001), whereas that with butylscopolamine (mean, 0.13 au) was significantly lower than that with placebo (mean, 0.30 au; P < .001). CONCLUSION: Quantification of small bowel motility with use of MR imaging in healthy volunteers is repeatable and sensitive to changes induced by means of pharmacologic manipulation. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13130151/-/DC1. PMID- 23801771 TI - Ileocolic versus small-bowel intussusception in children: can US enable reliable differentiation? AB - PURPOSE: To assess clinical and ultrasonographic (US) criteria that can be used to confidently differentiate ileocolic from small-bowel intussusception. MATERIALS AND METHODS: Institutional review board approval was obtained for this retrospective study, and the need to obtain informed consent was waived. US and clinical data for children given a diagnosis of intussusception in the years 2007 through 2011 were evaluated. The diameters of the intussusception and the inner fat core, the outer bowel wall thickness, and the presence or absence of lymph nodes inside the intussusception and mesentery were noted. The Student t test, the Mann-Whitney test, and the Levene test were used for comparison of parametric variables, while the chi(2) and Fisher exact tests were used for comparison of categoric data. RESULTS: There were 200 cases of intussusception in 174 patients (126 boys, 48 girls; mean age, 17.2 months (range, 0 years to 7 years 1 month); 57 (28.5%) were small-bowel and 143 (71.5%) were ileocolic intussusceptions. Mean lesion diameter was 2.63 cm (range, 1.3-4.0 cm) for ileocolic versus 1.42 cm (range, 0.8-3.0 cm) for small-bowel intussusception (P < .0001). Mean fat core diameter was 1.32 cm (range, 0.6-2.2 cm) for ileocolic versus 0.1 cm (range, 0 0.75 cm) for small-bowel intussusception (P < .0001). The ratio of inner fat core diameter to outer wall thickness was greater than 1.0 in all ileocolic intussusceptions and was less than 1.0 in all small-bowel intussusceptions (P < .0001). Lymph nodes inside the lesion were seen in 128 (89.5%) of the 143 ileocolic intussusceptions versus in eight (14.0%) of the 57 small-bowel intussusceptions (P < .0001). Children with ileocolic intussusception had more severe clinical symptoms and signs, with more vomiting (P = .003), leukocytosis (P = .003), and blood in the stool (P = .00005). CONCLUSION: The presence of an inner fatty core in the intussusception, lesion diameter, wall thickness, the ratio of fatty core thickness to outer wall thickness, and the presence of lymph nodes in the lesion may enable reliable differentiation between ileocolic and small-bowel intussusceptions. PMID- 23801772 TI - Apparent diffusion coefficients for detection of postoperative middle ear cholesteatoma on non-echo-planar diffusion-weighted images. AB - PURPOSE: To determine whether there is a difference between the apparent diffusion coefficients (ADCs) of postoperative middle ear cleft cholesteatoma and noncholesteatomatous tissue on half-Fourier acquisition single-shot turbo spin echo diffusion-weighted (DW) images and to determine, with interobserver agreement, a predictive accuracy for diagnosis of postoperative middle ear cleft cholesteatoma. MATERIALS AND METHODS: Patients who underwent DW magnetic resonance (MR) examination before repeat explorative surgery for postoperative cholesteatoma were included in this study. There were 72 patient episodes and 56 patients. DW MR images were acquired with b values 0 and 1000 sec/mm(2) and 2-mm section thicknesses. Two observers assessed images qualitatively for presence of cholesteatoma and recorded ADCs. Surgery with histologic confirmation established final diagnosis of abnormal middle ear cleft soft tissue. ADCs between cholesteatoma and noncholesteatomatous tissue were compared with Mann-Whitney test. Effects of ADCs and confidence intervals to indicate presence of cholesteatoma were examined by using receiver operating characteristic (ROC) curve analysis, logistic regression analysis, and interobserver agreement. RESULTS: Forty-six patients had cholesteatoma and 25 patients did not; sensitivity and specificity were 0.91 and 0.88, respectively, for the qualitative diagnosis of postoperative cholesteatoma by using a five-point confidence scale. ADC of cholesteatoma (median, 707 * 10(-6) mm(2)/sec; interquartile range, 539 858 * 10(-6) mm(2)/sec; P < .001) was significantly lower than that of noncholesteatomatous tissue (median, 1849 * 10(-6) mm(2)/sec; interquartile range, 1574-1982 * 10(-6) mm(2)/sec; P < .001). There was good accuracy (area under the ROC curve, 0.97) and interobserver agreement for detecting postoperative cholesteatoma with ADC threshold less than 1300 * 10(-6) mm(2)/sec. CONCLUSION: The ADC value of postoperative middle ear cleft cholesteatoma is significantly lower than that of noncholesteatomatous tissue and has good accuracy for detecting cholesteatoma. PMID- 23801773 TI - Bronchial artery embolization to control hemoptysis: comparison of N-butyl-2 cyanoacrylate and polyvinyl alcohol particles. AB - PURPOSE: To retrospectively compare safety and effectiveness of embolic agents polyvinyl alcohol (PVA) particles versus n-butyl-2-cyanoacrylate (NBCA) for bronchial artery embolization (BAE) for control of hemoptysis. MATERIALS AND METHODS: Institutional review board approved this retrospective study; informed consent was waived. From January 2005 to December 2008, 406 patients (242 men, 164 women; age range, 6-92 years) with major hemoptysis underwent BAE by using PVA particles (n = 293) or NBCA (n = 113). Technical and clinical success, complications, hemoptysis-free survival rates, and causes of recurrent hemoptysis were compared between PVA and NBCA groups. The differences in hemoptysis-free survival rates were assessed between subgroups stratified to underlying diseases. The predictive factor for recurrent hemoptysis was identified with Cox proportional hazard regression model. RESULTS: Technical success was achieved in 93.9% (275 of 293) and 96.5% (109 of 113) of patients for PVA and NBCA, respectively (P = .463); clinical success was achieved in 92.2% (270 of 293) and 96.5% (109 of 113) of patients for PVA and NBCA, respectively (P = .180). Overall and major complication rates were not statistically different (overall complication rates: 34.1% for PVA, 31.0% for NBCA; P = .56; major complication rates: 0.3% for PVA, 0% for NBCA; P > .999). The 1-, 3-, and 5-year hemoptysis free survival rates were, respectively, 77%, 68%, and 66% for PVA and 88%, 85%, and 83% for NBCA (P = .01). Recanalization of previously embolized vessels was more frequent in PVA group (21.5%) than in NBCA group (1.8%; P < .001). NBCA group showed hemoptysis-free survival rates superior to PVA group in patients with bronchiectasis (P = .016). PVA (P = .050) and aspergilloma (P < .001) were predictive factors for recurrent hemoptysis. CONCLUSION: BAE with NBCA provided higher hemoptysis-free survival rates compared with PVA particles without increasing complication rates. This improvement was evident in patients with bronchiectasis and was caused by more durable embolic effect than PVA particles. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13130046/-/DC1. PMID- 23801774 TI - Ovarian carcinoma: quantitative biexponential MR imaging relaxometry reveals the dynamic recruitment of ferritin-expressing fibroblasts to the angiogenic rim of tumors. AB - PURPOSE: To quantitatively monitor the dynamic perivascular recruitment of ferritin heavy chain (FHC)-overexpressing fibroblasts to ovarian carcinoma xenografts by using R2 mapping and biexponential magnetic resonance (MR) relaxometry. MATERIALS AND METHODS: In vivo studies of female mice were approved by the institutional animal care and use committee. In vitro analysis included MR based R2 relaxation measurements of monkey kidney cell line (CV1) fibroblasts that overexpress FHC, followed by inductively coupled plasma mass spectrometry to assess cellular iron content. For in vivo analysis, CV1-FHC fibroblasts were either mixed with fluorescent human ovarian carcinoma cells before subcutaneous implantation (coinjection) or injected intraperitoneally 4 days after the cancer cells were injected (remote recruitment). Dynamic changes in tumor R2 were used to derive CV1-FHC cell fraction in both models. In coinjection tumors, dynamic contrast material-enhanced MR imaging was used to measure tumor fractional blood volume. Whole-body fluorescence imaging and immunohistochemical staining were performed to validate MR results. One-way repeated measures analysis of variance was used to assess MR and fluorescence imaging results and tumor volume, and one way analysis of variance was used to assess spectrometric results, fractional blood volume, and immunohistochemical evaluation. RESULTS: CV1-FHC fibroblasts (vs CV1 fibroblasts) showed enhanced iron uptake (1.8 mmol +/- 0.5 * 10(-8) vs 0.9 mmol +/- 0.5 * 10(-8); P < .05), retention (1.6 mmol +/- 0.5 * 10(-8) vs 0.5 mmol +/- 0.5 * 10(-8), P < .05), and cell density-dependent R2 contrast. R2 mapping in vivo revealed preferential recruitment of CV1-FHC cells to the tumor rim in both models. Measurement of fractional blood volume was similar in all tumors (2.6 AU +/- 0.5 * 10(-3) for CV1, 2.3 AU +/- 0.3 * 10(-3) for CV1-FHC, 2.9 +/- 0.3 * 10(-3) for CV1-FHC-ferric citrate). Dynamic changes in CV1-FHC cell fraction determined at MR relaxometry in both models were confirmed at immunohistochemical analysis. CONCLUSION: FHC overexpression, when combined with R2 mapping and MR relaxometry, enabled in vivo detection of the dynamic recruitment of exogenously administered fibroblasts to the vasculature of solid tumors. PMID- 23801775 TI - Aortic disease in patients with Marfan syndrome: aortic volume assessment for surveillance. AB - PURPOSE: To assess the reproducibility of aortic volume estimates and to serially test their use in patients with Marfan syndrome. MATERIALS AND METHODS: The study was approved by the medical ethics committee and all subjects gave written informed consent. In 81 patients with Marfan syndrome and seven healthy control subjects, aortic volumes and diameters at baseline were estimated by means of contrast material-enhanced magnetic resonance (MR) imaging. At 3 years of follow up, aortic expansion rate were calculated in a subgroup of 22 patients with Marfan syndrome. Total aortic volume was defined as volume measurement from the level of the aortic annulus to the aortic bifurcation. Intra- and interobserver agreement of aortic volume were calculated by using the intraclass correlation coefficient. Differences in variables were analyzed with the Student t test and logistic regression. Effect size was calculated. RESULTS: Intra- and interobserver agreement of aortic volume calculation was 0.996 and 0.980, respectively. Mean aortic volume was significantly greater in patients with Marfan syndrome than in control subjects (104 mL/m(2); 95% confidence interval [CI]: 95, 114 mL/m(2) vs 74 mL/m(2); 95% CI: 62, 87 mL/m(2); P < .001). In 22 patients with Marfan syndrome, mean aortic volume was increased at 3 years of follow-up (17 mL; 95% CI: 8, 26 mL; P = .001; effect size, 0.29), while mean aortic diameter did not increase significantly (0.4 mm; 95% CI: 0.0, 0.9 mm; P = .171; effect size, 0.13). CONCLUSION: Assessment of aortic volume is highly reproducible and may be suited for use in the detection of aortic expansion in patients with Marfan syndrome. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13122310/-/DC1. PMID- 23801776 TI - Bone marrow edema in vertebral compression fractures: detection with dual-energy CT. AB - PURPOSE: To assess the use of the dual-energy computed tomographic (CT) virtual noncalcium technique in the evaluation of bone marrow edema in vertebral compression fractures. MATERIALS AND METHODS: This prospective study was approved by the institutional review board; informed consent was obtained from all patients. Sixty-three consecutive patients with 112 thoracic and/or lumbar vertebral compression fractures were studied between January 2011 and April 2012. All patients underwent both dual-energy CT (100 kV and Sn140 kV, where Sn indicates the use of a 0.4-mm tin filter) and magnetic resonance (MR) imaging. Dual-energy CT data were postprocessed by using a three-material decomposition algorithm for generating noncalcium images of the collapsed bodies. Two radiologists evaluated for the presence of abnormal attenuation alterations in the bone marrow by using color-coded maps and measured CT numbers on noncalcium grayscale images. Bone sclerosis and intravertebral air were evaluated with CT scans. MR images served as the reference standard. CT numbers were subjected to receiver operating characteristic curve analysis. RESULTS: MR imaging depicted 46 edematous and 66 nonedematous vertebral compression fractures. Eighty-two bodies were classified as having less than 50% sclerosis and/or air. Significant differences in noncalcium CT numbers between edematous and nonedematous vertebral compression fractures were found for both readers (P < .0001). CT numbers for the diagnosis of bone marrow edema on the basis of MR imaging revealed areas under the receiver operating characteristic curve of 0.799 and 0.841 for readers 1 and 2, respectively (P = .56). Use of a cutoff value of -80 to differentiate edematous vertebral bodies resulted in a sensitivity of 96.3%, specificity of 98.2%, and accuracy of 97.6% in the group of vertebral bodies with less than 50% sclerosis and/or air. CONCLUSION: Dual-energy CT virtual noncalcium images were able to depict bone marrow in the collapsed vertebral bodies, especially in those with less than 50% sclerosis and/or air. PMID- 23801777 TI - Patients who undergo preoperative chemoradiotherapy for locally advanced rectal cancer restaged by using diagnostic MR imaging: a systematic review and meta analysis. AB - PURPOSE: To obtain performance values of magnetic resonance (MR) imaging for restaging locally advanced rectal cancer after neoadjuvant treatment regarding tumor staging, nodal staging, and tumor-free circumferential resection margins (CRMs). MATERIALS AND METHODS: MEDLINE, EMBASE, and Cochrane databases were searched for studies regarding restaging compared with a reference standard by using the terms rectal neoplasms, MR imaging, and chemotherapy. The Quality Assessment of Diagnostic Accuracy Studies tool was used, and data on imaging criteria, histopathologic criteria, and restaging were extracted. Responders were defined as positives and nonresponders, as negatives. Mean sensitivity, mean specificity, and positive and negative likelihood ratios (LRs) were determined by using a bivariate random-effects model. A positive LR greater than 5 implied moderate results for responders. RESULTS: Thirty-three studies evaluated 1556 patients. For tumor stage, mean sensitivity was 50.4%, mean specificity was 91.2%, positive LR was 5.76, and negative LR was 0.54. Diffusion-weighted (DW) imaging showed comparable positive LR with significantly improved sensitivity (P = .01) and negative LR (P = .04). Experienced observers showed higher sensitivity (P = .01) and lower negative LR (P = .03) compared with less experienced observers. For CRM, mean sensitivity, mean specificity, positive LR, and negative LR were 76.3%, 85.9%, 5.40, and 0.28, respectively. For nodal stage per patient, mean sensitivity, mean specificity, positive LR, and negative LR were 76.5%, 59.8%, 1.90, and 0.39, respectively; and for nodal stage on a lesion basis, these values were 90.7%, 73.0%, 3.37, and 0.13, respectively. CONCLUSION: MR imaging showed heterogeneous results of diagnostic performances for restaging rectal cancer after neoadjuvant treatment, but significantly better results were demonstrated when DW imaging was used or with experienced observers. MR imaging can also be used for evaluation of CRM staging, but nodal staging remains challenging. PMID- 23801778 TI - Acute myocardial infarction: estimation of at-risk and salvaged myocardium at myocardial perfusion SPECT 1 month after infarction. AB - PURPOSE: To estimate at-risk and salvaged myocardium by using gated single photon emission computed tomography (SPECT) myocardial perfusion imaging after acute myocardial infarction (AMI). MATERIALS AND METHODS: The study was approved by the hospital's Ethical Committee on Clinical Trials (trial register number, PR(HG)36/2000), and all patients gave informed consent. Forty patients (mean age, 61.78 years; eight women) with a first AMI underwent two gated SPECT examinations -one before percutaneous coronary intervention (PCI) and one 4-5 weeks after PCI. Myocardium at risk was estimated by assessing the perfusion defect at the first gated SPECT examination, and salvaged myocardium was estimated by assessing the risk area minus necrosis at the second examination. Myocardium at risk was estimated by determining the discordance between the areas of left ventricular (LV) wall motion and perfusion at the second examination. Concordance between tests was analyzed by means of linear regression analysis, the Pearson correlation, the intraclass correlation coefficient, and Bland-Altman analysis. RESULTS: An improvement in perfusion, wall motion, wall thickening, and LV ejection fraction (P < .001) was observed at 1 month. At 1 month, the area with abnormal wall motion was greater than the area of altered perfusion (35.47 vs 23.1 cm(2); P = .007). The extent of myocardium at risk estimated from this discordance correlated well with myocardium at risk measured at the first gated SPECT examination and with salvaged myocardium between both studies (Pearson correlation: 0.78 and 0.6, respectively). Concordance for correct classification of patients with salvaged myocardium of 50% or greater was 83% (kappa = 0.65). CONCLUSION: Myocardial perfusion gated SPECT performed 1 month after early PCI in a first AMI provides potentially useful information on at-risk and salvaged myocardium. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13122324/-/DC1. PMID- 23801779 TI - Biochemical evidence for energy-independent flippase activity in bovine epididymal sperm membranes: an insight into membrane biogenesis. AB - During the maturation process spermatozoa undergo a series of changes in their lateral and horizontal lipid profiles. However, lipid metabolism in spermatozoa is not clearly understood for two reasons: i) the mature spermatozoa are devoid of endoplasmic reticulum, which is the major site of phospholipid (PL) synthesis in somatic cells, and ii) studies have been superficial due to the difficulty in culturing spermatozoa. We hypothesize that spermatozoa contain biogenic membrane flippases since immense changes in lipids occur during spermatogenic differentiation. To test this, we isolated spermatozoa from bovine epididymides and reconstituted the detergent extract of sperm membranes into proteoliposomes. In vitro assays showed that proteoliposomes reconstituted with sperm membrane proteins exhibit ATP-independent flip-flop movement of phosphatidylcholine (PC), phosphatidylserine, and phosphatidylglycerol. Half-life time of PC flipping was found to be ~3.2+/-1 min for whole sperm membrane, which otherwise would have taken ~11-12 h in the absence of protein. Further biochemical studies confirm the flip-flop movement to be protein-mediated, based on its sensitivity to protease and protein-modifying reagents. To further determine the cellular localization of flippases, we isolated mitochondria of spermatozoa and checked for ATP independent flippase activity. Interestingly, mitochondrial membranes showed flip flop movement but were specific for PC with half-life time of ~5+/-2 min. Our results also suggest that spermatozoa have different populations of flippases and that their localization within the cellular compartments depends on the type of PL synthesis. PMID- 23801780 TI - Differences in the metabolomic signatures of porcine follicular fluid collected from environments associated with good and poor oocyte quality. AB - The microenvironment of the developing follicle is critical to the acquisition of oocyte developmental competence, which is influenced by several factors including follicle size and season. The aim of this study was to characterise the metabolomic signatures of porcine follicular fluid (FF) collected from good and poor follicular environments, using high-resolution proton nuclear magnetic resonance (1H-NMR) spectroscopy. Sow ovaries were collected at slaughter, 4 days after weaning, in summer and winter. The contents of small (3-4 mm) and large (5 8 mm) diameter follicles were aspirated and pooled separately for each ovary pair. Groups classified as summer-small (n=8), summer-large (n=15), winter-small (n=9) and winter-large (n=15) were analysed by 1H-NMR spectroscopy. The concentrations of 11 metabolites differed due to follicle size alone (P<0.05), including glucose, lactate, hypoxanthine and five amino acids. The concentrations of all these metabolites, except for glucose, were lower in large FF compared with small FF. Significant interaction effects of follicle size and season were found for the concentrations of glutamate, glycine, N-acetyl groups and uridine. Succinate was the only metabolite that differed in concentration due to season alone (P<0.05). The FF levels of progesterone, androstenedione and oestradiol were correlated with the concentrations of most of the metabolites examined. The results indicate that there is a distinct shift in follicular glucose metabolism as follicles increase in diameter and suggest that follicular cells may be more vulnerable to oxidative stress during the summer months. Our findings demonstrate the power of 1H-NMR spectroscopy to expand our understanding of the dynamic and complex microenvironment of the developing follicle. PMID- 23801781 TI - Seeking the origin of female germline stem cells in the mammalian ovary. AB - The function of female germline stem cells (FGSCs, also called oogonial stem cells) in the adult mammalian ovary is currently debated in the scientific community. As the evidence to support or discard the possible crucial role of this new class of germ cells in mammals has been extensively discussed, in this review, we wonder which could be their origin. We will assume that FGSCs are present in the post-natal ovaries and speculate as to what origin and characteristics such cells could have. We believe that the definition of these features might shed light on future experimental approaches that could clarify the ongoing debate. PMID- 23801782 TI - Using sheep lines with mutations in single genes to better understand ovarian function. AB - Livestock populations have been subjected to strong selection pressure to improve reproductive success, and this has led to the identification of lines of animals with increased fecundity. These animals provide a rich biological resource for discovery of genes and regulatory mechanisms that underpin improved reproductive success. To date, three genes, all related to the transforming growth factor beta pathway, have been identified as having mutations that lead to alterations in ovulation in sheep. In addition, several other sheep lines have been identified with putative mutations in single genes with major effects on ovulation rate. This review is focused on the identification of the mutations affecting ovulation rate and how these discoveries have provided new insights into control of ovarian function. PMID- 23801783 TI - Beyond conventional therapy: role of pulse steroids in bleomycin induced lung injury. PMID- 23801784 TI - Pulmonary function test quality in the elderly: a comparison with younger adults. AB - BACKGROUND: Elderly patients may be at greater risk for misdiagnosis and inappropriate treatment as a consequence of pulmonary function test underutilization and tests being conducted with low quality expectations. This study sought to determine if elderly patients are able to achieve both spirometry and diffusion capacity (DLCO) quality scores comparable to a younger adult population. METHODS: This was a retrospective review of pulmonary function data over a 22 month period. A list of every subject age >= 80 years (elderly group) and ages 40-50 years (control group) tested during the time period was compiled. The quality of spirometry and DLCO testing were examined. RESULTS: Overall, 92.6% (139/150) of the elderly group and 91.5% (163/178) of the control group spirometry tests satisfied all American Thoracic Society/European Respiratory Society acceptability and reproducibility criteria (P = .84), and 84.9% (96/113) of the elderly group and 88.5% (108/122) of the control group DLCO tests satisfied all the acceptability and reproducibility criteria (P = .45). CONCLUSIONS: Elderly patients referred to a hospital-based pulmonary function test lab can be expected to achieve spirometry and DLCO quality scores comparable to younger adult patients. PMID- 23801785 TI - Oxygen supplementation in noninvasive home mechanical ventilation: the crucial roles of CO2 exhalation systems and leakages. AB - BACKGROUND: When supplemental oxygen is added to noninvasive ventilation using a non-ICU ventilator, it is usually introduced with a preset flow into the circuit near the ventilator; however, the impact of different CO2 exhalation systems and leaks on the actual FIO2 and gas exchange has not been elucidated. METHODS: In a randomized, open-label, 4-treatment (2-by-2), 4-period crossover design, 4 daytime measurements (60 min each) were performed in 20 subjects receiving home mechanical noninvasive ventilation plus supplemental oxygen (>= 2 L/min) inserted near the ventilator: active valve circuit or leak port circuit with or without artificial leakage (4 mm inner diameter). Oxygen concentration near the ventilator, oxygen concentration at the mask, and blood gases were measured. RESULTS: Overall, oxygen concentration at the mask (29 +/- 5%) was lower than oxygen concentration at the ventilator (34 +/- 4%), with a mean difference of 5.1% (95% CI 4.2-5.9%, P < .001)%. With the leak port circuit, oxygen concentration at the mask decreased by 3.2% (95% CI 2.6 to 3.9%, P < .001), compared to the active valve circuit. When artificial leakage was introduced into the circuit, oxygen concentration at the mask decreased by 5.7% (95% CI 5.1 to 6.4%, P < .001)%, PaO2 by 10.4 mm Hg (95% CI 3.1 to 17.7 mm Hg, P = .006), and PaCO2 increased by 1.8 mm Hg (95% CI 0.5 to 3.1 mm Hg, P = .008). CONCLUSIONS: The use of a leak port circuit and the occurrence of leak around the interface significantly reduced oxygen concentration at the mask and negatively impacted gas exchange in subjects receiving home noninvasive ventilation and supplemental oxygen. (German Clinical Trials Registry, www.drks.de, DRKS00000449). PMID- 23801786 TI - Upper and lower limb muscles in patients with COPD: similarities in muscle efficiency but differences in fatigue resistance. AB - BACKGROUND: Peripheral muscle dysfunction is a common finding in patients with COPD; however, the structural adaptation and functional impairment of the upper and lower limb muscles do not seem to be homogenous. We compared muscle fatigue and recovery time between 2 representative muscles: the middle deltoid and the quadriceps femoris. METHODS: Twenty-one subjects with COPD (FEV1 46.1 +/- 10.3% of predicted) underwent maximal voluntary isometric contraction and an endurance test (60% of maximal voluntary isometric contraction, to the limit of tolerance). The maximal voluntary isometric contraction test was repeated after 10 min, 30 min, 60 min, and 24 hours for both the quadriceps femoris and middle deltoid. Surface electromyography was recorded throughout the endurance test. RESULTS: Maximal voluntary isometric contraction significantly decreased only for the middle deltoid between 10 and 60 min after the endurance test. A significant increase of the root mean square and a greater decline in median frequency throughout the endurance test occurred for the middle deltoid, compared with the quadriceps femoris. When dyspnea and fatigue scores were corrected by endurance time, higher values were observed for the middle deltoid (0.07 and 0.08, respectively) in relation to the quadriceps femoris (0.02 and 0.03, respectively). CONCLUSIONS: Subjects with COPD had a higher fatigability of a representative upper limb muscle (middle deltoid) than a lower limb muscle (quadriceps femoris). PMID- 23801787 TI - Recurrent catamenial pneumothorax caused by diaphragmatic fenestration. PMID- 23801789 TI - Diurnal variations of radon and thoron activity concentrations and effective doses in dwellings in Niska Banja, Serbia. AB - In Niska Banja, a spa town in a radon-prone area in southern Serbia, radon ((222)Rn) and thoron ((220)Rn) activity concentrations were measured continuously for one day in indoor air of 10 dwellings with a SARAD RTM 2010-2 Radon/Thoron Monitor, and equilibrium factor between radon and its decay products and the fraction of unattached radon decay products with a SARAD EQF 3020-2 Equilibrium Factor Monitor. Radon concentration in winter time ranged from 26 to 73 100 Bq m( 3) and that of thoron, from 10 to 8650 Bq m(-3). In the same period, equilibrium factor and the unattached fraction varied in the range of 0.08 to 0.90 and 0.01 to 0.27, respectively. One-day effective doses were calculated and were in winter conditions from 4 to 2599 MUSv d(-1) for radon and from 0.2 to 73 MUSv d(-1) for thoron. PMID- 23801788 TI - Yeast Upf1 CH domain interacts with Rps26 of the 40S ribosomal subunit. AB - The central nonsense-mediated mRNA decay (NMD) regulator, Upf1, selectively targets nonsense-containing mRNAs for rapid degradation. In yeast, Upf1 preferentially associates with mRNAs that are NMD substrates, but the mechanism of its selective retention on these mRNAs has yet to be elucidated. Previously, we demonstrated that Upf1 associates with 40S ribosomal subunits. Here, we define more precisely the nature of this association using conventional and affinity based purification of ribosomal subunits, and a two-hybrid screen to identify Upf1-interacting ribosomal proteins. Upf1 coimmunoprecipitates specifically with epitope-tagged 40S ribosomal subunits, and Upf1 association with high-salt washed or puromycin-released 40S subunits was found to occur without simultaneous eRF1, eRF3, Upf2, or Upf3 association. Two-hybrid analyses and in vitro binding assays identified a specific interaction between Upf1 and Rps26. Using mutations in domains of UPF1 known to be crucial for its function, we found that Upf1:40S association is modulated by ATP, and Upf1:Rps26 interaction is dependent on the N terminal Upf1 CH domain. The specific association of Upf1 with the 40S subunit is consistent with the notion that this RNA helicase not only triggers rapid decay of nonsense-containing mRNAs, but may also have an important role in dissociation of the premature termination complex. PMID- 23801791 TI - Pathways to quality inpatient management of hyperglycemia and diabetes: a call to action. AB - Currently patients with diabetes comprise up to 25-30% of the census of adult wards and critical care units in our hospitals. Although evidence suggests that avoidance of hyperglycemia (>180 mg/dL) and hypoglycemia (<70 mg/dL) is beneficial for positive outcomes in the hospitalized patient, much of this evidence remains controversial and at times somewhat contradictory. We have recently formed a consortium for Planning Research in Inpatient Diabetes (PRIDE) with the goal of promoting clinical research in the area of management of hyperglycemia and diabetes in the hospital. In this article, we outline eight aspects of inpatient glucose management in which randomized clinical trials are needed. We refer to four as system-based issues and four as patient-based issues. We urge further progress in the science of inpatient diabetes management. We hope this call to action is supported by the American Diabetes Association, The Endocrine Society, the American Association of Clinical Endocrinologists, the American Heart Association, the European Association for the Study of Diabetes, the International Diabetes Federation, and the Society of Hospital Medicine. Appropriate federal research funding in this area will help ensure high-quality investigations, the results of which will advance the field. Future clinical trials will allow practitioners to develop optimal approaches for the management of hyperglycemia in the hospitalized patient and lessen the economic and human burden of poor glycemic control and its associated complications and comorbidities in the inpatient setting. PMID- 23801792 TI - Mind the gap: disparity between research funding and costs of care for diabetic foot ulcers. PMID- 23801793 TI - Continuous glucose monitoring in pregnancy: we have the technology but not all the answers. PMID- 23801794 TI - Preventing diabetes in American Indian communities. PMID- 23801795 TI - Osteoprotegerin is an independent predictor of vascular events in Finnish adults with type 1 diabetes. AB - OBJECTIVE: Osteoprotegerin (OPG) is involved in the process of vascular calcification. We investigated whether OPG is associated with the development and progression of diabetes complications in adults with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: Serum OPG was measured in 1,939 adults with T1D participating in the Finnish Diabetic Nephropathy (FinnDiane) Study. Patients with end-stage renal disease (dialysis or transplantation) at baseline were excluded from analysis. Data on cardiovascular (CV) events and mortality during follow-up were verified from hospital discharge registries (ICD codes) and the Finnish National Death Registry, respectively. The follow-up time was 10.4 +/- 2.0 (mean +/- SD) years. RESULTS: Only patients with macroalbuminuria and/or renal impairment had elevated OPG concentrations, when compared with participants without overt kidney disease. Patients with retinopathy or CV disease also had higher OPG concentrations, but this was attributable to their higher frequency of chronic kidney disease. OPG predicted an incident CV event (hazard ratio 1.21 [95% CI 1.01-1.45]; P = 0.035) and peripheral vascular disease/amputation events (1.46 [1.13-1.88]; P = 0.004) during follow-up. CONCLUSIONS: We showed that serum OPG is an independent predictor of CV complications. OPG may be directly involved in extraosseous calcification, resulting in stiffening of the arteries and subsequent vascular insufficiency in patients with T1D. PMID- 23801796 TI - Prognostic value of multidetector computed tomography coronary angiography in diabetes: excellent long-term prognosis in patients with normal coronary arteries. AB - OBJECTIVE: To assess the prognostic role of multidetector computed tomography coronary angiography (MDCT-CA) in patients with diabetes with suspected coronary artery disease (CAD). Use of MDCT-CA is increasing in patients with suspected CAD. However, data supporting its prognostic value in patients with diabetes are limited. RESEARCH DESIGN AND METHODS: Between January 2006 and September 2007, 429 consecutive diabetic patients were prospectively studied with MDCT-CA for detecting the presence and assessing the extent of CAD (disease extension and coronary plaque scores). Patients were classified according to the presence of normal coronary arteries and nonobstructive (<50%) and obstructive (>=50%) coronary lesions. The composite rates of hard cardiac events (cardiac death, nonfatal myocardial infarction, unstable angina) and all cardiac events (including revascularization) were the end points of the study. RESULTS: Twenty four patients were excluded because MDCT-CA data were not able to be interpreted. Of the remaining 405 patients, clinical follow-up (mean 62 +/- 9 months) was obtained in 390 (98%). Multivariate analysis showed that predictors of hard and all events were obstructive CAD, three-vessel CAD, and left main coronary artery (LMCA) disease. Cumulative event-free survival was 100% for hard and all events in patients with normal coronary arteries, 78% for hard events and 56% for all events in patients with nonobstructive CAD, and 60% for hard events and 16% for all events in patients with obstructive CAD. Three-vessel CAD and LMCA disease were associated with a higher rate of hard cardiac events. CONCLUSIONS: MDCT-CA provides long-term prognostic information for patients with diabetes with suspected CAD, showing excellent prognosis when there is no evidence of atherosclerosis and allowing risk stratification when CAD is present. PMID- 23801797 TI - Nutritional factors and preservation of C-peptide in youth with recently diagnosed type 1 diabetes: SEARCH Nutrition Ancillary Study. AB - OBJECTIVE: To test the novel hypothesis that nutritional factors previously associated with type 1 diabetes etiology or with insulin secretion are prospectively associated with fasting C-peptide (FCP) concentration among youth recently diagnosed with type 1 diabetes. RESEARCH DESIGN AND METHODS: Included were 1,316 youth with autoantibody-positive type 1 diabetes who participated in the SEARCH for Diabetes in Youth study (baseline disease duration, 9.9 months; SD, 6.3). Nutritional exposures included breastfeeding and age at introduction of complementary foods, baseline plasma long-chain omega-3 fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), vitamin D, vitamin E, and, from a baseline food frequency questionnaire, estimated intake of the branched-chain amino acid leucine and total carbohydrate. Multiple linear regression models were conducted to relate each nutritional factor to baseline FCP adjusted for demographics, disease-related factors, and other confounders. Prospective analyses included the subset of participants with preserved beta-cell function at baseline (baseline FCP >=0.23 ng/mL) with additional adjustment for baseline FCP and time (mean follow-up, 24.3 months; SD, 8.2; n = 656). FCP concentration was analyzed as log(FCP). RESULTS: In adjusted prospective analyses, baseline EPA (P = 0.02), EPA plus DHA (P = 0.03), and leucine (P = 0.03) were each associated positively and significantly with FCP at follow-up. Vitamin D was unexpectedly inversely associated with FCP (P = 0.002). CONCLUSIONS: Increased intake of branched-chain amino acids and long-chain omega 3 fatty acids may support preservation of beta-cell function. This represents a new direction for research to improve prognosis for type 1 diabetes. PMID- 23801798 TI - Feasibility of outpatient fully integrated closed-loop control: first studies of wearable artificial pancreas. AB - OBJECTIVE: To evaluate the feasibility of a wearable artificial pancreas system, the Diabetes Assistant (DiAs), which uses a smart phone as a closed-loop control platform. RESEARCH DESIGN AND METHODS: Twenty patients with type 1 diabetes were enrolled at the Universities of Padova, Montpellier, and Virginia and at Sansum Diabetes Research Institute. Each trial continued for 42 h. The United States studies were conducted entirely in outpatient setting (e.g., hotel or guest house); studies in Italy and France were hybrid hospital-hotel admissions. A continuous glucose monitoring/pump system (Dexcom Seven Plus/Omnipod) was placed on the subject and was connected to DiAs. The patient operated the system via the DiAs user interface in open-loop mode (first 14 h of study), switching to closed loop for the remaining 28 h. Study personnel monitored remotely via 3G or WiFi connection to DiAs and were available on site for assistance. RESULTS: The total duration of proper system communication functioning was 807.5 h (274 h in open loop and 533.5 h in closed-loop), which represented 97.7% of the total possible time from admission to discharge. This exceeded the predetermined primary end point of 80% system functionality. CONCLUSIONS: This study demonstrated that a contemporary smart phone is capable of running outpatient closed-loop control and introduced a prototype system (DiAs) for further investigation. Following this proof of concept, future steps should include equipping insulin pumps and sensors with wireless capabilities, as well as studies focusing on control efficacy and patient-oriented clinical outcomes. PMID- 23801799 TI - A role for fibroblast growth factor 19 and bile acids in diabetes remission after Roux-en-Y gastric bypass. AB - OBJECTIVE: Roux-en-Y gastric bypass (RYGB) in humans can remit type 2 diabetes, but the operative mechanism is not completely understood. In mice, fibroblast growth factor (FGF) 15 (FGF19 in humans) regulates hepatic bile acid (BA) production and can also resolve diabetes. In this study, we tested the hypothesis that the FGF19-BA pathway plays a role in the remission of human diabetes after RYGB surgery. RESEARCH DESIGN AND METHODS: Cohorts of diabetic and nondiabetic individuals of various body weights were used. In addition, RYGB patients without diabetes (No-Diabetes), RYGB patients with diabetes who experienced remission for at least 12 months after surgery (Diabetes-R), and RYGB patients with diabetes who did not go into remission after surgery (Diabetes-NoR) were studied. Circulating FGF19 and BA levels, hepatic glycogen content, and expression levels of genes regulating the FGF19-BA pathway were compared among these groups of patients using pre- and postoperative serum samples and intraoperative liver biopsies. RESULTS: Preoperatively, patients with diabetes had lower FGF19 and higher BA levels than nondiabetic patients, irrespective of body weight. In diabetic patients undergoing RYGB, lower FGF19 levels were significantly correlated with increased hepatic expression of the cholesterol 7alpha hydroxylase 1 (CYP7A1) gene, which modulates BA production. Following RYGB surgery, however, FGF19 and BA levels (particularly cholic and deoxycholic acids) exhibited larger increases in Diabetic-R patients compared with nondiabetic and Diabetic-NoR patients. CONCLUSIONS: Taken together, the baseline and postoperative data implicate the FGF19-CYP7A1-BA pathway in the etiology and remission of type 2 diabetes following RYGB surgery. PMID- 23801800 TI - Is incretin-based therapy ready for the care of hospitalized patients with type 2 diabetes?: The time has come for GLP-1 receptor agonists! AB - Significant data suggest that overt hyperglycemia, either observed with or without a prior diagnosis of diabetes, contributes to an increase in mortality and morbidity in hospitalized patients. In this regard, goal-directed insulin therapy has remained as the standard of care for achieving and maintaining glycemic control in hospitalized patients with critical and noncritical illness. As such, protocols to assist in the management of hyperglycemia in the inpatient setting have become commonplace in hospital settings. Clearly, insulin is a known entity, has been in clinical use for almost a century, and is effective. However, there are limitations to its use. Based on the observed mechanisms of action and efficacy, there has been a great interest in using incretin-based therapy with glucagon-like peptide-1 (GLP-1) receptor agonists instead of, or complementary to, an insulin-based approach to improve glycemic control in hospitalized, severely ill diabetic patients. To provide an understanding of both sides of the argument, we provide a discussion of this topic as part of this two-part point counterpoint narrative. In this point narrative as presented below, Drs. Schwartz and DeFronzo provide an opinion that now is the time to consider GLP-1 receptor agonists as a logical consideration for inpatient glycemic control. It is important to note the recommendations they propose under "incretin-based approach" with these agents represent their opinion for use and, as they point out, well-designed prospective studies comparing these agents with insulin will be required to establish their efficacy and safety. In the counterpoint narrative following Drs. Schwartz and DeFronzo's contribution, Drs. Umpierrez and Korytkowski provide a defense of insulin in the inpatient setting as the unquestioned gold standard for glycemic management in hospitalized settings. PMID- 23801801 TI - Is incretin-based therapy ready for the care of hospitalized patients with type 2 diabetes?: Insulin therapy has proven itself and is considered the mainstay of treatment. AB - Significant data suggest that overt hyperglycemia, either observed with or without a prior diagnosis of diabetes, contributes to an increase in mortality and morbidity in hospitalized patients. In this regard, goal-directed insulin therapy has remained as the standard of care for achieving and maintaining glycemic control in hospitalized patients with critical and noncritical illness. As such, protocols to assist in management of hyperglycemia in the inpatient setting have become commonplace in hospital settings. Clearly, insulin is a known entity, has been in clinical use for almost a century, and is effective. However, there are limitations to its use. Based on the observed mechanisms of action and efficacy, there has been a great interest in using incretin-based therapy with glucagon-like peptide-1 (GLP-1) receptor agonists instead of, or complementary to, an insulin-based approach to improve glycemic control in hospitalized, severely ill diabetic patients. To provide an understanding of both sides of the argument, we provide a discussion of this topic as part of this two-part point counterpoint narrative. In the point narrative preceding the counterpoint narrative below, Drs. Schwartz and DeFronzo provide an opinion that now is the time to consider GLP-1 receptor agonists as a logical consideration for inpatient glycemic control. In the counterpoint narrative provided below, Drs. Umpierrez and Korytkowski provide a defense of insulin in the inpatient setting as the unquestioned gold standard for glycemic management in hospitalized settings. PMID- 23801803 TI - Relationship of sex to diabetes risk in statin trials. PMID- 23801804 TI - Comment on: Bardenheier et al. Variation in prevalence of gestational diabetes mellitus among hospital discharges for obstetric delivery across 23 states in the United States. Diabetes Care 2013;36:1209-1214. PMID- 23801805 TI - Response to Comment on: Bardenheier et al. Variation in prevalence of gestational diabetes mellitus among hospital discharges for obstetric delivery across 23 states in the United States. Diabetes Care 2013;36:1209-1214. PMID- 23801806 TI - Comment on: Aeberli et al. Moderate amounts of fructose consumption impair insulin sensitivity in healthy young men: a randomized controlled trial. Diabetes Care 2013;36:150-156. PMID- 23801807 TI - Response to Comment on: Aeberli et al. Moderate amounts of fructose consumption impair insulin sensitivity in healthy young men: a randomized controlled trial. Diabetes Care 2013;36:150-156. PMID- 23801808 TI - Comment on: Bergenstal et al. A randomized, controlled study of once-daily LY2605541, a novel long-acting basal insulin, versus insulin glargine in basal insulin-treated patients with type 2 diabetes. Diabetes Care 2012;35:2140-2147. PMID- 23801809 TI - Response to Comment on: Bergenstal et al. A randomized, controlled study of once daily LY2605541, a novel long-acting basal insulin, versus insulin glargine in basal insulin-treated patients with type 2 diabetes. Diabetes Care 2012;35:2140 2147. PMID- 23801810 TI - Comment on: Satoh-Asahara et al. Highly purified eicosapentaenoic acid increases interleukin-10 levels of peripheral blood monocytes in obese patients with dyslipidemia. Diabetes Care 2012;35:2631-2639. PMID- 23801811 TI - Response to Comment on: Satoh-Asahara et al. Highly purified eicosapentaenoic acid increases interleukin-10 levels of peripheral blood monocytes in obese patients with dyslipidemia. Diabetes Care 2012;35:2631-2639. PMID- 23801812 TI - Comment on: Saisho et al. beta-cell mass and turnover in humans: effects of obesity and aging. Diabetes Care 2013;36:111-117. PMID- 23801813 TI - Response to Comment on: Saisho et al. beta-cell mass and turnover in humans: effects of obesity and aging. Diabetes Care 2013;36:111-117. PMID- 23801814 TI - A case of type 1 diabetes with nocturnal hypoglycemia after desensitization therapy for insulin allergy. PMID- 23801815 TI - Infliximab in the treatment of Crohn disease and type 1 diabetes. PMID- 23801816 TI - Cilostazol attenuates spontaneous microaggregation of platelets in type 2 diabetic patients with insufficient platelet response to aspirin. PMID- 23801817 TI - Adults with diabetes hospitalized with pandemic influenza A(H1N1)pdm09--U.S. 2009. PMID- 23801818 TI - Decreasing trends of the prevalence of diabetes and obesity in Korean women aged 30-59 years over the past decade: results from the Korean National Health and Nutrition Examination Survey, 2001-2010. PMID- 23801819 TI - Liver transplantation: a potential cure for hepatogenous diabetes? PMID- 23801820 TI - Can trained dogs detect a hypoglycemic scent in patients with type 1 diabetes? PMID- 23801821 TI - A systematic approach to evaluate herb-drug interaction mechanisms: investigation of milk thistle extracts and eight isolated constituents as CYP3A inhibitors. AB - Despite increasing recognition of potential untoward interactions between herbal products and conventional medications, a standard system for prospective assessment of these interactions remains elusive. This information gap was addressed by evaluating the drug interaction liability of the model herbal product milk thistle (Silybum marianum) with the CYP3A probe substrate midazolam. The inhibitory effects of commercially available milk thistle extracts and isolated constituents on midazolam 1'-hydroxylation were screened using human liver and intestinal microsomes. Relative to vehicle, the extract silymarin and constituents silybin A, isosilybin A, isosilybin B, and silychristin at 100 MUM demonstrated >50% inhibition of CYP3A activity with at least one microsomal preparation, prompting IC50 determination. The IC50s for isosilybin B and silychristin were ~60 and 90 MUM, respectively, whereas those for the remaining constituents were >100 MUM. Extracts and constituents that contained the 1,4 dioxane moiety demonstrated a >1.5-fold shift in IC50 when tested as potential mechanism-based inhibitors. The semipurified extract, silibinin, and the two associated constituents (silybin A and silybin B) demonstrated mechanism-based inhibition of recombinant CYP3A4 (KI, ~100 MUM; kinact, ~0.20 min(-1)) but not microsomal CYP3A activity. The maximum predicted increases in midazolam area under the curve using the static mechanistic equation and recombinant CYP3A4 data were 1.75-fold, which may necessitate clinical assessment. Evaluation of the interaction liability of single herbal product constituents, in addition to commercially available extracts, will enable elucidation of mechanisms underlying potential clinically significant herb-drug interactions. Application of this framework to other herbal products would permit predictions of herb-drug interactions and assist in prioritizing clinical evaluation. PMID- 23801823 TI - International comparison of treatment and long-term outcomes for acute myocardial infarction in the elderly: Minneapolis/St. Paul, MN, USA and Goteborg, Sweden. AB - AIMS: International studies provide an opportunity to compare treatment approaches and outcomes. The present study compares elderly hospitalized acute myocardial infarction (AMI) patients in Minneapolis/St. Paul, USA (MSP) and Goteborg, Sweden (GB). METHODS AND RESULTS: A population-based sample of hospitalized AMI (ICD-9 410) patients aged >=75 in MSP and GB in 2001-02 was abstracted by trained nurses. Mortality was ascertained from medical records and death certificates. Demographics, cardiovascular procedures, and prescription medications were compared using sex-specific generalized linear models. Adjusted hazard ratios (HR) were calculated with Cox regression. In MSP 839 (387 men, 452 women) and in GB 564 (275 men, 289 women) patients were identified. Age was similar (men: MSP 83 +/- 7, GB 82 +/- 5; women: MSP 84 +/- 6, GB 84 +/- 6) yet MSP patients had more previous cardiovascular comorbidities and procedures (PCI/CABG). Guideline-based medication use was high in both locations. MSP patients were significantly more likely to undergo PCI (men: MSP 33%, GB 7%; women: MSP 30%, GB 7%). Survival at 7.5 years was 27.8% among MSP patients (men: 26.6%, women: 28.8%) and 17.2% among GB patients (men: 17.5%, women: 17.0%). After adjustment for baseline characteristics and guideline-based therapies, survival was higher among MSP men [HR: 0.66, 95% confidence interval (CI): 0.50 0.88] and women (HR: 0.49, 95% CI: 0.36-0.67) compared with GB. CONCLUSION: In MSP and GB, guideline-based therapy use was high. However, PCI use was markedly higher in MSP. Long-term survival was better among elderly men and women in MSP compared with GB possibly related to greater utilization of PCI. PMID- 23801822 TI - 2013 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy: the Task Force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). PMID- 23801824 TI - Coronary atherosclerosis with vulnerable plaque and complicated lesions in transplant recipients: new insight into cardiac allograft vasculopathy by optical coherence tomography. AB - AIMS: Cardiac allograft vasculopathy (CAV) is a major limitation to long-term survival following cardiac transplantation. Conventional imaging modalities such as angiography and intravascular ultrasound fail to characterize CAV plaque morphology. Our aim was to characterize CAV in vivo using the high spatial resolution of intracoronary optical coherence tomography (OCT). METHODS AND RESULTS: We prospectively enrolled 53 cardiac transplant patients to undergo OCT of the left anterior descending coronary artery (LAD) in addition to annual CAV screening by coronary angiography and intravascular ultrasound (IVUS). The proximal 30 mm of the LAD was divided into three segments of 10 mm each (n = 156). Segments with CAV plaque on IVUS were analysed by OCT for specific CAV morphological characteristics within the framework of three groups according to follow-up time after heart transplantation: (i) 0-3 months (n = 18), (ii) 12-36 months (n = 55), and (iii) >=48 months (n = 83). The prevalence of atherosclerotic characteristics such as eccentric plaques, calcification, and lipid pools increased from 6, 0, and 6% in group 1 to 78, 42, and 61% in group 3, respectively (all P < 0.001). The prevalence of vulnerable plaque features such as thin-cap fibroatheroma, macrophages, and microchannels increased from 0% in group 1 to 12, 29, and 33% in group 3, respectively (P = 0.19, P = 0.006, and P = 0.003). Complicated coronary lesions such as intimal laceration, intraluminal thrombus, and layered complex plaque increased from 0% in group 1 to 18, 19, and 57% in group 3 (P = 0.009, P < 0.001, and P < 0.001). Plaque rupture was identified in 4% of group 3 segments. CONCLUSION: The current study gives new insight into CAV that extends far beyond the current concept of concentric and fibrosing vasculopathy, that is, the development of atherosclerosis with vulnerable plaque and complicated coronary lesions. PMID- 23801825 TI - Trends in age-specific coronary heart disease mortality in the European Union over three decades: 1980-2009. AB - AIMS: Recent decades have seen very large declines in coronary heart disease (CHD) mortality across most of Europe, partly due to declines in risk factors such as smoking. Cardiovascular diseases (predominantly CHD and stroke), remain, however, the main cause of death in most European countries, and many risk factors for CHD, particularly obesity, have been increasing substantially over the same period. It is hypothesized that observed reductions in CHD mortality have occurred largely within older age groups, and that rates in younger groups may be plateauing or increasing as the gains from reduced smoking rates are increasingly cancelled out by increasing rates of obesity and diabetes. The aim of this study was to examine sex-specific trends in CHD mortality between 1980 and 2009 in the European Union (EU) and compare trends between adult age groups. METHODS: Sex-specific data from the WHO global mortality database were analysed using the joinpoint software to examine trends and significant changes in trends in age-standardized mortality rates. Specific age groups analysed were: under 45, 45-54, 55-64, and 65 years and over. The number and location of significant joinpoints for each country by sex and age group was determined (maximum of 3) using a log-linear model, and the annual percentage change within each segment calculated. Average annual percentage change overall (1980-2009) and separately for each decade were calculated with respect to the underlying joinpoint model. RESULTS: Recent CHD rates are now less than half what they were in the early 1980s in many countries, in younger adult age groups as well as in the population overall. Trends in mortality rates vary markedly between EU countries, but less so between age groups and sexes within countries. Fifteen countries showed evidence of a recent plateauing of trends in at least one age group for men, as did 12 countries for women. This did not, however, appear to be any more common in younger age groups compared with older adults. There was little evidence to support the hypothesis that mortality rates have recently begun to plateau in younger age groups in the EU as a whole, although such plateaus and even a small number of increases in CHD mortality in younger subpopulations were observed in a minority of countries. CONCLUSION: There is limited evidence to support the hypothesis that CHD mortality rates in younger age groups in the member states of the EU have been more likely to plateau than in older age groups. There are, however, substantial and persistent inequalities between countries. It remains vitally important for the whole EU to monitor and work towards reducing preventable risk factors for CHD and other chronic conditions to promote wellbeing and equity across the region. PMID- 23801826 TI - Transforming growth factor beta1 is not a reliable biomarker for valvular fibrosis but could be a potential serum marker for invasiveness of prolactinomas (pilot study). AB - BACKGROUND: Transforming growth factor beta1 (TGFbeta1) signaling pathway is crucial for both human fibrogenesis and tumorigenesis. OBJECTIVE: This study aimed to investigate the usefulness of TGFbeta1 and matrix metalloproteinase 2 (MMP2) as potential circulating markers for fibrotic valvular heart disease (FVHD) and invasiveness as well as of Fetuin A as a marker for calcification in patients with prolactinomas. DESIGN: The study population consisted of 147 subjects divided into four groups: 30 dopamine agonist (DA)-treated prolactinoma patients with proven FVHD and three control groups with normal echocardiograms: 43 DA-treated patients, 26 naive patients, and 48 healthy subjects. RESULTS: We observed significantly higher serum TGFbeta1 levels in all three patient groups than in the healthy subjects (21.4 +/- 8.86 vs 19.1 +/- 9.03 vs 20.7+/-11.5 vs 15.8 +/- 7.2 ng/ml; P=0.032). Moreover, TGFbeta1 levels were significantly higher in patients with macroprolactinomas and invasive prolactinomas than in those with microprolactinomas and noninvasive tumors respectively. In addition, a strong positive linear relationship between TGFbeta1 levels and invasiveness score (rho=0.924; P<0.001) and a moderate correlation between TGFbeta1 levels and tumor volume (r=0.546; P<0.002) were observed in patients with invasive prolactinomas. By contrast, prolactin (PRL) levels exhibited a better correlation with tumor volume (r=0.721; P<0.001) than with invasiveness score (rho=0.436; P<0.020). No significant difference was observed in Fetuin A levels between patients with FVHD and healthy controls. Results concerning MMP2 were unclear. CONCLUSIONS: TGFbeta1, MMP2, and Fetuin A are not reliable biomarkers for valvular fibrosis and calcification in DA-treated patients with prolactinomas, but TGFbeta1 may represent a useful serum marker for tumor invasiveness. The simultaneous determination of TGFbeta1 and PRL levels could improve the noninvasive assessment of prolactinoma behavior. PMID- 23801827 TI - 2013 ESC guidelines on cardiac pacing and cardiac resynchronization therapy: the task force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). PMID- 23801828 TI - Controversy over the use of intraoperative blood salvage autotransfusion during liver transplantation for hepatocellular carcinoma patients. AB - Intraoperative blood salvage autotransfusion (IBSA) is used in various surgical procedures. However, because of the risk of reinfusion of salvaged blood contaminated by tumor cells, the use of IBSA in hepatocellular carcinoma (HCC) patients undergoing liver transplantation (LT) is controversial. The critical points include whether tumor cells can be cleared by IBSA, whether IBSA increases the risk of recurrence or metastasis, and what are the indications for IBSA. Moreover, is it warranted to take the risk of tumor dissemination by using IBSA to avoid allogeneic blood transfusion? Do the remaining tumor cells after additional filtration by leukocyte depletion filters still possess potential tumorigenicity? Does IBSA always work well? We have reviewed the literature and tried to address these questions. The available data indicate that IBSA is safe in LT for HCC, but randomized, controlled and prospective trials are urgently required to clarify the uncertainty. PMID- 23801829 TI - What about non-alcoholic fatty liver disease as a new criterion to define metabolic syndrome? AB - Non-alcoholic fatty liver disease (NAFLD) is currently not a component of the diagnostic criteria for metabolic syndrome (MetS); however, the development of NAFLD has some common mechanisms with the development of MetS, as they share the pathophysiologic basis of insulin resistance. It is also recognized that NAFLD is the hepatic manifestation of MetS. To define MetS, the presence of at least three of the proposed criteria is required, and sometimes it is sufficient to have only one laboratory value, modified by diet or drugs, for the classification of MetS. Ultrasonographically-detected NAFLD (US-NAFLD) is more stable, only changing during the middle- to long-term. Although controversies over MetS continue, and considering that abdominal ultrasonography for diagnosing NAFLD has high specificity and guidelines to modify the natural course of NAFLD by diet composition or lifestyle have not yet been established, why should we not introduce US-NAFLD as a new criterion to define MetS? PMID- 23801830 TI - Thinking outside the liver: induced pluripotent stem cells for hepatic applications. AB - The discovery of induced pluripotent stem cells (iPSCs) unraveled a mystery in stem cell research, after identification of four re-programming factors for generating pluripotent stem cells without the need of embryos. This breakthrough in generating iPSCs from somatic cells has overcome the ethical issues and immune rejection involved in the use of human embryonic stem cells. Hence, iPSCs form a great potential source for developing disease models, drug toxicity screening and cell-based therapies. These cells have the potential to differentiate into desired cell types, including hepatocytes, under in vitro as well as under in vivo conditions given the proper microenvironment. iPSC-derived hepatocytes could be useful as an unlimited source, which can be utilized in disease modeling, drug toxicity testing and producing autologous cell therapies that would avoid immune rejection and enable correction of gene defects prior to cell transplantation. In this review, we discuss the induction methods, role of reprogramming factors, and characterization of iPSCs, along with hepatocyte differentiation from iPSCs and potential applications. Further, we discuss the location and detection of liver stem cells and their role in liver regeneration. Although tumor formation and genetic mutations are a cause of concern, iPSCs still form a promising source for clinical applications. PMID- 23801831 TI - Endoscopic ultrasound-guided ethanol ablation therapy for tumors. AB - Endoscopic ultrasonography (EUS) has evolved into a useful therapeutic tool for treating a broad range of tumors since being introduced into clinical practice as a diagnostic modality nearly three decades ago. In particular, EUS-guided fine needle injection has proven a successful minimally invasive approach for treating benign lesions such as pancreatic cysts, relieving pancreatic pain through celiac plexus neurolysis, and controlling local tumor growth of unresectable malignancies by direct delivery of anti-tumor agents. One such ablative agent, ethanol, is capable of safely ablating solid or cystic lesions in hepatic tissues via percutaneous injection. Recent research and clinical interest has focused on the promise of EUS-guided ethanol ablation as a safe and effective method for treating pancreatic tumor patients with small lesions or who are poor operative candidates. Although it is not likely to replace radical resection of localized lesions or systemic treatment of metastatic tumors in all patients, EUS-guided ablation is an ideal method for patients who refuse or are not eligible for surgery. Moreover, this treatment modality may play an active role in the development of future pancreatic tumor treatments. This article reviews the most recent clinical applications of EUS-guided ethanol ablation in humans for treating pancreatic cystic tumors, pancreatic neuroendocrine tumors, and metastatic lesions. PMID- 23801832 TI - Fluctuations in butyrate-producing bacteria in ulcerative colitis patients of North India. AB - AIM: To study the interplay between butyrate concentration and butyrate-producing bacteria in fecal samples of ulcerative colitis (UC) patients vs control individuals. METHODS: Fecal samples were collected from 14 control individuals (hemorrhoid patients only) and 26 UC patients (severe: n = 12, moderate: n = 6, remission: n = 8), recruited by the gastroenterologist at the Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India. Disease activity in UC patients was determined by clinical colitis activity index. We employed fluorescent in situ hybridization in combination with flow cytometry to enumerate the clostridium cluster population targeted by 16S rRNA gene probe. Major butyrate-producing species within this cluster were quantified to see if any change existed in control vs UC patients with different disease activity. This observed change was further validated by quantitative polymerase chain reaction. In addition to this, we carried out gas chromatography to evaluate the changes in concentration of major short chain fatty acids (SCFAs), namely acetate, n-butyrate, iso-butyrate, in the above samples. Student t test and Graph pad prism-6 were used to compare the data statistically. RESULTS: There was a significant decrease of Clostridium coccoides (control, 25.69% +/- 1.62% vs severe, 9.8% +/- 2.4%, P = 0.0001) and Clostridium leptum clusters (control, 13.74% +/- 1.05% vs severe, 6.2% +/- 1.8%, P = 0.0001) in fecal samples of UC patients. Furthermore, we demonstrated that some butyrate-producing members of the clostridial cluster, like Fecalibacterium prausnitzii (control, 11.66% +/- 1.55% vs severe, 6.01% +/- 1.6%, P = 0.0001) and Roseburia intestinalis (control, 14.48% +/- 1.52% vs severe, 9% +/- 1.83%, P = 0.02) were differentially present in patients with different disease activity. In addition, we also demonstrated decreased concentrations of fecal SCFAs, especially of n-butyrate (control, 24.32 +/- 1.86 mmol/MUL vs severe, 12.74 +/- 2.75 mmol/MUL, P = 0.003), iso-butyrate (control, 1.70 +/- 0.41 mmol/MUL vs severe, 0.68 +/- 0.24 mmol/MUL, P = 0.0441) and acetate (control, 39.51 +/- 1.76 mmol/MUL vs severe, 32.12 +/- 2.95 mmol/MUL, P = 0.047), in the fecal samples of UC patients. The observed decrease of predominant butyrate producers of clostridial clusters correlated with the reduced SCFA levels in active UC patients. This was further confirmed by the restoration in the population of some butyrate producers with simultaneous increase in the level of SCFA in remission samples. CONCLUSION: Our observations indicate that decreases in members of the clostridial cluster resulting in reduced butyrate levels contribute to the etiology of UC. PMID- 23801833 TI - Disruption of interstitial cells of Cajal networks after massive small bowel resection. AB - AIM: To investigate the disruptions of interstitial cells of Cajal (ICC) in the remaining bowel in rats after massive small bowel resection (mSBR). METHODS: Thirty male Sprague-Dawley rats fitting entry criteria were divided randomly into three experimental groups (n = 10 each): Group A rats underwent bowel transection and re-anastomosis (sham) and tissue samples were harvested at day 7 post surgery. Group B and C rats underwent 80% small bowel resection with tissue harvested from Group B rats at day 7 post-surgery, and from Group C rats at day 14 post-surgery. The distribution of ICC at the site of the residual small bowel was evaluated by immunohistochemical analysis of small intestine samples. The ultrastructural changes of ICC in the remnant ileum of model rats 7 and 14 d after mSBR were analyzed by transmission electron microscopy. Intracellular recordings of slow wave oscillations were used to evaluate electrical pacemaking. The protein expression of c-kit, ICC phenotypic markers, and membrane-bound stem cell factor (mSCF) in intestinal smooth muscle of each group were detected by Western blotting. RESULTS: After mSBR, immunohistochemical analysis indicated that the number of c-kit-positive cells was dramatically decreased in Group B rats compared with sham tissues. Significant ultrastructural changes in ICC with associated smooth muscle hypertrophy were also observed. Disordered spontaneous rhythmic contractions with reduced amplitude (8.5 +/- 1.4 mV vs 24.8 +/- 1.3 mV, P = 0.037) and increased slow wave frequency (39.5 +/- 2.1 cycles/min vs 33.0 +/- 1.3 cycles/min, P = 0.044) were found in the residual intestinal smooth muscle 7 d post mSBR. The contractile function and electrical activity of intestinal circular smooth muscle returned to normal levels at 14 d post mSBR (amplitude, 14.9 +/- 1.6 mV vs 24.8 +/- 1.3 mV; frequency, 30.7 +/- 1.7 cycles/min vs 33.0 +/ 1.3 cycles/min). The expression of Mscf and c-kit protein was decreased at 7 d (P = 0.026), but gradually returned to normal levels at 14 d. The ICC and associated neural networks were disrupted, which was associated with the phenotype alterations of ICC. CONCLUSION: Massive small bowel resection in rats triggered damage to ICC networks and decreased the number of ICC leading to disordered intestinal rhythmicity. The mSCF/c-kit signaling pathway plays a role in the regulation and maintenance of ICC phenotypes. PMID- 23801834 TI - Human liver tissue metabolic profiling research on hepatitis B virus-related hepatocellular carcinoma. AB - AIM: To select characteristic endogenous metabolites in hepatitis B virus (HBV) related hepatocellular carcinoma (HCC) patients and to identify their molecular mechanism and potential clinical value. METHODS: An ultra performance liquid chromatography and linear trap quadrupole-Orbitrap XL-mass spectrometry platform was used to analyze endogenous metabolites in the homogenate of central tumor tissue, adjacent tissue and distant tissue obtained from 10 HBV-related HCC patients. After pretreatment with Mzmine software, including peak detection, alignment and normalization, the acquired data were treated with Simca-P+software to establish multivariate statistical analysis based on a pattern recognition technique and characteristic metabolites highly correlated with changing trends in metabolic profiling were selected and further identified. RESULTS: Based on data acquired using Mzmine software, a principal component analysis model (R2X = 66.9%, Q2 = 21.7%) with 6 principal components and an orthogonal partial least squares discriminant analysis model (R2X = 76.5%, R2Y = 93.7%, Q2 = 68.7%) with 2 predicted principal components and 5 orthogonal principal components were established in the three tissue groups. Forty-nine ions were selected, 33 ions passed the 2 related samples nonparametric test (P < 0.05) and 14 of these were further identified as characteristic metabolites that showed significant differences in levels between the central tumor tissue group and distant tumor tissue group, including 9 metabolites (L-phenylalanine, glycerophosphocholine, lysophosphatidylcholines, lysophosphatidylethanolamines and chenodeoxycholic acid glycine conjugate) which had been reported as serum metabolite biomarkers for HCC diagnosis in previous research, and 5 metabolites (beta-sitosterol, quinaldic acid, arachidyl carnitine, tetradecanal, and oleamide) which had not been reported before. CONCLUSION: Characteristic metabolites and metabolic pathways highly related to HCC pathogenesis and progression are identified through metabolic profiling analysis of HCC tissue homogenates. PMID- 23801835 TI - Polysomnographic sleep aspects in liver cirrhosis: a case control study. AB - AIM: To study sleep aspects and parameters in cirrhotic patients and assess the role of liver dysfunction severity in polysomnographic results. METHODS: This was a case-control study. Patients with a diagnosis of liver cirrhosis were consecutively enrolled in the study. Clinical examinations and laboratory liver tests were performed in all patients, and disease severity was assessed using the Child-Pugh score. The control group consisted of age- and gender-matched healthy volunteers. All individuals answered a questionnaire about habits, behaviors, and complaints related to sleep and were submitted to polysomnography. Sleep parameters were compared between the two groups, and separate analyses were performed among classes of Child-Pugh classification in the cirrhotic group. RESULTS: Forty-two cirrhotic patients and forty-two controls were enrolled. Compared to the control group, the cirrhotic group exhibited lower sleep efficiency (mean +/- SD: 73.89% +/- 14.99% vs 84.43% +/- 8.55%, P < 0.01), increased latency (151.27 +/- 93.24 min vs 90.62 +/- 54.74 min, P < 0.01) and a lower percentage of rapid eye movement (REM) sleep (14.04% +/- 5.64% vs 20.71% +/ 6.77%, P < 0.05) as well as a higher frequency of periodic limb movements (10.56 +/- 2.85/h vs 2.79 +/- 0.61/h, P < 0.01). The comparison of sleep parameters among Child A, B and C cirrhotic patients revealed a significant reduction of REM sleep stage occurrence in individuals with severe liver disease (Child C patients) compared to Child A/B patients (polysomnography percentage of REM sleep stage of patients Child A: 16.1% +/- 1.2%; Child B: 14.9% +/- 1.2%; Child C: 8.6% +/- 1.6%, P < 0.05). CONCLUSION: Cirrhosis was associated with shorter sleep time, reduced sleep efficiency, increased sleep latency, increased REM latency and reduced REM sleep. Additionally, disease severity influences sleep parameters. PMID- 23801836 TI - Deep sedation during gastrointestinal endoscopy: propofol-fentanyl and midazolam fentanyl regimens. AB - AIM: To compare deep sedation with propofol-fentanyl and midazolam-fentanyl regimens during upper gastrointestinal endoscopy. METHODS: After obtaining approval of the research ethics committee and informed consent, 200 patients were evaluated and referred for upper gastrointestinal endoscopy. Patients were randomized to receive propofol-fentanyl or midazolam-fentanyl (n = 100/group). We assessed the level of sedation using the observer's assessment of alertness/sedation (OAA/S) score and bispectral index (BIS). We evaluated patient and physician satisfaction, as well as the recovery time and complication rates. The statistical analysis was performed using SPSS statistical software and included the Mann-Whitney test, chi2 test, measurement of analysis of variance, and the kappa statistic. RESULTS: The times to induction of sedation, recovery, and discharge were shorter in the propofol-fentanyl group than the midazolam fentanyl group. According to the OAA/S score, deep sedation events occurred in 25% of the propofol-fentanyl group and 11% of the midazolam-fentanyl group (P = 0.014). Additionally, deep sedation events occurred in 19% of the propofol fentanyl group and 7% of the midazolam-fentanyl group according to the BIS scale (P = 0.039). There was good concordance between the OAA/S score and BIS for both groups (kappa = 0.71 and kappa = 0.63, respectively). Oxygen supplementation was required in 42% of the propofol-fentanyl group and 26% of the midazolam-fentanyl group (P = 0.025). The mean time to recovery was 28.82 and 44.13 min in the propofol-fentanyl and midazolam-fentanyl groups, respectively (P < 0.001). There were no severe complications in either group. Although patients were equally satisfied with both drug combinations, physicians were more satisfied with the propofol-fentanyl combination. CONCLUSION: Deep sedation occurred with propofol fentanyl and midazolam-fentanyl, but was more frequent in the former. Recovery was faster in the propofol-fentanyl group. PMID- 23801837 TI - Endoscopic gastrojejunostomy with a natural orifice transluminal endoscopic surgery technique. AB - AIM: To determine the technical feasibility and safety of an endoscopic gastrojejunostomy with a pure natural orifice transluminal endoscopic surgery (NOTES) technique using a T-anchoring device in a porcine survival model. METHODS: An endoscopic gastrojejunostomy with a pure NOTES technique using a T anchoring device was performed on 10 healthy female minipigs weighing approximately 40 kg each under general anesthesia. All procedures were performed with a transgastric approach using a 2-channel therapeutic endoscope. RESULTS: The transgastric gastrojejunostomy was technically successful in all cases. A total of four to six stitched pairs of a T-anchoring device were used to secure the anastomosis. The median time required to enter the peritoneal cavity and pull the small bowel into the stomach was 34 min (range: 19-41 min); the median time required to suture the anastomosis was 67 min (range: 44-78 min). An obstruction of the efferent limb occurred in one case, and a rupture of the anastomosis site occurred in another case. As a result, the functional success rate was 80% (8/10). Small bowel adhesion to the stomach and liver occurred in one case, but the anastomosis was intact without leakage or obstruction. CONCLUSION: A transgastric gastrojejunostomy with a T-anchoring device may be safe and technically feasible. A T-anchoring device may provide a simple and effective endoscopic suturing method. PMID- 23801838 TI - Incidental focal colorectal 18F-fluorodeoxyglucose uptake on positron emission tomography/computed tomography. AB - AIM: To assess the clinical significance of incidental focal colorectal 18F fluorodeoxyglucose (18F-FDG) uptake on 18F-FDG-positron emission tomography/computed tomography (PET/CT). METHODS: The records of all the cases which had undergone colonoscopy after PET/CT within a two weeks interval were reviewed. Adenomas were considered advanced when they were villous, >= 10 mm in size, or had high-grade dysplasia. Colorectal cancers and advanced adenomas are collectively referred to as advanced colorectal neoplasms. Receiver-operating characteristic curve analysis was used to determine the significant predictive maximum standardized uptake value (SUVmax) cutoff value for advanced colorectal neoplasms and cancer. RESULTS: Ninety-five colorectal lesions matched the site of incidental focal colorectal 18F-FDG uptake on PET/CT and 146 did not. Colonoscopy showed advanced colorectal neoplasms corresponding to the site of 18F-FDG uptake in 49 of the 95 (51.5%) lesions with incidental uptake. Of the lesions without incidental uptake, only 6 of 146 (4.1%) had advanced colorectal neoplasms on colonoscopy, indicating a statistically significant difference between the two groups (P < 0.001). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of incidental focal 18F-FDG uptake in identifying advanced colorectal neoplasms were 89.1%, 75.3%, 51.6%, 95.9%, and 78.4%, respectively. In detecting only CRC, these values were 89.2%, 69.6%, 34.7%, 97.3%, and 72.6%, respectively. The significant SUVmax cutoff value for advanced colorectal neoplasms (area under the curve 0.755, P < 0.001) was 4.35, with a sensitivity, specificity, PPV, NPV, and accuracy of 75.5%, 65.2%, 69.8%, 71.4% and 70.5%, respectively. For CRC, 5.05 was the significant SUVmax cutoff value (area under the curve 0.817, P < 0.001), with a sensitivity, specificity, PPV, NPV, and accuracy of 84.8%, 71.0%, 80.9%, 89.8%, and 75.8%, respectively. CONCLUSION: The presence of incidental focal colorectal 18F-FDG uptake on PET/CT with a SUVmax >= 4.35 increases the likelihood of an advanced colorectal neoplasm. PMID- 23801839 TI - Perceptions about preventing hepatocellular carcinoma among patients with chronic hepatitis in Taiwan. AB - AIM: To measure patient perceptions about preventing hepatocellular carcinoma (HCC) and to predict the factors that influence patient willingness to receive therapy. METHODS: A cross-sectional descriptive study was conducted at an outpatient clinic of a medical institution in southern Taiwan. Four hundred patients with chronic hepatitis B/C were recruited as participants. Two structured questionnaires based on the health belief model were utilized in this study, including the scales of perceptions about preventing HCC and knowledge of hepatitis B/C. RESULTS: The statistical results demonstrated that the participants' perceived susceptibility (r = -0.22, P < 0.001), benefits (r = 0.11, P = 0.028) and cues to action (r = -0.12, P = 0.014) about the prevention of HCC was significantly correlated with their age. The participants' perceptions were also associated with their educational levels, household incomes and knowledge of hepatitis. Older patients and those with a lower socioeconomic status tended to have negative perceptions and less knowledge of hepatitis. Multivariate logistic regression further indicated that the participants' age (B = -0.044, SE = 0.017, odds ratio = 0.957, P = 0.008, 95%CI: 0.926-0.989) and perceived barriers (B = -0.111, SE = 0.030, odds ratio = 0.895, P < 0.001, 95%CI: 0.845-0.949) were correlated with their willingness to receive antiviral therapy. CONCLUSION: Healthcare professionals should provide appropriate and effective guidance to increase their patients' awareness and to decrease the perceived barriers for continuing surveillance and antiviral therapy. PMID- 23801840 TI - Rockall score in predicting outcomes of elderly patients with acute upper gastrointestinal bleeding. AB - AIM: To validate the clinical Rockall score in predicting outcomes (rebleeding, surgery and mortality) in elderly patients with acute upper gastrointestinal bleeding (AUGIB). METHODS: A retrospective analysis was undertaken in 341 patients admitted to the emergency room and Intensive Care Unit of Xuanwu Hospital of Capital Medical University with non-variceal upper gastrointestinal bleeding. The Rockall scores were calculated, and the association between clinical Rockall scores and patient outcomes (rebleeding, surgery and mortality) was assessed. Based on the Rockall scores, patients were divided into three risk categories: low risk <= 3, moderate risk 3-4, high risk >= 4, and the percentages of rebleeding/death/surgery in each risk category were compared. The area under the receiver operating characteristic (ROC) curve was calculated to assess the validity of the Rockall system in predicting rebleeding, surgery and mortality of patients with AUGIB. RESULTS: A positive linear correlation between clinical Rockall scores and patient outcomes in terms of rebleeding, surgery and mortality was observed (r = 0.962, 0.955 and 0.946, respectively, P = 0.001). High clinical Rockall scores > 3 were associated with adverse outcomes (rebleeding, surgery and death). There was a significant correlation between high Rockall scores and the occurrence of rebleeding, surgery and mortality in the entire patient population (chi2 = 49.29, 23.10 and 27.64, respectively, P = 0.001). For rebleeding, the area under the ROC curve was 0.788 (95%CI: 0.726-0.849, P = 0.001); For surgery, the area under the ROC curve was 0.752 (95%CI: 0.679-0.825, P = 0.001) and for mortality, the area under the ROC curve was 0.787 (95%CI: 0.716-0.859, P = 0.001). CONCLUSION: The Rockall score is clinically useful, rapid and accurate in predicting rebleeding, surgery and mortality outcomes in elderly patients with AUGIB. PMID- 23801841 TI - Combination treatment with comprehensive cryoablation and immunotherapy in metastatic hepatocellular cancer. AB - AIM: To retrospectively assess the effect of comprehensive cryosurgery (ablation of intra- and extra-hepatic tumors) plus dendritic cell-cytokine-induced killer cell immunotherapy in metastatic hepatocellular cancer. METHODS: We divided 45 patients into cryo-immunotherapy (21 patients), cryotherapy (n = 12), immunotherapy (n = 5) and untreated (n = 7) groups. Overall survival (OS) after diagnosis of metastatic hepatocellular cancer was assessed after an 8-year follow up. RESULTS: Median OS was higher following cryo-immunotherapy (32 mo) or cryotherapy (17.5 mo; P < 0.05) than in the untreated group (3 mo) and was higher in the cryo-immunotherapy group than in the cryotherapy group (P < 0.05). In the cryo-immunotherapy group, median OS was higher after multiple treatments (36.5 mo) than after a single treatment (21 mo; P < 0.05). CONCLUSION: Cryotherapy and, especially, cryo-immunotherapy significantly increased OS in metastatic hepatocellular cancer patients. Multiple cryo-immunotherapy was associated with a better prognosis than single cryo-immunotherapy. PMID- 23801842 TI - Efficacy of combined therapy in patients with hepatitis B virus-related decompensated cirrhosis. AB - AIM: To investigate the efficacy and safety of combined de novo lamivudine (LAM) and adefovir dipivoxil (ADV) therapy in hepatitis B virus (HBV)-related decompensated liver cirrhosis patients. METHODS: One hundred and forty patients with HBV-related decompensated cirrhosis were recruited, 70 patients were treated with combined LAM and ADV de novo therapy, and the other 70 patients were treated with LAM alone as controls. The follow-up period was 144 wk. All patients with LAM resistance were shifted to ADV. RESULTS: The percentage of HBV-related decompensated cirrhosis patients with undetectable HBV DNA in de novo combination group was 51.6% (33/64), 84.2% (48/57), and 92.3% (49/53) by weeks 48, 96, and 144, respectively. In monotherapy group, HBV DNA negativity rate was 46.1% (30/65), 56.1% (32/57), and 39.2% (20/51) by weeks 48, 96 and 144, respectively. There was a significant difference between the two groups by weeks 96 and 144 (P = 0.012 and 0.001). The hepatitis B e antigen seroconversion rate was 28.1% (9/32), 40.0% (12/30), and 53.6% (15/28) in the combination group by weeks 48, 96 and 144, respectively, and 24.2% (8/33), 31.0% (9/29), and 37.0% (10/27) by weeks 48, 96 and 144, respectively, in monotherapy group. A total of 68.6% (44/64), 84.2% (48/57), and 92.5% (49/53) patients achieved alanine aminotransferase (ALT) normalization by weeks 48, 96 and 144, respectively in the combination group. In monotherpy group, the ALT normalization rate was 64.6% (42/65) by week 48, 73.7% (42/57) by week 96, and 80.4% (41/51) by week 144. No patients in the combination group exhibited detectable resistance for at least 144 wk. The cumulative resistance rate in monotherapy group at weeks 48, 96, and 144 was 20.0%, 36.8%, and 56.9%. Both combination group and monotherapy group demonstrated an improvement in Child-Turcotte Pugh and Model for End-Stage Liver Disease scores at weeks 48, 96, and 144. All patients tolerated both combination and monotherapy. The ceratinine levels and glomerular filtration rate remained normal in all patients during the follow-up period. CONCLUSION: In HBV-related decompensated liver cirrhosis patients, the combined de novo LAM and ADV therapy is more efficacious and safer compared to LAM alone. PMID- 23801844 TI - Psychometrics of chronic liver disease questionnaire in Chinese chronic hepatitis B patients. AB - AIM: To evaluate psychometrics of the Chinese (mainland) chronic liver disease questionnaire (CLDQ) in patients with chronic hepatitis B (CHB). METHODS: A cross sectional sample of 460 Chinese patients with CHB was selected from the Outpatient Department of the Eighth Hospital of Xi'an, including CHB (CHB without cirrhosis) (n = 323) and CHB-related cirrhosis (n = 137). The psychometrics includes reliability, validity and sensitivity. Internal consistency reliability was measured using Cronbach's alpha. Convergent and discriminant validity was evaluated by item-scale correlation. Factorial validity was explored by principal component analysis with varimax rotation. Sensitivity was assessed using Cohen's effect size (ES), and independent sample t test between CHB and CHB-related cirrhosis groups and between alanine aminotransferase (ALT) normal and abnormal groups after stratifying the disease (CHB and CHB-related cirrhosis). RESULTS: Internal consistency reliability of the CLDQ was 0.83 (range: 0.65-0.90). Most of the hypothesized item-scale correlations were 0.40 or over, and all of such hypothesized correlations were higher than the alternative ones, indicating satisfactory convergent and discriminant validity. Six factors were extracted after varimax rotation from the 29 items of CLDQ. The eligible Cohen's ES with statistically significant independent sample t test was found in the overall CLDQ and abdominal, systematic, activity scales (CHB vs CHB-related cirrhosis), and in the overall CLDQ and abdominal scale in the stratification of patients with CHB (ALT normal vs abnormal). CONCLUSION: The CLDQ has acceptable reliability, validity and sensitivity in Chinese (mainland) patients with CHB. PMID- 23801843 TI - Role of nesfatin-1 in a rat model of visceral hypersensitivity. AB - AIM: To explore the role of nesfatin-1 on irritable bowel syndrome (IBS)-like visceral hypersensitivity. METHODS: The animal model of IBS-like visceral hypersensitivity was induced by intracolonic infusion of 0.5% acetic acid (AA) in saline once daily from postnatal days 8-21. Experiments were performed when rats became adults. The visceral sensitivity of rats was evaluated by abdominal withdrawal reflex (AWR) and electromyographic (EMG) activity of the external oblique muscle to graded colorectal distension. The content of nesfatin-1 in serum was determined using enzyme-linked immunosorbent assay. After implantation of an intracerebroventricular (ICV) cannula and two electrodes into the external oblique muscle, model rats were randomly divided into four groups. Animals then received ICV injection of 8 MUg of anti-nesfatin-1/nucleobindin-2 (NUCB2), 50 MUg of alpha-helical corticotropin releasing factor (CRF) 9-41 (non-selective CRF receptor antagonist), 50 MUg of NBI-27914 (selective CRF1 receptor antagonist) or 5 MUL of vehicle. After 1 h of ICV administration, visceral sensitivity of each group was measured again, and comparisons between groups were made. RESULTS: Rats treated with AA showed higher mean AWR scores and EMG activity at all distension pressures compared with controls (P < 0.05). On histopathologic examination, no evidence of inflammation or abnormalities in structure were noted in the colon of either control or AA-treated groups. Myeloperoxidase values were not significantly different between the two groups. The level of nesfatin-1 in serum was significantly higher in the AA-treated group than in the control group (5.34 +/- 0.37 ng/mL vs 4.81 +/- 0.42 ng/mL, P < 0.01). Compared with rats injected with vehicle, rats which received ICV anti-nesfatin-1/NUCB2, alpha-helical CRF9 41 or NBI-27914 showed decreased mean AWR scores and EMG activity at all distension pressures (P < 0.05). CONCLUSION: Nesfatin-1 may be associated with IBS-like visceral hypersensitivity, which may be implicated in brain CRF/CRF1 signaling pathways. PMID- 23801845 TI - Nodular regenerative hyperplasia related portal hypertension in a patient with hypogammaglobulinaemia. AB - Nodular regenerative hyperplasia (NRH) of liver is a relatively rare liver disorder, but a frequent cause of noncirrhotic portal hypertension. We present a lady with common variable immune deficiency who presented with upper gastrointestinal bleeding and deranged liver function tests but preserved synthetic function. Upper gastrointestinal endoscope showed bleeding gastric varices and non-bleeding oesophageal varices. Although her oesophageal varices were eradicated by repeated endoscopic band ligation, the gastric varices failed to resolve after repeated endoscopic histocryl injection and she eventually needed transjugular intrahepatic portosystemic shunt placement. Liver biopsy showed NRH. We review the association of hypogammaglobinaemia and NRH and discuss the appropriate management of portal hypertension in NRH. PMID- 23801846 TI - Mini-loop ligation of a bleeding duodenal Dieulafoy's lesion. AB - Two percent of gastrointestinal hemorrhages are caused by Dieulafoy's lesions, which are located in duodenum in only 15% of cases. There are no recommendations regarding the prime endoscopic treatment technique for this condition. A 61-year old woman presented with melena without signs of hemodynamic instability. During an urgent upper endoscopy, blood oozing from the normal mucosa of the duodenum was seen and this was classified as a Dieulafoy's lesion. A mini-loop was opened at the rim of a transparent ligation chamber, at the end of the endoscope, and after aspiration of the lesion, closed and detached. Complete hemostasis was achieved without early or postponed complications. In every day clinical practice, mini-loop ligation is rarely used because of possible complications, such as site ulceration, organ perforation, re-bleeding and possible inexperience of the operator. To the best of our knowledge this is the first case of successful treatment of bleeding duodenal Dieulafoy's lesion by mini-loop ligation. PMID- 23801847 TI - Colonic mucormycosis presented with ischemic colitis in a liver transplant recipient. AB - Mucormycosis is an uncommon opportunistic fungal infection with high mortality in liver transplant recipients. Mucormycosis of the gastrointestinal tract can manifest with features similar to ischemic colitis. Typically signs and symptoms of non-gangrenous ischemic colitis resolve spontaneously within 24-48 h. On the other hand, the clinical course of the mucormycosis is commonly fulminant. We encountered a case of invasive fungal colitis presenting with abdominal pain and hematochezia in a liver transplant recipient. Endoscopic examination showed multiple shallow ulcerations and edema with mucosal friabilities on the sigmoid and distal descending colon, which was consistent with ischemic colitis. However, the histological examination obtained from endoscopic biopsies showed fungal hyphae with surrounding inflammatory cells and mucosal necrosis. The patient was successfully managed with antifungal agent without surgical treatment. Thus, early diagnosis and treatment is essential for improving the prognosis of invasive fungal infection after liver transplantation. PMID- 23801848 TI - Transarterial embolization of metastatic mediastinal hepatocellular carcinoma. AB - This paper introduces an innovative treatment for extra-hepatic metastasis of hepatocellular carcinoma. A 71-year-old patient had a stable liver condition following treatment for hepatocellular carcinoma, but later developed symptomatic mediastinal metastasis. This rapidly growing mediastinal mass induced symptoms including cough and hoarseness. Serial sessions of transarterial embolization (TAE) successfully controlled this mediastinal mass with limited side effects. The patient's survival time since the initial diagnosis of the mediastinal hepatocellular carcinoma was 32 mo, significantly longer than the 12 mo mean survival period of patients with similar diagnoses: metastatic hepatocellular carcinoma and a liver condition with a Child-Pugh class A score. Currently, oral sorafenib is the treatment of choice for metastatic hepatocellular carcinoma. Recent studies indicate that locoregional treatment of extra-hepatic metastasis of hepatocellular carcinomas might also significantly improve the prognosis in patients with their primary hepatic lesions under control. Many effective locoregional therapies for extrahepatic metastasis, including radiation and surgical resection, may provide palliative effects for hepatocellular carcinoma associated mediastinal metastasis. This case report demonstrates that TAE of metastatic mediastinal hepatocellular carcinoma provided this patient with tumor control and increased survival time. This finding is important as it can potentially provide an alternative treatment option for patients with similar symptoms and diagnoses. PMID- 23801849 TI - A long adult intussusception secondary to transverse colon cancer. AB - The occurrence of adult intussusception arising from colorectal cancer is quite rare. We present the case of a 76-year-old man with sudden abdominal pain and vomiting. Clinical symptoms included severe abdominal distension and tenderness. Computed tomography scan of the abdomen revealed left-sided colocolic intussusception with a lead point. The patient underwent a left hemicolectomy with right transverse colostomy. Pathologic evaluation revealed moderately differentiated adenocarcinoma invading the muscularis propria; the regional lymph nodes were negative for cancer cells. The postoperative course was uneventful. PMID- 23801850 TI - Hemolymphangioma: a rare differential diagnosis of cystic-solid or cystic tumors of the pancreas. AB - We report a case of pancreatic hemolymphangioma. Hemolymphangioma is a malformation of both lymphatic vessels and blood vessels. The incidence of this disease in the pancreas is extremely rare. To the best of our knowledge, only seven cases have been reported worldwide (PubMed). A 39-year-old woman with a one day history of abdominal pain was admitted to our hospital. There was no obvious precipitating factor. The preoperative examination, including ultrasonography and computed tomography, showed a cystic-solid tumor in the pancreas, and it was considered to be a mucinous cystadenoma or cystadenocarcinoma. Pancreatic body tail resection combined with splenectomy was performed. After the operation, the tumor was pathologically demonstrated to be a pancreatic hemolymphangioma. Although pancreatic hemolymphangioma is rare, we believe that it should be considered in the differential diagnosis of cystic-solid tumors of the pancreas, particularly when there is no sufficient evidence for diagnosing cystadenoma, cystadenocarcinoma or some other relatively common disease of the pancreas. PMID- 23801851 TI - Hepatoid adenocarcinoma of the extrahepatic duct. AB - Hepatoid carcinoma is a unique type of extrahepatic tumor associated with hepatic differentiation and displays the morphological and functional features of hepatocellular carcinoma. Hepatoid carcinoma of the extrahepatic duct has rarely been reported in the literature. We report a 62-year-old man who presented with epigastric discomfort, xanthochromia, dull pain of the right shoulder, nausea and pruitus. Microscopic examination of the extrahepatic duct indicated that the tumor was primarily composed of "hepatoid cells", which were characterized by an eosinophilic cytoplasm, enlarged nucleus and prominent nucleoli. The cells were arranged in nests or proliferated in a trabecular pattern. Immunohistochemistry indicated that the tumor cells were positive for hepatocyte paraffin 1 and cytokeratins 8 and 18. Based on these findings, this case was diagnosed as hepatoid carcinoma of the extrahepatic duct. PMID- 23801852 TI - Reducing risk of transjugular intrahepatic portosystemic shunt using ultrasound guided single needle pass. AB - Delayed liver laceration following transjugular intrahepatic portosystemic shunt (TIPS) is a serious and likely underdiagnosed complication. It is however an important complication following TIPS, which remains one of the most technically challenging interventional procedures performed. In addition to laceration, a number of complications regarding bleeding and perforation are well described following TIPS procedures. We feel the adoption of techniques such as ours and that of other authors described in the literature using an ultrasound-guided percutaneous transhepatic approach with a small caliber needle provides a safer and less traumatic procedure and should reduce complications of bleeding and almost completely eliminate the risk of liver laceration. Our procedure was successfully performed under conscious sedation rather than general anaesthesia further reducing the overall procedural risk to the patient. PMID- 23801853 TI - Microscopic colitis: a therapeutic challenge. AB - The treatment of microscopic colitis is mainly based on the use of budesonide, the only drug found effective in controlled clinical trials. After an initial course at a dose of 9 mg daily, however, most patients relapse when the drug is discontinued, hence a maintenance therapy at doses of 6 mg daily or lower is necessary. In order to avoid steroid dependence and drug toxicity different pharmacological agents should be considered as an alternative to indefinite long term budesonide treatment. Evidence-based guidelines are currently lacking due to the lack of conclusive data concerning the use of either immunosuppressive or anti-tumor necrosis factor agents. For the time being in clinical practice the skilled physician should therefore tailor long term management of microscopic colitis on the single patient. PMID- 23801854 TI - Liver-spleen axis: intersection between immunity, infections and metabolism. AB - Spleen has been considered a neglected organ so far, even though is strictly linked to liver. The spleen plays an important role in the modulation of the immune system and in the maintenance of peripheral tolerance via the clearance of circulating apoptotic cells, the differentiation and activation of T and B cells and production of antibodies in the white pulp. Moreover, splenic macrophages are able to remove bacteria from the blood and protect from sepsis during systemic infections. We review the spleen function and its assessment in humans starting from the description of spleen diseases, ranging from the congenital asplenia to secondary hyposplenism. From the literature data it is clear that obesity in humans affects different compartments of immune system, even thought there are still few data available on the implicated mechamisms. The intent is to enable clinicians to evaluate the newly recognized role of metabolic and endocrine functions of the spleen with special emphasis to obesity and nonalcoholic fatty liver disease in the context of the available literature. Moreover, understanding the spleen function could be important to develop appropriate prevention strategies in order to counteract the pandemia of obesity. In this direction, we suggest spleen longitudinal diameter at ultrasonography, as simple, cheap and largely available tool, be used as new marker for assessing splenic function, in the context of the so-called liver-spleen axis. PMID- 23801856 TI - Heme oxygenase-1 and gut ischemia/reperfusion injury: A short review. AB - Ischemia/reperfusion (I/R) injury of the gut is a significant problem in a variety of clinical settings and is associated with a high morbidity and mortality. Although the mechanisms involved in the pathogenesis of gut I/R injury have not been fully elucidated, it is generally believed that oxidative stress with subsequent inflammatory injury plays an important role. Heme oxygenase (HO) is the rate-limiting enzyme in the catabolism of heme, followed by production of CO, biliverdin, and free iron. The HO system is believed to confer cytoprotection by inhibiting inflammation, oxidation, and apoptosis, and maintaining microcirculation. HO-1, an inducible form of HO, serves a vital metabolic function as the rate-limiting step in the heme degradation pathway, and affords protection in models of intestinal I/R injury. HO-1 system is an important player in intestinal I/R injury condition, and may offer new targets for the management of this condition. PMID- 23801855 TI - Evaluation of hepatic cystic lesions. AB - Hepatic cysts are increasingly found as a mere coincidence on abdominal imaging techniques, such as ultrasonography (USG), computed tomography (CT) and magnetic resonance imaging (MRI). These cysts often present a diagnostic challenge. Therefore, we performed a review of the recent literature and developed an evidence-based diagnostic algorithm to guide clinicians in characterising these lesions. Simple cysts are the most common cystic liver disease, and diagnosis is based on typical USG characteristics. Serodiagnostic tests and microbubble contrast-enhanced ultrasound (CEUS) are invaluable in differentiating complicated cysts, echinococcosis and cystadenoma/cystadenocarcinoma when USG, CT and MRI show ambiguous findings. Therefore, serodiagnostic tests and CEUS reduce the need for invasive procedures. Polycystic liver disease (PLD) is arbitrarily defined as the presence of > 20 liver cysts and can present as two distinct genetic disorders: autosomal dominant polycystic kidney disease (ADPKD) and autosomal dominant polycystic liver disease (PCLD). Although genetic testing for ADPKD and PCLD is possible, it is rarely performed because it does not affect the therapeutic management of PLD. USG screening of the liver and both kidneys combined with extensive family history taking are the cornerstone of diagnostic decision making in PLD. In conclusion, an amalgamation of these recent advances results in a diagnostic algorithm that facilitates evidence-based clinical decision making. PMID- 23801858 TI - Aberrant glycosylation of the anti-Thomsen-Friedenreich glycotope immunoglobulin G in gastric cancer patients. AB - AIM: To study whether alterations in the glycosylation of immunoglobulin G (IgG) specific to the Thomsen-Friedenreich glycotope (TF) have diagnostic and prognostic potential in gastric cancer. METHODS: Serum samples were obtained from patients with histologically verified gastric carcinoma (n = 89), healthy blood donors (n = 40), and patients with benign stomach diseases (n = 22). The lectin enzyme-linked immunosorbent assay-based glycoprofiling of TF-specific IgG (anti TF IgG) was performed using synthetic TF-polyacrylamide conjugate as antigen, total IgG purified by affinity chromatography on protein G sepharose, and lectins of various sugar specificities: mannose-specific concanavalin A (ConA), fucose specific Aleuria aurantia lectin (AAL) and sialic acid-specific Sambucus nigra agglutinin (SNA). The sensitivity and specificity of the differences between cancer patients and controls were evaluated by receiver operator characteristic (ROC) curve analysis. Overall survival was analyzed by the Kaplan-Meier method. Time-dependent ROC curve statistics were applied to determine cut-off values for survival analysis. All calculations and comparisons were performed using the GraphPad Prism 5 and SPSS 15.0 software. RESULTS: The level of TF-specific IgG was significantly increased in cancer patients compared with non-cancer controls (P < 0.001). This increase was pronounced mostly in stage 1 of the disease. Cancer patients showed a higher level of ConA binding to anti-TF-IgG (P < 0.05) and a very low level of SNA lectin binding (P = 0.0001). No appreciable stage dependency of the binding of any lectin to anti-TF IgG was found. A strong positive correlation between the binding of AAL and SNA was found in all groups studied (r = 0.71-0.72; P < 0.0001). The changes in ConA reactivity were not related to those of the fucose- or sialic acid-specific lectin. Changes in the SNA binding index and the ConA/SNA binding ratio demonstrated good sensitivity and specificity for stomach cancer: sensitivity 78.79% (95%CI: 61.09-91.02) and 72.73% (95%CI: 57.21-85.04); specificity 79.17 (95%CI: 65.01-89.53) and 88.64% (95%CI: 71.8-96.6), for the SNA binding index and the ConA/SNA binding ratio, respectively. The other combinations of lectins did not improve the accuracy of the assay. The low level of ConA-positive anti-TF IgG was associated with a survival benefit in cancer patients (HR = 1.56; 95%CI: 0.78-3.09; P = 0.19), especially in stages 3-4 of the disease (HR = 2.17; 95%CI: 0.98-4.79; P = 0.048). A significantly better survival rate was found in all cancer patients with a low reactivity of anti-TF IgG to the fucose-specific AAL lectin (HR = 2.39; 95%CI: 1.0-5.7; P = 0.038). CONCLUSION: The changes in the TF-specific IgG glycosylation pattern can be used as a biomarker for stomach cancer detection, and to predict patient survival. PMID- 23801857 TI - Virulence factors of Enterococcus strains isolated from patients with inflammatory bowel disease. AB - AIM: To determine the features of Enterococcus that contribute to the development and maintenance of the inflammatory process in patients with inflammatory bowel disease (IBD). METHODS: Multiplex polymerase chain reaction (PCR) was applied to assess the presence of genes that encode virulence factors [surface aggregating protein (asa1), gelatinase (gelE), cytolysin (cylA), extracellular surface protein (esp) and hyaluronidase (hyl)] in the genomic DNA of 28 strains of Enterococcus isolated from the intestinal tissues of children with IBD (n = 16) and of children without IBD (controls; n = 12). Additionally, strains with confirmed presence of the gelE gene were tested by PCR for the presence of quorum sensing genes (fsrA, fsrB, fsrC) that control the gelatinase production. Gelatinase activity was tested on agar plates containing 1.6% gelatin. We also analysed the ability of Enterococcus strains to release and decompose hydrogen peroxide (using Analytical Merckoquant peroxide test strips) and tested their ability to adhere to Caco-2 human gut epithelium cells and form biofilms in vitro. RESULTS: A comparison of the genomes of Enterococcus strains isolated from the inflamed mucosa of patients with IBD with those of the control group showed statistically significant differences in the frequency of the asa1 gene and the gelE gene. Furthermore, the cumulative occurrence of different virulence genes in the genome of a single strain of Enterococcus isolated from the IBD patient group is greater than in a strain from the control group, although no significant difference was found. Statistically significant differences in the decomposition of hydrogen peroxide and adherence to the Caco-2 epithelial cell line between the strains from the patient group and control group were demonstrated. The results also showed that profuse biofilm production was more frequent among Enterococcus strains isolated from children with IBD than in control strains. CONCLUSION: Enterococcus strains that adhere strongly to the intestinal epithelium, form biofilms and possess antioxidant defence mechanisms seem to have the greatest influence on the inflammatory process. PMID- 23801859 TI - Bone-marrow mesenchymal stem cells reduce rat intestinal ischemia-reperfusion injury, ZO-1 downregulation and tight junction disruption via a TNF-alpha regulated mechanism. AB - AIM: To investigate the effect of bone-marrow mesenchymal stem cells (BM MSCs) on the intestinal mucosa barrier in ischemia/reperfusion (I/R) injury. METHODS: BM MSCs were isolated from male Sprague-Dawley rats by density gradient centrifugation, cultured, and analyzed by flow cytometry. I/R injury was induced by occlusion of the superior mesenteric artery for 30 min. Rats were treated with saline, BM MSCs (via intramucosal injection) or tumor necrosis factor (TNF)-alpha blocking antibodies (via the tail vein). I/R injury was assessed using transmission electron microscopy, hematoxylin and eosin (HE) staining, immunohistochemistry, western blotting and enzyme linked immunosorbent assay. RESULTS: Intestinal permeability increased, tight junctions (TJs) were disrupted, and zona occludens 1 (ZO-1) was downregulated after I/R injury. BM MSCs reduced intestinal mucosal barrier destruction, ZO-1 downregulation, and TJ disruption. The morphological abnormalities after intestinal I/R injury positively correlated with serum TNF-alpha levels. Administration of anti-TNF-alpha IgG or anti-TNF alpha receptor 1 antibodies attenuated the intestinal ultrastructural changes, ZO 1 downregulation, and TJ disruption. CONCLUSION: Altered serum TNF-alpha levels play an important role in the ability of BM MSCs to protect against intestinal I/R injury. PMID- 23801860 TI - Risk factors for colonoscopic perforation: a population-based study of 80118 cases. AB - AIM: To assess the incidence and risk factors associated with colonic perforation due to colonoscopy. METHODS: This was a retrospective cross-sectional study. Patients were retrospectively eligible for inclusion if they were 18 years and older and had an inpatient or outpatient colonoscopy procedure code in any facility within the Geisinger Health System during the period from January 1, 2002 to August 25, 2010. Data are presented as median and inter-quartile range, for continuous variables, and as frequency and percentage for categorical variables. Baseline comparisons across those with and without a perforation were made using the two-sample t-test and Pearson's chi2 test, as appropriate. RESULTS: A total of 50 perforations were diagnosed out of 80118 colonoscopies, which corresponded to an incidence of 0.06% (95%CI: 0.05-0.08) or a rate of 6.2 per 10000 colonoscopies. All possible risk factors associated with colonic perforation with a P-value < 0.1 were checked for inclusion in a multivariable log-binomial regression model predicting 7-d colonic perforation. The final model resulted in the following risk factors which were significantly associated with risk of colonic perforation: age, gender, body mass index, albumin level, intensive care unit (ICU) patients, inpatient setting, and abdominal pain and Crohn's disease as indications for colonoscopy. CONCLUSION: The cumulative 7 d incidence of colonic perforation in this cohort was 0.06%. Advanced age and female gender were significantly more likely to have perforation. Increasing albumin and BMI resulted in decreased risk of colonic perforation. Having a colonoscopy indication of abdominal pain or Crohn's disease resulted in a higher risk of colonic perforation. Colonoscopies performed in inpatients and particularly the ICU setting had substantially greater odds of perforation. Biopsy and polypectomy did not increase the risk of perforation and only three perforations occurred with screening colonoscopy. PMID- 23801862 TI - Diagnostic value of endothelial markers and HHV-8 staining in gastrointestinal Kaposi sarcoma and its difference in endoscopic tumor staging. AB - AIM: To clarify the diagnostic values of hematoxylin and eosin (HE), D2-40, CD31, CD34, and HHV-8 immunohistochemical (IHC) staining in gastrointestinal Kaposi's sarcoma (GI-KS) in relation to endoscopic tumor staging. METHODS: Biopsy samples (n = 133) from 41 human immunodeficiency virus-infected patients were reviewed. GI-KS was defined as histologically negative for other GI diseases and as a positive clinical response to KS therapy. The receiver operating characteristic area under the curve (ROC-AUC) was compared in relation to lesion size, GI location, and macroscopic appearances on endoscopy. RESULTS: GI-KS was confirmed in 84 lesions (81.6%). Other endoscopic findings were polyps (n = 9), inflammation (n = 4), malignant lymphoma (n = 4), and condyloma (n = 2), which mimicked GI-KS on endoscopy. ROC-AUC of HE, D2-40, blood vessel markers, and HHV 8 showed results of 0.83, 0.89, 0.80, and 0.82, respectively. For IHC staining, the ROC-AUC of D2-40 was significantly higher (P < 0.05) than that of HE staining only. In the analysis of endoscopic appearance, the ROC-AUC of HE and IHC showed a tendency toward an increase in tumor staging (e.g., small to large, patches, and polypoid to SMT appearance). D2-40 was significantly (P < 0.05) advantageous in the upper GI tract and for polypoid appearance compared with HE staining. CONCLUSION: The diagnostic value of endothelial markers and HHV-8 staining was found to be high, and its accuracy tended to increase with endoscopic tumor staging. D2-40 will be useful for complementing HE staining in the diagnosis of GI-KS, especially in the upper GI tract and for polypoid appearance. PMID- 23801861 TI - Evaluation of enterochromaffin cells and melatonin secretion exponents in ulcerative colitis. AB - AIM: To study an assessment of the number of enterochromaffin cells and expression of hydroxyindole-O-methyltransferase in colonic mucosa and urine excretion of 6-sulfatoxymelatonin in patients with ulcerative colitis. METHODS: The study included 30 healthy subjects (group I-C), 30 patients with ulcerative proctitis [group II-ulcerative proctitis (UP)] and 30 patients with ulcerative colitis [group III-ulcerative colitis (UC)] in acute phases of these diseases. The number of enterochromaffin cells (EC) was estimated in rectal and colonic mucosa. Bioptates were assembled from many different parts of the large intestine. Immunorective cells collected from various parts of the colon were counted according to the Eurovision DAKO (Dako A/S, Copenhagen, Denmark) System in the range of 10 fields in each bioptate at * 200 magnification. The level of mRNA expression of hydroxyindole-O-methyltransferase (HIOMT) in colonic mucosa was estimated with RT-PCR. Urine 6-sulfatoxymelatonin (6-HMS) excretion was determined immunoenzymatically using an IBL (IBL International GmbH, Hamburg, Germany) kit (RE 54031). RESULTS: The number of EC cells in healthy subjects (C) was 132.40 +/- 31.26. In patients of group II (UP) and group III (UC) the number of these cells was higher--225.40 +/- 37.35 (P < 0.001) and--225.24 +/- 40.50 (P < 0.001) respectively. Similar differences were related to HIOMT expression, which was 1.04 +/- 0.36 in group C, 1.56 +/- 0.56 (P < 0.01) in group UP and 2.00 +/- 0.35 (P < 0.001) in group UC. Twenty-four hour 6-HMS urinary excretion was as follows: C--6.32 +/- 4.95 MUg/24 h, UP - 26.30 +/- 7.29 MUg/24 h (P < 0.01), UC- 2.30 +/- 12.56 MUg/24 h (P < 0.001). A correlation between number of EC cells and 6-HMS excretion was noted in all groups: r = 0.766 in patients with UP, r = 0.703 with UC and r = 0.8551 in the control group; the correlation between the results is statistically significant. CONCLUSION: In the acute phases of both UP and UC, proliferation of EC cells and high expression of HIOMT and urine excretion of 6 HMS is noted. These changes may represent a beneficial response in the anti inflammatory and defense mechanism. PMID- 23801863 TI - Gastric precancerous lesions are associated with gene variants in Helicobacter pylori-susceptible ethnic Malays. AB - AIM: To identify genes associated with gastric precancerous lesions in Helicobacter pylori (H. pylori)-susceptible ethnic Malays. METHODS: Twenty-three Malay subjects with H. pylori infection and gastric precancerous lesions identified during endoscopy were included as "cases". Thirty-seven Malay subjects who were H. pylori negative and had no precancerous lesions were included as "controls". Venous blood was collected for genotyping with Affymetrix 50K Xba1 kit. Genotypes with call rates < 90% for autosomal single nucleotide polymorphisms (SNPs) were excluded. For each precancerous lesion, associated SNPs were identified from Manhattan plots, and only SNPs with a chi2 P value < 0.05 and Hardy Weinberg Equilibrium P value > 0.5 was considered as significant markers. RESULTS: Of the 23 H. pylori-positive subjects recruited, one sample was excluded from further analysis due to a low genotyping call rate. Of the 22 H. pylori-positive samples, atrophic gastritis only was present in 50.0%, complete intestinal metaplasia was present in 18.25%, both incomplete intestinal metaplasia and dysplasia was present in 22.7%, and dysplasia only was present in 9.1%. SNPs rs9315542 (UFM1 gene), rs6878265 (THBS4 gene), rs1042194 (CYP2C19 gene) and rs10505799 (MGST1 gene) were significantly associated with atrophic gastritis, complete intestinal metaplasia, incomplete metaplasia with foci of dysplasia and dysplasia, respectively. Allele frequencies in "cases" vs "controls" for rs9315542, rs6878265, rs1042194 and rs10505799 were 0.4 vs 0.06, 0.6 vs 0.01, 0.6 vs 0.01 and 0.5 vs 0.02, respectively. CONCLUSION: Genetic variants possibly related to gastric precancerous lesions in ethnic Malays susceptible to H. pylori infection were identified for testing in subsequent trials. PMID- 23801864 TI - XPC Lys939Gln polymorphism, smoking and risk of sporadic colorectal cancer among Malaysians. AB - AIM: To investigate the risk association of xeroderma pigmentosum group C (XPC) Lys939Gln polymorphism alone and in combination with cigarette smoking on colorectal cancer (CRC) predisposition. METHODS: Peripheral blood samples of 510 study subjects (255 CRC patients, 255 controls)were collected. DNA was extracted and genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism. The association between polymorphic genotype and CRC predisposition was determined using the OR and 95%CI. RESULTS: The frequency of the homozygous variant (Gln/Gln) genotype was significantly higher in cases compared with controls (16.0% vs 10.2%, P = 0.049). The Gln/Gln genotype of XPC showed a significantly higher association with the risk of CRC (OR = 1.884; 95%CI: 1.082-3.277; P = 0.025). In the case of allele frequencies, variant allele C was associated with a significantly increased risk of CRC (OR = 1.375; 95%CI: 1.050-1.802; P = 0.020). Moreover, the risk was markedly higher for those who were carriers of the Gln/Gln variant genotype and were also cigarette smokers (OR = 3.409; 95%CI: 1.061-10.949; P = 0.032). CONCLUSION: The XPC Gln/Gln genotype alone and in combination with smoking increases the risk of CRC among Malaysians. PMID- 23801865 TI - Role of international criteria in the diagnosis of autoimmune hepatitis. AB - AIM: To study the clinical and laboratory characteristics of autoimmune hepatitis (AIH), and compare them with International Autoimmune Hepatitis Group (IAHG) criteria. METHODS: Sixty consecutive patients with AIH attended the University Clinic at Tabriz University of Medical Sciences, Iran for a 12 mo period and were assessed in a case series study. Serological and biochemical evaluations were carried out in all patients. Autoantibodies, such as antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA), anti-liver-kidney microsomal antibody (ALKM 1) type 1, and perinuclear anti-neutrophil cytoplasmic antibodies (P-ANCA) were evaluated in these patients. A liver biopsy was performed after diagnosis of the disease. Patients were evaluated in terms of their signs and symptoms, and laboratory results and the degree to which they corresponded with the diagnostic criteria of IAHG. In this study, both a comprehensive diagnostic scoring system and a simplified diagnostic scoring system were employed for AIH. RESULTS: Sixty patients, 20 male, 40 female, mean age 39.45 +/- 17.50 years, participated in the study. Treatment began immediately after enrolment into the study. The percent distribution of the study population into definite and probable did not change after the treatment. The most common symptoms in descending order were fatigue (100%), icter (66.7%), abdominal discomfort (33.3%), abdominal distension (28.3%), dark urine (23.3%), edema (23.3%), hematemesis (20.0%), pruritus (20.0%), melena (11.7%) and pale stool (10.0%). At the physical examination, splenomegaly, ascites, hepatomegaly, epigastric tenderness and an abdominal mass were found in 50.0%, 16.7%, 13.3%, 5.0% and 3.3% of patients, respectively. Hypergammaglobulinemia was detected in 95.0% of cases. ALKM-1, P-ANCA, ANA and ASMA were positive in 71.4%, 66.7%, 42.4% and 19.4% of cases, respectively. Portal hypertensive gastropathy (45.0%), esophageal varices (41.7%) and cirrhosis (40.0%) were the most prevalent complications of AIH, and there was no evidence of primary sclerosing cholangitis, ulcerative colitis and overlap syndrome in these patients. According to IAHG criteria, 80.0% of cases had a definite diagnosis, 15.0% had a probable diagnosis and 5.0% had no AIH. The percent distribution of the study population into definite, probable and no AIH did not change after using the simplified diagnostic scoring system for AIH. CONCLUSION: This research showed that the majority of cases in our study were appropriately diagnosed according to the IAHG criteria and simplified scoring system. Thus, these criteria are very useful. PMID- 23801866 TI - Focal autoimmune pancreatitis: radiological characteristics help to distinguish from pancreatic cancer. AB - AIM: To identify the radiological characteristics of focal autoimmune pancreatitis (f-AIP) useful for differentiation from pancreatic cancer (PC). METHODS: Magnetic resonance imaging (MRI) and triple-phase computed tomography (CT) scans of 79 patients (19 with f-AIP, 30 with PC, and 30 with a normal pancreas) were evaluated retrospectively. A radiologist measured the CT attenuation of the pancreatic parenchyma, the f-AIP and PC lesions in triple phases. The mean CT attenuation values of the f-AIP lesions were compared with those of PC, and the mean CT attenuation values of pancreatic parenchyma in the three groups were compared. The diagnostic performance of CT attenuation changes from arterial phase to hepatic phase in the differentiation between f-AIP and PC was evaluated using receiver operating characteristic (ROC) curve analysis. We also investigated the incidence of previously reported radiological findings for differentiation between f-AIP and PC. RESULTS: The mean CT attenuation values of f-AIP lesions in enhanced phases were significantly higher than those of PC (arterial phase: 60 +/- 7 vs 48 +/- 10, P < 0.05; pancreatic phase: 85 +/- 6 vs 63 +/- 15, P < 0.05; hepatic phase: 95 +/- 7 vs 63 +/- 13, P < 0.05). The mean CT attenuation values of f-AIP lesions were significantly lower those of uninvolved pancreas and normal pancreas in the arterial and pancreatic phase of CT (P < 0.001, P < 0.001), with no significant difference at the hepatic phase or unenhanced scanning (P = 0.4, P = 0.1). When the attenuation value increase was equal or more than 28 HU this was considered diagnostic for f-AIP, and a sensitivity of 87.5%, specificity of 100% and an area under the ROC curve of 0.974 (95%CI: 0.928-1.021) were achieved. Five findings were more frequently observed in f-AIP patients: (1) sausage-shaped enlargement; (2) delayed homogeneous enhancement; (3) hypoattenuating capsule-like rim; (4) irregular narrowing of the main pancreatic duct (MPD) and/or stricture of the common bile duct (CBD); and (5) MPD upstream dilation <= 5 mm. CONCLUSION: Analysis of a combination of CT and MRI findings could improve the diagnostic accuracy of differentiating f-AIP from PC. PMID- 23801867 TI - Fast-track surgery could improve postoperative recovery in radical total gastrectomy patients. AB - AIM: To assess the impact of fast-track surgery (FTS) on hospital stay, cost of hospitalization and complications after radical total gastrectomy. METHODS: A randomized, controlled clinical trial was conducted from November 2011 to August 2012 in the Department of Digestive Surgery, Xijing Hospital of Digestive Diseases, the Fourth Military Medical University. A total of 122 gastric cancer patients who met the selection criteria were randomized into FTS and conventional care groups on the first day of hospitalization. All patients received elective standard D2 total gastrectomy. Clinical outcomes, including duration of flatus and defecation, white blood cell count, postoperative pain, duration of postoperative stay, cost of hospitalization and complications were recorded and evaluated. Two specially trained doctors who were blinded to the treatment were in charge of evaluating postoperative outcomes, discharge and follow-up. RESULTS: A total of 119 patients finished the study, including 60 patients in the conventional care group and 59 patients in the FTS group. Two patients were excluded from the FTS group due to withdrawal of consent. One patient was excluded from the conventional care group because of a non-resectable tumor. Compared with the conventional group, FTS shortened the duration of flatus (79.03 +/- 20.26 h vs 60.97 +/- 24.40 h, P = 0.000) and duration of defecation (93.03 +/ 27.95 h vs 68.00 +/- 25.42 h, P = 0.000), accelerated the decrease in white blood cell count [P < 0.05 on postoperative day (POD) 3 and 4], alleviated pain in patients after surgery (P < 0.05 on POD 1, 2 and 3), reduced complications (P < 0.05), shortened the duration of postoperative stay (7.10 +/- 2.13 d vs 5.68 +/ 1.22 d, P = 0.000), reduced the cost of hospitalization (43783.25 +/- 8102.36 RMB vs 39597.62 +/- 7529.98 RMB, P = 0.005), and promoted recovery of patients. CONCLUSION: FTS could be safely applied in radical total gastrectomy to accelerate clinical recovery of gastric cancer patients. PMID- 23801868 TI - Hepatocellular carcinoma: clinical study of long-term survival and choice of treatment modalities. AB - AIM: To analyze the prognostic factors of 5-year survival and 10-year survival in hepatocellular carcinoma (HCC) patients, and to explore the reasons for long-term survival and provide choice of treatment modalities for HCC patients. METHODS: From January 1990 to October 2012, 8450 HCC patients were included in a prospective database compiled by the Information Center after hospital admission. Long-term surviving patients were included in a 10-year survival group (520 patients) and a 5-year survival group (1516 patients) for analysis.The long-term survival of HCC patients was defined as the survival of 5 years or longer. Clinical and biologic variables were assessed using univariate and multivariate analyses. The survival of patients was evaluated by follow-up data. RESULTS: The long-term survival of HCC patients was associated with the number of lesions, liver cirrhosis and Child-Pugh classification. It was not found to be associated with tumor diameter, histological stage, and pretreatment level of serum alpha fetoprotein. The differences in clinical factors between the 5-year survival and the 10-year survival were found to be the number of lesions, liver cirrhosis, Child-Pugh classification, and time elapsed until first recurrence or metastasis. The survival period of different treatment modalities in the patients who survived for 5 years and 10 years showed significant differences: (in order of significance) surgery alone > surgery-transcatheter arterial chemoembolization (TACE) > TACE-radiofrequency ablation (RFA) > TACE alone > surgery-TACE-RFA. The 10-year survival of HCC patients was not associated with the choice of treatment modality. CONCLUSION: This retrospective study elucidated survival outcomes, prognostic factors affecting survival and treatment modalities in HCC patients. PMID- 23801869 TI - Analysis of long non-coding RNA expression profiles in gastric cancer. AB - AIM: To investigate the expression patterns of long non-coding RNAs (lncRNAs) in gastric cancer. METHODS: Two publicly available human exon arrays for gastric cancer and data for the corresponding normal tissue were downloaded from the Gene Expression Omnibus (GEO). We re-annotated the probes of the human exon arrays and retained the probes uniquely mapping to lncRNAs at the gene level. LncRNA expression profiles were generated by using robust multi-array average method in affymetrix power tools. The normalized data were then analyzed with a Bioconductor package linear models for microarray data and genes with adjusted P values below 0.01 were considered differentially expressed. An independent data set was used to validate the results. RESULTS: With the computational pipeline established to re-annotate over 6.5 million probes of the Affymetrix Human Exon 1.0 ST array, we identified 136053 probes uniquely mapping to lncRNAs at the gene level. These probes correspond to 9294 lncRNAs, covering nearly 76% of the GENCODE lncRNA data set. By analyzing GSE27342 consisting of 80 paired gastric cancer and normal adjacent tissue samples, we identified 88 lncRNAs that were differentially expressed in gastric cancer, some of which have been reported to play a role in cancer, such as LINC00152, taurine upregulated 1, urothelial cancer associated 1, Pvt1 oncogene, small nucleolar RNA host gene 1 and LINC00261. In the validation data set GSE33335, 59% of these differentially expressed lncRNAs showed significant expression changes (adjusted P-value < 0.01) with the same direction. CONCLUSION: We identified a set of lncRNAs differentially expressed in gastric cancer, providing useful information for discovery of new biomarkers and therapeutic targets in gastric cancer. PMID- 23801870 TI - Double-balloon enteroscopy in small bowel tumors: a Chinese single-center study. AB - AIM: To analyze the clinical characteristics of small bowel tumors detected by double-balloon enteroscopy (DBE) and to evaluate the diagnostic value of DBE in tumors. METHODS: Four hundred and forty consecutive DBE examinations were performed in 400 patients (250 males and 150 females, mean age 46.9 +/- 16.3 years, range 14-86 years) between January 2007 and April 2012. Of these, 252 patients underwent the antegrade approach, and 188 patients underwent the retrograde approach. All the patients enrolled in our study were suspected of having small bowel diseases with a negative etiological diagnosis following other routine examinations, such as upper and lower gastrointestinal endoscopy and radiography tests. Data on tumors, such as clinical information, endoscopic findings and operation results, were retrospectively collected. RESULTS: Small bowel tumors were diagnosed in 78 patients, of whom 67 were diagnosed using DBE, resulting in a diagnostic yield of 16.8% (67/400); the other 11 patients had negative DBE findings and were diagnosed through surgery or capsule endoscopy. Adenocarcinoma (29.5%, 23/78), gastrointestinal stromal tumor (24.4%, 19/78) and lymphoma (15.4%, 12/78) were the most common tumors. Among the 78 tumors, 60.3% (47/78) were located in the jejunum, and the overall number of malignant tumors was 74.4% (58/78). DBE examinations were frequently performed in patients with obscure gastrointestinal bleeding (47.4%) and abdominal pain (24.4%). The positive detection rate for DBE in the 78 patients with small bowel tumors was 85.9% (67/78), which was higher than that of a computed tomography scan (72.9%, 51/70). Based on the operation results, the accuracy rates of DBE for locating small bowel neoplasms, such as adenocarcinoma, gastrointestinal stromal tumor and lymphoma, were 94.4%, 100% and 100%, respectively. The positive biopsy rates for adenocarcinoma and lymphoma were 71.4% and 60%, respectively. CONCLUSION: DBE is a useful diagnostic tool with high clinical practice value and should be considered the gold standard for the investigation of small bowel tumors. PMID- 23801871 TI - Case-matched comparison of laparoscopy-assisted and open distal gastrectomy for gastric cancer. AB - AIM: To compare short- and long-term outcomes of laparoscopy-assisted and open distal gastrectomy for gastric cancer. METHODS: A retrospective study was performed by comparing the outcomes of 54 patients who underwent laparoscopy assisted distal gastrectomy (LADG) with those of 54 patients who underwent open distal gastrectomy (ODG) between October 2004 and October 2007. The patients' demographic data (age and gender), date of surgery, extent of lymphadenectomy, and differentiation and tumor-node-metastasis stage of the tumor were examined. The operative time, intraoperative blood loss, postoperative recovery, complications, pathological findings, and follow-up data were compared between the two groups. RESULTS: The mean operative time was significantly longer in the LADG group than in the ODG group (259.3 +/- 46.2 min vs 199.8 +/- 40.85 min; P < 0.05), whereas intraoperative blood loss and postoperative complications were significantly lower (160.2 +/- 85.9 mL vs 257.8 +/- 151.0 mL; 13.0% vs 24.1%, respectively, P < 0.05). In addition, the time to first flatus, time to initiate oral intake, and postoperative hospital stay were significantly shorter in the LADG group than in the ODG group (3.9 +/- 1.4 d vs 4.4 +/- 1.5 d; 4.6 +/- 1.2 d vs 5.6 +/- 2.1 d; and 9.5 +/- 2.7 d vs 11.1 +/- 4.1 d, respectively; P < 0.05). There was no significant difference between the LADG group and ODG group with regard to the number of harvested lymph nodes. The median follow-up was 60 mo (range, 5-97 mo). The 1-, 3-, and 5-year disease-free survival rates were 94.3%, 90.2%, and 76.7%, respectively, in the LADG group and 89.5%, 84.7%, and 82.3%, respectively, in the ODG group. The 1-, 3-, and 5-year overall survival rates were 98.0%, 91.9%, and 81.1%, respectively, in the LADG group and 91.5%, 86.9%, and 82.1%, respectively, in the ODG group. There was no significant difference between the two groups with regard to the survival rate. CONCLUSION: LADG is suitable and minimally invasive for treating distal gastric cancer and can achieve similar long-term results to ODG. PMID- 23801872 TI - Diagnostic accuracy of endoscopic ultrasound in pancreatic neuroendocrine tumors: a systematic review and meta analysis. AB - AIM: To detect pancreatic neuroendocrine tumors (PNETs) has been varied. This study is undertaken to evaluate the accuracy of endoscopic ultrasound (EUS) in detecting PNETs. METHODS: Only EUS studies confirmed by surgery or appropriate follow-up were selected. Articles were searched in Medline, Ovid journals, Medline nonindexed citations, and Cochrane Central Register of Controlled Trials and Database of Systematic Reviews. Pooling was conducted by both fixed and random effects model). RESULTS: Initial search identified 2610 reference articles, of these 140 relevant articles were selected and reviewed. Data was extracted from 13 studies (n = 456) which met the inclusion criteria. Pooled sensitivity of EUS in detecting a PNETs was 87.2% (95%CI: 82.2-91.2). EUS had a pooled specificity of 98.0% (95%CI: 94.3-99.6). The positive likelihood ratio of EUS was 11.1 (95%CI: 5.34-22.8) and negative likelihood ratio was 0.17 (95%CI: 0.13-0.24). The diagnostic odds ratio, the odds of having anatomic PNETs in positive as compared to negative EUS studies was 94.7 (95%CI: 37.9-236.1). Begg Mazumdar bias indicator for publication bias gave a Kendall's tau value of 0.31 (P = 0.16), indication no publication bias. The P for chi2 heterogeneity for all the pooled accuracy estimates was > 0.10. CONCLUSION: EUS has excellent sensitivity and specificity to detect PNETs. EUS should be strongly considered for evaluation of PNETs. PMID- 23801873 TI - Endoscopic transluminal pancreatic necrosectomy using a self-expanding metal stent and high-flow water-jet system. AB - Walled-off pancreatic necrosis and a pancreatic abscess are the most severe complications of acute pancreatitis. Surgery in such critically ill patients is often associated with significant morbidity and mortality within the first few weeks after the onset of symptoms. Minimal invasive approaches with high success and low mortality rates are therefore of considerable interest. Endoscopic therapy has the potential to offer safe and effective alternative treatment. We report here on 3 consecutive patients with infected walled-off pancreatic necrosis and 1 patient with a pancreatic abscess who underwent direct endoscopic necrosectomy 19-21 d after the onset of acute pancreatitis. The infected pancreatic necrosis or abscess was punctured transluminally with a cystostome and, after balloon dilatation, a non-covered self-expanding biliary metal stent was placed into the necrotic cavity. Following stent deployment, a nasobiliary pigtail catheter was placed into the cavity to ensure continuous irrigation. After 5-7 d, the metal stent was removed endoscopically and the necrotic cavity was entered with a therapeutic gastroscope. Endoscopic debridement was performed via the simultaneous application of a high-flow water-jet system; using a flush knife, a Dormia basket, and hot biopsy forceps. The transluminal endotherapy was repeated 2-5 times daily during the next 10 d. Supportive care included parenteral antibiotics and jejunal feeding. All patients improved dramatically and with resolution of their septic conditions; 3 patients were completely cured without any further complications or the need for surgery. One patient died from a complication of prolonged ventilation severe bilateral pneumonia, not related to the endoscopic procedure. No procedure related complications were observed. Transluminal endoscopic necrosectomy with temporary application of a self expanding metal stent and a high-flow water-jet system shows promise for enhancing the potential of this endoscopic approach in patients with walled-off pancreatic necrosis and/or a pancreatic abscess. PMID- 23801874 TI - Polyarteritis nodosa clinically mimicking nonocclusive mesenteric ischemia. AB - Here, we present the case of a 74-year-old Japanese man with segmental intestinal necrosis, which developed after treatment with pulsed methylprednisolone for mononeuritis multiplex. The patient was weakly positive for myeloperoxidase (MPO) anti-neutrophil cytoplasmic antibody (ANCA). Computed tomography and surgical findings were compatible with nonocclusive mesenteric ischemia (NOMI). He underwent small intestinal resection by emergency surgery and an intestinal fistula was made. Pathologically, necrotizing vasculitis with fibrinoid necrosis was present in medium to small-sized arteries, which was equivalent to Arkin's classification II-IV. Most of the arteries had fibrous intimal thickening, which was considered to obstruct the arteries and thus cause segmental intestinal necrosis. A diagnosis of polyarteritis nodosa (PAN) was made, and intravenous cyclophosphamide pulse therapy was added to the therapeutic regimen. This patient was successfully treated with these multidisciplinary therapies and his stoma was finally closed. This is a very rare and indicative case of PAN weakly positive for MPO-ANCA and clinically mimicking NOMI, which occurred even after treatment with pulsed methylprednisolone. PMID- 23801875 TI - Esophageal mucosal metastasis from adenocarcinoma of the distal stomach. AB - Dissemination of gastric cancer may usually occur by direct spread through the perigastric tissues to adjacent organ, lymphatic spread, and hematogenous spread. We report a rare case of gastric cancer with mucosal metastastic lesion on the upper esophagus that was diagnosed by endoscopy and endosonography. A biopsy of the esophageal mass was performed and the pathologic findings with immunohistochemical stain for Mucin-5AC are proved to be identical to that of gastric adenocarcinoma, suggesting metastasis from main lesion of the gastric cancer. The lesion could not be explained by lymphatic or hematogenous spread, and its metastasis mechanism is considered to be different from previous studies. We suggest that the gastroesophageal reflux of cancer cells could be one of the possible metastatic pathways for metastasis of esophagus from an adenocarcinoma of the stomach. PMID- 23801876 TI - Gastric body diaphragm-like stricture as a rare complication of nonsteroidal anti inflammatory drugs. AB - Increased risk due to nonsteroidal anti-inflammatory drugs (NSAIDs) therapy has been observed in patients. Although diaphragm-like stricture in the small bowel and colon induced by NSAIDs therapy has been rarely reported, gastric body diaphragm-like stricture has not been reported. We describe the first case of gastric body diaphragm-like stricture due to NSAIDs in a 44-year-old male patient who was successfully treated by an endoscopic approach to avoid complicated surgery. This case highlights new insight into the disadvantages of NSAIDs and provides new data for future clinical studies. PMID- 23801877 TI - Ileocecal endometriosis and a diagnosis dilemma: a case report and literature review. AB - Bowel endometriosis affects between 3.8% and 37% of women with endometriosis. The evaluation of symptoms and clinical examination are inadequate for an accurate diagnosis of intestinal endometriosis. We describe the case of a 41-year-old woman who presented to our hospital because of six months of recurrent abdominal pain, vomiting and diarrhea, without previous history of bowel disease. Physical examination revealed a palpable 3 cm * 5 cm mass in the right lower quadrant abdomen. Laboratory tests showed slightly elevated levels of CA19-9 and CA125. Small bowel computer tomography scanning revealed an ileocecal mass with bowel wall thickening and luminal narrowing. Small bowel endoscopy identified a deep longitudinal ulcer and mucosal edema in the distal ileum. All these findings supported the diagnosis of Crohn's disease. The patient underwent a laparotomy, which identified a 5 cm * 5 cm ileocecal mass with severe mucosal edema and luminal stricture in the distal ileum. Histopathological examination confirmed a diagnosis of ileocecal endometriosis without other areas involved. After one-year follow-up, there was no recurrence of the symptoms. PMID- 23801878 TI - Response to Abadi and Kusters, World J Gastroenterol 19:429-430. AB - In a recent study, Rafiei et al, reported a link between a C150T polymorphism in the human inducible nitric oxide gene and Helicobacter pylori infection as a risk factor for gastric cancer among an Iranian population. Subsequently, Abadi and Kusters published a letter to the editor questioning the validity of the study because of a supposed flaw in primer design. Here we respond to the claims of Abadi and Kusters and show that the results reported in the original article are valid. PMID- 23801879 TI - C-reactive protein and serum amyloid a overexpression in lung tissues of chronic obstructive pulmonary disease patients: a case-control study. AB - BACKGROUND: Although researchers have consistently demonstrated systemic inflammation in chronic obstructive pulmonary disease (COPD), its origin is yet unknown. We aimed to compare the lung bronchial and parenchymal tissues as potential sources of major acute-phase reactants in COPD patients and resistant smokers. METHODS: Consecutive patients undergoing elective surgery for suspected primary lung cancer were considered for the study. Patients were categorized as COPD or resistant smokers according to their spirometric results. Lung parenchyma and bronchus sections distant from the primary lesion were obtained. C-reactive protein (CRP) and serum amyloid A (SAA1, SAA2 and SAA4) gene expressions were evaluated by RT-PCR. Protein levels were evaluated in paraffin embedded lung tissues by immunohistochemistry and in serum samples by nephelometry. RESULTS: Our study included 85 patients with COPD and 87 resistant smokers. In bronchial and parenchymal tissues, both CRP and SAA were overexpressed in COPD patients. In the bronchus, CRP, SAA1, SAA2, and SA4 gene expressions in COPD patients were 1.89-fold, 4.36-fold, 3.65-fold, and 3.9-fold the control values, respectively. In the parenchyma, CRP, SAA1, and SAA2 gene expressions were 2.41-, 1.97-, and 1.76-fold the control values, respectively. Immunohistochemistry showed an over stained pattern of these markers on endovascular cells of COPD patients. There was no correlation with serum protein concentration. CONCLUSIONS: These results indicate an overexpression of CRP and SAA in both bronchial and parenchymal tissue in COPD, which differs between both locations, indicating tissue/cell type specificity. The endothelial cells might play a role in the production of theses markers. PMID- 23801880 TI - Down-regulated CK8 expression in human intervertebral disc degeneration. AB - As an intermediate filament protein, cytokeratin 8 (CK8) exerts multiple cellular functions. Moreover, it has been identified as a marker of notochord cells, which play essential roles in human nucleus pulposus (NP). However, the distribution of CK8 positive cells in human NP and their relationship with intervertebral disc degeneration (IDD) have not been clarified until now. Here, we found the percentage of CK8 positive cells in IDD (25.7+/-4.14%) was significantly lower than that in normal and scoliosis NP (51.9+/-9.73% and 47.8+/-5.51%, respectively, p<0.05). Western blotting and qRT-PCR results confirmed the down regulation of CK8 expression in IDD on both of protein and mRNA levels. Furthermore, approximately 37.4% of cell clusters were CK8 positive in IDD. Taken together, this is the first study to show a down-regulated CK8 expression and the percentage of CK8 positive cell clusters in IDD based upon multiple lines of evidence. Consequently, CK8 positive cells might be considered as a potential option in the development of cellular treatment strategies for NP repair. PMID- 23801881 TI - Inhibition of HCV 5'-NTR and core expression by a small hairpin RNA delivered by a histone gene carrier, HPhA. AB - siRNA (small interfering RNA) interference represents an exciting new technology that could have therapeutic applications for the treatment of viral infections. However, a major challenge in the use of siRNA as a therapeutic agent is the development of a suitable delivery system. We demonstrated that a new non-viral transgene carrier, recombinant archaeal histone from the hyperthermophile Pyrococcus horikoshii OT3 (HPhA), can transfect short hairpin RNA (shRNA) expressing plasmids into HL-7702 cells to inhibit the expression of HCV 5'NTR and Core protein and mRNA. Plasmids Psilencirle transfected by HPhA inhibited the expression of HCV 5'-NTR and Core protein and mRNA in HL-7702 cells. The transfection efficiency of HPhA in HL-7702 cells was not affected by 10% fetal calf serum (FCS). HPhA exhibited effects of transfection without apparent toxicity, and with high affinity for DNA. This suggests that HPhA may be useful for RNAi-based gene therapy in vivo. PMID- 23801882 TI - Pneumothorax as an adverse drug event: an exploratory aggregate analysis of the US FDA AERS database including a confounding by indication analysis inspired by Cornfield's condition. AB - INTRODUCTION: Pneumothorax is either primary or secondary. Secondary pneumothorax is usually due to trauma, including various non-pharmacologic iatrogenic triggers. Although not normally thought of as an adverse drug event (ADE) secondary pneumothorax is associated with numerous drugs, though it is often difficult to determine whether this association is causal in nature, or reflects an epiphenomenon of efficacy or inefficacy, or confounding by indication (CBI). Herein we explore this association in a large health authority drug safety surveillance database. METHODS: A quantitative pharmacovigilance (PhV) methodology known as disproportionality analysis was applied to the United States Food and Drug Administration (US FDA) Adverse Event Reporting System (AERS) database to explore the quantitative reporting dependencies between drugs and the adverse event pneumothorax as well the corresponding reporting dependencies between drugs and reported indications that may be risk factors for pneumothorax themselves in order to explore the potential contribution of CBI. RESULTS: We found 1. Multiple drugs are associated with pneumothorax; 2. Surfactants and oncology drugs account for most statistically distinctive associations with pneumothorax; 3. Pulmonary surfactants, pentamidine and nitric oxide have the largest statistical reporting associations 4. CBI may play a prominent role in reports of drug-associated pneumothorax. CONCLUSIONS: Disproportionality analysis (DA) can provide insights into the spontaneous reporting dependencies between drugs and pneumothorax. CBI assessment based on DA and Cornfield's inequality presents an additional novel option for the initial exploration of potential safety signals in PhV. PMID- 23801883 TI - Combination with anthropometric measurements and MQSGA to assess nutritional status in Chinese hemodialysis population. AB - AIMS: To assess the nutritional status, combination with anthropometric measurements and modified quantitative subjective global assessment (MQSGA) was used in multi-center hemodialysis population in South China. METHODS: A cross sectional, descriptive-analytic study was performed in 4 teaching hospitals in South China, dated from January 2010 to December 2011. Nutritional status was assessed with MQSGA and related anthropometric indexes. Serum albumin and transthyretin were also determined for nutritional assessment. RESULTS: Eighty two randomly selected hemodialysis patients participated in the nutritional assessment, of which 75 hemodialysis patients completed all assessments. The average age was 62.70 +/- 14.21 years. The mean duration of hemodialysis was 3.29 +/- 1.08 years. Of the included patients, 32% patients were well nourished, 60% were mild to moderately malnourished, and 8% were severely malnourished. Along with the malnutrition severity, the serum transthyretin significantly decreased. However, no obvious changes were found in serum albumin. The mean value (Mean +/- SD; 25.78 +/- 4.09 cm) of mid arm circumference (MAC) was negatively correlated with MQSGA (r = -0.365; P = 0.002). Body mass index (BMI) (Mean +/- SD; 21.6 +/- 3.1 kg/m2) was also significantly negatively correlated with MQSGA (r = -0.392; P = 0.001). The areas under the receiver operating characteristic curve were 0.664 and 0.726, respectively. CONCLUSIONS: Malnutrition is very common in South China hemodialysis population. Both BMI and MAC were effective markers for assessing nutritional status. PMID- 23801884 TI - A comprehensive study indicates PRSS1 gene is significantly associated with pancreatitis. AB - This comprehensive meta-analysis was applied to case-control studies of the association between pancreatitis and PRSS1 gene to assess the joint evidence for the association, the influence of individual studies, and evidence for publication bias. PubMed, EMBASE, and Cochrane Library were searched in order to identify longitudinal studies evaluating pancreatitis disease and PRSS1 gene. Odds ratios (ORs) were pooled using a random-effects model. For the case-control studies, the authors found 1) support for the association between total pancreatitis and PRSS1 gene, both totally analyzed and subdivided analyzed {total: [OR:10.799, 95%CI:(5.489-21.242), p<0.000]; Europe: [OR:9.795, 95%CI:(2.923-32.819), p<0.000]; Asia: [OR:11.994, 95%CI:(5.156-27.898), p<0.000]}. 2) no evidence showed that this association was accounted for by any one study, and 3) no evidence showed any publication bias exist. In conclusion, PRSS1 gene was significantly associated with total pancreatitis disease, both totally and separately. PMID- 23801885 TI - Lack of association of C-Met-N375S sequence variant with lung cancer susceptibility and prognosis. AB - BACKGROUND: Previously, we identified a sequence variant (N375S) of c-Met gene, however, its association with lung cancer risk and prognosis remain undefined. PATIENTS AND METHODS: We investigated the genotype distribution of the c-Met N375S sequence variant in 206 lung cancer patients and 207 non-cancer controls in the Taiwanese population by DNA sequencing. RESULTS: Lung cancer patients with variant A/G and G/G genotypes showed 1.08-fold increased cancer risk when compared to patients with the wild-type A/A genotype (95% CI, 0.60-1.91). There were no significant differences in postoperative survival between c-Met-N375S and wild-type patients. In the cell model, the c-Met-N375S cells showed a decrease in cell death upon treatment with MET inhibitor SU11274 compared to wild-type cells. CONCLUSION: Our data suggest that the c-Met-N375S sequence variant may not play a significant role in cancer susceptibility and the prognosis of lung cancer patients. The correlation with chemoresponse of c-Met-N375S is worth further investigation in patients receiving MET therapy. PMID- 23801886 TI - Overexpression of integrin-linked kinase promotes lung cancer cell migration and invasion via NF-kappaB-mediated upregulation of matrix metalloproteinase-9. AB - Integrin-linked kinase (ILK) is a highly conserved serine-threonine protein kinase which has been implicated in the regulation of various cellular processes. Previously, we have demonstrated that overexpression of ILK correlates with malignant phenotype in non-small cell lung cancer. Furthermore, forced overexpression of ILK promotes lung cancer cell invasion and migration. However, the molecular mechanisms by which ILK enhances the invasive phenotype of lung cancer cells are still not fully understood. In the present study, we found that overexpression of ILK stimulated matrix metalloproteinase-9 (MMP-9) expression and activity in lung cancer cells. ILK-induced cell migration and invasion were significantly inhibited by MMP inhibitor doxycycline as well as by anti-MMP-9 neutralizing antibody. In addition, overexpression of ILK induced phosphorylation and nuclear translocation of nuclear factor-kappaB (NF-kappaB) subunit p65. Finally, upregulation of MMP-9 was severely abolished by either BAY 11-7028, a specific NF-kappaB inhibitor, or small interfering RNA targeted to NF-kappaB p65 in ILK overexpression cells. Taken together, these findings suggest that ILK promotes lung cancer cell migration and invasion via NF-kappaB-mediated upregulation of MMP-9. PMID- 23801887 TI - Potential function of granulysin, other related effector molecules and lymphocyte subsets in patients with TB and HIV/TB coinfection. AB - BACKGROUND: Host effector mechanism against Mycobacterium tuberculosis (Mtb) infection is dependent on innate immune response by macrophages and neutrophils and the alterations in balanced adaptive immunity. Coordinated release of cytolytic effector molecules from NK cells and effector T cells and the subsequent granule-associated killing of infected cells have been documented; however, their role in clinical tuberculosis (TB) is still controversy. OBJECTIVE: To investigate whether circulating granulysin and other effector molecules are associated with the number of NK cells, iNKT cells, Vgamma9(+)Vdelta2(+) T cells, CD4(+) T cells and CD8(+) T cells, and such association influences the clinical outcome of the disease in patients with pulmonary TB and HIV/TB coinfection. METHODS: Circulating granulysin, perforin, granzyme-B and IFN-gamma levels were determined by ELISA. The isoforms of granulysin were analyzed by Western blot analysis. The effector cells were analyzed by flow cytometry. RESULTS: Circulating granulysin and perforin levels in TB patients were lower than healthy controls, whereas the granulysin levels in HIV/TB coinfection were much higher than in any other groups, TB and HIV with or without receiving HAART, which corresponded to the number of CD8(+) T cells which kept high, but not with NK cells and other possible cellular sources of granulysin. In addition, the 17kDa, 15kDa and 9kDa isoforms of granulysin were recognized in plasma of HIV/TB coinfection. Increased granulysin and decreased IFN-gamma levels in HIV/TB coinfection and TB after completion of anti-TB therapy were observed. CONCLUSION: The results suggested that the alteration of circulating granulysin has potential function in host immune response against TB and HIV/TB coinfection. This is the first demonstration so far of granulysin in HIV/TB coinfection. PMID- 23801888 TI - Alanine aminotransferase elevation during peginterferon alpha-2a or alpha-2b plus ribavirin treatment. AB - Alanine aminotransferase (ALT) elevation was occassionally observed during the treatment with combination peginterferon alpha plus ribavirin. Two forms of peginterferon are currently available as a standard of care with or without direct-acting antivirals against hepatitis C virus (HCV). Until the appearance of interferon-sparing regimen, peginterferon alpha plus ribavirin will play a central role in the eradication of HCV. In the present study, we compared ALT elevations in response to peginterferon alpha-2a plus ribavirin or peginterferon alpha-2b plus ribavirin in HCV genotype-1-infected patients. There were no significant differences in ALT elevations between treatments with the two peginterferons, but in a comparison of the proportions of patients with transient ALT elevation from baseline between the two groups, transient ALT elevation was observed more in sustained virological response (SVR) patients treated with peginterferon alpha-2a than with peginterferon alpha-2b. However, no patients discontinued treatment due to ALT elevation. Patients with transient ALT elevation from baseline during the treatment had less favorable IL28B rs8099917 genotype in the peginterferon alpha-2b group. Patients achieving SVR tended to have lower ALT levels, although some had persistent ALT elevation during treatment. In conclusion, clinicians should pay attention to possible ALT elevation during the treatment of chronic hepatitis C patients. PMID- 23801889 TI - Genetic polymorphisms of matrix metalloproteinases and clinical outcomes in colorectal cancer patients. AB - BACKGROUND: Colorectal cancer metastasis is a multistep process involving degradation of extracellular matrix components by proteolytic enzymes. Among them, matrix metalloproteinases (MMPs) are the principal degrading enzymes and their expressions/activities are also correlated with survival. Much research has showed the associations between genetic polymorphisms in MMPs and risk of colorectal cancer; however, their prognostic significance has not been well determined. METHODS: We selected and genotyped 4 cancer-associated single nucleotide polymorphisms (SNPs) in a cohort of 282 colorectal cancer patients. The associations of these SNPs with distant metastasis-free survival and overall survival were evaluated by Kaplan-Meier analysis, Cox regression model, and survival tree analysis. RESULTS: The relative risks of developing distant metastasis after curative surgery were higher in individuals with minor homozygote AA genotype than in those with GG/GA genotypes at MMP2 rs243866 (P = 0.012). Survival tree analysis also identified a higher-order genetic interaction profile consisting of MMP2 rs243866 and MMP2 rs2285053 that was significantly associated with distant metastasis-free survival (P trend = 0.016). After adjusting for possible confounders, the genetic interaction profile remained significant (P trend = 0.050). CONCLUSIONS: These results suggest that genetic variations in the MMP2 might be potential predictors of distant metastasis-free survival after curative surgery. PMID- 23801890 TI - Hemoglobin A1c can identify more cardiovascular and metabolic risk profile in OGTT-negative Chinese population. AB - OBJECTIVE: To investigate the significance of hemoglobin A1c (HbA1c) in cardiovascular and metabolic risk stratification among diabetes and non-diabetes in southern Chinese. METHODS: Indigenous adults (aged more than or equal to 35 years) without known diabetes were enrolled in the cross-sectional survey. According to oral glucose tolerance test (OGTT), participants were categorized into OGTT-negative group and OGTT-positive group. Cardiovascular and metabolic risk profile was compared between different HbA1c levels (>= 6.5% vs. < 6.5%) in each group. RESULTS: The prevalence of OGTT-diagnosed diabetes was 6.45% (422/6540). In OGTT-negative group, subjects with HbA1c >= 6.5% were older, had higher prevalence of coronary heart disease, current smoking, hypertension, obesity and abdominal obesity. They also had higher body weight, waist-hip ratio, body mass index, glucose levels (fasting plasma glucose, 2-hour plasma glucose and HbA1c), and lipid levels (total cholesterol and low density lipoprotein cholesterol). In OGTT-positive group, patients with HbA1c >= 6.5% identified less cardiovascular and metabolic risk file than that in OGTT-negative group. CONCLUSIONS: Subjects with HbA1c >= 6.5% have more unfavorable cardiovascular and metabolic risk profile than those with HbA1c < 6.5%, especially in OGTT-negative population. More attention should be paid to this subgroup in clinical practice. PMID- 23801892 TI - Ureteral obstruction swine model through laparoscopy and single port for training on laparoscopic pyeloplasty. AB - This study aims firstly to assess the most adequate surgical approach for the creation of an ureteropelvic juntion obstruction (UPJO) animal model, and secondly to validate this model for laparoscopic pyeloplasty training among urologists. Thirty six Large White pigs (28.29+/-5.48 Kg) were used. The left ureteropelvic junction was occluded by means of an endoclip. According to the surgical approach for model creation, pigs were randomized into: laparoscopic conventional surgery (LAP) or single port surgery (LSP). Each group was further divided into transperitoneal (+T) or retroperitoneal (+R) approach. Time needed for access, surgical field preparation, wound closure, and total surgical times were registered. Social behavior, tenderness to the touch and wound inflammation were evaluated in the early postoperative period. After ten days, all animals underwent an Anderson-Hynes pyeloplasty carried out by 9 urologists, who subsequently assessed the model by means of a subjective validation questionnaire. Total operative time was significantly greater in LSP+R (p=0.001). Tenderness to the touch was significantly increased in both retroperitoneal approaches, (p=0.0001). Surgeons rated the UPJO porcine model for training on laparoscopic pyeloplasty with high or very high scores, all above 4 on a 1-5 point Likert scale. Our UPJO animal model is useful for laparoscopic pyeloplasty training. The model created by retroperitoneal single port approach presented the best score in the subjective evaluation, whereas, as a whole, transabdominal laparoscopic approach was preferred. PMID- 23801891 TI - Establishment and characterization of the reversibly immortalized mouse fetal heart progenitors. AB - OBJECTIVE: Progenitor cell-based cardiomyocyte regeneration holds great promise of repairing an injured heart. Although cardiomyogenic differentiation has been reported for a variety of progenitor cell types, the biological factors that regulate effective cardiomyogenesis remain largely undefined. Primary cardiomyogenic progenitors (CPs) have a limited life span in culture, hampering the CPs' in vitro and in vivo studies. The objective of this study is to investigate if primary CPs isolated from fetal mouse heart can be reversibly immortalized with SV40 large T and maintain long-term cell proliferation without compromising cardiomyogenic differentiation potential. METHODS: Primary cardiomyocytes were isolated from mouse E15.5 fetal heart, and immortalized retrovirally with the expression of SV40 large T antigen flanked with loxP sites. Expression of cardiomyogenic markers were determined by quantitative RT-PCR and immunofluorescence staining. The immortalization phenotype was reversed by using an adenovirus-mediated expression of the Cre reconbinase. Cardiomyogenic differentiation induced by retinoids or dexamethasone was assessed by an alpha myosin heavy chain (MyHC) promoter-driven reporter. RESULTS: We demonstrate that the CPs derived from mouse E15.5 fetal heart can be efficiently immortalized by SV40 T antigen. The conditionally immortalized CPs (iCP15 clones) exhibit an increased proliferative activity and are able to maintain long-term proliferation, which can be reversed by Cre recombinase. The iCP15 cells express cardiomyogenic markers and retain differentiation potential as they can undergo terminal differentiate into cardiomyctes under appropriate differentiation conditions although the iCP15 clones represent a large repertoire of CPs at various differentiation stages. The removal of SV40 large T increases the iCPs' differentiation potential. Thus, the iCPs not only maintain long-term cell proliferative activity but also retain cardiomyogenic differentiation potential. CONCLUSIONS: Our results suggest that the reported reversible SV40 T antigen mediated immortalization represents an efficient approach for establishing long term culture of primary cardiomyogenic progenitors for basic and translational research. PMID- 23801893 TI - FasL expression on human nucleus pulposus cells contributes to the immune privilege of intervertebral disc by interacting with immunocytes. AB - The mechanisms of immune privilege in human nucleus pulposus (NP) remain unclear. Accumulating evidence indicates that Fas ligand (FasL) might play an important role in the immune privilege of the disc. We aimed for addressing the role of FasL expression in human intervertebral disc degeneration (IDD) and immune privilege in terms of the interaction between NP cells and immunocytes via the FasL-Fas machinery. We collected NP specimens from 20 patients with IDD as degenerative group and 8 normal cadaveric donors as control. FasL expression was detected by qRT-PCR, western blotting and flow cytometry (FCM). We also collected macrophages and CD8(+) T cells from the peripheral blood of patients with IDD for co-cultures with NP cells. And macrophages and CD8(+) T cells were harvested for apoptosis analysis by FCM after 2 days of co-cultures. We found that FasL expression in mRNA, protein and cellular resolutions demonstrated a significant decrease in degenerative group compared with normal control (p<0.05). FCM analysis found that human NP cells with increased FasL expression resulted in significantly increased apoptosis ratio of macrophages and CD8(+) T cells. Our study demonstrated that FasL expression tends to decrease in degenerated discs and FasL plays an important role in human disc immune privilege, which might provide a novel target for the treatment strategies for IDD. PMID- 23801894 TI - Clinicopathologic review of ovarian masses in Korean premenarchal girls. AB - OBJECTIVE: To review the clinicopathological characteristics of ovarian masses in Korean premenarchal girls. DESIGN: The data collected from hospital medical records were reviewed retrospectively regarding age, presentation, diagnosis, treatment, and outcome. PARTICIPANTS: There were 65 premenarcheal girls who underwent surgery at Seoul St. Mary's Hospital between January 1990 and March 2012. RESULTS: The most common presenting symptom was abdominal pain (n=31, 47.7%), followed by palpable abdominal masses 16 (n=16, 24.6%), abdominal distension (n=8, 12.3%), vaginal bleeding (n=4, 6.2%), incidental finding (n=3, 4.6%), difficulty in urination or defecation (n=2, 3.1%), and prenatal sonographic findings (n=1, 1.5%). Of the patients with benign tumors, including non-neoplastic lesions and benign cysts, 26 (51%) underwent cystectomy, 6 (11.8%) underwent oophorectomy, 17 (33.3%) underwent unilateral salpingo-oophorectomy and none underwent bilateral salpingo-oophorectomy. Of the patients with malignant tumors, 2 (14.3%) underwent bilateral salpingo-oophorectomy, 7 (50%) underwent unilateral salpingo-oophorectomy, 2 (14.3%) underwent oophorectomy, and 2 (14.3%) underwent cystectomy. CONCLUSION: Abdominal pain was the most common symptom. However, the incidence of abdominal distension was higher in patients with malignant tumors than in those with benign tumors. We assessed clinical features, operative outcomes, and histological classifications of Korean prememarchal girls with ovarian masses. Further studies with a larger number of subjects are needed to confirm our results. PMID- 23801895 TI - The corrosion resistance of composite arch wire laser-welded by NiTi shape memory alloy and stainless steel wires with Cu interlayer in artificial saliva with protein. AB - In this paper, the corrosion resistance of laser-welded composite arch wire (CoAW) with Cu interlayer between NiTi shape memory alloy and stainless steel wire in artificial saliva with different concentrations of protein was studied. It was found that protein addition had a significant influence on the corrosion behavior of CoAW. Low concentration of protein caused the corrosion resistance of CoAW decrease in electrochemical corrosion and immersion corrosion tests. High concentration of protein could reduce this effect. PMID- 23801896 TI - Single-port laparoscopic salpingectomy for surgical treatment of tubal pregnancy: comparison with multi-port laparoscopic salpingectomy. AB - BACKGROUND: This study investigates the safety and feasibility of transumbilical single-port laparoscopic salpingectomy (SPLS) using conventional laparoscopic instruments compared to conventional multi-port laparoscopic salpingectomy (MPLS) for surgical treatment of tubal pregnancy. MATERIAL AND METHODS: We conducted a retrospective analysis of 63 patients with tubal pregnancy who underwent SPLS and 71 patients who underwent conventional MPLS between January 2008 and December 2010. All patients in the SPLS group had a drainage tube placed through the umbilicus, and, in the MPLS group, through a 5-mm trocar site in one side of the lower abdomen. RESULTS: No significance difference was discovered between the groups with regard to adjusted hemoglobin values (SPLS, 1.9 +/- 1.0 g/dL versus MPLS, 1.7 +/- 1.0 g/dL, P = 0.335). Additionally, there was also no significant difference in clinical characteristics, intraoperative findings, or operative outcomes. CONCLUSIONS: Our study demonstrated that transumbilical SPLS using conventional laparoscopic instruments has operative outcomes comparable to MPLS for the surgical treatment of tubal pregnancy. Transumbilical SPLS may therefore be offered as a feasible alternative to MPLS. PMID- 23801898 TI - Patience and patients. PMID- 23801897 TI - Managing Hepatitis C in Users of Illicit Drugs. AB - Persons who inject illicit drugs are the group most severely affected by the hepatitis C epidemic but the least likely to receive treatment. Controlling the epidemic will require developing strategies for effectively treating drug users. A growing number of reports have shown that a substantial proportion of drug users treated for hepatitis C can achieve sustained virologic responses even if they have psychiatric comorbidity and even if they continue to use drugs while receiving hepatitis C treatment. Successfully treating hepatitis C in injection drug users requires collaboration between those with expertise in hepatitis and those with expertise in caring for substance users. Careful attention to management of adverse effects and strong links with mental health services are important. Further research is needed to better define which patients can be successfully treated and the program elements that are critical for success. In the meantime, substantial progress can be made using current knowledge if appropriate resources are brought to bear. PMID- 23801899 TI - The linda crane lecture from silos to bridges: preparing effective teams for a better delivery system. PMID- 23801900 TI - Safety and Efficacy of Mobility Interventions in Patients with Femoral Catheters in the ICU: A Prospective Observational Study. AB - INTRODUCTION: There are limited data describing mobility interventions provided to patients with femoral catheters. The purpose of this study was to examine the incidence of femoral catheter related adverse effects during physical therapy (PT) sessions in a cardiovascular intensive care unit (ICU). METHODS: This was a prospective, observational study and included patients with at least one femoral catheter. Data were collected after each PT session. RESULTS: There were 77 subjects with a total of 92 femoral catheters (50 arterial, 15 central venous, and 27 dialysis) treated. A total of 210 separate PT sessions occurred with 630 mobility activities including sitting on side of bed, standing at the bedside, transfers to stretcher chair or regular chair, and walking. There were no catheter related mechanical or thrombotic complications during any of the PT sessions. CONCLUSIONS: Physical therapy sessions, including standing and walking were feasible and safe in cardiovascular ICU patients with femoral catheters who met the criteria for mobility interventions. The results from this study support the hypothesis that early mobilization in patients with femoral catheters is important to minimize functional decline and provide evidence that the presence of femoral catheters alone should not be a reason to limit progressive mobility interventions. PMID- 23801901 TI - Physical therapists' perceptions of knowledge and clinical behavior regarding cardiovascular disease prevention. AB - PURPOSE: The study purpose was to assess perceptions of physical therapists (PTs) regarding the role of physical therapy in cardiovascular disease (CVD) prevention. METHODS: A 25-item survey, validated by expert cardiovascular/pulmonary (CVP) PTs, was sent electronically to 2,673 PTs. Each item represented an element of clinical practice behavior: education of CVD/risk factors (EDCVD), administration of primary CVD prevention (PRECVD), identifying underlying CVD/risk factors (IDCVD), monitoring CV status in patients with CVD (MONCVD). Responses were assigned numeric values (strongly agree = 5 to strongly disagree = 1), and mean element scores were analyzed. RESULTS: Most of the 516 respondents were APTA Section members (34% CVP Section, 42% other Section membership) and worked in academia (53%). Items showing a high (> 95%) level of agreement included patient education of smoking (97%) and monitoring exercise intensity (99%), assessing exercise benefits (99%), clinically identifying obesity (97%) and hypertension (97%), and monitoring CV response to exercise (99%). Items failing to reach 80% overall agreement were patient education of CVD medications (79%) and blood chemistry (72%), and assessing CVD family history (75%), patient BMI (60%), and body composition (33%). Identifying underlying CVD (77.2%) was the only practice behavior failing to reach 80% agreement. Outpatient PTs agreed significantly less to all elements vs. academics, and to IDCVD vs. all PTs except home health. CONCLUSIONS: Physical therapists support most CVD prevention behaviors, but not given elements of patient education and identifying underlying CVD/risk factors. PMID- 23801902 TI - Cardiorespiratory fitness levels and its correlates among adults with diabetes. AB - PURPOSE: The purpose of this study is to report cardiorespiratory fitness levels among adults with diabetes and report differences by demographic (eg, body mass index) and behavioral (eg, physical activity) variables. METHODS: Data from the 1999-2004 National Health and Nutrition Examination Survey (NHANES) were used in the analyses. Cardiorespiratory fitness was assessed using a non-exercise prediction equation and through a submaximal treadmill-based test using heart rate extrapolation. Participants completed a questionnaire to assess various demographic and behavior variables. Seventy eight participants met inclusion criteria and constituted the analyzed sample. RESULTS: The majority (55.1%) of participants were estimated as having low or moderate cardiorespiratory fitness. Results showed that for both methods normal weight individuals had greater cardiorespiratory fitness than obese individuals, and for the non-exercise prediction equation, participants who sat during the day and did not walk very much had lower cardiorespiratory fitness (mean = 26.1 mL/kg/min [95% CI: 18.9 33.4]) than those doing heavy work or carrying heavy loads (mean = 34.6 mL/kg/min [95% CI: 30.2-39.1]). CONCLUSION: These results suggest that obese and inactive adults with diabetes may be at an increased risk for morbidities and mortality associated with low cardiorespiratory fitness. Physical therapists are encouraged to apply evidence-based principles for exercise prescription and physical activity counseling to help patients with diabetes regulate their blood glucose control and improve cardiorespiratory fitness. PMID- 23801903 TI - Exercise guidelines for inpatients following ventricular assist device placement: a systematic review of the literature. AB - BACKGROUND: For patients with end-stage heart failure awaiting transplantation, lack of donor organs has created an increased need for alternatives such as left ventricular assist device (LVAD) implantation. The purpose of this study is to determine safe and effective exercise parameters for physical therapy in the acute care setting. METHODS: A systematic literature review was conducted according to PRISMA guidelines using Sackett's Levels of Evidence to rate the evidence. Multiple databases were searched with inclusion criteria of: available in English, inpatient care up to 6 months postoperatively, description of intervention type and exercise parameters. EXCLUSION CRITERIA: no defined exercise parameters, outpatient treatment, infection post VAD, or palliative or hospice care post VAD. RESULTS: Six studies out of 1,291 articles met inclusion criteria. Common exercise parameters used were the Borg Rating of Perceived Exertion scale 11-13 (6-20 scale) or > 4 (0-10 scale), Dyspnea scale > 2 (0-4 scale) and > 5 (0-10 scale), mean arterial pressure (MAP) 70-95 mmHg, and LVAD flow > 3L/min. Levels of evidence ranged from case controlled to expert opinion. CONCLUSION: Current evidence on inpatient exercise parameters for patient's status post LVAD implantation is not sufficient to suggest definitive guidelines; however, these exercise parameters provide a reference for patient care. PMID- 23801904 TI - The role of Fluorine-18-Fluorodeoxyglucose positron emission tomography in staging and restaging of patients with osteosarcoma. AB - BACKGROUND: The objective of this study is to systematically review the role of positron emission tomography (PET) and PET/computed tomography (PET/CT) with Fluorine-18-Fluorodeoxyglucose (FDG) in patients with osteosarcoma (OS). METHODS: A comprehensive literature search of published studies through October 10(th), 2012 in PubMed/MEDLINE, Embase and Scopus databases regarding whole-body FDG-PET and FDG-PET/CT in patients with OS was performed. RESULTS: We identified 13 studies including 289 patients with OS. With regard to the staging and restaging of OS, the diagnostic performance of FDG-PET and PET/CT seem to be high; FDG-PET and PET/CT seem to be superior to bone scintigraphy and conventional imaging methods in detecting bone metastases; conversely, spiral CT seems to be superior to FDG-PET in detecting pulmonary metastases from OS. CONCLUSIONS: Metabolic imaging may provide additional information in the evaluation of OS patients. The combination of FDG-PET or FDG-PET/CT with conventional imaging methods seems to be a valuable tool in the staging and restaging of OS and may have a relevant impact on the treatment planning. PMID- 23801905 TI - Brain and whole-body FDG-PET in diagnosis, treatment monitoring and long-term follow-up of primary CNS lymphoma. AB - BACKGROUND: Positron emission tomography (PET) with F-18-labeled fluorodeoxyglucose (FDG) provides remarkable accuracy in detection, treatment monitoring and follow-up of systemic malignant lymphoma. Its value in the management of patients with primary central nervous system lymphoma (PCNSL) is less clear. PATIENTS AND METHODS: In a prospective trial, 42 FDG-PET examinations were performed in ten immunocompetent patients with newly diagnosed or recurrent PCNSL before and repeatedly during and after the treatment. Brain and whole body FDG-PET were compared to brain MRI and extra-cerebral CT, respectively. RESULTS: Before the treatment, 6 of 10 patients had congruent findings on FDG-PET and MRI of the brain. Three patients had lesions on brain MRI, not detected by FDG-PET. One patient had additional FDG-PET positive lesions inconspicuous in MRI. The follow-up suggested FDG-PET to be false positive in these lesions. After the treatment, brain PET was in agreement with MRI in 6 of 8 patients. In the remaining 2 patients there were persistent lesions in brain MRI whereas FDG uptake was reduced to normal values. In the long-term follow-up of 5 patients (63 169 weeks), 3 patients retained normal in both PET and MRI. In 2 patients a new focal pathologic FDG-uptake was detected 69 and 52 weeks after the end of the treatment. In one of these patients, recurrence was confirmed by MRI not until 9 weeks after PET. CONCLUSIONS: Brain FDG-PET may contribute valuable information for the management of PCNSL, particularly in the assessment of the treatment response. Integration of FDG-PET into prospective interventional trials is warranted to investigate prognostic and therapeutic implications. PMID- 23801906 TI - Poor outcome of comprehensive therapy in a case of laryngeal synovial sarcoma. AB - BACKGROUND: Synovial sarcoma is common in the extremities. Our search revealed only 17 cases of synovial sarcoma of the larynx in the English-language literature. CASE REPORT: We report an additional case of a 37-year-old man with primary laryngeal synovial sarcoma who underwent positron emission tomography/computed tomography (PET/CT) following the treatment. Although the patient received comprehensive therapy including surgery, radiotherapy, repeated chemotherapies, and targeted therapies, he had an unfavourable outcome and died of distant metastases. CONCLUSIONS: In synovial sarcoma of the larynx, PET/CT can detect recurrence and metastasis. PET/CT can also predict the treatment effect in patients with synovial sarcoma. PMID- 23801907 TI - MRI evaluation of tibial tunnel wall cortical bone formation after platelet-rich plasma applied during anterior cruciate ligament reconstruction. AB - BACKGROUND: After anterior cruciate ligament (ACL) reconstruction, formation of cortical sclerotic bone encircling the femoral and tibial tunnel is a part of intratunnel graft healing. During the physiological cascades of soft tissue healing and bone growth, cellular and hormonal factors play an important role. The purpose of this study was to non-invasively but quantitatively assess the effect of intraoperatively applied platelet-rich plasma (PRP) on the formation of cortical bone encircling the tibial tunnel. PATIENTS AND METHODS: In fifty patients, standard arthroscopic ACL reconstructions were performed. The PRP group (n = 25) received a local application of PRP while the control group (n = 25) did not receive PRP. The proximal tibial tunnel was examined by MRI in the paraxial plane where the portion of the tibial tunnel wall circumference consisting of sclerotic cortical bone was assessed with testing occurring at one, two and a half and six months after surgery. RESULTS: At one month after surgery, differences between the groups in the amount of cortical sclerotic bone encircling the tunnel were not significant (p = 0.928). At two and a half months, the sclerotic portion of the tunnel wall in the PRP group (36.2%) was significantly larger than in the control (22.5%) group (p = 0.004). At six months, the portion of sclerotic bone in the PRP group (67.1%) was also significantly larger than in the control (53.5%) group (p = 0.003). CONCLUSIONS: Enhanced cortical bone formation encircling the tibial tunnel at 2.5 and 6 months after ACL graft reconstruction results from locally applied platelet-rich plasma. PMID- 23801908 TI - An incidental case of biliary fascioliasis with subtle clinical findings: US and MRCP findings. AB - BACKGROUND: Fascioliasis is a disease caused by the trematode Fasciola hepatica. Cholangitis is a common clinical manifestation. Although fascioliasis may show various radiological and clinical features, cases without biliary dilatation are rare. CASE REPORT: We present unique ultrasound (US) and magnetic resonance cholangiopancreatography (MRCP) findings of a biliary fascioliasis case which doesn't have biliary obstruction or cholestasis. Radiologically, curvilinear parasites compatible with juvenile and mature Fasciola hepatica within the gallbladder and common bile duct were found. The parasites appear as bright echogenic structures with no acoustic shadow on US and hypo-intense curvilinear lesions on T2 weighted MRCP images. CONCLUSIONS: Imaging studies may significantly contribute to the diagnosis of patients with subtle clinical and laboratory findings, particularly in endemic regions. PMID- 23801909 TI - Development and characterization of a novel mAb against bilitranslocase - a new biomarker of renal carcinoma. AB - BACKGROUND: Bilitranslocase (TC 2.A.65.1.1) is a bilirubin-specific membrane transporter, found on absorptive (stomach and intestine) and excretory (kidney and liver) epithelia and in vascular endothelium. Polyclonal antibodies have been raised in rabbits in the past, using a synthetic peptide corresponding to AA65-77 of rat liver bilitranslocase, as an antigen. Affinity-purified antibodies from immune sera have been found to inhibit various membrane transport functions, including the bilirubin uptake into human hepatocytes and the uptake of some flavonoids into human vascular endothelial cells. It was described by means of immunohistochemistry using polyclonal antibodies that bilitranslocase expression is severely down-regulated in clear cell renal carcinoma. The aim of our work was development and characterization of high-affinity, specific mAbs against bilitranslocase, which can be used as a potential diagnostic tool in renal cell carcinoma as well as in a wide variety of biological assays on different human tissues. MATERIALS AND METHODS: Mice were immunized with a multi-antigen peptide corresponding to segment 65-75 of predicted primary structure of the bilitranslocase protein. By a sequence of cloning, immune- and functional tests, we aimed at obtaining a specific monoclonal antibody which recognizes a 37 kDa membrane protein, and influences the transport activity of bilitranslocase. RESULTS: On the basis of previous results, specific IgM monoclonal antibodies were produced in BALB/c mice, in order to further improve and extend the immunological approach to the study of bilitranslocase in renal cancer cells as well as to develop its potential diagnostics use. CONCLUSIONS: In this article we show an immunological approach, based on newly developed monoclonal antibodies, to a detailed biochemical and functional characterization of a protein whose gene and protein structure is still unknown. We were able to demonstrate our novel mAb as a tumor marker candidate of renal cell carcinoma, which may prove useful in the diagnostic procedures. PMID- 23801910 TI - The correlation between the levels of tissue inhibitor of metalloproteinases 1 in plasma and tumour response and survival after preoperative radiochemotherapy in patients with rectal cancer. AB - BACKGROUND: The aim of this study was to analyse whether the level of tissue inhibitor of metalloproteinases (TIMP) 1 is associated with the tumour response and survival to preoperative radiochemotherapy in rectal cancer patients. PATIENTS AND METHODS: Ninety-two patients with histologically confirmed non metastatic rectal cancer of clinical stage I- III were treated with preoperative radiochemotherapy, surgery and postoperative chemotherapy. Plasma TIMP-1 concentrations were measured prior to the start of the treatment with an enzyme linked immunosorbent assay (ELISA). RESULTS: Median follow-up time was 68 months (range: 3-93 months) while in survivors it was 80 months (range: 68-93 months). The 5-year locoregional control (LRC), disease-free survival (DFS), disease specific survival (DSS) and overall survival (OS) rates for all patients were 80.2%, 56.4%, 63.7% and 52.2%, respectively. The median TIMP-1 level was 185 ng/mL (range: 22-523 ng/mL) and the mean level (+/-standard deviation) was 192 (+/-87) ng/mL. Serum TIMP-1 levels were found to be significantly increased in patients with preoperative CRP>12 mg/L and in those who died from rectal cancer or had cT4 tumours. No correlation was established for age, gender, carcinoembriogenic antigene (CEA) level, platelets count, histopathological grade, response to preoperative therapy, resectability and disease reappearance. On univariate analysis, various parameters favourably influenced one or more survival endpoints: TIMP-1 <170 ng/mL, CRP <12 mg/L, platelets count <290 10E9/L, CEA <3.4mg/L, age <69 years, male gender, early stage disease (cN0 and/or cT2-3), radical surgery (R0) and response to preoperative radiochemotherapy. In multivariate model, LRC was favourably influenced by N-downstage, DFS by lower CRP and N-downstage, DSS by lower CRP and N-downstage and OS by lower TIMP-1 level, lower CRP and N-downstage. CONCLUSIONS: Although we did not find any association between pretreatment serum TIMP-1 levels and primary tumour response to preoperative radiochemotherapy in our cohort of patients with rectal cancer, TIMP-1 levels were recognized as an independent prognostic factor for OS in these patients. PMID- 23801911 TI - Comparison of continuous local anaesthetic and systemic pain treatment after axillary lymphadenectomy in breast carcinoma patients - a prospective randomized study. AB - BACKGROUND: Acute pain after axillary lymphadenectomy is often related mainly to axillary surgery. The aim of the prospective randomized study was to find out if continuous wound infusion of local anaesthetic reduces postoperative pain, consumption of opioids and the incidence of chronic pain compared to the standard intravenous piritramide analgesia after axillary lymphadenectomy in breast carcinoma patients. METHODS: Altogether 60 patients were enrolled in the prospective randomized study; half in wound infusion of local anaesthetic and half in the standard (piritramide) group. RESULTS: In the recovery room and on the first day after surgical procedure, the wound infusion of local anaesthetic group reported less acute and chronic pain, a lower consumption of piritramide and metoclopramide, but their alertness after the surgical procedure was higher compared to the standard group. CONCLUSIONS: After axillary lymphadenectomy in breast carcinoma patients, wound infusion of local anaesthetic reduces acute pain and enables reduced opioid consumption, resulting in less postoperative sedation and a reduced need for antiemetic drugs. After wound infusion of local anaesthetic there is a statistical trend for reduction of chronic pain. PMID- 23801912 TI - Uterine perforation - 5-year experience in 3-D image guided gynaecological brachytherapy at Institute of Oncology Ljubljana. AB - BACKGROUND: Accurate applicator placement is a precondition for the success of gynaecological brachytherapy (BT). Unrecognized uterine perforation can lead to bleeding, infection, high doses to pelvic organs and underdosage of the target volume, resulting in acute morbidity, long-term complications and reduced chance of cure. We aimed to assess the incidence and clinical characteristics of our cases with uterine perforation, review their management and impact on the treatment course. PATINETS AND METHODS: In all patients, treated with utero vaginal image guided BT for gynaecological cancer between January 2006 and December 2011, the CT/MR images with the applicator in place were reviewed. The incidence of uterine perforations was recorded. Clinical factors that may have predisposed to increased risk of perforation were recorded. Management of perforations and their impact on treatment course was assessed. RESULTS: 219 patients (428 applications) were suitable for analysis. Uterine perforation was found in 13 (3.0%) applications in 10 (4.6%) patients. The most frequent perforation site was posterior uterine wall (n = 9), followed by anterior wall (n = 2) and fundus (n = 2). All cases were managed conservatively, without complications. Prophylactic antibiotics were administered in 8 cases. In 4 patients, abdominal and/or transrectal ultrasound (US) guidance was used on subsequent applications for applicator insertion; adequate applicator placement was achieved and treatment completed as planned in all cases. CONCLUSIONS: 3D imaging for BT planning enables accurate identification of uterine perforations. The incidence of perforations at our department is one of the lowest reported in the literature. US guidance of applicator insertion is useful and feasible, allowing to complete the planned treatment even in challenging cases. PMID- 23801913 TI - Long term follow-up report of cardiac toxicity in patients with multiple myeloma treated with tandem autologous hematopoietic stem cell transplantation. AB - BACKGROUND: Tandem autologous hematopoietic stem cell transplantation (ta-HSCT) is a standard treatment for multiple myeloma (MM). Patients receive a high-dose cyclophosphamide (CY), followed by two myeloablative cycles of melphalan (MEL). There are scarce data about long term cardiotoxicity. PATIENTS AND METHODS: We studied 12 patients (62.25 +/- 8.55 years) six years after the completion of MM treatment with ta-HCST. Late cardiotoxic effects were evaluated clinically and echocardiographically. RESULTS: None of the patients developed clinical signs of heart failure, all were in sinus rhythm and NT-pro BNP concentration was elevated (778 +/- 902.76 pg/mL). The left ventricular (LV) size remained normal. The LV ejection fraction did not decrease (73.75 +/- 5.67%, 69.27 +/- 6.13%, p = NS). The LV diastolic function parameters (E, A, ratio E/A and A/a) did not change significantly. In tissue Doppler parameters we observed a nonsignificant decrease in Em (10.26 +/- 2.63 cm/s, 7.57 +/- 1.43 cm/s) and Sm velocities (8.7 +/- 0.87 cm/s, 7.14 +/- 1.17 cm/s, p = NS). The E/Em values were in an abnormal range (8.66 +/- 1.05, 10.55 +/- 2.03). CONCLUSIONS: The treatment of MM with ta-HSCT, during which patients receive a high dose CY followed by two myeloablative cycles of MEL, causes mild, chronic, partially reversible and clinically silent cardiotoxic side-effects. However, ta-HSCT in patients with MM is a safe regarding cardiotoxic side effects, but, because of increasing life expectancy needs long term attention. PMID- 23801914 TI - A review of the treatment options for skin rash induced by EGFR-targeted therapies: Evidence from randomized clinical trials and a meta-analysis. AB - BACKGROUND: Agents targeting the epidermal growth factor receptor (EGFR) are amongst the most extensively used of the targeted agents in the therapy of some of the most common solid tumors. Although they avoid many of the classic side effects associated with cytotoxic chemotherapy, they are associated with unpleasant cutaneous toxicities which can affect treatment compliance and impinge on patient quality of life. To date, despite a plethora of consensus recommendations, expert opinions and reviews, there is a paucity of evidence based guidance for the management of the skin rash that occurs in the treatment of patients receiving EGFR-targeted therapies. METHODS: A literature search was conducted as a first step towards investigating not only an evidence-based approach to the management of skin rash, but also with a view to designing future randomized trials. RESULTS: The literature search identified seven randomized trials and a meta-analysis was conducted using the data from four of these trials involving oral antibiotics. The meta-analysis of the data from these four trials suggests that prophylactic antibiotics might reduce the relative risk of severe rash associated with EGFR-targeted agents by 42-77%. Vitamin K cream was also identified as having a potential role in the management EGFR-targeted agent induced rash. CONCLUSIONS: This review and meta-analysis clearly identify the need for further randomized studies of the role of oral antibiotics in this setting. The results of the ongoing randomized trials of the topical application of vitamin K cream plus or minus doxycycline and employing prophylactic versus reactive strategies are eagerly awaited. PMID- 23801915 TI - Does initial 45Gy of pelvic intensity-modulated radiotherapy reduce late complications in patients with locally advanced cervical cancer? A cohort control study using definitive chemoradiotherapy with high-dose rate brachytherapy. AB - BACKGROUND: Comparing initial 45 Gy of pelvic intensity-modulated radiation therapy (IMRT) and non-IMRT in terms of the late toxicities associated with advanced cervical cancer that has also been treated with definitive concurrent chemoradiotherapy and high-dose rate intracavitary brachytherapy (HDRICB). PATIENTS AND METHODS: This retrospective study included 320 stage IB2-IIIB cervical cancer patients treated with CCRT (83 IMRT and 237 non-IMRT). The two groups had similar stage and HDRICB ratings. Following 45 Gy to the pelvis, HDRICB of 24 Gy in four courses was prescribed. Late toxicities, including rectal complications (RC), bladder complications (BC) and non-rectal intestinal injury (NRRII), were scored by the Common Terminology Criteria for Adverse Events. A logistic regression was used to estimate the odds ratio (OR) of the complications. RESULTS: With a median follow-up duration of 33 and 77 months for IMRT and non-IMRT, 33 patients had Grade 2 or higher late RC (7.2% IMRT, 11.4% non-IMRT), whereas that for BC was 40 (9.6% IMRT, 13.5% non-IMRT) and for NRRII was 48 (12.0% IMRT, 16.0% non-IMRT). The cumulative rate for total grade 3 or higher gastrointestinal or genitourinary toxicities was 8.4% and 11.8% (p = 0.33). IMRT did not reduce the OR for all endpoints; however, the ORs for rectum and bladder reference doses to Point A were associated with RC and BC. CONCLUSIONS: Locally advanced cervical cancer patients treated with initial 45Gy of pelvic IMRT and HDRICB have similar treatment-related late toxicities as those treated with non-IMRT. Optimization of the brachytherapy scheme is essential to minimize late toxicities. PMID- 23801916 TI - Evaluation of acute/late toxicity and local recurrence in T1-T2 glottic carcinoma treated with accelerated hypofractionated 3D-conformal external beam radiotherapy (3D-CRT). AB - BACKGROUND: The aim of the study was to evaluate the efficacy, as well as the acute and late toxicity of an accelerated hypofractionated 3DCRT schedule as radical treatment in patients with organ confined glottic cancer cT1-2N0. PATIENTS AND METHODS: Between June of 2004 and September 2010, 47 retrospectively selected patients (29 males, 18 females) diagnosed with organ confined T1 or T2 glottic cancer, were treated with external 3DCRT in an accelerated hypofractionation schedule. The median age was 70 years. A dose of 64.4 Gy in 28 daily fractions was prescribed. The primary study endpoints were to assess the acute and late effects of radiation toxicity, according to the EORTC/ RTOG scale, as well as the therapeutic impact of this schedule in terms of local recurrence. RESULTS: The median follow up was 36 months. At the end of radiotherapy, grade I, II and III acute toxicity was observed in 34, 9 and4 patients, respectively. Late grade I and II toxicity was observed in 25 and in 8 patients respectively. Only two local recurrences were observed, 15 and 24 months post 3DCRT respectively. CONCLUSIONS: Our radiotherapy schedule achieves a high locoregional control rate with the advantage of voice preservation. The proposed hypofractionated schedule can be recommended as a standard radiotherapy treatment, since these results are comparable with those of conventional fractionation schedules. PMID- 23801917 TI - Central low-grade osteosarcoma with an unusual localization in the diaphysis of a 12-year old patient. AB - BACKGROUND: Low-grade central osteosarcoma is a very rare subtype of osteosarcoma with a predilection for the metaphysis of long bones and a peak incidence in the 3(rd) decade of life. Absence of specific clinical symptoms and a good prognosis after wide resection are the characteristics of this entity. Chemotherapy is not indicated in this highly differentiated tumour. CASE REPORT: A 12-year old girl presented with limping, swelling and pain in the mid of the left femur. Radiography showed a 12 cm long intraosseous expansion with lamellated periosteal reaction and contrast medium enhancement in MRI. Although radiology led to the differential diagnoses of Ewing's sarcoma, osteomyelitis and fibrous dysplasia, the histological specimen showed a hyopocellular spindle-cell proliferation arranged in fascicles with mild cytologic atypia and only single mitotic figures. In synopsis with radiology the diagnosis of low-grade central osteosarcoma was made and confirmed by reference pathology. The tumour was resected with wide margins and reconstruction was performed with a vascularized fibula, a homologous allograft and a plate. Staging was negative for recurrence and metastasis at a follow-up of 16 months. CONCLUSIONS: Low-grade osteosarcoma accounts for only 1% of all osteosarcomas with a peak incidence in the 3(rd) decade. The diaphyseal localization and the young age make this case special. To achieve the correct diagnosis of this rare low-grade entity and thereby the adequate treatment, despite a wide range of differential diagnoses, a multidisciplinary approach is essential. PMID- 23801918 TI - Aging and clearance of erythrocytes. PMID- 23801919 TI - What is aging? PMID- 23801920 TI - Measurement of red cell lifespan and aging. AB - SUMMARY: The measurement of red blood cell (RBC) survival has a long history, and a wide variety of methods have been utilized for this purpose. Current methods are of 2 types. First, those that label a representative sample of RBCs of all ages from the blood and then measure their rate of disappearance upon reinfusion. This category includes the (51)Cr and biotin labels. Second, those that use a metabolic precursor or product to determine the turnover of hemoglobin. Examples of these are carbon monoxide production and incorporation of labeled glycine. Recent studies with the covalent, nonradioactive biotin label show its unique suitability for both the accurate measurement of red cell survival and the determination of changes in red cell properties as they age in vivo. PMID- 23801921 TI - Physiology and pathophysiology of eryptosis. AB - SUMMARY: Suicidal erythrocyte death (eryptosis) is characterized by cell shrinkage, cell membrane blebbing, and cell membrane phospholipid scrambling with phosphatidylserine exposure at the cell surface. Eryptotic cells adhere to the vascular wall and are rapidly cleared from circulating blood. Eryptosis is stimulated by an increase in cytosolic Ca(2)+ activity, ceramide, hyperosmotic shock, oxidative stress, energy depletion, hyperthermia, and a wide variety of xenobiotics and endogenous substances. Inhibitors of eryptosis include erythropoietin and nitric oxide. Enhanced eryptosis is observed in diabetes, renal insufficiency, hemolytic uremic syndrome, sepsis, mycoplasma infection, malaria, iron deficiency, sickle cell anemia, beta-thalassemia, glucose-6 phosphate dehydrogenase-(G6PD) deficiency, hereditary spherocytosis, paroxysmal nocturnal hemoglobinuria, Wilson's disease, myelodysplastic syndrome, and phosphate depletion. Eryptosis is further enhanced in gene-targeted mice with deficient annexin 7, cGMP-dependent protein kinase type I (cGKI), AMP-activated protein kinase (AMPK), anion exchanger 1 (AE1), adenomatous polyposis coli (APC), and Klotho, as well as in mouse models of sickle cell anemia and thalassemia. Decreased eryptosis is observed in mice with deficient phosphoinositide-dependent kinase 1 (PDK1), platelet activating factor (PAF) receptor, transient receptor potential channel 6 (TRPC6), janus kinase 3 (JAK3), and taurine transporter (TAUT). Eryptosis may be a useful mechanism to remove defective erythrocytes prior to hemolysis. Excessive eryptosis may, however, compromise microcirculation and lead to anemia. PMID- 23801922 TI - Role of CD47 and Signal Regulatory Protein Alpha (SIRPalpha) in Regulating the Clearance of Viable or Aged Blood Cells. AB - SUMMARY: The ubiquitously expressed cell surface glycoprotein CD47 is expressed by virtually all cells in the host, where it can function to regulate integrin mediated responses, or constitute an important part of the erythrocyte band 3/Rh multi-protein complex. In addition, CD47 can protect viable cells from being phagocytosed by macrophages or dendritic cells. The latter mechanism is dependent on the interaction between target cell CD47 and SIRPalpha on the phagocyte. In this context, SIRPalpha functions to inhibit prophagocytic signaling from Fcgamma receptors, complement receptors, and LDL receptor-related protein-1 (LRP-1), but not scavenger receptors. The expression level and/or distribution of CD47 may be altered on the surface of apoptotic/senescent cells, rendering the phagocytosis inhibitory function of the CD47/SIRPalpha interaction reduced or eliminated. Instead, the interaction between these 2 proteins may serve to enhance the binding of apoptotic/senescent target cells to the phagocyte to promote phagocytosis. PMID- 23801923 TI - Naturally occurring anti-band 3 antibodies in clearance of senescent and oxidatively stressed human red blood cells. AB - SUMMARY: Naturally occurring anti-band 3 antibodies (anti-band 3 NAbs) are directed against the 55-kDa chymotryptic fragment of the anion transport protein (band 3) of red blood cells (RBCs). They bind to senescent and oxidatively stressed RBCs and induce their selective clearance. These IgG NAbs exist at low concentrations, and have a weak affinity that prevents them from actively recruiting second binding sites. Cellular senescence or oxidative damage induces a cascade of biochemical events that results in the detachment of band 3 from the cytoskeleton and in clustering of band 3 protein by bound hemichromes and Syk kinase. Clustered band 3 proteins allow bivalent binding of anti-band 3 NAbs. Bivalently bound anti-band 3 NAbs have the unique capacity to stimulate C3b deposition by preferentially generating C3b2-IgG complexes, which act as potent C3 convertase precursors of the alternative complement pathway. Antibody binding not only to clustered, but also to oligomerized band 3 protein further increases if the human plasma also contains induced anti-lactoferrin antibodies. These bind to the polylactosaminyl oligosaccharide, a carbohydrate that exists in lactoferrin and in the 38-kDa fragment of band 3 protein. Anti-lactoferrin antibodies are found primarily in plasma of patients with autoimmune diseases and who have anti-neutrophil cytoplasmic antibodies (ANCA). PMID- 23801924 TI - Life and Death of Glucose-6-Phosphate Dehydrogenase (G6PD) Deficient Erythrocytes - Role of Redox Stress and Band 3 Modifications. AB - SUMMARY: G6PD catalyzes the first, pace-making reaction of pentosephosphate cycle (PPC) which produces NADPH. NADPH maintains glutathione and thiol groups of proteins and enzymes in the reduced state which is essential for protection against oxidative stress. Individuals affected by G6PD deficiency are unable to regenerate reduced glutathione (GSH) and are undefended against oxidative stress. G6PD deficiency accelerates normal senescence and enhances the precocious removal of chronologically young, yet biologically old cells. The term hemolytic anemia is misleading because RBCs do not lyse but are removed by phagocytosis. Acute hemolysis by fava bean ingestion in G6PD deficient individuals (favism) is described being the best-studied natural model of oxidant damage. It bears strong analogies to hemolysis by oxidant drugs or chemicals. Membrane alterations observed in vivo during favism are superimposable to changes in senescent RBCs. In summary, RBC membranes isolated from favic patients contained elevated amounts of complexes between IgG and the complement fragment C3b/C3c and were prone to vesiculation. Anti-band 3 IgG reacted to aggregated band 3-complement complexes. In favism extensive clustering of band 3 and membrane deposition of hemichromes were also observed. Severely damaged RBCs isolated from early crises had extensive membrane cross-bonding and very low GSH levels and were phagocytosed 10 fold more intensely compared to normal RBCs. PMID- 23801925 TI - A Double in vivo Biotinylation Technique for Objective Assessment of Aging and Clearance of Mouse Erythrocytes in Blood Circulation. AB - SUMMARY: We have recently developed a new technique to objectively identify erythrocyte cohorts of defined age in mouse blood. The technique (termed double in vivo biotinylation, DIB) involves an initial biotinylation of all erythrocytes in circulation, followed after a few days by a second biotinylation, at a lower density, that labels the biotin-negative erythrocytes that have entered since the first biotinylation. The proportions of biotin(high), biotin(low), and biotin(negative) erythrocytes are enumerated by flow cytometry. The DIB technique allows us to track age-related changes on erythrocyte cohorts (Protocol A), and to simultaneously identify very young and older erythrocyte populations in the blood (Protocol B). Using this technique, we have reexamined: i) the relationship between age and buoyant density of erythrocytes, ii) erythrocyte destruction through a random removal mechanism, and iii) the expression of phosphatidylserine on aging erythrocytes. We have also used the DIB technique to study age-related changes in the expression of various markers like CD47 and CD147 and green autofluorescence in aging erythrocyte populations. PMID- 23801926 TI - Red blood cell microparticles: clinical relevance. AB - SUMMARY: Microparticles are small phospholipid vesicles of less than 1 um released into the blood flow by various types of cells such as endothelial, platelet, white or red blood cells. They are involved in many biological and physiological processes including hemostasis. In addition, an elevated number of microparticles in the blood is observed in various pathological situations. In the context of transfusion, erythrocyte-derived microparticles are found in red blood cell concentrates. Their role is not elucidated, and they are considered as a type of storage lesion. The purpose of this review is to present recent data showing that erythrocyte-derived microparticles most likely play a role in transfusion medicine and could cause transfusion complications. PMID- 23801927 TI - CD47 in Erythrocyte Ageing and Clearance - the Dutch Point of View. AB - Recently, an important role for CD47, a well-known 'don't eat me' signal, in the clearance of aged erythrocytes was revealed. Experimental data support the conversion of CD47 from a 'don't eat me' to an 'eat me' signal through a conformational change in CD47. Intriguingly, erythrocyte phagocytosis after this switch seems to be mediated by the same receptor that normally signals inhibition of phagocytosis, SIRPalpha. In this review, the possible molecular mechanisms leading to this conformational change in CD47 as well as the possible signal transduction events leading to phagocytosis after this switch are discussed. Lastly, the consequences of this newly identified mode of erythrocyte phagocytosis for the clearance of aged erythrocytes during normal turnover and after erythrocyte transfusion are addressed. PMID- 23801929 TI - Current trends in tissue banking. PMID- 23801928 TI - Red blood cell clearance in inflammation. AB - SUMMARY: Anemia is a frequently encountered problem in the critically ill patient. The inability to compensate for anemia includes several mechanisms, collectively referred to as anemia of inflammation: reduced production of erythropoietin, impaired bone marrow response to erythropoietin, reduced iron availability, and increased red blood cell (RBC) clearance. This review focuses on mechanisms of RBC clearance during inflammation. We state that phosphatidylserine (PS) expression in inflammation is mainly enhanced due to an increase in ceramide, caused by an increase in sphingomyelinase activity due to either platelet activating factor, tumor necrosis factor-alpha, or direct production by bacteria. Phagocytosis of RBCs during inflammation is mediated via RBC membrane protein band 3. Reduced deformability of RBCs seems an important feature in inflammation, also mediated by band 3 as well as by nitric oxide, reactive oxygen species, and sialic acid residues. Also, adherence of RBCs to the endothelium is increased during inflammation, most likely due to increased expression of endothelial adhesion molecules as well as PS on the RBC membrane, in combination with decreased capillary blood flow. Thereby, clearance of RBCs during inflammation shows similarities to clearance of senescent RBCs, but also has distinct entities, including increased adhesion to the endothelium. PMID- 23801930 TI - Coding of tissue preparations with eurocode in Germany. AB - SUMMARY: A safe look back of products requires their unique identification. Blood products are encoded in Germany with Eurocode since 1987. EU Directives 2004/23/EC und 2006/86/EC demanded unique identification and safe look back procedure also for tissues and cells. Eurocode IBLS e.V. and the DGTI working parties 'Tissue Preparations' and 'Automation and Data Processing' supplemented the already available Eurocode nomenclature for blood products with further data structures for tissue preparations and deliberated the federal authorities during the EU hearings. In result all EU member states can administer the coding system oneself, but have to take care about the 'key code' structure as defined and the common part at the begin of the ID number of the preparations. Eurocode today offers an EU-conform coding system considering various aspects of blood, tissue and cell preparations in an ISO-standardized form. PMID- 23801931 TI - Genotypes and phenotypes of 162 families with a glomulin mutation. AB - A decade ago, we identified a novel gene, glomulin (GLMN) in which mutations cause glomuvenous malformations (GVMs). GVMs are bluish-purple cutaneous vascular lesions with characteristic glomus cells in the walls of distended venous channels. The discovery of the genetic basis for GVMs allowed the definition of clinical features to distinguish GVMs from other venous anomalies. The variation in phenotype was also highlighted: from a single punctate blue dot to a large plaque-like lesion. In this study, we screened GLMN in a large cohort of patients to broaden the spectrum of mutations, define their frequency and search for possible genotype-phenotype correlations. Taking into account 6 families published by others, a mutation in GLMN has been found in 162 families. This represents 40 different mutations; the most frequent one being present in almost 45% of them. Expressivity varies largely, without a genotype/phenotype relationship. Among 381 individuals with a mutation, we discovered 37 unaffected carriers, implying a penetrance of 90%. As nonpenetrant individuals may transmit the disease to their descendants, knowledge on the mutational status is needed for appropriate genetic counseling. PMID- 23801932 TI - CCM3 Mutations Are Associated with Early-Onset Cerebral Hemorrhage and Multiple Meningiomas. AB - Mutations of CCM3/PDCD10 cause 10-15% of hereditary cerebral cavernous malformations. The phenotypic characterization of CCM3-mutated patients has been hampered by the limited number of patients harboring a mutation in this gene. This is the first report on molecular and clinical features of a large cohort of CCM3 patients. Molecular screening for point mutations and deletions was used to identify 54 CCM3-mutated index patients. Age at referral and clinical onset, type of inaugural events and presence of extra-axial lesions were investigated in these 54 index patients and 22 of their mutated relatives. Mean age at clinical onset was 23.0 +/- 16 years. Clinical onset occurred before 10 years in 26% of the patients, and cerebral hemorrhage was the initial presentation in 72% of these patients. Multiple extra-axial, dural-based lesions were detected in 7 unrelated patients. These lesions proved to be meningiomas in 3 patients who underwent neurosurgery and pathological examination. This 'multiple meningiomas' phenotype is not associated with a specific CCM3 mutation. Hence, CCM3 mutations are associated with a high risk of early-onset cerebral hemorrhage and with the presence of multiple meningiomas. PMID- 23801933 TI - Germline Mutations in RASA1 Are Not Found in Patients with Klippel-Trenaunay Syndrome or Capillary Malformation with Limb Overgrowth. AB - The RASA1 gene encodes p120RASGAP, a multidomain cytoplasmic protein that acts as a negative regulator of the RAS signalling pathway. Heterozygous loss-of-function RASA1 mutations were identified in patients with Parkes Weber syndrome and multifocal capillary malformations. This syndrome is characterised by a capillary blush on an extremity, arteriovenous microfistulas, and bony and soft tissue hypertrophy. The aim of this study was to test RASA1 in 2 disorders characterised by asymmetric limb enlargement and vascular malformations, namely Klippel Trenaunay syndrome and regional capillary malformation with overgrowth. We did not identify any clear pathogenic change in these patients. Thus, besides clinical and radiological criteria, RASA1 testing constitutes an additional tool to differentiate Parkes Weber syndrome of capillary malformation-arteriovenous malformation (CM-AVM) from overlapping disorders. PMID- 23801934 TI - Variable Somatic TIE2 Mutations in Half of Sporadic Venous Malformations. AB - Venous malformations (VMs) are the most frequent vascular malformations referred to specialized vascular anomaly centers. A rare (1-2%) familial form, termed cutaneomucosal venous malformation (VMCM), is caused by gain-of-function mutations in TIE2. More recently, sporadic VMs, characterized by the presence of large unifocal lesions, were shown to be caused by somatic mutations in TIE2. These include a frequent L914F change, and a series of double mutations in cis. All of which cause ligand-independent receptor hyperphosphorylation in vitro. Here, we expanded our study to assess the range of mutations that cause sporadic VM. To test for somatic changes, we screened the entire coding region of TIE2 in cDNA from resected VMs by direct sequencing. We detected TIE2 mutations in 17/30 (56.7%) of the samples. In addition to previously detected mutations, we identified 7 novel somatic intracellular TIE2 mutations in sporadic VMs, including 3 that cause premature protein truncation. PMID- 23801935 TI - Directional next-generation RNA sequencing and examination of premature termination codon mutations in endoglin/hereditary haemorrhagic telangiectasia. AB - Hereditary haemorrhagic telangiectasia (HHT) is a disease characterised by abnormal vascular structures, and most commonly caused by mutations in ENG, ACVRL1 or SMAD4 encoding endothelial cell-expressed proteins involved in TGF-beta superfamily signalling. The majority of mutations reported on the HHT mutation database are predicted to lead to stop codons, either due to frameshifts or direct nonsense substitutions. The proportion is higher for ENG (67%) and SMAD4 (65%) than for ACVRL1 (42%), p < 0.0001. Here, by focussing on ENG, we report why conventional views of these mutations may need to be revised. Of the 111 stop codon-generating ENG mutations, on ExPASy translation, all except one were premature termination codons (PTCs), sited at least 50-55 bp upstream of the final exon-exon boundary of the main endoglin isoform, L-endoglin. This strongly suggests that the mutated RNA species will undergo nonsense-mediated decay. We provide new in vitro expression data to support dominant negative activity of stable truncated endoglin proteins but suggest these will not generate HHT: the single natural stop codon mutation in L-endoglin (sited within 50-55 nucleotides of the final exon-exon boundary) is unlikely to generate functional protein since it replaces the entire transmembrane domain, as would 8 further natural stop codon mutations, if the minor S-endoglin isoform were implicated in HHT pathogenesis. Finally, next-generation RNA sequencing data of 7 different RNA libraries from primary human endothelial cells demonstrate that multiple intronic regions of ENG are transcribed. The potential consequences of heterozygous deletions or duplications of such regions are discussed. These data support the haploinsufficiency model for HHT pathogenesis, explain why final exon mutations have not been detected to date in HHT, emphasise the potential need for functional examination of non-PTC-generating mutations, and lead to proposals for an alternate stratification system of mutational types for HHT genotype-phenotype correlations. PMID- 23801936 TI - Aicardi syndrome associated with autosomal genomic imbalance: coincidence or evidence for autosomal inheritance with sex-limited expression? AB - Aicardi syndrome (AIS), a rare neurodevelopmental disorder thought to be caused by an X-linked dominant mutation, is characterized by 3 main features: agenesis of corpus callosum, infantile spams and chorioretinal lacunae. A genome-wide study of a girl with AIS lead us to identify a 6q deletion;12q duplication, derived from a maternal 6q;12q translocation. The two intellectually impaired brothers of the proband showed the same genomic anomalies, but not the constellation of features characterizing the AIS. This could be either a coincidental observation of 2 rare conditions, but can also suggest an alternative hypothesis for the genetic etiology of AIS, indicating the existence of a subset of autosomal genes whose mutation could act in a sex-confined manner. PMID- 23801937 TI - Mucopolysaccharidosis Type II and the G374sp Mutation. AB - Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, is a rare, X-linked disease caused by a deficiency of the lysosomal enzyme iduronate-2 sulfatase, which catalyses a step in the catabolism of glycosaminoglycans resulting in accumulation of heparan and dermatan sulfate in many organs and tissues. This accumulation favors the appearance of neurologic involvement, severe airway obstruction, skeletal deformities, and cardiomyopathy, especially mitral and aortic valve regurgitation. In severe cases, obstructive airway disease and cardiac failure due to valvular dysfunction are the most common causes of death within the second decade of life. However, in mild cases, intelligence remains normal, stature is almost normal and death usually occurs due to cardiac failure in the fourth decade of life. We report the presentation, diagnosis, management, and outcome of 2 siblings with MPS II and the G374sp mutation at the nucleotide c.1246 of the gene encoding for the iduronate-2 sulfatase. PMID- 23801938 TI - Alagille Syndrome: A New Missense Mutation Detected by Whole-Exome Sequencing in a Case Previously Found to Be Negative by DHPLC and MLPA. AB - Alagille syndrome (ALGS, MIM 118450) is an autosomal dominant, multisystem disorder with high variability. Two genes have been described: JAG1 and NOTCH2. The population prevalence is 1:70,000 based on the presence of neonatal liver disease. The majority of cases (~97%) are caused by haploinsufficiency of the JAG1 gene on 20p11.2p12, either due to mutations or deletions at the locus. Less than 1% of cases are caused by mutations in NOTCH2. The most widely used methods for mutational screening include denaturing high-performance liquid chromatography (DHPLC) and multiplex ligation-dependent probe amplification (MLPA). Very recently, whole-exome sequencing (WES) has become technically feasible due to the recent advances in next-generation sequencing technologies, therefore offering new opportunities for mutations/genes identification. A proband and its family, negative for the presence of mutations in JAG1 and NOTCH2 genes by neither DHPLC nor MLPA, were analyzed by WES. A missense mutation, not previously described, in JAG1 gene was identified. This result shows an improvement in the mutation detection rate due to novel sequencing technology suggesting the strong need to reanalyze all negative cases. PMID- 23801941 TI - A Hebbian learning rule gives rise to mirror neurons and links them to control theoretic inverse models. AB - Mirror neurons are neurons whose responses to the observation of a motor act resemble responses measured during production of that act. Computationally, mirror neurons have been viewed as evidence for the existence of internal inverse models. Such models, rooted within control theory, map-desired sensory targets onto the motor commands required to generate those targets. To jointly explore both the formation of mirrored responses and their functional contribution to inverse models, we develop a correlation-based theory of interactions between a sensory and a motor area. We show that a simple eligibility-weighted Hebbian learning rule, operating within a sensorimotor loop during motor explorations and stabilized by heterosynaptic competition, naturally gives rise to mirror neurons as well as control theoretic inverse models encoded in the synaptic weights from sensory to motor neurons. Crucially, we find that the correlational structure or stereotypy of the neural code underlying motor explorations determines the nature of the learned inverse model: random motor codes lead to causal inverses that map sensory activity patterns to their motor causes; such inverses are maximally useful, by allowing the imitation of arbitrary sensory target sequences. By contrast, stereotyped motor codes lead to less useful predictive inverses that map sensory activity to future motor actions. Our theory generalizes previous work on inverse models by showing that such models can be learned in a simple Hebbian framework without the need for error signals or backpropagation, and it makes new conceptual connections between the causal nature of inverse models, the statistical structure of motor variability, and the time-lag between sensory and motor responses of mirror neurons. Applied to bird song learning, our theory can account for puzzling aspects of the song system, including necessity of sensorimotor gating and selectivity of auditory responses to bird's own song (BOS) stimuli. PMID- 23801939 TI - Serotonin homeostasis and serotonin receptors as actors of cortical construction: special attention to the 5-HT3A and 5-HT6 receptor subtypes. AB - Cortical circuits control higher-order cognitive processes and their function is highly dependent on their structure that emerges during development. The construction of cortical circuits involves the coordinated interplay between different types of cellular processes such as proliferation, migration, and differentiation of neural and glial cell subtypes. Among the multiple factors that regulate the assembly of cortical circuits, 5-HT is an important developmental signal that impacts on a broad diversity of cellular processes. 5 HT is detected at the onset of embryonic telencephalic formation and a variety of serotonergic receptors are dynamically expressed in the embryonic developing cortex in a region and cell-type specific manner. Among these receptors, the ionotropic 5-HT3A receptor and the metabotropic 5-HT6 receptor have recently been identified as novel serotonergic targets regulating different aspects of cortical construction including neuronal migration and dendritic differentiation. In this review, we focus on the developmental impact of serotonergic systems on the construction of cortical circuits and discuss their potential role in programming risk for human psychiatric disorders. PMID- 23801940 TI - Autism as early neurodevelopmental disorder: evidence for an sAPPalpha-mediated anabolic pathway. AB - Autism is a neurodevelopmental disorder marked by social skills and communication deficits and interfering repetitive behavior. Intellectual disability often accompanies autism. In addition to behavioral deficits, autism is characterized by neuropathology and brain overgrowth. Increased intracranial volume often accompanies this brain growth. We have found that the Alzheimer's disease (AD) associated amyloid-beta precursor protein (APP), especially its neuroprotective processing product, secreted APP alpha, is elevated in persons with autism. This has led to the "anabolic hypothesis" of autism etiology, in which neuronal overgrowth in the brain results in interneuronal misconnections that may underlie multiple autism symptoms. We review the contribution of research in brain volume and of APP to the anabolic hypothesis, and relate APP to other proteins and pathways that have already been directly associated with autism, such as fragile X mental retardation protein, Ras small GTPase/extracellular signal-regulated kinase, and phosphoinositide 3 kinase/protein kinase B/mammalian target of rapamycin. We also present additional evidence of magnetic resonance imaging intracranial measurements in favor of the anabolic hypothesis. Finally, since it appears that APP's involvement in autism is part of a multi-partner network, we extend this concept into the inherently interactive realm of epigenetics. We speculate that the underlying molecular abnormalities that influence APP's contribution to autism are epigenetic markers overlaid onto potentially vulnerable gene sequences due to environmental influence. PMID- 23801942 TI - Multineuronal spike sequences repeat with millisecond precision. AB - Cortical microcircuits are nonrandomly wired by neurons. As a natural consequence, spikes emitted by microcircuits are also nonrandomly patterned in time and space. One of the prominent spike organizations is a repetition of fixed patterns of spike series across multiple neurons. However, several questions remain unsolved, including how precisely spike sequences repeat, how the sequences are spatially organized, how many neurons participate in sequences, and how different sequences are functionally linked. To address these questions, we monitored spontaneous spikes of hippocampal CA3 neurons ex vivo using a high speed functional multineuron calcium imaging (fMCI) technique that allowed us to monitor spikes with millisecond resolution and to record the location of spiking and non-spiking neurons. Multineuronal spike sequences (MSSs) were overrepresented in spontaneous activity compared to the statistical chance level. Approximately 75% of neurons participated in at least one sequence during our observation period. The participants were sparsely dispersed and did not show specific spatial organization. The number of sequences relative to the chance level decreased when larger time frames were used to detect sequences. Thus, sequences were precise at the millisecond level. Sequences often shared common spikes with other sequences; parts of sequences were subsequently relayed by following sequences, generating complex chains of multiple sequences. PMID- 23801944 TI - Oscillatory activity, phase differences, and phase resetting in the inferior olivary nucleus. AB - The generation of temporal patterns is one of the most fascinating functions of the brain. Unlike the response to external stimuli temporal patterns are generated within the system and recalled for a specific use. To generate temporal patterns one needs a timing machine, a "master clock" that determines the temporal framework within which temporal patterns can be generated and implemented. Here we present the concept that in this putative "master clock" phase and frequency interact to generate temporal patterns. We define the requirements for a neuronal "master clock" to be both reliable and versatile. We introduce this concept within the inferior olive nucleus which at least by some scientists is regarded as the source of timing for cerebellar function. We review the basic properties of the subthreshold oscillation recorded from olivary neurons, analyze the phase relationships between neurons and demonstrate that the phase and onset of oscillation is tightly controlled by synaptic input. These properties endowed the olivary nucleus with the ability to act as a "master clock." PMID- 23801943 TI - Enhanced representation of spectral contrasts in the primary auditory cortex. AB - The role of early auditory processing may be to extract some elementary features from an acoustic mixture in order to organize the auditory scene. To accomplish this task, the central auditory system may rely on the fact that sensory objects are often composed of spectral edges, i.e., regions where the stimulus energy changes abruptly over frequency. The processing of acoustic stimuli may benefit from a mechanism enhancing the internal representation of spectral edges. While the visual system is thought to rely heavily on this mechanism (enhancing spatial edges), it is still unclear whether a related process plays a significant role in audition. We investigated the cortical representation of spectral edges, using acoustic stimuli composed of multi-tone pips whose time-averaged spectral envelope contained suppressed or enhanced regions. Importantly, the stimuli were designed such that neural responses properties could be assessed as a function of stimulus frequency during stimulus presentation. Our results suggest that the representation of acoustic spectral edges is enhanced in the auditory cortex, and that this enhancement is sensitive to the characteristics of the spectral contrast profile, such as depth, sharpness and width. Spectral edges are maximally enhanced for sharp contrast and large depth. Cortical activity was also suppressed at frequencies within the suppressed region. To note, the suppression of firing was larger at frequencies nearby the lower edge of the suppressed region than at the upper edge. Overall, the present study gives critical insights into the processing of spectral contrasts in the auditory system. PMID- 23801945 TI - Flow parsing and heading perception show similar dependence on quality and quantity of optic flow. AB - Here we examine the relationship between the perception of heading and flow parsing. In a companion study we have investigated the pattern of dependence of human heading estimation on the quantity (amount of dots per frame) and quality (amount of directional noise) of motion information in an optic flow field. In the present study we investigated whether the flow parsing mechanism, which is thought to aid in the assessment of scene-relative object movement during observer movement, exhibits a similar pattern of dependence on these stimulus manipulations. Finding that the pattern of flow parsing effects was similar to that observed for heading thresholds would provide some evidence that these two complementary roles for optic flow processing are reliant on the same, or similar, neural computation. We found that the pattern of flow parsing effects observed does indeed display a striking similarity to the heading thresholds. As with judgements of heading, there is a critical value of around 25 dots per frame; below this value flow parsing effects rapidly deteriorate and above this value flow parsing effects are stable [see Warren et al. (1988) for similar results for heading]. Also, as with judgements of heading, when there were 50 or more dots there was a systematic effect of noise on the magnitude of the flow parsing effect. These results are discussed in the context of different possible schemes of flow processing to support both heading and flow parsing mechanisms. PMID- 23801946 TI - Heading recovery from optic flow: comparing performance of humans and computational models. AB - Human observers can perceive their direction of heading with a precision of about a degree. Several computational models of the processes underpinning the perception of heading have been proposed. In the present study we set out to assess which of four candidate models best captured human performance; the four models we selected reflected key differences in terms of approach and methods to modelling optic flow processing to recover movement parameters. We first generated a performance profile for human observers by measuring how performance changed as we systematically manipulated both the quantity (number of dots in the stimulus per frame) and quality (amount of 2D directional noise) of the flow field information. We then generated comparable performance profiles for the four candidate models. Models varied markedly in terms of both their performance and similarity to human data. To formally assess the match between the models and human performance we regressed the output of each of the four models against human performance data. We were able to rule out two models that produced very different performance profiles to human observers. The remaining two shared some similarities with human performance profiles in terms of the magnitude and pattern of thresholds. However none of the models tested could capture all aspect of the human data. PMID- 23801947 TI - Acetaldehyde involvement in ethanol's postabsortive effects during early ontogeny. AB - Clinical and biomedical studies sustains the notion that early ontogeny is a vulnerable window to the impact of alcohol. Experiences with the drug during these stages increase latter disposition to prefer, use or abuse ethanol. This period of enhanced sensitivity to ethanol is accompanied by a high rate of activity in the central catalase system, which metabolizes ethanol in the brain. Acetaldehyde (ACD), the first oxidation product of ethanol, has been found to share many neurobehavioral effects with the drug. Cumulative evidence supports this notion in models employing adults. Nevertheless very few studies have been conducted to analyze the role of ACD in ethanol postabsorptive effects, in newborns or infant rats. In this work we review recent experimental literature that syndicates ACD as a mediator agent of reinforcing aspects of ethanol, during early ontogenetic stages. We also show a meta-analytical correlational approach that proposes how differences in the activity of brain catalase across ontogeny, could be modulating patterns of ethanol consumption. PMID- 23801948 TI - Acetaldehyde and parkinsonism: role of CYP450 2E1. AB - The present review update the relationship between acetaldehyde (ACE) and parkinsonism with a specific focus on the role of P450 system and CYP 2E1 isozyme particularly. We have indicated that ACE is able to enhance the parkinsonism induced in mice by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a neurotoxin able to damage the nigrostriatal dopaminergic pathway. Similarly diethyldithiocarbamate, the main metabolite of disulfiram, a drug widely used to control alcoholism, diallylsulfide (DAS) and phenylisothiocyanate also markedly enhance the toxin-related parkinsonism. All these compounds are substrate/inhibitors of CYP450 2E1 isozyme. The presence of CYP 2E1 has been detected in the dopamine (DA) neurons of rodent Substantia Nigra (SN), but a precise function of the enzyme has not been elucidated yet. By treating CYP 2E1 knockout (KO) mice with the neurotoxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine, the SN induced lesion was significantly reduced when compared with the lesion observed in wild-type animals. Several in vivo and in vitro studies led to the conclusion that CYP 2E1 may enhance the 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine toxicity in mice by increasing free radical production inside the dopaminergic neurons. ACE is a good substrate for CYP 2E1 enzyme as the other substrate-inhibitors and by this way may facilitate the susceptibility of dopaminergic neurons to toxic events. The literature suggests that ethanol and/or disulfiram may be responsible for toxic parkinsonism in human and it indicates that basal ganglia are the major targets of disulfiram toxicity. A very recent study reports that there are a decreased methylation of the CYP 2E1 gene and increased expression of CYP 2E1 mRNA in Parkinson's disease (PD) patient brains. This study suggests that epigenetic variants of this cytochrome contribute to the susceptibility, thus confirming multiples lines of evidence which indicate a link between environmental toxins and PD. PMID- 23801949 TI - The prelimbic cortex is critical for context-dependent fear expression. AB - The ability to regulate emotional responses in various circumstances would provide adaptive advantages for an individual. Using a context-dependent fear discrimination (CDFD) task in which the tone conditioned stimulus (CS) is paired with the footshock unconditioned stimulus (US) in one context but presented alone in another context, we investigated the role of the prelimbic (PL) cortex in contextual modulation of the conditioned fear response. After 3 days of CDFD training, rats froze more to the CS presented in the fearful than in the safe context. Following bilateral lesions of the PL, rats showed similar levels of freezing to the CS in both contexts, in contrast to the sham-lesioned control animals. The lesions did not impair the rats' ability to discriminate contexts per se, as indicated by intact differential responses in a separate experiment which employed a simple context discrimination task. Consistent with the lesion data, single-unit recordings from the PL showed that the majority of CS responsive neurons fired at a higher rate in the fearful context than in the safe context, paralleling the behavioral discrimination. Taken together, the current results suggest that the PL is involved in selective expression of conditioned fear to an explicit (tone) cue that is fully dependent on contextual information. PMID- 23801950 TI - The modulation of somatosensory resonance by psychopathic traits and empathy. AB - A large number of neuroimaging studies have shown neural overlaps between first hand experiences of pain and the perception of pain in others. This shared neural representation of vicarious pain is thought to involve both affective and sensorimotor systems. A number of individual factors are thought to modulate the cerebral response to other's pain. The goal of this study was to investigate the impact of psychopathic traits on the relation between sensorimotor resonance to other's pain and self-reported empathy. Our group has previously shown that a steady-state response to non-painful stimulation is modulated by the observation of other people's bodily pain. This change in somatosensory response was interpreted as a form of somatosensory gating (SG). Here, using the same technique, SG was compared between two groups of 15 young adult males: one scoring very high on a self-reported measure of psychopathic traits [60.8 +/- 4.98; Levenson's Self-Report Psychopathy Scale (LSRP)] and one scoring very low (42.7 +/- 2.94). The results showed a significantly greater reduction of SG to pain observation for the high psychopathic traits group compared to the low psychopathic traits group. SG to pain observation was positively correlated with affective and interpersonal facet of psychopathy in the whole sample. The high psychopathic traits group also reported lower empathic concern (EC) scores than the low psychopathic traits group. Importantly, primary psychopathy, as assessed by the LSRP, mediated the relation between EC and SG to pain observation. Together, these results suggest that increase somatosensory resonance to other's pain is not exclusively explained by trait empathy and may be linked to other personality dimensions, such as psychopathic traits. PMID- 23801951 TI - Context counts! social anxiety modulates the processing of fearful faces in the context of chemosensory anxiety signals. AB - During emotion perception, context is an important source of information. Whether contextual cues from modalities other than vision or audition influence the perception of social emotional information has not been investigated. Thus, the present study aimed at testing emotion perception and regulation in response to fearful facial expressions presented in the context of chemosensory stimuli derived from sweat of anxious individuals. In groups of high (HSA) and low socially anxious (LSA) participants we recorded the startle reflex (Experiment I), and analysed event-related potentials (ERPs; Experiment II) while they viewed anxious facial expressions in the context of chemosensory anxiety signals and chemosensory control stimuli. Results revealed that N1/P1 and N170 amplitudes were larger while late positive potential (LPP) activity was smaller for facial expressions presented in the context of the anxiety and the chemosensory control stimulus as compared to facial expressions without a chemosensory context. Furthermore, HSA participants were highly sensitive to the contextual anxiety signals. They showed enhanced motivated attention allocation (LPP, Study II), as well as larger startle responses toward faces in the context of chemosensory anxiety signals than did LSA participants (Study I). Chemosensory context had no effect on emotion regulation, and both LSA and HSA participants showed effective emotion regulation (Study I and II). In conclusion, both anxiety and chemosensory sport context stimuli enhanced early attention allocation and structural encoding, but diminished motivated attention allocation to the facial expressions. The current results show that visual and chemosensory information is integrated on virtually all levels of stimulus processing and that socially anxious individuals might be especially sensitive to chemosensory contextual social information. PMID- 23801952 TI - Acute khat use reduces response conflict in habitual users. AB - Khat consumption has become a worldwide phenomenon broadening from Eastern Africa and the south west of the Arabian Peninsula to ethnic communities in the rest of the world. So far, the cognitive effects of khat use are poorly understood and no studies have looked into the relation between acute khat use and cognitive control functions, the way we control our thoughts and goal directed behavior. We studied how acute khat use affects the emergence and the resolution of response conflict, a central cognitive control function. Khat users (n = 11) and khat-free controls (n = 18) were matched in terms of education, sex, alcohol, and cannabis consumption. Groups were tested on response conflict, as measured by the Simon task. In one single session, participants worked through two task blocks: the khat group chewed exclusively khat whereas the khat-free group chewed solely a gum. Results showed that in the second block, which reflects the acute impact of khat, the khat group was better than controls in resolving stimulus-induced response conflict as indexed by a smaller Simon effect. These results suggest that the acute intake of khat may improve participants' ability of handling response conflict. PMID- 23801953 TI - Pain and (e)motion in postural responses. PMID- 23801954 TI - Essentializing the binary self: individualism and collectivism in cultural neuroscience. AB - Within the emerging field of cultural neuroscience (CN) one branch of research focuses on the neural underpinnings of "individualistic/Western" vs. "collectivistic/Eastern" self-views. These studies uncritically adopt essentialist assumptions from classic cross-cultural research, mainly following the tradition of Markus and Kitayama (1991), into the domain of functional neuroimaging. In this perspective article we analyze recent publications and conference proceedings of the 18th Annual Meeting of the Organization for Human Brain Mapping (2012) and problematize the essentialist and simplistic understanding of "culture" in these studies. Further, we argue against the binary structure of the drawn "cultural" comparisons and their underlying Eurocentrism. Finally we scrutinize whether valuations within the constructed binarities bear the risk of constructing and reproducing a postcolonial, orientalist argumentation pattern. PMID- 23801955 TI - The largest human cognitive performance dataset reveals insights into the effects of lifestyle factors and aging. AB - Making new breakthroughs in understanding the processes underlying human cognition may depend on the availability of very large datasets that have not historically existed in psychology and neuroscience. Lumosity is a web-based cognitive training platform that has grown to include over 600 million cognitive training task results from over 35 million individuals, comprising the largest existing dataset of human cognitive performance. As part of the Human Cognition Project, Lumosity's collaborative research program to understand the human mind, Lumos Labs researchers and external research collaborators have begun to explore this dataset in order uncover novel insights about the correlates of cognitive performance. This paper presents two preliminary demonstrations of some of the kinds of questions that can be examined with the dataset. The first example focuses on replicating known findings relating lifestyle factors to baseline cognitive performance in a demographically diverse, healthy population at a much larger scale than has previously been available. The second example examines a question that would likely be very difficult to study in laboratory-based and existing online experimental research approaches at a large scale: specifically, how learning ability for different types of cognitive tasks changes with age. We hope that these examples will provoke the imagination of researchers who are interested in collaborating to answer fundamental questions about human cognitive performance. PMID- 23801956 TI - Posterior cortical atrophy: visuomotor deficits in reaching and grasping. AB - Posterior Cortical Atrophy (PCA) is a rare clinical syndrome characterized by the predominance of higher-order visual disturbances such as optic ataxia, a characteristic of Balint's syndrome. Deficits result from progressive neurodegeneration of occipito-temporal and occipito-parietal cortices. The current study sought to explore the visuomotor functioning of four individuals with PCA by testing their ability to reach out and grasp real objects under various viewing conditions. Experiment 1 had participants reach out and grasp simple, rectangular blocks under visually- and memory-guided conditions. Experiment 2 explored participants' abilities to accurately reach for objects located in their visual periphery. This investigation revealed that PCA patients demonstrate many of the same deficits that have been previously reported in other individuals with optic ataxia, such as "magnetic misreaching"-a pathological reaching bias toward the point of visual fixation when grasping peripheral targets. Unlike many other individuals with optic ataxia, however, the patients in the current study also show symptoms indicative of damage to the more perceptual stream of visual processing, including abolished grip scaling during memory-guided grasping and deficits in face and object identification. These investigations are the first to perform a quantitative analysis of the visuomotor deficits exhibited by patients with PCA. Critically, this study helps characterize common symptoms of PCA, a vital first step for generating effective diagnostic criteria and therapeutic strategies for this understudied neurodegenerative disorder. PMID- 23801957 TI - Perceiving blocks of emotional pictures and sounds: effects on physiological variables. AB - Most studies on physiological effects of emotion-inducing images and sounds examine stimulus locked variables reflecting a state of at most a few seconds. We here aimed to induce longer lasting emotional states using blocks of repetitive visual, auditory, and bimodal stimuli corresponding to specific valence and arousal levels. The duration of these blocks enabled us to reliably measure heart rate variability as a possible indicator of arousal. In addition, heart rate and skin conductance were determined without taking stimulus timing into account. Heart rate was higher for pleasant and low arousal stimuli compared to unpleasant and high arousal stimuli. Heart rate variability and skin conductance increased with arousal. Effects of valence and arousal on cardiovascular measures habituated or remained the same over 2-min intervals whereas the arousal effect on skin conductance increased. We did not find any effect of stimulus modality. Our results indicate that blocks of images and sounds of specific valence and arousal levels consistently influence different physiological parameters. These parameters need not be stimulus locked. We found no evidence for differences in emotion induction between visual and auditory stimuli, nor did we find bimodal stimuli to be more potent than unimodal stimuli. The latter could be (partly) due to the fact that our bimodal stimuli were not optimally congruent. PMID- 23801958 TI - Pain and body awareness: evidence from brain-damaged patients with delusional body ownership. AB - A crucial aspect for the cognitive neuroscience of pain is the interplay between pain perception and body awareness. Here we report a novel neuropsychological condition in which right brain-damaged patients displayed a selective monothematic delusion of body ownership. Specifically, when both their own and the co-experimenter's left arms were present, these patients claimed that the latter belonged to them. We reasoned that this was an ideal condition to examine whether pain perception can be "referred" to an alien arm subjectively experienced as one's own. Seventeen patients (11 with, 6 without the delusion), and 10 healthy controls were administered a nociceptive stimulation protocol to assess pain perception. In the OWN condition, participants placed their arms on a table in front of them. In the ALIEN condition, the co-experimenter's left (or right) arm was placed alongside the participants' left (or right) arm, respectively. In the OWN condition, left (or right) participants' hand dorsum were stimulated. In the ALIEN condition, left (or right) co-experimenter's hand dorsum was stimulated. Participants had to rate the perceived pain on a 0-5 Likert scale (0 = no pain, 5 = maximal imaginable pain). Results showed that healthy controls and patients without delusion gave scores higher than zero only when their own hands were stimulated. On the contrary, patients with delusion gave scores higher than zero both when their own hands (left or right) were stimulated and when the co-experimenter's left hand was stimulated. Our results show that in pathological conditions, a body part of another person can become so deeply embedded in one's own somatosensory representation to effect the subjective feeling of pain. More in general, our findings are in line with a growing number of evidence emphasizing the role of the special and unique perceptual status of body ownership in giving rise to the phenomenological experience of pain. PMID- 23801959 TI - Dynamic primitives in the control of locomotion. AB - Humans achieve locomotor dexterity that far exceeds the capability of modern robots, yet this is achieved despite slower actuators, imprecise sensors, and vastly slower communication. We propose that this spectacular performance arises from encoding motor commands in terms of dynamic primitives. We propose three primitives as a foundation for a comprehensive theoretical framework that can embrace a wide range of upper- and lower-limb behaviors. Building on previous work that suggested discrete and rhythmic movements as elementary dynamic behaviors, we define submovements and oscillations: as discrete movements cannot be combined with sufficient flexibility, we argue that suitably-defined submovements are primitives. As the term "rhythmic" may be ambiguous, we define oscillations as the corresponding class of primitives. We further propose mechanical impedances as a third class of dynamic primitives, necessary for interaction with the physical environment. Combination of these three classes of primitive requires care. One approach is through a generalized equivalent network: a virtual trajectory composed of simultaneous and/or sequential submovements and/or oscillations that interacts with mechanical impedances to produce observable forces and motions. Reliable experimental identification of these dynamic primitives presents challenges: identification of mechanical impedances is exquisitely sensitive to assumptions about their dynamic structure; identification of submovements and oscillations is sensitive to their assumed form and to details of the algorithm used to extract them. Some methods to address these challenges are presented. Some implications of this theoretical framework for locomotor rehabilitation are considered. PMID- 23801960 TI - Signal enhancement in the output stage of the basal ganglia by synaptic short term plasticity in the direct, indirect, and hyperdirect pathways. AB - Many of the synapses in the basal ganglia display short-term plasticity. Still, computational models have not yet been used to investigate how this affects signaling. Here we use a model of the basal ganglia network, constrained by available data, to quantitatively investigate how synaptic short-term plasticity affects the substantia nigra reticulata (SNr), the basal ganglia output nucleus. We find that SNr becomes particularly responsive to the characteristic burst-like activity seen in both direct and indirect pathway striatal medium spiny neurons (MSN). As expected by the standard model, direct pathway MSNs are responsible for decreasing the activity in SNr. In particular, our simulations indicate that bursting in only a few percent of the direct pathway MSNs is sufficient for completely inhibiting SNr neuron activity. The standard model also suggests that SNr activity in the indirect pathway is controlled by MSNs disinhibiting the subthalamic nucleus (STN) via the globus pallidus externa (GPe). Our model rather indicates that SNr activity is controlled by the direct GPe-SNr projections. This is partly because GPe strongly inhibits SNr but also due to depressing STN-SNr synapses. Furthermore, depressing GPe-SNr synapses allow the system to become sensitive to irregularly firing GPe subpopulations, as seen in dopamine depleted conditions, even when the GPe mean firing rate does not change. Similar to the direct pathway, simulations indicate that only a few percent of bursting indirect pathway MSNs can significantly increase the activity in SNr. Finally, the model predicts depressing STN-SNr synapses, since such an assumption explains experiments showing that a brief transient activation of the hyperdirect pathway generates a tri-phasic response in SNr, while a sustained STN activation has minor effects. This can be explained if STN-SNr synapses are depressing such that their effects are counteracted by the (known) depressing GPe-SNr inputs. PMID- 23801961 TI - Learning and prospective recall of noisy spike pattern episodes. AB - Spike patterns in vivo are often incomplete or corrupted with noise that makes inputs to neuronal networks appear to vary although they may, in fact, be samples of a single underlying pattern or repeated presentation. Here we present a recurrent spiking neural network (SNN) model that learns noisy pattern sequences through the use of homeostasis and spike-timing dependent plasticity (STDP). We find that the changes in the synaptic weight vector during learning of patterns of random ensembles are approximately orthogonal in a reduced dimension space when the patterns are constructed to minimize overlap in representations. Using this model, representations of sparse patterns maybe associated through co activated firing and integrated into ensemble representations. While the model is tolerant to noise, prospective activity, and pattern completion differ in their ability to adapt in the presence of noise. One version of the model is able to demonstrate the recently discovered phenomena of preplay and replay reminiscent of hippocampal-like behaviors. PMID- 23801964 TI - Henry et al. (2012) homing failure formula, assumptions, and basic mathematics: a comment. PMID- 23801963 TI - Proton-dependent inhibition of the cardiac sodium channel Nav1.5 by ranolazine. AB - Ranolazine is clinically approved for treatment of angina pectoris and is a potential candidate for antiarrhythmic, antiepileptic, and analgesic applications. These therapeutic effects of ranolazine hinge on its ability to inhibit persistent or late Na(+) currents in a variety of voltage-gated sodium channels. Extracellular acidosis, typical of ischemic events, may alter the efficiency of drug/channel interactions. In this study, we examined pH modulation of ranolazine's interaction with the cardiac sodium channel, Nav1.5. We performed whole-cell path clamp experiments at extracellular pH 7.4 and 6.0 on Nav1.5 transiently expressed in HEK293 cell line. Consistent with previous studies, we found that ranolazine induced a stable conformational state in the cardiac sodium channel with onset/recovery kinetics and voltage-dependence resembling intrinsic slow inactivation. This interaction diminished the availability of the channels in a voltage- and use-dependent manner. Low extracellular pH impaired inactivation states leading to an increase in late Na(+) currents. Ranolazine interaction with the channel was also slowed 4-5 fold. However, ranolazine restored the voltage-dependent steady-state availability profile, thereby reducing window/persistent currents at pH 6.0 in a manner comparable to pH 7.4. These results suggest that ranolazine is effective at therapeutically relevant concentrations (10 MUM), in acidic extracellular pH, where it compensates for impaired native slow inactivation. PMID- 23801965 TI - Partitioning of heat production in growing pigs as a tool to improve the determination of efficiency of energy utilization. AB - In growing pigs, the feed cost accounts for more than 60% of total production costs. The determination of efficiency of energy utilization through calorimetry measurements is of importance to sustain suitable feeding practice. The objective of this paper is to describe a methodology to correct daily heat production (HP) obtained from measurements in respiration chamber for the difference in energy expenditure related to physical activity between animals. The calculation is based on a preliminary published approach for partitioning HP between HP due to physical activity (AHP), thermic effect of feeding (TEF) and basal metabolic rate (fasting HP; FHP). Measurements with male growing pigs [mean body weight (BW): 115 kg] which were surgically castrated (SC), castrated through immunization against GnRH (IC), or kept as entire male (EM) were used as an example. Animals were fed the same diet ad-libitum and were housed individually in two 12-m(3) open-circuit respiration chambers during 6 days when fed ad-libitum and one supplementary day when fasted. Physical activity was recorded through interruption of an infrared beam to detect standing and lying positions and with force transducers that recorded the mechanical force the animal exerted on the floor of the cage. Corrected AHP (AHPc), TEF (TEFc), and HP (HPc) were calculated to standardize the level of AHP between animals, assuming that the ratio between AHPc and ME intake should be constant. Inefficiency of energy utilization (sum of AHPc and TEFc) was lower than the inefficiency estimated from the slope of the classical relationship between HPc and ME intake but was associated with higher requirements for maintenance. Results indicate that EM pigs had higher FHP but lower TEFc than IC and SC pigs. These results agree with the higher contents in viscera of EM pigs that stimulate their basal metabolic rate and with the reduced utilization of dietary protein to provide energy for maintenance energy requirements and fat deposition (FD). PMID- 23801962 TI - Modeling Alzheimer's disease: from past to future. AB - Alzheimer's disease (AD) is emerging as the most prevalent and socially disruptive illness of aging populations, as more people live long enough to become affected. Although AD is placing a considerable and increasing burden on society, it represents the largest unmet medical need in neurology, because current drugs improve symptoms, but do not have profound disease-modifying effects. Although AD pathogenesis is multifaceted and difficult to pinpoint, genetic and cell biological studies led to the amyloid hypothesis, which posits that amyloid beta (Abeta) plays a pivotal role in AD pathogenesis. Amyloid precursor protein (APP), as well as beta- and gamma-secretases are the principal players involved in Abeta production, while alpha-secretase cleavage on APP prevents Abeta deposition. The association of early onset familial AD with mutations in the APP and gamma-secretase components provided a potential tool of generating animal models of the disease. However, a model that recapitulates all the aspects of AD has not yet been produced. Here, we face the problem of modeling AD pathology describing several models, which have played a major role in defining critical disease-related mechanisms and in exploring novel potential therapeutic approaches. In particular, we will provide an extensive overview on the distinct features and pros and contras of different AD models, ranging from invertebrate to rodent models and finally dealing with computational models and induced pluripotent stem cells. PMID- 23801966 TI - Mitochondria and FOXO3: breath or die. AB - Forkhead box O (FOXO) transcription factors are regulators of cell-type specific apoptosis and cell cycle arrest but also control longevity and reactive oxygen species (ROS). ROS-control by FOXO is mediated by transcriptional activation of detoxifying enzymes such as Superoxide dismutase 2 (SOD2), Catalase or Sestrins or by the repression of mitochondrial respiratory chain proteins resulting in reduced mitochondrial activity. FOXO3 also regulates the adaptation to hypoxia by reducing mitochondrial mass and oxygen consumption during HIF-1alpha activation. In neuronal tumor cells, FOXO3 triggers ROS-accumulation as a consequence of transient mitochondrial outer membrane permeabilization, which is essential for FOXO3-induced apoptosis in these cells. Cellular ROS levels are affected by the FOXO-targets Bim, BclxL, and Survivin. All three proteins localize to mitochondria and affect mitochondrial membrane potential, respiration and cellular ROS levels. Bim-activation by FOXO3 causes mitochondrial depolarization resulting in a transitory decrease of respiration and ROS production. Survivin, on the other hand, actively changes mitochondrial architecture, respiration efficacy and energy metabolism. This ability distinguishes Survivin from other anti-apoptotic proteins such as BclxL, which inhibits ROS by inactivating Bim but does not alter mitochondrial function. Importantly, FOXO3 simultaneously also activates ROS-detoxification via induction of SESN3. In this paper we discuss the hypothesis that the delicate balance between ROS-accumulation by Bim-triggered mitochondrial damage, mitochondrial architecture and ROS-detoxifying proteins determines cell fate. We provide evidence for a FOXO self-reactivating loop and for novel functions of FOXO3 in controlling mitochondrial respiration of neuronal cells, which further supports the current view that FOXO transcription factors are information-integrating sentinels of cellular stress and critical modulators of cell homeostasis. PMID- 23801967 TI - Microarray gene expression profiling reveals antioxidant-like effects of angiotensin II inhibition in atherosclerosis. AB - Reactive oxygen species (ROS) is a significant feature of atherosclerosis but the impact of ROS on atherogenesis is not clear since antioxidants such as vitamin E have little effect on atherosclerosis development in vivo. To investigate the role of ROS in atherosclerosis, we used ApoE-deficient mice, and compared the treatment effect of the antioxidant vitamin E with that of the angiotensin converting enzyme (ACE) inhibitor, captopril, because angiotensin II is a major source of ROS in the vasculature. Dihydroethidium (DHE) staining demonstrated that vitamin E and captopril both prevented the atherosclerosis-induced increase in aortic superoxide content. In contrast, seven months of vitamin E treatment retarded the development of atherosclerotic lesions by only 45.8 +/- 11.5% whereas captopril reduced the aortic plaque area by 88.1 +/- 7.5%. To discriminate between vitamin E-sensitive and -insensitive effects of ACE inhibition, we performed whole genome microarray gene expression profiling. Gene ontology (GO) and immunohistology analyses showed that vitamin E and captopril prevented atherosclerosis-related changes of aortic intima and media genes. However, vitamin E did not reduce the expression of probe sets detecting the aortic recruitment of pro-inflammatory immune cells while immune cell-specific genes were normalized by captopril treatment. Moreover, vitamin E did not prevent the atherosclerosis-dependent down-regulation of perivascular nerve-specific genes, which were preserved in captopril-treated aortas. Taken together, our study detected antioxidant vitamin E-like effects of angiotensin II inhibition in atherosclerosis treatment regarding preservation of aortic intima and media genes. Additional vitamin E-insensitive effects targeting atherosclerosis enhancing aortic immune cell recruitment and perivascular nerve degeneration could account for the stronger anti-atherogenic activity of ACE inhibition compared to vitamin E. PMID- 23801968 TI - Implicit Associations and Explicit Expectancies toward Cannabis in Heavy Cannabis Users and Controls. AB - Cognitive biases, including implicit memory associations are thought to play an important role in the development of addictive behaviors. The aim of the present study was to investigate implicit affective memory associations in heavy cannabis users. Implicit positive-arousal, sedation, and negative associations toward cannabis were measured with three Single Category Implicit Association Tests (SC IAT's) and compared between 59 heavy cannabis users and 89 controls. Moreover, we investigated the relationship between these implicit affective associations and explicit expectancies, subjective craving, cannabis use, and cannabis related problems. Results show that heavy cannabis users had stronger implicit positive arousal associations but weaker implicit negative associations toward cannabis compared to controls. Moreover, heavy cannabis users had stronger sedation but weaker negative explicit expectancies toward cannabis compared to controls. Within heavy cannabis users, more cannabis use was associated with stronger implicit negative associations whereas more cannabis use related problems was associated with stronger explicit negative expectancies, decreasing the overall difference on negative associations between cannabis users and controls. No other associations were observed between implicit associations, explicit expectancies, measures of cannabis use, cannabis use related problems, or subjective craving. These findings indicate that, in contrast to other substances of abuse like alcohol and tobacco, the relationship between implicit associations and cannabis use appears to be weak in heavy cannabis users. PMID- 23801969 TI - Learning to ignore salient color distractors during serial search: evidence for experience-dependent attention allocation strategies. AB - Previous research has investigated whether visual salience (i.e., how much an item stands out) or perceptual load (i.e., display complexity) is the dominant factor in visual selective attention. The evidence has been mixed, with some findings supporting a dominant role for visual salience and some findings supporting a dominant role for perceptual load. However, the complex displays used to impose high perceptual load also introduce a third factor that has gone understudied until recently: the interplay between identity dilution and exposure duration. Adding display items to increase perceptual load dilutes a distractor's identity, which could decrease interference, but the task generally takes longer, which could increase distractor interference. To clarify how these factors interact, the present study used converging measures of distractor interference both compatibility and singleton presence-to disambiguate effects due to salience, perceptual load, and identity dilution/exposure duration. Compatibility effects support perceptual load as the dominant factor, whereas singleton presence effects do not (Experiment 1). Consistent with salience-based mechanisms, significant distractor processing (both compatibility and presence effects) occurred under high perceptual load when singleton present trials preceded singleton absent trials (Experiment 2A). However, consistent with load based mechanisms, non-significant compatibility effects occurred under high perceptual load when singleton absent trials preceded singleton present trials (Experiment 2B). Thus, the competition between salience-based and load-based mechanisms depended on the amount of prior experience with singleton present vs. absent displays, which in turn depended on the use of broad vs. narrow attentional allocation strategies. These experience-dependent effects provide further evidence that attention allocation strategies are contingent on factors such as task context and experience. PMID- 23801970 TI - Age-related changes in visual exploratory behavior in a natural scene setting. AB - Diverse cognitive functions decline with increasing age, including the ability to process central and peripheral visual information in a laboratory testing situation (useful visual field of view). To investigate whether and how this influences activities of daily life, we studied age-related changes in visual exploratory behavior in a natural scene setting: a driving simulator paradigm of variable complexity was tested in subjects of varying ages with simultaneous eye- and head-movement recordings via a head-mounted camera. Detection and reaction times were also measured by visual fixation and manual reaction. We considered video computer game experience as a possible influence on performance. Data of 73 participants of varying ages were analyzed, driving two different courses. We analyzed the influence of route difficulty level, age, and eccentricity of test stimuli on oculomotor and driving behavior parameters. No significant age effects were found regarding saccadic parameters. In the older subjects head-movements increasingly contributed to gaze amplitude. More demanding courses and more peripheral stimuli locations induced longer reaction times in all age groups. Deterioration of the functionally useful visual field of view with increasing age was not suggested in our study group. However, video game-experienced subjects revealed larger saccade amplitudes and a broader distribution of fixations on the screen. They reacted faster to peripheral objects suggesting the notion of a general detection task rather than perceiving driving as a central task. As the video game-experienced population consisted of younger subjects, our study indicates that effects due to video game experience can easily be misinterpreted as age effects if not accounted for. We therefore view it as essential to consider video game experience in all testing methods using virtual media. PMID- 23801971 TI - Prediction and imitation in speech. AB - It has been suggested that intra- and inter-speaker variability in speech are correlated. Interlocutors have been shown to converge on various phonetic dimensions. In addition, speakers imitate the phonetic properties of voices they are exposed to in shadowing, repetition, and even passive listening tasks. We review three theoretical accounts of speech imitation and convergence phenomena: (i) the Episodic Theory (ET) of speech perception and production (Goldinger, 1998); (ii) the Motor Theory (MT) of speech perception (Liberman and Whalen, 2000; Galantucci et al., 2006); (iii) Communication Accommodation Theory (CAT; Giles and Coupland, 1991; Giles et al., 1991). We argue that no account is able to explain all the available evidence. In particular, there is a need to integrate low-level, mechanistic accounts (like ET and MT), and higher-level accounts (like CAT). We propose that this is possible within the framework of an integrated theory of production and comprehension (Pickering and Garrod, 2013). Similarly to both ET and MT, this theory assumes parity between production and perception. Uniquely, however, it posits that listeners simulate speakers' utterances by computing forward-model predictions at many different levels, which are then compared to the incoming phonetic input. In our account phonetic imitation can be achieved via the same mechanism that is responsible for sensorimotor adaptation; i.e., the correction of prediction errors. In addition, the model assumes that the degree to which sensory prediction errors lead to motor adjustments is context-dependent. The notion of context subsumes both the preceding linguistic input and non-linguistic attributes of the situation (e.g., the speaker's and listener's social identities, their conversational roles, the listener's intention to imitate). PMID- 23801972 TI - Perception of emotionally loaded vocal expressions and its connection to responses to music. A cross-cultural investigation: Estonia, Finland, Sweden, Russia, and the USA. AB - The present study focused on voice quality and the perception of the basic emotions from speech samples in cross-cultural conditions. It was examined whether voice quality, cultural, or language background, age, or gender were related to the identification of the emotions. Professional actors (n2) and actresses (n2) produced non-sense sentences (n32) and protracted vowels (n8) expressing the six basic emotions, interest, and a neutral emotional state. The impact of musical interests on the ability to distinguish between emotions or valence (on an axis positivity - neutrality - negativity) from voice samples was studied. Listening tests were conducted on location in five countries: Estonia, Finland, Russia, Sweden, and the USA with 50 randomly chosen participants (25 males and 25 females) in each country. The participants (total N = 250) completed a questionnaire eliciting their background information and musical interests. The responses in the listening test and the questionnaires were statistically analyzed. Voice quality parameters and the share of the emotions and valence identified correlated significantly with each other for both genders. The percentage of emotions and valence identified was clearly above the chance level in each of the five countries studied, however, the countries differed significantly from each other for the identified emotions and the gender of the speaker. The samples produced by females were identified significantly better than those produced by males. Listener's age was a significant variable. Only minor gender differences were found for the identification. Perceptual confusion in the listening test between emotions seemed to be dependent on their similar voice production types. Musical interests tended to have a positive effect on the identification of the emotions. The results also suggest that identifying emotions from speech samples may be easier for those listeners who share a similar language or cultural background with the speaker. PMID- 23801973 TI - Valence, arousal, and task effects in emotional prosody processing. AB - Previous research suggests that emotional prosody processing is a highly rapid and complex process. In particular, it has been shown that different basic emotions can be differentiated in an early event-related brain potential (ERP) component, the P200. Often, the P200 is followed by later long lasting ERPs such as the late positive complex. The current experiment set out to explore in how far emotionality and arousal can modulate these previously reported ERP components. In addition, we also investigated the influence of task demands (implicit vs. explicit evaluation of stimuli). Participants listened to pseudo sentences (sentences with no lexical content) spoken in six different emotions or in a neutral tone of voice while they either rated the arousal level of the speaker or their own arousal level. Results confirm that different emotional intonations can first be differentiated in the P200 component, reflecting a first emotional encoding of the stimulus possibly including a valence tagging process. A marginal significant arousal effect was also found in this time-window with high arousing stimuli eliciting a stronger P200 than low arousing stimuli. The P200 component was followed by a long lasting positive ERP between 400 and 750 ms. In this late time-window, both emotion and arousal effects were found. No effects of task were observed in either time-window. Taken together, results suggest that emotion relevant details are robustly decoded during early processing and late processing stages while arousal information is only reliably taken into consideration at a later stage of processing. PMID- 23801974 TI - How much imitation is there in a shadowing task? AB - Phonetic imitation, also called phonetic convergence, is currently at the heart of numerous investigations since it can inform us on both the nature of lexical representations and the link between production and perception processes in spoken language communication. A task that has been largely used to study phonetic imitation is the shadowing task, in which participants merely listen to and repeat isolated words. In this study, we examined the extent to which the phonetic convergence effect found when participants shadow auditory tokens, is an imitation of the speaker. We thus compared the phonetic convergence effect observed in a shadowing task to that observed when participants were explicitly instructed to imitate the productions they were exposed to. Although the phonetic convergence effect was greater when participants intentionally imitated the speaker's productions, shadowing and imitation instructions led to the same degree of convergence in a post-exposure task. Hence, the convergence effect found in a shadowing task and that found in an imitation task seem to share a general mechanism which is automatic and which taps into the long-term representations of the words in memory. At a more theoretical level, our results reinforce the claim that detailed auditory traces associated with perceived words are stored in memory and are later used for production. PMID- 23801975 TI - The brain basis of musicophilia: evidence from frontotemporal lobar degeneration. AB - Musicophilia, or abnormal craving for music, is a poorly understood phenomenon that has been associated in particular with focal degeneration of the temporal lobes. Here we addressed the brain basis of musicophilia using voxel-based morphometry (VBM) on MR volumetric brain images in a retrospectively ascertained cohort of patients meeting clinical consensus criteria for frontotemporal lobar degeneration: of 37 cases ascertained, 12 had musicophilia, and 25 did not exhibit the phenomenon. The syndrome of semantic dementia was relatively over represented among the musicophilic subgroup. A VBM analysis revealed significantly increased regional gray matter volume in left posterior hippocampus in the musicophilic subgroup relative to the non-musicophilic group (p < 0.05 corrected for regional comparisons); at a relaxed significance threshold (p < 0.001 uncorrected across the brain volume) musicophilia was associated with additional relative sparing of regional gray matter in other temporal lobe and prefrontal areas and atrophy of gray matter in posterior parietal and orbitofrontal areas. The present findings suggest a candidate brain substrate for musicophilia as a signature of distributed network damage that may reflect a shift of hedonic processing toward more abstract (non-social) stimuli, with some specificity for particular neurodegenerative pathologies. PMID- 23801976 TI - Child implant users' imitation of happy- and sad-sounding speech. AB - Cochlear implants have enabled many congenitally or prelingually deaf children to acquire their native language and communicate successfully on the basis of electrical rather than acoustic input. Nevertheless, degraded spectral input provided by the device reduces the ability to perceive emotion in speech. We compared the vocal imitations of 5- to 7-year-old deaf children who were highly successful bilateral implant users with those of a control sample of children who had normal hearing. First, the children imitated several happy and sad sentences produced by a child model. When adults in Experiment 1 rated the similarity of imitated to model utterances, ratings were significantly higher for the hearing children. Both hearing and deaf children produced poorer imitations of happy than sad utterances because of difficulty matching the greater pitch modulation of the happy versions. When adults in Experiment 2 rated electronically filtered versions of the utterances, which obscured the verbal content, ratings of happy and sad utterances were significantly differentiated for deaf as well as hearing children. The ratings of deaf children, however, were significantly less differentiated. Although deaf children's utterances exhibited culturally typical pitch modulation, their pitch modulation was reduced relative to that of hearing children. One practical implication is that therapeutic interventions for deaf children could expand their focus on suprasegmental aspects of speech perception and production, especially intonation patterns. PMID- 23801977 TI - Delaying gratification depends on social trust. AB - Delaying gratification is hard, yet predictive of important life outcomes, such as academic achievement and physical health. Prominent theories focus on the role of self-control, hypersensitivity to immediate rewards, and the cost of time spent waiting. However, delaying gratification may also require trust in people delivering future rewards as promised. To test the role of social trust, participants were presented with character vignettes and faces that varied in trustworthiness, and then choose between hypothetical smaller immediate or larger delayed rewards from those characters. Across two experiments, participants were less willing to wait for delayed rewards from less trustworthy characters, and perceived trustworthiness predicted willingness to delay gratification. These findings provide the first demonstration of a causal role for social trust in willingness to delay gratification, independent of other relevant factors, such as self-control or reward history. Thus, delaying gratification requires choosing not only a later reward, but a reward that is potentially less likely to be delivered, when there is doubt about the person promising it. Implications of this work include the need to revise prominent theories of delay of gratification, and new directions for interventions with populations characterized by impulsivity. PMID- 23801978 TI - Contour integration and aging: the effects of element spacing, orientation alignment and stimulus duration. AB - The ability to extract contours in cluttered visual scenes, which is a crucial step in visual processing, declines with healthy aging, but the reasons for this decline are not well understood. In three experiments, we examined how the effect of aging on contour discrimination varies as a function of contour and distracter inter-element spacing, collinearity, and stimulus duration. Spiral-shaped contours composed of Gabors were embedded within a field of distracter Gabors of uniform density. In a four alternative forced-choice task, younger and older subjects were required to report the global orientation of the contour. In Experiment 1, the absolute contour element spacing varied from two to eight times the Gabor wavelength and contour element collinearity was disrupted with five levels of orientation jitter. Contour discrimination accuracy was lower in older subjects, but the effect of aging did not vary with contour spacing or orientation jitter. Experiment 2 found that decreasing stimulus durations from 0.8 to 0.04 s had a greater effect on older subjects' performance, but only for less salient contours. Experiment 3 examined the effect of the background on contour discrimination by varying the spacing and orientation of the distracter elements for contours with small and large absolute spacing. As in Experiment, the effect of aging did not vary with absolute contour spacing. Decreasing the distracter spacing, however, had a greater detrimental effect on accuracy in older subjects compared to younger subjects. Finally, both groups showed equally high accuracy when all distracters were iso-oriented. In sum, these findings suggest that aging does not affect the sensitivity of contour integration to proximity or collinearity. However, contour integration in older adults is slower and is especially vulnerable when distracters are denser than contour elements. PMID- 23801979 TI - Adaptation improves face trustworthiness discrimination. AB - Adaptation to facial characteristics, such as gender and viewpoint, has been shown to both bias our perception of faces and improve facial discrimination. In this study, we examined whether adapting to two levels of face trustworthiness improved sensitivity around the adapted level. Facial trustworthiness was manipulated by morphing between trustworthy and untrustworthy prototypes, each generated by morphing eight trustworthy and eight untrustworthy faces, respectively. In the first experiment, just-noticeable differences (JNDs) were calculated for an untrustworthy face after participants adapted to an untrustworthy face, a trustworthy face, or did not adapt. In the second experiment, the three conditions were identical, except that JNDs were calculated for a trustworthy face. In the third experiment we examined whether adapting to an untrustworthy male face improved discrimination to an untrustworthy female face. In all experiments, participants completed a two-interval forced-choice (2 IFC) adaptive staircase procedure, in which they judged which face was more untrustworthy. JNDs were derived from a psychometric function fitted to the data. Adaptation improved sensitivity to faces conveying the same level of trustworthiness when compared to no adaptation. When adapting to and discriminating around a different level of face trustworthiness there was no improvement in sensitivity and JNDs were equivalent to those in the no adaptation condition. The improvement in sensitivity was found to occur even when adapting to a face with different gender and identity. These results suggest that adaptation to facial trustworthiness can selectively enhance mechanisms underlying the coding of facial trustworthiness to improve perceptual sensitivity. These findings have implications for the role of our visual experience in the decisions we make about the trustworthiness of other individuals. PMID- 23801981 TI - How to quantify individuality in music performance? Studying artistic expression with averaging procedures. PMID- 23801980 TI - Gated audiovisual speech identification in silence vs. noise: effects on time and accuracy. AB - This study investigated the degree to which audiovisual presentation (compared to auditory-only presentation) affected isolation point (IPs, the amount of time required for the correct identification of speech stimuli using a gating paradigm) in silence and noise conditions. The study expanded on the findings of Moradi et al. (under revision), using the same stimuli, but presented in an audiovisual instead of an auditory-only manner. The results showed that noise impeded the identification of consonants and words (i.e., delayed IPs and lowered accuracy), but not the identification of final words in sentences. In comparison with the previous study by Moradi et al., it can be concluded that the provision of visual cues expedited IPs and increased the accuracy of speech stimuli identification in both silence and noise. The implication of the results is discussed in terms of models for speech understanding. PMID- 23801982 TI - Interhemispheric vs. stimulus-response spatial compatibility effects in bimanual reaction times to lateralized visual stimuli. AB - In the present study, we tested right- and left-handed participants in a Poffenberger paradigm with bimanual responses and hands either in an anatomical or in a left-right inverted posture. We observed a significant positive crossed uncrossed difference (CUD) in RTs for both manual dominance groups and both response postures. These results rule out an explanation of the CUD in terms of stimulus-response spatial compatibility (SRSC) and provide convincing evidence on the important role of interhemispheric callosal transfer in bimanual responding in right- as well as left-handed individuals. PMID- 23801984 TI - Adenosine inhibits the excitatory synaptic inputs to Basal forebrain cholinergic, GABAergic, and parvalbumin neurons in mice. AB - Coffee and tea contain the stimulants caffeine and theophylline. These compounds act as antagonists of adenosine receptors. Adenosine promotes sleep and its extracellular concentration rises in association with prolonged wakefulness, particularly in the basal forebrain (BF) region involved in activating the cerebral cortex. However, the effect of adenosine on identified BF neurons, especially non-cholinergic neurons, is incompletely understood. Here we used whole-cell patch-clamp recordings in mouse brain slices prepared from two validated transgenic mouse lines with fluorescent proteins expressed in GABAergic or parvalbumin (PV) neurons to determine the effect of adenosine. Whole-cell recordings were made from BF cholinergic neurons and from BF GABAergic and PV neurons with the size (>20 MUm) and intrinsic membrane properties (prominent H currents) corresponding to cortically projecting neurons. A brief (2 min) bath application of adenosine (100 MUM) decreased the frequency but not the amplitude of spontaneous excitatory postsynaptic currents (EPSCs) in all groups of BF cholinergic, GABAergic, and PV neurons we recorded. In addition, adenosine decreased the frequency of miniature EPSCs in BF cholinergic neurons. Adenosine had no effect on the frequency of spontaneous inhibitory postsynaptic currents in cholinergic neurons or GABAergic neurons with large H-currents but reduced them in a group of GABAergic neurons with smaller H-currents. All effects of adenosine were blocked by a selective, adenosine A1 receptor antagonist, cyclopentyltheophylline (CPT, 1 MUM). Adenosine had no postsynaptic effects. Taken together, our work suggests that adenosine promotes sleep by an A1 receptor mediated inhibition of glutamatergic inputs to cortically projecting cholinergic and GABA/PV neurons. Conversely, caffeine and theophylline promote attentive wakefulness by inhibiting these A1 receptors in BF thereby promoting the high frequency oscillations in the cortex required for attention and cognition. PMID- 23801985 TI - A meta-analysis of soil microbial biomass responses to forest disturbances. AB - Climate warming is likely to increase the frequency and severity of forest disturbances, with uncertain consequences for soil microbial communities and their contribution to ecosystem C dynamics. To address this uncertainty, we conducted a meta-analysis of 139 published soil microbial responses to forest disturbances. These disturbances included abiotic (fire, harvesting, storm) and biotic (insect, pathogen) disturbances. We hypothesized that soil microbial biomass would decline following forest disturbances, but that abiotic disturbances would elicit greater reductions in microbial biomass than biotic disturbances. In support of this hypothesis, across all published studies, disturbances reduced soil microbial biomass by an average of 29.4%. However, microbial responses differed between abiotic and biotic disturbances. Microbial responses were significantly negative following fires, harvest, and storms (48.7, 19.1, and 41.7% reductions in microbial biomass, respectively). In contrast, changes in soil microbial biomass following insect infestation and pathogen induced tree mortality were non-significant, although biotic disturbances were poorly represented in the literature. When measured separately, fungal and bacterial responses to disturbances mirrored the response of the microbial community as a whole. Changes in microbial abundance following disturbance were significantly positively correlated with changes in microbial respiration. We propose that the differential effect of abiotic and biotic disturbances on microbial biomass may be attributable to differences in soil disruption and organic C removal from forests among disturbance types. Altogether, these results suggest that abiotic forest disturbances may significantly decrease soil microbial abundance, with corresponding consequences for microbial respiration. Further studies are needed on the effect of biotic disturbances on forest soil microbial communities and soil C dynamics. PMID- 23801986 TI - Tropical freshwater ecosystems have lower bacterial growth efficiency than temperate ones. AB - Current models and observations indicate that bacterial respiration should increase and growth efficiency (BGE) should decrease with increasing temperatures. However, these models and observations are mostly derived from data collected in temperate regions, and the tropics are under-represented. The aim of this work was to compare bacterial metabolism, namely bacterial production (BP) and respiration (BR), bacterial growth efficiency (BGE) and bacterial carbon demand (BCD) between tropical and temperate ecosystems via a literature review and using unpublished data. We hypothesized that (1) tropical ecosystems have higher metabolism than temperate ones and, (2) that BGE is lower in tropical relative to temperate ecosystems. We collected a total of 498 coupled BP and BR observations (N total = 498; N temperate = 301; N tropical = 197), calculated BGE (BP/(BP+BR)) and BCD (BP+BR) for each case and examined patterns using a model II regression analysis and compared each parameter between the two regions using non parametric Mann-Whitney U test. We observed a significant positive linear regression between BR and BP for the whole dataset, and also for tropical and temperate data separately. We found that BP, BR and BCD were higher in the tropics, but BGE was lower compared to temperate regions. Also, BR rates per BP unit were at least two fold higher in the tropics than in temperate ecosystems. We argue that higher temperature, nutrient limitation, and light exposure all contribute to lower BGE in the tropics, mediated through effects on thermodynamics, substrate stoichiometry, nutrient availability and interactions with photochemically produced compounds. More efforts are needed in this study area in the tropics, but our work indicates that bottom-up (nutrient availability and resource stoichiometry) and top-down (grazer pressure) processes, coupled with thermodynamic constraints, might contribute to the lower BGE in the tropics relative to temperate regions. PMID- 23801983 TI - Trinucleotide repeats: a structural perspective. AB - Trinucleotide repeat (TNR) expansions are present in a wide range of genes involved in several neurological disorders, being directly involved in the molecular mechanisms underlying pathogenesis through modulation of gene expression and/or the function of the RNA or protein it encodes. Structural and functional information on the role of TNR sequences in RNA and protein is crucial to understand the effect of TNR expansions in neurodegeneration. Therefore, this review intends to provide to the reader a structural and functional view of TNR and encoded homopeptide expansions, with a particular emphasis on polyQ expansions and its role at inducing the self-assembly, aggregation and functional alterations of the carrier protein, which culminates in neuronal toxicity and cell death. Detail will be given to the Machado-Joseph Disease-causative and polyQ-containing protein, ataxin-3, providing clues for the impact of polyQ expansion and its flanking regions in the modulation of ataxin-3 molecular interactions, function, and aggregation. PMID- 23801987 TI - Multilocus sequence analysis of Thermoanaerobacter isolates reveals recombining, but differentiated, populations from geothermal springs of the Uzon Caldera, Kamchatka, Russia. AB - Thermal environments have island-like characteristics and provide a unique opportunity to study population structure and diversity patterns of microbial taxa inhabiting these sites. Strains having >=98% 16S rRNA gene sequence similarity to the obligately anaerobic Firmicutes Thermoanaerobacter uzonensis were isolated from seven geothermal springs, separated by up to 1600 m, within the Uzon Caldera (Kamchatka, Russian Far East). The intraspecies variation and spatial patterns of diversity for this taxon were assessed by multilocus sequence analysis (MLSA) of 106 strains. Analysis of eight protein-coding loci (gyrB, lepA, leuS, pyrG, recA, recG, rplB, and rpoB) revealed that all loci were polymorphic and that nucleotide substitutions were mostly synonymous. There were 148 variable nucleotide sites across 8003 bp concatenates of the protein-coding loci. While pairwise F ST values indicated a small but significant level of genetic differentiation between most subpopulations, there was a negligible relationship between genetic divergence and spatial separation. Strains with the same allelic profile were only isolated from the same hot spring, occasionally from consecutive years, and single locus variant (SLV) sequence types were usually derived from the same spring. While recombination occurred, there was an "epidemic" population structure in which a particular T. uzonensis sequence type rose in frequency relative to the rest of the population. These results demonstrate spatial diversity patterns for an anaerobic bacterial species in a relative small geographic location and reinforce the view that terrestrial geothermal springs are excellent places to look for biogeographic diversity patterns regardless of the involved distances. PMID- 23801988 TI - Ca(2+) signaling in T-cell subsets with a focus on the role of cav1 channels: possible implications in therapeutics. PMID- 23801989 TI - Dendritic cells in the periphery control antigen-specific natural and induced regulatory T cells. AB - Dendritic cells (DCs) are specialized antigen-presenting cells that regulate both immunity and tolerance. DCs in the periphery play a key role in expanding naturally occurring Foxp3(+) CD25(+) CD4(+) regulatory T cells (Natural T-regs) and inducing Foxp3 expression (Induced T-regs) in Foxp3(-) CD4(+) T cells. DCs are phenotypically and functionally heterogeneous, and further classified into several subsets depending on distinct marker expression and their location. Recent findings indicate the presence of specialized DC subsets that act to expand Natural T-regs or induce Foxp3(+) T-regs from Foxp3(-) CD4(+) T cells. For example, two major subsets of DCs in lymphoid organs act differentially in inducing Foxp3(+) T-regs from Foxp3(-) cells or expanding Natural T-regs with model-antigen delivery by anti-DC subset monoclonal antibodies in vivo. Furthermore, DCs expressing CD103 in the intestine induce Foxp3(+) T-regs from Foxp3(-) CD4(+) T cells with endogenous TGF-beta and retinoic acid. In addition, antigen-presenting DCs have a capacity to generate Foxp3(+) T-regs in the oral cavity where many antigens and commensals exist, similar to intestine and skin. In skin and skin-draining lymph nodes, at least six DC subsets have been identified, suggesting a complex DC-T-reg network. Here, we will review the specific activity of DCs in expanding Natural T-regs and inducing Foxp3(+) T-regs from Foxp3(-) precursors, and further discuss the critical function of DCs in maintaining tolerance at various locations including skin and oral cavity. PMID- 23801990 TI - Generation and function of induced regulatory T cells. AB - CD4(+) CD25(+) Foxp3(+) regulatory T (Treg) cells are essential to the balance between pro- and anti-inflammatory responses. There are two major subsets of Treg cells, "natural" Treg (nTreg) cells that develop in the thymus, and "induced" Treg (iTreg) cells that arise in the periphery from CD4(+) Foxp3(-) conventional T cells and can be generated in vitro. Previous work has established that both subsets are required for immunological tolerance. Additionally, in vitro-derived iTreg cells can reestablish tolerance in situations where Treg cells are decreased or defective. This review will focus on iTreg cells, drawing comparisons to nTreg cells when possible. We discuss the molecular mechanisms of iTreg cell induction, both in vivo and in vitro, review the Foxp3-dependent and independent transcriptional landscape of iTreg cells, and examine the proposed suppressive mechanisms utilized by each Treg cell subset. We also compare the T cell receptor repertoire of the Treg cell subsets, discuss inflammatory conditions where iTreg cells are generated or have been used for treatment, and address the issue of iTreg cell stability. PMID- 23801991 TI - Molecular insights for optimizing T cell receptor specificity against cancer. AB - Cytotoxic CD8 T cells mediate immunity to pathogens and they are able to eliminate malignant cells. Immunity to viruses and bacteria primarily involves CD8 T cells bearing high affinity T cell receptors (TCRs), which are specific to pathogen-derived (non-self) antigens. Given the thorough elimination of high affinity self/tumor-antigen reactive T cells by central and peripheral tolerance mechanisms, anti-cancer immunity mostly depends on TCRs with intermediate-to-low affinity for self-antigens. Because of this, a promising novel therapeutic approach to increase the efficacy of tumor-reactive T cells is to engineer their TCRs, with the aim to enhance their binding kinetics to pMHC complexes, or to directly manipulate the TCR-signaling cascades. Such manipulations require a detailed knowledge on how pMHC-TCR and co-receptors binding kinetics impact the T cell response. In this review, we present the current knowledge in this field. We discuss future challenges in identifying and targeting the molecular mechanisms to enhance the function of natural or TCR-affinity optimized T cells, and we provide perspectives for the development of protective anti-tumor T cell responses. PMID- 23801993 TI - Interferon gamma in leishmaniasis. AB - Leishmaniasis is a complex disease that is caused by parasites of the Leishmania genus. Leishmania are further classified into several complexes, each of which can engage in distinct interactions with mammalian hosts resulting in differing disease presentations. It is therefore not unexpected that host immune responses to Leishmania are variable. The induction of interferon gamma (IFN-gamma) and response to it in these infections has received considerable attention. In this review, we summarize our current understanding of some of the host responses during Leishmania infections that are regulated by IFN-gamma. In addition, studies that explore the nature of parasite-derived molecular mediators that might affect the host response to IFN-gamma are also discussed. PMID- 23801992 TI - Role of cytokines in thymus- versus peripherally derived-regulatory T cell differentiation and function. AB - CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) are essential players in the control of immune responses. Recently, accordingly to their origin, two main subsets of Tregs have been described: thymus-derived Tregs (tTregs) and peripherally derived Tregs (pTregs). Numerous signaling pathways including the IL 2/STAT5 or the TGF-beta/Smad3 pathways play a crucial role in segregating the two lineages. Here, we review some of the information existing on the distinct requirements of IL-2, TGF-beta, and TNF-alpha three major cytokines involved in tTreg and pTreg generation, homeostasis and function. Today it is clear that signaling via the IL-2Rbeta chain (CD122) common to IL-2 and IL-15 is required for proper differentiation of tTregs and for tTreg and pTreg survival in the periphery. This notion has led to the development of promising therapeutic strategies based on low-dose IL-2 administration to boost the patients' own Treg compartment and dampen autoimmunity and inflammation. Also, solid evidence points to TGF-beta as the master regulator of pTreg differentiation and homeostasis. However, therapeutic administration of TGF-beta is difficult to implement due to toxicity and safety issues. Knowledge on the role of TNF-alpha on the biology of Tregs is fragmentary and inconsistent between mice and humans. Moreover, emerging results from the clinical use of TNF-alpha inhibitors indicate that part of their anti-inflammatory effect may be dependent on their action on Tregs. Given the profusion of clinical trials testing cytokine administration or blocking to modulate inflammatory diseases, a better knowledge of the effects of cytokines on tTregs and pTregs biology is necessary to improve the efficiency of these immunotherapies. PMID- 23801994 TI - Skin-resident antigen-presenting cells: instruction manual for vaccine development. AB - The induction of antigen-specific effector T cells is driven by proper antigen presentation and co-stimulation by dendritic cells (DCs). For this reason strategies have been developed to instruct DCs for the induction of CD4(+) and CD8(+) T cell responses. Since DCs are localized, amongst other locations, in peripheral tissues such as the skin, new vaccines are aiming at targeting antigens to DCs in situ. Optimal skin-DC targeting in combination with adequate adjuvant delivery facilitates DC maturation and migration to draining lymph nodes and enhances antigen cross-presentation and T cell priming. In this review we describe what DC subsets populate the human skin, as well as current vaccination strategies based on targeting strategies and alternative administration for the induction of robust long-lived anti-cancer effector T cells. PMID- 23801995 TI - Control of uterine microenvironment by foxp3(+) cells facilitates embryo implantation. AB - Implantation of the fertilized egg into the maternal uterus depends on the fine balance between inflammatory and anti-inflammatory processes. Whilst regulatory T cells (Tregs) are reportedly involved in protection of allogeneic fetuses against rejection by the maternal immune system, their role for pregnancy to establish, e.g., blastocyst implantation, is not clear. By using 2-photon imaging we show that Foxp3(+) cells accumulated in the mouse uterus during the receptive phase of the estrus cycle. Seminal fluid further fostered Treg expansion. Depletion of Tregs in two Foxp3.DTR-based models prior to pairing drastically impaired implantation and resulted in infiltration of activated T effector cells as well as in uterine inflammation and fibrosis in both allogeneic and syngeneic mating combinations. Genetic deletion of the homing receptor CCR7 interfered with accumulation of Tregs in the uterus and implantation indicating that homing of Tregs to the uterus was mediated by CCR7. Our results demonstrate that Tregs play a critical role in embryo implantation by preventing the development of a hostile uterine microenvironment. PMID- 23801997 TI - Increased Spironolactone in Advanced Heart Failure: Effect of Doses Greater than 25 mg/Day on Plasma Potassium Concentration. AB - BACKGROUND: Daily doses of spironolactone higher than 25 mg are rarely used in heart failure (HF) patients, presumably due to the concern for hyperkalemia. However, in advanced HF, doses >=50 mg have been found to be necessary to produce natriuresis. The aim of the present study was to examine the safety of natriuretic doses of spironolactone (50-200 mg) on serum potassium concentration in New York Heart Association (NYHA) class III/IV HF patients over several weeks. METHODS: 18 patients with advanced HF received 50-200 mg of spironolactone in addition to standard treatment. Serum electrolytes, BUN and serum creatinine were assessed at baseline, during increased doses of spironolactone and at the 1-month follow-up. RESULTS: During a total of 738 patient-weeks, there was no significant increase in mean serum potassium (4.0 vs. 4.2 mEq/l) or serum creatinine (1.3 vs. 1.4 mg/dl). However, in 3 patients, spironolactone treatment was stopped due to a mean increase in serum creatinine (1.9 vs. 2.6 mg/dl) and in one of them, an increase in serum potassium (4.4 vs. 5.2 mEq/l) was noted. CONCLUSION: Increased doses of spironolactone are generally safe during outpatient follow-up in selected patients with advanced HF, who are receiving treatment with ACE inhibitors, beta-blockers, and loop diuretics. PMID- 23801996 TI - Natural killer cells in asthma. AB - The worldwide prevalence, morbidity, and mortality of asthma have dramatically increased over the last few decades and there is a clear need to identify new effective therapeutic and prophylactic strategies. Despite high numbers of NK cells in the lung and their ability to generate a variety of immunomodulatory mediators, the potential of NK cells as therapeutic targets in allergic airway disease has been largely overlooked. The fact that IgE, acting through FcgammaRIII, can activate NK cells resulting in cytokine/chemokine production implies that NK cells may contribute to IgE-mediated allergic responses. Indeed, current evidence suggests that NK cells can promote allergic airway responses during sensitization and ongoing inflammation. In animal models, increased NK cells are observed in the lung following antigen challenge and depletion of the cells before immunization inhibits allergic airway inflammation. Moreover, in asthmatics, NK cell phenotype is altered and may contribute to the promotion of a pro-inflammatory Th2-type environment. Conversely, driving NK cells toward an IFN gamma-secreting phenotype can reduce features of the allergic airway response in animal models. However, we have limited knowledge of the signals that drive the development of distinct subsets and functional phenotypes of NK cells in the lung and thus the role and therapeutic potential of NK cells in the allergic airway remains unclear. Here we review the potentially diverse role of NK cells in allergic airway disease, identify gaps in current knowledge, and discuss the potential of modulating NK cell function as a treatment strategy in asthma. PMID- 23801998 TI - A Comparison of Traditional and Novel Definitions (RIFLE, AKIN, and KDIGO) of Acute Kidney Injury for the Prediction of Outcomes in Acute Decompensated Heart Failure. AB - AIMS: To determine if newer criteria for diagnosing and staging acute kidney injury (AKI) during heart failure (HF) admission are more predictive of clinical outcomes at 30 days and 1 year than the traditional worsening renal function (WRF) definition. METHODS: We analyzed prospectively collected clinical data on 637 HF admissions with 30-day and 1-year follow-up. The incidence, stages, and outcomes of AKI were determined using the following four definitions: KDIGO, RIFLE, AKIN, and WRF (serum creatinine rise >=0.3 mg/dl). Receiver operating curves were used to compare the predictive ability of each AKI definition for the occurrence of adverse outcomes (death, rehospitalization, dialysis). RESULTS: AKI by any definition occurred in 38.3% (244/637) of cases and was associated with an increased incidence of 30-day (32.3 vs. 6.9%, chi(2) = 70.1; p < 0.001) and 1 year adverse outcomes (67.5 vs. 31.0%, chi(2) = 81.4; p < 0.001). Most importantly, there was a stepwise increase in primary outcome with increasing stages of AKI severity using RIFLE, KDIGO, or AKIN (p < 0.001). In direct comparison, there were only small differences in predictive abilities between RIFLE and KDIGO and WRF concerning clinical outcomes at 30 days (AUC 0.76 and 0.74 vs. 0.72, chi(2) = 5.6; p = 0.02) as well as for KDIGO and WRF at 1 year (AUC 0.67 vs. 0.65, chi(2) = 4.8; p = 0.03). CONCLUSION: During admission for HF, the benefits of using newer AKI classification systems (RIFLE, AKIN, KDIGO) lie with the ability to identify those patients with more severe degrees of AKI who will go on to experience adverse events at 30 days and 1 year. The differences in terms of predictive abilities were only marginal. PMID- 23801999 TI - Urinary protein excretion is associated with left ventricular hypertrophy in treatment-naive hypertensive patients in an african hospital setting. AB - BACKGROUND: Left ventricular hypertrophy (LVH) is an independent predictor of fatal and non-fatal cardiovascular events in hypertensive patients. Current guidelines for the management of hypertension are based on cardiovascular risk stratification. This study evaluated the possibility that an inexpensive, simple random, single-void urinary protein-to-creatinine ratio (UPCR) would be associated to left ventricular (LV) mass in a black African setting, and therefore direct appropriate management of these patients. METHODS: We measured echocardiographic LV mass and a random spot UPCR in 34 untreated newly diagnosed hypertensive patients attending the cardiology consultation unit at the Yaounde General Hospital. LV mass was indexed to height (in m(2.7)) to obtain the LV mass index (LVMI). A regression model was used to verify the independent association between UPCR and LVMI. RESULTS: The mean age of our patients was 52.65 years, and the mean systolic and diastolic blood pressures were 152.44 and 92.84 mm Hg, respectively. The prevalence of LVH was 41.2%. UPCR was higher in patients with LVH compared to those without (p = 0.043). There was a significant correlation between UPCR and LVMI (r = 0.581, p < 0.001). In the multiple linear regression model, UPCR was associated with LVMI independent of systolic blood pressure (p < 0.001). CONCLUSION: Random spot UPCR is associated with an increased LV mass and may be very useful in screening and guiding appropriate management of high-risk untreated hypertensive patients. PMID- 23802000 TI - Periodontal disease in chronic kidney disease and end-stage renal disease patients: a review. AB - Periodontal disease is a chronic inflammatory disorder and being so it has been associated with accelerated atherosclerosis and malnutrition. Cardiovascular diseases are the leading cause of mortality in chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients [National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases: Annual Data Report, 2010]. A recent scientific statement released by the American Heart Association [Lockhart et al.: Circulation 2012;125:2520-2544] claims that, even though evidence exists to believe that periodontal interventions result in a reduction in systemic inflammation and endothelial dysfunction, there is little evidence that those interventions prevent atherosclerotic vascular disease or modify the outcomes. In this review, we discuss the periodontal findings and their association with an increased prevalence of inflammatory markers and cardiovascular mortality in ESRD patients and CKD. PMID- 23802001 TI - ARP2/3-dependent growth in the plant kingdom: SCARs for life. AB - In the human experience SCARs (suppressor of cAMP receptors) are permanent reminders of past events, not always based on bad decisions, but always those in which an interplay of opposing forces leaves behind a clear record in the form of some permanent watery mark. During plant morphogenesis, SCARs are important proteins that reflect an unusual evolutionary outcome, in which the plant kingdom relies heavily on this single class of actin-related protein (ARP) 2/3 complex activator to dictate the time and place of actin filament nucleation. This unusually simple arrangement may serve as a permanent reminder that cell shape control in plants is fundamentally different from that of crawling cells in mammals that use the power of actin polymerization to define and maintain cell shape. In plant cells, actin filaments indirectly affect cell shape by determining the transport properties of organelles and cargo molecules that modulate the mechanical properties of the wall. It is becoming increasingly clear that polarized bundles of actin filaments operate at whole cell spatial scales to organize the cytoplasm and dictate the patterns of long-distance intracellular transport and secretion. The number of actin-binding proteins and actin filament nucleators that are known to participate in the process of actin network formation are rapidly increasing. In plants, formins and ARP2/3 are two important actin filament nucleators. This review will focus on ARP2/3, and the apparent reliance of most plant species on the SCAR/WAVE (WASP family verprolin homologous) regulatory complex as the sole pathway for ARP2/3 activation. PMID- 23802002 TI - Comparative feedstock analysis in Setaria viridis L. as a model for C4 bioenergy grasses and Panicoid crop species. AB - Second generation feedstocks for bioethanol will likely include a sizable proportion of perennial C4 grasses, principally in the Panicoideae clade. The Panicoideae contain agronomically important annual grasses including Zea mays L. (maize), Sorghum bicolor (L.) Moench (sorghum), and Saccharum officinarum L. (sugar cane) as well as promising second generation perennial feedstocks including Miscanthus*giganteus and Panicum virgatum L. (switchgrass). The underlying complexity of these polyploid grass genomes is a major limitation for their direct manipulation and thus driving a need for rapidly cycling comparative model. Setaria viridis (green millet) is a rapid cycling C4 panicoid grass with a relatively small and sequenced diploid genome and abundant seed production. Stable, transient, and protoplast transformation technologies have also been developed for Setaria viridis making it a potentially excellent model for other C4 bioenergy grasses. Here, the lignocellulosic feedstock composition, cellulose biosynthesis inhibitor response and saccharification dynamics of Setaria viridis are compared with the annual sorghum and maize and the perennial switchgrass bioenergy crops as a baseline study into the applicability for translational research. A genome-wide systematic investigation of the cellulose synthase-A genes was performed identifying eight candidate sequences. Two developmental stages; (a) metabolically active young tissue and (b) metabolically plateaued (mature) material are examined to compare biomass performance metrics. PMID- 23802003 TI - Does Don Fisher's high-pressure manifold model account for phloem transport and resource partitioning? AB - The pressure flow model of phloem transport envisaged by Munch (1930) has gained wide acceptance. Recently, however, the model has been questioned on structural and physiological grounds. For instance, sub-structures of sieve elements may reduce their hydraulic conductances to levels that impede flow rates of phloem sap and observed magnitudes of pressure gradients to drive flow along sieve tubes could be inadequate in tall trees. A variant of the Munch pressure flow model, the high-pressure manifold model of phloem transport introduced by Donald Fisher may serve to reconcile at least some of these questions. To this end, key predicted features of the high-pressure manifold model of phloem transport are evaluated against current knowledge of the physiology of phloem transport. These features include: (1) An absence of significant gradients in axial hydrostatic pressure in sieve elements from collection to release phloem accompanied by transport properties of sieve elements that underpin this outcome; (2) Symplasmic pathways of phloem unloading into sink organs impose a major constraint over bulk flow rates of resources translocated through the source-path-sink system; (3) Hydraulic conductances of plasmodesmata, linking sieve elements with surrounding phloem parenchyma cells, are sufficient to support and also regulate bulk flow rates exiting from sieve elements of release phloem. The review identifies strong circumstantial evidence that resource transport through the source-path-sink system is consistent with the high-pressure manifold model of phloem transport. The analysis then moves to exploring mechanisms that may link demand for resources, by cells of meristematic and expansion/storage sinks, with plasmodesmal conductances of release phloem. The review concludes with a brief discussion of how these mechanisms may offer novel opportunities to enhance crop biomass yields. PMID- 23802004 TI - miRNAs mediate SnRK1-dependent energy signaling in Arabidopsis. AB - The SnRK1 protein kinase, the plant ortholog of mammalian AMPK and yeast Snf1, is activated by the energy depletion caused by adverse environmental conditions. Upon activation, SnRK1 triggers extensive transcriptional changes to restore homeostasis and promote stress tolerance and survival partly through the inhibition of anabolism and the activation of catabolism. Despite the identification of a few bZIP transcription factors as downstream effectors, the mechanisms underlying gene regulation, and in particular gene repression by SnRK1, remain mostly unknown. microRNAs (miRNAs) are 20-24 nt RNAs that regulate gene expression post-transcriptionally by driving the cleavage and/or translation attenuation of complementary mRNA targets. In addition to their role in plant development, mounting evidence implicates miRNAs in the response to environmental stress. Given the involvement of miRNAs in stress responses and the fact that some of the SnRK1-regulated genes are miRNA targets, we postulated that miRNAs drive part of the transcriptional reprogramming triggered by SnRK1. By comparing the transcriptional response to energy deprivation between WT and dcl1-9, a mutant deficient in miRNA biogenesis, we identified 831 starvation genes misregulated in the dcl1-9 mutant, out of which 155 are validated or predicted miRNA targets. Functional clustering analysis revealed that the main cellular processes potentially co-regulated by SnRK1 and miRNAs are translation and organelle function and uncover TCP transcription factors as one of the most highly enriched functional clusters. TCP repression during energy deprivation was impaired in miR319 knockdown (MIM319) plants, demonstrating the involvement of miR319 in the stress-dependent regulation of TCPs. Altogether, our data indicates that miRNAs are components of the SnRK1 signaling cascade contributing to the regulation of specific mRNA targets and possibly tuning down particular cellular processes during the stress response. PMID- 23802005 TI - Towards uncovering the roles of switchgrass peroxidases in plant processes. AB - Herbaceous perennial plants selected as potential biofuel feedstocks had been understudied at the genomic and functional genomic levels. Recent investments, primarily by the U.S. Department of Energy, have led to the development of a number of molecular resources for bioenergy grasses, such as the partially annotated genome for switchgrass (Panicum virgatum L.), and some related diploid species. In its current version, the switchgrass genome contains 65,878 gene models arising from the A and B genomes of this tetraploid grass. The availability of these gene sequences provides a framework to exploit transcriptomic data obtained from next-generation sequencing platforms to address questions of biological importance. One such question pertains to discovery of genes and proteins important for biotic and abiotic stress responses, and how these components might affect biomass quality and stress response in plants engineered for a specific end purpose. It can be expected that production of switchgrass on marginal lands will expose plants to diverse stresses, including herbivory by insects. Class III plant peroxidases have been implicated in many developmental responses such as lignification and in the adaptive responses of plants to insect feeding. Here, we have analyzed the class III peroxidases encoded by the switchgrass genome, and have mined available transcriptomic datasets to develop a first understanding of the expression profiles of the class III peroxidases in different plant tissues. Lastly, we have identified switchgrass peroxidases that appear to be orthologs of enzymes shown to play key roles in lignification and plant defense responses to hemipterans. PMID- 23802006 TI - Modeling the parameters for plasmodesmal sugar filtering in active symplasmic phloem loaders. AB - Plasmodesmata (PD) play a key role in loading of sugars into the phloem. In plant species that employ the so-called active symplasmic loading strategy, sucrose that diffuses into their unique intermediary cells (ICs) is converted into sugar oligomers. According to the prevalent hypothesis, the oligomers are too large to pass back through PD on the bundle sheath side, but can pass on into the sieve element to be transported in the phloem. Here, we investigate if the PD at the bundle sheath-IC interface can indeed fulfill the function of blocking transport of sugar oligomers while still enabling efficient diffusion of sucrose. Hindrance factors are derived via theoretical modeling for different PD substructure configurations: sub-nano channels, slit, and hydrogel. The results suggest that a strong discrimination could only be realized when the PD opening is almost as small as the sugar oligomers. In order to find model parameters that match the in vivo situation, we measured the effective diffusion coefficient across the interface in question in Cucurbita pepo with 3D-photoactivation microscopy. Calculations indicate that a PD substructure of several sub-nano channels with a radius around 7 A, a 10.4 A-wide slit or a hydrogel with 49% polymer fraction would be compatible with the effective diffusion coefficient. If these configurations can accommodate sufficient flux of sucrose into the IC, while blocking raffinose and stachyose movement was assessed using literature data. While the slit-configuration would efficiently prevent the sugar oligomers from "leaking" from the IC, none of the configurations could enable a diffusion-driven sucrose flux that matches the reported rates at a physiologically relevant concentration potential. The presented data provides a first insight on how the substructure of PD could enable selective transport, but indicates that additional factors are involved in efficient phloem loading in active symplasmic loading species. PMID- 23802007 TI - Detailed analysis of putative genes encoding small proteins in legume genomes. AB - Diverse plant genome sequencing projects coupled with powerful bioinformatics tools have facilitated massive data analysis to construct specialized databases classified according to cellular function. However, there are still a considerable number of genes encoding proteins whose function has not yet been characterized. Included in this category are small proteins (SPs, 30-150 amino acids) encoded by short open reading frames (sORFs). SPs play important roles in plant physiology, growth, and development. Unfortunately, protocols focused on the genome-wide identification and characterization of sORFs are scarce or remain poorly implemented. As a result, these genes are underrepresented in many genome annotations. In this work, we exploited publicly available genome sequences of Phaseolus vulgaris, Medicago truncatula, Glycine max, and Lotus japonicus to analyze the abundance of annotated SPs in plant legumes. Our strategy to uncover bona fide sORFs at the genome level was centered in bioinformatics analysis of characteristics such as evidence of expression (transcription), presence of known protein regions or domains, and identification of orthologous genes in the genomes explored. We collected 6170, 10,461, 30,521, and 23,599 putative sORFs from P. vulgaris, G. max, M. truncatula, and L. japonicus genomes, respectively. Expressed sequence tags (ESTs) available in the DFCI Gene Index database provided evidence that ~one-third of the predicted legume sORFs are expressed. Most potential SPs have a counterpart in a different plant species and counterpart regions or domains in larger proteins. Potential functional sORFs were also classified according to a reduced set of GO categories, and the expression of 13 of them during P. vulgaris nodule ontogeny was confirmed by qPCR. This analysis provides a collection of sORFs that potentially encode for meaningful SPs, and offers the possibility of their further functional evaluation. PMID- 23802009 TI - Effects of seasonal, ontogenetic, and genetic factors on lifespan of male and female progeny of Arvicola amphibius. AB - The water vole (Arvicola amphibius) in the forest-steppe of West Siberia is known to have wide fluctuations in abundance. These fluctuations are accompanied by changes in birth and death rates, sex-age structure of the population, and individual morphophysiological and behavioral characteristics of the animals. Survival of the animals depends on season, phase of population cycle, and sex. Based on the data of long-term captive breeding of water voles, the maximal lifespan of males was found to be 1188 days and that of females, 1108 days. There were no differences between the sexes in mean lifespan. The probability of living 2 years or longer was 0.21. Individuals who began breeding at an older age had a significantly longer lifespan and produced more offspring. The survival curves of the spring-born animals were steeper than of those summer-/autumn-born. Maternal factors had a differential effect on males and females with respect to lifespan. Male lifespan correlated negatively with maternal age, parity, and litter size, whereas female lifespan did not correlate with these characteristics. To estimate heritability, parent-offspring correlations of lifespan were calculated, as well as full-sib intraclass correlations. No statistically significant correlation was found for lifespan between sons and mothers, sons and fathers, and daughters and fathers. Daughters' lifespan correlated positively with maternal lifespan (r = 0.21, p < 0.001). Female full-sibs and male full-sibs had the same intraclass correlations, 0.22, p < 0.001. PMID- 23802008 TI - BRCA1 in the DNA damage response and at telomeres. AB - Mutations of the breast and ovarian cancer susceptibility gene 1 (BRCA1) account for about 40-45% of hereditary breast cancer cases. Moreover, a significant fraction of sporadic (non-hereditary) breast and ovarian cancers exhibit reduced or absent expression of the BRCA1 protein, suggesting an additional role for BRCA1 in sporadic cancers. BRCA1 follows the classic pattern of a highly penetrant Knudsen-type tumor suppressor gene in which one allele is inactivated through a germ-line mutation and the other is mutated or deleted within the tumor. BRCA1 is a multi-functional protein but it is not fully understood which function(s) is (are) most important for tumor suppression, nor is it clear why BRCA1-mutations confer a high risk for breast and ovarian cancers and not a broad spectrum of tumor types. Here, we will review BRCA1 functions in the DNA damage response (DDR), which are likely to contribute to tumor suppression. In the process, we will highlight some of the controversies and unresolved issues in the field. We will also describe a recently identified and under-investigated role for BRCA1 in the regulation of telomeres and the implications of this role in the DDR and cancer suppression. PMID- 23802011 TI - Polymer models of chromatin organization. PMID- 23802010 TI - Modeling regulatory cascades using Artificial Neural Networks: the case of transcriptional regulatory networks shaped during the yeast stress response. AB - Over the last decade, numerous computational methods have been developed in order to infer and model biological networks. Transcriptional networks in particular have attracted significant attention due to their critical role in cell survival. The majority of network inference methods use genome-wide experimental data to search for modules of genes with coherent expression profiles and common regulators, often ignoring the multi-layer structure of transcriptional cascades. Modeling methodologies on the other hand assume a given network structure and vary significantly in their algorithmic approach, ranging from over-simplified representations (e.g., Boolean networks) to detailed -but computationally expensive-network simulations (e.g., with differential equations). In this work we use Artificial Neural Networks (ANNs) to model transcriptional regulatory cascades that emerge during the stress response in Saccharomyces cerevisiae and extend in three layers. We confine the structure of the ANNs to match the structure of the biological networks as determined by gene expression, DNA protein interaction and experimental evidence provided in publicly available databases. Trained ANNs are able to predict the expression profile of 11 target genes across multiple experimental conditions with a correlation coefficient >0.7. When time-dependent interactions between upstream transcription factors (TFs) and their indirect targets are also included in the ANNs, accurate predictions are achieved for 30/34 target genes. Moreover, heterodimer formation is taken into account. We show that ANNs can be used to (1) accurately predict the expression of downstream genes in a 3-layer transcriptional cascade based on the expression of their indirect regulators and (2) infer the condition- and time dependent activity of various TFs as well as during heterodimer formation. We show that a three-layer regulatory cascade whose structure is determined by co expressed gene modules and their regulators can successfully be modeled using ANNs with a similar configuration. PMID- 23802012 TI - New insights into the pathogenesis of pseudoxanthoma elasticum and related soft tissue calcification disorders by identifying genetic interactions and modifiers. AB - Screening of the adenosine triphosphate binding cassette transporter protein subfamily C member 6 gene (ABCC6) in pseudoxanthoma elasticum (PXE) revealed a mutation detection rate of approximately 87%. Although 25% of the unidentified disease alleles underlie deletions/insertions, there remain several PXE patients with no clear genotype. The recent identification of PXE-related diseases and the high intra-familiar and inter-individual clinical variability of PXE led to the assumption that secondary genetic co-factors exist. Here, we summarize current knowledge of the genetics underlying PXE and PXE-related disorders based on human and animal studies. Furthermore, we discuss the role of genetic interactions and modifier genes in PXE and PXE-related diseases characterized by soft tissue calcification. PMID- 23802013 TI - Cancer diagnosis and prognosis decoded by blood-based circulating microRNA signatures. AB - In the recent years, circulating microRNAs (miRNAs) have garnered a lot of attention and interest in the field of disease biomarkers. With characteristics such as high stability, low cost, possibility of repeated sampling and minimal invasiveness, circulating miRNAs are ideal for development into diagnostic tests. There have been many studies reported on the potential of circulating miRNAs as early detection, prognostic, and predictive biomarkers in cancer. Here, we have reviewed the application of plasma and serum miRNAs as biomarkers for cancer focusing on epithelial carcinomas [prostate, breast, lung, colorectal, and gastric cancer (GC)] and hematological malignancies (leukemia and lymphoma). We have also addressed the common challenges that need to be overcome to achieve a successful bench to bedside transition. PMID- 23802014 TI - Unleashing the power of meta-threading for evolution/structure-based function inference of proteins. AB - Protein threading is widely used in the prediction of protein structure and the subsequent functional annotation. Most threading approaches employ similar criteria for the template identification for use in both protein structure and function modeling. Using structure similarity alone might result in a high false positive rate in protein function inference, which suggests that selecting functional templates should be subject to a different set of constraints. In this study, we extend the functionality of eThread, a recently developed approach to meta-threading, focusing on the optimal selection of functional templates. We optimized the selection of template proteins to cover a broad spectrum of protein molecular function: ligand, metal, inorganic cluster, protein, and nucleic acid binding. In large-scale benchmarks, we demonstrate that the recognition rates in identifying templates that bind molecular partners in similar locations are very high, typically 70-80%, at the expense of a relatively low false positive rate. eThread also provides useful insights into the chemical properties of binding molecules and the structural features of binding. For instance, the sensitivity in recognizing similar protein-binding interfaces is 58% at only 18% false positive rate. Furthermore, in comparative analysis, we demonstrate that meta threading supported by machine learning outperforms single-threading approaches in functional template selection. We show that meta-threading effectively detects many facets of protein molecular function, even in a low-sequence identity regime. The enhanced version of eThread is freely available as a webserver and stand-alone software at http://www.brylinski.org/ethread. PMID- 23802015 TI - Imatinib Mesylate Effectiveness in Chronic Myeloid Leukemia with Additional Cytogenetic Abnormalities at Diagnosis among Black Africans. AB - Imatinib mesylate provides good results in the treatment of CML in general. But what about the results of this treatment in CML associated with additional cytogenetic abnormalities at diagnosis among black Africans? For this, we retrospectively studied 27 cases of CML associated with additional cytogenetic abnormalities, diagnosed in the department of clinical hematology of the University Hospital of Yopougon in Cote d'Ivoire, from May 2005 to October 2011. The age of patients ranged from 13 to 68 years, with a mean age of 38 years and a sex ratio of 2. Patients were severely symptomatic with a high Sokal score of 67%. CML in chronic phase accounted for 67%. The prevalence of additional cytogenetic abnormalities was 29.7%. There were variants of the Philadelphia chromosome (18.5%), trisomy 8 (14.8%), complex cytogenetic abnormalities (18.5%), second Philadelphia chromosome (14.8%), and minor cytogenetic abnormalities (44.4%). Complete hematologic remission was achieved in 59%, with 52% of major cytogenetic remission. The outcome was fatal in 37% of patients. Death was related in 40% to hematologic toxicity and in 30% to acutisation. The median survival was 40 months. PMID- 23802016 TI - PTSD Symptoms Mediate the Effect of Attachment on Pain and Somatisation after Whiplash Injury. AB - INTRODUCTION: The development of persistent pain post-whiplash injury is still an unresolved mystery despite the fact that approximately 50% of individuals reporting whiplash develop persistent pain. There is agreement that high initial pain and PTSD symptoms are indicators of a poor prognosis after whiplash injury. Recently attachment insecurity has been proposed as a vulnerability factor for both pain and PTSD. In order to guide treatment it is important to examine possible mechanisms which may cause persistent pain and medically unexplained symptoms after a whiplash injury. AIM: The present study examines attachment insecurity and PTSD symptoms as possible vulnerability factors in relation to high levels of pain and somatisation after sub-acute whiplash injury. METHODS: Data were collected from 327 patients (women = 204) referred consecutively to the emergency unit after acute whiplash injury. Within 1-month post injury, patients answered a questionnaire regarding attachment insecurity, pain, somatisation, and PTSD symptoms. Multiple mediation analyses were performed to assess whether the PTSD symptom clusters mediated the association between attachment insecurity, pain, and somatisation. RESULTS: A total of 15% fulfilled the DSM-IV symptom cluster criteria for a possible PTSD diagnosis and 11.6% fulfilled the criteria for somatisation. PTSD increased the likelihood of belonging to the moderate severe pain group three-fold. In relation to somatisation the likelihood of belonging to the group was almost increased four-fold. The PTSD symptom clusters of avoidance and hyperarousal mediated the association between the attachment dimensions, pain, and somatisation. CONCLUSION: Acknowledging that PTSD is part of the aetiology involved in explaining persistent symptoms after whiplash, may help sufferers to gain early and more suited treatment, which in turn may prevent the condition from becoming chronic. PMID- 23802017 TI - The German version of the Material Values Scale. AB - AIM: The Material Values Scale is an instrument to assess beliefs about the importance to own material things. This instrument originally consists of the three subscales: 'centrality', 'success', and 'happiness'. The present study investigated the psychometric properties of the German version of the MVS (G MVS). METHOD: A population-based sample of 2,295 adult Germans completed the questionnaire in order to investigate the factorial structure. To test construct validity, additional samples were gathered among patients with compulsive buying (N=52) and medical students (N=347) who also answered the Compulsive Buying Scale (CBS) and the Patient Health Questionnaire depression scale (PHQ-8). RESULTS: In the German population-based sample we could not confirm the 3-factor model but rather suggest a 2-factor solution with a first collapsed factor 'centrality/success', and the second factor 'happiness'. Patients with compulsive buying showed the highest scores on the G-MVS. While G-MVS scores among compulsive buyers and medical students were significantly related to compulsive buying scores, the correlation between the G-MVS and the depression measure appeared substantially lower. We did not find any gender differences regarding materialism, neither in the population-based sample nor in the students' or compulsive buyers' samples. However, age was negatively related to G-MVS scores. CONCLUSION: Confirmatory factor analyses suggest a 2-factor model of the G-MVS. Overall, the results indicate the use of the G-MVS as a brief, psychometrically sound, and potentially valid measure for the assessment of material values. PMID- 23802018 TI - Activation Energy Calculations for Formamide-TiO2 and Formamide-Pt Interactions in the Presence of Water. AB - Formamide contains the four elements (C, H, O, and N) most required for life and it is attractive as a potential prebiotic starting material for nucleobase synthesis. In the presence of catalysts (for example, TiO2) and with moderate heating, formamide can pass surface energy barriers, yielding a complete set of nucleic bases and acyclonucleosides, and favoring both phosphorylations and transphosphorylations necessary for life. In the reaction mechanism, interaction with water seems to be an essential factor for the formamide molecule to function. In this paper, a formamide-water solution on a TiO$_2$ (anatase) surface is simulated using the molecular dynamics method, and activation energy calculations are performed for the temperature range of T = 250 K to T = 400 K. A correlation is established between the diffusion and density profiles for the formamide and water molecules on an anatase surface. Also, the calculated activation energies of the formamide-water-anatase and formamide-water-platinum systems are compared. A comparative analysis is performed of the behavior of formamide-water and ethanol-water interaction on the same (anatase and platinum) surfaces. PMID- 23802019 TI - Quantitative Immunohistochemistry of Desmosomal Proteins (Plakoglobin, Desmoplakin and Plakophilin), Connexin-43, and N-cadherin in Arrhythmogenic Cardiomyopathy: An Autopsy Study. AB - BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic disorder related to mutations in desmosomal proteins. The current study tests the hypothesis that immunohistochemical staining for desmosomal proteins is of diagnostic utility by studying autopsy-confirmed cases of ARVC. METHODS AND RESULTS: We studied 23 hearts from patients dying suddenly with ARVC. Control subject tissues were 21 hearts from people dying from non-cardiac causes (n=15), dilated cardiomyopathy (n=3) and coronary artery disease (n=3). Areas free of fibrofatty change or scarring were assessed on 50 sections from ARVC (24 left ventricle, 26 right ventricle) and 28 sections from controls. Immunohistochemical stains against plakoglobin, plakophilin, desmoplakin, connexin-43, and N-cadherin were applied and area expression analyzed by computerized morphometry. Desmin was stained as a control for fixation and similarly analyzed. The mean area of desmin expression was similar in controls and ARVC (86% vs. 85%, p=0.6). Plakoglobin expression was 4.9% +/- 0.3% in controls, vs. 4.6% +/- 0.3% in ARVC (p=0.3). Plakophilin staining was 4.8% +/- 0.3% in controls vs. 4.4% +/- 03% in ARVC (p=0.3). Desmoplakin staining was 3.4% in controls vs. 3.2 +/- 0.2% in ARVC (p=0.6). There were no significant differences when staining was compared between right and left ventricles (all p > 0.1). For non-desmosomal proteins, the mean area of connexin-43 staining showed no significant difference by presence of disease. CONCLUSIONS: The small and insignificant decrease in junction protein expression in ARVC suggests that immunohistochemistry is not a useful tool for the diagnosis. PMID- 23802020 TI - Characteristics of heart rate reduction with resumption of supine position in the postural tachycardia syndrome: factors influencing recovery. AB - OBJECTIVES: Postural orthostatic tachycardia syndrome (POTS), a heart rate (HR) rise with upright positioning, is dependent on autonomic influences. HR recovery (HR decrease after exercise cessation) is a measure of autonomic function. Characteristics of HR reduction during supine Recovery after head-up Tilt in POTS patients have not been elucidated. METHODS: 113 subjects (mean age 41.7 years, 86 female), diagnosed with POTS on head-up Tilt were analyzed. HR's were recorded during baseline supine position, 70-degree Tilt, and 20 sec, 1 min and 2 min of supine Recovery. Percent HR reduction during Recovery was calculated. RESULTS: Baseline HR was 68.7+/-13.4 bpm. Maximum HR during Tilt was 109+/-16.9 bpm. Mean HR was 84.2+/-20 bpm at 20 sec, 78.5+/-18.9 bpm at 1-min, and 77.1+/-18.3 bpm at 2 min of Recovery. Younger age and slower baseline HR were associated with greater HR reductions at 20 sec (p=0.006, p=0.000, respectively). Younger age, slower baseline HR and less time to achieve POTS were associated with greater HR reductions at 1 min (p=0.025, p=0.000, p=0.000, respectively) and at 2 min (p=0.004, p=0.000, p=0.000, respectively). Gender and baseline blood pressures were not significant. CONCLUSIONS: In POTS patients, HR quickly decreases upon resuming supine position. Younger age, slower baseline HR and less time to achieve POTS were associated with greater HR reductions during supine Recovery. Further study is needed to determine mechanisms, as well as analyze differences in symptoms or prognosis. PMID- 23802021 TI - Subject body mass index affects Doppler waveform in celiac artery by duplex ultrasound. AB - OBJECTIVE: The aim of this study is to evaluate the effect of body mass index (BMI) on peak systolic velocity (PSV) recording in the celiac artery (CA). SUBJECTS & METHODS: Forty male participants were entered prospectively into the study. The subjects were divided into two groups according to their body mass index. Group A included subjects with BMI <=25 Kg/m(2) and those in group B with BMI >25 Kg/m(2). The diameter and PSV at the origin of CA of subjects in both groups were recorded while the subject positioned in supine and during expiration phase and fasted for 4 hours using duplex ultrasound. Both groups were matched for age and sex. Independent Student's t-test was used to test if there is any statistical significance between diameter and PSV in both groups. RESULTS: Group A's, average age (year, +/-SD) was 29.35+/-1.35 and average BMI (Kg/m(2), +/-SD) was 23.1+/-1.60. Group B's, average age was 30+/-2.1 and their average BMI was 31+/-5.1. The average diameter (cm, +/-SD) of CA in group A was 0.66+/-0.076 and in group B was 0.80+/-0.066. However, the average PSV (cm/s, +/-SD) was 117+/ 28.1 in group A and 102+/-12.4 in group B. Independent student t-test showed statistical significance between both groups for the diameter (p=0.005) and just reached statistical significance for PSV (p=0.049). CONCLUSION: Subjects with higher BMI showed reduced PSV due to a larger CA diameter and probably due to more fatty tissue accumulation around the CA origin. PMID- 23802022 TI - Dietary strategies to optimize wound healing after periodontal and dental implant surgery: an evidence-based review. AB - Methods to optimize healing through dietary strategies present an attractive option for patients, such that healing from delicate oral surgeries occurs as optimally as possible with minimal patient-meditated complications through improper food choices. This review discusses findings from studies that have investigated the role of diet, either whole foods or individual dietary components, on periodontal health and their potential role in wound healing after periodontal surgery. To date, research in this area has largely focused on foods or individual dietary components that may attenuate inflammation or oxidant stress, or foster de novo bone formation. These studies suggest that a wide variety of dietary components, including macronutrients and micronutrients, are integral for optimal periodontal health and have the potential to accelerate oral wound healing after periodontal procedures. Moreover, this review provides guidance regarding dietary considerations that may help a patient achieve the best possible outcome after a periodontal procedure. PMID- 23802023 TI - Microstructural Observation with MicroCT and Histological Analysis of Human Alveolar Bone Biopsy from a Planned Implant Site: A Case Report. AB - The subject was a 53-year-old male. An alveolar bone sample was obtained from the site of the lower left first molar, before dental implant placement. Although the details of the trabecular structure were not visible with conventional computed tomography, micro-computed tomography (microCT) three-dimensional images of the alveolar bone biopsy sample showed several plate-like trabeculae extending from the lingual cortical bone. Histological observations of the bone sample revealed trabeculae, cuboidal osteoblasts, osteoclasts and hematopoietic cells existing in the bone tissue at the implantation site. Bone metabolic markers and calcaneal bone density were all within normal ranges, indicating no acceleration of the patient's bone metabolism. Using microCT, and histological and histomorphometrical techniques, a great deal of valuable information about the bone tissue was obtained from a biopsy sample extracted from the patient's planned implant site. PMID- 23802024 TI - Morphological and Functional Parameters in Patients with Tooth Wear before and after Treatment. AB - Advanced tooth wear often results in lost vertical dimension and impacts facial aesthetics. Complex restorative treatment can replace the lost tooth structure and improve functional occlusal and facial skeleton parameters. PURPOSE: The aim of the study is to assess changes in the morphological and functional occlusal parameters of the facial skeleton after prosthetic rehabilitation that increased lost occlusal vertical dimension. MATERIAL AND METHODOLOGY: 50 patients with advanced tooth wear were clinically examined, to assess the degree of wear. Each subject underwent cephalometric analysis, digital occlusal analysis, and electromyographic analysis, of the anterior temporalis, superficial masetter, anterior digastric, and the sternocleidomastoid muscles. Prosthodontic treatment was performed to restore the occlusal vertical dimension of each subject's occlusion, which was followed by repeating the pretreatment analyses. Pre and post treatment parameters were statistically compared. RESULTS: Pre-treatment cephalometric analysis showed that lost vertical dimension reduced anterior facial height and resulted in small angular skeletal parameters. Post treatment anterior facial height increased from the increased occlusal vertical dimension. The mean value of functional electrical activity during clenching post treatment, increased compared to pretreatment. CONCLUSION: Increasing the vertical dimension of occlusion improved facial aesthetics by positively affecting facial skeletal angles. The restored occlusal surface morphology changed the pre treatment flat broad occlusal contacts into more point contacts. The increased vertical dimension of occlusion after treatment also increased muscle activity levels over the pretreatment levels after three months period of adaptation. PMID- 23802025 TI - The Aggregation of Brucella abortus Occurs Under Microaerobic Conditions and Promotes Desiccation Tolerance and Biofilm Formation. AB - Brucella abortus causes brucellosis mainly in cattle. The infection is transmitted to humans by ingestion of animal products or direct contact with infected material. While the intracellular lifestyle of Brucella is well characterized, its extracellular survival is poorly understood. In nature, bacterial persistence is associated with biofilms, where aggregated cells are protected from adversity. The inability of Brucella abortus to aggregate under aerobiosis and that fact that the replicative niche of Brucella is characterized by microaerobic conditions prompted us to investigate the capacity of this pathogen to aggregate and grow in biofilms under microaerobiotic conditions. The results show that B. abortus aggregates and produces biofilms. The aggregates tolerate desiccation better than planktonic cells do, adhere and displace even in the absence of the lipopolysaccharide-O antigen, flagella, the transcriptional regulator VjbR, or the enzymes that synthesize, transport, and modify cyclic beta (1,2) glucan. PMID- 23802026 TI - Adaptation of Mycobacterium smegmatis to an Industrial Scale Medium and Isolation of the Mycobacterial PorinMspA. AB - The adaptation of the organism to a simple and cost-effective growth medium is mandatory in developing a process for large scale production of the octamericporinMspA, which is isolated from Mycobacterium smegmatis. A fermentation optimization with the minimal nutrients required for growth has been performed. During the fermentation, the iron- and ammonium chloride concentrations in the medium were varied to determine their impact on the observed growth rates and cell mass yields. Common antibiotics to control contamination were eliminated in favor of copper sulfate to reduce costs. MspA has been successfully isolated from the harvested M. smegmatisusing aqueous nOPOE (n-octyloligooxyethylene) at 65 degrees C. Because of the extraordinary stability of MspA, it is possible to denature and precipitate virtually all other proteins and contaminants by following this approach. To further purify the product, acetone is used for precipitation. Gel electrophoresis confirmed the presence and purity of MspA. A maximum of 840ug (via Bradford assay) of pure MspA per liter of the optimized simple growth medium has been obtained. This is a 40% increase with respect to the previously reported culture medium for MspA. PMID- 23802027 TI - Inflammatory cells in tissues of gout patients and their correlations with comorbidities. AB - BACKGROUND: The major pathological finding of gout is the deposition of monosodium urate monohydrate (MSU) crystals with inflammatory infiltrate in the tissue. There have been many reports of in vitro analysis of inflammatory mechanism and comorbidities in gout. However, the associations of immune response cells and comorbidities of gout have not been well documented. Our studies aimed to examine the immune cell types and quantity in gout tissues, and to define the association of individual cell type with comorbidities. METHODS: Surgically resected or biopsied tissues from 48 patients diagnosed as gout were used for this study. Cell count was performed on Hemotoxylin and Eosin stained sections for macrophages, plasma cells, neutrophils and on immunostained slides for T and B lymphocytes. RESULTS: Hyperlipidemia, hypertension and diabetes mellitus were seen in 70.8%, 87.5% and 37.5% of patients, respectively. There were 35.6% and 37.8% of patients who admitted history of smoking and alcohol intake, respectively. Mean serum uric acid level was 8.5 mg/dl. The average body mass index was 30.1 kg/m(2). H&E stained tissue sections demonstrated the crystalline deposits rimmed by palisading multinucleated giant cells, macrophages, neutrophils, plasma cells, T and B cells. Significant correlations between the clinical features and tissue inflammatory cells were observed in hyperlipidemia with number of T cells (p = 0.0363), hypertension with number of T cells and B cells (p = 0.0138 and 0.0033, respectively), diabetes mellitus with macrophages (p = 0.0016), and uric acid level with giant cells (p = 0.0088). CONCLUSION: Comorbidity factors including hyperlipidemia, hypertension and diabetes are significantly associated with the inflammatory cells in the tissues. PMID- 23802028 TI - The differentiation of chronic obstructive pulmonary disease from asthma: a review of current diagnostic and treatment recommendations. AB - AIM: Global and regional data have shown that chronic airway diseases such as chronic obstructive pulmonary disease (COPD) and asthma are increasing in incidence and prevalence, with detrimental consequences to healthcare resources and the quality of life of patients. A firm diagnosis of COPD or asthma is important because the natural history, treatment, and outcomes differ between the two respiratory diseases. The aim of this review is to provide nurse practitioners (NPs) with the requisite facts to understand and improve the diagnosis and treatment of affected individuals. METHODS: Articles on the differential diagnosis, treatment, and management of COPD and asthma published in peer-reviewed journals were retrieved from PubMed. Evidence-based respiratory guidelines, World Health Organization disease-related data, and US prescribing information for different respiratory medications served as additional data sources. CONCLUSIONS: NPs, along with other primary care professionals, form the frontline in diagnosing, treating, and managing COPD and asthma. Differentiating COPD from asthma has prognostic as well as significant therapeutic implications. Since NPs play a key role in diagnosing and managing patients with COPD and asthma, those with a comprehensive understanding of the diagnostic and therapeutic differences between the two diseases can help to lower the risks of exacerbations and hospitalizations, and improve the quality of life of these patients. PMID- 23802029 TI - Kangaroo care in a neonatal context: parents' experiences of information and communication of nurse-parents. AB - OBJECTIVE: Kangaroo Care (KC) is an evidence-based nursing practice with many benefits for infants and parents. The purpose of this study was to describe parents' experience of information and communication mediated by staff nurses before and during KC at neonatal wards. METHODOLOGY AND PARTICIPANTS: A qualitative study with semi-structured interviews was performed. The sample consisted of 20 parents. RESULTS: THE RESULTS SHOW THAT THE INFORMATION AND COMMUNICATION WERE EXPERIENCED AS BOTH OPTIMAL AND SUBOPTIMAL INCLUDING FOLLOWING CATEGORIES: initially conflicting emotions in relation to KC, participation and confidence in KC is evolving, strengthening preparation and context is decisive as well as parental sense and caution. The overall theme was that good preparation will contribute to a positive experience of KC. CONCLUSION: The conclusion is that most of the parents had positive experiences of KC. The information and communication from the staff nurses encouraged and motivated the parents to practice KC, in a sense that it was a natural way to get to know the infant, when the staff nurses were well versed in the method and coherent and supportive. Conflicting emotions emerged when staff nurses practised KC as a routine without deeper knowledge and skills of the method and its advantages as well as without sensitivity to parents' vulnerable situation. PMID- 23802030 TI - Beliefs about health and illness in latin-american migrants with diabetes living in sweden. AB - The study explored beliefs about health and illness in Latin American migrants diagnosed with diabetes mellitus (DM) living in Sweden, and investigated the influence on health-related behavior including self-care and care-seeking behavior. Migrants are particularly affected in the diabetes pandemia. Beliefs about health and illness determine health-related behaviour and health but no studies have been found on Latin American migrants with DM. An explorative study design with focus-group interviews of nine persons aged 36-77 years from a diabetes clinic was used. Health was described from a pathogenetic or a salutogenetic perspective: 'freedom from disease or feeling of well-being', and being autonomous and able to work. Economic hardship due to expenses for medications and food for DM affected health. Individual factors such as diet, exercise and compliance with advice, and social factors with good social relations and avoidance of stress, often caused by having experienced severe events related to migrational experiences, were considered important for maintaining health and could cause DM. Disturbed relations to others (social factors), punishment by God or Fate (supernatural factors), intake of diuretics and imbalance between warmth and cold (natural factors) were also perceived as causes. A mix of biomedical and traditional explanations and active self-care behaviour with frequent use of herbs was found. It is important to assess the individual's beliefs, and health professionals, particularly nurses, should incorporate discussions of alternative treatments and other components of explanatory models and co-operate with social workers to consider influence of finances and migrational experiences on health. PMID- 23802031 TI - Can participation in documentation influence experiences of involvement in care decision-making? AB - INTRODUCTION: Patients have the right to influence the care they receive, but their wish to participate in care decision-making is unclear. AIM: This study investigates whether participation in nursing documentation influences patient participation in care decision-making, mastery, self-esteem, empowerment and depressive feelings among adult in-patients with chronic disease. MATERIALS AND METHODOLOGY: Adult patients (n=39) with chronic diseases were randomized. The intervention group participated in nursing documentation. Upon departure, patients filled in questionnaires about participation in care decision-making, mastery, self-esteem, empowerment and depressive feelings. RESULTS: The majority of the patients preferred a collaborative or passive role regarding care decision making. Lack of knowledge was one reason for non-participation. Having been diagnosed more than five years previously meant stronger empowerment. CONCLUSION: It is a challenge for nurses to find strategies to assess patients' wishes regarding participation in care decision-making. Nurses must support patients' knowledge of their disease and empowerment. PMID- 23802032 TI - Short Text Messages to Motivate HIV Testing Among Men Who have Sex with Men: A Qualitative Study in Lima, Peru. AB - OBJECTIVE: The objective of this study is to identify features and content that short message service (SMS) should have in order to motivate HIV testing among men who have sex with men (MSM) in Lima, Peru. METHODS: From October, 2010 to February, 2011, we conducted focus groups at two stages; six focus groups were conducted to explore and identify SMS content and features and two additional focus groups were conducted to tailor SMS content. The text messages were elaborated within the theoretical framework of the Information-Motivation Behavioral Skills model and the Social Support Theory. RESULTS: A total of 62 individuals participated in the focus groups. The mean age of participants was 28 years (range 18-39). We identified important features and content items needed for the successful delivery of text messages, including: a) the use of neutral and coded language; b) appropriate frequency and time of delivery; c) avoiding mass and repetitive messages; and d) use of short, concise and creative messages. Although in Peru receiving text messages is usually a free service, it is important to remind participants that receiving messages will be free of charge. CONCLUSION: Text messages can be used to promote HIV testing among Peruvian MSM. It is important to consider adequate frequency, message content and cost when delivering messages to promote HIV testing in this population. PMID- 23802033 TI - Regulation of vascular smooth muscle mechanotransduction by microRNAs and L-type calcium channels. AB - The phenotype of smooth muscle cells is regulated by multiple environmental factors including mechanical forces. Mechanical stretch of mouse portal veins ex vivo has been shown to promote contractile differentiation by activation of the Rho-pathway, an effect that is dependent on the influx of calcium via L-type calcium channels. MicroRNAs have recently been demonstrated to play a significant role in the control of smooth muscle phenotype and in a recent report we investigated their role in vascular mechanosensing. By smooth muscle specific deletion of Dicer, we found that microRNAs are essential for smooth muscle differentiation in response to stretch by regulating CamKIIdelta and L-type calcium channel expression. Furthermore, we suggest that loss of L-type calcium channels in Dicer KO is due to reduced expression of the smooth muscle-enriched microRNA, miR-145, which targets CamKIIdelta. These results unveil a novel mechanism for miR-145 dependent regulation of smooth muscle phenotype. PMID- 23802034 TI - Dim scotopic illumination accelerates the reentrainment following simulated jetlags in a diurnal experimental model, Drosophila. AB - Jetlag results from the misalignment between the endogenous circadian timing and the civil timing after a transmeridian flight. Efficacy of the dim nocturnal illumination (0.03 lx) in accelerating the reentrainment following simulated jetlags in Drosophila biarmipes was examined by subjecting the flies to 24 h light-dark cycles in which the 12 h photophase was at 300 lx for all flies but the scotophase was at 0 and 0.03 lx for the control and experimental flies, respectively. Reentrainment was always faster in the experimental flies than the control ones. Moreover, unlike melatonin, the dimly lit nights accelerated the reentrainment following both, the phase advance and delay of the light-dark cycles. This study might have potential application as a non-drug jetlag treatment. PMID- 23802035 TI - Putting the Rit in cellular resistance: Rit, p38 MAPK and oxidative stress. AB - Cells mobilize diverse signaling pathways to protect against stress-mediated injury. Ras family GTPases play critical roles in this process, controlling the activation and integration of multiple regulatory cascades. p38 mitogen-activated protein kinase (MAPK) signaling serves as a critical fulcrum in this process, regulating networks that stimulate cellular apoptosis but also promote cell survival. However, this functional dichotomy is incompletely understood, particularly regulation of p38-dependent survival. Here, we discuss our recent evidence that the Rit GTPase associates with and is required for stress-mediated activation of a scaffolded p38-MK2-HSP27-Akt pro-survival signaling cascade. Drosophila lacking D-Ric, a Rit homologue, are susceptible to a variety of environmental stresses, while embryonic fibroblasts derived from Rit knockout mice display blunted stress-dependent signaling and decreased viability. Conversely, expression of constitutively active Rit triggers p38-Akt-dependent cell survival. Together, our studies establish Rit as the central regulator of an evolutionarily conserved, p38-dependent signaling cascade that functions as a critical survival mechanism in response to stress. PMID- 23802036 TI - Nutrient transfer to plants by phylogenetically diverse fungi suggests convergent evolutionary strategies in rhizospheric symbionts. AB - Most land plants are able to form symbiotic associations with fungi, and in many cases these associations are necessary for plant and fungal survival. These plant/fungal associations are formed with mycorrhizal (arbuscular mycorrhizal or ectomycorrhizal) or endophytic fungi, fungi from distinct phylogenetic lineages. While it has been shown that mycorrhizal fungi are able to transfer nutrients to plant roots in exchange for carbon, endophytes have been thought as asymptomatic colonizers. Recently, however, it has been shown that some insect pathogenic endophytic fungi are able to transfer insect derived nitrogen to plant roots, likely in exchange for plant sugars. Here we explore potential convergent evolutionary strategies for nutrient transfer between insect pathogenic endophytes and mycorrhizal fungus. PMID- 23802037 TI - Increased threat of island endemic tree's extirpation via invasion-induced decline of intrinsic resistance to recurring tropical cyclones. AB - Cycas micronesica populations in Guam have been threatened by the invasion of the armored scale Aulacaspis yasumatsui. I integrate four factors that illuminate an acute need for intervention to reduce an unprecedented threat caused by the invasion. First, mechanical failure of healthy C. micronesica trees during catastrophic winds is rare because of the cycad tree's unique pachycaulis stem design. Second, tree-winching and three-point bend stress tests revealed the natural resistance to damage from tropical cyclones has been compromised by the chronic feeding of this homopteran pest. Third, no typhoon event has occurred since the arthropod's invasion and its spread in the year 2005 to actually test extent of mechanical failure for the unhealthy remaining trees. Fourth, historical records indicate the probability that Guam will experience typhoon force winds is 0.51 in three years and 0.91 in 10 y. These four factors integrate to predict the next typhoon may eliminate the surviving C. micronesica trees and stewardship of this declining population requires intervention to counter this prediction. PMID- 23802038 TI - A simple model for the origin of quasiperiodic ultradian rhythms in sleep-wake state in the rat. AB - In a recent study,(1) ultradian rhythms of rat sleep-wake behavior were found, using several methods of time series analysis, to be "quasiperiodic." That is, ultradian period varied apparently randomly around a mean of approximately 4 h, with no relationship between ultradian period and time of day. Here it is proposed that a simple two-oscillator model can explain the quasiperiodic characteristic of these rhythms. Specifically, in this model a periodic oscillator interacts with a stochastic oscillator to generate a behavioral pattern in which the period and amplitude of the simulated ultradian waves vary randomly around an average value. Preliminary simulations support the plausibility of the model; simulated waveforms were closely similar to behavior patterns observed in adult male rats. It is hypothesized that ultradian rhythms in sleep-wake behavior may arise from a periodic feedback loop (e.g., the sleep wake homeostat) coupled to a stochastic sleep-wake "flip-flop" switch. PMID- 23802039 TI - Insects on flowers: The unexpectedly high biodiversity of flower-visiting beetles in a tropical rainforest canopy. AB - Insect biodiversity peaks in tropical rainforest environments where a large but as yet unknown proportion of species are found in the canopy. While there has been a proliferation of insect biodiversity research undertaken in the rainforest canopy, most studies focus solely on insects that inhabit the foliage. In a recent paper, we examined the distribution of canopy insects across five microhabitats (mature leaves, new leaves, flowers, fruit and suspended dead wood) in an Australian tropical rainforest, showing that the density (per dry weight gram of microhabitat) of insects on flowers were ten to ten thousand times higher than on the leaves. Flowers also supported a much higher number of species than expected based on their contribution to total forest biomass. Elsewhere we show that most of these beetle species were specialized to flowers with little overlap in species composition between different canopy microhabitats. Here we expand our discussion of the implications of our results with respect to specialization and the generation of insect biodiversity in the rainforest canopy. Lastly, we identify future directions for research into the biodiversity and specialization of flower-visitors in complex tropical rainforests. PMID- 23802040 TI - Cracking the bioelectric code: Probing endogenous ionic controls of pattern formation. AB - Patterns of resting potential in non-excitable cells of living tissue are now known to be instructive signals for pattern formation during embryogenesis, regeneration and cancer suppression. The development of molecular-level techniques for tracking ion flows and functionally manipulating the activity of ion channels and pumps has begun to reveal the mechanisms by which voltage gradients regulate cell behaviors and the assembly of complex large-scale structures. A recent paper demonstrated that a specific voltage range is necessary for demarcation of eye fields in the frog embryo. Remarkably, artificially setting other somatic cells to the eye-specific voltage range resulted in formation of eyes in aberrant locations, including tissues that are not in the normal anterior ectoderm lineage: eyes could be formed in the gut, on the tail, or in the lateral plate mesoderm. These data challenge the existing models of eye fate restriction and tissue competence maps, and suggest the presence of a bioelectric code-a mapping of physiological properties to anatomical outcomes. This Addendum summarizes the current state of knowledge in developmental bioelectricity, proposes three possible interpretations of the bioelectric code that functionally maps physiological states to anatomical outcomes, and highlights the biggest open questions in this field. We also suggest a speculative hypothesis at the intersection of cognitive science and developmental biology: that bioelectrical signaling among non-excitable cells coupled by gap junctions simulates neural network-like dynamics, and underlies the information processing functions required by complex pattern formation in vivo. Understanding and learning to control the information stored in physiological networks will have transformative implications for developmental biology, regenerative medicine and synthetic bioengineering. PMID- 23802041 TI - Potential role of nanotubes in context of clinical treatments? AB - The recent awareness that eukaryotic cells can be linked and communicate via membranous nanotubes (NTs) has extended previous conceptions of cell-to-cell interaction. Apart from mediating functional connectivity between a broad range of cells, facilitating intercellular transmission of electric signals or various cellular components, there is strong evidence for participation of NTs in pathological processes of particular medical interest. In our recent study, we showed for the first time the existence of nanotubular connections between human primary peritoneal mesothelial cells (HPMCs) and provided insights to their actin/filopodia mediated building mechanism. Furthermore, we showed that tumor necrosis factor (TNF) significantly increased NT formation between HPMCs, pointing to a crucial role of NTs during inflammatory processes. Moreover, our study showed a strong correlation of NT occurrence and cellular cholesterol contents, demonstrating an interdependence of NT mediated cell communication, cytokine action and cholesterol homeostasis. Here, we further provide analysis on NT-formation processes. PMID- 23802042 TI - The role of gamma and alpha oscillations for blocking out distraction. AB - Although alpha activity (10 Hz) is by far the strongest signal produced by the human brain, it has for decades been considered to reflect rest or idling. However, recent studies have clearly demonstrated that alpha activity plays a pivotal role for cognitive processing. Gamma oscillations (> 30 Hz) and their role for cognition have also been the subject of intensive research. While gamma activity is thought to reflect functional processing, alpha oscillations are now thought to reflect functional inhibition in order to suppress the processing of distracting information. In our recent magnetoencephalography study we found that both power and phase of posterior alpha oscillations are top-down modulated in order to prevent the incorporation of predictable distracters in working memory. We further discuss these results here. We additionally show that the processing of the distracters is clearly distinguishable from the processing of the items to be remembered. The former induced a weaker gamma power and evoked a higher alpha activity. The higher the evoked alpha activity, the better the efficiency of distracter suppression which also depends on the pre-distracter alpha power and phase adjustment. Altogether, these results emphasize the protecting role of alpha activity and its remarkable flexibility. This ability to inhibit distracter information is crucial in our complex environment, as illustrated by the difficulties encountered by patients suffering from attentional disorders. PMID- 23802043 TI - Modeling the genetic basis for human sleep disorders in Drosophila. AB - Sleep research in Drosophila is not only here to stay, but is making impressive strides towards helping us understand the biological basis for and the purpose of sleep-perhaps one of the most complex and enigmatic of behaviors. Thanks to over a decade of sleep-related studies in flies, more molecular methods are being applied than ever before towards understanding the genetic basis of sleep disorders. The advent of high-throughput technologies that can rapidly interrogate whole genomes, epigenomes and proteomes, has also revolutionized our ability to detect genetic variants that might be causal for a number of sleep disorders. In the coming years, mutational studies in model organisms such as Drosophila will need to be functionally connected to information being generated from these whole-genome approaches in humans. This will necessitate the development of appropriate methods for interpolating data and increased analytical power to synthesize useful network(s) of sleep regulatory pathways including appropriate discriminatory and predictive capabilities. Ultimately, such networks will also need to be interpreted in the context of fundamental neurobiological substrates for sleep in any given species. In this review, we highlight some emerging approaches, such as network analysis and mathematical modeling of sleep distributions, which can be applied to contemporary sleep research as a first step to achieving these aims. These methodologies should favorably impact not only a mechanistic understanding of sleep, but also future pharmacological intervention strategies to manage and treat sleep disorders in humans. PMID- 23802044 TI - Floral humidity and other indicators of energy rewards in pollination biology. AB - Floral traits that correlate with nectar availability or are linked functionally to nectar production carry the potential to enable remote assessment of energy rewards by pollinators. Such floral traits can be considered "honest" in the sense that they convey information about the quality or profitability of a flower to a pollinator. Recently a new sensory channel used in plant-pollinator interactions was identified. We demonstrated that evaporation of water from the nectar itself and the petals create local humidity gradients above Oenothera cespitosa (Onagraceae) flowers. Since these humidity gradients are directly linked to nectar volume, they convey reliable information about nectar rewards to hawkmoth pollinators (Sphingidae). Several studies document a variety of sensory cues that constitute honest signaling between plants and pollinators, and shed light on the central question of when the two parties should communicate honestly. In the following sections, I will comment on different honest signals mediating plant-pollinator interactions, with a special emphasis on our recent findings about floral humidity gradients. PMID- 23802045 TI - Atrial fibrillation in obstructive sleep apnea. AB - Atrial fibrillation (AF) is a common arrhythmia with rising incidence. Obstructive sleep apnea (OSA) is prevalent among patients with AF. This observation has prompted significant research in understanding the relationship between OSA and AF. Multiple studies support a role of OSA in the initiation and progression of AF. This association has been independent of obesity, body mass index and hypertension. Instability of autonomic tone and wide swings in intrathoracic pressure are seen in OSA. These have been mechanistically linked to initiation of AF in OSA patients by lowering atrial effective refractory period, promoting pulmonary vein discharges and atrial dilation. OSA not only promotes initiation of AF but also makes management of AF difficult. Drug therapy and electrical cardioversion for AF are less successful in presence of OSA. There has been higher rate of early and overall recurrence after catheter ablation of AF in patients with OSA. Treatment of OSA with continuous positive airway pressure has been shown to improve control of AF. However, additional studies are needed to establish a stronger relationship between OSA treatment and success of AF therapies. There should be heightened suspicion of OSA in patients with AF. There is a need for guidelines to screen for OSA as a part of AF management. PMID- 23802046 TI - Peroxisome-proliferator-activated receptors regulate redox signaling in the cardiovascular system. AB - Peroxisome-proliferator-activated receptors (PPARs) comprise three subtypes (PPARalpha, delta and gamma) to form a nuclear receptor superfamily. PPARs act as key transcriptional regulators of lipid metabolism, mitochondrial biogenesis, and anti-oxidant defense. While their roles in regulating lipid metabolism have been well established, the role of PPARs in regulating redox activity remains incompletely understood. Since redox activity is an integral part of oxidative metabolism, it is not surprising that changes in PPAR signaling in a specific cell or tissue will lead to alteration of redox state. The effects of PPAR signaling are directly related to PPAR expression, protein activities and PPAR interactions with their coregulators. The three subtypes of PPARs regulate cellular lipid and energy metabolism in most tissues in the body with overlapping and preferential effects on different metabolic steps depending on a specific tissue. Adding to the complexity, specific ligands of each PPAR subtype may also display different potencies and specificities of their role on regulating the redox pathways. Moreover, the intensity and extension of redox regulation by each PPAR subtype are varied depending on different tissues and cell types. Both beneficial and adverse effects of PPAR ligands against cardiovascular disorders have been extensively studied by many groups. The purpose of the review is to summarize the effects of each PPAR on regulating redox and the underlying mechanisms, as well as to discuss the implications in the cardiovascular system. PMID- 23802047 TI - Depression in adults with congenital heart disease-public health challenge in a rapidly expanding new patient population. AB - There is a growing population of adults with congenital heart disease (CHD) due to improved survival beyond childhood. It has been suggested that adults with CHD may be at increased risk for mental health problems, particularly depression. The reported incidence of depression in CHD varies from 9% to 30%. This review examines the evidence for a higher depression rate in CHD vs general population. Possible explanations are offered from a variety of disease models, ranging from brain injury to the psychoanalytical approach. Risk factors for an abnormal emotional adjustment and depression include early exposure to stress from illness and medical interventions in infancy, separation from the parents during hospitalizations and brain organic syndromes. Later in life, patients often have to cope with physical limitations. Recent improvements in care may be protective. Current patients may benefit from an earlier age at first surgical intervention, fewer reoperations and inclusion to the mainstream schooling, among other factors. At this point, there is little systematic knowledge about evidence-based therapeutic interventions for depression in adults with CHD. Health care providers of patients with CHD should be aware of mental health challenges and may take a more proactive approach to identifying patients at risk for depression. PMID- 23802048 TI - BLEED-Myocardial Infarction Score: Predicting mid-term post-discharge bleeding events. AB - AIM: To derive and validate a score for the prediction of mid-term bleeding events following discharge for myocardial infarction (MI). METHODS: One thousand and fifty patients admitted for MI and followed for 19.9 +/- 6.7 mo were assigned to a derivation cohort. A new risk model, called BLEED-MI, was developed for predicting clinically significant bleeding events during follow-up (primary endpoint) and a composite endpoint of significant hemorrhage plus all-cause mortality (secondary endpoint), incorporating the following variables: age, diabetes mellitus, arterial hypertension, smoking habits, blood urea nitrogen, glomerular filtration rate and hemoglobin at admission, history of stroke, bleeding during hospitalization or previous major bleeding, heart failure during hospitalization and anti-thrombotic therapies prescribed at discharge. The BLEED MI model was tested for calibration, accuracy and discrimination in the derivation sample and in a new, independent, validation cohort comprising 852 patients admitted at a later date. RESULTS: The BLEED-MI score showed good calibration in both derivation and validation samples (Hosmer-Lemeshow test P value 0.371 and 0.444, respectively) and high accuracy within each individual patient (Brier score 0.061 and 0.067, respectively). Its discriminative performance in predicting the primary outcome was relatively high (c-statistic of 0.753 +/- 0.032 in the derivation cohort and 0.718 +/- 0.033 in the validation sample). Incidence of primary/secondary endpoints increased progressively with increasing BLEED-MI scores. In the validation sample, a BLEED-MI score below 2 had a negative predictive value of 98.7% (152/154) for the occurrence of a clinically significant hemorrhagic episode during follow-up and for the composite endpoint of post-discharge hemorrhage plus all-cause mortality. An accurate prediction of bleeding events was shown independently of mortality, as BLEED-MI predicted bleeding with similar efficacy in patients who did not die during follow-up: Area Under the Curve 0.703, Hosmer-Lemeshow test P value 0.547, Brier score 0.060; low-risk (BLEED-MI score 0-3) event rate: 1.2%; intermediate risk (score 4-6) event rate: 5.6%; high risk (score >= 7) event rate: 12.5%. CONCLUSION: A new bedside prediction-scoring model for post-discharge mid-term bleeding has been derived and preliminarily validated. This is the first score designed to predict mid- term hemorrhagic risk in patients discharged following admission for acute MI. This model should be externally validated in larger cohorts of patients before its potential implementation. PMID- 23802049 TI - Unique presentation of Twiddler's syndrome. AB - We present a rare case of Twiddler's syndrome diagnosed in an asymptomatic patient on a routine follow up. This case reiterates the need for frequent monitoring of the implanted device. In addition, it was detected 4 years after implantation of an automatic implantable cardioverter defibrillator. This late representation is extremely uncommon. PMID- 23802051 TI - Effects of training attendance on muscle strength of young men after 11 weeks of resistance training. AB - PURPOSE: Training attendance is an important variable for attaining optimal results after a resistance training (RT) program, however, the association of attendance with the gains of muscle strength is not well defined. Therefore, the purpose of the present study is to verify if attendance would affect muscle strength gains in healthy young males. METHODS: Ninety two young males with no previous RT experience volunteered to participate in the study. RT was performed 2 days a week for 11 weeks. One repetition maximum (1RM) in the bench press and knee extensors peak torque (PT) were measured before and after the training period. After the training period, a two step cluster analysis was used to classify the participants in accordance to training attendance, resulting in three groups, defined as high (92 to 100%), intermediate (80 to 91%) and low (60 to 79%) training attendance. RESULTS: According to the results, there were no significant correlations between strength gains and training attendance, however, when attendance groups were compared, the low training attendance group showed lower increases in 1RM bench press (8.8%) than the other two groups (17.6% and 18.0% for high and intermediate attendance, respectively). CONCLUSIONS: Although there is not a direct correlation between training attendance and muscle strength gains, it is suggested that a minimum attendance of 80% is necessary to ensure optimal gains in upper body strength. PMID- 23802050 TI - Patellofemoral pain syndrome and modifiable intrinsic risk factors; how to assess and address? AB - Patellofemoral pain syndrome (PFPS) is a very common disorder of the knee. Due to multiple forces influencing the patellofemoral joint, clinical management of this ailment is particularly intricate. Patellofemoral pain syndrome has a multifactorial nature and multiple parameters have been proposed as potential risk factors, classified as intrinsic or extrinsic. Some of the intrinsic risk factors are modifiable and may be approached in treatment. A number of modifiable risk factors have been suggested, including quadriceps weakness, tightness of hamstring, iliopsoas and gastrosoleus muscles, hip muscles dysfunction, foot overpronation, tightness of iliotibial band, generalised joint laxity, limb length discrepancy, patellar malalignment and hypermobility. In general, the routine approach of physicians to this problem does not include assessment and modification of these risk factors and therefore, it may negatively affect the management outcomes. Changing this approach necessitates an easy and practical protocol for assessment of modifiable risk factors and effective and feasible measures to address them. In this review, we aimed to introduce assessment and intervention packages appropriate for this purpose. PMID- 23802052 TI - Comparison of Blue-Yellow Opponent Color Contrast Sensitivity Function between Female Badminton Players and Non-athletes. AB - PURPOSE: To compare the chromatic contrast sensitivity function (CSF) for the blue-yellow opponent channel (BYOC) between female badminton players and non athlete controls. METHODS: We recruited 40 young females (18-25 years old) who played badminton for at least 5 consecutive years as the test group, and 30 age matched female controls who had no history of regular physical activity. The Pattern GeneratorTM system was used to test the CSF for the BYOC which was performed at three spatial frequencies (SFs) of 2 cycles per degree (cpd), 5 cpd, and 25 cpd. RESULTS: Comparison of BYOC thresholds showed significantly better results in the test group for all three SFs (P<0.001). Band pass shift (better CSF in the middle SF) was seen in the test group. The control group had low pass (better CSF in the low SF). Ocular motility (heterophoria, fusional convergence and divergence at far and near distances, and near point of convergence) was better in the test group, but the inter-group difference was not significant. CONCLUSIONS: The BYOC threshold results for badminton players indicated a better visual performance which may be a result of enhanced performance of the parallel processing of the parvocellular and magnocellular systems. This may be inherent and/or acquired in badminton players. In addition, badminton players appear to have developed sensory-motor programmed activities. Testing the CSF for BYOC may be useful for athlete selection in different levels and/or used as a criterion for screening players in the field of badminton. PMID- 23802054 TI - Association between the Rating Perceived Exertion, Heart Rate and Blood Lactate in Successive Judo Fights (Randori). AB - PURPOSE: This study aims to investigate the association between the rating of perceived exertion (RPE), heart rate (HR) and the blood lactate concentration ([La]) in successive judo fight simulations (randori). METHODS: TEN ATHLETES PARTICIPATED IN THE STUDY (AGE: 25.6+/-2.1 years; stature: 1.75+/-0.07 m; body mass: 75.6+/-14.9kg; %BF: 11.5+/-7.8%; practice: 14.5+/-6.2 years) and completed 4 judo fight simulations (T1 to T4) with duration of 5 min separated by 5 min passive recovery periods. Before each randori, [La] and HR were collected, and after each randori, the same measures and the RPE (CR-10 scale) were collected. RESULTS: SIGNIFICANT CORRELATIONS WERE OBSERVED BETWEEN: (1) CR-10 and HR (T2: r =0.70; T3: r =0.64; both, P<0.05); (2) DeltaCR-10 and Delta[La] (T1-T2: r = .71, P< 0.05; T2-T3: r =0.92, P<0.01; T3-T4: r =0.73, P<0.05). Moreover, significant differences were noted in the behavior of the HR between the 2(nd) (T2) and 3(rd) (T3) judo fight simulations (P<0.05). CONCLUSION: The use of CR-10 in the evaluation process, as well as in deciding the load of training in judo, should be done with caution. PMID- 23802053 TI - Effects of a 6-Month Walking Study on Blood Pressure and Cardiorespiratory Fitness in U.S. and Swedish Adults: ASUKI Step Study. AB - PURPOSE: The aim of this study was to assess the effects of a six-month pedometer based workplace intervention on changes in resting blood pressure (BP) and cardiorespiratory fitness (CRF). METHODS: A subsample of ASUKI Step participants (n= 355) were randomly selected to have changes in their BP and CRF monitored during the intervention. Pedometers were used to monitor steps taken with a goal of walking more than 10,000 steps/day. Systolic and diastolic BP were taken using an Omron automated BP cuff. Estimated VO2 max was obtained using the Astrand Rhyming cycle ergometer test. A multi-level growth modeling approach, and a mixed model ANOVA were used to predict changes in systolic and diastolic BP, and estimated VO2 max over time by steps, age, gender, and university site. RESULTS: Steps/day averaged 12,256 (SD = 3,180) during month 1 and steadily decreased to month 6. There were significant linear and quadratic trends in systolic and diastolic BP over time. Age was positively related to initial starting values for systolic and diastolic BP, and approached significance for systolic BP changes over time. Steps/day approached significance for linear changes in systolic BP. There was a significant difference between ASU and KI participants' estimated VO2 max. There was a significant change over time in the estimated VO2 max. The number of steps taken was significantly related to changes in estimated VO2 max over time. CONCLUSIONS: The results of the present study indicate that healthy individuals who took part in a pedometer intervention improved several cardiovascular disease risk factors. PMID- 23802055 TI - Effect of glutamine and maltodextrin acute supplementation on anaerobic power. AB - PURPOSE: The aim of this study was to investigate whether supplementation of carbohydrate together with peptide glutamine would prevent anaerobic power decrease during repeated competitions. METHODS: Twenty eight physical education male students voluntarily participated in the study. Subjects were randomly divided on a maximal power (Max power) output value basis into four groups: 1) G group (oral ingestion of glutamine at the dose of 0.25 g/kg body mass in 250 ml of water), 2) M group (a single carbohydrate at a concentration of 50g of maltodextrin in 250 ml of water), 3) GM group (carbohydrate at a concentration of 50g of maltodextrin + glutamine at the dose of 0.25 g/kg body mass in 250 ml of water) and, 4) P group (just 250 ml of water and 30 gram sweetener). Each subject performed three times Running-based Anaerobic Sprint Test (RAST) with intervals of 1 hour. Max power, Minimal power (Min power) and fatigue were calculated for each participant. RESULTS: There was a significant decrease in Max and Min power in P group in time series (P<0.05). Furthermore, regarding the Max and Min power, there was significant difference between P and GM group in third bout indicating stronger influence of combination of maltodextrin and glutamine in comparison with pure consumption of glutamine and maltodextrin (P< 0.05). CONCLUSIONS: It seems acute supplementation of glutamine and maltodextrin combination, 2 hours before exercise is more efficient in prevention of anaerobic power decrease than consumption of a pure carbohydrate or glutamine in repeated bouts of RAST protocol. Thus, supplementation with both carbohydrate and peptide glutamine improved the physical performance of athletes during repeated competitions. Obviously, it is necessary to do further studies. PMID- 23802056 TI - Physiological and Technical-tactical Analysis in Brazilian Jiu-jitsu Competition. AB - PURPOSE: The present study aims at investigating the physiological response and technical-tactical parameters in Brazilian jiu-jitsu competition. METHODS: The study included 35 male Brazilian jiu-jitsu athletes (adult category, body mass: 80.2 +/- 13.0 kg), graded from white to brown belt, during combats fought at regional level. Twenty-two fights were analyzed in terms of technique and time structure. Blood glucose, lactate and maximal isometric grip strength were determined before and after the fights. The rate of perceived exertion was also assessed after the fight, using the 6-20 Borg rating. The fights were recorded and the following variables were determined: the exertion/pause ratio and subjective intensity of actions, categorized between low and high intensity. RESULTS: The results indicated that during Brazilian jiu-jitsu fights, the glycolytic pathway is only moderately activated (lactate before: 4.4 (4.0 - 4.6) mmol/L, after: 10.1 (8.0 - 11.3) mmol/L; glucose before: 112.4 +/- 22.3 mg/dL, after: 130.5 +/- 31.0 mg/dL). The exertion during the fight resulted in significant reductions in handgrip strength (right hand grip before: 45.9 +/- 10.3 kgf, after: 40.1 +/- 9.5 kgf; left hand grip before: 44.2 +/- 11.1 kgf, after: 37.0 +/- 10.2 kgf). The athletes rated the fight as hard: 15 (13 - 15). Effort/pause ratio was 6:1, while high-intensity actions lasted approximately 4 s, resulting in a low/high intensity? ratio of 8:1. CONCLUSION: It is recommended that coaches direct the training loads to simulate the energy demand imposed by the competitive matches, activating moderately the glycolytic pathway. Moreover, the time structure of combats can be used to prescribe both physical and technical-tactical training. PMID- 23802057 TI - The eccentric torque production capacity of the ankle, knee, and hip muscle groups in patients with unilateral chronic ankle instability. AB - PURPOSE: The aim of this study was to investigate eccentric torque production capacity of the ankle, knee and hip muscle groups in patients with unilateral chronic ankle instability (CAI) as compared to healthy matched controls. METHODS: In this case-control study, 40 participants (20 with CAI and 20 controls) were recruited based on convenient non-probability sampling. The average peak torque to body weight (APT/BW) ratio of reciprocal eccentric contraction of ankle dorsi flexor/plantar flexor, ankle evertor/invertor, knee flexor/extensor, hip flexor/extensor and hip abductor/adductor was determined using an isokinetic dynamometer. All subjects participated in two separate sessions with a rest interval of 48 to 72 hours. In each testing session, the torque production capacity of the ankle, knee, and hip muscle groups of only one lower limb was measured. At first, 3 repetitions of maximal eccentric-eccentric contraction were performed for the reciprocal muscles of a joint in a given movement direction. Then, the same procedure of practice and testing trials was repeated for the next randomly-ordered muscle group or joint of the same limb. RESULTS: There was no significant interaction of group (CAI and healthy controls) by limb (injured and non-injured) for any muscle groups. Main effect of limb was not significant. Main effect of group was only significant for eccentric torque production capacity of ankle dorsi flexor and hip flexor muscle groups. The APT/BW ratio of these muscles was significantly lower in the CAI group than the healthy controls (P<0.05). CONCLUSION: CAI is associated with eccentric strength deficit of ankle dorsi flexor and hip flexor muscles as indicated by reduction in torque production capacity of these muscles compared to healthy controls. This strength deficit appeared to exist in both the injured and non-injured limbs of the patients. PMID- 23802058 TI - Predicting body composition in college students using the womersley and durnin body mass index equation. AB - PURPOSE: When assessing fitness levels, body composition is usually measured. The purpose of this study was to determine the overall efficacy of a body mass index (BMI) equation for predicting body composition with respect to college aged participants. METHODS: Body composition was measured using dual-energy x-ray absorptiometry (DXA) and was estimated using the Womersley and Durnin BMI prediction equation. RESULTS: There was no significant (P=0.8) percent body fat (%BF) difference between the BMI prediction equation and DXA (BMI Predicted=25 (10) [min=6; max=52] %BF vs DXA=25 (6) [min=10; max=45] %BF). In addition, a significant correlation was found between the two approaches (r=0.791, P=0.001). However, both the standard error of estimate (6.32 %BF) and total error (6.63 %BF) were outside acceptable ranges for prediction equations. CONCLUSION: The Womersley and Durnin equation for estimating %BF was not found to be a good estimate. Therefore, although the BMI predicted %BF has been previously found to predict skinfold estimated %BF, it does not appear valid in estimating %BF from DXA. PMID- 23802059 TI - Use of platelet rich plasma in an isolated complete medial collateral ligament lesion in a professional football (soccer) player: a case report. AB - PURPOSE: Platelet-rich plasma (PRP) is derived from centrifuging whole blood to obtain a high platelet concentration containing numerous growth factors. Despite its widespread use, there is still a lack of high-level evidence regarding randomized clinical trials assessing the efficacy of PRP in treating ligament injuries. Although there is research showing an improvement in the early stages of healing in the animal model of acute medial collateral ligament (MCL) injury of the knee, there is no strong evidence to support the efficacy of PRP injections for treating MCL lesions in humans. CASE REPORT: In this report, we present a case of an elite football player, treated with multiple PRP local injections followed by rehabilitation, for a high grade MCL lesion of the knee. He was able to resume training at day 18, painfree, with full range of motion and the ability to complete a functional test based on all sport specific movements. He played matches at 25 days with no residual symptoms or functional deficit. There were no further complaints or recurrences at the 16 months follow up. CONCLUSIONS: On the basis of this report, we can assume that the treatment of high grade acute MCL lesions of the knee with PRP is a promising therapeutic option to be further explored with good quality Randomized Controlled Trials (RCTs). PMID- 23802060 TI - The Serum level of Nitric Oxide Metabolite in Two Different Protocols of Endurance and Speed Trainings in Healthy Young Men. PMID- 23802061 TI - Thyroid autoimmunity and obstetric outcomes in women with recurrent miscarriage: a case-control study. AB - OBJECTIVES: Thyroid antibody positivity during pregnancy has been associated with adverse outcomes including miscarriage and preterm delivery. The aim of the study is to evaluate the obstetric outcome in pregnant women with recurrent miscarriage and their response to levothyroxine (l-T4) therapy. STUDY DESIGN AND METHODS: All pregnant and non-pregnant women between 21 and 35 years of age with a history of two or more consecutive miscarriages were included in the study. A third group comprising 100 pregnant women without a history of miscarriage were taken as healthy controls. Thyroid autoimmunity, prevalence of subclinical hypothyroidism and maternal and foetal complications were analysed in all the groups with appropriate statistical methods. RESULTS: The mean age of the patients included in the study was 27.0+/-3.1 years. Of 100 pregnant patients with previous recurrent miscarriage, thyroid autoimmunity (thyroid peroxidase antibody (TPOAb(+)) >34 U/ml) was found in 31% of the cases. The incidence of subclinical hypothyroidism was higher in TPOAb(+) group than in TPOAb(-) group (52 vs 16%; P=0.0002). There was no difference in the prevalence of miscarriage or obstetric outcomes between recurrent miscarriage and healthy pregnant women group irrespective of TPO status. CONCLUSIONS: The prevalence of thyroid autoimmunity was higher in pregnant women with a history of recurrent abortion compared with healthy pregnant control population. Following l-T4 treatment, there was no difference in prevalence of miscarriage between hypothyroid and euthyroid individuals in TPOAb(+) women. PMID- 23802062 TI - Utilizing TH9 cells as a novel therapeutic strategy for malignancies. AB - TH9 cells join the ever-growing list of CD4+ T helper subsets and primarily mediate anti-parasite immune responses. We have recently demonstrated that tumor specific TH9 cells induce a CCL20-CCR6-dependent regulation of DCs while stimulating CD8+ T cell-mediated antitumor immunity. These findings offer a novel immunotherapeutic strategy against cancer. PMID- 23802063 TI - Exploiting the stress response to radiation to sensitize poorly immunogenic tumors to anti-CTLA-4 treatment. AB - Radiotherapy sensitizes unresponsive tumors to the antineoplastic activity of antibodies that target the inhibitory receptor CTLA-4 on T cells. One molecular mechanism accounting for this therapeutic synergy is the induction of NKG2D ligands on irradiated tumor cells. The fact that NKG2D receptors must be engaged for the elicitation of CD8+ T-cell antitumor responses has important clinical implications. PMID- 23802064 TI - DEC-205 is a cell surface receptor for CpG oligonucleotides. AB - We have recently demonstrated that synthetic CpG oligonucleotides (ODNs), which function as potent immunostimulators, bind to the multi-lectin receptor DEC-205, resulting in their internalization. DEC-205-deficient mice exhibit impaired dendritic-cell and B-cell maturation, impaired cytokine responses and suboptimal cytotoxic T-cell responses. As murine and human DEC-205 are highly conserved, CpG ODNs destined to clinical applications should be designed to maximize DEC-205 binding. PMID- 23802065 TI - COX2 regulation of breast cancer bone metastasis. AB - High expression levels of cyclooxygenase 2 expression and infiltration by regulatory T cells (Tregs) are often associated with tumor progression. We have recently reported a prostaglandin E2 (PGE2)-dependent recruitment of Tregs to the tumor, suggesting that targeting specific PGE2 receptors may constitute a valuable approach to ablate the immuno-editing that occurs along with disease progression. PMID- 23802066 TI - Immune effects of 5-fluorouracil: Ambivalence matters. AB - Cytotoxic anticancer drugs can promote antitumor immune responses. The anticancer activity of 5-fluorouracil (5FU) relies on the restoration of T-cell immunity following the elimination of myeloid-derived suppressor cells (MDSCs). We have recently discovered that the 5FU-driven activation of the NLRP3 inflammasome in MDSCs promotes tumor angiogenesis by eliciting TH17 responses that compromise anticancer immunity. This underscores the need to combine 5-FU with NLRP3 inhibitors to prevent tumor progression. PMID- 23802067 TI - Identification of human tissue cross-presenting dendritic cells: A new target for cancer vaccines. AB - Dendritic cells (DCs) are a heterogeneous group of functionally specialized antigen-presenting cells. We recently characterized the human tissue cross presenting DCs and aligned the human and mouse DC subsets. Our findings will facilitate the translation of murine DC studies to the human setting and aid the design of DC-based vaccine strategies for infection and cancer immunotherapy. PMID- 23802068 TI - Bacteria evade immune recognition via TLR13 and binding of their 23S rRNA by MLS antibiotics by the same mechanisms. AB - The immune system recognizes pathogens and other danger by means of pattern recognition receptors. Recently, we have demonstrated that the orphan Toll-like receptor 13 (TLR13) senses a defined sequence of the bacterial rRNA and that bacteria use specific mechanisms to evade macrolide lincosamide streptogramin (MLS) antibiotics detection via TLR13. PMID- 23802069 TI - ICOS is associated with poor prognosis in breast cancer as it promotes the amplification of immunosuppressive CD4+ T cells by plasmacytoid dendritic cells. AB - Regulatory T cells (Tregs) and plasmacytoid dendritic cells (pDCs) that infiltrate primary breast tumors impair patient survival. The ICOS-mediated interaction between tumor-infiltrating CD4+ T cells and pDCs leads to the amplification of Tregs and interleukin-10 secretion. Importantly, ICOS+ cell infiltration correlates with adverse patient prognosis, identifying ICOS as a new target for cancer immunotherapy. PMID- 23802070 TI - IL-10 control of dendritic cells in the skin. AB - Interleukin-10 (IL-10) is a potent immunomodulatory cytokine, whose cellular targets have not yet been precisely identified. Dendritic cell (DC)-specific IL 10 receptor knockout mice exhibit exaggerated T-cell reactivation in the skin, highlighting a key role of DCs in the maintenance of local immune homeostasis, beyond their classical function as regulators of T-cell priming in lymph nodes. PMID- 23802071 TI - Recruitment of myeloid cells to the tumor microenvironment supports liver metastasis. AB - Tumor-infiltrating immune cells play important roles in metastasis. We have recently revealed the recruitment of a specific myeloid cell subset (CD11b/Gr1mid) to hepatic metastases. Such a recruitment relies on CCL2/CCR2 signaling and acts to sustain metastatic growth. A similar cell subset was identified in patients bearing hepatic metastases of colorectal cancer, highlighting the potential therapeutic relevance of our findings. PMID- 23802072 TI - Targeting two co-operating cytokines efficiently shapes immune responses. AB - For simultaneously mobilizing the adaptive and innate immune system against cancer, we fused interleukin (IL)-2 and IL-12 to generate a dual cytokine moiety that is targeted to neoplastic lesions by an antibody-binding domain. This approach elicits a broader attack of the immune system against cancer than the use of each cytokine alone. PMID- 23802073 TI - HEPA and PARSE: Systematic discovery of clinically relevant tumor-specific antigens. AB - The effective discovery of tumor-specific antigens (TSAs) holds the key for the development of new diagnostic assays and immunotherapeutic approaches against cancer. Here, we discuss our recently developed technologies, HEPA and PARSE, which allow for the systematic identification of TSAs, generating a reservoir of immunologically and clinically relevant targets. PMID- 23802075 TI - A road less traveled paved by IDO silencing: Harnessing the antitumor activity of neutrophils. AB - Orchestrating a cytotoxic polymorphonuclear neutrophil (PMN) response strictly focused within the tumor tissue remains a formidable challenge for the successful therapeutic use of these cells. A Salmonella vector carrying an shRNA against indoleamine 2,3-dioxygenase has been shown to recruit PMNs and enhance their activation specifically in the tumor bed, resulting in significant anticancer effects. PMID- 23802074 TI - Human Vdelta2 versus non-Vdelta2 gammadelta T cells in antitumor immunity. AB - The Vdelta2 and non-Vdelta2 (mainly Vdelta1) subsets of human gammadelta T cells have distinct homing patterns and recognize different types of ligands, yet both exert potent antitumor effects. While the T-cell receptor of Vdelta2 T cells primarily recognizes tumor cell-derived pyrophosphates, non-Vdelta2 gammadelta T cells preferentially recognize stress-associated surface antigens. Here, we discuss the pros and cons of Vdelta2 versus non-Vdelta2 gammadelta T cells as tools for future immunotherapeutic interventions against cancer. PMID- 23802076 TI - Non-classical MHC Class I molecules regulating natural killer cell function. AB - Natural killer (NK) cells possess effector and immunoregulatory functions that are controlled by a myriad of receptor-ligand pairs, including human killer inhibitory receptor (KIR) and mouse Ly49-MHC class I interactions. We have recently shown that the NK cell inhibitory molecule Ly49A binds the non-classical MHC molecule H2-M3, thus regulating host innate immune responses to tumor initiation and metastasis. PMID- 23802077 TI - MIF: metastasis/MDSC-inducing factor? AB - Myeloid-derived suppressor cells (MDSCs) promote tumor growth and metastasis. We have recently demonstrated that the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) enhances the immunosuppressive microenvironment by increasing the abundance of monocytic MDSCs within the tumor. Our results suggest that MIF is a potential therapeutic target for the prevention of metastasis as it regulates the tumor microenvironment. PMID- 23802078 TI - A new strategy to target regulatory T cells in solid tumors. AB - The depletion of regulatory T cells (Tregs) is a promising therapeutic strategy to enhance antitumor immune responses. Our recent findings indicate that low doses of arsenic trioxide can delay tumor growth in murine models of colon and breast cancer by depleting Tregs through oxidative and nitrosative bursts. PMID- 23802079 TI - The natural killer cell response and tumor debulking are associated with prolonged survival in recurrent glioblastoma patients receiving dendritic cells loaded with autologous tumor lysates. AB - Recurrent glioblastomas (GBs) are highly aggressive tumors associated with a 6-8 mo survival rate. In this study, we evaluated the possible benefits of an immunotherapeutic strategy based on mature dendritic cells (DCs) loaded with autologous tumor-cell lysates in 15 patients affected by recurrent GB. The median progression-free survival (PFS) of this patient cohort was 4.4 mo, and the median overall survival (OS) was 8.0 mo. Patients with small tumors at the time of the first vaccination (< 20 cm3; n = 8) had significantly longer PFS and OS than the other patients (6.0 vs. 3.0 mo, p = 0.01; and 16.5 vs. 7.0 mo, p = 0.003, respectively). CD8+ T cells, CD56+ natural killer (NK) cells and other immune parameters, such as the levels of transforming growth factor beta, vascular endothelial growth factor, interleukin-12 and interferon gamma (IFNgamma), were measured in the peripheral blood and serum of patients before and after immunization, which enabled us to obtain a vaccination/baseline ratio (V/B ratio). An increased V/B ratio for NK cells, but not CD8+ T cells, was significantly associated with prolonged PFS and OS. Patients exhibiting NK-cell responses were characterized by high levels of circulating IFNgamma and E4BP4, an NK-cell transcription factor. Furthermore, the NK cell V/B ratio was inversely correlated with the TGFbeta2 and VEGF V/B ratios. These results suggest that tumor-loaded DCs may increase the survival rate of patients with recurrent GB after effective tumor debulking, and emphasize the role of the NK-cell response in this therapeutic setting. PMID- 23802080 TI - Anti-GD2 antibody 3F8 and barley-derived (1 -> 3),(1 -> 4)-beta-D-glucan: A Phase I study in patients with chemoresistant neuroblastoma. AB - beta-glucans are complex, naturally-occurring polysaccharides that prime leukocyte dectin and complement receptor 3. Based on our preclinical findings, indicating that oral barley-derived (1 -> 3),(1 -> 4)-beta-D-glucan (BG) synergizes with the murine anti-GD2 antibody 3F8 against neuroblastoma, we conducted a Phase I clinical study to evaluate the safety of this combinatorial regimen in patients affected by chemoresistant neuroblastoma. In this setting, four cohorts of six heavily pre-treated patients bearing recurrent or refractory advanced-stage neuroblastoma were treated with 3F8 plus BG. Each cycle consisted of intravenous 3F8 at a fixed dose of 10 mg/m2/day plus concurrent oral BG, dose escalated from 10 to 80 mg/Kg/day, for 10 d. Patients who did not develop human anti-mouse antibodies could be treated for up to 4 cycles. Twenty-four patients completed 50 cycles of therapy. All patients completed at least one cycle and were evaluable for the assessment of toxicity and responses. The maximum tolerated dose of BG was not reached, but two patients developed dose-limiting toxicities. These individuals developed grade 4 thrombocytopenia after one cycle of BG at doses of 20 mg/Kg/day and 40 mg/Kg/day, respectively. Platelet counts recovered following the administration of idiopathic thrombocytopenic purpura therapy. There were no other toxicities of grade > 2. Eleven and 13 patients manifested stable and progressive disease, respectively. Thirteen out of 22 patients with pre-treatment positive 123I-MIBG scans demonstrated clinical improvement on semiquantitative scoring. Responses did not correlate with BG dose or with in vitro cytotoxicity. In summary, 3F8 plus BG is well tolerated and shows antineoplastic activity in recurrent or refractory advanced-stage neuroblastoma patients. Further clinical investigation of this novel combinatorial immunotherapeutic regimen is warranted. PMID- 23802082 TI - Regulation of DC development and DC-mediated T-cell immunity via CISH. AB - Cytokine inducible SH2-containing protein (CISH) plays a crucial role in type 1 dendritic cell (DC) development as well as in the DC-mediated activation of cytotoxic T lymphocytes (CTLs). CISH expression at late DC developmental stages shuts down the proliferation of DC progenitors by negatively regulating signal transducer and activator of transcription 5 (STAT5) and facilitates the differentiation of DCs into potent stimulators of CTLs. PMID- 23802081 TI - Cancer vaccines: Looking to the future. AB - These are exciting times for the field of cancer immunotherapy. Although the clinical efficacy of monoclonal antibodies has been demonstrated since the early 1990s, the therapeutic profile of other immunotherapeutic approaches-especially vaccines-has not yet been formally clarified. However, the recent success of several immunotherapeutic regimens in cancer patients has boosted the development of this treatment modality. These achievements stemmed from recent scientific advances demonstrating the tolerogenic nature of cancer and the fundamental role of the tumor immune microenvironment in the suppression of antitumor immunity. New immunotherapeutic strategies against cancer attempt to promote protective antitumor immunity while disrupting the immunoregulatory circuits that contribute to tumor tolerance. Cancer vaccines differ from other anticancer immunotherapeutics in that they initiate the dynamic process of activating the immune system so as to successfully re-establish a state of equilibrium between tumor cells and the host. This article reviews recent clinical trials involving several different cancer vaccines and describes some of the most promising immunotherapeutic approaches that harness antitumor T-cell responses. In addition, we describe strategies whereby cancer vaccines can be exploited in combination with other therapeutic approach to overcome-in a synergistic fashion tumor immunoevasion. Finally, we discuss prospects for the future development of broad spectrum prophylactic anticancer vaccines. PMID- 23802083 TI - Indoleamine 2,3-dioxygenase activity and clinical outcome following induction chemotherapy and concurrent chemoradiation in Stage III non-small cell lung cancer. AB - Indoleamine 2,3-dioxygenase (IDO) has recently been proposed to account for tumor induced immunosuppression by influencing the conversion of tryptophan (Trp) into kynurenine (Kyn). The objective of our study was to correlate IDO activity with disease outcome in non-small cell lung cancer (NSCLC) patients treated with multimodal combination therapy. In a single-arm Phase II trial involving induction gemcitabine and carboplatin followed by concurrent paclitaxel, carboplatin and 74 Gy thoracic radiation in stage III NSCLC patients, plasma was drawn at baseline, post-induction, and post-concurrent therapy. The mean plasma Kyn/Trp ratio was used as a surrogate indicator of IDO activity. The 33 participants were distributed as follows: 15 females, 18 males; median age = 62; median overall survival (OS) = 22.4 (95% CI 19.3-25.1) months; median progression free survival (PFS) = 11.5 (95% CI 6.7-16.3) months. The mean Kyn/Trp ratio at baseline (4.5 +/- 2.8) was higher than that of healthy controls (2.9 +/- 1.9, p = 0.03) and increased after induction therapy (5.2 +/- 3.2, p = 0.08) and chemoradiation (5.8 +/- 3.9, p = 0.01). The post-treatment Kyn/Trp ratio and radiologic responses were not significantly associated at any time point. No significant correlation was found between baseline Kyn/Trp ratios and OS (HR = 1.1, 95% CI 0.45-2.5) or PFS (HR = 0.74, 95% CI 0.30-1.82). A post-induction chemotherapy increase in IDO activity portended worse OS (HR = 0.43, 95% CI 0.19 0.95, p = 0.037) and PFS (HR = 0.47, 95% CI 0.22-1.0, p = 0.055). This observed increase in IDO transcription may be a means for tumors to evade immunosurveillance. PMID- 23802084 TI - Early in vivo signaling profiles in MUC1-specific CD4+ T cells responding to two different MUC1-targeting vaccines in two different microenvironments. AB - Vaccines are beginning to be explored for as measures to prevent cancer. Since determining the efficacy of vaccines by evaluating disease outcome requires a long time, there is an urgent need for early predictive biomarkers. To this end, immunological endpoints that can be assessed weeks or months post-vaccination are currently being evaluated. However, when multiple vaccines are available, waiting for the development of humoral and cellular immunity could still cause delays, whereas early assessments would allow for a timely shift to more effective prevention modalities. Applying the phospho-flow technique to primary T cells, we examined the phosphorylation status of various proteins that shape the activation, proliferation, and differentiation of mucin 1 (MUC1)-specific CD4+ T cells within the first 24 hours post-immunization. It is known that a vaccine composed of a MUC1-derived peptide loaded on dendritic cells is more effective in eliciting T-cell responses than a vaccine including the same peptide plus an adjuvant. Both these vaccines stimulate T cells more effectively in wild-type (WT) than in MUC1-transgenic mice. We examined if the signaling events downstream of the TCR or linked to various proliferative and survival pathways, monitored in two different hosts as early as 3, 6, 12 and 24 hours post-immunization, could predict the differential potential of these two MUC1-targeting vaccines. The signaling signatures that we obtained primarily reflect differences between the vaccines rather than between the hosts. We demonstrate the feasibility of using a phospho-flow-based approach to evaluate the potential of a given vaccine to elicit a desired immune response. PMID- 23802085 TI - Universal tumor-reactive helper peptides from telomerase as new tools for anticancer vaccination. AB - Accumulating evidence demonstrates the importance of CD4+ T cells in antitumor immune responses. Identifying promiscuous MHC class II-binding peptides derived from relevant tumor-associated antigens that specifically target CD4+ helper T cells in vivo represent a powerful approach to fully exploit these cells for anticancer immunotherapy. PMID- 23802086 TI - Naturally circulating dendritic cells to vaccinate cancer patients. AB - Dendritic cell-based immunotherapy is a promising strategy against cancer that appears to be feasible, safe and to induce potent tumor-specific immune responses. The use of naturally circulating dendritic cells (DCs), rather than cultured monocyte-derived DCs, might constitute the next logical step to translate anticancer immune responses into long-lasting clinical benefits. PMID- 23802087 TI - Analysis of NKp30/NCR3 isoforms in untreated HIV-1-infected patients from the ANRS SEROCO cohort. AB - Natural killer (NK) cells play a prominent role at the intersection between innate and cognate immunity, thus influencing the development of multiple pathological conditions including HIV-1-induced AIDS. Not only NK cells directly kill HIV-1-infected cells, but also control the maturation and/or elimination of dendritic cells (DCs). These functions are regulated by the delicate balance between activating and inhibiting receptors expressed at the NK-cell surface. Among the former, NKp30 has raised significant interest since the alternative splicing of its intracellular domain leads to differential effector functions, dictating the prognosis of patients bearing gastrointestinal sarcoma, and B7-H6 has recently been identified as its main ligand. Since NKp30 is downregulated in CD56-/CD16+ NK cells expanded in viremic, chronically infected HIV-1+ patients, we decided to investigate the predictive value of NKp30 splice variants for spontaneous disease progression in 89 therapy-naive HIV-1-infected individuals enrolled in an historical cohort of patients followed since diagnosis (ANRS SEROCO cohort). We found no difference in the representation of NK-cell subsets (CD56bright, CD56dim, CD56neg) in HIV-1-infected patients as compared with healthy subjects. NKp30 downregulation was detected in CD56dim and CD56neg NK cell subsets, yet this did not convey any prognostic value. None of the NKp30 isoforms did affect disease progression, as measured in terms of time-to-loss of circulating CD4+ T cells, time-to-AIDS-defining events and overall survival. NKp30 isoforms do not seem to play a major role in the outcome of HIV-1 infection, but the heterogeneity of the immuno-virological status of patients at enrollment could have to be taken into account. PMID- 23802088 TI - Unique pulmonary antigen presentation may call for an alternative approach toward lung cancer immunotherapy. AB - Unlike other tumors, lung cancer appears to be poorly sensitive to immunotherapy. We have recently demonstrated an alternative pathway of lung cancer immunosurveillance. Our data indicate a failure of the adaptive immune system to mediate the immunosurveillance of lung cancer and emphasize the prominent role of natural killer cells in this setting. PMID- 23802089 TI - The microenvironment of human neuroblastoma supports the activation of tumor associated T lymphocytes. AB - Tumor infiltration by lymphocytes has been linked to improved clinical outcome in children with neuroblastoma (NB) but T-cell activation has never been demonstrated to occur within the NB microenvironment. Here we show that tumor associated lymphocytes (TALs) obtained from lesions representing all genetic subsets of NB and autologous peripheral blood lymphocytes (PBLs) analyzed on the day of tumor excision differed in composition, phenotype and functional characteristics. The NB microenvironment appeared to promote the accumulation of CD3+CD8+ T cells and contained a larger proportion of T cells expressing the interleukin-2 receptor alpha chain (CD25) and manifesting an effector memory (CCR7-CD45RA-) phenotype. Accordingly, the stimulation of PBLs with autologous tumor cells in short-term cultures increased the proportion of effector memory T cells, upregulated CD25, stimulated the expression of the TH1 cytokines interferon gamma and tumor necrosis factor alpha, and reduced the expression of transforming growth factor beta. In situ proliferation as well as a characteristic pattern of T-cell receptor aggregation at the contact sites with malignant cells was revealed by the immunohistochemical staining of TALs in primary tumors, indicating that the NB milieu is compatible with the activation of the immune system. Our results are compatible with the hypothesis that CD8+ T cells are specifically activated within the NB microenvironment, which appears to be permissive for effector memory responses. PMID- 23802090 TI - Novel multifunctional antibody approved for the treatment of breast cancer. PMID- 23802091 TI - Factors associated with delayed entry into HIV medical care after HIV diagnosis in a resource-limited setting: Data from a cohort study in India. AB - Studies from sub-Saharan Africa have shown that a substantial proportion of patients diagnosed with HIV enter into HIV medical care late. However, data from low or middle-income countries outside Africa are scarce. In this study, we investigated risk factors associated with delayed entry into care stratified by gender in a large cohort study in India. 7701 patients were diagnosed with HIV and 5410 entered into care within three months of HIV diagnosis. Nearly 80% entered into care within a year, but most patients who did not enter into care within a year remained lost to follow up or died. Patient with risk factors related to having a low socio-economic status (poverty, being homeless, belonging to a disadvantaged community and illiteracy) were more likely to enter into care late. In addition, male gender and being asymptomatic at the moment of HIV infection were factors associated with delayed entry into care. Substantial gender differences were found. Younger age was found to be associated with delayed entry in men, but not in women. Widows and unmarried men were more likely to enter into care within three months. Women belonging to disadvantaged communities or living far from a town were more likely to enter into care late. The results of this study highlight the need to improve the linkage between HIV diagnosis and HIV treatment in India. HIV programmes should monitor patients diagnosed with HIV until they engage in HIV medical care, especially those at increased risk of attrition. PMID- 23802092 TI - Qualitative community stability determines parasite establishment and richness in estuarine marshes. AB - The establishment of parasites with complex life cycles is generally thought to be regulated by free-living species richness and the stability of local ecological interactions. In this study, we test the prediction that stable host communities are prerequisite for the establishment of complex multi-host parasite life cycles. The colonization of naive killifish, Fundulus heteroclitus, by parasites was investigated in 4 salt marsh sites that differed in time since major ecological restoration, and which provided a gradient in free-living species richness. The richness of the parasite community, and the rate at which parasite species accumulated in the killifish, were similar between the low diversity unrestored site and the two high diversity (10- and 20-year) restored marsh sites. The parasite community in the newly restored marsh (0 year) included only directly-transmitted parasite species. To explain the paradox of a low diversity, highly invaded salt marsh (unrestored) having the same parasite community as highly diverse restored marsh sites (10 and 20 yrs) we assessed qualitative community stability. We find a significant correlation between system stability and parasite species richness. These data suggest a role for local stability in parasite community assembly, and support the idea that stable trophic relationships are required for the persistence of complex parasite life cycles. PMID- 23802093 TI - Arthroscopic trans-portal deep medial collateral ligament pie-crusting release. AB - Arthroscopic treatments of meniscal injuries of the knee are among the most common orthopaedic procedures performed. Adequate visualization of the posterior horn of the medial meniscus might be challenging, especially in patients with tight medial compartments. In these cases instrument manipulation in an attempt to reach the posterior horn of the meniscus can cause an iatrogenic chondral injury because of the narrow medial joint space. A transcutaneous medial collateral ligament (MCL) pie-crusting release facilitates expansion of the medial joint space in a case of a tight medial compartment. Nevertheless, it might cause injury to the superficial MCL, infection, and pain and injury to the saphenous nerve because of multiple needle punctures of the skin. We describe an inside-out, arthroscopic deep MCL pie-crusting release, which allows access to the medial meniscus through the anterior approach to provide good visualization of the footprint and sufficient working space. PMID- 23802094 TI - Hip arthroscopy for challenging deformities: posterior cam decompression. AB - Since the classic description of cam femoroacetabular impingement occurring in the anterolateral quadrant of the proximal femur, there has been growing evidence of cam impingement extending outside of this region. Although anteromedial cam decompression may be performed, posterior cam decompression is at higher theoretic risk of vascular embarrassment with osteonecrosis and/or tensile failure with fracture, leading some investigators to believe that these major deformities require open surgical correction. We present a less invasive method of arthroscopic posterior cam decompression using the modified midanterior portal while avoiding the posterolateral vasculature of the proximal femur. PMID- 23802095 TI - Improved limb positioning and hip access during hip arthroscopy with articulated traction device. AB - Surgeons use hip arthroscopy to address intra-articular pathology of the hip. To access the central compartment, traction must be applied to the leg. Various types of equipment and techniques have been used, but many have limitations. Improved ability to assess the offending pathology is achieved with improved ability to move the hip joint in space during surgery. Dynamic assessment of femoroacetabular impingement allows the surgeon to gauge the adequacy of resection. We describe the use of an articulated traction device that allows complete surgeon control over the leg position, as well as the freedom to place the leg in virtually any position with ease, unencumbered by the mechanics of a standard traction table. This device provides the surgeon with an improved ability to dynamically assess the hip and removes some of the responsibility of the operating room staff for intraoperative leg positioning. PMID- 23802096 TI - Epigenetic Therapy in Lung Cancer - Role of microRNAs. AB - Lung cancer is the leading cause of cancer deaths worldwide. microRNAs (miRNAs) are a class of small non-coding RNA species that have been implicated in the control of many fundamental cellular and physiological processes such as cellular differentiation, proliferation, apoptosis, and stem cell maintenance. Some miRNAs have been categorized as "oncomiRs" as opposed to "tumor suppressor miRs." This review focuses on the role of miRNAs in the lung cancer carcinogenesis and their potential as diagnostic, prognostic, or predictive markers. PMID- 23802097 TI - Improvement of radioimmunotherapy using pretargeting. AB - During the past two decades, considerable research has been devoted to radionuclide therapy using radiolabeled monoclonal antibodies and receptor binding agents. Conventional radioimmunotherapy (RIT) is now an established and important tool in the treatment of hematologic malignancies such as Non-Hodgkin lymphoma. For solid malignancies, the efficacy of RIT has not been as successful due to lower radiosensitivity, difficult penetration of the antibody into the tumor, and potential excessive radiation to normal tissues. Innovative approaches have been developed in order to enhance tumor absorbed dose while limiting toxicity to overcome the different limitations due to the tumor and host characteristics. Pretargeting techniques (pRIT) are a promising approach that consists of decoupling the delivery of a tumor monoclonal antibody (mAb) from the delivery of the radionuclide. This results in a much higher tumor-to-normal tissue ratio and is favorable for therapy as well and imaging. This includes various strategies based on avidin/streptavidin-biotin, DNA-complementary DNA, and bispecific antibody-hapten bindings. pRIT continuously evolves with the investigation of new molecular constructs and the development of radiochemistry. Pharmacokinetics improve dosimetry depending on the radionuclides used (alpha, beta, and Auger emitters) with prediction of tumor response and host toxicities. New constructs such as the Dock and Lock technology allow production of a variety of mABs directed against tumor-associated antigens. Survival benefit has already been shown in medullary thyroid carcinoma. Improvement in delivery of radioactivity to tumors with these pretargeting procedures associated with reduced hematologic toxicity will become the next generation of RIT. The following review addresses actual technical and clinical considerations and future development of pRIT. PMID- 23802098 TI - IL-23R is Epigenetically Regulated and Modulated by Chemotherapy in Non-Small Cell Lung Cancer. AB - The Interleukin-23 (IL-23)/IL-23R signaling axis is an important inflammatory pathway, involved in the stimulation and regulation of the T helper (Th) 17 lymphocytes, resulting in the production of IL-17. Aside from auto-immunity, this cytokine has also been linked to carcinogenesis and polymorphisms in the IL-23R gene are associated with an increased risk for the development of a number of different cancers. Activation of the IL-23 pathway results in the up-regulation of STAT3 and it is thought that the pathological consequences associated with this are in part due to the production of IL-17. We have previously identified IL 23A as pro-proliferative and epigenetically regulated in non-small cell lung cancer (NSCLC). The current study aims to evaluate IL-23R in greater detail in NSCLC. We demonstrate that IL-23R is expressed and epigenetically regulated in NSCLC through histone post-translation modifications and CpG island methylation. In addition, Gemcitabine treatment, a chemotherapy drug used in the treatment of NSCLC, resulted in the up-regulation of the IL-23R. Furthermore, Apilimod (STA 5326), a small molecule which blocks the expression of IL-23 and IL-12, reduced the proliferative capacity of NSCLC cells, particularly in the adenocarcinoma (A549) sub-type. Apilimod is currently undergoing investigation in a number of clinical trials for the treatment of auto-immune conditions such as Crohn's disease and Rheumatoid Arthritis. Our results may have implications for treating NSCLC patients with Gemcitabine or epigenetic targeted therapies. However, Apilimod may possibly provide a new treatment avenue for NSCLC patients. Work is currently ongoing to further delineate the IL-23/IL-23R axis in this disease. PMID- 23802099 TI - The Paradox of Akt-mTOR Interactions. AB - The serine threonine protein kinase, Akt, is at the central hub of signaling pathways that regulates cell growth, differentiation, and survival. The reciprocal relation that exists between the two activating phosphorylation sites of Akt, T308 and S473, and the two mTOR complexes, C1 and C2, forms the central controlling hub that regulates these cellular functions. In our previous review "PI3Kinase (PI3K)-AKT-mTOR and Wnt signaling pathways in cell cycle" we discussed the reciprocal relation between mTORC1 and C2 complexes in regulating cell metabolism and cell cycle progression in cancer cells. We present in this article, a hypothesis that activation of Akt-T308 phosphorylation in the presence of high ATP:AMP ratio promotes the stability of its phosphorylations and activates mTORC1 and the energy consuming biosynthetic processes. Depletion of energy leads to inactivation of mTORC1, activation of AMPK, FoxO, and promotes constitution of mTORC2 that leads to phosphorylation of Akt S473. Akt can also be activated independent of PI3K; this appears to have an advantage under situations like dietary restrictions, where insulin/insulin growth factor signaling could be a casualty. PMID- 23802101 TI - The mediterranean diet: a history of health. AB - The Mediterranean tradition offers a cousine rich in colors, aromas and memories, which support the taste and the spirit of those who live in harmony with nature. Everyone is talking about the Mediterranean diet, but few are those who do it properly, thus generating a lot of confusion in the reader. And so for some it coincides with the pizza, others identified it with the noodles with meat sauce, in a mixture of pseudo historical traditions and folklore that do not help to solve the question that is at the basis of any diet: combine and balance the food so as to satisfy the qualitative and quantitative needs of an individual and in a sense, preserves his health through the use of substances that help the body to perform normal vital functions. The purpose of our work is to demonstrate that the combination of taste and health is a goal that can be absolutely carried out by everybody, despite those who believe that only a generous caloric intake can guarantee the goodness of a dish and the satisfaction of the consumers. That should not be an absolute novelty, since the sound traditions of the Mediterranean cuisine we have used for some time in a wide variety of tasty gastronomic choices, from inviting colors and strong scents and absolutely in line with health. PMID- 23802100 TI - Lung dendritic cells facilitate extrapulmonary bacterial dissemination during pneumococcal pneumonia. AB - Streptococcus pneumoniae is a leading cause of bacterial pneumonia worldwide. Given the critical role of dendritic cells (DCs) in regulating and modulating the immune response to pathogens, we investigated here the role of DCs in S. pneumoniae lung infections. Using a well-established transgenic mouse line which allows the conditional transient depletion of DCs, we showed that ablation of DCs resulted in enhanced resistance to intranasal challenge with S. pneumoniae. DCs depleted mice exhibited delayed bacterial systemic dissemination, significantly reduced bacterial loads in the infected organs and lower levels of serum inflammatory mediators than non-depleted animals. The increased resistance of DCs depleted mice to S. pneumoniae was associated with a better capacity to restrict pneumococci extrapulmonary dissemination. Furthermore, we demonstrated that S. pneumoniae disseminated from the lungs into the regional lymph nodes in a cell independent manner and that this direct way of dissemination was much more efficient in the presence of DCs. We also provide evidence that S. pneumoniae induces expression and activation of matrix metalloproteinase-9 (MMP-9) in cultured bone marrow-derived DCs. MMP-9 is a protease involved in the breakdown of extracellular matrix proteins and is critical for DC trafficking across extracellular matrix and basement membranes during the migration from the periphery to the lymph nodes. MMP-9 was also significantly up-regulated in the lungs of mice after intranasal infection with S. pneumoniae. Notably, the expression levels of MMP-9 in the infected lungs were significantly decreased after depletion of DCs suggesting the involvement of DCs in MMP-9 production during pneumococcal pneumonia. Thus, we propose that S. pneumoniae can exploit the DC-derived proteolysis to open tissue barriers thereby facilitating its own dissemination from the local site of infection. PMID- 23802102 TI - Prevalence of Depression among Infertile Couples in Iran: A Meta-Analysis Study. AB - BACKGROUND: Several studies have been conducted in Iran in order to investigate the prevalence of depression among infertile couples. However, there is a remarkable diversity among the results. This meta-analysis was conducted to estimate an overall prevalence rate of depression among infertile couples in Iran. METHODS: International and national electronic databases were searched up to June 2011 including MEDLINE, Science Citation Index Expanded, Scopus, SID, MagIran, and IranMedex as well as conference databases. Furthermore, reference lists of articles were screened and the studies' authors were contacted for additional references. Cross-sectional studies addressing the prevalence of depression among infertile couples were included in this meta-analysis. We assessed 12 separate studies involving overall 2818 participants of which 1251 had depression. RESULTS: Overall prevalence rate of depression among infertile couples was 0.47 (95% CI: 0.40, 0.55). The prevalence rate of depression was 0.44 (95% CI: 0.32, 0.56) during 2000 to 2005 and 0.50 (95% CI: 0.43, 0.57 during 2006 to 2011. The prevalence rate of depression was 0.46 (95% CI: 0.39, 0.53) among women and 0.47 (95% CI: 0.40, 0.54) among men. CONCLUSION: Not only the prevalence of depression in infertile couples was high but also had increasing growth in recent years. Furthermore, despite many studies conducted addressing the prevalence of depression in infertile couples, there is however a remarkable diversity between the results. Thus, one can hardly give a precise estimation of the prevalence rate of depression among infertile couples in Iran now. PMID- 23802103 TI - Effectiveness of Nutrition Education vs. Non-Nutrition Education Intervention in Improving Awareness Pertaining Iron Deficiency among Anemic Adolescents. AB - BACKGROUND: This study was carried out to compare the effect between nutrition education intervention and non-nutrition education intervention on awareness regarding iron deficiency among schooling adolescents in Tanah Merah, one of rural district in Kelantan, Malaysia. METHODS: This study which was started in year 2010 involved 280 respondents (223 girls, 57 boys, age: 16 yr) from schools in Tanah Merah. The selection criteria were based on hemoglobin level (Hb = 7 - 11.9 g/dL for girls; Hb = 7 - 12.9 g/dL for boys). They were divided into 2 groups. The first group received nutrition education package (Nutrition education, NE), whereas another group was entitled to receive non-nutrition education intervention (Non-Nutrition Education, NNE) (supplement only). Both interventions were implemented for 3 months. The changes in awareness among respondents of both groups were evaluated using multi-choices questionnaire. RESULTS: Nutrition education receiver group (NE) demonstrated improvement in awareness at post-intervention. No substantial improvement was demonstrated by the counterpart group (NNE). CONCLUSION: Multimedia nutrition education program conducted at school setting was in fact practical and effective in improving awareness on iron deficiency among anemic adolescents. PMID- 23802104 TI - Off-Label and Off-NCCN Guidelines Uses of Antineoplastic Drugs in China. AB - BACKGROUND: To evaluate off-label and off-NCCN guidelines uses of antineoplastic drugs in a major Chinese hospital. METHODS: Totally 1122 patients were selected from July to December 2011. Then, the off-label and off-NCCN guidelines uses of antineoplastic drugs were analyzed. RESULTS: In 798 of 1122 patients (71.12%), drugs were used for off-label. In 317 of 1122 patients (28.25%), the drugs were prescribed for off-label and off-NCCN guidelines. 2591 medical orders for 1122 patients, 1051/2591 (40.56%) medical orders were off-label; 445/2591(17.17%) medical orders were off-label and off-NCCN guidelines. In 445 off-label and off NCCN medical orders, 399 (89.66%) were unapproved indications, 38 (8.54%) were unapproved drug concentration and 12 (2.70%) were unapproved route of administration. Percentage of off-label and off-NCCN guidelines drug uses in male was higher than that in female (21.92% vs. 11.39%, P<0.01). Compared with other lines of treatment, percentage of off-label and off-NCCN guidelines drug uses in postoperative adjuvant was the smallest (P<0.01) and percentage in three or multi line treatments was the highest (P<0.01). The pancreatic cancer possessed the highest percentage (38.74%) of off-label and off-NCCN guidelines drug uses among all types of cancer (P<0.01). CONCLUSION: Off-label uses of antineoplastic drugs are generally common in China hospitals based on NCCN guidelines. The fact suggests that anti-tumor treatment was relatively standard in China. Off-label and off-NCCN guidelines drug uses were mainly for individual treatment. Doctors should fully consider the adverse drug reaction, contraindication, cautions and increase the drug security monitoring. Uncorrected drug concentration should be avoided for drug risk. PMID- 23802105 TI - Do Biochemical Markers and Apa I Polymorphism in IGF-II Gene Play a Role in the Association of Birth Weight and Later BMI? AB - BACKGROUND: The aim of the study was to explore the mechanisms underlying the association of birth weight with later body mass index (BMI) from the biochemical markers related to metabolism and the Apa I polymorphism in IGF-II gene. METHODS: A total of 300 children were selected randomly from the Macrosomia Birth Cohort in Wuxi, China. The height and weight were measured and blood samples were collected. Plasma concentrations of 8 biochemical markers were detected. Apa I polymorphism was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: Biochemical markers were detected for 296 subjects and 271 subjects were genotyped for the Apa I polymorphism. No association was found between birth weight and 8 biochemical markers. In boys, the BMIs of AA, AG and GG genotypes were 16.10 +/- 2.24 kg/m(2), 17.40 +/- 3.20 kg/m(2), 17.65 +/- 2.66 kg/m(2). And there was statistical difference among the three genotypes. But in girls, there was no statistical difference. The birth weights of AA, AG and GG genotypes were 3751.13 +/- 492.43 g, 3734.00 +/- 456.88 g, 3782.00 +/- 461.78 g. And there was no statistical difference among the three genotypes. CONCLUSION: Biochemical markers are not associated with birth weight. Apa I polymorphism may be related to childhood BMI, but it may be not associated with birth weight. Therefore, biochemical markers and Apa I polymorphism might not play a role in the association of birth weight and BMI. PMID- 23802106 TI - Elevated Blood Pressure among Rural South African Children in Thohoyandou, South Africa. AB - BACKGROUND: Whilst there seem to be available data on blood pressure profiles of South African children, especially in urban areas, few data exist on rural children. The aims of this study were to determine the blood pressure profiles of rural South African children residing in Thohoyandou; and to examine the relationship between body mass index and blood pressure among the children. METHODS: The study involved 296 (134 boys and 135 girls) children aged 7-13 years. Body weight and height were measured using standard procedures. Overweight was defined by body mass index (BMI) for gender and age. Blood pressure was monitored in each child thrice using validated electronic devices (Omron 7051T). Hypertension was determined as the average of three separate blood pressure readings where the systolic or diastolic blood pressure was >= 90th percentile for age and sex. RESULTS: Overweight among the girls (4.7%) was higher compared with the boys (3.9%). Both systolic and diastolic pressures (SBP and DBP) increase with age in both sexes. The proportion of children with > 90th percentile occur at only ages 12 and 13 years. The incidence of hypertension (SBP > 90th percentile) was 0.4% and 0.2% in boys and girls, respectively. The SBP and DBP pressures significantly (P<0.05) correlate with age; body mass, height and BMI. CONCLUSION: Elevated blood pressure is prevalent among rural South African children residing in this region. Also, blood pressure increased with age in both boys and girls, and this positively correlated with age, body weight, height and BMI. PMID- 23802107 TI - Gastrointestinal helminth infection in pregnancy: disease incidence and hematological alterations. AB - BACKGROUND: The incidence and hematological effects of helminth infection during pregnancy were investigated among pregnant women in Isiala, Mbano, Southeast Nigeria. METHODS: Totally 282 pregnant women were enlisted for the study between October 2011 and September 2012. Stool samples were examined for intestinal helminths using formalin-ether sedimentation technique. Hemoglobin (Hb) and Packed Cell Volume (PCV) levels were evaluated in venous blood samples using Sahli's and microhaematocrit methods respectively. RESULTS: Forty six (16.3%) subjects were infected with at least one helminth parasite; 24 (8.5%) hookworm, 14(5.0%) and 2(0.7%) A. lumbricoides and Trichuris trichiura infections respectively. Intestinal helminthiases in pregnant women was significantly associated with age (P<0.05). The prevalence of intestinal helminthiases by parity was also significantly different (P<0.05) with primigravidae having the highest infection rate (27.5%). Hematological assessment showed that the prevalence of anemia among the women was 58.9% (mean+/-SD = 9.3+/-1.0). The differences in hemoglobin levels by age groups was statistically significant (P <0.05). The contributory effect of gastrointestinal helminths in anemia showed that infected pregnant women had lower mean hemoglobin (8.60+/-0.22g/dl) than the uninfected (9.72+/-0.07g/dl). Significant difference (t-value = 5.660, P<0.05) was observed between the Hb of the infected and uninfected pregnant women. In addition, infected pregnant women had mean PCV of 26.09+/-0.65% while the uninfected had 34.54+/-2.96%. The mean PCV of infected pregnant women was significantly different (t-value= 0.013, P<0.05) from that of the uninfected. CONCLUSION: Anti-helminthic therapy after the first trimester should be part of the antenatal programme. Intestinal helminth infection showed significant negative correlation with Hb and PCV and contributed moderately to anemia. PMID- 23802108 TI - Serum adiponectin and resistin levels in de novo and relapsed acute lymphoblastic leukemia children patients. AB - BACKGROUND: Adipose tissue secretes a large number of adipocytokines such as leptin, resistin, and adiponectin. Many of these hormones and cytokines are altered in obese individuals and may lead to disruption of the normal balance between cell proliferation, differentiation, and apoptosis. The aim of our work was to investigate the disturbance of secretion of adiponectin and resistin in de novo and relapsed acute lymphoblastic leukemia (ALL) in Egyptian children and determine whether adiponectin and resistin are implicated in increased risk relapse compared to healthy individuals. METHODS: Measurements of adiponectin and resistin were performed at diagnosis, in 32 patients with de novo ALL aged 3 to 18 years (mean 9.8 y) and 19 children with relapsed ALL aged 5 to 17 (mean 9.9 yr). 10 apparently healthy children with matched age and sex were used as controls. RESULTS: Mean adiponectin levels were low (P < 0.05), whereas mean resistin levels were high (P<0.05) at diagnosis and relapsed ALL (compared to healthy controls). A significant decrease of adiponectin levels was observed in relapsed ALL compared to de novo ALL. In contrast resistin was significantly increased in relapsed ALL compared to de novo patients. Adiponectin in ALL subjects inversely correlated with resistin level (r = -0.51, P < 0.001). CONCLUSION: Low adiponectin and high resistin level at diagnosis suggest their implication in ALL pathogenesis and may serve as potential clinically significant diagnostic markers to detect leukemic relapse. PMID- 23802109 TI - Novel Psychoactive Substances (NPS): a Study on Persian Language Websites. AB - BACKGROUND: During the past few years, there has been an increasing recognition that Internet is playing a significant role in the synthesis, the distribution and the consumption of Novel Psychoactive Substances (NPS).The aim of this study was to assess the online availability of NPS in Persian language websites. METHODS: The Google search engine was used to carry out an accurate qualitative assessment of information available on NPS in a sample of 104 websites. RESULTS: The monitoring has led to the identification of 14 NPS including herbal, synthetic, pharmaceutical and combination drugs that have been sold online. CONCLUSION: The availability of online marketing of NPS in Persian language websites may constitute a public health challenge at least across three Farsi speaking countries in the Middle East. Hence, descriptions of this phenomenon are valuable to clinicians and health professional in this region. Further international collaborative efforts may be able to tackle the growth and expansion of regular offer of NPS. PMID- 23802110 TI - Ethnic Differences and Motivation Based on Maslow's Theory on Iranian Employees. AB - BACKGROUND: The aim of this study was to assess the levels of Maslow's hierarchy of needs theory had been fulfilled and to compare the Maslow's hierarchy of needs among Iranian different ethnic groups at Tehran University of Medical Sciences (TUMS). METHODS: This research was a descriptive-analytical study which conducted among administrative employees of Tehran University of Medical Sciences; Tehran, Iran. The structured questionnaire consisted of 20 questions and demographic details. Each question had 4 parts to measure Maslow's hierarchy of needs. The questionnaire was distributed randomly among 133 employees to fill-up the demographic details and the other questions. Data was collected and analyzed by SPSS software, and One Way ANOVA, T-test, Spearman and Mann Whitney statistical methods. RESULTS: TUMS ethnic groups of the employees placed most importance on Basic, Self-esteem and Self-actualization. In addition, we found that Persians, Mazandaranians, and Turks ethnic groups, scored the most mean for Maslow's hierarchical needs compared to the other ethnic groups. CONCLUSION: Basic needs and safety needs is available amongst the different ethnic groups in Iran. As though, self-actualization needs are ultimate human goal, Iranian employees' ethnic groups pay emphasis on these needs. We believe that new structures and work practices such as prevailing cultural values and beliefs of the society or the organizations must be explored if Iranian-based organizations want to remain responsive to the needs of the workplace. PMID- 23802111 TI - Cross-Cultural Adaptation, Validation and Standardization of Ages and Stages Questionnaire (ASQ) in Iranian Children. AB - BACKGROUND: To provide the validated and standardized form of the Persian version of the Ages and Stages Questionnaires as an appropriate developmental screening tool for evaluation of Iranian children's development. METHODS: This was a cross sectional study. Translation and back-translation, content validity determination, cultural and lingual modifications, pilot study on 100 parents and inter-rater reliability determinations were performed, respectively. The national and final stage was carried out 11000, 4-60 month-old children in selected cities throughout the country in order to determine the validity, standard deviation, reliability, sensitivity, specificity, and mean scores points of the test. RESULTS: The reliability, determined by cronbach's alpha ranged from 0.76 to 0.86 and the inter-rater reliability was 0.93. The validity determined by factor analysis was satisfactory. The mean scores of Iranian children were identified and compared with those of the normative sample as well as with three other populations of children. The developmental status of Iranian children was higher in the communication, problem-solving and personal-social domains, especially under the age of 24 months, after which their developmental status seems to deteriorate, especially in the motor domains. CONCLUSION: The Persian version of the ASQ has appropriate validity and reliability for screening developmental disorders in Iran. PMID- 23802112 TI - Immunoglobulin A Nephropathy and Malaria falciparum Infection; a Rare Association. AB - Glomerular involvement occurs as a rare form of renal manifestation in Plasmodium falciparum malaria. Here, we report a rare case of falciparum malaria-associated IgA nephropathy. A 28-year-old man was admitted because of fever and abdominal pain. Ultrasound and computed tomography (CT) showed right kidney pyonenphrosis. Despite placing a nephrostomy tube, fever continued. Repeated CT was in favor of focal pyelonephritis. In addition, peripheral blood smear suggested malaria. Anti malarial drugs were initiated and right nephrectomy was performed. One year after recovery from malaria, a persistent rise in serum creatinine was detected. A left kidney biopsy showed mesangial proliferation and dominant IgA deposits in immunofluorescence study while C1q was not deposited. The impression was IgA nephropathy with M1E0S0T0 of Oxford classification. The patient was prescribed a combination of low dose prednisolone and angiotensin converting enzyme inhibitor. Six months after treatment serum creatinine decreased from 1.6 mg/dL to 1.3mg/dL and urine abnormalities were disappeared. Our findings suggest that malaria infection might be associated with IgA nephropathy. PMID- 23802113 TI - Galen's Viewpoint about Classification of Health States. AB - Priority of health preservation and disease prevention to disease treatment is clear. During years, numerous studies with various aims have been done in relation with classification of health states based on some classification systems in order to determine level of healthiness among different groups of people. However it is thought that the need to classify interventions emerged for the first time in 1971, study of ancient medical sources results in getting some interesting things else. This study done through Qualitative research method on "Resale fi Hefzossehhat"authored by Galen, discusses about Galen's viewpoint about classification of health states. PMID- 23802114 TI - Evaluation of Communication for Behavioral Impact (COMBI) Program in Dengue Prevention: A Qualitative and Quantitative Study in Selangor, Malaysia. PMID- 23802115 TI - Primary Health Care Strategic Key to Control HIV/AIDS in Iran. PMID- 23802116 TI - Explosion of hospital nursing services in china. PMID- 23802117 TI - Mineral and matrix changes in Brtl/+ teeth provide insights into mineralization mechanisms. AB - The Brtl/+ mouse is a knock-in model for osteogenesis imperfecta type IV in which a Gly349Cys substitution was introduced into one COL1A1 allele. To gain insight into the changes in dentin structure and mineral composition in these transgenic mice, the objective of this study was to use microcomputed tomography (micro-CT), scanning electron microscopy (SEM), and Fourier transform infrared imaging (FTIRI) to analyze these structures at 2 and 6 months of age. Results, consistent with the dental phenotype in humans with type IV OI, showed decreased molar volume and reduced mineralized tissue volume in the teeth without changes in enamel properties. Increased acid phosphate content was noted at 2 and 6 months by FTIRI, and a trend towards altered collagen structure was noted at 2 but not 6 months in the Brtl/+ teeth. The increase in acid phosphate content suggests a delay in the mineralization process, most likely associated with the defect in the collagen structure. It appears that in the Brtl/+ teeth slow maturation of the mineralized structures allows correction of altered mineral content and acid phosphate distribution. PMID- 23802118 TI - Delivery of RNA and its intracellular translation into protein mediated by SDS CTAB vesicles: potential use in nanobiotechnology. AB - Catanionic vesicles are supramolecular aggregates spontaneously forming in water by electrostatic attraction between two surfactants mixed in nonstoichiometric ratios. The outer surface charges allow adsorption to the biomembrane by electrostatic interactions. The lipoplex thus obtained penetrates the cell by endocytosis or membrane fusion. We examined the possible cytotoxic effects and evaluated the transfection efficiency of one vesicle type as compared to known commercial carriers. We show that the individual components of two different vesicles types, CTAB (cetyltrimethylammonium bromide) and DDAB (didodecyldimethylammonium bromide) are detrimental for cell survival. We also assayed the cytotoxicity of SDS-DDAB vesicles and showed dose and time dependency, with the DDAB component being per se extremely cytotoxic. The transfection efficiency of exogenous RNA mediated by SDS-CTAB increases if vesicles assemble in the presence of the reporter RNA; finally, freezing abrogates the transfection ability. The results of our experimental strategy suggest that catanionic vesicles may be adopted in gene therapy and control of antiproliferative diseases. PMID- 23802119 TI - Oleaceran: a novel spiro[isobenzofuran-1,2'-naptho[1,8-bc]furan] isolated from a terrestrial Streptomyces sp. AB - Chemical analysis of a terrestrial-derived Streptomyces sp. Lv20-195 cultivated from the root zone of Olea europea yielded oleaceran, 1, possessing a novel spiro[isobenzofuran-1,2'-naptho[1,8-b,c]furan] carbon skeleton. The structure of 1 was determined by detailed spectroscopic analysis. PMID- 23802120 TI - Autonomic correlates of children's concern and disregard for others. AB - Psychophysiological research on empathy and prosociality in children has focused most often on cardiac activity, heart rate (HR), and HR deceleration in particular. We examined these processes in 7-year-old children during two empathy mood inductions. We independently assessed children's responses to others' distress in two different contexts: structured probes (simulated pain) and maternal interviews. We identified three groups of children who showed either (1) concern for others in distress (i.e., empathy and prosocial behaviors), (2) active disregard (i.e., anger/hostility and antisocial behavior), or (3) passive disregard (i.e., little or no concern). We compared groups on HR and HR deceleration. The active disregard group consistently showed the lowest HR both when groups were based on structured probes and on mothers' reports. Children who showed passive disregard displayed little self-distress during other's distress and different patterns of association of self-distress and HR than the other two groups. Active and passive disregard thus may reflect two different aspects of lack of concern for others. HR deceleration was seen for all three groups, suggesting it is not necessarily a cardiac index of concern for others. Interdisciplinary approaches and multiple-systems analysis are needed to better understand psychobiological substrates. PMID- 23802121 TI - Modulation of interpersonal trust in borderline personality disorder by intranasal oxytocin and childhood trauma. AB - Borderline personality disorder (BPD) is characterized by interpersonal difficulties, whereby patients are negatively biased concerning the evaluation of others' trustworthiness. Here, we examined the effect of oxytocin on interpersonal behavior of BPD patients in a trust game, emphasizing the assessment of facial attractiveness of the patients' counterparts in the game, and patients' history of childhood trauma. Thirteen BPD patients and thirteen healthy controls played a trust game after receiving oxytocin or placebo in a randomized, double-blind crossover design. Childhood trauma was evaluated using the Childhood Trauma Questionnaire (CTQ). Patients transferred less money in the oxytocin condition compared to placebo. While healthy controls transferred more money units (MUs) to attractive counterparts than to unattractive ones only after the administration of oxytocin, BPD patients showed this pattern in both conditions. Emotional neglect during childhood negatively correlated with the amount of MUs transferred by patients under oxytocin, but not placebo. Oxytocin had a trust-lowering effect in BPD, which was correlated with patients' history of childhood trauma. Patients' evaluation of interpersonal trust seems to depend more on attractiveness features of their counterparts than in controls, a finding that may have important implications for further research on the usefulness of "prosocial" peptides as an adjunct to psychotherapeutic interventions. PMID- 23802122 TI - Perspective taking modulates positivity bias in self-appraisals: behavioral and event-related potential evidence. AB - Previous studies have reported that when people self-reflect--they typically judge the self as more positive (or less negative) compared to others on a range of dimensions (such as health, social skills, or achievement). In the present study, we investigated whether viewing the self through the eyes of other people reduces this egocentric (self-centered) bias. Event-related brain potentials (ERPs) were examined in 17 subjects who performed judgments of adjectives in positive or negative valences from either self-perspective or other-perspective. Reaction times revealed an interaction between the factors perspective and emotional valence. Faster responses occurred after positive words in the self perspective condition. A similar interaction was observed in the ERP waveforms in the time range of the N400 component: smaller N400 amplitudes were elicited by positive stimuli compared to negative stimuli in the self-perspective condition, but not in the other-perspective condition. Similarly, a reversed pattern was found in the late positive component (LPC) at 415-815 ms. The present study suggests that shifts in perspectives between self and others can change self appraisal, which in turn reduces egocentric biases of the self. On a neural level, this modulation may be associated with an increase in self-monitoring processes. PMID- 23802123 TI - Emotional intelligence correlates with functional responses to dynamic changes in facial trustworthiness. AB - Emotional intelligence (EI) refers to a constellation of traits, competencies, or abilities that allow individuals to understand emotional information and successfully navigate and solve social/emotional problems. While little is known about the neurobiological substrates that underlie EI, some evidence suggests that these capacities may involve a core neurocircuitry involved in emotional decision-making that includes the ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), insula, and amygdala. In a sample of 39 healthy volunteers (22 men; 17 women), scores on the Bar-On EQ-i (a trait/mixed model of EI) and Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT; an ability model of EI) were correlated with functional magnetic resonance imaging responses during brief presentations of moving facial expressions that changed in the level of perceived trustworthiness. Core emotion neurocircuitry was responsive to dynamic changes in facial features, regardless of whether they reflected increases or decreases in apparent trustworthiness. In response to facial movements indicating decreasing trustworthiness, MSCEIT correlated positively with functional responses of the vmPFC and rostral ACC, whereas the EQ-i was unrelated to regional activation. Systematic differences in EI ability appear to be significantly related to the responsiveness of the vmPFC and rostral ACC to facial movements suggesting potential trustworthiness. PMID- 23802124 TI - Cortical mechanisms of pretense observation. AB - Pretend play emerges in children the world over around 18 months and continues into adolescence and even adulthood. Observing and engaging in pretense are thought to rely on similar neural mechanisms, but little is known about them. Here we examined neural activation patterns associated with observing pretense acts, including high-likelihood, low-likelihood, and imaginary substitute objects, as compared with activation patterns when observing parallel real acts. The association between fantasy predisposition and cortical representations of pretense was also explored. Supporting prior research that used more limited types of pretense, observed pretense acts, when contrasted with real acts, elicited activity in regions associated with mentalizing. A novel contribution here is that substitute object pretense (high- and low-likelihood) elicited significantly more activity than imaginary (pantomime) acts not only in theory of mind regions but also in the superior parietal lobule, a region thought to aid in the prediction and error-monitoring of motor actions. Finally, when high likelihood pretense acts were contrasted with real acts, participants with elevated fantasy predispositions evidenced significantly different activation patterns than their more reality-prone peers. Future research will explore the intersection of fantasy predisposition and experience with the neural representation of pretense. PMID- 23802125 TI - Visioning in the brain: an fMRI study of inspirational coaching and mentoring. AB - Effective coaching and mentoring is crucial to the success of individuals and organizations, yet relatively little is known about its neural underpinnings. Coaching and mentoring to the Positive Emotional Attractor (PEA) emphasizes compassion for the individual's hopes and dreams and has been shown to enhance a behavioral change. In contrast, coaching to the Negative Emotional Attractor (NEA), by focusing on externally defined criteria for success and the individual's weaknesses in relation to them, does not show sustained change. We used fMRI to measure BOLD responses associated with these two coaching styles. We hypothesized that PEA coaching would be associated with increased global visual processing and with engagement of the parasympathetic nervous system (PNS), while the NEA coaching would involve greater engagement of the sympathetic nervous system (SNS). Regions showing more activity in PEA conditions included the lateral occipital cortex, superior temporal cortex, medial parietal, subgenual cingulate, nucleus accumbens, and left lateral prefrontal cortex. We relate these activations to visioning, PNS activity, and positive affect. Regions showing more activity in NEA conditions included medial prefrontal regions and right lateral prefrontal cortex. We relate these activations to SNS activity, self-trait attribution and negative affect. PMID- 23802126 TI - Stereoselective synthesis of 2-acetamido-1,2-dideoxyallonojirimycin (DAJNAc), a new potent hexosaminidase inhibitor. AB - A practical synthesis of the previously unreported N-acetyl-D-allosamine glycomimetic DAJNAc is described. The reaction sequence involves Pd-catalyzed allylic substitution by phthalimide in an azaheterobicyclic scaffold as the key step. The new iminosugar resulted in being a stronger beta-N acetylglucosaminidase (human placenta) competitive inhibitor than the D-gluco (DNJNAc) and D-galacto (DGJNAc) stereoisomers. PMID- 23802128 TI - Implementing technology-based embedded assessment in the home and community life of individuals aging with disabilities: a participatory research and development study. AB - PURPOSE: The goal of the study was to investigate the accuracy, feasibility and acceptability of implementing an embedded assessment system in the homes of individuals aging with disabilities. METHOD: We developed and studied a location tracking system, UbiTrack, which can be used for both indoor and outdoor location sensing. The system was deployed in the homes of five participants with spinal cord injuries, muscular dystrophy, multiple sclerosis and late effects of polio. We collected sensor data throughout the deployment, conducted pre and post interviews and collected weekly diaries to measure ground truth. RESULTS: The system was deployed successfully although there were challenges related to system installation and calibration. System accuracy ranged from 62% to 87% depending upon room configuration and number of wireless access points installed. In general, participants reported that the system was easy to use, did not require significant effort on their part and did not interfere with their daily lives. CONCLUSIONS: Embedded assessment has great potential as a mechanism to gather ongoing information about the health of individuals aging with disabilities; however, there are significant challenges to its implementation in real-world settings with people with disabilities that will need to be resolved before it can be practically implemented. IMPLICATIONS FOR REHABILITATION: Technology-based embedded assessment has the potential to promote health for adults with disabilities and allow for aging in place. It may also reduce the difficulty, cost and intrusiveness of health measurement. Many new commercial and non commercial products are available to support embedded assessment; however, most products have not been well-tested in real-world environments with individuals aging with disability. Community settings and diverse population of people with disabilities pose significant challenges to the implementation of embedded assessment systems. PMID- 23802127 TI - sFRP1 inhibits epithelial-mesenchymal transition in A549 human lung adenocarcinoma cell line. AB - Epithelial-mesenchymal transition (EMT) plays an important role in tumor metastasis of human nonsmall cell lung cancer (NSCLC). The Wnt pathway is identified as a key regulator of normal tissue development, and its aberrant activation contributes to the process of EMT. The secreted frizzled-related protein 1 (sFRP1), a Wnt-signaling antagonist, is downregulated in many tumors, including lung cancer. However, the role of sFRP1 in EMT and tumor metastasis remains unclear. In this study, we found that sFRP1 was dramatically downregulated in transforming growth factor beta1 (TGF-beta1)-induced EMT in the A549 human lung cancer cell line. Restoration of sFRP1 could inhibit the TGF beta1-induced EMT phenotype and tumor metastasis of the A549 cell line both in vitro and in vivo through inhibition of the Wnt pathway. Furthermore, FH535, a reversible Wnt-signaling inhibitor, exerted a similar effect on the TGF-beta1 induced EMT phenotype. These results indicate that sFRP1, an endogenous antagonist of the Wnt pathway, inhibits TGF-beta1-induced EMT, and might be a potential biomarker for the treatment of NSCLC. PMID- 23802129 TI - The experience of being a motorised mobility scooter user. AB - PURPOSE: To explore the individual experience of being a scooter user and the ways in which scooters impact the individual's community and social engagement, daily activities and enhances mobility. METHODS: A qualitative, constructive framework utilising purposive sampling and a semi structured interview was used with 14 individuals. Questions were categorised according to the International Classification of Functioning, Disability and Health framework into the three areas of activities, participation and environmental factors. RESULTS: The three main themes identified through the research were knowledge, engagement and environments. Knowledge included a lack of concise information, and adequate trialling and training prior to purchase. Engagement consisted of participation and interaction demonstrating scooter use resulted in increased participation, role maintenance, choice, freedom and social interaction. Environments highlighted discrimination from the wider population and building design and barriers. CONCLUSIONS: The research demonstrated a strong positive impact on individual's engagement from using a scooter, while highlighting a lack of adequate knowledge about scooters, batteries, skill ability and design along with environmental challenges of discriminatory attitudes and physical barriers. The research indicates the need for pre-purchase assessments and trials along with improvements in community attitudes and environments. IMPLICATIONS FOR REHABILITATION: Development of a pre-purchase assessment including specific core skills for scooter use is of great importance to minimise accidents and death as a consequence of scooter driving. Education and training of prescribers and suppliers of scooters is important to match needs and skills to enable a better fit of scooter to user. Incorporation of adjustability of features within the standard design of scooters, including type of driving controls, seat height, and adjustment of distance to controls, will enable greater fit of scooter to the user s needs. PMID- 23802130 TI - Costs and implications of discarded medication in hospice. AB - Symptom control for hospice patients frequently involves the use of pharmacologic agents for control of pain, dyspnea, and anxiety. Other troubling symptoms that will often require pharmacologic agents include nausea, vomiting, constipation, and delirium. While the Medicare requirement for hospice is a prognosis of six months or less, accurately predicting prognosis is very difficult. Because of this, medications for symptom control will often have to be prescribed and refilled without knowing exactly how much the hospice patient may require. The objective of the current study was to determine the amount of medication discarded at death. Additionally we wanted to estimate the cost related to discarded medication. We reviewed the records of 296 patients over a three-year period in a community hospice to characterize the medications that were discarded at death. Seventeen patients were not eligible for evaluation because of lack of complete information, leaving 279 study subjects. Cost calculations were used using a website cost calculator (HealthTrans.com). Fifty-six percent of the decedents were female and the majority were Hispanic (62%). The five most common diagnoses were cancer (36%); dementia (22%); and COPD, CVA, and congestive heart failure (CHF) (8%). The median length of stay in hospice was 16 days. The most frequent medication unused at the time of death was morphine solution followed by lorazepam. The cost of discarded morphine including tablets as well as solution totaled over $6,000 for the study period. The next highest medication cost was lorazepam for both solution and tablets, which came to over $1,600. The total estimated cost for all medications for the study period amounted to $14,980. The results of this study indicate that hospice patients have variable amounts of discarded medication at the time of death and that the cost involved of these unused medications can be significant. Hospice organizations should investigate creative ways to reduce the amount of discarded medications. PMID- 23802131 TI - Physician allocation of Medicare resources for patients with advanced cancer. AB - BACKGROUND: Little is known about what patients and physicians value in end-of life care, or how these groups would craft a health plan for those with advanced cancer. OBJECTIVE: The study objective was to assess how otolaryngology, head and neck surgery (OHNS) physicians would structure a Medicare benefit plan for patients with advanced cancer, and to compare this with cancer patient and cancer patient caregiver preferences. DESIGN: OHNS physicians used an online version of a validated tool for assessing preferences for health plans in the setting of limited resources. These data were compared to cancer patient and caregiver preferences. SETTING AND PARTICIPANTS: OHNS physicians nationwide were assessed with comparison to similar data obtained in a separate study of cancer patients and their caregivers treated at Duke University Medical Center. RESULTS: Otolaryngology physicians (n=767) completed the online assessment and this was compared with data from 146 patients and 114 caregivers. OHNS physician allocations differed significantly in 14 of the 15 benefit categories when compared with patients and caregivers. Physicians elected more coverage in the Advice, Emotional Care, Palliative Care, and Treatment for Cancer benefit categories. Patients and their caregivers elected more coverage in the Cash, Complementary Care, Cosmetic Care, Dental and Vision, Drug Coverage, Home Improvement, House Calls, Nursing Facility, Other Medical Care, and Primary Care benefit categories. CONCLUSIONS: Otolaryngology physicians have significantly different values in end-of-life care than cancer patients and their caregivers. This information is important for efficient allocation of scarce Medicare resources and for effective end-of-life discussions, both of which are key for developing appropriate health policy. PMID- 23802132 TI - Ion profiling in an ambient drift tube-ion mobility spectrometer using a high pixel density linear array detector IonCCD. AB - A linear pixel-based detector array, the IonCCD, is characterized for use under ambient conditions with thermal (<1 eV) positive ions derived from purified air and a 10 mCi (63)Ni foil. The IonCCD combined with a drift tube-ion mobility spectrometer permitted the direct detection of gas phase ions at atmospheric pressure and confirmed a limit of detection of 3000 ions/pixel/frame established previously in both the keV (1-2 keV) and the hyper-thermal (10-40 eV) regimes. Results demonstrate the "broad-band" application of the IonCCD over 10(5) orders in ion energy and over 10(10) in operating pressure. The Faraday detector of a drift tube for an ion mobility spectrometer was replaced with the IonCCD providing images of ion profiles over the cross-section of the drift tube. Patterns in the ion profiles were developed in the drift tube cross-section by control of electric fields between wires of Bradbury Nielson and Tyndall Powell shutter designs at distances of 1-8 cm from the detector. Results showed that ion beams formed in wire sets, retained their shape with limited mixing by diffusion and Coulombic repulsion. Beam broadening determined as 95 MUm/cm for hydrated protons in air with moisture of ~10 ppmv. These findings suggest a value of the IonCCD in further studies of ion motion and diffusion of thermalized ions, enhancing computational results from simulation programs, and in the design or operation of ion mobility spectrometers. PMID- 23802133 TI - Exploiting Leishmania tarentolae cell-free extracts for the synthesis of human solute carriers. AB - Cell-free protein production offers a versatile alternative to complement in vivo expression systems. However, usage of prokaryotic cell-free systems often leads to non-functional proteins. We modified a previously designed cell-free system based on the protozoan Leishmania tarentolae, a parasite of the Moorish gecko Tarentola mauritanica, together with a species-independent translational sequences-based plasmid to produce human membrane proteins in 2 hours reaction time. We successfully established all four commonly used expression modes for cell-free synthesis of membrane proteins with a human organic anion transporter, SLC17A3, as a model membrane protein: (i) As precipitates without the addition of any hydrophobic environment, (ii) in the presence of detergents, (iii) with the addition of liposomes, and (iv) supplemented with nanodiscs. We utilized this adapted system to synthesize 22 human solute carriers from 20 different families. Our results demonstrate the capability of the Leishmania tarentolae cell-free system for the production of a huge variety of human solute carriers in the precipitate mode. Furthermore, purified SLC17A3 shows the formation of an oligomeric state. PMID- 23802134 TI - Correlation of carotenoid accumulation with aggregation and biofilm development in Rhodococcus sp. SD-74. AB - Aggregation of bacterial populations substantially influences their characteristic properties and functions compared with the planktonic counterpart. It is also involved in the initial stages of biofilm development. Many studies have revealed important roles of bacterial aggregation in microbial production and biodegradation. Nevertheless, mechanistic understanding of bacterial aggregation in vivo and at the molecular level is far from complete. Here, we present a noninvasive, label-free Raman microspectroscopic approach to investigate the aggregation and biofilm development of the biotechnologically important Rhodococcus sp. SD-74. We found that the concentration of intracellular carotenoids increases more than 3-fold within 1 week as the biofilm develops. Raman imaging experiments confirmed that the carotenoid accumulation occurs throughout the Rhodococcus sp. SD-74 biofilm. The correlation between the carotenoid Raman intensities and biofilm development found in the present study provides a new means for quantitative, molecular-level assessment of the level of biofilm development, which is not possible with dye staining assay or electron microscopy. Moreover, our results suggest that microbial production of carotenoids in pigmented bacteria such as Rhodococcus sp. SD-74 may potentially be controlled via bacterial aggregation and biofilm formation. PMID- 23802136 TI - Short-term effect of the soil amendments activated carbon, biochar, and ferric oxyhydroxide on bacteria and invertebrates. AB - The aim of the present study was to evaluate the secondary ecotoxicological effects of soil amendment materials that can be added to contaminated soils in order to sequester harmful pollutants. To this end, a nonpolluted agricultural soil was amended with 0.5, 2, and 5% of the following four amendments: powder activated carbon (PAC), granular activated carbon, corn stover biochar, and ferric oxyhydroxide powder, which have previously been proven to sequester pollutants in soil. The resulting immediate effects (i.e., without aging the mixtures before carrying out tests) on the springtail Folsomia candida, the earthworm species Aporectodea caliginosa and Eisenia fetida, the marine bacteria Vibrio fischeri, a suite of ten prokaryotic species, and a eukaryote (the yeast species Pichia anomalia) were investigated. Reproduction of F. candida was significantly increased compared to the unamended soil when 2% biochar was added to it. None of the treatments caused a negative effect on reproduction. All amendments had a deleterious effect on the growth of A. caliginosa when compared to the unamended soil, except the 0.5% amendment of biochar. In avoidance tests, E. fetida preferred biochar compared to all other amendments including the unamended soil. All amendments reduced the inhibition of luminescence to V. fischeri, i.e., were beneficial for the bacteria, with PAC showing the greatest improvement. The effects of the amendments on the suite of prokaryotic species and the eukaryote were variable, but overall the 2% biochar dose provided the most frequent positive effect on growth. It is concluded that the four soil amendments had variable but never strongly deleterious effects on the bacteria and invertebrates studied here during the respective recommended experimental test periods. PMID- 23802135 TI - Sequencing analysis of the ATOH7 gene in individuals with optic nerve hypoplasia. AB - BACKGROUND: The Atonal Homolog 7 (ATOH7) gene has been implicated in association studies with optic nerve head diameter size. Hence, we screened optic nerve hypoplasia (ONH) patient DNA samples from Australia, France, and the United States for sequence variants in theATOH7 gene using Sanger sequencing. METHODS: Sanger sequencing of theATOH7 gene was performed on 34 affected individual DNA samples. Sequencing was also carried out in three unaffected family members to confirm segregation of identified single nucleotide variations. RESULTS: Seven sequence variations were identified in ATOH7. No disease-causing sequence changes in the ATOH7 gene was discovered in the ONH patient samples. CONCLUSIONS: Mutations within the ATOH7 gene are not implicated in the pathogenesis of optic nerve hypoplasia in our patient cohort. PMID- 23802138 TI - The role of initial physical activity experiences in promoting posttraumatic growth in Paralympic athletes with an acquired disability. AB - PURPOSE: To explore Paralympic athletes' lived experiences of becoming physically active after disability, and the role that this may have played in the development of posttraumatic growth. METHODS: Life history interviews were conducted with 7 individuals with an acquired and traumatic disability, who were aiming to take part in the London 2012 Paralympic Games. This was also informed by observation of sport participation. Data were analysed using a holistic content analysis. RESULTS: Three main themes were identified that reflected participants' initial physical activity experiences and which were linked to posttraumatic growth. These were recognizing possibility by acknowledging limitations, responsibility for choice and consequences, and re-establishing and enhancing meaning. CONCLUSIONS: Posttraumatic growth is a process and consequently, part of this process may include experiencing both positive and negative trauma symptoms. Participation in physical activity may assist an individual in achieving posttraumatic growth by facilitating meaning making, providing an environment where risks and responsibilities can be taken, and allowing an individual to understand their limitations and future possibilities. IMPLICATIONS FOR REHABILITATION: While posttraumatic growth is often associated with positive psychological outcomes, it is important to consider that this can occur alongside the experience of negative trauma symptoms. Participation in physical activity may induce both positive and negative responses following trauma. In order to foster posttraumatic growth, physical activity should be meaningful to the activity and allow a sense of control and personal responsibility. PMID- 23802137 TI - Mental health recovery on care farms and day centres: a qualitative comparative study of users' perspectives. AB - PURPOSE: Mental health services increasingly incorporate the vision of recovery. This qualitative study analysed and compared experiences of recovery on prevocational services, in order to assess if users make progress towards recovery, relative to a staged recovery model. METHOD: Data were collected through semi-structured interviews with participants on care farms (n = 14), work (n = 7) and creative projects (n = 5). RESULTS: The transition from past to current lives was described as a progressive, non-linear process, with different stages guided by different goals. Participants on creative projects lacked clear goals, presented less interest in peers and high need for emotional support. Participants on work projects aimed for occupational rehabilitation, but struggled with the patient culture of the peer community. Participants on care farms aimed for daytime occupations and closer contact with society. They experienced care farms as open, real-life work settings where they could exercise responsibility and connect with people. CONCLUSIONS: Participants progressed towards recovery, as care farms, work- and creative projects empowered them to leave behind inactive, isolated or disorganized living. In day centres, users focused on self-reflection and personal development (creative projects) or on occupational performance (work projects), whereas on care farms, users fulfilled worker roles in a real-life, open community environment. IMPLICATIONS FOR REHABILITATION: Organized as open communities in real-life settings, care farms facilitate the reflection on personal and social responsibility, and therefore have the potential to help users internalize worker identities and improve their motivation to progress towards recovery. Supervisors on care farms are regarded by users as close contacts within the social networks they develop on the service, a position that allows supervisors to actively engage and promote users' progress towards recovery. Elements of the farm environment (such as the "normal life", presence of family members and visitors, and nature) can serve as anchors for supporting the progress towards recovery. PMID- 23802139 TI - Occupational therapists' perspectives on addressing sexual concerns of older adults in the context of rehabilitation. AB - PURPOSE: To explore occupational therapists' perspectives on addressing sexuality in the context of rehabilitation services for older people. METHOD: A qualitative exploratory design was used. Data were collected using a series of focus groups (n = 5) among occupational therapists (n = 22) working with older people. Data were analysed using content analysis. RESULTS: Occupational therapists in this study rarely addressed sexuality in the context of rehabilitation services for older people. Three major categories emerged in relation to barriers which influence therapists' practice in this area: (i) the influence of culture on decisions regarding whether or not to address sexuality, (ii) perceived competence and confidence to address sexuality and (iii) the impact of resources regarding the inclusion or exclusion of sexuality from rehabilitation. CONCLUSIONS: Although sexuality is increasingly considered an important and relevant aspect of successful ageing the extent to which healthcare professionals are prepared to address sexual concerns identified by older people is less clear. If new expectations of healthy ageing are to be met, healthcare professionals must acknowledge the importance of sexuality and be prepared to be involved in sexual health management. Implications for Rehabilitation Healthcare professionals continue to be reluctant to respond to older peoples' concerns relating to sexuality. Occupational therapists in Ireland identified socio cultural norms relating to sexuality, perceived professional competence and confidence and prioritization of resources as key barriers. Education is needed to improve therapists' perceived competence and confidence in addressing sexuality with older adults. Policy change is required to consider the underlying assumptions about sexuality, ageing and disability. PMID- 23802140 TI - Transitional rehabilitation goals for people with spinal cord injury: looking beyond the hospital walls. AB - PURPOSE: This study aimed to identify, describe and classify the transitional rehabilitation goals of people with spinal cord injury (SCI) and map these goals to the International Classification of Functioning, Disability and Health (ICF). METHOD: The five most important rehabilitation goals as rated by clients were extracted from records for 220 clients of a transitional rehabilitation service for people with SCI in Australia over a 5-year period. These goals were thematically classified into domains and then mapped to the ICF framework. Goals were compared across age, gender, length of hospital stay, compensation status, level and completeness of injury. RESULTS: A total of 1100 goals were classified into 18 different goal domains, representing most aspects of the ICF framework. Age was negatively related to vocational goals. Length of hospital stay was positively related to personal care goals but negatively related to community access and vocational goals. Goals did not differ across gender or compensation status but did differ across level and completeness of injury. CONCLUSIONS: People with SCI have a range of transitional rehabilitation goals that represent most aspects of the ICF framework. Client-centred community rehabilitation during this transition period offers continuity of care to support the realisation of these rehabilitation goals. Implications for Rehabilitation Transitional rehabilitation is a relatively new community service model in the rehabilitation literature, especially for people with spinal cord injury. Client-centred goal setting is integral to these types of community rehabilitation models. Rehabilitation goals in transitional rehabilitation are varied and map well to the International Classification of Functioning, Disability and Health (ICF) with a focus on environmental goals. A typology of rehabilitation goals in this setting will assist in service planning and evaluation of hospital and community rehabilitation services. PMID- 23802141 TI - The efficacy of GMFM-88 and GMFM-66 to detect changes in gross motor function in children with cerebral palsy (CP): a literature review. AB - AIM: The purpose of this study was to review published research on the use of the Gross Motor Function Measure (GMFM-88) and (GMFM-66) as outcome measures to determine if these tools detect changes in gross motor function in children with cerebral palsy (CP) undergoing interventions. METHODS: A comprehensive literature search was conducted using Medline and PubMed to identify studies published from January 2000 through January 2011 that reported the accuracy of GMFM-88 and GMFM 66 to measure changes over time in children with CP undergoing interventions. The keywords used for the search were "GMFM" and "CP". Two of the authors (M.A. and S.B.) reviewed the titles and abstracts found in the databases. The methodological quality of the studies was assessed by using the Critical Review Form-Quantitative Studies. RESULTS: Of 62 papers initially identified, 21 studies fulfilled the inclusion criteria. These articles consist of three longitudinal studies, six randomized controlled trials, four repeated measure design, six pre post test design, a case series and one non-randomized prospective study. The included studies were generally of moderate to high methodological quality. The studies included children from a wide age range of 10 months to 16 years. According to the National Health and Medical Research Council, the study designs were level II, III-2, III-3 and IV. CONCLUSION: The review suggests that the GMFM 88 and GMFM-66 are useful as outcome measures to detect changes in gross motor function in children with CP undergoing interventions. Implications for Rehabilitation Accurate measurement of change in gross motor skill acquisition is important to determine effectiveness of intervention programs in children with cerebral palsy (CP). The Gross Motor Function Measure (GMFM-88 and GMFM-66) are common tools used by rehabilitation specialists to measure gross motor function in children with CP. The GMFM appears to be an effective outcome tool for measuring change in gross motor function according to a small number of randomized control studies utilizing participant populations of convenience. PMID- 23802142 TI - Understanding physical activity in spinal cord injury rehabilitation: translating and communicating research through stories. AB - PURPOSE: The purpose of this article is to develop an evidence-based resource for knowing and communicating the complexities involved for both males and females in implementing and sustaining a physically active lifestyle shortly after spinal cord injury (SCI). METHODS: Synthesizing a set of qualitative and quantitative studies with over 500 spinal cord injured people, the article represents research utilizing the genre of ethnographic creative non-fiction. This genre of representation holds enormous potential for researchers in terms of disseminating their findings to diverse audiences beyond the academy, and having real impact. RESULTS: The ethnographic creative non-fictions show together for the first time the barriers, determinants, benefits, trajectories, emotions, fears, preferred methods and messengers for delivering important physical activity information to men and women with a SCI. CONCLUSION: The article contributes to knowledge by showing the embodied complexities involved when in rehabilitation for both males and females in implementing and sustaining a physically active lifestyle shortly after SCI. It also makes a contribution to practice by providing researchers, health care professionals and disability user-groups with a theory and evidence based resource to assist in informing, teaching and enabling people living with SCI to initiate and maintain a physically active lifestyle. Stories may be a highly effective tool to communicate with and to influence spinal cord injured people's activity. IMPLICATIONS FOR REHABILITATION: The findings of this research showed the many benefits and barriers to developing and sustaining a physically active lifestyle shortly after spinal cord injury. The preferred methods and messengers for delivering physical activity information as well as the activity types, intensities and durations of physical activity for men and women were also shown. Within rehabilitation, spinal cord injured people need to be offered accessible knowledge about how to implement and sustain a physically active lifestyle over the life course. Stories may serve as a unique and powerful means to achieve this. PMID- 23802143 TI - Diagnosing HIV infection in primary care settings: missed opportunities. AB - In the United States, 20% of HIV-infected persons are unaware of their diagnosis. Improved application of HIV screening recommendations in healthcare settings may facilitate diagnosis. Clinical patient data and previous healthcare visits were reviewed from medical records of newly diagnosed HIV-infected persons in Durham County, North Carolina, who initiated HIV care at Duke University Medical Center in 2008-2011. Comparisons were made to similar data from 2002-2004 using the Pearson's chi-square test and logistic regression. 101 consecutive newly diagnosed patients were identified: 67 males; 73 black, 20 white, and 8 Hispanic/Latino. Mean age was 39 years (range, 17-69), and 73 had health insurance. Median baseline CD4 count was 313 cells/MUL (range, 4-1302), and HIV-1 viral load was 45,700 copies/mL (range, 165-10,000,000). One-third had a baseline CD4 count <50 cells/MUL, and 15% presented with opportunistic infections. Compared to patients newly diagnosed in 2002-2004, significantly greater proportions were black and less immunocompromised in 2008-2011. Most had been seen at least once by a healthcare provider in the year prior to HIV diagnosis: 72 had >=1 prior visits, and 47 had >=2 visits. Among those with prior visits, 37/72 (51%) were seen in an emergency department on the first or second visit. Men were three times more likely than women to be diagnosed at their first healthcare encounter (p=0.03, OR=3.2). Despite CDC recommendations for widespread HIV screening in healthcare settings, HIV diagnosis remains delayed, even among those with frequent healthcare encounters. Educating providers and removing barriers to HIV screening may improve this problem. PMID- 23802146 TI - Macrophages and recently identified forms of cell death. AB - Recent advances in cell death biology have uncovered an ever increasing range of cell death forms. Macrophages have a bidirectional relationship with cell death that modulates the immune response. Thus, macrophages engulf apoptotic cells and secrete cytokines that may promote cell death in parenchymal cells. Furthermore, the presence of apoptotic or necrotic dead cells in the microenvironment elicits differential macrophage responses. Apoptotic cells elicit anti-inflammatory responses in macrophages. By contrast macrophages may undergo a proinflammatory form of cell death (pyroptosis) in response to damage-associated molecular patterns (DAMPs) released from necrotic cells and also in response to pathogen associated molecular patterns (PAMPs). Pyroptosis is a recently identified form of cell death that occurs predominantly in subsets of inflammatory macrophages and is associated to the release of interleukin-1beta (IL-1beta) and IL-18. Deregulation of these processes may result in disease. Thus, failure of macrophages to engulf apoptotic cells may be a source of autoantigens in autoimmune diseases, excessive macrophage release of proapoptotic factors or sterile pyroptosis may contribute to tissue injury and failure of pathogen induced pyroptosis may contribute to pathogen survival. Ongoing research is exploring the therapeutic opportunities resulting this new knowledge. PMID- 23802144 TI - Counseling to reduce high-risk sexual behavior in HIV care: a multi-center, direct observation study. AB - A key opportunity to reduce HIV transmission lies with healthcare providers counseling HIV-infected patients about safer sex. We audio-recorded and transcribed clinical encounters between 45 healthcare providers and 417 of their HIV-infected patients at four outpatient sites in the United States. We used logistic regressions to evaluate associations between patient and provider characteristics, and the occurrence of discussion (any talk about sex) and counseling (advice about safer sex). Of the 417 encounters, discussion of sex occurred in 187 (45% of encounters, 95% CI: 40-50%). Counseling occurred for 49% (95% CI: 35-63%) of patients reporting unsafe sex. Discussion of sex was more likely with younger or less-educated patients and with less cultural difference between patient and provider, while counseling was associated with greater provider mindfulness and lower provider empathy. These findings suggest targets to improve communication regarding sexual risk reduction in HIV care. PMID- 23802147 TI - Novel application of polioviral capsid: development of a potent and prolonged oral calcitonin using polioviral binding ligand and Tat peptide. AB - CONTEXT: Poor absorption and proteolytic degradation are major obstacles of orally administered peptide drugs including calcitonin. Cell penetrating peptides (CPPs) and receptor binding ligands are interesting tools for the application in the delivery of these drugs. OBJECTIVE: To investigate the enhancements of in vitro and in vivo salmon calcitonin (sCT) activity by Tat, a trans-activating transcriptional peptide and VP1 peptide (V) from polioviral capsid. MATERIALS AND METHODS: Tat/sCT, V/sCT and V/Tat/sCT mixtures at various molar ratios were prepared and investigated for in vitro and in vivo activities of sCT. RESULTS: Tat could increase in vitro sCT activity both in colon adenocarcinoma (HT-29) and mouth epidermal carcinoma (KB) cells. V/sCT (6:1) showed significant increase of intracellular calcium in HT-29 cells. V/Tat/sCT (6:1:1) gave highest increase of intracellular calcium in both cells. Oral administered Tat/sCT (1:1) showed comparable hypocalcemic effect to sCT injection with prolonged action. V/Tat/sCT (6:1:1) demonstrated hypocalcemic effect at 12 h after administration but no hypocalcemic effect was observed from V/sCT. DISCUSSION: Positive charge from Tat might facilitate sCT uptake and absorption. Increasing of intracellular calcium in HT-29 cells by V but lacking of hypocalcemic effect from V/sCT in mice indicated the ligand-receptor mediated delivery of sCT by the interaction between V and PVR. CONCLUSION: Potential application of V and Tat in oral calcitonin delivery system was demonstrated. Further study in a proper PVR bearing host is still needed to provide more useful information for the application of V in the development of drug delivery systems. PMID- 23802148 TI - Evaluation of different screening methods to understand the dissolution behaviors of amorphous solid dispersions. AB - OBJECTIVE: The objectives of the current study were to understand the dissolution behaviors of amorphous solid dispersions (ASD) using different screening methods and their correlation to the dissolution of formulated products. MATERIALS AND METHODS: A poorly soluble compound, compound E, was used as a model compound. ASDs were prepared with HPMC, Kollidon VA64 and Eudragit EPO using hot-melt extrusion. Different techniques including precipitation, powder, capsule and compact dissolution and the dissolution of formulated products were conducted in USP simulated gastric fluid using a USP II dissolution apparatus. RESULTS AND DISCUSSIONS: It was found that a precipitation study could generally predict powder, capsule and compact dissolution. Yet, it was recommended to run the dissolution at a higher paddle speed or for a longer duration to improve the predictability. It was also recommended to run powder, capsule and compact dissolution at both slow and high speeds to gain insights into wetting, dispersion and the dissolution of a system. Sometimes, capsule or compact dissolution could not be predicted by precipitation or powder dissolution due to plug formation. In this case, properly designed dosage forms were needed to break up this plug to optimize the dissolution profiles. On the contrary, formulations and dissolution conditions would have minimal effects on the dissolution profiles of a fast-dissolving solid dispersion. CONCLUSIONS: Different techniques are available to select the right polymers to optimize dissolution behaviors. However, it is important to understand the merits and limitations of each technique in order to optimize the formulations for amorphous solid dispersions. PMID- 23802149 TI - Pharmacokinetic variations of tetramethylpyrazine phosphate after oral administration in hepatic precancerous mice and its hepatoprotective effects. AB - CONTEXT: Pharmacokinetics of drug may be altered by abnormal physiological functions in illness, which will affect its pharmacodynamic efficacy in turn. OBJECTIVE: To assess the preventive effects of tetramethylpyrazine (TMPZ) phosphate on hepatocarcinogenesis and its pharmacokinetic differentiations in model mice. METHODS: Diethylnitrosamine (DEN) was adopted to induce hepatic precancerous model in mice through intraperitoneal injection, and prevention efficacy of TMPZ at a dose of 162 mg/kg was examined by liver histological analysis and activities of serum marker enzymes. Pharmacokinetic variations of TMPZ between control and model mice were measured for single oral administration. RESULTS: DEN initiation led to a remarkable increase of serum marker enzymes, and abnormality such as bile canaliculi hyperplasia and presence of tumor cells were observed in liver histopathological examination in model mice, while the control ones revealed normal architecture. Oral treatment of TMPZ resulted in a marked reduction in serum marker enzymes and improvement in liver histopathology compared with model ones. In pharmacokinetic study, values of AUC and Tmax of TMPZ became significantly greater with increase of doses in both control and model mice, which elucidated the absorption was enhanced and delayed; meanwhile, its elimination was not affected markedly. When the mice were treated at same dose, the adsorption of TMPZ in model mice was greatly improved than that in control ones, while Tmax and MRT had no significant difference. CONCLUSION: TMPZ was partly effective to protect liver from carcinogenesis initiated by DEN, and hepatic insufficiency could change its pharmacokinetics. PMID- 23802150 TI - One-step peptide backbone dissociations in negative-ion free radical initiated peptide sequencing mass spectrometry. AB - Peptide dissociation behavior in TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) based FRIPS (free radical initiated peptide sequencing) mass spectrometry was analyzed in both positive- and negative-ion modes for a number of peptides including angiotensin II, kinetensin, glycoprotein IIb fragment (296-306), des Pro(2)-bradykinin, and ubiquitin tryptic fragment (43-48). In the positive mode, the .Bz-C(O)-peptide radical species was produced exclusively at the initial collisional activation of o-TEMPO-Bz-C(O)-peptides, and two consecutive applications of collisional activation were needed to observe peptide backbone fragments. In contrast, in the negative-ion mode, a single application of collisional activation to o-TEMPO-Bz-C(O)-peptides produced extensive peptide backbone fragmentations as well as .Bz-C(O)-peptide radical species. This result indicates that the duty cycle in the TEMPO-based FRIPS mass spectrometry can be reduced by one-half in the negative-ion mode. In addition, the fragment ions observed in the negative-ion experiments were mainly of the a-, c-, x-, and z types, indicating that radical-driven tandem mass spectrometry was mainly responsible for the TEMPO-based FRIPS even with a single application of collisional activation. Furthermore, the survival fraction analysis of o-TEMPO-Bz C(O)-peptides was made as a function of the applied normalized collision energy (NCE). This helped us to better understand the differences in FRIPS behavior between the positive- and negative-ion modes in terms of dissociation energetics. The duty-cycle improvement made in the present study provides a cornerstone for future research aiming to achieve a single-step FRIPS in the positive-ion mode. PMID- 23802151 TI - Design and synthesis of hydroxypyridinone-L-phenylalanine conjugates as potential tyrosinase inhibitors. AB - A range of hydroxypyridinone-L-phenylalanine conjugates were synthesized starting from kojic acid. Their tyrosinase activity was determined, and it was found that one of the compounds ((S)-(5-(benzyloxy)-1-octyl-4-oxo-1,4-dihydropyridin-2 yl)methyl 2-amino-3-phenylpropanoate, 5e) showed potent inhibitory effect against mushroom tyrosinase, the IC50 values for monophenolase and diphenolase activities being 12.6 and 4.0 MUM, respectively. It was also demonstrated that these conjugates are mixed-type inhibitors, suggesting they could bind to both the free enzyme and the enzyme-substrate complexes. MTT assay indicated that 5e was nontoxic to three cell lines. This compound may find applications in food preservation and cosmetics. PMID- 23802152 TI - From sequence to spike to spark: evo-devo-neuroethology of electric communication in mormyrid fishes. AB - Mormyrid fishes communicate using pulses of electricity, conveying information about their identity, behavioral state, and location. They have long been used as neuroethological model systems because they are uniquely suited to identifying cellular mechanisms for behavior. They are also remarkably diverse, and they have recently emerged as a model system for studying how communication systems may influence the process of speciation. These two lines of inquiry have now converged, generating insights into the neural basis of evolutionary change in behavior, as well as the influence of sensory and motor systems on behavioral diversification and speciation. Here, we review the mechanisms of electric signal generation, reception, and analysis and relate these to our current understanding of the evolution and development of electromotor and electrosensory systems. We highlight the enormous potential of mormyrids for studying evolutionary developmental mechanisms of behavioral diversification, and make the case for developing genomic and transcriptomic resources. A complete mormyrid genome sequence would enable studies that extend our understanding of mormyrid behavior to the molecular level by linking morphological and physiological mechanisms to their genetic basis. Applied in a comparative framework, genomic resources would facilitate analysis of evolutionary processes underlying mormyrid diversification, reveal the genetic basis of species differences in behavior, and illuminate the origins of a novel vertebrate sensory and motor system. Genomic approaches to studying the evo-devo-neuroethology of mormyrid communication represent a deeply integrative approach to understanding the evolution, function, development, and mechanisms of behavior. PMID- 23802153 TI - Microphyllandiolide, a new diterpene with an unprecedented skeleton from Salvia microphylla. AB - Microphyllandiolide (1), an unprecedented rearranged clerodane-type diterpene with a 9/3 bicyclic ring system, was isolated from the aerial parts of Salvia microphylla Kunth. Its structure was elucidated by analysis of its spectroscopic data and confirmed by single crystal X-ray diffraction analysis. A possible biogenesis for microphyllandiolide (1) is proposed. PMID- 23802154 TI - Correlation between total blood lead values and peripheral blood counts in workers occupationally exposed to urban stressors. AB - The aim of the study was to assess the relationship between occupational exposure to airborne lead (Pb) and alterations in peripheral blood counts in workers of the Municipal Police assigned to different types of outdoor tasks. Then, 337 both male and female subjects were enrolled and divided on the basis of sex, cigarette smoking habit and kind of task. Exposure to airborne Pb, dosage of total blood Pb and peripheral blood count were carried out. A significant positive correlation was detected between the values of total blood Pb and values of plasma reticulocytes (%RET) both in the total sample and for all the classes of the subdivision except for police drivers. Some statistically significant correlations were present but discontinuous for other variables of peripheral blood counts. Results suggest that occupational exposure to low doses of airborne Pb is able to influence lines of the hematopoietic system in exposed workers, with special reference to %RET. PMID- 23802155 TI - Potential human health risks from toxic metals, polycyclic aromatic hydrocarbons, polychlorinated biphenyls, and organochlorine pesticides via canned fish consumption: estimation of target hazard quotients. AB - Canned fish (tuna and sardine) of different geographical regions were collected randomly from supermarkets and were analyzed for heavy metal contents (Hg, Cd and Pb) polycyclic aromatic hydrocarbons, polychlorinated biphenyls, and pesticides. Canned fish samples (two brands of sardines, six brands of tuna) that were purchased from Egyptian cities between 2009 and 2010, represent four countries (Morocco, Republic of Yemen, Indonesia and Thailand). Health risks on humans via dietary intake of seafood were assessed by the target hazard quotients (THQs), potential non-carcinogenic and carcinogenic effects. The contents of trace metals in canned tuna and canned sardines were found as: 0.149-0.218 MUg/g for Cd; 0.312 0.937 MUg/g for Pb and 0.053-0.022 MUg/g for Hg. Canned sardines fluctuated between 0.55 and 1.82, 1.08 and 1.64, 11.91 and 26.24 ng/g for total HCHs, Total cyclodienes and DDTs respectively while the corresponding concentrations in canned tuna were 0.24-1.85, 0.24-1..85 and 6.56-49.73 ng/g, respectively. Total PCBs fluctuated between 21.75 and 55.10 for canned sardines and 8.56-208.11 ng/g for canned tuna. On the other hand the total PAHs fluctuated between 0.006-9.775 and 1.556-2.686 ng/g for tuna and sardines. From the human health point of view, there is no adverse health effect for both PAHs and heavy metals content on consumers. PMID- 23802156 TI - Changes in expression of BetV1 allergen of silver birch pollen in urbanized area of Ukraine. AB - The aim of the study was to determinate the level of expression of silver birch allergen Betv1 in pollen samples from different Ukraine areas by RT-qPCR SYBR Green assay. Protocol for quantifying the expression of Betv1 allergen was developed when testing of three housekeeping genes-cyclophylin, alpha-tubulin and transcription factor CBF1. Samples from urbanized area was analysed by real-time PCR when a sample from forest growth conditions was used as a calibrator. Real time PCR based quantifying of Betv1 provides a useful method for rapid and sensitive analyses of this silver birch allergen. Our results show higher expression levels in samples from central parts of urbanized area as housing estates when compared to the samples from borders of the urbanized area. PMID- 23802157 TI - Air sampling of mold spores by slit impactors: yield comparison. AB - The performance of simple slit impactors for air sampling of mold contamination was compared under field conditions. Samples were collected side-by-side, outdoors in quadruplicates with Burkhard (ambient sampler) and Allergenco MK3 spore traps and with two identical Allergenco slit cassettes operated at diverse flow rates of 5 and 15 L/min, respectively. The number and types of mold spores in each sample were quantified by microscopy. Results showed all four single stage slit impactors produced similar spore yields. Moreover, paired slit cassettes produced similar outcomes despite a three-fold difference in their sampling rate. No measurable difference in the amount or mix of mold spores per m(3)of air was detected. The implications for assessment of human exposures and interpretation of indoor/outdoor fungal burden are discussed. These findings demonstrate that slit cassettes capture most small spores, effectively and without bias, when operated at a range of flow rates including the lower flow rates used for personal sampling. Our findings indicate sampling data for mold spores correlate for different single stage impactor collection methodologies and that data quality is not deteriorated by operating conditions deviating from manufacturers' norms allowing such sampling results to be used for scientific, legal, investigative, or property insurance purposes. The same conclusion may not be applied to other particle sampling instruments and mulit-stage impactors used for ambient particulate sampling, which represent an entirely different scenario. This knowledge may help facilitate comparison between scientific studies where methodological differences exist. PMID- 23802158 TI - Methylmercury and trace elements in the marine fish from coasts of East China. AB - Fish consumption is an important source of human exposure to heavy metals. To determine the health risks for metals by consumption of marine fish in China, three species of fish, namely large yellow croaker (Pseudosciaena crocea), small yellow croaker (Pseudosciaena polyactis) and silver pomfret (Pampus argenteus) were collected and analyzed for methylmercury (MeHg), total mercury (T-Hg), selenium, cadmium, cobalt, chromium, copper, iron, manganese, nickel, lead, strontium and zinc. The large yellow croakers had the highest concentrations of mercury, lead, nickel and zinc, and the levels of MeHg were positively correlated to T-Hg. The ratios of MeHg to T-Hg in yellow croakers were significantly higher than those in silver pomfret, indicating differences in accumulation and magnification of MeHg in these two types of fish. The concentration of T-Hg was found to decrease as the Se level in fish tissues increased. Cadmium levels in 16% of the samples were higher than the criterion recommended by the European Commission Regulation. The concentrations of other metals were well below international standards. A human health risk assessment showed that the estimated daily intake of these metals did not exceed the reference dose established by the US Environmental Protection Agency. The hazard quotients (HQs) were all less than 1, indicating a situation of no risk for consumption of these fish. PMID- 23802159 TI - Relating monolithic and granular leaching from contaminated soil treated with different cementitious binders. AB - This work employed a clayey, silty, sandy gravel contaminated with a mixture of metals (Cd, Cu, Pb, Ni and Zn) and diesel. The contaminated soil was treated with 5 and 10% dosages of different cementitious binders. The binders include Portland cement, cement-fly ash, cement-slag and lime-slag mixtures. Monolithic leaching from the treated soils was evaluated over a 64-day period alongside granular leachability of 49- and 84-day old samples. Surface wash-off was the predominant leaching mechanism for monolithic samples. In this condition, with data from different binders and curing ages combined, granular leachability as a function of monolithic leaching generally followed degrees 4 and 6 polynomial functions. The only exception was for Cu, which followed the multistage dose-response model. The relationship between both leaching tests varied with the type of metal, curing age/residence time of monolithic samples in the leachant, and binder formulation. The results provide useful design information on the relationship between leachability of metals from monolithic forms of S/S treated soils and the ultimate leachability in the eventual breakdown of the stabilized/solidified soil. PMID- 23802160 TI - Study of enzymatic degradation and water absorption of composites carboxymethyl cellulose and poly (epsilon-caprolactone) containing SiO2nanoparticle by cellulase. AB - This study investigates the effect of Poly (epsilon-Caprolactone (PCL) and Nano SiO2content within the Carboxymethyl Cellulose (CMC) blends on the rate and extent of carboxymethyl cellulose enzymatic hydrolysis using the enzyme cellulase. The results reveal that blends with Nano-SiO2content at 5 wt% exhibit a significantly reduced rate and extent of CMC hydrolysis. This may be attributed to interactions between CMC and SiO2that prevent further enzymatic attack on the remaining CMC phases within the blend. The total solids that remained after 2880 min were 44.8 wt.% (CMC: PCL); 62.7 wt.% (CMC: PCL: 1% Nano-SiO2); 69.8 wt.% (CMC: PCL: 3% Nano-SiO2); 73.1 wt.% (CMC: PCL: 5% Nano-SiO2). Enzymatic degradation behaviour of CMC: PCL: Nano-SiO2was based on the determinations of water resistance, weight loss and the reducing sugars. The degraded residues have been examined by scanning electronic microscopy (SEM) and UV-Vis spectroscopy. PMID- 23802161 TI - Reference levels of natural radioactivity and (137)Cs in and around the surface soils of Kestanbol pluton in Ezine region of Canakkale province, Turkey. AB - The aim of the study was to conduct a systematic investigation on the natural gamma emitting radionuclides ((226)Ra, (232)Th and (40)K) as well as (137)Cs in the surface soils from Kestanbol/Ezine plutonic area in Canakkale province as part of the environmental monitoring program on radiologic impact of the granitoid areas in Western Anatolia. The activity measurements of the gamma emitters in the surface soil samples collected from 52 sites distributed all over the region has been carried out, by means of HPGe gamma-ray spectrometry system. The activity concentrations of the relevant radionuclides in the soil samples appeared in the ranges as follows: (226)Ra was 20-521 Bq kg(-1); (232)Th, 11-499 Bq kg(-1)and; (40)K, 126-3181 Bq kg(-1), yet the (137)Cs was much lower than 20 Bq kg(-1)at most. Furthermore, based on the available data, the radiation hazard parameters associated with the surveyed soils were calculated. The present data also allowed evaluation of some correlations that may exist in the investigated natural radionuclides of the soil samples from the plutonic area in Canakkale province. It is concluded from the above that the concerned region did not lead to any significant radiological exposure to the environment. PMID- 23802162 TI - Investigation of the effects of hydrogenotrophic denitrification and anammox on the improvement of the quality of the drinking water supply system. AB - A drinking water supply system operates at Chyasal (in the Kathmandu Valley, Nepal) for purifying the groundwater that has high levels of ammonium nitrogen (NH4-N). However, high NO3-N concentrations were seen in the water after treatment. To further improve the quality of the drinking water, two types of attached growth reactors were developed for the purification system: (i) a hydrogenotrophic denitrification (HD reactor) and (ii) a concurrent reactor with anammox and hydrogenotrophic denitrification (AnHD reactor). For the HD reactor fed by water containing NO3-N, the denitrification efficiency was high (95-98%) for all NO3-N feed rates (20-40 mg/L). The nitrite-nitrogen (NO2-N) and nitrate nitrogen (NO3-N) concentrations in the effluent were ~0.5 mg/L. On the other hand, the AnHD reactor fed with water containing NH4-N and NO2-N was operated under varying flow rates of H2(30-70 mL/min) and intermittent supply periods (1-2 h). The efficiency of the anammox process was found to increase with decreasing H2flow rates or with increasing intermittency of the H2supply, while the efficiency of denitrification decreased under these conditions. For the optimal condition of 1.5 h intermittent H2supply, the anammox and denitrification efficiencies of the AnHD reactor reached 80% and 42%, respectively, while the concentrations of both NH4-N and NO2-N in the effluent were <1.0 mg/L, and no NO3 N was detected. From the experimental results, it is clear that both HD and AnHD reactors can function as efficient and critical units of the water purification system. PMID- 23802163 TI - Treatment of winery wastewater by electrochemical methods and advanced oxidation processes. AB - The aim of this research was development of new system for the treatment of highly polluted wastewater (COD = 10240 mg/L; SS = 2860 mg/L) originating from vine-making industry. The system consisted of the main treatment that included electrochemical methods (electro oxidation, electrocoagulation using stainless steel, iron and aluminum electrode sets) with simultaneous sonication and recirculation in strong electromagnetic field. Ozonation combined with UV irradiation in the presence of added hydrogen peroxide was applied for the post treatment of the effluent. Following the combined treatment, the final removal efficiencies of the parameters color, turbidity, suspended solids and phosphates were over 99%, Fe, Cu and ammonia approximately 98%, while the removal of COD and sulfates was 77% and 62%, respectively. A new approach combining electrochemical methods with ultrasound in the strong electromagnetic field resulted in significantly better removal efficiencies for majority of the measured parameters compared to the biological methods, advanced oxidation processes or electrocoagulation. Reduction of the treatment time represents another advantage of this new approach. PMID- 23802164 TI - Performance and kinetic evaluation of the semi-continuous anaerobic digestion of sunflower oil cake pretreated with ultrasound. AB - A study of the semi-continuous anaerobic digestion of sunflower oil cake previously sonicated (at a specific energy of 24,000 kJ/kg TS, constant sonication frequency of 20 kHz and ultrasonic power of 120 W) was carried out in laboratory-scale completely stirred tank reactors at mesophilic temperature (35 degrees C). Two anaerobic inocula were used: a mixture of flocculant biomass (I) from a full-scale anaerobic reactor treating waste activated sludge and a granular inoculum (II) from an industrial UASB reactor treating brewery wastewater. Soluble COD (CODs) removal efficiencies ranged between 67.7% and 70.1% and between 61.3% and 67.7% at hydraulic retention times (HRTs) of between 24-10 days for inoculum I and 24-8 days for inoculum II. However, for HRTs lower than 8 days and 6.7 days, equivalent to organic loading rates (OLRs) higher than 2.62 and 3.15 g COD/(L.d), respectively, a sudden decrease in the CODs removal efficiency was observed in both cases. In any case, inoculum II allowed for a more stable and efficient operation for a wider range of both OLRs and HRTs, permitting an appropriate and reliable operation for OLRs as high as 3.15 g COD/(L.d) and HRTs as low as 6.7 days. The methane production rates achieved with inoculum II were always higher than those reached with inoculum I. The overall methane yield obtained with inoculum II was 13% higher than that achieved with inoculum I. In addition, this value was 1.9 times higher than the methane yield obtained with untreated (non-sonicated) SuOC. A second-order kinetic model was found to be adequate to fit the experimental results obtained for the two inocula used. The kinetic constant obtained with inoculum I was 3.5 times higher than that achieved with inoculum II. PMID- 23802165 TI - Formaldehyde degradation by Ralstonia eutropha in an immobilized cell bioreactor. AB - The formaldehyde (FA) degradation ability of the loofa-immobilized Ralstonia eutropha cells in a packed bed reactor was modeled using a statistically based design of the experiment (DOE) considering application of response surface methodology (RSM). The simultaneous effects of four operative test factors on the cells performance in terms of FA degradation rate and extent of the chemical oxygen demand (COD) removal were monitored. The combination of factors at initial FA concentration of 629.7 mg L(-1)h(-1), recycling substrate flow rate of 4.4 mL min(-1), aeration rate of 1.05 vvm, and the system's temperature of 28.8 degrees C resulted the optimal conditions for the FA biodegradation rate and COD removal efficiency. Loofa porous structure was found to be a protective environment for the cells in exposing to the toxic substances and the scanning electron microscopy (SEM) images revealed extensive cells penetration within this support. Oxygen transfer analysis in the form of evaluating K la value was also carried out and at the optimum conditions of the DOE was equaled to 9.96 h(-1)and oxygen uptake rate was 35.6 mg L(-1)h(-1). PMID- 23802166 TI - Optimization of coagulation-flocculation treatment on paper-recycling wastewater: Application of response surface methodology. AB - The application of coagulation-flocculation (CF) process for treating the paper recycling wastewater in jar-test experiment was employed. The purpose of the study was aimed to examine the efficiency of alum and poly aluminum chloride (PACl) in combination with a cationic polyacrylamide (C-PAM) in removal of chemical oxygen demand (COD) and turbidity from paper-recycling wastewater. Optimization of CF process were performed by varying independent parameters (coagulants dosage, flocculants dosage, initial COD and pH) using a central composite design (CCD) under response surface methodology (RSM). Maximum set required 4.5 as pH, 40 mg/L coagulants dosage and 4.5 mg/L flocculants dosage at which gave 92% reduction of turbidity, 97% of COD removal and SVI 80 mL/g. The best coagulant and flocculants were alum and chemfloc 3876 at dose of 41 and 7.52 mg/L, respectively, correspondingly at pH of 6.85. These conditions gave 91.30% COD and 95.82% turbidity removals and 12 mL/g SVI. PMID- 23802167 TI - Decolorization of methylene blue in aqueous suspensions of gold nanoparticles using parallel nanosecond pulsed laser. AB - Using 532 nm parallel nanosecond pulsed laser, the decolorization of methylene blue (MB) in aqueous suspensions of gold nanoparticles (GNPs) was studied. The effects of various experimental parameters, such as irradiation time, laser energy, and initial MB concentration on the decolorization rate were investigated. Experiments using real samples of textile dyeing wastewater were also carried out to examine the effectiveness of the method in more complex samples. From the results, the following conclusions may be drawn: (i) Under the optimum conditions (pH 7.19, 135 mJ laser energy, 4 mg/L MB concentration, and 11.6 mg/L GNP concentration), the rate of MB decolorization could reach 94% in 15 min. The decolorization follows pseudo-first-order kinetics; (ii) The amount of MB decreased rapidly during the decolorization. No intermediates of the decolorization could be detected by high-performance liquid chromatography. These observations indicate that MB was decolorized through a very rapid degradation mechanism; (iii) The rate of MB decolorization increased with the increase in laser energy (at laser energies of 0 to 135 mJ); and, (iv) The efficient decolorization of MB in real samples of textile dyeing wastewater was achieved at a decolorization rate of about 85% in 15 min. PMID- 23802168 TI - Synthesis and photoelectric properties of Cu2ZnGeS4 and Cu2ZnGeSe4 single crystalline nanowire arrays. AB - Cu2ZnGeS4 (CZGS) and Cu2ZnGeSe4 (CZGSe) single crystalline nanowire arrays have been prepared via a convenient one-step nanoconfined solvothermal approach. The porous anodic aluminum oxide was used as a morphology directing template by offering nanospace in the AAO pores for confined solvothermal reaction. The structure, morphology, composition, and optical absorption properties of the as prepared samples were characterized using X-ray powder diffraction, transmission electron microscopy, energy dispersive X-ray spectrometry, scanning electron microscopy, and a UV-vis spectrophotometer. The CZGS and CZGSe films are found to have obvious photoelectric response, indicating their potential in the application of photovoltaic devices. PMID- 23802169 TI - Promoted reduction of tellurite and formation of extracellular tellurium nanorods by concerted reaction between iron and Shewanella oneidensis MR-1. AB - The reduction of tellurite (Te(IV)) by dissimilatory metal reducing bacterium, Shewanella oneidensis MR-1, was promoted in the presence of Fe(III) in comparison with Te(IV) bioreduction in the absence of Fe(III). Electron microscopic analyses revealed that iron promoted Te(IV) reduction led to form exclusively extracellular crystalline Te(0) nanorods, as compared to the mostly intracellular formation of Te(0) nanorods in the absence of Fe(III). The Te K-edge X-ray absorption spectrometric analyses demonstrated that S. oneidensis MR-1 in the presence of Fe(III) reduced Te(IV) to less harmful metallic Te(0) nanorods through the precipitation of tellurite (Te(IV)Ox) complex by the bacterial respiration of Fe(III) to Fe(II) under anaerobic conditions. However, Fe(II) ion itself was only able to precipitate the solid tellurite (Te(IV)Ox) complex from the Te(IV) solution, which was not further reduced to Te(0). The results clearly indicated that bacterial S. oneidensis MR-1 plays important roles in the reduction and crystallization of Te(0) nanorods by as yet undetermined biochemical mechanisms. As compared to the slow bacterial Te(IV) reduction in the absence of Fe(III), the rapid reduction of Te(IV) to Te(0) by the concerted biogeochemical reaction between Fe(II) and S. oneidensis MR-1 could be applied for the sequestration and detoxification of Te(IV) in the environments as well as for the preparation of extracellular Te(0) nanorod structures. PMID- 23802171 TI - CTLA-4 +49 A/G and -318 C/T polymorphisms and susceptibility to multiple sclerosis: a meta-analysis. AB - OBJECTIVE: The aim of this study was to explore whether cytotoxic T lymphocyte antigen-4 (CTLA-4) +49 A/G, and -318 C/T polymorphisms confer susceptibility to multiple sclerosis (MS). METHODS: A meta-analysis of the associations between the CTLA-4 +49 A/G and -318 C/T polymorphisms and MS. RESULTS: A total of 23 separate comparisons from 19 studies of the CTLA-4 +49 A/G polymorphism and 10 comparisons (8 studies) of the CTLA-4 -318 C/T polymorphism were considered. Meta-analysis showed no association between MS and the CTLA-4 +49G allele in the analysis of all study subjects (OR = 1.026, 95% CI = 0.967-1.089, p = 0.395). Stratification by ethnicity indicated no association between the CTLA-4 +49G allele and MS in Caucasians, Asians, or Arabs. Meta-analysis showed no association between RA and the CTLA-4 -318C allele in all study subjects (OR = 0.909, 95% CI = 0.704-1.175, p = 0.467). In addition, meta-analysis stratified by ethnicity revealed no association between MS and the CTLA-4 -318 C/T polymorphism in Caucasian, Asian, or Arab populations. CONCLUSIONS: This meta-analysis of published studies did not find an association between the CTLA-4 +49 A/G and -318 C/T polymorphisms and susceptibility to MS in Caucasian, Asian, and Arab populations. PMID- 23802172 TI - Association study between nonsense polymorphism (rs2039381, Gln71Stop) of interferon-epsilon and susceptibility to vitiligo in Korean population. AB - Interferons (IFNs) are related to autoimmune responses. IFN-epsilon (IFNE) is included in IFN family, and may modulate immunological functions. Inflammation modulating functions of IFNE may be related with the pathophysiology of vitiligo. To investigate the association of nonsense polymorphism (rs2039381, Gln71Stop) of interferon-epsilon (IFNE) and susceptibility to vitiligo, we conducted a case control association study in 265 non-segmental vitiligo (NSV) patients and 320 healthy controls. The nonsense single nucleotide polymorphism (SNP) (rs2039381, Gln71Stop) of IFNE was genotyped by direct sequencing. Multiple logistic regression models (log-additive, dominant, and recessive models) were applied to determine odds ratios (OR), 95% confidence interval (CI), and p values. The rs2039381 (Gln71Stop) of IFNE did not show significant differences between NSV patient group and control group. However, we found that in childhood onset NSV groups, the IFNE nonsense polymorphism (rs2039381, Gln71Stop) showed a significant association. There was significantly different distribution of nonsense polymorphism of rs2039381 (Gln71Stop) of IFNE between NSV patients (childhood <18 years) and control subjects. This study suggests that rs2039381 (Gln71Stop) polymorphism of IFNE may be related to onset time of vitiligo in NSV patients. PMID- 23802173 TI - Double Negative (DN) [CD3+CD4-CD8-] T cells correlate with disease progression during HIV infection. AB - Although double negative T (DNT) cells (CD3+CD4-CD8-) share some characteristics with T regulatory cells, the relationship between DNT cells and disease progression in HIV infection is unclear. In this study, we analyzed the relationship between DNT cells and disease progression during the first 2 years of HIV infection. We found that DNT cell numbers tended to decrease with disease progression. There was a positive correlation between DNT cells and CD4 counts. The DNT cell numbers were significantly lower in the high viral load group compared with the low viral load group. Therefore, we conclude that DNT cells correlated with disease progression in HIV infection. These data provide valuable information for further understanding of the role of DNT cells during HIV infection. PMID- 23802174 TI - Inhibition of accelerated rejection mediated by alloreactive CD4+ memory T cells and prolonged allograft survival by arsenic trioxide. AB - The aim of this study was to evaluate and determine the potential mechanisms of As2O3 in accelerated rejection mediated by alloreactive CD4+ memory T cells. Vascularized heterotopic cardiac transplantation from C57BL/6 mice to nude mice (pre-transferred CD4+ memory T cells) was performed on Day 0, and As2O3 was administered to recipient mice from Day 0 to 10. As a result, As2O3 could reduce the proliferation of allo-primed CD4+ memory T cells in vitro in MLR and the baseline rate of proliferation was restored by the addition of exogenous IL-2. In vivo, compared with the control[+] group, the mean survival time of cardiac allografts in the As2O3 group was prolonged from 5.8 +/- 0.7 to 14.2 +/- 2.5 days. Five days after transplantation, the relative gene expression of IL-2, IFN gamma and Foxp3 was reduced in the grafts by As2O3 treatment, but the expression of IL-10 and TGF-beta was increased. Correspondingly, the proportions of CD4+ T cells, CD4+ memory T cells and regulatory T cells (Tregs), both in recipient spleens and lymph nodes, were lowered. These results indicate the potential of As2O3 as a novel immunosuppressant targeting CD4+ memory T cells. PMID- 23802175 TI - Announcing environmental science & technology letters. PMID- 23802176 TI - Enantioselective synthesis of the 5-6-7 carbocyclic core of the gagunin diterpenoids. AB - A catalytic enantioselective double allylic alkylation reaction has been employed in the synthesis of the core of the gagunin diterpenoids. Enantioenriched material was advanced in 11 steps to afford the core of the highly oxygenated target, which includes two all-carbon quaternary stereocenters. PMID- 23802177 TI - "Social jetlag" in morning-type college students living on campus: implications for physical and psychological well-being. AB - Although on-campus residence allows easier access to campus facilities, existing studies showed mixed results regarding the relationship between college residence and students' well-being indicators, such as sleep behaviors and mood. There was also a lack of studies investigating the role of chronotype in the relationship between on-campus residence and well-being. In particular, the temporal relationships among these factors were unclear. Hence, this longitudinal study aims to fill in these gaps by first reporting the well-being (measured in terms of mood, sleep, and quality of life) among students living on and off campus across two academic semesters. We explored factors predicting students' dropout in university residences. Although students living on campus differ in their chronotypes, activities in campus residence (if any) are mostly scheduled in the nighttime. We therefore tested if individual differences in chronotype interact with campus residence in affecting well-being. Our final sample consisted of 215 campus residents and 924 off-campus-living students from 10 different universities or colleges in Hong Kong or Macau. Their mean age was 20.2 years (SD=2.3); 6.5% of the participants are female. Participants completed self reported questionnaires online on their sleep duration, sleep quality, chronotype, mood, and physical and psychological quality of life. Across two academic semesters, we assessed if students living on and off campus differed in our well-being measures after we partialed out the effects of demographic information (including age, sex, family income, and parents' education) and the well-being measures at baseline (T1). The results showed that, campus residents exhibited longer sleep duration, greater sleep efficiency, better sleep quality, and less feeling of stress than off-campus-living students. From one semester to the next, around 10% of campus residents did not continue to live on campus. Logistic regression showed that a morning type was the strongest factor predicting dropout from campus residence. Chronotype significantly moderated the effects of campus residence on participants' physical and psychological quality of life. Although morning-type off-campus-living students have better well-being than their evening-type peers living off campus, morning-type campus residents had worse well-being than other campus residents and they were more likely to discontinue living on campus after one semester. Our findings bear practical significance to college management that morning-type campus residents are shown to be experiencing deteriorating well-being. The authorities may need to review and revise the room-allocation policy in campus residence in improving the well being among campus residents. PMID- 23802178 TI - Sulfopeptide probes of the CXCR4/CXCL12 interface reveal oligomer-specific contacts and chemokine allostery. AB - Tyrosine sulfation is a post-translational modification that enhances protein protein interactions and may identify druggable sites in the extracellular space. The G protein-coupled receptor CXCR4 is a prototypical example with three potential sulfation sites at positions 7, 12, and 21. Each receptor sulfotyrosine participates in specific contacts with its chemokine ligand in the structure of a soluble, dimeric CXCL12:CXCR4(1-38) complex, but their relative importance for CXCR4 binding and activation by the monomeric chemokine remains undefined. NMR titrations with short sulfopeptides showed that the tyrosine motifs of CXCR4 varied widely in their contributions to CXCL12 binding affinity and site specificity. Whereas the Tyr21 sulfopeptide bound the same site as in previously solved structures, the Tyr7 and Tyr12 sulfopeptides interacted nonspecifically. Surprisingly, the unsulfated Tyr7 peptide occupied a hydrophobic site on the CXCL12 monomer that is inaccessible in the CXCL12 dimer. Functional analysis of CXCR4 mutants validated the relative importance of individual CXCR4 sulfotyrosine modifications (Tyr21 > Tyr12 > Tyr7) for CXCL12 binding and receptor activation. Biophysical measurements also revealed a cooperative relationship between sulfopeptide binding at the Tyr21 site and CXCL12 dimerization, the first example of allosteric behavior in a chemokine. Future ligands that occupy the sTyr21 recognition site may act as both competitive inhibitors of receptor binding and allosteric modulators of chemokine function. Together, our data suggests that sulfation does not ubiquitously enhance complex affinity and that distinct patterns of tyrosine sulfation could encode oligomer selectivity, implying another layer of regulation for chemokine signaling. PMID- 23802181 TI - Low-bias active control of terahertz waves by coupling large-area CVD graphene to a terahertz metamaterial. AB - We propose an hybrid graphene/metamaterial device based on terahertz electronic split-ring resonators directly evaporated on top of a large-area single-layer CVD graphene. Room temperature time-domain spectroscopy measurements in the frequency range from 250 GHz to 2.75 THz show that the presence of the graphene strongly changes the THz metamaterial transmittance on the whole frequency range. The graphene gating allows active control of such interaction, showing a modulation depth of 11.5% with an applied bias of 10.6 V. Analytical modeling of the device provides a very good qualitative and quantitative agreement with the measured device behavior. The presented system shows potential as a THz modulator and can be relevant for strong light-matter coupling experiments. PMID- 23802180 TI - Glycoproteomic analysis of bronchoalveolar lavage (BAL) fluid identifies tumor associated glycoproteins from lung adenocarcinoma. AB - Cytological examination of cells from bronchoalveolar lavage (BAL) is commonly used for the diagnosis of lung cancer. Proteins released from lung cancer cells into BAL may serve as biomarkers for cancer detection. In this study, N glycoproteins in eight cases of BAL fluid, as well as eight lung adenocarcinoma tissues and eight tumor-matched normal lung tissues, were analyzed using the solid-phase extraction of N-glycoprotein (SPEG), iTRAQ labeling, and liquid chromatography tandem mass spectrometry (LC-MS/MS). Of 80 glycoproteins found in BAL specimens, 32 were identified in both cancer BAL and cancer tissues, with levels of 25 glycoproteins showing at least a 2-fold difference between cancer and benign BAL. Among them, eight glycoproteins showed greater than 2-fold elevations in cancer BAL, including Neutrophil elastase (NE), Integrin alpha-M, Cullin-4B, Napsin A, lysosome-associated membrane protein 2 (LAMP2), Cathepsin D, BPI fold-containing family B member 2, and Neutrophil gelatinase-associated lipocalin. The levels of Napsin A in cancer BAL were further verified in independently collected 39 BAL specimens using an ELISA assay. Our study demonstrates that potential protein biomarkers in BAL fluid can be detected and quantified. PMID- 23802182 TI - Successful repair of flayed tissue in a degloving injury of the hand by arteriovenous anastomosis. AB - We report the case of a 43-year-old man who had a degloving injury of the left hand from a printer machine. There was no response to a pin prick test over the peripheral portion of the degloved skin, so a branch of a digital artery was selected for anastomosis to a subcutaneous vein, which resulted in survival of the degloved tissue with no signs of congestion. Postoperative care and rehabilitation were straightforward, and functional results.were satisfactory. PMID- 23802183 TI - Benefits of conservative "wait and see" approach for recurrent plantar keloid. AB - Keloid formation of the plantar region is rare and a unique challenge to surgeons. We used a conservative "wait and see" approach for recurrent keloid in the plantar region in two patients and recommended that the patients used custom made shoes. Both patients were pleased with the result. The keloids regressed and flattened. During our minimum of five years follow-up the patients had no pain, tenderness, paraesthesiae, or problems with walking. We found no complications. Keloids should not be treated aggressively, and in plantar keloids the conservative "wait and see" approach may provide successful results without any complication. PMID- 23802184 TI - Extensor digitorum brevis manus muscle in association with a metacarpal boss. AB - Awareness of the existence of accessory muscles in the hand, such as the extensor digitorum brevis manus (EDBM) muscle, is important when making a differential diagnosis and considering the treatment of mass lesions with similar appearances. Cases of EDBM with associated dorsal wrist ganglion have been reported in earlier published reports. This report describes an unusual case of the EDBM muscle in association with carpometacarpal (CMC) boss. To the best of the authors' knowledge this has not been previously reported. PMID- 23802185 TI - Complete tissue expander coverage by musculo-fascial flaps in immediate breast mound reconstruction after mastectomy. AB - Immediate breast reconstruction with tissue expander has become an increasingly popular procedure. Complete coverage of the expander by a musculofascial layer provides an additional well-vascularised layer, reducing the rate of possible complications of skin necrosis, prosthesis displacement, and the late capsular contracture. Complete expander coverage can be achieved by a combination of pectoralis major muscle and adjacent thoracic fascia in selected patients. Seventy-five breast mounds in 59 patients were reconstructed, in the first stage a temporary tissue expander inserted immediately after mastectomy and a musculofascial layer composed of the pectoralis major muscle, the serratus anterior fascia, and the superficial pectoral fascia were created to cover the expander. The first stage was followed months later by implant insertion. Minor and major complications were reported in a period of follow-up ranging from 24-42 months (mean 31 months). Complete musculofascial coverage of the tissue expander was a simple and easy to learn technique providing that the patient has a well formed and intact superficial pectoral and serratus anterior fascia. From a total of 75 breast mounds reconstructed, major complications rate was 4% (overall rate of 19.8%), including major seroma (n = 4), haematoma (n = 1), partial skin loss (n = 3), wound dehiscence (n = 1), major infection (n = 2), severe capsule contracture (n = 1), and expander displacement (n = 3). The serratus anterior fascia and the superficial pectoral fascia flaps can be effectively used as an autologous tissue layer to cover the lower and the lateral aspect of tissue expanders in immediate breast reconstruction after mastectomy. PMID- 23802186 TI - Static reconstruction of malar region in facial paralysis: a new alternative technique for plasty of symmetric mouth appearance. AB - Static suspension using fascia lata graft is used as a reconstructive procedure against drooping of the mouth corner for treating longstanding facial paralysis. Although it achieves symmetry at rest, movement of the mouth corner at mouth opening is restricted to some extent because it is fixed with fascia lata to the immovable temporal fascia, the parotid fascia, or bones. This was overcome by suspending the mouth corner to the mandibular coronoid process with fascia lata, which enabled a shift of the mouth corner with mouth opening and closure. The nine patients discussed in this study were operated on since 1994 for longstanding facial paralysis and followed-up for over 1.5 years. As in conventional static suspension, the fascia lata was harvested and split into two bands. Next, one semi-oval fascial loop was inserted around the paralysed part of the mouth and tied with another fascial band at the mouth corner, which was looped to the mandibular coronoid process. The suspended fascia lata graft was relaxed with anteroinferior movement of the coronoid process at mouth opening, enabling the mouth corner to shift inferiorly. The mouth corner returned to its original position at mouth closure, and the nasolabial fold deepened during mastication. No limitation in mouth opening was observed. Suspension of the mouth corner to the mandibular coronoid process provided a dynamic element, thereby restoring a near-normal shift. The procedure is considered as an alternative for reconstructing the malar region of patients with facial paralysis and in whom dynamic reconstruction is not indicated. PMID- 23802187 TI - Changes in length of the radioulnar ligament and distal oblique bundle after Colles' fracture. AB - The purpose of this study was to investigate changes in length of the radioulnar ligament and distal oblique bundle (DOB) within the distal interosseous membrane after Colles' fracture and correlate the magnitude of the changes in length with clinical features. This study investigated 10 patients with malunion of a Colles' fracture. In three-dimensional computed tomography, the paths of the four limbs of the radioulnar ligament (superficial and deep, dorsal, and palmar limbs) and DOB were modelled and each path length was computed. Differences in length between the affected and contralateral unaffected side were calculated and correlated with the radiographic parameters of deformity on plain X-ray, subluxation of the DRUJ on CT, and limited range of forearm rotation in the clinical examination. In the malunited radius, the superficial and deep dorsal limbs of the radioulnar ligament were significantly elongated and DOB was significantly shortened compared with the contralateral side. These length changes correlated with radiographic radial shortening, subluxation of the DRUJ, and inversely correlated with limited range of forearm pronation. This study suggests that the dorsal radioulnar ligament would be overstretched and disrupted in Colles' fracture with severely increased radial shortening, producing laxity of the distal radioulnar joint that could negate limitation of pronation. PMID- 23802188 TI - The greatest risk of food is getting it! Foreword. PMID- 23802189 TI - One for all and all for one: the importance of shoaling on behavioral and stress responses in zebrafish. AB - Zebrafish has been increasingly used in behavioral studies, but data can present high variability. Most studies have been performed using isolated zebrafish, despite their interactive nature and shoaling behavior. We compared adult zebrafish behavior and cortisol levels after exposure to novelty as well as sensitivity to Pentylenetetrazole (PTZ)-induced seizures in animals tested individually or in groups of three (triplets). In the exploratory behavior task, data from single fish and triplets were not significantly different, but single fish data were more disperse in latency, to enter and time spent in the tank upper part, and crossings. In the light-dark task, time in the light zone and crossings were not different between groups, but latency to enter the dark zone and data variability were. We also observed that the latency to reach stage III seizures induced by PTZ was higher in triplets, but data dispersion was not different from single fish. Finally, cortisol levels of fish individually exposed to a novel environment were higher and more variable than triplets, while both groups had higher levels than unmanipulated animals. Thus, when tested individually, zebrafish are more stressed and present more variable behavior due to disruption of their natural shoal strategies. These features can be beneficial or detrimental depending on study aims and should be considered when designing, analyzing, and interpreting zebrafish behavioral data. PMID- 23802190 TI - Ethers and esters derived from apocynin avoid the interaction between p47phox and p22phox subunits of NADPH oxidase: evaluation in vitro and in silico. AB - NOX (NADPH oxidase) plays an important role during several pathologies because it produces the superoxide anion (O2*-), which reacts with NO (nitric oxide), diminishing its vasodilator effect. Although different isoforms of NOX are expressed in ECs (endothelial cells) of blood vessels, the NOX2 isoform has been considered the principal therapeutic target for vascular diseases because it can be up-regulated by inhibiting the interaction between its p47phox (cytosolic protein) and p22phox (transmembrane protein) subunits. In this research, two ethers, 4-(4-acetyl-2-methoxy-phenoxy)-acetic acid (1) and 4-(4-acetyl-2-methoxy phenoxy)-butyric acid (2) and two esters, pentanedioic acid mono-(4-acetyl-2 methoxy-phenyl) ester (3) and heptanedioic acid mono-(4-acetyl-2-methoxy-phenyl) ester (4), which are apocynin derivatives were designed, synthesized and evaluated as NOX inhibitors by quantifying O2*- production using EPR (electron paramagnetic resonance) measurements. In addition, the antioxidant activity of apocynin and its derivatives were determined. A docking study was used to identify the interactions between the NOX2's p47phox subunit and apocynin or its derivatives. The results showed that all of the compounds exhibit inhibitory activity on NOX, being 4 the best derivative. However, neither apocynin nor its derivatives were free radical scavengers. On the other hand, the in silico studies demonstrated that the apocynin and its derivatives were recognized by the polybasic SH3A and SH3B domains, which are regions of p47phox that interact with p22phox. Therefore this experimental and theoretical study suggests that compound 4 could prevent the formation of the complex between p47phox and p22phox without needing to be activated by MPO (myeloperoxidase), this being an advantage over apocynin. PMID- 23802191 TI - Water transport across the peritoneal membrane. AB - Peritoneal dialysis involves diffusive and convective transports and osmosis through the highly vascularized peritoneal membrane. The capillary endothelium offers the rate-limiting hindrance for solute and water transport. It can be functionally described in terms of a three-pore model including transcellular, ultrasmall pores responsible for free-water transport during crystalloid osmosis. Several lines of evidence have demonstrated that the water channel aquaporin-1 (AQP1) corresponds to the ultrasmall pore located in endothelial cells. Studies in Aqp1 mice have shown that deletion of AQP1 is reflected by a 50% decrease in ultrafiltration and a disappearance of the sodium sieving. Haploinsufficiency in AQP1 is also reflected by a significant attenuation of water transport. Conversely, studies in a rat model and in PD patients have shown that the induction of AQP1 in peritoneal capillaries by corticosteroids is reflected by increased water transport and ultrafiltration, without affecting the osmotic gradient and small-solute transport. Recent data have demonstrated that a novel agonist of AQP1, predicted to stabilize the open-state conformation of the channel, modulates water transport and improves ultrafiltration. Whether increasing the expression of AQP1 or gating the already existing channels would be clinically useful in PD patients remains to be investigated. PMID- 23802192 TI - Worldwide, mortality risk is high soon after initiation of hemodialysis. AB - Mortality rates for maintenance hemodialysis patients are much higher than the general population and are even greater soon after starting dialysis. Here we analyzed mortality patterns in 86,886 patients in 11 countries focusing on the early dialysis period using data from the Dialysis Outcomes and Practice Patterns Study, a prospective cohort study of in-center hemodialysis. The primary outcome was all-cause mortality, using time-dependent Cox regression, stratified by study phase adjusted for age, sex, race, and diabetes. The main predictor was time since dialysis start as divided into early (up to 120 days), intermediate (121 365 days), and late (over 365 days) periods. Mortality rates (deaths/100 patient years) were 26.7 (95% confidence intervals 25.6-27.9), 16.9 (16.2-17.6), and 13.7 (13.5-14.0) in the early, intermediate, and late periods, respectively. In each country, mortality was higher in the early compared to the intermediate period, with a range of adjusted mortality ratios from 3.10 (2.22-4.32) in Japan to 1.15 (0.87-1.53) in the United Kingdom. Adjusted mortality rates were similar for intermediate and late periods. The ratio of elevated mortality rates in the early to the intermediate period increased with age. Within each period, mortality was higher in the United States than in most other countries. Thus, internationally, the early hemodialysis period is a high-risk time for all countries studied, with substantial differences in mortality between countries. Efforts to improve outcomes should focus on the transition period and the first few months of dialysis. PMID- 23802193 TI - Maintaining calcineurin inhibition after the diagnosis of post-transplant lymphoproliferative disorder improves renal graft survival. AB - Post-transplant lymphoproliferative disorder (PTLD) is an uncontrolled proliferation of transformed lymphocytes fostered by immunosuppression. In addition to chemotherapy, treatment of PTLD includes a reduction of maintenance immunosuppression. Patients with PTLD have an increased risk of graft loss, suggesting that reduced immunosuppression strategy needs to be optimized with regard to graft outcome. Here we retrospectively reviewed 101 cases involving PTLD to identify the risks associated with graft loss. During a median follow-up of 70 months, 39 patients died and 21 lost their graft. Multivariate analysis found that an eGFR under 30 ml/min per 1.73 m(2) at PTLD diagnosis, a biopsy proven acute rejection episode following reduction of immunosuppression, and the absence of calcineurin inhibition in maintenance immunosuppression are independent risk factors for allograft loss. Neither the type of PTLD nor the chemotherapy regimen was predictive of allograft failure. Histological analysis of graft biopsies showed that maintaining calcineurin inhibition after the diagnosis of PTLD reduced the risk of developing de novo anti-HLA antibodies and humoral rejection. Remarkably, calcineurin inhibitor maintenance was neither associated with higher mortality nor with worse progression-free survival. Thus, maintaining calcineurin inhibition at a reduced dose after the diagnosis of PTLD seems safe and may improve renal graft outcome, possibly through better control of the recipient's humoral immune response. PMID- 23802195 TI - Tetrathiafulvalene: the advent of organic metals. AB - Tetrathiafulvalene (TTF) is among the most versatile and well-known molecules which exhibits outstanding redox properties and a remarkable electron donor character. Its first synthesis was published in a short communication by Wudl in 1970. In this viewpoint, its synthesis and characterization are discussed and, most importantly, the significance of TTF in the development of electrically conducting materials (organic or synthetic metals) and its further application in molecular electronics are highlighted. PMID- 23802194 TI - Recent advances in the noninvasive diagnosis of renal osteodystrophy. AB - Chronic kidney disease-mineral and bone disorder (CKD-MBD) is the term used to describe a constellation of biochemical abnormalities, bone disturbances that may lead to fractures, and extraskeletal calcification in soft tissues and arteries seen in CKD. This review focuses on the noninvasive diagnosis of renal osteodystrophy, the term used exclusively to define the bone pathology associated with CKD. Transiliac bone biopsy and histomorphometry with double-labeled tetracycline or its derivatives remains the gold standard for diagnosis of renal osteodystrophy. However, histomorphometry provides a 'window' into bone only at a single point in time, and is not clinically practical for studying continuous changes in bone morphology. Furthermore, the etiology of fractures in CKD is multifactorial and not fully explained by histomorphometry findings alone. The propensity of a bone to fracture is determined by bone strength, which is affected by bone mass and bone quality; the latter is a term used to describe the structure and composition of bone. Bone quantity is traditionally assessed by dual X-ray absorptiometry (DXA) and CT-based methods. Bone quality is more difficult to assess noninvasively, but newer techniques are emerging and are described in this review. Ultimately, the optimal diagnostic strategy for renal osteodystrophy may be a combination of multiple imaging techniques and biomarkers that are specific to each gender and race in CKD, with a goal of predicting fracture risk and optimizing therapy. PMID- 23802196 TI - A series of new star-shaped or branched platinum-acetylide derivatives: synthesis, characterization, and their aggregation behavior. AB - A series of branched or star-shaped platinum-acetylide derivatives were successfully prepared and their aggregation behaviour both in solution and on the surface was explored. PMID- 23802197 TI - Time-resolved fluorescent detection of Hg2+ in a complex environment by conjugating magnetic nanoparticles with a triple-helix molecular switch. AB - In this communication, we molecularly engineered a light-switching excimer oligonucleotide-based probe for time-resolved fluorescent detection of Hg(2+). By combining a time-resolved fluorescence technique and magnetic nanoparticles, Hg(2+) spiked in human urine was detected. PMID- 23802198 TI - Highly efficient construction of pentacyclic benzo[b]indeno-[1,2,3 de][1,8]naphthyridine derivatives via four-component domino reaction. AB - A series of new octahydrobenzo[b]indeno[1,2,3-de][1,8] naphthyridine and decahydropyrido[2,3,4-gh]phenanthridine derivatives were synthesized via a four component domino reaction under microwave irradiation. This one-pot transformation, which involved multiple steps and did not require the use of a catalyst, constructed four new C-C bonds, two new C-N bonds, and three new rings, with efficient use of all reactants. PMID- 23802199 TI - Zinc finger peptide cleavage by a dinuclear platinum compound. AB - Electrospray ionisation mass spectrometry (ESI-MS) and {(1)H, (15)N HSQC} NMR spectroscopy has elucidated the binding of a dinuclear platinum compound to a zinc finger peptide with induced backbone cleavage. Cleavage is selective on the N-terminal side of the cysteine residue following incubation at neutral pH, and is further dependent on structure of dinuclear compound. PMID- 23802201 TI - Evidence-based medicine - are we boiling the frog? AB - Evidence-based medicine has been defined as 'The conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients.' There are two major assumptions in this statement. First, it is assumed that the evidence is in fact the best. Unfortunately this is not necessarily so, and published evidence is affected by bias, sponsorship, and blind faith in mathematical probability which may not be clinically relevant. Second, the evidence is population based and may not be applicable to the individual, and blind adherence to this concept may cause harm. We must not abandon clinical experience and judgement in favour of a series of inanimate data points. Medicine is an uncertain science. PMID- 23802202 TI - Diabetic retinopathy - the Ophthalmology Society of Southern Africa screening programme. AB - Screening for diabetic retinopathy (DR) not only allows for detection of microvascular complications, but for detection of other comorbidities. Recent advances in digital camera technology have improved screening for DR and many countries have established systems that screen all diabetics for DR annually. However, South Africa has lagged behind due to pressures at the primary care level, with the result that many diabetics are not screened. In response, the Ophthalmology Society of Southern Africa has developed a low-cost 'scorecard' system for a national DR screening programme. PMID- 23802203 TI - Increasing pathology utilisation lies behind increasing pathology costs. AB - Recent increases in pathology costs per scheme member are a concern to medical schemes and pathologists alike. To better understand the observed increasing costs, the National Pathology Group commissioned Prognosys to analyse the trends affecting these increases. We found that these increases are driven by inflation, increases in utilisation, and redistribution of the burden of cost. The identification of utilisation as a cost driver for pathology services is noteworthy as almost all pathology services are by referral from another doctor. PMID- 23802200 TI - Inter-residue coupling contributes to high-affinity subtype-selective binding of alpha-bungarotoxin to nicotinic receptors. AB - The crystal structure of a pentameric alpha7 ligand-binding domain chimaera with bound alpha-btx (alpha-bungarotoxin) showed that of the five conserved aromatic residues in alpha7, only Tyr184 in loop C of the ligand-binding site was required for high-affinity binding. To determine whether the contribution of Tyr184 depends on local residues, we generated mutations in an alpha7/5HT(3A) (5 hydroxytryptamine type 3A) receptor chimaera, individually and in pairs, and measured 125I-labelled alpha-btx binding. The results show that mutations of individual residues near Tyr184 do not affect alpha-btx affinity, but pairwise mutations decrease affinity in an energetically coupled manner. Kinetic measurements show that the affinity decreases arise through increases in the alpha-btx dissociation rate with little change in the association rate. Replacing loop C in alpha7 with loop C from the alpha-btx-insensitive alpha2 or alpha3 subunits abolishes high-affinity alpha-btx binding, but preserves acetylcholine elicited single channel currents. However, in both the alpha2 and alpha3 construct, mutating either residue that flanks Tyr184 to its alpha7 counterpart restores high-affinity alpha-btx binding. Analogously, in alpha7, mutating both residues that flank Tyr184 to the alpha2 or alpha3 counterparts abolishes high affinity alpha-btx binding. Thus interaction between Tyr184 and local residues contributes to high-affinity subtype-selective alpha-btx binding. PMID- 23802204 TI - The importance of comprehensive protection in today's healthcare environment. PMID- 23802205 TI - Diabetes care in South Africa: a tale of two sectors. PMID- 23802206 TI - Otorhinolaryngology - not just tonsils and grommets: insights into the ENT scene in South Africa. PMID- 23802207 TI - The Biosulin equivalence in standard therapy (BEST) study - a multicentre, open label, non-randomised, interventional, observational study in subjects using Biosulin 30/70 for the treatment of insulin-dependent type 1 and type 2 diabetes mellitus. AB - INTRODUCTION: The need for more cost-effective insulin therapy is critical in reducing the burden on patients and health systems. Biosimilar insulins have the potential to dramatically lower healthcare costs by delivering insulin with a similar anti-glycaemic effect and adverse reaction profile. OBJECTIVES: The purpose of this study was to confirm equivalence in glycaemic outcomes and side effect profiles between Biosulin 30/70 and other human premixed insulin preparations on the South African market in a clinical practice setting. METHODS: Subjects in this interventional, observational, multicentre, open-label, prospective study were switched from their existing human premix insulin (Actraphane, Humulin 30/70 or Insuman) to the study insulin Biosulin 30/70. The primary endpoint was the change in HbA1c from baseline to 6 months. RESULTS: Seventy-seven adult patients with type 1(n=18) or type 2 (n=59) diabetes were enrolled. The baseline HbA1c in the overall cohort was 7.9%, 8.0% at 3 months (p=0.50) and 7.6% at 6 months (p=0.14).There was a small increase in the total daily dose of insulin used in both the type 1 and type 2 cohort, from 0.62 to 0.65 units/kg/day (p=0.0004). There was no significant difference in weight in the study subjects during the 6-month period on Biosulin 30/70 (p=0.67). CONCLUSION: Biosulin 30/70 achieved at least equivalent glycaemic control to existing human premix insulins, with no reported new or severe adverse events. Increased use of biosimilar insulins has the potential for significant cost savings. PMID- 23802208 TI - Exponential increase in postprandial blood-glucose exposure with increasing carbohydrate loads using a linear carbohydrate-to-insulin ratio. AB - BACKGROUND: Postprandial glucose excursions contribute significantly to average blood glucose, glycaemic variability and cardiovascular risk. Carbohydrate counting is a method of insulin dosing that balances carbohydrate load to insulin dose using a fixed ratio. Many patients and current insulin pumps calculate insulin delivery for meals based on a linear carbohydrate-to-insulin relationship. It is our hypothesis that a non-linear relationship exists between the amounts of carbohydrate consumed and the insulin required to cover it. AIM: To document blood glucose exposure in response to increasing carbohydrate loads on fixed carbohydrate-to-insulin ratios. METHODS: Five type 1 diabetic subjects receiving insulin pump therapy with good control were recruited. Morning basal rates and carbohydrate- to-insulin ratios were optimised. A Medtronic glucose sensor was used for 5 days to collect data for area-under-the-curve (AUC) analysis, during which standardised meals of increasing carbohydrate loads were consumed. RESULTS: Increasing carbohydrate loads using a fixed carbohydrate-to insulin ratio resulted in increasing glucose AUC. The relationship was found to be exponential rather than linear. Late postprandial hypoglycaemia followed carbohydrate loads of >60 g and this was often followed by rebound hyperglycaemia that lasted >6 hours. CONCLUSION: A non-linear relationship exists between carbohydrates consumed and the insulin required to cover them. This has implications for control of postprandial blood sugars, especially when consuming large carbohydrate loads. Further studies are required to look at the optimal ratios, duration and type of insulin boluses required to cover increasing carbohydrate loads. PMID- 23802209 TI - Otolaryngological, head and neck manifestations in HIV-infected patients seen at Steve Biko Academic Hospital in Pretoria, South Africa. AB - BACKGROUND: Sub-Saharan Africa has the highest incidence of HIV infection. According to recent census statistics, 5.6 million people in South Africa (SA) are HIV-positive, the highest number of infected individuals worldwide. Over 80% of HIV-infected individuals will present with ear, nose and throat (ENT) manifestations. Previous studies show that oral diseases seem to be the most common ENT-related manifestation, reported in about 40 - 50% of HIV-infected patients. In SA, there is lack of local information regarding the otolaryngological and head and neck manifestations in HIV-infected individuals. OBJECTIVE: To ascertain our local trends of ENT and head and neck manifestations in HIV-infected patients seen at our specialised ENT-HIV Clinic, Steve Biko Academic Hospital, Pretoria, Gauteng Province, SA. METHODS: A 1-year prospective study involving 153 HIV-infected patients was conducted in the clinic from January to December 2011. Patient history was taken and examinations were performed based on the World Health Organization (WHO) HIV/AIDS classification system. Data analysis was performed using Epi Info 7 software. RESULTS: The most common manifestations were adenoid hypertrophy/hyperplasia followed by cervical lymphadenopathy, chronic suppurative otitis media, otitis media with effusion and sensory-neural hearing loss. CONCLUSION: Patients typically presented with early manifestations during symptomatic WHO stages I and II in contrast to results reported in similar developing world studies from Iran, Nigeria and India. A possible explanation may lie in the SA government HIV Counselling and Testing campaign and the antiretroviral rollout programme, the effectiveness of which is becoming evident. PMID- 23802210 TI - Paediatric chronic suppurative otitis media in the Free State Province: clinical and audiological features. AB - BACKGROUND: Chronic suppurative otitis media (CSOM) is a chronic infection of the middle ear cleft. In sub-Saharan Africa >50% of cases occur in children <10 years of age. OBJECTIVES: To describe the otological, audiological and bacteriological findings in children with CSOM. METHODS: We conducted a prospective study at the Ear, Nose and Throat (ENT) Clinic at Universitas Academic Hospital between August 2009 and December 2010. We included all children with CSOM over this period. Patients underwent ENT and paediatric examination, and were tested for HIV. Pus swabs were taken after an ear toilet for routine microbiology, fungal and Mycobacterium tuberculosis culture. We performed audiological testing after the otorrhoea had resolved. RESULTS: Eighty-six children (113 ears) were included, with a median age of 4.6 years (range 1 - 12 years). The mean duration of otorrhoea was 161.7 weeks (range 4 - 572 weeks). Nine patients (10.5%) presented with coalescent mastoiditis and/or intracranial complications of CSOM. Of the 153 organisms identified; Gram-negative bacteria were present in 93 (82.3%) ears, with 94.8% of these being sensitive to quinolones. Only 1 case of tuberculous otitis media was identified. HIV infection was present in 54.6% of patients tested. There was a hearing loss in 44 (66.7%) of the tested affected ears. CONCLUSIONS: There was a long delay between the onset of symptoms and accessing ENT services. Most cases of CSOM were due to quinolone-sensitive Gram-negative aerobes. There was a high prevalence of cholesteatoma, hearing loss and other complications in children in this study. PMID- 23802211 TI - Chronic otorrhoea: spectrum of microorganisms and antibiotic sensitivity in a South African cohort. AB - BACKGROUND: Chronic otorrhoea is difficult to treat, with treatment in South Africa (SA) being protocol driven and generally initiated at the primary healthcare level. There is a lack of local studies that focus on the bacteriology and antimicrobial sensitivities of chronic otorrhoea, which underpins the management advice offered. AIMS: To determine the microbiological profile and antimicrobial susceptibility of patients with chronic otorrhoea and the validity of the Department of Health's (DoH) current guideline. METHODS: We conducted a prospective study at Groote Schuur Hospital from 2005 to 2009. We included patients with chronic otorrhoea classified as either otitis media or otitis externa, according to our definitions. Pus swabs were taken, from which microorganisms were cultured and tested for antimicrobial susceptibility. RESULTS: Of 79 patients with otorrhoea, 50 had otitis media, 21 had otitis externa and the condition was not determined in 8 patients. The most common organism isolated with otitis media was Proteus mirabilis (18/50; 36%) and with otitis externa, Pseudomonas aeruginosa (7/21; 33%). Otorrhoea had a different microbial spectrum compared with international reports, with methicillin resistant Staphylococcus aureus infection in a single patient. The organisms isolated were susceptible mainly to fluoroquinolones (96%) and aminoglycosides (81%). CONCLUSION: Amoxicillin is a poor choice of antibiotic due to its low sensitivity, which calls into question the current DoH guideline for otorrhoea. Antimicrobial treatment protocols should be based on local data and be revisited from time to time. This study suggests that, should first-line treatment fail, an antibiotic with Gram-negative cover, e.g. a topical fluoroquinolone, should be considered. PMID- 23802212 TI - Age of diagnosis of congenital hearing loss at Universitas Hospital, Bloemfontein. AB - BACKGROUND: Congenital hearing loss affects 3 - 6/1 000 children worldwide. The benefits of early identification of hearing loss and early intervention have been clearly established. There are no previous studies reporting on the age of diagnosis of congenital hearing loss in the Free State province. OBJECTIVES: To determine the age of diagnosis of congenital hearing loss in the Otorhinolaryngology Clinic at Universitas Hospital. Secondary aims included determining age at first visit, as well as the time delay between first visit and diagnosis, and documenting any interventions which took place. METHODS: A retrospective, descriptive study was undertaken, analysing data from 2001 to 2010. RESULTS: A total of 260 cases of congenital hearing loss were analysed. The median age of diagnosis of hearing loss was 44.5 months. The median age of first visit was 40.9 months, and the median delay between first visit and diagnosis was 49 days. CONCLUSIONS: The median age of diagnosis far exceeds national and international benchmarks. This has a profoundly negative impact on the development and outcomes of children with hearing loss. These results have been used to motivate for the expansion of hearing screening and diagnostic services in the province. PMID- 23802213 TI - NDM-1 imported from India--first reported case in South Africa. AB - Carbapenem-resistant Enterobacteriaceae have been increasingly reported throughout the world. The first South African report of a New Delhi metallo-beta lactamase was from Gauteng in August 2011. Despite maintaining a high degree of vigilance, the first such case was seen in KwaZulu-Natal almost a year later. Other cases have been unable to confirm a definite link to any other affected areas; this is the first case in South Africa showing this direct epidemiological link. PMID- 23802214 TI - Decline in adolescent treatment admissions for methamphetamine use in Cape Town. AB - BACKGROUND AND OBJECTIVES: The purpose of this report is to describe the changing trends in adolescent treatment admissions for methamphetamine in Cape Town, and to discuss possible implications. METHOD: Data were collected on admissions for drug abuse treatment through a regular monitoring system involving drug treatment centres and programmes in Cape Town, every 6 months as part of the South African Community Epidemiology Network on Drug Use (SACENDU). A one-page form was completed by treatment centre personnel for each patient to collect demographic and substance abuse data. RESULTS: The results indicate that between 2004 and 2006, a significant increase in the proportion of adolescent treatment admissions for methamphetamine abuse occurred, while a significant decrease occurred between 2006 and 2011. CONCLUSIONS: The initial increase in adolescent treatment admissions for methamphetamine abuse from 2004 to 2006, and subsequent decrease between 2006 and 2011, may suggest a change in methamphetamine abuse patterns among adolescents in Cape Town. PMID- 23802215 TI - Health conditions and support needs of persons living in residential facilities for adults with intellectual disability in Western Cape Province. AB - BACKGROUND: Intellectual disability (ID) is a relatively high-incidence disability, with an increased risk of poor physical and mental health. Persons with ID also have lifelong support needs that must be met if they are to achieve an acceptable quality of life. Little is known about these health conditions and support needs in the African context. This study examines persons over the age of 18 years with ID in residential facilities in Western Cape Province. OBJECTIVE: To analyse the health conditions and support needs of persons with ID in Western Cape Province. METHOD: A survey of residents' health conditions and support needs was conducted in face-to-face interviews with the managers of 37 out of 41 identified facilities. RESULTS AND CONCLUSION: The survey comprised 2 098 residents (54% of them female), representing less than 2% of the estimated population of persons with ID in the province. The survey suggests that such persons experience a wide range of health conditions (notably mental health and behavioural issues) but have limited access to general health care and rehabilitation services. Furthermore, the daily living supports required for an acceptable quality of life are limited. The findings highlight the need for better health and support provision to persons with ID. PMID- 23802216 TI - A case for revising the strength of the relationship between childhood asthma and atopy in the developing world. AB - INTRODUCTION: Asthma is the commonest chronic condition of children. Diagnosis remains difficult and many surrogate markers are used, such as documenting evidence of atopy. METHOD: Two studies investigated the role of atopy in childhood asthma. The first documented the prevalence and nature of allergy sensitivities in a group of asthmatic children compared with non-asthmatic children in Pretoria, South Africa. The second enrolled a random sample of asthmatic children and their mothers attending the Children's Chest and Allergy Clinic at Steve Biko Academic Hospital, Pretoria. Children were classified as having atopic or non-atopic asthma. Mothers completed a questionnaire to reveal atopic features. RESULTS: In the first study, only 45.0% of asthmatic children had a positive skin-prick test (SPT), as opposed to 16.2% of control children. This is a lower proportion than in many reported international studies. In the second study, 64 children with atopic asthma and 36 with non-atopic asthma were studied, along with their mothers. The proportion of children with atopic asthma did not differ for mothers with and without a positive SPT (p=0.836), a history of asthma (p=0.045) or symptoms suggestive of an allergic disease (p=1.000), or who were considered to be allergic (p=0.806). The odds ratio (OR) of a child having atopic asthma when he or she had a mother with a doctor-diagnosed history of asthma was 4.76, but the sensitivity was low (21.9%). CONCLUSION: The data demonstrate that fewer asthmatic children in South Africa are atopic than was previously thought. Also, all maternal allergic or asthmatic associations are poor predictors of childhood atopic asthma. Despite the increased risk of atopic asthma in a child of a mother who has a doctor diagnosis of asthma (OR 4.76; p=0.045), this is a poor predictor of atopic asthma (sensitivity 21.9%). PMID- 23802217 TI - Health risks of the clean-shave chiskop haircut. AB - The clean-shave haircut known locally as the chiskop is rare among females but popular with black South African men, who are also predisposed to folliculitis keloidalis nuchae (FKN) (keloids on the back of the head). During a previous study, participants described an unexpected symptom of haircut-associated bleeding. As this is not a widely recognised entity, we conducted the present study at an HIV clinic servicing the same population, with the objective of comparing the prevalences of haircut-associated bleeding and FKN in 390 HIV positive subjects with published data for Langa (Western Cape, South Africa). The results for HIV-positive participants were similar to the population data, but in both groups the prevalence of haircut-associated bleeding (24.5% v. 32%; p=0.17) was much higher than that of FKN (10.2% v. 10.5%), suggesting that the hairstyle increases the risk of bleeding even in people with healthy scalps without folliculitis. This study does not (and was not intended to) prove a higher HIV prevalence in chiskop wearers or in FKN sufferers, but it confirms a history of haircut-associated bleeding in at least a quarter of our male study participants. The risk of transmission of blood-borne infection via haircuts is likely to be low, but requires formal quantification. Public education on adequate sterilisation of barber equipment between haircuts and promotion of individual hair-clipper ownership for chiskop clients should not be delayed. Depilatory creams formulated for African hair offer a non-mechanical means of achieving clean-shave hairstyles. PMID- 23802218 TI - Participant verification: prevention of co-enrolment in clinical trials in South Africa. AB - BACKGROUND: As KwaZulu-Natal Province is the epicentre of the HIV epidemic in both South Africa (SA) and globally, it is an ideal location to conduct HIV prevention and therapeutic trials. Numerous prevention trials are currently being conducted here; the potential for participant co-enrolment may compromise the validity of these studies and is therefore of great concern. AIM: To report the development and feasibility of a digital, fingerprint-based participant identification method to prevent co-enrolment at multiple clinical trial sites. METHODS: The Medical Research Council (MRC) HIV Prevention Research Unit (HPRU) developed the Biometric Co-enrolment Prevention System (BCEPS), which uses fingerprint-based biometric technology to identify participants. A trial website was used to determine the robustness and usability of the system. After successful testing, the BCEPS was piloted in July 2010 across 7 HPRU clinical research sites. The BCEPS was pre-loaded with study names and clinical trial sites, with new participant information loaded at first visit to a trial site. RESULTS: We successfully implemented the BCEPS at the 7 HPRU sites. Using the BCEPS, we performed real-time 'flagging' of women who were already enrolled in another study as they entered a trial at an HPRU site and, where necessary, excluded them from participation on site. CONCLUSION: This system has promise in reducing co-enrolment in clinical trials and represents a valuable tool for future implementation by all groups conducting trials. The MRC is currently co ordinating this effort with clinical trial sites nationally. PMID- 23802219 TI - Microcirculatory mechanisms in postnatal hypotension affecting premature infants. AB - BACKGROUND: Hypotension remains a common complication in preterm infants and is associated with high neonatal morbidity and mortality. The underlying mechanisms are still not fully understood. We studied the microcirculation in extremely low birth weight infants to understand the relationship between blood pressure and skin perfusion. METHODS: In 21 patients (gestational age <30 wk, birth weight <1,225 g), functional vessel density (FVD) and diameter distribution were obtained prospectively by side stream dark-field imaging at the right arm in the first 48 h after birth. Infants with blood pressure below gestational age and receiving catecholamines were defined as hypotensive as compared with the remaining normotensive control group. RESULTS: In the first 6 h after birth, FVD was significantly higher in the hypotensive group than in the control group. After 12 h, there were no significant differences in either blood pressure or FVD between the two groups. FVD did not change significantly during the observation period in either group. CONCLUSION: Hypotensive infants have a higher FVD, possibly due to loss of microvascular tone leading to vasodilation and flow redistribution. However, the link between blood pressure and perfusion remains unclear, and no definitive correlation could be found. PMID- 23802220 TI - One-step DNA-programmed growth of CpG conjugated silver nanoclusters: a potential platform for simultaneous enhanced immune response and cell imaging. AB - We designed a one-pot synthesis that allows CpG-functionalized AgNCs to be prepared, combining attractive features of enhanced immune response and intracellular imaging. PMID- 23802221 TI - A novel ionic liquid-metal complex electrolyte for a remarkable increase in the efficiency of dye-sensitized solar cells. AB - A novel ionic liquid-metal complex (ILMC) electrolyte was developed for dye sensitized solar cells (DSCs). A high efficiency of nearly 7% was achieved, which was 69.2% higher compared with an ionic liquid (IL) electrolyte without a metal center. The high conductivity, inhibited electron recombination and longer electron lifetime contribute to the superior performance of the ILMC electrolyte. PMID- 23802222 TI - Generation of functionalized aryl and heteroaryl aluminum reagents by halogen lithium exchange. AB - Various functionalized aryl and heteroaryl aluminum reagents were obtained by performing I-Li or Br-Li exchange reactions with the corresponding unsaturated organic halides in the presence of i-Bu2AlCl. By means of an appropriate catalyst, the resulting new aluminum species were directly acylated, allylated or arylated. 1,4-Michael additions to enones have also been achieved. PMID- 23802223 TI - PEG-sheddable polyplex micelles as smart gene carriers based on MMP-cleavable peptide-linked block copolymers. AB - A matrix metalloproteinase-cleavable peptide-linked block copolymer was fabricated and utilized to construct PEG-sheddable polyplex micelles as smart gene delivery vectors, which were demonstrated to exhibit higher cellular uptake, improved endosomal escape, and high-efficiency gene transfection in the presence of matrix metalloproteinase-2. PMID- 23802224 TI - Theoretical and experimental studies of hydrogen adsorption and desorption on Ir surfaces. AB - We report adsorption and desorption of hydrogen on planar Ir(210) and faceted Ir(210), consisting of nanoscale {311} and (110) facets, by means of temperature programmed desorption (TPD) and density functional theory (DFT) in combination with the ab initio atomistic thermodynamics approach. TPD spectra show that only one H2 peak is seen from planar Ir(210) at all coverages whereas a single H2 peak is observed at around 440 K (F1) at fractional monolayer (ML) coverage and an additional H2 peak appears at around 360 K (F2) at 1 ML coverage on faceted Ir(210), implying structure sensitivity in recombination and desorption of hydrogen on faceted Ir(210) versus planar Ir(210), but no evidence is found for size effects in recombination and desorption of hydrogen on faceted Ir(210) for average facet sizes of 5-14 nm. Calculations indicate that H prefers to bind at the two-fold short-bridge sites of the Ir surfaces. In addition, we studied the stability of the Ir surfaces in the presence of hydrogen at different H coverages through surface free energy plots as a function of the chemical potential, which is also converted to a temperature scale. Moreover, the calculations revealed the origin of the two TPD peaks of H2 from faceted Ir(210): F1 from desorption of H2 on {311} facets while F2 from desorption of H2 on (110) facets. PMID- 23802225 TI - Dithiolene dimetallic molybdenum(V) complexes displaying intraligand charge transfer (ILCT) emission. AB - Bifunctional dithiolene ligands have been coordinated to the Mo(V)(O)(MU S2)Mo(V)(O) unit to afford [Mo2O2(MU-S)2(BPyDTS2)2](2-) (1(2-)) (BPyDTS2 (2-bis (2-pyridyl)methylene-1,3-dithiolene) dianions. Reaction of the 1(2-) molybdenum dimer with pentacarbonylchlorothenium(i) affords a tetrametallic complex of formula [Mo2O2(MU-S)2(BPyDTS2)2{Re(CO)3Cl}2](2-) (2(2-)). The monomeric (CH3)2Sn(BPyDTS2) (3) tin complex has also been prepared for comparative purposes. In the structure of (Et4N)2[1], the two metal atoms are in a square pyramidal coordination environment defined by two bridging sulfur atoms, one terminal oxygen atom and the two sulfur atoms of the bifunctional dithiolene ligand. This arrangement leaves two nitrogen atoms on each side which coordinate to two Re atoms in the 2(2-) tetrametallic complex. Compound 3 has a distorted tetrahedral structure defined by two carbon atoms of the methyl groups and two sulfur atoms of the dithiolene ligand. The luminescence properties of all three complexes in acetonitrile have been investigated. Detailed studies supported on quantum mechanical calculations revealed that complex 1(2-) shows photoluminescence in the 600-800 nm region with a maximum wavelength of 628 nm and an emission quantum yield of 0.092, associated with an intraligand charge transfer (ILCT) transition. Coordination of two Re(CO)3Cl fragments to 1(2-) to afford 2(2-) does not affect the emission spectrum and shape although it decreases the quantum yield, approximately by a factor of 4.6. Compound 3 exhibits a similar emission spectrum to those of the complexes 1(2-) and 2(2-) in good agreement with the ILCT assignment. The quantum yield of 3 lies between that of the 1(2-) and 2(2-) complexes. PMID- 23802226 TI - Differences in prostate cancer detection between Canadian and Saudi populations. AB - Few studies have addressed racial differences in prostate cancer (PCa) detection between Western and Arabian countries, although PCa has a significantly lower prevalence in Arabic populations compared to Western populations. Therefore, an explanation of this difference is lacking. Serum prostate-specific antigen (PSA) is a valuable marker used to select patients who should undergo prostate biopsies, although the manner in which it is used may require adjustments based on the ethnic population in question. We investigated racial differences in the PCa detection rate between Canadian and Saudi populations. A retrospective analysis was performed of data collected prospectively over 5 consecutive years in urology clinics at the McGill University Health Center (MUHC) and King Saud University Hospital (KSUH). Men who had high (>4'ng/mL) or rising PSA levels and a negative digital rectal examination were eligible. A total of 1403 Canadian and 414 Saudi patients were evaluated for the study; 717 and 158 men, median age 64 and 68 years, were included in the MUHC and KSUH cohorts, respectively, P<0.0001). Median serum PSA, prostate volume, and PSA density values were 6.1'ng/mL, 47.3 g, and 0.12'ng . mL(-1) . g(-1), respectively, for MUHC patients and 5.2'ng/mL, 64.5'g, and 0.08'ng . mL(-1) . g(-1), respectively, for KSUH patients (P<0.0001, t-test followed by one-way ANOVA). In addition, the KSUH group had a significantly lower PCa detection rate among patients younger than 60 years of age and with PSA values <10'ng/mL. PMID- 23802227 TI - Effects of propofol on damage of rat intestinal epithelial cells induced by heat stress and lipopolysaccharides. AB - Gut-derived endotoxin and pathogenic bacteria have been proposed as important causative factors of morbidity and death during heat stroke. However, it is still unclear what kind of damage is induced by heat stress. In this study, the rat intestinal epithelial cell line (IEC-6) was treated with heat stress or a combination of heat stress and lipopolysaccharide (LPS). In addition, propofol, which plays an important role in anti-inflammation and organ protection, was applied to study its effects on cellular viability and apoptosis. Heat stress, LPS, or heat stress combined with LPS stimulation can all cause intestinal epithelial cell damage, including early apoptosis and subsequent necrosis. However, propofol can alleviate injuries caused by heat stress, LPS, or the combination of heat stress and LPS. Interestingly, propofol can only mitigate LPS induced intestinal epithelial cell apoptosis, and has no protective role in heat stress-induced apoptosis. This study developed a model that can mimic the intestinal heat stress environment. It demonstrates the effects on intestinal epithelial cell damage, and indicated that propofol could be used as a therapeutic drug for the treatment of heat-stress-induced intestinal injuries. PMID- 23802228 TI - Effects of rosiglitazone on serum paraoxonase activity and metabolic parameters in patients with type 2 diabetes mellitus. AB - Human serum paraoxonase contributes to the anti-atherogenic effect of high density lipoprotein cholesterol (HDL-C) and has been shown to protect both low density lipoprotein cholesterol (LDL-C) and HDL-C against lipid peroxidation. We investigated the effects of rosiglitazone on paraoxonase activity and metabolic parameters in patients with type 2 diabetes mellitus [50 patients (30 males, 20 females); mean +/- SD age: 58.7 +/- 9.2 years, body mass index: 28.2 +/- 4.1'kg/m2], in whom glucose control could not be achieved despite treatment with metformin, sulphonylurea, and/or insulin. The patients were given 4'mg/day rosiglitazone for 3 months in addition to their usual treatment. Serum paraoxonase activity, malondialdehyde, homocysteine, and lipid profile were measured at the time of initiation and at the end of therapy with rosiglitazone. After rosiglitazone therapy, serum levels of HDL-C, apolipoprotein A-1, and paraoxonase activity increased significantly (P<0.05) and malondialdehyde, homocysteine, lipoprotein(a), and glucose levels decreased significantly (P<0.05), but no significant changes in levels of total cholesterol and apolipoprotein B were observed. Triglyceride levels also increased significantly (P<0.05). Rosiglitazone treatment led to an improvement in glycemic control and to an increase in paraoxonase activity and HDL-C levels. Although rosiglitazone showed favorable effects on oxidant/antioxidant balance and lipid profile, further studies are needed to determine the effect of rosiglitazone on cardiovascular risk factors and cardiovascular morbidity and mortality. PMID- 23802230 TI - Effect of tibiotarsal joint inflammation on gene expression and cross-sectional area in rat soleus muscle. AB - BACKGROUND: Joint inflammation is a common clinical problem in patients treated by physical therapists. The hypothesis of this study is that joint inflammation induces molecular and structural changes in the soleus muscle, which is composed mainly of slow-twitch muscle fibers. OBJECTIVE: To study the effect of tibiotarsal joint inflammation on muscle fiber cross-sectional area (CSA), gene expression levels (atrogin-1, MuRF1, MyoD, myostatin, p38MAPK, NFkappaB, TNF alpha), and TNF-alpha protein in the soleus muscle. METHOD: Wistar rats were randomly divided into 3 periods (2, 7 and 15 days) and assigned to 4 groups (control, sham, inflammation, and immobilization). RESULTS: In the inflammation group at 2 days, MuRF1 and p38MAPK expression had increased, and NFkappaB mRNA levels had decreased. At 7 days, myostatin expression had decreased. At 7 and 15 days, this group had muscle fiber CSA reduction. At 2 days, the immobilization group showed increased atrogin-1, MuRF1, NFkappaB, MyoD, and p38MAPK expressions and reduced muscle fiber CSA. At 7 and 15 days, myostatin mRNA levels had increased, and the CSA had decreased. The sham group showed increased p38MAPK and myostatin expressions at 2 and 7 days, respectively. No changes occurred in TNF alpha gene or protein expression. CONCLUSION: Acute joint inflammation induces gene expression related to the proteolytic pathway without reduction in muscle fiber CSA. Chronic joint inflammation induced muscle atrophy without up regulation of important genes belonging to the proteolytic pathway. Thus, muscle adaptation may differ according to the stage of joint inflammation, which suggests that the therapeutic modalities used by physical therapists at each stage should also be different. PMID- 23802235 TI - Seroprevalence and risk factors for cattle anaplasmosis, babesiosis, and trypanosomiasis in a Brazilian semiarid region. AB - The seroprevalence of Anaplasma marginale, Babesia bigemina, Babesia bovis and Trypanosoma vivax and the risk factors for these infections were investigated in 509 cows on 37 farms in the semiarid region of Paraiba, northeastern Brazil. Cow serum samples were tested by means of immunofluorescence assay (IFA) against each specific antigen. The mean seroprevalence values per farm were 15.0% (range: 0 75%) for A. marginale, 9.5% (range: 0-40%) for B. bigemina and 26.9% (range: 0 73.7%) for B. bovis. All cows tested negative for T. vivax. Higher prevalence for A. marginale was significantly associated with less frequent acaricide spraying per year and with higher use of injectable antihelminthics. Presence of cows positive for B. bigemina was significantly associated with acaricide use and with presence of horse flies on the farm. Both occurrence and higher prevalence of B. bovis were significantly associated with recent observations of ticks on cattle. Overall, the present results indicate that the region investigated is an enzootically unstable area for A. marginale, B. bigemina and B. bovis, since most animals were seronegative to at least one agent. PMID- 23802234 TI - Developments in the use of nanocapsules in oncology. AB - The application of nanotechnology to medicine can provide important benefits, especially in oncology, a fact that has resulted in the emergence of a new field called Nanooncology. Nanoparticles can be engineered to incorporate a wide variety of chemotherapeutic or diagnostic agents. A nanocapsule is a vesicular system that exhibits a typical core-shell structure in which active molecules are confined to a reservoir or within a cavity that is surrounded by a polymer membrane or coating. Delivery systems based on nanocapsules are usually transported to a targeted tumor site and then release their contents upon change in environmental conditions. An effective delivery of the therapeutic agent to the tumor site and to the infiltrating tumor cells is difficult to achieve in many cancer treatments. Therefore, new devices are being developed to facilitate intratumoral distribution, to protect the active agent from premature degradation and to allow its sustained and controlled release. This review focuses on recent studies on the use of nanocapsules for cancer therapy and diagnosis. PMID- 23802236 TI - Serosurvey for tick-borne diseases in dogs from the Eastern Amazon, Brazil. AB - Canine ehrlichiosis and babesiosis are the most prevalent tick-borne diseases in Brazilian dogs. Few studies have focused attention in surveying tick-borne diseases in the Brazilian Amazon region. A total of 129 blood samples were collected from dogs living in the Brazilian eastern Amazon. Seventy-two samples from dogs from rural areas of 19 municipalities and 57 samples from urban stray dogs from Santarem municipality were collected. Serum samples were submitted to Indirect Immunofluorescence Assay (IFA) with antigens of Babesia canis vogeli, Ehrlichia canis, and six Rickettsia species. The frequency of dogs containing anti-B. canis vogeli, anti-E. canis, and anti-Rickettsia spp. antibodies was 42.6%, 16.2%, and 31.7%, respectively. Anti-B. canis vogeli antibodies were detected in 59.6% of the urban dogs, and in 29.1% of the rural dogs (P < 0.05). For E. canis, seroprevalence was similar among urban (15.7%) and rural (16.6%) dogs. For Rickettsia spp., rural dogs presented significantly higher (P < 0.05) prevalence (40.3%) than urban animals (21.1%). This first study on tick-borne pathogens in dogs from the Brazilian eastern Amazon indicates that dogs are exposed to several agents, such as Babesia organisms, mostly in the urban area; Spotted Fever group Rickettsia organisms, mostly in the rural area; and Ehrlichia organisms, in dogs from both areas studied. PMID- 23802237 TI - Canine visceral leishmaniasis and Chagas disease among dogs in Araguaina, Tocantins. AB - The present study analyzed serum samples from 111 male and female dogs of various ages from the municipality of Araguaina in the State of Tocantins, Brazil. Serological diagnosis of canine visceral leishmaniasis (CVL) was initially performed at the Central Laboratory (Laboratorio Central - LACEN) of Araguaina, resulting in 61 positive samples by an indirect immunofluorescence assay (IIFA) (>=1:40) and 50 non-reactive samples. The same samples were analyzed at the Sao Paulo Institute of Tropical Medicine (Instituto de Medicina Tropical de Sao Paulo - IMTSP) by an enzyme-linked-immunosorbent assay (ELISA), resulting in 57 positive samples (51.35%) and 54 negative samples (48.64%). The Kappa coefficient of agreement between the tests was 0.74. The serum samples were also subjected to a diagnostic assay for Trypanosoma cruzi (Trypomastigote Excreted/Secreted Antigens -TESA-blot) that detected five suspect animals; three of those animals were positive for leishmaniasis by ELISA but negative by IIFA. These findings suggest that the canine population of Araguaina may be simultaneously infected with Leishmania chagasi and T. cruzi. The results obtained demonstrate the difficulty of using serology to detect CVL, thus emphasizing the necessity for a reference test to diagnose CVL, particularly in regions where the infection is endemic. PMID- 23802238 TI - Paratrichodina africana (Ciliophora: Trichodinidae) of wild and cultured Nile tilapia in the Northern Brazil. AB - The present work morphologically characterizes Paratrichodina africana from the gills of wild and farmed Nile tilapia from Northern Brazil (eastern Amazonia). Ninety fish were captured for parasitological analysis in Macapa, State of Amapa, from a wetland area bathed by the Amazon River commonly called 'Ressaca do Zerao' (n = 52), as well as from a local fish farm (n = 38). Wet smears of the skin and gills of the captured fish were air dried at room temperature and impregnated with silver nitrate by Klein's method for posterior examination of the adhesive disc structures. Total prevalence of parasitism was 16.6% (23% in fish from wetland and 7.8% in farmed fish). Characterized as a small-sized trichodinid, it presented the following measures: 33.2 +/- 4.7 um body diameter, 17.5 +/- 2.1 um adhesive disc, 10.0 +/- 0.9 um denticulate ring, and 22.6 +/- 2.0 denticles. Paratrichodina africana reported in this study strongly resembles those described for other localities, but it differs by presenting greater body length. This is the fourth report of P. africana parasitizing a host fish. PMID- 23802239 TI - Usefulness of serological ELISA assay for Taenia saginata to detect naturally infected bovines. AB - Bovine cysticercosis, a cosmopolitan disease caused by Taenia saginata, leads to economic losses due to carcass devaluation at slaughter. Sanitary inspection at slaughterhouses, the routine diagnostic method in Brazil, lacks the necessary sensitivity to detect the mildly infected cattle that are typically encoutered in Brazil. In this study we have tested cattle sera from animals diagnosed as positive and negative by veterianry inspection for (1) anti-parasite antibodies using metacestodes antigens (T. solium vesicular fluid and T. saginata secretions) and (2) the HP10 secreted antigen of viable metacestodes. The cut-off values were calculated by ROC curve for intense and mild infections conditions, and by the classical method ( for negative samples). The sensitivity and specificity of these diagnostic tests were different depending on the assumed cut off value and, importantly, whether the infection was mild or intense. In spite of these observations, however, such ELISA assays for serum antibodies and parasite antigens constitute an important tool for epidemiological porposes, and in establishing priorities for the control of bovine cysticercosis. PMID- 23802240 TI - Endovascular treatment for acute ischemic stroke. PMID- 23802241 TI - Endovascular treatment for acute ischemic stroke. PMID- 23802242 TI - Reply to H. Kantarjian et al. PMID- 23802243 TI - Reply to I.E. Haines. PMID- 23802245 TI - Clipboard. Study reveals why elderly often vulnerable to scams: research suggests aging adults are worse at spotting untrustworthy faces. PMID- 23802244 TI - Reply to K. Bujko and D. Tan et al. PMID- 23802246 TI - Clipboard. Hearing loss accelerates brain function decline in older adults. PMID- 23802247 TI - Prescription stimulant misuse among adolescent at-risk groups in Canada. PMID- 23802248 TI - Prescription stimulant misuse among adolescent at-risk groups in Canada. Reply. PMID- 23802250 TI - World Health Federation says: 'start heart health earlier than you think'. PMID- 23802249 TI - Should we drink black tea without milk? PMID- 23802251 TI - Bernard Lown: the nonagenarian blogger with a lifelong thirst for combining clinical practice and social responsibility. PMID- 23802252 TI - Profile: The Japanese Circulation Society. PMID- 23802254 TI - The martial art of stress management. PMID- 23802253 TI - [The histohematogenous barrier as a diagnostic criterion for morphological studies in forensic medicine]. PMID- 23802255 TI - Untethered. PMID- 23802256 TI - Purchasing medical devices should be collaborative. PMID- 23802257 TI - Label change for alcohol-based skin disinfectants poses workflow problems. PMID- 23802258 TI - CPOE systems can substantially reduce medication errors. PMID- 23802259 TI - Handover and communication errors in imaging compromise safety. PMID- 23802261 TI - Medline MDS600EL and MDS400SA patient lifts may have loose or sheared bolts. PMID- 23802260 TI - Care coordination program reduces readmissions. PMID- 23802262 TI - Maquet Servo-i ventilator alarm volume must be assessed in care environments. PMID- 23802263 TI - Engineered female-specific lethality for control of pest Lepidoptera. AB - The sterile insect technique (SIT) is a pest control strategy involving the mass release of radiation-sterilized insects, which reduce the target population through nonviable matings. In Lepidoptera, SIT could be more broadly applicable if the deleterious effects of sterilization by irradiation could be avoided. Moreover, male-only release can improve the efficacy of SIT. Adequate methods of male-only production in Lepidoptera are currently lacking, in contrast to some Diptera. We describe a synthetic genetic system that allows male-only moth production for SIT and also replaces radiation sterilization with inherited female-specific lethality. We sequenced and characterized the doublesex (dsx) gene from the pink bollworm (Pectinophora gossypiella). Sex-alternate splicing from dsx was used to develop a conditional lethal genetic sexing system in two pest moths: the diamondback moth (Plutella xylostella) and pink bollworm. This system shows promise for enhancing existing pink bollworm SIT, as well as broadening SIT-type control to diamondback moth and other Lepidoptera. PMID- 23802264 TI - [The emergency department--medical record slavery or learning mecca?]. PMID- 23802265 TI - [Thoughts about the four year rule--why do we put up with it?]. PMID- 23802266 TI - [The four year rule and humanitarian medical practice]. PMID- 23802267 TI - Nanoparticles deliver a sting to HIV-1 infectivity. PMID- 23802268 TI - Using nanomedicine to resolve inflammation and prevent tissue damage. PMID- 23802269 TI - Current world literature. Small bowel transplantation. PMID- 23802270 TI - Current world literature. Pathology. PMID- 23802271 TI - Authors' response. PMID- 23802272 TI - Red blood cell and platelet interactions in healthy females during early and late pregnancy, as well as postpartum. PMID- 23802273 TI - The MRC at 100. PMID- 23802274 TI - [Colon carcinoma and its lymph nodes]. PMID- 23802275 TI - Pakistan's drug problem. PMID- 23802276 TI - Guantanamo hunger strikers make a plea to their doctors. PMID- 23802277 TI - Health activism in a globalising era: lessons past for efforts future. PMID- 23802278 TI - ["Untreatable gonorrhea"]. PMID- 23802279 TI - Miriam B. Goodman. PMID- 23802280 TI - The psychology of GMO. PMID- 23802281 TI - Does the gut microbiome hold clues to obesity and diabetes? PMID- 23802282 TI - Frugal fishing at hand. PMID- 23802283 TI - The authors reply. PMID- 23802284 TI - Guest editors' introduction: special section on the IEEE conference on Visual Analytics Science and Technology (VAST). PMID- 23802285 TI - Authors' reply to 'explaining differential effects of tiotropium on mortality in COPD'. PMID- 23802286 TI - Author's response. PMID- 23802287 TI - The effect of whole body vibration on the H-reflex, the stretch reflex, and the short-latency response during hopping. AB - The effect of whole body vibration (WBV) on reflex responses is controversially discussed in the literature. In this study, three different modalities of reflex activation with increased motor complexity have been selected to clarify the effects of acute WBV on reflex activation: (1) the electrically evoked H-reflex, (2) the mechanically elicited stretch reflex, and (3) the short-latency response (SLR) during hopping. WBV-induced changes of the H-reflex, the stretch reflex, and the SLR during hopping were recorded in the soleus and gastrocnemius muscles and were analyzed before, during (only the H-reflex), immediately after, 5 min and 10 min after WBV. The main findings were that (1) the H-reflexes were significantly reduced during and at least up to 5 min after WBV, (2) the stretch reflex amplitudes were also significantly reduced immediately after WBV but recovered to their initial amplitudes within 5 min, and (3) the SLR during hopping showed no vibration-induced modulation. With regard to the modalities with low motor complexities, the decreased H- and stretch reflex responses are assumed to point toward a reduced Ia afferent transmission during and after WBV. However, it is assumed that during hopping, the suppression of reflex sensitivity is compensated by facilitatory mechanisms in this complex motor task. PMID- 23802288 TI - Effects of two weeks of daily apnea training on diving response, spleen contraction, and erythropoiesis in novel subjects. AB - Three potentially protective responses to hypoxia have been reported to be enhanced in divers: (1) the diving response, (2) the blood-boosting spleen contraction, and (3) a long-term enhancement of hemoglobin concentration (Hb). Longitudinal studies, however, have been lacking except concerning the diving response. Ten untrained subjects followed a 2-week training program with 10 maximal effort apneas per day, with pre- and posttraining measurements during three maximal duration apneas, and an additional post-training series when the apneic duration was kept identical to that before training. Cardiorespiratory parameters and venous blood samples were collected across tests, and spleen diameters were measured via ultrasound imaging. Maximal apneic duration increased by 44 s (P < 0.05). Diving bradycardia developed 3 s earlier and was more pronounced after training (P < 0.05). Spleen contraction during apneas was similar during all tests. The arterial hemoglobin desaturation (SaO2) nadir after apnea was 84% pretraining and 89% after the duration-mimicked apneas post training (P < 0.05), while it was 72% (P < 0.05) after maximal apneas post training. Baseline Hb remained unchanged after training, but reticulocyte count increased by 15% (P < 0.05). We concluded that the attenuated SaO2 decrease during mimic apneas was due mainly to the earlier and more pronounced diving bradycardia, as no enhancement of spleen contraction or Hb had occurred. Increased reticulocyte count suggests augmented erythropoiesis. PMID- 23802290 TI - Sending out an SOS. PMID- 23802289 TI - Differentiated mTOR but not AMPK signaling after strength vs endurance exercise in training-accustomed individuals. AB - The influence of adenosine mono phosphate (AMP)-activated protein kinase (AMPK) vs Akt-mammalian target of rapamycin C1 (mTORC1) protein signaling mechanisms on converting differentiated exercise into training specific adaptations is not well established. To investigate this, human subjects were divided into endurance, strength, and non-exercise control groups. Data were obtained before and during post-exercise recovery from single-bout exercise, conducted with an exercise mode to which the exercise subjects were accustomed through 10 weeks of prior training. Blood and muscle samples were analyzed for plasma substrates and hormones and for muscle markers of AMPK and Akt-mTORC1 protein signaling. Increases in plasma glucose, insulin, growth hormone (GH), and insulin-like growth factor (IGF)-1, and in phosphorylated muscle phospho-Akt substrate (PAS) of 160 kDa, mTOR, 70 kDa ribosomal protein S6 kinase, eukaryotic initiation factor 4E, and glycogen synthase kinase 3a were observed after strength exercise. Increased phosphorylation of AMPK, histone deacetylase5 (HDAC5), cAMP response element-binding protein, and acetyl-CoA carboxylase (ACC) was observed after endurance exercise, but not differently from after strength exercise. No changes in protein phosphorylation were observed in non-exercise controls. Endurance training produced an increase in maximal oxygen uptake and a decrease in submaximal exercise heart rate, while strength training produced increases in muscle cross-sectional area and strength. No changes in basal levels of signaling proteins were observed in response to training. The results support that in training-accustomed individuals, mTORC1 signaling is preferentially activated after hypertrophy-inducing exercise, while AMPK signaling is less specific for differentiated exercise. PMID- 23802291 TI - A novel approach. PMID- 23802292 TI - Happy trails. PMID- 23802293 TI - A voyage of discovery. PMID- 23802294 TI - Fathers know best. PMID- 23802295 TI - Fire & nice. PMID- 23802296 TI - [Peculiarities of forensic medical reconstruction of the mechanism of injuries in numerous victims of the explosion of a high-capacity blasting device]. AB - The systemic analysis of forensic medical practice in Moscow during the past 15 years has demonstrated the scientific, practical, and social significance of expertise of peace-time blast injuries resulting from many terrorist attacks with the use of improvised high-capacity explosive devices that caused multiple human victims. The authors emphasize the current lack of objective forensic medical criteria for the reconstruction of the mechanism of injuries in numerous victims of the explosion of a high-capacity blasting device. It dictates the necessity of their development and substantiation of their practical application. PMID- 23802297 TI - [The possibility of forensic medical assessment of the damage to clothes caused by a blank shots with the MP-79-9TM pistol]. AB - The authors undertook an analysis of constructional features of standard blank and non-lethal cartridges for the MP-79-9TM pistol. The composition of gunshot products and the maximum distance over which they propagate have been determined. Special attention is given to the peculiarities of the damage caused to the target cloths (cotton and woolen) by blank rounds shot from different distances. A new chemical method was used for the first time to detect the particles of gunpowder on the victim's cloth; the possibility of its application for differential diagnostics of gunshot damages inflicted by blank and traumatic cartridges affected from different distances was estimated. PMID- 23802298 TI - [Modern pneumatic weapons and injuries they cause]. AB - The data on the history of development and further improvement of pneumatic weapons are presented with special reference to specific features of different types and varieties of these weapons, cartridges for them, and the sphere of their application. Investigations into peculiarities of damages caused by high capacity pneumatic weapons to the objects of forensic medical expertise affected from different distances are reviewed. Results of forensic medical expertise and clinical studies on the structure of body injuries inflicted by gunshots from pneumatic weapons to the human body are discussed. The author emphasizes the necessity of developing up-to-date terminology and classification of gunshot injuries caused by shooting from pneumatic weapons. PMID- 23802299 TI - [A method for the determination of spatial orientation of wound canals caused by gunshot bullets to be applied in corpse examination]. AB - A new approach to the determination of spatial orientation of wound canals caused by gunshot bullets is proposed and substantiated; its application for the purpose of forensic medical expertise is described. The direction of penetrating wound canals in three dimensions was determined by measuring the distance of the input and output wound holes from the level of the soles, anterior and posterior midlines, and the posterior body surface; the results of the measurements were used to construct triangles. The parameters thus obtained allowed the spatial orientation of the wound canals to be determined in three dimensions for the subsequent judgment about the relative direction of the gun barrel with respect to the human body at the time of the shot and the objective expert conclusion concerning the circumstances of firearm-related injuries. PMID- 23802300 TI - [Analysis of stresses developing in the evidence-bearing material affected by a bladed article]. AB - The objective of the present study was to assess the possibility of using the finite element analysis for the elucidation of the mechanism of formation of stab cutting injuries. Stresses developing in the evidence-bearing material at different stages of penetration of a bladed article are estimated. The three dimensional modeling program was employed for the purpose. The finite element analysis demonstrated differing stress topography resulting from the prick of the blade and its plunging into the evidence-bearing material. PMID- 23802301 TI - [Characteristic of the hepatic tissue degradation processes underlying the development of its local and distant lesions]. AB - The processes associated with liver disruption caused by a blunt abdominal injury have been investigated on a model of continuous media deformation. It was shown that local primary injuries to the liver result from stress-induced tissue stretching, compression, and shear in the longitudinal direction. They have a layered relief due to transverse fissures. The peripheral ruptures result from tissue extension under effect of overall liver deformation. They are not deep and have a uniform relief created by alternating low tubercles and superficial fissures oriented at the right angle to the surface. Antishock ruptures are the consequences of tissue extension or stretching/compression during local and overall deformation of the liver surface. They develop in the longitudinal direction, have a non-uniform relief created by alternating high prominences and numerous fissures differing in both the depth and the extension and oriented at the right angle to the liver surface. Central ruptures result from tissue stretching accompanying overall deformation of the organ. They are directed perpendicular to the direction of the surface force, have the longitudinal direction and non-uniform relief. PMID- 23802302 TI - [The age-specific changes in the wall of the arterial circle of Willis]. AB - The objective of the present study was to create the database of morphometric and morphological characteristics of the wall of the vessels of the Willis arterial circle at the site of their bifurcation throughout the period of postnatal ontogenesis in man to be used for the postmortem determination of human age. Preparations of vascular cross sections were used to measure the intima thickness (intimal pads) in the region of lateral bifurcation angles on the terminal branch of the internal carotid and basilar arteries obtained from 130 corpses of the subjects aged between 0 and 75 years. The histological preparations were stained with hematoxylin/eosin and van Gieson's pyrofuchsin or by the Unnar-Tenzer method. Morphometry was performed using a Bioscan image analyser and the Scion Image v.402 software. The Microsoft Excel 2003 package was used for the primary treatment of the data obtained. They were used to draw the table of intimal pads developing throughout the period of postnatal ontogenesis in man that allows for the postmortem determination of approximate human age. The study showed that the thickening of intimal pads and concomitant thinning of the underlying muscular layer during the postnatal ontogenesis should be regarded as being normal age related changes. PMID- 23802303 TI - [Biochemical diagnostics of fatal opium intoxication]. AB - Biochemical diagnostics of fatal opium intoxication remains a topical problem in forensic medical science and practice. We investigated materials obtained in the course of forensic medical expertise of the cases of fatal opium intoxication. The study revealed significant differences between myoglobin levels in blood, urine, myocardium, and skeletal muscles. The proposed approach to biochemical diagnostics of fatal opium intoxication enhances the accuracy and the level of evidence of expert conclusions. PMID- 23802304 TI - [Specific features of 2-methyl hydroxybenzene and 3-methyl hydroxybenzene distribution in the organism of warm-blooded animals]. AB - The present work was designed to study the specific features of 2-methyl hydroxybezene and 3-methyl hydroxybenzene distribution after intragastric administration of these toxicants to warm-blooded animals (rats). They were detected in the unmetabolized form in the internal organs and blood of the animals. The levels of 2-methyl hydroxybezene were especially high in the stomach and blood whereas the maximum content of 3-methyl hydroxybenzene was found in brain, blood, small intestines of the poisoned rats. PMID- 23802305 TI - [Time of death software product as a readily available tool for the work of a forensic medical expert at the place of occurrence]. AB - The present paper is devoted to the possibility of using the Time of Death software product (free supplement for iPhone) as a readily available tool for the work of a forensic medical expert at the place of occurrence that may be helpful for the determination of prescription of death coming during the examination of a corpse in the early postmortem period at the place of occurrence (the site of discovery). PMID- 23802306 TI - [Participation of forensic medical experts in the examination at the place of occurrence: fundamental legal principles and organizational aspects]. AB - Discussed in this paper are fundamental legal principles and organizational aspects of the participation of forensic medical experts in the examination of the corpses at the place of occurrence. A detailed analysis of the current departmental and sectoral regulations governing the activities of specialists in the field of forensic medicine was performed The analysis demonstrated their positive and negative aspects. These findings were used to develop concrete recommendations for further improvement of these documents. PMID- 23802307 TI - [An injury by atmospheric electricity: case report]. PMID- 23802308 TI - [The use of scanning probe microscopy in forensic medicine studies]. PMID- 23802309 TI - [On the problem of unexpected death resulting from a disease of the central nervous system]. AB - The problem of unexpected death is challenging for many medical disciplines including forensic medicine. In 2011 the ratio of violent to non-violent deaths was 1:1.7. The structure of non-violent mortality changed due to the rise in the number of deaths from cerebrovascular diseases. International epidemiological studies demonstrated that stroke presently holds the second or third place in the structure of overall mortality in the world's population. The lethality rate attributable to hemorrhagic stroke is estimated at 79.5%. Of special interest for both forensic medical experts and general practitioners is the combination of cerebrovascular disease and the preceding craniocerebral injury. The discrepancy between clinical and pathologo-anatomical diagnoses amounts to 46.5%. According to the data collected by the Russian Centre of Forensic Medical Expertise in 2010, cerebrovascular pathology remained unrecognized in 62.4% of the cases and was erroneously diagnosed as a cerebrocranial injury in 52.2% of the patients. It is believed that forensic medical experts can render assistance to health facilities as regards the improvement of the quality of medical aid and preventive measures provided to the population by means of analysis of available information and the development of relevant recommendations. PMID- 23802310 TI - Assessment and treatment of three common anorectal conditions. AB - This is the second of two articles about the kinds of anorectal problem with which people can present at emergency departments. The first article concerns common symptoms and anorectal examination, while this one discusses the diagnosis and treatment of three common anorectal problems that can be managed by nurse practitioners: haemorrhoids, anal fissure and pruritus ani. Unexpected diagnoses might be found on examination and nurse practitioners should refer these patients to appropriate specialists. PMID- 23802311 TI - Commentary on "Drospirenone-containing oral contraceptive pills and the risk of venous and arterial thrombosis: a systematic review". PMID- 23802312 TI - Reviewer's Commentary on 'Familial risk of obstetric anal sphincter injuries: registry-based cohort study'. PMID- 23802313 TI - Transfusion medicine illustrated: The original Leukotrap. PMID- 23802314 TI - Imaging as a tool for global cancer control. PMID- 23802315 TI - Expression levels of 10 candidate genes in lung tissue of vaccinated and TB infected cynomolgus macaques. AB - The expression of ten tuberculosis candidate genes in lung and lymph nodes of cynomolgus macaques vaccinated and experimentally infected with Mycobacterium tuberculosis (Mtb) was quantified. The expression of TNFalpha, IL10, IL1beta, TLR4, IL17, IL6, IL12, and iNOS in the lungs of vaccinated animals was higher than that of non-vaccinated animals. PMID- 23802316 TI - Effect of physical restraint on glucose tolerance in cynomolgus monkeys. AB - BACKGROUND: Physiologic stress has been demonstrated to impair glucose tolerance. METHODS: Glucose tolerance tests were performed using six cynomolgus monkeys. RESULTS: Chair-restrained subjects elicited higher elevations of plasma glucose and cortisol compared with squeezing device-restrained subjects. CONCLUSIONS: The responses to a glucose challenge are altered by different restraint procedures. PMID- 23802317 TI - Retraction notice to "Antiglioma activity of curcumin-loaded lipid nanoparticles and its enhanced bioavailability in brain tissue for effective glioblastoma therapy" [Acta Biomaterialia 8 (2012) 2670-2687]. PMID- 23802319 TI - Retraction notice to "Epithelial cell adhesion molecule targeted nutlin-3a loaded immunonanoparticles for cancer therapy" [Acta Biomaterialia 7 (2011) 355-369]. PMID- 23802318 TI - Retraction notice to "Enhanced antiproliferative activity of carboplatin loaded chitosan-alginate nanoparticles in retinoblastoma cell line" [Acta Biomaterialia 6 (2010) 3120-3131]. PMID- 23802320 TI - Retraction notice to "Transferrin-conjugated curcumin-loaded superparamagnetic iron oxide nanoparticles induce augmented cellular uptake and apoptosis in K562 cells" [Acta Biomaterialia 8 (2011) 704-719]. PMID- 23802321 TI - Retraction notice to "Enhanced cellular uptake and in vivo pharmacokinetics of rapamycin loaded cubic phase nanoparticles for cancer therapy" [Acta BioMaterialia 7 (2011) 3656-3669]. PMID- 23802322 TI - Retraction notice to "Effect of nanostructure on osteoinduction of porous biphasic calcium phosphate ceramics" [Acta Biomaterialia 8 (2012) 3794-3804]. PMID- 23802323 TI - High-quality patient care pathways are central to the establishment of peritoneal dialysis. PMID- 23802324 TI - Schools at the centre of educational research in autism: possibilities, practices and promises. PMID- 23802326 TI - Hearing loss could be linked to dementia. Treat age-related hearing loss to help prevent dementia. PMID- 23802327 TI - Preserve muscle mass--and prevent falls--with proper nutrition. Protein, vitamin D, and a balanced diet counter the effects of low muscle mass, promoting strength and mobility as we age. PMID- 23802328 TI - Which heart tests should be questioned--and why. Website explains who needs many of today's tests...and who doesn't. PMID- 23802329 TI - Blood vessel damage in the brain may contribute to Alzheimer's risk. New study identifies white matter "hyperintensities" as risk factors secondary to beta amyloid plaques. PMID- 23802330 TI - Use of opioids to control arthritis pain under scrutiny. Increase in falls, fractures in older adults attributed to narcotic painkillers, such as oxycodone, Vicodin or Percocet. PMID- 23802331 TI - My father has been diagnosed with giant cell arteritis. What is this, and is it a serious? PMID- 23802332 TI - What can you tell me about glaucoma prevention and treatment? PMID- 23802333 TI - Is there any way I can prevent, or at least reduce my risk of developing Alzheimer's disease or other dementias? PMID- 23802334 TI - I've been reading a lot about probiotics. What can you tell me about them? PMID- 23802335 TI - Integrated information theory of consciousness: an updated account. AB - This article presents an updated account of integrated information theory of consciousness (liT) and some of its implications. /IT stems from thought experiments that lead to phenomenological axioms (existence, compositionality, information, integration, exclusion) and corresponding ontological postulates. The information axiom asserts that every experience is spec~fic - it is what it is by differing in its particular way from a large repertoire of alternatives. The integration axiom asserts that each experience is unified- it cannot be reduced to independent components. The exclusion axiom asserts that every experience is definite - it is limited to particular things and not others and flows at a particular speed and resolution. /IT formalizes these intuitions with postulates. The information postulate states that only "differences that make a difference" from the intrinsic perpective of a system matter: a mechanism generates cause-effect information if its present state has selective past causes and selective future effects within a system. The integration postulate states that only information that is irreducible matters: mechanisms generate integrated information only to the extent that the information they generate cannot be partitioned into that generated within independent components. The exclusion postulate states that only maxima of integrated information matter: a mechanism specifies only one maximally irreducible set of past causes and future effects - a concept. A complex is a set of elements specifying a maximally irreducible constellation of concepts, where the maximum is evaluated over elements and at the optimal spatiatemporal scale. Its concepts specify a maximally integrated conceptual information structure or quale, which is identical with an experience. Finally, changes in information integration upon exposure to the environment reflect a system's ability to match the causal structure of the world. After introducing an updated definition of information integration and related quantities, the article presents some theoretical considerations about the relationship between information and causation and about the relational structure of concepts within a qua/e. It also explores the relationship between the temporal grain size of information integration and the dynamic of metastable states in the corticothalamic complex. Finally, it summarizes how liT accounts for empirical findings about the neural substrate of consciousness, and how various aspects of phenomenology may in principle be addressed in terms of the geometry of information integration. PMID- 23802336 TI - [CIRS-AINS Special: awareness]. PMID- 23802337 TI - [Incident reporting: cannulas and redon bottles]. PMID- 23802338 TI - The future of off-label marketing regulations in the post-Sorrell era. PMID- 23802339 TI - The case for baccalaureate-prepared nurses. AB - The nursing workforce plays a central role in our present health care system, and will likely have an even greater role in the future. Nurses already provide the vast majority of care to patients in hospitals, and so it should come as no surprise that the quality of nursing care affects patient outcomes. Over the past decade, studies have linked certain nursing characteristics--such as staffing levels, education, job satisfaction, and work environment--with better outcomes in hospitals. This Issue Brief adds to that evidence with a longitudinal study that links changes in nurse education with improvements in surgical patients' survival. It also discusses how a more educated nurse workforce could fill a range of new roles in primary care, prevention, and care coordination as health reform is implemented. PMID- 23802340 TI - A cornucopia of food choice incentives. PMID- 23802341 TI - National Prevention Strategy to promote environmental health. PMID- 23802342 TI - Coordinating Medicaid and health insurance exchanges. PMID- 23802343 TI - [Nursing history - questions and perspectives]. PMID- 23802344 TI - [Problems arising from the professionalization of nursing in the German Empire in the late 19th and early 20th century compared to the USA. A contribution to the current discussion]. AB - The process of professionalization in Germany was hindered by several factors: the tradition of denominational nursing, the increasing segregation in the field of nursing, the resistance against nurses' professionalization, the late and sporadic institutionalization of nursing schools, and the classification of nursing as "arztlicher Heilhilfsberuf". On the basis of these five influencing factors this paper will discuss the development in Germany in comparison to the USA at the end of the 19th and early 20th centuries. The aim is to explain the differences in the process of professionalization in the German Reich and the USA which are rooted in that period. PMID- 23802345 TI - American Catholic nursing. An historical analysis. AB - This study analyzes the nursing activities of religious sister nurses as spiritual agents of care during wartime, in railroad and mining centers, and in cities in the United States in the 19th century. This is a story about the workings of religion, gender, social class, ethnicity, and nursing. The sisters' work demonstrates how an analysis of professional nursing is incomplete without an understanding of the roles that a number of Catholic religious women took in reaching out to both Catholics and non-Catholics in the United States. PMID- 23802346 TI - [The voluntary medical care during the First World War. The work of the nursing staff in the military field hospitals on the eastern and western frontlines]. AB - The voluntary medical care consisted of civilians who were provided to the medical corps in the First World War for the first time in this great dimension. The nursing staff on the eastern and the western German frontlines were sending letters back home, some of them were drafting diaries due to the special event or recorded their experiences after the war. Besides the narratives of their private impressions, these documents are reflecting their nursing work, which the nursing staff had to achieve. An important factor was, that the patients were soldiers. Conflicts in the cooperation with the medical staff and among the nurses did not seem to have influenced a good quality of care, however it facilitated a harmonic coexistence and above all, it helped to sustain behind the fronts. The study of the nursing care and the relationship with patients and among the staff reflects on the meaning of nursing care for the staff. PMID- 23802347 TI - [Rationalization of Protestant nursing. A comparison of Deaconess Motherhouses in West Germany and the United States, 1945-1970]. AB - Protestant Deaconess Motherhouses emerged as a German nursing organization in the nineteenth century to be later exported to many other countries including the United States. The motherhouse principle could not be simply transferred without being adapted to the situation prevailing in each of those countries. The essay investigates the conception and transformation of Protestant nursing by comparing a West German and American deaconess motherhouse each in their particular context. It shows that the deaconesses in the United States developed their own, more scientifically oriented understanding of nursing and were therefore more open to the rationalization of nursing than their West German counterpart. PMID- 23802348 TI - Person-centered policymaking: is it an answer to improving health and healthcare in Tennessee? PMID- 23802349 TI - ANA leads initiative to develop national safe patient handling standards. PMID- 23802350 TI - [The use of the axis "structure" of the OPD-CA as a helpful instrument for the concept of body psychotherapy in clinical treatment]. AB - Body psychotherapy is an important part of a multimodal approach in clinical treatment for many psychiatric disorders. The ICD-10 is not helpful for finding the appropriate kind of body psychotherapy among many different kinds in a psychodynamic orientated approach because the phenomenological categories of this instrument don't aim on the structure of the personality underlying the psychic disorder. In this article we suggest a concept of a development- and structure based body psychotherapy which refers to the axis "structure" of the OPD-CA. PMID- 23802351 TI - [Empirical basis of the Questionnaire for Crying, Feeding and Sleeping]. AB - The Questionnaire for Crying, Feeding and Sleeping of an infant, constructed based on theory and factor analysis, is assessed for internal consistency, inter correlations, and its relation to a behaviour diary. A clinical and a non clinical sample are compared. The sample of in total 704 infants younger than one year consists of different subsamples. To test the differences between a clinical and a non-clinical sample assessed with the questionnaire, data of 134 infants brought to the outpatient unit for parents with their infants and toddlers and a matched sample are used. The principal components analysis results in three well interpretable scales correlating with each other, which all show a high internal consistency. The connections to the diary records and the differences between the means of the clinical and the non-clinical sample are found in the expected directions. The results of the Questionnaire for Crying, Feeding and Sleeping, including the criterion of Wessel, are consistent with the behaviour diary as well as the clinical diagnostics. The Questionnaire for Crying, Feeding and Sleeping shows validity according to these criteria and can therefore be used in research and clinical practise for the assessment of problems concerning crying, feeding and sleeping in the first year of life. PMID- 23802352 TI - [Short- and long-term effects of parent training programmes of children with developmental disabilities]. AB - Due to the higher care needs of their children, parents of children with developmental disabilities are often burdened. An increased degree of stress correlates with dysfunctional parenting behaviour and a low sense of competence. Parent involvement in treatment implementation is essential so that parents can support the development of their children long-ranging and positively. Parenting training programmes are an appropriate method to reduce child behaviou problems. The effectiveness of two parenting training programmes is presented: Intervention A involves weekly training courses containing information about a normative child development. Furthermore all parents are given the possibility to take part in therapy sessions. Intervention B is modular and high structured. Parents are taught in small groups and receive information about the different areas of development and how to increase their parentin behaviour. The outcomes of a randomized clinical trial of the two intervention concepts are presented. 34 parents with children (between 54 and 77 months) with developmental dis abilities participated per group. Particularly, intervention B was associated with a reduction of dysfunctional parenting behaviour and fewer child behaviour problems; a decreased parental stress level was observed for both interventions similarly. PMID- 23802353 TI - [One more tool in the box]. PMID- 23802354 TI - [Nurses should take this opportunity]. PMID- 23802355 TI - [Impetus for a change in life style]. PMID- 23802356 TI - [Quality is a question of attitude]. PMID- 23802357 TI - [A link between "inside" and "outside"]. PMID- 23802358 TI - [Dispelling burnout taboos and prevention]. PMID- 23802359 TI - [We have to learn to argue more intelligently (interview by Martina Camenzind)]. PMID- 23802360 TI - [Constipation management in palliative care]. PMID- 23802361 TI - [A drive to share]. PMID- 23802362 TI - [The robot never has a backache]. PMID- 23802363 TI - [The equipment is unfeeling]. PMID- 23802364 TI - [The meaning of life to tbe end]. PMID- 23802365 TI - [When "being with" replaces "doing with"]. PMID- 23802366 TI - ["A breath came from outside"]. PMID- 23802367 TI - ["Without light, the lighthouse is useless"]. PMID- 23802368 TI - [Plantar reflexology]. PMID- 23802369 TI - [Entire network]. PMID- 23802370 TI - Solving a case: like playing a puzzle? PMID- 23802371 TI - Stretching educational boundaries. PMID- 23802372 TI - Focus on: digital impressions. PMID- 23802373 TI - The role of cements in dental implant success, Part 2. AB - Simple modeling systems can be used to demonstrate how cement flows, helping with the understanding of how luting cements work as liquids, knowledge of how much is required, application techniques, and how simple modifications to abutment design can be of benefit to the implant restoring dentist. PMID- 23802374 TI - Simplified technique for parallel placement of mini-implants. PMID- 23802375 TI - Aesthetic zone challenges: untreatable teeth, Part I: Using low intensity orthodontic eruption to safeguard gingival and bone levels. PMID- 23802376 TI - Mental imaging in endodontics: Living in a place you'll never see! PMID- 23802377 TI - Magnification alternatives: seeing is believing, Part I. PMID- 23802378 TI - System for success: Increasing revenue and patient comfort by embracing technology. PMID- 23802379 TI - The new science of strong teeth: Class II preps. PMID- 23802380 TI - Removing all-ceramic restorations with lasers. PMID- 23802381 TI - Demographics, shifting models of care and physician leadership. PMID- 23802382 TI - Specialty medical homes taking root. PMID- 23802383 TI - Myers-Briggs personality preferences may enhance physician leadership success in non-clinical jobs. PMID- 23802384 TI - Establishing patient-centered physician and nurse bedside rounding. PMID- 23802385 TI - An analytical approach to improving physician performance. PMID- 23802386 TI - Should physician executives stoop to popularizing medicine? PMID- 23802387 TI - Bridging the quality gap with medical-legal partnerships. PMID- 23802388 TI - Setting physician leaders up for success. PMID- 23802389 TI - How to prepare for your CMO/VPMA interview. PMID- 23802390 TI - Optimizing organizational change. PMID- 23802391 TI - What's in a word? PMID- 23802392 TI - Seven habits of unproductive thinking. PMID- 23802393 TI - Will health care costs come down? Watch the IPAB. PMID- 23802394 TI - CEO mindset for the future. PMID- 23802395 TI - Presentations offer insight on social media for physicians. PMID- 23802396 TI - Understanding the work done by NHS commissioning managers: an exploration of the microprocesses underlying day-to-day sensemaking in UK primary care organisations. AB - PURPOSE: The purpose of this paper is to explore the practical daily work undertaken by middle-level managers in Primary Care Trusts (PCTs), focusing upon the micro-processes by which these managers enact sensemaking in their organisations. DESIGN/METHODOLOGY/APPROACH: The research took a case study approach, undertaking detailed case studies in four PCTs in England. Data collection included shadowing managers, meeting observations and interviews. FINDINGS: The research elucidated two categories of enactment behaviour exhibited by PCT managers: presence/absence; and the production of artefacts. Being "present" in or "absent" from meetings enacted sensemaking over and above any concrete contribution to the meeting made by the actors involved. This paper explores the factors affecting these processes, and describes the situations in which enactment of sense is most likely to occur. Producing artefacts such as meeting minutes or PowerPoint slides also enacted sense in the study sites in addition to the content of the artefact. The factors affecting this are explored. PRACTICAL IMPLICATIONS: The study has practical implications for all managers seeking to maximise their influence in their organisations. It also provides specific evidence relevant to managers working in the new Clinical Commissioning Groups currently being formed in England. ORIGINALITY/VALUE: The study expands the understanding of sensemaking in organisations in two important ways. Firstly, it moves beyond discourse to explore the ways in which behaviours can enact sense. Secondly, it explores the distinction between active and unconscious sensemaking. PMID- 23802397 TI - Senior management leadership, social support, job design and stressor-to-strain relationships in hospital practice. AB - PURPOSE: The purpose of this paper is to examine the effect of the quality of senior management leadership on social support and job design, whose main effects on strains, and moderating effects on work stressors-to-strains relationships were assessed. DESIGN/METHODOLOGY/APPROACH: A survey involving distribution of questionnaires was carried out on a random sample of health care employees in acute hospital practice in the UK. The sample comprised 65,142 respondents. The work stressors tested were quantitative overload and hostile environment, whereas strains were measured through job satisfaction and turnover intentions. Structural equation modelling and moderated regression analyses were used in the analysis. FINDINGS: Quality of senior management leadership explained 75 per cent and 94 per cent of the variance of social support and job design respectively, whereas work stressors explained 51 per cent of the variance of strains. Social support and job design predicted job satisfaction and turnover intentions, as well as moderated significantly the relationships between quantitative workload/hostility and job satisfaction/turnover intentions. RESEARCH LIMITATIONS/IMPLICATIONS: The findings are useful to management and to health employees working in acute/specialist hospitals. Further research could be done in other counties to take into account cultural differences and variations in health systems. The limitations included self-reported data and percept-percept bias due to same source data collection. PRACTICAL IMPLICATIONS: The quality of senior management leaders in hospitals has an impact on the social environment, the support given to health employees, their job design, as well as work stressors and strains perceived. ORIGINALITY/VALUE: The study argues in favour of effective senior management leadership of hospitals, as well as ensuring adequate support structures and job design. The findings may be useful to health policy makers and human resources managers. PMID- 23802398 TI - Towards a new paradigm in health research and practice? Collaborations for Leadership in Applied Health Research and Care. AB - PURPOSE: Collaborations for Leadership in Applied Health Research and Care (CLAHRCs) are a new UK initiative to promote collaboration between universities and healthcare organisations in carrying out and applying the findings of applied health research. But they face significant, institutionalised barriers to their success. This paper seeks to analyse these challenges and discuss prospects for overcoming them. DESIGN/METHODOLOGY/APPROACH: The paper draws on in-depth qualitative interview data from the first round of an ongoing evaluation of one CLAHRC to understand the views of different stakeholders on its progress so far, challenges faced, and emergent solutions. FINDINGS: The breadth of CLAHRCs' missions seems crucial to mobilise the diverse stakeholders needed to succeed, but also produces disagreement about what the prime goal of the Collaborations should be. A process of consensus building is necessary to instil a common vision among CLAHRC members, but deep-seated institutional divisions continue to orient them in divergent directions, which may need to be overcome through other means. ORIGINALITY/VALUE: This analysis suggests some of the key means by which those involved in joint enterprises such as CLAHRCs can achieve consensus and action towards a current goal, and offers recommendations for those involved in their design, commissioning and performance management. PMID- 23802399 TI - Framing quality improvement tools and techniques in healthcare the case of improvement leaders' guides. AB - PURPOSE: The purpose of this paper is to present a study of how quality improvement tools and techniques are framed within healthcare settings. DESIGN/METHODOLOGY/APPROACH: The paper employs an interpretive approach to understand how quality improvement tools and techniques are mobilised and legitimated. It does so using a case study of the NHS Modernisation Agency Improvement Leaders' Guides in England. FINDINGS: Improvement Leaders' Guides were framed within a service improvement approach encouraging the use of quality improvement tools and techniques within healthcare settings. Their use formed part of enacting tools and techniques across different contexts. Whilst this enactment was believed to support the mobilisation of tools and techniques, the experience also illustrated the challenges in distributing such approaches. ORIGINALITY/VALUE: The paper provides an important contribution in furthering our understanding of framing the "social act" of quality improvement. Given the ongoing emphasis on quality improvement in health systems and the persistent challenges involved, it also provides important information for healthcare leaders globally in seeking to develop, implement or modify similar tools and distribute leadership within health and social care settings. PMID- 23802400 TI - Towards sustainable structures for neighbourhood development? Healthy city research in four Swedish municipalities 2003-2009. AB - PURPOSE: A vehicle to reduce health inequalities and improve public health has been provided by programmes at a neighbourhood level. The purpose of this paper is to analyse the development processes in four municipalities for achieving sustainable structures in area-based development programmes during and after a formal partnership period. DESIGN/METHODOLOGY/APPROACH: A case-study database was compiled based on the strategic and local work of four municipalities and four municipal housing companies who cooperated in the Partnership for Sustainable Welfare Development 2003-2009. The case-study database includes nine in-depth studies with interviews (n = 68), participant observations (n = 125), a survey (n = 1,160), and documents. The data are analysed using three theoretical concepts: political support, alliances, and citizen participation. FINDINGS: Political support, alliances, and citizen participation are important building blocks in neighbourhood development work. However, when the partnership ended there was little left that could function as a sustainable structure. Political support seems to be a means to reach the target, including ensuring a consistent approach and allocation of resources. However, the support must continue also after the intervention period, when the formal partnership collaboration ends, otherwise the established structure will soon decompose. Citizen participation is another precondition for a sustainable structure able to continue despite reduced municipal support. Alliances have the best chance of forming sustainable structures when they involve both the strategic and the operational level. ORIGINALITY/VALUE: Even though many evaluations have been conducted to capture the process of interventions, little attention has been given to the challenges facing the outcomes of the intervention when it comes to making permanent the activities for reducing health inequalities. This paper is an attempt to deal with these challenges. PMID- 23802401 TI - Multi-criteria development and incorporation into decision tools for health technology adoption. AB - PURPOSE: When introducing new health technologies, decision makers must integrate research evidence with local operational management information to guide decisions about whether and under what conditions the technology will be used. Multi-criteria decision analysis can support the adoption or prioritization of health interventions by using criteria to explicitly articulate the health organization's needs, limitations, and values in addition to evaluating evidence for safety and effectiveness. This paper seeks to describe the development of a framework to create agreed-upon criteria and decision tools to enhance a pre existing local health technology assessment (HTA) decision support program. DESIGN/METHODOLOGY/APPROACH: The authors compiled a list of published criteria from the literature, consulted with experts to refine the criteria list, and used a modified Delphi process with a group of key stakeholders to review, modify, and validate each criterion. In a workshop setting, the criteria were used to create decision tools. FINDINGS: A set of user-validated criteria for new health technology evaluation and adoption was developed and integrated into the local HTA decision support program. Technology evaluation and decision guideline tools were created using these criteria to ensure that the decision process is systematic, consistent, and transparent. PRACTICAL IMPLICATIONS: This framework can be used by others to develop decision-making criteria and tools to enhance similar technology adoption programs. ORIGINALITY/VALUE: The development of clear, user-validated criteria for evaluating new technologies adds a critical element to improve decision-making on technology adoption, and the decision tools ensure consistency, transparency, and real-world relevance. PMID- 23802402 TI - Intrinsic motivation: how can it play a pivotal role in changing clinician behaviour? AB - PURPOSE: In the light of an increasing healthcare burden, this paper seeks to offer insight about how intrinsic motivation could play a pivotal role in improving the pre-existing healthcare service delivery systems by altering clinician behaviour. The paper argues the case for four salient dimensions worth exploring through the lens of intrinsic motivation--non-financial incentives, positive affective states, organizational culture and prescribing quality. DESIGN/METHODOLOGY/APPROACH: This article reviews literature from both social sciences and health management practices to provide rationale on how intrinsic motivational approaches could optimize healthcare service delivery systems. FINDINGS: The scrutiny of the body of evidence leads to the assertion that there is neglect in the initiatives to reinforce intrinsic motivation as a method to address the ailing morale of doctors. This seems to have exacerbated negative outcomes that include job dissatisfaction, compromise in the quality of care and poor patient-doctor relationships. Diminution in positive affective states amongst doctors, largely controlled by intrinsic motivation, led to strained doctor-patient communication and poor quality of care. Barriers in a healthcare organizational culture that restricts autonomy and empowerment seem to directly undermine job satisfaction. ORIGINALITY/VALUE: The article argues that it is crucial to shift away from the conventional tendencies promoting tangible rewards. A more holistic approach should be adopted by conducting formal research into intrinsic motivation and how it could aid the formulation of policies tailored to meet the current demands of the healthcare system. PMID- 23802403 TI - Recognizing junior doctors' potential contribution to patient safety and health care quality improvement. AB - PURPOSE: The purpose of this paper is to re-frame perceptions surrounding junior doctors' capacity to contribute to patient safety and quality improvement. DESIGN/METHODOLOGY/APPROACH: A targeted literature review was conducted followed by individual telephone interviews and a half-day forum involving junior doctor representatives and selected leaders in the sector. FINDINGS: Junior doctors' entry into health care is an ideal time to cultivate practitioners' interest and expertise in improving the health system for better patient care. Junior doctors are more likely to bring or embrace new ideas, and recognize the importance of transparency and integration of technology into healthcare systems. Engaging with junior doctors in collaborative processes, rather than focusing on their more senior colleagues, may create a more effective culture. ORIGINALITY/VALUE: The attributes of junior doctors (as they are in the absence of specific quality improvement or leadership training) that are currently underutilized in patient safety and quality improvement are explored, along with the factors limiting and facilitating the utilization of these attributes. PMID- 23802404 TI - Nanomaterials in cancer-therapy drug delivery system. AB - Nanomaterials can enhance the delivery and treatment efficiency of anti-cancer drugs, and the mechanisms of the tumor-reducing activity of nanomaterials with cancer drug have been investigated. The task for drug to reach pathological areas has facilitated rapid advances in nanomedicine. Herein, we summarize promising findings with respect to cancer therapeutics based on nano-drug delivery vectors. Relatively high toxicity of uncoated nanoparticles restricts the use of these materials in humans. In order to reduce toxicity, many approaches have focused on the encapsulation of nanoparticles with biocompatible materials. Efficient delivery systems have been developed that utilized nanoparticles loaded with high dose of cancer drug in the presence of bilayer molecules. Well-established nanotechnologies have been designed for drug delivery with specific bonding. Surface-modified nanoparticles as vehicles for drug delivery system that contains multiple nano-components, each specially designed to achieve aimed task for the emerging application delivery of therapeutics. Drug-coated polymer nanoparticles could efficiently increase the intracellular accumulation of anti-cancer drugs. This review also introduces the nanomaterials with drug on the induction of apoptosis in cancer cells in vitro and in vivo. Direct interactions between the particles and cellular molecules to cause adverse biological responses are also discussed. PMID- 23802405 TI - Functionalization of iron oxide nanoparticles with biosurfactants and biocompatibility studies. AB - We present methodologies to functionalize iron oxide (Fe3O4) nanoparticles with biosurfactants and biocompatibility results. Positively charged Fe3O4 nanoparticles of average hydrodynamic size -26 nm is functionalized with four different molecules of interest, viz., surfactin, rhamnolipid, polyethylene glycol (PEG) and dextran. The functionalization results in dramatic alterations in surface potential and hydrodynamic size due to the presence of coated moieties on the nanoparticle interface. The Fourier transform infrared spectroscopy and thermogravimetric analysis confirm the presence of adsorbed moieties on nanoparticles. The phase contrast microscopy studies show the formation of reversible chains of functionalized nanoparticles under an external magnetic field. Cell viability studies using L929 mouse fibroblast cell line show that pure surfactin, rhamnolipid and dextran exhibit cytotoxicity with increase in concentration, whereas, pure PEG exhibit biocompatibility at different concentrations. Accordingly, surfactin and rhamnolipid coated nanoparticles are found to be cytotoxic with increase in concentration and PEG coated nanoparticles are found to be biocompatible. Dextran coated nanoparticles do not exhibit significant increase in biocompatibility. PMID- 23802406 TI - Ionic complexation as a non-covalent approach for the design of folate anchored rifampicin Gantrez nanoparticles. AB - The present study discloses the design of folate anchored Rifampicin-Poly methylvinylether maleic anhydride copolymer (Gantrez AN-119, Gantrez) nanoparticles (RFMGzFa) by ionic complexation. Folic acid was anchored to the preformed drug loaded nanoparticles. Folic acid was anchored in different concentration by simply varying the amount of folic acid added during preparation. RFMGzFa nanoparticles were prepared by emulsion solvent diffusion method. Gantrez AN-119 rapidly hydrolyzes in aqueous medium releasing carboxylic acid groups, to create an acidic environment. This facilitates protonation and subsequent ionic complexation of folic acid with the carboxylic groups, to enable anchoring. FTIR spectra confirmed this interaction. Infrared imaging revealed distribution of folic acid across the nanoparticle surface. Nanoparticles were obtained in the size range 350-450 nm with RFM loading of 12-14% w/w. Zeta potential confirmed colloidal stability. TEM/SEM revealed spherical morphology. RFMGzFa nanoparticles exhibited sustained release of RFM and folic acid. Folic acid showed sustained release upto 12 h, which was ion exchange mediated. A 480% enhancement in RFM uptake with RFMGzFa nanoparticles compared to 300% with RFMGz nanoparticles in-vitro, in human macrophage cell line U-937, suggested the role of folic acid in folate receptor mediated uptake. Ionic complexation represents a simple non-covalent approach for anchoring folic acid on polymeric nanoparticles of Gantrez. PMID- 23802407 TI - Poly(ethylene glycol) versus dendrimer prodrug conjugates: influence of prodrug architecture in cellular uptake and transferrin mediated targeting. AB - Many polymer based drug delivery nanosystems are currently being explored for delivering cytotoxic agents to the tumors. However, very few strategies delineate the comparative carrier ability of nanosystems, in similar experimental settings. As a result, it remains unclear how to optimally design polymer based multicomponent prodrug systems for delivery applications. The present study is aimed to design polymeric prodrug conjugate carriers for the comparative cellular delivery ability of anticancer drug doxorubicin hydrochloride (DOX) using linear poly(ethylene glycol) (PEG), hyperbranched poly(amido amine) (PAMAM) G4 dendrimer, and PAMAM G4 dendrimer-PEG conjugate using MCF-7 cells. Furthermore, the cellular targetability and in vitro anticancer activity of DOX conjugates is evaluated using transferrin (Tf) as a targeting ligand. Interestingly, conjugation of DOX to PAMAM G4-OH dendrimer significantly influences the cytotoxicity of DOX leading to -4 fold decrease in the IC50 dose when compared to pegylated DOX. This study establishes the rational and comparative structural activity relationship of polymeric prodrug carriers for delivery of anticancer drugs. The schematic representation of design of prodrug conjugates with varied polymeric architecures is as shown below (Fig. 1). PMID- 23802408 TI - Fabrication of fibrin based electrospun multiscale composite scaffold for tissue engineering applications. AB - Fabricating scaffolds mimicking the native extracellular matrix (ECM) in both structure and function is a key challenge in the field of tissue engineering. Previously we have demonstrated a novel electrospinnig method for the fabrication of fibrin nanofibers using Poly(vinyl alcohol) (PVA) as an 'electrospinning driving' polymer. Here we demonstrate the fabrication and characterization of a multiscale fibrin based composite scaffold with polycaprolactone (PCL) by sequential electrospinning of PCL microfibers and fibrin nanofibers. This multiscale scaffold has great potential for tissue engineering applications due to the combined benefits of biological nanofibers such as cell attachment and proliferation and that of microfibers such as open structure, larger pore size and adequate mechanical strength. Physico chemical characterization of the electrospun scaffold was done by Scanning Electron Microscopy (SEM), Contact angle analysis, fibrin specific Phosphotungstic acid haematoxyllin (PTAH) staining and evaluation of mechanical properties. SEM data revealed the formation of bead free nanofibers of fibrin with a fiber diameter ranging from 50-500 nm and microfibers of PCL in the size range of 1 microns to 2.5 microns. These dimensions mimic the hierarchical structure of ECM found in native tissues. Cell attachment and viability studies using human mesenchymal stem cells (hMSC) revealed that the scaffold is non toxic and supports cell attachment, spreading and proliferation. In addition, we examined the inflammatory potential of the scaffold to demonstrate its usefulness in tissue engineering applications. PMID- 23802409 TI - The in vitro anti-tumor efficacy and the pharmacokinetics of N3-o-toluyl fluorouracil loaded nanosuspension (TFu-LNS). AB - N3-o-toluyl-fluorouracil (TFu) was a potent water-insoluble prodrug of 5 fuorouracil (5-Fu). To improve the solubility of TFu, TFu loaded nanosuspension (TFu-LNS) was prepared by high-pressure homogenization method. The results of in vitro release studies showed that 5-Fu was sustained released from TFu-LNS. Then in vitro antitumor activity of TFu-LNS in terms of antiproliferative activity, induction of apoptosis and G1 cycle arrest on human breast adenocarcinoma cell line (MCF-7) and human gastric carcinoma cell line (BGC) was evaluated. The results of MTT assay showed that TFu-LNS exhibited higher antiproliferative activity against MCF-7 and BGC cells than TFu DMSO-water solution and 5-Fu solution. The apoptosis induced by TFu-LNS was assessed by Annexin V-FITC/PI double staining and Tunnel assay. And the results of two methods both clearly indicated that the superiority of TFu-LNS to TFu DMSO-water solution and 5-Fu solution in increasing the apoptosis rate of MCF-7 and BGC cells. The results of flow cytometric (FCM) analysis demonstrated that TFu-LNS could induce G1 cycle arrest of MCF-7 and BGC cells. Furthermore, in vivo pharmacokinetics study in Wistar rats indicated that TFu-LNS was capable of increasing the parameters of AUC(0-infinity) and MRT significantly by sustained releasing 5-Fu. Therefore, the overall results suggested that the TFu-LNS could enhance anti-tumor effect and hold great potential to be developed for cancer treatments. PMID- 23802410 TI - Photodynamic therapy leads to complete remission of tongue tumors and inhibits metastases to regional lymph nodes. AB - In patients diagnosed with oral cancer, the most important prognostic indicator for patient survival after primary treatment is metastasis to the cervical lymph nodes or distal sites. Therefore, we evaluated the utility of photodynamic therapy (PDT) mediated by aluminum-chloride-phthalocyanine entrapped in liposomes for the prevention of metastasis to regional cervical lymph nodes in the Erhlich tongue cancer model. The PDT protocol led to complete remission of tongue tumours and prevented the occurrence of regional metastasis. The prevention of regional metastasis was confirmed by histopathological and immunohistochemical analyses. In addition, PDT treatment increased the overall survival and reduced weight loss relative to control tumour-bearing mice. Thus, PDT should be clinically evaluated for use in the prevention of cervical lymph node metastasis in patients with oral cancer. PMID- 23802411 TI - Micropatterning of mammalian cells on indium tin oxide substrates using ion implantation. AB - In this study, a simple surface patterning method to create micropatterns of mammalian cells on indium tin oxide (ITO) substrates was developed using ion implantation. Thin polystyrene (PS) films spin-coated on an ITO glass was selectively implanted with accelerated proton ions through a pattern mask and then developed to generate PS micropatterns. Well-organized negative PS patterns were generated on the ITO glass. The results of the in vitro cell culture on the PS-patterned ITO glass with two types of cancer cell lines revealed the formation of well-defined cell patterns through a selective cell adhesion and proliferation only onto the ITO regions separated by PS regions. This facile method for cell patterning may be used to create a desired platform for cellular device applications, such as biosensors and cell microarrays. PMID- 23802412 TI - An innovative glucose biosensor using antibiofouling Au-F127 nanospheres. AB - Quantification of the blood glucose concentration in the whole blood was not easy to achieve because the detection process was affected by many factors, such as glucose metabolism and biofouling. In this paper, we established an amperometric glucose biosensor applied in whole blood directly, which was based on the direct electron transfer of glucose oxidase (GOx) entrapped onto the Au-F127 nanospheres. Here, the Au-F127 nanospheres could provide a blood compatible surface with antifouling property for determination of glucose in whole blood. The cyclic voltammetric results indicated that GOx immobilized on the Au-F127 nanospheres exhibited direct electron transfer reaction, and the cyclic voltammogram (CV) displayed a pair of well-defined and nearly symmetric redox peaks with a formal potential of 93 mV. The biosensor had good electrocatalytic activity toward glucose with a low detection limit 3.15 pM. The glucose biosensor did not respond to ascorbic acid (AA) and uric acid (UA) at their high concentration encountered in blood. In this method, the biosensor was used for quantification of the concentration of glucose in whole blood samples. The data obtained from the biosensor showed good agreement with those from a biochemical analyzer in hospital. PMID- 23802413 TI - Gene delivery with active targeting to ovarian cancer cells mediated by folate receptor alpha. AB - Folate receptor alpha (FRalpha) is overexpressed on ovarian cancer cells and is a promising molecular target for ovarian cancer gene therapy, but there was still no related report. In this study, folate modified cationic liposomes (F-PEG-CLPs) for ovarian cancer gene delivery were developed for the first time. Folate poly(ethylene glycol)-succinate-cholesterol (F-PEG-suc-Chol) was firstly synthesized and then used to prepare folate-targeted cationic liposomes/plasmid DNA complexes (F-targeted lipoplexes). F-targeted lipoplexes were prepared by post-insertion method, and displayed membrane structure by transmission electron microscopy observation with the diameter of 193 nm-200 nm and the zeta potential of 35 mV-38 mV. DNase degradation experiments showed that plasmid DNA could be effectively shielded by F-targeted lipoplexes in vitro. F-targeted lipoplexes could transfer gene into human ovarian carcinoma cell line SKOV-3, and 0.1% F-PEG CLPs composed by DOTAP/Chol/mPEG-Chol/F-PEG-suc-Chol (50:45:5:0.1, molar ratio) had the highest transfection efficiency. The transfection activity of F-targeted lipoplexes could be competitively inhibited by free folic acid, demonstrating that folate-FRalpha interaction caused high transfection efficiency of F-targeted lipoplexes. The uptake mechanism of F-targeted lipoplexes was further validated on human oral carcinoma cell line KB and human liver carcinoma cell line HepG2. The concentration-dependent and time-dependent cytotoxicity of targeted material F-PEG-suc-Chol was observed by MTT assay on SKOV-3 cell and its application would not increase the cytotoxicity of F-targeted lipoplexes in SKOV-3 cells. All the data indicated that F-PEG-CLPs would be a promising gene vector targeting for ovarian cancer therapy. PMID- 23802414 TI - Narrow size distribution of microbubbles for enhancement of harmonic imaging. AB - An ultrasound microbubble contrast agent is a promising technique in clinical diagnosis because ultrasound in combination with microbubbles enhances the ultrasound backscatter to produce an increased contrast images. In this study, we developed phospholipid-based microbubbles showing a relatively narrow size distribution of 0.8-1.3 microm. The optimal resonance frequency of developed microbubbles was determined to be 2.5-3.0 MHz by measuring echo signals at various frequencies. Ultrasound harmonic imaging was performed in a vessel phantom at the optimal resonance frequencies. Microbubble contrast-enhanced ultrasound images visualized a vessel tube clearly and demonstrated much improved image quality, compared to the control. In conclusion, the ultrasonography in the harmonic mode is capable of maximally resonating micrbubbles with a narrow size distribution at a specific frequency for enhanced ultrasound imaging. PMID- 23802415 TI - Analysis of nanoscale protein film consisting of lactoferrin/11-MUA bilayers for bioelectronic device. AB - We fabricated and analyzed a nanoscale biofilm of human lactoferrin making use of 11-mercapto-undecanoic acid (11-MUA) as chemical linker. The fabrication of the bimolecular/organic hetero monolayer (lactoferrin/11-MUA) on gold substrate was confirmed with Raman spectroscopy. Cyclic voltammetry (CV) was carried out to observe the electrochemical properties of the nanoscaled biofilm under various pH conditions and at different time intervals. The well-defined redox properties were observed, even in certain harsh pH conditions and after a long time, proving the stabilities of this biofilm. Atomic force microscopy (AFM) was further employed to confirm the retention time by investigating the morphology variety of the biofilm over time. All these results proved that, the proposed nanoscaled thin film composed of lactoferrin and 11-MUA is a powerful alternative for making bioelectronics devices. PMID- 23802416 TI - Conformation-dependent DNA damage induced by gold nanoparticles. AB - The sensitivity of two conformations of plasmid DNA, the A and B forms, to strand break formation induced by gold nanoparticles (GNPs) is investigated by varying the GNP to DNA ratio in solution and the degree of DNA hydration. Decreasing DNA hydration via lyophilisation or by replacement of water with ethanol in solution modifies its conformation from the B to the A form. The yields of single strand breaks (SSB) are found to be highly dependent on the amount of DNA in the A configuration. The damage also increases with the amount of GNPs bound to DNA. At a ratio of two GNPs for one plasmid in an 80%-ethanol, 20%-water solution, 50% of the initial supercoiled population is converted to SSB. Thus, close contact with GNPs causes extensive damage to DNA in the A form. Since during transcription the DNA-RNA duplexes adopt an A form, GNPs could be genotoxic. Our results suggest that GNPs may have potential as chemotherapeutic agents if conjugated to nuclear targeting ligands. Considering their additional radiotherapeutic properties, targeted GNPs could also become highly effective in the treatment of cancer with concomitant chemoradiation therapy. PMID- 23802417 TI - Gadolinium-loaded chitosan nanoparticles as magnetic resonance imaging contrast agents for the diagnosis of tumor. AB - The aim of our study was to prepare gadolinium loaded chitosan nanoparticles (Gd CSNPs) for magnetic resonance imaging (MRI). The chitosan nanoparticles (CSNPs) were prepared by ionic gelation method with sodium tripolyphosphate. The Gd ions were conjugated to the surface of CSNPs through diethylenetriamine pentaacetic acid (DTPA) using N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) to obtain Gd-CSNPs. The physicochemical properties of CSNPs and Gd-CSNPs were measured by transmission electron microscope, dynamic light scattering and inductively coupled plasma optical emission spectroscopy, respectively. The cell toxicity evaluation was performed in mouse B16 cells by MTT assay. The T1-weighed magnetic resonance images were measured by a 3.0 T Sigma scanner. The morphologies of the CSNPs and Gd-CSNPs were spherical or ellipsoidal in shape. The mean sizes of the CSNPs and Gd-CSNPs were 110.9 +/- 6.8 nm and 153.0 +/- 7.5 nm, respectively. The zeta potentials of the CSNPs and Gd-CSNPs were 22.30 +/- 0.77 mV and 13.91 +/- 4.26 mV, respectively. The relaxation rates of Gd-CSNPs and Magnevist were 7.509 mM(-1) x s(-1) and 3.052 mM(-1) x s(-1), respectively. The Gd-CSNPs exhibited high T1 relaxivity and no obvious cytotoxicity was observed under the experimental concentrations in mouse B16 melanoma cells. These results indicated that the Gd CSNPs had great potential as MRI contrast agents for the early diagnosis of tumor. PMID- 23802418 TI - In vitro ALP and osteocalcin gene expression analysis and in vivo biocompatibility of N-methylene phosphonic chitosan nanofibers for bone regeneration. AB - Most polymeric nanofibers used for bone tissue engineering lack adequate functional groups for bioactivity. This study explores the potential of nanofibers of phosphate functionalized derivative of chitosan-N-methylene phosphonic chitosan (NMPC) for bone tissue engineering. Nanofibers were fabricated by electrospinning of NMPC/PVA blend solutions. NMPC/PVA nanofibers exhibited 172% higher viability of MG-63 cells compared to pure PVA nanofibers. ALP and Collagen type I genes revealed higher expression in NMPC nanofibers on day 3 whereas osteocalcin gene was expressed on day 7. In rabbit tibial defects, NMPC based electrospun graft showed presence of no adverse tissue reaction by histological examination while radiological examination suggested acceleration of bone healing by 300% compared to defects without any scaffold. Thus it is concluded NMPC based nanofibers may have potential for bone grafting applications. PMID- 23802419 TI - Microfluidic chip for the detection of biological toxic effects of polychlorinated biphenyls on neuronal cells. AB - The aim of this study was to develop a microfluidic neuronal cell chip device to monitor the toxic effects of polychlorinated biphenyls (PCBs) on PC-12 neuronal cells. PCBs adversely influence the activities of neuronal cells in the nervous system. In PC-12 cells, the production and secretion of dopamine decreases in response to PCB exposure. The microfluidic device that we developed to measure the amount of dopamine by cyclic voltammetry is composed of a control layer, a fluidic layer, and a gold electrode-patterned glass wafer. The control channel in the control layer functions as a microvalve to control the flow of the fluidic channel in the fluidic layer. The fluidic layer consists of 3 reaction chambers as well as fluidic channels. Three electrodes, including the working electrode, counter electrodes, and a reference electrode, are placed in a fluidic chamber. The electrochemical signals of dopamine, either from a standard dopamine solution or from the culture supernatant from cultured PC-12 cells, were obtained using a fabricated microfluidic neuronal cell chip by cyclic voltammetry. When PCBs were added to cultures of PC-12 cells, the amount of dopamine secreted from the PC-12 cells decreased due to the reduced activity of PC-12 cells. The fabricated neuronal cell chip was capable of detecting the toxic effect of dopamine on neuronal cells at concentrations of 10 microg/L and over. The practicality of the developed microfluidic neuronal cell chip was validated using river water spiked with PCBs. PMID- 23802420 TI - The simple and fast isolation of Escherichia coli O157:H7 using magnet nanoparticle embedded silica nanotube for the nucleic acid based detection. AB - In this study, we developed a simple and fast isolation tool of Escherichia coli O157:H7 (E. coli O157:H7) using a magnet nanoparticle embedded silica nanotube (MNSNT) for the detection of E. coli O157:H7 in the sample with nucleic acid based amplification. This method does not require chaotropic salt and sophisticated equipment to isolate bacteria. The E. coli O157:H7 in the sample was effectively bound to the hydrophilic surface of MNSNT in low pH binding buffer containing divalent ions and PEG without the need for expensive biological reagents such as antibodies. This E. coli O157:H7 bound MNSNT was simply isolated by a magnet, prior to adding an amplification mixture to the same micro tube without transferring the sample to another tube. Using this novel method, the detection sensitivities of E. coli O157:H7 (102 cfu/1 g of seed sprout and 102 cfu/5 mL of water) were 80% and 100%, respectively, whereas that was 0% using the commercial method. PMID- 23802421 TI - Development of lipid nanoparticles of diacerein, an antiosteoarthritic drug for enhancement in bioavailability and reduction in its side effects. AB - Osteoarthritis is the most common, multi component joint disease mainly characterized by destruction of articular cartilage which leads up to subchondral bone. Current treatment by NSAID's gives only symptomatic relief but semi synthetic anthraquinone diacerein is novel chondroprotective agent intended for the treatment of osteoarthritis. Its active metabolite rhein inhibits the agents responsible for cartilage degradation. In the present study, stearic acid, long chain fatty acids, based solid lipid nanoparticles were prepared with enhanced oral bioavailability and lesser side effects. Diacerein loaded solid lipid nanoparticles were prepared by modified high shear homogenization with ultrasonication method using stearic acid as lipid. Pluronic F68 and soya lecithin was used as surfactant. Citric acid was added to give acidic environment to drug. Solid lipid nanoparticles were evaluated for different characterization parameters, in-vitro performance and in-vivo pharmacokinetics and anti-diarrhoeal study. Particle size of the diacerein loaded SLN was found in the range of 270 +/ 2.1 to 510 +/- 2.8 nm with zeta potential -13.78 +/- 3.4 mV to -19.66 +/- 2.1 mV. Maximum entrapment efficiency was achieved up to 88.1 +/- 1.3%. Surface and solid state characterization by TEM, XRD and DSC revealed that all particles are spherical in shape and drug entrapped inside lipid was in amorphous state. In vitro release was done by dialysis bag method in phosphate buffer (pH 5.8) which showed controlled and extended release profile up to 12 hr. In-vivo pharmacokinetic study reveals an increase in Area Under Curve from 26.68 +/- 1.63 to 71.25 +/- 1.25 hr microg ml(-1). Further diarrhoeal side effect of diacerein was also found to reduce up to 37% by lipid nanoparticles. These results suggest that diacerein loaded solid lipid nanoparticles can be prepared efficiently with stearic acid and produces controlled and prolonged drug release profile. The oral bioavailability was enhanced by around 2.7 times and with lesser diarrhoeal side effects. These all will leads to overall improvement in patient compliance for the treatment. PMID- 23802422 TI - Synthesis of gold coated magnetic microparticles and their application for electrochemical glucose sensing by the enzymatically precipitated prussian blue. AB - An enzyme stimulated deposition of prussian blue onto the gold-coated magnetic microparticles is described. We propose to synthesize the continuous outer gold layer on the magnetic particle for a gold working electrode and its superparamagnetic property. In-depth characterization of the gold shell formation was studied with scanning electron microscopy, energy-dispersive X-ray spectroscopy, cyclic voltammetry. The gold-coated magnetic microparticles offered adhesive layer for the immobilization of glucose oxidase catalyzing the generation of prussian blue in the presence of glucose. The assembled prussian blue on the gold shell surfaces was detected with electrochemical measurements depending on the glucose concentration. With accomplishing the linear response range from 0.2 mM to 10 mM of glucose, this approach successfully proposed the applicability of the magnetic core-gold shell structures to the electrochemical bioassay area. PMID- 23802423 TI - Enzyme-entrapped mesoporous silica for treatment of uric acid disorders. AB - Gout is an abnormality in the body resulting in the accumulation of uric acid mainly in joints. Dissolution of uric acid crystals into soluble allantoin by the enzyme uricase might provide a better alternative for the treatment of gout. This work aims to investigate the feasibility of a transdermal patch loaded with uricase for better patient compliance. Mesoporous silica (SBA-15) was chosen as the matrix for immobilisation of uricase. Highly oriented mesoporous SBA-15 was synthesized, characterized and uricase was physisorbed in the mesoporous material. The percentage adsorption and release of enzyme in borate buffer was monitored. The release followed linear kinetics and greater than 80% enzyme activity was retained indicating the potential of this system as an effective enzyme immobilization matrix. The enzyme permeability was studied with Wistar rat skin and human cadaver skin. It was found that in case of untreated rat skin 10% of enzyme permeated through skin in 100 h. The permeation increased by adding permeation enhancer (combination of oleic acid in propylene glycol (OA in PG)). The permeation enhancement was studied under two concentrations of OA in PG (1%, 5%) in both rat and human cadaver skin and it was found that 1% OA in PG showed better result in rat skin and 5% OA in PG showed good results in human cadaver skin. PMID- 23802424 TI - An insight into potential of nanoparticles-assisted chemotherapy of cancer using gemcitabine and its fatty acid prodrug:a comparative study. AB - Gemcitabine (dFdC) mediated cancer treatment faces obstacles, due to its high hydrophilicity. A valuable strategy was executed by synthesizing lipophilic fatty acid derivative of dFdC i.e., 4-(N)-stearoyl gemcitabine (C18dFdC), built-in into polymeric poly-lactic-co-glycolic acid nanoparticles (PLGA NPs) and compared with that of parent drug. Encapsulation of derivative within NPs was higher (68.24 +/- 3.64%) than dFdC and showed comparatively sustained drug release (19.87 +/- 1.73% within 12 hours), with a proof of increased biological half life. The cytotoxicity and flow cytometric analysis displayed enhanced MCF-7 cell inhibition by C18dFdC-NPs with higher uptake compared to dFdC-NPs. Interestingly, like gemcitabine, C18dFdC-NPs did not induce appreciable differences in blood parameters and in vivo tissue toxicity study demonstrating safe use of derivative at 40 mg/kg dose. In conclusion, the preclinical data obtained in vitro and in vivo demonstrate the C18dFdC-nanocarrier as an advantageous and promising delivery system for cancer treatment along with the potential to improve the clinical outcome of gemcitabine chemotherapy. PMID- 23802425 TI - Hepatocyte cytotoxicity evaluation with zinc oxide nanoparticles. AB - Our innate immunity is composed of several integral leukocytes including neutrophil, NK cell, macrophage or so. They are usually known to produce reactive oxygen species (ROS), in order to induce cell damages by these oxidizing reagents, and finally disrupting mitochondrial membrane to release cytochrome c. It is quite interesting to cancer therapy that the overexpressed cytochrome c level by ROS can lead to cancer cell death. Activated neutrophils exert anti tumor effects against several carcinomas such as human skin melanoma by the increased production of ROS. To mimic the natural killing system, several nanoparticulates which contain cytotoxic properties have been in demand. Representatively, zinc oxide (ZnO) nanoparticles have been reported to have anti bacterial and anti-cancer activity against various cancer cell lines due to production of ROS. They are shown to have preferential anti-cancer activity possibly due to higher level of oxidants and ROS in cancer cells. Inspired by these studies, we carried out the cytotoxicity evaluation of ZnO nanoparticulates against hepatocellular carcinoma. Our investigations were conducted by (1) screening the best size of ZnO (among 5, 50, and 100 nm) and the optimized time for anti-cancer effect against HepG2 cell line, (2) determining the apoptosis in the cells, and (3) regulating the production of intracellular ROS by ZnO nanoparticles. The ZnO nanoparticles revealed the dose-dependent toxic effect on HepG2 cells, irrespective of the sizes. PMID- 23802426 TI - Design, synthesis, and biological evaluation of acetophenone derivatives as dual binding acetylcholinesterase inhibitors. AB - As part of a project aimed at developing new agents for potential application in Alzheimer's disease, a new series of acetophenone derivatives which possess alkylamine side chains were designed, synthesized and assayed as acetylcholinesterase (AChE) inhibitors that could simultaneously bind to the peripheral and catalytic sites of the enzyme. The compounds were synthesized, and the inhibitory activities toward AChE and butyrylcholinesterase (BuChE) in vitro were determined using a modified Ellman method. Of the compounds tested, 6 derivatives were found to inhibit AChE in the micromolar range. The best compound, 2e, had an 1C50 of 0.13 microM. A detailed molecular modeling study was performed to explore the interaction of 2e with AChE. PMID- 23802427 TI - Separation of delta6- and delta9,11-estradiol: analytical method development, validation and practical application. AB - For estradiol (E2) the separation of the degradation products delta6- and delta9,11-E2 is especially challenging due to their structural similarity. There is no method described in the literature yet which adequately addresses this problem. The present study describes a HPLC method for the separation and quantitation of E2 and its degradation products 6alpha-hydroxy-E2, 6beta-hydroxy E2, 6-keto-E2, delta9,11-E2, beta-equilenol and delta6-E2. The method employs a Kinetex PFP analytical column, using methanol and deionized water as mobile phases. Different UV- and fluorescence detection modes were used for maximal sensitivity and specificity. The applicability and capability of the method was demonstrated for Vagifem tablets. Finally, the method was validated with respect to selectivity, sensitivity, linearity, precision and accuracy. PMID- 23802428 TI - Bivariate versus multivariate smart spectrophotometric calibration methods for the simultaneous determination of a quaternary mixture of mosapride, pantoprazole and their degradation products. AB - The ability of bivariate and multivariate spectrophotometric methods was demonstrated in the resolution of a quaternary mixture of mosapride, pantoprazole and their degradation products. The bivariate calibrations include bivariate spectrophotometric method (BSM) and H-point standard addition method (HPSAM), which were able to determine the two drugs, simultaneously, but not in the presence of their degradation products, the results showed that simultaneous determinations could be performed in the concentration ranges of 5.0-50.0 microg/ml for mosapride and 10.0-40.0 microg/ml for pantoprazole by bivariate spectrophotometric method and in the concentration ranges of 5.0-45.0 microg/ml for both drugs by H-point standard addition method. Moreover, the applied multivariate calibration methods were able for the determination of mosapride, pantoprazole and their degradation products using concentration residuals augmented classical least squares (CRACLS) and partial least squares (PLS). The proposed multivariate methods were applied to 17 synthetic samples in the concentration ranges of 3.0-12.0 microg/ml mosapride, 8.0-32.0 microg/ml pantoprazole, 1.5-6.0 microg/ml mosapride degradation products and 2.0-8.0 microg/ml pantoprazole degradation products. The proposed bivariate and multivariate calibration methods were successfully applied to the determination of mosapride and pantoprazole in their pharmaceutical preparations. PMID- 23802429 TI - Preparation and evaluation of metastable solid-state forms of lopinavir. AB - In this work, we present the preparation and evaluation of previously unreported metastable forms of the antiretroviral drug, lopinavir. By maintaining the chemical structure, physicochemical properties like the glass transition temperature (T(g)), dissolution and solubility can be readily attributed to the stability of the system. Commercially-available lopinavir was used to prepare partially amorphous crystals, semicrystalline needles, resins and glasses. The physicochemical properties of each were investigated using differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and powder X ray diffraction (PXRD). Each sample's thermal and spectroscopic analyses, as well as dissolution and solubility studies were performed one month after sample preparation, for better comparability. Glass transition temperature, activation energy for global molecular mobility (deltaE(Tg)), and activation energy for local molecular mobility (deltaE(beta)) were assessed as primary indicators for structural stability of the systems. Relating these properties to aqueous solubility revealed that each metastable form possessed its own unique equilibrium solubility. Cumulative dissolved fractions (alpha) were fitted against deceleratory kinetics models, and from the data hereby obtained the dissolution process was determined to followed first-order kinetics (R2 = 0.998). From the rate constants, the activation energy for dissolution (deltaE(Diss)) of each sample was calculated. The results suggest that multiple metastable solid state forms of lopinavir can exist under similar conditions, depending on the preparation conditions. PMID- 23802430 TI - Comparative pharmacokinetics of aloe-emodin, rhein and emodin determined by liquid chromatography-mass spectrometry after oral administration of a rhubarb peony decoction and rhubarb extract to rats. AB - This study aimed to clarify the rationality of herbaceous compatibility of a rhubarb peony decoction (DaHuang-Mu-Dan-Tang, RPD) by comparing the pharmacokinetics of aloe-emodin, rhein and emodin in rats' plasma after oral administration of RPD and rhubarb extract. A rapid, sensitive LC-MS method was developed and validated for the determination of the plasma concentrations of the three analytes after oral administration RPD and rhubarb extract. The developed method was successfully applied to a pharmacokinetic study of aloe-emodin, rhein and emodin in rats' plasma after oral administration. Compared with administration of single rhubarb, the C(max) of rhein in RPD was decreased significantly (p < 0.05). Meanwhile, the T1/2 of aloe-emodin and emodin were increased significantly (p < 0.05) after administration of RPD. In addition, the T(max) of rhein and emodin were also increased significantly (p < 0.05) in RPD. These results indicated that the absorption of rhein in rats was suppressed after oral administration RPD. Moreover, The time for rhein and emodin to reach the peak concentration was delayed and the elimination of aloe-emodin and emodin was also postponed in RPD. This study could provide a meaningful basis for evaluating the clinical application of traditional Chinese medicine in terms of pharmacokinetics. PMID- 23802431 TI - Response surface methodology and Taguchi approach to assess the combined effect of formulation factors on minocycline delivery from collagen sponges. AB - An important aspect to be considered in the healing of acute or chronic cutaneous wounds is the associated potential infection management. Collagen, the most abundant protein of the extracellular matrix, with proven properties in wounds healing and tissues regeneration, is one of the most widely used biopolymers as carrier matrix for controlled drug delivery systems. For this reason, the purpose of the current paper is the development of some minocycline-loaded collagen topical sponges uncross-linked and cross-linked with glutaraldehyde, obtained by lyophilization of appropriate hydrogels prepared according to the 3-factor, 3 level face-centered central composite design. The determination of drug delivery from the sponges was performed by assessment of some physicochemical parameters involved in this complex process: sponges surface wettability, swelling ratio and the percentage of minocycline released from the sponges. The application of the response surface methodology allowed the setting of the formulation parameters optimum ranges, which ensure an adequate minocycline release to the application site. The design robustness was checked using the signal-to-noise ratio performance indicator. The optimum collagen-minocycline sponges determined based on the statistical screening technique could be suitable for topical drug delivery in infected wounds healing with moderate to high exudate. PMID- 23802432 TI - Pharmacokinetics of the amidine prodrug of a novel oral anticoagulant factor VIIa inhibitor (AS1924269-00) in rats. AB - AS1924269-00 is a promising orally applicable anticoagulant that inhibits FVIIa but has very low oral absorption. Therefore, in this study, we aimed to develop a prodrug of AS1924269-00, which possesses a carbamate-added amidine functional group, with high membrane permeability. We investigated the pharmacokinetics of the carbamate-type prodrug of AS1924269-00 in rats. The Caco-2 cell monolayer was used as an in vitro model and in parallel an artificial membrane permeability assay (PAMPA) was performed to examine the transport mechanisms of the prodrug. The bioavailability of the active form was determined to be only 0.3% in rats, but the oral absorption of the prodrug was markedly improved, and its bioavailability was 36%. Our in vivo result was consistent with the finding that compared to AS1924269-00, the prodrug showed favorable permeability in Caco-2 cells and PAMPA. We introduced carbamate into the amidine functional group of the FVIIa inhibitor, which possesses the amidine backbone, and converted it to a prodrug using carboxylic acid ethyl ester. This novel prodrug had favorable absorption and membrane permeability in vivo and in vitro. Thus, we suggest a clinical application of the carbamate-added amidine prodrug of the FVIIa inhibitor. PMID- 23802433 TI - Rosuvastatin inhibits TGF-beta1 expression and alleviates myocardial fibrosis in diabetic rats. AB - This study aimed to investigate the effects of rosuvastatin on TGF-beta1 expression, cardiac fibrosis, ventricular remodeling and cardiac function in diabetic cardiomyopathy rats. Twenty-seven diabetic rats induced by streptozotocin intraperitoneal injection were randomly divided into three groups, viz. diabetic, rosuvastatin low-dose (Ros-L) and high dose group (Ros-H). Intervention group were given rosuvastatin 2 mg/kg/d and 5 mg/kg/d orally, respectively. After 10 weeks, the levels of glycosylated hemoglobin (HbA1c), creatine phosphokinase isoenzyme (CK-MB), plasma brain natriuretic peptide (BNP), myocardial collagen volume fraction (CVF) and left ventricular mass index (LVWI) were measured. CK-MB levels in Ros-H and Ros-L rats were lower than in the diabetic group. Rosuvastatin alleviated myofibrosis cordis and fibroplastic proliferation. LVWI, BNP, CVF and TGF-beta1 mRNA and protein levels in the diabetic group were higher than in the control, but were reduced after rosuvastatin treatment. These results demonstrate that rosuvastatin dose dependently reduces TGF-beta1 expression and inhibits the development of myocardial fibrosis in diabetic cardiomyopathy. PMID- 23802434 TI - Anti-tumor activity and immunogenicity of a mutated staphylococcal enterotoxin C2. AB - In this study, a novel SEC2 mutant with lower toxic activity, named 2M-118 (H118A/T20L/G22E), was engineered by site-directed mutagenesis of structural domains that are responsible for MHC class II molecule binding and TCR binding, respectively. Stimulating activity on murine splenocytes, anti-tumor effect and immunogenicity of 2M-118 were investigated in BALB/c mice. 2M-118 not only remained splenocyte stimulation activity, but also effectively inhibited the growth of S180 sarcoma in the BALB/c mice. Even though antibodies to 2M-118 could be induced after repeated administration, the action of 2M-118 was hardly neutralized or cross neutralized. Like other superantigens, immunosuppression could happen when 2M-118 was given at a greater dose. In conclusion, 2M-118 is a promising anti-tumor drug candidate for its acceptable toxicity and satisfying anti-tumour efficacy. PMID- 23802435 TI - Effects of repeated allopurinol administration on rat cytochrome P450 activity. AB - Allopurinol is a popular and widely-prescribed anti-hyperuricemic agent that has been implicated in drug interactions with substrates of several cytochrome P450 (CYP) enzymes. The effect of repeated allopurinol administration (20 mg/kg, once daily for 14 days) on metabolic activity of CYP was assessed in rats. This was a randomized, double-blind, two-way crossover study with a 4-week washout period between phases. The substrates used in this study were phenacetin (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19) and dextromethorphan (CYP2D6). Validated HPLC-MS/MS was used to quantify all compounds. Our study showed that allopurinol administration inhibited CYP1A2 activity, causing a significant increase in AUC (0-infinity) (P < 0.01) and t1/2 (P < 0.05) of phenacetin, and a distinct decline in CL (P < 0.01). However, there were no significant differences of another three probe drugs in plasma concentrations and the corresponding pharmacokinetic parameters between the allopurinol-treated and normal saline treated rats. The findings in this study suggested that allopurinol could inhibit CYP1A2 but did not influence CYP2C9, CYP2C19 and CYP2D6 enzymes. PMID- 23802436 TI - A novel flavonoid isolated from Sophora flavescens exhibited anti-angiogenesis activity, decreased VEGF expression and caused G0/G1 cell cycle arrest in vitro. AB - Kushen, the dried root of Sophora flavescens Ait, is a traditional Chinese herbal medicine. Kushen alkaloids have been developed in China as anticancer drugs, and more potent antitumor activities have been identified in kushen flavonoids than in kushen alkaloids. In this study, the anti-angiogenic properties of (2S) 7,2',4'-triihydroxy-5-methoxy-8-dimethylallyl flavanone (Compound 1, a novel flavonoid isolated from Kushen), were examined using the human umbilical vein endothelial cell line (ECV304) in vitro. The results indicated that compound 1 shows anti-angiogenesis activity via inhibitory effects on cell proliferation, cell migration, cell adhesion, and tube formation. Further studies indicated that compound 1 blocks cell cycles in the G0/G1 phase without inducing apoptosis, and down regulates vascular endothelial growth factor (VEGF) expression. The free radical scavenging activity of compound 1 was found through 2',7' dichlorofluorescin diacetate (DCFH-DA) incubation assay in cells. The anti angiogenic properties of compound 1 and its antiproliferative effect on endothelial cells without causing apoptosis make it a good candidate for development as a agent against development of tumors. PMID- 23802437 TI - Antiherpetic efficacy of aqueous extracts of the cyanobacterium Arthrospira fusiformis from Chad. AB - Natural substances offer interesting pharmacological perspectives for antiviral drug development with regard to broad spectrum antiviral properties and novel modes of action. Drugs currently used to treat cutaneous or genital herpetic infections are effective in limiting disease, but the emergence of drug-resistant viruses in immunocompromised individuals can be problematic. A nontoxic cyanobacterium Arthrospira strain from Chad has been characterized by sequence analysis of the intergenic spacer region of the phycocyanin gene. This cyanobacterium was identified as Arthrospira fusiformis by phylogenetic tree analysis. The antiherpetic activity of crude aqueous extracts from the Chad A. fusiformis isolate was determined. Antiviral efficacy against herpes simplex virus of cold water extract, hot water extract and phosphate buffer extract was assessed in plaque reduction assays and their mode of antiherpetic action was analysed. In virus suspension assays, cold water extract, hot water extract and phosphate buffer extract inhibited virus infectivity by 54.9%, 64.6%, and 99.8%, respectively, in a dose-dependent manner. The mode of antiviral action was determined by addition of cyanobacterial extracts separately at different time periods during the viral infection cycle. Extracts of A. fusiformis strain clearly inhibited herpesvirus multiplication before and during virus infection of host cells. The phosphate buffer extract of the A. fusiformis strain affected free herpes simplex virus prior to infection of host cells and inhibited intracellular viral replication. It is concluded, that Arthrospira compounds warrant further investigation to examine their potential role in the treatment of herpetic infections. PMID- 23802438 TI - Ethosomes as delivery system for transdermal administration of vinpocetine. AB - The purpose of the present study was to develop a novel transdermal vinpocetine patch containing a stable formulation and with good entrapment efficiency, and percutaneous absorption which via ethosome. Ethosome was found to be a more efficient delivery carrier with high encapsulation capacities (79.5% +/- 1.8%) and nanometric size (180.7 +/- 1.5 nm). In vitro percutaneous permeation experiments demonstrated that the permeation of vinpocetine through abdominal skin of Sprague Dawley was significantly increased when ethosome was used. The vinpocetine transdermal fluxes from ethosome gel (3.56 +/- 0.13 microg/cm2/h) were 6.72 and 3.10 times higher than that of vinpocetine gel solution and vinpocetine aueous solution, respectively. Furthermore, the AUC(0 --> infinity), and eliminiation half-life by the transdermal administration were significantly higher than those by the intragastric administration (P < 0.01). The study demonstrated that ethosome is a promising vesicular carrier for enhancing percutaneous absorption of vinpocetine. PMID- 23802439 TI - Assessment of the hemolytic activity and cytotoxicity of different PEG-based solubilizing agents. AB - The hemolytic activity and the cytotoxicity of PEG-based solubilizing agents on Caco-2 monolayer were investigated. In vitro tests can predict the irritancy potential and the delayed toxicity of the surfactants. There were significant concentration dependent differences between the result of the MTT (3-(4,5 dimethylthiazol-2-yl))-2,5-diphenyltetrazolium bromide) test and the data of the hemolytic activity test. Our investigations show that safer and more applicable tensides can be selected in order to form a more biocompatible medicament. PMID- 23802440 TI - Aedes (Stegomyia) aegypti in the continental United States: a vector at the cool margin of its geographic range. AB - After more than a half century without recognized local dengue outbreaks in the continental United States, there were recent outbreaks of autochthonous dengue in the southern parts of Texas (2004-2005) and Florida (2009-2011). This dengue reemergence has provoked interest in the extent of the future threat posed by the yellow fever mosquito, Aedes (Stegomyia) aegypti (L.), the primary vector of dengue and yellow fever viruses in urban settings, to human health in the continental United States. Ae. aegypti is an intriguing example of a vector species that not only occurs in the southernmost portions of the eastern United States today but also is incriminated as the likely primary vector in historical outbreaks of yellow fever as far north as New York, Philadelphia, and Boston, from the 1690s to the 1820s. For vector species with geographic ranges limited, in part, by low temperature and cool range margins occurring in the southern part of the continental United States, as is currently the case for Ae. aegypti, it is tempting to speculate that climate warming may result in a northward range expansion (similar to that seen for Ixodes tick vectors of Lyme borreliosis spirochetes in Scandinavia and southern Canada in recent decades). Although there is no doubt that climate conditions directly impact many aspects of the life history of Ae. aegypti, this mosquito also is closely linked to the human environment and directly influenced by the availability of water-holding containers for oviposition and larval development. Competition with other container-inhabiting mosquito species, particularly Aedes (Stegomyia) albopictus (Skuse), also may impact the presence and local abundance of Ae. aegypti. Field based studies that focus solely on the impact of weather or climate factors on the presence and abundance of Ae. aegypti, including assessments of the potential impact of climate warming on the mosquito's future range and abundance, do not consider the potential confounding effects of socioeconomic factors or biological competitors for establishment and proliferation of Ae. aegypti. The results of such studies therefore should not be assumed to apply in areas with different socioeconomic conditions or composition of container-inhabiting mosquito species. For example, results from field-based studies at the high altitude cool margins for Ae. aegypti in Mexico's central highlands or the Andes in South America cannot be assumed to be directly applicable to geographic areas in the United States with comparable climate conditions. Unfortunately, we have a very poor understanding of how climatic drivers interact with the human landscape and biological competitors to impact establishment and proliferation of Ae. aegypti at the cool margin of its range in the continental United States. A first step toward assessing the future threat this mosquito poses to human health in the continental United States is to design and conduct studies across strategic climatic and socioeconomic gradients in the United States (including the U.S. Mexico border area) to determine the permissiveness of the coupled natural and human environment for Ae. aegypti at the present time. This approach will require experimental studies and field surveys that focus specifically on climate conditions relevant to the continental United States. These studies also must include assessments of how the human landscape, particularly the impact of availability of larval developmental sites and the permissiveness of homes for mosquito intrusion, and the presence of other container-inhabiting mosquitoes that may compete with Ae. aegypti for larval habitat affects the ability of Ae. aegypti to establish and proliferate. Until we are armed with such knowledge, it is not possible to meaningfully assess the potential for climate warming to impact the proliferation potential for Ae. aegypti in the United States outside of the geographic areas where the mosquito already is firmly established, and even less so for dengue virus transmission and dengue disease in humans. PMID- 23802441 TI - A new species of Rhipicephalus (Acari: Ixodidae), a parasite of red river hogs and domestic pigs in the Democratic Republic of Congo. AB - A new tick species belonging to the genus Rhipicephalus Koch, 1844 (Acari: Ixodidae), namely, Rhipicephalus congolensis n. sp., is described. Males and females of this species are similar to those of Rhipicephalus complanatus Neumann, 1911 and Rhipicephalus planus Neumann, 1907, but it can be distinguished from them by a pattern of dense medium-sized punctations on the conscutum and scutum. Males of R. congolensis may be distinguished by the following characters: posterior half of the marginal groove deep with a sharp outer edge; anterior portion of the groove shallow with rounded edges; posteromedian groove distinct, long, and deep; adanal plates broadly sickle-shaped; bluntly pointed posteromedian spur on coxa I; and posterolateral spur on coxa I slightly longer or subequal to posteromedian spur. Females of R. congolensis may be distinguished by the following characters: outer edge of cervical grooves smooth and not clearly defined either by slope or punctations; genital aperture broad, bowl shaped, and tripartite in appearance, with central flap flanked on either side by an oval depression; and posteromedian spur on coxa I tapering to its apex. R. congolensis is known only from the Democratic Republic of Congo, where the adults were collected from red river hogs, Potamochoerus porcus (L.), and domestic pigs, Sus scrofa (L.), within the dense equatorial forest in the districts of Equateur and Tshuapa, in the province of Equateur. PMID- 23802442 TI - Comparative study of antennal and maxillary palp olfactory sensilla of female biting midges (Diptera: Ceratopogonidae: Culicoides) in the context of host preference and phylogeny. AB - Culicoides biting midges (Diptera Ceratopogonidae) are vectors of disease, including bluetongue and African horse sickness. Host preference of these insects is primarily regulated by olfactory cues, detected by olfactory sensilla on the antennae and maxillary palps. In this study, we analyzed the sensillum repertoire of biting midge species with known host preferences. Five different morphological sensillum types, sensilla trichodea, s. chaetica, s. ampullacea, s. coeloconica, and grooved peg sensilla, were present on the antennae of all species. In addition sensilla basiconica were present on the maxillary palps. We found that the numbers of short blunt-tipped s. trichodea, s. coeloconica, and s. basiconica are significantly higher in the ornithophilic Culicoides festivipennis (Kieffer) compared with the mammalophilic Culicoides obsoletus (Meigen) and Culicoides chiopterus (Meigen). In contrast, we found that the mammalophilic Culicoides pulicaris (L.) and the opportunistic Culicoides punctatus (Meigen) have intermediate numbers of these sensillum types. Comparison with available data from other species strongly suggests that these differences in the number of specific sensillum types, in general, are a reflection of host preference and not of phylogeny. We discuss the putative function of the individual sensillum types in relation to host volatile detection. PMID- 23802443 TI - Simulium (Asiosimulium) furvum, a new species of black fly (Diptera: Simuliidae) from Thailand. AB - Simulium (Asiosimulium) furvum sp. nov. (Diptera: Simuliidae) is described from female, male, pupal, and larval specimens collected from Maewa National Park, Lampang Province, Thailand. This new species represents the fourth member of the subgenus Asiosimulium Takaoka & Chochoote, one of two small black fly subgenera endemic in the Oriental Region. It is characterized by a pear-shaped spermatheca in the female; a ventral plate in the male with a laterally compressed median keel directed ventrally and with a deep notch posteromedially, and aedeagal membrane with stout spines; and by 22 gill filaments in the pupa. Taxonomic notes are provided to separate this new species from three known species, Simulium (Asiosimulium) oblongum Takaoka & Choochote and Simulium (Asiosimulium) wanchaii Takaoka & Choochote, both from Thailand, and Simulium (Asiosimulium) suchitrae Takaoka from Nepal. PMID- 23802444 TI - Mites of the subfamily Harpirhynchinae (Acariformes: Harpirhynchidae) from North American birds. AB - Three new harpirhynchid species of the subfamily Harpirhynchinae (Acariformes: Harpirhynchidae) are described from North American birds: Harpyrhynchoides aegolius sp. n. from Aegolius acadicus (Strigiformes: Strigidae), Harpyrhynchoides accipiter sp. n. from Accipiter striatus (Accipitriformes: Accipitridae), and Neharpyrhynchus icterus sp. n. from Icterus galbula (Passeriformes: Icteridae). Three species are recorded from new hosts from North America for the first time: Harpyrhynchoides tracheatus (Fritsch, 1954) from Buteo lineatus (Accipitriformes: Accipitridae), Harpyrhynchoides pectinifer (Lawrence, 1959) from Colaptes auratus (Piciformes: Picidae), and Harpyrhynchoides rubeculinus (Cerny & Sixl, 1971) from Catharus ustulatus (Passeriformes: Turdidae). Neharpyrhynchoides novoplumaris (Moss et al., 1968) previously recorded from Cardinalis cardinalis (Passeriformes: Cardinalidae) from the United States is recollected from this host. PMID- 23802445 TI - Range expansion of Dermacentor variabilis and Dermacentor andersoni (Acari: Ixodidae) near their northern distributional limits. AB - Distributional ranges of the ticks Dermacentor andersoni Stiles and Dermacentor variabilis (Say) in the Canadian Prairies were determined by passive surveillance and active collection. These findings were compared with historical records of both species, particularly in the province of Saskatchewan, where the northern distributional limits of both tick species occur. Before the 1960s, D. variabilis and D. andersoni were allopatric in Saskatchewan; however, since then, the distribution of D. variabilis has expanded westward and northward. Although the range of D. andersoni has remained relatively stable, range expansion of D. variabilis has resulted in a zone of sympatry at least 200 km wide. Twenty-nine species of mammals and three species of birds were identified as hosts for different life stages of these ticks. PMID- 23802446 TI - Effects of elevated atmospheric CO2 on competition between the mosquitoes Aedes albopictus and Ae. triseriatus via changes in litter quality and production. AB - Elevated atmospheric CO2 can alter aquatic communities via changes in allochthonous litter inputs. We tested effects of atmospheric CO2 on the invasive Aedes albopictus (Skuse) and native Aedes triseriatus (Say) (Diptera: Culicidae) via changes in competition for microbial food or resource inhibition/toxicity. Quercus alba L. litter was produced under elevated (879 ppm) and ambient (388 ppm) atmospheric CO2. Saplings grown at elevated CO2 produced greater litter biomass, which decayed faster and leached more tannins than saplings at ambient CO2. Competition was tested by raising larvae in different species and density combinations provisioned with elevated- or ambient-CO2 litter. Species-specific performance to water conditions was tested by providing single-species larval cohorts with increasing amounts of elevated- or ambient-CO2 litter, or increasing concentrations of tannic acid. Larval densities affected some fitness parameters of Ae. albopictus and Ae. triseriatus, but elevated-CO2 litter did not modify the effects of competition on population growth rates or any fitness parameters. Population growth rates and survival of each species generally were affected negatively by increasing amounts of both elevated- and ambient-CO2 litter from 0.252 to 2.016 g/liter, and tannic acid concentrations above 100 mg/liter were entirely lethal to both species. Aedes albopictus had consistently higher population growth rates than Ae. triseriatus. These results suggest that changes to litter production and chemistry from elevated CO2 are unlikely to affect the competitive outcome between Ae. albopictus and Ae. triseriatus, but that moderate increases in litter production increase population growth rates of both species until a threshold is exceeded that results in resource inhibition and toxicity. PMID- 23802447 TI - Estimating mosquito population size from mark-release-recapture data. AB - Accurate estimation of population size is key to understanding the ecology of disease vectors, as well as the epidemiology of the pathogens they carry and to plan effective control activities. Population size can be estimated through mark release-recapture (MRR) experiments that are based on the assumption that the ratio of recaptured individuals to the total captures approximates the ratio of marked individuals released to the total population. However, methods to obtain population size estimates usually consider pooled data and are often based on the total number of marked and unmarked captures. We here present a logistic regression model, based on the principle of the well-known Fisher-Ford method, specific for MRR experiments where the information available is the number of marked mosquitoes released, the number of marked and unmarked mosquitoes caught in each trap and on each day, and the geographic coordinates of the traps. The model estimates population size, taking into consideration the distance between release points and traps, the time between release and recapture, and the loss of marked mosquitoes to death or dispersal. The performance and accuracy of the logistic regression model has been assessed using simulated data from known population sizes. We then applied the model to data from MRR experiments with Aedes albopictus Skuse performed on the campus of "Sapienza" University in Rome (Italy). PMID- 23802448 TI - Effects of thermal heterogeneity and egg mortality on differences in the population dynamics of Aedes aegypti (Diptera: Culicidae) over short distances in temperate Argentina. AB - In temperate regions, the seasonal dynamics of Aedes aegypti (L.) (Diptera: Culicidae) is mainly influenced by temperature, whereas the probability of local extinction depends on the egg mortality during the cold season. The aim of the current study was to assess the importance of temperature and egg mortality in determining the differences in the oviposition dynamics of Ae. aegypti between favorable and less favorable areas in Buenos Aires City (Argentina). Year-round temperature dynamics were monitored, and oviposition dynamics were experimentally studied with ovitraps at two sites. Daily egg mortality values were calculated from a previous study performed at the same sites. The relative contribution of the differences in temperature and egg mortality between sites to the oviposition dynamics was assessed by means of a mathematical stochastic population dynamics model for Ae. aegypti. The results showed higher temperature and lower daily egg mortality at the site where higher oviposition activity was recorded. A larger influence of temperature than of egg mortality on population abundance during most of the activity season was detected in the results of the simulations. Our results showed a temperature gradient that relates to the distance to the Rio de la Plata river and contributes to explaining the spatial heterogeneity in Ae. aegypti population abundances previously reported. The hypothesis of local extinctions because of egg mortality during the winter was not supported by the present analysis. The differences between field oviposition dynamics and simulation results suggest that rainfall might also be an important variable under extremely dry conditions. PMID- 23802449 TI - The dance of male Anopheles gambiae in wild mating swarms. AB - An important element of mating in the malaria vector Anopheles gambiae Giles in nature is the crepuscular mating aggregation (swarm) composed almost entirely of males, where most coupling and insemination is generally believed to occur. In this study, we mathematically characterize the oscillatory movement of male An. gambiae in terms of an established individual-based mechanistic model that parameterizes the attraction of a mosquito toward the center of the swarm using the natural frequency of oscillation and the resistance to its motion, characterized by the damping ratio. Using three-dimensional trajectory data of ten wild mosquito swarms filmed in Mali, Africa, we show two new results for low and moderate wind conditions, and indicate how these results may vary in high wind. First, we show that in low and moderate wind the vertical component of the mosquito motion has a lower frequency of oscillation and higher damping ratio than horizontal motion. In high wind, the vertical and horizontal motions are similar to one another and the natural frequencies are higher than in low and moderate wind. Second, we show that the predicted average disagreement in the direction of motion of swarming mosquitoes moving randomly is greater than the average disagreement we observed between each mosquito and its three closest neighbors, with the smallest level of disagreement occurring for the nearest neighbor in seven out of 10 swarms. The alignment of the direction of motion between nearest neighbors is the highest in high wind. This result provides evidence for flight-path coordination between swarming male mosquitoes. PMID- 23802450 TI - Investigation of the population structure of the tick vector of Lyme disease Ixodes scapularis (Acari: Ixodidae) in Canada using mitochondrial cytochrome C oxidase subunit I gene sequences. AB - Genotyping of Ixodes scapularis Say (Acari: Ixodidae) ticks could enhance understanding of the occurrence and genotypes of I. scapularis-borne pathogens. We investigated the utility of mitochondrial (mt) Cytochrome C Oxidase subunit I gene (cox1) sequences as a tool for understanding the population structure of I. scapularis collected in Canada, where we also investigated the geographic occurrence of different cox1 haplotypes. Sequences obtained from 414 ticks were one of 55 unique haplotypes, most of which grouped into one of six clades. Demographic analysis suggested that cox1 sequences have haplotype and nucleotide diversity comparable to other mt genes. All haplotypes were connected in a single minimum spanning network tree. Despite low fixation index values there were significant differences in the frequency of occurrence of haplotypes of different clades among four geographic regions: 1) Alberta to western Ontario, 2) eastern Ontario, 3) Quebec, and 4) Atlantic Provinces; suggesting that cox1 sequences could reveal population structure differences between I. scapularis in geographically separated populations of northeastern and midwestern North America. Spatial clusters of ticks of the same haplotype identified in regions of southern Quebec and southern Ontario where I. scapularis is invading were consistent with population bottlenecks associated with founder events. These findings suggest that cox1 sequences are useful for the study of I. scapularis population structure, are of sufficient diversity that spatial analyses of haplotypes can be used to identify where I. scapularis is emerging in southern Canada, and may be useful for exploring differences between northeastern and midwestern populations of I. scapularis. PMID- 23802451 TI - Lucifensin II, a defensin of medicinal maggots of the blowfly Lucilia cuprina (Diptera: Calliphoridae). AB - A novel homolog of insect defensin, designated lucifensin II (Lucilia cuprina Wiedemann [Diptera: Calliphoridae] defensin), was purified from hemolymph extract from larvae of the blowfly L. cuprina. The full-length primary sequence of this peptide of 40 amino acid residues and three intramolecular disulfide bridges was determined by electrospray ionization-orbitrap mass spectrometry and Edman degradation and is almost identical to the previously identified sequence of lucifensin (Lucilia sericata Meigen defensin). Lucifensin II sequence differs from that of lucifensin by only one amino acid residue, that is, by isoleucine instead of valine at position 11. The presence of lucifensin II also was detected in the extracts of other larval tissues, such as gut, salivary glands, fat body, and whole body extract. PMID- 23802452 TI - Repellency of cassia bark, eucalyptus, and star anise oils and their major constituents to Leptotrombidium pallidum (Acari: Trombiculidae). AB - Leptotrombidium pallidum (Nagoya, Miyagawa, Mitamura & Tamiya) is a primary vector of Orientia tsutsugamushi (Hyashi), the causative agent of scrub typhus. An assessment is made of the repellency to L. pallidum larvae (chiggers) of cassia bark, eucalyptus, and star anise oils and major constituents (E) cinnamaldehyde, 1,8-cineole, and (E)-anethole of the corresponding oils. Results were compared with those of conventional repellents DEET (N,N-diethyl-3 methylbenzamide), IR3535 [(ethyl 3-[acetyl(butyl)amino]propanoate)], and permethrin. Based on the median repellent concentration (RC50) values, (E) cinnamaldehyde, (E)-anethole, cassia bark oil, and star anise oil (RC50, 0.95 1.52 mg/cm2) exhibited significantly more potent repellency than DEET (3.85 mg/cm2). (E)-cinnamaldehyde, (E)-anethole, cassiabark oil, 1,8-cineole, and star anise oil were approximately 43, 16, 11, 8, and 4 times more effective than IR3535 (CC5, 6.51%) as judged by the median climbing distance-disturbing concentration (CC50) values. The median residual duration time of repellency (RT50) was significantly more pronounced in DEET (RT50, 323 min) than in all essential oils and constituents (108-167 min). In the light of global efforts to reduce the level of highly toxic synthetic repellents, the three essential oils and their major constituents described merit further study as potential biorepellents for the control of L. pallidum populations. PMID- 23802453 TI - Permethrin resistance profiles in a field population of mosquitoes, Culex quinquefasciatus (Diptera: Culicidae). AB - Insecticides, especially pyrethroids, are important components in the vector control effort. To better understand the development of resistance, the current study characterized resistance profiles in individual single-egg-raft colonies of a field population of Culex quinquefasciatus Say, HAmCq(G0). Our study, with 104 colonies derived from each of the single-egg-rafts of HAmCq(G0), indicated that the levels of resistance to permethrin in fourth instar larvae ranged from 0.4- to 280-fold compared with laboratory susceptible S-Lab larvae. We characterized the distribution of single-egg-raft colonies with different levels of resistance in the HAmCq(G0) population and found that 65% individual colonies had < 10-fold levels of resistance to permethrin, 16% from 10- to 20- fold, 7% from 20- to 30 fold, and 12% < or = 30-fold. We further characterized the frequency of the L-to F kdr allelic expression of sodium channels in the single-egg-raft colonies with different levels of resistance to determine its possible role in resistance. The correlation between allelic expression and levels of resistance clearly showed the importance of L-to-F kdr mutation mediated sodium channel insensitivity in resistance development. However, our results also suggested that the sodium channel insensitivity is unlikely to be the sole mechanism and multiple mechanisms may present among the single colonies in response to insecticide resistance. PMID- 23802454 TI - Comparative susceptibilities of species T and U of the Anopheles fluviatilis complex to Plasmodium vinckei petteri sporogony. AB - Anopheles fluviatilis James is an important malaria vector in Indian subcontinent. An. fluviatilis exists as a complex of three sibling species, of which two species, T and U, have been colonized so far. Attempts were made to study the comparative susceptibility of species T and U of the An. fluviatilis complex to rodent malaria parasite Plasmodium vinckei petteri by using Anopheles stephensi Liston as calibrator for variable infectivity in different isolates. An. stephensi, which was used as control, became readily infected, with 60-65% mosquitoes carrying developing oocysts, whereas in species T and species U, approximately 50 and 63%, respectively, of mosquitoes carried oocyts. An. fluviatilis species T was found comparatively less susceptible to P. v. petteri sporogonic development compared with species U. Moreover, significantly lesser sporozoites rate (11%) was observed in species T compared with 31% in species U. Species T and species U are not considered as malaria vectors in India in the field. However, in the laboratory, both these species are able to support the malaria sporogony. PMID- 23802455 TI - Comparative study of distribution of anopheline vectors (Diptera: Culicidae) in areas with and without malaria transmission in the highlands of an extra Amazonian region in Brazil. AB - This study compares the distribution of anopheline mosquitoes in a malaria endemic municipality (MAL) and a malaria-free municipality (FREE) in an area of the Atlantic Forest in Brazil. Simultaneous quarterly nightly captures were made in three locations in each municipality. One Shannon light trap (Shannon light traps were home made according to specifications published in Am. J. Trop. Med. 1939; 19: 131-140) (SLT) and five CDC light traps (a kind of automatic trap fed by batteries of 12 V and 7 amp/h, with dry ice as a source of CO2; John W. Hock Company, Gainesville, FL) (CLT) (two in the canopy and three at ground level) were operated from 6:00 p.m. to 6:00 a.m. More specimens were captured in MAL (362 in SLTs and 126 in CLTs) than in FREE (66 in SLTs and 59 in CLTs). For the SLTs, Simpson's dominance index was similar in MAL and FREE (D = 0.15 versus D = 0.203, P > 0.7), but Shannon's diversity index was higher for MAL = 1.969 versus H = 1.641, P < 0.01). For the CLTs, Simpson's dominance index was higher in MAL (D = 0.416 versus 0.2688, P < 0.001), and the Shannon diversity index was higher in FREE (H = 1.5222 versus H = 1.115, P < 0.01). In SLTs, Anopheles (Kerteszia) cruzii s.l. frequencies were higher in MAL (chi2 = 23.39; P = 0.000001). In CLTs, An. cruzii s.l. was present in all strata in MAL but only in the canopy inside the forest in FREE (17 specimens). An. cruzii s.l. represented a higher proportion of anophelines in MAL (chi2 = 31; P < 0.000001). The factors that differed in these two areas were anopheline species density and An. cruzii s.l. abundance and distribution. PMID- 23802456 TI - Biology of mosquitoes that are potential vectors of Rift Valley Fever virus in different biotopes of the central highlands of Madagascar. AB - There were epidemic-epizootics of Rift Valley Fever (RVF) affecting humans and cattle in Madagascar in the district of Anjozorobe in 2008. Little is known about the role of Malagasy mosquitoes in the circulation of RVF virus. Therefore, we investigated the species diversity, dynamics and biology of potential RVF virus vectors in the rainforest, rainforest edge (village of Anorana), and savanna biotope (village of Antanifotsy) of this district between November 2008 and July 2010. We captured 56,605 adults of 35 different species. Anopheles squamosus (Theobald), Anopheles coustani (Laveran), Culex antennatus (Becker), Culex pipiens (L.), and Culex univittatus (Theobald) were the most abundant during the rainy season with Cx. pipiens the most abundant species in the rainforest (47%), and An. squamosus the most abundant species in the rainforest edge and in the savanna biotope (56%, 60%, respectively). Only Cx. univittatus was abundant in the dry season. The parous rate was > 60% throughout the rainy season for An. squamosus and it was > 50% from the middle to the end of the rainy season for Cx. pipiens. Two additional species have been found only at larval stage. Cattle were the most attractive bait for all species, followed by sheep and poultry. Human was the least attractive for all species. Most of the 163 bloodmeals tested were taken from cattle. Three were from poultry, one was from dog and one was a mixed bloodmeal taken from sheep and cattle. These results on vectorial capacity parameters may allow considering the involvement of mosquito transmission of the virus in the district of Anjozorobe during the recent epidemic-epizootic. PMID- 23802457 TI - Comparison of dragging and sweeping methods for collecting ticks and determining their seasonal distributions for various habitats, Gyeonggi Province, Republic of Korea. AB - As part of the 65th Medical Brigade tick-borne disease surveillance program to determine the abundance, geographical and seasonal distributions, and tick-borne pathogens present in the Republic of Korea, dragging and sweeping methods were compared to determine their efficiency for collecting ticks in grass and deciduous, conifer, and mixed forest habitats at military training sites and privately owned lands in northern Gyeonggi Province near the demilitarized zone from April-October, 2004-2005. Three species of Ixodid ticks, Haemaphysalis longicornis, Haemaphysalis flava, and Ixodes nipponensis, were collected. Overall, H. longicornis adults and nymphs were most frequently collected from grass and deciduous forest habitats, accounting for 98.2 and 66.2%, respectively, of all ticks collected. H. flava adults and nymphs were most frequently collected from conifer and mixed forests, accounting for 81.6, and 77.8%, respectively, of all ticks collected. I. nipponensis adults and nymphs accounted for 9.3% of all ticks collected from mixed forests, were less commonly collected from deciduous (4.1%) and conifer (4.1%) forests, and infrequently collected from grass habitats (0.9%). Overall, there were no significant differences between dragging and sweeping methods for the three species when the areas sampled were similar (sweeping = 2 x the area over the same transect). Adults and nymphs of H. longicornis were most commonly collected from April-August, while those of H. flava and I. nipponensis were most commonly collected during April-July and again during October. Larvae of all three species were most frequently observed from July-September. PMID- 23802458 TI - Evaluation of a nonanal-trimethylamine lure for collection of Culex quinquefasciatus (Diptera: Culicidae) in gravid traps. AB - Gravid traps are useful tools for monitoring vector-borne pathogens in mosquitoes, particularly for those pathogens transmitted by Culex quinquefasciatus Say. One of the primary challenges in the use of gravid traps is the necessity of the inclusion of an oviposition attractant, usually an infusion of organic material, which changes in attractiveness over time. However, a standardized lure, using nonanal and trimethylamine (N + TMA), has been developed and is commercially available. The N + TMA lure was tested against grass infusion and tap water in Tanzania, where Cx. quinquefasciatus is a vector of lymphatic filariasis. Traps baited with grass infusion collected significantly more mosquitoes than N + TMA-baited traps, which collected significantly more than traps baited with tap water. The advantages and disadvantages of the standardized lure are discussed. PMID- 23802459 TI - Novel estimates of Aedes aegypti (Diptera: Culicidae) population size and adult survival based on Wolbachia releases. AB - The size of Aedes aegypti (L.) mosquito populations and adult survival rates have proven difficult to estimate because of a lack of consistent quantitative measures to equate sampling methods, such as adult trapping, to actual population size. However, such estimates are critical for devising control methods and for modeling the transmission of dengue and other infectious agents carried by this species. Here we take advantage of recent releases of Wolbachia-infected Ae. aegypti coupled with the results of ongoing monitoring to estimate the size of adult Ae. aegypti populations around Cairns in far north Queensland, Australia. Based on the association between released adults infected with Wolbachia and data from Biogents Sentinel traps, we show that data from two locations are consistent with population estimates of approximately 5-10 females per house and daily survival rates of 0.7-0.9 for the released Wolbachia-infected females. Moreover, we estimate that networks of Biogents Sentinel traps at a density of one per 15 houses capture around 5-10% of the adult population per week, and provide a rapid estimate of the absolute population size of Ae. aegypti. These data are discussed with respect to release rates and monitoring in future Wolbachia releases and also the levels of suppression required to reduce dengue transmission. PMID- 23802460 TI - Hunter-killed deer surveillance to assess changes in the prevalence and distribution of Ixodes scapularis (Acari: Ixodidae) in Wisconsin. AB - As a result of the increasing incidence of Lyme disease and other tick-borne pathogens in Wisconsin, we assessed the distribution of adult blacklegged ticks through collections from hunter-killed deer in 2008 and 2009 and compared results with prior surveys beginning in 1981. Volunteers staffed 21 Wisconsin Department of Natural Resources registration stations in 21 counties in the eastern half of Wisconsin in 2008 and 10 stations in seven counties in northwestern Wisconsin in 2009. In total, 786 and 300 white-tailed deer (Odocoileus virginianus) were examined in 2008 and 2009, respectively. All but three stations in 2008 were positive for ticks and all stations in 2009 were positive for ticks. The three sites negative for ticks occurred within the eastern half of Wisconsin. The results indicate that range expansion of Ixodes scapularis (Say) is continuing and the risk of tick exposure is increasing, especially in the eastern one-third of the state. PMID- 23802461 TI - Novel Ehrlichia and Hepatozoon agents infecting the crab-eating fox (Cerdocyon thous) in southeastern Brazil. AB - This study evaluated infection by vector-borne agents in 58 crab-eating fox (Cerdocyon thous L.) that were road-killed in an Atlantic rainforest reserve in the state of Espirito Santo, southeastern Brazil. Spleen, lung, or blood samples collected from the foxes were tested in the laboratory by a battery of polymerase chain reaction (PCR) assays targeting bacteria of the genera Rickettsia, Borrelia, Coxiella, Anaplasma, and Ehrlichia; and protozoa of the genera Babesia, Hepatozoon, and Leishmania. Of the targeted organisms, evidence of infection in the foxes was detected for Ehrlichia and Hepatozoon organisms only. Overall, six (10.3%) foxes were infected by an ehrlichial agent closely related to an ehrlichial agent recently detected in free-ranging Jaguars [(Panthera onca (L.)] in central-western Brazil, and to Ehrlichia ruminantium. For Hepatozoon, 28 (48.3%) foxes were infected by an agent closely related to Hepatozoon sp. Curupira 2 and H. americanum; and one (1.7%) fox was infected by an organism closely related to reptile-associated Hepatozoon agents. Finally, 11 (19.0%) foxes were found infested by Amblyomma cajennense (F.) nymphs, which were all PCR negative for the range of vector-borne agents cited above. Because the haplotypes found in free-ranging foxes are genetically closely related to pathogens of great veterinary importance, namely E. ruminantium and H. americanum, it is highly desirable to know if these novel organisms have any important role as agents of diseases in domestic animals and wildlife in Brazil. PMID- 23802462 TI - A survey of bacterial diversity from successive life stages of black soldier fly (Diptera: Stratiomyidae) by using 16S rDNA pyrosequencing. AB - Sustainable methods for managing waste associated with people and animals have been proposed in the past. Black soldier fly, Hermetia illucens (L.), larvae represent one of the more promising methods. Larvae reduce dry matter, bacteria, offensive odor, and house fly populations. Prepupae can be used as feedstuff for livestock. However, it is not known if such a method results in the proliferation of potential pathogens. Although some bacterial species have been cultured and identified from black soldier fly, a true appreciation of fly associated bacterial diversity is not known. Such information is needed to understand pathogen colonization on decomposing animal and plant waste in the presence of black soldier fly larvae as well as develop research strategies for maximizing the use of this fly to reduce waste without risking environmental harm. Using 454 sequencing, we surveyed bacterial diversity associated with successive life stages of the black soldier fly reared on plant material. Bacteria diversity classified (99.8%) across all life stages spanned six bacterial phyla with > or = 80% bootstrap support. Bacteroidetes and Proteobacteria were the most dominant phyla associated with the black soldier fly accounting for two-thirds of the fauna identified. Many of these bacteria would go undetected because of their inability to be cultured. PMID- 23802463 TI - First record of Phlebotomus (Synphlebotomus) vansomerenae (Diptera: Psychodidae) in Ethiopia. AB - Male Phlebotomus (Synphlebotomus) vansomerenae, specimens were collected together with two other members of the same subgenus between August 2010 and December 2011 in Melka Guba village near Dawa River in Liben district, southeastern Ethiopia. This is the first record of the species in Ethiopia and the first time it has been found outside of Kenya where it was originally described, extending the known distribution of this species in East Africa. PMID- 23802464 TI - Repellency of DEET, picaridin, and three essential oils to Triatoma rubida (Hemiptera: Reduviidae: Triatominae). AB - The kissing bug, Triatoma rubida (Uhler) is a common hematophagous bug in Tucson, AZ, and is responsible for causing severe allergic reactions in some bitten individuals. DEET, picaridin, tea tree oil, peppermint oil, and citronella oil were tested for repellency to T. rubida and its ability to probe and feed on a small restrained rat. No long range repellency was observed with any of the test materials. The lowest repellent concentrations observed were: 10% DEET, 7% picaridin; 30% tea tree oil, 3.3% peppermint oil, and 0.165% citronella oil. Only citronella oil was able to stop all probing and feeding by T. rubida. Citronella oil appears to be a promising potential repellent to prevent sleeping people from being bitten by kissing bugs. PMID- 23802465 TI - Appropriate larval food quality and quantity for Aedes albopictus (Diptera: Culicidae). AB - The Asian tiger mosquito Aedes albopictus (Skuse, 1894) is a globally invasive prominent vector of viral and parasitic pathogens. To soundly guide insecticide use in control programs it is crucial to use standardized test systems under rigorously controlled environmental conditions that allow for comparisons across laboratories. An acute standard test procedure (24 h) for insecticide resistance monitoring of mosquitoes has been published by the World Health Organization in 1998, but a standardized chronic test to monitor sublethal insecticide effects on the life cycle of mosquitoes does not yet exist. As a first step toward a standardized chronic bioassay (half-life-cycle-test), the exclusion of qualitative and quantitative food effects by means of standardized, optimal larval feeding would greatly facilitate inter-laboratory comparisons. Against this background we evaluated food qualities and quantities for the aquatic part of the A. albopictus life cycle under different thermal conditions. Five mg TetraMin (Tetra, Melle, Germany) larva(-1) at 25 degrees C rendered the lowest mortality and large pupae. Our fundamental data on A. albopictus feeding provide an opportunity to standardize experiments and thus support interlaboratory comparisons of studies on the ecotoxicology of this dangerous vector mosquito. PMID- 23802466 TI - A survey of ectoparasites infesting urban and rural dogs of Maranhao state, Brazil. AB - This study evaluated for the first time, ectoparasite infestations on dogs from urban and rural areas of the continental land of the state of Maranhao, northeastern Brazil. In total, 622 dogs were examined for ectoparasite infestations. Overall, 392 (63.0%) were infested with ectoparasites, 154 (51.3%) of 300 urban dogs and 238 (73.9%) of 322 rural dogs. Five species of ectoparasites were found, three ticks [Rhipicephalus sanguineus (Latreille), Amblyomma ovale Koch, and Amblyomma cajennense (F.)], one flea [Ctenocephalides felis (Bouche)], and one louse [(Heterodoxus spininger (Enderlein)]. The frequency of infestation by R. sanguineus tended to be higher in urban than in rural areas, whereas infestations by Amblyomma ticks and C. felis fleas tended to be higher among rural dogs. Louse (H. spininger) infestations were similarly low among all areas. Mixed infestations by at least two species of ectoparasites on the same dog were significantly more frequent on rural than on urban dogs. The most frequent mixed infestation was by R. sanguineus and C. felis, found on 11.4% of the dogs. Further studies are warranted to evaluate canine vector-borne agents in Maranhao, especially because most of the ectoparasites here reported are vectors of major vector-borne diseases, including zoonoses of continental importance. PMID- 23802467 TI - Tar heel footprints in health care. Evan Richardson, CNM. PMID- 23802468 TI - Correlates of tanning facility densities in North Carolina. AB - BACKGROUND: The indoor tanning industry is currently receiving increased attention from policymakers, but this industry has not been well researched. Our study examines economic, demographic, and climate-related variables to better understand variations among North Carolina counties in terms of the number of tanning beds and booths per capita during a recent 3-year period. METHODS: This study used regression analysis to estimate the magnitude and statistical significance of correlations between the density of tanning beds and other relevant variables from 2007 through 2009. RESULTS: The number of indoor tanning beds per capita in a county is positively correlated with the county's unemployment rate and with the proportion of the county's population that consists of white females 18-49 years of age; there is also a weakly positive correlation with the number of days per year of hot weather in the county. All else being equal, tanning beds are marginally more common in counties with higher rates of unemployment, with a greater number of days when the temperature exeeds 90 degrees Fahrenheit, and with residents who are more likely to engage in risky behaviors (as measured by the gonorrhea infection rate and the percentage of the population who smoke cigarettes). LIMITATIONS: The data span a 3-year period (2007-2009) during which economic conditions were depressed. CONCLUSION: Economic, demographic, geographic, and climate-related factors should be considered when policies that affect the tanning industry in North Carolina are being developed and implemented. PMID- 23802469 TI - Analyzing state-based Silver Alert programs: the case of North Carolina. AB - BACKGROUND: Recent discussions about securing the autonomy and safety of older people in a cost-effective way have culminated in the establishment of "Silver Alert" media-alert policies in more than half of US states over the past 5 years. Although these policies have been established with exceptional legislative speed, research has not yet examined how these policies have been implemented across geographic areas. METHODS: Data from the 587 Silver Alerts activated in North Carolina in 2008, 2009, and 2010 were analyzed. Zero-inflated negative binomial regression and exploratory spatial analyses were employed. RESULTS: Despite a policy focus on older adults and individuals with cognitive impairment, activation of Silver Alerts in a county was not related to the proportion of the population 65 years of age or older or to the prevalence of poor mental health in the county. Rather, a 1-unit increase in the proportion of the population comprised of African Americans increased the rate of Silver Alert activation by a factor of 1.019 (P < 0.01). Additionally, spatial analyses suggested that the number of Silver Alerts in a county was related to its proximity to North Carolina's state capital, Raleigh. LIMITATIONS: These results should be interpreted with caution because an exploratory analytic approach was employed in both regression and spatial analyses. CONCLUSION: The current mission and implementation of the Silver Alert program should be reviewed, given that significant effects were observed for the proportion of African Americans in a county and the county's distance from the state capital, but not for the proportion of older adults in the county or for the prevalence of impaired mental status. PMID- 23802470 TI - Spotlight on quality. PMID- 23802471 TI - Transforming quality of care in North Carolina. AB - North Carolina is entering a period of transformative change in health care, as health system consolidation, health care reform, and payment reform combine to dramatically reshape health care. In this turbulent time, maintaining focus on quality of care will be critical. North Carolina has been a national leader in efforts to improve quality of care, starting from classic research in the 1950s on the measurement of quality and culminating in major statewide efforts to improve care through the North Carolina Area Health Education Centers Program, Community Care of North Carolina, the North Carolina Hospital Association, Medicaid, Blue Cross and Blue Shield of North Carolina, academic centers, and many other partners. The purpose of this issue of the NCMJ is to highlight initiatives to improve quality across the continuum of care and across the state. This overview puts these initiatives in context and addresses 3 fundamental questions: Can quality of care be measured and improved? What does the landscape of quality in North Carolina look like now? What should North Carolina's priorities be for improving quality of care moving forward? PMID- 23802472 TI - The NC Quality Center: empowering excellence in health care. AB - The NC Quality Center is transforming health care quality and patient safety in North Carolina by providing leadership, direction, and a vision to ensure that North Carolina delivers the best health care possible. PMID- 23802473 TI - Project to prevent central line-associated bloodstream infections in the medical intensive care unit. PMID- 23802474 TI - Eliminating early elective deliveries at New Hanover Regional Medical Center. PMID- 23802475 TI - Lean health care. AB - Principles of Lean management are being adopted more widely in health care as a way of improving quality and safety while controlling costs. The authors, who are chief executive officers of rural North Carolina hospitals, explain how their organizations are using Lean principles to improve quality and safety of health care delivery. PMID- 23802476 TI - Lean events at Columbus Regional Healthcare System and Sampson Regional Medical Center. PMID- 23802477 TI - Quality improvement in North Carolina's public health departments. AB - North Carolina has been a leader in the application of quality improvement (QI) to public health practice. Over the past decade, numerous developments have served to accelerate the adoption of QI in North Carolina's local health departments. The outstanding results from the widespread application of QI should help North Carolina to become a healthier state. PMID- 23802478 TI - Case study: quality improvement in the Macon County Health Department. PMID- 23802479 TI - Improving the quality of care for Medicaid patients with chronic diseases: Community Care of North Carolina. AB - Community Care of North Carolina's provider-driven approach to quality improvement has benefitted tens of thousands of North Carolinians with diabetes, asthma, hypertension, heart failure, and cardiovascular disease, and it has achieved better results than commercial Medicaid managed care nationally. Substantial opportunities remain, however, particularly for patients with complex care needs. PMID- 23802480 TI - Collaborative quality improvement efforts yield success for asthma patients. PMID- 23802481 TI - The role of the Quality Improvement Organization. AB - Quality Improvement Organizations (QIOs) are an unbiased source of quality improvement support and expertise for health care professionals and institutions across the nation. The Carolinas Center for Medical Excellence, the QIO in North Carolina and South Carolina, is supporting the advancement of the National Quality Strategy. PMID- 23802482 TI - Quality improvement in the age of electronic health records: the North Carolina Improving Performance in Practice program. AB - The Improving Performance in Practice program of the South East Area Health Education Center aims to assist primary care practices in using electronic health records to improve outcomes for patients with chronic diseases. This commentary describes the challenges and successes of practices that have participated in this program. PMID- 23802483 TI - The perils of quality improvement activities: a physician's perspective. AB - Clinical quality measurement remains an elusive goal, and it has the potential to result in adverse outcomes and unexpected consequences. Practicing physicians are wary of current efforts but should remain professionally committed to the development of effective, evidence-based quality measures. PMID- 23802484 TI - The role of health plans in improving quality of care. AB - Regulations and accrediting bodies have charged health plans with assuring and improving the quality of care delivered to plan members. Now, health plans also have an opportunity to promote payment reform designed to align incentives so that plans, providers, employers, and patients can all focus on achieving high quality care. PMID- 23802485 TI - Regional variation in quality of health care across North Carolina's 100 counties. PMID- 23802486 TI - Rural Health Group. PMID- 23802487 TI - Health care quality and patient safety: funding a movement. PMID- 23802488 TI - Pretty but imperfect. PMID- 23802489 TI - An alternative to emergency department care for dental pain and infection. PMID- 23802490 TI - North Carolina's oral health strategies. PMID- 23802491 TI - National Nurses' Week: making the economic case for nursing. PMID- 23802492 TI - The Wizard of Oz and medical-surgical nursing. PMID- 23802493 TI - The percutaneous endoscopic gastrostomy tube: a nurse's guide to PEG tubes. AB - Nurses are primarily responsible for the care and maintenance of percutaneous endoscopic gastrostomy (PEG) tubes and yet their care is not often included in nursing skills textbooks. Best practice recommendations to care for a person with a PEG tube are described. PMID- 23802494 TI - Critical thinking at the bedside: providing safe passage to patients. AB - The critical thinking ability of health care professionals can affect patient safety directly (Buerhaus, Donelan, Ulrich, Norman, & Dittus, 2005). The National League for Nursing (NLN, 2006) expects nursing graduates to be able to demonstrate critical thinking. Nursing programs are required to measure critical thinking as an outcome criterion for accreditation. This process of program accreditation is considered an indicator that a professional program offers a quality product. Based on NLN expectations, health care disciplines should diligently seek opportunities to enhance critical thinking by promoting qualitative and quantitative research that focuses on curriculum evaluation, enhancing educators' and faculty knowledge, and improving patient care outcomes. PMID- 23802495 TI - Nursing assessment of deep vein thrombosis. AB - The seriousness of deep vein thrombosis (DVT) and its accompanying morbidity and mortality make early and accurate diagnosis of key importance. Best clinical practice is supported by the use of a clinical decision model that determines risk based on predisposing factors and certain clinical signs and symptoms. PMID- 23802496 TI - Relationship of glucose values to sliding scale insulin (correctional insulin) dose delivery and meal time in acute care patients with diabetes mellitus. AB - Findings of this study suggest the traditional sliding scale insulin (SSI) method does not improve target glucose values among adult medical inpatients. Timing of blood glucose (BC) measurement does affect the required SSI dose. BC measurement and insulin dose administration should be accomplished immediately prior to mealtime. PMID- 23802497 TI - Culturally tailored education for African Americans with type 2 diabetes. AB - Research shows culturally tailored education can lead to significant improvements in self-care in African Americans with type 2 diabetes. Practical recommendations are provided for medical-surgical nurses to implement culturally tailored education in their patient care. PMID- 23802498 TI - 'Creating a protective picture:' a grounded theory of RN decision making when using a charting-by-exception documentation system. AB - Creating a protective picture, a grounded theory, describes the three-step process medical-surgical nurses use in deciding whether to follow a charting-by exception policy. PMID- 23802499 TI - A review of anticholinergic medications for overactive bladder symptoms. PMID- 23802500 TI - Grounded theory. PMID- 23802501 TI - Drainage pouch: palliating the persistent leak. PMID- 23802502 TI - Integrating procedural care with addiction support: an example from a PICC nurse. AB - Alcohol-related problems are substantial in this society. In support of national health goals, increased effectiveness of hospital-provided care, and patient's well-being, hospital nurses are called to address the issue of addiction and recovery with patients and their families. SBIRT involve a set of strategies useful for this purpose. Nurse-led use of SBIRT strategies into hospital procedural care was demonstrated through the scenario. This technique is applicable to patient encounters during most direct-care inpatient procedures. PMID- 23802503 TI - Changing times: enhancing clinical practice through evolving technology. PMID- 23802505 TI - Heck coupling of olefins to mixed methyl/thienyl monolayers on Si(111) surfaces. AB - The Heck reaction has been used to couple olefins to a Si(111) surface that was functionalized with a mixed monolayer comprised of methyl and thienyl groups. The coupling method maintained a conjugated linkage between the surface and the olefinic surface functionality, to allow for facile charge transfer from the silicon surface. While a Si(111) surface terminated only with thienyl groups displayed a surface recombination velocity, S, of 670 +/- 190 cm s(-1), the mixed CH3/SC4H3-Si(111) surfaces with a coverage of thetaSC4H3 = 0.15 +/- 0.02 displayed a substantially lower value of S = 27 +/- 9 cm s(-1). Accordingly, CH3/SC4H3-Si(111) surfaces were brominated with N-bromosuccinimide, to produce mixed CH3/SC4H2Br-Si(111) surfaces with coverages of thetaBr-Si < 0.05. The resulting aryl halide surfaces were activated using [Pd(PPh3)4] as a catalyst. After activation, Pd(II) was selectively coordinated by oxidative addition to the surface-bound aryl halide. The olefinic substrates 4-fluorostyrene, vinylferrocene, and protoporphyrin IX dimethyl ester were then coupled (in dimethylformamide at 100 degrees C) to the Pd-containing functionalized Si surfaces. The porphyrin-modified surface was then metalated with Co, Cu, or Zn. The vinylferrocene-modified Si(111) surface showed a linear dependence of the peak current on scan rate in cyclic voltammetry, indicating that facile electron transfer had been maintained and providing evidence of a robust linkage between the Si surface and the tethered ferrocene. The final Heck-coupled surface exhibited S = 70 cm s(-1), indicating that high-quality surfaces could be produced by this multistep synthetic approach for tethering small molecules to silicon photoelectrodes. PMID- 23802506 TI - Influence of immediate and early loading on bone metabolic activity around dental implants in rat tibiae. AB - OBJECTIVES: The aim of this study was to examine the influence of immediate and early loading on dynamic changes in bone metabolism around dental implants using bone scintigraphy. MATERIAL AND METHODS: Two titanium implants were inserted in the right tibiae of 21 rats. Closed coil springs with 4.0-N loads were applied parallel to the upper portion of the implants for 35 days. According to the load application timing, rats were divided into three groups: immediate loading (IL) group, early loading 1 day after implant insertion (1-D early loading [EL]) group, and loading 3 days after implant insertion (3-D EL) group. Rats were intravenously injected with technetium-99 m-methylene diphosphonate (Tc99 m-MDP) (74 MBq/rat) and scanned by bone scintigraphy at 1, 4, 7, 11, 14, 21, 28, and 35 days after load application. The ratio of accumulation of Tc99 m-MDP around the implants to that of a reference site (uptake ratio) was calculated to evaluate bone metabolism. RESULTS: In every group, the uptake ratio increased until 7 days after load application and then gradually decreased. It was significantly higher than baseline at 4, 7, 11, and 14 days (P < 0.001). The uptake ratio in the 1-D EL and 3-D EL groups were significantly higher than that in the control group and also that in the IL group (P < 0.001). CONCLUSIONS: Bone metabolism initially increased and then gradually decreased to baseline despite differences in load timing. Increases in bone metabolic activity differed according to load application timing; the later the load application, the more enhanced the bone metabolism. PMID- 23802504 TI - Novel drugs and intervention strategies for the treatment of chronic kidney disease. AB - Chronic kidney disease (CKD) is a worldwide health problem. The disease is most often progressive of nature with a high impact on patients and society. It is increasingly recognized that CKD can be detected in the early stages and should be managed as early as possible. Treatment of the cause, but in particular control of the main risk markers, such as high blood pressure, glucose and albuminuria, has been instrumental in delaying the progression to end-stage renal disease (ESRD). However, despite the state of the art therapy, the absolute risk of renal and cardiovascular morbidity and mortality in CKD patients remains devastatingly high. Novel drugs are therefore highly desirable to halt effectively the progressive renal (and cardiovascular) function loss. Recently, several novel strategies have been tested targeting traditional risk factors such as blood pressure (combination therapy of angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) and novel mineralocorticoid receptor antagonists) as well as dyslipidaemia (statins) with surprising results. In addition, drug targets specifically related to the kidney, such as vitamin D, uric acid, erythropoietin and phosphate, have been the subject of clinical trials, in some instances with unexpected results. Finally, novel targets including endothelin receptors and inflammatory pathways are increasingly explored as potential avenues to improve renal and cardiovascular protection, albeit that the drugs tested have not been unequivocally successful. In this article we review novel drugs or intervention strategies for the management of CKD, we try to provide explanations for the failure of some promising drugs and hypothesize on the potential success of new strategies. PMID- 23802507 TI - Lesional patterns associated with mycobacteriosis in an Atlantic horse mackerel, Trachurus trachurus (L.), aquarium population. PMID- 23802508 TI - A 12-week lifestyle intervention for middle-aged, overweight men who are supporters of local sporting clubs. AB - OBJECTIVE: To evaluate the effectiveness of a 12-week lifestyle program for changes in healthy lifestyle knowledge, health perceptions and body composition of middle-aged, overweight men. METHODS: A participatory, action-based experimental design was employed with a convenience sample (n = 24) of middle aged men who were supporters of either a local rugby league or rugby union club. Participants attended an introductory session and baseline testing in week one, participated in once-weekly group circuit exercise and lifestyle education sessions for 10 weeks and attended post-testing and project evaluation in week 12. RESULTS: Fourteen participants completed the project. Healthy lifestyle knowledge did not improve significantly. As a combined group there were significant improvements in both physical and mental components of the SF12 questionnaire and in waist girth. The rugby league cohort achieved significant improvement in the SF12 physical component, weight, BMI and waist girth. The rugby union cohort achieved significant improvement in the SF12 mental component and waist girth. Participants reported a variety of health improvement and lifestyle changes following the project and reported appreciation at the involvement of the sporting club. CONCLUSIONS: The men's lifestyle program resulted in significant improvement in body composition, resulting in a reduction in obesity-related disease risk in some participants. PMID- 23802509 TI - Association of eveningness with problem behavior in children: a mediating role of impaired sleep. AB - Eveningness, the preference of being active during the evening in contrast to the morning, has been associated with markedly increased problem behavior in adolescents; however, the underlying mechanisms are still not understood. This study investigates the association of eveningness with behavior and cognition in children aged 7-12 yrs, and explores the potential mediating role of a variety of sleep factors. Parents of 333 school-aged children (mean age=9.97 yrs; 55% girls) completed a sleep log and several questionnaires regarding eveningness, sleep habits, and behavioral problems. Intellectual abilities, working memory, and attention were assessed using the short-form of the Wechsler Intelligence Scale for Children (WISC) and subtasks of the Amsterdam Neuropsychological Tasks. Results showed that eveningness predicted behavioral problems over and above the effects of demographic variables (age, sex, and familial socioeconomic status) (p=0.003). Significant partial correlation was found for eveningness and sleep duration during weekdays (p=0.005), and not during weekends. Furthermore, evening orientation was associated with a reduced rested feeling on weekday mornings (p<0.001), but not on weekends. The most important sleep characteristic showing association with many cognitive and behavioral measures was the subjective feeling upon awakening-particularly during weekdays. Bootstrap mediation analyses demonstrated that sleep significantly mediated the effects of eveningness on behavioral problems, working memory, and sustained attention. Interestingly, mediation was only significant through the subjective feeling upon awakening on weekdays. The current findings indicate that the subjective feeling upon awakening is a much better predictor of daytime problems than subjective sleep quantity. Furthermore, the data suggest that negative outcomes in evening types are due to the fact that they wake up before their circadian drive for arousal and prior to complete dissipation of sleep pressure during weekdays. Interventions that target the misalignment of endogenous circadian rhythms and imposed rhythms are discussed. PMID- 23802510 TI - A new flavonoid glycoside and other chemical constituents from leaves of Rosa davurica and their antioxidant activity. AB - A 70% ethanol extract from the leaves of Rosa davurica showed significant antioxidant activity in both superoxide anion and 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical-scavenging assays. Phytochemical study of this extract resulted in the isolation of eight compounds, including a new flavonoid glycoside. The chemical structure was determined by various spectroscopic analyses. The isolated compounds and their structurally related compounds, belonging to two classes: quercetin 3-O-glycosides and gallic acid derivates, were evaluated for their superoxide anion- and DPPH free radical-scavenging activities. These compounds showed significant superoxide anion-scavenging activity with the EC50 values ranging from 1.68 to 18.09 MUM, and DPPH free radical-scavenging activity with the EC50 values ranging from 7.18 to 67.62 MUM. The structure-activity relationship was also reported. PMID- 23802511 TI - Scientific publications in ophthalmic journals from China and other top-ranking countries: a 12-year review of the literature. AB - BACKGROUND: Eye diseases with increasing mortality are common health problems that affect people of all ages and demographic backgrounds. In this study, we study the publication characteristics in international ophthalmic journals of the US, the UK, Germany, Australia, Japan, and China. METHODS: Articles published in 53 ophthalmic journals from 2000 to 2011 were retrieved from the PubMed database. We recorded the number of articles published each year, analyzed the publication type, and evaluated the accumulated and average impact factors (IFs), and the distribution of articles in ophthalmic journals in relation to IFs. The characteristics of publication outputs from China and other top-ranking countries were compared. RESULTS: The total number of articles increased significantly during the past 12 years, with an increase of 51.0%. The growth in the annual number of articles from the US, the UK, Australia, and China showed a significantly positive trend. Publications from the US exceeded those from any other country and had the highest IFs, largest number of total citations of articles, and the most articles published in leading ophthalmic journals. During the past 12 years, China contributed 3.5% of the total publications, and the number of Chinese articles showed a more than 6-fold increase (from 99 to 605, R2 =0.947, P<0.001). The numbers of IFs and citations of articles originating in China were mostly lower than for other top-ranking counties. CONCLUSIONS: Research on ophthalmic journals has maintained an upward growing trend from 2000 to 2011. Chinese ophthalmology research has developed rapidly, but the gap still exists between China and other top-ranking countries for the advanced level of research. PMID- 23802512 TI - Body composition in urban South Asian women; development of a bioelectrical impedance analysis prediction equation. AB - BACKGROUND: Assessment of body composition plays a significant role in combating chronic disease among South Asians. Accurate assessment of body composition by bioelectrical impedance analysis (BIA) requires population-specific equations which are currently unavailable for urban South Asian women. AIM: To assess validity of direct BIA assessment and selected equations for prediction of total body water (TBW), against Deuterium ((2)H2O) dilution and develop and validate a population-specific TBW equation for urban South Asian women. SUBJECTS AND METHOD: Data of 80 urban Sri Lankan women (30-45 years) were used for this analysis. Body composition was assessed by (2)H2O dilution (reference) and BIA. Available BIA equations were assessed for validity. A new TBW equation was generated and validated. RESULTS: Direct BIA measurements and other equations did not meet validation criteria in predicting TBW. TBW by the new equation (TBW = 3.443 + 0.342 * (height(2)/impedance) + 0.176 * weight) correlated (p < 0.001) with TBW by reference method. TBW using the new equation was not significantly different (25.30 +/- 2.4 kg) from the reference (25.32 +/- 2.7 kg). CONCLUSION: Direct use of TBW by instrument and existing equations are less suitable for this population. The new TBW equation is suitable for body composition assessment in urban South Asian women. PMID- 23802513 TI - From mindless to mindful practice--cognitive bias and clinical decision making. PMID- 23802514 TI - Uncertainty--the other side of prognosis. PMID- 23802515 TI - eReferral--a new model for integrated care. PMID- 23802517 TI - Images in clinical medicine. Eyelid swelling and primary Sjogren's syndrome. PMID- 23802516 TI - Mutations affecting G-protein subunit alpha11 in hypercalcemia and hypocalcemia. AB - BACKGROUND: Familial hypocalciuric hypercalcemia is a genetically heterogeneous disorder with three variants: types 1, 2, and 3. Type 1 is due to loss-of function mutations of the calcium-sensing receptor, a guanine nucleotide-binding protein (G-protein)-coupled receptor that signals through the G-protein subunit alpha11 (Galpha11). Type 3 is associated with adaptor-related protein complex 2, sigma 1 subunit (AP2S1) mutations, which result in altered calcium-sensing receptor endocytosis. We hypothesized that type 2 is due to mutations effecting Galpha11 loss of function, since Galpha11 is involved in calcium-sensing receptor signaling, and its gene (GNA11) and the type 2 locus are colocalized on chromosome 19p13.3. We also postulated that mutations effecting Galpha11 gain of function, like the mutations effecting calcium-sensing receptor gain of function that cause autosomal dominant hypocalcemia type 1, may lead to hypocalcemia. METHODS: We performed GNA11 mutational analysis in a kindred with familial hypocalciuric hypercalcemia type 2 and in nine unrelated patients with familial hypocalciuric hypercalcemia who did not have mutations in the gene encoding the calcium-sensing receptor (CASR) or AP2S1. We also performed this analysis in eight unrelated patients with hypocalcemia who did not have CASR mutations. In addition, we studied the effects of GNA11 mutations on Galpha11 protein structure and calcium-sensing receptor signaling in human embryonic kidney 293 (HEK293) cells. RESULTS: The kindred with familial hypocalciuric hypercalcemia type 2 had an in-frame deletion of a conserved Galpha11 isoleucine (Ile200del), and one of the nine unrelated patients with familial hypocalciuric hypercalcemia had a missense GNA11 mutation (Leu135Gln). Missense GNA11 mutations (Arg181Gln and Phe341Leu) were detected in two unrelated patients with hypocalcemia; they were therefore identified as having autosomal dominant hypocalcemia type 2. All four GNA11 mutations predicted disrupted protein structures, and assessment on the basis of in vitro expression showed that familial hypocalciuric hypercalcemia type 2-associated mutations decreased the sensitivity of cells expressing calcium sensing receptors to changes in extracellular calcium concentrations, whereas autosomal dominant hypocalcemia type 2-associated mutations increased cell sensitivity. CONCLUSIONS: Galpha11 mutants with loss of function cause familial hypocalciuric hypercalcemia type 2, and Galpha11 mutants with gain of function cause a clinical disorder designated as autosomal dominant hypocalcemia type 2. (Funded by the United Kingdom Medical Research Council and others.). PMID- 23802518 TI - Case records of the Massachusetts General Hospital. Case 20-2013. A 29-year-old man with anemia and jaundice. PMID- 23802519 TI - G proteins--the disease spectrum expands. PMID- 23802520 TI - A salty taste to autoimmunity. PMID- 23802521 TI - Combination antifungal therapy for cryptococcal meningitis. PMID- 23802522 TI - Combination antifungal therapy for cryptococcal meningitis. PMID- 23802523 TI - Ischemic heart disease after breast cancer radiotherapy. PMID- 23802524 TI - Ischemic heart disease after breast cancer radiotherapy. PMID- 23802525 TI - Ischemic heart disease after breast cancer radiotherapy. PMID- 23802526 TI - Ischemic heart disease after breast cancer radiotherapy. PMID- 23802527 TI - Ischemic heart disease after breast cancer radiotherapy. PMID- 23802528 TI - Ischemic heart disease after breast cancer radiotherapy. PMID- 23802529 TI - Omalizumab for chronic urticaria. PMID- 23802530 TI - Omalizumab for chronic urticaria. PMID- 23802531 TI - Omalizumab for chronic urticaria. PMID- 23802532 TI - Omalizumab for chronic urticaria. PMID- 23802533 TI - Salt in health and disease--a delicate balance. PMID- 23802534 TI - Salt in health and disease--a delicate balance. PMID- 23802535 TI - Salt in health and disease--a delicate balance. PMID- 23802536 TI - Germline mutations affecting Galpha11 in hypoparathyroidism. PMID- 23802540 TI - Images in clinical medicine. Enlarged spleen with a heterogeneous pattern. PMID- 23802541 TI - Clinical decisions. Family presence during cardiopulmonary resuscitation--polling results. PMID- 23802542 TI - Inhibitor development in previously treated hemophilia A patients: a systematic review, meta-analysis, and meta-regression. AB - BACKGROUND: The development of neutralizing alloantibodies (inhibitors) is the most serious complication of factor VIII (FVIII) replacement therapy in patients with hemophilia A. Unlike previously untreated patients, no definite risk factors for inhibitor development are known for previously treated patients (PTPs). The investigation of the development of inhibitors in PTPs is hindered by several methodological limitations in the available literature. We conducted a systematic review to account for these limitations. METHODS: We considered the studies reporting on PTPs that were included in the Wight and Paisley meta-analysis and a systematic search of MEDLINE, EMBASE, and The Cochrane Library was conducted to identify studies published after 2003. Studies that investigated the development of inhibitors in hemophilia A PTPs who were treated with any type of FVIII concentrate and that included at least 25 patients with follow-up were included in the analysis. RESULTS: Thirty-three independent cohorts of PTPs with 4323 subjects and 43 incident de novo inhibitors were found and analyzed. The pooled incidence rate of inhibitor development for the 25 studies providing data on follow-up was 3 (95% confidence interval 1-4) per 1000 person-years. A significant association was not found between putative risk factors and inhibitor development in PTPs at meta-regression analysis and subgroup analysis, but the model was sensitive enough to the inclusion of the reports on the Belgian-Dutch experience with a highly immunogenic factor VIII. CONCLUSION: We confirmed a low overall rate of de novo inhibitors in PTPs, without any significant effect of putative predictors, including the type of factor VIII concentrate. PMID- 23802543 TI - Case of Netherton syndrome with an elevated serum thymus and activation-regulated chemokine level. PMID- 23802544 TI - Identification of an intact ParaHox cluster with temporal colinearity but altered spatial colinearity in the hemichordate Ptychodera flava. AB - BACKGROUND: ParaHox and Hox genes are thought to have evolved from a common ancestral ProtoHox cluster or from tandem duplication prior to the divergence of cnidarians and bilaterians. Similar to Hox clusters, chordate ParaHox genes including Gsx, Xlox, and Cdx, are clustered and their expression exhibits temporal and spatial colinearity. In non-chordate animals, however, studies on the genomic organization of ParaHox genes are limited to only a few animal taxa. Hemichordates, such as the Enteropneust acorn worms, have been used to gain insights into the origins of chordate characters. In this study, we investigated the genomic organization and expression of ParaHox genes in the indirect developing hemichordate acorn worm Ptychodera flava. RESULTS: We found that P. flava contains an intact ParaHox cluster with a similar arrangement to that of chordates. The temporal expression order of the P. flava ParaHox genes is the same as that of the chordate ParaHox genes. During embryogenesis, the spatial expression pattern of PfCdx in the posterior endoderm represents a conserved feature similar to the expression of its orthologs in other animals. On the other hand, PfXlox and PfGsx show a novel expression pattern in the blastopore. Nevertheless, during metamorphosis, PfXlox and PfCdx are expressed in the endoderm in a spatially staggered pattern similar to the situation in chordates. CONCLUSIONS: Our study shows that P. flava ParaHox genes, despite forming an intact cluster, exhibit temporal colinearity but lose spatial colinearity during embryogenesis. During metamorphosis, partial spatial colinearity is retained in the transforming larva. These results strongly suggest that intact ParaHox gene clustering was retained in the deuterostome ancestor and is correlated with temporal colinearity. PMID- 23802545 TI - Directed evolution of a cellobiose utilization pathway in Saccharomyces cerevisiae by simultaneously engineering multiple proteins. AB - BACKGROUND: The optimization of metabolic pathways is critical for efficient and economical production of biofuels and specialty chemicals. One such significant pathway is the cellobiose utilization pathway, identified as a promising route in biomass utilization. Here we describe the optimization of cellobiose consumption and ethanol productivity by simultaneously engineering both proteins of the pathway, the beta-glucosidase (gh1-1) and the cellodextrin transporter (cdt-1), in an example of pathway engineering through directed evolution. RESULTS: The improved pathway was assessed based on the strain specific growth rate on cellobiose, with the final mutant exhibiting a 47% increase over the wild-type pathway. Metabolite analysis of the engineered pathway identified a 49% increase in cellobiose consumption (1.78 to 2.65 g cellobiose/(L . h)) and a 64% increase in ethanol productivity (0.611 to 1.00 g ethanol/(L . h)). CONCLUSIONS: By simultaneously engineering multiple proteins in the pathway, cellobiose utilization in S. cerevisiae was improved. This optimization can be generally applied to other metabolic pathways, provided a selection/screening method is available for the desired phenotype. The improved in vivo cellobiose utilization demonstrated here could help to decrease the in vitro enzyme load in biomass pretreatment, ultimately contributing to a reduction in the high cost of biofuel production. PMID- 23802546 TI - Differential control of Salmonella heat shock operons by structured mRNAs. AB - DnaK-DnaJ-GrpE and GroES-GroEL are the major chaperone machineries in bacteria. In many species, dnaKJ and groESL are encoded in bicistronic operons. Quantitative proteomics revealed that DnaK and GroEL amounts in Salmonella dominate over DnaJ and GroES respectively. An imperfect transcriptional terminator in the intergenic region of dnaKJ is known to result in higher transcript levels of the first gene. Here, we examined the groESL operon and asked how the second gene in a heat shock operon can be preferentially expressed and found that an RNA structure in the 5'untranslated region of groES is responsible. The secondary structure masks the Shine-Dalgarno (SD) sequence and AUG start codon and thereby modulates translation of groES mRNA. Reporter gene assays combined with structure probing and toeprinting analysis revealed a dynamic temperature-sensitive RNA structure. Following an increase in temperature, only the second of two RNA hairpins melts and partially liberates the SD sequence, thus facilitating translation. Translation of groEL is not temperature-regulated leading to an excess of the chaperonin in the cell at low temperature. Discussion in a broader context shows how structured RNA segments can differentially control expression of temperature-affected operons in various ways. PMID- 23802547 TI - Solitary (primary) uveal T-cell lymphoma in a horse. AB - A 22-year-old Australian stockhorse gelding was presented with anterior uveitis in the right eye which was nonresponsive to anti-inflammatory therapy. Clinical examination revealed corneal edema and vascularization, marked hypopyon, and thickening of the dorsal iris, which was confirmed by ultrasonography. Hematologic and biochemical analyses, abdominal and thoracic ultrasonography, and abdominocentesis with cytologic and biochemical analysis revealed no significant abnormalities. Cytological examination of an aqueous humor sample revealed a population of predominantly large lymphoblasts with high nuclear-to-cytoplasmic ratio, round or irregular nuclei, clumped nuclear chromatin, multiple large prominent nucleoli, and a small volume of basophilic cytoplasm. The cytologic diagnosis was intraocular lymphoma. Biopsy of the right submandibular lymph node revealed no evidence of neoplastic invasion. Euthanasia and a complete necropsy were performed and revealed no evidence of neoplasia in any tissue other than the right eye, which had an extensive, well-defined infiltrate of neoplastic lymphocytes expanding the ciliary body and iris, infiltrating the ciliary epithelium, and extending into the pars plana and peripheral choroid. Immunohistochemistry confirmed that neoplastic cells expressed the T-cell marker CD3. To the authors' knowledge, this is the first description of primary, solitary uveal T-cell lymphoma in a horse. Although apparently rare, lymphoma should be considered in horses with uveitis, even when inflammation is unilateral and in the absence of extraocular signs of neoplasia. Aqueocentesis and cytological examination provided an antemortem diagnosis in this case and should be considered as a diagnostic tool for investigation of uveal thickening and hypopyon. PMID- 23802548 TI - Apparent diffusion coefficient threshold for delineation of ischemic core. AB - BACKGROUND: MRI-based selection of patients for acute stroke interventions requires rapid accurate estimation of the infarct core on diffusion-weighted MRI. Typically used manual methods to delineate restricted diffusion lesions are subjective and time consuming. These limitations would be overcome by a fully automated method that can rapidly and objectively delineate the ischemic core. An automated method would require predefined criteria to identify the ischemic core. AIM: The aim of this study is to determine apparent diffusion coefficient-based criteria that can be implemented in a fully automated software solution for identification of the ischemic core. METHODS: Imaging data from patients enrolled in the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) study who had early revascularization following intravenous thrombolysis were included. The patients' baseline restricted diffusion and 30 day T2 -weighted fluid-attenuated inversion recovery lesions were manually delineated after coregistration. Parts of the restricted diffusion lesion that corresponded with 30-day infarct were considered ischemic core, whereas parts that corresponded with normal brain parenchyma at 30 days were considered noncore. The optimal apparent diffusion coefficient threshold to discriminate core from noncore voxels was determined by voxel-based receiver operating characteristics analysis using the Youden index. RESULTS: 51,045 diffusion positive voxels from 14 patients who met eligibility criteria were analyzed. The mean DWI lesion volume was 24 (+/- 23) ml. Of this, 18 (+/- 22) ml was ischemic core and 3 (+/- 5) ml was noncore. The remainder corresponded to preexisting gliosis, cerebrospinal fluid, or was lost to postinfarct atrophy. The apparent diffusion coefficient of core was lower than that of noncore voxels (P < 0.0001). The optimal threshold for identification of ischemic core was an apparent diffusion coefficient <= 620 * 10(-6) mm(2) /s (sensitivity 69% and specificity 78%). CONCLUSIONS: Our data suggest that the ischemic core can be identified with an absolute apparent diffusion coefficient threshold. This threshold can be implemented in image analysis software for fully automated segmentation of the ischemic core. PMID- 23802549 TI - Characterization of Ruminococcus albus cellodextrin phosphorylase and identification of a key phenylalanine residue for acceptor specificity and affinity to the phosphate group. AB - Ruminococcus albus has the ability to intracellularly degrade cello oligosaccharides primarily via phosphorolysis. In this study, the enzymatic characteristics of R. albus cellodextrin phosphorylase (RaCDP), which is a member of glycoside hydrolase family 94, was investigated. RaCDP catalyzes the phosphorolysis of cellotriose through an ordered 'bi bi' mechanism in which cellotriose binds to RaCDP before inorganic phosphate, and then cellobiose and glucose 1-phosphate (Glc1P) are released in that order. Among the cello oligosaccharides tested, RaCDP had the highest phosphorolytic and synthetic activities towards cellohexaose and cellopentaose, respectively. RaCDP successively transferred glucosyl residues from Glc1P to the growing cello oligosaccharide chain, and insoluble cello-oligosaccharides comprising a mean of eight residues were produced. Sophorose, laminaribiose, beta-1,4-xylobiose, beta 1,4-mannobiose and cellobiitol served as acceptors for RaCDP. RaCDP had very low affinity for phosphate groups in both the phosphorolysis and synthesis directions. A sequence comparison revealed that RaCDP has Gln at position 646 where His is normally conserved in the phosphate binding sites of related enzymes. A Q646H mutant showed approximately twofold lower apparent K(m) values for inorganic phosphate and Glc1P than the wild-type. RaCDP has Phe at position 633 corresponding to Tyr and Val in the +1 subsites of cellobiose phosphorylase and N,N'-diacetylchitobiose phosphorylase, respectively. A F633Y mutant showed higher preference for cellobiose over beta-1,4-mannobiose as an acceptor substrate in the synthetic reaction than the wild-type. Furthermore, the F633Y mutant showed 75- and 1100-fold lower apparent Km values for inorganic phosphate and Glc1P, respectively, in phosphorolysis and synthesis of cellotriose. PMID- 23802551 TI - Complexity of the genetic basis of ageing in nature revealed by a clinal study of lifespan and methuselah, a gene for ageing, in Drosophila from eastern Australia. AB - Clinal studies are a powerful tool for understanding the genetic basis of climatic adaptation. However, while clines in quantitative traits and genetic polymorphisms have been observed within and across continents, few studies have attempted to demonstrate direct links between them. The gene methuselah in Drosophila has been shown to have a major effect on stress response and longevity phenotypes based largely on laboratory studies of induced mutations in the mth gene. Clinal patterns in the most common mth haplotype and for lifespan (both increasing with latitude) have been observed in North American populations of D. melanogaster, implicating climatic selection. While these clinal patterns have led some to suggest that mth influences ageing in natural populations, limited evidence on the association between the two has so far been collected. Here, we describe a significant cline in the mth haplotype in eastern Australian D. melanogaster populations that parallel the cline in North America. We also describe a cline in mth gene expression. These findings further support the idea that mth is itself under selection. In contrast, we show that lifespan has a strong nonlinear clinal pattern, increasing southwards from the tropics, but then decreasing again from mid-latitudes. Furthermore, in association studies, we find no evidence for a direct link between mth haplotype and lifespan. Thus, while our data support a role for mth variation being under natural selection, we found no link to naturally occurring variation in lifespan and ageing in Australian populations of D. melanogaster. Our results indicate that the mth locus likely has genetic background and environment-specific effects. PMID- 23802552 TI - Signals of selection in outlier loci in a widely dispersing species across an environmental mosaic. AB - Local adaptation reflects a balance between natural selection and gene flow and is classically thought to require the retention of locally adapted alleles. However, organisms with high dispersal potential across a spatially or temporally heterogeneous landscape pose an interesting challenge to this view requiring local selection every generation or when environmental conditions change to generate adaptation in adults. Here, we test for geographical and sequence-based signals of selection in five putatively adaptive and two putatively neutral genes identified in a previous genome scan of the highly dispersing purple sea urchin, Strongylocentrotus purpuratus. Comparing six populations spanning the species' wide latitudinal range from Canada to Baja California, Mexico, we find positive tests for selection in the putative adaptive genes and not in the putative neutral genes. Specifically, we find an excess of low-frequency and nonsynonymous polymorphisms in two transcription factors and a transporter protein, and an excess of common amino acid polymorphisms in the two transcription factors, suggestive of spatially balancing selection. We test for a genetic correlation with temperature, a dominant environmental variable in this coastal ecosystem. We find mild clines and a stronger association of genetic variation with temperature than latitude in four of the five putative adaptive loci and a signal of local adaptation in the Southern California Bight. Overall, patterns of genetic variation match predictions based on spatially or temporally balancing selection in a heterogeneous landscape and illustrate the value of geographical and coalescent tests on candidate loci identified in a genome-wide scan for selection. PMID- 23802550 TI - Combined analyses of kinship and FST suggest potential drivers of chaotic genetic patchiness in high gene-flow populations. AB - We combine kinship estimates with traditional F-statistics to explain contemporary drivers of population genetic differentiation despite high gene flow. We investigate range-wide population genetic structure of the California spiny (or red rock) lobster (Panulirus interruptus) and find slight, but significant global population differentiation in mtDNA (PhiST = 0.006, P = 0.001; D(est_Chao) = 0.025) and seven nuclear microsatellites (F(ST) = 0.004, P < 0.001; D(est_Chao) = 0.03), despite the species' 240- to 330-day pelagic larval duration. Significant population structure does not correlate with distance between sampling locations, and pairwise FST between adjacent sites often exceeds that among geographically distant locations. This result would typically be interpreted as unexplainable, chaotic genetic patchiness. However, kinship levels differ significantly among sites (pseudo-F(16,988) = 1.39, P = 0.001), and ten of 17 sample sites have significantly greater numbers of kin than expected by chance (P < 0.05). Moreover, a higher proportion of kin within sites strongly correlates with greater genetic differentiation among sites (D(est_Chao), R(2) = 0.66, P < 0.005). Sites with elevated mean kinship were geographically proximate to regions of high upwelling intensity (R(2) = 0.41, P = 0.0009). These results indicate that P. interruptus does not maintain a single homogenous population, despite extreme dispersal potential. Instead, these lobsters appear to either have substantial localized recruitment or maintain planktonic larval cohesiveness whereby siblings more likely settle together than disperse across sites. More broadly, our results contribute to a growing number of studies showing that low F(ST) and high family structure across populations can coexist, illuminating the foundations of cryptic genetic patterns and the nature of marine dispersal. PMID- 23802553 TI - Influence of late Quaternary climate change on present patterns of genetic variation in valley oak, Quercus lobata Nee. AB - Phylogeography and ecological niche models (ENMs) suggest that late Quaternary glacial cycles have played a prominent role in shaping present population genetic structure and diversity, but have not applied quantitative methods to dissect the relative contribution of past and present climate vs. other forces. We integrate multilocus phylogeography, climate-based ENMs and multivariate statistical approaches to infer the effects of late Quaternary climate change on contemporary genetic variation of valley oak (Quercus lobata Nee). ENMs indicated that valley oak maintained a stable distribution with local migration from the last interglacial period (~120 ka) to the Last Glacial Maximum (~21 ka, LGM) to the present compared with large-scale range shifts for an eastern North American white oak (Quercus alba L.). Coast Range and Sierra Nevada foothill populations diverged in the late Pleistocene before the LGM [104 ka (28-1622)] and have occupied somewhat distinct climate niches, according to ENMs and coalescent analyses of divergence time. In accordance with neutral expectations for stable populations, nuclear microsatellite diversity positively correlated with niche stability from the LGM to present. Most strikingly, nuclear and chloroplast microsatellite variation significantly correlated with LGM climate, even after controlling for associations with geographic location and present climate using partial redundancy analyses. Variance partitioning showed that LGM climate uniquely explains a similar proportion of genetic variance as present climate (16% vs. 11-18%), and together, past and present climate explains more than geography (19%). Climate can influence local expansion-contraction dynamics, flowering phenology and thus gene flow, and/or impose selective pressures. These results highlight the lingering effect of past climate on genetic variation in species with stable distributions. PMID- 23802556 TI - Soil security is alarming in China's main grain producing areas. PMID- 23802554 TI - Color Doppler ultrasound and gamma imaging of intratumorally injected 500 nm iron silica nanoshells. AB - Perfluoropentane gas filled iron-silica nanoshells have been developed as stationary ultrasound contrast agents for marking tumors to guide surgical resection. It is critical to establish their long-term imaging efficacy, as well as biodistribution. This work shows that 500 nm Fe-SiO2 nanoshells can be imaged by color Doppler ultrasound over the course of 10 days in Py8119 tumor bearing mice. The 500 nm nonbiodegradable SiO2 and biodegradable Fe-SiO2 nanoshells were functionalized with diethylenetriamine pentaacetic acid (DTPA) ligand and radiolabeled with (111)In(3+) for biodistribution studies in nu/nu mice. The majority of radioactivity was detected in the liver and kidneys following intravenous (IV) administration of nanoshells to healthy animals. By contrast, after nanoshells were injected intratumorally, most of the radioactivity remained at the injection site; however, some nanoshells escaped into circulation and were distributed similarly as those given intravenously. For intratumoral delivery of nanoshells and IV delivery to healthy animals, little difference was seen between the biodistribution of SiO2 and biodegradable Fe-SiO2 nanoshells. However, when nanoshells were administered IV to tumor bearing mice, a significant increase was observed in liver accumulation of SiO2 nanoshells relative to biodegradable Fe SiO2 nanoshells. Both SiO2 and Fe-SiO2 nanoshells accumulate passively in proportion to tumor mass, during intravenous delivery of nanoshells. This is the first report of the biodistribution following intratumoral injection of any biodegradable silica particle, as well as the first report demonstrating the utility of DTPA-(111)In labeling for studying silica nanoparticle biodistributions. PMID- 23802557 TI - Wheat storage proteins in transgenic rice endosperm. AB - Transgenic rice seed expressing wheat HMW glutenin subunit was characterized to study the effects of the wheat prolamin on the protein expression pattern and protein size distribution in the endosperm and the functional and rheological properties of the rice flour and dough. Significant differences were found in the protein expression pattern between the transgenic and wild type samples. Comparing the protein expression profiles of transgenic and nontransgenic plants, combined with proteomic-based studies, indicated increased protein disulfide isomerase (PDI) levels in the transgenic rice lines. The accurate molecular size of HMW-GS in rice endosperm was identified by MALDI-TOF-MS analysis. The expressed wheat HMW (subunit 1Dx5) GS showed a positive effect on the functional properties of rice dough by significantly increasing the size distribution of the polymeric protein fraction and modifying the dough mixing parameters. PMID- 23802558 TI - Physical methods to promote drug delivery on mucosal tissues of the oral cavity. AB - INTRODUCTION: The success of drug delivery through the mucosal tissue of the oral cavity represents a current challenge as well as a great future perspective. The need for more rapid onset of action and improved absorption of medications has resulted in great development of drug delivery technologies that use physical methods to overcome the barrier properties of oral mucosae. AREAS COVERED: This review discusses the various physical techniques which have been, and are being, explored to sustain drug delivery in the oral cavity. In particular, supersaturation, eutectic formation, iontophoresis, electroporation, sonophoresis, laser radiation, photomechanical waves and needleless injection are considered. Following a careful selection of the most appropriate site and technique, in agreement with local variations of the oral mucosal permeability features, physical methods to promote drug delivery can improve treatment of diseases. EXPERT OPINION: Although physical methods are very promising to promote drug delivery through keratinized epithelial tissues, they are not extensively used on the oral cavity mucosae. The authors feel that, in the near future, these methods could be further developed to provide noninvasive and convenient means for locoregional/systemic delivery of drugs with poor bioavailability profile, short half-life and multiple doses scheduling. This review will help the readers in the selection of a suitable physical method for improving drug delivery in the oral cavity for future chances. The authors imagine that new formulations or devices will be marketed in the coming years. PMID- 23802559 TI - Cortical murine neurons lacking the neurofilament light chain protein have an attenuated response to injury in vitro. AB - Neurofilaments (NFs) have been proposed to have a significant role in attempted axonal regeneration following a variety of forms of injury. The NF triplet proteins of the central nervous system are comprised of light (NF-L), medium (NF M) and heavy (NF-H) chains and are part of the type IV intermediate filament family. We sought to define the role of NF-L in the neuronal response to trauma and regeneration by examining the effect of total absence of the NF-L protein on neuronal maturation and response to axotomy. This study utilized an in vitro model comprising relatively mature cortical murine neurons derived from either wild-type embryonic (E15) mice or mice with a genetic knockout of NF-L (NF-L KO). Whilst NF-L KO neurons developed to relative maturity at a comparable rate to wild-type control neurons, NF-L KO neurons demonstrated relatively increased expression of alpha-internexin and decreased expression of NF-M. Further, we demonstrate that alpha-internexin co-immunoprecipitates with the NF binding protein NDel1 in NFL-KO cortical neurons in vitro. Following localized axotomy, NF-L KO neurons demonstrated reduced amyloid precursor protein accumulation in damaged neurites as well as a significant reduction in the number of axons regenerating (4.79+/-0.58 sprouts) in comparison to control preparations (10.47+/ 1.11 sprouts) (p<0.05). These studies indicate that NFs comprising NF-L have a dynamic role in the reactive and regenerative changes in axons following injury. PMID- 23802560 TI - Anthropometric parameters in screening for excess of adiposity in Argentinian and Spanish adolescents: evaluation using receiver operating characteristic (ROC) methodology. AB - BACKGROUND: Various anthropometric parameters have been proposed for defining overweight in adolescence, but few studies have evaluated their diagnostic accuracy in comparative terms, using samples from different regions. AIM: To compare the performance of anthropometric parameters in determining the excess of adiposity in Argentinian and Spanish adolescents. SUBJECTS AND METHODS: The sample is composed of 1781 Argentinian and 1350 Spanish subjects, aged 12-17 years. Excess adiposity was defined as percentage BF in the 90th percentile or higher. ROC curves established the validity of parameters to define excess adiposity. RESULTS: Descriptive statistics showed differences between the Argentinian and Spanish samples. ROC curves indicate that all the parameters analysed had, in the Spanish and Argentinian samples, a positive and elevated association with excess of adiposity. The waist-to-height ratio had the highest value of the area under ROC curve (AUC), while conicity index and waist-to-hip ratio had the lowest. CONCLUSIONS: Differences exist with respect to size and body composition between the Argentinian and Spanish samples. ROC curves reflect a general pattern of variation. Waist-to-hip ratio and conicity index are less desirable in the diagnosis of excess adiposity and the most desirable is waist-to height ratio. PMID- 23802561 TI - Landscape structure and diseases profile: associating land use type composition with disease distribution. AB - Human health and well-being presuppose environmental quality. Several studies have documented the indicative role of land use types in environmental quality. However, the exact role of land use composition on disease distribution has remained scientifically vague. We assessed the congruence of diseases' distribution with land use composition, focusing on high environmental quality areas, defined as tranquil areas with view to indicating places offering well being. Landscape composition is linked to the presence of diseases across 51 prefectures of Greece. Agricultural and natural land use types proved to be the main drivers of disease distribution. Tranquility demonstrated a strong negative correlation with population density, thus could be considered as a quantitative spatial index of life-quality. We concluded that the landscape context affects the dominance of diseases' patterns. Special emphasis should be put on the role of tranquil areas in human health and the relative environmental health policies. PMID- 23802562 TI - Impact of standardized information provided by gynecologists on women's choice of combined hormonal contraception. AB - This prospective interventional study was designed to determine the impact of providing standardized information on different methods of combined hormonal contraception on women's selection of which method to use. A total of 952 Brazilian gynecologists were randomly selected. Each gynecologist recruited 15 consecutive patients for whom combined hormonal contraception was indicated. Each patient was asked which contraceptive method she would prefer (pill, patch, vaginal ring or injectable) before and after receiving a standardized explanation on each of these methods provided by her doctor. A total of 9507 women were included in the study. Prior to counseling, 66.5% of the women stated that they would prefer the pill, 17.9% the injectable, 8.9% the patch and 6.7% the vaginal ring. After counseling, 53.7% of the women stated that they would prefer the pill, 16.3% the injectable, 14% the patch and 16% the ring. In conclusion, the combined pill remains the most popular contraceptive method among Brazilian women; however, after receiving information on the various contraceptive methods available, the proportion of women choosing the vaginal ring or patch increased, while preference for the combined pill decreased. PMID- 23802563 TI - GnRH agonist versus GnRH antagonist in ovarian stimulation: the role of elevated peak serum progesterone levels. AB - AIM: We sought to evaluate the influence of subtle serum progesterone elevation on in vitro fertilization (IVF) cycle outcome and to assess the impact of the type of gonadotropin-releasing hormone (GnRH)-analogue used during controlled ovarian hyperstimulation (COH) on the probability of clinical pregnancy. PATIENTS AND METHODS: We reviewed the files of all consecutive patients undergoing COH with either GnRH-agonist or antagonist in our IVF unit during a 10-year period and who had their peak serum progesterone levels determined on the day of human chorionic gonadotropin (hCG) administration. RESULTS: Of the 2244 IVF cycles evaluated, 2103 had peak progesterone level of <1.5 ng/mL (normal-P group) and 141 of >1.5 ng/mL (high-P group) (6.28% of all the study population). Clinical pregnancy rate was significantly higher in the normal-P group (25.4% versus 16.6%; p < 0.006). Moreover, among the high-P group patients, the use of the long GnRH-agonist suppressive protocol (GnRH-ag) was more prevalent in patients who conceived as compared to those who did not (60.9% versus 39%, respectively; p < 0.05), with a tendency toward an increase pregnancy rate in those using GnRH-ag compared with GnRH-antagonist protocol (GnRH-antag; p < 0.059) COH protocols. CONCLUSION: While subtle progesterone elevation in patients undergoing COH using GnRH-antag COH protocols, should dictate embryo cryopreservation and cancelation of the fresh transfer, in those undergoing the GnRH-ag COH protocol, a fresh embryo transfer should be recommended. PMID- 23802564 TI - Relative free enthalpies for point mutations in two proteins with highly similar sequences but different folds. AB - Enveloping distribution sampling was used to calculate free-enthalpy changes associated with single amino acid mutations for a pair of proteins, GA95 and GB95, that show 95% sequence identity yet fold into topologically different structures. Of the L -> A, I -> F, and L -> Y mutations at positions 20, 30, and 45, respectively, of the 56-residue sequence, the first and the last contribute the most to the free-enthalpy difference between the native and non-native sequence-structure combinations, in agreement with the experimental findings for this protein pair. The individual free-enthalpy changes are almost sequence independent in the four-strand/one-helix structure, the stable form of GB95, while in the three-helix bundle structure, the stable form of GA95, an interplay between residues 20 and 45 is observed. PMID- 23802565 TI - Proteogenomic database construction driven from large scale RNA-seq data. AB - The advent of inexpensive RNA-seq technologies and other deep sequencing technologies for RNA has the promise to radically improve genomic annotation, providing information on transcribed regions and splicing events in a variety of cellular conditions. Using MS-based proteogenomics, many of these events can be confirmed directly at the protein level. However, the integration of large amounts of redundant RNA-seq data and mass spectrometry data poses a challenging problem. Our paper addresses this by construction of a compact database that contains all useful information expressed in RNA-seq reads. Applying our method to cumulative C. elegans data reduced 496.2 GB of aligned RNA-seq SAM files to 410 MB of splice graph database written in FASTA format. This corresponds to 1000* compression of data size, without loss of sensitivity. We performed a proteogenomics study using the custom data set, using a completely automated pipeline, and identified a total of 4044 novel events, including 215 novel genes, 808 novel exons, 12 alternative splicings, 618 gene-boundary corrections, 245 exon-boundary changes, 938 frame shifts, 1166 reverse strands, and 42 translated UTRs. Our results highlight the usefulness of transcript + proteomic integration for improved genome annotations. PMID- 23802566 TI - Mia40 and MINOS act in parallel with Ccs1 in the biogenesis of mitochondrial Sod1. AB - Superoxide dismutase 1 (Sod1) is a major superoxide-scavenging enzyme in the eukaryotic cell, and is localized in the cytosol and intermembrane space of mitochondria. Sod1 requires its specific chaperone Ccs1 and disulfide bond formation in order to be retained in the intermembrane space. Our study identified a pool of Sod1 that is present in the reduced state in mitochondria that lack Ccs1. We created yeast mutants with mutations in highly conserved amino acid residues corresponding to human mutations that cause amyotrophic lateral sclerosis, and found that some of the mutant proteins were present in the reduced state. These mutant variants of Sod1 were efficiently localized in mitochondria. Localization of the reduced, Ccs1-independent forms of Sod1 relied on Mia40, an essential component of the mitochondrial intermembrane space import and assembly pathway that is responsible for the biogenesis of intermembrane space proteins. Furthermore, the mitochondrial inner membrane organizing system (MINOS), which is responsible for mitochondrial membrane architecture, differentially modulated the presence of reduced Sod1 in mitochondria. Thus, we identified novel mitochondrial players that are possibly involved in pathological conditions caused by changes in the biogenesis of Sod1. PMID- 23802567 TI - MiR-492 impairs the angiogenic potential of endothelial cells. AB - Endothelial cells growing in high glucose-containing medium show reduced cell proliferation and in vitro angiogenesis. Evidence suggests that the molecular pathways leading to these cellular responses are controlled by microRNAs, endogenous post-transcriptional regulators of gene expression. To identify the microRNAs and their targeted genes involved in the glucose responses, we performed the miRNA signature of Human Umbelical Vein Endothelial Cells (HUVECs) exposed and unexposed to high glucose. Among differentially expressed microRNAs, we analysed miR-492 and showed that its overexpression was able to reduce proliferation, migration and tube formation of HUVEC. These effects were accompanied by the down-regulation of eNOS, a key regulator of the endothelial cell function. We showed that eNOS was indirectly down-regulated by miR-492 and we discovered that miR-492 was able to bind mRNAs involved in proliferation, migration, tube formation and regulation of eNOS activity and expression. Moreover, we found that miR-492 decreased VEGF expression in HUVEC and impaired in vivo angiogenesis in a tumour xenograft model, suggesting a role also in modulating the secretion of pro-angiogenic factors. Taken together, the data indicate that miR-492 exerts a potent anti-angiogenic activity in endothelial cells and therefore miR-492 seems a promising tool for anti-angiogenic therapy. PMID- 23802568 TI - Effect of topical naltrexone 0.3% on corneal sensitivity and tear parameters in normal brachycephalic dogs. AB - OBJECTIVE: To determine the effect of topical naltrexone 0.3% on tear production, corneal sensitivity, and tear film stability in normal brachycephalic dogs. ANIMALS STUDIED: Twenty-two normal brachycephalic dogs. PROCEDURES: Measurements of tear production (Schirmer tear test I and II), intraocular pressure (IOP), central corneal sensitivity (CS), and tear film breakup time (TFBUT) were collected at time 0, 1, and 24 h after administration of either naltrexone (NTX) 0.3% or placebo (SV). Naltrexone or SV was then administered once daily for 1 week, and the above measurements were repeated at 7 days, then again 7 days after discontinuing medication. Owners scored the degree of comfort, redness, rubbing, squinting, and tearing. Serum was collected at time 0, 1, 24 h, and 7 days to determine systemic concentrations. RESULTS: Owners reported no significant change in the degree of comfort, redness, rubbing, squinting, or tearing. Naltrexone was detected in serum of all treated dogs 1-h postadministration (average: 908 pg/mL, range: 319-1570 pg/mL) and in two dogs at the 1-week time point. Naltrexone was not detected at the 24-h time point. There was no significant effect of NTX on STT1, STT2, IOP, CS, or TFBUT. CONCLUSIONS: Naltrexone 0.3% is well tolerated and safe when applied topically to the eye once daily. Naltrexone 0.3% did not show any significant effects on corneal parameters as measured in this study. At once, daily dosing NTX is systemically absorbed; however, the degree of systemic absorption is not likely to be clinically significant. PMID- 23802569 TI - Etanercept decreases the innate immune wounding response in psoriasis. AB - Cathelicidin is increased when normal skin is injured and in psoriasis lesions where it has been suggested to play a pivotal role in inflammation through interactions with self-DNA and toll-like receptor 9 (TLR-9) in keratinocytes and plasmacytoid dendritic cells. Because of etanercept's success in treating psoriasis, we hypothesized that etanercept may suppress TLR-9 and cathelicidin induction. Examination of experimentally induced wounds of psoriatic lesional and non-lesional skin, and comparison with wounded normal skin, shows that the induction of cathelicidin and TLR-9 is greatly enhanced in lesional psoriatic skin. Six weeks of etanercept appears not to affect the baseline expression of cathelicidin or TLR-9, but does blunt the induction of cathelicidin in psoriasis with wounding. These findings support the role of cathelicidin in the enhancement of local inflammation in psoriasis and may partially explain one of the mechanisms enabling TNF-alpha inhibitors to successfully treat this disorder. PMID- 23802571 TI - Effects of predation pressure and resource use on morphological divergence in omnivorous prey fish. AB - BACKGROUND: Body shape is one of the most variable traits of organisms and responds to a broad array of local selective forces. In freshwater fish, divergent body shapes within single species have been repeatedly observed along the littoral-pelagic axes of lakes, where the structural complexity of near shore habitats provides a more diverse set of resources compared to the open-water zones. It remains poorly understood whether similar resource-driven polymorphism occurs among lakes that vary in structural complexity and predation pressure, and whether this variation is heritable. Here, we analyzed body shape in four populations of omnivorous roach (Rutilus rutilus) inhabiting shallow lakes. We tested the relationship between body shape, gradients of resources, predation pressure, and, in a subset of two lakes, diet composition. We used genome scans of 331 polymorphic AFLP markers to test whether there was a heritable component to the observed morphological diversification. RESULTS: Body shape differed among lakes and was significantly correlated to differences in predation pressure. Roach from the lake with highest predation pressure were most divergent from the average body shape of all populations, characterized by a more streamlined body and caudally inserted dorsal fins; features that facilitate predator escape. Surprisingly, diet composition was not associated with morphology. AFLP analysis revealed weak genetic differentiation among lakes and no isolation by distance (IBD). Outlier analysis detected three loci under positive selection with differing frequencies in the four populations. General linear models did not support an association of lake-specific genotypes with morphological variation. CONCLUSION: Body shape was divergent among lakes, suggesting that processes previously reported from within single lakes may also be operating at the scale of whole lakes. We found no evidence for body shape being heritable, although sample size was small in these natural populations. Rather than habitat structure and diet, we conclude that predation had a stronger effect on the prevalence of local morphotypes. A variable morphotype facilitating the efficient uptake of a variety of spatially and temporarily scattered resources seems to be favored in these small aquatic systems. PMID- 23802570 TI - The mobility of two kinase domains in the Escherichia coli chemoreceptor array varies with signalling state. AB - Motile bacteria sense their physical and chemical environment through highly cooperative, ordered arrays of chemoreceptors. These signalling complexes phosphorylate a response regulator which in turn governs flagellar motor reversals, driving cells towards favourable environments. The structural changes that translate chemoeffector binding into the appropriate kinase output are not known. Here, we apply high-resolution electron cryotomography to visualize mutant chemoreceptor signalling arrays in well-defined kinase activity states. The arrays were well ordered in all signalling states, with no discernible differences in receptor conformation at 2-3 nm resolution. Differences were observed, however, in a keel-like density that we identify here as CheA kinase domains P1 and P2, the phosphorylation site domain and the binding domain for response regulator target proteins. Mutant receptor arrays with high kinase activities all exhibited small keels and high proteolysis susceptibility, indicative of mobile P1 and P2 domains. In contrast, arrays in kinase-off signalling states exhibited a range of keel sizes. These findings confirm that chemoreceptor arrays do not undergo large structural changes during signalling, and suggest instead that kinase activity is modulated at least in part by changes in the mobility of key domains. PMID- 23802572 TI - Curcumin induces apoptosis in gallbladder carcinoma cell line GBC-SD cells. AB - BACKGROUND: Gallbladder carcinoma is a malignant tumor with a very low 5-year survival rate because of the difficulty with its early diagnosis and the very poor prognosis of the advanced cancer state. The aims of this study were to determine whether curcumin could induce the apoptosis of a gallbladder carcinoma cell line, GBC-SD, and to clarify its related mechanism. METHODS: First, the anti proliferative activities of curcumin-treated and untreated GBC-SD cells were determined using the MTT and colony formation assays. Then, the early apoptosis of cells was detected by the annexin V/propidium iodide double-staining assay and Hoechst 33342 staining assay. Detection of mitochondrial membrane potential was used to validate the ability of curcumin on inducing apoptosis in GBC-SD cells. Cell cycle changes were detected by flow cytometric analysis. Finally, the expressions of the apoptosis-related proteins or genes caspase-3, PARP, Bcl-2, and Bax were analyzed by western blot and quantitative real time PCR assay. Statistical analyses were performed using the Student's t-test for comparison of the results obtained from cells with or without curcumin treatment. RESULTS: The MTT assay revealed that curcumin had induced a dose- and a time-dependent decrease in cell viability. Colony counting indicated that curcumin had induced a dose-dependent decrease in the colony formation ability in GBC-SD cells. Cells treated with curcumin were arrested at the S phase, according to the flow cytometric analysis. A significant induction of both the early and late phases of apoptosis was shown by the annexin V-FITC and PI staining. Morphological changes in apoptotic cells were also found by the Hoechst 33342 staining. After treatment with curcumin fluorescence shifted from red to green as DeltaPsim decreased. Furthermore, western blot and quantitative real time PCR assays demonstrated that the curcumin induced apoptosis in GBC-SD cells by regulating the ratio of Bcl 2/Bax and activating the expression of cleaved caspase-3. CONCLUSIONS: Taken together, the results indicate that curcumin may be a potential agent for the treatment of gallbladder cancer. PMID- 23802573 TI - Strategies to improve recovery in acute ischemic stroke patients: Iberoamerican Stroke Group Consensus. AB - Stroke is not only a leading cause of death worldwide but also a main cause of disability. In developing countries, its burden is increasing as a consequence of a higher life expectancy. Whereas stroke mortality has decreased in developed countries, in Latin America, stroke mortality rates continue to rise as well as its socioeconomic dramatic consequences. Therefore, it is necessary to implement stroke care and surveillance programs to better describe the epidemiology of stroke in these countries in order to improve therapeutic strategies. Advances in the understanding of the pathogenic processes of brain ischemia have resulted in development of effective therapies during the acute phase. These include reperfusion therapies (both intravenous thrombolysis and interventional endovascular approaches) and treatment in stroke units that, through application of management protocols directed to maintain homeostasis and avoid complications, helps to exert effective brain protection that decreases further cerebral damage. Some drugs may enhance protection, and besides, there is increasing knowledge about brain plasticity and repair mechanisms that take place for longer periods beyond the acute phase. These mechanisms are responsible for recovery in certain patients and are the focus of basic and clinical research at present. This paper discusses recovery strategies that have demonstrated clinical effect, or that are promising and need further study. This rapidly evolving field needs to be carefully and critically evaluated so that investment in patient care is grounded on well-proven strategies. PMID- 23802574 TI - Rhodium-catalyzed C3-selective alkenylation of substituted thiophene-2-carboxylic acids and related compounds. AB - The regioselective C3-alkenylation of thiophene-2-carboxylic acids can be achieved effectively via rhodium/silver-catalyzed oxidative coupling with alkenes, unaccompanied by decarboxylation. A wide range of substrates including brominated thiophenecarboxylic acids and furan-2-carboxylic acids can be employed together with styrenes as well as acrylates. The present catalyst system is also applicable to ortho-alkenylation of benzoic acids. PMID- 23802575 TI - Transdermal nicotine patches for eosinophilic pustular folliculitis. AB - We previously reported the clinical effectiveness of transdermal nicotine patches for the treatment of skin disorders with eosinophilic infiltration such as Kimura's disease, erythema nodosum and eosinophilic pustular folliculitis (EPF). We assessed the efficacy and safety of transdermal nicotine patches for EPF. We treated eight patients with EPF with transdermal nicotine patches and evaluated the treatment response by performing overall lesional assessment. Excellent 77and good responses were obtained in five and one patient(s), respectively. In the other two patients, the lesions remained unchanged. No severe adverse effects were observed. Our results suggest that transdermal nicotine patches may be useful and safe in the treatment of EPF. PMID- 23802576 TI - Electrospun Sb/C fibers for a stable and fast sodium-ion battery anode. AB - Sodium-ion batteries (SIBs) are considered a top alternative to lithium-ion batteries (LIBs) for large-scale renewable energy storage units due to their low cost and the abundance of sodium-bearing precursors in the earth's mineral deposits. However, the development of anode materials for SIBs to date has been mainly limited to carbonaceous materials with minimal research devoted to high capacity alloy-based materials. In this study, an antimony (Sb)/carbon (C) electrode with ~30 nm Sb nanoparticles (NPs) uniformly encapsulated in interconnecting one-dimensional (1D) 400 nm carbon fibers (denoted as SbNP@C) was fabricated using a simple and scalable electrospinning method. This binder-free, current collector-free SbNP@C electrode demonstrated high capacity and stable long-term cycling performance at various current densities. The SbNP@C electrode showed an initial total capacity of 422 mAh/gelectrode and retained 350 mAh/gelectrode after 300 deep charge-discharge cycles under 100 mA/gSb. Moreover, because of the efficient 1D sodium-ion transport pathway and the highly conductive network of SbNP@C, the electrode preserved high overall capacities even when cycled at high currents, extending its usability to high power applications. PMID- 23802577 TI - African same-sex sexualities and gender-diversity: an introduction. PMID- 23802578 TI - Serum vascular adhesion protein-1 level is higher in smokers than non-smokers. AB - BACKGROUND: Semicarbazide-sensitive amine oxidase (SSAO)/vascular adhesion protein-1 (VAP-1) is involved in the pathogenesis of both atherosclerosis and cancer. Because chemical components and metabolites of cigarettes are deaminated by SSAO, the relationship between smoking and serum SSAO/VAP-1 was studied in humans. METHODS: A total of 451 non-diabetic and normoalbuminuric Han Chinese subjects were recruited to participate in this study. Smoking history was obtained by using a questionnaire and those who smoked more than 100 cigarettes during a 6-month period were considered smokers. Serum VAP-1 concentration was measured by time-resolved immunofluorometric assay. Age, gender, waist circumference and estimated glomerular filtration rate (GFR) were adjusted in different statistical models. RESULTS: Smokers were mainly male (85.7% versus 26.3%) and were more obese than non-smokers (p < 0.05). Subjects with higher serum VAP-1 concentrations were older (p < 0.001) and tended to have larger waist circumferences and lower estimated GFR. Serum VAP-1 concentration was higher in smokers than in non-smokers (p < 0.05) after adjusting for age, gender, waist circumference, estimated GFR, liver biochemistry and lipid profile. CONCLUSIONS: Cigarette smoking is associated with elevated serum VAP-1 concentration. Whether VAP-1 and its SSAO activity link the relationship between cigarette smoking, atherosclerosis and cancer requires further investigation. PMID- 23802579 TI - Effect of wind on the chemical uptake kinetics of a passive air sampler. AB - Passive air samplers (PASs) operate in different types of environment under various wind conditions, which may affect sampling rates and thus introduce uncertainty to PAS-derived air concentrations. To quantify the effect of wind speed and angle on the uptake in cylindrical PASs using XAD-resin as the sampling medium, we measured the uptake kinetics of polychlorinated biphenyls (PCBs) in XAD and of water in silica-gel, both under quasi wind-still condition and with lab-generated wind blowing toward the PASs at various speeds and angles. Passive sampling rates (PSRs) of PCBs under laboratory generated windy conditions were approximately 3-4 times higher than under wind-still indoor conditions. The rate of water uptake by silica-gel increased with wind speed, following a logarithmic function so that PSRs are more strongly influenced at lower wind speed. PSRs of both PCBs and water varied little with wind angle, which is consistent with computational fluid dynamic simulations showing that different angles of wind incidence cause only minor variations of air velocities within the cylindrical sampler housing. Because modifications of the design of the cylindrical PAS were not successful in eliminating the wind speed dependence of PSRs at low wind levels, indoor and outdoor deployments require different sets of PSRs. The effect of wind speed and angle on the PSRs of the cylindrical PAS are much smaller than what has been reported for the double-bowl polyurethane foam PAS. PSRs of the cylindrical XAD-PAS therefore tend to vary much less between sampling sites exposed to different wind conditions. PMID- 23802581 TI - Is the onset of disabling chronic conditions in later childhood associated with exposure to social disadvantage in earlier childhood? A prospective cohort study using the ONS Longitudinal Study for England and Wales. AB - BACKGROUND: The aetiology of disabling chronic conditions in childhood in high income countries is not fully understood, particularly the association with socio economic status (SES). Very few studies have used longitudinal datasets to examine whether exposure to social disadvantage in early childhood increases the risk of developing chronic conditions in later childhood. Here we examine this association, and its temporal ordering, with onset of all-cause disabling chronic later childhood in children reported as free from disability in early childhood. METHODS: The study comprised a prospective cohort study, using data from the Office for National Statistics Longitudinal Study (ONSLS) for England and Wales. The study sample included 52,839 children with complete data born between 1981 1991 with no disabling chronic condition/s in 1991. Index cases were children with disability recorded in 2001. Comparison cases were children with no recorded disability in 1991. A socio-economic disadvantage index (SDI) was constructed from data on social class, housing tenure and car/van access. Associations were explored with logistic regression modelling controlling sequentially for potentially confounding factors; age, gender, ethnicity and lone parenthood. RESULTS: By 2001, 2049 (4%) had at least one disability. Socio-economic disadvantage, age, gender and lone parenthood but not ethnicity were significantly associated with onset of disabling chronic conditions. The SDI showed a finely graded association with onset of disabling chronic conditions in the index group (most disadvantaged OR 2.11 [CI 1.76 to 2.53]; disadvantaged in two domains OR 1.45 [CI 1.20 to 1.75]; disadvantaged in one domain OR 1.14 [CI 0.93 to 1.39] that was unaffected by age, gender and ethnicity and slightly attenuated by lone parenthood. CONCLUSION: To our knowledge, this is the first study to identify socio-economic disadvantage in earlier childhood as a predisposing factor for onset of all-cause disabling chronic conditions in later childhood. Temporal ordering and gradation of the response indicate socio economic disadvantage may play a causal role. This suggests that targeting preventative efforts to reduce socio-economic disadvantage in early childhood is likely to be an important public health strategy to decease health inequalities in later childhood and early adulthood. PMID- 23802580 TI - Rho kinase inhibition in diabetic kidney disease. AB - Small GTPases of the Rho family and their down-stream effectors Rho associated kinases (ROCKs) are the molecules that converge a spectrum of pathophysiological signals triggered by the diabetic milieu and represent promising molecular targets for nephroprotective treatment in diabetes. The review discusses recent studies exploring the consequences of diabetes-induced Rho-ROCK activation in the kidney and the effects of ROCK inhibition (ROCKi) in experimental diabetic kidney disease (DKD). Studies in models of type 1 and type 2 diabetes have indicated blood pressure-independent nephroprotective actions of ROCKi in DKD. The underlying mechanisms include attenuation of diabetes-induced increases in renal expression of prosclerotic cytokines and extracellular matrix, anti-oxidant effects and protection of mitochondrial function, resulting in slower development of glomerulosclerosis and interstitial fibrosis. The studies have also shown antiproteinuric effects of ROCKi that could be related to reductions in permeability of the glomerular barrier and beneficial effects on podocytes. Glomerular haemodynamic mechanisms might also be involved. Despite remaining questions in this field, such as the effects in podocytes later in the course of DKD, specificity of currently available ROCKi, or the roles of individual ROCK isoforms, recent evidence in experimental diabetes suggests that ROCKi might in future broaden the spectrum of treatments available for patients with DKD. This is supported by the evidence generated in models of non-diabetic kidney disease and in clinical studies in patients with various cardiovascular disorders. PMID- 23802582 TI - Comparing the characteristics of snowboarders injured in a terrain park who present to the ski patrol, the emergency department or both. AB - Ski patrol report forms are a common data source in ski/snowboard research, but it is unclear if those who only present to the emergency department (ED) are systematically different from those who see the ski patrol. To determine the proportion and characteristics of injured snowboarders who bypass the ski patrol before presenting to the ED, three groups of injured snowboarders were compared: presented to the ED only, ski patrol only and ski patrol and ED. Data were collected from ski patrol Accident Report Forms (ARFs), ED medical records and telephone interviews. There were 333 injured snowboarders (ED only: 34, ski patrol only: 107, both: 192). Ability, time of day, snow conditions or drugs/alcohol predicted ED only presentation. Concussions (RRR: 4.66; 95% CI: 1.83, 11.90), sprains/strains (RRR: 4.22; 95% CI: 1.87, 9.49), head/neck (RRR: 2.90; 95% CI: 1.48, 5.78), trunk (RRR: 4.17; 95% CI: 1.92, 9.09) or lower extremity (RRR: 3.65; 95% CI: 1.32, 10.07) injuries were significantly more likely to present to ski patrol only versus ski patrol and ED. In conclusion, snowboarders who presented to the ED only had similar injuries as those who presented to both. PMID- 23802583 TI - Both species sorting and neutral processes drive assembly of bacterial communities in aquatic microcosms. AB - A focus of ecology is to determine drivers of community assembly. Here, we investigate effects of immigration and species sorting (environmental selection) on structuring aquatic bacterial communities in both colonised and previously uncolonised environments. We used nonsterilised and presterilised water from three chemically distinct ponds to establish microcosms, which were opened for 12, 24, 48, 96 or 167 h and then closed again to allow airborne bacterial immigration and subsequent succession. Community similarity, richness, evenness and the parameters of a neutral model were investigated after 167 h. Immigration appeared to govern the assembly of communities in the presterilised water as there were no significant differences in evenness among microcosm communities containing water from each pond. Statistical estimation of neutral model parameters confirmed these findings, because the estimated immigration rate changed significantly with time of exposure to immigration. Species sorting also occurred because significant differences in community similarity (for presterilised and nonsterilised communities) and evenness (only for nonsterilised communities) were detected among microcosms containing different pond water; the magnitude of these differences was greater for communities in nonsterilised microcosms. Our study provides evidence for both processes being important during the colonisation of aquatic environments and presents a novel way to apply the neutral model. PMID- 23802584 TI - Artificial neural network is highly predictive of outcome in paediatric acute liver failure. AB - Current prognostic models in PALF are unreliable, failing to account for complex, non-linear relationships existing between multiple prognostic factors. A computational approach using ANN should provide superior modelling to PELD-MELD scores. We assessed the prognostic accuracy of PELD-MELD scores and ANN in PALF in children presenting to the QLTS, Australia. A comprehensive registry-based data set was evaluated in 54 children (32M, 22F, median age 17 month) with PALF. PELD-MELD scores calculated at (i) meeting PALF criteria and (ii) peak. ANN was evaluated using stratified 10-fold cross-validation. Outcomes were classified as good (transplant-free survival) or poor (death or LT) and predictive accuracy compared using AUROC curves. Mean PELD-MELD scores were significantly higher in non-transplanted non-survivors (i) 37 and (ii) 46 and transplant recipients (i) 32 and (ii) 43 compared to transplant-free survivors (i) 26 and (ii) 30. Threshold PELD-MELD scores >=27 and >=42, at meeting PALF criteria and peak, gave AUROC 0.71 and 0.86, respectively, for poor outcome. ANN showed superior prediction for poor outcome with AUROC 0.96, sensitivity 82.6%, specificity 96%, PPV 96.2% and NPV 85.7% (cut-off 0.5). ANN is superior to PELD-MELD for predicting poor outcome in PALF. PMID- 23802585 TI - Development and optimization of polymeric nanoparticles of antitubercular drugs using central composite factorial design. AB - OBJECTIVE: The objective of the present study was to develop sustained release biodegradable polymeric nanoparticles (PNs) of two anti-tubercular drugs (ATDs), rifampicin (RIF) and isoniazid (INH) using circumscribed central composite factorial design (CCD) and evaluate in vivo uptake potential using rhodamine labeled PNs (RPNs). METHODS: CCD was employed to study the influence of independent formulation factors, drug:polymer ratio (D:P) and surfactant concentration (SC), on dependent physicochemical characteristics, particle size (PS), polydispersity index (PI) and percentage entrapment efficiency (%EE) of the drugs. Optimized PNs prepared using response surface methodology (RSM) were evaluated for in vitro kinetics at endosomal macrophage pH 5.2 and physiological pH 7.4 and in vivo targeting potential in peritoneal macrophages (PMs) by fluorescence microscopy (FM) and confocal laser scanning microscopy (CLSM). RESULTS: Optimized PNs exhibited spherical and porous surface with a mean PS of 202 nm, PI of 0.178, zeta potential of -25.49 mV and %EE of 76.12% and 54.25% for RIF and INH, respectively. CONCLUSIONS: Highly hydrophilic INH could be encapsulated with lypophilic RIF with efficiency. In vivo uptake studies of RPNs in PMs suggested endocytosis of RPNs without any surface adsorption phenomenon. Hence, further studies need to be performed for establishing the pharmacokinetic potential of PNs. PMID- 23802586 TI - Genetic evidence for a high diversity and wide distribution of endemic strains of the pathogenic chytrid fungus Batrachochytrium dendrobatidis in wild Asian amphibians. AB - Population declines and extinctions of amphibians have been attributed to the chytrid fungus Batrachochytrium dendrobatidis (Bd), especially one globally emerging recombinant lineage ('Bd-GPL'). We used PCR assays that target the ribosomal internal transcribed spacer region (ITS) of Bd to determine the prevalence and genetic diversity of Bd in South Korea, where Bd is widely distributed but is not known to cause morbidity or mortality in wild populations. We isolated Korean Bd strains from native amphibians with low infection loads and compared them to known worldwide Bd strains using 19 polymorphic SNP and microsatellite loci. Bd prevalence ranged between 12.5 and 48.0%, in 11 of 17 native Korean species, and 24.7% in the introduced bullfrog Lithobates catesbeianus. Based on ITS sequence variation, 47 of the 50 identified Korean haplotypes formed a group closely associated with a native Brazilian Bd lineage, separated from the Bd-GPL lineage. However, multilocus genotyping of three Korean Bd isolates revealed strong divergence from both Bd-GPL and the native Brazilian Bd lineages. Thus, the ITS region resolves genotypes that diverge from Bd-GPL but otherwise generates ambiguous phylogenies. Our results point to the presence of highly diversified endemic strains of Bd across Asian amphibian species. The rarity of Bd-GPL-associated haplotypes suggests that either this lineage was introduced into Korea only recently or Bd-GPL has been outcompeted by native Bd strains. Our results highlight the need to consider possible complex interactions among native Bd lineages, Bd-GPL and their associated amphibian hosts when assessing the spread and impact of Bd-GPL on worldwide amphibian populations. PMID- 23802587 TI - Dependence of the product chain-length on detergents for long-chain E-polyprenyl diphosphate synthases. AB - Long-chain E-polyprenyl diphosphate synthases (E-PDS) catalyze repetitive addition of isopentenyl diphosphate (IPP) to the growing prenyl chain of an allylic diphosphate. The polyprenyl diphosphate products are required for the biosynthesis of ubiquinones and menaquinones required for electron transport during oxidative phosphorylation to generate ATP. In vitro, the long-chain PDSs require addition of phospholipids or detergents to the assay buffer to enhance product release and maintain efficient turnover. During preliminary assays of product chain-length with anionic, zwitterionic, and nonionic detergents, we discovered considerable variability. Examination of a series of nonionic PEG detergents with several long-chain E-PDSs from different organisms revealed that in vitro incubations with nonaethylene glycol monododecyl ether or Triton X-100 typically gave chain-lengths that corresponded to those of the isoprenoid moieties in respiratory quinones synthesized in vivo. In contrast, incubations in buffer with n-butanol, CHAPS, DMSO, n-octyl-beta-glucopyranoside, or beta cyclodextrin or in buffer without detergent typically proceeded more slowly and gave a broad range of chain-lengths. PMID- 23802588 TI - Spatial relationships in the Q fever outbreaks 2007-2010 in the Netherlands. AB - We analyzed the Q fever epidemic in the Netherlands on a national scale from a spatial point of view. Data on dairy goat farms and Dutch population, whether or not infected, were geo-referenced. Human cases were counted in GIS at different distance classes for all dairy goat farms, farms with Q fever based on BTM analysis, and farms with clinical symptoms. In all selections, human incidence decreased with increasing distances from dairy goat farms. Incidence was highest around farms with clinical symptoms. Depending on the acceptable incidence value, a dairy goat-free zone around residential areas could be defined. Cluster analyses were performed to identify local clusters of both infected farms and human cases and to identify focused clusters of human cases. Focused clusters were detected for only 14 out of 29 farms with clinical symptoms, giving rise to a new hypothesis on the transmission of Q fever. PMID- 23802589 TI - Gustatory modulation of the responses of trigeminal subnucleus caudalis neurons to noxious stimulation of the tongue in rats. AB - Certain tastants inhibit oral irritation by capsaicin, whereas anesthesia of the chorda tympani (CT) enhances oral capsaicin burn. We tested the hypothesis that tastants activate the CT to suppress responses of trigeminal subnucleus caudalis (Vc) neurons to noxious oral stimuli. In anesthetized rats, we recorded Vc unit responses to noxious electrical, chemical (pentanoic acid, 200 MUm) and thermal (55 degrees C) stimulation of the tongue. Electrically evoked responses were significantly reduced by a tastant mix and individually applied NaCl, monosodium glutamate (MSG), and monopotassium glutamate. Sucrose, citric acid, quinine and water (control) had no effect. Pentanoic acid-evoked responses were similarly attenuated by NaCl and MSG, but not by other tastants. Responses to noxious heat were not affected by any tastant. Transection and/or anesthesia of the CT bilaterally affected neither Vc neuronal responses to electrical or pentanoic acid stimulation, nor the depressant effect of NaCl and MSG on electrically evoked responses. Calcium imaging showed that neither NaCl nor MSG directly excited any trigeminal ganglion cells or affected their responses to pentanoic acid. GABA also had no effect, arguing against peripheral effects of GABA, NaCl or MSG on lingual nocicepive nerve endings. The data also rule out a central mechanism, as the effects of NaCl and MSG were intact following CT transection. We speculate that the effect is mediated peripherally by the release from taste receptor cells (type III) of some mediator(s) other than GABA to indirectly inhibit trigeminal nociceptors. The results also indicate that the CT does not exert a tonic inhibitory effect on nociceptive Vc neurons. PMID- 23802590 TI - Davallialactone from mushroom reduced premature senescence and inflammation on glucose oxidative stress in human diploid fibroblast cells. AB - Mushrooms are both food and a source of natural compounds of biopharmaceutical interest. The purpose of this study was to clarify whether davallialactone from mushroom extract affected the pathogenesis of hyperglycemia oxidative stress and the aging process in human diploid fibroblast (HDF) cells. The high-glucose state with glucose oxidase resulted in glucose oxidative stress, induction of inflammatory molecules, dysfunction of antioxidant molecules, and activation of mitogen-activated protein kinase (MAPKs) and its downstream signaling in old HDF cells. The exposure of glucose oxidative stress in middle-stage cells led to stress-induced premature senescence (SIPS) via senescence-associated beta galactosidase (SA beta-gal) activity and displayed replicative senescence phenomena. However, davallialactone reduces the pathogenesis of glucose oxidative stress and the aging process through down-regulation of SA beta-gal activity. These results strongly suggest that natural compounds, especially mushroom extract davallialactone, improve the pathogenesis of glucose oxidative stress and the aging process. Hence, davallialactone has potential in the treatment of diabetes mellitus or age-related disease complications. PMID- 23802591 TI - Mast cell activity in the healing wound: more than meets the eye? AB - Mast cells (MCs) are an important part of the innate immune system and are abundant in barrier organs such as the skin. They are known primarily for initiating allergic reactions, but many other biological functions have now been described for these cells. Studies have indicated that during wound repair, MCs enhance acute inflammation, stimulate reepithelialization and angiogenesis, and promote scarring. MCs have also been linked to abnormal healing, with high numbers of MCs observed in chronic wounds, hypertrophic scars and keloids. Although MCs have gained attention in the wound healing field, several unique features of MCs have yet to be examined in the context of cutaneous repair. These include the ability of MCs to: (i) produce anti-inflammatory mediators; (ii) release mediators without degranulating; and (iii) change their phenotype. Recent findings highlight the complexity of MCs and suggest that more information is needed to understand their complete range of activities during repair. PMID- 23802592 TI - Effect of MK-467 on organ blood flow parameters detected by contrast-enhanced ultrasound in dogs treated with dexmedetomidine. AB - OBJECTIVE: To evaluate the dexmedetomidine-induced reduction in organ blood flow with quantitative contrast-enhanced ultrasound (CEUS) method and to observe the influence of MK-467 on such reduction. STUDY DESIGN: Randomized cross-over study. ANIMALS: Six adult purpose-bred laboratory beagle dogs (mean body weight 15.3 +/- 1.9 kg). METHODS: Contrast-enhanced ultrasound was performed on six conscious healthy laboratory beagles. The animals on separate occasions underwent three treatments: awake without any medication (CTRL), dexmedetomidine 10 MUg kg(-1) (DEX) and DEX + MK-467 500 MUg kg(-1) (DMK) intravenously (IV). The kidney (10-15 minutes post-treatment), spleen (25-30 minutes post-treatment), small intestine (40-45 minutes post-treatment) and liver (50-55 minutes post-treatment) were examined with CEUS. A time curve was generated and the following perfusion parameters were analysed: arrival time (AT), time to peak from injection (TTPinj), peak intensity (PI) and wash-in rate (Wi). In addition to CEUS, renal glomerular filtration rate was indirectly estimated by the rate of iohexol elimination. RESULTS: AT and TTPinj were significantly higher for DEX than for CTRL in all studied organs. The same parameters were significantly higher for DEX than for DMK in the kidney, spleen and small intestine. PI was significantly lower for DEX than for CTRL or DMK in the kidney. Wi was significantly lower for DEX than for CTRL or DMK in the kidney and significantly lower than for CTRL only in the small intestine. Plasma concentration of iohexol was significantly higher after DEX than CTRL administration. CONCLUSIONS: Contrast-enhanced ultrasound was effective in detecting DEX-induced changes in blood flow. MK-467 attenuated these changes. CLINICAL RELEVANCE: Clinicians should consider the effects of the sedation protocol when performing CEUS. Addition of MK-467 might beneficially impact the haemodynamic function of sedation with alpha-2 adrenoceptor agonists. PMID- 23802593 TI - Electromagnetic fields act via activation of voltage-gated calcium channels to produce beneficial or adverse effects. AB - The direct targets of extremely low and microwave frequency range electromagnetic fields (EMFs) in producing non-thermal effects have not been clearly established. However, studies in the literature, reviewed here, provide substantial support for such direct targets. Twenty-three studies have shown that voltage-gated calcium channels (VGCCs) produce these and other EMF effects, such that the L type or other VGCC blockers block or greatly lower diverse EMF effects. Furthermore, the voltage-gated properties of these channels may provide biophysically plausible mechanisms for EMF biological effects. Downstream responses of such EMF exposures may be mediated through Ca(2+) /calmodulin stimulation of nitric oxide synthesis. Potentially, physiological/therapeutic responses may be largely as a result of nitric oxide-cGMP-protein kinase G pathway stimulation. A well-studied example of such an apparent therapeutic response, EMF stimulation of bone growth, appears to work along this pathway. However, pathophysiological responses to EMFs may be as a result of nitric oxide peroxynitrite-oxidative stress pathway of action. A single such well-documented example, EMF induction of DNA single-strand breaks in cells, as measured by alkaline comet assays, is reviewed here. Such single-strand breaks are known to be produced through the action of this pathway. Data on the mechanism of EMF induction of such breaks are limited; what data are available support this proposed mechanism. Other Ca(2+) -mediated regulatory changes, independent of nitric oxide, may also have roles. This article reviews, then, a substantially supported set of targets, VGCCs, whose stimulation produces non-thermal EMF responses by humans/higher animals with downstream effects involving Ca(2+) /calmodulin-dependent nitric oxide increases, which may explain therapeutic and pathophysiological effects. PMID- 23802594 TI - Effects of changing mosquito host searching behaviour on the cost effectiveness of a mass distribution of long-lasting, insecticidal nets: a modelling study. AB - BACKGROUND: The effectiveness of long-lasting, insecticidal nets (LLINs) in preventing malaria is threatened by the changing biting behaviour of mosquitoes, from nocturnal and endophagic to crepuscular and exophagic, and by their increasing resistance to insecticides. METHODS: Using epidemiological stochastic simulation models, we studied the impact of a mass LLIN distribution on Plasmodium falciparum malaria. Specifically, we looked at impact in terms of episodes prevented during the effective life of the batch and in terms of net health benefits (NHB) expressed in disability adjusted life years (DALYs) averted, depending on biting behaviour, resistance (as measured in experimental hut studies), and on pre-intervention transmission levels. RESULTS: Results were very sensitive to assumptions about the probabilistic nature of host searching behaviour. With a shift towards crepuscular biting, under the assumption that individual mosquitoes repeat their behaviour each gonotrophic cycle, LLIN effectiveness was far less than when individual mosquitoes were assumed to vary their behaviour between gonotrophic cycles. LLIN effectiveness was equally sensitive to variations in host-searching behaviour (if repeated) and to variations in resistance. LLIN effectiveness was most sensitive to pre intervention transmission level, with LLINs being least effective at both very low and very high transmission levels, and most effective at around four infectious bites per adult per year. A single LLIN distribution round remained cost effective, except in transmission settings with a pre-intervention inoculation rate of over 128 bites per year and with resistant mosquitoes that displayed a high proportion (over 40%) of determined crepuscular host searching, where some model variants showed negative NHB. CONCLUSIONS: Shifts towards crepuscular host searching behaviour can be as important in reducing LLIN effectiveness and cost effectiveness as resistance to pyrethroids. As resistance to insecticides is likely to slow down the development of behavioural resistance and vice versa, the two types of resistance are unlikely to occur within the same mosquito population. LLINs are likely cost effective interventions against malaria, even in areas with strong resistance to pyrethroids or where a large proportion of host-mosquito contact occurs during times when LLIN users are not under their nets. PMID- 23802595 TI - Carbon anhydrase IX specific immune responses in patients with metastatic renal cell carcinoma potentially cured by interleukin-2 based immunotherapy. AB - The majority of clear-cell renal cell carcinomas (ccRCC) show high and homogeneous expression levels of the tumor associated antigen (TAA) carbonic anhydrase IX (CAIX), and treatment with interleukin-2 (IL-2) based immunotherapy can lead to cure in patients with metastatic renal cell carcinoma (mRCC). However, the involvement of CAIX specific CD8+ T cells and/or NK cells in the tumor eradication is unknown. We investigated T cell and antibody reactivity against overlapping 15-mer CAIX-peptides as well as HLA haplotype frequency and NK cell cytotoxicity in 11 patients with no evidence of disease (NED) following treatment with IL-2 based immunotherapy, and thus potentially cured. Immune reactivity in these patients was compared with samples from patients with dramatic tumor response obtained immediately at the cessation of therapy, samples from patients that experienced progressive disease during treatment and samples from healthy controls. We observed more focused but only weak and not consistent CAIX specific T-cells in the late observation and early observation response groups compared with the healthy control group. An increased frequency of the class II alleles HLA-DRB4 01:01, HLA-DPB 01:01 and HLA-DPB 03:01 was noted in the NED patients. In contrast, NK cytotoxicity was low even in the late observation response group as compared with controls. In particular, a HLA-B*40:01 restricted CD8+ T cell response recognizing the CAIX- derived peptide SEEEGSLKL was identified. This may have interest in future cancer vaccines, but more studies are needed to elucidate the immunological mechanisms of action in potentially cured patients treated with an immunotherapeutic agent. PMID- 23802596 TI - Perceptions of clinicians treating young people with first-episode psychosis for post-traumatic stress disorder. AB - AIM: Evidence shows that approximately half of young people with first-episode psychosis have post-traumatic stress disorder. Yet, post-traumatic stress disorder is often left untreated in the presence of psychosis. To support the development of a post-traumatic stress disorder intervention for young people with first-episode psychosis, clinicians' perceptions of trauma-focused interventions were sought. Two research questions were explored: What treatment barriers were associated with treating young people with first-episode psychosis? What supports would be useful to implement post-traumatic stress disorder intervention? METHODS: A mixed-methods design incorporated quantitative and qualitative data from a questionnaire with qualitative data from two focus groups. Sixteen (of 20) case managers from an early psychosis intervention centre participated in the study (16 completed a questionnaire, eight participated in focus groups). Descriptive statistics were generated for quantitative data and qualitative material was examined using a grounded theory approach. RESULTS: The results showed that perceived barriers to delivering trauma-focused intervention were increased mental health risks for clients with psychosis, workload pressures and poor client engagement. Targeted training and formal professional guidance were thought to best scaffold an intervention. CONCLUSIONS: Post-traumatic stress disorder intervention for first-episode psychosis clients should address engagement, make safeguarded provisions for family involvement and be sufficiently paced and flexible. Trauma-focused intervention is perceived with a degree of caution, is often not prioritized, lacks institutional support and requires more targeted training. It is important to conduct further research regarding the safety of trauma interventions alongside psychosis in order to address widespread concerns. PMID- 23802598 TI - The effectiveness and safety of ultrasound-guided removal of a Mirena((r)) intrauterine system when the strings are not visible and conventional office procedures have failed. AB - Missing threads are a common complication at the time of removal of a Mirena((r)) intrauterine system (IUS). In the office setting, various different instruments have been used to retrieve the threads, such as artery forceps to grasp the threads, or hooks to ensnare them. These procedures are usually performed blindly, and they have varying degrees of success. In cases where office procedures have failed, women are referred for hysteroscopic removal. Ultrasound guidance may improve the success rate of IUS removal without the need for more invasive procedures such as hysteroscopy. AIM: To assess the effectiveness and safety of ultrasound-guided Mirena((r)) intrauterine system removal when the strings are not visible and conventional office procedures have failed. METHOD: Information on women who were referred for ultrasound-guided removal of a Mirena((r)) device when office procedures had failed was collected prospectively. RESULTS: Of the 38 cases attempted, 33 devices were successfully removed without complication. CONCLUSION: Ultrasound guidance is a useful adjunct for the removal of a Mirena((r)) intrauterine system when the strings are not visible and outpatient procedures have failed. PMID- 23802597 TI - Genome-wide association mapping of frost tolerance in barley (Hordeum vulgare L.). AB - BACKGROUND: Frost tolerance is a key trait with economic and agronomic importance in barley because it is a major component of winter hardiness, and therefore limits the geographical distribution of the crop and the effective transfer of quality traits between spring and winter crop types. Three main frost tolerance QTL (Fr-H1, Fr-H2 and Fr-H3) have been identified from bi-parental genetic mapping but it can be argued that those mapping populations only capture a portion of the genetic diversity of the species. A genetically broad dataset consisting of 184 genotypes, representative of the barley gene pool cultivated in the Mediterranean basin over an extended time period, was genotyped with 1536 SNP markers. Frost tolerance phenotype scores were collected from two trial sites, Foradada (Spain) and Fiorenzuola (Italy) and combined with the genotypic data in genome wide association analyses (GWAS) using Eigenstrat and kinship approaches to account for population structure. RESULTS: GWAS analyses identified twelve and seven positive SNP associations at Foradada and Fiorenzuola, respectively, using Eigenstrat and six and four, respectively, using kinship. Linkage disequilibrium analyses of the significant SNP associations showed they are genetically independent. In the kinship analysis, two of the significant SNP associations were tightly linked to the Fr-H2 and HvBmy loci on chromosomes 5H and 4HL, respectively. The other significant kinship associations were located in genomic regions that have not previously been associated with cold stress. CONCLUSIONS: Haplotype analysis revealed that most of the significant SNP loci are fixed in the winter or facultative types, while they are freely segregating within the un adapted spring barley genepool. Although there is a major interest in detecting new variation to improve frost tolerance of available winter and facultative types, from a GWAS perspective, working within the un-adapted spring germplasm pool is an attractive alternative strategy which would minimize statistical issues, simplify the interpretation of the data and identify phenology independent genetic determinants of frost tolerance. PMID- 23802599 TI - Critical power derived from a 3-min all-out test predicts 16.1-km road time-trial performance. AB - It has been shown that the critical power (CP) in cycling estimated using a novel 3-min all-out protocol is reliable and closely matches the CP derived from conventional procedures. The purpose of this study was to assess the predictive validity of the all-out test CP estimate. We hypothesised that the all-out test CP would be significantly correlated with 16.1-km road time-trial (TT) performance and more strongly correlated with performance than the gas exchange threshold (GET), respiratory compensation point (RCP) and VO2 max. Ten club-level male cyclists (mean+/-SD: age 33.8+/-8.2 y, body mass 73.8+/-4.3 kg, VO2 max 60+/ 4 ml.kg(-1).min(-1)) performed a 10-mile road TT, a ramp incremental test to exhaustion, and two 3-min all-out tests, the first of which served as familiarisation. The 16.1-km TT performance (27.1+/-1.2 min) was significantly correlated with the CP (309+/-34 W; r = -0.83, P<0.01) and total work done during the all-out test (70.9+/-6.5 kJ; r = -0.86, P<0.01), the ramp incremental test peak power (433+/-30 W; r = -0.75, P<0.05) and the RCP (315+/-29 W; r = -0.68, P<0.05), but not with GET (151+/-32 W; r = -0.21) or the VO2 max (4.41+/-0.25 L.min(-1); r = -0.60). These data provide evidence for the predictive validity and practical performance relevance of the 3-min all-out test. The 3-min all-out test CP may represent a useful addition to the battery of tests employed by applied sport physiologists or coaches to track fitness and predict performance in atheletes. PMID- 23802600 TI - Positioning and configuration of key atoms influence the topology of [13] macrodiolides. AB - Key atoms at specific positions along the ring govern the shape, or "topology" of a group of [13]-macrodiolides. Here we report the synthesis of these macrocycles and their characterization by functional and structural methods. The [13] macrodiolides are organized by three four-atom planar units that help to rigidify them and one hinge atom that enables the planar units to orient themselves. The driving force for the organization of the structures is the minimization of steric strain on groups attached to the key atoms. When the key atom is a stereocenter, a macrocycle with planar chirality is observed. An alternative cup like topology arises when the key atom bears two alkyl groups. Additionally, the key atoms can work in a coordinated fashion to guide one topology over another. The synthesis relied on an acylation-ring closing metathesis sequence. Rigidity was demonstrated by variable-temperature NMR experiments and diastereoselective epoxidation reactions. X-ray crystal structures of representative [13] macrodiolides served as the basis of the structural observations made. The results provide a framework for the design of new macrocycles with well-defined structures as well as for understanding some general principles that influence the topology of natural product macrocycles. PMID- 23802601 TI - The relationship between neonatal developmental status and post-natal nutritional status in Hungarian children. AB - BACKGROUND: Neonatal development may have an influence on post-natal nutritional status. Age at adiposity rebound is critical for later development of nutritional status. AIM: The objective was to analyse the relationship between neonatal development and post-natal changes in nutritional status. SUBJECTS AND METHODS: Subjects were studied in a longitudinal national survey (1980-2001) from birth (n = 6219) to 18.0 years (n = 1448). Subjects were divided into small (SGA), appropriate (AGA) and large for gestational age (LGA) sub-groups. Nutritional status was assessed by BMI. The Reed-Asefa model was fitted to the subject's serial data of BMI. RESULTS: The body parameters of the neonatal developmental sub-groups differed significantly in all studied neonatal body dimensions: the higher the intra-uterine growth rate (the slowest growth rate was assumed in the SGA, the fastest in the LGA children), the heavier the body weight, the longer the length and the bigger the BMI values found. The nutritional status of the neonatal developmental sub-groups differed significantly during the studied post natal interval: the higher the pre-natal growth rate, the better nutritional status (the larger BMI) was found after birth. CONCLUSIONS: Neonatal development influenced strongly the post-natal nutritional status of children. The results indicate that not only age at adiposity rebound but also neonatal developmental status can be used as an indicator of later obesity. PMID- 23802602 TI - Effectiveness of structured patient-clinician communication with a solution focused approach (DIALOG+) in community treatment of patients with psychosis--a cluster randomised controlled trial. AB - BACKGROUND: Large numbers of patients with psychosis have regular meetings with key clinicians in the community. There is little evidence on how these meetings should be conducted to be therapeutically effective. DIALOG, a computer mediated procedure, was shown to improve outcomes in a European multi-centre trial. DIALOG structures the patient-clinician communication and makes it patient-centred, but does not guide clinicians as to how to respond to patients' concerns. DIALOG has been further developed into DIALOG+, which uses advanced software and, additionally, provides a four step approach--based on a solution focused model- for addressing patients' concerns. We designed a cluster randomised controlled trial to test the effectiveness of DIALOG+ in improving treatment outcomes of patients with psychosis in the community. METHODS/DESIGN: Key workers are recruited from community mental health teams in East London and randomly allocated to either the intervention or control group. Out of their case loads, we identify patients with schizophrenia (F 20-29) and a moderate or lower level of subjective quality of life (MANSA score <5), who are treated according to the allocation of their key workers. Key workers in the intervention group are trained in using DIALOG+ and use it with each patient over a six-month period. Control patients rate their satisfaction with life and treatment on a tablet to control for the effect of regular ratings and the use of modern technology. We are recruiting up to 42 key workers to reach a total sample size of 180 patients. Clinical and social outcomes including costs are assessed after 3, 6 and 12 months. Primary outcome is subjective quality-of-life at 6 months. DISCUSSION: The trial aims to evaluate the effectiveness of a novel intervention (DIALOG+) which uses modern technology to support routine patient-clinician meetings in community care, makes the communication patient centred and guides patients and clinicians to address concerns. DIALOG+ is a generic and widely applicable intervention. If shown as effective, it can be used to improve outcomes of community care on a large scale, ensuring that routine encounters are therapeutically effective. DIALOG+ can also be implemented across services at relatively low additional costs. TRIAL REGISTRATION: Current Controlled Trials ISRCTN34757603. PMID- 23802604 TI - Working memory development in children with mild to borderline intellectual disabilities. AB - BACKGROUND: The purpose of the current cross-sectional study was to examine the developmental progression in working memory (WM) between the ages of 9 and 16 years in a large sample of children with mild to borderline intellectual disabilities (MBID). Baddeley's influential WM model was used as a theoretical framework. Furthermore, the relations between WM on the one hand, and scholastic skills (arithmetic and reading) on the other were examined. METHOD: One hundred and ninety-seven children with MBID between 9 and 16 years old participated in this study. All children completed several tests measuring short-term memory, WM, inhibition, arithmetic and single word reading. RESULTS: WM, visuospatial short term memory and inhibition continued to develop until around age 15 years. However verbal short-term memory showed no further developmental increases after the age of 10 years. Verbal short-term memory was associated with single word reading, whereas inhibition was associated with arithmetic. DISCUSSION: The finding that verbal short-term memory ceases to develop beyond the age of 10 years in children with MBID contrasts with results of studies involving typically developing children, where verbal short-term memory develops until around age 15 years. This relative early developmental plateau might explain why verbal short term memory is consistently considered weak in children with MBID. PMID- 23802605 TI - Two-dimensional 31P,1H NMR spectroscopic profiling of phospholipids in cheese and fish. AB - Phospholipids (PLs) comprise an important lipid class in food because of their technological use as emulsifiers and their nutritional value. This study used one dimensional (31)P NMR and two-dimensional (2D) (31)P,(1)H COSY NMR spectroscopy for the determination of the PL composition of cheese and fish after liquid liquid enrichment. This extraction step enabled the identification of 10 PLs in cheese and 9 PLs in fish by 2D (31)P,(1)H NMR. Variations in the (31)P shifts indicated differences in the fatty acids attached to the individual PLs. The total PL content in cheese fat and fish oil ranged from 0.3 to 0.4% and from 5 to 12%, respectively. Phosphatidylcholine was the most prominent PL in both matrices (up to 65%). Minor PLs (limit of detection = 4 nmol, i.e. 500 MUL of an 8 MUM solution) were identified in forms of phosphatidic acid, lysophosphatidic acid, and phosphatidylglycerol. Specific cross couplings and (1)H fine structures in the 2D (31)P,(1)H NMR spectra proved to be valuable for the assignment and verification of known and uncommon PLs in the samples. PMID- 23802606 TI - Case of granuloma annulare resolving after repetitive pricking. PMID- 23802603 TI - Use of magnetic resonance imaging in pharmacogenomics. AB - Because of the large variation in the response to psychoactive medication, many studies have attempted to uncover genetic factors that determine response. While considerable knowledge exists on the large effects of genetic polymorphisms on pharmacokinetics and plasma concentrations of drugs, effects of the concentration at the target site and pharmacodynamic effects on brain functions in disease are much less known. This article reviews the role of magnetic resonance imaging (MRI) to visualize response to medication in brain behaviour circuits in vivo in humans and assess the influence of pharmacogenetic factors. Two types of studies have been used to characterize effects of medication and genetic variation. In task-related activation studies the focus is on changes in the activity of a neural circuit associated with a specific psychological process. The second type of study investigates resting state perfusion. These studies provide an assessment of vascular changes associated with bioavailability of drugs in the brain, but may also assess changes in neural activity after binding of centrally active agents. Task-related pharmacogenetic studies of cognitive function have characterized the effects in the prefrontal cortex of genetic polymorphisms of dopamine receptors (DRD2), metabolic enzymes (COMT) and in the post-synaptic signalling cascade under the administration of dopamine agonists and antagonists. In contrast, pharmacogenetic imaging with resting state perfusion is still in its infancy. However, the quantitative nature of perfusion imaging, its non-invasive character and its repeatability might be crucial assets in visualizing the effects of medication in vivo in man during therapy. PMID- 23802608 TI - Neuropeptidergic input pathways to the circadian pacemaker center of the Madeira cockroach analysed with an improved injection technique. AB - Light entrainment pathways synchronize the circadian clock of almost all species of the animal and plant kingdom to the daily light dark cycle. In the Madeira cockroach Rhyparobia (Leucophaea) maderae, the circadian clock is located in the accessory medulla of the brain's optic lobes. The clock has abundant neuropeptides with unknown functions. Previous studies suggested that myoinhibitory peptides (MIPs), orcokinins (ORCs), and allatotropin (AT) take part in light input pathways to the circadian clock. As the sequences of AT and ORCs of R. maderae have not yet been determined, with matrix-assisted laser desorption/ionization-time of flight mass spectrometry, the respective Rhyparobia peptides were characterized. To search for light-like phase-shifting inputs to the circadian clock, Rhyparobia-MIP-1, Rhyparobia-AT, and Rhyparobia-ORC were injected at different circadian times, combined with locomotor activity assays. An improved, less invasive injection method was developed that allowed for the analysis of peptide effects within <2 weeks after injection. Rhyparobia-MIP-1 and Rhyparobia-AT injections resulted in dose-dependent monophasic phase response curves with maximum delays at the beginning of the subjective night, similar to light-dependent phase delays. In contrast to Manduca sexta-AT, Rhyparobia-AT did not phase advance locomotor activity rhythms. Only injections of Rhyparobia-ORCs resulted in a biphasic light-like phase response curve. Thus, it is hypothesized that Rhyparobia-MIP-1 and -AT are candidates for relaying light-dependent delays and/or non-photic inputs to the clock, whereas Rhyparobia-ORCs might be part of the light-entrainment pathways relaying phase delays and advances to the circadian clock of the Madeira cockroach. PMID- 23802607 TI - A novel role for coenzyme A during hydride transfer in 3-hydroxy-3-methylglutaryl coenzyme A reductase. AB - In this study, we take advantage of the ability of HMG-CoA reductase (HMGR) from Pseudomonas mevalonii to remain active while in its crystallized form to study the changing interactions between the ligands and protein as the first reaction intermediate is created. HMG-CoA reductase catalyzes one of the few double oxidation-reduction reactions in intermediary metabolism that take place in a single active site. Our laboratory has undertaken an exploration of this reaction space using structures of HMG-CoA reductase complexed with various substrate, nucleotide, product, and inhibitor combinations. With a focus in this publication on the first hydride transfer, our structures follow this reduction reaction as the enzyme converts the HMG-CoA thioester from a flat sp(2)-like geometry to a pyramidal thiohemiacetal configuration consistent with a transition to an sp(3) orbital. This change in the geometry propagates through the coenzyme A (CoA) ligand whose first amide bond is rotated 180 degrees where it anchors a web of hydrogen bonds that weave together the nucleotide, the reaction intermediate, the enzyme, and the catalytic residues. This creates a stable intermediate structure prepared for nucleotide exchange and the second reduction reaction within the HMG CoA reductase active site. Identification of this reaction intermediate provides a template for the development of an inhibitor that would act as an antibiotic effective against the HMG-CoA reductase of methicillin-resistant Staphylococcus aureus. PMID- 23802609 TI - Effect of H2S on N2O reduction and accumulation during denitrification by methanol utilizing denitrifiers. AB - Sulfide is produced in sewer networks, and previous studies suggest that sulfide in sewage could alter the activity of heterotrophic denitrification and lead to N2O accumulation during biological wastewater treatment. However, the details of this phenomenon are poorly understood. In this study, the potential inhibitory effects of sulfide on nitrate, nitrite, and N2O reduction were assessed with a methanol-utilizing denitrifying culture both prior to and after its exposure and adaptation to sulfide. Hydrogen sulfide was found to be strongly inhibitory to N2O reduction, with 50% inhibition observed at H2S concentrations of 0.04 mg H2S S/L and 0.1 mg H2S-S/L for the unadapted and adapted cultures, respectively. In comparison, both nitrate and nitrite reduction was more tolerant to H2S. A 50% inhibition of nitrite reduction was observed at approximately 2.0 mg H2S-S/L for both unadapted and adapted cultures, while no inhibition of nitrate reduction occurred at the highest H2S concentrations applied (2.0 mg H2S-S/L) to either culture. N2O accumulation was observed during nitrate and nitrite reduction by the adapted culture when H2S concentrations were above 0.5 and 0.2 mg H2S-S/L, respectively. Additionally, we reveal that hydrogen sulfide (H2S), rather than sulfide, was likely the true inhibitor of N2O reduction, and the inhibitory effect was reversible. These findings suggest that sulfide management in sewers could potentially have a significant impact on N2O emission from wastewater treatment plants. PMID- 23802611 TI - Editorial. PMID- 23802610 TI - Tobacco smoke-induced skin pigmentation is mediated by the aryl hydrocarbon receptor. AB - It is widely recognized that tobacco smoke causes skin pigmentation. No studies, however, have directly evaluated the mechanisms of the changes in smoker's skin pigmentation. In this study, when cultured with water-soluble tobacco smoke extract, the human epidermal melanocytes grew to a large size and produced more melanins. We evaluated melanocyte activation by quantifying microphthalmia associated transcription factor (MITF) expression by real-time polymerase chain reaction. MITF expression was significantly and dose-dependently increased by exposure to tobacco smoke extract. The Wnt/beta-catenin signalling pathway seemed to mediate the tobacco smoke extract-induced melanocyte activation. Immunocytochemical studies revealed that the activated melanocytes actively expressed aryl hydrocarbon receptors (AhR) around the nuclear membrane. The tobacco smoke extract-induced MITF activation was inhibited by RNA silencing of the AhR. This study provides the evidence that tobacco smoke enhances pigmentation in vitro and that the increase in pigmentation may involve beta catenin- and AhR-mediated mechanisms inside human melanocytes. PMID- 23802612 TI - Forgotten family members: the importance of siblings in early psychosis. AB - OBJECTIVE: This paper reviews the evidence on the significance of sibling inclusion in family interventions and support during early psychosis. METHOD: This narrative review presents the current research related to the importance of family work during early psychosis, the needs and developmental significance of siblings during adolescence and early adulthood, the protective effects of sibling relationships, and the characteristics of early psychosis relevant to the sibling experience. It will also review the evidence of the sibling experience in chronic physical illness and disability, as well as long-term psychotic illness. CONCLUSIONS: Despite the evidence that working with families is important during early psychosis, siblings have been largely ignored. Siblings are an important reciprocal relationship of long duration. They play an important role in development during adolescence and early adulthood. These relationships may be an underutilized protective factor due to their inherent benefits and social support. Developmental theories imply that early psychosis could negatively impact the sibling relationship and their quality of life, effecting personality development and health outcomes. The evidence shows that adolescent physical illness or disability has a significantly negative impact on the sibling's quality of life and increases the risk for the onset of mental health issues. Long-term psychotic illness also results in negative experiences for siblings. Current evidence shows that siblings in early psychosis experience psychological distress and changes in functional performance. Further research using standard measures is required to understand the impact early psychosis has on the sibling relationship and their quality of life. PMID- 23802613 TI - Rainbow: a tool for large-scale whole-genome sequencing data analysis using cloud computing. AB - BACKGROUND: Technical improvements have decreased sequencing costs and, as a result, the size and number of genomic datasets have increased rapidly. Because of the lower cost, large amounts of sequence data are now being produced by small to midsize research groups. Crossbow is a software tool that can detect single nucleotide polymorphisms (SNPs) in whole-genome sequencing (WGS) data from a single subject; however, Crossbow has a number of limitations when applied to multiple subjects from large-scale WGS projects. The data storage and CPU resources that are required for large-scale whole genome sequencing data analyses are too large for many core facilities and individual laboratories to provide. To help meet these challenges, we have developed Rainbow, a cloud-based software package that can assist in the automation of large-scale WGS data analyses. RESULTS: Here, we evaluated the performance of Rainbow by analyzing 44 different whole-genome-sequenced subjects. Rainbow has the capacity to process genomic data from more than 500 subjects in two weeks using cloud computing provided by the Amazon Web Service. The time includes the import and export of the data using Amazon Import/Export service. The average cost of processing a single sample in the cloud was less than 120 US dollars. Compared with Crossbow, the main improvements incorporated into Rainbow include the ability: (1) to handle BAM as well as FASTQ input files; (2) to split large sequence files for better load balance downstream; (3) to log the running metrics in data processing and monitoring multiple Amazon Elastic Compute Cloud (EC2) instances; and (4) to merge SOAPsnp outputs for multiple individuals into a single file to facilitate downstream genome-wide association studies. CONCLUSIONS: Rainbow is a scalable, cost-effective, and open-source tool for large-scale WGS data analysis. For human WGS data sequenced by either the Illumina HiSeq 2000 or HiSeq 2500 platforms, Rainbow can be used straight out of the box. Rainbow is available for third-party implementation and use, and can be downloaded from http://s3.amazonaws.com/jnj_rainbow/index.html. PMID- 23802614 TI - Exposure to secondhand smoke promotes sympathetic activity and cardiac muscle cachexia. AB - Recent trials demonstrated that a single brief exposure to secondhand smoke (SHS) generates acute adverse health effects. We evaluated the acute (immediately after exposure) and short-term (0.5, 1, 2, 3 and 4 h after exposure) effects of SHS on cardiac autonomic control and myocardial integrity. Nineteen adult healthy never smokers underwent a 1 h exposure to SHS at bar/restaurant levels and a 1 h control exposure. Heart rate variability (HRV), serum cotinine, and six cardiac protein markers were assessed before, during, and up to four hours following each exposure. SHS reduced the standard deviation of normal-to-normal intervals and increased cotinine levels, creatine kinase (CK)-MB, and myoglobin (p < 0.05). We conclude that acute exposure to SHS suppresses HRV and augments CK-MB and myoglobin. The SHS-induced elevations in CK-MB and myoglobin may reflect a generalized lytic state, especially of the cardiac muscle, which is apparent for at least 2 h following the SHS exposure. PMID- 23802615 TI - Evidence and characteristics of a diverse and metabolically active microbial community in deep subsurface clay borehole water. AB - The Boom Clay in Belgium is investigated in the context of geological nuclear waste disposal, making use of the High Activity Disposal Experimental Site (HADES) underground research facility. This facility, located in the Boom Clay at a depth of 225 m below the surface, offers a unique access to a microbial community in an environment, of which all geological and geochemical characteristics are being thoroughly studied. This study presents the first elaborate description of a microbial community in water samples retrieved from a Boom Clay piezometer (borehole water). Using an integrated approach of microscopy, metagenomics, activity screening and cultivation, the presence and activity of this community are disclosed. Despite the presumed low-energy environment, microscopy and molecular analyses show a large bacterial diversity and richness, tending to correlate positively with the organic matter content of the environment. Among 10 borehole water samples, a core bacterial community comprising seven bacterial phyla is defined, including both aerobic and anaerobic genera with a range of metabolic preferences. In addition, a corresponding large fraction of this community is found cultivable and active. In conclusion, this study shows the possibility of a microbial community of relative complexity to persist in subsurface Boom Clay borehole water. PMID- 23802616 TI - Outcomes of haematopoietic stem cell transplantation for inherited metabolic disorders: a report from the Australian and New Zealand Children's Haematology Oncology Group and the Australasian Bone Marrow Transplant Recipient Registry. AB - We report a retrospective analysis of 53 haematopoietic stem cell transplants for inherited metabolic disorders performed at ANZCHOG transplant centres between 1992 and 2008. Indications for transplant included Hurler syndrome, ALD, and MLD. The majority of transplants utilized unrelated donor stem cells (66%) with 65% of those being unrelated cord blood. Conditioning therapy was largely myeloablative, with Bu plus another cytotoxic agent used in 89% of recipients. Primary graft failure was rare, occurring in three patients, all of whom remain long-term survivors following the second transplant. The CI of grade II-IV and grade III-IV acute GVHD at day +100 was 39% and 14%, respectively. Chronic GVHD occurred in 17% of recipients. TRM was 12% at day +100 and 19% at one yr post-transplant. OS at five yr was 78% for the cohort, 73% for patients with ALD and 83% for patients with Hurler syndrome. There was no statistically significant difference in overall survival between unrelated marrow and unrelated cord blood donor groups. The development of interstitial pneumonitis was an independent variable shown to significantly impact on TRM and OS. In summary, we report a large cohort of patients with inherited metabolic disorders with excellent survival post allogeneic transplant. PMID- 23802617 TI - Ethene/ethane and propene/propane separation via the olefin and paraffin selective metal-organic framework adsorbents CPO-27 and ZIF-8. AB - Two types of metal-organic frameworks (MOFs) have been synthesized and evaluated in the separation of C2 and C3 olefins and paraffins. Whereas Co2(dhtp) (=Co-CPO 27 = Co-MOF-74) and Mg2(dhtp) show an adsorption selectivity for the olefins ethene and propene over the paraffins ethane and propane, the zeolitic imidazolate framework ZIF-8 behaves in the opposite way and preferentially adsorbs the alkane. Consequently, in breakthrough experiments, the olefins or paraffins, respectively, can be separated. PMID- 23802618 TI - Carbon nanotube nanoelectromechanical systems as magnetometers for single molecule magnets. AB - Due to outstanding mechanical and electronic properties, carbon nanotube nanoelectromechanical systems (NEMS) were recently proposed as ultrasensitive magnetometers for single-molecule magnets (SMM). In this article, we describe a noninvasive grafting of a SMM on a carbon nanotube NEMS, which conserves both the mechanical properties of the carbon nanotube NEMS and the magnetic properties of the SMM. We will demonstrate that the nonlinearity of a carbon nanotube's mechanical motion can be used to probe the reversal of a molecular spin, associated with a bis(phthalocyaninato)terbium(III) single-molecule magnet, providing an experimental evidence for the detection of a single spin by a mechanical degree of freedom on a molecular level. PMID- 23802620 TI - The dark side of plasmonics. AB - Plasmonic dark modes are pure near-field modes that can arise from the plasmon hybridization in a set of interacting nanoparticles. When compared to bright modes, dark modes have longer lifetimes due to their lack of a net dipole moment, making them attractive for a number of applications. We demonstrate the excitation and optical detection of a collective dark plasmonic mode from individual plasmonic trimers. The trimers consist of triangular arrangements of gold nanorods, and due to this symmetry, the lowest-energy dark plasmonic mode can interact with radially polarized light. The experimental data presented confirm the excitation of this mode, and its assignment is supported with an electrostatic approximation wherein these dark modes are described in terms of plasmon hybridization. The strong confinement of energy in these modes and their associated near fields hold great promise for achieving strong coupling to single photon emitters. PMID- 23802619 TI - A compendium of molecules involved in vector-pathogen interactions pertaining to malaria. AB - Malaria is a vector-borne disease causing extensive morbidity, debility and mortality. Development of resistance to drugs among parasites and to conventional insecticides among vector-mosquitoes necessitates innovative measures to combat this disease. Identification of molecules involved in the maintenance of complex developmental cycles of the parasites within the vector and the host can provide attractive targets to intervene in the disease transmission. In the last decade, several efforts have been made in identifying such molecules involved in mosquito parasite interactions and, subsequently, validating their role in the development of parasites within the vector. In this study, a list of mosquito proteins, which facilitate or inhibit the development of malaria parasites in the midgut, haemolymph and salivary glands of mosquitoes, is compiled. A total of 94 molecules have been reported and validated for their role in the development of malaria parasites inside the vector. This compendium of molecules will serve as a centralized resource to biomedical researchers investigating vector-pathogen interactions and malaria transmission. PMID- 23802621 TI - Caput succedaneum thickness in prolonged second stage of labour: a clinical evaluation. AB - BACKGROUND: Data are scarce regarding the association between the presence of caput succedaneum and the mode of delivery. AIMS: To evaluate the presence and clinical significance of caput succedaneum thickness in prolonged second stage of labour. MATERIALS AND METHODS: We conducted a prospective study of women, beyond 37 weeks of gestation, during prolonged second stage of labour. Transperineal ultrasound was performed to assess the caput succedaneum thickness. The relationships between caput succedaneum thickness, feto-maternal characteristics, delivery mode and immediate post-natal outcomes were analysed. RESULTS: Fifty eight women, of whom 47 were nulliparas, in prolonged second stage of labour, were included in the study. The caput succedaneum thickness could be measured in all cases. Overall mean thickness was 21.9 (+/-4.9) mm (range 14-40 mm). No significant difference or correlation was found between caput succedaneum thickness, fetal head positions, modes of delivery, duration of second stage, head circumference or neonatal outcomes. CONCLUSIONS: Caput succedaneum is measurable in all cases at prolonged second stage using transperineal sonography. Its presence and dimensions presented in our pilot study seem to have no implication on delivery mode and neonatal outcome. PMID- 23802622 TI - Morphological restriction of human coronary artery endothelial cells substantially impacts global gene expression patterns. AB - Alterations in cell shape have been shown to modulate chromatin condensation and cell lineage specification; however, the mechanisms controlling these processes are largely unknown. Because endothelial cells experience cyclic mechanical changes from blood flow during normal physiological processes and disrupted mechanical changes as a result of abnormal blood flow, cell shape deformation and loss of polarization during coronary artery disease, we aimed to determine how morphological restriction affects global gene expression patterns. Human coronary artery endothelial cells (HCAECs) were cultured on spatially defined adhesive micropatterns, forcing them to conform to unique cellular morphologies differing in cellular polarization and angularity. We utilized pattern recognition algorithms and statistical analysis to validate the cytoskeletal pattern reproducibility and uniqueness of each micropattern, and performed microarray analysis on normal-shaped and micropatterned HCAECs to determine how constrained cellular morphology affects gene expression patterns. Analysis of the data revealed that forcing HCAECs to conform to geometrically-defined shapes significantly affects their global transcription patterns compared to nonrestricted shapes. Interestingly, gene expression patterns were altered in response to morphological restriction in general, although they were consistent regardless of the particular shape the cells conformed to. These data suggest that the ability of HCAECs to spread, although not necessarily their particular morphology, dictates their genomics patterns. PMID- 23802623 TI - Matrix infrared spectra and density functional calculations for new iso halomethanes: CHCl2-Cl, CHFCl-Cl, CFCl2-Cl, CHBr2-Br, and CBr3-Br in solid argon. AB - Laser ablation of transition metals for reactions with halocarbons to produce new metal bearing molecules also exposed these samples to laser plume radiation and its resulting photochemistry. Investigations with CCl4 also produced several known neutral and charged intermediate species, including the iso tetrachloromethane CCl3-Cl observed in previous work and identified by the Maier group. CHCl2-Cl, CHFCl-Cl, and CFCl2-Cl, photoisomers of CHCl3, CHFCl2, and CFCl3, were also identified in matrix IR spectra. The new C-X bonds are shorter than those of the reactants, and the Cl atom that is weakly bonded to the residual Cl atom forms an unusually strong C-Cl bond. NBO analysis reveals substantial C?Cl double-bond character, and the weak Cl...Cl bond is largely ionic. Therefore, the CHX2-X species can be represented as HXC?X(delta+)...X(delta-). Ionic properties are revealed for CCl3-Cl, which has an average C-Cl bond length near the median for the CCl3 radical and cation and a natural charge of +0.49 for the CCl3 subunit. IRC computations reproduce smooth interconversion between the reactants and products, and the transition state is energetically close to the product, which is consistent with its disappearance on visible irradiation. PMID- 23802625 TI - Interleukin-6 downregulation with mesenchymal stem cell differentiation results in loss of immunoprivilege. AB - Allogeneic mesenchymal stem cell (MSC) transplantation improves cardiac function, but cellular differentiation results in loss of immunoprivilege and rejection. To explore the mechanism involved in this immune rejection, we investigated the influence of interleukin-6 (IL-6), a factor secreted by MSCs, on immune privilege after myogenic, endothelial and smooth muscle cell differentiation induced by 5 azacytidine, VEGF, and transforming growth factor-beta (TGF-beta), respectively. Both RT-PCR and ELISA showed that myogenic differentiation of MSCs was associated with significant downregulation of IL-6 expression (P < 0.01), which was also observed following endothelial (P < 0.01) and smooth muscle cell differentiation (P < 0.05), indicating that IL-6 downregulation was dependent on differentiation but not cell phenotype. Flow cytometry demonstrated that IL-6 downregulation as a result of myogenic differentiation was associated with increased leucocyte mediated cell death in an allogeneic leucocyte co-culture study (P < 0.01). The allogeneic reactivity associated with IL-6 downregulation was also observed following MSC differentiation to endothelial and smooth muscle cells (P < 0.01), demonstrating that leucocyte-mediated cytotoxicity was also dependent on differentiation but not cell phenotype. Restoration of IL-6 partially rescued the differentiated cells from leucocyte-mediated cell death. These findings suggest that rejection of allogeneic MSCs after implantation may be because of a reduction in cellular IL-6 levels, and restoration of IL-6 may be a new target to retain MSC immunoprivilege. PMID- 23802624 TI - Measurement of renal function in patients with chronic kidney disease. AB - Chronic kidney disease affects millions of people worldwide and is associated with an increased morbidity and mortality as a result of kidney failure and cardiovascular disease. Accurate assessment of kidney function is important in the clinical setting as a screening tool and for monitoring disease progression and guiding prognosis. In clinical research, the development of new methods to measure kidney function accurately is important in the search for new therapeutic targets and the discovery of novel biomarkers to aid early identification of kidney injury. This review considers different methods for measuring kidney function and their contribution to the improvement of detection, monitoring and treatment of chronic kidney disease. PMID- 23802626 TI - TROPHI: development of a tool to measure complex, multi-factorial patient handling interventions. AB - Patient handling interventions are complex and multi-factorial. It has been difficult to make comparisons across different strategies due to the lack of a comprehensive outcome measurement method. The Tool for Risk Outstanding in Patient Handling Interventions (TROPHI) was developed to address this gap by measuring outcomes and comparing performance across interventions. Focus groups were held with expert patient handling practitioners (n = 36) in four European countries (Finland, Italy, Portugal and the UK) to identify preferred outcomes to be measured for interventions. A systematic literature review identified 598 outcome measures; these were critically appraised and the most appropriate measurement tool was selected for each outcome. TROPHI was evaluated in the four EU countries (eight sites) and by an expert panel (n = 16) from the European Panel of Patient Handling Ergonomics for usability and practical application. This final stage added external validity to the research by exploring transferability potential and presenting the data and analysis to allow respondent (participant) validation. PRACTITIONER SUMMARY: Patient handling interventions are complex and multi-factorial and it has been difficult to make comparisons due to the lack of a comprehensive outcome measurement method. The Tool for Risk Outstanding in Patient Handling Interventions (TROPHI) was developed to address this gap by measuring outcomes to compare performance across interventions. PMID- 23802627 TI - Investigational cytokine-targeted therapies for ulcerative colitis. AB - INTRODUCTION: Up to one-third of patients with ulcerative colitis (UC) do not respond to standard medications, including mesalamine, steroids and thiopurines. The recognition that UC-related pathological process is the result of an altered balance between inflammatory and counter-regulatory signals, mostly mediated by cytokines, has led to the development of novel compounds, which are now ready to move into clinical practice. This article summarizes the recent data on the development and use of compounds either inhibiting inflammatory cytokines or enhancing the activity of counter-regulatory cytokines in patients with UC and murine models of UC. AREAS COVERED: A PubMed search was performed using the following keywords: 'ulcerative colitis', 'therapy', 'treatment' and 'cytokine'. In addition, ongoing clinical trials were checked and compounds were searched on the website of pharmaceutical companies. EXPERT OPINION: Several investigational cytokine-based therapies have provided promising results in attenuating clinical activity in patients with UC and mice with experimental colitis. However, clinical and immunological heterogeneity of UC patients, therapy-related side effects and redundant biological functions of cytokines represent potential pitfalls and should be considered in optimizing therapeutic strategies. PMID- 23802628 TI - Type I phosphatidylinositol 4-phosphate 5-kinase gamma is required for neuronal migration in the mouse developing cerebral cortex. AB - Type I phosphatidylinositol 4-phosphate 5-kinase (PIP5KI)gamma is one of the phosphoinositide kinases that produce phosphatidylinositol 4,5-bisphosphate, which is a critical regulator of cell adhesion formation, actin dynamics and membrane trafficking. Here, we examined the functional roles of PIP5KIgamma in radial neuronal migration during cortical formation. Reverse transcription polymerase chain reaction analysis revealed that PIP5KIgamma_v2/v6 and PIP5KIgamma_v3 were expressed throughout cortical development with distinct expression patterns. In situ hybridisation analysis showed that PIP5KIgamma mRNA was expressed throughout the cortical layers. Immunohistochemical analysis revealed that PIP5KIgamma was localised in a punctate manner in the radial glia and migrating neuroblasts. Knockdown of PIP5KIgamma using in utero electroporation disturbed the radial neuronal migration and recruitment of talin and focal adhesion kinase to puncta beneath the plasma membrane. The same inhibitory effect on neuronal migration was observed by overexpression of a catalytically inactive mutant of PIP5KIgamma_v2 but not PIP5KIgamma_v1 or PIP5KIgamma_v3. These findings suggest an essential role of PIP5KIgamma, particularly PIP5KIgamma_i2, in neuronal migration, possibly through recruitment of adhesion components to the plasma membrane. PMID- 23802629 TI - Effects of raltegravir on 2-long terminal repeat circle junctions in HIV type 1 viremic and aviremic patients. AB - Although 2-long terminal repeat (2-LTR) circles are only a fraction of the total viral DNA in infected cells, sequence analysis of 2-LTR circles reveals critical information regarding viral DNA synthesis and the nature of actively replicating virus. It was observed that a large proportion of the 2-LTR circular molecules in the peripheral blood mononuclear cell (PBMC) DNA of infected individuals are mutated at the circle junction. The integrase inhibitor raltegravir (RAL) blocks the strand transfer step of the integration of HIV-1; as a consequence of abortive integration a significant increase of episomal 2-LTR circles is observed. Moreover, it was demonstrated that in patients treated with highly active retroviral therapy (HAART) changes in 2-LTR concentration did not affect junction sequences and flanking regions of 2-LTR. Here we evaluated whether RAL therapy could have a differential impact on the 2-LTR circle junctional sequences in patients with different virological profiles at the time of starting RAL therapy. Sequence analysis indicates that RAL acts differently in the two populations. PMID- 23802630 TI - Factors that facilitate registered nurses in their first-line nurse manager role. AB - AIM: To determine the factors that attract and retain Registered Nurses in the first-line nurse manager role. BACKGROUND: The first-line nurse manger role is pivotal in health-care organisations. National demographics suggest that Canada will face a first-line nurse manager shortage because of retirement in the next decade. Determination of factors that attract and retain Registered Nurses will assist organisations and policy makers to employ strategies to address this shortage. METHODS: The study used an exploratory, descriptive qualitative approach, consisting of semi-structured individual interviews with 11 Registered Nurses in first-line nurse manager roles. RESULTS: The findings revealed a discrepancy between the factors that attract and retain Registered Nurses in the first-line nurse manager role, underscored the importance of the mentor role and confirmed the challenges encountered by first-line nurse managers practicing in the current health-care environment. CONCLUSIONS: The first-line nurse manager role has been under studied. Further research is warranted to understand which strategies are most effective in supporting first-line nurse managers. IMPLICATIONS FOR NURSING MANAGEMENT: Strategies to support nurses in the first line nurse manager role are discussed for the individual, programme, organisation and health-care system/policy levels. PMID- 23802631 TI - A study on the immunomodulation of polysaccharopeptide through the TLR4-TIRAP/MAL MyD88 signaling pathway in PBMCs from breast cancer patients. AB - CONTEXT: Polysaccharopeptide (PSP), isolated from the Coriolus versicolor COV-1 strain, has been widely used as an immunoadjuvant for cancer immunotherapy. OBJECTIVE: The present study was undertaken to examine the role of PSP on the TLR4-TIRAP/MAL-MyD88 signaling pathway in peripheral blood mononuclear cells (PBMCs) from breast cancer patients. METHODS: For blockade of TLR4, cells were cultured with or without PSP and anti-TLR4 for 24 h, and then the mRNA and proteins (IL-12, IL-6, and TNF-alpha) levels in each group were detected by Q-PCR and ELISA. Meanwhile, Q-PCR and western blot analysis were used to detect the expression of TLR4-TIRAP/MAL-MyD88 pathway genes and proteins under the regulation of PSP. RESULTS: As anticipated, the transcription and expression of genes (IL-12 and TNF-alpha) in the anti-TLR4 group were significantly downregulated compared with the control group, while genes (IL-12, IL-6 and TNF alpha) in the PSP group were significantly upregulated. Moreover, the mRNA levels in the PSP+anti-TLR4 group were significantly upregulated compared with the anti TLR4 group. The results of ELISA were as the same as Q-PCR. Genes, kinase phosphorylation levels and proteins in the TLR4 pathway were significantly upregulated by PSP. CONCLUSIONS: Collectively, our study revealed that PSP has an immunoregulatory effect through regulation of the TLR4-TIRAP/MAL-MyD88 signaling pathway. PMID- 23802632 TI - Characterization of free-standing PEDOT:PSS/iron oxide nanoparticle composite thin films and application as conformable humidity sensors. AB - In this study, a new simple, fast, and inexpensive technique for the preparation of free-standing nanocomposite ultrathin films based on the conductive polymer poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) and embedding iron oxide nanoparticles (NPs) is presented. These nanofilms were fabricated by a single step of spin-coated assisted deposition in conjunction with a release technique ("supporting layer technique") to detach them from the substrate. Free standing nanofilms can be easily transferred onto several substrates due to their high conformability, preserving their functionalities. The effect of the addition of iron oxide nanoparticles on the structural and functional properties of the PEDOT:PSS nanofilms is investigated through topography, thickness, magnetic, magneto-optical activity, and conductivity characterizations. PEDOT:PSS and PEDOT:PSS/iron oxide NP nanofilms were tested as resistive humidity sensors. Their sensitivity to humidity was found to increase with increasing nanoparticle concentration. On the basis of these results, it is expected that these composites may furnish inexpensive and reliable means for relative humidity detection. PMID- 23802633 TI - BCL2 and BCLxL are key determinants of resistance to antitubulin chemotherapeutics in melanoma cells. AB - Malignant melanoma is refractory to various chemotherapeutics including antitubulin agents such as paclitaxel. Previous studies have suggested a link between betaIII-tubulin overexpression and paclitaxel resistance through alterations in the properties of the mitotic spindle. We found that paclitaxel treatment induced temporary mitotic arrest in 7 melanoma cell lines irrespective of the betaIII-tubulin level, suggesting that betaIII-tubulin had no significant influence on spindle properties. On the other hand, the amount of BCL2, an anti apoptotic protein, was well correlated with paclitaxel resistance. Treatment of the paclitaxel-resistant cell lines with ABT-737, an inhibitor of BCL2 and BCLxL, or simultaneous knock-down of BCL2 and BCLxL dramatically increased the cells' sensitivity, while knock-down of MCL1, another member of the BCL2 family, had only a minimal effect. Our results suggest that the paclitaxel sensitivity of melanoma cells is attributable to apoptosis susceptibility rather than a change in spindle properties and that BCL2 and BCLxL play a pivotal role in the former. PMID- 23802634 TI - Analysis of the Elodea nuttallii transcriptome in response to mercury and cadmium pollution: development of sensitive tools for rapid ecotoxicological testing. AB - Toxic metals polluting aquatic ecosystems are taken up by inhabitants and accumulate in the food web, affecting species at all trophic levels. It is therefore important to have good tools to assess the level of risk represented by toxic metals in the environment. Macrophytes are potential organisms for the identification of metal-responsive biomarkers but are still underrepresented in ecotoxicology. In the present study, we used next-generation sequencing to investigate the transcriptomic response of Elodea nuttallii exposed to enhanced concentrations of Hg and Cd. We de novo assembled more than 60 000 contigs, of which we found 170 to be regulated dose-dependently by Hg and 212 by Cd. Functional analysis showed that these genes were notably related to energy and metal homeostasis. Expression analysis using nCounter of a subset of genes showed that the gene expression pattern was able to assess toxic metal exposure in complex environmental samples and was more sensitive than other end points (e.g., bioaccumulation, photosynthesis, etc.). In conclusion, we demonstrate the feasibility of using gene expression signatures for the assessment of environmental contamination, using an organism without previous genetic information. This is of interest to ecotoxicology in a wider sense given the possibility to develop specific and sensitive bioassays. PMID- 23802636 TI - Frequency of restoration replacement in posterior teeth for U.S. Navy and Marine Corps personnel. AB - STATEMENT OF PROBLEM: There are no recent data that describe the replacement rates of resin composite and dental amalgam restorations placed by US Navy dentists. Information is needed to provide the best possible care for our military personnel which would minimize the probability of dental emergencies, especially for those who are deployed. PURPOSE: The purpose of this study was to determine if the frequency of posterior restoration replacement in military personnel differed based on the type of restorative material utilized. METHODS AND MATERIALS: Data contained in dental records in an observational study (retrospective cohort) were evaluated to identify resin composite and dental amalgam restorations placed by navy dentists in posterior teeth. The status of all erupted, unerupted, missing, and replaced teeth was documented. The type and condition of all existing restorations were recorded for each posterior tooth. Investigators reviewed 2921 dental records, and of those, 247 patients met the criteria for inclusion in the study. A total of 1050 restorations (485 resin composite and 565 amalgam) were evaluated. RESULTS: A Cox proportional hazards model was adjusted for number of tooth surfaces restored, caries risk, and filled posterior surfaces at initial exam. The overall rate of replacement for all restorations in the sample was 5.7% during the average 2.8-year follow-up. No significant elevation of risk for restoration replacement existed when comparing resin composite and amalgam. Both the number of restored surfaces and caries risk status were independent risk factors for replacement. When restoring multisurface cavity preparations, providers placed amalgams by an approximate 2:1 ratio over resin composites for this study population. CONCLUSION: The results for this study show that no difference existed in the rate of replacement for amalgam vs resin composite. When restorations increased from just a single occlusal surface to additional surfaces, the rate of replacement was elevated and statistically significant for both materials. A higher caries risk status was also significant in elevating replacement rates for both materials. PMID- 23802635 TI - The influence of skeletal muscle on systemic aging and lifespan. AB - Epidemiological studies in humans suggest that skeletal muscle aging is a risk factor for the development of several age-related diseases such as metabolic syndrome, cancer, Alzheimer's and Parkinson's disease. Here, we review recent studies in mammals and Drosophila highlighting how nutrient- and stress-sensing in skeletal muscle can influence lifespan and overall aging of the organism. In addition to exercise and indirect effects of muscle metabolism, growing evidence suggests that muscle-derived growth factors and cytokines, known as myokines, modulate systemic physiology. Myokines may influence the progression of age related diseases and contribute to the intertissue communication that underlies systemic aging. PMID- 23802637 TI - Effect of pre-reacted glass-ionomer filler extraction solution on demineralization of bovine enamel. AB - OBJECTIVE: To determine the effect of pre-reacted glass-ionomer (PRG) filler extraction solution on the demineralization of bovine enamel by measuring changes in the ultrasound transmission velocity. METHODS: The specimens were prepared by cutting bovine teeth into enamel blocks. The specimens were immersed in buffered lactic acid solution for 10 minutes twice a day, and then stored in artificial saliva. Other specimens were stored in PRG filler extraction solution for 10 minutes, followed by 10-minute immersion in the buffered lactic acid solution twice a day. The propagation time of longitudinal ultrasonic waves was measured by a pulser receiver. Six specimens were used for each condition, and analyses of variance followed by Tukey tests (alpha=0.05) were done. RESULTS: No changes in sonic velocity were found for specimens stored in the PRG filler extraction solution, indicating that the PRG extraction solution had an effect on inhibiting the demineralization of bovine enamel. CONCLUSIONS: The results obtained with the use of an ultrasound measurement technique suggested that PRG filler extraction solution has the ability to prevent demineralization of enamel. PMID- 23802638 TI - Comparison of enamel and dentin shear bond strengths of current dental bonding adhesives from three bond generations. AB - OBJECTIVE: Durability is still a major challenge in adhesive dentistry. One of the biggest areas of development has been to simplify the bonding process by using all-in-one adhesives. The aim of this study was to compare the shear bond strength (SBS) to dentin and enamel of nine dental bonding agents (DBAs) from three generations after simulated aging. METHODS AND MATERIALS: For this study, 108 sound extracted human molars were randomly assigned to nine groups (n=12). The sample teeth were mounted in self-cure acrylic resin sectioned to provide paired enamel and dentin samples. All samples were polished with 240 and 600-grit silicon carbide sandpaper and randomly grouped according to the product and substrates (enamel or dentin). Herculite Ultra resin composite cylinders were bonded on each test surface, stored in 100% humidity at 37 degrees C for 24 hours, and then thermocyled for 1,000 cycles at 5 degrees C and 55 degrees C. SBS testing was performed using an Ultratester at a crosshead speed of 0.5 mm/min. Statistical analysis included two-factor analysis of variance, one-sample Wilcoxon and Kruskal-Wallis tests, and the Scheffe post hoc test at an alpha level of 0.05 using SAS version 9.2. RESULTS: Significant differences in SBS were observed between the sixth- and seventh-generation DBAs (p=0.002) but not between the sixth- and fourth-generation DBAs. Scheffe post hoc tests for the sixth generation DBAs showed that some DBAs yielded significantly higher enamel SBS than others, but not as much as dentin SBS. As for the seventh-generation DBAs, similar post hoc tests showed significant variations in SBS between substrates (enamel and dentin) and DBAs tested. Significant main effects were also found for the different substrates for the fourth-generation (F[1,96]=10.532; p=0.003) and seventh-generation (F[1,96]=22.254; p<0.001) DBAs, but not for the sixth generation DBAs (F[1,96]=1.895, p=0.172). The SBS was higher on dentin than enamel for the fourth- and seventh-generation DBAs. CONCLUSION: As expected, fourth- and sixth-generation DBAs generally showed stronger SBS values than the seventh-generation all-in-one DBAs. The new sixth-generation DBA OptiBond XTR (Kerr) showed strong SBS values to both substrates and performed well in comparison to the other DBAs tested. PMID- 23802639 TI - The Normalized Failure Index: a method for summarizing the results of studies on restoration longevity? AB - Satisfactory restoration longevity is central to operative dentistry and is the subject of a wide variety of publications. However, combining the results of a number of studies to provide an overview, for example, for a meta-analysis may be problematic because of the heterogeneity of the data, and a high proportion of studies may therefore not be included. It is the purpose of this study to present a means whereby the data from cohort studies may be combined to present a representation of restoration longevity, termed the "Normalized Failure Index." PMID- 23802640 TI - Administration of ascorbic acid to prevent bleaching-induced tooth sensitivity: a randomized triple-blind clinical trial. AB - This study evaluated the effect of ascorbic acid, 500 mg every eight hours, on bleaching-induced tooth sensitivity. A triple-blind, parallel design, and placebo controlled randomized clinical trial was conducted on 39 adults. The pills (placebo or ascorbic acid) were administered three times per day for 48 hours; the first dose was given one hour prior to each bleaching session. Two bleaching sessions with 35% hydrogen peroxide gel were performed with a one-week interval. Tooth sensitivity was recorded up to 48 hours after bleaching. The color evaluation was performed before and 30 days after bleaching. The absolute risk and intensity of tooth sensitivity were evaluated by Fisher exact and Mann Whitney U-tests, respectively. Color changes were evaluated by unpaired t-test (alpha=0.05). There were no significant differences in the absolute risk and intensity of tooth sensitivity and color change between the groups. Both groups showed a similar risk of tooth sensitivity (p>0.05). The perioperative use of an antioxidant, such as ascorbic acid (500 mg, three times daily) perorally, was not able to prevent bleaching-induced tooth sensitivity or reduce its intensity. PMID- 23802641 TI - Influence of fiber inserts, type of composite, and gingival margin location on the microleakage in Class II resin composite restorations. AB - This study evaluated the influence of fiber inserts, type of composites, and location of the gingival seat on microleakage in Class II resin composite restorations. Fifty noncarious human third molars were selected for the study. Standardized Class II box type cavities were prepared on the mesial and distal side of 45 teeth. The gingival margin was placed above the cementoenamel junction (CEJ) on the mesial side and below the CEJ on the distal side. The remaining five teeth received no cavity preparations. The prepared samples were divided randomly on the basis of type of composite and presence or absence of fiber inserts, into four experimental groups of 10 teeth each and two control groups of five teeth each. The groups were defined as follows: group I (n=10) - Z350 XT; group II (n=10) - Z350 XT with fibers; group III (n=10) - P90; group IV (n=10) - P90 with fibers; and group V (n=5) - positive controls, cavities were not restored; group VI (n=5) - negative controls, no cavities were prepared. The samples were stored in distilled water in incubator at 37 degrees C for 24 hours and then subjected to 500 cycles of thermocycling (5 degrees C and 55 degrees C) with a dwell time of 15 seconds. They were then placed in a 2% methylene blue dye solution for 24 hours at 37 degrees C. Samples were sectioned longitudinally and evaluated for microleakage at the occlusal and gingival margin under a stereomicroscope at 20* magnification. Kruskal-Wallis and Mann-Whitney U-tests were used to compare the mean leakage scores. Restorations with gingival margins in enamel showed significantly less microleakage. Significant reduction in microleakage was observed in groups restored with P90 composite than those restored with Z350 XT. No improvement in microleakage was observed with the use of fiber inserts (p>0.05). PMID- 23802642 TI - Triethylene glycol dimethacrylate induction of apoptotic proteins in pulp fibroblasts. AB - OBJECTIVE: Monomers such as triethylene glycol dimethacrylate (TEGDMA) can leach from dental composites. TEGDMA-induced apoptosis in human pulp has been reported. However, the apoptotic (pro or anti) proteins involved in this process remain unclear. Therefore, the purpose of this study was to determine which apoptotic proteins are enhanced or suppressed during TEGDMA-induced apoptosis. MATERIALS AND METHODS: Human pulp fibroblasts (HPFs) were incubated with different TEGDMA concentrations (0.125-1.0 mM) and cytotoxicity was determined. TEGDMA was shown to be cell cytotoxic at concentrations of 0.50 mM and higher. The highest concentration with no significant cytotoxicity was then incubated (0.25 mM TEGDMA) with the HPFs. Cell lysates were then prepared and the protein concentrations determined. Human Apoptosis Array kits were utilized to detect the relative levels of 43 apoptotic proteins. RESULTS: HPFs exposed to TEGDMA showed significant increases in multiple pro-apoptotic proteins such as Bid, Bim, Caspase 3, Caspase 8, and Cytochrome c at 24 hours. Some anti-apoptotic proteins were also altered. CONCLUSIONS: The results indicated that TEGDMA activates both the extrinsic and intrinsic apoptotic pathways. PMID- 23802643 TI - Detection of marginal leakage of Class V restorations in vitro by micro-computed tomography. AB - This in vitro study evaluated the efficacy of micro-computed tomography (CT) in marginal leakage detection of Class V restorations. Standardized Class V preparations with cervical margins in dentin and occlusal margins in enamel were made in 20 extracted human molars and restored with dental bonding agents and resin composite. All teeth were then immersed in 50% ammoniacal silver nitrate solution for 12 hours, followed by a developing solution for eight hours. Each restoration was scanned by micro-CT, the depth of marginal silver leakage in the central scanning section was measured, and the three-dimensional images of the silver leakage around each restoration were reconstructed. Afterward, all restorations were cut through the center and examined for leakage depth using a microscope. The silver leakage depth of each restoration obtained by the micro-CT and the microscope were compared for equivalency. The silver leakage depth in cervical walls observed by micro-CT and microscope showed no significant difference; however, in certain cases the judgment of leakage depth in the occlusal wall in micro-CT image was affected by adjacent enamel structure, providing less leakage depth than was observed with the microscope (p<0.01). Micro-CT displayed the three-dimensional image of the leakage around the Class V restorations with clear borders only in the dentin region. It can be concluded that micro-CT can detect nondestructively the leakage around a resin composite restoration in two and three dimensions, with accuracy comparable to that of the conventional microscope method in the dentin region but with inferior accuracy in the enamel region. PMID- 23802644 TI - Transenamel and transdentinal penetration of hydrogen peroxide applied to cracked or microabrasioned enamel. AB - The present study evaluated transenamel and transdentinal penetration of hydrogen peroxide during tooth whitening recognized in altered enamel by the presence of cracks or microabrasion. We used 72 experimental units (n=20) obtained from bovine incisors: GI-sound enamel; GII-teeth showing visible enamel cracks (4 mm to 5.7 mm in length); and GIII-microabrasioned enamel. The 12 remaining specimens were used to analyze the enamel surface morphology using scanning electron microscopy. The specimens were cylindrical and 5.7 mm in diameter and 3.5 mm thick. A product based on 35% hydrogen peroxide was used for bleaching, following the manufacturer's recommendations for use. To quantify the H2O2 penetration, the specimens were placed in artificial pulp chambers containing an acetate buffer solution. After bleaching, the solution was collected and adequately proportioned with leucocrystal violet, peroxidase enzyme, and deionized water. The resulting solution was evaluated using ultraviolet visible reflectance spectrophotometer equipment. The data were analyzed by analysis of variance (ANOVA) and Fisher's PLSD at a significance level of 0.05, and significant differences in the penetration of peroxide in different substrate conditions were observed (p<0.0001). The penetration of hydrogen peroxide was more intense in cracked teeth. The group in which the enamel was microabraded showed intermediate values when compared to the control group. Microabrasion and the presence of cracks in the enamel make this substrate more susceptible to penetration of hydrogen peroxide during in-office whitening. PMID- 23802645 TI - A new universal simplified adhesive: 18-month clinical evaluation. AB - PURPOSE: To evaluate the 18-month clinical performance of a multimode adhesive (Scotchbond Universal Adhesive, SU, 3M ESPE, St Paul, MN, USA) in noncarious cervical lesions (NCCLs) using two evaluation criteria. MATERIALS AND METHODS: Thirty-nine patients participated in this study. Two-hundred restorations were assigned to four groups: ERm, etch-and-rinse + moist dentin; ERd, etch-and-rinse + dry dentin; Set, selective enamel etching; and SE, self-etch. The composite resin, Filtek Supreme Ultra (3M ESPE), was placed incrementally. The restorations were evaluated at baseline, and at 18 months, using both the World Dental Federation (FDI) and the United States Public Health Service (USPHS) criteria. Statistical analyses were performed using Friedman repeated-measures analysis of variance by rank and McNemar test for significance in each pair (alpha=0.05). RESULTS: Five restorations (SE: 3; Set: 1; and ERm: 1) were lost after 18 months (p>0.05 for either criteria). Marginal staining occurred in four and 10% of the restorations evaluated (p>0.05), respectively, for USPHS and FDI criteria. Nine restorations were scored as bravo for marginal adaptation using the USPHS criteria and 38%, 40%, 36%, and 44% for groups ERm, ERd, Set, and SE, respectively, when the FDI criteria were applied (p>0.05). However, when semiquantitative scores (or SQUACE) for marginal adaptation were used, SE resulted in a significantly greater number of restorations, with more than 30% of the total length of the interface showing marginal discrepancy (28%) in comparison with the other groups (8%, 6%, and 8%, respectively, for ERm, ERd, and Set). CONCLUSIONS: The clinical retention of the multimode adhesive at 18 months does not depend on the bonding strategy. The only differences between strategies were found for the parameter marginal adaptation, for which the FDI criteria were more sensitive than the USPHS criteria. PMID- 23802646 TI - Variation in training regimens in professional showjumping yards. AB - REASONS FOR PERFORMING STUDY: Training regimens of showjumping horses under field conditions are largely undocumented. OBJECTIVES: The aims of this study were to quantify and compare training regimens used in professional-level showjumping yards, with respect to time exercised and type of activity. STUDY DESIGN: Prospective cohort study. METHODS: A prospective 6-month cohort study of showjumping horses in 4 European countries (The Netherlands, Sweden, Switzerland, Great Britain) was designed to analyse training and health data, in yards with several horses in training and riders competing at professional level. Riders documented the daily frequency and duration of all physical activities of the horses. Variation in training routines were compared between riders, location and time. Mixed-models analysis was used to examine factors associated with total time exercised and time spent in flatwork. RESULTS: In 4 countries, the 31 participating riders trained 263 European Warmbloods. The total days at risk (e.g. days in which the horses were considered fit for exercise) was 39,262. Mean time spent in daily exercise, including ridden work, lungeing and treadmill exercise, varied between riders from 19-52 min/day at risk. There was considerable variation in activities and level of heavy work and light exercise, i.e. turnout. Total time exercised and time spent in flatwork differed with month, country and proportion of days lost to training. Low variation of activities was associated with decreased total time trained and increased time spent in flatwork. CONCLUSIONS: Riders at this elite professional level of showjumping used training regimens that vary substantially in time spent training and other physical activities and showjumping horses are challenged differently during training despite competing at the same level. Whether all training regimens prepare the horses equally for the demands of competition remains to be determined. PMID- 23802647 TI - Do common mental disorders decline over time in TB/HIV co-infected and HIV patients without TB who are on antiretroviral treatment? AB - BACKGROUND: The relationship between TB/HIV co-infection and common mental disorders (CMD) is not well investigated. A follow up study was conducted to assess the change in CMD over a 6-months period and its predictors among TB/HIV co-infected and HIV patients without TB in Ethiopia. METHODS: A longitudinal study was conducted in 2009. A total of 465 HIV/AIDS patients without TB and 124 TB/HIV co-infected patients from four antiretroviral treatment (ART) centers in Ethiopia were recruited to assess CMD and quality of life (QoL). CMD and QoL were assessed at baseline and at six month using the Kessler-10 scale and the short Amharic version of the World Health Organization Quality of Life Instrument for HIV clients (WHOQOL HIV-Bref) respectively. Multivariate analysis was conducted using generalized estimating equations (GEE) using STATA to assess change in CMD and its predictors. RESULTS: At the 6 month, 540 (97 TB/HIV co-infected and 455 HIV/AIDS patients without TB) patients completed the follow up and 8.6% (21% among TB/HIV co-infected and 2.2% among HIV patients without TB) lost to follow up.At baseline, 54.4% of TB/HIV co-infected patients had mild to severe mental disorder compared to 41.2% among HIV patients without TB. At the six month follow up, 18.1% of TB/HIV co-infected patients had mild to severe mental disorder compared to 21.8% among HIV patients without TB. The decline of the prevalence of any form of metal disorder was 36.3% among TB/HIV co-infected patients compared to 19.4% among HIV patients without TB (P<0.001).QoL was strongly associated with CMD in TB/HIV co-infected patients and HIV patients without TB (beta = -0.04, P<0.001) after controlling the effect of several confounding variables such as sex, income, WHO disease stage, duration on ART, CD4 lymphocyte count, adherence to ART and social support. CONCLUSION: The prevalence of CMD has significantly reduced particularly among TB/HIV co-infected patients over a 6 months period. Poor QoL is the major independent predictors of CMD. We recommend integration of mental health services in TB/HIV programs. Training of health care providers at TB/HIV clinics could help to screen and treat CMD among TB/HIV co-infected patients. PMID- 23802648 TI - Probenecid potentiates MPTP/MPP+ toxicity by interference with cellular energy metabolism. AB - The uricosuric agent probenecid is co-administered with the dopaminergic neurotoxin MPTP to produce a chronic mouse model of Parkinson's disease. It has been proposed that probenecid serves to elevate concentrations of MPTP in the brain by reducing renal elimination of the toxin. However, this mechanism has never been formally demonstrated to date and is questioned by our previous data showing that intracerebral concentrations of MPP(+), the active metabolite of MPTP, are not modified by co-injection of probenecid. In this study, we investigated the potentiating effects of probenecid in vivo and in vitro arguing against the possibility of altered metabolism or impaired renal elimination of MPTP. We find that probenecid (i) is toxic in itself to several neuronal populations apart from dopaminergic neurons, and (ii) that it also potentiates the effects of other mitochondrial complex I inhibitors such as rotenone. On a mechanistic level, we show that probenecid is able to lower intracellular ATP concentrations and that its toxic action on neuronal cells can be reversed by extracellular ATP. Probenecid can potentiate the effect of mitochondrial toxins due to its impact on ATP metabolism and could therefore be useful to model atypical parkinsonian syndromes. PMID- 23802649 TI - Spectroscopic and theoretical investigations of ThS and ThS+. AB - Gas-phase ThS has been produced via the reaction of laser ablated Th with H2S. Rotationally resolved electronic spectra were recorded by laser-induced fluorescence (LIF) over the range 17500-24000 cm(-1). Resonance-enhanced multiphoton ionization was used in conjunction with a time-of-flight mass spectrometer to confirm the assignments of nine LIF bands to ThS. Using excitation of a ThS band centered at 22118 cm(-1), a dispersed fluorescence spectrum revealed a vibrational progression of the X(1)Sigma(+) ground electronic state and the term energies of two low-lying excited states ((3)Delta1 and (3)Delta2). Two-color photoionization spectroscopy was used to study ThS(+). An accurate ionization energy for ThS was obtained (54425(3) cm(-1)); ThS(+) vibronic term energies up to v = 7 in the X(2)Sigma(+) ground state and v = 3 in the (2)Delta3/2 first excited state were recorded. High-level electronic structure calculations, with inclusion of the spin-orbit interactions yielded predictions that were in good agreement with the experimental data for ThS and ThS(+). The spectroscopic properties of ThS/ThS(+) are compared with those of the valence isoelectronic pairs ThO/ThO(+), HfO/HfO(+), and HfS/HfS(+). PMID- 23802650 TI - Early transcriptional responses of internalization defective Brucella abortus mutants in professional phagocytes, RAW 264.7. AB - BACKGROUND: Brucella abortus is an intracellular zoonotic pathogen which causes undulant fever, endocarditis, arthritis and osteomyelitis in human and abortion and infertility in cattle. This bacterium is able to invade and replicate in host macrophage instead of getting removed by this defense mechanism. Therefore, understanding the interaction between virulence of the bacteria and the host cell is important to control brucellosis. Previously, we generated internalization defective mutants and analyzed the envelope proteins. The present study was undertaken to evaluate the changes in early transcriptional responses between wild type and internalization defective mutants infected mouse macrophage, RAW 264.7. RESULTS: Both of the wild type and mutant infected macrophages showed increased expression levels in proinflammatory cytokines, chemokines, apoptosis and G-protein coupled receptors (Gpr84, Gpr109a and Adora2b) while the genes related with small GTPase which mediate intracellular trafficking was decreased. Moreover, cytohesin 1 interacting protein (Cytip) and genes related to ubiquitination (Arrdc3 and Fbxo21) were down-regulated, suggesting the survival strategy of this bacterium. However, we could not detect any significant changes in the mutant infected groups compared to the wild type infected group. CONCLUSIONS: In summary, it was very difficult to clarify the alterations in host cellular transcription in response to infection with internalization defective mutants. However, we found several novel gene changes related to the GPCR system, ubiquitin-proteosome system, and growth arrest and DNA damages in response to B. abortus infection. These findings may contribute to a better understanding of the molecular mechanisms underlying host-pathogen interactions and need to be studied further. PMID- 23802651 TI - Severe malaria in Battambang Referral Hospital, an area of multidrug resistance in Western-Cambodia: a retrospective analysis of cases from 2006-2009. AB - BACKGROUND: Despite recent malaria containment and control efforts leading to reduced incidence, Cambodia remains endemic for both Plasmodium vivax and multidrug-resistant Plasmodium falciparum malaria. Little has been reported in the peer-reviewed literature regarding the burden of severe malaria (SM) in Cambodia. METHODS: Medical records for all patients admitted to the Battambang Referral Hospital (BRH) with an admitting or discharge diagnosis of SM from 2006 to 2009 (suspected SM cases) were reviewed. Those meeting the case definition of SM according to retrospective chart review and investigator assessment of probable cases, based on published national guidelines available at the time, were analysed for trends in demographics, mortality and referral patterns. RESULTS: Of the 537 suspected SM cases at BRH during the study period, 393 (73%) met published WHO criteria for SM infection. Despite limited diagnostic and treatment facilities, overall mortality was 14%, with 7% mortality in children 14 and under, but 19% in adults (60% of cases). Cerebral malaria with coma was relatively rare (17%), but mortality was disproportionately high at 35%. Mean time to hospital presentation was five days (range one to 30 days) after onset of symptoms. While patients with delays in presentation had worse outcomes, there was no excess mortality based on treatment referral times, distance travelled or residence in artemisinin-resistance containment (ARC) Zone 1 compared to Zone 2. CONCLUSIONS: Despite limitations in diagnosis and treatment, and multiple confounding co-morbidities, mortality rates at BRH were similar to reports from other countries in the region. Interventions to improve access to early diagnosis and effective treatment, combined with modest improvements in intensive care, are likely to reduce mortality further. Patients referred from Zone 1 did not have excess mortality compared to Zone 2 ARC areas. A steep decrease in SM cases and deaths observed in the first half of 2009 has since continued, indicating some success from containment efforts despite the emergence of artemisinin resistance in this area. PMID- 23802652 TI - Cleansing of wounds by tap water? An evidence-based systemic analysis. PMID- 23802654 TI - Calibrating and controlling the quantum efficiency distribution of inhomogeneously broadened quantum rods by using a mirror ball. AB - We demonstrate that a simple silver coated ball lens can be used to accurately measure the entire distribution of radiative transition rates of quantum dot nanocrystals. This simple and cost-effective implementation of Drexhage's method that uses nanometer-controlled optical mode density variations near a mirror, not only allows an extraction of calibrated ensemble-averaged rates, but for the first time also to quantify the full inhomogeneous dispersion of radiative and non radiative decay rates across thousands of nanocrystals. We apply the technique to novel ultrastable CdSe/CdS dot-in-rod emitters. The emitters are of large current interest due to their improved stability and reduced blinking. We retrieve a room-temperature ensemble average quantum efficiency of 0.87 +/- 0.08 at a mean lifetime around 20 ns. We confirm a log-normal distribution of decay rates as often assumed in literature, and we show that the rate distribution width, that amounts to about 30% of the mean decay rate, is strongly dependent on the local density of optical states. PMID- 23802655 TI - Molecular fingerprinting of lacustrian cyanobacterial communities: regional patterns in summer diversity. AB - The assessment of lacustrian water quality is necessary to comply with environmental regulations. At the regional scale, difficulties reside in the selection of representative lakes. Given the risks towards water quality associated with phytoplankton blooms, a mesoscale survey was carried out in Irish lakes to identify patterns in the distribution and diversity of planktonic cyanobacteria. A stratified sampling strategy was carried out via geographic information systems (GIS) analysis of river catchment attributes due to the range of hydrogeomorphological features and the high number of lakes within the study area. 16S rRNA gene denaturing gradient gel electrophoresis analysis showed variation between the cyanobacterial communities sampled, with lower occurrence of cyanobacteria in August concomitant to increased wind and precipitation regimes. Multivariate analysis delineated three ecoregions based on land cover typology and revealed significant patterns in the distribution of cyanobacterial diversity. A majority of filamentous cyanobacteria genotypes occurred in larger lakes contained river catchments with substantial forest cover. In contrast, higher diversity of spherical cyanobacteria genotypes was observed in lakes of lesser trophic state. In the context of aquatic resource management, the combined use of GIS-based sampling strategy and molecular methods offers promising prospects for assessing microbial community structure at varying scales of space and time. PMID- 23802653 TI - Advances in the treatment of acute graft-versus-host disease. AB - Allogeneic hematopoietic stem cell transplantation (HSCT) has been widely used for the treatment of hematologic malignant and non-malignant hematologic diseases and other diseases. However, acute graft-versus-host disease (GVHD) is a life threatening complication of allogeneic transplantation. Acute GVHD may occur in 30% of transplant recipients, which is a syndrome of erythematous skin eruption, cholestatic liver disease and intestinal dysfunction, resulting from the activation of donor T lymphocytes by host antigen-presenting cells, resulting in an immune-mediated inflammatory response. Recent scientific advances in the understanding of the pathogenesis involved in the development of acute GVHD and clinical investigation have provided more effective therapeutic strategies for acute GVHD. This review focuses on major scientific and clinical advances in the treatment of acute GVHD. PMID- 23802657 TI - Corrosion/fragmentation of layered composite cathode and related capacity/voltage fading during cycling process. AB - The Li-rich, Mn-rich (LMR) layered structure materials exhibit very high discharge capacities exceeding 250 mAh g(-1) and are very promising cathodes to be used in lithium ion batteries. However, significant barriers, such as voltage fade and low rate capability, still need to be overcome before the practical applications of these materials. A detailed study of the voltage/capacity fading mechanism will be beneficial for further tailoring the electrode structure and thus improving the electrochemical performances of these layered cathodes. Here, we report detailed studies of structural changes of LMR layered cathode Li[Li0.2Ni0.2Mn0.6]O2 after long-term cycling by aberration-corrected scanning transmission electron microscopy (STEM) and electron energy loss spectroscopy (EELS). The fundamental findings provide new insights into capacity/voltage fading mechanism of Li[Li0.2Ni0.2Mn0.6]O2. Sponge-like structure and fragmented pieces were found on the surface of cathode after extended cycling. Formation of Mn(2+) species and reduced Li content in the fragments leads to the significant capacity loss during cycling. These results also imply the functional mechanism of surface coatings, for example, AlF3, which can protect the electrode from etching by acidic species in the electrolyte, suppress cathode corrosion/fragmentation, and thus improve long-term cycling stability. PMID- 23802656 TI - Renal function assessment in older adults. AB - AIMS: The Cockcroft-Gault (CG), the Modification of Diet in Renal Disease (MDRD) and the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formulae are often used to estimate glomerular filtration rate (GFR). The objective was to determine the best method for estimating GFR in older adults. METHODS: A cross sectional study was conducted at the geriatric wards of two hospitals in The Netherlands. Patients aged 70 years or above with an estimated (e)GFR below 60 ml min-1 1.73 m-2 were included. The CG, CG calculated with ideal bodyweight (IBW), MDRD and CKD-EPI formulae were compared with a criterion standard, sinistrin clearance. Renal function was classified into five stages according to the National Kidney Foundation Disease Outcomes Quality Initiative chronic kidney disease classification, as follows (in ml min-1 1.73 m)-2: stage 1, eGFR >= 90; stage 2, eGFR of 60-89; stage 3, eGFR of 30-59; stage 4, eGFR of 15-29; and stage 5, eGFR < 15. RESULTS: Sixteen patients, 50% male, with a mean age of 82 years (range 71-87 years) and mean body mass index 26 kg m-2 (range 18-36 kg m-2), were included. On average, all formulae slightly overestimated GFR, as follows (in ml min-1 1.73 m-2: CG +0.05 [95% confidence interval (CI) -28 to +28]; CG with IBW +0.03 (95% CI -20 to +20); MDRD +9 (95% CI -16 to +34); and CKD-EPI +5 (95% CI 20 to +29). They classified kidney disease correctly in 68.8% (CG), 75% (CG with IBW), 43.8% (MDRD) and 68.8% (CKD-EPI) of the participants, respectively. CONCLUSIONS: The CG, CG with IBW, MDRD and CKD-EPI formulae estimate the mean GFR of a population rather well. In individual cases, all formulae may misclassify kidney disease by one stage. PMID- 23802658 TI - Effects of water-damaged homes after flooding: health status of the residents and the environmental risk factors. AB - We evaluated the health status of residents and the environmental risk factors of housing after flooding. Questionnaires were distributed to 595 selected households (one adult resident per household) in six areas in Japan which were severely flooded between 2004 and 2010. A total of 379 responses were obtained. Indoor dampness and visible mold growth significantly increased in homes with greater flood damage. The incidence of respiratory, dermal, ocular, and nasal symptoms one week after flooding was significantly higher in flooded homes compared with non-flooded homes, the incidence of psychological disorders was significantly high for six months after flooding, and the incidence of post traumatic stress disorder was significantly high six months after flooding. Significant risk factors for respiratory and nasal symptoms included proximity to industrial and waste incineration plants. Our results suggest that rapid action should be taken after flooding to ensure adequate public health and environmental hygiene in the water-damaged homes. PMID- 23802660 TI - Assessment of Korean consumer exposure to sodium saccharin, aspartame and stevioside. AB - The dietary intakes of sodium saccharin, aspartame and stevioside were estimated on the basis of food consumption data of the Korean consumer and the concentration of sweeteners in processed foods. Results were compared with the acceptable daily intake (ADI) of sweeteners. Among the 28 food categories for which the application of sodium saccharin, aspartame and stevioside is permitted in Korea, they were detected in 5, 12 and 13 categories, respectively. The estimated daily intake (EDI) of sodium saccharin and aspartame were high in infants and children, whereas the EDI of stevioside was high in adolescents and adults. The most highly consumed sweetener was aspartame, and the highest EDI/ADI ratio was found for sodium saccharin. The main food categories contributing to sweetener consumption were beverages, including alcoholic beverages. For most Korean consumers, the EDIs were no greater than 20% of their corresponding ADI; however, the EDI of sodium saccharin for conservative consumers aged 1-2 years reached 60% of their ADI. PMID- 23802659 TI - Rituximab pharmacokinetics in children and adolescents with de novo intermediate and advanced mature B-cell lymphoma/leukaemia: a Children's Oncology Group report. AB - The ANHL01P1 trial was undertaken to determine pharmacokinetics and safety following the addition of rituximab to French-American-British/Lymphome Malins de Burkitt (FAB/LMB96) chemotherapy in 41 children and adolescents with Stage III/IV mature B-cell lymphoma/leukaemia. Patients received rituximab (375 mg/m(2) ) days -2 and 0 of two induction cycles and day 0 of two consolidation cycles. Highest peak levels were achieved following the second dose of each induction cycle [299 +/- 19 and 384 +/- 25 MUg/ml (Group-B); 245 +/- 31 and 321 +/- 32 MUg/ml (Group C)] with sustained troughs and t1/2 of 26-29 d. Rituximab can be safely added to FAB chemotherapy with high early rituximab peak/trough levels and a long t1/2. PMID- 23802661 TI - The use of transient elastography and non-invasive serum markers of fibrosis in pediatric liver transplant recipients. AB - The use of non-invasive markers to diagnose liver allograft fibrosis is not well established in children after LTx. TE, FT, and ELF score were performed in 117 liver-transplanted children (60M, 8.9 [0.5-18.5] yr) and 336 healthy controls. Liver biopsy was available in 36 children. Results of histology and non-invasive markers were compared using correlation coefficient or Mann-Whitney U-test as appropriate. TE correlated best with histological degree of fibrosis (r = 0.85 vs. r = 0.04 [FT] or r = -0.38 [ELF]). Liver stiffness values for transplanted children without fibrosis were significantly higher than those of healthy controls (7.55 [5.4-20.4] kPa vs. 4.5 [2.5-8.9] kPa). Presence of rejection was a potent confounder for the performance of TE. Both TE and FT reflected clinical changes (acute rejection, cholestasis, increasing fibrosis) in a total of 16 patients who underwent serial measurements. TE correlates better with histological degree of fibrosis in liver-transplanted children than FT or ELF, but an individual baseline value needs to be determined for each patient. Normal or cutoff values for pathological degrees of fibrosis cannot be transferred from non-transplanted children. Follow-up studies, preferably with protocol biopsies, might help to improve the diagnostic quality of TE. PMID- 23802662 TI - Malignant and benign tumors associated with multiple primary melanomas: just the starting block for the involvement of MITF, PTEN and CDKN2A in multiple cancerogenesis? PMID- 23802664 TI - Tepoxalin no longer available commercially. PMID- 23802666 TI - Pharmacokinetics of repeated oral administration of tramadol hydrochloride in Hispaniolan Amazon parrots (Amazona ventralis). AB - OBJECTIVE: To determine the pharmacokinetics of tramadol hydrochloride (30 mg/kg) following twice-daily oral administration in Hispaniolan Amazon parrots (Amazona ventralis). ANIMALS: 9 healthy adult Hispaniolan Amazon parrots. PROCEDURES: Tramadol hydrochloride was administered to each parrot at a dosage of 30 mg/kg, PO, every 12 hours for 5 days. Blood samples were collected just prior to dose 2 on the first day of administration (day 1) and 5 minutes before and 10, 20, 30, 60, 90, 180, 360, and 720 minutes after the morning dose was given on day 5. Plasma was harvested from blood samples and analyzed by high-performance liquid chromatography. Degree of sedation was evaluated in each parrot throughout the study. RESULTS: No changes in the parrots' behavior were observed. Twelve hours after the first dose was administered, mean +/- SD concentrations of tramadol and its only active metabolite M1 (O-desmethyltramadol) were 53 +/- 57 ng/mL and 6 +/ 6 ng/mL, respectively. At steady state following 4.5 days of twice-daily administration, the mean half-lives for plasma tramadol and M1 concentrations were 2.92 +/- 0.78 hours and 2.14 +/- 0.07 hours, respectively. On day 5 of tramadol administration, plasma concentrations remained in the therapeutic range for approximately 6 hours. Other tramadol metabolites (M2, M4, and M5) were also present. CONCLUSIONS AND CLINICAL RELEVANCE: On the basis of these results and modeling of the data, tramadol at a dosage of 30 mg/kg, PO, will likely need to be administered every 6 to 8 hours to maintain therapeutic plasma concentrations in Hispaniolan Amazon parrots. PMID- 23802663 TI - Sex differences in the cholinergic basal forebrain in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease. AB - In the Down syndrome (DS) population, there is an early incidence of dementia and neuropathology similar to that seen in sporadic Alzheimer's disease (AD), including dysfunction of the basal forebrain cholinergic neuron (BFCN) system. Using Ts65Dn mice, a model of DS and AD, we examined differences in the BFCN system between male and female segmentally trisomic (Ts65Dn) and disomic (2N) mice at ages 5-8 months. Quantitative stereology was applied to BFCN subfields immunolabeled for choline acetyltransferase (ChAT) within the medial septum/vertical limb of the diagonal band (MS/VDB), horizontal limb of the diagonal band (HDB) and nucleus basalis of Meynert/substantia innominata (NBM/SI). We found no sex differences in neuron number or subregion area measurement in the MS/VDB or HDB. However, 2N and Ts65Dn females showed an average 34% decrease in BFCN number and an average 20% smaller NBM/SI region area compared with genotype-matched males. Further, relative to genotype-matched males, female mice had smaller BFCNs in all subregions. These findings demonstrate that differences between the sexes in BFCNs of young adult Ts65Dn and 2N mice are region and genotype specific. In addition, changes in post-processing tissue thickness suggest altered parenchymal characteristics between male and female Ts65Dn mice. PMID- 23802667 TI - Effect of dexmedetomidine, morphine-lidocaine-ketamine, and dexmedetomidine morphine-lidocaine-ketamine constant rate infusions on the minimum alveolar concentration of isoflurane and bispectral index in dogs. AB - OBJECTIVE: To determine the effect of dexmedetomidine, morphine-lidocaine ketamine (MLK), and dexmedetomidine-morphine-lidocaine-ketamine (DMLK) constant rate infusions on the minimum alveolar concentration (MAC) of isoflurane and bispectral index (BIS) in dogs. ANIMALS: 6 healthy adult dogs. PROCEDURES: Each dog was anesthetized 4 times with a 7-day washout period between anesthetic episodes. During the first anesthetic episode, the MAC of isoflurane (baseline) was established. During the 3 subsequent anesthetic episodes, the MAC of isoflurane was determined following constant rate infusion of dexmedetomidine (0.5 MUg/kg/h), MLK (morphine, 0.2 mg/kg/h; lidocaine, 3 mg/kg/h; and ketamine, 0.6 mg/kg/h), or DMLK (dexmedetomidine, 0.5 MUg/kg/h; morphine, 0.2 mg/kg/h; lidocaine, 3 mg/kg/h; and ketamine 0.6 mg/kg/h). Among treatments, MAC of isoflurane was compared by means of a Friedman test with Conover posttest comparisons, and heart rate, direct arterial pressures, cardiac output, body temperature, inspired and expired gas concentrations, arterial blood gas values, and BIS were compared with repeated-measures ANOVA and a Dunn test for multiple comparisons. RESULTS: Infusion of dexmedetomidine, MLK, and DMLK decreased the MAC of isoflurane from baseline by 30%, 55%, and 90%, respectively. Mean heart rates during dexmedetomidine and DMLK treatments was lower than that during MLK treatment. Compared with baseline values, mean heart rate decreased for all treatments, arterial pressure increased for the DMLK treatment, cardiac output decreased for the dexmedetomidine treatment, and BIS increased for the MLK and DMLK treatments. Time to extubation and sternal recumbency did not differ among treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Infusion of dexmedetomidine, MLK, or DMLK reduced the MAC of isoflurane in dogs. PMID- 23802668 TI - Effect of underwater treadmill exercise on postural sway in horses with experimentally induced carpal joint osteoarthritis. AB - OBJECTIVE: To evaluate the effect of underwater treadmill exercise on static postural sway in horses with experimentally induced carpal joint osteoarthritis under various stance conditions. ANIMALS: 16 horses. PROCEDURES: On day 0, osteoarthritis was induced arthroscopically in 1 randomly selected middle carpal joint of each horse. Beginning on day 15, horses were assigned to either underwater or overground (without water) treadmill exercise at the same speed, frequency, and duration. Two serial force platforms were used to collect postural sway data from each horse on study days -7, 14, 42, and 70. Horses were made to stand stationary on the force platforms under 3 stance conditions: normal square stance, base-narrow placement of the thoracic limbs, and removal of visual cues (blindfolded) during a normal square stance. The mean of 3 consecutive, 10-second trials in each condition was calculated and used for analysis. RESULTS: Displacement of the center of pressure differed significantly depending on the stance condition. Among horses exercised on the underwater treadmill, postural stability in both the base-narrow and blindfolded stance conditions improved, compared with findings for horses exercised on the overground treadmill. Horses exercised on the overground treadmill were only successful at maintaining a stable center of pressure during the normal square stance position. CONCLUSIONS AND CLINICAL RELEVANCE: Variations in stance position had profound effects on the mechanics of standing balance in horses with experimentally induced carpal joint osteoarthritis. Underwater treadmill exercise significantly improved the horses' postural stability, which is fundamental in providing evidence-based support for equine aquatic exercise. PMID- 23802669 TI - Modulation of inflammation and oxidative stress in canine chondrocytes. AB - OBJECTIVE: To determine whether oxidative stress could be induced in canine chondrocytes in vitro. SAMPLE: Chondrocytes obtained from healthy adult mixed breed dogs. PROCEDURES: Harvested chondrocytes were maintained at 37 degrees C with 5% CO2 for 24 hours. To assess induction of oxidative stress, 2 stimuli were used: hydrogen peroxide and a combination of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha). To determine the effect of hydrogen peroxide, a set of chondrocyte-seeded plates was incubated with control medium alone or hydrogen peroxide (100, 200, or 300MUM) for 24 hours. For inhibition of oxidative stress, cells were incubated for 24 hours with N-acetylcysteine (NAC; 10mM) before exposure to hydrogen peroxide. Another set of chondrocyte-seeded plates was incubated with control medium alone or with IL-1beta (10 ng/mL) and TNF-alpha (1 ng/mL) for 24 hours. Supernatants were obtained for measurement of prostaglandin E2 production, and cell lysates were used for measurement of superoxide dismutase (SOD) activity and reduced-glutathione (GSH) concentration. RESULTS: Chondrocytes responded to the oxidative stressor hydrogen peroxide with a decrease in SOD activity and GSH concentration. Exposure to the antioxidant NAC caused an increase in SOD activity in hydrogen peroxide-stressed chondrocytes to a degree comparable with that in chondrocytes not exposed to hydrogen peroxide. Similarly, NAC exposure induced significant increases in GSH concentration. Activation with IL-1beta and TNF-alpha also led to a decrease in SOD activity and increase in prostaglandin E2 production. CONCLUSIONS AND CLINICAL RELEVANCE: Canine chondrocytes responded to the oxidative stress caused by exposure to hydrogen peroxide and cytokines. Exposure to oxidative stress inducers could result in perturbation of chondrocyte and cartilage homeostasis and could contribute to the pathophysiology of osteoarthritis. Use of antioxidants, on the other hand, may be helpful in the treatment of arthritic dogs. PMID- 23802670 TI - Comparative assessment of left ventricular function variables determined via cardiac computed tomography and cardiac magnetic resonance imaging in dogs. AB - OBJECTIVE: To evaluate the accuracy and reproducibility of left ventricular (LV) volumetric and function variables determined via contrast-enhanced cardiac CT and cardiac MRI in healthy dogs. ANIMALS: 10 healthy Beagles. PROCEDURES: Cardiac MRI and cardiac CT were performed in anesthetized Beagles; both examinations were conducted within a 2-hour period. Cardiac MRI was performed with a 3.0-T magnet, and contrast-enhanced cardiac CT was performed with a 64-row detector CT machine. Data sets were acquired during apnea with simultaneous ECG gating. Short-axis images were created to determine functional variables via the Simpson method. RESULTS: Cardiac CT values for mean end-diastolic and end-systolic LV volumes had excellent correlation (r = 0.95) with cardiac MRI measurements, whereas LV stroke volume (r = 0.67) and LV ejection fraction (r = 0.75) had good correlations. The only variable that differed significantly between imaging modalities was end diastolic LV volume. For each pair of values, Bland-Altman analysis revealed good limits of agreement. CONCLUSIONS AND CLINICAL RELEVANCE: The 3-D modalities cardiac CT and cardiac MRI were excellent techniques for use in assessing LV functional variables. Similar results were obtained for LV volume and function variables via both techniques. The major disadvantage of these modalities was the need to anesthetize the dogs for the examinations. PMID- 23802671 TI - Evaluation of neutrophil apoptosis in horses with acute abdominal disease. AB - OBJECTIVE: To quantify peripheral blood neutrophil apoptosis in equine patients with acute abdominal disease (ie, colic) caused by strangulating or nonstrangulating intestinal lesions and compare these values with values for horses undergoing elective arthroscopic surgery. ANIMALS: 20 client-owned adult horses. PROCEDURES: Peripheral blood was collected from horses immediately prior to and 24 hours after surgery for treatment of colic (n = 10) or elective arthroscopic surgery (10), and neutrophils were counted. Following isolation by means of a bilayer colloidal silica particle gradient and culture for 24 hours, the proportion of neutrophils in apoptosis was detected by flow cytometric evaluation of cells stained with annexin V and 7-aminoactinomycin D. Values were compared between the colic and arthroscopy groups; among horses with colic, values were further compared between horses with and without strangulating intestinal lesions. RESULTS: Percentage recovery of neutrophils was significantly smaller in preoperative samples (median, 32.5%) and in all samples combined (35.5%) for the colic group, compared with the arthroscopy group (median, 66.5% and 58.0%, respectively). No significant differences in the percentages of apoptotic neutrophils were detected between these groups. Among horses with colic, those with strangulating intestinal lesions had a significantly lower proportion of circulating apoptotic neutrophils in postoperative samples (median, 18.0%) than did those with nonstrangulating lesions (66.3%). CONCLUSIONS AND CLINICAL RELEVANCE: The smaller proportion of apoptotic neutrophils in horses with intestinal strangulation suggested that the inflammatory response could be greater or prolonged, compared with that of horses with nonstrangulating intestinal lesions. Further investigations are needed to better understand the relationship between neutrophil apoptosis and inflammation during intestinal injury. PMID- 23802672 TI - Endoscopic ultrasonographic evaluation of the esophagus in healthy dogs. AB - OBJECTIVE: To characterize the ultrasonographic appearance of the canine esophagus. ANIMALS: 14 healthy Beagles. PROCEDURES: Endoscopic ultrasonography (EUS) examinations were performed with a radial ultrasonographic gastrovideoscope in anesthetized dogs. Images were obtained at 3-cm intervals along the esophageal length to allow evaluation of the esophageal wall. Images were obtained with the probe in direct contact with the esophageal wall and with a water-filled balloon as a standoff. RESULTS: Images were obtained with (12 dogs) and without (10) the water-filled balloon. Median thickness of the esophageal wall was 2.19 mm (range, 1.03 to 5.62 mm) in the proximal third of the esophagus, 2.15 mm (range, 1.10 to 4.45 mm) in the middle third, and 2.84 mm (range, 1.35 to 5.92 mm) in the distal third. Wall thickness differed significantly between proximal and distal thirds. Results were similar when the water-filled balloon was used. Esophageal wall layers appeared as 5 alternating hyperechoic and hypoechoic bands that could not be consistently identified in all dogs. All layers could be identified in 26 of 198 (13%) images, 3 layers could be identified in 67 of 198 (34%) images, and 105 of 198 (53%) images had no layers. Visual identification of layers in images obtained with and without the balloon did not differ significantly. CONCLUSIONS AND CLINICAL RELEVANCE: EUS appeared to be a useful technique for assessing esophageal wall integrity in dogs; however, complete evaluation of all layers could not be accomplished in all instances. Further studies with this technique in dogs are needed. PMID- 23802673 TI - Effects of equine metabolic syndrome on inflammatory responses of horses to intravenous lipopolysaccharide infusion. AB - OBJECTIVE: To test the hypothesis that inflammatory responses to endotoxemia differ between healthy horses and horses with equine metabolic syndrome (EMS). Animals-6 healthy horses and 6 horses with EMS. PROCEDURES: Each horse randomly received an IV infusion of lipopolysaccharide (20 ng/kg [in 60 mL of sterile saline {0.9% NaCl} solution]) or saline solution, followed by the other treatment after a 7-day washout period. Baseline data were obtained 30 minutes before each infusion. After infusion, a physical examination was performed hourly for 9 hours and at 15 and 21 hours; a whole blood sample was collected at 30, 60, 90, 120, 180, and 240 minutes for assessment of inflammatory cytokine gene expression. Liver biopsy was performed between 240 and 360 minutes after infusion. Results Following lipopolysaccharide infusion in healthy horses and horses with EMS, mean rectal temperature, heart rate, and respiratory rate increased, compared with baseline findings, as did whole blood gene expression of interleukin (IL)-1beta, IL-6, IL-8, IL-10, and tumor necrosis factor-alpha. The magnitude of blood cytokine responses did not differ between groups, but increased expression of IL 6, IL-8, IL-10, and tumor necrosis factor-alpha persisted for longer periods in EMS-affected horses. Lipopolysaccharide infusion increased liver tissue gene expressions of IL-6 in healthy horses and IL-8 in both healthy and EMS-affected horses, but these gene expressions did not differ between groups. CONCLUSIONS AND CLINICAL RELEVANCE: Results supported the hypothesis that EMS affects horses' inflammatory responses to endotoxin by prolonging cytokine expression in circulating leukocytes. These findings are relevant to the association between obesity and laminitis in horses with EMS. PMID- 23802674 TI - Effects of intravenous lipopolysaccharide infusion on glucose and insulin dynamics in horses with equine metabolic syndrome. AB - OBJECTIVE: To test the hypothesis that glucose and insulin dynamics during endotoxemia differ between healthy horses and horses with equine metabolic syndrome (EMS). ANIMALS: 6 healthy adult mares and 6 horses with EMS. PROCEDURES: Each horse randomly received an IV infusion of lipopolysaccharide (20 ng/kg [in 60 mL of sterile saline {0.9% NaCl} solution]) or saline solution, followed by the other treatment after a 7-day washout period. Baseline insulin-modified frequently sampled IV glucose tolerance tests were performed 27 hours before and then repeated at 0.5 and 21 hours after infusion. Results were assessed via minimal model analysis and area under the curve values for plasma glucose and serum insulin concentrations. RESULTS: Lipopolysaccharide infusion decreased insulin sensitivity and increased area under the serum insulin concentration curve (treatment * time) in both healthy and EMS-affected horses, compared with findings following saline solution administration. The magnitude of increase in area under the plasma glucose curve following LPS administration was greater for the EMS-affected horses than it was for the healthy horses. Horses with EMS that received LPS or saline solution infusions had decreased insulin sensitivity over time. CONCLUSIONS AND CLINICAL RELEVANCE: Glucose and insulin responses to endotoxemia differed between healthy horses and horses with EMS, with greater loss of glycemic control in EMS-affected horses. Horses with EMS also had greater derangements in glucose and insulin homeostasis that were potentially stress induced. It may therefore be helpful to avoid exposure of these horses to stressful situations. PMID- 23802675 TI - Evaluation of the effects of age and pituitary pars intermedia dysfunction on corneal sensitivity in horses. AB - OBJECTIVE: To determine effects of age and pituitary pars intermedia dysfunction (PPID) on corneal sensitivity in horses. ANIMALS: 20 adult horses allocated into 3 groups (PPID group, old [> 15 years old] horses with PPID [n = 5]; old group, old [> 15 years old] horses without PPID [9]; and young group, young [<= 10 years old] horses without PPID [6]). All horses with PPID had hirsutism and abnormal fat deposition or laminitis; none of the old or young horses had hirsutism, abnormal fat deposition, or laminitis. PROCEDURES: A Cochet-Bonnet aesthesiometer was used to measure the corneal touch threshold (CTT) in both eyes of each horse. The nylon monofilament was applied at a maximum length of 60 mm to the central region of the cornea and length was decreased by 5-mm increments until a consistent blink response was elicited. Tear production was assessed in all eyes via the Shirmer tear test (STT). RESULTS: Mean +/- SD CTT was significantly greater for young horses (47.50 +/- 4.52 mm) than for horses in the old (28.06 +/ 5.72 mm) and PPID (21.5 +/- 3.37 mm) groups. Old horses had significantly higher CTT values than did horses with PPID. The STT values were within the reference range for all groups and did not differ significantly among groups. CONCLUSIONS AND CLINICAL RELEVANCE: Corneal sensitivity decreased with both age and PPID. Because decreased corneal sensitivity is associated with impaired wound healing, increasing age and PPID may increase the risk for nonhealing or recurrent corneal ulcers in horses. PMID- 23802676 TI - Effects of chemical restraint on electroretinograms recorded sequentially in awake, sedated, and anesthetized dogs. AB - OBJECTIVE: To quantitatively and qualitatively compare electroretinography (ERG) recordings in awake, sedated, and anesthetized dogs. ANIMALS: Six 6-month-old Beagles. PROCEDURES: A brief ERG protocol for dogs was used. Following 1-minute and subsequent 5-minute dark adaptation, mixed rod-cone responses were recorded bilaterally with a handheld multispecies ERG device with dogs in each of 3 states of consciousness: awake, sedated (dexmedetomidine and butorphanol), and anesthetized (atropine and hydromorphone, followed by propofol and midazolam and anesthetic maintenance with isoflurane). Low- and high-frequency noise levels were quantified via Fourier analysis, and the effect of consciousness state on signal amplitude, implicit time, and noise was analyzed via repeated-measures ANOVA. In addition, 13 veterinary ophthalmologists who were unaware of the dogs' consciousness states subjectively graded the ERG recording quality, and scores for each tracing were compared. RESULTS: ERG amplitudes were highest in awake dogs and lowest in anesthetized dogs. Implicit times were shortest in awake dogs and longest in anesthetized dogs. Differences in b-wave amplitudes and a-wave implicit times were significant. Neither low- nor high-frequency noise levels differed significantly among consciousness states. Furthermore, no significant differences were identified among observers' scores assigned to ERG tracings. CONCLUSIONS AND CLINICAL RELEVANCE: Anesthesia and sedation resulted in significant attenuation and delay of ERG responses in dogs. Chemical restraint of dogs had no consistently significant effect on low- or high-frequency noise levels or on observer perception of signal quality. PMID- 23802677 TI - Pharmacokinetics of single-dose intragastric and intravenous pregabalin administration in clinically normal horses. AB - OBJECTIVE: To assess pharmacokinetics of pregabalin in horses after a single intragastric or IV dose. ANIMALS: 5 healthy adult mares. PROCEDURES: Horses received 1 dose of pregabalin (approx 4 mg/kg) via nasogastric tube in a crossover-design study; after a 3-week washout period, the same dose was administered IV. Food was not withheld. Plasma pregabalin concentrations in samples obtained 0 to 36 hours after administration were measured by use of ultra performance liquid chromatography with triple quadrupole tandem mass spectrometry. Pharmacokinetic variables were estimated by means of noncompartmental analysis. RESULTS: Mild sedation was observed in 2 horses following intragastric and IV pregabalin administration. Signs of mild, transient colic or behavioral abnormalities were observed in all horses following IV administration. After intragastric administration, median (range) maximal plasma concentration was 5.0 MUg/mL (4.4 to 6.7 MUg/mL), time to maximal plasma concentration was 1. 0 hour (0.5 to 2.0 hours), elimination half-life was 8.0 hours (6.2 to 9.4 hours), and area under the curve from time 0 to infinity (AUC0 infinity) was 47.2 MUg.h/mL (36.4 to 58.4 MUg.h/mL). After IV administration, initial concentration was 22.2 MUg/mL (19.8 to 27.7 MUg/mL), elimination half life was 7.74 hours (6.94 to 8.17 hours), and AUC0-infinity was 48.3 MUg.h/mL (44.8 to 57.2 MUg.h/mL). Bioavailability was 97.7% (80.7% to 109.8%). Median predicted values for minimal, mean, and maximal steady-state plasma concentrations after intragastric administration assuming an 8-hour dosing interval were 3.9, 5.3, and 6.3 MUg/mL, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: At a simulated intragastric dosage of approximately 4 mg/kg every 8 hours, median pregabalin steady-state plasma concentration in healthy horses was within the therapeutic range reported for humans. Therapeutic concentrations and safety of this dosage have not been established in horses. PMID- 23802678 TI - Promotion of melanoma cell invasion and tumor metastasis by microcystin-LR via phosphatidylinositol 3-kinase/AKT pathway. AB - Recently, we have indicated that microcystin-LR, a cyanobacterial toxin produced in eutrophic lakes or reservoirs, can increase invasive ability of melanoma MDA MB-435 cells; however, the stimulatory effect needs identification by in vivo experiment and the related molecular mechanism is poorly understood. In this study, in vitro and in vivo experiments were conducted to investigate the effect of microcystin-LR on invasion and metastasis of human melanoma cells, and the underlying molecular mechanism was also explored. MDA-MB-435 xenograft model assay showed that oral administration of nude mice with microcystin-LR at 0.001 0.1 mg/kg/d posed no significant effect on tumor weight. Histological examination demonstrated that microcystin-LR could promote lung metastasis, which is confirmed by Matrigel chamber assay suggesting that microcystin-LR treatment at 25 nM can increase the invasiveness of MDA-MB-435 cells. In vitro and in vivo experiments consistently showed that microcystin-LR exposure increased mRNA and protein levels of matrix metalloproteinases (MMP-2/-9) by activating phosphatidylinositol 3-kinase (PI3-K)/AKT. Additionally, microcystin-LR treatment at low doses (<=25 nM) decreased lipid phosphatase PTEN expression, and the microcystin-induced invasiveness enhancement and MMP-2/-9 overexpression were reversed by the PI3-K/AKT chemical inhibitor LY294002 and AKT siRNA, indicating that microcystin-LR promotes invasion and metastasis of MDA-MB-435 cells via the PI3-K/AKT pathway. PMID- 23802679 TI - The association between diet quality, dietary patterns and depression in adults: a systematic review. AB - BACKGROUND: Recent evidence suggests that diet modifies key biological factors associated with the development of depression; however, associations between diet quality and depression are not fully understood. We performed a systematic review to evaluate existing evidence regarding the association between diet quality and depression. METHOD: A computer-aided literature search was conducted using Medline, CINAHL, and PsycINFO, January 1965 to October 2011, and a best-evidence analysis performed. RESULTS: Twenty-five studies from nine countries met eligibility criteria. Our best-evidence analyses found limited evidence to support an association between traditional diets (Mediterranean or Norwegian diets) and depression. We also observed a conflicting level of evidence for associations between (i) a traditional Japanese diet and depression, (ii) a "healthy" diet and depression, (iii) a Western diet and depression, and (iv) individuals with depression and the likelihood of eating a less healthy diet. CONCLUSION: To our knowledge, this is the first review to synthesize and critically analyze evidence regarding diet quality, dietary patterns and depression. Further studies are urgently required to elucidate whether a true causal association exists. PMID- 23802680 TI - The effect of Parkinson's disease and Huntington's disease on human visuomotor learning. AB - Visuomotor adaptation is often driven by error-based (EB) learning in which signed errors update motor commands. There are, however, visuomotor tasks where signed errors are unavailable or cannot be mapped onto appropriate motor command changes, rendering EB learning ineffective; and yet, healthy subjects can learn in these EB learning-free conditions. While EB learning depends on cerebellar integrity, the neural bases of EB-independent learning are poorly understood. As basal ganglia are involved in learning mechanisms that are independent of signed error feedback, here we tested whether patients with basal ganglia lesions, including those with Huntington's disease and Parkinson's disease, would show impairments in a visuomotor learning task that prevents the use of EB learning. We employed two visuomotor throwing tasks that were similar, but were profoundly different in the resulting visual feedback. This difference was implemented through the introduction of either a lateral displacement of the visual field via a wedge prism (EB learning) or a horizontal reversal of the visual field via a dove prism (non-EB learning). Our results show that patients with basal ganglia degeneration had normal EB learning in the wedge prism task, but were profoundly impaired in the reversing prism task that does not depend on the signed error signal feedback. These results represent the first evidence that human visuomotor learning in the absence of EB feedback depends on the integrity of the basal ganglia. PMID- 23802681 TI - Nicotine affects cutaneous wound healing in stressed mice. AB - Stress is an important condition of modern life. Nicotine addiction can modulate the physiological response to stress. Cutaneous healing is a complex process resulting in scar formation, which can be delayed by stress. Therefore, the aim of this study was to investigate the effects of nicotine administration on cutaneous wound healing in chronically stressed mice. Male mice were submitted to rotational stress, whereas control animals were not subjected to stress. These stressed and control animals were treated with a transdermal nicotine patch that was changed every day. A full-thickness excisional lesion was also generated, and 14 days later, lesions had recovered. However, the Stress + Nicotine group presented a delay in wound contraction. These wounds showed a decrease in inflammatory cell infiltration and lower expression of transforming growth factor beta (TGF-beta), whereas there was an increase in angiogenesis and tumor necrosis factor-alpha (TNF-alpha) expression. In vitro fibroblast migration was also impaired by the nicotine treatment of stressed-stimulated cells. In conclusion, nicotine administration potentiates the delay in wound closure observed in mice submitted to stress. PMID- 23802682 TI - Precise supramolecular control of selectivity in the Rh-catalyzed hydroformylation of terminal and internal alkenes. AB - In this study, we report a series of DIMPhos ligands L1-L3, bidentate phosphorus ligands equipped with an integral anion binding site (the DIM pocket). Coordination studies show that these ligands bind to a rhodium center in a bidentate fashion. Experiments under hydroformylation conditions confirm the formation of the mononuclear hydridobiscarbonyl rhodium complexes that are generally assumed to be active in hydroformylation. The metal complexes formed still strongly bind the anionic species in the binding site of the ligand, without affecting the metal coordination sphere. These bifunctional properties of DIMPhos are further demonstrated by the crystal structure of the rhodium complex with acetate anion bound in the binding site of the ligand. The catalytic studies demonstrate that substrate preorganization by binding in the DIM pocket of the ligand results in unprecedented selectivities in hydroformylation of terminal and internal alkenes functionalized with an anionic group. Remarkably, the selectivity controlling anionic group can be even 10 bonds away from the reactive double bond, demonstrating the potential of this supramolecular approach. Control experiments confirm the crucial role of the anion binding for the selectivity. DFT studies on the decisive intermediates reveal that the anion binding in the DIM pocket restricts the rotational freedom of the reactive double bound. As a consequence, the pathway to the undesired product is strongly hindered, whereas that for the desired product is lowered in energy. Detailed kinetic studies, together with the in situ spectroscopic measurements and isotope-labeling studies, support this mode of operation and reveal that these supramolecular systems follow enzymatic-type Michaelis-Menten kinetics, with competitive product inhibition. PMID- 23802683 TI - Expiratory model-based method to monitor ARDS disease state. AB - INTRODUCTION: Model-based methods can be used to characterise patient-specific condition and response to mechanical ventilation (MV) during treatment for acute respiratory distress syndrome (ARDS). Conventional metrics of respiratory mechanics are based on inspiration only, neglecting data from the expiration cycle. However, it is hypothesised that expiratory data can be used to determine an alternative metric, offering another means to track patient condition and guide positive end expiratory pressure (PEEP) selection. METHODS: Three fully sedated, oleic acid induced ARDS piglets underwent three experimental phases. Phase 1 was a healthy state recruitment manoeuvre. Phase 2 was a progression from a healthy state to an oleic acid induced ARDS state. Phase 3 was an ARDS state recruitment manoeuvre. The expiratory time-constant model parameter was determined for every breathing cycle for each subject. Trends were compared to estimates of lung elastance determined by means of an end-inspiratory pause method and an integral-based method. All experimental procedures, protocols and the use of data in this study were reviewed and approved by the Ethics Committee of the University of Liege Medical Faculty. RESULTS: The overall median absolute percentage fitting error for the expiratory time-constant model across all three phases was less than 10 %; for each subject, indicating the capability of the model to capture the mechanics of breathing during expiration. Provided the respiratory resistance was constant, the model was able to adequately identify trends and fundamental changes in respiratory mechanics. CONCLUSION: Overall, this is a proof of concept study that shows the potential of continuous monitoring of respiratory mechanics in clinical practice. Respiratory system mechanics vary with disease state development and in response to MV settings. Therefore, titrating PEEP to minimal elastance theoretically results in optimal PEEP selection. Trends matched clinical expectation demonstrating robustness and potential for guiding MV therapy. However, further research is required to confirm the use of such real-time methods in actual ARDS patients, both sedated and spontaneously breathing. PMID- 23802684 TI - Molecular docking characterizes substrate-binding sites and efflux modulation mechanisms within P-glycoprotein. AB - P-Glycoprotein (Pgp) is one of the best characterized ABC transporters, often involved in the multidrug-resistance phenotype overexpressed by several cancer cell lines. Experimental studies contributed to important knowledge concerning substrate polyspecificity, efflux mechanism, and drug-binding sites. This information is, however, scattered through different perspectives, not existing a unifying model for the knowledge available for this transporter. Using a previously refined structure of murine Pgp, three putative drug-binding sites were hereby characterized by means of molecular docking. The modulator site (M site) is characterized by cross interactions between both Pgp halves herein defined for the first time, having an important role in impairing conformational changes leading to substrate efflux. Two other binding sites, located next to the inner leaflet of the lipid bilayer, were identified as the substrate-binding H and R sites by matching docking and experimental results. A new classification model with the ability to discriminate substrates from modulators is also proposed, integrating a vast number of theoretical and experimental data. PMID- 23802685 TI - A novel proposal for labelling sunscreens based on compliance and performance. AB - OBJECTIVE: To propose a new way of classifying sunscreens, which combines the labelled SPF with an objective measure of compliance. METHODS: The in vitro determination of uniformity of sunscreen application was combined with an in vivo measure of applied thickness to derive a Compliance Factor for each of 10 sunscreens. RESULTS: The predicted SPF resulting from real-life application of each sunscreen product, which is termed the SPF(in vivo veritas), was calculated from the Compliance Factor and the labelled SPF. It was shown that for a number of products, there is expected to be a significant mismatch between labelled and delivered SPF. CONCLUSION: We believe that by adopting our proposal, consumers would be given more appropriate guidance on the delivered photoprotection they can expect to receive than relying solely on the labelled SPF. PMID- 23802686 TI - A universal scheme to convert aromatic molecular monolayers into functional carbon nanomembranes. AB - Free-standing nanomembranes with molecular or atomic thickness are currently explored for separation technologies, electronics, and sensing. Their engineering with well-defined structural and functional properties is a challenge for materials research. Here we present a broadly applicable scheme to create mechanically stable carbon nanomembranes (CNMs) with a thickness of ~0.5 to ~3 nm. Monolayers of polyaromatic molecules (oligophenyls, hexaphenylbenzene, and polycyclic aromatic hydrocarbons) were assembled and exposed to electrons that cross-link them into CNMs; subsequent pyrolysis converts the CNMs into graphene sheets. In this transformation the thickness, porosity, and surface functionality of the nanomembranes are determined by the monolayers, and structural and functional features are passed on from the molecules through their monolayers to the CNMs and finally on to the graphene. Our procedure is scalable to large areas and allows the engineering of ultrathin nanomembranes by controlling the composition and structure of precursor molecules and their monolayers. PMID- 23802687 TI - In vitro and in vivo antiproliferative effect of a combination of ultraviolet-A and alkoxy furocoumarins isolated from Umbelliferae medicinal plants, in melanoma cells. AB - We examined the effects of six furocoumarins with alkoxy groups at the C-5 or C-8 position isolated from Umbelliferae medicinal plants on cell proliferation, and their mechanisms of action against B16F10 melanoma cells or in melanin-possessing hairless mice implanted with B16F10 cells, under UVA irradiation. Three furocoumarins with an alkoxy group at C-5, isoimperatorin (1), oxypeucedanin (2) and oxypeucedanin hydrate (3), showed antiproliferative activity and caused G2/M arrest at concentrations of 0.1-10.0 MUm. Furthermore, three furocoumarins with an alkoxy group at C-8, imperatorin (4), heraclenin (5) and heraclenol (6), inhibited the proliferation of melanoma cells and cell cycle at G2/M at concentrations of 0.1-1.0 MUm. UVA plus 1, 2, 3, 4 and 6 reduced tumor growth and final tumor weight in B16F10-bearing mice at a dose of 0.3, 0.5 or 1.0 mg kg(-1) (intraperitoneal injection). UVA plus 1, 3 and 6 increased Chk1 phosphorylation and reduced cdc2 (Thr 161) phosphorylation in melanoma cells. We suggest that the antitumor actions of UVA plus furocoumarins with an alkoxy group at C-5 or C-8 were due to G2/M arrest of the cell cycle by an increase in phosphor-Chk1 and decrease in phospho-cdc2. PMID- 23802688 TI - Pressure-controlled motion of single polymers through solid-state nanopores. AB - Voltage-biased solid-state nanopores are well established in their ability to detect and characterize single polymers, such as DNA, in electrolytes. The addition of a pressure gradient across the nanopore yields a second molecular driving force that provides new freedom for studying molecules in nanopores. In this work, we show that opposing pressure and voltage bias enables nanopores to detect and resolve very short DNA molecules, as well as to detect near-neutral polymers. PMID- 23802690 TI - Evaluation of lorcaserin for the treatment of obesity. AB - INTRODUCTION: Obesity is an epidemic associated with significant morbidity. Lorcaserin , a novel serotonin 2C receptor antagonist, was recently approved as an adjunct to lifestyle modification for long-term weight loss and maintenance. Clinical studies in patients without diabetes demonstrated 5.8% mean weight loss from baseline with lorcaserin compared to 2.5% with placebo and over twice as many patients achieved >= 5% weight loss. Patients with diabetes achieved mean weight loss of 4.5% with lorcaserin compared to 1.5% with placebo as well as modest improvements in glycemic outcomes. AREAS COVERED: The authors review the pharmacology and clinical efficacy as well as the safety and tolerability of lorcaserin. This was achieved through a PubMed search (1960 - present) on lorcaserin to generate the key literature in the area. The lorcaserin package insert and Food and Drug Administration briefing documents were also used to identify relevant information. To assess long-term clinical efficacy and safety, the authors used studies with a minimum duration of one year. EXPERT OPINION: Lorcaserin induces moderate but significant weight loss compared to placebo as an adjunct to lifestyle modification. Although head-to-head comparison trials are not available, lorcaserin is likely less effective but better tolerated than its recently approved competitor, phentermine/topiramate. Cardiovascular outcome data will be invaluable in determining lorcaserin's eventual utilization and place in therapy. PMID- 23802689 TI - Three dimensional, radiosteriometric analysis (RSA) of equine stifle kinematics and articular surface contact: a cadaveric study. AB - REASONS FOR PERFORMING STUDY: Studies examining the effect of stifle joint angle on tibial rotation, adduction-abduction angle and articular contact area are lacking. OBJECTIVES: To test the hypothesis that tibial rotation, adduction abduction angle and articular contact area change with stifle joint angle. STUDY DESIGN: Descriptive study of normal kinematics and articular contact patterns of the equine stifle through the functional range of motion using 3 dimensional (3D) radiosteriometric analysis (RSA) and equine cadaver stifles. METHODS: Multiple, radiopaque markers were embedded in the distal femur and proximal tibia and sequential, biplanar x-rays captured as the stifle was passively extended from 110 degrees to full extension. Computer-programmed RSA was used to determine changes in abduction-adduction and internal-external rotation angles of the tibia during stifle extension as well as articular contact patterns (total area and areas of high contact) through the range of motion. RESULTS: The tibia rotated externally (P < 0.001) as the stifle was extended. Tibial abduction occurred from 110-135 degrees of extension (P < 0.001) and tibial adduction occurred from 135 degrees through full extension (P = 0.009). The centre of joint contact moved cranially on both tibial condyles during extension with the lateral moving a greater distance than the medial (P = 0.003). Articular contact area decreased (P = 0.001) in the medial compartment but not in the lateral compartment (P = 0.285) as the stifle was extended. The area of highest joint contact increased on the lateral tibial condyle (P < 0.001) with extension but decreased (P = 0.001) on the medial tibial condyle. CONCLUSIONS: Significant changes occur in tibial rotation, adduction-abduction angle and articular contact area of the equine stifle through the functional range of motion. Understanding the normal kinematics of the equine stifle and the relationship between joint positions and articular contact areas may provide important insight into the aetiology and location of common stifle joint pathologies (articular cartilage and meniscal lesions). PMID- 23802692 TI - Analysis of the neurotoxin anisatin in star anise by LC-MS/MS. AB - The aim of this work was to develop an analytical method capable of determining the presence of anisatin in star anise. This neurotoxin may induce severe side effects such as epileptic convulsions. It is therefore of prime importance to have rapid and accurate analytical methods able to detect and quantify anisatin in samples that are purportedly edible star anise. The sample preparation combined an automated accelerated solvent extraction with a solid-supported liquid-liquid purification step on EXtrelut(r). Samples were analysed on a porous graphitic carbon HPLC column and quantified by tandem mass spectrometry operating in the negative ionisation mode. The quantification range of anisatin was between 0.2 and 8 mg kg-1. The applicability of this validated method was demonstrated by the analysis of several Illicium species and star anise samples purchased on the Swiss market. High levels of anisatin were measured in Illicium lanceolatum, I. majus and I. anisatum, which may cause health concerns if they are misidentified or mixed with edible Illicium verum. PMID- 23802693 TI - Surgical extrusion as a treatment option for crown-root fracture in permanent anterior teeth: a systematic review. AB - BACKGROUND: A crown-root fracture is defined as a fracture involving enamel, dentin, and cementum. The possibility of saving and reconstructing teeth with such fractures has increasingly become a viable alternative to extraction and prosthetic therapy. One such treatment option available is surgical extrusion. OBJECTIVE: The aim of this review is to evaluate surgical extrusion as a treatment modality for management of crown-root fractures in permanent anterior teeth. METHODS: Electronic search of scientific papers was carried out on Entrez Pubmed and the Cochrane Central Register of Controlled Trials databases using specific keywords. The search yielded 130 papers, out of which 16 relevant papers were identified and included based on predetermined inclusion criteria and the remaining 114 were found to be irrelevant. Hand search yielded 10 articles, which were also included. These 26 articles which included only case reports and case series formed the basis of this systematic review. CONCLUSION: From the existing literature, we can conclude that surgical extrusion can be used to treat crown root fractures successfully. But the level of evidence is very low as the studies available are only case reports and case series. PMID- 23802694 TI - Isolated versus pierre robin sequence cleft palates: are they different? AB - OBJECTIVE: To determine if there are any differences in size between isolated cleft palates (CPs) and those associated with Pierre Robin (PR) sequence. STUDY DESIGN: Prospective case series. SETTINGS: Tertiary care hospital. SUBJECTS AND METHODS: From 1993 to 2011, nonsyndromic isolated CP and PR sequence cases were classified as severe if the patients had respiratory or feeding difficulties. While patients were under general anesthesia, seven anatomical cleft parameters were prospectively measured in the operating room at the time of palatoplasty. RESULTS: Fifty-seven patients without the PR sequence and 36 patients with the PR sequence were enrolled. Within the PR group, 61% of cases were mild and 39% were severe. A larger soft palate width was found to be statistically significant in a comparison of the severe PR cases with the isolated clefts (P < .005) and mild PR (P < .05), respectively. For the hard palate width, a statistically significant difference was found in a comparison of the narrower isolated cleft cases with the mild PR (P < .05) and the severe PR cases (P < .05), respectively. A shorter cleft length was found to be statistically significant in isolated clefts versus both the clefts of the mild PR (P < .05) and the severe PR cases (P < .05). CONCLUSIONS: The patients with PR sequence presented statistically significant different cleft characteristics. The increased width of the cleft at the soft palate level showed the greatest correlation with increased airway and feeding problems. PMID- 23802695 TI - High prevalence of IncP-1 plasmids and IS1071 insertion sequences in on-farm biopurification systems and other pesticide-polluted environments. AB - Mobile genetic elements (MGEs) are considered as key players in the adaptation of bacteria to degrade organic xenobiotic recalcitrant compounds such as pesticides. We examined the prevalence and abundance of IncP-1 plasmids and IS1071, two MGEs that are frequently linked with organic xenobiotic degradation, in laboratory and field ecosystems with and without pesticide pollution history. The ecosystems included on-farm biopurification systems (BPS) processing pesticide-contaminated wastewater and soil. Comparison of IncP-1/IS1071 prevalence between pesticide treated and nontreated soil and BPS microcosms suggested that both IncP-1 and IS1071 proliferated as a response to pesticide treatment. The increased prevalence of IncP-1 plasmids and IS1071-specific sequences in treated systems was accompanied by an increase in the capacity to mineralize the applied pesticides. Both elements were also encountered in high abundance in field BPS ecosystems that were in operation at farmyards and that showed the capacity to degrade/mineralize a wide range of chlorinated aromatics and pesticides. In contrast, IS1071 and especially IncP-1, MGE were less abundant in field ecosystems without pesticide history although some of them still showed a high IS1071 abundance. Our data suggest that MGE-containing organisms were enriched in pesticide-contaminated environments like BPS where they might contribute to spreading of catabolic genes and to pathway assembly. PMID- 23802696 TI - A fungal endophyte induces transcription of genes encoding a redundant fungicide pathway in its host plant. AB - BACKGROUND: Taxol is an anti-cancer drug harvested from Taxus trees, proposed ecologically to act as a fungicide. Taxus is host to fungal endophytes, defined as organisms that inhabit plants without causing disease. The Taxus endophytes have been shown to synthesize Taxol in vitro, providing Taxus with a second potential biosynthetic route for this protective metabolite. Taxol levels in plants vary 125-fold between individual trees, but the underlying reason has remained unknown. RESULTS: Comparing Taxus trees or branches within a tree, correlations were observed between Taxol content, and quantity of its resident Taxol-producing endophyte, Paraconiothyrium SSM001. Depletion of fungal endophyte in planta by fungicide reduced plant Taxol accumulation. Fungicide treatment of intact plants caused concomitant decreases in transcript and/or protein levels corresponding to two critical genes required for plant Taxol biosynthesis. Taxol showed fungicidal activity against fungal pathogens of conifer wood, the natural habitat of the Taxol-producing endophyte. Consistent with other Taxol-producing endophytes, SSM001 was resistant to Taxol. CONCLUSIONS: These results suggest that the variation in Taxol content between intact Taxus plants and/or tissues is at least in part caused by varying degrees of transcriptional elicitation of plant Taxol biosynthetic genes by its Taxol-producing endophyte. As Taxol is a fungicide, and the endophyte is resistant to Taxol, we discuss how this endophyte strategy may be to prevent colonization by its fungal competitors but at minimal metabolic cost to itself. PMID- 23802697 TI - Increased expression of CIP2A in aggressive subtypes of B-cell lymphoma. PMID- 23802698 TI - Effects of advanced treatment systems on the removal of antibiotic resistance genes in wastewater treatment plants from Hangzhou, China. AB - This study aimed at quantifying the concentration and removal of antibiotic resistance genes (ARGs) in three municipal wastewater treatment plants (WWTPs) employing different advanced treatment systems [biological aerated filter, constructed wetland, and ultraviolet (UV) disinfection]. The concentrations of tetM, tetO, tetQ, tetW, sulI, sulII, intI1, and 16S rDNA genes were examined in wastewater and biosolid samples. In municipal WWTPs, ARG reductions of 1-3 orders of magnitude were observed, and no difference was found among the three municipal WWTPs with different treatment processes (p > 0.05). In advanced treatment systems, 1-3 orders of magnitude of reductions in ARGs were observed in constructed wetlands, 0.6-1.2 orders of magnitude of reductions in ARGs were observed in the biological aerated filter, but no apparent decrease by UV disinfection was observed. A significant difference was found between constructed wetlands and biological filter (p < 0.05) and between constructed wetlands and UV disinfection (p < 0.05). In the constructed wetlands, significant correlations were observed in the removal of ARGs and 16S rDNA genes (R(2) = 0.391-0.866; p < 0.05). Constructed wetlands not only have the comparable ARG removal values with WWTP (p > 0.05) but also have the advantage in ARG relative abundance removal, and it should be given priority to be an advanced treatment system for further ARG attenuation from WWTP. PMID- 23802699 TI - Factors associated with topical retinoid prescriptions for acne. AB - BACKGROUND: Topical retinoids are recommended as the main therapy for most acne patients. OBJECTIVE: To examine the factors associated with topical retinoid prescriptions for acne. METHODS: Retrospective analyses used data from the 2005 2010 National Ambulatory Medical Care Survey (NAMCS) and the 2004-2007 Marketscan Medicaid Database. Multivariate logistic regression models were used to assess the impact of patient and physician factors on the probability of getting a topical retinoid prescription. RESULTS: Results from analyzing the NAMCS data showed that topical retinoids were prescribed in 40.9% of acne-related physician visits. Older age, male gender, and having Medicaid insurance were associated with a lower likelihood of getting a topical retinoid prescription. Moreover, we found in the Medicaid dataset that seeing a pediatrician or family doctor was associated with lower odds of getting a topical retinoid prescription than seeing a dermatologist (OR = 0.24, 95% CI: 0.23, 0.25). LIMITATIONS: The available databases do not provide an assessment of the severity of the lesions either at baseline or over time. CONCLUSION: The frequency of receiving a topical retinoid prescription among acne patients was low and it was associated with age, gender, insurance type and physician specialty. PMID- 23802700 TI - Health-related quality of life and congenital heart disease in Australia. AB - AIM: To determine whether, in children with congenital heart disease (CHD), disease severity is associated with health-related quality of life (HRQOL) and impact on the family. METHODS: Cross-sectional, single-centre study comparing HRQOL outcomes of age and sex matched children with hypoplasia of the left ventricle (HLV) (n = 31) and tetralogy of Fallot (n = 29) was performed in Queensland, Australia. HRQOL was assessed using generic and disease-specific components of the Paediatric Quality of Life Inventory Measurement Model (PedsQL). Intra-diagnostic age group comparisons of HRQOL were examined. Impact of CHD on families and parental HRQOL was assessed using the PedsQL Family Impact Scale. RESULTS: Child and parent-proxy reporting indicate children with HLV have significantly lower overall HRQOL than children with tetralogy of Fallot across generic domains of HRQOL (P < 0.0001), with significantly lower scores in physical (P < 0.0001) and psychosocial (P < 0.0001) health domains. No significant difference in child reporting across domains of the Cardiac Module is evident. Parent-proxy reporting indicates significantly lower scores on the symptom scales for children with HLV (P < 0.001), with greater cognitive problems (P < 0.02) and perceived treatment anxiety (P < 0.01). No significant differences in HRQOL were identified between age groups. HLV has a greater overall family impact, with significantly lower parental HRQOL (P = 0.0001) and family functioning (P < 0.0001) summary scores. CONCLUSIONS: The more severe condition of HLV is associated with poorer HRQOL in some domains and has greater impact on parental HRQOL and family functioning. PMID- 23802701 TI - Association between plasma free haem and incidence of vaso-occlusive episodes and acute chest syndrome in children with sickle cell disease. AB - We tested the hypothesis that extracellular haem is linked to the incidence of acute complications of sickle cell disease (SCD). Using multivariable regression analysis, higher plasma free haem, but not total plasma haem, was associated with increased odds of vaso-occlusive crisis (VOC) [P = 0.028, odds ratio (OR); 2.05, 95% Confidence Interval (CI) = 1.08-3.89] and acute chest syndrome (ACS) [P = 0.016, OR; 2.56, CI = 1.19, 5.47], after adjusting for age and gender in children with SCD. These findings suggest that haem and factors that influence its concentration in plasma may be informative of the risk of VOC and ACS in SCD patients. PMID- 23802702 TI - Sc3+-triggered oxoiron(IV) formation from O2 and its non-heme iron(II) precursor via a Sc3+-peroxo-Fe3+ intermediate. AB - We report that redox-inactive Sc(3+) can trigger O2 activation by the Fe(II)(TMC) center (TMC = tetramethylcyclam) to generate the corresponding oxoiron(IV) complex in the presence of BPh4(-) as an electron donor. To model a possible intermediate in the above reaction, we generated an unprecedented Sc(3+) adduct of [Fe(III)(eta(2)-O2)(TMC)](+) by an alternative route, which was found to have an Fe(3+)-(MU-eta(2):eta(2)-peroxo)-Sc(3+) core and to convert to the oxoiron(IV) complex. These results have important implications for the role a Lewis acid can play in facilitating O-O bond cleavage during the course of O2 activation at non heme iron centers. PMID- 23802703 TI - Increasing girls' knowledge about human papillomavirus vaccination with a pre test and a national leaflet: a quasi-experimental study. AB - BACKGROUND: Adolescent girls are at an age to be involved in the decision about HPV vaccination uptake and therefore need adequate information about the vaccination. This study assesses to what extent reading an official information leaflet about HPV contributes to girls' knowledge levels, and to what extent an increase in knowledge is boosted by a pre-test measurement. METHODS: Participants (girls aged 11-14 years) were systematically allocated to group A that completed a pre-test measurement (12 true/false statements) or to group B that did not complete it. Subsequently, both groups read the HPV leaflet and completed the post-test measurement. RESULTS: The response rate was 237/287 (83%). Pre-test scores in group A (M = 3.6, SD = 1.81, p < 0.001) were lower than post-test mean knowledge scores (0-10) in group B (M = 4.6, SD = 2.05). Post-test knowledge scores in group A were higher than those in group B [6.2 (SD = 2.06) versus 4.6 (SD = 2.05), p < 0.001]. In the post-test measurement, about a third of both groups knew that vaccinations do not give 100% protection against cervical cancer and that the duration of protection is unknown. CONCLUSIONS: Reading the information leaflet had a positive effect on knowledge, even more so when boosted by a pre-test measurement. However, knowledge on the degree and duration of protection against cervical cancer remained limited. Focusing girls' attention on important aspects before they start reading the leaflet (e.g. by including a quiz on the first page) may serve to raise their awareness of these aspects. PMID- 23802704 TI - Immobilization of glutaminase enzyme from Hypocria jecorina on polyacrylic acid: preparation and biochemical characterization. AB - L-glutaminase enzyme produced from Hypocrea jecorina pure culture and polyacrylic acid (PAA) in the presence (Cu2+) ions were composed the ternary complex at pH 7. The properties of free and immobilized enzyme were defined. The effect of various factors such as pH, temperature, heat, and storage stability on immobilized enzyme were investigated. The properties of immobilized enzyme were investigated and compared to those of free enzyme. Optimum pH and temperature of both enzyme were determined to be 8.0 and 50 degrees C, respectively. Kinetic parameters of the immobilized enzyme (Km and Vmax values) were also determined as 0.38 mM of the Km and 10.9 U/L of the Vmax. No drastic change was observed in the Km and Vmax values. Thermal and storage stability experiments were carried out. The thermal stability studies indicated that the immobilization process tends to stabilize the enzyme. PMID- 23802705 TI - Reliability and reproducibility of retinal oxygen saturation measurements using a predefined peri-papillary annulus. AB - PURPOSE: To determine the reliability and reproducibility of the Vesselmap Oximetry Module for arteriolar and venular oxygen saturation (SO2 ) of the same retinal area, specified by a peripapillary annulus, in healthy subjects. METHODS: Fundus oximetry images were obtained, using a standardized protocol by a single observer, from the right eye of 20 healthy individuals. Age range was 19-45 years old, and images were analysed using the oximetry module of the Vesselmap System (Imedos, UG, Germany). Intra-observer reliability (assessment of two measurements of SO2 values performed 5 days apart); interobserver reliability (assessment of SO2 performed by two different trained observers); and intrasubject reproducibility (comparison of SO2 measurements of two different images of the same subject and retinal area, taken 10 min apart) were assessed. The standard deviations between the repeated measurements (SDr), together with the intraclass correlation coefficient (ICC), of these three parameters were calculated. RESULTS: The SDr for intra-observer reliability was 0.56% and 0.55% for arteriolar and venular SO2 , respectively. The results were similar for intrasubject reproducibility (0.69% and 0.79% for arteriolar and venular SO2, respectively); interobserver reliability, however, was higher (SDr 1.22% and 1.01% for arteriolar and venular SO2 , respectively). The ICC values for intra observer reliability were 0.99 for both arteriolar and venular SO2 . The results were similar for both interobserver reliability (0.94 for arteriolar SO2 and 0.96 for venular SO2 ) and intrasubject reproducibility (0.98 for both arteriolar and venular SO2 ). CONCLUSION: Retinal oxygen saturation values taken using the oximetry module of the Vesselmap System are highly reliable and reproducible, provided the image quality is standardized, the same measurement area is analysed in each image, and the number of observers analysing the images is kept to a minimum. PMID- 23802707 TI - Gate-dependent carrier diffusion length in lead selenide quantum dot field-effect transistors. AB - We report a scanning photocurrent microscopy (SPCM) study of colloidal lead selenide (PbSe) quantum dot (QD) thin film field-effect transistors (FETs). PbSe QDs are chemically treated with sodium sulfide (Na2S) and coated with amorphous alumina (a-Al2O3) by atomic layer deposition (ALD) to obtain high mobility, air stable FETs with a strongly gate-dependent conductivity. SPCM reveals a long photocurrent decay length of 1.7 MUm at moderately positive gate bias that decreases to below 0.5 MUm at large positive gate voltage and all negative gate voltages. After excluding other possible mechanisms including thermoelectric effects, a thick depletion width, and fringing electric fields, we conclude from photocurrent lifetime measurements that the diffusion of a small fraction of long lived carriers accounts for the long photocurrent decay length. The long minority carrier lifetime is attributed to charge traps for majority carriers. PMID- 23802706 TI - A phase 3, randomized, double-blind comparison of analgesic efficacy and tolerability of Q8003 vs oxycodone or morphine for moderate-to-severe postoperative pain following bunionectomy surgery. AB - OBJECTIVE: Compare the efficacy and tolerability of the dual-opioid, Q8003((r)) (morphine/oxycodone combination) 12 mg/8 mg to morphine 12 mg or oxycodone 8 mg in subjects following bunionectomy surgery. DESIGN: This was a randomized, double blind study. SETTING: Hospitalized patients. PATIENTS: Healthy men or women aged >=18 years with moderate or severe pain (score >=2 on a 4-point Likert scale) and >=4 on the 11-point numerical pain rating scale following surgery. INTERVENTIONS: Study medication was initiated after surgery and was given for 48 hours. OUTCOMES: The primary efficacy variable was mean sum of the pain intensity difference (SPID) scores from the postsurgical baseline. RESULTS: Five hundred twenty-two subjects were randomized; 31 (5.9%) discontinued, including 19 (3.6%) for adverse events. The mean total morphine equivalent dose (MED) was 182.7 mg from Q8003 12 mg/8 mg, 92.4 mg for morphine 12 mg, and 92.1 mg for oxycodone 8 mg. SPID from baseline over 24 hours and SPID from baseline over 48 hours were significantly (P < 0.02) higher for Q8003 12 mg/8 mg vs morphine 12 mg or oxycodone 8 mg. Significantly (P < 0.015) fewer subjects in the Q8003 group required ibuprofen rescue medication, used lower doses of rescue medication, and had a longer median time to first use of rescue medication. Oxygen desaturation <90% occurred in 5.3% with Q8003, 2.8% with morphine 12 mg, and 2.3% with oxycodone 8 mg, and the cumulative median dose at first desaturation was twofold greater with Q8003. CONCLUSION: Q8003 provided superior efficacy to its individual components at twice the MED with only a modest increase in the incidence of adverse events. PMID- 23802708 TI - Prevalence of root caries among ambulant older adults living in central Chile. AB - OBJECTIVE: To assess the prevalence of root caries and the treatment needs in an ambulant population of older adults, living in the Maule Region, Chile. BASIC RESEARCH DESIGN: The source of primary data was the Regional Oral Health Survey. A random sample of 438 older adults, aged 65-74 years, living independently in the community was orally examined, and underwent an oral health interview. RESULTS: This was a largely dentate population (74.9%). Dentate participants had 70.4% of their root surfaces with recession. Those with exposed root surfaces had an average of 29.8 root surfaces exposed. The root caries index (RCI) was 8.23%, and a mean of 0.21 and 0.55 root surfaces filled and decayed, respectively. CONCLUSION: Participants had better oral health status than previously reported. Consistent with studies conducted in independent-living older adults, root caries occurred in a lower frequency among Chilean ambulant older adults. The proportion of unmet restorative needs could be reduced. Community-based preventive care programmes specifically tailored to older adults are needed to address this challenge. PMID- 23802709 TI - Chemical and thermodynamic control of the surface of semiconductor nanocrystals for designer white light emitters. AB - Small CdSe semiconductor nanocrystals with diameters below 2 nm are thought to emit white light due to random surface defects which result in a broad distribution of midgap emitting states, thereby preventing rational design of small nanocrystal white light emitters. We perform temperature dependent photoluminescence experiments before and after ligand exchange and electron transfer simulations to reveal a very simple microscopic picture of the origin of the white light. These experiments and simulations reveal that these small nanocrystals can be physically modeled in precisely the same way as normal-sized semiconductor nanocrystals; differences in their emission spectra arise from their surface thermodynamics. The white light emission is thus a consequence of the thermodynamic relationship between a core excitonic state and an optically bright surface state with good quantum yield. By virtue of this understanding of the surface and the manner in which it is coupled to the core excitonic states of these nanocrystals, we show both chemical and thermodynamic control of the photoluminescence spectra. We find that using both temperature and appropriate choice in ligands, one can rationally control the spectra so as to engineer the surface to target color rendering coordinates for displays and white light emitters. PMID- 23802710 TI - A method for estimating the residual risk of transfusion-transmitted HBV infection associated with occult hepatitis B virus infection in a donor population without universal anti-HBc screening. AB - BACKGROUND AND OBJECTIVES: This report describes a method for estimating the risk of transfusion-transmitted HBV infection attributable to blood components from donors with occult hepatitis B virus infection (OBI) applicable where universal anti-HBc screening is not performed. MATERIALS AND METHODS: In the context of parallel HBsAg and individual donation HBV DNA testing, we developed a mathematical function p(OBI) to estimate the probability of failing to detect [p(NAT nondetection)] a potentially infectious [p(transmission)] donation from a donor with OBI. RESULTS: Among 1 312 451 donations tested for HBsAg and HBV DNA, 29 (from 17 anti-HBc reactive donors classified as OBI) were individual donation NAT negative, giving a p(NAT nondetection) of 2.2096 (95 CI: 1.538-3.173) * 10( 5) . To date, lookback on OBI donors has identified 35 (8.2%) recipients with evidence of current or past HBV infection among 427 tested recipients. After correcting for the background anti-HBc rate in recipients, this results in a p(transmission) of 0.0384 (0.0167-0.0601). The product, pOBI is 1 in 981 920 (95% CI: 437 181-3 223 701). When this is summed with the WP risk for the 2011-2012 period, the overall HBV residual risk estimate is 1 in 538 224 (95% CI: 209 732-1 552 443). CONCLUSION: We estimate the OBI residual risk in Australia is approximately 1 in 982 000 per unit transfused, and this risk represents 55% of the total HBV residual risk and is declining as consequence of ID-NAT identifying repeat donors with OBI. PMID- 23802711 TI - The role of cytological follow-up after radical vaginal trachelectomy for early stage cervical cancer. AB - OBJECTIVES: To identify whether recurrences were picked up by cytology alone after radical vaginal trachelectomy and to determine the false-positive rate of abnormal cytology. METHODS: Retrospective collection of patients from the cancer registry since radical vaginal trachelectomy was first performed in Bristol in 1999. All cytology results were collated and re-reviewed by a senior consultant cellular pathologist at the cytopathology centre in Southmead Hospital, Bristol. Cytology results and pathology and survival data are discussed, and any downgrading or upgrading of reports is reviewed. RESULTS: Eighteen women were identified and 80 isthmic cytology samples were reviewed. Only one recurrence has occurred. Lower uterine segment sampling was apparent in 25 samples and other endometrial cells in 21 samples: thus 58% showed endometrial cell sampling. Odd metaplastic cells from the newly formed transformation zone were found in 25 samples (31%). Fifteen (19%) showed significant inflammation, two with actinomyces. After cytology review, seven of 80 reports were changed: two between negative and inadequate, two borderline changes in endocervical cells and one mild dyskaryosis were downgraded to negative, and two cases reported as ?glandular neoplasia were changed to squamous cell carcinoma and negative, respectively. CONCLUSIONS: Cytology reporting may be challenging after trachelectomy. Cytology in our series did not add to the diagnosis of recurrence in the one case in which it occurred. We propose a pragmatic follow-up regime, and discuss the importance of the centralization of cytology reporting in these patients. PMID- 23802712 TI - Patellofemoral contact patterns before and after total knee arthroplasty: an in vitro measurement. AB - BACKGROUND: Patellofemoral complications are one of the main problems after Total Knee Arthroplasty (TKA). Retropatellar pressure distribution after TKA can contribute to these symptoms. Therefore we evaluated retropatellar pressure distribution subdivided on the ridge, medial and lateral surface on non resurfaced patella before and after TKA. Additionally, we analyzed axial femorotibial rotation and quadriceps load before and after TKA. METHODS: Seven fresh frozen cadaver knees were tested in a force controlled knee rig before and after TKA (Aesculap, Tuttlingen, Germany, Columbus CR) while isokinetic flexing the knee from 20 degrees to 120 degrees under weight bearing. Ridge, medial and lateral retropatellar surface were defined and pressure distribution was dynamically measured while quadriceps muscles and hamstring forces were applied. Aside axial femorotibial rotation and quadriceps load was recorded. RESULTS: There was a significant change of patella pressure distribution before and after TKA (p = 0.004). In physiological knees pressure distribution on medial and lateral retropatellar surface was similar. After TKA the ridge of the patella was especially in higher flexion grades strongly loaded (6.09 +/-1.31 MPa) compared to the natural knee (2.92 +/-1.15 MPa, p < 0.0001). Axial femorotibial rotation showed typical internal rotation with increasing flexion both before and after TKA, but postoperatively it was significantly lower. The average amount of axial rotation was 3.5 degrees before and after TKA 1.3 degrees (p = 0.001). Mean quadriceps loading after implantation of knee prosthesis did not change significantly (575 N +/- 60 N in natural knee and after TKA 607 N +/- 96 N; p = 0.28). CONCLUSIONS: The increased retropatellar pressure especially on the ridge may be one important reason for anterior knee pain after TKA. The trochlea of the femoral component might highly influence the pressure distribution of the non resurfaced retropatellar surface. Additionally, lower axial femorotibial rotation after TKA might lead to patella maltracking. Changing the design of the prosthesis or a special way of patella shaping might increase the conformity of the patella to trochlea to maintain natural contact patterns. PMID- 23802713 TI - Sensitivity to itch and pain in patients with psoriasis and rheumatoid arthritis. AB - Symptoms of itch and pain in chronic inflammatory conditions of psoriasis (PS) and rheumatoid arthritis (RA) can highly affect patients' quality of life. Studies in other patient groups indicate that sensitivity to itch and pain is altered in line with the patient's main symptom of either chronic itch or pain, as a result of sensitization processes. This study directly compared whether patients with chronic inflammatory conditions associated with chronic itch or pain display a heightened sensitivity to itch and pain, respectively. Sensitivity to itch and pain was measured by applying stimuli of quantitative sensory testing (QST) in female patients with chronic itch due to PS or chronic pain due to RA. Levels of itch and pain evoked by the QST stimuli as well as the tolerance to the stimuli were determined. Patients with PS reacted to the stimuli with a higher itch response (histamine), while the patients with RA displayed a lowered tolerance to the stimuli (cold pressor test and mechanical stimulation) in comparison with the other patient group. In line with previous studies in other patient groups with chronic itch or pain, further support was found that somatosensory stimuli are processed in line with the patients' main symptom through generic sensitization processes, also in chronic inflammatory conditions such as PS and RA. PMID- 23802714 TI - Survey of peanut levels in selected Irish food products bearing peanut allergen advisory labels. AB - Peanut allergy affects up to 2% of consumers and is responsible for the majority of fatalities caused by food-induced anaphylaxis. Peanut-containing products must be clearly labelled. Manufacturers are not legally required to label peanut if its inclusion resulted from unintentional cross contact with foods manufactured in the same facility. However, the use of allergen advisory statements alerting consumers of the potential presence of peanut allergen has increased in recent years. In previous studies, the vast majority of foods with precautionary allergen statements did not contain detectable levels of peanut, but no data are available on Irish food products. Thirty-eight food products bearing peanut/nut allergen-related statements were purchased from multiple locations in the Republic of Ireland and analysed for the presence of peanut. Peanut was detected in at least one lot in 5.3% (2 of 38) of the products tested. The doses of peanut detected ranged from 0.14 mg to 0.52 mg per suggested serving size (0.035-0.13 mg peanut protein). No detectable levels of peanut were found in the products that indicated peanut/nuts as a minor ingredient. Quantitative risk assessment, based on the known distribution of individual threshold doses for peanut, indicates that only a very small percentage of the peanut-allergic population would be likely to experience an allergic reaction to those products while the majority of products with advisory labels appear safe for the peanut-allergic population. Food manufacturers should be encouraged to analyse products manufactured in shared facilities and even on shared equipment with peanuts for peanut residues to determine whether sufficient risk exists to warrant the use of advisory labelling. Although it appears that the majority of food products bearing advisory nut statements are in fact free of peanut contamination, advice to peanut allergy sufferers to avoid said foods should continue in Ireland and therefore in the wider European Union. PMID- 23802715 TI - Post-transplant lymphoproliferative disease in pediatric solid organ transplant recipients. AB - Post-transplant lymphoproliferative disease (PTLD) in solid organ transplant (SOT) recipients has become one of the most common forms of lymphoproliferation in childhood and is a serious complication of SOT. More than 90% of cases are of B-cell origin, Epstein Barr virus (EBV) positive and are mostly occurring in the early post-transplant period. Pathologically and clinically it is a heterogenous disease ranging from being responsive to reduced immunosuppression without further intervention to rapidly progressive fulminant PTLD requiring prompt initiation of therapy. Prognosis overall is favorable. Current treatment strategies as well new promising targeted immune-based therapies such as rituximab and EBV-specific cytotoxic T-lymphocytes are being discussed. PMID- 23802716 TI - Synthesis, in vitro, and in cell studies of a new series of [indoline-3,2' thiazolidine]-based p53 modulators. AB - Analogues of the previously described spiro[imidazo[1,5-c]thiazole-3,3'-indoline] 2',5,7(6H,7aH)-trione p53 modulators were prepared to explore new structural requirements at the thiazolidine domain for the antiproliferative activity and p53 modulation. In cell, antiproliferative activity was evaluated against two human tumor cell lines. Derivative 5-bromo-3'-(cyclohexane carbonyl)-1-methyl-2 oxospiro[indoline-3,2'-thiazolidine] (4n) emerged as the most potent compound of this series, inhibiting in vitro 30% of p53-MDM2 interaction at 5 MUM and the cell growth of different human tumor cells at nanomolar concentrations. Docking studies confirmed the interactions of 4n with the well-known Trp23 and Phe19 clefts, explaining the reasons for its binding affinity for MDM2. 4n at 50 nM is capable of inducing the accumulation of p53 protein, inducing significant apoptotic cell death without affecting the cell cycle progression. Comparative studies using nutlin in the same cellular system confirm the potential of 4n as a tool for increasing understanding of the process involved in the nontranscriptional proapoptotic activities of p53. PMID- 23802717 TI - Development of an in vitro model of menopause using primary human dermal fibroblasts. AB - OBJECTIVE: To overcome the current lack of in vitro models to specifically reproduce hormonal skin ageing in women, and in search of active ingredients with innovative efficacy claim for cosmetic skin care, we developed a cell culture based model by simulating menopause's hormonal decline and assessed several parameters of collagen metabolism. METHODS: Human dermal fibroblasts were incubated with media containing 17beta-oestradiol, progesterone, dehydroepiandrosterone, growth hormone and insulin-like growth factor-1 at concentrations corresponding to those of non-menopausal women's sera and then of menopausal women's sera. We measured cell proliferation [by 3-[4,5 dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT)], matrix metalloproteinase-1 and metalloproteinase-3 (MMPs) release (by enzyme-linked immunosorbent assay - ELISA), total collagen deposition (by Sirius red staining), types I and III collagen deposition (by ELISA), and types I and III procollagen gene expression (by real-time q-RT-PCR). RESULTS: Our results showed a significant decrease over time in cell proliferation, collagen deposition and type III/type I collagen ratio, together with an increase in MMP release, when cells were incubated in media containing sex hormones at menopausal levels. This is consistent with in vivo data from menopausal women available in the literature. Surprisingly, procollagen gene expression was only reduced within the first hours and increased afterwards when compared with non-menopausal culture conditions. CONCLUSION: Our results demonstrated that the increased procollagen synthesis with menopausal conditions was not sufficient to compensate for the MMPs' catabolic effects and/or the impaired procollagen protein maturation, resulting in a decrease in extracellular collagen content. These findings add to the overall understanding of hormone-dependent skin behaviour and highlight the suitability of this in vitro model for cosmetic actives testing aiming to underpin claims of anti-ageing efficacy, specifically for menopausal women, regarding collagen metabolism and balance of types, for maintenance of dermal mechanical properties. PMID- 23802718 TI - Sliding of water droplets on smooth hydrophobic silane coatings with regular triangle hydrophilic regions. AB - The effect of the triangular pinning region on the sliding of water droplets on the smooth hydrophobic surface was investigated. Smooth hydrophobic silane coatings with various regular triangle hydrophilic regions were prepared using photolithography and octadecyltrimethoxysilane (ODS). The hydrophilic area in the surfaces was aligned hexagonally with a constant area fraction. Thereby water contact angles of the coatings were almost equivalent. The water droplet sliding velocity increased continuously with increasing pattern size. Anisotropic sliding velocity was observed on the surface, suggesting different pinning effects. The sliding motion of water droplets on the gradient surface with changing hydrophilic region size deflects against the downward direction. The deflection length depends on the direction of triangle hydrophilic regions and the initial sliding position. These results demonstrate that control of the sliding velocity while sustaining the static contact angle is feasible by designing the shape and alignment of chemical heterogeneity. PMID- 23802719 TI - Reaching the Hispanic patient. PMID- 23802721 TI - Grading on a curve: the use and disadvantage of the standardized mortality ratio. PMID- 23802722 TI - B cell responses to allograft--more common than we thought? PMID- 23802723 TI - The burden of proof in the design of early phase clinical trials. PMID- 23802724 TI - Preserving flow in liver transplant recipients: mTOR inhibitors everolimus and sirolimus are not peas from a pod. PMID- 23802727 TI - Hydronephrotic kidney with photopenic defect on renal scintigram following dual kidney transplantation. PMID- 23802725 TI - Multicenter evaluation of a standardized protocol for noninvasive gene expression profiling. AB - Gene expression profiling of transplant recipient blood and urine can potentially be used to monitor graft function, but the multitude of protocols in use make sharing data and comparing results from different laboratories difficult. The goal of this study was to evaluate the performance of current methods of RNA isolation, reverse transcription and quantitative polymerase chain reaction (qPCR) and to test whether multiple centers using a standardized protocol can obtain the same results. Samples, reagents and detailed instructions were distributed to six participating sites that performed RNA isolation, reverse transcription and qPCR for 18S, PRF, GZB, IL8, CXCL9 and CXCL10 as instructed. All data were analyzed at a single site. All sites demonstrated proficiency in RNA isolation and qPCR analysis. Gene expression measurements for all targets and samples had correlations >0.938. The coefficient of variation of fold-changes between pairs of samples was less than 40%. All sites were able to accurately quantify a control sample of known concentration within a factor of 1.5. Collectively, we have formulated and validated detailed methods for measuring gene expression in blood and urine that can yield consistent results in multiple laboratories. PMID- 23802728 TI - Looking back to evaluate the causes of graft loss? A response to Dr. Halloran and Dr. Sellares. PMID- 23802729 TI - Is extended thromboprophylaxis necessary in elective colorectal cancer surgery? AB - BACKGROUND: Colorectal cancer surgery carries a high risk of venous thromboembolism (VTE) but the optimal duration of thromboprophylaxis is unknown. The cost-effectiveness of extended prophylaxis is not known in Australasia. The aims of this study were to determine the 30-day incidence of VTE in patients undergoing colorectal cancer surgery, to audit compliance with thromboprophylaxis protocols and to estimate the cost of treating all patients for 28 days with enoxaparin. METHODS: Patients undergoing elective colorectal cancer surgery from 2007 to 2009 at the Royal Adelaide and Queen Elizabeth hospitals were identified from a prospective database. Case note review was conducted for patient demographics, VTE risk factors, types of thromboprophylaxis used, complications, readmission rate and VTE rate. Documented compliance with unit VTE protocols was calculated. The cost of treating all patients with enoxaparin as prophylaxis for 28 days was then estimated. RESULTS: A total of 254 patients were identified. The in-hospital VTE rate was 0.79% (2 out of 254). The post-discharge VTE rate was 0.39% (1 out of 254). Compliance with thromboprophylaxis protocols was excellent. Pharmacological thromboprophylaxis was used in 97% of patients, graduated compression stockings in 84% and pneumatic compression devices in 53%. The estimated cost of extended prophylaxis for all 254 patients was $32,308.80. CONCLUSIONS: We have demonstrated excellent compliance with in-hospital thromboprophylaxis. Hence, we have low VTE rates in-particular, post-discharge VTE. The infrequency of post-discharge VTE means that the cost-effectiveness of extended prophylaxis might be questioned. PMID- 23802730 TI - Taxonomic and functional metagenomic profiling of gastrointestinal tract microbiome of the farmed adult turbot (Scophthalmus maximus). AB - Metagenomics combined with 16S rRNA gene sequence analyses was applied to unveil the taxonomic composition and functional diversity of the farmed adult turbot gastrointestinal (GI) microbiome. Proteobacteria and Firmicutes which existed in both GI content and mucus were dominated in the turbot GI microbiome. 16S rRNA gene sequence analyses also indicated that the turbot GI tract may harbor some bacteria which originated from associated seawater. Functional analyses indicated that the clustering-based subsystem and many metabolic subsystems were dominant in the turbot GI metagenome. Compared with other gut metagenomes, quorum sensing and biofilm formation was overabundant in the turbot GI metagenome. Genes associated with quorum sensing and biofilm formation were found in species within Vibrio, including Vibrio vulnificus, Vibrio cholerae and Vibrio parahaemolyticus. In farmed fish gut metagenomes, the stress response and protein folding subsystems were over-represented and several genes concerning antibiotic and heavy metal resistance were also detected. These data suggested that the turbot GI microbiome may be affected by human factors in aquaculture. Additionally, iron acquisition and the metabolism subsystem were more abundant in the turbot GI metagenome when compared with freshwater fish gut metagenome, suggesting that unique metabolic potential may be observed in marine animal GI microbiomes. PMID- 23802731 TI - The pharmacokinetics of ilaprazole for gastro-esophageal reflux treatment. AB - INTRODUCTION: Approximately 20% of the Western population is affected by gastro esophageal reflux disease (GERD). To date, proton pump inhibitors (PPIs) represent the mainstay of GERD medical treatment. However, despite their undoubted benefit, about 40% of GERD patients display an inadequate response to these drugs. Recently, a new PPI, ilaprazole , at oral doses of 10 mg has shown higher suppression of gastric acid secretion, more prolonged plasma half-life, and similar safety compared to 20 mg omeprazole. AREAS COVERED: This review provides an update on the following points: pharmacokinetic profile and metabolism of ilaprazole in relation to its pharmacodynamic properties; comparative data on the pharmacokinetics and pharmacodynamics of ilaprazole with currently available PPIs; and implications for studies on the therapeutic efficacy of ilaprazole in GERD. EXPERT OPINION: Different studies show that ilaprazole, a benzimidazole derivative, has an extended plasma half-life in comparison with all other approved PPIs. In addition, ilaprazole metabolism is not significantly influenced by CYP2C19, compared to the available PPIs. Furthermore, the pharmacological characteristics of ilaprazole confer theoretical advantages that are expected to translate into an improved acid control, particularly at night time. However, studies comparing the clinical pharmacokinetics and pharmacodynamics of ilaprazole with those of second generation PPIs are insufficient. Moreover, further investigations assessing the efficacy of ilaprazole in the management of GERD are required. In healthy volunteers, as well as in patients with gastric or duodenal ulcers, ilaprazole has not shown clinically relevant changes in hematology and biochemistry testing, nor significant treatment-related adverse symptoms. PMID- 23802732 TI - Interprofessional meetings in geriatric assessment units: a matter of care organization. AB - Inpatient geriatric assessment units (GAUs) exist in Quebec, Canada, to deliver comprehensive, integrated care to older vulnerable patients. Most cases should be discussed at interprofessional meetings (IMs), but research has shown this not to be so for 39% of GAU patients. Consequently, a study was undertaken to (1) describe GAU team composition and (2) identify GAU and patient characteristics associated with case discussion at IMs at least once during a patient's stay. To this end, 877 hospitalization records from 44 GAUs were reviewed. Results showed most teams were composed of attending physicians, nurses, physical and occupational therapists, dietitians and social workers; 66% included clinical pharmacists and 43% liaison nurses. Multilevel modeling showed longer length of stay to be the strongest predictor of case discussion at an IM. Case discussion was also more likely for patients admitted via in- or inter-hospital transfer rather than via the emergency department, if the GAU included a liaison nurse, and if the GAU was not located in an urban area. In summary, case discussion at an IM depended more on how and where a patient was admitted than on the patient characteristics per se, suggesting that this is a matter of care organization. PMID- 23802733 TI - The moving target: outcomes of interprofessional education. PMID- 23802734 TI - Can a single brief intervention improve participants' readiness for interprofessional learning? AB - Interprofessional learning (IPL) was introduced for University of Nottingham 3rd year medical and nursing students at the Lincoln County Hospital. An evaluation of the subsequently implemented IPL intervention allowed us to ask the research question: can a single brief IPL intervention improve attitudes to IPL? A low fidelity simulation intervention was chosen as the mode of IPL, focusing on teamwork in the context of the assessment of the acutely ill patient. To assess the intervention's effect on students' attitudes, a validated questionnaire (RIPLS) was completed before and after the session. Nine of the nineteen questions in RIPLS had significantly different responses following the intervention. This reflected a more positive attitude to IPL following the intervention. This evaluation of this intervention suggests that IPL is valued by students and significantly improves attitudes to IPL, at least in the immediate post-intervention period. PMID- 23802735 TI - Layered perovskite oxide: a reversible air electrode for oxygen evolution/reduction in rechargeable metal-air batteries. AB - For the development of a rechargeable metal-air battery, which is expected to become one of the most widely used batteries in the future, slow kinetics of discharging and charging reactions at the air electrode, i.e., oxygen reduction reaction (ORR) and oxygen evolution reaction (OER), respectively, are the most critical problems. Here we report that Ruddlesden-Popper-type layered perovskite, RP-LaSr3Fe3O10 (n = 3), functions as a reversible air electrode catalyst for both ORR and OER at an equilibrium potential of 1.23 V with almost no overpotentials. The function of RP-LaSr3Fe3O10 as an ORR catalyst was confirmed by using an alkaline fuel cell composed of Pd/LaSr3Fe3O10-2x(OH)2x.H2O/RP-LaSr3Fe3O10 as an open circuit voltage (OCV) of 1.23 V was obtained. RP-LaSr3Fe3O10 also catalyzed OER at an equilibrium potential of 1.23 V with almost no overpotentials. Reversible ORR and OER are achieved because of the easily removable oxygen present in RP-LaSr3Fe3O10. Thus, RP-LaSr3Fe3O10 minimizes efficiency losses caused by reactions during charging and discharging at the air electrode and can be considered to be the ORR/OER electrocatalyst for rechargeable metal-air batteries. PMID- 23802736 TI - Factors associated with grief and depression following the loss of a child: a multivariate analysis. AB - The present study aims to explore the factors which are associated with grief and depression outcomes in a group of bereaved parents in the first few years following the loss of a child. Sixty-four participants were recruited from bereavement support organisations, between two and 59 months post loss, mean 30 months (SD = 15). They completed a questionnaire packet which comprised standard instruments measuring grief, depression, coping styles, continuing bonds and optimism/pessimism, as well as a number of specific bereavement-related questions. Univariate analyses were conducted to establish which factors were associated with grief and depression. Those which were statistically significant were then entered into multivariate analyses to establish their relative importance. High levels of avoidance and depression and lower levels of cognitive restructuring (benefit finding) were associated with higher grief symptoms, whereas higher levels of avoidance and alcohol/substance use were associated with higher depression symptoms. The present study highlights the relative importance of different coping strategies adopted by this group of bereaved parents, compared to the relative unimportance of circumstances around the loss, e.g. sudden or violent death. The use of alcohol and other substances by bereaved parents requires urgent attention as a potentially life-threatening maladaptive coping strategy. The call for further research into risk factors for bereaved parents is emphasised. PMID- 23802737 TI - Realizing comparable oxidative and cytotoxic potential of single- and multiwalled carbon nanotubes through annealing. AB - The potential applications as well as the environmental and human health implications of carbon nanomaterials are well represented in the literature. There has been a recent focus on how specific physicochemical properties influence carbon nanotube (CNT) function as well as cytotoxicity. The ultimate goal is a better understanding of the causal relationship between fundamental physiochemical properties and cytotoxic mechanism in order to both advance functional design and to minimize unintended consequences of CNTs. This study provides characterization data on a series of multiwalled carbon nanotubes (MWNTs) that underwent acid treatment followed by annealing at increasing temperatures, ranging from 400 to 900 degrees C. These results show that MWNTs can be imparted with the same toxicity as single-walled carbon nanotubes (SWNTs) by acid treatment and annealing. Further, we were able to correlate this toxicity to the chemical reactivity of the MWNT suggesting that it is a chemical rather than physical hazard. This informs the design of MWNT to be less hazardous or enables their implementation in antimicrobial applications. Given the reduced cost and ready dispersivity of MWNTs as compared to SWNTs, there is a significant opportunity to pursue the use of MWNTs in novel applications previously thought reserved for SWNTs. PMID- 23802738 TI - Long term results of a phase 2 study of vincristine sulfate liposome injection (Marqibo((r)) ) substituted for non-liposomal vincristine in cyclophosphamide, doxorubicin, vincristine, prednisone with or without rituximab for patients with untreated aggressive non-Hodgkin lymphomas. AB - Vincristine sulfate liposome injection (VSLI; Marqibo((r)) ; M) is active in relapsed and refractory lymphomas, and approved in the United States for relapsed and refractory adult acute lymphocytic leukaemia. We evaluated VSLI (2.0 mg/m(2) without dose cap) substituted for non-liposomal vincristine (VCR) in a cyclophosphamide, doxorubicin, vincristine, prednisone +/- ritiximab (CHOP+/-R) regimen, creating CHMP+/-R in 72 untreated, aggressive non-Hodgkin lymphoma patients, including 60 with diffuse large B-cell lymphoma (DLBCL). The overall response rate was 96% (69/72) including complete response (CR) in 65 (90%) and unconfirmed CR in 2 (3%). Median progression-free survival (PFS) and overall survival (OS) were not reached at median follow-up of 8 and 10.2 years, respectively. The 5- and 10-year PFS and OS were 75%, 63%, 87%, and 77%, respectively. Despite VSLI exposure of up to 35 mg, the safety profile of CHMP+/ R was comparable to that reported for CHOP+/-R. Grade 3 peripheral neuropathy was reported in 2 (3%) patients; there was no reported Grade 3/4 constipation. CHMP+/ R was highly active, generally well tolerated, and compared favourably to historical trials with R-CHOP in DLBCL. This enhanced activity probably reflects VCR dose intensification, pharmacokinetic optimization, and enhanced delivery afforded by VSLI. A Phase 3 trial of R-CHMP versus R-CHOP in elderly patients with untreated DLBCL is ongoing. PMID- 23802739 TI - Tumour-associated macrophages might represent a favourable prognostic indicator in patients with papillary renal cell carcinoma. AB - AIMS: Tumour-associated macrophages (TAM) have been reported to be regulators of progression in various human cancers. We evaluated the prognostic relevance of TAM in a large series of patients with papillary renal cell carcinoma (PRCC). METHODS AND RESULTS: The impact of TAM on cancer-specific survival (CSS) in 177 patients with PRCC was assessed using the Kaplan-Meier method and log-rank test. A multivariate Cox regression analysis was performed with respect to CSS. The presence of TAM was noted in 112 of 177 (63%) tumours and was associated statistically significantly with favourable pathological parameters, including low pathological T stage, node-negative tumours, low tumour grade, absence of vascular invasion and papillary subtype (all P < 0.05), respectively. Five-year CSS probabilities for patients with TAM-positive tumours were 93.5%, compared with 72.5% in patients with TAM-negative tumours, respectively (P < 0.001). Multivariate analysis revealed node-positive tumours, distant metastases and UICC stage (I versus II-IV) as independent predictors of death from PRCC, whereas the presence of TAM was associated independently with favourable outcome (hazard ratio = 0.45, 95% confidence interval 0.24-0.84, P = 0.012). CONCLUSIONS: The presence of TAM was shown independently to reduce the risk of death from cancer by 55%. The presence of TAM should therefore become part of routine pathology reporting in PRCC. PMID- 23802740 TI - Optical microring resonators constructed from organic dye nanofibers and their application to miniaturized channel drop/add filters. AB - We fabricated micrometer-scale optical ring resonators by micromanipulation of thiacyanine (TC) dye nanofibers that propagate exciton polaritons (EPs) along the fiber axis. High mechanical flexibility of the nanofibers and a low bending loss property of EP propagation enabled the fabrication of microring resonators with an average radius (r(ave)) as small as 1.6 MUm. The performances of the fabricated resonators (r(ave) = 1.6-8.9 MUm) were investigated by spatially resolved microscopy techniques. The Q-factors and finesses were evaluated as Q ~ 300-3500 and F ~ 2-12. On the basis of the r(ave)-dependence of resonator performances, we revealed the origin of losses in the resonators. To demonstrate the applicability of the microring resonators to photonic devices, we fabricated a channel drop filter that comprises a ring resonator (r(ave) = 3.9 MUm) and an I/O bus channel nanofiber. The device exhibited high extinction ratios (4-6 dB) for its micrometer-scale dimensions. Moreover, we successfully fabricated a channel add filter comprising a ring resonator (r(ave) = 4.3 MUm) and two I/O bus channel nanofibers. Our results demonstrated a remarkable potential for the application of TC nanofibers to miniaturized photonic circuit devices. PMID- 23802741 TI - Useful screening tools for preventing foot problems of diabetics in rural areas: a cross-sectional study. AB - BACKGROUND: Preventing diabetic foot problems (DFP) and their associated consequences is a critical in rural regions. The objective is to present an association of non-invasive DFP assessment tools and physiological indicators for early detection among rural cases of diabetes in Taiwan. METHODS: Secondary data analysis of 387 participants previously diagnosed with type 2 diabetes was used. The Michigan Neuropathy Screening Instrument (MNSI), Ankle Brachial Index (ABI), optimal scaling combination (OSC) of MNSI, and age were used to examine peripheral neurovascular function. The King's College classification (KC) and Texas risk classification (TRC) were used to understand diabetic foot complications. RESULTS: The findings indicated that MNSI was negatively correlated with ABI, but positively with diabetes duration, age, KC, TRC, fasting blood glucose, low density of lipoprotein cholesterol, body mass index and waist circumference. The area under the receiver operating characteristic curves for assessing the risk of ABI based on OSC was larger than for MNSI, KC, and TRC. CONCLUSION: It is shown that using OSC, MNSI, and ABI as community screening tools is useful in detecting early neurovasculopathy. In addition, where an ABI machine is unavailable, primary healthcare providers that perform MNSI or OSC may be cost-effective. The study was approved by the institutional review board of the ethical committee (No 98-2224-B). PMID- 23802742 TI - Use of generalised additive models to categorise continuous variables in clinical prediction. AB - BACKGROUND: In medical practice many, essentially continuous, clinical parameters tend to be categorised by physicians for ease of decision-making. Indeed, categorisation is a common practice both in medical research and in the development of clinical prediction rules, particularly where the ensuing models are to be applied in daily clinical practice to support clinicians in the decision-making process. Since the number of categories into which a continuous predictor must be categorised depends partly on the relationship between the predictor and the outcome, the need for more than two categories must be borne in mind. METHODS: We propose a categorisation methodology for clinical-prediction models, using Generalised Additive Models (GAMs) with P-spline smoothers to determine the relationship between the continuous predictor and the outcome. The proposed method consists of creating at least one average-risk category along with high- and low-risk categories based on the GAM smooth function. We applied this methodology to a prospective cohort of patients with exacerbated chronic obstructive pulmonary disease. The predictors selected were respiratory rate and partial pressure of carbon dioxide in the blood (PCO2), and the response variable was poor evolution. An additive logistic regression model was used to show the relationship between the covariates and the dichotomous response variable. The proposed categorisation was compared to the continuous predictor as the best option, using the AIC and AUC evaluation parameters. The sample was divided into a derivation (60%) and validation (40%) samples. The first was used to obtain the cut points while the second was used to validate the proposed methodology. RESULTS: The three-category proposal for the respiratory rate was <= 20;(20,24];> 24, for which the following values were obtained: AIC=314.5 and AUC=0.638. The respective values for the continuous predictor were AIC=317.1 and AUC=0.634, with no statistically significant differences being found between the two AUCs (p =0.079). The four-category proposal for PCO2 was <= 43;(43,52];(52,65];> 65, for which the following values were obtained: AIC=258.1 and AUC=0.81. No statistically significant differences were found between the AUC of the four category option and that of the continuous predictor, which yielded an AIC of 250.3 and an AUC of 0.825 (p =0.115). CONCLUSIONS: Our proposed method provides clinicians with the number and location of cut points for categorising variables, and performs as successfully as the original continuous predictor when it comes to developing clinical prediction rules. PMID- 23802743 TI - Visual acuity and microperimetric mapping of lesion area in eyes with inflammatory cystoid macular oedema. AB - PURPOSE: To evaluate the effect of fluid accumulation on local visual function in inflammatory cystoid-macular-edema (ICME). METHODS: This cross-sectional study applied optical-coherence-tomography over a 12*12 fovea-centered field in 50 patients with ICME and mapped the extent of fluid-filled spaces in various retinal layers, of subretinal-fluid and of diffuse-edema. Regression analysis examined effect of planimetric fluid-distribution on best-corrected-visual-acuity (BCVA) and mean microperimetric-sensitivity. RESULTS: BCVA decreased with increasing central-neuroretinal-thickness (r= 0.52, p= 0.001), total central retinal-thickness, including subneuroretinal-fluid (r= 0.41, p= 0.006), total cystoid-and-diffuse edema-area (r= 0.35, p= 0.036) and cystoid inner-nuclear layer area (r= 0.39, p= 0.02). Mean retinal-sensitivity decreased with increasing diffuse edema-area (r= -0.86, p<0.0001), total cystoid-and-diffuse edema-area (r= -0.54, p= 0.001), cystoid inner-nuclear-layer area (r= -0.46, p= 0.008) and cystoid ganglion-cell-layer area (r= -0.6, p=0.049), central-neuroretinal thickness (r= -0.42, p= 0.028) and total central-retinal-thickness (r= -0.34, p= 0.039). In multivariate-analyses BCVA was best described by central-neuroretinal thickness, duration of edema, total cystoid-and-diffuse edema-area and cystoid inner-nuclear-layer area (R(2) = 0.5, p= 0.002). Mean retinal-sensitivity was best described by diffuse edema-area, total cystoid-and-diffuse edema-area and central-neuroretinal-thickness (R(2) = 0.75, p< 0.0001). Subretinal-fluid area and cystoid outer-nuclear/Henle's layer area had no effect on either BCVA or microperimetry. CONCLUSIONS: Thickening of the neurosensory-fovea, not subfoveal-fluid, had major impact on both BCVA and retinal-sensitivity. The extent of edema in inner retinal layers also had major impact on both of these two functional parameters. Visual-impairment seems to differ depending on the layers involved, thus different types of fluid accumulation may potentially be given varying treatment priorities. PMID- 23802744 TI - Iron status in infants with alloimmune haemolytic disease in the first three months of life. AB - BACKGROUND AND OBJECTIVES: Ferritin levels are often highly elevated at birth in neonates with alloimmune haemolytic disease of the fetus and newborn (HDFN). Data on ferritin levels in these infants in the first 3 months of life are lacking. Objective of this study was to examine the course of iron status and incidence of iron deficiency and overload in neonates with alloimmune HDFN up to 3 months of age. Secondary objective was to analyse bilirubin levels, liver enzymes and red blood-cell indices in the same time period and the association with intrauterine transfusion (IUT). MATERIALS AND METHODS: Observational study of neonates with alloimmune HDFN admitted to our centre between November 2010 and March 2012. Data on iron status, bilirubin levels, liver enzymes and red-blood-cell indices up to 3 months of age were routinely collected and compared between neonates treated with and without IUT. RESULTS: Thirty-five infants with alloimmune HDFN were included. Iron overload occurred in 70% of neonates at birth and in 50% and 18% at the age of 1 and 3 months, respectively. No cases of iron deficiency at birth and only one case of iron deficiency at 3 months of age were found. No infants received iron therapy. Infants who received IUT had a significantly lower haemoglobin level and reticulocyte count and higher ferritin level at birth. CONCLUSION: The vast majority of neonates with alloimmune HDFN have iron overload at birth. Incidence of iron overload gradually decreases within the first 3 months without iron supplementation. PMID- 23802745 TI - Cell-matrix Interactions of Factor IX (FIX)-engineered human mesenchymal stromal cells encapsulated in RGD-alginate vs. fibrinogen-alginate microcapsules. AB - The success of cell microencapsulation technology in tissue engineering and protein delivery applications depends on the viability and functionality of the encapsulated cells, which in turn are dependent upon cell/matrix interactions. In this work, we compared the viability of cord blood-derived mesenchymal stromal cells (CB MSCs), engineered to secrete factor IX (FIX) for hemophilia treatment, and encapsulated in arginine-glycine-aspartate (RGD)-alginate versus fibrinogen alginate microcapsules. We evaluated the effect of the biomimetic matrix on cell attachment, proliferation, and secretion of FIX. Compared with nonsupplemented alginate matrix, RGD-alginate significantly enhanced the viability of the encapsulated MSCs. Further, cells in RGD-alginate displayed distinct attachment morphology, thus suggesting that RGD-alginate can potentially be used for the encapsulation of MSCs in tissue engineering applications that require enhanced cell attachment and viability. However, our data also showed that RGD-alginate microcapsules, in contrast to fibrinogen-alginate microcapsules, did not significantly improve cell proliferation of or FIX secretion by encapsulated MSCs. Our findings suggest that evidence of cell attachment alone may not accurately predict the functionality of cells in biomimetic microcapsules. PMID- 23802746 TI - Body mass index and waist circumference: relationship to cardiometabolic risk factors in children--Busselton Health Study 2005-2007. AB - AIM: This study aims to analyse the continuous relationship of each cardiometabolic risk factor with body mass index (BMI) and waist circumference percentiles in a population-based sample of children. METHODS: A cross-sectional sample of 996 school children aged 6-16.9 years in Busselton, Western Australia, (2005-2007) had anthropometry and fasting blood tests for total cholesterol, high density lipoprotein, low density lipoprotein, triglycerides, glucose, insulin, high-sensitive C-reactive protein, liver function tests and adiponectin. Age- and menarche (for girls)-adjusted means of each risk factor were related to BMI and waist circumference centiles across the full normal-overweight-obese range. RESULTS: The correlations between BMI and waist circumference (boys 0.91 and girls 0.91) and between BMI z-score and waist z-score (boys 0.80 and girls 0.82) were high. An increase in insulin across all centile groups (for BMI and waist circumference) was found in both sexes. An increase was found for diastolic blood pressure and systolic blood pressure z-score, high density lipoprotein, high sensitive C-reactive protein, alanine transaminase and gamma-glutamyltransferase in only the centile groups >85% for BMI and waist circumference for both sexes. Mixed and sex-discordant results were found for triglycerides, adiponectin and glucose. CONCLUSION: There are important differences in the relationships between increasing BMI/adiposity, and each comorbidity and these relationships can differ between boys and girls. This information has implications for screening and management of adiposity-related cardiometabolic risk factors in children and for public health initiatives to reduce future burden of cardiovascular disease. PMID- 23802747 TI - A systematic review: current and future directions of dorsal root ganglion therapeutics to treat chronic pain. AB - OBJECTIVE: The purpose of the study was to systematically review the historical therapeutics for chronic pain care directed at the dorsal root ganglion (DRG) and to identify future trends and upcoming treatment strategies. METHODS: A literature search on bibliographic resources, including EMBASE, PubMed Cochrane Database of Systemic Reviews from literature published from 1966 to December 1, 2012 to identify studies and treatments directed at the DRG to treat chronic pain, and was limited to the English language. Case series, case reports, and preclinical work were excluded. Information on emerging technologies and pharmacologics were captured separately, as they did not meet the inclusion criteria. RESULTS: The literature review yielded three current clinical treatment strategies: ganglionectomy, conventional radiofrequency treatment of the dorsal root ganglion, and pulsed radiofrequency treatment of the DRG. Seven studies were identified utilizing ganglionectomy, 14 for conventional radiofrequency, and 16 for pulsed radiofrequency. Electrical stimulation and novel therapeutic delivery strategies have been proposed and are in development. CONCLUSIONS: Despite a robust understanding of the DRG and its importance in acute nociception, as well as the development and maintenance of chronic pain, relatively poor evidence exists regarding current therapeutic strategies. Novel therapies like electrical and pharmacologic strategies are on the horizon, and more prospective study is required to better qualify the role of the DRG in chronic pain care. PMID- 23802748 TI - Urinary perchlorate and thiocyanate concentrations in pregnant women from Toronto, Canada. PMID- 23802749 TI - Cloning and characterization of the GNA11 promoter and its regulation by early growth response 1. AB - GNAQ and GNA11, encoding the G-proteins Galpha(q) and Galpha11, are members of the Galpha(q)/Galpha11 subfamily, which transmits signals from the cell surface to intracellular signalling cascades. The GNAQ promoter was already characterized, and regulation by the transcription factor early growth response 1 (Egr-1) was demonstrated. Interestingly, in silico analysis revealed putative Egr 1 binding sites in sequences potentially representing the GNA11 promoter. However, the GNA11 promoter has not been characterized so far. Therefore, the purpose of the study was the characterization of the GNA11 promoter and investigation of its potential regulation by Egr-1. The putative GNA11 promoter was cloned, and deletion constructs were generated. Luciferase assays were performed, and essential regulatory regions identified between nt-805/-177. In electrophoretic mobility shift assays (EMSAs), one specific Egr-1 binding site at nt-475/-445 was identified. An Egr-1 expression plasmid was generated, which evoked increased Egr-1 content in nuclear extracts and a > 2-fold increase in GNA11 promoter activity in construct nt-805/+54 (p = 0.035). Finally, real-time PCR analysis was performed, and an increased Galpha11 mRNA (p = 0.035) expression induced by Egr-1 was found. Here, we characterize for the first time the GNA11 promoter and its specific interaction with Egr-1. Both the GNAQ and the GNA11 promoter appear to be regulated by the same transcription factor, Egr-1, which may be a molecular mechanism leading to Galpha(q)-/Galpha11-associated phenotypes. PMID- 23802750 TI - Polarity-driven 3-fold symmetry of GaAs/AlGaAs core multishell nanowires. AB - AlGaAs/GaAs quantum well heterostructures based on core-multishell nanowires exhibit excellent optical properties which are acutely sensitive to structure and morphology. We characterize these heterostructures and observe them to have 3 fold symmetry about the nanowire axis. Using aberration-corrected annular dark field scanning transmission electron microscopy (ADF-STEM), we measure directly the polarity of the crystal structure and correlate this with the shape and facet orientation of the GaAs core, quantum wells and cap, and the width of radial Al rich bands. We discuss how the underlying polarity of the crystal structure drives the growth of these heterostructures with a 3-fold symmetry resulting in a nonuniform GaAs quantum well tube and AlGaAs shell. These observations suggest that the AlGaAs growth rate is faster along the [112] B compared to the [112] A directions and/or that there is a polarity driven surface reconstruction generating AlGaAs growth fronts inclined to the {110} planes. In contrast, the observations suggest that the opposite is true for the GaAs growth, with the preferred surface reconstruction plane being parallel to {110} and an apparent faster growth rate along the [112] A. This two-dimensional layer growth of the nanowire multishells strongly depends on the surface energies and surface reconstruction of the facets which are related to the crystal polarity and lead to the 3-fold symmetry observed here. PMID- 23802751 TI - Senior dentists' perceptions of dental therapists' roles and education needs in Malaysia. AB - To describe the perceptions of senior dental officers (SDOs) on the roles of dental therapists (DTs) and their education needs in Malaysia. METHODS: A cross sectional survey was conducted using a self-administered postal questionnaire targeting all 112 SDOs in the Malaysian Ministry of Health. The SDOs were asked about their perceptions of DT's roles in relation to clinical tasks, oral health promotion, administration and the dental team and their perceptions of DT's future education needs. Data were analysed using spss software, version 17 (SPSS Inc., Chicago, IL, USA). RESULTS: The response rate was 60%. A majority of SDOs were women (68%) with a mean age of 44.9 (SD: 8.04). Generally, the majority of SDOs perceived the current roles of DT in non-complex clinical tasks such as examination and diagnosis, preventive treatment, extraction of deciduous teeth and oral health promotion as very important. Fewer than half of SDOs perceived DT's role in the extraction of permanent teeth as important. Most SDOs perceived the need to train DT in 'scaling and polishing for adults' (80.5%), 'delivering inferior alveolar nerve block' (57.3%) and 'pulp therapy' (59.2%). They also had positive perceptions of providing education for DT up to degree level (70.8%). CONCLUSION: This study suggests that Malaysian SDOs have positive perceptions of the current roles of DT and of the expansion of some of their clinical tasks to include broader client groups through further training and education. These findings indicate a need to revise the current curriculum and legislation pertaining to DT's education and scope of practice in Malaysia. PMID- 23802752 TI - Disparities in child mortality trends: what is the evidence from disadvantaged states in India? the case of Orissa and Madhya Pradesh. AB - INTRODUCTION: The Millennium Development Goals prompted renewed international efforts to reduce under-five mortality and measure national progress. However, scant evidence exists about the distribution of child mortality at low sub national levels, which in diverse and decentralized countries like India are required to inform policy-making. This study estimates changes in child mortality across a range of markers of inequalities in Orissa and Madhya Pradesh, two of India's largest, poorest, and most disadvantaged states. METHODS: Estimates of under-five and neonatal mortality rates were computed using seven datasets from three available sources--sample registration system, summary birth histories in surveys, and complete birth histories. Inequalities were gauged by comparison of mortality rates within four sub-state populations defined by the following characteristics: rural-urban location, ethnicity, wealth, and district. RESULTS: Trend estimates suggest that progress has been made in mortality rates at the state levels. However, reduction rates have been modest, particularly for neonatal mortality. Different mortality rates are observed across all the equity markers, although there is a pattern of convergence between rural and urban areas, largely due to inadequate progress in urban settings. Inter-district disparities and differences between socioeconomic groups are also evident. CONCLUSIONS: Although child mortality rates continue to decline at the national level, our evidence shows that considerable disparities persist. While progress in reducing under-five and neonatal mortality rates in urban areas appears to be levelling off, policies targeting rural populations and scheduled caste and tribe groups appear to have achieved some success in reducing mortality differentials. The results of this study thus add weight to recent government initiatives targeting these groups. Equitable progress, particularly for neonatal mortality, requires continuing efforts to strengthen health systems and overcome barriers to identify and reach vulnerable groups. PMID- 23802753 TI - Loeffler endocarditis in a pediatric patient. AB - Loefler endocarditis is a potential fatal adverse event of hypereosinophilic syndrome. We report a case of a 5-year-old girl diagnosed with peripheral hypereosinophilia refractory to corticosteroid therapy who developed eosinophilia related endocarditis. Echocardiography revealed infiltration of the left ventricular free wall and the posterior mitral leaflet causing moderate mitral regurgitation. Genetic tests failed to recognize FIPiLi-PDGRFA genotype; however imatinib, a tyrosine kinase inhibitor was initiated. After a 4-week period of treatment there was a complete resolution of eosinophilia and a complete recovery of cardiac manifestation. This case highlights the introduction of imatinib for the treatment of hypereosinophilic syndrome refractory to corticosteroid therapy even in the absence of FIPiLi-PDGRFA genotype in pediatric patients. PMID- 23802754 TI - Preservation of the smooth muscular internal (vesical) sphincter and of the proximal urethra for the early recovery of urinary continence after retropubic radical prostatectomy: a prospective case-control study. AB - OBJECTIVES: To evaluate the influence of preservation of the muscular internal sphincter and proximal urethra on continence recovery after radical prostatectomy. METHODS: This was a prospective single-center, case-control study. A total of 40 consecutive patients with organ-confined prostate cancer were submitted to radical prostatectomy with the preservation of the muscular internal sphincter and the proximal urethra (group 1), and their outcomes were compared with those of 40 patients submitted to a standard procedure (group 2). Continence rates were assessed using a self-administrated questionnaire at 3, 7 and 30 days, and 3 and 12 months after removal of the catheter. RESULTS: Group 1 had a faster recovery of early continence than group 2 at day 3 (45% vs 22%; P = 0.029) and at day 7 (75% vs 50%; P = 0.018). Considering the number of pads, group 1 had a faster recovery of continence at 3, 7 and 30 days, and also had less incidence of severe incontinence. There was no statistically significant difference in terms of continence at 3 and 12 months among the two groups. Multivariate logistic regression analysis showed that surgical technique and young age were significantly associated with earlier time to continence at 3 and 7 days. The two groups had no significant differences in terms of surgical margins. CONCLUSIONS: Our modified technique of radical retropubic prostatectomy with preservation of the smooth muscular internal sphincter, as well as of the proximal urethra during bladder neck dissection, results in a significantly increased urinary continence at 3, 7 and 30 days after catheter removal, with a minor incidence of severe incontinence. The technique is also oncologically safe, and it does not increase the operative duration of the procedure. PMID- 23802755 TI - Redox proteomic evaluation of bleaching and alkali damage in human hair. AB - OBJECTIVE: Protein modification and damage in human hair, resulting from environmental, cosmetic and grooming stresses, create changes to visual and tactile characteristics and correlates with consumer perception of quality. This study outlines molecular-level evaluation of modification resulting from peroxide (bleaching) and alkaline straightening (relaxing) treatments. METHODS: Redox proteomic profiling of virgin, bleached and relaxed hair tresses was performed, with comprehensive qualitative characterization of modification and semi quantitative evaluation of damage through adaptation of a new damage scoring system. Modifications were mapped to specific locations in the hair proteome and a range of potential damage marker peptides identified. RESULTS: Virgin hair contained a baseline level of modification, consistent with environmental oxidative insult during hair growth. Hydrogen peroxide bleaching resulted in significantly increased levels of oxidative damage observable at the molecular level. This treatment also resulted in enhanced levels of dehydroalanine and dehydration products; modifications typically associated with alkali or thermal treatment and not previously been reported as a product of hair bleaching. Relaxation treatment with sodium hydroxide increased the formation of dehydroalanine and dehydration products and moderately enhanced the levels of oxidation. Cysteine was the predominant modification site for both bleaching and alkali damage. CONCLUSION: This study validates the utility and power of redox proteomic-based approaches to characterizing hair modification. This offers potential application to a wide range of damage types, as well as evaluation of new damage mitigation and repair technologies. PMID- 23802756 TI - CuS2-passivated Au-core, Au3Cu-shell nanoparticles analyzed by atomistic resolution Cs-corrected STEM. AB - Au-core, Au3Cu-alloyed shell nanoparticles passivated with CuS2 were fabricated by the polyol method, and characterized by Cs-corrected scanning transmission electron microscopy. The analysis of the high-resolution micrographs reveals that these nanoparticles have decahedral structure with shell periodicity, and that each of the particles is composed by Au core and Au3Cu alloyed shell surrounded by CuS2 surface layer. X-ray diffraction measurements and results from numerical simulations confirm these findings. From the atomic resolution micrographs, we identified edge dislocations at the twin boundaries of the particles, as well as evidence of the diffusion of Cu atoms into the Au region, and the reordering of the lattice on the surface, close to the vertices of the particle. These defects will impact the atomic and electronic structures, thereby changing the physical and chemical properties of the nanoparticles. On the other hand, we show for the first time the formation of an ordered superlattice of Au3Cu and a self-capping layer made using one of the alloy metals. This has significant consequences on the physical mechanism that form multicomponent nanoparticles. PMID- 23802757 TI - Spontaneous intrahepatic haemorrhage: two cases of segmental arterial mediolysis. AB - BACKGROUND: Segmental arterial mediolysis (SAM) is an under-recognized degenerative vascular disorder with variable clinical presentations. It affects medium to large calibre arteries, typically those arising from the coeliac axis, and its diagnosis is complicated by overlap with other clinical entities like fibromuscular dysplasia. Diagnosis requires histopathological examination of the affected tissue, although radiographic appearances can be suggestive of SAM. METHODS: We report on two patients presenting with acute rupture of an intrahepatic artery affected by SAM. RESULTS: Both patients ultimately required right hemi-hepatectomy in order to either control ongoing bleeding or for removal of liver rendered ischaemic by intra-arterial embolization. This was achieved safely despite additional SAM lesions present throughout the vasculature. CONCLUSION: In both cases described, presentation followed recent, unrelated abdominal surgery and we propose a link between these two events. Recent research has identified the potential role of noradrenaline in the development of SAM lesions in greyhounds, with levels of endogenous noradrenaline known to rise in the setting of surgery. PMID- 23802758 TI - Differential arsenic mobilization from As-bearing ferrihydrite by iron-respiring Shewanella strains with different arsenic-reducing activities. AB - Arsenic immobilization and release in the environment is significantly influenced by bacterial oxidation and reduction of arsenic and arsenic-bearing minerals. In this study, we tested three iron-reducing bacteria, Shewanella oneidensis MR-1, Shewanella sp. HN-41, and Shewanella putrefaciens 200, which have diverse arsenate-reducing activities with regard to reduction of an As-bearing ferrihydrite slurry. In the cultures of S. oneidensis MR-1 and Shewanella sp. HN 41, which are not capable of respiratory reduction of As(V) to As(III), arsenic was maintained predominantly in its pentavalent form, existing in particulate poorly crystalline As-bearing ferrihydrite and formed small quantities of a stable ferrous arsenate [Fe3(AsO4)2] precipitate. However, in the culture of the As(V) reducer, S. putrefaciens 200, As(V) was reduced to As(III) and a small fraction of As-bearing ferrihydrite was transformed into ribbon-shaped siderite that subsequently re-released arsenic into the liquid phase. Our results indicated that release of arsenic and formation of diverse secondary nanoscale Fe As minerals are specifically closely related to the arsenic-reducing abilities of different bacteria. Therefore, bacterial arsenic reduction appears to significantly influence As mobilization in soils, minerals, and other Fe-rich environments. PMID- 23802759 TI - Partial oxidation of ethane to oxygenates using Fe- and Cu-containing ZSM-5. AB - Iron and copper containing ZSM-5 catalysts are effective for the partial oxidation of ethane with hydrogen peroxide giving combined oxygenate selectivities and productivities of up to 95.2% and 65 mol kgcat(-1) h(-1), respectively. High conversion of ethane (ca. 56%) to acetic acid (ca. 70% selectivity) can be observed. Detailed studies of this catalytic system reveal a complex reaction network in which the oxidation of ethane gives a range of C2 oxygenates, with sequential C-C bond cleavage generating C1 products. We demonstrate that ethene is also formed and can be subsequently oxidized. Ethanol can be directly produced from ethane, and does not originate from the decomposition of its corresponding alkylperoxy species, ethyl hydroperoxide. In contrast to our previously proposed mechanism for methane oxidation over similar zeolite catalysts, the mechanism of ethane oxidation involves carbon-based radicals, which lead to the high conversions we observe. PMID- 23802761 TI - Vaccination in the field of veterinary science today. PMID- 23802762 TI - Bovine herpesvirus-1 (BHV-1) - a re-emerging concern in livestock: a revisit to its biology, epidemiology, diagnosis, and prophylaxis. AB - Bovine herpesvirus-1 (BHV-1) is known to cause several diseases worldwide. It is a double-stranded DNA virus consisting of 33 structural proteins out of which 13 are associated with the envelope. Based on genomic analysis and viral peptide patterns, BHV-1 virus can be divided into several subtypes like BHV-1.1, BHV-1.2, and BHV-1.3. However, all subtypes are antigenically similar. The symptoms of the related diseases are mainly non-life-threatening but have a rather wide host range that limits animal trade. The different modes of transmission as unique feature of this virus and the tendency to cause infection in the early age with latency development in trigeminal and sacral ganglion cause huge economic losses around the world. The virus also affects endangered bovine species like mithun (Bos frontalis) and yak (Poephagus grunniens). The disease can be diagnosed by using conventional procedures (like cell culture, immune-histopathology, and enzyme-linked immunosorbent assay (ELISA)) as well as highly sensitive modern techniques (like nested PCR and southern hybridization) with the virus neutralization test regarded as gold standard. With the currently available diagnostic tests it is not possible to identify animals which have a latent BHV-1 infection. Different types of modern and conventional vaccines are available for immunoprophylaxis. Inactivated vaccines are not as efficacious as modified live virus (MLV) vaccines. Marker vaccines allow the distinction between vaccinated and naturally infected animals. In this review the present status of BHV-1 around the world will be addressed besides the current knowledge with regard to its biology, epidemiology, diagnosis, and prophylaxis. PMID- 23802763 TI - Graphitic carbon-water nonbonded interaction parameters. AB - In this study, we develop graphitic carbon-water nonbonded interaction parameters entirely from ab initio calculation data of interaction energies between graphene and a single water molecule. First, we employ the Moller-Plesset perturbation theory of the second order (MP2) method to compute the polycyclic aromatic hydrocarbon (PAH)-water interaction energies, with proper size of basis sets and energy component analysis to extrapolate to infinite-sized graphene limit. Then, we develop graphitic carbon-water interaction parameters based on the MP2 data from this work and the ab initio data available in the literature from other methods such as random-phase approximation (RPA), density functional theory symmetry-adapted perturbation theory (DFT-SAPT), and coupled cluster treatment with single and double excitations and perturbative triples (CCSD(T)). The accuracy of the interaction parameters is evaluated by predicting water contact angle on graphite and carbon nanotube (CNT) radial breathing mode (RBM) frequency shift and comparing them with experimental data. The interaction parameters obtained from MP2 data predict the CNT RBM frequency shift that is in good agreement with experiments. The interaction parameters obtained from RPA and DFT SAPT data predict the contact angles and the CNT RBM frequency shift that agree well with experiments. The interaction parameters obtained from CCSD(T) data underestimate the contact angles and overestimate the CNT RBM frequency shift probably due to the use of small basis sets in CCSD(T) calculations. PMID- 23802760 TI - Pulmonary arterial hypertension: basis of sex differences in incidence and treatment response. AB - Pulmonary arterial hypertension (PAH) is a complex disease characterized by elevated pulmonary arterial pressure, pulmonary vascular remodelling and occlusive pulmonary vascular lesions, leading to right heart failure. Evidence from recent epidemiological studies suggests the influence of gender on the development of PAH with an approximate female to male ratio of 4:1, depending on the underlying disease pathology. Overall, the therapeutic strategy for PAH remains suboptimal with poor survival rates observed in both genders. Endogenous sex hormones, in particular 17beta oestradiol and its metabolites, have been implicated in the development of the disease; however, the influence of sex hormones on the underlying pathobiology remains controversial. Further understanding of the influence of sex hormones on the normal and diseased pulmonary circulation will be critical to our understanding the pathology of PAH and future therapeutic strategies. In this review, we will discuss the influence of sex hormones on the development of PAH and address recent controversies. PMID- 23802764 TI - Neon and CO2 adsorption on open carbon nanohorns. AB - We present the results of a thermodynamics and kinetics study of the adsorption of neon and carbon dioxide on aggregates of chemically opened carbon nanohorns. Both the equilibrium adsorption characteristics, as well as the dependence of the kinetic behavior on sorbent loading, are different for these two adsorbates. For neon the adsorption isotherms display two steps before reaching the saturated vapor pressure, corresponding to adsorption on strong and on weak binding sites; the isosteric heat of adsorption is a decreasing function of sorbent loading (this quantity varies by about a factor of 2 on the range of loadings studied), and the speed of the adsorption kinetics increases with increasing loading. By contrast, for carbon dioxide there are no substeps in the adsorption isotherms; the isosteric heat is a nonmonotonic function of loading, the value of the isosteric heat never differs from the bulk heat of sublimation by more than 15%, and the kinetic behavior is opposite to that of neon, with equilibration times increasing for higher sorbent loadings. We explain the difference in the equilibrium properties observed for neon and carbon dioxide in terms of differences in the relative strengths of adsorbate-adsorbate to adsorbate-sorbent interaction for these species. PMID- 23802765 TI - A cross-sectional study examining Campylobacter and other zoonotic enteric pathogens in dogs that frequent dog parks in three cities in south-western Ontario and risk factors for shedding of Campylobacter spp. AB - An estimated 6 million pet dogs live in Canadian households with the potential to transmit zoonotic pathogens to humans. Dogs have been identified as carriers of Salmonella, Giardia and Campylobacter spp., particularly Campylobacter upsaliensis, but little is known about the prevalence and risk factors for these pathogens in pet dogs that visit dog parks. This study examined the prevalence of these organisms in the faeces of dogs visiting dog parks in three cities in south western Ontario, as well as risk factors for shedding Campylobacter spp. and C. upsaliensis. From May to August 2009, canine faecal samples were collected at ten dog parks in the cities of Guelph and Kitchener-Waterloo, Ontario, Canada. Owners were asked to complete a questionnaire related to pet characteristics and management factors including age, diet and activities in which the dog participates. Faecal samples were collected from 251 dogs, and 189 questionnaires were completed. Salmonella, Giardia and Campylobacter spp. were present in 1.2%, 6.4% and 43.0% of faecal samples, respectively. Of the Campylobacter spp. detected, 86.1% were C. upsaliensis, 13% were C. jejuni and 0.9% were C. coli. Statistically significant sparing factors associated with the shedding of Campylobacter spp. included the feeding of a commercial dry diet and the dog's exposure to compost. Age of dog had a quadratic effect, with young dogs and senior dogs having an increased probability of shedding Campylobacter spp. compared with adult dogs. The only statistically significant risk factor for shedding C. upsaliensis was outdoor water access including lakes and ditches, while dogs >1 year old were at a lower risk than young dogs. Understanding the pet-related risk factors for Campylobacter spp. and C. upsaliensis shedding in dogs may help in the development of awareness and management strategies to potentially reduce the risk of transmitting this pathogen from dogs to humans. PMID- 23802767 TI - The challenges of licensing drugs for use in pregnancy. AB - Most recommended obstetric therapeutic agents are not licensed for their purpose. There is a lack of funding for research and little development of new therapeutic agents for use in the treatment of pregnancy-related disorders. Current therapeutics used in maternal health and their licensing status are reviewed and suggestions for these shortfalls together with possible solutions considered. PMID- 23802766 TI - Measuring teamwork and taskwork of community-based "teams" delivering life-saving health interventions in rural Zambia: a qualitative study. AB - BACKGROUND: The use of teams is a well-known approach in a variety of settings, including health care, in both developed and developing countries. Team performance is comprised of teamwork and task work, and ascertaining whether a team is performing as expected to achieve the desired outcome has rarely been done in health care settings in resource-limited countries. Measuring teamwork requires identifying dimensions of teamwork or processes that comprise the teamwork construct, while taskwork requires identifying specific team functions. Since 2008 a community-based project in rural Zambia has teamed community health workers (CHWs) and traditional birth attendants (TBAs), supported by Neighborhood Health Committees (NHCs), to provide essential newborn and continuous curative care for children 0-59 months. This paper describes the process of developing a measure of teamwork and taskwork for community-based health teams in rural Zambia. METHODS: Six group discussions and pile-sorting sessions were conducted with three NHCs and three groups of CHW-TBA teams. Each session comprised six individuals. RESULTS: We selected 17 factors identified by participants as relevant for measuring teamwork in this rural setting. Participants endorsed seven functions as important to measure taskwork. To explain team performance, we assigned 20 factors into three sub-groups: personal, community-related and service-related. CONCLUSION: Community and culturally relevant processes, functions and factors were used to develop a tool for measuring teamwork and taskwork in this rural community and the tool was quite unique from tools used in developed countries. PMID- 23802768 TI - Impact of MET expression on outcome in BRAF(V600E/K) advanced melanoma. AB - AIMS: Preclinical data suggest that signalling through the HGF-MET pathway may confer resistance to BRAF inhibition in BRAF(V600E/K) melanoma. Therefore, blockade of HGF-MET signalling might be a valid therapeutic strategy, in combination with BRAF inhibition, in BRAF(V600E/K) melanoma. The aim of this study was to investigate the clinical relevance of these observations by evaluating the survival impact of MET expression in patients with BRAF(V600E/K) advanced melanoma treated with vemurafenib. METHODS AND RESULTS: Formalin-fixed tissue blocks were obtained of tumours from patients enrolled in the BRIM2 (n = 59) and BRIM3 (n = 150) trials of vemurafenib in advanced BRAF(V600E/K) melanoma. Immunohistochemistry for MET (SP44 rabbit monoclonal antibody) was performed with a highly validated assay and clinically validated scoring system. Pretreatment MET expression was frequent at the >=1 + cutoff (BRIM3, 31%; BRIM2, 49%), but relatively infrequent at the >=2 + cutoff (BRIM3, 9%; BRIM2, 19%). Retrospective subset analyses showed that, irrespective of the cutoff used or the treatment arm, MET expression did not show prognostic significance, in terms of objective response rate, progression-free survival, or overall survival. CONCLUSIONS: MET is expressed in a proportion of BRAF(V600E/K) advanced melanomas. Further analyses on appropriately powered subsets are needed to determine the prognostic and predictive significance of MET in vemurafenib-treated melanoma. PMID- 23802769 TI - Allergic transfusion reactions to platelets are more commonly associated with prepooled than apheresis components. AB - BACKGROUND AND OBJECTIVES: Transfusions of pooled or apheresis platelets are seen as equally effective in increasing platelet counts with similar rates of transfusion reactions. It has been suggested that allergic transfusion reactions (ATRs) to platelets are associated with recipient and donor factors. In this study, we assessed differences in ATR rates among individuals who received platelet components at two academic medical centres. MATERIALS AND METHODS: A total of 45 189 leukoreduced platelet products were transfused during the study period of which 31 748 were apheresis units and 13 441 were pooled units. RESULTS: Transfusion reactions were reported in 0.6% (277 of 45 189) of platelet transfusions. The reaction rate was significantly higher in pooled (102 of 13 441) than in apheresis (175 of 31 748) (0.76% vs. 0.55%, respectively, P = 0.01) components. However, an analysis of reactions by categories indicated that only the ATR rate was significantly higher in pooled (55 of 13 441) products as compared with apheresis (76 of 31 748) (0.41% vs. 0.24%, respectively, P = 0.0029) platelets. Moreover, there was no difference in the rate of ABO mismatch between pooled and apheresis products. CONCLUSION: Our data indicate that pooled platelet components are associated with higher ATR rates than apheresis platelets, suggesting that these components may not be completely equivalent from the standpoint of adverse events. Further investigation is needed to address whether differences in ATRs are related to the pooling process or the extent of donor antigen exposure. PMID- 23802770 TI - The relationship between resting heart rate variability and erectile tumescence among men with normal erectile function. AB - INTRODUCTION: Individuals with erectile dysfunction (ED) have been shown to display lower heart rate variability (HRV), suggesting dysregulation of cardiac autonomic function. No studies have explored whether HRV is predictive of erectile response among men with clinically normal erectile function. AIM: The study aims to examine associations between resting HRV and objective measures of genital response (i.e., resting penile circumference; erectile tumescence) and self-reported sexual function. METHODS: The sample comprised 59 male community volunteers (mean age = 20.15 years; SD = 2.52) selected from the control conditions of two previously published studies. Participants reported erectile function in the normal range (scoring >= 26 on the International Index of Erectile Function [IIEF]) and had no history of cardiovascular disease or myocardial infarct. During a laboratory visit, self-report, anthropometric, cardiovascular, and electrocardiographic data were assessed, as well as resting penile circumference and erectile tumescence in response to viewing an erotic film. MAIN OUTCOME MEASURES: Resting penile responses, erectile tumescence (circumferential change via penile plethysmography), self-reported sexual function per the IIEF, and both time-domain (standard deviation of beat-to-beat [NN] intervals, square root of the mean squared difference of successive NN intervals, and percent of NN intervals for which successive heartbeat intervals differed by at least 50 msec [pNN50]) and frequency-domain (low frequency [LF], high frequency [HF], LF/HF ratio) parameters of HRV were assessed. RESULTS: Higher-resting HF power and lower-resting LF/HF ratio were associated with greater erectile tumescence. There were marginally significant positive associations between mean NN interval and pNN50 and penile tumescence. HRV was not associated with self-reported sexual function or with resting penile circumference. CONCLUSIONS: Results suggested that, among men without ED, relatively elevated parasympathetic tone was predictive of larger erectile tumescence. Limited variance in sexual function scores may have accounted for the lack of association between HRV and IIEF scores. PMID- 23802771 TI - Effects of the carrier frequency of interferential current on pain modulation in patients with chronic nonspecific low back pain: a protocol of a randomised controlled trial. AB - BACKGROUND: Low back pain is an important public health problem that is associated with poor quality of life and disability. Among the electrophysical treatments, interferential current (IFC) has not been studied in patients with low back pain in a high-quality randomised controlled trial examining not only pain, but pain mechanisms and function. METHODS/DESIGN: A three-arm randomised controlled trial with patient and assessor blinded to the group allocation. One hundred fifty patients with chronic, nonspecific low back pain from outpatient physical therapy clinics in Brazil. The patients will be randomly allocated into 3 groups (IFC 1 kHz, IFC 4 kHz or Placebo IFC). The interferential current will be applied three days per week (30 minutes per session) over four weeks. PRIMARY OUTCOME: Pain intensity. SECONDARY OUTCOMES: The pressure pain threshold, global impression of recovery, disability, function, conditioned pain modulation and temporal summation of pain, discomfort caused by the current. All outcomes will be measured at 4 weeks and 4 months after randomisation. The between-group differences will be calculated by using linear mixed models and Tukey's post-hoc tests. DISCUSSION: The use of a placebo group and double-blinding assessor and patients strengthen this study. The present study is the first to compare different IFC carrier frequencies in patients with chronic low back pain. TRIAL REGISTRATION: Brazilian Registry of Clinical Trials: http://RBR-8n4hg2. PMID- 23802772 TI - The contemporary nucleus: a trip down memory lane. AB - The nucleus is one of the hallmarks of eukaryotic cells. The history of its discovery and characterisation is intimately entangled with that of cell biology as a discipline. Here, we provide a broad historical perspective of the nucleus, from its initial descriptions until the present. We describe the key events that led to the formulation of the chromosomal theory, the discovery of the nuclear pore complex, nucleo-cytoplasmic transport and the structure of chromatin. We also focus on the rising importance of the nuclear periphery as a key subject in nuclear research, with the characterisation of the multiple roles of nuclear lamina and the proteins involved in connecting the nuclear envelope and the cytoskeleton. Over the last decades, critical technical advancements from electron microscopy to protein structural characterisation have allowed us to gain in-depth knowledge of nuclear substructure and components, from its core to the envelope. This knowledge has set the stage for a rising challenge: understanding specialised nuclear configurations and their role in different tissues, developmental stages and disease. PMID- 23802773 TI - Where does the current flow in two-dimensional layered systems? AB - In this Letter, we map for the first time the current distribution among the individual layers of multilayer two-dimensional systems. Our findings suggest that in a multilayer MoS2 field-effect transistor the "HOT-SPOT" of the current flow migrates dynamically between the layers as a function of the applied back gate bias and manifests itself in a rather unusual "contact resistance" that cannot be explained using the conventional models for metal-to-semiconductor contacts. To interpret this unique contact resistance, extracted from a channel length scaling study, we employed a resistor network model based on Thomas-Fermi charge screening and interlayer coupling. By modeling our experimental data we have found that the charge screening length for MoS2 is rather large (lambdaMoS2 = 7 nm) and translates into a current distribution in multilayer MoS2 systems, which is distinctly different from the current distribution in multilayer graphene (lambdagraphene = 0.6 nm). In particular, our experimental results allow us to retrieve for the first time fundamental information about the carrier transport in two-dimensional layered systems that will likely play an important role in the implementation of future electronics components but that have not been evaluated in the past. PMID- 23802774 TI - Spatial and temporal estimation of air pollutants in New York City: exposure assignment for use in a birth outcomes study. AB - BACKGROUND: Recent epidemiological studies have examined the associations between air pollution and birth outcomes. Regulatory air quality monitors often used in these studies, however, were spatially sparse and unable to capture relevant within-city variation in exposure during pregnancy. METHODS: This study developed two-week average exposure estimates for fine particles (PM2.5) and nitrogen dioxide (NO2) during pregnancy for 274,996 New York City births in 2008-2010. The two-week average exposures were constructed by first developing land use regression (LUR) models of spatial variation in annual average PM2.5 and NO2 data from 150 locations in the New York City Community Air Survey and emissions source data near monitors. The annual average concentrations from the spatial models were adjusted to account for city-wide temporal trends using time series derived from regulatory monitors. Models were developed using Year 1 data and validated using Year 2 data. Two-week average exposures were then estimated for three buffers of maternal address and were averaged into the last six weeks, the trimesters, and the entire period of gestation. We characterized temporal variation of exposure estimates, correlation between PM2.5 and NO2, and correlation of exposures across trimesters. RESULTS: The LUR models of average annual concentrations explained a substantial amount of the spatial variation (R2 = 0.79 for PM2.5 and 0.80 for NO2). In the validation, predictions of Year 2 two week average concentrations showed strong agreement with measured concentrations (R2 = 0.83 for PM2.5 and 0.79 for NO2). PM2.5 exhibited greater temporal variation than NO2. The relative contribution of temporal vs. spatial variation in the estimated exposures varied by time window. The differing seasonal cycle of these pollutants (bi-annual for PM2.5 and annual for NO2) resulted in different patterns of correlations in the estimated exposures across trimesters. The three levels of spatial buffer did not make a substantive difference in estimated exposures. CONCLUSIONS: The combination of spatially resolved monitoring data, LUR models and temporal adjustment using regulatory monitoring data yielded exposure estimates for PM2.5 and NO2 that performed well in validation tests. The interaction between seasonality of air pollution and exposure intervals during pregnancy needs to be considered in future studies. PMID- 23802775 TI - BML-111, a lipoxin receptor agonist, ameliorates 'two-hit'-induced acute pancreatitis-associated lung injury in mice by the upregulation of heme oxygenase 1. AB - The objective of this study is to investigate the effects of BML-111 on acute pancreatitis-associated lung injury (APALI) induced by cerulein with subsequent an LPS administration in mice and its possible mechanisms. One hundred and twenty eight mice were randomly allocated to four groups, namely the APALI group, the BML-111 pretreatment group, the BM-111 control group, and the control group. The 'two-hit' mice APALI model was established by intraperitoneal injection of cerulein 7 times at hourly intervals and Escherichia coli lipopolysaccharide (LPS) once after the last dose of cerulein immediately. The samples were taken at 3, 6, 12, and 24 h after the last injection. Serum levels of amylase, TNF-a, IL 1beta and IL-10, were determined. Histological score of the pancreas and lung, the wet/dry weight ratio, and heme oxygenase-1 (HO-1) expression in the lung were also evaluated. BML-111 pretreatment significantly reduced the serum levels of amylase, TNF-alpha, IL-1beta, the wet/dry weight ratio of lung, and the pathology injury scores of pancreas and lung, and the serum levels of IL-10 were markedly increased. The severity of pancreatic and lung histology were also significantly improved by the administration of BML-111, and the expressions of HO-1 in lung tissues also increased in the BML-111 group compared with those in the APALI group. In conclusion, BML-111 exerts protective effects on APALI induced by cerulein and LPS. In addition to its anti-inflammatory effects, the beneficial effects may also be due to the upregulation of HO-1 expression in the lung tissues. PMID- 23802776 TI - Are angiotensin-converting enzyme inhibitors and angiotensin 2 receptor blockers teratogenic? PMID- 23802777 TI - Celiac plexus neurolysis for abdominal cancer pain: a systematic review. AB - OBJECTIVE: This systematic review assesses the effectiveness and side effects of celiac plexus neurolysis (CPN) in the treatment of upper abdominal cancer pain, and evaluates whether there are any differences between the percutaneous and endoscopic ultrasound-guided (EUS) denervation techniques. METHODS: Five databases were searched, expanded by assessing the reference lists of all retrieved papers. Sixty-six publications fulfilled the inclusion/exclusion criteria and were included in the systematic review. Randomized controlled trials were available for the percutaneous CPN, and therefore meta-analyses were performed for pain, opioid consumption, and specific side effects. The quality of life data were too heterogeneous to be assessed by a meta-analysis, and evidence for EUS CPN could only be evaluated by observational studies. RESULTS: Meta analyses show that percutaneous CPN significantly improves pain in patients with upper abdominal cancer, with a decrease in opioid consumption and side effects. It is unclear whether there is any change in quality of life. Case series suggest that EUS CPN improves pain. No conclusion can be made about EUS CPN's influence on opioid consumption. Although CPN is a safe procedure, side effects and complications can occur with both the percutaneous and EUS techniques. CONCLUSIONS: Following this review, evidence suggests that CPN should be considered in patients with upper abdominal cancer where the pain is not adequately controlled with systemic analgesics or when significant opioid-induced side effects are present. The percutaneous approach remains the standard technique as robust evidence for EUS CPN is lacking. PMID- 23802778 TI - Hypodermal delivery of cosmetic actives for improved facial skin morphology and functionality. AB - OBJECTIVE: Skin compartments traditionally targeted by cosmetic actives - epidermis and dermis - are anchored and nourished by the underlying hypodermis, which therefore should be a key target for skin-rejuvenating formulations. However, given the difficulty to reach even the superficial layers of the skin, and to its 'unglamorous' fatty composition, the regenerative potential of hypodermis remains largely untapped. Therefore, this study was to investigate the capacity of a cosmetic material to trigger a regenerative response in dermis and epidermis through a selective action on hypodermis. Furthermore, it aimed to establish the effect of such cosmetic material in transbuccal hypodermal delivery form, on the hypodermal precursor cells - the preadipocytes. METHODS: A combination of grape seed extract and soy phospholipids was formulated and standardized for elastase activity and free radical inhibition. This formulation was then used to contact the hypodermal layer of human skin biopsies and - under a transbuccal delivery vehicle form - the 3T3-L1 preadipocytes, and its effects were quantified using PCR arrays and histochemistry. RESULTS: Application of the standardized grape/soy material to the hypodermal layer of skin triggered modulation of gene expression in the upper layers of the skin and resulted in the clear morphological improvement at the dermal and epidermal levels. Furthermore, when this material was formulated in a mucoadhesive, intraoral film and applied on 3T3-L1 preadipocytes, the resulting modulation of gene expression in these cells was consistent with differentiation and detoxification effects. CONCLUSIONS: These results suggest that transbuccal formulations of nutraceutical grade cosmetics have potential to induce signal transduction pathways in facial hypodermis, resulting in anti-aging effects throughout all skin compartments, including dermal and epidermal layers. PMID- 23802779 TI - One world, two languages: cross-language semantic priming in bilingual toddlers. AB - The interconnectedness of bilingual memory remains a topic of great debate. Semantic priming provides a powerful methodological tool with which to investigate this issue in early bilingual toddlers. Semantic priming effects were investigated in 21 bilingual toddlers (2.5 years) within and across each of their languages. Results revealed the first evidence of cross-language and within language semantic priming in bilingual toddlers. However, priming effects were only observed when the prime was presented in the dominant language and were comparable in magnitude within and across languages. Findings point to high interconnectivity across languages; however, there appear to be strong influences of language dominance on semantic facilitation. Findings serve to inform and refine developmental models of bilingual memory. PMID- 23802780 TI - [New occupational disease of solar skin cancer and parallel improvements in UV GOA 2013]. PMID- 23802782 TI - Allergic contact dermatitis. AB - Allergic contact dermatitis is a frequent inflammatory skin disease. The suspected diagnosis is based on clinical symptoms, a plausible contact to allergens and a suitable history of dermatitis. Differential diagnoses should be considered only after careful exclusion of any causal contact sensitization. Hence, careful diagnosis by patch testing is of great importance. Modifications of the standardized test procedure are the strip patch test and the repeated open application test. The interpretation of the SLS (sodium lauryl sulfate) patch test as well as testing with the patients' own products and working materials are potential sources of error. Accurate patch test reading is affected in particular by the experience and individual factors of the examiner. Therefore, a high degree of standardization and continuous quality control is necessary and may be supported by use of an online patch test reading course made available by the German Contact Dermatitis Research Group. A critical relevance assessment of allergic patch test reactions helps to avoid relapses and the consideration of differential diagnoses. Any allergic test reaction should be documented in an allergy ID card including the INCI name, if appropriate. The diagnostics of allergic contact dermatitis is endangered by a seriously reduced financing of patch testing by the German statutory health insurances. Restrictive regulations by the German Drug Law block the approval of new contact allergens for routine patch testing. Beside the consistent avoidance of allergen contact, temporary use of systemic and topical corticosteroids is the therapy of first choice. PMID- 23802789 TI - [Letter to the editor to the article "Thick legs - not always lipedema" by Reich Schupke S, Altmeyer P und Stucker M. ]. PMID- 23802790 TI - [Opinion letter from Prof. Dr. W. Schmeller regarding our article "Thick legs - not always lipedema"]. PMID- 23802794 TI - [Obituaries. Professor Dr. Albrecht Scholz (1940-2013)]. PMID- 23802798 TI - [Association Dermatologic Oncology (ADO). Treatment of advanced squamous cell carcinoma]. PMID- 23802799 TI - Stable isotope tracer to determine uptake and efflux dynamics of ZnO Nano- and bulk particles and dissolved Zn to an estuarine snail. AB - Zinc oxide nanoparticles (ZnO NPs) are among the most commercialized engineered nanomaterials. Their biological impact in aquatic organisms has been associated with dissolution, but there is also evidence of nanospecific effects. In this study the waterborne uptake and efflux kinetics of isotopically labeled (68)ZnO NPs (7.8 +/- 1.2 nm), in comparison to aqueous (68)Zn and (68)ZnO bulk particles (up to 2 MUm), were determined for the estuarine snail Peringia ulvae following a 7 d exposure (nominally 20 MUg (68)Zn L(-1)) and 28 d depuration. Detection of the (68)Zn label was achieved by high precision multiple-collector ICP-MS (MC-ICP MS). Previous characterization in artificial estuarine water revealed that the NPs underwent initial aggregation and solubilized up to 60% within 1-2 days. Bulk and aqueous forms were significantly more bioavailable than (68)ZnO NPs (p < 0.05), but after correcting for dissolution, aqueous (0.074 L(-1) g(-1) d(-1)) and NP (0.070 L(-1) g(-1) d(-1)) uptake rate constants were highly comparable. The rate constant of loss for (68)Zn aqueous (0.012 +/- 0.005 d(-1)) and (68)ZnO NPs (0.012 +/- 0.007 d(-1)) were identical. These results strongly suggest that in this exposure scenario the bioaccumulation of Zn from ZnO NPs is primarily dependent upon solubility. PMID- 23802800 TI - Chemical sensing of polyols with shapeshifting boronic acids as a self-contained sensor array. AB - Boronic acid-substituted shapeshifting bullvalenes bearing a (13)C label are employed as sensor arrays for polyhydroxylated compounds, such as carbohydrates, flavanols, and sialic acids. The dynamic nature of the bullvalene core allows for covalent binding to a wide variety of analytes, allowing for specific analyte detection by a single NMR measurement. The resulting (13)C NMR patterns permit an inference to the identity of a particular analyte bound. Conversion of the (13)C NMR to an easy-to-read barcode provides a convenient method to catalog polyol analytes. The synthesis and study of a structurally related static sensor, which is not suitable for analyte recognition, underscores the advantages of the shapeshifting nature of the sensor. PMID- 23802801 TI - Poractant alfa versus beractant for respiratory distress syndrome in preterm infants: a retrospective cohort study. AB - AIM: Poractant alfa and beractant are the commonly used animal derived surfactants in preterm infants with respiratory distress syndrome. Between 2005 and 2007, poractant alfa and beractant were alternated every month in our neonatal intensive care unit for 27 months. The aim of this study was to compare the outcomes of preterm infants who received poractant alfa versus beractant. METHOD: Single-centre, retrospective cohort study of inborn preterm infants <32 weeks gestation (23-31(+6) ). RESULTS: Six hundred sixty-four preterm infants (<32 weeks) were born during the study period, of which 415 received surfactant (poractant alfa: 214; beractant: 201). Infants in the poractant alfa group were 2.8 days younger than beractant (27.0 +/- 2.3 vs. 27.4 +/- 2.3 weeks; P = 0.03). All other baseline characters including Clinical Risk Index for Babies II scores were similar for both groups. No significant differences were found for the following outcomes: death or chronic lung disease (78/212 vs. 59/200; P = 0.28); death (24/214 vs. 15/201, P = 0.24); moderate to severe chronic lung disease (63/212 vs. 46/200; P = 0.45) and moderate to severe disability (20/163 vs. 19/151, P = 0.98) between poractant alfa and beractant, respectively. CONCLUSIONS: The results of our study do not support the need for preferential use of poractant alfa or beractant. PMID- 23802802 TI - Molecular pathogenesis of juvenile nasopharyngeal angiofibroma in brazilian patients. AB - Juvenile nasopharyngeal angiofibroma (JNA) is a vascular tumor of the nasopharynx that accounts for 0.5% of all cancers of the head and neck. It primarily affects males aged 14-25 years. Of the many genes that mediate the development of JNA, GSTM1 has been most frequently associated with this vascular tumor. The loss of expression of GSTM1 (null genotype) is linked to the development of these tumors. The aim of this cross-sectional case study was to examine the prevalence of the GSTM1-null genotype in Brazilian patients with JNA. DNA was extracted from the leukocytes of blood samples from 10 patients. GSTM1 genotypes were analyzed using a PCR-based assay that was designed to identify the wild-type allele of GSTM1. All 10 patients (100%) were males, with a mean age of 17.8 years. The null genotype for GSTM1 was noted in 4 patients (40%)-1 (10%) at Fisch stage I, 1 (10%) at stage III, and 2 (20%) at stage II. No patient with this genotype had stage IV disease. There was no correlation between Fisch classification and GSTM1 genotype (P = .5695). The correlation between age at diagnosis and GSTM1 genotype was not significant (P = .728). The present findings indicate that there is evidence of an association between the GSTM1-null genotype and JNA in this studied Brazilian population. PMID- 23802803 TI - Fifth issue of JGSW's 56th volume. Introduction. PMID- 23802804 TI - Risk, security, and uncertainty: personal reflections. PMID- 23802805 TI - Explaining Andean megadiversity: the evolutionary and ecological causes of glassfrog elevational richness patterns. AB - The Tropical Andes are an important global biodiversity hotspot, harbouring extraordinarily high richness and endemism. Although elevational richness and speciation have been studied independently in some Andean groups, the evolutionary and ecological processes that explain elevational richness patterns in the Andes have not been analysed together. Herein, we elucidate the processes underlying Andean richness patterns using glassfrogs (Centrolenidae) as a model system. Glassfrogs show the widespread mid-elevation diversity peak for both local and regional richness. Remarkably, these patterns are explained by greater time (montane museum) rather than faster speciation at mid-elevations (montane species pump), despite the recency of the major Andean uplift. We also show for the first time that rates of climatic-niche evolution and elevational change are related, supporting the hypothesis that climatic-niche conservatism decelerates species' shifts in elevational distributions and underlies the mid-elevation richness peak. These results may be relevant to other Andean clades and montane systems globally. PMID- 23802806 TI - Systematic review of oral treatments for seborrheic dermatitis. AB - Seborrheic dermatitis (SD) is normally treated with topical corticosteroids and antifungals. Oral therapies can be prescribed in severe or unresponsive cases. This review aims to assess the quantity and quality of published reports on oral therapies for SD. MEDLINE and Embase databases and the reference listings of publications were searched for any publication using oral treatment for SD. The quality of the included publications was assessed using a modified 27 item checklist by Downs and Black. Twenty-one publications (randomized controlled trials, open trials and case reports) covering eight oral therapies (itraconazole, terbinafine, fluconazole, ketoconazole, pramiconazole, prednisone, isotretinoin and homeopathic mineral therapy) were identified. Most of the publications investigated oral antifungals and the quality of the evidence was generally low. The clinical efficacy outcome reported varied considerably between the studies, preventing statistical analysis and direct comparison between treatments. However, ketoconazole therapy was associated with more relapses compared with other treatments. Itraconazole dosing regimen for SD was generally 200 mg/day for the first week of the month followed by 200 mg/day for the first 2 days for 2-11 months. Terbinafine was prescribed at 250 mg/day either as a continuous (4-6 weeks) or as an intermittent regimen (12 days per month) for 3 months. Fluconazole has administered daily (50 mg/day for 2 weeks) or weekly (200 300 mg) for 2-4 weeks. Ketoconazole dosing regimen was 200 mg daily for 4 weeks. Finally, a single 200 mg dose of pramiconazole was administered to patients. This review also highlights key areas for consideration when designing future studies. PMID- 23802807 TI - Optimization and quantization in gradient symbol systems: a framework for integrating the continuous and the discrete in cognition. AB - Mental representations have continuous as well as discrete, combinatorial properties. For example, while predominantly discrete, phonological representations also vary continuously; this is reflected by gradient effects in instrumental studies of speech production. Can an integrated theoretical framework address both aspects of structure? The framework we introduce here, Gradient Symbol Processing, characterizes the emergence of grammatical macrostructure from the Parallel Distributed Processing microstructure (McClelland, Rumelhart, & The PDP Research Group, 1986) of language processing. The mental representations that emerge, Distributed Symbol Systems, have both combinatorial and gradient structure. They are processed through Subsymbolic Optimization-Quantization, in which an optimization process favoring representations that satisfy well-formedness constraints operates in parallel with a distributed quantization process favoring discrete symbolic structures. We apply a particular instantiation of this framework, lambda-Diffusion Theory, to phonological production. Simulations of the resulting model suggest that Gradient Symbol Processing offers a way to unify accounts of grammatical competence with both discrete and continuous patterns in language performance. PMID- 23802808 TI - An evaluation of microbial health risks to livestock fed with wastewater irrigated forage crops. AB - This paper presents the results of five experiments in which animal health risks associated with the consumption of crops irrigated with domestic wastewater were evaluated. Forage maize and Tanner grass were irrigated with treated wastewater and used in goats and calves feeding trials. The irrigated crops presented high levels of surface contamination with E. coli (10(4) -10(7) 25 g(-1) ) and salmonellae (up to 1.6 * 10(4) 25 g(-1)), but none of the animals showed signs of infection or of disease. Further, the microbiological quality of animal products always complied with the Brazilian and European Union standards for food safety. It is suggested that the WHO guideline values for restricted irrigation (<= 10(4) E. coli 100 ml(-1) and <= 1 helminth egg l(-1)), which were developed to protect the health of agricultural field workers, would be equally protective of the health of both animals fed with wastewater-irrigated crops and humans consuming products from such animals. PMID- 23802809 TI - Supporting smoking cessation in chronic obstructive pulmonary disease with behavioral intervention: a randomized controlled trial. AB - BACKGROUND: Cigarette smoking is the major risk factor for chronic obstructive pulmonary disease (COPD). But a fewer smoking cessation measures were conducted in communities for smokers with COPD in China. The aim of our study was to assess the preventive effects of behavioral interventions for smoking cessation and potential impact factors in smokers with COPD in China. METHODS: In a randomised controlled smoking cessation trial 3562 patients with COPD who were current smoker were allocated to intervention group received behavioral intervention and control group received the usual care for two years. The primary efficacy endpoint was the complete and continuous abstinence from smoking from the beginning of month 24 to the end of month 30. Participants were followed up at month 48. RESULTS: Continuous smoking abstinence rates from month 24 to 30 were significantly higher in participants receiving behavioral intervention than in those receiving usual care (46.4% vs 3.4%, p < 0.001). Continuous abstinence rates from months 24 to 36 (45.8% vs 4.0%) and months 24 to 48 (44.3% vs 5.1%) were also higher in participants receiving behavioral intervention than in those control group. Family members or family physicians/nurses smoking were first identified to influence smoking cessation. CONCLUSIONS: Behavioral intervention doubled the smoking cessation rate in patients with COPD and was complied well by the general practitioners. The family members and family physicians/nurses smoking were the main risk factors for smoking cessation. TRIAL REGISTRATION: Chinese Clinical Trials Registration (ChiCTR-TRC-12001958). PMID- 23802810 TI - Parallel comparison of apheresis-collected platelet concentrates stored in four different additive solutions. AB - BACKGROUND AND OBJECTIVES: Partially replacing plasma with additive solutions in platelet (PLT) concentrates (PCs) may help to reduce transfusion reactions. Constituents of PLT additive solutions (PASs) have been revealed to affect the quality of PCs. Previous studies involved pairwise comparison of identical PLTs with two different PASs or multicomparison using random PLTs with three or more PASs. In this study, we performed parallel comparison using PCs from identical donors with four PASs. In addition to traditional parameters, the release of bioactive substances and plasma proteins was assessed. MATERIALS AND METHODS: Platelets collected four times by apheresis from three donors were suspended in Intersol, SSP+, Composol or M-sol with 35% autologous plasma. The PC parameters, including PLT activation markers, glucose consumption, chemokines and plasma proteins, were assessed during 5-day storage. RESULTS: Mean PLT volumes were decreased in SSP+, Composol and M-sol after 5-day storage, with significant differences, whereas the hypertonic shock response (HSR) was decreased only in Intersol. Glucose consumption was faster in Intersol and M-sol than in SSP+ or Composol. PLT activation, determined as CD62P, sCD62P, sCD40L and RANTES, was significantly higher in Intersol than the other three PASs. No marked change was observed in fibrinopeptide A and C3a in any PASs. CONCLUSIONS: M-sol, SSP+ and Composol effectively preserved the quality of PCs. PLT activation was significantly enhanced in Intersol compared with the other three PASs. These effects seem to depend on magnesium and potassium as a constituent. Parallel comparison further verified that the PC quality largely depended on PASs but not donors. PMID- 23802811 TI - Rotatable reagent cartridge for high-performance microvalve system on a centrifugal microfluidic device. AB - Recently, microfluidic lab-on-a-CD (LabCD) has attracted attentions of researchers for its potential for pumpless, compact, and chip-inclusive on-site bioassay. To control the fluids in the LabCD, microvalves such as capillary, hydrophobic, siphon, and sacrificial valves have been employed. However, no microvalve can regulate more than one channel. In a complicated bioassay with many sequential mixing, washing, and wasting steps, thus, an intricate fluidic network with many microchannels, microvalves, and reservoirs is required, which increases assay costs in terms of both system development and chip preparation. To address this issue, we developed a rotatable reagent cartridge (RRC), which was a column-shaped tank and has several rooms to store different reagents. By embedding and rotating the RRC in the LabCD with a simple mechanical force, only the reagent in the room connected to the following channel was injected. By regulating the angle of the RRC to the LabCD, conservation and ejection of each reagent could be switched. Our developed RRC had no air vent hole, which was achieved by the gas-permeable gap between the bottle and cap parts of the RRC. The RRC could inject 230 nL-10 MUL of reagents with good recoveries more than 96%. Finally, an enzymatic assay of L-lactate was demonstrated, where the number of valves and reservoirs were well minimized, significantly simplifying the fluidic system and increasing the channel integratability. Well quantitative analyses of 0-100 MUM L-lactate could easily be carried out with R(2) > 0.999, indicating the practical utility of the RRC for microfluidic bioanalysis. PMID- 23802812 TI - Factors that drive peptide assembly and fibril formation: experimental and theoretical analysis of Sup35 NNQQNY mutants. AB - Residue mutations have substantial effects on aggregation kinetics and propensities of amyloid peptides and their aggregate morphologies. Such effects are attributed to conformational transitions accessed by various types of oligomers such as steric zipper or single beta-sheet. We have studied the aggregation propensities of six NNQQNY mutants: NVVVVY, NNVVNV, NNVVNY, VIQVVY, NVVQIY, and NVQVVY in water using a combination of ion-mobility mass spectrometry, transmission electron microscopy, atomic force microscopy, and all atom molecular dynamics simulations. Our data show a strong correlation between the tendency to form early beta-sheet oligomers and the subsequent aggregation propensity. Our molecular dynamics simulations indicate that the stability of a steric zipper structure can enhance the propensity for fibril formation. Such stability can be attained by either hydrophobic interactions in the mutant peptide or polar side-chain interdigitations in the wild-type peptide. The overall results display only modest agreement with the aggregation propensity prediction methods such as PASTA, Zyggregator, and RosettaProfile, suggesting the need for better parametrization and model peptides for these algorithms. PMID- 23802813 TI - Changes in cystic fibrosis airway microbiota at pulmonary exacerbation. AB - RATIONALE: In persons with cystic fibrosis (CF), repeated exacerbations of pulmonary symptoms are associated with a progressive decline in lung function. Changes in the airway microbiota around the time of exacerbations are not well understood. OBJECTIVES: To characterize changes in airway bacterial communities around the time of exacerbations and to identify predictors for these changes. METHODS: DNA prepared from 68 paired baseline and exacerbation sputum samples collected from 28 patients with CF were subjected to barcoded 16S rRNA gene pyrosequencing. Bacterial density was calculated by quantitative PCR. MEASUREMENTS AND MAIN RESULTS: Overall, significant differences in bacterial community diversity and bacterial density between baseline and exacerbation samples were not observed. However, considerable changes in community structures were observed in a subset of patients. In these patients, the dominant taxa and initial level of community diversity were significant predictors of the magnitude of community structure changes at exacerbation. Pseudomonas-dominant communities became more diverse at exacerbation compared with communities with other or no dominant species. The relative abundance of Gemella increased in 24 (83%) of 29 samples at exacerbation and was found to be the most discriminative genus between baseline and exacerbation samples. CONCLUSIONS: The magnitude of changes in the CF lung microbiota around the time of exacerbation was found to be largely dependent on community diversity and composition at baseline. Certain genera appear to play important roles in driving change in airway bacterial community composition at exacerbation. Gemella might play a direct role in and/or be a biomarker for pulmonary exacerbation. PMID- 23802815 TI - Application of a microsystem-based project to improve the inpatient care of adults with cystic fibrosis. AB - BACKGROUND: Patients with cystic fibrosis (CF) hospitalized for pulmonary exacerbations complained of delayed and missed treatments. We analyzed the complaints and implemented two microsystem-based quality initiatives to improve care. METHODS: A prospective, observational study using quantitative and qualitative data collection strategies was conducted. Two interventions were implemented: a CF order set followed 9 months later by a self-administration program. MEASUREMENTS AND MAIN RESULTS: Thirty-six of 40 patients with CF received initial respiratory therapy within 2 hours of admission compared with 1 of 17 before intervention. Initial antibiotic administration time was reduced from a mean of 18 hours to within 4 hours in the majority of admissions after implementation of quality initiatives. The interventions led to improved medication delivery and increased satisfaction. Hospital length of stay for patients with CF decreased from a mean of 9.5 to 7.8 days. CONCLUSION: Application of a microsystem-based strategy that engaged patients and families as well as caregivers brought about substantial changes in CF care delivery, increased satisfaction among staff and patients, and decreased hospital length of stay. PMID- 23802814 TI - Adult-onset asthma becomes the dominant phenotype among women by age 40 years. the longitudinal CARDIA study. AB - RATIONALE: Although asthma is usually considered to originate in childhood, adult onset disease is being increasingly reported. OBJECTIVES: To contrast the proportion and natural history of adult-onset versus pediatric-onset asthma in a community-based cohort. We hypothesized that asthma in women is predominantly of adult onset rather than of pediatric onset. METHODS: This study used data from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort in the United States over a 25-year period. Adult- and pediatric-onset asthma phenotypes were studied, as defined by age at onset of 18 years or older. Subjects with asthma were categorized by sex, obesity, atopy, smoking, and race by mean age/examination year, using a three-way analysis of covariance model. Natural history of disease was examined using probabilities derived from a Markov chain model. MEASUREMENTS AND MAIN RESULTS: Asthma of adult onset became the dominant (i.e., exceeded 50%) phenotype in women by age 40 years. The age by which adult onset asthma became the dominant phenotype was further lowered for obese, nonatopic, ever-smoking, or white women. The prevalence trend with increasing time for adult-onset disease was greater among subjects with nonatopic than atopic asthma among both sexes. Furthermore, adult-onset asthma had remarkable sex-related differences in risk factors. In both sexes, the quiescent state for adult-onset asthma was less frequent and also "less stable" over time than for pediatric-onset asthma. CONCLUSIONS: Using a large national cohort, this study challenges the dictum that most asthma in adults originates in childhood. Studies of the differences between pediatric- and adult-onset asthma may provide greater insight into the phenotypic heterogeneity of asthma. PMID- 23802817 TI - Long-term effects of pregnancy and motherhood on disease outcomes of women with cystic fibrosis. AB - RATIONALE: Studies of pregnancy in cystic fibrosis (CF) have shown no short-term harmful effects, but there are no long-term studies on the impact of motherhood. OBJECTIVES: This study sought to evaluate longer-term physiologic and functional outcomes in women with CF reporting a pregnancy, with the intent of assessing how the demands of parenting impacted on disease course. METHODS: Using 1994 to 2005 Epidemiologic Study of Cystic Fibrosis data, we developed a propensity score to match women reporting a pregnancy at a 1:10 ratio with never-pregnant control subjects and compared clinical outcomes, health-related quality of life, and health care use. MEASUREMENTS AND MAIN RESULTS: One hundred nineteen pregnant women presumed to have become mothers were matched with 1,190 control subjects, a median of 6.0 years (range 1.8-11.1 yr) from the pregnancy. No differences were found in annualized change from baseline FEV1 and body mass index, in respiratory signs and symptoms, or in prescribed chronic therapies. Women who had been pregnant were treated for more pulmonary exacerbations and had more illness related clinic visits but showed no increase in prescribed chronic therapies. They also reported lower health-related quality-of-life scores for Respiratory Symptoms, Physical Functioning, Vitality, and Health Perceptions. CONCLUSIONS: Pregnancy and motherhood do not appear to accelerate disease progression but lead to more illness-related visits, pulmonary exacerbations, and a decrease in some domains of quality of life. These differences presumably reflect the impact of the physical and emotional challenges of early motherhood on disease self management. PMID- 23802816 TI - Inhaled tobramycin effectively reduces FEV1 decline in cystic fibrosis. An instrumental variables analysis. AB - RATIONALE: The efficacy of inhaled tobramycin on chronic Pseudomonas aeruginosa infections in patients with cystic fibrosis (CF) has been established in clinical trials. However, little is known about its clinical effectiveness on lung function outside randomized controlled trial settings; conventional analysis of existing registry data has heretofore been confounded by treatment selection bias. OBJECTIVE: To determine effectiveness of inhaled tobramycin on FEV1 decline in patients with chronic P. aeruginosa infections using observational data from the Cystic Fibrosis Foundation Patient Registry. METHODS: Patient-level tobramycin use was measured at first chronic P. aeruginosa infection (n = 13,686 patients; age, 6-21 yr). Decline in FEV1 2 years after infection was estimated for patients treated with tobramycin and compared with untreated patients. Multiple linear regressions with confounder adjustment and propensity scores were used to estimate mean FEV1 decline for each group. Because care is organized by centers, we used center-specific prescription rates as an instrument to reduce treatment-by-condition bias. MEASUREMENTS AND MAIN RESULTS: Using center-level prescribing rates, instrumental variables analysis showed less FEV1 decline for patients who received tobramycin when first eligible compared with those who did not receive tobramycin (difference, 2.55% predicted; 95% confidence interval, 0.16-4.94; P = 0.0366). CONCLUSIONS: Inhaled tobramycin is effective in reducing lung function decline among patients 6 to 21 years of age with CF. Because CF care is organized by center, using center-specific prescription rates as an instrumental variable is a feasible approach to using the Cystic Fibrosis Foundation Patient Registry to determine treatment effectiveness. More generally, this approach can correct for treatment-by-condition bias arising from observational studies. PMID- 23802818 TI - Elements of a high-quality inpatient consultation in the intensive care unit. A qualitative study. AB - RATIONALE: Inpatient consultation by specialists is one of the most common medical interventions in the modern intensive care unit (ICU), but few data exist on components of high-quality consultation. OBJECTIVES: Our objective was to use qualitative methods to develop a conceptual framework of consultative quality in critically ill patients. METHODS: We conducted a qualitative study of medical ICU physicians at a single institution using a novel, semistructured interview guide. We elicited physicians' attitudes toward processes of obtaining specialty consultation, identified perceived elements of high-quality consults, and identified barriers to obtaining high-quality consults. We used grounded theory to identify themes. MEASUREMENTS AND MAIN RESULTS: ICU physicians described four common reasons for involving a consulting physician: the need for clinical or procedural expertise, an explicit or implicit protocol of the institution mandating the consult, an opportunity to provide education to the primary or consulting team, and/or at the family's request. Participants identified seven components of a high-quality consult, including the consulting teams' (1) decisiveness, (2) thoroughness, (3) level of interest, (4) professionalism, (5) expertise, (6) timeliness, and (7) involvement with the family of the patient. The intensive care team, the consult team, the health system, and the temporal context in which the consultation takes place may influence the quality of the consultation. CONCLUSIONS: Several key factors are necessary for a consult to be judged high quality. An opportunity exists to develop an instrument to assess and to improve specialty consultations in the ICU based on these findings. PMID- 23802819 TI - Critical care nurses' perception of time spent at rapid responses. AB - RATIONALE: Critical care nurses are an integral part of rapid response (RR) teams. The length of time they spend away from an intensive care unit (ICU) to attend RRs and how ICU nurses perceive the time away from the ICU has not been previously evaluated. OBJECTIVES: To determine: (1) the time an ICU nurse spends at RRs; (2) ICU nurses' view of nursing absence; and (3) RR characteristics associated with longer nursing time. METHODS: A prospective analysis of RRs in one 500-bed adult academic medical center over 1 year. Nurses' perception was assessed through surveys and semistructured interviews. MEASUREMENTS AND MAIN RESULTS: There were 536 RRs. An ICU nurse was present for 20 minutes or less in 54% of the RRs, 21-40 minutes in 26%, 41-60 minutes in 11%, and more than 60 minutes in 9% of RRs. Compared with nursing time required in RRs for neurologic instability (median [Q1 first quartile {25th percentile}, Q3 third quartile {75th percentile}] = 15.0 [10.0, 27.0] min), nursing time was longer in RRs for hemodynamic instability (30.0 [15.0, 45.0] min) and respiratory failure (25.0 [12.0, 45.0] min; P < 0.0001). Of the 85 nurses surveyed, 47% considered 41-60 minutes as a substantial amount of time at RRs; 99% perceived ICU workload as busier when a nurse attended RRs, and 87% believed ICU care was compromised, defined as reduction in the quality of care. CONCLUSIONS: In this study of one midsized academic medical center, about half of critical care nurse involvement in RRs takes them away from their ICU patients for less than 20 minutes. Nevertheless, nurses felt that ICU care was compromised when an ICU nurse responded to an RR. PMID- 23802820 TI - Purulent pericarditis secondary to community-acquired, methicillin-resistant Staphylococcus aureus in previously healthy children. A sign of the times? AB - RATIONALE: Purulent pericarditis secondary to community-acquired, methicillin resistant Staphylococcus aureus (CA-MRSA) is a potentially lethal infection that has yet to be described in the pediatric population. Only four cases of purulent pericarditis secondary to CA-MRSA have been described in the English literature, all of whom were adults. OBJECTIVES: We report on the first two pediatric cases of purulent pericarditis secondary to CA-MRSA to increase awareness of this potentially fatal condition. METHODS: Clinical data were obtained from an 8-year old male patient and a 7-month-old female patient, both previously healthy, who presented to our hospital for treatment of severe shock and multiorgan failure. Literature review was performed using MEDLINE and Cochrane databases. Pulsed field gel electrophoresis was performed to confirm the organism type. MEASUREMENTS AND MAIN RESULTS: Our previously healthy patients presented with refractory shock and were found to have purulent pericarditis with tamponade secondary to CA-MRSA. Both patients required emergent pericardiocentesis and surgical pericardial debridement. Isolates from both patients were found to be MRSA USA type 300, a common type of CA-MRSA that has become the most frequent cause of skin and soft tissue infections in the United States. CONCLUSIONS: Purulent pericarditis survival hinges upon early empiric antibiotic therapy targeting resistant Staphylococcus, rapid diagnostic efforts, and expeditious pericardial drainage when diagnosed. An aggressive multidisciplinary approach provided for complete recovery in both cases, and both children were discharged with normal cardiac function. These two cases emphasize the need for consideration of CA-MRSA presenting with purulent pericarditis as an etiology for refractory shock. PMID- 23802821 TI - Effects of marijuana smoking on the lung. AB - Regular smoking of marijuana by itself causes visible and microscopic injury to the large airways that is consistently associated with an increased likelihood of symptoms of chronic bronchitis that subside after cessation of use. On the other hand, habitual use of marijuana alone does not appear to lead to significant abnormalities in lung function when assessed either cross-sectionally or longitudinally, except for possible increases in lung volumes and modest increases in airway resistance of unclear clinical significance. Therefore, no clear link to chronic obstructive pulmonary disease has been established. Although marijuana smoke contains a number of carcinogens and cocarcinogens, findings from a limited number of well-designed epidemiological studies do not suggest an increased risk for the development of either lung or upper airway cancer from light or moderate use, although evidence is mixed concerning possible carcinogenic risks of heavy, long-term use. Although regular marijuana smoking leads to bronchial epithelial ciliary loss and impairs the microbicidal function of alveolar macrophages, evidence is inconclusive regarding possible associated risks for lower respiratory tract infection. Several case reports have implicated marijuana smoking as an etiologic factor in pneumothorax/pneumomediastinum and bullous lung disease, although evidence of a possible causal link from epidemiologic studies is lacking. In summary, the accumulated weight of evidence implies far lower risks for pulmonary complications of even regular heavy use of marijuana compared with the grave pulmonary consequences of tobacco. PMID- 23802822 TI - Cannabis and the lung: no more smoking gun? PMID- 23802823 TI - What to expect when you're expectorating: cystic fibrosis exacerbations and microbiota. PMID- 23802824 TI - Editors' introduction to ATS seminars: demystifying data. PMID- 23802825 TI - Editors' introduction to The Clinical Physiologist. PMID- 23802826 TI - Raising tobacco taxes: a timely prescription for U.S. public and fiscal health. PMID- 23802827 TI - Instrumental variable analyses. Exploiting natural randomness to understand causal mechanisms. AB - Instrumental variable analysis is a technique commonly used in the social sciences to provide evidence that a treatment causes an outcome, as contrasted with evidence that a treatment is merely associated with differences in an outcome. To extract such strong evidence from observational data, instrumental variable analysis exploits situations where some degree of randomness affects how patients are selected for a treatment. An instrumental variable is a characteristic of the world that leads some people to be more likely to get the specific treatment we want to study but does not otherwise change those patients' outcomes. This seminar explains, in nonmathematical language, the logic behind instrumental variable analyses, including several examples. It also provides three key questions that readers of instrumental variable analyses should ask to evaluate the quality of the evidence. (1) Does the instrumental variable lead to meaningful differences in the treatment being tested? (2) Other than through the specific treatment being tested, is there any other way the instrumental variable could influence the outcome? (3) Does anything cause patients to both receive the instrumental variable and receive the outcome? PMID- 23802828 TI - A typical case of atypical dyspnea. PMID- 23802829 TI - Under pressure. PMID- 23802830 TI - Acute respiratory failure secondary to achalasia. PMID- 23802831 TI - Improvement in sleep-disordered breathing after insertion of left ventricular assist device. PMID- 23802832 TI - The (pediatric pulmonary) world is flat. The spread of Internet-based pediatric pulmonary case conferences. PMID- 23802833 TI - C. Everett Koop, M.D. (1916-2013). United States Surgeon General, 1982-1989. PMID- 23802834 TI - Jules Arthur Peter Pare, M.D.C.M., B.Sc., F.A.C.P. (1917-2013). PMID- 23802838 TI - Spontaneous transport of microparticles across liquid-liquid interfaces. AB - Transporting micrometer-sized particles through the liquid-liquid interface generally requires high shear force and sometimes surfactant functionalization. Without these aids, particles adhere to the interface due to strong capillary forces (can be on the order of 10(6) kT). Thus, spontaneous transport of microparticles through the liquid-liquid interface has not yet been reported. However, we present a new phenomenon here: some ionic liquids (ILs) possess powerful extraction capabilities and can cause microparticles to migrate across the interface without the aid of any shear forces. Both single particles and clusters of particles were observed to adsorb to, then "jump" across the interface and finally detach. In the absence of external mixing, particles as large as 4 MUm (in diameter) could completely penetrate the IL/water interface, despite the significant adhesive forces. We have presented a hypothesis that these forces were overcome by ions dissolved in the non-IL phase, which helped by covering the particle surfaces, allowing for more favorable interactions with the IL. PMID- 23802839 TI - Sexual and relationship intimacy among women with provoked vestibulodynia and their partners: associations with sexual satisfaction, sexual function, and pain self-efficacy. AB - INTRODUCTION: Provoked vestibulodynia (PVD) is the most frequent subtype of vulvodynia. Women report negative consequences of PVD on their sexual and romantic relationships. Researchers have recently highlighted the importance of examining interpersonal factors such as intimacy, and of including both women and their partners in study designs. AIM: The aim of this study was to investigate sexual and relationship intimacy as defined by the Interpersonal Process Model of Intimacy and their associations with sexual satisfaction, sexual function, pain self-efficacy, and pain intensity among women with PVD and their partners. METHODS: Ninety-one heterosexual women (M age = 27.38, SD = 6.04) diagnosed with PVD and their partners (M age = 29.37, SD = 7.79) completed measures of sexual and relationship intimacy, sexual satisfaction, sexual function, pain self efficacy, and pain intensity. MAIN OUTCOME MEASURES: Dependent measures were the (i) Global Measure of Sexual Satisfaction Scale; (ii) Female Sexual Function Index; (iii) Painful Intercourse Self-Efficacy Scale; and (iv) visual analog scale of pain intensity during intercourse. RESULTS: After controlling for women's age, women's greater sexual intimacy (beta = 0.49, P < 0.001) was associated with women's greater sexual satisfaction and higher pain self-efficacy (beta = 0.39, P = 0.001), beyond the effects of partners' sexual intimacy. Also, women's greater sexual intimacy (beta = 0.24, P = 0.05) and women's greater relationship intimacy (beta = 0.54, P = 0.003) were associated with greater women's sexual function, beyond the effects of partners' sexual and relationship intimacy. CONCLUSIONS: Women's self-reported sexual and relationship intimacy in the couple relationship may promote higher sexual satisfaction, sexual function, and pain self-efficacy, as well as possibly foster greater sexual well-being among women with PVD. The authors discuss implications for the inclusion of emotional and interpersonal aspects of the couple's dynamic in clinical interventions and future research in PVD. PMID- 23802840 TI - Long-term 4-year safety of saxagliptin in drug-naive and metformin-treated patients with Type 2 diabetes. AB - AIMS: To evaluate the safety of saxagliptin +/- metformin over 4 years in patients with Type 2 diabetes mellitus. METHODS: Drug-naive (n = 401; study 11) or metformin-treated (n = 743; study 14) adults with HbA(1c) of 53-86 mmol/mol (7.0-10%) were enrolled in two randomized, placebo-controlled, double-blind trials of saxagliptin 2.5, 5 or 10 mg/day. Patients rescued during or completing 24 weeks of treatment could continue in a 42-month long-term blinded phase, for which the primary goal was assessment of safety and tolerability. Between-group efficacy was not evaluated in the long-term phase of study 11. Time to rescue or discontinuation because of inadequate glycaemic control, change from baseline in HbA(1c) and percentages of patients achieving HbA(1c) < 53 mmol/mol (< 7.0%) were assessed in study 14. RESULTS: No new safety findings were noted during the long term phase. Most adverse events were mild or moderate, with slightly greater frequency of upper respiratory infections with saxagliptin. Hypoglycaemic event rates were similar with saxagliptin and placebo. In study 14, time to rescue or discontinuation because of inadequate glycaemic control was longer with saxagliptin plus metformin than for placebo plus metformin. From baseline to week 154, HbA(1c) decreased with saxagliptin but increased with placebo. CONCLUSION: Saxagliptin monotherapy or add-on to metformin is generally safe and well tolerated, with no increased risk of hypoglycaemia, for up to 4 years. PMID- 23802841 TI - High level transient production of recombinant antibodies and antibody fusion proteins in HEK293 cells. AB - BACKGROUND: The demand of monospecific high affinity binding reagents, particularly monoclonal antibodies, has been steadily increasing over the last years. Enhanced throughput of antibody generation has been addressed by optimizing in vitro selection using phage display which moved the major bottleneck to the production and purification of recombinant antibodies in an end user friendly format. Single chain (sc)Fv antibody fragments require additional tags for detection and are not as suitable as immunoglobulins (Ig)G in many immunoassays. In contrast, the bivalent scFv-Fc antibody format shares many properties with IgG and has a very high application compatibility. RESULTS: In this study transient expression of scFv-Fc antibodies in human embryonic kidney (HEK) 293 cells was optimized. Production levels of 10-20 mg/L scFv-Fc antibody were achieved in adherent HEK293T cells. Employment of HEK293-6E suspension cells expressing a truncated variant of the Epstein Barr virus (EBV) nuclear antigen (EBNA) 1 in combination with production under serum free conditions increased the volumetric yield up to 10-fold to more than 140 mg/L scFv-Fc antibody. After vector optimization and process optimization the yield of an scFv-Fc antibody and a cytotoxic antibody-RNase fusion protein further increased 3-4-fold to more than 450 mg/L. Finally, an entirely new mammalian expression vector was constructed for single step in frame cloning of scFv genes from antibody phage display libraries. Transient expression of more than 20 different scFv-Fc antibodies resulted in volumetric yields of up to 600 mg/L and 400 mg/L in average. CONCLUSION: Transient production of recombinant scFv-Fc antibodies in HEK293-6E in combination with optimized vectors and fed batch shake flasks cultivation is efficient and robust, and integrates well into a high-throughput recombinant antibody generation pipeline. PMID- 23802842 TI - Infants' perception of emotion from body movements. AB - Adults recognize emotions conveyed by bodies with comparable accuracy to facial emotions. However, no prior study has explored infants' perception of body emotions. In Experiment 1, 6.5-month-olds (n = 32) preferred happy over neutral actions of actors with covered faces in upright but not inverted silent videos. In Experiment 2, infants (n = 32) matched happy and angry videos to corresponding vocalizations when the videos were upright but not when they were inverted. Experiment 3 (n = 16) demonstrated that infants' performance in Experiment 2 was not driven by information from the covered face and head. Thus, young infants are sensitive to emotions conveyed by bodies and match them to affective vocalizations, indicating sophisticated emotion processing capabilities early in life. PMID- 23802843 TI - Anti-cancer molecular targets of natural products. PMID- 23802844 TI - Outcome of pediatric acquired aplastic anemia: a developing world experience. AB - INTRODUCTION: Outcome data of children with acquired aplastic anemia (AA) are lacking from the developing world. Here, we describe the same from a centre in North India. METHODS: Retrospective data regarding medical history, physical examination, complete blood count, bone marrow aspirate, and biopsy were retrieved for all children <18 years, with acquired AA admitted between January 2005 and June 2012. In addition, the outcome data after immunosuppressive therapy (IST) or bone marrow transplant (BMT) was obtained. RESULTS: A total of 61 children were diagnosed with AA (Inherited-18 and acquired-43). Among 43 children with acquired AA, 3 had nonsevere and 40 had severe. One patient with nonsevere AA died of sepsis and 2 recovered spontaneously. Of the 40 remaining children with severe AA, 10 refused therapy and 3 died due to severe sepsis prior to any therapy. Five underwent upfront matched sibling donor BMT and one post-IST failure. Four year overall survival (OS) and event free survival (EFS) for children undergoing BMT was 100% and 80 +/- 17.9, respectively. Out of 22 treated with IST, 20 were evaluable for response. Seventeen received one course and 3 received two course of IST. The overall response to IST was seen in 14/20 (70%). Only two achieved complete response while remaining 12 had partial response. The 4-year estimated OS and EFS for children treated with IST was 74.4 +/- 12.1% and 65.6 +/- 12.2. CONCLUSION: Outcomes for children with AA are encouraging in the developing world although barriers like sepsis and treatment abandonment remain. BMT offers faster and complete recovery. PMID- 23802845 TI - Chemoselective transfer hydrogenation of alpha,beta-unsaturated ketones catalyzed by pincer-Pd complexes using alcohol as a hydrogen source. AB - A pincer-Pd complex was utilized in the chemoselective transfer hydrogenation of alpha,beta-unsaturated ketones using n-BuOH as a hydrogen source and solvent. Good to excellent yields were obtained for various substrates even with reducible groups. Based on deuterium-labeling experiments, the reaction mechanism is proposed to occur via a pincer-Pd-hydride intermediate. PMID- 23802847 TI - A journey to citizenship: constructions of citizenship and identity in the British Citizenship Test. AB - The British Citizenship Test was introduced in 2005 as one of a raft of new procedures aimed at addressing the perceived problems of integration and social cohesion in migrant communities. In this study, we argue that this new citizenship procedure signals a shift in British political discourse about citizenship - particularly, the institutionalization of a common British citizen identity that is intended to draw citizens together in a new form of political/national community. In line with this, we examine the British Citizenship Test from a social psychological perspective to interrogate the ways in which the test constitutes identity, constitutes citizenship, and constitutes citizenship-as-identity. Analysis of the test and its associated documents highlights three ways in which Britishness-as-identity is constituted, that is, as a collective identity, as a superordinate and national identity, and finally as both a destination and a journey. These findings are discussed in terms of their implications for models of citizenship and models of identity. PMID- 23802846 TI - Sex differences in the medical care of VA patients with chronic non-cancer pain. AB - OBJECTIVE: Despite a growing number of women seeking medical care in the veterans affairs (VA) system, little is known about the characteristics of their chronic pain or the pain care they receive. This study sought to determine if sex differences are present in the medical care veterans received for chronic pain. DESIGN: Retrospective cohort study using VA administrative data. SUBJECTS: The subjects were 17,583 veteran patients with moderate to severe chronic non-cancer pain treated in the Pacific Northwest during 2008. METHODS: Multivariate logistic regression assessed for sex differences in primary care utilization, prescription of chronic opioid therapy, visits to emergency departments for a pain-related diagnosis, and physical therapy referral. RESULTS: Compared with male veterans, female veterans were more often diagnosed with two or more pain conditions, and had more of the following pain-related diagnoses: fibromyalgia, low back pain, inflammatory bowel disease, migraine headache, neck or joint pain, and arthritis. After adjustment for demographic characteristics, pain diagnoses, mental health diagnoses, substance use disorders, and medical comorbidity, women had lower odds of being prescribed chronic opioid therapy (adjusted OR [AOR] 0.67, 95% CI 0.58 0.78), greater odds of visiting an emergency department for a pain-related complaint (AOR 1.40, 95% CI 1.18-1.65), and greater odds of receiving physical therapy (AOR 1.19, 95% CI 1.05-1.33). Primary care utilization was not significantly different between sexes. CONCLUSIONS: Sex differences are present in the care female veterans receive for chronic pain. Further research is necessary to understand the etiology of the observed differences and their associations with clinical outcomes. PMID- 23802848 TI - Panitumumab in metastatic colorectal cancer. AB - Increasing chemotherapeutic and targeted drug options has led to improved overall survival in metastatic colorectal cancer. Panitumumab is a fully humanized monoclonal antibody that binds to the EGF receptor and inhibits downstream cell signaling with net effects of inhibition of tumor growth, induction of apoptosis and inhibition of angiogenesis. Panitumumab leads to improved response rate and progression-free survival when used in combination with chemotherapy and as monotherapy in metastatic colorectal cancer. This benefit is limited to patients who have non-mutated KRAS tumors, and regulatory agencies worldwide have restricted panitumumab to this patient population. Rash is a common side effect of panitumumab, and prophylactic skin treatments are advised. The optimal use of panitumumab is evolving and will become further defined with results of upcoming clinical trials and improved identification of biomarkers predicting benefit of this class of drugs. PMID- 23802849 TI - Neurological events with tumour necrosis factor alpha inhibitors reported to the Food and Drug Administration Adverse Event Reporting System. AB - BACKGROUND: The association between inhibition of tumour necrosis factor alpha (TNF-alpha) and new onset of neurological adverse events (AEs) is unclear. AIMS: To evaluate neurological AEs with TNF-alpha inhibitors reported to the Food and Drug Administration Adverse Event Reporting System (FAERS) utilising a standardised scoring tool for drug-induced AEs. METHODS: A search of FAERS for neurological AEs (January 1, 2000 to December 31, 2009) reported with infliximab, adalimumab, certolizumab and etanercept was performed. Full-text reports were accessed using the Freedom of Information Act and scored using Naranjo score, while accounting for temporal association, previous conclusive reports of the neurological AE with any TNF-alpha inhibitor, and alternate explanations including underlying disease, concomitant medications and comorbidities, such as diabetes mellitus. RESULTS: There were 772 reports. Most were in patients who had rheumatoid arthritis (393, 50.9%) followed by inflammatory bowel disease (140, 18.1%). No significant differences in age or gender were seen between IBD patients compared with rheumatological diseases (P = 0.584 and P = 0.055 respectively). Etanercept was reported most (327, 42.4%) followed by infliximab (276, 35.8%) (P = 0.008). Peripheral neuropathy was the most common neurological AE (296 reports, 38.3%) followed by central nervous system and/or spinal cord demyelination (153 reports, 19.8%). Majority (551, 71.4%) of the reports were of 'possible' AE with the remaining 'probable' AE and none identified as 'definite' AE. CONCLUSION: While several neurological AEs have been described, definite association between de novo development of these AEs and exposure to TNF-alpha inhibitors was not established using the Naranjo score. PMID- 23802851 TI - Canadian licensure for the use of digital pathology for routine diagnoses: one more step toward a new era of pathology practice without borders. PMID- 23802850 TI - Quantifying longitudinal right ventricular dysfunction in patients with old myocardial infarction by using speckle-tracking strain echocardiography. AB - BACKGROUND: We investigated longitudinal right ventricular (RV) function assessed using speckle-tracking strain echocardiography in patient with myocardial infarction (MI), and identified the contributing factors for RV dysfunction. METHODS: We retrospectively studied 71 patients with old MI (the OMI group) and 45 normal subjects (the Control group) who underwent a transthoracic echocardiography. Global and free wall RV peak systolic strains (PSSs) in the longitudinal direction were measured by using speckle-tracking strain echocardiography. Left ventricular (LV) PSSs were measured in the longitudinal, radial and circumferential directions. Cardiac hemodynamics including peak systolic pulmonary artery pressure was also assessed non-invasively. Plasma brain natriuretic peptide (BNP) levels were measured in all patients. RESULTS: In the OMI group, 73% of the patients had a normal estimated peak systolic pulmonary artery pressure of less than 35 mmHg. Global and free wall RV PSS were impaired in the OMI group compared with the Control group, and these RV systolic indices were significantly associated with heart rate, logarithmic transformed plasma BNP, greater than 1 year after onset of MI, Doppler-derived estimated pulmonary vascular resistance, LV systolic indices, LV mass index, infarcted segments within a territory of the left circumflex artery and residual total occlusion in the culprit right coronary artery. Multivariable linear regression analysis indicated that reduced longitudinal LV PSS in the 4-chamber view and BNP levels >=500 pg/ml were independently associated with reduced global and free wall RV PSS. Moreover, when patients were divided into 3 groups according to plasma BNP levels (BNP <100 pg/ml; n = 31, 100 <=BNP <500 pg/ml; n = 24, and BNP >=500 pg/ml; n = 16), only patients with BNP >=500 pg/ml had a strong correlation between RV PSS and longitudinal LV PSS in the 4-chamber view (r = 0.78 for global RV PSS and r = 0.71 for free wall RV PSS, p <0.05). CONCLUSION: Longitudinal RV systolic strain depends significantly on longitudinal LV systolic strain especially in patients with high plasma BNP levels, but not on estimated peak systolic pulmonary artery pressure. These results indicate that process of RV myocardial dysfunction following MI may be governed by neurohormonal activation which causing ventricular remodeling rather than increased RV afterload. PMID- 23802852 TI - Lung adenocarcinoma biomarker incidence in Hispanic versus non-Hispanic white patients. AB - CONTEXT: Lung cancer is the leading cause of cancer deaths in the United States and worldwide. Biomarker testing is critical to personalized therapy in lung adenocarcinoma and has been extensively investigated in non-Hispanic whites, Asians, and African Americans. However, little information addresses the underlying genetic changes in lung adenocarcinoma among Hispanic patients in the United States. OBJECTIVE: To identify targetable biomarkers other than EGFR and EML4-ALK in Hispanic patients with lung adenocarcinoma. DESIGN: We tested DNA extracted from 85 lung adenocarcinoma specimens collected from 40 Hispanic and 43 non-Hispanic white patients for previously reported mutations in KRAS, MET, BRAF, mTOR, STAT3, JAK2, PIK3CA, AKT1 through AKT3, and PTEN with a custom Sequenom massARRAY assay (Sequenom, San Diego, California). RESULTS: Mutations in KRAS were identified in 11 cases (13%; 6 Hispanic [7%], 5 non-Hispanic white [6%]) and had no correlation with sex, age, or smoking history. Mutations in PIK3CA were identified in 2 of the 40 Hispanic patients (5%), including one patient (2.5%) with a concurrent KRAS mutation. The tumors were wild type for all other genes tested. CONCLUSIONS: Targetable biomarkers other than EGFR and EML4-ALK were identified in 7 of the 40 Hispanic patients (18%) and 5 of the 43 non-Hispanic white patients (12%), suggesting a similar mutational frequency. Our highly multiplexed genotyping assay detected actionable mutations in 14% (12 of 83) more patients than would have been identified by EGFR and EML4-ALK testing alone. PMID- 23802853 TI - Association of autoimmune diseases with oral lichen planus: a cross-sectional, clinical study. AB - BACKGROUND: The aim of this study was to investigate the association between autoimmune disease and oral lichen planus (OLP), comparing OLP patients with a control population. METHODS: This cross-sectional clinical study evaluated the prevalence of autoimmune diseases in male and female patients with OLP. The variables analysed were age, sex, tobacco and alcohol consumption, the clinical form of OLP, time of evolution and the presence of autoimmune diseases. RESULTS: Autoimmune diseases were present in 7% of OLP patients (10/130) and 4% of the control group (6/130) without statistically significant difference (P = 0.67). The estimated odds ratios (with 95% confidence intervals) of the presence of autoimmune disease in OLP sufferers was 1.033 (0.97-1.10). A logistic regression model for presence/absence of the risk autoimmune disease found statistically significant differences in relation to age. CONCLUSIONS: At present, there is no definitive hypothesis that explains the coexistence of OLP and autoimmune disease; further research is required into the mechanisms whereby this coexistence occurs. PMID- 23802854 TI - Determinants of Acidobacteria activity inferred from the relative abundances of 16S rRNA transcripts in German grassland and forest soils. AB - 16S rRNA genes and transcripts of Acidobacteria were investigated in 57 grassland and forest soils of three different geographic regions. Acidobacteria contributed 9-31% of bacterial 16S rRNA genes whereas the relative abundances of the respective transcripts were 4-16%. The specific cellular 16S rRNA content (determined as molar ratio of rRNA : rRNA genes) ranged between 3 and 80, indicating a low in situ growth rate. Correlations with flagellate numbers, vascular plant diversity and soil respiration suggest that biotic interactions are important determinants of Acidobacteria 16S rRNA transcript abundances in soils. While the phylogenetic composition of Acidobacteria differed significantly between grassland and forest soils, high throughput denaturing gradient gel electrophoresis and terminal restriction fragment length polymorphism fingerprinting detected 16S rRNA transcripts of most phylotypes in situ. Partial least squares regression suggested that chemical soil conditions such as pH, total nitrogen, C : N ratio, ammonia concentrations and total phosphorus affect the composition of this active fraction of Acidobacteria. Transcript abundance for individual Acidobacteria phylotypes was found to correlate with particular physicochemical (pH, temperature, nitrogen or phosphorus) and, most notably, biological parameters (respiration rates, abundances of ciliates or amoebae, vascular plant diversity), providing culture-independent evidence for a distinct niche specialization of different Acidobacteria even from the same subdivision. PMID- 23802855 TI - Secondary prophylaxis vs. on-demand treatment to improve quality of life in severe adult haemophilia A patients: a prospective study in a single centre. AB - BACKGROUND: Retrospective publications show a decrease in the bleeding frequency and an improvement in the quality of life (QoL) in severe adult haemophilia A (SAHA) after switching from the on-demand treatment (DT) to secondary prophylaxis (SP). But there are no prospective studies which demonstrate, using a haemophilia specific questionnaire, an improvement in the QoL after such treatment change. The main objective of this study is to prospectively compare the QoL and the musculoskeletal assessment after switching from DT to SP in SAHA using the A36 Hemofilia-QoL((r)) . As secondary objective, we compare the haemarthrosis frequency and factor VIII consumption in DT and SP during a similar period of time (12 months) after switching. MATERIALS AND METHODS: We have designed a prospective study including SAHA who have been under DT and were changed to a protocol, which combines SP (biweekly administration of factor VIII) with individualized physiotherapy programme. RESULTS: Twelve months after switching to SP, the QoL was significantly improved (P = 0.005). Musculoskeletal assessment of pathologic irreversible joints and joints with a reversible alteration was generally improved, although in only a few joints, this improvement was statistically significant. Haemarthrosis was strongly reduced (12.60-1.42, P < 0.001). CONCLUSIONS: This prospective study has demonstrated a statistically significant improvement in the QoL after 1 year from switching patients from DT to SP. The musculoskeletal assessment after 1 year was maintained similar or slightly improved. When we compared retrospective DT and prospective SP, haemarthrosis where strongly reduced requiring a slight increase in the consumption of factor VIII concentrates. PMID- 23802856 TI - Biogeochemical controls on hexavalent chromium formation in estuarine sediments. AB - Predicting the aquatic and human health impacts of chromium (Cr) necessitates one to determine its speciation as either relatively nontoxic Cr(III) or toxic Cr(VI) and elucidate the influence of biogeochemical changes on its behavior and fate. In the Baltimore Harbor, Cr predominantly exists as Cr(III) associated with sediments. While reduction of Cr(VI) to Cr(III) is dominant in these anoxic sediments, the potential of Cr(III) oxidation and Cr(VI) reoccurrence during sediment resuspension and oxygenation resulting from dredging, bioturbation, and flood events poses a serious concern. In batch experiments, aqueous Cr(VI) spiked into continuously mixed anoxic suspensions was reduced to product Cr(III) under anaerobic conditions. No Cr(VI) reoccurrence was observed when conditions remained anaerobic. Aeration caused Cr(VI) reoccurrence from the abiotic oxidation of product Cr(III). Rates of aeration-driven Cr(VI) reoccurrence increased with pH, and Cr(VI) reoccurrence positively correlated with dissolved manganese (Mn) decline at pH >= 7. Aeration-driven oxidation of Mn(II) to Mn(III,IV)(hydr)oxides was the underlying mechanism causing product Cr(III) oxidation. Cr(VI) reoccurrence decreased with sediment loading and negatively correlated with the acid volatile sulfide (AVS) concentration. Although sediment resuspension and oxygenation may create temporary conditions conducive to Cr(VI) formation, long-term Cr(VI) persistence is unlikely in the presence of sediment reductants. While such natural attenuation in reducing environments mitigates the risk associated with Cr toxicity, this risk may still persist in Mn-rich and reductant-deficient environments. PMID- 23802857 TI - Bioinspired templating synthesis of metal-polymer hybrid nanostructures within 3D electrospun nanofibers. AB - Novel metal nanostructures immobilized within three-dimensional (3D) porous polymeric scaffolds have been utilized for catalysts and biosensors. However, efficient, robust immobilization of the nanostructures both outside and inside of the 3D scaffolds is a challenging task. To address the challenge, we synthesized a redox-active polymer, catechol-grafted poly(vinyl alcohol), PVA-g-ct. The grafted catechol is inspired by the adhesion mechanism of marine mussels, which facilitates binding and reduction of noble metal ions. Electrospinning the PVA-g ct polymer results in highly open porous, 3D nanostructures, on which catechol mediates the spontaneous reduction of silver ions to solid silver nanocubes at an ambient temperature. Yet, gold and platinum ions are partially reduced and complexed with the nanofiber template, requiring an additional thermal treatment for complete reduction into solid metal nanostructures. Furthermore, silver-gold and silver-platinum hybrid nanostructures are generated by sequential treatments with metal ion precursor solutions of each. This study suggests that catechol grafted polymer nanofibers are an attractive reactive template for the facile synthesis and immobilization of noble metal nanostructures within a 3D porous matrix for the potential applications to sensors, catalysis, and tissue engineering. PMID- 23802858 TI - A cross-sectional study examining the prevalence and risk factors for anti microbial-resistant generic Escherichia coli in domestic dogs that frequent dog parks in three cities in south-western Ontario, Canada. AB - Anti-microbial resistance can threaten health by limiting treatment options and increasing the risk of hospitalization and severity of infection. Companion animals can shed anti-microbial-resistant bacteria that may result in the exposure of other dogs and humans to anti-microbial-resistant genes. The prevalence of anti-microbial-resistant generic Escherichia coli in the faeces of dogs that visited dog parks in south-western Ontario was examined and risk factors for shedding anti-microbial-resistant generic E. coli identified. From May to August 2009, canine faecal samples were collected at ten dog parks in three cities in south-western Ontario, Canada. Owners completed a questionnaire related to pet characteristics and management factors including recent treatment with antibiotics. Faecal samples were collected from 251 dogs, and 189 surveys were completed. Generic E. coli was isolated from 237 of the faecal samples, and up to three isolates per sample were tested for anti-microbial susceptibility. Eighty-nine percent of isolates were pan-susceptible; 82.3% of dogs shed isolates that were pan-susceptible. Multiclass resistance was detected in 7.2% of the isolates from 10.1% of the dogs. Based on multilevel multivariable logistic regression, a risk factor for the shedding of generic E. coli resistant to ampicillin was attending dog day care. Risk factors for the shedding of E. coli resistant to at least one anti-microbial included attending dog day care and being a large mixed breed dog, whereas consumption of commercial dry and home cooked diets was protective factor. In a multilevel multivariable model for the shedding of multiclass-resistant E. coli, exposure to compost and being a large mixed breed dog were risk factors, while consumption of a commercial dry diet was a sparing factor. Pet dogs are a potential reservoir of anti-microbial-resistant generic E. coli; some dog characteristics and management factors are associated with the prevalence of anti-microbial-resistant generic E. coli in dogs. PMID- 23802859 TI - Cameroonian medicinal plants: a bioactivity versus ethnobotanical survey and chemotaxonomic classification. AB - BACKGROUND: In Cameroon herbs are traditionally used to meet health care needs and plans are on the way to integrate traditional medicine in the health care system, even though the plans have not been put into action yet. The country however has a rich biodiversity, with ~8,620 plant species, some of which are commonly used in the treatment of several microbial infections and a range of diseases (malaria, trypanosomiasis, leishmaniasis, diabetes and tuberculosis). METHODS: Our survey consisted in collecting published data from the literature sources, mainly from PhD theses in Cameroonian university libraries and also using the author queries in major natural product and medicinal chemistry journals. The collected data includes plant sources, uses of plant material in traditional medicine, plant families, region of collection of plant material, isolated metabolites and type (e.g. flavonoid, terpenoid, etc.), measured biological activities of isolated compounds, and any comments on significance of isolated metabolites on the chemotaxonomic classification of the plant species. This data was compiled on a excel sheet and analysed. RESULTS: In this study, a literature survey led to the collection of data on 2,700 secondary metabolites, which have been previously isolated or derived from Cameroonian medicinal plants. This represents distinct phytochemicals derived from 312 plant species belonging to 67 plant families. The plant species are investigated in terms of chemical composition with respect to the various plant families. A correlation between the known biological activities of isolated compounds and the ethnobotanical uses of the plants is also attempted. Insight into future direction for natural product search within the Cameroonian forest and Savanna is provided. CONCLUSIONS: It can be verified that a phytochemical search of active secondary metabolites, which is inspired by knowledge from the ethnobotanical uses of medicinal plants could be very vital in a drug discovery program from plant-derived bioactive compounds. PMID- 23802860 TI - Droplet manipulation by an external electric field for crystalline film growth. AB - Combining droplet manipulation by the application of an electric field with inkjet printing is proposed as a unique technique to control the surface wettability of substrates for solution-processed organic field-effect transistors (FETs). With the use of this technique, uniform thin films of 2,7 dioctyl[1]benzothieno[2,3,-b][1]benzothiopene (C8-BTBT) could be fabricated on the channels of FET substrates without self-assembled monolayer treatment. High speed camera observation revealed that the crystals formed at the solid/liquid interface. The coverage of the crystals on the channels depended on the ac frequency of the external electric field applied during film formation, leading to a wide variation in the carrier transport of the films. The highest hole mobility of 0.03 cm(2) V(-1) s(-1) was obtained when the coverage was maximized with an ac frequency of 1 kHz. PMID- 23802861 TI - Several acneiform papules and nodules on the neck. PMID- 23802862 TI - The water supply system as a potential source of fungal infection in paediatric haematopoietic stem cell units. AB - BACKGROUND: We conducted a prospective study to investigate the presence of microfungal contamination in the water supply system of the Oncology Paediatric Institute, Sao Paulo-Brazil after the occurrence of one invasive Fusarium solani infection in a patient after Haematopoietic Stem Cell Transplantation (HSCT). During a twelve-month period, we investigated the water supply system of the HSCT unit by monitoring a total of fourteen different collection sites. METHODS: One litre of water was collected in each location, filtered through a 0.45 MUm membrane and cultured on SDA to detect the presence of filamentous fungi. Physicochemical analyses of samples were performed to evaluate the temperature, turbidity, pH, and the concentration of free residual chlorine. RESULTS: Over the 12 months of the study, 164 samples were collected from the water supply system of the HSCT unit, and 139 of the samples tested positive for filamentous fungi (84.8%), generating a total of 2,362 colonies. Cladosporium spp., Penicillium spp., Purpureocillium spp. and Aspergillus spp. were ranked as the most commonly found genera of mould in the collected samples. Of note, Fusarium solani complex isolates were obtained from 14 out of the 106 samples that were collected from tap water (mean of 20 CFU/L). There was a positive correlation between the total number of fungal CFU obtained in all cultures and both water turbidity and temperature parameters. Our findings emphasise the need for the establishment of strict measures to limit the exposure of high-risk patients to waterborne fungal propagules. CONCLUSIONS: We were able to isolate a wide variety of filamentous fungi from the water of the HSCT unit where several immunocompromised patients are assisted. PMID- 23802863 TI - Role of proximal gut exclusion from food on glucose homeostasis in patients with Type 2 diabetes. AB - AIMS: To report Type 2 diabetes-related outcomes after the implantation of a duodenal-jejunal bypass liner device and to investigate the role of proximal gut exclusion from food in glucose homeostasis using the model of this device. METHODS: Sixteen patients with Type 2 diabetes and BMI <36 kg/m(2) were evaluated before and 1, 12 and 52 weeks after duodenal-jejunal bypass liner implantation and 26 weeks after explantation. Mixed-meal tolerance tests were conducted over a period of 120 min and glucose, insulin and C-peptide levels were measured. The Matsuda index and the homeostatic model of assessment of insulin resistance were used for the estimation of insulin sensitivity and insulin resistance. The insulin secretion rate was calculated using deconvolution of C-peptide levels. RESULTS: Body weight decreased by 1.3 kg after 1 week and by 2.4 kg after 52 weeks (P < 0.001). One year after duodenal-jejunal bypass liner implantation, the mean (sem) HbA(1c) level decreased from 71.3 (2.4) mmol/mol (8.6[0.2]%) to 58.1 (4.4) mmol/mol (7.5 [0.4]%) and mean (sem) fasting glucose levels decreased from 203.3 (13.5) mg/dl to 155.1 (13.1) mg/dl (both P < 0.001). Insulin sensitivity improved by >50% as early as 1 week after implantation as measured by the Matsuda index and the homeostatic model of assessment of insulin resistance (P < 0.001), but there was a trend towards deterioration in all the above-mentioned variables 26 weeks after explantation. Fasting insulin levels, insulin area under the curve, fasting C-peptide, C-peptide area under the curve, fasting insulin and total insulin secretion rates did not change during the duodenal-jejunal bypass liner implantation period or after explantation. CONCLUSIONS: The duodenal jejunal bypass liner improves glycaemia in overweight and obese patients with Type 2 diabetes by rapidly improving insulin sensitivity. A reduction in hepatic glucose output is the most likely explanation for this improvement. PMID- 23802864 TI - Micronodular ultrasound lesions in the colonic submucosa of 42 dogs and 14 cats. AB - Micronodular ultrasound lesions have been detected in the colonic submucosa of dogs and cats at our hospital. The lesions had rounded/oval shapes, measured 1-3 mm in size, and exhibited a hypo/anechoic ultrasonographic pattern. To our knowledge, these lesions have not been previously reported in human or veterinary patients. The purpose of this retrospective study was to determine whether micronodular lesions were associated with other abdominal ultrasound abnormalities or clinical findings. Medical records of dogs and cats with sonographic reports describing micronodular lesions within the colonic submucosa were reviewed. Concurrent ultrasonographic abnormalities were recorded and compared with clinical sidgns and follow-up data. A total of 42 dogs and 14 cats met inclusion criteria. Concurrent sonographic abnormalities included the following: increased colon wall thickness (12.5%); small bowel wall thickening, altered layering, and/or hyperechoic mucosa (45%); abdominal effusion (29%); caudal mesenteric lymphadenopathy (46%); mesenteric lymphadenopathy (27%); and pericolic peritoneal fat reactivity (9%). Fifty of 56 animals presented with diarrhea. Twenty-seven cases had clinical signs of colitis and ultrasonographic lesions were limited to the colonic submucosa. In nine cases, follow-up examination at 6-8 weeks showed resolution of clinical and ultrasonographic signs. Ultrasonographic and clinical examinations in 17 patients at 12-18 months and in 20 patients at 18-30 months from initial diagnosis showed resolution of submucosal lesions and clinical signs of enteropathy. The authors propose that micronodular submucosal ultrasound lesions may represent reactive intraparietal lymphoid follicles and may be indicators of colonic inflammatory diseases in dogs and cats. PMID- 23802866 TI - Incontinentia pigmenti diagnostic criteria update. AB - In 1993 diagnostic criteria for incontinentia pigmenti (IP), a genodermatosis in which skin changes are usually combined with anomalies of other organs, were established. Approximately a decade ago, IKBKG gene mutation was discovered as a cause for IP. This finding has not been included in IP diagnosis so far. In addition, literature data pointed out a few other clinical findings as possible IP diagnostic criteria. Literature facts concerning IP diagnosis were analyzed. Different organ anomalies, their frequency and severity, were analyzed in the context of applicability as IP diagnostic criteria. Taking into account analyzed data from the literature, the proposal of updated IP diagnostic criteria was presented. We propose as major criteria one of the stages of IP skin lesions. As updated IP minor criteria in our proposal we included: dental, ocular; central nervous system (CNS), hair, nail, palate, breast and nipple anomalies; multiple male miscarriages, and IP pathohistological findings. In the diagnosis of IP, the presence of IKBKG mutation typical for IP, and existence of family relatives with diagnosed IP are taken into account. PMID- 23802867 TI - Characterization of orgasmic difficulties by women: focus group evaluation. AB - INTRODUCTION: Female orgasmic disorder (FOD) is the second most prevalent sexual disorder in women. According to the most recent revision of the Diagnostic and Statistical Manual of Mental Disorders, Fourth edition (DSM-IV-TR), the term "marked distress" is central to the diagnosis of FOD. In practice, the term "distress" for use as a criterion for a clinical diagnosis is a medical construct and may not correlate with the language used by women with FOD to describe what they are experiencing. AIM: The objective of this study was to explore the terminology used by women to describe their feeling associated with difficulties in achieving orgasm. METHODS: Women experiencing difficulties in achieving orgasm were invited to participate in a focus group. The focus groups included a characterization, picture sort and language exploration exercise and completing the Female Sexual Distress Scale-Desire, Arousal, Orgasm (FSDS-DAO) to determine the impact and emotional associations of decreased/lack of orgasms. MAIN OUTCOME MEASURES: Patient reported terminology for characterization of their FOD, and validity of question 15 of FSDS-DAO. RESULTS: Sixty-seven percent (44/66) of the women used the word "frustrated" when asked, "What one word would you use to describe your orgasm difficulties?" In the language exploration exercise, the most common term used to describe emotions associated with decreased orgasm was "frustration." Responses (0 = never to 4 = always) to question 15 (frustrated by problems with orgasm) of the FSDS-DAO, ranged from 1 to 4 (mean 3.0) indicating that women were very frustrated. CONCLUSIONS: The term "frustrated" was the most relevant and common emotion women feel when they have difficulties in achieving orgasm. Additionally, the women consistently supported the content validity of question 15 of the FSDS-DAO. Despite the use of the term "distress" in the DSM-IV TR criteria for FOD, the term reflects the medical construct required to become a sexual dysfunction and does not appear to be an accurate representation of most women's feelings of orgasm difficulties. PMID- 23802868 TI - Host-guest chemistry from solution to the gas phase: an essential role of direct interaction with water for high-affinity binding of cucurbit[n]urils. AB - An investigation of the host-guest chemistry of cucurbit[n]uril (CB[n], n = 6 and 7) with alpha,omega-alkyldiammonium guests (H2N(CH2)xNH2, x = 4, 6, 8, 10, and 12) both in solution and in the gas phase elucidates their intrinsic host-guest properties and the contribution of solvent water. Isothermal titration calorimetry and nuclear magnetic resonance measurements indicate that all alkyldiammonium cations have inclusion interactions with CB[n] except for the CB[7]-tetramethylenediamine complex in aqueous solution. The electrospray ionization of mixtures of CB[n] and the alkyldiammonium guests reflects their solution phase binding constants. Low-energy collision-induced dissociations indicate that, after the transfer of the CB[n]-alkyldiammonium complex to the gas phase, its stability is no longer correlated with the binding properties in solution. Gas phase structures obtained from density functional theory calculations, which support the results from the ion mobility measurements, and molecular dynamics simulated structures in water provide a detailed understanding of the solvated complexes. In the gas phase, the binding properties of complexation mostly depend on the ion-dipole interactions. However, the ion dipole integrity is strongly affected by hydrogen bonding with water molecules in the aqueous condition. Upon the inclusion of water molecules, the intrinsic characteristics of the host-guest binding are dominated by entropic-driven thermodynamics. PMID- 23802869 TI - Loop-mediated amplification of the Clavibacter michiganensis subsp. michiganensis micA gene is highly specific. AB - Loop-mediated amplification (LAMP) was used to specifically identify Clavibacter michiganensis subsp. michiganensis, causal agent of bacterial canker of tomato. LAMP primers were developed to detect micA, a chromosomally stable gene that encodes a type II lantibiotic, michiganin A, which inhibits growth of other C. michiganensis subspecies. In all, 409 bacterial strains (351 C. michiganensis subsp. michiganensis and 58 non-C. michiganensis subsp. michiganensis) from a worldwide collection were tested with LAMP to determine its specificity. LAMP results were compared with genetic profiles established using polymerase chain reaction (PCR) amplification of seven genes (dnaA, ppaJ, pat-1, chpC, tomA, ppaA, and ppaC). C. michiganensis subsp. michiganensis strains produced eight distinct profiles. The LAMP reaction identified all C. michiganensis subsp. michiganensis strains and discriminated them from other C. michiganensis subspecies and non Clavibacter bacteria. LAMP has advantages over immunodiagnostic and other molecular detection methods because of its specificity and isothermal nature, which allows for easy field application. The LAMP reaction is also not affected by as many inhibitors as PCR. This diagnostic tool has potential to provide an easy, one-step test for rapid identification of C. michiganensis subsp. michiganensis. PMID- 23802870 TI - Genetic diversity and potential vectors and reservoirs of Cucurbit aphid-borne yellows virus in southeastern Spain. AB - The genetic variability of a Cucurbit aphid-borne yellows virus (CABYV) (genus Polerovirus, family Luteoviridae) population was evaluated by determining the nucleotide sequences of two genomic regions of CABYV isolates collected in open field melon and squash crops during three consecutive years in Murcia (southeastern Spain). A phylogenetic analysis showed the existence of two major clades. The sequences did not cluster according to host, year, or locality of collection, and nucleotide similarities among isolates were 97 to 100 and 94 to 97% within and between clades, respectively. The ratio of nonsynonymous to synonymous nucleotide substitutions reflected that all open reading frames have been under purifying selection. Estimates of the population's genetic diversity were of the same magnitude as those previously reported for other plant virus populations sampled at larger spatial and temporal scales, suggesting either the presence of CABYV in the surveyed area long before it was first described, multiple introductions, or a particularly rapid diversification. We also determined the full-length sequences of three isolates, identifying the occurrence and location of recombination events along the CABYV genome. Furthermore, our field surveys indicated that Aphis gossypii was the major vector species of CABYV and the most abundant aphid species colonizing melon fields in the Murcia (Spain) region. Our surveys also suggested the importance of the weed species Ecballium elaterium as an alternative host and potential virus reservoir. PMID- 23802871 TI - Engineered applications of ureolytic biomineralization: a review. AB - Microbially-induced calcium carbonate (CaCO3) precipitation (MICP) is a widely explored and promising technology for use in various engineering applications. In this review, CaCO3 precipitation induced via urea hydrolysis (ureolysis) is examined for improving construction materials, cementing porous media, hydraulic control, and remediating environmental concerns. The control of MICP is explored through the manipulation of three factors: (1) the ureolytic activity (of microorganisms), (2) the reaction and transport rates of substrates, and (3) the saturation conditions of carbonate minerals. Many combinations of these factors have been researched to spatially and temporally control precipitation. This review discusses how optimization of MICP is attempted for different engineering applications in an effort to highlight the key research and development questions necessary to move MICP technologies toward commercial scale applications. PMID- 23802872 TI - Mini-review: barnacle adhesives and adhesion. AB - Barnacles are intriguing, not only with respect to their importance as fouling organisms, but also in terms of the mechanism of underwater adhesion, which provides a platform for biomimetic and bioinspired research. These aspects have prompted questions regarding how adult barnacles attach to surfaces under water. The multidisciplinary and interdisciplinary nature of the studies makes an overview covering all aspects challenging. This mini-review, therefore, attempts to bring together aspects of the adhesion of adult barnacles by looking at the achievements of research focused on both fouling and adhesion. Biological and biochemical studies, which have been motivated mainly by understanding the nature of the adhesion, indicate that the molecular characteristics of barnacle adhesive are unique. However, it is apparent from recent advances in molecular techniques that much remains undiscovered regarding the complex event of underwater attachment. Barnacles attached to silicone-based elastomeric coatings have been studied widely, particularly with respect to fouling-release technology. The fact that barnacles fail to attach tenaciously to silicone coatings, combined with the fact that the mode of attachment to these substrata is different to that for most other materials, indicates that knowledge about the natural mechanism of barnacle attachment is still incomplete. Further research on barnacles will enable a more comprehensive understanding of both the process of attachment and the adhesives used. Results from such studies will have a strong impact on technology aimed at fouling prevention as well as adhesion science and engineering. PMID- 23802873 TI - Pain assessment in patellar tendinopathy using pain pressure threshold algometry: an observational study. AB - OBJECTIVE: Assessing pain in patellar tendinopathy (PT) is difficult to perform in a standardized way. With this study, we measured pain in athletes with PT by means of pain pressure threshold (PPT) algometry in a standardized manner. Subsequently, the goal of this study is to determine normative values for clinical use. DESIGN: Observational study. SETTING: Patients and healthy subjects were recruited from an outpatient clinic of a university medical center and at different sports clubs in northern Netherlands. SUBJECTS: A total of 234 athletes, 114 diagnosed with PT and 120 healthy controls, were included. OUTCOME MEASURES: PPT, Victorian Institute of Sport Assessment-Patellar tendinopathy questionnaire, and visual analog scale-pain. RESULTS: PPT scores of PT athletes with tendinopathy were significantly lower compared with healthy athletes (Mann Whitney U-test; U = 293.5; P < 0.001). With a receiver operating characteristic (ROC) curve, the optimal cut-off point to distinguish between healthy athletes and PT athletes was calculated at 36.8 N. The area under the ROC curve was 0.98 (95% CI: 0.96-1.0). There was a positive predictive value of 96.5% that athletes with a PPT below 36.8 N. had PT. CONCLUSIONS: PPT algometry should be considered by clinicians as a pain assessment tool in patients with PT. The optimal cut-off point for the PPT to distinguish between PT athletes and healthy athletes was 36.8 N. PMID- 23802874 TI - A comparison of inflammatory mediator expression between palmoplantar pustulosis and pompholyx. AB - BACKGROUND: Both palmoplantar pustulosis (PPP) and pompholyx are clinically characterized by acute eruptions of vesicles or pustules on the palms or soles. OBJECTIVES: This study aims to compare the expression of certain inflammatory mediator genes and proteins between patients with PPP and pompholyx using skin tissue samples. METHODS: Skin biopsies obtained from lesional skin from patients with PPP (n = 7) and pompholyx (n = 5) were analysed by quantitative RT-PCR to measure the mRNA levels of nine genes, including IL-4, IL-8, IL-9, IL-17, IL-22, IFN-gamma, CCL-20, granzyme and perforin. For immunohistochemical analysis, 34 paraffin-embedded skin specimens (PPP, n = 22; pompholyx, n = 12) were stained with anti-IL-8, IL-17A, IL-22 and granzyme B antibodies. RESULTS: Of genes analysed, IL-8 and IL-17A mRNA expression levels were significantly higher in the PPP group than the pompholyx group (P = 0.012 in both), whereas the mRNA expression of granzyme B was significantly higher in pompholyx when compared with PPP (P = 0.004). Regarding the IL-17A immunohistochemical staining, tissue from the PPP lesions contained significantly more IL-17A(+) cells in both the epidermis and papillary dermis when compared with pompholyx (P < 0.001 and P = 0.019 respectively). Moreover, the intensity of the IL-8 immunoreactivity was also greater in the PPP skin lesions than the pompholyx tissue (P < 0.001). CONCLUSIONS: IL-8 and IL-17A, both are increased in PPP tissue, may represent important immunologic mediators that help to differentiate this clinical entity from pompholyx. This study may provide useful clues in distinguishing PPP from pompholyx, as well as helping to understand the pathogeneses of these two diseases. PMID- 23802875 TI - Proteomic profiling for the identification of serum diagnostic biomarkers for abdominal and thoracic aortic aneurysms. AB - BACKGROUND: Aortic aneurysm is an increasingly common vascular disorder with fatal implication. However, there is no established diagnosis other than that based on aneurysmal size. For this purpose, serum protein biomarkers for aortic aneurysms are valuable. Although most of the studies on serum biomarker discovery have been based on comparison of serum proteins from the patient group with those from the healthy group, we considered that comparison of serial protein profiles such as those in presurgical and postsurgical sera within one patient would facilitate identification of biomarkers since the variability of serial protein profiles within one patient is smaller than that between groups. In this study, we examined serum proteins with differential levels in postsurgery compared with those in presurgery after the removal of aneurysmal tissues in abdominal aortic aneurysm (AAA) and thoracic aortic aneurysm (TAA) patients in order to identify potential serum biomarkers for AAAs and TAAs. RESULTS: A proteomic approach with an isobaric tag for relative and absolute quantitation (iTRAQ) labeling followed by nano liquid chromatography (nanoLC)-matrix-assisted laser desorption ionization (MALDI)-time of flight (TOF/TOF)-tandem mass spectrometry (MS/MS) was used. In the sera of patients with AAAs and TAAs, a total of 63 and 71 proteins with differential levels were further narrowed down to 6 and 8 increased proteins (?1.3 fold, postsurgical vs. presurgical) (p < 0.05, patient vs. control) and 12 and 17 decreased proteins (< 0.77 fold, postsurgical vs. presurgical) (p < 0.05, patient vs. control) in postsurgical sera compared with those in presurgical sera, respectively. All of the increased proteins in postsurgical sera of both AAA and TAA patients included several known acute-phase proteins. On the other hand, in the decreased proteins, we found intriguing molecules such as alpha-2 macroglobulin, gelsolin, kallistatin, and so on. Among them, we confirmed that kallistatin in both AAA and TAA patients and alpha-2-macroglobulin in TAA patients showed decrease levels in postsurgical sera similar to those in control sera by Western blot analysis with other sera from AAA and TAA patients. CONCLUSIONS: Taken together, our findings suggest that Kallistatin and alpha-2 macroglobulin are potential serum biomarkers for both AAA and TAA and TAA, respectively. PMID- 23802876 TI - Horizontal transfers of feminizing versus non-feminizing Wolbachia strains: from harmless passengers to pathogens. AB - The endosymbiont Wolbachia pipientis infects various hosts in which it navigates vertically from mothers to offspring. However, horizontal transfers of Wolbachia can occur between hosts. The virulence of the horizontally acquired Wolbachia can change in the new host as it has been illustrated by the case of the feminizing strain wVulC from the woodlouse Armadillidium vulgare that turns to a pathogen when introduced into Porcellio dilatatus dilatatus. In the present study, we aim to show whether symbiotic traits, such as (i) host sex manipulation and (ii) colonization patterns, which differ between eight isopod Wolbachia strains, are connected to their virulence towards the recipient host P. d. dilatatus. Among the transferred Wolbachia, some feminizing strains gradually differing in feminizing intensity in their native hosts induced different levels of pathogenicity to P. d. dilatatus. Not a single feminizing strain passed vertically with high titres to the next generation. The non-feminizing Wolbachia strains, even if they reached high densities in the host, did not impact host life-history traits and some vertically passed with high titres to the offspring. These results suggest that a potential link between the manners Wolbachia manipulates its native host reproduction, its virulence and its ability to vertically infect the offspring. PMID- 23802877 TI - A metal-free tandem demethylenation/C(sp2)-H cycloamination process of N-benzyl-2 aminopyridines via C-C and C-N bond cleavage. AB - A mild, metal-free synthesis of pyrido[1,2-a]benzimidazoles starting with N benzyl-2-aminopyridines, which employs PhI(OPiv)2 as a stoichiometric oxidant, has been developed. The process is initiated by an unusual PhI(OPiv)2-mediated ipso S(E)Ar reaction, followed by solvent-assisted C-C and C-N bond cleavage. PMID- 23802879 TI - The category-sensitive and orientation-sensitive N170 adaptation in faces revealed by comparison with Chinese characters. AB - By comparing faces with Chinese characters, the category-sensitive and orientation-sensitive N170 adaptation effects were examined when the stimuli were adapted by category (within vs. between) and orientation (same vs. different). The category-sensitive N170 adaptation was present for both faces and characters, supporting the assertion that the perception of faces and characters recruits domain-specific processing rather than general processing of visual expertise. In addition, the orientation-sensitive N170 adaptation was present only for faces but not for characters, suggesting that only faces recruit orientation-specific processing. More importantly, the orientation-sensitive N170 adaptation was not only present for inverted faces but also for upright faces, indicating that there are distinct neuron populations respectively sensitive to upright and inverted faces. PMID- 23802878 TI - Emergency department-based brief intervention to reduce risky driving and hazardous/harmful drinking in young adults: a randomized controlled trial. AB - BACKGROUND: Risky driving and hazardous drinking are associated with significant human and economic costs. Brief interventions for more than one risky behavior have the potential to reduce health-compromising behaviors in populations with multiple risk-taking behaviors such as young adults. Emergency department (ED) visits provide a window of opportunity for interventions meant to reduce both risky driving and hazardous drinking. METHODS: We determined the efficacy of a Screening, Brief Intervention, and Referral to Treatment (SBIRT) protocol addressing risky driving and hazardous drinking. We used a randomized controlled trial design with follow-ups through 12 months. ED patients aged 18 to 44 who screened positive for both behaviors (n = 476) were randomized to brief intervention (BIG), contact control (CCG), or no-contact control (NCG) groups. The BIG (n = 150) received a 20-minute assessment and two 20-minute interventions. The CCG (n = 162) received a 20-minute assessment at baseline and no intervention. The NCG (n = 164) were asked for contact information at baseline and had no assessment or intervention. Outcomes at 3, 6, 9, and 12 months were self-reported driving behaviors and alcohol consumption. RESULTS: Outcomes were significantly lower in BIG compared with CCG through 6 or 9 months, but not at 12 months: Safety belt use at 3 months (adjusted odds ratio [AOR], 0.22; 95% confidence interval [CI], 0.08 to 0.65); 6 months (AOR, 0.13; 95% CI, 0.04 to 0.42); and 9 months (AOR, 0.18; 95% CI, 0.06 to 0.56); binge drinking at 3 months (adjusted rate ratio [ARR] 0.84; 95% CI, 0.74 to 0.97) and 6 months (ARR, 0.81; 95% CI, 0.67 to 0.97); and >=5 standard drinks/d at 3 months (AOR, 0.43; 95% CI, 0.20 to 0.91) and 6 months (AOR, 0.41; 95% CI, 0.17 to 0.98). No substantial differences were observed between BIG and NCG at 12 months. CONCLUSIONS: Our findings indicate that SBIRT reduced risky driving and hazardous drinking in young adults, but its effects did not persist after 9 months. Future research should explore methods for extending the intervention effect. PMID- 23802880 TI - C-H activation by multiply bonded complexes with potentially noninnocent ligands: a computational study. AB - Second- and third-row (typically precious metals) transition metal complexes are known to possess certain electronic features that define their structure and reactivity and are usually not observed in their first-row (base metal) congeners. Can these electronic features be conferred onto first-row transition metals with the aid of noninnocent and/or very high-field ligands? In this research, the impact upon methane C-H bond activation was modeled using the dipyridylazaallyl (smif) supporting ligand for late, first-row transition metal (M) imide, oxo, and carbene complexes (M = Fe, Co, Ni, or Cu; E = O, NMe, or CMe2). Density functional theory calculations suggest that the combination of smif with iron and the oxo activating ligand is the most energetically favorable complex for methane C-H activation. A change in the preferred transition state for methane C-H activation from [2+2] addition to hydrogen atom abstraction was observed upon going from Fe to Cu and for Fe as compared to precious metals. Contrary to expectations, it was the imide ligand rather than the dipyridylazaallyl ligand that was found to possess redox "noninnocent" characteristics. PMID- 23802881 TI - Rhamnogalacturonan II structure shows variation in the side chains monosaccharide composition and methylation status within and across different plant species. AB - A paradigm regarding rhamnogalacturonans II (RGII) is their strictly conserved structure within a given plant. We developed and employed a fast structural characterization method based on chromatography and mass spectrometry, allowing analysis of RGII side chains from microgram amounts of cell wall. We found that RGII structures are much more diverse than so far described. In chain A of wild type plants, up to 45% of the l-fucose is substituted by l-galactose, a state that is seemingly uncorrelated with RGII dimerization capacity. This led us to completely reinvestigate RGII structures of the Arabidopsis thaliana fucose deficient mutant mur1, which provided insights into RGII chain A biosynthesis, and suggested that chain A truncation, rather than l-fucose to l-galactose substitution, is responsible for the mur1 dwarf phenotype. Mass spectrometry data for chain A coupled with NMR analysis revealed a high degree of methyl esterification of its glucuronic acid, providing a plausible explanation for the puzzling RGII antibody recognition. The beta-galacturonic acid of chain A exhibits up to two methyl etherifications in an organ-specific manner. Combined with variation in the length of side chain B, this gives rise to a family of RGII structures instead of the unique structure described up to now. These findings pave the way for studies on the physiological roles of modulation of RGII composition. PMID- 23802882 TI - Complementary alternative medicine use among patients with type 2 diabetes mellitus in the primary care setting: a cross-sectional study in Malaysia. AB - BACKGROUND: Limited study on the use of complementary alternative medicine (CAM) among patients with diabetes mellitus (DM), particularly in primary -care settings. This study seeks to understand the prevalence, types, expenditures, attitudes, beliefs, and perceptions of CAM use among patients with DM visiting outpatient primary care clinics. METHODS: This is a descriptive, cross-sectional study of 240 diabetic patients. CAM is defined as a group of diverse medical and healthcare systems, practices, and products that are not generally considered part of conventional Western medicine. Data analysis was done using SPSS v. 19 and multiple logistic regressions were used to identify predictors of CAM use. RESULTS: The prevalence of CAM use was 62.5 percent. Female were 1.8 times more likely than male in using CAM. Malays (75%) were the most frequent users, followed Indians (18%) and Chinese (6%). Biological therapy (50.0%) were the most widely used, followed by manipulative-body based systems (9.2%), energy system (8.8%), alternative medicine systems (4.6%) and mind-body system (1.7%). In biological therapy, a total of 30.4 percent, 24.2 percent, 13.3 percent, and 7.9 percent of diabetic patients consumed bitter gourd (Momordica Charantia), followed by Misai Kucing (Orthosiphon Stamineus Benth), garlic (Allium Sativum), and Sabah snake grass (Clinacanthus Nutans Lindau) respectively. The mean of the expenditure on CAM usage was RM 52.8 +/- 101.9 (US $16.9 +/- 32.5) per month. According to multiple logistic regression analyses, being Muslim (OR 5.258, 95 percent CI 2.952-9.368) had significant positive association with CAM use. CONCLUSIONS: The prevalence of CAM use was high among diabetics. Islam faith is predictor for CAM use among Type 2 DM patients. The most-common herbs used were bitter gourd (Momordica Charantia) and Misai Kucing (Orthosiphon Stamineus, Benth). Further studies on the anti-glycemic activity of the isolated compound may be needed in the future. PMID- 23802884 TI - AtFH16, [corrected] an Arabidopsis type II formin, binds and bundles both microfilaments and microtubules, and preferentially binds to microtubules. AB - Formins are well-known regulators that participate in the organization of the actin cytoskeleton in organisms. The Arabidopsis thaliana L. genome encodes 21 formins, which can be divided into two distinct subfamilies. However, type II formins have to date been less well characterized. Here, we cloned a type II formin, AtFH16, and characterized its biochemical activities on actin and microtubule dynamics. The results show that the FH1FH2 structure of AtFH16 cannot nucleate actin polymerization efficiently, but can bind and bundle microfilaments. AtFH16 FH1FH2 is also able to bind and bundle microtubules, and preferentially binds microtubules over microfilaments in vitro. In addition, AtFH16 FH1FH2 co-localizes with microtubules in onion epidermal cells, indicating a higher binding affinity of AtFH16 FH1FH2 for microtubules rather than microfilaments in vivo. In conclusion, AtFH16 is able to interact with both microfilaments and microtubules, suggesting that AtFH16 probably functions as a bifunctional protein, and may thus participate in plant cellular processes. PMID- 23802883 TI - Functional consequences of radiation-induced oxidative stress in cultured neural stem cells and the brain exposed to charged particle irradiation. AB - AIMS: Redox homeostasis is critical in regulating the fate and function of multipotent cells in the central nervous system (CNS). Here, we investigated whether low dose charged particle irradiation could elicit oxidative stress in neural stem and precursor cells and whether radiation-induced changes in redox metabolism would coincide with cognitive impairment. RESULTS: Low doses (<1 Gy) of charged particles caused an acute and persistent oxidative stress. Early after (<1 week) irradiation, increased levels of reactive oxygen and nitrogen species were generally dose responsive, but were less dependent on dose weeks to months thereafter. Exposure to ion fluences resulting in less than one ion traversal per cell was sufficient to elicit radiation-induced oxidative stress. Whole body irradiation triggered a compensatory response in the rodent brain that led to a significant increase in antioxidant capacity 2 weeks following exposure, before returning to background levels at week 4. Low dose irradiation was also found to significantly impair novel object recognition in mice 2 and 12 weeks following irradiation. INNOVATION: Data provide evidence that acute exposure of neural stem cells and the CNS to very low doses and fluences of charged particles can elicit a persisting oxidative stress lasting weeks to months that is associated with impaired cognition. CONCLUSIONS: Exposure to low doses of charged particles causes a persistent oxidative stress and cognitive impairment over protracted times. Data suggest that astronauts subjected to space radiation may develop a heightened risk for mission critical performance decrements in space, along with a risk of developing long-term neurocognitive sequelae. PMID- 23802885 TI - Evaluation of cardiovascular disease burden and therapeutic goal attainment in US adults with chronic kidney disease: an analysis of national health and nutritional examination survey data, 2001-2010. AB - BACKGROUND: For chronic kidney disease (CKD) patients, national treatment guidelines recommend a low-density lipoprotein cholesterol (LDL-C) goal <100 mg/dL and blood pressure (BP) target <130/80 mmHg. This analysis assessed the current status of cardiovascular (CV) risk factor treatment and control in US adults with CKD. METHODS: Weighted prevalence estimates of CV-related comorbidities, utilization of lipid- and BP-lowering agents, and LDL-C and BP goal attainment in US adults with CKD were assessed among 9,915 men and nonpregnant women aged >=20 years identified from the fasting subsample of the 2001-2010 National Health and Nutritional Examination Survey (NHANES). Analyses were performed using SAS survey procedures that consider the complex, multistage, probability sampling design of NHANES. All estimates were standardized to the 2008 US adult population (>=20 years). Data were stratified by CKD stage based on presence of albuminuria and estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Stage 3 CKD was subdivided into 3a (eGFR 45-59 mL/min/1.73 m(2)) and 3b (eGFR 30-44 mL/min/1.73 m(2)); Stage 5 CKD and dialysis recipients were excluded. RESULTS: Of the 9,915 NHANES participants identified for analysis, 1,428 had CKD (Stage 1-4), corresponding to a prevalence estimate for US adults aged >=20 years of 10.2%. Prevalence of CV-related comorbidities increased markedly with CKD stage, with a ~6-12-fold increase in cardiovascular disease, coronary heart disease (CHD), stroke and congestive heart failure between CKD Stage 1 and 4; prevalence of diabetes, hyperlipidemia and hypertension increased by ~1.2-1.6 fold. Use of lipid-lowering agents increased with CKD stage, from 18.1% (Stage 1) to 44.8% (Stage 4). LDL-C goal attainment increased from 35.8% (Stage 1) to 52.8% (Stage 3b), but decreased in Stage 4 (50.7%). BP goal attainment decreased between Stage 1 and 4 (from 49.5% to 30.2%), despite increased use of antihypertensives (from 30.2% to 78.9%). CONCLUSIONS: Individuals with CKD have a high prevalence of CV-related comorbidities. However, attainment of LDL-C or BP goals was low regardless of disease stage. These findings highlight the potential for intensive risk factor modification to maximize CV event reduction in CKD patients at high risk for CHD. PMID- 23802887 TI - Integrative relational machine-learning for understanding drug side-effect profiles. AB - BACKGROUND: Drug side effects represent a common reason for stopping drug development during clinical trials. Improving our ability to understand drug side effects is necessary to reduce attrition rates during drug development as well as the risk of discovering novel side effects in available drugs. Today, most investigations deal with isolated side effects and overlook possible redundancy and their frequent co-occurrence. RESULTS: In this work, drug annotations are collected from SIDER and DrugBank databases. Terms describing individual side effects reported in SIDER are clustered with a semantic similarity measure into term clusters (TCs). Maximal frequent itemsets are extracted from the resulting drug x TC binary table, leading to the identification of what we call side-effect profiles (SEPs). A SEP is defined as the longest combination of TCs which are shared by a significant number of drugs. Frequent SEPs are explored on the basis of integrated drug and target descriptors using two machine learning methods: decision-trees and inductive-logic programming. Although both methods yield explicit models, inductive-logic programming method performs relational learning and is able to exploit not only drug properties but also background knowledge. Learning efficiency is evaluated by cross-validation and direct testing with new molecules. Comparison of the two machine-learning methods shows that the inductive-logic-programming method displays a greater sensitivity than decision trees and successfully exploit background knowledge such as functional annotations and pathways of drug targets, thereby producing rich and expressive rules. All models and theories are available on a dedicated web site. CONCLUSIONS: Side effect profiles covering significant number of drugs have been extracted from a drug *side-effect association table. Integration of background knowledge concerning both chemical and biological spaces has been combined with a relational learning method for discovering rules which explicitly characterize drug-SEP associations. These rules are successfully used for predicting SEPs associated with new drugs. PMID- 23802886 TI - Ceramide inhibitor myriocin restores insulin/insulin growth factor signaling for liver remodeling in experimental alcohol-related steatohepatitis. AB - BACKGROUND AND AIM: Alcohol-related liver disease (ALD) is mediated in part by insulin resistance. Attendant dysregulation of lipid metabolism increases accumulation of hepatic ceramides that worsen insulin resistance and compromise the structural and functional integrity of the liver. Insulin and insulin growth factor (IGF) stimulate aspartyl-asparaginyl-beta-hydroxylase (AAH), which promotes cell motility needed for structural maintenance and remodeling of the liver. AAH mediates its effects by activating Notch, and in ALD, insulin/IGF signaling, AAH, and Notch are inhibited. METHOD: To test the hypothesis that in ALD, hepatic ceramide load contributes to impairments in insulin, AAH, and Notch signaling, control and chronic ethanol-fed adult Long-Evans rats were treated with myriocin, an inhibitor of serine palmitoyl transferase. Livers were used to assess steatohepatitis, insulin/IGF pathway activation, and expression of AAH Notch signaling molecules. RESULTS: Chronic ethanol-fed rats had steatohepatitis with increased ceramide levels; impairments in signaling through the insulin receptor, insulin receptor substrate, and Akt; and decreased expression of AAH, Notch, Jagged, Hairy-Enhancer of Split-1, hypoxia-inducible factor 1alpha, and proliferating cell nuclear antigen. Myriocin abrogated many of these adverse effects of ethanol, particularly hepatic ceramide accumulation, steatohepatitis, and impairments of insulin signaling through Akt, AAH, and Notch. CONCLUSIONS: In ALD, the histopathology and impairments in insulin/IGF responsiveness can be substantially resolved by ceramide inhibitor treatments, even in the context of continued chronic ethanol exposure. PMID- 23802888 TI - Interferon-based therapy reduces risk of stroke in chronic hepatitis C patients: a population-based cohort study in Taiwan. AB - BACKGROUND: Hepatitis C virus (HCV) infection has been linked to an increased risk of insulin resistance and carotid atherosclerosis. AIM: To investigate the association between HCV infection and stroke, and the effect of interferon-based therapy (IBT) on stroke risk in chronic hepatitis C (CHC) patients. METHODS: We conducted a retrospective cohort study that followed up 3113 subjects with a newly detected HCV infection and 12 452 age- and gender-matched subjects without HCV infection selected from a random sample of 10(6) beneficiaries from the Taiwan National Health Insurance Program up to 5 years. Use of IBT was defined as treatment with interferon alpha, pegylated interferon alpha-2a or pegylated interferon alpha-2b for at least 3 months. The hazard ratio (HR) for newly detected stroke was calculated for subjects with HCV compared to those without HCV, and for IBT-treated HCV patients compared to non-IBT-treated HCV patients while adjusting for possible confounding factors. RESULTS: The overall person years of follow-up were 8624.11 in patients with HCV, 54,533.69 in patients without HCV, 666.65 in IBT-treated patients, and 7886.49 in nontreated patients. The multivariable-adjusted hazard ratio (HR) for newly detected stroke was 1.23 for subjects with HCV compared to the age- and sex-matched subjects without HCV (adjusted HR = 1.23, 95% CI = 1.06-1.42, P = 0.008). Moreover, use of IBT significantly reduced the risk of stroke in HCV patients (adjusted HR = 0.39, 95% CI = 0.16-0.95, P = 0.039) after adjusting for known prognostic factors. CONCLUSIONS: Interferon-based therapy may reduce the long-term risk of stroke in patients with chronic HCV infection. PMID- 23802890 TI - Mechanically induced gel formation. AB - Mechanical triggering of gelation of an organic solution by a carbazole-based bisurea organogelator is described. Both the duration of the mechanical stimulation and the gelator concentration control the gelation process and the characteristics of the gel obtained. PMID- 23802891 TI - Introduction: revising the common rule: prospects and challenges. PMID- 23802889 TI - Heteroaromatic and aniline derivatives of piperidines as potent ligands for vesicular acetylcholine transporter. AB - To identify suitable lipophilic compounds having high potency and selectivity for vesicular acetylcholine transporter (VAChT), a heteroaromatic ring or a phenyl group was introduced into the carbonyl-containing scaffold for VAChT ligands. Twenty new compounds with ALogD values between 0.53 and 3.2 were synthesized, and their in vitro binding affinities were assayed. Six of them (19a, 19e, 19g, 19k, and 24a-b) displayed high affinity for VAChT (Ki = 0.93-18 nM for racemates) and moderate to high selectivity for VAChT over sigma1 and sigma2 receptors (Ki = 44 4400-fold). These compounds have a methyl or a fluoro substitution that provides the position for incorporating PET radioisotopes C-11 or F-18. Compound (-) [(11)C]24b (Ki = 0.78 nM for VAChT, 1200-fold over sigma receptors) was successfully synthesized and evaluated in vivo in rats and nonhuman primates. The data revealed that (-)-[(11)C]24b has highest binding in striatum and has favorable pharmacokinetics in the brain. PMID- 23802892 TI - What the ANPRM missed: additional needs for IRB reform. AB - Institutional Review Boards are mandated to carry out the requirements of the Common Rule, and it is widely agreed that they are appropriate and necessary mechanisms to ensure the ethical conduct of human research. In this paper, we suggest that the changes proposed in ANPRM, although generally helpful, fail to take into consideration how IRBs actually review applications and therefore do not adequately address some of the problems that may be leading to ineffective human subject protection. PMID- 23802893 TI - Outsourcing ethical obligations: should the revised common rule address the responsibilities of investigators and sponsors? AB - The Common Rule creates a division of moral labor in research. It implies that investigators and sponsors can outsource their ethical obligations to IRBs and participants, thereby fostering a culture of compliance, rather than one of responsibility. The proposed revisions to the Common Rule are likely to exacerbate this problem. To harness the expressive power of the law, I propose the Common Rule be revised to include the ethical responsibilities of investigators and sponsors. PMID- 23802894 TI - Moral gridlock: conceptual barriers to no-fault compensation for injured research subjects. AB - The federal regulations that govern biomedical research, most notably those enshrined in the Common Rule, express a protectionist ethos aimed at safeguarding subjects of human experimentation from the potential harms of research participation. In at least one critical way, however, the regulations have always fallen short of this promise: if a subject suffers a research-related injury, then neither the investigator nor the sponsor has any legal obligation under the regulations to care for or compensate the subject. Because very few subjects with research-related injuries can meet the financial or evidentiary requirements associated with a successful legal claim to recover the costs associated with their injuries, most injured subjects must shoulder the burden of those expenses alone. For 40 years, national advisory panels have concluded that this result is out of step with the Common Rule's otherwise protectionist promise. When the Department of Health and Human Services released an Advance Notice of Proposed Rulemaking (ANPRM) in 2011, suggesting potential changes to the Common Rule, the time seemed ripe to address research-related injuries. The ANPRM, however, makes no mention of compensation for research-related injuries, and the federal government once again seems poised to stop short of addressing what has arguably become the most longstanding, frequent, and consistent plea for regulatory reform of research: protections for injured subjects. This article asks why, despite decades of federal-level panels recommending no-fault compensation for research related injuries, the United States has so strongly resisted change. I suggest that a central reason for our current impasse is that, despite consensus among federal advisory committees that there is an obligation to compensate injured subjects, the committees have not coalesced around a moral justification for that duty. Although multiple justifications can support and even strengthen a single ethical obligation, the reverse has occurred in this context. I demonstrate that the committees' articulation of multiple ethical principles - including humanitarianism, professional beneficence, and compensatory justice - results in incongruent obligations that favor different kinds of compensation systems. This outcome, which I call "moral gridlock," makes it extremely difficult to determine what kind of compensation scheme to implement. Recognizing that each moral argument for compensation creates a slightly different trajectory is, however, an important first step in moving toward a more systematic approach to compensating injured research subjects. PMID- 23802895 TI - Take another little piece of my heart: regulating the research use of human biospecimens. AB - This article reviews the history of the debate over use of biospecimens in research, the legal and ethical arguments that have been presented both in support of and in opposition to such use, court cases and judicial opinions involving disputes between specimen contributors, researchers, and institutions, and public attitudes regarding the use of biospecimens in research. The paper argues that proposed changes to the Common Rule are inadequate to resolve the legal and ethical concerns that have been raised with respect to the use of biospecimens. It argues that there is a need to distinguish between the dual roles - subject and donor - played by contributors of biospecimens. PMID- 23802896 TI - Biobanking, consent, and certificates of confidentiality: does the ANPRM muddy the water? AB - In its Advanced Notice of Proposed Rule Making (ANPRM), the U.S. Department of Health and Human Services proposed substantial changes to how biospecimen research is treated under the regulations governing human subjects research. Currently, much of this research can be conducted without consent because it may not be considered "human subjects" research, is considered exempt, or consent may be waived. Responding to criticisms that scientific changes have made biospecimen research riskier than contemplated when the Common Rule was last amended, the ANPRM proposes to require written consent for biospecimen research, even if they have been stripped of identifiers or initially collected for a non-research purpose. The ANPRM's recognition of these risks is consistent with relatively recent NIH recommendations that research projects involving genetics, genomics, or biospecimen repositories should consider getting a Certificate of Confidentiality to provide additional protections to participants where breach of confidentiality is typically the primary risk. Ironically, the ANPRM proposals may make it more difficult to provide these protections. Our paper explores the implications of the conflicting requirements of the Certificate and the ANPRM proposals and makes recommendations for achieving the dual goals of appropriate consent and adequate confidentiality protections. PMID- 23802897 TI - Are changes to the common rule necessary to address evolving areas of research? A case study focusing on the human microbiome project. AB - This article examines ways in which research conducted under the Human Microbiome Project, an effort to establish a "reference catalogue" of the micro-organisms present in the human body and determine how changes in those micro-organisms affect health and disease, raise challenging issues for regulation of human subject research. The article focuses on issues related to subject selection and recruitment, group stigma, and informational risks, and explores whether: (1) the Common Rule or proposed changes to the Rule adequately address these issues and (2) the Common Rule is the most appropriate vehicle to provide regulatory oversight and guidance on these topics. PMID- 23802898 TI - The apomediated world: regulating research when social media has changed research. AB - Social Media, like Facebook and Twitter, are having a profound effect on the way that human subjects research is being conducted. In light of the changes proposed in ANPRM, in this article I argue that traditional research ethics and regulations may not easily translate to the use of social media in human subjects research. Using the conceptual model of apomediation, which describes the peer-to peer way in which health information is shared via social media, I suggest that we may need to think again about the suitability of current regulations to deal with social media research. PMID- 23802899 TI - Advance directives, dementia, and physician-assisted death. AB - Physician-assisted suicide laws in Oregon and Washington require the person's current competency and a prognosis of terminal illness. In The Netherlands voluntariness and unbearable suffering are required for euthanasia. Many people are more concerned about the loss of autonomy and independence in years of severe dementia than about pain and suffering in their last months. To address this concern, people could write advance directives for physician-assisted death in dementia. Should such directives be implemented even though, at the time, the person is no longer competent and would not be either terminally ill or suffering unbearably? We argue that in many cases they should be, and that a sliding scale which considers both autonomy and the capacity for enjoyment provides the best justification for determining when: when written by a previously well-informed and competent person, such a directive gains in authority as the later person's capacities to generate new critical interests and to enjoy life decrease. Such an extension of legalized death assistance is grounded in the same central value of voluntariness that undergirds the current more limited legalization. PMID- 23802900 TI - Caring for elder parents: a comparative evaluation of family leave laws. AB - As the baby boomer generation ages, the need for laws to enhance quality of life for the elderly and meet the increasing demand for family caregivers will continue to grow. This paper reviews the national family leave laws of nine major OECD countries (Canada, Denmark, France, Germany, Italy, Japan, Netherlands, Spain, and the United Kingdom) and provides a state-by-state analysis within the U.S. We find that the U.S. has the least generous family leave laws among the nine OECD countries. With the exception of two states (California and New Jersey), the U.S. federal Family Medical Leave Act of 1993 provides no right to paid family leave for eldercare. We survey the current evidence from the literature on how paid leave can impact family caregivers' employment and health outcomes, gender equality, and economic arguments for and against such laws. We argue that a generous and flexible family leave law, financed through social insurance, would not only be equitable, but also financially sustainable. PMID- 23802901 TI - Social security survivors benefits: the effects of reproductive pathways and intestacy law on attitudes. AB - Most minor children are eligible for Social Security survivors benefits if a wage earning parent dies, but eligibility of children not in utero at the time of death is more nuanced. The purpose of this study was to examine attitudes concerning access to Social Security survivors benefits in the context of posthumous reproduction. A probability sample of 540 Florida households responded to a multiple-segment factorial vignette designed to examine the effects of state intestacy laws and five reproductive pathways - normative, posthumous birth, cryopreserved embryo, cryopreserved gametes, and posthumous gamete retrieval - on attitudes toward eligibility for the Social Security survivors benefits. Broad support was found for the survivors benefits following normative and posthumous birth pathways, but attitudes were decidedly less favorable when the child was not in utero at the time of parental death. In addition, in stark contrast to the recent U.S. Supreme Court decision in Astrue v. Capato, the vast majority of respondents did not believe state intestacy laws should determine eligibility for Social Security survivors benefits. PMID- 23802902 TI - HIPAA Privacy Rule 2.0. PMID- 23802903 TI - Legal responses to communal rejection in emergencies. PMID- 23802904 TI - Standard formaldehyde source for chamber testing of material emissions: model development, experimental evaluation, and impacts of environmental factors. AB - Formaldehyde, which is recognized as a harmful indoor air pollutant for human health, is emitted mainly from urea-formaldehyde resin in wood products. Chamber tests are used to evaluate formaldehyde emission rates from these products. However, there is no available formaldehyde standard reference emission source to assess the performance of chamber testing systems. In this work, a LIFE (liquid inner tube diffusion-film-emission) formaldehyde reference is described. The formaldehyde source consists of a polytetrafluoroethene (PTFE) tube that holds a formaldehyde-water solution with a concentration of 16 g formaldehyde per 100 mL water, with a thin polydimethylsiloxane (PDMS) film cover. Formaldehyde emission parameters for the PDMS film (diffusion coefficient and partition coefficient) were determined experimentally, thereby enabling the prediction of the formaldehyde emissions from the source for use as a reference value in a chamber. Chamber tests were conducted in a 51 L stainless steel ventilated chamber. The impacts of temperature and relative humidity on the emissions were investigated. Results show the LIFE's chamber test results match those predicted by a mass transfer model. As a result, this formaldehyde source may be used to generate a reference concentration in product emission testing chambers, thereby providing a powerful tool to evaluate the performance of the chamber testing systems. PMID- 23802905 TI - Trimethylamine-N-oxide's effect on polypeptide solvation at high pressure: a molecular dynamics simulation study. AB - The solvation characteristics of a 15-residue polypeptide and also the structure of the solution in the presence and absence of trimethylamine-N-oxide (TMAO), one of the strongest known protein stabilizers among the natural osmolytes both at low and high pressures, are investigated under high pressure conditions by employing the molecular dynamics simulation technique. The goal is to provide a molecular level understanding of how TMAO protects proteins at elevated pressures. Two different conformations of the polypeptide are used: helix and extended. Analysis of peptide hydration characteristics reveals that the pressure induced enhancement of hydration number is higher for the extended state as compared to the helix. TMAO shows an opposite effect and causes more dehydration of the extended state. The total number of atomic sites that solvate peptide residues increases in the presence of TMAO, whereas the number of hydrogen bonds formed by peptide with solution species reduces due to the inability of TMAO to donate its hydrogen to peptide hydrogen bonding sites. In solution, both hydrophobic and hydrogen bonding sites of TMAO are found to be well solvated by water molecules and solvation of TMAO enhances water structure and reduces the number of nearest identical neighbors for water. Pressure and TMAO are seen to have counteracting effects on water structural properties. Implications of these results for counteracting mechanism of TMAO are discussed. PMID- 23802906 TI - Augmented limb blood flow during neurovascular stress in physically fit women. AB - The study examined whether cardiorespiratory fitness modifies cardiovascular responses by normotensive men and women during the Stroop color-word interference test. Independent of age and an estimate of body fatness, fitness level was positively related (R2 = .39 and .51) to increases in limb blood flow and vascular conductance, coherent with cardiac-vagal withdrawal and a decrease in heart period, among women but not men. Fitness was unrelated to changes in systolic and diastolic blood pressures and muscle sympathetic nerve activity. The augmented hemodynamic responses among fitter women were not consistent with passive vasodilation via withdrawal of sympathetic neural tone. The results encourage further gender comparisons testing whether fitness augments limb blood flow during mental stress by neurohumoral and flow-mediated vasodilatory mechanisms or by increased cardiac output. PMID- 23802907 TI - Accuracy of 30-day recall for components of sexual function and the moderating effects of gender and mood. AB - INTRODUCTION: Despite the ubiquity of 1-month recall periods for measures of sexual function, there is limited evidence for how well recalled responses correspond to individuals' actual daily experiences. AIM: To characterize the correspondence between daily sexual experiences and 1-month recall of those experiences. METHODS: Following a baseline assessment of sexual functioning, health, and demographic characteristics, 202 adults from the general population (101 women, 101 men) were recruited to complete daily assessments of their sexual function online for 30 days and a single recall measure of sexual function at day 30. MAIN OUTCOME MEASURES: At the baseline and 30-day follow-ups, participants answered items asking about sexual satisfaction, sexual activities, interest, interfering factors, orgasm, sexual functioning, and use of therapeutic aids during the previous 30 days. Participants also completed a measure of positive and negative affect at follow-up. The main outcome measures were agreement between the daily and 1-month recall versions of the sexual function items. RESULTS: Accuracy of recall varied depending on the item and on the gender and mood of the respondent. Recall was better (low bias and higher correlations) for sexual activities, vaginal discomfort, erectile function, and more frequently used therapeutic aids. Recall was poorer for interest, affectionate behaviors (e.g., kissing), and orgasm-related items. Men more than women overestimated frequency of interest and masturbation. Concurrent mood was related to over- or underreporting for six items addressing the frequency of masturbation and vaginal intercourse, erectile function, and orgasm. CONCLUSIONS: A 1-month recall period seems acceptable for many aspects of sexual function in this population, but recall for some items was poor. Researchers should be aware that concurrent mood can have a powerful biasing effect on reports of sexual function. PMID- 23802908 TI - Primary alkylboronic acids as highly active catalysts for the dehydrative amide condensation of alpha-hydroxycarboxylic acids. AB - Primary alkylboronic acids such as methylboronic acid and butylboronic acid are highly active catalysts for the dehydrative amide condensation of alpha hydroxycarboxylic acids. The catalytic activities of these primary alkylboronic acids are much higher than those of the previously reported arylboronic acids. The present method was easily applied to a large-scale synthesis, and 14 g of an amide was obtained in a single reaction. PMID- 23802909 TI - Alpha-lipoic acid reduces ethanol self-administration in rats. AB - BACKGROUND: The main system of central ethanol (EtOH) oxidation is mediated by the enzyme catalase. By reacting with H2 O2 , brain catalase forms compound I (the catalase-H2 O2 system), which is able to oxidize EtOH to acetaldehyde (ACD) in the brain. We have previously shown that ACD regulates EtOH motivational properties and possesses reinforcing effects by itself. In this study, we investigate the effects of alpha-lipoic acid (ALA), a scavenging agent for H2 O2 , on oral EtOH self-administration. METHODS: To this end, we trained Wistar rats to orally self-administer EtOH (10%) by nose poking. The effect of intraperitoneal pretreatment with ALA was evaluated during (i) maintenance of EtOH self-administration, (ii) EtOH self-administration under a progressive ratio (PR) schedule of reinforcement, and (iii) oral EtOH priming to induce reinstatement of EtOH seeking behavior. Moreover, we tested the effect of ALA on saccharin (0.05%) reinforcement, as assessed by oral self-administration. RESULTS: The results indicate that ALA dose-dependently reduced the maintenance, the break point of EtOH self-administration under a PR and the reinstatement of EtOH seeking behavior without suppressing saccharin self-administration. CONCLUSIONS: These results support that ALA may have a potential use in alcoholism treatment. PMID- 23802910 TI - Beer and beer compounds: physiological effects on skin health. AB - Beer is one of the earliest human inventions and globally the most consumed alcoholic beverage in terms of volume. In addition to water, the 'German Beer Purity Law', based on the Bavarian Beer Purity Law from 1516, allows only barley, hops, yeasts and water for beer brewing. The extracts of these ingredients, especially the hops, contain an abundance of polyphenols such as kaempferol, quercetin, tyrosol, ferulic acid, xanthohumol/isoxanthohumol/8-prenylnaringenin, alpha-bitter acids like humulone and beta-bitter acids like lupulone. 8 prenylnaringenin is the most potent phytoestrogen known to date. These compounds have been shown to possess various anti-bacterial, anti-inflammatory, anti oxidative, anti-angiogenic, anti-melanogenic, anti-osteoporotic and anti carcinogenic effects. Epidemiological studies on the association between beer drinking and skin disease are limited while direct evidence of beer compounds in clinical application is lacking. Potential uses of these substances in dermatology may include treatment of atopic eczema, contact dermatitis, pigmentary disorders, skin infections, skin ageing, skin cancers and photoprotections, which require an optimization of the biostability and topical delivery of these compounds. Further studies are needed to determine the bioavailability of these compounds and their possible beneficial health effects when taken by moderate beer consumption. PMID- 23802911 TI - The role of FaBG3 in fruit ripening and B. cinerea fungal infection of strawberry. AB - In plants, beta-glucosidases (BG) have been implicated in developmental and pathogen defense, and are thought to take part in abscisic acid (ABA) synthesis via hydrolysis of ABA glucose ester to release active ABA; however, there is no genetic evidence for the role of BG genes in ripening and biotic/abiotic stress in fruits. To clarify the role of BG genes in fruit, eight Fa/FvBG genes encoding beta-glucosidase were isolated using information from the GenBank strawberry nucleotide database. Of the Fa/FvBG genes examined, expression of FaBG3 was the highest, showing peaks at the mature stage, coincident with the changes observed in ABA content. To verify the role of this gene, we suppressed the expression of FaBG3 via inoculation with Agrobacterium tumefaciens containing tobacco rattle virus carrying a FaBG3 fragment (RNAi). The expression of FaBG3 in FaBG3-RNAi treated fruit was markedly reduced, and the ABA content was lower than that of the control. FaBG3-RNAi-treated fruit did not exhibit full ripening, and were firmer, had lower sugar content, and were pale compared with the control due to down-regulation of ripening-related genes. FaBG3-RNAi-treated fruit with reduced ABA levels were much more resistant to Botrytis cinerea fungus but were more sensitive to dehydration stress than control fruit. These results indicate that FaBG3 may play key roles in fruit ripening, dehydration stress and B. cinerea fungal infection in strawberries via modulation of ABA homeostasis and transcriptional regulation of ripening-related genes. PMID- 23802912 TI - Toward a food service quality management system for compliance with the Mediterranean dietary model. AB - The traditional diet of Cretan people in the 1960s is the basis of the Mediterranean dietary model. This article investigates the potential of this model to inspire proposals of meals by food-serving businesses, and suggests a methodology for the development of a quality management system, which will certify the delivery of food service according to this dietary model. The proposed methodology is built upon the principles and structure of the ISO 9001:2008 quality standard to enable integration with other quality, environmental, and food safety management systems. PMID- 23802913 TI - Evaluating household food insecurity: applications and insights from rural Malaysia. AB - Hunger is complex, encompassing experiences ranging from a family's forced acceptance of a monotonous diet to individual physiological pain. I evaluate the Household Food Insecurity Access Scale (HFIAS) as a means of capturing the universal elements of hunger without doing violence to its culturally-specific expressions within two Malay communities. The HFIAS is assessed conceptually by comparing its assumptions and concept-to-measurement gap with competing indicators and practically with respect to village conditions and practices. This case study recommends the HFIAS for this site and for communities that similarly lack maternal buffering, while highlighting the unique features of the local hunger experience. PMID- 23802914 TI - Knowledge and use of wild food plants in areas of dry seasonal forests in Brazil. AB - The investigation aimed to compare the knowledge about food plants in rural communities of the Caatinga. The study was conducted in two rural communities in northeastern Brazil. Data collection utilized different ethnobotanical methods, including free listing, semi-structured interviews, and recall. Native species are less frequently consumed as food in both locations. Fruits are the most frequently cited wild resource, but in practice, most of this food availability potential is wasted. Despite community knowledge about wild species with potential food, few species are actually utilized, and thus, many plants are not included in the diets of the populations studied. PMID- 23802915 TI - Child feeding practices in families of working and nonworking mothers of Indonesian middle class urban families: what are the problems? AB - This study aims to explore the feeding practices in families of working and nonworking mothers with children (aged 12-36 months) of different nutritional status and types of domestic caregiver in Indonesian urban middle class families. It was designed as a qualitative multiple case study. Mothers and caregivers from 26 families were interviewed in depth, and caregivers were categorized as family and domestic-paid caregivers. The result suggested that offering formula milk to young children was a common practice, and there was a high recognition and familiarity toward a range of formula milk brands. Mothers reported challenges in encouraging their children to eat, and in some cases they appeared to lack knowledge on overcoming their child's feeding problem. The findings suggested the need to address the child feeding problems experienced by mothers in order to overcome the double burden of child nutrition in Indonesia. PMID- 23802916 TI - Duration of acute kidney injury and mortality in critically ill patients: a retrospective observational study. AB - BACKGROUND: The addition of relevant parameters to acute kidney injury (AKI) criteria might allow better prediction of patient mortality than AKI criteria alone. Here, we evaluated whether inclusion of AKI duration could address this issue. METHODS: AKI was defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines in 2,143 critically ill patients, within 15 days of patient admission. AKI cases were categorized according to tertiles of AKI duration: 1st tertile, 1-2 days; 2nd tertile, 3-5 days; and 3rd tertile, >=6 days. The hazard ratios (HRs) for overall survival rates in three groups were calculated after adjustment for multiple covariates compared with ICU patients without AKI as the reference group. The predictive ability for mortality was assessed by calculating the area under the curve (AUC) of the receiver operating characteristic curve. RESULTS: AKI increased the HRs for overall mortality, and the mortality rate increased with AKI duration: the adjusted HRs were 1.99 (1st tertile), 2.67 (2nd tertile), and 2.85 (3rd tertile) compared with the non-AKI group (all Ps < 0.001). The AUC of the ROC curve for overall mortality based on the AKI duration groups (0.716) was higher than the AUC of AKI staging using the KDIGO guidelines (0.696) (P = 0.001). When considering KDIGO stage and AKI duration together, the AUC (0.717) was also significantly higher than that using the KDIGO stage alone (P < 0.001). CONCLUSIONS: AKI duration is an additional parameter for the prediction of mortality in critically ill patients. The inclusion of AKI duration could be considered as a refinement of the AKI criteria. PMID- 23802918 TI - New approach toward reflective films and fibers using cholesteric liquid-crystal coatings. AB - A new approach for the production of oriented films and fibers with angular dependent reflective colors is presented. The process consists of spray coating a solution of cholesteric liquid-crystalline monomers onto a melt-processed and oriented polyamide-6 substrate followed by UV curing. Reflectivity measurements and optical microscopy show that a well-defined liquid-crystalline and planar alignment is obtained. It is further demonstrated that a reflection up to 80% is obtained by coating oriented films on both sides of the oriented substrate with a single-handedness cholesteric liquid-crystal coating. The high reflectivity is attributed to the close to half-wave retardation induced by the anisotropic polymer substrate. Also, polyamide-6 filaments are successfully coated and fibers are obtained with an angular-dependent color in a single dimension along the fiber direction, which originates from the planar cholesteric alignment on a curved surface. PMID- 23802917 TI - Psychological distress and its correlates among dental students: a survey of 17 Colombian dental schools. AB - BACKGROUND: Links between the demanding nature of studies in the health sciences, students' personality traits and psychological distress have been well established. While considerable amount of work has been done in medicine, evidence from the dental education arena is sparse and data from Latin America are lacking. The authors conducted a large-scale investigation of psychological distress among dental students in Colombia and sought to determine its curriculum and student-level correlates. METHODS: The Spanish version of the Derogatis' Symptoms Checklist Revised (SCL-90-R) was administered to all students officially registered and attending classes or clinics in 17 dental schools in 4 geographic districts of Colombia between January and April 2012. Additional information was collected on participants' socio-demographic information and first career choice, as well as school's characteristics such as class size. The Global Severity Index (GSI) score, a measure of overall psychological distress, served as the primary analytical endpoint. Analyses relied on multilevel mixed-effects linear and log binomial regression, accounting for study design and sample characteristics. RESULTS: A total of 5700 dental students completed the survey, a response rate of 67%. Pronounced gradients were noted in the association between socio-economic status and psychological distress, with students in higher strata reporting fewer problems. After adjustment for all important covariates, there was an evident pattern of increasing psychological distress corresponding to the transition from the didactic, to the preclinical and clinical phases of training, with few differences between male and female students. Independent of other factors, reliance on own funds for education and having dentistry as the first career choice were associated with lower psychological distress. CONCLUSIONS: Levels of psychological distress correlated with students' socio-economic and study-level characteristics. Above and beyond the influence of person-level factors, variations in levels of distress paralleled specific transitional stages of the 5 year dental curriculum, providing opportunities for targeted interventions. PMID- 23802919 TI - Bilateral pressure pain hypersensitivity over the hand as potential sign of sensitization mechanisms in individuals with thumb carpometacarpal osteoarthritis. AB - OBJECTIVE: To investigate whether bilateral deep tissue pressure hyperalgesia exists in individuals with unilateral thumb carpometacarpal osteoarthritis (CMC OA). METHODS: A total of 32 patients with CMC OA (29 females and 3 males, aged 69 90 years old) and 32 healthy matched controls (29 females and 3 males, aged 70-90 years) were recruited. Pressure pain thresholds (PPTs) were bilaterally assessed over the first CMC joint, the hamate bone and the lateral epicondyle in a blinded design. Mixed models analyses of variance were conducted to determine the differences in pressure pain sensitivity between groups and sides. RESULTS: The results showed that PPTs were significantly decreased over the first CMC joint (F = 6.551, P = 0.012) and the hamate bone (F = 9.783, P = 0.002) but not over the lateral epicondyle (F = 2.712, P = 0.102) in patients with thumb CMC OA as compared with healthy controls; patients with unilateral thumb CMC OA exhibited bilateral pressure pain hyperalgesia in both hands compared with healthy people. PPTs were not significantly associated to the intensity of pain (all, P > 0.05). DISCUSSION: This study revealed bilateral localized pressure pain hypersensitivity over the hand in individuals with unilateral thumb CMC OA, suggesting spinal cord sensitization mechanisms in this population. Future studies should analyze the presence of widespread pressure pain sensitivity in patients with thumb CMC OA to further determine the presence of central sensitization mechanisms. PMID- 23802920 TI - Two weeks of reduced-volume sprint interval or traditional exercise training does not improve metabolic functioning in sedentary obese men. AB - AIMS: To investigate the effects of short-term, reduced-volume sprint interval training (SIT) compared to traditional exercise recommendations (TER) in sedentary obese men. METHODS: Sixteen subjects [37.8 +/- 5.8 years; body mass index (BMI) 32.8 +/- 4.7 kg/m(2)] were randomly allocated to 2 weeks of either SIT (6 sessions of 8-12 * 10 s sprints) or TER [10 sessions of 30 min at 65% peak oxygen consumption (VO(2peak))] cycle exercise. Fasting plasma glucose, insulin, non-esterified fatty acids (NEFA), homeostasis model assessment of insulin sensitivity (HOMA-IR), body composition and VO(2peak) were assessed at baseline and approximately 72 h after the final training bout. Skeletal muscle biopsy samples were also obtained before and 72 h after training and analysed for AS160 phosphorylation and COX II, COX IV, GLUT-4, Nur77 and SIRT1 protein expression. RESULTS: No changes in BMI, body composition, VO(2peak), glucose, insulin, NEFA and HOMA-IR were observed after training, either within or between groups. Skeletal muscle markers of glucose metabolism and mitochondrial function also remained unaltered after 2 weeks of exercise training. CONCLUSIONS: Our findings show that 2 weeks of reduced-volume SIT or TER did not elicit any measurable metabolic adaptations in sedentary obese men. Further work is needed to determine the minimal amount of exercise required for short-term adaptations in this population. PMID- 23802921 TI - Estimating preferential flow in karstic aquifers using statistical mixed models. AB - Karst aquifers are highly productive groundwater systems often associated with conduit flow. These systems can be highly vulnerable to contamination, resulting in a high potential for contaminant exposure to humans and ecosystems. This work develops statistical models to spatially characterize flow and transport patterns in karstified limestone and determines the effect of aquifer flow rates on these patterns. A laboratory-scale Geo-HydroBed model is used to simulate flow and transport processes in a karstic limestone unit. The model consists of stainless steel tanks containing a karstified limestone block collected from a karst aquifer formation in northern Puerto Rico. Experimental work involves making a series of flow and tracer injections, while monitoring hydraulic and tracer response spatially and temporally. Statistical mixed models (SMMs) are applied to hydraulic data to determine likely pathways of preferential flow in the limestone units. The models indicate a highly heterogeneous system with dominant, flow dependent preferential flow regions. Results indicate that regions of preferential flow tend to expand at higher groundwater flow rates, suggesting a greater volume of the system being flushed by flowing water at higher rates. Spatial and temporal distribution of tracer concentrations indicates the presence of conduit-like and diffuse flow transport in the system, supporting the notion of both combined transport mechanisms in the limestone unit. The temporal response of tracer concentrations at different locations in the model coincide with, and confirms the preferential flow distribution generated with the SMMs used in the study. PMID- 23802922 TI - Using geometry to uncover relationships between isotropy, homogeneity, and modularity in cortical connectivity. AB - Inferences of strong modular and hierarchical structure from some cortical network studies conflict with the broadly isotropic homogeneous connectivity that has been found to a first approximation in classical anatomical studies. This conflict is resolved via consideration of the geometry of the cortex. A new geometrically based connection matrix (CM) visualization method is used to better compare experimental CMs with model CMs and thereby minimize appearance of artifacts. Model networks based on spherical geometry containing similar isotropic, homogeneous connection distributions to the experiment are shown to reproduce, interrelate, and explain key properties of experimentally derived networks, such as clustering coefficient (CC), path length, mean degree, and modularity score, using only two parameters that are fitted to an experimental spatial connectivity distribution. A greater CC in the experiment than the model indicates that, while isotropy and homogeneity of connections is a good first approximation, connections at shorter range may exhibit additional perturbations that increase clustering. These geometrically based models provide a comparative framework to assist in the next stage of revealing and analyzing anisotropic and/or inhomogeneous connections in data and their effects on network properties and visualization. PMID- 23802923 TI - Electrophilic Ln(III) cations protected by C-F -> Ln interactions and their coordination chemistry with weak sigma- and pi-donors. AB - A homoleptic cerium(III) amide complex, Ce(NPh(F)2)3 (1-Ce) (Ph(F) = pentafluorophenyl), in an unusual pseudo-trigonal planar geometry featuring six C F -> Ce interactions was prepared. The C-F -> Ln interactions in solution were evident by comparison of the (19)F NMR shifts for the paramagnetic 1-Ce with those of the 4f(0) lanthanum(III) analogue. Coordination of weak sigma- and pi donors, including ethers and neutral arene molecules, was achieved by the reversible displacement of the weak C-F -> Ce interactions. Computational studies on Ce(NPh(F)2)3 and Ce(NPh(F)2)3(eta(6)-C6H3Me3) provide information on the F -> Ce interactions and Ce-eta(6)-arene bonding. PMID- 23802924 TI - Health-related quality of life and physical functioning in people living with HIV/AIDS: a case-control design. AB - BACKGROUND: Health-Related Quality of Life (HRQoL) and functional exercise capacity are important area of therapeutic interventions needed to improve the general health of People Living with HIV/AIDS (PLWH). However, the relationship between self-report and Performance-based Measure of Functional Capacity (PMFC) of PLWH is still obscure. This study compared the HRQoL and PMFC between a homogenous sample of clinical stage I PLWH and apparently healthy controls. METHODS: This case-control study involved 74 consenting participants (37 PLWH and 37 controls) who completed the self-report SF-12 questionnaire and PMFC assessment using Six Minute Walk Test (6MWT). PMFC was expressed in terms of Six Minute Walk Distance (6MWD), Six-Minute Walk Work (6MWW) and Maximum oxygen uptake (VO2max). Data were analyzed using descriptive statistics of mean and inferential statistics of independent t-test, ANOVA and Pearson's product moment correlation. Alpha level was set at 0.05. RESULTS: There was no significant difference in the SF-12 Physical-health Component Score (PCS) of PLWH and the controls (p=0.782). However, the SF-12 Mental-health Component Score (MCS) of PLWH was higher than that of controls (p=0.040). 6MWD, 6MWW and VO2max were significantly lower for PLWH (p<0.05). Among PLWH, there was no significant gender differences in the PMFC (p>0.05) while PCS was higher among females. There was no significant correlation between PMFC variables and each of PCS and MCS for PLWH and controls (p>0.05) respectively. CONCLUSION: Self-report physical health of clinical stage 1 PLWH and controls was comparable, while self-report mental health capacity was higher in PLWH than the controls. PMFC of PLWH was significantly lower compared to healthy controls without gender bias. Overall, self-report and performance-based measure of physical functional capacity of PLWH was not inter-related. Therefore understanding the factors that may influence exercise capacity of PLWH may help to develop effective exercise programmes for PLWH. PMID- 23802925 TI - Rural population estimates: an analysis of a large secondary data set. AB - PURPOSE: Health services research often utilizes secondary data sources such as the Behavioral Risk Factor Surveillance System (BRFSS). Since 2006, the released BRFSS data do not include respondents who live in counties with 10,000 or fewer residents, and the CDC no longer offers the opportunity to access the unrestricted data set. As a result, rural residents can be underrepresented in BRFSS data after 2005. The purpose of this analysis is to examine the potential for bias introduced by rural underestimation. METHODS: We utilized 6 BRFSS data sets; the 2005 full data and the 2005-2009 restricted data. We estimated population sizes for each survey year, and we compared these estimates to comparable data from the US Census intercensal estimates. We also compared estimates of preventive service utilization (mammography, Pap tests, colorectal cancer screening, and influenza vaccinations) between the two 2005 data versions. RESULTS: Rural populations were underrepresented, particularly with the smaller counties excluded. Remote rural residents were the most consistently underrepresented. Preventive service delivery estimates differed between the full and restricted 2005 data versions. Mammography and Pap test estimates tended to be higher in the restricted data, while colorectal cancer screening and influenza vaccinations were similar or inconsistent. These results indicate that restricting by county size introduced bias in these estimates. CONCLUSIONS: Having quality, nationally representative data is important to study disparities in service delivery. The potential bias introduced by the BRFSS county restriction may result in rural research being less effective for policy recommendations and interventions. PMID- 23802926 TI - Association between physical activity and insomnia symptoms in rural communities of southeastern Missouri, Tennessee, and Arkansas. AB - PURPOSE: The purpose of this study is to examine whether physical activity is associated with less insomnia symptoms in the rural communities. METHODS: This study used cross-sectional data collected from a 2005 telephone survey for evaluation of a community walking trails intervention to promote physical activity in rural communities including 6 communities in the Missouri Ozark region and 6 communities in Arkansas and Tennessee (n = 1,234). The exposure variable is self-reported regular current physical activity. The outcome includes symptoms of insomnia operationalized as having trouble falling asleep, staying asleep, and waking up too early nearly every day. Logistic regression was used to calculate prevalence odds ratios (PORs) and 95% confidence intervals (95% CI). FINDINGS: The study sample includes mostly white (95%), married (62%), overweight/obese (61%) women with a high school degree and a mean age of 54. Fourteen percent of participants reported having insomnia symptoms. Self-report of currently being physically active regularly was associated with decreased odds of insomnia symptoms (adjusted POR: .37; 95% CI, 0.14-0.99) among participants with under or normal body weight, after controlling for age, gender, education level, marital status, and chronic diseases. There was also a negative linear correlation between the number of days and total minutes of vigorous physical activity and insomnia symptoms. CONCLUSIONS: In these rural communities, we observed a significant relationship between regular physical activity and decreased insomnia symptoms. PMID- 23802927 TI - Promoting heart health in rural women. AB - PURPOSE: To compare 2 strategies, stage-matched nursing and community intervention (SMN+CI) and community intervention (CI) alone in changing cardiovascular risk factors in up to 3 behavioral areas: diet, physical activity, and/or smoking among rural women. METHODS: A 14-month, multisite randomized controlled trial of 117 rural women was conducted. Transtheoretical model was used in identification of stage of change and development of the SMN+CI nursing interventions. A social-ecological model was used to address issues of rurality in the development of interventions. FINDINGS: The SMN + CI group was superior on 4 outcomes. There were significant increases in 2 measures of dietary intake; improvement in dietary stage of change for fruits and vegetables; and reduced diastolic blood pressure (DBP) in the SMN + CI group. After log transformation DBP significance was lost. The CI group had a significant reduction in change in total cholesterol; however, significance was lost after control for the initiation of lipid lowering medications. There was a significant reduction in Framingham risk scores pre- to postintervention, regardless of group. CONCLUSIONS: There continues to be a need to improve cardiovascular risk factors in rural women. There should be an exploration of whether intensified dose and fidelity of the intervention strategies of diet and physical activity are effective in improving anthropometric and laboratory values. Further investigation is warranted into factors influencing the pre- to postreduction in Framingham risk scores. PMID- 23802928 TI - Frontier America's health system challenges and population health outcomes. AB - PURPOSE: The objective of this cross-sectional descriptive study was to examine and compare the county-level characteristics including demographic factors, health system factors, and population health outcomes of frontier and nonfrontier counties in the United States. All counties in the United States were studied using the merged County Health Rankings 2011 and the Area Resource File 2009 databases. Of a total of 3,141 counties in the County Health Rankings 2011 database, 438 were identified as frontier counties using the conventional definition of fewer than 7 persons per square mile. FINDINGS: Frontier counties were found to have a significantly higher proportion of elderly, Hispanic, and Native American residents than nonfrontier counties. Frontier counties have lower household income and lower levels of illiteracy. Frontier counties also have significantly fewer primary care physicians and higher uninsurance rates. Although frontier counties have a lower percentage of ZIP codes with healthy food and recreational facilities, the incidence of obesity is lower in frontier areas. CONCLUSIONS: Empirical literature on the population health outcomes and health system factors of frontier areas is limited. Frontier communities in the United States face significant challenges in terms of having populations with a higher need for primary care such as the elderly and poor. In addition, they face access barriers due to geographic remoteness. The availability of reliable data on population outcomes will enable policy makers to monitor the health status of frontier populations and to design solutions to the access issues that these populations face. PMID- 23802929 TI - Rural AIDS diagnoses in Florida: changing demographics and factors associated with survival. AB - PURPOSE: To compare demographic characteristics and predictors of survival of rural residents diagnosed with acquired immunodeficiency syndrome (AIDS) with those of urban residents. METHODS: Florida surveillance data for people diagnosed with AIDS during 1993-2007 were merged with 2000 Census data using ZIP code tabulation areas (ZCTAs). Rural status was classified based on the ZCTA's rural urban commuting area classification. Survival rates were compared between rural and urban areas using survival curves and Cox proportional hazards models controlling for demographic, clinical, and area-level socioeconomic and health care access factors. FINDINGS: Of the 73,590 people diagnosed with AIDS, 1,991 (2.7%) resided in rural areas. People in the most recent rural cohorts were more likely than those in earlier cohorts to be female, non-Hispanic black, older, and have a reported transmission mode of heterosexual sex. There were no statistically significant differences in the 3-, 5-, or 10-year survival rates between rural and urban residents. Older age at the time of diagnosis, diagnosis during the 1993-1995 period, other/unknown transmission mode, and lower CD4 count/percent categories were associated with lower survival in both rural and urban areas. In urban areas only, being non-Hispanic black or Hispanic, being US born, more poverty, less community social support, and lower physician density were also associated with lower survival. CONCLUSIONS: In rural Florida, the demographic characteristics of people diagnosed with AIDS have been changing, which may necessitate modifications in the delivery of AIDS-related services. Rural residents diagnosed with AIDS did not have a significant survival disadvantage relative to urban residents. PMID- 23802930 TI - Characteristics of the residential neighborhood environment differentiate intimate partner femicide in urban versus rural settings. AB - PURPOSE: A growing body of work examines the association between neighborhood environment and intimate partner violence (IPV). As in the larger literature examining the influence of place context on health, rural settings are understudied and urban and rural residential environments are rarely compared. In addition, despite increased attention to the linkages between neighborhood environment and IPV, few studies have examined the influence of neighborhood context on intimate partner femicide (IPF). In this paper, we examine the role for neighborhood-level factors in differentiating urban and rural IPFs in Wisconsin, USA. METHODS: We use a combination of Wisconsin Violent Death Reporting System (WVDRS) data and Wisconsin Coalition Against Domestic Violence (WCADV) reports from 2004 to 2008, in concert with neighborhood-level information from the US Census Bureau and US Department of Agriculture, to compare urban and rural IPFs. FINDINGS: Rates of IPF vary based on degree of rurality, and bivariate analyses show differences between urban and rural victims in race/ethnicity, marital status, country of birth, and neighborhood characteristics. After controlling for individual characteristics, the nature of the residential neighborhood environment significantly differentiates urban and rural IPFs. CONCLUSIONS: Our findings suggest a different role for neighborhood context in affecting intimate violence risk in rural settings, and that different measures may be needed to capture the qualities of rural environments that affect intimate violence risk. Our findings reinforce the argument that multilevel strategies are required to understand and reduce the burden of intimate violence, and that interventions may need to be crafted for specific geographical contexts. PMID- 23802931 TI - Disparities in knowledge of mouth or throat cancer among rural Floridians. AB - OBJECTIVE: The aim of this study was to examine risk factors for reduced mouth or throat cancer (MTC) knowledge using a sample of rural North Floridian adults. METHODS: Telephone interviews were conducted across rural census tracts throughout North Florida in 2009-2010, using a survey adapted for cultural appropriateness. The sample consisted of 2,393 individuals (1,059 males and 1,334 females; 1,681 whites and 712 blacks). FINDINGS: Only 9% of the study respondents indicated they had not heard of MTC; however, only 12% endorsed knowing "a lot." Higher education levels and health literacy indicated they had more MTC knowledge. Among female participants, whites had more knowledge than blacks (OR = 1.9). Among black participants, males had more knowledge than females (OR = 1.7). Conversely, greater concern with MTC was associated with lower education levels, health literacy, and financial status, but higher depression scores. Awareness that excessive sun exposure is a risk factor for MTC was lower than for earlier studies using more urban samples. CONCLUSIONS: This study adds to the literature on MTC knowledge and concern because this sample was drawn exclusively from rural populations in North Florida, a group with the highest MTC morbidity and mortality. An unanticipated finding was that blacks were more concerned than their white rural counterparts. This study was also the first to report that depression was associated with increased concern about MTC. The goal is to persuade at-risk groups to obtain MTC screenings with the goal of reducing disparities in MTC whenever they occur. PMID- 23802932 TI - Rural native veterans in the Veterans Health Administration: characteristics and service utilization patterns. AB - PURPOSE: The Department of Veterans Affairs (VA) and the Indian Health Service (IHS) signed a Memo of Understanding in 2010 to strengthen their partnership in improving health care services for Native veterans, who are disproportionately rural. This paper describes the demographic and service use profile of rural Native veterans who access VA health care. METHODS: Data were abstracted from the 2008 Veteran Health Administration (VHA) medical dataset, and the characteristics of rural Native veterans were compared to rural non-Native veterans. FINDINGS: Rural Native veterans were more rural (41% vs 35%) and more highly rural (8% vs 2%) compared to non-Native veterans. Rural Native veterans were younger, more likely to be female, and earned about the same median income compared to rural non-Native veterans. Although rural Native veterans had fewer diagnoses on average, they were more likely to have served in combat areas and to have higher levels of service-connected disability compared to other rural veterans. CONCLUSIONS: Demographic and service-related characteristics of rural Native veterans who accessed VA care differ from those of rural non-Native veterans. Identifying specific health care and service use characteristics will assist in the development of appropriate policy and programs to serve rural Native veterans. PMID- 23802933 TI - Alcohol consumption, obesity, and psychological distress in farming communities an Australian study. AB - PURPOSE: Alcohol consumption patterns nationally and internationally have been identified as elevated in rural and remote populations. In the general Australian population, 20.5% of adult males and 16.9% of adult females drink at short-term, high-risk levels. Farmers are more likely to drink excessively than those living in major cities. This study seeks to explore the relationships between farmers' physical and mental health and their alcohol consumption patterns. Our hypothesis is that farmers consume alcohol at high-risk levels more often than the Australian average and that this consumption is associated with obesity and psychological distress. METHODS: Cross-sectional descriptive data were collected within Australian farming communities from 1,792 consenting adults in 97 locations across Australia. Data on anthropometric measurements, general physical attributes and biochemical assessments were used to explore the interrelationships of self-reported alcohol consumption patterns with obesity, psychological distress, and other physical health parameters. FINDINGS: There was a higher prevalence of short-term, high-risk alcohol consumption (56.9% in men and 27.5% in women) reported in the study compared with national data. There was also a significant positive association between the prevalence of high-risk alcohol consumption and the prevalence of obesity and abdominal adiposity in psychologically distressed participants. CONCLUSIONS: The prevalence of short term, high-risk alcohol consumption practices in this cohort of farming men and women is significantly higher than the Australian average. These consumption practices are coupled with a range of other measurable health issues within the farming population, such as obesity, hypertension, psychological distress, and age. PMID- 23802934 TI - Larger regional and rural areas in Victoria, Australia, experience more alcohol related injury presentations at emergency departments. AB - PURPOSE: Alcohol consumption is higher in regional and rural areas compared to metropolitan locations, but it is unclear which areas suffer different levels of harm. The current study investigated the rates of alcohol-related injury presentations at emergency departments (EDs) in Victoria, Australia, across metropolitan, regional, rural, and remote areas, and within coastal locations. METHODS: Using ED injury presentations data for Victorian hospitals from June 1999 to June 2011, the trends in alcohol-related injury rates over time were investigated. FINDINGS: Compared to metropolitan locations, alcohol-related injuries were higher in larger regional and rural areas and similar in small rural towns. The rates of alcohol-related injuries are also significantly increasing over time for regional and rural locations. Lastly, for males, rates of alcohol-related injuries increased in coastal areas during November to February compared to the remaining months. CONCLUSIONS: Regional and coastal areas experience increased alcohol-related injury rates. The causes of this have yet to be investigated and future research is required to determine why and what interventions may be most effective at reducing these harms. PMID- 23802935 TI - Rural considerations in establishing network adequacy standards for qualified health plans in state and regional health insurance exchanges. AB - PURPOSE: The Affordable Care Act (ACA) requires Health Insurance Exchanges (HIEs) to specify network adequacy standards for the Qualified Health Plans (QHPs) they offer to consumers. This article examines rural issues surrounding network adequacy standards, and offers recommendations for crafting standards that optimize rural access. METHOD: This policy analysis reviews ACA requirements for QHP network adequacy standards, considering Medicaid managed care and Medicare Advantage (MA) standards as models. We analyze the implications of stringent vs flexible access standards in terms of how choices might affect health plans' participation in rural markets and rural enrollees' access to care. Finally, we propose strategies for designing standards with the degree of flexibility most likely to benefit rural consumers. FINDINGS: A traditional approach to safeguarding rural access is to impose strict network adequacy standards on plans in rural areas. However, if strict standards prove difficult to meet due to rural provider scarcity, they might diminish QHPs' willingness to serve rural areas. Thus, they could exacerbate rather than alleviate rural access problems. CONCLUSIONS: To benefit rural communities, network adequacy standards must be strong enough to provide real protections for beneficiaries, yet flexible enough to accommodate rural delivery system constraints and remain attainable for QHPs. Useful strategies to achieve this balance might include: adjusting standards according to degrees of rurality and rural utilization norms; counting midlevel clinicians toward fulfillment of patient-provider ratios; and allowing plans to ensure rural access through delivery system innovations such as telehealth. PMID- 23802936 TI - MeSH indexing based on automatically generated summaries. AB - BACKGROUND: MEDLINE citations are manually indexed at the U.S. National Library of Medicine (NLM) using as reference the Medical Subject Headings (MeSH) controlled vocabulary. For this task, the human indexers read the full text of the article. Due to the growth of MEDLINE, the NLM Indexing Initiative explores indexing methodologies that can support the task of the indexers. Medical Text Indexer (MTI) is a tool developed by the NLM Indexing Initiative to provide MeSH indexing recommendations to indexers. Currently, the input to MTI is MEDLINE citations, title and abstract only. Previous work has shown that using full text as input to MTI increases recall, but decreases precision sharply. We propose using summaries generated automatically from the full text for the input to MTI to use in the task of suggesting MeSH headings to indexers. Summaries distill the most salient information from the full text, which might increase the coverage of automatic indexing approaches based on MEDLINE. We hypothesize that if the results were good enough, manual indexers could possibly use automatic summaries instead of the full texts, along with the recommendations of MTI, to speed up the process while maintaining high quality of indexing results. RESULTS: We have generated summaries of different lengths using two different summarizers, and evaluated the MTI indexing on the summaries using different algorithms: MTI, individual MTI components, and machine learning. The results are compared to those of full text articles and MEDLINE citations. Our results show that automatically generated summaries achieve similar recall but higher precision compared to full text articles. Compared to MEDLINE citations, summaries achieve higher recall but lower precision. CONCLUSIONS: Our results show that automatic summaries produce better indexing than full text articles. Summaries produce similar recall to full text but much better precision, which seems to indicate that automatic summaries can efficiently capture the most important contents within the original articles. The combination of MEDLINE citations and automatically generated summaries could improve the recommendations suggested by MTI. On the other hand, indexing performance might be dependent on the MeSH heading being indexed. Summarization techniques could thus be considered as a feature selection algorithm that might have to be tuned individually for each MeSH heading. PMID- 23802937 TI - Pathophysiologic and anesthetic considerations for patients with myotonia congenita or periodic paralyses. AB - Myotonia congenita and periodic paralyses are hereditary skeletal muscle channelopathies. In these disorders, various channel defects in the sarcolemma lead to a severely disturbed membrane excitability of the affected skeletal muscles. The clinical picture can range from severe myotonic reactions (e.g., masseter spasm, opisthotonus) to attacks of weakness and paralysis. Provided here is a short overview of the pathomechanisms behind such wide-ranging phenotypic presentations in these patients, followed by recommendations concerning the management of anesthesia in such populations. PMID- 23802938 TI - The authors' reply: total thyroidectomy vs bilateral subtotal thyroidectomy in patients with Graves' diseases: a meta-analysis of randomized clinical trials. PMID- 23802939 TI - Utility of cystatin C for renal function in amyotrophic lateral sclerosis. AB - OBJECTIVES: Creatinine (Cr) as a marker of renal function has limited value in amyotrophic lateral sclerosis (ALS) because patients with ALS have reduced muscle mass. Thus, there is a need for alternative methods of assessing renal function. Cystatin C (CysC), which is unaffected by muscle mass, is potentially an ideal biomarker of nephrotoxicity in ALS; however, its utility requires validation. MATERIAL AND METHODS: One hundred and six subjects were recruited for the study: 76 ALS patients and 30 healthy controls. We compared the Cr-based estimated glomerular filtration rate (eGFR) with the CysC-based eGFR in the ALS patients and healthy controls. The results were further analysed according to the severity of ALS in the patients. RESULTS: The mean Cr-based eGFRs were 257.2 +/- 383.1 ml/min/1.73 m(2) in the ALS group and 98.1 +/- 34.9 in the control group; however, the mean CysC-based eGFRs were not significantly different between both groups. Thus, the Cr-based eGFR in the ALS group was markedly higher than any of the other values. Although serum CysC levels did not correlate with the severity of ALS according to the ALS Functional Rating Scale-Revised, strong simple correlations were observed between serum Cr levels and the severity of ALS (correlation coefficient = 0.734, P < 0.001). CONCLUSIONS: This study demonstrates the potential usefulness of CysC as a biomarker of renal function in ALS patients. Furthermore, its applicability could be extended to other neuromuscular diseases. PMID- 23802940 TI - Mathematical models for the van der Waals force and capillary force between a rough particle and surface. AB - The capability of predicting the adhesion forces between a rough particle and surface including the van der Waals force and capillary force is important for modeling various processes involving particle surface retention and resuspension. On the basis of the fractal theory describing the behavior of multiple roughness scales and the Gaussian roughness distribution, a set of mathematical models for the van der Waals force and capillary force is proposed. The proposed models provide the adhesion force predictions in good agreement with the existing experimental data and converge to the previous classical solutions of the adhesion forces between a smooth particle and surface as the roughness goes to zero. The influences of roughness for the combination of particle and surface, relative humidity (RH), contact angle, and Hurst exponent toward the adhesion forces are examined using the proposed models. The decline mode of the adhesion force with surface roughness and contact angle, as well as the increase mode with RH and the Hurst exponent are reasonably predicted by the proposed models. The comparison between the proposed models and those from the existing studies is also performed, which shows the similarities and differences between the proposed models and the existing models. PMID- 23802941 TI - Syncytial hepatitis of farmed tilapia, Oreochromis niloticus (L.): a case report. PMID- 23802943 TI - Mineralogical controls on aluminum and magnesium in uranium mill tailings: Key Lake, Saskatchewan, Canada. AB - The mineralogy and evolution of Al and Mg in U mill tailings are poorly understood. Elemental analyses (ICP-MS) of both solid and aqueous phases show that precipitation of large masses of secondary Al and Mg mineral phases occurs throughout the raffinate neutralization process (pH 1-11) at the Key Lake U mill, Saskatchewan, Canada. Data from a suite of analytical methods (ICP-MS, EMPA, laboratory- and synchrotron-based XRD, ATR-IR, Raman, TEM, EDX, ED) and equilibrium thermodynamic modeling showed that nanoparticle-sized, spongy, porous, Mg-Al hydrotalcite is the dominant mineralogical control on Al and Mg in the neutralized raffinate (pH >= 6.7). The presence of this secondary Mg-Al hydrotalcite in mineral samples of both fresh and 15-year-old tailings indicates that the Mg-Al hydrotalcite is geochemically stable, even after >16 years in the oxic tailings body. Data shows an association between the Mg-Al hydrotalcite and both As and Ni and point to this Mg-Al hydrotalcite exerting a mineralogical control on the solubility of these contaminants. PMID- 23802942 TI - Thioredoxin reductase was nitrated in the aging heart after myocardial ischemia/reperfusion. AB - The age-related loss of anti-oxidant defense reduces recovery from myocardial ischemia/reperfusion injury (MI/R) in aged people. Our previous data showed that inactivation of thioredoxin (Trx) was involved in enhanced aging MI/R injury. Thioredoxin reductase (TrxR), the enzyme known to regulate Trx, is less efficient with age. The aim of the current study was to determine why TrxR activity was reduced and whether reduced TrxR activity contributed to enhanced aging MI/R injury. Both Trx and TrxR activity were decreased in the aging heart, and this difference was further amplified after MI/R. However, MI/R injury did not change TrxR expression between young and aging rats. Increased nitrogen oxide (NOx) but decreased nitric oxide (NO) bioavailability (decreased phosphorylated vasodilator stimulated phosphoprotein) was observed in aging hearts. Peroxynitrite (ONOO-) was increased in aging hearts and was further amplified after MI/R. TrxR nitration in young and aging hearts was detected by immunoprecipitation (anti nitrotyrosine) followed by immunoblotting (anti-TrxR). Compared with young hearts, TrxR nitration was increased in the aging hearts, and this was further intensified after MI/R. The ONOO- decomposition catalyst (FeTMPyp) reduced TrxR nitration and increased TrxR and Trx activity. More importantly, FeTMPyp attenuated the MI/R injury in aging hearts as evidenced by decreased caspase-3 and malondialdehyde (MDA) concentration and increased cardiac function. Increased ONOO- nitrated TrxR in the aging heart as a post-translational modification, which may be related to the enhanced MI/R injury of aging rats. Interventions that inhibit nitration and restore TrxR activity might be a therapy for attenuating enhanced MI/R injury in aging heart. PMID- 23802944 TI - Osteosarcoma with cardiac metastasis in a 22-year-old man: a case report and review of cardiac tumors. AB - Primary osteosarcoma accounts for 3% of all childhood cancer. It commonly occurs during the adolescent growth spurt and is more common in boys than girls and in African Americans than white people. The 5-year survival is approximately 79%. Cardiac metastasis of osteosarcoma is exceedingly rare; we present an unusual case in a 22-year-old man with significant intracardiac tumor burden. Additionally, we review the current pediatric cardiac tumor literature. PMID- 23802945 TI - Features in chemical kinetics. I. Signatures of self-emerging dimensional reduction from a general format of the evolution law. AB - Simplification of chemical kinetics description through dimensional reduction is particularly important to achieve an accurate numerical treatment of complex reacting systems, especially when stiff kinetics are considered and a comprehensive picture of the evolving system is required. To this aim several tools have been proposed in the past decades, such as sensitivity analysis, lumping approaches, and exploitation of time scales separation. In addition, there are methods based on the existence of the so-called slow manifolds, which are hyper-surfaces of lower dimension than the one of the whole phase-space and in whose neighborhood the slow evolution occurs after an initial fast transient. On the other hand, all tools contain to some extent a degree of subjectivity which seems to be irremovable. With reference to macroscopic and spatially homogeneous reacting systems under isothermal conditions, in this work we shall adopt a phenomenological approach to let self-emerge the dimensional reduction from the mathematical structure of the evolution law. By transforming the original system of polynomial differential equations, which describes the chemical evolution, into a universal quadratic format, and making a direct inspection of the high-order time-derivatives of the new dynamic variables, we then formulate a conjecture which leads to the concept of an "attractiveness" region in the phase-space where a well-defined state-dependent rate function omega has the simple evolution omega[over dot]=-omega(2) along any trajectory up to the stationary state. This constitutes, by itself, a drastic dimensional reduction from a system of N-dimensional equations (being N the number of chemical species) to a one-dimensional and universal evolution law for such a characteristic rate. Step-by-step numerical inspections on model kinetic schemes are presented. In the companion paper [P. Nicolini and D. Frezzato, J. Chem. Phys. 138, 234102 (2013)] this outcome will be naturally related to the appearance (and hence, to the definition) of the slow manifolds. PMID- 23802946 TI - Features in chemical kinetics. II. A self-emerging definition of slow manifolds. AB - In the preceding paper of this series (Part I [P. Nicolini and D. Frezzato, J. Chem. Phys. 138, 234101 (2013)]) we have unveiled some ubiquitous features encoded in the systems of polynomial differential equations normally applied in the description of homogeneous and isothermal chemical kinetics (mass-action law). Here we proceed by investigating a deeply related feature: the appearance of so-called slow manifolds (SMs) which are low-dimensional hyper-surfaces in the neighborhood of which the slow evolution of the reacting system occurs after an initial fast transient. Indeed a geometrical definition of SM, devoid of subjectivity, "naturally" follows in terms of a specific sub-dimensional domain embedded in the peculiar region of the concentrations phase-space that in Part I we termed as "attractiveness region." Numerical inspections on simple low dimensional model cases are presented, including the benchmark case of Davis and Skodje [J. Chem. Phys. 111, 859 (1999)] and the preliminary analysis of a simplified model mechanism of hydrogen combustion. PMID- 23802947 TI - On the analytical representation of free energy profiles with a Morse/long-range model: application to the water dimer. AB - We investigate the analytical representation of potentials of mean force (pmf) using the Morse/long-range (MLR) potential approach. The MLR method had previously been used to represent potential energy surfaces, and we assess its validity for representing free-energies. The advantage of the approach is that the potential of mean force data only needs to be calculated in the short to medium range region of the reaction coordinate while the long range can be handled analytically. This can result in significant savings in terms of computational effort since one does not need to cover the whole range of the reaction coordinate during simulations. The water dimer with rigid monomers whose interactions are described by the commonly used TIP4P model [W. Jorgensen and J. Madura, Mol. Phys. 56, 1381 (1985)] is used as a test case. We first calculate an "exact" pmf using direct Monte Carlo (MC) integration and term such a calculation as our gold standard (GS). Second, we compare this GS with several MLR fits to the GS to test the validity of the fitting procedure. We then obtain the water dimer pmf using metadynamics simulations in a limited range of the reaction coordinate and show how the MLR treatment allows the accurate generation of the full pmf. We finally calculate the transition state theory rate constant for the water dimer dissociation process using the GS, the GS MLR fits, and the metadynamics MLR fits. Our approach can yield a compact, smooth, and accurate analytical representation of pmf data with reduced computational cost. PMID- 23802948 TI - Relative efficacy of vibrational vs. translational excitation in promoting atom diatom reactivity: rigorous examination of Polanyi's rules and proposition of sudden vector projection (SVP) model. AB - To provide a systematic and rigorous re-examination of the well-known Polanyi's rules, excitation functions of several A + BC(v = 0, 1) reactions are determined using the Chebyshev real wave packet method on accurate potential energy surfaces. Reactions with early (F + H2 and F + HCl), late (Cl + H2), and central (H/D/Mu + H2, where Mu is a short-lived light isotope of H) barriers are represented. Although Polanyi's rules are in general consistent with the quantum dynamical results, their predictions are strictly valid only in certain energy ranges divided by a cross-over point. In particular, vibrational excitation of the diatomic reactant typically enhances reactivity more effectively than translational excitation at high energies, while reverse is true at low energies. This feature persists irrespective of the barrier location. A sudden vector projection model is proposed as an alternative to Polanyi's rules. It is found to give similar, but more quantitative, predictions about mode selectivity in these reactions, and has the advantage to be extendible to reactions involving polyatomic molecules. PMID- 23802949 TI - Multiscale modeling with smoothed dissipative particle dynamics. AB - In this work, we consider two issues related to the use of Smoothed Dissipative Particle Dynamics (SDPD) as an intermediate mesoscale model in a multiscale scheme for solution of flow problems when there are local parts of a macroscopic domain that require molecular resolution. The first is to demonstrate that SDPD with different levels of resolution can accurately represent the fluid properties from the continuum scale all the way to the molecular scale. Specifically, while the thermodynamic quantities such as temperature, pressure, and average density remain scale-invariant, we demonstrate that the dynamic properties are quantitatively consistent with an all-atom Lennard-Jones reference system when the SDPD resolution approaches the atomistic scale. This supports the idea that SDPD can serve as a natural bridge between molecular and continuum descriptions. In the second part, a simple multiscale methodology is proposed within the SDPD framework that allows several levels of resolution within a single domain. Each particle is characterized by a unique physical length scale called the smoothing length, which is inversely related to the local number density and can change on the-fly. This multiscale methodology is shown to accurately reproduce fluid properties for the simple problem of steady and transient shear flow. PMID- 23802950 TI - Grand canonical Monte Carlo simulations of vapor-liquid equilibria using a bias potential from an analytic equation of state. AB - This article introduces an efficient technique for the calculation of vapor liquid equilibria of fluids. Umbrella Sampling Monte Carlo simulations in the grand canonical ensemble were conducted for various types of molecules. In Umbrella Sampling, a weight function is used for allowing the simulation to reach unlikely states in the phase space. In the present case this weight function, that allows the system to overcome the energetic barrier between a vapor and liquid phase, was determined by a trivialized Density Functional Theory (DFT) using the PC-SAFT equation of state. The implementation presented here makes use of a multicanonical ensemble approach to divide the space of fluctuating particle number N into various subsystems. The a priori estimate of the weight function from the analytic DFT allows the parallelization of the calculation, which significantly reduces the computation time. In addition, it is shown that the analytic equation of state can be used to substitute sampling the dense liquid phase, where the sampling of insertion and deletion moves become demanding. PMID- 23802951 TI - Predicting the thermodynamics by using state-dependent interactions. AB - We reconsider the structure-based route to coarse graining in which the coarse grained model is defined in such a way to reproduce some distribution functions of the original system as accurately as possible. We consider standard expressions for pressure and chemical potential applied to this family of coarse grained models with density-dependent interactions and show that they only provide approximations to the pressure and chemical potential of the underlying original system. These approximations are then carefully compared in two cases: we consider a generic microscopic system in the low-density regime and polymer solutions under good-solvent conditions. Moreover, we show that the state dependent potentials depend on the ensemble in which they have been derived. Therefore, care must be used in applying canonical state-dependent potentials to predict phase lines, which is typically performed in other ensembles. PMID- 23802952 TI - A gauge invariant multiscale approach to magnetic spectroscopies in condensed phase: general three-layer model, computational implementation and pilot applications. AB - Analytical equations to calculate second order electric and magnetic properties of a molecular system embedded into a polarizable environment are presented. The treatment is limited to molecules described at the self consistent field level of theory, including Hartree-Fock theory as well as Kohn-Sham density functional theory and is extended to the Gauge-Including Atomic Orbital method. The polarizable embedding is described by means of our already implemented polarizable quantum mechanical/molecular mechanical (MM) methodology, where the polarization in the MM layer is handled by means of the fluctuating charge (FQ) model. A further layer of description, i.e, the polarizable continuum model, can also be included. The FQ(/polarizable continuum model) contributions to the properties are derived, with reference to the calculation of the magnetic susceptibility, the nuclear magnetic resonance shielding tensor, electron spin resonance g-tensors, and hyperfine couplings. PMID- 23802953 TI - Parahydrogen-induced polarization at zero magnetic field. AB - We use symmetry arguments and simple model systems to describe the conversion of the singlet state of parahydrogen into an oscillating sample magnetization at zero magnetic field. During an initial period of free evolution governed by the scalar-coupling Hamiltonian HJ, the singlet state is converted into scalar spin order involving spins throughout the molecule. A short dc pulse along the z axis rotates the transverse spin components of nuclear species I and S through different angles, converting a portion of the scalar order into vector order. The development of vector order can be described analytically by means of single transition operators, and it is found to be maximal when the transverse components of I are rotated by an angle of +/-pi/2 relative to those of S. A period of free evolution follows the pulse, during which the vector order evolves as a set of oscillating coherences. The imaginary parts of the coherences represent spin order that is not directly detectable, while the real parts can be identified with oscillations in the z component of the molecular spin dipole. The dipole oscillations are due to a periodic exchange between Iz and Sz, which have different gyromagnetic ratios. The frequency components of the resulting spectrum are imaginary, since the pulse cannot directly induce magnetization in the sample; it is only during the evolution under HJ that the vector order present at the end of the pulse evolves into detectable magnetization. PMID- 23802954 TI - Ab initio potential energy surface and vibration-rotation energy levels of lithium monohydroxide. AB - The accurate ground-state potential energy surface of lithium monohydroxide (LiOH) has been determined from ab initio calculations using the coupled-cluster approach in conjunction with the correlation-consistent core-valence basis sets up to septuple-zeta quality. Results obtained with the conventional and explicitly correlated coupled-cluster methods were compared. The higher-order electron correlation, scalar relativistic, and adiabatic effects were taken into account. The vibration-rotation energy levels of the LiOH, LiOD, Li(18)OH, and (6)LiOH isotopologues were predicted to near "spectroscopic" accuracy. PMID- 23802955 TI - Gyroscopic destabilisation in polyatomic molecules: rotational structure of the low-frequency bending vibrational states nu(23) and nu(11) of dimethylsulfoxide. AB - We give details of the spectroscopic observation of the gyroscopic destabilisation in the nu23 vibrational state of dimethylsulfoxide (DMSO) announced by Cuisset, Pirali, and Sadovskii [Phys. Rev. Lett. 109, 094101 (2012)]. Following the first successful high-resolution spectroscopic study of the rotational structure of the "perpendicular" band of DMSO at 324 cm(-1) associated with the nu23 bending vibrational mode, the rare subsystem of nu23 rotational levels consisting of a series of fourfold quasidegenerate levels (4 clusters) was identified. Our complete analysis of the underlying rotational dynamics uncovered a bifurcation leading to the gyroscopic destabilisation of one of the two stable principal axes of inertia, a phenomenon known previously only in a few triatomic molecules. PMID- 23802957 TI - Negative ions of p-nitroaniline: photodetachment, collisions, and ab initio calculations. AB - The structures of parent anion, M(-), and deprotonated molecule, [M-H](-), anions of the highly polar p-nitroaniline (pNA) molecule are studied experimentally and theoretically. Photoelectron spectroscopy (PES) of the parent anion is employed to estimate the adiabatic electron affinity (EAa = 0.75 +/- 0.1 eV) and vertical detachment energy (VDE = 1.1 eV). These measured energies are in good agreement with computed values of 0.73 eV for the EAa and the range of 0.85 to 1.0 eV for the VDE at the EOM-CCSD/Aug-cc-pVTZ level. Collision induced dissociation (CID) of deprotonated pNA, [pNA - H](-), with argon yielded [pNA - H - NO](-) (i.e., rearrangement to give loss of NO) with a threshold energy of 2.36 eV. Calculations of the energy difference between [pNA - H](-) and [pNA - H - NO](-) give 1.64 eV, allowing an estimate of a 0.72 eV activation barrier for the rearrangement reaction. Direct dissociation of [pNA - H](-) yielding NO2(-) occurs at a threshold energy of 3.80 eV, in good agreement with theory (between 3.39 eV and 4.30 eV). As a result of the exceedingly large dipole moment for pNA (6.2 Debye measured in acetone), we predict two dipole-bound states, one at ~110 meV and an excited state at 2 meV. No dipole-bound states are observed in the photodetachment experiments due the pronounced mixing between states with dipole bound and valence character similar to what has been observed in other nitro systems. For the same reason, dipole-bound states are expected to provide highly efficient "doorway states" for the formation of the pNA(-) valence anion, and these states should be observable as resonances in the reverse process, that is, in the photodetachment spectrum of pNA(-) near the photodetachment threshold. PMID- 23802956 TI - Accurate structure, thermodynamics, and spectroscopy of medium-sized radicals by hybrid coupled cluster/density functional theory approaches: the case of phenyl radical. AB - The coupled-cluster singles doubles model with perturbative treatment of triples (CCSD(T)) coupled with extrapolation to the complete basis-set limit and additive approaches represent the "golden standard" for the structural and spectroscopic characterization of building blocks of biomolecules and nanosystems. However, when open-shell systems are considered, additional problems related to both specific computational difficulties and the need of obtaining spin-dependent properties appear. In this contribution, we present a comprehensive study of the molecular structure and spectroscopic (IR, Raman, EPR) properties of the phenyl radical with the aim of validating an accurate computational protocol able to deal with conjugated open-shell species. We succeeded in obtaining reliable and accurate results, thus confirming and, partly, extending the available experimental data. The main issue to be pointed out is the need of going beyond the CCSD(T) level by including a full treatment of triple excitations in order to fulfil the accuracy requirements. On the other hand, the reliability of density functional theory in properly treating open-shell systems has been further confirmed. PMID- 23802958 TI - Ultrafast dynamics in C 1s core-excited CF4 revealed by two-dimensional resonant Auger spectroscopy. AB - Following core excitation in an isolated molecule, ultrafast dissociation of one particular chemical bond can occur, where "ultrafast" is defined as taking place during the lifetime of the core hole, of the order of few femtoseconds. The signature of such phenomenon can be observed in resonant Auger spectra following core excitation. We present here an investigation of ultrafast dissociation following C 1s-to-sigma* core excitation in CF4, with high-resolution resonant Auger spectroscopy. We are able to characterize final states of both the molecular ion and the CF3 (+) fragment. We use two-dimensional (2D) maps to record resonant Auger spectra across the resonance as a function of photon energy and to characterize ultrafast dynamics. This method provides immediate visual evidence of one of the important characteristics of the study of spectral features related to molecular versus fragment ionic final states, and namely their dispersion law. In the 2D maps we are also able to identify the dissociation limit for one of the molecular final states. PMID- 23802959 TI - The photoelectron angular distribution of water clusters. AB - The angular distribution of photoelectrons emitted from water clusters has been measured by linearly polarized synchrotron radiation of 40 and 60 eV photon energy. Results are given for the three outermost valence orbitals. The emission patterns are found more isotropic than for isolated molecules. While a simple scattering model is able to explain most of the deviation from molecular behavior, some of our data also suggest an intrinsic change of the angular distribution parameter. The angular distribution function was mapped by rotating the axis of linear polarization of the synchrotron radiation. PMID- 23802960 TI - Theoretical explanation of the low-lying nu(6) vibrational fundamental of the FSO3 radical by the linear vibronic coupling approach. AB - The first attempt for a theoretical explanation of the nu6 fundamental energy levels of the fluorosulfate radical (FSO3) electronic ground state has been made. The vibronic interaction of the two lowest electronic states of the radical (X (2)A2 and A (2)E) has been taken into consideration in the basis of the linear vibronic coupling (LVC) approximation. The strengths of the intrastate and interstate vibronic couplings have been calculated within the framework of the Koppel, Domcke, and Cederbaum (KDC) model Hamiltonian. Already this simple KDC LVC model provides the nu6 fundamental energy, which is in very good agreement with the experimental results. From the inclusion of vibronic interactions such as the pseudo-Jahn-Teller and Jahn-Teller effects into the calculation of the fundamental energy of the nu6 mode, it can be said that mainly the interstate coupling with the electronic excited state E causes the unexpectedly low fundamental energy nu6 of the FSO3 radical. PMID- 23802961 TI - Quantum decoherence of I2 in liquid xenon: a classical Wigner approach. AB - Vibrational decoherence of a "breathing sphere" oscillator in a thermal Lennard Jones bath is examined using a classical analog approach. The equivalence between this approach and the linearized semiclassical initial value representation (IVR) is established and the method is exploited to produce a useful computational strategy that can efficiently evaluate the time dependence of the decoherence in these systems. A comparison between Harmonic and Morse "breathing sphere" models is presented and the rate of decoherence is found to depend on the choice of model, the initial state of the oscillator, the initial conditions of the bath (temperature, density), and the choice of quantity measuring the decoherence rate. The results are used to examine the utility of the Caldeira-Leggett model in this realistic system. PMID- 23802962 TI - Dissociative electron attachment to hexafluoroacetylacetone and its bidentate metal complexes M(hfac)2; M = Cu, Pd. AB - Beta-diketones are a versatile class of compounds that can complex almost any metal in the periodic table of elements. Their metal complexes are found to be fairly stable and generally have sufficient vapor pressure for deposition techniques requiring volatile metal sources. Motivated by the potential role of low energy electrons in focused electron beam induced deposition, we have carried out a crossed electron/molecular beam study on the dissociative electron attachment and non-dissociative electron attachment (NDEA) to hexafluoroacetylacetone (HFAc) and its bidentate metal complexes: bis hexafluoroacetylacetonate copper(II), Cu(hfac)2 and bis-hexafluoroacetylacetonate palladium(II), Pd(hfac)2. The relative ion yield curves for the native precursor to the ligand as well as its stable, 16 valence electron Pd(II) complex and open shell, 17 valence electron Cu(II) complex, are presented and compared. For HFAc, the loss of HF leads to the dominant anion observed, and while NDEA is only weakly pronounced for Pd(hfac)2 and loss of hfac(-) is the main dissociation channel, [Cu(hfac)2](-) formation from Cu(hfac)2 dominates. A comparison of the ion yield curves and the associated resonances gives insight into the role of the ligand in the attachment process and highlights the influence of the central metal atom. PMID- 23802963 TI - Intensity oscillations in the carbon 1s ionization cross sections of 2-butyne. AB - Carbon 1s photoelectron spectra for 2-butyne (CH3C=CCH3) measured in the photon energy range from threshold to 150 eV above threshold show oscillations in the intensity ratio C2,3/C1,4. Similar oscillations have been seen in chloroethanes, where the effect has been attributed to EXAFS-type scattering from the substituent chlorine atoms. In 2-butyne, however, there is no high-Z atom to provide a scattering center and, hence, oscillations of the magnitude observed are surprising. The results have been analyzed in terms of two different theoretical models: a density-functional model with B-spline atom-centered functions to represent the continuum electrons and a multiple-scattering model using muffin-tin potentials to represent the scattering centers. Both methods give a reasonable description of the energy dependence of the intensity ratios. PMID- 23802964 TI - Low-energy electron scattering from the aza-derivatives of pyrrole, furan, and thiophene. AB - We report elastic integral and differential cross sections for electron scattering from the aza-derivatives of pyrrole, furan, and thiophene, namely, pyrazole, imidazole, isoxazole, oxazole, isothiazole, and thiazole. The calculations were performed within the Schwinger multichannel method with pseudopotentials, with inclusion of static, exchange, and polarization interactions, for energies up to 10 eV. We found two pi* shape resonances and a high-lying sigma* shape resonance in each system. A sharp low-energy sigma* resonance was also identified in isothiazole and thiazole. Pyrazole and imidazole presented yet a broad low-lying sigma* resonance. The positions of the resonances agree very well with existing experimental results. We discuss the similarities and differences among the resonances of these compounds. PMID- 23802965 TI - Thermodynamic scaling of dynamics in polymer melts: predictions from the generalized entropy theory. AB - Many glass-forming fluids exhibit a remarkable thermodynamic scaling in which dynamic properties, such as the viscosity, the relaxation time, and the diffusion constant, can be described under different thermodynamic conditions in terms of a unique scaling function of the ratio rho(gamma)/T, where rho is the density, T is the temperature, and gamma is a material dependent constant. Interest in the scaling is also heightened because the exponent gamma enters prominently into considerations of the relative contributions to the dynamics from pressure effects (e.g., activation barriers) vs. volume effects (e.g., free volume). Although this scaling is clearly of great practical use, a molecular understanding of the scaling remains elusive. Providing this molecular understanding would greatly enhance the utility of the empirically observed scaling in assisting the rational design of materials by describing how controllable molecular factors, such as monomer structures, interactions, flexibility, etc., influence the scaling exponent gamma and, hence, the dynamics. Given the successes of the generalized entropy theory in elucidating the influence of molecular details on the universal properties of glass-forming polymers, this theory is extended here to investigate the thermodynamic scaling in polymer melts. The predictions of theory are in accord with the appearance of thermodynamic scaling for pressures not in excess of ~50 MPa. (The failure at higher pressures arises due to inherent limitations of a lattice model.) In line with arguments relating the magnitude of gamma to the steepness of the repulsive part of the intermolecular potential, the abrupt, square-well nature of the lattice model interactions lead, as expected, to much larger values of the scaling exponent. Nevertheless, the theory is employed to study how individual molecular parameters affect the scaling exponent in order to extract a molecular understanding of the information content contained in the exponent. The chain rigidity, cohesive energy, chain length, and the side group length are all found to significantly affect the magnitude of the scaling exponent, and the computed trends agree well with available experiments. The variations of gamma with these molecular parameters are explained by establishing a correlation between the computed molecular dependence of the scaling exponent and the fragility. Thus, the efficiency of packing the polymers is established as the universal physical mechanism determining both the fragility and the scaling exponent gamma. PMID- 23802966 TI - Critical asymmetry in renormalization group theory for fluids. AB - The renormalization-group (RG) approaches for fluids are employed to investigate critical asymmetry of vapour-liquid equilibrium (VLE) of fluids. Three different approaches based on RG theory for fluids are reviewed and compared. RG approaches are applied to various fluid systems: hard-core square-well fluids of variable ranges, hard-core Yukawa fluids, and square-well dimer fluids and modelling VLE of n-alkane molecules. Phase diagrams of simple model fluids and alkanes described by RG approaches are analyzed to assess the capability of describing the VLE critical asymmetry which is suggested in complete scaling theory. Results of thermodynamic properties obtained by RG theory for fluids agree with the simulation and experimental data. Coexistence diameters, which are smaller than the critical densities, are found in the RG descriptions of critical asymmetries of several fluids. Our calculation and analysis show that the approach coupling local free energy with White's RG iteration which aims to incorporate density fluctuations into free energy is not adequate for VLE critical asymmetry due to the inadequate order parameter and the local free energy functional used in the partition function. PMID- 23802967 TI - Common features of simple water models. AB - We compare three different simple models for water. They all show a phase behavior and anomalies that are characteristic of water. We compare these models and their features and evaluate the phase diagram, the density anomaly, and the liquid-liquid transition line. Additionally, we show that the characteristic behavior present in all three models can be deduced from the fact that all three models include three microscopic states for nearest neighbor configurations. We therefore propose an even simpler three-state model for water that still captures the phase transitions and the density anomaly. Finally, we show that this simple three-state model shows in fact all four possible scenarios discussed in the literature for the phase behavior of liquid water, if the parameters are adjusted accordingly. PMID- 23802968 TI - Equation of state and phase diagram of ammonia at high pressures from ab initio simulations. AB - We present an equation of state as well as a phase diagram of ammonia at high pressures and high temperatures derived from ab initio molecular dynamics simulations. The predicted phases of ammonia are characterized by analyzing diffusion coefficients and structural properties. Both the phase diagram and the subsequently computed Hugoniot curves are compared to experimental results. Furthermore, we discuss two methods that allow us to take into account nuclear quantum effects, which are of considerable importance in molecular fluids. Our data cover pressures up to 330 GPa and a temperature range from 500 K to 10,000 K. This regime is of great interest for interior models of the giant planets Uranus and Neptune, which contain, besides water and methane, significant amounts of ammonia. PMID- 23802969 TI - Molecular dynamics simulation of radiation damage in CaCd6 quasicrystal cubic approximant up to 10 keV. AB - Due to the peculiar nature of the atomic order in quasicrystals, examining phase transitions in this class of materials is of particular interest. Energetic particle irradiation can provide a way to modify the structure locally in a quasicrystal. To examine irradiation-induced phase transitions in quasicrystals on the atomic scale, we have carried out molecular dynamics simulations of collision cascades in CaCd6 quasicrystal cubic approximant with energies up to 10 keV at 0 and 300 K. The results show that the threshold energies depend surprisingly strongly on the local coordination environments. The energy dependence of stable defect formation exhibits a power-law dependence on cascade energy, and surviving defects are dominated by Cd interstitials and vacancies. Only a modest effect of temperature is observed on defect survival, while irradiation temperature increases lead to a slight increase in the average size of both vacancy clusters and interstitial clusters. PMID- 23802970 TI - Experimental and theoretical study of electronic structure of lutetium bi phthalocyanine. AB - Using Near Edge X-Ray Absorption Fine Structure (NEXAFS) Spectroscopy, the thickness dependent formation of Lutetium Phthalocyanine (LuPc2) films on a stepped passivated Si(100)2*1 reconstructed surface was studied. Density functional theory (DFT) calculations were employed to gain detailed insights into the electronic structure. Photoelectron spectroscopy measurements have not revealed any noticeable interaction of LuPc2 with the H-passivated Si surface. The presented study can be considered to give a comprehensive description of the LuPc2 molecular electronic structure. The DFT calculations reveal the interaction of the two molecular rings with each other and with the metallic center forming new kinds of orbitals in between the phthalocyanine rings, which allows to better understand the experimentally obtained NEXAFS results. PMID- 23802971 TI - Comparison of density functionals for nitrogen impurities in ZnO. AB - Hybrid functionals and empirical correction schemes are compared to conventional semi-local density functional theory (DFT) calculations in order to assess the predictive power of these methods concerning the formation energy and the charge transfer level of impurities in the wide-gap semiconductor ZnO. While the generalized gradient approximation fails to describe the electronic structure of the N impurity in ZnO correctly, methods that widen the band gap of ZnO by introducing additional non-local potentials yield the formation energy and charge transfer level of the impurity in reasonable agreement with hybrid functional calculations. Summarizing the results obtained with different methods, we corroborate earlier findings that the formation of substitutional N impurities at the oxygen site in ZnO from N atoms is most likely slightly endothermic under oxygen-rich preparation conditions, and introduces a deep level more than 1 eV above the valence band edge of ZnO. Moreover, the comparison of methods elucidates subtle differences in the predicted electronic structure, e.g., concerning the orientation of unoccupied orbitals in the crystal field and the stability of the charged triplet state of the N impurity. Further experimental or theoretical analysis of these features could provide useful tests for validating the performance of DFT methods in their application to defects in wide-gap materials. PMID- 23802972 TI - Dependence between velocity slip and temperature jump in shear flows. AB - In this paper, we investigate the dependence of coupled velocity slip (quantified by the slip length) and temperature jump (quantified by the Kapitza length) on solid-liquid bonding strength and shear rate in shear flows. We find that the interfacial behaviors of nano-confined liquid are distinctly different in the weak and strong solid-liquid interaction regimes identified by a threshold of beta = 2 (beta being the proportional factor of solid-liquid bonding strength). In the weak solid-liquid interaction regime, the liquid molecules adjacent to the surface of the wall are randomly distributed and are free to slip. The variations of the slip and Kapitza lengths against solid-liquid bonding strength and shear rate are regular and monotonic. In the strong solid-liquid interaction regime, the liquid molecules in the vicinity of the wall are in multi-layered ordering and are largely restricted. The slip length becomes multivalued with increasing solid-liquid bonding strength and shear rate, while the Kapitza length seems insensitive to these two parameters. Furthermore, we find that (1) the temperature jump monotonically increases with velocity slip in the weak solid liquid interaction regime, while it varies non-monotonically with a minimum value in the strong solid-liquid interaction regime; (2) the Kapitza length grows as a power function of the slip length in the weak solid-liquid interaction regime, while it keeps constant in the strong solid-liquid interaction regime. PMID- 23802973 TI - Phase transition in porous electrodes. III. For the case of a two component electrolyte. AB - The electrochemical thermodynamics of electrolytes in porous electrodes is qualitatively different from that in the bulk with planar electrodes when the pore size is comparable to the size of the electrolyte ions. In this paper, we discuss the thermodynamics of a two component electrolyte in a porous electrode by using Monte Carlo simulation. We show that electrolyte ions are selectively adsorbed in porous electrodes and the relative concentration of the two components significantly changes as a function of the applied voltage and the pore size. This selectivity is observed not only for the counterions but also for the coions. PMID- 23802974 TI - Direct measurements of forces between different charged colloidal particles and their prediction by the theory of Derjaguin, Landau, Verwey, and Overbeek (DLVO). AB - Force measurements between three types of latex particles of diameters down to 1 MUm with sulfate and carboxyl surface functionalities were carried out with the multi-particle colloidal probe technique. The experiments were performed in monovalent electrolyte up to concentrations of about 5 mM. The force profiles could be quantified with the theory of Derjaguin, Landau, Verwey, and Overbeek (DLVO) by invoking non-retarded van der Waals forces and the Poisson-Boltzmann description of double layer forces within the constant regulation approximation. The forces measured in the symmetric systems were used to extract particle and surface properties, namely, the Hamaker constant, surface potentials, and regulation parameters. The regulation parameter is found to be independent of solution composition. With these values at hand, the DLVO theory is capable to accurately predict the measured forces in the asymmetric systems down to distances of 2-3 nm without adjustable parameters. This success indicates that DLVO theory is highly reliable to quantify interaction forces in such systems. However, charge regulation effects are found to be important, and they must be considered to obtain correct description of the forces. The use of the classical constant charge or constant potential boundary conditions may lead to erroneous results. To make reliable predictions of the force profiles, the surface potentials must be extracted from direct force measurements too. For highly charged surfaces, the commonly used electrophoresis techniques are found to yield incorrect estimates of this quantity. PMID- 23802975 TI - Critical behavior of self-assembled rigid rods on two-dimensional lattices: Bethe Peierls approximation and Monte Carlo simulations. AB - The critical behavior of adsorbed monomers that reversibly polymerize into linear chains with restricted orientations relative to the substrate has been studied. In the model considered here, which is known as self-assembled rigid rods (SARRs) model, the surface is represented by a two-dimensional lattice and a continuous orientational transition occurs as a function of temperature and coverage. The phase diagrams were obtained for the square, triangular, and honeycomb lattices by means of Monte Carlo simulations and finite-size scaling analysis. The numerical results were compared with Bethe-Peierls analytical predictions about the orientational transition for the square and triangular lattices. The analysis of the phase diagrams, along with the behavior of the critical average rod lengths, showed that the critical properties of the model do not depend on the structure of the lattice at low temperatures (coverage), revealing a quasi-one dimensional behavior in this regime. Finally, the universality class of the SARRs model, which has been subject of controversy, has been revisited. PMID- 23802976 TI - Hydrogen termination of CVD diamond films by high-temperature annealing at atmospheric pressure. AB - A high-temperature procedure to hydrogenate diamond films using molecular hydrogen at atmospheric pressure was explored. Undoped and doped chemical vapour deposited (CVD) polycrystalline diamond films were treated according to our annealing method using a H2 gas flow down to ~50 ml/min (STP) at ~850 degrees C. The films were extensively evaluated by surface wettability, electron affinity, elemental composition, photoconductivity, and redox studies. In addition, electrografting experiments were performed. The surface characteristics as well as the optoelectronic and redox properties of the annealed films were found to be very similar to hydrogen plasma-treated films. Moreover, the presented method is compatible with atmospheric pressure and provides a low-cost solution to hydrogenate CVD diamond, which makes it interesting for industrial applications. The plausible mechanism for the hydrogen termination of CVD diamond films is based on the formation of surface carbon dangling bonds and carbon-carbon unsaturated bonds at the applied tempera-ture, which react with molecular hydrogen to produce a hydrogen-terminated surface. PMID- 23802977 TI - Unique water-water coordination tailored by a metal surface. AB - At low coverage of water on Cu(110), substrate-mediated electrostatics lead to zigzagging chains along [001] as observed with STM [T. Yamada, S. Tamamori, H. Okuyama, and T. Aruga, "Anisotropic water chain growth on Cu(110) observed with scanning tunneling microscopy" Phys. Rev. Lett. 96, 036105 (2006)]. Using x-ray absorption spectroscopy we find an anomalous low-energy resonance at ~533.1 eV which, based on density functional theory spectrum simulations, we assign to an unexpected configuration of water units whose uncoordinated O-H bonds directly face those of their neighbors; this interaction repeats over trough sites with enhanced electron density and is analogous to the case of a hydrated electron. PMID- 23802978 TI - Dynamics of capillary condensation in lattice gas models of confined fluids: a comparison of dynamic mean field theory with dynamic Monte Carlo simulations. AB - This article addresses the accuracy of a dynamic mean field theory (DMFT) for fluids in porous materials [P. A. Monson, J. Chem. Phys. 128, 084701 (2008)]. The theory is used to study the relaxation processes of fluids in pores driven by step changes made to a bulk reservoir in contact with the pore. We compare the results of the DMFT to those obtained by averaging over large numbers of dynamic Monte Carlo (DMC) simulation trajectories. The problem chosen for comparison is capillary condensation in slit pores, driven by step changes in the chemical potential in the bulk reservoir and involving a nucleation process via the formation of a liquid bridge. The principal difference between the DMFT results and DMC is the replacement of a distribution of nucleation times and location along the pore for the formation of liquid bridges by a single time and location. DMFT is seen to yield an otherwise qualitatively accurate description of the dynamic behavior. PMID- 23802979 TI - Anomalous viscosity effect in the early stages of the ion-assisted adhesion/fusion event between lipid bilayers: a theoretical and computational study. AB - The effect of viscosity on the encounter rate of two interacting membranes was investigated by combining a non-equilibrium Fokker-Planck model together with extensive Molecular Dynamics (MD) calculations. The encounter probability and stabilization of transient contact points represent the preliminary steps toward short-range adhesion and fusion of lipid leaflets. To strengthen our analytical model, we used a Coarse Grained MD method to follow the behavior of two charged palmitoyl oleoyl phosphatidylglycerol membranes embedded in a electrolyte containing box at different viscosity regimes. Solvent friction was modulated by varying the concentration of a neutral, water-soluble polymer, polyethylene glycol, while contact points were stabilized by divalent ions that form bridges among juxtaposed membranes. While a naive picture foresees a monotonous decrease of the membranes encounter rate with solvent viscosity, both the analytical model and MD simulations show a complex behavior. Under particular conditions, the encounter rate could exhibit a maximum at a critical viscosity value or for a critical concentration of bridging ions. These results seem to be confirmed by experimental observations taken from the literature. PMID- 23802980 TI - Nonlinear dynamics of spherical particles in Poiseuille flow under creeping-flow condition. AB - We study the nonlinear dynamics of spherical colloids under the influence of a pressure driven flow at vanishing Reynolds number. The colloids are confined between two parallel planar walls with a distance comparable to the particle diameter and they interact hydrodynamically via the solvent. We show that the bounded Poiseuille flow gives rise to new classes of trajectories resulting in cross-streamline migration. Two particles moving on these new trajectories exhibit either bound or unbound states. In the first case they oscillate on closed trajectories in the center-of-mass frame. In the second case, they exhibit cross-swapping trajectories in addition to swapping trajectories which were already observed in unbounded or bounded linear shear flow. The different classes of trajectories occur depending on the initial positions of the two particles and their size. We present state diagrams in the lateral positions, where we categorize the trajectories and color code the oscillation frequencies of the bound states. Finally we discuss how the results on the two-particle system help to understand the stability of particle trains composed of several particles. PMID- 23802981 TI - Wall-induced orientational order in athermal semidilute solutions of semiflexible polymers: Monte Carlo simulations of a lattice model. AB - An athermal solution of semiflexible macromolecules with excluded volume interactions has been studied at various concentrations (dilute, semidilute, and concentrated solutions) in a film of thickness D between two hard walls by grand canonical Monte Carlo simulations of the bond fluctuation lattice model. Analyzing profiles of orientational order parameters across the film, we find that for thick films two phase transitions occur at chemical potentials of the polymers (or polymer densities, respectively) where the bulk polymer solution still is in the disordered isotropic phase. At rather small polymer densities, polymers accumulate at the walls due to an entropic attraction and undergo a transition to two-dimensional nematic order. Due to the properties of the lattice model, this order has Ising character, and the simulation results seem to be compatible with a second-order transition. Increasing the polymer density, nematically ordered "wetting" layers form at both walls; the increase of thickness of these layers is compatible with a logarithmic divergence when the chemical potential of the isotropic-nematic transition in the bulk is approached. In a system of finite width, D, between the walls, this leads to capillary nematization, exhibiting a reduction of the transition chemical potential inversely proportional to D. This transition exists only if D exceeds some critical value Dc, while the transition from the isotropic phase to the two dimensional nematic state is suggested to persist down to ultrathin films. PMID- 23802982 TI - Dynamics of two-dimensional and quasi-two-dimensional polymers. AB - The dynamic properties of dense two-dimensional (2D) polymer melts are studied using discontinuous molecular dynamics simulations. Both strictly 2D and quasi-2D systems are investigated. The strictly 2D model system consists of a fluid of freely jointed tangent hard disc chains. The translational diffusion coefficient, D, is strongly system size dependent with D ~ ln L where L is the linear dimension of the square simulation cell. The rotational correlation time, taurot, is, however, independent of system size. The dynamics is consistent with Rouse behavior with D/ln L ~ N(-1) and taurot ~ N(2) for all area fractions. Analysis of the intermediate scattering function, Fs(k, t), shows that the dynamics becomes slow for N = 256 and the area fraction of 0.454 and that there might be a glass transition for long polymers at sufficiently high area fractions. The polymer mobility is not correlated with the conformation of the molecules. In the quasi-2D system hard sphere chains are confined between corrugated surfaces so that chains cannot go over each other or into the surfaces. The conformational properties are identical to the 2D case, but D and taurot are independent of system size. The scaling of D and taurot with N is similar to that of strictly 2D systems. The simulations suggest that 2D polymers are never entangled and follow Rouse dynamics at all densities. PMID- 23802983 TI - Effect of confinement on polymer-induced depletion interactions between nanoparticles. AB - Using a numerical implementation of polymer mean-field theory, we probe the effects of a structureless wall on the insertion free energies and the depletion interactions between nanoparticles in polymer solutions. Our results indicate that the insertion free energies and the polymer-induced interactions become mitigated in the presence of a wall. The range of influence of the walls is shown to correspond to the correlation length of the polymer solution. Surprisingly, our results demonstrate that even for particle sizes comparable to the correlation length of the polymer solution, the polymer depletion density profiles near the wall (in the absence of particles) can be used as a means to quantitatively predict the influence of the wall on both the insertion free energies and the depletion interactions. PMID- 23802984 TI - Reconstructing the free-energy landscape of Met-enkephalin using dihedral principal component analysis and well-tempered metadynamics. AB - Well-Tempered Metadynamics (WTmetaD) is an efficient method to enhance the reconstruction of the free-energy surface of proteins. WTmetaD guarantees a faster convergence in the long time limit in comparison with the standard metadynamics. It still suffers, however, from the same limitation, i.e., the non trivial choice of pertinent collective variables (CVs). To circumvent this problem, we couple WTmetaD with a set of CVs generated from a dihedral Principal Component Analysis (dPCA) on the Ramachandran dihedral angles describing the backbone structure of the protein. The dPCA provides a generic method to extract relevant CVs built from internal coordinates, and does not depend on the alignment to an arbitrarily chosen reference structure as usual in Cartesian PCA. We illustrate the robustness of this method in the case of a reference model protein, the small and very diffusive Met-enkephalin pentapeptide. We propose a justification a posteriori of the considered number of CVs necessary to bias the metadynamics simulation in terms of the one-dimensional free-energy profiles associated with Ramachandran dihedral angles along the amino-acid sequence. PMID- 23802985 TI - Change of caged dynamics at T(g) in hydrated proteins: trend of mean squared displacements after correcting for the methyl-group rotation contribution. AB - The question whether the dynamics of hydrated proteins changes with temperature on crossing the glass transition temperature like that found in conventional glassformers is an interesting one. Recently, we have shown that a change of temperature dependence of the mean square displacement (MSD) at Tg is present in proteins solvated with bioprotectants, such as sugars or glycerol with or without the addition of water, coexisting with the dynamic transition at a higher temperature Td. The dynamical change at Tg is similar to that in conventional glassformers at sufficiently short times and low enough temperatures, where molecules are mutually caged by the intermolecular potential. This is a general and fundamental property of glassformers which is always observed at or near Tg independent of the energy resolution of the spectrometer, and is also the basis of the dynamical change of solvated proteins at Tg. When proteins are solvated with bioprotectants they show higher Tg and Td than the proteins hydrated by water alone, due to the stabilizing action of excipients, thus the observation of the change of T-dependence of the MSD at Tg is unobstructed by the methyl-group rotation contribution at lower temperatures [S. Capaccioli, K. L. Ngai, S. Ancherbak, and A. Paciaroni, J. Phys. Chem. B 116, 1745 (2012)]. On the other hand, in the case of proteins hydrated by water alone unambiguous evidence of the break at Tg is hard to find, because of their lower Tg and Td. Notwithstanding, in this paper, we provide evidence for the change at Tg of the T-dependence of proteins hydrated by pure water. This evidence turns out from (i) neutron scattering experimental investigations where the sample has been manipulated by either full or partial deuteration to suppress the methyl-group rotation contribution, and (ii) neutron scattering experimental investigations where the energy resolution is such that only motions with characteristic times shorter than 15 ps can be sensed, thus shifting the onset of both the methyl-group rotation and the dynamic transition contribution to higher temperatures. We propose that, in general, coexistence of the break of the elastic intensity or the MSD at Tg with the dynamic transition at Td in hydrated and solvated proteins. Recognition of this fact helps to remove inconsistency and conundrum encountered in interpreting data of hydrated proteins that thwart progress in understanding the origin of the dynamic transition. PMID- 23802987 TI - Electron-induced degradation of 8-bromo-2'-deoxyadenosine 3',5'-diphosphate, a DNA radiosensitizing nucleotide. AB - The phosphodiester bond cleavage in 8-bromo-2'-deoxyadenosine 3',5'-diphosphate (BrdADP), as a model of electron induced single strand break (SSB) in labeled DNA, was investigated at the B3LYP/6-31++G(d,p) level of theory both in the gas phase and in water solution. Barrier-free and highly exergonic, especially in water solution (-2.83 eV), release of the bromide anion due to electron attachment confirms radiosensitizing properties of 8-bromoadenine. Thermodynamically (-19 kcal/mol) and kinetically (barrier of 10-13 kcal/mol) feasible hydrogen atom transfer from the C3' or C5' sites of the deoxyribose moiety to the C8 center of adenine radical is followed by a relatively low (14-18 kcal/mol) activation barrier O-P bond cleavage at either the 3'- or the 5'-site. The C5' radical may also stabilize via the formation of 5',8-cycloadenosine. The latter process has favorable thermodynamic and kinetic characteristics, which makes the O-P bond breakage at the 5'-site highly unlikely. Thus, the O-P cleavage reaction, being an equivalent of SSB in DNA labeled with 8-bromoadenine, should lead to the formation of cyclic ketone, which if identified in a radiolytic experiment, would confirm the mechanism proposed in the current study. PMID- 23802988 TI - Acceptability and adoption of handheld computer data collection for public health research in China: a case study. AB - BACKGROUND: Handheld computers for data collection (HCDC) and management have become increasingly common in health research. However, current knowledge about the use of HCDC in health research in China is very limited. In this study, we administered a survey to a hard-to-reach population in China using HCDC and assessed the acceptability and adoption of HCDC in China. METHODS: Handheld computers operating Windows Mobile and Questionnaire Development Studio (QDS) software (Nova Research Company) were used for this survey. Questions on tobacco use and susceptibility were drawn from the Global Adult Tobacco Survey (GATS) and other validated instruments, and these were programmed in Chinese characters by local staff. We conducted a half-day training session for survey supervisors and a three-day training session for 20 interviewers and 9 supervisors. After the training, all trainees completed a self-assessment of their skill level using HCDC. The main study was implemented in fall 2010 in 10 sites, with data managed centrally in Beijing. Study interviewers completed a post-survey evaluation questionnaire on the acceptability and utility of HCDC in survey research. RESULTS: Twenty-nine trainees completed post-training surveys, and 20 interviewers completed post-data collection questionnaires. After training, more than 90% felt confident about their ability to collect survey data using HCDC, to transfer study data from a handheld computer to a laptop, and to encrypt the survey data file. After data collection, 80% of the interviewers thought data collection and management were easy and 60% of staff felt confident they could solve problems they might encounter. Overall, after data collection, nearly 70% of interviewers reported that they would prefer to use handheld computers for future surveys. More than half (55%) felt the HCDC was a particularly useful data collection tool for studies conducted in China. CONCLUSIONS: We successfully conducted a health-related survey using HCDC. Using handheld computers for data collection was a feasible, acceptable, and preferred method by Chinese interviewers. Despite minor technical issues that occurred during data collection, HCDC is a promising methodology to be used in survey-based research in China. PMID- 23802989 TI - The effectiveness of problem solving therapy for stroke patients: study protocol for a pragmatic randomized controlled trial. AB - BACKGROUND: Coping style is one of the determinants of health-related quality of life after stroke. Stroke patients make less use of active problem-oriented coping styles than other brain damaged patients. Coping styles can be influenced by means of intervention. The primary aim of this study is to investigate if Problem Solving Therapy is an effective group intervention for improving coping style and health-related quality of life in stroke patients. The secondary aim is to determine the effect of Problem Solving Therapy on depression, social participation, health care consumption, and to determine the cost-effectiveness of the intervention. METHODS/DESIGN: We strive to include 200 stroke patients in the outpatient phase of rehabilitation treatment, using a multicenter pragmatic randomized controlled trial with one year follow-up. Patients in the intervention group will receive Problem Solving Therapy in addition to the standard rehabilitation program. The intervention will be provided in an open group design, with a continuous flow of patients. Primary outcome measures are coping style and health-related quality of life. Secondary outcome measures are depression, social participation, health care consumption, and the cost effectiveness of the intervention. DISCUSSION: We designed our study as close to the implementation in practice as possible, using a pragmatic randomized trial and open group design, to represent a realistic estimate of the effectiveness of the intervention. If effective, Problem Solving Therapy is an inexpensive, deliverable and sustainable group intervention for stroke rehabilitation programs. TRIAL REGISTRATION: Nederlands Trial Register, NTR2509. PMID- 23802990 TI - Bound to Succeed: transcription factor binding-site prediction and its contribution to understanding virulence and environmental adaptation in bacterial plant pathogens. AB - Bacterial plant pathogens rely on a battalion of transcription factors to fine tune their response to changing environmental conditions and to marshal the genetic resources required for successful pathogenesis. Prediction of transcription factor binding sites (TFBS) represents an important tool for elucidating regulatory networks and has been conducted in multiple genera of plant-pathogenic bacteria for the purpose of better understanding mechanisms of survival and pathogenesis. The major categories of TFBS that have been characterized are reviewed here, with emphasis on in silico methods used for site identification and challenges therein, their applicability to different types of sequence datasets, and insights into mechanisms of virulence and survival that have been gained through binding-site mapping. An improved strategy for establishing E-value cutoffs when using existing models to screen uncharacterized genomes is also discussed. PMID- 23802991 TI - Zantholic acid, a new monoterpenoid from Zanthoxylum zanthoxyloides. AB - From the extract of Zanthoxylum zanthoxyloides fruits, a new menthane monoterpenoid, (4R,7R)-8-carboxy-7,9-dihydroxy-trans-menthane, tentatively, named as zantholic acid along with several known compounds was isolated. Its structure was determined using spectroscopic methods. The cytotoxic activity of zantholic acid against a panel of cancer cell lines was evaluated using the MTT assay. The results show that zantholic acid possesses a selective cytotoxic activity towards breast cancer cell lines. PMID- 23802992 TI - Multiple fates of non-mature lumenal proteins in thylakoids. AB - Most proteins found in the thylakoid lumen are synthesized in the cytosol with an N-terminal extension consisting of transient signals for chloroplast import and thylakoid transfer in tandem. The thylakoid-transfer signal is required for protein sorting from the stroma to thylakoids, mainly via the cpSEC or cpTAT pathway, and is removed by the thylakoidal processing peptidase in the lumen. An Arabidopsis mutant lacking one of the thylakoidal processing peptidase homologs, Plsp1, contains plastids with anomalous thylakoids and is seedling-lethal. Furthermore, the mutant plastids accumulate two cpSEC substrates (PsbO and PetE) and one cpTAT substrate (PsbP) as intermediate forms. These properties of plsp1 null plastids suggest that complete maturation of lumenal proteins is a critical step for proper thylakoid assembly. Here we tested the effects of inhibition of thylakoid-transfer signal removal on protein targeting and accumulation by examining the localization of non-mature lumenal proteins in the Arabidopsis plsp1-null mutant and performing a protein import assay using pea chloroplasts. In plsp1-null plastids, the two cpSEC substrates were shown to be tightly associated with the membrane, while non-mature PsbP was found in the stroma. The import assay revealed that inhibition of thylakoid-transfer signal removal did not disrupt cpSEC- and cpTAT-dependent translocation, but prevented release of proteins from the membrane. Interestingly, non-mature PetE2 was quickly degraded under light, and unprocessed PsbO1 and PsbP1 were found in a 440-kDa complex and as a monomer, respectively. These results indicate that the cpTAT pathway may be disrupted in the plsp1-null mutant, and that there are multiple mechanisms to control unprocessed lumenal proteins in thylakoids. PMID- 23802993 TI - Diagnostic usefulness of findings in Doppler sonography for amelanotic melanoma. AB - To evaluate the diagnostic usefulness of Doppler sonography for amelanotic melanoma (AM), the correspondence between the findings of dermoscopy and Doppler sonography was investigated in AM in comparison with other hypopigmented tumors. Seven cases with AM and 11 cases with squamous cell carcinoma (SCC), 10 cases with non- or hypopigmented basal cell carcinoma (NP-BCC) and six cases with eccrine poroma (EP) as hypopigmented tumors were investigated. EP is readily recognized by differences from AM and SCC based on a single vertical and non torvtuous vessels. NP-BCC is distinguished from AM based on tortuosity running in a vertical direction. Though findings of tortuosity in vessels and heterogeneity of vessel size are recognized both in AM and SCC: (i) abundant blood flow was recognized more clearly in AM; (ii) total blood flow was more than 40% in most cases of AM (average, 60.9%); and (iii) more vessels which flow into a tumor are found in AM (85.7%). There is no relationship between dermoscopic findings of vessel types and Doppler sonography findings of vessels. In this study, the diagnostic usefulness of the above-mentioned specific findings in examination may suggest using Doppler sonography for AM as one non-invasive method. PMID- 23802986 TI - Antimicrobial strategies centered around reactive oxygen species--bactericidal antibiotics, photodynamic therapy, and beyond. AB - Reactive oxygen species (ROS) can attack a diverse range of targets to exert antimicrobial activity, which accounts for their versatility in mediating host defense against a broad range of pathogens. Most ROS are formed by the partial reduction in molecular oxygen. Four major ROS are recognized comprising superoxide (O2*-), hydrogen peroxide (H2O2), hydroxyl radical (*OH), and singlet oxygen ((1)O2), but they display very different kinetics and levels of activity. The effects of O2*- and H2O2 are less acute than those of *OH and (1)O2, because the former are much less reactive and can be detoxified by endogenous antioxidants (both enzymatic and nonenzymatic) that are induced by oxidative stress. In contrast, no enzyme can detoxify *OH or (1)O2, making them extremely toxic and acutely lethal. The present review will highlight the various methods of ROS formation and their mechanism of action. Antioxidant defenses against ROS in microbial cells and the use of ROS by antimicrobial host defense systems are covered. Antimicrobial approaches primarily utilizing ROS comprise both bactericidal antibiotics and nonpharmacological methods such as photodynamic therapy, titanium dioxide photocatalysis, cold plasma, and medicinal honey. A brief final section covers reactive nitrogen species and related therapeutics, such as acidified nitrite and nitric oxide-releasing nanoparticles. PMID- 23802994 TI - Membrane interface probe protocol for contaminants in low-permeability zones. AB - Accurate characterization of contaminant mass in zones of low hydraulic conductivity (low k) is essential for site management because this difficult-to treat mass can be a long-term secondary source. This study developed a protocol for the membrane interface probe (MIP) as a low-cost, rapid data-acquisition tool for qualitatively evaluating the location and relative distribution of mass in low-k zones. MIP operating parameters were varied systematically at high and low concentration locations at a contaminated site to evaluate the impact of the parameters on data quality relative to a detailed adjacent profile of soil concentrations. Evaluation of the relative location of maximum concentrations and the shape of the MIP vs. soil profiles led to a standard operating procedure (SOP) for the MIP to delineate contamination in low-k zones. This includes recommendations for: (1) preferred detector (ECD for low concentration zones, PID or ECD for higher concentration zones); (2) combining downlogged and uplogged data to reduce carryover; and (3) higher carrier gas flow rate in high concentration zones. Linear regression indicated scatter in all MIP-to-soil comparisons, including R(2) values using the SOP of 0.32 in the low concentration boring and 0.49 in the high concentration boring. In contrast, a control dataset with soil-to-soil correlations from borings 1-m apart exhibited an R(2) of >= 0.88, highlighting the uncertainty in predicting soil concentrations using MIP data. This study demonstrates that the MIP provides lower-precision contaminant distribution and heterogeneity data compared to more intensive high-resolution characterization methods. This is consistent with its use as a complementary screening tool. PMID- 23802995 TI - Cationic clathrate of type-III Ge(172-x)P(x)Te(y) (y ~ 21.5, x ~ 2y): synthesis, crystal structure and thermoelectric properties. AB - A first germanium-based cationic clathrate of type-III, Ge(129.3)P(42.7)Te(21.53), was synthesized and structurally characterized (space group P4(2)/mnm, a = 19.948(3) A, c = 10.440(2) A, Z = 1). In its crystal structure, germanium and phosphorus atoms form three types of polyhedral cages centered with Te atoms. The polyhedra share pentagonal and hexagonal faces to form a 3D framework. Despite the complexity of the crystal structure, the Ge(129.3)P(42.7)Te(21.53) composition corresponds to the Zintl counting scheme with a good accuracy. Ge(129.3)P(42.7)Te(21.53) demonstrates semiconducting/insulating behavior of electric resistivity, high positive Seebeck coefficient (500 MUV K(-1) at 300 K), and low thermal conductivity (<0.92 W m(-1) K(-1)) within the measured temperature range. PMID- 23802996 TI - Clinical effectiveness of percutaneous adhesiolysis and predictive factors of treatment efficacy in patients with lumbosacral spinal stenosis. AB - OBJECTIVE: Patients with lumbosacral spinal stenosis (LSS) do not always obtain satisfactory pain relief from transforaminal epidural steroid injection (TFESI) because perineural/epidural adhesions prevent the spread of injectate into the epidural space. Percutaneous adhesiolysis (PA) can eliminate the deleterious effects of adhesion. This study was to evaluate the effectiveness of PA among patients with LSS refractory to TFESI and to ascertain the prognostic factors determining PA efficacy. DESIGN: Retrospective study. SETTING: Spine hospital. SUBJECTS: Sixty-five patients with LSS refractory to TFESI who underwent PA with NaviCath(r) were reviewed. METHODS: We recorded Numeric Rating Scale for back pain (NRS back) and leg pain (NRS leg), and Oswestry Disability Index (ODI), at pretreatment, 2 weeks, and 3 months after treatment. Successful pain relief and functional improvement were described as a 50% and 40% or more reduction in NRS and ODI, respectively. Clinical data and radiological findings were obtained to assess the possible predictive factors for PA efficacy. RESULTS: Among the 65 patients, 45 (69.2%), 40 (61.5%), and 39 (60.0%) patients showed successful outcomes in NRS back, NRS leg, and ODI at 2 weeks, respectively. Among 63 patients who were followed up at 3 months, 34 (54.0%), 32 (50.8%), and 30 (47.6%) patients showed successful results, respectively. Spondylolisthesis, previous lumbar surgery, and foraminal stenosis were associated with a significantly higher proportion of unsuccessful result in NRS and ODI (%). CONCLUSION: PA may be a useful treatment in patients with LSS refractory to TFESI and reduce the surgical requirement. Previous surgery, spondylolisthesis, and foraminal stenosis may be associated with poor prognosis. PMID- 23802998 TI - Photolysis triggered sealing of multilayer capsules to entrap small molecules. AB - Novel microcapsule systems containing UV-responsive diazonium groups were fabricated as microcontainers for cargo substance encapsulation by using a layer by-layer (LbL) assembly technique. Upon direct exposure to UV light with a wavelength of approximately 380 nm, the diazonium groups of diazoresion (DAR) rapidly reacted with sulfonate or diazo-sulfonate groups of counterpart polyelectrolytes, which converted electrostatic interactions to covalent bonds, demonstrating an effective in situ cross-linking within multilayers via photolysis. Such chemical transition eliminated the paired ionic groups, therefore generating more hydrophobic multilayer shells, offering a unique approach to seal the porous polyelectrolyte capsule shells. Fluorescent molecule rhodamine B (RhB) was consequently studied as a typical example for small molecule encapsulation. Results indicated that the dye was remarkably retained within the microcapsules after UV-triggered capsule shell sealing. PMID- 23802997 TI - Risk of acute coronary events associated with glyburide compared with gliclazide use in patients with type 2 diabetes: a nested case-control study. AB - AIM: Sulfonylureas might increase the risk of adverse cardiovascular events; however, emerging evidence suggests there may be important differences amongst these drugs. Some, like glyburide, inhibit KATP channels in the heart and pancreas, while others, like gliclazide, are more likely to selectively inhibit KATP channels in the pancreas. We hypothesized that the risk of acute coronary syndrome (ACS) events would be higher in patients using glyburide compared with gliclazide. METHODS: This nested case-control study used administrative health data from Alberta, Canada. New users of glyburide or gliclazide aged >=66 years between 1998 and 2010 were included. Cases were individuals with an ACS-related hospitalization or death. Up to four controls were matched based on birth year, sex, cohort-entry year and follow-up time. Multivariable conditional logistic regression was used to estimate adjusted odds ratios (OR), controlling for baseline drug use and co-morbidities. RESULTS: Our cohort included 7441 gliclazide and 13 884 glyburide users; 51.4% men, mean (s.d.) age 75.5 (6.6) years and mean (s.d.) duration of follow-up 5.5 (4.0) years. A total of 4239 patients had an ACS-related hospitalization or death and were matched to 16 723 controls. Compared with gliclazide use, glyburide use was associated with a higher risk (adjusted OR 1.14; 95% CI 1.06-1.23) of ACS-related hospitalization or death over 5.5 years (number needed to harm: 50). CONCLUSION: In this observational study, glyburide use was associated with a 14% higher risk of ACS events compared with gliclazide use. Although the difference is small and probably to have implications at the population level rather than the individual patient or clinician, any causal inferences regarding sulfonylurea use and adverse cardiovascular risk should be tested in a large-scale randomized controlled trial. PMID- 23802999 TI - Resting-state functional magnetic resonance imaging analysis with seed definition constrained by regional homogeneity. AB - Researchers have recently focused their attention on the intrinsic functional connectivity (FC) in the brain using resting-state functional magnetic resonance imaging. Seed-based correlation analysis (SCAC), which correlates a predefined seed region with other voxels in the brain, is a common index for FC. However, definition of seed sizes and locations was ambiguous in previous studies and this may lead to spurious results for people with a unique functional anatomy. To address this issue, this study proposes a novel method (SCAReHo) that provides a data-driven seed selection (including sizes and locations) method by incorporating regional homogeneity (ReHo) in the SCAC method. The disparities between SCAC and SCAReHo methods among 12 healthy participants were evaluated in the FC of default mode network (DMN), task-positive network (TPN), and amygdala network. The SCAReHo method bypasses the seed-selection ambiguity and enhances the sensitivity in detecting FC of the DMN, TPN, and amygdala network. This study suggests that the SCAReHo method improves the sensitivity of FC analysis and reduces the uncertainty of seed selection. Thus, this method may be particularly useful for psychiatric and neurological investigations. PMID- 23803000 TI - Cross-cultural translation and measurement properties of the Polish version of the Knee injury and Osteoarthritis Outcome Score (KOOS) following anterior cruciate ligament reconstruction. AB - BACKGROUND: Knee Injury and Osteoarthritis Outcome Score (KOOS) is available in over 30 languages and a commonly used Patient-Reported Outcome (PRO) for assessment of treatment effects following knee surgery. The aim of the study was to report the linguistic translational process and evaluate the psychometric properties of the Polish version of the KOOS questionnaire. METHODS: We translated and culturally adapted the KOOS according to current guidelines for use in Poland. Patients who had undergone anterior cruciate ligament reconstruction (ACLR) completed the KOOS and Short Form 36 Health Survey (SF-36). We evaluated floor/ceiling effects, reliability (using Cronbach's alpha, intraclass correlation coefficients (ICC) and measurement error), convergent and divergent construct validity (using four a priori stated hypotheses) and responsiveness (using data obtained prior to and one year after ACLR and described by both effect size (ES) and standardized response mean (SRM)). RESULTS: The clinical study population consisted of 72 subjects (mean age 29.8, 28% women). We did not observe floor effects in any KOOS subscales neither pre- nor postoperatively. As expected, ceiling effects were found postoperatively for the subscales Pain and ADL in this cohort assessed on average 1.3 year after surgery as more than 15% reported no pain or limitations in daily activities. The Cronbach's alpha was above 0.9 for all subscales indicating excellent internal consistency. The test-retest reliability of all KOOS subscales at one-year postoperatively was excellent with ICCs exceeding 0.86 for all subscales. The minimal detectable change on group level ranged from 1.3 to 2.4, and on an individual level from 10.9 to 20.2. Responsiveness was demonstrated since the expected pattern of effect sizes between subscales following ACLR was found. CONCLUSIONS: We found the Polish version of the KOOS to be a valid and reliable instrument for use in patient groups having ACLR. We caution against monitoring individual patients since the smallest change considered clinically relevant cannot reliably be detected. PMID- 23803001 TI - GenPhyloData: realistic simulation of gene family evolution. AB - BACKGROUND: PrIME-GenPhyloData is a suite of tools for creating realistic simulated phylogenetic trees, in particular for families of homologous genes. It supports generation of trees based on a birth-death process and--perhaps more interestingly--also supports generation of gene family trees guided by a known (synthetic or biological) species tree while accounting for events such as gene duplication, gene loss, and lateral gene transfer (LGT). The suite also supports a wide range of branch rate models enabling relaxation of the molecular clock. RESULT: Simulated data created with PrIME-GenPhyloData can be used for benchmarking phylogenetic approaches, or for characterizing models or model parameters with respect to biological data. CONCLUSION: The concept of tree-in tree evolution can also be used to model, for instance, biogeography or host parasite co-evolution. PMID- 23803002 TI - Age-dependent effect of static magnetic field on brain tissue hydration. AB - Age-dependent effect of Static Magnetic Field (SMF) on rats in a condition of active and inactive Na(+)/K(+) pump was studied for comparison of brain tissues hydration state changes and magnetic sensitivity. Influence of 15 min 0, 2 Tesla (T) SMF on brain tissue hydration of three aged groups of male albino rats was studied. Tyrode's physiological solution and 10(-4) M ouabain was used for intraperitoneal injections. For animal immobilization, the liquid nitrogen was used and the definition of tissue water content was performed by tissue drying method. Initial water content in brain tissues of young animals is significantly higher than in those of adult and aged ones. SMF exposure leads to decrease of water content in brain tissues of young animals and increase in brain tissues of adult and aged ones. In case of ouabain-poisoned animals, SMF gives reversal effects on brain tissue's hydration both in young and aged animals, while no significant effect on adults is observed. It is suggested that initial state of tissue hydration could play a crucial role in animal age-dependent magnetic sensitivity and the main reason for this could be age-dependent dysfunction of Na(+)/K(+) pump. PMID- 23803003 TI - Insights into lomaiviticin biosynthesis. Isolation and structure elucidation of ( )-homoseongomycin. AB - The dimeric diazofluorenes known as the lomaiviticins are produced by the marine bacterium Salinispora pacifica DPJ-0019. Investigation of the fermentation broth of DPJ-0019 has yielded the first monomeric benzo[b]fluorene isolated from this species, (-)-homoseongomycin (13). (-)-Homoseongomycin (13) is related to the known natural product seongomycin (10), which is co-produced with the monomeric diazofluorenes known as the kinamycins. We describe the synthesis of the isotopically labeled derivative homoseongomycin-d5 (14), via the intermediacy of the diazofluorene "prelomaiviticin-d5" (12). Our studies establish that (-) homoseongomycin (13) may be derived from prelomaiviticin (11) and suggest that 13 and 10 are shunt or detoxification metabolites in lomaiviticin and kinamycin biosynthesis, respectively. PMID- 23803004 TI - Kininogen-dependent antiphosphatidylethanolamine antibodies and autoantibodies to factor XII in patients with recurrent pregnancy losses. AB - Factor XII, plasma prekallikrein and high-molecular-weight kininogen were first identified as coagulation proteins in the intrinsic pathway because patients deficient in these proteins had marked prolongation of in vitro surface-activated coagulation time. However, deficiencies of these proteins are not associated with clinical bleeding. Paradoxically, studies suggest that these proteins have anticoagulant and profibrinolytic activities. In fact, association between deficiencies of these proteins and thrombosis has been reported. Recently, autoantibodies to these proteins and antiphospholipid antibodies are frequent coagulation-related abnormalities found in unexplained recurrent aborters. Evidence has accumulated for the presence of the kallikrein-kininogen-kinin system in the fetoplacental unit. The contact system, or kallikrein-kininogen kinin system, in the reproductive tract plays an essential roll in the regulation of thrombosis, hemostasis, angiogenesis and in the defense against invasive bacterial infection. Autoantibodies to these proteins may be associated with pregnancy losses due to disruption of this system. These possibilities will be reviewed, the functions of the individual components will be summarized, and their role in blood coagulation and pregnancy discussed. PMID- 23803005 TI - Establishment of a new diagnostic method for hydropic villi by using TSSC3 antibody. AB - A total of 297 samples of hydropic villi were classified according to DNA polymorphisms as androgenetic moles, dispermic triploids, or biparental diploids. A subset of 267 appropriate samples was included in the study. Most of the macroscopically diagnosed complete mole cases were genetically androgenetic in origin. The partial mole cases consisted of 30 androgenetic moles and 12 dispermic triploids. For the 59 cases macroscopically categorized as hydropic abortion, the genetic analysis revealed 38 androgenetic moles, seven dispermic triploids and 14 biparental diploids. These results showed that a new diagnostic method was required for the management of patients with hydropic villi. We identified the TSSC imprint gene of which expression was shown in normal and partial mole villi but was silenced in complete mole villi. Immunohistochemistry using the TSSC3 antibody demonstrated its efficacy as the differential diagnostic method. TSSC3 play an important role in the differentiation from trophoblast stem cells to progenitors and/or labyrinth trophoblast through the TSSC3/PI3K/Akt/Mash2 signaling pathway. PMID- 23803006 TI - Amniotic fluid urocortin-1 concentrations for the prediction of preterm delivery. AB - AIM: The aim of this study was to analyze whether urocortin-1 concentration in midtrimester amniotic fluid could serve as an indicative marker of preterm labor. MATERIAL AND METHODS: A retrospective cohort study was conducted. Urocortin-1 concentrations in midtrimester amniotic fluid were measured in 22 pregnant women with preterm deliveries and 45 women who delivered at term using enzyme-linked immunosorbent assay. RESULTS: The median amniotic fluid urocortin-1 concentration was significantly lower in the women with preterm birth (40.06 pg/mL; range, 13.77-67.58 pg/mL) than in the women who gave birth at term (49.56 pg/mL; range, 26.25-175.9 pg/mL; P = 0.022). The result of receiver-operator curve analysis indicates that an amniotic fluid urocortin-1 concentration <= 57.88 pg/mL had an area under the curve of 0.673 (95% confidence interval, 0.55-0.78; P = 0.01) with a sensitivity of 81.8%, specificity of 40.0%, positive predictive value of 40%, and a negative predictive value of 82% in identifying which of the patients subsequently delivered prematurely. CONCLUSIONS: These results suggest that low urocortin-1 concentration in midtrimester amniotic fluid could be used as an indicative marker of preterm birth. PMID- 23803007 TI - Impact of new gestational diabetes mellitus criteria on stillbirth: a regional population-based study in Japan. AB - AIM: The aim of this study was to determine whether the new gestational diabetes mellitus (GDM) criteria increase the prevalence of diabetes-mellitus-related stillbirths by using a regional population-based approach. MATERIAL AND METHODS: A retrospective, population-based study was conducted to assess 114 036 deliveries from 2000 to 2010 in Miyazaki, Japan. During this period 318 stillbirths occurred after 22 weeks of gestation. Of these cases, 236 were examined to determine the cause of death. The remaining 82 cases were not fully investigated. In particular, we investigated the prevalence of pregestational diabetes mellitus and GDM among the stillbirths. We also applied new GDM criteria to evaluate the impact of these factors on stillbirth. RESULTS: Of the 236 stillbirths, 47% were due to an explainable cause. Application of previous criteria indicated two cases of pregestational diabetes mellitus and three GDM cases in the remaining unexplained stillbirths. By applying new GDM criteria, the GDM count increased to 17. CONCLUSIONS: In an unselected population in southern Japan, the application of new GDM criteria resulted in a 5.7-fold increase (from 2.4% [3/126] to 13.5% [17/126]) in the number of GDM cases in unexplained stillbirths. Even in women with a mild degree of GDM, proper management of both mother and fetus could reduce the number of unexplained stillbirths. PMID- 23803008 TI - Effects of bipolar electrocoagulation versus suture after laparoscopic excision of ovarian endometrioma on the ovarian reserve and outcome of in vitro fertilization. AB - AIM: The aim of this study was to assess the effect of coagulation versus suture used for hemostasis during laparoscopic excision of a unilateral endometrioma for outcome of in vitro fertilization (IVF). MATERIAL AND METHODS: This retrospective study was set in a university hospital. A total of 44 sterile patients underwent laparoscopic excision of a unilateral ovarian endometrioma. Bipolar electrocoagulation was performed for hemostasis in 21 patients and the remaining 23 patients underwent suturing. Samples of blood were taken on day 3 of menstruation before the operation. Serum levels of anti-Mullerian hormone, follicle-stimulating hormone and estradiol were measured. Number of antral follicles, follicular flushings, oocytes retrieved, and embryos were counted and the outcomes of IVF were recorded. RESULTS: No significant differences in the serum levels of any of the hormones were found between the pre- and postoperative samples, in either group. The mean antral follicle count, number of follicular flushings, oocytes retrieved and embryos obtained were significantly lower in the treated ovary as compared with the corresponding values in the contralateral intact ovary in the suture group. The pregnancy rates were similar in the two groups. CONCLUSIONS: There was no difference in the outcome of IVF between the two different methods of hemostasis. PMID- 23803009 TI - Effect of ovariectomy, 17-beta estradiol, and progesterone on histology and estrogen receptors of bladder in female partial bladder outlet obstruction rat model. AB - AIM: The aim of this study was to investigate the effect of bilateral ovariectomy (OVX), 17-beta estradiol (E2), and progesterone (P4) on the histology and estrogen receptor (ER) expression of the bladder using a female partial bladder outlet obstruction (pBOO) rat model. MATERIAL AND METHODS: A total of 60 female Sprague-Dawley rats were evenly assigned into six groups of 10 each. Group A served as the control. Groups B-F underwent induced pBOO. Groups C-F underwent OVX. Groups D-F were given E2 (0.1 mg/kg/day), Group E was given P4 (1 mg/kg/day), and Group F was given P4 and dehydroepiandrosterone (DHEA) (300 MUg/kg/day) by an Alzet pump. Four weeks later, serum E2 and P4 levels were evaluated. Each rat was anesthetized and the urinary bladder was removed for weighing and histological study. RESULTS: Expression of ER-beta was not significantly different between the control group and the other study groups. pBOO was shown to increase both bladder weight and detrusor muscle thickness. OVX had an additive effect to BOO on increased blood vessel density in the bladder. E2 was shown to increase blood vessel density, while P4 supplementation decreased blood vessel density. DHEA did not cause any significant effects on blood vessel density. CONCLUSION: Hormone therapy did not change the expression of ER in bladder outlet obstruction. Estradiol stimulated the increased angiogenesis of the bladder detrusor but P4 decreased the angiogenesis of the bladder detrusor. DHEA had no effect on the bladder detrusor. PMID- 23803010 TI - High levels of circulating CD34+/VEGFR3+ lymphatic/vascular endothelial progenitor cells is correlated with lymph node metastasis in patients with epithelial ovarian cancer. AB - AIM: Lymph node metastasis is one of the predictive factors associated with poor prognosis of epithelial ovarian cancer. To clarify the role of CD34 and vascular endothelial growth factor receptor-3-positive (CD34+/VEGFR3+) lymphatic/vascular endothelial progenitor cells (LVEPC) in patients with lymph node metastasis and epithelial ovarian cancer progression, the levels of circulating CD34+/VEGFR3+ LVEPC in epithelial ovarian cancer patients were detected. We also tested the plasma protein levels of VEGF and stromal cell-derived factor to find out their possible relationships with lymph node metastasis in our epithelial ovarian cancer cohort. MATERIAL AND METHODS: Peripheral blood samples were collected from 54 patients diagnosed as epithelial ovarian cancer, and 31 normal samples as control. The circulating levels of LVEPC were carried out by flow cytometry, and blood protein levels of biomarkers were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The level of circulating LVEPC was significantly higher in patients with ovarian cancer compared with that of healthy controls. There was also a statistically significant correlation between LVEPC levels and surgical staging of epithelial ovarian cancer (P < 0.01). CONCLUSION: The circulating levels of bone marrow-derived LVEPC are significantly increased in epithelial ovarian cancer patients and these levels correlate with lymph node metastasis too. PMID- 23803011 TI - Risk factor burden predicts long-term mortality after cerebral infarction. AB - OBJECTIVE: Previous studies have shown significant association between the number of traditional risk factors and long-term mortality of cerebral infarction in young stroke patients. The aim was to investigate risk factors separately and in sum in relation to long-term mortality after cerebral infarction, irrespective of age. MATERIALS AND METHODS: Long-term mortality in relation to number of traditional risk factors (angina pectoris, myocardial infarction, intermittent claudication, hypertension, diabetes mellitus, and smoking at the time of the index stroke) and etiology was studied in patients with acute cerebral infarction admitted to the Stroke Unit, Department of Neurology, Haukeland University Hospital, between February 2006 and February 2011. Only patients alive 30 days after stroke onset were included. Cox regression analyses were performed. RESULTS: After a mean follow-up time of 2.4 years, 14% with no risk factors had died, while the corresponding frequencies in patients with 1-3 or more risk factors were 13%, 19%, and 26%, respectively (P < 0.001). The number of risk factors was associated with mortality on Cox regression analysis (HR = 1.3, P < 0.001). CONCLUSION: Increasing number of traditional risk factors is associated with long-term mortality in patients with cerebral infarction, irrespective of age. Careful long-term follow-up is important, especially among patients with several risk factors. PMID- 23803013 TI - The predisposition to thyrotoxic periodic paralysis (TPP) is due to a genetic variant in the inward-rectifying potassium channel, KCNJ2. PMID- 23803012 TI - Accuracy of dialysis medical records in determining patients' interest in and suitability for transplantation. AB - BACKGROUND: We sought to determine the accuracy of dialysis medical records in identifying patients' interest in and suitability for transplantation. STUDY DESIGN: Cluster randomized controlled trial. SETTING AND PARTICIPANTS: A total of 167 patients recruited from 23 hemodialysis facilities. INTERVENTION: Navigators met with intervention patients to provide transplant information and assistance. Control patients continued to receive usual care. OUTCOMES: Agreement at study initiation between medical records and (i) patient self-reported interest in transplantation and (ii) study assessments of medical suitability for transplant referral. MEASUREMENTS: Medical record assessments, self-reports, and study assessments of patient's interest in and suitability for transplantation. RESULTS: There was disagreement between medical records and patient self-reported interest in transplantation for 66 (40%) of the 167 study patients. In most of these cases, patients reported being more interested in transplantation than their medical records indicated. The study team determined that all 92 intervention patients were medically suitable for transplant referral. However, for 38 (41%) intervention patients, medical records indicated that they were not suitable. About two-thirds of these patients successfully moved forward in the transplant process. CONCLUSION: Dialysis medical records are frequently inaccurate in determining patient's interest in and suitability for transplantation. PMID- 23803014 TI - Broth microdilution protocol for minimum inhibitory concentration (MIC) determinations of the intracellular salmonid pathogen Piscirickettsia salmonis to florfenicol and oxytetracycline. PMID- 23803015 TI - Delayed success of balloon dilation for coexisting pulmonary valve stenosis and sinotubular narrowing. AB - OBJECTIVES: We evaluated the outcomes of children at a single institution who underwent balloon pulmonary valvuloplasty (BPV) for coexisting pulmonary valve stenosis (PVS) and sinotubular narrowing (STN). BACKGROUND: BPV is the treatment of choice for PVS in children. Current practice favors surgical repair of moderate, severe, and symptomatic pulmonary stenosis when STN exists. This practice arose from lack of reduction in total pulmonary gradient (TPG) and frequent adverse events from BPV. METHODS: A retrospective analysis of outcomes in children with coexisting PVS and STN following BPV at a single institution was performed. RESULTS: Twenty-three patients were identified. Median age at BPV was 0.5 years (interquartile range (IQR) 0.3-2). Surgery was avoided in 15/23 (65%) (Group 1) and required in 8/23 (35%) (Group 2) following BPV. Group 1 had a mean baseline peak echo TPG of 60 mm Hg (+/-12) that decreased to 44 mm Hg (+/-10) following BPV (P < 0.01) and further to 21 mm Hg (+/-13) at 3.6 years (+/-2.2) following BPV (P < 0.01). Group 2 had a mean baseline peak echo TPG of 68 mm Hg (+/-17). TPG was unchanged by first echo after BPV at 56 mm Hg (+/-13) and just prior to surgery at 63 mm Hg (+/-15) (P > 0.10). CONCLUSIONS: BPV has minimal acute effect on PVS when STN exists; however; long-term benefits are achieved in most. BPV should be considered first-line therapy given its safety and effectiveness. Only those with worsening clinical signs and symptoms should be referred for surgical repair following BPV. PMID- 23803016 TI - Epithelial-mesenchymal transition and its role in the pathogenesis of colorectal cancer. AB - Epithelial-to-mesenchymal transition (EMT) is a collection of events that allows the conversion of adherent epithelial cells, tightly bound to each other within an organized tissue, into independent fibroblastic cells possessing migratory properties and the ability to invade the extracellular matrix. EMT contributes to the complex architecture of the embryo by permitting the progression of embryogenesis from a simple single-cell layer epithelium to a complex three dimensional organism composed of both epithelial and mesenchymal cells. However, in most tissues EMT is a developmentally restricted process and fully differentiated epithelia typically maintain their epithelial phenotype. Recently, elements of EMT, specially the loss of epithelial markers and the gain of mesenchymal markers, have been observed in pathological states, including epithelial cancers. Increasing evidence has confirmed its presence in human colon during colorectal carcinogenesis. In general, chronic inflammation is considered to be one of the causes of many human cancers including colorectal cancer(CRC). Accordingly, epidemiologic and clinical studies indicate that patients affected by ulcerative colitis and Crohn's disease, the two major forms of inflammatory bowel disease, have an increased risk of developing CRC. A large body of evidence supports roles for the SMAD/STAT3 signaling pathway, the NF-kB pathway, the Ras mitogen- activated protein kinase/Snail/Slug and microRNAs in the development of colorectal cancers via epithelial-to- mesenchymal transition. Thus, EMT appears to be closely involved in the pathogenesis of colorectal cancer, and analysis refered to it can yield novel targets for therapy. PMID- 23803017 TI - Oncogenesis and the clinical significance of K-ras in pancreatic adenocarcinoma. AB - The RAS family genes encode small GTP-binding cytoplasmic proteins. Activated KRAS engages multiple effector pathways, notably the RAF-mitogen-activated protein kinase, phosphoinositide-3-kinase (PI3K) and RalGDS pathways. In the clinical field, K-ras oncogene activation is frequently found in human cancers and thus may serve as a potential diagnostic marker for cancer cells in circulation. This mini-review aims to summarise information on Ras-induced oncogenesis and the clinical significance of K-ras. PMID- 23803018 TI - Phase II study on pemetrexed-based chemotherapy in treating patients with metastatic gastric cancer not responding to prior palliative chemotherapy. AB - PURPOSE: This study was to determine the efficacy and safety of pemetrexed based chemotherapy in treating patients with metastatic gastric cancer who failed to respond to first and (or) second line chemotherapy. PATIENTS AND METHODS: Metastatic gastric cancer patients who failed first and (or) second line chemotherapy, were enrolled. All patients were recruited from Jiangsu Cancer Hospital and Research Institute, and were treated with pemetrexed 500 mg/m2 (intravenous; on day 1), and a platinum (or irinotecan) every 3 weeks until disease progression, or intolerable toxicity. Evaluation on efficacy was conducted after two cycles of chemotherapy using the Response Evaluation Criteria for Solid Tumors. Toxicity was recorded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. RESULTS: From Jun 2011 to May 2013, 23 patients were enrolled. All eligible 23 patients completed at least 2 cycles of chemotherapy with pemetrexed based chemotherapy, and were evaluable. Their median age was 55 years (range 40 to 78 years). Seventeen patients were male and 6 female. Three patients (13%) achieved partial response, five patients (22%) stable, 15 patients (65%) with disease progression, and none with complete response. Grade 2 neutrophil suppression occurred in 4.3%, grade 3 in 13% of patients, and no grade 4 was reported. Thrombocytopenia was encountered as follows: 4.3% grade 2, 4.3% grade 3 and 4.3% grade 4. Incidence of anemia was 34.8% in grade 2, 8.7% grade 3 and 0% grade 4. Only 4.3% of patients required packed red blood cell infusion. Elevated transaminase were 4.3% in grade 2 and 0% in grade 3 or 4. Other toxicity included oral mucositis. CONCLUSIONS: Pemetrexed based chemotherapy is mildly effective in treating patients with metastatic gastric cancer with tolerable toxicity. PMID- 23803019 TI - Serum hepatitis a antibody positivity correlates with higher pancreas cancer mortality in adults: implications for hepatitis vaccination in high risk areas. AB - BACKGROUND: This study used pre-hepatitis A vaccination era data in U.S. to study the relationship between serum hepatitis A antibody positivity with pancreas cancer mortality in adults. PATIENTS AND METHODS: Public use National Health and Nutrition Examination Survey (NHANES III) data were employed. NHANES III uses complex probabilistic methods to sample nationally representative samples. Household adult laboratory and mortality data were merged. Sample persons who were available to be examined in the Mobile Examination Center (MEC) were included in this study. All results were obtained by using specialized survey software taking into account the primary sampling unit and stratification variables and the weights assigned to the sample persons examined in the MEC. Thus they are representative of the U.S. population. RESULTS: The mean risk (95%CI) of death in the study population for pancreas cancer was 0.0014 ( 0.000069 -.0029); their mean age (95%CI) at the mobile examination center (MXPAXTMR) was 473.43 (463.85-482.10); the follow up in months from their medical examination (permth_exm) was 170.12 (164.17-176.07). The odds ratios (S.E.) of the statistically significant univariables were: age, 1.007 (1.005-1.009); serum anti-hepatitis antibody status, 0.038 (0.004-0.376); and drinking hard liquor, 1.014 (1.004-1.023). The coefficients (S.E.) of the statistically significant variables after multivariate analysis were 0.006 (0.002-0.010) for age and -2.528 (-4.945--0.111) for serum anti-hepatitis A antibody negativity (using serum anti hepatitis A antibody positivity as a reference). CONCLUSION: Serum hepatitis A antibody positivity correlates with higher pancreas cancer mortality in adults. PMID- 23803020 TI - Cyclin D1, retinoblastoma and p16 protein expression in carcinoma of the gallbladder. AB - BACKGROUND: Cancer of the gallbladder is a relatively rare neoplasm with a poor prognosis. The exact mechanisms of its genesis are not known and very little information is available on molecular events leading to labeling this as an orphan cancer. MATERIALS AND METHODS: In this prospective case control study we evaluated the expression of p16, pRb and cyclin D1 by immunohistochemistry to study the G1-S cell-cycle check point and its possible role in gallbladder carcinogenesis. A total of 25 patients with gallbladder carcinoma (group I), 25 with cholelithiasis (group II) and 10 normal controls. were enrolled. RESULTS: Cyclin D1 expression was seen in 10 (40%) patients each with carcinoma and cholelithiasis while only in 2 (20%) of the normal gallbladders but differences were not statistically significant (p value=0.488). p16 was expressed in 12% patients of carcinoma of the gallbladder and 28% of cholelithiasis, however this difference was not statistically significant (p value=0.095). Retinoblastoma protein was found to be expressed in 50% of normal gallbladders and 6 (24%) of carcinoma and 8 (32%) of gallstones. The present study failed to demonstrate any conclusive role of cyclin D1/RB/ p16 pathway in carcinoma of the gallbladder. CONCLUSIONS: The positive relation observed between tumor metastasis and cyclinD1 expression and p16 with nodal metastasis suggested that higher cyclin D1/p16 expression may act as a predictive biomarker for aggressive behavior of gallbladder malignancies. PMID- 23803021 TI - Suggestion for a new grading scale for radiation induced pneumonitis based on radiological findings of computerized tomography: correlation with clinical and radiotherapeutic parameters in lung cancer patients. AB - BACKGROUND: The objective of this research is the computed axial tomography (CT) imaging grading of radiation induced pneumonitis (RP) and its correlation with clinical and radiotherapeutic parameters. MATERIALS AND METHODS: The chest CT films of 20 patients with non-small cell lung cancer who have undergone three- dimensional conformal radiation therapy were reviewed. The proposed CT grading of RP is supported on solely radiological diagnosis criteria and distinguishes five grades. The manifestation of RP was also correlated with any positive pre existing chronic obstructive pulmonary disease (COPD) history, smoking history, the FEV1 value, and the dosimetric variable V20. RESULTS: The CT grading of RP was as follows: 3 patients (15%) presented with ground glass opacity (grade 1), 9 patients (45%) were classified as grade 2, 7 patients (35%) presented with focal consolidation, with or without elements of fibrosis (grade 3), and only one patient (5%) presented with opacity with accompanying atelectasis and loss of pulmonary volume (grade 4). Both univariate and multivariate analysis revealed as prognostic factors for the radiological grading of RP the reduction of FEV1 and the V20 (P=0.026 and P=0.003, respectively). There was also a significant (P<0.001) correlation of radiological grading of RP with FEV1 and V20 (spearman rho 0.92 and 0.93, respectively). CONCLUSIONS: The high correlation of the proposed radiological grading with the FEV1 and the V20 is giving a satisfactory clinical validity. Although the proposed grading scale seems relevant to clinical practice, further studies are needed for the confirmation of its validity and reliability. PMID- 23803022 TI - Hospital outpatients are satisfactory for case-control studies on cancer and diet in China: a comparison of population versus hospital controls. AB - BACKGROUND: To investigate the internal validity of a food-frequency questionnaire (FFQ) developed for use in Chinese women and to compare habitual dietary intakes between population and hospital controls measured by the FFQ. MATERIALS AND METHODS: A quantitative FFQ and a short food habit questionnaire (SFHQ) were developed and adapted for cancer and nutritional studies. Habitual dietary intakes were assessed in 814 Chinese women aged 18-81 years (407 outpatients and 407 population controls) by face-to-face interview using the FFQ in Shenyang, Northeast China in 2009-2010. The Goldberg formula (ratio of energy intake to basal metabolic rate, EI/BMR) was used to assess the validity of the FFQ. Correlation analyses compared the SFHQ variables with those of the quantitative FFQ. Differences in dietary intakes between hospital and population controls were investigated. Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained using conditional logistic regression analyses. RESULTS: The partial correlation coefficients were moderate to high (0.42 to 0.80; all p<0.05) for preserved food intake, fat consumption and tea drinking variables between the SFHQ and the FFQ. The average EI/BMR was 1.93 with 88.5% of subjects exceeding the Goldberg cut-off value of 1.35. Hospital controls were comparable to population controls in consumption of 17 measured food groups and mean daily intakes of energy and selected nutrients. CONCLUSIONS: The FFQ had reasonable validity to measure habitual dietary intakes of Chinese women. Hospital outpatients provide a satisfactory control group for food consumption and intakes of energy and nutrients measured by the FFQ in a Chinese hospital setting. PMID- 23803023 TI - Translation and validation of the activities of daily living scale with Iranian elderly cancer patients treated in an oncology unit. AB - BACKGROUND: This study evaluated the validity and reliability of applying the Katz's Activities of Daily Living (ADL) scale in an Iranian sample of elderly oncologic patients following initial cancer treatment. MATERIALS AND METHODS: The scale was translated with the forward-backward procedure to give an Iranian version. The ADL scale was then applied in a random sample of 400 oncologic patients aged 60 and older following initial cancer treatment. Assessment of the scale stability was twice, with a 14-days (two weeks) interval, to 30 (of the 400) eligible elderly cancer patients in March 2012. To measure treatment effects, the index was run with 150 patients in a three month recall, following oncology processing. Exploratory and confirmatory factor analysis was performed for assessment of construct validity of the Katz's ADL. Reliability was measured with internal consistency (Cronbach's alpha co-efficient), and test/retest (Spearman's r value) of the instrument. Criterion validity was evaluated by comparing the Katz with Physical Function (PF) subscale of SF 36. Known-group validity was approved by comparing of Katz' ADL between quartile groups of PF subscale of SF 36. RESULTS: In our study the ADL demonstrated a high degree of internal homogeneity (Cronbach's alpha 0.923). There was a high correlation between scores of two time measurement of Katz's ADL (p value of two- related- samples test was 0.3). Construct validity showed a correlation coefficient of 0.572 between the ADL and PF scores. In factor analysis, 2 factors were extracted. Evidence for the reliability of the questionnaire was good and known group validity was approved by significant differences of ADL score between quartiles of the PF subscale of SF36. CONCLUSIONS: The results suggest that the Iranian version of ADL applied for oncologic older adult patients following initial cancer treatment is a reliable and a valid clinical instrument and comparable to those reported in other studies. PMID- 23803024 TI - Neuroblastoma in Iran: an experience of 32 years at a referral childrens hospital. AB - BACKGROUND: This survey aim was to evaluate the epidemiology and outcomes of neuroblastoma patients in one the most important children referral hospitals in Iran as a model from developing countries. MATERIALS AND METHODS: This retrospective, non-randomized analytic study was conducted on 219 newly diagnosed neuroblastoma cases. RESULTS: The age of patients ranged from 1-156 months with the average of 40.5+/-2.44, with a male/female ratio of 1.9/1. Of the total, 172 (78.5%) were children and 47 (21.5%) were infants The adrenals were the most common primary site (60%). Stage 4 at diagnosis accounted for about 54% of all enrolled patients. Infants had significantly better cumulative survival (85+/-8%) than children (33+/-7%) during the follow up period and the survival rate improved from 33+/-7% in 1974-1994 to 58+/-9% in 1995-2005. CONCLUSIONS: This study indicates that our patient population with neuroblastomas tends to have more advanced disease, perhaps with poor biologic markers, but our analysis shows that the outcomes have improved over 32 years although the overall survival of Iranian neuroblastoma patients is still lower than developed countries. Late diagnosis, inability to determine risk group during the years of study and using single protocol for all enrolled patients can be the reasons of lower survival rate. PMID- 23803025 TI - Comprehensive mutation analysis of PIK3CA, p14ARF, p16INK4a and p21Waf1/Cip1 genes is suggestive of a non- neoplastic nature of phenytoin induced gingival overgrowth. AB - BACKGROUND: Dilantin sodium (phenytoin) is an antiepileptic drug, which is routinely used to control generalized tonic clonic seizure and partial seizure episodes. A few case reports of oral squamous cell carcinomas arising from regions of phenytoin induced gingival overgrowth (GO), and overexpression of mitogenic factors and p53 have presented this condition as a pathology with potential to transform into malignancy. We recently investigated the genetic status of p53 and H-ras, which are known to be frequently mutated in Indian oral carcinomas in GO tissues and found them to only contain wild type sequences, which suggested a non-neoplastic nature of phenytoin induced GO. However, besides p53 and H-ras, other oncogenes and tumor suppressors such as PIK3CA, p14ARF, p16INK4a and p21Waf1/Cip1, are frequently altered in oral squamous cell carcinoma, and hence are required to be analyzed in phenytoin induced GO tissues to be affirmative of its non-neoplastic nature. METHODS: 100ng of chromosomal DNA isolated from twenty gingival overgrowth tissues were amplified with primers for exons 9 and 20 of PIK3CA, exons 1alpha, 1beta and 2 of p16INK4a and p14ARF, and exon 2 of p21Waf1/Cip1, in independent reactions. PCR amplicons were subsequently gel purified and eluted products were sequenced. RESULTS: Sequencing analysis of the twenty samples of phenytoin induced gingival growth showed no mutations in the analyzed exons of PIK3CA, p14ARF, p16INK4a and p21Waf1/Cip1. CONCLUSION: The present data indicate that the mutational alterations of genes, PIK3CA, p14ARF, p16INK4a and p21Waf1/Cip1 that are frequently mutated in oral squamous cell carcinomas are rare in phenytoin induced gingival growth. Thus the findings provide further evidence that phenytoin induced gingival overgrowth as a non neoplastic lesion, which may be considered as clinically significant given the fact that the epileptic patients are routinely administered with phenytoin for the rest of their lives to control seizure episodes. PMID- 23803026 TI - Dietary phytochemical index and the risk of breast cancer: a case control study in a population of Iranian women. AB - In this study we assessed the dietary phytochemical index in relation to the risk of breast cancer in women. This case-control study was conducted on 100 incident breast cancer cases and 175 healthy controls. Data regarding socio-demographic factors, medical history, medications, and anthropometric measurements were collected. Dietary data were obtained using a validated food frequency questionnaire and a energy-adjusted dietary phytochemical index (PI) was calculated. The odds ratios of breast cancer were assessed across energy- adjusted PI quartile categories. The mean age of participants was 46.2+/-8.9 and 45.9+/-9.4 years in cases and controls, respectively. The mean PI across quartile categories was 13.9+/-2.6, 21.1+/-1.8, 26.7+/-2.1, 41.6+/-10.2 in the first, second, third and fourth quartiles, respectively. After adjustment for all potential confounders, the risk of breast cancer in the forth quartile of dietary PI was significantly decreased (OR=0.08, 95%CI=0.01-0.84). Higher intake of phytochemical-rich foods is associated with lower risk of breast cancer. PMID- 23803027 TI - Meta-analysis of associations of the ezrin gene with human osteosarcoma response to chemotherapy and prognosis. AB - Various studies examining the relationship between Ezrin overexpression and response to chemotherapy and clinical outcome in patients with osteosarcoma have yielded inconclusive results. We accordingly conducted a meta-analysis of 7 studies (n = 318 patients) that evaluated the correlation between Ezrin and histologic response to chemotherapy and clinical prognosis (death). Data were synthesized in receiver operating characteristic curves and with fixed-effects and random-effects likelihood ratios and risk ratios. Quantitative synthesis showed that Ezrin is not a prognostic factor for the response to chemotherapy. The positive likelihood ratio was 0.538 (95% confidence interval [95% CI], 0.296- 0.979; random-effects calculation), and the negative likelihood ratio was 2.151 (95% CI, 0.905- 5.114; random-effects calculations). There was some between-study heterogeneity, but no study showed strong discriminating ability. Conversely, Ezrin positive status tended to be associated with a lower 2-year survival (risk ratio, 2.45; 95% CI, 1.26-4.76; random-effects calculation) with some between study heterogeneity that disappeared when only studies that employed immunohistochemistry were considered (risk ratio, 2.97; 95% CI, 2.01- 4.40; fixed effects calculation). To conclude, Ezrin is not associated with the histologic response to chemotherapy in patients with osteosarcoma, whereas Ezrin positivity was associated with a lower 2-year survival rate regarding risk of death at 2 years. Expression change of Ezrin is an independent prognostic factor in patients with osteosarcoma. PMID- 23803028 TI - Ischemia modified albumin levels and oxidative stress in patients with bladder cancer. AB - BACKGROUND: Impaired oxidative/antioxidative status plays an important role in the pathogenesis of many diseases like cancer. The aim of this study was to evaluate the levels of the novel marker ischemia modified albumin (IMA) and albumin adjusted-IMA (Adj-IMA) in patients with bladder cancer (BC) as well as its association with total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI). MATERIALS AND METHODS: Forty male patients with BC (mean age, 67.4+/-12 years) and forty age-sex matched healthy persons (mean age 56.0+/-1.7 years) were included in this study. Serum levels of IMA, TAS, TOS were analyzed and Adj- IMA and OSI was calculated. RESULTS: Serum IMA, TOS and OSI values were significantly higher in patients with BC compared to controls (p<0.0001, p=0.01 and p=0.01, respectively), whereas TAS was significantly lower in BC patients (p=0.04). There was no significant difference for serum albumin adjusted IMA levels between groups (p=0.4). CONCLUSIONS: In this study, it was found that there was an impaired oxidative/antioxidant status in favor of oxidative stress in BC patients. This observation was not confirmed by Adj-IMA calculation. There is no published report about serum concentrations of IMA in patients with BC. Further studies are needed to establish the relationship of IMA and oxidative stress parameters in BC and the significance of IMA to other cancers. PMID- 23803029 TI - Correlation between magnifying narrow-band imaging endoscopy results and organoid differentiation indicated by cancer cell differentiation and its distribution in depressed- type early gastric carcinoma. AB - BACKGROUND: A close association between patterns identified by magnifying narrow band imaging (M-NBI) and histological type has been described. M-NBI patterns were also recently reported to be related to the mucin phenotype; however, detials remain unclear. MATERIALS AND METHODS: We investigated the cellular differentiation of gastric cancer lesions, along with their mucosal distribution observed by M-NBI. Ninety-seven depressed-type early gastric cancer lesions (74 differentiated and 23 undifferentiated adenocarcinomas) were visualized by M-NBI. Findings were divided into 4 patterns based on abnormal microvascular architecture: a chain loop pattern (CLP), a fine network pattern (FNP), a corkscrew pattern (CSP), and an unclassified pattern. Mucin phenotypes were judged as gastric (G-type), intestinal (I-type), mixed gastric and intestinal (M type), and null (N-type) based on 4 markers (MAC5AC, MUC6, MUC2, and CD10). The relationship of each pattern of microvascular architecture with organoid differentiation indicated by cancer cell differentiation and its distribution in each histological type of early gastric cancer was investigated. RESULTS: All CLP and FNP lesions were differentiated. The cancer cell distribution showed organoid differentiation in 84.2% (16/19) and 61.1% (22/36) of the two types of lesions, respectively, and there was a significant difference from the unclassified pattern with organoid differentiation (p<0.001). Almost all (94.7%; 18/19) CSP lesions were undifferentiated, and organoid differentiation was observed in 72.2% (13/18). There was a significant difference from the unclassified pattern with organoid differentiation (p<0.05). CONCLUSIONS: Cellular differentiation and distribution are associated with microvascular architecture observed by M-NBI. PMID- 23803030 TI - Evaluation of quality of life of breast cancer patient next- of-kin in Turkey. AB - INTRODUCTION: Quality of life (QoL) issues are of importance in relatives of women with breast cancer (BC)as caregivers in neglecting their own needs due to care of a patient and also as women regarding the potential risk of themselves developing BC. The objectives in the present study were to compare the QoL of female relatives of women in treatment for breast cancer. To date, no study had examined multi-dimensional QoL in accompanying people as compared them into two groups of female relatives whose first degree and second degree. METHODS: QoL of female relatives was assessed using the Quality of Life-Family Version (QOL-FV) scale. Relationships between socio-demographic characteristics and QoL scores were analyzed using the Mann-Whitney U, Kruskal Wallis and Crosstabs tests. RESULTS: The mean age of the female relatives was 37.6 years, and nearly 48% had a university education. It was found that first degree relatives had worse QoL in all domains except physical well- being than second degree relatives. CONCLUSION: This study showed that being female relatives of BC, especially first-degree, affect QoL negatively. Health care providers are of an important role in the stage of information related to genetic influence of BC. PMID- 23803031 TI - Assessment of a questionnaire for breast cancer case-control studies. AB - The aim of the present study was to assess criterion validity and external reliability of a questionnaire on risk factors for breast cancer. Materials and Methods. Women with breast cancer diagnosis (the cases) (N=40) and matched individuals without cancer (the controls) (N=40) were asked to fill in a questionnaire twice: on a day of admission to hospital (Q1) and on a day before discharge (Q2), with a time interval of 4-6 days. The questionnaire included questions (N=150) on demographic and socioeconomic factors, diseases in the past, family history of cancer, woman's health, smoking, alcohol use, diet, physical activity, and work environment. Criterion validity of the questionnaire Q2 relative to reference questionnaire Q1 was assessed with the Spearman correlation coefficient (SCC); external reliability of the questionnaire was measured in terms of the intraclass correlation coefficient (ICC). Statistical analysis was performed with SPSS 16. Results. The responses to most of the questions on socioeconomic factors, family history on cancer, female health, lifestyle risk factors (smoking, alcohol use, physical activity) correlated substantially in both the cases and the controls with SCC and ICC>0.7 (p<0.01). Statistically non significant relationships defined only between the responses on amount of beer the cases drank at the ages up to 25 years and 26-35 years as well as time of use of estrogen and estrogens-progestin during menopause by the cases. Moderate and substantial SCC and ICC were determined for different food items. Only the response of the cases on veal consumption did not correlate significantly. Conclusions. The questionnaire on breast cancer risk factors is valid and reliable for most of the questions included. PMID- 23803032 TI - Cancer risk from medical radiation procedures for coronary artery disease: a nationwide population-based cohort study. AB - To assess the risk of cancer incidence after medical radiation exposure for coronary artery disease (CAD), a retrospective cohort study was conducted based on Taiwan's National Health Insurance Research Database (NHIRD). Patients with CAD were identified according to the International Classification of Diseases code, 9th Revision, Clinical Modification (ICD-9-CM), and their records of medical radiation procedures were collected from 1997 to 2010. A total of 18,697 subjects with radiation exposure from cardiac imaging or therapeutic procedures for CAD were enrolled, and 19,109 subjects receiving cardiac diagnostic procedures without radiation were adopted as the control group. The distributions of age and gender were similar between the two populations. Cancer risks were evaluated by age-adjusted incidence rate ratio (aIRR) and association with cumulative exposure were further evaluated with relative risks by Poisson regression analysis. A total of 954 and 885 subjects with various types of cancers in both cohorts after following up for over 10 years were found, with incidences of 409.8 and 388.0 per 100,000 person-years, respectively. The risk of breast cancer (aIRR=1.85, 95% confidence interval: 1.14-3.00) was significantly elevated in the exposed female subjects, but no significant cancer risk was found in the exposed males. In addition, cancer risks of the breast and lung were increased with the exposure level. The study suggests that radiation exposure from cardiac imaging or therapeutic procedures for CAD may be associated with the increased risk of breast and lung cancers in CAD patients. PMID- 23803033 TI - Application of stem cells in targeted therapy of breast cancer: a systematic review. AB - BACKGROUND: The aim of this systematic review was to investigate whether stem cells could be effectively applied in targeted therapy of breast cancer. MATERIAL AND METHOD: A systematic literature search was performed for original articles published from January 2007 until May 2012. RESULTS: Nine studies met the inclusion criteria for phase I or II clinical trials, of which three used stem cells as vehicles, two trials used autologous hematopoetic stem cells and in four trials cancer stem cells were targeted. Mesenchymal stem cells (MSCs) were applied as cellular vehicles to transfer therapeutic agents. Cell therapy with MSC can successfully target resistant cancers. Cancer stem cells were selectively targeted via a proteasome-dependent suicide gene leading to tumor regression. Wnt/beta-catenin signaling pathway has been also evidenced to be an attractive CSC-target. CONCLUSIONS: This systematic review focused on two different concepts of stem cells and breast cancer marking a turning point in the trials that applied stem cells as cellular vehicles for targeted delivery therapy as well as CSC-targeted therapies. Applying stem cells as targeted therapy could be an effective therapeutic approach for treatment of breast cancer in the clinic and in therapeutic marketing; however this needs to be confirmed with further clinical investigations. PMID- 23803034 TI - Association of ABO blood group and risk of lung cancer in a multicenter study in Turkey. AB - BACKGROUND: The ABO blood groups and Rh factor may affect the risk of lung cancer. MATERIALS AND METHODS: We analyzed 2,044 lung cancer patients with serologically confirmed ABO/Rh blood group. A group of 3,022,883 healthy blood donors of Turkish Red Crescent was identified as a control group. We compared the distributions of ABO/Rh blood group between them. RESULTS: The median age was 62 years (range: 17-90). There was a clear male predominance (84% vs. 16%). Overall distributions of ABO blood groups were significantly different between patients and controls (p=0.01). There were also significant differences between patients and controls with respect to Rh positive vs. Rh negative (p=0.04) and O vs. non-O (p=0.002). There were no statistically significant differences of blood groups with respect to sex, age, or histology. CONCLUSIONS: In the study population, ABO blood types were associated with the lung cancer. Having non-O blood type and Rh negative feature increased the risk of lung cancer. However, further prospective studies are necessary to define the mechanisms by which ABO blood type may influence the lung cancer risk. PMID- 23803035 TI - High cytoplasmic expression of the orphan nuclear receptor NR4A2 predicts poor survival in nasopharyngeal carcinoma. AB - OBJECTIVE: This study aimed at investigating whether the orphan nuclear receptor NR4A2 is significantly associated with clinicopathologic features and overall survival of patients with nasopharyngeal carcinoma (NPC). METHODS: Immunohistochemistry was performed to determine NR4A2 protein expression in 84 NPC tissues and 20 non-cancerous nasopharyngeal (NP) tissues. The prognostic significance of NR4A2 protein expression was evaluated using Cox proportional hazards regression models and Kaplan-Meier survival analysis. RESULTS: We did not find a significant association between total NR4A2 expression and clinicopathological variables in 84 patients with NPC. However, we observed that high cytoplasmic expression of NR4A2 was significantly associated with tumor size (T classification) (P = 0.006), lymph node metastasis (N classification) (P = 0.002) and clinical stage (P = 0.017). Patients with higher cytoplasmic NR4A2 expression had a significantly lower survival rate than those with lower cytoplasmic NR4A2 expression (P = 0.004). Multivariate Cox regression analysis analysis suggested that the level of cytoplasmic NR4A2 expression was an independent prognostic indicator for overall survival of patients with NPC (P = 0.033). CONCLUSIONS: High cytoplasmic expression of NR4A2 is a potential unfavorable prognostic factor for patients with NPC. PMID- 23803036 TI - Insights into smoking and its cessation among current smokers in India. AB - BACKGROUND: Initiation, perpetuation and cessation of smoking are all multifactorial. It is essential to explore interactions among various parameters influencing smoking and its cessation for effective smoking cessation interventions. OBJECTIVES: To obtain insights into smoking and its cessation among current smokers in India. MATERIALS AND METHODS: The present study was conducted among current smokers visiting the Department of Oral Medicine and Radiology, Manipal College of Dental Sciences (MCODS), Manipal University, Mangalore. Knowledge, attitudes, behavior, worksite practices towards smoking and its cessation, barriers to smoking cessation and socio-demographic variables were explored using a structured, pretested, self-administered questionnaire. RESULTS: A total of 175 current smokers participated in the study. Mean knowledge, attitude, worksite practice and barrier scores were 15.2+/-5.67 (66.1%), 57.5+/ 7.67(82.1%), 4.18+/-2.02 (41.8%) and 57.4+/-12.37 (63.7%) respectively. Correlation analysis revealed: association of knowledge with education, occupation and religion; attitude with education and occupation; worksite practices with occupation; knowledge with attitude; and barriers negatively with worksite practices. The majority (85.7%) of respondents intended to quit smoking and this was associated with higher attitude scores, whereas actual quit attempts were associated with high knowledge, attitudes, worksite practices and low barrier scores. CONCLUSIONS: Various socio-demographic factors associated with smoking and its cessation were identified. The present study highlights the importance of identifying and targeting these interactions while framing guidelines and interventions for effective tobacco cessation in a developing country like India. PMID- 23803037 TI - Effects of femara and tamoxifen on proliferation of FM3A cells in culture. AB - In this study, antiproliferative effects of the selective estrogen receptor modulator Tamoxifen and the aromatase inhibitor letrozole (Femara) were evaluated and compared using the FM3A cell line, originating from a C3H mouse mammary carcinoma and positive in terms of estrogen receptor (ER) expression. Cell kinetic parameters including labelling index, mitotic index and labelling index were assessed after exposure of the. FM3A cell line to 0.001MUg/ml of Tamoxifen and 0.25MUg/ml of Femara for 4, 8, 16 and 32 h for all parameters. The results showed that cell growth was inhibited by both agents. There was a significant decrease in labelling index and mitotic index and significant increase in apoptotic index for all experimental groups. The differences between control and all experimental groups were statistically significant (p<0.001) for all applications. PMID- 23803038 TI - Hopelessness, depression and social support with end of life Turkish cancer patients. AB - BACKGROUND: This study was performed to evaluate relationships between different demographic variables and hopelessness and depression in end of life Turkish cancer patients. This study was a descriptive survey with repeated measures conducted a university hospital in the city of Erzurum, in the eastern part of Turkey. The study enrolled 216 patients undergoing palliative treatment at the hospital. MATERIALS AND METHODS: Data were collected using questionnaires (demographic questionnaire, Beck Hopelessness Scale (BHS), Beck Depression Scale (BDS) and analyzed for demographic and disease-related variable effects on hopelessness and depression. RESULTS: Th hopelessness score was significantly high in female, illiterate, married, and living in rural areas cancer patients. Both hopelessness and depression scores were significantly higher with longer disease duration, receiving radiotherapy treatment, and having metastatic disease. CONCLUSIONS: These findings demonstrate the coexistence of the physical, psychological, and cognitive problems faced by patients with cancer. Nurses can conduct brief screening assessments to identify patients with probable distress and and psychosocial support, as well as referrals to support services. PMID- 23803039 TI - Clinical audit in radiation oncology: results from one academic centre in Delhi, India. AB - The objective was to analyze the radiotherapy (RT) practice at the cancer centre of a tertiary academic medical institution in Delhi. This audit from an Indian public institution covered patient care processes related to cancer diagnosis, integration of RT with other anti-cancer modalities, waiting time, overall treatment time, and compliance with RT. Over a period of one year, all consecutively registered patients in radiotherapy were analyzed for the audit cycle. Analysis of 1,030 patients showed median age of 49.6 years, with presentation as stage I and II in 14.2%, stage III and IV in 71.2% and unknown stage in 14.6%. A total of 974 (95%) were advised for RT appointment; 669 (68.6%) for curative intent and 31.4% for palliation. Mean times for diagnostic workup and from registration at cancer centre to radiotherapy referral were 33 and 31 days respectively. Median waiting time to start of RT course was 41 days. Overall RT compliance was 75% and overall duration for a curative RT course ranged from 50 days to 61 days. Non-completion and interruption of RT course were observed in 12% and 13% respectively. Radiotherapy machine burden in a public cancer hospital in India increases the waiting time and 25% of advised patients do not comply with the prescribed treatment. Infrastructure, machine and manpower constraints lead to more patients being treated on cobalt (74%) and by two-dimensional (78%) techniques. PMID- 23803040 TI - Prostate cancer screening in a healthy population cohort in eastern Nepal: an explanatory trial study. AB - BACKGROUND: Prostate cancer features a substantial incidence and mortality burden, similarly to breast cancer, and it ranks among the top ten specific causes of death in males. OBJECTIVE: To explore the situation of prostate cancer in a healthy population cohort in Eastern Nepal. MATERIALS AND METHODS: This study was conducted in the Department of General Surgery at B. P. Koirala Institute of Health Sciences, Dharan, Nepal from July 2010 to June 2011. Males above 50 years visiting the Surgical Outpatient Department in BPKIHS were enrolled in the study and screening camps were organized in four Teaching District Hospitals of BPKIHS, all in Eastern Nepal. Digital rectal examination (DRE) was conducted by trained professionals after collecting blood for assessment of serum prostatic specific antigen (PSA). Trucut biopsies were performed for all individuals with abnormal PSA/DRE findings. RESULTS: A total of 1,521 males more than 50 years of age were assessed and screened after meeting the inclusion criteria. The vast majority of individuals, 1,452 (96.2%), had PSA <=4.0 ng/ml. Abnormal PSA (>4 ng/ml) was found in 58 (3.8%). Abnormal DRE was found in 26 (1.72%). DRE and PSA were both abnormal in 26 (1.72%) individuals. On the basis of raised PSA or abnormal DRE 58 (3.84%) individuals were subjected to digitally guided trucut biopsy. Biopsy report revealed benign prostatic hyperplasia in 47 (3.11%) and adenocarcinoma prostate in 11 (0.73%). The specificity of DRE was 66.0%with a sensitivity of 90.9% and a positive predictive value of 38.5%. The sensitivity of PSA more than 4ng/ml in detecting carcinoma prostate was 100% and the positive predictive value for serum PSA was 19.0% CONCLUSIONS: The overall cancer detection rate in this study was 0.73% and those detected were locally advanced. Larger community-based studies are highly warranted specially among high-risk groups. PMID- 23803041 TI - Effects of microRNA-106 on proliferation of gastric cancer cell through regulating p21 and E2F5. AB - OBJECTIVE: To investigate the effects of miR-106b on malignant characteristics of gastric cancer cells, and explore possible mechanisms. METHODS: Expression of miR 106b, p21 and E2F was determined by real-time PCR. Transfection with miR-106b mimics was conducted, and gastric cancer cells with miR-106b overexpression were obtained. Cells transfected with mimic mutants and those without transfection served as negative and blank controls, respectively. Flow cytometry and transwell assays were adopted to detect the effects of miR-106b overexpression on cell cycle, migration and invasion of gastric cancer cells. RESULTS: . The expression of miR- 106b in gastric cancer cells was significantly higher than that in normal gastric mucosa cells. Furthermore, the expression level of miR-106b rose according to the degree of malignacy among the three GC cell strains (MKN- 45 > SGC-7901 > MKN-28). Overexpression of miR-106b shortened the G0/G1 phase and accelerated cell cycle progression, while reducing p21 and E2F5, without any significant effects on the capacity for migration and invasion of gastric cancer cells. CONCLUSIONS: miR-106b may promote cell cycling of gastric cancer cells through regulation of p21 and E2F5 target gene expression. PMID- 23803042 TI - Change in adiponectin and oxidative stress after modifiable lifestyle interventions in breast cancer cases. AB - BACKGROUND: Breast cancer is one of the most frequent diseases in women today. Little information exists on modifiable lifestyle factors including effects of ginger supplements (as an anti-oxidant and anti-inflammatory herbal) and water based exercise on biomarkers related to oxidative stress such as malondialdehyde (MDA), nitric oxide (NO) and glutathione peroxidase (GPx) and adiponectin in obese women with breast cancer. The aim of this study was to determine the single and concomitant effect of 6-wks water-based exercise and oral ginger supplement on the aforesaid markers in obese women with breast cancer. MATERIALS AND METHODS: Forty women diagnosed with breast cancer (48 +/- 5.4 years, 76 +/- 9 kg, fat mass 41.8 +/- 4%), volunteered to participate in the study. Subjects were randomly assigned into four groups; placebo, water-based exercise, ginger supplement and water-based exercise+ginger supplement groups. Subjects in the ginger supplement group and the water-based exercise+ginger supplement group orally received 4 capsules (each capsule contained 750 mg), 7 days a week for 6 weeks. The water-based exercise program featured progressive increase in intensity and time, ranging from 50% to 75% of heart rate reserve, in a pool with 15 meters width, 4 times a week for 6 weeks. Fasting blood samples were collected at pre-test and post-test time points. RESULTS: The ginger supplementation and or the water-base exercise resulted in an increase of adiponectin, NO and GPx and reduction MDA, as compared to pre-test values. However, the combined intervention (water-base exercise and ginger supplement) group showed significantly a far better effect on the biomarkers related to oxidative stress and adiponectin levels, as compared to the water- base exercise or ginger supplement alone groups and the age-matched placebo group. CONCLUSIONS: Our results revealed that water base exercise is a non-drug therapeutic strategy to reduce systemic stress in obese women suffering from breast cancer. Further, ginger supplementation alone or in combination with training, also play an important role in the pathogenesis of oxidative stress in obese women diagnosed with breast cancer. PMID- 23803043 TI - Expression and clinical significance of REPS2 in human esophageal squamous cell carcinoma. AB - OBJECTIVE: REPS2 plays important roles in inhibiting cell proliferation, migration and in inducing apoptosis of cancer cells, now being identified as a useful biomarker for favorable prognosis in prostate and breast cancers. The purpose of this study was to assess REPS2 expression and to explore its role in esophageal squamous cell carcinoma (ESCC). METHODS: Protein expression of REPS2 in ESCCs and adjacent non-cancerous tissues from 120 patients was analyzed by immunohistochemistry and correlated with clinicopathological parameters and patient outcome. Additionally, thirty paired ESCC tissues and four ESCC cell lines and one normal human esophageal epithelial cell line were evaluated for REPS2 mRNA and protein expression levels by quantitative RT-PCR and Western blotting. RESULTS: REPS2 mRNA and protein expression levels were down-regulated in ESCC tissues and cell lines. Low protein levels were significantly associated with primary tumour, TNM stage, lymph node metastasis and recurrence (all, P < 0.05). Survival analysis demonstrated that decreased REPS2 expression was significantly associated with shorter overall survival and disease-free survival (both, P < 0.001), especially in early stage ESCC patients. When REPS2 expression and lymph node metastasis status were combined, patients with low REPS2 expression/lymph node (+) had both poorer overall and disease-free survival than others (both, P < 0.001). Cox multivariate regression analysis further revealed REPS2 to be an independent prognostic factor for ESCC patients. CONCLUSIONS: Our findings demonstrate that downregulation of REPS2 may contribute to malignant progression of ESCC and represent a novel prognostic marker and a potential therapeutic target for ESCC patients. PMID- 23803044 TI - Ellagic acid inhibits migration and invasion by prostate cancer cell lines. AB - Polyphenolic compounds from pomegranate fruit extracts (PFEs) have been reported to possess antiproliferative, pro-apoptotic, anti-inflammatory and anti-invasion effects in prostate and other cancers. However, the mechanisms responsible for the inhibition of cancer invasion remain to be clarified. In the present study, we investigated anti-invasive effects of ellagic acid (EA) in androgen independent human (PC-3) and rat (PLS10) prostate cancer cell lines in vitro. The results indicated that non-toxic concentrations of EA significantly inhibited the motility and invasion of cells examined in migration and invasion assays. The EA treatment slightly decreased secretion of matrix metalloproteinase (MMP)-2 but not MMP-9 from both cell lines. We further found that EA significantly reduced proteolytic activity of collagenase/gelatinase secreted from the PLS-10 cell line. Collagenase IV activity was also concentration-dependently inhibited by EA. These results demonstrated that EA has an ability to inhibit invasive potential of prostate cancer cells through action on protease activity. PMID- 23803045 TI - The KIF1B (rs17401966) single nucleotide polymorphism is not associated with the development of HBV-related hepatocellular carcinoma in Thai patients. AB - Hepatitis B virus (HBV) infection can become chronic and if left untreated can progress to hepatocellular carcinoma (HCC).Thailand is endemic for HBV and HCC is one of the top five cancers, causing deaths among Thai HBV-infected males. A single nucleotide polymorphism (SNP) at the KIF1B gene locus, rs17401966, has been shown to be strongly associated with the development of HBV-related HCC. However, there are no Thai data on genotypic distribution and allele frequencies of rs17401966. Thai HBV patients seropositive for HBsAg (n=398) were therefore divided into two groups: a case group (chronic HBV with HCC; n=202) and a control group (HBV carriers without HCC; n=196). rs17401966 was amplified by polymerase chain reaction (PCR) and analyzed by direct nucleotide sequencing. The genotypic distribution of rs174019660 for homozygous major genotype (AA), heterozygous minor genotype (AG) and homozygous minor genotype (GG) in the case group was 49.5% (n=100), 40.1% (n=81) and 10.4% (n=21), respectively, and in controls was 49.5% (n=97), 42.3% (n=83) and 8.2% (n=16). Binary logistic regression showed that rs17401966 was not statistically associated with the risk of HCC development in Thai chronic HBV patients (p-value=0.998, OR=1.00 and 95% CI=0.68-1.48). In conclusion, the KIF1B gene SNP (rs174019660) investigated in this study showed no significant association with HBV-related HCC in Thai patients infected with HBV, indicating that there must be other mechanisms or pathways involved in the development of HCC. PMID- 23803046 TI - Video-assisted thoracoscopic surgery for treatment of early- stage non-small cell lung cancer. AB - OBJECTIVES: To evaluate the safety, efficacy, and invasiveness of lobectomy by video-assisted thoracoscopic surgery (VATS) in the treatment of stage I/II non small cell lung cancer (NSCLC). METHODS: A total of 148 patients presenting with Stage I or II NSCLC were enrolled into our study, comprising 71 who underwent VATS and 77 patients undergoing conventional thoracotomic lobectomy, in combination with systematic lymph node resection. RESULTS: It was found that VATS was superior to conventional thoracotomy in terms of the duration of surgery, intraoperative blood loss, frequency of the need to administer postoperative analgesia, thoracic intubation indwelling time, post-operative hospital stay, and survival rate (P<0.05). We saw no obvious difference in the number of resected lymph nodes with either approach. CONCLUSIONS: VATS lobectomy is a safe and reliable surgical approach for the treatment of Stage I/II NSCLC, characterized by significantly minimal invasiveness, rapid post-operative recovery, and markedly lower loss of blood. PMID- 23803047 TI - Differences in epidermal growth factor receptor gene mutations and relationship with clinicopathological features in NSCLC between Uygur and Han ethnic groups. AB - OBJECTIVE: To investigate differences in mutations of epidermal growth factor receptor (EGFR) gene and relationships with clinicopathological features in patients with non-small cell lung cancer (NSCLC) between Uygur and Han ethnic groups. METHODS: The Scorpions amplification refractory mutation system (Scorpions ARMS) was used to measure mutations in exons 18, 19, 20 and 21 of the EGFR gene in paraffin-embedded tumor tissue from NSCLC cases, and statistical analysis was performed to investigate links with clinicopathological features in different histological types of NSCLC. RESULTS: Results from ARMS testing showed EGFR mutations in tumor tissues from six (6) of 50 NSCLC patients of Uygur ethnic group, with a positive rate of 12.0%; four of them (4) had exon 19 deletion in EGFR, and two (2) had L858R point mutation in exon 21 of EGFR. Statistically significant difference was noted in EGFR genetic mutation between adenocarcinoma and non-adenocarcinoma (P < 0.05), but no differences with gender, age group, smoking status, or stage (P > 0.05). EGFR mutations were detected in tumor tissues from 27 of 49 NSCLC patients of Han ethnic group , with a positive rate of 55.1%; 19 of them had exon 19 deletions, seven (7) had L858R point mutations in exon 21 of EGFR and one (1) had mutations in both exon 18 G719X and exon 20 T790M of EGFR. Statistically significant differences were noted in EGFR genetic mutations between genders and between adenocarcinoma and non-adenocarcinoma (P<0.05), but not with age group, smoking status, or stage (P > 0.05). CONCLUSION: Statistically significant differences were noted in the positive rates of EGFR genetic mutations in NSCLC patients between Uygur and Han ethnic groups, with lower positive rates for the Uygur cases. PMID- 23803048 TI - Apoptosis induction in human leukemic promyelocytic HL-60 and monocytic U937 cell lines by goniothalamin. AB - Goniothalamin is an active compound extracted from Goniothalamus griffithii, a local plant found in northern Thailand. Goniothalamin inhibits cancer cell growth but is also toxic to normal cells. The aims of this study were to identify the cytotoxic effect of goniothalamin and the mechanism of cell death in human HL-60 and U937 cells. Cytotoxicity was determined by MTT assay and cell cycle profiles were demonstrated by staining with propidium iodide (PI) and flow cytometry. Apoptosis was confirmed by staining with annexin V-FITC/propidium iodide (PI) and flow cytometry. Reduction of mitochondrial transmembrane potential was determined by staining with dihexyloxacarbocyanine iodide and flow cytometry and expression of Smac, caspase-8 and -9 was demonstrated by Western blotting. Goniothalamin inhibited growth of HL-60 and U937 cell lines. An increase of SubG1 phase was found in their cell cycle profiles, indicating apoptosis as the mode of cell death. Apoptosis was confirmed by the flip-flop of phosphatidylserine using annexin V-FITC/PI assay in HL60 and U937 cells in a dose response manner. Furthermore, reduction of mitochondrial transmembrane potential was found in both cell types while expression of caspase-8, -9 and Smac/Diablo was increased in HL 60 cells. Taken together, our results indicate that goniothalamin-treated human leukemic cells undergo apoptosis via intrinsic and extrinsic pathways. PMID- 23803049 TI - Multiple approaches and participation rate for a community based smoking cessation intervention trial in rural Kerala, India. AB - BACKGROUND: To illustrate multiple approaches and to assess participation rates adopted for a community based smoking cessation intervention programme in rural Kerala. MATERIALS AND METHODS: Resident males in the age group 18-60 years who were 'current daily smokers' from 4 randomly allocated community development blocks of rural Thiruvananthapuram district, Kerala (2 intervention and 2 control groups) were selected. Smoking status was assessed through house-to-house survey using trained volunteers. Multiple approaches included awareness on tobacco hazards during baseline survey and distribution of multicolour anti-tobacco leaflets for intervention and control groups. Further, the intervention group received a tobacco cessation booklet and four sessions of counselling which included a one-time group counselling cum medical camp, followed by proactive counselling through face-to-face (FTF) interview and mobile phone. In the second and fourth session, motivational counselling was conducted. RESULTS: Among 928 smokers identified, smokers in intervention and control groups numbered 474 (mean age: 44.6 years, SD: 9.66 years) and 454 respectively (44.5 years, SD: 10.30 years). Among the 474 subjects, 75 (16%) had attended the group counselling cum medical camp after completion of baseline survey in the intervention group, Among the remaining subjects (n=399), 88% were contacted through FTF and mobile phone (8.5%). In the second session (4-6 weeks time period), the response rate for individual counselling was 94% (78% through FTF and 16% through mobile phone). At 3 months, 70.4% were contacted by their mobile phone and further, 19.6% through FTF (total 90%) while at 6 months (fourth session), the response rate was 74% and 16.4% for FTF and mobile phone respectively, covering 90.4% of the total subjects. Overall, in the intervention group, 97.4% of subjects were being contacted at least once and individual counselling given. CONCLUSION: Proactive community centred intervention programmes using multiple approaches were found to be successful to increase the participation rate for intervention. PMID- 23803050 TI - A population-based case-control study on risk factors for gastric cardia cancer in rural areas of Linzhou. AB - Gastric cancer is the second most common cause of cancer-related deaths in the world. Although certain dietary factors and lifestyles have been suggested to be associated with gastric carcinogenesis, there have been few investigations focusing on rural areas. A case-control study was therefore carried out to investigate the risk factors of gastric cardia cancer (GCC) in rural areas of Linzhou. A total of 470 newly diagnosed cases of GCC and 470 healthy controls were included. Face-to-face interviews were conducted, using a uniform questionnaire containing questions on demographics, per capita income, living habits, dietary habits and family history of tumors. The relationship between putative risk factors and GCC was assessed by odds ratios (OR) and their 95% confidence intervals (95%CI) derived from conditional logistic regression model by the COXREG command using SPSS 12.00. Multivariate logistic regression analysis was used to evaluate simultaneously the effects of multiple factors and other potential confounding factors. Multivariate logistic analysis showed that smoking (OR=1.939, 95%CI:1.097-3.426), alcohol drinking (OR=2.360, 95%CI: 1.292-4.311), hot food consumption (OR=2.034, 95%CI: 1.507-2.745), fast eating (OR=1.616, 95%CI: 1.171-2.230), mouldy food (OR=4.564, 95%CI: 2.682-7.767), leftover food (OR=1.881. 95%CI: 1.324-2.671), and family history of tumor (OR=2.831, 95%CI: 1.588-5.050) were risk factors for GCC. High per capita income (OR=0.709, 95%CI: 0.533-0.942), high education level (OR=0.354, 95%CI: 0.163-0.765), consumption of fresh fruits (OR=0.186, 95%CI: 0.111-0.311) and vegetables (OR=0.243, 95%CI: 0.142-0.415), and high BMI (OR=0.367, 95%CI: 0.242-0.557) were protective factors for GCC. Our data indicate that unhealthy lifestyle and dietary habits might be important contributors to GCC in this population. PMID- 23803051 TI - Germ-line MTHFR C677T, FV H1299R and PAI-1 5G/4G variations in breast carcinoma. AB - BACKGROUND: Various oncogenes related to cancer have been extensively studied and several polymorphisms have been found to be associated with breast cancer. The current report outlines analysis of germ-line polymorphisms for C677T, A1298C (MTHFR), Leiden, R2 (FV) and 5G/4G (PAI-1) in Turkish breast cancer patients. We studied 51 cases diagnosed with invasive ductal and operable with lymph node positive breast cancer and 106 women as a control group. MATERIALS AND METHODS: Peripheric blood-DNA samples were used for genotyping by StripAssay technique which is based on the reverse-hybridization principle and real-time PCR methods and results were compared statistically. RESULTS: The frequency of the MTHFR gene 677T and 1298A alleles were significantly higher in cancer patients than in the healthy subjects. The T allele frequency in codon 677 was 2.3-fold and C allele frequency was 3.1-fold increased in BC when compared to the control group for the MTHFR gene. Both differences were statistically significant (OR: 2.295, CI: 1.283 4.106), p<0.006 and (OR: 3.131, CI:1.826-5.369), p<0.0001 respectively. The R2 allele frequency of FV gene was 5.1-fold increased in the current BC when compared to the control group and that difference was also statistically significant (OR: 5.133, CI: 1.299-20.28), p<0.02. CONCLUSIONS: The present data suggest that germ-line polymorphisms of C677T, C1298A for MTHFR and R2 for FV are associated in breast cancer and may be additional prognostic markers related to breast cancer survival. The results now need to be confirmed in a larger group of patients. PMID- 23803052 TI - Sleep quality in lung cancer patients. AB - BACKGROUND: The aim of this study was to determine factors affecting sleep quality of 100 patients with advanced stage lung cancer. METHODS AND RESULTS: it was a descriptive study. A variety of assessment tools were used to provide sleep scores to examine the relation between adverse effects caused by the treatment (nausea, vomiting, fatigue) and sleep quality. As a result, no statistically significant relation between coughing and respiratory problems of patients, or existing depression, and average sleep quality score was found (KW:0.872, p=0.646, KW: 3.174, p=0.205, u: 441.000 p=0.916). It was revealed that nausea and loss of appetite experienced also did not affect the sleep quality score (p>0.05), whereas problems such as vomiting and fatigue did exert effects (p<0.01). CONCLUSIONS: Patients with advanced stage lung cancer suffer from sleep problems and cancer related symptoms also affect their sleep quality negatively. Nurses should plan interventions that can control symptoms such as pain, vomiting and fatigue, which affect the sleep of patients. PMID- 23803053 TI - 3-Deazaneplanocin A is a promising therapeutic agent for ovarian cancer cells. AB - BACKGROUND: Recent studies have shown that 3-deazaneplanocin A (DZNep), a well known histone methyltransferase inhibitor, disrupts polycomb-repressive complex 2 (PRC2), and induces apoptosis, while inhibiting proliferation and metastasis, in cancer cells, including acute myeloid leukemia, breast cancer and glioblastoma. However, little is known about effects of DZNep on ovarian cancer cells. MATERIALS AND METHODS: We here therefore studied DZNep-treated A2780 ovarian cancer cells in vitro. Proliferation of ovarian cancer cells under treatment of DZNep was assessed by MTT and apoptosis by flow cytometry. Cell wound healing was applied to detect the migration. Finally, we used q-PCR to assess the migration related gene, E-cadherin. RESULTS: DZNep could inhibit the proliferation of A2780 and induce apoptosis Furthermore, it inhibited migration and increased the expression of E-cadherin (P<0.05). CONCLUSION: DZNep is a promising therapeutic agent for ovarian cancer cells, with potential to inhibite proliferation, induce apoptosis and decrease migration. PMID- 23803054 TI - Utility of serum peptidome patterns of esophageal squamous cell carcinoma patients for comprehensive treatment. AB - Esophageal cancer (EC) is one of the most common malignant tumors, and the incidence of esophageal squamous cell carcinoma (ESCC) is highest in China. Early diagnosis and effective monitoring are keys to comprehensive treatment and discovering tumor metastases and recurrence in time. The aim of this study was to confirm serum peptidome pattern utility for diagnosis of ESCC, and assessment of operation success, postoperative chemotherapy results, tumor metastasis and recurrence. Serum samples were collected from 61 patients treated with surgery and chemotherapy and 20 healthy individuals. Spectral data generated with weak cationic-exchanger magnetic beads (WCX-MB) and MALDI-TOF MS by a support vector machine (SVM), were used to construct diagnostic models and system training as potential biomarkers. A pattern consisting of 11 protein peaks, separated ESCC (m/z 650.75), operated (m/z 676.61, 786.1, 786.58), postoperative chemotherapy (m/z 622.77, 650.66, 676.46) and tumor metastasis and recurrence (m/z 622.63, 650.56, 690.77, 676.12) from the healthy individuals with a sensitivity of 100.0% and a specificity of 100.0%. These results suggested that MALDI- TOF MS combined with MB separation yields significantly higher sensitivity and specificity for the detection of serum protein in patients with EC patients treated with surgery and chemotherapy. PMID- 23803055 TI - FDG PET-CT in non-small cell lung cancer: relationship between primary tumor FDG uptake and extensional or metastatic potential. AB - OBJECTIVE: To explore the relationships between primary tumor 18F-FDG uptake measured as the SUVmax and local extension, and nodal or distant organ metastasis in patients with NSCLC on pretreatment PET-CT. METHODS: 93 patients with NSCLC who underwent 18F-FDG PET-CT scans before the treatment were included in the study. Primary tumor SUVmax was calculated; clinical stages, presence of local extension, nodal and distant organ metastases were recorded. The patients with SUVmax >= 2.5 were divided into low and high SUVmax groups by using the median SUVmax. The low SUVmax group consisted of 45 patients with SUVmax<10.5, the high SUVmax group consisted of 46 patients with SUVmax >= 10.5. Their data were compared statistically. RESULTS: 91 cases with SUVmax>=2.5 were included for analysis. The mean SUVmax in patients without any metastasis was 7.42 +/- 2.91 and this was significantly lower than that (12.18 +/- 4.94) in patients with nodal and/or distant organ metastasis (P=0.000). In the low SUV group, 19 patients had local extension, 22 had nodal metastasis, and 9 had distant organ metastasis. In the high SUV group, 31 patients had local extension, 37 had nodal metastasis, and 18 had distant organ metastases. There was a significant difference in local extension (P =0.016), distant organ metastasis (P =0.046), and most significant difference in nodal metastasis rate (P =0.002) between the two groups. In addition, there was a moderate correlation between SUVmax and tumor size (r = 0.642, P<0.001), tumor stage (r = 0.546, P<0.001), node stage (r = 0.388, P<0.001), and overall stage (r = 0.445, P= 0.000). CONCLUSION: Higher primary tumor SUVmax predicts higher extensional or metastatic potential in patients with NSCLC. Patients with higher SUVmax may need a close follow-up and more reasonable individual treatment because of their higher extensional and metastatic potential. PMID- 23803056 TI - Pretreatment hepatoprotective effect of regular aerobic training against hepatic toxicity induced by Doxorubicin in rats. AB - BACKGROUND: Doxorubicin is an anthracycline antibiotic commonly used to treat a variety of cancers as a most effective antitumor. However, its clinical use is associated with the toxic effects in numerous healthy tissues. Here we investigated the pretreatment effect of regular aerobic exercise on oxidative stress in rats acutely exposed to DOX-induced hepatotoxicity. MATERIALS AND METHODS: Forty-eight Wistar male rats were randomly divided into 2 groups: control and training. The training protocol included treadmill running between 25 to 54 min/day and 15 to 20 m/min, 5 days/week for 6 weeks. At the end of the exercise training protocol, rats from the control and trained groups were again randomly separated into 3 subgroups: DOX 10 mg/kg, DOX 20 mg/kg and saline. All treatments were carried 24 h after the last exercise bout and animals were sacrificed 24 h after DOX and saline injections. RESULTS: Administration of DOX (10 and 20 mg.kg-1) resulted in imbalance in biomarkers related to oxidants and antioxidants in liver tissue, as compared to control groups. Six weeks of pretreatment training led to a significant increase in nitric oxide (NO), superoxide dismutase (SOD) and glutathione peroxidase (GPX) as compared to the control+DOX 10 mg/kg group. Training before DOX 20 mg/kg administration also led to a significant increase in NO and SOD, and a significant decrease in malondialdehyde (MDA). In addition, there was a significant difference between DOX 10 mg/kg and DOX 20 mg/kg treatments in MDA levels, only. CONCLUSIONS: The results of the present study indicate that pretreatment with aerobic exercise induces positive adaptations and has a potential protective effect against doxorubicin (DOX)-induced hepatotoxicity with doses of 10 and 20 mg.kg. PMID- 23803057 TI - Gene polymorphisms of OPRM1 A118G and ABCB1 C3435T may influence opioid requirements in Chinese patients with cancer pain. AB - BACKGROUNDS: Polymorphisms of OPRM1 A118G and ABCB1 C3435T have been suggested to contribute to inter-individual variability regarding pain sensitivity, opioid usage, tolerance and dependence and incidence of adverse effects in patients with chronic pain. This study aimed to investigate the association of both two polymorphisms with opioid requirements in Chinese patients with cancer pain. METHODS: The genotypes of rs1799971 (OPRM1) and rs1045642 (ABCB1) were determined by PCR-RFLP and direct sequencing methods respectively in 112 patients with cancer-related pain. Comparisons between the different genotype or allele groups were performed with t-tests or one-way ANOVA tests, as appropriate. The potential relationship of allele number with opioid response was performed with a trend Jonckheere-Terpstra test. RESULTS: In the 112 subjects, the frequencies of variant 118 G and 3435T allele were 38.4% and 37.9%, respectively. Significant higher 24h-opioid doses were observed in patients with GG (P=0.0004) and AG + GG (P=0.005) genotypes than the AA carriers. The dominant mutant 118G allele tended to be associated with progressively increasing 24h-opioiddoses (P=0.001). Compared with CC/CT, patients with ABCB1 TT genotype received higher 24h- and weight-surface area-adjusted-24h- opioids doses (P=0.057 and 0.028, respectively). CONCLUSIONS: The OPRM1 A118G single nucleotide polymorphism (SNP) is a key contributor for the inter-individual variability in opioidrequirements in Chinese cancer pain patients. This may possibly extend to the ABCB1 C3435T SNP. PMID- 23803058 TI - Lack of detection of the mouse mammary tumor-like virus (MMTV) Env gene in Iranian women breast cancer using real time PCR. AB - BACKGROUND: Mouse mammary tumor virus (MMTV) is the major cause of mammary tumors in mice. There is limited controversial evidence about the probable etiologic role of MMTV- like virus in human breast cancer. MATERIALS AND METHODS: A total of 40 Formalin fixed paraffin embedded samples with diagnosis of breast cancer were collected in a period of 3 years from cancer institute of Iran. We selected both pre-menopausal and post-menopausal patients with different histologic grades and different ethnic groups. We evaluated presence of MMTV-like virus env gene through real time PCR method. RESULTS: Forty patients (20 pre and 20 post- menopausal women) were evaluated with the mean age of 49.67. The average tumor size was 39 mm. None of the studied samples were positive for MMTV-like virus env gene target sequences. CONCLUSIONS: We found no evidence on the potential role of MMTV-like virus in the carcinogenicity of breast cancer among Iranian women. PMID- 23803059 TI - Adherence to health-related lifestyle behavior recommendations and association with quality of life among cancer survivors and age-matched controls in Korea. AB - BACKGROUND: This study was conducted to determine the relationship between lifestyle behavior and quality of life (QoL) among cancer survivors in Korea. MATERIALS AND METHODS: Data for a total of 471 (173 men, 298 women) cancer survivors (CS) over 40 years old were obtained from the database of the 4th Korean National Health and Nutrition Examination Survey (KNHANES IV). An identical number of subjects of the same age, sex, and education who had no restrictions in physical activity were randomly selected from the database and represented the control group (CG). Drinking, smoking, and exercise behavior were assessed. RESULTS: The number of heavy drinkers was lower in CS (9.4%) than in CG (15.8%) (p<0.01); similarly, there were fewer smokers in CS (9.1%) than in CG (14.0%) (p<0.05). The percentage of individuals engaging in vigorous, moderate, and low-intensity exercise did not differ between CS (13.6%, 14.7%, and 50.0%) and CG (14.3%, 13.4%, and 49.7%, respectively). No differences in Euro QoL Questionnaire 5-Dimensional Classification (EQ-5D) scores on both drinking and smoking behaviors were noted. Compared to the non-exercisers, the low-intensity exercisers in CG (0.91+/-0.10 vs. 0.94+/-0.09), vigorous-intensity exercisers in CS (0.84+/-0.62 vs. 0.91+/-0.11), and low-intensity exercisers in CS (0.82+/-0.22 vs. 0.88+/-0.13) scored higher on the EQ-5D. CONCLUSIONS: Although cancer survivors practiced more conscious health behavior in drinking and smoking, their engagement in exercise did not differ from that of non-cancer survivors. Since exercise engagement increases QoL in general, implementation of an educational program that promotes exercise engagement in cancer survivors may be required. PMID- 23803060 TI - Serum level of mast cell tryptase in patients with oral squamous cell carcinoma: lack of correlation with clinicopathologic factors. AB - BACKGROUND: Mast cells can influence tumor progression via different pathways and increased mast cell density has been demonstrated in oral squamous cell carcinoma (OSCC). It has been shown that the serum tryptase level is elevated with some malignant tumours and may thus be a useful parameter. However, there are no data available about OSCC. The main aim of this study was the evaluation of mast cell tryptase (MCT) level in OSCC patient serum. MATERIALS AND METHODS: In this cross sectional, analytic study, the circulating levels of MCT were assessed in sera of 55 OSCC patients and 34 healthy individuals with ELISA technique. RESULTS: The serum MCT level in OSCC patients was 12-14 ng/ml, which was not significantly higher than the healthy control group. While the serum level of MCT was higher with larger tumours, there was no apparent correlation with clinico-pathological features such as patient age, gender, tumor location, stage, nodal status, distant metastasis, histological grade and smoking. CONCLUSIONS: Our findings showed that despite the results obtained from studies of other malignant tumors, serum level of MCT in OSCC patients could not be a credited as a reliable indicator of the presence or progression of tumours. PMID- 23803061 TI - Impact of treatment strategies on local control and survival in uterine carcinosarcomas in Turkey. AB - BACKGROUND: The purpose of this study was to determine the clinical characteristics, patterns of recurrence and survival outcomes in patients with uterine carcinosarcomas treated in our institution. MATERIALS AND METHODS: Records of 26 patients diagnosed between 2007 and 2011 with uterine carcinosarcoma were retrospectively evaluated for demographic features, tumor characteristics, treatment regimens and patient outcomes in terms of DFS and OS RESULTS: Median age was 61 (range 43-78). 10 patients (38%) had stage I disease at diagnosis, 3 (12%) had stage II, 4 (15%) had stage III and 9 (35%) had stage IV. Sixteen patients (62%) received chemotherapy with paclitaxel and carboplatin for 6 cycles. One patient underwent radiotherapy. Median follow up was 17 months. Sixteen patients relapsed and 13 died during follow up. Considering recurrence, 5 out of 16 patients had lung metastases, one had brain metastases and 9 had only intraabdominal recurrence. The 3 year DFS was 37% and the 3 year OS was 30%. CONCLUSIONS: Our data show that uterine carcinosarcomas tend to be at advanced stage at diagnosis and despite the use of chemotherapy, overall prognosis is poor. Surgery remains the mainstay of treatment. More effective adjuvant strategies are needed to reduce relapse and death rates. PMID- 23803062 TI - Infection with Opisthorchis viverrini and use of praziquantel among a working-age population in northeast Thailand. AB - Infection with Opisthorchis viverrini (OV) due to eating certain traditional freshwater fish dishes is the principal risk factor for cholangiocarcinoma in Northeast Thailand where the infection is endemic and the incidence of this form of primary liver cancer has been the highest in the world. This paper is the second report of a prospective research project to monitor the impacts of a national liver fluke control programme in a rural community of Northeast Thailand. A sample of 684 villagers aged 20-65 years completed an interview questionnaire and were tested for infection using the Kato thick smear technique. The questionnaire was designed for the exploration of associations between OV infection, previous treatment with praziquantel, and knowledge and beliefs about the drug. The data were analysed using descriptive statistics and multiple logistic regression. The overall prevalence of OV infection was 37.2% and was highest in the 20-35 year age group, in those with a university degree and in those employed in the government sector. As many as 91.8% reported eating fish dishes known to place them at risk of infection. In the multiple regression analysis, previous use of praziquantel and lack of knowledge about whether or not the drug has a protective effect against re-infection were the only factors related to OV infection (ORadj= 2.31, 95%CI =1.40-3.79 and ORadj= 1.95, 95%CI= 1.24-3.05). The findings were discussed in terms of the possibly unwise dependency on praziquantel as a primary element in a control programme. PMID- 23803063 TI - Extraskeletal Ewing sarcomas in late adolescence and adults: a study of 37 patients. AB - BACKGROUND: Extraskeletal Ewing sarcoma (EES)/primitive neuroectodermal tumours (PNET) are rare soft tissue sarcomas. Prognostic factors and optimal therapy are still unconfirmed. MATERIALS AND METHODS: We performed a retrospective analysis on patients to explore the clinic characteristics and prognostic factors of this rare disease. A total of 37 patients older than 15 years referred to our institute from Jan., 2002 to Jan., 2012 were reviewed. The characteristics, treatment and outcome were collected and analyzed. RESULTS: The median age was 28 years (range 15-65); the median size of primary tumours was 8.2 cm (range 2-19). Sixteen patients (43%) had metastatic disease at the initial presentation. Wide surgical margins were achieved in 14 cases (38%). Anthracycline or platinum-based chemotherapy was performed on 29 patients (74%). Radiotherapy was delivered in 13 (35%). At a median follow-up visit of 24 months (range 2-81), the media event free survival (EFS) and overall survival (OS) were 15.8 and 30.2 months, respectively. The 3-year EFS and OS rates were 24% and 43%, respectively. Metastases at presentation and wide surgical margins were significantly associated with OS and EFS. Tumour size was significantly associated with OS but not EFS. There were no significant differences between anthracycline and platinum based chemotherapy regarding EFS and OS. CONCLUSIONS: EES/PNET is a malignant tumour with high recurrence and frequent distant metastasis. Multimodality therapy featuring wide surgical margins, aggressive chemotherapy and adjuvant local radiotherapy is necessary for this rare disease. Platinum-based chemotherapy can be used as an adjuvant therapy. PMID- 23803064 TI - Fermented Prunus mume with probiotics inhibits 7,12-dimethylbenz[a]anthracene and 12-o-tetradecanoyl phorbol-13-acetate induced skin carcinogenesis through alleviation of oxidative stress. AB - Maesil (Prunus mume Siebold and Zucc.), a member of the genus Rosaceae, has been reported to have antioxidative effects, as well as anticancer influence in many cancer lines. Thus, this present study was designed to investigate the inhibitory effect of fermented Maesil with probiotics against 7,12-dimethylbenz[a]anthracene (DMBA), 12-O-tetradecanoyl phorbol 13-acetate (TPA)-induced mouse skin carcinogenesis via its antioxidative potential. Mice were fed a diet containing fermented Maesil, containing either 1% (1% FM fed group) or 2% (2% FM fed group) along with probiotics following DMBA and TPA exposure. Continuous ingestion of the experimental feed markedly inhibited skin carcinogenesis, as evidenced by a marked decrease in papilloma numbers and epidermal hyperplasia as well as cellular proliferation and the percentage of proliferating-cell nuclear antigen positive cells. Also, the FM fed group showed an increase of total antioxidant capacity as well as an increased level of phase II detoxifying enzymes such as superoxide dismutase, concurrent with a decreased lipid peroxidation activity level. Taken together, these results suggest that fermented Maesil has the ability to suppress the development of DMBA-TPA induced skin carcinogenesis, via the reduction of lipid peroxidation, enhancing total antioxidant capacity and phase II detoxifying enzyme. PMID- 23803065 TI - Application of human papillomavirus in screening for cervical cancer and precancerous lesions. AB - Cervical cancer is a commonly-encountered malignant tumor in women. Cervical screening is particularly important due to early symptoms being deficient in specificity. The main purpose of the study is to assess the application value of cervical thinprep cytologic test (TCT) and human papillomavirus (HPV) detection in screening for cervical cancer and precancerous lesions. In the study, cervical TCT and HPV detection were simultaneously performed on 12,500 patients selected in a gynecological clinic. Three hundred patients with positive results demonstrated by cervical TCT and/or HPV detection underwent cervical tissue biopsy under colposcopy, and pathological results were considered as the gold standard. The results revealed that 200 out of 12,500 patients were abnormal by TCT, in which 30 cases pertained to equivocal atypical squamous cells (ASCUS), 80 cases to low squamous intraepithelial lesion (LSIL), 70 cases to high squamous intraepithelial lesion (HSIL) and 20 cases to squamous cell carcinoma (SCC). With increasing pathological grade of cervical biopsy, however, TCT positive rates did not rise. Two hundred and eighty out of 12,500 patients were detected as positive for HPV infection, in which 50 cases were chronic cervicitis and squamous metaplasia, 70 cases cervical intraepithelial neoplasia (CIN) I, 60 cases CIN II, 70 cases CIN III and 30 cases invasive cervical carcinoma. Two hundred and thirty patients with high-risk HPV infection were detected. With increase in pathological grade, the positive rate of high-risk HPV also rose. The detection rates of HPV detection to CIN III and invasive cervical carcinoma as well as the total detection rate of lesions were significantly higher than that of TCT. Hence, HPV detection is a better method for screening of cervical cancer at present. PMID- 23803066 TI - miR-153 silencing induces apoptosis in the MDA-MB-231 breast cancer cell line. AB - MicroRNAs (miRNAs) are small, non-coding RNAs (18-25 nucleotides) that post transcriptionally modulate gene expression by negatively regulating the stability or translational efficiency of their target mRNAs. In this context, the present study aimed to evaluate the in vitro effects of miR-153 inhibition in the breast carcinoma cell line MDA-MB-231. Forty-eight hours after MDA-MB-231 cells were transfected with the miR-153 inhibitor, an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide) assay was utilized to determine the effects of miR 153 on cell viability. Flow cytometry analysis and assessment of caspase 3/7 activity were adopted to determine whether miR-153 affects the proliferation rates and apoptosis levels of MDA-MB-231 cells. Our results showed that silencing of miR-153 significantly inhibited growth when compared to controls at 48 hours, reducing proliferation by 37.6%, and inducing apoptosis. Further studies are necessary to corroborate our findings and examine the potential use of this microRNA in future diagnostic and therapeutic interventions. PMID- 23803067 TI - mRNA expression and clinical significance of ERCC1, BRCA1, RRM1, TYMS and TUBB3 in postoperative patients with non-small cell lung cancer. AB - BACKGROUND: To explore mRNA expression and clinical significance of ERCC1, BRCA1, RRM1, TYMS and TUBB3 genes in tumor tissue of postoperative patients with non small cell lung cancer (NSCLC). MATERIALS AND METHODS: Sixty NSCLC patients undergoing radical operation in our hospital from Nov., 2011 to Jun., 2012 were selected. Plasmid standards of ERCC1, BRCA1, RRM1, TYMS and TUBB3 were established and standard curves were prepared by SYBR fluorescent real-time quantitative PCR analysis. Samples from tumor centers were taken to detect mRNA expression of ERCC1, BRCA1, RRM1, TYMS and TUBB3 genes in cancerous tissue during operation. The total mRNA expression quantities were compared according to different clinical characteristics. RESULTS: The total expression quantities of 5 genotypes from high to low were ERCC1>RRM1>TUBB3>TYMS>BRCA1 in turn. By pairwise comparisons, other differences showed statistical significance (p<0.05 or p<0.01) except for TYMS and TUBB3 (p>0.05); the low expression rates from high to low were ERCC1>TYMS>TUBB3>TUBB3>RRM1>BRCA1 in turn. The expression quantities of BRCA1, RRM1 and TYMS in males, smokers and patients without adenocarcinoma were all significantly higher than that in females, non-smokers and patients with adenocarcinoma, and significant differences were present (p<0.05 or p<0.01). In terms of pathological staging, the expression quantities of BRCA1, RRM1 and TYMS in phases IIa~IIb and IIIa~IIIb had a tendency to be greater than in phases I and IV. CONCLUSIONS: Resistance to chemotherapy and sensitivity to targeted therapy differ among patients with NSCLC. Differences in gene expression in different individuals were also revealed. Only according to personalized detection results can individualized therapeutic regimens be worked out, which is a new direction for oncotherapy. PMID- 23803068 TI - National HPV immunisation programme: knowledge and acceptance of mothers attending an obstetrics clinic at a teaching hospital, Kuala Lumpur. AB - BACKGROUND: Introduction of the HPV vaccine is a forefront primary prevention method in reducing the incidence of carcinogenic human papillomavirus (HPV) and cervical cancer. The Malaysia government has implemented the National HPV immunisation programme since 2010, supplying HPV vaccine free to targeted 13 year olds. This study aimed to explore the level of knowledge among mothers on cervical cancer, HPV, HPV vaccine and National HPV (NHPV) immunisation programme since its' implementation. It also assessed acceptance of mothers towards HPV vaccine being administered to their daughter, son or themselves. MATERIALS AND METHODS: A cross sectional study was conducted on 155 respondents using self administered questionnaires; conducted in December 2012 at the Obstetrics and Gynaecology Clinic in a teaching hospital in Kuala Lumpur. Respondents were selected using a multistage sampling technique. RESULTS: A response rate of 100% was obtained. Overall, 51.0% of mothers had good knowledge, with 55% having good knowledge of cervical cancer, 54.2% for both HPV and the National HPV immunisation programme and 51.0% for the HPV vaccine. Regression analyses showed that ethnicity was associated with knowledge on cervical cancer (p=0.003) while education was associated with knowledge on HPV (p=0.049). Three factors are associated with knowledge of the National HPV immunisation programme; ethnicity (p=0.017), mothers' education (p=0.0005) and number of children (p=0.020). The acceptance of HPV vaccine to be administered among daughter was the highest at 87.1%, followed by for mothers themselves at 73.5%, and the least is for sons 62.6%. CONCLUSIONS: This study found that the overall level of knowledge was moderate. Adequate information on cervical cancer, HPV, HPV vaccination and the National HPV immunisation programme should be provided to mothers in order to increase acceptance of the HPV vaccine which can reduce the disease burden in the future. PMID- 23803069 TI - Inhibitory effects of syk transfection on lung cancer cell invasion. AB - OBJECTIVE: Spleen tyrosine kinase (Syk) is closely related to tumor invasion and metastasis, and has been shown to have potential inhibitory effects in tumors. In this study, we constructed a eukaryotic expression vector for Syk and analyzed its effects on invasive ability of the A549 non-small cell lung cancer cell line in vitro. METHODS: A fragment of Syk was obtained by RT-PCR from human lung cancer cells and cloned into the expression vector pLNCXSyk. After restriction endonuclease digestion, PCR and DNA sequencing confirmation, the recombinant Syk expression plasmid was transfected into A549 human lung cancer cells using lipofectamine protocols. After selection, the cells stably expressed Syk. Detection of Syk expression of the cells by RT-PCR, and invasive ability were examined. RESULTS: The eukaryotic expression plamid pLNCXSyk was constructed and expressed stably in the A549 human lung cancer cells. The RT-PCR results showed that Syk mRNA expression was upregulated significantly (P<0.05). Lower invasion through a basal membrane were apparent after transfection (P<0.05). CONCLUSIONS: A eukaryotic expression plasmid to cause Syk expression in lung cancer cells can obviously inhibit their invasive ability in vitro. PMID- 23803070 TI - Overview of benign and malignant prostatic disease in Pakistani patients: a clinical and histopathological perspective. AB - BACKGROUND: To present the overall clinical and histological perspective of benign and malignant prostatic disease as seen in our practice in the Section of Histopathology, Department of Pathology and Microbiology, Aga Khan University Hospital, Karachi, Pakistan. MATERIALS AND METHODS: All consecutive prostate specimens (transurethral resection or TUR, enucleation, needle biopsies) received between July 1, 2012 and December 31, 2012 were included in the study. RESULTS: Of the total of 785 cases, 621 (79.1%) were TUR specimens, 80 (10.2%) enucleation specimens, and 84 (10.7%) needle biopsies. Some 595 (75.8%) were benign, while 190 (24.2%) were malignant. Mean weight of BPH specimens was 19 grams and 43 grams for TUR and enucleation specimens respectively. Almost 67% of adenocarcinomas were detected on TUR or enucleation specimens. Of the above cases, 41.7% were clinically benign while 58.3% were clinically malignant. The average volume of carcinoma in all cases ranged between 60 to 65%. The average number of cores involved in needle biopsies was 5. In general, higher Gleason scores were seen in TUR/enucleation specimens than in needle biopsies. Overall, in all types of specimens, commonest Gleason score was 7, seen in 74 (38.9%) cases, followed by Gleason score 9 seen in 47 (24.7%) cases. Out of the 63 needle biopsies with carcinoma, radical prostatectomy was performed in 16 cases (25.4%). CONCLUSIONS: Benign prostatic hyperplasia (BPH) is extremely common and constitutes the bulk of prostate specimens. TMajority of prostatic carcinomas are still diagnosed on TUR or enucleation specimens. These included both clinically benign and clinically malignant cases. The volume of carcinoma in these specimens was quite high indicating extensive disease. Gleason scores were also generally high compared with scores from needle biopsies. Commonest Gleason score in all type of specimens was 7. Pathologic staging was possible in very few cases since radical prostatectomies are rarely performed. PMID- 23803071 TI - B7-H4 expression is associated with cancer progression and predicts patient survival in human thyroid cancer. AB - OBJECTIVE: This study aimed to investigate the expression of B7-H4 in human thyroid cancer and determine any association with patient clinicopathological parameters and survival. METHODS: B7-H4 expression in 64 clinical thyroid cancer specimens was assessed with immunohistochemistry. Moreover, B7-H4 mRNA expression in 10 fresh resected specimens were evaluated by the reverse transcription polymerase chain reaction (RT-PCR). Immunohistochemical staining of CD3 was performed to assess the number of tumor infiltrating T lymphocytes (TILs) in thyroid cancers. RESULTS: Positive B7-H4 immunohistochemical staining was observed in 61 out of 64 (95.3%) specimens of thyroid cancer tissues. Significantly more B7-H4 mRNA copies were found in thyroid cancer tissue than that adjacent normal tissue. Moreover, B7-H4 expression in human thyroid cancer tissues was significantly correlated with patient TNM stages and extrathyroidal extension (P<0.05), being inversely correlated with the number of TILs (P<0.05). The overall survival rate of the patients with higher B7-H4 expression was significantly worse than that of the patients with lower B7-H4 expression. CONCLUSIONS: This present study suggests that high B7-H4 expression is associated with cancer progression, reduced tumor immunosurveillance and worse patient outcomes in human thyroid cancer. PMID- 23803072 TI - Cross Sectional Assessment of Health Related Quality of Life (HRQoL) among patients with cancer in Malaysia. AB - BACKGROUND: Health Related Quality of Life (HRQoL) is an important aspect in identifying cancer patients' perceptions of being diagnosed with cancer and the assessment of treatment outcomes. The present study aimedto assess the profile and predicators of HRQoL of Malaysian oncology patients. MATERIALS AND METHODS: A cross sectional study adopting the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) was conducted. All cancer patients attending Penang General Hospital between August-November 2011 were approached. Descriptive statistics were used to assess demographic and disease related characteristics of the patients. All analyses were performed using SPSS v 16.0. RESULTS: Three hundred and ninety three cancer patients met the inclusion criteria and were enrolled in the study. The mean age was 53.9 (SD+/-13) years. The cohort was dominated by females (n=260, 66.2%). Nearly half (n=190, 48.3%) of the participants were of Malay ethnicity, practicing Islam as their religion (n=194, 49.4%). Two hundred and ninety six (n=296, 75.3%) had beene diagnosed with cancer within six months to 3 years previously. The most common primary cancer site was breast (n=143, 36.4%). The mean Global Health Status (GHS) score was 60.7 (SD=21.3). Females (mean GHS score of 62.3, p=0.035) with Malay ethnicity (mean GHS score of 63.8, p=0.047), practicing Islam as their religion (mean GHS score of 63.0, p=0.011) had better GHS scores. Patients having medical insurance had good scores (mean 65.6, p=0.021). Marital status was significantly associated with GHS scores (p=0.022). Bone cancer patientshad the lowest mean GHS score of 49.2 (p=0.044). Patients at very advanced stages of cancer featured a low GHS mean score of 52.2 (p<0.001). CONCLUSIONS: The present study identified many demographic and disease related factors which may contribute to the HRQoL of cancer patients, pointing to the necessity for improved management of disease symptoms and provision of psychological and financial support. PMID- 23803073 TI - Synergistic anticancer activity of 5-aminolevulinic acid photodynamic therapy in combination with low-dose cisplatin on Hela cells. AB - OBJECTIVE: Photodynamic therapy (PDT ) is a promising modality for the treatment of various tumors. In order to assist in optimizing treatment, we applied 5 ALA/PDT in combination with low-dose cisplatin to evaluate cytotoxicity in Hela cells. METHODS: Antiproliferative effects of 5-ALA/PDT and cisplatin, alone and in combination, were assessed using MTT assay. To examine levels of apoptosis, Hela cells treated with 5-ALA/PDT, and combination treatment were assessed with Annexin-V/PI by flow cytometry. To investigate the molecular mechanisms underlying alterations in cell proliferation and apoptosis, Western blot analysis was conducted to determine the expression of p53, p21, Bax and Bcl-2 proteins. RESULTS: MTT assays indicated that combination treatment obviously decreased the viability of Hela cells compared to individual drug treatment. In addition, it was confirmed that exposure of Hela cells to 5-ALA/PDT in combination with low dose cisplatin resulted in more apoptosis in vitro. Synergistic anticancer activity was related to upregulation p53 expression and alteration in expression of p21, Bcl-2 and Bax. CONCLUSION: Our findings suggest that administration of 5 ALA/PDT in combination with the low-dose cisplatin may be an effective and feasible therapy for cervical cancer. PMID- 23803074 TI - Primary study on providing a basic system for uterine cervical screening in a developing country: analysis of acceptability of self-sampling in Lao PDR. AB - BACKGROUND: Most developing countries have been unable to implement well organized health care systems, especially comprehensive Pap smear screening-based programs. One of the reasons for this is regional differences in medical services, and a low-cost portable cervical screening system is necessary. To improve regional discrepancies in cervical screening systems, we investigated the usefulness and acceptability of cervical self- sampling by liquid-based cytology (LBC) for 290 volunteers in the Lao PDR. MATERIALS AND METHODS: Following health education with comprehensive documents, cervical self-sampling kits by LBC were distributed in three provincial, district, and village areas to a total of 290 volunteers, who were asked to take cytology samples by themselves. Subsequently, the acceptability of self-sampling was evaluated using a questionnaire. RESULTS: The documents were well understood in all three regions. Regarding the acceptability of self-sampling, the selections for subsequent screening were 62% self-sampling, 36% gynecologist-sampling, 1% either method, and 1% other methods. The acceptability rates were higher in the district and the village than in the province. For the relationship between acceptability and pregnancy, the self sampling selection rate was higher in the pregnancy-experienced group (75%) than in the pregnancy-inexperienced group (60%). For the relationship between selection of self-sampling and experience of screening, the self-sampling selection rate was higher in the screening-inexperienced group (62%) than in the screening-experienced group (52%). CONCLUSIONS: Our data show that this new way forward, involving a combination of self-sampling and LBC, is highly acceptable regardless of age, educational background, and residence in rural areas in a developing country. PMID- 23803075 TI - Role of breast tomosynthesis in diagnosis of breast cancer for Japanese women. AB - INTRODUCTION: Mammography is the most basic modality in breast cancer imaging. However, the overlap of breast tissue depicted on conventional two-dimensional mammography (2DMMG) may create significant obstacles to detecting abnormalities, especially in dense or heterogeneously dense breasts. In three-dimensional digital breast tomosynthesis (3DBT), tomographic images of the breast are reconstructed from multiple projections acquired at different angles. It has reported that this technology allows the generation of 3D data, therefore overcoming the limitations of conventional 2DMMG for Western women. We assessed the detectability of lesions by conventional 2DMMG and 3DBT in diagnosis of breast cancer for Japanese women. METHODS: The subjects were 195 breasts of 99 patients (median age of 48 years, range 34~82 years) that had been pathologically diagnosed with breast cancer from December 20, 2010 through March 31, 2011. Both conventional 2DMMG and 3DBT imaging were performed for all patients. Detectability of lesions was assessed based on differences in category class. RESULTS: Of the affected breasts, 77 (75.5%) had lesions assigned to the same categories by 2DMMG and 3DBT. For 24 (23.5%) lesions, the category increased in 3DBT indicating improvement in diagnostic performance compared to 2DMMG. 3DBT improved diagnostic sensitivity for patients with mass, focal asymmetric density (FAD), and architectural distortion. However, 3DBT was not statistically superior in diagnosis of the presence or absence of calcification. CONCLUSIONS: In this study, 3DBT was superior in diagnosing lesions in form of mass, FAD, and/or architectural distortion. 3DBT is a novel technique that may provide a breakthrough in solving the difficulties of diagnosis caused by parenchyma overlap for Japanese women. PMID- 23803076 TI - Enhanced anti-tumor efficacy of aspirin combined with triptolide in cervical cancer cells. AB - BACKGROUND: The non-steroidal anti-inflammatory drug (NSAID) aspirin (acetylsalicylic acid) is an inhibitor of cyclooxygenase enzymes. Recent studies have shown that aspirin could be used as an anti-tumor drug. Triptolide, the major compound extracted from the Chinese herb Tripteryglum wilfordii Hook.f, has now been shown that it can inhibit tumor growth. The aim of this study was to analyze the anti-tumor efficiency of aspirin and triptolide in cervical cancer cells. METHODS: Viability of cervical cancer cell lines was assessed by the MTT method at various concentrations of aspirin and triptolide. Siha and HeLa cell apoptotic analysis was performed by flow cytometry. Real time-PCR and Western Blotting were used to analyze the expression of Bcl-2/Bax, Cyclin D1 and p16. RESULTS: Viability in the combination group was significantly decreased as compared with either drug used alone. Expression change of Bcl-2/Bax, CyclinD1 and p16 appeared to play an important role in the synergistic killing effect on cervical cancer cell apoptosis. CONCLUSION: Aspirin and triptolide combination treatment may have synergistic anti-tumor effects on cervical cancer cells. PMID- 23803077 TI - Evaluation of computer-assisted quantitative volumetric analysis for pre operative resectability assessment of huge hepatocellular carcinoma. AB - PURPOSE: Hepatic resection is arguably the preferred treatment for huge hepatocellular carcinoma (H-HCC). Estimating the remnant liver volume is therefore essential. This study aimed to evaluate the feasibility of using computer-assisted volumetric analysis for this purpose. METHODS: The study involved 40 patients with H-HCC. Laboratory examinations were conducted, and a contrast CT-scan revealed that 30 cases out of the participating 40 had single lesion tumors. The remaining 10 had less than three satellite tumors. With the consensus of the team, two physicians conducted computer-assisted 3D segmentation of the liver, tumor, and vessels in each case. Volume was automatically computed from each segmented/labeled anatomical field. To estimate the resection volume, virtual lobectomy was applied to the main tumor. A margin greater than 1 cm was applied to the satellite tumors. Resectability was predicted by computing a ratio of functional liver resection (R) as (Vresected- Vtumor)/(Vtotal-Vtumor) x 100%, applying a threshold of 50% and 60% for cirrhotic and non-cirrhotic cases, respectively. This estimation was then compared with surgical findings. RESULTS: Out of the 22 patients who had undergone hepatectomies, only one had an R that exceeded the threshold. Among the remaining 18 patients with non-resectable H HCC, 12 had Rs that exceeded the specified ratio and the remaining 6 had Rs that were < 50%. Four of the patients who had Rs less than 50% underwent incomplete surgery due to operative findings of more extensive satellite tumors, vascular invasion, or metastasis. The other two cases did not undergo surgery because of the high risk involved in removing the tumor. Overall, the ratio of functional liver resection for estimating resectability correlated well with the other surgical findings. CONCLUSION: Efficient pre-operative resectability assessment of H-HCC using computer-assisted volumetric analysis is feasible. PMID- 23803078 TI - The C allele of a synonymous SNP (rs1805414, Ala284Ala) in PARP1 is a risk factor for susceptibility to breast cancer in Saudi patients. AB - BACKGROUND: Genetic aberrations of DNA repair enzymes are known to be common events associated with different cancer entities. The aim of the present study was to analyze genetic associations of rs1805404 (Asp81Asp) and rs1805414 (Ala284Ala) in the PARP1 gene with the risk of breast cancer in Saudi Arabia. MATERIALS AND METHODS: These two SNP's were analyzed in a primary study group of breast cancer patients and healthy control subjects. Genotypes were determined by TaqMan SNP testing and analyzed using Chi-square or t test and logistic regression analysis with SPSS16.0 software. RESULTS AND CONCLUSIONS: Results showed that rs1805414 was associated with a significantly increased susceptibility to breast cancer, significant risk being observed for the TC, CC and TC+CC genotypes. In conclusion PARP1 rs1805414 SNP polymorphisms may be involved in the etiology of breast cancer in the Saudi population. In contrast, PARP1 rs1805404 did not show any significant association in overall in breast cancer samples when compared to healthy controls. Confirmation of our findings in larger populations of different ethnicities may provide evidence for a role of the PARP1 gene in breast carcinoma developnment. PMID- 23803079 TI - Prediction of chemotherapeutic response in unresectable non-small-cell lung cancer (NSCLC) patients by 3-(4,5-dimethylthiazol-2-yl)-5-(3 carboxymethoxyphenyl)-2- (4-sulfophenyl)-2H-tetrazolium (MTS) assay. AB - BACKGROUND: Selecting chemotherapy regimens guided by chemosensitivity tests can provide individualized therapies for cancer patients. The 3-(4,5-dimethylthiazol 2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H- tetrazolium, inner salt (MTS) assay is one in vitro assay which has become widely used to evaluate the sensitivity to anticancer agents. The aim of this study was to evaluate the clinical applicability and accuracy of MTS assay for predicting chemotherapeutic response in unresectable NSCLC patients. METHODS: Cancer cells were isolated from malignant pleural effusions of patients by density gradient centrifugation, and their sensitivity to eight chemotherapeutic agents was examined by MTS assay and compared with clinical response. RESULTS: A total of 37 patients participated in this study, and MTS assay produced results successfully in 34 patients (91.9%). The sensitivity rates ranged from 8.8% to 88.2%. Twenty-four of 34 patients who received chemotherapy were evaluated for in vitro-in vivo response analysis. The correlation between in vitro chemosensitivity result and in vivo response was highly significant (P=0.003), and the total predictive accuracy, sensitivity, specificity, positive predictive value, and negative predictive value for MTS assay were 87.5%, 94.1%, 71.4%, 88.9%, and 83.3%, respectively. The in vitro sensitivity for CDDP also showed a significant correlation with in vivo response (P=0.018, r=0.522). CONCLUSION: MTS assay is a preferable in vitro chemosensitivity assay that could be use to predict the response to chemotherapy and select the appropriate chemotherapy regimens for unresectable NSCLC patients, which could greatly improve therapeutic efficacy and reduce unnecessary adverse effects. PMID- 23803080 TI - Upregulation of microRNA 181c expression in gastric cancer tissues and plasma. AB - OBJECTIVE: To test the microRNA-181c (miR-181c) expression in tissues and plasma of gastric cancer (GC) cases, analyze any correlations, and explore the possibility of miR-181c as a potential molecular marker for GC diagnosis. MATERIALS AND METHODS: Relative miR-181c expression levels in cancers and plasma from 30 GC patients was tested using reverse transcription?real-time fluorescent quantitation PCR and compared to that in samples from 30 gastric ulcer and 30 chronic gastritis patients. RESULTS: The miR-181c expression level in the GC tissues was significantly higher than that in the gastric ulcer and chronic gastritis tissues (P = 0.000), as was the miR-181c expression level in the GC plasma (P = 0.000). We determined that miR-181c expression in GC plasma was positively correlated to its expression in the GC tissues (P = 0.000). CONCLUSIONS: The expression of miR-181c is upregulated in GC tissues and plasma, and the miR-181c expression level in GC plasma is positively correlated to that in the corresponding cancer tissues. Plasma miR-181c is possibly a new serological marker for GC diagnosis. PMID- 23803081 TI - Acupuncture and moxibustion for cancer-related fatigue: a systematic review and meta-analysis. AB - BACKGROUND: Faced with highly prevalent and recalcitrant cancer-related fatigue (CRF), together with the absence of any official guidelines on management, numerous groups have been striving to seek and test alternative therapies including acupuncture and moxibustion. However, different patients have various feedbacks, and the many clinical trials have given rise to varied conclusions. In terms of the therapeutic effect of acupuncture and moxibustion, there exist vast inconsistencies. OBJECTIVE: The aim of the study was to evaluate the auxiliary effectiveness of acupuncture and moxibustion in the treatment of CRF, and to provide more reliable evidence to guide clinical practice. METHODS: Randomized controlled trials (RCTs) published before December 2012 were all aggregated, focusing on evaluation of acupuncture or moxibustion for CRF. The quality of the included studies was assessed basing on Cochrane handbook 5.1.0, and the available data were analyzed with RevMan software (version 5.2.0). Descriptive techniques were performed when no available data could be used. RESULTS: A total of 7 studies involving 804 participants were eligible. With real acupuncture versus sham acupuncture, subjects receiving true acupuncture benefited more in the reduction of fatigue. With real acupuncture versus acupressure or sham acupressure, fatigue level appeared 36% improved in the acupuncture group, but 19% in the acupressure group and only 0.6% with sham acupressure. When real acupuncture plus enhanced routine care was compared with enhanced routine care, the combination group improved mean scores for general fatigue, together with physical and mental fatigue. With real acupuncture versus sham acupuncture or wait list controls, the real acupuncture group displayed significant advantages over the wait list controls at 2 weeks for fatigue improvement and better well being effects at 6 weeks. When moxibustion plus routine care was compared with routine care alone, the meta-analyses demonstrated the combination had a relatively significant benefit in improving severe fatigue and QLQ-C30. CONCLUSION: Up to the search date, there exist few high quality RCTs to evaluate the effect of acupuncture and moxibustion, especially moxibustion in English. Yet acupuncture and moxibustion still appeared to be efficacious auxiliary therapeutic methods for CRF, in spite of several inherent defects of the included studies. Much more high-quality studies are urgently needed. PMID- 23803082 TI - Susceptibility loci associations with prostate cancer risk in northern Chinese men. AB - BACKGROUND: KLK3 gene products, like human prostate-specific antigen (PSA), are important biomarkers in the clinical diagnosis of prostate cancer (PCa). G protein-coupled receptor RFX6, C2orf43 and FOXP4 signaling plays important roles in the development of PCa. However, associations of these genes with PCa in northern Chinese men remain to be detailed. This study aimed to investigate their impact on occurrence and level of malignancy. METHODS: All subjects were from Beijing and Tianjin, including 266 cases with prostate cancer and 288 normal individuals as controls. We evaluated associations between clinical covariates (age at diagnosis, prostate specific antigen, Gleason score, tumor stage and aggressive) and 6 candidate PCa risk loci, genotyped by PCR- high resolution melting curve and sequencing methods. RESULTS: Case-control analysis of allelic frequency of PCa associated with PCa showed that one of the 6 candidate risk loci, rs339331 in the RFX6 gene, was associated with reduced risk of prostate cancer (odds ratio (OR) = 0.73, 95% confidence interval (CI) =0.57-0.94, P = 0.013) in northern Chinese men. In addition, subjects with CX (CC+TC) genotypes had a decreased risk for prostrate cancer compared to those carrying the TT homozygote (OR =0.64, 95% CI = 0.45- 0.90, P = 0.008). The TT genotype of 13q22 (rs9600079, T) was associated with tumor stage (P=0.044, OR=2.34, 95% CI=0.94 5.87). Other SNPs were not significantly associated with clinical covariates in prostate cancer (P > 0.05). CONCLUSIONS. rs339331 in the RFX6 gene may be associated with prostate cancer as a susceptibility locus in northern Chinese men. PMID- 23803083 TI - Endostar combined with cisplatin inhibits tumor growth and lymphatic metastasis of lewis lung carcinoma xenografts in mice. AB - OBJECTIVE: To investigate the effects of endostar, a recombined humanized endostatin, plus cisplatin on the growth, lymphangiogenesis and lymphatic metastasis of the Lewis lung carcinoma (LLC) in mice. METHODS: A tumor model were established in C57BL/6 mice by intravenious transplantation of LLC cells. Then the mice were randomized to receive administration with NS, endostar, cisplatin, or endostar plus cisplatin. After the mice were sacrificed, tumor multiplicity, tumor size and lymph node metastasis were assessed. Then the expression of vascular endothelial growth factor-c (VEGF-C) and podoplanin were determined by immunohistochemical staining. RESULTS: Endostar plus cisplatin significantly suppressed tumor growth. lymphatic metastasis and prolonged survival time of the mice without obvious toxicity. The inhibition of lymphatic metastasis was associated with decreased microlymphatic vessel density (MLVD) and expression of VEGF-C. CONCLUSIONS: Endostar combined with cisplatin was more effective to suppress tumor growth and lymphatic metastasis than either agent alone. Thus this may provide a rational alternative for lung carcinoma treatment. PMID- 23803084 TI - Associations of ABCB1 and XPC genetic polymorphisms with susceptibility to colorectal cancer and therapeutic prognosis in a Chinese population. AB - Associations between ABCB1 and XPC genetic polymorphisms and risk of developing colorectal cancer (CRC) as well as clinical outcomes in CRCs with chemotherapy were investigated. A case-control study was performed on the ABCB1 C3435T, G2677T/A and XPC Lys939Gln polymorphisms in 428 CRC cases and 450 hospital- based, age and sex frequency-matched controls using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assays. We observed that the ABCB1 3435CT or CC+CT variants were significantly linked with increasing risk of developing CRC (adjusted OR (95% CI): 1.814 (1.237-2.660), P=0.0022; adjusted OR (95% CI): 1.605 (1.117-2.306), P=0.0102, respectively). Moreover, the distribution frequency of XPC AC genotype or AC+CC genotypes also showed a tendency towards increasing the suscepbility for CRC (P=0.0759 and P=0.0903, respectively). Kaplan-Meier curves showed that the ABCB1 C3435T variant was associated with a tendency toward longer progression-free survival (PFS) (n=343, Log-rank test: P=0.063), and the G2677T/A variant genotypes (GT+TT+GA+AA) with a tendency for longer OS in postoperative oxaliplatin-based patients (n=343, Log rank test: P=0.082). However, no correlation of the XPC Lys939Gln polymorphism was found with PFS and OS in patients with postoperative oxaliplatin-based chemotherapy (n=343). Our study indicated that ABCB1 polymorphisms might be candidate pharmacogenomic factors for the prediction of CRC susceptibility, but not for prognosis with oxaliplatin chemosensitivity in CRC patients. PMID- 23803085 TI - Suppression of beta-catenin and cyclooxygenase-2 expression and cell proliferation in azoxymethane-induced colonic cancer in rats by rice bran phytic acid (PA). AB - BACKGROUND: Phytic acid (PA) is a polyphosphorylated carbohydrate that can be found in high amounts in most cereals, legumes, nut oil, seeds and soy beans. It has been suggested to play a significant role in inhibition of colorectal cancer. This study was conducted to investigate expression changes of beta-catenin and cyclooxygenase-2 (COX-2) and cell proliferation in the adenoma-carcinoma sequence after treatment with rice bran PA by immunocytochemistry. MATERIALS AND METHODS: Seventy-two male Sprague-Dawley rats were divided into 6 equal groups with 12 rats in each group. For cancer induction two intraperitoneal injections of azoxymethane (AOM) were given at 15 mg/kg bodyweight over a 2-weeks period. During the post initiation phase, two different concentrations of PA, 0.2% (w/v) and 0.5% (w/v) were administered in the diet. RESULTS: Results of beta-catenin, COX-2 expressions and cell proliferation of Ki-67 showed a significant contribution in colonic cancer progression. For beta-catenin and COX-2 expression, there was a significant difference between groups at p<0.05. With Ki 67, there was a statistically significant lowering the proliferating index as compared to AOM alone (p<0.05). A significant positive correlation (p=0.01) was noted between COX-2 expression and proliferation. Total beta-catenin also demonstrated a significant positive linear relationship with total COX-2 (p=0.044). CONCLUSIONS: This study indicated potential value of PA extracted from rice bran in reducing colonic cancer risk in rats. PMID- 23803086 TI - Cancer prevalence in Easter Island population - 2006-2010. AB - In Easter Island, population is composed by original habitants, the Rapa Nui culture and introduced people, mainly from continental Chile, who have a different ethnic origin. The aim of this research was to describe cancer frequency in resident population in Easter Island, and secondarily compare the findings with other islands of Polynesia and continental Chile. We reviewed the statistics of patients treated in Hanga Roa Hospital during the period 2006-2010, finding a total of 49 patients with cancer during the study. The most frequent cancers in Easter Island's people were breast cancer (8 cases), skin (8 cases), cervical (8 cases), lung (5 cases) and gastric (4 cases). According to gender, in females the most frequent cancer was breast, followed by skin and cervical, while in men, lung, prostate and hematopoietic cancers were the most frequent. Most cases of cervical cancer occurred in women of Rapa Nui ethnicity, while most skin cancers were found in non-Rapa Nui people. In case of the most common cancer in Easter Island, education (e.g. Papanicolaou and mammography screening) and prevention in the community (e.g. use sun block, avoid cigarettes) should be useful tools to reduce incidence. PMID- 23803087 TI - Blood lead concentration correlates with all cause, all cancer and lung cancer mortality in adults: a population based study. AB - BACKGROUND: This study used National Health and Nutrition Examination Survey III to study the relationship between blood lead concentration and all cause, all cancer and lung cancer mortality in adults. PATIENTS AND METHODS: Public use National Health and Nutrition Examination Survey (NHANES III) data were used. NHANES III uses stratified, multistage probabilistic methods to sample nationally representative samples. Household adult, laboratory and mortality data were merged. Sample persons who were available to be examined in aMobile Examination Center (MEC) were included in this study. Specialized survey analysis software was used. RESULTS: A total of 3,482 sample participants with complete information for all variables were included in this analysis. For all cause death, the odds ratios (S.E.) for statistically significant variables were body mass index, 1.03 (1.01- 1.06); age 1.01 (1.01-1.01); blood lead concentration, 1.05 (1.01-1.08); poverty income ratio, 0.823 (0.76-0 .89); and drinking hard liquor, 1.01 (1.00 1.02). For all cancer mortality, the odds ratios (S.E.) of the statistically significant variables were: age, 1.01 (1.01-1.01); blood lead concentration, 1.07 (1.04-1.12), black race, using non-Hispanic white as reference, 1.69 (1.12-2.56); and smoking, 1.02 (1.01-1.04). For lung cancer mortality, the odds ratios (S.E.) of the statistically significant variables were: age, 1.01 (1.01-1.01); blood lead concentration, 1.09 (1.05-1.13); Mexican Americans, using non-Hispanic white as reference, 0.33 (0.129-0.850); other races, 1.80 (0.53-6.18); and smoking, 1.03 (1.02-1.05). CONCLUSION: Blood lead concentration correlated with all cause, all cancer, and lung cancer mortality in adults. PMID- 23803088 TI - Anti-tumor efficacy of a hepatocellular carcinoma vaccine based on dendritic cells combined with tumor-derived autophagosomes in murine models. AB - The majority of hepatocellular carcinoma (HCC) patients have a poor prognosis with current therapies, and new approaches are urgently needed. We have developed a novel therapeutic cancer vaccine platform based on tumor cell derived autophagosomes (DRibbles) for cancer immunotherapy. We here evaluated the effectiveness of DRibbles-pulsed dendritic cell (DC) immunization to induce anti tumor immunity in BALB/c mouse HCC and humanized HCC mouse models generated by transplantation of human HCC cells (HepG2) into BALB/c-nu mice. DRibbles were enriched from H22 or BNL cells, BALB/c-derived HCC cell lines, by inducing autophagy and blocking protein degradation. DRibbles-pulsed DC immunization induced a specific T cell response against HCC and resulted in significant inhibition of tumor growth compared to mice treated with DCs alone. Anti- tumor efficacy of the DCs-DRibbles vaccine was also demonstrated in a humanized HCC mouse model. The results indicated that HCC/DRibbles-pulsed DCs immunotherapy might be useful for suppressing the growth of residual tumors after primary therapy of human HCC. PMID- 23803089 TI - Obesity and risk of bladder cancer: a meta-analysis of cohort studies. AB - OBJECTIVE: Previous epidemiologic studies demonstrated that obesity might associated with the risk of bladder cancer. However, many of the actual association findings remained conflicting. To better clarify and provide a comprehensive summary of the correlation between obesity and bladder cancer risk, we conducted a meta-analysis to summarize results of studies on the issue. Stratified analyses were also performed on potential variables and characteristics. METHODS: Studies were identified by searching in PubMed and Wanfang databases, covering all the papers published from their inception to March 10, 2013. Summary relative risks (SRRs) with their corresponding 95% confidence intervals (CIs) were calculated by either random-effect or fixed effect models. RESULTS: A total of 11 cohort studies were included in our meta analysis, which showed that obesity was associated with an increased risk for bladder cancer in all subjects (RR=1.10, 95% CI=1.06-1.16; p=0.215 for heterogeneity; I2=24.0%). Among the 9 studies that controlled for cigarette smoking, the pooled RR was 1.09 (95% CI 1.01-1.17; p=0.131 for heterogeneity; I2=35.9%). No significant publication bias was detected (p = 0.244 for Egger's regression asymmetry test). CONCLUSIONS: Our results support the conclusion that obesity is associated with the increased risk of bladder cancer. Further research is needed to generate a better understanding of the correlation and to provide more convincing evidence for clinical intervention in the prevention of bladder cancer. PMID- 23803090 TI - Protective effects of [6]-paradol on histological lesions and immunohistochemical gene expression in DMBA induced hamster buccal pouch carcinogenesis. AB - BACKGROUND: The search for naturally occurring agents in routinely consumed foods that may inhibit cancer development is of high priority. [6]-Paradol is a pungent phenolic bioactive component from ginger with well- documented health promoting antioxidant, antimutagenic, antigenotoxic and anti-inflammatory properties. However, anticarcinogenic effects have yet to be fully explored. The objectives of the present study were therefore to assess protective effects against 7,12 dimethylbenz(a)anthracene (DMBA) induced buccal pouch carcinogenesis in male golden Syrian hamsters. METHODS: Oral squamous cell carcinomas developed in the left buccal pouch of hamsters on painting with 0.5% of DMBA, three times in a week. To assess the apoptotic associated gene expressing potential of [6] paradol, it was orally administered to DMBA treated hamsters on alternate days from DMBA painting for 14 weeks. RESULTS: We observed 100% tumor formation with marked levels of neoplastic changes and altered the expression of apoptotic associated gene (p53, bcl-2, caspase-3 and TNF-alpha) was observed in the DMBA alone painted hamsters as compared to control hamsters. Oral administration of [6]-paradol at a dose of 30 mg/kg b.wt to DMBA treated animals on alternative days for 14 weeks significantly reduced the neoplastic changes and improved the status of apoptosis associated gene expression. CONCLUSION: These observations confirmed that [6]-paradol acts as a tumor suppressing agent against DMBA induced oral carcinogenesis. We also conclude that [6]-paradol also effectively enhances apoptosis- associated gene expression in DMBA treated animals. PMID- 23803091 TI - Role of print and audiovisual media in cervical cancer prevention in Bangladesh. AB - BACKGROUND: Visual inspection of cervix with acetic acid (VIA) is offered at 252 centers in 64 districts of Bangladesh. VIA+ve women are managed at colposcopy clinics of Bangabandhu Sheikh Mujib Medical University (BSMMU) and 14 Medical College Hospitals (MCHs). This research work has been supported by 'UICC Cancer Prevention Campaign' programme. OBJECTIVES: This study explored the role of print materials and electronic media to improve cervical cancer screening in the present socio-cultural context of Bangladesh. METHODS: This study was performed from January to August 2011 at two upazilas of Bangladesh (Singair with screening facility and Sonargaon without screening facility). Data were collected by focus group discussion (FGD) with women, husbands and community people before and after intervention. Information on cervical cancer screening and VIA camps was disseminated using advertisement through local cable line of the television, microphone announcement, service providers and leaflet throughout the week prior to a VIA camp. Three-day VIA camps were organized at the upazila health complex (UHC) of both upazilas. Quantitative data was gathered from women at the camps on source of information on VIA and the best method of awareness creation. RESULTS: The population was aware of "cancer" and a notable number knew about cervical cancer. Baseline awareness on prevention and VIA was low and it was negligible where screening services were unavailable. Awareness was increased fourfold in both upazilas after interventions and half of the women and the majority of the community people became aware of screening and available facilities. Cable line advertisement (25.5%), microphone announcement (21.4%), and discussion sessions (20.4%) were effective for awareness creation on VIA. Television was mentioned as the best method (37.4%) of awareness creation. CONCLUSION: Television should be used for nation-wide awareness creation. For local awareness creation, cable line advertisement, microphone announcements and health education at Uthan Baithaks/ EPI sessions can easily be adopted by the government. PMID- 23803092 TI - Aberrant DNA methylation of P16, MGMT, hMLH1 and hMSH2 genes in combination with the MTHFR C677T genetic polymorphism in gastric cancer. AB - Associations of P16, MGMT, hMLH1 and hMLH2 with gastric cancer and their relation with MTHFR status in gastric patients who were confirmed with pathological diagnosis were assessed. Aberrant DNA methylation of P16, MGMT, hMLH1 and hMLH2 and polymorphisms of MTHFR C677T were assayed. The proportional DNA hypermethylation in P16, MGMT, hMLH1 and hMLH2 in cancer tissues was significantly higher than in remote normal-appearing tissues. DNA hypermethylation of P16 and MGMT was correlated with the T and N stages. Individuals with homozygotes (TT) of MTHFR C677T had significant risk of hypermethylation of MGMT in cancer tissues [OR (95% CI)= 3.47(1.41-7.93)]. However, we did not find association between polymorphism in MTHFR C677T and risk of hypermethylation in P16, MGMT, hMLH1 and hMLH2 genes either in cancer or remote normal-appearing tissues. Aberrant hypermethylation of P16, MGMT, hMLH1 and hMLH2 could be predictive of gastric cancer. PMID- 23803093 TI - Experiences of Turkish women with breast cancer during the treatment process and facilitating coping factors. AB - BACKGROUND: Breast cancer is the most common type of cancer among women in Turkey and around the world. Treatment adversely affects women's physical, psychological, and social conditions. The purpose of this study was to identify the experiences of Turkish women with breast cancer and the facilitating coping factors when they receive chemotherapy. METHODS: A phenomenological approach was used to explain the experiences and facilitating factors of breast cancer patients during the treatment period. Data were collected through individual semi structured interviews. The sample comprised 11 women with breast cancer receiving treatment. RESULTS: At the end of the interviews conducted with women with breast cancer, two main themes were identified: adjustment and facilitating coping factors. The adjustment main theme had two sub-themes: strains and coping. Women with breast cancer suffer physical and psychological strains as well as stress related to social and health systems. While coping with these situations, they receive social support, turn to spirituality and make new senses of their lives. The facilitating coping factors main theme had four sub-themes: social support, disease-related factors, treatment-related factors and relationships with nurses. It has been determined that women receiving good social support, having undergone preventive breast surgery and/or getting attention and affection from nurses can cope with breast cancer more easily. CONCLUSIONS: Women with breast cancer have difficulty in all areas of their lives in the course of the disease and during the treatment process. Therefore, nurses should provide holistic care, teaching patients how to cope with the new situation and supporting them spiritually. Since family support is very important in Turkish culture, patients' relatives should be informed and supported at every stage of the treatment. PMID- 23803094 TI - Lack of relationships between FGF19 staining pattern, lymph node metastasis and locally invasive characteristics of the tumor in colorectal cancers. AB - INTRODUCTION: Colorectal cancers are in the top of the cancer-related causes of death in the world and lymph node metastasis is accepted as the primary prognostic factor. In this study, correlations of FGF19 staining pattern with local invasion and lymph node metastasis in a series of colorectal cancers were investigated. METHODS: This studyincluded 81 colorectal cancer patients who underwent surgery in our hospital with no evidence of preoperative radiological distant metastasis. Routine pathological examination of the resection material was performed in order to identify vascular, perineural and serosal infiltration, regional lymph node metastasis and the degree of differentiation. Tumor tissue samples were stained with an immunohistochemistry method for FGF 19 evaluation and the staining pattern was statistically compared with the above mentioned characteristics of the tumors. RESULTS: The patient population consisted of 47 females and 34 males with a median age of 70 years. In 40 patients regional lymph nodes were positive and 51%, 32% and 38% had serosal, perineural and vascular invasion. While 64 cases were moderately-differentiated, 11 cases were well differentiated and 6 poorly- differentiated, there was no association with FGF 19 staining, including intensity. CONCLUSION: No evidence of significant statistically correlation was found between FGF 19 staining pattern and serosal, perineural, vascular invasion, lymph node involvement and degree of differentiation. PMID- 23803095 TI - Meta-analysis of the CYP1A2 -163C>A polymorphism and lung cancer risk. AB - Many published studies have concerned associations between the CYP1A2 -163 C>A polymorphism and risk of lung cancer, but the results have been inconsistent. Therefore, we performed a meta-analysis to obtain a more precise estimate. We searched the PubMed database up to March 1, 2013 for relevant cohort and case control studies. Supplementary search was conducted manually by searching the references of the included studies and relevant meta-analyses. A meta-analysis was performed using RevMan 5.2 software for calculation of pooled odds ratios (ORs) and relevant 95% confidence intervals (CIs) after data extraction. Finally, seven case-control studies and one nested case-control study involving 1,675 lung cancer patients and 2,393 controls were included. The meta-analysis showed that there was no association of CYP1A2 -163 C>A polymorphism with risk of lung cancer overall [(OR=0.89, 95%CI= 0.74-1.07) for C vs. A; (OR=0.73, 95%CI= 0.50-1.07) for AA vs. CC ; (OR=0.82, 95%CI= 0.62-1.09) for AC vs. CC; (OR=0.79, 95%CI= 0.58 1.07) for (AC+AA) vs. CC; and (OR=0.87, 95%CI= 0.67-1.13) for AA vs. (CC+AC)]. Subgroup analysis indicated that there was an associationbetween CYP1A2 -163C>A polymorphism and lung cancer risk for population-based controls, a trend risk for SCCL (squamous cell carcinoma of lung) and Caucasians. These results suggested that -163 C>A polymorphism is likely to be associated with risk of lung cancer compared with population-based controls. PMID- 23803096 TI - Relationship between colonic polyp type and the neutrophil/ lymphocyte ratio as a biomarker. AB - AIM: We designed this study to investigate the neutrophil lymphocyte ratio as a biomarker in distinguishing colonic polyps which are neoplastic or non neoplastic. MATERIALS AND METHODS: One hundred and twenty-five patients with colonic polyps were enrolled into the study. The following data were obtained from a computerized patient registry database: mean platelet volume (MPV), uric acid (UA), platelet count (PC), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT) and the neutrophil to lymphocyte ratio (NLR). Exclusion criteria were active infectious disease, hematological disorders, and malignancies. Colonic polyps divided into two groups as neoplastic polyps (tubular adenoma, villous adenoma, tubulovillous adenoma) and non-neoplastic polyps (hyperplastic polyps, inflammatory pseudopolyps etc). The relationship between colonic polyp type and NLR was evaluated with statistical analysis. RESULTS: There were 67 patients (53.6%) with neoplastic and 58 (46.4%) patients with non-neoplastic polyps. Mean NLRs of neoplastic and non-neoplastic groups were respectively 3.32+/-2.54 and 2.98+/-3.16 (P<0.05). CONCLUSION: Although sensitivity and specificity are not high, NLR may be used as a biomarker of neoplastic condition of colonic polyps. PMID- 23803097 TI - The methylenetetrahydrofolate reductase C677T polymorphism influences risk of esophageal cancer in Chinese. AB - Methylenetetrahydrofolate reductase (MTHFR) plays a central role in folate metabolism. This study with 381 esophageal cancer patients and 432 healthy controls was conducted to examine the association of MTHFR C677T and A1298C polymorphisms with susceptibility to esophageal cancer (EC) in a Chinese population. Compared with the CC genotype of MTHFR C677T, subjects carrying homozygote TT and variant genotypes (CT+TT) demonstrated reduced risk of EC with adjusted ORs (95% CI) of 0.44 (0.28-0.71) and 0.57 (0.37-0.88), respectively. However, no association was found between the MTHFR A1298C polymorphism and the risk of EC. Comparing to haplotype CA, haplotypes TA and TC could reduce the susceptibility to EC with adjusted ORs (95% CI) of 0.61(0.47-0.79) and 0.06 (0.01 0.43), respectively. In conclusion, the present study suggested that the MTHFR C677T polymorphism can markedly influence the risk of EC in Chinese. PMID- 23803098 TI - The XRCC3 Thr241Met polymorphism influences glioma risk - a meta-analysis. AB - BACKGROUND: Findings from previous published studies regarding the association of the XRCC3 Thr241Met polymorphism with glioma susceptibility have often been conflicting. Therefore, a meta-analysis including all available publications was carried out to make a more precise estimation of the potential relationship. METHODS: By searching the electronic databases of Pubmed and Embase (up to April 1st, 2013), a total of nine case-control studies with 3,752 cases and 4,849 controls could be identified for inclusion in the current meta-analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the strength of the association. RESULTS: This meta-analysis showed the XRCC3 Thr241Met polymorphism to be significantly associated with decreased glioma risk in the allelic model (Met allele vs. Thr allele: OR= 0.708, 95%CI= 0.631-0.795). Moreover, we also observed a statistically significant association between the XRCC3 Thr241Met polymorphism and reduced glioma risk in analyses stratified by ethnicity (Asian) and source of controls (hospital based) in the allelic model. CONCLUSIONS: Current evidence suggests that the XRCC3 Thr241Met polymorphism may be a risk factor for glioma development, especially in Asians. PMID- 23803099 TI - Viral hepatitis and liver cancer on the Island of Guam. AB - Patient records from the Guam Cancer Registry were compared with patients listed in a health department viral hepatitis case registry and the numbers of liver cancer and viral hepatitis cases were compared by ethnicity. Hepatitis C was the form of viral hepatitis most common among liver cancer cases on Guam (63.3% of viral hepatitis-associated liver cancer cases). Since viral hepatitis is an important cause of liver cancer, studies such as the present one may provide the information necessary to establish programs (screening of populations at risk and infant vaccination in the case of hepatitis B, for example) that may lessen the impact of liver cancer in the future. PMID- 23803100 TI - Prevalence of human papillomavirus in women from Saudi Arabia. AB - BACKGROUND: Human papillomavirus (HPV) infection is the main causes of cervical cancer in women worldwide. The goal of the present study was to determine the prevalence and distribution of HPV genotypes in women from Saudi Arabia. Recently, several HPV detection methods have been developed, each with different sensitivities and specificities. METHODS: In this study, total forty cervical samples were subjected to polymerase chain reaction and hybridization to BioFilmChip microarray assessment. RESULTS: Human papillomavirus (HPV) infections were found in 43% of the specimens. The most prevalent genotypes were HPV 16 (30%) HPV 18 (8.0%) followed by type HPV 45, occurring at 5.0%. CONCLUSION: Our finding showed the HPV infection and prevalence is increasing at alarming rate in women of Saudi Arabia. There was no low risk infection detected in the tested samples. The BioFilmChip microarray detection system is highly accurate and suitable for detection of single and multiple infections, allowing rapid detection with less time-consumption and easier performance as compared with other methods. PMID- 23803101 TI - Prognostic value of subcarinal lymph node metastasis in patients with esophageal squamous cell carcinoma. AB - PURPOSE: The 7th edition of the American Joint Committee on Cancer Staging Manual for esophageal cancer (EC) categorizes N stage according to the number of metastatic lymph nodes (LNs), irrespective of the site. The aim of this study was to determine the prognostic value of subcarinal LN metastasis in patients undergoing esophagectomy for esophageal squamous cell carcinoma (ESCC). METHODS: A retrospective analysis of 507 consecutive patients with ESCC was conducted. Potential clinicopathological factors that could influence subcarinal LN metastasis were statistically analyzed. Univariate and multivariate analyses were also performed to evaluate the prognostic parameters for survival. RESULTS: The frequency of subcarinal LN metastasis was 22.9% (116/507). Logistic regression analysis showed that tumor length (>3 cm vs <= 3 cm; P=0.027), tumor location (lower vs upper/middle; P=0.009), vessel involvement (Yes vs No; P=0.001) and depth of invasion (T3-4a vs T1-2; P=0.012) were associated with 2.085-, 1.810-, 2.535- and 2.201- fold increases, respectively, for risk of subcarinal LN metastasis. Multivariate analyses showed that differentiation (poor vs well/moderate; P=0.001), subcarinal LN metastasis (yes vs no; P=0.033), depth of invasion (T3-4a vs T1-2; P=0.014) and N staging (N1-3 vs N0; P=0.001) were independent prognostic factors. In addition, patients with subcarinal LN metastasis had a significantly lower 5-year cumulative survival rate than those without (26.7% vs 60.9%; P<0.001). CONCLUSIONS: Subcarinal LN metastasis is a predictive factor for long-term survival in patients with ESCC. PMID- 23803102 TI - Epidermal growth factor receptor gene polymorphisms and gastric cancer in Iran. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) is a transmembrane receptor which contributes to many processes involved in cell survival, proliferation and inhibits apoptosis, that may lead to cancer development. Gastric cancer is one of the most common diseases of digestive system that has low 5-year-survival. The aim of this research was to determine the significance of EGFR tyrosine kinase domain gene polymorphisms in gastric cancer in Iran. MATERIALS AND METHODS: In the present study, 83 patients with gastric cancer and 40 normal subjects were investigated for EGFR gene polymorphisms in exons 18-21 by PCR-SSCP. Then, DNA sequencing was conducted for different mobility shift bands. Finally the data were statistically analyzed using the chi-2 test and the SPSSver.16 program. RESULTS: Exon 18 of EGFR gene showed three different bands in SSCP pattern and DNA sequencing displayed one mutation. SSCP pattern of Exons 19 and 21 did not show different migration bands. Exon 20 of EGFR gene revealed multiple migrate bands in SSCP pattern. DNA sequencing displayed 2 mutations in this exon: one mutation was caused amino acid change and another mutation was silent. CONCLUSION: It may be that EGFR tyrosine kinase gene polymorphisms differ between populations and screening could be useful in gastric cancer patients who might benefit from tyrosine kinase inhibitor therapy. PMID- 23803103 TI - In vitro antitumor properties of an isolate from leaves of Cassia alata L. AB - Leaf extracts of Cassia alata L (akapulko), traditionally used for treatment of a variety of diseases, were evaluated for their potential antitumor properties in vitro. MTT assays were used to examine the cytotoxic effects of crude extracts on five human cancer cell lines, namely MCF-7, derived from a breast carcinoma, SK BR-3, another breast carcinoma, T24 a bladder carcinoma, Col 2, a colorectal carcinoma, and A549, a non- small cell lung adenocarcinoma. Hexane extracts showed remarkable cytotoxicity against MCF-7, T24, and Col 2 in a dose-dependent manner. This observation was confirmed by morphological investigation using light microscopy. Further bioassay-directed fractionation of the cytotoxic extract led to the isolation of a TLC-pure isolate labeled as f6l. Isolate f6l was further evaluated using MTT assay and morphological and biochemical investigations, which likewise showed selectivity to MCF-7, T24, and Col 2 cells with IC50 values of 16, 17, and 17 MUg/ml, respectively. Isolate f6l, however, showed no cytotoxicity towards the non-cancer Chinese hamster ovarian cell line (CHO-AA8). Cytochemical investigation using DAPI staining and biochemical investigation using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-a method used to detect DNA fragmentation-together with caspase assay, demonstrated apoptotic cell death. Spectral characterization of isolate f6l revealed that it contained polyunsaturated fatty acid esters. Considering the cytotoxicity profile and its mode of action, f6l might represent a new promising compound with potential for development as an anticancer drug with low or no toxicity to non cancer cells used in this study. PMID- 23803104 TI - Differential distribution of microRNAs in breast cancer grouped by clinicopathological subtypes. AB - BACKGROUND: microRNAs (miRNAs) that regulate proliferation, invasion and metastasis are considered to be the principal molecular basis of tumor heterogeneity. Breast cancer is not a homogeneous tissue. Thus, it is very important to perform microarray-based miRNA screening of tumors at different sites. METHODS: Breast tissue samples from the centers and edges of tumors of 30 patients were classified into 5 clinicopathological subtypes. In each group, 6 specimens were examined by microRNA array. All differential miRNAs were analyzed between the edges and centers of the tumors. RESULTS: Seventeen kinds of miRNAs were heterogeneously distributed in the tumors from different clinicopathological subtypes that included 1 kind of miRNA in Luminal A and Luminal B Her2+ subtypes, 4 kinds in Luminal A and Her2 overexpression subtypes, 6 kinds in Luminal B Ki67+ and Luminal B Her2+ subtypes, 2 kinds between Luminal B Ki67+ and triple-negative breast cancer (TNBC) subtypes, 2 kinds between Luminal B Her2+ and TNBC subtypes, and 2 kinds between Luminal B Ki67+, Luminal B Her2+, and TNBC subtypes. Twenty kinds of miRNAs were homogenously distributed in the tumors from different clinicopathological subtypes that included 6 kinds of miRNAs in Luminal B Ki67+ and Luminal B Her2+ subtypes, 1 kind in Luminal B Ki67+ and Her2 overexpression subtypes, 10 kinds between Luminal B Ki67+ and TNBC subtypes, 2 kinds in Luminal B Her2+ and TNBC subtypes, and 1 kind between Luminal B Ki67+, Luminal B Her2+, and TNBC subtypes. CONCLUSIONS: A total of 37 miRNAs were significantly distributed in tumors from the centers to edges, and in all clinicopathological subtypes. PMID- 23803105 TI - Urinary bladder cancer risk factors: a Lebanese case- control study. AB - BACKGROUND: Bladder cancer is the second most incident malignancy among Lebanese men. The purpose of this study was to investigate potential risk factors associated with this observed high incidence. METHODS: A case-control study (54 cases and 105 hospital-based controls) was conducted in two major hospitals in Beirut. Cases were randomly selected from patients diagnosed in the period of 2002-2008. Controls were conveniently selected from the same settings. Data were collected using interview questionnaire and blood analysis. Exposure data were collected using a structured face-to-face interview questionnaire. Blood samples were collected to determine N-acetyltransferase1 (NAT1) genotype by PCR-RFLP. Analyses revolved around univariate, bivariate and multivariate logistic regression, along with checks for effect modification. RESULTS: The odds of having bladder cancer among smokers was 1.02 times significantly higher in cases vs. controls. The odds of exposure to occupational diesel or fuel combustion fumes were 4.1 times significantly higher in cases vs controls. The odds of prostate-related morbidity were 5.6 times significantly higher in cases vs controls. Cases and controls showed different clustering patterns of NAT1 alleles. No significant differences between cases and controls were found for consumption of alcohol, coffee, tea, or artificial sweeteners. CONCLUSIONS: This is the first case-control study investigating bladder cancer risk factors in the Lebanese context. Results confirmed established risk factors in the literature, particularly smoking and occupational exposure to diesel. The herein observed associations should be used to develop appropriate prevention policies and intervention strategies, in order to control this alarming disease in Lebanon. PMID- 23803106 TI - Possible roles of the xenobiotic transporter P-glycoproteins encoded by the MDR1 3435 C>T gene polymorphism in differentiated thyroid cancers. AB - BACKGROUND: P-glycoprotein (Pgp), encoded by the multidrug resistance 1 (MDR1) gene, is an efflux transporter which plays an important role in pharmacokinetics. The current preliminary study was designed to determine associations between a germ-line polymorphism in the MDR1 gene with differentiated thyroid carcinoma (DTC). MATERIALS AND METHODS: In the current case-control study, 60 differentiated thyroid cancers (DTC)- 45 papillary TC (PTC), 9 follicular TC(FTC) and 6 well-differentiated tumors of uncertain malignant potential (WDT-UMP) were examined. Results were compared to a healthy control group (n=58) from the same population. Genomic DNA was extracted from peripheral blood with EDTA and the target gene was genotyped by real-time PCR. RESULTS: Carriers of the variant allele of MDR1 exon 26 polymorphism were at 2.8-fold higher risk of DTC than the control group (odds ratio [OR]: 0.3805, 95% confidence interval [Cl]: 0.1597 0.9065 (p> 0.046). CONCLUSIONS: Presented results suggest that the MDR1 3435TT genotype might influence risk of development of DTC and that the CC genotype might be linked to a poor prognosis. Large-scale studies are now needed to validate this association. PMID- 23803107 TI - Using SEER data to quantify effects of low income neighborhoods on cause specific survival of skin melanoma. AB - BACKGROUND: This study used receiver operating characteristic (ROC) curves to screen Surveillance, Epidemiology and End Results (SEER) skin melanoma data to identify and quantify the effects of socioeconomic factors on cause specific survival. METHODS: 'SEER cause-specific death classification' was used as the outcome variable. The area under the ROC curve was to select best pretreatment predictors for further multivariate analysis with socioeconomic factors. Race and other socioeconomic factors including rural-urban residence, county level % college graduate and county level family income were used as predictors. Univariate and multivariate analyses were performed to identify and quantify the independent socioeconomic predictors. RESULTS: This study included 49,666 patients. The mean follow up time (SD) was 59.4 (17.1) months. SEER staging (ROC area of 0.80) was the most predictive factor. Race, lower county family income, rural residence, and lower county education attainment were significant univariates, but rural residence was not significant under multivariate analysis. Living in poor neighborhoods was associated with a 2-4% disadvantage in actuarial cause specific survival. CONCLUSIONS: Racial and socioeconomic factors have a significant impact on the survival of melanoma patients. This generates the hypothesis that ensuring access to cancer care may eliminate these outcome disparities. PMID- 23803108 TI - Association of immunohistochemically defined molecular subtypes with clinical response to presurgical chemotherapy in patients with advanced breast cancer. AB - Gene expression profiling (GEP) has identified several molecular subtypes of breast cancer, with different clinico-pathologic features and exhibiting different responses to chemotherapy. However, GEP is expensive and not available in the developing countries where the majority of patients present at advanced stage. The St Gallen Consensus in 2011 proposed use of a simplified, four immunohistochemical (IHC) biomarker panel (ER, PR, HER2, Ki67/Tumor Grade) for molecular classification. The present study was conducted in 75 newly diagnosed patients of breast cancer with large (>5cm) tumors to evaluate the association of IHC surrogate molecular subtype with the clinical response to presurgical chemotherapy, evaluated by the WHO criteria, 3 weeks after the third cycle of 5 flourouracil, adriamycin, cyclophosphamide (FAC regimen). The subtypes of luminal, basal-like and HER2 enriched were found to account for 36.0 % (27/75), 34.7 % (26/75) and 29.3% (22/75) of patients respectively. Ten were luminal A and 14 luminal B (8 HER2 negative and 6HER2 positive). The triple negative breast cancer (TNBC) was most sensitive to chemotherapy with 19% achieving clinical complete-response (cCR) followed by HER2 enriched (2/22 (9%) cCR), luminal B (1/6 (7%) cCR) and luminal A (0/10 (0%) cCR). Heterogeneity was observed within each subgroup, being most marked in the TNBC although the most responding tumors, 8% developing clinical-progressive-disease. The study supports association of molecular subtypes with response to chemotherapy in patients with advanced breast cancer and the existence of further heterogeneity within subtypes. PMID- 23803109 TI - Identification of a novel BRCA2 and CHEK2 A-C-G-C haplotype in Turkish patients affected with breast cancer. AB - BACKGROUND: Many breast cancers are caused by certain rare and familial mutations in the high or moderate penetrance genes BRCA1, BRCA2 and CHEK2. The aim of this study was to examine the allele and genotype frequencies of seven mutations in BRCA1, BRCA2 and CHEK2 genes in breast cancer patients and to investigate their isolated and combined associations with breast cancer risk. METHODS: We genotyped seven mutations in BRCA1, BRCA2 and CHEK2 genes and then analyzed single variations and haplotype associations in 106 breast cancer patients and 80 healthy controls. RESULTS: We found significant associations in the analyses of CHEK2- 1100delC (p=0.001) and BRCA1-5382insC (p=0.021) mutations in breast cancer patients compared to controls. The highest risk was observed among breast cancer patients carrying both CHEK2-1100delC and BRCA2- Met784Val mutations (OR=0.093; 95%CI 0.021-0.423; p=0.001). We identified one previously undescribed BRCA2 and a CHEK2 four-marker haplotype of A-C-G-C which was overrepresented (?2=7.655; p=0.0057) in the patient group compared to controls. CONCLUSION: In this study, we identified a previously undescribed BRCA2 and CHEK2 A-C-G-C haplotype in association with the breast cancer in our population. Our results further suggest that the CHEK2-1100delC mutation in combination with BRCA2-Met784Val may lead to an unexpected high risk which needs to be confirmed in larger cohorts in order to better understand their role in the development and prognosis of breast cancer. PMID- 23803110 TI - Estimation of cancer cases using capture-recapture method in Northwest Iran. AB - BACKGROUND: Under-ascertainment and over-ascertainment are common phenomena in surveillance and registry systems of health-related events. Capture-recapture is one of the methods which is applied to determine the sensitivity of surveillance or registry systems to recognize cancer cases. This study aimed to estimate the number of cancers using data available both in the Cancer Registry Center of Northwestern Iran and in the Population-based Cancer Registry Center of Iran. MATERIAL AND METHODS: The studied population consisted of all cancerous cases in the northwest of Iran from 2008 to 2010. All data were extracted from two resources and entered into Microsoft Excel software. After removing common and repeat cases the data were statistically analyzed using a capture-recapture studies' specific software "CARE 1.4". Estimations were calculated by Chapman and Petersen methods with the approximate confidence interval of 95%. RESULTS: From 2008 to 2010, the number of all cancer cases was estimated to be 21,652 (CI 95%: 19,863-22,101). Sensitivity rate of all cancer cases was 83.9% and that of Population-based Cancer Registry Center of Iran was 52%. It was 93.1% considering both resources. CONCLUSION: Using two resources and the capture-recapture method rather than a single resource may be a more reliable method to estimate the number of cancer cases. PMID- 23803111 TI - Fingerprint of carcinogenic semi-volatile organic compounds (SVOCs) during bonfire night. AB - It is well known that increased incidences of lung, skin, and bladder cancers are associated with occupational exposure to PAHs. Animal studies show that certain PAHs also can affect the hematopoietic and immune systems and can produce reproductive, neurologic, and developmental effects. As a consequence, several studies have been attempted to investigate the fate of PAHs in atmospheric environment during the past decades. However, there is still a lack of information in regard to the atmospheric concentration of PAHs during the "Bon Fire Night". In this study, twenty-three polycyclic aromatic hydrocarbons and twenty-eight aliphatics were identified and quantified in the PM10 and vapour range in Birmingham (27th November 2001-19th January 2004). The measured concentrations of total particulate and vapour (P+V) PAHs were consistently higher at the BROS in both winter and summer. Arithmetic mean total (P+V) PAH concentrations were 51.04+/-47.62 ng m-3 and 22.30+/-19.18 ng m-3 at the Bristol Road Observatory Site (BROS) and Elms Road Observatory Site (EROS) respectively. In addition arithmetic mean total (P+V) B[a]P concentrations at the BROS were 0.47+/-0.39 ng m-3 which exceeded the EPAQS air quality standard of 0.25 ng m-3. On the other hand, the arithmetic mean total (P+V) aliphatics were 81.80+/-69.58 ng m-3 and 48.00+/-35.38 ng m-3 at the BROS and EROS in that order. The lowest average of CPI and Cmax measured at the BROS supports the idea of traffic emissions being a principle source of SVOCs in an urban atmosphere. The annual trend of PAHs was investigated by using an independent t-test and one- way independent ANOVA analysis. Generally, there is no evidence of a significant decline of heavier MW PAHs from the two data sets, with only Ac, Fl, Ph, An, 2 MePh, 1+9-MePh, Fluo and B[b+j+k]F showing a statistically significant decline (p<0.05). A further attempt for statistical analysis had been conducted by dividing the data set into three groups (i.e. 2000, 2001-2002 and 2003-2004). For lighter MW compounds a significant level of decline was observed by using one-way independent ANOVA analysis. Since the annual mean of O3 measured in Birmingham City Centre from 2001 to 2004 increased significantly (p<0.05), it may be possible to attribute the annul reduction of more volatile PAHs to the enhanced level of annual average O3. By contrast, the heavier MW PAHs measured at the BROS did not show any significant annual reduction, implying the difficulties of 5- and 6-ring PAHs to be subject to photochemical decomposition. The deviation of SVOCs profile measured at the EROS was visually confirmed during the "Bonfire Night" festival closest to the 6th November 2003. In this study, the atmospheric PAH concentrations were generally elevated on this day with concentrations of Fl, Ac, B[a]A, B[b+j+k]F, Ind and B[g,h,i]P being particularly high. PMID- 23803112 TI - Clinical outcomes and prognostic factors associated with the response to erlotinib in non-small-cell lung cancer patients with unknown EGFR mutational status. AB - BACKGROUND: The efficacy of erlotinib is controversial in patients with unknown EGFR mutational status. The aim of this study was to identify the clinicopathological factors that are predictive of erlotinob treatment outcomes for NSCLC patients with unknown EGFR mutational status. MATERIALS AND METHODS: A retrospective analysis of 109 patients with advanced NSCLC who had previously failed at least one line of chemotherapy and received subsequent treatment with erlotinib (150 mg/day orally) was performed. A Cox proportional hazard model for univariate and multivariate analyses was used to identify the baseline clinical parameters correlating with treatment outcome, expressed in terms of hazard ratios (HRs) and 95% confidence intervals. RESULTS: The median treatment duration was 15 weeks (range, 4-184). The disease control rate was 55%, including disease stability for >= 3 months for 40% of the patients. Median progression-free survival and median overall survival (OS) were 4.2 and 8.5 months, respectively. The Cox model indicated that an Eastern Cooperative Oncology Group performance status (ECOG PS) >= 2 (HR 3.82; p<0.001), presence of intra-abdominal metastasis (HR 3.42; p=0.002), 2 or more prior chemotherapy regimens (HR 2.29; p=0.021), and weight loss >5% (HR 2.05; p=0.034) were independent adverse prognostic factors for OS in NSCLC patients treated with erlotinib. CONCLUSIONS: This study suggests that NSCLC patients should be enrolled in erlotinib treatment after a first round of unsuccessful chemotherapy to improve treatment success, during which they should be monitored for intra-abdominal metastasis and weight loss. PMID- 23803113 TI - Review of strategies in promoting attendance for cervical screening. AB - BACKGROUND: The importance of cervical screening has been addressed in numerous studies. However, reviews conducted to explore of strategies to promoting attendance for cervical screening have been limited. This study aimed to explore strategies to promote attendance for cervical screening. MATERIALS AND METHODS: A literature search from databases (1994-2011) was undertaken to include papers that identified strategies related to the cervical screening. RESULTS: Twenty four papers were included in this review. The review of existing strategies identified valuable information on cervical screening and areas that could be improved in meeting womens' needs. CONCLUSIONS: The review highlighted important aspects of cervical screening that could be further addressed by promoting strategies to attendance. Assessing women's health beliefs, inpatient cervical cancer screening, nurse-led screening, and cognition-emotion focused programs are among the strategies to promote attendance for pap smear testing. PMID- 23803114 TI - Lifestyle behaviors and early diagnosis practices of cancer patients. AB - BACKGROUND: The aim was to determine the lifestyle behaviors and the practices for early diagnosis of cancer of cancer patients. MATERIALS AND METHODS: A descriptive cross-sectional design was used for this study. The sample consisted of 222 patients with a diagnosis of cancer (non-random sample method). Ethical permission was obtained of the Non-interventional Research Ethics Committee of our Institution. Values of p<0.05 were accepted as statistically significant. RESULTS: It was observed that 54.4% of the patients had never performed breast self-examination, 60.8% had never had a mammography, and 71.2% had never had a Pap smear. Sixty-six point two percent of patients had never had screening for colon cancer within the past ten years. GIS cancers were higher in smokers and ex smokers (p=0.005), in drinkers and in ex-drinkers (p=0.000). The breast cancer rate was higher in obese people (p=0.019). CONCLUSIONS: The results of this study provide information on the healthy lifestyle behavior of cancer patients before their diagnosis, and their use of early diagnosis practices. The important aspect of this study is to extend cancer patients' period of life after the diagnosis and treatment process, to make them conscious of risky lifestyle and nutritional behavior so that they can maintain a high quality of life, and to start initiatives in this direction that would ensure changes in behavior. PMID- 23803115 TI - Tumor necrosis factor-alpha 238 G/A polymorphism and risk of hepatocellular carcinoma: evidence from a meta-analysis. AB - BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) plays a very important role in the development and progression of cancer. Many epidemiological studies have evaluated associations between the TNF-alpha 238 G/A polymorphism and hepatocellular carcinoma (HCC) risk, but the published data are inconclusive. Therefore, we performed the present meta-analysis. METHODS: Electronic searches of several databases were conducted for all publications on the association between TNF-alpha 238 G/A polymorphism and HCC through July 2012. Asummary odds ratio (OR) with its 95% confidence interval (CI) were calculated to evaluate the strength of this association. RESULTS: Eleven case-control studies with a total of 1,572 HCC cases and 1,875 controls were finally included in this meta analysis. Overall, the TNF-alpha 238 G/A polymorphism was significantly associated with increased risk of hepatocellular carcinoma in three genetic comparison models (For A versus G: OR 1.32, 95%CI 1.04-1.69, P = 0.02, I2 = 40%; for AG versus GG: OR 1.32, 95%CI 1.02-1.71, P = 0.03, I2 = 40%; for AA/AG versus GG: OR 1.33, 95%CI 1.03-1.72, P = 0.03, I2 = 41%) when all studies were pooled. Subgroup analysis by ethnicity further showed that there was a significant association between the TNF-alpha 238 G/A polymorphism and risk of HCC in Asians under three genetic comparison models (For A versus G: OR 1.30, 95%CI 1.00-1.68, P = 0.05, I2 = 45% for AA/AG versus GG: OR 1.31, 95%CI 1.00-1.71, P = 0.05, I2 = 46%). CONCLUSIONS: This meta-analysis provided convincing evidence that the TNF alpha 238 G/A polymorphism is associated with increased susceptibility to HCC. However, more well-designed studies with large sample size are needed to validate this association in Caucasians. PMID- 23803116 TI - Determining the awareness of and compliance with breast cancer screening among Turkish residential women. AB - BACKGROUND: Breast cancer is the leading cause of cancer-related deaths in women. Despite being associated with high morbidity and mortality, breast cancer is a disease that can be diagnosed and treated early. MATERIALS AND METHODS: In this cross-sectional study of 321 women, data were collected by Questionnaire, Breast Cancer Risk Assessment Form and Champion's Health Belief Model Scale. Mann Whitney U, Kruskal-Wallis, Chi- squared tests and logistic regression were used in the statistical analysis. RESULTS: It was found that only 2.2% of women have high and very high risk levels of breast cancer risk. There is a positive correlation between early diagnosis techniques and Health Belief Model Sub Dimension scores which are sensibility, health motivation, BSE (Breast self examination) self-efficient perception and negative correlation between mammography barrier score and BSE barrier score (p 0.05). When factors for not having BSE were examined, it was determined that the women who do not have information about breast cancer and the women who smoke have a higher risk of not having BSE. CONCLUSIONS: It is important to determine health beliefs and breast cancer risk levels of women to increase the frequency of early diagnosis. Women's health beliefs are thought to be a good guide for planning health education programs for nurses working in this area. PMID- 23803117 TI - Retrospective study of predictors of bone metastasis in prostate cancer cases. AB - INTRODUCTION: The purpose of this study was to identify clinical profiles of patients with low risk of having bone metastases, for which bone scanning could be safely eliminated. MATERIALS AND METHODS: This retrospective cross sectional study looked at prostate cancer patients seen in the Urology Departments in 2 tertiary centres over the 11 year period starting from January 2000 to May 2011. Patient demographic data, levels of PSA at diagnosis, Gleason score for the biopsy core, T-staging as well as the lymph node status were recorded and analysed. RESULTS: 258 men were included. The mean age of those 90 men (34.9%) with bone metastasis was 69.2 +/- 7.3 years. Logistic regression found that PSA level (P=0.000) at diagnosis and patient's nodal-stage (P=0.02) were the only two independent variables able to predict the probability of bone metastasis among the newly diagnosed prostate cancer patients. Among those with a low PSA level less than 20 ng/ml, and less than 10 ng/ml, bone metastasis were detected in 10.3% (12 out of 117) and 9.7% (7 out of 72), respectively. However, by combining PSA level of 10 ng/ml or lower, and nodal negative as the two criteria to predict negative bone scan, a relatively high negative predictive value of 93.8% was obtained. The probability of bone metastasis in prostate cancer can be calculated with this formula: -1.069+0.007(PSA value, ng/ml) +1.021(Nodal status, 0 or 1)=x Probability of bone metastasis=2.718 x/1+2.718 x. CONCLUSION: Newly diagnosed prostate cancer patients with a PSA level of 10 ng/ml or lower and negative nodes have a very low risk of bone metastasis (negative predictive value 93.8%) and therefore bone scans may not be necessary. PMID- 23803118 TI - Roles of illness attributions and cultural views of cancer in determining participation in cancer-smart lifestyle among Chinese and Western youth in Australia. AB - BACKGROUND: The study investigated the influence of culturally-based health beliefs on engagement in healthy lifestyle behaviour. Specifically, the study compared levels of engagement between Western and Chinese youth in Australia and assessed the extent to which culture-specific attributions about the causes of illness, and health beliefs, predict engagement in healthy lifestyle behaviour. MATERIALS AND METHODS: Ninety-four Western and 95 Chinese (N=189; Mean Age=20.8 years, SD=3 years) young adults completed an online questionnaire. Predictor variables were cultural health beliefs measured by the Chinese Cultural Views on Health and Illness scale (CCVH, Liang et al., 2008), and illness attributions beliefs measured by the Cause of Illness Questionnaire (CIQ, Armstrong and Swartzman, 1999). Outcomes variables were levels of engagement in healthy lifestyle behaviour. RESULTS: Results indicated that Chinese participants have a significantly lower exercising rate and healthy dietary habits compared to the Western sample. Moreover, Chinese participants were found to believe more strongly than Westerners that cancer was associated with factors measured by the Traditional-Chinese-Model (TCM). Finally, the observed relationship between cultural health beliefs and physical inactivity was mediated by attributions of illness, in particular to the supernatural subscale, with the Sobel Test showing a significant mediation (z=-2.63, p=0.004). CONCLUSIONS: Mainstream approaches to encourage healthy lifestyles are unlikely to be effective when educating Chinese youth. Instead, health promotion programs should attempt to address the illness attribution beliefs and educate Chinese youth about the role of diet and exercise in prevention of diseases such as cancer. PMID- 23803119 TI - Global Adult Tobacco Survey (GATS): a case for change in definition, analysis and interpretation of "cigarettes" and "cigarettes per day" in completed and future surveys. AB - BACKGROUND: The Global Adult Tobacco Survey has 15 key indicators, cigarettes smoked per day (CPD) among daily smokers being one of them. The first wave of GATS in 14 countries indicated that mean CPD use is higher in women than men in India only, which is contrary to the current understanding of tobacco use globally. This study was undertaken to understand the unusual findings for mean CPD use in the GATS-India survey. MATERIALS AND METHODS: Items B06a and B06b of the GATS India survey questionnaire that collected information on daily consumption of manufactured and rolled cigarettes were analyzed using SPSS software. Exclusive users were identified from these items after excluding the concurrent users of other tobacco products. Cigarette type, exclusive use and gender stratified analyses were made. Consumption of different types of cigarettes among the mixed users of manufactured and rolled cigarettes were correlated. RESULTS: Higher mean number of CPD use among male daily-smokers was observed than their female counterparts in product specific analysis. Mean CPD as per GATS cigarette definition was higher in males than females for exclusive users but a reverse trend was observed in case of non-exclusive users. Use of manufactured cigarettes increased with increase in use of rolled cigarette among the mixed users and around half of these users reported equal CPD frequency for the both types of cigarettes. CONCLUSIONS: The anomaly in mean CPD estimate in GATS-India data was due to inclusion of two heterogeneous products to define cigarettes, variation in cigarette product specific user proportions contributing to the average and non-exclusive concurrent use of other tobacco products. The consumption pattern of cigarettes among the mixed users highlights bias in CPD reporting. Definition, analysis and interpretation of 'cigarettes per day' in the GATS India survey need to be improved by redefining cigarettes and making product specific analyses. PMID- 23803120 TI - Evaluation of human papillomavirus infections in prostatic disease: a cross sectional study in Iran. AB - BACKGROUND: The role of inflammation in prostate diseases is suggested by the presence of inflammatory cells within the prostate in benign prostatic hyperplasia (BPH) and prostate cancer (PCa) patients. In addition, bacterial and viral infection may lead to chronic and recurrent inflammation of the prostate. The human papillomaviruses (HPVs) are a family of sexually transmitted viruses which have been implicated in the aetiology of cervical cancer and several other malignancies. This study evaluated the frequency of HPV infection in individuals with prostatic disease in Iran. MATERIALS AND METHODS: The study included formalin fixed paraffin- embedded tissue samples of 196 primary prostate cases, including 29 PCa and 167 BPH samples. HPV DNA was purified and amplified through MY09/MY11 and GP5+/GP6+ primers with nested PCR. All patients were interviewed using a questionnaire to collect demographic information. RESULTS: Nested PCR showed that HPV DNA was found in 17.2 percent of PCa samples and 4.8 percent of BPH samples (not significant). CONCLUSIONS: Our data do not support a significant role of HPV infection in prostatic disease in Iranian patients, but demographic data indicated a probable association between presence of HPV DNA and risk of inflammation in prostate tissue which might lead to prostate carcinoma. Further studies are required to elucidate any roles of HPV infection in prostatic disease. PMID- 23803121 TI - Association of SYK genetic variations with breast cancer pathogenesis. AB - Spleen tyrosine kinase (SYK) is a non-receptor type cytoplasmic protein and a known tumor suppressor gene in breast cancer. Polymorphisms in SYK have been reported to be associated with cell invasion/cell morality and an increased risk of cancer development. In this case control study, all exons of the SYK gene and its exon/ intron boundaries were amplified in 200 breast cancer cases and 100 matched controls and then analyzed by single stranded conformational polymorphism. Amplified products showing altered mobility patterns were sequenced and analyzed. Twelve variations were identified in exonic and intronic regions of DNA encoding SH2 domain and kinase domain of the SYK gene. All of these mutations are novel. Among them, 5 missense mutations were observed in exon 15 while one missense mutation was found in exon 8. In addition to these mutations, six mutations were also identified in intronic regions. We found a significant association between SYK mutations and breast cancer and observed that Glu241Arg, a missense mutation is associated with an increase risk of ~7 fold (OR=6.7, 95% CI=1.54-28.8), Thr581Pro (missense mutation) is associated with increased risk of ~16 fold (OR=15.5, 95%CI=2.07-115.45) and 63367 T>G (missense mutation) is associated with increased risk of ~13 fold (OR=12.8, 95%CI=1.71-96.71) for breast cancer. Significant associations were observed for each of these variations with both late menopause (p<0.01) and early menarche (p<0.005) cases when compared to controls. Our findings suggest that the polymorphic gene SYK may contribute to the development of breast cancer in at least the Pakistani population. This study provides an insight view of SYK which may provide a significant finding for the pharmaceutical and biotechnology industry. PMID- 23803122 TI - Impact of routine histopathological examination of gall bladder specimens on early detection of malignancy - a study of 4,115 cholecystectomy specimens. AB - Gall bladder carcinoma is the most common cancer of biliary tree, characterized by rapid progression and a very high mortality rate. Detection at an early stage, however, is indicative of a very good prognosis and prolonged survival. The practice of histopathological examination of gall bladder specimens removed for clinically benign conditions and its usefulness has been a subject of controversy. The present prospective study was carried out over a period of four years in order to find out the incidence of unsuspected gallbladder carcinoma in cholecystectomy specimens received in our histopathology laboratory and to analyze their clinico-pathological features. A total of 4,115 cases were examined. Incidentally detected cases comprised 0.44%, which accounted for 72% of all gall bladder carcinomas detected. The majority were in an early, surgically resectable stage. From the results of this study we recommend that in India and other countries with relatively high incidences of gall bladder carcinoma, all cholecystectomy specimens should be submitted to histopathology laboratory, as this is the only means by which malignancies can be detected at an early, potentially curable stage. PMID- 23803123 TI - Is Helicobacter pylori a poor prognostic factor for HER-2 SISH positive gastric cancer? AB - BACKGROUND: Helicobacter pylori (H. pylori) is one of the risk factors for gastric cancer (GC). Any prognostic effect of HER-2 status in gastric lymph node metastasis in H. pylori positive cases is unknown. MATERIALS AND METHODS: A total of 74 patients, 47 (64%) male, and 27 (34%) female, who had subtotal or total gastrectomy and also positive lymph nodes, were included in the study. Age range was 29-87 years, and median age was 58 years. HER-2 expression was assessed in both gastric resection samples and lymph node material with carcinoma metastasis of the same patient by immunohistochemistry (IHC) and silver in situ hybridization (SISH) methods. H. pylori status was examined in gastric materials of all patients. Relationships between HER-2 status in gastric cancers and lymph nodes and H. pylori status were investigated. RESULTS: H. pylori was positive in 40 cases (54%), and negative in 34 (46%). While in the primary tissues of H. pylori positive cases, SISH positivity for HER-2 was observed in 13 cases (86%), SISH negativity was observed in 2 (14%), in metastatic lymph nodes 21 cases (72%) were SISH positive and 8 cases (28%) were SISH negative (P=0.005 and P=0.019, respectively). Initial CEA values were high in 18 cases (78%) with positive H. pylori and in 5 cases (22%) with negative H. pylori (P=0.009). While SISH data of patients were negative in 59 cases (80%) and positive in 15 cases (20%) in primary tissues, they were negative in 56 cases (75%) and positive in 18 cases (25%) in lymph nodes. Discrepancy between primary tissue and lymph node results was detected in 3 cases, in which SISH was negative in the primary tissue and HER 2 expression was positive in the lymph nodes. CONCLUSIONS: Clinical progression was poor in H. pylori positive cases with HER-2 negativity in primary gastric tissue, but HER-2 positivity in the lymph nodes. SISH positivity can be expected in H. pylori positive cases, and it may be predicted that these cases can benefit from trastuzumab treatment. PMID- 23803124 TI - Burden of smoked and smokeless tobacco consumption in India - results from the Global adult Tobacco Survey India (GATS-India)- 2009-201. AB - BACKGROUND: The Global Adult Tobacco Survey (GATS) was carried out for systematically monitoring tobacco use and for tracking key tobacco control indicators. MATERIALS AND METHODS: A total of 70,802 households, including 42,647 in rural areas and 28,155 in urban areas, were covered with a three stage sampling design. Data were collected on sociodemographic characteristics, knowledge, attitude and practices of tobacco consumption. RESULTS: GATS-India highlighted that total tobacco use among its residents is overall 34.6%, varying for males (47.9%) and females (20.7%). The rural areas of the country exhibit comparatively higher prevalence rates (38.4%) in comparison to urban areas (25.3%). Overall, Khaini, a smokeless tobacco product (12.0%), is the most popular form of tobacco use among males and females, followed by bidi smoking (9.0%). CONCLUSION: Results of GATS data can be used as baseline for evaluation of new tobacco control approaches in India integrating culturally acceptable and cost effective measures. PMID- 23803125 TI - Overexpression of matrix metalloproteinase 11 in Thai prostatic adenocarcinoma is associated with poor survival. AB - BACKGROUND: The incidence of prostate cancer, one of the most common cancers in elderly men, is increasing annually in Thailand. Matrix metalloproteinase 11 (MMP 11) is a member of the extracellular matrix metalloproteases which has been associated with human tumor progression and clinical outcome. AIM: To quantify MMP-11 expression in prostatic adenocarcinoma tissues and to determine whether its overexpression correlates with survival outcome, and to assess its potential as a new prognostic marker. MATERIALS AND METHODS: Expression of MMP-11 was analyzed using immunohistochemistry in 103 Thai patients with prostatic adenocarcinoma. Overall survival was analyzed using Kaplan-Meier methods and Cox regression models. RESULTS: Immunoreactivity of MMP-11 was seen in the stroma of prostatic adenocarcinoma tissue samples, high expression being significantly correlated with poor differentiation in Gleason grading, pathologic tumor stage 4 (pT4), and positive-bone metastasis (p<0.05), but not age and prostatic-specific antigen (PSA) level. Patients with high levels of MMP-11 expression demonstrated significantly shorter survival (p<0.001) when compared to those with low levels. Multivariate analysis showed that MMP-11 expression and pT stage were related with survival in prostatic adenocarcinoma [hazard ratio (HR)=0.448, 95% confidence interval (95%CI)=0.212-0.946, HR=0.333, 95%CI=0.15-0.74, respectively]. CONCLUSIONS: Expression of MMP-11 is significantly associated with survival in prostatic adenocarcinoma. High levels may potentially be used for prediction of a poor prognosis. PMID- 23803126 TI - Bisphosphonates for osteoporosis in nonmetastatic prostate cancer patients receiving androgen-deprivation therapy: a systematic review and meta-analysis. AB - This systematic review was conducted to assess the efficacy and safety of bisphosphonates for prevention and treatment of osteopenia or osteoporosis in men with non-metastatic prostate cancer receiving androgen- deprivation therapy. We searched for randomised controlled trials (RCTs) of bisphosphonates compared with placebo from Pubmed, Embase, the Cochrane Library, and ISI - Science Citation Index. Meta-analyses of pre- specified outcomes (bone mineral density, fractures, and adverse events) were performed using Review Manager. Ten RCTs with a total patient population of 1,017 were identified. There was generally more improvement in bone mineral density of the lumbar spine for patients who received bisphosphonate treatment than placebo or other medical treatment at 12 months (WMD 6.02,95%CI 5.39 to 6.65). Similar effects were also observed for total hip, trochanter or femoral neck bone mineral density. However, there was no significant reduction in fractures. Fever and gastrointestinal symptoms were the most common adverse events (10.4% vs. 1.2%; 0.10% vs. 0.03%). Currently, our meta analysis suggested that oral and intravenous bisphosphonates caused a rapid increase in spine and hip or femoral BMD in non-metastatic prostate cancer patients receiving androgen-deprivation therapy. Fever and gastrointestinal symptoms were common with the use of bisphosphonates. These short-term trials (maximum of 12 months) did not show fracture reduction. In future, more efficient performance of higher quality, more rigorous, large sample, long-term randomised controlled trials (>12 months) are needed where outcomes are detailed. PMID- 23803127 TI - Associations of CYP1A1, GSTM1 and GSTT1 polymorphisms with lung cancer susceptibility in a Northern Indian population. AB - BACKGROUND: Susceptibility to lung cancer has been shown to be modulated by inheritance of polymorphic genes encoding cytochrome P450 1A1 (CYP1A1) and glutathione S transferases (GSTM1 and GSTT1), which are involved in the bioactivation and detoxification of environmental toxins. This might be a factor in the variation in lung cancer incidence with ethnicity. MATERIALS AND METHODS: We conducted a case-control study of 218 northern Indian lung cancer patients along with 238 healthy controls, to assess any association between CYP1A1, GSTM1 and GSTT1 polymorphisms, either separately or in combination, with the likelihood of development of Lung cancer in our population. RESULTS: We observed a significant difference in the GSTT1 null deletion frequency in this population when compared with other populations (OR=1.87, 95%CI: 1.25-2.80-0.73, P=0.002). However, GSTM1 null genotype was found associated with lung cancer in the non smoking subgroup. (P=0.170). CONCLUSIONS: Our study showed the GSTT1 null polymorphism to be associated with smoking-induced lung cancer and the GSTM1 null polymorphism to have a link with non-smoking related lung cancer. PMID- 23803128 TI - Benzochloroporphyrin derivative induced cytotoxicity and inhibition of tumor recurrence during photodynamic therapy for osteosarcoma. AB - Photodynamic therapy (PDT) is a promising cancer treatment modality that uses dye sensitized photooxidation of biologic matter in target tissue. This study explored effects of the photosensitizer BCPD-17 during PDT for osteosarcoma. LM-8 osteosarcoma cells were treated with BCPD-17 and cell viability after laser irradiation was assessed in vitro with the 3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide assay. The effects of BCPD-17 during PDT recurrence were then examined on tumor-bearing mice in vivo. BCPD-17 had dose- dependent cytotoxic effects on LM-8 osteosarcoma cells after laser irradiation which also had energy-dependent effects on the cells. The rate of local recurrence was reduced when marginal resection of mice tumors was followed by BCPD-17-mediated PDT. Our results indicated BCPD-17-mediated PDT in combination with marginal resection of tumors is a potentially new effective treatment for osteosarcoma. PMID- 23803129 TI - Skeletal-related events among breast and prostate cancer patients: towards new treatment initiation in Malaysia's hospital setting. AB - The human skeleton is the most common organ to be affected by metastatic cancer and bone metastases are a major cause of cancer morbidity. The five most frequent cancers in Malaysia among males includes prostate whereas breast cancer is among those in females, both being associated with skeletal lesions. Bone metastases weaken bone structure, causing a range of symptoms and complications thus developing skeletal-related events (SRE). Patients with SRE may require palliative radiotherapy or surgery to bone for pain, having hypercalcaemia, pathologic fractures, and spinal cord compression. These complications contribute to a decline in patient health- related quality of life. The multidimensional assessment of health-related quality of life for those patients is important other than considering a beneficial treatment impact on patient survival, since the side effects of treatment and disease symptoms can significantly impact health-related quality of life. Cancer treatment could contribute to significant financial implications for the healthcare system. Therefore, it is essential to assess the health-related quality of life and treatment cost, among prostate and breast cancer patients in countries like Malaysia to rationalized cost-effective way for budget allocation or utilization of health care resources, hence helping in providing more personalized treatment for cancer patients. PMID- 23803130 TI - Beyond limitations: practical strategies for improving cancer care in Nigeria. AB - BACKGROUND: The burden due to cancers is an emerging public health concern especially in resource-limited countries like Nigeria. The WHO estimates that cancer kills more people than tuberculosis, HIV/AIDS and malaria combined. As people in Nigeria and other developing countries are beginning to survive infectious diseases, there is an observed epidemiologic transition to chronic diseases, such as cancers. In 2008, 75 out of 1,000 Nigerians died of cancer. Despite the rising incidence and public health importance, Nigeria lacks an organized and comprehensive strategy to deal with cancers. MATERIALS AND METHODS: This article reviewed 30 peer-reviewed manuscripts on cancer care in four countries. It highlights the limitations to cancer care in Nigeria; due to lack of awareness, low health literacy, absence of organized screening programs, inadequate manpower (in terms of quality and quantity) as well as limited treatment options. RESULTS: This review led to the formulation of a proposal for Nigerian National Cancer Policy, mainly drawn from effective strategies used in Canada, Brazil and Kenya. This is a vertical cancer program that is patient centered with an emphasis on tobacco control and cancer disease screening (similar to Canada and Brazil). Additionally, it emphasizes primary cancer prevention (similar to Kenya). Its horizontal integration with other disease programs like HIV/AIDS will improve affordability in a poor resourced country like Nigeria. Capacity building for health professionals, hub-and-spoke implementation of screening services, as well as investment in effective treatment options and increased research in cancer care are essential. International 'twinning collaborations' between institutions in richer countries and Nigeria will enhance effective knowledge translation and improve the quality of patient care. CONCLUSIONS: A national cancer policy must be developed and implemented in Nigeria in order to overcome the present limitations which help contribute to the observed increases in cancer morbidity and mortality rates. Cancer control is feasible in Nigeria if the nation was to consider and employ some of the cost-effective strategies proposed here. PMID- 23803131 TI - Dilemmas of oral cancer screening: an update. AB - Oral cancer is a global health burden with high mortality and morbidity. Advances in treatment have failed to improve the relatively poor survival rate due to late stage diagnosis. Early detection and screening have been shown to be effective in reducing mortality and morbidity of most common cancers. Several studies have evaluated the effectiveness of oral cancer screening programs but clear results were not obtained. This narrative commentary aimed to give a critical insight into the dilemma of oral cancer screening and to suggest recommendations for future trends. Conventional oral examination still constitutes the gold standard screening tool for potentially malignant oral lesions and cancer. Interestingly, the findings of the most lasting (15-year) randomized controlled trial on oral cancer screening using visual examination (Kerala) supported the introduction of a screening program in high-risk individuals. Several screening adjuncts exist but are still not at the introduction stage. Further research to find an appropriate adjunct reliable tool for oral cancer screening is needed. In conclusion, oral cancer fulfills most of the essential principles of cancer screening but still many points need to be clarified. Therefore, there is a striking need to establish a global consortium on oral cancer screening that will oversee research and provide recommendations for health authorities at regular intervals. PMID- 23803132 TI - Absence of EZH2 gene mutation in chronic myeloid leukemia patients in blast crisis. PMID- 23803133 TI - Prescription for patient-centered care and cost containment. PMID- 23803134 TI - The OHRP and SUPPORT--another view. PMID- 23803137 TI - The FDA's graphic tobacco warnings and the first amendment. PMID- 23803138 TI - Dual antiplatelet therapy in acute transient ischemic attack and minor stroke. PMID- 23803139 TI - The FDA and graphic cigarette-pack warnings--thwarted by the courts. PMID- 23803140 TI - Assessing participation in a community-based health planning and services programme in Ghana. AB - BACKGROUND: Community participation is increasingly seen as a pre-requisite for successful health service uptake. It is notoriously difficult to assess participation and little has been done to advance tools for the assessment of community participation. In this paper we illustrate an approach that combines a 'social psychology of participation' (theory) with 'spider-grams' (method) to assess participation and apply it to a Community-based Health Planning and Services (CHPS) programme in rural Ghana. METHODS: We draw on data from 17 individual in-depth interviews, two focus group discussions and a community conversation with a mix of service users, providers and community health committee members. It was during the community conversation that stakeholders collectively evaluated community participation in the CHPS programme and drew up a spider-gram. RESULTS: Thematic analysis of our data shows that participation was sustained through the recognition and use of community resources, CHPS integration with pre-existing community structures, and alignment of CHPS services with community interests. However, male dominance and didactic community leadership and management styles undermined real opportunities for broad-based community empowerment, particularly of women, young people and marginalised men. CONCLUSION: We conclude that combining the 'spider-gram' tool and the 'social psychology of participation' framework provide health professionals with a useful starting point for assessing community participation and developing recommendations for more participatory and empowering health care programmes. PMID- 23803136 TI - Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. AB - BACKGROUND: Stroke is common during the first few weeks after a transient ischemic attack (TIA) or minor ischemic stroke. Combination therapy with clopidogrel and aspirin may provide greater protection against subsequent stroke than aspirin alone. METHODS: In a randomized, double-blind, placebo-controlled trial conducted at 114 centers in China, we randomly assigned 5170 patients within 24 hours after the onset of minor ischemic stroke or high-risk TIA to combination therapy with clopidogrel and aspirin (clopidogrel at an initial dose of 300 mg, followed by 75 mg per day for 90 days, plus aspirin at a dose of 75 mg per day for the first 21 days) or to placebo plus aspirin (75 mg per day for 90 days). All participants received open-label aspirin at a clinician-determined dose of 75 to 300 mg on day 1. The primary outcome was stroke (ischemic or hemorrhagic) during 90 days of follow-up in an intention-to-treat analysis. Treatment differences were assessed with the use of a Cox proportional-hazards model, with study center as a random effect. RESULTS: Stroke occurred in 8.2% of patients in the clopidogrel-aspirin group, as compared with 11.7% of those in the aspirin group (hazard ratio, 0.68; 95% confidence interval, 0.57 to 0.81; P<0.001). Moderate or severe hemorrhage occurred in seven patients (0.3%) in the clopidogrel-aspirin group and in eight (0.3%) in the aspirin group (P=0.73); the rate of hemorrhagic stroke was 0.3% in each group. CONCLUSIONS: Among patients with TIA or minor stroke who can be treated within 24 hours after the onset of symptoms, the combination of clopidogrel and aspirin is superior to aspirin alone for reducing the risk of stroke in the first 90 days and does not increase the risk of hemorrhage. (Funded by the Ministry of Science and Technology of the People's Republic of China; CHANCE ClinicalTrials.gov number, NCT00979589.). PMID- 23803141 TI - Patient with dyschromatosis symmetrica hereditaria treated with miniature punch grafting, followed by excimer light therapy. PMID- 23803142 TI - Uncertainty estimation in one-dimensional heat transport model for heterogeneous porous medium. AB - In many practical applications, the rates for ground water recharge and discharge are determined based on the analytical solution developed by Bredehoeft and Papadopulos (1965) to the one-dimensional steady-state heat transport equation. Groundwater flow processes are affected by the heterogeneity of subsurface systems; yet, the details of which cannot be anticipated precisely. There exists a great deal of uncertainty (variability) associated with the application of Bredehoeft and Papadopulos' solution (1965) to the field-scale heat transport problems. However, the quantification of uncertainty involved in such application has so far not been addressed, which is the objective of this wok. In addition, the influence of the statistical properties of log hydraulic conductivity field on the variability in temperature field in a heterogeneous aquifer is also investigated. The results of the analysis demonstrate that the variability (or uncertainty) in the temperature field increases with the correlation scale of the log hydraulic conductivity covariance function and the variability of temperature field also depends positively on the position. PMID- 23803143 TI - Effect of estimated glomerular filtration rate on periprocedural myocardial infarction in patients undergoing elective percutaneous coronary intervention. AB - BACKGROUNDS: Little is known about the effect of the estimated glomerular filtration rate (eGFR) on the periprocedural myocardial infarction (PMI). The aim of this study was to determine an eGFR value that is related with PMI development in patients with stable angina undergoing elective percutaneous coronary intervention (PCI). METHOD: A retrospective analysis was conducted of 257 consecutive PCI patients with stable angina pectoris. The patients were divided into three groups according to eGFR: Group 1: eGFR > 90 mL/min/1.73 m(2), Group 2: eGFR = 60-89 mL/min/1.73 m(2), and Group 3: eGFR = 30-59 mL/min/1.73 m(2). Cardiac biomarkers were measured before, at 8, and at 24 h after the procedure. RESULTS: Periprocedural myocardial infarction occurred in 19% of the study patients. The frequency of PMI was 13.8% in group 1, 15.2% in group 2, and 35% in group 3 (p = 0.002). There was an inverse relationship with increasing cardiac biomarkers and decreasing eGFR values. Multiple regression analysis showed that an eGFR value between 30 and 59 mL/min/1.73 m(2) was an independent variable that significantly affected PMI development after PCI. CONCLUSIONS: An estimated glomerular filtration rate between 30 and 59 mL/min/1.73 m(2) is a predictor of developing PMI after elective PCI in patients with stable angina pectoris. PMID- 23803144 TI - Fine mapping of a supernumerary proleg mutant (E(Cs) -l) and comparative expression analysis of the abdominal-A gene in silkworm, Bombyx mori. AB - Patterning and phenotypic variations of appendages in insects provide important clues on developmental genetics. In the silkworm Bombyx mori, morphological variations associated with the E complex, an analogue of the Drosophila melanogaster bithorax complex, mainly determine the shape and number of prolegs on abdominal segments. Here, we report the identification and characterization of the allele responsible for the supernumerary crescents and legs-like (E(Cs) -l) mutant, a model derived from spontaneous mutation of the E complex, with supernumerary legs and extra crescents. Fine mapping with 1605 individuals revealed a ~68 kb sequence in the upstream intergenic region of B. mori abdominal A (Bmabd-A) clustered with the E(Cs) -l locus. Quantitative real-time PCR (qRT PCR) and Western blotting analyses disclosed a marked increase in Bmabd-A expression in the E(Cs) -l mutant at both the transcriptional and translational levels, compared to wild-type Dazao. Furthermore, we observed ectopic expression of the Bmabd-A protein in the second abdominal segment (A2) of the E(Cs) -l mutant. Our results collectively suggest that the 68 kb region contains important regulatory elements of the Bmabd-A gene, and provide evidence that the gene is required for limb development in abdominal segments in the silkworm. PMID- 23803145 TI - Impact of obesity on endometrial blood flow in women without polycystic ovarian syndrome during intracytoplasmic sperm injection. AB - BACKGROUND: Obesity may exert a negative effect on in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment. However, the effect of obesity on the endometrium remains unknown. This study was designed to assess the effect of isolated body mass index (BMI) on endometrial blood supply in non polycystic ovary syndrome (PCOS) women during ICSI by power Doppler Ultrasound. METHODS: An observational prospective study was carried out. A total of 206 patients without PCOS were divided into 4 groups based on Chinese BMI classification (kg/m(2): underweight (BMI < 18.5), normal weight (18.5 less than or equal to BMI < 24), overweight (24 less than or equal to BMI < 28), and obese (BMI greater than or equal to 28). Endometrial thickness, endometrial pattern, endometrial spiral arterial resistance index (RI) and pulsatility index (PI) values and systolic/diastolic ratio (S/D) were assessed on the day of human chorionic gonadotropin administration. RESULTS: Obese patients required more doses of gonadotrophin and longer stimulation duration than the normal weight patients (P < 0.05). Endometrial thickness and pattern were not statistically different between the 4 BMI subgroups (P > 0.05). Subendometrial blood flow was detected in 165 (80.1%) patients and spiral arterial PI was significantly higher in the obese group than in the normal weight and underweight groups (P < 0.05). All parameters of ICSI outcome were comparable, including pregnancy and miscarriage rates. CONCLUSIONS: Obesity (BMI greater than or equal to 28 kg/m(2)) appears to exert a negative effect on endometrial and subendometrial blood flow based on the Chinese standard of obesity; however, it seems to have no significant effect on ICSI outcomes in non-PCOS women. PMID- 23803146 TI - Efficacy and safety of dipeptidyl peptidase-4 inhibitors and metformin as initial combination therapy and as monotherapy in patients with type 2 diabetes mellitus: a meta-analysis. AB - AIMS: This meta-analysis was performed to provide an update on the efficacy and safety of dipeptidyl peptidase-4 (DPP-4) inhibitors and metformin as initial combination therapy and as monotherapy in patients with type 2 diabetes mellitus (T2DM). METHODS: We conducted a search on MEDLINE, Embase and Cochrane Collaborative database for randomized controlled trials (RCTs) of DPP-4 inhibitors and metformin as initial combination therapy or as monotherapy in patients with T2DM by the end of December 2012, using the key words 'alogliptin', 'dutogliptin', 'linagliptin', 'saxagliptin', 'sitagliptin', 'vildagliptin' and 'metformin'. RCTs were selected for meta-analysis if (1) they were RCTs comparing DPP-4 inhibitors plus metformin as initial combination therapy or DPP-4 inhibitor monotherapy to metformin monotherapy, (2) duration of treatment was >=12 weeks and (3) reported data on haemoglobin A1c (HbA1c) change, fasting plasma glucose (FPG) change, weight change, adverse cardiovascular (CV) events, hypoglycaemia or gastrointestinal adverse events (AEs). RESULTS: A total of eight RCTs were included. Compared with metformin monotherapy, DPP-4 inhibitors monotherapy was associated with lower reduction in HbA1c level [weighted mean differences (MD) = 0.28, 95% confidence intervals (CIs) (0.17, 0.40), p < 0.00001], lower reduction in FPG level [MD = 0.81, 95% CI(0.60, 1.02), p <0.00001], lower weight loss [MD = 1.51, 95% CI (0.89, 2.13), p < 0.00001], but lower risk of adverse CV events [risk ratio (RR) = 0.36, 95% CI (0.15, 0.85), p = 0.02], lower risk of hypoglycaemia [RR = 0.44, 95% CI (0.27, 0.72), p = 0.001] and lower risk of gastrointestinal AEs [RR = 0.63, 95% CI(0.55, 0.70), p <0.00001]. Compared with metformin monotherapy, DPP-4 inhibitors plus metformin as initial combination therapy was associated with higher reduction in HbA1c level [MD = -0.49, 95% CI ( 0.57, -0.40), p < 0.00001], higher reduction in FPG level [MD = -0.80, 95% CI ( 0.87, -0.74), p < 0.00001], lower weight loss [MD = 0.44, 95% CI (0.22, 0.67), p = 0.0001]; but was not associated with a further reduction in adverse CV events [RR=0.54, 95% CI (0.25, 1.19), p = 0.13], nor the higher risk of hypoglycaemia [RR = 1.04, 95% CI (0.72, 1.50), p = 0.82], nor the prolonged risk of gastrointestinal AEs [RR = 0.98, 95% CI (0.88, 1.10), p = 0.77]. CONCLUSIONS: DPP 4 inhibitors, which are safe and effective in controlling the blood glucose, may possibly decrease the risk of CV events in patients with T2DM. It could be a credible alternative for T2DM patients who, for some reason, cannot use metformin, or are in high risk of CV exposure. High-quality, large sample and long-term follow-up clinical trails are needed to confirm the long-term conclusions. PMID- 23803147 TI - Antimicrobial activity and evolution of the composition of essential oil from Algerian Anacyclus pyrethrum L. through the vegetative cycle. AB - Essential oils from the aerial parts of Anacyclus pyrethrum L. were analysed at three developmental stages (vegetative, floral budding and flowering). Oil yield was found to vary depending on the stage of development, and the highest content of oil (0.019% w/w) was obtained at flowering stage. The chemical composition of essential oils studied by GC and GC-MS showed a total of 91 compounds. Whatever the analysed stage is, oxygenated sesquiterpenes were the most abundant group. Their level significantly increased during ripening and varied from 37.1% to 58.6%. The oil showed activity against Candida albicans and Staphylococcus aureus bacteria strains. Thus, they represent an inexpensive source of natural antibacterial substances that may potentially be used in pathogenic systems. PMID- 23803149 TI - Sulfonated poly(arylene ether phosphine oxide ketone) block copolymers as oxidatively stable proton conductive membranes. AB - The introduction of triphenylphosphine oxide moiety into the hydrophilic segments of aromatic multiblock copolymers provided outstanding oxidative stability and high proton conductivity. Our designed multiblock copolymers are composed of highly sulfonated phenylene ether phosphine oxide ketone units as hydrophilic blocks and phenylene ether biphenylene sulfone units as hydrophobic blocks. High molecular weight block copolymers (Mw = 204-309 kDa and Mn = 72-94 kDa) with different copolymer compositions (number of repeat unit in the hydrophobic blocks, X = 30, and that of hydrophilic blocks, Y = 4, 6, or 8) were synthesized, resulting in self-standing, transparent, and bendable membranes by solution casting. The block copolymer membranes exhibited well-developed hydrophilic/hydrophobic phase separation, high proton conductivity, and excellent oxidative stability due to the highly sulfonated hydrophilic blocks, which contained phenylene rings with sulfonic acid groups and electron-withdrawing phosphine oxide or ketone groups. PMID- 23803148 TI - Risk of bladder cancer in patients with diabetes mellitus: an updated meta analysis of 36 observational studies. AB - BACKGROUND: Increasing evidence suggests that a history of diabetes mellitus (DM) may be associated with an increased risk of bladder cancer. We performed a systematic review with meta-analysis to explore this relationship. METHODS: We identified studies by a literature search of Medline (from 1 January 1966) and EMBASE (from 1 January 1974), through 29 February 2012, and by searching the reference lists of pertinent articles. Summary relative risks (RRs) with corresponding 95% confidence intervals (CIs) were calculated with a random effects model. RESULTS: A total of 36 studies (9 case-control studies, 19 cohort studies and 8 cohort studies of patients with diabetes) fulfilled the inclusion criteria. Analysis of all studies showed that DM was associated with an increased risk of bladder cancer (the summary RR = 1.35, 95% CI 1.17-1.56, p < 0.001, I2 = 94.7%). In analysis stratified by study design, diabetes was positively associated with risk of bladder cancer in case-control studies (RR = 1.45, 95% CI 1.13-1.86, p = 0.005, I2 = 63.8%) and cohort studies (RR = 1.35, 95% CI 1.12 1.62, p < 0.001, I2 = 94.3%), but not in cohort studies of diabetic patients (RR = 1.25, 95% CI 0.86-1.81, p < 0.001, I2 = 97.4%). The RRs of bladder cancer were 1.38 (1.08-1.78) for men and 1.38 (0.90-2.10) for women with diabetes, respectively. Noteworthy, the relative risk of bladder cancer was negatively correlated with the duration of DM, with the higher risk of bladder cancer found among patients diagnosed within less than 5 years. CONCLUSIONS: These findings support the hypothesis that men with diabetes have a modestly increased risk of bladder cancer, while women with diabetes were not the case. PMID- 23803150 TI - Functional improvement is accompanied by reduced pain in adolescent chronic fatigue syndrome. PMID- 23803151 TI - "I don't blame that guy that gave it to me": contested discourses of victimisation and culpability in the narratives of heterosexual women infected with HIV. AB - In Australia, most women with HIV were infected through heterosexual sex, echoing global patterns. In media coverage, these women are typically portrayed as having been deceived by men they trusted, or as victims in criminal cases against HIV positive men from high-prevalence countries. Heterosexuals are clearly overrepresented in such cases, a pattern consistent across high-income countries. It has been suggested that the victim/perpetrator distinction that defines criminal cases and media stories has some resonance among heterosexuals because of gender power dynamics. But less attention has been paid to the ways women themselves make sense of heterosexual transmission of HIV. Drawing on qualitative interviews from two larger studies, this article shows how the victim-culprit binary is challenged by women's own accounts of acquiring HIV. None presented themselves as "victims" in any straightforward sense, or placed the blame squarely on the men, including men who had not disclosed HIV. Instead, their narratives revealed themes of "mutual vulnerability" and far more ambivalent allocations of responsibility. I conclude that the tendency to position women who become infected with HIV in a victim discourse obscures the complex realities of sexual practice and gender that play a part in the epidemic in any cultural context and that have implications for HIV prevention. PMID- 23803152 TI - 3D organization of telomeres in porcine neutrophils and analysis of LPS activation effect. AB - BACKGROUND: While the essential role of 3D nuclear architecture on nuclear functions has been demonstrated for various cell types, information available for neutrophils, essential components of the immune system, remains limited. In this study, we analysed the spatial arrangements of telomeres which play a central role in cell fate. Our studies were carried out in swine, which is an excellent model organism for both biomedical research and agronomic applications. We isolated bacterial artificial chromosome (BAC)-containing subtelomeric p and q sequences specific to each porcine chromosome. This allowed us to study the behaviour of p and q telomeres of homologous chromosomes for seven pairs chosen for their difference in length and morphology. This was performed using 3D-FISH on structurally preserved neutrophils, and confocal microscopy. Resting and lipopolysaccharide (LPS)-activated states were investigated to ascertain whether a response to a pathogen aggression modifies this organization. RESULTS: The positions of the p and q telomeres relative to the nuclear outer border were determined in the two states. All p telomeres changed their position significantly during the activation process, although the effect was less pronounced for the q telomeres. The patterns of telomeric associations between homologs and their frequencies were analysed for 7 pairs of chromosomes. This analysis revealed that the distribution of pp, qq and pq associations differs significantly among the 7 chromosomes. This distribution does not fit with the theoretical distribution for each chromosome, suggesting that preferential associations occur between subtelomeres. CONCLUSIONS: The percentage of nuclei harbouring at least one telomeric association between homologs varies significantly among the chromosomes, the smallest metacentric chromosome SSC12, which is also the richest in gene-density, harbouring the highest value. The distribution of types of telomeric associations is highly dependent on the chromosomes and is not affected by the activation process. The frequencies of telomeric associations are also highly dependent on the type of association and the type of chromosome. Overall, the LPS-activation process induces only minor changes in these patterns of associations. When telomeric associations occur, the associations of p and q arms from the same chromosome are the most frequent, suggesting that "chromosome bending" occurs in neutrophils as previously observed in gametes. PMID- 23803153 TI - Potential of magnetic resonance-guided focused ultrasound for intracranial hemorrhage: an in vitro feasibility study. AB - BACKGROUND: Intracranial hemorrhage has a mortality rate of up to 40-60% due to the lack of effective treatment. Magnetic resonance-guided focused ultrasound may offer a breakthrough noninvasive technology, by allowing accurate delivery of focused ultrasound, under the guidance of real-time magnetic resonance imaging. AIM: The purpose of the current study was to optimize the acoustic parameters of magnetic resonance-guided focused ultrasound for effective clot liquefaction, in order to evaluate the feasibility of magnetic resonance-guided focused ultrasound for thrombolysis. METHODS: Body (1.1 MHz) and brain (220 kHz) magnetic resonance guided focused ultrasound systems (InSightec Ltd, Tirat Carmel, Israel) were used to treat tube-like (4 cc), round (10 cc), and bulk (300 cc) porcine blood clots in vitro, using burst sonications of one-second to five-seconds, a duty cycle of 5-50%, and peak acoustic powers between 600 and 1200 W. Liquefied volumes were measured as hyperintense regions on T2-weighted magnetic resonance images for body unit sonications (duration of one-second, duty cycle of 10%, and power of 500-1200 W). Liquefaction efficiency was calculated for brain unit sonications (duration of one-second, duty cycle of 10%, power of 600 W, and burst length between 0.1 ms and 100 ms). RESULTS: Liquified lesion volume increased as power was raised, without a thermal rise. For brain unit sonications, a power setting of 600 W and ultrashort sonications (burst length between 0.1 and 1.0 ms) resulted in liquefaction efficacy above 50%, while longer burst duration yielded lower efficacy. CONCLUSIONS: These results demonstrate the feasibility of obtaining reproducible, rapid, efficient, and accurate blood clot lysis using the magnetic resonance-guided focused ultrasound system. Further in vivo studies are needed to validate the feasibility of magnetic resonance-guided focused ultrasound as a treatment modality for intracranial hemorrhage. PMID- 23803154 TI - Hypothesis: the reversal of the relation between economic growth and health progress in Sweden in the nineteenth and twentieth centuries was caused by electrification. AB - The expected decline of health indicators with economic recessions and improvement with economic growth in the nineteenth century Sweden was reversed in the twentieth century, giving the counterintuitive pattern of higher mortality and lower life expectancy in economic expansions and improvement of these indices in recessions. The change or "tipping point" occurred at the end of the nineteenth century or early in the twentieth century when electrification was introduced into Sweden. All 5 of the reversals of annual industrial electric energy use in the US between 1912 and 1970 were accompanied by recessions with lowered GDP, increased unemployment, decreased mortality and increased life expectancy. The health indices were not related to residential electricity use. The mortality improvement between 1931 and 1932 by state in the US strongly favored urban areas over rural areas. Rural unemployment by state in 1930 was significantly positively correlated with residential electrification percentage by state in 1930. The health effects of economic change are mediated by electrical exposure. PMID- 23803155 TI - Frontiers of torenia research: innovative ornamental traits and study of ecological interaction networks through genetic engineering. AB - Advances in research in the past few years on the ornamental plant torenia (Torenia spps.) have made it notable as a model plant on the frontier of genetic engineering aimed at studying ornamental characteristics and pest control in horticultural ecosystems. The remarkable advantage of torenia over other ornamental plant species is the availability of an easy and high-efficiency transformation system for it. Unfortunately, most of the current torenia research is still not very widespread, because this species has not become prominent as an alternative to other successful model plants such as Arabidopsis, snapdragon and petunia. However, nowadays, a more global view using not only a few selected models but also several additional species are required for creating innovative ornamental traits and studying horticultural ecosystems. We therefore introduce and discuss recent research on torenia, the family Scrophulariaceae, for secondary metabolite bioengineering, in which global insights into horticulture, agriculture and ecology have been advanced. Floral traits, in torenia particularly floral color, have been extensively studied by manipulating the flavonoid biosynthetic pathways in flower organs. Plant aroma, including volatile terpenoids, has also been genetically modulated in order to understand the complicated nature of multi-trophic interactions that affect the behavior of predators and pollinators in the ecosystem. Torenia would accordingly be of great use for investigating both the variation in ornamental plants and the infochemical-mediated interactions with arthropods. PMID- 23803156 TI - Normal values for esophageal high-resolution manometry. AB - BACKGROUND: Esophageal high-resolution manometry (HRM) is a novel method to assess esophageal motility. Several software and hardware systems are currently available. A set of normal values for HRM parameters was established in the US, using proprietary tactile-sensing catheter technology (Given Imaging). We wished to determine normal values for HRM performed with another type of catheter (Unisensor). METHODS: Fifty-two healthy volunteers underwent supine HRM. Each subject swallowed 10 liquid water boluses. Esophageal contraction parameters were evaluated and normal values were calculated (defined as 5th and 95th percentile of values). KEY RESULTS: The normal range for the following parameters was calculated; distal contractile integral (mean 1319.44, with a 5-95th percentile range [185.65-3407.60]), contractile front velocity (mean 3.98, 5-95th percentile range [2.40-6.50]), Intrabolus pressure (mean 9.68, range [1.00-19.00]), contraction amplitude measured 5 cm above the esophagogastric junction (EGJ; mean 78.76, range [23.00-146.00]), contraction amplitude 15 cm above the EGJ (mean 43.66, range [3.60-96.00]), transition zone (TZ) length (mean 1.34, range [0.00 5.63]), upper esophageal sphincter (UES) pressure (mean 81.63, range [19.50 165.10]), EGJ length (mean 2.97, range [2.17-4.00]), EGJ resting pressure (mean 29.35, range [8.95-51.40]), EGJ relaxation pressure (mean 16.79, range [1.00 39.35]), IRPs4 (mean 13.42, range [2.59-28.28]), and gastric pressure (mean 5.06, range [0.00-9.46]). CONCLUSIONS & INFERENCES: Overall, the normal values of esophageal HRM parameters obtained with the Unisensor catheter resemble those of the previously published series. Marked differences in upper limits of normal were found for parameters related to the esophageal sphincters and TZ length. Users of HRM should be aware of these differences and define pathology based on comparison to appropriate normal values. PMID- 23803157 TI - Mathematical modeling of apoptosis. AB - Apoptosis is a form of programmed cell death, which is fundamental to all multicellular organisms. Deregulation of apoptosis leads to a number of severe diseases including cancer. Apoptosis is initiated either by extrinsic signals via stimulation of receptors at the cellular surface or intrinsic signals, such as DNA damage or growth factor withdrawal. Apoptosis has been extensively studied using systems biology which substantially contributed to the understanding of this death signaling network. This review gives an overview of mathematical models of apoptosis and the potential of systems biology to contribute to the development of novel therapies for cancer or other apoptosis-related diseases. PMID- 23803159 TI - The effects of mannitol on the transport of ciprofloxacin across respiratory epithelia. AB - Inhalation of antibiotics and mucolytics is the most important combination of inhaled drugs for chronic obstructive lung diseases and has become a standard part of treatment. However, it is yet to be determined whether the administration of a mucolytic has an effect on the transport rate of antibiotics across the airway epithelial cells. Consequently, the aim of this study was to investigate the effects of inhalation dry powder, specifically mannitol, on ciprofloxacin transport using a Calu-3 air-interface cell model. Transport studies of ciprofloxacin HCl were performed using different configurations including single spray-dried ciprofloxacin alone, co-spray-dried ciprofloxacin with mannitol, and deposition of mannitol prior to ciprofloxacin deposition. To understand the mechanism of transport and interactions between the drugs, pH measurements of apical surface liquid (ASL) and further transport studies were performed with ciprofloxacin base, with and without the presence of ion channel/transport inhibitors such as disodium cromoglycate and furosemide. Mannitol was found to delay absorption of ciprofloxacin HCl through the increase in ASL volume and subsequent reduction in pH. Conversely, ciprofloxacin base had a higher transport rate after mannitol deposition. This study clearly demonstrates that the deposition of mannitol prior to ciprofloxacin on the air-interface Calu-3 cell model has an effect on its transport rate. This was also dependent on the salt form of the drug and the timing and sequence of formulations administered. PMID- 23803160 TI - Differences in human birth weight and corollary attributes as a result of temperature regime. AB - BACKGROUND: Birth weight (BW) is an important attribute of human populations affecting post-natal mortality and later life morbidity, such as diabetes and reduced cognitive skills. BW is influenced by many factors, whereof temperature regime represents an important factor. METHODS: By applying a generalized linear model, the impact of temperatures, altitude, nutrition, age at motherhood and other potential causes for BW variation were evaluated in more than 60 countries worldwide. National IQ scores were analysed in the same model. RESULTS: This study identified a model explaining 2/3 of the global variation in BW. This model suggests that BW will decrease by 0.44-1.05% per degrees C increase in temperature under projected climate change. National IQ scores revealed a close relationship between IQ and BW. However, the model of IQ variation did not appear robust when challenged with variables not correlated with BW. CONCLUSION: Climate change will affect BW, but it cannot be assumed that other human attributes such as IQ will change because (i) BW, in mainly being sensitive to intra-uterine conditions in the last quarter of pregnancy, is a poor predictor of intra-uterine conditions as such and (ii) developmental plasticity may require post-natal stimuli to unfold. PMID- 23803158 TI - Competence and natural transformation in vibrios. AB - Natural transformation is a major mechanism of horizontal gene transfer in bacteria. By incorporating exogenous DNA elements into chromosomes, bacteria are able to acquire new traits that can enhance their fitness in different environments. Within the past decade, numerous studies have revealed that natural transformation is prevalent among members of the Vibrionaceae, including the pathogen Vibrio cholerae. Four environmental factors: (i) nutrient limitation, (ii) availability of extracellular nucleosides, (iii) high cell density and (iv) the presence of chitin, promote genetic competence and natural transformation in Vibrio cholerae by co-ordinating expression of the regulators CRP, CytR, HapR and TfoX respectively. Studies of other Vibrionaceae members highlight the general importance of natural transformation within this bacterial family. PMID- 23803161 TI - Multiorgan procurement increases systemic inflammation in brain dead donors. AB - Organs available for solid organ transplantation are mainly procured from brain dead donors. The inflammation associated with brain death may reduce organ quality and increase organ immunogenicity, thus leading to inferior recipient outcome. We hypothesized that the extensive surgical procedure performed during multiorgan procurement enhances the levels of systemic inflammatory biomarkers. We measured the levels of 27 cytokines and the terminal complement complex (TCC) in plasma samples from brain dead organ donors (n = 34) drawn before and at three specific time points during procurement surgery. Baseline levels of G-CSF, interferon-gamma, IL-1ra, IL-4, IL-6, IL-7, IL-8, IL-10, IP-10, MCP-1, macrophage inflammatory protein (MIP)-1beta, platelet derived growth factor (PDGF), regulated upon activation T cell expressed and secreted, and tumor necrosis factor-alpha were significantly elevated in brain dead donors compared with normal individuals (n = 14), but they were not associated with time on ventilator or any other registered clinical variable. Notably, the secretion of G-CSF, IL1 ra, IL-6, IL-8, IL-10, IP-10, MCP-1, MIP-1beta, PDGF, and TCC, the latter reflecting ongoing complement activation, increased significantly during surgery. None of the biomarker increases were correlated with operation duration. Multiorgan procurement surgery significantly adds to the inflammatory response revealed by both pro- and anti-inflammatory biomarkers associated with brain death. Future studies should determine whether this is associated with inferior recipient outcome. PMID- 23803162 TI - Successful use of aromatase inhibitor letrozole in NOA with an elevated FSH level: a case report. AB - Aromatase inhibitors inhibit the conversion of testosterone to oestrogens and could reduce serum oestradiol concentrations. Letrozole is one of aromatase inhibitors frequently used in treatment of men with oligospermia. We present the case of an infertile man with small testes and an elevated FSH level, which was diagnosed as NOA, hypospermatogenesis proven by testicular biopsy. After taking letrozole for 3 months, semen analyses by computer-aided sperm analysis present that this man had normal spermatogenesis. This is the first case report of the activation of spermatogenesis, in man who was NOA with elevated FSH level, resulting from the use of the one of aromatase inhibitors. PMID- 23803163 TI - Anabolic deficiencies in men with systolic heart failure: do co-morbidities and therapies really contribute significantly? AB - BACKGROUND: Deficiencies of anabolic hormones are common in men with heart failure (HF). It remains unclear whether the deranged metabolism of these hormones is the pathophysiological element of HF itself or is the consequence of co-morbidities or/and treatment in HF. METHODS: We examined 382 men with systolic HF. Serum hormones (i.e. total testosterone [TT], DHEAS, IGF-1) were assessed using immunoassays, serum free testosterone (eFT) - using the Vermeulen equation. RESULTS: Prevalence of TT and eFT deficiencies was similar in men with HF aged < versus >=60 years (23% and 32% for TT and eFT deficiencies). Deficiencies in DHEAS and IGF-1 were more common in younger (63% and 92%) than older patients (48% and 73%). In men <60 years, TT deficiency was accompanied by the therapy with digoxin, eFT deficiency - the therapy with digoxin and the presence of diabetes, DHEAS deficiency - the therapy with loop diuretic (all p < 0.05). In men >=60 years, TT deficiency - the therapy with loop diuretic, DHEAS deficiency the therapy with spironolactone and digoxin, and hsCRP, IGF-1 deficiency - the high hsCRP (all p < 0.05). CONCLUSIONS: Deficiencies in anabolic hormones are common in younger and older men with HF. Some therapies (but not major co morbidities) may contribute to anabolic deficiencies. PMID- 23803164 TI - Testosterone supplementation's effects on age-related bladder remodeling - experimental study in rats. AB - OBJECTIVE: This study was designed to evaluate the effect of testosterone replacement on the fibrotic process of the detrusor bladder muscle during the normal aging process. METHODS: 15 Wistar senile rats, aged between 18 and 20 months were divided into two groups: testosterone group - 11 animals submitted to the administration of testosterone undecanoate (50 mg/kg intramuscular), once per month; and, Control group - four animals underwent a sham procedure. At the end of eight weeks, animals from both groups were sacrificed; bladders were removed and subsequently stereologically evaluated to determine the volumetric density of collagen fibers. The success of testosterone administration was confirmed by the measurement of serum testosterone at the beginning and end of the experiment. RESULTS: In the replacement group, testosterone average was 3.2 ng/ml, whereas in the control group, the mean testosterone at the end of the experiment was 0.64 ng/ml (p < 0.05). Analysis of stereological collagenous fiber showed higher density in the control group compared to the testosterone group I (56% versus 37.02%, respectively). The difference of volume concentration of collagen between both groups was statistically significant (p < 0.000). CONCLUSION: Bladder wall fibrosis was reduced in senile rats subjected to testosterone replacement. PMID- 23803165 TI - A study of physician collaborations through social network and exponential random graph. AB - BACKGROUND: Physician collaboration, which evolves among physicians during the course of providing healthcare services to hospitalised patients, has been seen crucial to effective patient outcomes in healthcare organisations and hospitals. This study aims to explore physician collaborations using measures of social network analysis (SNA) and exponential random graph (ERG) model. METHODS: Based on the underlying assumption that collaborations evolve among physicians when they visit a common hospitalised patient, this study first proposes an approach to map collaboration network among physicians from the details of their visits to patients. This paper terms this network as physician collaboration network (PCN). Second, SNA measures of degree centralisation, betweenness centralisation and density are used to examine the impact of SNA measures on hospitalisation cost and readmission rate. As a control variable, the impact of patient age on the relation between network measures (i.e. degree centralisation, betweenness centralisation and density) and hospital outcome variables (i.e. hospitalisation cost and readmission rate) are also explored. Finally, ERG models are developed to identify micro-level structural properties of (i) high-cost versus low-cost PCN; and (ii) high-readmission rate versus low-readmission rate PCN. An electronic health insurance claim dataset of a very large Australian health insurance organisation is utilised to construct and explore PCN in this study. RESULTS: It is revealed that the density of PCN is positively correlated with hospitalisation cost and readmission rate. In contrast, betweenness centralisation is found negatively correlated with hospitalisation cost and readmission rate. Degree centralisation shows a negative correlation with readmission rate, but does not show any correlation with hospitalisation cost. Patient age does not have any impact for the relation of SNA measures with hospitalisation cost and hospital readmission rate. The 2-star parameter of ERG model has significant impact on hospitalisation cost. Furthermore, it is found that alternative-k-star and alternative-k-two-path parameters of ERG model have impact on readmission rate. CONCLUSIONS: Collaboration structures among physicians affect hospitalisation cost and hospital readmission rate. The implications of the findings of this study in terms of their potentiality in developing guidelines to improve the performance of collaborative environments among healthcare professionals within healthcare organisations are discussed in this paper. PMID- 23803166 TI - Coumarin compounds of Biebersteinia multifida roots show potential anxiolytic effects in mice. AB - BACKGROUND: Traditional preparations of the root of Biebersteinia multifida DC (Geraniaceae), a native medicinal plant of Irano-Turanian floristic region, have been used for the treatment of phobias as anxiolytic herbal preparation. METHODS: We utilized the phobic behavior of mice in an elevated plus-maze as a model to evaluate the anxiolytic effect of the plant extract and bio-guided fractionation was applied to isolate the active compounds. Total root extract, alkaline and ether fraction were administered to mice at different doses 30 and 90 min prior to the maze test. Saline and diazepam were administered as negative and positive controls, respectively. The time spent in open and closed arms, an index of anxiety behavior and entry time, was measured as an index of animal activity. RESULTS: The total root extract exhibited anxiolytic effect which was comparable to diazepam but with longer duration. This sustained effect of the crude extract was sustained for 90 min and was even more after injection of 45 mg/kg while the effect of diazepam had been reduced by 90 min. The anxiolytic effect factor was only present in the alkaline fraction and displayed its effect at lower doses than diazepam while pure vasicinone as the previously known alkaloid did not shown anxiolytic effect. The effect of the alkaline fraction was in a dose dependent manner starting at 0.2 mg/kg with a maximum at 1.0 mg/kg. Bio-guided fractionation using a variety of chromatographic methods led to isolation and purification of three coumarin derivatives from the bioactive fraction, including umbelliferone, scopoletin, and ferulic acid. CONCLUSION: For the first time, bio guided fractionation of the root extract of B. multifida indicates significant sustained anxiolytic effects which led to isolation of three coumarin derivatives with well-known potent MAO inhibitory and anti-anxiety effects. These data contribute to evidence-based traditional use of B. multifida root for anxiety disorders. PMID- 23803167 TI - Long-term prognosis after surgical excision of basal cell carcinoma: a single institutional study in Japan. AB - Conventional surgical excision (SE) is commonly used to treat patients with basal cell carcinoma (BCC). There have been few studies, however, evaluating the long term prognosis of Japanese patients receiving SE for treatment of BCC. The purpose of this retrospective study is to determine the effectiveness of SE in accomplishing the long-term cure of patients with BCC. We enrolled 290 patients with primary BCC who underwent SE during 1998-2006. The prognosis of treated patients was subsequently investigated using data obtained through our hospital cancer registration section. In total, 205 patients (70.7%) were treated for BCC lesions located on the face. The mean tumor diameter of excised lesions was 12.8 mm. A majority of patients in the study (256 patients, 88.3%) had pigmented BCC. The mean surgical margin at SE was 3.8 mm. Two patients developed local recurrence during the postoperative course of 290 patients (mean duration, 80 months). One patient developed recurrent disease 21 months after surgery, and the other developed recurrence at 66 months after surgery. The 5- and 10-year cumulative recurrence rates were 0.4% and 0.8%, respectively. In conclusion, this study demonstrated that long-term high cure rates of BCC in Japanese patients may be achieved through conventional SE. A better prognosis was obtained in this study compared with similar studies reported previously in Caucasians. This may be related to the predominance of pigmented versus non-pigmented lesions in the Japanese population. PMID- 23803168 TI - Recovery of injected freshwater from a brackish aquifer with a multiwell system. AB - Herein we propose a multiple injection and recovery well system strategically operated for freshwater storage in a brackish aquifer. With the system we call aquifer storage transfer and recovery (ASTR) by using four injection and two production wells, we are capable of achieving both high recovery efficiency of injected freshwater and attenuation of contaminants through adequately long residence times and travel distances within the aquifer. The usual aquifer storage and recovery (ASR) scheme, in which a single well is used for injection and recovery, does not warrant consistent treatment of injected water due to the shorter minimum residence times and travel distances. We tested the design and operation of the system over 3 years in a layered heterogeneous limestone aquifer in Salisbury, South Australia. We demonstrate how a combination of detailed aquifer characterization and solute transport modeling can be used to maintain acceptable salinity of recovered water for its intended use along with natural treatment of recharge water. ASTR can be used to reduce treatment costs and take advantage of aquifers with impaired water quality that might locally not be otherwise beneficially used. PMID- 23803169 TI - Catalytic function of an epsilon-class glutathione S-transferase of the silkworm. AB - The glutathione S-transferase (GST) superfamily is involved in the detoxification of various xenobiotics. A silkworm GST, belonging to a previously reported Epsilon-class GST family, was identified, named bmGSTE, cloned, and produced in Escherichia coli. Investigation of this enzyme's properties showed that it was able to catalyse glutathione (GSH) with 1-chloro-2,4-dinitrobenzene and ethacrynic acid, and also that it possessed GSH-dependent peroxidase activity. The enzyme's highly conserved amino acid residues, including Ser11, His53, Val55, Ser68 and Arg112, were of interest regarding their possible involvement in its catalytic activity. These residues were replaced with alanine by site-directed mutagenesis and subsequent kinetic analysis of bmGSTE mutants indicated that His53, Val55, and Ser68 were important for enzyme function. PMID- 23803170 TI - Characterization of the oculocardiac reflex during compression of the globe in Beagle dogs and rabbits. AB - OBJECTIVE: This investigation characterizes the occurrence of oculocardiac reflex (OCR) in conscious rabbits and dogs by observing the effect of an ocular compression stimulus on heart rate (HR). ANIMALS STUDIED: Thirty-four clinically healthy adult rabbits and 15 clinically healthy adult Beagle dogs were studied. PROCEDURES: An electrocardiogram was used to record the heart rhythm and HR continuously. Digital pressure was exerted over the eyelid on right eye, left eye and both eyes together for 1 min, with one-minute intervals between each compression. Variations in HR were observed in each minute by counting complexes on the electrocardiographs. RESULTS: There were no differences in HR between stages without ocular compressions both in dogs and in rabbits. HR reduction caused by ocular compression was statistically significant in rabbits only when both eyes were compressed in contrast with all stages without compression. In dogs, a statistically significant reduction in HR was seen during compression of just the right eye or the left eye compared with the baseline HR, and when both the right and left eyes were compressed together compared with baseline or after compression of the right eye. In dogs, compression of individual eyes produced a change similar to that seen during compression of both eyes. CONCLUSIONS: This study shows that OCR can occur during experimental ocular compression in conscious rabbits and Beagle dogs and characterizes the reduction in HR. Knowledge of this physiological response is important for veterinary anesthetists and ophthalmologists during ophthalmic surgery or eye manipulations. PMID- 23803171 TI - Modeling approaches for qualitative and semi-quantitative analysis of cellular signaling networks. AB - A central goal of systems biology is the construction of predictive models of bio molecular networks. Cellular networks of moderate size have been modeled successfully in a quantitative way based on differential equations. However, in large-scale networks, knowledge of mechanistic details and kinetic parameters is often too limited to allow for the set-up of predictive quantitative models.Here, we review methodologies for qualitative and semi-quantitative modeling of cellular signal transduction networks. In particular, we focus on three different but related formalisms facilitating modeling of signaling processes with different levels of detail: interaction graphs, logical/Boolean networks, and logic-based ordinary differential equations (ODEs). Albeit the simplest models possible, interaction graphs allow the identification of important network properties such as signaling paths, feedback loops, or global interdependencies. Logical or Boolean models can be derived from interaction graphs by constraining the logical combination of edges. Logical models can be used to study the basic input-output behavior of the system under investigation and to analyze its qualitative dynamic properties by discrete simulations. They also provide a suitable framework to identify proper intervention strategies enforcing or repressing certain behaviors. Finally, as a third formalism, Boolean networks can be transformed into logic-based ODEs enabling studies on essential quantitative and dynamic features of a signaling network, where time and states are continuous.We describe and illustrate key methods and applications of the different modeling formalisms and discuss their relationships. In particular, as one important aspect for model reuse, we will show how these three modeling approaches can be combined to a modeling pipeline (or model hierarchy) allowing one to start with the simplest representation of a signaling network (interaction graph), which can later be refined to logical and eventually to logic-based ODE models. Importantly, systems and network properties determined in the rougher representation are conserved during these transformations. PMID- 23803172 TI - Expression and significance of HMGB1, TLR4 and NF-kappaB p65 in human epidermal tumors. AB - BACKGROUND: High mobility group protein box 1 (HMGB1) is a DNA binding protein located in nucleus. It is released into extracellular fluid where it acts as a novel proinflammatory cytokine which interacts with Toll like receptor 4 (TLR4) to activate nuclear factor-kappaB (NF-kappaB). This sequence of events is involved in tumor growth and progression. However, the effects of HMGB1, TLR4 and NF-kappaB on epidermal tumors remain unclear. METHODS: Human epidermal tumor specimens were obtained from 96 patients. Immunohistochemistry was used to detect expression of HMGB1, TLR4 and NF-kappaB p65 in human epidermal tumor and normal skin specimens. Western blot analysis was used to detect the expression of NF kappaB p65 in epithelial cell nuclei in human epidermal tumor and normal tissues. RESULTS: Immunohistochemistry and western blot analysis indicated a progressive but statistically significant increase in p65 expression in epithelial nuclei in benign seborrheic keratosis (SK), precancerous lesions (PCL), low malignancy basal cell carcinoma (BCC) and high malignancy squamous cell carcinoma (SCC) (P <0.01). The level of extracellular HMGB1 in SK was significantly higher than in normal skin (NS) (P <0.01), and was higher than in SCC but without statistical significance. The level of TLR4 on epithelial membranes of SCC cells was significantly higher than in SK, PCL, BCC and NS (P <0.01). There was a significant positive correlation between p65 expression in the epithelial nuclei and TLR4 expression on the epithelial cell membranes (r = 0.3212, P <0.01). CONCLUSIONS: These findings indicate that inflammation is intensified in parallel with increasing malignancy. They also indicate that the TLR4 signaling pathway, rather than HMGB1, may be the principal mediator of inflammation in high-grade malignant epidermal tumors. Combined detection of p65 in the epithelial nuclei and TLR4 on the epithelial membranes may assist the accurate diagnosis of malignant epidermal tumors. PMID- 23803173 TI - Factors that might impact intrathecal drug delivery (IDD) dose escalation: a longitudinal study. AB - BACKGROUND: Intrathecal drug delivery (IDD) system with implantable pumps has been used to treat cancer-related pain as well as noncancer-related chronic pain. Opioids, including morphine and hydromorphone, are the most commonly used intrathecal (IT) agents. Although technology, techniques, and knowledge of IDD have improved, dose escalation occurs relatively rapidly in noncancer pain. METHODS: Retrospective chart review of IDD pump patients, implanted for a minimum of 2 years, was designed to investigate possible existing predictors that might impact IDD dose escalation, such as patient's demographic risk factors, duration of the treatment, and diagnosis of the patient's pain correlates with increase in medication requirement. Primary outcome was defined as the annual percent escalation in daily opioid dosage, and secondary outcome was the average annual percent reduction in VRS pain scores. RESULTS: Median dosage escalation was 17% per year for patients with neuropathic pain compared with 12% per year for patients with other pain modalities. Mean opioid dosage increased 30.4% more rapidly for patients with neuropathic pain than for other pain modalities. The adjusted difference in means was 28.8% (P = 0.001). None of the secondary exposures were statistically significant after the Bonferroni adjustment. No association was found between pain modality and annual percent change in VRS pain score. CONCLUSION: Annual increases in daily opioid dosage were higher among patients with neuropathic pain than among patients with other modalities; we also found no evidence of difference in annual pain reduction. PMID- 23803174 TI - Regression analysis of ordinal stroke clinical trial outcomes: an application to the NINDS t-PA trial. AB - BACKGROUND: The modified Rankin scale (mRS) is the most common functional outcome assessed in stroke trials. The proportional odds model is commonly used to analyze this ordinal outcome but it requires a restrictive assumption that a single odds ratio applies across the entire outcome scale. AIMS: The study aims to model the effect of tissue-type plasminogen activator on ordinal mRS, test model assumptions, and compare fits and predictive ability of the statistical models. METHODS: Several ordinal regression methods are presented and applied to a re-analysis of the 1995 NINDS tissue-type plasminogen activator study. Violations of the proportional odds assumption are demonstrated using graphs and statistical tests, and the partial proportional odds model is introduced and recommended as an alternative for the analysis of mRS. RESULTS: The partial proportional odds model relaxes the assumptions about treatment effect on the ordinal outcome scale and provides a better fit to the data than the commonly used proportional odds model (likelihood ratio test chi-square = 8.05, P = 0.005). It provides easily interpretable odds ratios and it is able to detect efficacy at the lower end and a lack of efficacy at the upper end of the mRS scale. Further, it provides lower prediction error than the proportional odds model (0.002 versus 0.005). CONCLUSIONS: Assuming proportional odds when it does not hold can mask differential treatment effects at the upper end of the ordinal mRS scale and has implications for reduced power when studies are designed under this assumption. PMID- 23803175 TI - Beneficial effects of beta-conglycinin on renal function and nephrin expression in early streptozotocin-induced diabetic nephropathy rats. AB - The objective of the present study was to investigate the effects of beta conglycinin and soya isoflavones on diabetic nephropathy (DN). DN was induced by an intravenous injection of streptozotocin (25 mg/kg) in spontaneously hypertensive rats. DN rats were divided into a non-diabetic group (C, control group) and three DN groups (D, DN with control diet; B, DN+control diet with one eighth of casein replaced by beta-conglycinin as the protein source; and I, DN+control diet with 0.01 % soya isoflavones). After a 4-week experimental period, we found that fasting blood sugar and plasma and kidney advanced glycation end product levels and 24 h urinary protein excretion of the B group were significantly lower than those of the D group and insulin sensitivity and nephrin expression of the B group were significantly higher than those of the D group. In addition, systolic blood pressure, angiotensin-converting enzyme activity, angiotensin II level and plasma TAG level of the B group were significantly lower than those of the D group, whereas only the levels of plasma TAG and thiobarbituric acid-reactive substances of the I group were lower than those of the D group. In conclusion, beta-conglycinin may be beneficial for retarding DN progression and this effect cannot be completely explained by its isoflavone content. PMID- 23803177 TI - Water exclusion layers probed by depth scan confocal Raman microscopy. AB - Depth scan confocal Raman microscopy was employed to map water and air spatial distributions in immersed superhydrophobic films. Due to the lack of visible nanobubbles on flat surfaces, we have probed heterogeneous surfaces where solid liquid, liquid-vapor, and vapor-solid coexist. Depth scan profiles show liquid exclusion (vapor) layers inside the fiber arrangement and water in contact only at the fiber apex. PMID- 23803176 TI - Corneal cross-linking in 9 horses with ulcerative keratitis. AB - BACKGROUND: Corneal ulcers are one of the most common eye problems in the horse and can cause varying degrees of visual impairment. Secondary infection and protease activity causing melting of the corneal stroma are always concerns in patients with corneal ulcers. Corneal collagen cross-linking (CXL), induced by illumination of the corneal stroma with ultraviolet light (UVA) after instillation of riboflavin (vitamin B2) eye drops, introduces crosslinks which stabilize melting corneas, and has been used to successfully treat infectious ulcerative keratitis in human patients. Therefore we decided to study if CXL can be performed in sedated, standing horses with ulcerative keratitis with or without stromal melting. RESULTS: Nine horses, aged 1 month to 16 years (median 5 years) were treated with a combination of CXL and medical therapy. Two horses were diagnosed with mycotic, 5 with bacterial and 2 with aseptic ulcerative keratitis. A modified Dresden-protocol for CXL could readily be performed in all 9 horses after sedation. Stromal melting, diagnosed in 4 horses, stopped within 24 h. Eight of nine eyes became fluorescein negative in 13.5 days (median time; range 4-26 days) days after CXL. One horse developed a bacterial conjunctivitis the day after CXL, which was successfully treated with topical antibiotics. One horse with fungal ulcerative keratitis and severe uveitis was enucleated 4 days after treatment due to panophthalmitis. CONCLUSIONS: CXL can be performed in standing, sedated horses. We did not observe any deleterious effects attributed to riboflavin or UVA irradiation per se during the follow-up, neither in horses with infectious nor aseptic ulcerative keratitis. These data support that CXL can be performed in the standing horse, but further studies are required to compare CXL to conventional medical treatment in equine keratitis and to optimize the CXL protocol in this species. PMID- 23803178 TI - Membrane lipid saturation activates IRE1alpha without inducing clustering. AB - The unfolded protein response (UPR) is an adaptive stress response that responds to the accumulation of unfolded proteins in the lumen of the endoplasmic reticulum (ER) and that adjusts the protein-folding capacity to the needs of the cell. Perturbation of cellular lipids also activates the UPR. Lipid-induced UPR has attracted much attention because it is associated with the pathology of some metabolic diseases. However, how the lipid-induced UPR is activated remains unclear. We previously showed that palmitic acid treatment or knockdown of stearoyl-CoA desaturase in HeLa cells promotes membrane lipid saturation and activates the UPR. In this study, we compared UPR activation by membrane lipid saturation with UPR activation by conventional ER stressors that cause the accumulation of unfolded proteins such as tunicamycin and thapsigargin. Membrane lipid saturation induced autophosphorylation of inositol-requiring 1alpha (IRE1alpha) and protein kinase RNA-like ER kinase, but not the conversion of activating transcription factor-6alpha to the active form. A conventional ER stressor induced clustering of fluorescently tagged IRE1alpha fusion protein, but palmitic acid treatment did not, suggesting that IRE1alpha was activated without large cluster formation by membrane lipid saturation. Together, these results suggest membrane lipid saturation, and unfolded proteins activate the UPR through different mechanisms. PMID- 23803179 TI - Forty-eight hour kidney transplant admissions. AB - Forty-eight hour kidney transplantation admissions are a feasible option in selected recipients of live-donor allografts through the use of standardized post operative protocols, multidisciplinary team patient care, and intensive follow-up at outpatient centers. Age, gender, and pre-transplant dialysis status did not impact the ability to achieve 48-hour admissions. We did not identify any other pre-operative risk factors that contributed to increased length of stay. Although ABO and highly sensitized recipients had longer lengths of stay, the subgroup was too small to achieve statistical significance. We did not encounter any readmissions within the first seven post-operative days. Further improvements in clinical management will enhance the potential to shorten the length of hospital stay for all kidney transplant recipients. PMID- 23803180 TI - Individual, socio-cultural and environmental predictors of uptake and maintenance of active commuting in children: longitudinal results from the SPEEDY study. AB - BACKGROUND: Active commuting is prospectively associated with physical activity in children. Few longitudinal studies have assessed predictors of change in commuting mode. PURPOSE: To investigate the individual, socio-cultural and environmental predictors of uptake and maintenance of active commuting in 10-year old children. METHODS: Children were recruited in 2007 and followed-up 12 months later. Children self-reported usual travel mode to school. 31 child, parent, socio-cultural and physical environment characteristics were assessed via self reported and objective methods. Associations with uptake and maintenance of active travel were studied using multi-level multiple logistic regression models in 2012. RESULTS: Of the 912 children (59.1% girls, mean +/- SD baseline age 10.2 +/- 0.3 yrs) with complete data, 15% changed their travel mode. Those children who lived less than 1 km from school were more likely to take up (OR: 4.73, 95% CI: 1.97, 11.32, p = 0.001) and maintain active commuting (OR: 2.80 95% CI: 0.98, 7.96, p = 0.02). Children whose parents reported it was inconvenient to use the car for school travel were also more likely to take up (OR: 2.04, 95% CI: 1.08, 3.85, p = 0.027) and maintain their active commuting (OR: 5.43 95% CI: 1.95, 15.13, p = 0.001). Lower socio-economic status and higher road safety were also associated with uptake. CONCLUSIONS: Findings from this longitudinal study suggest that reducing the convenience of the car and improving the convenience of active modes as well as improving the safety of routes to school may promote uptake and maintenance of active commuting and the effectiveness of these interventions should be evaluated. PMID- 23803181 TI - Impairment of fragile X mental retardation protein-metabotropic glutamate receptor 5 signaling and its downstream cognates ras-related C3 botulinum toxin substrate 1, amyloid beta A4 precursor protein, striatal-enriched protein tyrosine phosphatase, and homer 1, in autism: a postmortem study in cerebellar vermis and superior frontal cortex. AB - BACKGROUND: Candidate genes associated with idiopathic forms of autism overlap with other disorders including fragile X syndrome. Our laboratory has previously shown reduction in fragile X mental retardation protein (FMRP) and increase in metabotropic glutamate receptor 5 (mGluR5) in cerebellar vermis and superior frontal cortex (BA9) of individuals with autism. METHODS: In the current study we have investigated expression of four targets of FMRP and mGluR5 signaling - homer 1, amyloid beta A4 precursor protein (APP), ras-related C3 botulinum toxin substrate 1 (RAC1), and striatal-enriched protein tyrosine phosphatase (STEP) - in the cerebellar vermis and superior frontal cortex (BA9) via SDS-PAGE and western blotting. Data were analyzed based on stratification with respect to age (children and adolescents vs. adults), anatomic region of the brain (BA9 vs. cerebellar vermis), and impact of medications (children and adolescents on medications (n = 4) vs. total children and adolescents (n = 12); adults on medications (n = 6) vs. total adults (n = 12)). RESULTS: There were significant increases in RAC1, APP 120 kDa and APP 80 kDa proteins in BA9 of children with autism vs. healthy controls. None of the same proteins were significantly affected in cerebellar vermis of children with autism. In BA9 of adults with autism there were significant increases in RAC1 and STEP 46 kDa and a significant decrease in homer 1 vs. controls. In the vermis of adult subjects with autism, RAC1 was significantly increased while APP 120, STEP 66 kDa, STEP 27 kDa, and homer 1 were significantly decreased when compared with healthy controls. No changes were observed in vermis of children with autism. There was a significant effect of anticonvulsant use on STEP 46 kDa/beta-actin and a potential effect on homer 1/NSE, in BA9 of adults with autism. However, no other significant confound effects were observed in this study. CONCLUSIONS: Our findings provide further evidence of abnormalities in FMRP and mGluR5 signaling partners in brains of individuals with autism and open the door to potential targeted treatments which could help ameliorate the symptoms of autism. PMID- 23803182 TI - Targeted inhibition of VEGF receptor 2: an update on ramucirumab. AB - INTRODUCTION: Ramucirumab (IMC-1121B) is a fully humanized IgG1 monoclonal antibody, targeting the extracellular domain of VEGF receptor 2 (VEGFR2). Numerous Phase I - II trials in various malignancies have shown promising clinical antitumor efficacy and tolerability. Most recently, the large Phase III REGARD trial evaluated ramucirumab in patients with refractory metastatic gastric cancer. Patients receiving ramucirumab experienced a median overall survival of 5.2 months compared to 3.8 months on placebo. AREAS COVERED: The purpose of this article is to review the preclinical motivation for VEGFR2-targeted therapies and survey recent data from clinical trials involving ramucirumab, as well as highlight ongoing studies. EXPERT OPINION: Rational multi-target approaches to angiogenesis are needed to overcome resistance mechanisms. Predictive angiogenic biomarkers are also needed to optimize patient selection for novel anti angiogenic agents. PMID- 23803183 TI - Facial follicular cysts: a case of lichen planus follicularis tumidus? AB - Lichen planus follicularis tumidus (LPFT) represents an uncommon variety of lichen planus (LP). Clinically, it presents with prominent purplish lesions or white-pigmented yellowish cysts and comedones. Histopathologically, it is similar to lichen planopilaris, and it is additionally characterized by follicles and cysts surrounded by a lichenoid lymphocytic infiltrate. The most common location is the retroauricular region, and it may be associated with other variants of LP. Herein, we describe the case of a 50-year-old woman with a history of lower limb hypertrophic LP who subsequently presented with multiple pink, tumid, pruritic plaques with white-yellow cysts and comedones extensively affecting the bilateral face. Histopathologic examination revealed a lichenoid infiltrate surrounding the follicles and cysts. We diagnosed LPFT and began treatment with topical corticosteroids, antihistamines, systemic corticosteroids and oral acitretin without improvement. Subsequently, the patient had an acceptable response to cyclosporine at doses of 5 mg/kg/day with remission of itching and tumidity but with residual cysts and comedones remaining. To date, the literature contains only 16 cases of LPFT. To our knowledge, this is the most severe case and is the only one with cessation of disease activity in response to cyclosporine. PMID- 23803184 TI - A novel strategy for synthesis of 5-iodo ((125/131)I)-1, 2, 3-triazoles via click chemistry. AB - We report a facile and effective method for radioiodine-labeled radiopharmaceuticals via copper (I)-catalyzed click chemistry route. In the novel radioiodination method, 5-iodo ((125/131)I)-1, 2, 3-triazoles were synthesized after a 24-h click reaction in organic solvent with a radiochemical yield of 13%. However, in the aqueous phase, the radiochemical yield of the conjugation radioiodine to RGD via click chemistry was 0. This suggested an exchange between hydrogen ion and iodine ion in aqueous phase so that no enough radioiodine was left to conjugate with RGD. We propose different mechanisms of Cu (I)-catalyzed cycloaddition of organic azides and 1-iodo-alkynes in organic phase and aqueous phase. PMID- 23803185 TI - Comparison of tonal response properties of primary auditory cortex neurons of adult rats under urethane and ketamine anesthesia. AB - OBJECTIVE: To compare tonal response properties of neurons in the primary auditory cortex of Sprague-Dawley rats anesthetized with urethane and ketamine xylazine. METHODS: Forty-five female Sprague-Dawley rats (200-250 g) were randomized into two groups and anesthetized with urethane or ketamine-xylazine. Tone pips were chosen as the stimuli to obtain the action potentials of the single neurons by in vivo cell-attached recording. The features of the action potentials were extracted with Matlab software to comparatively analyze the acoustic response properties of the neurons between the two anesthetic groups. RESULTS: The Q values and the characteristic frequencies were independent of the types of anesthetic agents, but with urethane anesthesia, the neurons tended to have higher minimum thresholds, lower spontaneous firing rates, longer response latencies, and more frequent occurrence of tuning with stronger inhibition compared to those in ketamine-xylazine group. CONCLUSION: Urethane and ketamine might have no obvious impact on the transmission pathway of frequency tuning from the periphery to the auditory cortex, but neurons from rats with urethane anesthesia receive enhanced inhibition mediated by the interneurons or have a lower intrinsic excitability. PMID- 23803186 TI - Follicular immunoblastic lymphoma: a clinicopathologic and immunohistochemical study of a case. AB - Primary follicular immunoblastic lymphoma (FIBL) is an extremely rare lymphoma. The positive expression of CD10 suggests the lymphoma originating from germinal centers (GC) and CD138-positive expression generally indicates plasmablastic or plasmacytic differentiation. We report such a rare case in a Chinese female patient and analyze the clinicopathologic and immunohistochemical features of this disease. PET-CT examination was performed to detect signs of systemic lymph node metastasis. We also discussed the differential diagnosis of FIBL from follicular lymphoma (FL) and reactive follicular hyperplasia (RFH). As a rare variant of human follicular lymphoma, FIBL is featured by a neoplastic overgrowth of intrafollicular immunoblasts. Compared with FL, FIBL has a greater chance to evolve into diffuse large B-cell lymphoma with therefore a poorer prognosis. PMID- 23803187 TI - [Expression of chemokine CXCL14 in primary osteosarcoma and its association with prognosis]. AB - OBJECTIVE: To detect the expression of CXCL14 in human osteosarcoma cell lines and tissues and investigate its association with the prognosis of the patients. METHODS: RT-PCR, enzyme-linked immunosorbent assay (ELISA) and real-time PCR were used to detect the expression of CXCL14 in 4 osteosarcoma cell lines and in 40 pairs of osteosarcoma tissues and adjacent muscular tissues. CCK8 assay and colony formation assay was used to assess the effect of CXCL14 suppression mediated by two specific siRNAs on the proliferation of U2OS osteosarcoma cells. Immunohistochemistry was performed to detect the expression of CXCL14 in 58 osteosarcoma tissues, and Kaplan-Meier method and log-rank test were performed for survival analysis of the patients. RESULTS: Significant up-regulation of CXCL14 expression was found in the osteosarcoma cell lines and in osteosarcoma tissues compared with the adjacent muscles (P<0.01). In U2OS cell, suppression of CXCL14 expression by siRNA significantly inhibited the cell proliferation (P<0.01) and colony formation rate (P<0.05). Kaplan-Meier survival analysis indicated that patients with high CXCL14 expression had worse prognosis than those with low CXCL14 expression (P=0.02). CONCLUSION: CXCL14 is up-regulated in both osteosarcoma cell lines and primary osteosarcoma tissues to promote the proliferation of osteosarcoma cells. A high CXCL14 expression in osteosarcoma tissues is associated with a poor prognosis, suggesting the that CXCL14 serve as a potential therapeutic target for osteosarcoma. PMID- 23803188 TI - [Roles of miR-590-5p and miR-590-3p in the development of hepatocellular carcinoma]. AB - OBJECTIVE: To study the effect of the two arms of miR-590, miR-590-5p and miR-590 3p, on hepatoma cell proliferation and their roles in tumor development. METHODS: We analyzed and verified the expression pattern of miR-590 in liver cancer specimens and cell lines by miRNA microarrays and QPCR. MiR-590 mimic or inhibitor was transfected into normal liver cells or liver cancer cells via liposome, and the changes in cell proliferation and survival were determined by MTT assay and soft agar colony formation assay. The target genes of miR-590-5p and miR-590-3p were predicated with Targetscan and validated by luciferase reporter system and Western blotting. RESULTS: The expressions of miR-590-5p and miR-590-3ps were up-regulated in 3 hepatocellular carcinoma (HCC) tissues and their synchronization was significantly up-regulated in 8 out of 10 HCC tissues as compared with the adjacent tissues. QPCR further showed that miR-590-5p/3p was up-regulated in 3 HCC cell lines (HepG2, Hep3B, and Huh7) in comparison with the normal liver cell line L-O2. L-O2 cells over-expressing miR-590-5p and miR-590-3p exhibited significantly increased proliferation (P<0.05), while down-regulation of miR-590-5p and miR-590-3p caused significantly suppressed proliferation in HepG2, Hep3B, and Huh7 cells. Targetscan predicted PDCD4 and PTEN as the potential target genes of miR-590-5p and miR-590-3p, which was verified by luciferase reporter system and Western blotting. miR-590-3p was found to activate PI3K-AKT signaling pathway by down-regulating PTEN to promote AKT1-S473 phosphorylation. CONCLUSION: MiR-590 is an important tumorigenic factor for HCC, and its two arms can both promote tumorigenesis by regulating the expression of their target tumor suppressor gene, PDCD4 and PTEN, to promote HCC cell proliferation and survival and activate the core tumor signal pathway PI3K-AKT. PMID- 23803189 TI - [Expression of Id1 and Id3 in endometrial carcinoma and their roles in regulating biological behaviors of endometrial carcinoma cells in vitro]. AB - OBJECTIVE: To investigate the expression of inhibitor of DNA differentiation/DNA binding 1 (Id1) and Id3 in endometrial carcinoma and explore their roles in regulating the proliferation, invasion, migration and adhesion of endometrial carcinoma cells in vitro. METHODS: Id1 and Id3 expression in 4 fresh endometrial cancer tissue specimens and matched adjacent tissues were detected using Western blotting. Two endometrial cancer cell lines, HEC-1-B and RL-952, were both divided into 4 groups, namely the untreated group, blank virus group, promoter group and Id1/Id3 double-knockdown group, and their expressions of MMP2, CXCR4 and P21 were detected by qRT-PCR and Western blotting. The proliferation, invasion, migration and adhesion of the cells were evaluated with MTT, Transwell, wound-healing, and adhesion assays. RESULTS: Endometrial carcinoma tissues showed significantly higher Id1 and Id3 expression than the adjacent tissues (P<0.05). In the two endometrial carcinoma cell lines, Id1/Id3 double-knockdown significantly decreased MMP2 and CXCR4 expression and increased P21 expression at both mRNA and protein levels (P<0.05), and resulted in suppressed cell proliferation, invasion, migration and adhesion. CONCLUSION: Id1 and Id3 expressions are up-regulated in endometrial carcinoma to promote the proliferation, invasion, migration and adhesion of the tumor cells by increasing MMP2 and CXCR4 expression and reducing P21 expression. Therapies targeting Id1/Id3 can be a novel strategy for treatment of endometrial carcinoma. PMID- 23803190 TI - [Diagnosis of obstructive coronary artery disease using CT coronary angiography combined with CT first-pass myocardial perfusion imaging at rest]. AB - OBJECTIVE: To assess the feasibility and accuracy of CT coronary angiography (CTCA) combined with CT first-pass myocardial perfusion imaging (CT first-pass MPI) at rest for diagnosis of obstructive coronary artery disease (CAD). METHODS: Fifty-five patients, suspected or diagnosed as CAD, were performed with CTCA and CAG within 2 weeks. CT first-pass MPI detected myocardial ischemia through analyzing the raw date of CTCA. RESULTS: Comparison with the results of CAG, the sensibility, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of CT first-pass MPI at rest for detecting obstructive CAD were 84.6%, 68.8%, 86.8%, 64.7% and 80.0%, respectively; and 92.3%, 93.8%, 97.3%, 83.3%, 92.7% for CTCA combined with CT first-pass MPI, respectively. CONCLUSION: CTCA combined with CT first-pass MPI at rest could detect obstructive CAD feasible and accurately. PMID- 23803191 TI - [Virtual screening of small molecular HIV-1 entry inhibitor NC-2 targeting gp120 and its action mechanism]. AB - OBJECTIVE: To screen the HIV-1 entry inhibitors targeting HIV-1 gp120 from the IBS natural product database by virtual screening based on the binding mode of the neutralizing antibody VRC01 with HIV-1 gp120 and investigate the anti-viral activities of the inhibitors and their action mechanisms. METHODS: The binding interaction of the candidate molecules binding gp120 and changes of the binding free energy were analyzed by MM-PBSA calculation. The anti-HIV-1 activities of the tested compounds were detected by HIV-1 pseudotyped virus, laboratory-adapted HIV-1 and a cell-cell fusion assay. The cytotoxicity of the studied molecules was examined by XTT colorimetric assay. The mechanisms of the anti-viral activities of the candidate molecules were analyzed using enzyme-linked immunosorbent assay. RESULTS: A total of 19 molecules with distinct reduction of the binding free energy after binding with gp120 were screened from 40000 molecules. Among them, NC-2 showed anti-HIV-1 activities against HIV-1 pseudotyped virus and laboratory adapted HIV-1, and was capable of blocking HIV-1 envelope-mediated cell-cell fusion. The IC50 of NC-2 for inhibiting HIV-1IIIB and pseudotyped HIV-1JRFL infection were 1.95?0.44 umol/L and 10.58?0.13 umol/L, respectively. The results of ELISA suggested that NC-2 could inhibit the binding of HIV-1 gp120 to CD4 without blocking the formation of gp41 six-helix bundle in vitro. CONCLUSION: This computer-based virtual screening method can be used to screen HIV-1 entry inhibitors targeting gp120. Using this virtual screening approach combined with anti-viral activity screening, we obtained a potent HIV-1 entry inhibitor NC-2 with novel structure. PMID- 23803192 TI - [Effects of immunization with recombinant fusion protein of extracellular near transmembrane domain of Tibet minipig leptin receptor on fat deposition in SD rats]. AB - OBJECTIVE: To investigate the effect of immunization with prokaryotically expressed recombinant fusion protein of extracellular near-transmembrane domain of Tibet minipig leptin receptor (OBR) on fat deposition in SD rats. METHODS: A pair of specific primers containing BamHI and HindIII restriction enzyme sites was designed to amplify the extracellular near-transmembrane domain (1705-2364 bp) of Tibet minipig OBR gene. After digestion, the amplified fragment was inserted into the plasmid pRSETA between BamHI and HindIII sites. The recombinant plasmid was transformed and expressed in E.coli BL21(DE3) and the product was analyzed by SDS-PAGE and Western blotting. SD rats were immunized with the fusion protein, and the changes in body weight, feed intake, body length, Lee's index, percentage of abdominal fat, liver fat deposition and subcutaneous fat deposition were assessed. RESULTS: The recombinant fusion protein obtained (about 27.6 kD) was expressed in E.coli induced by IPTG and identified by SDS-PAGE and Western blotting. The rats immunized with the fusion protein showed no significant changes in body weight, body length, Lee's index, percentage of abdominal fat or liver fat deposition as compared with the control rats. Nevertheless, the immunization caused significantly increased feed intake and significantly decreased volume of subcutaneous fat cells. CONCLUSION: Immunization with the fusion protein of extracellular near-transmembrane domain of Tibet minipig OBR can promote feed intake and suppress subcutaneous fat deposition in SD rats. PMID- 23803193 TI - [Role of muscarinic cholinergic receptor subtypes in regulating glutamatergic synaptic transmission in rat spinal dorsal horn]. AB - OBJECTIVE: To investigate the role of muscarinic cholinergic receptor (mAChR) subtypes in the regulation of glutamatergic input to the spinal dorsal horn neurons and the possible mechanism. METHODS: Whole-cell voltage-clamp recordings on acute spinal slice was utilized to investigate the effect of activation of mAChRs and blockade of M2/M4 subtypes on glutamatergic synaptic transmission in rat spinal dorsal horn neurons. RESULTS: The nonselective mAChRs agonist oxotremorine-M concentration-dependently decreased the amplitude of monosynaptic and polysynaptic evoked glutamate-mediated excitatory postsynaptic currents (eEPSCs) in most of the neurons. The M2/M4 antagonist himbacine completely blocked the inhibitory effect of oxotremorine-M in 92.3% of monosynaptic and 75% of polysynaptic neurons in the spinal cord slices. In the remaining 16% neurons, himbacine partially blocked the inhibitory effect of oxotremorine-M. CONCLUSIONS: Activation of mAChRs in the spinal cord attenuates synaptic glutamate release to the dorsal horn neurons mainly through M2 and M4 receptor subtypes, indicating that a presynaptic inhibition in the spinal cord may be involved in the regulation of nociception by the cholinergic system and mAChRs. PMID- 23803194 TI - [Effects of mannan-binding lectin on the functions of human polymorphonuclear cells]. AB - OBJECTIVE: To investigate the effects of mannan-binding lectin (MBL) on the functions of human polymorphonuclear cells (PMNs). METHODS: ELISA and Dot blot were performed to examine the binding between MBL and the microorganisms. Flow cytometry and fluorescence microscopy were employed to analyze the phagocytosis of FITC-labeled microorganisms by the PMNs. Real-time quantitative PCR was used to detect the expression levels of IL-1beta, TNF-alpha and CD11b mRNA in the PMNs, and ELISA used to detect the levels of TNF-alpha and IL-6 in the supernatants of PMN culture. Nitro-blue tetrazolium reduction assay was used to estimate the levels of superoxide production. RESULTS: MBL bound to the microorganisms in a dose-dependent manner. MBL had no significant effect on phagocytosis of C. albicans and E.coli by the PMNs in the absence of human serum, but in presence of mixed MBL-deficient human sera, MBL promoted the phagocytosis of C. albicans, which could be blocked by mannan. Mannan treatment increased the expressions of IL-1beta, TNF-alpha, IL-6 and CD11b and enhanced superoxide production in the PMNs. CONCLUSION: MBL can promote phagocytosis of microorganisms by PMNs and increase the expressions of proinflammatory cytokines from PMNs in a complement lectin pathway-dependent manner. PMID- 23803195 TI - [Construction of dengue virus-specific full-length fully human antibody libraries by mammalian display technology]. AB - OBJECTIVE: To construct dengue virus-specific full-length fully human antibody libraries using mammalian cell surface display technique. METHODS: Total RNA was extracted from peripheral blood mononuclear cells (PBMCs) from convalescent patients with dengue fever. The reservoirs of the light chain and heavy chain variable regions (LCkappa and VH) of the antibody genes were amplified by RT-PCR and inserted into the vector pDGB-HC-TM separately to construct the light chain and heavy chain libraries. The library DNAs were transfected into CHO cells and the expression of full-length fully human antibodies on the surface of CHO cells was analyzed by flow cytometry. RESULTS: Using 1.2 ug of the total RNA isolated from the PBMCs as the template, the LCkappa and VH were amplified and the full length fully human antibody mammalian display libraries were constructed. The kappa light chain gene library had a size of 1.45*10(4) and the heavy chain gene library had a size of 1.8*10(5). Sequence analysis showed that 8 out of the 10 light chain clones and 7 out of the 10 heavy chain clones randomly picked up from the constructed libraries contained correct open reading frames. FACS analysis demonstrated that all the 15 clones with correct open reading frames expressed full-length antibodies, which could be detected on CHO cell surfaces. After co transfection of the heavy chain and light chain gene libraries into CHO cells, the expression of full-length antibodies on CHO cell surfaces could be detected by FACS analysis with an expressible diversity of the antibody library reaching 1.46*10(9) [(1.45*10(4)*80%)*(1.8*10(5)*70%)]. CONCLUSION: Using 1.2 ug of total RNA as template, the LCkappa and VH full-length fully human antibody libraries against dengue virus have been successfully constructed with an expressible diversity of 10(9). PMID- 23803196 TI - [Identification of hepatitis B virus YMDD point mutation using peptide nucleic acid clamping PCR]. AB - OBJECTIVE: To establish a peptide nucleic acid clamping PCR assay for detecting hepatitis B virus (HBV) drug resistance mutation. METHODS: RtM204I (ATT) mutant, rtM204V (GTG) mutant and rtM204 (ATG) wild-type plasmids mixed at different ratios were detected for mutations by PNA clamping PCR assay and direct sequencing, and the sensitivity and specificity of the two methods were compared. Serum samples from 85 patients with chronic HBV infection were detected for drug resistance using the two methods. RESULTS: The sensitivity of PNA-PCR assay was 0.001% in a 10(5)-fold excess of wild-type HBV DNA with a detection limit of 10(1) copies. The sensitivity of direct sequencing was 10% with a detection limit of 10(4) copies. Mutants were detected in 73 of the 85 serum samples (85.9%), including YIDD in 40 samples, YVDD in 23 samples, and YIDD+YVDD in 10 samples. The agreement of PNA-PCR assay with direct sequencing was only 40% (34/85, YIDD in 21 samples, YVDD in 11 samples, and YIDD+YVDD in 2 samples). Neither of the two methods yielded positive results for the negative control samples, suggesting their good specificity. CONCLUSION: PNA-PCR assay appears to be a more sensitive and rapid assay for detection of HBV genotypic resistance. PMID- 23803197 TI - [Effect of basal serum luteinizing hormone and luteinizing hormone/follicle stimulating hormone ratio on outcomes of in vitro fertilization-embryo transfer in patients with polycystic ovarian syndrome]. AB - OBJECTIVE: To evaluate the effect of basal serum luteinizing hormone (LH) and luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratio on the clinical outcomes of in vitro fertilization-embryo transfer (IVF-ET) in patients with polycystic ovary syndrome (PCOS). METHODS: A retrospective analysis was performed of 134 IVF cycles in patients with PCOS. The cycles were classified into 2 groups according to serum levels of LH and also into 2 groups according to LH/FSH ratio, namely group A1 (LH<=10 IU/L), group A2 (LH>10 IU/L), group B1 (LH/FSH ratio<2), and group B2 (LH/FSH ratio>=2). The clinical characteristics, embryological data and pregnancy outcomes were compared between the groups. RESULTS: Patients in group A2 showed significantly higher FSH, T level, and LH/FSH ratio with a greater number of oocytes retrieved than those in group A1, but the time for down regulation, duration of stimulation, AFC, LH and LH/FSH on the first day of stimulation, embryological data and pregnancy outcomes did not differ significantly between the two groups. Compared with group B1, group B2 showed higher basal LH, E2 level on the day of HCG, more oocytes retrieved and lower dose of gonadotropins used, but the time for down-regulation, duration of stimulation, LH and LH/FSH on the first day of stimulation and pregnancy outcomes were comparable between the two groups. CONCLUSION: A high basal LH level or a high LH/FSH ratio does not produce obvious deleterious effect on the clinical outcomes of IVF-ET in women with PCOS who take oral contraceptives for pretreatment before long GnRH-agonist protocol. PMID- 23803198 TI - [Effects of oral dydrogesterone on clinical outcomes of frozen-thawed embryo transfer cycles]. AB - OBJECTIVE: To investigate the effects of oral dydrogesterone for luteal phase support after frozen embryo transfer (FET) cycles on the clinical outcomes. METHODS: A total of 1643 FET cycles in our center between January, 2010 and September, 2011 were analyzed. The patients were divided into group A with natural-cycle FET and group B with hormone replacement cycle (HRT-FET). The two groups were further divided into two subgroups to receive oral dydrogesterone (groups AI and BI, n=358 and 185, respectively) or intramuscular progesterone with progynova (groups AII and BII, n=634 and 466, respectively) as luteal phase support. The clinical pregnancy rates, implantation rates, early miscarriage rates, ectopic pregnancy rates, ongoing pregnancy rates and delivery rates were compared between the subgroups. RESULTS: There were no significant differences in the clinical outcomes between the patients receiving dydrogesterone and intramuscular progesterone as luteal phase support in either natural-cycle FET or HRT FET (P>0.05). CONCLUSION: In the FET cycles, oral dydrogesterone tablets for luteal support can achieve good clinical outcomes comparable with those by intramuscular progesterone and serves as a good alternative for luteal phase support. PMID- 23803199 TI - [EZH2 gene silenced by siRNA suppresses the growth and invasion of endometrial carcinoma cells]. AB - OBJECTIVE: To explore the effects on cell proliferation and invasion as well as molecular basis after suppressing EZH2 expression in endometrial carcinoma cells by using siRNAs. METHODS: RT-PCR was used to examine the expression of EZH2 in endometrial carcinoma and their paracancerous tissues. SiRNAs targeting to EZH2 were transfected to endometrial carcinoma cells, and MTT, FACS, and boyden assays were utilized to examine cell proliferation, cell cycle change, and cell invasion. Finally, the molecular mechanisms of EZH2 on cell function alteration were investigated. RESULTS: Compared with paracancerous tissues, increased expression trend of EZH2 mRNA was showed in endometrial carcinoma tissues. Further, knocking down EZH2 expression inhibited cell growth, cell cycle transition from G1 to S phase, and cell invasion ability. Molecular basis indicated that suppression of EZH2 downregulated the expression of E2F1 and MMP9 and upregulated tumor suppressor p21 expression. CONCLUSION: EZH2 expression is increased in endometrial carcinoma tissues. Knocking down EZH2 expression suppresses the cell growth, cell cycle transition and cell invasion by downregulated E2F1 and MMP9, and upregulated tumor suppressor p21 expression. PMID- 23803200 TI - [A quantitative investigation of E2F1-regulated cell cycle compensation mechanism]. AB - OBJECTIVE: To explore the core mechanism of cell cycle compensation using a mathematical model. METHODS: A set of ordinary differential equations were used to describe the interactions between the core cell cycle molecules. Continuous and cyclic changes of the concentrations of these molecules were computed to capture the discrete events of molecular interactions. RESULTS: The calculated molecule concentrations and captured signaling events agreed with the experimental results. CONCLUSION: E2F transcription factor 1 is the pivotal element linking the positive and negative feedbacks and regulating G1/S and G2/M phase compensation. PMID- 23803201 TI - [An automatic subregion delineation method for T2 measurement of articular cartilage in the knee]. AB - OBJECTIVE: To propose a new method for automatic segmentation of manually determined knee articular cartilage into 9 subregions for T2 measurement. METHODS: The middle line and normal line were automatically obtained based on the outline of articular cartilage manually drawn by experienced radiologists. The region of articular cartilage was then equidistantly divided into 3 layers along the direction of the normal line, and each layer was further equidistantly divided into 3 segments along the direction of the middle line. Finally the mean T2 value of each subregion was calculated. Bland-Altman analysis was used to evaluate the agreement between the proposed and manual subregion segmentation methods. RESULTS: The 95% limits of agreement of manual and automatic methods ranged from -3.04 to 3.20 ms, demonstrating a narrow 95% limits of agreement (less than half of the minimum average). The coefficient of variation between the manual and proposed subregion methods was 4.04%. CONCLUSION: The proposed subregion segmentation method shows a good agreement with the manual segmentation method and minimizes potential subjectivity of the manual method. PMID- 23803202 TI - [Analysis of the factors for predicting the outcomes of interferon-alpha and entecavir treatments for chronic hepatitis B with positive HBeAg]. AB - OBJECTIVE: To analyze the predictive factors of the therapeutic effects of interferons (IFNs) and entecavir (ETV) treatments for 48 weeks in patients with chronic hepatitis B (CHB) positive for HBeAg. METHODS: This retrospective analysis compared the treatment efficacy of IFNs and ETV in 129 CHB patients positive for HBeAg. Twenty-seven of the patients were treated with PEG-IFNalpha 2a (180 ug once a week, PEG-IFN group), 51 patients with conventional IFNalpha (5 MIU three times a week, IFN group), and 51 with ETV (0.5 mg once daily, ETV group) for 48 weeks. RESULTS: After completion of the treatment cycles, the patients in ETV group showed a significantly higher HBV DNA undetectable rate and a significantly lower HBeAg seroconversion rate than those in PEG-IFN and IFN groups (P<0.05); HBeAg seroconversion rates were similar between PEG-IFN group and IFN group (Chi(2)=0.709, P=0.400). In PEG-IFN and ETV groups, HBeAg seroconversion rates were not associated with age, gender, baseline HBeAg, baseline HBV DNA and baseline ALT. In IFN group, HBeAg seroconversion rates were associated with baseline HBeAg (P=0.048) but not with age, gender, baseline HBV DNA and baseline ALT. In PEG-IFNalpha-2a group, ROC analysis showed that the sensitivity and specificity of HBeAg seroconversion at 48 weeks were 0.778 and 0.889, respectively, when the decline rate of HBeAg between baseline and week 24 exceeded 97.81%, with the corresponding positive and negative predictive values (PPV and NPV) of 0.778 and 0.889, respectively; the sensitivity and specificity of HBeAg seroconversion at 48 weeks were 0.889 and 0.722, respectively, when the decline rate of HBeAg between week 12 and week 24 was over 42.75%, with the corresponding PPV and NPV of 0.615 and 0.929, respectively. CONCLUSION: Treatments with PEG-IFNalpha-2a and conventional IFNalpha for 48 weeks can achieve a higher HBeAg seroconversion rate than ETV, but the latter produces a higher HBV DNA undetectable rate. For PEG-IFNalpha-2a treatment, the decline rate of HBeAg between baseline and week 24 over 97.81% is the best predicting factor for HBeAg seroconversion at week 48 in CHB patients positive for HBeAg. PMID- 23803203 TI - [Cytoplasmic expression of P27 protein and its correlation with clinicopathologic features of nasopharyngeal carcinoma]. AB - OBJECTIVE: To evaluate the correlation of p27 protein expression in the cytoplasm with the clinicopathologic features of nasopharyngeal carcinoma (NPC). METHODS: Immunohistochemistry was employed to examine P27 protein expression in the cytoplasm of NPC samples and nasopharyngeal (NP) tissue samples. The differential expression of P27 protein between NPCs and NPs and the correlation of cytoplasmic P27 protein expression with the clinicopathologic parameters of NPC patients was analyzed. RESULTS Immunohistochemistry indicated significantly down-regulated t p27 protein expression in NPC tissues compared to that in NP tissues (P=0.047). The reduction of P27 expression was inversely correlated with T classification of NPC (P=0.033). Although cytoplasmic p27 protein expression was not significantly correlated with lymph node metastasis (P=0.157) or clinical stages of NPC (P=0.090), an obvious trend of inverse correlations between them was noted. CONCLUSION: Down-regulated cytoplasmic p27 protein expression may promote the carcinogenesis of NPC and can be an unfavorable prognostic factor for survival of NPC patients. PMID- 23803204 TI - [Celecoxib enhances chemosensitivity of oral cancer cells by blocking cell cycle progression in vitro]. AB - OBJECTIVE: To investigate the effect of celecoxib in enhancing the chemosensitivity of oral cancer cells and the correlation of this effect with cell cycle arrest. METHODS: KB/VCR cell line was treated with celecoxib (10, 20, 40, and 80 umol/L) and/or VCR (0.375, 0.75, 1.5, and 3 umol/L), and the growth inhibition rates of KB/VCR cells were assessed with MTT assay. Flow cytometry was employed to analyze the distribution of cell cycle. Western blotting was performed to detect the expression of P-glycoprotein (P-gp) and the cell cycle related proteins Cyclin D1 and p21(WAF1/CIP1). RESULTS: Low concentrations of celecoxib (<20 umol/L) produced no obvious effect on the proliferation of the cells. But at 10 umol/L, celecoxib significantly enhanced the toxicity of VCR in a time-dependent manner, and the combined treatments for 24, 48, and 72 h caused growth inhibition rates of (37.53?2.05)%, (46.67?3.17)% and (54.02?1.53)%, respectively, significantly higher than those following treatments with celecoxib or VCR alone (P<0.01). Compared with the cells treated with VCR alone , the cells with combined treatments showed a significantly increased cell percentage in G0/G1 phase [(56.08?0.46)%] with decrease percentages in S phase [(22.83?0.20)%] and G2/M phase [(21.09%?0.66)%]. The combined treatment also significantly down regulated cyclin D1, up-regulated p21(WAF1/CIP1), and reduced P-gp expressions in the cells. CONCLUSIONS: Celecoxib enhances the chemosensitivity of KB/VCR cells by down-regulating P-gp expression, which is partially mediated by modification of cyclin D1 and p21(WAF1/CIP1) to result in cell cycle arrest. PMID- 23803205 TI - [CD133(+) Colo205 colorectal cancer cells express high levels of ALDH1 in serum free culture]. AB - OBJECTIVE: To investigate the expression pattern of CD133 and ALDH1 in colorectal cancer cells line Colo205 cultured in serum-free medium (SFM) containing recombinant human epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). METHODS: Colo205 cells were cultured in serum-free medium (SFM) containing human recombinant EGF and bFGF or in serum-supplemented medium (SSM). The expression of CD133 was analyzed in both groups, and CD133(+) and CD133(-) cells sorted from the SFM group using flow cytometry and observed microscopically for their growth status. The expression of CD133 and ALDH1 in CD133(+) cells and CD133(-) cells was detected by immunofluorescence assay. CD133(+) cells and CD133(-) cells were then injected subcutaneously into NOD/SCID mice and the expression of ALDH1 in the tumor tissues was detected by immunohistochemistry. RESULTS: The cells in SFM group showed a significantly higher percentage of CD133(+) cells than those in SSM group (P<0.05). In SFM, CD133(+) cells were capable of forming tumor spheres while CD133(-) cells could not; CD133(+)cells strongly expressed CD133 and ALDH1 and CD133(-) cells did not. In mice, tumors generated by CD133(+) cells, but not by CD133(-) cells, positively expressed ALDH1. CONCLUSIONS: CD133(+) Colo205 colorectal cancer cells in SFM containing human recombinant EGF and bFGF can form tumor spheres and strongly express ALDH1. ALDH1 may be one of the candidate markers of colorectal cancer stem cells. PMID- 23803206 TI - [Intracranial lageniform aneurysms: imaging features, diagnosis and treatment strategies]. AB - OBJECTIVE: To explore the imaging features, diagnosis and treatment strategies of intracranial lageniform aneurysms. METHODS: The clinical characteristics and therapeutic outcomes of 6 patients with intracranial lageniform aneurysms were retrospectively analyzed. RESULTS: All the 6 aneurysms, including 5 anterior communicating artery aneurysms and 1 middle cerebral artery (MCA) aneurysm, were diagnosed by CT, DSA and (or) MRA. Pretreatment CT revealed subarachnoid hemorrhage and intracranial hematoma surrounding the ruptured aneurysm. Three dimensional DSA showed that all the lageniform aneurysms contained two parts, the larger false aneurysm and the smaller true aneurysms. All the 5 Acom aneurysms were coiled and the MCA aneurysm was clipped. Two patients with coiling developed serious brain edema, and acute decompressive craniectomy was performed to 1 of them. Pathological examination of the surgical specimens confirmed that pseudoaneurysm formed the larger part of the lageniform aneurysm. One patient died of brain hernia, and the other 5 patients were discharged with good GOS. All the patients showed stable neurological status during the 3-month follow-up. CONCLUSION: Lageniform aneurysm is a complex aneurysm consisting in larger part of false aneurysm and in smaller part of true aneurysm, and early intervention with individualized surgeries is recommended. PMID- 23803207 TI - [Expression and clinical significance of secretory leucocyte protease inhibitor in colon carcinoma]. AB - OBJECTIVE: To investigate the expression of secretory leucocyte protease inhibitor (SLPI) in colon cancer and their clinical significance. METHODS: Immunohistochemistry was performed to detect the SLPI expression in colon cancer tissue microarray. The expression of SLPI was scored by two pathologists and was analyzed using Chi(2) test to explore its influence on the pathologic characteristics of colon carcinoma. RESULTS: SLPI was up-regulated in colon cancer tissue compared to normal mucosa. Overexpression of SLPI protein was correlated with differentiation grade (low differentiation: 42.1% vs 57.9%; moderate/well differentiation: 2.3% vs 97.7%, TNM stages(III-IV:29.4% vs 70.6%;I II:3.1% vs 96.9%), lymph node metastasis (28.6% vs 71.4%) and distant metastasis (84.6% vs 15.4%), but not with patient age or sex. CONCLUSION: SLPI overexpression correlates with aggressive pathologic characteristics of colon cancer and it may server as prognostic factor of colon cancer patients. Further research will be carried out to verify whether SLPI can become a new target for colon cancer treatment. PMID- 23803208 TI - [Evaluation of co-cultured CL-1 hepatocytes and hepatic stellate cells in rotatory cell culture system]. AB - OBJECTIVE: To explore whether the function of the CL-1 hepatocytes, co-cultured with human hepatic stellate cells (HSC) on microcarriers was better than that cultured without HSC. METHODS: CL-1 hepatocytes were divided into 2 groups. The co-culture group was cultured with HSC in DMEM culture medium containing 10% fetal bovine serum, and HSC were not added in single-culture group. The cytomorphology was observed by inverted microscope and scanning electron microscopy. The effects of different culture method on the proliferation in vitro were analyzed by MTT assay. The function of hepatocytes was evaluated through measuring the concentration of ALT and albumin. RESULTS: The inverted microscope and the MTT staining results showed that the quantity and viability of the human hepatocyte (C3A) in bidirectional bioreactor group were much better than the RCMW group. The growth curve results showed that the density of the human hepatocyte (C3A) was firstly increased and then decreased in both groups, and the peak of the curve appeared in day 5. The density of human liver cells in the second generation of bi-directional rotation and perfusion microgravity bioreactor group was significantly higher than the RCMW group from day1 to day 7 (P<0.05). The functional results showed that the albumin and urea concentration, which reached the peak on day 5, also gone up firstly and then gradually gone down in both teams. And the albumin and urea concentration in bidirectional bioreactor group was significantly higher than RCMW group from day 1 to day7 (P<0.01). Besides, the concentration of ALT and AST in bidirectional bioreactor group was significantly lower than RCMW group from day 1 to day 7 (P<0.05). CONCLUSION: This study shows that this new culture method is advantageous in enhancing cell viability and function. It indicates that co-culturing hepatocytes with HSC has a good application prospect in the development of artificial liver technology. PMID- 23803209 TI - [Application of computer-aided osteotomy template design in treatment of developmental dysplasia of the hip with steel osteotomy]. AB - OBJECTIVE: To provide an accurate method for osteotomy in the treatment of developmental dysplasia of the hip with steel osteotomy by three-dimensional reconstruction and Reverse Engineering technique. METHODS: Between January 2011 and December 2012, 13 children with developmental dysplasia of the hip underwent steel osteotomy. 3D CT scan pelvic images were obtained and transferred via a DICOM network into a computer workstation to construct 3D models of the hip using Materialise Mimics 14.1 software in STL format. These models were imported into Imageware 12.0 software for steel osteotomy simulation until a stable hip was attained in the anatomical position for dislocation or subluxation of the hip in older children. The osteotomy navigational templates were designed according to the anatomical features after a stable hip was reconstructed. These navigational templates were manufactured using a rapid prototyping technique. RESULTS: The reconstruction hips in these children show good matching property and acetabulum cover. CONCLUSION: The computer-aided design of osteotomy template provides personalized and accurate solutions in the treatment of developmental dysplasia of the hip with steel osteotomy in older children. PMID- 23803210 TI - [Sexual function in premenopausal women before and after renal transplantation]. AB - OBJECTIVE: To study the changes in sexual function in premenopausal women after renal transplantation. METHODS: Forty-two married premenopausal women receiving dialysis therapy for at least 6 months with normal renal function for 6 months after renal transplantation were examined for hormonal profiles and menstrual cycles. The sexual functions of the patients were evaluated using Female Sexual Function Index (FSFI) before and 6 months after the transplantation. RESULTS: Before renal transplantation, amenorrhea, oligomenorrhea, polymenorrhea, and eumenorrhea were found in 18 cases (42.9%), 10 cases (23.8%), 5 cases (11.9%) and 9 cases (21.4%), as compared to 7 cases (16.7%), 5 cases (11.9%), 6 cases (14.3%) and 24 cases (57.1%) after the transplantation, respectively. Prolactin (PRL), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels significantly decreased and estradiol (E2) and progesterone (P) significantly increased after renal transplantation (P<0.001). Nineteen patients (45.2%) before and 36 patients (85.7%) after the surgery reported to have an active sexual life (P<0.001). The total incidences of female sexual dysfunction before and after kidney transplantation were 90.5% and 40.5% (P<0.001), respectively. The scores for sexual desire, arousal, lubrication, satisfaction, orgasm, and pain in FSFI were significantly increased after kidney transplantation (P<0.001). CONCLUSIONS: A successful renal transplantation can significantly improve sexual functions in premenopausal women. PMID- 23803211 TI - [The influence and safety of denosumab on bone mineral density of lumbar spine in women with low bone mass: a meta-analysis]. AB - OBJECTIVE: To evaluate the influence and safety of denosumab on bone mineral density (BMD) of lumbar spine in women with low bone mass. METHODS: The clinical literatures concerning denosumab for the treatment of osteopenia or osteoporosis in women were searched from Medline, Embase, Cochrane Central Register of Controlled Trials, Wanfang database, China National Knowledge Infrastructure database, Chinese Biomedical Database. Randomized controlled trials (RCT) were selected by the inclusive and exclusive criteria. The jadad scale was used in the quality assessment of included studies. Meta-analysis of valid data picked from included studies was performed by RevMan 5.0.24 software. RESULTS: 5 RCT were included in this meta-analysis. The results of meta-analysis using the fixed effects model showed that, the increase level of lumbar BMD after 12 month was 5.45% (95% CI, 5.05%~5.84%) higher in denosumab group than in placebo control group (P<0.00001). The serious adverse event, serious infection event and pack pain occurred during the followed-up were analysed using fixed effects model. The results showed no significant difference between two groups. CONCLUSION: Compared with placebo control group, denosumab can significant increase the BMD of lumbar spine, and the safety of two groups is similar. PMID- 23803212 TI - [Value of three risk-stratification criteria in Chinese patients with gastrointestinal stromal tumors]. AB - OBJECTIVE: To evaluate the application value of three risk-stratification criteria in domestic GIST risk assessment. METHODS: The clinical data of 144 patients with GIST who were admitted to our hospital from January 2008 to December 2010 were analyzed retrospectively. 144 cases of GISTs were evaluated for their biologic potential by the risk-stratification criteria of Fletcher, NIH2008, and among those, 119 cases of GISTs were evaluated by the risk stratification criteria of Miettinen. Fletcher and Miettinen criteria were compared by Kaplan-Meier survival analysis. The Logistic regression model was established to analyze the comparison of Miettinen and NIH2008 criteria. RESULTS: (1) According to Fletcher criteria in the intermediate risk GISTs, the recurrence free survival (RFS) of non gastric(small intestinal, rectal and so on) GISTs and gastric GISTs were statistically different (P=0.001). According to Miettinen criteria, in the risk subgroup of GISTs, the recurrence-free survival of different location of GISTs had no statistical difference(P>0.05); (2)Logistic regression model judgment rate: Miettinen criteria (89.4)>NIH2008 criteria (85.2). CONCLUSION: Fletcher criteria is simple and easy to use, but may misjudge the prognosis of the GIST in different part; Miettinen criteria may be a potential supplementary way of NIH2008 criteria in domestic GIST risk assessment. PMID- 23803213 TI - [Expression of Dickkopf-1 in human colon carcinoma cell lines]. AB - OBJECTIVE: To investigate the expression of Dickkopf-1(DKK1) in 6 different colon carcinoma cell lines. METHODS: The expression of DKK1 protein were detected in SW480, SW620, HT29, LS174T, LOVO, and HCT116 cells lines using Western blot analysis and immunocytochemistry, and the mRNA levels of DKK1 was detected using quantitative real-time PCR (qPCR). RESULTS: The results of qPCR showed significantly higher expressions of DKK1 mRNA in HT29 and HCT116 cells than in the other 4 cells (P<0.05). Western blotting demonstrated that DKK1 was over expressed in HCT116 and HT29 cells compared with that in the other cell lines. All the 6 cell lines were found to have positive DKK1 expression by immunocytochemical staining. CONCLUSION: DKK1 shows differential expression patterns among the 6 human colon carcinoma cell lines. PMID- 23803214 TI - [Effect of folic acid in preventing aberrant methylation of fetal endometriosis susceptibility gene HOXA10]. AB - OBJECTIVE: To detect aberrant methylation in the promoter region of fetal endometriosis susceptibility gene homeobox-10 (HOXA10) in women with and without folic acid supplementation and explore the effect of folic acid in optimizing intrauterine environment. METHODS: Thirty-six cord blood specimens were collected between January, 2010 and December, 2012 from pregnant women with endometriosis, including 22 with folic acid treatment and 15 without. Methylation-specific polymerase chain reaction (MSP) and bisulfite salt modified sequencing (BSP) were employed to detect aberrant methylation of HOXA10 gene in these specimens. RESULTS: The methylation rate of HOXA10 gene differed significantly between pregnant women with endometriosis taking folic acid and those who did (P<0.05). CONCLUSION: Folic acid treatment can significantly reduce the methylation rate of fetal endometriosis susceptibility gene HOXA10. PMID- 23803215 TI - [Effect of exendin-4 on monocyte chemoattractant protein-1 expression in cultured rat glomerular mesangial cells induced by tumor necrosis factor-alpha in vitro]. AB - OBJECTIVE: To investigate the effect of exendin-4 on the expression of monocyte chemoattractant protein-1 (MCP-1) and fibronectin (FN) in rat glomerular mesangial cells in vitro. METHODS: Rat glomerular mesangial cells were divided into 5 groups, namely control group, tumor necrosis factor-alpha (TNF-alpha) group (10 ng/ml), TNF-alpha (10 ng/ml)+E1 (1 nmol/L exendin-4) group, TNF-alpha (10 ng/ml)+E5 (5 nmol/L exendin-4) group, and TNF-alpha (10 ng/ml)+E10 (10 nmol/L exendin-4) group. After cultured 24 h or 48 h, RNA were extracted to determine the expression of MCP-1 with real-time PCR, the supernatant were collected to determine the expression of MCP-1 and FN with ELISA. RESULTS: Compared with control group, the cells treated with TNF-alpha for 24 h showed significantly increase the expression of MCP-1 and FN (P<0.01), exendin-4 significantly reduced the expression of MCP-1 and FN in TNF-alpha+E5 group and TNF-alpha+E10 group (P<0.05). After 48h incubation, the expression of MCP-1 and FN increased significantly in TNF-alpha group (P<0.01), which was lowered by exendin-4 in TNF alpha+E1,TNF-alpha+E5 and TNF-alpha+E10 groups (P<0.05). CONCLUSION: Exendin-4 has an intrinsic capability to concentration- and time-dependently inhibit TNF alpha-induced expression of MCP-1 and FN in rat mesangial cells, suggesting the beneficial effect of exendin-4 in preventing and treating diabetic nephropathy. PMID- 23803216 TI - [Behcet's disease complicated by malignant lymphoma: a case report and literature review]. AB - Malignant lymphoma complicated by Behcet's disease (BD) is a rare clinical entity. We report a case of BD complicated by malignant lymphoma in a 26-year-old male patient. The patient was diagnosed to have terminal ileum extranodal NK/T cell lymphoma (nasal type) during treatment for BD with cyclophosphamide (CTX), immunoregulants and biological agents. This is the first case reported in China and the second case globally. The pathogenesis of BD complicated by malignant lymphoma remains unclear. We reviewed the relevant literatures to summarize the clinical characteristics of BD complicated by extranodal NK/T-cell lymphoma (nasal type) and discuss the possible pathogenesis in light of immunology, EB virus infection and medications. PMID- 23803217 TI - [Expression of Nusap1 in the surgical margins of hepatocellular carcinoma and its association with early recurrence]. AB - OBJECTIVE: To detect the expression of Nusap1 of surgical margins in hepatocellular carcinoma (HCC) and investigate its association with early tumor recurrence. METHODS: The expression of Nusap1 in the surgical margins of HCC, which were histopathologically negative for tumor cells, was examined using immunohistochemistry in 61 HCC cases. RESULTS: Fifteen of 21 (71.4%) cases with immunohistochemical positivity for Nusap1 expression in the surgical margins had early recurrence of HCC, a rate significantly higher than that in patients with negative Nusap1 expression (12/40, 30%) (P<0.05). CONCLUSIONS: Nusap1 expression in the surgical margins of HCC is closely correlated to early postoperative recurrence and can serve as an indicator for predicting early recurrence of HCC. PMID- 23803218 TI - A scanning transmission electron microscopy approach to analyzing large volumes of tissue to detect nanoparticles. AB - The use of nanoparticles for the diagnosis and treatment of cancer requires the complete characterization of their toxicity, including accurately locating them within biological tissues. Owing to their size, traditional light microscopy techniques are unable to resolve them. Transmission electron microscopy provides the necessary spatial resolution to image individual nanoparticles in tissue, but is severely limited by the very small analysis volume, usually on the order of tens of cubic microns. In this work, we developed a scanning transmission electron microscopy (STEM) approach to analyze large volumes of tissue for the presence of polyethylene glycol-coated Raman-active-silica-gold-nanoparticles (PEG-R-Si-Au-NPs). This approach utilizes the simultaneous bright and dark field imaging capabilities of STEM along with careful control of the image contrast settings to readily identify PEG-R-Si-Au-NPs in mouse liver tissue without the need for additional time-consuming analytical characterization. We utilized this technique to analyze 243,000 mm3 of mouse liver tissue for the presence of PEG-R Si-Au-NPs. Nanoparticles injected into the mice intravenously via the tail vein accumulated in the liver, whereas those injected intrarectally did not, indicating that they remain in the colon and do not pass through the colon wall into the systemic circulation. PMID- 23803219 TI - Impact of immune system stimulation on the ileal nutrient digestibility and utilisation of methionine plus cysteine intake for whole-body protein deposition in growing pigs. AB - The impact of immune system stimulation (ISS) on the ileal nutrient digestibility and utilisation of dietary methionine plus cysteine (SAA) intake for whole-body protein deposition (PD) was evaluated in growing pigs. For this purpose, sixty barrows were used in two experiments: thirty-six pigs in Expt I and twenty-four pigs in Expt II. Pigs were feed restricted and assigned to five levels of dietary SAA allowance (three and two levels in Expt I and II, respectively) from SAA limiting diets. Following adaptation, pigs at each dietary SAA level were injected with either increasing amounts of Escherichia coli lipopolysaccharide (ISS+; eight and six pigs per dietary SAA level in Expt I and II, respectively) or saline (ISS - ; four and six pigs in Expt I and II, respectively) while measuring the whole-body nitrogen (N) balance. After N-balance observations, pigs were euthanised, organs were removed and ileal digesta were collected for determining nutrient digestibility. Ileal digestibility of gross energy, crude protein and amino acids was not affected by ISS (P>0.20). ISS reduced PD at all levels of dietary SAA intake (P< 0.01). The linear relationship between daily dietary SAA intake and PD observed at the three lowest dietary SAA intake levels indicated that ISS increased extrapolated maintenance SAA requirements (P< 0.05), but had no effect on the partial efficiency of the utilisation of dietary SAA intake for PD (P>0.20). Physiological and metabolic changes associated with systemic ISS had no effect on the ileal digestibility of nutrients per se, but altered SAA requirements for PD in growing pigs. PMID- 23803220 TI - Kinetic and temporospatial parameters in male and female cats walking over a pressure sensing walkway. AB - BACKGROUND: Several factors may influence kinetic data measurements, including body conformation and body mass. In addition, gender differences in gait pattern have been observed in healthy humans. Therefore, the aim of this study was to compare the kinetic and temporospatial parameters in clinically healthy male and female cats using a pressure-sensitive walkway. Eighteen crossbreed adult cats were divided into two groups: G1 had ten male cats (nine neutered) aged from 1 to 4 years and body mass 3.1-6.8 kg; G2 had eight spayed female cats, aged from 1 to 6 years and body mass 3.3-4.75 kg. The data from the first five valid trials were collected for each cat. A trial was considered valid if the cat maintained a velocity between 0.54-0.74 m/s and acceleration from -0.20 to 0.20 m/s2. The peak vertical force (PVF), vertical impulse (VI), gait cycle time, stance time, swing time, stride length, and percentage body weight distribution among the four limbs were determined. In addition, the lengths of each forelimb and each hind limb were measured using a tape with the animal standing. RESULTS: No significant differences were observed in each group in either the forelimbs or the hind limbs or between the left and right sides for any of the variables. For both groups, the PVF (%BW), the VI, and the percentage body weight distribution were higher at the forelimbs than the hind limbs. The stride length was larger for males; however, the other kinetic and temporospatial variables did not show any statistically significant differences between the groups. The lengths of the forelimbs and hind limbs were larger in the male cats. There was a significant moderate positive correlation between the stride length and the length of the limbs. CONCLUSIONS: In conclusion, the only difference observed between male and female cats was the stride length, and this was due to the greater body size of male cats. This difference did not affect other temporospatial or kinetics variables. PMID- 23803221 TI - 3'-Oxo-, amino-, thio- and sulfone-acetic acid modified thymidines: effect of increased acidity on ribonuclease A inhibition. AB - A family of 3'-functionalized thymidines carrying XCH2COOH (X=O, NH, S, SO2) groups has been designed as inhibitors of RNase A. This is because it is possible to manipulate the overall acidity of this new class of nucleic 'acids' by changing X from oxygen to the SO2 group in the series. It is also expected that the acyclic nature of the XCH2COOH group would provide enough flexibility to the COOH group to have maximum interactions with the catalytic subsite P1 of RNase A. As the -SO2CH2COOH substituted derivative showed better potency partially because of the increased acidity of the -COOH group, the inhibitory properties of both 5' substituted and 3',5'-disubstituted sulfone acetic acid modified thymidines were investigated. Two -SO2CH2COOH groups were incorporated with the expectation of targeting two phosphate binding sites simultaneously. Thus, 3',5'-dideoxy-3',5' bis-S-[(carboxymethyl)sulfonyl]thymidine emerged as the best inhibitor in this series with a Ki value of 25 +/- 2 MUM. PMID- 23803222 TI - Specific structure and unique function define the hemicentin. AB - Hemicentin has come a long way from when it was first identified in C. elegans as him-4 (High incidence of males). The protein is now a recognized player in maintaining the architectural integrity of vertebrate tissues and organs. Highly conserved hemicentin sequences across species indicate this gene's ancient evolutionary roots and functional importance. In mouse, hemicentin is liberally distributed on the cell surface of many cell types, including epithelial cells, endothelial cells of the eye, lung, and uterus, and trophectodermal cells of blastocyst. Recent discoveries have uncovered yet another vital purpose of hemicentin 1. The protein also serves a unique function in mitotic cytokinesis, during which this extracellular matrix protein plays a key role in cleavage furrow maturation. Though understanding of hemicentin function has improved through new discoveries, much about this protein remains mysterious. PMID- 23803223 TI - Feeding styles and evening family meals among recent immigrants. AB - The protective effect of family meals on unhealthy weight gain and diet has been shown across multiple age groups; however, it is unknown whether a similar effect is present among diverse immigrant populations. In addition, little research has focused on factors associated with the frequency of evening family meals, such as feeding styles (how parents interact with their child around feeding). Therefore the goals of this paper are to explore the 1) association between the frequency of evening family meals and child weight status among new immigrant families, and 2) influence of immigrant mothers' feeding styles on the frequency of evening family meals. Baseline self-reported socio-demographic information and measured heights and weights were collected for both mother and child (age range: 3-12 years) among 387 mother-child dyads enrolled in Live Well, a community-based, participatory-research, randomized controlled lifestyle intervention to prevent excessive weight gain in recent (<10 years in the U.S.) immigrant mothers and children. For children, height and weight measurements were transformed into BMI z-scores using age-and sex-specific CDC standards and categorized as overweight (85th-94th percentile) and obese (>=95th percentile); mothers' BMI was calculated. Frequency of evening family meals, eating dinner in front of the TV, acculturation and responses to the Caregiver's Feeding Styles Questionnaire (CFSQ) were also obtained from the mother. Children were categorized as "eating evening family meals regularly" if they had an evening family meal >=5 times per week. Overall, 20% of children were overweight and 25% were obese. Less than half (40.9%) of families had regular evening family meals. In multivariate analyses, adjusting for covariates, children who were overweight/obese were significantly less likely to have >=5 evening family meals/week compared with normal weight children (OR = 0.51, 95% CI 0.32-0.82) . Mothers who had a low demanding/high responsive or a low demanding/low responsive feeding style, were less likely to have >=5 evening family meals/week compared to mothers with a high demanding/high responsive feeding style (OR = 0.41, 95% CI 0.18-0.0.96, OR = 0.33, 95% CI 0.13 0.87, respectively). Future interventions and programs that seek to help parents establish healthy household routines, such as family meals, may consider tailoring to specific maternal feeding styles. PMID- 23803224 TI - Surgical treatment for coronary artery aneurysm: a single-centre experience. AB - OBJECTIVES: Coronary artery aneurysm is a rare condition with a reported incidence of 0.14-4.9% in patients undergoing coronary angiography and 0.3-5.3% in patients after percutaneous transluminal coronary angioplasty (PTCA). Optimum surgical therapy for this entity is difficult to standardize. We present here a series of 4 cases with the aim of establishing an optimal surgical therapy for this rare entity. METHODS: Four cases of coronary artery aneurysm were admitted in the Department of Cardiology and Department of Cardiothoracic and Vascular Surgery, King George's Medical University, Lucknow, from April 2010 to April 2012. All patients underwent a surgical procedure that involved ligation and plication of the aneurysm with coronary artery bypass grafting. RESULTS: Out of the four coronary artery aneurysm patients, 1 was atherosclerotic and the remaining 3 patients developed coronary artery aneurysm after PTCA with a drug eluting stent to the left anterior descending artery. After surgery, all patients recovered uneventfully without any recurrence of symptoms in the follow-up. CONCLUSIONS: Coronary artery aneurysm is a rare entity and is being seen more frequently with the increasing use of stents during PTCA. Proximal ligation and plication of the aneurysm with coronary artery bypass grafting in the present series provided good results. With this case series, we seek to establish an optimal surgical therapy for this rare entity. PMID- 23803225 TI - A multinational phase II trial of bevacizumab with low-dose interferon-alpha2a as first-line treatment of metastatic renal cell carcinoma: BEVLiN. AB - BACKGROUND: Avastin and Roferon in Renal Cell Carcinoma (AVOREN) demonstrated efficacy for bevacizumab plus interferon-alpha2a (IFN; 9 MIU tiw) in first-line metastatic renal cell carcinoma (mRCC). We evaluated bevacizumab with low-dose IFN in mRCC to determine whether clinical benefit could be maintained with reduced toxicity. METHODS: BEVLiN was an open-label, single-arm, multinational, phase II trial. Nephrectomized patients with treatment-naive, clear cell mRCC and favourable/intermediate Memorial Sloan-Kettering Cancer Center scores received bevacizumab (10 mg/kg every 2 weeks) and IFN (3 MIU thrice weekly) until disease progression. Descriptive comparisons with AVOREN patients having favourable/intermediate MSKCC scores treated with bevacizumab plus IFN (9 MIU) were made. Primary end points were grade >=3 IFN-associated adverse events (AEs) and progression-free survival (PFS). All grade >=3 AEs and bevacizumab/IFN related grade 1-2 AEs occurring from first administration until 28 days after last treatment were reported. RESULTS: A total of 146 patients were treated; the median follow-up was 29.4 months. Any-grade and grade >=3 IFN-associated AEs occurred in 53.4% and 10.3% of patients, respectively. The median PFS and overall survival were 15.3 [95% confidence interval (CI): 11.7-18.0] and 30.7 months (95% CI: 25.7-not reached), respectively. The ORR was 28.8%. CONCLUSIONS: Compared with a historical control AVOREN subgroup, low-dose IFN with bevacizumab resulted in a reduction in incidence rates of IFN-related AEs, without compromising efficacy [NCT00796757]. PMID- 23803226 TI - Survey on radioactive contamination in Beijing following the Japanese Fukushima nuclear accident. AB - The radioactive contamination in Beijing caused by the Japanese Fukushima nuclear accident was monitored. In this research, samples of air, rainwater, surface water and vegetables in Beijing were collected and measured to estimate the radioactive contamination levels in Beijing. During the period from the 15th to the 41st day after the first emission of radioactive material (first emission) from the Japanese Fukushima nuclear power station (NPS) on 12 March 2011, obvious radioactive contamination was found in the Beijing air samples. The maximum concentration of I-131 was 5.89 mBq m(-3) in the air samples detected on the 22nd day after the first emission, and the maximum concentration of Cs-137 and Cs-134 was found on the 20th day after the first emission. Except for one sample of rainwater, no artificial radionuclides associated with Fukushima were found in surface water. The measurement results showed that there was no harm to the health of local Beijing residents. PMID- 23803227 TI - Survey of clinical doses from computed tomography examinations in the Canadian province of Manitoba. AB - The purpose of this study was to document CT doses for common CT examinations performed throughout the province of Manitoba. Survey forms were sent out to all provincial CT sites. Thirteen out of sixteen (81 %) sites participated. The authors assessed scans of the brain, routine abdomen-pelvis, routine chest, sinuses, lumbar spine, low-dose lung nodule studies, CT pulmonary angiograms, CT KUBs, CT colonographies and combination chest-abdomen-pelvis exams. Sites recorded scanner model, protocol techniques and patient and dose data for 100 consecutive patients who were scanned with any of the aforementioned examinations. Mean effective doses and standard deviations for the province and for individual scanners were computed. The Kruskal-Wallis test was used to compare the variability of effective doses amongst scanners. The t test was used to compare doses and their provincial ranges between newer and older scanners and scanners that used dose saving tools and those that did not. Abdomen-pelvis, chest and brain scans accounted for over 70 % of scans. Their mean effective doses were 18.0 +/- 6.7, 13.2 +/- 6.4 and 3.0 +/- 1.0 mSv, respectively. Variations in doses amongst scanners were statistically significant. Most examinations were performed at 120 kVp, and no lower kVp was used. Dose variations due to scanner age and use of dose saving tools were not statistically significant. Clinical CT doses in Manitoba are broadly similar to but higher than those reported in other Canadian provinces. Results suggest that further dose reduction can be achieved by modifying scanning techniques, such as using lower kVp. Wide variation in doses amongst different scanners suggests that standardisation of scanning protocols can reduce patient dose. New technological advances, such as dose-reduction software algorithms, can be adopted to reduce patient dose. PMID- 23803228 TI - Aldosterone, organ damage and dietary salt. AB - Long-term exposure to elevated aldosterone levels or activation of the mineralocorticoid receptors results in cardiac, vascular and renal tissue injury with mechanisms that are independent of blood pressure levels. This evidence has been obtained in experiments carried out in hypertensive animal models, and clinical studies involving patients with heart failure, essential hypertension and primary aldosteronism. Animal studies have shown that aldosterone causes cardiovascular and renal tissue damage only in the context of an inappropriate salt status. It has also been suggested that some of the untoward effects of high salt intake might depend on activation of mineralocorticoid receptors resulting from increased generation of reactive oxygen species and changes in the intracellular redox potential. Although the interaction between dietary salt intake and circulating aldosterone in causing organ damage has received robust support from the results of animal experiments, the evidence of such interaction in the clinical setting is only preliminary and will require further investigation in appropriately designed studies. PMID- 23803229 TI - Success rates of endoscopic-assisted probing for congenital nasolacrimal duct obstruction in children. AB - OBJECTIVE: To determine the success rate of initial probing in children with congenital nasolacrimal duct obstruction at different ages, using nasal endoscopy. METHODS: Fifty eyes of 38 consecutive children with congenital nasolacrimal duct obstruction underwent endoscopic nasolacrimal duct probing under general anaesthesia. Patients were followed up for at least three months. Probing success was defined as complete remission of symptoms and a normal fluorescein dye disappearance test result. RESULTS: The age range of patients was 17-109 months. The success rates of probing were: 100 per cent (29 out of 29) for cases of stenosis at the lower nasolacrimal duct, 100 per cent (7 out of 7) for functional epiphora cases and 92.86 per cent (13 out of 14) for nasolacrimal atresia cases. Overall, there was only one child for whom the probing treatment for nasolacrimal duct obstruction was not successful; this child had Down's syndrome and a more complex developmental abnormality of the nasolacrimal duct. Age and site of obstruction were not found to significantly affect the outcome of probing. CONCLUSION: Probing of the nasolacrimal system using an endoscopic approach allows direct visualisation of the nasolacrimal duct. This can facilitate diagnosis of the anomaly and significantly increase the procedure success rate. PMID- 23803230 TI - Estimating the plasma effect-site equilibrium rate constant (Ke0) of propofol by fitting time of loss and recovery of consciousness. AB - The present paper proposes a new approach for fitting the plasma effect-site equilibrium rate constant (Ke0) of propofol to satisfy the condition that the effect-site concentration (Ce) is equal at the time of loss of consciousness (LOC) and recovery of consciousness (ROC). Forty patients receiving intravenous anesthesia were divided into 4 groups and injected propofol 1.4, 1.6, 1.8, or 2 mg/kg at 1,200 mL/h. Durations from the start of injection to LOC and to ROC were recorded. LOC and ROC were defined as an observer's assessment of alertness and sedation scale change from 3 to 2 and from 2 to 3, respectively. Software utilizing bisection method iteration algorithms was built. Then, Ke0 satisfying the CeLOC=CeROC condition was estimated. The accuracy of the Ke0 estimated by our method was compared with the Diprifusor TCI Pump built-in Ke0 (0.26 min(-1)), and the Orchestra Workstation built-in Ke0 (1.21 min(-1)) in another group of 21 patients who were injected propofol 1.4 to 2 mg/kg. Our results show that the population Ke0 of propofol was 0.53 +/- 0.18 min(-1). The regression equation for adjustment by dose (mg/kg) and age was Ke0=1.42-0.30 * dose-0.0074 * age. Only Ke0 adjusted by dose and age achieved the level of accuracy required for clinical applications. We conclude that the Ke0 estimated based on clinical signs and the two-point fitting method significantly improved the ability of CeLOC to predict CeROC. However, only the Ke0 adjusted by dose and age and not a fixed Ke0 value can meet clinical requirements of accuracy. PMID- 23803231 TI - The behaviour and welfare of buffaloes (Bubalus bubalis) in modern dairy enterprises. AB - This review deals with the behaviour of river buffaloes (Bubalus bubalis), in confinement and in extensive conditions, also focusing on the effects of different housing and rearing conditions on their welfare. The behavioural repertoire expressed by buffaloes in extensive and intensive conditions is similar to those displayed by other domestic ruminants. However, through natural selection, buffaloes have also acquired several morphological, physiological and behavioural (i.e. wallowing) adaptations to hot climatic conditions. Buffaloes kept in intensive conditions and having no access to pasture and water for wallowing extend their periods of idling and are less often involved in investigative activities. Confinement is also associated with a reduction of space; however, no specific studies have been carried out to determine the specific requirements of this species. Space restriction can adversely affect various aspects of buffalo welfare, such as health (increased levels of lesions and injuries), social behaviour (increased number of agonistic interactions) and heat dissipation. The buffaloes, originating from tropical areas, are well adapted to large variations in food availability and quality, and to dietetic unbalances. As to human animal relationship, it has been observed that the incidence of stepping and kicking behaviour of buffaloes in the milking parlour is positively correlated with the frequency of oxytocin injections, whereas the frequency of positive stockperson interactions with the animals such as talking quietly, petting and gentle touching are negatively correlated with the number of kicks during milking. Data from farms where both dairy cattle and buffaloes are present show that avoidance distance measured in the pen is lower in buffaloes than in cattle. This may be attributed to the fact that buffaloes are generally recognised to be curious animals. Finally, the effects of different farming practices on animal-related indicators are described. However, these measures should be integrated into a monitoring protocol, such as the Welfare Quality(r) scheme, to reliably assess buffalo welfare in the current intensive farming conditions. PMID- 23803232 TI - Atlas-based automatic segmentation of head and neck organs at risk and nodal target volumes: a clinical validation. AB - BACKGROUND: Intensity modulated radiotherapy for head and neck cancer necessitates accurate definition of organs at risk (OAR) and clinical target volumes (CTV). This crucial step is time consuming and prone to inter- and intra observer variations. Automatic segmentation by atlas deformable registration may help to reduce time and variations. We aim to test a new commercial atlas algorithm for automatic segmentation of OAR and CTV in both ideal and clinical conditions. METHODS: The updated Brainlab automatic head and neck atlas segmentation was tested on 20 patients: 10 cN0-stages (ideal population) and 10 unselected N-stages (clinical population). Following manual delineation of OAR and CTV, automatic segmentation of the same set of structures was performed and afterwards manually corrected. Dice Similarity Coefficient (DSC), Average Surface Distance (ASD) and Maximal Surface Distance (MSD) were calculated for "manual to automatic" and "manual to corrected" volumes comparisons. RESULTS: In both groups, automatic segmentation saved about 40% of the corresponding manual segmentation time. This effect was more pronounced for OAR than for CTV. The edition of the automatically obtained contours significantly improved DSC, ASD and MSD. Large distortions of normal anatomy or lack of iodine contrast were the limiting factors. CONCLUSIONS: The updated Brainlab atlas-based automatic segmentation tool for head and neck Cancer patients is timesaving but still necessitates review and corrections by an expert. PMID- 23803234 TI - Experience with a minimally invasive approach to combined valve surgery and coronary artery bypass grafting through bilateral thoracotomies. AB - BACKGROUND: Minimally invasive coronary artery bypass grafting (MICS-CABG) and minimally invasive valve surgery (MIVS) have been used independently to manage occlusive coronary artery disease and valvular diseases, respectively. We present 12 patients who underwent combined MICS-CABG and MIVS via bilateral mini thoracotomies. METHODS: We retrospectively reviewed 116 consecutive valve/CABG operations by a single surgeon and compared the outcomes obtained via sternotomy with those obtained via bilateral minithoracotomies. RESULTS: Six patients in the MIVS group underwent aortic valve replacement (sternotomy group, n = 70), 3 patients underwent mitral valve repair (sternotomy group, n = 9), and 3 underwent mitral valve replacement (sternotomy group, n = 25). The minimally invasive valve surgeries were combined with MICS-CABG for single- (n = 2), double- (n = 9), and triple-vessel (n = 1) coronary artery disease in a single operation. The mean SD duration of cardiopulmonary bypass was 164 +/- 44.6 minutes (mean time via sternotomy, 152 +/- 50.5 minutes; P = .4146), and the mean aortic cross-clamp time was 87.8 +/- 22.1 minutes (mean time via sternotomy, 105 +/- 39.8 minutes; P = .1455). The use of perioperative blood transfusions averaged to 2.3 +/- 5.6 units (mean usage via sternotomy, 2.7 +/- 4.9 units; P = .8326). There were no conversions to sternotomy in the minimally invasive group. Patients in the minimally invasive group were extubated earlier (24 +/- 11 hours; sternotomy group, 40 +/- 61 hours; P = .3684) and discharged earlier (7 +/- 4 days) than patients who underwent median sternotomy (9 +/- 10 days; P = .4027). CONCLUSION: MICS-CABG combined with MIVS via bilateral minithoracotomies yielded short-term results comparable to those for CABG and valve repair via median sternotomy. There were no operative mortalities or reoperations. The possible advantages of the minimally invasive approach included earlier extubation and earlier discharge from the hospital. Combined CABG and valve surgery can be safely performed via bilateral thoracotomies. PMID- 23803233 TI - Decision making and results of coronary artery bypass grafting for patients with poor left ventricular function. AB - BACKGROUND: The aim of this study is to determine the results of coronary artery bypass surgery in patients with a low ejection fraction. Between January 2007 and January 2011, 3556 consecutive patients who underwent coronary artery bypass grafting at the Cardiovascular Surgery Clinic at Sifa University Hospital, Izmir, Turkey, were analyzed retrospectively. METHODS: The patients were divided into 2 groups. Patients undergoing isolated first-time elective coronary bypass surgery were classified according to their preoperative ejection fraction; Patients in Group I had an ejection fraction between 20% and 35% with poor left ventricular function (n = 1246; 695 men and 551 women; mean age, 62.25 +/- 5.72 years, range, 47-78 years). Control patients in Group II underwent elective coronary artery bypass grafting at the same time and had left ventricular ejection fraction between 36% and 49% (n = 2310; 1211 men and 1099 women; mean age, 61.83 +/- 8.12 years, range, 41-81 years). The mean follow-up time for all patients was 24 +/- 9.4 months (range, 12-48 months). Patients were followed postoperatively at the end of the first month and every 6 months. The left ventricular ejection fraction was assessed by transthoracic echocardiography. RESULTS: The mean number of distal anastomoses, myocardial infarction, and mean age was not significantly different between the 2 groups; however, cross-clamp time was longer in Group I. Patient recovery time was significantly longer in Group I. Morbidity (14.5% in Group I versus 7.4% in Group II, P < .005) and mortality (1.76% versus 0.30%, P < .005) were higher in Group I. During late follow-up, the 2-year survival rate (85.1% versus 94.5%) and 2-year event-free rate (77.6% versus 86.9%) were significantly lower in Group I when compared to Group II. Postoperative left ventricular ejection fraction values were significantly superior in Group I compared to Group II. CONCLUSION: Coronary artery bypass grafting can be safely performed in patients with low ejection fraction with minimal postoperative morbidity and mortality. The viable myocardium could be reliably determined by positron emission tomography. Low ejection fraction patients could greatly benefit from coronary bypass surgery regarding postoperative ejection fraction, increased long-term survival, improvement in New York Heart Association classification, and higher quality of life. PMID- 23803235 TI - Associated risk of recombinant activated factor VIIa application. AB - BACKGROUND: The recombinant human coagulation FVIIa was approved for the treatment of bleeding in hemophilia patients. The reports of a good hemostatic effect were followed by studies and applications without a regulatory extension of the therapeutic indication (off-label use). The aim of this retrospective study is the evaluation of thromboembolic adverse events and side effects in a large cohort of patients with FVIIa therapy. METHODS: In the period from January 2009 to March 2011, a total of 143/2453 (5.8%) cardiac surgical patients (69% male; age 67 +/- 11 years; 39% thoracic aorta) were treated with different doses (mean, 6.1 mg; range, 1 to 27.2 mg) of factor VIIa. The administration of FVIIa was seen as a last therapeutic option and administered at the end of the treatment algorithm for severe bleeding. RESULTS: Due to an acute bleeding situation in 143 patients, 7.9 +/- 5.8 units of packed red blood cells, 9.5 +/- 6.1 units of fresh frozen plasma, 1740 +/- 1860 IU PPSB (Prothrombin-Proconvertin Stuart Factor-Antihemophilic Factor B), 5.6 +/- 4 g fibrinogen, and 7.9 +/- 7.6 units of platelets were administered. A re-thoracotomy was necessary, despite maximal procoagulant therapy, in 55% of patients. The in-hospital mortality was 36% (51/2453 = 2%). Thrombotic complications occurred with a frequency of 16% (mesenteric infarction, n = 9; stroke/transient ischemic attack, n = 3; myocardial infarction, n = 3; other, n = 8). CONCLUSION: The proof of direct causality of the events in relation to the administration of FVIIa is difficult because the temporal and therapeutic relationships with concomitant vasoconstrictive and procoagulant therapies were not obvious. However, there remains a suspicion that a higher rate of mesenteric infarctions may be provoked by the administration of FVIIa. PMID- 23803236 TI - Complete preservation of the mitral valve apparatus during mitral valve replacement for rheumatic mitral regurgitation in patients with an enlarged left ventricular chamber. AB - BACKGROUND AND AIMS: The merits of retaining the subvalvular apparatus during mitral valve replacement (MVR) for chronic mitral regurgitation have been demonstrated in clinical investigations. This study was to investigate the feasibility of total preservation of the leaflet and subvalvular apparatus at the native anatomic position during MVR in a rheumatic population with enlarged left ventricular chamber. MATERIAL AND METHODS: The techniques of valvular apparatus preservation used during MVR with or without aortic valve replacement were investigated in 128 patients with an enlarged left ventricular chamber suffering from rheumatic mitral regurgitation between October 2003 and December 2007. Seventy patients had the anterior leaflet and subvalvular apparatus excised but the posterior leaflet and subvlvular apparatus preserved during the mitral valve replacement (P-MVR group), and 58 patients had the anterior and posterior mitral leaflets and the subvalvalur apparatus completely preserved at the native anatomical position during the mitral valve replacement (C-MVR group). Echocardiography was performed preoperatively, at discharge, and after 3 months, 1 year, and 3 years to determine the left ventricular dimensions and function. RESULTS: There were 2 cases (3.4%) of early death in the C-MVR group, and there were 4 cases (5.7%) of early death in the P-MVR group. There were 3 cases of late death 1 year after surgery, of which 1 case in the C-MVR group was caused by congestive heart failure and the other 2 cases in the P-MVR group were due to sudden death. Both groups exhibited significant improvement (P < .05) in left ventricular function instantly and late postoperatively. The reduction of the left ventricular end-diastolic diameter was more significant in the C-MVR group as compared to the P-MVR group (P < .05). A statistically significant increase in fractional shortening (FS) occurred in the C-MVR group compared to the P-MVR group. CONCLUSION: This study shows that complete mitral leaflet preservation at the native anatomical position during MVR is feasible in rheumatic patients with an enlarged left ventricular chamber and confers significant short-term and long term advantages by preserving left ventricular function and geometry. Therefore, it is a safe, simple, and effective surgical technique and should be individualized during clinical use. PMID- 23803237 TI - An atypical temporal sequence for right heart endocarditis: case report. AB - In 2010, an 82-year-old patient received a diagnosis of stage IV chronic obstructive pulmonary disease, ischemic dilated cardiomyopathy, severe secondary pulmonary hypertension, atrial fibrillation with slow ventricular response, and severe tricuspid regurgitation. In December 2011, he was hospitalized for exacerbation of chronic obstructive pulmonary disease. The patient received antibiotics via injections (for 2 weeks through a peripheral venous catheter). In February 2012, he returned to the hospital with congestive heart failure and vascular purpura skin lesions. The echocardiography examination revealed a rupture of cordage afferent to the septal tricuspid valve. Because blood cultures were sterile after 10 days and no vegetation was revealed, the Duke criteria were not fulfilled. In March 2012, the patient returned with congestive heart failure, fatigue, and anorexia. Echocardiography evaluation then revealed attached septal tricuspid valve vegetation. The Duke criteria were now satisfied. The patient received antibiotics at doses recommended for infective endocarditis, with a favorable outcome. PMID- 23803238 TI - Simultaneous repair of a sinus of valsalva aneurysm and a bicuspid aortic valve. AB - Sinus of Valsalva aneurysms (SOVA) are rare cardiac abnormalities that are most commonly congenital in origin and frequently associated with aortic valve pathology. Unruptured SOVA are more frequently identified currently, owing to the increased use and accuracy of diagnostic investigations. Early surgical intervention is recommended to prevent complications. We describe a case of a young patient with an enlarging right SOVA and a regurgitant bicuspid aortic valve who subsequently underwent simultaneous patch repair of the SOVA and primary aortic valve repair. PMID- 23803239 TI - Percutaneous ventricular assist device and extracorporeal membrane oxygenation support in a patient with postinfarction ventricular septal defect and free wall rupture. AB - We describe the case of a 54-year-old woman with a postinfarction ventricular septal defect (VSD) and ventricular free wall rupture who was stabilized with a percutaneous ventricular assist device (pVAD) to allow for myocardial infarct stabilization. Following the rupture of the right ventricular free wall and cardiopulmonary arrest on hospital day 10, pVAD support was promptly converted to extracorporeal membrane oxygenation (ECMO) support for stabilization. After surgical repair was completed, pVAD support was continued for 4 days to allow recovery. The patient was discharged on postoperative day 11 and is alive and well 4 years later. Postinfarction VSD with free wall rupture may be salvaged with pVAD and ECMO support. PMID- 23803240 TI - Simplified temporary right ventricular support after implantation of a left ventricular assist device. AB - Right ventricular failure is one of the most feared complications after implantation of a left ventricular assist device. We provide the technical details for a simplified, percutaneous approach to temporary right heart support. PMID- 23803241 TI - Use of a totally artificial heart for a complex postinfarction ventricular septal defect. AB - The incidence of cardiac rupture complicating myocardial infarction has declined since the introduction of thrombolytic therapy. Despite the advances in the management of myocardial infarction, cardiac rupture remains an important cause of death among infarction-related fatalities. We discuss a patient who presented to our hospital with myocardial infarction and who subsequently developed a complex ventricular septal rupture, for which surgical repair was not feasible. Implantation of a CardioWest Total Artificial Heart (SynCardia Systems) allowed for immediate hemodynamic stabilization and served as a bridge to transplantation. PMID- 23803242 TI - Comparison of rosuvastatin versus atorvastatin for preventing postoperative atrial fibrillation. AB - BACKGROUND: Postoperative atrial fibrillation (AF) following cardiac surgery is associated with an increased risk of stroke, prolonged hospitalization, and increased costs. Statin therapy is associated with a lower incidence of postoperative AF. We aimed to compare the preventive effects of rosuvastatin and atorvastatin on postoperative AF. METHODS: This study included 168 patients undergoing elective cardiac surgery with cardiopulmonary bypass. Patients were divided into 2 groups according to treatment of statin. Group 1 (n = 96) was patients receiving atorvastatin, and group 2 (n = 72) was patients receiving rosuvastatin. Postoperative electrocardiographs (ECGs) and telemetry strips were examined for AF within postoperative period during hospitalization. RESULTS: The incidences of postoperative AF were 17.9% (n = 17) in group 1 and 22.2% (n = 16) in group 2 (P = .48). Left ventricular end-diastolic diameter (LVEDD) and ejection fraction (EF) were not different between groups. Incidence of diabetes, hypertension, hyperlipidemia, smoking, myocardial infarction in past medical history, family history of atherosclerosis, male sex, drug use, and perioperative features were similar between groups. CONCLUSIONS: The present study revealed that preoperative rosuvastatin or atorvastatin treatment did not have a different effect in preventing postoperative AF. PMID- 23803243 TI - Right atrium clot formation following percutaneous transmitral valvuloplasty. AB - This case report describes a rare complication of percutaneous transmitral commissurotomy (PTMC). A patient with severe mitral stenosis developed a clot in the right atrium after an unsuccessful PTMC procedure. Because of the high risk of thromboembolism, the patient underwent urgent surgery to remove the clot and to replace the mitral valve with a mechanical prosthesis. PMID- 23803244 TI - A case of primary cardiac rhabdomyosarcoma with surgical removal and mitral valve repair. AB - Primary cardiac tumors are rare. Nearly 25% of primary cardiac tumors are malignant, with rhabdomyosarcoma being the second most common primary sarcoma. Symptoms are variable, and the clinical presentation depends on the location and propagation of the tumor. Transthoracic and transesophageal echocardiography are preliminary tests in diagnosing the disease. Echocardiographic findings should be supported by other imaging methods. In appropriate cases, surgery combined with chemotherapy and radiotherapy is suggested. We present a case of primary cardiac rhabdomyosarcoma with surgical removal and mitral valve repair. PMID- 23803245 TI - Giant right coronary artery (RCA) aneurysm. AB - Coronary artery aneurysm (CAA) is a rare type of coronary artery disease. The angiographic incidence of the coronary artery aneurysm is reportedly between 1.5% to 4.9%, and it is more frequent in men. We have successfully carried out a simultaneous "coronary bypass together with aneurysm ligation" operation on a patient with coronary heart disease and an aneurysm within the right coronary artery. PMID- 23803246 TI - The role of right ventricular function in mitral valve surgery. AB - BACKGROUND: An impaired right ventricular function is associated with a poor survival rate in patients with heart failure. Few investigations have analyzed the prognostic value of right ventricular function on the outcomes of mitral valve (MV) surgery. The objectives of this study were to define the effect of right ventricular function on postoperative outcomes after MV repair (MVP) or replacement (MVR). METHODS: From September 2007 to February 2012, 335 consecutive patients underwent MVP or MVR at our institution. Preoperative transthoracic and transesophageal echocardiography (TEE) and postoperative TEE were used to define right ventricular function and MV performance. Preoperative right ventricular function was graded as normal to mild (grade 1-2) or as moderate to severe (grade 3-4). MV or tricuspid valve regurgitation was graded as non-trivial to mild (grade 0-2) or as moderate to severe (grade 3-4) preoperatively and postoperatively. Survival rate was evaluated at 1 year after surgery. RESULTS: Of the 334 patients in the study, 280 patients showed a normal to a mildly impaired right ventricular function preoperatively (group 1). Fifty-four patients presented with moderate to severe right ventricular dysfunction (group 2). Patients with a compromised right ventricular function were more likely to undergo MVR (28.6% versus 53.7%, P <.001). The mean pulmonary artery pressure was 23.6 mm Hg in group 1 and 34 mm Hg in group 2 (P <.001). The left atrial diameter was 4.6 cm in group 1 and 5.3 cm in group 2 (P <.001). The 2 groups were not different with respect to operative mortality, but the patients in group 2 experienced more transfusion of blood products (588.4 mL versus 1180.6 mL, P <.001), longer intensive care unit stays (83.9 versus 149.6 hours, P <.001), and hospital stays (8.9 versus 12.8 days, P = .005). The rate of postoperative MV regurgitation was significantly higher in group 2 (1.8 versus 14.8%, P <.001). The overall 1-year survival rate was 92.5% in group 1 and 94.5% in group 2 (P = .59). CONCLUSIONS: This study has shown that a dysfunctional preoperative right ventricular function uses more resources and is associated with postoperative MV regurgitation, but it is not associated short- and mid-term mortality after MV surgery. PMID- 23803247 TI - Postpartum vaginal cystic lesions: everyday practice or a differential diagnosis challenge? AB - Postpartum vaginal cystic lesions constitute a common situation that is caused either by inflammation or by accumulation of lymph. We report a case of a 33-year old woman who had bilateral duplication of the pelvicalyceal system and ureter, and after the labor of her second child, she had one ureter prolapse into the vagina after initially appearing as a cystic lesion. Ureteral duplication is the most common renal abnormality, occurring in approximately 1% of the population and in 10% of children who are diagnosed with urinary tract infections. In our case we consider possible that this clinical situation was a result of a combination of postpartum pelvic floor trauma and prolapse of the ureter. There are only several of these cases in the literature where ureter prolapse is associated and complicated by pelvic floor trauma caused during or after labor. The clinical approach of the cystic lesions located in the vagina during the postpartum period should include a meticulous examination of the urinary system before any other medical practice. PMID- 23803248 TI - Residential mobility of populations near UK power lines and implications for childhood leukaemia. AB - Epidemiological studies suggest associations between childhood leukaemia and living near high-voltage power lines, but the most obvious potential causative agent, the magnetic fields produced by the power lines, is not supported by laboratory studies or a known mechanism. An alternative hypothesised explanation is if there is greater population mobility near power lines, linking to the findings of Kinlen that population mixing increases leukaemia rates. We used the names recorded in electoral registers to see whether people near power lines move house more often than the population as a whole. We did find variations, but only small ones, and not such as to support the hypothesis. PMID- 23803250 TI - Duodenal switch for intractable reflux gastroesophagitis after proximal gastrectomy. AB - Reflux gastroesophagitis is a common postgastrectomy complication after proximal gastrectomy, and conservative treatments including protease inhibitors and proton pump inhibitors are effective in most patients. Here we report a patient with severe reflux gastroesophagitis after proximal gastrectomy, in whom surgical treatment of duodenal switch was effective. An 80-year-old man complained of intractable heartburn, anorexia, and body weight loss after having undergone proximal gastrectomy, with reconstruction by esophagogastrostomy with valvuloplasty and pyloroplasty, for early gastric cancer 14 months before referral to our department. Oral administration of protease inhibitors and proton pump inhibitors was ineffective. Laboratory evaluation showed poor nutritional status. On endoscopic examination, we noted the redness, bleeding, and multiple erosions in the esophagus and the gastric remnant. He was diagnosed to have severe gastroesophagitis due to reflux of duodenal juice into the gastric remnant and esophagus. We performed duodenal switch to divert duodenal juice from the gastric remnant and esophagus; the duodenum was transected 2 cm distal to the pylorus, the duodenal distal end was closed, and a 50-cm Roux limb from the proximal jejunum was anastomosed to the proximal end of the duodenum. The heartburn disappeared postoperatively, and endoscopic examination revealed marked improvement of the reflux gastroesophagitis. One year postoperatively, the patient is free from symptoms including heartburn. His body weight increased, and laboratory data showed improvement in nutritional status. In conclusion, the duodenal switch may be surgical treatment of choice for intractable reflux gastroesophagitis after proximal gastrectomy. PMID- 23803249 TI - What are validated self-report adherence scales really measuring?: a systematic review. AB - AIMS: Medication non-adherence is a significant health problem. There are numerous methods for measuring adherence, but no single method performs well on all criteria. The purpose of this systematic review is to (i) identify self report medication adherence scales that have been correlated with comparison measures of medication-taking behaviour, (ii) assess how these scales measure adherence and (iii) explore how these adherence scales have been validated. METHODS: Cinahl and PubMed databases were used to search articles written in English on the development or validation of medication adherence scales dating to August 2012. The search terms used were medication adherence, medication non adherence, medication compliance and names of each scale. Data such as barriers identified and validation comparison measures were extracted and compared. RESULTS: Sixty articles were included in the review, which consisted of 43 adherence scales. Adherence scales include items that either elicit information regarding the patient's medication-taking behaviour and/or attempts to identify barriers to good medication-taking behaviour or beliefs associated with adherence. The validation strategies employed depended on whether the focus of the scale was to measure medication-taking behaviour or identify barriers or beliefs. CONCLUSIONS: Supporting patients to be adherent requires information on their medication-taking behaviour, barriers to adherence and beliefs about medicines. Adherence scales have the potential to explore these aspects of adherence, but currently there has been a greater focus on measuring medication taking behaviour. Selecting the 'right' adherence scale(s) requires consideration of what needs to be measured and how (and in whom) the scale has been validated. PMID- 23803251 TI - Effects of hepatocyte nuclear factor-1A and -4A on pancreatic stone protein/regenerating protein and C-reactive protein gene expression: implications for maturity-onset diabetes of the young. AB - BACKGROUND: There is a significant clinical overlap between patients with hepatocyte nuclear factor (HNF)-1A and HNF4A maturity-onset diabetes of the young (MODY), two forms of monogenic diabetes. HNF1A and HNF4A are transcription factors that control common and partly overlapping sets of target genes. We have previously shown that elevated serum pancreatic stone protein / regenerating protein A (PSP/reg1A) levels can be detected in subjects with HNF1A-MODY. In this study, we investigated whether PSP/reg is differentially regulated by HNF1A and HNF4A. METHODS: Quantitative real-time PCR (qPCR) and Western blotting were used to validate gene and protein expression in cellular models of HNF1A- and HNF4A MODY. Serum PSP/reg1A levels and high-sensitivity C-reactive protein (hsCRP) were measured by ELISA in 31 HNF1A- and 9 HNF4A-MODY subjects. The two groups were matched for age, body mass index, diabetes duration, blood pressure, lipid profile and aspirin and statin use. RESULTS: Inducible repression of HNF1A and HNF4A function in INS-1 cells suggested that PSP/reg induction required HNF4A, but not HNF1A. In contrast, crp gene expression was significantly reduced by repression of HNF1A, but not HNF4A function. PSP/reg levels were significantly lower in HNF4A subjects when compared to HNF1A subjects [9.25 (7.85-12.85) ng/ml vs. 12.5 (10.61-17.87) ng/ml, U-test P = 0.025]. hsCRP levels were significantly lower in HNF1A-MODY [0.22 (0.17-0.35) mg/L] compared to HNF4A-MODY group [0.81 (0.38-1.41) mg/L, U-test P = 0.002], Parallel measurements of serum PSP/reg1A and hsCRP levels were able to discriminate HNF1A- and HNF4A-MODY subjects. CONCLUSION: Our study demonstrates that two distinct target genes, PSP/reg and crp, are differentially regulated by HNF1A and HNF4A, and provides clinical proof of-concept that serum PSP/reg1A and hsCRP levels may distinguish HNF1A-MODY from HNF4A-MODY subjects. PMID- 23803252 TI - Correlation of dynamic changes in gamma-H2AX expression in peripheral blood lymphocytes from head and neck cancer patients with radiation-induced oral mucositis. AB - BACKGROUND: To evaluate the role of gamma-H2AX in peripheral blood lymphocytes (PBLs) as a predictive biomarker of the severity of oral mucositis (OM) in head and neck cancer (HNC) patients with receiving radiotherapy. METHODS: In vitro assays for evaluating DNA damage and repair kinetics were performed on blood samples withdrawn from 25 HNC patients undergoing radiotherapy or chemoradiotherapy before radiotherapy. As for the in vivo study, blood samples were also withdrawn before radiotherapy, and 1 hour after radiotherapy on the fourth and last days. Flow cytometry was used to assess the expression of gamma H2AX in PBLs. OM was assessed using the World Health Organization (WHO) scores twice a week and correlated with the expression of gamma-H2AX. RESULTS: The in vitro assay results showed that patients with severe OM had higher gamma-H2AX specific relative fluorescence at various irradiation doses in the damage kinetics assay, with significantly higher gamma-H2AX expression at 8 Gy (p = 0.039), and also at 24 hours after irradiation at a dose of 2 Gy in the repair kinetics assay, compared to the patients with mild OM (p = 0.008). The optimal cutoff value for relative fluorescence of gamma-H2AX was 0.960, 24 hours post irradiation. However, there were no significant differences in gamma-H2AX expression at different times between the two groups, as assessed with the in vivo assay. CONCLUSIONS: These results suggest that the damage and repair kinetics of gamma-H2AX from PBLs in the in vitro study may have predictive value for identifying the grades of OM among HNC patients prior to radiotherapy. PMID- 23803253 TI - Sexual maturation in hens is not associated with increases in serum leptin and the expression of leptin receptor mRNA in hypothalamus. AB - BACKGROUND: In mammals, leptin is an attractive candidate for mediating the metabolic signal and the reproductive function via the specific receptor in hypothalamus. However, till now, the role of leptin on reproduction in birds is less well established. This experiment was conducted to elucidate the role of leptin on the onset of reproduction in bird, as a first step, to detect the changes of peripheral leptin and leptin receptor mRNA expression in hypothalamus between mature and immature hens at the same age. 120 ISA brown pullets at D60 were allocated randomly into two groups, long light (LL) group being raised under artificial light regimes with incrementally increased light phase (from 8 L:16D to 14 L:12D) and short light (SL) group raised on consistent light (8 L:16D) for 12 wk. RESULTS: The results showed that pullets in LL group reached sexual maturation 15 d earlier than those in SL group. Serum E2 showed a significant increase with age, but no difference was observed between two groups. Serum leptin concentration decreased significantly from D112 to D136 in LL, and was markedly higher in LL group than that in SL at D112, while there was no significant difference between two groups at D136. Leptin receptor and GnRH-I mRNA expression in hypothalamus were significantly increased with age, yet there was no significant difference between SL and LL chickens at the same age. The expression of FSH-beta and LH-beta mRNA in pituitary was increased with age but did not show significant difference between LL and SL group. GnRH-I mRNA expression was very rich in pineal gland, and decreased from D112 to D136 in LL but not in SL group, and there was no difference between two groups at the same age. CONCLUSIONS: These results indicate that the earlier sexual maturation in hens induced by long-light regime is not accompanied with an increase in serum leptin or leptin receptor gene expression in hypothalamus, or genes expression in HPG axis. PMID- 23803254 TI - The JSSX Annual Meeting: today and the future. PMID- 23803255 TI - Cardiac troponin T: from diagnosis of myocardial infarction to cardiovascular risk prediction. AB - Cardiac troponins (cTns) T and I are exclusively expressed at high concentrations in cardiac muscle and have emerged as the preferred biomarker in the universal definition of myocardial infarction (MI). With the recent introduction of high sensitivity (hs) assays, diagnostic sensitivity for earlier detection of MI has substantially improved. However, lowering the diagnostic cut-off has increased the detection of myocardial injuries in various non-acute coronary syndrome (ACS) conditions, which are not related to myocardial ischemia, leading to rising difficulties in diagnosing MI in clinical situations. Several approaches, such as serial sampling and incorporation of relative or absolute delta-changes, have been proposed to overcome the limitation of decreased sensitivity for MI diagnosis with hs-cTn assays. Current consensus for rapid rule-in proposes a 20% increase within 3 or 6h when baseline cTn levels are elevated. In the case of negative baseline values, relative increases >=50% above the 99(th) percentile were found to be adequate to improve accuracy of MI diagnosis. Besides improved diagnostic accuracy for myocardial injury, even minor cTn elevations provide important prognostic information, and increased levels of cTn are associated with adverse outcomes in both the ACS and non-ACS condition, irrespective of whether the underlying cause is an acute or chronic illness. Thus, it is highly likely that lowering the diagnostic cut-off with even more sensitive assays might improve risk stratification in both conditions. PMID- 23803256 TI - Guidelines on the use of iodinated contrast media in patients with kidney disease 2012: digest version. PMID- 23803259 TI - Multi-contrast late enhancement CMR determined gray zone and papillary muscle involvement predict appropriate ICD therapy in patients with ischemic heart disease. AB - BACKGROUND: Myocardial infarct heterogeneity indices including peri-infarct gray zone are predictors for spontaneous ventricular arrhythmias events after ICD implantation in patients with ischemic heart disease. In this study we hypothesize that the extent of peri-infarct gray zone and papillary muscle infarct scores determined by a new multi-contrast late enhancement (MCLE) method may predict appropriate ICD therapy in patients with ischemic heart disease. METHODS: The cardiovascular magnetic resonance (CMR) protocol included LV functional parameter assessment and late gadolinium enhancement (LGE) CMR using the conventional method and MCLE post-contrast. The proportion of peri-infarct gray zone, core infarct, total infarct relative to LV myocardium mass, papillary muscle infarct scores, and LV functional parameters were statistically compared between groups with and without appropriate ICD therapy during follow-up. RESULTS: Twenty-five patients with prior myocardial infarct for planned ICD implantation (age 64+/-10 yrs, 88% men, average LVEF 26.2+/-10.4%) were enrolled. All patients completed the CMR protocol and 6-46 months follow-up at the ICD clinic. Twelve patients had at least one appropriate ICD therapy for ventricular arrhythmias at follow-up. Only the proportion of gray zone measured with MCLE and papillary muscle infarct scores demonstrated a statistically significant difference (P < 0.05) between patients with and without appropriate ICD therapy for ventricular arrhythmias; other CMR derived parameters such as LVEF, core infarct and total infarct did not show a statistically significant difference between these two groups. CONCLUSIONS: Peri-infarct gray zone measurement using MCLE, compared to using conventional LGE-CMR, might be more sensitive in predicting appropriate ICD therapy for ventricular arrhythmia events. Papillary muscle infarct scores might have a specific role for predicting appropriate ICD therapy although the exact mechanism needs further investigation. PMID- 23803261 TI - Scar tissue in the heart. PMID- 23803260 TI - Pre- and perinatal hypoxia associated with hippocampus/amygdala volume in bipolar disorder. AB - BACKGROUND: Pre- and perinatal adversities may increase the risk for schizophrenia and bipolar disorder. Hypoxia-related obstetric complications (OCs) are associated with brain anatomical abnormalities in schizophrenia, but their association with brain anatomy variation in bipolar disorder is unknown. METHOD: Magnetic resonance imaging brain scans, clinical examinations and data from the Medical Birth Registry of Norway were obtained for 219 adults, including 79 patients with a DSM-IV diagnosis of bipolar disorder (age 29.4 years, s.d. = 11.8 years, 39% male) and 140 healthy controls (age 30.8 years, s.d. = 12.0 years, 53% male). Severe hypoxia-related OCs throughout pregnancy/birth and perinatal asphyxia were each studied in relation to a priori selected brain volumes (hippocampus, lateral ventricles and amygdala, obtained with FreeSurfer), using linear regression models covarying for age, sex, medication use and intracranial volume. Multiple comparison adjustment was applied. RESULTS: Perinatal asphyxia was associated with smaller left amygdala volume (t = -2.59, p = 0.012) in bipolar disorder patients, but not in healthy controls. Patients with psychotic bipolar disorder showed distinct associations between perinatal asphyxia and smaller left amygdala volume (t = -2.69, p = 0.010), whereas patients with non psychotic bipolar disorder showed smaller right hippocampal volumes related to both perinatal asphyxia (t = -2.60, p = 0.015) and severe OCs (t = -3.25, p = 0.003). No associations between asphyxia or severe OCs and the lateral ventricles were found. CONCLUSIONS: Pre- and perinatal hypoxia-related OCs are related to brain morphometry in bipolar disorder in adulthood, with specific patterns in patients with psychotic versus non-psychotic illness. PMID- 23803262 TI - Tough courage: Oncology Nursing Forum addresses childhood cancer then and now. AB - Cancer is a devastating diagnosis for anyone, but none more so than for children and their parents--so many questions to be asked, so much information to sift through and absorb, and so many difficult decisions to be made. It is no wonder that a diagnosis of childhood cancer is often met with fear, anger, guilt, and feelings of being overwhelmed, yet also a determined resilience on the part of families to do whatever it takes to help their child get well again (Rishel, 2010). PMID- 23803263 TI - Integrating quality and breast cancer care: role of the clinical nurse leader. PMID- 23803264 TI - Heartaches: malignant pericardial effusions. PMID- 23803265 TI - Pharmacogenomics: why standard codeine doses can have serious toxicities or no therapeutic effect. PMID- 23803266 TI - Older breast cancer survivors: can interaction analyses identify vulnerable subgroups? A report from the American Cancer Society Studies of Cancer Survivors. AB - PURPOSE/OBJECTIVES: To explore interactions among personal, cancer, aging, and symptom variables relative to physical function (PF) in older adult breast cancer survivors to better identify vulnerable subgroups. DESIGN: Secondary analysis of the American Cancer Society Studies of Cancer Survivors II. SETTING: U.S. population-based mail and telephone survey. SAMPLE: 2,885 breast cancer survivors from 14 different state cancer registries stratified by cancer type and time since diagnosis. A total of 184 female breast cancer survivors, aged 70 years or older, had complete data on variables of interest and were, therefore, included in this analysis. METHODS: Chi-Square Automatic Interaction Detector (CHAID) analysis was used to examine variable interactions. MAIN RESEARCH VARIABLES: PF, symptom bother, comorbidity, social support, length of survivorship, treatment, stage, body mass index, physical activity, emotional health, and personal characteristics. FINDINGS: An interaction effect between symptom bother and comorbidity was found in 39% of older adult breast cancer survivors, and an interaction effect between symptom bother and marital status was found in 40%. The most vulnerable group (8%) had high symptom bother and more than four comorbid conditions. CONCLUSIONS: Symptom bother, comorbidity, and marital status were found to have significant interactions such that high comorbidity and high symptom bother were significantly related to lower PF. Married participants with lower symptom bother had significantly higher PF scores. Comorbidity may be the best predictor of PF for the extreme ends of the symptom bother continuum. Advancing age alone was not a sufficient predictor of PF in this analysis. IMPLICATIONS FOR NURSING: Specific attention to symptom reports, comorbidity, and marital status can guide identification of older adult cancer survivors in need of ongoing survivorship care. The findings support use of a comprehensive assessment and tailored approach to care based on factors other than age. KNOWLEDGE TRANSLATION: CHAID interaction analysis may be useful in exploring complex nursing problems, such as the needs of older adult cancer survivors, and help oncology nurses develop appropriate interventions and referrals. PMID- 23803267 TI - Family caregiver burden, skills preparedness, and quality of life in non-small cell lung cancer. AB - PURPOSE/OBJECTIVES: To describe burden, skills preparedness, and quality of life (QOL) for caregivers of patients with non-small cell lung cancer (NSCLC), and describe how the findings informed the development of a caregiver palliative care intervention that aims to reduce caregiver burden, improve caregiving skills, and promote self-care. DESIGN: Descriptive, longitudinal. SETTING: A National Cancer Institute-designated comprehensive cancer center in southern California. SAMPLE: 163 family members or friends aged 18 years or older and identified by patients as being a caregiver. METHODS: All eligible caregivers were approached by advanced practice nurses during a regularly scheduled patient clinic visit. Informed consent was obtained prior to study participation. Outcome measures were completed at baseline and repeated at 7, 12, 18, and 24 weeks. Descriptive statistics were computed for all variables, and one-way repeated-measures analysis of variance was used to test for change over time for all predictor and outcome variables. MAIN RESEARCH VARIABLES: Caregiver burden, skills preparedness, psychological distress, and QOL. FINDINGS: Caregivers were highly functional. Caregiver burden related to subjective demands increased significantly over time. Perceived skills preparedness was high at baseline but decreased over time. Psychological distress was moderate but increased in the study period. Overall QOL was moderate at baseline and decreased significantly over time. Psychological well-being had the worst QOL score. CONCLUSIONS: Caregivers experienced high levels of caregiver burden and reported deteriorations in psychological well-being and overall QOL. IMPLICATIONS FOR NURSING: Oncology nurses need to ensure that caregivers receive information that supports the caregiving role throughout the cancer trajectory. KNOWLEDGE TRANSLATION: Although family caregivers are profoundly impacted by a loved one's lung cancer diagnosis, the literature about caregiver burden, skills preparedness, and QOL is limited. Current evidence suggests that family caregivers can be negatively impacted by a loved one's cancer diagnosis. Caregiver-specific support interventions are needed to eliminate the burden of caregiving in lung cancer. PMID- 23803269 TI - Feasibility of a targeted breast health education intervention for Chinese American immigrant women. AB - PURPOSE/OBJECTIVES: To assess the feasibility and acceptability of a targeted educational intervention to increase mammography screening among Chinese American women. DESIGN: One-group pre- and post-test quasiexperimental design. SETTING: Metropolitan areas of Portland, OR. SAMPLE: 44 foreign-born Chinese American women aged 40 years and older. METHODS: Participants who had not had a mammogram within the past 12 months were recruited and enrolled to a targeted breast health educational program. Before starting the group session, participants completed a baseline survey, which was administered again 12 weeks postintervention. MAIN RESEARCH VARIABLES: Completion of mammography screening test, movement in stage of readiness, mammography and breast cancer knowledge, perceived susceptibility, perceived benefits, and perceived common and cultural barriers. FINDINGS: The study response rate was high (71%). Of the 42 women who completed the study, 21 (50%) had a mammogram postintervention. The top three reasons for not completing a mammogram at the end of the study were no need or no symptom, busy, and reliance on family for assistance. Mean breast cancer susceptibility scores increased significantly at post-test as theorized (t[40] = -2.88, p < 0.01). Participants were more likely to obtain a mammogram when they had been in the United States for 3-15 years. CONCLUSIONS: A targeted program that aims to increase breast health knowledge, improve access, and remove barriers may promote mammography screening among Chinese American immigrant women. IMPLICATIONS FOR NURSING: This promising intervention now being tested under a randomized, controlled design can be adapted to other Asian subgroups. KNOWLEDGE TRANSLATION: Targeted breast health intervention is feasible for improving mammography screening among Chinese immigrant women. Educating these women about early detection is important, as the first sign of breast cancer usually shows on a woman's mammogram before it can be felt or any other symptoms are present. Immigrant women may be too busy to dedicate proper time to self-care behaviors; therefore, making it easier and faster for them to obtain a mammogram may improve the screening rate. PMID- 23803268 TI - Health-related quality of life after treatment of Hodgkin lymphoma in young adults. AB - PURPOSE/OBJECTIVES: To describe changes in health-related quality of life (HRQOL) and to identify supportive care services used after treatment for Hodgkin lymphoma (HL) in young adults. DESIGN: A longitudinal, repeated-measures study design was used to test the feasibility of data collection at the conclusion of treatment for HL and at one, three, and six months post-treatment. SETTING: Participants were identified from two large comprehensive cancer centers in New England. SAMPLE: 40 young adults with newly diagnosed HL were enrolled in the study prior to the completion of chemotherapy or radiation. METHODS: Data were collected by interviews, standardized questionnaires, and medical record reviews. MAIN RESEARCH VARIABLES: HRQOL variables defined as symptom distress, functional status, emotional distress, and intimate relationships; use of specific supportive care services; and baseline demographic and disease-related information. FINDINGS: Results indicate that symptom distress improved at one month post-treatment and remained low at three and six months. Similarly, functional status improved at one month post-treatment. Only 13% of the sample had significant emotional distress at baseline, and this decreased to 8% over time. Patients placed high value on their intimate relationships (i.e., family and friends or sexual partners). A variety of supportive care services were used after treatment, the most common of which were related to economic issues. However, by six months post-treatment, services shifted toward enhancing nutrition and fitness. CONCLUSIONS: The results from this study suggest that HRQOL in young adults with HL improved one-month post-treatment and that interest in using supportive care services was high. IMPLICATIONS FOR NURSING: Facilitating the use of supportive care services at the end of cancer treatment appears to be an important part of helping young adults transition to survivorship. KNOWLEDGE TRANSLATION: Supportive care services appear to be a vital component of the transition to survivorship and often change over time from an emphasis on economic issues to enhancing wellness through nutrition and fitness programs. PMID- 23803270 TI - A pilot randomized trial evaluating low-level laser therapy as an alternative treatment to manual lymphatic drainage for breast cancer-related lymphedema. AB - PURPOSE/OBJECTIVES: To examine the impact of advanced practice nurse (APN) administered low-level laser therapy (LLLT) as both a stand-alone and complementary treatment for arm volume, symptoms, and quality of life (QOL) in women with breast cancer-related lymphedema. DESIGN: A three-group, pilot, randomized clinical trial. SETTING: A private rehabilitation practice in the southeastern United States. SAMPLE: 46 breast cancer survivors with treatment related lymphedema. METHODS: Patients were screened for eligibility and then randomized to either manual lymphatic drainage (MLD) for 40 minutes, LLLT for 20 minutes, or 20 minutes of MLD followed by 20 minutes of LLLT. Compression bandaging was applied after each treatment. Data were collected pretreatment, daily, weekly, and at the end of treatment. MAIN RESEARCH VARIABLES: Independent variables consisted of three types of APN-administered lymphedema treatment. Outcome variables included limb volume, extracellular fluid, psychological and physical symptoms, and QOL. FINDINGS: No statistically significant between-group differences were found in volume reduction; however, all groups had clinically and statistically significant reduction in volume. No group differences were noted in psychological and physical symptoms or QOL; however, treatment-related improvements were noted in symptom burden within all groups. Skin improvement was noted in each group that received LLLT. CONCLUSIONS: LLLT with bandaging may offer a time-saving therapeutic option to conventional MLD. Alternatively, compression bandaging alone could account for the demonstrated volume reduction. IMPLICATIONS FOR NURSING: APNs can effectively treat lymphedema. APNs in private healthcare practices can serve as valuable research collaborators. KNOWLEDGE TRANSLATION: Lasers may provide effective, less burdensome treatment for lymphedema. APNs with lymphedema certification can effectively treat this patient population with the use of LLLT. In addition, bioelectrical impedance and tape measurements can be used to assess lymphedema. PMID- 23803274 TI - A comparison of burnout among oncology nurses working in adult and pediatric inpatient and outpatient settings. AB - PURPOSE/OBJECTIVES: To investigate differences in burnout among oncology nurses by type of work setting, coping strategies, and job satisfaction. DESIGN: Descriptive. SETTING: A metropolitan cancer center. SAMPLE: A convenience sample of 74 oncology nurses. METHODS: Participants completed a demographic data form, the Nursing Satisfaction and Retention Survey, and the Maslach Burnout Inventory. MAIN RESEARCH VARIABLES: Burnout, coping strategies, job satisfaction, and oncology work setting (inpatient versus outpatient and adult versus pediatric). FINDINGS: The participants most often used spirituality and coworker support to cope. Emotional exhaustion was lowest for youngest nurses and highest for outpatient RNs. Personal accomplishment was highest in adult settings. Job satisfaction correlated inversely with emotional exhaustion and the desire to leave oncology nursing. CONCLUSIONS: The findings support that the social context within the work environment may impact emotional exhaustion and depersonalization, and that demographics may be more significant in determining burnout than setting. IMPLICATIONS FOR NURSING: The findings raise questions of whether demographics or setting plays a bigger role in burnout and supports organizational strategies that enhance coworker camaraderie, encourage nurses to discuss high-stress situations, and share ways to manage their emotions in oncology settings. KNOWLEDGE TRANSLATION: Spirituality and coworker relationships were positive coping strategies among oncology nurses to prevent emotional exhaustion. Nurses who rely on supportive social networks as a coping mechanism have lower levels of depersonalization. Age was inversely related to emotional exhaustion. PMID- 23803271 TI - Psychosocial predictors of depression among older African American patients with cancer. AB - PURPOSE/OBJECTIVES: To determine whether psychosocial factors predict depression among older African American patients with cancer. DESIGN: A descriptive correlational study. SETTING: Outpatient oncology clinic of a National Cancer Institute-designated cancer center in the southeastern United States. SAMPLE: African American patients with cancer aged 50-88 years. METHODS: Fisher's exact and Wilcoxon rank-sum tests were used to evaluate differences between patients who were possibly depressed (Geriatric Depression Scale) or not. Multivariate linear regression statistics were used to identify the psychosocial factors that predicted higher depression scores. Education and gender were included as covariates. MAIN RESEARCH VARIABLES: Religiosity, emotional support, collectivism, perceived stigma, and depression. FINDINGS: Participants (N = 77) had a mean age of 61 years (SD = 8.4), and a majority were well-educated, insured, religiously affiliated, and currently in treatment. Participants who were in the lowest income category, not married, or male had higher depression scores. The multivariable model consisting of organized religion, emotional support, collectivism, education, and gender explained 52% (adjusted R2) of the variation in depression scores. Stigma became insignificant in the multivariable model. CONCLUSIONS: Psychosocial factors are important predictors of depression. Emotional support and organized religious activities may represent protective factors against depression, whereas collectivism may increase their risk. IMPLICATIONS FOR NURSING: Nurses need to be particularly aware of the potential psychological strain for patients with collectivist values, experienced stigma, disruptions in church attendance, and lack of emotional support. In addition, the treatment plans for these patients should ensure that family members are knowledgeable about cancer, its treatment, and side effects so they are empowered to meet support needs. KNOWLEDGE TRANSLATION: Among older African American patients with cancer, emotional support and reassurance from family and friends that they will not abandon them decreases the likelihood of depressive symptoms and minimizes the impact of stigmatizing responses, but the perception that the illness is placing a strain on the family increases the likelihood of such symptoms. Emotional support likely is a stronger predictor of depressive symptoms than religious service attendance. PMID- 23803275 TI - Mobile health-based approaches for smoking cessation resources. AB - PURPOSE/OBJECTIVES: To describe how the National Cancer Institute's Cancer Information Service (CIS) smoking-related resources on a mobile health (mHealth) platform were integrated into the workflow of RNs in advanced practice nurse (APN) training and to examine awareness and use of CIS resources and nurses' perceptions of the usefulness of those CIS resources. DESIGN: Descriptive analyses. SETTING: Acute and primary care sites affiliated with the School of Nursing at Columbia University. SAMPLE: 156 RNs enrolled in APN training. METHODS: The integration was comprised of (a) inclusion of CIS information into mHealth decision support system (DSS) plan of care, (b) addition of infobutton in the mHealth DSS, (c) Web-based information portal for smoking cessation accessible via desktop and the mHealth DSS, and (d) information prescriptions for patient referral. MAIN RESEARCH VARIABLES: Use and perceived usefulness of the CIS resources. FINDINGS: 86% of nurses used the mHealth DSS with integrated CIS resources. Of the 145 care plan items chosen, 122 were referrals to CIS resources; infobutton was used 1,571 times. Use of CIS resources by smokers and healthcare providers in the metropolitan area of New York City increased during the study period compared to the prestudy period. More than 60% of nurses perceived CIS resources as useful or somewhat useful. CONCLUSIONS: Integration of CIS resources into an mHealth DSS was seen as useful by most participants. IMPLICATIONS FOR NURSING: Implementation of evidence into workflow using an mHealth DSS can assist nurses in managing smoking cessation in patients and may expand their roles in referring smokers to reliable sources of information. KNOWLEDGE TRANSLATION: mHealth DSS and information prescriptions may support smoking cessation interventions in primary care settings. Smoking cessation interventions can be facilitated through informatics methods and mHealth platforms. Nurses' referrals of patients to smoking-related CIS resources may result in patients' use of the resources and subsequent smoking cessation. PMID- 23803276 TI - Staff members' perceptions of an animal-assisted activity. AB - PURPOSE/OBJECTIVES: To examine the perceptions of staff members toward the implementation of an animal-assisted activity (AAA) in an outpatient regional cancer center. DESIGN: Quasi-experimental, post-test design. SETTING: An adult outpatient regional cancer center in northern California. SAMPLE: 34 facility staff members. METHODS: Self-report questionnaire following four weeks of AAA visitation. Visits took place three times a week for a total of 12 visits. MAIN RESEARCH VARIABLES: Perceptions of the AAA. FINDINGS: Previous perceptions toward AAA influenced the perceptions of the visitation's efficacy. Direct and indirect interaction with the visiting AAA teams was positively associated with perceptions of the AAA. A disagreement occurred that the AAA had caused extra stress or work for staff. Enjoyment of interacting with the dog handler was not significantly different from interacting with the dog; however, it was more positively correlated to acceptance of the AAA. CONCLUSIONS: The study provided evidence that the AAA was generally accepted by staff members. IMPLICATIONS FOR NURSING: Individual staff members' perceptions of dogs and AAAs can influence their receptivity to AAA interventions. Interaction with AAA teams should be voluntary and available for patients and staff members. KNOWLEDGE TRANSLATION: AAA may be introduced into facilities without creating the perception of extra stress or work for staff members. Providing staff the opportunity to interact with visiting AAA teams may be beneficial for the success of such programs. The human handler in AAA teams may play a vital role in the staff acceptance of such programs. PMID- 23803277 TI - Development and evaluation of targeted psychological skills training for oncology nurses in managing stressful patient and family encounters. AB - PURPOSE/OBJECTIVES: To reduce workplace stress by developing a brief psychological skills training for nurses and to evaluate program feasibility, acceptability, and preliminary efficacy in decreasing burnout and stress. DESIGN: Intervention development and evaluation. SETTING: Outpatient chemotherapy unit at a comprehensive cancer center. SAMPLE: 26 infusion nurses and oncology social workers. METHODS: Focus groups were conducted with nurses. Results informed the development and evaluation of training for nurses. Participants completed the Maslach Burnout Inventory and Perceived Stress Scale post-training. MAIN RESEARCH VARIABLES: Burnout and stress. FINDINGS: Focus groups indicated strong commitment among nurses to psychosocial care and supported the idea that relationships with patients and families were sources of reward and stress. Stressors included factors that interfered with psychosocial care such as difficult family dynamics, patient behaviors and end-of-life care issues. Psychological skills training was developed to address these stressors. Evaluations suggested that the program was feasible and acceptable to nurses. At two months, participants showed reductions in emotional exhaustion (p = 0.02) and stress (p = 0.04). CONCLUSIONS: Psychological skills training for managing difficult encounters showed feasibility, acceptability, and potential benefit in reducing emotional exhaustion and stress. IMPLICATIONS FOR NURSING: Brief training that targets sources of clinical stress may be useful for nurses in outpatient chemotherapy units. KNOWLEDGE TRANSLATION: Specific stressors in relationships with patients and families present challenges to nurses' therapeutic use of self. Targeted psychological skills training may help nurses problem-solve difficult encounters while taking care of themselves. System-level strategies are needed to support and promote training participation. PMID- 23803278 TI - Preferences for photographic art among hospitalized patients with cancer. AB - PURPOSE/OBJECTIVES: To determine the preferences of patients with cancer for viewing photographic art in an inpatient hospital setting and to evaluate the impact of viewing photographic art. DESIGN: Quantitative, exploratory, single group, post-test descriptive design incorporating qualitative survey questions. SETTING: An academic medical center in the midwestern United States. SAMPLE: 80 men (n = 44) and women (n = 36) aged 19-85 years (X = 49) and hospitalized for cancer treatment. METHODS: Participants viewed photographs via computers and then completed a five-instrument electronic survey. MAIN RESEARCH VARIABLES: Fatigue, quality of life, performance status, perceptions of distraction and restoration, and content categories of photographs. FINDINGS: Ninety-six percent of participants enjoyed looking at the study photographs. The photographs they preferred most often were lake sunset (76%), rocky river (66%), and autumn waterfall (66%). The most rejected photographs were amusement park (54%), farmer's market vegetable table (51%), and kayakers (49%). The qualitative categories selected were landscape (28%), animals (15%), people (14%), entertainment (10%), imagery (10%), water (7%), spiritual (7%), flowers (6%), and landmark (3%). Some discrepancy between the quantitative and qualitative sections may be related to participants considering water to be a landscape. CONCLUSIONS: The hypothesis that patients' preferences for a category of photographic art are affected by the psychophysical and psychological qualities of the photographs, as well as the patients' moods and characteristics, was supported. IMPLICATIONS FOR NURSING: Nurses can play an active role in helping patients deal with the challenges of long hospital stays and life-threatening diagnoses through distraction and restoration interventions such as viewing photographic images of nature. KNOWLEDGE TRANSLATION: Nurses can use photographic imagery to provide a restorative intervention during the hospital experience. Photographic art can be used as a distraction from the hospital stay and the uncertainty of a cancer diagnosis. Having patients view photographs of nature is congruent with the core nursing values of promoting health, healing, and hope. PMID- 23803279 TI - The use of 1.5-anhydroglucitol for monitoring glycemic control in islet transplant recipients. AB - We evaluated whether 1,5-anhydroglucitol (1,5-AG) (GlycoMark((r))), a test for measuring postprandial glucose and glucose variability, could be a tool for assessing short-term glycemic control in islet cell transplant (ICT) subjects. Data of 21 subjects, with type 1 DM and allogenic islet transplantation, who had concomitant fructosamine, HbA1c, 1,5-AG (n = 85 samples), and capillary glucose self-monitoring measurements (n = 2,979) were analyzed retrospectively at different time points after ICT. A significant negative association was observed between 1,5-AG and HbA1c (p = 0.02), but not with fructosamine. When HbA1c was divided in quartiles as <5.6, 5.6-5.9, 5.9-6.2, and >6.2, a decrease of an estimated 0.70 +/- 0.30 ug/ml in 1,5-AG was associated with each quartile of increase in HbA1c (p < 0.0001). There was a significant decline of 1.64 +/- 0.3mg/dl in postprandial glucose values for each 1 unit increase in 1,5-AG (p < 0.0001). For those with HbA1c >= 6.0% when 1,5-AG was >=8.15 ug/ml, the mean estimated glucose level was 103.71 +/- 3.66 mg/dl, whereas it was 132.12 +/- 3.71 mg/dl when 1,5-AG was <8.15 ug/ml. The glucose variability (Glumax - Glumin) in subjects with 1,5-AG <8.15 ug/ml was 46.23 mg/dl greater than the subjects with 1,5-AG >=8.15 ug/ml (HbA1c >= 6.0%). There was no significant association between GlycoMark and glucose variability where HbA1c < 6%. 1,5-AG significantly associated with postprandial glucose levels and glucose variability in ICT recipients with near-normal HbA1c (6.0-6.5%) levels. These findings suggest that 1,5-AG can be used to differentiate those ICT subjects with higher glucose variability despite having near-normal HbA1c. However, prospective studies are needed to evaluate the association between GlycoMark levels and the parameters of graft dysfunction/failure. PMID- 23803280 TI - Microstructure alterations in beef intramuscular connective tissue caused by hydrodynamic pressure processing. AB - Scanning electron microscopy (SEM) was utilized to evaluate microstructural changes in intramuscular connective tissue of beef semimembranosus muscle subjected to hydrodynamic pressure processing (HDP). Samples were HDP treated in a plastic container (HDP-PC) or a steel commercial unit (HDP-CU). Control and HDP samples were obtained immediately post-treatment and after 14days of aging for SEM and Warner-Bratzler shear force (WBSF) analysis. Immediately post-treatment, HDP treated samples exhibited lower (P<0.01) WBSF than did controls. After aging, HDP-PC samples had lower (P<0.01) WBSF than that of aged controls. SEM analysis indicated that HDP-PC treatment disrupted the integrity of the collagen fibril network of the endomysium in both the non-aged and aged samples. Aging effects on the intramuscular connective tissue were observed in the HDP-PC and control samples. Both WBSF and connective tissue changes were greater in the HDP-PC than in the HDP-CU treated samples. Data suggest that shockwave alterations to connective tissue contribute to the meat tenderization of HDP. PMID- 23803282 TI - Effect of the local morphology in the field emission properties of conducting polymer surfaces. AB - In this work, we present systematic theoretical evidence of a relationship between the point local roughness exponent (PLRE) (which quantifies the heterogeneity of an irregular surface) and the cold field emission properties (indicated by the local current density and the macroscopic current density) of real polyaniline (PANI) surfaces, considered nowadays as very good candidates in the design of field emission devices. The latter are obtained from atomic force microscopy data. The electric field and potential are calculated in a region bounded by the rough PANI surface and a distant plane, both boundaries held at distinct potential values. We numerically solve Laplace's equation subject to appropriate Dirichlet's condition. Our results show that local roughness reveals the presence of specific sharp emitting spots with a smooth geometry, which are the main ones responsible (but not the only) for the emission efficiency of such surfaces for larger deposition times. Moreover, we have found, with a proper choice of a scale interval encompassing the experimentally measurable average grain length, a highly structured dependence of local current density on PLRE, considering different ticks of PANI surfaces. PMID- 23803281 TI - Effects of focus and definiteness on children's word order: evidence from German five-year-olds' reproductions of double object constructions. AB - Two experiments tested how faithfully German children aged 4 ;5 to 5 ;6 reproduce ditransitive sentences that are unmarked or marked with respect to word order and focus (Exp1) or definiteness (Exp2). Adopting an optimality theory (OT) approach, it is assumed that in the German adult grammar word order is ranked lower than focus and definiteness. Faithfulness of children's reproductions decreased as markedness of inputs increased; unmarked structures were reproduced most faithfully and unfaithful outputs had most often an unmarked form. Consistent with the OT proposal, children were more tolerant against inputs marked for word order than for focus; in conflict with the proposal, children were less tolerant against inputs marked for word order than for definiteness. Our results suggest that the linearization of objects in German double object constructions is affected by focus and definiteness, but that prosodic principles may have an impact on the position of a focused constituent. PMID- 23803283 TI - Fabrication of vertical GaN/InGaN heterostructure nanowires using Ni-Au bi-metal catalysts. AB - We have fabricated the vertically aligned coaxial or longitudinal heterostructure GaN/InGaN nanowires. The GaN nanowires are first vertically grown by vapor-liquid solid mechanism using Au/Ni bi-metal catalysts. The GaN nanowires are single crystal grown in the [0001] direction, with a length and diameter of 1 to 10 MUm and 100 nm, respectively. The vertical GaN/InGaN coaxial heterostructure nanowires (COHN) are then fabricated by the subsequent deposition of 2 nm of InxGa1-xN shell on the surface of GaN nanowires. The vertical GaN/InGaN longitudinal heterostructure nanowires (LOHN) are also fabricated by subsequent growth of an InGaN layer on the vertically aligned GaN nanowires using the catalyst. The photoluminescence from the COHN and LOHN indicates that the optical properties of GaN nanowires can be tuned by the formation of a coaxial or longitudinal InGaN layer. Our study demonstrates that the bi-metal catalysts are useful for growing vertical as well as heterostructure GaN nanowires. These vertically aligned GaN/InGaN heterostructure nanowires may be useful for the development of high-performance optoelectronic devices. PMID- 23803285 TI - Simplicity, skills, and pitfalls of ascending aortic cannulation for type A aortic dissection. AB - BACKGROUND: Ascending aortic cannulation for an antegrade central perfusion during surgery for type A aortic dissection is simple and can be performed within median sternotomy. This cannulation is performed routinely without problems in our hospital. Using our experience, the skills and pitfalls were clarified to make this challenging procedure successful. METHODS: 29 cases of ascending aortic cannulation using the Seldinger technique for insertion were studied. All insertions were performed with the guidance of transesophageal echocardiography alone. The cannulas were inserted after decompressing the aorta by initiating cardiopulmonary bypass with femoral artery cannulation. From our experience, the skills required for this procedure are the abilities to carefully assess the needle insertion site preoperatively, sense resistance to needle insertion twice, and ensure the guide wire is in the descending aorta and distal arch. The pitfalls are entrance of the guide wire into the false lumen and dilatation of the false lumen during the insertion procedure. RESULTS: There were no complications associated with ascending aortic cannulation. Regarding morbidity, 2 cases of brain infarction occurred. There were 3 hospital deaths unrelated to the procedure. CONCLUSIONS: In surgery for type A aortic dissection, ascending aortic cannulation using the Seldinger technique is simple to perform. We found that some practical skills and precautions were required to make this procedure successful. PMID- 23803284 TI - Using online health communities to deliver patient-centered care to people with chronic conditions. AB - BACKGROUND: Our health care system faces major threats as the number of people with multiple chronic conditions rises dramatically. OBJECTIVE: To study the use of Online Health Communities (OHCs) as a tool to facilitate high-quality and affordable health care for future generations. METHODS: OHCs are Internet-based platforms that unite either a group of patients, a group of professionals, or a mixture of both. Members interact using modern communication technologies such as blogs, chats, forums, and wikis. We illustrate the use of OHCs for ParkinsonNet, a professional network for Parkinson disease whose participants-both patients and professionals-use various types of OHCs to deliver patient-centered care. RESULTS: We discuss several potential applications in clinical practice. First, due to rapid advances in medical knowledge, many health professionals lack sufficient expertise to address the complex health care needs of chronic patients. OHCs can be used to share experiences, exchange knowledge, and increase disease-specific expertise. Second, current health care delivery is fragmented, as many patients acquire relationships with multiple professionals and institutions. OHCs can bridge geographical distances and enable interdisciplinary collaboration across institutions and traditional echelons. Third, chronic patients lack adequate tools to self-manage their disease. OHCs can be used to actively engage and empower patients in their health care process and to tailor care to their individual needs. Personal health communities of individual patients offer unique opportunities to store all medical information in one central place, while allowing transparent communication across all members of each patient's health care team. CONCLUSIONS: OHCs are a powerful tool to address some of the challenges chronic care faces today. OHCs help to facilitate communication among professionals and patients and support coordination of care across traditional echelons, which does not happen spontaneously in busy practice. PMID- 23803286 TI - Retrospective genomic analysis of sorghum adaptation to temperate-zone grain production. AB - BACKGROUND: Sorghum is a tropical C4 cereal that recently adapted to temperate latitudes and mechanized grain harvest through selection for dwarfism and photoperiod-insensitivity. Quantitative trait loci for these traits have been introgressed from a dwarf temperate donor into hundreds of diverse sorghum landraces to yield the Sorghum Conversion lines. Here, we report the first comprehensive genomic analysis of the molecular changes underlying this adaptation. RESULTS: We apply genotyping-by-sequencing to 1,160 Sorghum Conversion lines and their exotic progenitors, and map donor introgressions in each Sorghum Conversion line. Many Sorghum Conversion lines carry unexpected haplotypes not found in either presumed parent. Genome-wide mapping of introgression frequencies reveals three genomic regions necessary for temperate adaptation across all Sorghum Conversion lines, containing the Dw1, Dw2, and Dw3 loci on chromosomes 9, 6, and 7 respectively. Association mapping of plant height and flowering time in Sorghum Conversion lines detects significant associations in the Dw1 but not the Dw2 or Dw3 regions. Subpopulation-specific introgression mapping suggests that chromosome 6 contains at least four loci required for temperate adaptation in different sorghum genetic backgrounds. The Dw1 region fractionates into separate quantitative trait loci for plant height and flowering time. CONCLUSIONS: Generating Sorghum Conversion lines has been accompanied by substantial unintended gene flow. Sorghum adaptation to temperate-zone grain production involves a small number of genomic regions, each containing multiple linked loci for plant height and flowering time. Further characterization of these loci will accelerate the adaptation of sorghum and related grasses to new production systems for food and fuel. PMID- 23803287 TI - A mathematical model for the progression of dental caries. AB - A model for the progression of dental caries is derived. The analysis starts at the microscopic reaction and diffusion process. The local equations are averaged to derive a set of macroscopic equations. The global system includes features such as anisotropic diffusion and local changes in the geometry due to the melting of the enamel. The equations are then solved numerically. The simulations highlight the effect of anisotropy. In addition, we draw conclusions on the progression rate of caries, and discuss them in light of a number of experiments. PMID- 23803288 TI - The verapamil transporter expressed in human alveolar epithelial cells (A549) does not interact with beta2-receptor agonists. AB - Affinity of different organs for verapamil is highly variable and organ specific. For example, the drug exhibits high levels of accumulation in lung tissues. A transporter recognising verapamil as a substrate has previously been identified in human retinal pigment epithelial (RPE) and in rat retinal capillary endothelial (TR-iBRB2) cells. This transporter is distinct from any of the cloned organic cation transporters. Therefore, we hypothesised that the verapamil transporter is also functionally expressed in the human respiratory mucosa. Moreover, we tested the hypothesis that this transporter interacts with pulmonary administered cationic drugs such as beta2-agonists. The uptake of [(3)H]verapamil was studied in A549 human alveolar epithelial cell monolayers at different times and concentrations. The influence of extracellular proton concentration and various organic cations on verapamil uptake was determined. Verapamil uptake into A549 cells was time- and concentration-dependent, sensitive to pH and had a Km value of 39.8 +/- 8.2 uM. Verapamil uptake was also sensitive to inhibition by amantadine, quinidine and pyrilamine, but insensitive to other typical modulators of organic cation and choline transporters. Whilst we demonstrated functional activity of the elusive verapamil transporter at the lung epithelium, our data suggest that this transporter does not interact with beta2-agonists at therapeutic concentrations. PMID- 23803289 TI - Outcomes in complex patients with delirium and subsyndromal delirium one year after hospital discharge. PMID- 23803290 TI - Neonatal livers: a source for the isolation of good-performing hepatocytes for cell transplantation. AB - Hepatocyte transplantation is an alternative therapy to orthotopic liver transplantation for the treatment of liver diseases. However, the supply of hepatocytes is limited given the shortage of organs available to isolate good functioning quality cells. Neonatal livers may be a potential source alternative to adult livers to obtain good-performing hepatic cells for hepatocyte transplantation, which has not yet been explored profoundly. High-yield preparations of viable hepatocytes were isolated from 1- to 23-day-old liver donors, cryopreserved, and banked. Cell integrity and functional quality assessment were performed after thawing. Neonatal hepatocytes showed better postthawing recovery compared with adult hepatocytes, as shown by the viability values that did not differ significantly from freshly isolated cells, a higher expression of adhesion molecules (beta1-integrin, beta-catenin, and E-cadherin), better attachment efficiency, cell survival, and a lower number of apoptotic cells. The metabolic performance of thawed hepatocytes has been assessed by ureogenesis and drug-metabolizing capability (cytochrome P450 and UDP glucuronosyltransferase enzymes). CYP2A6, CYP2C9, CYP2E1, and CYP3A4 activities were found in all cell preparations, while CYP1A2, CYP2B6, CYP2C19, and CYP2D6 activities were detected only in hepatocytes from a few neonatal donors. The expression of UGT1A1 and UGT1A9 (transcripts and protein) was detected in all hepatocyte preparations, while activity was measured only in some preparations, probably due to lack of maturity of the enzymes. However, isoforms UGT1A6 and UGT2B7 showed considerable activity in all preparations. Compared to adult liver, the hepatocyte isolation procedure in neonatal livers also provides thawed cell suspensions with a higher proportion of hepatic progenitor cells (EpCAM(+) staining), which could also participate in regeneration of liver parenchyma after transplantation. These results could imply important advantages of neonatal hepatocytes as a source of high-quality cells to improve human hepatocyte transplantation applicability. PMID- 23803291 TI - Glucosylceramidase degradation in fibroblasts carrying bi-allelic Parkin mutations. PMID- 23803292 TI - Pressure-induced frustration in charge ordered spinel AlV2O4. AB - AlV2O4 is the only spinel compound so far known that exists in the charge ordered state at room temperature. It is known to transform to a charge frustrated cubic spinel structure above 427 degrees C. The presence of multivalent V ions in the pyrochlore lattice of the cubic spinel phase brings about the charge frustration that is relieved in the room temperature rhombohedral phase by the clustering of vanadium into a heptamer molecular unit along with a lone V atom. The present work is the first demonstration of pressure-induced frustration in the charge ordered state of AlV2O4. Synchrotron powder x-ray diffraction studies carried out at room temperature on AlV2O4 subjected to high pressure in a diamond anvil cell show that the charge ordered rhombohedral phase becomes unstable under the application of pressure and transforms to the frustrated cubic spinel structure. The frustration is found to be present even after pressure recovery. The possible role of pressure on vanadium t2g orbitals in understanding these observations is discussed. PMID- 23803293 TI - Photonics based on carbon nanotubes. AB - Among direct-bandgap semiconducting nanomaterials, single-walled carbon nanotubes (SWCNT) exhibit strong quasi-one-dimensional excitonic optical properties, which confer them a great potential for their integration in future photonics devices as an alternative solution to conventional inorganic semiconductors. In this paper, we will highlight SWCNT optical properties for passive as well as active applications in future optical networking. For passive applications, we directly compare the efficiency and power consumption of saturable absorbers (SAs) based on SWCNT with SA based on conventional multiple quantum wells. For active applications, exceptional photoluminescence properties of SWCNT, such as excellent light-emission stabilities with temperature and excitation power, hold these nanometer-scale materials as prime candidates for future active photonics devices with superior performances. PMID- 23803294 TI - Cardiovascular disease epidemiology in Asia: an overview. AB - Cardiovascular disease (CVD) is the leading cause of death in the world and half of the cases of CVD are estimated to occur in Asia. Compared with Western countries, most Asian countries, except for Japan, South Korea, Singapore and Thailand, have higher age-adjusted mortality from CVD. In Japan, the mortality from CVD, especially stroke, has declined continuously from the 1960s to the 2000s, which has contributed to making Japan into the top-ranking country for longevity in the world. Hypertension and smoking are the most notable risk factors for stroke and coronary artery disease, whereas dyslipidemia and diabetes mellitus are risk factors for ischemic heart disease and ischemic stroke. The nationwide approach to hypertension prevention and control has contributed to a substantial decline in stroke mortality in Japan. Recent antismoking campaigns have contributed to a decline in the smoking rate among men. Conversely, the prevalence of dyslipidemia and diabetes mellitus increased from the 1980s to the 2000s and, therefore, the population-attributable risks of CVD for dyslipidemia and diabetes mellitus have increased moderately. To prevent future CVD in Asia, the intensive prevention programs for hypertension and smoking should be continued and that for emerging metabolic risk factors should be intensified in Japan. The successful intervention programs in Japan can be applied to other Asian countries. PMID- 23803295 TI - Exploring the value of plasma BIN1 as a potential biomarker for alzheimer's disease. AB - BIN1, as an important genetic susceptibility locus in late-onset Alzheimer's disease (AD), is overexpressed in AD brains. Our study investigated BIN1 diagnostic value by quantifying its transcription level and plasma expression from 112 AD and 200 control subjects. We observed significant increase in BIN1 mRNA and protein levels in AD patients. Receiver operating characteristic curve analysis shown the sensitivity and specificity were 73% and 75% for plasma BIN1 in identifying AD. Although this is a pilot study requiring corroboration on a larger cohort of patients, our results highlight the possible use of plasma BIN1 as a biomarker for AD diagnosis. PMID- 23803296 TI - Understanding placebo responses in Alzheimer's disease clinical trials from the literature meta-data and CAMD database. AB - BACKGROUND: The placebo response and the underlying disease progression is difficult to differentiate in longitudinal Alzheimer's disease (AD) studies, yet it is crucial to understand for designing clinical trials and interpreting results. OBJECTIVES: The placebo response in ADAS-cog11 from various studies was evaluated against model predictions derived from historical placebo data to demonstrate potential interpretation of study results using a prior understanding of expected disease progression. METHODS: The placebo response component from a previously published disease progression model was used to estimate the longitudinal placebo response, and the disease progression in the placebo group in various case studies were evaluated. In addition, placebo data from the Coalition Against Major Diseases (CAMD) database in mild to moderate AD patients is described. RESULTS: The case studies demonstrated potential different results in disease progression in a placebo group, and the impact on understanding the magnitude of drug effect. Baseline cognitive function is an important covariate of disease progression, therefore, it is important to evaluate the baseline severity and predict disease progression accordingly when comparing trial results. Furthermore, study duration, sample size, and study design may affect the placebo response, all of which have the potential to confound understanding of study results. CONCLUSION: The recent failures in Phase III AD studies are not likely due to insufficient cognitive decline in the control groups. A meta analytic approach using all available data provides a robust understanding of placebo effect, disease progression, and potential interpretation of treatment effects, and offers a useful tool to aid in both trial design and interpretation. PMID- 23803297 TI - Improved spatial learning strategy and memory in aged Alzheimer AbetaPPswe/PS1dE9 mice on a multi-nutrient diet. AB - There is accumulating evidence showing that lifestyle factors like diet may influence the onset and progression of Alzheimer's disease (AD). Our previous studies suggest that a multi-nutrient diet, Fortasyn, containing nutritional precursors and cofactors for membrane synthesis, viz. docosahexaenoic acid, eicosapentaenoic acid, uridine-mono-phosphate, choline, phospholipids, folic acid, vitamins B6, B12, C, E, and selenium, has an ameliorating effect on cognitive deficits in an AD mouse model. In the present study we analyzed learning strategies and memory of 11-month-old AbetaPPswe/PS1dE9 (AbetaPP/PS1) mice in the Morris water maze (MWM) task performed after nine months of dietary intervention with a control diet or a Fortasyn diet to characterize diet-induced changes in cognitive performance. The Fortasyn diet had no significant effect on MWM task acquisition. To assess hippocampus-dependent learning, the strategies that the mice used to find the hidden platform in the MWM were analyzed using the swim path data. During the fourth day of the MWM, AbetaPP/PS1 mice on control diet more often used the non-spatial random search strategy, while on the Fortasyn diet, the transgenic animals exhibited more chaining strategy than their wild-type littermates. During the probe trial, AbetaPP/PS1 mice displayed no clear preference for the target quadrant. Notably, in both transgenic and nontransgenic mice on Fortasyn diet, the latency to reach the former platform position was decreased compared to mice on the control diet. In conclusion, this specific nutrient combination showed a tendency to improve searching behavior in AbetaPP/PS1 mice by increasing the use of a more efficient search strategy and improving their swim efficiency by decreasing the latency to reach the former platform position. PMID- 23803298 TI - Semantic memory functional MRI and cognitive function after exercise intervention in mild cognitive impairment. AB - Mild cognitive impairment (MCI) is associated with early memory loss, Alzheimer's disease (AD) neuropathology, inefficient or ineffective neural processing, and increased risk for AD. Unfortunately, treatments aimed at improving clinical symptoms or markers of brain function generally have been of limited value. Physical exercise is often recommended for people diagnosed with MCI, primarily because of its widely reported cognitive benefits in healthy older adults. However, it is unknown if exercise actually benefits brain function during memory retrieval in MCI. Here, we examined the effects of exercise training on semantic memory activation during functional magnetic resonance imaging (fMRI). Seventeen MCI participants and 18 cognitively intact controls, similar in sex, age, education, genetic risk, and medication use, volunteered for a 12-week exercise intervention consisting of supervised treadmill walking at a moderate intensity. Both MCI and control participants significantly increased their cardiorespiratory fitness by approximately 10% on a treadmill exercise test. Before and after the exercise intervention, participants completed an fMRI famous name discrimination task and a neuropsychological battery, Performance on Trial 1 of a list-learning task significantly improved in the MCI participants. Eleven brain regions activated during the semantic memory task showed a significant decrease in activation intensity following the intervention that was similar between groups (p-values ranged 0.048 to 0.0001). These findings suggest exercise may improve neural efficiency during semantic memory retrieval in MCI and cognitively intact older adults, and may lead to improvement in cognitive function. Clinical trials are needed to determine if exercise is effective to delay conversion to AD. PMID- 23803299 TI - Utilization and perceived problems of online medical resources and search tools among different groups of European physicians. AB - BACKGROUND: There is a large body of research suggesting that medical professionals have unmet information needs during their daily routines. OBJECTIVE: To investigate which online resources and tools different groups of European physicians use to gather medical information and to identify barriers that prevent the successful retrieval of medical information from the Internet. METHODS: A detailed Web-based questionnaire was sent out to approximately 15,000 physicians across Europe and disseminated through partner websites. 500 European physicians of different levels of academic qualification and medical specialization were included in the analysis. Self-reported frequency of use of different types of online resources, perceived importance of search tools, and perceived search barriers were measured. Comparisons were made across different levels of qualification (qualified physicians vs physicians in training, medical specialists without professorships vs medical professors) and specialization (general practitioners vs specialists). RESULTS: Most participants were Internet savvy, came from Austria (43%, 190/440) and Switzerland (31%, 137/440), were above 50 years old (56%, 239/430), stated high levels of medical work experience, had regular patient contact and were employed in nonacademic health care settings (41%, 177/432). All groups reported frequent use of general search engines and cited "restricted accessibility to good quality information" as a dominant barrier to finding medical information on the Internet. Physicians in training reported the most frequent use of Wikipedia (56%, 31/55). Specialists were more likely than general practitioners to use medical research databases (68%, 185/274 vs 27%, 24/88; chi22=44.905, P<.001). General practitioners were more likely than specialists to report "lack of time" as a barrier towards finding information on the Internet (59%, 50/85 vs 43%, 111/260; chi21=7.231, P=.007) and to restrict their search by language (48%, 43/89 vs 35%, 97/278; chi21=5.148, P=.023). They frequently consult general health websites (36%, 31/87 vs 19%, 51/269; chi22=12.813, P=.002) and online physician network communities (17%, 15/86, chi22=9.841 vs 6%, 17/270, P<.001). CONCLUSIONS: The reported inaccessibility of relevant, trustworthy resources on the Internet and frequent reliance on general search engines and social media among physicians require further attention. Possible solutions may be increased governmental support for the development and popularization of user-tailored medical search tools and open access to high quality content for physicians. The potential role of collaborative tools in providing the psychological support and affirmation normally given by medical colleagues needs further consideration. Tools that speed up quality evaluation and aid selection of relevant search results need to be identified. In order to develop an adequate search tool, a differentiated approach considering the differing needs of physician subgroups may be beneficial. PMID- 23803300 TI - Fighting against uncertainty: an essential issue in bioinformatics. AB - Many bioinformatics problems, such as sequence alignment, gene prediction, phylogenetic tree estimation and RNA secondary structure prediction, are often affected by the 'uncertainty' of a solution, that is, the probability of the solution is extremely small. This situation arises for estimation problems on high-dimensional discrete spaces in which the number of possible discrete solutions is immense. In the analysis of biological data or the development of prediction algorithms, this uncertainty should be handled carefully and appropriately. In this review, I will explain several methods to combat this uncertainty, presenting a number of examples in bioinformatics. The methods include (i) avoiding point estimation, (ii) maximum expected accuracy (MEA) estimations and (iii) several strategies to design a pipeline involving several prediction methods. I believe that the basic concepts and ideas described in this review will be generally useful for estimation problems in various areas of bioinformatics. PMID- 23803301 TI - Best practices in bioinformatics training for life scientists. AB - The mountains of data thrusting from the new landscape of modern high-throughput biology are irrevocably changing biomedical research and creating a near insatiable demand for training in data management and manipulation and data mining and analysis. Among life scientists, from clinicians to environmental researchers, a common theme is the need not just to use, and gain familiarity with, bioinformatics tools and resources but also to understand their underlying fundamental theoretical and practical concepts. Providing bioinformatics training to empower life scientists to handle and analyse their data efficiently, and progress their research, is a challenge across the globe. Delivering good training goes beyond traditional lectures and resource-centric demos, using interactivity, problem-solving exercises and cooperative learning to substantially enhance training quality and learning outcomes. In this context, this article discusses various pragmatic criteria for identifying training needs and learning objectives, for selecting suitable trainees and trainers, for developing and maintaining training skills and evaluating training quality. Adherence to these criteria may help not only to guide course organizers and trainers on the path towards bioinformatics training excellence but, importantly, also to improve the training experience for life scientists. PMID- 23803302 TI - Reply: autosomal recessive epilepsy associated with contactin 2 mutation is different from familial cortical tremor, myoclonus and epilepsy. PMID- 23803303 TI - Examining language functions: a reassessment of Bastian's contribution to aphasia assessment. AB - Henry Charlton Bastian (1837-1915) developed his network model of language processing, modality deficits and correlated lesion localizations in the 1860s and was a leading clinical authority for over four decades. Although his ideas are little referenced today, having been overshadowed by his more eminent Queen Square colleague John Hughlings Jackson, his work on aphasia and paralysis was highly regarded by contemporaries. This paper traces Bastian's lasting but largely unattributed contribution to the development of standardized clinical assessment of language disorders. From 1867 onwards, Bastian trained generations of medical students in neurology. In his 1875 book On Paralysis there is evidence in his case descriptions that Bastian had already implemented a detailed set of procedures for examining aphasic patients. In 1886, Bastian published a 'Schema for the Examination of Aphasic and Amnesic Persons'. Bastian insisted on the utility of this battery for diagnosis, classification and lesion localization; he argued that its consistent use would allow the development of a patient corpus and the comparison of cases from other hospitals. In 1898 his Treatise on Aphasia included a list of 34 questions that were to be used to examine all patients to provide detailed and systematic evidence of spared and impaired abilities in all receptive and expressive modalities. Bastian's contribution to the development of standardized clinical aphasia assessment is reassessed through detailed analysis of his publications and those of his contemporaries as well as new material from archives and casebooks. This evidence demonstrates that his approach to diagnosis of language and other cognitive impairments has propagated through the decades. His legacy can be seen in the approach to standardized aphasia testing developed in the latter 20th century through to today. PMID- 23803304 TI - Autosomal recessive epilepsy associated with contactin 2 mutation is different from familial cortical tremor, myoclonus and epilepsy. PMID- 23803305 TI - Network oscillations modulate interictal epileptiform spike rate during human memory. AB - Eleven patients being evaluated with intracranial electroencephalography for medically resistant temporal lobe epilepsy participated in a visual recognition memory task. Interictal epileptiform spikes were manually marked and their rate of occurrence compared between baseline and three 2 s periods spanning a 6 s viewing period. During successful, but not unsuccessful, encoding of the images there was a significant reduction in interictal epileptiform spike rate in the amygdala, hippocampus, and temporal cortex. During the earliest encoding period (0-2000 ms after image presentation) in these trials there was a widespread decrease in the power of theta, alpha and beta band local field potential oscillations that coincided with emergent focal gamma frequency activity. Interictal epileptiform spike rate correlated with spectral band power changes and broadband (4-150 Hz) desynchronization, which predicted significant reduction in interictal epileptiform spike rate. Spike-triggered averaging of the field potential power spectrum detected a burst of low frequency synchronization 200 ms before the interictal epileptiform spikes that arose during this period of encoding. We conclude that interictal epileptiform spikes are modulated by the patterns of network oscillatory activity that accompany human memory offering a new mechanistic insight into the interplay of cognitive processing, local field potential dynamics and interictal epileptiform spike generation. PMID- 23803306 TI - Associations between inflammation, nocturnal back pain and fatigue in ankylosing spondylitis and improvements with etanercept therapy. AB - OBJECTIVES: To investigate the relationships between inflammation, nocturnal back pain and fatigue in ankylosing spondylitis (AS) and the impact of 12 weeks' etanercept treatment versus sulfasalazine or placebo. METHODS: Data were combined from four clinical trials for patients with AS who received at least one dose of etanercept, sulfasalazine or placebo and had at least one postbaseline assessment value. Linear regression was performed (controlling for site, protocol and demographics), to explore the relationship between inflammation (C-reactive protein [CRP]), nocturnal back pain (visual analog scale [VAS] 0-100 mm) and fatigue (VAS 0-100 mm Bath AS Disease Activity Index fatigue item). RESULTS: Out of 1283 patients (etanercept, n = 867; sulfasalazine, n = 187; placebo, n = 229), improvement in nocturnal back pain was a significant predictor of improvement in fatigue. Significant correlations were found between nocturnal back pain and fatigue, but not CRP levels. Etanercept provided significantly greater pain/fatigue improvement than sulfasalazine or placebo. Improvements in nocturnal back pain and fatigue had weak relationships with improvement in inflammation (CRP level). CONCLUSIONS: AS patients treated with etanercept demonstrated superior improvement in nocturnal back pain and fatigue versus sulfasalazine or placebo. Decrease in nocturnal back pain can improve fatigue. Assessing treatment response using CRP levels alone may be misleading without also examining patient reported outcomes such as back pain and fatigue. PMID- 23803307 TI - The impact of pulmonary Acinetobacter baumannii infection on the prognosis of inpatients in a neurological intensive care unit. AB - OBJECTIVE: To investigate the impact of pulmonary Acinetobacter baumannii infection on the prognosis of patients in a Chinese neurological intensive care unit (NICU). METHODS: Patients with pulmonary infection and positive sputum culture findings were retrospectively enrolled. Logistic regression analysis was used to determine the factors influencing prognosis. Neurological disease improvement/nonimprovement and mortality rates were assessed. RESULTS: The study included 374 NICU patients with pulmonary infection (110 [29.4%] with A. baumannii, 264 [70.6%] with other micro-organisms). A. baumannii infection (OR = 2.987) and invasive mechanical ventilation (OR = 16.898) were independent factors in disease prognosis. A. baumannii infection was associated with longer NICU stay, fewer improved patients and increased mortality rate compared with other pulmonary infections. CONCLUSIONS: A. baumannii infection prolongs the duration of the NICU stay and negatively impacts on prognosis. Prognosis of NICU patients could be improved by controlling A. baumannii infection. PMID- 23803308 TI - Simultaneous bilateral quadriceps tendon rupture in a patient with hyperparathyroidism undergoing long-term haemodialysis: a case report and literature review. AB - Simultaneous bilateral quadriceps tendon rupture is a rare injury that represents < 5% of all quadriceps tendon ruptures. It is generally associated with chronic metabolic disorders and is seen in patients with uraemia undergoing maintenance haemodialysis. The present case was a 46-year-old man who presented with pain and the inability to extend his knees following a minor accident. A physical examination combined with X-radiography and magnetic resonance imaging investigations resulted in a diagnosis of bilateral quadriceps tendon rupture. He had a history of uraemia and had received regular haemodialysis for 7 years. He had high levels of serum parathyroid hormone and he was diagnosed with secondary hyperparathyroidism. Following surgical repair of both quadriceps tendons, in addition to management of the secondary hyperparathyroidism, the patient regained full active mobility of both knee joints and was able to participate in normal activities of daily living. PMID- 23803309 TI - Comparison of cardiac output derived from FloTracTM/VigileoTM and impedance cardiography during major abdominal surgery. AB - OBJECTIVES: Impedance cardiography (ICG) is a noninvasive technique that provides reasonably accurate measurements of cardiac output, but the usefulness of ICG in patients undergoing open abdominal surgery has not been validated. METHODS: Cardiac output was measured while patients underwent open gastrectomy using an ICG monitor (niccomoTM; ICG-CO); the results were compared with those measured using a FloTracTM/VigileoTM monitor (Flo-CO), which measures cardiac output by analysing the arterial waveform. Data collection commenced at the beginning of anaesthetic induction and continued until the patient was awake. Data were compared using the Bland-Altman analysis, and the clinical significance of the difference between the two methods was evaluated by calculating the percentage error (%). RESULTS: Eleven patients were monitored during surgery. The bias of the Flo-CO and ICG-CO values was -0.45 l/min. The upper and lower limits of agreement were 0.96 l/min and -1.85 l/min, respectively. The percentage error was 28.5%. Electrocautery induced interference that transiently impaired the performance of the ICG monitor. CONCLUSIONS: ICG provided useful information in evaluating the cardiac output of patients during abdominal surgery. PMID- 23803310 TI - Two nonsynonymous polymorphisms (F31I and V57I) of the STK15 gene and breast cancer risk: a meta-analysis based on 5966 cases and 7609 controls. AB - OBJECTIVES: This meta-analysis examined the relationship between two nonsynonymous polymorphisms (F31I and V57I) of the aurora kinase A (STK15) gene and breast cancer risk. METHODS: A systematic search of the PubMed(r) and EMBASETM databases was undertaken to identify case-control studies that investigated the relationship between STK15 gene polymorphisms and breast cancer risk. RESULTS: This meta-analysis included seven case-control studies (5966 breast cancer cases; 7609 controls). Combined results, based on all seven studies, showed that breast cancer cases had a significantly higher frequency of the 31 Ile/Ile genotype. In a subgroup analysis by race, breast cancer cases had a significantly higher frequency of the 31 Ile/Ile genotype in Asians and Caucasians. Combined results, based on four studies, suggested that the STK15 V57I gene polymorphism was unlikely to be associated with breast cancer risk in either Asians or Caucasians. CONCLUSIONS: The present meta-analysis suggests that the STK15 F31I polymorphism is a strong predisposing risk factor for breast cancer, but no significant association existed between the STK15 V57I polymorphism and the risk of breast cancer. PMID- 23803311 TI - Consensus and conflict cards for metabolic pathway databases. AB - BACKGROUND: The metabolic network of H. sapiens and many other organisms is described in multiple pathway databases. The level of agreement between these descriptions, however, has proven to be low. We can use these different descriptions to our advantage by identifying conflicting information and combining their knowledge into a single, more accurate, and more complete description. This task is, however, far from trivial. RESULTS: We introduce the concept of Consensus and Conflict Cards (C2Cards) to provide concise overviews of what the databases do or do not agree on. Each card is centered at a single gene, EC number or reaction. These three complementary perspectives make it possible to distinguish disagreements on the underlying biology of a metabolic process from differences that can be explained by different decisions on how and in what detail to represent knowledge. As a proof-of-concept, we implemented C2Cards(Human), as a web application http://www.molgenis.org/c2cards, covering five human pathway databases. CONCLUSIONS: C2Cards can contribute to ongoing reconciliation efforts by simplifying the identification of consensus and conflicts between pathway databases and lowering the threshold for experts to contribute. Several case studies illustrate the potential of the C2Cards in identifying disagreements on the underlying biology of a metabolic process. The overviews may also point out controversial biological knowledge that should be subject of further research. Finally, the examples provided emphasize the importance of manual curation and the need for a broad community involvement. PMID- 23803312 TI - Accelerating atomic orbital-based electronic structure calculation via pole expansion and selected inversion. AB - We describe how to apply the recently developed pole expansion and selected inversion (PEXSI) technique to Kohn-Sham density function theory (DFT) electronic structure calculations that are based on atomic orbital discretization. We give analytic expressions for evaluating the charge density, the total energy, the Helmholtz free energy and the atomic forces (including both the Hellmann-Feynman force and the Pulay force) without using the eigenvalues and eigenvectors of the Kohn-Sham Hamiltonian. We also show how to update the chemical potential without using Kohn-Sham eigenvalues. The advantage of using PEXSI is that it has a computational complexity much lower than that associated with the matrix diagonalization procedure. We demonstrate the performance gain by comparing the timing of PEXSI with that of diagonalization on insulating and metallic nanotubes. For these quasi-1D systems, the complexity of PEXSI is linear with respect to the number of atoms. This linear scaling can be observed in our computational experiments when the number of atoms in a nanotube is larger than a few hundreds. Both the wall clock time and the memory requirement of PEXSI are modest. This even makes it possible to perform Kohn-Sham DFT calculations for 10 000-atom nanotubes with a sequential implementation of the selected inversion algorithm. We also perform an accurate geometry optimization calculation on a truncated (8, 0) boron nitride nanotube system containing 1024 atoms. Numerical results indicate that the use of PEXSI does not lead to loss of the accuracy required in a practical DFT calculation. PMID- 23803313 TI - Trends in paediatric, neonatal, and adult cardiology publications over the past 10 years. AB - OBJECTIVE: Medline classifies publications as clinical trials, randomised control trials, meta-analyses, practice guidelines, reviews, case reports, editorials, and letters. We tested the hypothesis that cardiology-related publications have increased with a shift in the type of publications over the past 10 years by age category. METHODS: To retrieve from Medline the cardiology articles, we used the keyword "heart disease", but limited the search to articles in English from 2000 to 2009. We repeated the search using one limit according to the publication type and using age tags. We used regression analysis to determine the effect of the year of publication on the number of publications of each type. RESULTS: During the 10-year period, Medline registered 152,849 cardiology articles, doubling from 10,452 in 2000 to 20,841 in 2009, of which 8.5% were tagged as both paediatric and adult. There was a linear increase in the number over the study period in the total number of publications and in all categories, except for practice guidelines. There was almost a twofold increase in adult and neonatal articles, but ~ 70% in paediatric articles. The rate of increase was 66% for randomised control trials, 73% for clinical trials, 124% for meta-analyses, 117% for editorials, 36% for reviews, and 103% for case reports. Practice guidelines remained very low, increasing significantly for paediatric and neonatal articles. CONCLUSIONS: There was a substantial increase in cardiology articles over the past 10 years, being greater for adult and neonatal articles compared with paediatric articles. The increase varied according to the type of article. PMID- 23803314 TI - Preclinical Alzheimer disease and risk of falls. AB - OBJECTIVE: We determined the rate of falls among cognitively normal, community dwelling older adults, some of whom had presumptive preclinical Alzheimer disease (AD) as detected by in vivo imaging of fibrillar amyloid plaques using Pittsburgh compound B (PiB) and PET and/or by assays of CSF to identify Abeta42, tau, and phosphorylated tau. METHODS: We conducted a 12-month prospective cohort study to examine the cumulative incidence of falls. Participants were evaluated clinically and underwent PiB PET imaging and lumbar puncture. Falls were reported monthly using an individualized calendar journal returned by mail. A Cox proportional hazards model was used to test whether time to first fall was associated with each biomarker and the ratio of CSF tau/Abeta42 and CSF phosphorylated tau/Abeta42, after adjustment for common fall risk factors. RESULTS: The sample (n = 125) was predominately female (62.4%) and white (96%) with a mean age of 74.4 years. When controlled for ability to perform activities of daily living, higher levels of PiB retention (hazard ratio = 2.95 [95% confidence interval 1.01 6.45], p = 0.05) and of CSF biomarker ratios (p < 0.001) were associated with a faster time to first fall. CONCLUSIONS: Presumptive preclinical AD is a risk factor for falls in older adults. This study suggests that subtle noncognitive changes that predispose older adults to falls are associated with AD and may precede detectable cognitive changes. PMID- 23803315 TI - Traumatic brain injury may be an independent risk factor for stroke. AB - OBJECTIVE: To explore whether traumatic brain injury (TBI) may be a risk factor for subsequent ischemic stroke. METHODS: Patients with any emergency department visit or hospitalization for TBI (exposed group) or non-TBI trauma (control) based on statewide emergency department and inpatient databases in California from 2005 to 2009 were included in a retrospective cohort. TBI was defined using the Centers for Disease Control definition. Our primary outcome was subsequent hospitalization for acute ischemic stroke. The association between TBI and stroke was estimated using Cox proportional hazards modeling adjusting for demographics, vascular risk factors, comorbidities, trauma severity, and trauma mechanism. RESULTS: The cohort included a total of 1,173,353 trauma subjects, 436,630 (37%) with TBI. The patients with TBI were slightly younger than the controls (mean age 49.2 vs 50.3 years), less likely to be female (46.8% vs 49.3%), and had a higher mean injury severity score (4.6 vs 4.1). Subsequent stroke was identified in 1.1% of the TBI group and 0.9% of the control group over a median follow-up period of 28 months (interquartile range 14-44). After adjustment, TBI was independently associated with subsequent ischemic stroke (hazard ratio 1.31, 95% confidence interval 1.25-1.36). CONCLUSIONS: In this large cohort, TBI is associated with ischemic stroke, independent of other major predictors. PMID- 23803316 TI - From the thalamus with love: a rare window into the locus of emotional synesthesia. PMID- 23803317 TI - Motor function in the elderly: evidence for the reserve hypothesis. AB - OBJECTIVE: The reserve hypothesis accounts for the lack of direct relationship between brain pathology and its clinical manifestations. Research has mostly focused on cognition; our objective is to examine whether the reserve hypothesis applies to motor function. We investigated whether education, a marker of reserve, modifies the association between white matter lesions (WMLs), a marker of vascular brain damage, and maximum walking speed (WS), an objective measure of motor function. We also examined the cross-sectional and longitudinal association between education and WS. METHODS: Data are from 4,010 participants aged 65-85 years in the longitudinal Three-City-Dijon Study with up to 4 WS measures over 10 years. We examined the interaction between education and WMLs for baseline WS. We studied the association between education and repeated WS measures using linear mixed models, and the role of covariates in explaining the education-WS association. RESULTS: Education was strongly associated with baseline WS; the difference in mean WS between the high and low education groups (0.145 m/s, 95% confidence interval = 0.125-0.165) was equivalent to 7.4 years of age. WMLs were associated with slow WS only in the low education group (p interaction = 0.026). WS declined significantly over time (-0.194 m/s/10 years, 95% confidence interval = -0.206, -0.182), but education did not influence rate of decline. Anthropometric characteristics, parental education, general health, and cognition had the strongest role in explaining the baseline education-WS association. CONCLUSIONS: Participants with more education were less susceptible to WMLs' effect on motor function. Higher education was associated with better motor performances but not with motor decline. These results are consistent with the passive reserve hypothesis. PMID- 23803318 TI - High pro-BNP levels predict the occurrence of atrial fibrillation after cryptogenic stroke. AB - OBJECTIVE: Antiplatelets are recommended for secondary prevention in patients with cryptogenic stroke; however, some patients may present with a cardioembolic source that has not been detected, which may modify the treatment. Because high pro-brain natriuretic peptide (BNP) levels are associated with cardioembolic stroke, our objective was to determine whether pro-BNP levels in the acute phase of stroke predict the development of atrial fibrillation (AF) in patients with cryptogenic stroke. METHODS: A prospective study including patients with cryptogenic stroke was conducted. Demographic data, medical history, and stroke characteristics were assessed at admission. A blood sample was obtained within the first 24 hours from stroke onset to determine pro-BNP levels. Patients were followed by a neurologist at 3 and 6 months and later by a primary care physician for 2 years to evaluate the development of AF. RESULTS: One thousand fifty patients with ischemic stroke were evaluated. Three hundred seventy-two patients (35%) had cryptogenic stroke. One hundred eight patients were excluded from the study, so 264 patients were valid for the analysis. AF was detected in 15 patients (5.6%) during the follow-up. Patients who developed AF were older, had hypertension more frequently, and showed higher levels of pro-BNP. In the logistic regression model, we found that pro-BNP >=360 pg/mL was the only variable independently associated with the risk of developing AF (odds ratio 5.70, 95% confidence interval 1.11-29.29, p = 0.037). CONCLUSIONS: Pro-BNP >=360 pg/mL increases by 5-fold the possibility of detecting AF during follow-up in patients with cryptogenic stroke. PMID- 23803319 TI - Comment: Brain amyloid increases the risk of falls. PMID- 23803320 TI - Syndromes dominated by apraxia of speech show distinct characteristics from agrammatic PPA. AB - OBJECTIVE: We assessed whether clinical and imaging features of subjects with apraxia of speech (AOS) more severe than aphasia (dominant AOS) are more similar to agrammatic primary progressive aphasia (agPPA) or to primary progressive AOS (PPAOS). METHODS: Sixty-seven subjects (PPAOS = 18, dominant AOS = 10, agPPA = 9, age-matched controls = 30) who all had volumetric MRI, diffusion tensor imaging, F18-fluorodeoxyglucose and C11-labeled Pittsburgh compound B (PiB)-PET scanning, as well as neurologic and speech and language assessments, were included in this case-control study. AOS was classified as either type 1, predominated by sound distortions and distorted sound substitutions, or type 2, predominated by syllabically segmented prosodic speech patterns. RESULTS: The dominant AOS subjects most often had AOS type 2, similar to PPAOS. In contrast, agPPA subjects most often had type 1 (p = 0.01). Both dominant AOS and PPAOS showed focal imaging abnormalities in premotor cortex, whereas agPPA showed widespread involvement affecting premotor, prefrontal, temporal and parietal lobes, caudate, and insula. Only the dominant AOS and PPAOS groups showed midbrain atrophy compared with controls. No differences were observed in PiB binding across all 3 groups, with the majority being PiB negative. CONCLUSION: These results suggest that dominant AOS is more similar to PPAOS than agPPA, with dominant AOS and PPAOS exhibiting a clinically distinguishable subtype of progressive AOS compared with agPPA. PMID- 23803321 TI - Liver fat accumulation after islet transplantation and graft survival. AB - Our objective is to evaluate if there is an association between liver fat accumulation after islet transplantation (ITx) and graft survival. A cohort study was conducted in 34 subjects with type 1 diabetes postallogeneic ITx. Liver fat content was evaluated by magnetic resonance imaging (MRI) (change in liver signal intensity on in-phase and opposed-phase images). Kaplan-Meier curves and Cox regression analysis were performed with islet dysfunction duration as the dependent variable and fat liver content as an independent one. Values of p < 0.05 were significant (SSPS((r))18.0 and MedCalc((r))12.5). Patients' mean age was 40 +/- 8 years (diabetes duration: 31 +/- 12 years; male: 41%). Islet survival did not differ in patients without (51 months, 95% CI 40-62 months) or with steatosis (48 months, 95% CI 38-58 months; p = 0.55) during islet dysfunction period. Nevertheless, survival curves appear to separate late in the follow-up, and after 40 months steatosis was associated with shorter graft survival (p log rank = 0.049). This association remained (RR 23.5, 95% CI 1.1 516.0; p = 0.045) after adjustments for possible confounding factors. In this sample of subjects with type 1 diabetes submitted to ITx, steatosis was not associated with islet failure in the whole cohort. However, in subjects with functional islets after 40 months, a shorter graft survival was observed in those with steatosis during the islet dysfunction period, even after adjustments to variables known to be associated with islet failure. PMID- 23803322 TI - Prevention versus intervention of type 1 diabetes. AB - Type 1 diabetes (T1D) is a cell-mediated autoimmune disease. New cases of T1D are on the increase and exogenous insulin therapy is the only intervention regularly initiated for T1D patients. Though tremendous strides have been made in prediction of T1D, prevention and intervention strategies have not experienced the same success. In this review, we will discuss some possible reasons why new intervention therapies for T1D have not been implemented into the mainstream treatment regimen for T1D patients. We will also discuss potential caveats for why prevention and intervention trials in T1D may not have experienced the same success as prediction trials. PMID- 23803323 TI - Intact cluster and chordate-like expression of ParaHox genes in a sea star. AB - BACKGROUND: The ParaHox genes are thought to be major players in patterning the gut of several bilaterian taxa. Though this is a fundamental role that these transcription factors play, their activities are not limited to the endoderm and extend to both ectodermal and mesodermal tissues. Three genes compose the ParaHox group: Gsx, Xlox and Cdx. In some taxa (mostly chordates but to some degree also in protostomes) the three genes are arranged into a genomic cluster, in a similar fashion to what has been shown for the better-known Hox genes. Sea urchins possess the full complement of ParaHox genes but they are all dispersed throughout the genome, an arrangement that, perhaps, represented the primitive condition for all echinoderms. In order to understand the evolutionary history of this group of genes we cloned and characterized all ParaHox genes, studied their expression patterns and identified their genomic loci in a member of an earlier branching group of echinoderms, the asteroid Patiria miniata. RESULTS: We identified the three ParaHox orthologs in the genome of P. miniata. While one of them, PmGsx is provided as maternal message, with no zygotic activation afterwards, the other two, PmLox and PmCdx are expressed during embryogenesis, within restricted domains of both endoderm and ectoderm. Screening of a Patiria bacterial artificial chromosome (BAC) library led to the identification of a clone containing the three genes. The transcriptional directions of PmGsx and PmLox are opposed to that of the PmCdx gene within the cluster. CONCLUSIONS: The identification of P. miniata ParaHox genes has revealed the fact that these genes are clustered in the genome, in contrast to what has been reported for echinoids. Since the presence of an intact cluster, or at least a partial cluster, has been reported in chordates and polychaetes respectively, it becomes clear that within echinoderms, sea urchins have modified the original bilaterian arrangement. Moreover, the sea star ParaHox domains of expression show chordate-like features not found in the sea urchin, confirming that the dynamics of gene expression for the respective genes and their putative regulatory interactions have clearly changed over evolutionary time within the echinoid lineage. PMID- 23803324 TI - Glycine transporter 1 modulates GABA release from amacrine cells by controlling occupancy of coagonist binding site of NMDA receptors. AB - The occupancy of coagonist binding sites of NMDA receptors (NMDARs) by glycine or d-serine has been thought to mediate NMDAR-dependent excitatory signaling, as simultaneous binding of glutamate and a coagonist is obligatory for NMDAR activation. Amacrine cells (ACs) mediating GABAergic feedback inhibition of mixed bipolar cells (Mbs) in the goldfish retina have been shown to express NMDARs. Here we studied whether NMDAR-mediated GABAergic inhibitory currents (IGABA) recorded from the axon terminals of Mbs are influenced by experimental manipulations altering retinal glycine and d-serine levels. Feedback IGABA in Mb axon terminals was triggered by focal NMDA application or by synaptically released glutamate from depolarized Mb terminals. In both cases, blocking the coagonist binding sites of NMDARs eliminated the NMDAR-dependent IGABA, demonstrating that coagonist binding is critical in mediating NMDAR activity triggered GABA release. Glycine transporter 1 (GLYT1) inhibition increased IGABA, indicating that coagonist binding sites of NMDARs on ACs providing GABAergic feedback inhibition to Mbs were not saturated. Focal glycine application, in the presence of the ionotropic glycine receptor blocker strychnine, triggered a GLYT1 dependent current in ACs, suggesting that GLYT1 expressed by putative glycinergic ACs controls the saturation level of NMDARs' coagonist sites. External d-serine also increased NMDAR activation-triggered IGABA in Mbs, further substantiating that the coagonist sites were unsaturated. Together, our findings demonstrate that coagonist modulation of glutamatergic input to GABAergic ACs via NMDARs is strongly reflected in the AC neuronal output (i.e., transmitter release) and thus is critical in GABAergic signal transfer function in the inner retina. PMID- 23803326 TI - Neuromuscular mechanisms and neural strategies in the control of time-varying muscle contractions. AB - The organization of the neural input to motoneurons that underlies time-varying muscle force is assumed to depend on muscle transfer characteristics and neural strategies or control modes utilizing sensory signals. We jointly addressed these interlinked, but previously studied individually and partially, issues for sinusoidal (range 0.5-5.0 Hz) force-tracking contractions of a human finger muscle. Using spectral and correlation analyses of target signal, force signal, and motor unit (MU) discharges, we studied 1) patterns of such discharges, allowing inferences on the motoneuronal input; 2) transformation of MU population activity (EMG) into quasi-sinusoidal force; and 3) relation of force oscillation to target, carrying information on the input's organization. A broad view of force control mechanisms and strategies emerged. Specifically, synchronized MU and EMG modulations, reflecting a frequency-modulated motoneuronal input, accompanied the force variations. Gain and delay drops between EMG modulation and force oscillation, critical for the appropriate organization of this input, occurred with increasing target frequency. According to our analyses, gain compensation was achieved primarily through rhythmical activation/deactivation of higher-threshold MUs and secondarily through the adaptation of the input's strength expected during tracking tasks. However, the input's timing was not adapted to delay behaviors and seemed to depend on the control modes employed. Thus, for low-frequency targets, the force oscillation was highly coherent with, but led, a target, this timing error being compatible with predictive feedforward control partly based on the target's derivatives. In contrast, the force oscillation was weakly coherent, but in phase, with high-frequency targets, suggesting control mainly based on a target's rhythm. PMID- 23803325 TI - Long-latency muscle activity reflects continuous, delayed sensorimotor feedback of task-level and not joint-level error. AB - In both the upper and lower limbs, evidence suggests that short-latency electromyographic (EMG) responses to mechanical perturbations are modulated based on muscle stretch or joint motion, whereas long-latency responses are modulated based on attainment of task-level goals, e.g., desired direction of limb movement. We hypothesized that long-latency responses are modulated continuously by task-level error feedback. Previously, we identified an error-based sensorimotor feedback transformation that describes the time course of EMG responses to ramp-and-hold perturbations during standing balance (Safavynia and Ting 2013; Welch and Ting 2008, 2009). Here, our goals were 1) to test the robustness of the sensorimotor transformation over a richer set of perturbation conditions and postural states; and 2) to explicitly test whether the sensorimotor transformation is based on task-level vs. joint-level error. We developed novel perturbation trains of acceleration pulses such that perturbations were applied when the body deviated from the desired, upright state while recovering from preceding perturbations. The entire time course of EMG responses (~4 s) in an antagonistic muscle pair was reconstructed using a weighted sum of center of mass (CoM) kinematics preceding EMGs at long-latency delays (~100 ms). Furthermore, CoM and joint kinematic trajectories became decorrelated during perturbation trains, allowing us to explicitly compare task level vs. joint feedback in the same experimental condition. Reconstruction of EMGs was poorer using joint kinematics compared with CoM kinematics and required unphysiologically short (~10 ms) delays. Thus continuous, long-latency feedback of task-level variables may be a common mechanism regulating long-latency responses in the upper and lower limbs. PMID- 23803328 TI - Laminar profile of visual response properties in ferret superior colliculus. AB - In the superior colliculus (SC), visual afferent inputs from various sources converge in a highly organized way such that all layers form topographically aligned representations of contralateral external space. Despite this anatomical organization, it remains unclear how the layer-specific termination of different visual input pathways is reflected in the nature of visual response properties and their distribution across layers. To uncover the physiological correlates underlying the laminar organization of the SC, we recorded multiunit and local field potential activity simultaneously from all layers with dual-shank multichannel linear probes. We found that the location of spatial receptive fields was strongly conserved across all visual responsive layers. There was a tendency for receptive field size to increase with depth in the SC, with superficial receptive fields significantly smaller than deep receptive fields. Additionally, superficial layers responded significantly faster than deeper layers to flash stimulation. In some recordings, flash-evoked responses were characterized by the presence of gamma oscillatory activity (40-60 Hz) in multiunit and field potential signals, which was strongest in retinorecipient layers. While SC neurons tended to respond only weakly to full-field drifting gratings, we observed very similar oscillatory responses to the offset of grating stimuli, suggesting gamma oscillations are produced following light offset. Oscillatory spiking activity was highly correlated between horizontally distributed neurons within these layers, with oscillations temporally locked to the stimulus. Together, visual response properties provide physiological evidence reflecting the laminar-specific termination of visual afferent pathways in the SC, most notably characterized by the oscillatory entrainment of superficial neurons. PMID- 23803327 TI - Absence of postural muscle synergies for balance after spinal cord transection. AB - Although cats that have been spinalized can also be trained to stand and step with full weight support, directionally appropriate long-latency responses to perturbations are impaired, suggesting that these behaviors are mediated by distinct neural mechanisms. However, it remains unclear whether these responses reflect an attenuated postural response using the appropriate muscular coordination patterns for balance or are due to fundamentally different neural mechanisms such as increased muscular cocontraction or short-latency stretch responses. Here we used muscle synergy analysis on previously collected data to identify whether there are changes in the spatial organization of muscle activity for balance within an animal after spinalization. We hypothesized that the modular organization of muscle activity for balance control is disrupted by spinal cord transection. In each of four animals, muscle synergies were extracted from postural muscle activity both before and after spinalization with nonnegative matrix factorization. Muscle synergy number was reduced after spinalization in three animals and increased in one animal. However, muscle synergy structure was greatly altered after spinalization with reduced direction tuning, suggesting little consistent organization of muscle activity. Furthermore, muscle synergy recruitment was correlated to subsequent force production in the intact but not spinalized condition. Our results demonstrate that the modular structure of sensorimotor feedback responses for balance control is severely disrupted after spinalization, suggesting that the muscle synergies for balance control are not accessible by spinal circuits alone. Moreover, we demonstrate that spinal mechanisms underlying weight support are distinct from brain stem mechanisms underlying directional balance control. PMID- 23803329 TI - Activation of individual extrinsic thumb muscles and compartments of extrinsic finger muscles. AB - Mechanical and neurological couplings exist between musculotendon units of the human hand and digits. Studies have begun to understand how these muscles interact when accomplishing everyday tasks, but there are still unanswered questions regarding the control limitations of individual muscles. Using intramuscular electromyographic (EMG) electrodes, this study examined subjects' ability to individually initiate and sustain three levels of normalized muscular activity in the index and middle finger muscle compartments of extensor digitorum communis (EDC), flexor digitorum profundus (FDP), and flexor digitorum superficialis (FDS), as well as the extrinsic thumb muscles abductor pollicis longus (APL), extensor pollicis brevis (EPB), extensor pollicis longus (EPL), and flexor pollicis longus (FPL). The index and middle finger compartments each sustained activations with significantly different levels of coactivity from the other finger muscle compartments. The middle finger compartment of EDC was the exception. Only two extrinsic thumb muscles, EPL and FPL, were capable of sustaining individual activations from the other thumb muscles, at all tested activity levels. Activation of APL was achieved at 20 and 30% MVC activity levels with significantly different levels of coactivity. Activation of EPB elicited coactivity levels from EPL and APL that were not significantly different. These results suggest that most finger muscle compartments receive unique motor commands, but of the four thumb muscles, only EPL and FPL were capable of individually activating. This work is encouraging for the neural control of prosthetic limbs because these muscles and compartments may potentially serve as additional user inputs to command prostheses. PMID- 23803330 TI - Immediate compensation for variations in self-generated Coriolis torques related to body dynamics and carried objects. AB - We have previously shown that the Coriolis torques that result when an arm movement is performed during torso rotation do not affect movement trajectory. Our purpose in the present study was to examine whether torso motion-induced Coriolis and other interaction torques are counteracted during a turn and reach (T&R) movement when the effective mass of the hand is augmented, and whether the dominant arm has an advantage in coordinating intersegmental dynamics as predicted by the dynamic dominance hypothesis (Sainburg RL. Exp Brain Res 142: 241-258, 2002). Subjects made slow and fast T&R movements in the dark to just extinguished targets with either arm, while holding or not holding a 454-g object. Movement endpoints were equally accurate at both speeds, with either hand, and in both weight conditions, but subjects tended to angularly undershoot and produce more variable endpoints for targets requiring greater torso rotation. There were no changes in endpoint accuracy or trajectory deviation over repeated movements. The dominant right arm was more stable in its control of trajectory direction across targets, whereas the nondominant left arm had an improved ability to stop accurately on the target for higher levels of interaction torques. The trajectories to more eccentric targets were straighter when performed at higher speeds but slightly more deviated when subjects held the weight. Subjects did not slow their torso velocity or change the timing of the arm and torso velocities when holding the weight, although there was a slight decrease in their hand velocity relative to the torso. The delay between the onsets of torso and finger movements was almost twice as large for the right arm than the left, suggesting the right arm was better able to account for torso rotation in the arm movement. Holding the weight increased the peak Coriolis torque by 40% at the shoulder and 45% at the elbow and, for the most eccentric target, increased the peak net torque by 12% at the shoulder and 34% at the elbow. In accordance with Sainburg's dynamic dominance hypothesis, the right arm exhibited an advantage for coordinating intersegmental dynamics, showing a more stable finger velocity in relation to the torso across targets, decreasing error variability with movement speed, and more synchronized peaks of finger relative and torso angular velocities in conditions with greater joint torque requirements. The arm used had little effect on the movement path and the magnitude of the joint torques in any of the conditions. These results indicate that compensations for forthcoming Coriolis torque variations take into account the dynamic properties of the body and of external objects, as well as the planned velocities of the torso and arm. PMID- 23803331 TI - How attention extracts objects from noise. AB - The visual system is remarkably proficient at extracting relevant object information from noisy, cluttered environments. Although attention is known to enhance sensory processing, the mechanisms by which attention extracts relevant information from noise are not well understood. According to the perceptual template model, attention may act to amplify responses to all visual input, or it may act as a noise filter, dampening responses to irrelevant visual noise. Amplification allows for improved performance in the absence of visual noise, whereas a noise-filtering mechanism can only improve performance if the target stimulus appears in noise. Here, we used fMRI to investigate how attention modulates cortical responses to objects at multiple levels of the visual pathway. Participants viewed images of faces, houses, chairs, and shoes, presented in various levels of visual noise. We used multivoxel pattern analysis to predict the viewed object category, for attended and unattended stimuli, from cortical activity patterns in individual visual areas. Early visual areas, V1 and V2, exhibited a benefit of attention only at high levels of visual noise, suggesting that attention operates via a noise-filtering mechanism at these early sites. By contrast, attention led to enhanced processing of noise-free images (i.e., amplification) only in higher visual areas, including area V4, fusiform face area, mid-Fusiform area, and the lateral occipital cortex. Together, these results suggest that attention improves people's ability to discriminate objects by de-noising visual input in early visual areas and amplifying this noise reduced signal at higher stages of visual processing. PMID- 23803333 TI - Novel oral prostacyclin analog with thromboxane synthase inhibitory activity for management of pulmonary arterial hypertension. PMID- 23803332 TI - GABAB receptor gene transfer into the nucleus tractus solitarii induces chronic blood pressure elevation in normotensive rats. AB - BACKGROUND: Increasing evidence indicates that GABAergic neurons in the nucleus of the solitary tract (NTS) play a significant role in the arterial baroreceptor reflex and control of cardiovascular homeostasis. However, the role of these neurons in the development of hypertension is not yet fully clear. METHODS AND RESULTS: In the present study, we first confirmed that GABAB receptor (GBR) expression is enhanced in the NTS of SHR as compared with WKY rats using real time RT-PCR and western blots. To study the functional consequence of upregulated GBR expression, GBR was overexpressed in the NTS by bilateral microinjection of the AAV2-GBR1 viral vector into the NTS of WKY rats. Immunofluorescence staining and western blots demonstrated that microinjection of AAV2-GBR1 into the NTS of WKY rats resulted in a significant increase in GBR1 expression in the NTS neurons. Overexpression of GBR in the NTS induced a chronic elevation in blood pressure and heart rate in the normotensive WKY rats. In an acute study, the pressor response to baclofen microinjected into the NTS was enhanced in SHR as compared with WKY rats. CONCLUSIONS: GBR1 expression is enhanced in the NTS of SHR vs. WKY rats and overexpression of this gene in the NTS results in chronic elevation of blood pressure and heart rate in normotensive rats. PMID- 23803334 TI - Seven-year clinical outcomes of unprotected left main coronary artery stenting with drug-eluting stent and bare-metal stent. AB - BACKGROUND: The superiority of drug-eluting stents (DES) over bare-metal stents (BMS) 7 years after unprotected left main coronary artery (LMCA) stenting has not been investigated. METHODS AND RESULTS: From 2003 to 2005, 182 patients underwent stent implantation for unprotected LMCA disease (DES, 96 patients; BMS, 86 patients; acute coronary syndrome cases excluded), and the 7-year clinical outcomes between the DES and BMS groups were compared. The incidence of cardiac death or non-fatal myocardial infarction was similar between the DES and BMS groups (11.0% vs. 13.5%, P=0.78). The incidence of target lesion revascularization (TLR) at 7 years was significantly lower in the DES group than in the BMS group (26.4% vs. 40.5%, P=0.009); the incidence from 1 to 4 years and that beyond 4 years were similar between the DES and BMS groups (8.9% vs. 7.9%, P=0.97; 10.0% vs. 8.7%, P=0.74, respectively). Among patients with bifurcation lesions, whereas the incidence of 7-year TLR was significantly lower in the DES group than the BMS group in patients undergoing single-stent procedures (15.9% vs. 48.6%, P=0.002), it was similar between the 2 groups in patients undergoing 2 stent procedures (38.5% vs. 39.3%, P=0.49). CONCLUSIONS: With the exception of the 2-stent procedure, the 7-year outcomes after DES implantation for LMCA disease were superior to those after BMS implantation because of the lower TLR rate, when considering TLR during the late phase. PMID- 23803336 TI - Psychosocial risk in families of infants undergoing surgery for a serious congenital heart disease. AB - OBJECTIVE: The aim of this study was to explore the acute psychosocial risk in families with infants undergoing surgery for a congenital heart disease and, secondarily, to explore the psychosocial impact of antenatal versus post-natal diagnoses. METHOD: The study sample comprised 39 caregivers (28 mothers) of 29 children diagnosed with a congenital heart disease and requiring surgery within the first 4 weeks of life. Psychosocial risk was measured using the Psychosocial Assessment Tool, which was adapted to include four novel items examining infant risk factors, namely, sleeping, feeding, crying, and bonding difficulties. Parents' psychosocial risk was measured within 4 weeks after their child's surgery and stratified into a three-tiered framework: Universal, Targeted, and Clinical risk. RESULTS: Of the total sample, 61.5% of parents were classified as Universal, that is, at lowest risk; 35.9% as Targeted, and 2.6% as Clinical. The within-family parent total Psychosocial Assessment Tool score correlations were non-significant, and there were no differences between families of infants who received post-natal versus antenatal diagnosis or single ventricle versus biventricular repair. Linear regression found that a higher parent education significantly predicted a lower total Psychosocial Assessment Tool score. CONCLUSIONS: Findings indicate that, although the majority of parents adapt to the acute stress of surgery for a serious cardiac illness in their infant, the remaining 38.5% report an increased psychosocial risk associated with higher rates of emotional distress, which may impact on the parental quality of life and capacity for optimal parenting. The distribution of psychosocial risk in parents of children undergoing surgery for a congenital heart disease is consistent with that described for parents of children with other serious paediatric diagnoses. PMID- 23803335 TI - Evaluation design for community-based physical activity programs for socially disadvantaged groups: communities on the move. AB - BACKGROUND: As interventions are not yet successful in substantially improving physical activity levels of low socioeconomic status groups in the Netherlands, it is a challenge to undertake more effective interventions. Participatory community-based physical activity interventions such as Communities on the Move (CoM) seem promising. Evaluating their effectiveness, however, calls for appropriate evaluation approaches. OBJECTIVE: This paper provides the conceptual model for the development of a context-sensitive monitoring and evaluation approach in order to (1) measure the effectiveness and cost-effectiveness of CoM, and (2) develop an evaluation design enabling the identification of underlying mechanisms which explain what works and why in community-based physical activity programs. METHODS: A cohort design is proposed, based on multiple cases, measuring impact, processes, and changes at each of the distinguished levels. The methods described in this paper will evaluate both short- and long-term effects, costs, and benefits of CoM. RESULTS: Testing of the proposed model began in October 2012 and is on-going. CONCLUSIONS: The design offers a valid research strategy for evaluating the effectiveness of community-based physical activity programs. Internal validity is guaranteed by the use of several verification techniques such as triangulation. The multiple case studies at the program and community levels enhance external validity. PMID- 23803337 TI - Time is of the essence for ParaHox homeobox gene clustering. AB - ParaHox genes, and their evolutionary sisters the Hox genes, are integral to patterning the anterior-posterior axis of most animals. Like the Hox genes, ParaHox genes can be clustered and exhibit the phenomenon of colinearity - gene order within the cluster matching gene activation. Two new instances of ParaHox clustering provide the first examples of intact clusters outside chordates, with gene expression lending weight to the argument that temporal colinearity is the key to understanding clustering. PMID- 23803339 TI - Developmental, emotional and behavioral co-morbidities across the chronic health condition spectrum. AB - AIMS: Estimate the prevalence of specific developmental, emotional, and behavioral (DEB) problems across selected chronic health conditions; examine the relationship of chronic health conditions to functional activities and participation; determine the potential confounding effect of sociodemographic factors on the prevalence of DEB problems. METHODS: The 2007 National Survey of Children's Health, conducted by the Centers for Disease Control and Prevention, served as the primary data source for this study. A total of 91.642 interviews (66.6% response rate for identified households with children) were performed. Population-based estimates were obtained for variables of interest by assigning sampling weights to each child for whom an interview was completed. RESULTS: Parents were two to 30 times more likely to report DEB problems, such as Attention Deficit/Hyperactivity Disorder, depression, learning problems, and challenging behaviors, for children with chronic health conditions. These children had a greater number and range of difficulties with social interaction and school functioning as well as a lower rate of participation in community activities. Although highest rates of DEB problems were reported for those conditions involving the nervous or sensory systems, children with asthma, diabetes, and musculoskeletal conditions also had a higher rate of problems than children without the conditions. The higher prevalence of DEB problems remained after statistical adjustment for socio-demographic factors. CONCLUSIONS: Children with a spectrum of chronic health conditions are at high risk for DEB problems that affect learning, behavior, and emotional well-being. As part of a comprehensive approach to the management of chronic health conditions, children should be screened for these problems and referred for appropriate further evaluation and remediation. Attention to these common co-morbidities will not only result in enhanced quality of life but will also promote better adherence to medical recommendations and, thereby, optimal disease control. PMID- 23803340 TI - Course of recovery and prediction of outcome in young patients in a prolonged vegetative or minimally conscious state after severe brain injury: An exploratory study. AB - AIMS: To explore the course of recovery of consciousness and factors predicting the outcome of severe brain injury with a prolonged period of unconsciousness in children and young adults receiving a specialized rehabilitation treatment, the Early Intensive Neurorehabilitation Programme (EINP). METHODS: A cohort of forty four patients aged 1.6-25.5 years (M=16.0) with traumatic acquired brain injury (TBI) or non-traumatic acquired brain injury (nTBI) were examined using the Western Neuro Sensory Stimulation Profile every two weeks, from the application for EINP until discharge. The level of consciousness was assessed with the Post Acute Level of Consciousness Scale, and the level of disability was determined by the Disability Rating Scale. Long-term level of disability of all TBI patients (N=32) was assessed between 2.0 and 4.4 years after discharge from EINP. RESULTS: Two-thirds of all patients recovered to consciousness. Three recovery patterns were identified: remaining in a vegetative state (VS), slow recovery of consciousness, and fast recovery of consciousness. In the long-term, 11 of the TBI patients were severely disabled, 13 were moderately disabled, and 4 were mildly disabled. All TBI patients who were in VS at discharge either had deceased, or recovered to a very severely disabled state. CONCLUSIONS: Three recovery patterns identified in an early stage after starting EINP made it possible to predict long-term level of disability. PMID- 23803341 TI - Oral risedronate sodium improves bone mineral density in non-ambulatory patients: a randomized, double-blind, placebo controlled trial. AB - AIMS: Investigate the efficacy of risedronate sodium (Procter and Gamble, Cincinnati, USA) for treating reduced lumbar spine (LS) bone mineral density (BMD) in non-ambulatory patients. METHODS: Nine (10-39 years, mean age 23.0 years, 7 males) in the risedronate arm and 10 (10-35 years, mean age 21.4 years, 8 males) in the placebo arm completed 24 months of therapy at baseline, 6, 12, 18, and 24 months. The primary outcome was change in LS BMD assessed by dual energy x-ray absorptiometry (DXA). Secondary outcomes included changes in serum bone markers, bone specific alkaline phosphatase, osteocalcin, and N telopeptides. Mixed models examined group, time, and the group by time interaction for the 4 post-baseline time points. RESULTS: The change in LS BMD score from baseline to 24 months was 0.069 (95% CI 0.014 to 0.124) in risedronate participants compared to -0.015 (95% CI -0.073 to 0.042) (t Value = -2.40, P > t=0.03) in the controls. When controlling for baseline scores, the difference was consistent across four post-baseline time points tested (F=5.67, Pr > F=0.03). No differences in serum bone markers were observed. CONCLUSIONS: Risedronate increases LS BMD in non-ambulatory patients with minimal side effects. PMID- 23803342 TI - Inpatient care for children, ages 1-20 years, with spina bifida in the United States. AB - AIMS: To describe the inpatient health service use and insurance types for hospitalized children with spina bifida compared to children generally and to evaluate hospital discharge and insurance type trends over a 10-year study period. METHODS: The cross-sectional secondary data analyses were conducted using the 2000, 2003, 2006 and 2009 Kid's Inpatient Databases. Diagnoses were identified by ICD-9 codes and hospital type was categorized based on the National Association of Children's Hospitals and Related Institutions designations. Chi squared tests and the Wald test of trend were used for the statistical analyses. RESULTS: Children with spina bifida are more likely to receive their inpatient care in children's hospitals or pediatric units compared to all children. Children with spina bifida were most commonly admitted for shunt malfunction and repair. The percentage of children covered by Medicaid rose during the study period for both children with spina bifida and children generally. CONCLUSIONS: This study is the first of its kind to document longitudinal trends in inpatient utilization, insurance type, and reason for admission for children with spina bifida. The changing trends in insurance coverage should be closely monitored because insurance is closely linked to health care access, which is linked to health outcomes. PMID- 23803343 TI - Validation of the Actical and Actiheart monitor in ambulatory children with spina bifida. AB - BACKGROUND: Ambulatory children with Spina Bifida (SB) often show a decline in physical activity leading to deconditioning and functional decline. Therefore, assessment and promotion of physical activity is important. Because energy expenditure during activities is higher in these children, the use of existing pediatric equations to predict physical activity energy expenditure (PAEE) may not be valid. AIMS: (1) To evaluate criterion validity of existing predictions converting accelerocounts into PAEE in ambulatory children with SB and (2) to establish new disease-specific equations for PAEE. METHODS: Simultaneous measurements using the Actical, the Actiheart, and indirect calorimetry took place to determine PAEE in 26 ambulatory children with SB. DATA ANALYSIS: Paired T-tests, Intra-class correlations limits of agreement (LoA), and explained variance (R(2)) were used to analyze validity of the prediction equations using true PAEE as criterion. New equations were derived using regression techniques. RESULTS: While T-tests showed no significant differences for some models, the predictions developed in healthy children showed moderate ICC's and large LoA with true PAEE. The best regression models to predict PAEE were: PAEE=174.049+3.861 * HRAR - 60.285 * ambulatory status (R(2) =0.720) and PAEE=220.484+0.67 * Actical counts - 60.717 * ambulatory status (R(2) =0.681). CONCLUSIONS: Existing equations to predict PAEE are not valid for use in children with SB for the individual evaluation of PAEE. The best regression model was based on HRAR in combination with ambulatory status, followed by a new model for the Actical monitor. A benefit of HRAR is that it does not require the use of expensive accelerometry equipment. Further cross-validation of these models is still needed. PMID- 23803344 TI - Differences of respiratory function in children with spastic diplegic and hemiplegic cerebral palsy, compared with normally developed children. AB - PURPOSE: The purpose of this study was to investigate differences between respiratory function in children with spastic cerebral palsy (CP) and children with normal development, and to compare respiratory function between children with spastic diplegic and those with hemiplegic CP. METHOD: Fourteen children with spastic diplegic CP, 14 children with spastic hemiplegic CP, and 14 normal children were enrolled, whose age, gender, height, weight, and body surface area were matched. All participants performed respiratory function tests by inhaling a breath and then blowing the entire volume through a spirometer, as deeply and rapidly as possible. RESULTS: In general, children with spastic diplegic CP and those with hemiplegic CP showed lower respiratory function compared to children with normal development. In comparison between children with spastic CP and those with hemiplegic CP, statistical significance was observed only in FVC, FEV_1, and PEF. CONCLUSION: Findings revealed significantly weaker respiratory function in children with CP as compared to normal children. In addition, children with spastic diplegic CP showed significantly lower forced expiratory function than those with spastic hemiplegic CP. Therefore, clinical assessment and therapeutic intervention for respiratory function should be carefully considered for children with spastic diplegic and hemiplegic CP. PMID- 23803346 TI - Past, present, and future of cervical arthroplasty. AB - Cervical arthroplasty was developed in an attempt to maintain cervical motion and potentially to avoid or minimize adjacent-segment degeneration. If cervical arthroplasty is successful, the long-term results of surgery for cervical disc disease should improve. However, problems associated with cervical arthroplasty have been reported: these include kyphosis, heterotopic ossification-induced motion limitation, no motion preservation even at the index level, and a higher revision rate in a limited number of cases compared with anterior cervical discectomy and fusion (ACDF). In addition, for degenerative cervical disc disorders, the risk of developing adjacent segment degeneration more than 2 years after surgery is reportedly similar for ACDF and cervical arthroplasty. Cervical disc arthroplasty is an emerging motion-sparing technology and is currently undergoing evaluation in many countries as an alternative to arthrodesis for the treatment of cervical radiculopathy and myelopathy. The decision whether to use arthrodesis or arthroplasty is a difficult one. The achievement of good prosthetic performance demands exacting implantation techniques to ensure correct placement. This fact underlines the increasing importance of special instrumentation and surgical skills that involve an understanding of prosthetic lubrication, wear, and biologic effects and familiarity with currently available information regarding kinematics, basic science, testing, and early clinical results. Fortunately, a number of devices are at the late preclinical study stage or at the early clinical trial stage, and results in many cases are promising. In the near future, it is likely that new designs will be produced to replace spinal discs totally or partially in a pathologic entity-specific manner. PMID- 23803347 TI - Out of equilibrium plasticity dynamics and the annealing of supersolidity in solid 4He. AB - We present a numerical study of a continuum plasticity field coupled to a Ginzburg-Landau model for superfluidity. The results suggest that a supersolid fraction may appear as a long-lived transient during the time evolution of the plasticity field at higher temperatures where both dislocation climb and glide are allowed. Supersolidity, however, vanishes with annealing. As the temperature is decreased, dislocation climb is arrested and any residual supersolidity due to incomplete annealing remains frozen. Our results may provide a resolution of many perplexing issues concerning a variety of experiments on bulk solid (4)He. PMID- 23803349 TI - Front-line ownership: generating a cure mindset for patient safety. AB - Great advances have been made in standardization and human factors engineering that have reduced variability and increased reliability in healthcare. As important as these advances are, the authors believe there is another important but largely ignored layer to the safety story in healthcare that has prevented us from progressing. In the field of infection prevention and control (IPAC), despite great attempts over several decades to improve compliance with hand hygiene, surveillance, environmental cleaning, isolation protocols and other control measures, very significant challenges remain. We believe this failure is in part due to the power gradients, often dysfunctional relationships and lack of safety mindfulness that exist in hospitals and healthcare more generally. Furthermore, safety culture requires different approaches and considerable ongoing attentiveness. If this is the case, and the authors contend in this paper that it is, then the role of the front line is much more important than many of our healthcare safety and IPAC approaches suggest. PMID- 23803348 TI - Transcriptome meta-analysis reveals a central role for sex steroids in the degeneration of hippocampal neurons in Alzheimer's disease. AB - BACKGROUND: Alzheimer's disease is the most prevalent form of dementia. While a number of transcriptomic studies have been performed on the brains of Alzheimer's specimens, no clear picture has emerged on the basis of neuronal transcriptional alterations linked to the disease. Therefore we performed a meta-analysis of studies comparing hippocampal neurons in Alzheimer's disease to controls. RESULTS: Homeostatic processes, encompassing control of gene expression, apoptosis, and protein synthesis, were identified as disrupted during Alzheimer's disease. Focusing on the genes carrying out these functions, a protein-protein interaction network was produced for graph theory and cluster exploration. This approach identified the androgen and estrogen receptors as key components and regulators of the disrupted homeostatic processes. CONCLUSIONS: Our systems biology approach was able to identify the importance of the androgen and estrogen receptors in not only homeostatic cellular processes but also the role of other highly central genes in Alzheimer's neuronal dysfunction. This is important due to the controversies and current work concerning hormone replacement therapy in postmenopausal women, and possibly men, as preventative approaches to ward off this neurodegenerative disorder. PMID- 23803350 TI - One hundred fifty years of infection prevention and control: still searching for the cure. AB - In this issue, Zimmerman and colleagues propose a "cure" for our seeming inability to deliver safer healthcare for patients. They suggest that the solution lies in engaging front-line healthcare workers to generate ideas for improving patient safety at the local level and empowering them to implement these ideas - front-line ownership. However, our current environment lacks performance measures and fails to hold individuals and teams accountable for their performance in improving patient safety. Healthcare leaders must commit to supporting front-line workers by providing performance measures and an accountability framework. Only then can we achieve authentic and sustainable front-line ownership. PMID- 23803351 TI - There is a need for a multidisciplinary approach to patient safety. AB - In the lead paper, Zimmerman et al. explore the role of problem and solution ownership in solution adoption by front-line healthcare staff. The front-line ownership (FLO) approach suggested by the authors proposes a shift in leadership style such that managers act as enablers of patient safety improvement efforts by front-line staff (i.e., a bottom-up management style). From a systems perspective, it would be necessary to examine contributing factors to patient safety problems, including process, workflow, task requirements etc., in order to effectively utilize a solution-oriented approach such as FLO. These factors would be difficult to identify by clinical staff alone. There is a need for a multidisciplinary approach to patient safety management in healthcare. PMID- 23803352 TI - FLO: the solution to knowing but not doing. AB - Dealing with the failure of many patient safety initiatives to positively impact patient safety is one of the most daunting issues healthcare systems now face. The concept of front-line ownership (FLO) and the research documenting the success of this approach is thus critical to all involved in the effort to make healthcare safer for patients. Focusing on why it is so important to involve front-line workers at every level in designing, implementing and evaluating patient safety initiatives is the subject of this commentary and, in the author's view, the only way to move from theory to practice, and from exhortation to the kinds of changes in behaviour and attitudes upon which patient safety depends. PMID- 23803353 TI - The Ebb and FLO of improving patient safety. AB - Patient safety in Canada has improved. Yet, dramatic transformation in safety across the continuum of care remains elusive. Front-line ownership (FLO) as outlined by Zimmerman and colleagues represents a novel bottom-up, or "discovery," approach to surmounting the challenges of further improving patient safety. Zimmerman et al.'s rationale and pilot study results suggest, however, that answers to important questions are required prior to the general adoption of FLO. For instance, in FLO's front-line collaborations, what is senior leadership's role? Is it limited to support, or is there a critical role in setting priorities and networking outside organizational boundaries to avoid reinventing the wheel? Who is included in the FLO team? Are housekeepers, doctors and patients all key teammates and contributors to success? In the near term, health organizations' support for FLO should be balanced with more directive safety solutions, within a broad framework that values both evidence-based practice and the generation of practice-based evidence. In this context, the authors of this commentary probe particular dimensions of FLO's theory and practice to promote the best positioning of FLO to enhance its optimal application of knowledge to reduce harm and improve patient safety. PMID- 23803354 TI - Leadership needs to shift in the health system: three emerging perspectives to inform our way forward. AB - Zimmerman et al. have brought to light a number of issues that lead to a collective failure in healthcare safety culture, and propose how to overcome them. Front-line ownership (FLO) is a great success story in that respect, acknowledging that much of the problem and, therefore, solution, relates to how, not what, approaches and solutions have been implemented. In service of the healthy dialogue the authors have invited, this commentary suggests that there needs to be a purposeful shift in leadership, not only in the important area of patient safety but more generally throughout the health system. Three emerging perspectives around leadership are briefly introduced that provide some insight into FLO's success - complexity leadership, neuroleadership and phronetic leadership. Together, these reflect the importance of the underlying dynamics of how we could (re)frame our approaches to change, engage the right people in the right context and achieve sustainable solutions throughout the health system. PMID- 23803355 TI - Staff ownership would revolutionize patient safety - if we let it. AB - Healthcare has failed to make the same progress as other high-risk industries when it comes to creating safety - despite over a decade of research, education and implementation of safety systems in health services. Safe care is created by systems and standardization, and also by proactive, thinking staff working in partnership with consumers and each other; but the healthcare industry appears to struggle to reconcile these concepts. Even with our evolved knowledge of how human beings operate in organizations, and the best intentions, the dominant change paradigm in healthcare is still hierarchical, based on top-down policies implemented by managers and staff. Although the power spread in health services is being tested through generational change, we have a long way to go before proactivity and initiative at the front line are universally fostered and welcomed by healthcare managers and senior clinicians. "Front Line Ownership: Generating a Cure Mindset for Patient Safety," by Zimmerman et al., presents a persuasive example of how staff ownership of improving consumer safety is a powerful tool for change, one that deserves its place at the front line of safety and quality improvement methods. PMID- 23803356 TI - Go with the FLO? A novel approach to quality and safety. AB - In their paper "Front-Line Ownership: Generating a Cure Mindset for Patient Safety," Zimmerman and her colleagues introduce us to the novel concept of FLO - front-line ownership - within the quality and safety arena. Based on their 18 month study of nosocomial infections within five Canadian hospitals, the authors highlight the benefits of allowing front-line staff to own and manage patient safety problems as opposed to imposing programs on them that were created by leaders who did not consult them in developing appropriate solutions.Their paper highlights many of the benefits of FLO, particularly around social networking, interdisciplinary team work and clinician engagement. But how does FLO measure up in the context of other more technical methods of managing adverse events within healthcare organizations? What are the benefits and weakness of FLO? Is FLO consistent with external accreditation requirements and the drive for greater standardization? Will its necessarily longer time frame consign it to a few small scale research projects or is there real potential to use FLO techniques for other quality and safety problems beyond nosocomial infections? PMID- 23803357 TI - Doing the dance of culture change: complexity, evidence and leadership. AB - The challenge of culture change in hospitals must address three distinct but interwoven tensions: the need to shift paradigm and understand healthcare as a complex adaptive system; the challenge of knitting together the contributions of both evidence-based medicine and practice-based evidence; and the critical role of distributed, problem-focused leadership.The authors of the lead paper highlight five key issues in addressing this challenge: (1) the implementation of strategies like front-line ownership (FLO) in the context of macro-level social forces; (2) the central role of distributed leadership and its strengthening within the organization; (3) the need to attend to developing systems thinking skills at all levels; (4) the very significant challenge of how to scale up the labour-intensive change strategies within FLO, the role of "simple rules" and the potential for systems thinking tools such as concept mapping and dynamic modelling; and (5) the concurrent orchestration of not one culture change but three tensions in the challenge FLO represents to simpler versus complex adaptive systems, leadership and management and the balance between evidence-based medicine and practice-based evidence, at the clinical, organizational and macro system levels. PMID- 23803358 TI - Front-line ownership: imagine. AB - When used in a military context, the term front line refers to the interface between enemies in action on the battlefield. In a non-military context, the front line is the site where the core activity defining a particular industry takes place, and those working there are key to successful operations. In healthcare, the need to improve patient safety has become a global imperative, and an armamentarium of strategies, tools and technological approaches have been adapted or developed for this context. Often neglected, however, have been strategies to engage the healthcare workers, those at the front line, in the cause.In order for healthcare to function error free, we must assume the characteristics of high-reliability organizations. In particular, the ability to bounce back, to be resilient in the face of a catastrophe, is of paramount importance. Those working at the front line may have the answers. We need to create an opportunity for them to be heard.' PMID- 23803359 TI - FLO: a cure for what ails healthcare? AB - Zimmerman et al. contend that it is only by providing front-line staff with the tools and the power to change practice that patient safety can be truly embedded in an institution. In this commentary, the author agrees with this argument and adds that patients and families must also have a central place at the table when it comes to addressing healthcare's failings. PMID- 23803361 TI - Atrioventricular septal defect in a case of Shwachman-Diamond syndrome. AB - Shwachman-Diamond syndrome is an inherited bone marrow failure and cancer predisposition syndrome that affects multiple organ systems, including bone, pancreas, and, to a lesser extent, the heart. Myocardial fibrosis, necrosis, and a case of dilated cardiomyopathy have, so far, been described. We report the first case of atrioventricular septal defect in a patient with Shwachman-Diamond syndrome. PMID- 23803362 TI - High resectability of colorectal liver metastases with aggressive chemotherapy in the era of molecular target-based agents. AB - BACKGROUND/AIMS: Advances in chemotherapy have expanded the resectability of colorectal liver (CRC) metastases. We studied treatment results in CRC patients with liver metastases in the era of molecular target-based agents. METHODOLOGY: Based on data collected retrospectively, we analyzed the demographics, operative and pathological outcomes, and adjuvant chemotherapy, of 91 consecutive CRC patients with liver metastases treated between January, 2008 and June, 2010. RESULTS: Of the 91 patients, 42 (46.2%) underwent liver resection (group 1), 41 underwent only resection of the primary tumor without hepatectomy (group 2), and 8 underwent palliative surgery (group 3). According to multivariate analysis, resection of liver metastases was significantly influenced by the number of metastases and the existence of extrahepatic metastases. Disease-free survival (DFS) differed significantly between patients who received adjuvant therapy and those treated by surgery alone (p<0.001). The regimen (p=0.01) and duration (p<0.0001) of adjuvant chemotherapy also affected DFS. Overall survival after 1 and 3 years was 97.6% and 94.0%, respectively, in group 1, 71.9% and 30.6% in group 2, and 33.3% and 0% in group 3. CONCLUSIONS: Although the observation period was short, our findings suggest that high resectability and effective chemotherapy will prolong the survival of patients with colorectal liver metastases. PMID- 23803363 TI - Co-expression of CD44 and ABCG2 in spheroid body-forming cells of gastric cancer cell line MKN45. AB - BACKGROUND/AIMS: The cancer stem cell (CSC) theory hypothesizes that CSCs are regarded as the cause of tumor formation, recurrence and metastasis. This study aimed to investigate whether spheroid body-forming cells in human gastric cancer cell were enriched for CSC properties, and to assess the expression of candidate CSC markers, cluster of differentiation 44 (CD44) and adenosine triphosphate binding cassette transporter G 2 (ABCG2) in the MKN45 spheroid body cells. METHODOLOGY: Human gastric cancer cell line MKN45 were plated in stem cell conditioned culture system allowed for spheroid body forming. The expression levels of CD44 and ABCG2 in the spheroid body cells were assessed by quantitative real-time PCR, western blot analysis and immunofluorescence staining, and the tumorigenicity of the spheroid body-forming cells were assessed by in vivo xenograft studies in nude mice. RESULTS: The MKN45 cells could form spheroid bodies cultured in stem cell conditioned medium. The spheroid body-forming cells showed a significantly greater (p <0.05) expression of CD44 and ABCG2 than the parental cells. CONCLUSIONS: Spheroid body cells from gastric cancer cell line MKN45 cultured in stem cell conditioned medium possessed gastric CSC properties. The cells co-expressed of CD44 and ABCG2 might represent a subpopulation of gastric CSCs. PMID- 23803364 TI - Prediction of outcome in multiorgan resections for cancer using a bayes-network. AB - BACKGROUND/AIMS: The long-term success of multivisceral resections for cancer is difficult to forecast due to the complexity of factors influencing the prognosis. The aim of our study was to assess the predictivity of a Bayes network for the postoperative outcome and survival. METHODOLOGY: We included each oncologic patient undergoing resection of 4 or more organs from 2002 till 2005 at the Ulm university hospital. Preoperative data were assessed as well as the tumour classification, the resected organs, intra- and postoperative complications and overall survival. Using the Genie 2.0 software we developed a Bayes network. RESULTS: Multivisceral tumour resections were performed in 22 patients. The receiver operating curve areas of the variables "survival >12 months" and "hospitalisation >28 days" as predicted by the Bayes network were 0.81 and 0.77 and differed significantly from 0.5 (p: 0.019 and 0.028, respectively). The positive predictive values of the Bayes network for these variables were 1 and 0.8 and the negative ones 0.71 and 0.88, respectively. CONCLUSIONS: Bayes networks are useful for the prognosis estimation of individual patients and can help to decide whether to perform a multivisceral resection for cancer. PMID- 23803365 TI - Patchy innervation confirmed in pull-through bowel with normal conventional biopsy results in Hirschsprung's disease - the benefit of circumferential biopsying. AB - The effectiveness of pull-through for Hirschsprung's disease is dependent on accurate identification of normoganglionic bowel in intraoperative biopsy specimens. We report 2 cases of patchy innervation of pull-through bowel in children with Hirschsprung's disease only identified by circumferential biopsying. Case 1 was an 8-month-old boy. During laparoscopy-assisted transanal endorectal pull-through, extra biopsies of bowel were taken circumferentially, 2 cm proximal to the level of normoganglionosis confirmed by laparoscopic colon biopsies. Aganglionosis was found at 3 o'clock, suggesting that bowel innervation at this level was patchy. Circumferential biopsies were performed a further 2cm proximally, and all sites were normoganglionic. This level was used for pull through with excellent outcome. Case 2 was a 27-day-old boy. Similarly, extra biopsies were taken circumferentially, 2cm proximal to the level of "normoganglionosis" as indicated by conventional biopsying. Normoganglionosis was found only at 3 o'clock, while all other sites were hypoganglionic. A further series of circumferential biopsies was performed 2 cm proximally and hypoganglionosis was still identified, but only at 6 o'clock. Circumferential biopsies were repeated another 2cm proximally, and all sites were normoganglionic. We recommend circumferential biopsies be performed routinely to prevent bowel with patchy innervation from being used for pull-through and possibly causing postoperative bowel dysmotility in a subgroup of Hirschsprung's disease patients. PMID- 23803366 TI - Applying transductal invaginational pancreaticojejunostomy to decrease pancreatic leakage after pancreaticoduodenectomy. AB - Pancreatic leakage after pancreaticoduodenectomy is not fully prevented despite pancreaticojejunostomy or pancreaticogastrostomy being applied. Here, a new type of transductal invaginational pancreaticojejunostomy (TDI) was devised to prevent pancreatic leakage. Briefly, prolene was penetrated from inside the pancreatic duct through the pancreatic stump at ventral and dorsal sides, respectively, and penetrated from the jejunal cavity outwards; so the pancreatic duct was kept patently and pancreaticojejunostomy was fixed by the prolene stitches. From August 2009 to March 2012, 29 patients received TDI with their consent. No pancreatic leakage was found postoperatively. The postoperative complications included 1 instance of biliojejunostomy leakage, 1 abscess and 2 incision infections. Our primary experience of applying TDI suggests that it is a simple and effective technique to prevent pancreatic leakage after pancreatoduodenectomy, especially in those cases with soft pancreas and normal pancreatic duct diameter. PMID- 23803367 TI - factors influencing mucosal healing in Crohn's disease during infliximab treatment. AB - BACKGROUND/AIMS: The effect of infliximab (IFX) on mucosal healing (MH) in clinical setting, as well as what is the effect of scaring of profound ulcers on bowel, is not well known. Aim of our study was to assess how MH occurs in Crohn's disease (CD) in clinical setting during treatment with IFX. METHODOLOGY: Forty patients with CD were followed-up. MH and endoscopic remission (ER) were assessed. Some factors were investigated in predicting development of "uncomplicated" (ulcer healing without alteration of bowel profile) or "complicated" (ulcer healing with alteration of bowel profile) MH. RESULTS: IFX was administered for a mean of 36 months. MH ranged from 67.5% of cases after 6 months to 42.5% of cases after 3 year of treatment. ER ranged from 87.5% of cases after 6 months to 52.5% of cases after 3 year of treatment. Mean CDEIS score decreased from 28 to 8 at the end of follow-up. Uncomplicated MH occurs in 70.37% of patients, complicated MH occurred in 29.63% of patients. Complicated MH was recorded more frequently in patients with severe CDAI (>300 vs. <300, p <0.0362) and higher CDEIS (>35 vs. <35, p >0.0342). CONCLUSIONS: Complicated MH seems to occur frequently in clinical practice when using IFX, especially in patients with higher indexes of activity at entry. PMID- 23803368 TI - Clinical significance of the first surveillance colonoscopy after endoscopic early colorectal cancer removal. AB - BACKGROUND/AIMS: We investigated the clinical significance of the first surveillance colonoscopy after endoscopic cancer removal. METHODOLOGY: We conducted a retrospective cohort study at a single center. Patients diagnosed with early colon cancer after endoscopic removal (index colonoscopy) and who underwent surveillance colonoscopy within 1 year were enrolled. All visible lesions were removed during index colonoscopy. Polyps newly detected at surveillance colonoscopy considered as lesions missed during index colonoscopy were analyzed. We investigated risk factors for missing an advanced lesion. RESULTS: In total, 139 patients diagnosed with early colorectal cancer were enrolled. Overall 774 lesions were removed during index colonoscopy and an additional 222 lesions were newly detected at the surveillance colonoscopy. The lesion miss rate during index colonoscopy was 22.3%. The miss rates for advanced adenoma and cancer were 11.4% and 3.6%, respectively. Total number of polyps during index colonoscopy was an associated risk factor for missing an advanced lesion (odds ratio 1.176, 95% interval 1.062-1.303). CONCLUSIONS: Synchronous advanced neoplasms can be missed during endoscopic removal in patients with early colorectal cancer. Clinical significance of the first surveillance colonoscopy after endoscopic early colorectal cancer removal is detection of missed synchronous advanced neoplasms during index colonoscopy. PMID- 23803369 TI - Comparison of primarily diet-modifiable intestinal factors, connexin 43 and E cadherin with TP53 and TGFB1 in colorectal cancer. AB - BACKGROUND/AIMS: Primarily, a diet (particularly dietary lipids and vitamins) can reversibly modify intestinal expressions of a few factors like connexin 43 (Cx43), E-cadherin (Cdh1), TP53 and TGFB1 with a special impact on immunity and mutagenesis. Malignant phenotype constitutes a diet-resistant signal streaming with engagement of these molecules which are generated in autonomous ways in colorectal cancer. METHODOLOGY: We aimed to compare adhesion proteins: (Cx43) and Cdh1 with TP53 and TGFB1 in colorectal adenocarcinomas. GJA1P1 and Cdh1 with TP53 and TGFB1 were detected with immunohistochemistry in the study of 106 colorectal adenocarcinomas. RESULTS: There was aberrant cytoplasmic expression instead of membranous one of Cx43 and Cdh1 reflecting constitutive destruction of intercellular ties while TP53 showed nuclear expression and TGFB1 accumulated in the cytoplasm. TP53 did not correlate with Cx43 (r=0.083, p=0.397) but correlated with Cdh1 (r=0.199, p=0.041). Cdh1 associated with TGFB1 reaching almost statistical significance (r=0.188, p=0.054), while TGFB1 correlated with Cx43 (r=0.359, p=0.001). CONCLUSIONS: The consequent and constant impairment of cancer intercellular communication seems to engage correlated with each other expressions of Cx43 and TGFB1 in colorectal cancer cells. PMID- 23803370 TI - The lasso technique' - a simple intracorporeal two-port laparoscopic appendectomy: technical considerations and review of four other intracorporeal two-port techniques. AB - BACKGROUND/AIMS: To decrease surgical trauma and scar formation we present intracorporeal two-port procedure in selected patients. METHODOLOGY: Supraumbilical 5mm port is used for the laparoscope. Suprapubic 12mm port is in the midline or left paramedian position below the underpants line. Pretied loop suture is tied around the base, 1-2 cm distally from the origin of the appendix, or below the macroscopically changed appendix. Endoclose is introduced 1-2 cm cranially from the location of appendiceal base and the endoloop is exteriorized and the appendix elevated. Harmonic scalpel is used for dissection and skeletonization and the appendix is divided with 45 mm linear cutting stapler. RESULTS: Two-port appendectomy was attempted in 11 consecutive patients. In 3 patients operation was converted to open procedure and in 2 patients the third port was needed. Finally 6 (54%) patients were operated with the similar operating time (36-51 min) as standard three-port technique with the same postoperative pain and bowel function recovery. The postoperative stay ranged 2 - 4 days. There was one wound infection of 12-mm port. CONCLUSIONS: This intracorporeal two-port appendectomy in selected patients does not prolong operation time and further improves the minimal invasiveness and contributes to excellent cosmetic results. PMID- 23803371 TI - The activities of acid DNase and 5'nucleotidase in erosive reflux esophagitis and Barrett's epithelium. AB - BACKGROUND/AIMS: The study examines the relationship between activity of acid DNase and 5'nucleotidase (5'NT) and histological changes in reflux esophagitis. METHODOLOGY: Thirty-three patients were examined, 15 of whom with mild esophagitis, 12 with severe esophagitis and 6 with Barrett's epithelium. Patients were classified into 3 groups, according to Ismail-Beigi histological criteria: mild esophagitis group (ME); severe esophagitis group (SE); Barrett's esophagitis group (BE). DNase and 5'NT levels were measured biochemically both in healthy and injured tissue samples. RESULTS: Difference of acid DNase and 5'NT activity in healthy tissue versus injured tissue samples was the lowest in ME group: 0.55+/ 4.47 U/g for acid DNase and 11.56+/-37.11 U/g for 5'NT, the difference increased to 4.43+/-1.64 U/g for acid DNase and 105.57+/-54.11 U/g for 5'NT in the SE group, while 6.07+/-2.92 U/g for acid DNase and 109.83+/-14.02 U/g for 5'NT as the highest levels were measured in the BE group. Difference in BE group is statistically significantly higher (p <0.05) compared to the ME group, confirmed by ANOVA with Dunnett's post hoc test. CONCLUSIONS: The study shows significant decrease of apotosis level that is detectable even before metaplasia was morphologically defined. PMID- 23803372 TI - Maintenance treatment of mild gastroesophageal reflux disease with proton pump inhibitors taken on-demand: a meta-analysis. AB - BACKGROUND/AIMS: To evaluate the efficacy of on-demand strategy with proton pump inhibitors (PPIs) in mild gastroesophageal reflux disease (GERD). METHODOLOGY: A literature search was conducted to identify randomized controlled clinical trials which investigating on-demand treatment with PPIs in mild GERD. The control group should be placebo or once-daily treatment. Comparison of treatment effect was performed. RESULTS: Eight studies met the inclusion criteria, of which six were compared with placebo, two others with once-daily treatment. The percentage of patients unwilling to continue the study was 12.1% in the on-demand group while 39.6% in the placebo group. The meta-analysis revealed a statistically significant difference between the two groups (RR: 0.32; 95% CI: 0.23, 0.43). We obtained a similar result when compared with once-daily treatment (RR: 0.52; 95% CI: 0.34, 0.79). CONCLUSIONS: This meta-analysis indicates that on-demand therapy with PPIs is superior to placebo or once-daily treatment in terms of mild GERD. PMID- 23803373 TI - Evaluation of MELD score and Maddrey discriminant function for mortality prediction in patients with alcoholic hepatitis. AB - BACKGROUND/AIMS: Maddrey discriminant function (DF) is the traditional model for evaluating the severity and prognosis in alcoholic hepatitis (AH). However, MELD has also been used for this purpose. We aimed to determine the predictive parameters and compare the ability of Maddrey DF and MELD to predict short-term mortality in patients with AH. METHODOLOGY: Retrospective study of 45 patients admitted in our department with AH between 2000 and 2010. Demographic, clinical and laboratory parameters were collected. MELD and Maddrey DF were calculated on admission. Short-term mortality was assessed at 30 and 90 days. Student t-test, chi2 test, univariate analysis, logistic regression and receiver operating characteristic curves were performed. RESULTS: Thirty-day and 90-day mortality was 27% and 42%, respectively. In multivariate analysis, Maddrey DF was the only independent predictor of mortality for these two periods. Receiver operating characteristic curves for Maddrey DF revealed an excellent discriminatory ability to predict 30-day and 90-day mortality for a Maddrey DF greater than 65 and 60, respectively. Discriminatory ability to predict 30-day and 90-day mortality for MELD was low. CONCLUSIONS: AH remains associated with a high short-term mortality. Maddrey DF is a more valuable model than MELD to predict short-term mortality in patients with AH. PMID- 23803374 TI - Serum liver fatty acid binding protein shows good correlation with liver histology in NASH. AB - BACKGROUND/AIMS: Simple, reproducible and non-invasive tests that can be used to determine the severity of non-alcoholic steatohepatitis (NASH) are needed. Liver type fatty acid binding protein (L-FABP) plays a key role in the fatty acid metabolism of the liver. We aimed to determine whether serum L-FABP levels in patients with NASH were different from those in healthy controls, and if so, whether this was associated with the degree of fibrosis, steatosis and inflammatory activity. METHODOLOGY: Forty-seven patients with histologically confirmed NASH and 41 healthy controls were included in the study. Serum L-FABP levels were measured in all participants. RESULTS: Mean L-FABP levels were significantly higher in patients with NASH compared to the control group (2703.19+/-1603.47 vs. 1684.58+/-860.19, p<0.001). Serum L-FABP levels showed a significant positive correlation with NAS score (p=0.03, r=0.312), the degree of fibrosis (p=0.02, r=0.324) and inflammation (p=0.03, r=0.312), BMI (p=0.05, r=0.303), serum ALT (p=0.01, r=0.28), AST (p=0.04, r=0.315), and triglyceride levels (p=0.03, r=0.328). CONCLUSIONS: Serum L-FABP levels are elevated in NASH and this elevation is positively correlated with the degree of fibrosis and inflammation. L-FABP levels may aid as a non-invasive marker in determining the severity of fibrosis and inflammation in patients with NASH. PMID- 23803375 TI - Argon beam coagulation versus fibrin sealant for hemostasis following liver resection: a randomized study in a porcine model. AB - BACKGROUND/AIMS: Bleeding from the raw liver surface represents a significant surgical complication after elective liver resection or hepatic trauma. The application of argon beam coagulation (ABC) has been proposed to improve hemostasis, but is associated with significant necrosis of the liver parenchyma. Topical hemostatic agents, i.e. fibrin sealant (FS), have also been recommended, yet the optimal management is under debate. This study compares the efficacy and safety of both methods following liver resection in an animal model. METHODOLOGY: Twenty pigs underwent liver resection, and were then randomized into ABC or FS group for treatment of raw liver surfaces. Intraoperative and postoperative parameters were studied. Animals were sacrificed at day 12, and extent of necrosis was assessed using a scoring system and morphometry. RESULTS: Intraoperative parameters did not show any significant difference between two groups except for shorter time of application in the FS group. Postoperatively, animals in the FS group showed significantly higher hemoglobin levels (p=0.0001). Histologically, FS showed a smaller depth of necrosis than ABC (p=0.022). CONCLUSIONS: The use of FS is superior to ABC for management of the raw liver surface after liver resection, in terms of application time, postoperative bleeding and the extent of liver tissue necrosis. PMID- 23803376 TI - Polymorphisms of interferon gamma gene and risk of hepatocellular carcinoma in korean patients with chronic hepatitis B viral infection. AB - BACKGROUNDS/AIMS: Increasing evidence supports the contribution of the pro-/anti inflammatory cytokine balance and genetic factors to hepatocellular carcinoma (HCC). Here, we investigated whether genetic interferon gamma polymorphisms were associated with HCC in Korean patients with chronic hepatitis B. METHODOLOGY: We genotyped a single nucleotide polymorphism (SNP, rs2430561, +874A/T) and a microsatellite (rs3138557, (CA)n repeat), located in the first intron of the interferon gamma gene, by direct sequencing and the gene scan method. A population-based case-control study of HCC was conducted and included 170 patients with chronic hepatitis and HCC, and 171 with chronic hepatitis B patients without hepatocellular carcinoma in a Korean population. RESULTS: Genotype and allele distributions of the interferon gamma gene SNP were associated with HCC. The frequencies of the AA genotype and the A allele were significantly increased in hepatocellular carcinoma subjects (p<0.05). Combined analysis using the genotype of rs2430561 and the number of microsatellites revealed that the frequencies of AT-CA12 and TT-CA12 increased significantly in hepatocellular carcinoma subjects (p<0.0001). CONCLUSIONS: Our results suggest that the interferon gamma gene may be a susceptibility gene and a risk factor for HCC in the Korean population. PMID- 23803377 TI - Significance of incorporation of model for end-stage liver disease score with TNM staging in patients with hepatocellular carcinoma undergoing hepatic resection. AB - BACKGROUND/AIMS: Currently, the tumor-node-metastasis (TNM) system is used in hepatectomy patients for tumor staging of HCC patients. However this can only evaluate the histopathological factor. MELD score is an objective measure for liver function widely used as a severity index for priority on the waiting list for liver transplantation. Here we suggest a modified TNM staging system based on the MELD score and test its relation with post-operative outcome of HCC. METHODOLOGY: We retrospectively collected 922 HCC patients undergoing hepatic resection, with TNM stage I (n=239), stage II (n=375) and stage III (n=308); giving points 0 to 2 for each stage (from I to III). Pre-operative MELD score was calculated and assigned 0 points for MELD <6; 1 for 6-8; 2 for >8. The two scores were added together to form a modified MELD-base TNM stage score and tested the correlation of this new scoring system with outcome after liver resection. RESULTS: The modified MELD-base TNM stage score resulted in score 0 (n=114), score 1 (n=247), score 2 (n=335), score 3 (n=164), and score 4 (n=62). The disease-free survival in each group showed significant difference (p<0.05), the lower the score, the better the outcome. CONCLUSIONS: The MELD-based TNM staging system reliably separates patients with HCC into homogeneous groups with respect to post-resectional prognosis. Further prospective validation studies are required to confirm the feasibility of this strategy. PMID- 23803378 TI - Hepatocyte growth on polycapronolactone and 2-hydroxyethylmethacrylate nanofiber sheets enhanced by bone marrow-derived mesenchymal stromal cells. AB - BACKGROUND/AIMS: The development of hepatocyte-based Bioartificial Liver Assist Devices, intended for the therapy of chronic and fulminant liver failure, is one of the important tasks in the area of tissue engineering. New advances in the development of semipermeable non-woven nanofiber biomaterials and the co cultivation of bone marrow mesenchymal stromal cells (BMSC) and hepatocytes could be utilized in order to maintain hepatocyte cultures in these devices. METHODOLOGY: We have compared rat hepatocyte growth on nanofiber biomaterials from different polymers, 2-hydroxyethylmethacrylate (HEMA) and ethoxyethylmethacrylate (EOEMA) copolymers, polyurethane (PUR), chitosan and polycapronolactone (PCL) spun from different solvent mixtures. RESULTS: In all cases the adhesion of hepatocytes to nanofibers was significantly better/stronger than to unstructured polymer surfaces; coating the nanofibers with collagen did not increase cell adhesion. We found the best hepatocyte adhesion on HEMA/EOEMA copolymer nanofibers and PCL nanofibers spun from a mixture of ethylacetate and dimethyl sulphoxide. Using a migration assay, we observed the migration of BMSC towards hepatocytes; hepatocytes cocultivated with BMSC excreted lower amounts of stress enzymes. CONCLUSIONS: The results demonstrate that nonwoven nanofiber layers, particularly those containing BMSC, are a suitable biocompatible support for functional hepatocyte cultures and that they can be used in a laboratory bioreactor or potentially in clinical setting. PMID- 23803379 TI - Lower incidence of hepatic metastases of colorectal cancer in patients with chronic liver diseases: meta-analysis. AB - BACKGROUND/AIMS: The rarity of metastatic malignancy in injured liver has been noticed. This meta-analysis evaluates the difference in occurrence of metastatic colorectal cancer in healthy and chronically injured liver. METHODOLOGY: Literature search of occurrence of metastatic colorectal cancer in chronically injured liver opposed to healthy liver was conducted. Chronically injured/damaged liver included cirrhosis, steatosis or fatty liver and infection with Hepatitis virus B or C. RESULTS: A total of 7 retrospective studies between 1992 and 2010 matched the selection criteria with total of 4049 patients. Results suggest significantly lower incidence of colorectal metastasis in chronically injured liver (Pooled odds ratio = 0.260 (95% CI = 0.18 to 0.38); chi2 (test odds ratio differs from 1) = 45.90 (df = 1); p <0.0001). CONCLUSIONS: Patients with chronic liver injury have significantly lower occurrence of hepatic metastasis of primary colorectal cancer than the patients with healthy liver. PMID- 23803380 TI - Inhibiting K-ras signaling reserves the epithelial-mesenchymal transition of pancreatic cancer cells and its mechanisms. AB - BACKGROUND/AIMS: To investigate the effects of K-ras siRNA on pancreatic cancer cells and the expression levels of GLI1, E-cadherin and vimentin in pancreatic cancer cells transfected with K-ras siRNA. METHODOLOGY: Ppancreatic cancer cells PANC-1 were transfected with K-ras siRNA. Growth inhibition ratio of the cells were measured by MTT assay, apoptosis was detected by flow cytometery, expression level of GLI1, E-cadherin and vimentin were detected by Western blot. RESULTS: The expression of K-ras protein was efficiently inhibited by K-ras siRNA in PANC 1 cells. The growth inhibition rates of the cells were significantly different to the control groups. Apoptosis rates were significantly different with that of control group. The expression of GLI1 was significantly down-regulated, E cadherin was up-regulated, while vimentin was also down-regulated in K-ras siRNA transfected cells compared with that of control groups. CONCLUSIONS: Inhibiting K ras signaling by K-ras siRNA can inhibit proliferation and induce apoptosis of pancreatic cancer cells, down-regulate GLI1's and vimentin's expression, and up regulate E-cadherin's expression. Inhibiting K-ras signaling by K-ras siRNA may reduce epithelial to mesenchymal transition of pancreatic cancer cell PANC-1. PMID- 23803381 TI - Comparison of results between pylorus-preserving pancreaticoduodenectomy and subtotal stomach-preserving pancreaticoduodenectomy: report at a single cancer institute. AB - BACKGROUND/AIMS: Pylorus-preserving pancreaticoduodenectomy (PPPD) has the advantage of achieving good nutritional status postoperatively, but delayed gastric empty (DGE) is a frequent complication leading to a longer fasting period. Subtotal stomach-preserving pancreaticoduodenectomy (SSPPD) is an alternative option to preserve nutritional status and shorten the fasting period. We retrospectively compared clinical results between PPPD and SSPPD. METHODOLOGY: PPPD was performed in 28 patients and SSPPD in 27, between 2000 and 2009. RESULTS: Pancreatic carcinoma was more frequent in the SSPPD group (p = 0.041). Operating time was longer in the SSPPD group (610 min) than in the PPPD group (540 min; p = 0.031). Blood loss was greater in the SSPPD group (1810 mL) than in the PPPD group (1306 mL; p = 0.048). Period of NG intubation and fasting period were shorter in the SSPPD group (6 days and 9 days, respectively) compared to the PPPD group (15 days and 19 days, respectively; p <0.01 each). Severe DGE was 7% in the SSPPD group and 46% in the PPPD group (p <0.01). Postoperative complications and nutritional status in the early period did not differ between groups, although incidence of fatty liver was higher in the SSPPD group (78%) than in the PPPD group (25%; p <0.01). CONCLUSIONS: SSPPD is a useful alternative for pancreaticoduodenectomy. Further prospective studies with longer follow-up are warranted to clarify the superiority and problems associated with this procedure. PMID- 23803382 TI - The importance of invasion and resection of superior mesenteric and portal veins in adenocarcinoma of the pancreas. AB - BACKGROUND/AIMS: To achieve a negative surgical margin, resection of superior mesenteric/portal vein is necessary in pancreatic cancer. This study is designed to demonstrate the demographic and clinical differences of the patients requiring major vein resection and the incidence of histopathological vein invasion. METHODOLOGY: A retrospective analysis of patients that underwent pancreaticoduodenectomy for adenocarcinoma of the pancreas between January 2000 and September 2011 was performed. Macroscopic adhesion to vein was considered as an invasion and a resection was performed. RESULTS: Twenty three of 100 patients that underwent pancreaticoduodenectomy for adenocarcinoma of the pancreas had vein resection. Although the operation time (p=0.001), blood loss (p<0.001) and perioperative blood transfusion (p<0.001) were higher in the vein resection group, there were no differences in perioperative and hospital mortality, complication rate and hospitalization time. The tumor was larger (p=0.001) and lymphovascular invasion (p=0.030), perineural invasion (p=0.011), median metastatic lymph nodes (p=0.007), rate of R1 resection (p=0.007) were higher in vein resection group. Only 9 patients out of 23 patients had histopathological vein wall invasion. Overall survival was also not significantly different (p=0.14). CONCLUSIONS: Overall survival in vein resected group was also not significantly different than patients with standard pancreaticoduodenectomy and not all macroscopic vein adhesion means histopathological vein wall invasion. PMID- 23803383 TI - Antiproliferative effect of 1alpha,25-dihydroxyvitamin D3 involves upregulation of cyclin-dependent kinase inhibitor p21 in human pancreatic cancer cells. AB - BACKGROUND/AIMS: The aim of this study was to investigate the effect of 1alpha,25 dihydroxyvitamin D3 on proliferation of human pancreatic cancer cell lines and to identify related cell cycle regulatory proteins with antiproliferative effects. METHODOLOGY: Human pancreatic cancer cell lines SUIT-2 and its four sublines, and Panc-1, AsPC-1, and MiaPaCa-2 were treated with1alpha,25-dihydroxyvitamin D3. The number of cells was measured by the MTT method, and the cell cycle regulatory proteins were then analyzed by Western blotting. RESULTS: Eight human pancreatic cancer cell lines expressed vitamin D receptor (VDR) mRNA. 1alpha,25 dihydroxyvitamin D3 inhibited proliferation of SUIT-2 and its sublines. We found p21 to be upregulated after 24 hours in S2-028, the cell line in which proliferation was most inhibited by 1alpha,25-dihydroxyvitamin D3. CONCLUSIONS: 1alpha,25-dihydroxyvitamin D3 inhibited proliferation of pancreatic cancer cells and is involved in the upregulation of cyclin-dependent kinase inhibitor p21. PMID- 23803384 TI - Laparoscopic pancreatic resection without advanced laparoscopic devices. AB - BACKGROUND/AIMS: Laparoscopic pancreatic resection has been slow to develop because of the high degree of technical difficulty and generally expensive laparoscopic devices required. We evaluate our experience with laparoscopic resections for pancreatic pathologies without expensive and advanced laparoscopic devices. METHODOLOGY: A prospective evaluation was carried out of consecutive laparoscopic pancreatic resections performed between July 2003-June 2011. RESULTS: Laparoscopic pancreatic resections were attempted in 13 and performed in 10 patients: 6 laparoscopic spleen-preserving distal pancreatectomy and 4 laparoscopic enucleation. Pathological diagnoses: four insulinomas, two serous cystadenoma, two pancreatic pseudocyst, one microcystic serous cystadenoma, two non-functioning neuroendocrine tumors, one leiomyosarcoma, and one case of solid pseudopapillary tumor. In the laparoscopic operations the mean operative time was 195min and no blood transfusions were required. The mean postoperative hospital stay was 4.7 days. There were three pancreatic fistulas. No patients required a second operation. There were no deaths. Follow-up was available for all patients. CONCLUSIONS: Laparoscopic pancreatic resection is feasible and relatively safe without advanced laparoscopic devices. As with open resections, pancreatic fistula is the dominant morbidity. The best indications for a laparoscopic approach are benign pancreatic tumors that are not inside the neck of the pancreas and do not require pancreaticoenteric reconstruction. PMID- 23803385 TI - Predictive parameters of intraoperative blood loss in patients who underwent pancreatectomy. AB - BACKGROUND/AIMS: Despite recent advances in surgical techniques, blood loss is an important factor associated with postoperative outcomes in pancreatectomy. It is useful to identify risk factors of increased blood loss. METHODOLOGY: The clinical records of 161 patients who underwent an elective pancreatectomy for peripancreatic diseases between 1994 and March 2011 were retrospectively examined. Univariate and multivariate analysis of clinicopathological and surgical parameters influencing intraoperative blood loss were performed. We determined the cut-off value of the amount of blood loss based on the analyzed results. RESULTS: The mean and median blood loss was 1346+/-901 and 1070 mL, respectively. Red cell blood transfusion was performed in 72 patients (45%). Based on ROC analysis, the predictive value of blood loss in patients who received red cell blood transfusion was 880 mL (p <0.001); however, blood loss was not significantly associated with postoperative complications (p = 0.40). The cut-off level of estimated amount of blood loss in the present study was set at 880 mL. Male patients, fatty pancreas, higher serum alkaline phosphatase level, longer operating time, performance of pancreaticoduodenectomy (PD) and combined resections of adjacent major vessels were associated with significantly more increased blood loss (p <0.05). Based on multivariate analysis, longer operation time over 480 minutes and performance of PD were significantly associated with increased blood loss (p <0.05). CONCLUSIONS: Attempting to reduce operating time in cases of PD is necessary to reduce intraoperative blood loss. PMID- 23803386 TI - Rupture of pseudoaneurysm into hepaticojejunal anastomosis: report of three cases. AB - Bleeding complications are less common after major pancreatic resections. They are more often associated with pancreatic fistula. The authors present three cases of a unique situation, when pseudoaneurysm of the common hepatic artery ruptured into the hepaticojejunal anastomosis, causing massive upper gastrointestinal haemorrhage. The basic operations were pancreatic resections for malignancy. In two out of the three cases intra-abdominal infection developed postoperatively. Computer tomographic angiography was a useful tool to reveal the source of bleeding. A re-do surgery was carried out whereby bleeding control was achieved with haemostatic sutures and the biliodigestive anastomoses were also repaired. Re-bleeding did not occur postoperatively and the liver function remained normal. The authors emphasize that in case of severe gastrointestinal bleeding after pancreatic resection, this rare entity ought to be taken into account in the differential diagnosis. PMID- 23803388 TI - When the threat comes from inside the body: a neuroscience based learning perspective of the etiology of panic disorder. AB - Unexpected, recurrent panic attacks and anxious apprehension are two distinct emotional phenomena that constitute the core symptoms for diagnosing panic disorder. Taking a neuroscience perspective the current review paper presents both epidemiological and experimental psychophysiological evidence suggesting that panic attacks can be conceptualized as an unconditioned circa defense response pattern to intense internal threat stimuli, characterized by strong autonomic surge and escape behavior and abnormal plastic changes of the brain. Anxious apprehension develops after the experience of such severe panic attacks as conditioned responses to mild body symptoms. Theoretically these conditioned fear responses can be considered as post-encounter defense characterized by increased selective attention, increased threat appraisal and defensive freezing and startle potentiation evidencing altered brain circuits evoked by mild body symptoms. Agoraphobic avoidance starts very early during the defensive cascade and can be conceived as motivated behavior driven by the incentive to be in a safe context that is under control of the individual. PMID- 23803387 TI - New insights into mechanisms behind miscarriage. AB - Sporadic miscarriage is the most common complication of early pregnancy. Two or three consecutive pregnancy losses is a less common phenomenon, and this is considered a distinct disease entity. Sporadic miscarriages are considered to primarily represent failure of abnormal embryos to progress to viability. Recurrent miscarriage is thought to have multiple etiologies, including parental chromosomal anomalies, maternal thrombophilic disorders, immune dysfunction and various endocrine disturbances. However, none of these conditions is specific to recurrent miscarriage or always associated with repeated early pregnancy loss. In recent years, new theories about the mechanisms behind sporadic and recurrent miscarriage have emerged. Epidemiological and genetic studies suggest a multifactorial background where immunological dysregulation in pregnancy may play a role, as well as lifestyle factors and changes in sperm DNA integrity. Recent experimental evidence has led to the concept that the decidualized endometrium acts as biosensor of embryo quality, which if disrupted, may lead to implantation of embryos destined to miscarry. These new insights into the mechanisms behind miscarriage offer the prospect of novel effective interventions that may prevent this distressing condition. PMID- 23803389 TI - Assessment of the performances of AcuStar HIT and the combination with heparin induced multiple electrode aggregometry: a retrospective study. AB - BACKGROUND: Early diagnosis of immune heparin-induced thrombocytopenia (HIT) is challenging. HemosIL(r) AcuStar HIT and heparin-induced multiple electrode aggregometry (HIMEA) were recently proposed as rapid diagnostic methods. OBJECTIVES: We conducted a study to assess performances of AcuStar HIT-IgG (PF4 H) and AcuStar HIT-Ab (PF4-H). The secondary objective was to compare the performances of the combination of Acustar HIT and HIMEA with standardised clinical diagnosis. METHODS: Sera of 104 suspected HIT patients were retrospectively tested with AcuStar HIT. HIMEA was performed on available sera (n=81). The clinical diagnosis was established by analysing in a standardized manner the patient's medical records. These tests were also compared with PF4 Enhanced(r), LTA, and SRA in subsets of patients. Thresholds were determined using ROC curve analysis with clinical outcome as reference. RESULTS: Using the recommended thresholds (1.00AU), the negative predictive value (NPV) of HIT-IgG and HIT-Ab were 100.0% (95% CI: 95.9%-100.0% and 95.7%-100.0%). The positive predictive value (PPV) were 64.3% (95% CI: 35.1%-87.2.2%) and 45.0% (95% CI: 23.2%-68.6%), respectively. Using our thresholds (HIT-IgG: 2.89AU, HIT-Ab: 9.41AU), NPV of HIT-IgG and HIT-Ab were 100.0% (95% CI: 96.0%-100.0% and 96.1% 100.0%). PPV were 75.0% (95% CI: 42.7%-94.5%) and 81.8% (95% CI: 48.3%-97.7%), respectively. Of the 79 patients with a medium-high pretest probability score, 67 were negative using HIT-IgG (PF4-H) test at our thresholds. HIMEA was performed on HIT-IgG positive patients. Using this combination, only one patient on 79 was incorrectly diagnosed. CONCLUSION: Acustar HIT showed good performances to exclude the diagnosis of HIT. Combination with HIMEA improves PPV. PMID- 23803390 TI - The challenge of the "estrogen paradox" in pulmonary arterial hypertension. PMID- 23803391 TI - Improvement of pneumatosis cystoides intestinalis after steroid tapering in a patient with bronchial asthma: a case report. AB - INTRODUCTION: We report the case of a patient who was diagnosed as having pneumatosis cystoides intestinalis while being treated with prednisolone for bronchial asthma. Even before we had experienced a case of this, the relationship between pneumatosis cystoides intestinalis and prednisolone was unclear. In this case, pneumatosis cystoides intestinalis was improved with the reduction of prednisolone, and therefore we thought a direct relationship between pneumatosis cystoides intestinalis and prednisolone might become clear, such as whether it is dose dependent. CASE PRESENTATION: A 62-year-old Japanese woman had been treated for bronchial asthma for approximately 40 years. She presented with abdominal distension, and a radiographic examination showed intraperitoneal free gas and intramural gas, suggestive of pneumatosis cystoides intestinalis. However, when her prednisolone dose was decreased from 30 mg to 0 mg for approximately a year because of improvement in her asthma symptoms, her abdominal symptom resolved, and the frequency of her bowel movements returned to normal. CONCLUSION: Amelioration of pneumatosis cystoides intestinalis was observed with tapering of the prednisolone, suggesting that prednisolone may have been involved in the pathogenesis of pneumatosis cystoides intestinalis in this patient. PMID- 23803392 TI - Energy levels of interacting curved nanomagnets in a frustrated geometry: increasing accuracy when using finite difference methods. AB - The accuracy of finite difference methods is related to the mesh choice and cell size. Concerning the micromagnetism of nano-objects, we show here that discretization issues can drastically affect the symmetry of the problem and therefore the resulting computed properties of lattices of interacting curved nanomagnets. In this paper, we detail these effects for the multi-axis kagome lattice. Using the OOMMF finite difference method, we propose an alternative way of discretizing the nanomagnet shape via a variable moment per cell scheme. This method is shown to be efficient in reducing discretization effects. PMID- 23803393 TI - German medical students' beliefs about the effectiveness of different methods of stopping smoking. AB - INTRODUCTION: In many countries, smoking cessation interventions are not routinely delivered as recommended in national and international guidelines. This may be because of incorrect beliefs about their effectiveness. This study assessed which cessation methods are believed to be effective by medical students in different years of undergraduate education as well as predictors of correct beliefs about effectiveness. METHODS: In this cross-sectional study, undergraduate students from 27 German medical schools were invited to complete a survey addressing demographic characteristics, smoking status, self-rated knowledge of health consequences, and treatment options for smoking and beliefs about the effectiveness of 8 different methods to achieve long-term smoking cessation. Predictors of beliefs were identified by means of multilevel modeling. RESULTS: A total of 19,526 students completed the survey. Students greatly overestimated the effectiveness of unaided quitting, and differences between years of undergraduate education were small. In the final year, 51% of students wrongly believed that willpower alone was more effective than a comprehensive group cessation program, including nicotine replacement therapy. Multilevel modeling revealed that having never smoked, supporting public smoking bans, and recalling theoretical training in smoking cessation were associated with correct beliefs. CONCLUSIONS: A considerable proportion of German medical students believe that willpower alone is more effective than comprehensive treatment programs to support a quit attempt. PMID- 23803395 TI - The future of health service delivery and policy development. Editorial. PMID- 23803394 TI - Impact of cigarette smoking on utilization of nursing home services. AB - INTRODUCTION: Few studies have examined the effects of smoking on nursing home utilization, generally using poor data on smoking status. No previous study has distinguished utilization for recent from long-term quitters. METHODS: Using the Health and Retirement Study, we assessed nursing home utilization by never smokers, long-term quitters (quit >3 years), recent quitters (quit <=3 years), and current smokers. We used logistic regression to evaluate the likelihood of a nursing home admission. For those with an admission, we used negative binomial regression on the number of nursing home nights. Finally, we employed zero inflated negative binomial regression to estimate nights for the full sample. RESULTS: Controlling for other variables, compared with never-smokers, long-term quitters have an odds ratio (OR) for nursing home admission of 1.18 (95% CI: 1.07 1.2), current smokers 1.39 (1.23-1.57), and recent quitters 1.55 (1.29-1.87). The probability of admission rises rapidly with age and is lower for African Americans and Hispanics, more affluent respondents, respondents with a spouse present in the home, and respondents with a living child. Given admission, smoking status is not associated with length of stay (LOS). LOS is longer for older respondents and women and shorter for more affluent respondents and those with spouses present. CONCLUSIONS: Compared with otherwise identical never smokers, former and current smokers have a significantly increased risk of nursing home admission. That recent quitters are at greatest risk of admission is consistent with evidence that many stop smoking because they are sick, often due to smoking. PMID- 23803396 TI - Gambling: a unique policy challenge. PMID- 23803398 TI - Medication use among Canadian seniors. AB - As they age, many seniors develop a progressively more complex mix of health conditions. Multiple prescription medications are often required to help manage these conditions and control symptoms, with the goal of maintaining seniors' health for as long as possible. This article explores trends in the number and types of medications used by seniors on public drug programs in Canada. Our findings suggest that a high proportion of Canadian seniors are taking several medications, highlighting the need for medication management systems focusing on this population. PMID- 23803399 TI - The Institute for Clinical Evaluative Sciences: 20 years and counting. PMID- 23803400 TI - In conversation with Howard Waldner. Interview by Ken Tremblay. PMID- 23803401 TI - Taking the pulse of lean healthcare. PMID- 23803402 TI - Alberta Health Services: journey to accreditation. AB - In October 2010, Alberta Health Services (AHS) successfully completed phase one of its journey to accreditation, meeting 683 of 774 criteria and earning Accreditation with Condition. AHS entered accreditation during its infancy (18 months, to be exact) in an environment shaped by seismic organizational and structural changes. In this article, the authors share some of the successes, challenges and ongoing opportunities that have emerged during the first years of AHS's accreditation journey, as well as details of the strong collaborative relationship between AHS and Accreditation Canada. PMID- 23803403 TI - Inter-professional collaboration as a health human resources strategy: moving forward with a western provinces research agenda. AB - The current gap in research on inter-professional collaboration and health human resources outcomes is explored by the Western Canadian Interprofessional Health Collaborative (WCIHC). In a recent research planning workshop with the four western provinces, 82 stakeholders from various sectors including health, provincial governments, research and education engaged with WCIHC to consider aligning their respective research agendas relevant to inter-professional collaboration and health human resources. Key research recommendations from a recent knowledge synthesis on inter-professional collaboration and health human resources as well as current provincial health priorities framed the discussions at the workshop. This knowledge exchange has helped to consolidate a shared current understanding of inter-professional education and practice and health workforce planning and management among the participating stakeholders. Ultimately, through a focused research program, a well-aligned approach between sectors to finding health human resources solutions will result in sustainable health systems reform. PMID- 23803404 TI - An extra-organizational mentorship pilot for Canadian health leaders. AB - There are two sectors in the Canadian health ecosystem: the public sector, composed of hospitals, and the private sector, consisting of suppliers of drugs and services; both are aimed at providing optimal patient care. Currently, both sectors are struggling with the uncertainty and unpredictability plaguing the health environment. A mentoring pilot was aimed at providing solutions for both sectors by strengthening leadership development and accelerating the relationships with organizations from the other sector. The extra-organizational mentoring program included people from Roche Canada (private sector) and hospitals (public sector) whose participants are members of the Canadian College of Health Leaders. An evaluation of the program demonstrated that it was a positive and productive leadership development process for the majority of participants. The mentoring pilot helped advance partnerships based on trust and respect across the two sectors. The pragmatic process and demonstrable success of the program have gained far-reaching attention, and the program has influenced the development of other mentorship initiatives. Extra-organizational mentoring should be encouraged and actively developed with other health organizations. PMID- 23803405 TI - Hospital-legal partnership at Toronto Hospital for Sick Children: the first Canadian experience. AB - Operating a hospital-legal partnership on a pro bono basis positively impacts patients' families by providing legal assistance for non-medical issues that affect the health of their children and their ability to care for their children. This article describes a formative evaluation of the first hospital-legal partnership in Canada, established at The Hospital for Sick Children in Toronto in 2009, which was carried out through file reviews and interviews with staff, lawyers and family members. The early indications of success of this partnership suggest that its use as a template for similar programs at other Canadian healthcare institutions should be considered. PMID- 23803406 TI - Understanding the patients' perspective of emotional support to significantly improve overall patient satisfaction. AB - This article presents the results of a research study that laid out important considerations for organizations to improve their patient satisfaction scores. It addresses a dimension of patient satisfaction that appears to garner little attention in healthcare contexts: emotional support. Though the literature strongly suggests that emotional support is correlated to overall patient satisfaction, few organizations have systematically attempted to understand the elements of outstanding emotional support. Research at a community teaching hospital in Ontario has shed light on the essential components of emotional support. In this article, a typology of emotional support is offered. With a better understanding of the components of emotional support, organizations may be able to undertake actions that could potentially improve patient satisfaction scores and, in turn, the overall quality of patient care. PMID- 23803407 TI - Are the creation and maintenance of databases in healthcare worthwhile? An example of a unique, population-based, radiation therapy database. AB - A population-based prospective database targeting 15 key radiation therapy (RT) features was initiated in British Columbia in 1984. This 25-year outcome report assessed the utility of the database and demonstrated that such a database can be used to (1) describe population-based utilization of a health service, (2) inform treatment policy recommendations, (3) inform system planning and resource allocation, (4) audit regional and individual oncology practices, (5) assess whether new observations from randomized trials have been translated into population health gains and (6) produce peer-reviewed publications. Health system managers and researchers could benefit from the development and support of such databases. PMID- 23803408 TI - Tissue motion annular displacement of the mitral valve using two-dimensional speckle tracking echocardiography predicts the left ventricular ejection fraction in normal children. AB - BACKGROUND: The gold standard for determining the left ventricular ejection fraction is cardiac magnetic resonance imaging. Other parameters for determining the ejection fraction such as M-mode echocardiography are operator-dependant and often inaccurate. Assessment of the displacement of the mitral valve annulus using two-dimensional speckle tracking echocardiography may provide an accurate and simple method of determining the left ventricular ejection fraction in children. METHOD: We retrospectively studied 70 healthy 9-year-old children with no history of cardiovascular disease who had been assessed using cardiac magnetic resonance imaging and two-dimensional transthoracic echocardiography. Mitral displacement was determined using the tissue motion annular displacement (TMAD) feature of Philips QLAB version 9. The midpoint displacement of the mitral valve was calculated, and the predicted left ventricular ejection fraction was compared with magnetic resonance imaging-derived and M-mode-derived ejection fractions. RESULTS: The mean ejection fraction derived from magnetic resonance imaging (64.5 (4.6)) was similar to that derived from the TMAD midpoint (60.9 (2.7), p = 0.001) and the M-mode (61.9 (7), p = 0.012). The TMAD midpoint correlated strongly with the magnetic resonance imaging-derived ejection fraction (r = 0.69, p < 0.001), as did the predicted fraction (r = 0.67, p < 0.001). The M-mode ejection fraction showed a poor linear correlation with both magnetic resonance imaging-derived and TMAD-derived fractions (r = 0.33 and 0.04, respectively). CONCLUSION: TMAD of the mitral valve is a simple, effective, and highly reproducible method of assessing the ejection fraction in normal children. It shows a strong linear correlation with magnetic resonance imaging-derived ejection fraction and is superior to M mode-derived ejection fractions. PMID- 23803409 TI - A novel activation-induced cytidine deaminase (AID) mutation in Brazilian patients with hyper-IgM type 2 syndrome. AB - Activation-induced cytidine deaminase (AID) is a DNA editing protein that plays an essential role in three major events of immunoglobulin (Ig) diversification: somatic hypermutation, class switch recombination and Ig gene conversion. Mutations in the AID gene (AICDA) have been found in patients with autosomal recessive Hyper-IgM (HIGM) syndrome type 2. Here, two 9- and 14-year-old Brazilian sisters, from a consanguineous family, were diagnosed with HIGM2 syndrome. Sequencing analysis of the exons from AICDA revealed that both patients are homozygous for a single C to G transversion in the third position of codon 15, which replaces a conserved Phenylalanine with a Leucine. To our knowledge, this is a new AICDA mutation found in HIGM2 patients. Functional studies confirm that the homologous murine mutation leads to a dysfunctional protein with diminished intrinsic cytidine deaminase activity and is unable to rescue CSR when introduced in Aicda(-/-)stimulated murine B cells. We briefly discuss the relevance of AICDA mutations found in patients for the biology of this molecule. PMID- 23803410 TI - Conformational mobility of active and E-64-inhibited actinidin. AB - BACKGROUND: Actinidin, a protease from kiwifruit, belongs to the C1 family of cysteine proteases. Cysteine proteases were found to be involved in many disease states and are valid therapeutic targets. Actinidin has a wide pH activity range and wide substrate specificity, which makes it a good model system for studying enzyme-substrate interactions. METHODS: The influence of inhibitor (E-64) binding on the conformation of actinidin was examined by 2D PAGE, circular dichroism (CD) spectroscopy, hydrophobic ligand binding assay, and molecular dynamics simulations. RESULTS: Significant differences were observed in electrophoretic mobility of proteolytically active and E-64-inhibited actinidin. CD spectrometry and hydrophobic ligand binding assay revealed a difference in conformation between active and inhibited actinidin. Molecular dynamics simulations showed that a loop defined by amino-acid residues 88-104 had greater conformational mobility in the inhibited enzyme than in the active one. During MD simulations, the covalently bound inhibitor was found to change its conformation from extended to folded, with the guanidino moiety approaching the carboxylate. CONCLUSIONS: Conformational mobility of actinidin changes upon binding of the inhibitor, leading to a sequence of events that enables water and ions to protrude into a newly formed cavity of the inhibited enzyme. Drastic conformational mobility of E 64, a common inhibitor of cysteine proteases found in many crystal structures stored in PDB, was also observed. GENERAL SIGNIFICANCE: The analysis of structural changes which occur upon binding of an inhibitor to a cysteine protease provides a valuable starting point for the future design of therapeutic agents. PMID- 23803411 TI - Geniposide decreases the level of Abeta1-42 in the hippocampus of streptozotocin induced diabetic rats. AB - Although cognitive dysfunction in diabetic patients has been explored extensively, diabetic complications of the central nervous system have not been studied. We have reported previously that geniposide has neurotrophic and neuroprotective activities with the activation of glucagons-like peptide 1 receptor, and regulates glucose-stimulated insulin secretion in vitro. But the role of geniposide on diabetic complications, especially on the neurodegenerative diseases, remains to be investigated. In this study, we investigated the effect of geniposide on the level of Abeta1-42 in the hippocampi of streptozotocin induced diabetic rats and explored its possible mechanism. The results demonstrated that, accompanied with the improvement of insulin and blood glucose, treatment with geniposide decreased the Abeta1-42 level and improved the expression of insulin-degrading enzyme, which is the key degrading enzyme of Abeta peptide. The results of present study will help to understand the biochemical mechanisms of neuronal dysfunction and death in diabetes and to develop an efficient therapeutic strategy on Alzheimer's disease. PMID- 23803412 TI - Ganoderma lucidum stimulates NK cell cytotoxicity by inducing NKG2D/NCR activation and secretion of perforin and granulysin. AB - Ganoderma lucidum (G. lucidum) is a medicinal mushroom long used in Asia as a folk remedy to promote health and longevity. Recent studies indicate that G. lucidum activates NK cells, but the molecular mechanism underlying this effect has not been studied so far. To address this question, we prepared a water extract of G. lucidum and examined its effect on NK cells. We observed that G. lucidum treatment increases NK cell cytotoxicity by stimulating secretion of perforin and granulysin. The mechanism of activation involves an increased expression of NKG2D and natural cytotoxicity receptors (NCRs), as well as increased phosphorylation of intracellular MAPKs. Our results indicate that G. lucidum induces NK cell cytotoxicity against various cancer cell lines by activating NKG2D/NCR receptors and MAPK signaling pathways, which together culminate in exocytosis of perforin and granulysin. These observations provide a cellular and molecular mechanism to account for the reported anticancer effects of G. lucidum extracts in humans. PMID- 23803413 TI - Inflammatory response to Porphyromonas gingivalis partially requires interferon regulatory factor (IRF) 3. AB - Innate immune activation with expression of pro-inflammatory molecules such as TNF-alpha is a hallmark of the chronic inflammation associated with periodontal disease (PD). Porphyromonas gingivalis, a bacterium associated with PD, engages TLRs and activates MyD88-dependent and TIR-domain-containing adapter-inducing IFN beta (TRIF)-dependent signaling pathways. IFN regulatory factor (IRF) 3 is activated in a TRIF-dependent manner and participates in production of cytokines such as TNF-alpha; however, little is known regarding IRF3 and the host response to PD pathogens. We speculated that IRF3 participates in the host inflammatory response to P. gingivalis. Our results show that bone marrow macrophages (MO) from WT mice respond to P. gingivalis with activation and nuclear translocation of IRF3. Compared with WT, MO from IRF3(-/-), TRIF(-/-), and TLR4(-/-) mice responded with reduced levels of TNF-alpha on P. gingivalis challenge. In addition, full expression of IL-6 and RANTES by MO to P. gingivalis was dependent on IRF3. Lastly, employing MO from IRF3(-/-) and IRF7(-/-) mice we observed a significant role for IRF3 and a modest role for IRF7 in the P. gingivalis elicited TNF-alpha response. These studies identify a role for IRF3 in the inflammatory response by MO to the periodontal pathogen P. gingivalis. PMID- 23803415 TI - Garcinol, a polyisoprenylated benzophenone modulates multiple proinflammatory signaling cascades leading to the suppression of growth and survival of head and neck carcinoma. AB - Constitutive activation of proinflammatory transcription factors such as STAT3 and NF-kappaB plays a pivotal role in the proliferation and survival of squamous cell carcinoma of the head and neck (HNSCC). Thus, the agents that can modulate deregulated STAT3 and NF-kappaB activation have a great potential both for the prevention and treatment of HNSCC. In the present report, we investigated the potential effects of garcinol, an active component of Garcinia indica on various inflammatory mediators involved in HNSCC progression using cell lines and xenograft mouse model. We found that garcinol inhibited constitutively activated STAT3 in HNSCC cells in a time- and dose-dependent manner, which correlated with the suppression of the upstream kinases (c-Src, JAK1, and JAK2) in HNSCC cells. Also, we noticed that the generation of reactive oxygen species is involved in STAT3 inhibitory effect of garcinol. Furthermore, garcinol exhibited an inhibitory effect on the constitutive NF-kappaB activation, mediated through the suppression of TGF-beta-activated kinase 1 (TAK1) and inhibitor of IkappaB kinase (IKK) activation in HNSCC cells. Garcinol also downregulated the expression of various gene products involved in proliferation, survival, and angiogenesis that led to the reduction of cell viability and induction of apoptosis in HNSCC cells. When administered intraperitoneally, garcinol inhibited the growth of human HNSCC xenograft tumors in male athymic nu/nu mice. Overall, our results suggest for the first time that garcinol mediates its antitumor effects in HNSCC cells and mouse model through the suppression of multiple proinflammatory cascades. PMID- 23803416 TI - A prospective analysis of body size during childhood, adolescence, and adulthood and risk of non-Hodgkin lymphoma. AB - The etiology of non-Hodgkin lymphoma (NHL) is poorly understood. Obesity is associated with inflammation, a cytokine milieu conducive to lymphocyte proliferation, and has been associated with NHL risk in some epidemiologic studies. To prospectively examine NHL risk in relation to adult and earlier life obesity, we documented 635 incident NHL diagnoses among 46,390 men in the Health Professionals Follow-up Study and 1,254 diagnoses among 116,794 women in the Nurses' Health Study over 22 to 32 years of follow-up. Using multivariable Cox proportional hazards models, we estimated cohort-specific incidence rate ratios (RR) and 95% confidence intervals (CI) for risk of NHL and major histologic subtypes associated with cumulative average middle and young adult (ages, 18-21 years) body mass index (BMI) and adolescent and childhood somatotype. NHL risk was modestly increased in men (but not women) with a cumulative average middle adult BMI >= 30 kg/m(2) (vs. 15-22.9 kg/m(2); RR, 1.28; 95% CI, 0.92-1.77; Ptrend = 0.05). In meta-analyses across cohorts, higher young adult BMI was associated with increased risk of all NHL (pooled RR per 5 kg/m(2), 1.19; 95% CI, 1.05 1.37), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma (all Ptrend <= 0.02). Adolescent somatotype was also positively associated with all NHL, DLBCL, and follicular lymphoma in pooled analyses (all Ptrend <= 0.03), whereas childhood somatotype was positively associated with NHL overall among women only (Ptrend < 0.01). These findings in two large prospective cohorts provide novel evidence that larger body size in childhood, adolescence, and young adulthood predicts increased risk of NHL, and particularly of DLBCL and follicular lymphoma. PMID- 23803417 TI - DACT2 is a candidate tumor suppressor and prognostic marker in esophageal squamous cell carcinoma. AB - In animals ranging from fish to mice, the function of DACT2 as a negative regulator of the TGF-beta/Nodal signal pathway is conserved in evolution, indicating that it might play an important role in human cancer. In this study, we showed that tumors with higher DACT2 protein level were correlated with better differentiation and better survival rate in patients with esophageal squamous cell carcinoma. Restored expression of DACT2 significantly inhibited growth, migration, and invasion of ESCC cells in vitro, and reduced tumorigenicity in vivo. Furthermore, when DACT2 expression was restored, the activity of TGF beta/SMAD2/3 was suppressed via both proteasome and lysosomal degradation pathways, leading to F-actin rearrangement that might depend on the involvement of cofilin and ezrin-redixin-moesin (ERM) proteins. Taken together, we propose here that DACT2 serves as a prognostic marker that reduces tumor cell malignancy by suppressing TGF-beta signaling and promotes actin rearrangement in ESCC. PMID- 23803418 TI - "Affect of anaerobiosis on the antibiotic susceptibility of H. influenzae". AB - BACKGROUND: Haemophilus influenzae is a human-restricted facultative anaerobe which resides mostly in the oropharynx. The majority of isolates recovered from the throat are unencapsulated commensals (NTHi), but depending on host susceptibility they cause bronchitis, otitis media and on occasion bacteremia and meningitis. Because of the variable oxygen availability in the various niche permitting bacterium replication, the organism must thrive in well oxygenated surfaces, such as pharyngeal epithelium to anoxic environments like the bottom of a Biofilm and in airway mucus. Other reports indicate that H. influenzae use aerobic respiration, anaerobic respiration and fermentation to generate ATP. To gain insight in to the activity of several classes of antibiotics against five well-characterized unencapsulated H. influenzae in room air, in 5% CO2 and under strict anaerobiosis. We also tested for the role of oxidative killing by all cidal antibiotics. RESULTS: In comparison to room air, testing in 5% CO2 had minimal effects on the susceptibility to aminoglycosides, cephalosporins, tetracycline and chloramphenicol: the MIC of rifampin and ciprofloxacin increased eight fold with certain strains in 5% CO2. All antibiotics, except trimethoprim were cidal under both growth conditions. Aminoglycosides remained bactericidal in a strict anaerobic environment, while a reliable MBC was obtained with trimethoprim only under anaerobic conditions. Kinetic analysis of the cidal action of spectinomycin and tetracycline indicated slower killing anaerobically. An oxidative mechanism for aerobic killing could not be demonstrated. CONCLUSIONS: We conclude that beta-lactams, cephalosporins, macrolides, tetracycline's, aminoglycosides, chloramphenicol, rifampin and ciprofloxacin are bactericidal against five well-characterizes H. influenzae in an aerobic and anaerobic environment. The activity of trimethoprim was increased in anaerobic conditions. PMID- 23803419 TI - Quadrupole effects in tetragonal crystals PrCu2Si2 and DyCu2Si2. AB - We have investigated quadrupole effects in tetragonal crystals of PrCu2Si2 and DyCu2Si2 by means of low-temperature ultrasonic measurements. The elastic constant C44 of PrCu2Si2 exhibits pronounced softening below 70 K down to a Neel temperature TN = 20 K, which is described in terms of a quadrupole susceptibility for a Gamma5 doublet ground state and a Gamma3 singlet first excited state located at 15.6 K in the crystalline electric field scheme. The C44 and C66 of DyCu2Si2 also show softening below 70 K down to TN1 = 9.7 K. A low-lying pseudo sextet state consisting of three Kramers doublets of Gamma6?2Gamma7 brings about softening of C44 and C66 in DyCu2Si2. PMID- 23803420 TI - Aortic arch augmentation using a pulmonary artery autograft patch and a reversed left subclavian artery flap for an interrupted aortic arch type B complex. AB - Adequate arch augmentation for interrupted aortic arch repair is quite important to avoid post-operative recoarctation and bronchial compression. We describe here two successful cases of aortic arch reconstruction using autologous materials such as a pulmonary artery patch and a reversed left subclavian artery flap in infants with an interrupted aortic arch type B complex. PMID- 23803421 TI - Something old, something new, something borrowed, the onus is on you. PMID- 23803422 TI - A prescription for safer care: medication reconciliation. PMID- 23803423 TI - Innovation in transformative nursing leadership: nursing informatics competencies and roles. AB - In a recent brief to the Canadian Nurses Association's National Expert Commission on the Health of Our Nation, the Academy of Canadian Executive Nurses (ACEN) discussed leadership needs in the Canadian healthcare system, and promoted the pivotal role of nursing executives in transforming Canada's healthcare system into an integrated patient-centric system. Included among several recommendations was the need to develop innovative leadership competencies that enable nurse leaders to lead and advance transformative health system change. This paper focuses on an emerging "avant-garde executive leadership competency" recommended for today's health leaders to guide health system transformation. Specifically, this competency is articulated as "state of the art communication and technology savvy," and it implies linkages between nursing informatics competencies and transformational leadership roles for nurse executive. The authors of this paper propose that distinct nursing informatics competencies are required to augment traditional executive skills to support transformational outcomes of safe, integrated, high-quality care delivery through knowledge-driven care. International trends involving nursing informatics competencies and the evolution of new corporate informatics roles, such as chief nursing informatics officers (CNIOs), are demonstrating value and advanced transformational leadership as nursing executive roles that are informed by clinical data. PMID- 23803414 TI - HIV-1 transcription and latency: an update. AB - Combination antiretroviral therapy, despite being potent and life-prolonging, is not curative and does not eradicate HIV-1 infection since interruption of treatment inevitably results in a rapid rebound of viremia. Reactivation of latently infected cells harboring transcriptionally silent but replication competent proviruses is a potential source of persistent residual viremia in cART treated patients. Although multiple reservoirs may exist, the persistence of resting CD4+ T cells carrying a latent infection represents a major barrier to eradication. In this review, we will discuss the latest reports on the molecular mechanisms that may regulate HIV-1 latency at the transcriptional level, including transcriptional interference, the role of cellular factors, chromatin organization and epigenetic modifications, the viral Tat trans-activator and its cellular cofactors. Since latency mechanisms may also operate at the post transcriptional level, we will consider inhibition of nuclear RNA export and inhibition of translation by microRNAs as potential barriers to HIV-1 gene expression. Finally, we will review the therapeutic approaches and clinical studies aimed at achieving either a sterilizing cure or a functional cure of HIV 1 infection, with a special emphasis on the most recent pharmacological strategies to reactivate the latent viruses and decrease the pool of viral reservoirs. PMID- 23803424 TI - Why not just any nurse can be a nurse informatician. PMID- 23803425 TI - Process of seeking connectivity: social relations of power between staff nurses and nurse managers. AB - This study explored the process of how power is exercised in nurse-manager relationships in the hospital setting, to better understand what fosters and constrains staff nurse empowerment. Semi-structured interviews and participant observations were conducted with 26 participants in a hospital in Western Canada. Seeking connectivity was the basic social process in which nurses strive to connect with their manager to create a workable partnership in the provision of high-quality patient care while responding to the demands of the organizational context. The overarching finding was that the manager plays a critical role in modifying the work environment for nurses and, as such, nurses seek connection with their manager. Findings revealed two patterns within the process of seeking connectivity: (a) in the absence of a meaningful engagement with the manager, power was held over nurses through institutional patterns of behaviour and practices, and nurses employed a variety of resistance strategies; (b) when managers provided guidance and engaged nurses as co-collaborators, power was shared and nurses were able to influence patient outcomes positively. The results of this study support Laschinger's program of research on nurse empowerment from an organizational perspective, and advance nurse empowerment from a critical perspective. PMID- 23803426 TI - Linking HOBIC measures with length of stay and alternate levels of care: implications for nurse leaders in their efforts to improve patient flow and quality of care. AB - Integral to understanding and leveraging performance data to monitor and drive quality improvement (QI) efforts to enhance patient care is a partnership between researchers (who generate data) and nurse executives (who lead QI efforts). In Canada, evidence-based, nursing-sensitive patient outcome data are included in the Health Outcomes for Better Information and Care (HOBIC) initiative. A descriptive study was undertaken to examine the relationships and predictive abilities of HOBIC measures with length of stay (LOS) and alternate levels of care (ALC) measures. Specifically, we were interested in determining (a) whether relationships among the HOBIC measures exist and (b) whether any of the HOBIC measures are associated with, and could subsequently be used to predict, the patient and the destination to which he or she is discharged (ALC). Our interest in understanding these relationships and predictive abilities was both research driven and practice driven, with the intent eventually to use study findings to target clinical practice and data feedback strategies. To address the two research aims, this study employed both descriptive and inferential statistical approaches with multiple analytic approaches. Study results suggest that many of the HOBIC measures are related, with a higher score in one measure corresponding to a higher score in another measure. The exception is the therapeutic self-care (TSC) measure, in which higher scores on other HOBIC measures were correlated with lower TSC scores. Associations were also found with the predictive ability of certain HOBIC measures on LOS and ALC. Our study findings call for nurse leaders to emphasize the importance to clinical nurses on hospital units of focusing their efforts on assisting patients in managing their fatigue and dyspnoea effectively; increasing their ability to engage in activities of daily living, functional status and therapeutic self-care; and preventing or minimizing pressure ulcers and falls in acute care patients. In turn, these efforts may decrease patients' LOS. PMID- 23803427 TI - Developing and sustaining leadership in public health nursing: findings from one British Columbia health authority. AB - OBJECTIVE: To develop clinical leadership among front-line public health nurses (PHNs). METHODS: This paper describes a quality improvement process to develop clinical leadership among front-line PHNs. Three activities were undertaken by a working group consisting mainly of front-line staff: engaging PHNs in an online change-readiness questionnaire, administering a survey to clients who had ever used public health services delivered by one Vancouver Community Infant, Child and Youth (ICY) program team and conducting three group interviews with public health providers. The group interviews asked about PHN practice. They were analyzed using thematic content analysis. RESULTS: This quality improvement project suggests that PHNs (n=70) strongly believed in opportunities for system improvement. Client surveys (n=429) and community partner surveys (n=79) revealed the importance of the PHN role. Group interview data yielded three themes: PHNs were the "hub" of community care; PHNs lacked a common language to describe their work; PHNs envisioned their future practice encompassing their full scope of competencies. PHNs developed the "ICY Public Health Nursing Model," which articulates 14 public health interventions and identifies the scope of their work. CONCLUSION: Developing and sustaining clinical leadership in front-line PHNs was accomplished through these various quality assurance activities. PMID- 23803430 TI - Primary health care needs for a priority population: a survey of professional truck drivers. AB - BACKGROUND: There are no Canadian data regarding health and wellness of transport truck drivers. OBJECTIVES: We pilot-tested a survey instrument to examine the risk factors and health needs of Canadian truck drivers. METHODS: A self administered survey was completed by truck drivers employed in 13 companies in and-near Hamilton, Ontario, Canada. The survey was developed using published tools with input from focus groups and included demographics, health issues, health service utilization, and awareness of workplace health programs. Descriptive statistics were used to estimate prevalence of health issues and risk factors. RESULTS: 822 surveys were distributed and 406 drivers (49.4%) responded; 48.5% were 50 years and older, 96.0% were male. Diabetes, heart disease, stroke, arthritis, and lung problems were reported by 7%, 4.1%, 0.6%, 10.8% and 2.8% respectively. 96% had salt intake above the recommended daily intake, 31.5% smoked daily and the prevalence of being overweight and with poor diet was 53.2% and 48.4%. CONCLUSIONS: Prevalence of current disease was low; however, prevalence of risk factors for chronic disease was substantial. The survey was feasible to administer and provided benchmark data regarding truck drivers' perceived health. A national survey of Canadian drivers is suggested to improve generalizability and facilitate analysis for associations to poorer driver health. PMID- 23803431 TI - Help-seeking in transit workers exposed to acute psychological trauma: a qualitative analysis. AB - BACKGROUND: Traumatic events often occur in workplace settings and can lead to stress reactions such as Post-Traumatic Stress Disorder (PTSD). One such workplace is the transportation industry, where employees are often exposed to trauma. However, extant research shows that a considerable proportion of people with PTSD do not seek specialty mental health treatment. OBJECTIVE: In this qualitative study, we sought to better understand the experience of a traumatic event at work and the barriers and motivating factors for seeking mental health treatment. PARTICIPANTS: Twenty-nine Toronto Transit Commission (TTC) employees participated in a one-on-one interview, 18 soon after the traumatic event and 11 after entering a specialized treatment program. METHODS: Semi-structured, one-on one interviews were conducting using qualitative description and analyzed using content analysis. RESULTS: Participants described emotional responses after the trauma such as guilt, anger, disbelief as particularly difficult, and explained that barriers to seeking help included the overwhelming amount and timing of paperwork related to the incident as well as negative interactions with management. Motivating factors included family and peer support, as well as financial and emotional issues which persuaded some to seek help. CONCLUSIONS: Seeking treatment is a multifactorial process. Implications and recommendations for the organization are discussed. PMID- 23803432 TI - The relationship between employment and veteran status, disability and gender from 2004-2011 Behavioral Risk Factor Surveillance System (BRFSS). AB - BACKGROUND: In 2011, about 1.8 million or 8 percent of the 22.2 million veterans were women in the US. The unemployment rate for female veterans of the wars in Iraq and Afghanistan rose to 13.5%, above the 8.4% for non-veteran adult women. OBJECTIVE: To examine data from the Behavioral Risk Factor Surveillance System (BRFSS), from 2004-2011 to determine the relationship between employment and veteran status, disability and gender. METHODS: Chi square analysis was used to determine if significant differences existed between the employment rate of female veterans with disabilities and female veterans without disabilities, female non-veterans with disabilities and male veterans with disabilities. Binomial logistic regression analysis was used to determine how veteran status, disability and gender affected the likelihood of not being employed. RESULTS: Significant differences were found in employment rate between female veterans with disabilities and female veterans without disabilities, but not when compared to female non-veterans with disabilities or male veterans with disabilities. Disability was the strongest factor increasing the likelihood of not being employed, though veteran status and female gender were also predictive. CONCLUSIONS: Female veterans with disabilities experience low levels of employment. Policies and programs are needed to address the unique needs of these veterans. PMID- 23803433 TI - How to integrate the aging of employees into occupational health policies: the approach of a French company. AB - BACKGROUND: Since 2010, French companies must integrate or retain seniors to avoid a fine of 1% of their payroll. OBJECTIVE: This work examines how to integrate the aging of employees into occupational health policies. METHODS: The literature on the complex relationships between age, work and health has been reviewed, and the feasibility of potential actions has been addressed. RESULTS: In the company setting, few diseases are specific to seniors. With retirement age postponing, chronic diseases may appear more frequently in people still working. Physiological aging linked to a functional decline is variable. Occupational wear and tear can result in some functional deterioration. Seniors can experience difficulties coping with heavy time demands that restrict their ability to organize the work, with physical stresses due to their diminished muscular capacity, and with unconventional schedules that have long-term deleterious effects on sleep quality and alertness. CONCLUSIONS: This position paper makes recommendations for adapting work organization and occupational medical care. Protective measures for seniors should be integrated in a global approach to improving work conditions for all. Aging employees need some leeway to develop experience-based strategies for bypassing new difficulties. Revising work rhythms and developing autonomy seem to be means for progress. PMID- 23803434 TI - A longitudinal and comparative study of psychological distress among professional workers in regulated occupations in Canada. AB - BACKGROUND: Although several studies are concerned by the phenomenon of psychological distress at work, few studies have looked at the prevalence of psychological distress among professional workers in the regulated occupations and compare this prevalence with other occupations. OBJECTIVES: This study propose to define regulated occupations by laying out the theoretical boundaries that apply to the practice of these occupations and try to understand how regulated occupations contributed to the experience of psychological distress in the Canadian workforce over time. METHOD: Multilevel logistical regression analyses on longitudinal data were performed to compare the odds of experiencing psychological distress over time among professional workers in regulated occupations (n=276) and among other professional workers, classified into 6 categories (n=6731), over a 12-year period. RESULTS: The results show that proportion of distress in the workforce decreases for all occupations between Cycle 1 and Cycle 7 of the NPHS, but this decrease is not linear over time. The results show also that regulated occupations present a lower probability of psychological distress only when compared with white-collar workers. CONCLUSIONS: These results suggest that occupation contributes little toward understanding the prevalence of psychological distress in the Canadian workforce. Further research needs are also discussed. PMID- 23803435 TI - Measuring employment precariousness in the European Working Conditions Survey: the social distribution in Europe. AB - BACKGROUND: Precarious employment is becoming an increasingly important social determinant of health inequalities among workers. The way in which contemporary employment arrangements and their health consequences are addressed in empirical research is mostly based on the contract-related or employment instability dimension. A broader conceptual approach including various important characteristics of the degrading of employment conditions and relations is needed. OBJECTIVE: The general objective of this paper is to empirically test a new multidimensional construct for measuring precarious employment in an existing database. Special focus is on the social distribution of precarious employment. METHODS: A subsample of 21,415 participants in the EU-27 from the Fourth European Working Conditions Survey-2005 was analysed. A cross-sectional study of the social distribution of precarious employment was conducted through the analysis of proportional differences according to gender, social class and credentials for the European Union as a whole and within each country. The 8 dimensions of the employment precariousness construct were represented by 11 indicators. RESULTS: In general, women, workers without supervisory authority, those with fewer credentials, and those living in Eastern and Southern European countries suffer the highest levels of precarious employment. Exceptionally, men, workers with supervisory authority and those with the highest credentials suffer the highest levels of long working hours, schedule unpredictability and uncompensated flexible working times. CONCLUSIONS: This article offers the first validation for an innovative multidimensional conceptualisation of employment precariousness applied to the analysis of existing survey data, showing the unequal distribution of precarious employment across the European labour force. This set of indicators can be useful for monitoring precarious employment. PMID- 23803436 TI - Getting the desired candidate: an exploration of the covert strategies. AB - BACKGROUND: Many people across the world believe that employment decisions are based on merit, on factors related to job knowledge, skills or abilities. People believe that decisions are biased or discriminatory if based on demographic criteria such as gender, race, caste, community, creed etc... unrelated to the job. OBJECTIVES: The aim of this study is to explore the covert motives that might exist amongst senior managers when recruiting their desired candidates. PARTICIPANTS: Sixty senior managers belonging to two international corporations based in western India participated. METHODS: Using the Theory of Planned Behavior as the theoretical foundation qualitative data was obtained through in depth interviews with the sixty participants and analyzed using content analysis. RESULTS: Content analysis based on the Theory of Planned Behavior revealed five main strategies of covert recruitment practices: fulfilling vested interests, obligation creation, cultural bias, mirror reflection and status enhancement. The research findings indicate that 25% of those interviewed used premeditated strategies when recruiting their desired candidates which they concealed from coworkers. However in order to generalize the findings of the present study, a study with a larger sample size across different industries need to be done. CONCLUSIONS: Covert actions were central to employee recruitment in these settings and are likely fundamental to a more complete understanding of managers' recruitment behaviors beyond the context of this study. PMID- 23803437 TI - Insomnia in clients with chronic, work-related musculoskeletal pain in a work recovery rehabilitation program. AB - BACKGROUND: There is a high prevalence of sleep disturbance with people experiencing chronic pain. Although multi-disciplinary rehabilitation programs address many contributing factors for chronic pain, the impact of insomnia on clients is not often measured. OBJECTIVE: Two studies were used to: first explore the experience of insomnia in a group of clients with chronic pain and then, in a group enrolled in a six-week work recovery rehabilitation program, compare measures of sleep disturbance at entry and upon its completion. PARTICIPANTS: Sixteen clients participated in focus groups and 29 completed questionnaires; 46% were women and the average age was 43 years. They had a wide range of work related musculoskeletal injuries and all had chronic pain. METHODS: First two, semi-structured focus group interviews explored sleep disturbance. Then a different set of participants completed three sleep questionnaires before and after completing a rehabilitation program. RESULTS: Focus group participants described sleep disturbance consistent with clinical insomnia and how it had a considerable impact on their lives. Completed questionnaires confirmed the presence of sleep disturbance at admission into a six-week rehabilitation program and at discharge, most measures were unchanged. CONCLUSIONS: Although chronic pain rehabilitation generally includes interdisciplinary approaches, specific attention to insomnia is not part of this chronic pain rehabilitation program and therefore it is not surprising that there was no appreciable change by the end of the program. However, because sleep disturbance is prevalent in the chronic pain population and in this sample, and has such a strong impact on the individual's daytime functioning, effective interventions directed at sleep restriction and stimulus control should complement chronic pain rehabilitation programs. PMID- 23803438 TI - Occupational stress among healthcare workers in Japan. AB - BACKGROUND: High distress levels in healthcare workers in Japan may deteriorate safe service provision. OBJECTIVE: To clarify job stress of healthcare workers, we compared Brief Job Stress Questionnaire (BJSQ) scores among physicians, nursing staff and administrative workers. METHODS: Healthcare workers (n=9,137) in 20 hospitals in Japan were asked to answer BJSQ. BJSQ is job stress questionnaire to measure "Job Stressors", "Stress Responses" and "Social Supports". RESULTS: The "Total Health Risk" of the healthcare workers was 10% higher than the national average. While the physicians felt the stress of the quantitative and qualitative job overload, they had support from supervisors and coworkers and showed mild "Stress Responses". The nursing staff felt the stress of the quantitative and qualitative job overload at the same level as the physicians, but they did not have sufficient support from supervisors and coworkers, and showed high "Stress Responses". The administrative workers did not have sufficient support from supervisors and coworkers, but they experienced less stress as measured by the quantitative and qualitative job overload than the physicians or the nursing staff and showed moderate "Stress Responses". CONCLUSIONS: Further studies are needed to clarify the mechanisms and the influence of other factors to the stress trait in healthcare workers. PMID- 23803439 TI - Change in job stress and job satisfaction over a two-year interval using the Brief Job Stress Questionnaire. AB - BACKGROUND: The relationship between job stress and job satisfaction by the follow-up study should be more evaluated for workers' health support. OBJECTIVE: Job stress is strongly affected by the content of the job and the personality of a worker. This study was focused on determining the changes of the job stress and job satisfaction levels over a two-year interval, using the Brief Job Stress Questionnaire (BJSQ). METHODS: This self-administered questionnaire was distributed to the same 310 employees of a Japanese industrial company in 2009 and 2011. Sixty-one employees were lost from 371 responders in 2009. Data of 16 items from 57 items graded on a four-point Likert-type scale to measure the job stressors, psycho-physical complaints and support for workers, job overload (six items), job control (three items), support (six items) and job satisfaction score (one item) were selected for the analysis. RESULTS: The age-adjusted partial correlation coefficients for job overload, job control and support were 0.684 (p< 0.001), 0.474 (p< 0.001) and 0.612 (p< 0.001), respectively. The concordance correlation coefficient (and 95% confidence interval indicated within parentheses) for job overload, job control and support were 0.681 (0.616-0.736), 0.473 (0.382-0.555), and 0.623 (0.549-0.687), respectively. There were no significant differences in the mean score for job overload, job control or support, although significant decline in the job satisfaction level was apparent at the end of the two-year period (p< 0.05). There was also a significant decline in the job satisfaction in 2009 and in 2011 for subjects with keeping low job strain. CONCLUSIONS: No significant changes in the scores on the three elements of job stress were observed over the two-year study period, and the job satisfaction level deteriorated significantly during this period. There was a decline in the job satisfaction in the two-year period, although subjects did not suffer from job stress at the same period. PMID- 23803440 TI - Understanding working class lives: an examination of the quality of life of low income construction workers. AB - BACKGROUND: The construction industry is considered to be one of the oldest trades of mankind. Even though this industry has shown phenomenal growth in the developing economies like India, hardly any research has been done to understand the living condition and status of the people who have contributed with their sweat and blood for the growth of this industry. OBJECTIVES: The study aims at understanding the living condition of the low income construction workers from one of the small construction companies of eastern India, from the state of Jharkhand. PARTICIPANTS: In all twelve families staying at the construction site agreed to volunteer. The average age of the respondent parents (i.e. mother as well as father) was 28.5 years. METHODS: Qualitative methods have been used in order to collect the data. Ethnography and photo elicitation was used as a primary method of data collection. Apart from this, in-depth interviews were also conducted with the workers of the construction company. RESULTS: Discussion with the participants led to the emergence of four themes. They were (1) Daily Rituals, (2) Living Condition, (3) Quality of food and (4) Health and Hygiene. The research findings indicate that the conditions at which the workers live at the construction site can be considered to be in a state of pitiful situation which is mainly due to their acute level of poverty. CONCLUSIONS: Based on the study findings, there is an imperative that the societal forerunners, policy makers and philanthropists continue to use research findings to understand the living condition of the low income construction workers and draft strategies accordingly, to improve their status and Quality of Life. PMID- 23803441 TI - Environmental and personal factors that support early return-to-work: a qualitative study using the ICF as a framework. AB - BACKGROUND: Occupational health professionals such as occupational physicians (OPs) increasingly understand that in addition to health improvement, environmental factors (such as work adaptations) and personal factors (such as an employee's attitude towards return-to-work (RTW)) may stimulate employees on sick leave to return to work early. To target their professional interventions more specifically according to these factors, occupational health professionals need further insight into environmental and personal factors that stimulate RTW. OBJECTIVE: The objectives of this study are (1) to identify which and how environmental and personal factors support RTW, and (2) to examine whether the International Classification of Functioning, Disability and Health (ICF) can be used to describe these factors. METHODS: We performed interviews with 14 employees, 15 employers and 4 OPs from multiple organisations with varying organisational sizes and types of industry such as healthcare and education. We used a qualitative data analysis partially based on the Qualitative Analysis Guide of Leuven. RESULTS: The following environmental factors were found to support early RTW: 'social support from relatives', 'belief that work stimulates health', 'adequate cooperation between stakeholders in RTW' (e.g., employees, employers and OPs) and 'the employers' communicative skills'. One personal factor stimulated RTW: 'positive perception of the working situation' (e.g. enjoyment of work). Most factors stimulated RTW directly. In addition, adequate treatment and social support stimulated medical recovery. Environmental factors can either fully (social support, belief that RTW stimulates health), partially (effective cooperation), or not (employers' communicative skills) be described using ICF codes. The personal factor could not be classified because the ICF does not contain codes for personal factors. CONCLUSIONS: RTW interventions should aim at the environmental and personal factors mentioned above. Professionals can use the ICF to describe most environmental factors. PMID- 23803442 TI - Function, health and psychosocial needs in job-seekers with anxiety, mood, and psychotic disorders who access disability employment services. AB - BACKGROUND: Labour force participation of people with mental disorders varies according to the nature of their disorder. Research that compares function and psychosocial need in job-seekers with different mental disorders, however, is scant especially in the Australian setting. Identifying rehabilitation needs of job-seekers with mental disorders receiving employment services is of interest to providers of disability employment services in Australia. OBJECTIVE: This study sought to identify differences in health, social needs and function in people with anxiety, mood, or psychotic disorders accessing disability employment services to inform disability service providers of vocational rehabilitation interventions. PARTICIPANTS: 106 adult job-seekers with anxiety (29%), mood (51%), and psychotic (20%) disorders receiving job placement services from a disability employment service provider consented to participate in this study. METHODS: Self-report measures and the Executive Interview (EXIT) were used to document function. Differences between disorders were determined using one-way analysis of variance. RESULTS: Significantly better estimates of social functioning as measured by the Behaviour and Symptom Identification Scale (BASIS 32) were reported by job-seekers with psychotic disorders compared to those with anxiety or mood disorders. However, job-seekers with psychotic disorders reported longer periods of unemployment compared to those with mood disorders and longer estimates of the time it would take to obtain work compared to both the other groups. CONCLUSIONS: Perceived psychosocial problems, such as poor social function in job-seekers with anxiety and mood disorders and perceptions of poor employability in those with psychotic disorders, should be considered when developing vocational rehabilitation interventions, or where additional support may be required once employment is obtained. PMID- 23803443 TI - Measuring individual work performance: identifying and selecting indicators. AB - BACKGROUND: Theoretically, individual work performance (IWP) can be divided into four dimensions: task performance, contextual performance, adaptive performance, and counterproductive work behavior. However, there is no consensus on the indicators used to measure these dimensions. OBJECTIVE: This study was designed to (1) identify indicators for each dimension, (2) select the most relevant indicators, and (3) determine the relative weight of each dimension in ratings of work performance. METHODS: IWP indicators were identified from multiple research disciplines, via literature, existing questionnaires, and expert interviews. Subsequently, experts selected the most relevant indicators per dimension and scored the relative weight of each dimension in ratings of IWP. RESULTS: In total, 128 unique indicators were identified. Twenty-three of these indicators were selected by experts as most relevant for measuring IWP. Task performance determined 36% of the work performance rating, while the other three dimensions respectively determined 22%, 20% and 21% of the rating. CONCLUSIONS: Notable consensus was found on relevant indicators of IWP, reducing the number from 128 to 23 relevant indicators. This provides an important step towards the development of a standardized, generic and short measurement instrument for assessing IWP. PMID- 23803444 TI - Prevention of disability: the opinion of claimants applying for a disability benefit. AB - BACKGROUND: A great number of workers suffer from problems to continue their work due to chronic health conditions. This leads to a large number of workers applying for a disability benefit. In order to prevent the application of a disability benefit, insight in the background of these applicants is needed. OBJECTIVE: To assess the expectations of Dutch claimants applying for a disability benefit, the rationale behind these expectations and the value of these expectations in the process of evaluating disability. PARTICIPANTS: Applicants for a disability benefit were invited to participate in the study. METHOD: Claimants for a disability benefit filled out an internet questionnaire. The questions focused on the expectation of being granted a disability benefit and the rationale behind these expectations. Additionally, data on claimants' characteristics and responses to the first question of the Work Ability Index (WAI) were collected. The actual outcome of the application for a disability benefit was also recorded. RESULTS: Of the 206 claimants, 84% expected to receive a disability benefit, while 72% of the claims were assigned. Low education level, higher age and a low WAI score were correlated with the expectation of receiving a benefit. The combination of a low WAI score and expectation of a disability benefit actually predicted the outcome. CONCLUSIONS: Patients are capable of predicting the outcome of their application for a disability benefit. Application for a disability benefit could be prevented if information on the WAI score and the expectation of a disability benefit is known at an earlier stage of the sickness absence process. PMID- 23803445 TI - An assessment of hand volumetric and temperature changes during office related repetitive activities. AB - BACKGROUND: Hand usage and movement is routinely performed by all individuals daily irrespective of age. These movements can vary and can be repetitive in nature. Exposure of the hard and soft tissues of the hand to prolonged repetitive activities could contribute to the development of work related upper limb disorders (WRULD). OBJECTIVE: Within the work setting, work related upper limb disorders (WRULDs) rank high in the United Kingdom (UK), second only to back complaints. This paper reports the amount of tendon travel and swelling that occurs in the hand during repetitive office activities associated with WRULDs. PARTICIPANTS: Nine healthy adults (five males; four females) participated in the study. METHODS: A 30-minute laboratory-based simulated office activity that consisted of data entry, mouse clicking and dragging, and mouse scrolling tasks was performed. Participants wore a custom-made cost effective flexible electrogoniometric glove (FEG) as two experimental conditions were tested; namely, FEG - only, and FEG using a Splint (FEG - Splint). RESULTS: The FEG - only condition produced a higher overall tendon travel compared to the FEG - Splint condition. Both hands presented no statistically significant differences in hand temperature (p > 0.05) and hand volume increments (p > 0.05) with respect to the FEG - only and FEG - Splint office activity experiments. All participants that showed a decrease in hand volumetric measurement produced final temperature measurements lower than initial temperature measurements taken at the commencement of the experiment. Based on participants' perception, the mouse scrolling task was deemed as most strenuous. CONCLUSION: The findings can help to advise patients on biomechanical 'risks' associated with repetitive activities. PMID- 23803446 TI - Methodological framework for the ergonomic design of children's playground equipment: a Serbian experience. AB - BACKGROUND: Adequate application of the static and dynamic anthropometric measures of pre-school children in ergonometric design of children's playground equipment should eliminate all dangers and difficulties in their use. Possibilities of injuries, insecure movements, discomfort able positions and some other dangerous actions may be minimized; and safety and health protection of pre school children will be increased. OBJECTIVE: Children's playground represents a significant space of activity for pre-school children. Therefore, it is necessary to apply ergonomic principles which contribute to the adjustment of the playground elements to children's anatomic features. Based on the results presented in this paper, new constructions were designed and new playgrounds were installed in Serbia. PARTICIPANTS: Participants were children from three pre school age groups: Junior age group (3-4 years of age, 17 children), Medium age group (4-5 years of age, 22 children), and Senior age group (5-6 years of age, 26 children). METHODS: Thirty-one static anthropometric measures (12 in standing position, 11 in sitting position, 7 related to dimensions of hand, foot an head, with body weight and shoe size) and 15 dynamic anthropometric measures (7 in standing position, 6 in sitting position and 2 dimension of foot and hand) were defined for the study. Measurements were taken using an anthrop-meter, a flexible measuring tape. Equations for ergonomic design of children's playground elements were also defined. RESULTS: Basic statistical data of static and dynamic anthropometric measurements of the pre-school children are presented in this paper, as well as the statistical calculation of the corrective anthropometric measurements. Measurements were performed in "Poletarac" kindergarten, part of the pre-school institution "Radost" in Cacak. Elements of playground equipment in "Bambi" kindergarten in Kragujevac (the Indian tent "wigwam", gate-house, swing and carousel) were designed and built using these parameters. CONCLUSION: Based on the obtained results, several playgrounds were designed, manufactured and equipped with the appropriate items. PMID- 23803448 TI - Do we value empowerment? PMID- 23803447 TI - Transcriptional profiling of Drosophila S2 cells in early response to Drosophila C virus. AB - BACKGROUND: The innate immune response like phagocytosis, encapsulation and antimicrobial peptide (AMP) production often occur in the early stage of host pathogen interactions in Drosophila melanogaster. To investigate the Drosophila early immune response to Drosophila C virus, we characterized the DCV infection response transcriptome of Drosophila Schneider 2 (S2) cells at one hour post inoculation. METHOD: The total RNA was extracted from treated S2 cells by using Trizol reagent and then analyzed by CapitalBio Corp for Drosophila GeneChip (Affymetrix) assay. Then the results of signaling pathway and protein interaction about these genes were analyzed by MAS 3.0 software. RESULTS: Most significantly affected genes (656 genes) by DCV infection were regulated as the same way in inactivated DCV treatment, but inactivated white spot syndrome virus (WSSV) showed a different transcriptome. DCV infection up-regulated the expression levels of 275 genes and down-regulated that of 442 genes significantly and some affected genes were related to phagocytosis. DCV infection activated the JAK/STAT pathway by 1 hour post incubation. The Imd pathway was activated and transcriptional induction of antimicrobial peptides (AMPs) from this pathway was enhanced by 1 hour post incubation. But the Toll pathway was not activated like Imd pathway and the expression levels of AMPs from this pathway was reduced. In addition, most pattern-recognition receptors were inhibited and the antiviral RNAi pathway was not activated in the early stage of DCV infection. CONCLUSIONS: In conclusion, the present study demonstrates that DCV infection may activate phagocytosis, JAK/STAT pathway and Imd pathway in the early host-virus interactions. These results indicate that DCV is capable of activating or inhibiting some immune responses in the host cells and these changes would be vital for virus entry and replication. PMID- 23803449 TI - Comparison of the efficacy between oral rinse, oral gargle, and oral spray. AB - INTRODUCTION AND AIMS: Patients with sore throats are often treated with oral gargles or oral sprays. Some may rinse instead of gargle, leading to unsatisfactory outcome. The authors studied the efficacy of oral rinses, gargles, and sprays and the effect of Friedman palate position on the outcome. METHODS: Ten subjects used specially prepared solutions to rinse, gargle, and then spray their oral cavities at 2-hour intervals. The blue dye indicated the areas stained by the solution, which were scored. RESULTS: Although there was no difference in reaching the oropharynx between the gargles and sprays, they were both better than were the oral rinses (P < .001). The difference in Friedman palate position did not have an effect on the efficacy of the different modalities. CONCLUSION: Oral gargles and sprays have been shown to be significantly better than are oral rinses if the oropharynx is the targeted site, and the size of the oral airway does not impede their efficacy. PMID- 23803450 TI - Association Between Physician Recommendation for Adolescents to Join a Weight Loss Program and BMI Change. AB - OBJECTIVE: To explore whether reasons for enrollment in a pediatric multidisciplinary weight management program (PMWMP) are associated with subsequent weight loss. METHOD: A retrospective analysis of obese adolescents (12 18 years old, body mass index [BMI] > 95th percentile) who enrolled in a PMWMP from April 2007 to March 2009, and had BMI measurements at weeks 1 and 12. Reasons for enrollment were obtained from parents' responses to an enrollment questionnaire (which allowed selection of more than one reason). The most common reasons for enrollment were computed. Linear regression was used to explore associations between mean change in BMI and reasons for enrollment, controlling for demographic and anthropometric factors. RESULTS: Most of the 90 adolescents who met the inclusion criteria were female (70%) and white (57%). Mean age was 14.5 years and mean initial BMI was 42 kg/m(2). The most common reasons for enrolling in the PMWMP were due to concerns about adolescents' physical health (96%), concerns about adolescents' mental health (76%), and because of a physician recommendation (73%). The mean 12-week change in BMI showed a greater decrease for those who enrolled due to a physicians' recommendation versus those who did not (-1.5 vs -0.5 kg/m(2): P < .05). This finding remained significant even when controlling for the covariates of interest. CONCLUSIONS: A physician's recommendation to join a PMWMP appears to be associated with greater weight loss among obese adolescents than other reasons for enrollment. Further research should explore how physician involvement affects long-term weight loss. PMID- 23803451 TI - Implementation of a diabetes management program for patients in a rural primary care office. AB - OBJECTIVE: A diabetes management program was implemented in a rural primary care office for those who did not choose to consult a multidisciplinary specialty care. The purposes of this study were to describe the current practices and health care provider management of patients with diabetes in a rural primary care office and determine differences between Hispanic and non-Hispanic persons concerning diabetes self-care behaviors, barriers to self-care, and their association with glycosylated hemoglobin level. METHODS: A retrospective medical record review of diabetes-related medical information was completed. RESULTS: Sixty-one (74%) of the 83 patients with diabetes completed the questionnaire and had the diabetes management program implemented (problem summary and clinical summary generated). Medical record review was completed for 83 (100%) subjects. Glycosylated hemoglobin was significantly higher for the younger group and women. Hispanic women and married persons had significantly higher glycosylated hemoglobin than did non-Hispanic and unmarried persons. Hispanic persons who were obese had significantly higher glycosylated hemoglobin. Self-care behaviors for managing diabetes were different by group. Non-Hispanic subjects reported taking their diabetes medications 99% of the time and Hispanic subjects 50% of the time. DISCUSSION: It was feasible to implement a diabetes management program in a rural primary care setting, and its implementation highlighted the ethnic differences for Hispanics and non-Hispanics in diabetes self-care behavior, barriers to self care, and family support for diabetes management. The implementation of the diabetes management program, though, was time-consuming and costly and was facilitated outside of the usual realm of practice. PMID- 23803452 TI - Adolescents' views on barriers to health care: a pilot study. AB - OBJECTIVES: To determine from adolescents using health care their: 1) perceptions of barriers to obtaining health services, 2) views on how to overcome the barriers and 3) views on how to create an adolescent-friendly primary care practice. DESIGN: Six focus group interviews. METHODS: Adolescents 11-21 years old from three health centers in the Bronx were recruited. MAIN OUTCOME MEASURES: 1) barriers to accessing health care such as insurance, language barriers, transportation, making an appointment; 2) identifying barriers related to issues of consent and confidentiality; 3) exploring barriers to accessing mental health and related issues; and 4) their visions of an adolescent-friendly office. RESULTS: Thirty-one adolescents, aged 11-21 years old, participated. The majority were Hispanic and 52% were female. Fifty percent of adolescents had a routine visit within the past month. Most adolescents reported experiencing barriers to making an appointment. Additionally, they complained about long waiting times to be seen by providers on the day of their scheduled appointment. Another key barrier was related to knowledge and perceptions about consent and confidentiality. Further, in regard to mental health, many adolescents from focus groups reported that they felt that their primary providers had little interest in this topic and limited knowledge about it. Most of the adolescents reported no barriers with insurance, language or transportation. Their visions of an adolescent-friendly office would include a separate adolescent waiting area equipped with entertainment units. CONCLUSION: In this study of adolescents who already have primary care providers and are seemingly well-connected to the health care system, there remained significant reported barriers to accessing necessary health services. PMID- 23803453 TI - Breast and cervical cancer screening among rural midwestern latina migrant and seasonal farmworkers. AB - BACKGROUND: While cancer control and prevention efforts are well documented, limited information on this topic exists for Latina farmworkers in the rural Midwest. This study sought to examine correlates of breast cancer and cervical cancer screening practices of English- and Spanish-speaking Latina farmworkers in Michigan. METHODS: Survey and anthropometric data were collected from a community based cross-sectional sample of 173 Latina agricultural laborers in Michigan. Psychosocial-cultural and socioeconomic variables were examined as predictors of mammography and Papanicolaou screening. FINDINGS: Results showed that individual characteristics that were significantly associated with having a Papanicolaou examination in the last 12 months included having higher language-based acculturation (odds ratio = 3.81), having ever done a breast self-examination (odds ratio = 2.82), and having health insurance (odds ratio = 5.58). CONCLUSIONS: Acculturation, insurance, and performance of breast self-examination were key correlates of recent cervical cancer screening among Midwest Latina farmworkers. Findings suggest that education and targeted outreach strategies for Spanish-speaking Latina farmworker women in rural settings are urgently needed. PMID- 23803454 TI - Patient-level evaluation of community-based, multifactorial intervention to prevent diabetic nephropathy in northern alberta, Canada. AB - OBJECTIVE: To examine whether patients with type 2 diabetes enrolled in community based clinics uniformly benefit from interventions designed to achieve multiple risk factor targets. METHODS: Using data from community-based clinics in Alberta, Canada, we examined whether patients achieved targets for blood pressure (<130/80 mm Hg), A1c (<=7%), low-density lipoprotein (LDL) cholesterol (<2.5 mmol/L), weight reduction, exercising, smoking cessation, and meal plan management among 235 patients between 2004 to 2007 with a 1-year follow-up. The effectiveness of the clinics was assessed by the number of targets achieved by individual patients. Patients achieving different degrees of success (0-2, 3-4, and >=5 targets) were compared. RESULTS: Mean age of patients at baseline was 62 years (standard deviation [SD], 12 years), 43% were female, 77% had a history of cardiovascular disease, and mean diabetes duration was 9 years (SD, 9 years). Overall, 47 patients achieved 0 to 2 targets (group 1), 132 achieved 3 to 4 targets (group 2), and 56 achieved >=5 targets (group 3) out of 7 targets. More patients in group 1 were male and had longer diabetes duration and were more likely to smoke or use insulin. Despite reductions in A1c in all groups and similar use of antihypertensives, there was no improvement in weight or systolic blood pressure (which actually increased) in group 1. Successful patients (group 3) were more likely to report adherence with exercise and a meal plan. CONCLUSIONS: Despite equally intensive, target-driven pharmacotherapy, this community-based multifactorial intervention was less effective among a subset of patients who did not adhere to lifestyle changes. Strategies to effectively address lifestyle factors will be important as this intervention is refined. PMID- 23803455 TI - The impact of patient and provider factors on depression screening of american Indian and alaska native people in primary care. AB - INTRODUCTION: The US Preventive Services Task Force recommends routine depression screening in primary care, yet regular screening does not occur in most health systems serving Alaska Native and American Indian people. The authors examined factors associated with administration of depression screening among Alaska Native and American Indian people in a large urban clinic. METHODS: Medical records of 18 625 Alaska Native and American Indian adults were examined 1 year after implementation of a depression screening initiative. Multilevel logistic regression models examined associations between patient and provider factors and administration of the Patient Health Questionnaire-9. RESULTS: Forty-seven percent of patients were screened. Women were more likely than men to be screened (50% vs 43%, P < .001). Increased screening odds were associated with older age, increased service use, and chronic disease (P < .001) but not with substance abuse disorders or prior antidepressant dispensation. Women previously diagnosed with depression had higher odds of screening (P = .002). Men seen by male providers had higher odds of screening than did men seen by female providers (P = .040). Screening rates peaked among providers with 2 to 5 years of employment with the clinic. LIMITATIONS: Cross-sectional analysis of medical record data was of unknown reliability; there were limited sociodemographic data. CONCLUSIONS: Even with significant organizational support for annual depression screening, primary care providers systematically missed men and patients with infrequent primary care visits. Outreach to male patients and additional supports for primary care providers, especially in the first years of practice, may improve screening and treatment for depression among Alaska Native and American Indian people. PMID- 23803456 TI - Patient preferences in choosing a primary care physician. AB - BACKGROUND AND AIMS: Studies have identified factors important to patients in consideration of a primary care physician (PCP). Few have explored relevant differences in choosing between family medicine (FM) and internal medicine (IM) physicians. The objective of this study was to identify differences in rating of factors perceived to be important to racially diverse FM and IM patients in the selection of a PCP, and to determine patient knowledge of PCP training. SETTINGS, DESIGN, METHODS, AND MATERIAL: This observational study used self-administered questionnaires to obtain information from adult participants at 2 continuity clinics, FM and IM. Participants rated 16 factors on their importance in selecting a PCP. Demographics and information regarding participants' knowledge of PCP training were collected. STATISTICAL ANALYSES USED AND RESULTS: 857 surveys were completed. Data were analyzed using descriptive statistics, Student t test, chi(2), and multivariate logistic regression. Sixty-five percent and 32% of participants were Caucasian or African American, respectively. Combined responses from both clinics revealed good patient care as the factor ranked highest in importance for selecting a PCP, followed by good communication skills. Forty-eight percent and 35% of FM and IM participants, respectively, did not know whether their PCP was trained in IM or FM. More than 50% of participants were not familiar with the scope of their physicians' practice. CONCLUSIONS: Our results suggest that good patient care and communication are similarly important to all patients, regardless of race. Practices should maintain focus on these qualities, as well as on patient education regarding the relevant differences between FM and IM physicians. Results from this study are consistent with prior research on these issues in more racially homogenous populations. PMID- 23803457 TI - Determinants of fruits and vegetables consumption among persons with doctor diagnosed chronic diseases. AB - OBJECTIVE: The objective of this study was to examine the factors associated with fruits and vegetables consumption pattern among persons with doctor-diagnosed chronic diseases. METHOD: The authors examined cross-sectional, random-digit dialed health survey data collected in 2008 in Houston, Texas, a city with a diverse ethnic population. The survey sample, which was designed to represent all households with telephones, was drawn using standard list-assisted random-digit dialing methodology from telephone exchanges that serve the study area. A total of 1001 households were interviewed, and data obtained were subjected to both bivariate and multivariate analyses. RESULTS: Findings from this study indicate that fruits and vegetables consumption for persons with single chronic disease was significantly predicted (R (2) = 0.83) by the participants' age, educational level, and insurance status. None of the covariates considered in the study were significant predictors of fruits and vegetables consumption pattern among persons who had multiple chronic diseases. But when the subpopulation with any number of chronic diseases was considered, only gender (P < .05) and marital status (P < .001) were noted as the significant predictors of fruits and vegetables (R (2) = 0.34). CONCLUSION: More public health efforts are needed to make individuals with chronic diseases aware of the importance of consumption of fruits and vegetables. Clinicians and health care professionals should be encouraged to emphasize the importance of consumption of fruits and vegetables in their routine practice to the patients with chronic disease(s), especially to those who are unmarried and male. PMID- 23803458 TI - Abdominal aortic aneurysms: an overview of screening and management in primary care. AB - Abdominal aortic aneurysms represent both an individual risk of mortality and a socioeconomic burden for health care systems worldwide, but screening is not performed in all countries. Here, the authors summarize the pros and cons of screening to reduce abdominal aortic aneurysm-related mortality. PMID- 23803459 TI - Hyperferritinemia in dogs with splenic hemangiosarcoma. AB - Serum ferritin concentration increases in dogs in association with various diseases. In this study, we measured serum ferritin levels in dogs with splenic masses, using a sandwich ELISA assay. Eleven dogs with hemangiosarcoma (HSA), six with hematoma, 1 with hemangioma and 3 with lymphoma were enrolled. All dogs with HSA had serum ferritin concentrations above the normal limit (1,357 ng/ml, mean + 2* standard deviation of normal). Increased serum ferritin concentrations have also been observed in few cases of hematoma, hemangioma and lymphoma. Therefore, hyperferritinemia is not specific for splenic HSA, but may have clinical usefulness as a sensitive test for the disease. Further evaluation of serum ferritin concentrations in dogs with splenic HSA is needed. PMID- 23803460 TI - Change in serum ferritin concentration in experimentally induced anemia of chronic inflammation in dogs. AB - In veterinary medicine, hyperferritinemia is often observed in dogs with various diseases (e.g., histiocytic sarcoma and immune-mediated hemolytic anemia) without evidence of iron overload. The mechanism underlying hyperferritinemia development is not well understood. Anemia caused by inflammation is termed as anemia of chronic disease (ACD), and experimentally induced ACD is known to cause slight hyperferritinemia. However, almost all these studies were based on short-term acute inflammation. Hepcidin, a protein mainly produced by hepatocytes, is thought to be a key regulator in iron release from reticuloendothelial cells (RECs), and its expression is related to ACD. We hypothesized that in the case of long-term ACD, iron deposition in RECs increases through hepcidin, causing a diachronic increase in serum ferritin levels. In the present study, we used a canine model with repeated subcutaneous administration of turpentine oil every 3 days over a period of 42 days (15 injections) and induced long-term inflammatory conditions; furthermore, we evaluated the change in serum ferritin concentration. Hypoproliferative anemia, bone marrow iron deposition and hypoferremia, which are characteristic of ACD, were observed on administering the turpentine injections. Hepatic iron content, hepatic hepcidin mRNA expression and serum ferritin concentration increased during the early period after turpentine injection, but returned to normal levels later. These results show that experimentally induced long-term ACD caused hypoproliferative anemia without sustained increase in hepcidin expression and did not cause systemic iron overload. Thus, chronic inflammation may not contribute greatly to increase in hyperferritinemia. PMID- 23803461 TI - The amazing odontoblast: activity, autophagy, and aging. AB - Odontoblasts are dentin-secreting cells that survive for the whole life of a healthy tooth. Once teeth are completely erupted, odontoblasts transform into a mature stage that allows for their functional conservation for decades, while maintaining the capacity for secondary and reactionary dentin secretion. Odontoblasts are also critically involved in the transmission of sensory stimuli from the dentin-pulp complex and in the cellular defense against pathogens. Their longevity is sustained by an elaborate autophagic-lysosomal system that ensures organelle and protein renewal. However, progressive dysfunction of this system, in part caused by lipofuscin accumulation, reduces the fitness of odontoblasts and eventually impairs their dentin maintenance capacity. Here we review the functional activities assumed by mature odontoblasts throughout life. Understanding the biological basis of age-related changes in human odontoblasts is crucial to improving tooth preservation in the elderly. PMID- 23803462 TI - Radiological protection issues arising during and after the Fukushima nuclear reactor accident. AB - Following the Fukushima accident, the International Commission on Radiological Protection (ICRP) convened a task group to compile lessons learned from the nuclear reactor accident at the Fukushima Daiichi nuclear power plant in Japan, with respect to the ICRP system of radiological protection. In this memorandum the members of the task group express their personal views on issues arising during and after the accident, without explicit endorsement of or approval by the ICRP. While the affected people were largely protected against radiation exposure and no one incurred a lethal dose of radiation (or a dose sufficiently large to cause radiation sickness), many radiological protection questions were raised. The following issues were identified: inferring radiation risks (and the misunderstanding of nominal risk coefficients); attributing radiation effects from low dose exposures; quantifying radiation exposure; assessing the importance of internal exposures; managing emergency crises; protecting rescuers and volunteers; responding with medical aid; justifying necessary but disruptive protective actions; transiting from an emergency to an existing situation; rehabilitating evacuated areas; restricting individual doses of members of the public; caring for infants and children; categorising public exposures due to an accident; considering pregnant women and their foetuses and embryos; monitoring public protection; dealing with 'contamination' of territories, rubble and residues and consumer products; recognising the importance of psychological consequences; and fostering the sharing of information. Relevant ICRP Recommendations were scrutinised, lessons were collected and suggestions were compiled. It was concluded that the radiological protection community has an ethical duty to learn from the lessons of Fukushima and resolve any identified challenges. Before another large accident occurs, it should be ensured that inter alia: radiation risk coefficients of potential health effects are properly interpreted; the limitations of epidemiological studies for attributing radiation effects following low exposures are understood; any confusion on protection quantities and units is resolved; the potential hazard from the intake of radionuclides into the body is elucidated; rescuers and volunteers are protected with an ad hoc system; clear recommendations on crisis management and medical care and on recovery and rehabilitation are available; recommendations on public protection levels (including infant, children and pregnant women and their expected offspring) and associated issues are consistent and understandable; updated recommendations on public monitoring policy are available; acceptable (or tolerable) 'contamination' levels are clearly stated and defined; strategies for mitigating the serious psychological consequences arising from radiological accidents are sought; and, last but not least, failures in fostering information sharing on radiological protection policy after an accident need to be addressed with recommendations to minimise such lapses in communication. PMID- 23803463 TI - Fatal hemolytic uremic syndrome associated with day care surgery and anaesthesia: a case report. AB - BACKGROUND: Thrombotic angiopathies, i.e. haemolytic uremic syndrome and thrombotic thrombocytopenic purpura, are thought to occur in patients with a combination of risk factors (e.g., an infection with shiga-toxin-producing Escherichia coli (E. coli) or low activity of the metalloproteinase Adamts-13) and a pathophysiological trigger (e.g., anti-endothelial antibodies, cytokines or activation of chemokine receptor 4). To our knowledge, this is the first report describing an association between haemolytic uremic syndrome and routine surgery and anaesthesia. CASE PRESENTATION: We present a case in which a 67-year-old Caucasian female developed fatal haemolytic uremic syndrome in the immediate postoperative period of uncomplicated day care surgery. The patient had suffered gastrointestinal symptoms followed by confusion approximately two weeks before surgery, but had been without any symptoms in the week before surgery. Haemolytic uremic syndrome with cerebral symptoms ranging from initial anxiety to subsequent seizures and coma developed within a few hours after the end of surgery. In addition, acute kidney failure and severe thrombocytopenia occurred about the same time. During intensive care, the patient was found to be positive for enterohaemorrhagic E. coli (EHEC) in faeces. CONCLUSION: Anaesthesiologists should be notified that haemolytic uremic syndrome is an uncommon differential diagnosis in patients with postoperative seizures and coma. Patients with a recent enterohemmoragic E.Coli infection should be followed postoperatively for signs of haemolytic uremic syndrome. PMID- 23803464 TI - Incidence of fatal airway obstruction in police officers feloniously killed in the line of duty: a 10-year retrospective analysis. AB - BACKGROUND: According to US military data, airway obstruction is the third leading cause of possibly preventable death in combat. In the absence of law enforcement-specific medical training, military experience has been translated to the law enforcement sector. The purpose of this study was to determine whether airway obstruction represents a significant cause of possibly preventable death in police officers, and whether current military combat lifesaver training programs might have prevented these fatalities. METHODS: De-identified, open source US Federal Bureau of Investigation (FBI) Uniform Crime Report Law Enforcement Officers Killed and Assaulted (LEOKA) data for the years 1998-2007 were reviewed. Cases were included if officers were on duty at the time of fatal injury and died within one hour from time of wounding from penetrating face or neck trauma. After case identification, letters requesting autopsy reports were sent to the departments of victim officers. Reports were abstracted into a Microsoft Excel database. RESULTS: During the study period, 42 of 533 victim officers met inclusion criteria. Departmental response rate was 85.7%. Autopsy reports were provided for 29 officers; 23 (54.8%) cases remained in the final analysis. All officers died from gunshot wounds. No coroner specifically identified airway obstruction as either a direct cause of death or contributing factor. Based upon autopsy findings, three of 341 officers possibly succumbed to airway trauma (0.9%; 95% CI, 0.0%-1.9%). Endotracheal intubation was the most common advanced airway management technique utilized during attempted resuscitation. CONCLUSION: The limited LEOKA data suggests that acute airway obstruction secondary to penetrating trauma appears to be a rare cause of possibly preventable death in police officers. Based upon the nature of airway trauma, nasopharyngeal airways would not be expected to be an effective lifesaving intervention. This study highlights the requirement for a comprehensive mortality and "near miss" database for law enforcement officers. PMID- 23803465 TI - Reprogramming the chromatin landscape: interplay of the estrogen and glucocorticoid receptors at the genomic level. AB - Cross-talk between estrogen receptors (ER) and glucocorticoid receptors (GR) has been shown to contribute to the development and progression of breast cancer. Importantly, the ER and GR status in breast cancer cells is a significant factor in determining the outcome of the disease. However, mechanistic details defining the cellular interactions between ER and GR are poorly understood. We investigated genome-wide binding profiles for ER and GR upon coactivation and characterized the status of the chromatin landscape. We describe a novel mechanism dictating the molecular interplay between ER and GR. Upon induction, GR modulates access of ER to specific sites in the genome by reorganization of the chromatin configuration for these elements. Binding to these newly accessible sites occurs either by direct recognition of ER response elements or indirectly through interactions with other factors. The unveiling of this mechanism is important for understanding cellular interactions between ER and GR and may represent a general mechanism for cross-talk between nuclear receptors in human disease. PMID- 23803466 TI - Prediction of site-specific interactions in antibody-antigen complexes: the proABC method and server. AB - MOTIVATION: Antibodies or immunoglobulins are proteins of paramount importance in the immune system. They are extremely relevant as diagnostic, biotechnological and therapeutic tools. Their modular structure makes it easy to re-engineer them for specific purposes. Short of undergoing a trial and error process, these experiments, as well as others, need to rely on an understanding of the specific determinants of the antibody binding mode. RESULTS: In this article, we present a method to identify, on the basis of the antibody sequence alone, which residues of an antibody directly interact with its cognate antigen. The method, based on the random forest automatic learning techniques, reaches a recall and specificity as high as 80% and is implemented as a free and easy-to-use server, named prediction of Antibody Contacts. We believe that it can be of great help in re design experiments as well as a guide for molecular docking experiments. The results that we obtained also allowed us to dissect which features of the antibody sequence contribute most to the involvement of specific residues in binding to the antigen. AVAILABILITY: http://www.biocomputing.it/proABC. CONTACT: anna.tramontano@uniroma1.it or paolo.marcatili@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23803467 TI - GRN2SBML: automated encoding and annotation of inferred gene regulatory networks complying with SBML. AB - GRN2SBML automatically encodes gene regulatory networks derived from several inference tools in systems biology markup language. Providing a graphical user interface, the networks can be annotated via the simple object access protocol (SOAP)-based application programming interface of BioMart Central Portal and minimum information required in the annotation of models registry. Additionally, we provide an R-package, which processes the output of supported inference algorithms and automatically passes all required parameters to GRN2SBML. Therefore, GRN2SBML closes a gap in the processing pipeline between the inference of gene regulatory networks and their subsequent analysis, visualization and storage. AVAILABILITY: GRN2SBML is freely available under the GNU Public License version 3 and can be downloaded from http://www.hki-jena.de/index.php/0/2/490. SUPPLEMENTARY INFORMATION: General information on GRN2SBML, examples and tutorials are available at the tool's web page. PMID- 23803468 TI - Pipit: visualizing functional impacts of structural variations. AB - SUMMARY: Pipit is a gene-centric interactive visualization tool designed to study structural genomic variations. Through focusing on individual genes as the functional unit, researchers are able to study and generate hypotheses on the biological impact of different structural variations, for instance, the deletion of dosage-sensitive genes or the formation of fusion genes. Pipit is a cross platform Java application that visualizes structural variation data from Genome Variation Format files. AVAILABILITY: Executables, source code, sample data, documentation and screencast are available at https://bitbucket.org/biovizleuven/pipit. PMID- 23803469 TI - Cake: a bioinformatics pipeline for the integrated analysis of somatic variants in cancer genomes. AB - We have developed Cake, a bioinformatics software pipeline that integrates four publicly available somatic variant-calling algorithms to identify single nucleotide variants with higher sensitivity and accuracy than any one algorithm alone. Cake can be run on a high-performance computer cluster or used as a stand alone application. Availabilty: Cake is open-source and is available from http://cakesomatic.sourceforge.net/ PMID- 23803470 TI - Aptamer-based electrochemical biosensor for detection of adenosine triphosphate using a nanoporous gold platform. AB - In spite of the promising applications of aptamers in the bioassays, the development of aptamer-based electrochemical biosensors with the improved limit of detection has remained a great challenge. A strategy for the amplification of signal, based on application of nanostructures as platforms for the construction of an electrochemical adenosine triphosphate (ATP) aptasensor, is introduced in the present manuscript. A sandwich assay is designed by immobilizing a fragment of aptamer on a nanoporous gold electrode (NPGE) and its association to second fragment in the presence of ATP. Consequently, 3, 4-diaminobenzoic acid (DABA), as a molecular reporter, is covalently attached to the amine-label of the second fragment, and the direct oxidation signal of DABA is followed as the analytical signal. The sensor can detect the concentrations of ATP as low as submicromolar scales. Furthermore, 3.2% decrease in signal is observed by keeping the aptasensor at 4 degrees C for a week in buffer solution, implying a desirable stability. Moreover, analog nucleotides, including GTP, UTP and CTP, do not show serious interferences and this sensor easily detects its target in deproteinized human blood plasma. PMID- 23803471 TI - Early-stage primary school children attending a school in the Malawian School Feeding Program (SFP) have better reversal learning and lean muscle mass growth than those attending a non-SFP school. AB - In developing countries, schoolchildren encounter a number of challenges, including failure to complete school, poor health and nutrition, and poor academic performance. Implementation of school feeding programs (SFPs) in less developed countries is increasing and yet there is mixed evidence regarding their positive effects on nutrition, education, and cognition at the population level. This study evaluated cognitive and anthropometric outcomes in entry-level primary school children in Malawi with the aim of generating evidence for the ongoing debate about SFPs in Malawi and other developing countries. A total of 226 schoolchildren aged 6-8 y in 2 rural Malawian public primary schools were followed for one school year. Children attending one school (SFP school) received a daily ration of corn-soy blend porridge, while those attending the other (non SFP school) did not. Baseline and post-baseline outcomes included the Cambridge Neurological Test Automated Battery cognitive tests of paired associate learning, rapid visual information processing and intra-extra dimensional shift, and anthropometric measurements of weight, height, and mid-upper arm circumference (MUAC). At follow-up, the SFP subcohort had a greater reduction than the non-SFP subcohort in the number of intra-extra predimensional shift errors made (mean 18.5 and 24.9, respectively; P-interaction = 0.02) and also showed an increase in MUAC (from 16.3 to 17.0; P-interaction <0.0001). The results indicate that the SFP in Malawi is associated with an improvement in reversal learning and catch-up growth in lean muscle mass in children in the SFP school compared with children in the non-SFP school. These findings suggest that the Malawian SFP, if well managed and ration sizes are sustained, may have the potential to improve nutritional and cognitive indicators of the most disadvantaged children. PMID- 23803473 TI - A new target for simultaneous inhibition of hem- and lymphangiogenesis. PMID- 23803472 TI - High concentrations of a urinary biomarker of polyphenol intake are associated with decreased mortality in older adults. AB - Polyphenols might have a role in the prevention of several chronic diseases, but evaluating total dietary polyphenol (TDP) intake from self-reported questionnaires is inaccurate and unreliable. A promising alternative is to use total urinary polyphenol (TUP) concentration as a proxy measure of intake. The current study evaluated the relationship between TUPs and TDPs and all-cause mortality during a 12-y period among older adult participants. The study population included 807 men and women aged 65 y and older from the Invecchiare in Chianti study, a population-based cohort study of older adults living in the Chianti region of Tuscany, Italy. TUP concentrations were measured at enrolment (1998-2000) using the Folin-Ciocalteau assay after a solid-phase extraction. TDPs were also estimated at baseline throughout a validated food frequency questionnaire and using our database based on USDA and Phenol-Explorer databases. We modeled associations using Kaplan-Meier survival and Cox proportional hazards models, with adjustment for potential confounders. During the 12-y follow-up, 274 participants (34%) died. At enrollment, TUP excretion adjusted for age and sex tended to be greater in participants who survived [163 +/- 62 mg gallic acid equivalents (GAE)/d)] than in those who died (143 +/- 63 mg GAE/d) (P = 0.07). However, no significant differences were observed for TDPs. In the multivariable Cox model, participants in the highest tertile of TUP at enrolment had a lower mortality rate than those in the lowest tertile [HR = 0.70 (95% CI: 0.49-0.99); P trend = 0.045], whereas no significant associations were found between TDP and overall mortality. TUP is an independent risk factor for mortality among community-dwelling older adults, suggesting that high dietary intake of polyphenols may be associated with longevity. PMID- 23803474 TI - Meet the challenge. PMID- 23803475 TI - Uveitis in developing countries. PMID- 23803476 TI - Algorithmic approach in the diagnosis of uveitis. AB - Uveitis is caused by disorders of diverse etiologies including wide spectrum of infectious and non-infectious causes. Often clinical signs are less specific and shared by different diseases. On several occasions, uveitis represents diseases that are developing elsewhere in the body and ocular signs may be the first evidence of such systemic diseases. Uveitis specialists need to have a thorough knowledge of all entities and their work up has to be systematic and complete including systemic and ocular examinations. Creating an algorithmic approach on critical steps to be taken would help the ophthalmologist in arriving at the etiological diagnosis. PMID- 23803477 TI - Ancillary investigations in uveitis. AB - Ancillary investigations are the backbone of uveitis work-up both for anterior and posterior segment diseases. They help in making the diagnosis, ruling out certain differential diagnosis and monitoring inflammation during the follow-up. This review aims to be an overview describing the role of commonly used investigations for uveitis. PMID- 23803478 TI - Laboratory support in the diagnosis of uveitis. AB - Intraocular inflammations are still a diagnostic challenge for ophthalmologists. It is often difficult to make a precise etiological diagnosis in certain situations. Recently, there have been several advances in the investigations of uveitis, which has helped the ophthalmologists a lot in the management of such clinical conditions. A tailored approach to laboratory diagnosis of uveitic cases should be directed by the history, patient's symptoms and signs, and clinical examination. This review summarizes various modalities of laboratory investigations and their role in the diagnosis of uveitis. PMID- 23803479 TI - Medical management of uveitis - current trends. AB - Uveitis is a challenging disease to treat. Corticosteroids have been used in the treatment of uveitis for many years. Immunosuppressives are gaining momentum in recent years in the treatment of uveitis. In this article we present an overview of current treatment of uveitis and the major breakthroughs and advances in drugs and ocular drug delivery systems in the treatment of uveitis. PMID- 23803480 TI - Surgical management in patient with uveitis. AB - Surgery in the management of uveitis can be divided based on indication: either for therapeutic or can be for diagnostic purposes or to manage complications. The commonest indications include: Visual rehabilitation: surgery for removal of cataract, band keratopathy, corneal scars, pupillary membranes, removal of dense vitreous membranes, management of complications: anti-glaucoma surgery, vitreous hemorrhage, retinal detachment and chronic hypotony and diagnostic: aqueous tap, vitreous biopsy, tissue biopsy (iris, choroid). In this review, we shall describe the surgical technique for visual rehabilitation and for management of complications. PMID- 23803481 TI - Peripheral choroidal nodules in a case of proven systemic sarcoidosis. AB - A case of sarcoidosis presenting as peripheral choroidal nodules has been described. PMID- 23803482 TI - Red eye: rule out Ophthalmomyiasis too. AB - Ophthalmomyiasis is the infestation of human eye by the larvae of certain flies. Sheep botfly commonly manifests as Ophthalmomyiasis externa when there is conjunctival involvement or rarely as Opthalmomyiasis interna when there is larval penetration into the eyeball. It appears to be more common than what has been indicated by previously published reports. We present a report of seven cases of Ophthalmomyiasis by Oestrus ovis, from central India who presented with features of conjunctivitis varying between mild to severe. The larvae were seen in bulbar and palpebral conjunctiva and also entangled in lashes with discharge. Since the larvae are photophobic, it is prudent to look for them in the fornices and also in discharge. Prompt removal of the larvae from the conjunctiva helps in relieving the symptoms and also prevents serious complications. Taxonomic identification of the species is important to estimate the risk of globe penetration by the larvae. PMID- 23803483 TI - Periorbital dirofilariasis-clinical and imaging findings: live worm on ultrasound. AB - Ocular dirofilariasis is a zoonotic filariasis caused by nematode worm,Dirofilaria. We present a case of dirofilariasis affecting the upper eyelid in a 2-year-old child presenting as an acutely inflammed cyst, from southern Indian state of Kerala. Live adult worm was surgically removed and confirmed to be Dirofilaria repens. Live worm showing continuous movement was seen on the pre operative high-resolution ultrasound. Ultrasound can be helpful in pre-operative identification of live worm.Imaging findings reported in literature are very few. We describe the clinical, ultrasound, and magnetic resonance imaging (MRI) findings. PMID- 23803484 TI - Pseudomonas aeruginosa endophthalmitis masquerading as chronic uveitis. AB - A 65-year-old male presented with decreased vision in the left eye of 15-day duration after having undergone an uneventful cataract surgery 10 months back. He had been previously treated with systemic steroids for recurrent uveitis postoperatively on three occasions in the same eye. B-scan ultrasonography showed multiple clumplike echoes suggestive of vitreous inflammation. Aqueous tap revealed Pseudomonas aeruginosa sensitive to ciprofloxacin. The patient was treated with intravitreal ciprofloxacin and vancomycin along with systemic ciprofloxacin with good clinical response. Even a virulent organism such as P.aeruginosa can present as a chronic uveitis, which, if missed, can lead to a delay in accurate diagnosis and appropriate management. PMID- 23803485 TI - Our experience of fibrin sealant-assisted implantation of Ahmed glaucoma valve. PMID- 23803486 TI - Timely estimates of influenza A H7N9 infection severity. PMID- 23803489 TI - From the Editor-in-Chief. PMID- 23803487 TI - Human infection with avian influenza A H7N9 virus: an assessment of clinical severity. AB - BACKGROUND: Characterisation of the severity profile of human infections with influenza viruses of animal origin is a part of pandemic risk assessment, and an important part of the assessment of disease epidemiology. Our objective was to assess the clinical severity of human infections with avian influenza A H7N9 virus, which emerged in China in early 2013. METHODS: We obtained information about laboratory-confirmed cases of avian influenza A H7N9 virus infection reported as of May 28, 2013, from an integrated database built by the Chinese Center for Disease Control and Prevention. We estimated the risk of fatality, mechanical ventilation, and admission to the intensive care unit for patients who required hospital admission for medical reasons. We also used information about laboratory-confirmed cases detected through sentinel influenza-like illness surveillance to estimate the symptomatic case fatality risk. FINDINGS: Of 123 patients with laboratory-confirmed avian influenza A H7N9 virus infection who were admitted to hospital, 37 (30%) had died and 69 (56%) had recovered by May 28, 2013. After we accounted for incomplete data for 17 patients who were still in hospital, we estimated the fatality risk for all ages to be 36% (95% CI 26-45) on admission to hospital. Risks of mechanical ventilation or fatality (69%, 95% CI 60-77) and of admission to an intensive care unit, mechanical ventilation, or fatality (83%, 76-90) were high. With assumptions about coverage of the sentinel surveillance network and health-care-seeking behaviour for patients with influenza-like illness associated with influenza A H7N9 virus infection, and pro rata extrapolation, we estimated that the symptomatic case fatality risk could be between 160 (63-460) and 2800 (1000-9400) per 100,000 symptomatic cases. INTERPRETATION: Human infections with avian influenza A H7N9 virus seem to be less serious than has been previously reported. Many mild cases might already have occurred. Continued vigilance and sustained intensive control efforts are needed to minimise the risk of human infection. FUNDING: Chinese Ministry of Science and Technology; Research Fund for the Control of Infectious Disease; Hong Kong University Grants Committee; China-US Collaborative Program on Emerging and Re-emerging Infectious Diseases; Harvard Center for Communicable Disease Dynamics; US National Institute of Allergy and Infectious Disease; and the US National Institutes of Health. PMID- 23803488 TI - Comparative epidemiology of human infections with avian influenza A H7N9 and H5N1 viruses in China: a population-based study of laboratory-confirmed cases. AB - BACKGROUND: The novel influenza A H7N9 virus emerged recently in mainland China, whereas the influenza A H5N1 virus has infected people in China since 2003. Both infections are thought to be mainly zoonotic. We aimed to compare the epidemiological characteristics of the complete series of laboratory-confirmed cases of both viruses in mainland China so far. METHODS: An integrated database was constructed with information about demographic, epidemiological, and clinical variables of laboratory-confirmed cases of H7N9 (130 patients) and H5N1 (43 patients) that were reported to the Chinese Centre for Disease Control and Prevention until May 24, 2013. We described disease occurrence by age, sex, and geography, and estimated key epidemiological variables. We used survival analysis techniques to estimate the following distributions: infection to onset, onset to admission, onset to laboratory confirmation, admission to death, and admission to discharge. FINDINGS: The median age of the 130 individuals with confirmed infection with H7N9 was 62 years and of the 43 with H5N1 was 26 years. In urban areas, 74% of cases of both viruses were in men, whereas in rural areas the proportions of the viruses in men were 62% for H7N9 and 33% for H5N1. 75% of patients infected with H7N9 and 71% of those with H5N1 reported recent exposure to poultry. The mean incubation period of H7N9 was 3.1 days and of H5N1 was 3.3 days. On average, 21 contacts were traced for each case of H7N9 in urban areas and 18 in rural areas, compared with 90 and 63 for H5N1. The fatality risk on admission to hospital was 36% (95% CI 26-45) for H7N9 and 70% (56-83%) for H5N1. INTERPRETATION: The sex ratios in urban compared with rural cases are consistent with exposure to poultry driving the risk of infection--a higher risk in men was only recorded in urban areas but not in rural areas, and the increased risk for men was of a similar magnitude for H7N9 and H5N1. However, the difference in susceptibility to serious illness with the two different viruses remains unexplained, since most cases of H7N9 were in older adults whereas most cases of H5N1 were in younger people. A limitation of our study is that we compared laboratory-confirmed cases of H7N9 and H5N1 infection, and some infections might not have been ascertained. FUNDING: Ministry of Science and Technology, China; Research Fund for the Control of Infectious Disease and University Grants Committee, Hong Kong Special Administrative Region, China; and the US National Institutes of Health. PMID- 23803490 TI - Reasons for inconsistent condom use among female sex workers: need for integrated reproductive and prevention services. AB - BACKGROUND: Interventions for condom use promotion have been undertaken for HIV prevention among female sex workers (FSWs). Our aims are to (1) assess the frequency of inconsistent condom use with clients and with the main regular non client sex partner (RNCP); and (2) investigate factors associated with inconsistent condom use with the RNCP, particularly the desire to have children and links of the RNCP with commercial sex work. METHODS: A cross-sectional study was conducted in Conakry, Guinea, among 223 FSWs. A questionnaire on socio demographic characteristics, behaviours and desire for children was administered. Descriptive statistics and logistic regression were performed. RESULTS: Inconsistent condom use was frequent with the RNCP but rare with the clients (80.4% vs. 1.3%). FSWs' desire for children was strongly associated with inconsistent condom use with the RNCP. CONCLUSION: Interventions that take into account reproductive health are needed to prevent HIV among FSWs and their children. PMID- 23803491 TI - Reasons for persistence of dwelling vulnerability to Chagas disease (American trypanosomiasis): a qualitative study in northeastern Brazil. AB - Interaction between Chagas disease vectors and man is continuous in vulnerable dwellings, in which the vectors feed on man and find conditions for reproduction. This study explores factors that affect the choice of home construction methods in a rural community in Brazil, emphasizing the rationale for the persistence of dwelling vulnerability. Information on local resident perspectives regarding safety and home construction methods was gathered through domiciliary interviews with open questionnaires. The study revealed a large proportion of vulnerable mud huts, with others under construction. Insecurity over land tenure inhibits the construction of definitive houses. Mud homes are associated with greater structural stability. Cultural and economic factors have clearly been linked to the choice of method for home construction. The economic evolution of family conflicts with traditional aspects as well as the relative increased cost of the materials needed for mud house construction has not completely inhibited building with mud. PMID- 23803492 TI - Resource allocation in Pakistan's health sector: a critical appraisal and a path toward the Millennium Development Goals. AB - Pakistan is trying hard to sustain its progress toward the Millennium Development Goals. However, because of a lack of political commitment to innovative solutions to improve its financing mechanism, the health system is unable to provide even essential and basic services to the people. The country, with more than 70% of the population living on less than two US dollars a day, largely depends on direct taxes for its revenue. Because of inadequate financing, the quality of government services is inexcusably poor; therefore, a majority of people seek healthcare in the private sector. This has led to a horde of issues pertaining to equity, accessibility and fairness. High out-of-pocket expenses on health jeopardize a family's livelihood, pushing it into a vicious circle of poverty. In the wake of recent devolution, this paper presents options for future health financing that enables the provinces to exert their autonomy to safeguard the health of the most vulnerable in the country. Our recommendations follow the vision of the World Health Organization and the Commission on Macroeconomics and Health, to achieve universal health coverage and social protection for the poor. PMID- 23803493 TI - Global access to safe water: accounting for water quality and the resulting impact on MDG progress. AB - Monitoring of progress towards the Millennium Development Goal (MDG) drinking water target relies on classification of water sources as "improved" or "unimproved" as an indicator for water safety. We adjust the current Joint Monitoring Programme (JMP) estimate by accounting for microbial water quality and sanitary risk using the only-nationally representative water quality data currently available, that from the WHO and UNICEF "Rapid Assessment of Drinking Water Quality". A principal components analysis (PCA) of national environmental and development indicators was used to create models that predicted, for most countries, the proportions of piped and of other-improved water supplies that are faecally contaminated; and of these sources, the proportions that lack basic sanitary protection against contamination. We estimate that 1.8 billion people (28% of the global population) used unsafe water in 2010. The 2010 JMP estimate is that 783 million people (11%) use unimproved sources. Our estimates revise the 1990 baseline from 23% to 37%, and the target from 12% to 18%, resulting in a shortfall of 10% of the global population towards the MDG target in 2010. In contrast, using the indicator "use of an improved source" suggests that the MDG target for drinkingwater has already been achieved. We estimate that an additional 1.2 billion (18%) use water from sources or systems with significant sanitary risks. While our estimate is imprecise, the magnitude of the estimate and the health and development implications suggest that greater attention is needed to better understand and manage drinking water safety. PMID- 23803494 TI - Determination of phylogenetic relationships among Eimeria species, which parasitize cattle, on the basis of nuclear 18S rDNA sequence. AB - We analyzed almost complete 18S rDNA sequences of 10 bovine Eimeria species, namely Eimeria alabamensis, E. auburnensis, E. bovis, E. bukidnonensis, E. canadensis, E. cylindrica, E. ellipsoidalis, E. subspherica, E. wyomingensis and E. zuernii. Although these sequences showed intraspecific variation in 8 species, the sequences of each species were clustered in monophyletic groups in all species, except E. auburnensis. The sequences constituted 3 distinct clusters in a phylogenetic tree with relatively high bootstrap values; however, the members including each cluster shared no similarities in oocyst morphology. PMID- 23803495 TI - Myotonic dystrophy type 1 presenting with stroke-like episodes: a case report. AB - BACKGROUND: It is well known that myotonic dystrophy type 1 (DM1)--Curschmann Steinert disease--is associated with white matter lesions in the brain. Further, DM1 patients may suffer from cardiac involvement and cardioembolic strokes. We report on the unique case of an adult-onset DM1 without cardiac or vascular abnormalities presenting with stroke-like episodes. CASE PRESENTATION: A 40 y old white female was admitted twice to our stroke unit with apoplectic dizziness, nausea, headaches, and numbness in the right arm. She was suffering from type 2 diabetes, cataract, and endometriosis. Magnetic resonance imaging (MRI) revealed confluent white matter lesions in all cerebral lobes. There was no hyperintensity on diffusion-weighted imaging (DWI) and no gadolinium enhancement. Cerebrospinal fluid was normal. Surprisingly, myotonic discharges were detected in electromyography (EMG). Genetic testing revealed 200 +/- 10 CTG repeats in the dystrophia myotonica protein kinase (DMPK) gene on chromosome 19 and DM1 was diagnosed. CONCLUSIONS: DM1 may be the cause of cerebral white matter lesions. This is the first case of DM1 presenting with stroke-like episodes. PMID- 23803496 TI - Health care costs and the socioeconomic consequences of work injuries in Brazil: a longitudinal study. AB - Work injuries are a worldwide public health problem but little is known about their socioeconomic impact. This prospective longitudinal study estimates the direct health care costs and socioeconomic consequences of work injuries for 406 workers identified in the emergency departments of the two largest public hospitals in Salvador, Brazil, from June through September 2005. After hospital discharge workers were followed up monthly until their return to work. Most insured workers were unaware of their rights or of how to obtain insurance benefits (81.6%). Approximately half the cases suffered loss of earnings, and women were more frequently dismissed than men. The most frequently reported family consequences were: need for a family member to act as a caregiver and difficulties with daily expenses. Total costs were US$40,077.00 but individual costs varied widely, according to injury severity. Out-of-pocket costs accounted for the highest proportion of total costs (50.5%) and increased with severity (57.6%). Most out-of-pocket costs were related to transport and purchasing medicines and other wound care products. The second largest contribution (40.6%) came from the public National Health System - SUS. Employer participation was negligible. Health care funding must be discussed to alleviate the economic burden of work injuries on workers. PMID- 23803498 TI - Increase in psychotropic drug deliveries after the Xynthia storm, France, 2010. AB - INTRODUCTION: During the night of February 27 and the early morning of February 28, 2010, 15 coastal municipalities situated in two French departments, Vendee and Charente-Maritime, were violently stricken by a severe windstorm named "Xynthia." This storm caused the death of 12 individuals in Charente-Maritime and 29 people in Vendee. Houses, agricultural fields, and shellfish companies were severely flooded with seawater. Several thousand people temporarily had to leave their homes. The objective of this study was to estimate the short-term mental health impact of Xynthia, in terms of psychotropic drug delivery, on the resident population of the 15 coastal municipalities severely hit by the flooding. METHODS: The French national health insurance database was used to calculate a daily number of new psychotropic treatments from September 1, 2008 through December 24, 2010. New treatments were calculated for each of the following European Pharmaceutical Marketing Research Association (EphMRA) classes: tranquilizers (N05C), hypnotics (N05B), and antidepressants (N06A). A period of three weeks following the storm was defined as the exposure period. A generalized additive model with a Poisson distribution that allows for over-dispersion was used to analyze the correlation between the Xynthia variable and the number of new psychotropic treatments. RESULTS: With a relative risk (RR) of 1.54 (95% CI, 1.39-1.62) corresponding to an estimate of 409 new deliveries of psychotropic drugs during the three weeks following the storm, this study confirms the importance of the psychological impact of Xynthia. This impact is seen on all three classes of psychotropic drugs studied. The impact is greater for tranquilizers (RR of 1.78; 95% CI, 1.59-1.89) than for hypnotics (RR of 1.53; 95% CI, 1.31-1.67) and antidepressants (RR of 1.26; 95% CI, 1.06-1.40). The RR was higher for females than for males. CONCLUSION: This study shows the importance of the psychological impact of the storm as observed clinically by health workers who intervened in the field during the aftermath of Xynthia. It confirms that administrative databases can be used to show a health impact of a disaster even at a local level. This is one more step in the direction of a comprehensive strategy of collecting information to allow the assessment of the health impact of an extreme event, the detection of vulnerable populations, and the orientation of the short-, mid- and long-term public health response. PMID- 23803497 TI - Effects of shift and night work in the offshore petroleum industry: a systematic review. AB - Shift and night work are associated with several negative outcomes. The aim of this study was to make a systematic review of all studies which examine effects of shift and night work in the offshore petroleum industry, to synthesize the knowledge of how shift work offshore may affect the workers. Searches for studies concerning effects on health, sleep, adaptation, safety, working conditions, family- and social life and turnover were conducted via the databases Web of Knowledge, PsycINFO and PubMed. Search was also conducted through inspection of reference lists of relevant literature. We identified studies describing effects of shift work in terms of sleep, adaptation and re-adaptation of circadian rhythms, health outcomes, safety and accidents, family and social life, and work perceptions. Twenty-nine studies were included. In conclusion, the longitudinal studies were generally consistent in showing that adaptation to night work was complete within one to two weeks of work, while re-adaptation to a daytime schedule was slower. Shift workers reported more sleep problems than day workers. The data regarding mental and physical health, family and social life, and accidents yielded inconsistent results, and were insufficient as a base for drawing general conclusions. More research in the field is warranted. PMID- 23803499 TI - GLP-1 receptor is expressed in human stomach mucosa: analysis of its cellular association and distribution within gastric glands. AB - The stomach is a target organ of the incretin hormone glucagon-like peptide-1 (GLP-1). However, the cellular expression and glandular distribution of its receptor (GLP-1R) in human gastric mucosa are not known. We determined the expression of GLP-1R in different regions of human stomach mucosa and its specific cellular association and distribution within gastric glands. Tissue samples from stomach body and antrum were obtained from 20 patients during routine esophagogastroduodenoscopy. mRNA encoding GLP-1R protein expression was evaluated by RT-PCR. Determination of cell types bearing GLP-1R, their localization, and their frequency in gastric glands in different gastric regions were estimated by immunohistochemical morphological analysis. Levels of GLP-1R mRNA were similar in body and antrum. GLP-1R immunoreactivity was found throughout the gastric mucosa in various types of glandular cells. The highest frequency of GLP-1R immunoreactive cells was found in the neck area of the principal glands in cells morphologically identified as parietal cells. GLP-1R immunostaining was also found on enteroendocrine-like cells in the pyloric glands. This study provides the first description of GLP-1R expression in human gastric glands and its specific cellular association. Our data suggest that GLP-1 may act directly on the gastric mucosa to modulate its complex functions. PMID- 23803501 TI - Abiotic formation of methyl iodide on synthetic birnessite: a mechanistic study. AB - Methyl iodide is a well-known volatile halogenated organic compound that contributes to the iodine content in the troposphere, potentially resulting in damage to the ozone layer. Most methyl iodide sources derive from biological activity in oceans and soils with very few abiotic mechanisms proposed in the literature. In this study we report that synthetic manganese oxide (birnessite delta-MnO2) can catalyze the formation of methyl iodide in the presence of natural organic matter (NOM) and iodide. Methyl iodide formation was only observed at acidic pH (4-5) where iodide is oxidized to iodine and NOM is adsorbed on delta-MnO2. The effect of delta-MnO2, iodide and NOM concentrations, nature of NOM and ionic strength was investigated. High concentrations of methyl iodide were formed in experiments conducted with the model compound pyruvate. The Lewis acid property of delta-MnO2 leads to a polarization of the iodine molecule, and catalyzes the reaction with natural organic matter. As manganese oxides are strong oxidants and are ubiquitous in the environment, this mechanism could significantly contribute to the global atmospheric input of iodine. PMID- 23803502 TI - Reducing indoor air pollution by air conditioning is associated with improvements in cardiovascular health among the general population. AB - Indoor air pollution is associated with cardiovascular effects, however, little is known about the effects of improving indoor air quality on cardiovascular health. The aim of this study was to explore whether improving indoor air quality through air conditioning can improve cardiovascular health in human subjects. We recruited a panel of 300 healthy subjects from Taipei, aged 20 and over, to participate in six home visits each, to measure a variety of cardiovascular endpoints, including high sensitivity-C-reactive protein (hs-CRP), 8-hydroxy-2' deoxyguanosine (8-OHdG), fibrinogen in plasma and heart rate variability (HRV). Indoor particles and total volatile organic compounds (VOCs) were measured simultaneously at the participant's home during each visit. Three exposure conditions were investigated in this study: participants were requested to keep their windows open during the first two visits, close their windows during the next two visits, and close the windows and turn on their air conditioners during the last two visits. We used linear mixed-effects models to associate the cardiovascular endpoints with individual indoor air pollutants. The results showed that increases in hs-CRP, 8-OHdG and fibrinogen, and decreases in HRV indices were associated with increased levels of indoor particles and total VOCs in single-pollutant and two-pollutant models. The effects of indoor particles and total VOCs on cardiovascular endpoints were greatest during visits with the windows open. During visits with the air conditioners turned on, no significant changes in cardiovascular endpoints were observed. In conclusion, indoor air pollution is associated with inflammation, oxidative stress, blood coagulation and autonomic dysfunction. Reductions in indoor air pollution and subsequent improvements in cardiovascular health can be achieved by closing windows and turning on air conditioners at home. PMID- 23803500 TI - Suicide in Hungary-epidemiological and clinical perspectives. AB - Annual suicide rates of Hungary were unexpectedly high in the previous century. In our narrative review, we try to depict, with presentation of the raw data, the main descriptive epidemiological features of the Hungarian suicide scene of the past decades. Accordingly, we present the annual suicide rates of the period mentioned and also data on how they varied by gender, age, urban vs. rural living, seasons, marital status, etc. Furthermore, the overview of trends of other factors that may have influenced suicidal behavior (e.g., alcohol and tobacco consumption, antidepressant prescription, unemployment rate) in the past decades is appended as well. Based on raw data and also on results of the relevant papers of Hungarian suicidology we tried to explain the observable trends of the Hungarian suicide rate. Eventually, we discuss the results, the possibilities, and the future tasks of suicide prevention in Hungary. PMID- 23803503 TI - Uncertainties in estimating health risks associated with exposure to ionising radiation. AB - The information for the present discussion on the uncertainties associated with estimation of radiation risks and probability of disease causation was assembled for the recently published NCRP Report No. 171 on this topic. This memorandum provides a timely overview of the topic, given that quantitative uncertainty analysis is the state of the art in health risk assessment and given its potential importance to developments in radiation protection. Over the past decade the increasing volume of epidemiology data and the supporting radiobiology findings have aided in the reduction of uncertainty in the risk estimates derived. However, it is equally apparent that there remain significant uncertainties related to dose assessment, low dose and low dose-rate extrapolation approaches (e.g. the selection of an appropriate dose and dose-rate effectiveness factor), the biological effectiveness where considerations of the health effects of high-LET and lower-energy low-LET radiations are required and the transfer of risks from a population for which health effects data are available to one for which such data are not available. The impact of radiation on human health has focused in recent years on cancer, although there has been a decided increase in the data for noncancer effects together with more reliable estimates of the risk following radiation exposure, even at relatively low doses (notably for cataracts and cardiovascular disease). New approaches for the estimation of hereditary risk have been developed with the use of human data whenever feasible, although the current estimates of heritable radiation effects still are based on mouse data because of an absence of effects in human studies. Uncertainties associated with estimation of these different types of health effects are discussed in a qualitative and semi-quantitative manner as appropriate. The way forward would seem to require additional epidemiological studies, especially studies of low dose and low dose-rate occupational and perhaps environmental exposures and for exposures to x rays and high-LET radiations used in medicine. The development of models for more reliably combining the epidemiology data with experimental laboratory animal and cellular data can enhance the overall risk assessment approach by providing biologically refined data to strengthen the estimation of effects at low doses as opposed to the sole use of mathematical models of epidemiological data that are primarily driven by medium/high doses. NASA's approach to radiation protection for astronauts, although a unique occupational group, indicates the possible applicability of estimates of risk and their uncertainty in a broader context for developing recommendations on: (1) dose limits for occupational exposure and exposure of members of the public; (2) criteria to limit exposures of workers and members of the public to radon and its short-lived decay products; and (3) the dosimetric quantity (effective dose) used in radiation protection. PMID- 23803504 TI - A huge aortic arch aneurysm in a non-Marfan elderly patient. PMID- 23803505 TI - Three-dimensional imaging of a thoracic duct cyst before thoracoscopic surgery. PMID- 23803506 TI - The most versatile and useful appendage on earth. PMID- 23803507 TI - Infective endocarditis in transcatheter aortic valve implantation. PMID- 23803508 TI - Survival and quality of life in an elderly cardiac surgery population: 5-year follow-up. AB - OBJECTIVES: As survival after cardiac surgery has become very satisfactory even in elderly patients, more attention is being directed towards improved health related quality of life (HRQOL). However, longitudinal prospective cohort studies describing HRQOL after cardiac surgery are still scarce. The purpose of this study was to explore HRQOL and survival in patients undergoing cardiac surgery after 5 years, emphasizing on older patients (>=75 years). METHODS: In a prospective population-based study, 534 patients (23% >=75 years, 67% males) were consecutively included before surgery. HRQOL and medical and sociodemographic variables were measured by questionnaires at baseline, 6 and 12 months after surgery and again after 5 years. HRQOL was measured by the Short-Form 36 Health Survey (SF-36). RESULTS: Four hundred and fifty-eight patients were alive after 5 years, with a response rate of 82%. Older patients had lower 5-year survival than younger patients (P = 0.042), but it was similar to that of the general population. After 5 years, both older and younger patients had slightly lower scores on some SF-36 dimensions, compared with scores after 6 and 12 months. However, on seven of eight subscales of the SF-36, the scores after 5 years were still higher than before surgery. Older patients improved less from baseline to the follow-up, and had more profound reductions in scores from 12 months to 5 years on three subscales; physical functioning (P = 0.013), role physical (P < 0.001) and vitality (P = 0.036). CONCLUSIONS: HRQOL improved from baseline to 6 months postoperatively, and remained relatively stable 5 years after cardiac surgery even in elderly patients. The study showed that survival and HRQOL can match that of the general population. PMID- 23803509 TI - Pulmonary metastasectomy and the use of molecular and radiological markers: is this a way to reduce unavailing surgery? PMID- 23803510 TI - Modified Cabrol shunt by means of a saphenous vein graft after redo aortic root surgery due to a graft infection. PMID- 23803511 TI - Editorial comment: Arterial switch, reparation a l'etage ventriculaire, Rastelli or Nikaidoh? PMID- 23803512 TI - Mechanical impairment of the aortic media caused by vasa vasorum dysfunction: a potential key element in the pathogenesis of aortic dissection in hypertensive patients. PMID- 23803513 TI - Reply to Da Col. PMID- 23803514 TI - Challenging valve replacement in posterior mitral annular calcification. PMID- 23803515 TI - Extended cervical mediastinoscopy revisited. AB - OBJECTIVES: To describe the diagnostic value of selective extended cervical mediastinoscopy (ECM) in combination with video-assisted mediastinoscopic lymphadenectomy (VAMLA) in mediastinal staging of potentially resectable left sided lung carcinoma. METHODS: Institutional report on 110 ECM procedures indicated for enlarged lymph nodes within the aorto-pulmonary (AP) zone on computed tomography. Staging sensitivity, negative predictive value (NPV) and specificity of ECM, combined VAMLA and ECM, VAMLA alone and systematic dissection for lung resection via left-sided video-assisted thoracoscopic surgery (VATS) or thoracotomy were calculated from a subset of 92 patients with left-sided lung carcinoma. RESULTS: Selective ECM was performed in 12.6% of all video mediastinoscopic procedures, and added, except for one vascular complication, there was no morbidity. ECM had an impact on mediastinal staging in 78.0% of the lung cancer cases. Sensitivity, NPV and specificity were 0.94, 0.96 and 1 for ECM to detect nodal involvement within the AP zone. Sensitivity, NPV and specificity to detect any mediastinal diseases were 0.94, 0.96 and 1 for the combination of ECM and VAMLA; 0.64, 0.80 and 1 for VAMLA alone and 0.76, 0.84 and 1 for systematic mediastinal dissection via left-sided VATS or thoracotomy approach. CONCLUSIONS: ECM complements VAMLA in comprehensive mediastinal dissection. Selective ECM is a valuable addendum to mediastinoscopic staging procedures for left-sided tumours, as it enhances sensitivity and NPV. Precaution and experience are required to circumvent the rare risk of potentially fatal vascular accidents. PMID- 23803516 TI - Anatomical factors determining surgical decision-making in patients with transposition of the great arteries with left ventricular outflow tract obstruction. AB - OBJECTIVES: Transposition of the great arteries (TGA) and left ventricular outflow tract obstruction (LVOTO) with or without ventricular septal defect have multiple surgical treatment options. We sought to identify pre- and intraoperative factors that determine the timing of repair, procedure type and subsequent LVOT outcome. METHODS: Twenty-eight (8.2% of all TGA) patients with TGA with LVOTO (double outlet ventricle, n = 5, TGA/intact septum, n = 1) between 2000 and 2012 were reviewed. Anatomical factors were identified by prerepair echocardiography. LVOTO complexity was characterized by the degree of obstruction (0 = none, 0.33 = mild, 0.66 moderate and 1 = severe) at various levels: pulmonary valve (PV) dysplasia/hypoplasia, posterior deviation of the infundibular septum, fibromuscular ridge, tissue tag and abnormal chordal attachment. Summation of the obstruction score, at each level, yielded the LVOT complexity score. The descriptive analysis of intraoperative decision-making at late repair was performed. RESULTS: OPERATIONS: early arterial switch operation (ASO) + LVOT resection (n = 9, 32%), late ASO + LVOT resection (n = 3, 10%), Nikaidoh (n = 8, 29%), Rastelli (n = 6, 21%), single-ventricle palliation (n = 2, 7%). The primary LVOT obstruction mechanism was posterior deviation of the infundibular septum (n = 16, 57%) and PV dysplasia (n = 6, 21%). The early ASO group had a lower PV complexity score (0.42 +/- 0.22 vs 0.96 +/- 0.55, P = 0.007), tissue tag score (0.03 +/- 0.15 vs 0.26 +/- 0.34, P = 0.018) and LVOT complexity score (2.11 +/- 0.86 vs 3.2 +/- 0.96, P = 0.006). The LVOT complexity score in the Nikaidoh group was higher than in the late ASO group (P = 0.019). Of 16 candidates for the Nikaidoh procedure, 6 patients underwent a Rastelli operation due to coronary artery patterns (single coronary, n = 3, 1RL-2Cx, n = 2 or an abnormal left anterior descending coronary artery course, n = 1). Two patients underwent single-ventricle palliation due to the interference of essential chordae. All patients survived the operation. The 3-year survival was 96%. One patient who underwent late ASO required re-LVOT resection. CONCLUSIONS: A newly developed scoring system, the LVOT complexity score, helped to quantify the LVOT complexity and was correlated with our choice of the surgical procedure of TGA with LVOTO. The current strategy achieved reasonable survival and LVOT outcome with three quarters of the patients having an anatomically aligned LVOT. The coronary anatomy pattern was the primary determinant in the decision-making between the Nikaidoh procedure and the Rastelli operation. PMID- 23803517 TI - The plastidic DEAD-box RNA helicase 22, HS3, is essential for plastid functions both in seed development and in seedling growth. AB - Plants accumulate large amounts of storage products in seeds to provide an energy reserve and to supply nutrients for germination and post-germinative growth. Arabidopsis thaliana belongs to the Brassica family, and oil is the main storage product in Arabidopsis seeds. To elucidate the regulatory mechanisms of oil biosynthesis in seeds, we screened for high density seeds (heavy seed) that have a low oil content. HS3 (heavy seed 3) encodes the DEAD-box RNA helicase 22 that is localized to plastids. The triacylglycerol (TAG) content of hs3-1 seeds was 10% lower than that of wild-type (WT) seeds, while the protein content was unchanged. The hs3-1 plants displayed a pale-green phenotype in developing seeds and seedlings, but not in adult leaves. The HS3 expression level was high in developing seeds and seedlings, but was low in stems, rosette leaves and flowers. The plastid gene expression profile of WT developing seeds and seedlings differed from that of hs3-1 developing seeds and seedlings. The expression of several genes was reduced in developing hs3-1 seeds, including accD, a gene that encodes the beta subunit of carboxyltransferase, which is one component of acetyl-CoA carboxylase in plastids. In contrast, no differences were observed between the expression profiles of WT and hs3-1 rosette leaves. These results show that HS3 is essential for proper mRNA accumulation of plastid genes during seed development and seedling growth, and suggest that HS3 ensures seed oil biosynthesis by maintaining plastid mRNA levels. PMID- 23803518 TI - Stress-related psychological symptoms are associated with increased attentional capture by visually salient distractors. AB - Research has shown that attention can be abnormally drawn to salient threat- or trauma-related information in individuals with posttraumatic stress and related psychological symptoms. The nature of this attentional bias is thought to derive from capture of attention toward potential threat overpowering the volitional, goal-directed attentional system. However, it is unclear whether this pattern of attentional dysregulation generalizes to salient, but non-emotional types of information. Using a well-established and sensitive measure of attentional capture, the current study demonstrates that posttraumatic psychological symptom severity is associated with the capture of attention by visually salient, non emotional distractors. Specifically, during visual search for a unique shape, the presence of a task-irrelevant but salient color singleton disrupted search efficiency, and this disruption was correlated with both posttraumatic stress disorder (PTSD) and depression symptom severity as assessed by self-report. These findings suggest that posttraumatic stress and depression may be characterized as involving a general alteration of the balance between salience-based and goal directed attentional systems. PMID- 23803519 TI - Double trouble: preseptal cellulitis due to two species with multidrug resistance. AB - A 2 Year old boy presented with painful ballooning of both eyes with the 2 days history of trauma to the head while playing. His vaccination was complete. On examination he was afebrile. The Eyes were ballooned with blackish crust over both lids. On local examination, eye swelling was tense with severe tenderness. The diagnosis of Preseptal cellulitis was made .We did an Emergency drainage and pus was sent for culture that came out to be positive for Pseudomonas aeruginosa and Proteus mirabilis with multiple drug resistance. The coverage was given by Imipenem+cilastatin and child had wonderful recovery. PMID- 23803520 TI - [Analyses on the characteristics and the trends of pneumoconiosis notified between 1997 and 2009, in China]. AB - OBJECTIVE: To describe the incidence of pneumoconiosis reported in China from 1997 to 2009 and investigate the epidemiological trends and characteristics of pneumoconiosis, and to provide basic data for formulating the guidelines and policies for control of pneumoconiosis, research on pneumoconiosis, and establishing the time series model for monitoring and early warning of pneumoconiosis. METHODS: The national database of new cases of pneumoconiosis reported from 1997 to 2009 was subjected to systematic arrangement, descriptive analysis, and trend test using SPSS 15.0. The statistical indices included number of new pneumoconiosis cases in each year, types of pneumoconiosis, regional and industrial distributions of pneumoconiosis cases, work types of pneumoconiosis cases, and the annual changes in mean length of service and mean age at the onset of pneumoconiosis. RESULTS: From 1997 to 2009, a total of 122 333 new cases of pneumoconiosis were reported; the number of new cases increased since 1998, but fell to 7620 in 2003, and then it increased again to a maximum of 12 492 in 2009. Of all patients, 87.5% were cases of coal-workers' pneumoconiosis and silicosis; 54 068 (44.2%) were coal-workers' pneumoconiosis cases, and 52 930 (43.3%) were silicosis cases. The pneumoconiosis cases were distributed mainly in Hunan Province (12 995 cases, 10.6%), Shandong Province (8952 cases, 7.3%), and Sichuan Province (8417 cases, 6.9%). Most cases were distributed in coal industry (61270 cases, 50.1%), architectural, material industry (9754 cases, 8.0%), nonferrous metals industry (9380 cases, 7.7%), and metallurgical industry (8773 cases, 7.2%). The work types of these cases mainly included tunneling as the main work (15 659 cases, 12.8%), mining as the main work (15 009 cases, 12.3%), drilling (14 010 cases, 11.5%), tunneling (12 122 cases, 9.9%), and hybrid coalmine work (10 612 cases, 8.7%). The mean length of service at the onset of pneumoconiosis in new cases of pneumoconiosis was shortened from 1997 to 2009, with a median length of service of 20.00 years; the median lengths of service at the onsets of coal-workers' pneumoconiosis, silicosis, and asbestosis were 21.58, 17.00, and 20.00 years, respectively. The median age at the onset of pneumoconiosis was 51.00 years, and the mean age of onset in new cases of pneumoconiosis increased over the 13 years. CONCLUSION: The incidence of pneumoconiosis is still high, with a marked concentrated trend in several industries, work types, and pneumoconiosis types, a marked rising trend in number of new cases, and a marked shortening trend in length of service at the onset of pneumoconiosis. The prevention and control of pneumoconiosis should be enhanced in key industries and for people engaging in key types of work according to the epidemiological characteristics of pneumoconiosis. In addition, the demonstration project of comprehensive prevention and control of occupational dust hazards should be carried out, and the monitoring and early warning system for pneumoconiosis should be established. PMID- 23803521 TI - [Regulating effect of N-acetyl-seryl-aspartyl-lysyl-proline on activation of c jun N-terminal kinase pathway in rats with silicosis]. AB - OBJECTIVE: To investigate the regulatory effect of N-acetyl-seryl-aspartyl-lysyl proline (AcSDKP) on the activation of c-jun N-terminal kinase (JNK) signal transduction pathway and its role in silicotic fibrosis. METHODS: A rat model of silicosis was developed by intratracheal instillation. Sixty rats were randomly divided into 4-week control group (n = 10), 8-week control group (n = 10), 4-week silicosis model group (n = 10), 8-week silicosis model group (n = 10), AcSDKP treatment group (n = 10), and AcSDKP prevention group (n = 10). The content of hydroxyproline in lung tissue was measured using a p-dimethylaminoben-zaldehyde reagent; the expression levels of transforming growth factor (TGF)-beta 1 (TGF beta1), phospho-JNK, JNK, and c-jun in lung tissue were measured by Western blot. The lung fibroblasts from neonatal rats were cultured, and the 4th generation of cells were used in the experiment; these cells were divided into control group, TGF-beta1 stimulation group, SP600125 intervention group, and AcSDKP intervention group. The distributions of phospho-JNK and c-jun in lung fibroblasts were observed by immunocytochemistry; the expression levels of type I collagen and type III collagen in lung fibroblasts were measured by Western blot. RESULTS: The expression levels of TGF-beta1, phospho-JNK, and c-jun and the content of hydroxyproline in the AcSDKP treatment group were 70.60%, 78.03%, 79.85%, and 71.28%, respectively, of those in the 4-week silicosis model group (P < 0.05) and 77.99%, 66.73%, 69.94%, and 64.82%, respectively, of those in the 8-week silicosis model group (P < 0.05); the expression levels of TGF-beta1, phospho JNK, and c-jun and the content of hydroxyproline in the AcSDKP prevention group were 84.56%, 61.18%, 64.73%, and 74.96%, respectively, of those in the 8-week silicosis model group (P < 0.05). The expression levels of phospho-JNK and c-jun in the AcSDKP intervention group were 54.59% and 55.56%, respectively, of those in the TGF-beta1 stimulation group; the expression levels of type I collagen and type III collagen in the AcSDKP intervention group were 79.9% and 84.4%, respectively, of those in the TGF-beta1 stimulation group (P < 0.05). CONCLUSION: AcSDKP exerts anti-silicotic fibrosis effect probably by inhibiting the activation of JNK signal transduction pathway mediated by TGF-beta1 and the deposition of interstitial collagen. PMID- 23803522 TI - [Effects of pyrrolidine dithiocarbamate on expressions of alpha-smooth muscle actin, integrin alpha5 and fibronectin in acute paraquat poisoned rats]. AB - OBJECTIVE: To observe the expressions of alpha-SMA, integrin alpha5 and fibronectin (Fn) in acute paraquat poisoned rats and the effect of PDTC. To investigate the mechanism of paraquat-induced pulmonary fibrosis. METHODS: Sprague-Dawley rats were randomly divided into three experimental groups: Control group (6 rats), PQ group (36 rats) and PQ+PDTC group (36 rats). On the 1st, 3rd, the 7th, the 14th, the 28th and the 56th day after exposure, the protein expression of alpha smooth muscle actin (alpha-SMA) was evaluated by western blot. The mRNA levels of integrin alpha5 and fibronectin (Fn) were analyzed with real-time quantitative PCR (RT-PCR). Meanwhile, the lung pathological changes were observed and semi-quantified. RESULTS: T With the time passing, the expression of alpha-SMA in PQ group increased gradually compared with control group (P < 0.05 or P < 0.01). The increasing extent was gently on the 3 rd, the 7 th day. While increasing extent was rapidly from the 28 th to the 56 th day. RT PCR showed PQ significantly increased Fn mRNA level on all time points and increased integrin alpha5 mRNA level from the 7 rd to 56 th day compared with control group (P < 0.05 or P < 0.01). PDTC treatment significantly deceased alpha SMA, Fn, and integrin alpha5 levels compared with PQ group in corresponding time points (P < 0.05 or P < 0.01) Noteworthy, in PQ+PDTC group, the occurrence of pathological changes were drastically attenuated and pathologic score significantly decreased (P < 0.05 or P < 0.01). CONCLUSIONS: alpha-SMA, integrin alpha5 and fibronectin could play an important role in the development of pulmonary fibrosis caused by paraquat poisoning. PDTC, asa strong NF-kappaB inhibitor, may inhibit NF-kappaB activity and further significantly decreased expressions of alpha-SMA, integrin alpha5 and fibronectin which were important part of ECM, leading to drastically attenuated pulmonary fibrosis. However, the mechanisms of PDTC intervention still remains to be explored. PMID- 23803523 TI - [Effects of p38 mitogen-activated protein kinases on the apoptosis of human bronchial epithelial cells induced by refractory ceramic fibers in vitro]. AB - OBJECTIVE: To investigate the role of p38 mitogen-activated protein kinases (MAPKs) in the apoptosis of human bronchial epithelial cells (BEAS-2B) induced by refractory ceramic fibers (RCFs). METHODS: BEAS-2B cells were exposed to 10, 20, 40, 80, and 160 ug/cm(2) RCF1, RCF2, and RCF3 for 24 h, and the cell viability was measured by CCK-8 assay. BEAS-2B cells were exposed to 20, 40, and 100 ug/cm(2) RCF1, RCF2, and RCF3 for 24 h, and the cell apoptosis rate was measured by flow cytometry. BEAS-2B cells were exposed to 40 ug/cm(2) RCF1, RCF2, and RCF3, and the expression levels of phospho-p38 MAPK and caspase-3 were measured by Western blot. In each of the above treatments, the BEAS-2B cells were divided into positive control, p38 inhibitor SB203580 intervention, and normal groups. RESULTS: As the concentration of RCFs rose, the RCF exposure groups showed decreased cell viability and increased cell apoptosis rate. After SB203580 intervention, the intervention groups (all concentrations of asbestos + SB, 20, 40, 80, and 160 ug/cm(2)RCF1+SB, and 40, 80, and 160 ug/cm(2) RCF2 and RCF3+SB) had significantly increased cell viabilities (P < 0.05), and the intervention groups (asbestos + SB and 20, 40, and 100 ug/cm(2) RCF1, RCF2, and RCF3 + SB) had significantly decreased cell apoptosis rates (P < 0.05). Compared with the normal group, the RCF (40 ug/cm(2)) exposure and positive control groups had significantly increased expression of phospho-p38 MAPK (P < 0.05), and the RCF (40 ug/cm(2)) exposure group had significantly increased expression of caspase-3 (P < 0.05). The intervention groups (asbestos + SB and 40 ug/cm(2) RCF1, RCF2, and RCF3 + SB) had significantly decreased expression of caspase-3 after SB203580 intervention. CONCLUSION: p38 MAPKs play an important role in RCF-induced apoptosis of BEAS-2B cells. PMID- 23803524 TI - [Effect of digital radiography processing parameters on digital chest radiograph for occupational exposed workers]. AB - OBJECTIVE: To investigate the effect of different processing parameters of digital radiography (DR) on the image quality of digital chest radiograph in dust exposed workers. METHODS: One hundred and five dust-exposed workers underwent both high-KV radiography and DR to obtain chest radiographs; the image processing parameters were set by the conventional processing method for digital chest radiograph (method A) and the processing method based on the special requirements of occupational diseases (method B). With the high-KV chest radiograph as the reference, the image qualities at 10 anatomic sites of DR image were graded. The images acquired by DR and high-KV radiography were compared, and the DR images acquired by methods A and B were also compared. RESULTS: For method A, the scores at the 10 anatomic sites of DR image were mostly 0 and +1, accounting for over 88%, and the mean score was 0.23 ~ 0.65, there was a significant difference between the mean score of DR image and the score of high-KV image (P < 0.001). For method B, the scores at the 10 anatomic sites of DR image were mostly 0, accounting for over 65%, and the mean score was -0.01~ +0.02 except at the pleura and chest wall; there was no significant difference between the mean score of DR image and the score of high-KV image (P > 0.05). There were significant differences in the scores at the 10 anatomic sites between the DR images acquired by methods A and B (P < 0.01). CONCLUSION: The DR images acquired based on different processing parameters are different. The quality of DR image acquired by the processing method based on the special requirements of occupational diseases is similar to that of high-KV image at the anatomic sites. PMID- 23803525 TI - [Co-occurrence of musculoskeletal disorders and influence factors among Chinese auto workers]. AB - OBJECTIVE: To analyze the prevalence and risk factors of multiple musculoskeletal disorders (MSDs) in auto workers and the associations between MSDs at different sites. METHODS: A cross-sectional survey was conducted in 3998 workers, who were selected from a Chinese auto corporation by cluster random sampling, using the revised Nordic MSDs standard questionnaire; 3800 completed questionnaires were returned. Multinomial logistic regression analysis was performed to assess the risk factors for multiple MSDs. The logbinomial model was used to calculate the prevalence ratios (PRs) of MSDs at different sites and evaluate the associations between MSDs at different sites. RESULTS: Of the 3800 subjects, 2452 (64.5%) had MSDs at two or more sites, and 469 (12.3%) had MSDs at one site. The PRs varied from 1.5 to 6.7, with significant differences among different sites (P < 0.01). Relatively close associations were found between the MSDs at neck and shoulders, back and shoulders/waist, elbows and wrists/hands, waist and neck, wrists/hands and waist, hip and waist, knees and waist, and ankles/feet and elbows. The multinomial logistic regression analysis indicated that the highest risk factor for MSDs was poor posture, including often working in an uncomfortable posture, neck bending forward, and neck twisting (ORs = 3.39, 1.93, and 1.38), followed by labor organization, in which break between tasks could decrease the risk of MSDs at three or more sites to 31%, staff shortage, which could increase the risk of MSDs by 75%, and pushing and pulling heavy objects (> 20 kg) (OR = 1.76). CONCLUSION: Most auto workers with MSDs have multiple sites affected, and there are high associations between the MSDs at different sites. The major risk factors for multiple MSDs in auto workers include poor posture, labor organization, and heavy physical labor. PMID- 23803526 TI - [Research on functional dyspepsia prevalence and related factors of naval]. AB - OBJECTIVE: To analyze functional dyspepsia prevalence and associated factors of naval forces. METHOD: By stratified random cluster sampling method, conducted a questionnaire survey and diagnosis of functional dyspepsia to 11 520 military sea forces, and analyzed risk in clinical factors. Large sample size of 3084 cases in the diagnosis of functional dyspepsia, analyzed correlation of the selected 100 patients by single sample random sampling method. RESULT: Naval forces, functional dyspepsia prevalence was 29.27% (3084/10537), and logistic regression analysis showed that job factors of military service, military rank, the nature of the work, the training intensity, training environmental P = 0.028, 0.023, 0.000, 0.000, 0.014, OR = 10.308, 6.288, 22.504, 26.720, 9.825; life factors of daily water intake, eating fruits and frequency of sleep time, spicy eating habits, drinking history factors P = 0.000, 0.012, 0.025, 0.017, 0.027, OR = 28.467, 20.335, 11.358, 10.249, 9.578; psychological factors, depression, anxiety factor P = 0.024, 0.019, OR = 16.878, 18.025;generally age, gender, ethnicity, BMI index, gastrointestinal history, history of drug, educational background, geographic factors P = 0.042, 0.033, 0.417, 0.000, 0.000, 0.012, 0.392, 0.440, OR = 3.406, 7.511, 2.643, 42.073, 88.457, 21.680, 1.752, 5.561.When value of P < 0.05, clinical risk factors were screened. Clinical symptom scores and work, life factor score and SAS, SDS score of randomly selected patient samples was positively correlated, r = 0.816, 0.763, 0.795, 0.923, P = 0.000, indicating statistically significant. CONCLUSION: Naval forces functional dyspepsia prevalence was higher than the general population, which risk factors included work, life, psychological, physical fitness factors, closely related with military service and military personnel, military rank, the nature of the work, the training intensity and environment, eating habits, daily sleep time, drinking history, depression, anxiety level, age, gender, BMI index, history of gastrointestinal disease, use of drugs, high priority should be given to the risk factors listed above, the development of rational targeted programs to strengthen the cause of prevention measures. PMID- 23803527 TI - Bendiocarb resistance in Anopheles gambiae s.l. populations from Atacora department in Benin, West Africa: a threat for malaria vector control. AB - BACKGROUND: Owing to pyrethroid resistance in An. gambiae, the carbamate and organophosphate insecticides are currently regarded as alternatives or supplements to pyrethroids for use on mosquito net treatments. Resistance monitoring is therefore essential to investigate the susceptibility of An. gambiae s.l to these alternative products. METHODS: Two to three day old adult female Anopheles mosquitoes were reared from larvae collected in the five districts (Kouande, Natitingou, Materi, Pehunco, Tanguieta) of the Atacora department. Mosquitoes were then exposed to WHO impregnated papers. The four treatments consisted of: carbamates (0.1% bendiocarb, 0.1% propoxur) and organophosphates (0.25% pirimiphosmethyl, 1% fenitrothion). PCR assays were run to determine the members of the An. gambiae complex, the molecular forms (M) and (S), as well as phenotypes for insensitive acetylcholinesterase (AChE1) due to ace-1(R) mutation. RESULTS: Bioassays showed bendiocarb resistance in all populations of An. gambiae s.s. tested. Propoxur resistance was observed in Materi, Pehunco and Tanguieta, while it was suspected in Kouande and Natitingou. As for the organophosphates, susceptibility to pirimiphos-methyl was assessed in all populations. Fenitrothion resistance was detected in Kouande, Pehunco and Tanguieta, while it was suspected in Materi and Natitingou. The S-form was predominant in tested samples (94.44%). M and S molecular forms were sympatric but no M/S hybrids were detected. The ace-1(R) mutation was found in both S and M molecular forms with frequency from 3.6 to 12%. Although the homozygous resistant genotype was the most prevalent genotype among survivors, the genotypes could not entirely explain the bioassay results. CONCLUSION: Evidence of bendiocarb resistance in An. gambiae populations is a clear indication that calls for the implementation of insecticide resistance management strategies. The ace-1(R) mutation could not entirely explain the resistance to bendiocarb observed and is highly suggestive of involvement of other resistance mechanisms such as metabolic detoxification. PMID- 23803528 TI - State of the art in research into the risk of low dose radiation exposure- findings of the fourth MELODI workshop. AB - The fourth workshop of the Multidisciplinary European Low Dose Initiative (MELODI) was organised by STUK-Radiation and Nuclear Safety Authority of Finland. It took place from 12 to 14 September 2012 in Helsinki, Finland. The meeting was attended by 179 scientists and professionals engaged in radiation research and radiation protection. We summarise the major scientific findings of the workshop and the recommendations for updating the MELODI Strategic Research Agenda and Road Map for future low dose research activities. PMID- 23803529 TI - Pharmacokinetic-pharmacodynamic modeling of antibacterial drugs. AB - Pharmacokinetic-pharmacodynamic (PKPD) modeling and simulation has evolved as an important tool for rational drug development and drug use, where developed models characterize both the typical trends in the data and quantify the variability in relationships between dose, concentration, and desired effects and side effects. In parallel, rapid emergence of antibiotic-resistant bacteria imposes new challenges on modern health care. Models that can characterize bacterial growth, bacterial killing by antibiotics and immune system, and selection of resistance can provide valuable information on the interactions between antibiotics, bacteria, and host. Simulations from developed models allow for outcome predictions of untested scenarios, improved study designs, and optimized dosing regimens. Today, much quantitative information on antibiotic PKPD is thrown away by summarizing data into variables with limited possibilities for extrapolation to different dosing regimens and study populations. In vitro studies allow for flexible study designs and valuable information on time courses of antibiotic drug action. Such experiments have formed the basis for development of a variety of PKPD models that primarily differ in how antibiotic drug exposure induces amplification of resistant bacteria. The models have shown promise for efficacy predictions in patients, but few PKPD models describe time courses of antibiotic drug effects in animals and patients. We promote more extensive use of modeling and simulation to speed up development of new antibiotics and promising antibiotic drug combinations. This review summarizes the value of PKPD modeling and provides an overview of the characteristics of available PKPD models of antibiotics based on in vitro, animal, and patient data. PMID- 23803530 TI - A simple in vitro method to measure autophosphorylation of protein kinases. AB - Receptor-like protein kinases (RLKs) are a large and important group of plant proteins involved in numerous aspects of development and stress response. Within this family, homo-oligermization of receptors followed by autophosphorylation of the intracellular protein kinase domain appears to be a widespread mechanism to regulate protein kinase activity. In vitro studies of several RLKs have identified autophosphorylation sites involved in regulation of catalytic activity and signaling in vivo. Recent work has established that multiple RLKs are biochemically active when expressed in E. coli and readily autophosphorylate prior to purification or subsequent manipulation. This observation has led us to develop a simplified method for assaying RLK phosphorylation status as an indirect measure of intrinsic autophosphorylation activity. The method involves expressing a recombinant RLK protein kinase domain in E. coli, followed by SDS PAGE of boiled cell lysate, and sequential staining with the phosphoprotein stain Pro-Q Diamond and a colloidal Coomassie total protein stain. We show this method can be used to measure and quantify in vitro autophosphorylation levels of recombinant wildtype and mutant versions of the Arabidopsis RLK HAESA, as well as to detect transphosphorylation activity of recombinant HAESA against a protein kinase inactive version of itself. Our method has several advantages over traditional protein kinase assays. It does not require protein purification, transfer, blotting, or radioactive reagents. It allows for rapid and quantitative assessment of autophosphorylation levels and should have general utility in the study of any autophosphorylating protein kinase expressed in E. coli. PMID- 23803531 TI - Extralobar pulmonary sequestration in a 55-year-old man. AB - Pulmonary sequestration is a rare congenital lung malformation that more commonly occurs in the left lung, mainly near the lower mediastinum. It is rarely observed in patients with extralobar sequestration in adulthood. We report the case of a 55-year-old man with recurrent fever and cough lasting for about 1 month, who was admitted to our hospital. His past history was unremarkable. The final diagnosis of extralobar sequestration was dependent on three-dimensional computed tomography angiography (3D CTA), which showed an abnormal blood supply vessel to the consolidation from the aortic arch. The patient underwent a left pulmonary sequestration resection, and the pathological examination also verified the diagnosis postoperatively. 3D CTA images can provide an aberrant vessel anatomy map for the surgeon and play a decisive role in the detection of pulmonary sequestration. PMID- 23803532 TI - Massive calcified tricuspid valve endocarditis in a patient with dual lumen tunneled venous catheter. AB - Infection is the most common cause of death in hemodialysis patients after cardiovascular complications. The long-term use of venous catheters for dialysis elevates the risk. Valvular calcification is of special concern in developing infective endocarditis and is often found in chronic dialysis patients. The right sided endocarditis is rarely reported in the literature and may be overseen until the development of further complications. In our case tricuspid valve endocarditis, with severe insufficiency and stenosis due to a calcified laminar plate was found in a 57-year-old female patient undergoing dialysis due to end stage renal disease. The calcification aroused from the tip of the dual lumen tunneled venous catheter used for routine dialysis. We replaced the tricuspid valve with mechanical valve prosthesis and reconstructed the right atrium. PMID- 23803533 TI - Effects of the fluoroquinolone antibacterial drug ciprofloxacin on ventricular repolarization in the halothane-anesthetized Guinea pig. AB - The fluoroquinolone antibiotic ciprofloxacin has been reported to block delayed rectifier K(+) channels at much higher concentrations than those at which it exerts its bactericidal activity. In this study using the halothane-anesthetized guinea pig, we assessed whether ciprofloxacin has a proarrhythmic activity. Ciprofloxacin at a clinically relevant dose of 3 mg/kg, i.v. did not affect any electrocardiographic parameters. At 10 mg/kg, it prolonged the QT interval and the duration of the monophasic action potential of the ventricle under sinus rhythm and constant ventricular pacing (n = 6). The extents of its effects on the ventricular repolarization phase were comparable to those of another fluoroquinolone antibiotic moxifloxacin at a clinically relevant dose of 3 mg/kg (n = 6). Meanwhile, the PR interval and QRS width were also increased by ciprofloxacin at 10 mg/kg, suggesting that the drug inhibited cardiac K(+) channels as well as Na(+) and Ca(2+) channels in vivo. These results suggest that ciprofloxacin exerted a multi-ion channel-blocking action in the heart within the supra-therapeutic dose range. Therefore, careful observation may be necessary for patients with heart disease receiving a higher dose of ciprofloxacin in order to prevent the emergence of resistance. PMID- 23803535 TI - [Relationship between XRCC3 gene polymorphism and susceptibility to lead poisoning in male lead-exposed workers]. AB - OBJECTIVE: To investigate the relationship between genetic polymorphism of X-ray repair cross-complementing gene 3 (XRCC3) and susceptibility to lead poisoning in male lead-exposed workers. METHODS: Peripheral venous blood and morning urine samples were collected from 326 male lead-exposed workers in a storage battery factory in Fuzhou. Blood lead, urine lead, blood zinc protoporphyrin (ZPP), blood calcium, and blood iron were measured. The genotype of XRCC3 was determined by polymerase chain reaction-restriction fragment length polymorphism method. The relationship between XRCC3 gene polymorphism and susceptibility to lead poisoning in male lead-exposed workers was analyzed. RESULTS: Genetic polymorphism of XRCC3 was seen in the 326 subjects. The frequency distribution of XRCC3 genotypes, XRCC3-241CC (wild type), XRCC3-241CT (heterozygous mutation), and XRCC3-241TT (homozygous mutation), was in accordance with the Hardy-Weinberg equilibrium (P > 0.05). There were no significant differences in urine lead, blood ZPP, blood calcium, and blood iron between the lead-exposed workers with different XRCC3 genotypes (P > 0.05). The workers with XRCC3-241CT/TT had a significantly higher mean blood lead level than those with XRCC3-241CC (P < 0.05). With a blood lead level of 1.90 umol/L as the cutoff value, the chi-square test and logistic regression analysis showed that the proportion of workers with XRCC3-241CT/TT was significantly higher than that of workers with XRCC3-241CC in the subjects with high blood leads (P < 0.05) and that the risk of high blood lead was significantly higher in the workers with XRCC3-241CT/TT than in those with XRCC3 241CC (OR = 2.34, 95%CI = 1.61 ~ 5.13); the multivariate linear regression analysis showed that the workers with XRCC3-241CT/TT had high blood lead levels (beta = 0.116, P < 0.05), the workers with smoking habit demonstrated marked lead absorption (beta = 0.188, P < 0.05), good individual protection could reduce lead absorption (beta = -0.247, P < 0.05), and the individuals with low serum Ca2+ levels had high blood lead levels (beta = -0.145, P < 0.05). CONCLUSION: When exposed to the same level of lead at workplace, the workers with XRCC3-241CT/TT have a significantly higher blood lead level than those with XRCC3-241CC, so the genotype of XRCC3-241CT/TT accounts for higher susceptibility to lead poisoning. PMID- 23803534 TI - A systematic review and meta-analysis of dynamic tests and related force plate parameters used to evaluate neuromusculoskeletal function in foot and ankle pathology. AB - BACKGROUND: Force plates are commonly used to register ground reaction forces in order to assess neuromusculoskeletal function of the ankle joint. There exists a great variety in dynamic tests on force plates and in parameters calculated from ground reaction forces in order to evaluate neuromusculoskeletal function of the ankle. The purpose of this study was to evaluate which dynamic tests and force plate parameters are most sensitive to differences between and within groups with regard to foot and ankle pathology. METHODS: A systematic review and meta analysis was performed evaluating studies that compared force plate parameters of dynamic tests between patients with foot and ankle pathology, and healthy controls. Data were pooled per parameter and test category. Given the clinical heterogeneity, we constructed comprehensive recommendation criteria to indicate a 'proven relevant parameter' or 'candidate relevant parameter'. RESULTS: A total of 34 studies were included, and 58 relevant comparisons were identified. Results were subdivided by test category: walking, running, landing (in anteroposterior direction), sideways (movement in mediolateral direction) and termination (movement in anteroposterior direction). The 'walking' test showed significant differences in a great variety of pathologies, with the magnitude and timing of the 'second peak vertical force' as proven relevant parameters. The 'landing' test detected differences due to ankle instability, with 'time to stabilization in anteroposterior direction' as proven relevant parameter. INTERPRETATION: This study provides recommendations concerning the potential of various dynamic tests and force plate parameters as a tool to compare neuromusculoskeletal function between patients with foot and ankle pathology and healthy controls. PMID- 23803536 TI - [Role of ubiquitin ligase Ring2 in DNA damage induced by benzo[a]pyrene]. AB - OBJECTIVE: To investigate the role of ubiquitin ligase Ring2 in the DNA damage induced by benzo[a]pyrene (B[a]P). METHODS: The expression of Ring2 in human bronchial epithelial (16HBE) cells was inhibited by small interfering RNA (siRNA) to obtain siRNA-Ring2 16HBE cells. The siRNA-Ring2 16HBE cells, as well as normal 16HBE cells, were exposed to B[a]P (0, 1, 2, 4, 8, 16, and 32 umol/L) for 24 h; other siRNA-Ring2 16HBE cells and normal 16HBE cells were exposed to B [a]P (16 umol/L) for 0, 1, 2, 4, 8, 12, and 24 h. The levels of DNA damage were evaluated by alkaline single cell gel electrophoresis assay. RESULTS: After being treated with siRNA for 36 h, the siRNA-Ring2 16HBE cells showed a 72% decrease in Ring2 expression compared with normal 16HBE cells. The analysis of covariance showed that whether to be treated with siRNA and concentration of B[a]P had impacts on Olive tail moment (OTM) (P = 0.032 and P < 0.001); the adjusted mean of OTM was significantly higher in siRNA-Ring2 16HBE cells than in normal 16HBE cells. Whether to be treated with siRNA and B[a]P exposure time had impacts on OTM (P = 0.031 and P < 0.001); the adjusted mean of OTM was significantly higher in siRNA Ring2 16HBE cells than in normal 16HBE cells. CONCLUSION: The DNA of 16HBE cells with decreased Ring2 expression has increased susceptibility to B[a]P, which may be due to reduced H2A monoubiquitination following decrease in Ring2 expression. PMID- 23803537 TI - [Effects of enriched environment and impoverished environment on learning and memory ability of manganese-exposed mice]. AB - OBJECTIVE: To investigate the effects of enriched environment and impoverished environment on the learning and memory ability of manganese-exposed mice and the mechanism. METHODS: Forty female Kunming mice were randomly and equally divided into 4 group: control group (CG), standard environment and manganese exposure group (SEG), enriched environment and manganese exposure group (EEG), and impoverished environment and manganese exposure group (IEG). The mouse model of manganese poisoning was established by intraperitoneal injection of manganese chloride. The learning and memory ability was tested by Morris water maze. The expression of cAMP response element-binding protein (CREB) in area CA1 of the hippocampus was measured by immunohistochemistry. RESULTS: In place navigation test, the SEG had a significantly longer escape latency than the CG (P < 0.05), and the EEG had a significantly shorter escape latency than the SEG (P < 0.05); there was no significant difference in escape latency between IEG and SEG (P > 0.05). In spatial probe test, the EEG had a significantly greater number of platform crossings than the SEG (P < 0.05), and the IEG had a significantly smaller number of platform crossings than the SEG (P < 0.05). The expression of CREB in area CA1 of the hippocampus was significantly lower in IEG and SEG than in CG (P < 0.05), and it was significantly higher in EEG than in SEG (P < 0.05). CONCLUSION: In the enriched environment, the learning and memory ability of manganese-exposed mice can be improved, which may be due to the increased expression of CREB in the hippocampus. PMID- 23803538 TI - [Relationship between parental exposure to chemicals and risk of childhood acute leukemia]. AB - OBJECTIVE: To investigate the relationship between parental exposure to chemicals and the risk of childhood acute leukemia. METHODS: An exploratory case-control study was conducted among 201 new cases of childhood acute leukemia under 15 years old who went to 3 children's hospitals in Shanghai, China from January 1, 2009 to December 31, 2010, as well as 201 sex- and age-matched children (as controls) who went to the child health care clinic or department of orthopedics in the above hospitals. A survey was performed by face-to-face interviews with children's mothers. RESULTS: The risk factors for childhood acute leukemia might include maternal exposure to total chemicals (diesel oil, gasoline, paints, insecticides, pesticides, herbicides, and chemical fertilizers) from 3 months before pregnancy to the end of pregnancy (OR = 2.9, 95%CI = 1.1 ~ 7.8), paternal exposure to insecticides (OR = 10.1, 95%CI = 1.2 ~ 82.9) and chemical fertilizers (OR = 9.5, 95%CI = 1.1 ~ 79.6) within 3 months before pregnancy, maternal working experiences in agriculture and forestry before pregnancy (OR = 8.4, 95%CI = 1.4 ~ 50.2) and in spinning, leather processing, decoration, and vehicle repair before pregnancy (OR = 3.0, 95%CI = 1.2 ~ 7.9) and during pregnancy (OR = 3.2, 95%CI = 1.1 ~ 9.6), and paternal working experiences in agriculture and forestry (OR = 9.6, 95%CI = 2.1-44.8) and in spinning, leather processing, decoration, and vehicle repair (OR = 2.3, 95%CI = 1.1-5.0). CONCLUSION: Parental exposure to chemicals may increase the risk of childhood acute leukemia in their offspring. PMID- 23803539 TI - [Study on mechanism of thyroid cytotoxicity of ammonium perchlorate]. AB - OBJECTIVE: To investigate the mechanism of thyroid cytotoxicity mechanism of ammonium perchlorate (AP). METHODS: Thyroid cells were cultured in vitro to a certain stage and then exposed to AP (0, 5, 10, 20, 40, and 60 mmol/L) in culture solution; the cultured cells and supernatant were collected. Cell viability was measured by MTT assay; cell apoptosis was determined by flow cytometry; the concentration of thyroglobulin was measured by enzyme-linked immunosorbent assay; the lactate dehydrogenase (LDH) activity, superoxide dismutase (SOD) activity, malondialdehyde (MDA) level, and so on were measured by colorimetry. RESULTS: The cells exposed to 60 mmol/L AP for 12, 24, 48, and 72 h had cell viabilities of 74.93%, 42.26%, 2.66%, and 0.99%, respectively, and the cells exposed to 40 mmol/L AP for 24, 48, and 72 h had cell viabilities of 73.15%, 30.91%, and 3.03%, respectively, all significantly lower than that of the control group (100%)(P < 0.05 or P < 0.01). The overall apoptosis rate of all AP-exposed cells was significantly higher than that of the control group; the cells exposed to 20, 40, and 60 mmol/L AP had early apoptosis rates of 15.70%, 15.84%, and 16.96%, respectively, significantly higher than that of the control group (9.54%)(P < 0.05 or P < 0.01); the cells exposed to 60 mmol/L AP had a late apoptosis rate of 16.54%, significantly higher than that of the control group (6.11%)(P < 0.05 or P < 0.01). The cells exposed to 40 mmol/L AP had a significantly higher LDH activity than the control group (0.70 U/ml vs 0.55 U/ml, P < 0.01). The cells exposed to 5 mmol/L AP had a significantly higher MDA level than the control group (1.08 mmol/L vs 2.36 mmol/L, P < 0.05). CONCLUSION: AP can markedly change the cell morphology and decrease the cell viability of thyroid cells, which may be because AP inhibits cell proliferation, induces cell apoptosis, and destroys cell membranes. However, AP does not result in significant oxidative damage to thyroid cells. PMID- 23803540 TI - [An epidemiological survey of snoring disease and OSAHS among 374 truck drivers in Guangzhou, China]. AB - OBJECTIVE: To investigate the prevalence rates of snoring disease and obstructive sleep apnea-hypopnea syndrome (OSAHS) and their risk factors among truck drivers in Guangzhou, China. METHODS: A questionnaire survey was conducted in 374 truck drivers who were selected from 5 logistics companies in Guangzhou by cluster sampling. Those who had potential snoring disease or OSAHS underwent polysomnographic monitoring at night. The obtained data were analyzed to calculate the prevalence rates of snoring disease and OSAHS and determine the risk factors for OSAHS. RESULTS: A total of 335 subjects completely questionnaires, with a response rate of 90%. Among the 335 subjects, 125 (37.3%) had habitual snoring, and 42 (12.5%) had OSAHS according to the diagnostic criterion (apnea-hypopnea index >= 5 times/h). The multiple stepwise regression analysis showed that the risk factors for OSAHS were age, alcohol use, family history of snoring, body mass index, and upper airway abnormality. Of the subjects with grade >= 2 snoring and OSAHS, 65.4% often felt sleepy when driving during daytime, and 42% had suffered or nearly suffered traffic accidents due to sleepiness when driving. Moreover, 95.5% (320) of the 335 truck drivers did not consider snoring a disease, and 98% did not think traffic accident might be related to snoring. CONCLUSION: The prevalence rates of snoring disease and OSAHS among truck drivers are 37.3% and 12.5%, respectively. Therefore, prevention measures should be established according to the epidemiological characteristics to help the truck drivers realize the hazards of snoring disease and OSAHS, thus minimizing the prevalence and hazards of the diseases. PMID- 23803541 TI - [A survey of occupational health among polyether-exposed workers]. AB - OBJECTIVE: To investigate the occupational health of the workers simultaneously exposed to acrylonitrile, epoxyethane, epoxypropane, and styrene. METHODS: A questionnaire survey was conducted in 70 front-line workers simultaneously exposed to acrylonitrile, epoxyethane, epoxypropane, and styrene (exposure group) and 50 managers (control group) in a polyether manufacturer; in addition, air monitoring at workplace and occupational health examination were also performed. The obtained data were analyzed. RESULTS: The female workers in exposure group and the spouses of male workers in exposure group had significantly higher spontaneous abortion rates than their counterparts in control group (P < 0.01). The exposure group had a significantly higher abnormal rate of blood urea nitrogen than the control group (P < 0.01). The workers with different polyether exposed working years had significantly higher mean levels of DNA damage than the control group (P < 0.01); the workers with not less than 5 and less than 20 polyether-exposed working years and those with not less than 20 polyether-exposed working years had significantly higher mean micronucleus rates than the control group (P < 0.01); there were no significant differences in overall chromosome aberration rate and mean level of DNA damage between each two groups of workers with different polyether-exposed working years (P > 0.05); the workers with not less than 5 and less than 20 polyether-exposed working years and workers with not less than 20 polyether-exposed working years had significantly higher mean micronucleus rates than those with less than 5 polyether-exposed working years (P < 0.01). CONCLUSION: Simultaneous exposure to acrylonitrile, epoxyethane, epoxypropane, and styrene causes occupational hazards among the workers in polyether manufacturer. PMID- 23803542 TI - [Effects of whole lung lavage on pulmonary function and exercise capacity in patients with pneumoconiosis]. AB - OBJECTIVE: To investigate the effects of whole lung lavage (WLL) on the pulmonary function and exercise capacity in patients with pneumoconiosis. METHODS: Forty one patients with pneumoconiosis who quit dust-exposed work not more than 6 months before underwent WLL. Clinical symptom assessment, pulmonary function test, and cardiopulmonary exercise test were performed before and one week after WLL, and the results were compared. RESULTS: The patients with pneumoconiosis showed no significant changes in clinical symptoms after WLL. At one week after WLL, the patients with pneumoconiosis showed nonsignificant increases in forced vital capacity, forced expiratory volume in one second (FEV1.0), and percent predicted FEV1 (P > 0.05); peak oxygen uptake (peak VO2) increased from 2140.6 +/ 353.2 ml/min before WLL to 2374.6 +/- 362.4 ml/min after WLL, percent predicted peak VO2 increased from 82.2 +/- 13.7% before WLL to 91.0 +/- 14.0% after WLL, peak VO2/kg increased from 30.6 +/- 3.5 ml/min*kg before WLL to 34.2 +/- 3.7 ml/min*kg after WLL, and ventilatory equivalent for carbon dioxide decreased from 30.6 +/- 3.1 before WLL to 26.1 +/- 2.7 after WLL (P < 0.05). CONCLUSION: WLL can remarkably improve the oxygen uptake and ventilatory efficiency in patients with pneumoconiosis during exercise, so it can improve the exercise capacity of these patients. PMID- 23803543 TI - [An epidemiological survey of malignant tumors among fluoride-exposed workers in aluminum industry]. AB - OBJECTIVE: To investigate the incidence of malignant tumors among fluoride exposed workers in aluminum industry. METHODS: Sampling points were set in the working positions at different radii around an workshop for treating the waste gas from aluminum electrolysis, and the concentrations of fluoride ions, aluminum, and benzo[a]pyrene (B[a]P) in air were measured by electrode method, atomic absorption spectrophotometry, and high performance liquid chromatography, respectively. The incidence of tumors among the workers in the aluminum plant from 1995 to 2009 was investigated by questionnaires and medical records and then statistically analyzed. RESULTS: There was a negative correlation between the concentrations of fluoride and aluminum and the radius around the fluoride source at each sampling point. B[a]P was not detected at each sampling point. The crude incidence rate of tumors among factory workers was 117.95/100 000 (standardized rate = 58.81/100 000); the standardized incidence rate of tumors was higher in female workers than in male workers (male-to-female ratio = 1:2.64). The peak age of onset of tumors was 40 ~ 49 years. The most and second most common tumors were liver cancer and lung cancer in male workers and breast cancer and lung cancer in female workers. Compared with the unexposed population in the city where the aluminum plant was located, the female fluoride-exposed workers had an increased tumor incidence, 2.14 times that of the city's average level, and the fluoride exposed workers had a younger age of onset of tumors and approximately the same types of tumors. CONCLUSION: Fluoride exposure may lead to an increasing trend in tumor incidence among female workers in aluminum industry. PMID- 23803544 TI - [Study on the humoral immune responses to serum myelin proteins in mediating the occurrence and development of n-hexane peripheral neuropathy]. PMID- 23803545 TI - [Effects of Xingnaojing in treating acute dichloroethane ethylene dichloride poisoning]. PMID- 23803546 TI - [A clinical curative effect of acupuncture with drug in treatment of pneumoconiosis complicated with chronic obstructive pulmonary disease]. PMID- 23803547 TI - [Analysis of pneumoconiosis complicated with pulmonary emphysema patients with lung injury]. PMID- 23803548 TI - [Clinical efficacy of ulinastatin combined with penehyclidine hydrochloride in prevention and treatment of highly irritant gas poisoning]. PMID- 23803549 TI - [Determination of 36 volatile organic compounds in the workplace air by GC/MS]. PMID- 23803550 TI - [Determination of1-bromopropane in the workplace air by GC-FID]. AB - OBJECTIVE: To establish a method for determination 1-bromopropane (1-BP) in workplace air by gas chromatography-flame ionization detector (GC-FID). METHOD: 1 bromopropane in workplace air was collected with activated charcoal tube, then desorbed by carbon disulfide and determined by GC-FID. 1-bromopropane was quantitatively measured using retention time and peak area. RESULTS: Linear regression formula was Y = 3353.4x-10064 in a range of 2.50 ~ 500.00 ug/ml with regression coefficient R = 0.9998. Detection limit was 0.25 ug/ml and the lowest detection concentration of 1-brmopropane in air was 0.14 mg/m(3) (at air volume 1.8L). The mean recoveries of 1-BP were between 96.8% and 102.6%, and relative standard deviation of inter and intra-assay was less than 10%. The average desorption efficiencies were between 93.2% and 104.4%. The samples in activated charcoal tube could be stably stored for 5 days at room temperature. CONCLUSION: The method could be feasible to determine 1-bromopropane in workplace air. PMID- 23803551 TI - [Determination of p-toluenesulfonic acid in the air of workplace by HPLC]. PMID- 23803552 TI - [Twenty-two cases of system contact dermatitis by 4-nitrobenzyl chlorides]. PMID- 23803553 TI - [miRNA and its research advance in occupational medicine]. PMID- 23803554 TI - Mouse cloning using a drop of peripheral blood. AB - Somatic cell nuclear transfer (SCNT) is a unique technology that produces cloned animals from single cells. It is desirable from a practical viewpoint that donor cells can be collected noninvasively and used readily for nuclear transfer. The present study was undertaken to determine whether peripheral blood cells freshly collected from living mice could be used for SCNT. We collected a drop of peripheral blood (15-45 MUl) from the tail of a donor. A nucleated cell (leukocyte) suspension was prepared by lysing the red blood cells. Following SCNT using randomly selected leukocyte nuclei, cloned offspring were born at a 2.8% birth rate. Fluorescence-activated cell sorting revealed that granulocytes/monocytes and lymphocytes could be roughly distinguished by their sizes, the former being significantly larger. We then cloned putative granulocytes/monocytes and lymphocytes separately and obtained 2.1% and 1.7% birth rates, respectively (P > 0.05). Because the use of lymphocyte nuclei inevitably results in the birth of offspring with DNA rearrangements, we applied granulocyte/monocyte cloning to two genetically modified strains and two recombinant inbred strains. Normal-looking offspring were obtained from all four strains tested. The present study clearly indicated that genetic copies of mice could be produced using a drop of peripheral blood from living donors. This strategy will be applied to the rescue of infertile founder animals or a "last-of line" animal possessing invaluable genetic resources. PMID- 23803555 TI - Epididymosomes convey different repertoires of microRNAs throughout the bovine epididymis. AB - Epididymosomes are small membrane vesicles that are secreted by epididymal epithelial cells and are involved in posttesticular sperm maturation. Although their role in protein transfer to the sperm membrane is well documented, we report their capacity to transport microRNAs (miRNAs), which are potent regulators of posttranscriptional gene expression. Using a microperfusion technique combined with a global microarray approach, we demonstrated that epididymosomes from two discrete bovine epididymal regions (caput and cauda) possess distinct miRNA signatures. In addition, we also established that miRNA repertoires contained within epididymosomes differ from those of their parent epithelial cells, suggesting that miRNA populations released from the cells may be selectively sorted. Binding of DilC12-labeled epididymosomes to primary cultured epididymal cells was measured by flow cytometry, and the results indicated that epididymosomes from the median caput and their miRNA content may be incorporated into distal caput epithelial cells. Overall, these findings reveal that distinct miRNA repertoires are released into the intraluminal fluid in a region-specific manner and could be involved in a novel mechanism of intercellular communication throughout the epididymis via epididymosomes. PMID- 23803557 TI - Oxygen affects the ability of mouse blastocysts to regulate ammonium. AB - During embryo culture, ammonium is generated by amino acid metabolism and from the spontaneous deamination of amino acids at 37 degrees C. Although ammonium has been shown to be embryo toxic, few studies have investigated the mechanism(s) by which the early embryo can regulate ammonium. Whilst 20% oxygen represents a source of stress to the developing embryo, it is not known how oxygen affects the physiology of the embryo in the presence of other sources of stress. The aim of this study was, therefore, to investigate possible pathways involved in ammonium sequestration in the preimplantation embryo and the effect of oxygen on the regulation of these pathways. Glutamine and alanine were investigated as possible ammonium sequestration pathways. Amino acid utilization by blastocysts was determined after culture from the postcompaction stage with 0, 150, or 300 MUM ammonium (in either 5% or 20% oxygen) and with or without 500 MUM L-methionine sulfoximine (MSO), an inhibitor of glutamine synthetase. In the presence of MSO, ammonium production was significantly increased and glutamate was no longer consumed. Glutamine synthetase inhibition with MSO significantly decreased glutamine formation. Ammonium and oxygen independently altered overall amino acid turnover. Together, 5% oxygen and ammonium promoted glutamine production, whereas in the presence of 20% oxygen and ammonium, glutamine was consumed. Data reveal that both oxygen and ammonium affect amino acid utilization by the developing embryo, however, 20% oxygen appears to have the greater impact. Mouse blastocysts can alleviate ammonium stress by its transamination to both glutamine and alanine, but only under physiological conditions. PMID- 23803556 TI - The unique expression and function of miR-424 in human placental trophoblasts. AB - Placental hypoperfusion causes cellular hypoxia and is associated with fetal growth restriction and preeclampsia. In response to hypoxia, the repertoire of genes expressed in placental trophoblasts changes, which influences key cellular processes such as differentiation and fusion. Diverse miRNAs were recently found to modulate the cellular response to hypoxia. Here we show that miR-424, which was previously shown to be upregulated by hypoxia in nontrophoblastic cell types, is uniquely downregulated in primary human trophoblasts by hypoxia or chemicals known to hinder cell differentiation. We also identify FGFR1 as a direct target of miR-424 in human trophoblasts. This effect is unique to miR-424 and is not seen with other members of this miRNA family that are expressed in trophoblasts, such as miR-15 and miR-16. Our findings establish a unique role for miR-424 during differentiation of human trophoblasts. PMID- 23803558 TI - Sarcoidosis in tuberculosis-endemic regions: India. AB - Sarcoidosis is a multisystem inflammatory disease of unknown etiology affecting multiple organs. Earlier reports suggested that sarcoidosis was a disease of the developed world. However, recent reports suggest that the disease is found in the developing countries as well. Clinical, radiological, and histopathological similarities with tuberculosis pose a great challenge in countries endemic for tuberculosis. Mantoux test, high resolution computed tomography, and transbronchial lymph node and lung biopsies are diagnostic modalities, which play an important role in the diagnosis of sarcoid. In this review, we look at the epidemiology of sarcoid in tuberculosis-endemic regions, the sarcoidosis tuberculosis link, clinical profile, diagnostic modalities, dilemma in the diagnosis, and the treatment of this disease. PMID- 23803559 TI - [Treatment of complete traumatic avulsion of an incisor tooth in adults]. AB - It is possible to replant an incisor tooth completely avulsed after trauma in adults. These cases are relatively frequent among athletes. It is essential to conserve the tooth in saline solution. The time before replantation must be as short as possible. The simple technique described here, which requires a minimum of material and no dental chair, makes it possible to replant an avulsed incisor with a good success rate. PMID- 23803560 TI - Mapping radon-prone areas using gamma-radiation dose rate and geological information. AB - Identifying radon-prone areas is key to policies on the control of this environmental carcinogen. In the current paper, we present the methodology followed to delineate radon-prone areas in Spain. It combines information from indoor radon measurements with gamma-radiation and geological maps. The advantage of the proposed approach is that it lessens the requirement for a high density of measurements by making use of commonly available information. It can be applied for an initial definition of radon-prone areas in countries committed to introducing a national radon policy or to improving existing radon maps in low population regions. PMID- 23803561 TI - Validation of a food quantification picture book targeting children of 0-10 years of age for pan-European and national dietary surveys. AB - The aim of the present study was to validate thirty-eight picture series of six pictures each developed within the PANCAKE (Pilot study for the Assessment of Nutrient intake and food Consumption Among Kids in Europe) project for portion size estimation of foods consumed by infants, toddlers and children for future pan-European and national dietary surveys. Identical validation sessions were conducted in three European countries. In each country, forty-five foods were evaluated; thirty-eight foods were the same as the depicted foods, and seven foods were different, but meant to be quantified by the use of one of the thirty eight picture series. Each single picture within a picture series was evaluated six times by means of predefined portions. Therefore, thirty-six pre-weighed portions of each food were evaluated by convenience samples of parents having children aged from 3 months to 10 years. The percentages of participants choosing the correct picture, the picture adjacent to the correct picture or a distant picture were calculated, and the performance of individual pictures within the series was assessed. For twenty foods, the picture series performed acceptably (mean difference between the estimated portion number and the served portion number less than 0.4 (SD < 1.1)). In addition, twelve foods were rated acceptable after adjustment for density differences. Some other series became acceptable after analyses at the country level. In conclusion, all picture series were acceptable for inclusion in the PANCAKE picture book. However, the picture series of baby food, salads and cakes either can only be used for foods that are very similar to those depicted or need to be substituted by another quantification tool. PMID- 23803562 TI - The effectiveness and cost-effectiveness of acupressure for the control and management of chemotherapy-related acute and delayed nausea: Assessment of Nausea in Chemotherapy Research (ANCHoR), a randomised controlled trial. AB - BACKGROUND: Chemotherapy-induced nausea and vomiting remain difficult symptoms to manage in clinical practice. As standard antiemetic drugs do not fully eliminate these symptoms, it is important to explore the adjuvant role of non pharmacological and complementary therapies in antiemetic management approaches. Acupressure is one such treatment showing highly suggestive evidence so far of a positive effect, meriting further investigation. OBJECTIVES: The primary objective was to assess the effectiveness and cost-effectiveness of self acupressure using wristbands compared with sham acupressure wristbands and standard care alone in the management of chemotherapy-induced nausea. Secondary objectives included assessment of the effectiveness and cost-effectiveness of the wristbands in relation to vomiting and quality of life and exploration of any age, gender and emetogenic risk effects. DESIGN: Randomised three-arm sham controlled trial (Assessment of Nausea in Chemotherapy Research or ANCHoR) with an economic evaluation. Arms include the wristband arm, the sham wristband arm and the standard care only arm. Randomisation consisted of minimisation with a random element balancing for gender, age (16-24, > 24-50, >50 years) and three levels of emetogenic chemotherapy (low, moderate and high). Qualitative interviews were incorporated to shed more light on the quantitative findings. SETTING: Outpatient chemotherapy clinics in three regions in the UK involving 14 different cancer units/centres. PARTICIPANTS: Chemotherapy-naive cancer patients receiving chemotherapy of low, moderate and high emetogenic risk. INTERVENTION: The intervention was acupressure wristbands pressing the P6 point (anterior surface of the forearm). MAIN OUTCOME MEASURES: The Rhodes Index for Nausea/Vomiting, the Multinational Association of Supportive Care in Cancer (MASCC) Antiemesis Tool and the Functional Assessment of Cancer Therapy - General (FACT-G). At baseline participants completed measures of anxiety/depression, nausea/vomiting expectation and expectations from using the wristbands. RESULTS: In total, 500 patients were randomised in the study arms (166 standard care, 166 sham acupressure and 168 acupressure) and data were available for 361 participants for the primary outcome. The primary outcome analysis (nausea in cycle 1) revealed no statistically significant differences between the three arms, although the median nausea experience in patients using wristbands (both real and sham ones) was somewhat lower than that in the antiemetics only group (median nausea experience scores for the four cycles: standard care arm 1.43, 1.71, 1.14, 1.14; sham acupressure arm 0.57, 0.71, 0.71, 0.43; acupressure arm 1.00, 0.93, 0.43, 0). A gender effect was evident (p= 0.002), with women responding more favourably to the use of sham acupressure wristbands than men (odds ratio 0.35 for men and 2.02 for women in the sham acupressure group; 1.27 for men and 1.17 for women in the acupressure group). This suggests a placebo effect. No significant differences were detected in relation to vomiting outcomes, anxiety and quality of life. Some transient adverse effects were reported, including tightness in the area of the wristbands, feeling uncomfortable when wearing them and minor swelling in the wristband area (n= 6).There were no statistically significant cost differences associated with the use of real acupressure bands (L70.66 for the acupressure group, L111.13 for the standard care group and L161.92 for the sham acupressure group). In total, 26 subjects took part in qualitative interviews. The qualitative data suggested that participants perceived the wristbands (both real and sham) as effective and helpful in managing their nausea during chemotherapy. CONCLUSIONS: There were no statistically significant differences between the three arms in terms of nausea, vomiting and quality of life, although apparent resource use was less in both the real acupressure arm and the sham acupressure arm compared with standard care only; therefore; no clear conclusions can be drawn about the use of acupressure wristbands in the management of chemotherapy-related nausea and vomiting. However, the study provided encouraging evidence in relation to an improved nausea experience and some indications of possible cost savings to warrant further consideration of acupressure both in practice and in further clinical trials. TRIAL REGISTRATION: ISRCTN87604299. SOURCE OF FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 17, No. 26. See the HTA programme website for further project information. PMID- 23803563 TI - How Setswana Cultural Beliefs and Practices on Sexuality Affect Teachers' and Adolescents' Sexual Decisions, Practices, and Experiences as well as HIV/AIDS and STI Prevention in Select Botswanan Secondary Schools. AB - The article reports on the aspects of a Botswana Ministry of Education and Skills Development (MoE & SD) HIV/AIDS Instructional Television (ITV) project modeled on a similar HIV/AIDS program implemented in Brazil. This Teacher Capacity Building Project (TCBP) in Botswana is in its initial years of implementation. Its overall goal is to contribute to the prevention and mitigation of the impact of HIV and AIDS by strengthening the capacity of the education and communication sectors to deliver interactive, distance HIV/AIDS education primarily to teachers so that they act as agents of behavior change among the in-school youth. One of the components of the TCBP program is a live teacher education television HIV/AIDS program called Talk Back program. Talk Back is a collaborative effort of the MoE & SD and the Botswana national television station. The Talk Back program involves development and implementation of weekly 1 hour live HIV/AIDS education interactive TV broadcasts for teachers. The development of the live programs is guided by a curriculum that provides a wide range of themes related to HIV/AIDS and education. This article reports the results of a survey of a sample of teachers and students at junior secondary schools and senior secondary schools, first, on their views and opinions regarding the Talk Back program as a TCBP. Second, how Setswana cultural beliefs, myths, and practices on sexuality affect teachers' and adolescents' sexual decisions, practices, and experiences as well as HIV/AIDS and sexually transmitted infection prevention. A questionnaire survey and focus group interviews were used as data collection instruments in selected secondary schools. The findings of the study suggest that the Talk Back program has not met much success as a TCBP. The findings further suggest that several myths, beliefs, misconceptions, and attitudes about HIV/AIDS exist among Botswana teachers and students and thus make it difficult for the Talk Back program to impart the HIV/AIDS message successfully. Therefore, there is a need for more stakeholders in HIV/AIDS education, where appropriate learning techniques are used, to bring about the desired behavioral change. PMID- 23803564 TI - Performance of rapid tests and algorithms for HIV screening in Abidjan, Ivory Coast. AB - Seven rapid diagnosis tests (RDTs) of HIV were evaluated by a panel group who collected serum samples from patients in Abidjan (HIV-1 = 203, HIV-2 = 25, HIV dual = 25, HIV = 305). Kit performances were recorded after the reference techniques (enzyme-linked immunosorbent assay). The following RDTs showed a sensitivity of 100% and a specificity higher than 99%: Determine, Oraquick, SD Bioline, BCP, and Stat-Pak. These kits were used to establish infection screening strategies. The combination with 2 or 3 of these tests in series or parallel algorithms showed that series combinations with 2 tests (Oraquick and Bioline) and 3 tests (Determine, BCP, and Stat-Pak) gave the best performances (sensitivity, specificity, positive predictive value, and negative predictive value of 100%). However, the combination with 2 tests appeared to be more onerous than the combination with 3 tests. The combination with Determine, BCP, and Stat Pak tests serving as a tiebreaker could be an alternative to the HIV/AIDS serological screening in Abidjan. PMID- 23803565 TI - A rare case of secondary syphilis manifesting as immune reconstitution syndrome in an HIV-positive patient. AB - A 44-year-old HIV-infected male, having a low CD4 count, was on antiretroviral therapy for the last 2 months, when he developed a skin rash. He gave a history of solitary unprotected extramarital sexual contact 6 months before onset of the rash. Dermatological examination revealed a bilaterally symmetrical, maculopapular erythematous rash involving the palms, forearms, and neck. He showed a positive sign of Buschke-Ollendorff. In the meanwhile, the CD4 count had improved to 196 cells/mm(3) from the previous count of 92 cells/mm(3) and the viral load had decreased. Serum venereal disease research laboratory (VDRL) test was reactor at 1:64. He was found to be positive result for treponema pallidum hemagglutination test. Skin biopsy revealed features of secondary syphilis. The rash responded well to a single injection of benzathine penicillin, resulting in the lowering of the VDRL titers. There was no evidence of neurosyphilis. This is a very rare instance of secondary syphilis manifesting as immune reconstitution syndrome in an HIV-positive patient. PMID- 23803566 TI - Recurrent immune reconstitution inflammatory syndrome of tuberculous brain infection in people living with HIV/AIDS: a case report. AB - HIV infection has changed the scenario of infectious disease. HIV-associated immunodeficiency resulted in a wide spectrum of new opportunistic infections. After introduction of antiretroviral therapy (ART), immune reconstitution inflammatory syndrome (IRIS) became an important challenge in management of 10% to 25% of the patients. Meta-analyses of IRIS from various reports published worldwide by Monika Muller et al described 12% IRIS incidence and 15.7% IRIS tuberculosis. Among IRIS tuberculosis, central nervous system involvement with IRIS tuberculous meningitis forms only 7%. Only 9 cases of tuberculous brain abscess is reported in patients with AIDS so far. The IRIS tuberculous brain abscess is very rare, and so far only 1 case is reported as a paradoxical reaction after ART initiation. Here, we report a case of recurrent IRIS tuberculosis meningitis and brain abscess. PMID- 23803568 TI - Isolation and characterization of the microflora of nixtamalized corn masa. AB - Corn tortillas are a staple in the diet among the Mexican population, and are traditionally produced through a process known as nixtamalization. This traditional process involves steeping whole-kernel corn in an alkaline solution overnight and then grinding the corn into dough (masa), which is then baked. While the masa is held before baking, significant microbial change can occur which leads to fermentation and spoilage. The objective of this research was to characterize and identify the microflora of nixtamalized corn masa from six different commercial tortilla mills throughout Guadalajara, Mexico. The identification of samples was conducted using the microbial identification system (MIS), which analyzes cellular fatty acids via gas chromatography to identify bacterial species. Lactic acid bacteria and aerobic mesophiles were the predominant organisms, with both groups having counts ranging from 10(4) to 10(7)cfu/g across all mills. Coliform populations were observed at counts of 10(2) to 10(3)cfu/g, while yeast and mold counts were typically less than 10(1)cfu/g. Some mills showed no presence of coliforms or yeast or mold. Streptococcus bovis and Lactobacillus oris were isolated from all mills, and were the most prevalent organisms representing 43% and 17% of all lactic acid bacteria isolated, respectively. S. bovis was also isolated on the aerobic tryptic soy plates and was the most prevalent species representing 19% of the total organisms from these aerobic plates. PMID- 23803567 TI - High folate gestational and post-weaning diets alter hypothalamic feeding pathways by DNA methylation in Wistar rat offspring. AB - Excess vitamins, especially folate, are consumed during pregnancy but later-life effects on the offspring are unknown. High multivitamin (10-fold AIN-93G, HV) gestational diets increase characteristics of metabolic syndrome in Wistar rat offspring. We hypothesized that folate, the vitamin active in DNA methylation, accounts for these effects through epigenetic modification of food intake regulatory genes. Male offspring of dams fed 10-fold folate (HFol) diet during pregnancy and weaned to recommended vitamin (RV) or HFol diets were compared with those born to RV dams and weaned to RV diet for 29 weeks. Food intake and body weight were highest in offspring of HFol dams fed the RV diet. In contrast, the HFol pup diet in offspring of HFol dams reduced food intake (7%, p = 0.02), body weight (9%, p = 0.03) and glucose response to a glucose load (21%, p = 0.02), and improved glucose response to an insulin load (20%, p = 0.009). HFol alone in either gestational or pup diet modified gene expression of feeding-related neuropeptides. Hypomethylation of the pro-opiomelanocortin (POMC) promoter occurred with the HFol pup diet. POMC-specific methylation was positively associated with glucose response to a glucose load (r = 0.7, p = 0.03). In conclusion, the obesogenic phenotype of offspring from dams fed the HFol gestational diet can be corrected by feeding them a HFol diet. Our work is novel in showing post-weaning epigenetic plasticity of the hypothalamus and that in utero programming by vitamin gestational diets can be modified by vitamin content of the pup diet. PMID- 23803570 TI - Efficacy of gaseous ozone against Salmonella and microbial population on dried oregano. AB - Interest in potential food applications of ozone has expanded in recent years in response to consumer demands for green technologies. This study was conducted to evaluate the efficacy of gaseous ozone for the microbial reduction and elimination of Salmonella on dried oregano. Ozone treatment was performed up to 120min under continuous stream of two different constant ozone concentrations (2.8 and 5.3mg/L). Significant (P<0.05) reductions of 2.7 and 1.8 log were observed in aerobic plate counts and yeast and mold counts after ozonation at 2.8mg/L for 120min, respectively. Ozonation performed at 5.3mg/L for 90min yielded a reduction of over 3.2 log in the aerobic plate counts. Initial population of a cocktail of Salmonella serotypes (S. Typhimurium, S. Newport and S. Montevideo) on inoculated oregano determined as 5.8logCFU/g decreased significantly by 2.8 and 3.7 log after ozonation at 2.8 and 5.3mg/L for 120min, respectively. Sensory evaluation results suggested that over the 2 log reduction in the microbial population can be obtained on dried oregano by gaseous ozone treatments with an acceptable taste, flavor and appearance. The results demonstrated that the gaseous ozone treatment is an effective alternative microbial reduction technique for dried oregano. PMID- 23803569 TI - Efficacy of different antimicrobials on inhibition of Listeria monocytogenes growth in laboratory medium and on cold-smoked salmon. AB - Listeria monocytogenes is of particular concern in cold-smoked fish products as it can survive curing and cold-smoking, and can subsequently grow from low numbers to potentially hazardous levels during refrigerated storage. The purpose of this study was to (i) quantify the effects of organic acids, nisin, and their combinations on controlling L. monocytogenes growth on cold-smoked salmon at refrigeration temperatures, (ii) identify synergistic interactions of binary combinations of these antimicrobials, and (iii) determine if results from laboratory growth media can predict antimicrobial efficacy on cold-smoked salmon. Strains representing the genetic diversity of L. monocytogenes lineages I and II were grown in brain heart infusion (BHI) broth as well as on the surface of commercially produced wet-cured, cold-smoked salmon slices at 7 degrees C. BHI broth and cold-smoked salmon were supplemented with sodium diacetate (SDA, 0.14% water phase (w.p.)), potassium lactate (PL, 2% w.p.), nisin (NI, 50ppm), and binary combinations of inhibitors at the same levels. Cell densities of L. monocytogenes were measured over time and used to calculate growth parameters, including initial cell density (N0), lag phase (lambda), maximum growth rate (MUmax), and maximum cell density (Nmax) for each antimicrobial treatment. N0 was significantly lowered by addition of NI with a similar average reduction on salmon (2.02+/-0.99 log(CFU/g)) and in BHI (1.51+/-0.83 log(CFU/ml)). Among all antimicrobial treatments, the combination of PL and SDA led to the greatest increase in lambda both on salmon (7.1+/-3.6days) and in BHI (9.7+/-3.8days) when compared to the controls. The combination of PL and SDA had synergistic effects on increasing lambda and lowering Nmax both in BHI and on salmon. Among all the treatments tested, the combination of NI and PL led to the greatest reductions in Nmax on salmon. We observed positive correlations between the growth parameters obtained from BHI broth and cold-smoked salmon, indicating that growth of L. monocytogenes in broth, to some extent, qualitatively reflected characteristics of growth on cold-smoked salmon under antimicrobial stresses. Results from BHI could quantitatively predict the variability of growth parameters obtained from salmon for lineage II strains, but not for lineage I strains. Although results from laboratory growth medium may not provide exact predictions of antimicrobial efficacy on cold-smoked salmon, they could be used to rapidly identify effective combinations for further examination on cold-smoked salmon. PMID- 23803571 TI - Prevalence, genetic characterization and virulence genes of sorbitol-fermenting Escherichia coli O157:H- and E. coli O157:H7 isolated from retail beef. AB - Sorbitol-fermenting (SF) Escherichia coli O157:H- strains have emerged as important pathogens and have been associated with a higher incidence of progression to hemolytic-uremic syndrome (HUS) than non-sorbitol fermenting (NSF) E. coli O157:H7. The present study was carried out to determine the prevalence of SF E. coli O157:H- and NSF E. coli O157:H7 strains in retail beef products in Mansoura, Egypt. The contamination rates with rfbEO157-positive E. coli O157 strains were 26.7% (8/30), 10% (3/30) and 3.7% (1/27) in ground beef, beef burger, and fresh beef samples, respectively with an overall mean of 13.8% (12/87) among all meat products tested. SF E. coli O157:H- were the most dominant among the isolated O157 strains. Of the fifteen O157 strains isolated, 11 (73.3%) were SF E. coli O157:H-, while the remaining 4 (26.7%) were NSF E. coli O157:H7. The 11 SF O157H- strains were genetically positive for sfpA gene. Restriction fragment length polymorphism (RFLP) analysis for fliC gene demonstrated a similar pattern for both SF and NSF O157 isolates. PCR assays verified the existence of stx1 gene in 7 (46.7%) and stx2 gene in 13 (86.7%) of the 15 O157 strains isolated. Unexpectedly, two of the 15 O157 strains isolated were negative for Shiga toxin genes. The eae gene was identified in all of the 15 O157 strains except in one NSF O157:H7 strain. EHEC-hlyA gene was detected in 14 (93.3%) of the 15 O157 isolates, nonetheless only 11 strains showed enterohemolytic phenotype on blood agar. A combination of the four virulence genes, stx1, stx2, eae and EHEC-hlyA were detected in 7 (46.7%) strains, while six (40%) strains were positive for stx2, eae and hlyA genes. This is the first record for isolation of E. coli O157: H- in Egypt as well as in the African continent. PMID- 23803572 TI - Influence of yeast strain on Shiraz wine quality indicators. AB - Wine styles are defined by complex and highly diverse chemical compositions. Evidence suggests that some of this complexity is determined by the choice of yeast strain used in fermentation. There are hundreds of different commercially available wine yeast strains that, potentially, provide a means by which winemakers can tailor their wines for different consumer market segments. In this study we evaluated the impacts of fermenting Shiraz must with different yeast strains, with a focus on chemical composition and tannin content of the finished wines. Principal Component Analysis (PCA) of the wines indicated that choice of yeast strain had a strong influence on a number of wine compositional parameters, including tannin. In three fermentation experiments, across two vintages and using different winemaking protocols, a compelling case for yeast strain 'signature' was evident. The results demonstrate that there is an opportunity to use commercial wine yeast diversity to modulate red wine composition and, by implication, the style of finished wines. PMID- 23803573 TI - [Current profile of cerebral toxoplasmosis in a hospital setting in Dakar]. AB - OBJECTIVE: To describe the current epidemiologic, clinical, diagnostic, and prognostic characteristics of cerebral toxoplasmosis in a hospital setting in Dakar. METHODS: This descriptive and analytic study examined the records of all HIV-positive patients with cerebral toxoplasmosis hospitalized at the infectious disease department at Fann (teaching) Hospital from January 2007 through December 2010. The diagnosis was based on clinical and computed tomography criteria completed by a therapeutic test with Cotrimoxazole. RESULTS: There were 26 cases of cerebral toxoplasmosis during the study period. The sex ratio (F/M) was 1.4. The mean age was 41.5 +/- 11.2 years. The clinical signs were predominantly fever (88.5%), headache (77.5%), focal signs (64.5%), and disorders of consciousness (61.5%). Brain lesions were most often multiple (64.3%), with mass effects (54.1%) and peripheral edema (77.8%). Seven of the 26 patients died (lethality rate: 29.1%). Impaired consciousness (p = 0.023), high CD8 T-cell counts (p = 0.009), and anemia (p = 0.003) were significantly associated with a higher mortality rate. CONCLUSION: Cerebral toxoplasmosis remains a complication of AIDS in Dakar. Anemia, impaired consciousness, and high CD8(+) T cell counts were factors indicative of poor prognosis. PMID- 23803574 TI - Association between alkaline phosphatase and hypertension in a rural Japanese population: the Nagasaki Islands study. AB - BACKGROUND: Although serum alkaline phosphatase (ALP) levels have been associated with hypertension, and ALP is known as an enzyme affected by alcohol consumption, no study has been published on the associations between ALP and the risk of hypertension in relation to drinking status. METHODS: We conducted a cross sectional study of 2,681 participants (837 men and 1,846 women) aged 30 to 89 years undergoing a general health check-up to investigate the associations between ALP and hypertension in relation to drinking status. RESULTS: Of the 2,681 participants, 1,549 (514 men and 1,035 women) were diagnosed with hypertension. A sex difference was observed for the relationship between ALP and hypertension. While no significant association was observed for men, the association was significantly positive for women. The multivariable adjusted odds ratio and 95% coincidence interval (CI) of hypertension per increment of 1-log ALP were 0.95 (95% CI: 0.56 to 1.59) for men and 1.57 (95% CI: 1.07 to 2.33) for women. When this analysis was restricted to nondrinkers, a significantly elevated risk of hypertension was observed for men and remained significant for women; that is, 3.32 (95% CI: 1.38 to 8.02) for men and 1.68 (95% CI: 1.11 to 2.55) for women. CONCLUSION: ALP is associated with hypertension for both male and female nondrinkers, but not for drinkers. For analyses of associations between ALP and blood pressure, alcohol consumption should thus be considered a potential confounder. PMID- 23803575 TI - Paediatric x-ray radiation dose reduction and image quality analysis. AB - Collaboration of multiple staff groups has resulted in significant reduction in the risk of radiation-induced cancer from radiographic x-ray exposure during childhood. In this study at an acute NHS hospital trust, a preliminary audit identified initial exposure factors. These were compared with European and UK guidance, leading to the introduction of new factors that were in compliance with European guidance on x-ray tube potentials. Image quality was assessed using standard anatomical criteria scoring, and visual grading characteristics analysis assessed the impact on image quality of changes in exposure factors. This analysis determined the acceptability of gradual radiation dose reduction below the European and UK guidance levels. Chest and pelvis exposures were optimised, achieving dose reduction for each age group, with 7%-55% decrease in critical organ dose. Clinicians confirmed diagnostic image quality throughout the iterative process. Analysis of images acquired with preliminary and final exposure factors indicated an average visual grading analysis result of 0.5, demonstrating equivalent image quality. The optimisation process and final radiation doses are reported for Carestream computed radiography to aid other hospitals in minimising radiation risks to children. PMID- 23803576 TI - Interstitial fluid lipoproteins. AB - PURPOSE OF REVIEW: The interstitium represents the fluid, proteins, solutes, and extracellular matrix comprising the microenvironment of tissues. We here review attempts to characterize the levels and composition of lipoproteins in human interstitial fluid, and identify potentially important questions for future research. RECENT FINDINGS: Despite the high relevance of understanding how lipoproteins enter and exit the interstitial compartment, and how they interact with extracellular and cellular molecules, scientific progress in this field has been rather slow. This is partly due to methodological difficulties, both regarding how to obtain representative samples and how to perform appropriate measurements to compare patient cohorts and to evaluate responses to treatment. Predominant techniques include peripheral lymph cannulation and suction blister creation, both of which have inherent advantages and disadvantages. Detailed studies comparing the effects of long-term incubation of serum and lymph lipoproteins are compatible with the view that HDL in interstitial fluid takes up free cholesterol from cells and transfers it into the circulation. SUMMARY: Studies of the concentration, composition, functionality, and turnover of interstitial fluid lipoproteins will be of great future interest for understanding how tissue cholesterol metabolism is regulated, and how different diseases link to increased risk for development of atherosclerosis. PMID- 23803577 TI - ANGPT2 promoter methylation is strongly associated with gene expression and prognosis in chronic lymphocytic leukemia. AB - Increasing evidence suggests a key role for angiopoietin-2 (ANGPT2) in influencing the aggressiveness of chronic lymphocytic leukemia (CLL). In the presence of vascular endothelial growth factor (VEGF), ANGPT2 causes vessel destabilization leading to neoangiogenesis. Accordingly, high expression levels of ANGPT2 and high degree of angiogenesis have consistently been associated with poor prognosis in CLL; however, the molecular mechanisms behind the variability in ANGPT2 expression are still to be discovered. Here, for the first time, we investigated the DNA methylation status of the ANGPT2 promoter in a large CLL cohort (n = 88) using pyrosequencing and correlated methylation data with ANGPT2 expression levels, prognostic factors and outcome. Importantly, methylation levels of the ANGPT2 gene correlated inversely with its mRNA expression levels (p<0.001). Moreover, low ANGPT2 methylation status was highly associated with adverse prognostic markers, shorter time to first treatment and overall survival. Finally, treatment with methyl inhibitors induced re-expression of ANGPT2 in two B-cell lymphoma cell lines, underscoring the importance of DNA methylation in regulating transcriptional silencing of this gene. In conclusion, we believe that the known variability in ANGPT2 expression among CLL patients could be explained by differential promoter DNA methylation and that low methylation levels of the ANGPT2 promoter have an adverse prognostic impact in CLL. PMID- 23803578 TI - The effect of socioeconomic status on the language outcome of preterm infants at toddler age. AB - BACKGROUND: Independently, both prematurity and low socioeconomic status (SES) compromise language outcome but less is known regarding the effects of low SES on outcome of prior preterm infants at toddler age. AIM: To assess SES effects on the language outcome of prior preterm infants at toddler age. STUDY DESIGN: Retrospective chart review of infants born at <=32 weeks, matched for gestational age (GA), birth weight (BW), chronic lung disease (CLD), periventricular leukomalacia (PVL), right and left intraventricular hemorrhage (IVH-R, L), and age at Bayley Scales of Infant Development III (BSID-III) testing. SUBJECTS: Using insurance status as a proxy for SES, 65 children with private insurance (P Ins) were matched with 65 children with Medicaid-type insurance (M-Ins). OUTCOME MEASURES: Bayley Scales of Infant Development-III Language Composite. RESULTS: M Ins vs. P-Ins were similar in GA, BW, and age at BSID-III testing (mean 22.6 months adjusted), as well as other matched characteristics (all p >= 0.16). BSID III Language Composite scores were lower in M-Ins than P-Ins (87.9 +/- 11.3 vs. 101.9 +/- 13.6) with a clinically significant effect size of 0.93 (p < 0.001). Overall, 45% of M-Ins exhibited mild to moderate language delay compared to 8% of P-Ins. Receptive and Expressive subscale scores also were lower in M-Ins than in P-Ins (both p < 0.001). CONCLUSIONS: In this preterm cohort, by toddler age, M Ins was associated with lower scores on measures of overall language as well as receptive and expressive language skills. Our findings, showing such an early influence of SES on language outcome in a cohort matched for biomedical risk, suggest that very early language interventions may be especially important for low SES preterm toddlers. PMID- 23803580 TI - Quantitative analysis of methylation status at 11p15 and 7q21 for the genetic diagnosis of Beckwith-Wiedemann syndrome and Silver-Russell syndrome. AB - Methylation-specific (MS) multiplex ligation-dependent probe amplification (MLPA) at two differentially methylated regions (DMRs) at chromosome 11p15, H19-DMR and LIT1-DMR, and microsatellite analysis for uniparental disomy (UPD) at chromosome 7 or 11, have been recommended for the genetic diagnosis of the Beckwith Wiedemann syndrome (BWS) and the Silver-Russell syndrome (SRS). In this study, the efficacy of the MS pyrosequencing method at H19-DMR and LIT1-DMR at 11p15 and SGCE-DMR at 7q21 was evaluated for the genetic diagnosis of BWS (n=18) and SRS (n=20) patients. Epigenetic alterations or UPD were detected in 83% of BWS and 50% of SRS individuals by MS-MLPA, but the detection rate increased to 95% of BWS and 70% of SRS by MS pyrosequencing. Thirteen BWS patients (72%) harbored loss-of methylation (LOM) at LIT1-DMR and two patients (11%) harbored gain-of-methylation (GOM) at H19-DMR, whereas two patients (11%) had both LOM at LIT1-DMR and GOM at H19-DMR, reflecting paternal UPD 11. Thirteen SRS patients (65%) harbored LOM at H19-DMR, whereas one patient (5%) had GOM at SGCE-DMR, reflecting maternal UPD 7. Birth anthropometric profiles were significantly correlated to methylation scores at either H19-DMR or LIT1-DMR. In conclusion, MS pyrosequencing enhanced the detection rate of molecular defects in BWS and SRS. Moreover, it indicates that methylation status at 11p15.5 might have an important role in fetal growth. PMID- 23803581 TI - [Treatment of inguinal hernia in a difficult environment: feasibility and efficacy of ilioinguinal and iliohypogastric blocks]. AB - Hernia repair is a very frequent surgical procedure; it is estimated that one African in five undergoes this procedure during his lifetime. Patients and methods. We evaluated the feasibility of this surgery under ilioinguinal and iliohypogastric nerve blocks in difficult environments. The medical-surgical group supporting Operation Unicorn has treated 48 inguinal hernias as medical aid to population, including 34 with these nerve blocks. Results. The block did not fail in any case. The mean time until discharge was 6.85 h, which meant that outpatient surgery was possible. Discussion and conclusion. This type of anesthesia is interesting in difficult environments. It is a safe, inexpensive, and easy to learn technique. These qualities should promote its use in countries with a low GNP. PMID- 23803582 TI - Extremity and eye lens dosimetry for medical staff performing vertebroplasty and kyphoplasty procedures. AB - Measurements of doses to hands, legs and eyes are reported for operators in four different hospitals performing vertebroplasty or kyphoplasty. The results confirm that occupational doses can be high for interventional spine procedures. Extremity and eye lens doses were measured with thermoluminescent dosimeters positioned on the ring fingers, wrists, legs and near the eyes of interventional radiologists and neurosurgeons, over a period of 15 months. Doses were generally larger on the left side for all positions monitored. The median dose to the left finger was 225 MUSv per procedure, although a maximum of 7.3 mSv was found. The median dose to the right finger was 118 MUSv, but with an even higher maximum of 7.7 mSv. A median left eye dose of 34 MUSv (maximum 836 MUSv) was found, while the legs received the lowest doses with a median of 13 MUSv (maximum 332 MUSv) to the left leg. Annual dose to the hand assessed by the cumulated doses almost reached the annual dose limit of 500 mSv, while annual dose to the eyes exceeded the eye lens dose limit of 20 mSv yr(-1). Different x-ray systems and radiation protection measures were tested, like the use of lead gloves and glasses, tweezers, cement delivery systems and a magnetic navigation system. These measurements showed that doses can be significantly reduced. The use of lead glasses is strongly recommended for protection of the eyes. PMID- 23803583 TI - A rice virescent-yellow leaf mutant reveals new insights into the role and assembly of plastid caseinolytic protease in higher plants. AB - The plastidic caseinolytic protease (Clp) of higher plants is an evolutionarily conserved protein degradation apparatus composed of a proteolytic core complex (the P and R rings) and a set of accessory proteins (ClpT, ClpC, and ClpS). The role and molecular composition of Clps in higher plants has just begun to be unraveled, mostly from studies with the model dicotyledonous plant Arabidopsis (Arabidopsis thaliana). In this work, we isolated a virescent yellow leaf (vyl) mutant in rice (Oryza sativa), which produces chlorotic leaves throughout the entire growth period. The young chlorotic leaves turn green in later developmental stages, accompanied by alterations in chlorophyll accumulation, chloroplast ultrastructure, and the expression of chloroplast development- and photosynthesis-related genes. Positional cloning revealed that the VYL gene encodes a protein homologous to the Arabidopsis ClpP6 subunit and that it is targeted to the chloroplast. VYL expression is constitutive in most tissues examined but most abundant in leaf sections containing chloroplasts in early stages of development. The mutation in vyl causes premature termination of the predicted gene product and loss of the conserved catalytic triad (serine histidine-aspartate) and the polypeptide-binding site of VYL. Using a tandem affinity purification approach and mass spectrometry analysis, we identified OsClpP4 as a VYL-associated protein in vivo. In addition, yeast two-hybrid assays demonstrated that VYL directly interacts with OsClpP3 and OsClpP4. Furthermore, we found that OsClpP3 directly interacts with OsClpT, that OsClpP4 directly interacts with OsClpP5 and OsClpT, and that both OsClpP4 and OsClpT can homodimerize. Together, our data provide new insights into the function, assembly, and regulation of Clps in higher plants. PMID- 23803584 TI - Class I HDAC imaging using [ (3)H]CI-994 autoradiography. AB - [ (3)H]CI-994, a radioactive isotopologue of the benzamide CI-994, a class I histone deacetylase inhibitor (HDACi), was evaluated as an autoradiography probe for ex vivo labeling and localizing of class I HDAC (isoforms 1-3) in the rodent brain. After protocol optimization, up to 80% of total binding was attributed to specific binding. Notably, like other benzamide HDACi, [ (3)H]CI-994 exhibits slow binding kinetics when measured in vitro with isolated enzymes and ex vivo when used for autoradiographic mapping of HDAC1-3 density. The regional distribution and density of HDAC1-3 was determined through a series of saturation and kinetics experiments. The binding properties of [ (3)H]CI-994 to HDAC1-3 were characterized and the data were used to determine the regional Bmax of the target proteins. Kd values, determined from slice autoradiography, were between 9.17 and 15.6 nM. The HDAC1-3 density (Bmax), averaged over whole brain sections, was of 12.9 picomol . mg(-1) protein. The highest HDAC1-3 density was found in the cerebellum, followed by hippocampus and cortex. Moderate to low receptor density was found in striatum, hypothalamus and thalamus. These data were correlated with semi-quantitative measures of each HDAC isoform using western blot analysis and it was determined that autoradiographic images most likely represent the sum of HDAC1, HDAC2, and HDAC3 protein density. In competition experiments, [ (3)H]CI 994 binding can be dose-dependently blocked with other HDAC inhibitors, including suberoylanilide hydroxamic acid (SAHA). In summary, we have developed the first known autoradiography tool for imaging class I HDAC enzymes. Although validated in the CNS, [ (3)H]CI-994 will be applicable and beneficial to other target tissues and can be used to evaluate HDAC inhibition in tissues for novel therapies being developed. [ (3)H]CI-994 is now an enabling imaging tool to study the relationship between diseases and epigenetic regulation. PMID- 23803585 TI - Effects of the methoxy group in the side chain of debromoaplysiatoxin on its tumor-promoting and anti-proliferative activities. AB - Debromoaplysiatoxin (DAT) is a tumor promoter isolated from sea hare and exhibits anti-proliferative activity against several cancer cell lines. To clarify key residues that are responsible for its tumor-promoting activity, we focused on the chiral methoxy group in the side chain, whose role had not yet been discussed or examined before. Demethoxy-DAT (8) was derived from DAT and we evaluated its tumor-promoting activity, anti-proliferative activity, and ability to bind to protein kinase C (PKC) isozymes. Compound 8 showed somewhat weaker tumor promoting activity than that of DAT both in vitro and in vivo, but showed higher anti-proliferative activity against several cancer cell lines. Although the affinity to novel PKC isozymes of 8 was comparable to that of DAT, the affinity to conventional PKC isozymes decreased slightly. These results suggest that the methoxy group of DAT is one of the key residues critical for tumor-promoting activity but not for anti-proliferative activity. Since the methoxy group has little influence on the molecular hydrophobicity, this is the first report showing that structural factors other than hydrophobicity in the side chain of DAT affected its biological activities. PMID- 23803586 TI - HCV NS5A replication complex inhibitors. Part 5: discovery of potent and pan genotypic glycinamide cap derivatives. AB - The isoquinolinamide series of HCV NS5A inhibitors exemplified by compounds 2b and 2c provided the first dual genotype-1a/1b (GT-1a/1b) inhibitor class that demonstrated a significant improvement in potency toward GT-1a replicons compared to that of the initial program lead, stilbene 2a. Structure-activity relationship (SAR) studies that uncovered an alternate phenylglycine-based cap series that exhibit further improvements in virology profile, along with some insights into the pharmacophoric elements associated with the GT-1a potency, are described. PMID- 23803587 TI - Homeostatic regulation of dendritic dynamics in a motor map in vivo. AB - Neurons and circuits are remarkably dynamic. Their gross structure can change within minutes as neurons sprout and retract processes to form new synapses. Homeostatic processes acting to regulate neuronal activity contribute to these dynamics and predict that the dendritic dynamics within pools of neurons should vary systematically in accord with the activity levels of individual neurons in the pool during behaviour. Here we test this by taking advantage of a topographic map of recruitment of spinal motoneurons in zebrafish. In vivo imaging reveals that the dendritic filopodial dynamics of motoneurons map onto their recruitment pattern, with the most electrically active cells having the lowest dynamics. Genetic reduction of activity inverts this map of dynamics. We conclude that homeostatic mechanisms driven by a gradient of activity levels in a pool of neurons can drive an associated gradation in neuronal dendritic dynamics, potentially shaping connectivity within a functionally heterogenous pool of neurons. PMID- 23803588 TI - Bi-PROF: bisulfite profiling of target regions using 454 GS FLX Titanium technology. AB - The use of next generation sequencing has expanded our view on whole mammalian methylome patterns. In particular, it provides a genome-wide insight of local DNA methylation diversity at single nucleotide level and enables the examination of single chromosome sequence sections at a sufficient statistical power. We describe a bisulfite-based sequence profiling pipeline, Bi-PROF, which is based on the 454 GS-FLX Titanium technology that allows to obtain up to one million sequence stretches at single base pair resolution without laborious subcloning. To illustrate the performance of the experimental workflow connected to a bioinformatics program pipeline (BiQ Analyzer HT) we present a test analysis set of 68 different epigenetic marker regions (amplicons) in five individual patient derived xenograft tissue samples of colorectal cancer and one healthy colon epithelium sample as a control. After the 454 GS-FLX Titanium run, sequence read processing and sample decoding, the obtained alignments are quality controlled and statistically evaluated. Comprehensive methylation pattern interpretation (profiling) assessed by analyzing 10 (2)-10 (4) sequence reads per amplicon allows an unprecedented deep view on pattern formation and methylation marker heterogeneity in tissues concerned by complex diseases like cancer. PMID- 23803589 TI - [Invasive aspergillosis of sphenoidal sinus in a patient in Djibouti, revealed by palsy of cranial nerves: a case report]. AB - The authors report a case of invasive aspergillosis of a sphenoid sinus mucocele revealed in a patient with diabetes in Djibouti by homolateral palsy of the 3rd, 4th, 5th and 6th nerves. This rare condition occurs preferentially in immunodeficient subjects. Because of its clinical polymorphism, its diagnosis is difficult and is often not made until complications develop. Endonasal surgery with anatomopathological and mycological examination is both a diagnostic and therapeutic procedure. It must be performed early, to avoid functional or even life-threatening complications. PMID- 23803590 TI - Polymorphisms of the adiponectin gene in gestational hypertension and pre eclampsia. AB - Adiponectin is a hormone involved in energy homeostasis by regulating glucose and lipid metabolism. In addition, the adiponectin gene (ADIPOQ) has polymorphisms that can modulate the circulating concentration of adiponectin. Abnormal adiponectin levels have been associated with pre-eclampsia (PE); however, the influence of genetic polymorphisms on the development of hypertensive disorders of pregnancy is unclear. The aim of this study was to examine whether ADIPOQ polymorphisms are associated with gestational hypertension (GH) and/or PE. We studied 401 pregnant women: 161 healthy pregnant (HP), 113 pregnant with GH and 127 pregnant with PE. ADIPOQ polymorphisms -11391G>A (rs17300539), -11377C>G (rs266729), 45T>G (rs2241766) and 276G>T (rs1501299) were genotyped by allelic discrimination assays using real-time PCR. Haplotypes were inferred using the PHASE 2.1 program. We observed that the genotypic frequencies of the -11377C>G polymorphism were different in PE compared with HP (P<0.0125), with the CT genotype being more commonly found in PE patients than in HP women (P<0.0125). However, allelic frequencies of this single-nucleotide polymorphism were similar between PE and HP (P>0.0125). No difference was observed when GH and HP groups were compared (both P>0.0125). In addition, we found no difference in genotype or allele distributions for the -11391G>A, 45T>G and 276G>T polymorphisms when we compared GH or PE with HP (all P>0.0125). In conclusion, we found a modest association between the CG genotype of the -11377C>G polymorphism and PE. PMID- 23803591 TI - Efficacy of newer versus older antihypertensive drugs in black patients living in sub-Saharan Africa. AB - To address the epidemic of hypertension in blacks born and living in sub-Saharan Africa, we compared in a randomised clinical trial (NCT01030458) single-pill combinations of old and new antihypertensive drugs in patients (30-69 years) with uncomplicated hypertension (140-179/90-109 mm Hg). After >=4 weeks off treatment, 183 of 294 screened patients were assigned to once daily bisoprolol/hydrochlorothiazide 5/6.25 mg (n=89; R) or amlodipine/valsartan 5/160 mg (n=94; E) and followed up for 6 months. To control blood pressure (<140/<90 mm Hg), bisoprolol and amlodipine could be doubled (10 mg per day) and alpha methyldopa (0.5-2 g per day) added. Sitting blood pressure fell by 19.5/12.0 mm Hg in R patients and by 24.8/13.2 mm Hg in E patients and heart rate decreased by 9.7 beats per minute in R patients with no change in E patients (-0.2 beats per minute). The between-group differences (R minus E) were 5.2 mm Hg (P<0.0001) systolic, 1.3 mm Hg (P=0.12) diastolic, and 9.6 beats per minute (P<0.0001). In 57 R and 67 E patients with data available at all visits, these estimates were 5.5 mm Hg (P<0.0001) systolic, 1.8 mm Hg (P=0.07) diastolic and 9.8 beats per minute (P<0.0001). In R compared with E patients, 45 vs 37% (P=0.13) proceeded to the higher dose of randomised treatment and 33 vs 9% (P<0.0001) had alpha methyldopa added. There were no between-group differences in symptoms except for ankle oedema in E patients (P=0.012). In conclusion, new compared with old drugs lowered systolic blood pressure more and therefore controlled hypertension better in native African black patients. PMID- 23803592 TI - Hypertension and kidneys: unraveling complex molecular mechanisms underlying hypertensive renal damage. AB - Kidney damage represents a frequent event in the course of hypertension, ranging from a benign to a malignant form of nephropathy depending on several factors, that is, individual susceptibility, degree of hypertension, type of etiology and underlying kidney disease. Multiple mechanisms are involved in determination of kidney glomerular, tubular and interstitial injuries in hypertension. The present review article discusses relevant contributory molecular mechanisms underpinning the promotion of hypertensive renal damage, such as the renin-angiotensin aldosterone system (RAAS), oxidative stress, endothelial dysfunction, and genetic and epigenetic determinants. We highlighted major pathways involved in the progression of inflammation and fibrosis leading to glomerular sclerosis, tubular atrophy and interstitial fibrosis, thus providing a state of the art review of the pathogenetic background useful for a better understanding of current and future therapeutic strategies toward hypertensive nephropathy. An adequate control of high blood pressure, obtained through an appropriate therapeutic intervention, still represents the key strategy to achieve a satisfactory control of renal damage in hypertension. In this regard, we reviewed the impact of currently available antihypertensive pharmacological treatment on kidney damage, with particular regard to RAAS inhibitors. Notably, recent findings underscored the ability of the kidneys to regenerate and to repair tissue injuries through the differentiation of resident embryonic stem cells. Pharmacological modulation of the renal endogenous reparative process (that is, with angiotensin-converting enzyme inhibitors and AT1 angiotensin II receptor blockers), as well as future therapeutic strategies targeted to the renopoietic system, offers interesting perspectives for the management of hypertensive nephropathy. PMID- 23803593 TI - Visit-to-visit systolic blood pressure variability and outcomes in hemodialysis. AB - Visit-to-visit blood pressure variability (VTV-BPV) is an independent risk factor for cardiovascular events and death in the general population. We sought to determine the association of VTV-BPV with outcomes in patients on hemodialysis, using data from a National Institutes of Health-sponsored randomized trial (the HEMO study). We used the coefficient of variation (CV) and the average real variability in systolic blood pressure (SBP) as metrics of VTV-BPV. In all, 1844 out of 1846 randomized subjects had at least three visits with SBP measurements and were included in the analysis. Median follow-up was 2.5 years (interquartile range 1.3-4.3 years), during which time there were 869 deaths from any cause and 408 (adjudicated) cardiovascular deaths. The mean pre-dialysis SBP CV was 9.9 +/- 4.6%. In unadjusted models, we found a 31% higher risk of death from any cause per 10% increase in VTV-BPV. This association was attenuated after multivariable adjustment but remained statistically significant. Similarly, we found a 28% higher risk of cardiovascular death per 10% increase in VTV-BPV, which was attenuated and no longer statistically significant in fully adjusted models. The associations among VTV-BPV, death and cardiovascular death were modified by baseline SBP. In a diverse, well-dialyzed cohort of patients on maintenance hemodialysis, VTV-BPV, assessed using metrics of variability in pre-dialysis SBP, was associated with a higher risk of all-cause mortality and a trend toward higher risk of cardiovascular mortality, particularly in patients with a lower baseline SBP. PMID- 23803594 TI - Low-dose neostigmine to antagonise shallow atracurium neuromuscular block during inhalational anaesthesia: A randomised controlled trial. AB - BACKGROUND: Even shallow residual neuromuscular block [i.e. train-of-four (TOF) ratio around 0.6] is harmful. It can be effectively antagonised by small doses of neostigmine, but reports are limited to intravenous anaesthesia. Inhalational anaesthesia may enhance neuromuscular block and delay recovery. It is not known whether low doses of neostigmine are still effective in the context of inhalational anaesthesia. OBJECTIVE: To assess the effectiveness of low doses of neostigmine to antagonise shallow atracurium block during desflurane anaesthesia. DESIGN: Randomised controlled trial, four groups. SETTING: Single centre, University Hospital, May 2010 to March 2011. PARTICIPANTS: Forty-eight American Society of Anesthesiologists I-III patients undergoing desflurane anaesthesia. INTERVENTION: At TOF ratio 0.6, patients were randomised to one of four treatments (physiological saline, 10, 20 or 30 ug kg(-1) neostigmine, n = 12 for each). MAIN OUTCOME MEASURE: Primary efficacy endpoint: time interval between study drug injection and a TOF ratio more than 0.9 using acceleromyography. Secondary efficacy endpoint: neuromuscular recovery after 5 and 10 min. RESULTS: After physiological saline, the time interval [median (range)] between a TOF ratio of 0.6 and 0.9 was 14 (7 to 18) min. After 10, 20 and 30 ug kg(-1) neostigmine, it was reduced to 5 (3 to 8) min, 5 (3 to 10) and 4 (2 to 6) min, respectively (P < 0.001 compared to physiological saline). At 5 min after physiological saline, the TOF ratio [mean (SD)] was 0.73 (0.05) and 0.91 (0.06), 0.90 (0.10), 0.96 (0.02) after neostigmine 10, 20 or 30 ug kg(-1), respectively (P < 0.01 compared to physiological saline). At 10 min after physiological saline, the TOF ratio was 0.86 (0.08) and 1.0 (0), 0.98 (0.03), 1.0 (0) after neostigmine 10, 20 or 30 ug kg(-1), respectively (P < 0.01 compared to physiological saline). CONCLUSION: Under desflurane anaesthesia, neostigmine 10 ug kg(-1) is effective in antagonising shallow atracurium block. Compared to no neostigmine, the time to a TOF ratio more than 0.9 was shortened and neuromuscular recovery at 5 and 10 min was more advanced. TRIAL REGISTRATION: EudraCT Nr. is 2009 -018214-19. PMID- 23803595 TI - An alternative way of managing acute pain in patients who are in buprenorphine opioid substitution therapy programs. PMID- 23803597 TI - Anti-glomerular basement membrane disease treated with mycophenolate mofetil, corticosteroids, and plasmapheresis. AB - An 18-year-old woman presented with anemia, pulmonary hemorrhage, and necrotizing glomerulonephritis, and was diagnosed with anti-glomerular basement membrane (anti-GBM) disease. Treatment was undertaken with plasma exchange, mycophenolate mofetil and corticosteroids, due to patient refusal of cyclophosphamide. Clinical remission was successfully induced with this fertility-sparing regimen. A relapse due to therapy non-adherence was successfully treated with a second course of plasmapheresis, mycophenolate, and steroids. Thereafter, 6 months of directly observed therapy resulted in a favorable outcome with well-preserved pulmonary and renal function. This case suggests the possibility that mycophenolate may have a role in the treatment of anti-GBM disease. PMID- 23803596 TI - The association of chronic kidney disease complications by albuminuria and glomerular filtration rate: a cross-sectional analysis. AB - BACKGROUND: Albuminuria is strongly associated with future risk for cardiovascular and kidney outcomes, and has been proposed to be included in the classification of chronic kidney disease (CKD) along with glomerular filtration rate (GFR). Few data are available on whether albuminuria is associated with concurrent complications of CKD. METHODS: A cross-sectional analysis of 1,665 participants screened for the Modification of Diet in Renal Disease (MDRD) study was performed to examine the association between albuminuria (determined using urine albumin-creatinine ratio (ACR)) and measured GFR (determined using urinary clearance of iothalamate) with anemia, acidosis, hyperphosphatemia, and hypertension. RESULTS: Mean GFR (+/- SD) was 39 ml/min/1.73 m2 (+/- 21) and the median (25 - 75th percentile) ACR was 161 (38 - 680) mg/g. In multivariable models adjusted for age, sex, race, kidney disease etiology, and GFR, higher ACR levels were not associated with any complication. For example, comparing ACR > 300 mg/g vs. < 30 mg/g, the prevalence ratio (95% CI) for anemia was 0.98 (0.81 - 1.20), acidosis 1.13 (0.86 - 1.48), hyperphosphatemia 1.69 (0.91 - 3.17), and hypertension 1.04 (0.97 - 1.12). Lower levels of GFR were associated with all complications. For example, GFR levels < 30 ml/min/1.73 m2 vs. GFR levels 60 - 89 ml/min/1.73 m2 were associated with prevalence ratios (95% CI) of anemia 4.35 (3.18 - 5.96), acidosis 5.31 (3.41 - 8.29), hyperphosphatemia 23.8 (7.71 - 73.6), and hypertension 1.21 (1.10 - 1.32). CONCLUSIONS: Albuminuria is not associated with complications after controlling for GFR in patients younger than 70 years of age with non-diabetic CKD and GFR less than 90 ml/min/1.73 m2 and thus would not affect clinical action plans for decisions regarding evaluation and treatment of complications in similar populations. PMID- 23803598 TI - Cytomegalovirus polyradiculopathy of late onset in a young renal transplant recipient. AB - Although cytomegalovirus (CMV) disease in CMV IgM/IgG-negative renal transplant recipients from CMV-positive donors (D+/R-) can occur after discontinuation of prophylaxis treatment as a flu-like syndrome or tissue invasive disease, involvement of the central nervous system is rare. Here, we report a case of CMV polyradiculopathy 6 months after renal transplantation that presented as a Guillain-Barre like syndrome and was successfully treated with foscarnet. This case highlights an uncommon aspect of CMV invasive disease which we should keep in mind in CMV (D+/R-) renal transplant recipients. PMID- 23803599 TI - An assessment of lead eyewear in interventional radiology. AB - The International Commission on Radiological Protection (ICRP) has recently issued a proposal to reduce the occupational eye dose limit from 150 to 20 mSv. A series of experiments has been performed to determine the level of protection from scattered radiation afforded to the interventional radiology operator by protective lead glasses, taking into account variation in operator position and angle of head rotation. The lenses of the glasses have a lead equivalence of 0.75 mm lead with 0.5 mm lead present in the side shields. Our results have led us to propose the use of a general dose reduction factor of 5 when using eyewear with this lead equivalence and construction. We have also concluded that the forehead of the wearer provides the most robust position to site a dosemeter that will be used to estimate the dose to both eyes as part of a personal monitoring regime. We have confirmed that backscatter from the head itself is the limiting factor for the dose reduction potential of lead eyewear. PMID- 23803600 TI - Urinary connective tissue growth factor is associated with human renal allograft fibrogenesis. AB - BACKGROUND: Connective tissue growth factor (CTGF) is a key mediator of tissue fibrogenesis in kidney disease. Its involvement in renal allograft fibrosis was recently demonstrated in a mouse model. METHODS: We prospectively studied the association between urinary CTGF (CTGFu) levels and renal allograft fibrosis during the first 2 years after transplantation. Histologic and biochemical data were collected from 315 kidney transplant recipients enrolled in a protocol biopsy-based clinical program. RESULTS: At 3, 12, and 24 months after transplantation, CTGFu levels were independently associated with the degree of interstitial fibrosis in protocol biopsies, scored according to the revised 1997 Banff criteria. In a subgroup of 164 patients with pristine biopsies at 3 months, higher CTGFu levels at 3 months were associated with moderate and severe interstitial fibrosis developed at 24 months after transplantation. CONCLUSIONS: As it is readily quantifiable in urine, a role for CTGFu as a noninvasive candidate biomarker and predictor of human renal allograft fibrogenesis deserves further study. PMID- 23803601 TI - Iatrogenic instability of the lateral meniscus after partial meniscectomy. AB - BACKGROUND: Partial resection of the lateral meniscus can lead to iatrogenic instability of the remnant, resulting in recurrent locking episodes. Due to the innocuous appearance on MRI, the etiology of the locking episodes can be difficult to determine, leading to delays in diagnosis and treatment of this entity. CASE DESCRIPTION: We describe two cases of unstable lateral meniscus posterior horn remnants after previous partial meniscectomy for meniscal tear. Both patients initially presented with lateral pain without mechanical symptoms and were treated with partial meniscectomies. They developed new locking symptoms after initial arthroscopies, and worsened after repeat arthroscopy with removal of additional meniscal tissue. Both patients had their locking symptoms questioned and been accused of malingering by previous physicians due to the benign MRI findings. They were treated successfully by completion meniscectomy. LITERATURE REVIEW: Few studies investigate atypical locking symptoms secondary to undiagnosed lateral meniscus tears. No previous case reports have described knee locking after partial lateral meniscectomy secondary to iatrogenic posterior horn remnants instability. CLINICAL RELEVANCE: New onset mechanical symptoms after partial resection of the lateral meniscus body can be due to posterior horn instability with subluxation under the femoral condyle. This entity appears benign on MRI, requiring a high index of suspicion to make the diagnosis. PMID- 23803602 TI - Chronic traumatic encephalopathy in sport: a systematic review. AB - OBJECTIVE: To provide a critical review of chronic traumatic encephalopathy (CTE) by considering the range of clinical presentations, neuropathology and the strength of evidence for CTE as a distinct syndrome. DATA SOURCES: Seven electronic databases were searched using a combination of MeSH terms and key words to identify relevant articles. REVIEW METHODS: Specific inclusion and exclusion criteria were used to select studies for review. Data extracted where present included study population, exposure/outcome measures, clinical data, neurological examination findings, cognitive assessment, investigation results and neuropathology results. RESULTS: The data from 158 published case studies were reviewed. Critical differences between the older descriptions of CTE (the 'classic' syndrome) and the recent descriptions (the 'modern' syndrome) exist in the age of onset, natural history, clinical features, pathological findings and diagnostic criteria, which suggests that modern CTE is a different syndrome. The methodology of the current studies does not allow determination of aetiology or risk factors. CONCLUSIONS: The clinicopathological differences between the 'classic' CTE syndrome and the 'modern' syndrome suggest that the new syndrome needs a different nomenclature. Further research is required to clearly define the clinical phenotype of the modern CTE syndrome and establish the underlying aetiology. Future research needs to address these issues through large-scale, prospective clinicopathological studies. PMID- 23803604 TI - Phosphorylation of the activation loop tyrosine 823 in c-Kit is crucial for cell survival and proliferation. AB - The receptor tyrosine kinase c-Kit, also known as the stem cell factor receptor, plays a key role in several developmental processes. Activating mutations in c Kit lead to alteration of these cellular processes and have been implicated in many human cancers such as gastrointestinal stromal tumors, acute myeloid leukemia, testicular seminomas and mastocytosis. Regulation of the catalytic activity of several kinases is known to be governed by phosphorylation of tyrosine residues in the activation loop of the kinase domain. However, in the case of c-Kit phosphorylation of Tyr-823 has been demonstrated to be a late event that is not required for kinase activation. However, because phosphorylation of Tyr-823 is a ligand-activated event, we sought to investigate the functional consequences of Tyr-823 phosphorylation. By using a tyrosine-to-phenylalanine mutant of tyrosine 823, we investigated the impact of Tyr-823 on c-Kit signaling. We demonstrate here that Tyr-823 is crucial for cell survival and proliferation and that mutation of Tyr-823 to phenylalanine leads to decreased sustained phosphorylation and ubiquitination of c-Kit as compared with the wild-type receptor. Furthermore, the mutated receptor was, upon ligand-stimulation, quickly internalized and degraded. Phosphorylation of the E3 ubiquitin ligase Cbl was transient, followed by a substantial reduction in phosphorylation of downstream signaling molecules such as Akt, Erk, p38, Shc, and Gab2. Thus, we propose that activation loop tyrosine 823 is crucial for activation of both the MAPK and PI3K pathways and that its disruption leads to a destabilization of the c-Kit receptor and decreased survival of cells. PMID- 23803603 TI - Plasma membrane calcium ATPase activity is regulated by actin oligomers through direct interaction. AB - As recently described by our group, plasma membrane calcium ATPase (PMCA) activity can be regulated by the actin cytoskeleton. In this study, we characterize the interaction of purified G-actin with isolated PMCA and examine the effect of G-actin during the first polymerization steps. As measured by surface plasmon resonance, G-actin directly interacts with PMCA with an apparent 1:1 stoichiometry in the presence of Ca(2+) with an apparent affinity in the micromolar range. As assessed by the photoactivatable probe 1-O-hexadecanoyl-2-O [9-[[[2-[(125)I]iodo-4-(trifluoromethyl-3H-diazirin-3 yl)benzyl]oxy]carbonyl]nonanoyl]-sn-glycero-3-phosphocholine, the association of PMCA to actin produced a shift in the distribution of the conformers of the pump toward a calmodulin-activated conformation. G-actin stimulates Ca(2+)-ATPase activity of the enzyme when incubated under polymerizing conditions, displaying a cooperative behavior. The increase in the Ca(2+)-ATPase activity was related to an increase in the apparent affinity for Ca(2+) and an increase in the phosphoenzyme levels at steady state. Although surface plasmon resonance experiments revealed only one binding site for G-actin, results clearly indicate that more than one molecule of G-actin was needed for a regulatory effect on the pump. Polymerization studies showed that the experimental conditions are compatible with the presence of actin in the first stages of assembly. Altogether, these observations suggest that the stimulatory effect is exerted by short oligomers of actin. The functional interaction between actin oligomers and PMCA represents a novel regulatory pathway by which the cortical actin cytoskeleton participates in the regulation of cytosolic Ca(2+) homeostasis. PMID- 23803605 TI - Structural basis for interaction between Mycobacterium smegmatis Ms6564, a TetR family master regulator, and its target DNA. AB - Master regulators, which broadly affect expression of diverse genes, play critical roles in bacterial growth and environmental adaptation. However, the underlying mechanism by which such regulators interact with their cognate DNA remains to be elucidated. In this study, we solved the crystal structure of a broad regulator Ms6564 in Mycobacterium smegmatis and its protein-operator complex at resolutions of 1.9 and 2.5 A, respectively. Similar to other typical TetR family regulators, two dimeric Ms6564 molecules were found to bind to opposite sides of target DNA. However, the recognition helix of Ms6564 inserted only slightly into the DNA major groove. Unexpectedly, 11 disordered water molecules bridged the interface of TetR family regulator DNA. Although the DNA was deformed upon Ms6564 binding, it still retained the conformation of B-form DNA. Within the DNA-binding domain of Ms6564, only two amino acids residues directly interacted with the bases of cognate DNA. Lys-47 was found to be essential for the specific DNA binding ability of Ms6564. These data indicate that Ms6564 can bind DNA with strong affinity but makes flexible contacts with DNA. Our study suggests that Ms6564 might slide more easily along the genomic DNA and extensively regulate the expression of diverse genes in M. smegmatis. PMID- 23803606 TI - Chaperonin-mediated protein folding. AB - We have been studying chaperonins these past twenty years through an initial discovery of an action in protein folding, analysis of structure, and elucidation of mechanism. Some of the highlights of these studies were presented recently upon sharing the honor of the 2013 Herbert Tabor Award with my early collaborator, Ulrich Hartl, at the annual meeting of the American Society for Biochemistry and Molecular Biology in Boston. Here, some of the major findings are recounted, particularly recognizing my collaborators, describing how I met them and how our great times together propelled our thinking and experiments. PMID- 23803607 TI - Calmodulin-dependent protein kinase II/cAMP response element-binding protein/Wnt/beta-catenin signaling cascade regulates angiotensin II-induced podocyte injury and albuminuria. AB - Angiotensin II (Ang II) plays a pivotal role in promoting podocyte dysfunction and albuminuria, however, the underlying mechanisms have not been fully delineated. In this study, we found that Ang II induced Wnt1 expression and beta catenin nuclear translocation in cultured mouse podocytes. Blocking Wnt signaling with Dickkopf-1 (Dkk1) or beta-catenin siRNA attenuated Ang II-induced podocyte injury. Ang II could also induce the phosphorylation of calmodulin-dependent protein kinase (CaMK) II and cAMP response element-binding protein (CREB) in cultured podocytes. Blockade of this pathway with CK59 or CREB siRNA could significantly inhibit Ang II-induced Wnt/beta-catenin signaling and podocyte injury. In in vivo studies, administration of Ang II promoted Wnt/beta-catenin signaling, aggregated podocyte damage, and albuminuria in mice. CK59 could remarkably ameliorate Ang II-induced podocyte injury and albuminuria. Furthermore, ectopic expression of exogenous Dkk1 also attenuated Ang II-induced podocytopathy in mice. Taken together, this study demonstrates that the CaMK II/CREB/Wnt/beta-catenin signaling cascade plays an important role in regulating Ang II-induced podocytopathy. Targeting this signaling pathway may offer renal protection against the development of proteinuric kidney diseases. PMID- 23803608 TI - Membrane damage by an alpha-helical pore-forming protein, Equinatoxin II, proceeds through a succession of ordered steps. AB - Actinoporin equinatoxin II (EqtII) is an archetypal example of alpha-helical pore forming toxins that porate cellular membranes by the use of alpha-helices. Previous studies proposed several steps in the pore formation: binding of monomeric protein onto the membrane, followed by oligomerization and insertion of the N-terminal alpha-helix into the lipid bilayer. We studied these separate steps with an EqtII triple cysteine mutant. The mutant was engineered to monitor the insertion of the N terminus into the lipid bilayer by labeling Cys-18 with a fluorescence probe and at the same time to control the flexibility of the N terminal region by the disulfide bond formed between cysteines introduced at positions 8 and 69. The insertion of the N terminus into the membrane proceeded shortly after the toxin binding and was followed by oligomerization. The oxidized, non-lytic, form of the mutant was still able to bind to membranes and oligomerize at the same level as the wild-type or the reduced form. However, the kinetics of the N-terminal helix insertion, the release of calcein from erythrocyte ghosts, and hemolysis of erythrocytes was much slower when membrane bound oxidized mutant was reduced by the addition of the reductant. Results show that the N-terminal region needs to be inserted in the lipid membrane before the oligomerization into the final pore and imply that there is no need for a stable prepore formation. This is different from beta-pore-forming toxins that often form beta-barrel pores via a stable prepore complex. PMID- 23803612 TI - Changes in cognitive function after carotid endarterectomy in older patients: comparison with younger patients. AB - Objective and subjective assessments of changes in cognition after carotid endarterectomy (CEA) were compared between older patients (>=76 years old) and younger patients (<76 years old). Patients underwent subjective cognitive assessment by a neurosurgeon and the patient's next of kin, and neuropsychological testing (five parameters) before and after surgery. Of 37 older patients studied, 4 (11%), 28 (75%), and 5 (14%) patients were defined as having subjectively improved, unchanged, and impaired cognition, respectively, following surgery. Differences in test scores (postoperative test score - preoperative test score: Delta score) in all neuropsychological tests were significantly lower in the older patients than in the 213 younger patients. The Delta score was able to statistically differentiate older patients with subjectively improved, unchanged, and impaired cognition after surgery. Receiver operating characteristic analysis showed that the Delta score cut-off point for detecting subjective improvement (upper cut-off point) and impairment (lower cut off point) in cognition after surgery in older patients was identical to the mean or the mean +0.5 standard deviation (SD) and the mean -1.5 SD or the mean -1 SD, respectively, of the control value obtained from normal subjects. The upper and lower cut-off points were lower and higher, respectively, than those in younger patients. In conclusion, although neuropsychological test scores reflect the subjective assessment of postoperative change in cognition in older patients, the optimal cut-off points for the test scores to detect subjective improvement and impairment in cognition after CEA are different in older patients compared with younger patients. PMID- 23803609 TI - Cytotoxic necrotizing factor-Y boosts Yersinia effector translocation by activating Rac protein. AB - Pathogenic Yersinia spp. translocate the effectors YopT, YopE, and YopO/YpkA into target cells to inactivate Rho family GTP-binding proteins and block immune responses. Some Yersinia spp. also secrete the Rho protein activator cytotoxic necrotizing factor-Y (CNF-Y), but it has been unclear how the bacteria may benefit from Rho protein activation. We show here that CNF-Y increases Yop translocation in Yersinia enterocolitica-infected cells up to 5-fold. CNF-Y strongly activated RhoA and also delayed in time Rac1 and Cdc42, but when individually expressed, constitutively active mutants of Rac1, but not of RhoA, increased Yop translocation. Consistently, knock-out or knockdown of Rac1 but not of RhoA, -B, or -C inhibited Yersinia effector translocation in CNF-Y-treated and control cells. Activation or knockdown of Cdc42 also affected Yop translocation but much less efficiently than Rac. The increase in Yop translocation induced by CNF-Y was essentially independent of the presence of YopE, YopT, or YopO in the infecting Yersinia strain, indicating that none of the Yops reported to inhibit translocation could reverse the CNF-Y effect. In summary, the CNF-Y activity of Yersinia strongly enhances Yop translocation through activation of Rac. PMID- 23803610 TI - FOXO1 competes with carbohydrate response element-binding protein (ChREBP) and inhibits thioredoxin-interacting protein (TXNIP) transcription in pancreatic beta cells. AB - Thioredoxin-interacting protein (TXNIP) has emerged as an important factor in pancreatic beta cell biology, and tight regulation of TXNIP levels is necessary for beta cell survival. However, the mechanisms regulating TXNIP expression have only started to be elucidated. The forkhead boxO1 transcription factor (FOXO1) has been reported to up-regulate TXNIP expression in neurons and endothelial cells but to down-regulate TXNIP in liver, and the effects on beta cells have remained unknown. We now have found that FOXO1 binds to the TXNIP promoter in vivo in human islets and INS-1 beta cells and significantly decreases TXNIP expression. TXNIP promoter deletion analyses revealed that an E-box motif conferring carbohydrate response element-binding protein (ChREBP)-mediated, glucose-induced TXNIP expression is necessary and sufficient for this effect, and electromobility shift assays confirmed FOXO1 binding to this site. Moreover, FOXO1 blocked glucose-induced TXNIP expression and reduced glucose-induced ChREBP binding at the TXNIP promoter without affecting ChREBP expression or nuclear localization, suggesting that FOXO1 may compete with ChREBP for binding to the TXNIP promoter. In fact, a FOXO1 DNA-binding mutant (FOXO1-H215R) failed to inhibit TXNIP transcription, and the effects were not restricted to TXNIP as FOXO1 also inhibited transcription of other ChREBP target genes such as liver pyruvate kinase. Together, these results demonstrate that FOXO1 inhibits beta cell TXNIP transcription and suggest that FOXO1 confers this inhibition by interfering with ChREBP DNA binding at target gene promoters. Our findings thereby reveal a novel gene regulatory mechanism and a previously unappreciated cross-talk between FOXO1 and ChREBP, two major metabolic signaling pathways. PMID- 23803613 TI - Surgical results of microvascular decompression procedures and patient's postoperative quality of life: review of 139 cases. AB - Microvascular decompression (MVD) is effective for the relief of symptoms, but little is known about the impact of the MVD procedure on patient's quality of life (QoL) or which QoL factors are important. The surgical results of MVD and the impact of this procedure were evaluated on patient's QoL in 139 patients, 74 with hemifacial spasm (HFS) and 65 with trigeminal neuralgia (TN), who underwent MVD between 2004 and 2011 using the 36-Item Short Form Health Survey questionnaire. Symptoms had resolved in approximately 95% of patients after MVD. The QoL questionnaire was completed by 54 HFS patients and 38 TN patients. Although long-term QoL scores for both groups were comparable to the average national value, scores related to physical role, emotional role, and social function were significantly lower for patients within 12 months of receiving MVD for HFS, compared with the reference scores. Symptomatic improvements and complications were correlated with the QoL scores related to the social function domain for patients with HFS. No other significant relationships were observed between any of the factors or scores in any of the respective domains or periods. Subjective symptoms were the main self-reported causes of delayed recovery of QoL domains. Some QoL domains take a long time to recover and postoperative subjective symptoms might be major causes in addition to delayed relief of symptoms. PMID- 23803614 TI - Anti-inflammatory effect of D-allose in cerebral ischemia/reperfusion injury in rats. AB - D-allose, a type of rare sugar, can produce inhibitory effects on activated leukocytes in various organs, including immunosuppressive effects and anti inflammatory effects, as well as anti-oxyradical effects. The present experiment was performed to investigate the potential anti-inflammatory effects of D-allose in acute cerebral ischemia/reperfusion (I/R) injury. Transient middle cerebral artery occlusion model was applied in rats. D-allose was administered two times via a tail vein (300 mg/kg, 1 hour before ischemia and 10 hours after reperfusion). After 22 hours of reperfusion following 2 hours of ischemia, brain damage was evaluated by cerebral infarct volume. Myeloperoxidase (MPO) activity assay by enzyme-linked immunosorbent assay, and protein expression of MPO and cyclooxygenase-2 (COX-2) by immunohistochemistry were evaluated to investigate the potential mechanisms of D-allose. The experimental results showed that D allose exhibited significant neuroprotective effects against acute cerebral I/R injury. The infarct volume in D-allose-treated rats (90.9 +/- 13.5 mm(3)) was significantly smaller than that in vehicle rats (114.9 +/- 15.3 mm(3), p < 0.01). D-allose treatment significantly suppressed the MPO activity and the number of MPO-positive cells compared with those in the vehicle group, suggesting that treatment with D-allose can reduce the infiltration of leukocytes into the ischemic tissue. Treatment of D-allose also significantly decreased the number of COX-2-positive cells and microglial activation in the ischemic tissue. The present results demonstrate that D-allose exerts potent neuroprotective effects against acute cerebral I/R injury, and constitute the first evidence of anti inflammatory effects of D-allose which considerably contributes to the beneficial effects. Treatment with D-allose might provide a new strategy and clinically beneficial outcome for acute ischemic stroke. PMID- 23803615 TI - Hemodynamic instability increases new ischemic brain lesions on diffusion weighted imaging after carotid artery stenting. AB - Hemodynamic instability (HI) may impair the washout of debris during distal intracranial circulation and increase the risk of clinically evident cerebral ischemia. However, the interaction between HI and new ischemic brain lesions detected on diffusion-weighted imaging (DWI) has not been examined. This study evaluated whether HI was significantly associated with the incidence of new ischemic brain lesions on DWI. Data on 128 patients who underwent carotid artery stenting (CAS) with the same devices and procedures between January 2005 and May 2010 were retrospectively analyzed. HI was noted in 31 (24.2%) patients. New ischemic brain lesions were detected on DWI in 25 (19.5%) patients. Ten of 31 (32.2%) patients with HI showed new ischemic brain lesions on DWI. Fifteen of 97 (15.5%) patients without HI showed new lesions. Univariate analysis showed that patients with HI had a significantly higher incidence of new ischemic brain lesions than patients without HI (p = 0.04). A multivariable model showed that age and HI were significantly associated with the incidence of new ischemic brain lesions. In patients with carotid artery stenosis, decreased blood pressure produced no active vascular response, but reduced the cerebral blood volume and velocity due to impaired dynamic cerebral autoregulation. The results of this study suggest that HI with CAS induces impaired clearance of microembolisms and causes an increased number of new ischemic brain lesions detected on DWI. PMID- 23803616 TI - Risk factors of ischemic lesions related to cerebral angiography and neuro interventional procedures. AB - Embolic stroke is not a rare complication of cerebral angiography. The risk factors for incidental embolism after cerebral angiography were retrospectively examined using diffusion-weighted magnetic resonance imaging (DWI) in 180 patients who underwent 247 angiography procedures, consisting of 174 diagnostic angiography and 73 interventional procedures, and magnetic resonance imaging including DWI within 72 hours after angiography. The two neuroradiologists in our hospital detected embolism after cerebral angiography as high-intensity lesions (HIL) on DWI. The relationships between HIL on DWI and procedural factors were evaluated. DWI after cerebral angiography revealed HIL related to the procedure in 72 of 247 angiographies. In all procedures, age (p < 0.01), past history of cerebral infarction (p < 0.05), anti-platelet therapy (p < 0.05), neuro intervention (p < 0.01), and total amount of contrast medium (odds ratio [OR] 2.125, 95% confidence interval [CI] 1.045-4.321) were significantly correlated with HIL. In diagnostic angiography, the performance of the procedure by a resident operator (OR 2.526, 95% CI 1.214-5.254) was significantly correlated with HIL. Age, past history of cerebral infarction, and previous anti-platelet therapy determined the risk of atherosclerotic changes in patients. The neuro intervention and total amount of contrast medium used could predict the risk of time limitations for angiography. Resident operator is also a risk factor. This study demonstrates the importance of improving the risk of time limitations for angiography and the risk due to operator inexperience. Further training of residents may be needed to reduce the occurrence of embolic complications. PMID- 23803617 TI - Electroencephalographic evaluation of cerebral hyperperfusion syndrome following superficial temporal artery-middle cerebral artery anastomosis. AB - Low-flow bypass, such as superficial temporal artery-middle cerebral artery (STA MCA) anastomosis, can result in cerebral hyperperfusion syndrome (CHS). The present study evaluated the pathophysiological conditions of CHS through the use of repeated electroencephalography (EEG). Among a total of 22 patients who underwent STA-MCA anastomosis over a course of 4 years, 3 patients were diagnosed with CHS based on clinical symptoms and neuroradiological examinations, including cerebral blood flow evaluation. Case 1 and Case 2 developed CHS on postoperative day 1, when EEG demonstrated focal slow waves on the frontal region of the operated side, indicating cortical dysfunction in these areas. Although prompt recovery of these EEG findings was noted with improvement of the clinical symptoms in Case 1, Case 2 developed an intracranial hemorrhage on postoperative day 5, when EEG clearly depicted persistent nonconvulsive status epilepticus (NCSE) after control of convulsive status epilepticus. In contrast, the clinical onset in Case 3 was delayed to postoperative day 6 and EEG revealed frequent ictal discharges in the operated hemisphere, although convulsive seizures were not apparent. Administration of anticonvulsants was performed after the diagnosis of NCSE, and complete recovery from CHS was achieved. Although the pathophysiology of CHS is cortical dysfunction, ictal hyperperfusion associated with NCSE could be included. The present findings emphasize the importance of repeated EEG examinations in the differential diagnosis of the various types of pathophysiological conditions of CHS. PMID- 23803618 TI - Prediction of cerebral vasospasm using early stage transcranial Doppler. AB - Transcranial Doppler (TCD) is widely used to monitor vasospasm after subarachnoid hemorrhage (SAH), but its ability to predict the future occurrence of the symptomatic vasospasm (SVS) remains controversial. We investigated the utility of TCD for predicting the future occurrence of SVS after SAH in 45 patients with aneurysmal SAH. TCD was performed on days 1, 3, 5, 7, 10, and 14 after SAH. The mean flow velocity (MFV) of the horizontal portion of the middle cerebral artery (M1) was recorded. SVS occurred in 24.4% of patients (n = 11). MFV of M1 increased progressively in patients with SVS, but did not increase in patients without SVS. The mean MFV values were significantly higher in patients with SVS than in patients without SVS (p = 0.031). The mean MFV value on day 3 was already significantly higher in patients with SVS than in patients without SVS (88.5 cm/sec versus 62.7 cm/sec, respectively) (p = 0.018). The receiver operating characteristic curve of MFV on day 3 showed the threshold of 72.5 cm/sec for predictive value of SVS in the future (sensitivity 71.4%, specificity 68.1%, and accuracy 82.3%). Increased MFV of M1 during the early stage of SAH may predict the future occurrence of SVS. The threshold value of 72.5 cm/sec MFV of M1 on SAH day 3 was one of the best predictor of future SVS. To prevent delayed cerebral ischemia, aggressive treatment for vasospasm is needed for patients with increased MFV in the early stages of SAH. PMID- 23803619 TI - Analysis of closed-cell intracranial stent characteristics using cone-beam computed tomography with contrast material. AB - The intracranial nitinol stent named the Enterprise Vascular Reconstruction Device has poor radiographic visibility. The characteristics of closed-cell intracranial stents were investigated and the efficacy of intraoperative stent visualization examined with the 80 kV high-resolution XperCT protocol, which is a flat detector C-arm volume acquisition functionality system integrated with the angiography equipment. We treated 39 aneurysms with stent-assisted coil embolization. The aneurysms were located on the internal carotid artery in 24 cases, the anterior communicating artery (AcomA) in three, the basilar artery (BA) in 10, and the vertebral artery in two. Intraoperative 80 kV XperCT was performed in all cases after deposition of the stent. We evaluated the coverage of the aneurysm neck, incomplete stent apposition (ISA), and shift of vessels. Accurate stent visualization was achieved in 29 of the 39 cases without coil and delivery wire artifact. Coverage of the aneurysm neck succeeded in 28 cases; there was one case of BA top Y-configuration stenting in which the stent was dislocated into the aneurysm. ISA was detected in nine cases, including seven kinks and one flattening in the carotid siphon and one kink in the BA top. We detected linearization of vessels due to stent deployment in three AcomA cases and three BA top cases. We conclude that intraoperative 80 kV XperCT is an efficient modality for the evaluation of ISA. Stent kinking in the carotid siphon and linearization in distal vessels can be detected with this protocol. PMID- 23803620 TI - Endovascular coiling as the first treatment strategy for ruptured pericallosal artery aneurysms: results, complications, and follow up. AB - We apply endovascular coiling as the first treatment option for ruptured pericallosal artery aneurysms. We conducted a retrospective analysis of the clinical and radiological outcomes of this treatment strategy and morphological factors associated with the success of endovascular coiling, to assess the safety and feasibility of our management strategy. From January 2003 to January 2012, we attempted endovascular coiling as the first-intention treatment for 30 consecutive patients with ruptured pericallosal artery aneurysms including those with intracerebral hematoma. Twenty-seven cases of ruptured pericallosal artery aneurysms were successfully embolized with coiling whereas three failures required surgery. Four patients experienced periprocedural complications including thromboembolic event in two and hematoma enlargement after coiling in two. A maximum aneurysm diameter of <3 mm was most strongly associated with failure of endovascular coiling. Of the 27 coil-treated aneurysms, immediate angiographic results showed complete aneurysm occlusion in 19 cases, neck remnant in 6, and residual aneurysm in 2. One patient had a major aneurysm recurrence that was uneventfully reembolized. Sixteen of our 30 patients had good outcomes (modified Rankin scale [mRS] 0-2), 7 had moderate disability (mRS 3), and 4 had severe disability (mRS 4-5) at 3 months after treatment. The management strategy for coiling as the first-intention treatment for ruptured pericallosal artery aneurysms has the potential to become an acceptable alternative to surgical clipping for selected cases, although a larger study population and longer follow up periods are needed before definitive conclusions can be drawn. PMID- 23803621 TI - Deterioration of glaucoma after carotid endarterectomy. AB - A 64-year-old man with a long history of untreated diabetes mellitus had suffered from visual disturbance in his right eye. Neovascular glaucoma in the right eye and diabetic retinopathy in both eyes were found, and ischemic ocular syndrome was suspected for the right eye. Neuroimaging revealed severe stenosis of the right internal carotid artery. He was first treated for diabetes and glaucoma, and then, after these conditions were stabilized, right carotid endarterectomy (CEA) was carried out. Although the operation was uneventful, he suffered from headache and his right sight was blurred on the day after surgery. Right intraocular pressure was markedly increased, and corneal edema and increased iris neovascularization were also recognized. Intensive ophthalmologic care was carried out, but his right vision worsened and was eventually lost. Ocular ischemia causes not only neovascularization of the iris, which leads to insufficient resorption of the aqueous humor, but also insufficient production of the aqueous humor. After CEA, production of the humor is immediately activated, but the resorption capacity does not change, which results in an extraordinary increase in intraocular pressure. Neurosurgeons should be aware that CEA not only improves or avoids worsening of vision in patients with ischemic oculopathy, but can also rarely cause paradoxical devastating visual deterioration. PMID- 23803622 TI - Endovascular angioplasty for extracranial vertebral artery occlusion without visualization of the stump of the artery ostium. AB - An 87-year-old man presented with extracranial vertebral artery (VA) occlusion and progressive vertebrobasilar ischemia despite maximal medical management. Cerebral angiography showed left proximal VA occlusion, termination of the right VA at the ipsilateral posterior inferior cerebellar artery, and hypoplastic bilateral posterior communicating arteries. Although the stump of the left VA ostium was not visualized, the distal patent artery was reconstituted via muscular branches from the left subclavian artery (SCA). Endovascular angioplasty with a stent for left VA occlusion was performed. The non-visualized VA ostium was extrapolated from the computed tomography angiography findings of the distal patent VA and the partial calcification of the SCA. The occluded VA was penetrated by the guide wire and revascularized by balloon angioplasty with the stent using the support of a snare wire inserted via the left brachial artery for stabilization of the guide catheter. This treatment resulted in resolution of the severe neurological findings. PMID- 23803624 TI - Perspective: the late preterm infant. PMID- 23803625 TI - Most striking, perhaps, is the outcome of the extremely low birth weight neonate. Foreword. PMID- 23803626 TI - Multidisciplinary guidelines for the care of late preterm infants. Introduction. PMID- 23803628 TI - [Silver economy: a challenge for the geriatric medicine?]. PMID- 23803629 TI - [Expert consensus of the French society of geriatrics and gerontology and the French society of cardiology on the management of atrial fibrillation in elderly people]. AB - The prevalence of atrial fibrillation (AF) increase with ageing. In France AF affects between 400,000 to 660,000 people aged 75 years or more. In the elderly, AF is a major risk factor of stroke and a predictive factor for mortality. Comorbidities are frequent and worsen the prognosis of AF. They can be the cause or the consequence of AF and their management is a major therapeutic objective. Comprehensive geriatric assessment (CGA), is required to analyse both medical and psychosocial elements, and to identify co-morbidities and geriatrics syndrome as cognitive disorders, risk of falls, malnutrition, mood disorders, and lack of dependency and social isolation. The objectives of AF treatment in the elderly are to prevent AF complications, particularly stroke, and to improve quality of life. Specific precautions for treatment must be taken because of the co morbidities and age-related changes in pharmacokinetics or pharmacodynamics. Preventing AF complications relies mainly on anticoagulant therapy. Anticoagulants are recommended in patients with AF aged >= 75 years after assessing the bleeding risk using Hemorr2hages or HAS-BLED scores. Novel oral anticoagulants (NOACs) are promising treatments especially due to a lower risk of intracerebral haemorrhage. However, their prescriptions should take into account renal function (creatinine clearance assessed with Cockcroft formula) and cognitive function (for adherence to treatment). Studies including very old patients with several comorbidities in 'real life' are necessary to evaluate tolerance of NOACs in this population. The management of AF also involves the treatment of underlying cardiomyopathy and heart rate control rather than rhythm control strategy as first-line therapy in the elderly. PMID- 23803627 TI - Multidisciplinary guidelines for the care of late preterm infants. PMID- 23803630 TI - [Oral ecosystem in elderly people]. AB - The mouth is a complex natural cavity which constitutes the initial segment of the digestive tract. It is an essential actor of the vital functions as nutrition, language, communication. The whole mouth (teeth, periodontium, mucous membranes, tongue) is constantly hydrated and lubricated by the saliva. At any age, a balance becomes established between the bacterial proliferations, the salivary flow, the adapted tissular answer: it is the oral ecosystem. The regulation of this ecosystem participates in the protection of the oral complex against current inflammatory and infectious pathologies (caries, gingivitis, periodontitis, candidiasis). In elderly, the modification of the salivary flow, the appearance of specific pathologies (root caries, edentulism, periodontitis), the local conditions (removable dentures), the development of general pathologies, the development of general pathologies (diabetes, hypertension, immunosuppression, the insufficient oral care are so many elements which are going to destabilize the oral ecosystem, to favor the formation of the dental plaque and to weaken oral tissues. The preservation of this ecosystem is essential for elderly: it allows to eat in good conditions and so to prevent the risks of undernutrition. The authors describe the oral physiopathology (oral microflora, salivary secretion) and the strategies to be adopted to protect the balance of the oral ecosystem in geriatric population. PMID- 23803631 TI - [Description of cognitive-behavioral specialized units in France: results of a national investigation]. AB - Through a national survey, the SFGG's UCC Task Force worked and liaised with the DGOS as to establish a national inventory of the UCCs in France. 43 of the 55 newly opened UCCs in 2011 filled up the survey. These UCCs largely supported patients meeting the admission criteria's from the book of specifications edited by the public department. Those patients were demented, valid and with disruptive behavior disorders. Earnings for the stay were commonly measured by a reduced NPI (32 to 18). Body therapies, cognitive and sensory were mainly performed, even if a quarter of the UCCs also provided acute missions (diagnosis and management of acute diseases). Medical staff and caregivers were very different. Nearly half of the UCCs reported an insufficient staffing and a third of them reported a lack of training. Among the most often claimed difficulty (81% of UCCs), the release of patients is noted, with an average length of stay of 36 days. From an architectural point of view and even if the amount of beds was by the book (in average: 11), 58% of the UCCs proposed only single rooms. The lack of homogeneity shown with this survey tells us to share more our practice. PMID- 23803632 TI - [Determinants of support for dementia patients in general practice: a qualitative approach based on an epidemiological cohort]. AB - BACKGROUND: the analysis of access to diagnosis and care pathway for dementia patients shows that the disease is not considered as a priority for the general practitioner (GP). Different studies have point out under diagnosis of dementia. PURPOSE: the purpose of this qualitative study was to document the determinants of the diagnosis and management of dementia by GP. METHODS: recruitment of GPs (n = 12) was made from incident cases of dementia who were identified during the follow-up of subject enrolled in the 3 Cities cohort study. A semi-structured interview was conducted with an interview guide focused on the experience of the doctors. A phenomenological and pragmatic analysis, taking into account all the linguistic and extra linguistic evidence contained in the transcript was conducted. RESULTS: several emerging categories have been described: the doctors believe that the management of Alzheimer's disease is a public health problem and not an individual, the positioning of the GP in the care system is central. Determinants that influence the management are the identity of the physician, the impression of a fuzzy nosology, the finding of a therapeutic ineffectiveness, the priority given to severe co-morbidities and the workload of the general practitioner. However, the ordering of these categories according to the pragmatic phenomenological approach showed that the identity of the doctor, professional and personal, is at the origin of behavioral variability in their medical care. CONCLUSION: in a context of increased workload, the GP favors the assumption of comorbidities in the elderly given fuzzy nosology of dementia and uncertainty about the therapeutic efficacy. The phenomenological approach allows understanding that the human identity of the doctor, personal and professional identity, is the major factor that influence its care attitude for demented patients. PMID- 23803634 TI - [Current concepts in vascular dementia]. AB - Vascular dementias, VD, are dementias due to cerebrovascular lesions. Subgroups of VD include multi-infarct dementia, single infarct (or strategic infarct) dementia, subcortical ischemic vascular dementia, hemorrhagic dementia, hypoperfusion dementia. VD are also related to post-stroke dementia, mixed Alzheimer's disease and vascular dementia and vascular cognitive impairment. These various entities allow to characterize more homogenous subgroups within the heterogeneous group of vascular dementias. However, ambiguities in their definitions, associated with frequent overlaps as well as lack of consensual definition for mixed dementia limit both their theoretical value and use in clinical practice. The diagnosis of cerebrovascular diseases should be dissociated from that of dementia, which could be associated with other pathologies. PMID- 23803635 TI - [Epidemiology of psychiatric disorders in elderly and their impact on somatic health]. AB - Increasing life expectancy over the past half century results in higher demand for healthcare of the aging population, therefore adapting the health system to the needs. The prevalence of psychiatric disorders is high in the elderly, especially for depression. Several studies have shown that twenty percent of elderly residents of public facilities meet the criteria for major depressive episode. Depression is a major burden in the elderly, with increased risk of suicide, impaired quality of life and functional autonomy, consequences on somatic morbidity and elevated mortality rates. It is thus necessary to find out how to improve physicians' abilities to detect and treat depression in older adults. Moreover, use of psychotropic drugs is frequent and increases the risk of injury in this population more vulnerable to drug effects. It is also necessary to develop specific gerontopsychiatric wards in large general hospitals and nursing homes. PMID- 23803636 TI - [Relationship between memory disorders and self-consciousness in Alzheimer's disease]. AB - Episodic memory deficits are almost always the first cognitive impairment in Alzheimer disease (AD). AD is also characterized by a loss of self-awareness. The aim of this article is to give an interpretation of AD patients' episodic impairments through the study of the relationship between memory and the self. Using the Remember/Know paradigm associated with the self-reference effect and emotional valence, we showed that this relationship may be impaired in AD. On the one hand, this could explain AD patients' difficulty accessing autonoetic consciousness, that is to say mentally bring back events of the past. On the other hand, the difficulty to precisely relieve previous events may be in turn at the root of AD patients' loss of self-awareness, namely anosognosia. Thus, based on the previous studies in the field of self-referential processing and on our findings, we proposed that the combination of an emotion analysis and a cognitive approach of AD patients' episodic memory impairments is an interesting way to better understand the complete functioning of AD patients. PMID- 23803637 TI - [Role of demotivation and affective disorders in apathy in patients with Parkinson's disease without dementia and depression]. AB - OBJECTIVE: to assess the role of demotivation and various affective factors in apathy in patients with Parkinson's disease (PD) without dementia and depression. SUBJECTS: 20 patients and 20 control subjects matched with age, education level, and genre. METHODS: apathy was assessed by the Apathy evaluation scale (AES) and by a specific scale including a quantitative evaluation of 32 intentional activities and a qualitative assessment of the causes of attribution of restricted activities by a semi-structured interview (GDAS). Four causal attributions were distinguished: E = related to external factors, M = disease symptoms related, C = affective disturbances with preservation of motivation, and D = demotivation. The results were compared to a battery of tests including cognitive evaluation (mini-mental state and Mattis dementia rating scale for global evaluation, selecting reminding test for memory; Stroop test for inhibition, and six element test for planification); affective evaluation (Montgomery & Asberg and Hamilton depression rating scales for depression, emotional disturbances by the Abrams and Taylor scale, the Depression mood scale, and the International picture system), premorbid personality (NEOPI-R), and defensive psychological mechanisms (DSQ-40); functional assessment by a combined scale including the Self-maintenance physical scale and the Instrumental activities of daily living (Lawton) and the Social activities scale (Katz & Lyerly), the Disability assessment scale, and the UPDRS. RESULTS: apathy was found in 25% of the patients according to the AES, but only in 15% according to the GDAS. Scores on cognitive and affective evaluation were higher in patients than in controls but only emotional blunting was correlated to apathy. Some results coud be interpreted in favor of a premorbid personality disorder in patients with PD, but were not correlated to apathy. Causal attribution was M in 38% of cases of reduced activities, D in 30%, E in 22%, and C in 10%. CONCLUSION: emotional blunting was the main correlate of apathy in PD patients without dementia and depression. Demotivation was the causal mechanism in only 30% of the patients with apathy. PMID- 23803638 TI - [Are non-literal language comprehension deficits related to a theory of mind deficit in Parkinson's disease?]. AB - Theory of mind (TOM), i.e. the capacity to attribute mental states to oneself and others, would be impaired in Parkinson's disease (PD). Nonliteral language (NLL) comprehension would also be impaired in this disease. The goal of this study was to verify the presence of an association between the TOM and NLL comprehension deficits. We assessed 15 individuals in the early stages of PD and 17 healthy controls (HC), comparable on gender, age and education. Each subject completed a TOM evaluation task and a NLL task (i.e. metaphor comprehension). They also completed executive functioning (mental flexibility, inhibition and working memory) evaluation tasks. Our results showed that patients with PD had significant difficulties in the TOM and NLL comprehension tasks compared to HC participants. A significant relationship was found between TOM and NLL comprehension results. Moreover, NLL scores were associated with a task evaluating mental flexibility. Thus, PD might cause both TOM and NLL comprehension deficit even in the early stages of the disease. Our results showed that there would be a close relationship between TOM and NLL in people with PD. PMID- 23803639 TI - [Decision-making and apathy in early stage of Alzheimer's disease and in mild cognitive impairment]. AB - Decision-making and apathy have common neuropsychological processes and neuroanatomical substrates. However, their links in mild cognitive impairment (MCI) and Alzheimer's disease (AD) remain unclear. OBJECTIVE AND METHODS: in order to evaluate these links, we compared 3 groups of 20 control subjects to 20 patients with MCI and 20 patients with mild AD. All participants completed the mini mental state examination (MMSE), the Lille apathy rating scale (LARS, a multidimensional scale of apathy), the game of dice task (GDT, assessing decision under risk) and the Iowa gambling task (IGT, assessing decision under ambiguity). RESULTS: 60% of patients in both clinical groups were apathetic versus 5% of control subjects. In both clinical groups the IGT and GDT net scores were comparable (respectively: p = 0.76 and p = 0.84), while the control group had higher scores than MCI and AD's groups (respectively, GDT p < 0.02 and p < 0.05; IGT: p < 0.05 and p < 0.05). Cognitive impairment increased the risk of disadvantageous choices in decision under risk (* 6), and under ambiguity (* 3.5). No global contribution of apathy was found for decision-making performances (all PS > 0.05), but on the LARS, the "intellectual curiosity" (cognitive dimension) was a predictor for the performances on GDT's (OR = 1.73, p = 0.05), while the "action initiation" (behavioral dimension) was a predictor of those on IGT (OR = 1.57, p = 0.05). DISCUSSION: these results highlight the behavioral and the cognitive sensitivity of the IGT and the GDT, and are analyzed according to Levy and Dubois's model of apathy, and to the three steps of the decision-making process of Gleichgerrcht et al. (2010). However, more researches are necessary to explain the causality links between action initiation and decision under ambiguity. PMID- 23803641 TI - Stimulated emission depletion-based raster image correlation spectroscopy reveals biomolecular dynamics in live cells. AB - Raster image correlation spectroscopy is a powerful tool to study fast molecular dynamics such as protein diffusion or receptor-ligand interactions inside living cells and tissues. By analysing spatio-temporal correlations of fluorescence intensity fluctuations from raster-scanned microscopy images, molecular motions can be revealed in a spatially resolved manner. Because of the diffraction limited optical resolution, however, conventional raster image correlation spectroscopy can only distinguish larger regions of interest and requires low fluorophore concentrations in the nanomolar range. Here, to overcome these limitations, we combine raster image correlation spectroscopy with stimulated emission depletion microscopy. With imaging experiments on model membranes and live cells, we show that stimulated emission depletion-raster image correlation spectroscopy offers an enhanced multiplexing capability because of the enhanced spatial resolution as well as access to 10-100 times higher fluorophore concentrations. PMID- 23803642 TI - Perspectives to performance of environment and health assessments and models- from outputs to outcomes? AB - The calls for knowledge-based policy and policy-relevant research invoke a need to evaluate and manage environment and health assessments and models according to their societal outcomes. This review explores how well the existing approaches to assessment and model performance serve this need. The perspectives to assessment and model performance in the scientific literature can be called: (1) quality assurance/control, (2) uncertainty analysis, (3) technical assessment of models, (4) effectiveness and (5) other perspectives, according to what is primarily seen to constitute the goodness of assessments and models. The categorization is not strict and methods, tools and frameworks in different perspectives may overlap. However, altogether it seems that most approaches to assessment and model performance are relatively narrow in their scope. The focus in most approaches is on the outputs and making of assessments and models. Practical application of the outputs and the consequential outcomes are often left unaddressed. It appears that more comprehensive approaches that combine the essential characteristics of different perspectives are needed. This necessitates a better account of the mechanisms of collective knowledge creation and the relations between knowledge and practical action. Some new approaches to assessment, modeling and their evaluation and management span the chain from knowledge creation to societal outcomes, but the complexity of evaluating societal outcomes remains a challenge. PMID- 23803644 TI - An initial evaluation of direct care staff resilience workshops in intellectual disabilities services. AB - The emotional responses to challenging behaviour of direct care staff who support people with intellectual disabilities is thought to be an important mediating factor within the stress experienced by staff and a potential maintaining factor in challenging behaviour. A brief workshop to improve direct care staff resilience was developed and initially evaluated using a measure of emotional reaction to challenging behaviour and a measure of burnout. It was found that negative emotional reactions to challenging behaviour significantly reduced following the workshop, but a measure of burnout did not. This may indicate the usefulness of this intervention with direct care staff in managing their emotional reactions to challenging behaviour. However, further development and evaluation of such interventions with direct care staff is required to explore ways of impacting upon burnout and managing the display of challenging behaviour. PMID- 23803643 TI - CpG dinucleotide-specific hypermethylation of the TNS3 gene promoter in human renal cell carcinoma. AB - Tensin3 is a cytoskeletal regulatory protein that inhibits cell motility. Downregulation of the gene encoding Tensin3 (TNS3) in human renal cell carcinoma (RCC) may contribute to cancer cell metastatic behavior. We speculated that epigenetic mechanisms, e.g., gene promoter hypermethylation, might account for TNS3 downregulation. In this study, we identified and validated a TNS3 gene promoter containing a CpG island, and quantified the methylation level within this region in RCC. Using a luciferase reporter assay we demonstrated a functional minimal promoter activity for a 500-bp sequence within the TNS3 CpG island. Pyrosequencing enabled quantitative determination of DNA methylation of each CpG dinucleotide (a total of 43) in the TNS3 gene promoter. Across the entire analyzed CpG stretch, RCC DNA showed a higher methylation level than both non-tumor kidney DNA and normal control DNA. Out of all the CpGs analyzed, two CpG dinucleotides, specifically position 2 and 8, showed the most pronounced increases in methylation levels in tumor samples. Furthermore, CpG-specific higher methylation levels were correlated with lower TNS3 gene expression levels in RCC samples. In addition, pharmacological demethylation treatment of cultured kidney cells caused a 3-fold upregulation of Tensin3 expression. In conclusion, these results reveal a differential methylation pattern in the TNS3 promoter occurring in human RCC, suggesting an epigenetic mechanism for aberrant Tensin downregulation in human kidney cancer. PMID- 23803645 TI - Supported employment for young people with intellectual disabilities facilitated through peer support: a pilot study. AB - The article reports the evaluation of a small-scale-supported employment project in a local authority in England. The study examined whether or not the peer support model could be used to deliver supported employment to a group of young people with intellectual disabilities. We utilised a mixed-method approach involving activity data, family interviews and a postal survey with participating employers. Five families took part in the study. Our findings show that families viewed the project positively, although it was insufficiently embedded in the wider transition planning. The study indicates that the peer support model may represent a useful addition to the conventional supported employment efforts for this population. However, more research is needed to demonstrate the benefits of peer support over and above the benefits of conventional supported employment for young people in post-school transition. In particular, producing a better evidence base on the exact impact of peer support on service users' experiences is recommended. PMID- 23803646 TI - Exploring fathers' perceptions of parenting a child with Asperger syndrome. AB - This study explores Irish fathers' perceptions of parenting a child with Asperger syndrome (AS). Ethical approval was granted by the service provider, and Husserlian phenomenological approach facilitated the exploration. Data were collected through semi-structured interviews of nine fathers in the West region of Ireland. Data were transcribed and analysed using Colaizzi's (1978) method. The study highlighted that parenting a child with AS is an arduous task, but while there are difficulties, many positive aspects to their parenting experience were reported. Overall, the study highlights the importance of listening to parents and their initial concerns regarding their child's development. PMID- 23803647 TI - The contribution of human activities to dissolved inorganic carbon fluxes in a karst underground river system: evidence from major elements and delta13C(DIC) in Nandong, Southwest China. AB - Generally, the DIC in karst groundwater is dominantly derived from carbonate dissolution by carbonic acid. However, recently increases in the inorganic carbon flux have been linked to human activities, which nitric and sulfuric acids may contribute to carbonate dissolution. In order to quantify the sources and fluxes of DIC, and evaluate the carbon isotopic evolution of groundwater in Southwest China, the carbonate dissolution by carbonic, sulfuric and nitric acids was evaluated by hydrochemistry and delta13C(DIC)of groundwater. The results show that: (1) groundwater collected from residential and agricultural areas, showed higher DIC concentrations and delta13C(DIC) than those in groundwater collected from forested and grass land areas; (2) the contributions of carbonate dissolution by carbonic acid to total DIC concentrations in groundwater collected from forested and grass land areas averaged 99%; (3) the contributions of carbonate dissolution by carbonic acid to total DIC concentrations in groundwater, collected from residential and agricultural areas, varied from 40% to 77% with a mean percentage of 62%; (4) while the contributions of carbonate dissolution by sulfuric and nitric acids to total DIC concentrations in groundwater, collected from residential and agricultural areas, varied from 23% to 60% with a mean percentage of 38%; and (5) the delta13C(DIC) approaching a value of around -140/00, with a molar ratio between (Ca2++Mg2+) and HCO3- of around 0.5 in groundwater, indicated that the carbonate was dissolved by soil CO2 from C3 vegetation under open system conditions. While the delta13C(DIC) varying from -50/00 to -110/00, with a variational molar ratio between (Ca2++Mg2+) and HCO3- of 0.5 to 0.8 in groundwater, indicated that carbonate dissolution was controlled by soil CO2 (from C3 vegetation), HNO3 and H2SO4. Also, this study indicated that the amount of soil or atmospheric CO2 consumed during carbonate weathering should be critically evaluated when sulfuric or nitric acids are involved. Thus, not only the exports of inorganic carbon have been enhanced, but also the concentrations of nitrate and sulfate in karst groundwater have been elevated due to carbonate dissolution by sulfuric or nitric acid. PMID- 23803650 TI - Chemical vapour deposition growth of large single crystals of monolayer and bilayer graphene. AB - The growth of large-domain single crystalline graphene with the controllable number of layers is of central importance for large-scale integration of graphene devices. Here we report a new pathway to greatly reduce the graphene nucleation density from ~10(6) to 4 nuclei cm(-2), enabling the growth of giant single crystals of monolayer graphene with a lateral size up to 5 mm and Bernal-stacked bilayer graphene with the lateral size up to 300 MUm, both the largest reported to date. The formation of the giant graphene single crystals eliminates the grain boundary scattering to ensure excellent device-to-device uniformity and remarkable electronic properties with the expected quantum Hall effect and the highest carrier mobility up to 16,000 cm(2) V(-1) s(-1). The availability of the ultra large graphene single crystals can allow for high-yield fabrication of integrated graphene devices, paving a pathway to scalable electronic and photonic devices based on graphene materials. PMID- 23803651 TI - Salience network-based classification and prediction of symptom severity in children with autism. AB - IMPORTANCE: Autism spectrum disorder (ASD) affects 1 in 88 children and is characterized by a complex phenotype, including social, communicative, and sensorimotor deficits. Autism spectrum disorder has been linked with atypical connectivity across multiple brain systems, yet the nature of these differences in young children with the disorder is not well understood. OBJECTIVES: To examine connectivity of large-scale brain networks and determine whether specific networks can distinguish children with ASD from typically developing (TD) children and predict symptom severity in children with ASD. DESIGN, SETTING, AND PARTICIPANTS: Case-control study performed at Stanford University School of Medicine of 20 children 7 to 12 years old with ASD and 20 age-, sex-, and IQ matched TD children. MAIN OUTCOMES AND MEASURES: Between-group differences in intrinsic functional connectivity of large-scale brain networks, performance of a classifier built to discriminate children with ASD from TD children based on specific brain networks, and correlations between brain networks and core symptoms of ASD. RESULTS: We observed stronger functional connectivity within several large-scale brain networks in children with ASD compared with TD children. This hyperconnectivity in ASD encompassed salience, default mode, frontotemporal, motor, and visual networks. This hyperconnectivity result was replicated in an independent cohort obtained from publicly available databases. Using maps of each individual's salience network, children with ASD could be discriminated from TD children with a classification accuracy of 78%, with 75% sensitivity and 80% specificity. The salience network showed the highest classification accuracy among all networks examined, and the blood oxygen-level dependent signal in this network predicted restricted and repetitive behavior scores. The classifier discriminated ASD from TD in the independent sample with 83% accuracy, 67% sensitivity, and 100% specificity. CONCLUSIONS AND RELEVANCE: Salience network hyperconnectivity may be a distinguishing feature in children with ASD. Quantification of brain network connectivity is a step toward developing biomarkers for objectively identifying children with ASD. PMID- 23803652 TI - Comparison of cellular uptake and inflammatory response via toll-like receptor 4 to lipopolysaccharide and titanium dioxide nanoparticles. AB - The innate immune response is the earliest cellular response to infectious agents and mediates the interactions between microbes and cells. Toll-like receptors (TLRs) play an important role in these interactions. We have already shown that TLRs are involved with the uptake of titanium dioxide nanoparticles (TiO2 NPs) and promote inflammatory responses. In this paper, we compared role of cellular uptake and inflammatory response via TLR 4 to lipopolysaccharide (LPS) and TiO2 NPs. In the case of LPS, LPS binds to LPS binding protein (LBP) and CD 14, and then this complex binds to TLR 4. In the case of TiO2 NPs, the necessity of LBP and CD 14 to induce the inflammatory response and for uptake by cells was investigated using over-expression, antibody blocking, and siRNA knockdown experiments. Our results suggested that for cellular uptake of TiO2 NPs, TLR 4 did not form a complex with LBP and CD 14. In the TiO2 NP-mediated inflammatory response, TLR 4 acted as the signaling receptor without protein complex of LPS, LBP and CD 14. The results suggested that character of TiO2 NPs might be similar to the complex of LPS, LBP and CD 14. These results are important for development of safer nanomaterials. PMID- 23803653 TI - Alleviation of osmotic stress effects by exogenous application of salicylic or abscisic acid on wheat seedlings. AB - The aim of the study was to assess the role of salicylic acid (SA) and abscisic acid (ABA) in osmotic stress tolerance of wheat seedlings. This was accomplished by determining the impact of the acids applied exogenously on seedlings grown under osmotic stress in hydroponics. The investigation was unique in its comprehensiveness, examining changes under osmotic stress and other conditions, and testing a number of parameters simultaneously. In both drought susceptible (SQ1) and drought resistant (CS) wheat cultivars, significant physiological and biochemical changes were observed upon the addition of SA (0.05 mM) or ABA (0.1 MUM) to solutions containing half-strength Hoagland medium and PEG 6000 (-0.75 MPa). The most noticeable result of supplementing SA or ABA to the medium (PEG + SA and PEG + ABA) was a decrease in the length of leaves and roots in both cultivars. While PEG treatment reduced gas exchange parameters, chlorophyll content in CS, and osmotic potential, and conversely, increased lipid peroxidation, soluble carbohydrates in SQ1, proline content in both cultivars and total antioxidants activity in SQ1, PEG + SA or PEG + ABA did not change the values of these parameters. Furthermore, PEG caused a two-fold increase of endogenous ABA content in SQ1 and a four-fold increase in CS. PEG + ABA increased endogenous ABA only in SQ1, whereas PEG + SA caused a greater increase of ABA content in both cultivars compared to PEG. In PEG-treated plants growing until the harvest, a greater decrease of yield components was observed in SQ1 than in CS. PEG + SA, and particularly PEG + ABA, caused a greater increase of these yield parameters in CS compared to SQ1. In conclusion, SA and ABA ameliorate, particularly in the tolerant wheat cultivar, the harmful effects and after effects of osmotic stress induced by PEG in hydroponics through better osmotic adjustment achieved by an increase in proline and carbohydrate content as well as by an increase in antioxidant activity. PMID- 23803654 TI - Reinvestigation of the oxidative folding pathways of hen egg white lysozyme: switching of the major pathways by temperature control. AB - It has been well established that in the oxidative folding of hen egg white lysozyme (HEL), which has four SS linkages in the native state (N), three des intermediates, i.e., des[76-94], des[64-80], and des [6-127], are populated at 20 degrees C and N is dominantly formed by the oxidation of des[64-80] and des[6 127]. To elucidate the temperature effects, the oxidative folding pathways of HEL were reinvestigated at 5-45 degrees C in the presence of 2 M urea at pH 8.0 by using a selenoxide reagent, DHSox. When reduced HEL was reacted with 1-4 equivalents of DHSox, 1S, 2S, 3S, and 4S intermediate ensembles with 1-4 SS linkages, respectively, were produced within 1 min. After the oxidation, 3S was slowly converted to the des intermediates with formation of the native structures through SS rearrangement. At 5 degrees C, des[76-94] was populated in the largest amount, but the oxidation to N was slower than that of des[64-80] and des[6-127]. At 35 degrees C, on the other hand, des[64-80] and des[6-127] were no longer stable, and only des[76-94] was populated. The results suggested that the major folding pathways of HEL can be switched from one to the other by temperature control. PMID- 23803655 TI - Toll-like receptor and accessory molecule mRNA expression in humans and mice as well as in murine autoimmunity, transient inflammation, and progressive fibrosis. AB - The cell type-, organ-, and species-specific expression of the Toll-like receptors (TLRs) are well described, but little is known about the respective expression profiles of their accessory molecules. We therefore determined the mRNA expression levels of LBP, MD2, CD36, CD14, granulin, HMGB1, LL37, GRP94, UNC93b1, TRIL, PRAT4A, AP3B1, AEP and the respective TLRs in human and mouse solid organs. Humans and mice displayed significant differences between their respective mRNA expression patterns of these factors. In addition, the expression profiles in transient tissue inflammation upon renal ischemia-reperfusion injury, in spleens and kidneys from mice with lupus-like systemic autoimmunity, and in progressive tissue fibrosis upon unilateral ureteral obstruction were studied. Several TLR co-factors were specifically regulated during the different phases of these disease entities, suggesting a functional involvement in the disease process. Thus, the organ- and species-specific expression patterns need to be considered in the design and interpretation of studies related to TLR-mediated innate immunity, which seems to be involved in the tissue injury phase, in the phase of tissue regeneration, and in progressive tissue remodelling. PMID- 23803656 TI - Up-regulation of microRNA* strands by their target transcripts. AB - During microRNA (miRNA) biogenesis, one strand of a 21-23 nucleotide RNA duplex is preferentially selected for entry into an RNA-induced silencing complex (RISC). The other strand, known as the miRNA* species, is typically thought to be degraded. Previous studies have provided miRNA* selection models, but it remains unclear how the dominance of one arm arises during the biogenesis of miRNA. Using miRNA sponge-like methods, we cloned four tandem target sequences (artificial target) of miR-7b* and then measured miR-7b* expression levels after transfection of the artificial target. miR-7b* levels were found to significantly increase after transfection of the artificial target. We postulate that the abundance of target transcripts drives miRNA arm selection. PMID- 23803657 TI - Comparison of membrane targeting strategies for the accumulation of the human immunodeficiency virus p24 protein in transgenic tobacco. AB - Membrane anchorage was tested as a strategy to accumulate recombinant proteins in transgenic plants. Transmembrane domains of different lengths and topology were fused to the cytosolic HIV antigen p24, to promote endoplasmic reticulum (ER) residence or traffic to distal compartments of the secretory pathway in transgenic tobacco. Fusions to a domain of the maize seed storage protein gamma zein were also expressed, as a reference strategy that leads to very high stability via the formation of large polymers in the ER lumen. Although all the membrane anchored constructs were less stable compared to the zein fusions, residence at the ER membrane either as a type I fusion (where the p24 sequence is luminal) or a tail-anchored fusion (where the p24 sequence is cytosolic) resulted in much higher stability than delivery to the plasma membrane or intermediate traffic compartments. Delivery to the tonoplast was never observed. The inclusion of a thrombin cleavage site allowed for the quantitative in vitro recovery of p24 from all constructs. These results point to the ER as suitable compartment for the accumulation of membrane-anchored recombinant proteins in plants. PMID- 23803658 TI - CD44 is associated with the aggressive phenotype of nasopharyngeal carcinoma through redox regulation. AB - Recent studies have shown that cancer stem-like cells (CSCs) within a tumor have the capacity for self-renewal and differentiation, and are associated with an aggressive phenotype and therapeutic resistance. Studies have also associated tumor progression with alterations in the levels of intracellular reactive oxygen species (ROS). In this study, we cultured nasopharyngeal carcinoma (NPC) CSCs in conditions that allowed sphere formation. The resulting sphere cells displayed stemness properties, characteristics of the epithelial-mesenchymal transition (EMT), and increased expression of the CSC surface marker CD44. We further evaluated the association between CD44 expression and EMT marker expression, and any correlation with redox status, in these CSCs. We showed that the EMT in sphere cells is associated with the upregulation of CD44 expression and increased ROS generation, which might promote NPC aggressiveness. We also identified the coexpression of CD44 with the EMT marker N-cadherin in sphere cells, and downregulated CD44 expression after the addition of the antioxidant N-acetyl cysteine. Our results indicate that CD44 plays a role in the EMT phenotype of CSCs in NPC, and suggest its involvement in EMT-associated ROS production. These findings might facilitate the development of a novel therapy for the prevention of NPC recurrence and metastasis. PMID- 23803659 TI - NS3 protease from hepatitis C virus: biophysical studies on an intrinsically disordered protein domain. AB - The nonstructural protein 3 (NS3) from the hepatitis C virus (HCV) is responsible for processing the non-structural region of the viral precursor polyprotein in infected hepatic cells. NS3 protease activity, located at the N-terminal domain, is a zinc-dependent serine protease. A zinc ion, required for the hydrolytic activity, has been considered as a structural metal ion essential for the structural integrity of the protein. In addition, NS3 interacts with another cofactor, NS4A, an accessory viral protein that induces a conformational change enhancing the hydrolytic activity. Biophysical studies on the isolated protease domain, whose behavior is similar to that of the full-length protein (e.g., catalytic activity, allosteric mechanism and susceptibility to inhibitors), suggest that a considerable global conformational change in the protein is coupled to zinc binding. Zinc binding to NS3 protease can be considered as a folding event, an extreme case of induced-fit binding. Therefore, NS3 protease is an intrinsically (partially) disordered protein with a complex conformational landscape due to its inherent plasticity and to the interaction with its different effectors. Here we summarize the results from a detailed biophysical characterization of this enzyme and present new experimental data. PMID- 23803662 TI - HPS publications implement society's "SI Only" position. PMID- 23803663 TI - RSO interview with Matthew Barnett. Interview by Rene Michel. PMID- 23803660 TI - The intertwining of transposable elements and non-coding RNAs. AB - Growing evidence shows a close association of transposable elements (TE) with non coding RNAs (ncRNA), and a significant number of small ncRNAs originate from TEs. Further, ncRNAs linked with TE sequences participate in a wide-range of regulatory functions. Alu elements in particular are critical players in gene regulation and molecular pathways. Alu sequences embedded in both long non-coding RNAs (lncRNA) and mRNAs form the basis of targeted mRNA decay via short imperfect base-pairing. Imperfect pairing is prominent in most ncRNA/target RNA interactions and found throughout all biological kingdoms. The piRNA-Piwi complex is multifunctional, but plays a major role in protection against invasion by transposons. This is an RNA-based genetic immune system similar to the one found in prokaryotes, the CRISPR system. Thousands of long intergenic non-coding RNAs (lincRNAs) are associated with endogenous retrovirus LTR transposable elements in human cells. These TEs can provide regulatory signals for lincRNA genes. A surprisingly large number of long circular ncRNAs have been discovered in human fibroblasts. These serve as "sponges" for miRNAs. Alu sequences, encoded in introns that flank exons are proposed to participate in RNA circularization via Alu/Alu base-pairing. Diseases are increasingly found to have a TE/ncRNA etiology. A single point mutation in a SINE/Alu sequence in a human long non coding RNA leads to brainstem atrophy and death. On the other hand, genomic clusters of repeat sequences as well as lncRNAs function in epigenetic regulation. Some clusters are unstable, which can lead to formation of diseases such as facioscapulohumeral muscular dystrophy. The future may hold more surprises regarding diseases associated with ncRNAs andTEs. PMID- 23803661 TI - Involvement of intercellular adhesion molecule-1 up-regulation in bradykinin promotes cell motility in human prostate cancers. AB - Prostate cancer is the most commonly diagnosed malignancy in men and shows a predilection for metastasis to distant organs. Bradykinin (BK) is an inflammatory mediator and has recently been shown to mediate tumor growth and metastasis. The adhesion molecule intercellular adhesion molecule-1 (ICAM-1) plays a critical role during tumor metastasis. The aim of this study was to examine whether BK promotes prostate cancer cell migration via ICAM-1 expression. The motility of cancer cells was increased following BK treatment. Stimulation of prostate cancer cells with BK induced mRNA and protein expression of ICAM-1. Transfection of cells with ICAM-1 small interfering RNA reduced BK-increased cell migration. Pretreatment of prostate cancer cells with B2 receptor, phosphatidylinositol 3 kinase (PI3K), Akt, and activator protein 1 (AP-1) inhibitors or mutants abolished BK-promoted migration and ICAM-1 expression. In addition, treatment with a B2 receptor, PI3K, or Akt inhibitor also reduced BK-mediated AP-1 activation. Our results indicate that BK enhances the migration of prostate cancer cells by increasing ICAM-1 expression through a signal transduction pathway that involves the B2 receptor, PI3K, Akt, and AP-1. Thus, BK represents a promising new target for treating prostate cancer metastasis. PMID- 23803664 TI - Evaluation and measurements of radioactive air emission and off-site doses at SLAC. AB - SLAC, a high-energy (GeV) electron accelerator facility, performs experimental and theoretical research using high-energy electron and/or positron beams that can produce secondary neutron and gamma radiation when beam losses occur. Radioactive gas production (mainly C, N, O, Ar) and release is one of the environmental protection program issues. U.S. DOE Order 458.1 requires that 40 CFR 61 Subpart H's NESHAP requirements be followed. These regulations prescribe a total dose limit of 0.1 mSv y to the Maximally Exposed Individual (MEI) of the general public, a requirement for a continuous air monitoring system if a release point within a facility can cause > 1 * 10 mSv y to the MEI, and a requirement for periodic confirmatory measurements for minor sources which give releases that contribute <= 1 * 10 mSv y to the MEI. At SLAC, all air release points for current operations are evaluated to be minor sources. This paper describes SLAC's evaluation following NESHAP requirements; measurements using the Air Monitoring Station (AMS) as periodic confirmatory measurements are also discussed. PMID- 23803665 TI - Assessment of an improved stack sample collection system for 3H and 14C. AB - Lawrence Berkeley National Laboratory developed a simple, efficient, and cost effective replacement for the traditional glass column system used to monitor H and C emissions from rooftop stacks. The primary goals in developing a replacement (the modified jar system) were to 1) maintain or improve collection efficiency while keeping leakage to less than 5%, 2) simplify the set-up process, and 3) reduce costs. Both the traditional glass column assembly and the modified jar system were operated in tandem for a 13-mo period. Results showed that the modified sample jar system provided equivalent or improved collection efficiency for both H and C. Additional advantages included reduced leak-test errors, quicker and simpler set-up, and material costs that were reduced by nearly an order of magnitude. PMID- 23803666 TI - A comparison of dose results from the Clean Air Act Assessment Package-1988, personal computer (CAP88-PC), version 3 to previous versions. AB - Computer software packages approved by the U.S. Environmental Protection Agency (U.S. EPA), including CAP88-PC, are used by U.S. Department of Energy (U.S. DOE) sites to demonstrate compliance with the radionuclide air emission standard under the Clean Air Act. CAP88-PC version 3, was approved by the U.S. EPA in February 2006 for use by U.S. DOE facilities. Version 3 incorporates several major changes that have the potential to affect calculated doses relative to calculations using earlier versions. This analysis examined the types and magnitudes of changes to dose estimates for specific radionuclides calculated using the version 3 software compared with the previous versions. For parent radionuclides and for the total dose from radionuclide chains, total effective dose calculated with version 3 was compared to effective dose equivalent calculated with previous versions. Various comparisons were also performed to determine which of the updates in version 3 accounted for changes in overall dose estimates. CAP88-PC version 3 would produce substantially different results relative to previous versions of the code for a number of radionuclides, including some isotopes that may be present at U.S. DOE facilities, as well as those used for industrial and medical applications. In general, doses for many radionuclides were lower using version 3 but doses for a few key radionuclides increased relative to the previous versions. PMID- 23803667 TI - A best fit approach to estimating multiple diffuse source terms using ambient air monitoring data and an air dispersion model. AB - Lawrence Livermore National Laboratory uses CAP88-PC Version 1.0 modeling software to demonstrate compliance with the Code of Federal Regulations Title 40 Part 61 Subpart H (National Emission Standards for Emissions of Radionuclides Other Than Radon From Department of Energy Facilities). Annual air emissions from both well characterized stack sources and difficult to characterize diffuse sources must be assessed. This paper describes a process that uses a mathematical optimization routine to find a set of estimated diffuse source terms that together with the measured stack source terms provides a best fit of modeled air concentrations to measured air concentrations at available sampling locations. The estimated and measured source terms may then be used in subsequent CAP88-PC modeling to estimate dose at the off-site maximally exposed individual. LLNL has found this process to be an effective way to deal with the required assessment of diffuse sources that have otherwise been difficult to assess. PMID- 23803668 TI - Basis and implications of the CAP88 age-specific dose coefficients. AB - Recent versions of CAP88 incorporate age-specific dose coefficients based on biokinetic and dosimetric models applied in Federal Guidance Report 13, "Cancer Risk Coefficients for Environmental Exposure to Radionuclides." With a few exceptions the models are those recommended in a series of reports by the International Commission on Radiological Protection (ICRP) on estimation of doses to the public from environmental radionuclides. This paper describes the basis for the ICRP's age-specific biokinetic and dosimetric models and examines differences with age in dose coefficients derived from those models. PMID- 23803669 TI - Comparison of CAP88 PC Ver. 3.0 and MAXDOSE dose assessment models involving co located stack releases at the Savannah River site. AB - The Savannah River National Laboratory's Environmental Dosimetry Group performs dosimetry assessments for Savannah River Site (SRS) radionuclide air emissions utilizing the Clean Air Act Assessment Package-1988 (CAP88) code (CAP88 PC Ver. 3.0) and the MAXDOSE-SR Ver. 2011 code, which is an SRS-specific version of the Nuclear Regulatory Commission's MAXIGASP code. CAP88 PC and MAXDOSE-SR are used at SRS for demonstrating compliance with Environmental Protection Agency dose standards for radionuclide emissions to the atmosphere and Department of Energy Order 458.1 dose standards, respectively. During a routine comparison of these two assessment models, it was discovered that CAP88 PC Ver. 3.0 was not producing the expected results when using multiple co-located stacks in a single run. Specifically, if the stack heights are considered separately, the results for several radionuclides (but not all) differ from the combined run [i.e., 1 + 2 does not equal (1+2)]. Additionally, when two or more stack heights are considered in a run, the results depend on the order of the selected stack heights. For example, for a two stack-height run of 0 meter and 61 m input produces different results from a 61 m and 0 m input run. This study presents a comparison of CAP88 PC Ver. 3.0 and MAXDOSE-SR Ver. 2011 based on SRS input data and on two-stack release scenarios. The selected radionuclides for this study included gases/vapors (H, C, Kr, and I) and particulates (Sr, Cs, Pu, and Am) commonly encountered at SRS. PMID- 23803670 TI - Use of CAP88 at Department of Energy sites. AB - The U.S. Department of Energy is committed to protecting the public and environment against undue risk from radiation associated with radiological activities conducted under its control. Some U.S. Department of Energy Site activities result in emissions of radioactive materials to the air. CAP88 codes are used to model these emissions and the subsequent maximum estimated dose to a member of the public in the vicinity of the U.S. Department of Energy Site. This paper reviews the use of the CAP88 code at the variety of U.S. Department of Energy sites that use it for compliance reporting under Title 40 of the Code of Federal Regulations Part 61, Subpart H. PMID- 23803671 TI - CAP88-PC Version 4, an updated radionuclide NESHAPS model. AB - The latest version of the CAP88-PC computer model, Version 4, has many changes and improvements from previous versions. The most significant of these changes from a user perspective are the incorporation of age-dependent radionuclide dose and risk factors for ingestion and inhalation, the increase in the number of included radionuclides, and a change in the file management system used by the program. Other changes less visible to the user include new code architecture, incorporation of numerical solvers for the calculation of radioactive decay chains, including the ingrowth of decay products during air transport and ground surface deposition, enhanced error messages, updated on-line help, and a utility for migrating Version 3 datasets, wind files, and population files to Version 4. The modifications have produced a significant improvement in speed and stability for Version 4 relative to Version 3 and eliminated the solution approximations used in Version 3. The U.S. Environmental Protection Agency has implemented an extensive testing and documentation program for CAP88-PC Version 4 to address user concerns with past versions, resulting in enhanced documentation supporting compatibility with user software quality assurance programs. PMID- 23803672 TI - Validation test for CAP88 predictions of tritium dispersion at Los Alamos National Laboratory. AB - Gaussian plume models, such as CAP88, are used regularly for estimating downwind concentrations from stack emissions. At many facilities, the U.S. Environmental Protection Agency (U.S. EPA) requires that CAP88 be used to demonstrate compliance with air quality regulations for public protection from emissions of radionuclides. Gaussian plume models have the advantage of being relatively simple and their use pragmatic; however, these models are based on simplifying assumptions and generally they are not capable of incorporating dynamic meteorological conditions or complex topography. These limitations encourage validation tests to understand the capabilities and limitations of the model for the specific application. Los Alamos National Laboratory (LANL) has complex topography but is required to use CAP88 for compliance with the Clean Air Act Subpart H. The purpose of this study was to test the accuracy of the CAP88 predictions against ambient air measurements using released tritium as a tracer. Stack emissions of tritium from two LANL stacks were measured and the dispersion modeled with CAP88 using local meteorology. Ambient air measurements of tritium were made at various distances and directions from the stacks. Model predictions and ambient air measurements were compared over the course of a full year's data. Comparative results were consistent with other studies and showed the CAP88 predictions of downwind tritium concentrations were on average about three times higher than those measured, and the accuracy of the model predictions were generally more consistent for annual averages than for bi-weekly data. PMID- 23803673 TI - Addressing nuclides not in the CAP88-PC Version-3 library. AB - Versions of the computer program, CAP88, are widely used to calculate the radiological doses from radionuclides emitted into the air. CAP88-PC Version-3 includes an extensive library of radionuclides, but there are many more that are not included. Surrogates are often used to substitute for nuclides not in the library, though the results are usually overestimates. This paper addresses nuclides that are not in the library and describes methods to obtain more accurate results. PMID- 23803674 TI - Circulating microparticles of glial origin and tissue factor bearing in high grade glioma: a potential prothrombotic role. AB - Venous thromboembolism (VTE) may complicate the clinical course of glioblastoma multiforme (GBM). Circulating microparticles (MPs) have been associated with cancer-related VTE. Sixty-one consecutive patients with GBM undergoing gross total (41) or subtotal (20) surgical resection followed by radio-chemotherapy were prospectively evaluated. MPs numbers according to cellular origin and the procoagulant activity of annexin V positive (AV+) MPs (MP-activity) were measured before surgery and then 1 week and 1, 4, and 7 months after surgery. Glial (GFAP+) and endothelial (CD62E+) derived MPs, AV+ and tissue factor-bearing (TF+) MPs were measured using flow cytometry. Baseline levels of GFAP+/TF-, TF+/GFAP-, and GFAP+/TF+ MPs were significantly higher in GBM patients than in healthy controls, and significantly increased at each time point after surgery; at 7 months, a further significant increase over the level found a week after surgery was only seen in the subtotally resected patients. The number AV+/CD62E- MPs increased in GBM patients and correlated with MP activity. TF+/GFAP- MPs numbers were significantly higher in 11 GBM patients who developed VTE than in those who did not (p 0.04). TF+/GFAP- MPs levels above the 90th percentile (calculated in GBM patients without VTE) were associated with a higher risk of VTE (RR 4.17, 95% CI 1.57-11.03). In conclusion, the numbers of glial-derived and/or TF-bearing MPs were high in GBM patients both before and even more after the neoplasm was treated, especially in patients with subtotal resection likely according to disease progression. A contribution of TF+/GFAP- MPs to the risk of VTE is suggested. PMID- 23803675 TI - Decision making for seriously compromised newborns: the importance of exploring cultural differences and unintended consequences. PMID- 23803676 TI - Infertility, in vitro fertilization and congenital tuberculosis. AB - Congenital tuberculosis (CTB) due to maternal genitourinary (GU) TB infection is a rare occurrence, as infection of the genital tract in women generally leads to infertility. Increasing availability of assisted reproductive technology creates the potential for CTB to emerge as a significant problem. We describe five infants (two sets of twins and a singleton birth) conceived by in vitro fertilization who developed CTB. All five infants were born to mothers who had immigrated to the United States from India and none had GU TB diagnosed before the birth of their infected infants. PMID- 23803677 TI - Hemophagocytic lymphohistiocytosis in a newborn infant born to a mother with Sjogren syndrome antibodies. AB - We encountered a neonatal patient with hemophagocytic lymphohistiocytosis (HLH) whose mother was positive for anti-Ro/SSA and anti-La/SSB antibodies. Complete atrioventricular block was found in a male patient at 29 weeks of gestation. The patient was born at 40 weeks of gestation. He showed severe circulatory disturbance at 22 h after the birth, and he also had elevated serum levels of aspartate aminotransferase (1027 IU l(-1)), alanine aminotransferase (121 IU l( 1)), lactic dehydrogenase (3490 IU l(-1)), ferritin (9769.7 ng ml(-1)) and soluble interleukin-2 (IL-2) receptor (3230 U ml(-1)). We could not find any known HLH genetic abnormality in the patient, but he fulfilled seven of the eight criteria for HLH. Serum levels of IL-6 and IL-8 had been already elevated in his cord blood, and serum levels of granulocyte-macrophage colony-stimulating factor and IL-8 were significantly increased on the second day of life. His symptoms regressed with the administration of hydrocortisone. We presumed that transplacental transfer of maternal antibodies could be related to the occurrence of HLH. PMID- 23803678 TI - A unique variant of Poland-Mobius syndrome with dextrocardia and a 3q23 gain. AB - The combined Poland and Mobius syndrome occurs rarely and with a wide range of features. There is no consensus on the etiology of this syndrome; familial, sporadic cases and likely environmental insult cases have been reported. This sporadic case represents a unique variant in the spectrum of this syndrome. PMID- 23803679 TI - Bilateral cataracts associated with glucose-6-phosphate dehydrogenase deficiency. AB - Glucose-6-phosphate dehydrogenase (G6PD) has an essential role in the defense against cellular oxidative injury. In neonates, the most common manifestation of G6PD deficiency is jaundice and hemolysis due to factors causing oxidative stress. Less known are the ocular associations described with G6PD deficiency, including cataracts. Oxidative injury is involved in the pathogenesis of almost all forms of cataracts, causing the lens proteins to undergo modifications, denaturation and form insoluble aggregates resulting in cataracts. Although cataracts in adult males have been reported in several studies, there are few reports of cataracts in infants with G6PD deficiency. We describe a preterm male neonate with G6PD deficiency who developed bilateral cataracts following an episode of neonatal sepsis and severe hemolysis necessitating an exchange blood transfusion. PMID- 23803680 TI - A case of diaphragmatic infantile hemangioma. PMID- 23803682 TI - Routine blood typing and DAT in infants of group O mothers. PMID- 23803683 TI - Absolute nucleated red blood cell count and retinopathy of prematurity (ROP). PMID- 23803687 TI - Training communication partners of people with severe traumatic brain injury improves everyday conversations: a multicenter single blind clinical trial. AB - OBJECTIVE: To determine effectiveness of communication training for partners of people with severe traumatic brain injury. DESIGN: Three arm non-randomized controlled trial comparing communication partner training (JOINT) with individual treatment (TBI SOLO) and a waitlist control group with 6 month follow-up. PARTICIPANTS: Forty-four outpatients with severe chronic traumatic brain injuries were recruited. INTERVENTION: Ten-week conversational skills treatment program encompassing weekly group and individual sessions for both treatment groups. The JOINT condition focused on both the partner and the person with traumatic brain injury while the TBI SOLO condition focused on the individual with TBI only. MAIN OUTCOME MEASURES: Primary outcomes were blind ratings of the person with traumatic brain injury's level of participation during conversation on the Measure of Participation in Communication Adapted Kagan scales. RESULTS: Communication partner training improved conversational performance relative to training the person with traumatic brain injury alone and a waitlist control group on the primary outcome measures. Results were maintained at six months post training. CONCLUSION: Training communication partners of people with chronic severe traumatic brain injury was more efficacious than training the person with traumatic brain injury alone. The Adapted Kagan scales proved to be a robust and sensitive outcome measure for a conversational skills training program. PMID- 23803689 TI - Electrophysiological indices of response inhibition in human polydrug users. AB - Previous research in ecstasy users suggests impairment of various executive functions. In general, the executive function of response inhibition appears unaffected by ecstasy use. Nonetheless, it remains a possibility that cognitive tasks alone are not sensitive enough to pick up subtle changes in function. The current study sought to investigate behavioural measures of response inhibition and their electrophysiological correlates in drug users. Twenty ecstasy polydrug users, 20 non-ecstasy polydrug users and 20 drug naive controls were recruited. Participants completed questionnaires about their background drug use, sleep quality, fluid intelligence and mood state. Each individual also completed a Go/NoGo response inhibition task whilst electroencephalography (EEG) measures were recorded. Analysis of variance (ANOVA) revealed that there were no between group differences on the behavioural measure of response inhibition. Multivariate analysis of variance (MANOVA) revealed no main effect of group across midline electrodes for the P3, N2 and P2 components. Univariate ANOVA revealed significant between-group differences in the P2 component with the ecstasy user group having a significantly higher mean amplitude than drug naive controls at two midline frontal electrodes: at Fz and significantly higher mean amplitude than both control groups at FCz. The present study provides evidence of atypical early processing in ecstasy users that is suggestive of compensatory mechanisms ameliorating any behavioural differences. PMID- 23803688 TI - Blood glutathione redox status and global methylation of peripheral blood mononuclear cell DNA in Bangladeshi adults. AB - Oxidative stress and DNA methylation are metabolically linked through the relationship between one-carbon metabolism and the transsulfuration pathway, but possible modulating effects of oxidative stress on DNA methylation have not been extensively studied in humans. Enzymes involved in DNA methylation, including DNA methyltransferases and histone deacetylases, may show altered activity under oxidized cellular conditions. Additionally, in vitro studies suggest that glutathione (GSH) depletion leads to global DNA hypomethylation, possibly through the depletion of S-adenosylmethionine (SAM). We tested the hypothesis that a more oxidized blood GSH redox status is associated with decreased global peripheral blood mononuclear cell (PBMC) DNA methylation in a sample of Bangladeshi adults. Global PBMC DNA methylation and whole blood GSH, glutathione disulfide (GSSG), and SAM concentrations were measured in 320 adults. DNA methylation was measured by using the [ (3)H]-methyl incorporation assay; values are inversely related to global DNA methylation. Whole blood GSH redox status (Eh) was calculated using the Nernst equation. We found that a more oxidized blood GSH Eh was associated with decreased global DNA methylation (B +/- SE, 271 +/- 103, p = 0.009). Blood SAM and blood GSH were associated with global DNA methylation, but these relationships did not achieve statistical significance. Our findings support the hypothesis that a more oxidized blood GSH redox status is associated with decreased global methylation of PBMC DNA. Furthermore, blood SAM does not appear to mediate this association. Future research should explore mechanisms through which cellular redox might influence global DNA methylation. PMID- 23803690 TI - Comparative benefits of Nab-paclitaxel over gemcitabine or polysorbate-based docetaxel in experimental pancreatic cancer. AB - Gemcitabine has limited clinical benefits in pancreatic ductal adenocarcinoma. The solvent-based traditional taxanes docetaxel and paclitaxel have not shown clinical results superior to gemcitabine. Nab-paclitaxel, a water-soluble albumin bound paclitaxel, may carry superior distribution properties into the tumor microenvironment and has shown efficacy in multiple tumor types. We evaluated nab paclitaxel effects compared with gemcitabine or docetaxel. For pancreatic ductal adenocarcinoma cells AsPC-1, BxPC-3, MIA PaCa-2 and Panc-1, gemcitabine IC50 ranged from 494nM to 23.9 MUM; docetaxel IC50 range was from 5 to 34nM; nab paclitaxel IC50 range was from 243nM to 4.9 MUM. Addition of IC25 dose of docetaxel or nab-paclitaxel decreased gemcitabine IC50. Net tumor growth inhibition after gemcitabine, docetaxel or nab-paclitaxel was 67, 31 and 72%, which corresponded with intratumoral proliferative and apoptotic indices. Tumor stromal density was decreased by nab-paclitaxel and to a lesser extent by docetaxel as measured through reduction in alpha-smooth muscle actin, S100A4 and collagen 1 expression. Animal survival was prolonged after nab-paclitaxel treatment (41 days, P < 0.002) compared with gemcitabine (32 days, P = 0.005), docetaxel (32 days, P = 0.005) and controls (20 days). Survival in nab paclitaxel/gemcitabine and docetaxel/gemcitabine sequential treatment groups was not superior to nab-paclitaxel alone. Low-dose combination of gemcitabine with nab-paclitaxel or docetaxel was more effective compared with controls or gemcitabine alone but not superior to regular dose nab-paclitaxel alone. Combination treatment of gemcitabine+nab-paclitaxel or gemcitabine+docetaxel increased gemcitabine concentration in plasma and tumor. The superior antitumor activity of nab-paclitaxel provides a strong rationale for considering nab paclitaxel as first-line monotherapy in pancreatic ductal adenocarcinoma. PMID- 23803691 TI - GPR48, a poor prognostic factor, promotes tumor metastasis and activates beta catenin/TCF signaling in colorectal cancer. AB - G-protein-coupled receptor 48 (GPR48) is an orphan receptor belonging to the G protein-coupled receptors family, which plays an important role in the development of various organs and cancer development and progression such as gastric cancer and colorectal cancer (CRC). However, the prognostic value of GPR48 expression in patients with CRC has not been reported. In this study, we observed that GPR48 was overexpressed in primary CRC and metastatic lymph nodes and closely correlated with tumor invasion and metastasis. Multivariate analysis indicated that high GPR48 expression was a poor prognostic factor for overall survival in CRC patients. In vitro and in vivo assays demonstrated that enforced expression of GPR48 contributed to enhance migration and invasion of cancer cells and tumor metastasis. In addition, we found that GPR48 increased nuclear beta catenin accumulation, T-cell factor 4 (TCF4) transcription activity, and expression of its target genes including Cyclin D1 and c-Myc in CRC cells. Correlation analysis showed that GPR48 expression in CRC tissues was positively associated with beta-catenin expression. Upregulation of GPR48 resulted in increased phosphorylation of glycogen synthase kinase 3beta, Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) in CRC cells, while inhibition of PI3K/Akt and mitogen-activated protein kinase /ERK1/2 pathways was sufficient to abolish the effect of GPR48 on beta-catenin/TCF signaling. Taken together, GPR48 could serve as both a prognostic biomarker and a therapeutic target for resectable CRC patients. PMID- 23803692 TI - Association of mitochondrial DNA copy number in peripheral blood leukocytes with risk of esophageal adenocarcinoma. AB - Alterations of mitochondrial DNA (mtDNA) have been associated with the risk of a number of human cancers; however, the relationship between mtDNA copy number in peripheral blood leukocytes and the risk of esophageal adenocarcinoma (EAC) has not been reported. In this study, we determined relative mtDNA copy number in peripheral blood leukocytes of 218 EAC cases and 218 frequency-matched controls. We calculated odds ratios and 95% confidence intervals using unconditional logistic regression, adjusting for age, sex and smoking status. MtDNA copy number was significantly lower in cases than in controls (mean +/- SD, 1.16 +/- 0.30 versus 1.27 +/- 0.43, P = 0.002). Dichotomized at the median value of mtDNA copy number in the controls, low mtDNA copy number was significantly associated with an increased risk of EAC (odds ratio: 1.55, 95% confidence interval: 1.05-2.29). A significant dose-response relationship was observed between mtDNA copy number and risk of EAC in quartile analysis. Our results suggest that low mtDNA copy number in peripheral blood leukocytes is associated with increased susceptibility to EAC. PMID- 23803693 TI - Metformin inhibits pancreatic cancer cell and tumor growth and downregulates Sp transcription factors. AB - Metformin is a widely used antidiabetic drug, and epidemiology studies for pancreatic and other cancers indicate that metformin exhibits both chemopreventive and chemotherapeutic activities. Several metformin-induced responses and genes are similar to those observed after knockdown of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 by RNA interference, and we hypothesized that the mechanism of action of metformin in pancreatic cancer cells was due, in part, to downregulation of Sp transcription factors. Treatment of Panc1, L3.6pL and Panc28 pancreatic cancer cells with metformin downregulated Sp1, Sp3 and Sp4 proteins and several pro-oncogenic Sp-regulated genes including bcl-2, survivin, cyclin D1, vascular endothelial growth factor and its receptor, and fatty acid synthase. Metformin induced proteasome-dependent degradation of Sps in L3.6pL and Panc28 cells, whereas in Panc1 cells metformin decreased microRNA-27a and induced the Sp repressor, ZBTB10, and disruption of miR 27a:ZBTB10 by metformin was phosphatase dependent. Metformin also inhibited pancreatic tumor growth and downregulated Sp1, Sp3 and Sp4 in tumors in an orthotopic model where L3.6pL cells were injected directly into the pancreas. The results demonstrate for the first time that the anticancer activities of metformin are also due, in part, to downregulation of Sp transcription factors and Sp-regulated genes. PMID- 23803694 TI - NQO1 prevents radiation-induced aneuploidy by interacting with Aurora-A. AB - Aneuploidy is the most common characteristic of human cancer cells. It also causes genomic instability, which is involved in the initiation of cancer development. Various lines of evidence indicate that nicotinamide adenine dinucleotide(P)H quinone oxidoreductase 1 (NQO1) plays an important role in cancer prevention, but the molecular mechanisms underlying this effect have not yet been fully elucidated. Here, we report that ionizing radiation (IR) induces substantial aneuploidy and centrosome amplification in NQO1-deficient cancer cells, suggesting that NQO1 plays a crucial role in preventing aneuploidy. NQO1 deficiency markedly increased the protein stability of Aurora-A in irradiated cancer cells. Small interfering RNA targeting Aurora-A effectively attenuated IR induced centrosome amplification concerned with aneuploidy in NQO1-deficient cancer cells. Furthermore, we found that NQO1 specifically binds to Aurora-A via competing with the microtubule-binding protein, TPX2 (targeting protein for Xklp2), and contributes to the degradation of Aurora-A. Our results collectively demonstrate that NQO1 plays a key role in suppressing IR-induced centrosome amplification and aneuploidy through a direct interaction with Aurora-A. PMID- 23803695 TI - Metallopanstimulin-1 regulates invasion and migration of gastric cancer cells partially through integrin beta4. AB - MPS-1 (metallopanstimulin-1), also known as ribosomal protein S27, was overexpressed in gastric cancer cells. However, how MPS-1 contributes to gastric carcinogenesis has not been well characterized. Here, we show that high expression of MPS-1 was observed in gastric cancer tissues and associated with gastric cancer cell metastasis. Alteration of MPS-1 expression regulates invasion and migration of gastric cancer cells both in vitro and in vivo. Furthermore, by using Signal-Net and cluster analyses of microarray data we identified integrin beta4 (ITGB4) as a downstream target of MPS-1 that mediates its effects on cell metastasis. Knockdown of MPS-1 expression in gastric cancer cells led to significant reduction of ITGB4 expression at both the RNA and protein levels. Mechanically, we found that overexpression of ITGB4 in MPS-1 knockdown cells largely recovers the ability of invasion and migration. Conversely, knockdown of ITGB4 partially reduced cell invading/migrating ability induced by MPS-1 overexpression. Moreover, MPS-1 and ITGB4 expressions are positively correlated in gastric cancer cell lines and tissues. Finally, the survival analyses show that the expression of MPS-1 and ITGB4 is associated with poor outcomes in gastric cancer patients. Collectively, our findings suggest that MPS-1 regulates cell invasiveness and migration partially through ITGB4 and that MPS-1/ITGB4 signaling axis may serve as therapeutic targets in the treatment of gastric cancer. PMID- 23803696 TI - Innate immunity gene polymorphisms and the risk of colorectal neoplasia. AB - Inherited variation in genes that regulate innate immunity and inflammation may contribute to colorectal neoplasia risk. To evaluate this association, we conducted a nested case-control study of 451 colorectal cancer cases, 694 colorectal advanced adenoma cases and 696 controls of European descent within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. A total of 935 tag single-nucleotide polymorphisms (SNPs) in 98 genes were evaluated. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association with colorectal neoplasia. Sixteen SNPs were associated with colorectal neoplasia risk at P < 0.01, but after adjustment for multiple testing, only rs2838732 (ITGB2) remained suggestively associated with colorectal neoplasia (OR(per T allele) = 0.68, 95% CI: 0.57-0.83, P = 7.7 * 10(-5), adjusted P = 0.07). ITGB2 codes for the CD18 protein in the integrin beta chain family. The ITGB2 association was stronger for colorectal cancer (OR(per T allele) = 0.41, 95% CI: 0.30-0.55, P = 2.4 * 10(-) (9)) than for adenoma (OR(per T allele) = 0.84, 95%CI: 0.69-1.03, P = 0.08), but it did not replicate in the validation study. The ITGB2 rs2838732 association was significantly modified by smoking status (P value for interaction = 0.003). Among never and former smokers, it was inversely associated with colorectal neoplasia (OR(per T allele) = 0.5, 95% CI: 0.37-0.69 and OR(per T allele) = 0.72, 95% CI: 0.54-0.95, respectively), but no association was seen among current smokers. Other notable findings were observed for SNPs in BPI/LBP and MYD88. Although the results need to be replicated, our findings suggest that genetic variation in inflammation-related genes may be related to the risk of colorectal neoplasia. PMID- 23803701 TI - Getting to the heart of influenza. PMID- 23803700 TI - Effects of methylphenidate on resting-state functional connectivity of the mesocorticolimbic dopamine pathways in cocaine addiction. AB - IMPORTANCE: Cocaine addiction is associated with altered resting-state functional connectivity among regions of the mesocorticolimbic dopamine pathways. Methylphenidate hydrochloride, an indirect dopamine agonist, normalizes task related regional brain activity and associated behavior in cocaine users; however, the neural systems-level effects of methylphenidate in this population have not yet been described. OBJECTIVE: To use resting-state functional magnetic resonance imaging to examine changes in mesocorticolimbic connectivity with methylphenidate and how connectivity of affected pathways relates to severity of cocaine addiction. DESIGN: Randomized, placebo-controlled, before-after, crossover study. SETTING: Clinical research center. PARTICIPANTS: Eighteen nonabstaining individuals with cocaine use disorders. INTERVENTIONS: Single doses of oral methylphenidate (20 mg) or placebo were administered at each of 2 study sessions. At each session, resting scans were acquired twice: immediately after drug administration (before the onset of effects [baseline]) and 120 minutes later (within the window of peak effects). MAIN OUTCOMES AND MEASURES: Functional connectivity strength was evaluated using a seed voxel correlation approach. Changes in this measure were examined to characterize the neural systems-level effects of methylphenidate; severity of cocaine addiction was assessed by interview and questionnaire. RESULTS: Short-term methylphenidate administration reduced an abnormally strong connectivity of the ventral striatum with the dorsal striatum (putamen/globus pallidus), and lower connectivity between these regions during placebo administration uniquely correlated with less severe addiction. In contrast, methylphenidate strengthened several corticolimbic and corticocortical connections. CONCLUSIONS AND RELEVANCE: These findings help elucidate the neural systems-level effects of methylphenidate and suggest that short-term methylphenidate can, at least transiently, remodel abnormal circuitry relevant to the pathophysiologic characteristics of cocaine addiction. In particular, the effects of methylphenidate within striatal and cortical pathways constitute a potentially viable mechanism by which methylphenidate could facilitate control of behavior in cocaine addiction. PMID- 23803703 TI - Coinfection: doing the math. AB - A transmission model clarifies the effects of influenza on pneumococcal pneumonia and bridges the gap between individual animal experiments and human epidemiological data (Shrestha et al., this issue). PMID- 23803704 TI - Plasmid-encoded proinsulin preserves C-peptide while specifically reducing proinsulin-specific CD8+ T cells in type 1 diabetes. AB - In type 1 diabetes (T1D), there is an intense inflammatory response that destroys the beta cells in the pancreatic islets of Langerhans, the site where insulin is produced and released. A therapy for T1D that targets the specific autoimmune response in this disease while leaving the remainder of the immune system intact, has long been sought. Proinsulin is a major target of the adaptive immune response in T1D. We hypothesized that an engineered DNA plasmid encoding proinsulin (BHT-3021) would preserve beta cell function in T1D patients through reduction of insulin-specific CD8+ T cells. We studied 80 subjects over 18 years of age who were diagnosed with T1D within the past 5 years. Subjects were randomized 2:1 to receive intramuscular injections of BHT-3021 or BHT-placebo, weekly for 12 weeks, and then monitored for safety and immune responses in a blinded fashion. Four dose levels of BHT-3021 were evaluated: 0.3, 1.0, 3.0, and 6.0 mg. C-peptide was used both as an exploratory efficacy measure and as a safety measure. Islet-specific CD8+ T cell frequencies were assessed with multimers of monomeric human leukocyte antigen class I molecules loaded with peptides from pancreatic and unrelated antigens. No serious adverse events related to BHT-3021 were observed. C-peptide levels improved relative to placebo at all doses, at 1 mg at the 15-week time point (+19.5% BHT-3021 versus -8.8% BHT placebo, P < 0.026). Proinsulin-reactive CD8+ T cells, but not T cells against unrelated islet or foreign molecules, declined in the BHT-3021 arm (P < 0.006). No significant changes were noted in interferon-gamma, interleukin-4 (IL-4), or IL-10 production in CD4 T cells. Thus, we demonstrate that a plasmid encoding proinsulin reduces the frequency of CD8+ T cells reactive to proinsulin while preserving C-peptide over the course of dosing. PMID- 23803705 TI - Surface-mediated bone tissue morphogenesis from tunable nanolayered implant coatings. AB - The functional success of a biomedical implant critically depends on its stable bonding with the host tissue. Aseptic implant loosening accounts for more than half of all joint replacement failures. Various materials, including metals and plastic, confer mechanical integrity to the device, but often these materials are not suitable for direct integration with the host tissue, which leads to implant loosening and patient morbidity. We describe a self-assembled, osteogenic, polymer-based conformal coating that promotes stable mechanical fixation of an implant in a surrogate rodent model. A single modular, polymer-based multilayered coating was deposited using a water-based layer-by-layer approach, by which each element was introduced on the surface in nanoscale layers. Osteoconductive hydroxyapatite (HAP) and osteoinductive bone morphogenetic protein-2 (BMP-2) contained within the nanostructured coating acted synergistically to induce osteoblastic differentiation of endogenous progenitor cells within the bone marrow, without indications of a foreign body response. The tuned release of BMP 2, controlled by a hydrolytically degradable poly(beta-amino ester), was essential for tissue regeneration, and in the presence of HAP, the modular coating encouraged the direct deposition of highly cohesive trabecular bone on the implant surface. In vivo, the bone-implant interfacial tensile strength was significantly higher than standard bioactive bone cement, did not fracture at the interface, and had long-term stability. Collectively, these results suggest that the multilayered coating system promotes biological fixation of orthopedic and dental implants to improve surgical outcomes by preventing loosening and premature failure. PMID- 23803706 TI - Identifying the interaction between influenza and pneumococcal pneumonia using incidence data. AB - The association between influenza virus and the bacterium Streptococcus pneumoniae (pneumococcus) has been proposed as a polymicrobial system, whereby transmission and pathogenicity of one pathogen (the bacterium) are affected by interactions with the other (the virus). However, studies focusing on different scales of resolution have painted an inconsistent picture: Individual-scale animal experiments have unequivocally demonstrated an association, whereas epidemiological support in human populations is, at best, inconclusive. We integrate weekly incidence reports and a mechanistic transmission model within a likelihood-based inference framework to characterize the nature, timing, and magnitude of this interaction. We find support for a strong but short-lived interaction, with influenza infection increasing susceptibility to pneumococcal pneumonia ~100-fold. We infer modest population-level impacts arising from strong processes at the level of an individual, thereby resolving the dichotomy in seemingly inconsistent observations across scales. An accurate characterization of the influenza-pneumococcal interaction can form a basis for more effective clinical care and public health measures for pneumococcal pneumonia. PMID- 23803708 TI - Clinicopathological characteristics and prognosis of Chinese patients with sarcomatoid carcinoma of the bladder. AB - OBJECTIVES: The purpose of this study was to retrospectively analyze the clinicopathological features and prognosis of Chinese patients diagnosed with sarcomatoid carcinoma (SC) of the bladder. METHODS: 13 patients admitted to the General Hospital of People's Liberation Army (PLA) between 1999 and 2010 (study group) and 74 Chinese patients diagnosed between 1994 and 2010 and reported in one of two Chinese databases (literature group). RESULTS: The two groups were similar in all demographic and clinical characteristics except depth of tumor invasion. SC of the bladder was most common in older males and most patients had high-grade or late-stage disease at diagnosis. The 6-month, 1-year, 2-year, and 5 years survival rates were 78.9%, 42.7%, 28.0%, and 21.0%, respectively. Analysis of the association of demographic and clinical characteristics with prognosis indicated no significant effect of sex, age, lesion location, tumor diameter, tumor type, depth of invasion, type of surgery, gross hematuria, and urinary tract infection. CONCLUSIONS: Our results suggest that the pathologic tumor stage was unrelated to prognosis. Early diagnosis and surgical intervention are preferred strategies for improvement of prognosis. The association between clinical stage and survival time requires further analysis. PMID- 23803710 TI - Comparison of vascular growth factors in the murine brain reveals placenta growth factor as prime candidate for CNS revascularization. AB - Vascular bypass procedures in the central nervous system (CNS) remain technically challenging, hindered by complications and often failing to prevent adverse outcome such as stroke. Thus, there is an unmet clinical need for a safe and effective CNS revascularization. Vascular endothelial growth factors (VEGFs) are promising candidates for revascularization; however, their effects appear to be tissue-specific and their potential in the CNS has not been fully explored. To test growth factors for angiogenesis in the CNS, we characterized the effects of endothelium-specific growth factors on the brain vasculature and parenchyma. Recombinant adeno-associated virus (AAV) vectors encoding the growth factors were injected transcranially to the frontoparietal cerebrum of mice. Angiogenesis, mural cell investment, leukocyte recruitment, vascular permeability, reactive gliosis and neuronal patterning were evaluated by 3-dimensional immunofluorescence, electron microscopy, optical projection tomography, and magnetic resonance imaging. Placenta growth factor (PlGF) stimulated robust angiogenesis and arteriogenesis without significant side effects, whereas VEGF and VEGF-C incited growth of aberrant vessels, severe edema, and inflammation. VEGF-B, angiopoietin-1, angiopoietin-2, and a VEGF/angiopoietin-1 chimera had minimal effects on the brain vessels or parenchyma. Of the growth factors tested, PlGF emerged as the most efficient and safe angiogenic factor, hence making it a candidate for therapeutic CNS revascularization. PMID- 23803711 TI - Usefulness of multiple dimensions of fatigue in fibromyalgia. AB - OBJECTIVES: To explore in which contexts ratings of multiple dimensions of fatigue are useful in fibromyalgia, and to compare multidimensional fatigue between women with fibromyalgia and healthy women. DESIGN: A cross-sectional study. SUBJECTS AND METHODS: The Multidimensional Fatigue Inventory (MFI-20), comprising 5 subscales of fatigue, was compared with the 1-dimensional subscale of fatigue from the Fibromyalgia Impact Questionnaire (FIQ) in 133 women with fibromyalgia (mean age 46 years; standard deviation 8.6), in association with socio-demographic and health-related aspects and analyses of explanatory variables of severe fatigue. The patients were also compared with 158 healthy women (mean age 45 years; standard deviation 9.1) for scores on MFI-20 and FIQ fatigue. RESULTS: The MFI-20 was associated with employment, physical activity and walking capacity (rs = -0.27 to -0.36), while FIQ fatigue was not. MFI-20 and FIQ fatigue were equally associated with pain, sleep, depression and anxiety (rs = 0.32-0.63). Regression analyses showed that the MFI-20 increased the explained variance (R2) for the models of pain intensity, sleep, depression and anxiety, by between 7 and 29 percentage points, compared with if FIQ fatigue alone was included in the models. Women with fibromyalgia rated their fatigue higher than healthy women for all subscales of the MFI-20 and the FIQ fatigue (p < 0.001). CONCLUSION: Dimensions of fatigue, assessed by the MFI-20, appear to be valuable in studies of employment, pain intensity, sleep, distress and physical function in women with fibromyalgia. The patients reported higher levels on all fatigue dimensions in comparison with healthy women. PMID- 23803712 TI - The need to include animal protection in public health policies. AB - Many critical public health issues require non-traditional approaches. Although many novel strategies are used, one approach not widely applied involves improving the treatment of animals. Emerging infectious diseases are pressing public health challenges that could benefit from improving the treatment of animals. Other human health issues, that overlap with animal treatment issues, and that warrant further exploration, are medical research and domestic violence. The diverse nature of these health issues and their connection with animal treatment suggest that there may be other similar intersections. Public health would benefit by including the treatment of animals as a topic of study and policy development. PMID- 23803713 TI - A procurement-based pathway for promoting public health: innovative purchasing approaches for state and local government agencies. AB - Through their purchasing powers, government agencies can play a critical role in leveraging markets to create healthier foods. In the United States, state and local governments are implementing creative approaches to procuring healthier foods, moving beyond the traditional regulatory relationship between government and vendors. They are forging new partnerships between government, non-profits, and researchers to increase healthier purchasing. On the basis of case examples, this article proposes a pathway in which state and local government agencies can use the procurement cycle to improve healthy eating. PMID- 23803709 TI - European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. AB - Advances in chronic myeloid leukemia treatment, particularly regarding tyrosine kinase inhibitors, mandate regular updating of concepts and management. A European LeukemiaNet expert panel reviewed prior and new studies to update recommendations made in 2009. We recommend as initial treatment imatinib, nilotinib, or dasatinib. Response is assessed with standardized real quantitative polymerase chain reaction and/or cytogenetics at 3, 6, and 12 months. BCR-ABL1 transcript levels <=10% at 3 months, <1% at 6 months, and <=0.1% from 12 months onward define optimal response, whereas >10% at 6 months and >1% from 12 months onward define failure, mandating a change in treatment. Similarly, partial cytogenetic response (PCyR) at 3 months and complete cytogenetic response (CCyR) from 6 months onward define optimal response, whereas no CyR (Philadelphia chromosome-positive [Ph+] >95%) at 3 months, less than PCyR at 6 months, and less than CCyR from 12 months onward define failure. Between optimal and failure, there is an intermediate warning zone requiring more frequent monitoring. Similar definitions are provided for response to second-line therapy. Specific recommendations are made for patients in the accelerated and blastic phases, and for allogeneic stem cell transplantation. Optimal responders should continue therapy indefinitely, with careful surveillance, or they can be enrolled in controlled studies of treatment discontinuation once a deeper molecular response is achieved. PMID- 23803714 TI - How can the public health community help to invigorate a 'health first' perspective in global drug development debates? PMID- 23803715 TI - Synthesis and evaluation of some 17-acetamidoandrostane and N,N-dimethyl-7 deoxycholic amide derivatives as cytotoxic agents: structure/activity studies. AB - Using pregnenolone and 7-deoxycholic acid as starting materials, some 17 acetamidoandrostane and N,N-dimethyl-7-deoxycholic amide derivatives were synthesized. The cytotoxicity of the synthesized compounds was tested in vitro against two tumor cell lines: SGC 7901 (human gastric carcinoma) and Bel 7404 (human liver carcinoma). The result showed that the blockage of the interaction of the amide group with outside groups might cause a decrease of the cytotoxicity, and an O-benzyloximino group at the 3-position of N,N-dimethyl-7 deoxycholic amide could enhance the cytotoxic activity of the compound. The information obtained from the studies provides the structure-activity relationship for these compounds and may be useful for the design of novel chemotherapeutic drugs. PMID- 23803716 TI - A novel 3alpha-p-Nitrobenzoylmultiflora-7:9(11)-diene-29-benzoate and two new triterpenoids from the seeds of zucchini (Cucurbita pepo L). AB - Three novel multiflorane-type triterpenoids, 3alpha-p-nitrobenzoylmultiflora 7:9(11)-diene-29-benzoate (1), 3alpha-acetoxymultiflora-7:9(11)-diene-29-benzoate (2), and 3alpha-acetoxymultiflora-5(6):7:9(11)-triene-29-benzoate (3), along with two known related compounds 4 and 5 were isolated from the seeds of zucchini (Cucurbita pepo L). Their structures were determined on the basis of 1D and 2D NMR spectroscopy and HREIMS. Triterpenoids possessing a nitro group were not isolated previously. PMID- 23803717 TI - Study on the potential toxicity of a thymoquinone-rich fraction nanoemulsion in Sprague Dawley rats. AB - Toxicological studies constitute an essential part of the effort in developing an herbal medicine into a drug product. A newly developed thymoquinone-rich fraction nanoemulsion (TQRFNE) has been prepared using a high pressure homogenizer. The purpose of this study was to investigate the potential acute toxicity of this nanoemulsion in Sprague Dawley rats. The acute toxicity studies were conducted as per the OECD guidelines 425, allowing for the use of test dose limit of 20 mL TQRFNE (containing 44.5 mg TQ)/kg. TQRFNE and distilled water (DW) as a control were administered orally to both sexes of rats on Day 0 and observed for 14 days. All the animals appeared normal, and healthy throughout the study. There was no observed mortality or any signs of toxicity during the experimental period. The effects of the TQRFNE and DW groups on general behavior, body weight, food and water consumption, relative organ weight, hematology, histopathology, and clinical biochemistry were measured. All the parameters measured were unaffected as compared to the control (DW) group. The administration of 20 mL TQRFNE /kg was not toxic after an acute exposure. PMID- 23803718 TI - Meaning and methadone: patient perceptions of methadone dose and a model to promote adherence to maintenance treatment. AB - OBJECTIVES: Methadone maintenance treatment (MMT) effectively reduces illicit opioid use and its negative consequences when patients participate in and adhere to treatment. Patients' participation and adherence may relate to their perceptions about methadone doses and dose adjustments and the meanings that patients associate with treatment. This study assessed patient perceptions about methadone dosing and the meanings associated with methadone treatment to better support patient adherence to and success in MMT. METHODS: We conducted semistructured interviews with 19 patients in an urban MMT program. Interviews were transcribed verbatim and analyzed through an iterative process. RESULTS: Participants' expressed perceptions about methadone doses related to ideas of "comfort" and "function," suggesting a model for determining dose appropriateness and "ideal" methadone dose based on various factors both intrinsic and extrinsic to MMT. Intrinsic factors included those exerting downward pressure on "ideal" methadone dose such as lack of control in treatment, disdain for getting "high," concerns about methadone dependence, and desire to avoid adverse effects; those exerting upward pressure such as concern about withdrawal; and those exerting mixed pressures such as methadone formulations. Extrinsic factors included those exerting downward pressure such as shame about and stigma around MMT; those exerting upward pressure such as medical conditions and medication interactions; and those exerting mixed pressures such as family and peer relationships. CONCLUSIONS: Participants held perceptions about methadone dosing that included considerations beyond typical medical parameters used by physicians and other MMT providers to determine appropriate methadone doses. The model that emerged from our data could help inform MMT providers to support greater patient comfort with methadone doses and dose changes, as well as adherence to and success in MMT. PMID- 23803720 TI - Epigenetic modulation of the immune function: a potential target for tolerance. AB - Great efforts in the field of solid organ transplantation are being devoted to identifying biomarkers that allow a transplanted patient's immune status to be established. Recently, it has been well documented that epigenetic mechanisms like DNA methylation and histone modifications regulate the expression of immune system-related genes, modifying the development of the innate and adaptive immune responses. An in-depth knowledge of these epigenetic mechanisms could modulate the immune response after transplantation and to develop new therapeutic strategies. Epigenetic modifiers, such as histone deacetylase (HDAC) inhibitors have considerable potential as anti-inflammatory and immunosuppressive agents, but their effect on transplantation has not hitherto been known. Moreover, the detection of epigenetic marks in key immune genes could be useful as biomarkers of rejection and progression among transplanted patients. Here, we describe recent discoveries concerning the epigenetic regulation of the immune system, and how this knowledge could be translated to the field of transplantation. PMID- 23803721 TI - Body mass index, a major confounder to insulin resistance association with unprovoked venous thromboembolism. Results from the EDITH case-control study. AB - Shared risk factors help explain the association between venous thromboembolism (VTE) and atherothrombosis. The potential association between insulin resistance and VTE has been poorly evaluated. Thus, we aimed to assess the association between insulin resistance and VTE in the EDITH hospital-based case-control study. Between May 2000 and December 2004, 677 patients with unprovoked VTE and their age- and sex-matched controls were included. Fasting glycaemia and insulinaemia were measured and insulin resistance was estimated with the homeostasis model assessment of insulin resistance (HOMA-IR) equation. The association between HOMA-IR and VTE was determined in non-diabetic patients in a quintile-based analysis. A total of 590 non-diabetic cases (median age 73.0 years, 255 men) and 581 non-diabetic controls (median age 72.0 years, 247 men) were analysed. There was a trend for a higher median level of HOMA-IR index in cases than in controls (1.21 [interquartile range 0.84-2.10] vs1.19 [interquartile range 0.72-2.02], p=0.08). The unadjusted analysis showed an increased risk of unprovoked VTE associated with increasing HOMA-IR (odds ratio [OR] 1.53; 95% confidence interval [CI] 1.00-2.34 for the highest quintile of HOMA-IR compared with the first quintile). Adjustment for lipid lowering drugs and antiplatelet agents use slightly modified the association (OR 1.51; 95% CI 0.97-2.34). When body mass index was added in the adjusted model, HOMA-IR was no longer associated with VTE (OR 1.08; 95% CI 0.67-1.73). Our results highlight the role of body mass index in the association between cardiovascular risk factors and VTE. PMID- 23803722 TI - A novel risk-adjusted nomogram for rectal cancer surgery outcomes. AB - IMPORTANCE: The circumferential resection margin is the primary determinant of local recurrence and a major factor in survival in rectal cancer. Neither chemotherapy nor chemoradiation compensates for a margin positive for cancer. OBJECTIVE: To identify treatment-related factors associated with hospital margin positive resection and to develop a tool that could be used by individual hospitals to assess their outcomes based on their unique mix of patient and tumor characteristics. DESIGN: Retrospective review of the National Cancer Data Base, 1998-2007. SETTINGS: Community and academic/research hospitals. PARTICIPANTS: Individuals with histologically confirmed localized rectal/rectosigmoid adenocarcinoma. EXPOSURE: All individuals underwent radical resection for rectal cancer with or without neoadjuvant therapy. MAIN OUTCOMES AND MEASURES: Rate of margin positivity determined and adjusted for patient- and tumor-related factors to calculate expected margin positivity per hospital. An observed to expected ratio was calculated based on patient- and tumor-related factors to identify treatment-associated variation. RESULTS: The overall margin-positive resection rate was 5.2%. Patients with margins positive for cancer were more likely to be older, male, and African American; not have private insurance; and have their cancer diagnosed later in the study period. Associated tumor-related factors include rectal location, higher American Joint Committee on Cancer stage, signet/mucinous histology, and poor/undifferentiated grade. Among hospitals that were significantly low outliers, 47% were comprehensive community hospitals, and 43.9% were academic/research hospitals; of those that were significantly high outliers, 52.3% were comprehensive community hospitals, and 17.8% were academic/research hospitals. High-volume centers made up 80% of significantly low outlier hospitals and 17% of significantly high outlier hospitals. The rates of chemotherapy and radiation were similar, but low outlier hospitals gave more neoadjuvant radiation (26.3% vs 17%). CONCLUSIONS AND RELEVANCE: After adjustment for patient- and tumor-related factors, we identified both low and high outlier hospitals for margin positivity at resection, as well as potentially modifiable risk factors. The nomogram created in this model allows for the evaluation of observed and expected event rates for individual hospitals, providing a hospital self-assessment tool for identifying targets for improvement. PMID- 23803723 TI - Neutrophil gelatinase-associated lipocalin predicts worsening of renal function in acute heart failure: methodological and clinical issues. AB - BACKGROUND: Worsening of renal function (WRF) in acute heart failure (AHF) strongly predicts adverse clinical outcome. Plasma neutrophil gelatinase associated lipocalin (NGAL) has been proposed as an earlier biomarker of tubular damage, but important methodological issues remain unsolved, particularly in AHF. METHODS AND RESULTS: In 30 consecutive patients admitted for AHF, 108 serum NGAL (Alere system) measurements were performed at entry and in the first days of recovery, and reproducibility within the same blood samples was very high (r = 0.98). NGAL at entry was related to kidney function [r = 0.51 vs. creatinine (Cr) and r = -0.49 vs. estimated glomerular filtration rate (eGFR), both P < 0.001], and weakly with hemoglobin (r = -0.36, P < 0.05) and C-reactive protein (CRP) (r = 0.26, P < 0.05). During hospitalization, WRF occurred in 26.7% of the patients. Baseline NGAL was only slightly higher in patients who developed WRF as compared to those who did not (151 +/- 90 vs. 119 +/- 75 ng/ml, NS), but it increased significantly in the following days, always preceding WRF occurrence (max. previous 24 h, average 95%, range 25-200%). The area under the Receiver Operating Characteristic (ROC) curve (AUC-ROC) was 0.69 for pathological NGAL at entry and 0.91 for delta NGAL changes during the first days. CONCLUSIONS: In patients with AHF, serum NGAL measurement is highly reproducible and at entry it is related to baseline Cr and eGFR, but does not predict WRF during subsequent hospitalization. On the contrary, serial measurements of NGAL in the first days of hospitalization can accurately predict WRF. PMID- 23803724 TI - Background changing patterns of neonatal fungal sepsis in a developing country. AB - BACKGROUND: Candida albicans is the predominant isolate in many neonatal fungal bloodstream infections (BSIs), so fluconazole is used as empiric antifungal therapy. AIM: To determine the predominant organisms, antifungal sensitivity patterns, clinical and demographic risk factors and crude mortality rate in neonatal fungal BSI cases. SUBJECTS AND METHODS: This is a review of all neonatal fungal BSI cases between January 2007 and December 2011. RESULTS: Fifty-nine patients were included in the study. Candida parapsilosis (54.2%) was isolated in majority of the cases, followed by C. albicans (27.1%). Fluconazole resistance was present in 16 of 32 cases of C. parapsilosis versus 1 of 16 cases of C. albicans (P = 0.003). Mortality rate was 45.8%. Surgical problems were present in 55.9%. Death was significantly associated with lower birth weight (P = 0.046) and necrotizing enterocolitis (P = 0.034). CONCLUSIONS: The increase in neonatal fungal BSI and resistant organisms highlights the need to review use of routine empiric fluconazole and to implement preventive measures. PMID- 23803725 TI - 3D culture adds an extra dimension to targeted epigenetic therapies. PMID- 23803726 TI - Connecting the dots in cutaneous T cell lymphoma (CTCL): STAT5 regulates malignant T cell proliferation via miR-155. PMID- 23803727 TI - Keeping each other in check: a reciprocal relationship between cytokines and miRNA. PMID- 23803728 TI - miR-155 meets the JAK/STAT pathway. PMID- 23803729 TI - Control of cancer-associated fibroblast function by oxidative stress: A new piece in the puzzle. PMID- 23803730 TI - A reversible Warburg effect is induced by Theileria parasites to transform host leukocytes. PMID- 23803731 TI - Transcriptional regulation of blood vessel formation: the role of the CASZ1/Egfl7/RhoA pathway. PMID- 23803732 TI - VEGFR2 trafficking: speed doesn't kill. PMID- 23803733 TI - Regulation of Rb family proteins by Cdk6/Ccnd1 in growth plates. PMID- 23803734 TI - Chronic growth factor receptor signaling and lineage inappropriate gene expression in AML: the polycomb connection. PMID- 23803735 TI - Socs3 induction by PPARgamma restrains cancer-promoting inflammation. PMID- 23803736 TI - The ORC/Cdc6/MCM2-7 complex, a new power player for regulated helicase loading. PMID- 23803738 TI - Interfacial properties of bilayer and trilayer graphene on metal substrates. AB - One popular approach to prepare graphene is to grow them on transition metal substrates via chemical vapor deposition. By using the density functional theory with dispersion correction, we systematically investigate for the first time the interfacial properties of bilayer (BLG) and trilayer graphene (TLG) on metal substrates. Three categories of interfacial structures are revealed. The adsorption of B(T)LG on Al, Ag, Cu, Au, and Pt substrates is a weak physisorption, but a band gap can be opened. The adsorption of B(T)LG on Ti, Ni, and Co substrates is a strong chemisorption, and a stacking-insensitive band gap is opened for the two uncontacted layers of TLG. The adsorption of B(T)LG on Pd substrate is a weaker chemisorption, with a band gap opened for the uncontacted layers. This fundamental study also helps for B(T)LG device study due to inevitable graphene/metal contact. PMID- 23803739 TI - Vitamin D status is associated with disease activity among rheumatology outpatients. AB - The co-existence of high prevalence of vitamin D inadequacy among Canadians and high prevalence of systematic autoimmune rheumatic diseases (SARDs) raise the question on relationship between the two situations. OBJECTIVE: To determine vitamin D status in known cases of common SARDs and compare to those with non autoimmune diseases; further, to evaluate the impact of vitamin D on disease activity in rheumatoid arthritis (RA) cases. METHODS: In a retrospective case control study design, we evaluated 116 patients in a community clinic classified in two groups, CONTROL GROUP: patients with non-rheumatic disease (n = 56), and Case group: those with rheumatic diseases (n = 60). We compared plasma vitamin D status (25(OH)D), indicators of disease activity and other potential confounders. Further, we determined factors associated with disease activity in RA cases. RESULTS: The plasma 25(OH)D was significantly lower in Case group (64.8 +/- 29.8) compared to CONTROL GROUP (86.8 +/- 37.7). High number of SARDs outpatients 56%) had considerably low plasma 25(OH)D concentration. RA cases with low plasma 25(OH)D had over five times higher risk of disease activity (OR = 5.15 95% CI 1.16, 22.9; p = 0.031). CONCLUSION: Inadequate vitamin D status in SARDs cases, along with considerably strong association with disease activity in RA cases, indicate the need for proper evaluation of vitamin D status in this clinical population. Moreover, appropriate training should be given to the patients to ensure the intake of the recommended amount of vitamin D per day through diet or supplement. PMID- 23803740 TI - Assessment of daily food and nutrient intake in Japanese type 2 diabetes mellitus patients using dietary reference intakes. AB - Medical nutrition therapy for the management of diabetes plays an important role in preventing diabetes complications and managing metabolic control. However, little is known about actual eating habits of individuals with type 2 diabetic mellitus (T2DM), especially in Japan. Therefore, we sought to (1) assess the dietary intake of individuals with T2DM, and (2) characterize their intake relative to national recommendations. This cross-sectional study involved 149 patients (77 males and 72 females) aged 40-79 years with T2DM recruited at a Kyoto hospital. Dietary intake was assessed using a validated self-administered diet history questionnaire. Under-consumption, adequacy, and over-consumption, of nutrients were compared to the age- and sex-based standards of the Japanese Dietary Reference Intakes. Among the results, most notable are (1) the inadequacy of diets in men with respect to intake of vitamins and minerals, likely owing to low intake of vegetables and fruits; (2) excess contributions of fat intake to total energy in both sexes; and (3) excess consumption of sweets and beverages relative to the national average. The prevalence of diabetes complications may be increasing because of a major gap between the typical dietary intake of individuals with T2DM and dietary recommendation. PMID- 23803741 TI - Diffuser-incorporated transmission NIR measurement for reliable analysis of packed granular samples. AB - A diffuser-incorporated transmission near-infrared (NIR) scheme that enables direct spectral collection of packed granular samples with reliable sample representation and reproducibility has been demonstrated. The analytical utility of this method has been evaluated for the determination of polyethylene (PE) pellet density and the discrimination of the geographical origin of rice samples. Based on the preliminary observation of transmission spectral features acquired from spherical polyoxymethylene (POM) packings composed of different particle sizes as well as packing thickness, a portion of the radiation was propagated through the void space in the packing without fully interacting with the POM pellets. This type of radiation, so-called non-fully interacted radiation (NFIR), adversely affected the sample representation as well as the reproducibility of transmission measurements. To maximize the interaction of NIR radiation with granular samples, a polytetrafluoroethylene (PTFE) diffuser was positioned in front of the sample packing to introduce isotropically diffused radiation into the sample. This diffuser-incorporated scheme resulted in highly reproducible transmission spectra for both packed granular samples. Consequently, the density determination of PE pellets as well as discrimination of rice samples according to geographical origin was more accurate using the proposed scheme. PMID- 23803742 TI - The role of metal binding and phosphorylation domains in the regulation of cisplatin-induced trafficking of ATP7B. AB - The copper (Cu) exporter ATP7B mediates cellular resistance to cisplatin (cDDP) by increasing drug efflux. ATP7B binds and sequesters cDDP in into secretory vesicles. Upon cDDP exposure ATP7B traffics from the trans-Golgi network (TGN) to the periphery of the cell in a manner that requires the cysteine residues in its metal binding domains (MBD). To elucidate the role of the various domains of ATP7B in its cDDP-induced trafficking we expressed a series of mCherry-tagged variants of ATP7B in HEK293T cells and analyzed their subcellular localization in basal media and after a 1 h exposure to 30 MUM cDDP. The wild type ATP7B and a variant in which the cysteines in the CXXC motifs of MBD 1-5 were converted to serines trafficked out of the trans-Golgi (TGN) when exposed to cDDP. Conversion of the cysteines in all 6 of the CXXC motifs to serines, or in only the sixth MBD, rendered ATP7B incapable of trafficking on exposure to cDDP. Truncation of MBD1-5 or MBD1-6 resulted in the loss of TGN localization. Addition of the first 63 amino acids of ATP7B to these variants restored TGN localization to a great extent and enabled the MBD1-5 variant to undergo cDDP-induced trafficking. A variant of ATP7B in which the aspartate 1027 residue in the phosphorylation domain was converted to glutamine localized to the TGN but was incapable of cDDP induced trafficking. These results demonstrate that the CXXC motif in the sixth MBD and the catalytic activity of ATP7B are required for cDDP-induced trafficking as they are for Cu-induced redistribution of ATP7B; this provides further evidence that cDDP mimics Cu with respect to the molecular mechanisms by they control the subcellular distribution of ATP7B. PMID- 23803743 TI - The Arabidopsis DDB1 interacting protein WDR55 is required for vegetative development. AB - The CULLIN family of E3 ubiquitin ligases are important regulators of plant development and function. A newly identified class of CULLIN4-RING-E3 ligases (CRL4s) interacts with substrate receptors referred to as DDB1-CUL4 ASSOCIATED FACTORS (DCAFs) via a DDB1 linker protein. We have previously reported that the WD40 protein WDR55 interacts with DDB1A and is thus a putative DCAF. Mutants of WDR55 are embryo lethal, suggesting that a DDB1(WDR55) complex could regulate embryo and endosperm development. Here we report that a weak allele homozygous for wdr55 display pleiotropic phenotypes in the seedling and adult stages, suggesting a novel regulatory role for WDR55 in vegetative development. PMID- 23803744 TI - Effect of overexpression of kinase- or RNase-deficient OsIRE1 on the endoplasmic reticulum stress response in transgenic rice plants. AB - IRE1 is an endoplasmic reticulum (ER) stress sensor protein in eukaryotes. In this study, we generated transgenic rice plants overexpressing three types of OsIRE1, including wild-type OsIRE1 (IRE1-OE) and two disrupted-IRE1s deficient in either kinase activity (K519A-OE) or RNase activity (K833A-OE), under the control of a constitutive promoter. Overexpression of wild-type IRE1 induced the ER stress response in transgenic rice even under non-stress conditions, whereas K519A-OE and K833A-OE had dominant negative effects on endogenous OsIRE1 expression in these transgenic plants. These lines exhibited phenotypes that were quite similar to those of OsIRE1 knock-down rice. These observations suggest that the two types of functionally disrupted OsIRE1 proteins behave as competitive inhibitors toward the ER stress response in transgenic rice plants. Furthermore, OsIRE1 may have a vital, as yet unidentified function, as determined through the characterization of the transgenic plants generated in this study. PMID- 23803745 TI - The novel GrCEP12 peptide from the plant-parasitic nematode Globodera rostochiensis suppresses flg22-mediated PTI. AB - The potato cyst nematode Globodera rostochiensis is a biotrophic pathogen that secretes effector proteins into host root cells to promote successful plant parasitism. In addition to the role in generating within root tissue the feeding cells essential for nematode development, (1) nematode secreted effectors are becoming recognized as suppressors of plant immunity. (2)(-) (4) Recently we reported that the effector ubiquitin carboxyl extension protein (GrUBCEP12) from G. rostochiensis is processed into free ubiquitin and a 12-amino acid GrCEP12 peptide in planta. Transgenic potato lines overexpressing the derived GrCEP12 peptide showed increased susceptibility to G. rostochiensis and to an unrelated bacterial pathogen Streptomyces scabies, suggesting that GrCEP12 has a role in suppressing host basal defense or possibly pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) during the parasitic interaction. (3) To determine if GrCEP12 functions as a PTI suppressor we evaluated whether GrCEP12 suppresses flg22-induced PTI responses in Nicotiana benthamiana. Interestingly, we found that transient expression of GrCEP12 in N. benthamiana leaves suppressed reactive oxygen species (ROS) production and the induction of two PTI marker genes triggered by the bacterial PAMP flg22, providing direct evidence that GrCEP12 indeed has an activity in PTI suppression. PMID- 23803746 TI - MOS2 has redundant function with its homolog MOS2H and is required for proper splicing of SNC1. AB - Plant immunity is essential for plant survival and resistance (R) proteins serve essential roles in pathogen detection and defense signal initiation. A gain-of function mutation in SNC1, a TIR-type R gene, results in a characteristic autoimmune phenotype in Arabidopsis. From a forward genetic suppressor screen using snc1, MOS2 (MODIFIER of snc1), which encodes an RNA-binding protein, was identified. When MOS2 function is lost, the autoimmunity caused by snc1 is abolished and basal resistance against virulent pathogens is attenuated. Recently, it was shown that mos2 mutants also have defects in miRNA processing. However, it is not known how the role of MOS2 in miRNA production is related to the suppression of snc1-mediated autoimmunity. Here, we show that MOS2 contributes to proper splicing of SNC1 transcript, agreeing with its potential association with the MOS4-associated complex (MAC). In addition, although mutant plants carrying a mutation in the MOS2 homolog MOS2H are wild-type like, the double mutant mos2 mos2h is lethal. These data suggest that MOS2 and MOS2H have unequally redundant functions. Overall, MOS2 and MOS2H probably have diverse functions in both alternative splicing and miRNA processing. PMID- 23803747 TI - Retromer association with membranes: plants have their own rules! AB - The retromer is an endosome-localized complex involved in protein trafficking. To better understand its function and regulation in plants, we recently investigated how Arabidopsis retromer subunits assemble and are targeted to endosomal membranes and highlighted original features compared with mammals. We characterized Arabidopsis vps26 null mutant and showed that it displays severe developmental defaults similar to those observed in vps29 mutant. Here, we go further by describing new phenotypic defects associated with loss of VPS26 function, such as inhibition of lateral root initiation. Recently, we showed that VPS35 subunit plays a crucial role in the recruitment of the plant retromer to endosomes, probably through an interaction with the Rab7 homolog RABG3f. In this work, we now show that contrary to mammals, Arabidopsis Rab5 homologs do not seem to be necessary for the recruitment of the core retromer to endosomal membranes, which highlights a new specificity of the plant retromer. PMID- 23803748 TI - Individual amino acid residues in CLV3 peptide contribute to its stability in vitro. AB - CLV3 acts as a peptide ligand to interact with leucine-rich repeat (LRR) receptor kinases in neighboring cells to restrict the size of shoot apical meristems (SAMs) in Arabidopsis. To examine contributions of individual amino acid residues in CLV3 peptide in SAM maintenance, 12 synthetic Ala-substituted CLV3 peptides were applied to clv3-2 seedlings cultured in vitro, and the sizes of SAMs were measured after 9 d. The result showed that Pro-9 and His-11 are the most critical residues, while Val-3 and Ser-5 are the least important ones for CLV3 functions in SAMs in vitro. With MALDI-TOF mass spectrum analyses, we further showed that Ala substitution in His-11 led to a greatly reduced stability of the peptide, leading to a complete degradation of the peptide after cultured with seedlings for only one hour. The substitution of Pro-9 by Ala also led to a complete degradation of the peptides after 2 d incubation. In contrast, Ala substitutions in Val-3 or Ser-5 gave very little changes on peptide stabilities. These results suggested that stabilities of Ala-substituted CLV3 peptides are positively correlated with their activities in SAMs. We thus propose that the stability of CLV3 may partially contribute to its function in SAM maintenance. PMID- 23803749 TI - Presence of LYM2 dependent but CERK1 independent disease resistance in Arabidopsis. AB - Plants have the ability to detect invading fungi through the perception of chitin fragments released from the fungal cell walls. Plant chitin receptor consists of two types of plasma membrane proteins, CEBiP and CERK1. However, the contribution of these proteins to chitin signaling is different between Arabidopsis and rice. In Arabidopsis, it seems CERK1 receptor kinase is enough for both ligand perception and signaling, whereas both CEBiP and OsCERK1 are required for chitin signaling in rice. Here we report that Arabidopsis CEBiP homolog, LYM2, is not involved in chitin signaling but contributes to resistance against a fungal pathogen, Alternaria brassicicola, indicating the presence of a novel disease resistance mechanism in Arabidopsis. PMID- 23803750 TI - Several MAMPs, including chitin fragments, enhance AtPep-triggered oxidative burst independently of wounding. AB - AtPeps are a family of small peptides in Arabidopsis that are believed to act as endogenous amplifiers of the plant's innate immune response. In our recent study, (10) we showed that in Arabidopsis leaf disks, bacterial MAMPs (microbe associated molecular patterns) such as the flagellin derived elicitor flg22, greatly enhanced the release of reactive oxygen species (ROS) triggered by a subsequent AtPep-perception. This enhanced ROS production could be a hallmark either of improved local defense or of the initiation of ROS-based systemic signaling. Here, we established a superior ROS detection system based on a new derivative of luminol (L-012). With this sensitive system we were able to show that chitin, too, acts as an enhancer of AtPep-triggered ROS, linking this specific defense response amplification also to the recognition of fungal pathogens. In addition we used the more sensitive ROS assay to transfer the experimental setup from cut leaf disks to unwounded seedlings. Thereby we revealed that wounding is not a prerequisite to enable the MAMP-induced enhancement of the AtPep-triggered ROS response. PMID- 23803751 TI - New insights into the role of Arabidopsis RABA1 GTPases in salinity stress tolerance. AB - RAB11 GTPases, widely conserved members of RAB small GTPases, have evolved in a unique way in plants; plant RAB11 has notable diversity compared with animals and yeast. Recently, we have shown that members of RABA1, a subgroup in Arabidopsis RAB11 group, are required for salinity stress tolerance. To obtain a clue to understand its underlying mechanism, here we investigate whether RABA1 regulates sodium transport across the plasma membrane and accumulation in the vacuole. The results indicate that the raba1 quadruple mutant is not defective in the import and intracellular distribution of sodium, implying that RABA1 members are involved in a more indirect way in the responses to salinity stress. PMID- 23803752 TI - Fine-motor skills testing and prediction of endovascular performance. AB - BACKGROUND: Performing endovascular procedures requires good control of fine motor digital movements and hand-eye coordination. Objective assessment of such skills is difficult. Trainees acquire control of catheter/wire movements at various paces. However, little is known to what extent talent plays for novice candidates at entry to practice. PURPOSE: To study the association between performance in a novel aptitude test of fine-motor skills and performance in simulated procedures. MATERIAL AND METHODS: The test was based on manual course tracking using a proprietary hand-operated roller-bar device coupled to a personal computer with monitor view rotation. A total of 40 test repetitions were conducted separately with each hand. Test scores were correlated with simulator performance. Group A (n = 14), clinicians with various levels of endovascular experience, performed a simulated procedure of contralateral iliac artery stenting. Group B (n = 19), medical students, performed 10 repetitions of crossing a challenging aortic bifurcation in a simulator. RESULTS: The test score differed markedly between the individuals in both groups, in particular with the non-dominant hand. Group A: the test score with the non-dominant hand correlated significantly with simulator performance assessed with the global rating scale SAVE (R = -0.69, P = 0.007). There was no association observed from performances with the dominant hand. Group B: there was no significant association between the test score and endovascular skills acquisition neither with the dominant nor with the non-dominant hand. CONCLUSION: Clinicians with increasing levels of endovascular technical experience had developed good fine-motor control of the non-dominant hand, in particular, that was associated with good procedural performance in the simulator. The aptitude test did not predict endovascular skills acquisition among medical students, thus, cannot be suggested for selection of novice candidates. Procedural experience and practice probably supplant the influence of innate abilities (talent) over time. PMID- 23803753 TI - The vulnerable coronary plaque: update on imaging technologies. AB - Several studies have been carried out on vulnerable plaque as the main culprit for ischaemic cardiac events. Historically, the most important diagnostic technique for studying coronary atherosclerotic disease was to determine the residual luminal diameter by angiographic measurement of the stenosis. However, it has become clear that vulnerable plaque rupture as well as thrombosis, rather than stenosis, triggers most acute ischaemic events and that the quantification of risk based merely on severity of the arterial stenosis is not sufficient. In the last decades, substantial progresses have been made on optimisation of techniques detecting the arterial wall morphology, plaque composition and inflammation. To date, the use of a single technique is not recommended to precisely identify the progression of the atherosclerotic process in human beings. In contrast, the integration of data that can be derived from multiple methods might improve our knowledge about plaque destabilisation. The aim of this narrative review is to update evidence on the accuracy of the currently available non-invasive and invasive imaging techniques in identifying components and morphologic characteristics associated with coronary plaque vulnerability. PMID- 23803754 TI - Fetal dysrhythmias: a primer for the obstetrician/gynecologist. AB - During routine fetal auscultation, it is not uncommon to encounter an abnormal fetal heart rate. The rate may be abnormally slow or fast, or irregular. This article focuses on fetal dysrhythmias, defined as any irregular fetal cardiac rhythm or a regular rhythm with an abnormal rate outside the range of 120 to 160 beats per minute (Am J Obstet Gynecol. 2000;182:813-819). This article also helps the reader to recognize the most common types of fetal arrhythmias, understand the fetal risks associated with many fetal arrhythmias, and identify some of the pharmacological options used to treat fetal arrhythmias. PMID- 23803755 TI - Mechanisms and prevention of alloimmunization in pregnancy. AB - Transfusion only occasionally gives rise to antibody production, because blood cells per se are not markedly immunogenic. However, the immunological changes that occur during pregnancy increase the risk of alloimmunization against red blood cells, platelets, and/or leukocytes. Fetal-maternal bleeding during pregnancy or in relation to delivery is the antigenic stimuli for immunization against red blood cells, whereas other mechanisms, such as trophoblast-derived microparticles, may also play a role in the production of antibodies against platelets. Antibody-mediated immune suppression has for 4 decades successfully been used for prevention of RhD immunization. Result from a mouse model of fetal and neonatal alloimmune thrombocytopenia (FNAIT) suggests that the same principle may be applied for the prevention of FNAIT. A European Union-funded consortium is presently in the process of developing a hyperimmune anti-human platelet antigen 1a (HPA-1a) immunoglobulin G. The idea is to prevent HPA-1a immunization by administering the drug to nonimmunized HPA-1a-negative women after delivery of an HPA-1a-positive child. The anti-HPA-1a will be purified from plasma collected from women who previously have given birth to a child with FNAIT caused by anti HPA-1a. If the results of the planned phase III trial are favorable, it is possible that a product for prevention of FNAIT will be available within this decade. PMID- 23803756 TI - The role of surgery in the management of gestational trophoblastic neoplasia. AB - Although sensitive human chorionic gonadotropin assays and advances in chemotherapy have assumed primary importance in the management of gestational trophoblastic neoplasia, surgery remains important in the overall care of these patients. Management of molar pregnancies consists of surgical evacuation and subsequent monitoring. Hysterectomy decreases the risk of post-molar trophoblastic disease in appropriate patients and, when incorporated to primary management of gestational trophoblastic neoplasia, can decrease the chemotherapy requirements of patients with low-risk disease. In patients with high-risk disease, surgical intervention is frequently required to control complications of disease or as therapy to stabilize patients during chemotherapy. Hysterectomy, thoracotomy, or other extirpative procedures may be integrated into the management of patients with chemorefractory disease. Interventional procedures are useful adjuncts to control bleeding from metastases. PMID- 23803757 TI - It's time to ban junk food on hospital premises. PMID- 23803758 TI - Formal cardiac rehabilitation and exercise training programs in heart failure: evidence for substantial clinical benefits. PMID- 23803761 TI - Planetary science: The robustness of planet formation. PMID- 23803760 TI - Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. AB - Obesity has become more prevalent in most developed countries over the past few decades, and is increasingly recognized as a major risk factor for several common types of cancer. As the worldwide obesity epidemic has shown no signs of abating, better understanding of the mechanisms underlying obesity-associated cancer is urgently needed. Although several events were proposed to be involved in obesity associated cancer, the exact molecular mechanisms that integrate these events have remained largely unclear. Here we show that senescence-associated secretory phenotype (SASP) has crucial roles in promoting obesity-associated hepatocellular carcinoma (HCC) development in mice. Dietary or genetic obesity induces alterations of gut microbiota, thereby increasing the levels of deoxycholic acid (DCA), a gut bacterial metabolite known to cause DNA damage. The enterohepatic circulation of DCA provokes SASP phenotype in hepatic stellate cells (HSCs), which in turn secretes various inflammatory and tumour-promoting factors in the liver, thus facilitating HCC development in mice after exposure to chemical carcinogen. Notably, blocking DCA production or reducing gut bacteria efficiently prevents HCC development in obese mice. Similar results were also observed in mice lacking an SASP inducer or depleted of senescent HSCs, indicating that the DCA-SASP axis in HSCs has key roles in obesity-associated HCC development. Moreover, signs of SASP were also observed in the HSCs in the area of HCC arising in patients with non-alcoholic steatohepatitis, indicating that a similar pathway may contribute to at least certain aspects of obesity-associated HCC development in humans as well. These findings provide valuable new insights into the development of obesity-associated cancer and open up new possibilities for its control. PMID- 23803763 TI - Bioinorganic chemistry: Enzymes activated by synthetic components. PMID- 23803762 TI - AID stabilizes stem-cell phenotype by removing epigenetic memory of pluripotency genes. AB - The activation-induced cytidine deaminase (AID; also known as AICDA) enzyme is required for somatic hypermutation and class switch recombination at the immunoglobulin locus. In germinal-centre B cells, AID is highly expressed, and has an inherent mutator activity that helps generate antibody diversity. However, AID may also regulate gene expression epigenetically by directly deaminating 5 methylcytosine in concert with base-excision repair to exchange cytosine. This pathway promotes gene demethylation, thereby removing epigenetic memory. For example, AID promotes active demethylation of the genome in primordial germ cells. However, different studies have suggested either a requirement or a lack of function for AID in promoting pluripotency in somatic nuclei after fusion with embryonic stem cells. Here we tested directly whether AID regulates epigenetic memory by comparing the relative ability of cells lacking AID to reprogram from a differentiated murine cell type to an induced pluripotent stem cell. We show that Aid-null cells are transiently hyper-responsive to the reprogramming process. Although they initiate expression of pluripotency genes, they fail to stabilize in the pluripotent state. The genome of Aid-null cells remains hypermethylated in reprogramming cells, and hypermethylated genes associated with pluripotency fail to be stably upregulated, including many MYC target genes. Recent studies identified a late step of reprogramming associated with methylation status, and implicated a secondary set of pluripotency network components. AID regulates this late step, removing epigenetic memory to stabilize the pluripotent state. PMID- 23803764 TI - The same frequency of planets inside and outside open clusters of stars. AB - Most stars and their planets form in open clusters. Over 95 per cent of such clusters have stellar densities too low (less than a hundred stars per cubic parsec) to withstand internal and external dynamical stresses and fall apart within a few hundred million years. Older open clusters have survived by virtue of being richer and denser in stars (1,000 to 10,000 per cubic parsec) when they formed. Such clusters represent a stellar environment very different from the birthplace of the Sun and other planet-hosting field stars. So far more than 800 planets have been found around Sun-like stars in the field. The field planets are usually the size of Neptune or smaller. In contrast, only four planets have been found orbiting stars in open clusters, all with masses similar to or greater than that of Jupiter. Here we report observations of the transits of two Sun-like stars by planets smaller than Neptune in the billion-year-old open cluster NGC6811. This demonstrates that small planets can form and survive in a dense cluster environment, and implies that the frequency and properties of planets in open clusters are consistent with those of planets around field stars in the Galaxy. PMID- 23803766 TI - Attention enhances synaptic efficacy and the signal-to-noise ratio in neural circuits. AB - Attention is a critical component of perception. However, the mechanisms by which attention modulates neuronal communication to guide behaviour are poorly understood. To elucidate the synaptic mechanisms of attention, we developed a sensitive assay of attentional modulation of neuronal communication. In alert monkeys performing a visual spatial attention task, we probed thalamocortical communication by electrically stimulating neurons in the lateral geniculate nucleus of the thalamus while simultaneously recording shock-evoked responses from monosynaptically connected neurons in primary visual cortex. We found that attention enhances neuronal communication by increasing the efficacy of presynaptic input in driving postsynaptic responses, by increasing synchronous responses among ensembles of postsynaptic neurons receiving independent input, and by decreasing redundant signals between postsynaptic neurons receiving common input. The results demonstrate that attention finely tunes neuronal communication at the synaptic level by selectively altering synaptic weights, enabling enhanced detection of salient events in the noisy sensory environment. PMID- 23803767 TI - The role of behaviour in adaptive morphological evolution of African proboscideans. AB - The fossil record richly illustrates the origin of morphological adaptation through time. However, our understanding of the selective forces responsible in a given case, and the role of behaviour in the process, is hindered by assumptions of synchrony between environmental change, behavioural innovation and morphological response. Here I show, from independent proxy data through a 20 million-year sequence of fossil proboscideans in East Africa, that changes in environment, diet and morphology are often significantly offset chronologically, allowing dissection of the roles of behaviour and different selective drivers. These findings point the way to hypothesis-driven testing of the interplay between habitat change, behaviour and morphological adaptation with the use of independent proxies in the fossil record. PMID- 23803765 TI - Recalibrating Equus evolution using the genome sequence of an early Middle Pleistocene horse. AB - The rich fossil record of equids has made them a model for evolutionary processes. Here we present a 1.12-times coverage draft genome from a horse bone recovered from permafrost dated to approximately 560-780 thousand years before present (kyr BP). Our data represent the oldest full genome sequence determined so far by almost an order of magnitude. For comparison, we sequenced the genome of a Late Pleistocene horse (43 kyr BP), and modern genomes of five domestic horse breeds (Equus ferus caballus), a Przewalski's horse (E. f. przewalskii) and a donkey (E. asinus). Our analyses suggest that the Equus lineage giving rise to all contemporary horses, zebras and donkeys originated 4.0-4.5 million years before present (Myr BP), twice the conventionally accepted time to the most recent common ancestor of the genus Equus. We also find that horse population size fluctuated multiple times over the past 2 Myr, particularly during periods of severe climatic changes. We estimate that the Przewalski's and domestic horse populations diverged 38-72 kyr BP, and find no evidence of recent admixture between the domestic horse breeds and the Przewalski's horse investigated. This supports the contention that Przewalski's horses represent the last surviving wild horse population. We find similar levels of genetic variation among Przewalski's and domestic populations, indicating that the former are genetically viable and worthy of conservation efforts. We also find evidence for continuous selection on the immune system and olfaction throughout horse evolution. Finally, we identify 29 genomic regions among horse breeds that deviate from neutrality and show low levels of genetic variation compared to the Przewalski's horse. Such regions could correspond to loci selected early during domestication. PMID- 23803768 TI - Cancer: An acidic link. PMID- 23803770 TI - Ancient DNA: Towards a million-year-old genome. PMID- 23803769 TI - Biomimetic assembly and activation of [FeFe]-hydrogenases. AB - Hydrogenases are the most active molecular catalysts for hydrogen production and uptake, and could therefore facilitate the development of new types of fuel cell. In [FeFe]-hydrogenases, catalysis takes place at a unique di-iron centre (the [2Fe] subsite), which contains a bridging dithiolate ligand, three CO ligands and two CN(-) ligands. Through a complex multienzymatic biosynthetic process, this [2Fe] subsite is first assembled on a maturation enzyme, HydF, and then delivered to the apo-hydrogenase for activation. Synthetic chemistry has been used to prepare remarkably similar mimics of that subsite, but it has failed to reproduce the natural enzymatic activities thus far. Here we show that three synthetic mimics (containing different bridging dithiolate ligands) can be loaded onto bacterial Thermotoga maritima HydF and then transferred to apo-HydA1, one of the hydrogenases of Chlamydomonas reinhardtii algae. Full activation of HydA1 was achieved only when using the HydF hybrid protein containing the mimic with an azadithiolate bridge, confirming the presence of this ligand in the active site of native [FeFe]-hydrogenases. This is an example of controlled metalloenzyme activation using the combination of a specific protein scaffold and active-site synthetic analogues. This simple methodology provides both new mechanistic and structural insight into hydrogenase maturation and a unique tool for producing recombinant wild-type and variant [FeFe]-hydrogenases, with no requirement for the complete maturation machinery. PMID- 23803771 TI - Multidisciplinary treatment of rectal cancer: the way of the future. PMID- 23803772 TI - Nanocomposite based flexible ultrasensitive resistive gas sensor for chemical reactions studies. AB - Room temperature operation, low detection limit and fast response time are highly desirable for a wide range of gas sensing applications. However, the available gas sensors suffer mainly from high temperature operation or external stimulation for response/recovery. Here, we report an ultrasensitive-flexible-silver nanoparticle based nanocomposite resistive sensor for ammonia detection and established the sensing mechanism. We show that the nanocomposite can detect ammonia as low as 500 parts-per-trillion at room temperature in a minute time. Furthermore, the evolution of ammonia from different chemical reactions has been demonstrated using the nanocomposite sensor as an example. Our results demonstrate the proof-of-concept for the new detector to be used in several applications including homeland security, environmental pollution and leak detection in research laboratories and many others. PMID- 23803773 TI - Older adult opinions about driving cessation: a role for advanced driving directives. AB - OBJECTIVES: To describe older adults' opinions about driving cessation and driver retesting. METHODS: Older adult (>= 65 years) patients visiting the emergency department or geriatric clinic at a university hospital completed a confidential survey regarding attitudes toward driving tests and restrictions. RESULTS: The response rate was 50% (N = 169). The median age was 75 years (range, 65-98); 53% were women. Most reported driving at least occasionally (78%; 95% confidence interval [95% CI], 72-84). Twelve percent (95% CI, 7-18) reported a crash in the prior year; most (84%; 95% CI, 78-90) reported at least 1 medical diagnosis possibly linked to increased crash risk. Most participants (74%; 95% CI, 67-81) supported mandatory, age-based driver retesting but thought family (73%; 95% CI, 68-81) or physicians (60%; 95% CI, 54-69) should determine license revocation for an unsafe driver rather than the Department of Motor Vehicles (34%; 95% CI, 28 42) or the police (30%; 95% CI, 23-37). Almost all reported they would consider driving cessation if recommended by a physician (88%; 95% CI, 82-94) or family member (71%; 95% CI, 63-79), without significant age or sex differences. CONCLUSIONS: Older drivers support mandatory age-based testing but appear more likely to follow recommendations from physicians or family members, thereby supporting a role for physician counseling, driver evaluations, and advanced driving directives. PMID- 23803774 TI - PHQ-9 Response Curve: Rate of Improvement for Depression Treatment With Collaborative Care Management. AB - Major depressive disorder is common in primary care. Depression Improvement Across Minnesota-Offering a New Direction (DIAMOND), using a collaborative care model, was first implemented in March 2008 starting with 5 clinics and expanding to more than 70 clinics statewide by 2010. This was intended to improve depression management and to augment the relationship between the patient, the primary care provider, and the psychiatrist. Prior retrospective studies have demonstrated the clinical effectiveness of our program. This study was designed to examine those patients who were in clinical remission (defined as a Patient Health Questionnaire-9 [PHQ-9] score <5) at 6 months (180 days) after enrollment in collaborative care management. By determining the subsequent PHQ-9 data that were obtained, a PHQ-9 response curve was developed for those patients who did improve. The pilot study demonstrated that there appeared to be rapid response to depression treatment, evident by the first month of treatment and more pronounced in severely depressed patients. Also, it demonstrated that in the patients who did respond, there was no any difference in the remission rates over the study period when evaluated by the initial severity of the depression. PMID- 23803775 TI - Use and Quality of Care at a VA Outreach Clinic in Northern Maine. AB - OBJECTIVE: To assess use and quality of care at a new 1-day-per-week Veterans Administration Outreach Clinic in remote northern Maine. METHODS: Veterans Administration electronic medical records were abstracted to compare outreach clinic patients seen in its first year to patients seen at the nearest outpatient treatment sites, a small-staff, full-time VA clinic 81 miles away and a community based outpatient clinic 55 miles away. Chart abstractions (N = 1251) yielded counts of visits, patients newly enrolled in VA care, patients transferring to the outreach clinic, and patients who had and maintained a local non-VA primary care physician, as well as multiple quality of care performance measures using standard VA criteria. RESULTS: The outreach clinic enrolled very few patients new to VA; 96% of its patients were transfers from other sites. For transfers, the average one-way driving burden to reach primary care was reduced by 52.9 miles and 58.1 minutes to reach. Compared to community-based outpatient clinic patients, outreach clinic patients were more likely to have three or more provider visits during the year. Some quality of care measures were lower at the outreach clinic: obesity screenings, referrals to smoking cessation services, diabetes management, and hypertension control. At all three sites, most patients had health insurance coverage and kept a local, non-VA doctor throughout the year. CONCLUSIONS: A part-time outreach clinic improved the convenience of primary care for rural VA outpatients, though quality of care was reduced for some measures related to equipment and staffing limitations. Most patients at any VA site had a local, non-VA medical doctor with whom they remained in care while using VA services. PMID- 23803776 TI - Colorectal cancer educational intervention targeting latino patients attending a community health center. AB - OBJECTIVE: Colorectal cancer (CRC) is the third leading cause of cancer death for Latino men and women; and Latinos are more likely to be diagnosed at a later stage, which is most likely due to underutilization of CRC preventive screening. The purpose of this study was to determine whether a brief, clinic-based intervention by a community health advisor (CHA) would increase CRC knowledge compared with traditional educational methodologies (eg, use of print materials). METHODS: Latino adults 50 years and older attending a San Diego community health center were recruited while waiting for their primary care provider routine visit and were randomly assigned to receive 1 of 3 CRC educational interventions: community health advisor (CHA) plus CRC educational brochure (CHA intervention group), CRC educational brochure (minimal intervention group), or 5-a-day nutrition brochure (usual care). CRC knowledge was assessed before and after the primary care provider visit for 130 participants. RESULTS: Results demonstrate that the CRC educational brochure (minimal intervention group) was effective at increasing CRC screening knowledge as compared to usual care. CONCLUSIONS: Future research is needed to explore innovative health education strategies that improve knowledge and subsequent CRC screening behaviors among low-income, low-literacy, unacculturated Latinos. PMID- 23803777 TI - Pilot study: health behaviors associated with human papillomavirus vaccine acceptance among adolescents. AB - BACKGROUND: Despite approval of a vaccine found to be very effective in preventing human papillomavirus infection and related cancers, many young people have not yet been vaccinated. Because health behaviors tend to co-occur, the purpose of the current study was to examine relationships among human papillomavirus vaccine uptake and other health behaviors among adolescents. METHODS: Fifty-nine high school students completed a paper-and-pencil pilot survey regarding human papillomavirus vaccine knowledge and attitudes as well as human papillomavirus vaccination and other health behaviors. RESULTS: The authors found that human papillomavirus vaccination was significantly associated with health-promoting behaviors among girls (eg, not smoking, P = .02), whereas vaccination willingness was associated with health risk behaviors among boys (eg, higher sugar diet, P = .03). CONCLUSIONS: Effective interventions to promote human papillomavirus vaccination among adolescents may benefit from a simultaneous focus on multiple health behaviors and/or health in general. Interventions tailored by gender may also be beneficial. PMID- 23803778 TI - Time required for screening for visual impairment in primary care: a randomized comparison of 3 common visual tests. AB - OBJECTIVE: To determine the time required for adults older than 50 years to complete 1 of 3 vision impairment assessment tools in a family medicine residency office. METHODS: Patients older than 50 years with no known cognitive or physical deficits that impaired ability to follow directions or complete screening tasks were invited to participate in this trial. Participants were randomized to complete 1 of 3 screening modalities, namely, the Functional Vision Screening Questionnaire (questionnaire), mixed contrast sensitivity reading card (card), or Snellen eye chart (Snellen). The time required to complete the vision assessment was obtained and recorded. RESULTS: Sixty-nine patients, with a mean age of 63 years (SD, 10), participated in the study. The card required 94 less seconds to administer than did the questionnaire (95% confidence interval, 61.24 to 127.11 seconds). Similarly, the card required 67 less seconds to administer than did the Snellen (95% confidence interval, 34.20 to 100.06 seconds). No significant difference existed between time to administer the questionnaire and the Snellen (mean difference, 27 seconds; 95% confidence interval, -5.89 to 59.97 seconds). CONCLUSIONS: Primary care-based vision screening may detect patients with impairment who would otherwise not have vision assessment. However, a time intensive screen will not likely be successfully implemented in a primary care office. The card required statistically significantly less time to administer than did the questionnaire or Snellen. With all modalities requiring at least 1 minute, perhaps none are suitable for use for universal, primary care-based vision screening programs. Further work is needed to characterize the reliability and ease of use of each tool. PMID- 23803779 TI - The need for office systems to improve colorectal cancer screening. AB - Patients generally access colorectal cancer (CRC) screening through primary care physicians. National guidelines recommend CRC screening for adults beginning at age 50, yet one-third of Americans are not up to date. METHODS: A self administered questionnaire was administered to family physicians from 16 practices in a Midwestern state who attended an information session for a randomized study to improve CRC screening. The questionnaire assessed CRC screening practices, knowledge of CRC screening guidelines, and office strategies for improving screening. RESULTS: Of 131 health care providers, 85 (65%) completed the questionnaire. Two-thirds were aware of the CRC screening guidelines; 91% knew that the follow-up interval for screening depends on the test chosen. Twenty-five percent incorrectly stated that a single-sample in office fecal occult blood test is an acceptable screening test. Only 8% had a written policy regarding CRC screening; 18% had offices that used chart reminders; and 32% had charts organized to easily identify patient screening status. Regarding perceptions, those who agreed that they encourage their office staff to participate in screening estimated that they offer screening to more patients than those who disagreed (82.8% vs 70.2%, P < .0001); in addition, those who agreed with and tried to follow the guidelines estimated that they offer screening to more patients than those who disagreed (77.4% vs 60.5%, P = .004). CONCLUSION: Although physicians were knowledgeable about CRC screening guidelines, 25% mistakenly believed that single-sample in-office fecal testing was appropriate. There was a striking lack of office systems for identifying eligible patients and facilitating CRC screening. PMID- 23803780 TI - American primary care physicians' decisions to leave their practice: evidence from the 2009 commonwealth fund survey of primary care doctors. AB - The status of the primary care workforce is a major health policy concern. It is affected not only by the specialty choices of young physicians but also by decisions of physicians to leave their practices. This study examines factors that may contribute to such decisions. We analyzed data from a 2009 Commonwealth Fund mail survey of American physicians in internal medicine, family or general practice, or pediatrics to examine characteristics associated with their plans to retire or leave their practice for other reasons in the next 5 years. Just over half (53%) of the physicians age 50 years or older and 30% of physicians between age 35 and 49 years may leave their practices for these reasons. Having such plans was associated with many factors, but the strongest predictor concerned problems regarding time spent coordinating care for their patients, possibly reflecting dissatisfaction with tasks that do not require medical expertise and are not generally paid for in fee-for-service medicine. Factors that predict plans to retire differ from those associated with plans to leave practices for other reasons. Provisions of the Patient Protection and Affordable Care Act that reduce the number of uninsured patients as well as innovations such as medical homes and accountable care organizations may reduce pressures that lead to attrition in the primary care workforce. Reasons why primary care physicians' decide to leave their practices deserve more attention from researchers and policy makers. PMID- 23803781 TI - Examining role change in primary care practice. AB - PURPOSE: While experts suggest that primary care needs far-reaching transformation that includes adding or reconfiguring roles to improve patient care, little is known about how role change occurs in practice settings. Methods This was a cross-case comparative analysis of 3 projects designed to improve health behavior counseling in primary care practices by adding to or changing clinical support staff roles. Qualitative data (site visits notes, grantee reports, interviews with grantees, and online diary entries) were analyzed to examine instances of role change in depth, using role change theory as an organizing framework. Results Practice team members had greater success taking on new roles when patients valued the services provided. Often, it was easier to a hire a new person into a new role rather than have an existing practice member shift responsibilities. This was because new personnel had the structural autonomy, credibility, and organizational support needed to develop new responsibilities and routines. CONCLUSION: As primary care delivery systems are redesigned in ways that rely on new roles to deliver care, understanding how to effectively add or change staff roles is essential and requires attention to patients', practice members', and institutions' support for new roles. PMID- 23803782 TI - Fruit and vegetable consumption and body mass index: a quantile regression approach. AB - BACKGROUND: Empirical evidence on the relationship between consumption of fruits and vegetables and body weight is inconclusive. Previous studies mostly use linear regression methods to study the correlates of the conditional mean of body mass index (BMI). This approach may be less informative if the association between fruit and vegetable consumption and BMI significantly varies across the BMI distribution. OBJECTIVE: The association between fruit and vegetable consumption and the BMI is examined using quantile regression. METHODS: A nationally representative sample of 11,818 individuals from the Canadian Community Health Survey (2004) is used. A quantile regression model is estimated to account for the potential heterogeneous association between fruit and vegetable intake and BMI at different points of the conditional BMI distribution. The analyses are stratified by gender. RESULTS: The multivariate analyses reveal that the association between fruit and vegetable intake and BMI is negative and statistically significant for both males and females; however, this association varies across the conditional quantiles of the BMI distribution. In particular, the estimates are larger for individuals at the higher quantiles of the distribution. The ordinary least squares (OLS) model overstates (understates) the association between FV intake and BMI at the lower (higher) half of the conditional BMI distribution. CONCLUSION: Findings of the standard models that assume uniform response across different quantiles of BMI distribution may be misleading. The findings of this paper suggest that increasing the intake of fruits and vegetables may be an effective dietary strategy to control weight and mitigate the risk of obesity. PMID- 23803783 TI - Advancing primary care in france and the United States: parallel opportunities and barriers. AB - Primary care has been identified as key to improving health care delivery systems across the globe. France and the United States have been ranked low on scales of primary care orientation. However, each nation has developed significant approaches to structuring primary care and organizing primary care-focused systems. This article reviews those efforts and finds that both nations face similar barriers to implementing many primary care initiatives. PMID- 23803787 TI - Measurements of the weak UV absorptions of isoprene and acetone at 261-275 nm using cavity ringdown spectroscopy for evaluation of a potential portable ringdown breath analyzer. AB - The weak absorption spectra of isoprene and acetone have been measured in the wavelength range of 261-275 nm using cavity ringdown spectroscopy. The measured absorption cross-sections of isoprene in the wavelength region of 261-266 nm range from 3.65 * 10-21 cm2.molecule-1 at 261 nm to 1.42 * 10-21 cm2.molecule-1 at 266 nm; these numbers are in good agreement with the values reported in the literature. In the longer wavelength range of 270-275 nm, however, where attractive applications using a single wavelength compact diode laser operating at 274 nm is located, isoprene has been reported in the literature to have no absorption (too weak to be detected). Small absorption cross-sections of isoprene in this longer wavelength region are measured using cavity ringdown spectroscopy for the first time in this work, i.e., 6.20 * 10-23 cm2.molecule-1 at 275 nm. With the same experimental system, wavelength-dependent absorption cross-sections of acetone have also been measured. Theoretical detection limits of isoprene and comparisons of absorbance of isoprene, acetone, and healthy breath gas in this wavelength region are also discussed. PMID- 23803788 TI - Rapid detection of viable microorganisms based on a plate count technique using arrayed microelectrodes. AB - Development of a miniaturized biosensor system that can be used for rapid detection and counting of microorganisms in food or water samples is described. The developed microsystem employs a highly sensitive impedimetric array of biosensors to monitor the growth of bacterial colonies that are dispersed across an agar growth medium. To use the system, a sample containing the bacteria is cultured above the agar layer. Using a multiplexing network, the electrical properties of the medium at different locations are continuously measured, recorded, and compared against a baseline signal. Variations of signals from different biosensors are used to reveal the presence of bacteria in the sample, as well as the locations of bacterial colonies across the biochip. This technique forms the basis for a label-free bacterial detection for rapid analysis of food samples, reducing the detection time by at least a factor of four compared to the current required incubation times of 24 to 72 hours for plate count techniques. The developed microsystem has the potential for miniaturization to a stage where it could be deployed for rapid analysis of food samples at commercial scale at laboratories, food processing facilities, and retailers. PMID- 23803789 TI - Improving driver alertness through music selection using a mobile EEG to detect brainwaves. AB - Driving safety has become a global topic of discussion with the recent development of the Smart Car concept. Many of the current car safety monitoring systems are based on image discrimination techniques, such as sensing the vehicle drifting from the main road, or changes in the driver's facial expressions. However, these techniques are either too simplistic or have a low success rate as image processing is easily affected by external factors, such as weather and illumination. We developed a drowsiness detection mechanism based on an electroencephalogram (EEG) reading collected from the driver with an off-the shelf mobile sensor. This sensor employs wireless transmission technology and is suitable for wear by the driver of a vehicle. The following classification techniques were incorporated: Artificial Neural Networks, Support Vector Machine, and k Nearest Neighbor. These classifiers were integrated with integration functions after a genetic algorithm was first used to adjust the weighting for each classifier in the integration function. In addition, since past studies have shown effects of music on a person's state-of-mind, we propose a personalized music recommendation mechanism as a part of our system. Through the in-car stereo system, this music recommendation mechanism can help prevent a driver from becoming drowsy due to monotonous road conditions. Experimental results demonstrate the effectiveness of our proposed drowsiness detection method to determine a driver's state of mind, and the music recommendation system is therefore able to reduce drowsiness. PMID- 23803790 TI - Measurement of cell respiration and oxygenation in standard multichannel biochips using phosphorescent O2-sensitive probes. AB - Measurement of cell oxygenation and oxygen consumption is useful for studies of cell bioenergetics, metabolism, mitochondrial function, drug toxicity and common pathophysiological conditions. Here we present a new platform for such applications which uses commercial multichannel biochips (MU-slides, Ibidi) and phosphorescent O2 sensitive probes. This platform was evaluated with both extracellular and intracellular O2 probes, several different cell types and treatments including mitochondrial uncoupling and inhibition, depletion of extracellular Ca(2+) and inhibition of V-ATPase and histone deacetylases. The results show that compared to the standard microwell plates currently used, the MU-slide platform provides facile O2 measurements with both suspension and adherent cells, higher sensitivity and reproducibility, and faster measurement time. It also allows re-perfusion and multiple treatments of cells and multi parametric analyses in conjunction with other probes. Optical measurements are conducted on standard fluorescence readers and microscopes. PMID- 23803791 TI - One-step solvothermal synthesis of highly water-soluble, negatively charged superparamagnetic Fe3O4 colloidal nanocrystal clusters. AB - Highly charged hydrophilic superparamagnetic Fe3O4 colloidal nanocrystal clusters with an average diameter of 195 nm have been successfully synthesized using a modified one-step solvothermal method. Anionic polyelectrolyte poly(4 styrenesulfonic acid-co-maleic acid) sodium salt containing both sulfonate and carboxylate groups was used as the stabilizer. The clusters synthesized under different experimental conditions were characterized with transmission electron microscopy and dynamic light scattering; it was found that the size distribution and water dispersity were significantly affected by the concentration of the polyelectrolyte stabilizer and iron sources in the reaction mixtures. A possible mechanism involving novel gel-like large molecular networks that confined the nucleation and aggregation process was proposed and discussed. The colloidal nanocrystal clusters remained negatively charged in the experimental pH ranges from 2 to 11, and also showed high colloidal stability in phosphate buffered saline (PBS) and ethanol. These highly colloidal stable superparamagnetic Fe3O4 clusters could find potential applications in bioseparation, targeted drug delivery, and photonics. PMID- 23803792 TI - Tissue factor expressed by microparticles is associated with mortality but not with thrombosis in cancer patients. AB - A prothrombotic state is one of the hallmarks of malignancy and a major contributor to morbidity and mortality in cancer patients.Tissue factor (TF) is often overexpressed in malignancy and is a prime candidate in predicting the hypercoagulable state. Moreover, increased number of TF-exposing microparticles (MPs) in cancer patients may contribute to venous thromboembolism (VTE). We have conducted a prospective cohort study to determine whether elevated TF antigen, TF activity and TF associated to MPs (MPs-TF) are predictive of VTE and mortality in cancer patients. The studied population consisted of 252 cancer patients and 36 healthy controls. TF antigen and activity and MPs-TF were determined by ELISA and chromogenic assays. During a median follow-up of 10 months, 40 thrombotic events were recorded in 34 patients (13.5%), and 73 patients (28.9%) died. TF antigen and activity were significantly higher in patients than in controls (p<0.01) mainly in patients with advanced stages, whereas no differences were observed for TF activity of isolated MPs. We did not find a statistically significant association of TF variables with the risk of VTE. Multivariate analysis adjusting for age, sex, type of cancer and other confounding variables showed that TF activity (p<0.01) and MPs-TF activity (p<0.05) were independently associated with mortality. In conclusion, while TF variables were not associated with future VTE in cancer patients, we found a strong association of TF and MPs-TF activity with mortality, thus suggesting they might be good prognostic markers in cancer patients. PMID- 23803793 TI - Concomitant anal and cervical human papillomavirusV infections and intraepithelial neoplasia in HIV-infected and uninfected women. AB - OBJECTIVE: To assess factors associated with concomitant anal and cervical human papillomavirus (HPV) infections in HIV-infected and at-risk women. DESIGN: A study nested within the Women's Interagency HIV Study (WIHS), a multicenter longitudinal study of HIV-1 infection in women conducted in six centers within the United States. METHODS: Four hundred and seventy HIV-infected and 185 HIV uninfected WIHS participants were interviewed and examined with anal and cervical cytology testing. Exfoliated cervical and anal specimens were assessed for HPV using PCR and type-specific HPV testing. Women with abnormal cytologic results had colposcopy or anoscopy-guided biopsy of visible lesions. Logistic regression analyses were performed and odds ratios (ORs) measured the association for concomitant anal and cervical HPV infection. RESULTS: One hundred and sixty-three (42%) HIV-infected women had detectable anal and cervical HPV infection compared with 12 (8%) of the HIV-uninfected women (P < 0.001). HIV-infected women were more likely to have the same human papillomavirus (HPV) genotype in the anus and cervix than HIV-uninfected women (18 vs. 3%, P < 0.001). This was true for both oncogenic (9 vs. 2%, P = 0.003) and nononcogenic (12 vs. 1%, P < 0.001) HPV types. In multivariable analysis, the strongest factor associated with both oncogenic and nononcogenic concomitant HPV infection was being HIV-infected (OR = 4.6 and OR = 16.9, respectively). In multivariable analysis of HIV-infected women, CD4 cell count of less than 200 was the strongest factor associated with concomitant oncogenic (OR = 4.2) and nononcogenic (OR = 16.5) HPV infection. CONCLUSION: HIV-infected women, particularly those women with low CD4 cell counts, may be good candidates for HPV screening and monitoring for both cervical and anal disease. PMID- 23803795 TI - Home HIV testing: if you build it, will they come? PMID- 23803794 TI - Impact of HIV drug resistance on virologic and immunologic failure and mortality in a cohort of patients on antiretroviral therapy in China. AB - OBJECTIVES: To study the dynamics of HIV drug resistance (HIVDR) and its association with virologic and immunologic failure as well as mortality among patients on combination antiretroviral therapy (cART) in China. DESIGN: We recruited 365 patients on cART in two rural Chinese counties in 2003-2004 and followed them every 6 months until May 2010. METHODS: Virologic failure, HIVDR, immunologic failure and death were documented. We used Kaplan-Meier and the proportional hazards models to identify the timing of the events, and risk factors for mortality. RESULTS: At the end of study, patients had been followed for 1974.3 person-years, a median of 6.1 years. HIVDR mutations were found in 235 (64.4%) patients and 75 died (20.5%, 3.8/100 person-years). Median time from cART to detection of virologic failure was 17.5 months, to HIVDR 36.6 months and to immunologic failure 55.2 months (~ 18-month median interval between each adverse milestone). Being male, having a baseline CD4 cell count of less than 50 cells/MUl and HIVDR were associated with higher mortality. Patients who developed HIVDR in the first year of treatment had higher mortality than those developing HIVDR later (adjusted hazard ratio 1.90, 95% confidence interval 1.01-3.48). CONCLUSION: HIVDR was common and was associated with higher mortality among Chinese patients on cART, particular when HIVDR was detected early in therapy. Our study reinforces the importance of improving patient adherence to cART in order to delay the emergence of HIVDR and obviate the need to switch to costly second-line drug regimens too early. PMID- 23803796 TI - Cytomegalovirus immune reconstitution inflammatory syndrome manifesting as sialadenitis in an HIV-infected patient. PMID- 23803797 TI - A new time limited psychotherapy for BPD: preliminary results of a randomized and controlled trial. AB - INTRODUCTION: Psychic Representation focused Psychotherapy (PRFP) is a new time limited dynamic psychotherapy for the treatment of Borderline Personality Disorder. It is a psychodynamic technique based on brief psychoanalytic psychotherapy principles. It is manualized and designed to be applied in the framework of public health care services. A randomized and controlled study with a sample of 53 patients was conducted to assess PRFP efficacy. This work presents the results for the first 44 trial completers at termination of treatment. METHODS: Both groups, the experimental (n= 18) and control group (n= 26), received treatment as usual. The experimental group received an additional 20 (PRFP) sessions, conducted by four therapists with homogenous characteristics specifically trained in this technique. The main outcome variables measures were: Severity global index of SCL-90-R, Barrat Impulsivity Scale scores and Social Adaptation (SASS score). Baseline and final condition at termination was compared. CONCLUSIONS: Preliminary results showed significantly better outcomes for the experimental group in all the main variables measured and in most of the secondary ones. PRFP may represent an important contribution for the treatment of BPD patients. Follow-up assessment at 6 and 12 months is planned. PMID- 23803798 TI - Chronotype as modulator of morning serum melatonin levels. AB - BACKGROUND: The search for biological markers of individual characteristics has produced scanty results. Melatonin (MLT), the main hormonal product of the pineal gland, has been used as a biological marker of neuroticism, introversion extroversion and morningness-eveningness. Morningness-eveningness indicates preferences associated with morning or evening activities. The goal of this research is to study if serum MLT levels are related to morningness-eveningness preference. METHODS: Twenty-three morning type and twenty-one evening type healthy volunteers took part in the study. Morningness-eveningness was evaluated with the Composite Scale of Morningness. Blood was drawn at 09:00, 12:00 and 00:00 h. MLT levels were measured with an ELISA. RESULTS: At 09:00 h evening type subjects had significantly higher serum MLT levels than morning type subjects (8.4+/-3.6 pg./ml. vs. 4.6+/-3.2 pg./ml., p<0.02). CONCLUSIONS: Morning serum MLT may be used as a biological peripheral marker of morningness-eveningness preference. Our results emphasise the convenience of expanding MLT studies until 09:00 h when differences between morning type and evening type subjects may still be found. PMID- 23803799 TI - Gene expression profiles of nucleus accumbens, prefrontal cortex and hippocampus in an animal model of schizophrenia: proposed candidate genes. AB - INTRODUCTION: It has been suggested that schizophrenia may be induced by "accidents" or injuries that occur during early brain development and result in a reduction of the neural connections in different regions. In this study, we evaluated differences in the expression of brain genes using a recognized experimental prototype of schizophrenia: the animal model of ventral hippocampal lesion in neonate rats (VHLN) compared to control animals. METHODS: Using microarray technology, we obtained gene expression profiles of three brain areas (nucleus accumbens, prefrontal cortex and hippocampus) of juvenile (45 days) and adult (90 days) Wistar male rats that underwent either VHLN or sham VHLN. RESULTS: Based on three criteria: 1) expression in more than one brain area, 2) participation in cellular pathways relevant to the central nervous system (CNS), 3) Z-score values >2 (overexpression) and <-2 (underexpression), we found overexpression of the ppp3cb, dctn1, jag1, ide, limk2 and cpz genes and underexpression of chrna4 and sod1. CONCLUSIONS: Two of the genes proposed in this paper, limk2 and cpz, have not been previously associated with schizophrenia, so future studies will be necessary to understand their possible role in the pathogenesis of this disease. PMID- 23803800 TI - A comparative cost-analysis of initiating pregabalin or SSRI/SNRI therapy in benzodiazepine-resistant patients with generalized anxiety disorder in Spain. AB - OBJECTIVE: To compare the relative healthcare costs, from the perspective of the Spanish National Healthcare System (NHS), of initiating treatment with either pregabalin, or SSRI/SNRI, as add-on therapies, in patients with generalized anxiety disorder (GAD), who are resistant to benzodiazepine-based therapy (BR). METHODS: BR out-patients with GAD (DSM-IV) who were included in a 6-month, prospective, multicentre, observational cohort study were selected for this post hoc economic analysis. BR was defined as insufficient response, with persistence of symptoms of anxiety (HAM-Anxiety scale>=16), after a 6-month course of benzodiazepines. Patients had not been previously exposed to pregabalin or SSRI/SNRI. Healthcare resource utilization (drugs, medical visits, hospitalizations, etc.) associated with GAD was collected at baseline and end-of trial visits. Related costs were estimated at each visit and adjusted changes were compared using ANCOVA. RESULTS: A total of 128 patients with refractory GAD were treated with pregabalin and 126 SSRI/SNRI. Compared with SSRI/SNRI, pregabalin was associated with significantly lower percentage of benzodiazepines users; 57.0% vs 87.3%, p<0.001, and greater reduction in medical visits; -15.1 vs -13.0, p=0.029. Mean total healthcare resource utilization costs decreased significantly in the pregabalin cohort only; -289 (p=0.003), although six months costs were not significantly different in both groups; 977 vs 822, respectively. CONCLUSION: Initiating treatment with pregabalin was associated with significant reduction in medical visits and total health care resource costs of GAD compared to SSRI/ SNRI in BR patients in the Spanish NHS setting. Compared with SSRI/SNRI, pregabalin therapy was accompanied by significantly less percentage of patients on concomitant benzodiazepines therapy. PMID- 23803801 TI - Measuring the impact factor of individual researchers in biomedical disciplines. AB - The authors propose an algorithm for calculating the cumulative personal impact factor of the publications of any researcher whose research activity involves reporting findings in scientific journals or books in the researcher’s field of specialization. This algorithm takes into account the number of times that each published article or book is cited, self-citations, the position of the researcher’s name in the authorship list of each article or book chapter, and the density of this cumulative impact in relation to the researcher’s total production. In addition, it takes into account the type of article or book assessed (review or original research paper), and the length of time since the researcher’s last publication. This algorithm could be useful for the evaluation of the investigational quality of the subjects, in personnel selection processes in which the candidate’s research performance comparisons of the personal scientific influence of various subjects and different research centers. PMID- 23803802 TI - Attention Deficit Hyperactivity Disorder (ADHD) in the adult patients: view of the clinician. AB - INTRODUCTION: ADHD is a clinical entity that persists during adolescence and even into adulthood in many cases. Assuming that most adults with ADHD will not have been diagnosed in childhood, the GEDA-A group (Adult ADHD study group) considered that it was important to assess how much knowledge the clinicians had about ADHD in order to provide for the identification of the disorder in the adult. METHODOLOGY: A cross-sectional survey to be fill out by specialists involved in the diagnosis and treatment of ADHD was designed. This survey included questions on awareness of the disease in the different stages of life (childhood, adolescence and adulthood). RESULTS: 484 clinicians, with a mean age of 45 years (95% CI 44-46) and 17 years of professional experience (95% CI 16-18) filled out the survey. 384 were psychiatrists (79.5%), 67 neurologists (13.9%) and 19 addictive behavior specialists (3.9%). When their opinions were compared about the diagnosis and treatment of ADHD in childhood, adolescence and adulthood, significant differences of opinion were found regarding the three stages in all the dimensions analyzed (p<0.0001). Assessment in adulthood systematically showed a lower degree of awareness compared to ADHD in childhood and adolescence. CONCLUSIONS: In the clinician's opinion, ADHD in adulthood is a clinical entity that is less defined and whose diagnosis is not as clear, compared to ADHD in the other stages in life. The GEDA-A group suggests that it is necessary to have more comprehensive training that makes the diagnosis and treatment of ADHD in adults easier. PMID- 23803803 TI - Pharmacological treatments for obsessive-compulsive disorder in children and adolescents: a qualitative review. AB - We present the results of a systematic review on the effectiveness of pharmacological treatments for children and adolescents with obsessive-compulsive disorder. Sixty-four studies fulfilled the selection criteria, being the most of them focused in SSRI and Clomipramine. The trials on augmentation strategies and third line monotherapies are scarce, being the majority open-trials and case series. Similarly, studies on combined treatment (psychological and pharmacological) are few; furthermore this is a relevant future research line. It is also remarkable the lack of quasi-experimental and experimental comparison studies and the long-term follow-up measures. PMID- 23803804 TI - Electroconvusive therapy in dementia. AB - The use of electroconvulsive therapy (ECT) in the clinical practice in patients with dementia syndromes continues to cause controversy. In this case, the clinical difficulty existing when making a differential diagnosis between depressive episodes and incipient dementia picture is presented. The interrelation between these two pictures and the possible common etiological origin are also evaluated. Electroconvulsive therapy is effective and safe in functional improvement in affective and dementia disorders in elderly patients. PMID- 23803805 TI - Lack of cannabis consumption registry. PMID- 23803806 TI - Granular cell tumor of the vulva: retraction. PMID- 23803807 TI - Europe should rethink its stance on GM crops. PMID- 23803818 TI - Gas drilling taints groundwater. PMID- 23803819 TI - Sulphur back in vogue for batteries. PMID- 23803820 TI - Bid to cure HIV ramps up. PMID- 23803821 TI - Father's genetic quest pays off. PMID- 23803822 TI - Proof mooted for quantum uncertainty. PMID- 23803823 TI - Floating tubes test sea-life sensitivity. PMID- 23803825 TI - Medical research: cell division. PMID- 23803826 TI - Chronobiology: the human sleep project. PMID- 23803831 TI - Q&A: sound chaser. Interview by Jascha Hoffman. PMID- 23803827 TI - Marine science: get ready for ocean acidification. PMID- 23803832 TI - Brazil: nuclear plans add to pressure on Caatinga. PMID- 23803833 TI - Goal-line technology: American football is clear on uncertainty. PMID- 23803834 TI - Tuberculosis: society should decide on UK badger cull. PMID- 23803835 TI - Conservation: relaxed laws imperil Australian wildlife. PMID- 23803836 TI - Global networks: InterAcademy Panel to inform policy. PMID- 23803837 TI - Joe Farman (1930-2013). PMID- 23803838 TI - Applied physics: cloaking of heat. PMID- 23803839 TI - Electronics: the road to carbon nanotube transistors. PMID- 23803840 TI - Cell signalling: nutrient sensing lost in cancer. PMID- 23803842 TI - Animal behaviour: brain food. PMID- 23803843 TI - Epidemiology: resistance mapping in malaria. PMID- 23803844 TI - Photonics: an ultra-small silicon laser. PMID- 23803845 TI - Multi-periodic pulsations of a stripped red-giant star in an eclipsing binary system. AB - Low-mass white-dwarf stars are the remnants of disrupted red-giant stars in binary millisecond pulsars and other exotic binary star systems. Some low-mass white dwarfs cool rapidly, whereas others stay bright for millions of years because of stable fusion in thick surface hydrogen layers. This dichotomy is not well understood, so the potential use of low-mass white dwarfs as independent clocks with which to test the spin-down ages of pulsars or as probes of the extreme environments in which low-mass white dwarfs form cannot fully be exploited. Here we report precise mass and radius measurements for the precursor to a low-mass white dwarf. We find that only models in which this disrupted red giant star has a thick hydrogen envelope can match the strong constraints provided by our data. Very cool low-mass white dwarfs must therefore have lost their thick hydrogen envelopes by irradiation from pulsar companions or by episodes of unstable hydrogen fusion (shell flashes). We also find that this low mass white-dwarf precursor is a type of pulsating star not hitherto seen. The observed pulsation frequencies are sensitive to internal processes that determine whether this star will undergo shell flashes. PMID- 23803846 TI - A micrometre-scale Raman silicon laser with a microwatt threshold. AB - The application of novel technologies to silicon electronics has been intensively studied with a view to overcoming the physical limitations of Moore's law, that is, the observation that the number of components on integrated chips tends to double every two years. For example, silicon devices have enormous potential for photonic integrated circuits on chips compatible with complementary metal-oxide semiconductor devices, with various key elements having been demonstrated in the past decade. In particular, a focus on the exploitation of the Raman effect has added active optical functionality to pure silicon, culminating in the realization of a continuous-wave all-silicon laser. This achievement is an important step towards silicon photonics, but the desired miniaturization to micrometre dimensions and the reduction of the threshold for laser action to microwatt powers have yet to be achieved: such lasers remain limited to centimetre-sized cavities with thresholds higher than 20 milliwatts, even with the assistance of reverse-biased p-i-n diodes. Here we demonstrate a continuous wave Raman silicon laser using a photonic-crystal, high-quality-factor nanocavity without any p-i-n diodes, yielding a device with a cavity size of less than 10 micrometres and an unprecedentedly low lasing threshold of 1 microwatt. Our nanocavity design exploits the principle that the strength of light-matter interactions is proportional to the ratio of quality factor to the cavity volume and allows drastic enhancement of the Raman gain beyond that predicted theoretically. Such a device may make it possible to construct practical silicon lasers and amplifiers for large-scale integration in photonic circuits. PMID- 23803847 TI - Lifespan of mountain ranges scaled by feedbacks between landsliding and erosion by rivers. AB - An important challenge in geomorphology is the reconciliation of the high fluvial incision rates observed in tectonically active mountain ranges with the long-term preservation of significant mountain-range relief in ancient, tectonically inactive orogenic belts. River bedrock erosion and sediment transport are widely recognized to be the principal controls on the lifespan of mountain ranges. But the factors controlling the rate of erosion and the reasons why they seem to vary significantly as a function of tectonic activity remain controversial. Here we use computational simulations to show that the key to understanding variations in the rate of erosion between tectonically active and inactive mountain ranges may relate to a bidirectional coupling between bedrock river incision and landslides. Whereas fluvial incision steepens surrounding hillslopes and increases landslide frequency, landsliding affects fluvial erosion rates in two fundamentally distinct ways. On the one hand, large landslides overwhelm the river transport capacity and cause upstream build up of sediment that protects the river bed from further erosion. On the other hand, in delivering abrasive agents to the streams, landslides help accelerate fluvial erosion. Our models illustrate how this coupling has fundamentally different implications for rates of fluvial incision in active and inactive mountain ranges. The coupling therefore provides a plausible physical explanation for the preservation of significant mountain-range relief in old orogenic belts, up to several hundred million years after tectonic activity has effectively ceased. PMID- 23803848 TI - Stability of active mantle upwelling revealed by net characteristics of plate tectonics. AB - Viscous convection within the mantle is linked to tectonic plate motions and deforms Earth's surface across wide areas. Such close links between surface geology and deep mantle dynamics presumably operated throughout Earth's history, but are difficult to investigate for past times because the history of mantle flow is poorly known. Here we show that the time dependence of global-scale mantle flow can be deduced from the net behaviour of surface plate motions. In particular, we tracked the geographic locations of net convergence and divergence for harmonic degrees 1 and 2 by computing the dipole and quadrupole moments of plate motions from tectonic reconstructions extended back to the early Mesozoic era. For present-day plate motions, we find dipole convergence in eastern Asia and quadrupole divergence in both central Africa and the central Pacific. These orientations are nearly identical to the dipole and quadrupole orientations of underlying mantle flow, which indicates that these 'net characteristics' of plate motions reveal deeper flow patterns. The positions of quadrupole divergence have not moved significantly during the past 250 million years, which suggests long term stability of mantle upwelling beneath Africa and the Pacific Ocean. These upwelling locations are positioned above two compositionally and seismologically distinct regions of the lowermost mantle, which may organize global mantle flow as they remain stationary over geologic time. PMID- 23803849 TI - Elastic energy storage in the shoulder and the evolution of high-speed throwing in Homo. AB - Some primates, including chimpanzees, throw objects occasionally, but only humans regularly throw projectiles with high speed and accuracy. Darwin noted that the unique throwing abilities of humans, which were made possible when bipedalism emancipated the arms, enabled foragers to hunt effectively using projectiles. However, there has been little consideration of the evolution of throwing in the years since Darwin made his observations, in part because of a lack of evidence of when, how and why hominins evolved the ability to generate high-speed throws. Here we use experimental studies of humans throwing projectiles to show that our throwing capabilities largely result from several derived anatomical features that enable elastic energy storage and release at the shoulder. These features first appear together approximately 2 million years ago in the species Homo erectus. Taking into consideration archaeological evidence suggesting that hunting activity intensified around this time, we conclude that selection for throwing as a means to hunt probably had an important role in the evolution of the genus Homo. PMID- 23803851 TI - Diatom flickering prior to regime shift. PMID- 23803852 TI - Wang et al. reply. PMID- 23803854 TI - Global patterns of terrestrial vertebrate diversity and conservation. AB - Identifying priority areas for biodiversity is essential for directing conservation resources. Fundamentally, we must know where individual species live, which ones are vulnerable, where human actions threaten them, and their levels of protection. As conservation knowledge and threats change, we must reevaluate priorities. We mapped priority areas for vertebrates using newly updated data on >21,000 species of mammals, amphibians, and birds. For each taxon, we identified centers of richness for all species, small-ranged species, and threatened species listed with the International Union for the Conservation of Nature. Importantly, all analyses were at a spatial grain of 10 * 10 km, 100 times finer than previous assessments. This fine scale is a significant methodological improvement, because it brings mapping to scales comparable with regional decisions on where to place protected areas. We also mapped recent species discoveries, because they suggest where as-yet-unknown species might be living. To assess the protection of the priority areas, we calculated the percentage of priority areas within protected areas using the latest data from the World Database of Protected Areas, providing a snapshot of how well the planet's protected area system encompasses vertebrate biodiversity. Although the priority areas do have more protection than the global average, the level of protection still is insufficient given the importance of these areas for preventing vertebrate extinctions. We also found substantial differences between our identified vertebrate priorities and the leading map of global conservation priorities, the biodiversity hotspots. Our findings suggest a need to reassess the global allocation of conservation resources to reflect today's improved knowledge of biodiversity and conservation. PMID- 23803853 TI - Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers. AB - Myc is one of the most commonly deregulated oncogenes in human cancer, yet therapies directly targeting Myc hyperactivation are not presently available in the clinic. The evolutionarily conserved function of Myc in modulating protein synthesis control is critical to the Myc oncogenic program. Indeed, enhancing the protein synthesis capacity of cancer cells directly contributes to their survival, proliferation, and genome instability. Therefore, inhibiting enhanced protein synthesis may represent a highly relevant strategy for the treatment of Myc-dependent human cancers. However, components of the translation machinery that can be exploited as therapeutic targets for Myc-driven cancers remain poorly defined. Here, we uncover a surprising and important functional link between Myc and mammalian target of rapamycin (mTOR)-dependent phosphorylation of eukaryotic translation initiation factor 4E binding protein-1 (4EBP1), a master regulator of protein synthesis control. Using a pharmacogenetic approach, we find that mTOR dependent phosphorylation of 4EBP1 is required for cancer cell survival in Myc dependent tumor initiation and maintenance. We further show that a clinical mTOR active site inhibitor, which is capable of blocking mTOR-dependent 4EBP1 phosphorylation, has remarkable therapeutic efficacy in Myc-driven hematological cancers. Additionally, we demonstrate the clinical implications of these results by delineating a significant link between Myc and mTOR-dependent phosphorylation of 4EBP1 and therapeutic response in human lymphomas. Together, these findings reveal that an important mTOR substrate is found hyperactivated downstream of Myc oncogenic activity to promote tumor survival and confers synthetic lethality, thereby revealing a unique therapeutic approach to render Myc druggable in the clinic. PMID- 23803855 TI - Olfactory searches with limited space perception. AB - Various insects and small animals can navigate in turbulent streams to find their mates (or food) from sparse pheromone (odor) detections. Their access to internal space perception and use of cognitive maps still are heavily debated, but for some of them, limited space perception seems to be the rule. However, this poor space perception does not prevent them from impressive search capacities. Here, as an attempt to model these behaviors, we propose a scheme that can perform, even without a detailed internal space map, searches in turbulent streams. The algorithm is based on a standardized projection of the probability of the source position to remove space perception and on the evaluation of a free energy, whose minimization along the path gives direction to the searcher. An internal "temperature" allows active control of the exploration/exploitation balance during the search. We demonstrate the efficiency of the scheme numerically, with a computational model of odor plume propagation, and experimentally, with robotic searches of thermal sources in turbulent streams. In addition to being a model to describe animals' searches, this scheme may be applied to robotic searches in complex varying media without odometry error corrections and in problems in which active control of the exploration/exploitation balance is profitable. PMID- 23803856 TI - Catalysis of Na+ permeation in the bacterial sodium channel Na(V)Ab. AB - Determination of a high-resolution 3D structure of voltage-gated sodium channel Na(V)Ab opens the way to elucidating the mechanism of ion conductance and selectivity. To examine permeation of Na(+) through the selectivity filter of the channel, we performed large-scale molecular dynamics simulations of Na(V)Ab in an explicit, hydrated lipid bilayer at 0 mV in 150 mM NaCl, for a total simulation time of 21.6 MUs. Although the cytoplasmic end of the pore is closed, reversible influx and efflux of Na(+) through the selectivity filter occurred spontaneously during simulations, leading to equilibrium movement of Na(+) between the extracellular medium and the central cavity of the channel. Analysis of Na(+) dynamics reveals a knock-on mechanism of ion permeation characterized by alternating occupancy of the channel by 2 and 3 Na(+) ions, with a computed rate of translocation of (6 +/- 1) * 10(6) ions?s(-1) that is consistent with expectations from electrophysiological studies. The binding of Na(+) is intimately coupled to conformational isomerization of the four E177 side chains lining the extracellular end of the selectivity filter. The reciprocal coordination of variable numbers of Na(+) ions and carboxylate groups leads to their condensation into ionic clusters of variable charge and spatial arrangement. Structural fluctuations of these ionic clusters result in a myriad of ion binding modes and foster a highly degenerate, liquid-like energy landscape propitious to Na(+) diffusion. By stabilizing multiple ionic occupancy states while helping Na(+) ions diffuse within the selectivity filter, the conformational flexibility of E177 side chains underpins the knock-on mechanism of Na(+) permeation. PMID- 23803857 TI - Structure of NKp65 bound to its keratinocyte ligand reveals basis for genetically linked recognition in natural killer gene complex. AB - The natural killer (NK) gene complex (NKC) encodes numerous C-type lectin-like receptors that govern the activity of NK cells. Although some of these receptors (Ly49s, NKG2D, CD94/NKG2A) recognize MHC or MHC-like molecules, others (Nkrp1, NKRP1A, NKp80, NKp65) instead bind C-type lectin-like ligands to which they are genetically linked in the NKC. To understand the basis for this recognition, we determined the structure of human NKp65, an activating receptor implicated in the immunosurveillance of skin, bound to its NKC-encoded ligand keratinocyte associated C-type lectin (KACL). Whereas KACL forms a homodimer resembling other C-type lectin-like dimers, NKp65 is monomeric. The binding mode in the NKp65-KACL complex, in which a monomeric receptor engages a dimeric ligand, is completely distinct from those used by Ly49s, NKG2D, or CD94/NKG2A. The structure explains the exceptionally high affinity of the NKp65-KACL interaction compared with other cell-cell interaction pairs (KD = 6.7 * 10(-10) M), which may compensate for the monomeric nature of NKp65 to achieve cell activation. This previously unreported structure of an NKC-encoded receptor-ligand complex, coupled with mutational analysis of the interface, establishes a docking template that is directly applicable to other genetically linked pairs in the NKC, including Nkrp1-Clr, NKRP1A-LLT1, and NKp80-AICL. PMID- 23803858 TI - Comparative transcriptomics reveals patterns of selection in domesticated and wild tomato. AB - Although applied over extremely short timescales, artificial selection has dramatically altered the form, physiology, and life history of cultivated plants. We have used RNAseq to define both gene sequence and expression divergence between cultivated tomato and five related wild species. Based on sequence differences, we detect footprints of positive selection in over 50 genes. We also document thousands of shifts in gene-expression level, many of which resulted from changes in selection pressure. These rapidly evolving genes are commonly associated with environmental response and stress tolerance. The importance of environmental inputs during evolution of gene expression is further highlighted by large-scale alteration of the light response coexpression network between wild and cultivated accessions. Human manipulation of the genome has heavily impacted the tomato transcriptome through directed admixture and by indirectly favoring nonsynonymous over synonymous substitutions. Taken together, our results shed light on the pervasive effects artificial and natural selection have had on the transcriptomes of tomato and its wild relatives. PMID- 23803859 TI - Dissecting genealogy and cell cycle as sources of cell-to-cell variability in MAPK signaling using high-throughput lineage tracking. AB - Cells, even those having identical genotype, exhibit variability in their response to external stimuli. This variability arises from differences in the abundance, localization, and state of cellular components. Such nongenetic differences are likely heritable between successive generations and can also be influenced by processes such as cell cycle, age, or interplay between different pathways. To address the contribution of nongenetic heritability and cell cycle in cell-to-cell variability we developed a high-throughput and fully automated microfluidic platform that allows for concurrent measurement of gene expression, cell-cycle periods, age, and lineage information under a large number of temporally changing medium conditions and using multiple strains. We apply this technology to examine the role of nongenetic inheritance in cell heterogeneity of yeast pheromone signaling. Our data demonstrate that the capacity to respond to pheromone is passed across generations and that the strength of the response correlations between related cells is affected by perturbations in the signaling pathway. We observe that a ste50Delta mutant strain exhibits highly heterogeneous response to pheromone originating from a unique asymmetry between mother and daughter response. On the other hand, fus3Delta cells were found to exhibit an unusually high correlation between mother and daughter cells that arose from a combination of extended cell-cycle periods of fus3Delta mothers, and decreased cell-cycle modulation of the pheromone pathway. Our results contribute to the understanding of the origins of cell heterogeneity and demonstrate the importance of automated platforms that generate single-cell data on several parameters. PMID- 23803860 TI - Systemic review and meta-analysis of randomized clinical trials comparing primary vs delayed primary skin closure in contaminated and dirty abdominal incisions. AB - IMPORTANCE: Surgical site infection remains a major challenge in surgery. Delayed primary closure of dirty wounds is widely practiced in war surgery; we present a meta-analysis of evidence to help guide application of the technique in wider context. OBJECTIVE: To determine using meta-analysis whether delayed primary skin closure (DPC) of contaminated and dirty abdominal incisions reduces the rate of surgical site infection (SSI) compared with primary skin closure (PC). DATA SOURCES: A systematic review of the literature published after 1990 was conducted of the Medline, PubMed, Current Controlled Trials, and Cochrane databases. The last search was performed on October 6, 2012. No language restrictions were applied. STUDY SELECTION: Randomized clinical trials comparing PC vs DPC were included. DATA EXTRACTION AND SYNTHESIS: Two of us independently selected studies based on quality assessment using the Cochrane Collaboration tool for assessing risk of bias in randomized trials. Data were pooled using fixed- and random effects models. MAIN OUTCOME AND MEASURE: Rate of SSI, as defined by the individual study. RESULTS: The final analysis included 8 studies randomizing 623 patients with contaminated or dirty abdominal wounds to either DPC or PC. The most common diagnosis was appendicitis (77.4%), followed by perforated abdominal viscus (11.5%), ileostomy closure (6.5%), trauma (2.7%), and intra-abdominal abscess/other peritonitis (1.9%). The time to first review for DPC was provided at between 2 and 5 days postoperatively. All studies were found to be at high risk of bias, with marked deficiencies in study design and outcome assessment. When SSI was assessed across all studies using a fixed-effect model, DPC significantly reduced the chance of SSI (odds ratio, 0.65; 95% CI, 0.40-0.93; P = .02). However, heterogeneity was high (72%), and using a random-effects model, the effect was no longer significant (odds ratio, 0.65; 95% CI, 0.25-1.64; P = .36). CONCLUSIONS AND RELEVANCE: Delayed primary skin closure may reduce the rate of SSI, but current trials fail to provide definitive evidence because of poor design. Well-designed, large-numbered randomized clinical trials are warranted. PMID- 23803861 TI - Ultrathin and lightweight microwave absorbers made of mu-near-zero metamaterials. AB - We present a theory of perfect absorption in a bilayer model composed of a mu near-zero (MNZ) metamaterial (MM) absorbing layer on a metallic substrate. Our analytical solutions reveal that a MM layer with a large purely imaginary permeability and a moderate permittivity backed by a metallic plane has a zero reflection at normal incidence when the thickness is ultrathin. The impedance mismatched metamaterial absorber (MA) can be 77.3% thinner than conventional impedance-matched MAs with the same material loss in order to get the same absorption. A microwave absorber using double-layered spiral MMs with a thickness of only about one percent of the operating wavelength is designed and realized. An absorption efficiency above 93% at 1.74 GHz is demonstrated experimentally at illumination angles up to 60 degrees. Our absorber is 98% lighter than traditional microwave absorbers made of natural materials working at the same frequencies. PMID- 23803862 TI - Multiple myeloma. PMID- 23803863 TI - Burnout syndrome in medical professionals: a manifestation of chronic stress with counterintuitive passive characteristics. AB - By operational criteria, burnout appears to be a multifaceted behavioral syndrome consisting of maladaptive individual responses subsequent to prolonged stressful situations. Given the intense physical and cognitive demands of providing high quality healthcare to a wide spectrum of patients, healthcare professionals are particularly susceptible to developing burnout syndrome, a notable phenomenon that has gleaned significant societal attention in recent years. Clearly, widespread manifestation of burnout by health care professionals represents a serious potential threat to the overall quality of patient care and to the realization of positive outcomes to multiple treatment strategies. It will most certainly engender a serious negative impact on the economic viability of the entire healthcare system. Presently, our brief review focuses on current research efforts to 1) provide precise behavioral and psychiatric diagnostic criteria for burnout syndrome in healthcare professionals, 2) identify potential etiological factors and ongoing stressors, and 3) outline an integrative approach for treatment and prevention. PMID- 23803864 TI - Deep endometriosis of the colon. AB - The article presents a case of deep intestinal endometriosis in a 27-year-old woman who complained of dysmenorrhea and infertility. The diagnostic process included ultrasonography as well as colonoscopy, barium enema and CT imaging. Because of the presence of two distant changes which involved nearly the full thickness of the rectal wall and the major part of its circumference, the decision to perform an anterior rectal resection with a simultaneous retroperitoneal colorectostomy was made. The Knight technique was implemented. The surgery involved the anterior rectal resection, the transverse rectal stump closure by use of a stapling device (TA50), and the creation of colorectal circular anastomosis with the CEEA 31 stapler. PMID- 23803865 TI - Effects of melatonin on superovulation and transgenic embryo transplantation in small-tailed han sheep (Ovis aries). AB - OBJECTIVE: In this study, the effects of melatonin on superovulation and the transfer of transgenic embryos were investigated in Small-Tailed Han sheep. DESIGN: Different doses of melatonin (0, 40 or 80 mg/animal) were subcutaneously implanted into both multiparous (4-5 years old) donors and recipients before superovulation and estrus synchronization. The one-year-old young ewes without melatonin treatment served to evaluate the reproductive efficiency of the adult multiparous ewes. Ewes with superovulation were used as embryo donors. The estrus were induced in embryo recipients after embryo transpimplanted. RESULTS: The results showed that the number of corpora lutea of the ewes received subcutaneous 40 or 80 mg melatonin implant (13.4+/-1.05/ewe, 15.1+/-1.62/ewe) were significantly higher than that of in control group (8.8+/-0.37/ewe) (p<0.05). Similarily the number of recovered embryos from the ewes received subcutaneous 40 or 80 mg melatonin implant (10.3+/-0.84/ewe, 10.9+/-1.21/ewe) was significantly higher than the control group (6.2+/-0.60/ewe) (p<0.05). The transimplantd embryos from 40 or 80 mg melatonin treated donors dramatically improved the pregnancy and birth rates compared to control ewes. In addition, both 40 mg and 80 mg melatonin implatation lead to more lambs born per embryo. CONCLUSIONS: These observations provide valuable information for the application of melatonin in increasing superovulation and transgenic embryo transplantation efficiency in sheep. PMID- 23803866 TI - Electrical chronic vagus nerve stimulation activates the hypothalamic-pituitary adrenal axis in rats fed high-fat diet. AB - OBJECTIVES: The brain and the gut communicate bi-directionally through the brain gut axis. The key role in such interactions plays autonomic nervous system and its major component, the vagus nerve. There is growing evidence that vagus nerve stimulation (VNS) has a suppressive effect on both short- and long-term feeding in animal models. In the present study, we investigated the effect of VNS on the hypothalamic pituitary adrenal axis, feeding behavior and appetite in rats fed a high-fat diet. METHODS: Adult male Wistar rats were implanted with a microstimulator (MS) and fed a high-fat diet throughout the study (42 days). The left vagus nerve was stimulated subdiaphragmatically by electrical pulses (10 ms, 200 mV, 1 Hz or 10 Hz respectively, 12 h a day) generated by the MS. Daily food intake and body weight were measured. At the end of the experiment, animals were euthanized and serum corticosterone levels were assessed by immunoassays. Adipose tissue content was evaluated by measuring epididymal fat pads' weight. To determine whether VNS activated food-related areas of the brain, neuronal c-Fos induction in the nucleus of the solitary tract (NTS) was assessed. RESULTS: Chronic VNS decreased food intake, body weight gain and epididymal fat pad weight in stimulated animals compared to control animals. Serum corticosterone concentrations were significantly elevated following VNS, and neuronal responses in the NTS were observed. CONCLUSIONS: The study demonstrates that chronic electrical VNS exerts anorexigenic effects on food intake and body weight gain, and the hypothalamic pituitary adrenal axis activation may contribute to these effects. PMID- 23803867 TI - Fasting insulin serum levels and psychopathology profiles in male schizophrenic inpatients treated with olanzapine or risperidone. AB - OBJECTIVE: Recent studies have suggested that higher insulin levels are associated with better psychopathology profiles in cross-sectional samples of patients with schizophrenia. This study examines whether drug-induced fasting insulin changes between third and eight week of treatment are related to clinical improvement in non-diabetic patients receiving the atypical neuroleptics: risperidone or olanzapine. METHODS: non-diabetic men with a diagnosis of schizophrenia according to the DSM-IV diagnostic classification were recruited from psychiatric inpatient units. Following a drug-free period, neuroleptic treatment was initiated (risperidone n=36, olanzapine n=35) and doses were adjusted to achieve maximal clinical efficacy. All patients were hospitalized throughout the study. Initial and final evaluations of serum insulin levels and psychopathology (assessed with the Positive and Negative Syndrome Scale, PANSS), were carried out at weeks 3 and 8 after the onset of treatment, respectively. RESULTS: There were no differences between and within the risperidone and olanzapine groups in changes of serum insulin level between the third and eighth week of treatment. In the olanzapine group, Pearson correlation analysis revealed a significant negative correlation between changes in fasting serum insulin levels and the PANSS-Total, Positive and General Psychopathology subscale scores. Only improvement in the PANSS-Negative Symptom subscale score was not correlated with insulin level change between the third and eighth week of treatment. In the risperidone group, correlations between PANSS subscales scores and the corresponding serum insulin levels change were positive, albeit statistically non significant. In both groups the improvement in PANSS-Total scores was not correlated with changes in BMI. CONCLUSION: Olanzapine-related changes in endogenous fasting insulin levels were correlated with clinical improvement in acutely ill non-diabetic schizophrenic patients. Because the interesting linkage between insulin and positive and negative symptoms could be an epiphenomenon, randomized studies are needed to further explore the role of insulin in therapeutic responses in patients with schizophrenia. PMID- 23803868 TI - Impressive shrinkage of a giant prolactinoma treated with cabergoline in a prepubescent girl. What now? AB - Giant prolactinomas are extremely rare in the pediatric population. We describe the case of a giant prolactinoma in a girl aged 14 years and 9 months old presented with delayed puberty. Medical treatment with dopamine agonist cabergoline resulted in a rapid normalization of prolactine levels and an impressive shrinkage and liquefaction of the mass as illustrated in serial MRIs. The therapeutic dilemma regarding the type of treatment (medical versus surgical) has now been replaced by the dilemma regarding the optimal treatment strategy and duration. Initial, rather optimistic, estimations regarding the probability of treatment discontinuation without increased relapsing risk have now been replaced by guidelines with more strict criteria for selecting candidates for treatment discontinuation. PMID- 23803869 TI - Lipoprotein Lp(a) in lipoprotein spectrum indentified by Lipoprint LDL system. AB - OBJECTIVE: Identification of lipoprotein subfractions in lipoprotein profile by Lipoprint LDL system, where a lipoprotein(a), an independent risk factor for the development of cardiovascular disease, migrates with. The concentration of lipoprotein(a) in serum over 0.3 g/l increases the risk of athero-thrombosis and a brain stroke. The persons with increased levels of lipoprotein(a) and contemporarily increased cholesterol level in serum, are at increased risk of the inception of cardiovascular or cerebrovascular event even 3-times. PATIENTS AND METHODS: In a general group of subjects with increased serum concentration of lipoprotein(a) a lipoprotein profile analysis was performed. The general group of subjects was divided into two groups: subgroup with the lipoprotein(a) concentration in the range between 0.3-0.8 g/l and a subgroup with the lipoprotein(a) concentration over 0.8 g/l, to learn if the lipoprotein(a) particles of different serum concentration and different size do not migrate in different positions of the lipoprotein spectrum. For the analysis of serum lipoproteins an innovated electrophoresis method on polyacrylamide gel (PAG) - Lipoprint LDL system USA, was used. Lipids: a total cholesterol and triglycerides in serum were analysed by an enzymatic method CHOD PAP (Roche Diagnostics, FRG), lipoprotein(a) was analysed by an immuno-nephelometric method (Roche Diagnostics, FRG). RESULTS: In the Lipoprint LDL system using a polyacrylamide gel (PAG) for the lipoprotein separation, lipoprotein(a) migrates in the position IDL2-IDL3. In the band of IDL2 a high Lp(a) values can be identified, when the increment of IDL2 subfraction is over the value of 0.015 g/l, i.e. 15 mg/dl (reference range for IDL2) and when the increment of IDL3 subfraction is over the value of 25 mg/dl, i.e. 0.025 g/l (reference range for IDL3). CONCLUSIONS: A clear contribution of new method is: identification of the lipoprotein subpopulations where the lipoprotein(a) migrates with different migration position for the mild increased lipoprotein(a) concentration and high lipoprotein(a) concentration in serum was not confirmed. PMID- 23803870 TI - Pitfall in follow-up imaging of pancreatic neuroendocrine tumor by somatostatin receptor PET. AB - 56-year old woman was operated of a pancreatic NET in May 2011. Abdominal pain had led to imaging and consecutively the finding of cholecystolithiasis and the tumor. The gall bladder, left hemi-pancreas, regional lymph nodes and the (unintentional injured) spleen were resected. At routine control examination in October 2012 CT presented three contract enhancing intra-abdominal lesions with a diameter of 2-3.5 cm. Consecutively 68Ga-DOTA-NOC PET-CT showed high tracer uptake (SUV 10-12) at these lesions. Therefore a relapse of the neuro-endocrine tumor was suspected. After reoperation in December 2012 histology did not reveal any sign of neuroendocrine tumor but identified spleen tissue most probably caused by splenosis accidentally seeded at the first operation. Physiologically the spleen is highly avid at 68Ga-DOTATOC PET, but splenosis presents with less standard uptake value. In our case the described lesions presented with an SUV quite comparable to that of neuroendocrine tumor tissue. PMID- 23803871 TI - Relationship of ketamine's antidepressant and psychotomimetic effects in unipolar depression. AB - OBJECTIVES: Ketamine and other NMDA (N-methyl-D-aspartate) antagonists produce fast-acting antidepressant-like effects, although the underlying mechanism is unclear. Furthermore, high affinity NMDA antagonists such as ketamine are associated with psychotomimetic effects. To date the link between the antidepressant and psychotomimetic effects of ketamine has not been explored. We examined the relationship between the antidepressant and psychotomimetic effects of a single ketamine infusion in subjects diagnosed with major depressive disorder. METHODS: In a double-blind, cross-over, placebo-controlled, two weeks clinical trial we studied the effects of ketamine (0.54 mg/kg within 30 min) in a group of 27 hospitalized depressive patients. RESULTS: Higher intensity of psychotomimetic symptoms, measured using BPRS, during ketamine administration correlated with alleviation in mood ratings during the following week with maximum on day seven. Ketamine was superior to placebo in all visits (day 1, 4, and 7) assessed by MADRS with effect size (Cohen's d) of 0.62, 0.57, and 0.44 respectively. There was no significant correlation between ketamine and nor ketamine plasma levels and MADRS score change at any study time point. CONCLUSION: The substantial relationship between ketamine's antidepressant and psychotomimetic effects was found. This relationship could be mediated by the initial steps of ketamine's action, trough NMDA receptors, shared by both ketamine's clinical effects. PMID- 23803872 TI - Self-stigmatization in patients with bipolar disorder. AB - BACKGROUND: Prejudicial beliefs, emotions, and behaviours cause discrimination against people labeled as mentally ill. This stigmatization is sometimes internalized by the patients, leading to self-stigmatization. Specific features and impacts of stigmatization and self-stigmatization in patients with bipolar illness are the subjects of this review. METHOD: Studies were identified through PUBMED, Web of Science and Scopus databases as well as existing reviews. The search terms included "bipolar disorder", "stigma", "self-stigma" psychoeducation", "psychotherapy", "psychosocial treatment". Key articles listed in reference lists were searched. RESULTS: Considerable recent evidence indicates that bipolar patients and their families are stigmatized, and that this stigmatization affects their quality of life as well as social functioning. The severity of stigmatization in bipolar disorder is greater than that in people with depression. There is also evidence of self-stigmatization which further decreases the quality of life. Stigmatization and self-stigmatization were shown to be one of the barriers that delay or prevent effective treatment, and thus exert adverse effects on the outcomes of bipolar disorder. CONCLUSION: Stigma affects the experience of illness as well as social functioning in patients with bipolar disorder. The impact of stigma on the lives and treatment outcomes of patients with bipolar disorder mandates intensive effort of mental health research and policy to address this problem. Much has been done against the stigmatization of the mentally ill. But the fight against stigma remains a fundamental objective of health programs for mental health. PMID- 23803873 TI - Shift work and cancer research: a thought experiment into a potential chronobiological fallacy of past and perspectives for future epidemiological studies. AB - With their 2007 classification - shift work involving "circadian disruption" is probably carcinogenic to humans (Group 2A) - the International Agency for Research on Cancer [IARC] provided a riddle for scientists and the public alike. Thereafter, eighteen epidemiological investigations into shift work and a host of malignant endpoints (including cancers of the breast, prostate, lung, colon, rectum, pancreas, bladder, skin and non-Hodgkin lymphoma [NHL]) as well as mortality were published. Although IARC experts identified "circadian disruption" as the critical link in the "probable" chains of cancer causation, almost none of the post-IARC studies specifically considered a disturbed temporal organization of biology. This implies that epidemiological research to-date is less focused than it should be. To illustrate a potential chronobiological fallacy of past studies, we offer a thought experiment. In addition, we consider first empirical evidence from recent research which avoided such bias. Methodological perspectives for future chronobiology-driven epidemiological research are outlined. PMID- 23803874 TI - The effect of valproate (VPA) treatment on inositol phosphates (IPs) accumulation in non-stimulated and GnRH-treated female rat anterior pituitary cells in vitro. AB - OBJECTIVE: Mechanism(s) responsible for VPA-induced effects on reproductive axis activity are not fully recognized. Previously we reported that VPA suppressed only GnRH-stimulated but not the basal LH release from rat anterior pituitary (AP) cells in vitro. Since the inhibitory effect of VPA was exerted only in GnRH activated cells, potential VPA impact on GnRH-R-coupled IP3/PKC signaling could not be excluded. In this study the effect of VPA on IPs synthesis in non stimulated and GnRH-treated rat AP cells was examined. MATERIAL AND METHODS: In the first experiment 5 * 105 cells/ml were incubated for 3h with VPA (10 nM-10 MUM), PMA (100 nM), GnRH (100 nM), PMA (100 nM) + VPA (10 nM-10 MUM), GnRH (100 nM) + VPA (10 nM-10 MUM). In the second experiment cells were preincubated for 24h with 1MUCi myo-[23 H]-inositol, then for 30 min with 10 mM LiCl and finally for 3hr with GnRH (100 nM) VPA (1 MUM, 10 MUM), GnRH (100 nM) + VPA (1 MUM, 10 MUM). LH concentration was measured by RIA and intracellular IPs accumulation by ion-exchange chromatography analysis. RESULTS: VPA diminished GnRH-stimulated LH release without affecting PMA-induced LH release at any dose tested. Moreover, VPA-induced increase of IPs accumulation occurred in both non-stimulated and GnRH treated cells and intensity of cellular response was similar in both groups. CONCLUSION: VPA affects IP3/PKC pathway activity through its up-regulatory effect on IPs synthesis in AP cells. VPA-induced inhibition of GnRH-stimulated LH release from gonadotrope cells appears to be the result of still unrecognized cellular mechanism. PMID- 23803875 TI - Contra: "New oral anticoagulants should not be used as 1st choice for secondary stroke prevention in atrial fibrillation". PMID- 23803876 TI - Bio-nanohybrids of quantum dots and photoproteins facilitating strong nonradiative energy transfer. AB - Utilization of light is crucial for the life cycle of many organisms. Also, many organisms can create light by utilizing chemical energy emerged from biochemical reactions. Being the most important structural units of the organisms, proteins play a vital role in the formation of light in the form of bioluminescence. Such photoproteins have been isolated and identified for a long time; the exact mechanism of their bioluminescence is well established. Here we show a biomimetic approach to build a photoprotein based excitonic nanoassembly model system using colloidal quantum dots (QDs) for a new bioluminescent couple to be utilized in biotechnological and photonic applications. We concentrated on the formation mechanism of nanohybrids using a kinetic and thermodynamic approach. Finally we propose a biosensing scheme with an ON/OFF switch using the QD-GFP hybrid. The QD GFP hybrid system promises strong exciton-exciton coupling between the protein and the quantum dot at a high efficiency level, possessing enhanced capabilities of light harvesting, which may bring new technological opportunities to mimic biophotonic events. PMID- 23803877 TI - Performance of conventional and dispersion-corrected density-functional theory methods for hydrogen bonding interaction energies. AB - The approximate CCSD(T)/CBS binding energies for the set of 23 hydrogen-bonded dimers (HB23) of the S66 set reported by Rezac et al. (J. Chem. Theory Comput. 2011, 7, 2427-2438) were expected to be under-estimated based on the known under binding tendency of the counterpoise correction combined with small basis sets. In this work, we present binding energies for the HB23 set of dimers obtained using a composite approach recently described by Mackie and DiLabio (J. Chem. Phys. 2011, 135, 134318) that averages the counterpoise- and non-counterpoise corrected energies, while utilizing standard approaches to obtain CCSD(T)/CBS type energies. The binding energies for the HB23 set are revised upward by an average of 0.12 kcal mol(-1) and as much as 0.35 kcal mol(-1). We use these improved benchmark-level binding energies to evaluate the ability of pure, hybrid, long-range-corrected, and dispersion-corrected density-functional theory (DFT) methods to accurately predict the binding energies of hydrogen-bonded dimers. We find that, in general, the inclusion of dispersion into the DFT approach is required in order to obtain reasonable results for the HB23 set. We find that the dispersion-corrected DFT methods we tested produce results of variable quality, as measured by mean absolute deviation relative to the revised reference values we computed: B97D, 0.57 kcal mol(-1); B3LYP-D3, 0.44 kcal mol( 1); omegaB97XD, 0.25 kcal mol(-1); LC-omegaPBE-D3, 0.24 kcal mol(-1); M06-2X, 0.21 kcal mol(-1); B3LYP-DCP, 0.23 kcal mol(-1); B971-XDM, 0.18 kcal mol(-1). PMID- 23803878 TI - Effect of green tea on glucose control and insulin sensitivity: a meta-analysis of 17 randomized controlled trials. AB - BACKGROUND: The results of studies investigating the effect of green tea on glucose control and insulin sensitivity in humans are inconsistent. OBJECTIVE: We aimed to quantitatively evaluate the effect of green tea on glucose control and insulin sensitivity. DESIGN: We performed a strategic literature search of PubMed, EMBASE, and the Cochrane Library (updated to January 2013) for randomized controlled trials that evaluated the effects of green tea and green tea extract on glucose control and insulin sensitivity. Study quality was assessed by using the Jadad scale. Weighted mean differences were calculated for net changes in glycemic measures by using fixed-effects or random-effects models. We conducted prespecified subgroup and sensitivity analyses to explore potential heterogeneity. Meta-regression analyses were conducted to investigate dose effects of green tea on fasting glucose and insulin concentrations. RESULTS: Seventeen trials comprising a total of 1133 subjects were included in the current meta-analysis. Green tea consumption significantly reduced the fasting glucose and hemoglobin A1c (Hb A1c) concentrations by -0.09 mmol/L (95% CI: -0.15, -0.03 mmol/L; P < 0.01) and -0.30% (95% CI: -0.37, -0.22%; P < 0.01), respectively. Further stratified analyses from high Jadad score studies showed that green tea significantly reduced fasting insulin concentrations (-1.16 MUIU/mL; 95% CI: 1.91, -0.40 MUIU/mL; P = 0.03). CONCLUSIONS: This meta-analysis suggested that green tea had favorable effects, ie, decreased fasting glucose and Hb A1c concentrations. Subgroup analyses showed a significant reduction in fasting insulin concentrations in trials with high Jadad scores. PMID- 23803879 TI - Associations of erythrocyte fatty acids in the de novo lipogenesis pathway with risk of metabolic syndrome in a cohort study of middle-aged and older Chinese. AB - BACKGROUND: Experimental studies suggest that elevated de novo lipogenesis (DNL) might be involved in the pathogenesis of metabolic disorders. Few prospective studies have been conducted, especially among populations with a high carbohydrate intake, to determine whether DNL fatty acids are associated with the risk of the metabolic syndrome (MetS). OBJECTIVE: We aimed to investigate associations of erythrocyte fatty acids in the DNL pathway-including myristic acid (14:0), palmitic acid (16:0), palmitoleic acid (16:1n-7), hexadecenoic acid (16:1n-9), stearic acid (18:0), vaccenic acid (18:1n-7), and oleic acid (18:1n-9) with the risk of MetS in a Chinese population with an average carbohydrate intake of >60% of energy. DESIGN: A total of 1176 free-living Chinese men and women aged 50-70 y from Beijing and Shanghai were included in our analysis, giving rise to 412 incident MetS cases during 6 y of follow-up. Erythrocyte fatty acids and metabolic traits were measured in these participants. RESULTS: Erythrocyte fatty acids in the DNL pathway were correlated with a high ratio of carbohydrate-to-fat intake, less favorable lipid profiles, and elevated liver enzymes at baseline. In comparison with the lowest quartile, RRs (95% CIs) of MetS in the highest quartile were 1.30 (1.04, 1.62; P-trend = 0.007) for 16:1n-7, 1.48 (1.17, 1.86; P trend < 0.001) for 16:1n-9, 1.26 (1.01, 1.56; P-trend = 0.06) for 18:1n-7, and 1.51 (1.19, 1.92; P-trend < 0.001) for 18:1n-9 after multivariate adjustment for lifestyle factors and body mass index. Moreover, 16:0 and 16:1n-7 were associated with an elevated risk of diabetes. CONCLUSION: Our findings suggest that fatty acids in the DNL pathway are independently associated with an elevated risk of metabolic disorders. PMID- 23803880 TI - Fruit and vegetable consumption and all-cause mortality: a dose-response analysis. AB - BACKGROUND: The association between fruit and vegetable (FV) consumption and overall mortality has seldom been investigated in large cohort studies. Findings from the few available studies are inconsistent. OBJECTIVE: The objective was to examine the dose-response relation between FV consumption and mortality, in terms of both time and rate, in a large prospective cohort of Swedish men and women. DESIGN: FV consumption was assessed through a self-administrated questionnaire in a population-based cohort of 71,706 participants (38,221 men and 33,485 women) aged 45-83 y. We performed a dose-response analysis to evaluate 10th survival percentile differences (PDs) by using Laplace regression and estimated HRs by using Cox regression. RESULTS: During 13 y of follow-up, 11,439 deaths (6803 men and 4636 women) occurred in the cohort. In comparison with 5 servings FV/d, a lower consumption was progressively associated with shorter survival and higher mortality rates. Those who never consumed FV lived 3 y shorter (PD: -37 mo; 95% CI: -58, -16 mo) and had a 53% higher mortality rate (HR: 1.53; 95% CI: 1.19, 1.99) than did those who consumed 5 servings FV/d. Consideration of fruit and vegetables separately showed that those who never consumed fruit lived 19 mo shorter (PD: -19 mo; 95% CI: -29, -10 mo) than did those who ate 1 fruit/d. Participants who consumed 3 vegetables/d lived 32 mo longer than did those who never consumed vegetables (PD: 32 mo; 96% CI: 13, 51 mo). CONCLUSION: FV consumption <5 servings/d is associated with progressively shorter survival and higher mortality rates. The Swedish Mammography Cohort and the Cohort of Swedish Men were registered at clinicaltrials.gov as NCT01127698 and NCT01127711, respectively. PMID- 23803881 TI - Effects of dietary glycemic index on brain regions related to reward and craving in men. AB - BACKGROUND: Qualitative aspects of diet influence eating behavior, but the physiologic mechanisms for these calorie-independent effects remain speculative. OBJECTIVE: We examined effects of the glycemic index (GI) on brain activity in the late postprandial period after a typical intermeal interval. DESIGN: With the use of a randomized, blinded, crossover design, 12 overweight or obese men aged 18-35 y consumed high- and low-GI meals controlled for calories, macronutrients, and palatability on 2 occasions. The primary outcome was cerebral blood flow as a measure of resting brain activity, which was assessed by using arterial spin labeling functional magnetic resonance imaging 4 h after test meals. We hypothesized that brain activity would be greater after the high-GI meal in prespecified regions involved in eating behavior, reward, and craving. RESULTS: Incremental venous plasma glucose (2-h area under the curve) was 2.4-fold greater after the high- than the low-GI meal (P = 0.0001). Plasma glucose was lower (mean +/- SE: 4.7 +/- 0.14 compared with 5.3 +/- 0.16 mmol/L; P = 0.005) and reported hunger was greater (P = 0.04) 4 h after the high- than the low-GI meal. At this time, the high-GI meal elicited greater brain activity centered in the right nucleus accumbens (a prespecified area; P = 0.0006 with adjustment for multiple comparisons) that spread to other areas of the right striatum and to the olfactory area. CONCLUSIONS: Compared with an isocaloric low-GI meal, a high-GI meal decreased plasma glucose, increased hunger, and selectively stimulated brain regions associated with reward and craving in the late postprandial period, which is a time with special significance to eating behavior at the next meal. This trial was registered at clinicaltrials.gov as NCT01064778. PMID- 23803882 TI - Association between water consumption and body weight outcomes: a systematic review. AB - BACKGROUND: Drinking water is often applied as a dietary means for weight loss and overweight/obesity prevention, but no evidence-based recommendation exists for this indication. OBJECTIVE: We summarized the existing evidence on the association between water consumption and body weight outcomes in adults of any body weight status. DESIGN: In a systematic review, we retrieved studies from 4 electronic databases (MEDLINE, EMBASE, CINAHL, and COCHRANE), cross-references by PubMed functions and hand-searching, and experts' recommendations. Any type of study including adults aged >18 y that reported the association between daily water consumption and any weight-related outcome, such as body weight, body mass index, or body weight classifications, was eligible. RESULTS: Of 4963 retrieved records, 11 original studies and 2 systematic reviews were included. In participants dieting for weight loss or maintenance, a randomized controlled trial, a nonrandomized controlled trial, and an observational longitudinal study showed that increased water consumption, in addition to a program for weight loss or maintenance, reduced body weight after 3-12 mo compared with such a program alone. In mixed-weight populations not primarily dieting for weight loss or maintenance, 2 short-term randomized trials showed no effect of water consumption on body weight; 6 cross-sectional studies showed inconsistent results. CONCLUSIONS: Studies of individuals dieting for weight loss or maintenance suggest a weight-reducing effect of increased water consumption, whereas studies in general mixed-weight populations yielded inconsistent results. The evidence for this association is still low, mostly because of the lack of good-quality studies. This trial was registered at www.crd.york.ac.uk/Prospero as CRD42012002585. PMID- 23803883 TI - Modeling a methylmalonic acid-derived change point for serum vitamin B-12 for adults in NHANES. AB - BACKGROUND: No consensus exists about which cutoff point should be applied for serum vitamin B-12 (SB-12) concentrations to define vitamin B-12 status in population-based research. OBJECTIVE: The study's aim was to identify whether a change point exists at which the relation between plasma methylmalonic acid (MMA) and SB-12 changes slope to differentiate between inadequate and adequate vitamin B-12 status by using various statistical models. DESIGN: We used data on adults (>=19 y; n = 12,683) from NHANES 1999-2004-a nationally representative, cross sectional survey. We evaluated 6 piece-wise polynomial and exponential decay models that used different control levels for known covariates. RESULTS: The MMA defined change point for SB-12 varied depending on the statistical model used. A linear-splines model was determined to best fit the data, as determined by the approximate permutation test; 3 slopes relating SB-12 and MMA and resulting in 2 change points and 3 subgroups were shown. The first group (SB-12 <126 pmol/L) was small and had the highest MMA concentration (median: 281 nmol/L; 95% CI: 245, 366 nmol/L; n = 157, 1.2%); many in this group could be considered at high risk of severe deficiency because combined abnormalities of MMA and homocysteine were very frequent and the concentrations themselves were significantly higher. The highest SB-12 group (SB-12 >287 pmol/L; n = 8569, 67.6%) likely had adequate vitamin B-12 status (median MMA: 120 nmol/L; 95% CI: 119, 125 nmol/L). The vitamin B-12 status of the sizable intermediate group (n = 3957, 33%) was difficult to interpret. CONCLUSIONS: The 3 distinct slopes for the relation between SB-12 and MMA challenges the conventional use of one cutoff point for classifying vitamin B-12 status. In epidemiologic research, the use of one cutoff point would fail to separate the small, severely deficient group from the intermediate group that has neither normal nor clearly deficient vitamin B-12 concentrations (ie, unknown vitamin B-12 status). This intermediate group requires further characterization. PMID- 23803885 TI - Consumption of cereal fiber, mixtures of whole grains and bran, and whole grains and risk reduction in type 2 diabetes, obesity, and cardiovascular disease. AB - BACKGROUND: Studies of whole grain and chronic disease have often included bran enriched foods and other ingredients that do not meet the current definition of whole grains. Therefore, we assessed the literature to test whether whole grains alone had benefits on these diseases. OBJECTIVE: The objective was to assess the contribution of bran or cereal fiber on the impact of whole grains on the risk of type 2 diabetes (T2D), obesity and body weight measures, and cardiovascular disease (CVD) in human studies as the basis for establishing an American Society for Nutrition (ASN) position on this subject. DESIGN: We performed a comprehensive PubMed search of human studies published from 1965 to December 2010. RESULTS: Most whole-grain studies included mixtures of whole grains and foods with >=25% bran. Prospective studies consistently showed a reduced risk of T2D with high intakes of cereal fiber or mixtures of whole grains and bran. For body weight, a limited number of prospective studies on cereal fiber and whole grains reported small but significant reductions in weight gain. For CVD, studies found reduced risk with high intakes of cereal fiber or mixtures of whole grains and bran. CONCLUSIONS: The ASN position, based on the current state of the science, is that consumption of foods rich in cereal fiber or mixtures of whole grains and bran is modestly associated with a reduced risk of obesity, T2D, and CVD. The data for whole grains alone are limited primarily because of varying definitions among epidemiologic studies of what, and how much, was included in that food category. PMID- 23803884 TI - Long-term effects of LCPUFA supplementation on childhood cognitive outcomes. AB - BACKGROUND: The effect of long-chain polyunsaturated fatty acid (LCPUFA) intake on cognitive development is controversial. Most randomized trials have assessed cognition at 18 mo, although significant development of cognitive abilities (early executive function) emerge later. OBJECTIVE: The objective was to evaluate cognition beyond 18 mo and longitudinal cognitive change from 18 mo to 6 y in children who were fed variable amounts of docosahexaenoic acid (0.32%, 0.64%, and 0.96% of total fatty acids) and arachidonic acid (ARA; 0.64%) compared with children who were not fed LCPUFA as infants. DESIGN: Eighty-one children (19 placebo, 62 LCPUFA) who participated in a double-blind, randomized trial of LCPUFA supplementation as infants were re-enrolled at 18 mo and tested every 6 mo until 6 y on age-appropriate standardized and specific cognitive tests. RESULTS: LCPUFA supplementation did not influence performance on standardized tests of language and performance at 18 mo; however, significant positive effects were observed from 3 to 5 y on rule-learning and inhibition tasks, the Peabody Picture Vocabulary Test at 5 y, and the Weschler Primary Preschool Scales of Intelligence at 6 y. Effects of LCPUFAs were not found on tasks of spatial memory, simple inhibition, or advanced problem solving. CONCLUSIONS: The data from this relatively small trial suggest that, although the effects of LCPUFAs may not always be evident on standardized developmental tasks at 18 mo, significant effects may emerge later on more specific or fine-grained tasks. The results imply that studies of nutrition and cognitive development should be powered to continue through early childhood. This parent trial was registered at clinicaltrials.gov as NCT00266825. PMID- 23803886 TI - Metabolomic profile of response to supplementation with beta-carotene in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. AB - BACKGROUND: Two chemoprevention trials found that supplementation with beta carotene increased the risk of lung cancer and overall mortality. The biologic basis of these findings remains poorly understood. OBJECTIVE: The objective was to compare the on-study change in metabolomic profiles of men randomly assigned to receive or not receive beta-carotene supplements in the Alpha-Tocopherol, Beta Carotene Cancer Prevention (ATBC) Study. DESIGN: The ATBC Study was a randomized, double-blind, placebo-controlled, primary cancer prevention trial; participants were Finnish male smokers assigned to 1 of 4 intervention groups: 1) alpha tocopherol, 2) beta-carotene, 3) both, or 4) placebo. Fifty participants with both baseline and follow-up fasting serum samples were randomly selected from each of these groups. Metabolomic profiling was conducted by mass spectrometry. The association between change in each metabolite over time and trial assignment (beta-carotene or no beta-carotene) was estimated by linear regression. RESULTS: We measured 489 metabolites, and 17 changed significantly (P < 0.05) in response to beta-carotene supplementation. More of these 17 metabolites were of xenobiotic origin than would be expected by chance (9 of 60, or 15%; P = 0.00004). We also found a suggestive association with 1,5-anhydroglucitol-a marker of glycemic control (beta = -0.379, P = 0.0071). CONCLUSIONS: Male smokers supplemented with beta-carotene developed metabolomic profiles consistent with the induction of cytochrome P450 enzymes, the primary metabolizers of xenobiotics in humans. These findings may shed light on the increased mortality associated with beta-carotene supplementation in the ATBC Study and suggest the need to explore potential interactions between medication use and dietary supplements, particularly among smokers. This trial was registered at clinicaltrials.gov as NCT00342992. PMID- 23803887 TI - Relevance of dietary iron intake and bioavailability in the management of HFE hemochromatosis: a systematic review. AB - BACKGROUND: Hereditary hemochromatosis (HH) leads to iron loading because of a disturbance in the negative-feedback mechanism between dietary iron absorption and iron status. The management of HH is achieved by repeated phlebotomies. OBJECTIVE: We investigated whether HH patients would benefit from a diet with low iron intake and bioavailability. DESIGN: We performed a systematic review of studies that linked iron bioavailability and status with dietary factors in subjects with diagnosed HH. Studies on heterozygotes for the HFE mutation were excluded. RESULTS: No prospective, randomized study was reported. Nine studies that directly measured iron bioavailability from test meals in HH patients have been described as well as 3 small, prospective, longitudinal studies in HH patients. Eight cross-sectional studies were identified that investigated the effect of dietary composition on iron status. Calculations of iron bioavailability in HH were made by extrapolating data on hepcidin concentrations and their association with iron bioavailability. The potential reduction in the yearly amount of blood to be phlebotomized when restricting dietary iron absorbed was estimated in the 3 longitudinal studies and ranged between 0.5 and 1.5 L. This amount would be dependent on individual disease penetrance as well as the dietary intervention. CONCLUSIONS: Despite the limited quantitative evidence and the lack of randomized, prospective trials, dietary interventions that modify iron intake and bioavailability may affect iron accumulation in HH patients. Although this measure may be welcome in patients willing to contribute to their disease management, limited data exist on the clinical and quality-of-life benefit. PMID- 23803888 TI - beta,beta-carotene 15,15'-monooxygenase and its substrate beta-carotene modulate migration and invasion in colorectal carcinoma cells. AB - BACKGROUND: beta,beta-Carotene 15,15'-monooxygenase (BCMO1) converts beta carotene to retinaldehyde. Increased beta-carotene consumption is linked to antitumor effects. Retinoic acid reduces the invasiveness in cancer, through inhibition of matrix metalloproteinases (MMPs). In our studies of a mouse model that develops intestinal tumors after low dietary folate, we found reduced BCMO1 expression in normal preneoplastic intestine of folate-deficient tumor-prone mice. OBJECTIVE: Our goal was to determine whether BCMO1 expression could influence transformation potential in human colorectal carcinoma cells, by examining the effect of BCMO1 modulation on cellular migration and invasion, and on expression of MMPs. DESIGN: LoVo colon carcinoma cells were transfected with BCMO1 small interfering RNA (siRNA) or scrambled siRNA. Migration and invasion were measured, and the expression of BCMO1, MMP7, and MMP28 was assessed by quantitative reverse-transcriptase polymerase chain reaction. These variables were also measured after treatment of cells with retinoic acid, 5-aza-2' deoxycytidine, folate-depleted/high-methionine medium, and beta-carotene. RESULTS: Retinoic acid decreased the migration, invasion, and expression of MMP28 mRNA. Transfection of cells with BCMO1 siRNA inhibited BCMO1 expression, enhanced migration and invasion, and increased expression of MMP7 and MMP28. 5-Aza-2' deoxycytidine decreased, whereas folate-depleted/high-methionine medium increased invasiveness. beta-Carotene increased BCMO1 expression and reduced invasiveness with a decrease in expression of MMP7 and MMP28. CONCLUSIONS: Inhibition of BCMO1 expression is associated with increased invasiveness of colon cancer cells and increased expression of MMP7 and MMP28. beta-Carotene can upregulate BCMO1 and reverse these effects. These novel associations suggest a critical role for BCMO1 in cancer and provide a mechanism for the proposed antitumor effects of beta carotene. PMID- 23803889 TI - Maternal serum 25-hydroxyvitamin D and placental vascular pathology in a multicenter US cohort. AB - BACKGROUND: Maternal vitamin D deficiency has been linked to fetal growth restriction, but the underlying mechanisms are unclear. OBJECTIVE: We tested the hypothesis that poor maternal 25-hydroxyvitamin D [25(OH)D] is associated with increased risk of placental vascular pathology. DESIGN: Maternal serum 25(OH)D was measured at <=26 wk of gestation in a random subcohort of term, singleton infants in the Collaborative Perinatal Project (1959-1966; n = 2048). A dichotomous vascular construct was created from the presence of any of 12 pathologies identified on placental examinations, including evidence of placental abruption, infarction, hypoxia, decidual vasculopathy, or thrombosis of fetal vessels (n = 240 cases). RESULTS: The relation between 25(OH)D and vascular pathology was modified by infant sex (P = 0.003). A maternal 25(OH)D concentration >=80 compared with <50 nmol/L was associated with 49% lower risk of pathology in boys [adjusted OR (95% CI): 0.27, 0.95] after conditioning on study site. No associations were observed between maternal 25(OH)D and pathology in mothers with female offspring. Subsequent analyses showed that, in pregnancies with a female fetus, vascular pathology was associated with a reduced birth weight z score when the mother's 25(OH)D concentration was <30 nmol/L (beta: 0.73; 95% CI: -1.17, -0.30). No association was observed between pathology and birth weight in mothers of female offspring with 25(OH)D concentrations >=30 nmol/L or in boys, regardless of maternal 25(OH)D status. CONCLUSIONS: Our findings suggest complex relations between vitamin D, placental vascular pathology, and birth weight that differ by infant sex. Maternal vitamin D status may be beneficial for male and female offspring through different mechanisms. PMID- 23803890 TI - Eating breakfast more frequently is cross-sectionally associated with greater physical activity and lower levels of adiposity in overweight Latina and African American girls. AB - BACKGROUND: Eating breakfast is believed to promote a healthy body weight. Yet, few studies have examined the contribution of energy balance-related behavioral factors to this relation in minority youth. OBJECTIVE: We assessed the associations between breakfast consumption and dietary intake, physical activity (PA), and adiposity before and after accounting for energy intake and PA in minority girls. DESIGN: Cross-sectional data were obtained on body mass index (BMI), percentage body fat (measured by BodPod), dietary intake (measured with 3 d dietary records), and PA (measured with 7-d accelerometry) from 87 Latina and African American girls 8-17 y of age (75% Latina, 80% overweight). Dietary records were used to categorize girls as more frequent breakfast eaters (MF; 2 or 3 of 3 d; n = 57) or less frequent breakfast eaters (LF; 0 or 1 of 3 d; n = 30). Chi-square tests, ANCOVA, and multiple regression analyses were conducted. Mediation was assessed with a Sobel test. RESULTS: Compared with the MF group, the LF group spent 30% less time (12.6 min/d) in moderate-to-vigorous-intensity PA (MVPA; P = 0.004) and had a higher percentage body fat (P = 0.029). MVPA accounted for 25% (95% CI: -8.8%, 58.1%; P = 0.139) of the relation between breakfast consumption and percentage body fat. We were unable to show that energy intake or MVPA was a significant mediator of the relation between breakfast consumption and adiposity in this sample. CONCLUSIONS: Evidence suggests that among predominantly overweight minority girls, MVPA, but not energy intake, was associated with both breakfast consumption and adiposity; however, a lack of power reduced our ability to detect a significant mediation effect. Other unobserved variables likely contribute to this relation. PMID- 23803891 TI - Anthropometric predictors of mortality in undernourished adults in the Ajiep Feeding Programme in Southern Sudan. AB - BACKGROUND: Various nutritional assessment tools are available to assess adult undernutrition, but few are practical in poorly served areas of low-income countries. OBJECTIVE: The objective was to assess the relation between midupper arm circumference (MUAC), weight, body mass index (BMI), and clinical assessment for edema in predicting mortality in adults with severe acute undernutrition. DESIGN: Demographic and anthropometric data that were collected in an observational study of 197 adults were analyzed. Participants were aged 18-59 y and were admitted to a therapeutic feeding center in Ajiep, Southern Sudan, during the height of the 1998 famine. Receiver operating curves were calculated and compared. RESULTS: The mean (+/-SD) age of the participants was 40.1 +/-10.8 y, and the mean (+/-SD) MUAC, weight, and BMI (in kg/m(2)) were 16.4 +/- 1.3 cm, 35.1 +/- 5.2 kg, and 12.6 +/- 1.5, respectively. The area under the receiver operating curve for MUAC (0.71) was higher (P = 0.01) than those of BMI (0.57) and weight (0.51). Mean age, weight, and BMI on admission did not differ between survivors and nonsurvivors (P > 0.17). MUAC and edema were independently associated with mortality. For every 1-cm increase in admission MUAC, the odds of subsequent mortality decreased by 58% (adjusted OR: 0.42; 95% CI: 0.28, 0.63; P < 0.001). CONCLUSIONS: In this study, which was conducted at the height of a major famine among adults with extremely severe grades of undernutrition, MUAC and edema were better indicators of short-term prognosis than was BMI. Further studies are needed to define a critical MUAC threshold for the diagnosis of acute adult undernutrition. PMID- 23803892 TI - Are sugar-sweetened beverages the whole story? PMID- 23803893 TI - Breaking prolonged sitting reduces postprandial glycemia in healthy, normal weight adults: a randomized crossover trial. AB - BACKGROUND: Sedentary behavior is a risk factor for cardiometabolic disease. Regularly interrupting sedentary behavior with activity breaks may lower this risk. OBJECTIVE: We compared the effects of prolonged sitting, continuous physical activity combined with prolonged sitting, and regular activity breaks on postprandial metabolism. DESIGN: Seventy adults participated in a randomized crossover study. The prolonged sitting intervention involved sitting for 9 h, the physical activity intervention involved walking for 30 min and then sitting, and the regular-activity-break intervention involved walking for 1 min 40 s every 30 min. Participants consumed a meal-replacement beverage at 60, 240, and 420 min. RESULTS: The plasma incremental area under the curve (iAUC) for insulin differed between interventions (overall P < 0.001). Regular activity breaks lowered values by 866.7 IU . L(-1) . 9 h(-1) (95% CI: 506.0, 1227.5 IU . L(-1) . 9 h(-1); P < 0.001) when compared with prolonged sitting and by 542.0 IU . L(-1) . 9 h(-1) (95% CI: 179.9, 904.2 IU . L(-1) . 9 h(-1); P = 0.003) when compared with physical activity. Plasma glucose iAUC also differed between interventions (overall P < 0.001). Regular activity breaks lowered values by 18.9 mmol . L(-1) . 9 h(-1) (95% CI: 10.0, 28.0 mmol . L(-1) . 9 h(-1); P < 0.001) when compared with prolonged sitting and by 17.4 mmol . L(-1) . 9 h(-1) (95% CI: 8.4, 26.3 mmol . L(-1) . 9 h(-1); P < 0.001) when compared with physical activity. Plasma triglyceride iAUC differed between interventions (overall P = 0.023). Physical activity lowered values by 6.3 mmol . L(-1) . 9 h(-1) (95% CI: 1.8, 10.7 mmol . L(-1) . 9 h(-1); P = 0.006) when compared with regular activity breaks. CONCLUSION: Regular activity breaks were more effective than continuous physical activity at decreasing postprandial glycemia and insulinemia in healthy, normal weight adults. This trial was registered with the Australian New Zealand Clinical Trials registry as ACTRN12610000953033. PMID- 23803894 TI - Disadvantageous shift in energy balance is primarily expressed in high-quality sleepers after a decline in quality sleep because of disturbance. AB - BACKGROUND: Epidemiologic studies have shown an inverse or U-shaped relation between sleep duration and body mass index (BMI; in kg/m(2)). Moreover, associations between energy balance (EB) and characteristics of quality sleep (QS) have recently been reported. OBJECTIVE: We assessed the relation between total energy expenditure (TEE) as well as substrate oxidation and QS after disturbed compared with nondisturbed sleep in EB. DESIGN: Fifteen healthy men (mean +/- SD BMI: 24.1 +/- 1.9; age: 23.7 +/- 3.5 y) were included in a randomized crossover study. TEE and substrate oxidation were measured twice for 48 h in a respiration chamber, whereas slow-wave sleep (SWS), rapid eye movement (REM)-sleep, total sleeping time (TST), sleep stage 2 (S2), and QS [(SWS + REM) / TST * 100%] were determined by using electroencephalography. During 2 nights, sleep (2330-0730) was either disturbed or nondisturbed (control). RESULTS: Positive correlations were shown for TEE, activity-induced energy expenditure corrected for body mass (AEE/BM), respiratory quotient (RQ), and carbohydrate oxidation with QS and SWS during nondisturbed sleep. Fat oxidation was inversely correlated with QS and SWS. RQ and carbohydrate oxidation were inversely related to REM sleep. During the disturbed condition SWS, REM, TST, and S2 were reduced, and positive correlations were shown between TEE and AEE/BM with QS. The reduction in QS was stronger in high-quality sleepers; QS reduction was positively associated with increases in energy intake, TEE, and EB. CONCLUSION: A disadvantageous shift in energy balance is primarily expressed in high-quality sleepers after a decline in QS because of disturbance, implying that good sleepers are most liable to a positive energy balance because of sleep disturbance. This trial was registered at ISRCTN as NTR1919. PMID- 23803895 TI - Effects of intraduodenal lipid and protein on gut motility and hormone release, glycemia, appetite, and energy intake in lean men. AB - BACKGROUND: Intraduodenal lipid modulates gastrointestinal motility and hormone release and suppresses energy intake (EI) more than does intraduodenal glucose. Oral protein is the most satiating macronutrient and modulates postprandial glycemia; the comparative effects of intraduodenal protein and lipid and their combined effects are unclear. OBJECTIVE: We investigated the effects of intraduodenal protein and lipid, alone or in combination, on antropyloroduodenal motility, gastrointestinal hormone release, glycemia, and EI. DESIGN: Twenty lean men were studied on 5 randomized, double-blind occasions. Antropyloroduodenal motility, cholecystokinin, glucagon-like peptide-1 (GLP-1), insulin, glucagon, blood glucose, appetite, and nausea were measured during 90-min isocaloric (3 kcal/min) intraduodenal infusions of lipid [pure lipid condition (L3)], protein [pure protein condition (P3)], a 2:1 combination of lipid and protein [2:1 lipid:protein condition (L2P1)], a 1:2 combination of lipid and protein [1:2 lipid:protein condition (L1P2)], or a control. Immediately after the infusion, EI from a buffet lunch was quantified. RESULTS: In comparison with the control, all nutrient infusions suppressed antral and duodenal and stimulated pyloric pressures (P < 0.05). Cholecystokinin and GLP-1 release and pyloric stimulation were lipid-load dependent (r >= 0.39, P < 0.01), insulin and glucagon releases were protein-load dependent (r = 0.83, P < 0.001), and normoglycemia was maintained. L3 but not P3 increased nausea (P < 0.05). Compared with the control, L3 and P3 but not L2P1 or L1P2 suppressed EI (P < 0.05) without major effects on appetite. CONCLUSIONS: In lean men, despite differing effects on gut function, intraduodenal lipid and protein produce comparable reductions in energy intake. The effects of lipid may be a result of nausea. Protein also regulates blood glucose by stimulating insulin and glucagon. In contrast, at the loads selected, lipid:protein combinations did not suppress energy intake, suggesting that a threshold load is required to elicit effects. This trial was registered at Australia and New Zealand Clinical Trial Registry (http://www.anzctr.org.au) as 12609000949280. PMID- 23803896 TI - A highly sensitive electrically driven electrochemiluminescent assay for quantification of bile acids in human serum. AB - A capillary electrically driven assay with electrochemiluminescent (ECL) detection for total bile acids in human serum was developed and fully validated. Quantification was performed by multiple reactions. First, the bile acids react with nicotinamide adenine dinucleotide (NAD(+)) under catalysis of 3alpha hydroxysteroid dehydrogenase (3alpha-HSD), which is converted to 3-ketosteroid and concomitantly NAD(+) turns into reduced nicotinamide adenine dinucleotide (NADH). And then Ru(bpy)3(2+) is oxidized to be Ru(bpy)3(3+), which serves as an electron mediator, and reacts immediately with NADH coexisting in a carrier solution and is converted to Ru(bpy)3(2+*). NADH transfers an electron to form NAD(+) and the unstable excited-state species, Ru(bpy)3(2+*), which emits photons and gives out light when it decays to the ground state, Ru(bpy)3(2+). Consequently, the concentration of total bile acids could be determined by the electrochemiluminescent intensity. The assay was linear from 0.1 fmol L(-1) to 1000 fmol L(-1), with a detection limit of 0.02 fmol L(-1). The intra-day and inter-day precision had a coefficient of variation of less than 5.0%. The developed ECL assay had an acceptable correlation with an enzymatic cycling method commonly adopted in clinics for the determination of total bile acids (r = 0.7216). Based on the above-mentioned principle, we established a simple, accurate and highly sensitive approach for the determination of total bile acids. Furthermore, this assay has been applied successfully to the detection of total bile acids in human serum, indicating its practicality for bioanalysis. PMID- 23803897 TI - Cough syrup psychosis: Is it under-recognised? PMID- 23803898 TI - Asking the unanswerable: stymied again by the impossibility of sensible controls. PMID- 23803899 TI - A redesigned pressure ulcer program based on nurses' beliefs about the Braden Scale. AB - We examined nurses' perceptions about the value and applicability of the Braden Scale as an evidence-based practice assessment tool for determining nursing interventions. Findings revealed that nurses most often chose interventions associated with improving mobility over all other components of the Braden Scale assessment. The redesign of a clinical education program using targeted scenarios for aligning nurses' practice beliefs with comprehensive evidence-based practice interventions is described. PMID- 23803900 TI - An inactivated, adjuvanted whole virion clade 2.2 H5N1 (A/Chicken/Astana/6/05) influenza vaccine is safe and immunogenic in a single dose in humans. AB - In this study, we assessed in humans the immunogenicity and safety of one dose (7.5 or 15 MUg of hemagglutinin [HA]) of a whole-virion inactivated prepandemic influenza vaccine adjuvanted with aluminum hydroxide. The vaccine strain was made by reverse genetics from the highly pathogenic avian A/Chicken/Astana/6/05 (H5N1) clade 2.2 strain isolated from a dead bird in Kazakhstan. The humoral immune response was evaluated after a single vaccination by hemagglutination inhibition (HI) and microneutralization (MN) assays. The vaccine was safe and immunogenic, inducing seroconversion in 55% of the evaluated patients, with a geometric mean titer (GMT) of 17.1 and a geometric mean increase (GMI) of 3.42 after a dose of 7.5 MUg in the HI test against the vaccine strain. The rate of seroconversion increased up to 70% when the dose of 15 MUg was used. The percentages of individuals achieving anti-HA titers of >=1:40 were 52.5% and 57.5% for the 7.5- and 15-MUg dose groups, respectively. Similar results were obtained when antibodies were analyzed in an MN test. Substantial cross-neutralization titers (seroconversion in 35% and 52.5% of subjects in the two dose groups, respectively) were detected against heterologous clade 1 strain NIBRG14 (H5N1). Thus, one dose of this whole-virion prepandemic vaccine adjuvanted with aluminum has the potential to be effective against H5N1 viruses of different clades. PMID- 23803901 TI - Immunogenicity analysis of Staphylococcus aureus clumping factor A genetic variants. AB - The staphylococcal adhesin clumping factor A (ClfA) has a variant amino acid sequence, generating the potential for alterations in epitope structure and immunogenicity of this vaccine candidate. We demonstrated for two recombinant ClfA(40-531) (a slightly truncated version of the fibrinogen-binding domain of ClfA containing amino acids 40 to 531) genetic variants that strain-specific epitopes are immunodominant. This work indicates that immune responses elicited by ClfA may, at least in part, be dependent on the strain of origin of the ClfA. PMID- 23803902 TI - Macaque paneth cells express lymphoid chemokine CXCL13 and other antimicrobial peptides not previously described as expressed in intestinal crypts. AB - CXCL13 is a constitutively expressed chemokine that controls migration of immune cells to lymphoid follicles. Previously, we found CXCL13 mRNA levels increased in rhesus macaque spleen tissues during AIDS. This led us to examine the levels and locations of CXCL13 by detailed in situ methods in cynomolgus macaque lymphoid and intestinal tissues. Our results revealed that there were distinct localization patterns of CXCL13 mRNA compared to protein in germinal centers. These patterns shifted during the course of simian immunodeficiency virus (SIV) infection, with increased mRNA expression within and around follicles during AIDS compared to uninfected or acutely infected animals. Unexpectedly, CXCL13 expression was also found in abundance in Paneth cells in crypts throughout the small intestine. Therefore, we expanded our analyses to include chemokines and antimicrobial peptides (AMPs) not previously demonstrated to be expressed by Paneth cells in intestinal tissues. We examined the expression patterns of multiple chemokines, including CCL25, as well as alpha-defensin 6 (DEFA6), beta defensin 2 (BDEF2), rhesus theta-defensin 1 (RTD-1), and Reg3gamma in situ in intestinal tissues. Of the 10 chemokines examined, CXCL13 was unique in its expression by Paneth cells. BDEF2, RTD-1, and Reg3gamma were also expressed by Paneth cells. BDEF2 and RTD-1 previously have not been shown to be expressed by Paneth cells. These findings expand our understanding of mucosal immunology, innate antimicrobial defenses, homeostatic chemokine function, and host protective mechanisms against microbial translocation. PMID- 23803903 TI - Recombinant secreted antigens from Mycoplasma hyopneumoniae delivered as a cocktail vaccine enhance the immune response of mice. AB - Mycoplasma hyopneumoniae is the etiological agent of porcine enzootic pneumonia (EP), which is a respiratory disease responsible for huge economic losses in the pig industry worldwide. The commercially available vaccines provide only partial protection and are expensive. Thus, the development of alternatives for the prophylaxis of EP is critical for improving pig health. The use of multiple antigens in the same immunization may represent a promising alternative. In the present study, seven secreted proteins of M. hyopneumoniae were cloned, expressed in Escherichia coli, and evaluated for antigenicity using serum from naturally and experimentally infected pigs. In addition, the immunogenicity of the seven recombinant proteins delivered individually or in protein cocktail vaccines was evaluated in mice. In Western blot assays and enzyme-linked immunosorbent assays, most of the recombinant proteins evaluated were recognized by convalescent-phase serum from the animals, indicating that they are expressed during the infectious process. The recombinant proteins were also immunogenic, and most induced a mixed IgG1/IgG2a humoral immune response. The use of these proteins in a cocktail vaccine formulation enhanced the immune response compared to their use as antigens delivered individually, providing evidence of the efficacy of the multiple-antigen administration strategy for the induction of an immune response against M. hyopneumoniae. PMID- 23803904 TI - Role of antilipopolysaccharide antibodies in serum bactericidal activity against Salmonella enterica serovar Typhimurium in healthy adults and children in the United States. AB - Recent observations from Africa have rekindled interest in the role of serum bactericidal antibodies in protecting against systemic infection with Salmonella enterica serovar Typhimurium. To determine whether the findings are applicable to other populations, we analyzed serum samples collected from healthy individuals in the United States. We found that all but 1 of the 49 adult samples tested had robust bactericidal activity against S. Typhimurium in a standard in vitro assay. The activity was dependent on complement and could be reproduced by immunoglobulin G (IgG) purified from the sera. The bactericidal activity was inhibited by competition with soluble lipopolysaccharide (LPS) from S. Typhimurium but not from Escherichia coli, consistent with recognition of a determinant in the O-antigen polysaccharide. Sera from healthy children aged 10 to 48 months also had bactericidal activity, although it was significantly less than in the adults, correlating with lower levels of LPS-specific IgM and IgG. The lone sample in our collection that lacked bactericidal activity was able to inhibit killing of S. Typhimurium by the other sera. The inhibition correlated with the presence of an LPS-specific IgM and was associated with decreased complement deposition on the bacterial surface. Our results indicate that healthy individuals can have circulating antibodies to LPS that either mediate or inhibit killing of S. Typhimurium. The findings contrast with the observations from Africa, which linked bactericidal activity to antibodies against an S. Typhimurium outer membrane protein and correlated the presence of inhibitory anti LPS antibodies with human immunodeficiency virus infection. PMID- 23803906 TI - To be young, female, and at war. PMID- 23803905 TI - Genetic distribution of noncapsular meningococcal group B vaccine antigens in Neisseria lactamica. AB - The poor immunogenicity of the meningococcal serogroup B (MenB) capsule has led to the development of vaccines targeting subcapsular antigens, in particular the immunodominant and diverse outer membrane porin, PorA. These vaccines are largely strain specific; however, they offer limited protection against the diverse MenB associated diseases observed in many industrialized nations. To broaden the scope of its protection, the multicomponent vaccine (4CMenB) incorporates a PorA containing outer membrane vesicle (OMV) alongside relatively conserved recombinant protein components, including factor H-binding protein (fHbp), Neisseria adhesin A (NadA), and neisserial heparin-binding antigen (NHBA). The expression of PorA is unique to meningococci (Neisseria meningitidis); however, many subcapsular antigens are shared with nonpathogenic members of the genus Neisseria that also inhabit the nasopharynx. These organisms may elicit cross protective immunity against meningococci and/or occupy a niche that might otherwise accommodate pathogens. The potential for 4CMenB responses to impact such species (and vice versa) was investigated by determining the genetic distribution of the primary 4CMenB antigens among diverse members of the common childhood commensal, Neisseria lactamica. All the isolates possessed nhba but were devoid of fhbp and nadA. The nhba alleles were mainly distinct from but closely related to those observed among a representative panel of invasive MenB isolates from the same broad geographic region. We made similar findings for the immunogenic typing antigen, FetA, which constitutes a major part of the 4CMenB OMV. Thus, 4CMenB vaccine responses may impact or be impacted by nasopharyngeal carriage of commensal neisseriae. This highlights an area for further research and surveillance should the vaccine be routinely implemented. PMID- 23803907 TI - A son's seizures. PMID- 23803908 TI - Listening to nurses. PMID- 23803909 TI - Listening to nurses. PMID- 23803910 TI - Staffing disclosure. PMID- 23803911 TI - Fall prevention. PMID- 23803912 TI - The right balance between hand sanitizers and handwashing. PMID- 23803913 TI - New York nurses win wage-fixing lawsuit. PMID- 23803916 TI - The power of the lullaby. PMID- 23803918 TI - Delaware eliminates racial disparities in colorectal cancer. PMID- 23803922 TI - Rough seas across the pond for UK nurses. PMID- 23803926 TI - Women and health insurance: whose interests are covered? AB - Despite health care reform, being female can carry added expense. PMID- 23803930 TI - Mucolytic agents for COPD and chronic bronchitis. AB - This is a summary of a nursing care-related systematic review from the Cochrane Library. PMID- 23803934 TI - A project to reengineer discharges reduces 30-day readmission rates. AB - A Texas hospital achieves improvement in its readmission rate by implementing Project RED. PMID- 23803937 TI - Helping patients who don't help themselves. PMID- 23803938 TI - The quintessential nursing population. AB - A past nursing model for 'chronically critically ill' patients provides lessons for health care today.As part of its Raise the Voice campaign to showcase nurses who are key players in transforming health care, the American Academy of Nursing has identified nurses they call edge runners-"practical innovators who have led the way in bringing new thinking and new methods to a wide range of health care challenges." This is the fourth in AJN's series of profiles of these nursing innovators. Read and be proud of what nurses can accomplish. PMID- 23803940 TI - [The discussion about the application and impact of music on depressive diseases throughout history and at present]. AB - Music therapy is the customised application of music for therapeutic use. For the treatment of depression it is mostly applied within a multimodal therapeutic approach. Since music was already used in prehistoric societies to cure diseases, it can be considered as a traditional therapy. As early as the antiquity physicians discussed the kind of music, the duration and frequency of its application. In the 19th century the pioneers of modern scientific psychiatry began to follow these questions with empirical experimental research. Since the 20th century, research has been investigating the influence of music on biological and psychological parameters. Current studies show that music therapy appears to improve symptoms of depression, especially in combination with antidepressants. Due to the limited number of randomised studies, the validity of its efficiency is limited. Further research is necessary to provide evidence based recommendations regarding music therapy for the treatment of depression. PMID- 23803941 TI - Leukaemia. PMID- 23803942 TI - Epigenetics: reversible tags. PMID- 23803943 TI - Stem cells: bad seeds. PMID- 23803944 TI - Drug safety: double jeopardy. PMID- 23803945 TI - Cell banks: life blood. PMID- 23803946 TI - Perspective: assembly line immunotherapy. PMID- 23803947 TI - Living with leukaemia. PMID- 23803948 TI - Genetics: written in blood. PMID- 23803949 TI - Perspective: combined forces. PMID- 23803950 TI - Drug development: target practice. PMID- 23803951 TI - Efficacy and safety of ivabradine in chronic heart failure across the age spectrum: insights from the SHIFT study. AB - AIMS: To test whether the efficacy and safety of the selective heart rate reducing agent ivabradine changes according to age in chronic heart failure (HF) patients. METHODS AND RESULTS: The ivabradine and placebo arms of SHIFT, which enrolled 6505 chronic HF patients, were combined and age distribution was divided by quartiles to give four groups (<53 years, n = 1522; 53 to <60 years, n = 1521; 60 to <69 years, n = 1750; and >=69 years, n = 1712). The effects of ivabradine on cardiovascular outcomes, changes in heart rate, and adverse events, particularly bradycardia, were evaluated according to age group. A subgroup (602 patients) underwent 24 h ambulatory ECG Holter monitoring. The relative risk of the primary endpoint (cardiovascular death or hospitalization for worsening HF) was reduced by ivabradine in all age groups, ranging from 38% [hazard ratio (HR) 0.62, 95% confidence interval (CI) 0.50-0.78, P < 0.001] in the youngest patients <53 years to 16% (HR 0.84, 95% CI 0.71-0.99, P = 0.035) in the oldest patients >=69 years. Ivabradine up-titration reduced heart rate similarly in all age groups, by 11 b.p.m. As anticipated, bradycardia and phosphenes occurred more frequently with ivabradine, at a similar rate whatever the age. In the Holter substudy, there were no episodes of severe bradycardia and no clinically relevant pauses with ivabradine in any age group. CONCLUSIONS: Age does not limit the appropriate use of ivabradine in patients with chronic HF and systolic dysfunction. The safety and efficacy of ivabradine are comparable across all age groups. PMID- 23803953 TI - Please pack open your dirty wounds! PMID- 23803954 TI - How to use the entrainment test in the diagnosis of functional tremor. PMID- 23803952 TI - Known and missing left ventricular ejection fraction and survival in patients with heart failure: a MAGGIC meta-analysis report. AB - AIMS: Treatment of patients with heart failure (HF) relies on measurement of LVEF. However, the extent to which EF is recorded varies markedly. We sought to characterize the patient group that is missing a measure of EF, and to explore the association between missing EF and outcome. METHODS AND RESULTS: Individual data on 30 445 patients from 28 observational studies in the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) project were used to compare the prevalence of co-morbidities and outcome across three groups of HF patients: those with missing EF (HF-mEF), reduced EF (HF-REF), and preserved EF (HF-PEF). A total of 29% had HF-mEF, 52% HF-REF, and 19% HF-PEF. Compared with patients in whom EF was known, patients with HF-mEF were older, had a greater prevalence of COPD and previous stroke, and were smokers. Patients with HF-mEF were less likely to receive evidence-based treatment than those with HF-REF. Adjusted mortality in HF-mEF was similar to that in HF-REF and greater than that in HF-PEF at 3 years [HF-REF, hazard ratio (HR) 1.03, 95% confidence interval (CI) 0.95-1.12); HF-PEF, HR 0.78, 95% CI 0.71-0.86]. CONCLUSION: Missing EF is common. The short- and long term outcome of patients with HF-mEF is poor and they exhibit different co morbidity profiles and treatment patterns compared with patients with known EF. HF patients with missing EF represent a high risk group. PMID- 23803956 TI - Great enhancements in the thermoelectric power factor of BiSbTe nanostructured films with well-ordered interfaces. AB - An innovative concept of twin-enhanced thermoelectricity was proposed to fundamentally resolve the high electrical resistance while not degrading the phonon scattering of the thermoelectric nanoassemblies. Under this frame, a variety of highly oriented and twinned bismuth antimony telluride (BixSb2-xTe3) nanocrystals were successfully fabricated by a large-area pulsed-laser deposition (PLD) technique on insulated silicon substrates at various deposition temperatures. The significant presence of the nonbasal- and basal-plane twins across the hexagonal BiSbTe nanocrystals, which were experimentally and systematically observed for the first time, evidently contributes to the unusually high electrical conductivity of ~2700 S cm(-1) and the power factor of ~25 MUW cm(-1) K(-2) as well as the relatively low thermal conductivity of ~1.1 W m(-1) K(-1) found in these nanostructured films. PMID- 23803955 TI - Sustained production of ROS triggers compensatory proliferation and is required for regeneration to proceed. AB - A major issue in regenerative medicine is the role of injury in promoting cell plasticity. Here we explore the function of reactive oxygen species (ROS) induced through lesions in adult zebrafish. We show that ROS production, following adult fin amputation, is tightly regulated in time and space for at least 24 hours, whereas ROS production remains transient (2 hours) in mere wound healing. In regenerative tissue, ROS signaling triggers two distinct parallel pathways: one pathway is responsible for apoptosis, and the other pathway is responsible for JNK activation. Both events are involved in the compensatory proliferation of stump epidermal cells and are necessary for the progression of regeneration. Both events impact the Wnt, SDF1 and IGF pathways, while apoptosis only impacts progenitor marker expression. These results implicate oxidative stress in regeneration and provide new insights into the differences between healing and regeneration. PMID- 23803957 TI - Pro: "The novel oral anticoagulants should be used as 1st choice for secondary prevention in patients with atrial fibrillation.". PMID- 23803959 TI - West Nile virus and other arboviral diseases--United States, 2012. AB - Arthropod-borne viruses (arboviruses) are transmitted to humans primarily through the bites of infected mosquitoes and ticks. West Nile virus (WNV) is the leading cause of domestically acquired arboviral disease in the United States. However, several other arboviruses also cause sporadic cases and seasonal outbreaks of neuroinvasive disease (e.g., meningitis, encephalitis, and acute flaccid paralysis). In 2012, CDC received reports of 5,780 nationally notifiable arboviral disease cases (excluding dengue). A large multistate outbreak of WNV disease accounted for 5,674 (98%) of reported cases, the highest number reported since 2003. Other reported etiologies included Eastern equine encephalitis virus (EEEV), Powassan virus (POWV), St. Louis encephalitis virus (SLEV), and California serogroup viruses such as La Crosse virus (LACV) and Jamestown Canyon virus (JCV). Arboviruses continue to cause serious illness in substantial numbers of persons in the United States. Maintaining surveillance remains important to identify outbreaks and guide prevention efforts. PMID- 23803960 TI - HIV and syphilis infection among men who have sex with men--Bangkok, Thailand, 2005-2011. AB - Although efforts to control the heterosexual human immunodeficiency virus (HIV) epidemic in Thailand had shown success by the late 1990s, HIV continued to spread in other risk groups, including men who have sex with men (MSM). In 2003, the Thailand Ministry of Public Health-U.S. CDC Collaboration (TUC) started surveillance among MSM in Bangkok, finding an HIV prevalence of 17.3%. By 2005, HIV prevalence in this group had risen to 28.3% and has since stabilized at around 30%. To obtain additional information about HIV and sexually transmitted infection (STI) prevalence and incidence in a clinic-based population of MSM, TUC, in collaboration with the Thai Red Cross AIDS Research Center, analyzed data collected at the Silom Community Clinic (SCC), an HIV and STI testing center targeting MSM. This report describes trends in HIV and syphilis prevalence and incidence seen among SCC MSM clients during 2005-2011. At first clinic visit, the prevalence of HIV infection among 4,762 clients was 28.3% and of syphilis (all stages) was 9.8%. Among those returning for HIV or syphilis testing before the end of 2011, the incidence of HIV infection was 6.3 per 100 person-years (PY) and 3.6 per 100 PY for syphilis. These results show ongoing epidemics of HIV and syphilis infection in MSM in Bangkok, underscoring the urgent need for preventive interventions to reduce the spread of HIV and STI in this population. PMID- 23803961 TI - Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among children aged 6-18 years with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP). AB - On February 20, 2013, the Advisory Committee on Immunization Practices (ACIP) recommended routine use of 13-valent pneumococcal conjugate vaccine (PCV13; Prevnar 13, Wyeth Pharmaceuticals, Inc., a subsidiary of Pfizer, Inc.) for children aged 6-18 years with immunocompromising conditions, functional or anatomic asplenia, cerebrospinal fluid (CSF) leaks, or cochlear implants who have not previously received PCV13. PCV13 should be administered to these children regardless of whether they received the 7-valent pneumococcal conjugate vaccine (PCV7) or the 23-valent pneumococcal polysaccharide vaccine (PPSV23). Recommendations for PPSV23 use for children in this age group remain unchanged. The evidence for the benefits and risks associated with PCV13 vaccination of children with immunocompromising conditions was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework. This recommendation reflects a policy change from permissive and off-label recommendation of PCV13 in the pediatric immunocompromised population to a category A recommendation. This report summarizes the evidence considered by ACIP to make this recommendation and reviews the recommendations for use of PCV13 and PPSV23 for children aged 6-18 years. PMID- 23803962 TI - Occupationally acquired Salmonella I 4,12:i:1,2 infection in a phlebotomist- Minnesota, January 2013. AB - On January 25, 2013, the Minnesota Department of Health (MDH) was notified of two clinical cases of Salmonella I 4,12:i:1,2 infection with isolates that had indistinguishable pulsed-field gel electrophoresis (PFGE) patterns. Illness onset dates were January 3 and January 9, 2013. Patients A and B were hospitalized at the same hospital during January 12-15 for dehydration. Investigations indicated that these cases were part of a multistate outbreak associated with frozen mice purchased to feed snakes. PMID- 23803963 TI - Immunomodulatory interventions for focal epilepsy syndromes. AB - BACKGROUND: Epilepsy is a common neurological disorder made particularly disabling in the 30% of patients who do not achieve freedom from seizures despite multiple trials of antiepileptic drugs (AEDs). Experimental and clinical evidence supports a role for inflammatory pathway activation in the pathogenesis of epilepsy which, if effectively targeted by immunomodulatory interventions, highlights a potentially novel therapeutic strategy. OBJECTIVES: To evaluate the efficacy and tolerability of immunomodulatory interventions as additional therapy in focal epilepsy syndromes in adults. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialised Register (2 August 2012), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2012, Issue 7), MEDLINE (Ovid, 1946 to July week 3, 2012), the World Health Organization's International Clinical Trials Registry (2 August 2012), ClinicalTrials.gov (2 August 2012) and the Current Controlled Trials International Standard Randomised Controlled Trial Number Register (2 August 2012). There were no language restrictions. We reviewed the bibliographies of retrieved studies to search for additional reports of relevant studies. SELECTION CRITERIA: Randomised controlled trials of add-on immunomodulatory drug interventions for the treatment of focal epilepsy in adults (aged over 16 years). DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trial quality and extracted data. The primary outcomes were 50% or greater reduction in seizure frequency and seizure freedom; the secondary outcomes included serious and commonly occurring adverse effects, allergy, withdrawal and quality of life assessment. MAIN RESULTS: We identified one study involving both children and adults (n=61) that assessed the effect of intravenous immunoglobulin (IVIG) as add-on therapy for the treatment of epilepsy. The authors found no significant difference between IVIG and placebo for the primary outcomes of seizure freedom or 50% or greater reduction in seizure frequency. The study reported a statistically significant effect for global blind assessment (rating scale involving multiple seizure-related parameters) in favour of IVIG. Secondary outcomes including adverse effects and allergies were not demonstrated. AUTHORS' CONCLUSIONS: It is not possible to draw any conclusions about the role of immunomodulatory interventions in reducing seizure frequency or the safety of these agents in adults with epilepsy. Further randomised controlled trials are needed. PMID- 23803964 TI - Interfacial phenomena in (de)hydrogenation reactions. PMID- 23803965 TI - A new method to measure oxygen solubility in organic solvents through optical oxygen sensing. AB - A new method to measure oxygen concentration in air-saturated organic solvents and binary mixtures has been developed. The methodology relies on the ability of HPLC columns to retain the molecular oxygen contained in different types of solvents which are injected into the system at 298.15 K. The outlet of the HPLC is coupled with an optical oxygen sensor which continuously measures changes in oxygen partial pressure. PMID- 23803966 TI - Realistic control of network dynamics. AB - The control of complex networks is of paramount importance in areas as diverse as ecosystem management, emergency response and cell reprogramming. A fundamental property of networks is that perturbations to one node can affect other nodes, potentially causing the entire system to change behaviour or fail. Here we show that it is possible to exploit the same principle to control network behaviour. Our approach accounts for the nonlinear dynamics inherent to real systems, and allows bringing the system to a desired target state even when this state is not directly accessible due to constraints that limit the allowed interventions. Applications show that this framework permits reprogramming a network to a desired task, as well as rescuing networks from the brink of failure-which we illustrate through the mitigation of cascading failures in a power-grid network and the identification of potential drug targets in a signalling network of human cancer. PMID- 23803968 TI - Activation of receptors delta (PPARdelta) by agonist (GW0742) may enhance lipid metabolism in heart both in vivo and in vitro. AB - It has been documented that cardiac agents may regulate the lipid metabolism through increased expression of PPARdelta in cardiac cells. However, the effect on lipid metabolism by direct activation of PPARdelta is still unknown. The present study applied specific PPARdelta agonist (GW0742) to investigate this point in the heart of Wistar rats and in the primary cultured cardiomyocytes from neonatal rat. Expressions of PPARdelta in the heart and cardiomyocytes after treatment with GW0742 were detected using Western blots. The fatty acid (FA) oxidation and the citric acid (TCA) cycle related genes in cardiomyocytes were also examined. In addition, PPARdelta antagonist (GSK0660) and siRNA-PPARdelta were employed to characterize the potential mechanisms. After a 7-day treatment with GW0742, expressions of PPARdelta in the heart were markedly increased. Increased expressions of FA oxidation and TCA cycle related genes were also observed both in vivo and in vitro. This action of GW0742 was blocked by GSK0660 or by siRNA-PPARdelta. The obtained results show that activation of PPARdelta by GW0742 is responsible for the increase of FA oxidation and TCA cycle related genes in hearts. Role of PPARdelta in the regulation of lipid metabolism in heart is then established. PMID- 23803967 TI - Mammalian DNA demethylation: multiple faces and upstream regulation. AB - DNA cytosine methylation is a reversible epigenetic mark regulating gene expression. Aberrant methylation profiles are concomitant with developmental defects and cancer. Numerous studies in the past decade have identified enzymes and pathways responsible for active DNA demethylation both on a genome-wide as well as gene-specific scale. Recent findings have strengthened the idea that 5 methylcytosine oxidation catalyzed by members of the ten-eleven translocation (Tet1-3) oxygenases in conjunction with replication-coupled dilution of the conversion products causes the majority of genome-wide erasure of methylation marks during early development. In contrast, short and long patch DNA excision repair seems to be implicated mainly in gene-specific demethylation. Growth arrest and DNA damage-inducible protein 45 a (Gadd45a) regulates gene-specific demethylation within regulatory sequences of limited lengths raising the question of how such site specificity is achieved. A new study identified the protein inhibitor of growth 1 (Ing1) as a reader of the active chromatin mark histone H3 lysine 4 trimethylation (H3K4me3). Ing1 binds and directs Gadd45a to target sites, thus linking the histone code with DNA demethylation. PMID- 23803969 TI - Diet-dependent alterations of hepatic Scd1 expression are accompanied by differences in promoter methylation. AB - Obesity and alterations of lipid homeostasis are hallmarks of the metabolic syndrome and largely influenced by the dietary conditions of the individual. Although heritability is considered to be a major risk factor, the almost 40 candidate genes identified by genome-wide association studies (GWAS) so far account for only 5-10% of the observed variance in BMI in human subjects. Alternatively, diet-induced changes of epigenetic gene regulation might be involved in disturbed lipid homeostasis and weight development. The aim of this study was to investigate how a high-carbohydrate diet (HCD; 70 kcal% from carbohydrates, 10 kcal% from fat) or a high-fat diet (HFD; 20 kcal% from carbohydrates, 60 kcal% from fat) affects hepatic expression of genes involved in fatty acid metabolism and if these alterations are correlated to changes in promoter methylation. Expression of stearoyl-CoA desaturase 1 (Scd1) was lower in livers from HFD-fed C57BL/6 J mice compared to HCD-fed animals and correlated inversely with the degree of DNA methylation at 2 distinct, adjacent CpG sites in the Scd1 promoter. In contrast, expression of transcription factors peroxisome proliferator activated receptor alpha and gamma (Ppara, Pparg), and sterol regulatory element binding transcription factor 1 (Srebf1) was not affected. The degree of hepatic Scd1 promoter methylation at these CpG sites correlated positively to fat mass and serum leptin levels, whereas serum ghrelin levels were inversely correlated with methylation at both CpG sites. Taken together, hepatic expression of Scd1 is differentially affected by carbohydrate- and lipid content of the diet. These differences in Scd1 expression are associated with altered promoter methylation, indicating that diets affect lipid metabolism in the liver via epigenetic mechanisms. PMID- 23803970 TI - Brown adipose tissue: research milestones of a potential player in human energy balance and obesity. AB - Obesity and diabetes mellitus are worldwide epidemics driven by the disruption in energy balance. In recent years, it was discovered that functional brown adipose tissue (BAT), once thought to exist mainly in infants, is present in adults, and can be detected during cold stimulation, and is associated with decreased adiposity. Brown fat pads were shown to be highly vascularized and metabolically active and on stimulation, they caused enhanced energy expenditure and increased glucose and fatty acid uptake. These observations drew attention to the possibility that nonshivering thermogenesis mediated by activation of BAT might be important in human energy balance and a potential tool to counter obesity. Recent investigations have revealed significant advances in the understanding of the role of BAT-mediated thermogenesis, uncovering essential knowledge on the origin, differentiation, activation, and regulation of BAT in both murine models and humans. In addition to classic BAT depots, transformation of white adipocytes into brown-like adipocytes, and the development of "beige" cells from distinct precursors, were demonstrated in different animal models and resulted in increased thermogenic activity. Several transcription factors, activating proteins, and hormones are increasingly identified as regulating the development and function of both brown-like adipocytes and classic brown fat pads. This review will summarize the evolution of research on BAT in humans, in light of the renewed scientific interest and growing body of evidence showing that recruitment and activation of BAT and browning of white adipose tissue can affect energy expenditure and may be a future feasible target in the treatment of metabolic diseases. PMID- 23803972 TI - Advances in nanosized zeolites. AB - This review highlights recent developments in the synthesis of nanosized zeolites. The strategies available for their preparation (organic-template assisted, organic-template free, and alternative procedures) are discussed. Major breakthroughs achieved by the so-called zeolite crystal engineering and encompass items such as mastering and using the physicochemical properties of the precursor synthesis gel/suspension, optimizing the use of silicon and aluminium precursor sources, the rational use of organic templates and structure-directing inorganic cations, and careful adjustment of synthesis conditions (temperature, pressure, time, heating processes from conventional to microwave and sonication) are addressed. An on-going broad and deep fundamental understanding of the crystallization process, explaining the influence of all variables of this complex set of reactions, underpins an even more rational design of nanosized zeolites with exceptional properties. Finally, the advantages and limitations of these methods are addressed with particular attention to their industrial prospects and utilization in existing and advanced applications. PMID- 23803973 TI - Biosafety Recommendations for Work with Influenza Viruses Containing a Hemagglutinin from the A/goose/Guangdong/1/96 Lineage. AB - The CDC and National Institutes of Health (NIH) Biosafety in Microbiological and Biomedical Laboratories (BMBL) manual describes biosafety recommendations for work involving highly pathogenic avian influenza (HPAI) (US Department of Health and Human Services [HHS], CDC. Biosafety in microbiological and biomedical laboratories, 5th ed. Atlanta, GA: CDC; 2009. HHS publication no. [CDC] 21-1112. Available at http://www.cdc.gov/biosafety/publications/bmbl5). The U.S. Department of Agriculture Guidelines for Avian Influenza Viruses builds on the BMBL manual and provides additional biosafety and biocontainment guidelines for laboratories working with HPAI (US Department of Agriculture, Animal and Plant Health Inspection Service, Agricultural Select Agent Program. Guidelines for avian influenza viruses. Washington, DC: US Department of Agriculture; 2011. Available at http://www.selectagents.gov/Guidelines_for_Avian_Influenza_Viruses.html). The recommendations in this report, which are intended for laboratories in the United States, outline the essential baseline biosafety measures for working with the subset of influenza viruses that contain a hemagglutinin (HA) from the HPAI influenza A/goose/Guangdong/1/96 lineage, including reassortant influenza viruses created in a laboratory setting. All H5N1 influenza virus clades known to infect humans to date have been derived from this lineage (WHO/OIE/FAO H5N1 Evolution Working Group. Continued evolution of highly pathogenic avian influenza A [H5N1]: updated nomenclature. Influenza Other Respir Viruses 2012;6:1-5). In 2009, the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules were amended to include specific biosafety and biocontainment recommendations for laboratories working with Recombinant Risk Group 3 influenza viruses, including HPAI H5N1 influenza viruses within the Goose/Guangdong/1/96 like H5 lineage. In February 2013, the NIH guidelines were further revised to provide additional biosafety containment enhancements and practices for research with HPAI H5N1 viruses that are transmissible among mammals by respiratory droplets (i.e., mammalian-transmissible HPAI H5N1) (National Institutes of Health, Office of Biotechnology Activities. NIH guidelines for research involving recombinant or synthetic nucleic acid molecules. Appendix G-II-C-5: biosafety level 3 enhanced for research involving risk group 3 influenza viruses. Bethesda, MD: National Institutes of Health; 2013. Available at http://oba.od.nih.gov/rdna/nih_guidelines_oba.html). The recent revisions to the NIH guidelines focus on a smaller subset of viruses but are applicable and consistent with the recommendations in this report. The biosafety recommendations in this report were developed by CDC with advice from the Intragovernmental Select Agents and Toxins Technical Advisory Committee, which is a panel composed of federal government subject-matter experts, and from public input received in response to the request for information that was published in the Federal Register on October 17, 2012 (US Department of Health and Human Services, CDC. Influenza viruses containing the hemagglutinin from the Goose/ Guangdong/1/96 lineage; proposed rule; request for information and comment. 42 CFR, Part 73. Federal Register 2012;77:63783-5). Work with HPAI H5N1 virus should be conducted, at a minimum, at biosafety level 3 (BSL-3), with specific enhancements to protect workers, the public, animal health, and animal products. Original clinical specimens suspected of containing viruses of this lineage can only be handled at BSL-2 if the procedures do not involve the propagation of the virus. An appropriate biosafety level should be determined in accordance with a biosafety risk assessment. Additional information on performing biosafety risk assessments and establishing effective biosafety containment is available in the BMBL manual. PMID- 23803971 TI - Characterization and distribution of Reelin-positive interneuron subtypes in the rat barrel cortex. AB - GABAergic inhibitory interneurons (IN) represent a heterogeneous population with different electrophysiological, morphological, and molecular properties. The correct balance between interneuronal subtypes is important for brain function and is impaired in several neurological and psychiatric disorders. Here we show the data of 123 molecularly and electrophysiologically characterized neurons of juvenile rat barrel cortex acute slices, 48 of which expressed Reelin (Reln). Reln mRNA was exclusively detected in Gad65/67-positive cells but was found in interneuronal subtypes in different proportions: all cells of the adapting Somatostatin (SST) cluster expressed Reln, whereas 63% of the adapting neuropeptide Y (NPY, 50% of the fast-spiking Parvalbumin (PVALB), and 27% of the adapting/bursting-Vasoactive Intestinal Peptide (VIP) cluster were Reln-positive. Silhouette analysis revealed a high impact of the parameter Reln on cluster quality. By analyzing the co-localization of RELN immunoreactivity with those of different IN-markers, we found that RELN is produced layer-independently in SST-, NPY-, and NOS1-expressing INs, whereas co-localization of RELN and VIP was mostly absent. Of note, RELN co-localized with PVALB, predominantly in INs of layers IV/V (>30%). Our findings emphasize RELN's role as an important IN-marker protein and provide a basis for the functional characterization of Reln-expressing INs and its role in the regulation of inhibitory IN networks. PMID- 23803974 TI - Impact of intravenous heparin on quantification of circulating microRNAs in patients with coronary artery disease. AB - MicroRNAs are small non-coding RNAs that are detectable in plasma and serum. Circulating levels of microRNAs have been measured in various studies related to cardiovascular disease. Heparin is a potential confounder of microRNA measurements due to its known interference with polymerase chain reactions. In this study, platelet-poor plasma was obtained from patients undergoing cardiac catheterisation for diagnostic coronary angiography, or for percutaneous coronary intervention, both before and after heparin administration. Heparin had pronounced effects on the assessment of the exogenous C. elegans spike-in control (decrease by approx. 3 cycles), which disappeared 6 hours after the heparin bolus. Measurements of endogenous microRNAs were less sensitive to heparin medication. Normalisation of individual microRNAs with the average cycle threshold value of all microRNAs provided a suitable alternative to normalisation with exogenous C. elegans spike-in control in this setting. Thus, both the timing of blood sampling relative to heparin dosing and the normalisation procedure are critical for reliable microRNA measurements in patients receiving intravenous heparin. This has to be taken into account when designing studies to investigate the relation of circulating microRNAs to acute cardiovascular events or coronary intervention. PMID- 23803975 TI - Improved newborn hearing screening follow-up results in more infants identified. AB - Longitudinal research suggests that efforts at the national, state, and local levels are leading to improved follow-up and data reporting. Data now support the assumption that the number of deaf or hard-of-hearing infants identified through newborn hearing screening increases with a reduction in the number of infants lost to follow-up. Documenting the receipt of services has made a noticeable impact on reducing lost to follow-up rates and early identification of infants with hearing loss; however, continued improvement and monitoring of services are still needed. PMID- 23803976 TI - Comparison of chemical interactions with Li+ and catalytic reactivity of electrochemically generated [FeICl(L)]2- and [CoI(L)]- complexes (L = salen or salophen). AB - The cyclic voltammetric behavior of [FeIIICl(salen)] complexes has been investigated in CH3CN and compared to that obtained with [CoII(salen)] analogues. Details of the mechanism associated with iron- and cobalt-salen complex reduction in the presence of the lithium cation have been elucidated by comparison of simulated and experimental voltammograms. Electrogenerated [FeICl(salen)]2- and [FeICl(salophen)]2- complexes catalyze the dehalogenation of halo-alkyl compounds as is the case with [CoI(salen)]- complexes, even in the presence of the lithium cation which allows the reduction to occur at a less negative potential. PMID- 23803977 TI - Solution-processed flexible fluorine-doped indium zinc oxide thin-film transistors fabricated on plastic film at low temperature. AB - Transparent flexible fluorine-doped indium zinc oxide (IZO:F) thin-film transistors (TFTs) were demonstrated using the spin-coating method of the metal fluoride precursor aqueous solution with annealing at 200 degrees C for 2 hrs on polyethylene naphthalate films. The proposed thermal evolution mechanism of metal fluoride aqueous precursor solution examined by thermogravimetric analysis and Raman spectroscopy can easily explain oxide formation. The chemical composition analysed by XPS confirms that the fluorine was doped in the thin films annealed below 250 degrees C. In the IZO:F thin films, a doped fluorine atom substitutes for an oxygen atom generating a free electron or occupies an oxygen vacancy site eliminating an electron trap site. These dual roles of the doped fluorine can enhance the mobility and improve the gate bias stability of the TFTs. Therefore, the transparent flexible IZO:F TFT shows a high mobility of up to 4.1 cm(2)/V.s and stable characteristics under the various gate bias and temperature stresses. PMID- 23803978 TI - A progressively enlarging mass and abdominal distention. PMID- 23803979 TI - Progress in the treatment of peripheral T-cell lymphomas: an orphan no more. PMID- 23803980 TI - Case report series of left atrial thrombus formation in patients on dabigatran therapy. AB - Dabigatran etexilate mesylate, a direct thrombin inhibitor, has been approved in the United States as an alternative to warfarin for the prevention of stroke and systemic thromboembolism in patients with nonvalvular atrial fibrillation. The authors report 2 cases of development of large left atrial thrombi and unfortunate occurrence of thromboembolic events in patients with chronic atrial fibrillation, despite these patients being compliant with recommended dabigatran therapy. The authors postulate that certain unique pharmacologic characteristics of the drug may be disadvantageous toward providing a therapeutic level of anticoagulation in all patients and may provide an explanation of occurrence of these thrombotic events, namely, (1) a competitive, reversible, and incomplete inhibition of only one coagulation factor (thrombin), as opposed to warfarin that leads to noncompetitive inhibition of multiple coagulation factors, (2) a short half-life (12-17 hours) and linear pharmacodynamics related to drug levels that conceivably causes an hourly variation of the level of anticoagulation, (3) a much lower incidence of supratherapeutic anticoagulation ("overshoot") with dabigatran as compared with warfarin, and (4) a reported increase in the coagulation factors that follows long-term use of dabigatran. Also, the absence of routine monitoring to test the therapeutic efficacy of the drug prevents diagnosis of cases where anticoagulation remains subtherapeutic. These factors could explain occurrence of the thrombotic and thromboembolic events in our cases. PMID- 23803981 TI - The passing of the baton. PMID- 23803982 TI - In memoriam: john a. Hawkins, 1955-2011. PMID- 23803983 TI - Anomalous aortic origin of a coronary artery: preoperative diagnosis and surgical planning. AB - BACKGROUND: Anomalous aortic origin of a coronary artery (AAOCA), the anomalous coronary artery arises from an inappropriate coronary sinus and travels between the aorta and pulmonary artery. Proper surgical management depends upon correct diagnosis and accurate characterization of the origin and course of the coronary artery. Transthoracic echocardiography (TTE) has been the mainstay for diagnosis, but magnetic resonance imaging (MRI) and computed tomographic angiography (CTA) have been increasingly utilized. In this study, we report the largest series of surgically repaired AAOCA and accuracy of preoperative diagnostic studies. METHODS: A review of 53 consecutive patients (mean age 13.9 years, range 4-65 years) undergoing repair of an AAOCA from 1995 to 2009 was performed. In all, 40 patients were identified with an anomalous right coronary artery (ARCA) from the left sinus of Valsalva, 13 patients had an anomalous left coronary artery (ALCA) arising from the opposite sinus. Symptoms of angina or syncope were present in 58% and 46% of cases with ARCA and ALCA, respectively. RESULTS of preoperative diagnostic testing were compared to actual surgical findings to determine the accuracy of the tests. RESULTS: Lack of an intramural course was observed intraoperatively in 7 cases (5 ARCA and 2 ALCA). Preoperative TTE accurately predicted whether the AAOCA was intramural or extramural in 49 (92.5%) of 53 cases. Magnetic resonance imaging was predictive in 5 (83.3%) of 6 patients and CTA in 11 (64.7%) of 17. Survival was 100%. Complications occurred in 4 (7.5%) of 53 patients (mean follow-up 29 months). Patency was confirmed in 97.7% with TTE, and 23 (95.8%) of 24 patients had a negative postoperative functional study. CONCLUSIONS: Transthoracic echocardiography was found to be very accurate at defining the presence or absence of an intramural course in AAOCA. Both MRI and CTA can provide additional information but may not be as accurate as TTE. PMID- 23803984 TI - Persistent institutional difficulties in surgery for transposition of the great arteries in guatemala: analysis with the aristotle basic and comprehensive scores. AB - Background. Neonates with complex congenital cardiac lesions are largely inadequately managed in Guatemala. Methods. Between 1997 and 2009, 79 patients who underwent operations for transposition of the great arteries were identified; 51 (63.3%) had an arterial switch operation (ASO) and 28 (36%) an atrial switch operation (ATSO). The Aristotle Basic Complexity score (ABC score) and the Aristotle Comprehensive Complexity score (ACC score) have been used to aid in the evaluation of quality of care associated with pediatric cardiac surgery by adjusting for operative complexity. Results. In-hospital mortality was 47% for the ASO and 25% for the ATSO group; 36.7% were beyond 1 month of age and many exhibited increased preoperative risk factors. The mean ABC score was 9.75 +/- 0.89 and the ACC score was 12.12 +/- 2.7, with a mean 2.36-point increase (P < .05). Comparing survivors and nonsurvivors with both scores, significant differences were identified (ABC: P < .04 and ACC: P < .02). Conclusion. During this 13-year period, a low volume of surgery for transposition of the great arteries (TGA) was performed at our institution with a relatively high surgical mortality. Many patients with TGA in Guatemala are either never referred for surgery or referred late. Strategies to improve outcomes for neonates with TGA in Guatemala must include increases in early diagnosis countrywide and prompt referral to our unit. Based on the larger number of neonates with TGA that would be referred to our center, we anticipate that this strategy should substantially improve surgical outcomes and favor overall team-related skills. PMID- 23803985 TI - Association of thymectomy with infection following congenital heart surgery. AB - BACKGROUND: Congenital absence of the thymus can lead to profound immunodeficiency, suggesting that thymic function during fetal development is essential to normal lymphocyte development. How vital the thymus after birth is to human immune competence and regulation is not known. Routine thymectomy, especially at an early age, may influence immunity, and therefore the risk of infection, autoimmunity, or malignancy. METHODS: A retrospective review of cardiac surgery patients followed at Seattle Children's Hospital was performed. The primary outcome was rate of serious infections requiring hospitalization. Secondary analyses included age, type of infection, cardiac diagnosis, surgical procedure, and comorbidities. RESULTS: Patients fell into 2 groups: 60 with complete thymectomy and 35 with partial or no thymectomy. There was no statistical difference between groups in the overall prevalence of serious infections (16.7% vs 17.2%, P = 1.0). There was a nonsignificant trend toward reduced time between surgery and onset of first infection in patients in the total thymectomy group versus those without thymectomy (1.7 years vs 4.6 years, P = .07). Total thymectomy before 6 months of age also tended to increase infection rate, but the effect was not significant (0.09/year vs 0.02, P = .14). Gastroesophageal reflux in patients with total thymectomy increased the risk of infection (P = .013), suggesting a cumulative effect. CONCLUSIONS: Though infections occurred frequently in the childhood cardiac surgery population, total thymectomy was not associated with increased risk of serious infection. Comorbid conditions may be more important contributing factors increasing the risk of infection in this complex and vulnerable population. PMID- 23803986 TI - Association between postoperative Fever and atelectasis in pediatric patients. AB - BACKGROUND: Postoperative fever is common after cardiac surgery. In the absence of documented infection, atelectasis is often suggested as a cause of postoperative fever. However, this link is not well supported by pathophysiologic mechanisms. The purpose of this study was to investigate whether an association exists between atelectasis and postoperative fever in pediatric patients undergoing cardiac surgery. METHODS: A retrospective review was performed on consecutive pediatric patients who underwent cardiac surgery on cardiopulmonary bypass at a single cardiac surgery center from January 1, 2009, to December 31, 2009. Postoperative chest radiographs were evaluated and each lung was scored independently for atelectasis. Clinical parameters including the highest daily recorded temperature were noted and compared to atelectasis data. RESULTS: A total of 203 patients were enrolled; 139 patients (68.5%) had fever at least once during the first 3 postoperative days. The incidence of atelectasis on each day was 41%, 57%, and 71%, respectively. There was no association between fever and atelectasis on any postoperative day (P = .21). Microbiological cultures were performed on 81 patients, and infection was found in 7 patients (3.5%). The frequency of either fever or atelectasis was similar between cyanotic and acyanotic patients. CONCLUSIONS: Postoperative fever and atelectasis are both common after pediatric cardiac surgery. In our study, there was no significant association between postoperative fever and atelectasis. In children undergoing cardiac surgery with cardiopulmonary bypass, fever in the postoperative period should not be attributed to atelectasis. PMID- 23803987 TI - Anesthetic and cardiopulmonary bypass considerations for cardiac surgery in unique pediatric patient populations: sickle cell disease and cold agglutinin disease. AB - Physiological disturbances induced by cardiopulmonary bypass (CPB) and hypothermia during cardiac surgery are particularly pronounced in certain unique patient populations, such as patients with sickle cell disease (SCD) and cold agglutinin disease. Red blood cells containing hemoglobin S (HbS) are at increased risk of sickling under conditions encountered during cardiac surgery, leading to SCD-related complications such as vaso-occlusive events. While a target level of HbS has not been determined for patients with SCD undergoing CPB, a safe practice includes increasing the Hb level to 10 g/dL and reducing the proportion of HbS to approximately 30%. This can be accomplished through simple or exchange transfusion prior to surgery or via the modification of the CPB circuit prime. There is no clear consensus on the formulation or the delivery temperature of the cardioplegia solution necessary to prevent sickling and microvascular occlusion. The presence of cold agglutinins is another entity requiring extra vigilance for the conduct of CPB, where hypothermia can lead to activation of cold agglutinins inducing massive hemagglutination, hemolysis, microvascular thrombosis, and possibly intracoronary thrombosis. Determination of thermal amplitude is important to provide a safe reference range of temperature during surgery. High-volume plasmapheresis may be warranted to reduce cold agglutinin titers. Both warm blood cardioplegia and cold crystalloid cardioplegia above the thermal amplitude have been utilized with success. PMID- 23803988 TI - An alternative technique for cannulation of the left superior caval vein by dislocating the heart into the right thoracic cavity. AB - We describe a technique of direct cannulation of the left superior vena cava in patients undergoing intracardiac repair of tetralogy of Fallot and univentricular type of repairs. The technique consists of dislocation of the heart into the right pleural cavity, thus allowing easy performance of left superior vena cava cannulation and pulmonary arterioplasty. PMID- 23803989 TI - Pulmonary artery aneurysmal dilatation in adult patients with congenital heart disease. AB - BACKGROUND: Aneurysmal dilatation of the main pulmonary artery and its peripheral branches are rare lesions that account for less than 1% of all thoracic aneurysms and have a number of possible pathogenetic causes such as congenital heart disease (CHD), pulmonary artery hypertension, vasculitis, mycotic aneurysm, neoplasm, iatrogenic causes, trauma-related events, or connective tissue abnormalities. METHODS: We conducted a retrospective review of the demographic data and the results of clinical examinations, laboratory tests, echocardiography, and angiography of patients managed at the Adult Congenital Heart Disease Unit of the Complejo Hospitalario Universitario Insular-Materno Infantil, between January 2004 and May 2010. RESULTS: A total of 352 adult patients with CHD were studied. Of these, 8 (2.3%) patients had pulmonary artery aneurysmal dilatation (PAAD): 4 with low pressure of the pulmonary artery and 4 with pulmonary hypertension. Only 1 patient showed PAAD-related symptoms. Patients with CHD having PAAD had significantly higher prevalence of pulmonary artery hypertension and higher levels of C-reactive protein (CRP) than those without PAAD (incidence: 4 patients [50%] vs 18 patients [5.2%], P < .000; CRP in mg/dL: 0.52 [0.4; 1.2] vs 0.2 [0.0; 1.6], P = .016). No significant differences were found in cholesterol levels (total cholesterol, low-density lipoprotein [LDL], high-density lipoprotein [HDL], or triglycerides) between CHD patients with or without PAAD. CONCLUSION: In patients with CHD, PAAD is a rare finding. The PAAD size, etiology, symptoms, and association with pulmonary hypertension should guide decisions on whether conservative or surgical treatment should be applied. PMID- 23803990 TI - Introduction to the proceedings of the eighth international conference of the pediatric cardiac intensive care society. PMID- 23803991 TI - Blood utilization in neonates and infants undergoing cardiac surgery requiring cardiopulmonary bypass. AB - Neonates and infants undergoing cardiac surgery with cardiopulmonary bypass are exposed to multiple blood products from different donors. The volume of the bypass circuit is often as large as the patient's total blood volume and asanguineous bypass primes are unusual. As a result, blood products are required for the cardiopulmonary bypass prime and are often used to treat the postbypass dilutional coagulopathy. We review clot formation and strength, cardiopulmonary bypass prime considerations, assessment of postbypass coagulopathy, component therapy use, ultrafiltration techniques, and use of antifibrinolytic medications. A combined approach including techniques to minimize the prime volume, utilization of ultrafiltration, administration of antifibrinolytics during surgery, and the proper treatment of the dilutional coagulopathy can limit the transfusion requirements. PMID- 23803992 TI - Endocrinopathies in the cardiac ICU. AB - The past several years have seen an increased appreciation of the potential role of the endocrine system in the recovery process following surgery for congenital heart disease. Many of the hormonal changes following cardiac surgery are adaptive and necessary, whereas activation of proinflammatory cytokine and chemokine responses and some of the metabolic changes following surgery are likely mediators leading to detrimental outcomes. Additionally, other hormonal perturbations may contribute to adverse outcomes. This review examines the pain and the stress response, thyroid function and hyperglycemia following cardiopulmonary bypass (CPB), and the potential role of corticosteroids in the pediatric cardiac critical care unit. PMID- 23803993 TI - Acute kidney injury and critical cardiac disease. AB - The field of cardiac intensive care continues to advance in tandem with congenital heart surgery. The survival of patients with critical congenital heart disease is seldom in question. Consequently, the focus has now shifted to that of morbidity reduction and eventual elimination. Acute kidney injury (AKI) after cardiac surgery is associated with adverse outcomes, including prolonged intensive care and hospital stays, diminished quality of life, and increased long term mortality. Acute kidney injury occurs frequently, complicating 30% to 40% of adult and pediatric cardiac surgeries. Patients who require dialysis are at high risk of mortality, but even minor degrees of postoperative AKI portend a significant increase in mortality and morbidity. PMID- 23803994 TI - Acute cardiac resynchronization therapy for the failing left, right, or single ventricle after repaired congenital heart disease. AB - Use of cardiac resynchronization in children and young adults with congenital heart disease has been described in a variety of anecdotal cases and pooled institutional summaries which report mid-term results. This manuscript addresses use of cardiac resynchronization and/or multisite pacing in children in the acute postoperative period with a failing right, left, or single ventricle. PMID- 23803995 TI - Cardiac intensive care of the adult with congenital heart disease: basic principles in the management of common problems. AB - Although there has been an intense interest in the care of the adult with congenital heart disease (ACHD), these guidelines are usually not focused on the concepts of immediate postoperative care. The 2 most common perioperative complications are heart failure and atrial dysrhythmias. The broad etiological categories for ACHD and heart failure include primary pump failure (systolic dysfunction) and hypertrophy (diastolic dysfunction) of the right, left, or single ventricle. Some conditions with a pressure-loaded systemic right ventricle as well as patients with a functionally single ventricle may be particularly prone to develop heart failure; in others, right heart failure may occur in patients with Ebstein anomaly or with tetralogy of Fallot after corrective repair but with varying degrees of pulmonary insufficiency, and left heart failure can be a result of mitral or aortic insufficiency. The management of postoperative atrial tachycardia in the ACHD patient actually begins prior to surgery. Assessment of arrhythmia history, complete determination of risk, inducibility and arrhythmia substrate, preoperative planning of pacing sites, and optimal pacing strategies all assist to bring about optimal postoperative outcomes. Ideal perioperative care of the ACHD involves a multidisciplinary team of pediatric and adult cardiologists, pediatric and adult intensivists, cardiac surgeons, and nursing staff along with a myriad of adult subspecialists such as pulmonology, nephrology, endocrinology, and others including psychiatry. PMID- 23803996 TI - Can randomized clinical trials impact the surgical approach for hypoplastic left heart syndrome? AB - The Eighth International Conference of the Pediatric Cardiac Intensive Care Society was held in Miami, Florida, December 8 to 11, 2010. The program included a session dedicated to the management of hypoplastic left heart syndrome (HLHS), with particular emphasis on the innovations that have led to contemporary schemes of management and the role of clinical trials in the evolution and acceptance of these strategies. An invited panel of experts reviewed the historical evolution of staged surgical reconstruction, the randomized clinical trials that have been undertaken thus far, and the extent to which these have, or have not, influenced individual and institutional approaches to management of HLHS. PMID- 23803997 TI - Prematurity and congenital heart disease. AB - Significant advances in technology and therapy have led to dramatic improvements in the survival of preterm babies over the last 2 decades. Similarly, improvements in surgical and cardiac intensive care techniques have increased the feasibility of supporting even very small babies to the point of surgical repair, leading some to adopt an approach of early and complete surgical repair in preterm infants, with the aim of minimizing potential preoperative morbidity associated with extended medical management or surgical palliation. (1,2) However, multiple diagnostic and therapeutic challenges complicate the care of premature infants. Major errors in echocardiography are more common in neonates weighing less than 2.5 kg, (3) and the ideal timing and type of surgical intervention in premature infants remains unknown. These problems are compounded by the need for critical care practices that optimize management of immature cardiopulmonary, gastrointestinal, and neurological systems. This review will summarize some of the recent advances in neonatal and perinatal medicine, which have the potential to contribute to improved management of preterm infants with critical cardiac disease. PMID- 23803998 TI - Risky business: human factors in critical care. AB - Remarkable achievements have occurred in pediatric cardiac critical care over the past two decades. The specialty has become well defined and extremely resource intense. A great deal of focus has been centered on optimizing patient outcomes, particularly mortality and early morbidity, and this has been achieved through a focused and multidisciplinary approach to management. Delivering high-quality and safe care is our goal, and during the Risky Business symposium and simulation sessions at the Eighth International Conference of the Pediatric Cardiac Intensive Care Society in Miami, December 2010, human factors, systems analysis, team training, and lessons learned from malpractice claims were presented. PMID- 23803999 TI - Hexagonal Six-point Traction Technique for Optimum Surgical Exposure of the Subaortic Region. AB - Surgery of the subaortic region is challenging because of spatial limitations. We present our technique of enhanced exposure of this region that allows for a smooth, expeditious, and safe repair of such lesions as subaortic stenosis, hypertrophic cardiomyopathy, subaortic ventricular septal defects, and related pathologies. Using a hexagonal 6-point traction technique, approximately 84% of the cross-sectional area of the aortic root is made available to the surgeon for a transaortic subaortic resection keeping the use of retractors to a minimum. The technique ensures protection of the aortic valve leaflets and the enhanced exposure may contribute to improved surgical outcomes. PMID- 23804001 TI - Reversal of fortune: surgical management of transposition in the pre-arterial switch era. AB - The development of operations for transposition of the great arteries (TGA) culminating in the eventual success of the arterial switch operation (ASO) remains one of the most intriguing demonstrations of ingenuity in the history of cardiac surgery. Very early attempts at switching the great arteries were daring but unsuccessful. This early lack of success with the ASO proved daunting, and yielded to "venous" switches, with increasing success. These venous switches evolved into the atrial baffle procedures, which began in the first golden age of TGA surgery of the 1960s and 1970s. The continued quest for an anatomic correction resulted in other clever operations before the modern era of the ASO. PMID- 23804000 TI - Translational research in pediatric extracorporeal life support systems and cardiopulmonary bypass procedures: 2011 update. AB - Over the past 6 years at Penn State Hershey, we have established the pediatric cardiovascular research center with a multidisciplinary research team with the goal to improve the outcomes for children undergoing cardiac surgery with cardiopulmonary bypass (CPB) and extracorporeal life support (ECLS). Due to the variety of commercially available pediatric CPB and ECLS devices, both in vitro and in vivo translational research have been conducted to achieve the optimal choice for our patients. By now, every component being used in our clinical settings in Penn State Hershey has been selected based on the results of our translational research. The objective of this review is to summarize our translational research in Penn State Hershey Pediatric Cardiovascular Research Center and to share the latest results with all the interested centers. PMID- 23804002 TI - A gratifying surgical repair of anomalous left coronary artery from pulmonary artery: three decades of follow-up. AB - Establishing a two coronary system is the best treatment option for anomalous origin of left coronary artery from the pulmonary artery (ALCAPA). We describe a case of ALCAPA with three decades of follow up after an end-to-end anastomosis of left subclavian artery and left coronary artery with mitral valve replacement. This technique of establishing a two coronary system was done in an era when coronary transfer technique was not established and myocardial protection techniques were not available. This case is also the longest follow up of prosthetic mitral valve replacement in a child with ALCAPA. PMID- 23804003 TI - One-Stage Surgical Repair for Berry Syndrome With Preoperative Diagnosis by 3 Dimensional CT. AB - Berry syndrome is a rare congenital combination of an aortopulmonary window, an aortic origin of the right pulmonary artery, an interrupted aortic arch with a patent ductus arteriosus, and an intact ventricular septum. We report a successful one-stage surgical correction of Berry syndrome. Also, we demonstrate the importance of prompt clinical recognition with echocardiography and 3 dimensional reconstruction of computed tomography (3D-CT) and timely operation for the management of this rare cardiac anomaly. PMID- 23804004 TI - Novel use of extracellular matrix graft for creation of pulmonary valved conduit. AB - We report the use of a commercially available graft material to create a trileaflet pulmonary valved conduit, which was implanted in a 12-year-old girl with mixed aortic valve disease as part of a Ross procedure. The patient presented with severe aortic insufficiency and left ventricular dilatation following balloon valvuloplasty. The patient lives in Ecuador, where most commonly used replacements for the pulmonary valve are either unavailable or unaffordable. Our technique involves the use of porcine small intestinal submucosal extracellular matrix (SIS-ECM), commercially available as CorMatrix ECM (CorMatrix Cardiovascular, Inc, Tallahassee, Florida) to create a trileaflet valved conduit. PMID- 23804005 TI - Left Main Coronary Artery Compression by Right Ventricle-to-Pulmonary Artery Conduit Relieved by Anterior Translocation of the Right Pulmonary Artery. AB - Pulmonary artery translocation has been described as an alternative surgical strategy to treat anomalous aortic origin of the coronary artery from the wrong sinus of Valsalva. We describe another application of this strategy in a patient who underwent complete repair of pulmonary atresia with ventricular septal defect and presented years later with ischemic symptoms due to compression of the left main coronary artery by the right ventricular-to-pulmonary artery conduit. To our knowledge, this is the first application of the pulmonary artery translocation technique to treat such a problem. PMID- 23804006 TI - Two cases of double-outlet left ventricle detected prenatally. AB - Double-outlet left ventricle is an exceedingly rare congenital heart defect. Its prenatal detection and precise anatomical definition are challenging for a variety of reasons and have never been previously reported. Here described are 2 cases of prenatally diagnosed double-outlet left ventricle. The technical limitations of prenatal diagnosis and its implications for the surgical management of patients affected by such a rare condition are discussed. PMID- 23804007 TI - Surgical repair of a cause of sudden death: left coronary artery originating from right coronary sinus. AB - Left coronary artery originating from the right coronary sinus is one of the most frequent causes of sudden death in young people. We present a reconstructive surgical technique for left coronary artery and main pulmonary artery in a case with anomalous origin of the left coronary artery from the right coronary sinus. A 15-year-old boy underwent unroofing of the left main coronary artery and patch arterioplasty with autologous pericardium after transection of the main pulmonary artery. The pulmonary artery was reconstructed with autologous pericardium and a piece of dacron patch in order to prevent coronary artery compression. This surgical approach resulted in successful clinical outcome. PMID- 23804008 TI - Successful closure of large congenital coronary fistula with an amplatzer vascular plug: a case report and review of the literature. AB - We describe the case of a 3.5-year-old-girl with large coronary fistula that originated from the proximal left coronary artery and, after a tortuous distal course, drained into the right atrium. The narrowest fistula diameter was 6.7 mm. Fistula was successfully closed with a 12-mm Amplatzer vascular plug type 1 using a retrograde approach without creating an arteriovenous loop. Femoral artery damage that required thrombolytic (streptokinase) therapy was observed after the procedure. Retrograde approach does not require creation of an arteriovenous loop. However, potential benefits have to be considered in the light of potential peripheral artery damage and subsequent thrombolytic therapy. PMID- 23804009 TI - Use of Intra-Aortic Balloon Counterpulsation in an Adult Patient With Left Ventricular Failure following Repair of Tetralogy of Fallot: A Case Report. AB - We report the case of a 26-year-old male patient who developed primary left ventricular failure with subsequent biventricular failure early following intracardiac repair of tetralogy of Fallot. The failing biventricular circulation was successfully supported using intra-aortic balloon counterpulsation. Aortic counterpulsation facilitates recovery of biventricular function and appears to be a reasonable alternative in select instances of systemic ventricular failure following repair of tetralogy of Fallot. PMID- 23804010 TI - Transposition of the great arteries in situs inversus totalis. AB - A rare case of a newborn with situs inversus totalis associated with simple transposition of the great arteries is reported. A successful anatomical surgical repair was accomplished on day 10 of life, consisting of an arterial switch operation with reimplantation of the coronary arteries. PMID- 23804011 TI - Calcified right atrial myxoma in an adolescent. AB - Images are presented of a 14-year-old patient with chest pain discovered to have a calcified mass overlying the cardiac silhouette on lateral chest radiograph. Further imaging led to a diagnosis of a right atrial myxoma, which was surgically excised. While cardiac neoplasms are typically diagnosed with advanced imaging, the tendency for myxomas to calcify may allow for detection on plain radiographs. PMID- 23804012 TI - Large tortuous patent ductus arteriosus with proximal left pulmonary artery hypoplasia. AB - A 3-year-old male child was diagnosed with patent ductus arteriosus. The evaluation of this patient by computed tomography (CT) angiography revealed a big tortuous patent ductus arteriosus and proximal left pulmonary artery stenosis. Successful elective surgical repair was undertaken. PMID- 23804013 TI - Expressive writing and wound healing in older adults: a randomized controlled trial. AB - OBJECTIVE: To investigate whether expressive writing could speed wound reepithelialization in healthy, older adults. METHODS: In this randomized controlled trial, 49 healthy older adults aged 64 to 97 years were assigned to write for 20 minutes a day either about upsetting life events (Expressive Writing) or about daily activities (Time Management) for 3 consecutive days. Two weeks postwriting, 4-mm punch biopsy wounds were created on the inner, upper arm. Wounds were photographed routinely for 21 days to monitor wound reepithelialization. Perceived stress, depressive symptoms, health-related behaviors, number of doctor visits, and lipopolysaccharide-stimulated proinflammatory cytokine production were also measured throughout the study. RESULTS: Participants in the Expressive Writing group had a greater proportion of fully reepithelialized wounds at Day 11 postbiopsy compared with the Time Management group, with 76.2% versus 42.1% healed, chi(2)(1, n = 40) = 4.83, p = .028. Ordinal logistic regression showed more sleep in the week before wounding also predicted faster healing wounds. There were no significant group differences in changes to perceived stress, depressive symptoms, health-related behaviors, lipopolysaccharide-induced proinflammatory cytokine production, or number of doctor visits over the study period. CONCLUSIONS: This study extends previous research by showing that expressive writing can improve wound healing in older adults and women. Future research is needed to better understand the underlying cognitive, psychosocial, and biological mechanisms contributing to improved wound healing from these simple, yet effective, writing exercises. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (trial number 343095). PMID- 23804015 TI - Authors' response to the correspondence entitled 'too ill for an implantable cardioverter defibrillator?'. PMID- 23804016 TI - Eruptive, hard cutaneous nodules in a 61-year-old woman. Osteoma cutis in a patient with Albright hereditary osteodystrophy (AHO). PMID- 23804014 TI - An empirical review of the neural underpinnings of receiving and giving social support: implications for health. AB - Decades of research have demonstrated strong links between social ties and health. Although considerable evidence has shown that social support can attenuate downstream physiological stress responses that are relevant to health, the neurocognitive mechanisms that translate perceptions of social ties into altered physiological responses are still not fully understood. This review integrates research from social and affective neuroscience to illuminate some of the neural mechanisms involved in social support processes, which may further our understanding of the ways in which social support influences health. This review focuses on two types of social support that have been shown to relate to health: receiving and giving social support. As the neural basis of receiving support, this article reviews the hypothesis that receiving support may benefit health through the activation of neural regions that respond to safety and inhibit threat-related neural and physiological responding. This article will then review neuroimaging studies in which participants were primed with or received support during a negative experience as well as studies in which self-reports of perceived support were correlated with neural responses to a negative experience. As the neural basis of giving support, this article reviews the hypothesis that neural regions involved in maternal caregiving behavior may be critical for the health benefits of support-giving through the inhibition of threat-related neural and physiological responding. Neuroimaging studies in which participants provided support to others or engaged in other related forms of prosocial behavior will then be reviewed. Implications of these findings for furthering our understanding of the relationships between social support and health are discussed. PMID- 23804017 TI - Radiofluorination of diaryliodonium tosylates under aqueous-organic and cryptand free conditions. AB - Positron emission tomography (PET) has growing importance as a molecular imaging technique in clinical research and drug development. Methods for producing PET radiotracers utilizing cyclotron-produced [(18)F]fluoride ion (t1/2 = 109.7 min) without the need for complete removal of irradiated target [(18)O]water and addition of cryptand are keenly sought for practical convenience and efficiency. Several structurally diverse diaryliodonium tosylates, XArI(+)Ar'Y TsO(-) (X = H or p-MeO), were investigated in a microfluidic apparatus for their reactivity towards radiofluorination with high specific activity (no-carrier-added) [(18)F]fluoride ion in mixtures of DMF and irradiated target [(18)O]water in the absence of cryptand. Salts bearing a para or ortho electron-withdrawing group Y (e.g., Y = p-CN) reacted rapidly (~3 min) to give the expected major [(18)F]fluoroarene product, [(18)F]FArY, in useful moderate radiochemical yields even when the solvent had an [(18)O]water content up to 28%. Salts bearing electron-withdrawing groups in meta position (e.g., Y = m-NO2), or an electron donating substituent (Y = p-OMe), gave low radiochemical yields under the same conditions. PMID- 23804019 TI - Application of chromatographic data in QSAR Studies of 3-[omega-(4-Arylpiperazin 1-yl)alkyl]pyrimido[5,4-c]quinolin-4(3H)-one derivatives as 5-HT1A receptor ligands. AB - The activity of several 3-[omega-(4-arylpiperazin-1-yl)alkyl]pyrimido[5,4 c]quinolin-4(3H)-ones (LCAPs) with well-defined serotonin 1A (5-HT1A) receptor affinity was described by using chromatographic and calculated physicochemical parameters in quantitative structure-activity relationship analysis. Normal-phase thin-layer chromatography plates impregnated with solutions of L-aspartic acid, L serine, L-phenylalanine, L-tryptophan, L-tyrosine, L-asparagine, L-threonine and their mixtures (denoted as S1-S11 biochromatographic models) were used with two mobile phases as a model of the interaction between LCAP and 5-HT1A receptors. Molecular descriptors for the investigated compounds were calculated by using HyperChem and ACD/Labs programs. The significant relationship explains that 82% of the variance was successfully validated by leave-one-out and leave-many-out tests. The results demonstrated that this model has significant predictive ability and can be used for the preliminary screening of newly synthesized potential 5-HT1A receptor ligands. PMID- 23804018 TI - Association between hypermethylation of DNA repetitive elements in white blood cell DNA and early-onset colorectal cancer. AB - Changes in the methylation levels of DNA from white blood cells (WBCs) are putatively associated with an elevated risk for several cancers. The aim of this study was to investigate the association between colorectal cancer (CRC) and the methylation status of three DNA repetitive elements in DNA from peripheral blood. WBC DNA from 539 CRC cases diagnosed before 60 years of age and 242 sex and age frequency-matched healthy controls from the Australasian Colorectal Cancer Family Registry were assessed for methylation across DNA repetitive elements Alu, LINE-1 and Sat2 using MethyLight. The percentage of methylated reference (PMR) of cases and controls was calculated for each marker. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression adjusted for potential confounders. CRC cases demonstrated a significantly higher median PMR for LINE-1 (p < 0.001), Sat2 (p < 0.001) and Alu repeats (p = 0.02) when compared with controls. For each of the DNA repetitive elements, individuals with PMR values in the highest quartile were significantly more likely to have CRC compared with those in the lowest quartile (LINE-1 OR = 2.34, 95%CI = 1.48-3.70; p < 0.001, Alu OR = 1.83, 95%CI = 1.17-2.86; p = 0.01, Sat2 OR = 1.72, 95%CI = 1.10-2.71; p = 0.02). When comparing the OR for the PMR of each marker across subgroups of CRC, only the Alu marker showed a significant difference in the 5 fluoruracil treated and nodal involvement subgroups (both p = 0.002). This association between increasing methylation levels of three DNA repetitive elements in WBC DNA and early-onset CRC is novel and may represent a potential epigenetic biomarker for early CRC detection. PMID- 23804020 TI - Modified classification and single-stage microsurgical repair of posttraumatic infected massive bone defects in lower extremities. AB - Posttraumatic infected massive bone defects in lower extremities are difficult to repair because they frequently exhibit massive bone and/or soft tissue defects, serious bone infection, and excessive scar proliferation. This study aimed to determine whether these defects could be classified and repaired at a single stage. A total of 51 cases of posttraumatic infected massive bone defect in lower extremity were included in this study. They were classified into four types on the basis of the conditions of the bone defects, soft tissue defects, and injured limb length, including Type A (without soft tissue defects), Type B (with soft tissue defects of 10 * 20 cm or less), Type C (with soft tissue defects of 10 * 20 cm or more), and Type D (with the limb shortening of 3 cm or more). Four types of single-stage microsurgical repair protocols were planned accordingly and implemented respectively. These protocols included the following: Protocol A, where vascularized fibular graft was implemented for Type A; Protocol B, where vascularized fibular osteoseptocutaneous graft was implemented for Type B; Protocol C, where vascularized fibular graft and anterior lateral thigh flap were used for Type C; and Protocol D, where limb lengthening and Protocols A, B, or C were used for Type D. There were 12, 33, 4, and 2 cases of Types A, B, C, and D, respectively, according to this classification. During the surgery, three cases of planned Protocol B had to be shifted into Protocol C; however, all microsurgical repairs were completed. With reference to Johner-Wruhs evaluation method, the total percentage of excellent and good results was 82.35% after 6 to 41 months of follow-up. It was concluded that posttraumatic massive bone defects could be accurately classified into four types on the basis of the conditions of bone defects, soft tissue coverage, and injured limb length, and successfully repaired with the single-stage repair protocols after thorough debridement. PMID- 23804021 TI - Microsurgical reconstruction of the mandible in a patient with evans syndrome: a case report and review of the literature. AB - In this report, we describe the first successful case of microvascular free tissue transfer in a patient with Evans Syndrome (ES), a rare form of idiopathic thrombocytopenic purpura (ITP) and associated autoimmune hemolytic anemia (AIHA). Microvascular surgery in the setting of ES is likely to have higher complication rates because of the increased risk of postoperative bleeding and free flap thrombosis. The case presented here opens up to the feasibility of microvascular reconstruction of patients with coagulation disorders like ES. Every effort should be made to control for hemolytic, thrombocytopenic, and thrombophilic states associated with ES. In the absence of evidence-based treatment guidelines for ES, personalized treatment protocols with high-dose corticosteroids, immunoglobulin, and postoperative anticoagulation regimen are highly recommended. PMID- 23804022 TI - The syntheses, structures and properties of three new lanthanoid thioarsenates: the only example of thioarsenate acting as a ligand to a lanthanide complex. AB - Three new lanthanoid thioarsenates [Eu(en)3(eta2-AsS4)] (1, en = ethylenediamine), [Er(teta)(en)(eta2-AsS4)] (2, teta = triethylenetetramine) and [La2(tepa)2(MU-eta1,eta3-AsS3)2] (3, tepa = tetraethylenepentamine) have been solvothermally synthesized and structurally characterized. In compounds 1 and 2, the tetrathioarsenate [AsS4]3- anions act as eta2-AsS4 chelating ligands to the lanthanide complexes [Eu(en)3]3+/[Er(teta)(en)]3+, leading to neutral molecules [Eu(en)3(eta2-AsS4)]/[Er(teta)(en)(eta2-AsS4)], whereas the [AsS3]3- anion in compound 3 acts as a MU-eta1,eta3-AsS3 tetradentate bridging ligand to link [La(tepa)]3+ ions into neutral centrosymmetric [La2(tepa)2(MU-eta1,eta3-AsS3)2] moieties, where a new coordination mode of MU-eta1,eta3-AsS3 is observed for the [AsS3]3- ligand. Compounds 1-3 are the only examples of solvothermally synthesized thioarsenates where the [AsS4]3-/[AsS3]3- anions act as ligands in the lanthanide complex. Compound 1 exhibits a fluorescence emission at room temperature. Density functional theory calculations for compounds 2 and 3 also have been performed, and the absorption edges of compounds 1-3 have been investigated by UV-vis spectroscopy. PMID- 23804023 TI - alpha-Tanycytes of the adult hypothalamic third ventricle include distinct populations of FGF-responsive neural progenitors. AB - Emerging evidence suggests that new cells, including neurons, can be generated within the adult hypothalamus, suggesting the existence of a local neural stem/progenitor cell niche. Here, we identify alpha-tanycytes as key components of a hypothalamic niche in the adult mouse. Long-term lineage tracing in vivo using a GLAST::CreER(T2) conditional driver indicates that alpha-tanycytes are self-renewing cells that constitutively give rise to new tanycytes, astrocytes and sparse numbers of neurons. In vitro studies demonstrate that alpha-tanycytes, but not beta-tanycytes or parenchymal cells, are neurospherogenic. Distinct subpopulations of alpha-tanycytes exist, amongst which only GFAP-positive dorsal alpha2-tanycytes possess stem-like neurospherogenic activity. Fgf-10 and Fgf-18 are expressed specifically within ventral tanycyte subpopulations; alpha tanycytes require fibroblast growth factor signalling to maintain their proliferation ex vivo and elevated fibroblast growth factor levels lead to enhanced proliferation of alpha-tanycytes in vivo. Our results suggest that alpha tanycytes form the critical component of a hypothalamic stem cell niche, and that local fibroblast growth factor signalling governs their proliferation. PMID- 23804024 TI - Surveillance for foodborne disease outbreaks - United States, 1998-2008. AB - PROBLEM/CONDITION: Foodborne diseases cause an estimated 48 million illnesses each year in the United States, including 9.4 million caused by known pathogens. Foodborne disease outbreak surveillance provides valuable insights into the agents and foods that cause illness and the settings in which transmission occurs. CDC maintains a surveillance program for collection and periodic reporting of data on the occurrence and causes of foodborne disease outbreaks in the United States. This surveillance system is the primary source of national data describing the numbers of illnesses, hospitalizations, and deaths; etiologic agents; implicated foods; contributing factors; and settings of food preparation and consumption associated with recognized foodborne disease outbreaks in the United States. REPORTING PERIOD: 1998-2008. DESCRIPTION OF THE SYSTEM: The Foodborne Disease Outbreak Surveillance System collects data on foodborne disease outbreaks, defined as the occurrence of two or more cases of a similar illness resulting from the ingestion of a common food. Public health agencies in all 50 states, the District of Columbia, U.S. territories, and Freely Associated States have primary responsibility for identifying and investigating outbreaks and use a standard form to report outbreaks voluntarily to CDC. During 1998-2008, reporting was made through the electronic Foodborne Outbreak Reporting System (eFORS). RESULTS: During 1998-2008, CDC received reports of 13,405 foodborne disease outbreaks, which resulted in 273,120 reported cases of illness, 9,109 hospitalizations, and 200 deaths. Of the 7,998 outbreaks with a known etiology, 3,633 (45%) were caused by viruses, 3,613 (45%) were caused by bacteria, 685 (5%) were caused by chemical and toxic agents, and 67 (1%) were caused by parasites. Among the 7,724 (58%) outbreaks with an implicated food or contaminated ingredient reported, 3,264 (42%) could be assigned to one of 17 predefined commodity categories: fish, crustaceans, mollusks, dairy, eggs, beef, game, pork, poultry, grains/beans, oils/sugars, fruits/nuts, fungi, leafy vegetables, root vegetables, sprouts, and vegetables from a vine or stalk. The commodities implicated most commonly were poultry (18.9%; 95% confidence interval [CI] = 17.4 20.3) and fish (18.6%; CI = 17.2-20), followed by beef (11.9%; CI = 10.8-13.1). The pathogen-commodity pairs most commonly responsible for outbreaks were scombroid toxin/histamine and fish (317 outbreaks), ciguatoxin and fish (172 outbreaks), Salmonella and poultry (145 outbreaks), and norovirus and leafy vegetables (141 outbreaks). The pathogen-commodity pairs most commonly responsible for outbreak-related illnesses were norovirus and leafy vegetables (4,011 illnesses), Clostridium perfringens and poultry (3,452 illnesses), Salmonella and vine-stalk vegetables (3,216 illnesses), and Clostridium perfringens and beef (2,963 illnesses). Compared with the first 2 years of the study (1998-1999), the percentage of outbreaks associated with leafy vegetables and dairy increased substantially during 2006-2008, while the percentage of outbreaks associated with eggs decreased. INTERPRETATION: Outbreak reporting rates and implicated foods varied by state and year, respectively; analysis of surveillance data for this 11-year period provides important information regarding changes in sources of illness over time. A substantial percentage of foodborne disease outbreaks were associated with poultry, fish, and beef, whereas many outbreak-related illnesses were associated with poultry, leafy vegetables, beef, and fruits/nuts. The percentage of outbreaks associated with leafy vegetables and dairy increased during the surveillance period, while the percentage associated with eggs decreased. PUBLIC HEALTH ACTIONS: Outbreak surveillance data highlight the etiologic agents, foods, and settings involved most often in foodborne disease outbreaks and can help to identify food commodities and preparation settings in which interventions might be most effective. Analysis of data collected over several years of surveillance provides a means to assess changes in the food commodities associated most frequently with outbreaks that might occur following improvements in food safety or changes in consumption patterns or food preparation practices. Prevention of foodborne disease depends on targeted interventions at appropriate points from food production to food preparation. Efforts to reduce foodborne illness should focus on the pathogens and food commodities causing the most outbreaks and outbreak associated illnesses, including beef, poultry, fish, and produce. PMID- 23804025 TI - A cyclodextrin dimer as a supramolecular reaction platform for aqueous organometallic catalysis. AB - A reaction platform based on a cyclodextrin dimer, which is able to simultaneously include a substrate in one cavity and an organometallic catalyst into the other, proved to be highly efficient for aqueous hydroformylation reaction of higher olefins. PMID- 23804026 TI - Enhancing graphene reinforcing potential in composites by hydrogen passivation induced dispersion. AB - To take full advantages of the structural uniqueness and exceptional properties of graphene as reinforcement in composites, harvesting well-dispersed graphene is essential. On the other hand, it is challenging to achieve simultaneously high stiffness, strength and toughness in engineered materials because of the trade off relations between these properties. Here we demonstrate that the graphene reinforcing potential can be significantly enhanced through the excellent dispersion of graphene sheets in the matrix material and the strong graphene matrix bonding by the coupled hydrogen passivation and ultrasonication technique. The fabricated graphene/epoxy composites exhibit simultaneously remarkable increase in elastic modulus, fracture strength, and fracture energy. We found that the inlet hydrogen atoms in the hydrogen passivation serve as a source of the second atoms to terminate the C dangling bonds and form more stable C-H bonds, separating graphene flakes and promoting the binding with the matrix material. PMID- 23804027 TI - Erlotinib versus gefitinib for control of leptomeningeal carcinomatosis in non small-cell lung cancer. AB - INTRODUCTION: Leptomeningeal carcinomatosis (LMC) from non-small-cell lung cancer (NSCLC) is a clinically important neurological complication in the era of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). The purpose of this study was to compare the efficacy of gefitinib and erlotinib for control of LMC in NSCLC. METHODS: We retrospectively reviewed medical records of 25 EGFR TKI-treated NSCLC patients with LMC between 2004 and 2012 at Seoul National University Hospital. Cytologic negative conversion was defined as absence of malignant cells in the cerebrospinal fluid three times in succession. Cytologic conversion rates were compared between the gefitinib arm and the erlotinib arm. RESULTS: Nine patients had exon 21 point mutations and eight patients had exon 19 deletional mutations. Nine of 25 patients had already used EGFR TKIs and switched to another EGFR TKI after LMC occurrence. The other 16 patients received EGFR TKIs after LMC diagnoses. All the patients received intrathecal chemotherapy, including methotrexate, and six of them were treated with combined whole-brain radiotherapy. Gefitinib and erlotinib were administered to 11 and 14 patients, respectively. Ten patients had LMC controlled with cytologic negative conversion, whereas in 15 patients, cytological clearance of the cerebrospinal fluid could not be achieved. Patients treated with erlotinib showed better cytologic conversion rate of LMC than those with gefitinib (64.3% [9 of 14] in the erlotinib arm versus 9.1% [1 of 11] in the gefitinib arm; p = 0.012). CONCLUSION: This study suggested that erlotinib had better control rate for LMC in NSCLC than gefitinib. Further prospective study is warranted. PMID- 23804028 TI - The innervated gracilis muscle for microsurgical functional lip reconstruction: review of the literature. AB - Reconstruction of the lower and upper lip should meet both aesthetic and functional requirements, whenever possible. Achievement of these goals presents a major challenge particularly in extensive lip defects requiring microsurgical reconstruction. Successful reconstructive outcomes have been reported using free fasciocutaneous flaps such as composite radial forearm flap or anterolateral thigh flap in conjunction with static tendon slings. In recent years, neurovascular gracilis muscle transfer has been introduced in hopes to overcome noncontractile properties of these flaps and to restore oral competence by muscle contractility. This article reviews the available data on the innervated gracilis muscle transfer for functional lip reconstruction. Tips and techniques gleaned from all of the current literature are discussed. PMID- 23804029 TI - Study on distribution of terminal branches of the facial nerve in mimetic muscles (orbicularis oculi muscle and orbicularis oris muscle). AB - There have been many anatomical reports to date regarding the course of the facial nerve to the mimetic muscles. However, reports are relatively scarce on the detailed distribution of the terminal branches of the facial nerve to the mimetic muscles. In this study, we performed detailed examination of the terminal facial nerve branches to the mimetic muscles, particularly the branches terminating in the orbicularis oculi muscle and orbicularis oris muscle. Examination was performed on 25 Japanese adult autopsy cases, involving 25 hemifaces. The mean age was 87.4 years (range, 60-102 years). There were 12 men and 13 women (12 left hemifaces and 13 right hemifaces). In each case, the facial nerve was exposed through a preauricular skin incision. The main trunk of the facial nerve was dissected from the stylomastoid foramen. A microscope was used to dissect the terminal branches to the periphery and observe them. The course and distribution were examined for all terminal branches of the facial nerve. However, focus was placed on the course and distribution of the zygomatic branch, buccal branch, and mandibular branch to the orbicularis oculi muscle and orbicularis oris muscle. The temporal branch was distributed to the orbicularis oculi muscle in all cases and the marginal mandibular branch was distributed to the orbicularis oris muscle in all cases. The zygomatic branch was distributed to the orbicularis oculi muscle in all cases, but it was also distributed to the orbicularis oris muscle in 10 of 25 cases. The buccal branch was not distributed to the orbicularis oris muscle in 3 of 25 cases, and it was distributed to the orbicularis oculi muscle in 8 cases. There was no significant difference in the variations. The orbicularis oculi muscle and orbicularis oris muscle perform particularly important movements among the facial mimetic muscles. According to textbooks, the temporal branch and zygomatic branch innervate the orbicularis oculi muscle, and the buccal branch (or the buccal branch and marginal mandibular branch) innervates the orbicularis oris muscle. In this study, we performed dissection of the terminal facial nerve branches that terminate in the orbicularis oculi muscle and orbicularis oris muscle and performed detailed examination of their courses. The results revealed 5 multiple anomalies not in conventional books, and the movements of the muscles might be compensated. PMID- 23804030 TI - Asymmetrically substituted 5,5'-bistriazoles--nitrogen-rich materials with various energetic functionalities. AB - In this contribution the synthesis and full structural and spectroscopic characterization of three asymmetrically substituted bis-1,2,4-triazoles, along with different energetic moieties like amino, nitro, nitrimino and azido moieties, is presented. Additionally, selected nitrogen-rich ionic derivatives have been prepared and characterized. This comparative study on the influence of these energetic moieties on structural and energetic properties constitutes a complete characterization including IR, Raman and multinuclear NMR spectroscopy. Single crystal X-ray crystallographic measurements were performed and provide insight into structural characteristics as well as inter- and intramolecular interactions. The standard enthalpies of formation were calculated for all compounds at the CBS-4M level of theory, revealing highly positive heats of formation for all compounds. The detonation parameters were calculated using the EXPLO5 program and compared to the common secondary explosive RDX as well as recently published symmetric bistriazoles. As expected, the measured sensitivities to mechanical stimuli and decomposition temperatures strongly depend on the energetic moiety of the triazole ring. All compounds were characterized in terms of sensitivities (impact, friction, electrostatic) and thermal stabilities, the ionic derivatives were found to be thermally stable, insensitive compounds. PMID- 23804031 TI - Human enterovirus species B in ileocecal Crohn's disease. AB - OBJECTIVES: Advanced ileocecal Crohn's disease (ICD) is characterized by strictures, inflammation in the enteric nervous system (myenteric plexitis), and a high frequency of NOD2 mutations. Recent findings implicate a role of NOD2 and another CD susceptibility gene, ATG16L1, in the host response against single stranded RNA (ssRNA) viruses. However, the role of viruses in CD is unknown. We hypothesized that human enterovirus species B (HEV-B), which are ssRNA viruses with dual tropism both for the intestinal epithelium and the nervous system, could play a role in ICD. METHODS: We used immunohistochemistry and in situ hybridization to study the general presence of HEV-B and the presence of the two HEV-B subspecies, Coxsackie B virus (CBV) and Echovirus, in ileocecal resections from 9 children with advanced, stricturing ICD and 6 patients with volvulus, and in intestinal biopsies from 15 CD patients at the time of diagnosis. RESULTS: All patients with ICD had disease-associated polymorphisms in NOD2 or ATG16L1. Positive staining for HEV-B was detected both in the mucosa and in myenteric nerve ganglia in all ICD patients, but in none of the volvulus patients. Expression of the cellular receptor for CBV, CAR, was detected in nerve cell ganglia. CONCLUSIONS: The common presence of HEV-B in the mucosa and enteric nervous system of ICD patients in this small cohort is a novel finding that warrants further investigation to analyze whether HEV-B has a role in disease onset or progress. The presence of CAR in myenteric nerve cell ganglia provides a possible route of entry for CBV into the enteric nervous system. PMID- 23804033 TI - Kindlin-1 regulates mitotic spindle formation by interacting with integrins and Plk-1. AB - Kindlin-1 binds to integrins and regulates integrin activation at cell adhesions. Here we report a new function of Kindlin-1 in regulating spindle assembly. We show that Kindlin-1 localizes to centrosomes, its concentration peaking during G2/M, where it associates with various pericentriolar material proteins, including Polo-like kinase 1. Short interfering RNA-mediated depletion of Kindlin 1 increases formation of abnormal mitotic spindles and decreases cellular survival. This effect is dependent not only on the ability of Kindlin-1 to bind integrins but also on Polo-like kinase 1-mediated Kindlin-1 phosphorylation. We demonstrate that a subcellular pool of phosphorylated Kindlin-1 is located exclusively at centrosomes. Our work identifies a novel cellular role for Kindlin 1 in ensuring mitotic spindle assembly and cellular survival that is controlled by phosphorylation via Polo-like kinase 1. PMID- 23804035 TI - Altered spontaneous activity in antisocial personality disorder revealed by regional homogeneity. AB - There is increasing evidence that antisocial personality disorder (ASPD) stems from brain abnormalities. However, there are only a few studies investigating brain structure in ASPD. The aim of this study was to find regional coherence abnormalities in resting-state functional MRI of ASPD. Thirty-two ASPD individuals and 34 controls underwent a resting-state functional MRI scan. The regional homogeneity (ReHo) approach was used to examine whether ASPD was related to alterations in resting-state neural activity. Support vector machine discriminant analysis was used to evaluate the sensitivity/specificity characteristics of the ReHo index in discriminating between the ASPD individuals and controls. The results showed that, compared with controls, ASPD individuals show lower ReHo in the right cerebellum posterior lobe (Crus1) and the right middle frontal gyrus, as well as higher ReHo in the right middle occipital gyrus (BA 19), left inferior temporal gyrus (BA 37), and right inferior occipital gyrus (cuneus, BA 18). All alternation regions reported a predictive accuracy above 70%. To our knowledge, this study was the first to study the change in regional activity coherence in the resting brain of ASPD individuals. These results not only elucidated the pathological mechanism of ASPD from a resting-state functional viewpoint but also showed that these alterations in ReHo may serve as potential markers for the detection of ASPD. PMID- 23804036 TI - Extraordinary hall balance. AB - Magnetoresistance (MR) effects are at the heart of modern information technology. However, future progress of giant and tunnelling MR based storage and logic devices is limited by the usable MR ratios of currently about 200% at room temperature. Colossal MR structures, on the other hand, achieve their high MR ratios of up to 10(6)% only at low temperatures and high magnetic fields. We introduce the extraordinary Hall balance (EHB) and demonstrate room-temperature MR ratios in excess of 31,000%. The new device concept exploits the extraordinary Hall effect in two separated ferromagnetic layers with perpendicular anisotropy in which the Hall voltages can be configured to be carefully balanced or tipped out of balance. Reprogrammable logic and memory is realised using a single EHB element. PACS numbers: 85.75.Nn,85.70.Kh,72.15.Gd,75.60.Ej. PMID- 23804038 TI - Triterpene saponins from Clematis mandshurica and their antiproliferative activity. AB - Six new triterpene saponins, clematomandshurica saponins F-K (1-6), together with a known compound (7), were isolated from the roots and rhizomes of Clematis mandshurica. Their structures were elucidated on the basis of spectroscopic evidence and hydrolysis. Compounds 5-7 exhibited antiproliferative effects against PC-3 human prostate cancer cells with GI50 values of 1.29, 1.50, and 0.71 uM, respectively. PMID- 23804034 TI - The MORC family: new epigenetic regulators of transcription and DNA damage response. AB - Microrchidia (MORC) is a highly conserved nuclear protein superfamily with widespread domain architectures that intimately link MORCs with signaling dependent chromatin remodeling and epigenetic regulation. Accumulating structural and biochemical evidence has shed new light on the mechanistic action and emerging role of MORCs as epigenetic regulators in diverse nuclear processes. In this Point of View, we focus on discussing recent advances in our understanding of the unique domain architectures of MORC family of chromatin remodelers and their potential contribution to epigenetic control of DNA template-dependent processes such as transcription and DNA damage response. Given that the deregulation of MORCs has been linked with human cancer and other diseases, further efforts to uncover the structure and function of MORCs may ultimately lead to the development of new approaches to intersect with the functionality of MORC family of chromatin remodeling proteins to correct associated pathogenesis. PMID- 23804039 TI - Dodoviscin a inhibits melanogenesis in mouse b16-f10 melanoma cells. AB - Nowadays, abnormal hyperpigmentation in human skin such as melasma, freckles, and chloasma has become a serious esthetic problem. Cutaneous depigmenting agents could be used to treat these hyperpigmentation-associated dieseases. Dodoviscin A is a natural product isolated from the aerial parts of Dodonaea viscosa. In the present study, we evaluated the effect of dodoviscin A on melanin production in B16-F10 melanoma cells for the first time. We found that dodoviscin A inhibited melanin biosynthesis induced by 3-isobutyl-1-methylxanthine and PD98059 significantly, and there was no obvious effect on the viability of dodoviscin A treated B16-F10 cells. Meanwhile, dodoviscin A could suppress the activity of mushroom tyrosinase in the cell-free assay system and also decrease 3-isobutyl-1 methylxanthine-induced tyrosinase activity and expression of mature tyrosinase protein in B16-F10 cells. Western blotting analysis showed that dodoviscin A inhibited 3-isobutyl-1-methylxanthine and forskolin-induced phosphorylation of the cAMP response element binding protein in B16-F10 cells. These results indicate that dodoviscin A may be a new promising pigmentation-altering agent for cosmetic and therapeutic applications. PMID- 23804040 TI - Antiproliferative triterpenoid saponins from the stem of Psychotria sp. AB - Six new triterpenoid saponins, psychotrianosides A-F (1-6), and two known triterpenoid saponins, psychotrianoside G (7) and ardisianoside D (8), were isolated from Psychotria sp. Their structures were determined mainly by spectroscopic methods. The cytotoxic activities of 1-8 against five human cancer cell lines (MDA-MB-231, MCF-7, MCF-7/ADM, HepG2, and HepG2/ADM) are reported for the first time. Psychotrianoside C (3) showed the most potent antiproliferative activity among these saponins, and the IC50 value of 3 against MDA-MB-231 was 2.391 +/- 0.161 uM. Compound 3 was also found to induce apoptosis. PMID- 23804041 TI - Centenary symposium. Introduction. PMID- 23804043 TI - Surgery 1913: the genesis of the British Journal of Surgery. PMID- 23804044 TI - Surgical research and its impact. PMID- 23804045 TI - Surgical innovation and the introduction of new technologies. PMID- 23804046 TI - Knowledge management. PMID- 23804047 TI - BJS: the good, the bad and the ugly. PMID- 23804048 TI - Volume 1 of the BJS. PMID- 23804049 TI - Surgical training. PMID- 23804050 TI - Surgical ethics. PMID- 23804051 TI - Surgical leadership. PMID- 23804052 TI - Surgical innovation. PMID- 23804053 TI - Surgical publishing. PMID- 23804054 TI - Surgical behaviour. PMID- 23804055 TI - Surgical sepsis. PMID- 23804056 TI - Surgical safety. PMID- 23804057 TI - Surgical specialization. PMID- 23804059 TI - From the editor. PMID- 23804058 TI - Surgical collaboration. PMID- 23804060 TI - A transtheoretical, case management approach to the treatment of pediatric obesity. AB - OBJECTIVE: The percentage of obese children in the United States has increased dramatically over the past three decades, particularly among ethnic/ racial minorities. This study sought to examine the impact of a clinical case-management intervention based upon the Transtheoretical Model (TTM) to reduce obesity and increase physical activity in children. METHODS: Nineteen obese African-American children ages 8-12 were recruited from two pediatric clinics and were randomized to either a 12-week intervention group or a control group. Dependent variables included body mass index (BMI) percentile, physical activity, and stage of change for the child and parent. RESULTS: In comparison to the control group, the intervention group demonstrated significant decreases in BMI and improvements in daily vigorous physical activity. The children in the intervention group demonstrated movement toward action/maintenance stages of change. CONCLUSIONS: A 12-week TTM-based case management intervention can have a favorable impact on obesity and physical activity in African-American child. PMID- 23804061 TI - Increased frequency of no-shows in residents' primary care clinic is associated with more visits to the emergency department. AB - The high prevalence of no-shows in residents' primary care clinic acts as a barrier to continuity of care, results in loss of outpatient learning opportunities, and may result in more emergency department (ED) visits. The authors seek to identify if high rates of no-shows correlate with more ED visits. In a selected primary care internal medicine (PCIM) continuity clinic, 650 patients were randomly selected, with 325 patients each from the faculty and resident practices. The number of ED visits between January 1, 2006, and December 30, 2008, was recorded. Demographic characteristics of the population were obtained, and comparisons between the faculty and resident groups were performed using Student t test. Linear multiple regression analysis was performed to compare frequency of ED visits between the faculty and the resident groups, controlling for age, interpreter requirement, number of ED visits, proportion of no-shows, and insurance type. A P value <.05 was considered statistically significant. During 2006-2008, the average number of ED visits per patient in the faculty's practice was 2.1 compared with 4.1 in the resident's practice (P < .001). A multiple linear regression model showed that patients who had more ED visits were likely to be younger (P = .004), had shorter duration of care in the PCIM clinic (P < .001), and had a higher proportion of no-shows to the PCIM clinic (P < .001). There was no statistical difference between faculty and resident practice after adjusting for the above-mentioned variables. Shorter duration in the PCIM clinic and higher proportion of missed appointments were associated with more ED visits, but the use of interpreters and Medicaid insurance did not result in more ED visits. Future interventions are necessary to reduce the no-show rate in the clinic as this may result in a reduction of ED visits. PMID- 23804062 TI - Patients in a depression collaborative care model of care: comparison of 6-month cost utilization data with usual care. AB - A collaborative care model (CCM) has been implemented for management of depression. This paper studies the impact that the CCM had on cost measures for the period of six months after initial diagnosis of depression compared to patients receiving usual care (UC). There was a significant increase in the CPT costs for the six months following diagnosis in the CCM group ($451.35 vs. $323.50, P < 0.001). The average CPT cost rank and CPT cost differential were also significantly increased in the CCM group. The adjusted means of the CPT costs were (when controlling for prior utilization) $452.11 for the CCM group and $322.09 for UC (P < 0.001). In the CCM group; there were 161 patients (73.5%) that achieved a clinical response for their depression compared to the UC group, which had a 15.1% (18/119) response rate (P < 0.001). There also was a significant difference between the groups in those who were symptoms free of their depression (PHQ-9 score < 5), with the CCM having 59.4% of the patients symptom-free compared to 10.9% of the UC group (P < 0.001). In this group of patients, CCM is associated with markedly improved clinical outcomes for depression, however with a modest short-term increase in CPT costs. PMID- 23804063 TI - Is appropriate management of atrial fibrillation in primary care a utopia? AB - OBJECTIVE: The authors aimed at reporting on whether or not primary care doctors follow atrial fibrillation (AF) treatment protocols, and on the mental distress of such patients. METHODS: A total of 138 patients with first detected or recurrent AF were examined in a health center. Demographic data were collected and their lifestyle and medical history for rhythm-related pathologies and chronic medication were investigated. Physical examination, electrocardiogram (EKG), and in selected cases, lab analysis were carried-out. CHADS2 index was used for assessing the stroke risk in patients with AF, while the General Health Questionnaire-12 (GHQ-12) for personal health perception was performed in all patients. RESULTS: According to CHADS2 the majority of the patients had at least 1 risk factor and half of those receiving oral vitamin K antagonists presented an out-of-range international normalized ratio (INR). In 24 cases, patients used both aspirin and oral anticoagulants, while in 41 cases, medication was corrected according to index. GHQ-12 seemed to be significantly worse in paroxysmal and persistent cases, as well as in women with recurrent AF. Many paroxysmal AF patients under 75 years continued caffeine intake, whereas an extensive use of benzodiazepines was noticed in the majority of patients. CONCLUSIONS: Shortages and limitations of the peripheral or rural units and health centers and inadequate knowledge and application of the guidelines, seemed to be major factors responsible for mismanaging AF patients. More education in prehospital cardiology may contribute in improving management of arrhythmias in primary care. PMID- 23804064 TI - Lifestyle change interventions for children and adolescents with diabetes or kidney disease. AB - The purpose of this research letter is to report on the availability of evidence based interventions for promoting lifestyle change in children and adolescents with diabetes or kidney disease. References for this review were obtained using several electronic databases, including Ebsco Host, PsychInfo, Medline, and CINAHL. Search topics included transplant adherence, diabetes adherence, kidney adherence, obesity and transplant, kidney disease, transplant noncompliance, renal failure, renal disease, chronic kidney failure, end-stage renal disease, obesity and diabetes, overweight and kidney disease, overweight and diabetes, overweight, treatment interventions and overweight, treatment interventions for obesity, children and obesity, growth chart, diabetes intervention, kidney disease intervention, obesity intervention, obesity and transplantation, obesity transplant intervention, motivational interviewing, physical activity level, physical activity, exercise intervention, body mass index measurement, body fat percentage, psychosocial issues of kidney disease, psychosocial issues of transplant, and coping with kidney disease. Search results included English language only and between the years 2000 and 2009. Very few lifestyle interventions have been shown to be effective for obese children or adolescents with diabetes and none for obese children and adolescents with kidney diseases. More research is needed to develop effective interventions for this vulnerable population. PMID- 23804065 TI - Dashboard impact evaluation for primary care and community health programs. AB - Dashboard impact evaluations are studies that assess the short-term effects of health programs on performance indicators that are of interest to senior managers. Evaluations of this type can be performed rapidly and at relatively low cost if evaluators are experienced and independent, and use standard methods. Assessment of short-term impacts can provide valuable encouragement or raise concerns that call for close monitoring or redirection of program activities. Preliminary results can be in hand as early as 60 days after a program begins operations. PMID- 23804066 TI - Organizational culture, job satisfaction, and clinician turnover in primary care. AB - The purpose of this study is to examine how organizational culture and job satisfaction affect clinician turnover in primary care pediatric practices. One hundred thirty clinicians from 36 primary care pediatric practices completed the Primary Care Organizational Questionnaire (PCOQ), which evaluates interactions among members of the practice and job-related attributes measuring 8 organizational factors, along with a separate 3-item instrument measuring job satisfaction. Random effects logistic models were used to assess the associations between job satisfaction, the organizational factors from the PCOQ, and clinician turnover over the subsequent year. All 8 measured organizational factors from the PCOQ, particularly perceived effectiveness, were associated with job satisfaction. Five of the 8 organizational factors were also associated with clinician turnover. The effects of the organizational factors on turnover were substantially reduced in a model that included job satisfaction; only 1 organizational factor, communication between clinicians and nonclinicians, remained significant (P = .05). This suggests that organizational culture affects subsequent clinician turnover primarily through its effect on job satisfaction. Organizational culture, in particular perceived effectiveness and communication, affects job satisfaction, which in turn affects clinician turnover in primary care pediatric practices. Strategies to improve job satisfaction through changes in organizational culture could potentially reduce clinician turnover. PMID- 23804067 TI - Gender differences in prevalence of somatoform disorders in patients visiting primary care centers. AB - The aim of this study was to examine the gender differences in the prevalence of somatoform disorders among a sample of Qatari patients who were visiting primary health care centers and to investigate the severity of diagnostic categories and the most frequent somatic symptoms in these patients. The first stage of the study was conducted with the help of general practitioners, using the somatic symptom module of the Patient Health Questionnaire 12-item General Health Questionnaire. Overall, 2320 subjects were approached, and a total of 1689 patients, of whom 892 were men and 797 were women, agreed to participate in the study. The prevalence rate of somatoform disorders among the total screened sample was 23.9%. The prevalence rate was slightly higher in Qatari women (24.2%) than in Qatari men (23.7%). Housewives (43.5%) and men in administrative posts (37.9%) reported higher somatic symptoms compared to other professions. Prolonged depressive reaction was significantly higher in women compared to men (P = .003). There was a significant gender difference in certain psychiatric diagnostic categories such as depressive episode, recurrent depressive disorder, dysthymia, and brief depressive reaction. Backache was the most common reported symptom in men, whereas headache was more common in women. The present study revealed that the prevalence of somatoform disorders in Qatar is as high as the overall prevalence reported in prior studies done in other primary care settings. The prevalence of somatoform disorders was slightly higher in Qatari women than in men. PMID- 23804068 TI - The "Iowa get screened" colon cancer screening program. AB - OBJECTIVE: To implement a colon cancer screening program for uninsured or underinsured Iowans. METHODS: All 1995 uninsured patients or patients with Iowa Care insurance aged 50 to 64 years attending the University of Iowa Clinic or the Iowa City Free Medical Clinic were mailed information about the project. Recruitment also took place in person, by having the clinic receptionist hand subjects a research packet, and through community posters. Individuals with colonic symptoms or who were up to date with screening were ineligible. Eligible subjects received a free fecal immunochemical test (FIT), and those with positive FITs were provided with a colonoscopy at no cost to them. RESULTS: Of 449 individuals who completed eligibility forms (23% of the study population), 297 (66%) were eligible and were provided with an FIT. Two-hundred thirty-five (79%) returned a stool sample, with 49 (21%) testing positive. Thirty of the 49 (61%) individuals had a colonoscopy, and 20 individuals had at least 1 polyp biopsied. Thirteen individuals had at least 1 tubular adenoma; 2 had adenomas more than 1 cm in diameter, with no colon cancers identified. Face-to-face recruitment had the highest rate of returned FITs (72%) compared with handing the subject a research packet (3%) or a mailing only (9%) (Chi-square, P < .001). CONCLUSION: There was high interest in and compliance with colon cancer screening using a FIT among underinsured individuals. Although the FIT positivity rate was higher than expected, many individuals did not complete recommended follow-up colonoscopies. Population-based strategies for offering FIT could significantly increase colon cancer screening among disadvantaged individuals, but programs will have to develop sustainable mechanisms to include the necessary organization and address substantial costs of providing mass screening, as well as facilitating and providing colonoscopies for those who test positive. PMID- 23804069 TI - Lessons learned from a Boston community health center promoting the human papilloma virus vaccine in a minority adult population. AB - This quality improvement study aims to examine knowledge and attitudes about human papillomavirus (HPV) vaccination among women ages 18 through 26 in a Boston community health center to increase uptake of the HPV vaccine in the local community. This cross-sectional study was conducted from August 2007 to July 2008 at an urban community health center in Roxbury, Massachusetts. Women offered HPV vaccines were asked to complete a questionnaire. Eighty-four percent of participants had heard of the HPV vaccine. A higher percentage (69%) of minority women in this study as compared with those in other studies knew the vaccine protects against cervical cancer. Forty-two percent of women came to their appointment for the purpose of being vaccinated. The remaining 58% came for another reason and received vaccination upon health care provider recommendation. Only 38% of participants reported perceived risk for HPV infection as a motivation for vaccination. These findings suggest that generalizations of attitudes and knowledge about the HPV vaccine should not be made with regard to race and ethnicity alone, but rather need to be based on surveys of the specific local population served. In addition, education about HPV risk should be continued, especially about risk factors for HPV infection. PMID- 23804070 TI - Is depression a modifiable risk factor for diabetes burden? AB - The purpose of this review article was to examine the empirical evidence supporting depression as a risk factor for diabetes complications and associated burden. A database search using keywords located recent clinical and population studies addressing the association between depression and type 2 diabetes. Both cross-sectional and cohort studies were reviewed. Depression appears to exacerbate the progression of type 2 diabetes. The evidence is strong supporting the hypothesis that depression in persons with diabetes increases the risk of diabetes-related burden, including suboptimal glycemic control, complications, functionality, mortality, and health care utilization. Screening for depression among patients with diabetes should be increased in primary care. Newer approaches to diabetes care management may help to slow the progression of diabetes. PMID- 23804071 TI - Evaluation of rational use of medications in the United States. AB - Rational medication use means taking medication appropriately for curing and relieving the symptoms of disease on the basis of evidence and sound judgment. We compare US policy experience on rational use of medications with the World Health Organization (WHO) list of interventions designed to promote such use. Current US performance and educational, managerial, and regulatory interventions to improve it are discussed. We conclude that, while most of the WHO guidelines for rational medication use are practiced in some form in one or more of the various US health care subsystems today, overall performance based on outcomes is not comparable with that of other industrialized countries. This is due to the absence of a national drug policy, the presence of a few strong stakeholders with committed policy preferences, and the altogether fragmented character of the US state and federal health systems. Practical suggestions are offered as to how the US could improve its overall less-than-optimal policies on rational medication use. PMID- 23804072 TI - E-Factor minimized hydrophosphonylation of aldehydes catalyzed by polystyryl-BEMP under solvent-free conditions. AB - An efficient protocol for the hydrophosphonylation of aromatic and aliphatic aldehydes catalyzed by PS-BEMP under solvent-free conditions (SolFC) has been reported. Addition reactions were performed by using equimolar amounts of reagents and the resulting alpha-hydroxyphosphonates were isolated with simple workup procedures. A large scale protocol for the preparation of a representative alpha-hydroxyphosphonate 3a has been also set up using a flow reactor. PMID- 23804073 TI - Modulation of TSC-mTOR signaling on immune cells in immunity and autoimmunity. AB - The mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase which has a central role in the regulation of cell growth and metabolism. In the study of the mTOR signaling pathway, tuberous sclerosis complex (TSC) 1/2 complex is identified as a critical regulator of mTOR activity. TSC1/2 plays important roles for immune cell homeostasis and differentiation by negative control of mTOR signaling pathway. TSC1/2-mTOR pathway is proving to be a central point in regulating immune function of diverse immune cells. In this review, we discuss the function of TSC1/2-mTOR to direct the innate and adaptive immune cell development and function. Furthermore, we focus on the role of TSC1/2 mTOR signaling pathway in immune cell mediated diseases, especially autoimmunity. PMID- 23804074 TI - Chemical and genetic validation of thiamine utilization as an antimalarial drug target. AB - Thiamine is metabolized into an essential cofactor for several enzymes. Here we show that oxythiamine, a thiamine analog, inhibits proliferation of the malaria parasite Plasmodium falciparum in vitro via a thiamine-related pathway and significantly reduces parasite growth in a mouse malaria model. Overexpression of thiamine pyrophosphokinase (the enzyme that converts thiamine into its active form, thiamine pyrophosphate) hypersensitizes parasites to oxythiamine by up to 1,700-fold, consistent with oxythiamine being a substrate for thiamine pyrophosphokinase and its conversion into an antimetabolite. We show that parasites overexpressing the thiamine pyrophosphate-dependent enzymes oxoglutarate dehydrogenase and pyruvate dehydrogenase are up to 15-fold more resistant to oxythiamine, consistent with the antimetabolite inactivating thiamine pyrophosphate-dependent enzymes. Our studies therefore validate thiamine utilization as an antimalarial drug target and demonstrate that a single antimalarial can simultaneously target several enzymes located within distinct organelles. PMID- 23804075 TI - De-targeting by miR-143 decreases unwanted transgene expression in non tumorigenic cells. AB - MicroRNA dysregulation often results in the development and progression of cancer. miR-143 is ubiquitously expressed in most human and murine tissues but downregulated in many cancer types. This differential miRNA expression can be utilized for targeted cancer gene therapies. Multiple copies of the miR-143 complementary target sequence were inserted into the 3'UTR of plasmid vectors encoding either for different reporter genes or for the therapeutic gene TNFalpha. With these transgenes, we analyzed the miR-143-dependent gene expression in cancer cells and normal cells. Moreover, we investigated miR-143 regulated luciferase expression in an NMRI nude/HUH7 xenograft mouse model using a nonviral carrier system for in vivo transfections. We showed low and high levels of miR-143 in cancer cells and normal cells, respectively, leading to a differential gene expression of the reporters and the therapeutic TNFalpha. According to the miR-143 levels, the luciferase reporter gene expression was silenced in the mouse lungs but not in HUH7 tumors. Thus, we utilized the differential miR-143 expression in healthy and cancerous tissues to de-target the lung by specifically targeting the tumor in an in vivo HUH7 xenograft mouse model. The use of an miR-143-regulated therapeutic transgene may present a promising approach for cancer gene therapy. PMID- 23804076 TI - Long-term efficacy of ciliary muscle gene transfer of three sFlt-1 variants in a rat model of laser-induced choroidal neovascularization. AB - Inhibition of vascular endothelial growth factor (VEGF) has become the standard of care for patients presenting with wet age-related macular degeneration. However, monthly intravitreal injections are required for optimal efficacy. We have previously shown that electroporation enabled ciliary muscle gene transfer results in sustained protein secretion into the vitreous for up to 9 months. Here, we evaluated the long-term efficacy of ciliary muscle gene transfer of three soluble VEGF receptor-1 (sFlt-1) variants in a rat model of laser-induced choroidal neovascularization (CNV). All three sFlt-1 variants significantly diminished vascular leakage and neovascularization as measured by fluorescein angiography (FA) and flatmount choroid at 3 weeks. FA and infracyanine angiography demonstrated that inhibition of CNV was maintained for up to 6 months after gene transfer of the two shortest sFlt-1 variants. Throughout, clinical efficacy was correlated with sustained VEGF neutralization in the ocular media. Interestingly, treatment with sFlt-1 induced a 50% downregulation of VEGF messenger RNA levels in the retinal pigment epithelium and the choroid. We demonstrate for the first time that non-viral gene transfer can achieve a long term reduction of VEGF levels and efficacy in the treatment of CNV. PMID- 23804077 TI - Downregulation of Stat3 in melanoma: reprogramming the immune microenvironment as an anticancer therapeutic strategy. AB - Persistent activation of the transcription factor, signal transducer and activator of transcription 3 (Stat3) has been shown to mediate several oncogenic features in many types of cancers, including melanoma. In this study, we investigated whether lentiviral (LV) delivery of Stat3-targeting short hairpin RNA (shRNA; LV-shStat3) to K1735-C4 melanoma cells modulates antitumor immunity. Three shStat3 sequences, starting at the position 446, 830 and 1412, were cloned into a mir30 cassette. A shRNA with scrambled sequence served as a control. Transduction with LV-shStat3 resulted in downregulation of Stat3 in vitro. The latter coincided with low cell viability, a reduced expression of survivin and matrix metalloproteinase (MMP)-2. A single injection of LV-shStat3 in K1735-C4 tumors efficiently downregulated Stat3 in vivo and resulted in reduction of both vascular endothelial growth factor secretion and in myeloid-derived suppressor cell (MDSC) numbers. In contrast, we observed an increase in interleukin-6 and interferon-gamma secretion, mature dendritic cells (DCs) and CD8(+) T cells. Both DCs and CD8(+) T cells displayed enhanced activity, whereas granulocytic MDSCs lost their suppressive capacity upon Stat3 downregulation. Importantly, a single injection of LV-shStat3 was sufficient to reduce tumor growth, hence prolong survival of tumor-bearing mice. These data demonstrate that Stat3 downregulation in melanoma reinvigorates existing antitumor immunity. PMID- 23804078 TI - Immunotherapy with gene-modified T cells: limiting side effects provides new challenges. AB - Genetic tools have been developed to efficiently engineer T-cell specificity and enhance T-cell function. Chimeric antigen receptors (CAR) use the antibody variable segments to direct specificity against cell surface molecules. T-cell receptors (TCR) can redirect T cells to intracellular target proteins, fragments of which are presented in the peptide-binding groove of HLA molecules. A recent clinical trial with CAR-modified T cells redirected against the B-cell lineage antigen CD19 showed dramatic clinical benefit in chronic lymphocytic leukaemia patients. Similarly, impressive clinical responses were seen in melanoma and synovial cell carcinoma with TCR-modified T cells redirected against the melanocyte lineage antigen MART-1 and the testis-cancer antigen NY-ESO-1. However, on and off-target toxicity was associated with most of these clinical responses, and fatal complications have been observed in some patients treated with gene modified T cells. This review will discuss factors that might contribute to toxic side effects of therapy with gene modified T cells, and outline potential strategies to retain anticancer activity while reducing unwanted side effects. PMID- 23804079 TI - An analysis of subject areas and country participation for all health-related projects in the EU's FP5 and FP6 programmes. AB - BACKGROUND: Previous analyses concerning health components of European Union (EU) funded research have shown low project participation levels of the 12 newest member states (EU-12). Additionally, there has been a lack of subject-area analysis. In the Health Research for Europe project, we screened all projects of the EU's Framework Programmes for research FP5 and FP6 (1998-2006) to identify health research projects and describe participation by country and subject area. METHODS: FP5 and FP6 project databases were acquired and screened by coders to identify health-related projects, which were then categorized according to the 47 divisions of the EU Health Portal (N = 2728 projects) plus an extra group of 'basic/biotech' projects (N = 1743). Country participation and coordination rates for projects were also analyzed. RESULTS: Approximately 20% of the 26 946 projects (value ?29.2bn) were health-related (N = 4756. Value ?6.04bn). Within the health categories, the largest expenditures were cancer (11.9%), 'other' (i.e. not mental health or cardiovascular) non-communicable diseases (9.5%) and food safety (9.4%). One hundred thirty-two countries participated in these projects. Of the 27 EU countries (and five partner countries), north-western and Nordic states acquired more projects per capita. The UK led coordination with > 20% of projects. EU-12 countries were generally under-represented for participation and coordination. CONCLUSIONS: Combining our findings with the associated literature, we comment on drivers determining distribution of participation and funds across countries and subject areas. Additionally, we discuss changes needed in the core EU projects database to provide greater transparency, data exploitation and return on investment in health research. PMID- 23804080 TI - The effect of the late 2000s financial crisis on suicides in Spain: an interrupted time-series analysis. AB - BACKGROUND: The current financial crisis is having a major impact on European economies, especially that of Spain. Past evidence suggests that adverse macro economic conditions exacerbate mental illness, but evidence from the current crisis is limited. This study analyses the association between the financial crisis and suicide rates in Spain. METHODS: An interrupted time-series analysis of national suicides data between 2005 and 2010 was used to establish whether there has been any deviation in the underlying trend in suicide rates associated with the financial crisis. Segmented regression with a seasonally adjusted quasi Poisson model was used for the analysis. Stratified analyses were performed to establish whether the effect of the crisis on suicides varied by region, sex and age group. RESULTS: The mean monthly suicide rate in Spain during the study period was 0.61 per 100 000 with an underlying trend of a 0.3% decrease per month. We found an 8.0% increase in the suicide rate above this underlying trend since the financial crisis (95% CI: 1.009-1.156; P = 0.03); this was robust to sensitivity analysis. A control analysis showed no change in deaths from accidental falls associated with the crisis. Stratified analyses suggested that the association between the crisis and suicide rates is greatest in the Mediterranean and Northern areas, in males and amongst those of working age. CONCLUSIONS: The financial crisis in Spain has been associated with a relative increase in suicides. Males and those of working age may be at particular risk of suicide associated with the crisis and may benefit from targeted interventions. PMID- 23804081 TI - Proprioceptive eye position signals are still missing a sensory receptor. PMID- 23804082 TI - Brain dynamical networks: contextualizing the function of primary cortices. PMID- 23804083 TI - Nerve regeneration restores supraspinal control of bladder function after complete spinal cord injury. AB - A life-threatening disability after complete spinal cord injury is urinary dysfunction, which is attributable to lack of regeneration of supraspinal pathways that control the bladder. Although numerous strategies have been proposed that can promote the regrowth of severed axons in the adult CNS, at present, the approaches by which this can be accomplished after complete cord transection are quite limited. In the present study, we modified a classic peripheral nerve grafting technique with the use of chondroitinase to facilitate the regeneration of axons across and beyond an extensive thoracic spinal cord transection lesion in adult rats. The novel combination treatment allows for remarkably lengthy regeneration of certain subtypes of brainstem and propriospinal axons across the injury site and is followed by markedly improved urinary function. Our studies provide evidence that an enhanced nerve grafting strategy represents a potential regenerative treatment after severe spinal cord injury. PMID- 23804084 TI - Tired and apprehensive: anxiety amplifies the impact of sleep loss on aversive brain anticipation. AB - Anticipation is an adaptive process, aiding preparatory responses to potentially threatening events. However, excessive anticipatory responding and associated hyper-reactivity in the amygdala and insula are integral to anxiety disorders. Despite the co-occurrence of sleep disruption and anxiety disorders, the impact of sleep loss on affective anticipatory brain mechanisms, and the interaction with anxiety, remains unknown. Here, we demonstrate that sleep loss amplifies preemptive responding in the amygdala and anterior insula during affective anticipation in humans, especially for cues with high predictive certainty. Furthermore, trait anxiety significantly determined the degree of such neural vulnerability to sleep loss: individuals with highest trait anxiety showed the greatest increase in anticipatory insula activity when sleep deprived. Together, these data support a neuropathological model in which sleep disruption may contribute to the maintenance and/or exacerbation of anxiety through its impact on anticipatory brain function. They further raise the therapeutic possibility that targeted sleep restoration in anxiety may ameliorate excessive anticipatory responding and associated clinical symptomatology. PMID- 23804085 TI - Emergence of orientation selectivity in the Mammalian visual pathway. AB - Orientation selectivity is a property of mammalian primary visual cortex (V1) neurons, yet its emergence along the visual pathway varies across species. In carnivores and primates, elongated receptive fields first appear in V1, whereas in lagomorphs such receptive fields emerge earlier, in the retina. Here we examine the mouse visual pathway and reveal the existence of orientation selectivity in lateral geniculate nucleus (LGN) relay cells. Cortical inactivation does not reduce this orientation selectivity, indicating that cortical feedback is not its source. Orientation selectivity is similar for LGN relay cells spiking and subthreshold input to V1 neurons, suggesting that cortical orientation selectivity is inherited from the LGN in mouse. In contrast, orientation selectivity of cat LGN relay cells is small relative to subthreshold inputs onto V1 simple cells. Together, these differences show that although orientation selectivity exists in visual neurons of both rodents and carnivores, its emergence along the visual pathway, and thus its underlying neuronal circuitry, is fundamentally different. PMID- 23804086 TI - The differential effects of reward on space- and object-based attentional allocation. AB - Estimating reward contingencies and allocating attentional resources to a subset of relevant information are the most important contributors to increasing adaptability of an organism. Although recent evidence suggests that reward- and attention-based guidance recruits overlapping cortical regions and has similar effects on sensory responses, the exact nature of the relationship between the two remains elusive. Here, using event-related fMRI on human participants, we contrasted the effects of reward on space- and object-based selection in the same experimental setting. Reward was either distributed randomly or biased a particular object. Behavioral and neuroimaging results show that space- and object-based attention is influenced by reward differentially. Space-based attentional allocation is mandatory, integrating reward information over time, whereas object-based attentional allocation is a default setting that is completely replaced by the reward signal. Nonadditivity of the effects of reward and object-based attention was observed consistently at multiple levels of analysis in early visual areas as well as in control regions. These results provide strong evidence that space- and object-based allocation are two independent attentional mechanisms, and suggest that reward serves to constrain attentional selection. PMID- 23804087 TI - Sorting of the vesicular GABA transporter to functional vesicle pools by an atypical dileucine-like motif. AB - Increasing evidence indicates that individual synaptic vesicle proteins may use different signals, endocytic adaptors, and trafficking pathways for sorting to distinct pools of synaptic vesicles. Here, we report the identification of a unique amino acid motif in the vesicular GABA transporter (VGAT) that controls its synaptic localization and activity-dependent recycling. Mutational analysis of this atypical dileucine-like motif in rat VGAT indicates that the transporter recycles by interacting with the clathrin adaptor protein AP-2. However, mutation of a single acidic residue upstream of the dileucine-like motif leads to a shift to an AP-3-dependent trafficking pathway that preferentially targets the transporter to the readily releasable and recycling pool of vesicles. Real-time imaging with a VGAT-pHluorin fusion provides a useful approach to explore how unique sorting sequences target individual proteins to synaptic vesicles with distinct functional properties. PMID- 23804089 TI - Concurrent maturation of inner hair cell synaptic Ca2+ influx and auditory nerve spontaneous activity around hearing onset in mice. AB - Hearing over a wide range of sound intensities is thought to require complementary coding by functionally diverse spiral ganglion neurons (SGNs), each changing activity only over a subrange. The foundations of SGN diversity are not well understood but likely include differences among their inputs: the presynaptic active zones (AZs) of inner hair cells (IHCs). Here we studied one candidate mechanism for causing SGN diversity-heterogeneity of Ca(2+) influx among the AZs of IHCs-during postnatal development of the mouse cochlea. Ca(2+) imaging revealed a change from regenerative to graded synaptic Ca(2+) signaling after the onset of hearing, when in vivo SGN spike timing changed from patterned to Poissonian. Furthermore, we detected the concurrent emergence of stronger synaptic Ca(2+) signals in IHCs and higher spontaneous spike rates in SGNs. The strengthening of Ca(2+) signaling at a subset of AZs primarily reflected a gain of Ca(2+) channels. We hypothesize that the number of Ca(2+) channels at each IHC AZ critically determines the firing properties of its corresponding SGN and propose that AZ heterogeneity enables IHCs to decompose auditory information into functionally diverse SGNs. PMID- 23804088 TI - Multiple dileucine-like motifs direct VGLUT1 trafficking. AB - The vesicular glutamate transporters (VGLUTs) package glutamate into synaptic vesicles, and the two principal isoforms VGLUT1 and VGLUT2 have been suggested to influence the properties of release. To understand how a VGLUT isoform might influence transmitter release, we have studied their trafficking and previously identified a dileucine-like endocytic motif in the C terminus of VGLUT1. Disruption of this motif impairs the activity-dependent recycling of VGLUT1, but does not eliminate its endocytosis. We now report the identification of two additional dileucine-like motifs in the N terminus of VGLUT1 that are not well conserved in the other isoforms. In the absence of all three motifs, rat VGLUT1 shows limited accumulation at synaptic sites and no longer responds to stimulation. In addition, shRNA-mediated knockdown of clathrin adaptor proteins AP-1 and AP-2 shows that the C-terminal motif acts largely via AP-2, whereas the N-terminal motifs use AP-1. Without the C-terminal motif, knockdown of AP-1 reduces the proportion of VGLUT1 that responds to stimulation. VGLUT1 thus contains multiple sorting signals that engage distinct trafficking mechanisms. In contrast to VGLUT1, the trafficking of VGLUT2 depends almost entirely on the conserved C-terminal dileucine-like motif: without this motif, a substantial fraction of VGLUT2 redistributes to the plasma membrane and the transporter's synaptic localization is disrupted. Consistent with these differences in trafficking signals, wild-type VGLUT1 and VGLUT2 differ in their response to stimulation. PMID- 23804090 TI - Tlx3 controls cholinergic transmitter and Peptide phenotypes in a subset of prenatal sympathetic neurons. AB - The embryonic sympathetic nervous system consists of predominantly noradrenergic neurons and a very small population of cholinergic neurons. Postnatal development further allows target-dependent switch of a subset of noradrenergic neurons into cholinergic phenotype. How embryonic cholinergic neurons are specified at the prenatal stages remains largely unknown. In this study, we found that the expression of transcription factor Tlx3 was progressively restricted to a small population of embryonic sympathetic neurons in mice. Immunostaining for vesicular acetylcholine transporter (VAChT) showed that Tlx3 was highly expressed in cholinergic neurons at the late embryonic stage E18.5. Deletion of Tlx3 resulted in the loss of Vacht expression at E18.5 but not E12.5. By contrast, Tlx3 was required for expression of the cholinergic peptide vasoactive intestinal polypeptide (VIP), and somatostatin (SOM) at both E12.5 and E18.5. Furthermore, we found that, at E18.5 these putative cholinergic neurons expressed glial cell line-derived neurotrophic factor family coreceptor Ret but not tyrosine hydroxylase (Ret(+)/TH(-)). Deletion of Tlx3 also resulted in disappearance of high-level Ret expression. Last, unlike Tlx3, Ret was required for the expression of VIP and SOM at E18.5 but not E12.5. Together, these results indicate that transcription factor Tlx3 is required for the acquisition of cholinergic phenotype at the late embryonic stage as well as the expression and maintenance of cholinergic peptides VIP and SOM throughout prenatal development of mouse sympathetic neurons. PMID- 23804091 TI - Probabilistic diffusion tractography and graph theory analysis reveal abnormal white matter structural connectivity networks in drug-naive boys with attention deficit/hyperactivity disorder. AB - Attention-deficit/hyperactivity disorder (ADHD), which is characterized by core symptoms of inattention and hyperactivity/impulsivity, is one of the most common neurodevelopmental disorders of childhood. Neuroimaging studies have suggested that these behavioral disturbances are associated with abnormal functional connectivity among brain regions. However, the alterations in the structural connections that underlie these behavioral and functional deficits remain poorly understood. Here, we used diffusion magnetic resonance imaging and probabilistic tractography method to examine whole-brain white matter (WM) structural connectivity in 30 drug-naive boys with ADHD and 30 healthy controls. The WM networks of the human brain were constructed by estimating inter-regional connectivity probability. The topological properties of the resultant networks (e.g., small-world and network efficiency) were then analyzed using graph theoretical approaches. Nonparametric permutation tests were applied for between group comparisons of these graphic metrics. We found that both the ADHD and control groups showed an efficient small-world organization in the whole-brain WM networks, suggesting a balance between structurally segregated and integrated connectivity patterns. However, relative to controls, patients with ADHD exhibited decreased global efficiency and increased shortest path length, with the most pronounced efficiency decreases in the left parietal, frontal, and occipital cortices. Intriguingly, the ADHD group showed decreased structural connectivity in the prefrontal-dominant circuitry and increased connectivity in the orbitofrontal-striatal circuitry, and these changes significantly correlated with the inattention and hyperactivity/impulsivity symptoms, respectively. The present study shows disrupted topological organization of large-scale WM networks in ADHD, extending our understanding of how structural disruptions of neuronal circuits underlie behavioral disturbances in patients with ADHD. PMID- 23804092 TI - The brain dynamics of rapid perceptual adaptation to adverse listening conditions. AB - Listeners show a remarkable ability to quickly adjust to degraded speech input. Here, we aimed to identify the neural mechanisms of such short-term perceptual adaptation. In a sparse-sampling, cardiac-gated functional magnetic resonance imaging (fMRI) acquisition, human listeners heard and repeated back 4-band vocoded sentences (in which the temporal envelope of the acoustic signal is preserved, while spectral information is highly degraded). Clear-speech trials were included as baseline. An additional fMRI experiment on amplitude modulation rate discrimination quantified the convergence of neural mechanisms that subserve coping with challenging listening conditions for speech and non-speech. First, the degraded speech task revealed an "executive" network (comprising the anterior insula and anterior cingulate cortex), parts of which were also activated in the non-speech discrimination task. Second, trial-by-trial fluctuations in successful comprehension of degraded speech drove hemodynamic signal change in classic "language" areas (bilateral temporal cortices). Third, as listeners perceptually adapted to degraded speech, downregulation in a cortico-striato-thalamo-cortical circuit was observable. The present data highlight differential upregulation and downregulation in auditory-language and executive networks, respectively, with important subcortical contributions when successfully adapting to a challenging listening situation. PMID- 23804093 TI - A novel activator of CBP/p300 acetyltransferases promotes neurogenesis and extends memory duration in adult mice. AB - Although the brain functions of specific acetyltransferases such as the CREB binding protein (CBP) and p300 have been well documented using mutant transgenic mice models, studies based on their direct pharmacological activation are still missing due to the lack of cell-permeable activators. Here we present a small molecule (TTK21) activator of the histone acetyltransferases CBP/p300, which, when conjugated to glucose-based carbon nanosphere (CSP), passed the blood-brain barrier, induced no toxicity, and reached different parts of the brain. After intraperitoneal administration in mice, CSP-TTK21 significantly acetylated histones in the hippocampus and frontal cortex. Remarkably, CSP-TTK21 treatment promoted the formation of long and highly branched doublecortin-positive neurons in the subgranular zone of the dentate gyrus and reduced BrdU incorporation, suggesting that CBP/p300 activation favors maturation and differentiation of adult neuronal progenitors. In addition, mRNA levels of the neuroD1 differentiation marker and BDNF, a neurotrophin required for the terminal differentiation of newly generated neurons, were both increased in the hippocampus concomitantly with an enrichment of acetylated-histone on their proximal promoter. Finally, we found that CBP/p300 activation during a spatial training, while not improving retention of a recent memory, resulted in a significant extension of memory duration. This report is the first evidence for CBP/p300-mediated histone acetylation in the brain by an activator molecule, which has beneficial implications for the brain functions of adult neurogenesis and long-term memory. We propose that direct stimulation of acetyltransferase function could be useful in terms of therapeutic options for brain diseases. PMID- 23804094 TI - Cortical inhibition reduces information redundancy at presentation of communication sounds in the primary auditory cortex. AB - In all sensory modalities, intracortical inhibition shapes the functional properties of cortical neurons but also influences the responses to natural stimuli. Studies performed in various species have revealed that auditory cortex neurons respond to conspecific vocalizations by temporal spike patterns displaying a high trial-to-trial reliability, which might result from precise timing between excitation and inhibition. Studying the guinea pig auditory cortex, we show that partial blockage of GABAA receptors by gabazine (GBZ) application (10 MUm, a concentration that promotes expansion of cortical receptive fields) increased the evoked firing rate and the spike-timing reliability during presentation of communication sounds (conspecific and heterospecific vocalizations), whereas GABAB receptor antagonists [10 MUm saclofen; 10-50 MUm CGP55845 (p-3-aminopropyl-p-diethoxymethyl phosphoric acid)] had nonsignificant effects. Computing mutual information (MI) from the responses to vocalizations using either the evoked firing rate or the temporal spike patterns revealed that GBZ application increased the MI derived from the activity of single cortical site but did not change the MI derived from population activity. In addition, quantification of information redundancy showed that GBZ significantly increased redundancy at the population level. This result suggests that a potential role of intracortical inhibition is to reduce information redundancy during the processing of natural stimuli. PMID- 23804095 TI - PAK inactivation impairs social recognition in 3xTg-AD Mice without increasing brain deposition of tau and Abeta. AB - Defects in p21-activated kinase (PAK) are suspected to play a role in cognitive symptoms of Alzheimer's disease (AD). Dysfunction in PAK leads to cofilin activation, drebrin displacement from its actin-binding site, actin depolymerization/severing, and, ultimately, defects in spine dynamics and cognitive impairment in mice. To determine the role of PAK in AD, we first quantified PAK by immunoblotting in homogenates from the parietal neocortex of subjects with a clinical diagnosis of no cognitive impairment (n = 12), mild cognitive impairment (n = 12), or AD (n = 12). A loss of total PAK, detected in the cortex of AD patients (-39% versus controls), was correlated with cognitive impairment (r(2) = 0.148, p = 0.027) and deposition of total and phosphorylated tau (r(2) = 0.235 and r(2) = 0.206, respectively), but not with Abeta42 (r(2) = 0.056). Accordingly, we found a decrease of total PAK in the cortex of 12- and 20 month-old 3xTg-AD mice, an animal model of AD-like Abeta and tau neuropathologies. To determine whether PAK dysfunction aggravates AD phenotype, 3xTg-AD mice were crossed with dominant-negative PAK mice. PAK inactivation led to obliteration of social recognition in old 3xTg-AD mice, which was associated with a decrease in cortical drebrin (-25%), but without enhancement of Abeta/tau pathology or any clear electrophysiological signature. Overall, our data suggest that PAK decrease is a consequence of AD neuropathology and that therapeutic activation of PAK may exert symptomatic benefits on high brain function. PMID- 23804096 TI - Ionotropic glutamate receptors IR64a and IR8a form a functional odorant receptor complex in vivo in Drosophila. AB - Drosophila olfactory sensory neurons express either odorant receptors or ionotropic glutamate receptors (IRs). The sensory neurons that express IR64a, a member of the IR family, send axonal projections to either the DC4 or DP1m glomeruli in the antennal lobe. DC4 neurons respond specifically to acids/protons, whereas DP1m neurons respond to a broad spectrum of odorants. The molecular composition of IR64a-containing receptor complexes in either DC4 or DP1m neurons is not known, however. Here, we immunoprecipitated the IR64a protein from lysates of fly antennal tissue and identified IR8a as a receptor subunit physically associated with IR64a by mass spectrometry. IR8a mutants and flies in which IR8a was knocked down by RNAi in IR64a+ neurons exhibited defects in acid evoked physiological and behavioral responses. Furthermore, we found that the loss of IR8a caused a significant reduction in IR64a protein levels. When expressed in Xenopus oocytes, IR64a and IR8a formed a functional ion channel that allowed ligand-evoked cation currents. These findings provide direct evidence that IR8a is a subunit that forms a functional olfactory receptor with IR64a in vivo to mediate odor detection. PMID- 23804097 TI - A neocortical delta rhythm facilitates reciprocal interlaminar interactions via nested theta rhythms. AB - Delta oscillations (1-4 Hz) associate with deep sleep and are implicated in memory consolidation and replay of cortical responses elicited during wake states. A potent local generator has been characterized in thalamus, and local generators in neocortex have been suggested. Here we demonstrate that isolated rat neocortex generates delta rhythms in conditions mimicking the neuromodulatory state during deep sleep (low cholinergic and dopaminergic tone). The rhythm originated in an NMDA receptor-driven network of intrinsic bursting (IB) neurons in layer 5, activating a source of GABAB receptor-mediated inhibition. In contrast, regular spiking (RS) neurons in layer 5 generated theta-frequency outputs. In layer 2/3 principal cells, outputs from IB cells associated with IPSPs, whereas those from layer 5 RS neurons related to nested bursts of theta frequency EPSPs. Both interlaminar spike and field correlations revealed a sequence of events whereby sparse spiking in layer 2/3 was partially reflected back from layer 5 on each delta period. We suggest that these reciprocal, interlaminar interactions may represent a "Helmholtz machine"-like process to control synaptic rescaling during deep sleep. PMID- 23804098 TI - Bradykinin controls pool size of sensory neurons expressing functional delta opioid receptors. AB - Analgesics targeting the delta-opioid receptor (DOR) may lead to fewer side effects than conventional opioid drugs, which mainly act on MU-opioid receptors (MOR), because of the less abundant expression of DOR in the CNS compared with MOR. Analgesic potential of DOR agonists increases after inflammation, an effect that may be mediated by DOR expressed in the peripheral sensory fibers. However, the expression of functional DOR at the plasma membrane of sensory neurons is controversial. Here we have used patch-clamp recordings and total internal reflection fluorescence microscopy to study the functional expression of DOR in sensory neurons from rat trigeminal (TG) and dorsal root ganglia (DRG). Real-time total internal reflection fluorescence microscopy revealed that treatment of TG and DRG cultures with the inflammatory mediator bradykinin (BK) caused robust trafficking of heterologously expressed GFP-tagged DOR to the plasma membrane. By contrast, treatment of neurons with the DOR agonist [d-Ala(2), d-Leu(5)] enkephalin (DADLE) caused a decrease in the membrane abundance of DOR, suggesting internalization of the receptor after agonist binding. Patch-clamp experiments revealed that DADLE inhibited voltage-gated Ca(2+) channels (VGCCs) in 23% of small-diameter TG neurons. Pretreatment with BK resulted in more than twice as many DADLE responsive neurons (54%) but did not affect the efficacy of VGCC inhibition by DADLE. Our data suggest that inflammatory mediator-induced membrane insertion of DOR into the plasma membrane of peripheral sensory neurons may underlie increased DOR analgesia in inflamed tissue. Furthermore, the majority of BK-responsive TG neurons may have a potential to become responsive to DOR ligands in inflammatory conditions. PMID- 23804099 TI - The generalization of visuomotor learning to untrained movements and movement sequences based on movement vector and goal location remapping. AB - The planning of goal-directed movements is highly adaptable; however, the basic mechanisms underlying this adaptability are not well understood. Even the features of movement that drive adaptation are hotly debated, with some studies suggesting remapping of goal locations and others suggesting remapping of the movement vectors leading to goal locations. However, several previous motor learning studies and the multiplicity of the neural coding underlying visually guided reaching movements stand in contrast to this either/or debate on the modes of motor planning and adaptation. Here we hypothesize that, during visuomotor learning, the target location and movement vector of trained movements are separately remapped, and we propose a novel computational model for how motor plans based on these remappings are combined during the control of visually guided reaching in humans. To test this hypothesis, we designed a set of experimental manipulations that effectively dissociated the effects of remapping goal location and movement vector by examining the transfer of visuomotor adaptation to untrained movements and movement sequences throughout the workspace. The results reveal that (1) motor adaptation differentially remaps goal locations and movement vectors, and (2) separate motor plans based on these features are effectively averaged during motor execution. We then show that, without any free parameters, the computational model we developed for combining movement-vector-based and goal-location-based planning predicts nearly 90% of the variance in novel movement sequences, even when multiple attributes are simultaneously adapted, demonstrating for the first time the ability to predict how motor adaptation affects movement sequence planning. PMID- 23804100 TI - The impact of pathogenic mitochondrial DNA mutations on substantia nigra neurons. AB - Mitochondrial defects within substantia nigra (SN) neurons are implicated in the pathogenesis of Parkinson's disease. SN neurons show increased mitochondrial defects, mitochondrial DNA deletion levels, and susceptibility to such dysfunction, although the role of mitochondria in neuronal degeneration remains uncertain. In this study, we addressed this important question by exploring changes within the mitochondria of SN neurons from patients with primary mitochondrial diseases to determine whether mitochondrial dysfunction leads directly to neuronal cell loss. We counted the pigmented neurons and quantified mitochondrial respiratory activity, deficiencies in mitochondrial proteins, and the percentage of pathogenic mutations in single neurons. We found evidence of defects of both complex I and complex IV of the respiratory chain in all patients. We found that marked neuronal cell loss was only observed in a few patients with mitochondrial disease and that all these patients had mutations in polymerase gamma (POLG), which leads to the formation of multiple mitochondrial DNA deletions over time, similar to aging and Parkinson's disease. Interestingly, we detected alpha-synuclein pathology in two mitochondrial patients with POLG mutations. Our observations highlight the complex relationship between mitochondrial dysfunction and the susceptibility of SN neurons to degeneration and alpha-synuclein pathology. Our finding that the loss of SN neurons was only severe in patients with POLG mutations suggests that acquired mitochondrial defects may be less well tolerated by SN neurons than by inherited ones. PMID- 23804101 TI - Cortical gyrification induced by fibroblast growth factor 2 in the mouse brain. AB - Gyrification allows an expanded cortex with greater functionality to fit into a smaller cranium. However, the mechanisms of gyrus formation have been elusive. We show that ventricular injection of FGF2 protein at embryonic day 11.5-before neurogenesis and before the formation of intrahemispheric axonal connections altered the overall size and shape of the cortex and induced the formation of prominent, bilateral gyri and sulci in the rostrolateral neocortex. We show increased tangential growth of the rostral ventricular zone (VZ) but decreased Wnt3a and Lef1 expression in the cortical hem and adjacent hippocampal promordium and consequent impaired growth of the caudal cortical primordium, including the hippocampus. At the same time, we observed ectopic Er81 expression, increased proliferation of Tbr2-expressing (Tbr2(+)) intermediate neuronal progenitors (INPs), and elevated Tbr1(+) neurogenesis in the regions that undergo gyrification, indicating region-specific actions of FGF2 on the VZ and subventricular zone (SVZ). However, the relative number of basal radial glia recently proposed to be important in gyrification-appeared to be unchanged. These findings are consistent with the hypothesis that increased radial unit production together with rapid SVZ growth and heightened localized neurogenesis can cause cortical gyrification in lissencephalic species. These data also suggest that the position of cortical gyri can be molecularly specified in mice. In contrast, a different ligand, FGF8b, elicited surface area expansion throughout the cortical primordium but no gyrification. Our findings demonstrate that individual members of the diverse Fgf gene family differentially regulate global as well as regional cortical growth rates while maintaining cortical layer structure. PMID- 23804103 TI - Estrous cycle plasticity in the hyperpolarization-activated current ih is mediated by circulating 17beta-estradiol in preoptic area kisspeptin neurons. AB - Circulating gonadal steroid hormones are thought to modulate a wide range of brain functions. However, the effects of steroid fluctuations through the ovarian cycle on the intrinsic properties of neurons are not well understood. We examined here whether gonadal steroids modulated the excitability of kisspeptin neurons located in the rostral periventricular region of the third ventricle (RP3V) of female mice. These cells are strongly implicated in sensing the high levels of circulating estradiol on proestrus to activate gonadotropin-releasing hormone (GnRH) neurons that, in turn, trigger ovulation. Electrophysiological studies were undertaken in brain slices from ovariectomized (OVX), diestrous, and proestrous kisspeptin-GFP mice. RP3V kisspeptin neurons exhibited marked changes in the hyperpolarization-evoked depolarizing sag and rebound firing across these groups. The hyperpolarization-activated current Ih was identified to be responsible for the depolarizing sag and was increased across OVX -> diestrous -> proestrous mice. Experiments in OVX mice given estradiol replacement identified an estradiol-dependent increase in Ih within RP3V kisspeptin neurons. Ih in these cells was found to contribute to their subthreshold membrane properties and the dynamics of rebound firing following hyperpolarizing stimuli in an estrous cycle dependent manner. Only a minor role was found for Ih in modulating the spontaneous burst firing of RP3V kisspeptin neurons. These observations identify Ih as an ionic current that is regulated in a cyclical manner by circulating estradiol within the female brain, and suggest that such plasticity in the intrinsic properties of RP3V kisspeptin neurons may contribute to the generation of the preovulatory GnRH surge. PMID- 23804102 TI - Lysosomal membrane permeability stimulates protein aggregate formation in neurons of a lysosomal disease. AB - Protein aggregates are a common pathological feature of neurodegenerative diseases and several lysosomal diseases, but it is currently unclear what aggregates represent for pathogenesis. Here we report the accumulation of intraneuronal aggregates containing the macroautophagy adapter proteins p62 and NBR1 in the neurodegenerative lysosomal disease late-infantile neuronal ceroid lipofuscinosis (CLN2 disease). CLN2 disease is caused by a deficiency in the lysosomal enzyme tripeptidyl peptidase I, which results in aberrant lysosomal storage of catabolites, including the subunit c of mitochondrial ATP synthase (SCMAS). In an effort to define the role of aggregates in CLN2, we evaluated p62 and NBR1 accumulation in the CNS of Cln2(-/-) mice. Although increases in p62 and NBR1 often suggest compromised degradative mechanisms, we found normal ubiquitin proteasome system function and only modest inefficiency in macroautophagy late in disease. Importantly, we identified that SCMAS colocalizes with p62 in extra lysosomal aggregates in Cln2(-/-) neurons in vivo. This finding is consistent with SCMAS being released from lysosomes, an event known as lysosomal membrane permeability (LMP). We predicted that LMP and storage release from lysosomes results in the sequestration of this material as cytosolic aggregates by p62 and NBR1. Notably, LMP induction in primary neuronal cultures generates p62-positive aggregates and promotes p62 localization to lysosomal membranes, supporting our in vivo findings. We conclude that LMP is a previously unrecognized pathogenic event in CLN2 disease that stimulates cytosolic aggregate formation. Furthermore, we offer a novel role for p62 in response to LMP that may be relevant for other diseases exhibiting p62 accumulation. PMID- 23804105 TI - Somatosensory demands modulate muscular Beta oscillations, independent of motor demands. AB - Neural oscillations in the beta band (15-30 Hz) occur coherently throughout the primate somatomotor network, comprising somatomotor cortices, basal ganglia, thalamus, cerebellum, and spinal cord, with the latter resulting in beta oscillations in muscular activity. In accordance with the anatomy of this network, these oscillations have traditionally been associated strictly with motor function. Here we show in humans that somatosensory demands, both in anticipation and during the processing of tactile stimuli, also modulate beta oscillations throughout this network. Specifically, somatosensory demands suppress the degree to which not only cortical activity but also muscular activity oscillates in the beta band. This suppression of muscular beta oscillations by perceptual demands is specific to demands in the somatosensory modality and occurs independent of movement preparation and execution: it occurs even when no movement is required at all. This places touch perception as an important computation within this widely distributed somatomotor beta network and suggests that, at least in healthy subjects, somatosensation and action should not be considered as separable processes, not even at the level of the muscles. PMID- 23804104 TI - Interactive effects of dehydroepiandrosterone and testosterone on cortical thickness during early brain development. AB - Humans and the great apes are the only species demonstrated to exhibit adrenarche, a key endocrine event associated with prepubertal increases in the adrenal production of androgens, most significantly dehydroepiandrosterone (DHEA) and to a certain degree testosterone. Adrenarche also coincides with the emergence of the prosocial and neurobehavioral skills of middle childhood and may therefore represent a human-specific stage of development. Both DHEA and testosterone have been reported in animal and in vitro studies to enhance neuronal survival and programmed cell death depending on the timing, dose, and hormonal context involved, and to potentially compete for the same signaling pathways. Yet no extant brain-hormone studies have examined the interaction between DHEA- and testosterone-related cortical maturation in humans. Here, we used linear mixed models to examine changes in cortical thickness associated with salivary DHEA and testosterone levels in a longitudinal sample of developmentally healthy children and adolescents 4-22 years old. DHEA levels were associated with increases in cortical thickness of the left dorsolateral prefrontal cortex, right temporoparietal junction, right premotor and right entorhinal cortex between the ages of 4-13 years, a period marked by the androgenic changes of adrenarche. There was also an interaction between DHEA and testosterone on cortical thickness of the right cingulate cortex and occipital pole that was most significant in prepubertal subjects. DHEA and testosterone appear to interact and modulate the complex process of cortical maturation during middle childhood, consistent with evidence at the molecular level of fast/nongenomic and slow/genomic or conversion based mechanisms underlying androgen-related brain development. PMID- 23804106 TI - NG2 regulates directional migration of oligodendrocyte precursor cells via Rho GTPases and polarity complex proteins. AB - The transmembrane proteoglycan NG2 is expressed by oligodendrocyte precursor cells (OPC), which migrate to axons during developmental myelination and remyelinate in the adult after migration to injured sites. Highly invasive glial tumors also express NG2. Despite the fact that NG2 has been implicated in control of OPC migration, its mode of action remains unknown. Here, we show in vitro and in vivo that NG2 controls migration of OPC through the regulation of cell polarity. In stab wounds in adult mice we show that NG2 controls orientation of OPC toward the wound. NG2 stimulates RhoA activity at the cell periphery via the MUPP1/Syx1 signaling pathway, which favors the bipolar shape of migrating OPC and thus directional migration. Upon phosphorylation of Thr-2256, downstream signaling of NG2 switches from RhoA to Rac stimulation. This triggers process outgrowth through regulators of front-rear polarity and we show using a phospho mimetic form of NG2 that indeed NG2 recruits proteins of the CRB and the PAR polarity complexes to stimulate Rac activity via the GEF Tiam1. Our findings demonstrate that NG2 is a core organizer of Rho GTPase activity and localization in the cell, which controls OPC polarity and directional migration. This work also reveals CRB and PAR polarity complexes as new effectors of NG2 signaling in the establishment of front-rear polarity. PMID- 23804107 TI - Pattern of innervation and recruitment of different classes of motoneurons in adult zebrafish. AB - In vertebrates, spinal circuits drive rhythmic firing in motoneurons in the appropriate sequence to produce locomotor movements. These circuits become active early during development and mature gradually to acquire the flexibility necessary to accommodate the increased behavioral repertoire of adult animals. The focus here is to elucidate how different pools of motoneurons are organized and recruited and how membrane properties contribute to their mode of operation. For this purpose, we have used the in vitro preparation of adult zebrafish. We show that different motoneuron pools are organized in a somatotopic fashion in the motor column related to the type of muscle fibers (slow, intermediate, fast) they innervate. During swimming, the different motoneuron pools are recruited in a stepwise manner from slow, to intermediate, to fast to cover the full range of locomotor frequencies seen in intact animals. The spike threshold, filtering properties, and firing patterns of the different motoneuron pools are graded in a manner that relates to their order of recruitment. Our results thus show that motoneurons in adult zebrafish are organized into distinct modules, each with defined locations, properties, and recruitment patterns tuned to precisely match the muscle properties and hence produce swimming of different speeds and modalities. PMID- 23804108 TI - The human brain encodes event frequencies while forming subjective beliefs. AB - To make adaptive choices, humans need to estimate the probability of future events. Based on a Bayesian approach, it is assumed that probabilities are inferred by combining a priori, potentially subjective, knowledge with factual observations, but the precise neurobiological mechanism remains unknown. Here, we study whether neural encoding centers on subjective posterior probabilities, and data merely lead to updates of posteriors, or whether objective data are encoded separately alongside subjective knowledge. During fMRI, young adults acquired prior knowledge regarding uncertain events, repeatedly observed evidence in the form of stimuli, and estimated event probabilities. Participants combined prior knowledge with factual evidence using Bayesian principles. Expected reward inferred from prior knowledge was encoded in striatum. BOLD response in specific nodes of the default mode network (angular gyri, posterior cingulate, and medial prefrontal cortex) encoded the actual frequency of stimuli, unaffected by prior knowledge. In this network, activity increased with frequencies and thus reflected the accumulation of evidence. In contrast, Bayesian posterior probabilities, computed from prior knowledge and stimulus frequencies, were encoded in bilateral inferior frontal gyrus. Here activity increased for improbable events and thus signaled the violation of Bayesian predictions. Thus, subjective beliefs and stimulus frequencies were encoded in separate cortical regions. The advantage of such a separation is that objective evidence can be recombined with newly acquired knowledge when a reinterpretation of the evidence is called for. Overall this study reveals the coexistence in the brain of an experience-based system of inference and a knowledge-based system of inference. PMID- 23804109 TI - The temporal evolution of feedback gains rapidly update to task demands. AB - Recent theoretical frameworks such as optimal feedback control suggest that feedback gains should modulate throughout a movement and be tuned to task demands. Here we measured the visuomotor feedback gain throughout the course of movements made to "near" or "far" targets in human subjects. The visuomotor gain showed a systematic modulation over the time course of the reach, with the gain peaking at the middle of the movement and dropping rapidly as the target is approached. This modulation depends primarily on the proportion of the movement remaining, rather than hand position, suggesting that the modulation is sensitive to task demands. Model-predictive control suggests that the gains should be continuously recomputed throughout a movement. To test this, we investigated whether feedback gains update when the task goal is altered during a movement, that is when the target of the reach jumped. We measured the visuomotor gain either simultaneously with the jump or 100 ms after the jump. The visuomotor gain nonspecifically reduced for all target jumps when measured synchronously with the jump. However, the visuomotor gain 100 ms later showed an appropriate modulation for the revised task goal by increasing for jumps that increased the distance to the target and reducing for jumps that decreased the distance. We conclude that visuomotor feedback gain shows a temporal evolution related to task demands and that this evolution can be flexibly recomputed within 100 ms to accommodate online modifications to task goals. PMID- 23804110 TI - Prefrontal activity links nonoverlapping events in memory. AB - The medial prefrontal cortex (mPFC) plays an important role in memory. By maintaining a working memory buffer, neurons in prelimbic (PL) mPFC may selectively contribute to learning associations between stimuli that are separated in time, as in trace fear conditioning (TFC). Until now, evidence for this bridging role was largely descriptive. Here we used optogenetics to silence neurons in the PL mPFC of rats during learning in TFC. Memory formation was prevented when mPFC was silenced specifically during the interval separating the cue and shock. Our results provide support for a working memory function for these cells and indicate that associating two noncontiguous stimuli requires bridging activity in PL mPFC. PMID- 23804111 TI - Distinct familiarity-based response patterns for faces and buildings in perirhinal and parahippocampal cortex. AB - An unresolved question in our understanding of the medial temporal lobes is how functional differences between structures pertaining to stimulus category relate to the distinction between item-based and contextually based recognition-memory processes. Specifically, it remains unclear whether perirhinal cortex (PrC) supports item-based familiarity signals for all stimulus categories or whether parahippocampal cortex (PhC) may also play a role for stimulus categories that are known to engage this structure in other task contexts. Here, we used multivoxel pattern analyses of fMRI data to compare patterns of activity in humans that are associated with the perceived familiarity of faces, buildings, and chairs. During scanning, participants judged the familiarity of previously studied and novel items from all three categories. Instances in which recognition was based on recollection were removed from all analyses. In right PrC, we found patterns of activity that distinguished familiar from novel faces. By contrast, in right PhC, we observed such patterns for buildings. Familiarity signals for chairs were present in both structures but shared little overlap with the patterns observed for faces and buildings on a more fine-grained scale. In the hippocampus, we found no evidence for familiarity signals for any object category. Our findings show that both PrC and PhC contribute to the assessment of item familiarity. They suggest that PhC does not only represent episodic context but can also represent item information for some object categories in recognition memory decisions. In turn, our findings also indicate that the involvement of PrC in representing item familiarity is not ubiquitous. PMID- 23804113 TI - Seeking asylum in Australia: immigration detention, human rights and mental health care. AB - OBJECTIVE: The article aims to discuss the impact of mandatory detention and human rights violations on the mental health of asylum seekers and the implications for psychiatrists and health professionals. CONCLUSIONS: Advocacy for human rights and engagement in social debate are core ethical and professional responsibilities. Clinicians need to maintain a focus on ethical obligations. PMID- 23804114 TI - Clozapine and agranulocytosis: re-assessing the risks. AB - OBJECTIVE: The aim of the study was to estimate the maximum incidence of agranulocytosis which clozapine would have caused between 2006 and 2010 had there been no blood monitoring system; and to determine the number of clozapine associated cases of agranulocytosis and related deaths recorded between 1993 and 2011. METHOD: Records associating clozapine use with white blood cell deficiency (WBCD), in the Therapeutic Goods Administration's Case Line Listing of adverse drug reactions, were examined. The figure of 11,000 was used as the population on clozapine each year from 2006-2010. RESULTS: Between 2006 and 2010 there were 209 cases of clozapine-associated WBCD recorded, probably caused by clozapine in 141 cases. WBCD caused by clozapine could have progressed to agranulocytosis if clozapine had not been withdrawn. The risk of WBCD/agranulocytosis decreased with increasing duration of clozapine use. Between 1993 and 2011 there were 141 recorded cases of agranulocytosis, and four deaths, from clozapine-associated WBDC. CONCLUSIONS: During 2006-2010, without any monitoring system, the maximum annual incidence of agranulocytosis caused by clozapine would have been 0.26%. The risks of agranulocytosis, and related deaths, decreased with length of time on clozapine. During 1993-2011 141 cases of agranulocytosis, with four deaths, were recorded in association with clozapine use. The monitoring system could have successfully prevented relatively few deaths. PMID- 23804112 TI - Estrogen mediates neuroprotection and anti-inflammatory effects during EAE through ERalpha signaling on astrocytes but not through ERbeta signaling on astrocytes or neurons. AB - Estrogens can signal through either estrogen receptor alpha (ERalpha) or beta (ERbeta) to ameliorate experimental autoimmune encephalomyelitis (EAE), the most widely used mouse model of multiple sclerosis (MS). Cellular targets of estrogen mediated neuroprotection are still being elucidated. Previously, we demonstrated that ERalpha on astrocytes, but not neurons, was critical for ERalpha ligand mediated neuroprotection in EAE, including decreased T-cell and macrophage inflammation and decreased axonal loss. Here, we determined whether ERbeta on astrocytes or neurons could mediate neuroprotection in EAE, by selectively removing ERbeta from either of these cell types using Cre-loxP gene deletion. Our results demonstrated that, even though ERbeta ligand treatment was neuroprotective in EAE, this neuroprotection was not mediated through ERbeta on either astrocytes or neurons and did not involve a reduction in levels of CNS inflammation. Given the differential neuroprotective and anti-inflammatory effects mediated via ERalpha versus ERbeta on astrocytes, we looked for molecules within astrocytes that were affected by signaling through ERalpha, but not ERbeta. We found that ERalpha ligand treatment, but not ERbeta ligand treatment, decreased expression of the chemokines CCL2 and CCL7 by astrocytes in EAE. Together, our data show that neuroprotection in EAE mediated via ERbeta signaling does not require ERbeta on either astrocytes or neurons, whereas neuroprotection in EAE mediated via ERalpha signaling requires ERalpha on astrocytes and reduces astrocyte expression of proinflammatory chemokines. These findings reveal important cellular differences in the neuroprotective mechanisms of estrogen signaling through ERalpha and ERbeta in EAE. PMID- 23804115 TI - The Australian contribution to the literature on atypical antipsychotic drugs: a bibliometric study. AB - OBJECTIVE: We performed a bibliometric study on scientific publications on atypical antipsychotic drugs (AADs) from Australia. METHODS: Using the EMBASE and MEDLINE databases, we chose those documents produced in Australia between 1993 and 2011, whose title included the descriptors atypic* (atypical*), antipsychotic*, second-generation antipsychotic*, clozapine, risperidone, olanzapine, ziprasidone, quetiapine, sertindole, aripiprazole, paliperidone, amisulpride, zotepine, asenapine, iloperidone, lurasidone, perospirone and blonanserin. We applied bibliometric indicators of production as well as dispersion. RESULTS: We identified 438 relevant publications. The most widely studied AADs were clozapine (162 documents), olanzapine (103), risperidone (77) and quetiapine (42). There was a lack of exponential growth in publications over time, indicated by non-fulfilment of Price's Law (correlation coefficient r=0.9195 after exponential adjustment vs. r=0.9253 after linear adjustment). Publications appeared in 148 different journals, with four of the top nine journals having an impact factor greater than 3; 84 of the articles appeared in the Australian and New Zealand Journal of Psychiatry. CONCLUSION: Despite Australian publications on AADs appearing in reasonably high impact journals, most were confined to a single Australian psychiatry journal and overall publications did not show exponential growth over the period studied. This might reflect, inter alia, the relative paucity of medication trials being performed in Australia. PMID- 23804116 TI - Paradigms lost and gained: has psychiatry in Australasia lost its voice? AB - OBJECTIVE: The evolution of views about causes and management models in psychiatry is of keen interest to those who respect the field's history. The objective of this study was to identify international paradigm shifts since 1950 in psychiatric theorising and management models. METHOD: Multiple methods were used, including citation analysis, qualitative judgments by highly cited researchers and obtaining the views of historians of psychiatry. RESULTS: The quantitative citation analysis was of low yield, seemingly reflecting limitations intrinsic to such an approach, but it did identify some 'signals' to broader domain shifts, such as the progressive loss of salience of psychoanalysis and a contrasting emphasis on a science-weighted model. Also, the highly cited researchers tend to nominate narrow exemplars. Nominations by the historians were more panoramic and, while capturing the domains identified by the two other strategies, went further in proposing a wide set of additional candidates for consideration. CONCLUSION: Of the three strategies employed, the qualitative approach (canvassing the views of historians and of highly cited authors) captured the paradigm changes, or at least theoretical or research trends, more accurately than the quantitative citation analysis. Changes in Australasian psychiatry would appear to generally mirror such international changes, rather than evidence a distinctive voice. PMID- 23804117 TI - Competency based advanced training in Intellectual Disability Psychiatry: a NSW prototype. AB - OBJECTIVE: This paper describes a competency based advanced training year in adult Intellectual Disability Psychiatry enabled through a partnership between disability and mental health sectors. This training experience could be viewed as a prototype for further specialised training schemes in Intellectual Disability Psychiatry, and has relevance for the implementation of competency based psychiatric training schemes in Australia. CONCLUSIONS: The need for a specific training curriculum in Intellectual Disability Psychiatry is outlined with reference to epidemiological evidence and human rights. The formulation of the training programme and the training experience itself is described and evaluated. Conclusions on the implications of this experience for the future competency based training schemes are drawn. Building a skilled workforce is necessary to address the significant inequalities in mental health experienced by people with intellectual and developmental disabilities. A significant initial step for this would be the development of a specialised training curriculum. Service provision for this population is scattered across many disciplines and organisations with historically little mutual cooperation. Additionally, proposed competency-based training schemes stipulate that a medical expert develops a wide skill set across multiple domains. Thus, formal cross sector collaboration is fundamental for any competency based training scheme to be feasible. PMID- 23804118 TI - Treatment of Western Australia's mentally ill during the early colonial period, 1826-1865. AB - OBJECTIVE: This paper describes the early settlement of Western Australia and colonial strategies implemented to manage the mentally ill. CONCLUSIONS: Western Australian Colonial treatment of the mentally ill began in 1829 with the first mentally ill patient, Dr Nicholas Were Langley. Building commenced to house the mentally ill with the use of a prison, 'The Round House', and later the temporary shelter 'Scott's Warehouse'. Both convicts and the mentally ill were initially housed together, but evidence exists of attempts to provide therapeutic diversions at Scott's Warehouse. PMID- 23804119 TI - Therapy implications of child abuse in multi-risk families. AB - OBJECTIVES: Our aim is to critique Australian child maltreatment policy, outline abuse trends and provide data on family risk factors. METHOD: We identified policy gaps and reviewed family profiles within selective child maltreatment databases. Data sources included international and Australian literature, Queensland Department of Child Safety reports and a research clinical database. RESULTS: Data reviewed suggest that a pattern of co-occurring complex multiple system family problems characterize substantiated abuse cases. CONCLUSIONS: The presence of multiple family problems suggests the need for a new treatment paradigm. Multisystemic Therapy for child physical abuse and neglect is an evidence-based intervention that matches the therapeutic needs of such families. PMID- 23804120 TI - A theoretical study on the ring expansion of NHCs by silanes. AB - A theoretical study focusing on the ring expansion that occurs in the reaction of N-heterocyclic carbenes with silanes has been carried out. A detailed reaction pathway was determined which indicates that formation of C-H bonds is the crucial factor in the transformation. PMID- 23804122 TI - Population-based incidence of invasive haemophilus influenzae and pneumococcal diseases before the introduction of vaccines in Japan. AB - Before the introduction of vaccines, the incidence of bacterial meningitis among children aged 28 days to 5 years was 8.48, Haemophilus influenzae type-b meningitis was 5.65 and Streptococcus pneumoniae meningitis was 1.85 per 100,000 person-years in Hokkaido, Japan. The incidence of bacteremia caused by S. pneumoniae was 60.15 and H. influenzae was 18.80. PMID- 23804121 TI - Novel inflammatory markers, clinical risk factors and virus type associated with severe respiratory syncytial virus infection. AB - BACKGROUND: Virus-induced inflammation contributes to respiratory syncytial virus (RSV) pathogenesis. We sought to determine the specific mediators that are associated with more severe illness in young children. METHODS: Children <= 5 years of age seen in our emergency department for respiratory symptoms from September 1998 to May 2008 were eligible for enrollment. Nasopharyngeal wash samples were collected from all eligible patients, and clinical data were recorded. Individuals were included in this study if nasopharyngeal wash samples were positive for RSV only. Patients enrolled in the study were stratified by disease severity, defined as mild (not hospitalized), moderate (hospitalized) or severe (requiring intensive care unit stay). Concentrations of individual inflammatory biomarkers in nasopharyngeal wash fluids were determined using the Luminex human 30-plex assay. RESULTS: Eight hundred fifty-one patients met study criteria: 268 (31.5%) with mild, 503 (59.1%) with moderate and 80 (9.4%) with severe illness. As expected, illness severity was directly associated with young age, prematurity, heart or lung disease, infection with RSV group A and elevated concentrations of interleukin (IL)-2R, IL-6, CXCL8, tumor necrosis factor-alpha, interferon-alpha, CCL3, CCL4 and CCL2. In addition, we report several novel and mechanistically important inflammatory biomarkers of severe RSV disease, including IL-1beta, IL1-RA, IL-7, epidermal growth factor and hepatocyte growth factor. CONCLUSIONS: In a large, longitudinal study (10 years, 851 enrolled patients) limited to RSV infection only, in which well-known risk factors are confirmed, we identified 5 novel biomarkers specifically of severe disease. These markers may ultimately serve to elucidate disease mechanisms. PMID- 23804123 TI - Management of carotid stenosis in women. AB - The management of carotid stenosis in women remains a topic of controversy. In this review article, we aimed to define carotid disease burden in women, review outcomes of carotid endarterectomy and carotid artery stenting in women, discuss differences in practice patterns based on sex, and provide guidelines for management of women with carotid stenosis. Symptomatic women with high-grade stenosis derive benefit from carotid endarterectomy, although they have different risk profiles than men and are often not taking appropriate medical therapy. Women with asymptomatic carotid artery stenosis have less stroke risk reduction with CEA than their male counterparts; therefore, they should be screened for other treatable risk factors for stroke, with the institution of lifestyle changes and the appropriate medical therapy. After medical optimization, the decision to proceed with CEA in asymptomatic women must be made by carefully assessing that the benefits of stroke risk reduction outweigh perioperative risks. PMID- 23804124 TI - [Advantages of volume perfusion CT for evaluating the response of solid tumors to treatment with sunitinib]. PMID- 23804125 TI - [Unclear chest pain - diagnostic imaging for evaluation]. PMID- 23804126 TI - [Mild cognitive impairment/Alzheimer disease - combined marker for prediction of cognitive decline]. PMID- 23804127 TI - [Hyperintense hepatocellular carcinoma in MRI - clinical and pathologic features]. PMID- 23804128 TI - [Digital breast tomosynthesis - a replacement for conventional additional adjustment? ]. PMID- 23804129 TI - [Imaging of tumor-related, pathologic fractures - differentiating primary and secondary bone tumors]. PMID- 23804130 TI - [Coronary angiography and radiation dose - generation 2 devices provide high image quality at reduced radiation dose]. PMID- 23804131 TI - [Radiology & the law -- the agreement on objectives in medical reimbursement]. PMID- 23804133 TI - RAGE blockade and hepatic microcirculation in experimental endotoxaemic liver failure. AB - BACKGROUND: Activation of the receptor for advanced glycation endproducts (RAGE) causes sustained activation of multiple inflammatory pathways. Therefore, RAGE has potential as a new therapeutic target in sepsis. The aim of this study was to analyse whether RAGE blockade in vivo prevents microcirculatory dysfunction and subsequent tissue injury in endotoxaemic liver failure. METHODS: The hepatic microcirculation was analysed using intravital fluorescence microscopy in murine livers exposed to galactosamine/lipopolysaccharide (G/L) and treated with an anti RAGE antibody (abRAGE) either 12 h before or h after exposure to G/L. Blood and liver tissue samples were harvested for analysis of leucocyte tissue infiltration, apoptotic and necrotic damage as well as RAGE downstream pathway signalling. RESULTS: Sinusoidal perfusion failure in livers exposed to G/L was reduced significantly by both pretreatment and post-treatment with abRAGE. Hepatic inflammation induced by exposure to G/L was also attenuated by abRAGE administration, as shown by a 55 per cent reduction in sinusoidal leucocyte stasis, a 65 per cent decrease in venular leucocyte rolling and adhesion, and an 85 per cent reduction in leucocyte tissue infiltration. Treatment with abRAGE markedly reduced hepatocellular apoptosis and necrosis in livers exposed to G/L, and blunted the rise in plasma high-mobility group protein B1 levels. Finally, G/L-induced activation of the mitogen-activated protein kinase cascade was also reduced significantly by blockade of RAGE. CONCLUSION: RAGE plays an important role in mediating endotoxaemic liver damage. RAGE blockade may have potential therapeutic value. SURGICAL RELEVANCE: The innate immune response to endoxaemia is initiated by a group of pattern recognition receptors, including the receptor for advanced glycation endproducts (RAGE). As RAGE is well known for perpetuation of inflammatory processes, blockade of this receptor might be of particular value in reducing or even halting endoxaemia-related organ disorders. Using intravital fluorescence microscopy this study demonstrated in vivo that pretreatment, but also post-treatment, with a RAGE-blocking antibody attenuated hepatic microcirculatory deterioration and leucocyte recruitment, and thus diminished liver injury in a murine model of endotoxaemic organ failure. These data underline the important role of RAGE in the innate immune response and support the potential therapeutic value of blocking this pattern recognition receptor. PMID- 23804134 TI - Spin-valley lifetimes in a silicon quantum dot with tunable valley splitting. AB - Although silicon is a promising material for quantum computation, the degeneracy of the conduction band minima (valleys) must be lifted with a splitting sufficient to ensure the formation of well-defined and long-lived spin qubits. Here we demonstrate that valley separation can be accurately tuned via electrostatic gate control in a metal-oxide-semiconductor quantum dot, providing splittings spanning 0.3-0.8 meV. The splitting varies linearly with applied electric field, with a ratio in agreement with atomistic tight-binding predictions. We demonstrate single-shot spin read-out and measure the spin relaxation for different valley configurations and dot occupancies, finding one electron lifetimes exceeding 2 s. Spin relaxation occurs via phonon emission due to spin-orbit coupling between the valley states, a process not previously anticipated for silicon quantum dots. An analytical theory describes the magnetic field dependence of the relaxation rate, including the presence of a dramatic rate enhancement (or hot-spot) when Zeeman and valley splittings coincide. PMID- 23804135 TI - Cell cycle abnormality in metabolic syndrome and nuclear receptors as an emerging therapeutic target. AB - In recent years, many researchers have emphasized the importance of metabolic syndrome based on its increasing prevalence and its adverse prognosis due to associated chronic vascular complications. Upstream of a cluster of metabolic and vascular disorders is the accumulation of visceral adipose tissue, which plays a central role in the pathophysiology. In the accumulation of adipose tissues, cell cycle regulation is tightly linked to cellular processes such as proliferation, hypertrophy and apoptosis. In addition, various cell cycle abnormalities have also been observed in other tissues, such as kidneys and the cardiovascular system, and they are critically involved in the progression of disease. Here, we discuss cell cycle abnormalities in metabolic syndrome in various tissues. Furthermore, we describe the role of nuclear receptors in cell growth and survival, and glucose and lipid metabolism in the whole body. Therapeutic strategies for modulating various cell cycles in metabolic disorders by targeting nuclear receptors may overcome obesity and its chronic vascular complications in the future. PMID- 23804136 TI - Somatosensory and visual deprivation each decrease the density of parvalbumin neurons and their synapse terminals in the prefrontal cortex and hippocampus of mice. AB - In the phenomenon known as cross-modal plasticity, the loss of one sensory system is followed by improved functioning of other intact sensory systems. MRI and functional MRI studies suggested a role of the prefrontal cortex and the temporal lobe in cross-modal plasticity. We used a mouse model to examine the effects of sensory deprivation achieved by whisker trimming and visual deprivation achieved by dark rearing in neonatal mice on the appearance of parvalbumin (PV) neurons and the formation of glutamic acid decarboxylase 67 (GAD67)-positive puncta around pyramidal neurons in the prefrontal cortex and hippocampus. Whisker trimming, but not dark rearing, decreased the density of PV neurons in the hippocampus at postnatal day 28 (P28). In the prefrontal cortex, whisker trimming and dark rearing decreased the density of PV neurons in layer 5/6 (L5/6) at P28 and in L2/3 at P56, respectively, whereas dark rearing increased the density of PV neurons in L5/6 at P56. Whisker trimming decreased the density of GAD67 positive puncta in CA1 of the hippocampus at both P28 and P56 and in L5/6 of the prefrontal cortex at P28. Dark rearing decreased the density of GAD67-positive puncta in CA1 of the hippocampus and in both L2/3 and L5/6 of the prefrontal cortex at P28, and in L2/3 of the prefrontal cortex at P56. These results demonstrate that somatosensory or visual deprivation causes changes in the PV interneuronal network in the mouse prefrontal cortex and hippocampus. The results also suggest that the alteration of the PV-interneuronal network, especially in the prefrontal cortex, may contribute to cross-modal plasticity. PMID- 23804137 TI - Association between mammographic breast density and lifestyle in Japanese women. AB - A high mammographic breast density is considered to be a risk factor for breast cancer. However, only a small number of studies on the association between breast density and lifestyle have been performed. A cross-sectional study was performed using a survey with 29 questions on life history and lifestyle. The breast density on mammography was classified into 4 categories following the BI-RADS criteria. The subjects were 522 women with no medical history of breast cancer. The mean age was 53.3 years old. On multivariate analysis, only BMI was a significant factor determining breast density in premenopausal women (parameter estimate, -0.403; p value, 0.0005), and the density decreased as BMI rose. In postmenopausal women, BMI (parameter estimate, -0.196; p value, 0.0143) and number of deliveries (parameter estimate, -0.388; p value, 0.0186) were significant factors determining breast density;breast density decreased as BMI and number of deliveries increased. Only BMI and number of deliveries were identified as factors significantly influencing breast density. BMI was inversely correlated with breast density before and after menopause, whereas the influence of number of deliveries on breast density was significant only in postmenopausal women in their 50 and 60s. PMID- 23804138 TI - Improvement of the efficacy of 5-aminolevulinic acid-mediated photodynamic treatment in human oral squamous cell carcinoma HSC-4. AB - Ever since protoporphyrin IX (PpIX) was discovered to accumulate preferentially in cancer cells after 5-aminolevulinic acid (ALA) treatment, photodynamic treatment or therapy (PDT) has been developed as an exciting new treatment option for cancer patients. However, the level of PpIX accumulation in oral cancer is fairly low and insufficient for PDT. Ferrochelatase (FECH) and ATP-binding cassette transporter G2 (ABCG2) are known to regulate PpIX accumulation. In addition, serum enhances PpIX export by ABCG2. We investigated here whether and how inhibitors of FECH and ABCG2 and their combination could improve PpIX accumulation and PDT efficacy in an oral cancer cell line in serum-containing medium. ABCG2 inhibitor and the combination of ABCG2 and FECH inhibitors increased PpIX in the presence of fetal bovine serum (FBS) in an oral cancer cell line. Analysis of ABCG2 gene silencing also revealed the involvement of ABCG2 in the regulation of PpIX accumulation. Inhibitors of FECH and ABCG2, and their combination increased the efficiency of ALA-PDT even in the presence of FBS. ALA PDT-induced cell death was accompanied by apoptotic events and lipid peroxidation. These results suggest that accumulation of PpIX is determined by the activities of ABCG2 and FECH and that treatment with a combination of their inhibitors improves the efficacy of PDT for oral cancer, especially in the presence of serum. PMID- 23804139 TI - p53 expression in pretreatment specimen predicts response to neoadjuvant chemotherapy including anthracycline and taxane in patients with primary breast cancer. AB - While clinical and pathologic responses are important prognostic parameters, biological markers from core needle biopsy (CNB) are needed to predict neoadjuvant chemotherapy (NAC) response, to individualize treatment, and to achieve maximal efficacy. We retrospectively evaluated the cases of 183 patients with primary breast cancer who underwent surgery after NAC (anthracycline and taxane) at the National Cancer Center Hospital (NCCH). We analyzed EGFR, HER2, and p53 expression and common clinicopathological features from the CNB and surgical specimens of these patients. These biological markers were compared between sensitive patients (pathological complete response;pCR) and insensitive patients (clinical no change;cNC and clinical progressinve disease;cPD). In a comparison between the 9 (5%) sensitive patients and 30 (16%) insensitive patients, overexpression of p53 but not overexpression of either HER2 or EGFR was associated with a good response to NAC. p53 (p=0.045) and histological grade 3 (p=0.011) were important and significant predictors of the response to NAC. The correspondence rates for histological type, histological grade 3, ER, PgR, HER2, p53, and EGFR in insensitive patients between CNB and surgical specimens were 70%, 73%, 67%, 70%, 80%, 93%, and 73%. The pathologic response was significantly associated with p53 expression and histological grade 3. The correspondence rate of p53 expression between CNB and surgical specimens was higher than that of other factors. We conclude that the level of p53 expression in the CNB was an effective and reliable predictor of treatment response to NAC. PMID- 23804140 TI - Application of a first impression triage in the Japan railway west disaster. AB - On April 25, 2005, a Japanese express train derailed into a building, resulting in 107 deaths and 549 injuries. We used "First Impression Triage (FIT)", our new triage strategy based on general inspection and palpation without counting pulse/respiratory rates, and determined the feasibility of FIT in the chaotic situation of treating a large number of injured people in a brief time period. The subjects included 39 patients who required hospitalization among 113 victims transferred to our hospital. After initial assessment with FIT by an emergency physician, patients were retrospectively reassessed with the preexisting the modified Simple Triage and Rapid Treatment (START) methodology, based on Injury Severity Score, probability of survival, and ICU stay. FIT resulted in shorter waiting time for triage. FIT designations comprised 11 red (immediate), 28 yellow (delayed), while START assigned six to red and 32 to yellow. There were no statistical differences between FIT and START in the accuracy rate calculated by means of probability of survival and ICU stay. Overall validity and reliability of FIT determined by outcome assessment were similar to those of START. FIT would be a simple and accurate technique to quickly triage a large number of patients. PMID- 23804141 TI - Postural stability changes during large vertical diplopia induced by prism wear in normal subjects. AB - To test the effect of double vision on postural stability, we measured postural stability by electric stabilometry before prism-wearing and immediately, 15, 30, and 60min after continuous prism-wearing with 6 prism diopters in total (a 3 prism-diopter prism placed with the base up in front of one eye and with the base down in front of the other eye) in 20 normal adult individuals with their eyes open or closed. Changes in stabilometric parameters in the time course of 60min were analyzed statistically by repeated-measure analysis of variance. When subjects? eyes were closed, the total linear length (cm) and the unit-time length (cm/sec) of the sway path were significantly shortened during the 60-minute prism wearing (p<0.05). No significant change was noted in any stabilometric parameters obtained with the eyes open during the time course. In conclusion, postural stability did not change with the eyes open in the condition of large vertical diplopia, induced by prism-wearing for 60min, while the stability became better when measured with the eyes closed. A postural control mechanism other than that derived from visual input might be reinforced under abnormal visual input such as non-fusionable diplopia. PMID- 23804142 TI - Development of dysphagia and trismus developed after c1-2 posterior fusion in extended position. AB - Cervical misalignment after upper cervical fusion including the occipital bone may cause trismus or dysphagia, because the occipito-atlanto joint is associated with most of the flex and extended motion of the cervical spine. There are no reports of dysphagia and trismus after C1-2 fusion. The purpose of this paper is to demonstrate the potential risk of dysphagia and trismus even after upper cervical short fusion without the occipital bone. The patient was a 69-year-old man with myelopathy caused by os odontoideum and Klippel-Feil syndrome, who developed dysphagia and trismus immediately after C1-2 fusion and C3-6 laminoplasty. Radiographs and CT revealed that his neck posture was extended, but his symptoms still existed a week after surgery. The fixation angle was hyperextended 12 days after the first surgery. His symptoms disappeared immediately after revision surgery. The fixation in the neck-flexed position is thought to be the main cause of the patient's post-operative dysphagia and trismus. Dysphagia and trismus may occur even after short upper cervical fusion without the occipital bone or cervical fusion in the neck-extended position. The pre-operative cervical alignment and range of motion of each segment should be thoroughly evaluated. PMID- 23804143 TI - Three cases of struma ovarii underwent laparoscopic surgery with definite preoperative diagnosis. AB - Struma ovarii is a rare neoplasm that accounts for approximately 0.3% of ovarian tumors. Due to its ultrasound morphology, which is quite similar to that of malignant ovarian carcinoma, most struma ovarii cases are open operated with laparotomy rather than laparoscopy. We present 3 cases of struma ovarii, which were diagnosed preoperatively by imaging studies and removed by laparoscopic surgery. All patients were premenopausal women between ages 31-50. The magnetic resonance imaging (MRI) findings were complex masses composed of multiple cysts and solid components with T2-hypointense regions as well as multiple T1 hyperintense cystic areas, findings that are typical for struma ovarii. A combination of plain computed tomography (CT), positron emission tomography (PET) CT, and scintigraphy was useful for diagnosis. Laboratory examination revealed elevated serum thyroglobulin, which led to the diagnosis of struma ovarii. Laparoscopic surgeries were performed without rupturing the tumors. Although it has been difficult to differentiate between struma ovarii and malignant tumors by conventional methods, recently MRI techniques appear make it possible to diagnose struma ovarii preoperatively from the abovementioned imaging characteristic, together with laboratory data. As for treatment, we think laparoscopy could be successful for struma ovarii, but the surgeon must be careful not to rupture the tumor intra-abdominally in order to prevent dissemination, which could lead to malignancy. PMID- 23804144 TI - Proximal vertebral body fracture after 4-level fusion using l1 as the upper instrumented vertebra for lumbar degenerative disease: report of 2 cases with literature review. AB - Some cases with lumbar degenerative diseases require multi-level fusion surgeries. At our institute, 27 and 4 procedures of 3- and 4-level fusion were performed out of a total 672 posterior lumbar interfusions (PLIFs) on patients with lumbar degenerative disease from 2005 to 2010. We present 2 osteoporotic patients who developed proximal vertebral body fracture after 4-level fusion. Both cases presented with gait disability for leg pain by degenerative lumbar scoliosis and canal stenosis at the levels of L1/2-4/5. After 4-level fusion using L1 as the upper instrumented vertebra, proximal vertebral body fractures were found along with the right pedicle fractures of L1 in both cases. One of these patients, aged 82 years, was treated as an outpatient using a hard corset for 24 months, but the fractures were exacerbated over time. In the other patient, posterolateral fusion was extended from Th10 to L5. Both patients can walk alone and have been thoroughly followed up. In both cases, the fracture of the right L1 pedicle might be related to the subsequent fractures and fusion failure. In consideration of multi-level fusion, L1 should be avoided as an upper instrumented vertebra to prevent junctional kyphosis, especially in cases with osteoporosis and flat back posture. PMID- 23804145 TI - Underrecognition of the heterogeneous clinical spectrum of bullous pemphigoid. PMID- 23804146 TI - Comparison of epigenetic profiles of human oral epithelial cells from HIV positive (on HAART) and HIV-negative subjects. AB - HIV-infected subjects on highly active antiretroviral therapy (HAART) are susceptible to comorbid microbial infections in the oral cavity. We observed that primary oral epithelial cells (POECs) isolated from HIV+ subjects on HAART grow more slowly and are less innate immune responsive to microbial challenge when compared with POECs from normal subjects. These aberrant cells also demonstrate epigenetic differences that include reduction in histone deacetylase 1 (HDAC-1) levels and reduced total DNA methyltransferase (DNMT) activity specific to enzymes DNMT1 and DNMT3A. The DNMT activity correlates well with global DNA methylation, indicating that aberrant DNMT activity in HIV+ (on HAART) POECs leads to an aberrantly methylated epithelial cell phenotype. Overall, our results lead us to hypothesize that, in patients with chronic HIV infection on HAART, epigenetic changes in key genes result in increased vulnerability to microbial infection in the oral cavity. PMID- 23804148 TI - An appreciation of Professor David Cole-Hamilton. PMID- 23804149 TI - Comprehensive geriatric assessment of risk factors associated with adverse outcomes and resource utilization in cancer patients undergoing abdominal surgery. AB - BACKGROUND: The purpose of this prospective study was to identify risk factors for adverse outcomes or increased resource utilization after abdominal cancer surgery in geriatric patients. METHODS: Baseline clinical and geriatric assessment variables including functional status, nutritional status, comorbidity index, mental status, depression scale score, fatigue inventory scale, and polypharmacy scale were prospectively recorded for patients age >=65 undergoing intra-abdominal oncologic surgery. Outcome variables included morbidity, mortality, discharge to nursing facility, prolonged hospital stay, and readmission. RESULTS: Of 111 patients, surgery type was colorectal in 40%, hepatopancreatobiliary in 30%, and gastric/duodenal in 14%. Variables associated with discharge to a nursing facility on multivariate analysis included weight loss >=10% (OR 6.52 [95% CI: 1.43-29.76], P = 0.02), ASA score >=2 (OR 5.08 [1.13 22.77], P = 0.03), and ECOG score >=2 (OR 4.51 [1.03-19.71], P = 0.04). Variables independently associated with prolonged hospital stay included weight loss >=10% (OR 4.03 [1.13-14.43], P = 0.03), the presence of polypharmacy (OR 2.45 [1.09 5.48], P = 0.03), and distant disease (OR 0.37 [0.15-0.91], P = 0.03). No variables were associated with morbidity or readmission. CONCLUSIONS: Pre operative clinical and geriatric assessment tools can help predict the need for discharge to a nursing facility or increased length of stay. Future studies will be required to identify patients suitable for interventions to decrease hospital and post-discharge resource utilization. PMID- 23804150 TI - The protective role of endogenous bacterial communities in chironomid egg masses and larvae. AB - Insects of the family Chironomidae, also known as chironomids, are distributed worldwide in a variety of water habitats. These insects display a wide range of tolerance toward metals and organic pollutions. Bacterial species known for their ability to degrade toxicants were identified from chironomid egg masses, leading to the hypothesis that bacteria may contribute to the survival of chironomids in polluted environments. To gain a better understanding of the bacterial communities that inhabit chironomids, the endogenous bacteria of egg masses and larvae were studied by 454-pyrosequencing. The microbial community of the egg masses was distinct from that of the larval stage, most likely due to the presence of one dominant bacterial Firmicutes taxon, which consisted of 28% of the total sequence reads from the larvae. This taxon may be an insect symbiont. The bacterial communities of both the egg masses and the larvae were found to include operational taxonomic units, which were closely related to species known as toxicant degraders. Furthermore, various bacterial species with the ability to detoxify metals were isolated from egg masses and larvae. Koch-like postulates were applied to demonstrate that chironomid endogenous bacterial species protect the insect from toxic heavy metals. We conclude that chironomids, which are considered pollution tolerant, are inhabited by stable endogenous bacterial communities that have a role in protecting their hosts from toxicants. This phenomenon, in which bacteria enable the continued existence of their host in hostile environments, may not be restricted only to chironomids. PMID- 23804151 TI - Specific carbonate-microbe interactions in the modern microbialites of Lake Alchichica (Mexico). AB - The role of microorganisms in microbialite formation remains unresolved: do they induce mineral precipitation (microbes first) or do they colonize and/or entrap abiotic mineral precipitates (minerals first)? Does this role vary from one species to another? And what is the impact of mineral precipitation on microbial ecology? To explore potential biogenic carbonate precipitation, we studied cyanobacteria-carbonate assemblages in modern hydromagnesite-dominated microbialites from the alkaline Lake Alchichica (Mexico), by coupling three dimensional imaging of molecular fluorescence emitted by microorganisms, using confocal laser scanning microscopy, and Raman scattering/spectrometry from the associated minerals at a microscale level. Both hydromagnesite and aragonite precipitate within a complex biofilm composed of photosynthetic and other microorganisms. Morphology and pigment-content analysis of dominant photosynthetic microorganisms revealed up to six different cyanobacterial morphotypes belonging to Oscillatoriales, Chroococcales, Nostocales and Pleurocapsales, as well as several diatoms and other eukaryotic microalgae. Interestingly, one of these morphotypes, Pleurocapsa-like, appeared specifically associated with aragonite minerals, the oldest parts of actively growing Pleurocapsa-like colonies being always aragonite-encrusted. We hypothesize that actively growing cells of Pleurocapsales modify local environmental conditions favoring aragonite precipitation at the expense of hydromagnesite, which precipitates at seemingly random locations within the biofilm. Therefore, at least part of the mineral precipitation in Alchichica microbialites is most likely biogenic and the type of biominerals formed depends on the nature of the phylogenetic lineage involved. This observation may provide clues to identify lineage-specific biosignatures in fossil stromatolites from modern to Precambrian times. PMID- 23804153 TI - Synthesis and biological activity of phosphoglycolipids from Thermus thermophilus. AB - An extreme thermophile, Thermus thermophilus, has very unique glycolipids on the cell surface. The acidic immunostimulatory phosphoglycolipid of T. thermophilus was synthesized for the first time, with newly developed glycosylation methods using 3-nitropyridyl (3NPy) and 4,6-dimethoxy-1,3,5-triazin-2-yl (DMT) glycosides as glycosyl donors. The analogues of the phosphoglycolipid, which include a diastereomer possessing the opposite configuration at the diacyl glycerol moiety, were also synthesized. The biological activities of the synthesized compounds were elucidated with cytokine inductions (IL-6 and TNF-alpha). A synthetic phosphoglycolipid with a natural-type diacyl glycerol configuration showed apparent immunostimulatory activity, whereas its diastereomer did not. The present study revealed that the configuration at the diacyl glycerol moiety of the phosphoglycolipids is important for immunostimulation, suggesting the existence of the particular receptor/recognizing protein that can recognize the stereochemistry of the glycerol part. PMID- 23804154 TI - [S3 guideline--Diagnosis and treatment of colorectal carcinoma: relevance for radiologic imaging and interventions]. AB - The new German S3 guideline "Colorectal Carcinoma" was created as part of the German Guideline Program in Oncology of the Association of the Scientific Medical Societies in Germany, the German Cancer Society and the German Cancer Aid under the auspices of the German Society for Digestive and Metabolic Diseases and replaces the guideline from 2008. With its evidence-based treatment recommendations, the guideline contains numerous updates and detailed definitions regarding the diagnosis and treatment of colon and rectal cancer. In particular, consensus-based recommendations regarding early detection, preoperative diagnostic method selection, and the use of interventional radiological treatment methods are detailed. The guideline also includes quality indicators so that standardized quality assurance methods can be used to optimize patient-related processes.The present article discusses the significance of the current recommendations for radiological diagnosis and treatment and is intended to enhance the quality of patient information and care by increasing distribution. PMID- 23804155 TI - Advanced hyphenated chromatographic-mass spectrometry in mycotoxin determination: current status and prospects. AB - Mass spectrometric techniques are essential for advanced research in food safety and environmental monitoring. These fields are important for securing the health of humans and animals, and for ensuring environmental security. Mycotoxins, toxic secondary metabolites of filamentous fungi, are major contaminants of agricultural products, food and feed, biological samples, and the environment as a whole. Mycotoxins can cause cancers, nephritic and hepatic diseases, various hemorrhagic syndromes, and immune and neurological disorders. Mycotoxin contaminated food and feed can provoke trade conflicts, resulting in massive economic losses. Risk assessment of mycotoxin contamination for humans and animals generally depends on clear identification and reliable quantitation in diversified matrices. Pioneering work on mycotoxin quantitation using mass spectrometry (MS) was performed in the early 1970s. Now, unambiguous confirmation and quantitation of mycotoxins can be readily achieved with a variety hyphenated techniques that combine chromatographic separation with MS, including liquid chromatography (LC) or gas chromatography (GC). With the advent of atmospheric pressure ionization, LC-MS has become a routine technique. Recently, the co occurrence of multiple mycotoxins in the same sample has drawn an increasing amount of attention. Thus, modern analyses must be able to detect and quantitate multiple mycotoxins in a single run. Improvements in tandem MS techniques have been made to achieve this purpose. This review describes the advanced research that has been done regarding mycotoxin determination using hyphenated chromatographic-MS techniques, but is not a full-circle survey of all the literature published on this topic. The present work provides an overview of the various hyphenated chromatographic-MS-based strategies that have been applied to mycotoxin analysis, with a focus on recent developments. The use of chromatographic-MS to measure levels of mycotoxins, including aflatoxins, ochratoxins, patulin, trichothecenes, zearalenone, and fumonisins, is discussed in detail. Both free and masked mycotoxins are included in this review due to different methods of sample preparation. Techniques are described in terms of sample preparation, internal standards, LC/ultra performance LC (UPLC) optimization, and applications and survey. Several future hyphenated MS techniques are discussed as well, including multidimensional chromatography-MS, capillary electrophoresis-MS, and surface plasmon resonance array-MS. PMID- 23804156 TI - Local recurrence after surgery for primary extra-abdominal desmoid-type fibromatosis. AB - BACKGROUND: Desmoid-type fibromatosis is a locally aggressive soft tissue tumour with a biological behaviour that varies between relatively indolent and progressive growth. Although there is a trend towards conservative treatment, surgery remains the standard treatment for extra-abdominal desmoid tumours. METHODS: Databases of three hospitals were searched to identify patients who had been treated for desmoid-type fibromatosis between November 1989 and May 2011. The risk of local recurrence was evaluated and predictive factors were assessed in patients who underwent surgical resection as initial treatment for a primary tumour. RESULTS: A total of 132 patients had surgical treatment for a primary tumour. A complete resection (R0) was achieved in 87 patients (65.9 per cent). In addition to surgery, 54 patients received radiotherapy. During a median follow-up of 38 months, 18 local recurrences were detected. The estimated 5-year cumulative risk of local recurrence was 17.6 per cent. Univariable Cox regression analysis demonstrated that the risk of local recurrence increased for extremity lesions compared with desmoids on the trunk (odds ratio 6.69, 95 per cent confidence interval 1.42 to 31.54). No significant influence of age, resection margins or adjuvant radiotherapy on the risk for local recurrence was observed. CONCLUSION: Following surgical treatment of a primary extra-abdominal desmoid tumour, the 5 year risk of local recurrence is modest and not influenced by microscopically clear resection margins or adjuvant radiotherapy. PMID- 23804157 TI - Cement directed kyphoplasty reduces cement leakage as compared with vertebroplasty: results of a controlled, randomized trial. AB - STUDY DESIGN: A novel randomized, controlled, unblinded clinical trial comparing 2 procedural interventions for painful osteoporotic vertebral compression fractures. OBJECTIVE: The primary study objective was to evaluate cement leakage for a cement directed kyphoplasty system (CDKS) with anteriorly biased cement flow and vertebroplasty. The secondary study objective was to compare adjacent level fracture rates and vertebral body height for these 2 intervention methods. SUMMARY OF BACKGROUND DATA: Cement leakage remains a significant clinical problem associated with vertebroplasty and kyphoplasty procedures. Uncontrolled cement flow in the posterior direction can result in leakage into the vertebral veins or spinal canal, leading to potentially serious clinical complications. METHODS: Seventy-seven patients with painful osteoporotic vertebral compression fractures were enrolled. Patients were randomized 2:1 for treatment with CDKS (49 patients, 65 levels) or vertebroplasty (28 patients, 39 levels). Cement leakage was evaluated from radiographs and computed tomographic scans. Three- and 12-month follow-ups included additional radiographs and computed tomographic scans to assess changes in vertebral body height and the incidence of new fractures. RESULTS: Treatment with CDKS significantly reduced the number of levels with leaks and the total number of leaks per level, as compared with vertebroplasty (P = 0.0132 and P = 0.0012, respectively). Significantly, fewer lateral cortical and spinal canal leaks (posterior leaks) occurred in the CDKS group (P = 0.0050, P = 0.02260, respectively). Three adjacent level fractures occurred in the vertebroplasty group, as compared with 2 in the CDKS group. Vertebral body height maintenance was equivalent. CONCLUSION: Cement directed kyphoplasty effectively reduces posterior cement leakage, reducing the risk of leakage related complications. LEVEL OF EVIDENCE: 2. PMID- 23804158 TI - Reliability analysis of shoulder balance measures: comparison of the 4 available methods. AB - STUDY DESIGN: Observational study with 3 examiners. OBJECTIVE: To compare the reliability of shoulder balance measurement methods. SUMMARY OF BACKGROUND DATA: There are several measurement methods for shoulder balance. No reliability analysis has been performed despite the clinical importance of this measurement. METHODS: Whole spine posteroanterior radiographs (n = 270) were collected to compare the reliability of the 4 shoulder balance measures in patients with adolescent idiopathic scoliosis. Each radiograph was measured twice by each of the 3 examiners using 4 measurement methods. The data were analyzed statistically to determine the inter- and intraobserver reliability. RESULTS: Overall, the 4 radiographical methods showed an excellent intraclass correlation coefficient regardless of severity in intraobserver comparisons (>0.904). In addition, the mean absolute difference values in all methods were low and were comparatively similar (<1.73 degrees ). However, in interobserver comparisons, reliabilities were significantly decreased in the less severe radiographs, firstly on radiographical shoulder height measures (intraclass correlation coefficients >0.445, mean absolute difference <3.91 degrees ). However, the intraclass correlation coefficients in the coracoid height difference and clavicular angle methods were in the excellent range (>0.810 and >0.787, respectively) regardless of severity. In addition, the mean absolute difference values in the clavicular angle method were lower (<0.62 degrees ) than others. CONCLUSION: The higher reliability of the clavicular angle and coracoid height difference methods indicate the clinical usefulness of these methods. Physicians should selectively use the shoulder balance measurement method clinically. LEVEL OF EVIDENCE: 3. PMID- 23804152 TI - Nitrite oxidation in the upper water column and oxygen minimum zone of the eastern tropical North Pacific Ocean. AB - Nitrogen (N) is an essential nutrient in the sea and its distribution is controlled by microorganisms. Within the N cycle, nitrite (NO2(-)) has a central role because its intermediate redox state allows both oxidation and reduction, and so it may be used by several coupled and/or competing microbial processes. In the upper water column and oxygen minimum zone (OMZ) of the eastern tropical North Pacific Ocean (ETNP), we investigated aerobic NO2(-) oxidation, and its relationship to ammonia (NH3) oxidation, using rate measurements, quantification of NO2(-)-oxidizing bacteria via quantitative PCR (QPCR), and pyrosequencing. (15)NO2(-) oxidation rates typically exhibited two subsurface maxima at six stations sampled: one located below the euphotic zone and beneath NH3 oxidation rate maxima, and another within the OMZ. (15)NO2(-) oxidation rates were highest where dissolved oxygen concentrations were <5 MUM, where NO2(-) accumulated, and when nitrate (NO3(-)) reductase genes were expressed; they are likely sustained by NO3(-) reduction at these depths. QPCR and pyrosequencing data were strongly correlated (r(2)=0.79), and indicated that Nitrospina bacteria numbered up to 9.25% of bacterial communities. Different Nitrospina groups were distributed across different depth ranges, suggesting significant ecological diversity within Nitrospina as a whole. Across the data set, (15)NO2(-) oxidation rates were decoupled from (15)NH4(+) oxidation rates, but correlated with Nitrospina (r(2)=0.246, P<0.05) and NO2(-) concentrations (r(2)=0.276, P<0.05). Our findings suggest that Nitrospina have a quantitatively important role in NO2(-) oxidation and N cycling in the ETNP, and provide new insight into their ecology and interactions with other N-cycling processes in this biogeochemically important region of the ocean. PMID- 23804159 TI - Integrated Mach-Zehnder interferometer for Bose-Einstein condensates. AB - Particle-wave duality enables the construction of interferometers for matter waves, which complement optical interferometers in precision measurement devices. This requires the development of atom-optics analogues to beam splitters, phase shifters and recombiners. Integrating these elements into a single device has been a long-standing goal. Here we demonstrate a full Mach-Zehnder sequence with trapped Bose-Einstein condensates confined on an atom chip. Particle interactions in our Bose-Einstein condensate matter waves lead to a nonlinearity, absent in photon optics. We exploit it to generate a non-classical state having reduced number fluctuations inside the interferometer. Making use of spatially separated wave packets, a controlled phase shift is applied and read out by a non-adiabatic matter-wave recombiner. We demonstrate coherence times a factor of three beyond what is expected for coherent states, highlighting the potential of entanglement as a resource for metrology. Our results pave the way for integrated quantum enhanced matter-wave sensors. PMID- 23804161 TI - Low-glycaemic index diets in the management of blood lipids: a systematic review and meta-analysis. AB - BACKGROUND: Dietary glycaemic index (GI) is a measure of the postprandial glycaemic response to carbohydrates. Observational studies have found increased triglycerides and decreased high-density lipoprotein levels in patients consuming higher GI foods. OBJECTIVE: Our aim was to review and synthesize the evidence on the effect of low-glucose index diets on serum lipid levels. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials on the effect of low-GI diets on serum lipid levels. We searched PubMed, Embase and Cochrane Library for published, English-language, randomized controlled trials comparing low-GI and high-GI diets for the management of blood lipids in the general population with at least 4 weeks of follow-up. We conducted a meta analysis assuming a random effects model. RESULTS: Four studies met the criteria for inclusion in the systematic review and meta-analysis. The individual studies did not always show a significant effect of a low-GI diet on serum lipids; however, when combined in a meta-analysis, low-GI diets were shown to have a significant effect on decreasing total cholesterol and low-density lipoprotein (LDL) cholesterol over a short time span (5-12 weeks). There was no significant effect on high-density lipoprotein or triglyceride levels. The forest plots for total cholesterol and LDL cholesterol did not show significant statistical heterogeneity (I (2) = 0%). CONCLUSION: This meta-analysis suggests that a low-GI diet may help lower total and LDL cholesterol. The generalizability of these findings is likely limited by heterogeneity in individual study definitions of low- or high-GI diets. PMID- 23804162 TI - Nuclear medicine infection. PMID- 23804160 TI - Melanoma survival disadvantage in young, non-Hispanic white males compared with females. AB - IMPORTANCE: Worse survival among patients with melanoma has been demonstrated in middle-aged and older men compared with women, but few studies have explored survival differences by sex in adolescents and young adults, in whom melanoma is the third most common cancer. Focusing on sex disparities in survival among younger individuals may provide further evidence of biological rather than behavioral factors that affect melanoma outcome. OBJECTIVE: To determine whether long-term survival varies between white male and female adolescents and young adults with melanoma (15 to 39 years of age at diagnosis) in the United States. DESIGN, SETTING, AND PARTICIPANTS: Population-based cohort with a mean follow-up of 7.5 years of 26,107 non-Hispanic white adolescents and young adults with primary invasive melanoma of the skin diagnosed from January 1, 1989, through December 31, 2009, and reported to the Surveillance, Epidemiology, and End Results network of cancer registries. MAIN OUTCOME AND MEASURE: Melanoma-specific survival. RESULTS: There were 1561 melanoma-specific deaths in the study population. Although adolescent and young adult males accounted for fewer overall melanoma cases (39.8%) than females, they comprised 63.6% of melanoma-specific deaths. Adolescent and young adult males were 55% more likely to die of melanoma than age-matched females after adjustment for tumor thickness, histologic subtype, presence and extent of metastasis, and anatomical location (hazard ratio, 1.55; 95% CI, 1.39-1.73). Males were also more likely to die within each age range assessed (eg, 15-24, 25-29, 30-34, and 35-39 years), and even those with thin melanomas (<=1.00 mm) were twice as likely to die as age-matched females (hazard ratio, 1.95; 95% CI, 1.57-2.42). Adjustment for health insurance and socioeconomic status in a subanalysis did not significantly alter these results. CONCLUSIONS AND RELEVANCE: Male sex is associated with worse survival among white adolescents and young adults with melanoma after controlling for thickness and other prognostic factors. Continued public health efforts are necessary to raise awareness of the outcome of melanoma in young men. Further investigation of possible biological mechanisms that account for these sex differences is merited. PMID- 23804163 TI - Motion-contrast laser speckle imaging of microcirculation within tissue beds in vivo. AB - Laser speckle imaging is widely used to monitor functional blood perfusion within tissue beds in vivo but traditionally has difficulty visualizing small blood vessels even when the exposure time of the detector is long. We report a simple method that uses the motion contrast of dynamic speckle patterns to noninvasively visualize the distribution of blood flow within tissue beds in vivo. We experimentally demonstrate that the motion contrast can significantly suppress the effect of static scattering, leading to enhanced visibility of the functional blood vessels, including capillaries when compared to the traditional laser speckle contrast imaging. PMID- 23804164 TI - Neuromuscular disease classification system. AB - Diagnosis of neuromuscular diseases is based on subjective visual assessment of biopsies from patients by the pathologist specialist. A system for objective analysis and classification of muscular dystrophies and neurogenic atrophies through muscle biopsy images of fluorescence microscopy is presented. The procedure starts with an accurate segmentation of the muscle fibers using mathematical morphology and a watershed transform. A feature extraction step is carried out in two parts: 24 features that pathologists take into account to diagnose the diseases and 58 structural features that the human eye cannot see, based on the assumption that the biopsy is considered as a graph, where the nodes are represented by each fiber, and two nodes are connected if two fibers are adjacent. A feature selection using sequential forward selection and sequential backward selection methods, a classification using a Fuzzy ARTMAP neural network, and a study of grading the severity are performed on these two sets of features. A database consisting of 91 images was used: 71 images for the training step and 20 as the test. A classification error of 0% was obtained. It is concluded that the addition of features undetectable by the human visual inspection improves the categorization of atrophic patterns. PMID- 23804165 TI - Patients' expectations of the health advice conversation with the diabetes nurse practitioner. AB - Type 2-diabetes usually makes its first appearance in adult age. In order for patients to feel in control of the disease, they need support and information that can easily be understood and which is relevant for the individual. By educating and supporting them, patients can conduct self-care and take control. The aim of this study was to highlight the expectations that patients with type 2 diabetes have of the health advice conversation with the nurse practitioner. A qualitative method using interviews was conducted and the data material was analysed according to manifest and latent content analysis. Three categories emerged in the results. Firstly, providing good accessibility to the diabetes nurse practitioner is of importance. Secondly, there is a demand for group activities in which patients have the opportunity to talk with other individuals who have diabetes. Finally, knowledge about self-care means that the patients themselves are able to change the intake of medication, their eating habits, and exercise according to need, as this leads to increased independence and self management. The latent content demonstrates that the patient is striving towards competence and self-confidence in order to achieve a balance between lifestyle and the normalisation of blood sugar levels, which means empowerment. In addition, the informants expressed a demand for group activities where they can discuss the disease with others in the same situation. A combination of knowledge about the disease, receiving individual advice, and participation in groups can be beneficial in order to motivate the informants about lifestyle changes and to gain the ability to manage the disease. PMID- 23804166 TI - A Single A1C >= 6.5% Accurately Identifies Type 2 Diabetes/Impaired Glucose Tolerance in African Americans. AB - OBJECTIVE: In 2010, the American Diabetes Association revised its criteria for the diagnosis of diabetes to include A1C >= 6.5%; however, this has remained controversial, particularly for African Americans. The objective of this pilot study was to examine the usefulness of a single A1C determination in comparison with a same day 2-hour oral glucose tolerance test to diagnose type 2 diabetes in African Americans. METHODS: In sum, 195 oral glucose tolerance tests and A1Cs were obtained on the same day from 77 overweight and obese African American women and 6 men over a period of 15 months. RESULTS: A1C >= 6.5% was present in 31 of 195 patients, with 15 of these having type 2 diabetes by oral glucose tolerance test, another 12 having impaired glucose tolerance, and 4 having normal glucose tolerance. This gives a sensitivity of 50% and a specificity of 90%, with a positive predictive value of 48% and a negative predictive value of 91%. A1C <= 5.6%, proposed by the American Diabetes Association to indicate normal glucose tolerance, was present in only 28 patients, 10 (35.7%) of whom had normal glucose tolerance, whereas 18 (64.3%) had either impaired glucose tolerance (15 patients) or type 2 diabetes (3 patients). Fasting plasma glucose >= 126 mg/dL was present in 5 of 29 patients with type 2 diabetes (sensitivity, 17.2%; specificity, 100%). CONCLUSIONS: First, A1C >= 6.5% was a good "rule in" value to identify impaired glucose tolerance and type 2 diabetes (ie, patients at high risk for micro- and macrovascular complications). Second, A1C <= 5.6% did not rule out impaired glucose tolerance or type 2 diabetes. Last, fasting plasma glucose >= 126 mg/dL detected less than 1 in 5 cases with type 2 diabetes. PMID- 23804167 TI - Diabetes Implementation of a Self-management Program in Resource Poor and Rural Community Clinics. AB - PURPOSE: To evaluate the implementation of a brief diabetes self-management support intervention designed for resource-poor community clinics. METHODS: The authors conducted a pilot study among patients with type 2 diabetes in 3 community clinics. The intervention consisted of research assistants introducing and reviewing a diabetes self-management guide, helping patients set an achievable behavioral action plan, and following up with 2 telephone sessions. The primary outcome was patients' success setting and achieving behavioral goals. RESULTS: All participants set an action plan (N = 247); most focused on physical activity or diet (97%). The initial session took an average of 15 minutes. At 2 to 4 weeks, 200 participants were contacted; 68% recalled their action plan; and 84% of these achieved it. At 6 to 9 weeks, approximately half of those who completed the first call were reached for the second call. Of those who remained in the intervention, 79% recalled their action plan, and 80% of these achieved it. At the end of the study, 62% of those initially enrolled reported behavior change. Most participants who did not complete the intervention could not be reached for telephone follow-up. CONCLUSIONS: Although only about a third of patients remained engaged through the 2 follow-up calls, most of those who did reported they had achieved their action plan. This pilot study provides insight into initiating brief diabetes self-management strategies in resource-poor community clinics. Although telephone follow-up was challenging, using the self management guide and action plan framework, particularly during the initial clinic visit, helped focus patients on behavior change. PMID- 23804168 TI - After-hours Access of Convenient Care Clinics and Cost Savings Associated With Avoidance of Higher-Cost Sites of Care. AB - This study examines the utilization of convenient care clinic services outside of typical physician office hours and estimates the cost savings from potentially avoided visits to the emergency room, urgent care center, and primary care physician associated with convenient care clinic encounters. The results show that 44.6% of convenient care clinic visits occurred on weekdays, 5 pm or later, or on weekends. Savings from avoided encounters with the emergency room, urgent care, and primary care physician were estimated at $135.53 million. PMID- 23804169 TI - Poor compliance makes treatment of latent tuberculosis infection unsatisfactory. AB - OBJECTIVES: The recommended treatment for latent tuberculosis infection is isoniazid for 9 months, but this regimen has a low completion rate. The authors wanted to compare treatment with isoniazid and treatment with isoniazid and rifampin in the typical public health setting in a large diverse state and recover as much information as possible from a state database. METHODS: Patients who received latent tuberculosis infection treatment were identified in the Texas Department of State Health Services database for the years 1995-2002. Treatment completion, adverse reactions, and disease development were recorded. Results were analyzed using logistic regression to predict disease development. RESULTS: In sum, 50 578 patients received isoniazid, and 280 received isoniazid/rifampin. Sixty-one percent of the isoniazid group and 54% of the isoniazid/rifampin group completed treatment. Eighteen percent of the isoniazid/rifampin group possibly had adverse reactions and discontinued treatment; 3% of the isoniazid group discontinued therapy because of side effects. More than 70% of patients with adverse reactions in the isoniazid/rifampin group took the treatment for more than 4 months. Overall, 168 patients in the isoniazid group with a normal chest X ray and a positive skin test developed tuberculosis during follow-up to 2008; no patients in the isoniazid/rifampin group who had a normal X-ray and completed chemoprophylaxis developed tuberculosis during follow-up. CONCLUSIONS: The isoniazid/rifampin regimen appears to be as effective as the isoniazid regimen. However, completion rates on combination therapy were slightly lower. This regimen needs more formal clinical study since it has the potential to decrease administrative costs and improve completion rates. In addition, state departments of health need to develop networks using community-based resources to reach patients and increase completion rates. PMID- 23804170 TI - A pilot randomized trial comparing a commercial weight loss program with a clinic based intervention for weight loss. AB - OBJECTIVE: To compare the efficacy of a popular commercial program with that of a clinic-based intervention for weight loss. METHODS: Randomized clinical trial conducted at an internal medicine clinic affiliated with a city hospital in Denver, Colorado. Participant (n = 46) had a body mass index >= 30 kg/m(2) and no life-threatening medical conditions. They either were provided a voucher to attend Weight Watchers for 17 weeks (n = 23), or they were assigned to the clinic group (n = 23), which provided 12 visits over 17 weeks and the option to augment weight loss using either meal replacements or weight loss medication. The primary study outcome was weight change. RESULTS: Participants assigned to the clinic arm lost 4.0 +/- 1.2 kg, compared to 0.4 +/- 1.1 for those assigned to the commercial program (P = .04 for difference). Weight losses in the clinic arm were 3.2 kg for meal replacements (n = 10) and 5.0 kg for phentermine (n = 13). CONCLUSIONS: In this single-site trial, a clinic-based intervention was more effective than a popular commercial program for weight loss. Primary care providers in the United States are under increasing pressure to combat the epidemic of obesity. This trial, although small, begins to address how the primary care setting might play that role. PMID- 23804171 TI - Pediatric primary care physicians' practices regarding newborn hearing screening. AB - OBJECTIVE: Approximately 2 to 3 out of 1000 infants are born with hearing loss in the United States each year. Pediatric primary care physicians (PCPs) can play an important role in ensuring that infants with hearing loss are identified early and provided appropriate services. In this study, pediatric PCPs were surveyed about their practices regarding early hearing detection and intervention. METHODS: Responses from the 2008 DocStyles survey were used to examine patient, physician, and practice variables associated with actions consistent with the 2007 Joint Committee on Infant Hearing position statement, which includes follow up protocols for medical home providers. RESULTS: Pediatricians working in a group setting were more likely to receive hearing screening results than were those in individual practices or hospitals and clinics. Family/general physicians with heavier caseloads were more likely to receive hearing screening results for their pediatric patients than were those with lighter caseloads. Few pediatric PCPs reported contacting their state's early hearing detection and intervention program if they knew that an infant failed the newborn hearing screening. Although high proportions of pediatric PCPs reported referring an infant with hearing loss to an otolaryngologist, only about half reported referring a child with risk factors for hearing loss for audiological and speech-language assessment, even if the parents expressed concern or if the results of a developmental screening indicated a possible delay. Few respondents reported referring an infant with hearing loss under their care to an ophthalmologist. CONCLUSIONS: This study highlights the need to improve infrastructure for pediatric PCPs to receive and request infant hearing screening results to facilitate reporting and coordinate follow-up services for infants identified with hearing loss. PMID- 23804172 TI - Patterns of arthritis medication use in a community sample. AB - BACKGROUND: Although arthritis is disabling, highly prevalent, and often treated without health professional input, little is known about the treatments selected by affected individuals. Such information is important because of the toxicity associated with some arthritis treatments. OBJECTIVE: To describe the pattern of drug treatment use in a sample of persons with arthritis. METHOD: The authors distributed an 11-item survey to veterans attending veterans' organization post meetings in southeastern Wisconsin during November and December 2009. Of 32 posts, 26 (81%) returned surveys from 446 persons; survey count and attendance figures suggest that the majority of attendees completed surveys at participating posts. Most respondents were older (75% aged 60 years or older) men (90%). Respondents with arthritis reported whether they had used each of seven drug therapies in the past year. RESULTS: Almost all members of participating posts responded to the survey, increasing the likelihood that this was a representative sample. Most respondents (290 of 446, 65%) reported having arthritis, which impaired function in 78.6% of them. Most of those with arthritis (252 of 290, 86.9%) had used at least one drug treatment for arthritis in the last year. Acetaminophen use (41.0%) and use of an over-the-counter nonsteroidal anti inflammatory drug (42.1%) were common. Nonsteroidal anti-inflammatory drug use did not decrease with older age or increase with greater functional impairment. CONCLUSIONS: Self-medication for arthritis is common and often does not follow clinical guidelines. Efforts to improve the quality of osteoarthritis care that focus solely on health care providers are unlikely to ensure optimal osteoarthritis care. PMID- 23804173 TI - Evidence-based guidance for culturally sensitive assessment and interventions for perinatal depression in black american women: a synthesis of published research, 2008-2011. AB - PURPOSE: This article provides a review of published evidence-based guidance about culturally sensitive assessment and treatment intervention strategies addressing perinatal depression in black American women. Culturally sensitive approaches focus more on the woman's environment than on her race and thus may improve access to treatment for perinatal depression by increasing health literacy. METHODS: The authors abstracted evidence-based guidance from articles published between November 2005 and September 2011, including only articles specifically analyzing a discrete sample of black American women during pregnancy or within 6 months postpartum. They also examined research on unique cultural characteristics of black American women. To obtain relevant studies, the authors searched for research literature indexed in PubMed, using key terms associated with 2 systematic reviews of prevalence and risk factors for perinatal depression and additional keywords as used in the articles found. They abstracted the focus, design and methods, population, and results for each article in a table; discussed the findings; and suggested assessment and intervention strategies based on the studies' results. FINDINGS: Sixteen articles from 13 journals provide compelling evidence of culture-based risk factors for perinatal depression for black American women and information to guide culturally sensitive assessments and interventions. The literature provides a rich compendium of relevant and useful implications for clinical practice in assessing and addressing depression among pregnant black American women. CONCLUSIONS: Primary care providers may want to incorporate culturally sensitive screening questions to early identify and facilitate treatment interventions for depressive symptoms in their pregnant black American patients. PMID- 23804174 TI - Commentary: opportunities for innovation and improvement in advance care planning using a tethered patient portal in the electronic health record. AB - In the last 20 years, progress has been made to develop resources for advance care planning (ACP). Several ACP delivery tools have demonstrated progress, but more are needed to improve ACP delivery systems. Providers continue to indicate that increasing patient volume, increasing patient complexity, and an increasing paperwork burden have adversely affected quality ACP delivery. An increasing and ubiquitous use of health information technology, such as electronic health records and electronic health record-tethered patient portals, affords opportunities for innovation to streamline communication methods between providers and patients. In a medical culture that provides only limited time for physician and patient interactions, physician-patient communication using electronic health record-tethered patient portals may provide a time-efficient, low-cost mechanism for effective ACP. PMID- 23804175 TI - A web-based patient tool for preventive health: preliminary report. AB - BACKGROUND: The Internet is a promising medium for engaging the community in preventive care and health promotion, particularly among those who do not routinely access health care. OBJECTIVE: The authors pilot-tested a novel website that translates evidence-based preventive health guidelines into a patient health education tool. The web-based tool allows individuals to enter their health risk factors and receive a tailored checklist of recommended preventive health services based on up-to-date guidelines from the US Preventive Services Task Force and the Advisory Committee on Immunization Practices. METHODS: The authors conducted surveys and in-depth interviews among a purposive sample of adults from an urban African American community who pilot-tested the website in a standardized setting. Interviews were designed to assess the usability, navigability, and content of the website and capture patient perceptions about its educational value and usefulness. Each interview was audiotaped, transcribed, and examined using the constant comparative method. RESULTS: Twenty-five participants piloted the tool: 96% found it easy to use and 64% reported learning something new. Many participants reported that, in addition to improving clinical preventive care (the intended purpose), the website could serve as a stand-alone tool to improve self-awareness and motivate behavior change. CONCLUSIONS: A web based tool designed to translate preventive health guidelines for the community may serve the dual purpose of improving the delivery of preventive health care and encouraging health promotion. The website developed here is publicly available for use by practitioners and the community. PMID- 23804176 TI - Know your audience: analysis of chief complaints at clinica esperanza, a student run free clinic in memphis, tennessee. AB - PURPOSE: To identify the chief complaints and demographics at Clinica Esperanza, a student-run free clinic for an underserved Hispanic population. METHODS: A retrospective chart review of patient files from 2005 through 2010 was undertaken, as approved by the University of Tennessee Health Science Center's Institutional Review Board. RESULTS: From 2005 through 2010, Clinica Esperanza fielded 2551 patient visits, consisting of 951 unique patients, 609 females and 342 males. Mean age was 34 years, and 60% of patients presented once, while 13% followed up for 1 year, 9% for 2 years, 6% for 3, 6% for 4, and 4% for 5. "Pap smear," "abdominal pain," and "follow-up lab results" ranked, in order, as the 3 top chief complaints. DISCUSSION: Resulting data have led to several improvements. The clinic has remained open weekly to improve patient continuity. With the top 10 chief complaints identified, they are better addressed. More funding is allocated for speculums and proper training of Pap smear technique. Systematic reporting of lab results is being implemented. Physical therapists and pharmacists now participate to address musculoskeletal and medication-based needs, respectively. A volunteer gastroenterologist has been recruited to provide specialized care for abdominal pain. An electrocardiogram machine is now used to evaluate chest pain. To improve student-patient communication, online language learning modules have been created. CONCLUSIONS: Based on these data, improvements in health care services have been made, including better continuity, emphasis on top chief complaints, and provider education in medical Spanish. Future plans include on-site pharmacy, smoother referrals, and similar clinics on the University of Tennessee Health Science Center's other campuses. PMID- 23804177 TI - Diagnosis and management of chronic hepatitis B in children, young people, and adults: summary of NICE guidance. PMID- 23804178 TI - Malaria prevalence highest among the poorest of the poor. PMID- 23804179 TI - Forty per cent of murdered women are killed by a partner. PMID- 23804180 TI - Red meat linked to diabetes, again. PMID- 23804181 TI - High prevalence of self reported brain injury among schoolchildren in Canada. PMID- 23804182 TI - Legalising assisted dying puts vulnerable patients at risk and doctors must speak up. PMID- 23804183 TI - H7N9 kills one third of confirmed cases admitted to hospital. PMID- 23804184 TI - Hormone therapy has no effect on cognition in younger postmenopausal women. PMID- 23804185 TI - Suspend NHS competition rules in London to allow for urgent remodelling of healthcare, says think tank. PMID- 23804186 TI - EMA consults public on plan to increase transparency of drug trial data. PMID- 23804187 TI - A polarizable ellipsoidal force field for halogen bonds. AB - The anisotropic effects and short-range quantum effects are essential characters in the formation of halogen bonds. Since there are an array of applications of halogen bonds and much difficulty in modeling them in classical force fields, the current research reports solely the polarizable ellipsoidal force field (PEff) for halogen bonds. The anisotropic charge distribution was represented with the combination of a negative charged sphere and a positively charged ellipsoid. The polarization energy was incorporated by the induced dipole model. The resulting force field is "physically motivated," which includes separate, explicit terms to account for the electrostatic, repulsion/dispersion, and polarization interaction. Furthermore, it is largely compatible with existing, standard simulation packages. The fitted parameters are transferable and compatible with the general AMBER force field. This PEff model could correctly reproduces the potential energy surface of halogen bonds at MP2 level. Finally, the prediction of the halogen bond properties of human Cathepsin L (hcatL) has been found to be in excellent qualitative agreement with the cocrystal structures. PMID- 23804189 TI - Cyclization-carbonylation-cyclization coupling reaction of alpha,beta-alkynic hydrazones with palladium(II)-bisoxazoline catalyst. AB - A cyclization-carbonylation-cyclization coupling reaction (CCC-coupling reaction) of alpha,beta-alkynic hydrazones, catalyzed by (box)Pd(II) complexes, afforded symmetrical ketones bearing two pyrazole groups in good to excellent yields. This method is applicable to a broad range of substrates. PMID- 23804188 TI - Measurement of SAR-induced temperature increase in a phantom and in vivo with comparison to numerical simulation. AB - PURPOSE: To compare numerically simulated and experimentally measured temperature increase due to specific energy absorption rate from radiofrequency fields. METHODS: Temperature increase induced in both a phantom and in the human forearm when driving an adjacent circular surface coil was mapped using the proton resonance frequency shift technique of magnetic resonance thermography. The phantom and forearm were also modeled from magnetic resonance image data, and both specific energy absorption rate and temperature change as induced by the same coil were simulated numerically. RESULTS: The simulated and measured temperature increase distributions were generally in good agreement for the phantom. The relative distributions for the human forearm were very similar, with the simulations giving maximum temperature increase about 25% higher than measured. CONCLUSION: Although a number of parameters and uncertainties are involved, it should be possible to use numerical simulations to produce reasonably accurate and conservative estimates of temperature distribution to ensure safety in magnetic resonance imaging. R01 EB006563 PMID- 23804191 TI - Comparative immunogenicity and efficacy of 13-valent and 7-valent pneumococcal conjugate vaccines in reducing nasopharyngeal colonization: a randomized double blind trial. AB - BACKGROUND: The 13-valent pneumococcal conjugate vaccine (PCV13) was licensed to replace the 7-valent pneumococcal conjugate vaccine (PCV7) based on serological noninferiority criteria. To date no randomized PCV13 pediatric trial has included clinical endpoints. METHODS: This randomized double-blind trial compared the impact of PCV13 versus PCV7 on nasopharyngeal (NP) colonization and immunogenicity. Healthy infants were randomized (1:1) to receive PCV7 or PCV13 at ages 2, 4, 6, and 12 months; NP swabs were collected at 2, 4, 6, 7, 12, 13, 18, and 24 months, and blood was drawn at 7 and 13 months. Rates of NP acquisition and prevalence, and serotype-specific immunoglobulin G (IgG) concentrations were assessed. RESULTS: The per protocol analysis population included 881 PCV13 and 873 PCV7 recipients. PCV13 significantly reduced NP acquisition of the additional PCV13 serotypes 1, 6A, 7F, and 19A; the cross-reacting serotype 6C; and the common PCV7 serotype 19F. For serotype 3, and the other PCV7 serotypes, there were no significant differences between the vaccine groups. There were too few serotype 5 events to draw inference. The impact on prevalence at predefined time points was similar to that observed with NP acquisition. PCV13 elicited significantly higher IgG responses for PCV13 additional serotypes and serotype 19F, and similar or lower responses for 6/7 PCV7 serotypes. CONCLUSIONS: PCV13 resulted in lower acquisition and prevalence of NP colonization than PCV7 did for 4 additional PCV13 serotypes, and serotypes 6C and 19F. It was comparable with PCV7 for all other common serotypes. These findings predict vaccine effectiveness through both direct and indirect protection. CLINICAL TRIALS REGISTRATION: NCT00508742. PMID- 23804192 TI - Strongly decreased risk of genital warts after vaccination against human papillomavirus: nationwide follow-up of vaccinated and unvaccinated girls in Denmark. AB - BACKGROUND: A reduction in the incidence of genital warts (GWs) is one of the first markers of the effectiveness of vaccination against human papillomavirus (HPV) at the population level. The aim of this cohort study was to use individual information on HPV vaccination status to assess the effect on risk of GWs. METHODS: Population-based registries were used to identify all girls in the birth cohorts 1989-1999 in Denmark, and information about HPV vaccination was obtained for the period 2006-2012. The cohort was linked to incident cases of GWs, and vaccinated and unvaccinated girls were compared using Cox proportional hazards models. RESULTS: A total of 248 403 girls were vaccinated. The relative risk of GWs among girls who had received at least 1 dose of vaccine compared with unvaccinated girls was 0.12, 0.22, 0.25, and 0.62 for those born in 1995-1996, 1993-1994, 1991-1992, and 1989-1990, respectively (P for trend < .0001). No GWs occurred among vaccinated girls in the youngest birth cohort (1997-1999). CONCLUSIONS: The strong, highly significant reduction in the occurrence of GWs among vaccinated girls indicates an early and marked population effect of the national HPV vaccination program and may forecast a similar effect on cervical precancerous lesions. PMID- 23804193 TI - Is neurobrucellosis the Pandora's Box of modern medicine? PMID- 23804194 TI - Reply to Kesav et al. PMID- 23804196 TI - Suppression of adipogenic differentiation by muscle cell-induced decrease in genes related to lipogenesis in muscle and fat co-culture system. AB - Intercellular signalling communication between adipose and muscle tissue has been investigated. To test the effect of muscle cells on adipogenic gene expression, we utilised an in vitro co-culture system, in which fat (3T3-L1) and muscle (L-6) cells were physically separated but chemically exposed each other via insert with 0.4 um porous membrane. When 3T3-L1 and L-6 cells reached at 80 and 40% confluence, respectively in separate wells, L-6 cells grown in insert were transferred onto 6-well plates where 3T3-L1 cells were being grown. When both cells were fully differentiated in co-culture plates, morphology of 3T3-L1 was examined by staining with Oil-red-O. Activity of glycerol-3-phosphate dehydrogenase (GPDH) and adipogenic gene expression including lipoprotein lipase (LPL), adipsin, GPDH, peroxisome proliferator-activated receptor-gamma (PPARgamma) and CCAAT/enhancer binding protein (C/EBPalpha) were analysed. The presence of muscle cells during preadipocyte differentiation inhibited (P < 0.05) lipogenesis by suppressing lipogenic gene expression including LPL, adipsin and GPDH. Furthermore, GPDH activity was also decreased (P < 0.05) in 3T3-L1 cells by the presence of L-6 cells. These results suggest that presence of muscle cells suppresses adipogenic differentiation by inhibiting the adipogenic gene expression and GPDH activity in the muscle and fat cell co-culture system. PMID- 23804195 TI - Outcome of patients activating an unrelated donor search for severe acquired aplastic anemia. AB - Patients with severe aplastic anemia (SAA) without a sibling donor receive immunosuppressive treatment (IST) with anti-thymocyte globulin (ATG). In the case of no response to IST, a voluntary unrelated donor (VUD) search is usually started. This study analyzes the outcome of ATG-refractory SAA patients activating a VUD search. Of 179 patients, 68 had at least one HLA-A, -B, and -DR matched donor identified and underwent HSCT while 50 also with a donor were not transplanted because of early death (8), late response to IST (34), transplant refusal (1), or other (7). Conversely, 61 had no matched donor, 13 of those ultimately received a mismatched HSCT. All but one received marrow stem cells. Among patients aged <17 years, those with at least one matched donor had a significant higher 4-year survival as compared to others (79% +/- 6% versus 53% +/- 10%, P = 0.01). There was also a survival advantage independent of recipient age when the donor search was initiated in the recent 2000-2005 study-period (74% +/- 6% versus 47% +/- 10%, P < 0.05). In multivariate analysis, the identification of a matched VUD tended to impact favourably on survival in patients with a recent donor search (P = 0.07). This study provides evidence for the use of unrelated donor HSCT in children and adults with IST-refractory SAA. PMID- 23804197 TI - [Intracavitary contrast medium ultrasound - different applications, a review of the literature ad future prospects]. PMID- 23804198 TI - Production of free glutamate in milk requires the leucine transporter LAT1. AB - The concentration of free glutamate (Glu) in rat's milk is ~10 times higher than that in plasma. Previous work has shown that mammary tissue actively transports circulatory leucine (Leu), which is transaminated to synthesize other amino acids such as Glu and aspartate (Asp). To investigate the molecular basis of Leu transport and its conversion into Glu in the mammary gland, we characterized the expression of Leu transporters and [(3)H]Leu uptake in rat mammary cells. Gene expression analysis indicated that mammary cells express two Leu transporters, LAT1 and LAT2, with LAT1 being more abundant than LAT2. This transport system is sodium independent and transports large neutral amino acids. The Leu transport system in isolated rat mammary cells could be specifically blocked by the LAT1 inhibitors 2-aminobicyclo-[2.2.1]-heptane-2-carboxylic acid (BCH) and triiodothyronine (T3). In organ cultures, Glu secretion was markedly inhibited by these LAT1 inhibitors. Furthermore, the profiles of Leu uptake inhibition by amino acids in mammary cells were similar to those reported for LAT1. In vivo, concentrations of free Glu and Asp increased in milk by oral gavage with Leu at 6, 12, and 18 days of lactation. These results indicate that the main Leu transporter in mammary tissue is LAT1 and the transport of Leu is a limiting factor for the synthesis and release of Glu and Asp into milk. Our studies provide the bases for the molecular mechanism of Leu transport in mammary tissue by LAT1 and its active role on free Glu secretion in milk, which confer umami taste in suckling pups. PMID- 23804199 TI - Chronic alcohol feeding inhibits physiological and molecular parameters of intestinal and renal riboflavin transport. AB - Vitamin B2 (riboflavin, RF) is essential for normal human health. Mammals obtain RF from exogenous sources via intestinal absorption and prevent its urinary loss by reabsorption in the kidneys. Both of these absorptive events are carrier mediated and involve specific RF transporters (RFVTs). Chronic alcohol consumption in humans is associated with a high prevalence of RF deficiency and suboptimal levels, but little is known about the effect of chronic alcohol exposure on physiological and molecular parameters of the intestinal and renal RF transport events. We addressed these issues using rats chronically fed an alcohol liquid diet and pair-fed controls as a model. The results showed that chronic alcohol feeding significantly inhibits carrier-mediated RF transport across the intestinal brush-border and basolateral membrane domains of the polarized enterocytes. This inhibition was associated with a parallel reduction in the expression of the rat RFVT-1 and -3 at the protein, mRNA, and heterogeneous nuclear RNA (hnRNA) levels. Chronic alcohol feeding also caused a significant inhibition in RF uptake in the colon. Similarly, a significant inhibition in carrier-mediated RF transport across the renal brush-border and basolateral membrane domains was observed, which again was associated with a significant reduction in the level of expression of RFVT-1 and -3 at the protein, mRNA, and hnRNA levels. These findings demonstrate that chronic alcohol exposure impairs both intestinal absorption and renal reabsorption processes of RF and that these effects are, at least in part, mediated via transcriptional mechanism(s) involving the slc52a1 and slc52a3 genes. PMID- 23804200 TI - Mechanisms underlying activation of transient BK current in rabbit urethral smooth muscle cells and its modulation by IP3-generating agonists. AB - We used the perforated patch-clamp technique at 37 degrees C to investigate the mechanisms underlying the activation of a transient large-conductance K(+) (tBK) current in rabbit urethral smooth muscle cells. The tBK current required an elevation of intracellular Ca(2+), resulting from ryanodine receptor (RyR) activation via Ca(2+)-induced Ca(2+) release, triggered by Ca(2+) influx through L-type Ca(2+) (CaV) channels. Carbachol inhibited tBK current by reducing Ca(2+) influx and Ca(2+) release and altered the shape of spike complexes recorded under current-clamp conditions. The tBK currents were blocked by iberiotoxin and penitrem A (300 and 100 nM, respectively) and were also inhibited when external Ca(2+) was removed or the CaV channel inhibitors nifedipine (10 MUM) and Cd(2+) (100 MUM) were applied. The tBK current was inhibited by caffeine (10 mM), ryanodine (30 MUM), and tetracaine (100 MUM), suggesting that RyR-mediated Ca(2+) release contributed to the activation of the tBK current. When IP3 receptors (IP3Rs) were blocked with 2-aminoethoxydiphenyl borate (2-APB, 100 MUM), the amplitude of the tBK current was not reduced. However, when Ca(2+) release via IP3Rs was evoked with phenylephrine (1 MUM) or carbachol (1 MUM), the tBK current was inhibited. The effect of carbachol was abolished when IP3Rs were blocked with 2-APB or by inhibition of muscarinic receptors with the M3 receptor antagonist 4 diphenylacetoxy-N-methylpiperidine methiodide (1 MUM). Under current-clamp conditions, bursts of action potentials could be evoked with depolarizing current injection. Carbachol reduced the number and amplitude of spikes in each burst, and these effects were reduced in the presence of 2-APB. In the presence of ryanodine, the number and amplitude of spikes were also reduced, and carbachol was without further effect. These data suggest that IP3-generating agonists can modulate the electrical activity of rabbit urethral smooth muscle cells and may contribute to the effects of neurotransmitters on urethral tone. PMID- 23804202 TI - Human-induced pluripotent stem cell-derived cardiomyocytes for studies of cardiac ion transporters. AB - Human-induced pluripotent stem cells (hiPSCs) can differentiate into functional cardiomyocytes (iCell Cardiomyocytes) with ion channel activities that are remarkably similar to adult cardiomyocytes. Here, we extend this characterization to cardiac ion transporters. Additionally, we document facile molecular biological manipulation of iCell Cardiomyocytes to overexpress and knockdown transporters and regulatory proteins. Na/Ca exchange (NCX1) and Na/K pump currents were recorded via patch clamp, and Na/H and Cl/OH exchanges were recorded via oscillating proton-selective microelectrodes during patch clamp. Flux densities of all transport systems are similar to those of nonrodent adult cardiomyocytes. NCX1 protein and NCX1 currents decline after NCX1 small interfering (si)RNA transfection with similar time courses (tau ~ 2 days), and an NCX1-Halo fusion protein is internalized after its extracellular labeling by AlexaFluor488 Ligand with a similar time course. Loss of the cardiac regulatory protein phospholemman (PLM) occurs over a longer time course (tau ~ 60 h) after PLM small interfering RNA transfection. Similar to multiple previous reports for adult cardiomyocytes, Na/K pump currents in iCell Cardiomyocytes are not enhanced by activating cAMP production with either maximal or submaximal cytoplasmic Na and using either forskolin or isoproterenol to activate adenylate cyclases. Finally, we describe Ca influx-dependent changes of iCell Cardiomyocyte capacitance (Cm). Large increases of Cm occur during Ca influx via NCX1, thereby documenting large internal membrane reserves that can fuse to the sarcolemma, and subsequent declines of Cm document active endocytic processes. Together, these results document a great potential of iCell Cardiomyocytes for both short- and long-term studies of cardiac ion transporters and their regulation. PMID- 23804201 TI - TREK-1 currents in smooth muscle cells from pregnant human myometrium. AB - The mechanisms governing maintenance of quiescence during pregnancy remain largely unknown. The current study characterizes a stretch-activated, tetraethylammonium-insensitive K(+) current in smooth muscle cells isolated from pregnant human myometrium. This study hypothesizes that these K(+) currents can be attributed to TREK-1 and that upregulation of this channel during pregnancy assists with the maintenance of a negative cell membrane potential, conceivably contributing to uterine quiescence until full term. The results of this study demonstrate that, in pregnant human myometrial cells, outward currents at 80 mV increased from 4.8 +/- 1.5 to 19.4 +/- 7.5 pA/pF and from 3.0 +/- 0.8 to 11.8 +/- 2.7 pA/pF with application of arachidonic acid (AA) and NaHCO3, respectively, causing intracellular acidification. Similarly, outward currents were inhibited following application of 10 MUM fluphenazine by 51.2 +/- 9.8% after activation by AA and by 73.9 +/- 4.2% after activation by NaHCO3. In human embryonic kidney (HEK-293) cells stably expressing TREK-1, outward currents at 80 mV increased from 91.0 +/- 23.8 to 247.5 +/- 73.3 pA/pF and from 34.8 +/- 8.9 to 218.6 +/- 45.0 pA/pF with application of AA and NaHCO3, respectively. Correspondingly, outward currents were inhibited 89.5 +/- 2.3% by 10 MUM fluphenazine following activation by AA and by 91.6 +/- 3.4% following activation by NaHCO3. Moreover, currents in human myometrial cells were activated by stretch and were reduced by transfection with small interfering RNA or extracellular acidification. Understanding gestational regulation of expression and gating of TREK-1 channels could be important in determining appropriate maintenance of uterine quiescence during pregnancy. PMID- 23804203 TI - Resveratrol inhibits K(v)2.2 currents through the estrogen receptor GPR30 mediated PKC pathway. AB - Resveratrol (REV) is a naturally occurring phytoalexin that inhibits neuronal K+ channels; however, the molecular mechanisms behind the effects of REV and the relevant alpha-subunit are not well defined. With the use of patch-clamp technique, cultured cerebellar granule cells, and HEK-293 cells transfected with the K(v)2.1 and K(v)2.2 alpha-subunits, we investigated the effect of REV on K(v)2.1 and K(v)2.2 alpha-subunits. Our data demonstrated that REV significantly suppressed Kv2.2 but not Kv2.1 currents with a fast, reversible, and mildly concentration-dependent manner and shifted the activation or inactivation curve of Kv2.2 channels. Activating or inhibiting the cAMP/PKA pathway did not abolish the inhibition of K(v)2.2 current by REV. In contrast, activation of PKC with phorbol 12-myristate 13-acetate mimicked the inhibitory effect of REV on K(v)2.2 by modifying the activation or inactivation properties of Kv2.2 channels and eliminated any further inhibition by REV. PKC and PKC-alpha inhibitor completely eliminated the REV-induced inhibition of K(v)2.2. Moreover, the effect of REV on K(v)2.2 was reduced by preincubation with antagonists of GPR30 receptor and shRNA for GPR30 receptor. Western blotting results indicated that the levels of PKC alpha and PKC-beta were significantly increased in response to REV application. Our data reveal, for the first time, that REV inhibited K(v)2.2 currents through PKC-dependent pathways and a nongenomic action of the oestrogen receptor GPR30. PMID- 23804204 TI - Oatp58Dc contributes to blood-brain barrier function by excluding organic anions from the Drosophila brain. AB - The blood-brain barrier (BBB) physiologically isolates the brain from the blood and, thus, plays a vital role in brain homeostasis. Ion transporters play a critical role in this process by effectively regulating access of chemicals to the brain. Organic anion-transporting polypeptides (Oatps) transport a wide range of amphipathic substrates and are involved in efflux of chemicals across the vertebrate BBB. The anatomic complexity of the vascularized vertebrate BBB, however, creates challenges for experimental analysis of these processes. The less complex structure of the Drosophila BBB facilitates measurement of solute transport. Here we investigate a physiological function for Oatp58Dc in transporting small organic anions across the BBB. We used genetic manipulation, immunocytochemistry, and molecular techniques to supplement a whole animal approach to study the BBB. For this whole animal approach, the traceable small organic anion fluorescein was injected into the hemolymph. This research shows that Oatp58Dc is involved in maintaining a chemical barrier against fluorescein permeation into the brain. Oatp58Dc expression was found in the perineurial and subperineurial glia, as well as in postmitotic neurons. We specifically targeted knockdown of Oatp58Dc expression in the perineurial and subperineurial glia to reveal that Oatp58Dc expression in the perineurial glia is necessary to maintain the barrier against fluorescein influx into the brain. Our results show that Oatp58Dc contributes to maintenance of a functional barrier against fluorescein influx past the BBB into the brain. PMID- 23804205 TI - Elevated nuclear Foxo1 suppresses excitability of skeletal muscle fibers. AB - Forkhead box O 1 (Foxo1) controls the expression of proteins that carry out processes leading to skeletal muscle atrophy, making Foxo1 of therapeutic interest in conditions of muscle wasting. The transcription of Foxo1-regulated proteins is dependent on the translocation of Foxo1 to the nucleus, which can be repressed by insulin-like growth factor-1 (IGF-1) treatment. The role of Foxo1 in muscle atrophy has been explored at length, but whether Foxo1 nuclear activity affects skeletal muscle excitation-contraction (EC) coupling has not yet been examined. Here, we use cultured adult mouse skeletal muscle fibers to investigate the effects of Foxo1 overexpression on EC coupling. Fibers expressing Foxo1-green fluorescent protein (GFP) exhibit an inability to contract, impaired propagation of action potentials, and ablation of calcium transients in response to electrical stimulation compared with fibers expressing GFP alone. Evaluation of the transverse (T)-tubule system morphology, the membranous system involved in the radial propagation of the action potential, revealed an intact T-tubule network in fibers overexpressing Foxo1-GFP. Interestingly, long-term IGF-1 treatment of Foxo1-GFP fibers, which maintains Foxo1-GFP outside the nucleus, prevented the loss of normal calcium transients, indicating that Foxo1 translocation and the atrogenes it regulates affect the expression of proteins involved in the generation and/or propagation of action potentials. A reduction in the sodium channel Nav1.4 expression in fibers overexpressing Foxo1-GFP was also observed in the absence of IGF-1. We conclude that increased nuclear activity of Foxo1 prevents the normal muscle responses to electrical stimulation and that this indicates a novel capability of Foxo1 to disable the functional activity of skeletal muscle. PMID- 23804207 TI - Heightened risk of second primary carcinoma of the head and neck following cervical neoplasia. AB - BACKGROUND: Cervical cancers have been shown to increase the risk of cancers at distant sites, including the head and neck region. This study investigated the relative risk of developing head and neck cancer subsequent to cervical cancer in an Australian population. METHODS: Cervical cancers, head and neck cancers, and cervical dysplasias among women registered with the Queensland Oncology Repository were identified for the period 1982 to 2008. RESULTS: Over the 26-year period, 3328 women were diagnosed with a cervical cancer and followed up for 30,375 person-years at risk. Eighteen women (0.5%) developed head and neck cancer within a mean time of 8.1 years (SD = 5.56). The relative risk of head and neck cancer development subsequent to cervical cancer was 6.7 (95% confidence interval [CI], 4.06-10.91). CONCLUSION: This study demonstrates that women with cervical cancer were almost 7 times more likely to develop head and neck cancer compared to the general female population. PMID- 23804206 TI - Regulation of L-type calcium channel sparklet activity by c-Src and PKC-alpha. AB - The activity of persistent Ca2+ sparklets, which are characterized by longer and more frequent channel open events than low-activity sparklets, contributes substantially to steady-state Ca2+ entry under physiological conditions. Here, we addressed two questions related to the regulation of Ca2+ sparklets by PKC-alpha and c-Src, both of which increase whole cell Cav1.2 current: 1) Does c-Src activation enhance persistent Ca2+ sparklet activity? 2) Does PKC-alpha activate c-Src to produce persistent Ca2+ sparklets? With the use of total internal reflection fluorescence microscopy, Ca2+ sparklets were recorded from voltage clamped tsA-201 cells coexpressing wild-type (WT) or mutant Cav1.2c (the neuronal isoform of Cav1.2) constructs +/- active or inactive PKC-alpha/c-Src. Cells expressing Cav1.2c exhibited both low-activity and persistent Ca2+ sparklets. Persistent Ca2+ sparklet activity was significantly reduced by acute application of the c-Src inhibitor PP2 or coexpression of kinase-dead c-Src. Cav1.2c constructs mutated at one of two COOH-terminal residues (Y2122F and Y2139F) were used to test the effect of blocking putative phosphorylation sites for c-Src. Expression of Y2122F but not Y2139F Cav1.2c abrogated the potentiating effect of c-Src on Ca2+ sparklet activity. We could not detect a significant change in persistent Ca2+ sparklet activity or density in cells coexpressing Cav1.2c + PKC alpha, regardless of whether WT or Y2122F Cav1.2c was used, or after PP2 application, suggesting that PKC-alpha does not act upstream of c-Src to produce persistent Ca2+ sparklets. However, our results indicate that persistent Ca2+ sparklet activity is promoted by the action of c-Src on residue Y2122 of the Cav1.2c COOH terminus. PMID- 23804208 TI - ab Initio Diabatic energies and dipole moments of the electronic states of RbLi molecule. AB - For all states dissociating below the ionic limit Li(-) Rb(+) , we perform a diabatic study for (1) Sigma(+) electronic states dissociating into Rb (5s, 5p, 4d, 6s, 6p, 5d, 7s, 4f) + Li (2s, 2p, 3s). Furthermore, we present the diabatic results for the 1-11 (3) sigma, 1-8 (1,3) Pi, and 1-4 (1,3) Delta states. The present calculations on the RbLi molecule are complementary to previous theoretical work on this system, including recently observed electronic states that had not been calculated previously. The calculations rely on ab-initio pseudopotential, core polarization potential operators for the core-valence correlation and full valence configuration interaction approaches, combined to an efficient diabatization procedure. For the low-lying states, diabatic potentials and permanent dipole moments are analyzed, revealing the strong imprint of the ionic state in the (1) Sigma(+) adiabatic states. The transition dipole moment is used to evaluate the radiative lifetimes of the vibrational levels trapped in the 2 (1) Sigma(+) excited states for the first time. In addition to the bound-bound contribution, the bound-free term has been evaluated using the Franck-Condon approximation and also exactly added to the total radiative lifetime. PMID- 23804210 TI - A dreadful infestation. PMID- 23804209 TI - Demographic and clinical characteristics of consistent and inconsistent longitudinal reporters of lifetime suicide attempts in adolescence through young adulthood. AB - BACKGROUND: Within the context of the recent release of the 2012 National Suicide Prevention Strategy, and as the third leading cause of death for individuals 10- to 24-years-old, suicide prevention is a national priority. A consistently reported and robust risk factor for suicide is a prior suicide attempt; however few studies have investigated the consistency of self-reported lifetime suicide attempts. The goal of this study is to describe the prevalence and characteristics of inconsistent reporting of suicide attempt in a longitudinal cohort of participants annually assessed in 12 waves of data collected from middle school (age 12) to early adulthood (age 22). METHODS: Among this cohort (n = 678), we compared those who consistently, inconsistently, and never reported a suicide attempt according to demographic and clinical variables. RESULTS: Almost 90% (88.5%) of our sample inconsistently reported a lifetime suicide attempt. Consistent and inconsistent reporters of lifetime suicide attempt did not differ on demographic or clinical variables with the exception of higher rates of lifetime suicidal ideation among consistent reporters (P < .001). Significant clinical differences were evident between inconsistent reporters and nonattempters. CONCLUSIONS: Some level of inconsistent reporting of suicide attempt is inevitable when schools or health care systems systematically screen for suicide risk in adolescents. Inconsistent and consistent reporters of suicide attempt differ on few demographic or clinical variables; further prospective research should investigate the reasons for inconsistent reporting as well as the validity and stability of reporting in predicting future suicidal behavior. PMID- 23804211 TI - Enantioselective isomerization of primary allylic alcohols into chiral aldehydes with the tol-binap/dbapen/ruthenium(II) catalyst. AB - Efficient isomerization: The title reaction was catalyzed by the [RuCl2{(S)-tol binap}{(R)-dbapen}]/KOH system in ethanol at 25 degrees C (see scheme). A series of E- and Z-configured aromatic and aliphatic allylic alcohols, including a simple primary alkyl-substituted compound (E)-3-methyl-2-hepten-1-ol, were transformed into the chiral aldehydes with at least 99 % ee. dbapen = 2 dibutylamino-1-phenylethylamine, tol-binap = 2,2'-bis(di-4-tolylphosphanyl)-1,1' binaphthyl. PMID- 23804212 TI - Dispersion of relaxation rates in the rotating frame under the action of spin locking pulses and diffusion in inhomogeneous magnetic fields. AB - PURPOSE: A method is described for characterizing magnetically inhomogeneous media and the spatial scales of intrinsic susceptibility variations within samples. The rate of spin-lattice relaxation in the rotating frame, R1rho , is affected by diffusion effects to a degree that depends on the magnitude of an applied spin-locking field. Appropriate analysis of the dispersion of R1rho with locking field may be used to characterize susceptibility variations in inhomogeneous tissues. THEORY AND METHODS: The contribution of diffusion to R1rho is quantified by an analytic expression derived by analyzing of the effects of diffusion through periodic variations of magnetic susceptibility and is used to predict the effects of inhomogeneities in simple phantoms. The theory is further applied to imaging to derive parametric images that portray the dimensions of susceptibility inhomogeneities independent of their magnitude. RESULTS: Significant dispersion of R1rho with locking field was predicted and measured experimentally for suspensions of microspheres ranging from 1 to 90 MUm in diameter. For scales of practical interest, these dispersion effects occur at much lower locking fields than the range in which chemical exchange effects cause similar dispersion. CONCLUSION: There is good agreement between theory and experiment, and the method has potential for quantitative tissue characterization and functional imaging. PMID- 23804214 TI - The role of ultrasound in fetal congenital myopathy detection: a novel case of fetal-onset cap myopathy. PMID- 23804213 TI - Fibroblast growth factor homologous factors modulate cardiac calcium channels. AB - RATIONALE: Fibroblast growth factor (FGF) homologous factors (FHFs; FGF11-14) are intracellular modulators of voltage-gated Na+ channels, but their cellular distribution in cardiomyocytes indicated that they performed other functions. OBJECTIVE: We aimed to uncover novel roles for FHFs in cardiomyocytes, starting with a proteomic approach to identify novel interacting proteins. METHODS AND RESULTS: Affinity purification of FGF13 from rodent ventricular lysates followed by mass spectroscopy revealed an interaction with junctophilin-2, a protein that organizes the close apposition of the L-type Ca2+ channel CaV1.2 and the ryanodine receptor 2 in the dyad. Immunocytochemical analysis revealed that overall T-tubule structure and localization of ryanodine receptor 2 were unaffected by FGF13 knockdown in adult ventricular cardiomyocytes but localization of CaV1.2 was affected. FGF13 knockdown decreased CaV1.2 current density and reduced the amount of CaV1.2 at the surface as a result of aberrant localization of the channels. CaV1.2 current density and channel localization were rescued by expression of an shRNA-insensitive FGF13, indicating a specific role for FGF13. Consistent with these newly discovered effects on CaV1.2, we demonstrated that FGF13 also regulated Ca(2+)-induced Ca2+ release, indicated by a smaller Ca2+ transient after FGF13 knockdown. Furthermore, FGF13 knockdown caused a profound decrease in the cardiac action potential half-width. CONCLUSIONS: This study demonstrates that FHFs not only are potent modulators of voltage-gated Na+ channels but also affect Ca2+ channels and their function. We predict that FHF loss-of-function mutations would adversely affect currents through both Na+ and Ca2+ channels, suggesting that FHFs may be arrhythmogenic loci, leading to arrhythmias through a novel, dual-ion channel mechanism. PMID- 23804215 TI - Optical identification of subjects at high risk for developing breast cancer. AB - A time-domain multiwavelength (635 to 1060 nm) optical mammography was performed on 147 subjects with recent x-ray mammograms available, and average breast tissue composition (water, lipid, collagen, oxy- and deoxyhemoglobin) and scattering parameters (amplitude a and slope b) were estimated. Correlation was observed between optically derived parameters and mammographic density [Breast Imaging and Reporting Data System (BI-RADS) categories], which is a strong risk factor for breast cancer. A regression logistic model was obtained to best identify high risk (BI-RADS 4) subjects, based on collagen content and scattering parameters. The model presents a total misclassification error of 12.3%, sensitivity of 69%, specificity of 94%, and simple kappa of 0.84, which compares favorably even with intraradiologist assignments of BI-RADS categories. PMID- 23804216 TI - Detection and characterization of glaucoma-like canine retinal tissues using Raman spectroscopy. AB - Early detection of pathological changes and progression in glaucoma and other neuroretinal diseases remains a great challenge and is critical to reduce permanent structural and functional retina and optic nerve damage. Raman spectroscopy is a sensitive technique that provides rapid biochemical characterization of tissues in a nondestructive and noninvasive fashion. In this study, spectroscopic analysis was conducted on the retinal tissues of seven beagles with acute elevation of intraocular pressure (AEIOP), six beagles with compressive optic neuropathy (CON), and five healthy beagles. Spectroscopic markers were identified associated with the different neuropathic conditions. Furthermore, the Raman spectra were subjected to multivariate discriminate analysis to classify independent tissue samples into diseased/healthy categories. The multivariate discriminant model yielded an average optimal classification accuracy of 72.6% for AEIOP and 63.4% for CON with 20 principal components being used that accounted for 87% of the total variance in the data set. A strong correlation (R2>0.92) was observed between pattern electroretinography characteristics of AEIOP dogs and Raman separation distance that measures the separation of spectra of diseased tissues from normal tissues; however, the underlining mechanism of this correlation remains to be understood. Since AEIOP mimics the pathological symptoms of acute/early-stage glaucoma, it was demonstrated that Raman spectroscopic screening has the potential to become a powerful tool for the detection and characterization of early-stage disease. PMID- 23804217 TI - Time-resolved fluorescence spectroscopy investigation of the effect of 4 hydroxynonenal on endogenous NAD(P)H in living cardiac myocytes. AB - Lipid peroxidation is a major biochemical consequence of the oxidative deterioration of polyunsaturated lipids in cell membranes and causes damage to membrane integrity and loss of protein function. 4-hydroxy-2-nonenal (HNE), one of the most reactive products of n-6 polyunsaturated fatty acid peroxidation of membrane phospholipids, has been shown to be capable of affecting both nicotinamide adenine dinucleotide (phosphate) reduced [NAD(P)H] as well as NADH production. However, the understanding of its effects in living cardiac cells is still lacking. Our goal was to therefore investigate HNE effects on NAD(P)H noninvasively in living cardiomyocytes. Spectrally resolved lifetime detection of endogenous fluorescence, an innovative noninvasive technique, was employed. Individual fluorescence components were resolved by spectral linear unmixing approach. Gathered results revealed that HNE reduced the amplitude of both resolved NAD(P)H components in a concentration-dependent manner. In addition, HNE increased flavoprotein fluorescence and responsiveness of the NAD(P)H component ratio to glutathione reductase (GR) inhibitor. HNE also increased the percentage of oxidized nucleotides and decreased maximal NADH production. Presented data indicate that HNE provoked an important cell oxidation by acting on NAD(P)H regulating systems in cardiomyocytes. Understanding the precise role of oxidative processes and their products in living cells is crucial for finding new noninvasive tools for biomedical diagnostics of pathophysiological states. PMID- 23804218 TI - Blood pressure evaluation using sphygmomanometry assisted by arterial pulse waveform detection by fiber Bragg grating pulse device. AB - We report a blood pressure evaluation methodology by recording the radial arterial pulse waveform in real time using a fiber Bragg grating pulse device (FBGPD). Here, the pressure responses of the arterial pulse in the form of beat to-beat pulse amplitude and arterial diametrical variations are monitored. Particularly, the unique signatures of pulse pressure variations have been recorded in the arterial pulse waveform, which indicate the systolic and diastolic blood pressure while the patient is subjected to the sphygmomanometric blood pressure examination. The proposed method of blood pressure evaluation using FBGPD has been validated with the auscultatory method of detecting the acoustic pulses (Korotkoff sounds) by an electronic stethoscope. PMID- 23804220 TI - The clinical utility of accelerometry in patients with rheumatoid arthritis. AB - OBJECTIVES: To assess habitual physical activity levels in patients with RA compared with healthy control participants and to compare these measures with health-related quality of life and disease activity in the RA patients. METHODS. Fifty RA patients [age 48 (13) years] and 22 BMI, sex and geographically matched control participants were recruited. Habitual physical activity was measured using an Actical accelerometer worn on the hip for 2 consecutive weeks. Patients completed the Short Form-36 (SF-36) and modified Health Assessment Questionnaires (HAQ-DI). Disease activity was assessed using the Simplified Disease Activity Index (SDAI). RA patients were further categorized as more physically active (n = 25) and less physically active (n = 25) according to their average activity counts. RESULTS: The RA group spent more time in sedentary activity than the control group (71% vs 62% of the day respectively, P = 0.002) and had bimodal decreases in diurnal physical activity compared with the control group in the morning (P < 0.001) and late afternoon (P < 0.001). HAQ-DI, when adjusted for age and disease duration, was negatively correlated with physical activity in the RA group (r = -0.343, P = 0.026). The more physically active patients scored better than the less physically active patients on every component of the SF-36. CONCLUSION: Patients with RA lead a significantly more sedentary lifestyle than healthy controls and show diurnal differences in physical activity due to morning stiffness and fatigue. Higher levels of habitual physical activity may be protective of functional capacity and are highly associated with improved health related quality of life in RA patients. PMID- 23804219 TI - The arthritis-associated HLA-B*27:05 allele forms more cell surface B27 dimer and free heavy chain ligands for KIR3DL2 than HLA-B*27:09. AB - OBJECTIVES: HLA-B*27:05 is associated with AS whereas HLA-B*27:09 is not associated. We hypothesized that different interactions with KIR immune receptors could contribute to the difference in disease association between HLA-B*27:05 and HLAB*27:09. Thus, the objective of this study was to compare the formation of beta2m-free heavy chain (FHC) including B27 dimers (B272) by HLA-B*27:05 and HLA B*27:09 and their binding to KIR immunoreceptors. METHODS: We studied the formation of HLA-B*27:05 and HLA-B*27:09 heterotrimers and FHC forms including dimers in vitro and in transfected cells. We investigated HLA-B*27:05 and HLA B*27:09 binding to KIR3DL1, KIR3DL2 and LILRB2 by FACS staining with class I tetramers and by quantifying interactions with KIR3DL2CD3epsilon-reporter cells and KIR3DL2-expressing NK cells. We also measured KIR expression on peripheral blood NK and CD4 T cells from 18 HLA-B*27:05 AS patients, 8 HLA-B27 negative and 12 HLA-B*27:05+ and HLA-B*27:09+ healthy controls by FACS staining. RESULTS: HLA B*27:09 formed less B272 and FHC than HLA-B*27:05. HLA-B*27:05-expressing cells stimulated KIR3DL2CD3epsilon-reporter T cells more effectively. Cells expressing HLA-B*27:05 promoted KIR3DL2+ NK cell survival more strongly than HLA-B*27:09. HLA-B*27:05 and HLA-B*27:09 dimer tetramers stained KIR3DL1, KIR3DL2 and LILRB2 equivalently. Increased proportions of NK and CD4 T cells expressed KIR3DL2 in HLA-B*27:05+ AS patients compared with HLA-B*27:05+, HLA-B*27:09+ and HLA-B27- healthy controls. CONCLUSION: Differences in the formation of FHC ligands for KIR3DL2 by HLA-B*27:05 and HLA-B*27:09 could contribute to the differential association of these alleles with AS. PMID- 23804221 TI - Prospective purification of a subpopulation of human synovial mesenchymal stem cells with enhanced chondro-osteogenic potency. AB - OBJECTIVE: We previously reported the coexistence, within cultured mesenchymal stem cells (MSCs) from human synovial membrane, of single-cell-derived clonal cell populations with distinct differentiation potency. The aim of this study was to investigate marker sets for prospective purification of functionally distinct MSC subsets. METHODS: Cells were enzymatically released from human synovium and culture expanded. Phenotype analysis was performed by flow cytometry using combinations of MSC markers. Sorting was carried out using the FACS DiVA cell sorter. Sorted cell populations were assessed for clonogenicity, kinetics of growth, cell senescence and chondro-osteogenic potency. RESULTS: During culture expansion, the co-localization of CD39 within the CD73(+) cell population identified a small cell subset that was maintained from passage 1 (P1) up to at least P12 in all donors tested. The CD73(+)CD39(+) cell subset displayed higher expression levels of Sox9 and Runx2 and a significantly greater chondro osteogenic potency than the CD73(+)CD39(-) cell subset. In contrast, it was less clonogenic and proliferative. There was no difference in cell senescence between the sorted MSC subsets and the parental MSCs. Notably, there were no detectable differences in chondro-osteogenic potency between the CD73(+)CD39(-) and CD73(+)CD39(+) cell subsets purified from fresh synovial cell populations. CONCLUSION: Our findings indicate that the combination of CD73 and CD39 allows the prospective purification from culture-expanded heterogeneous synovial MSC populations of a distinct MSC subset with greater chondro-osteogenic potency. We anticipate that such an approach will enhance the consistency of cell-based therapeutic protocols for the repair of osteochondral defects. PMID- 23804222 TI - Sleep disturbances in systemic sclerosis: evidence for the role of gastrointestinal symptoms, pain and pruritus. AB - OBJECTIVE: SSc is a rare autoimmune CTD characterized by thickening and fibrosis of skin and internal organs. There is significant mortality and no cure. Sleep disturbance has been identified as an important contributor to poor quality of life. The objective was to investigate socio-demographic and medical factors potentially associated with sleep disturbance in SSc. METHODS: The sample consisted of patients from the Canadian Scleroderma Research Group's (CSRG) 15 centre, pan-Canadian Registry assessed with the 8-item Patient-Reported Outcome Measurement Information System (PROMIS) sleep disturbance scale short form, version 1.0. Pearson's correlations were used to assess bivariate association of socio-demographic and medical variables with PROMIS sleep scores. The independent association of PROMIS sleep disturbance scores and factors previously identified as associated with sleep disturbance in the general population, in SSc and other rheumatic diseases, was assessed using multiple linear regression. RESULTS: Among 397 patients in the study (88% female, mean age 57.5 years), 25% (n = 98) had diffuse cutaneous SSc. Mean duration since onset of non-RP symptoms was 10.6 years. Number of gastrointestinal symptoms (standardized regression coefficient beta = 0.19, P = 0.001), pain severity (beta = 0.21, P < 0.001) and pruritus severity (beta = 0.13, P = 0.024) were independently associated with more severe sleep disturbance. CONCLUSION: Gastrointestinal symptoms, pain and pruritus were associated with sleep disturbance in SSc. Additional research is needed on sleep in SSc so that well-informed sleep interventions can be developed and tested. PMID- 23804223 TI - Work productivity in a population-based cohort of patients with spondyloarthritis. AB - OBJECTIVE: To assess work productivity and associated factors in patients with SpA. METHODS: This cross-sectional postal survey included 1773 patients with SpA identified in a regional health care register. Items on presenteeism (reduced productivity at work, 0-100%, 0 = no reduction) were answered by 1447 individuals. Absenteeism was defined as register-based sick leave using data from a national register. Disease duration, disease activity (BASDAI), physical function (BASFI), health-related quality of life (EQ-5D), anxiety (HAD-a), depression (HAD-d), self-efficacy [Arthritis Self-efficacy Scale (ASES) pain and symptom], physical activity and education were also measured. RESULTS: Forty-five per cent reported reduced productivity at work with a mean reduction of 20% (95% CI 18, 21) and women reported a higher mean reduction than men (mean 23% vs 17%, P < 0.001). Worse quality of life, disease activity, physical function and anxiety all correlated with reduced productivity (r = 0.52-0.66, P < 0.001), while sick leave did not. Worse outcomes on the EQ-5D (beta-est -9.6, P < 0.001), BASDAI (beta-est 7.8, P < 0.001), BASFI (beta-est 7.3, P < 0.001), ASES pain (beta-est -0.5, P < 0.001) and HAD-d (beta-est 3.4, P < 0.001) were associated with reduced productivity at work in patients with SpA regardless of age, gender and disease subgroup. ASES symptoms, HAD-a and education level <12 years were associated with reduced productivity but were not significant in all strata for age, gender and disease subgroup. CONCLUSION: Work productivity was reduced in patients with SpA and more so in women. Worse quality of life, disease activity, physical function, self-efficacy and depression were all associated with reduced productivity at work in patients with SpA. PMID- 23804224 TI - Surgical anatomy of the supraglottic larynx using the da Vinci robot. AB - BACKGROUND: Transoral robotic surgery (TORS) has facilitated organ-preserving surgery of the larynx. It has also presented a change in the surgical perspective. We performed cadaveric dissections using the robot to highlight the vascular and muscular anatomy of the supraglottic larynx. METHODS: Cadaveric specimens underwent injection of their vasculature, and after injection a robotic surgical system was used to perform a transoral dissection of the supraglottic region. Care was taken to preserve anatomic landmarks and microvascular structures. RESULTS: Five fresh frozen cadaveric human heads were injected with silicone and used for the dissection. The superior laryngeal neurovascular bundle was identified and an absent superior laryngeal vein (SLV) was noted on 1 specimen. Using the robotic endoscope allowed us to visualize and identify the microvasculature of the head and neck. CONCLUSION: These dissections revealed anatomic variations in the superior laryngeal neurovascular bundle and also highlighted the differences in view using a surgical robotic system. PMID- 23804225 TI - US revamps website to promote health insurance exchanges. PMID- 23804226 TI - Highly hydrophobic isoreticular porous metal-organic frameworks for the capture of harmful volatile organic compounds. PMID- 23804227 TI - Iron-catalyzed hydrogenation for the in situ regeneration of an NAD(P)H model: biomimetic reduction of alpha-keto-/alpha-iminoesters. PMID- 23804228 TI - Disproportionate burden of melanoma mortality in young U.S. men: the possible role of biology and behavior. PMID- 23804229 TI - Intracranial glioblastoma with drop metastases to the spine after stereotactic biopsy. AB - BACKGROUND: Glioblastoma (GBM) is the most common primary intracranial tumor, but metastases are rarely reported. Previous reports have documented the occurrence of drop metastases to the spine. However, few of these reports have demonstrated the occurrence of spinal metastases after biopsy with stable intracranial disease. Here we present such a case. CASE DESCRIPTION: We present a case of GBM metastatic to the spinal cord after a stereotactic biopsy with stable intracranial disease. To our knowledge, this occurrence has only been reported in one previous case. CONCLUSION: We propose that traversing the lateral ventricle at the time of biopsy contributed to cerebrospinal fluid seeding with tumor cells and subsequent development of spinal disease. PMID- 23804230 TI - Lack of association between factor V Leiden and sepsis: a meta-analysis. AB - Some studies evaluated the association of factor V Leiden (FVL) with sepsis risk and mortality risk. However, the results were conflicting. Thus, we performed a meta-analysis to address the association between FVL and sepsis. PubMed and EMBASE databases were searched to find relevant studies. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using random effects model. Five case-control studies and 3 cohort studies were included. Overall, no significant association between FVL and sepsis risk was observed (OR = 0.93; 95% CI 0.74-1.15; P = .49). In addition, there was no significant association between FVL and sepsis-related mortality (OR = 1.17; 95% CI 0.73-1.88; P = .52). In the subgroup analysis, no increased sepsis risk and mortality risk were found in caucasian population. This meta-analysis suggested that FVL was not a risk factor for sepsis and sepsis mortality. PMID- 23804231 TI - Relationship between red cell distribution width and stroke in patients with stable chronic heart failure: a propensity score matching analysis. AB - AIM: We aimed to investigate the association between baseline red cell distribution width (RDW) level and the risk of stroke in patients with heart failure (HF). METHODS: A total of 153 consecutive patients with HF (New York Heart Association [NYHA] I-III and left ventricular ejection fraction of <40%) were included in this prospective study. All the patients were followed up for 1 year, and during this period the cerebrovascular disease was questioned. RESULTS: In matched population, using propensity score matching comparing patients with HF having stroke with patients without stroke, we found significantly increased basal RDW and serum uric acid. The receiver-operating characteristic curves of RDW for predicting stroke are performed. An RDW >= 15.2% measured on admission had 87% sensitivity and 74% specificity in predicting stroke in patients with HF (area under the curve: 0.923, 95% confidence interval: 0.852-0.994, P < .001). CONCLUSION: In conclusion, this study demonstrated that RDW may be important hematological indices for stroke in patients with HF using propensity score analysis. PMID- 23804232 TI - Thrombin generation mediators and markers in sepsis-associated coagulopathy and their modulation by recombinant thrombomodulin. AB - Severe sepsis remains the most common cause of death in critically ill patients, and thrombin plays a crucial role in the pathogenesis of sepsis-associated disseminated intravascular coagulation (DIC). The purpose of this study was to profile prothrombin fragment (F1.2), thrombin-antithrombin complex (TAT), and d dimer (DD) throughout the course of hospital stay in patients identified with sepsis. Plasma samples from patients enrolled in the ART-123 study, a phase 2b, international, multicenter, randomized placebo-controlled trial were analyzed for various parameters using enzyme-linked immunosorbent assay methods. Plasma levels of F1.2, DD, and TAT were measured at several time points following administration of recombinant thrombomodulin or placebo, and the results were tabulated. In the group treated with thrombomodulin, the median F1.2 levels demonstrated a 16% decrease from the baseline to day 7, while the placebo group showed an 8% increase. Both the treatment groups showed a gradual decrease in the TAT and DD, with the group treated with thrombomodulin demonstrating twice the decrease over the 7-day period. Although the data were widely scattered, these results show that DIC represents a hypercoagulable state along with other hemostatic abnormalities and the activation of the inflammatory process. Modulation of these activation processes through targets such as DD, F1.2, and TAT may play an important regulatory role in the pathogenesis of sepsis associated coagulopathy. Moreover, this study validates the hypothesis that thrombomodulin downregulates the thrombin generation mediators/markers in sepsis associated DIC. PMID- 23804233 TI - MicroRNA-23a modulates tumor necrosis factor-alpha-induced osteoblasts apoptosis by directly targeting Fas. AB - Tumor necrosis factor (TNF)-alpha is a key cytokine regulator of bone and mediates inflammatory bone loss. The molecular signaling that regulates bone loss downstream of TNF-alpha is poorly defined. Recent studies implicated an important role of microRNAs (miRNAs) in TNF-alpha-mediated bone metabolism, including osteoblasts differentiation, osteoclasts differentiation and apoptosis. However, there are very few studies on the complex regulation of miRNAs during TNF-alpha induced osteoblasts apoptosis. In the present study, the clonal murine osteoblastic cell line, MC3T3-E1, was used. We screened for differentially expressed miRNAs during TNF-alpha induced MC3T3-E1 cell apoptosis and identified microRNA-23a as a potential inhibitor of apoptosis. To delineate the role of microRNA-23a in apoptosis, we respectively silenced and overexpressed microRNA 23a in MC3T3-E1 cells. We found that microRNA-23a depletion significantly enhances TNF-alpha-induced MC3T3-E1 cell apoptosis and over-expressing microRNA 23a remarkably attenuates this phenomenon. Mechanistic studies showed that microRNA-23a inhibits Fas expression through a microRNA-23a-binding site within the 3'-untranslational region of Fas. The post-transcriptional repression of Fas was further confirmed by luciferase reporter assay. These results showed that microRNA-23a, an important protecting factor, plays a significant role in the process of TNF-alpha induced MC3T3-E1 cell apoptosis, by regulating Fas expression. PMID- 23804234 TI - Synthesis and photochromic properties of oxime derivatives of 2,3-diarylcyclopent 2-en-1-ones. AB - A wide range of new oxime-based photochromic diarylethenes of the cyclopentenone series have been synthesized. Their spectral properties have been investigated in detail upon UV/vis light irradiation in acetonitrile solution, and distinct correlations between photochromic characteristics and substance structures are revealed. It was found that the introduction of an oxime group into the cyclopentene ring has a significant influence on the switching characteristics primarily on the thermal stability, and a series of thermally stable oxime-based photochromic diarylcyclopentenones have been prepared. The results obtained suggest that the modifications of the ethene "bridge" are a promising way to tune the spectral parameters of diarylethenes in an accurate manner and thus to synthesize the photochromic compounds with desired properties. PMID- 23804235 TI - Recombinant thrombomodulin of different domains for pharmaceutical, biomedical, and cell transplantation applications. AB - Thrombomodulin (TM) is a membrane glycoprotein mainly expressed by vascular endothelial cells and is involved in many physiological and pathological processes, such as coagulation, inflammation, cancer development, and embryogenesis. Human TM consists of 557 amino acids divided into five distinct domains: N-terminal lectin-like domain (designated as TMD1); six epidermal growth factor (EGF)-like domain (TMD2); Ser/Thr-rich domain (TMD3); transmembrane domain (TMD4); and cytoplasmic tail domain (TMD5). The different domains are responsible for different biological functions of TM. In the past decades, various domains of TM have been cloned and expressed for TM structural and functional study. Further, recombinant TMs of different domains show promising antithrombotic and anti-inflammatory activity in both rodents and primates and a recombinant soluble TM has been approved for therapeutic application. This review highlights recombinant TMs of diverse structures and their biological functions, as well as the complex interactions of TM with factors involved in the related biological processes. Particularly, recent advances in exploring recombinant TM of different domains for pharmaceutical, biomedical, and cell transplantation applications are summarized. PMID- 23804236 TI - Neurological picture. Rituximab for tumefactive demyelination refractory to corticosteroids and plasma exchange. PMID- 23804237 TI - Pharyngeal-cervical-brachial variant of Guillain-Barre syndrome. AB - The pharyngeal-cervical-brachial (PCB) variant of Guillain-Barre syndrome is defined by rapidly progressive oropharyngeal and cervicobrachial weakness associated with areflexia in the upper limbs. Serial nerve conduction studies suggest that PCB represents a localised subtype of Guillain-Barre syndrome characterised by axonal rather than demyelinating neuropathy. Many neurologists are unfamiliar with PCB, which is often misdiagnosed as brainstem stroke, myasthenia gravis or botulism. The presence of additional ophthalmoplegia and ataxia indicates overlap with Fisher syndrome. Half of patients with PCB carry IgG anti-GT1a antibodies which often cross-react with GQ1b, whereas most patients with Fisher syndrome carry IgG anti-GQ1b antibodies which always cross-react with GT1a. Significant overlap between the clinical and serological profiles of these patients supports the view that PCB and Fisher syndrome form a continuous spectrum. In this review, we highlight the clinical features of PCB and outline new diagnostic criteria. PMID- 23804238 TI - Tagging of cardiac magnetic resonance images in the polar coordinate system: physical principles and practical implementation. AB - PURPOSE: In current magnetic resonance practice, myocardial tagging is implemented by laying down a rectilinear presaturation grid over the heart. Although both the geometry and the deformation of the heart are better described in the polar coordinate system, practical methods for laying down polar grids have been elusive. The theory and implementation of high-density tagging in the polar coordinate system is described in this study. METHODS: Tagging sequences for generating high-density tagging patterns in both radial and circular directions have been developed. The approach, theoretical basis, and experimental results of the suggested sequences for efficient polar tagging are described in this article. RESULTS: A 10-ms preparation tagging sequence was tested for generating compact radial and circular tag patterns in a magnetization preparation time comparable to binomial rectilinear grid tagging. The sequence was successfully tested on both phantoms and human subjects. CONCLUSION: Direct myocardial tagging in the polar coordinate system is practical in acquisition times similar to Cartesian tagging. The deformation patterns of radial and circular tag lines can be used to isolate and analyze the circumferential and radial components of myocardial motion. Further work remains to establish the reliability and robustness of the techniques for a variety of clinical applications. PMID- 23804239 TI - Extracellular HSP27 mediates angiogenesis through Toll-like receptor 3. AB - The heat-shock protein 27 (HSP27) is up-regulated in tumor cells and released in their microenvironment. Here, we show that extracellular HSP27 has a proangiogenic effect evidenced on chick chorioallantoic membrane. To explore this effect, we test the recombinant human protein (rhHSP27) at physiopathological doses (0.1-10 MUg/ml) onto human microvascular endothelial cells (HMECs) grown as monolayers or spheroids. When added onto HMECs, rhHSP27 dose-dependently accelerates cell migration (with a peak at 5 MUg/ml) and favors spheroid sprouting within 12-24 h. rhHSP27 increases VEGF gene transcription and promotes secretion of VEGF-activating VEGF receptor type 2. Increased VEGF transcription is related to NF-kappaB activation in 30 min. All of these effects are initiated by rhHSP27 interaction with Toll-like receptor 3 (TLR3). Such an interaction can be detected by immunoprecipitation but does not seem to be direct, as we failed to detect an interaction between rhHSP27 and monomeric TLR3 by SPR analysis. rhHSP27 is rapidly internalized with a pool of TLR3 to the endosomal compartment (within 15-30 min), which is required for NF-kappaB activation in a cytosolic Ca(2+)-dependent manner. The HSP27/TLR3 interaction induces NF-kappaB activation, leading to VEGF-mediated cell migration and angiogenesis. Such a pathway provides alternative targets for antiangiogenic cancer therapy. PMID- 23804240 TI - Abnormal protein turnover and anabolic resistance to exercise in sarcopenic obesity. AB - Obesity may impair protein synthesis rates and cause anabolic resistance to growth factors, hormones, and exercise, ultimately affecting skeletal muscle mass and function. To better understand muscle wasting and anabolic resistance with obesity, we assessed protein 24-h fractional synthesis rates (24-h FSRs) in selected hind-limb muscles of sedentary and resistance-exercised lean and obese Zucker rats. Despite atrophied hind-limb muscles (-28% vs. lean rats), 24-h FSRs of mixed proteins were significantly higher in quadriceps (+18%) and red or white gastrocnemius (+22 or +38%, respectively) of obese animals when compared to lean littermates. Basal synthesis rates of myofibrillar (+8%) and mitochondrial proteins (-1%) in quadriceps were not different between phenotypes, while manufacture of cytosolic proteins (+12%) was moderately elevated in obese cohorts. Western blot analyses revealed a robust activation of p70S6k (+178%) and a lower expression of the endogenous mTOR inhibitor DEPTOR (-28%) in obese rats, collectively suggesting that there is an obesity-induced increase in net protein turnover favoring degradation. Lastly, the protein synthetic response to exercise of mixed (-7%), myofibrillar (+6%), and cytosolic (+7%) quadriceps subfractions was blunted compared to the lean phenotype (+34, +40, and +17%, respectively), indicating a muscle- and subfraction-specific desensitization to the anabolic stimulus of exercise in obese animals. PMID- 23804241 TI - Hypermethylation reduces expression of tumor-suppressor PLZF and regulates proliferation and apoptosis in non-small-cell lung cancers. AB - Deregulation of promyelocytic leukemia zinc finger protein (PLZF), a tumor suppressor gene, was reported in different types of solid tumors. This study for the first time explored the reduced expression of PLZF and its effects in non small-cell lung cancer (NSCLC) carcinogenesis. PLZF was found to be down regulated by 62.8% in 87.1% of 154 paired NSCLC samples by quantitative real-time PCR, and its expression was found to be associated with the sex of the patient (P=0.02). Further analysis showed that down-regulation of PLZF in 35.6% NSCLC samples (31 out of 87) was triggered by hypermethylation in the promoter region. This was validated by demethylation analysis using the A549 cell line. Dual luciferase reporter assay indicated that CTCF binding to the promoter region could activate PLZF transcription. Overexpression of PLZF in both A549 and LTEP lung cancer cell lines was found to inhibit proliferation and increase apoptosis. Therefore, reduced expression of PLZF was found to be common in NSCLC. PLZF down regulation was partially correlated with hypermethylation in the promoter region. Decreased levels of PLZF expression may contribute to the pathogenesis of NSCLC by promoting cell survival. Therefore, the restoration of PLZF expression may serve as a new strategy for NSCLC therapy. PMID- 23804242 TI - Evaluating the economic impact of a targeted medication intervention program. AB - OBJECTIVE: To calculate the return on investment (ROI) for a targeted medication intervention program developed by corporate management of a community pharmacy. DESIGN: Retrospective analysis and cross-sectional survey. SETTING: Regional community pharmacy chain in North Carolina. PARTICIPANTS: Targeted medication interventions completed from February 1, 2010, to July 31, 2010, were included in the retrospective analysis. Community pharmacists employed by the pharmacy chain that completed the questionnaire were included in the cross-sectional analysis. INTERVENTION: Targeted medication intervention services were provided to the patient and documented by the pharmacist. MAIN OUTCOME MEASURE: The ROI for a community pharmacist-provided targeted medication intervention program. RESULTS: Of the 180 pharmacists, 69 completed the questionnaire (38% response rate). The average time to complete one targeted medication intervention was calculated to be 22.63 minutes. The total cost for providing a targeted medication intervention program during the study time frame was $15 760.86. Total revenue was $15 216.00; therefore, the program resulted in an ROI to the pharmacy chain of negative 3%. CONCLUSION: This 6-month study resulted in an ROI to the pharmacy chain of negative 3%. Under the current reimbursement model, for this program to break even, the average time to complete one targeted medication intervention must equal 21.85 minutes or less. PMID- 23804243 TI - Effect of pharmacy practice program on pharmacy student learning, satisfaction, and efficiency: assessment of introductory pharmacy practice course. AB - INTRODUCTION: The Lebanese American University (LAU) offers first-year pharmacy students with Introductory Pharmacy Practice Experience (IPPE) courses comprising various activities that provide students with direct patient contact so that they can be geared up for "real-world" pharmacy practice. Routine assessment and improvement in these courses are imperative to ensure efficiency of these courses. This study was conducted to evaluate the quality of our IPPEs courses, determine its impact on student learning and satisfaction, and identify shortcomings in the program for quality improvement purposes. METHODS: A literature review-based questionnaire, consisting of 76 questions with a response options following a 4-point scale (strongly agree = 4 to strongly disagree = 1), was completed by 92 first professional year pharmacy students who finished their hospital and community IPPE at LAU. RESULTS: The students reported a high degree of satisfaction in community and hospital sites in terms of site selection, program schedule, site and school preceptors, and overall satisfaction with the experience. Compared to the hospital setting, students practicing in the community reported significantly higher scores in overall satisfaction. Besides the high satisfaction rate, our results identified improvement measures in some aspects of the program. CONCLUSION: Our IPPE program serves as a successful experiential learning for pharmacy students. PMID- 23804245 TI - Domino cycloaddition organocascades of dendralenes. PMID- 23804246 TI - Structured water molecules in the binding site of bromodomains can be displaced by cosolvent. AB - Bromodomains are alpha-helical bundles of approximately 110 residues that recognize acetylated lysine side chains mainly on histone tails. Bromodomains are known to play an important role in cancer and inflammation, and as such, significant efforts are being made to identify small-molecule inhibitors of these epigenetic reader proteins. Here, explicit solvent molecular dynamics (MD) simulations of two bromodomains (BAZ2B and CREBBP) are used to analyze the water molecules that seem to be conserved at the bottom of the acetyl-lysine binding site in most crystal structures of bromodomains. The MD runs suggest that the occupancy of the structured water molecules is influenced by conformational transitions of the loop that connects helices Z and A. Additional simulations in the presence of 50 molecules of cosolvent (i.e., 440 mM of dimethylsulfoxide, methanol, or ethanol) indicate that some of the structured water molecules can be displaced transiently. The residence time in the acetyl-lysine binding site is calculated to be about 1 ns, 2-5 ns, and 10-30 ns for methanol, ethanol, and dimethylsulfoxide, respectively, while the affinity of the three cosolvents for BAZ2B and CREBBP is in the range of 50-500 mM. The results described have implications for ligand design, suggesting that only structured water molecules that do not exchange with cosolvent should be maintained in crystal structures used for docking campaigns, and that hydroxy substituents should be incorporated in the ligand so as to map the structured water molecules replaced by (m)ethanol. PMID- 23804244 TI - Hfq binding changes the structure of Escherichia coli small noncoding RNAs OxyS and RprA, which are involved in the riboregulation of rpoS. AB - OxyS and RprA are two small noncoding RNAs (sRNAs) that modulate the expression of rpoS, encoding an alternative sigma factor that activates transcription of multiple Escherichia coli stress-response genes. While RprA activates rpoS for translation, OxyS down-regulates the transcript. Crucially, the RNA binding protein Hfq is required for both sRNAs to function, although the specific role played by Hfq remains unclear. We have investigated RprA and OxyS interactions with Hfq using biochemical and biophysical approaches. In particular, we have obtained the molecular envelopes of the Hfq-sRNA complexes using small-angle scattering methods, which reveal key molecular details. These data indicate that Hfq does not substantially change shape upon complex formation, whereas the sRNAs do. We link the impact of Hfq binding, and the sRNA structural changes induced, to transcript stability with respect to RNase E degradation. In light of these findings, we discuss the role of Hfq in the opposing regulatory functions played by RprA and OxyS in rpoS regulation. PMID- 23804247 TI - Age-related prevalence of dermoscopic patterns in acquired melanocytic nevus on acral volar skin. PMID- 23804248 TI - Increased local failure risk with prolonged radiation treatment time in head and neck cancer treated with concurrent chemotherapy. AB - BACKGROUND: Prolonged radiation treatment time (RTT) in head and neck squamous cell carcinoma (HNSCC) is associated with inferior tumor control in patients treated with radiation therapy (RT) alone. However, the significance of prolonged RTT with concurrent chemotherapy is less clear. METHODS: We reviewed outcomes for 171 patients with primary HNSCC treated with curative intent RT and concurrent drug therapy from 2001 to 2009. The effects of RTT and other variables on local control and survival were analyzed. RESULTS: Patients with RTT >7 weeks had a significantly increased risk of local failure (hazard ratio [HR], 2.6; p = .018) and death (HR, 1.9 p = .035). These results retained significance even after adjustment for tumor stage (age was not significant). CONCLUSION: For patients treated with concurrent chemoradiotherapy (chemoRT), prolonged RTT may compromise tumor control as has been established in the setting of RT alone. Symptoms of patients with HNSCC undergoing definitive chemoRT should be managed aggressively to limit treatment interruptions. PMID- 23804250 TI - Pharmacological studies on Myrica rubra Sieb et zucc. Effects on the cardiovascular system and platelets. AB - The effects of 50% Drink of Myrica rubra (MRD) on the cardiovascular system of the rat and on the platelets aggregation of rats and guinea pigs were studied. METHOD: Different groups of male Wistar rats were treated either with 50% Myrica rubra drink as drinking vehicle (4 weeks) or water. The animals were then prepared for the measurement of arterial blood pressure and heart rate, ECG, sensitivity of the baroreceptors, platelets' aggregation, blood clotting time and cardiac parasympathetic ganglia. The mechanism of action of any induced effect was elucidated using different receptor blockers. RESULTS: Treatment induced a significant decrease in the arterial blood pressure and heart rate on Wistar rats, but no significant changes in the ECG were observed. Pretreatment of rats with MRD 10 or 20 ml/kg (i. p.) significantly suppressed vagal electrical stimulation to the heart and nicotine-induced bradycardia, via decreasing phenylephrine-induced rise in the arterial blood pressure and the reflexly induced bradycardia. It significantly suppressed the Baroreceptor Sensitivity Index (BSI). The treatment also significantly suppressed ADP-induced platelets aggregation in rats and arachidonic acid-induced aggregation in guinea pigs.All these actions seemed to be mediated by the MRD constituents such as proanthocyanidins, polyphenols and flavonoids. The decreases in the heart rate and BSI were probably caused by an inherent ability to block the parasympathetic ganglia. CONCLUSION: The results of this study regarding the effects of MRD actions on the cardiovascular system and platelets qualify the drink to be classified as a functional food. PMID- 23804251 TI - Microwave-assisted synthesis and spasmolytic activity of 4 indolylhexahydroquinoline derivatives. AB - In the present study a microwave-assisted one-pot method was applied for the synthesis of 18 novel condensed 1,4-dihydropyridines carrying the indole moiety. The compounds were achieved by the reaction of appropriate 1,3-cyclohexanedione, substituted indole carboxaldehyde derivative, alkyl acetoacetate and ammonium acetate in methanol, according to a modified Hantzsch reaction. The structure elucidation of the compounds was carried out by spectral methods including X-ray studies. Their spasmolytic activities through calcium channel blockade were assayed on isolated rat ileum. The obtained results indicated that the introduction of the brom atom on the indole ring altered the mentioned activity positively. PMID- 23804253 TI - Learning minimally invasive mitral valve surgery: a cumulative sum sequential probability analysis of 3895 operations from a single high-volume center. AB - BACKGROUND: Learning curves are vigorously discussed and viewed as a negative aspect of adopting new procedures. However, very few publications have methodically examined learning curves in cardiac surgery, which could lead to a better understanding and a more meaningful discussion of their consequences. The purpose of this study was to assess the learning process involved in the performance of minimally invasive surgery of the mitral valve using data from a large, single-center experience. METHODS AND RESULTS: All mitral (including tricuspid, or atrial fibrillation ablation) operations performed over a 17-year period through a right lateral mini-thoracotomy with peripheral cannulation for cardiopulmonary bypass (n=3907) were analyzed. Data were obtained from a prospective database. Individual learning curves for operation time and complication rates (using sequential probability cumulative sum failure analysis) and average results were calculated. A total of 3895 operations by 17 surgeons performing their first minimally invasive surgery of the mitral valve operation at our institution could be evaluated. The typical number of operations to overcome the learning curve was between 75 and 125. Furthermore, >1 such operation per week was necessary to maintain good results. Individual learning curves varied markedly, proving the need for good monitoring or mentoring in the initial phase. CONCLUSIONS: A true learning curve exists for minimally invasive surgery of the mitral valve. Although the number of operations required to overcome the learning curve is substantial, marked variation exists between individual surgeons. Such information could be very helpful in structuring future training and maintenance of competence programs for this kind of surgery. PMID- 23804252 TI - Stress cardiac magnetic resonance imaging provides effective cardiac risk reclassification in patients with known or suspected stable coronary artery disease. AB - BACKGROUND: A recent large-scale clinical trial found that an initial invasive strategy does not improve cardiac outcomes beyond optimized medical therapy in patients with stable coronary artery disease. Novel methods to stratify at-risk patients may refine therapeutic decisions to improve outcomes. METHODS AND RESULTS: In a cohort of 815 consecutive patients referred for evaluation of myocardial ischemia, we determined the net reclassification improvement of the risk of cardiac death or nonfatal myocardial infarction (major adverse cardiac events) incremental to clinical risk models, using guideline-based low (<1%), moderate (1% to 3%), and high (>3%) annual risk categories. In the whole cohort, inducible ischemia demonstrated a strong association with major adverse cardiac events (hazard ratio=14.66; P<0.0001) with low negative event rates of major adverse cardiac events and cardiac death (0.6% and 0.4%, respectively). This prognostic robustness was maintained in patients with previous coronary artery disease (hazard ratio=8.17; P<0.0001; 1.3% and 0.6%, respectively). Adding inducible ischemia to the multivariable clinical risk model (adjusted for age and previous coronary artery disease) improved discrimination of major adverse cardiac events (C statistic, 0.81-0.86; P=0.04; adjusted hazard ratio=7.37; P<0.0001) and reclassified 91.5% of patients at moderate pretest risk (65.7% to low risk; 25.8% to high risk) with corresponding changes in the observed event rates (0.3%/y and 4.9%/y for low and high risk posttest, respectively). Categorical net reclassification index was 0.229 (95% confidence interval, 0.063 0.391). Continuous net reclassification improvement was 1.11 (95% confidence interval, 0.81-1.39). CONCLUSIONS: Stress cardiac magnetic resonance imaging effectively reclassifies patient risk beyond standard clinical variables, specifically in patients at moderate to high pretest clinical risk and in patients with previous coronary artery disease. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01821924. PMID- 23804255 TI - Tailoring surface-confined nanopores with photoresponsive groups. PMID- 23804254 TI - Therapeutic efficacy of AAV1.SERCA2a in monocrotaline-induced pulmonary arterial hypertension. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is characterized by dysregulated proliferation of pulmonary artery smooth muscle cells leading to (mal)adaptive vascular remodeling. In the systemic circulation, vascular injury is associated with downregulation of sarcoplasmic reticulum Ca(2+)-ATPase 2a (SERCA2a) and alterations in Ca(2+) homeostasis in vascular smooth muscle cells that stimulate proliferation. We, therefore, hypothesized that downregulation of SERCA2a is permissive for pulmonary vascular remodeling and the development of PAH. METHODS AND RESULTS: SERCA2a expression was decreased significantly in remodeled pulmonary arteries from patients with PAH and the rat monocrotaline model of PAH in comparison with controls. In human pulmonary artery smooth muscle cells in vitro, SERCA2a overexpression by gene transfer decreased proliferation and migration significantly by inhibiting NFAT/STAT3. Overexpresion of SERCA2a in human pulmonary artery endothelial cells in vitro increased endothelial nitric oxide synthase expression and activation. In monocrotaline rats with established PAH, gene transfer of SERCA2a via intratracheal delivery of aerosolized adeno associated virus serotype 1 (AAV1) carrying the human SERCA2a gene (AAV1.SERCA2a) decreased pulmonary artery pressure, vascular remodeling, right ventricular hypertrophy, and fibrosis in comparison with monocrotaline-PAH rats treated with a control AAV1 carrying beta-galactosidase or saline. In a prevention protocol, aerosolized AAV1.SERCA2a delivered at the time of monocrotaline administration limited adverse hemodynamic profiles and indices of pulmonary and cardiac remodeling in comparison with rats administered AAV1 carrying beta-galactosidase or saline. CONCLUSIONS: Downregulation of SERCA2a plays a critical role in modulating the vascular and right ventricular pathophenotype associated with PAH. Selective pulmonary SERCA2a gene transfer may offer benefit as a therapeutic intervention in PAH. PMID- 23804256 TI - An unusual death in the community. PMID- 23804257 TI - Genetic analysis of type 1 diabetes: embryonic stem cells as new tools to unlock biological mechanisms in type 1 diabetes. AB - The nonobese diabetic (NOD) mouse has provided an important animal model for studying the mechanism and genetics of type 1 diabetes over the past 30 years. Arguably, the bio-breeding (BB) rat model may be an even closer phenotypic mimic of the typical human disease. A large number of distinct genetic traits which influence diabetes development have been defined through an extraordinary effort, most conspicuously in the mouse model. However, in both NOD and BB models the lack of availability of robust means for experimental genetic manipulation has restricted our understanding of the mechanisms underlying this spontaneous autoimmune disease. Recent developments in the derivation of embryonic stem (ES) cells have the potential to transform this picture. We argue here that targeting of NOD strain ES cells can bring much needed certainty to our present understanding of the genetics of type 1 diabetes in the NOD mouse. In addition, ES cells can play important roles in the future, in both the NOD mouse and BB rat models, through the generation of new tools to investigate the mechanisms by which genetic variation acts to promote diabetes. PMID- 23804258 TI - Pathogenic mechanisms in type 1 diabetes: the islet is both target and driver of disease. AB - Recent advances in our understanding of the pathogenesis of type 1 diabetes have occurred in all steps of the disease. This review outlines the pathogenic mechanisms utilized by the immune system to mediate destruction of the pancreatic beta-cells. The autoimmune response against beta-cells appears to begin in the pancreatic lymph node where T cells, which have escaped negative selection in the thymus, first meet beta-cell antigens presented by dendritic cells. Proinsulin is an important antigen in early diabetes. T cells migrate to the islets via the circulation and establish insulitis initially around the islets. T cells within insulitis are specific for islet antigens rather than bystanders. Pathogenic CD4+ T cells may recognize peptides from proinsulin which are produced locally within the islet. CD8+ T cells differentiate into effector T cells in islets and then kill beta-cells, primarily via the perforin-granzyme pathway. Cytokines do not appear to be important cytotoxic molecules in vivo. Maturation of the immune response within the islet is now understood to contribute to diabetes, and highlights the islet as both driver and target of the disease. The majority of our knowledge of these pathogenic processes is derived from the NOD mouse model, although some processes are mirrored in the human disease. However, more work is required to translate the data from the NOD mouse to our understanding of human diabetes pathogenesis. New technology, especially MHC tetramers and modern imaging, will enhance our understanding of the pathogenic mechanisms. PMID- 23804259 TI - Comparative genetics: synergizing human and NOD mouse studies for identifying genetic causation of type 1 diabetes. AB - Although once widely anticipated to unlock how human type 1 diabetes (T1D) develops, extensive study of the nonobese diabetic (NOD) mouse has failed to yield effective treatments for patients with the disease. This has led many to question the usefulness of this animal model. While criticism about the differences between NOD and human T1D is legitimate, in many cases disease in both species results from perturbations modulated by the same genes or different genes that function within the same biological pathways. Like in humans, unusual polymorphisms within an MHC class II molecule contributes the most T1D risk in NOD mice. This insight supports the validity of this model and suggests the NOD has been improperly utilized to study how to cure or prevent disease in patients. Indeed, clinical trials are far from administering T1D therapeutics to humans at the same concentration ranges and pathological states that inhibit disease in NOD mice. Until these obstacles are overcome it is premature to label the NOD mouse a poor surrogate to test agents that cure or prevent T1D. An additional criticism of the NOD mouse is the past difficulty in identifying genes underlying T1D using conventional mapping studies. However, most of the few diabetogenic alleles identified to date appear relevant to the human disorder. This suggests that rather than abandoning genetic studies in NOD mice, future efforts should focus on improving the efficiency with which diabetes susceptibility genes are detected. The current review highlights why the NOD mouse remains a relevant and valuable tool to understand the genes and their interactions that promote autoimmune diabetes and therapeutics that inhibit this disease. It also describes a new range of technologies that will likely transform how the NOD mouse is used to uncover the genetic causes of T1D for years to come. PMID- 23804260 TI - Protein tyrosine phosphatases and type 1 diabetes: genetic and functional implications of PTPN2 and PTPN22. AB - Protein tyrosine phosphatases (PTPs) play a central role in modulating the transduction of cellular signals, including the cells of the immune system. Several PTPs, PTPN22, PTPN2, and UBASH3A, have been associated with risk of type 1 diabetes (T1D) by genome wide association studies. Based on the current understanding of PTPs, it is clear that these variants impact antigen receptor signaling and cytokine signaling. This impact likely contributes to the development and progression of autoimmunity through multiple mechanisms, including failures of central and peripheral tolerance and the promotion of proinflammatory T cell responses. In this review, we discuss the genetic and functional implications of two of these PTPs, PTPN22 and PTPN2, in the development of T1D. We describe the known roles of these proteins in immune function, and how the expression and function of these proteins is altered by the genetic variants associated with T1D. Yet, there are still controversies in the field that require further study and the development of new approaches to extend our understanding of these PTP variants, with the goal of using the information gained to improve our ability to predict and cure T1D. PMID- 23804262 TI - Novel biomarkers in type 1 diabetes. AB - Biomarkers are useful tools for research into type 1 diabetes (T1D) for a number of purposes, including elucidation of disease pathogenesis, risk prediction, and therapeutic monitoring. Susceptibility genes and islet autoantibodies are currently the most useful biomarkers for T1D risk prediction. However, these markers do not fully meet the needs of scientists and physicians for several reasons. First, improvement of the specificity and sensitivity is still desirable to achieve better positive predictive values. Second, autoantibodies appear relatively late in the disease process, thus limiting their value in early disease prediction. Third, the currently available biomarkers are not useful for assessing therapeutic outcomes because some are not involved in the disease process (autoantibodies) and others do not change during disease progression (susceptibility genes). Therefore, considerable effort has been devoted to the discovery of novel T1D biomarkers in the last three decades. The advent of high throughput technologies for genetic, transcriptomic, and proteomic studies has allowed genome-wide examinations of genetic polymorphisms, global gene changes, and protein expression changes in T1D patients and prediabetic subjects. These large-scale studies resulted in the discovery of a large number of susceptibility genes and changes in gene and protein expression. While these studies have provided a number of novel biomarker candidates, their clinical benefits remain to be evaluated in prospective studies, and no new "star biomarker" has been identified until now. Previous studies suggest that significant improvements in study design and analytical methodologies have to be made to identify clinically relevant biomarkers. In this review, we discuss progress, opportunities, challenges, and future directions in the development of T1D biomarkers, mainly by focusing on the genetic, transcriptomic, and proteomic aspects. PMID- 23804263 TI - Metabolomics in the studies of islet autoimmunity and type 1 diabetes. AB - The metabolome is sensitive to genetic and environmental factors contributing to complex diseases such as type 1 diabetes (T1D). Metabolomics is the study of biochemical and physiological processes involving metabolites. It is therefore one of the key platforms for the discovery and study of pathophysiological phenomena leading to T1D and the development of T1D-associated complications. Although the application of metabolomics in T1D research is still rare, metabolomic research has already advanced across the full spectrum, from disease progression to the development of diabetic complications. Metabolomic studies in T1D have contributed to an improved etiopathogenic understanding and demonstrated their potential in the clinic. For example, metabolomic data from recent T1D studies suggest that a specific metabolic profile, or metabotype, precedes islet autoimmunity and the development of overt T1D. These early metabolic changes are attributed to many biochemical pathways, thus suggesting a systemic change in metabolism which may be inborn. Based on this evidence, the role of the metabolome in the progression to T1D is therefore to facilitate specific biochemical processes associated with T1D, and to contribute to the development of a vulnerable state in which disease is more likely to be triggered. This may have important implications for the understanding of T1D pathophysiology and early disease detection and prevention. PMID- 23804261 TI - From markers to molecular mechanisms: type 1 diabetes in the post-GWAS era. AB - By the year 2000, a draft of the human genome sequence was completed. Millions of single-nucleotide polymorphisms (SNPs) had been deposited into public databases, and high throughput technologies were under development for SNP genotyping. At that time, it was predicted that large case control association studies would provide far better resolution and power than genome-wide linkage studies. Type 1 diabetes was one of the first phenotypes to be examined by genome-wide association studies (GWAS), and to date over 50 genomic regions have been associated with the disease. In general, the great majority of these loci individually contribute a relatively small degree of risk, and most loci lie outside of coding sequences. The identification of molecular mechanisms from these genomic data therefore remains a significant challenge. Here, we summarize genetic candidate, linkage, and association studies of type 1 diabetes and discuss a potential strategy to identify mechanisms of disease from genomic data. PMID- 23804264 TI - Gut microbiota and type 1 diabetes. AB - The gut immune system has a key role in the development of autoimmune diabetes, and factors that control the gut immune system are also regulators of beta-cell autoimmunity. Gut microbiota modulate the function of the gut immune system by their effect on the innate immune system, such as the intestinal epithelial cells and dendritic cells, and on the adaptive immune system, in particular intestinal T cells. Due to the immunological link between gut and pancreas, e.g. the shared lymphocyte homing receptors, the immunological changes in the gut are reflected in the pancreas. According to animal studies, changes in gut microbiota alter the development of autoimmune diabetes. This has been demonstrated by antibiotics that induce changes in the gut microbiota. Furthermore, gut-colonizing microbes may modify the incidence of autoimmune diabetes in animal models. Deficient toll like receptor (TLR) signaling, mediating microbial stimulus in immune cells, prevents autoimmune diabetes, which appears to be dependent on alterations in the intestinal microbiota. Although few studies have been conducted in humans, recent studies suggest that the abundance of Bacteroides and lack of butyrate-producing bacteria in fecal microbiota are associated with beta-cell autoimmunity and type 1 diabetes. It is possible that altered gut microbiota are associated with immunological aberrancies in type 1 diabetes. The changes in gut microbiota could lead to alterations in the gut immune system, such as increased gut permeability, small intestinal inflammation, and impaired tolerance to food antigens, all of which are observed in type 1 diabetes. Poor fitness of gut microbiota could explain why children who develop type 1 diabetes are prone to enterovirus infections, and do not develop tolerance to cow milk antigens. These candidate risk factors of type 1 diabetes may imply an increased risk of type 1 diabetes due to the presence of gut microbiota that do not support health. Despite the complex interaction of microbiota, host, environment, and disease mechanisms, gut microbiota are promising novel targets in the prevention of type 1 diabetes. PMID- 23804265 TI - Virus infections as potential targets of preventive treatments for type 1 diabetes. AB - Environmental factors play an important role in the pathogenesis of type 1 diabetes, and are attractive targets for preventive interventions. Several studies have shown that viruses can cause diabetes in animals, indicating their potential as candidates for environmental triggering agents. However, human studies have been hampered by the complex nature of the disease pathogenesis, leaving the question of viral etiology unanswered. Significant progress has recently been made in this field by searching for viruses within pancreatic tissue samples, and by carrying out prospective studies. Consequently, there is increasing evidence for a group of enteroviruses acting as possible environmental key triggers. In past studies, these viruses have been linked to type 1 diabetes. Recent studies have shown that they exert tropism to pancreatic islets, and that they are associated with the start of the beta-cell damaging process. Also, polymorphisms of the gene coding for the innate immune system sensor for enteroviruses (IFIH1) were found to modulate the risk of diabetes. Based on these findings, interest in the possible development of vaccines against these viruses has increased. However, even if enterovirus vaccines (polio vaccines) are effective and safe, we currently lack necessary information for the development of a vaccine against diabetogenic enteroviruses, e.g. regarding the identification of their specific serotypes and the causal relationship between these viruses and diabetes initiation. Ongoing research projects are currently addressing these questions, and will hopefully increase the consensus in this field. Also, new sequencing technologies will provide additional information about the whole virome, which could enable the discovery of new candidate viruses. PMID- 23804266 TI - Helminth infection and type 1 diabetes. AB - The increasing incidence of type 1 diabetes (T1D) and autoimmune diseases in industrialized countries cannot be exclusively explained by genetic factors. Human epidemiological studies and animal experimental data provide accumulating evidence for the role of environmental factors, such as infections, in the regulation of allergy and autoimmune diseases. The hygiene hypothesis has formally provided a rationale for these observations, suggesting that our co evolution with pathogens has contributed to the shaping of the present-day human immune system. Therefore, improved sanitation, together with infection control, has removed immunoregulatory mechanisms on which our immune system may depend. Helminths are multicellular organisms that have developed a wide range of strategies to manipulate the host immune system to survive and complete their reproductive cycles successfully. Immunity to helminths involves profound changes in both the innate and adaptive immune compartments, which can have a protective effect in inflammation and autoimmunity. Recently, helminth-derived antigens and molecules have been tested in vitro and in vivo to explore possible applications in the treatment of inflammatory and autoimmune diseases, including T1D. This exciting approach presents numerous challenges that will need to be addressed before it can reach safe clinical application. This review outlines basic insight into the ability of helminths to modulate the onset and progression of T1D, and frames some of the challenges that helminth-derived therapies may face in the context of clinical translation. PMID- 23804267 TI - Type 1 diabetes therapy beyond T cell targeting: monocytes, B cells, and innate lymphocytes. AB - Recent clinical trials, investigating type 1 diabetes (T1D), have focused mainly on newly diagnosed individuals who have developed diabetes. We need to continue our efforts to understand disease processes and to rationally design interventions that will be safe and specific for disease, but at the same time not induce undesirable immunosuppression. T cells are clearly involved in the pathogenesis of T1D, and have been a major focus for both antigen-specific and non-antigen-specific therapy, but thus far no single strategy has emerged as superior. As T1D is a multifactorial disease, in which multiple cell types are involved, some of these pathogenic and regulatory cell pathways may be important to consider. In this review, we examine evidence for whether monocytes, B cells, and innate lymphocytes, including natural killer cells, may be suitable targets for intervention. PMID- 23804268 TI - Targeted antigen delivery to DEC-205+ dendritic cells for tolerogenic vaccination. AB - Dendritic cells (DCs) and Foxp3-expressing CD4+ regulatory T (Treg) cells play non-redundant roles in the maintenance of peripheral tolerance to self-antigens, thereby preventing fatal autoimmunity. A common hallmark of intra- and extra thymic Treg cell lineage commitment is the induction of Foxp3 expression as a consequence of appropriate T cell receptor engagement with MHC class II:agonist ligand. It has now become increasingly clear that agonist ligand presentation by immature DCs in the steady state induces T cell tolerance by both recessive and dominant mechanisms, rather than promoting productive T helper cell responses. In this context, the ability of steady-state DCs to promote the extrathymic conversion of initially naive CD4+Foxp3- T cells into Foxp3+ Treg cells is of particular interest as it provides novel perspectives to enhance antigen-specific Treg cell function in clinical settings of unwanted immunity, such as beta-cell autoimmunity. PMID- 23804269 TI - Tolerance strategies employing antigen-coupled apoptotic cells and carboxylated PLG nanoparticles for the treatment of type 1 diabetes. AB - The development of therapies that specifically target autoreactive immune cells for the prevention and treatment of type 1 diabetes (T1D) without inducing generalized immunosuppression that often compromises the host's ability to clear non-self antigen is highly desired. This review discusses the mechanisms and potential therapeutic applications of antigen-specific T cell tolerance techniques using syngeneic apoptotic cellular carriers and synthetic nanoparticles that are covalently cross-linked to diabetogenic peptides or proteins through ethylene carbodiimide (ECDI) to prevent and treat T1D. Experimental models have demonstrated that intravenous injection of autoantigen decorated splenocytes and biodegradable nanoparticles through ECDI fixation effectively induce and maintain antigen-specific T cell abortive activation and anergy by T cell intrinsic and extrinsic mechanisms. The putative mechanisms include, but are not limited to, the uptake and processing of antigen-coupled nanoparticles or apoptotic cellular carriers for tolerogenic presentation by host splenic antigen-presenting cells, the induction of regulatory T cells, and the secretion of immune-suppressive cytokines, such as IL-10 and TGF-beta. The safety profile and efficacy of this approach in preclinical animal models of T1D, including non-obese diabetic (NOD), BDC2.5 transgenic, and humanized mice, have been extensively investigated, and will be the focus of this review. Translation of this approach to clinical trials of T1D and other T cell-mediated autoimmune diseases will also be reviewed in this chapter. PMID- 23804270 TI - Clinical potential of antigen-specific therapies in type 1 diabetes. AB - In type 1 diabetes (T1D), pancreatic beta-cells are attacked and destroyed by the immune system, which leads to a loss of endogenous insulin secretion. The desirable outcome of therapeutic intervention in autoimmune diseases is the restoration of immune tolerance to prevent organ damage. Past trials with immune suppressive drugs highlight the fact that T1D is in principle a curable condition. However, the barrier in T1D therapy in terms of drug safety is set particularly high because of the predominantly young population and the good prognosis associated with modern exogenous insulin therapy. Thus, there is a general consensus that chronic immune suppression is associated with unacceptable long-term safety risks. On the other hand, immune-modulatory biologicals have recently failed to confer significant protection in phase 3 clinical trials. However, the concept of antigen-specific tolerization may offer a unique strategy to safely induce long-term protection against T1D. In this review, we analyze the potential reasons for the failure of the different tolerization therapies, and describe how the concept of antigen-specific toleraization may overcome the obstacles associated with clinical therapy in T1D. PMID- 23804271 TI - Interleukin-1 antagonists and other cytokine blockade strategies for type 1 diabetes. AB - Proinflammatory cytokines stimulate adaptive immunity and attenuate T cell regulation and tolerance induction. They also profoundly impair beta-cell function, proliferation, and viability, activities of similar importance in the context of type 1 diabetes (T1D). Detailed knowledge of the molecular mechanisms of beta-cell toxicity has been gathered within the last 2-3 decades. However, the efficacy of individual proinflammatory cytokine blockade in animal models of T1D has been inconsistent and generally modest, except in the context of islet transplantation. This suggests that the timing of the cytokine blockade relative to anti-beta-cell immune activation is critical, and that combination therapy may be required. In randomized, placebo-controlled, clinical trials of limited power, TNF-alpha (but not IL-1) blockade has yielded moderate but significant improvements in glycemia, insulin requirement, and beta-cell function. The safety experience with anti-cytokine biologics is still very limited in T1D. However, combinations with other biologics, at doses of adaptive and innate immune inhibitors/modulators that are suboptimal or ineffective in themselves, may generate synergies of true therapeutic benefit and safety in T1D. Critical and balanced appraisal of the preclinical and clinical evidence of efficacy and safety of anti-immune, anti-inflammatory, and anti-dysmetabolic therapeutics should thus guide future studies to move closer to novel treatments, targeting the underlying causes of beta-cell failure and destruction in T1D. PMID- 23804272 TI - In vivo delivery of nucleic acid-formulated microparticles as a potential tolerogenic vaccine for type 1 diabetes. AB - Originally conceived as a method to silence transcription/translation of nascent RNA, nucleic acids aimed at downregulating gene expression have been shown to act at multiple levels. Some of the intriguing features of these gene-silencing nucleic acids include activation of molecular signals in immune cells which confer tolerogenic properties. We have discovered a method to induce stable tolerogenic ability to dendritic cells ex vivo using a mixture of phosphorothioate-modified antisense DNA targeting the primary transcripts of CD40, CD80 and CD86. Autologous human dendritic cells generated in the presence of these oligonucleotides prevent and reverse type 1 diabetes (T1D) in the non obese diabetic (NOD) strain mouse model of the human disease, and have been shown to be safe in established diabetic human patients. Even though this ex vivo approach is clinically feasible, we have gone beyond a cell therapy approach to develop a "population-targeting" microsphere formulation of the three antisense oligonucleotides. Effectively, such a product could constitute an "off-the-shelf" vaccine. In this paper, we describe the progress made in developing this approach, as well as providing some insight into potential molecular mechanisms of action. PMID- 23804273 TI - Immune-directed therapy for type 1 diabetes at the clinical level: the Immune Tolerance Network (ITN) experience. AB - Reestablishing immune tolerance in type 1 diabetes (T1D), a chronic autoimmune disease, is a major goal. The Immune Tolerance Network (ITN) has initiated eight clinical trials of immunomodulatory therapies in recent-onset T1D over the past decade. Results have been mixed in terms of clinical efficacy, but the studies have provided valuable mechanistic insight that are enhancing our understanding of the disease and guiding the design of future trials. Trials of non-Fc-binding anti-CD3 mAbs have revealed that modulation of this target leads to partial responses, and ITN's AbATE trial led to identification of a robust responder group that could be distinguished from non-responders by baseline metabolic and immunologic features. A pilot study of the combination of IL-2 and rapamycin gave the first demonstration that frequency and function of regulatory T cells (Tregs) can be enhanced in T1D subjects, although the therapy triggered the activation of effectors with transient beta-cell dysfunction. Similarly, therapy with anti thymocyte globulin led to substantial lymphocyte depletion, but also to the activation of the acute-phase response with no clinical benefit during preliminary analyses. These and other results provide mechanistic tools that can be used as biomarkers for safety and efficacy in future trials. Furthermore, our results, together with those of other organizations, notably TrialNet, delineate the roles of the major components of the immune response in T1D. This information is setting the stage for future combination therapy trials. The development of disease-relevant biomarkers will also enable the implementation of innovative trial designs, notably adaptive trials, which will increase efficiencies in terms of study duration and sample size, and which will expedite the conduct of trials in which there are uncertainties about dose response and effect size. PMID- 23804274 TI - CD3 monoclonal antibodies: a first step towards operational immune tolerance in the clinic. AB - Type 1 diabetes (T1D) is a prototypic organ-specific autoimmune disease resulting from the selective destruction of insulin-secreting beta-cells within the pancreatic islets of Langerhans. It is caused by an immune-mediated inflammation, involving autoreactive CD4+ and CD8+ T lymphocytes that infiltrate the islets and initiate insulitis. The use of exogenous insulin is the current standard treatment. However, in spite of significant advances, this therapy is still associated with major constraints, including risk of hypoglycemia and severe degenerative complications. As T1D mainly affects children and young adults, any candidate immune therapy must be safe, and it must avoid a sustained depression of immune responses with all its attendant problems of recurrent infection and drug toxicity. In this context, inducing or restoring immune tolerance to target autoantigens would be the ideal approach. We refer to immune tolerance here as the selective damping of the damaging autoimmune response following a short treatment, while keeping intact the capacity of the host to respond normally to exogenous antigens. The therapeutic approach we discuss in this article originates from attempts to induce tolerance both to soluble antigens and tissue antigens (i.e. alloantigens and autoantigens) by using biological agents that selectively interfere with lymphocyte activation, namely polyclonal and monoclonal anti-T cell antibodies. The challenged dogma was that, in an adult primed immune system, it was not possible to restore self-tolerance therapeutically without the use of exogenous autoantigen administration. The reality has been that, in diabetes, endogenous host autoantigen can fulfill this role because a significant amount of functioning beta-cells remains, even at the time of established hyperglycemia. Experimental results obtained in the 1990s showed that a short-term CD3 antibody treatment in recently diagnosed diabetic non-obese diabetic (NOD) mice induced permanent remission of the disease by restoring self-tolerance. Based on these findings, phase I, II, and III trials were conducted using two distinct humanized Fc-mutated antibodies to human CD3, namely ChAglyCD3 (otelixizumab) and OKT3gamma1 Ala-Ala (teplizumab). Overall, when dosing was adequate, the results demonstrated that CD3 antibodies preserved beta-cell function very efficiently, maintaining significantly high levels of endogenous insulin secretion in treated patients for up to 24 months after treatment. These data provided the first proof of concept for a long-term therapeutic effect in T1D following a short course administration of a therapeutic agent. Our aim is to review these data and to discuss them in the context of the pitfalls linked to pharmaceutical development, especially in the context of pediatric patients, as in autoimmune diabetes. PMID- 23804277 TI - Night-shift work and breast cancer--a systematic review and meta-analysis. AB - OBJECTIVE: The aim of this review was to synthesize the evidence on the potential relationship between nightshift work and breast cancer. METHODS: We searched multiple databases for studies comparing women in shift work to those with no shift work reporting incidence of breast cancer. We calculated incremental risk ratios (RR) per five years of night-shift work and per 300 night shift increases in exposure and combined these in a random effects dose-response meta-analysis. We assessed study quality in ten domains of bias. RESULTS: We identified 16 studies: 12 case-control and 4 cohort studies. There was a 9% risk increase per five years of night-shift work exposure in case-control studies [RR 1.09, 95% confidence interval (95% CI) 1.02-1.20; I (2) = 37%, 9 studies], but not in cohort studies (RR 1.01, 95% CI 0.97-1.05; I (2) = 53%, 3 studies). Heterogeneity was significant overall (I (2) = 55%, 12 studies). Results for 300 night shifts were similar (RR 1.04, 95% CI 1.00-1.10; I (2) = 58%, 8 studies). Sensitivity analysis using exposure transformations such as cubic splines, a fixed-effect model, or including only better quality studies did not change the results. None of the 16 studies had a low risk of bias, and 6 studies had a moderate risk. CONCLUSIONS: Based on the low quality of exposure data and the difference in effect by study design, our findings indicate insufficient evidence for a link between night-shift work and breast cancer. Objective prospective exposure measurement is needed in future studies. PMID- 23804276 TI - Islet neogenesis: a possible pathway for beta-cell replenishment. AB - Diabetes, particularly type 1 diabetes, results from the lack of pancreatic beta cells. beta-cell replenishment can functionally reverse diabetes, but two critical challenges face the field: 1. protection of the new beta-cells from autoimmunity and allorejection, and 2. development of beta-cells that are readily available and reliably functional. This chapter will examine the potential of endogenous replenishment of pancreatic beta-cells as a possible therapeutic tool if autoimmunity could be blunted. Two pathways for endogenous replenishment exist in the pancreas: replication and neogenesis, defined as the formation of new islet cells from pancreatic progenitor/stem cells. These pathways of beta-cell expansion are not mutually exclusive and both occur in embryonic development, in postnatal growth, and in response to some injuries. Since the beta-cell population is dramatically reduced in the pancreas of type 1 diabetes patients, with only a small fraction of the beta-cells surviving years after onset, replication of preexisting beta-cells would not be a reasonable start for replenishment. However, induction of neogenesis could provide a starting population that could be further expanded by replication. It is widely accepted that neogenesis occurs in the initial embryonic formation of the endocrine pancreas, but its occurrence anytime after birth has become controversial because of discordant data from lineage tracing experiments. However, the concept was built upon many observations from different models and species over many years. Herein, we discuss the role of neogenesis in normal growth and regeneration, as learned from rodent models, followed by an analysis of what has been found in humans. PMID- 23804275 TI - Islet transplantation in type 1 diabetes: ongoing challenges, refined procedures, and long-term outcome. AB - Remarkable progress has been made in islet transplantation over a span of 40 years. Once just an experimental curiosity in mice, this therapy has moved forward, and can now provide robust therapy for highly selected patients with type 1 diabetes (T1D), refractory to stabilization by other means. This progress could not have occurred without extensive dynamic international collaboration. Currently, 1,085 patients have undergone islet transplantation at 40 international sites since the Edmonton Protocol was reported in 2000 (752 allografts, 333 autografts), according to the Collaborative Islet Transplant Registry. The long-term results of islet transplantation in selected centers now match registry data of pancreas-alone transplantation, with 6 sites reporting five-year insulin independence rates >=50%. Islet transplantation has been criticized for the use of multiple donor pancreas organs, but progress has also occurred in single-donor success, with 10 sites reporting increased single-donor engraftment. The next wave of innovative clinical trial interventions will address instant blood-mediated inflammatory reaction (IBMIR), apoptosis, and inflammation, and will translate into further marked improvements in single-donor success. Effective control of auto- and alloimmunity is the key to long-term islet function, and high-resolution cellular and antibody-based assays will add considerable precision to this process. Advances in immunosuppression, with new antibody-based targeting of costimulatory blockade and other T-B cellular signaling, will have further profound impact on the safety record of immunotherapy. Clinical trials will move forward shortly to test out new human stem cell derived islets, and in parallel trials will move forward, testing pig islets for compatibility in patients. Induction of immunological tolerance to self-islet antigens and to allografts is a difficult challenge, but potentially within our grasp. PMID- 23804278 TI - Oral clopidogrel improves cutaneous microvascular function through EDHF-dependent mechanisms in middle-aged humans. AB - Platelet P2Y12-ADP and COX-1 receptor inhibition with oral clopidogrel (CLO) and low-dose aspirin (ASA), respectively, attenuates reflex-mediated cutaneous vasodilation, but little is known about how these medications affect local vasodilatory signaling. Reactive hyperemia (RH) results in vasodilation that is mediated by sensory nerves and endothelium-derived hyperpolarization factors (EDHF) through large-conductance calcium-activated potassium channels, whereas slow local heating (LH) elicits vasodilation largely through the production of nitric oxide (NO). We hypothesized that CLO and ASA would attenuate locally mediated cutaneous vasodilation assessed by RH and LH (0.5 degrees C/min). In a randomized, cross-over, double-blind placebo-controlled study, nine healthy men and women (56 +/- 1 yr) took CLO (75 mg), ASA (81 mg), and placebo for 7 days. Skin blood flow was measured (laser-Doppler flowmetry, LDF) and cutaneous vascular conductance (CVC) was calculated (LDF/mean arterial pressure) and normalized to maximal CVC (%CVCmax: 43 degrees C and 28 mM sodium nitroprusside). RH response parameters, including area under the curve (AUC), total hyperemic response (THR), and the decay constant tau (lambda) were calculated. NO-dependent vasodilation during LH was assessed by calculating the difference in %CVCmax between a control site and an NO synthase-inhibited site (10 mM l-NAME: intradermal microdialysis). CLO augmented the AUC and THR (AUCclo = 3,783 +/- 342; THRclo = 2,306 +/- 266% CVCmax/s) of the RH response compared with ASA (AUCASA = 3,101 +/- 325; THRASA = 1,695 +/- 197% CVCmax/s) and placebo (AUCPlacebo = 3,000 +/- 283; THRPlacebo = 1,675 +/- 170% CVCmax/s; all P < 0.0001 vs. CLO). There was no difference in the LH response or calculated NO-dependent vasodilation among treatments (all P > 0.05). Oral CLO treatment augments vasodilation during RH but not LH, suggesting that CLO may improve cutaneous microvascular function. PMID- 23804280 TI - Thiosulfate: a readily accessible source of hydrogen sulfide in oxygen sensing. AB - H2S derived from organic thiol metabolism has been proposed serve as an oxygen sensor in a variety of systems because of its susceptibility to oxidation and its ability to mimic hypoxic responses in numerous oxygen-sensing tissues. Thiosulfate, an intermediate in oxidative H2S metabolism can alternatively be reduced and regenerate H2S. We propose that this contributes to the H2S-mediated oxygen-sensing mechanism. H2S formation from thiosulfate in buffers and in a variety of mammalian tissues and in lamprey dorsal aorta was examined in real time using a polarographic H2S sensor. Inferences of intracellular H2S production were made by examining hypoxic pulmonary vasoconstriction (HPV) in bovine pulmonary arteries under conditions in which increased H2S production would be expected and in mouse and rat aortas, where reducing conditions should mediate vasorelaxation. In Krebs-Henseleit (mammalian) and Cortland (lamprey) buffers, H2S was generated from thiosulfate in the presence of the exogenous reducing agent, DTT, or the endogenous reductant dihydrolipoic acid (DHLA). Both the magnitude and rate of H2S production were greatly increased by these reductants in the presence of tissue, with the most notable effects occurring in the liver. H2S production was only observed when tissues were hypoxic; exposure to room air, or injecting oxygen inhibited H2S production and resulted in net H2S consumption. Both DTT and DHLA augmented HPV, and DHLA dose-dependently relaxed precontracted mouse and rat aortas. These results indicate that thiosulfate can contribute to H2S signaling under hypoxic conditions and that this is not only a ready source of H2S production but also serves as a means of recycling sulfur and thereby conserving biologically relevant thiols. PMID- 23804279 TI - Anti-ghrelin Spiegelmer inhibits exogenous ghrelin-induced increases in food intake, hoarding, and neural activation, but not food deprivation-induced increases. AB - Circulating concentrations of the stomach-derived "hunger-peptide" ghrelin increase in direct proportion to the time since the last meal. Exogenous ghrelin also increases food intake in rodents and humans, suggesting ghrelin may increase post-fast ingestive behaviors. Food intake after food deprivation is increased by laboratory rats and mice, but not by humans (despite dogma to the contrary) or by Siberian hamsters; instead, humans and Siberian hamsters increase food hoarding, suggesting the latter as a model of fasting-induced changes in human ingestive behavior. Exogenous ghrelin markedly increases food hoarding by ad libitum-fed Siberian hamsters similarly to that after food deprivation, indicating sufficiency. Here, we tested the necessity of ghrelin to increase food foraging, food hoarding, and food intake, and neural activation [c-Fos immunoreactivity (c Fos-ir)] using anti-ghrelin Spiegelmer NOX-B11-2 (SPM), an l-oligonucleotide that specifically binds active ghrelin, inhibiting peptide-receptor interaction. SPM blocked exogenous ghrelin-induced increases in food hoarding the first 2 days after injection, and foraging and food intake at 1-2 h and 2-4 h, respectively, and inhibited hypothalamic c-Fos-ir. SPM given every 24 h across 48-h food deprivation inconsistently inhibited food hoarding after refeeding and c-Fos-ir, similarly to inabilities to do so in laboratory rats and mice. These results suggest that ghrelin may not be necessary for food deprivation-induced foraging and hoarding and neural activation. A possible compensatory response, however, may underlie these findings because SPM treatment led to marked increases in circulating ghrelin concentrations. Collectively, these results show that SPM can block exogenous ghrelin-induced ingestive behaviors, but the necessity of ghrelin for food deprivation-induced ingestive behaviors remains unclear. PMID- 23804281 TI - Both cell-autonomous mechanisms and hormones contribute to sexual development in vertebrates and insects. AB - The differentiation of male and female characteristics in vertebrates and insects has long been thought to proceed via different mechanisms. Traditionally, vertebrate sexual development was thought to occur in two phases: a primary and a secondary phase, the primary phase involving the differentiation of the gonads, and the secondary phase involving the differentiation of other sexual traits via the influence of sex hormones secreted by the gonads. In contrast, insect sexual development was thought to depend exclusively on cell-autonomous expression of sex-specific genes. Recently, however, new evidence indicates that both vertebrates and insects rely on sex hormones as well as cell-autonomous mechanisms to develop sexual traits. Collectively, these new data challenge the traditional vertebrate definitions of primary and secondary sexual development, call for a redefinition of these terms, and indicate the need for research aimed at explaining the relative dependence on cell-autonomous versus hormonally guided sexual development in animals. PMID- 23804282 TI - Impact of kanamycin on melanogenesis and antioxidant enzymes activity in melanocytes--an in vitro study. AB - Aminoglycosides, broad spectrum aminoglycoside antibiotics, are used in various infections therapy due to their good antimicrobial characteristics. However, their adverse effects such as nephrotoxicity and auditory ototoxicity, as well as some toxic effects directed to pigmented tissues, complicate the use of these agents. This study was undertaken to investigate the effect of aminoglycoside antibiotic-kanamycin on viability, melanogenesis and antioxidant enzymes activity in cultured human normal melanocytes (HEMa-LP). It has been demonstrated that kanamycin induces concentration-dependent loss in melanocytes viability. The value of EC50 was found to be ~6.0 mM. Kanamycin suppressed melanin biosynthesis: antibiotic was shown to inhibit cellular tyrosinase activity and to reduce melanin content in normal human melanocytes. Significant changes in the cellular antioxidant enzymes: SOD, CAT and GPx were stated in melanocytes exposed to kanamycin. Moreover, it was observed that kanamycin caused depletion of antioxidant defense sytem. It is concluded that the inhibitory effect of kanamycin on melanogenesis and not sufficient antioxidant defense mechanism in melanocytes in vitro may explain the potential mechanisms of undesirable side effects of this drug directed to pigmented tissues in vivo. PMID- 23804283 TI - Legacy, legitimacy, and possibility: an exploration of community health worker experience across the generations in Khayelitsha, South Africa. AB - In South Africa, the response to HIV and TB epidemics is complex, varied, and contextually defined. "Task-shifting" and a movement toward a decentralized model of care have led to an increased reliance on community health workers (CHWs) providing health care services to residents of impoverished, peri-urban areas. Public health policy tends to present CHWs as a homogeneous group, with little attention paid to the nuances of experience, motivation, and understanding, which distinguish these care workers from one another and from other kinds of health workers. An exploration of the layered meanings of providing community health care services under financially, politically, and socially difficult conditions reveals clear distinctions of experience across the generations. Many older CHWs say that ubuntu, a notion of shared African humanity, is being "killed off" by the younger generation, whereas younger CHWs often describe older women as being "jealous" of the opportunities that this younger generation has for education, training, and employment. The structure of the South African health system, past and present responses to disease epidemics, and the legacy of apartheid's structural violence have amplified these generational differences among CHWs. Using ethnographic data collected from approximately 20 CHWS in a peri-urban settlement in Cape Town, South Africa, I explore how CHWs experience and understand legitimacy in the moral economy of care. A call for closer attention to the experiences of CHWs is critical when designing public health policies for the delivery of health care services in impoverished communities in South Africa. PMID- 23804284 TI - Diaminodiacid-based solid-phase synthesis of peptide disulfide bond mimics. PMID- 23804285 TI - Musculoskeletal physical outcome measures in individuals with tension-type headache: a scoping review. AB - INTRODUCTION: Individuals with tension-type headache (TTH), in addition to headache pain, typically suffer from pericranial muscle tenderness and increased cervical muscle tone. Physical and physiological outcomes related to musculoskeletal function, however, are not commonly assessed in clinical studies and not systematically proposed as outcome measures in headache-related practice guidelines. OBJECTIVES: To review which musculoskeletal outcomes are used in the clinical assessment of patients with TTH and which are associated with headache pain and related dysfunction. METHODS: Literature searches were performed in MEDLINE, PubMed, the Cochrane databases and EMBASE using terms relating to musculoskeletal physical outcomes in TTH. RESULTS: Twenty-six studies met selection criteria. Physiological outcomes typically reported in laboratory studies were trigger points, pressure pain threshold, range of motion and tenderness. A greater number of trigger points and lower pressure pain threshold were reported in patients with episodic TTH in comparison with healthy subjects. Individuals with chronic TTH, when compared with non-headache controls, consistently showed a greater number of trigger points, a lower value of pressure pain threshold and a more severe forward head posture. CONCLUSION: Musculoskeletal outcomes, such as trigger points, pressure pain threshold and forward head posture should inform TTH pathophysiology, diagnosis and interdisciplinary patient care. PMID- 23804286 TI - Bullous pemphigoid as pruritus in the elderly: a common presentation. AB - IMPORTANCE: In the literature, patients with bullous pemphigoid have been reported to have itch without blisters. Clinical observations in these patients have varied from eczematous or urticarial to papular or nodular skin lesions. Here we investigated the spectrum of clinical variants. OBSERVATIONS: Fifteen patients with itch without blisters had immunopathologic findings of bullous pemphigoid. Mean age at diagnosis was 81.7 years. No blistering occurred during the mean 2.2 years of follow-up. Mean delay of diagnosis was 2.8 years. Clinical symptoms were heterogeneous: pruritus sine materia (no primary skin lesions), eczematous, urticarial, papular, and/or nodular skin lesions were seen. Treatment with potent topical corticosteroids or methotrexate sodium led to remission in 11 patients. CONCLUSIONS AND RELEVANCE: Itch without skin lesions can be the only symptom of bullous pemphigoid. Therefore, it is important to include serologic and direct immunofluorescence in the diagnostic algorithm of itch. We propose the unifying term pruritic nonbullous pemphigoid for all patients with immunopathologic findings of bullous pemphigoid, itch, and no blisters. PMID- 23804287 TI - Clinical factors associated with weight loss outcomes after Roux-en-Y gastric bypass surgery. AB - OBJECTIVE: Gastric bypass surgery is an effective therapy for extreme obesity. However, substantial variability in weight loss outcomes exists that remains largely unexplained. Our objective was to determine whether any commonly collected preoperative clinical variables were associated with weight loss following Roux-en-Y gastric bypass (RYGB) surgery. METHODS: The analysis was based on a prospectively recruited observational cohort of 2,365 patients who underwent Roux-en-Y gastric bypass surgery from 2004 to 2009. Weight loss was stratified into three major phases, early (0-6 months), nadir, and long-term (>36 months). Multivariate regression models were constructed using a database of over 350 variables. RESULTS: A total of 12-14 preoperative variables were independently associated (P < 0.05) with each of the temporal weight loss phases. Preoperative variables associated with poorer nadir and long-term weight loss included higher baseline BMI, higher preoperative weight loss, iron deficiency, use of any diabetes medication, nonuse of bupropion medication, no history of smoking, age >50 years, and the presence of fibrosis on liver biopsy. CONCLUSIONS: Several variables previously associated with poorer weight loss after RYGB surgery including age, baseline BMI, and type 2 diabetes were replicated. Several others suggest possible clinical interventions for postoperative management of RYGB patients to improve weight loss outcomes. PMID- 23804288 TI - Unusual case of Cowden-like syndrome, neck paraganglioma, and pituitary adenoma. AB - BACKGROUND: Pituitary tumors, paragangliomas, and Cowden syndrome do not usually occur together. METHODS: The synchronous presentation of papillary thyroid carcinoma and neck paraganglioma was revealed in a 43-year-old woman who had been diagnosed with a microprolactinoma one decade before and now presented with a constellation of characteristics that are components of Cowden syndrome, specifically macrocephaly, multiple skin papules, fibrocystic mammary disease, and uterine leiomyofibroma. RESULTS: Germline mutation analysis of phosphatase and tensin homolog (PTEN), succinate dehydrogenase subunit B (SDHB), succinate dehydrogenase subunit C (SDHC), and succinate dehydrogenase subunit D (SDHD) was performed with revelation of 3 polymorphic sites in introns 1, 4, and 8 of the PTEN gene and 1 polymorphic site in exon 1 of the SDHB gene, but absence of known pathogenic mutations. CONCLUSION: The coexistence of Cowden-like syndrome, neck paraganglioma, and pituitary adenoma is described for the first time, and could represent a novel genetic syndrome with an as yet unidentified common genetic basis. PMID- 23804289 TI - Probing the key interactions between human Atg5 and Atg16 proteins: a prospective application of molecular modeling. PMID- 23804290 TI - The state of overuse measurement: a critical review. AB - Health care overuse contributes to unnecessary expenditures and patient exposure to harm. Understanding and addressing this problem requires a comprehensive set of valid metrics. This article describes and critiques the current state of overuse measurement through a review of the published and gray literature, measures clearinghouses and ongoing work by major measure developers. Our review identified 37 fully specified measures and 123 measurement development opportunities. Many services were considered overuse due to the extension of diagnostic or screening services to low-risk populations. There were more diagnostic or therapeutic overuse measures than for screening or monitoring/surveillance. Imaging services is a major focus of current measures, but opportunities exist to expand overuse measurement in medication, laboratory services. Future development of overuse measures would benefit from new empirical research and clinical guidelines focused on identifying indications or populations for which there is likely to be no or low benefit. PMID- 23804291 TI - Shape-controlled synthesis of surface-clean ultrathin palladium nanosheets by simply mixing a dinuclear Pd(I) carbonyl chloride complex with H2O. PMID- 23804292 TI - Coping with the cold: predictors of survival in wild Barbary macaques, Macaca sylvanus. AB - We report the death of 30 wild Barbary macaques, living in two groups, during an exceptionally cold and snowy winter in the Middle Atlas Mountains, Morocco. We examined whether an individual's time spent feeding, the quality and number of its social relationships, sex and rank predicted whether it survived the winter or not. The time an individual spent feeding and the number of social relationships that an individual had in the group were positive and significant predictors of survival. This is the first study to show that the degree of sociality affects an individual's chance of survival following extreme environmental conditions. Our findings support the view that sociality is directly related to an individual's fitness, and that factors promoting the establishment and maintenance of social relationships are favoured by natural selection. PMID- 23804293 TI - Assessing the exposure risk and impacts of pharmaceuticals in the environment on individuals and ecosystems. AB - The use of human and veterinary pharmaceuticals is increasing. Over the past decade, there has been a proliferation of research into potential environmental impacts of pharmaceuticals in the environment. A Royal Society-supported seminar brought together experts from diverse scientific fields to discuss the risks posed by pharmaceuticals to wildlife. Recent analytical advances have revealed that pharmaceuticals are entering habitats via water, sewage, manure and animal carcases, and dispersing through food chains. Pharmaceuticals are designed to alter physiology at low doses and so can be particularly potent contaminants. The near extinction of Asian vultures following exposure to diclofenac is the key example where exposure to a pharmaceutical caused a population-level impact on non-target wildlife. However, more subtle changes to behaviour and physiology are rarely studied and poorly understood. Grand challenges for the future include developing more realistic exposure assessments for wildlife, assessing the impacts of mixtures of pharmaceuticals in combination with other environmental stressors and estimating the risks from pharmaceutical manufacturing and usage in developing countries. We concluded that an integration of diverse approaches is required to predict 'unexpected' risks; specifically, ecologically relevant, often long-term and non-lethal, consequences of pharmaceuticals in the environment for wildlife and ecosystems. PMID- 23804294 TI - Should the chancellor of the exchequer lift the ringfence on England's health budget? PMID- 23804295 TI - Comparative physiology and hyperuricemia as a causal factor for hypertension. PMID- 23804296 TI - beta-catenin at the centrosome: discrete pools of beta-catenin communicate during mitosis and may co-ordinate centrosome functions and cell cycle progression. AB - Beta-catenin is a multifunctional protein with critical roles in cell-cell adhesion, Wnt-signaling and the centrosome cycle. Whereas the roles of beta catenin in cell-cell adhesion and Wnt-signaling have been studied extensively, the mechanism(s) involving beta-catenin in centrosome functions are poorly understood. beta-Catenin localizes to centrosomes and promotes mitotic progression. NIMA-related protein kinase 2 (Nek2), which stimulates centrosome separation, binds to and phosphorylates beta-catenin. beta-Catenin interacting proteins involved in Wnt signaling such as adenomatous polyposis coli, Axin, and GSK3beta, are also localized at centrosomes and play roles in promoting mitotic progression. Additionally, proteins associated with cell-cell adhesion sites, such as dynein, regulate mitotic spindle positioning. These roles of proteins at the cell cortex and Wnt signaling that involve beta-catenin indicate a cross-talk between different sub-cellular sites in the cell at mitosis, and that different pools of beta-catenin may co-ordinate centrosome functions and cell cycle progression. PMID- 23804297 TI - Sleep duration and ischemic heart disease and all-cause mortality: prospective cohort study on effects of tranquilizers/hypnotics and perceived stress. AB - OBJECTIVES: This prospective study aimed to examine if sleep duration is a risk indicator for ischemic heart disease (IHD) and all-cause mortality, and how perceived stress during work and leisure time and use of tranquilizers/hypnotics modifies the association. METHOD: A 30-year follow-up study was carried out in the Copenhagen Male Study comprising 5249 men (40-59 years old). Confounders included lifestyle factors (smoking, alcohol, and leisure-time physical activity), clinical and health-related factors (body mass index, blood pressure, diabetes, hypertension, and physical fitness) and social class. Men with a history of cardiovascular disease at baseline were excluded. RESULTS: During follow-up, 587 men (11.9%) died from IHD and 2663 (53.9%) due to all-cause mortality. There were 276 short (<6 hours), 3837 medium (6-7 hours), and 828 long (>=8 hours) sleepers. Men who slept <6 hours had an increased risk of IHD mortality but not all-cause mortality, when referencing medium sleepers. Perceived psychological pressure during work and leisure was not a significant effect modifier for the association between sleep duration and IHD mortality. In contrast, among men using tranquilizers/hypnotics (rarely or regularly), short sleepers had a two-to-three fold increased risk of IHD mortality compared to medium sleepers. Among those never using tranquilizers/hypnotics, no association was observed between sleep duration and IHD mortality. CONCLUSION: Short sleep duration is a risk factor for IHD mortality among middle-aged and elderly men, particularly those using tranquilizers/hypnotics on a regular or even a rare basis, but not among men not using tranquilizers/hypnotics. PMID- 23804298 TI - Limb arteriovenous malformation identified after radiofrequency ablation for selective termination in twin-to-twin transfusion syndrome. PMID- 23804299 TI - Safety of snake antivenom immunoglobulins: efficacy of viral inactivation in a complete downstream process. AB - Viral safety remains a challenge when processing a plasma-derived product. A variety of pathogens might be present in the starting material, which requires a downstream process capable of broad viral reduction. In this article, we used a wide panel of viruses to assess viral removal/inactivation of our downstream process for Snake Antivenom Immunoglobulin (SAI). First, we screened and excluded equine plasma that cross-reacted with any model virus, a procedure not published before for antivenoms. In addition, we evaluated for the first time the virucidal capacity of phenol applied to SAI products. Among the steps analyzed in the process, phenol addition was the most effective one, followed by heat, caprylic acid, and pepsin. All viruses were fully inactivated only by phenol treatment; heat, the second most effective step, did not inactivate the rotavirus and the adenovirus used. We therefore present a SAI downstream method that is cost effective and eliminates viruses to the extent required by WHO for a safe product. PMID- 23804300 TI - Conceiving modernity: discourses on reproduction in a community of Tibetan refugees. AB - This article examines the trope of reproduction in narratives of Tibetan refugees living in Dharamsala, India. As they make sense of their personal histories, Tibetan refugees invoke a collective story that mirrors human rights literature on Tibet. Women come into contact with this literature through its incorporation into a political discourse expressed by the exile government and health institutions. The article traces facets of this discourse that deal centrally with reproduction. Political discourse on reproduction articulates pronatalism as a solution to the refugee community's concern with survival, and the discourse frames modernity as a site of violence through China's reproductive regulations. And yet, Tibetan refugees also employ the notion of modernity when discussing their own free reproductive decision-making, positioning modern reproductive interventions in opposition to Indian society. The article demonstrates that Tibetan refugees navigate competing figurations of modernity by expressing political resistance and affiliation through the idiom of reproduction. PMID- 23804301 TI - Transglutaminase-2 mediates calcium-regulated crosslinking of the Y-box 1 (YB-1) translation-regulatory protein in TGFbeta1-activated myofibroblasts. AB - Myofibroblast differentiation is required for wound healing and accompanied by activation of smooth muscle alpha-actin (SMalphaA) gene expression. The stress response protein, Y-box binding protein-1 (YB-1) binds SMalphaA mRNA and regulates its translational activity. Activation of SMalphaA gene expression in human pulmonary myofibroblasts by TGFbeta1 was associated with formation of denaturation-resistant YB-1 oligomers with selective affinity for a known translation-silencer sequence in SMalphaA mRNA. We have determined that YB-1 is a substrate for the protein-crosslinking enzyme transglutaminase 2 (TG2) that catalyzes calcium-dependent formation of covalent gamma-glutamyl-isopeptide linkages in response to reactive oxygen signaling. TG2 transamidation reactions using intact cells, cell lysates, and recombinant YB-1 revealed covalent crosslinking of the 50 kDa YB-1 polypeptide into protein oligomers that were distributed during SDS-PAGE over a 75-250 kDa size range. In vitro YB-1 transamidation required nanomolar levels of calcium and was enhanced by the presence of SMalphaA mRNA. In human pulmonary fibroblasts, YB-1 crosslinking was inhibited by (a) anti-oxidant cystamine, (b) the reactive-oxygen antagonist, diphenyleneiodonium, (c) competitive inhibition of TG2 transamidation using the aminyl-surrogate substrate, monodansylcadaverine, and (d) transfection with small interfering RNA specific for human TG2 mRNA. YB-1 crosslinking was partially reversible as a function of oligomer-substrate availability and TG2 enzyme concentration. Intracellular calcium accumulation and peroxidative stress in injury-activated myofibroblasts may govern SMalphaA mRNA translational activity during wound healing via TG2-mediated crosslinking of the YB-1 mRNA-binding protein. PMID- 23804302 TI - Carbon ion beams induce hepatoma cell death by NADPH oxidase-mediated mitochondrial damage. AB - Mitochondria are a major source of reactive oxygen species (ROS) and are also the target of cellular ROS. ROS damage to mitochondria leads to dysfunction that further enhances the production of mitochondrial ROS. This feed-forward vicious cycle between mitochondria and ROS induces cell death. Within a few minutes of radiation exposure, NADPH oxidase is activated to elevate the ROS level. Activated NADPH oxidase might induce the feed-forward cycle of mitochondria and this is a possible mechanism for cancer cell death induced by heavy ion irradiation. We found that after 4 Gy of (12) C(6+) ion radiation of HepG2 cells, the NADPH oxidase membrane subunit gp91(phox) was not involved in enzyme activation through increased expression; however, the subunit p47(phox) was involved in activation by being translocated to the membrane. (12) C(6+) ion radiation clearly decreased the DeltaPsim of HepG2 cells, increasing mitochondrial DNA damage and inducing cell death. Pretreatment with apocynin (APO, an NADPH oxidase inhibitor) effectively prevented the DeltaPsim decrease, mitochondrial DNA damage, and cell death induced by radiation. However, these protective effects were not observed with APO treatment after irradiation exposure. These data demonstrated that NADPH oxidase activation was an initiator in mitochondrial damage. Once mitochondria entered the feed-forward cycle, cell fate was no longer controlled by NADPH oxidase. Only antioxidants that targeted mitochondria such as MitoQ could break the cycle and release cells from death. PMID- 23804303 TI - Cross-sectional associations of objectively measured physical activity, cardiorespiratory fitness and anthropometry in European adults. AB - OBJECTIVE: To quantify the independent associations between objectively measured physical activity (PA), cardiorespiratory fitness (CRF), and anthropometry in European men and women. METHODS: 2,056 volunteers from 12 centers across Europe were fitted with a heart rate and movement sensor at 2 visits 4 months apart for a total of 8 days. CRF (ml/kg/min) was estimated from an 8 minute ramped step test. A cross-sectional analysis of the independent associations between objectively measured PA (m/s(2)/d), moderate and vigorous physical activity (MVPA) (%time/d), sedentary time (%time/d), CRF, and anthropometry using sex stratified multiple linear regression was performed. RESULTS: In mutually adjusted models, CRF, PA, and MVPA were inversely associated with all anthropometric markers in women. In men, CRF, PA, and MVPA were inversely associated with BMI, whereas only CRF was significantly associated with the other anthropometric markers. Sedentary time was positively associated with all anthropometric markers, however, after adjustment for CRF significant in women only. CONCLUSION: CRF, PA, MVPA, and sedentary time are differently associated with anthropometric markers in men and women. CRF appears to attenuate associations between PA, MVPA, and sedentary time. These observations may have implications for prevention of obesity. PMID- 23804304 TI - Achievement of public health recommendations for physical activity and prevention of gains in adiposity in adults. AB - Physical activity (PA) is considered a cornerstone in weight control and public health guidelines recommend regular participation to prevent gains in adiposity. It may therefore come as a surprise that the cumulative evidence from observational studies to support this is not strong. A weakness of many published observational studies on this topic has been a reliance on a single baseline assessment of PA. Using only the baseline information on PA in a prospective study cause misclassification because of participants often change activity level during follow-up. In turn this causes regression dilution bias and decreases the precision of the estimate of an association between PA and adiposity. Furthermore, because gains in adiposity often are caused by a small average daily energy imbalance over many years, following individuals for longer periods of time is essential to characterize a relationship. PMID- 23804305 TI - Pyrimido[4,5-d]pyrimidin-4(1H)-one derivatives as selective inhibitors of EGFR threonine790 to methionine790 (T790M) mutants. PMID- 23804306 TI - Safe direct synthesis of high purity H2O2 through a H2/O2 plasma reaction. PMID- 23804307 TI - Abstracts of the 2013 International Headache Congress, 27-30 June 2013, Boston, MA, USA. PMID- 23804309 TI - Protein Science "Best Paper" awards to Youngil Chang and Liam Longo. PMID- 23804308 TI - Psychosocial functioning and vascular endothelial growth factor in patients with head and neck cancer. AB - BACKGROUND: Psychosocial functioning is associated with vascular endothelial growth factor (VEGF) in various patient populations. This study examined whether psychosocial functioning in patients with head and neck squamous cell carcinoma (HNSCC) is associated with tumor VEGF expression, a protein that stimulates angiogenesis and is associated with poor prognosis. METHODS: Forty-two newly diagnosed patients completed assessments of psychosocial functioning (ie, depressive symptoms, perceived stress, anxiety, social support) before surgery. Tumor samples were obtained for VEGF analysis and human papillomavirus (HPV) typing. RESULTS: Poorer psychosocial functioning was associated with greater VEGF expression controlling for disease stage (odds ratio [OR], 4.55; 95% confidence interval [CI], 1.72-12.0; p < .01). When examined by HPV status, the association between psychosocial functioning and VEGF remained significant among patients who were HPV negative (OR, 5.50; 95% CI, 1.68-17.3; p < .01), but not among patients who were HPV positive. CONCLUSION: These findings inform our understanding of the biobehavioral pathways that may contribute to poor outcomes in non-HPV-associated HNSCCs. PMID- 23804311 TI - Chronic exposure to arsenic, estrogen, and their combination causes increased growth and transformation in human prostate epithelial cells potentially by hypermethylation-mediated silencing of MLH1. AB - BACKGROUND: Chronic exposure to arsenic and estrogen is associated with risk of prostate cancer, but their mechanism is not fully understood. Additionally, the carcinogenic effects of their co-exposure are not known. Therefore, the objective of this study was to evaluate the effects of chronic exposure to arsenic, estrogen, and their combination, on cell growth and transformation, and identify the mechanism behind these effects. METHODS: RWPE-1 human prostate epithelial cells were chronically exposed to arsenic and estrogen alone and in combination. Cell growth was measured by cell count and cell cycle, whereas cell transformation was evaluated by colony formation assay. Gene expression was measured by quantitative real-time PCR and confirmed at protein level by Western blot analysis. MLH1 promoter methylation was determined by pyrosequencing method. RESULTS: Exposure to arsenic, estrogen, and their combinations increases cell growth and transformation in RWPE-1 cells. Increased expression of Cyclin D1 and Bcl2, whereas decreased expression of mismatch repair genes MSH4, MSH6, and MLH1 was also observed. Hypermethylation of MLH1 promoter further suggested the epigenetic inactivation of MLH1 expression in arsenic and estrogen treated cells. Arsenic and estrogen combination caused greater changes than their individual treatments. CONCLUSIONS: Findings of this study for the first time suggest that arsenic and estrogen exposures cause increased cell growth and survival potentially through epigenetic inactivation of MLH1 resulting in decreased MLH1 mediated apoptotic response, and consequently increased cellular transformation. PMID- 23804312 TI - Improved heterologous erythromycin A production through expression plasmid re design. AB - The production of complex compounds from technically convenient microorganisms is an emerging route to the chemical diversity found in the surrounding environment. In this study, the antibiotic compound erythromycin A is produced from Escherichia coli as an alternative to native production through the soil bacterium Saccharopolyspora erythraea. By doing so, there is an opportunity to apply and refine engineering strategies for the manipulation of the erythromycin biosynthetic pathway and for the overproduction of this and other complex natural compounds. Previously, E. coli-derived production was enabled by the introduction of the entire erythromycin pathway (20 genes total) using separately selectable expression plasmids which demonstrated negative effects on final biosynthesis through metabolic burden and plasmid instability. In this study, improvements to final production were made by altering the design of the expression plasmids needed for biosynthetic pathway introduction. Specifically, the total number of genes and plasmids was pruned to reduce both metabolic burden and plasmid instability. Further, a comparison was conducted between species-specific (E. coli vs. S. coelicolor) protein chaperonins. Results indicate improvements in growth and plasmid retention metrics. The newly designed expression platform also increased erythromycin A production levels 5-fold. In conclusion, the steps outlined in this report were designed to upgrade the E. coli erythromycin A production system, led to improved final compound titers, and suggest additional forms of pathway engineering to further improve results from heterologous production attempts. PMID- 23804313 TI - National trends in hospital-acquired preventable adverse events after major cancer surgery in the USA. AB - OBJECTIVES: While multiple studies have demonstrated variations in the quality of cancer care in the USA, payers are increasingly assessing structure-level and process-level measures to promote quality improvement. Hospital-acquired adverse events are one such measure and we examine their national trends after major cancer surgery. DESIGN: Retrospective, cross-sectional analysis of a weighted national estimate from the Nationwide Inpatient Sample (NIS) undergoing major oncological procedures (colectomy, cystectomy, oesophagectomy, gastrectomy, hysterectomy, lung resection, pancreatectomy and prostatectomy). The Agency for Healthcare Research and Quality Patient Safety Indicators (PSIs) were utilised to identify trends in hospital-acquired adverse events. SETTING: Secondary and tertiary care, US hospitals in NIS PARTICIPANTS: A weighted-national estimate of 2 508 917 patients (>18 years, 1999-2009) from NIS. PRIMARY OUTCOME MEASURES: Hospital-acquired adverse events. RESULTS: 324 852 patients experienced >=1-PSI event (12.9%). Patients with >=1-PSI experienced higher rates of in-hospital mortality (OR 19.38, 95% CI 18.44 to 20.37), prolonged length of stay (OR 4.43, 95% CI 4.31 to 4.54) and excessive hospital-charges (OR 5.21, 95% CI 5.10 to 5.32). Patients treated at lower volume hospitals experienced both higher PSI events and failure-to-rescue rates. While a steady increase in the frequency of PSI events after major cancer surgery has occurred over the last 10 years (estimated annual % change (EAPC): 3.5%, p<0.001), a concomitant decrease in failure-to-rescue rates (EAPC -3.01%) and overall mortality (EAPC -2.30%) was noted (all p<0.001). CONCLUSIONS: Over the past decade, there has been a substantial increase in the national frequency of potentially avoidable adverse events after major cancer surgery, with a detrimental effect on numerous outcome level measures. However, there was a concomitant reduction in failure-to-rescue rates and overall mortality rates. Policy changes to improve the increasing burden of specific adverse events, such as postoperative sepsis, pressure ulcers and respiratory failure, are required. PMID- 23804314 TI - Synthesis of wurtzite Cu2ZnGeSe4 nanocrystals and their thermoelectric properties. AB - An unusual wurtzite phase of Cu2ZnGeSe4 (CZGSe) has been discovered and its corresponding nanocrystals (NCs) were synthesized by using a facile hot-injection solution-phase synthesis method. Moreover, the formation mechanism of this new phase of CZGSe, instead of the typically observed stannite structure, has been investigated in detail, which indicates that wurtzite CZGSe, which represents the kinetic phase, could be prepared by using a kinetic growth process without phase transformation into the thermodynamically stable stannite structure during the colloidal synthesis. In addition, the potential of wurtzite CZGSe as a thermoelectric material is demonstrated by characterizing the thermoelectric properties of as-synthesized wurtzite CZGSe NCs. This work allows for a rational manipulation of the NCs with a desired crystal structure through adjusting the thermodynamics and kinetics without using any additives and, because of its simplicity and versatility, it may be extended to the phase-controlled synthesis of other chalcogenide NCs. PMID- 23804315 TI - A new orthosis for subluxed, flaccid shoulder after stroke facilitates gait symmetry: a preliminary study. AB - OBJECTIVE: The aims of this study were: (i) to evaluate the immediate effects on subluxation and gait pattern of a new shoulder orthosis, developed for treatment of painful shoulder syndrome in subacute stroke patients; and (ii) to evaluate patients' and therapists' opinions about its fit and benefits after 4 weeks. METHODS: A total of 40 subacute in-rehabilitation stroke patients with non functional arm and painful shoulder were included in the study. Of these, 12 subjects underwent shoulder radiography and gait analysis with and without the orthosis to determine the immediate effects of the orthosis. All 40 patients wore the orthosis during the daytime for 4 weeks before completing a survey. Outcome measures were: repositioning of the humeral head, gait cycle parameters, and qualitative lower limb muscle activation patterns. Patients and therapists rated wearing comfort, odour nuisance, effect on pain and performing gait and mobility related activities. RESULTS: When using the shoulder orthosis the humeral head was repositioned in 10 of 12 patients, patients walked more symmetrically due to a prolonged hemiparetic stance phase (p < 0.01), and the paretic quadriceps muscle activity was higher and more appropriately timed. The majority of patients and therapists rated the wearing comfort positive, the odour nuisance minimal, and that the orthosis helped with performing activities. However, less than half of patients and therapists reported improvement in pain. CONCLUSION: The well tolerated shoulder orthosis improved gait quality and repositioned the subluxated humeral head, offered a good fit, and eased performing activities, but did not reduce pain. This preliminary study does not warrant any definite conclusions on the effectiveness of the orthosis; more studies are needed to compare its effect with other models. PMID- 23804316 TI - Levels and distribution of tetrabromobisphenol A and hexabromocyclododecane in Taihu Lake, China. AB - The occurrence and distribution characteristics of tetrabromobisphenol A (TBBPA) and hexabromocyclododecane (HBCD) in water and sediments from Taihu Lake, China, were investigated. The analytes were quantified by reversed-phase liquid chromatography coupled to electrospray ionization mass spectrometry. The TBBPA levels in water ranged from below the limit of detection (LOD) to 1.12 ng/L, whereas levels in sediments were between 0.056 ng/g dry weight and 2.15 ng/g dry weight. Regarding HBCD, concentrations were from below the LOD to 0.37 ng/L for water samples and from 0.046 ng/g dry weight to 2.56 ng/g dry weight for sediments. No correlation was found between sediment total organic carbon content and TBBPA/HBCDs, while significant positive correlations (r2 = 0.63, p < 0.005) were observed between TBBPA concentrations and HBCD concentrations in sediments. The highest TBBPA (2.15 ng/g dry wt) and total HBCD concentration (2.56 ng/g dry wt) was found at sampling site 1 (S1), while total HBCD levels fell dramatically with increasing distance from S1, suggesting that the estuary inputs around Taihu Lake were important sources of TBBPA and HBCDs. Compared with the pollution levels in the other regions of the world, the concentrations of TBBPA and HBCDs in Taihu Lake were at a moderate or low level. Further study on the sources of TBBPA and HBCDs is required for both assessment of their potential risks and better pollution management in Taihu Lake. PMID- 23804317 TI - Making sense of HIV in southeastern Nigeria: fictional narratives, cultural meanings, and methodologies in medical anthropology. AB - Fictional narratives have rarely been used in medical anthropological research. This article illustrates the value of such narratives by examining how young people in southeastern Nigeria navigate the cultural resources available to them to make sense of HIV in their creative writing. Using thematic data analysis and narrative-based methodologies, it analyzes a sample (N = 120) from 1,849 narratives submitted by Nigerian youth to the 2005 Scenarios from Africa scriptwriting contest on the theme of HIV. The narratives are characterized by five salient themes: tragedy arising from the incompatibility of sex outside marriage and kinship obligations; female vulnerability and blame; peer pressure and moral ambivalence; conservative Christian sexual morality; and the social and family consequences of HIV. We consider the strengths and limitations of this narrative approach from a theoretical perspective and by juxtaposing our findings with those generated by Daniel Jordan Smith using standard ethnographic research methods with a similar Igbo youth population. PMID- 23804318 TI - Comparison of abluminal biodegradable polymer biolimus-eluting stents and durable polymer everolimus-eluting stents in the treatment of coronary bifurcations. AB - OBJECTIVES: To compare biodegradable polymer biolimus-eluting (BES) with abluminal drug elution and durable polymer everolimus-eluting (EES) stents in the treatment of bifurcation lesions. BACKGROUND: The persistence of a polymer in drug-eluting stents (DES) following drug elution has been viewed as a possible culprit for restenosis. DES with biodegradable polymer may thus be associated with improved clinical outcomes, especially in high-risk lesions such as those at bifurcation sites. METHODS: We performed a retrospective study of consecutive de novo bifurcation lesions treated with EES between October 2006 and October 2011 and BES between February 2008 and March 2012. Study endpoints included major adverse cardiac events (MACE) defined as all-cause death, myocardial infarction (MI), including peri-procedural MI, and target vessel revascularization (TVR) as well as target lesion revascularization (TLR) separately. RESULTS: We analyzed 236 bifurcation lesions treated with either BES (79 lesions in 69 patients) or EES (157 lesions in 154 patients). Patient and procedural characteristics were broadly similar between the two groups. Estimated MACE and TVR rates at 2-year follow-up were similar between the BES and EES groups (MACE = 13.6 +/- 4.6% vs. 14.6 +/- 3.2% (P = 0.871); TVR = 6.9 +/- 3.5% vs. 8.0 +/- 2.7% (P = 0.889). No significant differences were noted between the two groups following propensity score matched analysis. There was no probable or definite stent thrombosis. CONCLUSION: BES use in the treatment of bifurcation lesions appears to be associated with good clinical outcomes, comparable to those seen with EES, at long-term follow-up. These results are hypothesis-generating and need to be validated with larger studies. PMID- 23804319 TI - Obesity and people with disabilities: the implications for health care expenditures. AB - OBJECTIVE: This study estimates additional average health care expenditures for overweight and obesity for adults with disabilities vs. without. DESIGN AND METHODS: Descriptive and multivariate methods were used to estimate additional health expenditures by service type, age group, and payer using 2004-2007 Medical Expenditure Panel Survey data. RESULTS: In 2007, 37% of community-dwelling Americans with disabilities were obese vs. 27% of the total population. People with disabilities had almost three times ($2,459) the additional average obesity cost of people without disabilities ($889). Prescription drug expenditures for obese people with disabilities were three times as high and outpatient expenditures were 74% higher. People with disabilities in the 45- to 64-year age group had the highest obesity expenditures. Medicare had the highest additional average obesity expenditures among payers. Among people with prescription drug expenditures, obese people with disabilities had nine times the prevalence of diabetes as normal weight people with disabilities. Overweight people with and without disabilities had lower expenditures than normal-weight people with and without disabilities. CONCLUSIONS: Obesity results in substantial additional health care expenditures for people with disabilities. These additional expenditures pose a serious current and future problem, given the potential for higher obesity prevalence in the coming decade. PMID- 23804320 TI - Activated ERK/FOXM1 pathway by low-power laser irradiation inhibits UVB-induced senescence through down-regulating p21 expression. AB - Cellular senescence is a growth-arrest program that limits cell proliferation. Low-power laser irradiation (LPLI) has been demonstrated to promote cell proliferation. However, whether LPLI can inhibit cellular senescence remains unknown. In the present study, to investigate the functional role of LPLI against skin aging, we used ultraviolet radiation b (UVB) to induce cell senescence. We first report that LPLI can delay UVB-induced cell senescence. The senescence associated beta-galactosidase (SA-beta-Gal) activity and p21 expression, hallmarks of senescent cells, were decreased in the Forkhead box transcription factor FOXM1-dependent manner under treatment with LPLI. The effect of LPLI was further enhanced with an overexpression of FOXM1, and abolished when FOXM1 was knockdown with short hairpin RNA (shRNA). Furthermore, LPLI activated the extracellular regulated protein kinases (ERK) that was upstream of FOXM1. This led to FOXM1 phosphorylation and nuclear translocation. Nuclear translocation enhanced FOXM1 transcriptional activity and promoted its downstream target gene c Myc expression that could inhibit p21 expression. These findings highlight the protective effects of ERK/FOXM1 pathway against UVB-induced cell senescence, suggesting a potential protecting strategy for treating skin aging by LPLI. PMID- 23804321 TI - Association of ambient indoor temperature with body mass index in England. AB - OBJECTIVE: Raised ambient temperatures may result in a negative energy balance characterized by decreased food intake and raised energy expenditure. This study tested whether indoor temperatures above the thermoneutral zone for clothed humans (~23 degrees C) were associated with a reduced body mass index (BMI). METHODS: Participants were 100,152 adults (>=16 years) drawn from 13 consecutive annual waves of the nationally representative Health Survey for England (1995 2007). RESULTS: BMI levels of those residing in air temperatures above 23 degrees C were lower than those living in an ambient temperature of under 19 degrees C (b = -0.233, SE = 0.053, P < 0.001), in analyses that adjusted for participant age, gender, social class, health and the month/year of assessment. Robustness tests showed that high indoor temperatures were associated with reduced BMI levels in winter and non-winter months and early (1995-2000) and later (2001-2007) survey waves. Including additional demographic, environmental, and health behavior variables did not diminish the link between high indoor temperatures and reduced BMI. CONCLUSIONS: Elevated ambient indoor temperatures are associated with low BMI levels. Further research is needed to establish the potential causal nature of this relationship. PMID- 23804322 TI - A brief overview of some physical studies on the relaxation dynamics and Forster resonance energy transfer of semiconductor quantum dots. AB - This article highlights some physical studies on the relaxation dynamics and Forster resonance energy transfer (FRET) of semiconductor quantum dots (QDs) and the way these phenomena change with size, shape, and composition of the QDs. The understanding of the excited-state dynamics of photoexcited QDs is essential for technological applications such as efficient solar energy conversion, light emitting diodes, and photovoltaic cells. Here, our emphasis is directed at describing the influence of size, shape, and composition of the QDs on their different relaxation processes, that is, radiative relaxation rate, nonradiative relaxation rate, and number of trap states. A stochastic model of carrier relaxation dynamics in semiconductor QDs was proposed to correlate with the experimental results. Many recent studies reveal that the energy transfer between the QDs and a dye is a FRET process, as established from 1/d(6) distance dependence. QD-based energy-transfer processes have been used in applications such as luminescence tagging, imaging, sensors, and light harvesting. Thus, the understanding of the interaction between the excited state of the QD and the dye molecule and quantitative estimation of the number of dye molecules attached to the surface of the QD by using a kinetic model is important. Here, we highlight the influence of size, shape, and composition of QDs on the kinetics of energy transfer. Interesting findings reveal that QD-based energy-transfer processes offer exciting opportunities for future applications. Finally, a tentative outlook on future developments in this research field is given. PMID- 23804323 TI - Light-triggered self-assembly of gold nanoparticles based on photoisomerization of spirothiopyran. PMID- 23804324 TI - 3'-Deoxy-3'-18F-fluorothymidine PET for the early prediction of response to leucovorin, 5-fluorouracil, and oxaliplatin therapy in patients with metastatic colorectal cancer. AB - The aim of this study was to evaluate 3'-deoxy-3'-(18)F-fluorothymidine ((18)F FLT) PET for early prediction of the standard anatomic response and survival outcomes in patients with metastatic colorectal cancer (mCRC) receiving leucovorin, 5-fluorouracil (5-FU), and oxaliplatin (FOLFOX). METHODS: The main eligibility criteria included histologically confirmed mCRC, >= 1 extrahepatic measurable lesions, and no prior chemotherapy in a metastatic setting. Chemotherapy consisted of leucovorin on day 1, followed by the continuous infusion of 5-FU on days 1 and 2, and oxaliplatin on day 3. In the second and subsequent cycles of chemotherapy, oxaliplatin was administered simultaneously with leucovorin on day 1. (18)F-FLT PET scans were obtained 3 times during the first cycle of chemotherapy: before chemotherapy, 24 h after infusion of 5-FU (day 2), and 48 h after completion of chemotherapy (day 5). The maximum standardized uptake value (SUVMAX) of (18)F-FLT was measured. Treatment responses were assessed by CT after 3 cycles of FOLFOX. RESULTS: Eighteen patients were included in the study. The response rate after 3 cycles of FOLFOX was 27.8% (5/18). The SUVMAX was increased in responders (P = 0.043) and nonresponders (P < 0.001) on day 2 and was decreased, compared with baseline values, on day 5 in responders only (P = 0.043). Receiver-operating-characteristic curve analysis indicated that the use of a threshold of an SUVMAX increase on day 2 of <= 45.8% resulted in a sensitivity of 100%, specificity of 69.2%, and relative risk of 2.250 (P = 0.029) for the diagnosis of responders. Use of a threshold of an SUVMAX decrease on day 5 of >= 10.6% resulted in a sensitivity of 100%, specificity of 76.9%, and relative risk of 2.667 (P = 0.007). Patients with low (18)F-FLT flare tended to have longer survivals than patients with high flare (2 y overall survival rate, 77.8% vs. 44.4%; P = 0.051). CONCLUSION: The (18)F-FLT flare observed during 5-FU infusion was associated with poor treatment response in patients with mCRC. The degree of (18)F-FLT flare might be used to predict the outcome of patients who receive infusional 5-FU-based chemotherapy. PMID- 23804325 TI - Loss of olfactory tract integrity affects cortical metabolism in the brain and olfactory regions in aging and mild cognitive impairment. AB - Olfactory dysfunction is an early feature of Alzheimer disease. This study used multimodal imaging of PET and (18)F-FDG combined with diffusion tensor imaging (DTI) to investigate the association of fiber tract integrity in the olfactory tract with cortical glucose metabolism in subjects with mild cognitive impairment (MCI) and normal controls. We hypothesized that MCI subjects would show loss of olfactory tract integrity and may have altered associations with glucose metabolism. METHODS: Subjects diagnosed with amnestic MCI (n = 12) and normal controls (n = 23) received standard brain (18)F-FDG PET and DTI with 32 gradient directions on a 3-T MR imaging scanner. Fractional anisotropy (FA) maps were generated. Voxelwise correlation analysis of olfactory tract FA values with (18)F FDG PET images was performed. RESULTS: Integrated analysis over all subjects indicated a positive correlation between white matter integrity in the olfactory tract and metabolic activity in olfactory processing structures, including the rostral prefrontal cortex, dorsomedial thalamus, hypothalamus, orbitofrontal cortex, and uncus, and in the superior temporal gyrus, insula, and anterior cingulate cortex. Subjects with MCI, compared with normal controls, showed differential associations of olfactory tract integrity with medial temporal lobe and posterior cortical structures. CONCLUSION: These findings indicate that impairment of axonal integrity or neuronal loss may be linked to functional metabolic changes and that disease-specific neurodegeneration may affect this relationship. Multimodal imaging using (18)F-FDG PET and DTI may provide better insights into aging and neurodegenerative processes. PMID- 23804326 TI - Pharmacokinetic properties of peptidic radiopharmaceuticals: reduced uptake of (EH)3-conjugates in important organs. AB - The translation of radiolabeled tumor-targeting peptides into clinical routine is often hampered by an enhanced accumulation into the excreting organs. It has recently been reported that the (EH)3 purification tag is able to improve the biodistribution of Affibody molecules. Therefore, the aim of this study was to prove the positive influence of (EH)3 on the biodistribution of 2 peptidic radiopharmaceuticals, Glu-urea-Lys(Ahx)-HBED-CC and TATE-PEG2-HBED-CC (HBED-CC is N,N'-bis [2-hydroxy-5(carboxyethyl)benzyl] ethylenediamine-N,N'- diacetic acid, TATE is octreotate, and PEG2 is 8-amino-3,6-dioxaoctanoic acid spacer). METHODS: Both compounds were compared with their respective (EH)3-conjugated variants in cell-based in vitro assays and organ distribution. RESULTS: The introduction of (EH)3 to HBED-CC significantly changed the biodistribution profiles. In both cases, the uptake in several organs was reduced whereas tumor uptake was not affected. Most importantly, (EH)3 lowered the kidney and liver uptake of the prostate-specific membrane antigen inhibitor each by a factor of 2.8 and, in the case of octreotate, the liver accumulation by a factor of 51. CONCLUSION: The biodistribution data suggest that (EH)3 is able to improve the pharmacokinetic properties of peptidic radiopharmaceuticals, leading to reduced uptake in organs such as the liver, an important site of metastatic disease. PMID- 23804328 TI - The intratumoral distribution of radiolabeled 177Lu-BR96 monoclonal antibodies changes in relation to tumor histology over time in a syngeneic rat colon carcinoma model. AB - The therapeutic effect of radioimmunotherapy depends on the distribution of the absorbed dose in relation to viable cancer cells within the tumor, which in turn is a function of the activity distribution. The aim of this study was to investigate the distribution of (177)Lu-DOTA-BR96 monoclonal antibodies targeting the Lewis Y antigen over 7 d using a syngeneic rat model of colon carcinoma. METHODS: Thirty-eight tumor-bearing rats were intravenously given 25 or 50 MBq of (177)Lu-DOTA-BR96 per kilogram of body weight and were sacrificed 2, 8, 24, 48, 72, 96, 120, or 168 h after injection, with activity measured in blood and tumor samples. Adjacent cryosections of each tumor were analyzed in 3 ways: imaging using a silicon-strip detector for digital autoradiography, staining for histologic characterization, or staining to determine the distribution of the antigen, vasculature, and proliferating cells using immunohistochemistry. Absorbed-dose rate distribution images at the moment of sacrifice were calculated using the activity distribution and a point-dose kernel. The correlations between antigen expression and both activity uptake and absorbed-dose rate were calculated for several regions of interest in each tumor. Nine additional animals with tumors were given unlabeled antibody to evaluate possible immunologic effects. RESULTS: At 2-8 h after injection, activity was found in the tumor margins; at 24 h, in viable antigen-expressing areas within the tumor; and at 48 h and later, increasingly in antigen-negative areas of granulation tissue. The correlation between antigen expression and both the mean activity and the absorbed-dose rate in regions of interest changed from positive to negative after 24 h after injection. Antigen-negative areas also increased over time in animals injected with unlabeled BR96, compared with untreated tumors. CONCLUSION: The results indicate that viable Lewis Y-expressing tumor cells are most efficiently treated during the initial uptake period. The activity then seems to remain in these initial uptake regions after the elimination of tumor cells and formation of granulation tissue. Further studies using these techniques could aid in determining the effects of the intratumoral activity distribution on overall therapeutic efficacy. PMID- 23804327 TI - Whole-body imaging of high-dose ionizing irradiation-induced tissue injuries using 99mTc-duramycin. AB - High-dose ionizing irradiation can cause extensive injuries in susceptible tissues. A noninvasive imaging technique that detects a surrogate marker of apoptosis may help characterize the dynamics of radiation-induced tissue damage. The goal of this study was to prove the concept of imaging the temporal and spatial distribution of damage in susceptible tissues after high-dose radiation exposure, using (99m)Tc-duramycin as a phosphatidylethanolamine-binding radiopharmaceutical. METHODS: Rats were subjected to 15 Gy of total-body irradiation with x-rays. Planar whole-body (99m)Tc-duramycin scanning (n = 4 per time point) was conducted at 24, 48, and 72 h using a clinical gamma-camera. On the basis of findings from planar imaging, preclinical SPECT data were acquired on control rats and on irradiated rats at 6 and 24 h after irradiation (n = 4 per time point). Imaging data were validated by gamma-counting and histology, using harvested tissues in parallel groups of animals (n = 4). RESULTS: Prominent focal uptake was detected in the thymus as early as 6 h after irradiation, followed by a gradual decline in (99m)Tc-duramycin binding accompanied by extensive thymic atrophy. Early (6-24 h) radioactivity uptake in the gastrointestinal region was detected. Significant signal was seen in major bones in a slightly delayed fashion, at 24 h, which persisted for at least 2 d. This finding was paralleled by an elevation in signal intensity in the kidneys, spleen, and liver. The imaging results were consistent with ex vivo gamma-counting results and histology. Relatively high levels of apoptosis were detected from histology in the thymus, guts, and bones, with the thymus undergoing substantial atrophy. CONCLUSION: As a proof of principle, this study demonstrated a noninvasive imaging technique that allows characterization of the temporal and spatial dynamics of injuries in susceptible tissues during the acute phase after high dose ionizing irradiation. Such an imaging capability will potentially be useful for global, whole-body, assessment of tissue damage after radiation exposure. These data, in turn, will contribute to our general knowledge of tissue susceptibility to ionizing irradiation, as well as the onset and progression of tissue injuries. PMID- 23804330 TI - In response to Cost analysis of asymmetric sensorineural hearing loss investigations. PMID- 23804329 TI - Initial human PET studies of metabotropic glutamate receptor type 1 ligand 11C ITMM. AB - N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-4-(11)C-methoxy-N methylbenzamide ((11)C-ITMM) is a potential radioligand for mapping metabotropic glutamate receptor type 1 (mGluR1) in the brain by PET. The present study was performed to determine the safety, distribution, radiation dosimetry, and initial brain imaging of (11)C-ITMM in healthy human subjects. METHODS: The multiorgan biodistribution and radiation dosimetry of (11)C-ITMM were assessed in 3 healthy human subjects, who underwent 2-h whole-body PET scans. Radiation dosimetry was estimated from the normalized number of disintegrations of source organs using the OLINDA/EXM program. Five healthy human subjects underwent 90-min dynamic (11)C-ITMM scans of brain regions with arterial blood sampling. For anatomic coregistration, T1-weighted MR imaging was performed. Metabolites in plasma and urine samples were analyzed by high-performance liquid chromatography. (11)C-ITMM uptake was assessed quantitatively using a 2-tissue-compartment model. RESULTS: There were no serious adverse events in any of the subjects throughout the study period. (11)C-ITMM PET demonstrated high uptake in the urinary bladder and gallbladder, indicating both urinary and fecal excretion of radioactivity. The absorbed dose (MUGy/MBq) was highest in the urinary bladder wall (13.2 +/- 3.5), small intestine (9.8 +/- 1.7), and liver (9.1 +/- 2.0). The estimated effective dose for (11)C-ITMM was 4.6 +/- 0.3 MUSv/MBq. (11)C-ITMM showed a gradual increase of radioactivity in the cerebellar cortex. The total distribution volume in the brain regions ranged from 2.61 +/- 0.30 (cerebellar cortex) to 0.52 +/- 0.17 (pons), and the rank order of the corresponding total distribution volume of (11)C-ITMM was cerebellar cortex > thalamus > frontal cortex > striatum ~ pons, which was consistent with the known distribution of mGluR1 in the primate brain. The rate of (11)C-ITMM metabolism in plasma was moderate: at 60 min after injection, 62.2% +/- 8.2% of the radioactivity in plasma was intact parent compound. CONCLUSION: The initial findings of the present study indicated that (11)C-ITMM PET is feasible for imaging of mGluR1 in the brain. The low effective dose will permit serial examinations in the same subjects. PMID- 23804332 TI - Would you buy a used car from this editor? PMID- 23804331 TI - Genes, race, and culture in clinical care: racial profiling in the management of chronic illness. AB - Race, although an unscientific concept, remains prominent in health research and clinical guidelines, and is routinely invoked in clinical practice. In interviews with 58 primary care clinicians we explored how they understand and apply concepts of racial difference. We found wide agreement that race is important to consider in clinical care. They explained the effect of race on health, drawing on common assumptions about the biological, class, and cultural characteristics of racial minorities. They identified specific race-based clinical strategies for only a handful of conditions and were inconsistent in the details of what they said should be done for minority patients. We conclude that using race in clinical medicine promotes and maintains the illusion of inherent racial differences and may result in minority patients receiving care aimed at presumed racial group characteristics, rather than care selected as specifically appropriate for them as individuals. PMID- 23804333 TI - Sonographically guided lumbar spine procedures. PMID- 23804334 TI - Is sonothrombolysis an effective stroke treatment? AB - New therapeutic strategies under development aim to improve recanalization rates and clinical outcomes after ischemic stroke. One such approach is ultrasound (US) enhanced thrombolysis, or sonothrombolysis, which can improve thrombolytic drug actions and even intrinsic fibrinolysis. Although the mechanisms are not fully understood, it is postulated that thrombolysis enhancement is related to nonthermal mechanical effects of US. Recent results indicate that US with or without microbubbles may be effective in clot lysis of ischemic stroke even without additional thrombolytic drugs. Sonothrombolysis is a promising tool for treating acute ischemic stroke, but its efficacy, safety, and technical details have not been elucidated and proved yet in stroke treatment. PMID- 23804335 TI - Automated analysis of intima-media thickness: analysis and performance of CARES 3.0. AB - OBJECTIVES: In recent years, the use of computer-based techniques has been advocated to improve intima-media thickness (IMT) quantification and its reproducibility. The purpose of this study was to test the diagnostic performance of a new IMT automated algorithm, CARES 3.0, which is a patented class of IMT measurement systems called AtheroEdge (AtheroPoint, LLC, Roseville, CA). METHODS: From 2 different institutions, we analyzed the carotid arteries of 250 patients. The automated CARES 3.0 algorithm was tested versus 2 other automated algorithms, 1 semiautomated algorithm, and a reader reference to assess the IMT measurements. Bland-Altman analysis, regression analysis, and the Student t test were performed. RESULTS: CARES 3.0 showed an IMT measurement bias +/- SD of -0.022 +/- 0.288 mm compared with the expert reader. The average IMT by CARES 3.0 was 0.852 +/- 0.248 mm, and that of the reader was 0.872 +/- 0.325 mm. In the Bland-Altman plots, the CARES 3.0 IMT measurements showed accurate values, with about 80% of the images having an IMT measurement bias ranging between -50% and +50%. These values were better than those of the previous CARES releases and the semiautomated algorithm. Regression analysis showed that, among all techniques, the best t value was between CARES 3.0 and the reader. CONCLUSIONS: We have developed an improved fully automated technique for carotid IMT measurement on longitudinal ultrasound images. This new version, called CARES 3.0, consists of a new heuristic for lumen-intima and media-adventitia detection, which showed high accuracy and reproducibility for IMT measurement. PMID- 23804336 TI - Effectiveness of mastoid process percussion for identification of the vertebral artery ostium on Doppler studies. AB - OBJECTIVES: The pretransverse or first segment of the vertebral artery may be confused with adjacent branches of the proximal subclavian artery during Doppler assessment. This study investigated the effectiveness of mastoid process percussion, the "mastoid tap" maneuver, for identification of the vertebral artery ostium. METHODS: Fifty patients presenting consecutively for carotid sonography were recruited. Doppler waveforms were collected at the vertebral artery ostia, thyrocervical trunks, and proximal subclavian arteries while the mastoid tap maneuver was performed. The outcome indicator was serrate distortion of the Doppler waveform. Two raters graded the waveforms according to a 3-grade system: grade 0, no distortion; grade 1, mild distortion; and grade 3, marked distortion. The difference between the proportions of the vertebral artery ostia and thyrocervical trunks showing waveform distortion was evaluated with the chi(2) test. The differences in the extents of waveform distortion in the ipsilateral vertebral artery ostia, thyrocervical trunks, and subclavian arteries were evaluated with Friedman and Wilcoxon signed rank tests. RESULTS: Ninety-five vertebral artery ostia in 50 patients were successfully assessed. There was a significant difference between the proportions of vertebral artery ostia (95 of 95 [100%]) and thyrocervical trunks (9 of 95 [9.5%]) that showed waveform distortion (P < .001). There were significant differences in the extents of distortion between the ipsilateral vertebral artery ostia and thyrocervical trunks and between the ipsilateral vertebral artery ostia and subclavian arteries, with the vertebral artery ostia showing a higher degree of distortion in both cases (P < .001). CONCLUSIONS: The mastoid tap maneuver is useful for distinguishing between the vertebral arteries and thyrocervical trunks on Doppler studies. PMID- 23804337 TI - Perfusion heterogeneity in breast tumors for assessment of angiogenesis. AB - OBJECTIVES: The purpose of this study was to investigate the perfusion heterogeneity of malignant and benign breast tumors and assay their vascular architecture changes and molecular expression, thereby evaluating the relevance between imaging and histologic characteristics of angiogenesis. METHODS: Real time grayscale contrast-enhanced sonography was performed in 310 women with 317 breast tumors. The enhancement patterns and perfusion parameters for malignant and benign tumors were analyzed by contrast-enhanced sonography with microvascular imaging and quantitative time-intensity curve analysis. Structural characteristics were observed by light and electron microscopy. The microvessel density, vascular endothelial growth factor (VEGF) expression, and human kinase insert domain-containing receptor (KDR) expression for all tumors were assessed by immunohistochemical staining of CD31, KDR, and VEGF. RESULTS: Surgical pathologic analysis showed 163 malignant and 154 benign tumors. Significant morphologic differences, including perfusion defects, vessel distortion, vessel dilatation, and heterogeneous enhancement, were observed between the malignant and benign groups (P < .05). The mean perfusion parameters (peak intensity, ascending slope, area under the curve, and wash-out time) were greater in the malignant tumors (P < .05). There were significant differences in the peak intensity, ascending slope, area under the curve, and wash-out time between peripheral and central regions of the malignant tumors (P < .05) but none in the benign tumors. Vessels had various morphologic and distributional characteristics in the peripheral and central regions of the malignant tumors. The microvessel density and VEGF and KDR expression were significantly higher in the malignant group (P < .05), especially in the peripheral regions. CONCLUSIONS: Perfusion heterogeneity was closely associated with the tumor microvascular architecture and molecular expression. Perfusion features, especially regional morphologic and hemodynamic features, can provide valuable information for differentiating malignant from benign breast tumors. PMID- 23804338 TI - Evaluation of the vascular architecture of focal liver lesions using micro flow imaging. AB - OBJECTIVES: To identify the vascular architecture of focal liver lesions using micro flow imaging and compare it with characteristics on contrast harmonic imaging during the arterial phase. METHODS: Micro flow imaging and contrast harmonic imaging were performed in 118 patients with various focal liver lesions: hepatocellular carcinoma (n = 70), metastasis(n = 19), intrahepatic cholangiocarcinoma (n = 3), lymphoma (n = 1), hemangioma (n = 17), and focal nodular hyperplasia (n = 8). The vascular architecture of the lesions on micro flow imaging was evaluated by 2 investigators independently to reveal 6 patterns (types IVI). Enhancement characteristics on contrast harmonic imaging were also evaluated. RESULTS: Inter-reader agreement for delineating the vascular architecture was higher on contrast harmonic imaging (kappa= 0.856) than micro flow imaging (kappa= 0.613). On micro flow imaging, the vascular patterns of hepatocellular carcinomas were types I (28.6%), II (65.7%), and III (5.7%). On contrast harmonic imaging, 44 of 70 (62.9%) hepatocellular carcinomas showed chaotic vessels, of which 40 were type II and 4 were type II. The vascular patterns of metastases were types IV (78.9%), I (10.5%), and II (10.5%). Typical rim enhancement was identified in 57.9% of metastases on contrast harmonic imaging, and all were type IV. The vascular patterns of focal nodular hyperplasia were types VI (87.5%) and I (12.5%). Typical spoked wheel arteries were identified on contrast harmonic imaging in 2 focal nodular hyperplasia cases. The vascular patterns of hemangiomas were types V (94.1%) and II (5.9%). Typical peripheral nodular enhancement was identified in 88.2% of hemangiomas on contrast harmonic imaging, and all were type V. The chi(2) test revealed that differences in vascular architecture between the lesions were significant on micro flow imaging (P < .001). CONCLUSIONS: Micro flow imaging permitted detailed delineation of the vascular architecture of focal liver lesions. Hepatocellular carcinoma, metastasis, focal nodular hyperplasia, and hemangioma showed characteristic vascular architecture. PMID- 23804339 TI - Sonographic features of cervical lymph nodes after thyroidectomy for papillary thyroid carcinoma. AB - OBJECTIVES: Unlike the preoperative findings in patients with papillary thyroid carcinoma, the postoperative sonographic features of cervical lymph nodes have not been established. This study aimed to assess the sonographic features of metastatic lymph nodes after thyroidectomy for papillary thyroid carcinoma. METHODS: The study population consisted of 104 consecutively registered patients who had undergone thyroidectomy for papillary thyroid carcinoma and underwent sonographically guided fine-needle aspiration of lymph nodes in the neck. The sonographic features of each lymph node were retrospectively evaluated by a single radiologist. The confirmation methods for the 115 lymph nodes included surgery (n = 35), measurement of thyroglobulin levels in the aspirates (n = 2), malignant cytologic analysis (n = 10), and benign cytologic analysis with sonographic follow-up over 12 months (n = 68). We determined the diagnostic indices of individual sonographic features for differentiating between metastatic and benign lymph nodes by comparing these features with the final diagnoses. RESULTS: Of the 104 patients, 67 underwent at least 1 cycle of radioisotope therapy after thyroidectomy. The malignancy rate for the lymph nodes was 42.6% (49 of 115). A significant relationship was found between malignancy and the presence of an intranodal cystic component, intranodal microcalcifications, diffusely increased echogenicity, a microlobulated margin, a round shape, loss of echogenic hila, and mixed or central vascularity on color Doppler sonography (P < .05). CONCLUSIONS: The sonographic features of metastatic cervical lymph nodes in postoperative patients with papillary thyroid carcinoma were similar to those in preoperative patients. PMID- 23804340 TI - Use of pelvic computed tomography and sonography in women of reproductive age in the emergency department. AB - OBJECTIVES: The purpose of this study was to review use of pelvic computed tomography (CT) and sonography in the emergency department for women of reproductive age and to identify cases in which sonography might have been adequate. METHODS: Computed tomographic and sonographic examinations of the pelvis performed on women up to 55 years of age in our emergency department during a 6-month period were reviewed. Repeated CT and CT with indications for which sonography would not be the first-line imaging modality (eg, diverticulitis and trauma) were excluded. For the sonographic-only assessment, repeated sonography and sonography with indications for which CT would not be the first line imaging modality (eg, vaginal bleeding) were excluded. Patient referral indications, imaging diagnoses, and discharge diagnoses were compared for the groups with CT only, CT first, sonography first, and sonography only. RESULTS: Of 509 women who underwent CT, 407 (80%) underwent CT only; 54 (11%) underwent CT first; and 48 (9%) underwent pelvic sonography first. The percentages with negative CT findings were 42%,17%, and 50%, respectively. Overall, 63 (CT only), 38 (CT first), and 12 (sonography first) patients had CT diagnoses of pelvic conditions only (113 of 509 women [22%]). Of the patients with CT and discharge diagnoses of pelvic conditions, 36 of 44 (82%) had CT only or CT first; 58 of 110 (53%) of cases with sonography only showed acute pelvic conditions. CONCLUSIONS: Twenty-two percent of pelvic CT examinations performed in women of reproductive age in our emergency department showed only pelvic conditions, suggesting that sonography would have been a reasonable primary imaging test for these patients. PMID- 23804342 TI - Sonographic evaluation of the iliotibial band at the lateral femoral epicondyle: does the iliotibial band move? AB - OBJECTIVES: The purpose of this study was to determine whether the iliotibial band (ITB) moves relative to the lateral femoral epicondyle (LFE) as a function of knee flexion in both non-weight-bearing and weight-bearing positions in asymptomatic recreational runners. METHODS: Five male and 15 female asymptomatic recreational runners (10-30 miles/wk) aged 18 to 40 years were examined with sonography to assess the distance between the anterior fibers of the ITB and the LFE in full extension, 30 degrees of knee flexion, and 45 degrees of knee flexion. Measurements were obtained on both knees in the supine (non-weight bearing) and standing (weight-bearing) positions. RESULTS: The distance between the anterior fibers of the ITB and the LFE decreased significantly from full extension to 45 degrees of knee flexion in both supine (0.38-cm average decrease; P < .001) and standing (0.71-cm average decrease; P < .001) positions. These changes reflect posterior translation of the ITB during the 0 degrees to 45 degrees flexion arc of motion in both the supine and standing positions. CONCLUSIONS: Sonographic evaluation of the ITB in our study population clearly revealed anteroposterior motion of the ITB relative to the LFE during knee flexion-extension. Our results indicate that the ITB does in fact move relative to the femur during the functional ranges of knee motion. Future investigations examining ITB motion in symptomatic populations may provide further insight into the pathophysiologic mechanisms of ITB syndrome and facilitate the development of more effective treatment strategies. PMID- 23804341 TI - Normative data for quantitative calcaneal ultrasonometry in Turkish children aged 6 to 14 years: relationship of the stiffness index with age, pubertal stage, physical characteristics, and lifestyle. AB - OBJECTIVES: Quantitative ultrasonometry is commonly used to assess bone health. The aim of this study was to define normative data for the stiffness index of the calcaneus in healthy Turkish children. METHODS: Quantitative ultrasonometric measurements of the calcaneus were obtained in 1617 healthy schoolchildren (811 boys and 806 girls) aged 6 to 14 years. RESULTS: The stiffness index increased by 19.3% and 12% in boys and girls, respectively. The greatest increases were seen in the age groups of 12 to 13 and 13 to 14 years in boys (3.9%) and 11 to 12 and 12 to 13 years in girls (4.1%). There was a significant increase in stiffness index values among all Tanner stages except stage 4 (P < .05). Although the stiffness index was related to age, weight, and height, no correlation was seen between the stiffness index and calcium intake or physical activity. CONCLUSIONS: This study provides stiffness index data by age group and Tanner stage that may be useful for assessment of the bone status of Turkish children and can serve as comparative data for other patient groups. PMID- 23804343 TI - Double sac sign and intradecidual sign in early pregnancy: interobserver reliability and frequency of occurrence. AB - OBJECTIVES: To assess the interobserver agreement, frequency of occurrence, and prognostic importance of the double sac sign (DSS), intradecidual sign (IDS), and other sonographic findings in early intrauterine pregnancies. METHODS: We retrospectively identified all sonograms obtained between January 1, 2006, and December 31, 2011, in which: (1) the scan demonstrated an intrauterine fluid collection without a yolk sac or embryo; (2) a follow-up scan confirmed an intrauterine pregnancy; and (3) the first-trimester outcome was known. Each coinvestigator characterized the 199 study sonograms as demonstrating or not demonstrating a DSS or an IDS, based on judgment about whether the scan met published criteria defining these signs. RESULTS: Interobserver agreement was poor for the DSS (kappa= 0.24) and IDS (kappa= 0.23). Scans frequently demonstrated neither sign: 150 cases (75.4%) if we considered a sign to be present when both investigators graded it as present and 69 cases (34.7%) using the looser criterion that either graded it as present. The presence of a DSS or an IDS was unrelated to the beta-human chorionic gonadotropin (beta-hCG) value (P > .05, t test, all comparisons). An inner echogenic ring was present in 158 cases (79.4%), and the decidua was brighter peripherally than centrally in 102 (51.3%). The first-trimester outcome was unrelated to the presence of a DSS or an IDS, presence of an inner echogenic ring, or decidual appearance (P > .05, chi(2), all comparisons). CONCLUSIONS: The sonographic appearance of early gestational sacs, before visualization of a yolk sac or embryo, is highly variable. The DSS and IDS are often absent; there is poor interobserver agreement regarding these signs; and the prognosis is unrelated to their presence or absence. A round or oval intrauterine fluid collection in a woman with positive beta-hCG should be treated as a gestational sac until proven otherwise, regardless of whether it demonstrates a DSS or an IDS. PMID- 23804344 TI - Fetal size charts for a population from Cali, Colombia: sonographic measurements of biparietal diameter, head circumference, abdominal circumference, and femur length. AB - OBJECTIVES: To create reference charts for fetal sonographic biometric measurements in a population of pregnant women living in the third largest city in Colombia and compare them with charts included in ultrasound machines. METHODS: The data were obtained from women with a single pregnancy and confirmed gestational (menstrual) age between 12 and 40 weeks. All women were recruited specifically for the study, and every fetus was measured only once for biparietal diameter, head circumference, abdominal circumference, and femur length. Raw data for each fetal measurement were modeled by fitting regression models separately to estimate the mean and standard deviation as a function of gestational age. Percentile curves were constructed for each measurement by gestational age using these two regression models. We compared our mean z scores with those expected by reference equations. RESULTS: Measurements were obtained for 792 fetuses. A cubic polynomial model was the best-fitted regression model to describe the relationships between each fetal measurement and gestational age. The standard deviation for each measurement was estimated by simple linear regression as a function of gestational age. Comparison of our mean z scores with those by reference equations showed significant differences in some fetal measurements (P < .01). CONCLUSIONS: We present a set of reference percentile charts, tables, and formulas for fetal biometric measurements from a Colombian population. We believe that our fetal charts could be used nationwide in Colombia; nevertheless, a national sample will contribute to their validation and promotion of the development of Colombian fetal size charts. PMID- 23804345 TI - Fetal dorsalis pedis artery velocimetry in the second and third trimesters. AB - OBJECTIVES: This study aimed to establish reference ranges for Doppler parameters of the fetal dorsalis pedis artery and to compare them with those of the anterior tibial artery. METHODS: Dorsalis pedis artery velocimetry was performed in 138 singleton fetuses. Intraobserver repeatability coefficients and differences between measurements of bilateral legs were also evaluated. Comparisons were made between the pulsatility index in the dorsalis pedis and anterior tibial arteries. RESULTS: The average maximum velocity of the dorsalis pedis artery increased from approximately 12.2 cm/s at 18 weeks' gestation to 33.6 cm/s at 39 weeks' gestation, whereas the minimum velocity did not show any significant variation during the observed gestational weeks. The average pulsatility index increased from about 2.0 at 18 weeks' gestation to 3.1 at 39 weeks' gestation. The pulsatility index was lower in the dorsalis pedis artery than in the anterior tibial artery. CONCLUSIONS: Doppler parameters of the dorsalis pedis artery can be easily and accurately acquired by trained examiners and therefore are potential means for evaluating related fetal vascular development. However, it is still unclear whether changes exist in fetuses with limb diseases, and further investigation is needed. PMID- 23804346 TI - First experience using 4-dimensional hysterosalpingo-contrast sonography with SonoVue for assessing fallopian tube patency. AB - This study was conducted to describe our first experience using transvaginal 4 dimensional (4D) hysterosalpingo-contrast sonography with SonoVue (Bracco International BV, Amsterdam, the Netherlands) for diagnosis of fallopian tube patency. The study was prospective and conducted in a university hospital setting. The sonographic procedures included 2-dimensional transvaginal sonography for evaluating uterine and ovarian mobility, observing intubation, and determining the initial plane and 4D hysterosalpingo-contrast sonography for observing periovarian and pelvic diffusion. Ninety-six outpatients visiting infertility clinics underwent 4D hysterosalpingo-contrast sonography. All patients finished the examination successfully. A total of 192 fallopian tubes were assessed, of which 95 (49.5%) were classified as type A (the tube was patent, and the contrast agent flowed smoothly through it), 72 (37.5%) as type B (the tube was patent, but the contrast agent did not flow smoothly inside it), and 25 (13.0%) as type C (blocked). Sixteen patients underwent laparoscopy or laparoscopy combined with hysteroscopy; 28 tubes (87.5%) were concordant with laparoscopy. The sensitivity, specificity, positive predictive value, negative predictive value, and Youden index for 4D hysterosalpingo-contrast sonography versus laparoscopy were 81.8%, 90.5%, 81.8%, 90.5%, and 0.72 respectively. In total, 92.7% of patients did not require a hospital stay after 4D hysterosalpingo contrast sonography, and none need resuscitation. The others stayed in the hospital for clinical observation because of a severe vasovagal reaction or severe pain but received only bed rest without any medical treatment. Forty patients (41.7%) felt slight pain; 39 (40.6%) felt moderate pain; and 15 (15.6%) had a vasovagal reaction. No procedure or postprocedure complications occurred in any patient. In conclusion, 4D hysterosalpingo-contrast sonography with SonoVue is an available screening method for assessment of tubal patency and is tolerable for most patients. PMID- 23804347 TI - Photoacoustic imaging of the bladder: a pilot study. AB - Photoacoustic imaging is a promising new technology that combines tissue optical characteristics with ultrasound transmission and can potentially visualize tumor depth in bladder cancer. We imaged simulated tumors in 5 fresh porcine bladders with conventional pulse-echo sonography and photoacoustic imaging. Isoechoic biomaterials of different optical qualities were used. In all 5 of the bladder specimens, photoacoustic imaging showed injected biomaterials, containing varying degrees of pigment, better than control pulse-echo sonography. Photoacoustic imaging may be complementary to diagnostic information obtained by cystoscopy and urine cytologic analysis and could potentially obviate the need for biopsy in some tumors before definitive treatment. PMID- 23804348 TI - Static and dynamic sonography for diagnosis of abdominal wall hernias. AB - Sonography is a fast, painless, inexpensive, and widely available tool usually regarded as a first-line imaging modality for abdominal wall evaluation. This article provides illustrative images and videos on the use of sonography for diagnosis of abdominal wall hernias. A variety of pitfalls that may present clinically as pseudohernias are also described. PMID- 23804349 TI - Sonographic findings of axillary masses: what can be imaged in this space? AB - The diagnosis of axillary masses can be challenging because various tumors can develop in parts of the axilla other than lymph nodes, even though we frequently encounter axillary masses in daily practice. These lesions include soft tissue masses associated with nontumorous conditions (accessory breast tissue and chronic granulomatous inflammation) and benign and malignant tumorous conditions (lipomas, epidermal inclusion cysts, lymphangiomas, fibroadenomas, schwannomas, malignant neuroendocrine tumors, and lymph node-associated diseases). In this pictorial essay, we display commonly encountered sonographic findings of various axillary lesions to assist in the differential diagnosis of axillary masses. PMID- 23804350 TI - Sonographic evaluation of plantar hindfoot and midfoot pain. AB - Plantar hindfoot and midfoot pain is a common orthopedic condition. Plantar fasciopathy is the most common cause of plantar foot pain, and sonographic evaluation can easily show the characteristic pathologic changes. In addition, sonography is well suited to evaluate other potential causes of plantar foot pain. We present a review of the sonographic findings of plantar fasciopathy and other potential causes of plantar hindfoot and midfoot pain. PMID- 23804351 TI - Hyperreactio luteinalis (enlarged ovaries) during the second and third trimesters of pregnancy: common clinical associations. AB - The objective of this series was to assess sonographic and clinical findings in patients with hyperreactio luteinalis (HL; enlarged ovaries). We retrospectively identified 31 patients with HL and collected data including gestational age, maximum ovarian size, and pregnancy outcomes. Hyperreactio luteinalis was detected at a mean gestational age of 21.6 weeks, reaching average maximum ovarian volumes of 417 and 359 mL on the right and left, respectively. After the first trimester, HL appears to be associated with multiple gestations, twin-twin transfusion syndrome, gestational trophoblastic disease, and Beckwith-Wiedemann syndrome. When HL is present, maternal complications such as preeclampsia are common, and preterm delivery often results. PMID- 23804352 TI - Premature closure or restriction of the foramen ovale: prenatal diagnosis by directional enhanced flow imaging. AB - Premature closure or restriction of the foramen ovale may occur at any time during pregnancy and may be due to various causes. We describe 2 patients with premature closure or restriction of the foramen ovale during the third trimester. In both patients the foramen ovale was detected by directional enhanced flow imaging technology (DeFLOW; Hitachi-Aloka Medical, Ltd, Tokyo, Japan), a novel method of imaging blood flow dynamics. Our findings indicate that D-eFLOW can display blood flow information with higher sensitivity and resolution than conventional methods, helping obstetricians and pregnant women make timely decisions about delivery. PMID- 23804353 TI - Cesarean scar pregnancy: diagnosis, management, and follow-up. AB - Cesarean scar pregnancy is a very rare form of pregnancy and a life-threatening situation. It has become an important and serious problem over the last 10 years, as a result of the worldwide increase in cesarean births. In this retrospective series, the diagnosis of cesarean scar pregnancy, management, treatment methods, risk factors, and possibility of subsequent normal pregnancy are discussed, and case descriptions are presented. PMID- 23804354 TI - Limitations of 3-dimensional sonography in the prenatal evaluation of a skin denudation syndrome. PMID- 23804355 TI - Fetal conversion of a 3-vessel to 2-vessel umbilical cord: sonographic depiction. PMID- 23804356 TI - AIUM practice guideline for the performance of an ultrasound examination for detection and assessment of developmental dysplasia of the hip. PMID- 23804357 TI - AIUM practice guideline for the performance of a thyroid and parathyroid ultrasound examination. PMID- 23804358 TI - AIUM practice guideline for the performance of native renal artery duplex sonography. PMID- 23804359 TI - Relationship between intravascular ultrasound parameters and fractional flow reserve in intermediate coronary artery stenosis of left anterior descending artery: intravascular ultrasound volumetric analysis. AB - OBJECTIVES: The objective of this study was to assess the relationship between intravascular ultrasound (IVUS) parameters, including volumetric analysis, and fractional flow reserve (FFR). BACKGROUND: Although it is known that coronary atherosclerosis burden measured by IVUS volumetric analysis is related with clinical outcomes, its relationship with functional significance remains unknown. METHODS: Both IVUS and FFR were performed in 206 cases of intermediate stenosis of the left anterior descending artery (LAD). Myocardial ischemia was assessed by FFR and maximal hyperemia was induced by continuous intracoronary adenosine infusion. FFR < 0.80 was considered as significant inducible myocardial ischemia. We performed standard IVUS parameter measurements and volumetric analyses. IVUS parameter comparison was performed in the presence (n = 90) or absence (n =116) of significant myocardial ischemia. RESULTS: Lesions with minimal lumen area (MLA) >= 4.0 mm2 had FFR >= 0.80 in 91.4% of cases, while 50.9% of lesions with MLA < 4.0 mm2 had FFR < 0.80. The independent predictors of FFR < 0.80 were IVUS lesion length (odds ratio [OR]: 1.1, 95% confidence interval [CI] = 1.06-1.18, P < 0.001) and MLA significance according to the lesion location (OR: 7.01, 95% CI = 3.09-15.92, P = 0.001). FFR correlated with plaque volume (r = -0.345, P < 0.001) and percent atheroma volume (PAV) (r = -0.398, P < 0.001). Lesions with significant ischemia (FFR < 0.80) as compared to those with FFR > 0.80 were associated with larger plaque volume (181.8 +/- 82.3 vs. 125.9 +/- 77.9 mm3, P < 0.001) and PAV (58.9 +/- 5.6 vs. 53.8 +/- 7.9%, P < 0.001). CONCLUSIONS: IVUS parameters representing severity and extent of atheromatous plaque correlated with functional significance in LAD lesions with intermediate stenosis. PMID- 23804360 TI - Cerebellar hemorrhage in very low birth weight premature infants: the advantage of the posterolateral fontanelle view. AB - OBJECTIVE: The purpose of this study was to determine the prevalence of cerebellar hemorrhage in very low birth weight infants using the posterolateral fontanelle for ultrasound (US) examination. METHODS: The study included 125 very low birth weight premature infants (defined as equal or less than 1500 grams at birth) hospitalized in the premature or neonatal intensive care departments that had at least one head US examination including both anterior and posterolateral fontanelle scans. RESULTS: On US performed through the posterolateral fontanelle, four (3.2%) infants had echogenic posterior fossa lesions interpreted as hemorrhages. None of these lesions were initially or retrospectively observed through the standard anterior fontanelle scan. Two infants died at age 4 and 39 days, respectively. All survivors are being followed up in the hospital's neurodevelopment outpatient clinic. CONCLUSIONS: Cerebellar hemorrhage may be overlooked on standard anterior fontanelle views. The posterolateral approach may assist in diagnosing these lesions. PMID- 23804361 TI - Relationship between epicardial adipose tissue and subclinical coronary artery disease in patients with extra-cardiac arterial disease. AB - OBJECTIVE: Epicardial adipose tissue (EAT) and mediastinal adipose tissue (MAT) are linked to coronary artery disease (CAD). The association between EAT, MAT, and severity of CAD in known extra-cardiac arterial disease was investigated. DESIGN AND METHODS: Sixty-five cardiac asymptomatic patients (mean age 65 +/- 8 years, 69% male) with peripheral arterial disease, carotid stenosis, or aortic aneurysm underwent coronary computed tomography angiography. Patients were divided into non-significant (<50% stenosis, N = 35), single vessel (N = 15) and multi-vessel CAD (N = 15). EAT and MAT were quantified on computed tomography images using volumetric software. RESULTS: Subgroups did not significantly differ by age, gender, or cardiovascular risk factors. Median EAT was 99.5, 98.0, and 112.0 cm(3) (P = 0.38) and median MAT was 66.0, 90.0, and 81.0 cm(3) (P = 0.53) for non-significant, single vessel, and multi-vessel CAD, respectively. In age- and gender-adjusted analysis, only EAT was significantly associated with CAD (odds ratio [OR] 1.12 [95% confidence interval, 1.01-1.25] per 10 cm(3) increase in EAT; P = 0.04). This remained in multivariate-adjusted analysis (OR 1.21 [1.04 1.39]; P = 0.01). CONCLUSIONS: In patients with known extra-cardiac arterial disease, CAD is correlated with EAT, but not with MAT. These results suggest that EAT has a local effect on coronary atherosclerosis, apart from the endocrine effect of visceral fat. PMID- 23804362 TI - Osmotic second virial cross-coefficient measurements for binary combination of lysozyme, ovalbumin, and alpha-amylase in salt solutions. AB - Interactions measurement is a valuable tool to predict equilibrium phase separation of a desired protein in the presence of unwanted macromolecules. In this study, cross-interactions were measured as the osmotic second virial cross coefficients (B23 ) for the three binary protein systems involving lysozyme, ovalbumin, and alpha-amylase in salt solutions (sodium chloride and ammonium sulfate). They were correlated with solubility for the binary protein mixtures. The cross-interaction behavior at different salt concentrations was interpreted by either electrostatic or hydrophobic interaction forces. At low salt concentrations, the protein surface charge dominates cross-interaction behavior as a function of pH. With added ovalbumin, the lysozyme solubility decreased linearly at low salt concentration in sodium chloride and increased at high salt concentration in ammonium sulfate. The B23 value was found to be proportional to the slope of the lysozyme solubility against ovalbumin concentration and the correlation was explained by preferential interaction theory. PMID- 23804364 TI - Nonrandomized impact evaluation studies: errors and tips. PMID- 23804365 TI - Collaborative care management for depression: comparison of cost metrics and clinical response to usual care. AB - The collaborative care management (CCM) model has been demonstrated to be significantly more effective compared to usual care (UC) in depression management although an initial increase in cost measures was seen. In this paper, cost measures as well as clinical response were analyzed on patients with available follow-up data at six months. Records of 219 patients with follow-up data in CCM group and 119 in UC group were reviewed. At six months, there was a statistically significant clinical response rate among patients in CCM compared to UC group (P < 0.0001). Likewise, 65% in CCM group was "symptom-free" at 6 months vs. 31.9% in UC group (P < 0.0001). Among the responders in both groups, there was no statistical difference in cost measures. However, cost measures were significantly higher among non-responders compared to responders within CCM. Between the two models, the non-responders in UC had lower cost measures than the non-responders under CCM. PMID- 23804363 TI - The role of S100B in the interaction between adipocytes and macrophages. AB - OBJECTIVE: The S100 calcium binding protein B (S100B) implicated in brain inflammation acts via the receptor of advanced glycation end products (RAGE) and is also secreted from adipocytes. We investigated the role of S100B in the interaction between adipocytes and macrophages using a cell-culture model. DESIGN AND METHODS: RAW264.7 macrophages (RAW) were stimulated by recombinant S100B to observe alterations in TNF-alpha and M1 markers; 3T3-L1 adipocytes (L1) were stimulated by TNF-alpha to examine S100B secretion. RAW and L1 were then mutually stimulated with conditioned media of each other, or co-cultured. The effects of S100B silencing or a RAGE-neutralizing antibody were also investigated. RESULTS: S100B upregulated TNF-alpha and M1 markers in RAW, and TNF-alpha augmented S100B secretion from L1. L1 conditioned media stimulated TNF-alpha secretion from RAW, and RAW conditioned media increased S100B secretion from L1. The co-culture of RAW and L1 increased TNF-alpha, S100B, and the expression of M1 markers and the MCP-1 receptor CCR2. The silencing of S100B or RAGE neutralization significantly ameliorated TNF-alpha hypersecretion from RAW that were stimulated with L1 conditioned media. CONCLUSIONS: Thus, S100B as an adipokine may play a role in the interaction between adipocytes and macrophages to establish a vicious paracrine loop. PMID- 23804366 TI - Why do homeless people use a mobile health unit in a country with universal health care? AB - Mobile health units (MHUs) are an important source of health care for the uninsured; however, it is unclear what role these units play in Canada, where a universal health insurance system exists. The purpose of this study was to understand why individuals who live in a country with universal health insurance seek care at an MHU and to determine whether MHUs are used in addition to or in place of the client's usual source of care. This study investigated the use of the Rotary Club of Toronto Health Bus among 150 homeless and marginally housed adults in Toronto, Ontario, over a 3-month period. Data were collected on demographic characteristics, current and lifetime homelessness, health care use, and reasons for using the Health Bus. The majority of participants (94.6%) had a regular health care source, primarily doctor's offices (41.6%) and community health centers (16.1%); 18 (12.1%) stated that the Health Bus was their usual source of care. Participants were frequent users of the Health Bus, reporting a median of 7.0 visits (interquartile range, 3.5-12.0 visits) in the past 3 months. Most clients (86.0%) reported using the Health Bus to obtain basic supplies (eg, vitamins, socks); health problems were cited as reasons for using the Health Bus for 55 (36.7%) participants. The findings suggest that in a country with universal health insurance, MHUs supplement other sources of health care, providing essential supplies and offering important outreach services to a high needs population. PMID- 23804367 TI - Sustainability of a culturally informed community-based diabetes prevention program for obese latino youth. AB - Latino youth are disproportionately impacted by obesity and type 2 diabetes; however, few lifestyle interventions have targeted this population. Therefore, the purpose of this study was to assess the impact of a culturally informed lifestyle education program on nutrition and physical activity behaviors among obese Latino youth. A retrospective chart review of 67 youths was conducted with self-reported nutrition and physical activity assessed both immediately following the program and after long-term follow-up. Body mass index (BMI) was evaluated to determine the impact of behavior changes on adiposity. Healthy nutrition and physical activity changes were reported by 20%-59% of youths immediately following the program. However, most of these changes were attenuated over the 261 +/- 49 day follow-up with reported walking (25.4%) and sports participation (34.3%) sustained to a greater extent than dietary changes (3.4-14.9%). Nonetheless, children who continued walking at follow-up exhibited significantly larger reductions in BMI compared with those who did not (-1.63 +/- 0.56 vs. 0.44 +/- 0.30 kg/m(2), P < .05). Based on our pilot study, we conclude that community based lifestyle education programs can support behavior modification and weight management in obese Latino youth. Ongoing support may be necessary to encourage sustained behavior change to facilitate greater weight loss. PMID- 23804368 TI - Promoting patient-centered preventive care using a wellness portal: preliminary findings. AB - Optimal delivery of preventive services requires appropriate information processing and patient involvement. However, information is limited in preventive service delivery that integrates health information technology (HIT). This study aimed to develop and pilot test an Internet-based wellness portal to facilitate patient-centered care. Guiding portal development, an advisory panel systematically identified portal elements/features and engaged in the Delphi technique to achieve consensus on portal structure. To pilot test the portal, 30 patients were randomly recruited from 2 practices to complete a questionnaire. Frequency statistics were compiled for structured questions, and content analyses were conducted to examine qualitative responses on portal utility. Participant age ranged from 23 to 83 years (mean, 41 years). About 78% were female, 22% were ethnic minorities, and 80% had some college education. The portal provides a personalized wellness plan for preventive services based on patient demographics, medical history, risk factors, medications, laboratory tests, and functions like symptoms tracking, access to education materials, and secure patient-practice communication. Patients rated the portal in ease of use, importance, and utility/value. Over 90% found the portal easy to use in terms of navigation, finding information, comprehension, and instructions. Patients regarded the portal as an important tool in achieving wellness, improving patient-practice interactions, and a valuable resource. Contents analyses showed that patients found the portal helpful, particularly its reminder and tracking functions. Patients with basic computer literacy may use a simple, consumer-oriented Web site to manage their preventive care. The portal exemplifies how HIT may encourage active patient participation in their care and potentially improve health outcomes. PMID- 23804369 TI - Situated health promotion: reflections on implementing situated learning approaches in health promotion. AB - Handing down health knowledge and behavior patterns is a main objective of health promotion. Often, interventions do not bring about the intended change of behavior. This could be due, among other things, to the fact that the majority of intervention programs are not based on principles of instructional design to bridge the gap between knowledge and action. A situated design of health promotion measures is to be considered particularly suitable. That accounts for the fact that the acquisition and application of knowledge is an active construction process on the part of the individuals involved, and one that includes the possibility to improve the quality of learning processes in the area of health promotion, and thus increases the probability that acquired knowledge can be applied in real situations. In the context of the problem that most health promotion interventions frequently do not show the desired permanent behavioral changes of the participating individuals, from a pedagogical perspective, it is crucial that current didactic-methodological principles be taken into account. This, too, should be taken into account in connection with an empirical analysis of the reflections in this article. In the following paper, various suggestions for implementation are explained and discussed. PMID- 23804370 TI - Needle Syringe Program-Based Primary HealthCare Centers: Advantages and Disadvantages. AB - Needle syringe programs (NSPs) are now on a strong platform mainly because of their crucial role in controlling/containing blood-borne virus infections. In many parts of the world, NSPs are gradually augmenting their role as a primary health care centers. Health care from NSPs are found to be better accessible by injecting drug users (IDUs). However, these outlets are becoming a separate source of health care for IDUs-mainly because (i) nondrug users very rarely access these and (ii) IDUs do not access other sources of primary care readily. Moreover, offering health care from NSPs is also relatively cost-intensive, therefore, has some disadvantages. The aim of this commentary is to examine and discuss the advantages and disadvantages of NSP-based primary health care outlets. The benefits NSPs can accrue through offering health care services are immense, as an NSP is a critical junction for service providers to offer health care services to IDUs, who traditionally have been hard to reach by conventional health care. Despite some disadvantages, NSP-based health care is very valuable for IDUs until they are duly taken care by the conventional health care centers. PMID- 23804371 TI - Effects of interval walking on physical fitness in middle-aged individuals. AB - The purpose of this study is to examine the effects of a 3-month interval walking program on peak aerobic capacity and cardiovascular risk factors in middle-aged sedentary individuals. Participants were divided into 2 groups: a nontraining control group (n = 17) and an interval walking training group (n = 29). Participants in the interval walking training group were instructed to perform 5 or more sets of 3-min low-intensity walking interspersed by 3-min of moderate to high-intensity walking (>70% of peak aerobic capacity) on 4 or more days/week. Measurements of peak aerobic capacity, blood pressure, blood lipids, and glucose concentration were performed before and after training. Twenty-six individuals completed the interval walking program averaging 4 days/week for 34 min, of which 16 min were moderate to high-intensity walking, with a total energy expenditure of 776 kcal/week. Three months of interval walking increased peak aerobic capacity (from 20.4 +/- 3.0 to 26.0 +/- 5.2 mL/kg/min; P < .001) and reduced resting systolic blood pressure (127 +/- 11 to 119 +/- 11 mm Hg; P = .01). There was an inverse correlation between initial level and training-induced changes in glucose, HbA1c, high-density lipoprotein, and low-density lipoprotein. Conversely, 3 months of nontraining did not improve physical fitness or cardiovascular risk factors. Very modest amounts of aerobic exercise involving brief periods of interspersed higher intensity exercise can significantly increase peak aerobic capacity and reduce resting systolic blood pressure in middle-aged sedentary individuals and contribute to a normalization of cardiovascular risk factors in individuals with elevated initial values. PMID- 23804372 TI - Epidemiological survey of knowledge, attitudes, and health literacy concerning mental illness in a national community sample: a global burden. AB - The aim of this study was to examine the knowledge, attitudes, and practices concerning mental illness among Qatari and other Arab expatriates. METHOD: This is a cross-sectional survey conducted from October 2008 to March 2009. A questionnaire was designed to assess knowledge, attitude, and practice regarding mental illness. RESULTS: Of 2254 subjects surveyed, 49.6% were Qataris, 50.4% other Arab expatriates, 54.8% males, and 45.2% females. A majority of the respondents thought that substance abuse like alcohol or drugs could result in mental illness (84.7%). Fewer than half of the subjects believed that mentally ill people are mentally retarded (40.6%). 48.3% believed that mental illness could result from punishment from God. The most common information source on mental illness was media (64.2%). Recognition of common mental disorders in the studied population was poor (72.5%). CONCLUSION: Knowledge of mental illness among the Arabic-speaking population of Qatar was quite poor. PMID- 23804373 TI - The Introduction of a New Screening Tool for the Identification of Cognitively Impaired Medically At-Risk Drivers: The SIMARD A Modification of the DemTect. AB - The number of drivers with a cognitive impairment due to dementia or other age associated pathologies will increase significantly over the next 3 decades. Physicians are well placed to identify medically at-risk drivers, but are hampered by the lack of a valid, easy to administer screening tool. This research develops and validates a brief screening tool for use in the primary care setting to identify drivers with cognitive impairment with or without dementia. Initial Study Participants: A cohort of 146 consecutive referrals from community-based family physicians, diagnosed with an undifferentiated cognitive impairment or dementia, as well as 35 community dwelling healthy controls. Validation Study: A cohort of 192 consecutive referrals carrying the same diagnosis as above and 52 community dwelling healthy controls. Criterion Measure: Pass/fail on an On-Road evaluation. Predictor Measures: Subtests of the DemTect, a screening test for cognitive impairment or dementia developed by Kalbe and colleagues.(1) Initial Study: Three of the DemTect measures predicted On-Road outcomes (R(2) = .262). Regression results were used to develop a simple scoring algorithm, with cut points then derived by identifying those most at risk for failing and passing the On-Road assessment, and those needing a driving assessment for determination of driving competency. 89 individuals scored in the indeterminate range, with 49 and 43 predicted to fail and pass, respectively-86% and 84% of those predicted to fail and pass did subsequently fail and pass. Validation Study: 123 individuals scored in the indeterminate range, with 66 and 55 predicted to fail and pass, respectively-80% and 87% of those predicted to fail and pass did subsequently fail and pass. CONCLUSIONS: The SIMARD A Modification of the DemTect ( S creen for the I dentification of cognitively impaired M edically A t- R isk D rivers) is a brief paper and pencil screening tool with a high degree of accuracy that can be used for immediate decisions in the clinical setting. PMID- 23804374 TI - Challenges in developing community and clinician partnerships for prevention. AB - Developing links between primary care practices and community organizations to help manage patients with unhealthy behaviors has been proposed as a strategy to improve health care delivery. The objective of this study was to evaluate easily reproducible interventions to improve referral rates between primary care practices and community organizations to help manage tobacco use, poor diet, and physical inactivity. A 6-month, 3-group clinical trial involving 9 adult primary care practices was conducted beginning in February 2008. The 3 groups included usual care, a passive intervention in which practices received referral material, and an active intervention group in which practices also nominated a "champion" to support the project and had access to a Web site to assist in the development of links with community organizations. Charts were abstracted at baseline, at the midpoint of the project (3 months), and at the completion of the project (6 months). Field notes were collected from the project members during the intervention period. Over the course of the project, regardless of group, the rate of detection of the 3 unhealthy behaviors was lower than expected. Few of those identified with an unhealthy behavior were referred to a community organization. Barriers included concerns among the health care providers about costs to their patients, lack of time to facilitate referral, and staff turnover at the community organizations that precluded the development of partnerships. Thus, the interventions evaluated to develop links between primary care practices and community organizations were not successful. PMID- 23804375 TI - Teaching primary prevention of Alzheimer's disease: does it make a difference? AB - Alzheimer's disease (AD) is one of the most feared illnesses among older adults. Although no cure exists, an emerging body of literature has outlined potentially risk-reducing behaviors. As evidence has become available on risk reduction, community organizations and advocacy groups have developed health education courses on the topic. This study examines the impact of one educational program on the audience's efficacy expectations and outcome expectations for behavior change. Participants included 53 older adults residing in a continuing care retirement community. The study used a pretest-posttest design with an experimental group (n = 33) and a control group (n = 20). Topics on weekly classes included the relationship between cardiovascular factors and AD, dietary factors implicated in AD, and mental stimulation to reduce AD risk. Class sessions consisted of lecture, discussion, and demonstration. Between-group differences were found for both efficacy (P = .016) and outcome expectations (P = .000). Within-group differences were only significant for increased outcome expectations related to literature-derived behaviors (P = .000). Future work should focus on action and prevention and on replication of the educational program's evaluation in a more diverse population. PMID- 23804376 TI - Influenza vaccination and cardiovascular mortality in women and men at least 60 years of age in the metropolitan area of sao paulo, Brazil. AB - OBJECTIVES: Influenza (flu) vaccination has been associated with a reduction in cardiovascular mortality in a metropolitan area of Brazil. Nevertheless, it is unknown whether sex influences this outcome. The aim of the study was analyze the cardiovascular disease (CVD) mortality in women and men before and after the initiation of a flu vaccination program. METHODS: We analyzed the mortality of ischemic heart disease (IHD), stroke, and external causes (EC) in women and men at least 60 years of age in the metropolitan area of Sao Paulo before and after the initiation of a flu vaccination program. Estimates of the population were obtained from the Brazilian Institute of Geography and Statistics and the mortality data from the Ministry of Health for the period between 1980 and 2006. The risk of death was adjusted by the direct method using the 1960 world standard population. RESULTS: Change in trend in mortality after vaccination was significant only for IHD (-9.3% vs -30.2%; P = .022) and remained unchanged for stroke (-31.4% vs -25.3%; P =.931) and EC (-8.5% vs -1.2%; P = .941). The decline in IHD pre- (1980-1995) and post-vaccination (1996-2006) was greater in women ( 3.8% vs -28.8%; P = .001) than in men (-12.9% vs -30.4%; P = .054). CONCLUSION: Flu vaccination was associated with a significant reduction of IHD mortality, more so in women than in men. PMID- 23804377 TI - Biochemical biomarkers in liver and gill tissues of freshwater fish Carassius auratus following in vivo exposure to hexabromobenzene. AB - Hexabromobenzene (HBB) is a novel brominated flame retardant (BFR) with ample evidence of its ubiquitous existence in the aquatic ecosystems. However, to date, the toxicological effects of this BFR on fish have been inadequately researched. The present study was conducted, based on an in vivo model, to investigate HBB induced biochemical changes in liver and gill tissues of Carassius auratus after medium-term exposure to different concentrations (10, 150, and 300 mg/kg) for 7, 14, and 25 days. Oxidative stress was evoked evidently for the prolonged exposure, demonstrated by significant inhibition in antioxidant enzymes activities including superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase, and glutathione S-transferase, and a decrease in reduced glutathione level, as well as simultaneous elevation in malondialdehyde content. Moreover, Na(+) , K(+) -ATPase activity, and protein level were remarkably reduced in fish tissues. Based on the integrated biomarker response, the toxic potency in each treatment was distinguished, and the more severe stress was mainly noted with the increasing concentrations and the extending durations. It was also observed that liver exhibited more pronounced alterations in biochemical parameters than gill, probably indicating the vulnerability of liver to HBB triggered oxidative stress. Taken together, the results of this study clearly showed that HBB was capable of inducing oxidative stress and inhibiting Na(+) , K(+) -ATPase activity in different tissues of C. auratus after medium-term exposure. PMID- 23804378 TI - Recombinant human coxsackievirus B3 from children with acute myocarditis in China. AB - Recombination events were found in two human coxsackievirus B3 strains, Beijing0811 and SD2012CHN. The strains were isolated separately from five newborns diagnosed with severe hospital-acquired acute myocarditis in Beijing in 2008 and from two children diagnosed with hand, foot, and mouth disease with concurrent acute myocarditis in Shandong in 2012. PMID- 23804379 TI - Identification of mycobacteria from solid and liquid media by matrix-assisted laser desorption ionization-time of flight mass spectrometry in the clinical laboratory. AB - Mycobacteria cause significant morbidity in humans. Rapid and accurate mycobacterial identification is important for improvement of patient outcomes. However, identification may be challenging due to the slow and fastidious growth of mycobacteria. Several diagnostic methods, such as biochemical, sequencing, and probe methods, are used for mycobacterial identification. We compared the matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) Biotyper system (Bruker Daltonics) to 16S rRNA/hsp65 sequencing and/or DNA probes (Gen-Probe) for mycobacterial identification. One hundred seventy-eight mycobacterial isolates grown on solid and/or broth medium were included in the study. MALDI-TOF MS identified 93.8% of the mycobacteria isolates accurately to the species level and 98.3% to the genus level, independent of the type of medium used for isolation. The identification of mycobacteria directly from cultures using MALDI-TOF MS allows for precise identification in an hour compared to traditional biochemical and phenotypic methods that can take weeks or probes and sequencing that may take a few hours. Identification by MALDI-TOF MS potentially reduces the turnaround time and cost, thereby saving resources within the health care system. PMID- 23804380 TI - Algorithm-based prediction of HIV-1 subtype D coreceptor use. AB - We compared the coreceptor tropism-predicting performance of a specific genotypic algorithm for HIV-1 subtype D and that of the geno2pheno algorithm with different cutoffs. The D-specific algorithm and geno2pheno with a false-positivity rate cutoff of 2.5% had the same concordance with the phenotypic determination. The geno2pheno algorithm with a false-positivity rate cutoff of 2.5%, more sensitive but slightly less specific, seems to be an appropriate alternative. PMID- 23804381 TI - Intestinal dysbiosis and depletion of butyrogenic bacteria in Clostridium difficile infection and nosocomial diarrhea. AB - Clostridium difficile infection (CDI) causes nearly half a million cases of diarrhea and colitis in the United States each year. Although the importance of the gut microbiota in C. difficile pathogenesis is well recognized, components of the human gut flora critical for colonization resistance are not known. Culture independent high-density Roche 454 pyrosequencing was used to survey the distal gut microbiota for 39 individuals with CDI, 36 subjects with C. difficile negative nosocomial diarrhea (CDN), and 40 healthy control subjects. A total of 526,071 partial 16S rRNA sequence reads of the V1 to V3 regions were aligned with 16S databases, identifying 3,531 bacterial phylotypes from 115 fecal samples. Genomic analysis revealed significant alterations of organism lineages in both the CDI and CDN groups, which were accompanied by marked decreases in microbial diversity and species richness driven primarily by a paucity of phylotypes within the Firmicutes phylum. Normally abundant gut commensal organisms, including the Ruminococcaceae and Lachnospiraceae families and butyrate-producing C2 to C4 anaerobic fermenters, were significantly depleted in the CDI and CDN groups. These data demonstrate associations between the depletion of Ruminococcaceae, Lachnospiraceae, and butyrogenic bacteria in the gut microbiota and nosocomial diarrhea, including C. difficile infection. Mechanistic studies focusing on the functional roles of these organisms in diarrheal diseases and resistance against C. difficile colonization are warranted. PMID- 23804382 TI - PCR for detection of herpes simplex virus in cerebrospinal fluid: alternative acceptance criteria for diagnostic workup. AB - The determination of herpes simplex virus (HSV) infection using a PCR assay is one of the most commonly requested tests for analysis of cerebrospinal fluid (CSF), although only a very low proportion of results are positive. A previously reported study showed that selecting only those CSF samples with >5 leukocytes/mm(3) or a protein level of >50 mg/dl was adequate for the diagnostic workup. The aim of the present study was to assess the reliability of alternative acceptance criteria based on elevated CSF white blood cell counts (>10 cells/mm(3)). We analyzed all requests for HSV PCR received between January 2008 and December 2011. CSF samples were accepted for analysis if they had >10 cells/mm(3) or if the sample was from an immunocompromised patient or a child aged <2 years. In order to evaluate our selection criteria, we identified those CSF samples with a leukocyte count of 5 to 10 cells/mm(3) or protein levels of >50 mg/dl in order to test them for HSV type 1 and 2 (HSV-1 and HSV-2) DNA. During the study period, 466 CSF samples were submitted to the microbiology laboratory for HSV PCR. Of these, 268 (57.5%) were rejected, and 198 (42.5%) were tested according to our routine criteria. Of the tested samples, 11 (5.5%) were positive for HSV DNA (7 for HSV-1 and 4 for HSV-2). Of the 268 rejected specimens, 74 met the criteria of >5 cells/mm(3) and/or protein levels of >50 mg/dl. Of these, 70 (94.6%) were available for analysis. None of the samples yielded a positive HSV PCR result. Acceptance criteria based on CSF leukocyte counts, host immune status, and age can help to streamline the application of HSV PCR without reducing sensitivity. PMID- 23804383 TI - Ultrasensitive amplification refractory mutation system real-time PCR (ARMS RT PCR) assay for detection of minority hepatitis B virus-resistant strains in the era of personalized medicine. AB - Resistance to antiviral treatment for chronic hepatitis B virus (HBV) has been associated with mutations in the HBV polymerase region. This study aimed at developing an ultrasensitive method for quantifying viral populations with all major HBV resistance-associated mutations, combining the amplification refractory mutation system real-time PCR (ARMS RT-PCR) with a molecular beacon using a LightCycler. The discriminatory ability of this method, the ARMS RT-PCR with molecular beacon assay, was 0.01 to 0.25% for the different HBV resistance associated mutations, as determined by laboratory-synthesized wild-type (WT) and mutant (Mut) target sequences. The assay showed 100% sensitivity for the detection of mutant variants A181V, T184A, and N236T in samples from 41 chronically HBV-infected patients under antiviral therapy who had developed resistance-associated mutations detected by direct PCR Sanger sequencing. The ratio of mutant to wild-type viral populations (the Mut/WT ratio) was >1% in 38 (63.3%) of 60 samples from chronically HBV-infected nucleos(t)ide analogue-naive patients; combinations of mutations were also detected in half of these samples. The ARMS RT-PCR with molecular beacon assay achieved high sensitivity and discriminatory ability compared to the gold standard of direct PCR Sanger sequencing in identifying resistant viral populations in chronically HBV-infected patients receiving antiviral therapy. Apart from the dominant clones, other quasispecies were also quantified. In samples from chronically HBV-infected nucleos(t)ide analogue-naive patients, the assay proved to be a useful tool in detecting minor variant populations before the initiation of the treatment. These observations need further evaluation with prospective studies before they can be implemented in daily practice. PMID- 23804384 TI - Blind evaluation of the microwave-accelerated metal-enhanced fluorescence ultrarapid and sensitive Chlamydia trachomatis test by use of clinical samples. AB - Accurate point-of-care (POC) diagnostic tests for Chlamydia trachomatis infection are urgently needed for the rapid treatment of patients. In a blind comparative study, we evaluated microwave-accelerated metal-enhanced fluorescence (MAMEF) assays for ultrafast and sensitive detection of C. trachomatis DNA from vaginal swabs. The results of two distinct MAMEF assays were compared to those of nucleic acid amplification tests (NAATs). The first assay targeted the C. trachomatis 16S rRNA gene, and the second assay targeted the C. trachomatis cryptic plasmid. Using pure C. trachomatis, the MAMEF assays detected as few as 10 inclusion forming units/ml of C. trachomatis in less than 9 min, including DNA extraction and detection. A total of 257 dry vaginal swabs from 245 female adolescents aged 14 to 22 years were analyzed. Swabs were eluted with water, the solutions were lysed to release and to fragment genomic DNA, and MAMEF-based DNA detection was performed. The prevalence of C. trachomatis by NAATs was 17.5%. Of the 45 samples that were C. trachomatis positive and the 212 samples that were C. trachomatis negative by NAATs, 33/45 and 197/212 were correctly identified by the MAMEF assays if both assays were required to be positive (sensitivity, 73.3%; specificity, 92.9%). Using the plasmid-based assay alone, 37/45 C. trachomatis positive and 197/212 C. trachomatis-negative samples were detected (sensitivity, 82.2%; specificity, 92.9%). Using the 16S rRNA assay alone, 34/45 C. trachomatis positive and 197/212 C. trachomatis-negative samples were detected (sensitivity, 75.5%; specificity, 92.9%). The overall rates of agreement with NAAT results for the individual 16S rRNA and cryptic plasmid assays were 89.5% and 91.0%, respectively. Given the sensitivity, specificity, and rapid detection of the plasmid-based assay, the plasmid-based MAMEF assay appears to be suited for clinical POC testing. PMID- 23804385 TI - Clinical impact of the analytical specificity of the hybrid capture 2 test: data from the New Technologies for Cervical Cancer (NTCC) study. AB - The Hybrid Capture 2 (HC2) test targets 13 human papillomavirus (HPV) types. Here, cross-reactivity with non-HC2-targeted HPV types is described. We aimed to define the proportion of HC2-positive women who had negative results with HC2 targeted HPV types and estimate its determinants and impact on women's health management. The New Technologies for Cervical Cancer (NTCC) trial was followed in two predetermined phases. Women in the experimental arm were tested for the presence of HPV DNA by HC2 following a sample collection in PreservCyt (first phase) or Digene specimen transport medium (STM) (second phase). HPV genotyping was performed on DNA samples from HC2-positive women by PCR with GP5(+)/GP6(+) primers and reverse line blot (RLB) hybridization. Untyped samples were submitted to direct sequencing or restriction fragment length polymorphism. Multivariate logistic regression analysis estimated the adjusted odds ratios (ORs) between the presence of HC2-targeted types and age, viral load, and type of transport medium. Out of 2,920 HC2-positive samples, 2,310 (79.1%) were positive on RLB for HC2 targeted types, 396 were positive (13.6%) for only non-HC2-targeted types (mostly represented by HPV-53, HPV-66, and HPV-70), and in 214 (7.33%) samples, no HPV types were detected. The probability of detecting HC2-targeted types increased with increasing viral load expressed as the relative light unit/positive-control specimen ratio (RLU/PC) (OR for unitary increase of log RLU/PC, 1.35; 95% confidence interval [CI], 1.30 to 1.42) and with STM versus PreservCyt (OR, 1.56; 95% CI, 1.25 to 1.84). If only the samples containing HC2-targeted types tested positive, the positive predictive value (PPV) would have increased from 7.0% (95% CI, 6.1% to 8.0%) to 8.4% (95% CI, 7.3 to 9.6), although 4.9% (95% CI, 2.4% to 8.8%) of cervical intraepithelial neoplasia grade 2(+) (CIN2(+)) cases would have been missed. In conclusion, STM use and an increased cutoff would reduce the HC2 analytical false-positive rate and increase the positive predictive value for high-grade CIN. The gain in clinical sensitivity by detecting non-HC2-targeted HPV types is limited. PMID- 23804386 TI - Evaluation of a new automated homogeneous PCR assay, GenomEra C. difficile, for rapid detection of Toxigenic Clostridium difficile in fecal specimens. AB - We evaluated a new automated homogeneous PCR assay to detect toxigenic Clostridium difficile, the GenomEra C. difficile assay (Abacus Diagnostica, Finland), with 310 diarrheal stool specimens and with a collection of 33 known clostridial and nonclostridial isolates. Results were compared with toxigenic culture results, with discrepancies being resolved by the GeneXpert C. difficile PCR assay (Cepheid). Among the 80 toxigenic culture-positive or GeneXpert C. difficile assay-positive fecal specimens, 79 were also positive with the GenomEra C. difficile assay. Additionally, one specimen was positive with the GenomEra assay but negative with the confirmatory methods. Thus, the sensitivity and specificity were 98.8% and 99.6%, respectively. With the culture collection, no false-positive or -negative results were observed. The analytical sensitivity of the GenomEra C. difficile assay was approximately 5 CFU per PCR test. The short hands-on (<5 min for 1 to 4 samples) and total turnaround (<1 h) times, together with the high positive and negative predictive values (98.8% and 99.6%, respectively), make the GenomEra C. difficile assay an excellent option for toxigenic C. difficile detection in fecal specimens. PMID- 23804387 TI - Multiplex 5' nuclease quantitative real-time PCR for clinical diagnosis of malaria and species-level identification and epidemiologic evaluation of malaria causing parasites, including Plasmodium knowlesi. AB - Molecular diagnosis of malaria offers many potential advantages over microscopy, including identification of malaria to the species level in an era with few experienced microscopists. We developed high-throughput multiplex 5' nuclease quantitative PCR (qPCR) assays, with the potential to support large studies, to specifically identify Plasmodium falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi. We compared qPCR to microscopy and confirmed discordant results with an alternative target PCR assay. The assays specifically detected 1 to 6 parasites/MUl of blood. The clinical sensitivities (95% confidence intervals [CIs]) of the 4-plex assay to detect microscopically confirmed malaria were 95.8% (88.3 to 99.1%) for P. falciparum, 89.5% (75.2 to 97.1%) for P. vivax, 94.1% (71.3 to 99.9%) for P. ovale, and 100% (66.4 to 100%) for P. malariae. The specificities (95% CIs) were 98.6% (92.4 to 100%) for P. falciparum, 99% (84.8 to 100%) for P. vivax, 98.4% (94.4 to 99.8%) for P. ovale, and 99.3% (95.9 to 100%) for P. malariae. The clinical specificity for samples without malaria was 100%. The clinical sensitivity of the 5-plex assay for confirmed P. knowlesi malaria was 100% (95% CI, 69.2 to 100%), and the clinical specificity was 100% (95% CI, 87.2 to 100%). Coded retesting and testing with an alternative target PCR assay showed improved sensitivity and specificity of multiplex qPCR versus microscopy. Additionally, 91.7% (11/12) of the samples with uncertain species by microscopy were identified to the species level identically by both our multiplex qPCR assay and the alternative target PCR assay, including 9 P. falciparum infections. Multiplex qPCR can rapidly and simultaneously identify all 5 Plasmodium species known to cause malaria in humans, and it offers an alternative or adjunct to microscopy for clinical diagnosis as well as a needed high-throughput tool for research. PMID- 23804389 TI - Increased sensitivity in diagnosis of tuberculosis in HIV-positive patients through the small-membrane-filter method of microscopy. AB - The sensitivity of microscopy for the diagnosis of tuberculosis (TB) is around 50% but decreases by about 15% in patients with suspected TB who are coinfected with HIV. Here, we compared the accuracies of three microscopy methods for processing sputum smears (concentration by centrifugation with or without N acetyl-L-cysteine [NALC] and concentration by filtration on a polycarbonate membrane) to that of culture on Ogawa-Kudoh medium as the gold standard method. Sputum samples were obtained from 432 patients with suspected pulmonary TB, of whom 60% were infected with HIV. Analysis was performed using the first specimen. Compared to the gold standard culture, the small-membrane-filter (SMF) method was the most sensitive microscopic method. In HIV-infected TB patients, the sensitivity of the SMF method was significantly higher than those for centrifugation of sputum samples with or without NALC treatment (61.9%, 47.6%, and 45.2%, respectively; P = 0.001). Similarly, in TB patients without HIV infection, the sensitivity of the SMF method was significantly higher than those for centrifugation of sputum samples with or without NALC treatment (81.8%, 63.6%, and 57.5%, respectively; P = 0.001). In the two study groups, TB patients with or without HIV, no significant differences between the specificities of the three methods were observed. Handling of the second sputum sample similarly by centrifugation with or without NALC and by the SMF method increased positivities by 13%, 11%, and 4%, respectively. The overall agreement between microscopy and culture was above 90% for all groups. Microscopic evaluation of the sputum samples treated with NALC compared to those not treated with NALC did not show any increase in sensitivity. Altogether, the sensitivity of the SMF method is higher than those of the other two microscopic methods studied without a loss of specificity. PMID- 23804388 TI - Isavuconazole activity against Aspergillus lentulus, Neosartorya udagawae, and Cryptococcus gattii, emerging fungal pathogens with reduced azole susceptibility. AB - Isavuconazole is an extended-spectrum triazole with in vitro activity against a wide variety of fungal pathogens. Clinical isolates of molds Aspergillus lentulus and Neosartorya udagawae and yeast Cryptococcus gattii VGII (implicated in the outbreak in the Pacific Northwest, North America) exhibit reduced susceptibilities to several azoles but higher susceptibilities to isavuconazole. PMID- 23804390 TI - Epidemiological and microbiological characteristics of an outbreak caused by OXA 48-producing Enterobacteriaceae in a neonatal intensive care unit in Jerusalem, Israel. AB - This study describes the course of an OXA-48-producing Enterobacteriaceae (OPE) outbreak that started in March 2012 in a neonatal intensive care unit (NICU) in Jerusalem, Israel. During the peak of the outbreak (January to August 2012), there were 49 patients who had proven or suspected acquisition of OPE in the NICU, including 16 with invasive infections, out of a total of 156 patients who were hospitalized during that period. Three children hospitalized in the pediatric ICU were identified as carriers of OPE. Three patients with a previous stay in the affected NICU were identified as OPE carriers upon admission to another hospital. The Ministry of Health was notified and then intervened in July 2012. Intervention included cohorting colonized patients, conducting frequent rectal-culture surveillance, and improving the implementation of infection control practices. As a result, the incidence of OPE acquisition declined to 5 cases in the first 4 months, followed by no new cases in the next 3 months. Thirty-one patient-unique isolates were available for analysis: 29 Klebsiella pneumoniae isolates, all belonging to a single clone (sequence type 39 [ST39]), and 2 isolates from Enterobacter cloacae. All isolates possessed the blaOXA-48 and blaCTX-M-14 genes, which are located on the same plasmid. This plasmid, similar to the global blaOXA-48-harboring vector, has now acquired blaCTX-M-14, leading to resistance to all beta-lactam agents. PMID- 23804391 TI - New rapid scheme for distinguishing the subspecies of the Mycobacterium abscessus group and identifying Mycobacterium massiliense isolates with inducible clarithromycin resistance. AB - Mycobacterium abscessus (M. abscessus sensu lato, or the M. abscessus group) comprises three closely related taxa whose taxonomic statuses are under revision, i.e., M. abscessus sensu stricto, Mycobacterium bolletii, and Mycobacterium massiliense. We describe here a simple, robust, and cost-effective PCR-based method for distinguishing among M. abscessus, M. massiliense, and M. bolletii. Based on the M. abscessus ATCC 19977(T) genome, regions that discriminated between M. abscessus and M. massiliense were identified through array-based comparative genomic hybridization. A typing scheme using PCR primers designed for four of these locations was applied to 46 well-characterized clinical isolates comprising 29 M. abscessus, 15 M. massiliense, and 2 M. bolletii isolates previously identified by multitarget sequencing. Interestingly, 2 isolates unequivocally identified as M. massiliense were shown to have a full-length erm(41) gene instead of the expected gene deletion and showed inducible clarithromycin resistance after 14 days. We propose using this PCR-based typing scheme combined with erm(41) PCR for straightforward identification of M. abscessus, M. massiliense, and M. bolletii and the assessment of inducible clarithromycin resistance. This method can be easily integrated into a routine workflow to provide subspecies-level identification within 24 h after isolation of the M. abscessus group. PMID- 23804392 TI - Evaluation of cycloserine-cefoxitin fructose agar (CCFA), CCFA with horse blood and taurocholate, and cycloserine-cefoxitin mannitol broth with taurocholate and lysozyme for recovery of Clostridium difficile isolates from fecal samples. AB - Cycloserine-cefoxitin fructose agar (CCFA), CCFA with horse blood and taurocholate (CCFA-HT), and cycloserine-cefoxitin mannitol broth with taurocholate and lysozyme (CCMB-TAL) were compared for recovery of Clostridium difficile from 120 stool specimens. Compared to CCFA, CCFA-HT enhanced C. difficile growth and improved recovery by 4%. In a separate study, 9% (8/91) of stool samples previously C. difficile negative on plate medium were C. difficile positive when cultured in CCMB-TAL. PMID- 23804393 TI - Evaluation of the BinaxNOW Staphylococcus aureus test for rapid identification of Gram-positive cocci from VersaTREK blood culture bottles. AB - The ability of the rapid BinaxNOW Staphylococcus aureus (BNSA) immunochromatographic test (Alere Scarborough, Inc., ME) to accurately differentiate S. aureus from coagulase-negative staphylococci (CoNS) and other Gram-positive cocci (GPC) directly from VersaTREK blood culture bottles was evaluated. A total of 319 positive patient blood culture bottles with GPC seen in clusters with Gram staining were tested using the BNSA test and a direct tube coagulase test (DTCT). The BNSA test was accurate for the detection and differentiation of S. aureus from CoNS and other GPC within 30 min from the time of blood culture positivity and demonstrated a test sensitivity and specificity of 95.8% and 99.6%, respectively. BNSA test results were faxed to the antimicrobial stewardship pharmacist by noon each day in order to evaluate empirical antimicrobial therapy and facilitate more rapid changes or modifications if necessary. Same-day reporting of BNSA test results in conjunction with an antimicrobial stewardship program was more impactful in improving treatment for inpatients with documented S. aureus bacteremia than in reducing empirical vancomycin use in inpatients with CoNS during the first 24 h following reporting. PMID- 23804394 TI - Interactive effects of pesticide mixtures, predators, and environmental regimes on the toxicity of two pesticides to red-eyed tree frog larvae. AB - Global amphibian declines have many corroborative causes, and the use of pesticides in agriculture is a likely contributor. In places with high pesticide usage, such as Costa Rica, agrochemical pesticides may interact with other factors to contribute to rapid species losses. Classical ecotoxicological studies rarely address the effects of a pesticide in combination with other stressors. The present study investigated the synergistic roles of 2 pesticides (chlorothalonil and endosulfan), predator stress, and environmental regimes (controlled laboratory environments versus ambient conditions) on the survival of red-eyed tree frog larvae (Agalychnis callidryas). No synergistic effects of pesticide mixtures or predator stress were found on the toxicity of either chlorothalonil or endosulfan. Both pesticides, however, were considerably more toxic under realistic ambient temperature regimes than in a climate-controlled laboratory. Overall, endosulfan displayed the highest toxicity to tadpoles, although chlorothalonil was also highly toxic. The median lethal concentration estimated to kill 50% of a tested population (LC50) for endosulfan treatments under ambient temperatures was less than one-half of that for laboratory treatments (3.26 ug/L and 8.39 ug/L, respectively). Studies commonly performed in stable temperature-controlled laboratories may significantly underestimate toxicity compared with more realistic environmental regimes. Furthermore, global climatic changes are leading to warmer and more variable climates and may increase impacts of pesticides on amphibians. PMID- 23804395 TI - Analysis of outcomes in treatment of obstructive sleep apnea in infants. AB - OBJECTIVES/HYPOTHESIS: To investigate interventions used for treatment of obstructive sleep apnea (OSA) in infants. STUDY DESIGN: Retrospective medical record review. METHODS: Patients 3 to 24 months old at the time of diagnosis of OSA by polysomnography (PSG) were studied at a tertiary care children's hospital. The main outcome measures were demographic data, PSG data, intervention data, subjective results of interventions, and medical comorbidities. RESULTS: Of the 295 patients included, 196 (66%) were males and 99 (34%) were females. The most common interventions with average age at the time of intervention were: adenotonsillectomy, 115 patients (31.8%, 22.3 months); adenoidectomy, 82 patients (22.5%, 17.7 months); observation, 76 patients (20.9%, 12.8 months); supplemental oxygen, 27 patients (7.4%, 11.7 months); continuous positive airway pressure (CPAP)/bilevel positive airway pressure (BiPAP), 18 patients (4.9%, 15.6 months); tonsillectomy, 16 patients (4.4%, 25.7 months); and tracheostomy, six patients (1.7%, 15.3 months). In the youngest patients (3-5 months of age), 89.3% of interventions were nonsurgical and 10.7% were surgical. In the oldest patients (older than 24 months), 17.5% of interventions were nonsurgical and 82.5% were surgical. Subjective improvement following intervention was highest after adenotonsillectomy. The intervention with the greatest percentage decrease in apnea-hypopnea index (objective efficacy) was tracheostomy, followed by CPAP/BiPAP. Average time from diagnosis to intervention was 35.5 days for nonsurgical interventions and 92.4 days for surgical interventions. CONCLUSIONS: Observation was the most common nonsurgical intervention and the most common intervention in patients younger than 12 months. Adenotonsillectomy was the most common surgical and overall intervention. Adenotonsillectomy had the greatest subjective efficacy, and tracheostomy had the greatest objective efficacy. PMID- 23804396 TI - Study of the phase transformation of single particles of Ga2O3 by UV-Raman spectroscopy and high-resolution TEM. AB - By taking advantage of UV-Raman spectroscopy and high-resolution TEM (HRTEM), combined with the focused ion beam (FIB) technique, the transformation from GaOOH into alpha-Ga2O3 and then into beta-Ga2O3 was followed. We found that the stepwise transformations took place from the surface region before developing into the bulk of single particles without particle agglomeration and growth. During the transformation from GaOOH into alpha-Ga2O3, the elimination of water vapor through the dehydroxylation of GaOOH resulted in the formation of micropores in the single particles, whilst maintaining their particle size. For the phase transformation from alpha-Ga2O3 into beta-Ga2O3, the nucleation of beta Ga2O3 was found to occur at the surface defects and this process could be retarded by occupying these defects with a small amount of La2O3. By finely controlling the process of the phase transformation, the beta-Ga2O3 domains gradually developed from the surface into the bulk of the single particles without particle agglomeration. Therefore, the surface structure of the alpha Ga2O3 single particles can be easily tuned and a particle with an alpha@beta core shell phase structure has been obtained. PMID- 23804397 TI - IKZF1 and CRLF2 gene alterations correlate with poor prognosis in Japanese BCR ABL1-negative high-risk B-cell precursor acute lymphoblastic leukemia. AB - BACKGROUND: Genome-wide analysis studies have demonstrated that IKZF1, CRLF2, and JAK2 gene alterations correlate with poor prognosis in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, the prognostic significance for these gene alterations has not been clarified in Japanese patients. PROCEDURE: A total of 194 patients with BCP-ALL enrolled in the Japanese Children's Cancer & Leukemia Study Group ALL 2004 clinical trial were assessed for the presence of three different gene alterations: IKZF1 deletions, CRLF2 expression and JAK2 mutation. RESULTS: IKZF1 deletions and CRLF2-high expression were identified in 22 of 177 (12%) patients and in 15 of 141 (11%) patients, respectively. However, JAK2 R683 mutation was detected only one of 177 patients. The 4-year event-free survival (4y-EFS) was different when comparing patients with or without IKZF1 deletions (68.2% vs. 85.2%; P = 0.04) and was also different when comparing patients with different CRLF2 expression levels (high, 66.7% vs. low, 88.1%; P = 0.03). The differences in 4y-EFS were statistically significant in patients with ALL in the National Cancer Institute (NCI)-high risk group (HR-ALL) (IKZF1 deletions: yes, 58.3% vs. no, 87.0%, P = 0.02; CRLF2 expression: high, 55.6% vs. low, 85.3%, P = 0.04) but not in patients with ALL in the NCI-standard risk group (SR-ALL; IKZF1 deletions: yes, 80.0% vs. no, 84.4%, P = 0.75; CRLF2 expression: high, 83.3% vs. low, 89.2%, P = 0.77). Coexistence of IKZF1 deletions and CRLF2 high expression associated with poor outcomes. CONCLUSIONS: IKZF1 deletions and CRLF2-high expression predicted poor outcomes in patients with HR-ALL but not in patients with SR-ALL in our Japanese cohort. PMID- 23804398 TI - Children's roles in tuberculosis treatment regimes: constructing childhood and kinship in urban Zambia. AB - In Zambia, the burden of HIV-related diseases such as tuberculosis has received substantial international attention. Zambians experience and participate in a range of globally produced programs to manage TB and cure TB sufferers. Guided by WHO's Directly Observed Treatment, Short-course protocol, TB treatment regimens now emphasize adherence to medications as the primary way to achieve cure. This article aims to understand how adherence models enter into the daily lives of children who live with and care for adult TB patients in an area disproportionately affected by the disease. I suggest that children domesticate adherence models, using them as strategies to safeguard identities, relationships, livelihoods, and futures that are increasingly under threat in the age of HIV. They draw on TB treatment and the hope and agency it affords to hold onto a version of childhood in which they are cared for by adults who will advocate for their well-being. PMID- 23804399 TI - Crossing a PDA: the "straightening" technique. PMID- 23804401 TI - Estimating absolute methylation levels at single-CpG resolution from methylation enrichment and restriction enzyme sequencing methods. AB - Recent advancements in sequencing-based DNA methylation profiling methods provide an unprecedented opportunity to map complete DNA methylomes. These include whole genome bisulfite sequencing (WGBS, MethylC-seq, or BS-seq), reduced representation bisulfite sequencing (RRBS), and enrichment-based methods such as MeDIP-seq, MBD-seq, and MRE-seq. These methods yield largely comparable results but differ significantly in extent of genomic CpG coverage, resolution, quantitative accuracy, and cost, at least while using current algorithms to interrogate the data. None of these existing methods provides single-CpG resolution, comprehensive genome-wide coverage, and cost feasibility for a typical laboratory. We introduce methylCRF, a novel conditional random fields based algorithm that integrates methylated DNA immunoprecipitation (MeDIP-seq) and methylation-sensitive restriction enzyme (MRE-seq) sequencing data to predict DNA methylation levels at single-CpG resolution. Our method is a combined computational and experimental strategy to produce DNA methylomes of all 28 million CpGs in the human genome for a fraction (<10%) of the cost of whole genome bisulfite sequencing methods. methylCRF was benchmarked for accuracy against Infinium arrays, RRBS, WGBS sequencing, and locus-specific bisulfite sequencing performed on the same human embryonic stem cell line. methylCRF transformation of MeDIP-seq/MRE-seq was equivalent to a biological replicate of WGBS in quantification, coverage, and resolution. We used conventional bisulfite conversion, PCR, cloning, and sequencing to validate loci where our predictions do not agree with whole-genome bisulfite data, and in 11 out of 12 cases, methylCRF predictions of methylation level agree better with validated results than does whole-genome bisulfite sequencing. Therefore, methylCRF transformation of MeDIP-seq/MRE-seq data provides an accurate, inexpensive, and widely accessible strategy to create full DNA methylomes. PMID- 23804400 TI - Functional DNA methylation differences between tissues, cell types, and across individuals discovered using the M&M algorithm. AB - DNA methylation plays key roles in diverse biological processes such as X chromosome inactivation, transposable element repression, genomic imprinting, and tissue-specific gene expression. Sequencing-based DNA methylation profiling provides an unprecedented opportunity to map and compare complete DNA methylomes. This includes one of the most widely applied technologies for measuring DNA methylation: methylated DNA immunoprecipitation followed by sequencing (MeDIP seq), coupled with a complementary method, methylation-sensitive restriction enzyme sequencing (MRE-seq). A computational approach that integrates data from these two different but complementary assays and predicts methylation differences between samples has been unavailable. Here, we present a novel integrative statistical framework M&M (for integration of MeDIP-seq and MRE-seq) that dynamically scales, normalizes, and combines MeDIP-seq and MRE-seq data to detect differentially methylated regions. Using sample-matched whole-genome bisulfite sequencing (WGBS) as a gold standard, we demonstrate superior accuracy and reproducibility of M&M compared to existing analytical methods for MeDIP-seq data alone. M&M leverages the complementary nature of MeDIP-seq and MRE-seq data to allow rapid comparative analysis between whole methylomes at a fraction of the cost of WGBS. Comprehensive analysis of nineteen human DNA methylomes with M&M reveals distinct DNA methylation patterns among different tissue types, cell types, and individuals, potentially underscoring divergent epigenetic regulation at different scales of phenotypic diversity. We find that differential DNA methylation at enhancer elements, with concurrent changes in histone modifications and transcription factor binding, is common at the cell, tissue, and individual levels, whereas promoter methylation is more prominent in reinforcing fundamental tissue identities. PMID- 23804402 TI - Sympatric chimpanzees and gorillas harbor convergent gut microbial communities. AB - The gut microbial communities within great apes have been shown to reflect the phylogenetic history of their hosts, indicating codiversification between great apes and their gut microbiota over evolutionary timescales. But because the great apes examined to date represent geographically isolated populations whose diets derive from different sources, it is unclear whether this pattern of codiversification has resulted from a long history of coadaptation between microbes and hosts (heritable factors) or from the ecological and geographic separation among host species (environmental factors). To evaluate the relative influences of heritable and environmental factors on the evolution of the great ape gut microbiota, we assayed the gut communities of sympatric and allopatric populations of chimpanzees, bonobos, and gorillas residing throughout equatorial Africa. Comparisons of these populations revealed that the gut communities of different host species can always be distinguished from one another but that the gut communities of sympatric chimpanzees and gorillas have converged in terms of community composition, sharing on average 53% more bacterial phylotypes than the gut communities of allopatric hosts. Host environment, independent of host genetics and evolutionary history, shaped the distribution of bacterial phylotypes across the Bacteroidetes, Firmicutes, Proteobacteria, and Actinobacteria, the four most common phyla of gut bacteria. Moreover, the specific patterns of phylotype sharing among hosts suggest that chimpanzees living in sympatry with gorillas have acquired bacteria from gorillas. These results indicate that geographic isolation between host species has promoted the evolutionary differentiation of great ape gut bacterial communities. PMID- 23804404 TI - The archaeal exosome: identification and quantification of site-specific motions that correlate with cap and RNA binding. PMID- 23804403 TI - Genome-wide and parental allele-specific analysis of CTCF and cohesin DNA binding in mouse brain reveals a tissue-specific binding pattern and an association with imprinted differentially methylated regions. AB - DNA binding factors are essential for regulating gene expression. CTCF and cohesin are DNA binding factors with central roles in chromatin organization and gene expression. We determined the sites of CTCF and cohesin binding to DNA in mouse brain, genome wide and in an allele-specific manner with high read-depth ChIP-seq. By comparing our results with existing data for mouse liver and embryonic stem (ES) cells, we investigated the tissue specificity of CTCF binding sites. ES cells have fewer unique CTCF binding sites occupied than liver and brain, consistent with a ground-state pattern of CTCF binding that is elaborated during differentiation. CTCF binding sites without the canonical consensus motif were highly tissue specific. In brain, a third of CTCF and cohesin binding sites coincide, consistent with the potential for many interactions between cohesin and CTCF but also many instances of independent action. In the context of genomic imprinting, CTCF and/or cohesin bind to a majority but not all differentially methylated regions, with preferential binding to the unmethylated parental allele. Whether the parental allele-specific methylation was established in the parental germlines or post-fertilization in the embryo is not a determinant in CTCF or cohesin binding. These findings link CTCF and cohesin with the control regions of a subset of imprinted genes, supporting the notion that imprinting control is mechanistically diverse. PMID- 23804405 TI - Evaluation of cytotoxic, oxidative stress, proinflammatory and genotoxic effect of silver nanoparticles in human lung epithelial cells. AB - Silver nanoparticles are increasingly used in various products, due to their antibacterial properties. Despite its wide spread use, only little information on possible adverse health effects exists. Therefore, the aim of this study was to assess the toxic potential of silver nanoparticles (<100 nm) in human lung epithelial (A549) cells and the underlying mechanism of its cellular toxicity. Silver nanoparticles induced dose and time-dependent cytotoxicity in A549 cells demonstrated by MTT and LDH assays. Silver nanoparticles were also found to induce oxidative stress in dose and time-dependent manner indicated by depletion of GSH and induction of ROS, LPO, SOD, and catalase. Further, the activities of caspases and the level of proinflammatory cytokines, namely interleukin-1beta (IL 1beta) and interleukin-6 (IL-6) were significantly higher in treated cells. DNA damage, as measured by single cell gel electrophoresis, was also dose and time dependent signicants in A549 cells. This study investigating the effects of silver nanoparticles in human lung epithelial cells has provided valuable insights into the mechanism of potential toxicity induced by silver nanoparticles and warrants more careful assessment of silver nanoparticles before their industrial applications. PMID- 23804406 TI - Development and reliability of a correction factor for family-reported medication adherence: pediatric inflammatory bowel disease as an exemplar. AB - OBJECTIVES: To examine the issue of accurate adherence assessment and illustrate methodologies for correcting parent-reported medication adherence. METHODS: 40 children with inflammatory bowel disease provided medication adherence data using electronic monitoring. Parents provided subjective reports of medication adherence. Receiver operating characteristic analyses were used to examine the detection of non-adherence at several adherence cut-points. 2 methods for empirically deriving a correction factor for subjectively reported adherence were applied. RESULTS: Although parent-report and EM adherence were significantly correlated, parent-reported adherence was significantly higher than EM adherence. A 90% cut-point provided the highest sensitivity and specificity. Both correction factors reliably adjusted parent-reported adherence based on EM adherence. CONCLUSIONS: Application of an empirically derived correction factor for parent reported adherence using methodologies, such as those illustrated in the current study, could yield more accurate adherence assessment. Obtaining more accurate adherence assessments based on parent-report will have implications for self management interventions, clinician prescribing behavior, and medication safety. PMID- 23804407 TI - Schmallenberg virus: a seroprevalence survey in cattle and sheep, France, winter 2011-2012. AB - In France, a national surveillance plan to monitor congenital Schmallenberg virus (SBV) outbreaks was set up in January 2012, and has shown that SBV had become widespread throughout the country since mid-2011. However, the number of SBV infected farms cannot accurately be estimated through congenital SBV reporting alone. Therefore, GDS France (National Animal Health Farmers' Organization) conducted serological investigations in cattle and sheep holdings in several departments in spring 2012 to assess SBV exposure in 2011. A serological study was also conducted in the department of Saone-et-Loire (southern Burgundy) to establish an accurate local overview of circulation of virus in 2011 among cattle. The study was conducted following guidelines elaborated by the French Platform for animal health surveillance. Results indicated differences in within herd seroprevalence between cattle herds and sheep herds in departments where outbreaks of congenital SBV were reported in early 2012 and a great heterogeneity in seroprevalence between areas (even between areas geographically close to each other). In departments which had been severely affected in early 2012, the overall impact of SBV infection in cattle herds during the 2012-2013 calving season will probably be low. On the other hand, given the low proportion of immunised ewes in sheep SBV outbreaks, sheep flocks which were already affected in early 2012 may once again face congenital cases of SBV. PMID- 23804408 TI - Read anything mean lately? associations between reading aggression in books and aggressive behavior in adolescents. AB - Although there have been hundreds of studies on media violence, few have focused on literature, with none examining novels. Accordingly, the aim of the current study was to examine whether reading physical and relational aggression in books was associated with aggressive behavior in adolescents. Participants consisted of 223 adolescents who completed a variety of measures detailing their media use and aggressive behavior. A non-recursive structural equation model revealed that reading aggression in books was positively associated with aggressive behavior, even after controlling for exposure to aggression in other forms of media. Associations were only found for congruent forms of aggression. Implications regarding books as a form of media are discussed. PMID- 23804409 TI - Serological data analyses show that adenovirus 36 infection is associated with obesity: a meta-analysis involving 5739 subjects. AB - OBJECTIVE: Serological studies on the relationship between adenovirus 36 (Ad36) and an increased risk of obesity development have shown conflicting results. We reviewed the published studies and carried out a meta-analysis to explore this relationship. METHODS: PubMed was searched until December 2012 for the relative references with sufficient information to estimate odds ratios (ORs) and 95% confidence intervals (CIs). A total of 11 case-control studies, including 2508 obese subjects and 3005 controls, were selected. RESULTS: Compared with nonobese controls, Ad36 infection significantly increased the obesity risk by a pooled OR of 1.60 (95% CI = 1.14-2.25; P < 0.01). Meta-regression showed that the types of subject and obesity assessments were potential risk factors. In the subgroup analysis, a significantly increased risk was found in children (OR = 1.95; 95% CI = 1.34-2.85; z = 3.45; P < 0.01) and those with an obesity assessment of BMI >= 30 kg/cm2 (OR = 1.89; 95% CI = 1.15-3.10; P < 0.05). CONCLUSIONS: Ad36 infection is associated with an increased risk of obesity development. To our knowledge, this is the first report to reveal the significant relationship in children with a serological data analysis. PMID- 23804410 TI - Multivariate logistic regression analysis for prediction of clinically relevant pancreatic fistula in the early phase after pancreaticoduodenectomy. AB - BACKGROUND: Postoperative pancreatic fistula (PF) remains a major complication after pancreaticoduodenectomy (PD). We aimed to investigate the predictors of clinically relevant PF after PD. METHODS: We retrospectively analyzed the predictive factors of relevant grade B/C PF using logistic regression analysis of 100 consecutive patients who underwent PD. PF was defined in accordance with the International Study Group on PF (ISGPF). RESULTS: White blood cell count (WBC) of 73.6 * 10(2) /MUl, C-reactive protein (CRP) of 9.3 mg/dl and amylase value in drains (d-amylase) of 647 U/I on postoperative day (POD) 4 were proposed as the cut-off values for predicting grade B/C PF with high accuracy by the receiver operating characteristic (ROC) curve. Multivariate logistic regression analysis revealed that the three factors as significant predictive factors and the predicted probability of detecting grade B/C PF was calculated by the following formula; P = 1/[1 + exp{-(2.033 * WBC+3.269 * CRP+2.698 * d-amylase-4.122)}]. P > 0.5 indicates the prospective incidence of the PF. When the cut-off values of the three significant predictors were substituted into the formula, P always showed above 0.5 if more than two predictors were above their cut-off values, indicating a high probability of grade B/C PF. CONCLUSIONS: White blood cell count, CRP and d-amylase on POD4 were predictive factors for clinically relevant PF after PD. These findings indicate that our formula is useful for management of drain after PD. PMID- 23804411 TI - Unprotected carotid artery stenting in modern practice. AB - BACKGROUND & PURPOSE: Embolic protection devices (EPD) may provide a mechanism to reduce peri-procedural strokes. They are advocated by consensus guidelines and mandated for Medicare reimbursement. However, outcomes data remain mixed. We aimed to characterize the population of patients undergoing unprotected carotid artery stenting (CAS) and assess the utility of distal filter EPD (F-EPD) in elective CAS. METHODS: We analyzed patients enrolled in the CARE Registry(r) undergoing CAS between May, 2005 and January, 2012. We assessed the relationship between distal F-EPD use versus no use (No-EPD) and the composite of in-hospital death or stroke (MAE) in unadjusted and 1:3 propensity-matched analyses. RESULTS: Embolic protection was not attempted in a total of 579 out of 13,263 cases performed (4.4%). Patients in the No-EPD group had worse preprocedure neurologic risk factors including higher rates of acute evolving stroke, prior TIA/stroke, symptomatic lesion status, spontaneous carotid artery dissection, and use of general anesthesia intraprocedurally (all Standardized Differences{sd} >10). After exclusion of nonelective cases there was no significant difference in MAE between the No-EPD and F-EPD groups (1.6% vs. 2.3%, sd = 4.72). Additionally, after propensity matching, rates of MAE did not differ between the No-EPD (n = 355) and F-EPD (n = 1065) groups (1.7% vs. 2.5%, sd = 5.87). CONCLUSIONS: Patients selected to undergo unprotected CAS in contemporary practice have high rates of adverse preprocedure neurologic risk factors. Our propensity-matched analysis did not demonstrate evidence of significant benefit or harm associated with use of F-EPD in elective CAS patients. PMID- 23804412 TI - Spatial olfactory learning facilitates long-term depression in the hippocampus. AB - Recently, it has emerged that visual spatial exploration facilitates synaptic plasticity at different synapses within the trisynaptic network. Particularly striking is the finding that visuospatial contexts facilitate hippocampal long term depression (LTD), raising the possibility that this form of plasticity may be important for memory formation. It is not known whether other sensory modalities elicit similar permissive effects on LTD. Here, we explored if spatial olfactory learning facilitates LTD in the hippocampus region of freely behaving rats. Patterned afferent stimulation of the Schaffer collaterals elicited short term depression (STD) (<1 h) of evoked responses in the Stratum radiatum of the CA1 region. Coupling of this protocol with novel exploration of a spatial constellation of olfactory cues facilitated short-term depression into LTD that lasted for over 24 h. Facilitation of LTD did not occur when animals were re exposed 1 week later to the same odors in the same spatial constellation. Evaluation of learning behavior revealed that 1 week after the 1st odor exposure, the animals remembered the odors and their relative positions. These data support that the hippocampus can use nonvisuospatial resources, and specifically can use spatial olfactory information, to facilitate LTD and to generate spatial representations. The data also support that a tight relationship exists between the processing of spatial contextual information and the expression of LTD in the hippocampus. PMID- 23804413 TI - Oligoethylene glycols prevent thermal aggregation of alpha-chymotrypsin in a temperature-dependent manner: implications for design guidelines. AB - Protein aggregation is problematic in various fields, where aggregation can frequently occur during routine experiments. This study showed that tetraethylene glycol (TEG) and tetraethylene glycol dimethyl ether (TEGDE) act as aggregation suppressors that have different unique properties from typical additives to prevent protein aggregation, such as arginine (Arg) and NaCl. Thermal aggregation of alpha-chymotrypsin was well suppressed with the addition of both TEG and TEGDE. Interestingly, the suppressive effects of Arg and NaCl on thermal aggregation were almost unchanged when temperature was shifted from 65 degrees C to 85 degrees C, whereas both TEG and TEGDE significantly decreased the aggregation rate with increasing temperature. Note that the effects of TEG and TEGDE were higher than Arg above 75 degrees C. This temperature-dependent behavior of TEG and TEGDE provides a novel design guideline to develop aggregation suppressors for use at high temperature, i.e., the importance of the ethylene oxide group. PMID- 23804414 TI - Hypoxic tumor microenvironment in advanced retinoblastoma. AB - PURPOSE: Retinoblastoma (RB) is a malignant tumor of infancy and childhood. Unfavorable therapeutic response is still a quest in many tumors, including retinoblastoma. Hypoxic tumor microenvironment is one of the factors that determine the therapeutic response in many tumors. The purpose of this study was to determine the presence of hypoxia and its related proteins; Hypoxia inducible factor-1alpha (HIF-1alpha), Carbonic anhydrase IX (CA IX) and survivin in RB and their association with clinicopathological features. MATERIALS AND METHODS: We evaluated the expression of HIF-1alpha and survivin by immunohistochemistry in 42 archival retinoblastoma tumors and CA IX; a hypoxia marker in 33 tumors in the same cohort. The expression was correlated with tumor groups based on invasion, differentiation and IIRC. RESULTS: Expression of HIF-1alpha, survivin and CA IX was observed in 83% (35/42), 86% (36/42), and 93% (31/33) of tumors respectively. We observed no significance between HIF-1alpha and CA IX expression in tumors with invasion, differentiation and in IIRC tumor groups. An increased survivin expression was observed in group E tumors than in group D tumors (P = 0.044). A significant association was observed between HIF-1alpha and survivin in differentiated (r = -0.582; P = < 0.01) and undifferentiated tumors groups (r = 0.513; P = <0.012). A similar significant association was observed between HIF 1alpha and CA IX in tumors with high immunoreactivity for HIF-1alpha (r = 0.833; P = <0.01). CONCLUSION: Based on these observations, we propose that HIF-1alpha pathway is deregulated in RB. The role of drug resistance and the potential of targeting HIF-1alpha, CA IX, and survivin in RB should further examined. PMID- 23804417 TI - Critical issues in using the common mixture toxicity models concentration addition or response addition on species sensitivity distributions: a theoretical approach. AB - The risk of chemical mixtures to ecosystems is often assessed by applying the model of concentration addition or response addition combined with species sensitivity distribution (SSD) curves. Mixture effect predictions have been shown to be consistent only when these models are applied for a single species, however, and not with several species simultaneously aggregated to SSDs. The more stringent procedure for mixture risk assessment would hence be to apply first the concentration addition or response addition models to each species separately and, in a second step, to combine the results to construct an SSD for a mixture. Unfortunately, this methodology is not applicable in most cases because the large data sets it requires are usually unavailable. Based on theoretical data sets generated, the authors aimed to characterize the difference that can exist between these 2 methodologies. Results show that the use of concentration addition on SSD directly may lead to underestimations of the mixture concentration affecting 5% or 50% of species, especially when substances present a large standard deviation in ecotoxicity data constructing their SSD. The application of response addition can lead to over- or underestimations, depending mainly on the slope of the dose-response curves of the individual species. When assessing the risk of mixtures, one must therefore keep in mind this source of error when applying concentration addition or response addition to SSDs directly. PMID- 23804416 TI - Vertical sleeve gastrectomy reduces hepatic steatosis while increasing serum bile acids in a weight-loss-independent manner. AB - OBJECTIVE: Our objective was to investigate the role of bile acids in hepatic steatosis reduction after vertical sleeve gastrectomy (VSG). DESIGN AND METHODS: High fat diet (HFD)-induced obese C57Bl/6 mice were randomized to VSG, Sham operation (Sham), Sham operation with pair feeding to VSG (Sham-PF), or nonsurgical controls (Naive). All mice were on HFD until sacrifice. Mice were observed postsurgery and data for body weight, body composition, metabolic parameters, serum bile acid level and composition were collected. Further hepatic gene expression by mRNA-seq and RT-PCR analysis was assessed. RESULTS: VSG and Sham-PF mice lost equal weight postsurgery while VSG mice had the lowest hepatic triglyceride content at sacrifice. The VSG mice had elevated serum bile acid levels that positively correlated with maximal weight loss. Serum bile composition in the VSG group had increased cholic and tauroursodeoxycholic acid. These bile acid composition changes in VSG mice explained observed downregulation of hepatic lipogenic and bile acid synthetic genes. CONCLUSION: VSG in obese mice results in greater hepatic steatosis reduction than seen with caloric restriction alone. VSG surgery increases serum bile acids that correlate with weight lost postsurgery and changes serum bile composition that could explain suppression of hepatic genes responsible for lipogenesis. PMID- 23804418 TI - A highly active and support-free oxygen reduction catalyst prepared from ultrahigh-surface-area porous polyporphyrin. PMID- 23804419 TI - Enhanced constitutive invasion activity in human nontumorigenic keratinocytes exposed to a low level of barium for a long time. AB - We have recently demonstrated that exposure to barium for a short time (<=4 days) and at a low level (5 uM = 687 ug/L) promotes invasion of human nontumorigenic HaCaT cells, which have characteristics similar to those of normal keratinocytes, suggesting that exposure to barium for a short time enhances malignant characteristics. Here we examined the effect of exposure to low level of barium for a long time, a condition mimicking the exposure to barium through well water, on malignant characteristics of HaCaT keratinocytes. Constitutive invasion activity, focal adhesion kinase (FAK) protein expression and activity, and matrix metalloproteinase 14 (MMP14) protein expression in primary cultured normal human epidermal keratinocytes, HaCaT keratinocytes, and HSC5 and A431 human squamous cell carcinoma cells were augmented following an increase in malignancy grade of the cells. Constitutive invasion activity, FAK phosphorylation, and MMP14 expression levels of HaCaT keratinocytes after treatment with 5 uM barium for 4 months were significantly higher than those of control untreated HaCaT keratinocytes. Taken together, our results suggest that exposure to a low level of barium for a long time enhances constitutive malignant characteristics of HaCaT keratinocytes via regulatory molecules (FAK and MMP14) for invasion. PMID- 23804420 TI - Health and the Great Depression: a reply to Stuckler et al. PMID- 23804421 TI - Remote ischemic conditioning in percutaneous coronary intervention: renal effect beyond the cardioprotection. PMID- 23804422 TI - Sensitization of pancreatic cancer to chemoradiation by the Chk1 inhibitor MK8776. AB - PURPOSE: The combination of radiation with chemotherapy is the most effective therapy for unresectable pancreatic cancer. To improve upon this regimen, we combined the selective Checkpoint kinase 1 (Chk1) inhibitor MK8776 with gemcitabine-based chemoradiation in preclinical pancreatic cancer models. EXPERIMENTAL DESIGN: We tested the ability of MK8776 to sensitize to gemcitabine radiation in homologous recombination repair (HRR)-proficient and -deficient pancreatic cancer cells and assessed Rad51 focus formation. In vivo, we investigated the efficacy, tumor cell selectivity, and pharmacodynamic biomarkers of sensitization by MK8776. RESULTS: We found that MK8776 significantly sensitized HRR-proficient (AsPC-1, MiaPaCa-2, BxPC-3) but not -deficient (Capan 1) pancreatic cancer cells to gemcitabine-radiation and inhibited Rad51 focus formation in HRR-proficient cells. In vivo, MiaPaCa-2 xenografts were significantly sensitized to gemcitabine-radiation by MK8776 without significant weight loss or observable toxicity in the small intestine, the dose-limiting organ for chemoradiation therapy in pancreatic cancer. We also assessed pChk1 (S345), a pharmacodynamic biomarker of DNA damage in response to Chk1 inhibition in both tumor and small intestine and found that MK8776 combined with gemcitabine or gemcitabine-radiation produced a significantly greater increase in pChk1 (S345) in tumor relative to small intestine, suggesting greater DNA damage in tumor than in normal tissue. Furthermore, we demonstrated the utility of an ex vivo platform for assessment of pharmacodynamic biomarkers of Chk1 inhibition in pancreatic cancer. CONCLUSIONS: Together, our results suggest that MK8776 selectively sensitizes HRR-proficient pancreatic cancer cells and xenografts to gemcitabine-radiation and support the clinical investigation of MK8776 in combination with gemcitabine-radiation in locally advanced pancreatic cancer. PMID- 23804423 TI - Acquired resistance to anti-VEGF therapy in glioblastoma is associated with a mesenchymal transition. AB - PURPOSE: Antiangiogenic therapy reduces vascular permeability and delays progression but may ultimately promote an aggressive treatment-resistant phenotype. The aim of the present study was to identify mechanisms responsible for glioblastoma resistance to antiangiogenic therapy. EXPERIMENTAL DESIGN: Glioma stem cell (GSC) NSC11 and U87 cell lines with acquired resistance to bevacizumab were developed from orthotopic xenografts in nude mice treated with bevacizumab. Genome-wide analyses were used to identify changes in tumor subtype and specific factors associated with resistance. RESULTS: Mice with established parental NSC11 and U87 cells responded to bevacizumab, whereas glioma cell lines derived at the time of acquired resistance to anti-VEGF therapy were resistant to bevacizumab and did not have prolongation of survival compared with untreated controls. Gene expression profiling comparing anti-VEGF therapy-resistant cell lines to untreated controls showed an increase in genes associated with a mesenchymal origin, cellular migration/invasion, and inflammation. Gene-set enrichment analysis showed that bevacizumab-treated tumors showed a highly significant correlation to published mesenchymal gene signatures. Mice bearing resistant tumors showed significantly greater infiltration of myeloid cells in NSC11- and U87-resistant tumors. Invasion-related genes were also upregulated in both NSC11 and U87 resistant cells which had higher invasion rates in vitro compared with their respective parental cell lines. CONCLUSIONS: Our studies identify multiple proinflammatory factors associated with resistance and identify a proneural to mesenchymal transition in tumors resistant to antiangiogenic therapy. PMID- 23804424 TI - Stromal responses among common carcinomas correlated with clinicopathologic features. AB - PURPOSE: We have previously characterized a tumor stroma expression signature in a subset of breast tumors that correlates with better clinical outcome. The purpose of this study is to determine whether this stromal signature, termed the "DTF fibroblast" (desmoid-type fibromatosis) signature, is specific to breast cancer or is a common stromal response found in different types of cancer. EXPERIMENTAL DESIGNS: The DTF fibroblast signature was applied to gene expression profiles from five ovarian, five lung, two colon, and three prostate cancer expression microarray datasets. In addition, two different tissue microarrays of 204 ovarian tumors and 140 colon tumors were examined for the expression of previously characterized protein markers of DTF fibroblast signature. The DTF fibroblast stromal response was then correlated with clinicopathologic features. RESULTS: The DTF fibroblast signature is robustly present in ovarian, lung, and colon carcinomas. Both expression microarray data and immunohistochemistry show that the subset of ovarian tumors with strong DTF fibroblast signature expression has statistically significant, worse survival outcomes. No reproducible survival differences were found in either the lung or the colon cancers. The prostate cancers failed to show a DTF fibroblast signature. Multivariant analysis showed that DTF fibroblast signature was significantly more prognostic than the proliferation status in ovarian carcinomas. CONCLUSIONS: Our results suggest that the DTF fibroblast signature is a common tumor stroma signature in different types of cancer, including ovarian, lung, and colon carcinomas. Our findings provide further insight into the DTF fibroblast stromal responses across different types of carcinomas and their potential as prognostic and therapeutic targets. PMID- 23804425 TI - Novel targeting of phospho-cMET overcomes drug resistance and induces antitumor activity in multiple myeloma. AB - PURPOSE: The aim of the study was to verify the hypothesis that the cMet oncogene is implicated in chemio- and novel drug resistance in multiple myeloma. EXPERIMENTAL DESIGN: We have evaluated the expression levels of cMET/phospho-cMET (p-cMET) and the activity of the novel selective p-cMET inhibitor (SU11274) in multiple myeloma cells, either sensitive (RPMI-8226 and MM.1S) or resistant (R5 and MM.1R) to anti-multiple myeloma drugs, in primary plasma cells and in multiple myeloma xenograft models. RESULTS: We found that resistant R5 and MM.1R cells presented with higher cMET phosphorylation, thus leading to constitutive activation of cMET-dependent signaling pathways. R5 cells exhibited a higher susceptibility to the SU11274 inhibitory effects on viability, proliferation, chemotaxis, adhesion, and to its apoptogenic effects. SU11274 was able to revert drug resistance in R5 cells. R5 but not RPMI-8226 cells displayed cMET-dependent activation of mitogen-activated protein kinase pathway. The cMET and p-cMET expression was higher on plasma cells from patients with multiple myeloma at relapse or on drug resistance than on those from patients at diagnosis, complete/partial remission, or from patients with monoclonal gammopathy of unknown significance. Viability, chemotaxis, adhesion to fibronectin or paired bone marrow stromal cells of plasma cells from relapsed or resistant patients was markedly inhibited by SU11274. Importantly, SU11274 showed higher therapeutic activity in R5- than in RPMI-8226-induced plasmocytomas. In R5 tumors, it caused apoptosis and necrosis and reverted bortezomib resistance. CONCLUSION: Our findings suggest that the cMET pathway is constitutively activated in relapsed and resistant multiple myeloma where it may also be responsible for induction of drug resistance, thus providing the preclinical rationale for targeting cMET in patients with relapsed/refractory multiple myeloma. PMID- 23804427 TI - The importance of heat flow direction for reproducible and homogeneous freezing of bulk protein solutions. AB - Freezing is an important operation in biotherapeutics industry. However, water crystallization in solution, containing electrolytes, sugars and proteins, is difficult to control and usually leads to substantial spatial solute heterogeneity. Herein, we address the influence of the geometry of freezing direction (axial or radial) on the heterogeneity of the frozen matrix, in terms of local concentration of solutes and thermal history. Solutions of hemoglobin were frozen radially and axially using small-scale and pilot-scale freezing systems. Concentration of hemoglobin, sucrose and pH values were measured by ice core sampling and temperature profiles were measured at several locations. The results showed that natural convection is the major source for the cryoconcentration heterogeneity of solutes over the geometry of the container. A significant improvement in this spatial heterogeneity was observed when the freezing geometry was nonconvective, i.e., the freezing front progression was unidirectional from bottom to top. Using this geometry, less than 10% variation in solutes concentration was obtained throughout the frozen solutions. This result was reproducible, even when the volume was increased by two orders of magnitude (from 30 mL to 3 L). The temperature profiles obtained for the nonconvective freezing geometry were predicted using a relatively simple computational fluid dynamics model. The reproducible solutes distribution, predictable temperature profiles, and scalability demonstrate that the bottom to top freezing geometry enables an extended control over the freezing process. This geometry has therefore shown the potential to contribute to a better understanding and control of the risks inherent to frozen storage. PMID- 23804428 TI - PYY3-36 and pancreatic polypeptide reduce food intake in an additive manner via distinct hypothalamic dependent pathways in mice. AB - OBJECTIVE: Peptide YY (PYY3-36) and pancreatic polypeptide (PP) potently inhibit food intake in rodents and humans, however, it is unclear whether they have any synergistic/additive interaction in decreasing food intake. DESIGN AND METHODS: Fasted WT, Y2(-) (/) (-) , Y4(-) (/) (-) , or Y2Y4(-) (/) (-) mice were i.p. administrated with saline, PYY3-36, and/or PP. RESULTS: Combined injection of PYY3-36 and PP reduces food intake in an additive manner was demonstrated in this study. This effect is mediated via Y2 and Y4 receptors, respectively. It was demonstrated that PYY3-36 and PP activate distinct neuronal pathways in the hypothalamus, as demonstrated by immunostaining for c-fos, which shows distinct patterns in response to either hormone. After PYY3-36 injection, neurons in the dorsal aspect of the arcuate nucleus (Arc), paraventricular nucleus, and dorso medial nucleus of the hypothalamus (DMH) are activated with minimal responses seen in the ventro-medial nucleus of the hypothalamus (VMH) and lateral hypothalamic area (LHA) of WT mice. These effects are absent in Y2(-) (/) (-) mice. PP activates preferably the lateral aspect of the Arc, the DMH, VMH, and LHA in a Y4 receptor-dependent manner. Importantly, the expression pattern of c fos immunoreactive neurons induced by combined treatment appears to be the sum of the effects of single treatments rather than a result of synergistic interaction. CONCLUSIONS: These findings demonstrate that PYY3-36 and PP activate distinct pathways in the hypothalamus to reduce food intake in an additive manner. PMID- 23804426 TI - beta-mannosylceramide activates type I natural killer t cells to induce tumor immunity without inducing long-term functional anergy. AB - PURPOSE: Most studies characterizing antitumor properties of invariant natural killer T (iNKT) cells have used the agonist, alpha-galactosylceramide (alpha GalCer). However, alpha-GalCer induces strong, long-lasting anergy of iNKT cells, which could be a major detriment for clinical therapy. A novel iNKT cell agonist, beta-mannosylceramide (beta-ManCer), induces strong antitumor immunity through a mechanism distinct from that of alpha-GalCer. The objective of this study was to determine whether beta-ManCer induces anergy of iNKT cells. EXPERIMENTAL DESIGN: Induction of anergy was determined by ex vivo analysis of splenocytes from mice pretreated with iNKT cell agonists as well as in the CT26 lung metastasis in vivo tumor model. RESULTS: beta-ManCer activated iNKT cells without inducing long-term anergy. The transience of anergy induction correlated with a shortened duration of PD-1 upregulation on iNKT cells activated with beta-ManCer, compared with alpha-GalCer. Moreover, whereas mice pretreated with alpha-GalCer were unable to respond to a second glycolipid stimulation to induce tumor protection for up to 2 months, mice pretreated with beta-ManCer were protected from tumors by a second stimulation equivalently to vehicle-treated mice. CONCLUSIONS: The lack of long term functional anergy induced by beta-ManCer, which allows for a second dose to still give therapeutic benefit, suggests the strong potential for this iNKT cell agonist to succeed in settings where alpha-GalCer has failed. PMID- 23804429 TI - Chronic over-expression of TGFbeta1 alters hippocampal structure and causes learning deficits. AB - The cytokine transforming growth factor beta1 (TGFbeta1) is chronically upregulated in several neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jacob disease, amyotrophic lateral sclerosis and multiple sclerosis, and following stroke. Although previous studies have shown that TGFbeta1 may be neuroprotective, chronic exposure to elevated levels of this cytokine may contribute to disease pathology on its own. In order to study the effects of chronic exposure to TGFbeta1 in isolation, we used transgenic mice that over-express a constitutively active porcine TGFbeta1 in astrocytes. We found that TGFbeta1 over-expression altered brain structure, with the most pronounced volumetric increases localized to the hippocampus. Within the dentate gyrus (DG) of the hippocampus, increases in granule cell number and astrocyte size were responsible for volumetric expansion, with the increased granule cell number primarily related to a marked reduction in death of new granule cells generated in adulthood. Finally, these cumulative changes in DG microstructure and macrostructure were associated with the age-dependent emergence of spatial learning deficits in TGFbeta1 over-expressing mice. Together, our data indicate that chronic upregulation of TGFbeta1 negatively impacts hippocampal structure and, even in the absence of disease, impairs hippocampus-dependent learning. PMID- 23804430 TI - Childlessness and subjective well-being in Chinese widowed persons. AB - OBJECTIVES: This study examined the effect of childlessness on psychological well being in widowhood taking into account the influences of social network variables. METHOD: A total of 273 Chinese widowed individuals who were community dwelling formed the sample of this study. Sixteen percent (n = 44) were childless. Social network variables, instrumental activities of daily living, chronic illnesses, depressive symptoms, life satisfaction, positive affect, and negative affect were assessed. RESULTS: Childlessness was significantly associated with all outcomes of psychological well-being even after controlling for network size. After positive and negative exchanges were taken into account, the effect of childlessness on depression and life satisfaction became nonsignificant but remained significant on positive and negative affect. Furthermore, the effects of childlessness on depression and life satisfaction were significantly stronger in women than in men. Childlessness also had a stronger association with depression in those with functional impairments. DISCUSSION: Findings support the importance of children, and supportive exchanges with them, for the subjective well-being of Chinese widowed persons. Being women and having physical dependencies might amplify the effects of childlessness. PMID- 23804431 TI - Adult age differences in learning on a sequentially cued prediction task. AB - OBJECTIVES: Much of adaptive behavior relies on the ability to learn and generate predictions about relationships in the environment. Research on aging suggests both that there is an age deficit in the ability to learn sequential relationships and that this deficit in learning could underlie age differences reported in many decision-making tasks. This article introduces the Triplets Prediction Task (TPT) to investigate the learning of sequential relationships that underlies adaptive behavior. METHOD: In the TPT, participants see 2 successive visual cues and then predict which target will follow. Unknown to participants, there is a predictive relationship between the first cue and the target such that each of 4 cues predicts 1 of 4 targets 85% of the time. RESULTS: Although both age groups demonstrated learning on this task, an age deficit in learning appeared early and performance differences persisted throughout training. There was also evidence of age differences in the learning systems engaged during the task. DISCUSSION: These results are consistent with previous studies of learning and prediction, and they support the growing literature showing adult age differences in decision making from experience. PMID- 23804432 TI - Sleep discrepancy, sleep complaint, and poor sleep among older adults. AB - OBJECTIVES: Discrepancy between self-report- and actigraphy-measured sleep, often considered an artifact of measurement error, has been well documented among insomnia patients. Sleep problems are common among older adults, and this discrepancy may represent meaningful sleep-related phenomenon, which could have clinical and research significance. METHOD: Sleep discrepancy was examined in 4 groups of older adults (N = 152, mean age = 71.93 years) based on sleep complaint versus no complaint and presence versus absence of insomnia symptoms. Participants completed the Beck Depression Inventory-second edition (BDI-II) and 14 nights of sleep diaries and actigraphy. RESULTS: Controlling for covariates, group differences were found in the duration and frequency of discrepancy in sleep onset latency (SOLd) and wake after sleep onset (WASOd). Those with insomnia symptoms and complaints reported greater duration and frequency of WASOd than the other 3 groups. Quantities of SOLd and WASOd were related to BDI-II score and group status, indicating that sleep discrepancy has meaningful clinical correlates. DISCUSSION: Discrepancy occurred across all groups but was pronounced among the group with both insomnia symptoms and complaints. This discrepancy may provide a means of quantifying and conceptualizing the transition from wake to sleep among older adults, particularly those with sleeping problems. PMID- 23804433 TI - Message from the president talking about it: Engaging the public in advancing nursing research. PMID- 23804434 TI - Physical activity and gestational weight gain in Hispanic women. AB - OBJECTIVE: Hispanic women have high rates of excessive and inadequate gestational weight gain (GWG) according to Institute of Medicine (IOM) guidelines. Observational studies suggest that physical activity may be associated with GWG but have been conflicting and were largely conducted in non-Hispanic white populations. METHODS: The association between physical activity and compliance with GWG guidelines, total GWG, and rate of GWG among 1,276 Hispanic participants in Proyecto Buena Salud, a cohort study in Western Massachusetts was prospectively evaluated. The Pregnancy Physical Activity Questionnaire was used to assess pre, early, mid, and late pregnancy physical activity according to both intensity (i.e., sedentary, moderate, and vigorous) and type (i.e., housework/caregiving, occupational, and sports/exercise). RESULTS: A total of 26.9% of women gained within IOM guidelines, 21.2% had inadequate GWG, and 51.9% experienced excessive GWG. Overall, we did not observe statistically significant associations between type or intensity of physical activity during pre, early, mid, and late pregnancy and inadequate or excessive GWG, total GWG, or rate of GWG. CONCLUSIONS: In this prospective cohort study of Hispanic women, after controlling for important risk factors, pregnancy physical activity did not appear to be associated with GWG. PMID- 23804435 TI - Electrochemical synthesis of one-dimensional mesoporous Pt nanorods using the assembly of surfactant micelles in confined space. PMID- 23804436 TI - Less morbidity after introduction of a new departmental policy for patients who undergo open distal pancreatectomy. AB - BACKGROUND: The aim of this study was to retrospectively compare morbidity and mortality before and after introduction of a new departmental policy for patients who undergo distal pancreatectomy. METHODS: We have introduced the use of an ultrasonically-activated device in distal pancreatectomy, an "early removal of drains" policy and perioperative management using a clinical pathway since May 2006. Group A consisted of 52 consecutive patients from 2000 to February 2006. Group B consisted of 57 consecutive patients from May 2006 to 2010. RESULTS: Although there was no difference in the fluid collection rate within 30 postoperative days (Group A, 44% vs. Group B, 35%), the rates of intra-abdominal abscess (A, 19% vs. B, 4%) and grade 3/4 of the Clavien classification (A, 23% vs. B, 9%) in Group B were significantly lower than in Group A (P < 0.05). Time of drain removal (median 3 days vs. 8 days) and length of in-hospital stay (median 8 days vs. 17 days) in Group B were significantly shorter than in Group A (P < 0.001). CONCLUSION: The implementation of new departmental guidelines for distal pancreatectomy was closely associated with a low frequency of intra abdominal abscess and grade 3/4 Clavien score, resulting in a shorter in-hospital stay. PMID- 23804437 TI - Three-dimensional distribution of polymorphs and magnesium in a calcified underwater attachment system by diffraction tomography. AB - Biological materials display complicated three-dimensional hierarchical structures. Determining these structures is essential in understanding the link between material design and properties. Herein, we show how diffraction tomography can be used to determine the relative placement of the calcium carbonate polymorphs calcite and aragonite in the highly mineralized holdfast system of the bivalve Anomia simplex. In addition to high fidelity and non destructive mapping of polymorphs, we use detailed analysis of X-ray diffraction peak positions in reconstructed powder diffraction data to determine the local degree of Mg substitution in the calcite phase. These data show how diffraction tomography can provide detailed multi-length scale information on complex materials in general and of biomineralized tissues in particular. PMID- 23804438 TI - Computational modelling of Smad-mediated negative feedback and crosstalk in the TGF-beta superfamily network. AB - The transforming growth factor-beta (TGF-beta) signal transduction pathway controls many cellular processes, including differentiation, proliferation and apoptosis. It plays a fundamental role during development and it is dysregulated in many diseases. The factors that control the dynamics of the pathway, however, are not fully elucidated yet and so far computational approaches have been very limited in capturing the distinct types of behaviour observed under different cellular backgrounds and conditions into a single-model description. Here, we develop a detailed computational model for TGF-beta signalling that incorporates elements of previous models together with crosstalking between Smad1/5/8 and Smad2/3 channels through a negative feedback loop dependent on Smad7. The resulting model accurately reproduces the diverse behaviour of experimental datasets for human keratinocytes, bovine aortic endothelial cells and mouse mesenchymal cells, capturing the dynamics of activation and nucleocytoplasmic shuttling of both R-Smad channels. The analysis of the model dynamics and its system properties revealed Smad7-mediated crosstalking between Smad1/5/8 and Smad2/3 channels as a major determinant in shaping the distinct responses to single and multiple ligand stimulation for different cell types. PMID- 23804440 TI - Air speeds of migrating birds observed by ornithodolite and compared with predictions from flight theory. AB - We measured the air speeds of 31 bird species, for which we had body mass and wing measurements, migrating along the east coast of Sweden in autumn, using a Vectronix Vector 21 ornithodolite and a Gill WindSonic anemometer. We expected each species' average air speed to exceed its calculated minimum-power speed (Vmp), and to fall below its maximum-range speed (Vmr), but found some exceptions to both limits. To resolve these discrepancies, we first reduced the assumed induced power factor for all species from 1.2 to 0.9, attributing this to splayed and up-turned primary feathers, and then assigned body drag coefficients for different species down to 0.060 for small waders, and up to 0.12 for the mute swan, in the Reynolds number range 25 000-250 000. These results will be used to amend the default values in existing software that estimates fuel consumption in migration, energy heights on arrival and other aspects of flight performance, using classical aeronautical theory. The body drag coefficients are central to range calculations. Although they cannot be measured on dead bird bodies, they could be checked against wind tunnel measurements on living birds, using existing methods. PMID- 23804439 TI - Electrophoretic coating of amphiphilic chitosan colloids on regulating cellular behaviour. AB - In this communication, we report a facile nanotopographical control over a stainless steel surface via an electrophoretic deposition of colloidal amphiphilic chitosan for preferential growth, proliferation or migration of vascular smooth muscle cells (VSMCs) and human umbilical vein endothelial cells (HUVECs). Atomic force microscopy revealed that the colloidal surface exhibited a deposition time-dependent nanotopographical evolution, wherein two different nanotopographic textures indexed by 'kurtosis' (Rkur) value were easily designed, which were termed as 'sharp' (i.e. high peak-to-valley texture) surface and 'flat' (i.e. low peak-to-valley texture) surface. Cellular behaviour of VSMCs and HUVECs on both surfaces demonstrated topographically dependent morphogenesis, adherent responses and biochemical properties in comparison with bare stainless steel. The formation of a biofunctionalized surface upon a facile colloidal chitosan deposition envisions the potential application towards numerous biomedical devices, and this is especially promising for cardiovascular stents wherein a new surface with optimized texture can be designed and is expected to create an advantageous environment to stimulate HUVEC growth for improved healing performance. PMID- 23804441 TI - Numerical metrics for automated quantification of interstitial cell of Cajal network structural properties. AB - Depletion of interstitial cells of Cajal (ICC) networks is known to occur in several gastrointestinal motility disorders. Although confocal microscopy can effectively image and visualize the spatial distribution of ICC networks, current descriptors of ICC depletion are limited to cell numbers and volume computations. Spatial changes in ICC network structural properties have not been quantified. Given that ICC generate electrical signals, the organization of a network may also affect physiology. In this study, six numerical metrics were formulated to automatically determine complex ICC network structural properties from confocal images: density, thickness, hole size, contact ratio, connectivity and anisotropy. These metrics were validated and applied in proof-of-concept studies to quantitatively determine jejunal ICC network changes in mouse models with decreased (5-HT2B receptor knockout (KO)) and normal (Ano1 KO) ICC numbers, and during post-natal network maturation. Results revealed a novel remodelling phenomenon occurring during ICC depletion, namely a spatial rearrangement of ICC and the preferential longitudinal alignment. In the post-natal networks, an apparent pruning of the ICC network was demonstrated. The metrics developed here enabled the first detailed quantitative analyses of structural changes that may occur in ICC networks during depletion and development. PMID- 23804442 TI - Crystallographic orientation inhomogeneity and crystal splitting in biogenic calcite. AB - The calcitic prismatic units forming the outer shell of the bivalve Pinctada margaritifera have been analysed using scanning electron microscopy-electron back scatter diffraction, transmission electron microscopy and atomic force microscopy. In the initial stages of growth, the individual prismatic units are single crystals. Their crystalline orientation is not consistent but rather changes gradually during growth. The gradients in crystallographic orientation occur mainly in a direction parallel to the long axis of the prism, i.e. perpendicular to the shell surface and do not show preferential tilting along any of the calcite lattice axes. At a certain growth stage, gradients begin to spread and diverge, implying that the prismatic units split into several crystalline domains. In this way, a branched crystal, in which the ends of the branches are independent crystalline domains, is formed. At the nanometre scale, the material is composed of slightly misoriented domains, which are separated by planes approximately perpendicular to the c-axis. Orientational gradients and splitting processes are described in biocrystals for the first time and are undoubtedly related to the high content of intracrystalline organic molecules, although the way in which these act to induce the observed crystalline patterns is a matter of future research. PMID- 23804443 TI - A rule-based kinetic model of RNA polymerase II C-terminal domain phosphorylation. AB - The complexity of many RNA processing pathways is such that a conventional systems modelling approach is inadequate to represent all the molecular species involved. We demonstrate that rule-based modelling permits a detailed model of a complex RNA signalling pathway to be defined. Phosphorylation of the RNA polymerase II (RNAPII) C-terminal domain (CTD; a flexible tail-like extension of the largest subunit) couples pre-messenger RNA capping, splicing and 3' end maturation to transcriptional elongation and termination, and plays a central role in integrating these processes. The phosphorylation states of the serine residues of many heptapeptide repeats of the CTD alter along the coding region of genes as a function of distance from the promoter. From a mechanistic perspective, both the changes in phosphorylation and the location at which they take place on the genes are a function of the time spent by RNAPII in elongation as this interval provides the opportunity for the kinases and phosphatases to interact with the CTD. On this basis, we synthesize the available data to create a kinetic model of the action of the known kinases and phosphatases to resolve the phosphorylation pathways and their kinetics. PMID- 23804444 TI - Cranial sutures work collectively to distribute strain throughout the reptile skull. AB - The skull is composed of many bones that come together at sutures. These sutures are important sites of growth, and as growth ceases some become fused while others remain patent. Their mechanical behaviour and how they interact with changing form and loadings to ensure balanced craniofacial development is still poorly understood. Early suture fusion often leads to disfiguring syndromes, thus is it imperative that we understand the function of sutures more clearly. By applying advanced engineering modelling techniques, we reveal for the first time that patent sutures generate a more widely distributed, high level of strain throughout the reptile skull. Without patent sutures, large regions of the skull are only subjected to infrequent low-level strains that could weaken the bone and result in abnormal development. Sutures are therefore not only sites of bone growth, but could also be essential for the modulation of strains necessary for normal growth and development in reptiles. PMID- 23804445 TI - Emergence of an optimal search strategy from a simple random walk. AB - In reports addressing animal foraging strategies, it has been stated that Levy like algorithms represent an optimal search strategy in an unknown environment, because of their super-diffusion properties and power-law-distributed step lengths. Here, starting with a simple random walk algorithm, which offers the agent a randomly determined direction at each time step with a fixed move length, we investigated how flexible exploration is achieved if an agent alters its randomly determined next step forward and the rule that controls its random movement based on its own directional moving experiences. We showed that our algorithm led to an effective food-searching performance compared with a simple random walk algorithm and exhibited super-diffusion properties, despite the uniform step lengths. Moreover, our algorithm exhibited a power-law distribution independent of uniform step lengths. PMID- 23804446 TI - Vitamin D deficiency: a nontraditional risk factor in polycystic kidney disease? PMID- 23804447 TI - Proximal tubule PPARalpha attenuates renal fibrosis and inflammation caused by unilateral ureteral obstruction. AB - We examined the effects of increased expression of proximal tubule peroxisome proliferator-activated receptor (PPAR)alpha in a mouse model of renal fibrosis. After 5 days of unilateral ureteral obstruction (UUO), PPARalpha expression was significantly reduced in kidney tissue of wild-type mice but this downregulation was attenuated in proximal tubules of PPARalpha transgenic (Tg) mice. When compared with wild-type mice subjected to UUO, PPARalpha Tg mice had reduced mRNA and protein expression of proximal tubule transforming growth factor (TGF)-beta1, with reduced production of extracellular matrix proteins including collagen 1, fibronectin, alpha-smooth muscle actin, and reduced tubulointerstitial fibrosis. UUO-mediated increased expression of microRNA 21 in kidney tissue was also reduced in PPARalpha Tg mice. Overexpression of PPARalpha in cultured proximal tubular cells by adenoviral transduction reduced aristolochic acid-mediated increased production of TGF-beta, demonstrating PPARalpha signaling reduces epithelial TGF-beta production. Flow cytometry studies of dissociated whole kidneys demonstrated reduced macrophage infiltration to kidney tissue in PPARalpha Tg mice after UUO. Increased expression of proinflammatory cytokines including IL-1beta, IL-6, and TNF-alpha in wild-type mice was also significantly reduced in kidney tissue of PPARalpha Tg mice. In contrast, the expression of anti-inflammatory cytokines IL-10 and arginase-1 was significantly increased in kidney tissue of PPARalpha Tg mice when compared with wild-type mice subjected to UUO. Our studies demonstrate several mechanisms by which preserved expression of proximal tubule PPARalpha reduces tubulointerstitial fibrosis and inflammation associated with obstructive uropathy. PMID- 23804449 TI - Prediction and assessment of responses to renal artery revascularization with dynamic contrast-enhanced magnetic resonance imaging: a pilot study. AB - The aim of this study was to assess the potential of dynamic contrast-enhanced (DCE) MRI to predict and evaluate functional outcomes after renal artery revascularization for renal artery stenosis (RAS). The single-kidney glomerular filtration rate (SK-GFR) was measured in 15 patients with atherosclerotic RAS with DCE-MRI and radioisotopes at baseline and 4 mo after revascularization. DCE MRI also produced measurements of blood flow, blood volume, extraction fraction, tubular transit time, and functional volume. Stented kidneys (n = 22) were divided into three response groups on the basis of the changes in radioisotope SK GFR: improved (n = 5), stable (n = 13), and deteriorated (n = 4). A good agreement was found between SK-GFR values from DCE-MRI and radioisotopes (correlation coefficient: 0.91). Before intervention, kidneys that improved had lower extraction fraction, higher blood volume, longer tubular transit time, and lower SK-GFR. After intervention, improved kidneys had increased functional volume, and deteriorated kidneys had reduced functional volume and extraction fraction. Revascularization improved blood flow and blood volume in all groups. This pilot study led to the hypothesis that well-vascularized kidneys with reduced extraction fractions are most likely to benefit from revascularization. More generally, DCE-MRI has the potential to replace radioisotope measurement of SK-GFR and may improve patient management by providing additional information on tissue perfusion. PMID- 23804448 TI - Proteomic profiling and pathway analysis of the response of rat renal proximal convoluted tubules to metabolic acidosis. AB - Metabolic acidosis is a relatively common pathological condition that is defined as a decrease in blood pH and bicarbonate concentration. The renal proximal convoluted tubule responds to this condition by increasing the extraction of plasma glutamine and activating ammoniagenesis and gluconeogenesis. The combined processes increase the excretion of acid and produce bicarbonate ions that are added to the blood to partially restore acid-base homeostasis. Only a few cytosolic proteins, such as phosphoenolpyruvate carboxykinase, have been determined to play a role in the renal response to metabolic acidosis. Therefore, further analysis was performed to better characterize the response of the cytosolic proteome. Proximal convoluted tubule cells were isolated from rat kidney cortex at various times after onset of acidosis and fractionated to separate the soluble cytosolic proteins from the remainder of the cellular components. The cytosolic proteins were analyzed using two-dimensional liquid chromatography and tandem mass spectrometry (MS/MS). Spectral counting along with average MS/MS total ion current were used to quantify temporal changes in relative protein abundance. In all, 461 proteins were confidently identified, of which 24 exhibited statistically significant changes in abundance. To validate these techniques, several of the observed abundance changes were confirmed by Western blotting. Data from the cytosolic fractions were then combined with previous proteomic data, and pathway analyses were performed to identify the primary pathways that are activated or inhibited in the proximal convoluted tubule during the onset of metabolic acidosis. PMID- 23804451 TI - Role of fibrinogen in acute ischemic kidney injury. AB - Renal ischemia-reperfusion (I/R) is associated with activation of the coagulation system and accumulation of blood clotting factors in the kidney. The aim of the present study was to examine the functional impact of fibrinogen on renal inflammation, damage, and repair in the context of I/R injury. In this study, we found that I/R was associated with a significant increase in the renal deposition of circulating fibrinogen. In parallel, I/R stress induced the de novo expression of fibrinogen in tubular epithelial cells, as reflected by RT-PCR, immunofluorescence, and in situ hybridization. In vitro, fibrinogen expression was induced by oncostatin M and hyper-IL-6 in primary tubular epithelial cells, and fibrinogen-containing medium had an inhibitory effect on tubular epithelial cell adhesion and migration. Fibrinogen(+/-) mice showed similar survival as wild type mice but better preservation in early postischemic renal function. In fibrinogen(-/-) mice, renal function and survival were significantly worse than in fibrinogen(+/-) mice. Renal transplant experiments revealed reduced expression of tubular damage markers and attenuated proinflammatory cytokine expression but increased inflammatory cell infiltrates and transforming growth factor-beta expression in fibrinogen(-/-) isografts. These data point to heterogeneous effects of fibrinogen in renal I/R injury. While a complete lack of fibrinogen may be detrimental, partial reduction of fibrinogen in heterozygous mice can improve renal function and overall outcome. PMID- 23804450 TI - Protein kinase C-alpha interaction with iHSP70 in mitochondria promotes recovery of mitochondrial function after injury in renal proximal tubular cells. AB - This study determined the role of PKC-alpha and associated inducible heat shock protein 70 (iHSP70) in the repair of mitochondrial function in renal proximal tubular cells (RPTCs) after oxidant injury. Wild-type PKC-alpha (wtPKC-alpha) and an inactive PKC-alpha [dominant negative dn; PKC-alpha] mutant were overexpressed in primary cultures of RPTCs, and iHSP70 levels and RPTC regeneration were assessed after treatment with the oxidant tert-butylhydroperoxide (TBHP). TBHP exposure increased ROS production and induced RPTC death, which was prevented by ferrostatin and necrostatin-1 but not by cyclosporin A. Overexpression of wtPKC alpha maintained mitochondrial levels of active PKC-alpha, reduced cell death, and accelerated proliferation without altering ROS production in TBHP-injured RPTCs. In contrast, dnPKC-alpha blocked proliferation and monolayer regeneration. Coimmunoprecipitation and proteomic analysis demonstrated an association between inactive, but not active, PKC-alpha and iHSP70 in mitochondria. Mitochondrial iHSP70 levels increased as levels of active PKC-alpha decreased after injury. Overexpression of dnPKC-alpha augmented, whereas overexpression of wtPKC-alpha abrogated, oxidant-induced increases in mitochondrial iHSP70 levels. iHSP70 overexpression (1) maintained mitochondrial levels of phosphorylated PKC-alpha, (2) improved the recovery of state 3 respiration and ATP content, (3) decreased RPTC death (an effect abrogated by cyclosporine A), and (4) accelerated proliferation after oxidant injury. In contrast, iHSP70 inhibition blocked the recovery of ATP content and exacerbated RPTC death. Inhibition of PKC-alpha in RPTC overexpressing iHSP70 blocked the protective effects of iHSP70. We conclude that active PKC-alpha maintains mitochondrial function and decreases cell death after oxidant injury. iHSP70 is recruited to mitochondria in response to PKC alpha dephosphorylation and associates with and reactivates inactive PKC-alpha, which promotes the recovery of mitochondrial function, decreases RPTC death, and improves regeneration. PMID- 23804452 TI - Expression of glutamine synthetase in the mouse kidney: localization in multiple epithelial cell types and differential regulation by hypokalemia. AB - Renal glutamine synthetase catalyzes the reaction of NH4+ with glutamate, forming glutamine and decreasing the ammonia available for net acid excretion. The purpose of the present study was to determine glutamine synthetase's specific cellular expression in the mouse kidney and its regulation by hypokalemia, a common cause of altered renal ammonia metabolism. Glutamine synthetase mRNA and protein were present in the renal cortex and in both the outer and inner stripes of the outer medulla. Immunohistochemistry showed glutamine synthetase expression throughout the entire proximal tubule and in nonproximal tubule cells. Double immunolabel with cell-specific markers demonstrated glutamine synthetase expression in type A intercalated cells, non-A, non-B intercalated cells, and distal convoluted tubule cells, but not in principal cells, type B intercalated cells, or connecting segment cells. Hypokalemia induced by feeding a nominally K+ -free diet for 12 days decreased glutamine synthetase expression throughout the entire proximal tubule and in the distal convoluted tubule and simultaneously increased glutamine synthetase expression in type A intercalated cells in both the cortical and outer medullary collecting duct. We conclude that glutamine synthetase is widely and specifically expressed in renal epithelial cells and that the regulation of expression differs in specific cell populations. Glutamine synthetase is likely to mediate an important role in renal ammonia metabolism. PMID- 23804453 TI - Sp1 trans-activates and is required for maximal aldosterone induction of the alphaENaC gene in collecting duct cells. AB - The epithelial Na+ channel (ENaC) in the distal nephron constitutes the rate limiting step for renal sodium reabsorption. Aldosterone increases tubular sodium absorption in large part by increasing alphaENaC transcription in collecting duct principal cells. We previously reported that Af9 binds to +78/+92 of alphaENaC and recruits Dot1a to repress basal and aldosterone-sensitive alphaENaC transcription in mouse inner medullary collecting duct (mIMCD)3 cells. Despite this epigenetic repression, basal alphaENaC transcription is still evident and physiologically necessary, indicating basal operation of positive regulators. In the present study, we identified Sp1 as one such regulator. Gel shift and antibody competition assays using a +208/+240 probe revealed DNA-Sp1-containing complexes in mIMCD3 cells. Mutation of the +222/+229 element abrogated Sp1 binding in vitro and in promoter-reporter constructs stably expressed in mIMCD3 cells. Compared with the wild-type promoter, an alphaENaC promoter-luciferase construct with +222/+229 mutations exhibited much lower activity and impaired trans-activation in Sp1 overexpression experiments. Conversely, Sp1 knockdown inhibited endogenous alphaENaC mRNA and the activity of the wild-type alphaENaC promoter but not the mutated construct. Aldosterone triggered Sp1 recruitment to the alphaENaC promoter, which was required for maximal induction of alphaENaC promoter activity and was blocked by spironolactone. Sequential chromatin immunoprecipitation assays and functional tests of +78/+92 and +222/+229 alphaENaC promoter mutants indicated that while Sp1, Dot1a, and Af9 co-occupy the alphaENaC promoter, the Sp1 effects are functionally independent from Dot1a and Af9. In summary, Sp1 binding to a cis-element at +222/+229 represents the first identified constitutive driver of alphaENaC transcription, and it contributes to maximal aldosterone trans-activation of alphaENaC. PMID- 23804454 TI - Meprin A impairs epithelial barrier function, enhances monocyte migration, and cleaves the tight junction protein occludin. AB - Meprin metalloproteases are highly expressed at the luminal interface of the intestine and kidney and in certain leukocytes. Meprins cleave a variety of substrates in vitro, including extracellular matrix proteins, adherens junction proteins, and cytokines, and have been implicated in a number of inflammatory diseases. The linkage between results in vitro and pathogenesis, however, has not been elucidated. The present study aimed to determine whether meprins are determinative factors in disrupting the barrier function of the epithelium. Active meprin A or meprin B applied to Madin-Darby canine kidney (MDCK) cell monolayers increased permeability to fluorescein isothiocyanate-dextran and disrupted immunostaining of the tight junction protein occludin but not claudin 4. Meprin A, but not meprin B, cleaved occludin in MDCK monolayers. Experiments with recombinant occludin demonstrated that meprin A cleaves the protein between Gly(100) and Ser(101) on the first extracellular loop. In vivo experiments demonstrated that meprin A infused into the mouse bladder increased the epithelium permeability to sodium fluorescein. Furthermore, monocytes from meprin knockout mice on a C57BL/6 background were less able to migrate through an MDCK monolayer than monocytes from their wild-type counterparts. These results demonstrate the capability of meprin A to disrupt epithelial barriers and implicate occludin as one of the important targets of meprin A that may modulate inflammation. PMID- 23804456 TI - Urate-induced acute renal failure and chronic inflammation in liver-specific Glut9 knockout mice. AB - Plasma urate levels are higher in humans than rodents (240-360 vs. ~30 MUM) because humans lack the liver enzyme uricase. High uricemia in humans may protect against oxidative stress, but hyperuricemia also associates with the metabolic syndrome, and urate and uric acid can crystallize to cause gout and renal dysfunctions. Thus, hyperuricemic animal models to study urate-induced pathologies are needed. We recently generated mice with liver-specific ablation of Glut9, a urate transporter providing access of urate to uricase (LG9KO mice). LG9KO mice had moderately high uricemia (~120 MUM). To further increase their uricemia, here we gavaged LG9KO mice for 3 days with inosine, a urate precursor; this treatment was applied in both chow- and high-fat-fed mice. In chow-fed LG9KO mice, uricemia peaked at 300 MUM 2 h after the first gavage and normalized 24 h after the last gavage. In contrast, in high-fat-fed LG9KO mice, uricemia further rose to 500 MUM. Plasma creatinine strongly increased, indicating acute renal failure. Kidneys showed tubule dilation, macrophage infiltration, and urate and uric acid crystals, associated with a more acidic urine. Six weeks after inosine gavage, plasma urate and creatinine had normalized. However, renal inflammation, fibrosis, and organ remodeling had developed despite the disappearance of urate and uric acid crystals. Thus, hyperuricemia and high-fat diet feeding combined to induce acute renal failure. Furthermore, a sterile inflammation caused by the initial crystal-induced lesions developed despite the disappearance of urate and uric acid crystals. PMID- 23804455 TI - The antioxidant silybin prevents high glucose-induced oxidative stress and podocyte injury in vitro and in vivo. AB - Podocyte injury, a major contributor to the pathogenesis of diabetic nephropathy, is caused at least in part by the excessive generation of reactive oxygen species (ROS). Overproduction of superoxide by the NADPH oxidase isoform Nox4 plays an important role in podocyte injury. The plant extract silymarin is attributed antioxidant and antiproteinuric effects in humans and in animal models of diabetic nephropathy. We investigated the effect of silybin, the active constituent of silymarin, in cultures of mouse podocytes and in the OVE26 mouse, a model of type 1 diabetes mellitus and diabetic nephropathy. Exposure of podocytes to high glucose (HG) increased 60% the intracellular superoxide production, 90% the NADPH oxidase activity, 100% the Nox4 expression, and 150% the number of apoptotic cells, effects that were completely blocked by 10 MUM silybin. These in vitro observations were confirmed by similar in vivo findings. The kidney cortex of vehicle-treated control OVE26 mice displayed greater Nox4 expression and twice as much superoxide production than cortex of silybin-treated mice. The glomeruli of control OVE26 mice displayed 35% podocyte drop out that was not present in the silybin-treated mice. Finally, the OVE26 mice experienced 54% more pronounced albuminuria than the silybin-treated animals. In conclusion, this study demonstrates a protective effect of silybin against HG-induced podocyte injury and extends this finding to an animal model of diabetic nephropathy. PMID- 23804457 TI - Red cell exchange transfusion for severe carbon monoxide poisoning merits further study. PMID- 23804458 TI - How much does it hurt to be lonely? Mental and physical differences between older men and women in the KORA-Age Study. AB - OBJECTIVE: Loneliness has a deep impact on quality of life in older people. Findings on sex-specific differences on the experience of loneliness remain sparse. This study compared the intensity of and factors associated with loneliness between men and women. METHODS: Analyses are based on the 2008/2009 data of the KORA-Age Study, comprising 4127 participants in the age range of 64 94 years. An age-stratified random subsample of 1079 subjects participated in a face-to-face interview. Loneliness was measured by using a short German version of the UCLA-Loneliness-Scale (12 items, Likert scaled, ranging from 0 to 36 points). Multiple logistic regression analysis was conducted to analyze the associations of socio-demographic, physical, and psychological factors with loneliness. RESULTS: The mean level of loneliness did not significantly differ between men (17.0 +/- 4.5) and women (17.5 +/- 5.1). However, among the oldest old (>=85 years), loneliness was higher in women (p value = 0.047). Depression, low satisfaction with life, and low resilience were associated significantly with loneliness, which was more pronounced in men. Living alone was not associated with loneliness, whereas lower social network was associated with a three time higher risk for feeling lonely in both men and women. CONCLUSIONS: The extent of loneliness was equally distributed between men and women, although women were more disadvantaged regarding living arrangements as well as physical and mental health. However, loneliness was stronger associated with adverse mental health conditions in men. These findings should be considered when developing intervention strategies to reduce loneliness. PMID- 23804459 TI - Genotoxicity of cadmium chloride in the marine gastropod Nerita chamaeleon using comet assay and alkaline unwinding assay. AB - This paper presents an evaluation of the genotoxic effects of cadmium chloride (CdCl2 ) on marine gastropod, Nerita chamaeleon following the technique of comet assay and the DNA alkaline unwinding assay (DAUA). In this study, the extent of DNA damage in gill cells of N. chamaeleon was measured after in vivo exposure to four different concentrations (10, 25, 50, and 75 ug/L) of CdCl2 . In vitro exposure of hydrogen peroxide (H2 O2 ; 1, 10, 25, and 50 uM) of the gill cells showed a significant increase in the percentage tail DNA, Olive tail moment, and tail length (TL). Significant changes in percentage tail DNA by CdCl2 exposure were observed in all exposed groups of snails with respect to those in control. Exposure to 75 ug/L of CdCl2 produced significant decrease in DNA integrity as measured by DAUA at all duration with respect to control. In vivo exposure to different concentrations of CdCl2 (10, 25, 50, and 75 ug/L) to N. chamaeleon showed considerable increase in DNA damage as observed by both alkaline comet assay and the DAUA. The extent of DNA damage in marine gastropods determined by the application of alkaline comet assay and DAUA clearly indicated the genotoxic responses of marine gastropod, N. chamaeleon to a wide range of cadmium concentration in the marine environment. PMID- 23804460 TI - Comparison of intermittent intratympanic steroid injection and near-continual transtympanic steroid perfusion as salvage treatments for sudden sensorineural hearing loss. AB - OBJECTIVES/HYPOTHESIS: The purpose of this study was to investigate whether near continual transtympanic steroid perfusion is more effective than intermittent intratympanic steroid injection as a salvage therapy for idiopathic sudden sensorineural hearing loss. STUDY DESIGN: Case control study. METHODS: We designed a case-control study consisting of 60 patients with sudden sensorineural hearing loss who did not respond well to systemic steroid therapy. From November 2008 to October 2010, we prospectively enrolled subjects for the transtympanic steroid perfusion therapy. We retrospectively collected data from age- and sex matched patients who had undergone intratympanic steroid injection between January 2003 and October 2008. The audiological results of the two groups were compared. RESULTS: The presalvage pure tone threshold was 65.4 +/- 13.5 dB in the transtympanic steroid perfusion group. After the therapy, the hearing threshold was improved by an average of 15.0 +/- 9.7 dB, and 53.3% of subjects had improved by 10 dB or more. The speech discrimination score was improved from 12.6% +/- 7.0% to 54.4 +/- 6.4%. In the intratympanic steroid injection group, the presalvage pure tone threshold was 68.8 +/- 16.0 dB. After the therapy, the hearing threshold was improved by an average of 10.7 +/- 9.8 dB, and 43.3% of subjects had improved by 10 dB or more. The speech discrimination score was improved from 13.3 +/- 6.0% to 46.4 +/- 12%. The degree of hearing improvement was significantly greater in the transtympanic group. CONCLUSIONS: Both transtympanic steroid perfusion and intratympanic steroid injection can be used as salvage therapies for idiopathic sudden sensorineural hearing loss. Near continual transtympanic steroid perfusions may provide better audiological results. PMID- 23804463 TI - An update from istanbul. PMID- 23804461 TI - Low molecular weight dextran provides similar optical coherence tomography coronary imaging compared to radiographic contrast media. AB - BACKGROUND: Optical coherence tomography (OCT) coronary imaging requires displacement of red blood cells from the vessel lumen. This is usually accomplished using radiographic contrast. Low molecular weight dextran has low cost and is safe in low volumes. In the present study, we compared dextran with contrast for coronary OCT imaging. METHODS: Fifty-one vessels in 26 patients were sequentially imaged using manual injection of radiographic contrast (iodixanol) and dextran. OCT images were analyzed at 1 mm intervals to determine the image clarity (defined as a visible lumen border > 270 degrees ) and to measure the lumen area and lumen diameter. To correct for the refractive index of dextran, the dextran area measurements were multiplied by 1.117 and the dextran length measurements were multiplied by 1.057. RESULTS: A total of 3,418 cross-sections (1,709 with contrast and 1,709 with dextran) were analyzed. There were no complications related to OCT imaging or to contrast or dextran administration. Clear image segments were observed in 97.0% vs. 96.7% of the cross-sections obtained with contrast and dextran, respectively (P = 0.45). The mean lumen areas were also similar: 6.69 +/- 1.95 mm(2) with iodixanol vs. 7.06 +/- 2.06 mm(2) with dextran (correlation coefficient 0.984). CONCLUSIONS: The image quality and measurements during OCT image acquisition are similar for dextran and contrast. Dextran could be used instead of contrast for OCT imaging, especially in patients in whom contrast load minimization is desired. PMID- 23804464 TI - Near-infrared spectroscopy monitoring to predict postoperative renal insufficiency following repair of congenital heart disease. AB - BACKGROUND: Infants undergoing repair or palliation of congenital heart disease are at risk of renal insufficiency. Development of renal insufficiency increases mortality. This project seeks to determine whether intra- and postoperative renal near-infrared spectroscopy (NIRS) monitoring can reliably predict renal insufficiency after cardiac surgery in infants. METHODS: In this prospective, observational cohort study 48 patients undergoing repair or palliation of congenital heart disease in the first 6 months of life were studied intraoperatively and on postoperative day 1 and 2. The NIRS mean and nadir were recorded for the 3 time periods, as were urine output, fluid balance, and serum creatinine. Renal insufficiency was defined as rise in creatinine >=40% from baseline or oliguria for >4 hours. Near-infrared spectroscopy data were compared to creatinine increase, oliguria, and fluid balance on postoperative day 0, 1, and 2 by regression analysis. RESULTS: Mean renal regional saturation on postoperative day 1 has a strong correlation with increase in creatinine (P < .001 and R (2) = .6). Mean renal saturation less than 80% predicts renal insufficiency with a sensitivity of 100% and a specificity of 75% (P < .001). CONCLUSION: Monitoring of intra- and postoperative renal regional saturation may provide an early, noninvasive marker of renal insufficiency after cardiac surgery in infants. This would be clinically significant if interventions to improve renal regional saturation prevent renal insufficiency. PMID- 23804462 TI - Effect of cell culture medium components on color of formulated monoclonal antibody drug substance. AB - As the industry moves toward subcutaneous delivery as a preferred route of drug administration, high drug substance concentrations are becoming the norm for monoclonal antibodies. At such high concentrations, the drug substance may display a more intense color than at the historically lower concentrations. The effect of process conditions and/or changes on color is more readily observed in the higher color, high concentration formulations. Since color is a product quality attribute that needs to be controlled, it is useful to study the impact of process conditions and/or modifications on color. This manuscript summarizes cell culture experiments and reports on findings regarding the effect of various media components that contribute to drug substance color for a specific monoclonal antibody. In this work, lower drug substance color was achieved via optimization of the cell culture medium. Specifically, lowering the concentrations of B-vitamins in the cell culture medium has the effect of reducing color intensity by as much as 25%. In addition, decreasing concentration of iron was also directly correlated color intensity decrease of as much as 37%. It was also shown that the color of the drug substance directly correlates with increased acidic variants, especially when increased iron levels cause increased color. Potential mechanisms that could lead to antibody coloration are briefly discussed. PMID- 23804465 TI - Contegra versus pulmonary homografts for right ventricular outflow tract reconstruction: a ten-year single-institution comparison. AB - OBJECTIVE: Repair of congenital heart defects involving the right ventricular outflow tract (RVOT) may require pulmonary valve replacement at the time of primary repair or reoperation. This study compares the outcomes of bovine jugular vein grafts (BJV, Contegra, Medtronic Inc.) with cryopreserved pulmonary homografts (PHs) in patients with RVOT obstruction at a single institution. METHODS: We reviewed the outcomes of all BJVs and PHs implanted for RVOT reconstruction from 1999 to 2010. Echocardiographic data were reviewed to evaluate valve performance. Graft dysfunction is defined as RVOT obstruction with peak echo-Doppler gradient >40 mm Hg and/or grade III/IV conduit valve regurgitation. Graft failure is defined as need for conduit replacement or need for catheter or surgical reintervention. RESULTS: A total of 216 patients who received BJVs (n = 153) and PHs (n = 63) were studied. There was no significant difference between the groups with respect to mean age, body surface area, conduit indication, or conduit diameter, though mean follow-up duration was longer in patients that received homografts. Conduit dysfunction and conduit failure and need for explantation were worse for homografts, albeit at longer follow-up interval. Distal stenosis and actuarial survival were similar. CONCLUSIONS: In the first ten years after pulmonary implantation of BJVs and PHs, survival and freedom from distal stenosis are statistically similar, but freedom from failure, dysfunction, and explantation are significantly better for BJV conduits. The BJV conduit is a good alternative in patients who require RVOT reconstruction. PMID- 23804466 TI - Midterm outcome after surgical correction of anomalous left coronary artery from pulmonary artery. AB - BACKGROUND: Early establishment of a two-coronary artery system has become the standard surgical approach in patients with anomalous origin of the left coronary artery from the pulmonary artery. After surgical repair, presentation of severely impaired ventricular function and mitral regurgitation is a common finding. METHODS: We reviewed midterm outcome of 18 consecutive patients with anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) undergoing surgical repair for establishment of dual coronary system operated on between September 1999 and July 2009. Mortality, morbidity, echocardiography assessment of left ventricular function, mitral valve regurgitation, and indications for reoperation were studied retrospectively. RESULTS: The mean age at the time of surgery was 26 +/- 44 months (range, 14 days-12.7 years), 14 patients were younger than 6 months. There was no in-hospital or late mortality. Recovery of left ventricular function was associated with improvement in the degree of mitral valve regurgitation. At the latest follow-up, mitral valve regurgitation was none or trace in 14 patients (78%), mild to moderate in 3 patients (16%), and remained severe in 1 patient (6%). Left ventricular function normalized in 16 patients and remained mildly impaired in 2 patients. Late postoperative echocardiograms demonstrated a patent left coronary artery in 17 patients. In 5 patients temporary left heart bypass (LHB) was needed. CONCLUSIONS: Early establishment of a 2-coronary artery system artery results in complete recovery of left ventricular function and without relevant mitral valve dysfunction. Reoperation rates are acceptable. Our results support the use of LHB in patients with refractory low cardiac output. The need of mechanical circulatory support was short and very effective in our patient cohort. PMID- 23804467 TI - Current Trends in the Management of Neonates With Ebstein's Anomaly. AB - BACKGROUND: The optimal management strategy for neonates with Ebstein's anomaly is unknown. This analysis was undertaken to assess current trends in the management and prognosis of neonates born with Ebstein's anomaly in the United States, as reflected in an administrative database. METHODS: The Pediatric Health Information System database (40 children's hospitals) was used to review the reported incidence and available data on neonates with Ebstein's anomaly treated in the United States between 2003 and 2007. Primary outcome was hospital survival. Of the 415 patients identified, 257 (62%) did not undergo initial surgical intervention as neonates. Aortopulmonary shunt only was done on 63 patients (15%), single-ventricle palliation on 36 (9%), two-ventricle repair on 16 (4%), heart transplantation in 3 (1%), and a catheter-based intervention or a hybrid palliative approach was applied in 40 (10%). Intergroup comparisons were done using chi-square analyses. RESULTS: Mortality for the entire cohort was 24% (100 of 415). For medically treated patients, this was 22% (56 of 257). For surgically treated and hybrid patients, this was 30% and 23%, respectively (P = NS). CONCLUSIONS: The majority of patients born with Ebstein's anomaly currently do not undergo surgical intervention as neonates. Significant early mortality in this group suggests that certain subsets of patients may benefit from earlier surgical intervention. Among the severely symptomatic neonates who do undergo early surgical intervention, the mortality remains high, irrespective of the surgical approach taken. A multicenter trial may be appropriate to identify strategies to optimize care for these critically ill neonates. Further analysis of risk factors for early mortality is warranted. PMID- 23804468 TI - Second-Stage Palliation After Bilateral Pulmonary Artery Bands for HLHS and its Variants--Which is Better, Modified Norwood or Norwood Plus Bidirectional Glenn? AB - Background. The purpose of this study was to evaluate the surgical outcomes and pulmonary artery (PA) development associated with a new strategy wherein the modified Norwood (N) procedure is performed at 1-2 months after bilateral pulmonary artery banding (PAB). Methods. Between January 2008 and February 2010, 16 patients underwent Norwood-type operation after previous bilateral PAB. For analysis, patients were divided into two groups. Group I (n = 11) underwent modified Norwood procedure with either right modified Blalock Taussig (RMBT) shunt (n = 4) or right ventricle to pulmonary artery (RV-PA) conduit (n = 7). Group II (n = 5) underwent Norwood procedure plus bidirectional Glenn anastomosis. Diagnoses were hypoplastic left heart syndrome in 6 and its variants in 10. Results. There was no surgical death and no late death. Pulmonary artery interventions were performed at the time of the Norwood procedure in 27% in Group I and in 100% in Group II (p < 0.05). Additional PA interventions were performed during the period of follow-up in 4 cases in Group I (36.4%), and in 4 cases in Group II (80.0%). Additional Blalock Taussig shunts were performed in 7 patients, resulting in significant increase in PA index. In all, four patients have reached total cavopulmonary connection, and one has undergone biventricular repair. Eight patients in Group I and one patient in II Group reached bidirectional Glenn anastomosis. In Gp II, two patients showed LPA narrowing or obstruction with PA index of 80 +/- 12 mm(2)/m(2). Conclusions. Regarding the second-stage palliation after bilateral PAB, modified Norwood procedure with either RMBT or RV-PA conduit has some advantages compared with Norwood plus BDG with respect to subsequent pulmonary artery development. Additional BT shunt may contribute to PA development, even in the patients with Norwood procedure with RV-PA conduit. PMID- 23804469 TI - Medical test results do not tell the whole story: health-related quality of life offers a patient perspective on outcomes. AB - Children born today with congenital heart disease (CHD) are likely to reach adulthood, even those with complex disease. As survival rates have increased, attention has focused on the longer-term morbidity associated with CHD and its treatment, but this has largely addressed the physical and physiological outcomes rather than psychosocial morbidity and health-related quality of life (QoL). The purpose of this article is to outline the arguments in favor of routine evaluation of health-related QoL, describe how such measurements might be used, and the barriers and challenges associated with the collection of the data. Finally, a strategy is suggested for the routine collection and use of health related QoL data with children and adolescents with CHD. PMID- 23804470 TI - Using statistical process control to identify early growth failure among infants with hypoplastic left heart syndrome. AB - Although interventions to improve outcomes for children with congenital heart disease may be designed and tested, the rarity of any one specific defect presents a barrier to using traditional statistical methods to measure the effects of these interventions. The purpose of this report is to describe the innovative statistical approach taken by the Joint Council on Congenital Heart Disease (JCCHD) National Pediatric Cardiology Quality Improvement Collaborative (NPC-QIC) to measure outcomes for infants with hypoplastic left heart syndrome-a relatively rare disease. We report our experience with the application of statistical process control methods to generate measures capable of identifying statistically significant change in the incidence of early growth failure-a clinically important outcome in this relatively small patient population. PMID- 23804471 TI - Databases and outcomes in congenital cardiac anesthesia. AB - Anesthesia practitioners have long been at the forefront of patient safety initiatives in the operating room and beyond. The Congenital Cardiac Anesthesia Society has partnered with the Society of Thoracic Surgeons Congenital Heart Surgery Database to develop a patient registry for patients with congenital heart defects in order to determine patient outcomes related to anesthesia in this high risk population. A review of existing database efforts is also undertaken to determine their strengths and weaknesses. PMID- 23804473 TI - Invited commentary: the assessment of outcomes and the improvement of quality of the treatment of patients with congenital and pediatric cardiac disease. PMID- 23804472 TI - Use of an administrative database to determine clinical management and outcomes in congenital heart disease. AB - We review our 16-year experience using the large, multi-institutional database of the University HealthSystem Consortium to study management and outcomes in congenital heart surgery for hypoplastic left heart syndrome, transposition of the great arteries, and neonatal coarctation. The advantages, limitations, and use of administrative databases by others to study congenital heart surgery are reviewed. PMID- 23804474 TI - Heart transplantation for congenital heart disease. AB - Congenital heart disease affects 0.8% of all live-born infants. Some of the malformed hearts can at best be palliated by conventional surgical or catheter interventions from the start. Others fail slowly from chronic overloading. Patients with congenital heart disease have been among the first transplant recipients since 1967. Primary therapy with infant heart transplant is a convincing concept from an immunological perspective but large-scale implementation is limited by donor organ shortages. Another growing area is rescue therapy for older patients with end-stage heart failure after palliative procedures, particularly those with single-ventricle hearts, systemic right ventricles, and associated arrhythmias. PMID- 23804475 TI - Mechanical ventilation in the pediatric cardiac intensive care unit: the essentials. AB - Ventilating a child or newborn in the postoperative course after repair of congenital heart disease requires a solid basic understanding of respiratory system mechanics (pressure-volume relationship of the respiratory system and the concept of its time constants) and cardiopulmonary physiology. Furthermore, careful attention has to be paid to avoid damaging the lungs by potentially injurious mechanical ventilation. Optimizing ventilator settings during controlled and assisted ventilation, allowing as early as possible for spontaneous ventilation by still assisting mechanically the patient's respiratory efforts are important features for lung protection, for minimizing potential hemodynamic side effects of positive pressure ventilation, and for early weaning from mechanical ventilation. In the search for being less invasive, the use of noninvasive ventilation in the cardiac intensive care setting is rapidly increasing despite still lacking evidence of its theoretical superiority and requires good knowledge of specific techniques and equipment available for this approach in this setting. This review will address many of these aspects and highlight the essentials to be known when ventilating a child in the Cardiac Intensive Care Unit (CICU). PMID- 23804476 TI - Outcomes analysis and quality improvement for the treatment of patients with pediatric and congenital cardiac disease. AB - Tremendous progress has been made in the science of assessing the outcomes of the treatments of patients with pediatric and congenital cardiac disease. Multi institutional databases have been developed that span subspecialty, geographic, and temporal boundaries. Linking of different databases enables additional analyses not possible using the individual data sets alone and can facilitate quality improvement initiatives. Measures of quality can be developed, in the domains of structure, process, and outcome, which can facilitate quality improvement. Parents are an integral part of the health care team and are key partners with regard to quality improvement. The role of the parent in the process of health care delivery can be facilitated by enhancing the organizational culture and creating methods of transparency, empowering parents, and implementing effective strategies of communication. The professionals caring for patients with pediatric and congenital cardiac disease, in collaboration with the patients and their families, now have the opportunity to capitalize on the power of our databases and move beyond outcome assessment and benchmarking, to collaborative quality improvement. PMID- 23804477 TI - A novel provisional aortopulmonary shunt may help avoid neonatal cardiopulmonary bypass: report of two cases. AB - A novel temporary aortopulmonary shunt, constructed between the aorta and main pulmonary artery with flexible cannulas, was used to facilitate right ventricular outflow tract reconstruction in one neonate and creation of a central aortopulmonary shunt in a second neonate. Although cardiopulmonary bypass is readily available in Turkey, the strategy described in the case report may prove especially useful in developing nations with limited access to cardiopulmonary bypass (CPB). PMID- 23804478 TI - A case of heterotopic heart transplant as a "biologic left ventricular assist" in restrictive cardiomyopathy. AB - Heterotopic heart transplant (HHT) has traditionally been thought of as creating 2 parallel circulations. We present a case of using the donor heart as a "biologic left ventricular assist" (bio-LVA). The heterotopic technique used consisted of 4 anastomoses: the donor heart pulmonary artery (PA) to the native heart right atrium, the superior vena cava to superior vena cava, the left atrium to left atrium, and the aorta to aorta. A 9-year-old boy with restrictive cardiomyopathy, a PA pressure of 85/53 mmHg, received a HHT because he would probably not be able to tolerate an orthotopic heart transplant secondary to elevated PA pressure. He is currently alive 14 years post-transplantation. PMID- 23804479 TI - Blalock-taussig shunt thrombosis prophylaxis in a patient with jacobsen syndrome and thrombocytopenia. AB - Jacobsen syndrome (JS) is a rare chromosomal anomaly caused by deletions in the distal long arm of chromosome 11. Features of the syndrome include growth and developmental delays, a distinctive facial appearance, and a variety of physical problems including heart defects and bleeding disorders. Congenital heart defects occur in approximately 50% of children with JS. Hypoplastic left heart syndrome (HLHS) has been occasionally reported in association with JS. In such cases, the hematological abnormalities may influence the outcome from single-ventricle palliation through staged surgical reconstruction. Thrombotic obstruction or occlusion of the modified Blalock-Taussig (BT) shunt is a well-documented cause of interstage mortality following the Norwood operation. Although there is no consensus regarding the therapeutic value of antiplatelet therapy during the interstage period following the first stage of palliation, maintenance of shunt patency is critically important. For patients with JS undergoing single-ventricle palliation, decisions regarding antiplatelet therapy during the interstage period may be further complicated by the presence of thrombocytopenia and platelet dysfunction related to JS. We report the case of a patient with HLHS, JS, and thrombocytopenia who underwent the Norwood procedure, and we describe our strategy for prophylaxis against thrombosis of the BT shunt. PMID- 23804480 TI - Left ventricular pseudoaneurysm: a rare complication of infective endocarditis. AB - Left ventricular (LV) pseudoaneurysm is rare in children. This report describes the case of a 2-year-old previously healthy girl who was diagnosed with endocarditis and underwent resection of a large mitral valve vegetation from the posterior mitral leaflet. One month after this surgery, she was diagnosed with a large LV pseudoaneurysm based on echocardiography performed during routine outpatient follow-up. Cardiac surgery was performed urgently to address the pseudoaneurysm, given its potential to rupture spontaneously. This case emphasizes the need for a close follow-up of children with endocarditis for development of pseudoaneurysms, which is a rare but potentially fatal complication of endocarditis. PMID- 23804481 TI - Correction of tetralogy of fallot with combination of operative and interventional methods. AB - A one-stage repair was planned for an 11-year-old boy with tetralogy of Fallot. After initial attempts to wean from cardiopulmonary bypass were unsuccessful, an atrial septal defect and a ventricular septal defect were created in order to achieve hemodynamic stability. The boy recovered from the operation but had large volume of chest drainage. Transthoracic echocardiography revealed left to right shunting at both atrial and ventricular levels. Interventional catheter-directed devices were used to repair the residual shunts successfully in the catheterization laboratory. PMID- 23804482 TI - The role of methylene blue in the pediatric patient with vasoplegic syndrome. AB - Patients with vasoplegic syndrome (VPS) in the post-cardiopulmonary bypass setting usually require escalating vasopressor support. The utilization of methylene blue (MB) in the treatment of VPS in the adult population has been well described. We present a 5-year-old girl who developed vasodilatory shock due to VPS that was resistant to escalating doses of adrenergic agonists following cardiac transplantation. After receiving 1 mg/kg of MB, there was a significant improvement in the patient's mean arterial pressure which allowed for progressive weaning of the vasopressor support. To date, there are limited data regarding the use of MB in pediatric patients with VPS following cardiothoracic surgery. The cellular mechanisms of MB in VPS are discussed and reports of its use in the adult and pediatric population are reviewed. Dosing regimens and potential adverse effects of MB are presented. PMID- 23804483 TI - Left main coronary artery atresia and associated cardiac defects: report on concomitant surgical treatment. AB - A 9-year-old boy with congenital atresia of the left main coronary artery underwent myocardial revascularization. Coarctation of the aorta and ventricular septal defect were diagnosed at the age of 1 year. At age 7 years, the child presented with syncope while exercising. Preoperative evaluation included cardiac catheterization which revealed the unexpected finding of congenital atresia of the left main coronary artery with origin of the circumflex artery from the right coronary artery. Surgical correction included myocardial revascularization by means of left internal mammary artery graft to the anterior descending coronary artery, coarctation resection, and ventricular septal defect repair. The patient recovered uneventfully. We report the details of this extremely rare case with successful concomitant surgical management of the congenital coronary artery anomaly and the associated structural heart disease. PMID- 23804484 TI - Feasibility of VSD Closure and Debanding Without Pulmonary Artery Patch Repair in VSD Patients After PA Banding. AB - From 2004 to 2008, 64 infants with large ventricular septal defects were managed using a two-stage surgical approach. In the first stage, banding of the main pulmonary trunk was performed. The defect was then repaired months later. Debanding of pulmonary artery was accomplished without the need for pulmonary artery reconstruction. PMID- 23804485 TI - The transesophageal echocardiography probe: an unusual source of pulmonary venous obstruction. AB - We present a newborn patient who had surgical correction of supracardiac total anomalous pulmonary venous connection repair with an unusual cause of residual postoperative pulmonary venous obstruction secondary to compression from the transesophageal echocardiography (TEE) probe. PMID- 23804486 TI - Distinct increased metabotropic glutamate receptor type 5 (mGluR5) in temporal lobe epilepsy with and without hippocampal sclerosis. AB - Metabotropic glutamate receptor type 5 (mGluR5) upregulation in temporal lobe epilepsy (TLE) and the correlation of its expression with features of hippocampal sclerosis (HS) remains unclear. Here we characterized mGluR5 immunoreactivity in hippocampus, entorhinal cortex (EC), and subiculum of TLE specimens with confirmed HS, with neocortical TLE (non-HS) and necropsy controls. We correlated mGluR5 immunoreactivity with neuronal density, mossy fiber sprouting, astrogliosis (GFAP), and dendritic alterations (MAP2). TLE specimens showed increased mGluR5 expression, which was most pronounced in the EC, subiculum, CA2, and dentate gyrus outer molecular layer. Increased mGluR5 expression was seen in hippocampal head and body segments and was independent of neuronal density, astrogliosis, or dendritic alterations. Positive correlation between mGluR5 expression with mossy fiber sprouting and with MAP2 in CA3 and CA1 was found only in HS specimens. Negative correlation between mGluR5 expression with seizure frequency and epilepsy duration was found only in non-HS cases. Specimens from HS patients without previous history of febrile seizure (FS) showed higher mGluR5 and MAP2 expression in CA2. Our study suggests that mGluR5 upregulation is part of a repertoire of post-synaptic adaptations that might control overexcitation and excessive glutamate release rather than a dysfunction that leads to seizure facilitation. That would explain why non-HS cases, on which seizures are likely to originate outside the hippocampal formation, also exhibit upregulated mGluR5. On the other hand, lower mGluR5 expression was related to increased seizure frequency. In addition to its role in hyperexcitability, mGluR5 upregulation could play a role in counterbalance mechanisms along the hyperexcitable circuitry uniquely altered in sclerotic hippocampal formation. Inefficient post-synaptic compensatory morphological (dendritic branching) and glutamatergic (mGluR5 expression) mechanisms in CA2 subfield could potentially underlie the association of FS with HS and TLE. PMID- 23804487 TI - Dynamic model predicting overweight, obesity, and extreme obesity prevalence trends. AB - OBJECTIVE: Obesity prevalence in the United States appears to be leveling, but the reasons behind the plateau remain unknown. Mechanistic insights can be provided from a mathematical model. The objective of this study is to model known multiple population parameters associated with changes in body mass index (BMI) classes and to establish conditions under which obesity prevalence will plateau. DESIGN AND METHODS: A differential equation system was developed that predicts population-wide obesity prevalence trends. The model considers both social and nonsocial influences on weight gain, incorporates other known parameters affecting obesity trends, and allows for country specific population growth. RESULTS: The dynamic model predicts that: obesity prevalence is a function of birthrate and the probability of being born in an obesogenic environment; obesity prevalence will plateau independent of current prevention strategies; and the US prevalence of overweight, obesity, and extreme obesity will plateau by about 2030 at 28%, 32%, and 9% respectively. CONCLUSIONS: The US prevalence of obesity is stabilizing and will plateau, independent of current preventative strategies. This trend has important implications in accurately evaluating the impact of various anti-obesity strategies aimed at reducing obesity prevalence. PMID- 23804488 TI - MIF deficiency does not alter glucose homeostasis or adipose tissue inflammatory cell infiltrates during diet-induced obesity. AB - OBJECTIVE: Circulating macrophage migration inhibitory factor (MIF) levels have been shown to positively correlate with body mass index (BMI) in humans. Our objective in this study was to determine the effects of MIF deficiency in a model of high-fat diet-induced obesity. DESIGN AND METHODS: MIF wild type (MIF WT) and MIF deficient (MIF(-/-)) C57Bl/6J mice were fed a high-fat diet (HFD) for up to 15 weeks. Weight and metabolic responses were measured over the course of the disease. Immune cell infiltrates in visceral and subcutaneous adipose tissue were examined by flow cytometry. RESULTS: There was no difference in weight gain or adipose tissue mass in MIF(-/-) mice compared to MIF WT mice. Both groups fed HFD developed glucose intolerance at the same rate and had similar elevations in fasted blood insulin. MDSC abundance was evaluated and showed no MIF-dependent differences. Macrophages were elevated in the visceral adipose tissue of obese mice, but there was no difference between the two groups. CONCLUSIONS: While HFD feeding induced obesity with the expected perturbations in glucose homeostasis and adipose tissue inflammation, the presence or absence of MIF had no effect on any parameter examined. PMID- 23804490 TI - The measurement and analysis of surface geometric structure of ceramic femoral heads. AB - The surface functionality of interacting components is determined by evaluating geometric surface structure. Hence, the ceramic femoral heads originated from precision machining were subject to measurement and analysis with regard to roughness, surface damages and deviation from roundness. A variety of measurement techniques were applied in order to thoroughly examine the product quality. The obtained results proved in accordance with the specification: Ra was not greater than 0.05 um, whereas Delta was less than 10 um (5 um) when ceramic balls were used in conjunction with a polyethylene (ceramic) socket. Additionally, the surface damages which can affect the life of a friction pair were analyzed. PMID- 23804489 TI - CRF type 2 receptors mediate the metabolic effects of ghrelin in C2C12 cells. AB - OBJECTIVE: Ghrelin is known to regulate appetite control and cellular metabolism. The corticotropin-releasing factor (CRF) family is also known to regulate energy balance. In this study, the links between ghrelin and the CRF family in C2C12 cells, a mouse myoblast cell line was investigated. DESIGN AND METHODS: C2C12 cells were treated with ghrelin in the presence or absence of CRF receptor antagonists and then subjected to different metabolic analyses. RESULTS: Ghrelin enhanced glucose uptake by C2C12 cells, induced GLUT4 translocation to the cell surface and decreased RBP4 expression. A CRF-R2 selective antagonist, anti sauvagine-30, blocked ghrelin-induced glucose uptake, Ghrelin upregulated CRF-R2 but not CRF-R1 levels. Moreover, ghrelin-treated C2C12 cells displayed a cAMP and pERK activation in response to Ucn3, a CRF-R2 specific ligand, but not in response to CRF or stressin, CRF-R1 specific ligands. Ghrelin also induced UCP2 and UCP3 expression, which were blocked by anti- sauvagine-30. Ghrelin did not induce fatty acids uptake by C2C12 cells or ACC expression. Even though C2C12 cells clearly exhibited responses to ghrelin, the known ghrelin receptor, GHSR1a, was not detectable in C2C12 cells. CONCLUSION: The results suggest that, ghrelin plays a role in regulating muscle glucose and, raise the possibility that suppression of the CRF-R2 pathway might provide benefits in high ghrelin states. PMID- 23804491 TI - Venous thromboembolism in otolaryngology surgical inpatients receiving chemoprophylaxis. AB - BACKGROUND: The Caprini risk assessment model for stratifying patients' risk for venous thromboembolism (VTE) has been validated in the otolaryngology literature. We sought to determine the incidence of VTE in patients receiving chemoprophylaxis and correlate with the Caprini risk assessment model. METHODS: A retrospective chart review of adult surgical admissions to an academic otolaryngology service from 2007 to 2012 was performed. Caprini risk assessment model scores were calculated and compared to incidence of VTE based on diagnosis codes. RESULTS: Seven hundred four patients met our inclusion criteria. Fifteen (2.13%) developed VTE. The Caprini risk assessment model score averaged 5.7 (range, 2-16). Patients with VTE had an average score of 9.87 versus 5.62 for those without (p < .0001). No patients with a score of 6 and below, 3.01% with 7 8, and 13.16% with a score >9 developed VTE. CONCLUSION: The incidence of VTE increases with Caprini risk assessment model score, and a score of >8 predicts a high risk (>13%) of VTE in postoperative otolaryngology inpatients despite chemoprophylaxis. PMID- 23804492 TI - Modernising health visiting practice whilst keeping compassion in care. PMID- 23804493 TI - Management of acute blunt and penetrating external laryngeal trauma. AB - OBJECTIVES/HYPOTHESIS: Improve the care of acute external laryngeal trauma by reviewing controversies and the evolution of treatment. DATA SOURCE: Internet based search engines, civilian and military databases, and manual search of references from these sources over the past 90 years. REVIEW METHODS: Utilizing the above-mentioned sources, electronic and manual searches of primary topics such as laryngeal trauma or injury, emergency tracheotomy, airway trauma, intubation versus tracheotomy, cricothyrotomy, esophageal trauma, and emergent management of airway injuries in civilian and combat zones. Citations were reviewed, selected reports analyzed, and the most relevant articles referenced. RESULTS: Optimal treatment of acute laryngeal trauma includes early identification of injuries utilizing a directed history and physical examination. Timely management of the wounded airway is essential. The choice of intubation, tracheotomy, or cricothyrotomy must be individualized. Computed tomography (CT) may assist in differentiating patients who can be observed versus those who require surgical exploration. In selected patients, laryngeal electromyography and stroboscopy may also be useful. Surgery should begin with direct laryngoscopy and rigid esophagoscopy to evaluate the hard and soft tissues of the larynx, and to visualize the pharynx and esophagus. Minor endolaryngeal lacerations and abrasions may be observed, whereas more significant injuries require primary closure via a thyrotomy. Laryngeal skeletal fractures should be reduced and fixated. Endolaryngeal stenting is reversed for massive mucosal trauma, comminuted fractures, and traumatic anterior commissure disruption. CONCLUSIONS: Acute external injury to the larynx is both life threatening and a potential long term management challenge. Although a rare injury, sufficient experience now exists to recommend specific treatments, and to preserve voice and airway function. PMID- 23804494 TI - Initial evaluation of protein throughput and yield characteristics on nylon 6 capillary-channeled polymer (C-CP) fiber stationary phases by frontal analysis. AB - Nylon 6 capillary-channeled polymer (C-CP) fibers are investigated as an alternative support/stationary phase for downstream processing of macromolecules. Ionizable amine and carboxylic acid end groups on the native fiber surface allow for ion exchange chromatography (IEC). The low cost and ability to operate at high linear velocities and low back pressures are practical advantages of C-CP fibers for preparative-scale macromolecule separations. The lack of fiber porosity ensures facile adsorption/desorption that is conducive to high throughput and recoveries/yields. Described here is a preliminary investigation of the processing characteristics of lysozyme on nylon 6 fibers with an eye toward downstream processing applications. Fibers were packed into microbore (0.8 mm i.d.) and analytical-size (2.1 mm i.d.) columns for the evaluation of the role of linear velocity on pressure drop, frontal throughput, and yield. Protein isolation by frontal development involved three steps: loading of the column to breakthrough, an aqueous wash, and a salt wash to recover the protein. Frontal throughput was evaluated with different salt concentrations (0-1000 mM NaCl) and different linear velocities (6-24 mm s(-1)). The observed throughput values are in the range of 0.12-0.20 mg min(-1) when 0.25 mg mL(-1) lysozyme (in 20 mM Tris HCl) is loaded onto 78 mg of C-CP fiber in 0.52 mL volume analytical columns. Increased throughput and yield were found when protein was loaded and eluted at high linear velocity. Results of this study lend credence to the further development of C-CP fibers for biomacromolecule processing on larger scales. PMID- 23804495 TI - The combined effects of DEHP and PCBs on phospholipase in the livers of mice. AB - Di(2-ethylhexyl) phthalate (DEHP) and polychlorinated biphenyls (PCBs) are two widely distributed pollutants that are of great concern due to their adverse health effects. However, few studies have investigated the combined effects of DEHP and PCBs. In this study, adult mice were continuously exposed to mixtures of DEHP (15 mg/kg bodyweight/day) and Aroclor 1254 (7.5 mg/kg bodyweight/day) for 12 days to investigate the combined effects of these compounds. The results showed that the ratio of the liver weight to the body weight was higher in the treated group than that in the control group. The effects of combined exposure on three important receptors, the proliferator-activated receptor (PPAR), estrogen receptor (ER), and aryl hydrocarbon receptor (AHR), were investigated. The mRNA level of PPARgamma was significantly up-regulated after exposure. The expression level of ERalpha was decreased in the male treated group. In contrast, the expression levels of AHR and related genes (cyp1a1 and cyp1b1) were not markedly affected. The expression level of phospholipase A (PLA) was significantly down regulated at both the mRNA and protein levels in male mice after combined treatment. In all, our study demonstrated the combined effects of DEHP and PCBs on the expression levels of key receptors in mice. The combined exposure led to a decrease in phospholipase in male mice. PMID- 23804496 TI - An advanced selenium-carbon cathode for rechargeable lithium-selenium batteries. PMID- 23804497 TI - Stenting of a left main coronary artery compressed by a dilated main pulmonary artery. AB - Left main coronary artery (LMCA) disease caused by external compression by a dilated main pulmonary artery (MPA) is an uncommon clinical entity but is one of the reversible causes of chest pain in patients with pulmonary hypertension. Traditionally, treatment of LMCA disease involves coronary artery bypass graft surgery. However, for LMCA compression by a dilated MPA, coronary angioplasty with stenting has recently been reported to have good outcomes and might be more suitable in some patients with high risk associated with surgery. Herein, we describe a 54-year-old man with pulmonary arterial hypertension and external compression of the LMCA by the dilated main pulmonary artery that was treated with angiographic and intravascular ultrasound-guided coronary angioplasty and stenting. Also we briefly review current literatures about LMCA compression by a dilated MPA. PMID- 23804498 TI - Rho activation is apically restricted by Arhgap1 in neural crest cells and drives epithelial-to-mesenchymal transition. AB - Epithelial-to-mesenchymal transitions (EMTs) are crucial for morphogenesis and carcinoma metastasis, yet mechanisms controlling the underlying cell behaviors are poorly understood. RhoGTPase signaling has been implicated in EMT; however, previous studies have yielded conflicting results regarding Rho function, and its role in EMT remains poorly understood. Elucidation of precise Rho functions has been challenging because Rho signaling is highly context dependent and its activity is tightly regulated spatiotemporally within the cell. To date, few studies have examined how Rho affects cell motility in intact organisms, and the pattern of Rho activity during motile cell behaviors of EMT has not been determined in any system. Here, we image endogenous active Rho during EMT in vivo, and analyze effects of Rho and Rho-kinase (ROCK) manipulation on cell motility in vivo. We show that Rho is activated in a discrete apical region of premigratory neural crest cells during EMT, and Rho-ROCK signaling is essential for apical detachment and generation of motility within the neuroepithelium, a process that has been poorly understood. Furthermore, we find that Arhgap1 restricts Rho activation to apical areas, and this restriction is necessary for detachment. Our results provide new insight into mechanisms controlling local Rho activation and how it affects dynamic cell behaviors and actomyosin contraction during key steps of EMT in an intact living organism. PMID- 23804499 TI - Analysis of Gpr126 function defines distinct mechanisms controlling the initiation and maturation of myelin. AB - In peripheral nerves, Schwann cells form the myelin sheath, which allows the efficient propagation of action potentials along axons. The transcription factor Krox20 regulates the initiation of myelination in Schwann cells and is also required to maintain mature myelin. The adhesion G protein-coupled receptor (GPCR) Gpr126 is essential for Schwann cells to initiate myelination, but previous studies have not addressed the role of Gpr126 signaling in myelin maturation and maintenance. Through analysis of Gpr126 in zebrafish, we define two distinct mechanisms controlling the initiation and maturation of myelin. We show that gpr126 mutant Schwann cells elaborate mature myelin sheaths and maintain krox20 expression for months, provided that the early signaling defect is bypassed by transient elevation of cAMP. At the onset of myelination, Gpr126 and protein kinase A (PKA) function as a switch that allows Schwann cells to initiate krox20 expression and myelination. After myelination is initiated, krox20 expression is maintained and myelin maturation proceeds independently of Gpr126 signaling. Transgenic analysis indicates that the Krox20 cis-regulatory myelinating Schwann cell element (MSE) becomes active at the onset of myelination and that this activity is dependent on Gpr126 signaling. Activity of the MSE declines after initiation, suggesting that other elements are responsible for maintaining krox20 expression in mature nerves. We also show that elevated cAMP does not initiate myelination in the absence of functional Neuregulin 1 (Nrg1) signaling. These results indicate that the mechanisms regulating the initiation of myelination are distinct from those mediating the maturation and maintenance of myelin. PMID- 23804501 TI - Hematopoietic progenitor cell mobilization using low-dose cyclophosphamide and granulocyte colony-stimulating factor for multiple myeloma. AB - High-dose chemotherapy (HDT) supported by autologous stem cell transplantation (ASCT) has long been one of the standards of care for younger patients with multiple myeloma (MM). Cyclophosphamide (CY) plus granulocyte colony-stimulating factor (G-CSF) has been the conventional preparation for hematopoietic progenitor cell (HPC) mobilization, although the optimal dosage of CY in this setting has not yet been clearly defined. This study investigated the efficacy and safety of low-dose (LD-)CY (1.5 g/m(2)) plus G-CSF for conditioning for HPC apheresis harvest (HPC-A) in 18 MM patients, and compared it with a regimen consisting of intermediate-dose (ID)-CY (4 g/m(2)) plus G-CSF for 13 MM patients. Eleven patients in the former and six in the latter were treated with bortezomib (BTZ) during the induction therapy. Both regimens were comparably effective in terms of CD34(+) cell yields, while adverse events, such as leukopenia, thrombocytopenia, and febrile neutropenia, occurred significantly less frequently in the LD-CY cohort. All patients in LD-CY cohort started and completed their apheresis on day 7 or 8, whereas for the ID-CY cohort the day of first apheresis varied widely from day 8 to 15. These findings indicate that the LD-CY regimen is as effective as ID-CY for HPC mobilization, while the former is clearly more practicable and convenient than the ID-CY regimen for patients with MM. PMID- 23804500 TI - The role of ergonomic and psychosocial workplace factors in the reporting of back injuries among U.S. home health aides. AB - BACKGROUND: Due to the aging population and a shift to patient home care, home health aides (HHAs) are a fast-growing occupation. Since little is known about workplace risk factors for back injuries among HHAs, we examined the role of ergonomic and psychosocial factors in injury reporting among HHAs. METHODS: We used the 2007 U.S. National Home Health Aide Survey data (weighted n = 160,720) to predict the risk of back injuries by use of/need for ergonomic equipment and supervisor support with logistic regression, adjusted for socio-demographic variables. RESULTS: The annual prevalence of back injuries for U.S. HHAs was 5.2%. Injury risk was increased in HHAs reporting the need of additional ergonomic equipment in patient homes, and marginally associated with low reported supervisor support. CONCLUSIONS: Improvement of workplace ergonomic and psychosocial factors could be targeted as a strategy to decrease work-related injuries in HHAs. PMID- 23804502 TI - Gluco-oligomers initially formed by the reuteransucrase enzyme of Lactobacillus reuteri 121 incubated with sucrose and malto-oligosaccharides. AB - The probiotic bacterium Lactobacillus reuteri 121 produces a complex, branched (1 -> 4, 1 -> 6)-alpha-D-glucan as extracellular polysaccharide (reuteran) from sucrose (Suc), using a single glucansucrase/glucosyltransferase (GTFA) enzyme (reuteransucrase). To gain insight into the reaction/product specificity of the GTFA enzyme and the mechanism of reuteran formation, incubations with Suc and/or a series of malto-oligosaccharides (MOSs) (degree of polymerization (DP2-DP6)) were followed in time. The structures of the initially formed products, isolated via high-performance anion-exchange chromatography, were analyzed by matrix assisted laser-desorption ionization time-of-flight mass spectrometry and 1D/2D (1)H/(13)C NMR spectroscopy. Incubations with Suc only, acting as both donor and acceptor, resulted in elongation of Suc with glucose (Glc) units via alternating (alpha1 -> 4) and (alpha1 -> 6) linkages, yielding linear gluco-oligosaccharides up to at least DP ~ 12. Simultaneously with the ensemble of oligosaccharides, polymeric material was formed early on, suggesting that alternan fragments longer than DP ~ 12 have higher affinity with the GTFA enzyme and are quickly extended, yielding high-molecular-mass branched reuteran (4 * 10(7) Da). MOSs (DP2-DP6) in the absence of Suc turned out to be poor substrates. Incubations of GTFA with Suc plus MOSs as substrates resulted in preferential elongation of MOSs (acceptors) with Glc units from Suc (donor). This apparently reflects the higher affinity of GTFA for MOSs compared with Suc. In accordance with the GTFA specificity, most prominent products were oligosaccharides with an (alpha1 -> 4)/(alpha1 -> 6) alternating structure. PMID- 23804503 TI - Oral administration of interferon tau enhances oxidation of energy substrates and reduces adiposity in Zucker diabetic fatty rats. AB - Male Zucker diabetic fatty (ZDF) rats were used to study effects of oral administration of interferon tau (IFNT) in reducing obesity. Eighteen ZDF rats (28 days of age) were assigned randomly to receive 0, 4, or 8 MUg IFNT/kg body weight (BW) per day (n = 6/group) for 8 weeks. Water consumption was measured every two days. Food intake and BW were recorded weekly. Energy expenditure in 4 , 6-, 8-, and 10-week-old rats was determined using indirect calorimetry. Starting at 7 weeks of age, urinary glucose, and ketone bodies were tested daily. Rates of glucose and oleate oxidation in liver, brown adipose tissue, and abdominal adipose tissue, as well as leucine catabolism in skeletal muscle, and lipolysis in white and brown adipose tissues were greater for rats treated with 8 MUg IFNT/kg BW/day in comparison with control rats. Treatment with 8 MUg IFNT/kg BW/day increased heat production, reduced BW gain and adiposity, ameliorated fatty liver syndrome, delayed the onset of diabetes, and decreased concentrations of glucose, free fatty acids, triacylglycerol, cholesterol, and branched-chain amino acids in plasma, compared with control rats. Oral administration of 8 ug IFNT/kg BW/day ameliorated oxidative stress in skeletal muscle, liver, and adipose tissue, as indicated by decreased ratios of oxidized glutathione to reduced glutathione and increased concentrations of tetrahydrobiopterin. These results indicate that IFNT stimulates oxidation of energy substrates and reduces obesity in ZDF rats and may have broad important implications for preventing and treating obesity-related diseases in mammals. PMID- 23804504 TI - Ethnic differences in the effects of hepatic fat deposition on insulin resistance in nonobese middle school girls. AB - OBJECTIVE: In nonobese youth, to investigate whether hepatic fat deposition and its metabolic consequences vary between ethnic groups. DESIGN AND METHODS: Thirty two nonobese girls (12 Hispanic White [H] and 20 non-Hispanic White [NHW] girls), aged 11-14 years old were recruited. Outcome measures were MRI measured hepatic proton density fat fraction (hepatic PDFF), BMI Z-score, waist circumference, fasting insulin, glucose, adiponectin, sex hormone-binding globulin [SHBG], ALT, AST, triglycerides, and HOMA-IR. RESULTS: There were no significant differences in mean BMI Z-scores (P = 0.546) or hepatic PDFF (P = 0.275) between H and NHW girls; however, H girls showed significant correlations between hepatic PDFF and markers of IR (fasting insulin, HOMA-IR, adiponectin, SHBG, triglycerides; all P < 0.05), while NHW girls showed no significant correlations. Matched by hepatic PDFF or BMI Z-score, H girls had more evidence of IR for a given hepatic PDFF (mean insulin, HOMA-IR, and SHBG; all P < 0.05) or BMI Z-score (mean insulin and HOMA-IR; all P < 0.01) than NHW girls. CONCLUSIONS: In nonobese female youth, ethnicity-related differences in effects of hepatic fat on IR are evident, so that in H girls, a given amount of hepatic fat appears to result in a more predictable and greater degree of IR than in NHW girls. PMID- 23804505 TI - Measurement of distress and its alteration during treatment in patients with nasopharyngeal carcinoma. AB - BACKGROUND: We examined the criterion-related validity of the Distress Thermometer (DT) for screening distress in patients with nasopharyngeal carcinoma (NPC) and investigated prospectively how distress changes. METHODS: In the cross sectional study, the DT was tested against the Hospital Anxiety and Depression Scale (HADS) in 295 patients with NPC. In the prospective study, 61 newly diagnosed patients with NPC completed the DT and HADS 6 times. RESULTS: Adopting HADS as the standard tool for screening distress, 31.5% of the patients with NPC had distress. A DT cutoff score >= 4 had best sensitivity (0.73) and specificity (0.85). In the prospective study, the proportion of patients with distress rose significantly during treatment. CONCLUSION: Receiver operating characteristic (ROC) findings provide initial support for the validity of the DT among patients with NPC. Nearly one third of patients with NPC exceeded cutoff values for distress in the cross-sectional study. In the prospective study, the level of distress increased significantly during concurrent chemoradiotherapy for patients with NPC. PMID- 23804506 TI - Evidence synthesis for decision making 1: introduction. AB - We introduce the series of 7 tutorial papers on evidence synthesis methods for decision making, based on the Technical Support Documents in Evidence Synthesis prepared for the National Institute for Health and Clinical Excellence (NICE) Decision Support Unit. Although oriented to NICE's Technology Appraisal process, which examines new pharmaceutical products in a cost-effectiveness framework, the methods presented throughout the tutorials are equally relevant to clinical guideline development and to comparisons between medical devices, or public health interventions. Detailed guidance is given on how to use the other tutorials in the series, which propose a single evidence synthesis framework that covers fixed and random effects models, pairwise meta-analysis, indirect comparisons, and network meta-analysis, and where outcomes expressed in several different reporting formats can be analyzed without recourse to normal approximations. We describe the principles of evidence synthesis required by the 2008 revision of the NICE Guide to the Methods of Technology Appraisal and explain how the approach proposed in these tutorials was designed to conform to those requirements. We finish with some suggestions on how to present the evidence, the synthesis methods, and the results. PMID- 23804507 TI - Evidence synthesis for decision making 3: heterogeneity--subgroups, meta regression, bias, and bias-adjustment. AB - In meta-analysis, between-study heterogeneity indicates the presence of effect modifiers and has implications for the interpretation of results in cost effectiveness analysis and decision making. A distinction is usually made between true variability in treatment effects due to variation in patient populations or settings and biases related to the way in which trials were conducted. Variability in relative treatment effects threatens the external validity of trial evidence and limits the ability to generalize from the results; imperfections in trial conduct represent threats to internal validity. We provide guidance on methods for meta-regression and bias-adjustment, in pairwise and network meta-analysis (including indirect comparisons), using illustrative examples. We argue that the predictive distribution of a treatment effect in a "new" trial may, in many cases, be more relevant to decision making than the distribution of the mean effect. Investigators should consider the relative contribution of true variability and random variation due to biases when considering their response to heterogeneity. In network meta-analyses, various types of meta-regression models are possible when trial-level effect-modifying covariates are present or suspected. We argue that a model with a single interaction term is the one most likely to be useful in a decision-making context. Illustrative examples of Bayesian meta-regression against a continuous covariate and meta-regression against "baseline" risk are provided. Annotated WinBUGS code is set out in an appendix. PMID- 23804508 TI - Evidence synthesis for decision making 4: inconsistency in networks of evidence based on randomized controlled trials. AB - Inconsistency can be thought of as a conflict between "direct" evidence on a comparison between treatments B and C and "indirect" evidence gained from AC and AB trials. Like heterogeneity, inconsistency is caused by effect modifiers and specifically by an imbalance in the distribution of effect modifiers in the direct and indirect evidence. Defining inconsistency as a property of loops of evidence, the relation between inconsistency and heterogeneity and the difficulties created by multiarm trials are described. We set out an approach to assessing consistency in 3-treatment triangular networks and in larger circuit structures, its extension to certain special structures in which independent tests for inconsistencies can be created, and describe methods suitable for more complex networks. Sample WinBUGS code is given in an appendix. Steps that can be taken to minimize the risk of drawing incorrect conclusions from indirect comparisons and network meta-analysis are the same steps that will minimize heterogeneity in pairwise meta-analysis. Empirical indicators that can provide reassurance and the question of how to respond to inconsistency are also discussed. PMID- 23804509 TI - Evidence synthesis for decision making 5: the baseline natural history model. AB - Most cost-effectiveness analyses consist of a baseline model that represents the absolute natural history under a standard treatment in a comparator set and a model for relative treatment effects. We review synthesis issues that arise on the construction of the baseline natural history model. We cover both the absolute response to treatment on the outcome measures on which comparative effectiveness is defined and the other elements of the natural history model, usually "downstream" of the shorter-term effects reported in trials. We recommend that the same framework be used to model the absolute effects of a "standard treatment" or placebo comparator as that used for synthesis of relative treatment effects and that the baseline model is constructed independently from the model for relative treatment effects, to ensure that the latter are not affected by assumptions made about the baseline. However, simultaneous modeling of baseline and treatment effects could have some advantages when evidence is very sparse or when other research or study designs give strong reasons for believing in a particular baseline model. The predictive distribution, rather than the fixed effect or random effects mean, should be used to represent the baseline to reflect the observed variation in baseline rates. Joint modeling of multiple baseline outcomes based on data from trials or combinations of trial and observational data is recommended where possible, as this is likely to make better use of available evidence, produce more robust results, and ensure that the model is internally coherent. PMID- 23804510 TI - Evidence synthesis for decision making 6: embedding evidence synthesis in probabilistic cost-effectiveness analysis. AB - When multiple parameters are estimated from the same synthesis model, it is likely that correlations will be induced between them. Network meta-analysis (mixed treatment comparisons) is one example where such correlations occur, along with meta-regression and syntheses involving multiple related outcomes. These correlations may affect the uncertainty in incremental net benefit when treatment options are compared in a probabilistic decision model, and it is therefore essential that methods are adopted that propagate the joint parameter uncertainty, including correlation structure, through the cost-effectiveness model. This tutorial paper sets out 4 generic approaches to evidence synthesis that are compatible with probabilistic cost-effectiveness analysis. The first is evidence synthesis by Bayesian posterior estimation and posterior sampling where other parameters of the cost-effectiveness model can be incorporated into the same software platform. Bayesian Markov chain Monte Carlo simulation methods with WinBUGS software are the most popular choice for this option. A second possibility is to conduct evidence synthesis by Bayesian posterior estimation and then export the posterior samples to another package where other parameters are generated and the cost-effectiveness model is evaluated. Frequentist methods of parameter estimation followed by forward Monte Carlo simulation from the maximum likelihood estimates and their variance-covariance matrix represent'a third approach. A fourth option is bootstrap resampling--a frequentist simulation approach to parameter uncertainty. This tutorial paper also provides guidance on how to identify situations in which no correlations exist and therefore simpler approaches can be adopted. Software suitable for transferring data between different packages, and software that provides a user-friendly interface for integrated software platforms, offering investigators a flexible way of examining alternative scenarios, are reviewed. PMID- 23804511 TI - Evidence synthesis for decision making 7: a reviewer's checklist. AB - This checklist is for the review of evidence syntheses for treatment efficacy used in decision making based on either efficacy or cost-effectiveness. It is intended to be used for pairwise meta-analysis, indirect comparisons, and network meta-analysis, without distinction. It does not generate a quality rating and is not prescriptive. Instead, it focuses on a series of questions aimed at revealing the assumptions that the authors of the synthesis are expecting readers to accept, the adequacy of the arguments authors advance in support of their position, and the need for further analyses or sensitivity analyses. The checklist is intended primarily for those who review evidence syntheses, including indirect comparisons and network meta-analyses, in the context of decision making but will also be of value to those submitting syntheses for review, whether to decision-making bodies or journals. The checklist has 4 main headings: A) definition of the decision problem, B) methods of analysis and presentation of results, C) issues specific to network synthesis, and D) embedding the synthesis in a probabilistic cost-effectiveness model. The headings and implicit advice follow directly from the other tutorials in this series. A simple table is provided that could serve as a pro forma checklist. PMID- 23804512 TI - Energy balance in adolescent girls: the trial of activity for adolescent girls cohort. AB - OBJECTIVES: To study correlates of change in BMI percentile and body fat among adolescent girls. METHODS: A longitudinal prospective study following 265 girls from the Trial of Activity for Adolescent Girls (TAAG) cohort measured in 8th grade and during 10 and 11th grade or 11th and 12th grade. Twice during 2009-2011 girls wore an accelerometer and completed a food frequency questionnaire and 7 day diary documenting trips and food eaten away from home and school. Physical activity, BMI, and percent body fat were objectively measured at each time point. RESULTS: Moderate to vigorous physical activity (MVPA) declined, but the change was not independently associated with changes in BMI percentile. Increased vigorous physical activity was associated with reductions in body fat. Diet was associated with both changes in BMI percentile and body fat. Girls who increased the percentage of caloric intake from snacks and desserts reduced their BMI percentile and body fat. CONCLUSIONS: Some relationships between energy balance behaviors and BMI and body composition were counter-intuitive. While it is plausible that vigorous physical activity would result in reductions of body fat, until more accurate methods are devised to measure diet, the precise contribution of dietary composition to health will be difficult to assess. PMID- 23804513 TI - Hoarseness evaluation: a transatlantic survey of laryngeal experts. AB - OBJECTIVES/HYPOTHESIS: Hoarseness is a symptom of laryngeal dysfunction, without an existing consensus regarding its appropriate evaluation. A survey of laryngeal specialists is proposed to establish expert opinion on the methodology for evaluation of hoarseness, and to identify divergence of opinion regarding appropriate management. STUDY DESIGN: Cross-sectional survey. METHODS: A 13-item questionnaire was submitted electronically to the membership of the American Laryngological Association, the American Broncho-Esophagological Association, and the European Laryngological Society. Responses were collated anonymously and subjected to cross-tabulated data analysis. RESULTS: A total of 195 responses were included for review. The majority of respondents identified themselves as laryngologists/phoniatricians (54.9%). Two-thirds (64.1%) of the providers dedicated more than 25% of their practice to voice management, and 48.8% managed more than 10 dysphonic patients weekly. Most respondents defined hoarseness and dysphonia as symptoms and not diseases. The panel recommended a mandated time to laryngoscopy of 1 week to 1 month from the onset of symptoms for most acutely dysphonic patients, regardless of risk factors for malignancy, while it was not advised to defer laryngoscopy beyond 2 months of symptom persistence in any situation. A majority (96.2%) felt that an otolaryngologist ought to perform the initial laryngoscopy of a newly hoarse patient. CONCLUSION: This survey demonstrates an agreement to expedite specialized laryngeal visualization for cases of hoarseness not subsiding within 1 month, and exemplifies controversies stemming from a recently published clinical practice guideline. Ongoing research and practice evaluation will contribute to set forth improved standards of care and to appropriately counsel dysphonic patients. PMID- 23804515 TI - Photovoltaic wire with high efficiency attached onto and detached from a substrate using a magnetic field. PMID- 23804514 TI - Association of Rgs7/Gbeta5 complexes with Girk channels and GABAB receptors in hippocampal CA1 pyramidal neurons. AB - In the hippocampus, signaling through G protein-coupled receptors is modulated by Regulators of G protein signaling (Rgs) proteins, which act to stimulate the rate of GTP hydrolysis, and consequently, G protein inactivation. The R7-Rgs subfamily selectively deactivates the G(i/o)-class of Galpha subunits that mediate the action of several GPCRs. Here, we used co-immunoprecipitation, electrophysiology and immunoelectron microscopy techniques to investigate the formation of macromolecular complexes and spatial relationship of Rgs7/Gbeta5 complexes and its prototypical signaling partners, the GABAB receptor and Girk channel. Co expression of recombinant GABAB receptors and Girk channels in combination with co-immunoprecipitation experiments established that the Rgs7/Gbeta5 forms complexes with GABAB receptors or Girk channels. Using electrophysiological experiments, we found that GABAB -Girk current deactivation kinetics was markedly faster in cells coexpressing Rgs7/Gbeta5. At the electron microscopic level, immunolabeling for Rgs7 and Gbeta5 proteins was found primarily in the dendritic layers of the hippocampus and showed similar distribution patterns. Immunoreactivity was mostly localized along the extrasynaptic plasma membrane of dendritic shafts and spines of pyramidal cells and, to a lesser extent, to that of presynaptic terminals. Quantitative analysis of immunogold particles for Rgs7 and Gbeta5 revealed an enrichment of the two proteins around excitatory synapses on dendritic spines, virtually identical to that of Girk2 and GABAB1 . These data support the existence of macromolecular complexes composed of GABAB receptor-G protein-Rgs7-Girk channels in which Rgs7 and Gbeta5 proteins may preferentialy modulate GABAB receptor signaling through the deactivation of Girk channels on dendritic spines. In contrast, Rgs7 and Girk2 were associated but mainly segregated from GABAB1 in dendritic shafts, where Rgs7/Gbeta5 signaling complexes might modulate Girk-dependent signaling via a different metabotropic receptor(s). PMID- 23804516 TI - Estimating occupational exposure to carcinogens in Quebec. AB - BACKGROUND: We estimated the extent of exposure to occupational carcinogens in Quebec, Canada, to help raise awareness of occupational cancers. METHODS: Proportions of workers exposed to 21 recognized and 17 probable carcinogens (according to Quebec occupational health regulation and the International Agency for Research on Cancer [IARC] classification) were extracted from various sources: workplace monitoring data, research projects, a population survey, radiation protection data, exposure estimates from the Carcinogen Exposure Canada (CAREX Canada) Project database, and published exposure data. These proportions were applied to Quebec labor force data. RESULTS: Among the 38 studied, carcinogens with the largest proportions of exposed workers were solar radiation (6.6% of workers), night shift work/rotating shift work including nights (6.0%), diesel exhaust fumes (4.4%), wood dust (2.9%) and polycyclic aromatic hydrocarbons (2.0%). More than 15 carcinogens were identified in several industrial sectors, and up to 100,000 young workers are employed in these sectors. CONCLUSION: Although crude, estimates obtained with different data sources allow identification of research and intervention priorities for cancer in Quebec. PMID- 23804517 TI - Bile acids and gut peptide secretion after bariatric surgery: a 1-year prospective randomized pilot trial. AB - OBJECTIVE: Increased delivery of bile acid salts (BA) to distal L-cells and altered TGR5 receptor activation may contribute to the early and substantial increases in gut peptide secretion seen after bariatric surgery. To further elucidate a potential role of BA in the secretion of GLP-1 and PYY, we analyzed plasma BA concentrations in 14 morbidly obese patients undergoing gastric bypass or sleeve gastrectomy in a prospective, randomized 1-year trial. DESIGN AND METHODS: Patients received a standard test meal and blood was collected before and after eating, prior to, and 1 week, 3 months, and 12 months after surgery. RESULTS: Pre-surgery, basal BA concentrations were significantly lower in bariatric patients than in healthy controls. One year post-surgery, bariatric patients expressed variably increased BA concentrations (gastric bypass patients ~2 fold increase, P <= 0.05). However, whereas in both patient groups, marked increases in GLP-1 and PYY and improved glycemic control was seen already 1 week and 3 months post-surgery, changes in plasma BA followed a different pattern: basal and postprandial plasma BA concentrations increased much slower, more progressively with significant increases only 1-year post-surgery. CONCLUSIONS: Based on these findings, BA do not appear to be key mediators of the early increase in GLP-1 and PYY response in post-bariatric patients. PMID- 23804518 TI - Transcriptional engineering of Escherichia coli K4 for fructosylated chondroitin production. AB - The capsule polysaccharide (CPS) of Escherichia coli K4 (K4CPS) is identical to fructosylated chondroitin, which can be modified to chondroitin sulfate, a commercially valuable biopolymer commonly used in pharmaceutical applications. In this study, we homologously overexpressed the transcriptional regulator SlyA to enhance the expression of K4 capsule gene cluster and production of CPS. The iTRAQ quantificaton of proteomics revealed 77 up-regulated proteins and 143 down regulated proteins in E. coli THslyA. Most enzymes of glycolysis and citrate cycle pathway were weakened, while proteins associated with K4CPS synthesis were up-regulated, showing a shift of carbon flux from cell growth to K4CPS production. Further, the production of K4CPS by the recombinant strain was 1 and 2.6 g/L in a shake flask and 7-L batch bioreactor, which was 1.85- and 1.53-fold higher than that of the wild-type strain, respectively. Thus, this study provides a viable strategy for improving the production of K4CPS through a transcriptional level manipulation. PMID- 23804519 TI - No electrophysiological evidence for Onuf's nucleus degeneration causing bladder and bowel symptoms in Huntington's disease patients. AB - AIMS: In several degenerative neurologic diseases degeneration of Onuf's nucleus has been demonstrated using histologic and electromyographic (EMG) methods. Although Huntington's disease (HD) patients also frequently complain of bladder and bowel symptoms, degeneration of Onuf's nucleus has not been systematically studied in this group. METHODS: From our inventory of patients with genetically confirmed HD, all patients willing and capable of participating in the study, which utilized several standard questionnaires, were included. The patients reporting bladder/bowel symptoms were also asked to participate in anal sphincter EMG and sacral reflex studies. RESULTS: Of 52 patients (23 men) with genetically confirmed HD, 34 reported bladder/bowel symptoms, and 16 (8 men) of them consented to anal sphincter EMG and sacral reflex studies. Complete pattern of urinary and fecal urgency with incontinence reported 6 (38%), and incomplete 3 (19%) patients, accompanied with episodic diarrhea in another 3 (19%) patients. No patient exhibited quantitative anal sphincter EMG or sacral reflex abnormalities. However, in 81% of patients, decreased tonic anal sphincter activity and/or decreased voluntary activation were found on qualitative EMG. Lower sacral sensory thresholds and shorter reflex latencies were also found in HD patients compared to controls. CONCLUSIONS: We found no EMG signs of Onuf's nucleus degeneration in HD patients. The observed decreased anal sphincter tonic activity and voluntary activation, lower sacral sensory thresholds and shorter reflex latencies as well as the reported bladder/bowel symptoms, are probably caused by degeneration of other central nervous system structures. Neurourol. Urodynam. 33:524-530, 2014. (c) 2013 Wiley Periodicals, Inc. PMID- 23804520 TI - Aggressive coil embolization for connected aortopulmonary collateral arteries with large shunts developed after diaphragmatic plication performed after cavopulmonary connection to facilitate Fontan circulation. AB - We present two patients of univentricular physiology, who underwent diaphragmatic plication following the complication of diaphragmatic paralysis resulting from a bidirectional Glenn procedure. Over several months, complex connections developed between aortopulmonary collateral arteries, resulting in large shunts around the plication sites and an increased central pulmonary artery (PA) pressure to 14-15 mmHg. Most blood flow from these connections was reversed in the lower PAs of the affected side, reaching the contralateral lungs through the central PAs. Selective angiography identified almost all of the feeding arteries and complex connections. Aggressive coil embolization at these sites decreased the PA pressure to approximately 10 mmHg, enabling the Fontan procedure. PMID- 23804521 TI - Promoter hypermethylation of CDKN2A, MGMT, MLH1, and DAPK genes in laryngeal squamous cell carcinoma and their associations with clinical profiles of the patients. AB - BACKGROUND: Laryngeal squamous cell carcinoma (laryngeal SCC) is a frequently occurring cancer of the head and neck area. Epigenetic changes of tumor-related genes contribute to its genesis and progression. METHODS: We assessed promoter methylation status of the selected genes (CDKN2A, MGMT, MLH1, and DAPK) using methylation-sensitive high resolution melting (MS-HRM) in 100 patients with laryngeal SCC and studied the correlations with clinical characteristics. RESULTS: The prevalence of promoter methylation in MGMT, CDKN2A, MLH1, and DAPK was 59 of 97 (60.8%), 46 of 97 (47.4%), 45 of 97 (46.4%), and 41 of 97 patients (42.3%), respectively. Significantly increased methylation of CDKN2A was observed in heavy smokers. Epigenetic inactivation of CDKN2A and MLH1 were found to be associated with lymph node involvement. An inverse correlation was present between MLH1 methylation and alcohol consumption. CONCLUSION: Our results strongly suggest that deregulation of p16-associated, and MLH1-associated pathways, because of promoter hypermethylation, is associated with increased cancer cell migration, tumor invasiveness, and, thus, aggressive phenotype. PMID- 23804522 TI - Zinc signals and immune function. AB - For more than 50 years, it has been known that zinc deficiency compromises immune function. During this time, knowledge about the biochemistry of zinc has continued to grow, but only recent years have provided in-depth molecular insights into the multiple aspects of zinc as a regulator of immunity. A network based on ZnT and ZIP proteins for transport and metallothionein for storage tightly regulates zinc availability, and virtually all aspects of innate and adaptive immunity are affected by zinc. In vivo, zinc deficiency alters the number and function of neutrophil granulocytes, monocytes, natural killer (NK)-, T-, and B-cells. T cell functions and balance between the different subsets are particularly susceptible to changes in zinc status. This article focuses in particular on the main mechanisms by which zinc ions exert essential functions in the immune system. On the one hand, this includes tightly protein bound zinc ions serving catalytic or structural functions in a multitude of different proteins, in particular enzymes and transcription factors. On the other hand, increasing evidence arises for a regulatory role of free zinc ions in signal transduction, especially in cells of the immune system. Identification of several molecular targets, including phosphatases, phosphodiesterases, caspases, and kinases suggest that zinc ions are a second messenger regulating signal transduction in various kinds of immune cells. PMID- 23804523 TI - Formation of threohydrobupropion from bupropion is dependent on 11beta hydroxysteroid dehydrogenase 1. AB - Bupropion is widely used for treatment of depression and as a smoking-cessation drug. Despite more than 20 years of therapeutic use, its metabolism is not fully understood. While CYP2B6 is known to form hydroxybupropion, the enzyme(s) generating erythro- and threohydrobupropion have long remained unclear. Previous experiments using microsomal preparations and the nonspecific inhibitor glycyrrhetinic acid suggested a role for 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) in the formation of both erythro- and threohydrobupropion. 11beta HSD1 catalyzes the conversion of inactive glucocorticoids (cortisone, prednisone) to their active forms (cortisol, prednisolone). Moreover, it accepts several other substrates. Here, we used for the first time recombinant 11beta-HSD1 to assess its role in the carbonyl reduction of bupropion. Furthermore, we applied human, rat, and mouse liver microsomes and a selective inhibitor to characterize species-specific differences and to estimate the relative contribution of 11beta HSD1 to bupropion metabolism. The results revealed 11beta-HSD1 as the major enzyme responsible for threohydrobupropion formation. The reaction was stereoselective and no erythrohydrobupropion was formed. Human liver microsomes showed 10 and 80 times higher activity than rat and mouse liver microsomes, respectively. The formation of erythrohydrobupropion was not altered in experiments with microsomes from 11beta-HSD1-deficient mice or upon incubation with 11beta-HSD1 inhibitor, indicating the existence of another carbonyl reductase that generates erythrohydrobupropion. Molecular docking supported the experimental findings and suggested that 11beta-HSD1 selectively converts R bupropion to threohydrobupropion. Enzyme inhibition experiments suggested that exposure to bupropion is not likely to impair 11beta-HSD1-dependent glucocorticoid activation but that pharmacological administration of cortisone or prednisone may inhibit 11beta-HSD1-dependent bupropion metabolism. PMID- 23804524 TI - Binary genetic cassettes for selecting XNA-templated DNA synthesis in vivo. PMID- 23804526 TI - Myocardial deformation and twist mechanics in adults with metabolic syndrome: impact of cumulative metabolic burden. AB - OBJECTIVE: The aim of the study is to characterize left ventricular (LV) myocardial mechanics in adults with metabolic syndrome (MetS), and elucidate the effects of multiple risk-factors on myocardial function using speckle tracking echocardiography (STE); a more sensitive method than conventional echocardiography for detecting subclinical myocardial dysfunction. DESIGN AND METHODS: Cross-sectional analyses of 92 adults (50-70 years) with MetS, and 50 healthy controls included conventional echocardiography, blood biochemistry, and STE-derived myocardial longitudinal, circumferential, and twist mechanics. RESULTS: Using conventional measures, MetS participants revealed LV hypertrophy and reduced diastolic function compared with controls, while systolic function was preserved. From STE, MetS participants showed attenuated longitudinal strain (-16.8% +/- 2.8% vs. -20.6% +/- 2.7%), and both diastolic (1.1 +/- 0.2 vs. 1.4 +/ 0.3 s s(-1) ) and systolic (-1.0 +/- 0.1 vs. -1.2 +/- 0.2 s s(-1) ) strain rate (SR). Circumferential strain, SR, and twist mechanics did not differ. Participants with the highest number of MetS factors or diabetes demonstrated the greatest reduction in longitudinal strain and SR. Abdominal obesity, TNF-alpha, HbA1c , and systolic dyssynchrony explained 48% of impairment in longitudinal strain. CONCLUSIONS: Impaired longitudinal myocardial diastolic and systolic function, but preserved circumferential function and twist mechanics were found in MetS participants, indicative of altered subendocardial function. This dysfunction was best predicted by abdominal obesity, inflammation, glucose intolerance, and systolic dyssynchrony. PMID- 23804527 TI - First principle and ReaxFF molecular dynamics investigations of formaldehyde dissociation on Fe(100) surface. AB - Detailed formaldehyde adsorption and dissociation reactions on Fe(100) surface were studied using first principle calculations and molecular dynamics (MD) simulations, and results were compared with available experimental data. The study includes formaldehyde, formyl radical (HCO), and CO adsorption and dissociation energy calculations on the surface, adsorbate vibrational frequency calculations, density of states analysis of clean and adsorbed surfaces, complete potential energy diagram construction from formaldehyde to atomic carbon (C), hydrogen (H), and oxygen (O), simulation of formaldehyde adsorption and dissociation reaction on the surface using reactive force field, ReaxFF MD, and reaction rate calculations of adsorbates using transition state theory (TST). Formaldehyde and HCO were adsorbed most strongly at the hollow (fourfold) site. Adsorption energies ranged from -22.9 to -33.9 kcal/mol for formaldehyde, and from -44.3 to -66.3 kcal/mol for HCO, depending on adsorption sites and molecular direction. The dissociation energies were investigated for the dissociation paths: formaldehyde -> HCO + H, HCO -> H + CO, and CO -> C + O, and the calculated energies were 11.0, 4.1, and 26.3 kcal/mol, respectively. ReaxFF MD simulation results were compared with experimental surface analysis using high resolution electron energy loss spectrometry (HREELS) and TST based reaction rates. ReaxFF simulation showed less reactivity than HREELS observation at 310 and 523 K. ReaxFF simulation showed more reactivity than the TST based rate for formaldehyde dissociation and less reactivity than TST based rate for HCO dissociation at 523 K. TST-based rates are consistent with HREELS observation. PMID- 23804525 TI - Pattern separation and pattern completion in Alzheimer's disease: evidence of rapid forgetting in amnestic mild cognitive impairment. AB - Over the past four decades, the characterization of memory loss associated with Alzheimer's disease (AD) has been extensively debated. Recent iterations have focused on disordered encoding versus rapid forgetting. To address this issue, we used a behavioral pattern separation task to assess the ability of the hippocampus to create and maintain distinct and orthogonalized visual memory representations in patients with amnestic mild cognitive impairment (aMCI) and mild AD. We specifically used a lag-based continuous recognition paradigm to determine whether patients with aMCI and mild AD fail to encode visual memory representations or whether these patients properly encode representations that are rapidly forgotten. Consistent with the rapid forgetting hypothesis of AD, we found that patients with aMCI demonstrated decreasing pattern separation rates as the lag of interfering objects increased. In contrast, patients with AD demonstrated consistently poor pattern separation rates across three increasingly longer lags. We propose a continuum that reflects underlying hippocampal neuropathology whereby patients with aMCI are able to properly encode information into memory but rapidly lose these memory representations, and patients with AD, who have extensive hippocampal and parahippocampal damage, cannot properly encode information in distinct, orthogonal representations. Our results also revealed that whereas patients with aMCI demonstrated similar behavioral pattern completion rates to healthy older adults, patients with AD showed lower pattern completion rates when we corrected for response bias. Finally, these behavioral pattern separation and pattern completion results are discussed in terms of the dual process model of recognition memory. PMID- 23804529 TI - Postconditioning in patients treated with primary percutaneous coronary intervention: an updated meta-analysis. AB - OBJECTIVE: The aim of present analysis was to evaluate the effect of postconditioning in primary percutaneous coronary intervention (pPCI). BACKGROUND: Although postconditioning in pPCI has shown potential favorable effects on reperfusion injury, recent trials have yielded divergent results. METHODS: Randomized controlled trials were identified using relevant databases published up to August 15, 2012. Weighted mean difference (WMD) and standardized mean difference (SMD) were calculated using meta-analysis through fixed- or random-effects models. Statistical analysis was performed using RevMan 5.17 and Stata 12.0. RESULTS: Thirteen studies providing myocardial biomarkers, left ventricular ejection fraction (LVEF) or infarct size evaluated by cardiac magnetic resonance (CMR) in a total of 725 ST-elevation acute myocardial infarction (STEMI) patients were identified. Compared with usual care, postconditioning significantly reduced myocardial injury biomarkers (SMD = -0.61; 95% Confidence Interval (CI): [-0.98, -0.23]; P = 0.001; I(2) = 78%). Univariate meta-regression analysis suggested potential source of heterogeneity were the type of biomarkers and the use of glycoprotein IIb/IIIa inhibitors (I(2) reg = 44.84% and 67.24%, respectively; R(2) = 91.53% and 49.46%, respectively). Secondary analysis showed statistical significant improvement of LVEF with postconditioning (WMD = 3.22%; 95%CI: [0.88%, 5.57%]; P = 0.007; I(2) = 60%) relative to usual care. The effect diminished during medium (<6 months) and long terms (>=6 months) (P = 0.86 and 0.15, respectively). There was no significant decrease in infarct size among patients treated with postconditioning compared to usual care (SMD = 0.20; 95%CI: [-0.03, 0.43]; P = 0.08; I(2) = 46%). CONCLUSION: In STEMI patients undergoing pPCI, postconditioning is associated with significant lower level of myocardial injury biomarkers and a statistical significant improvement of LVEF relative to usual care. However, this adjunctive therapy may fails to reduce infarct size evaluated by CMR. PMID- 23804530 TI - Three-year follow-up of sentinel node-negative patients with early oral cavity squamous cell carcinoma. AB - BACKGROUND: Resection of the primary tumor followed by sentinel node biopsy (SNB) for the clinically N0 patient has been implemented in our Head and Neck University Center. The purpose of this study was to report on the outcome for patients with negative SNB. METHODS: From April 2007 to October 2009, 53 consecutive SNB-negative patients with oral cavity squamous cell carcinoma (SCC) T1 to T2 were accrued. Follow-up was done continuously with the most recent examination in October 2011. The location of the sentinel lymph nodes was determined using dynamic and planar lymphoscintigraphy and single photon emission CT (SPECT)-CT. Intraoperatively, a hand-held gamma probe was applied. The harvested sentinel lymph nodes underwent histopathologic examination using step serial sectioning at 150-MUm intervals and immunohistochemistry. In the follow-up period, we observed and examined the SNB-negative patients for recurrence, morbidity, and mortality. RESULTS: Fifty-three SNB-negative patients were identified. Eight patients received adjuvant radiotherapy (RT) because of incomplete excision on the T site after the primary operation. An additional 2 patients received RT because of recurrences on the T site and N site. One patient died of recurrence on the T site and N site without having received additional treatment. Six patients died of nonrelated causes. During follow-up, 3 patients with both T-site and N-site recurrence were found. No case of isolated recurrence on the N site only was found. Thirty-six SNB-negative patients treated only surgically with a median follow-up of 37 months (range, 25-52 months) and no recurrence remain under active review. CONCLUSION: Only 3 of the SNB-negative patients subsequently developed recurrence in the T site and N site. The remaining 36 patients had no N-site recurrence at median follow-up of 37 months. PMID- 23804528 TI - Genetic and clinical markers of elevated liver fat content in overweight and obese Hispanic children. AB - OBJECTIVE: Genetic variation in six genes has been associated with elevated liver fat and nonalcoholic fatty liver disease in adults. The influence of these genes on liver fat and whether a genetic risk score (GRS) would improve upon the ability of common clinical risk factors to predict elevated liver fat content (ELF) in Hispanic children was determined. DESIGN AND METHODS: 223 obese Hispanic children were genotyped for six SNPs. MRI was used to measure liver fat. A GRS was tested for association with ELF using multivariate linear regression. Predictors were assessed via ROC curves and pair-wise analysis was used to determine significance alone and combined with clinical markers. RESULTS: Only variants in PNPLA3 and APOC3 genes were associated with liver fat (P < 0.001, P = 0.01, respectively). Subjects with a GRS = 4 had ~3-fold higher liver fat content than subjects with GRS of 0 (15.1 +/- 12.7 vs. 5.1 +/- 3.7%, P = 0.03). While the addition of the GRS to a model containing BMI and liver enzymes increased ROC AUC from 0.83 to 0.85 [95% CI, 0.79-0.89], (P = 0.01), it does not improve detection of ELF from a clinical perspective. CONCLUSIONS: Only PNPLA3 and APOC3 were related to ELF and a GRS comprised of these susceptibility alleles did not add to the discriminatory power of traditional biomarkers for clinical assessment of liver fat. PMID- 23804531 TI - Clinical characteristics and outcomes of chediak-Higashi syndrome: a nationwide survey of Japan. AB - BACKGROUND: Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder characterized by immunodeficiency, neurological dysfunction, and oculocutaneous albinism. Recently, several clinical CHS phenotypes have been reported. Here, we report results of a nationwide survey performed to clarify clinical characteristics and outcomes of CHS patients in Japan. METHODS: Questionnaires were sent to 287 institutions to collect data regarding CHS patients diagnosed between 2000 and 2010, including results of lysosomal trafficking regulator (LYST) gene analysis. Cytotoxicity and degranulation activity of cytotoxic T lymphocytes were analyzed in available patient samples. RESULTS: A total of 15 patients diagnosed with CHS were eligible for enrollment in this study. Of these, 10 (67%) had recurrent bacterial infections, five (33%) developed life threatening hemophagocytic lymphohistiocytosis (HLH), and one patient had complicated malignant lymphoma. Hematopoietic stem cell transplantation (HSCT) was performed for six patients including three with HLH, and 10 of the enrolled patients have survived at the time of this writing. LYST analysis was performed for 10 patients; seven different mutations were detected in seven patients, whereas no mutation was identified in three patients. Cytotoxicity and degranulation activity were impaired in patients with and without LYST mutation. DISCUSSION: Results of this survey indicate that one or two patients with CHS were newly diagnosed each year in Japan. The incidence of HLH was not as high as expected. Mutations of genes other than LYST were suspected in some cases. We conclude that determining indication for HSCT for CHS patients should be based on genetic and cytotoxic analysis. PMID- 23804532 TI - Pudendal nerve stimulation: a potential tool for neurogenic bowel dysfunction! AB - Neurogenic bowel disease occurs after damage to the spinal cord, which affects the bowel's extrinsic innervation resulting in a lack of control of the colon with incontinence or constipation. To avoid more invasive procedures, sacral and pudendal nerve stimulation (PNS) have been recently considered as emerging treatment for patients with intractable constipation. In particular, PNS effects are thought to be secondary to interactions between the somatic and autonomic pathways within both the spinal cord and higher centers. Thus, PNS may be considered a potential tool in the treatment of neurogenic bowel dysfunction, even after a complete spinal cord damage. PMID- 23804533 TI - Cadaveric study for skull base reconstruction using anteriorly based inferior turbinate flap. AB - OBJECTIVES/HYPOTHESIS: To demonstrate the feasibility of an anteriorly pedicled inferior turbinate flap (AITF) as a method for endoscopic reconstruction of anterior skull base defects in the absence of a nasal septal flap. STUDY DESIGN: Cadaveric feasibility study. SETTING: University-affiliated tertiary medical center. MATERIALS AND PATIENTS: A cadaveric model was used to investigate the feasibility of harvesting and skull base reconstruction with an AITF. The size and extent of coverage of the flap were investigated. Subsequently, defects resulting from an endoscopic resection of various anterior skull base pathologies were reconstructed with an AITF in patients. RESULTS: In the cadaveric model (n = 11), the mean length, width, and area of the AITFs were 4.76 +/- 0.52 cm, 1.8 +/- 0.34 cm, and 4.31 +/- 0.87 cm(2), respectively. The flap provided a mean of 111 +/- 12% (range 95%-133%) coverage of the anterior skull base from the posterior table of the frontal sinus to the sella. Following that experience, ten patients were successfully reconstructed with AITFs, and there were no postoperative cerebrospinal fluid (CSF) leaks or occurrence of meningitis. CONCLUSION: The results of this study demonstrate the feasibility of AITFs for the reconstruction of anterior skull base defects in the absence of alternative vascularized flaps. PMID- 23804534 TI - Impaired HDL function in obese adolescents: impact of lifestyle intervention and bariatric surgery. AB - OBJECTIVE: HDL regulates endothelial function via stimulation of nitric oxide production. It is documented that endothelial function is impaired in obese adolescents, and improved by lifestyle interventions (LI). DESIGN AND METHODS: HDL function in obese adolescents and the impact of LI or Roux-en-Y gastric bypass surgery (RYGB) was assessed. HDL was isolated from 14 adolescents with normal body mass index (HDLcontrol ), 10 obese (HDLobese ) before and after 6 month LI, and five severe obese adolescents before and one year after RYGB. HDL mediated phosphorylation of endothelial nitric oxide synthase (eNOS)-Ser(1177) , eNOS-Thr(495) , and PKC-betaII was evaluated. In addition the HDL proteome was analyzed. RESULTS: HDLobese -mediated eNOS-Ser(1177) phosphorylation was reduced, whereas eNOS-Thr(495) phosphorylation increased significantly when compared to HDLcontrol . No impact of obesity was observed on PKC-betaII phosphorylation. LI and RYGB had no impact on HDL-mediated phosphorylation of eNOS and PKC-betaII. A principle component plot analysis of the HDL particle separated controls and severe obese, whereas the interventions did not trigger sufficient differences to the HDL proteome to permit distinction. CONCLUSION: These results demonstrated that HDL-function is impaired in obese adolescents, and that LI or RYGB did not correct this dysfunction. This might be an argument for developing earlier prevention strategies in obese adolescents to avoid HDL dysfunction. PMID- 23804535 TI - Potential role of tocotrienols in the treatment and prevention of breast cancer. AB - Vitamin E is a generic term that refers to a family of compounds that is further divided into two subgroups called tocopherols and tocotrienols. Although all natural forms of vitamin E display potent antioxidant activity, tocotrienols are significantly more potent than tocopherols in inhibiting tumor cell growth and viability, and anticancer activity of tocotrienols is mediated independently of their antioxidant activity. In addition, the anticancer effects of tocotrienols are observed using treatment doses that have little or no effect on normal cell function or viability. This review will summarize experimental studies that have identified the intracellular mechanism mediating the anticancer effects of tocotrienols. Evidence is also provided showing that combined treatment of tocotrienol with other cancer chemotherapies can result in a synergistic inhibition in cancer cell growth and viability. Taken together, these findings strongly indicate that tocotrienols may provide significant health benefits in the prevention and/or treatment of cancer when used either alone as monotherapy or in combination with other anticancer agents. PMID- 23804536 TI - Anatomy in occupational therapy program curriculum: practitioners' perspectives. AB - Anatomy education is undergoing significant transformation. It is unknown whether changes are in accordance with occupational therapy (OT) practice needs. The purpose of this pilot study was to survey OT clinicians to determine their perspectives on the value of anatomy in OT curricula, and anatomical knowledge required for practice. In addition to demographics, the survey asked questions on the value of a standalone anatomy course, integration of anatomical content in other coursework, practice areas requiring anatomy knowledge, course content, teaching media recommendations, and their opinions regarding whether graduates have adequate anatomy knowledge for competent practice. Surveys were distributed to OT practitioners in the state of Arizona (n = 107). Response rate was 51% on electronic surveys, 29% on mailed surveys. All respondents recommended an anatomy course in OT curricula; 97% as a standalone course with integration of course content throughout the curriculum. The most recommended teaching method was cadaver dissection. Content areas identified as important to cover included skeletal, muscular, and nervous systems. Regions recommended were the upper limb, thorax/trunk, head and neck, and lower limb. Practice areas requiring anatomy knowledge included joint range of motion and strengthening treatment interventions, goniometry, muscle strength testing, assessing muscle tone, wheelchair assessment/prescription, orthotics, physical agent modalities, and activity adaptation. Eighty-one percent felt that entry-level practitioners had adequate knowledge for competent practice. This study supports inclusion of a separate anatomy course in OT curricula, continued use of cadavers, and the importance of including input from practicing clinicians when determining anatomy course content. PMID- 23804537 TI - Selective C(sp2)-C(sp) bond cleavage: the nitrogenation of alkynes to amides. AB - Breakthrough: A novel catalyzed direct highly selective C(sp2)-C(sp) bond functionalization of alkynes to amides has been developed. Nitrogenation is achieved by the highly selective C(sp2)-C(sp) bond cleavage of aryl-substituted alkynes. The oxidant-free and mild conditions and wide substrate scope make this method very practical. PMID- 23804538 TI - Maternal vitamin D levels during pregnancy and offspring eating disorder risk in adolescence. AB - OBJECTIVE: To determine if maternal vitamin D concentrations at 18 weeks gestation predict offspring eating disorder risk in adolescence. METHOD: Participants were 526 Caucasian mother-child dyads from the Western Australian Pregnancy Cohort (Raine) Study. The Raine Study has followed participants from 18 weeks gestation to 20 years of age. Maternal serum 25(OH)-vitamin D concentrations were measured at 18 weeks pregnancy and grouped into quartiles. Offspring eating disorder symptoms were assessed at ages 14, 17 and 20 years. Core analyses were limited to female offspring (n = 308). RESULTS: Maternal 25(OH)-vitamin D quartiles were a significant predictor of eating disorder risk in female offspring, in multivariate logistic regression models. Vitamin D in the lowest quartile was associated with a 1.8-fold increase in eating disorder risk relative to concentrations in the highest quartile. This association also accounted for the relationship between offspring season of birth and eating disorder risk. Results were significant after adjusting for sociodemographic characteristics, body mass index and depressive symptoms. DISCUSSION: This is the first study to link low gestational vitamin D to increased eating disorder risk in female offspring of Caucasian mothers. Research is needed to extend these findings and to consider how gestational vitamin D may relate to the pathogenesis of eating disorders. PMID- 23804539 TI - Propranolol for cerebral cavernous angiomatosis: a magic bullet. PMID- 23804540 TI - The relationship between temperament, gender, and childhood dysfunctional voiding. AB - OBJECTIVE: Dysfunctional voiding (DV) is an extremely common pediatric complaint. The goal of this study was to examine the relationship between DV and childhood temperament. METHODS: Information about the voiding behaviors and temperaments of 50 children was examined using a case-control model. Caregivers were asked to fill out the Children's Behavior Questionnaire in order to rate their child on the dimensions of surgency, negative affect, and effortful control. The relationship between DV and these dimensions was then evaluated. RESULTS: Males with DV were found to have lower effortful control than males with normal voiding habits. Females with DV did not demonstrate a difference in effortful control, but did demonstrate a higher rate of surgency. CONCLUSIONS: The results suggest that temperament does have an association with DV. These findings are in line with temperamental associations with other externalizing trouble behaviors and may inform potential treatment strategies for DV. PMID- 23804541 TI - Clival chordomas: A pathological, surgical, and radiotherapeutic review. AB - BACKGROUND: The purpose of this study was to discuss the optimal management of patients with clival chordomas and provide an up-to-date review of the field. METHODS: A schematic description of the anatomy of the clivus and its surrounding structures is provided based on the modular classification of the surgical corridors used in endoscopic skull base surgery. Postoperative radiotherapy (RT) techniques are described. RESULTS: The optimal treatment is gross total resection. Recent advances in endoscopic endonasal skull base surgery have allowed very high rates of macroscopic and radiographic complete tumor resection in spite of the challenging location of these lesions. When the tumor location or extension is too lateral or inferior to be effectively resected with an endoscopic approach, an open approach or a combination of endoscopic and open approaches in stages should be considered. Postoperative RT is usually indicated because the likelihood of recurrence is high in spite of complete surgical resection. The main site of recurrence is local and late recurrences are relatively common. The probability of cure is approximately 50% at 10 years and significantly increases when complete tumor resection has been achieved. CONCLUSION: The preferred treatment for patients with clival chordoma is gross total resection (via endoscopic endonasal surgery when possible) followed by postoperative RT. Treatment at experienced multidisciplinary cranial base centers is key to minimize complications and to enhance the probability of total removal of the tumors. PMID- 23804542 TI - Percutaneous Edwards SAPIEN(TM) valve implantation for significant pulmonary regurgitation after previous surgical repair with a right ventricular outflow patch. AB - BACKGROUND: Current indications for percutaneous pulmonary valve implantation (PPVI) are limited to patients who had their outflow tracts repaired with the use of a "full" condui-homograft. Patients after a patch repair are believed to have an unfavorable anatomy for PPVI. OBJECTIVES: To evaluate a novel use of Edwards SAPIEN(TM) valve for percutaneous treatment of moderate and severe pulmonary regurgitation after tetralogy of Fallot (TF) repair with a right ventricular outflow (RVOT) patch. METHODS: PPVI was intended in 10 patients (age 21-39 years, 2 ?) with regurgitant fraction of 30-59%, measured by cardiac magnetic resonance imaging (CMRI) 16-30 years after repair with a RVOT patch. Balloon test inflations were used for definitive measurements and location of the landing site for the valve. All RVOTs were prestented. RESULTS: Successful valve implantation was achieved in nine patients. In one patient a bare-metal stent used for prestenting embolized into pulmonary artery. A 26-mm valve was implanted in seven and a 23-mm in two patients. CMRI at 1-2 month follow-up (n = 8) demonstrated both, sustained relief of pulmonary incompetence (regurgitant fraction = 0-14%) and significant decrease of the right ventricular end-diastolic volume indexes (from 169.9 +/- 43.8 to 140.0 +/- 40.3 ml/m(2) , P < 0.001). At that follow-up no adverse event occurred. No stent fractures were observed. CONCLUSIONS: We report the first case series of patients with significant PR after a RVOT patch repair, successfully treated with a percutaneous Edwards SAPIEN(TM) valve implantation. The procedure is technically feasible and may be offered to patients with the outflow tracts larger than those limited by the Melody((r)) system available currently. PMID- 23804543 TI - Increase in the mediators of asthma in obesity and obesity with type 2 diabetes: reduction with weight loss. AB - OBJECTIVE: To determine whether the expression of key asthma related genes, IL-4, LIGHT, LTBR, MMP-9, CCR-2, and ADAM-33 in mononuclear cells and the plasma concentration of nitric oxide metabolites (NOM) and MMP-9 are increased in the obese, obese type 2 diabetics (T2DM) and in morbidly obese patients prior to and after gastric bypass surgery (RYGB). DESIGN AND METHODS: The expression of these genes in MNC and plasma concentrations of these indices was measured in healthy lean and in obese with and without T2DM and following RYGB in obese T2DM. RESULTS: The expression of IL-4, MMP-9, LIGHT and CCR-2 and plasma NOM concentrations was significantly higher in the obese subjects and in obese T2DM patients than in normal subjects. The expression of IL-4, LIGHT, MMP-9, and CCR-2 expression was related to BMI and HOMA-IR. The expression of IL-4, LIGHT, LTBR, ADAM-33, MMP-9, and CCR-2 fell after RYGB surgery as did plasma concentrations of MMP-9 and NOM. CONCLUSIONS: Obesity with and without T2DM is associated with an increase in the expression of IL-4, LIGHT, MMP-9 and CCR-2; plasma NOM and MMP-9 concentrations are also increased. Following RYGB surgery and weight loss, the expression of these factors in MNC and plasma concentrations falls significantly. PMID- 23804544 TI - Transitivity performance, relational hierarchy knowledge and awareness: results of an instructional framing manipulation. AB - The transitive inference (TI) paradigm has been widely used to examine the role of the hippocampus in generalization. Here we consider a surprising feature of experimental findings in this task: the relatively poor transitivity performance and levels of hierarchy knowledge achieved by adult human subjects. We focused on the influence of the task instructions on participants' subsequent performance--a single-word framing manipulation which either specified the relation between items as transitive (i.e., OLD-FRAME: choose which item is "older") or left it ambiguous (i.e., NO-FRAME: choose which item is "correct"). We show a marked but highly specific effect of manipulating prior knowledge through instruction: transitivity performance and levels of relational hierarchy knowledge were enhanced, but premise performance unchanged. Further, we show that hierarchy recall accuracy, but not conventional awareness scores, was a significant predictor of inferential performance across the entire group of participants. The current study has four main implications: first, our findings establish the importance of the task instructions, and prior knowledge, in the TI paradigm- suggesting that they influence the size of the overall hypothesis space (e.g., to favor a linear hierarchical structure over other possibilities in the OLD-FRAME). Second, the dissociable effects of the instructional frame on premise and inference performance provide evidence for the operation of distinct underlying mechanisms (i.e., an associative mechanism vs. relational hierarchy knowledge). Third, our findings suggest that a detailed measurement of hierarchy recall accuracy may be a more sensitive index of relational hierarchy knowledge, than conventional awareness score--and should be used in future studies investigating links between awareness and inferential performance. Finally, our study motivates an experimental setting that ensures robust hierarchy learning across participants--therefore facilitating study of the neural mechanisms underlying the learning and representation of linear hierarchies. PMID- 23804545 TI - Nutritional and physical characteristics of commercial hand-feeding formulas for parrots. AB - Hand-rearing is a common practice for the propagation of captive psittacines, however, research on their nutrition is limited and the requirements of growing chicks are not well understood. The nutrition of 15 commercially available parrot hand-feeding formulas was compared with the average content of the crops of free living Scarlet Macaw (Ara macao) chicks, as well as with the requirements of 6- to 12-week-old leghorn chickens. When the formulas were prepared for a 1-week-old chick, all except three maintained >90% of solids in suspension after 15 min and >60 after 30 min. On average the formulas had a similar metabolizable energy density as wild macaw crop samples. The concentration of crude protein in the formulas was higher than that of the crop sample average, while the crude fat was lower than the average crop samples. More than 50% of the formulas had concentrations of K, Mg, and Mn less than the crop sample average, and Ca and Na concentrations below the requirements established for 6- to 12-week-old leghorn chickens. For >45% of the formulas the concentrations of arginine, leucine, and methionine + cystine were below the requirements of 6- to 12-week leghorns. When commercial formulas were prepared according to the manufacturer's instructions, the different dilutions greatly magnified the nutritional differences among them. Overall, the inconsistency in the nutrient concentrations among the formulas suggests that there is no consensus among manufacturers of the correct nutrition for growing psittacines and the industry could benefit from continued research in this area. PMID- 23804546 TI - Antiobesity effect of Gynostemma pentaphyllum extract (actiponin): a randomized, double-blind, placebo-controlled trial. AB - OBJECTIVE: The effects of actiponin was investigated, a heat-processed Gynostemma pentaphyllum extract, on body weight, fat loss, and metabolic markers of Korean participants in a 12-week, randomized, double-blind, placebo-controlled clinical trial. DESIGN AND METHODS: Obese participants (BMI >= 25 kg m(-2) and WHR >= 0.90 for male or WHR >= 0.85 for female) who had not been diagnosed with any disease and met the inclusion criteria were recruited for this study. The 80 subjects were randomly divided into actiponin (n = 40, 450 mg day(-1) ) and placebo (n = 40) groups. Outcomes included measurement of efficacy (abdominal fat distribution, anthropometric parameters, and blood lipid profiles) and safety (adverse events, laboratory test results, electrocardiogram data, and vital signs). RESULTS: During 12-week of actiponin supplementation, total abdominal fat area, body weight, body fat mass, percent body fat, and BMI were significantly decreased (P = 0.044, P < 0.05, P < 0.0001, P < 0.0001, and P < 0.05, respectively) in the actiponin group compared to the placebo group. No clinically significant changes in any safety parameter were observed. CONCLUSION: Our study revealed that actiponin is a potent antiobesity reagent that does not produce any significant adverse effects. These results suggest that actiponin supplementation may be effective for treating obese individuals. PMID- 23804547 TI - Podosomes in adhesion, migration, mechanosensing and matrix remodeling. AB - Cells use various actin-based motile structures to allow them to move across and through matrix of varying density and composition. Podosomes are actin cytoskeletal structures that form in motile cells and that mediate adhesion to substrate, migration, and other specialized functions such as transmigration through cell and matrix barriers. The podosome is a unique and interesting entity, which appears in the light microscope as an individual punctum, but is linked to other podosomes like a node on a network of the underlying cytoskeleton. Here, we discuss the signals that control podosome assembly and dynamics in different cell types and the actin organising proteins that regulate both the inner actin core and integrin-rich surrounding ring structures. We review the structure and composition of podosomes and also their functions in various cell types of both myeloid and endothelial lineage. We also discuss the emerging idea that podosomes can sense matrix stiffness and enable cells to respond to their environment. PMID- 23804548 TI - Cancer incidence and survival among adolescents in Israel during the years 1998 to 2009. AB - PURPOSE: Our goal was to describe adolescent cancer incidence and survival in Israel, and to identify demographic and epidemiologic variations among adolescents with cancer. PATIENTS AND METHODS: We used data from the Israel National Cancer Registry in order to examine the incidence and survival of adolescent cancer in Israeli adolescents aged 15-19 years, diagnosed during the years 1998-2009. Cases were analyzed according to sex, ethnicity and geographical region, as well as comparison to other countries in the region and other western countries. RESULTS: Among the 1,532 new cases of adolescent cancer, there was a total incidence rate of 226 cases per million. The incidence rate for males was higher than for females (230 and 222, respectively) and higher for Jewish adolescents than for Arab adolescents (235 and 194, respectively). The largest groups were Lymphomas (69 per million), Malignant Epithelial Neoplasms (49 per million), and Leukemias (21 per million). We estimated the survival probability updated to December 2009, and calculated the 5-year survival for new cases until the end of 2004. The overall survival at 5 years was 78%, with 62% for the Arabic population and 81% for the Jewish population, dependent on the diagnosis. CONCLUSIONS: The results of this study show little difference in the predominance of some adolescent cancers in comparison with other developed countries. This study may add more information for further investigation of the genetic and environmental factors that cause adolescent cancer in Israel. As well as delineate the genetic basis for ethnic origin disparities in survival. PMID- 23804549 TI - Ghrelin and bone. AB - Ghrelin is a gut-derived peptide hormone, first isolated from the stomach. Ghrelin was initially characterized as a growth hormone (GH) secretagogue, but it plays a more important role as a potent orexigen and modulator of whole-body energy homeostasis. Ghrelin itself is closely regulated by metabolic status. Bone remodeling constantly renews the skeleton in a highly energy-dependent fashion. Accordingly, bone metabolism is tightly coupled to energy metabolism through the integration of peripheral and central mechanisms, involving the sympathetic nervous system and factors such as leptin. Ghrelin has been shown to modulate osteoblast differentiation and function, both directly and perhaps also through regulation of the GH-insulin-like growth factor axis. However, recently it has also been shown that ghrelin interacts with leptin in modulating bone structure, constituting a new mechanism that couples bone metabolism with energy homeostasis. In this review, we discuss the role that ghrelin plays modulating bone cell function, and its integrative role in coupling bone metabolism with energy metabolism. PMID- 23804550 TI - Supramolecular photosensitizers with enhanced antibacterial efficiency. PMID- 23804551 TI - Residual shunting after percutaneous PFO closure: how to manage and how to close. AB - INTRODUCTION: Initial transcatheter Percutaneous patent foramen ovale (PFO) closure attempt may be incomplete and result in persistent residual shunting. The optimal treatment strategy for these patients remains unknown. PATIENTS AND METHODS: Twenty-seven patients were diagnosed to have a moderate-large residual shunt at least 12 months after initial PFO closure associated or not to a recurrent ischemic event and underwent a second procedure. Residual shunt characteristics were classified in two types: Type I: tunnel-like or between the disk defect (11 patients); Type II: accessory defect next to a device rim or accessory defect (16 patients). RESULTS: Fourteen subjects had a recurrent transient ischemic attack/stroke (52%). Median time between the first and the second PFO closure procedure was 17 months (range 12-60 months). Deployment of a second device was successful in 92% (25/27) patients. A Type I defect was closed by using a coil or Amplatzer Vascular Plugs. In two patients a surgical option was chosen as a first option. A Type II defect was closed by using a double disc device. At a median follow-up of 36 months (range 12-60 months), two subjects showed significant residual shunting between the two disks of the device (Type I) at 12 months follow-up and were sent to surgery. CONCLUSIONS: Significant residual shunts can be successfully closed by using a second device. Care is required to select an optimal device depending on anatomy and original device. In some subjects, lack of endothelial covering account for the persistence of a significant residual shunting. PMID- 23804552 TI - Nitrogen deposition, plant carbon allocation, and soil microbes: changing interactions due to enrichment. AB - PREMISE OF THE STUDY: Nitrogen (N) inputs to the terrestrial environment have doubled worldwide during the past century. N negatively impacts plant diversity, but it is unknown why some species are more susceptible than others. While it is often assumed that competition drives species decline, N enrichment also strongly affects soil microbial communities. Can these changes affect plant-microbe interactions in ways that differentially influence success of plant species? Furthermore, can altered plant-microbe interactions lead to carbon (C) limitation in plants? METHODS: We focused on a species that increases (Deschampsia cespitosa) and one that decreases (Geum rossii) in abundance in N-fertilized plots in alpine tundra. We measured soil microbes using phospholipid fatty acids, and C limitation and transfer using a (13)C tracer experiment, C:N ratios, nonstructural carbohydrates, and leaf preformation. KEY RESULTS: While N profoundly influenced microbial communities, this change occurred similarly in association with both plant species. N addition did not alter total C allocation to microbes in either species, but it changed patterns of microbial C acquisition more in Geum, specifically in gram-negative bacteria. Geum showed evidence of C limitation: it allocated less C to storage organs, had lower C:N and carbohydrate stores, and fewer preformed leaves in N plots. CONCLUSIONS: Carbon limitation may explain why some species decline with N enrichment, and the decline may be due to physiological responses of plants to N rather than to altered plant-microbe interactions. Global change will alter many processes important in structuring plant communities; noncompetitive mechanisms of species decline may be more widespread than previously thought. PMID- 23804553 TI - Historical ecology: using unconventional data sources to test for effects of global environmental change. AB - Predicting the future ecological impact of global change drivers requires understanding how these same drivers have acted in the past to produce the plant populations and communities we see today. Historical ecological data sources have made contributions of central importance to global change biology, but remain outside the toolkit of most ecologists. Here we review the strengths and weaknesses of four unconventional sources of historical ecological data: land survey records, "legacy" vegetation data, historical maps and photographs, and herbarium specimens. We discuss recent contributions made using these data sources to understanding the impacts of habitat disturbance and climate change on plant populations and communities, and the duration of extinction-colonization time lags in response to landscape change. Historical data frequently support inferences made using conventional ecological studies (e.g., increases in warm adapted species as temperature rises), but there are cases when the addition of different data sources leads to different conclusions (e.g., temporal vegetation change not as predicted by chronosequence studies). The explicit combination of historical and contemporary data sources is an especially powerful approach for unraveling long-term consequences of multiple drivers of global change. Despite the limitations of historical data, which include spotty and potentially biased spatial and temporal coverage, they often represent the only means of characterizing ecological phenomena in the past and have proven indispensable for characterizing the nature, magnitude, and generality of global change impacts on plant populations and communities. PMID- 23804554 TI - Progression in disability and regional grey matter atrophy in relapsing-remitting multiple sclerosis. AB - BACKGROUND: In multiple sclerosis (MS) regional grey matter (GM) atrophy has been associated with disability progression. OBJECTIVE: The aim of this study was to compare regional GM volume changes in relapsing-remitting MS (RRMS) patients with progressive and stable disability, using voxel-based morphometry (VBM). METHODS: We acquired baseline and 1-year follow-up 3-dimensional (3D) T1-weighted magnetic resonance imaging (MRI) data of RRMS patients, using two 1.5-Tesla scanners. Patients were matched pair-wise with respect to age, gender, disease duration, medication, scanner and baseline Expanded Disability Status Scale (EDSS) into 13 pairs, with either progressive EDSS (>= 1 point change y(-1)) or stable EDSS, as well as into 29 pairs with either progressive Multiple Sclerosis Functional Composite (MSFC) at >= 0.25% decrease in y(-1) in any component, or stable MSFC. We analysed longitudinal regional differences in GM volumes in the progressive and stable EDSS and MSFC groups, respectively, using VBM. RESULTS: Significant GM volume reductions occurred in the right precuneus, in the progressive EDSS group. Differential between-group effects occurred in the right precuneus and in the postcentral gyrus. Further longitudinal GM volume reductions occurred in the right orbicular gyrus, in the progressive MSFC group, but no between-group differences were observed (non-stationary cluster-wise inference, all P(corrected) < 0.05). CONCLUSION: These results suggested a direct association of disability progression and regional GM atrophy in RRMS. PMID- 23804555 TI - Neuropsychological rehabilitation does not improve cognitive performance but reduces perceived cognitive deficits in patients with multiple sclerosis: a randomised, controlled, multi-centre trial. AB - BACKGROUND: There is preliminary evidence on the positive effects of neuropsychological rehabilitation on cognition in multiple sclerosis (MS), but the generalisability of the findings is limited by methodological problems. OBJECTIVE: The aim of the present study was to determine the effects of strategy oriented neuropsychological rehabilitation on MS. METHODS: A total of 102 relapsing-remitting MS patients with subjective and objective attentional deficits were randomised into an intervention and a control group. Neuropsychological assessments were performed at baseline, at three months immediately after the intervention, and at six months. Patients in the intervention group received neuropsychological rehabilitation once a week in 60 minute sessions for 13 consecutive weeks. The control group received no intervention. RESULTS: Neuropsychological rehabilitation including computer-based attention and working memory retraining, psychoeducation, strategy learning and psychological support did not improve cognitive performance but had a positive effect on perceived cognitive deficits. The intervention group perceived significantly fewer deficits than the control group both immediately after the intervention and at six months. The personal rehabilitation goals were also well achieved. CONCLUSIONS: Strategy-oriented neuropsychological rehabilitation did not improve cognitive performance but reduced perceived cognitive deficits in MS. PMID- 23804556 TI - The control region of mitochondrial DNA shows an unusual CpG and non-CpG methylation pattern. AB - DNA methylation is a common epigenetic modification of the mammalian genome. Conflicting data regarding the possible presence of methylated cytosines within mitochondrial DNA (mtDNA) have been reported. To clarify this point, we analysed the methylation status of mtDNA control region (D-loop) on human and murine DNA samples from blood and cultured cells by bisulphite sequencing and methylated/hydroxymethylated DNA immunoprecipitation assays. We found methylated and hydroxymethylated cytosines in the L-strand of all samples analysed. MtDNA methylation particularly occurs within non-C-phosphate-G (non-CpG) nucleotides, mainly in the promoter region of the heavy strand and in conserved sequence blocks, suggesting its involvement in regulating mtDNA replication and/or transcription. We observed DNA methyltransferases within the mitochondria, but the inactivation of Dnmt1, Dnmt3a, and Dnmt3b in mouse embryonic stem (ES) cells results in a reduction of the CpG methylation, while the non-CpG methylation shows to be not affected. This suggests that D-loop epigenetic modification is only partially established by these enzymes. Our data show that DNA methylation occurs in the mtDNA control region of mammals, not only at symmetrical CpG dinucleotides, typical of nuclear genome, but in a peculiar non-CpG pattern previously reported for plants and fungi. The molecular mechanisms responsible for this pattern remain an open question. PMID- 23804558 TI - Comparison of different cardiac risk scores for coronary artery disease in symptomatic women: do female-specific risk factors matter? AB - BACKGROUND: Cardiovascular diseases remain the leading cause of death in women and there is a need for more accurate risk assessment scores. The aims of our study were to compare the accuracy of several widely used cardiac risk assessment scores in predicting the likelihood of obstructive coronary artery disease (CAD) on CT coronary angiography (CTCA) in symptomatic women and to explore which female-specific risk factors were independent predictors of obstructive CAD on CTCA and whether adding these risk factors to pre-test probability scores would improve their predictive value. METHODS AND RESULTS: Data were obtained from a cohort of 228 consecutively included symptomatic women undergoing evaluation for CAD and referred for CTCA. Obstructive CAD was defined as >=50% luminal stenosis on CTCA. Pre-test probability for CAD was calculated according to the Diamond and Forrester score, New score, Duke clinical score, and an updated Diamond and Forrester score. Female-specific factors were obtained by a written questionnaire. Pre-test probability scores were compared with ROC analysis and showed that only the New score and the updated Diamond and Forrester score were significant predictive scores for obstructive CAD on CTCA (area under the curve, AUC, 0.67, p < 0.01; AUC 0.61, p = 0.04, respectively). Multivariable logistic regression analysis identified that gestational diabetes mellitus (GDM) and oestrogen status were independent predictors of obstructive CAD when adjusted for the pre-test probability scores. The updated Diamond and Forrester score was used for net reclassification improvement (NRI) analysis, since the New score already accounts for oestrogen status. Adding GDM and oestrogen status to the updated Diamond and Forrester score resulted in a significant NRI (p = 0.04). CONCLUSIONS: There is a large variability in prediction of obstructive CAD using different pre-test probability risk scores in symptomatic women. Logistic regression analysis revealed that oestrogen status and GDM were independently associated with the occurrence of obstructive stenosis on CTCA. The predictive ability of cardiac pre-test probability scores improved significantly with the addition of oestrogen status and GDM. PMID- 23804557 TI - Development and characterization of simple sequence repeat markers providing genome-wide coverage and high resolution in maize. AB - Simple sequence repeats (SSRs) have been widely used in maize genetics and breeding, because they are co-dominant, easy to score, and highly abundant. In this study, we used whole-genome sequences from 16 maize inbreds and 1 wild relative to determine SSR abundance and to develop a set of high-density polymorphic SSR markers. A total of 264 658 SSRs were identified across the 17 genomes, with an average of 135 693 SSRs per genome. Marker density was one SSR every of 15.48 kb. (C/G)n, (AT)n, (CAG/CTG)n, and (AAAT/ATTT)n were the most frequent motifs for mono, di-, tri-, and tetra-nucleotide SSRs, respectively. SSRs were most abundant in intergenic region and least frequent in untranslated regions, as revealed by comparing SSR distributions of three representative resequenced genomes. Comparing SSR sequences and e-polymerase chain reaction analysis among the 17 tested genomes created a new database, including 111 887 SSRs, that could be develop as polymorphic markers in silico. Among these markers, 58.00, 26.09, 7.20, 3.00, 3.93, and 1.78% of them had mono, di-, tri-, tetra-, penta-, and hexa-nucleotide motifs, respectively. Polymorphic information content for 35 573 polymorphic SSRs out of 111 887 loci varied from 0.05 to 0.83, with an average of 0.31 in the 17 tested genomes. Experimental validation of polymorphic SSR markers showed that over 70% of the primer pairs could generate the target bands with length polymorphism, and these markers would be very powerful when they are used for genetic populations derived from various types of maize germplasms that were sampled for this study. PMID- 23804559 TI - Cholangitis and subsequent gastrointestinal cancer risk: a Danish population based cohort study. AB - OBJECTIVE: While patients with gastrointestinal cancer are at increased risk of cholangitis, it is less clear whether cholangitis is also a marker for occult gastrointestinal cancer. If an undiagnosed cancer obstructs the bile duct system and causes cholangitis, the short-term risk of cancer will appear increased. However, an increased long-term risk of cancer may originate from chronic inflammatory processes. We assessed the risk of a gastrointestinal cancer diagnosis subsequent to a cholangitis diagnosis during a 17-year period in Denmark. DESIGN: We conducted a nationwide population-based cohort study by linking Danish medical registries during 1994-2010. We quantified the excess risk of cancer in cholangitis patients using relative (standardised incidence ratio; SIR) and absolute (excess absolute risk per 1000 person-years at risk; EAR) risk calculations. RESULTS: 4333 patients with cholangitis (including 178 with primary sclerosing cholangitis) were followed for 17 222 person-years. During the follow up period, 477 gastrointestinal cancers occurred versus 59 expected, corresponding to a SIR of 8.12 (95% CI 7.41 to 8.88). Risk was increased mainly for cancer in the small intestine (SIR 18.2; 95% CI 8.69 to 33.4), liver (SIR 16.3; 95% CI 11.6 to 22.2), gallbladder and biliary tract (SIR 70.9; 95% CI 59.0 to 84.4) and pancreas (SIR 31.7; 95% CI 27.8 to 36.0). During the first 6 months of follow-up, 314 patients were diagnosed with gastrointestinal cancer, corresponding to a SIR of 49.8 (95% CI 44.4 to 55.6) and an EAR of 175. CONCLUSIONS: Cholangitis is a marker of occult gastrointestinal cancer. PMID- 23804560 TI - NKp46+ expression on NK cells as a biomarker for liver pathology and IFN responiveness in HCV infection. PMID- 23804561 TI - An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. AB - BACKGROUND: Recent evidence indicates that the composition of the gut microbiota contributes to the development of metabolic disorders by affecting the physiology and metabolism of the host. Metformin is one of the most widely prescribed type 2 diabetes (T2D) therapeutic agents. OBJECTIVE: To determine whether the antidiabetic effect of metformin is related to alterations of intestinal microbial composition. DESIGN: C57BL/6 mice, fed either a normal-chow diet or a high-fat diet (HFD), were treated with metformin for 6 weeks. The effect of metformin on the composition of the gut microbiota was assessed by analysing 16S rRNA gene sequences with 454 pyrosequencing. Adipose tissue inflammation was examined by flow cytometric analysis of the immune cells present in visceral adipose tissue (VAT). RESULTS: Metformin treatment significantly improved the glycaemic profile of HFD-fed mice. HFD-fed mice treated with metformin showed a higher abundance of the mucin-degrading bacterium Akkermansia than HFD-fed control mice. In addition, the number of mucin-producing goblet cells was significantly increased by metformin treatment (p<0.0001). Oral administration of Akkermansia muciniphila to HFD-fed mice without metformin significantly enhanced glucose tolerance and attenuated adipose tissue inflammation by inducing Foxp3 regulatory T cells (Tregs) in the VAT. CONCLUSIONS: Modulation of the gut microbiota (by an increase in the Akkermansia spp. population) may contribute to the antidiabetic effects of metformin, thereby providing a new mechanism for the therapeutic effect of metformin in patients with T2D. This suggests that pharmacological manipulation of the gut microbiota in favour of Akkermansia may be a potential treatment for T2D. PMID- 23804562 TI - Effect of physical activity on weight loss, energy expenditure, and energy intake during diet induced weight loss. AB - OBJECTIVE: Objective measurements of physical activity (PA), energy expenditure (EE) and energy intake can provide valuable information regarding appropriate strategies for successful sustained weight loss. DESIGN AND METHODS: The total EE was examined by doubly labeled water, resting metabolic rate by indirect calorimetry, PA with activity monitors, and energy intake by the intake/balance technique in 116 severely obese undergoing intervention with diet alone (DO) or diet plus PA (D-PA). RESULTS: Weight loss of 9.6 +/- 6.8 kg resulted in decreased EE which was not minimized in the D-PA group. Comparing the highest and lowest quartiles of increase in PA revealed a lower decrease in TDEE (-122 +/- 319 vs. 376 +/- 305 kcal day-1), elimination of the drop in AEE (83 +/- 279 vs. -211 +/- 284 kcal day-1) and greater weight loss (13.0 +/- 7.0 vs. 8.1 +/- 6.3 kg). Increased PA was associated with greater adherence to energy restriction and maintenance of greater weight loss during months 7-12. CONCLUSION: Noncompliance to prescribed PA in the DO and D-PA groups partially masked the effects of PA to increase weight loss and to minimize the reduced EE. Increased PA was also associated with improved adherence to prescribed caloric restriction. A strong recommendation needs to be made to improve interventions that promote PA within the context of behavioral weight loss interventions. PMID- 23804563 TI - The Sac1 domain of SYNJ1 identified mutated in a family with early-onset progressive Parkinsonism with generalized seizures. AB - This study aimed to elucidate the genetic causes underlying early-onset Parkinsonism (EOP) in a consanguineous Iranian family. To attain this, homozygosity mapping and whole-exome sequencing were performed. As a result, a homozygous mutation (c.773G>A; p.Arg258Gln) lying within the NH2 -terminal Sac1 like inositol phosphatase domain of polyphosphoinositide phosphatase synaptojanin 1 (SYNJ1), which has been implicated in the regulation of endocytic traffic at synapses, was identified as the disease-segregating mutation. This mutation impaired the phosphatase activity of SYNJ1 against its Sac1 domain substrates in vitro. We concluded that the SYNJ1 mutation identified here is responsible for the EOP phenotype seen in our patients probably due to deficiencies in its phosphatase activity and consequent impairment of its synaptic functions. Our finding not only opens new avenues of investigation in the synaptic dysfunction mechanisms associated with Parkinsonism, but also suggests phosphoinositide metabolism as a novel therapeutic target for Parkinsonism. PMID- 23804564 TI - Reverse transcriptase backbone can alter the polymerization and RNase activities of non-nucleoside reverse transcriptase mutants K101E+G190S. AB - Previous work by our group showed that human immunodeficiency virus type 1 (HIV 1) reverse transcriptase (RT) containing non-nucleoside RT inhibitor (NNRTI) drug resistance mutations has defects in RNase H activity as well as reduced amounts of RT protein in virions. These deficits correlate with replication fitness in the absence of NNRTIs. Viruses with the mutant combination K101E+G190S replicated better in the presence of NNRTIs than in the absence of drug. Stimulation of virus growth by NNRTIs occurred during the early steps of the virus life cycle and was modulated by the RT backbone sequence in which the resistance mutations arose. We wanted to determine what effects RT backbone sequence would have on RT content and polymerization and RNase H activities in the absence of NNRTIs. We compared a NL4-3 RT with K101E+G190S to a patient-isolate RT sequence D10 with K101E+G190S. We show here that, unlike the NL4-3 backbone, the D10 backbone sequence decreased the RNA-dependent DNA polymerization activity of purified recombinant RT compared to WT. In contrast, RTs with the D10 backbone had increased RNase H activity compared to WT and K101E+G190S in the NL4-3 backbone. D10 virions also had increased amounts of RT compared to K101E+G190S in the NL4-3 backbone. We conclude that the backbone sequence of RT can alter the activities of the NNRTI drug-resistant mutant K101E+G190S, and that identification of the amino acids responsible will aid in understanding the mechanism by which NNRTI drug-resistant mutants alter fitness and NNRTIs stimulate HIV-1 virus replication. PMID- 23804565 TI - Evolutionary dynamics of bovine coronaviruses: natural selection pattern of the spike gene implies adaptive evolution of the strains. AB - Coronaviruses demonstrate great potential for interspecies transmission, including zoonotic outbreaks. Although bovine coronavirus (BCoV) strains are frequently circulating in cattle farms worldwide, causing both enteric and respiratory disease, little is known about their genomic evolution. We sequenced and analysed the full-length spike (S) protein gene of 33 BCoV strains from dairy and feedlot farms collected during outbreaks that occurred from 2002 to 2010 in Sweden and Denmark. Amino acid identities were >97 % for the BCoV strains analysed in this work. These strains formed a clade together with Italian BCoV strains and were highly similar to human enteric coronavirus HECV-4408/US/94. A high similarity was observed between BCoV, canine respiratory coronavirus (CRCoV) and human coronavirus OC43 (HCoV-OC43). Molecular clock analysis of the S gene sequences estimated BCoV and CRCoV diverged from a common ancestor in 1951, while the time of divergence from a common ancestor of BCoV and HCoV-OC43 was estimated to be 1899. BCoV strains showed the lowest similarity to equine coronavirus, placing the date of divergence at the end of the eighteenth century. Two strongly positive selection sites were detected along the receptor-binding subunit of the S protein gene: spanning amino acid residues 109-131 and 495-527. By contrast, the fusion subunit was observed to be under negative selection. The selection pattern along the S glycoprotein implies adaptive evolution of BCoVs, suggesting a successful mechanism for BCoV to continuously circulate among cattle and other ruminants without disappearance. PMID- 23804566 TI - Genetic characterization of a novel picornavirus distantly related to the marine mammal-infecting aquamaviruses in a long-distance migrant bird species, European roller (Coracias garrulus). AB - Despite the continuously growing number of known avian picornaviruses (family Picornaviridae), knowledge of their genetic diversity in wild birds, especially in long-distance migrant species is very limited. In this study, we report the presence of a novel picornavirus identified from one of 18 analysed faecal samples of an Afro-Palearctic migrant bird, the European roller (Coracias garrulus L., 1758), which is distantly related to the marine-mammal-infecting seal aquamavirus A1 (genus Aquamavirus). The phylogenetic analyses and the low sequence identity (P1 26.3 %, P2 25.8 % and P3 28.4 %) suggest that this picornavirus could be the founding member of a novel picornavirus genus that we have provisionally named 'Kunsagivirus', with 'Greplavirus A' (strain roller/SZAL6-KuV/2011/HUN, GenBank accession no. KC935379) as the candidate type species. PMID- 23804567 TI - Complete genome sequence of invertebrate iridescent virus 22 isolated from a blackfly larva. AB - Members of the family Iridoviridae are animal viruses that infect only invertebrates and poikilothermic vertebrates. Invertebrate iridescent virus 22 (IIV-22) was originally isolated from the larva of a blackfly (Simulium sp., order Diptera) found in the Ystwyth river, near Aberystwyth, Wales, UK. IIV-22 virions are icosahedral, with a diameter of about 130 nm and contain a dsDNA genome that is 197.7 kb in length, has a G+C content of 28.05 mol% and contains 167 coding sequences. Here, we describe the complete genome sequence of this virus and its annotation. This is the fourth genome sequence of an invertebrate iridovirus to be reported. PMID- 23804568 TI - Median infectious dose of human norovirus GII.4 in gnotobiotic pigs is decreased by simvastatin treatment and increased by age. AB - Human noroviruses (NoVs), a major cause of viral gastroenteritis, are difficult to study due to the lack of a cell-culture and a small-animal model. Pigs share with humans the types A and H histo-blood group antigens on the intestinal epithelium and have been suggested as a potential model for studies of NoV pathogenesis, immunity and vaccines. In this study, the effects of age and a cholesterol-lowering drug, simvastatin, on the susceptibility of pigs to NoV infection were evaluated. The median infectious dose (ID50) of a genogroup II, genotype 4 (GII.4) 2006b variant was determined. The ID50 in neonatal (4-5 days of age) pigs was <=2.74*10(3) viral RNA copies. In older pigs (33-34 days of age), the ID50 was 6.43*10(4) but decreased to <2.74*10(3) in simvastatin-fed older pigs. Evidence of NoV infection was obtained by increased virus load in the intestinal contents, cytopathological changes in the small intestine, including irregular microvilli, necrosis and apoptosis, and detection of viral antigen in the tip of villi in duodenum. This GII.4 variant was isolated in 2008 from a patient from whom a large volume of stool was collected. GII.4 NoVs are continuously subjected to selective pressure by human immunity, and antigenically different GII.4 NoV variants emerge every 1-2 years. The determination of the ID50 of this challenge virus is valuable for evaluation of protection against different GII.4 variants conferred by NoV vaccines in concurrence with other GII.4 variants in the gnotobiotic pig model. PMID- 23804570 TI - Population dynamics and in vitro antibody pressure of porcine parvovirus indicate a decrease in variability. AB - To estimate the impact of porcine parvovirus (PPV) vaccines on the emergence of new phenotypes, the population dynamic history of the virus was calculated using the Bayesian Markov chain Monte Carlo method with a Bayesian skyline coalescent model. Additionally, an in vitro model was performed with consecutive passages of the 'Challenge' strain (a virulent field strain) and NADL2 strain (a vaccine strain) in a PK-15 cell line supplemented with polyclonal antibodies raised against the vaccine strain. A decrease in genetic diversity was observed in the presence of antibodies in vitro or after vaccination (as estimated by the in silico model). We hypothesized that the antibodies induced a selective pressure that may reduce the incidence of neutral selection, which should play a major role in the emergence of new mutations. In this scenario, vaccine failures and non-vaccinated populations (e.g. wild boars) may have an important impact in the emergence of new phenotypes. PMID- 23804571 TI - A tumorigenic actin mutant alters fibroblast morphology and multicellular assembly properties. AB - Tumor initiation and progression are accompanied by complex changes in the cytoarchitecture that at the cellular level involve remodeling of the cytoskeleton. We report on the impact of a mutant beta-actin (G245D-actin) on cell structure and multicellular assembly properties. To appreciate the effects of the Gly245Asp substitution on the organization of the actin cytoskeleton, we examined the polymerization properties of G245D-actin in vitro by pyrene polymerization assays and total internal reflection fluorescence microscopy (TIRF). The mutant actin on its own has a significantly reduced polymerization efficiency compared to native actin but also modifies the polymerization of actin in copolymerization experiments. Comparison of the structure of Rat-2 fibroblasts and a stably transfected derivate called Rat-2-sm9 revealed the effects of G245D actin in a cellular environment. The overall actin levels in Rat-2-sm9 show a 1.6 fold increase with similar amounts of mutant and wild-type actin. G245D-actin expression renders Rat-2-sm9 cells highly tumorigenic in nude mice. In Rat-2-sm9 monolayers, G245D-actin triggers the formation of extensive membrane ruffles, which is a characteristic feature of many transformed cells. To approximate complex cell-cell and cell-matrix interactions that occur in tumors and might modulate the effects of G245D-actin, we extended our studies to scaffold-free 3D spheroid cultures. Bright field and scanning electron microscopy (SEM) show that Rat-2-sm9 and Rat-2 cells share essential features of spheroid formation and compaction. However, the resulting spheroids exhibit distinct phenotypes that differ mainly in surface structure and size. The systematic comparison of transformed and normal spheroids by SEM provides new insights into scaffold-free fibroblast spheroid formation. PMID- 23804572 TI - In vivo hip joint contact distribution and bony impingement in normal and dysplastic human hips. AB - Our objectives were to clarify the 3D articular contact areas of the in vivo normal hip joint and acetabular dysplasia during specific positions using magnetic resonance imaging (MRI), voxel-based registration, and proximity mapping. Forty-two normal and 24 dysplastic hips were examined. MRI was performed at four positions: neutral; 45 degrees flexion; 15 degrees extension; and the Patrick position. Femur and pelvis bone models were reconstructed at the neutral position and superimposed over the images of each different position using voxel based registration. The inferred cartilage contact and bony impingement were investigated using proximity mapping. The femoral head translated in the anterior or posteroinferior, anterosuperior, and posteroinferior direction from neutral to 45 degrees flexion, 15 degrees extension, and the Patrick position, respectively. Multiple regression analyses showed age, femoral head sphericity, and acetabular sphericity to be associated with higher hip instability. The present technique using subject-specific models revealed the in vivo hip joint contact area in a population of healthy individuals and dysplastic patients without radioactive exposure. These results can be used for analyzing disease progression in the dysplastic hip and pathogenesis of acetabular labral tear. PMID- 23804569 TI - Diversity of picornaviruses in rural Bolivia. AB - The family Picornaviridae is a large and diverse group of viruses that infect humans and animals. Picornaviruses are among the most common infections of humans and cause a wide spectrum of acute human disease. This study began as an investigation of acute flaccid paralysis (AFP) in a small area of eastern Bolivia, where surveillance had identified a persistently high AFP rate in children. Stools were collected and diagnostic studies ruled out poliovirus. We tested stool specimens from 51 AFP cases and 34 healthy household or community contacts collected during 2002-2003 using real-time and semi-nested reverse transcription polymerase chain reaction assays for enterovirus, parechovirus, cardiovirus, kobuvirus, salivirus and cosavirus. Anecdotal reports suggested a temporal association with neurological disease in domestic pigs, so six porcine stools were also collected and tested with the same set of assays, with the addition of an assay for porcine teschovirus. A total of 126 picornaviruses were detected in 73 of 85 human individuals, consisting of 53 different picornavirus types encompassing five genera (all except Kobuvirus). All six porcine stools contained porcine and/or human picornaviruses. No single virus, or combination of viruses, specifically correlated with AFP; however, the study revealed a surprising complexity of enteric picornaviruses in a single community. PMID- 23804573 TI - The effect of GWAS identified BMI loci on changes in body weight among middle aged Danes during a five-year period. AB - OBJECTIVE: Genome-wide association studies have identified genetic variants associating with BMI, however, it is un-clarified whether the same variants also influence body weight fluctuations. METHODS: Among 3,982 adult individuals that attended both a baseline and a five-year follow-up examination in the Danish Inter99 intervention study, a genetic risk score (GRS) was constructed based on 30 BMI variants to address whether it is associated with body weight changes. Moreover, it was examined whether the effect of lifestyle changes was modulated by the GRS. RESULTS: The GRS associated strongly with baseline body weight, with a per risk allele increase of 0.45 (0.33-0.58) kg (P = 2.7 * 10(-12) ), corresponding to a body weight difference of 3.41 (2.21-4.60) kg comparing the highest (>= 30 risk alleles) and lowest (<= 26 risk alleles) risk allele tertile. No association was observed with changes in body weight during the five years. Changes in lifestyle, including physical activity, diet and smoking habits associated strongly with body weight changes, however, no interactions with the GRS was observed. CONCLUSION: The GRS associated with body weight cross sectionally, but not with changes over a five-year period. Body weight changes were influenced by lifestyle changes, however, independently of the GRS. PMID- 23804574 TI - Dempster-Shafer theory applied to regulatory decision process for selecting safer alternatives to toxic chemicals in consumer products. AB - Regulatory agencies often face a dilemma when regulating chemicals in consumer products-namely, that of making decisions in the face of multiple, and sometimes conflicting, lines of evidence. We present an integrative approach for dealing with uncertainty and multiple pieces of evidence in toxics regulation. The integrative risk analytic framework is grounded in the Dempster-Shafer (D-S) theory that allows the analyst to combine multiple pieces of evidence and judgments from independent sources of information. We apply the integrative approach to the comparative risk assessment of bisphenol-A (BPA)-based polycarbonate and the functionally equivalent alternative, Eastman Tritan copolyester (ETC). Our results show that according to cumulative empirical evidence, the estimated probability of toxicity of BPA is 0.034, whereas the toxicity probability for ETC is 0.097. However, when we combine extant evidence with strength of confidence in the source (or expert judgment), we are guided by a richer interval measure, (Bel(t), Pl(t)). With the D-S derived measure, we arrive at various intervals for BPA, with the low-range estimate at (0.034, 0.250), and (0.097,0.688) for ETC. These new measures allow a reasonable basis for comparison and a justifiable procedure for decision making that takes advantage of multiple sources of evidence. Through the application of D-S theory to toxicity risk assessment, we show how a multiplicity of scientific evidence can be converted into a unified risk estimate, and how this information can be effectively used for comparative assessments to select potentially less toxic alternative chemicals. PMID- 23804575 TI - Technical challenges of atrial septal stent placement in fetuses with hypoplastic left heart syndrome and intact atrial septum. AB - OBJECTIVES: The objective of this study was to describe our single-institution experience with prenatal atrial septal stent placement for fetuses with hypoplastic left heart syndrome and an intact atrial septum (HLHS/IAS). BACKGROUND: Infants born with HLHS/IAS are at high risk for neonatal death, despite maximal postnatal therapy. Prenatal atrial septoplasty by static balloon dilation has been effective in decompressing the left atrium (LA) in utero, but several factors have limited the size of septal defects. We attempted to overcome the limitations of balloon septoplasty using transcatheter atrial septal stents. METHODS: All records from our institution of fetuses with HLHS/IAS that underwent prenatal atrial septal stent placement were reviewed, including operative notes and echocardiograms. RESULTS: Nine fetuses between 24 and 31 weeks gestation with HLHS/IAS underwent attempted fetal atrial septal stent placement. A stent was deployed across the atrial septum in five fetuses, with four fetuses demonstrating flow across the stent at the time of intervention. In four cases, stent placement failed due to malposition or embolization, but in three of the four cases, atrial balloon septoplasty at the same in-utero procedure successfully and acutely decompressed the LA. There were no maternal complications. There was one fetal demise. The remaining eight fetuses survived to delivery, but four died in the neonatal period (two of which had been stented). CONCLUSIONS: Ultrasound-guided atrial septal stent placement is feasible in some fetuses with HLHS/IAS. Visualization of the septum and catheter tip is critical to technical success. Additional experience is necessary to determine the clinical impact of this intervention. (c) 2013 Wiley Periodicals, Inc. PMID- 23804576 TI - Do weight loss and adherence cluster within behavioral treatment groups? AB - OBJECTIVE: Weight loss programs are often conducted in a group format, but it is unclear whether weight losses or adherence cluster within treatment group and whether characteristics of the group (e.g., size or homogeneity) affect outcomes. We examined these questions within Look AHEAD, a multicenter study of the effects of an intensive lifestyle intervention (ILI) in overweight/obese individuals with type 2 diabetes. METHODS: Weight losses and adherence (attendance, use of meal replacement products, and minutes of activity) were examined over one year of intervention in 2329 ILI participants in 209 treatment groups, which all received the same weight loss program. RESULTS: Weight losses did not cluster among members of a treatment group (intra-class correlation [ICC] of 0.007), whereas measures of adherence had small/moderate clustering (ICCs of 0.05-0.11). The 209 groups varied in weight losses, with a mean of 8.64% (SD = 2.35%, interquartile range = 6.82%, 10.32%), but neither size nor baseline homogeneity of members affected the outcome. CONCLUSIONS: Although these findings suggest that it may not be necessary to control for clustering in behavioral weight loss studies, they also indicate that merely treating individuals in groups is not sufficient to harness social influences on weight loss. PMID- 23804577 TI - Mutation in the SYNJ1 gene associated with autosomal recessive, early-onset Parkinsonism. AB - Autosomal recessive, early-onset Parkinsonism is clinically and genetically heterogeneous. Here, we report the identification, by homozygosity mapping and exome sequencing, of a SYNJ1 homozygous mutation (p.Arg258Gln) segregating with disease in an Italian consanguineous family with Parkinsonism, dystonia, and cognitive deterioration. Response to levodopa was poor, and limited by side effects. Neuroimaging revealed brain atrophy, nigrostriatal dopaminergic defects, and cerebral hypometabolism. SYNJ1 encodes synaptojanin 1, a phosphoinositide phosphatase protein with essential roles in the postendocytic recycling of synaptic vesicles. The mutation is absent in variation databases and in ethnically matched controls, is damaging according to all prediction programs, and replaces an amino acid that is extremely conserved in the synaptojanin 1 homologues and in SAC1-like domains of other proteins. Sequencing the SYNJ1 ORF in unrelated patients revealed another heterozygous mutation (p.Ser1422Arg), predicted as damaging, in a patient who also carries a heterozygous PINK1 truncating mutation. The SYNJ1 gene is a compelling candidate for Parkinsonism; mutations in the functionally linked protein auxilin cause a similar early-onset phenotype, and other findings implicate endosomal dysfunctions in the pathogenesis. Our data delineate a novel form of human Mendelian Parkinsonism, and provide further evidence for abnormal synaptic vesicle recycling as a central theme in the pathogenesis. PMID- 23804579 TI - Obesity rather than regional fat depots marks the metabolomic pattern of adipose tissue: an untargeted metabolomic approach. AB - OBJECTIVE: This study compares the patterns of visceral (VIS) and subcutaneous (SC) adipose tissue (AT)-derived metabolites from non-obese (BMI 24-26 kg/m2) and obese subjects (BMI > 40 kg/m2) with no major metabolic risk factors other than BMI. METHODS: SC- and VIS- AT obtained from obese (Ob) and non-obese (NOb) subjects during surgery were incubated to obtain their metabolites. Differences related to obesity or anatomical provenances of AT were assessed using an untargeted metabolomics approach based on gas chromatography-mass spectrometry. RESULTS: The overall effect of obesity on the metabolite profile resulted more remarkable than the effect of regional AT. Only the depletion of 2-ketoisocaproic (2-KIC) acid reached statistical significance for the SC-AT alone, although it was observed in both depots. Obesity induced more significant changes in several amino acids levels of the VIS-AT metabolites. On the one hand, higher released levels of glutamine and alanine were detected in the VIS- obese AT, whereas on the other, the VIS- obese AT presented a diminished uptake of essential amino acids (methionine, threonine, lysine), BCAAs, leucine, and serine. CONCLUSION: This study shows that obesity markedly affects the amino acid metabolic signature of the AT before the clinical onset of other significant metabolic alterations aside from BMI. PMID- 23804578 TI - Centenarians as super-controls to assess the biological relevance of genetic risk factors for common age-related diseases: a proof of principle on type 2 diabetes. AB - Genetic association studies of age-related, chronic human diseases often suffer from a lack of power to detect modest effects. Here we propose an alternative approach of including healthy centenarians as a more homogeneous and extreme control group. As a proof of principle we focused on type 2 diabetes (T2D) and assessed /genotypic associations of 31 SNPs associated with T2D, diabetes complications and metabolic diseases and SNPs of genes relevant for telomere stability and age-related diseases. We hypothesized that the frequencies of risk variants are inversely correlated with decreasing health and longevity. We performed association analyses comparing diabetic patients and non-diabetic controls followed by association analyses with extreme phenotypic groups (T2D patients with complications and centenarians). Results drew attention to rs7903146 (TCF7L2 gene) that showed a constant increase in the frequencies of risk genotype (TT) from centenarians to diabetic patients who developed macro complications and the strongest genotypic association was detected when diabetic patients were compared to centenarians (p_value = 9.066*10-7). We conclude that robust and biologically relevant associations can be obtained when extreme phenotypes, even with a small sample size, are compared. PMID- 23804580 TI - Isolation of intraflagellar transport trains. AB - The intraflagellar transport (IFT) system was first identified in situ by electron microscopy in thin sections of plastic-embedded flagella as linear arrays of electrondense particles, located between the B tubules of the outer doublets and the flagellar membrane. These arrays of particles are referred to as IFT trains. Upon membrane rupture, IFT trains are thought to easily dissociate to yield soluble IFT particles, which are commonly purified through sucrose gradients as ~16-17S complexes. The latters easily dissociate into two subcomplexes, named A and B. We report here the isolation, visualization, and identification by immunolabeling of flexible strings of IFT particles, which are structurally similar to in situ IFT trains and appear to be formed by both complex A and complex B polypeptides. Moreover, the particles forming isolated IFT trains are structurally similar to the individual particles found in the ~17S gradient peak. Our results provide the first direct evidence that ~17S particles do indeed compose the IFT trains. The paper also represents the first isolation of the IFT trains, and opens new possibilities for higher resolution studies on their structure and how particles are attached to each other to form the particle trains. PMID- 23804581 TI - Osteogenesis imperfecta type V: clinical and radiographic manifestations in mutation confirmed patients. AB - Osteogenesis imperfecta (OI) type V is a specific OI phenotype with interosseous membrane calcification of the forearm and hyperplastic callus formation as typical features. The causative gene mutation for OI type V has been recently discovered. The purpose of this report is to review the clinical and radiographic characteristics of mutation confirmed OI type V in detail. Sixteen (nine familial and seven sporadic) patients were enrolled in the study. Blue sclera and dentinogenesis imperfecta were not evident in any patient. However, hypodontia in the permanent teeth, ectopic eruption, and short roots in molars were additionally observed in 11 patients. Of the radiographic abnormalities, cortical thickening and bony excrescence of interosseous margin of the ulna was the most common finding, followed by overgrowth of the olecranon and/or coronoid process of the ulna. Slender ribs and sloping of the posterior ribs with or without fractures were also a consistent finding. Hyperplastic callus was detected in 75% of patients and was commonly encountered at the femur. Heterotopic ossification in the muscles and tendon insertion sites were noted in four patients, which resulted in bony ankylosis or contracture of joints. The current study confirms common clinical and radiographic findings of OI type V and reports additional phenotypic information. These observations provide clues to recognize OI type V more promptly and guide to direct targeted molecular study. (c) 2013 Wiley Periodicals, Inc. PMID- 23804583 TI - Laryngeal anomalies: Pitfalls in adult forensic autopsies. AB - OBJECTIVE: This is the first paper to group together most of adult laryngeal anomalies or malformations which may be misinterpreted by the forensic pathologist and taken for a proof of violence. MATERIAL AND METHODS: A review of the literature, to list the main pitfalls, to explain their nature and their origins. RESULTS: We found two main categories, the congenital defects and the acquired anomalies. CONCLUSIONS: The laryngeal region is complex. The pathologist must keep in mind anatomical variations or malformations, but also sequelae of old injuries and iatrogenic lesions. The survey, the patient's clinical history, the findings of the whole autopsy and, if necessary, histology may help to interpret a laryngeal anomaly. PMID- 23804582 TI - Sex steroid levels and response to weight loss interventions among postmenopausal women in the diabetes prevention program. AB - OBJECTIVES: To examine whether estrogen use potentiates weight loss interventions via sex steroid levels and whether endogenous sex steroid levels predict response to weight loss interventions among women not using estrogen. METHODS: The Diabetes Prevention Program randomized overweight or obese dysglycemic participants to lifestyle change with the goals of weight reduction of >7% of initial weight and 150 minutes per week of exercise, metformin, or placebo. In this secondary analysis, we examined sex steroid levels and reductions in weight and waist circumference (WC) among postmenopausal women using (n = 324) and not using (n = 382) oral estrogen. RESULTS: Estrogen users and nonusers randomized to lifestyle change and metformin both lost significant amounts of weight compared to placebo. Reductions in weight and WC over 1 year associated with randomization arm were not associated with baseline sex steroid levels among estrogen users or nonusers. CONCLUSIONS: Among estrogen users, baseline sex steroids were not associated with reductions in weight or WC, suggesting that exogenous estrogen does not potentiate weight loss by altering sex steroids. Among nonestrogen users, baseline sex steroids were not associated with reductions in weight or WC. PMID- 23804584 TI - Medicaid 'welcome-mat' effect of Affordable Care Act implementation could be substantial. AB - The Affordable Care Act will have important impacts on state Medicaid programs, likely increasing participation among populations that are currently eligible but not enrolled. The size of this "welcome-mat" effect is of concern for two reasons. First, the eligible but uninsured constitute a substantial share of the uninsured population in some states. Second, the newly eligible population will affect states' Medicaid caseloads and budgets. Using the Massachusetts 2006 health reforms as a case study and controlling for other factors, we found that among low-income parents who were previously eligible for Medicaid in Massachusetts, Medicaid enrollment increased by 16.3 percentage points, and Medicaid participation by those without private coverage increased by 19.4 percentage points, in comparison to a group of control states. In many states the potential size of the welcome-mat effect could be even larger than what we observed in Massachusetts. Our analysis has potentially important implications for other states attempting to predict the impact of this effect on their budgets. PMID- 23804586 TI - Vessel repair: do progenitor cells hitchhike a piggyback ride? PMID- 23804585 TI - Increased risk of coronary heart disease among individuals reporting adverse impact of stress on their health: the Whitehall II prospective cohort study. AB - AIM: Response to stress can vary greatly between individuals. However, it remains unknown whether perceived impact of stress on health is associated with adverse health outcomes. We examined whether individuals who report that stress adversely affects their health are at increased risk of coronary heart disease (CHD) compared with those who report that stress has no adverse health impact. METHODS AND RESULTS: Analyses are based on 7268 men and women (mean age: 49.5 years, interquartile range: 11 years) from the British Whitehall II cohort study. Over 18 years of follow-up, there were 352 coronary deaths or first non-fatal myocardial infarction (MI) events. After adjustment for sociodemographic characteristics, participants who reported at baseline that stress has affected their health 'a lot or extremely' had a 2.12 times higher (95% CI 1.52-2.98) risk of coronary death or incident non-fatal MI when compared with those who reported no effect of stress on their health. This association was attenuated but remained statistically significant after adjustment for biological, behavioural, and other psychological risk factors including perceived stress levels, and measures of social support; fully adjusted hazard ratio: 1.49 (95% CI 1.01-2.22). CONCLUSIONS: In this prospective cohort study, the perception that stress affects health, different from perceived stress levels, was associated with an increased risk of coronary heart disease. Randomized controlled trials are needed to determine whether disease risk can be reduced by increasing clinical attention to those who complain that stress greatly affects their health. PMID- 23804587 TI - Improving the rapid and reliable diagnosis of complete distal biceps tendon rupture: a nuanced approach to the clinical examination. AB - BACKGROUND: Diagnosis of complete distal biceps tendon rupture (DBTR) is frequently missed or delayed on clinical examination. No single clinical test, including MRI, has demonstrated 100% efficacy in assessing the integrity of the distal biceps tendon. HYPOTHESIS: Combining 3 validated clinical tests for identifying complete rupture can maximize a true-positive diagnosis for complete DBTR without the need for confirmatory soft tissue imaging when performed in concert with other important factors from the history and clinical examination. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 2. METHODS: The hook test, the passive forearm pronation (PFP) test, and the biceps crease interval (BCI) test were applied in sequence in conjunction with a standard patient history and physical examination on 48 patients with suspected distal biceps tendon injuries. If results on all 3 special tests were positive for complete rupture, the patient was referred for surgical repair; diagnosis was confirmed intraoperatively. If results on all 3 special tests were negative, diagnosis was confirmed with soft tissue imaging and patients were managed nonoperatively. If results of the 3 tests were not in agreement, soft tissue imaging was used to clarify the disagreement and to confirm the diagnosis. RESULTS: Thirty-five patients had unequivocal results based on history, physical examination, and special tests. Thirty-two tested in agreement positive for complete rupture, which were confirmed intraoperatively. Three tested in agreement negative, with subsequent imaging confirming partial rupture. Thirteen patients had equivocal special test results; soft tissue imaging suggested complete rupture in 10 and partial rupture in 3. CONCLUSION: Application in sequence of the hook test, the PFP test, and the BCI test results in 100% sensitivity and specificity when the outcomes on all 3 special tests are in agreement. PMID- 23804588 TI - Arthroscopic capsulolabral reconstruction for posterior instability of the shoulder: a prospective study of 200 shoulders. AB - BACKGROUND: There are few reports in the literature detailing the arthroscopic treatment of unidirectional posterior shoulder instability. HYPOTHESIS: Arthroscopic capsulolabral reconstruction is effective in restoring stability and function and alleviating pain in athletes with symptomatic unidirectional posterior instability. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: One hundred eighty-three athletes (200 shoulders) with unidirectional recurrent posterior shoulder instability were treated with arthroscopic posterior capsulolabral reconstruction and underwent an evaluation at a mean of 36 months postoperatively. A subset of 117 shoulders of contact athletes was compared with the entire group of 200 shoulders. Patients were evaluated prospectively with the American Shoulder and Elbow Surgeons (ASES) scoring system. Stability, strength, and range of motion were evaluated preoperatively and postoperatively with standardized subjective scales. Methods of intraoperative soft tissue fixation as well as anchorless (n = 44) and anchored (n = 156) plications were recorded for each patient. RESULTS: At a mean of 36 months postoperatively, the mean ASES score improved from 45.9 to 85.1 (P < .001). There were also significant improvements in stability, pain, and function based on previously used scales (P < .001). The contact athletes did not demonstrate any significant differences when compared with the entire cohort for any outcome measure. With regard to the method of internal fixation, patients who underwent capsulolabral plications with suture-anchors showed significantly greater improvement in ASES scores (P < .001) and a higher rate of return to play (P < .05) when compared with patients with anchorless capsulolabral plications. CONCLUSION: Arthroscopic capsulolabral reconstruction is an effective, reliable treatment for symptomatic, unidirectional recurrent posterior glenohumeral instability in an athletic population. Overall, 90% of patients were able to return to sport, with 64% of patients able to return to the same level postoperatively. With the incorporation of bone suture-anchors in capsulolabral reconstruction, patients had greater improvements in ASES scores and a higher rate of return to play. PMID- 23804590 TI - Tracking a dietary pattern associated with increased adiposity in childhood and adolescence. AB - OBJECTIVE: Understanding dietary tracking may help to inform interventions to improve dietary intakes and health outcomes. This study investigated how a dietary pattern (DP) associated with increased adiposity in childhood tracked from 7 to 13 years of age, in the Avon Longitudinal Study of Parents and Children (ALSPAC). DESIGN AND METHODS: Three-day food diaries were collected at 7, 10 and 13 years. Reduced rank regression was used to score respondents for an energy dense, high fat, low fiber DP at each age. Tracking coefficients were estimated for the DP and its key foods using data from 7,027 children. RESULTS: The DP tracking coefficient was 0.48 (95% CI: 0.44-0.52) for boys and 0.38 (95% CI: 0.35 0.41) for girls. Of 10 key food groups, fruit, vegetables, high fiber bread, high fiber breakfast cereals and full fat milk intakes exhibited the strongest tracking, particularly among low consumers. Lower maternal education and greater prepregnancy maternal BMI predicted higher DP z scores and lower fruit and vegetable intakes. CONCLUSIONS: A dietary pattern associated with increased adiposity tracks moderately from 7 to 13 years of age in this large UK cohort. Specific groups of families may require additional support to foster lifelong healthy dietary habits in their children. PMID- 23804591 TI - Textural versus electrostatic exclusion-enrichment effects in the effective chemical transport within the cortical bone: a numerical investigation. AB - Interstitial fluid within bone tissue is known to govern the remodelling signals' expression. Bone fluid flow is generated by skeleton deformation during the daily activities. Due to the presence of charged surfaces in the bone porous matrix, the electrochemical phenomena occurring in the vicinity of mechanosensitive bone cells, the osteocytes, are key elements in the cellular communication. In this study, a multiscale model of interstitial fluid transport within bone tissues is proposed. Based on an asymptotic homogenization method, our modelling takes into account the physicochemical properties of bone tissue. Thanks to this multiphysical approach, the transport of nutrients and waste between the blood vessels and the bone cells can be quantified to better understand the mechanotransduction of bone remodelling. In particular, it is shown that the electrochemical tortuosity may have stronger implications in the mass transport within the bone than the purely morphological one. PMID- 23804589 TI - Fat cell size and adipokine expression in relation to gender, depot, and metabolic risk factors in morbidly obese adolescents. AB - OBJECTIVE: To understand the regulation of adipocyte size and adipokine expression in relation to gender, anatomic location, adiposity, and metabolic risk factors in adolescents with morbid obesity. METHODS: Adipocyte size and adipokine expression in paired abdominal subcutaneous (SAT) and omental (VAT) surgical adipose tissues were related to gender, anatomic location, adiposity, and metabolic risk factors in a group of morbidly obese adolescents. RESULTS: Significant depot- and/or gender-related differences in adipocyte size and adipokine expression were detected. Adjusted for body mass index, adipocyte size in both depots was larger in males than in females and was a major predictor of mRNA levels of leptin, plasminogen activator inhibitor-1, and adiponectin. Gender, but not adipocyte size, was significantly correlated with proinflammatory cytokine expression. Body mass index and waist circumference were correlated positively with VAT adipocyte size and negatively with SAT adipocyte size. VAT adiponectin and interleukin-6 expression levels were major predictors of high density lipoprotein cholesterol concentrations, independent of gender, adiposity, and insulin sensitivity. CONCLUSIONS: Adipose tissue morphology and function in obese adolescents are influenced by gender and anatomic location; the pattern of gender- and depot-related differences in adipocyte size and adipokine expression suggests that adolescent males, relative to the females, are at increased risk for obesity-related metabolic comorbidities. PMID- 23804592 TI - FGF21 drives a shift in adipokine tone to restore metabolic health. PMID- 23804594 TI - Validity of body adiposity index in predicting body fat in a sample of Brazilian women. AB - OBJECTIVE: This study aimed to verify the validity of BAI in predicting %BF in a sample of Brazilian women DESIGN AND METHODS: A total of 102 women (average age 60.3 +/- 9.8) were assessed. To determine percentage body fat (% BF), dual-energy X-ray absorptiometry (DXA) was used as the "gold standard." To evaluate the association between body adiposity index (BAI) and % BF assessed by DXA, we used Pearson's correlation coefficient. Paired sample t-test was used to test differences in mean % BF between BAI and DXA. To evaluate the concordance between % BF measured by DXA and estimated by BAI, we used the Lin's concordance correlation coefficient and the agreement analysis of Bland-Altman. RESULTS: The correlation between % BF obtained by DXA and that estimated by BAI was r = 0.65, P < 0.001. Paired t-test showed significant mean difference between methods (P < 0.0001). Lin's concordance correlation coefficient was C_b = 0.73, which is classified as poor, while the Bland-Altman plots showed BAI underestimating % BF in relation to the used criterion measure in a large portion of the sample. CONCLUSIONS: Results of the present study show that BAI presented low agreement with % BF measured by DXA, which is not recommended for % BF prediction in this studied sample. PMID- 23804593 TI - Clinical features of three girls with mosaic genome-wide paternal uniparental isodisomy. AB - Here we describe three subjects with mosaic genome-wide paternal uniparental isodisomy (GWpUPD) each of whom presented initially with overgrowth, hemihyperplasia (HH), and hyperinsulinism (HI). Due to the severity of findings and the presence of additional features, SNP array testing was performed, which demonstrated mosaic GWpUPD. Comparing these individuals to 10 other live-born subjects reported in the literature, the predominant phenotype is that of pUPD11 and notable for a very high incidence of tumor development. Our subjects developed non-metastatic tumors of the adrenal gland, kidney, and/or liver. All three subjects had pancreatic hyperplasia resulting in HI. Notably, our subjects to date display minimal features of other diseases associated with paternal UPD loci. Both children who survived the neonatal period have displayed near-normal cognitive development, likely due to a favorable tissue distribution of the mosaicism. To understand the range of UPD mosaicism levels, we studied multiple tissues using SNP array analysis and detected levels of 5-95%, roughly correlating with the extent of tissue involvement. Given the rapidity of tumor growth and the difficulty distinguishing malignant and benign tumors in these GWpUPD subjects, we have utilized increased frequency of ultrasound (US) and alpha-fetoprotein (AFP) screening in the first years of life. Because of a later age of onset of additional tumors, continued tumor surveillance into adolescence may need to be considered in these rare patients. PMID- 23804595 TI - Progeroid laminopathy with restrictive dermopathy-like features caused by an isodisomic LMNA mutation p.R435C. AB - The clinical course of a female patient affected by a progeroid syndrome with Restrictive Dermopathy (RD)-like features was followed up. Besides missing hairiness, stagnating weight and growth, RD-like features including progressive skin swelling and solidification, acrocontractures, osteolysis and muscular hypotension were observed until the patient died at the age of 11 months. A homozygousLMNA mutation c.1303C>T (p.R435C) was found by Sanger sequencing. Haplotyping revealed a partial uniparental disomy of chromosome 1 (1q21.3 to 1q23.1) including the LMNA gene. In contrast to reported RD patients with LMNA mutations, LMNA p.R435C is not located at the cleavage site necessary for processing of prelamin A by ZMPSTE24 and leads to a distinct phenotype combining clinical features of Restrictive Dermopathy, Mandibuloacral Dysplasia and Hutchinson-Gilford Progeria. Functionally, LMNA p.R435C is associated with increasing DNA double strand breaks and decreased recruitment of P53 binding protein 1 (53BP1) to DNA-damage sites indicating delayed DNA repair. The follow up of the complete clinical course in the patient combined with functional studies showed for the first time that a progressive loss of lamin A rather than abnormal accumulation of prelamin A species could be a pathophysiological mechanism in progeroid laminopathies, which leads to DNA repair deficiency accompanied by advancing tissue degeneration. PMID- 23804597 TI - Surgical management of the posterior fibula fracture dislocation: case report. PMID- 23804596 TI - Secondhand smoke exposure in preterm infants with bronchopulmonary dysplasia. AB - OBJECTIVES: Preterm infants and children with bronchopulmonary dysplasia (BPD) often experience significant respiratory morbidities during the first two years of life. Second hand smoke (SHS) has been demonstrated to lead to respiratory morbidities in the general population. The objectives of this study were to assess the prevalence/impact of SHS on preterm infants and children with BPD. METHODS: Subjects (n = 352) were recruited from the Johns Hopkins BPD outpatient clinic between January 2008 and August 2012. Second hand smoke exposure and respiratory morbidities were assessed through questionnaires and chart review. RESULTS: Twenty-eight percent of preterm infants with BPD were exposed to SHS in the home setting, despite having significant lung disease. SHS was associated with multiple measures of socio-economic status, including lower household income (P < 0.001), lower caregiver education level (P = 0.013), and having public versus private insurance (P = 0.002). We found no difference in acute care use or chronic symptoms with SHS exposure. We observed trends that preterm infants who were exposed to SHS were more likely to be prescribed inhaled corticosteroids (P = 0.054) and were weaned off of supplemental oxygen over 2 months later (P = 0.13) than infants not exposed to SHS. CONCLUSION: SHS exposure in preterm infants with BPD is common, even in those receiving supplemental oxygen and respiratory medications. Although there were no associations between respiratory outcomes and self-reported SHS exposure, trends toward increased use of inhaled steroids and a longer duration of supplemental oxygen use were noted. Further work is needed to determine more accurate means of assessing SHS risk in this vulnerable population. PMID- 23804598 TI - Hallux metatarsophalangeal joint arthrodesis with a hybrid locking plate and a plantar neutralization screw: a prospective study. AB - BACKGROUND: Many techniques have been described for arthrodesis of the first metatarsophalangeal (MTP) joint. The purpose of this study was to determine the results of fixation using a low-profile dorsal titanium plate with locking screws in the phalanx, nonlocking screws in the metatarsal, and a plantar neutralization screw. METHODS: Forty-nine consecutive patients (51 feet) underwent a first MTP joint arthrodesis during an enrollment period of 1 year from October 2010 to November, 2011. All patients were evaluated preoperatively for primary pathology, pain, function, radiographic findings, AOFAS scores, and physical exam findings. First MTP joint arthrodesis was performed with a precontoured dorsal titanium plate with preset valgus and dorsiflexion after the joint surfaces were prepared with dome-shaped power reamers to achieve congruous cancellous bone surfaces. At a minimum of 1-year follow-up, patients returned for postoperative evaluation of pain, function, radiographic findings, satisfaction, AOFAS scores, and physical exam findings. RESULTS: Forty-six of 49 (48 feet) patients returned for final follow-up examination at least 12 months after operative intervention. Forty-one patients (89%) reported good to excellent results. Visual analog pain scores improved from an average of 6.6 preoperatively to an average of 1.6 postoperatively (t = -9.3339, df = 45, P < .001). Functional capacity scores improved from a preoperative mean of 2.5 to a postoperative mean of 1.4 (t = 5.2648, df = 46, P < .001). AOFAS hallux MTP joint scores improved from a preoperative mean of 45 to a postoperative mean of 77 (t = 9.9498, df = 46, P < .003). Eighteen of 48 great toes (38%) had preoperative pronation whereas, 2 of 48 great toes (4%) had postoperative pronation. Eleven of 46 patients (24%) were unable to perform preoperative toe rise, and 8 of 46 (17%) were unable to perform postoperative toe rise. Twenty-five of 46 patients (54%) had gait improvement, while 19 patients (44%) had no change in gait, and 2 patients (4%) had gait deterioration. The mean preoperative hallux valgus angle of 27 degrees improved to a mean postoperative angle of 13 degrees (t = -6.1982, df = 46, P < .001). The mean preoperative 1-2 intermetatarsal angle of 12 degrees improved to a mean postoperative angle of 9 degrees (t = -5.2614, df = 46, P < .001). There was 1 delayed union (2%) and 1 nonunion (2%). CONCLUSION: Our outcome scores indicate that first MTP joint arthrodesis with a precontoured dorsal titanium plate with locking screws in the phalanx and nonlocking screws in the first metatarsal is both reliable and reproducible with a very high bony union rate. LEVEL OF EVIDENCE: Level IV, prospective case series. PMID- 23804599 TI - Applications of the medial femoral condyle free flap for foot and ankle reconstruction. AB - BACKGROUND: Avascular necrosis (AVN) or persistent nonunion occurs in situations of poor vascular supply. Some specific situations that plague the foot and ankle surgeon are talus nonunion, talus AVN, navicular AVN, and failed ankle arthrodesis with bone loss. The medial femoral condyle (MFC) flap has emerged as a popular source of vascularized corticocancelous bone. We present a series of cases demonstrating the versatility of the MFC flap in complex foot and ankle pathology. METHODS: A retrospective review was completed of all MFC flaps used in the foot and ankle over the past 5 years. Five patients were identified (average age 48). Surgical indications included talar AVN and ankle arthritis, talar nonunion, and navicular AVN. All patients had undergone conventional bone grafting techniques, which failed, prior to being treated with a MFC free flap; this series of patients did not possess significant medical comorbidities. Fixation techniques included compression screw fixation, plate osteosynthesis, or fine wire external fixation. The average follow-up was 20 months (range 8 to 40 months). RESULTS: There was a 100% flap success rate with no returns to the operating room for thrombosis. The volume of the bone flaps was 5.6 cm(3) (range 1 cm(3) to 12 cm(3)). The average follow-up time was 20 months (range 8 to 40 months). All cases resulted in union, and full weight bearing status was achieved at a mean of 23.8 weeks (range 10 to 52 weeks) postoperatively. CONCLUSIONS: Vascularized bone transfer in the form of the MFC free flap was a valuable method for foot and ankle reconstruction. The MFC flap provided an alternative for those defects that were smaller then 3 cm in length. In our experience, for small bone defects requiring vascularized bone, the MFC flap is currently the ideal donor location supplanting the iliac crest. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 23804600 TI - Focusing the spotlight on GSK-3 in aging. PMID- 23804601 TI - From the editor. PMID- 23804602 TI - Improving risk assessment in family medicine through the family history. AB - The family history is used as a screening tool to identify persons who may be at risk for a heritable disorder. Primary care providers sometimes do not thoroughly gather and document the family history. This pilot study was undertaken to determine whether having a genetic counselor on site at our family medicine clinic 2 days a week for 3 months would improve the quality of the family history field in patient records. We compared 7 elements in the family history field for patients seen before and after the genetic counselor was on site. Documentation of 1 of the 7 elements (major disease) improved significantly after the intervention period (P = .02). Changing provider behavior with regard to gathering and documenting family history of major disease may be facilitated by tools to help collect the family history and by using the increasing number of available genetic tests. PMID- 23804603 TI - Challenges to accessing pediatric health care in the Mississippi delta: a survey of emergency department patients seeking nonemergency care. AB - BACKGROUND: Increases in hospital emergency department use have been driven by insured patients with problems accessing primary care services. Access problems are especially pronounced in rural communities with health professional shortages. This qualitative study explored reasons for nonurgent pediatric emergency department use in the Mississippi Delta. METHOD: Using a community based participatory research framework, a semistructured survey was administered face-to-face in a hospital emergency department waiting room with parents/caregivers who brought their children. Interviews were done over 144 hours in 2-hour blocks covering regular "business hours" and "after hours" (evenings/weekends). Open-ended items allowed qualitative data to be gathered describing reasons for emergency department use and perceptions of urgency of the visit in the parents'/caregivers' own words. RESULTS: There were 112 children, with a response rate of 87%. The mean child age was 5.7 years; 52% were male; 95% were African American and 5% white; 80.6% had Medicaid/SCHIP, 7.8% commercial, and 3.9% other insurance; 7.8% were uninsured. Most (88%) had a usual source of pediatric care. Only 24.3% tried to obtain care before emergency department visit; 23.2% said their children required "urgent" care. Mean distance from home to usual source of care was 10 miles. Ten percent cited transportation as a barrier to keeping health care appointments; 5.5% cited insurance or cost. Families who used the emergency department during evening/weekends were significantly more likely to have cited clinic hours of operation as a reason care was not sought previously than were "business hours" users, who emphasized convenience. CONCLUSION: Nonurgent pediatric emergency department use could be reduced by extending clinic hours, adding a walk-in service, and making transportation more available. PMID- 23804604 TI - Postpartum depression screening: initial implementation in a multispecialty practice with collaborative care managers. AB - Postpartum depression (PPD) has emerged as an important issue for pediatricians and family practitioners because of detrimental effects on children. PPD occurs in 10% to 22% of women who have recently given birth, but fewer than half of cases are recognized. Despite the impact of PPD, many primary care clinicians do not have systemic screening approaches implemented. This paper will review the development of a screening protocol for PPD in a multispecialty clinic, with the implementation utilizing depression care managers and the preliminary results of our process. Of the 333 screened examinations during the 4-month study, 38.1% (n = 127) were performed for the 2-month well child examination; 33.6% (n = 112) were for the 4-month examination, with 28.2% (n = 94) being performed for the 6 month well child examination. Only 15 (4.5%) were positive for possible depression with a screening compliance rate of 47.9%. No significant difference was noted in the timing of the well child visit with a positive screening test result, nor was there any difference in family medicine versus pediatric colleagues in the utilization of the screening or diagnosis of PPD. Implementation of PPD screening in a multispecialty clinic can be effective, given utilization of depression care managers. PMID- 23804605 TI - Immigration, drinking, and frequent mental distress: an internet survey. AB - OBJECTIVE: The objective of this study was to investigate the importance of immigration as a risk factor for self-reported frequent mental distress (FMD) among black respondents to an Internet survey. METHOD: Snowball sampling was used to obtain Internet survey responses from immigrant and non-immigrant black adults in the United States. Multiple logistic regression analysis was used to control for the effects of personal characteristics (N = 301). RESULTS: In this sample of black adults, 13.3% had FMD. Being an immigrant was not associated with FMD in this sample (adjusted odds ratio [OR] = 0.75, P = .53). However, more drinking days was an independent risk factor (OR = 1.07, P < .01). CONCLUSIONS: Being an immigrant was not an independent risk factor for FMD in this sample of black adults. However, drinking more days per month was a significant risk factor. Primary care providers should be alert for FMD and alcohol consumption in this population. Directing health education about hazardous drinking toward high-risk individuals should be considered. PMID- 23804606 TI - Impact of an evidence based prenatal care model on patient outcomes. AB - Health care providers face many challenges when providing prenatal care. This article reports on a program called Prenatal Care: the Beginning of a Lifetime (PCBL), to implement standardized prenatal care in central North Carolina. The purpose of this pilot study was to determine if there were differences in patient outcomes between a control group and 3 groups (A, B, and C) of increasing levels of intervention in standardized prenatal care. A total of 150 patients were enrolled and followed through delivery. There were no significant differences between the groups in cigarette smoking status, weight gain, genetic screening, sexually transmitted infection screening, diabetes screening, domestic violence assessment, 17P candidacy assessment, gestational age at delivery, or infant birth weight. However, a significant difference was found in depression screening. An association between intervention group membership and likelihood of being screened for depression was found in each trimester. As the level of intervention increased, the number of participants screened for depression increased significantly. PMID- 23804607 TI - Physician counseling and longer term physical activity. AB - While physician counseling has been suggested as a strategy to promote physical activity, there is insufficient evidence to support its effectiveness at present. The purpose of this study was to examine the effect of brief physician counseling (modified PACE protocol) and telephone follow-ups on changes in the energy expenditure levels of patients over a 20-month period. Forty-five participants completed physical activity questionnaires at both baseline and 20 months. Following brief physician counseling (modified PACE protocol), patients were randomized into a counseling-only group or an enhanced counseling group that included 3 telephone follow-ups. Energy expenditure significantly increased from baseline (1.5 kcal/kg/d [KKD]) to 20 months (2.2 KKD, P < .05) in both groups. Neither the group nor group-by-time interaction was significant (P > .05). In line with the counseling provided by physicians, participants showed an increase in moderate intensity activities and a decrease in light intensity activities (Ps < .001). These findings provide support for the effectiveness of brief physician counseling. However, the additional telephone support did not appear to enhance the physician counseling. PMID- 23804608 TI - Exploring the Role of Body Mass Index on Balance Reactions and Gait in Overweight Sedentary Middle-aged Adults: A Pilot Study. AB - BACKGROUND/PURPOSE: Being overweight is defined as having a body mass index greater than 25. Reduced postural control has been implicated in the presence of increased body mass index. The purpose of this study was to assess the effects of body mass index on postural stability in healthy sedentary middle-aged adults. Based on body mass index, subjects were divided into 2 groups (25.00-27.49 and 27.50-29.99) to assess for differences in postural control. METHODS: Twenty healthy sedentary subjects between 40 and 64 years (13 women and 7 men) with a mean age of 52.45 years were recruited by convenience. After determination of body mass index, postural control was assessed on all subjects using the Activities Specific Balance Confidence Scale, Berg Balance Scale, Timed Up and Go Test, gait speed measurement, and Biodex Stability Index testing. RESULTS: The Timed Up and Go Test duration was increased in these subjects when compared with normative data. Gait speed was also reduced in those subjects in the fifth and sixth decades when compared with established norms. Biodex SD balance system scores demonstrated reduced postural stability. A 2-tailed t test revealed no significant difference between body mass index ranges of 25.0 to 27.5 and 27.6 to 29.99. CONCLUSION: There may be increased risk for falls with increases in body mass short of obesity thresholds of body mass index 30% for this sedentary middle aged adult population. Future studies, with larger groups of subjects, that address postural stability and body mass index are necessary. Although these subjects are younger, falls screening measures may prove beneficial as a prevention strategy for sedentary overweight middle-aged adults. PMID- 23804609 TI - Nutritional profile of children under 5 years of age in a tribal community in the district of maldah, west bengal. AB - OBJECTIVES: To determine the nutritional status of under-5 tribal children. DESIGN: Community-based cross-sectional observational study. SETTING: Three tribal villages of the Chanchal II block of the Maldah district in West Bengal. SUBJECTS AND METHODS: In 3 tribal villages, 188 children under 5 years of age were examined to detect nutritional deficiency disorders. By anthropometric measurement, nutritional grading of them was determined. Interviews of mothers provided breast-feeding and weaning practices. RESULTS: 63.83% of study subjects were suffering from different grades of malnutrition. Prevalence of anaemia and angular stomatitis was 45.74% and 19.12%, respectively, among them. PMID- 23804610 TI - Purulent skin and soft tissue infection: antibiotic selection in the community. AB - INTRODUCTION: Community-acquired methicillin-resistant Staphylococcus aureus (CA MRSA) requently causes skin and soft tissue infections (SSTIs). Referring primary care physicians often prescribe inactive antibiotics when referring SSTIs caused by MRSA for incision and debridement. METHODS: Demographics and culture results (organism and sensitivity) were collected for patients treated for SSTI between 2007-2009. Antibiotic regimens started by referring PCPs were noted. Prevalence of MRSA and antibiotic resistance profiles were tabulated. Isolates resistant to the drug initially prescribed were also noted. RESULTS: Of 187 patients, 40.1% grew MRSA. All MRSA was sensitive to doxycycline and trimethoprim sulfamethoxazole, whereas 88% were sensitive to clindamycin and 79% to levofloxacin. 48% of patients received an antibiotic inadequate for their isolate before referral. CONCLUSIONS: CA-MRSA is extremely common. Patients are often prescribed antibiotics inadequate for MRSA. Doxycycline or trimethoprim sulfamethoxazole with incision/drainage should be used as initial therapy for SSTI when MRSA is suspected. PMID- 23804611 TI - Population attributable risk fraction for selected chronic diseases in India. AB - BACKGROUND: India's current health transition stage poses a critical challenge of dealing with the unfinished agenda of communicable diseases and the steadily rising burden of noncommunicable diseases. A significant burden of chronic diseases in India is attributable to household and individual level health risk factors coupled with socioeconomic conditions. From this perspective, this article made a first time effort to assess disease burden attributable to health risk factors using cross-sectional population health survey data. METHODS: Population attributable fractions (PAF) were estimated for a cluster of health risk factors that include unsafe water, lack of sanitation, exposure to cooking smoke, tobacco and alcohol use, physical inactivity, and socioeconomic conditions on a set of widely prevalent chronic diseases such as tuberculosis, malaria, diarrhea, diabetes, angina, and asthma. Data from the 2003 World Health Survey was used. RESULTS: The analysis revealed evidence of a significant contribution of health risk factors to India's escalating chronic disease burden. The contribution of health risk factors toward chronic disease burden varied by residence. CONCLUSION: Results suggest that promotional health care based policies to deal with health risks should be a major priority in policy agenda to combat with the challenge of emerging noncommunicable disease coupled with the persistent burden of communicable diseases. Disease burden in India could be halved by effectively modifying exposure to the risk factors through promotional health care. PMID- 23804612 TI - Racial differences in barriers to blood pressure control in a family practice setting. AB - OBJECTIVE: Hypertension prevalence in the African American community is greater than in all other ethnic groups. Cultural perceptions of health and disease introduce barriers to providing effective care. The purpose of this study was to identify racial differences in the perceived causes of hypertension, current behaviors performed to control blood pressure, and perceived barriers to preventing or treating hypertension. METHODS: A self-administered survey of patients seen for medical care in a primary care network was conducted. The survey was developed to measure perceptions of hypertension etiology and treatments. Data from African American (n = 69) and Caucasian (n = 218) respondents were used to assess racial differences in perceptions of blood pressure control. RESULTS: About half of respondents knew their current blood pressures. African American patients were significantly less likely to believe that hypertension was caused by a lack of exercise and obesity. Significantly more Caucasians were less likely to report cutting down on table salt and taking prescription medications for blood pressure control. Both African Americans and Caucasians believed that sodium reduction was the most easily changed behavior to control their blood pressure, while both groups identified weight loss as being the most difficult. CONCLUSION: Racial differences exist in the perceived causes and treatments of high blood pressure, indicating a need for further patient education. When treating and counseling patients, physicians and support staff members must be sensitive to racial diversity and strive to offer culturally relevant solutions, especially for behaviors perceived as most difficult to change. PMID- 23804613 TI - Intervention to reduce parental bypass of community pediatric primary health facilities in asmara, eritrea. AB - OBJECTIVE: To reduce direct parental referral of low acuity ill pediatric patients to the outpatient facilities of a nation's only pediatric referral hospital. PATIENTS AND METHODS: Longitudinal monitoring of outpatient visits at Orotta Children's Hospital (OCH) and primary health facilities (PHFs) following implementation of an intervention designed in response to information provided by parents and health-care providers. Parental surveys were undertaken before and after exposure to the intervention to assess effects on knowledge, attitudes, and behavioral intentions. RESULTS: We analyzed 5,639 visits between baseline and follow-up, documenting a decline in parental referral among OCH outpatients from 95% to approximately 80%. Educational intervention increased the proportion of parents intending to use PHF for future outpatient care from 28% to 82%. Staff of the PHFs responded enthusiastically to this intervention program and requested further activities. CONCLUSIONS: Self-referral to tertiary care hospital was reduced following a modest program of parental education designed and implemented by residents in training. PMID- 23804614 TI - Dilution effect in bovine tuberculosis: risk factors for regional disease occurrence in Africa. AB - Changes in host diversity have been postulated to influence the risk of infectious diseases, including both dilution and amplification effects. The dilution effect refers to a negative relationship between biodiversity and disease risk, whereas the amplification effect occurs when biodiversity increases disease risk. We tested these effects with an influential disease, bovine tuberculosis (BTB), which is widespread in many countries, causing severe economic losses. Based on the BTB outbreak data in cattle from 2005 to 2010, we also tested, using generalized linear mixed models, which other factors were associated with the regional BTB presence in cattle in Africa. The interdependencies of predictors and their correlations with BTB presence were examined using path analysis. Our results suggested a dilution effect, where increased mammal species richness was associated with reduced probability of BTB presence after adjustment for cattle density. In addition, our results also suggested that areas with BTB infection in the preceding year, higher cattle density and larger percentage of area occupied by African buffalo were more likely to report BTB outbreaks. Climatic variables only indirectly influenced the risk of BTB presence through their effects on cattle density and wildlife distribution. Since most studies investigating the role of wildlife species on BTB transmission only involve single-species analysis, more efforts are needed to better understand the effect of the structure of wildlife communities on BTB dynamics. PMID- 23804615 TI - Mapping the navigational knowledge of individually foraging ants, Myrmecia croslandi. AB - Ants are efficient navigators, guided by path integration and visual landmarks. Path integration is the primary strategy in landmark-poor habitats, but landmarks are readily used when available. The landmark panorama provides reliable information about heading direction, routes and specific location. Visual memories for guidance are often acquired along routes or near to significant places. Over what area can such locally acquired memories provide information for reaching a place? This question is unusually approachable in the solitary foraging Australian jack jumper ant, since individual foragers typically travel to one or two nest-specific foraging trees. We find that within 10 m from the nest, ants both with and without home vector information available from path integration return directly to the nest from all compass directions, after briefly scanning the panorama. By reconstructing panoramic views within the successful homing range, we show that in the open woodland habitat of these ants, snapshot memories acquired close to the nest provide sufficient navigational information to determine nest-directed heading direction over a surprisingly large area, including areas that animals may have not visited previously. PMID- 23804616 TI - Social learning of predators in the dark: understanding the role of visual, chemical and mechanical information. AB - The ability of prey to observe and learn to recognize potential predators from the behaviour of nearby individuals can dramatically increase survival and, not surprisingly, is widespread across animal taxa. A range of sensory modalities are available for this learning, with visual and chemical cues being well-established modes of transmission in aquatic systems. The use of other sensory cues in mediating social learning in fishes, including mechano-sensory cues, remains unexplored. Here, we examine the role of different sensory cues in social learning of predator recognition, using juvenile damselfish (Amphiprion percula). Specifically, we show that a predator-naive observer can socially learn to recognize a novel predator when paired with a predator-experienced conspecific in total darkness. Furthermore, this study demonstrates that when threatened, individuals release chemical cues (known as disturbance cues) into the water. These cues induce an anti-predator response in nearby individuals; however, they do not facilitate learnt recognition of the predator. As such, another sensory modality, probably mechano-sensory in origin, is responsible for information transfer in the dark. This study highlights the diversity of sensory cues used by coral reef fishes in a social learning context. PMID- 23804617 TI - Convergent evolution of floral signals underlies the success of Neotropical orchids. AB - The great majority of plant species in the tropics require animals to achieve pollination, but the exact role of floral signals in attraction of animal pollinators is often debated. Many plants provide a floral reward to attract a guild of pollinators, and it has been proposed that floral signals of non rewarding species may converge on those of rewarding species to exploit the relationship of the latter with their pollinators. In the orchid family (Orchidaceae), pollination is almost universally animal-mediated, but a third of species provide no floral reward, which suggests that deceptive pollination mechanisms are prevalent. Here, we examine floral colour and shape convergence in Neotropical plant communities, focusing on certain food-deceptive Oncidiinae orchids (e.g. Trichocentrum ascendens and Oncidium nebulosum) and rewarding species of Malpighiaceae. We show that the species from these two distantly related families are often more similar in floral colour and shape than expected by chance and propose that a system of multifarious floral mimicry--a form of Batesian mimicry that involves multiple models and is more complex than a simple one model-one mimic system--operates in these orchids. The same mimetic pollination system has evolved at least 14 times within the species-rich Oncidiinae throughout the Neotropics. These results help explain the extraordinary diversification of Neotropical orchids and highlight the complexity of plant-animal interactions. PMID- 23804618 TI - Suppressors of RNAi from plant viruses are subject to episodic positive selection. AB - Viral suppressors of RNAi (VSRs) are proteins that actively inhibit the antiviral RNA interference (RNAi) immune response, providing an immune evasion route for viruses. It has been hypothesized that VSRs are engaged in a molecular 'arms race' with RNAi pathway genes. Two lines of evidence support this. First, VSRs from plant viruses display high sequence diversity, and are frequently gained and lost over evolutionary time scales. Second, Drosophila antiviral RNAi genes show high rates of adaptive evolution. Here, we investigate whether VSRs diversify faster than other genes and, if so, whether this is a result of positive selection, as might be expected in an arms race. By analysis of 12 plant RNA viruses, we show that the relative rate of protein evolution is higher for VSRs than for other genes, but that this is not attributable to pervasive positive selection. We argue that, because evolutionary time scales are extremely different for viruses and eukaryotes, it is improbable that viral adaptation (as measured by the ratio of non-synonymous to synonymous change) will be dominated by one-to-one coevolution with eukaryotes. Instead, for plant virus VSRs, we find strong evidence of episodic selection--diversifying selection that acts on a subset of lineages--which might be attributable to frequent shifts between different host genotypes or species. PMID- 23804619 TI - Can settlement in natal-like habitat explain maladaptive habitat selection? AB - The study of habitat selection has long been influenced by the ideal free model, which maintains that young adults settle in habitat according to its inherent quality and the density of conspecifics within it. The model has gained support in recent years from the finding that conspecifics produce cues inadvertently that help prebreeders locate good habitat. Yet abundant evidence shows that animals often fail to occupy habitats that ecologists have identified as those of highest quality, leading to the conclusion that young animals settle on breeding spaces by means not widely understood. Here, we report that a phenomenon virtually unknown in nature, natal habitat preference induction (NHPI), is a strong predictor of territory settlement in both male and female common loons (Gavia immer). NHPI causes young animals to settle on natal-like breeding spaces, but not necessarily those that maximize reproductive success. If widespread, NHPI might explain apparently maladaptive habitat settlement. PMID- 23804620 TI - Mate sampling and choosiness in the sand goby. AB - To date, mate choice studies have mostly focused on establishing which mates are chosen or how the choices are performed. Here, we combined these two approaches by empirically testing how latency to mate is affected by various search costs, variation in mate quality and female quality in the sand goby (Pomatoschistus minutus). Our results show that females adjust their mating behaviour according to the costs and benefits of the choice situation. Specifically, they mated sooner when access to males was delayed and when the presence of other females presented a mate sampling cost. We also found a positive link between size variation among potential mating partners and spawning delay in some (but not all) experimental conditions. By contrast, we did not find the number of available males or the females' own body size ('quality') to affect mating latency. Finally, female mating behaviour varied significantly between years. These findings are notable for demonstrating that (i) mate sampling time is particularly sensitive to costs and, to a lesser degree, to variation among mate candidates, (ii) females' mating behaviour is sensitive to qualitative rather than to quantitative variation in their environment, and (iii) a snapshot view may describe mate sampling behaviour unreliably. PMID- 23804621 TI - Social encounter networks: characterizing Great Britain. AB - A major goal of infectious disease epidemiology is to understand and predict the spread of infections within human populations, with the intention of better informing decisions regarding control and intervention. However, the development of fully mechanistic models of transmission requires a quantitative understanding of social interactions and collective properties of social networks. We performed a cross-sectional study of the social contacts on given days for more than 5000 respondents in England, Scotland and Wales, through postal and online survey methods. The survey was designed to elicit detailed and previously unreported measures of the immediate social network of participants relevant to infection spread. Here, we describe individual-level contact patterns, focusing on the range of heterogeneity observed and discuss the correlations between contact patterns and other socio-demographic factors. We find that the distribution of the number of contacts approximates a power-law distribution, but postulate that total contact time (which has a shorter-tailed distribution) is more epidemiologically relevant. We observe that children, public-sector and healthcare workers have the highest number of total contact hours and are therefore most likely to catch and transmit infectious disease. Our study also quantifies the transitive connections made between an individual's contacts (or clustering); this is a key structural characteristic of social networks with important implications for disease transmission and control efficacy. Respondents' networks exhibit high levels of clustering, which varies across social settings and increases with duration, frequency of contact and distance from home. Finally, we discuss the implications of these findings for the transmission and control of pathogens spread through close contact. PMID- 23804623 TI - Processing power limits social group size: computational evidence for the cognitive costs of sociality. AB - Sociality is primarily a coordination problem. However, the social (or communication) complexity hypothesis suggests that the kinds of information that can be acquired and processed may limit the size and/or complexity of social groups that a species can maintain. We use an agent-based model to test the hypothesis that the complexity of information processed influences the computational demands involved. We show that successive increases in the kinds of information processed allow organisms to break through the glass ceilings that otherwise limit the size of social groups: larger groups can only be achieved at the cost of more sophisticated kinds of information processing that are disadvantageous when optimal group size is small. These results simultaneously support both the social brain and the social complexity hypotheses. PMID- 23804622 TI - The body beyond the body: expectation of a sensory event is enough to induce ownership over a fake hand. AB - More than 100 papers have been published on the rubber hand illusion since its discovery 14 years ago. The illusion has been proposed as a demonstration that the body is distinguished from other objects by its participation in specific forms of intermodal perceptual correlation. Here, we radically challenge this view by claiming that perceptual correlation is not necessary to produce the experience of this body as mine. Each of 15 participants was seated with his/her right arm resting upon a table just below another smaller table. Thus, the real hand was hidden from the participant's view and a life-sized rubber model of a right hand was placed on the small table in front of the participant. The participant observed the experimenter's hand while approaching--without touching- the rubber hand. Phenomenology of the illusion was measured by means of skin conductance response and questionnaire. Both measures indicated that participants experienced the illusion that the experimenter's hand was about to touch their hidden hand rather than the rubber hand, as if the latter replaced their own hand. This did not occur when the rubber hand was rotated by 180 degrees or replaced by a piece of wood. This illusion indicates that our brain does not build a sense of self in a merely reactive way, via perceptual correlations; rather it generates predictions on what may or may not belong to itself. PMID- 23804624 TI - Cambrian spiral-plated echinoderms from Gondwana reveal the earliest pentaradial body plan. AB - Echinoderms are unique among animal phyla in having a pentaradial body plan, and their fossil record provides critical data on how this novel organization came about by revealing intermediate stages. Here, we report a spiral-plated animal from the early Cambrian of Morocco that is the most primitive pentaradial echinoderm yet discovered. It is intermediate between helicoplacoids (a bizarre group of spiral-bodied echinoderms) and crown-group pentaradiate echinoderms. By filling an important gap, this fossil reveals the common pattern that underpins the body plans of the two major echinoderm clades (pelmatozoans and eleutherozoans), showing that differential growth played an important role in their divergence. It also adds to the striking disparity of novel body plans appearing in the Cambrian explosion. PMID- 23804625 TI - Do drug interaction alerts between a chemotherapy order-entry system and an electronic medical record affect clinician behavior? AB - INTRODUCTION: We developed an enhancement to a chemotherapy order-entry system that alerted prescribers to potential drug interactions between patients' usual outpatient medications and those prescribed for onsite cancer treatment. This report summarizes the interactions and analyzes the impact of alerts on clinician behavior. METHODS: We studied electronic orders created from November 2010 to December 2011 by oncology clinicians at two comprehensive cancer centers who shared a chemotherapy order-entry system and an ambulatory electronic medical record. The enhancement generated an alert if a new chemotherapy system order for an antineoplastic agent or supportive care medication interacted with an existing medication in the ambulatory record, and tracked prescribers' responses. RESULTS: New chemotherapy system orders triggered 29,592 drug interaction alerts. New orders for antineoplastic agents accounted for 495 (32.6%) of 1518 high- and medium-severity alerts. Interactions with antibiotics accounted for the majority of these alerts. New chemotherapy system orders for antiemetics triggered 352 (23.2%) alerts and more than two-thirds were attributed to interactions with analgesic opioids. High- and medium-severity alerts changed prescriber behavior in 224 (14.8%) occurrences, including potentially fatal interactions between meperidine and monoamine oxidase inhibitors. Clinicians who overrode alerts indicated that they would monitor the patient (54.6%), the patient already tolerated the combination (24.5%), and they would adjust the dose (15.1%). CONCLUSION: Cancer patients are at risk of serious interactions between medications ordered for cancer care and those provided for general medical care. Organizations and order-entry applications should develop countermeasures to identify and prevent potentially serious drug interactions. PMID- 23804626 TI - Grade 3 trastuzumab-induced neutropenia in breast cancer patient. AB - Trastuzumab, a humanized monoclonal antibody, is widely considered the most important development in the treatment of breast cancer since tamoxifen. Previous studies have found trastuzumab reduces the risk of relapse in breast cancer patients significantly when given in the adjuvant setting. As a targeted therapy, it has lesser side effects in comparison with conventional chemotherapy. However, the administration of this agent can cause serious side effects. We report on a 45-year-old woman with breast cancer, positive for human epidermal growth factor receptor 2 by immunohistochemistry score 3+, who was treated in an adjuvant setting with trastuzumab and developed severe neutropenia. Twenty seven weeks after initiation of trastuzumab, the patient developed fever, neutropenia (grade 3), and oral stomatitis (grade 4). The maintenance therapy was stopped for approximately 8 weeks. After recovery of the neutrophils, trastuzumab was restarted. Two weeks later, the patient developed the same pattern of toxicity. The situation necessitated the discontinuation of trastuzumab. Thereafter, the neutrophils normalized and the patient's condition improved. To our knowledge, this is the first case in the literature describing severe neutropenia directly related to trastuzumab during the adjuvant maintenance therapy. Clinicians should be aware of this rare side effect of trastuzumab, as stopping this agent can prevent severe complications. PMID- 23804627 TI - A retrospective review of metronidazole and vancomycin in the management of Clostridium difficile infection in patients with hematologic malignancies. AB - BACKGROUND: The incidence and severity of Clostridium difficile infection has significantly increased over the past decade. Although the epidemiology and treatment of C. difficile infection is well elucidated in the non-oncology population, it is poorly understood among cancer patients. This illustrates great concern as the majority of these patients are immunosuppressed, which puts them at higher risk for developing severe disease. Furthermore, suboptimal treatment of C. difficile infection can compromise care of underlying malignancy. Due to limited amount of data, we conducted this study to better ascertain the epidemiology and treatment outcomes of C. difficile infection in a subset of oncology patients at our institution. OBJECTIVES: The primary objective was to assess the incidence and severity of C. difficile infection in patients with hematologic malignancies, including those undergoing hematopoietic stem cell transplant for a hematologic condition. The secondary objectives were to assess: (a) the outcome of C. difficile infection after therapy with metronidazole and/or vancomycin and (b) mortality following C. difficile infection. METHODS: We performed a retrospective study to assess the incidence and severity of C. difficile infection and to evaluate outcomes of therapy with metronidazole and/or vancomycin among adult patients admitted to the Malignant Hematology/Blood and Marrow Transplantation service at our center from January 2009 to 2012. RESULTS: Of the 390 admitted patients during the 3-year study period, the overall incidence of C. difficile infection was 18.7% (n = 73). Forty-six patients (63.0%) were deemed to have mild-moderate C. difficile infection. With regards to outcome of therapy, less exposure to antimicrobial agents was significantly associated with a higher resolution rate (p = 0.0029). Response rates to metronidazole were 53.7%, vancomycin 50%, and combination therapy 38.5%, although no difference in achievement of resolution was found among the three treatment modalities (p = 0.5533). Older patients were more likely to experience recurrent C. difficile infection (p = 0.0007). It was found that 55 patients (75.3%) were alive at 6 months. CONCLUSIONS: These results highlight the high incidence of C. difficile infection in a subset of cancer patients at our institution. Although most patients presented with mild-moderate disease, severity of C. difficile infection in cancer patients may be underestimated due to the frequent presence of neutropenia. This study is the first analysis conducted, which directly compares outcomes of C. difficile infection after therapy with metronidazole, vancomycin, or combination therapy exclusively in patients with hematologic malignancies, including those undergoing hematopoietic stem cell transplant for a hematologic condition. We found no difference in treatment outcomes among metronidazole, vancomycin, or combination therapy. The recommendation from the literature to use metronidazole as the initial drug of choice for mild-moderate C. difficile infection is a reasonable option, although the rate of cure is low. This study highlights the critical need for better treatment options, due to suboptimal response rates to current therapy. Larger scale studies are needed to better understand the epidemiology and management of C. difficile infection in this patient population. PMID- 23804628 TI - Emerging role of lymphatic vessels in reverse cholesterol transport. PMID- 23804629 TI - Very late relapse after discontinuation of antiviral therapy for chronic hepatitis C. AB - Serum HCV RNA rebound beyond 24 weeks after completing hepatitis C therapy has been rarely reported. From 744 patients treated for chronic hepatitis C at our institution, 4 became HCV-RNA-positive again between weeks 36 and 48 post treatment. Epidemiological and phylogenetic analyses supported very late HCV relapse instead of re-infection in two of them. This observation may have important implications in the pathogenesis and therapeutics of HCV infection. PMID- 23804630 TI - Hearing thresholds and FMRI of auditory cortex following eighth cranial nerve surgery. AB - OBJECTIVE: Determine whether auditory cortex (AC) organization changed following eighth cranial nerve surgery in adults with vestibular-cochlear nerve pathologies. We examined whether hearing thresholds before and after surgery correlated with increased ipsilateral activation of AC from the intact ear. STUDY DESIGN: During magnetic resonance imaging sessions before and 3 and 6 months after surgery, subjects listened with the intact ear to noise-like random spectrogram sounds. SETTING: Departments of Radiology and Otolaryngology of Washington University School of Medicine. SUBJECTS AND METHODS: Three patients with acoustic neuromas received Gamma Knife radiosurgery (GK); 1 patient with Meniere's disease and 5 with acoustic neuromas had surgical resections (SR); 2 of the latter also had GK. Hearing thresholds in each ear were for pure tone stimuli from 250 to 8000 Hz before and after surgery (3 and 6 months). At the same intervals, we imaged blood oxygen level-dependent responses to auditory stimulation of the intact ear using an interrupted single-event design. RESULTS: Hearing thresholds in 2 of 3 individuals treated with GK did not change. Five of 6 individuals became unilaterally deaf after SRs. Ipsilateral AC activity was present before surgery in 6 of 9 individuals with ipsilateral spatial extents greater than contralateral in 3 of 9. Greater contralateral predominance was significant especially in left compared to right ear affected individuals, including those treated by GK. CONCLUSION: Lateralization of auditory-evoked responses in AC did not change significantly after surgery possibly due to preexisting sensory loss before surgery, indicating that less than profound loss may prompt cortical reorganization. PMID- 23804631 TI - Randomized study of asunaprevir plus pegylated interferon-alpha and ribavirin for previously untreated genotype 1 chronic hepatitis C. AB - BACKGROUND: Asunaprevir is a selective NS3 protease inhibitor with in vitro activity against HCV genotypes 1 and 4. METHODS: In this Phase IIa double-blind study, treatment-naive HCV genotype-1-infected patients in the United States and France were randomly assigned 1:1:1:1 to placebo or asunaprevir 200 mg twice daily, 600 mg twice daily or 600 mg once daily in combination with pegylated interferon (PEG-IFN)-alpha2a and ribavirin for 48 weeks. The primary efficacy end point was undetectable HCV RNA at weeks 4 and 12 (extended rapid virological response [eRVR]). Other end points included safety and undetectable HCV RNA at 24 weeks post-treatment (24-week sustained virological response [SVR24]). RESULTS: A total of 47 patients were randomized and treated. eRVR was achieved by 75% (9/12), 75% (9/12) and 92% (11/12) of patients in the asunaprevir 200 mg twice daily, 600 mg twice-daily and 600 mg once-daily groups, respectively, versus 0% (0/11) in the placebo group. Corresponding SVR24 rates were 83% (10/12), 83% (10/12) and 92% (11/12) in the asunaprevir groups and 46% (5/11) in the placebo group. There was no virological breakthrough in any asunaprevir group. Following the 12-week analysis, the 600 mg doses were reduced to 200 mg twice daily because of a greater frequency of transaminase elevations at the 600 mg dose. The most common grade 3-4 laboratory abnormalities were consistent with those reported for PEG-IFN and ribavirin. CONCLUSIONS: Asunaprevir plus PEG-IFN and ribavirin achieved higher response rates than placebo plus PEG-IFN and ribavirin, with a tolerable adverse event profile at the 200 mg twice-daily dose. This dose is being evaluated in the Phase IIb and Phase III studies. PMID- 23804632 TI - Latent HIV-1 can be reactivated by cellular superinfection in a Tat-dependent manner, which can lead to the emergence of multidrug-resistant recombinant viruses. AB - The HIV-1 latent reservoir represents an important source of genetic diversity that could contribute to viral evolution and multidrug resistance following latent virus reactivation. This could occur by superinfection of a latently infected cell. We asked whether latent viruses might be reactivated when their host cells are superinfected, and if so, whether they could contribute to the generation of recombinant viruses. Using populations of latently infected Jurkat cells, we found that latent viruses were efficiently reactivated upon superinfection. Pathways leading to latent virus reactivation via superinfection might include gp120-CD4/CXCR4-induced signaling, modulation of the cellular environment by Nef, and/or the activity of Tat produced upon superinfection. Using a range of antiviral compounds and genetic approaches, we show that gp120 and Nef are not required for latent virus reactivation by superinfection, but this process depends on production of functional Tat by the superinfecting virus. In a primary cell model of latency in unstimulated CD4 T cells, superinfection also led to latent virus reactivation. Drug-resistant latent viruses were also reactivated following superinfection in Jurkat cells and were able to undergo recombination with the superinfecting virus. Under drug-selective pressure, this generated multidrug-resistant recombinants that were identified by unique restriction digestion band patterns and by population-level sequencing. During conditions of poor drug adherence, treatment interruption or treatment failure, or in drug-impermeable sanctuary sites, reactivation of latent viruses by superinfection or other means could provide for the emergence or spread of replicatively fit viruses in the face of strong selective pressures. PMID- 23804633 TI - Efficacy of parainfluenza virus 5 mutants expressing hemagglutinin from H5N1 influenza A virus in mice. AB - Parainfluenza virus 5 (PIV5) is a promising viral vector for vaccine development. PIV5 is safe, stable, efficacious, cost-effective to produce and, most interestingly, it overcomes preexisting antivector immunity. We have recently reported that PIV5 expressing the hemagglutinin (HA) from highly pathogenic avian influenza (HPAI) virus H5N1 (PIV5-H5) provides sterilizing immunity against lethal doses of HPAI H5N1 infection in mice. It is thought that induction of apoptosis can lead to enhanced antigen presentation. Previously, we have shown that deleting the SH gene and the conserved C terminus of the V gene in PIV5 results in mutant viruses (PIV5DeltaSH and PIV5VDeltaC) that enhance induction of apoptosis. In this study, we inserted the HA gene of H5N1 into PIV5DeltaSH (PIV5DeltaSH-H5) or PIV5VDeltaC (PIV5VDeltaC-H5) and compared their efficacies as vaccine candidates to PIV5-H5. We have found that PIV5DeltaSH-H5 induced the highest levels of anti-HA antibodies, the strongest T cell responses, and the best protection against an H5N1 lethal challenge in mice. These results suggest that PIV5DeltaSH is a better vaccine vector than wild-type PIV5. PMID- 23804634 TI - Measles virus nonstructural C protein modulates viral RNA polymerase activity by interacting with host protein SHCBP1. AB - Most viruses possess strategies to circumvent host immune responses. The measles virus (MV) nonstructural C protein suppresses the interferon response, thereby allowing efficient viral growth, but its detailed mechanism has been unknown. We identified Shc Src homology 2 domain-binding protein 1 (SHCBP1) as one of the host proteins interacting with the C protein. Knockdown of SHCBP1 using a short hairpin RNA greatly reduced MV growth. SHCBP1 was found to be required for viral RNA synthesis in the minigenome assay and to bind to the MV phosphoprotein, a subunit of the viral RNA polymerase. A stretch of 12 amino acid residues in the C protein were sufficient for SHCBP1 binding, and the peptide containing these 12 residues could suppress MV RNA synthesis, like the full-length C protein. The central region of SHCBP1 was found to bind to the C protein, as well as the phosphoprotein, but the two viral proteins did not compete for SHCBP1 binding. Our results indicate that the C protein modulates MV RNA polymerase activity by binding to the host protein SHCBP1. SHCBP1 may be exploited as a target of antiviral compounds. PMID- 23804635 TI - Palmitoylation on conserved and nonconserved cysteines of murine IFITM1 regulates its stability and anti-influenza A virus activity. AB - The interferon-induced transmembrane proteins (IFITMs) restrict infection by numerous viruses, yet the importance and regulation of individual isoforms remains unclear. Here, we report that murine IFITM1 (mIFITM1) is palmitoylated on one nonconserved cysteine and three conserved cysteines that are required for anti-influenza A virus activity. Additionally, palmitoylation of mIFITM1 regulates protein stability by preventing proteasomal degradation, and modification of the nonconserved cysteine at the mIFITM1 C terminus supports an intramembrane topology with mechanistic implications. PMID- 23804636 TI - A cholesterol tag at the N terminus of the relatively broad-spectrum fusion inhibitory peptide targets an earlier stage of fusion glycoprotein activation and increases the peptide's antiviral potency in vivo. AB - In previous work, we designed peptides that showed potent inhibition of Newcastle disease virus (NDV) and infectious bronchitis virus (IBV) infections in chicken embryos. In this study, we demonstrate that peptides modified with cholesterol or 3 U of polyethylene glycol (PEG3) conjugated to the peptides' N termini showed even more promising antiviral activities when tested in animal models. Both cholesterol- and cholesterol-PEG3-tagged peptides were able to protect chicken embryos from infection with different serotypes of NDV and IBV when administered 12 h prior to virus inoculation. In comparison, the untagged peptides required intervention closer to the time of viral inoculation to achieve a similar level of protection. Intramuscular injection of cholesterol-tagged peptide at 1.6 mg/kg 1 day before virus infection and then three times at 3-day intervals after viral inoculation protected 70% of the chickens from NDV infection. We further demonstrate that the cholesterol-tagged peptide has an in vivo half-life greater than that of untagged peptides. It also has the potential to cross the blood brain barrier to enter the avian central nervous system (CNS). Finally, we show that the cholesterol-tagged peptide could play a role before the viral fusion peptide's insertion into the host cell and thereby target an earlier stage of fusion glycoprotein activation. Our findings are of importance for the further development of antivirals with broad-spectrum protective effects. PMID- 23804637 TI - Glycoproteins gE and gI are required for efficient KIF1A-dependent anterograde axonal transport of alphaherpesvirus particles in neurons. AB - Alphaherpesviruses, including pseudorabies virus (PRV), spread directionally within the nervous systems of their mammalian hosts. Three viral membrane proteins are required for efficient anterograde-directed spread of infection in neurons, including Us9 and a heterodimer composed of the glycoproteins gE and gI. We previously demonstrated that the kinesin-3 motor KIF1A mediates anterograde directed transport of viral particles in axons of cultured peripheral nervous system (PNS) neurons. The PRV Us9 protein copurifies with KIF1A, recruiting the motor to transport vesicles, but at least one unidentified additional viral protein is necessary for this interaction. Here we show that gE/gI are required for efficient anterograde transport of viral particles in axons by mediating the interaction between Us9 and KIF1A. In the absence of gE/gI, viral particles containing green fluorescent protein (GFP)-tagged Us9 are assembled in the cell body but are not sorted efficiently into axons. Importantly, we found that gE/gI are necessary for efficient copurification of KIF1A with Us9, especially at early times after infection. We also constructed a PRV recombinant that expresses a functional gE-GFP fusion protein and used affinity purification coupled with mass spectrometry to identify gE-interacting proteins. Several viral and host proteins were found to associate with gE-GFP. Importantly, both gI and Us9, but not KIF1A, copurified with gE-GFP. We propose that gE/gI are required for efficient KIF1A mediated anterograde transport of viral particles because they indirectly facilitate or stabilize the interaction between Us9 and KIF1A. PMID- 23804638 TI - Coagulation factor binding orientation and dimerization may influence infectivity of adenovirus-coagulation factor complexes. AB - Adenoviruses (Ads) are promising vectors for therapeutic interventions in humans. When injected into the bloodstream, Ad vectors can bind several vitamin K dependent blood coagulation factors, which contributes to virus sequestration in the liver by facilitating transduction of hepatocytes. Although both coagulation factors FVII and FX bind the hexon protein of human Ad serotype 5 (HAdv5) with a very high affinity, only FX appears to play a role in mediating Ad-hepatocyte transduction in vivo. To understand the discrepancy between efficacy of FVII binding to hexon and its apparently poor capacity for supporting virus cell entry, we analyzed the HAdv5-FVII complex by using high-resolution cryo-electron microscopy (cryo-EM) followed by molecular dynamic flexible fitting (MDFF) simulations. The results indicate that although hexon amino acids T423, E424, and T425, identified earlier as critical for FX binding, are also involved in mediating binding of FVII, the FVII GLA domain sits within the surface-exposed hexon trimer depression in a different orientation from that found for FX. Furthermore, we found that when bound to hexon, two proximal FVII molecules interact via their serine protease (SP) domains and bury potential heparan sulfate proteoglycan (HSPG) receptor binding residues within the dimer interface. In contrast, earlier cryo-EM studies of the Ad-FX interaction showed no evidence of dimer formation. Dimerization of FVII bound to Ad may be a contributing mechanistic factor for the differential infectivity of Ad-FX and Ad-FVII complexes, despite high-affinity binding of both these coagulation factors to the virus. PMID- 23804639 TI - Histo-blood group antigen-like substances of human enteric bacteria as specific adsorbents for human noroviruses. AB - Histo-blood group antigens (HBGAs) have been suggested to be receptors or coreceptors for human noroviruses (HuNoVs) expressed on the intestinal epithelium. We isolated an enteric bacterium strain (SENG-6), closely related to Enterobacter cloacae, bearing HBGA-like substances from a fecal sample of a healthy individual by using a biopanning technique with anti-HBGA antibodies. The binding capacities of four genotypes of norovirus-like particles (NoVLPs) to Enterobacter sp. SENG-6 cells were confirmed by enzyme-linked immunosorbent assay (ELISA). Transmission electron microscopy demonstrated that NoVLPs bound mainly to extracellular polymeric substances (EPS) of Enterobacter sp. SENG-6, where the HBGA-like substances were localized. EPS that contained HBGA-like substances extracted from Enterobacter sp. SENG-6 was shown by enzyme-linked immunosorbent assay (ELISA) to be capable of binding to NoVLPs of a GI.1 wild-type strain (8fIIa) and a GII.6 strain that can recognize A antigen but not to an NoVLP GI.1 mutant strain (W375A) that loses the ability to bind to A antigen. Enzymatic cleavage of terminal N-acetyl-galactosamine residues in the bacterial EPS weakened bacterial EPS binding to the GI.1 wild-type strain (8fIIa). These results indicate that A-like substances in the bacterial EPS play a key role in binding to NoVLPs. Since the specific binding of HuNoVs to HBGA-positive enteric bacteria is likely to affect the transmission and infection processes of HuNoVs in their hosts and in the environment, further studies of human enteric bacteria and their binding capacity to HuNoVs will provide a new scientific platform for understanding interactions between two types of microbes that were previously regarded as biologically unrelated. PMID- 23804640 TI - Expression strategy of Aedes albopictus densovirus. AB - The transcription map of the Aedes albopictus densovirus (AalDNV) brevidensovirus was identified by Northern blotting, rapid amplification of cDNA ends (RACE) analysis, and RNase protection assays. AalDNV produced mRNAs of 3,359 (NS1), 3,345 (NS2), and 1,246 (VP) nucleotides. The two overlapping P7/7.4 NS promoters employed closely located alternate transcription initiation sites, positioned at either side of the NS1 initiation codon. All NS mRNAs coterminated with VP mRNA. All promoters, explored using luciferase assays, were functional in insect and human cell lines. PMID- 23804641 TI - Aberrant virion assembly and limited glycoprotein C production in varicella zoster virus-infected neurons. AB - Highly pure (>95%) terminally differentiated neurons derived from pluripotent stem cells appear healthy at 2 weeks after infection with varicella-zoster virus (VZV), and the cell culture medium contains no infectious virus. Analysis of the healthy-appearing neurons revealed VZV DNA, transcripts, and proteins corresponding to the VZV immediate early, early, and late kinetic phases of replication. Herein, we further characterized virus in these neuronal cells, focusing on (i) transcription and expression of late VZV glycoprotein C (gC) open reading frame 14 (ORF14) and (ii) ultrastructural features of virus particles in neurons. The analysis showed that gC was not expressed in most infected neurons and gC expression was markedly reduced in a minority of VZV-infected neurons. In contrast, expression of the early-late VZV gE glycoprotein (ORF68) was abundant. Transcript analysis also showed decreased gC transcription compared with gE. Examination of viral structure by high-resolution transmission electron microscopy revealed fewer viral particles than typically observed in cells productively infected with VZV. Furthermore, viral particles were more aberrant, in that most capsids in the nuclei lacked a dense core and most enveloped particles in the cytoplasm were light particles (envelopes without capsids). Together, these results suggest a considerable deficiency in late-phase replication and viral assembly during VZV infection of neurons in culture. PMID- 23804642 TI - Complex reassortment of multiple subtypes of avian influenza viruses in domestic ducks at the Dongting Lake Region of China. AB - To gain insight into the ecology of avian influenza viruses (AIV), we conducted active influenza virus surveillance in domestic ducks on farms located on the flyway of migratory birds in the Dongting Lake region of Hunan Province, China, from winter 2011 until spring 2012. Specimens comprising 3,030 duck swab samples and 1,010 environmental samples were collected from 101 duck farms. We isolated AIV of various HA subtypes, including H3, H4, H5, H6, H9, H10, H11, and H12. We sequenced the entire coding sequences of the genomes of 28 representative isolates constituting 13 specific subtypes. When the phylogenetic relationships among these isolates were examined, we observed that extensive reassortment events had occurred. Among the 28 Dongting Lake viruses, 21 genotypes involving the six internal genes were identified. Furthermore, we identified viruses or viral genes introduced from other countries, viral gene segments of unknown origin, and a novel HA/NA combination. Our findings emphasize the importance of farmed domestic ducks in the Dongting Lake region to the genesis and evolution of AIV and highlight the need for continued surveillance of domestic ducks in this region. PMID- 23804643 TI - Comparative analysis of gO isoforms reveals that strains of human cytomegalovirus differ in the ratio of gH/gL/gO and gH/gL/UL128-131 in the virion envelope. AB - Herpesvirus glycoprotein complex gH/gL provides a core entry function through interactions with the fusion protein gB and can also influence tropism through receptor interactions. The Epstein-Barr virus gH/gL and gH/gL/gp42 serve both functions for entry into epithelial and B cells, respectively. Human cytomegalovirus (HCMV) gH/gL can be bound by the UL128-131 proteins or gO. The phenotypes of gO and UL128-131 mutants suggest that gO-gH/gL interactions are necessary for the core entry function on all cell types, whereas the binding of UL128-131 to gH/gL likely relates to a distinct receptor-binding function for entry into some specific cell types (e.g., epithelial) but not others (e.g., fibroblasts and neurons). There are at least eight isoforms of gO that differ by 10 to 30% of amino acids, and previous analysis of two HCMV strains suggested that some isoforms of gO function like chaperones, disassociating during assembly to leave unbound gH/gL in the virion envelope, while others remain bound to gH/gL. For the current report, we analyzed the gH/gL complexes present in the virion envelope of several HCMV strains, each of which encodes a distinct gO isoform. Results indicate that all strains of HCMV contain stable gH/gL/gO trimers and gH/gL/UL128-131 pentamers and little, if any, unbound gH/gL. TR, TB40/e, AD169, and PH virions contained vastly more gH/gL/gO than gH/gL/UL128 131, whereas Merlin virions contained mostly gH/gL/UL128-131, despite abundant unbound gO remaining in the infected cells. Suppression of UL128-131 expression during Merlin replication dramatically shifted the ratio toward gH/gL/gO. These data suggest that Merlin gO is less efficient than other gO isoforms at competing with UL128-131 for binding to gH/gL. Thus, gO diversity may influence the pathogenesis of HCMV through effects on the assembly of the core versus tropism gH/gL complexes. PMID- 23804644 TI - The bracovirus genome of the parasitoid wasp Cotesia congregata is amplified within 13 replication units, including sequences not packaged in the particles. AB - The relationship between parasitoid wasps and polydnaviruses constitutes one of the few known mutualisms between viruses and eukaryotes. Viral particles are injected with the wasp eggs into parasitized larvae, and the viral genes thus introduced are used to manipulate lepidopteran host physiology. The genome packaged in the particles is composed of 35 double-stranded DNA (dsDNA) circles produced in wasp ovaries by amplification of viral sequences from proviral segments integrated in tandem arrays in the wasp genome. These segments and their flanking regions within the genome of the wasp Cotesia congregata were recently isolated, allowing extensive mapping of amplified sequences. The bracovirus DNAs packaged in the particles were found to be amplified within more than 12 replication units. Strikingly, the nudiviral cluster, the genes of which encode particle structural components, was also amplified, although not encapsidated. Amplification of bracoviral sequences was shown to involve successive head-to head and tail-to-tail concatemers, which was not expected given the nudiviral origin of bracoviruses. PMID- 23804645 TI - Immunological and virological analyses of rhesus macaques immunized with chimpanzee adenoviruses expressing the simian immunodeficiency virus Gag/Tat fusion protein and challenged intrarectally with repeated low doses of SIVmac. AB - Human adenovirus (AdHu)-based candidate AIDS vaccine can provide protection from simian immunodeficiency virus (SIV) transmission and disease progression. However, their potential use may be limited by widespread preexisting immunity to the vector. In contrast, preexisting immunity to chimpanzee adenoviruses (AdC) is relatively rare. In this study, we utilized two regimens of prime-boost immunizations with AdC serotype SAd-V23 (also called AdC6) and SAd-V24 (also called AdC7) expressing SIV Gag/Tat to test their immunogenicity and ability to protect rhesus macaques (RMs) from a repeated low-dose SIVmac239 challenge. Both AdC6 followed by AdC7 (AdC6/7) and AdC7 followed by AdC6 (AdC7/6) induced robust SIV Gag/Tat-specific T cell responses as measured by tetramer staining and functional assays. However, no significant protection from SIV transmission was observed in either AdC7/6- or AdC7/6-vaccinated RMs. Interestingly, in the RMs showing breakthrough infections, AdC7/6-SIV immunization was associated with a transient but significant (P = 0.035 at day 90 and P = 0.033 at day 120 postinfection) reduction in the setpoint viral load compared to unvaccinated controls. None of the measured immunological markers (i.e., number or functionality of SIV-specific CD8(+) and CD4(+) T cell responses and level of activated and/or CCR5(+) CD4(+) target cells) at the time of challenge correlated with protection from SIV transmission in the AdC-SIV-vaccinated RMs. The robust immunogenicity observed in all AdC-immunized RMs and the transient signal of protection from SIV replication exhibited by AdC7/6-vaccinated RMs even in the absence of any envelope immunogen suggest that AdC-based vectors may represent a promising platform for candidate AIDS vaccines. PMID- 23804646 TI - Interferon regulatory factor 4 is activated through c-Src-mediated tyrosine phosphorylation in virus-transformed cells. AB - The importance of the oncogenic transcription factor interferon regulatory factor 4 (IRF4) in hematological malignancies has been increasingly recognized. We have previously identified the B cell integration cluster (BIC), the gene encoding miR 155, as the first microRNA (miRNA)-encoding gene transcriptionally targeted by IRF4 in virus-transformed cancer cells. Activation of IRFs is prerequisite for their functions. However, how IRF4 is activated in cancer is an open question. Our phosphoproteome profiling has identified several tyrosine phosphorylation sites on IRF4 in Epstein-Barr virus (EBV)-transformed cells. Further, we show here that c-Src dramatically stimulates IRF4 phosphorylation and activity and that Y61 and Y124 are two key sites responding to c-Src-mediated activation. Consistently, c-Src is constitutively expressed and active in EBV-transformed cells. However, c-Src is unlikely to be a direct kinase for IRF4. Furthermore, we have a polyclonal antibody specific to phospho-IRF4(Y121/124) developed in rabbit. We have further shown that inhibition of c-Src activity reduces p IRF4(Y121/124) and significantly represses transcription of the IRF4 target BIC in EBV-transformed cells. Our results therefore, for the first time, demonstrate that IRF4 is phosphorylated and activated through a c-Src-mediated pathway in virus-transformed cells. These findings will improve our understanding of IRF4 in neoplasia and will provide profound insights into the interaction of oncogenic viruses with IRF4 in the development of hematological malignancies. PMID- 23804647 TI - The role of protein kinase A regulation of the E6 PDZ-binding domain during the differentiation-dependent life cycle of human papillomavirus type 18. AB - Human papillomavirus (HPV) E6 proteins of high-risk alpha types target a select group of PSD95/DLG1/ZO1 (PDZ) domain-containing proteins by using a C-terminal PDZ-binding motif (PBM), an interaction that can be negatively regulated by phosphorylation of the E6 PBM by protein kinase A (PKA). Here, we have mutated the canonical PKA recognition motif that partially overlaps with the E6 PBM in the HPV18 genome (E6153PKA) and compared the effect of this mutation on the HPVl8 life cycle in primary keratinocytes with the wild-type genome and with a second mutant genome that lacks the E6 PBM (E6DeltaPDZ). Loss of PKA recognition of E6 was associated with increased growth of the genome-containing cells relative to cells carrying the wild-type genome, and upon stratification, a more hyperplastic phenotype, with an increase in the number of S-phase competent cells in the upper suprabasal layers, while the opposite was seen with the E6DeltaPDZ genome. Moreover, the growth of wild-type genome-containing cells was sensitive to changes in PKA activity, and these changes were associated with increased phosphorylation of the E6 PBM. In marked contrast to E6DeltaPDZ genomes, the E6153PKA mutation exhibited no deleterious effects on viral genome amplification or expression of late proteins. Our data suggest that the E6 PBM function is differentially regulated by phosphorylation in the HPV18 life cycle. We speculate that perturbation of protein kinase signaling pathways could lead to changes in E6 PBM function, which in turn could have a bearing on tumor promotion and progression. PMID- 23804648 TI - The membrane-proximal "stem" region increases the stability of the flavivirus E protein postfusion trimer and modulates its structure. AB - The flavivirus fusion protein E contains a "stem" region which is hypothesized to be crucial for driving fusion. This sequence element connects the ectodomain to the membrane anchor, and its structure in the trimeric postfusion conformation is still poorly defined. Using E trimers of tick-borne encephalitis virus with stem truncations of different lengths, we show that the N-terminal part of the stem increases trimer stability and also modulates the trimer structure outside the stem interaction site. PMID- 23804649 TI - Piloting a psycho-social intervention for incarcerated women with trauma histories: lessons learned and future recommendations. AB - Trauma and related mental health disorders are common among incarcerated women, but empirically sound mental health interventions are lacking in prisons. Implementing such interventions is fraught with legal and logistical barriers. These barriers can be particularly detrimental for trauma-specific interventions given the unique needs of trauma survivors, yet there is little documentation of these issues or how to address them. This study describes a pilot study of an 8 week, strengths-based, trauma-focused intervention for 26 incarcerated women. Women reported considerable mental health problems and trauma. The study highlights the importance of adapting stringent research methodologies for prison based trauma interventions. For instance, women with trauma were reluctant to participate in an intervention advertised as trauma-based. Moreover, a randomized wait list control design was unfeasible because women wanted the support of their friends when discussing trauma and could not control their schedules 9 weeks in advance. Ultimately, this work may inform future efforts to implement effective trauma-based interventions behind prison walls. PMID- 23804650 TI - Manufacture of a weakly denatured collagen fiber scaffold with excellent biocompatibility and space maintenance ability. AB - Although collagen scaffolds have been used for regenerative medicine, they have insufficient mechanical strength. We made a weakly denatured collagen fiber scaffold from a collagen fiber suspension (physiological pH 7.4) through a process of freeze drying and denaturation with heat under low pressure (1 * 10( 1) Pa). Heat treatment formed cross-links between the collagen fibers, providing the scaffold with sufficient mechanical strength to maintain the space for tissue regeneration in vivo. The scaffold was embedded under the back skin of a rat, and biocompatibility and space maintenance ability were examined after 2 weeks. These were evaluated by using the ratio of foreign body giant cells and thickness of the residual scaffold. A weakly denatured collagen fiber scaffold with moderate biocompatibility and space maintenance ability was made by freezing at -10 degrees C, followed by denaturation at 140 degrees C for 6 h. In addition, the direction of the collagen fibers in the scaffold was adjusted by cooling the suspension only from the bottom of the container. This process increased the ratio of cells that infiltrated into the scaffold. A weakly denatured collagen fiber scaffold thus made can be used for tissue regeneration or delivery of cells or proteins to a target site. PMID- 23804651 TI - Polycaprolactone nanofiber interspersed collagen type-I scaffold for bone regeneration: a unique injectable osteogenic scaffold. AB - There is an increasing demand for an injectable cell coupled three-dimensional (3D) scaffold to be used as bone fracture augmentation material. To address this demand, a novel injectable osteogenic scaffold called PN-COL was developed using cells, a natural polymer (collagen type-I), and a synthetic polymer (polycaprolactone (PCL)). The injectable nanofibrous PN-COL is created by interspersing PCL nanofibers within pre-osteoblast cell embedded collagen type-I. This simple yet novel and powerful approach provides a great benefit as an injectable bone scaffold over other non-living bone fracture stabilization polymers, such as polymethylmethacrylate and calcium content resin-based materials. The advantages of injectability and the biomimicry of collagen was coupled with the structural support of PCL nanofibers, to create cell encapsulated injectable 3D bone scaffolds with intricate porous internal architecture and high osteoconductivity. The effects of PCL nanofiber inclusion within the cell encapsulated collagen matrix has been evaluated for scaffold size retention and osteocompatibility, as well as for MC3T3-E1 cells osteogenic activity. The structural analysis of novel bioactive material proved that the material is chemically stable enough in an aqueous solution for an extended period of time without using crosslinking reagents, but it is also viscous enough to be injected through a syringe needle. Data from long-term in vitro proliferation and differentiation data suggests that novel PN-COL scaffolds promote the osteoblast proliferation, phenotype expression, and formation of mineralized matrix. This study demonstrates for the first time the feasibility of creating a structurally competent, injectable, cell embedded bone tissue scaffold. Furthermore, the results demonstrate the advantages of mimicking the hierarchical architecture of native bone with nano- and micro-size formation through introducing PCL nanofibers within macron-size collagen fibers and in promoting osteoblast phenotype progression for bone regeneration. PMID- 23804654 TI - The patient-centered medical home: putting the patient at the center of care. PMID- 23804652 TI - The intracellular fate of zonula occludens 2 is regulated by the phosphorylation of SR repeats and the phosphorylation/O-GlcNAcylation of S257. AB - Zona occludens 2 (ZO-2) has a dual localization. In confluent epithelia, ZO-2 is present at tight junctions (TJs), whereas in sparse proliferating cells it is also found at the nucleus. Previously we demonstrated that in sparse cultures, newly synthesized ZO-2 travels to the nucleus before reaching the plasma membrane. Now we find that in confluent cultures newly synthesized ZO-2 goes directly to the plasma membrane. Epidermal growth factor induces through AKT activation the phosphorylation of the kinase for SR repeats, serine arginine protein kinase 1, which in turn phosphorylates ZO-2, which contains 16 SR repeats. This phosphorylation induces ZO-2 entry into the nucleus and accumulation in speckles. ZO-2 departure from the nucleus requires intact S257, and stabilizing the beta-O-linked N-acetylglucosylation (O-GlcNAc) of S257 with O (2-acetamido-2-deoxy-d-glucopyranosylidene)amino-N-phenylcarbamate, an inhibitor of O-GlcNAcase, triggers nuclear exportation and proteosomal degradation of ZO-2. At the plasma membrane ZO-2 is not O-GlcNAc, and instead, as TJs mature, it becomes phosphorylated at S257 by protein kinase Czeta. This late phosphorylation of S257 is required for the correct cytoarchitecture to develop, as cells transfected with ZO-2 mutant S257A or S257E form aberrant cysts with multiple lumens. These results reveal novel posttranslational modifications of ZO-2 that regulate the intracellular fate of this protein. PMID- 23804655 TI - Health beliefs and their associations with dietary intake, exercise, and metabolic syndrome characteristics in an overweight and obese family medicine population. AB - Increasing prevalences of obesity and type 2 diabetes (T2DM) increase cardiovascular risks. Since poor diet and inadequate exercise are primary behavioral causes of obesity and T2DM, our objective was to examine health beliefs and associations with diet, exercise, and metabolic syndrome (MetSyndr) characteristics. A total of 117 overweight and obese family medicine patients enrolled in this study. Subjects completed questionnaires for health beliefs and vegetable, fruit, and fat intake; other data were from medical charts. Seventy four percent of subjects were women; 69% were black, 72% were obese, 36% were hypertensive, 22% had T2DM, and 23% had hypertriglyceridemia. MetSyndr subjects had significantly higher triglyceride levels and a higher percentage of hypertension and T2DM. Although not statistically significant, overweight subjects without MetSyndr had higher vegetable and fruit intake and lower fat intake than obese subjects without MetSyndr and subjects with MetSyndr. More exercise was associated with less MetSyndr and less obesity; however, this also was not statistically significant. For health beliefs, there were no significant differences between subjects with MetSyndr versus those without MetSyndr or for subjects without MetSyndr who were obese versus those who were overweight. However, for subjects with above-median nutrition scores and exercise, scores were significantly higher for the health belief "certainty" compared to those with below-median scores (P < .0001). This research suggests that health beliefs and specifically less certainty may be a useful marker for individuals who require more education and/or training. Effective programs that address certainty may promote better diets, more exercise, and reduced cardiovascular risk. PMID- 23804653 TI - Specialized sorting of GLUT4 and its recruitment to the cell surface are independently regulated by distinct Rabs. AB - Adipocyte glucose uptake in response to insulin is essential for physiological glucose homeostasis: stimulation of adipocytes with insulin results in insertion of the glucose transporter GLUT4 into the plasma membrane and subsequent glucose uptake. Here we establish that RAB10 and RAB14 are key regulators of GLUT4 trafficking that function at independent, sequential steps of GLUT4 translocation. RAB14 functions upstream of RAB10 in the sorting of GLUT4 to the specialized transport vesicles that ferry GLUT4 to the plasma membrane. RAB10 and its GTPase-activating protein (GAP) AS160 comprise the principal signaling module downstream of insulin receptor activation that regulates the accumulation of GLUT4 transport vesicles at the plasma membrane. Although both RAB10 and RAB14 are regulated by the GAP activity of AS160 in vitro, only RAB10 is under the control of AS160 in vivo. Insulin regulation of the pool of RAB10 required for GLUT4 translocation occurs through regulation of AS160, since activation of RAB10 by DENND4C, its GTP exchange factor, does not require insulin stimulation. PMID- 23804656 TI - Moving from street to home: health status of entrants to a housing first program. AB - Housing First (HF) is an evidence-based practice that ends chronic homelessness for individuals with serious mental illness by providing immediate access to permanent independent housing and team-based community supports. Little is known about the health status of homeless individuals entering HF programs. Through a cross-sectional analysis, this paper reports on the chronic physical disease burden of people entering a newly established HF program and examines whether these individuals recognize and request support for ongoing health-related issues. The authors' evaluation confirmed significantly higher rates of chronic disease (60%) and fair/poor self-reported health status (47%) than the general urban population of Philadelphia. The majority of clients reported they wanted to address both medical (67%) and mental health (68%) problems, but a much lower percentage reported wanting to reduce substance use (23%) or take psychiatric medications (25%). The authors conclude that formerly homeless entrants to HF programs have a high burden of chronic disease with complex health-related needs. Additionally, these individuals look to the program for health-related assistance. As the HF model is disseminated throughout the United States to end chronic homelessness, these findings support the development of flexible, integrated, person-centered health services within the HF service delivery system as a potentially effective method to address complex health needs. PMID- 23804657 TI - Impact of a housing first program on health utilization outcomes among chronically homeless persons. AB - The authors examined the impact of a Housing First program on the use of specific health services, detoxification services, and criminal activity of long-term homeless individuals. The study sample consisted of eligible members of the inception cohort (18 enrollees) in the Single Adults Residential Assistance program (SARA) in Minneapolis, Minnesota. Analyses examined participant housing stability after enrollment in SARA and compared the use of a county medical center, detoxification programs, and criminal activity in the 2 years before and after enrollment in SARA. Only 1 of the 18 enrollees studied experienced homelessness during the 2-year follow-up after enrollment in SARA. There was a significant reduction in the amount of criminal activity in the 2-year period after SARA enrollment. The direction of association observed for other service uses remained consistent with expectations in existing literature, but were not statistically significant. Supportive housing for chronically homeless individuals may be successful at decreasing homelessness among this fragile population and may help reduce criminal activity. PMID- 23804658 TI - The role of community health workers in combating type 2 diabetes in the rio grande valley. AB - The purpose of this study was to determine the effectiveness of the use of community health workers (CHWs, aka promotoras de salud in Spanish) in the control of type 2 diabetes (diabetes mellitus) in the Rio Grande Valley (RGV). Known from the literature as "a disease of the 21st century" and being the third leading cause of death in the United States, type 2 diabetes is a very common disease in the RGV because of its predominantly Mexican American population, a group genetically vulnerable to the disease. Unlike prior studies that examined the overall effectiveness of the CHW model, the authors used registered CHWs as primary diabetes educators. Another innovation of this study was the authors monitored a wide range of biologic (HbA1c and body mass index [BMI]) and behavioral (diabetes knowledge, self-efficacy, self-management activities scores) outcomes. The research hypothesis was that the educational service provided by CHWs to the diabetic patients would assist them in controlling their disease. The design of the study was experimental. The target population consisted of Mexican American adults from RGV diagnosed with type 2 diabetes and willing to participate. The intervention group received monthly visits from CHWs. The results showed a significant improvement after one year of intervention in all outcomes, except BMI, in the experimental group. PMID- 23804659 TI - Classifying medication use in clinical research. AB - BACKGROUND: Medication use data are usually collected in clinical research. Yet no standardized method for categorizing these exists, either for sample description or for the study of medication use as a variable. OBJECTIVE: The present investigation was designed to develop a simple, empirically based classification scheme for medication use categorization. METHOD: The authors used factor analysis to reduce the number of possible medication groupings. This permitted a pattern of medication usage to emerge that appeared to characterize specific clinical constellations. To illustrate the technique's potential, the authors applied this classification system to samples where sleep disorders are prominent: chronic fatigue syndrome and sleep apnea. RESULTS: The authors' classification approach resulted in 5 factors that appear to cohere in a logical fashion. These were labeled Cardiovascular or Metabolic Syndrome Medication, Symptom Relief Medication, Psychotropic Medication, Preventative Medication, and Hormonal Medication. CONCLUSIONS: The findings show that medication profile varies according to clinical sample. The medication profile for participants with sleep apnea reflects known comorbid conditions; the medication profile associated with chronic fatigue syndrome appears to reflect the common perception of this condition as a psychogenic disorder. PMID- 23804660 TI - Prenatal Care Barriers in an Inner-city Neighborhood of Houston, Texas. AB - The objective of this qualitative pilot study was to explore barriers to prenatal care among women (aged 17 to 30 years) with pregnancy experience who resided in an underserved and predominantly African American neighborhood in Houston, Texas. The authors conducted 5 focus group discussions with, and collected demographic information from, the 32 participants. Discussions were audiotaped, transcribed, and analyzed manually. The data analysis suggested 5 key barriers to prenatal care services among the study populations: unplanned pregnancy, lack of information, lack of support system (eg, lack of emotional and instrumental support from family members), psychosocial challenges (eg, emotions and stress related to the condition of pregnancy), and economic hardships (eg, lack of money to maintain healthy pregnancy and basic needs). Addressing the causes of unplanned pregnancy, such as low risk perception, behavior-related causes, and attitude toward pregnancy, may be helpful to improve the utilization of prenatal care by underserved women. PMID- 23804661 TI - Pain management and the primary care encounter: opportunities for quality improvement. AB - PURPOSE: The purpose of this pilot study was to create a comprehensive pain management educational toolkit for the primary care physician that offers guidance on current standards of care and quality improvement techniques to help curb educational and quality gaps in managing patients with pain. SCOPE: Pain often goes undetected in the primary care encounter, and when acknowledged, is often undertreated. METHODS: This pilot study utilized a pre-/postintervention design. Data were collected using a unique survey developed for this project. The intervention consisted of an online educational toolkit designed to improve the quality of care primary care physicians offer their patients with pain. RESULTS: Results demonstrated statistically significant improvements from pre- to postintervention for various measures including the following: (1) reported comfort in managing patients with cancer and fibromyalgia; (2) number of physicians who set functional goals for patients with pain; (3) screening for depression, substance abuse, and alcoholism; (4) documentation of efficacy of nonpharmacologic modalities; and (5) knowledge scores. CONCLUSION: The improvements seen from pre- to postintervention suggest the online toolkit had a positive impact on physician knowledge, practice patterns, and behavior toward pain management. PMID- 23804662 TI - Preliminary benefits of information therapy. AB - Information therapy (ie, information prescriptions) is a potential new tool for primary care physicians that could improve patient knowledge, decision making, and communication between physicians and patients. Although patients have access to numerous health-related articles online, the availability of this health information does not ensure improved knowledge or better health decisions by patients. Communication between patients and physicians is often limited and messages are commonly misunderstood. Information therapy offers a potential solution for the primary care environment. METHOD: Two employers, in different geographical locations of the Midwest, offered the MedEncentive program to employees and their dependents as a part of their health plans. This program also offers primary care physicians the opportunity to prescribe information to patients during office visits. Patients were then eligible to participate in this information therapy (Ix) through a Web-based platform. Both primary care physicians and patients were financially incentivized for participation. Physicians received a monetary stipend for prescribing evidence-based information therapy and patients were refunded part or all of their copayment for reading their condition-specific Ix and answering questions about knowledge, compliance, health status, and satisfaction with the care they received compared to the evidence from the Ix. RESULTS: Patients received information therapy from their primary care physicians and reported a high level of satisfaction with care, improved health status, and compliance with pharmaceutical prescriptions. DISCUSSION: This case study had a number of limitations and as such the results should be interpreted with caution. However, there is a need for an immediate solution as patient satisfaction with their care and compliance with pharmaceutical prescriptions continue to decrease, despite the amounts of widely available health information. These preliminary findings suggest that information therapy through a Web-based platform, augmented by doctor-patient mutual accountability, could be part of the solution for the current ambulatory health care environment. PMID- 23804663 TI - Identifying patients with ischemic heart disease in an electronic medical record. AB - PURPOSE: Increasing utilization of electronic medical records (EMRs) presents an opportunity to efficiently measure quality indicators in primary care. Achieving this goal requires the development of accurate patient-disease registries. This study aimed to develop and validate an algorithm for identifying patients with ischemic heart disease (IHD) within the EMR. METHODS: An algorithm was developed to search the unstructured text within the medical history fields in the EMR for IHD-related terminology. This algorithm was applied to a 5% random sample of adult patient charts (n = 969) drawn from a convenience sample of 17 Ontario family physicians. The accuracy of the algorithm for identifying patients with IHD was compared to the results of 3 trained chart abstractors. RESULTS: The manual chart abstraction identified 87 patients with IHD in the random sample (prevalence = 8.98%). The accuracy of the algorithm for identifying patients with IHD was as follows: sensitivity = 72.4% (95% confidence interval [CI]: 61.8 81.5); specificity = 99.3% (95% CI: 98.5-99.8); positive predictive value = 91.3% (95% CI: 82.0-96.7); negative predictive value = 97.3 (95% CI: 96.1-98.3); and kappa = 0.79 (95% CI: 0.72-0.86). CONCLUSIONS: Patients with IHD can be accurately identified by applying a search algorithm for the medical history fields in the EMR of primary care providers who were not using standardized approaches to code diagnoses. The accuracy compares favorably to other methods for identifying patients with IHD. The results of this study may aid policy makers, researchers, and clinicians to develop registries and to examine quality indicators for IHD in primary care. PMID- 23804664 TI - Prevalence and comorbidities of somatoform disorders in a rural california outpatient psychiatric clinic. AB - OBJECTIVE: This study examines the prevalence and comorbidities of somatoform disorders in a rural setting with a diverse ethnic population. METHOD: A retrospective chart review was conducted of active psychiatric outpatients in a clinic located in a rural community. Data abstracted included demographic variables, multi-axial diagnoses (DSM-IV-TR), length of treatment, psychotropic medications, and number of medications discontinued because of side effects. Improvement in level of function with treatment was measured by change in global assessment of functioning (GAF) scores. RESULTS: Of 737 records reviewed, 37 (5%) contained a diagnosis of somatoform disorder. The most common comorbidities in the somatoform group were depression (P < .01), hypertension (P < .01), and arthritis (P < .05). The somatoform group was significantly more likely to have a chronic medical illness (P < .01) and history of surgeries (P < .05). The somatoform group patients' DeltaGAF was one fourth the DeltaGAF scores in all other psychiatric outpatients (1.41 vs 6.79, P < .01). The somatoform group changed medications more often because of side effects (1.35 times vs 0.71 times, P < .01), received a greater number of psychotropic medications (2.05 vs 1.62, P < .05), and was more likely to be taking an antidepressant (P < .05) than the nonsomatoform group. CONCLUSION: Somatoform disorder patients had a higher prevalence of depression, chronic medical conditions, and surgeries. They responded less favorably to treatment when compared to patients without a somatoform disorder, and manifested a decreased tolerance to medication side effects. Female gender, fewer years of education, and Latino ethnicity did not increase the probability of having a somatoform disorder. PMID- 23804665 TI - Beyond crisis care in brain injury rehabilitation in australia: a conversation worth having. AB - OBJECTIVE: The aim of this commentary was to bring together the various significant issues associated with delivering brain injury rehabilitation in Australia. Through observational critique, the authors aimed to identify gaps in practice and opportunities for change. APPROACH: In light of Australia's national health reform process, it is necessary to consider rehabilitation practices and models for brain injury service delivery. There are lessons to be learned within the Australian system, but also opportunities to apply international reform. CONCLUSION: For those within the service delivery system, brain injury rehabilitation can often appear to be a crisis-driven response. Gaps in service provision persist, leaving individuals who have reduced cognitive and emotional capacity to self-navigate an unpredictable health system at a time in their lives when they are least prepared to do so. Deficiencies in the delivery of timely and appropriate psychosocial or behavioral rehabilitation services undoubtedly contribute to the current pressures on the health system created by increased length of stay in neurological and slow-to-recover rehabilitation units, repeat presentations to primary care, and frequent use of community mental health services. IMPLICATION: The experiences of people with acquired brain injury highlights the need for early and targeted interventions that can deal with emerging complexities and support needs, interorganizational approaches, and new accommodation options with a matched service philosophy. Rather than count on good fortune, individual outcomes, and the future of brain injury, rehabilitation ought to depend on deliberate and systemic design. PMID- 23804666 TI - Public health and primary care: struggling to "win friends and influence people". AB - Why are the goals of public health and primary care less politically popular and financially supported than those of curative medicine? A major part of the answer to this question lies in the fact that humans often worry wrongly by assessing risk poorly. This reality is a significant obstacle to the adequate promotion of and investment in public health, primary care, and prevention. Also, public health's tendency to infringe on personal privacy-as well as to call for difficult behavioral change-often sparks intense controversy and interest group opposition that discourage broader political support. Finally, in contrast to curative medicine, both the cost-benefit structure of public health (costs now, benefits later) and the way in which the profession operates make it largely invisible to and, thus, underappreciated by the general public. When curative medicine works well, most everybody notices. When public health and primary care work well, virtually nobody notices. PMID- 23804667 TI - A serendipitous milestone in respiratory neurobiology. PMID- 23804668 TI - Like mother, like offspring: maternal and offspring wound healing correlate in snakes. AB - Immune function early in life can be influenced by parental effects and the environment, but it remains unclear how these two factors may interact to influence immunocompetence. We evaluated maternal and environmental contributions to offspring healing ability in a viviparous reptile, the northern watersnake (Nerodia sipedon). We measured wound healing rates, a highly integrative and biologically relevant measure of innate immunity, of females and their offspring collected from sites contaminated with a toxic heavy metal and compared them with those of individuals from reference sites. We found that female watersnakes that healed the fastest produced offspring that also exhibited faster healing rates. However, we detected no influence of environmental pollution on maternal or offspring healing rates. To our knowledge, our study is the first to correlate maternal and offspring wound healing ability in a wild vertebrate. PMID- 23804669 TI - Cardiovascular design in fin whales: high-stiffness arteries protect against adverse pressure gradients at depth. AB - Fin whales have an incompliant aorta, which, we hypothesize, represents an adaptation to large, depth-induced variations in arterial transmural pressures. We hypothesize these variations arise from a limited ability of tissues to respond to rapid changes in ambient ocean pressures during a dive. We tested this hypothesis by measuring arterial mechanics experimentally and modelling arterial transmural pressures mathematically. The mechanical properties of mammalian arteries reflect the physiological loads they experience, so we examined a wide range of fin whale arteries. All arteries had abundant adventitial collagen that was usually recruited at very low stretches and inflation pressures (2-3 kPa), making arterial diameter largely independent of transmural pressure. Arteries withstood significant negative transmural pressures (-7 to -50 kPa) before collapsing. Collapse was resisted by recruitment of adventitial collagen at very low stretches. These findings are compatible with the hypothesis of depth-induced variation of arterial transmural pressure. Because transmural pressures depend on thoracic pressures, we modelled the thorax of a diving fin whale to assess the likelihood of significant variation in transmural pressures. The model predicted that deformation of the thorax body wall and diaphragm could not always equalize thoracic and ambient pressures because of asymmetrical conditions on dive descent and ascent. Redistribution of blood could partially compensate for asymmetrical conditions, but inertial and viscoelastic lag necessarily limits tissue response rates. Without pressure equilibrium, particularly when ambient pressures change rapidly, internal pressure gradients will develop and expose arteries to transient pressure fluctuations, but with minimal hemodynamic consequence due to their low compliance. PMID- 23804670 TI - Hydrodynamic resistance and flow patterns in the gills of a tilapine fish. AB - The gills of teleost fishes are often discussed as an archetypal counter-current exchange system, capable of supporting the relatively high metabolic rates of some fishes despite the low oxygen solubility of water. Despite an appreciation for the physiology of exchange at the gills, many questions remain regarding the hydrodynamical basis of ventilation in teleost fishes. In this study, the hydrodynamic resistance and flow fields around the isolated gills of a tilapia, Oreochromis mossambicus, were measured as a function of the applied pressure head. At ventilatory pressures typical of a fish at rest, the hydrodynamic resistance of the gills was nearly constant, the flow was laminar, shunting of water around the gills was essentially absent, and the distribution of water flow was relatively uniform. However, at the higher pressures typical of an active or stressed fish, some of these qualities were lost. In particular, at elevated pressures there was a decrease in the hydrodynamic resistance of the gills and substantial shunting of water around the gills. These effects suggest mechanical limits to maximum aerobic performance during activity or under adverse environmental conditions. PMID- 23804671 TI - The impact behaviour of silk cocoons. AB - Silk cocoons, constructed by silkmoths (Lepidoptera), are protective structural composites. Some cocoons appear to have evolved towards structural and material optimisation in order to sustain impact strikes from predators and hinder parasite ingress. This study investigates the protective properties of silk cocoons with different morphologies by evaluating their impact resistance and damage tolerance. Finite element analysis was used to analyse empirical observations of the quasi-static impact response of the silk cocoons, and to evaluate the separate benefits of the structures and materials through the deformation and damage mechanism. We use design principles from composite engineering in order to understand the structure-property-function relationship of silkworm cocoons. Understanding the highly evolved survival strategies of the organisms building natural cocoons will hopefully lead to inspiration that in turn could lead to improved composite design. PMID- 23804675 TI - Percutaneous mitral valve repair using the MitraClip system: time to move forward. PMID- 23804672 TI - A thermogenic secondary sexual character in male sea lamprey. AB - Secondary sexual characters in animals are exaggerated ornaments or weapons for intrasexual competition. Unexpectedly, we found that a male secondary sexual character in sea lamprey (Petromyzon marinus) is a thermogenic adipose tissue that instantly increases its heat production during sexual encounters. This secondary sexual character, developed in front of the anterior dorsal fin of mature males, is a swollen dorsal ridge known as the 'rope' tissue. It contains nerve bundles, multivacuolar adipocytes and interstitial cells packed with small lipid droplets and mitochondria with dense and highly organized cristae. The fatty acid composition of the rope tissue is rich in unsaturated fatty acids. The cytochrome c oxidase activity is high but the ATP concentration is very low in the mitochondria of the rope tissue compared with those of the gill and muscle tissues. The rope tissue temperature immediately rose up to 0.3 degrees C when the male encountered a conspecific. Mature males generated more heat in the rope and muscle tissues when presented with a mature female than when presented with a male (paired t-test, P<0.05). On average, the rope generated 0.027+/-0.013 W cm( 3) more heat than the muscle in 10 min. Transcriptome analyses revealed that genes involved in fat cell differentiation are upregulated whereas those involved in oxidative-phosphorylation-coupled ATP synthesis are downregulated in the rope tissue compared with the gill and muscle tissues. Sexually mature male sea lamprey possess the only known thermogenic secondary sexual character that shows differential heat generation toward individual conspecifics. PMID- 23804677 TI - "The respect of his colleagues ...". PMID- 23804678 TI - Is the ross procedure a suitable choice for aortic valve replacement in children with rheumatic aortic valve disease? AB - BACKGROUND: Ross procedure is the aortic valve replacement of choice in children. Nonetheless, late autograft reoperation for dilatation and/or regurgitation is concerning. We examine whether Ross procedure is suitable in children with rheumatic fever. METHODS: Medical records of 104 children with rheumatic fever who underwent Ross procedure were reviewed (1991-2004). Competing risks methodology determined time-related prevalence and associated factors for two mutually exclusive end states: autograft reoperation and death prior to subsequent reoperation. RESULTS: Mean age was 13.8 +/- 2.7, 83 (80%) were males. Hemodynamic dysfunction was primarily regurgitation (n = 92, 88%) and stenosis/mixed (n = 12, 12%). Competing risks analysis showed that in ten years after the Ross procedure, 1% of patients died, 32% underwent autograft reoperation, and 67% were alive and free from reoperation. Ten-year freedom from aortic regurgitation greater than or equal to moderate was 63%. Ten-year freedom from autograft reoperation was 65% for regurgitation versus 90% for stenosis/mixed disease. Risk factors for autograft reoperation were earlier surgery year (PE: 0.26 +/- 0.06 per year; P < .001), additional surgery (PE: 0.82 +/- 0.39, P = .04), no annular stabilization (PE: 1.21 +/- 0.61, P = .05). Ten year freedom from homograft replacement was 83%. Risk factors were fresh homografts (PE: 1.36 +/- 0.71; P = .06) and aortic homografts (PE: 1.15 +/- 0.59; P = .05). Ten-year freedom from any cardiac reoperation was 53%. Concomitant cardiac surgery was risk factor (PE: 1.37 +/- 0.47; P = .004). CONCLUSIONS: Ross procedure in children with rheumatic fever is associated with excellent survival but results are plagued by aortic regurgitation and frequent autograft reoperation. Risk factors include preoperative regurgitation, concomitant surgery, dilated annulus, and earlier surgery era. Better patient selection in later era has mitigated autograft reoperation risk. Continued, improved candidate selection, along with modifications in autograft implantation and root/sinotubular stabilization techniques, may further decrease late autograft failure. PMID- 23804679 TI - Surgical Decision Making in Neonatal Ebstein's Anomaly: An Algorithmic Approach Based on 48 Consecutive Neonates. AB - OBJECTIVE: There is currently no consensus of opinion regarding the optimal surgical management of Ebstein's anomaly (EA) in neonates and young infants. Reported early mortality rates range from 25% to 100%. In this study, we present an algorithm for choosing the best management option for neonates with EA based on analysis of our experience. PATIENTS AND METHODS: From 1994 to June, 2011, 48 neonates with a diagnosis of EA were managed by the same surgical team. Of these, two died before intervention; the remaining 46 either were managed medically initially (n = 20) or underwent surgical intervention during the neonatal period (n = 26) or early infancy (n = 9). RESULTS: The mean weight was 3.6 +/- 1.7 kg (1.9-8.6) and mean follow-up time was 6.3 +/- 4.5 years (0.2-16). Of the 20 patients initially managed medically, 11 remain well without intervention and nine required complete repair in infancy, with 100% survival. Of the 26 neonatal operations, 23 (88%) were complete biventricular repairs, 1 Starnes' palliation, and two Blalock-Taussig shunts (BTSs) +/- pulmonary valvotomy. Among those having a two-ventricle repair, anatomic pulmonary atresia (APA) was a risk factor for early mortality (46.1%, 6 of 13) compared with those without pulmonary atresia (EA/no-PA; 10%, 1 of 10), P < .05. CONCLUSIONS: Most symptomatic neonates with EA will require early operation. For those with APA and mild tricuspid regurgitation (TR), a modified BTS and reduction atrioplasty may be the best initial option. For those with functional pulmonary atresia and severe TR and pulmonary regurgitation, ligation of the main pulmonary artery and placement of a BTS may provide the best initial palliation. For the rest, either a biventricular repair or a single-ventricle palliation is indicated. PMID- 23804680 TI - Arterial switch operation with unidirectional valved patch closure of ventricular septal defect in patients with transposition of great arteries and severe pulmonary hypertension. AB - OBJECTIVE: For patients with dextro-transposition of great arteries (d-TGAs), ventricular septal defect (VSD), and severe pulmonary arterial hypertension (PAH), the common surgical options are palliative arterial switch operation (ASO) or palliative atrial switch operation leaving the VSD open. We evaluated the role of ASO with VSD closure using a fenestrated unidirectional valved patch (UVP). METHODS: Between July 2009 and February 2011, six patients with TGAs, VSD, and severe PAH (mean age 39.8 +/- 47.4 months, median 21, range 8-132 months), weighing 10.7 +/- 9.2 kg (median 8.6, range 4.3-29 kg), underwent ASO with VSD closure using our simple technique of UVP. Mean pulmonary artery systolic pressure before the operation was 106 +/- 12.7 mm Hg (median 107.5, range 95-126 mm Hg) and pulmonary vascular resistance was 9.5 +/- 4.22 units (median 9.5, range 6.6-17.1 Wood units). RESULTS: There were no deaths. All patients had a postoperative systemic arterial saturation of more than 95%, although there were frequent episodes of systemic desaturation due to right-to-left shunt across the valved VSD patch (as seen on transesophageal and transthoracic echocardiograms). Mean follow-up was 10 +/- 7.6 months (median 7.5, range 1-22 months). At most recent follow-up, all patients had systemic arterial saturation of more than 95% and no right-to-left shunt through the VSD patch. In one patient, the follow-up cardiac catheterization showed a fall in pulmonary artery systolic pressure to 49 mm Hg. CONCLUSION: Arterial switch operation with UVP VSD closure is feasible with acceptable early results. It avoids complications of palliative atrial switch (arrhythmia and baffle obstruction) and partially or completely open VSD. PMID- 23804681 TI - Inhaled nitric oxide for elevated cavopulmonary pressure and hypoxemia after cavopulmonary operations. AB - Background. Elevated cavopulmonary pressure early after surgical creation of cavopulmonary connections is an important hemodynamic problem with grave prognostic significance. We examined the effect of administration of inhaled nitric oxide (iNO) to patients with elevated cavopulmonary pressure in the early postoperative period. Methods. We retrospectively reviewed data pertaining to all 14 patients with superior (n = 6) and total (n = 8) cavopulmonary connections who were treated with iNO in the early postoperative period during an interval of six years. Changes in the cavopulmonary pressure, the transpulmonary gradient, and the oxygen saturation after the institution of iNO were evaluated. The preoperative characteristics of the patients were compared to those of a control group of patients with cavopulmonary operations not treated with iNO postoperatively. Results. Twelve hours after the initiation of iNO therapy, significant reduction in the cavopulmonary pressure (16.6 +/- 3.5 mm Hg vs 18.1 +/- 2.3 mm Hg, P = .006), reduction in the cavopulmonary gradient (7.0 +/- 3.5 mm Hg vs 9.8 +/- 3.7 mm Hg, P = .009), and elevation of the arterial oxygen saturation (84.5% +/- 6.0% vs 78.7% +/- 5.9%, P = .001) were observed. Linear correlation analysis confirmed tendencies for reduction in the cavopulmonary pressure (P = .13), reduction in the cavopulmonary gradient (P = .02), and elevation of the oxygen saturation (P = .10). Compared to the control group, the treated patients tended to have higher preoperative pulmonary arterial pressures (PAPs) 17 (11-30) mm Hg versus 12 (10-25) mm Hg, P = .10; higher pulmonary vascular resistance (PVR) 2.04 (0.27-6.94) Wood units versus 1.02 (0.49-5.20) Wood units, P = .37; and longer bypass times 154 (41-218) versus 91 (15-276) minutes, P = .13. Conclusions. Administration of iNO was associated with diminuition of cavopulmonary pressure and transpulmonary gradient and increasing oxygen saturation in our small group of patients. In our experience selected patients with preoperatively elevated PAP above 17 mm and PVR above 2 Wood units can undergo cavopulmonary operations with iNO treatment early postoperatively. PMID- 23804682 TI - Quality measures for congenital and pediatric cardiac surgery. AB - This article presents 21 "Quality Measures for Congenital and Pediatric Cardiac Surgery" that were developed and approved by the Society of Thoracic Surgeons (STS) and endorsed by the Congenital Heart Surgeons' Society (CHSS). These Quality Measures are organized according to Donabedian's Triad of Structure, Process, and Outcome. It is hoped that these quality measures can aid in congenital and pediatric cardiac surgical quality assessment and quality improvement initiatives. PMID- 23804683 TI - CPR and E-CPR: What is New? AB - In October 2010, the American Heart Association released updated guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Major changes in the pediatric basic and advanced life support guidelines are reviewed in this article. The use of extracorporeal membrane oxygenation in cardiopulmonary resuscitation (CPR) is also reviewed including the results of two recent large studies and preliminary reports on long-term neurologic outcome of survivors. PMID- 23804684 TI - To cool or not to cool during cardiopulmonary resuscitation. AB - Therapeutic hypothermia following cardiac arrest improves neurologic outcome following adult ventricular fibrillation (VF) cardiac arrest and perinatal hypoxic ischemic encephalopathy. Evaluation of therapeutic hypothermia in the pediatric cardiac arrest population has been limited thus far to retrospective evaluations and to date there have been no published prospective efficacy trials. Two retrospective pediatric cohort studies showed no benefit from hypothermia compared to usual care. The timing (intra-arrest or post-arrest) and duration of hypothermia may impact patient outcome. While overshoot hypothermia <32 degrees C, hypokalemia, and bradycardia are commonly associated with induced hypothermia, the risks of severe arrhythmia and bleeding are no worse than in normothermic controls. Despite this, rewarming has been identified as a vulnerable time for hypotension and seizure activity and may attribute to worse outcome. The American Heart Association's current recommendation is "therapeutic hypothermia (32-34 degrees C) may be considered for children who remain comatose after resuscitation from cardiac arrest. It is reasonable for adolescents resuscitated from sudden, witnessed, out-of-hospital VF cardiac arrest." Ongoing research will help delineate whether induced hypothermia following pediatric cardiac arrest improves neurologic outcome. PMID- 23804685 TI - Intensive care of the pediatric ventricular assist device patient. AB - Utilization of ventricular assist devices (VADs) in children is increasing, as is the complexity of patients supported. We review the intensive care management of pediatric patients with VAD in the perioperative and rehabilitation phases, highlighting the technical aspects and physiology of VADs which impact care. Indications for VAD placement and the preoperative assessment of risk are discussed. Specific aspects of postoperative and long-term care including device troubleshooting, hemostasis and anticoagulation, support of the right ventricle, incidence and prevention of neurologic injury, and other complications are reviewed. PMID- 23804686 TI - Challenges at the Bedside With ECMO and VAD. AB - Patients on circulatory support can be the source of multiple challenges including optimizing the circuit for specific congenital heart lesions, troubleshooting circuit failures, transporting patients on the circuit, anticoagulation and bleeding, transitioning to more mobile ventricular assist device, listing for thoracic organ transplantation, weaning from the circuit, and educating the patient and family about mechanical support. These challenges ideally require a specialized multidisciplinary team, which includes anesthesiologists, child life specialists, extracorporeal membrane oxygenation (ECMO) specialists, intensivists, nurses, nutritionists, perfusionists, pharmacists, respiratory therapists, social workers, and surgeons. PMID- 23804687 TI - Safety of Long-Term Mechanical Support With Berlin Heart EXCOR in Pediatric Patients. AB - Background. The Berlin Heart EXCOR Pediatrics is utilized at our center as a bridge to transplantation or bridge to recovery. This retrospective study reviews our results regarding the safety of long-term support and outcome. Methods. Between January 2008 and December 2010, 12 patients (6 females and 6 males) underwent implantation of a ventricular assist device. The median weight was 14.2 kg (range 4.2-51.6 kg) and the median age was 4.12 years (range 0.25-11.83 years). All patients were on inotropes, five patients required mechanical ventilation and three patients experienced cardiopulmonary resuscitation. Results. Eight patients received a left ventricular assist device and four patients received a biventricular assist device. Of the 12 patients, 8 were bridge to heart transplantation, in 2 patients explantation was possible, and 1 patient died on support. The median support time for these 11 patients was 151 days (range 4-488 days), with 2124 days of cardiac support. One patient is on support. Survival rate was 91.6%. Seven patients had a blood pump change once. Four patients had local signs of infection. There was no mediastinitis and thromboembolism. One patient had intracerebral hemorrhage. There was no death after heart transplantation or after explantation of the device. Conclusions. The Berlin Heart EXCOR is effective in bridging children of almost all ages and sizes to cardiac transplantation or myocardial recovery. Our experience proved that long-term support is possible with a low rate of adverse events. PMID- 23804688 TI - Design control requirements for medical device development. AB - Medical devices used in the United States must comply with federal regulations established to ensure that specified requirements have been met. The article will focus on 1 of 14 elements of the Quality System Regulation (QSR)-Design Controls. A high-level overview of these design control requirements is provided to increase awareness of the device development process and provide a basis for mutual understanding for continued dialogue with end users. Design control requirements were established by the US Food and Drug Administration (FDA) as an element of the QSR in 1996. Device manufacturers are required to have a quality management system (QMS) to ensure their devices are safe and effective. The QMS is established by writing operating procedures to achieve consistent application of the methods used to control quality and comply with regulatory requirements. The FDA has the responsibility to audit device manufacturers for compliance with the regulation. The requirements of the QSR and the resulting device design control procedures lend themselves to what is commonly known as the waterfall development process. This iterative process results in documented evidence that is defined in the QSR as the Design History File. This record of development is essential for managing the product life cycle. The elements and purpose of the design control process will be presented to illuminate today's development environment. CONCLUSION: Collaboration between device developers and the practitioner is essential for improving clinical outcomes and reducing time to market of innovative devices. PMID- 23804689 TI - Pediatric Ventricular Assist Devices: The Future (as of 2011). AB - In the last decade, there have been enormous advances in the field of pediatric specific mechanical circulatory support. In the past, small children requiring bridge to transplant or recovery were limited to extracorporeal membrane oxygenation. Now, in various stages of development, there are several devices that offer the promise of the same quality of support enjoyed by older teenagers and adolescents, with the potential to substantially reduce transplant waiting list mortality and optimize transplant outcomes. Advances have been driven by both industry and, for the first time, by funding from the US National Institutes of Health. PMID- 23804690 TI - Multimodality neuromonitoring for pediatric cardiac surgery: our approach and a critical appraisal of the available evidence. AB - Brain injury remains a source of morbidity associated with congenital heart surgery. Intraoperative neuromonitoring is used by many centers to help minimize neurologic injury and improve outcomes. Neuromonitoring at our institution is performed using a combination of near-infrared spectroscopy, transcranial Doppler ultrasound, electroencephalography, and somatosensory evoked potentials. Adverse or concerning parameters instigate attempts at corrective intervention. A review of the literature regarding neuromonitoring studies in pediatric cardiac surgery shows that evidence is limited to demonstrate that intraoperative neuromonitoring is associated with improved neurologic outcomes. Further clinical research is needed to assess the utility and cost-effectiveness of intraoperative neuromonitoring for pediatric heart surgery. PMID- 23804691 TI - Atrial switch operation in the current era: modifications and pitfalls. AB - Although rarely performed today, atrial switch operations continue to have an important role in the management of some forms of congenital heart disease. In developing countries, delayed diagnosis and presentation of patients with transposition of the great arteries is not uncommon. For some patients who are referred for surgery beyond the newborn period, the atrial switch operations are still considered to be the best option. Also, as part of surgical repair of congenitally corrected transposition, an atrial switch operation is combined with arterial switch or the Rastelli procedure as an alternative to physiologic repair. In isolated ventricular inversion (atrioventricular discordance with ventriculoarterial concordance), the atrial switch operation alone leads to complete anatomical correction. Finally, management of late complications of atrial switch operations requires a thorough understanding of the procedures. PMID- 23804692 TI - Ventricular assist devices for mechanical circulatory support in children. AB - Ventricular assist devices (VADs) are increasingly used in children to provide mechanical circulatory support as a bridge to cardiac transplantation. In this article, we review information on the current status, outcomes, and future directions for the use of VADs in children. PMID- 23804693 TI - The walter sisulu paediatric cardiac centre for Africa: proceedings of the march 2011 symposium. AB - The 2011 symposium opened with a consideration of the challenges in the management of children undergoing the Fontan operation. Management options for patients with congenitally corrected transposition were then discussed, using several illustrative case examples and a review of the results from the Texas Children's Hospital. There was a session dedicated to borderline hypoplastic left heart syndrome, concluding with a review of the results of the Single Ventricle Reconstruction (SVR) Trial in North America. Results of pediatric mechanical circulatory support were considered in the context of surgery for anomalous left coronary artery from the pulmonary artery after a more general overview of pediatric applications of extracorporeal membrane oxygenation and ventricular assist devices. Problems of monitoring in the intensive care unit, quality assurance, feeding algorithms for children, and morbidity associated with mechanical ventilation occupied most of the second day's sessions. Results of the arterial switch operation for transposition, issues related to neonatal brain protection during open cardiac procedures, and, finally, training paradigms for congenital heart surgeons concluded the symposium's talks. PMID- 23804694 TI - Neonatal brain protection in cardiac surgery and the role of intraoperative neuromonitoring. AB - Improving mortality rates in children undergoing surgery for congenital heart disease has enabled a shift in focus to improving morbidity, particularly with respect to neurological complications. Various factors have been implicated in influencing neurological outcomes. We share our experience in formulating a customized cardiopulmonary bypass (CPB) protocol based on currently available evidence. Theoretical advantages of intraoperative neuromonitoring during CPB, specifically use of near-infrared spectroscopy, will be discussed in the context of methodologies to monitor cerebral perfusion during surgery. PMID- 23804695 TI - Right coronary sinus of valsalva aneurysm with rupture into the right ventricle. AB - We report a case of right coronary sinus of Valsalva aneurysm (SVA) with rupture into the right ventricle in a 23-year-old man. The problem was successfully managed with surgical closure of both ruptured SVA and the ventricular defect with cardiopulmonary bypass through median sternotomy. PMID- 23804696 TI - Unoperated congenitally corrected transposition of the great arteries, nonrestrictive ventricular septal defect, and pulmonary stenosis in middle adulthood: do multiple wrongs make a right? AB - Submitted May 6, 2011; Accepted August 3, 2011. The survival into adulthood of patients with unoperated complex congenital heart disease with anomalies often considered life threatening in infancy and childhood requires a complex interplay of "balanced" defects allowing for cardiovascular physiology compatible with long term survival. We report on a series of three cases from our advanced imaging database of middle-aged adults presenting with multiple similar defects providing a hemodynamically balanced circulation. The constellation of defects seen in each of these patients included congenitally corrected transposition of the great arteries, a large nonrestrictive ventricular septal defect, valvular pulmonary stenosis, and in two cases anomalous coronary arteries. Cardiovascular computed tomographic angiography (CCTA) and cardiovascular magnetic resonance imaging (CMR) were important to the characterization of the multiple defects and their three-dimensional relationships in these cases. Treatment decisions in patients with this constellation of findings are challenging, given the limited data due to the rarity of survival of patients with these defects into middle adulthood and the paucity of data related to decisions and approaches to medical management, surgical correction, or transplantation. PMID- 23804697 TI - An uncommon course of the right superior vena cava in a patient with heterotaxy syndrome. AB - We present the case of an infant with congenital heart disease which includes a partial atrioventricular canal defect with the absence of the atrial septum (common atrium) and an extremely uncommon course of the right-sided superior vena cava (SVC) including an intra-atrial segment coursing intramurally along the right posterolateral atrial wall, with an intracardiac orifice situated low within the right side of the atrium, close to the atrial orifice of the right hepatic veins. This feature of the anatomy was discovered intraoperatively at the time of surgical repair. Systemic venous anatomy also included interrupted inferior vena cava (IVC) with azygos continuation to a left-sided SVC draining directly into the left side of the atrium. The successful surgical procedure included tunneling of the left-sided SVC to the right side of the common atrium and atrial septation with a patch. PMID- 23804698 TI - Invited commentary: left isomerism or "isolated atrial inversion"? AB - In the accompanying article, Chenu and colleagues describe "an uncommon course of the right superior vena cava in a patient with heterotaxy syndrome." In their discussion, they pose the question, "Is this an isolated atrial inversion, or a case of left isomerism?" They proceed to comment "this remains a debate among cardiac morphologists." I can agree with them on their first description, since although I have previously examined many hearts from patients with isomerism of the left atrial appendages, or "polysplenia syndrome," I had not noticed the unusual feature they have emphasized in their case report; although, as I will show, the evidence was there for me to observe their feature of emphasis. They deserve great credit, therefore, for bringing this feature to our attention. I also agree with their first statement, namely that their patient has the left isomeric variant of the so-called visceral heterotaxy, but I must question their suggestion that the patient may exhibit mirror-imaged arrangement of the atrial chambers or "atrial situs inversus." I would question even more strongly their comment that the distinction remains "a debate among cardiac morphologists." As I will further show, the distinction has major clinical implications, not only for pediatric cardiac surgeons but also for those involved with genetic counseling. PMID- 23804699 TI - Infective endocarditis in infancy after complete atrioventricular septal defect repair. AB - We report a rare case of infective endocarditis after repair of a complete atrioventricular (AV) septal defect in a four-month-old patient. Perforation of a valve leaflet with progressive severe left AV valve regurgitation required surgical intervention. Valve reconstruction using fresh autologous pericardium was successfully accomplished. This reconstruction in association with prolonged antibiotic therapy resulted in complete recovery of the patient. PMID- 23804700 TI - Successful hybrid stage I palliation for hypoplastic left heart syndrome in a developing nation. AB - The first successful stage I palliation for hypoplastic left heart syndrome (HLHS) in a four-day-old female in the Philippines is reported, along with a discussion of the particular dynamics and challenges of performing this kind of surgery in a developing nation. Challenges met were not limited to the preoperative and perioperative period but involved the interstage period as well. In the face of such challenges, our experience, reported here, is the cause for cautious optimism. PMID- 23804701 TI - Dexmedetomidine-ketamine sedation in a child with a mediastinal mass. AB - Sedation during invasive procedures provides appropriate humanitarian care as well as facilitates the completion of procedures. Although generally safe and effective, adverse effects may occur especially in patients with comorbid diseases. One particularly challenging situation is the child with an anterior mediastinal mass who requires sedation during performance of a biopsy to obtain a tissue diagnosis. When there is evidence of airway compromise, it is generally accepted that the maintenance of spontaneous ventilation is necessary as complete airway obstruction may occur, if positive pressure ventilation is chosen. We present the use of a dexmedetomidine-ketamine combination for procedural sedation in a three-year-old child who presented with a large mediastinal mass and respiratory compromise. Previous reports regarding the use of dexmedetomidine and ketamine for procedural sedation are reviewed and the potential efficacy of this combination is discussed. PMID- 23804702 TI - Cyclin G1 expands liver tumor-initiating cells by Sox2 induction via Akt/mTOR signaling. AB - Recurrence and chemoresistance of liver cancer has been attributed to the existence of liver tumor-initiating cells (T-ICs). It is important to decipher the molecular mechanism for acquisition of drug resistance and to design combinatorial therapeutic strategies. Cyclin G1 has been shown to play a pivotal role in initiation and metastasis of hepatocellular carcinoma. In this study, we found that enhanced cyclin G1 expression was associated with drug resistance of hepatoma cells and higher recurrence rate in hepatocellular carcinoma patients. Expression of cyclin G1 was elevated in liver T-ICs and closely correlated with the expression of liver T-IC markers. Forced cyclin G1 expression remarkably enhanced self-renewal and tumorigenicity of hepatoma cells. Cyclin G1 overexpression dramatically upregulated the expression of Sox2 both in vitro and in vivo, which was impaired by chemical inhibitors of Akt/mTOR signaling. Furthermore, blockade of Akt/mTOR signaling or interference of Sox2 expression suppressed cyclin G1-enhanced self-renewal, chemoresistance, and tumorigenicity of hepatoma cells, indicating that cyclin G1 expands liver T-ICs through Sox2 induction via Akt/mTOR signaling pathway. These results suggest that cyclin G1 induced liver T-IC expansion contributes to the recurrence and chemoresistance of hepatoma, and cyclin G1 may be a promising biomarker for individualized therapy of hepatocellular carcinoma patients. PMID- 23804704 TI - S49076 is a novel kinase inhibitor of MET, AXL, and FGFR with strong preclinical activity alone and in association with bevacizumab. AB - Aberrant activity of the receptor tyrosine kinases MET, AXL, and FGFR1/2/3 has been associated with tumor progression in a wide variety of human malignancies, notably in instances of primary or acquired resistance to existing or emerging anticancer therapies. This study describes the preclinical characterization of S49076, a novel, potent inhibitor of MET, AXL/MER, and FGFR1/2/3. S49076 potently blocked cellular phosphorylation of MET, AXL, and FGFRs and inhibited downstream signaling in vitro and in vivo. In cell models, S49076 inhibited the proliferation of MET- and FGFR2-dependent gastric cancer cells, blocked MET driven migration of lung carcinoma cells, and inhibited colony formation of hepatocarcinoma cells expressing FGFR1/2 and AXL. In tumor xenograft models, a good pharmacokinetic/pharmacodynamic relationship for MET and FGFR2 inhibition following oral administration of S49076 was established and correlated well with impact on tumor growth. MET, AXL, and the FGFRs have all been implicated in resistance to VEGF/VEGFR inhibitors such as bevacizumab. Accordingly, combination of S49076 with bevacizumab in colon carcinoma xenograft models led to near total inhibition of tumor growth. Moreover, S49076 alone caused tumor growth arrest in bevacizumab-resistant tumors. On the basis of these preclinical studies showing a favorable and novel pharmacologic profile of S49076, a phase I study is currently underway in patients with advanced solid tumors. Mol Cancer Ther; 12(9); 1749-62. (c)2013 AACR. PMID- 23804703 TI - Sulindac selectively inhibits colon tumor cell growth by activating the cGMP/PKG pathway to suppress Wnt/beta-catenin signaling. AB - Nonsteroidal anti-inflammatory drugs (NSAID) display promising antineoplastic activity for colorectal and other cancers, but toxicity from COX inhibition limits their long-term use for chemoprevention. Previous studies have concluded that the basis for their tumor cell growth inhibitory activity does not require COX inhibition, although the underlying mechanism is poorly understood. Here, we report that the NSAID sulindac sulfide inhibits cyclic guanosine 3',5' monophosphate phosphodiesterase (cGMP PDE) activity to increase intracellular cGMP levels and activate cGMP-dependent protein kinase (PKG) at concentrations that inhibit proliferation and induce apoptosis of colon tumor cells. Sulindac sulfide did not activate the cGMP/PKG pathway, nor affect proliferation or apoptosis in normal colonocytes. Knockdown of the cGMP-specific PDE5 isozyme by siRNA and PDE5-specific inhibitors tadalafil and sildenafil also selectively inhibited the growth of colon tumor cells that expressed high levels of PDE5 compared with colonocytes. The mechanism by which sulindac sulfide and the cGMP/PKG pathway inhibits colon tumor cell growth involves the transcriptional suppression of beta-catenin to inhibit Wnt/beta-catenin T-cell factor transcriptional activity, leading to downregulation of cyclin D1 and survivin. These observations suggest that safer and more efficacious sulindac derivatives can be developed for colorectal cancer chemoprevention by targeting PDE5 and possibly other cGMP-degrading isozymes. PMID- 23804705 TI - Pharmacologic inhibition of MEK signaling prevents growth of canine hemangiosarcoma. AB - Angiosarcoma is a rare neoplasm of endothelial origin that has limited treatment options and poor five-year survival. As a model for human angiosarcoma, we studied primary cells and tumorgrafts derived from canine hemangiosarcoma (HSA), which is also an endothelial malignancy with similar presentation and histology. Primary cells isolated from HSA showed constitutive extracellular signal regulated kinase (ERK) activation. The mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor CI-1040 reduced ERK activation and the viability of primary cells derived from visceral, cutaneous, and cardiac HSA in vitro. HSA-derived primary cells were also sensitive to sorafenib, an inhibitor of B-Raf and multireceptor tyrosine kinases. In vivo, CI-1040 or PD0325901 decreased the growth of cutaneous cell-derived xenografts and cardiac-derived tumorgrafts. Sorafenib decreased tumor size in both in vivo models, although cardiac tumorgrafts were more sensitive. In human angiosarcoma, we noted that 50% of tumors stained positively for phosphorylated ERK1/2 and that the expression of several MEK-responsive transcription factors was upregulated. Our data showed that MEK signaling is essential for the growth of HSA in vitro and in vivo and provided evidence that the same pathways are activated in human angiosarcoma. This indicates that MEK inhibitors may form part of an effective therapeutic strategy for the treatment of canine HSA or human angiosarcoma, and it highlights the use of spontaneous canine cancers as a model of human disease. PMID- 23804706 TI - Ethacrynic acid oxadiazole analogs induce apoptosis in malignant hematologic cells through downregulation of Mcl-1 and c-FLIP, which was attenuated by GSTP1 1. AB - Ethacrynic acid, a diuretic, inhibits glutathione S-transferase P1-1 (GSTP1-1) activity and induces cell death in malignant cells at high concentrations. To improve ethacrynic acid activity, ethacrynic acid oxadiazole analogs 6s and 6u were synthesized. Although both compounds have greater antiproliferative effects than ethacrynic acid in human HL-60 cells, 6u has a reduced ability to inhibit GSTP1-1 activity. The mechanisms of both 6s- and 6u-induced cell death as well as the role of GSTP1-1 in their actions were studied. Both 6s and 6u equally induced apoptosis in HL-60 cells due to the activation of caspase-3, -9, and -8, which was correlated with the downregulation of antiapoptotic proteins c-FLIP, Mcl-1, and XIAP. The caspase inhibitor Z-VAD-FMK blocked the reduction of XIAP, but not of c-FLIP and Mcl-1, in 6s-treated cells. The reduction of c-FLIP and Mcl-1 by 6s was not blocked by the proteasomal inhibitor MG132, but was correlated with inhibition of the phosphorylation of extracellular signal-regulated kinase (ERK) and eIF4E. Both 6s and 6u decreased the intracellular glutathione (GSH) levels. N acetylcysteine blocked reduction in the levels of Mcl-1, c-FLIP, and intracellular GSH as well as apoptosis in HL-60 cells treated by either compound. Silencing of GSTP1-1 in K562 cells sensitized, but overexpression of GSTP1-1 in Raji cells blocked, apoptosis induction by either compound. GSH conjugation at the methylene group abrogated the ability of inducing apoptosis. These data suggest that the methylene group plays an important role in the downregulation of c-FLIP and Mcl-1 proteins and apoptosis induction, which is inactivated by GSTP1 1 by forming GSH conjugates. PMID- 23804708 TI - A functional polymorphism in the promoter of ERK5 gene interacts with tobacco smoking to increase the risk of lung cancer in Chinese populations. AB - Mitogen/extracellular signal-regulated kinase-5 (MEK5)/extracellular signal regulated protein kinase-5 (ERK5) pathway plays a pro-oncogenic role in tumourigenesis by anticell apoptosis, promoting cell proliferation and differentiation in response to extracellular stimuli. As overexpressed MEK5/ERK5 is involved in the development of lung cancer, we hypothesised that the single nucleotide polymorphisms (SNPs) in MEK5 and ERK5 genes may influence gene expression and thus be associated with lung cancer risk. Five putative functional polymorphisms (rs3743353T>C, rs7172582C>T and rs2278076A>G of MEK5 and rs3866958G>T and rs2233083C>T of ERK5) were genotyped in two independent case control studies with a total of 1559 lung cancer patients and 1679 controls in southern and eastern Chinese population. We found the rs3866958G>T of ERK5 was significantly associated with lung cancer risk, while other SNPs were not. Compared with the rs3866958TG/TT genotypes, the GG genotype conferred an increased risk of lung cancer (odds ratio = 1.30, 95% confidence interval = 1.12 1.51, P = 5.0*10(-4)), and this effect was more pronounced in smokers, accompanying with a significant interaction with smoking (P interaction = 0.013). The GG genotype also had significant higher mRNA levels of ERK5 in lung cancer tissues than TG/TT genotypes (P = 1.0*10(-4)); the luciferase reporter with the G allele showed significant higher transcription activities than the T allele, especially after the treatment with tobacco extract in vitro. Our data indicated that the functional polymorphism rs3866958G>T in ERK5 was associated with an increased lung cancer risk in smokers by virtue of the positive interaction with smoking on promoting the ERK5 expression, which might be a valuable indicator for predicting lung cancer risk in smokers. PMID- 23804707 TI - A robust immunoassay for pregnancy-associated plasma protein-A2 based on analysis of circulating antigen: establishment of normal ranges in pregnancy. AB - Pregnancy-associated plasma protein-A (PAPP-A) and PAPP-A2, two homologous metzincin metalloproteases, are both tightly linked to regulation within the insulin-like growth factor (IGF) system because of their specific cleavage of IGF binding proteins. Recent studies suggest that PAPP-A may be involved in clinical conditions related to unwanted cellular growth, and the circulating levels of PAPP-A is an established biomarker in prenatal screening for chromosomal abnormalities. Microarray data indicate that PAPP-A2 has potential as a biomarker for pre-eclampsia. However, well-characterized immunological methods of quantification are not available. We therefore developed monoclonal antibodies against recombinant PAPP-A2. The antibodies were epitope mapped against recombinantly expressed chimeras between PAPP-A2 and PAPP-A. Furthermore, circulating PAPP-A2 was immunoaffinity purified and characterized by sequence analysis and mass spectrometry. Unlike PAPP-A, PAPP-A2 is a noncovalent dimer in which each subunit of 1558 amino acids originates from all of the 22 predicted coding exons. A previously hypothesized variant (PAPP-E) does not exist, but low amounts of a C-terminally truncated PAPP-A2 variant was detected. A sensitive and robust ELISA for full-length PAPP-A2 was developed and used to establish normal ranges of PAPP-A2 through pregnancy. The functional sensitivity of this ELISA at 20% CV was 0.08 ng/ml, and the serum concentration of PAPP-A2 was found to increase during pregnancy in agreement with placental synthesis. The existence of this assay will enable an assessment of the biomarker potential of PAPP-A2 in pre eclampsia as well as other clinical conditions. PMID- 23804709 TI - Myeloid-derived suppressor cells play crucial roles in the regulation of mouse collagen-induced arthritis. AB - Myeloid-derived suppressor cells (MDSCs) are of myeloid origin and are able to suppress T cell responses. The role of MDSCs in autoimmune diseases remains controversial, and little is known about the function of MDSCs in autoimmune arthritis. In this study, we clarify that MDSCs play crucial roles in the regulation of proinflammatory immune response in a collagen-induced arthritis (CIA) mouse model. MDSCs accumulated in the spleens of mice with CIA when arthritis severity peaked. These MDSCs inhibited the proliferation of CD4(+) T cells and their differentiation into Th17 cells in vitro. Moreover, MDSCs inhibited the production of IFN-gamma, IL-2, TNF-alpha, and IL-6 by CD4(+) T cells in vitro, whereas they promoted the production of IL-10. Adoptive transfer of MDSCs reduced the severity of CIA in vivo, which was accompanied by a decrease in the number of CD4(+) T cells and Th17 cells in the draining lymph nodes. However, depletion of MDSCs abrogated the spontaneous improvement of CIA. In conclusion, MDSCs in CIA suppress the progression of CIA by inhibiting the proinflammatory immune response of CD4(+) T cells. These observations suggest that MDSCs play crucial roles in the regulation of autoimmune arthritis, which could be exploited in new cell-based therapies for human rheumatoid arthritis. PMID- 23804711 TI - Chemokine unresponsiveness of chronic lymphocytic leukemia cells results from impaired endosomal recycling of Rap1 and is associated with a distinctive type of immunological anergy. AB - Trafficking of malignant lymphocytes is fundamental to the biology of chronic lymphocytic leukemia (CLL). Transendothelial migration (TEM) of normal lymphocytes into lymph nodes requires the chemokine-induced activation of Rap1 and alphaLbeta2 integrin. However, in most cases of CLL, Rap1 is refractory to chemokine stimulation, resulting in failed alphaLbeta2 activation and TEM unless alpha4beta1 is coexpressed. In this study, we show that the inability of CXCL12 to induce Rap1 GTP loading in CLL cells results from failure of Rap1-containing endosomes to translocate to the plasma membrane. Furthermore, failure of chemokine-induced Rap1 translocation/GTP loading was associated with a specific pattern of cellular IgD distribution resembling that observed in normal B cells anergized by DNA-based Ags. Anergic features and chemokine unresponsiveness could be simultaneously reversed by culturing CLL cells ex vivo, suggesting that these two features are coupled and driven by stimuli present in the in vivo microenvironment. Finally, we show that failure of Rap1 translocation/GTP loading is linked to defective activation of phospholipase D1 and its upstream activator Arf1. Taken together, our findings indicate that chemokine unresponsiveness in CLL lymphocytes results from failure of Arf1/phospholipase D1-mediated translocation of Rap1 to the plasma membrane for GTP loading and may be a specific feature of anergy induced by DNA Ags. PMID- 23804710 TI - T cell-dependent IgM memory B cells generated during bacterial infection are required for IgG responses to antigen challenge. AB - Immunological memory has long considered to be harbored in B cells that express high-affinity class-switched IgG. IgM-positive memory B cells can also be generated following immunization, although their physiological role has been unclear. In this study, we show that bacterial infection elicited a relatively large population of IgM memory B cells that were uniquely identified by their surface expression of CD11c, CD73, and programmed death-ligand 2. The cells lacked expression of cell surface markers typically expressed by germinal center B cells, were CD138 negative, and did not secrete Ab ex vivo. The population was also largely quiescent and accumulated somatic mutations. The IgM memory B cells were located in the region of the splenic marginal zone and were not detected in blood or other secondary lymphoid organs. Generation of the memory cells was CD4 T cell dependent and required IL-21R signaling. In vivo depletion of the IgM memory B cells abrogated the IgG recall responses to specific Ag challenge, demonstrating that the cell population was required for humoral memory, and underwent class-switch recombination following Ag encounter. Our findings demonstrate that T cell-dependent IgM memory B cells can be elicited at high frequency and can play an important role in maintaining long-term immunity during bacterial infection. PMID- 23804712 TI - Cutting edge: IL-12 and type I IFN differentially program CD8 T cells for programmed death 1 re-expression levels and tumor control. AB - Naive CD8 T cells proliferate in response to TCR and CD28 signals, but require IL 12 or type I IFN to survive and develop optimal effector functions. Although murine CTL generated in vitro in response to IL-12 or IFN-alpha had comparable effector functions, IL-12-stimulated cells were significantly more effective in controlling tumor in an adoptive immunotherapy model. They maintained high numbers and function, whereas IFN-alpha-stimulated cells declined in number and became exhausted. Consistent with this, IFN-alpha-stimulated cells in the tumor expressed higher levels of programmed death 1 (PD-1) inhibitory receptor than did IL-12-stimulated cells. When blocking Ab specific for the PD-L1 ligand of PD-1 was administered, the efficacy of IFN-alpha-stimulated CTL became comparable with that of IL-12-stimulated cells. Thus, IL-12 and IFN-alpha differentially program CD8 T cells to re-express distinct levels of PD-1 upon re-encountering Ag, resulting in IL-12-stimulated cells being less susceptible to exhaustion in the face of sustained tumor Ag. PMID- 23804713 TI - Neonatal follicular Th cell responses are impaired and modulated by IL-4. AB - Newborns are characterized by poor responses to vaccines. Defective B cell responses and a Th2-type polarization can account for this impaired protection in early life. We in this study investigated the generation of follicular Th (TFH) cells, involved in the development of Ab response and germinal center reaction, upon vaccination in neonates. We showed that, compared with adults, Ab production, affinity maturation, and germinal center formation were reduced in neonates immunized with OVA-aluminum hydroxide. Although this vaccination induced CD4(+) CXCR5(+) PD-1(+) TFH cells in newborns, their frequency, as well as their Bcl6 expression and IL-21 and IL-4 mRNA induction, was decreased in early life. Moreover, neonatal TFH cells were mainly localized in interfollicular regions of lymphoid tissues. The prototypic Th2 cytokine IL-4 was found to promote the emergence and the localization in germinal centers of neonatal TFH cells, as well as the neonatal germinal center reaction itself. In addition, IL-4 dampened expression of Th17-related molecules in neonatal TFH cells, as TFH cells from immunized IL-4-deficient neonates displayed enhanced expression of RORgammat and IL-17. This Th17-like profile correlated with an increased secretion of OVA specific IgG2a. Our study thus suggests that defective humoral immunity in early life is associated with limited and IL-4-modulated TFH cell responses. PMID- 23804714 TI - Depletion of alveolar macrophages during influenza infection facilitates bacterial superinfections. AB - Viruses such as influenza suppress host immune function by a variety of methods. This may result in significant morbidity through several pathways, including facilitation of secondary bacterial pneumonia from pathogens such as Streptococcus pneumoniae. PKH26-phagocytic cell labeling dye was administered intranasally to label resident alveolar macrophages (AMs) in a well-established murine model before influenza infection to determine turnover kinetics during the course of infection. More than 90% of resident AMs were lost in the first week after influenza, whereas the remaining cells had a necrotic phenotype. To establish the impact of this innate immune defect, influenza-infected mice were challenged with S. pneumoniae. Early AM-mediated bacterial clearance was significantly impaired in influenza-infected mice: ~50% of the initial bacterial inoculum could be harvested from the alveolar airspace 3 h later. In mock infected mice, by contrast, >95% of inocula up to 50-fold higher was efficiently cleared. Coinfection during the AM depletion phase caused significant body weight loss and mortality. Two weeks after influenza, the AM population was fully replenished with successful re-establishment of early innate host protection. Local GM-CSF treatment partially restored the impaired early bacterial clearance with efficient protection against secondary pneumococcal pneumonia. We conclude that resident AM depletion occurs during influenza infection. Among other potential effects, this establishes a niche for secondary pneumococcal infection by altering early cellular innate immunity in the lungs, resulting in pneumococcal outgrowth and lethal pneumonia. This novel mechanism will inform development of novel therapeutic approaches to restore lung innate immunity against bacterial superinfections. PMID- 23804717 TI - Welcome. PMID- 23804716 TI - NKG2D induces Mcl-1 expression and mediates survival of CD8 memory T cell precursors via phosphatidylinositol 3-kinase. AB - Memory formation of activated CD8 T cells is the result of a specific combination of signals that promote long-term survival and inhibit differentiation into effector cells. Much is known about initial cues that drive memory formation, but it is poorly understood which signals are essential during the intermediate stages before terminal differentiation. NKG2D is an activating coreceptor on Ag experienced CD8 T cells that promotes effector cell functions. Its role in memory formation is currently unknown. In this study, we show that NKG2D controls formation of CD8 memory T cells by promoting survival of precursor cells. We demonstrate that NKG2D enhances IL-15-mediated PI3K signaling of activated CD8 T cells, in a specific phase of memory cell commitment, after activation but before terminal differentiation. This signal is essential for the induction of prosurvival protein Mcl-1 and precursor cell survival. In vivo, NKG2D deficiency results in reduced memory cell formation and impaired protection against reinfection. Our findings show a new role for PI3K and the NKG2D/IL-15 axis in an underappreciated stage of effector to memory cell transition that is essential for the generation of antiviral immunity. Moreover, we provide novel insights how these receptors control both effector and memory T cell differentiation. PMID- 23804715 TI - Role of IRF4 in IFN-stimulated gene induction and maintenance of Kaposi sarcoma associated herpesvirus latency in primary effusion lymphoma cells. AB - IFN regulatory factor (IRF) 4 is a hematopoietic cell-specific transcription factor that regulates the maturation and differentiation of immune cells. Using an inducible expression system, we found that IRF4 directly induced a specific subset of IFN-stimulated genes (ISGs) in a type I IFN-independent manner in both epithelial and B cell lines. Moreover, Kaposi sarcoma-associated herpesvirus (KSHV)-encoded viral FLICE inhibitory protein (vFLIP) enhances IRF4-mediated gene induction. Coexpression of IRF4 with vFLIP significantly increased ISG60 (IFIT3) and Cig5 (RSAD2) transcription that was dependent on the ability of vFLIP to activate NF-kappaB. A vFLIP mutant (A57L) defective in NF-kappaB activation failed to enhance IRF4-mediated ISG induction. Thus, we provide a physiologically relevant mechanism by which viral protein-mediated NF-kappaB activation modulates specific ISG induction by IRF4. In contrast, IRF4 also acted as a negative regulator of KSHV replication and transcription activator expression after induction of KSHV lytic reactivation in KSHV-positive primary effusion lymphoma cells. Taken together, these results suggest a dual role for IRF4 in regulating ISG induction and KSHV lytic reactivation in primary effusion lymphoma cells. PMID- 23804718 TI - Long-term Outcome and Risk of Heart Block After Surgical Treatment of Subaortic Stenosis. AB - Although mortality following repair of subaortic obstruction is low, aggressive resection may increase morbidity. We sought to evaluate outcomes and risk of atrioventricular heart block (AVB) after subaortic resection in the current era. Simple obstruction was defined as a discrete subaortic membrane and complex as multilevel or diffuse narrowing. Limited resection included membranectomy and limited myomectomy. Aggressive resection included Konno, modified Konno, and Ross. Specified variables were obtained from a chart review. The 185 consecutive patients (1991-2008) ranged in age from 1 day to 21.8 years (5.1 +/- 5.1 years) with 2 early and 4 late deaths. Actuarial survival was 97%, 95%, and 95% at 1, 5, and 10 years, respectively. Reoperations were required in 29 of 185 patients (15.7%); 2 required a third operation (1%). Freedom from reoperation in all patients was 97%, 83%, and 73% at 1, 5, and 10 years, respectively. Accessory mitral valve tissue (P < .001) and age <3 months (P = .004) predicted the need for reoperation. Transient or permanent high-degree AVB was documented in 33 of 185 patients (17.8%). Complex anatomy (P = .01) and aggressive resection (P < .001) increased the risk of acquiring AVB. The AVB was permanent in 21 of 185 (11.4%) patients, and pacemaker implantation was undertaken in 20 of 185 (10.8%) patients. Complex anatomy (P = .04) and modified Konno procedure (P = .03) increased the risk of acquiring a pacemaker. Aggressive resection lowered the frequency of recurrence but increased the risk of AVB. When aggressive resection is considered for long-term relief of subaortic obstruction, the risk of reobstruction must be balanced with the risk of AVB and the need for pacemaker implantation. PMID- 23804719 TI - Polytetrafluoroethylene bicuspid pulmonary valve implantation: experience with 126 patients. AB - This article reports our initial experience in 126 consecutive patients treated with placement of a surgically created polytetrafluoroethylene (PTFE) bicuspid pulmonary valve at The Congenital Heart Institute of Florida (CHIF). A bicuspid pulmonary valve is created with PTFE and sutured into the right ventricular outflow tract. PTFE bicuspid pulmonary valves were placed in 126 patients (age: range, 3.1-64.7 years, mean, 17.9 years; weight: range, 14.2-113.6 kg, mean, 55.4 kg). All patients had pulmonary insufficiency, pulmonary stenosis, or both, most commonly after previous repair of tetralogy of Fallot (71 patients). Follow-up was up to 8.3 years (range, 0-8.3 years, mean, 3.34 years). Operative mortality was 1 patient (0.8%). Late mortality was non-valve-related in 3 patients (2.4%). The initial 84 patents in this series received valves constructed from PTFE with 0.6-mm thickness. The next 42 patients received valves constructed from PTFE with 0.1-mm thickness. Six patients of 126 (4.8%) required replacement of the PTFE bicuspid pulmonary valve because of immobile and calcified leaflets. All 6 who required replacement of the PTFE bicuspid pulmonary valve initially received a valve constructed from porous 0.6-mm PTFE material. We currently use nonporous 0.1-mm PTFE, which does not allow cellular in-growth and thickening. Early echocardiographic follow-up of these valve leaflets made with 0.1-mm PTFE has demonstrated improved leaflet mobility and pliability and lower transvalvar gradients. PTFE bicuspid pulmonary valve implantation is safe and effective and demonstrates acceptable performance for the intermediate term. It is anticipated that using thinner 0.1-mm PTFE will improve valve function and durability. Long term follow-up is necessary to determine the true value of this technique. PMID- 23804720 TI - Ross-konno procedure in children: midterm results. AB - The aim of this study was to analyze the midterm results following the Ross-Konno procedure in children. Between 1999 and 2008, 29 patients with complex left ventricular outflow tract obstruction underwent the Ross-Konno procedure. There were 12 (41%) infants (group A) and 17 (59%) older patients (group B). The median age at operation was 3.3 years (range, 6 days to 16 years). At 7 years of follow up, survival was 96% (1 late death), with no differences between groups A and B. Freedom from aortic regurgitation >= mild was 81%, with no differences between groups A and B. No residual gradient was noted in the left ventricular outflow tract in either group. Freedom from mitral regurgitation >= mild was 100% in group B and 41% in group A (P = .0029). The mitral regurgitation was associated with morphological abnormalities of the mitral valve and with development of endocardial fibroelastosis after failed intervention during the newborn period. Freedom from reoperation was 73% in group B and 24% in group A (P = .0093). All patients are now in sinus rhythm, and 43% are without medication. With the technical aspects of this procedure well accomplished, mortality is low, and the functional outcome is encouraging. At midterm follow-up, there was no residual or recurrent outflow tract obstruction and an excellent function of the neoaortic valve. The higher incidence of mitral regurgitation in infants, which was associated with morphological abnormalities of mitral valve and development of endocardial fibroelastosis, is worrisome. PMID- 23804721 TI - Rationale and use of perfusion variables in the 2010 update of the society of thoracic surgeons congenital heart surgery database. AB - Patients undergoing congenital heart surgery are at risk of morbidity and mortality. The reasons underlying this risk are complex. To identify opportunities to reduce adverse sequelae, the cardiovascular perfusion community was invited to amend existing perfusion-related fields as well as add new ones to the current version of the Society of Thoracic Surgeons Congenital Heart Surgery Database (STS-CHSD). The International Consortium for Evidence-Based Perfusion (ICEBP) was invited by the STS-CHSD Task Force to identify and resolve ambiguities related to definitions among the 3 current perfusion-related fields as well as to propose new variables (and definitions) for inclusion in the 2010 update of the STS-CHSD. The ICEBP used teleconferences, wiki-based communication software, and e-mail to discuss current definitions and create new fields with definitions. The ICEBP created modified definitions to existing fields related to cardiovascular perfusion and also developed and defined new fields that focus on (1) techniques of circulatory arrest and cerebral perfusion, (2) strategies of myocardial protection, and (3) techniques to minimize hemodilution and allogeneic blood transfusions. Three fields in the STS-CHSD related to perfusion were redefined, and 23 new variables and definitions were selected for inclusion. Identifying and defining fields specific to the practice of perfusion are requisite for assessing and subsequently improving the care provided to patients undergoing congenital heart surgery. The article describes the methods and justification for adjudicating extant and new perfusion-related fields added to the 2010 update of the STS-CHSD. PMID- 23804722 TI - Right Ventricle-to-Pulmonary Artery Shunt in Norwood Procedure: Early Results. AB - The aim of this study was to evaluate experience and predictors of early mortality in patients with hypoplastic left heart syndrome (HLHS)-type defects undergoing Norwood procedure (NP) with right ventricle-to-pulmonary artery (RV PA) shunt. Between 2001 and 2009, a consecutive series of 229 children with HLHS type single ventricle underwent NP with application of RV-PA shunt. Demographic, echocardiographic, and clinical perioperative data were retrospectively analyzed. The mean duration of follow-up of survivors was 4.5 +/- 2.1 years (60 days to 8.1 years). Follow-up was complete for 92.1% of patients. Major early postoperative complications included sepsis/generalized infection in 40 (17.5%), pericardial effusion in 9 (3.9%), and wound infection in 8 (3.5%). The early (30-day) survival was 87.8% (n = 201). In the late postoperative period, 12 (5.9%) died. Early nonsurvivors were more frequently older than 14 days (P = .045) at initial surgery, had lower operative weight (P = .024), had more frequent associated cardiac (P < .001) and/or extracardiac anomalies (P < .001), and were more likely to have a restrictive interatrial communication before operation (P = .024). Use of the right RV-PA shunt has helped to mitigate some previously described predictors of early death after NP. Longer follow-up will be required to determine whether the RV-PA shunt modification confers an important survival benefit. PMID- 23804723 TI - Neoaortic valve function 10 to 18 years after arterial switch operation. AB - Anatomical correction is a procedure of choice for transposition of the great arteries (TGA) in neonates. During surgery, the aorta and pulmonary artery are switched-the native pulmonary valve becomes the neoaortic valve. The fate of this valve remains uncertain. Many reports suggest that its ability to function worsens with time after surgery. Of 519 patients with TGA operated on between 1991 and 2008, 161 met inclusion criteria for this retrospective study and were followed 10 years or more to assess neoaortic valve regurgitation (NeoAR) occurrence and development and to estimate potential risk factors. The subjects were divided into 2 groups: group 1 (simple TGA) and group 2 (TGA + ventricle septal defect). Within the analyzed group, the frequency of significant regurgitation increased from 9% 1 year after the operation to 47% at the most recent follow-up. No severe regurgitation necessitating reoperation was observed. Analysis of potential risk factors revealed that pulmonary/aortic valve diameter discrepancy and nonfacing commissures were associated with increased risk of development of neoaortic insufficiency. NeoAR arises and develops over time after correction of the defect. No hemodynamic repercussions necessitating cardiac surgical interventions were observed. The majority of insufficiencies are detected between 2 and 6 years after surgery. The degree of incompetence is usually mild and increases during follow-up by about 0.5 or 1 degree. The risk factors for NeoAR appearance are pulmonary artery/aortic annulus discrepancy and nonfacing commissures. PMID- 23804724 TI - Morphology and morphogenesis of atrioventricular septal defect with common atrioventricular junction. AB - For many years, the lesions now often described as atrioventricular septal defects were considered to represent atrioventricular canal malformations or endocardial cushion defects. It was also long recognized that patients with the so-called ostium primum defect should be included in this category. The phenotypic feature of these hearts is the presence of a common atrioventricular junction, as opposed to separate right and left atrioventricular junctions. The presence of the common atrioventricular junction underscores the associated phenotypic features, such as the presence of a trifoliate left atrioventricular valve, which has no resemblance to a cleft mitral valve; unwedging of the subaortic outflow tract; and disproportion between the inlet and outlet dimensions of the left ventricle. These features are comparable in patients having the so-called partial, intermediate, and complete variants of the malformation. Anatomical differentiation depends on the morphology of the leaflets of the common atrioventricular valve that bridge the ventricular septum. If these bridging leaflets are fused one to the other, then there are dual orifices, rather than a common orifice, within the common atrioventricular junction. The relationships of the bridging leaflets to the septal structures determine the potential for shunting across the atrioventricular septal defect, which can occur at atrial and ventricular levels or exclusively at either atrial or ventricular level. Rarely, the atrioventricular septal defect may close spontaneously. Recent evidence from studies of cardiac development shows that rather than being an endocardial cushion defect, the malformation results from failure of ingrowth into the developing heart from the dorsal mesenchymal tissues. PMID- 23804725 TI - Atrioventricular septal defects: lessons learned about patterns of practice and outcomes from the congenital heart surgery database of the society of thoracic surgeons. AB - During the 4-year time interval of 2005 through 2008, the Society of Thoracic Surgeons Congenital Heart Surgery Database documented data about 2882 operations to repair atrioventricular (AV) canal defects: partial, 623 (21.5%); intermediate, 342 (11.8%);. complete, 1917 (66.3%). Mean age at complete repair (years) was as follows: partial, 6.1; intermediate, 2.9; complete, 0.6. Median age at complete repair (years) was as follows: partial, 2.6; intermediate, 0.9; complete, 0.4. Down syndrome was present in 1767 patients (61.1%). Debanding of the pulmonary artery was rarely performed: partial, 1 (0.2%); intermediate, 0 (0.0%); complete, 66 (3.4%). Deep hypothermic circulatory arrest was rarely used: partial, 6 (1.0%); intermediate, 5 (1.5%); complete, 52 (2.7%). Discharge mortality was low: partial, 2 (0.3%); intermediate, 3 (0.9%); complete, 38 (2.0%). Atrioventricular block requiring permanent pacemaker occurred but was uncommon: partial, 6 (1.0%); intermediate, 2 (0.6%); complete, 29 (1.5%). Unplanned reoperation prior to hospital discharge occurred in 3.9% of complete AV canal repairs. The sternum was left open in 3.0% of complete AV canal repairs. Postoperative cardiac arrest occurred in 1.9% of complete AV canal repairs. Mean postoperative length of stay (days) was as follows: partial, 5.2; intermediate, 7; complete, 13.1. Median postoperative length of stay (days) was as follows: partial, 4; intermediate, 4; complete, 7. This review of data from the Society of Thoracic Surgeons Congenital Heart Surgery Database allows for unique documentation of patterns of practice and outcomes. From this review, we learned that 98% to 99% of patients survive complete repair of AV canal and 96% to 97% survive complete repair of AV canal with no major complications. PMID- 23804726 TI - Individualized approach to repair of complete atrioventricular canal: selective use of the traditional single-patch technique versus the Australian technique. AB - The traditional single-patch technique for repair of complete atrioventricular (AV) canal requires surgical division of the superior and inferior common leaflets. In the neonate and young infant, subsequent resuspension of very delicate AV valve tissue on the pericardial patch can be problematic. Selective application of the modified single-patch technique as described by Nunn (Australian technique) minimizes manipulation of the AV valve leaflet tissue. Previous reports have documented that since the late 1980s, the traditional single-patch approach with leaflet resuspension is possible with a mortality of 3% or less. A review of the initial 33 patients managed with the Australian technique was undertaken. The ventricular septal defect was moderate or large in 29 patients (88%). In the balanced canal subgroup, there was no early mortality; 1 patient underwent reoperative mitral repair for cleft dehiscence 1 year postoperatively, and 1 patient with heterotaxy required pacemaker implantation. In the unbalanced canal subgroup, 2 patients died perioperatively (22%). There have been no late deaths or new left ventricular outflow tract obstruction in either subgroup. Selective application of the single-patch technique currently allows excellent results for surgical repair in the neonatal period or early infancy. Even during the learning phase of the Australian technique, satisfactory results were achieved. PMID- 23804727 TI - Challenges in delayed repair of atrioventricular septal defects. AB - Delayed diagnosis and surgery for atrioventricular septal defects are not uncommon in the developing world. This review details the challenges faced in managing this difficult subset of patients. PMID- 23804728 TI - Unbalanced atrioventricular septal defect: definition and decision making. AB - Unbalanced atrioventricular septal defect is an uncommon lesion with widely varying anatomic manifestations. When unbalance is severe, diagnosis and treatment is straightforward, directed toward single-ventricle palliation. Milder forms, however, pose a challenge to current diagnostic and therapeutic approaches. The transition from anatomies that are capable of sustaining biventricular physiology to those that cannot is obscure, resulting in uneven application of surgical strategy and excess mortality. Imprecise assessments of ventricular competence have dominated clinical decision making in this regard. Malalignment of the atrioventricular junction and its attendant derangement of inflow physiology is a critical factor in determining the feasibility of biventricular repair in the setting of unbalanced atrioventricular septal defect. The atrioventricular valve index accurately identifies unbalanced atrioventricular septal defect and also brings into focus a zone of transition from anatomies that can support a biventricular end state and those that cannot. PMID- 23804729 TI - Reoperations after repair of partial and complete atrioventricular septal defect. AB - The most common cause of reoperation following repair of atrioventricular septal defect (AVSD) is left atrioventricular valve regurgitation. However, reoperation for subaortic obstruction is required in some, especially after initial repair of partial AVSD. Etiology of reoperation and late outcome were evaluated. Between 1962 and 2007, 146 patients (59 male) underwent reoperation at the authors' institution after prior repair of partial (n = 96) and complete (n = 50) AVSD. Median age at reoperation after repair of partial AVSD was 26 years (range, 10 months to 71 years) and 4.5 years (range, 53 days to 38 years) after repair of complete AVSD. The 3 most common indications for reoperation included left atrioventricular (AV) valve regurgitation in 105 patients, subaortic stenosis in 29, and right AV valve regurgitation in 21. The most common procedures performed included left AV valve repair in 59 (40%) patients, left AV valve replacement in 56 (38%), subaortic fibrous resection/myectomy in 24 (16%), and right AV valve surgery in 19 (13%). Freedom from subsequent reoperation at 10 years was 48% after initial repair of complete AVSD and 84% after initial repair of partial AVSD. During late follow-up, 10-year actuarial survival was 91% and 77% after initial repair of complete and partial AVSD, respectively. The most common indication for reoperation after initial repair of partial or complete AVSD is left AV valve pathology; left ventricular outflow tract obstruction was more common in partial AVSD. Although freedom from subsequent reoperations is higher after initial repair of partial AVSD, these patients have reduced long-term survival when compared with complete AVSD. PMID- 23804730 TI - Intensive care and perioperative management of patients with complete atrioventricular septal defect. AB - Operative repair of an atrioventricular septal defect is not without risk. The purpose of this review is to highlight various key topics in the perioperative treatment of patients with atrioventricular septal defects, including challenges related to Down syndrome, postoperative arrhythmias, pulmonary hypertension, hypothyroidism, postoperative residual and recurrent lesions, including systemic atrioventricular valvar regurgitation and left ventricular outflow tract obstruction, sedation and analgesia, and vascular access. PMID- 23804731 TI - Anatomy of common atrioventricular junction with complex associated lesions. AB - The essence of the lesion increasingly described as atrioventricular septal defect is the presence of a common atrioventricular junction. In most instances, the common junction is itself shared in more or less equal fashion between the cardiac chambers, producing the so-called balanced arrangement, which can be considered the default option. Complexity can be produced at various levels within this standard lesion. The most complex malformations are seen in the setting of visceral heterotaxy. Greatest complexity is seen with right isomerism. This always includes totally anomalous pulmonary venous connection, even when the pulmonary veins return to the heart. Still further complexity is often added by the presence of pulmonary stenosis or atresia. Imbalance can involve either the atrial or ventricular chambers. Imbalance at atrial level produces one form of double outlet atrium, but typically with balanced ventricles. Ventricular imbalance represents spectrums extending either to double inlet left or right ventricle through a common atrioventricular valve. Complexity at the level of the ventriculoarterial junctions is seen in the form of abnormal ventriculoarterial connections, notably tetralogy of Fallot or double outlet right ventricle. In these settings, the superior bridging leaflet is free-floating. Hypoplasia of the left atrioventricular valve is part of right ventricular dominance and is often associated with the so-called parachute malformation. Dual orifice is also a problem. In both these lesions, the zone of apposition between the bridging leaflets is the effective inlet to the left ventricle. PMID- 23804732 TI - Repair of atrioventricular canal with double-outlet right ventricle, transposition, or truncus arteriosus. AB - Atrioventricular canal and conotruncal anomalies are a heterogeneous group of lesions presenting unique challenges for surgical repair. These are the establishment of unobstructed pathways from left ventricle (LV) to aorta and from right ventricle (RV) to pulmonary artery, closure of the inlet ventricular septal defect (VSD) and atrial septal defect (ASD) ostium primum, and the avoidance of significant left and right atrioventricular valve (AV) regurgitation. Repair of complete atrioventricular canal (CAVC) with tetralogy of Fallot (TOF) has been most commonly achieved, either using a single-patch or a 2-patch technique. In patients with CAVC with double-outlet right ventricle (DORV) with subaortic VSD extension, the 2-patch repair is not unlike that of CAVC with TOF. However, biventricular repair is most challenging in patients with CAVC and complete origin of the aorta from the RV, as in CAVC with DORV and noncommitted VSD and those with CAVC with transposition of the great arteries (TGA) and LVOTO. The technique of VSD translocation allows anatomic biventricular repair for these particularly challenging patients. The arterial switch operation with CAVC repair can be used for patients with CAVC with DORV with subpulmonary VSD extension and CAVC with TGA without left ventricular outflow tract obstruction. Biventricular repair is achievable in most patients with balanced complete atrioventricular canal and conotruncal anomaly. The extreme heterogeneity of CAVC with conotruncal anomalies requires a highly individual approach that is tailored to the specific constellation of lesions in each patient. PMID- 23804733 TI - Our roots, our future. PMID- 23804734 TI - Preliminary experience with cardiac reconstruction using decellularized porcine extracellular matrix scaffold: human applications in congenital heart disease. AB - An ideal material for repair of congenitally malformed hearts would encourage tissue regeneration with growth potential. Decellularized porcine small intestinal submucosa extracellular matrix (SIS-ECM) promotes tissue regeneration in animal models and noncardiac human applications. This retrospective review evaluates SIS-ECM for reconstruction of congenital heart defects. From June 2007 to May 2009, SIS-ECM patches were used in 43 operations on 40 patients aged 2 days to 13 years. In 16 cases, the SIS-ECM was used for pericardial closure. The SIS-ECM was used for cardiac or great vessel repair in 37 cases: atrial septal defect repair in 11, pulmonary arterioplasty in 10, right ventricular outflow tract patch in 6, pulmonary monocusp valve creation in 5, superior vena cava patch in 2 and aortoplasty in 2, valve leaflet augmentation in 2, and repair of unroofed coronary sinus in 1. Follow-up was complete. There were 5 deaths, all unrelated to the SIS-ECM. Mean follow-up was 7.85 months (0.5-24 months). No pericardial effusions or intracardiac or intravascular thromboses occurred related to the SIS-ECM. The patches did not shrink or calcify. Four of 5 monocusp valves were competent and none were stenotic. One patient who underwent tricuspid valve anterior leaflet augmentation with SIS-ECM required tricuspid valve replacement 4 months later for severe regurgitation following a catheter-based procedure. Explanted tissue showed resorption of the SIS-ECM, replacement with organized collagen, and re-endothelialization. Repair of congenital heart defects using SIS-ECM is feasible and safe. In valve reconstruction, this procedure shows potential for replacement by autologous tissue. Longer-term follow-up is required to assess the potential for growth. PMID- 23804735 TI - Shepherd hook anomaly of ductus arteriosus with sudden intrapartum fetal demise: two case reports. AB - Patency of the ductus arteriosus is critical in maintaining fetal circulation, and premature closure is associated with fetal and early neonatal death. We present 2 cases of sudden demise in the delivery room associated with atypical ductal anatomy with obstruction due to kinking and intraluminal intimal ridges. Shepherd hook anomaly of the ductus arteriosus may represent a new congenital heart lesion associated with poor fetal outcome. PMID- 23804738 TI - Outpatient chaplaincy: an underdeveloped resource. PMID- 23804736 TI - Closure of a two-hole secundum atrial septal defect through a transthoracic atrial septal defect occlusion device. AB - A simple method to close a 2-hole secundum atrial septal defect (ASD) is described. The right atrium was approached through a minithoracotomy. A double ring purse string suture was made for the introducer shaft of the ASD occlusion device, and another purse string was made for a slim tissue scissors. A slim tissue scissors was introduced to the right atrium, and the bridge of tissue between the 2 holes was cut. The maximum diameter of the neo-ASD was measured. Thus, the ASD occlusion device of appropriate size could be selected and be placed in position. PMID- 23804739 TI - Multidisciplinary team meetings about a patient in primary care: an explorative study. AB - Multidisciplinary team meetings (MTM) about a patient are a way to coordinate fragmented care. The Minimal Data Set/Resident Assessment Instrument (MDS/RAI) is a tool to prepare and support these meetings. METHODS: An exploratory, qualitative study was used to examine the factors that influence the need for an MTM and to determine the value of MDS/RAI supporting the MTM. RESULTS: Key elements are awareness of the health care professionals that "something is wrong" and the presence of sufficient family caregivers with enough capacity. The MDS/RAI is an aid because registration provides all health care professionals with the same type of preparation, allows possible blind spots to be discovered, and provides structure to the multidisciplinary meeting. Multidisciplinary meetings were found to contribute to sharing of information, knowledge, goals, and mutual respect. CONCLUSION: The evaluation of the patient's care needs by MDS/RAI registration, performed by health care professionals involved in the care, and discussion of the results leads to more efficient MTMs. PMID- 23804740 TI - Increased Anxiety and Length of Treatment Associated With Depressed Patients Who are Readmitted to Collaborative Care. AB - In 2008, the Institute for Clinical Systems Improvement (ICSI) in Minnesota implemented a model of collaborative care management (CCM) for treatment of depression in primary care. This resulted in significant improvements on both clinical response and remission over usual care, although an increase in utilization metrics has been observed. Mental health comorbidities have previously been significantly associated with an increased likelihood of not responding to initial treatment. This retrospective study hypothesized that patients with mental health comorbidities are more likely to be associated with patients who were readmitted into CCM with recurrent depression. A total of 145 patients who had completed CCM were studied; of these, 32 were diagnosed with recurrent depression and were readmitted to CCM, and 113 were in remission for at least 4 months. There were no statistically significant demographic differences between the 2 groups. The initial screening GAD-7 score for anxiety was significantly increased in the readmission group (12.81 vs 9.20, P = .001) as was the average length of treatment from initial diagnosis to remission (168.09 vs 120.99 days, P = .002). All other initial screening tests were not different between the groups. When controlling for the independent variables by multiple logistic regression, the odds ratio for GAD-7 was 1.1156 (CI = 1.0.192 to 1.2212, P = .0177) and for days of treatment in CCM was 1.0123 (CI = 1.0041 to 1.0206, P = .0033). Patients who are readmitted to CCM for recurrent depression have a statistically increased risk of associated anxiety and a longer treatment course than those who have remained in remission for at least 4 months. PMID- 23804741 TI - Maternal acculturation: could it impact oral health practices of mexican-american mothers and their children? AB - A mother's cultural beliefs can affect her infant's health, but the influence of acculturation of Mexican-American women on their young children's oral health is unknown. The authors hypothesized that maternal acculturation impacts very young children's oral health practices favoring, in particular, the mothers who are more Anglo-oriented. A convenience sample of 204 predominantly Mexican-American women attending the Women, Infants, and Children Clinic in San Antonio, Texas, completed the Knowledge, Attitudes, Beliefs, Social Support, and Self-Efficacy of Oral Health (KASE-OH) and Acculturation Questionnaires. Results indicated that mothers with strong Anglo orientation were more likely educated in the United States, first visited a dentist while in elementary school, and breast-fed their children. Children belonging to Anglo-oriented Mexican-American mothers had stronger oral health practices, were more likely to breast-feed, were exposed to more sugary and acidic drinks, consumed higher levels of candy, had Medicaid coverage, and had stronger supervisions of tooth brushing practices. PMID- 23804742 TI - Evaluation of beliefs about hypertension in a general population. AB - PURPOSE: Hypertension affects millions of people in the United States, yet many do not reach their blood pressure goals. Existing data indicate that self management skills improve chronic disease management. Beliefs and attitudes are an important component of self management. This pilot study was designed to evaluate the beliefs of the general public on hypertension. METHODS: One hundred patients of Duke Family Medicine were verbally consented to receive a survey consisting of 16 true/false questions. Included subjects were 18 years and older and comfortable answering questions in English. The questions addressed self management behaviors, definition, and complications of hypertension. Basic demographic data were collected. Descriptive statistics were performed on the data. RESULTS: Of 120 patients screened, 100 met inclusion criteria and agreed to participate in the study. Demographic data indicated that surveyed subjects were similar to the general clinic population: 69% were women, 51% African American, and 55% age 45 years and older. A total of 79% of subjects answered 13 or more questions correctly. The 3 most commonly missed questions addressed fatality of hypertension, adverse effects of medications, and potential for curing hypertension. CONCLUSION: Hypertension is a prevalent issue affected by many factors. Beliefs of the general population, including the role of self management, seem consistent with current medical knowledge. However, this study only evaluated beliefs not behaviors of patients. Further study is needed to elucidate patient-oriented factors that may limit control of hypertension. PMID- 23804743 TI - Usability of an atrial fibrillation anticoagulation decision-support tool. AB - INTRODUCTION: In individuals with nonvalvular atrial fibrillation, anticoagulant therapy with warfarin reduces the rate of thromboembolic events but increases the risk of bleeding. Treatment decisions frequently are inconsistent with guidelines. A new web-based atrial fibrillation decision-support tool (AF-DST) provides patient-specific information on the risk-benefit tradeoff of anticoagulation. METHODS: The authors performed a pilot usability testing study of the AF-DST with 4 medical house officers and 4 attending physicians by simulating 9 outpatient clinical encounters involving tradeoffs between risks and benefits of anticoagulation. They recorded positive and negative critical incidents in the simulations and assessed satisfaction with use of the AF-DST by the Computer System Usability Questionnaire (CSUQ; score range on each item: 1 = strongly disagree to 7 = strongly agree). RESULTS: Users found the AF-DST to be helpful and had high CSUQ scores (mean item score, 6.3). Usability testing identified 6 positive and 14 negative critical incidents. Participants felt that the AF-DST guided them toward the correct decision. Nevertheless, they desired more information on the "black box" calculations and ignored alerts. Training level appeared to affect how the AF-DST was used, in particular, how users interacted with the AF-DST. CONCLUSIONS: Overall satisfaction with the AF-DST was high and the tool effectively communicated recommendations and uncertainty. Usability testing identified design issues and potential errors caused by decision-support tool use; these gaps should be addressed prior to clinical implementation. PMID- 23804744 TI - Family medicine and internal medicine physicians' attitudes and beliefs about depression: implications for treatment decisions. AB - Studies have long shown that some patients receive less than optimal care for depression in primary care settings. However, few studies have uncovered factors that predict and explain this deficiency. The authors administered a survey to 408 primary care physicians. They examined how physicians' attitudes (eg, feeling positively or negatively about treating depression in their patients), physicians' beliefs (eg, beliefs about what their patients think and prefer in terms of depression care), and demographic characteristics (independent variables) predicted optimal depression care (dependent variable). Using logistical regression analyses, they identified differences in treatment decisions between family and internal medicine physicians. Physicians' specialty and race (family physicians and white physicians were more likely to prescribe a medication) were unique determinants of whether the physician treated depression by prescribing medication; physicians' specialty and race (family physicians and nonwhite physicians were more likely to provide office-based counseling) were unique determinants of whether the physician treated depression by providing office-based counseling; physicians' beliefs about depression care and physician age were unique statistically significant determinants of whether the physician treated depression by providing a referral to a mental health specialist. These findings help clarify how physicians' specialty and beliefs about depression care influence treatment. In addition, the results in this study suggest that there are differences between family and internal medicine physicians in terms of their practice patterns and beliefs in types of treatment that patients would be willing to receive. Implications for future research on primary care depression treatment are discussed. PMID- 23804745 TI - Diabetic retinopathy and its risk factors in a population-based study. AB - AIM: To assess the prevalence of diabetic retinopathy and its risk factors among people with diabetes using a population-based survey and discuss strategies that can be used to both prevent and manage diabetes-related complications in a primary care setting. METHODS: The prevalence of self-reported doctor-diagnosed diabetic retinopathy and its risk factors were estimated using data from the Arkansas Behavioral Risk Factor Survey, 2003-2007. Five years of survey data were combined and weighted to the population to assess the risk factors that predict the prevalence of diabetic retinopathy. The study involved 2477 people who reported that they have been diagnosed with diabetes. RESULTS: Twenty-two percent of survey respondents with diabetes had been diagnosed with diabetic retinopathy. Using a multivariate adjusted model, blacks (odds ratio [OR] = 1.76, 95% confidence interval [CI], 1.26, 2.45), those with some high school education (OR = 2.78, 95% CI, 1.80, 4.28), people with diabetes for more than 10 years (OR = 2.14, 95% CI 1.61, 2.85), people on insulin treatment (OR = 2.35, 95% CI 1.78, 3.08), those who had taken a course to manage their diabetes (OR = 1.54, 95% CI 1.20, 1.99), and those with chronic foot ulcers (OR = 2.24, 95% CI 1.62, 3.09) were more likely to have been diagnosed with diabetic retinopathy. CONCLUSIONS: The prevalence of diabetic retinopathy and its risk factors are evident. Novel approaches to increase the screening and treatment of these frequent complications are key to optimize diabetes care. PMID- 23804746 TI - Toward Continuous Primary Care in the United States: Differences in Patient Satisfaction Between First and Return Visits to Primary Care Physicians/Analysis of DrScore--The National e-Survey Data. AB - BACKGROUND: As stated by Donabedian, the father of quality assurance, satisfaction is an integral component of quality in medical care. Patient satisfaction is an important predictor of health-related behaviors, use of medical services, and health outcomes. Impressive literature exists in examining various aspects of patient satisfaction, however, no study thus far has examined differences in patient satisfaction between first and return visits to primary care physicians. OBJECTIVE: Our interest is to determine whether there are differences in patient satisfaction between first and return visits to primary care physicians, with the hypothesis that patients returning for their visits have a higher satisfaction level compared to their first initial visit. METHODS: The authors conducted a cross-sectional analysis of the national Web-based survey DrScore. Via DrScore, patients anonymously rated their physician on the basis of treatment satisfaction received from their most recent outpatient visit. The association between physician satisfaction and total care patient ratings of first and return visits was assessed via regression analysis. RESULTS: In total, 15,341 patients were included in this study. Our findings indicate that for a 1 unit change from first visit to return visits, the coefficient of patient satisfaction for the return visits is approximately 10 times higher compared to that of the first visit. Furthermore, the mean satisfaction score for the return visit group is higher than that for the first visit group, 80.28 versus 64.48, respectively (P < .05). CONCLUSION: Return visits to primary care physicians are associated with higher patient satisfaction compared to the first initial visit. PMID- 23804747 TI - The SIMARD Screening Tool to Identify Unfit Drivers: Are We There Now? AB - Dobbs and Schopflocher published an article in which they introduced a tool to identify people who are unfit to drive because of cognitive impairment. In our view, their conclusion that this tool has ". . . a high degree of accuracy that can be used for immediate decisions in the clinical setting"(1(p119)) is too strongly stated, particularly given that the cut-points they used yield false positive (FP) and false negative (FN) percentages in the 6% to 11% range. We believe the reason for using dual cut-points is to ensure that FP and FN fractions are both controlled very stringently, and that it would be more appropriate to set cut-offs that maintain both of them closer to 1%. Using our own data, we constructed two pairs of dual cut-points-one pair that yielded FP and FN percentages similar to those from the Dobbs and Schopflocher article and another pair that yielded FP and FN percentages no greater than 1%. For the first pair of cut-points, 53% of test results were indeterminate (compared to 50% for Dobbs and Schopflocher). For the second pair of cut-points, 86% of test results were indeterminate. Presumably, the same pattern would be observed in Dobbs and Schopflocher's data if their current dual cut-points were replaced with cut points that controlled the FP and FN percentages at more appropriate levels. We also plotted receiver operating characteristic curves, and calculated the area under the curve (AUC) for the Screen for the Identification of Cognitively Impaired Medically At-Risk Drivers, A Modification of the DemTect (SIMARD-MD) and for the combination of the Mini-Mental State Examination and Trail-Making Test A (using our data for the latter). The difference between them was trivial (AUC = 0.75 and 0.72, respectively). Taken together, the results of the two analytic approaches suggest that other tools currently in use by physicians perform at least as well as the SIMARD-MD, and that it does not represent a significant breakthrough. PMID- 23804748 TI - Evaluating the SIMARD MD a New Screening Tool to Identify Cognitively Impaired Drivers: A Leap Forward. PMID- 23804749 TI - RNA binding mediates neurotoxicity in the transgenic Drosophila model of TDP-43 proteinopathy. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive and selective loss of motor neurons. The discovery of mutations in the gene encoding an RNA-binding protein, TAR DNA-binding protein of 43 kD (TDP 43), in familial ALS, strongly implicated abnormalities in RNA processing in the pathogenesis of ALS, although the mechanisms whereby TDP-43 leads to neurodegeneration remain elusive. To clarify the mechanism of degeneration caused by TDP-43, we generated transgenic Drosophila melanogaster expressing a series of systematically modified human TDP-43 genes in the retinal photoreceptor neurons. Overexpression of wild-type TDP-43 resulted in vacuolar degeneration of the photoreceptor neurons associated with thinning of the retina, which was significantly exacerbated by mutations of TDP-43 linked to familial ALS or disrupting its nuclear localization signal (NLS). Remarkably, these degenerative phenotypes were completely normalized by addition of a mutation or deletion of the RNA recognition motif that abolishes the RNA binding ability of TDP-43. Altogether, our results suggest that RNA binding is key to the neurodegeneration caused by overexpression of TDP-43, and that abnormalities in RNA processing may be crucial to the pathogenesis of TDP-43 proteinopathy. PMID- 23804750 TI - Chemical genetics unveils a key role of mitochondrial dynamics, cytochrome c release and IP3R activity in muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) is a neuromuscular disease caused by mutations in the dystrophin gene. The subcellular mechanisms of DMD remain poorly understood and there is currently no curative treatment available. Using a Caenorhabditis elegans model for DMD as a pharmacologic and genetic tool, we found that cyclosporine A (CsA) reduces muscle degeneration at low dose and acts, at least in part, through a mitochondrial cyclophilin D, CYN-1. We thus hypothesized that CsA acts on mitochondrial permeability modulation through cyclophilin D inhibition. Mitochondrial patterns and dynamics were analyzed, which revealed dramatic mitochondrial fragmentation not only in dystrophic nematodes, but also in a zebrafish model for DMD. This abnormal mitochondrial fragmentation occurs before any obvious sign of degeneration can be detected. Moreover, we demonstrate that blocking/delaying mitochondrial fragmentation by knocking down the fission-promoting gene drp-1 reduces muscle degeneration and improves locomotion abilities of dystrophic nematodes. Further experiments revealed that cytochrome c is involved in muscle degeneration in C. elegans and seems to act, at least in part, through an interaction with the inositol trisphosphate receptor calcium channel, ITR-1. Altogether, our findings reveal that mitochondria play a key role in the early process of muscle degeneration and may be a target of choice for the design of novel therapeutics for DMD. In addition, our results provide the first indication in the nematode that (i) mitochondrial permeability transition can occur and (ii) cytochrome c can act in cell death. PMID- 23804751 TI - IGF-1 receptor antagonism inhibits autophagy. AB - Inhibition of the insulin/insulin-like growth factor signalling pathway increases lifespan and protects against neurodegeneration in model organisms, and has been considered as a potential therapeutic target. This pathway is upstream of mTORC1, a negative regulator of autophagy. Thus, we expected autophagy to be activated by insulin-like growth factor-1 (IGF-1) inhibition, which could account for many of its beneficial effects. Paradoxically, we found that IGF-1 inhibition attenuates autophagosome formation. The reduced amount of autophagosomes present in IGF-1R depleted cells can be, at least in part, explained by a reduced formation of autophagosomal precursors at the plasma membrane. In particular, IGF-1R depletion inhibits mTORC2, which, in turn, reduces the activity of protein kinase C (PKCalpha/beta). This perturbs the actin cytoskeleton dynamics and decreases the rate of clathrin-dependent endocytosis, which impacts autophagosome precursor formation. Finally, with important implications for human diseases, we demonstrate that pharmacological inhibition of the IGF-1R signalling cascade reduces autophagy also in zebrafish and mice models. The novel link we describe here has important consequences for the interpretation of genetic experiments in mammalian systems and for evaluating the potential of targeting the IGF-1R receptor or modulating its signalling through the downstream pathway for therapeutic purposes under clinically relevant conditions, such as neurodegenerative diseases, where autophagy stimulation is considered beneficial. PMID- 23804752 TI - Deficiency of the purine metabolic gene HPRT dysregulates microRNA-17 family cluster and guanine-based cellular functions: a role for EPAC in Lesch-Nyhan syndrome. AB - Lesch-Nyhan syndrome (LNS) is a neurodevelopmental disorder caused by mutations in the gene encoding the purine metabolic enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). A series of motor, cognitive and neurobehavioral anomalies characterize this disease phenotype, which is still poorly understood. The clinical manifestations of this syndrome are believed to be the consequences of deficiencies in neurodevelopmental pathways that lead to disordered brain function. We have used microRNA array and gene ontology analysis to evaluate the gene expression of differentiating HPRT-deficient human neuron like cell lines. We set out to identify dysregulated genes implicated in purine based cellular functions. Our approach was based on the premise that HPRT deficiency affects preeminently the expression and the function of purine-based molecular complexes, such as guanine nucleotide exchange factors (GEFs) and small GTPases. We found that several microRNAs from the miR-17 family cluster and genes encoding GEF are dysregulated in HPRT deficiency. Most notably, our data show that the expression of the exchange protein activated by cAMP (EPAC) is blunted in HPRT-deficient human neuron-like cell lines and fibroblast cells from LNS patients, and is altered in the cortex, striatum and midbrain of HPRT knockout mouse. We also show a marked impairment in the activation of small GTPase RAP1 in the HPRT-deficient cells, as well as differences in cytoskeleton dynamics that lead to increased motility for HPRT-deficient neuron-like cell lines relative to control. We propose that the alterations in EPAC/RAP1 signaling and cell migration in HPRT deficiency are crucial for neuro-developmental events that may contribute to the neurological dysfunctions in LNS. PMID- 23804753 TI - LHX2 regulates the neural differentiation of human embryonic stem cells via transcriptional modulation of PAX6 and CER1. AB - The LIM homeobox 2 transcription factor Lhx2 is known to control crucial aspects of neural development in various species. However, its function in human neural development is still elusive. Here, we demonstrate that LHX2 plays a critical role in human neural differentiation, using human embryonic stem cells (hESCs) as a model. In hESC-derived neural progenitors (hESC-NPs), LHX2 was found to be expressed before PAX6, and co-expressed with early neural markers. Conditional ectopic expression of LHX2 promoted neural differentiation, whereas disruption of LHX2 expression in hESCs significantly impaired neural differentiation. Furthermore, we have demonstrated that LHX2 regulates neural differentiation at two levels: first, it promotes expression of PAX6 by binding to its active enhancers, and second, it attenuates BMP and WNT signaling by promoting expression of the BMP and WNT antagonist Cerberus 1 gene (CER1), to inhibit non neural differentiation. These findings indicate that LHX2 regulates the transcription of downstream intrinsic and extrinsic molecules that are essential for early neural differentiation in human. PMID- 23804755 TI - The tRNA recognition mechanism of the minimalist SPOUT methyltransferase, TrmL. AB - Unlike other transfer RNAs (tRNA)-modifying enzymes from the SPOUT methyltransferase superfamily, the tRNA (Um34/Cm34) methyltransferase TrmL lacks the usual extension domain for tRNA binding and consists only of a SPOUT domain. Both the catalytic and tRNA recognition mechanisms of this enzyme remain elusive. By using tRNAs purified from an Escherichia coli strain with the TrmL gene deleted, we found that TrmL can independently catalyze the methyl transfer from S adenosyl-L-methionine to and isoacceptors without the involvement of other tRNA binding proteins. We have solved the crystal structures of TrmL in apo form and in complex with S-adenosyl-homocysteine and identified the cofactor binding site and a possible active site. Methyltransferase activity and tRNA-binding affinity of TrmL mutants were measured to identify residues important for tRNA binding of TrmL. Our results suggest that TrmL functions as a homodimer by using the conserved C-terminal half of the SPOUT domain for catalysis, whereas residues from the less-conserved N-terminal half of the other subunit participate in tRNA recognition. PMID- 23804754 TI - DNA double-strand-break complexity levels and their possible contributions to the probability for error-prone processing and repair pathway choice. AB - Although the DNA double-strand break (DSB) is defined as a rupture in the double stranded DNA molecule that can occur without chemical modification in any of the constituent building blocks, it is recognized that this form is restricted to enzyme-induced DSBs. DSBs generated by physical or chemical agents can include at the break site a spectrum of base alterations (lesions). The nature and number of such chemical alterations define the complexity of the DSB and are considered putative determinants for repair pathway choice and the probability that errors will occur during this processing. As the pathways engaged in DSB processing show distinct and frequently inherent propensities for errors, pathway choice also defines the error-levels cells opt to accept. Here, we present a classification of DSBs on the basis of increasing complexity and discuss how complexity may affect processing, as well as how it may cause lethal or carcinogenic processing errors. By critically analyzing the characteristics of DSB repair pathways, we suggest that all repair pathways can in principle remove lesions clustering at the DSB but are likely to fail when they encounter clusters of DSBs that cause a local form of chromothripsis. In the same framework, we also analyze the rational of DSB repair pathway choice. PMID- 23804756 TI - Structural and biochemical studies of SLIP1-SLBP identify DBP5 and eIF3g as SLIP1 binding proteins. AB - In metazoans, replication-dependent histone mRNAs end in a stem-loop structure instead of the poly(A) tail characteristic of all other mature mRNAs. This specialized 3' end is bound by stem-loop binding protein (SLBP), a protein that participates in the nuclear export and translation of histone mRNAs. The translational activity of SLBP is mediated by interaction with SLIP1, a middle domain of initiation factor 4G (MIF4G)-like protein that connects to translation initiation. We determined the 2.5 A resolution crystal structure of zebrafish SLIP1 bound to the translation-activation domain of SLBP and identified the determinants of the recognition. We discovered a SLIP1-binding motif (SBM) in two additional proteins: the translation initiation factor eIF3g and the mRNA-export factor DBP5. We confirmed the binding of SLIP1 to DBP5 and eIF3g by pull-down assays and determined the 3.25 A resolution structure of SLIP1 bound to the DBP5 SBM. The SBM-binding and homodimerization residues of SLIP1 are conserved in the MIF4G domain of CBP80/20-dependent translation initiation factor (CTIF). The results suggest how the SLIP1 homodimer or a SLIP1-CTIF heterodimer can function as platforms to bridge SLBP with SBM-containing proteins involved in different steps of mRNA metabolism. PMID- 23804757 TI - An evolutionary conserved pattern of 18S rRNA sequence complementarity to mRNA 5' UTRs and its implications for eukaryotic gene translation regulation. AB - There are several key mechanisms regulating eukaryotic gene expression at the level of protein synthesis. Interestingly, the least explored mechanisms of translational control are those that involve the translating ribosome per se, mediated for example via predicted interactions between the ribosomal RNAs (rRNAs) and mRNAs. Here, we took advantage of robustly growing large-scale data sets of mRNA sequences for numerous organisms, solved ribosomal structures and computational power to computationally explore the mRNA-rRNA complementarity that is statistically significant across the species. Our predictions reveal highly specific sequence complementarity of 18S rRNA sequences with mRNA 5' untranslated regions (UTRs) forming a well-defined 3D pattern on the rRNA sequence of the 40S subunit. Broader evolutionary conservation of this pattern may imply that 5' UTRs of eukaryotic mRNAs, which have already emerged from the mRNA-binding channel, may contact several complementary spots on 18S rRNA situated near the exit of the mRNA binding channel and on the middle-to-lower body of the solvent-exposed 40S ribosome including its left foot. We discuss physiological significance of this structurally conserved pattern and, in the context of previously published experimental results, propose that it modulates scanning of the 40S subunit through 5' UTRs of mRNAs. PMID- 23804758 TI - miR-195 competes with HuR to modulate stim1 mRNA stability and regulate cell migration. AB - Stromal interaction molecule 1 (Stim1) functions as a sensor of Ca2+ within stores and plays an essential role in the activation of store-operated Ca2+ entry (SOCE). Although lowering Stim1 levels reduces store-operated Ca2+ entry and inhibits intestinal epithelial repair after wounding, the mechanisms that control Stim1 expression remain unknown. Here, we show that cellular Stim1 abundance is controlled posttranscriptionally via factors that associate with 3'-untranslated region (3'-UTR) of stim1 mRNA. MicroRNA-195 (miR-195) and the RNA-binding protein HuR competed for association with the stim1 3'-UTR and regulated stim1 mRNA decay in opposite directions. Interaction of miR-195 with the stim1 3'-UTR destabilized stim1 mRNA, whereas the stability of stim1 mRNA increased with HuR association. Interestingly, ectopic miR-195 overexpression enhanced stim1 mRNA association with argonaute-containing complexes and increased the colocalization of tagged stim1 RNA with processing bodies (P-bodies); the translocation of stim1 mRNA was abolished by HuR overexpression. Moreover, decreased levels of Stim1 by miR-195 overexpression inhibited cell migration over the denuded area after wounding but was rescued by increasing HuR levels. In sum, Stim1 expression is controlled by two factors competing for influence on stim1 mRNA stability: the mRNA-stabilizing protein HuR and the decay-promoting miR-195. PMID- 23804759 TI - Structural insight into negative DNA supercoiling by DNA gyrase, a bacterial type 2A DNA topoisomerase. AB - Type 2A DNA topoisomerases (Topo2A) remodel DNA topology during replication, transcription and chromosome segregation. These multisubunit enzymes catalyze the transport of a double-stranded DNA through a transient break formed in another duplex. The bacterial DNA gyrase, a target for broad-spectrum antibiotics, is the sole Topo2A enzyme able to introduce negative supercoils. We reveal here for the first time the architecture of the full-length Thermus thermophilus DNA gyrase alone and in a cleavage complex with a 155 bp DNA duplex in the presence of the antibiotic ciprofloxacin, using cryo-electron microscopy. The structural organization of the subunits of the full-length DNA gyrase points to a central role of the ATPase domain acting like a 'crossover trap' that may help to sequester the DNA positive crossover before strand passage. Our structural data unveil how DNA is asymmetrically wrapped around the gyrase-specific C-terminal beta-pinwheel domains and guided to introduce negative supercoils through cooperativity between the ATPase and beta-pinwheel domains. The overall conformation of the drug-induced DNA binding-cleavage complex also suggests that ciprofloxacin traps a DNA pre-transport conformation. PMID- 23804760 TI - Structural basis for S-adenosylmethionine binding and methyltransferase activity by mitochondrial transcription factor B1. AB - Eukaryotic transcription factor B (TFB) proteins are homologous to KsgA/Dim1 ribosomal RNA (rRNA) methyltransferases. The mammalian TFB1, mitochondrial (TFB1M) factor is an essential protein necessary for mitochondrial gene expression. TFB1M mediates an rRNA modification in the small ribosomal subunit and thus plays a role analogous to KsgA/Dim1 proteins. This modification has been linked to mitochondrial dysfunctions leading to maternally inherited deafness, aminoglycoside sensitivity and diabetes. Here, we present the first structural characterization of the mammalian TFB1 factor. We have solved two X-ray crystallographic structures of TFB1M with (2.1 A) and without (2.0 A) its cofactor S-adenosyl-L-methionine. These structures reveal that TFB1M shares a conserved methyltransferase core with other KsgA/Dim1 methyltransferases and shed light on the structural basis of S-adenosyl-L-methionine binding and methyltransferase activity. Together with mutagenesis studies, these data suggest a model for substrate binding and provide insight into the mechanism of methyl transfer, clarifying the role of this factor in an essential process for mitochondrial function. PMID- 23804762 TI - Silencing subtelomeric VSGs by Trypanosoma brucei RAP1 at the insect stage involves chromatin structure changes. AB - Trypanosoma brucei causes human African trypanosomiasis and regularly switches its major surface antigen variant surface glycoprotein (VSG) to evade mammalian host immune responses at the bloodstream form (BF) stage. Monoallelic expression of BF Expression Site (BES)-linked VSGs and silencing of metacyclic VSGs (mVSGs) in BF cells are essential for antigenic variation, whereas silencing of both BES linked and mVSGs in the procyclic form (PF) cells is important for cell survival in the midgut of its insect vector. We have previously shown that silencing BES linked VSGs in BF cells depends on TbRAP1. We now show that TbRAP1 silences both BES-linked and mVSGs at both BF and PF stages. The strength of TbRAP1-mediated BES-linked VSG silencing is stronger in the PF cells than that in BF cells. In addition, Formaldehyde-Assisted Isolation of Regulatory Elements analysis and MNase digestion demonstrated that depletion of TbRAP1 in PF cells led to a chromatin structure change, which is significantly stronger at the subtelomeric VSG loci than at chromosome internal loci. On the contrary, no significant chromatin structure changes were detected on depletion of TbRAP1 in BF cells. Our observations indicate that TbRAP1 helps to determine the chromatin structure at the insect stage, which likely contributes to its strong silencing effect on VSGs. PMID- 23804761 TI - Polyethylene glycol binding alters human telomere G-quadruplex structure by conformational selection. AB - Polyethylene glycols (PEGs) are widely used to perturb the conformations of nucleic acids, including G-quadruplexes. The mechanism by which PEG alters G quadruplex conformation is poorly understood. We describe here studies designed to determine how PEG and other co-solutes affect the conformation of the human telomeric quadruplex. Osmotic stress studies using acetonitrile and ethylene glycol show that conversion of the 'hybrid' conformation to an all-parallel 'propeller' conformation is accompanied by the release of about 17 water molecules per quadruplex and is energetically unfavorable in pure aqueous solutions. Sedimentation velocity experiments show that the propeller form is hydrodynamically larger than hybrid forms, ruling out a crowding mechanism for the conversion by PEG. PEGs do not alter water activity sufficiently to perturb quadruplex hydration by osmotic stress. PEG titration experiments are most consistent with a conformational selection mechanism in which PEG binds more strongly to the propeller conformation, and binding is coupled to the conformational transition between forms. Molecular dynamics simulations show that PEG binding to the propeller form is sterically feasible and energetically favorable. We conclude that PEG does not act by crowding and is a poor mimic of the intranuclear environment, keeping open the question of the physiologically relevant quadruplex conformation. PMID- 23804763 TI - Molecular mechanism of sequence-dependent stability of RecA filament. AB - RecA is a DNA-dependent ATPase and mediates homologous recombination by first forming a filament on a single-stranded (ss) DNA. RecA binds preferentially to TGG repeat sequence, which resembles the recombination hot spot Chi (5'-GCTGGTGG 3') and is the most frequent pattern (GTG) of the codon usage in Escherichia coli. Because of the highly dynamic nature of RecA filament formation, which consists of filament nucleation, growth and shrinkage, we need experimental approaches that can resolve each of these processes separately to gain detailed insights into the molecular mechanism of sequence preference. By using a single molecule fluorescence assay, we examined the effect of sequence on individual stages of nucleation, monomer binding and dissociation. We found that RecA does not recognize the Chi sequence as a nucleation site. In contrast, we observed that it is the reduced monomer dissociation that mainly determines the high filament stability on TGG repeats. This sequence dependence of monomer dissociation is well-correlated with that of ATP hydrolysis, suggesting that DNA sequence dictates filament stability through modulation of ATP hydrolysis. PMID- 23804764 TI - Zinc-finger-nucleases mediate specific and efficient excision of HIV-1 proviral DNA from infected and latently infected human T cells. AB - HIV-infected individuals currently cannot be completely cured because existing antiviral therapy regimens do not address HIV provirus DNA, flanked by long terminal repeats (LTRs), already integrated into host genome. Here, we present a possible alternative therapeutic approach to specifically and directly mediate deletion of the integrated full-length HIV provirus from infected and latently infected human T cell genomes by using specially designed zinc-finger nucleases (ZFNs) to target a sequence within the LTR that is well conserved across all clades. We designed and screened one pair of ZFN to target the highly conserved HIV-1 5'-LTR and 3'-LTR DNA sequences, named ZFN-LTR. We found that ZFN-LTR can specifically target and cleave the full-length HIV-1 proviral DNA in several infected and latently infected cell types and also HIV-1 infected human primary cells in vitro. We observed that the frequency of excision was 45.9% in infected human cell lines after treatment with ZFN-LTR, without significant host-cell genotoxicity. Taken together, our data demonstrate that a single ZFN-LTR pair can specifically and effectively cleave integrated full-length HIV-1 proviral DNA and mediate antiretroviral activity in infected and latently infected cells, suggesting that this strategy could offer a novel approach to eradicate the HIV-1 virus from the infected host in the future. PMID- 23804765 TI - Nuclear CaMKII enhances histone H3 phosphorylation and remodels chromatin during cardiac hypertrophy. AB - Calcium/calmodulin-dependent protein kinase II (CaMKII) plays a central role in pathological cardiac hypertrophy, but the mechanisms by which it modulates gene activity in the nucleus to mediate hypertrophic signaling remain unclear. Here, we report that nuclear CaMKII activates cardiac transcription by directly binding to chromatin and regulating the phosphorylation of histone H3 at serine-10. These specific activities are demonstrated both in vitro and in primary neonatal rat cardiomyocytes. Activation of CaMKII signaling by hypertrophic agonists increases H3 phosphorylation in primary cardiac cells and is accompanied by concomitant cellular hypertrophy. Conversely, specific silencing of nuclear CaMKII using RNA interference reduces both H3 phosphorylation and cellular hypertrophy. The hyper phosphorylation of H3 associated with increased chromatin binding of CaMKII occurs at specific gene loci reactivated during cardiac hypertrophy. Importantly, H3 Ser-10 phosphorylation and CaMKII recruitment are associated with increased chromatin accessibility and are required for chromatin-mediated transcription of the Mef2 transcription factor. Unlike phosphorylation of H3 by other kinases, which regulates cellular proliferation and immediate early gene activation, CaMKII-mediated signaling to H3 is associated with hypertrophic growth. These observations reveal a previously unrecognized function of CaMKII as a kinase signaling to histone H3 and remodeling chromatin. They suggest a new epigenetic mechanism controlling cardiac hypertrophy. PMID- 23804768 TI - On "the importance of being earnest". PMID- 23804766 TI - Co-expression of RNA-protein complexes in Escherichia coli and applications to RNA biology. AB - RNA has emerged as a major player in many cellular processes. Understanding these processes at the molecular level requires homogeneous RNA samples for structural, biochemical and pharmacological studies. We previously devised a generic approach that allows efficient in vivo expression of recombinant RNA in Escherichia coli. In this work, we have extended this method to RNA/protein co-expression. We have engineered several plasmids that allow overexpression of RNA-protein complexes in E. coli. We have investigated the potential of these tools in many applications, including the production of nuclease-sensitive RNAs encapsulated in viral protein pseudo-particles, the co-production of non-coding RNAs with chaperone proteins, the incorporation of a post-transcriptional RNA modification by co-production with the appropriate modifying enzyme and finally the production and purification of an RNA-His-tagged protein complex by nickel affinity chromatography. We show that this last application easily provides pure material for crystallographic studies. The new tools we report will pave the way to large-scale structural and molecular investigations of RNA function and interactions with proteins. PMID- 23804769 TI - A tribute to francis fontan, MD, and guillermo kreutzer, MD. AB - At the Third Scientific Meeting of the World Society for Pediatric and Congenital Heart Surgery in June 2011 in Istanbul, Turkey, Professor Francis Fontan and Dr Guillermo Kreutzer were honored for their contributions to the world of pediatric and congenital heart surgery. The presentation included a video of each physician being interviewed about their clinical and historical experiences. The presentation and videos are summarized herein. PMID- 23804767 TI - The eIF2alpha/ATF4 pathway is essential for stress-induced autophagy gene expression. AB - In response to different environmental stresses, eIF2alpha phosphorylation represses global translation coincident with preferential translation of ATF4, a master regulator controlling the transcription of key genes essential for adaptative functions. Here, we establish that the eIF2alpha/ATF4 pathway directs an autophagy gene transcriptional program in response to amino acid starvation or endoplasmic reticulum stress. The eIF2alpha-kinases GCN2 and PERK and the transcription factors ATF4 and CHOP are also required to increase the transcription of a set of genes implicated in the formation, elongation and function of the autophagosome. We also identify three classes of autophagy genes according to their dependence on ATF4 and CHOP and the binding of these factors to specific promoter cis elements. Furthermore, different combinations of CHOP and ATF4 bindings to target promoters allow the trigger of a differential transcriptional response according to the stress intensity. Overall, this study reveals a novel regulatory role of the eIF2alpha-ATF4 pathway in the fine-tuning of the autophagy gene transcription program in response to stresses. PMID- 23804770 TI - Anatomy of functionally single ventricle. AB - Hearts that have previously been called univentricular hearts, or single ventricles, can be described as having a univentricular atrioventricular connection. Most such hearts have two ventricular chambers, albeit one is small and incomplete-lacking an inlet component. The atriums of these hearts connect only to one of these ventricular chambers, which is usually the larger and dominant ventricle. Other hearts, with biventricular atrioventricular connections, may have hypoplasia of one ventricle, making it impossible to restore a biventricular circulation and such hearts are functionally univentricular. The term "functionally single ventricle" (or functionally univentricular heart) encompasses both these categories of malformation. PMID- 23804771 TI - Optimal initial palliation for patients with functionally univentricular hearts. AB - This review will outline the optimal, initial palliation for children who are born with a functionally univentricular heart. Optimizing the initial palliation is of critical importance in this patient population to prevent potential problems such as systemic outflow and pulmonary vein obstruction that may complicate further surgical intervention. The palliative techniques that are discussed include pulmonary artery banding, modified Blalock-Taussig shunt, Damus Kaye-Stansel procedure, modified Norwood, hybrid, and early bidirectional Glenn. Our recommendations for optimal palliation for children with a univentricular heart are based on our experience with nearly 200 patients who had either a lateral tunnel or extracardiac Fontan procedure and 130 patients who had Fontan conversion with arrhythmia surgery. PMID- 23804772 TI - The fontan connections: past, present, and future. AB - The Fontan procedure is now considered the final common pathway for patients with anatomical or functional single ventricle. These patients initially have their systemic and pulmonary circulations in parallel, supported by one functional ventricular chamber. The ultimate goal with this procedure is to separate the two circulations, to prevent mixing of venous and arterial blood, and to provide adequate tissue oxygenation. The objective of this article is to review the Fontan procedure with its various modifications and refinements since its introduction to clinical practice in 1971, by Fontan and Baudet. PMID- 23804773 TI - Cardiac transplantation and mechanical support for functional single ventricle. AB - Cardiac transplantation has played a pivotal role in the therapeutic algorithm for anatomically uncorrectable congenital heart disease, particularly the failing single ventricle. The historical evolution from Kantrowitz to Bailey and beyond challenges the application of this scarce resource to complex cardiac malformations in the presence of physiologic and circulatory failure. While selection of cardiac transplantation as primary therapy for hypoplastic-left heart syndrome is currently rare, the failing single ventricle in various stages of the Fontan pathway is increasingly considered for this therapy. The results of transplantation in this complex situation have progressively improved and now approached the late outcomes for other conditions. Mechanical circulatory support for the failing single ventricle has recently carried infants and children to successful transplant. The development of miniaturized continuous flow pumps offers the hope of major new avenues of successful circulatory support for single ventricle patients. PMID- 23804774 TI - Late arrhythmias following fontan surgery. AB - The incidence of atrial arrhythmias following Fontan repairs varies by the type of surgery and duration of follow-up. The incidence of late atrial tachycardia has been reduced from 60% to less than 20% by surgical modifications. Late ventricular tachycardia is reported in 3% to 12% of patients. Aggressive efforts to eliminate tachycardia and improve hemodynamics may improve clinical status. PMID- 23804775 TI - Extracardiac fontan with direct cavopulmonary connections: midterm results. AB - BACKGROUND: The aim of this study was to analyze the midterm results following direct superior and inferior cavopulmonary connections (DCPC) to create Fontan circulation in patients with functionally univentricular hearts. METHODS: Retrospective review of patients operated between January 2005 and May 2011. RESULTS: The 25 consecutive patients who underwent this type of operation were retrospectively reviewed. There were 15 (60%) males and ten (40%) females, with median age of 73 months (range: 16-150 months) and median weight of 25 kg (range: 11-46 kg). Aortic cross-clamping used in ten patients, with median cross-clamp time of 40 minutes (range: 23-99) and median cardiopulmonary bypass (CPB) time of 135 minutes (range: 76-179 minutes). The remaining 15 patients were operated without aortic cross-clamping. Their median CPB time was 112 minutes (range: 82 139 minutes). Fenestration was performed in 15 cases. Associated intracardiac procedures were performed on ten patients. The follow-up period ranged from two months to six years. Operative mortality and late mortality after discharge were zero. Major postoperative complications included supraventricular tachycardia in one patient, oliguria and peritoneal dialysis in one patient, chest drainage persisting more than seven days in five patients (20%). One patient developed sinus bradycardia in association with sinus pauses two months after discharge. One patient developed pericardial effusion one month after discharge. CONCLUSIONS: Direct superior and inferior cavopulmonary connections to create Fontan circulation in appropriately selected patients with functionally univentricular hearts can be performed with low risk and a low rate of reintervention. The midterm results are favorable. PMID- 23804776 TI - Fontan Procedure at 2,240 m Above Sea Level. AB - The modified Fontan procedure represents the final stage of reconstructive surgery for most patients with functionally univentricular hearts. Although outcomes following Fontan procedures performed at sea level are widely reported, less has been documented and reported concerning outcomes in regions at high altitude. To clarify the main features involved, we present our institutional experience with Fontan operations performed in Mexico city (2,240 m above the sea level), with an emphasis on historical evolution of treatment. A retrospective and observational study was undertaken, which included 98 patients over a period of 18 years, and clinical outcomes in terms of morbidity and mortality were analyzed. A change in operative technique from intra-cardiac nonfenestrated Fontan procedure to extra-cardiac fenestrated technique occurred in 2001. Early mortality rates before and after this change in surgical approach were 26% and 4.7%, respectively. The most common morbidity was the occurrence of pleural effusions (98% of patients), which also appears to be a risk factor for operative mortality. Much remains unknown about the pathophysiology of the Fontan circulation at high altitude, and we need to develop morphological study protocols that include pulmonary biopsy to increase our knowledge and inform our therapeutic actions. PMID- 23804777 TI - Postoperative serum cortisol concentration and adrenal insufficiency in neonates undergoing open-heart surgery. AB - BACKGROUND: We sought to determine whether immediate postoperative serum cortisol concentration predicts adrenal insufficiency in neonates after cardiac surgery with cardiopulmonary bypass. We hypothesized that cortisol <10 ug/dL would be associated with increased catecholamine requirements and fluid resuscitation and would predict hemodynamic responsiveness to exogenous steroids. METHODS: Retrospective study of 41 neonates was carried out for the levels of cortisol in the immediate postoperative period; of whom, 15 received steroids due to high levels of inotropic support. Laboratory and clinical outcomes were collected. RESULTS: Median cortisol was 12 ug/dL (interquartile range: 5.2-27.4). Levels of cortisol <10 ug/dL was not associated with any clinical variable indicative of increased illness severity. Peak lactate (9.1 vs 11.8 mmol/L, P = .04) and maximum arteriovenous saturation difference ([Sao 2 - Svo 2] 28% vs 32%, P = .05) were both lower among patients with levels of cortisol <10 ug/dL. Six (40%) patients had a significant hemodynamic improvement within 24 hours after receiving steroids (responders), although there was no statistical difference between levels of cortisol in responders versus nonresponders. Level of cortisol was positively correlated with maximum lactate (P < .001), maximum Sao 2 - Svo 2 (P < .001), maximum inotrope score (P = .014), initial 24-hour fluid intake (P = .012), and time to negative fluid balance (P = .008) and was negatively correlated with initial 24-hour urine output (P < .001). CONCLUSIONS: Low cortisol obtained in the immediate postoperative period is not associated with worse postoperative outcomes or predictive of steroid responsiveness. In contrast, elevated levels of cortisol are positively correlated with severity of illness. The use of an absolute cortisol threshold to identify adrenal insufficiency and/or guide steroid therapy in neonates after cardiac surgery is unjustified. PMID- 23804778 TI - Prognostic value of perioperative near-infrared spectroscopy during neonatal and infant congenital heart surgery for adverse in-hospital clinical events. AB - BACKGROUND: Perioperative monitoring with multisite near-infrared spectroscopy (NIRS) for congenital cardiac surgery with cardiopulmonary bypass may aid in predicting adverse clinical outcomes. METHODS: Forty-one consecutive neonates and infants undergoing bypass were monitored with right + left cerebral and renal NIRS. Near-infrared spectroscopy and lactate were measured at 20 time points, from baseline 1 day preoperatively, during bypass and modified ultrafiltration (MUF; 10 minutes), until 24 hours postoperatively. Adverse events were extracorporeal membrane oxygenation (ECMO)/death, prolonged intensive care unit (ICU) or length of hospital stay. RESULTS: Perioperative mean renal NIRS remained higher than baseline (n = 41) as did cerebral NIRS in all undergoing biventricular repair. During bypass (n = 41), mean right and left cerebral NIRS were equal. During MUF, cerebral and renal NIRS values increased (P < .001). Cerebral NIRS and lactate inversely correlated during the first six postoperative hours. Extracorporeal membrane oxygenation /death occurred in four patients, correlating with cerebral and renal NIRS below 45% (P = .030) and 40% (P = .019) at anytime, respectively, and with mean lactate levels >9.3 mmol/L in the first postoperative 24 hours (P < .001). Among survivors, renal NIRS below 30% at any time predicted a longer ICU stay. CONCLUSIONS: At bypass conclusion, 10 minutes of MUF does not adversely affect cerebral or renal NIRS. Left and right cerebral NIRS are equal, so that biparietal cerebral NIRS monitoring is probably not warranted. Perioperative cerebral and renal NIRS readings, respectively, below 45% and 40% correlate with ECMO/death and renal NIRS below 30% with prolonged ICU stay. Cerebral NIRS and lactate levels showed a strong inverse correlation during the first six postoperative hours. PMID- 23804779 TI - Indications and risks of delayed sternal closure after open heart surgery in neonates and early infants. AB - BACKGROUND: Delayed sternal closure (DSC) has been an essential part of neonatal and infant heart surgery. Here, we report our single institution experience of DSC for eight years. METHODS: The successive 188 patients were analyzed retrospectively. Sternum was closed at the end of the operation in 97 (51.6%) patients (primary sternal closure [PSC] group). Sternum was left open in 91 (48.4%) patients. Among them, 45 (23.9%) had only skin closure (DSCs group) and 46 (24.4%) had membrane patch closure (DSC membrane [DSCm] group). Median age was higher in PSC group (90 days) than DSCs (11 days) and DSCm groups (9.5 days). RESULTS: Mortality was 1%, 11.1%, and 28.2% in PSC, DSCs, and DSCm groups, respectively (P < .05). Univariate analysis recognized the neonatal age (odds ratio [OR] = 4.2), preoperative critical condition (OR = 5.3), cardiopulmonary bypass time >180 minutes (OR = 4), and cross clamp time >99 minutes (OR = 3.9) as risk factors for mortality. Total morbidity rate was higher in DSCm group (73.9%) than DSCs group (51.1%) and PSC group (23.7%; P < .001). Mechanical ventilation time, intensive care unit stay, and hospital stay were longer in DSCs and DSCm groups than PSC group (P < .001). The incidence of hospital infection was also higher in DSCs (43.5%) and DSCm (33.3%) groups than PSC group (20.6%; P < .05). But there was no difference in the incidence of sternal wound complications, including both deep and superficial (4.1%, 8.8%, and 4.4%, respectively). CONCLUSION: Although the risk of sternal wound complications is not different, patients who necessitate DSC (using both skin and membrane closure techniques) have more complicated postoperative course than patients with PSC. PMID- 23804780 TI - Air transported pediatric rescue extracorporeal membrane oxygenation: a single institutional review. AB - BACKGROUND: Pediatric extracorporeal membrane oxygenation (ECMO) programs are sophisticated endeavors usually found only in high-volume cardiac surgical programs. Worldwide, many cardiology programs do not have on-site pediatric cardiac surgery expertise. Our single-center experience shows that an organized multidisciplinary rescue-ECMO program, in collaboration with an accepting facility, can achieve survival rates comparable to modern era on-site ECMO. METHODS: A retrospective review was conducted of all patients initiated on rescue ECMO from 2004 to 2009 in a single academic pediatric hospital without a pediatric cardiac surgery program. All aspects of ECMO were formalized using Failure Mode Effects Analysis. RESULTS: Eight patients were initially cannulated for ECMO at our institution. Six were subsequently transported by air to the receiving facility 1,305 km away. Extracorporeal membrane oxygenation was initiated in 0.2% of our Pediatric Intensive Care Unit admissions and in 0.52% of all our pediatric cardiac patients. Mean age was 4.0 years (7 weeks to 15 years). Indications for ECMO initiations were cardiogenic shock (n = 5) and acute respiratory distress syndrome (n = 3). Six had veno-arterial- and two had veno veno ECMO. Two patients were not transported (one death and one weaned locally). Six patients were successfully transported within 2 to 24 hours, with a survival to hospital discharge rate of 67% (four of six). Median total time on ECMO was 5.5 days. Complication rate was 50% (4/8). CONCLUSIONS: Our rescue-ECMO survival results were comparable to that of current published results from established pediatric ECMO programs. Air transport of ECMO patients can be performed safely using an organized multidisciplinary team approach. PMID- 23804781 TI - The third aldo castaneda lecture: the neglect of neonatal/infant cardiac disease in Africa--continental genocide? AB - The advances made in pediatric cardiology and cardiac surgery now make it possible for survival into adulthood of the majority of children born with congenitally malformed hearts. On the African continent, unfortunately, this is only a dream as roughly 280,000 neonates born every year on the continent are left untreated, demonstrating the natural history of the congenitally malformed heart by default. Pediatric cardiac surgery is available in very few countries on this continent. This article takes a look at the problem of neonates and infants born with cardiac defects on the continent and attempts an extrapolation of the magnitude of the problem. Using the experience gained at the Walter Sisulu Pediatric Cardiac Center since its inception in 2003, issues of financing indigent patients, training local personnel, and building capacity through infrastructure development and regional cooperation are discussed. The success of the Walter Sisulu model demonstrates the benefits of treatment for the neonates and infants with congenitally malformed heart, on the continent. It is emphasized that African governments and all stakeholders must participate to ensure a good outcome for the African child with congenital cardiac defect. PMID- 23804782 TI - The Switch Back Ross Operation: Report of Two Cases With Good Medium-to-Long-Term Follow-Up. AB - Submitted July 20, 2011; Accepted October 6, 2011. Neoaortic root dilatation and neoaortic valve regurgitation following the arterial switch operation for transposition of the great arteries may ultimately require neoaortic root and/or neoaortic valve surgery. The ideal surgical approach to these lesions remains debatable. Hazekamp et al, in 1997, introduced the replacement of the neoaortic root by the neopulmonary autograft and named this procedure the switch back Ross operation. We report two patients who were successfully treated at our institution with the switch back Ross operation, with good results at, respectively, four- and five-year follow-up. PMID- 23804783 TI - Successful Bridge to Transplant Using the TandemHeart(R) Left Ventricular Assist Device in a Pediatric Patient. AB - A nine-year-old girl ( 23 kg) was successfully bridged to heart transplantation with the TandemHeart((r)) centrifugal pump for 10 days. Although this cardiac assist device has been used in adults for short-term mechanical support, its use in the pediatric population has not been widely reported. The TandemHeart((r)) was easy to implant, achieved appropriate flows in this pediatric patient, and allowed for extubation and ambulation while awaiting a donor heart. PMID- 23804784 TI - Fontan operation for patients with complex anatomy: the intra-atrial conduit technique. AB - The extracardiac conduit type of total cavopulmonary connection (TCPC) is the most common variation of the modified Fontan operation in current use. For patients with some forms of complex anatomy (eg, dextrocardia in situs solitus or asplenia syndrome), we have adopted a different technique: interposition of an intra-atrial conduit between the inferior vena cava (IVC) and the superior vena cava-right pulmonary artery (SVC-RPA) connection. We report our experience with six patients. PMID- 23804785 TI - A rare coronary collateral in pulmonary atresia and intact septum with coronary sinusoids. AB - A neonate with pulmonary atresia and intract ventricular septum, ventriculocoronary sinusoids, bilateral coronary ostial atresia, and a rare collateral vessel between the descending thoracic aorta and the coronary system is described. The clinical course in this infant included extracorporeal life support and coil occlusion of the collateral in order to manage multiple ischemic events. PMID- 23804786 TI - Concordant ventriculoarterial connections with parallel arterial trunks, divided left atrium, and juxtaposed atrial appendages. AB - We describe a patient with concordant ventriculoarterial connections with parallel arterial trunks, divided left atrium (cor triatriatum sinister), ventricular septal defect, bilateral superior caval veins, and juxtaposed atrial appendages. The aorta was anterior and left sided. We discuss the morphological features of this rare condition, and the diagnostic dilemma it produced. PMID- 23804787 TI - Successful immediate newborn ross-konno and mitral valve repair following fetal aortic valvuloplasty. AB - Perinatal management of severe mitral regurgitation (MR) and aortic stenosis (AS) is difficult; mortality is high, and there are few reports of successful postnatal biventricular repairs. We report a patient with severe MR and AS, diagnosed prenatally, that underwent a fetal aortic valvuloplasty and a successful modified Ross-Konno procedure with concomitant mitral valve repair shortly after birth. PMID- 23804788 TI - Repair of anomalous left coronary artery from pulmonary artery in an infant with respiratory syncytial virus bronchiolitis. AB - In anomalous left coronary artery from the pulmonary artery (ALCAPA), infants 6 to 12 weeks will often present with symptoms consistent with reflux or bronchiolitis. In those infants diagnosed with both ALCAPA and concomitant active respiratory syncytial virus (RSV) bronchiolitis, others have reported delaying revascularization therapy until resolution of the RSV bronchiolitis. Here, we report the case of a three-month-old infant, diagnosed with ALCAPA and active RSV bronchiolitis, who underwent successful myocardial revascularization within 24 hours of presentation and diagnosis. PMID- 23804789 TI - Anomalous origin of the right coronary artery from the pulmonary artery: unusual presentation in an adult. AB - We report an anomalous right coronary artery origin from the pulmonary artery presenting in an adult patient. PMID- 23804790 TI - Classical windsock deformity of ruptured sinus of valsalva seen in transesophageal echocardiography. AB - A 25-year-old male patient found to have ruptured sinus of Valsalva aneurysm with subpulmonic ventricular septal defect was repaired successfully. Intraoperative transesophageal echocardiography images showed classical windsock deformity. PMID- 23804791 TI - Select abstracts from cardiology 2012: the 16th annual update on pediatric and congenital cardiovascular disease orlando, Florida, february 22-26, 2012. PMID- 23804792 TI - Disparities in fruits and vegetables consumption in houston, Texas: implications for health promotion. AB - BACKGROUND: The consumption of the recommended amount of fruits and vegetables is believed to help prevent nutrient deficiency disorders and lower the risk of several chronic diseases. Information on the disparity of fruit and vegetable consumption may be useful in designing targeted health promotion programs for increasing fruit and vegetable consumption. The objective of this pilot study was to examine disparities in fruit and vegetable consumption among Houston residents based on sociodemographic characteristics. METHODS: The authors conducted bivariate and multivariate analyses to examine the associations between sociodemographic characteristics and fruit and vegetable consumption using a random digit dialing (RDD) health survey data (N = 1001) collected in Houston, Texas. RESULTS: Bivariate analysis showed that there were significant associations between fruit and vegetable consumption and education (P < .01); race/ethnicity (P < .001); marital status (P < .001); and employment status (P < .05). Multivariate analysis indicated that fruit and vegetable consumption pattern could be significantly (P <= .05) predicted by gender, race, and marital status. Respondents who were of other race category were less likely than whites to consume fruits and vegetables, while married respondents and women were more likely to consume fruits and vegetables compared to the unmarried and men, respectively. IMPLICATIONS: Health promotion programs aimed at increasing the consumption of fruits and vegetables should consider developing targeted intervention for men, people with less formal education, minority race/ethnicity, people who are unemployed, and those who are unmarried. PMID- 23804793 TI - A collaborative approach to control hypertension in diabetes: outcomes of a pilot intervention. AB - We sought to develop and pilot an intervention to improve blood pressure (BP) and other intermediate outcomes (hemoglobin A1c, low-density lipoprotein cholesterol) of diabetes in a low-income, ethnically diverse population. English- or Spanish speaking primary care patients with BP >= 140/90 on 2 visits in the past 12 months and any level of A1c were randomized to usual care (n = 24) or intervention (n = 31). Home health nurses assessed self-management and medication adherence, and they performed health behavior counseling. Participants transmitted daily BP and glucose results using simple home telemetry units to the nurse coordinator; these results were then aggregated and transmitted weekly to primary care providers to facilitate intensified treatment. After controlling for baseline levels, a significantly larger proportion of the intervention group was at goal for BP (adjusted OR = 9.3, P = .006) and A1c (AOR = 4.3, P = .049), but not for low-density lipoprotein cholesterol (AOR = 1.1, P =.86). Clinicians made more BP medication changes in the intervention group compared to the control group (8.3 vs 3.8, approaching significance at P = .06). Self-reported medication adherence and self-care behaviors were not significantly improved. We successfully developed a telephone- and email-based collaboration between home health nurses and primary care clinicians to address poorly controlled hypertension in an ethnically diverse population. The intervention, combining enhanced feedback to patients and their primary care providers and individualized behavior change support by home health nurses, is effective for improving BP and glucose in this setting. PMID- 23804794 TI - An Integrated, Clinician-focused Telehealth Monitoring System to Reduce Hospitalization Rates for Home Health Care Patients with Diabetes. AB - Diabetes is one of the leading causes of death and disability in the United States, and hospitalization rates related to this health condition are high and costly to the United States health care system. The purpose of this study was to examine the effect of an integrated, clinician-focused telehealth monitoring system on the probability of hospitalization for home health care patients with diabetes. The study included 2009 data from 699 Medicare beneficiaries receiving home health services in Texas and Louisiana. Propensity score matching, logistic regression, and post-estimation parameter simulation were used to assess how telehealth affects the probability of hospitalization during the first 30 days of home health care. The 30-day hospitalization probability for telehealth and non telehealth patients was 7% and 19%, respectively. Patients in the telehealth group had a 12 (95% confidence interval = 4.2-20.3) percentage point-lower probability of hospitalization within the first 30 days of home health care than non-telehealth matched patients. The results suggest that telehealth monitoring systems that integrate skilled clinicians with critical care experience can lead to substantially lower hospitalization rates during the first 30 days of home health care, large cost savings, and more effective home health management of patients with diabetes. PMID- 23804795 TI - Prevalence of diagnosis and staging of chronic kidney disease by primary care providers in a rural state. AB - CONTEXT: The Kidney Disease Outcomes and Quality Initiative guidelines are the most widely disseminated guidelines regarding the clinical evaluation and management of chronic kidney disease (CKD). PURPOSE: Assess the prevalence of diagnosis and staging of CKD by primary care providers (PCPs). METHODS: For the purpose of this assessment, stage 3 CKD was defined as an estimated glomerular filtration rate (eGFR) between 30 and 59 mL/min/1.73 m(2) for at least 3 months. Eligible individuals were 1447 white, nondiabetic patients 40-74 years of age. RESULTS: Information on a random sample of 110 patients was analyzed. Chronic kidney disease was reported in 22% of the patients, whereas only 7% of patients had both CKD and stage 3 reported in their medical record. PCPs were significantly more likely to record CKD in male than in female patients (79% vs 34%; P < .001). Patients who had CKD recorded were significantly more likely to be referred to a nephrologist (46% vs 3%; P < .001). Even among patients who had a diagnosis of coronary artery disease, were older, or had lower eGFR, a diagnosis of CKD was less likely to be recorded. Only 22% had their serum phosphorus, 12% their parathyroid hormone, and 64% a urinalysis recorded. CONCLUSIONS: This study found that the prevalence of recording CKD and staging by PCPs was low. Primary care providers were more likely to record CKD in male than in female patients. Finally, testing for bone disease is underperformed. There is a need to identify mechanisms to improve evaluation and management of CKD by PCPs. PMID- 23804796 TI - The evaluation of electrocardiogram findings in acute abdominal pain patients admitted to the emergency department. AB - The aim of this study was to determine the diagnostic value of electrocardiogram in differential diagnosis of patients with nonspecific abdominal pain. This prospective observational study was conducted in a university emergency department over 2 weeks. One hundred twenty patients with complaints of abdominal pain were admitted to the emergency department. During the study period, a total of 120 cases were evaluated. The final emergency department disposition status of the 120 patients was 1 (0.8%) died in the emergency department, 28 (23.3%) were admitted to the general ward, 27 (22.5%) were admitted to other services, and 10 (8.3%) were admitted to the cardiology service and coronary care unit. The examination indicated that 38 (31.7%) patients with abdominal pain showed cardiac pathologies on their electrocardiograms; 3 (2.5%) patients with abdominal pain admitted to cardiology service had ST elevation, and 2 (1.6%) had electrocardiogram depression on their electrocardiograms. According to the results, the authors claim that the electrocardiogram played an important role in the treatment and diagnosis of patients presenting with abdominal pain in emergency medicine. For this reason, it was thought that emergency medicine specialists should understand the basis of the perception of abdominal pain and develop a focused approach to the initial evaluation of these patients. PMID- 23804797 TI - JeffHOPE: The Development and Operation of a Student-Run Clinic. AB - Established in 1992, JeffHOPE (Health Opportunities, Prevention and Education) of Jefferson Medical College in Philadelphia, Pennsylvania, is one of the largest and most robust Student-Run Clinics (SRCs) in the country. It operates 5 weekly clinics at 6 locations throughout Philadelphia, sees over 2000 patient visits annually, and has a staff of over 60 medical student volunteers. This case study describes JeffHOPE's origins, mission, services, organizational structure, and funding. Pertinent SRC topics from the literature are examined, revealing potential areas of research, growth and development for the organization. Finally, suggestions are made as to how JeffHOPE can apply a framework to better fulfill its mission, providing a template for reflection and planning internally and for SRCs nationwide. PMID- 23804798 TI - Underevaluation of cardiovascular risk factors in patients with nonaccidental falls. AB - BACKGROUND: The incidence of adult patients with falls seeking medical assistance in the Salt Lake City area, Utah, is 28,000 per million adult inhabitants. OBJECTIVE: We sought to evaluate the prevalence of cardiovascular risk assessment and cardiovascular abnormalities in patients presenting with nonaccidental falls at the University of Utah hospital and its affiliated clinics. METHODS: We conducted a search of all patients in the University of Utah patient database as well as 9 affiliated primary care and family practice clinics in Utah who were evaluated for a "fall" during October 2009. We analyzed the records of 338 patients who had a fall within the previous 3 months. Nonaccidental falls were defined as falls unrelated to a contact incident or "slip or trip." RESULTS: Nonaccidental falls occurred in 81 (24%) patients, 39 of these being >=65 years old. Cardiovascular risk assessment and specifically orthostatic testing were evaluated in 40% and 3% of the patients, respectively. In patients >=65 years old, the prevalence of cardiovascular risk assessment, orthostatic testing, and carotid sinus massage were equally low at 56%, 5%, and 0%, respectively. Cardiovascular abnormalities were present in 17 (21%) patients, with 9 of them being referred for cardiac evaluation. CONCLUSION: Our results highlight the inconsistent assessment of potential cardiovascular risk factors in patients with nonaccidental falls, supporting the adoption of a standardized approach in these patients. PMID- 23804799 TI - Attitudes of general practitioner registrars and their trainers toward obesity prevention in adults. AB - Obesity prevalence in developed countries is around 25% and rising. Prevention is beginning to receive attention. In the United Kingdom, general practice provides services to most of the population; on average, a patient is seen 4 times a year. Doctors' attitudes toward obesity prevention have not been well documented. OBJECTIVES: Obtain doctors' views toward obesity prevention and determine any differences between registrars and their trainers. METHODS: During 2006-2007, a postal questionnaire was sent to all general practitioner registrars in Scotland and their trainers. The questions included individual details, opinions about current obesity prevention strategies, and facts about current obesity prevention practices. RESULTS: Of those targeted (103 registrars, 91 trainers), 51% responded, representing 5% of all general practitioners in Scotland. Most agreed obesity and its prevention were important. However, more experienced practitioners were less convinced as to whether primary care could or should help with obesity prevention. Individual change was viewed as important, whereas primary care screening was of least importance. CONCLUSION: As the largest survey on doctors' attitudes about obesity prevention, these results indicate that obesity and its prevention are important but that there are concerns and differences between registrars and trainers, in that trainers are more neutral about their agreement. A multifaceted approach building on current good practices of general practitioners with support from other specialty care providers may help to minimize the risk of alienation, fear, and resistance to primary care involvement for both treatment and prevention of obesity. However, resources and training would be necessary, along with methods to protect the doctor/patient relationship. PMID- 23804800 TI - Provider practices in prediabetes intervention and diabetes prevention: application of evidence-based research in the medical office setting. AB - A cross-sectional study was performed to determine if evidence-based research in prediabetes management is utilized in the medical office setting in an effort to reduce the incidence of type 2 diabetes, and to determine whether any particular demographic variables including body mass index (BMI) and provider type (physician and nonphysician) predict referrals for prediabetes management (P = .05). Electronic medical records (n = 82 317) were examined for International Classification of Diseases (ICD) codes and keywords disclosing a diagnosis of prediabetes. The records of individuals with diagnosed prediabetes were subsequently examined for keywords and ICD codes for lifestyle intervention. Logistic regression was utilized to determine whether any particular demographic factors significantly predicted whether medical providers will provide recommendations or referrals for lifestyle management of prediabetes. Age, BMI, and race were found to be significant predictors for recommendations/referrals, although overall rates of recommendation or referral were poor. Provider education and enhancements in organizational policy related to referral procedures and continuity of care from the clinical setting to the community health setting are crucial in promoting early interventions in prediabetes to offset the current projections for an increase in diabetes incidence. PMID- 23804801 TI - Primary care physician reports of amount of time spent with male patients in prostate cancer screening discussions. AB - BACKGROUND: Major health organizations recommend that physicians discuss the risks and benefits of prostate cancer screening with men before ordering tests. The length of time that health care providers spend discussing prostate cancer screening-related issues with patients has been given little attention. The purpose of this study was to determine the amount of time that primary care physicians (PCP) in the United States reported spending in discussions about prostate cancer screening with patients by selected PCP individual, practice related, and screening-related factors. METHODS: Data were obtained from the 2007 2008 National Survey of Primary Care Physician Practices Regarding Prostate Cancer Screening. We determined whether PCP characteristics were associated with amount of time spent with patients. RESULTS: Results showed that female, African American or other race, and older PCP spend more time (above the median) with patients compared to their referents. Also, more time spent with male patients was more often associated with PCP having practices in urban inner city areas as well as when the screening decision was shared between the PCP and the patient/family. CONCLUSION: Results from this study offer some insight into the amount of time that PCP report spending with patients in discussing prostate cancer screening-related issues specifically, and confirms the involvement of individual as well as practice-level factors. PMID- 23804802 TI - Frequency of Monitoring Hemoglobin A1C and Achieving Diabetes Control. AB - OBJECTIVES: The American Diabetes Association recommends measuring hemoglobin A1C levels (A1C) at least semiannually in diabetic patients who have stable glycemic control and quarterly in patients whose therapy has changed or who are not meeting glycemic goals. These guidelines were based on expert consensus without reference to actual clinical data. The main objective of this study was to assess association between meeting a target A1C level of <7% and adherence to monitoring guidelines. Secondary objectives were to determine the proportion of diabetic patients in the authors' practice who met the A1C monitoring guidelines and to assess whether meeting the target A1C level is associated with other information easily abstracted from patients records, namely age, gender, and types of therapy. METHODS: This study employed a case control design. Records of 193 type 2 diabetic patients seen over a 6-month period in a rural family medicine clinic were analyzed. Assessment of diabetes control was based on the most recent A1C level, with <7% considered controlled. Adherence to guidelines was assessed by determining frequency of testing during the preceding 12-month period. RESULTS: Ninety-eight patients (51%) adhered to the American Diabetes Association guidelines on frequency of monitoring A1C. Median levels of adherent and nonadherent patients differed significantly (6.5 vs 7.3, P < .001, Mann-Whitney test). Logistic regression analysis showed that "diabetes control" based on the A1C level is positively associated with adherence to the guidelines, negatively associated with intensity of therapy, and not associated with gender or age. CONCLUSION: This study supports the usefulness of American Diabetes Association practice guidelines on the frequency of monitoring A1C levels in diabetic patients. PMID- 23804803 TI - Testing adolescents for sexually transmitted infections in urban primary care practices: results from a baseline study. AB - OBJECTIVE: Sexually active urban adolescents experience a high burden of sexually transmitted infections (STI). Adolescents often access medical care through general primary care providers; their time alone with a provider increases the likelihood that youth will disclose risky behavior, which may result in STI testing. Our goals were to assess the association (if any) between the provision of time alone and STI testing, and describe the rates of STI testing among sexually active adolescents in urban primary care. METHODS: Youth (aged 12-19 years) presenting for care at 4 urban health centers were invited to complete post-visit surveys of their experience. Sexually transmitted infection screening rates were obtained from the clinical information systems (CIS); CIS data were linked to survey responses. RESULTS: We received 101 surveys. Surveyed youth experienced time alone in 69% of all visits. Time alone varied by age (older teens experienced more time alone), and it occurred more frequently in preventive visits (71%) versus nonpreventive visits (33%). It did not vary by gender. Forty two of the 46 sexually active youth experienced time alone. Screening rates for sexually active females, either at the index visit or within 6 months prior to the index visit, were 17.9% for human immunodeficiency virus and 32.1% for gonorrhea/Chlamydia. No sexually active surveyed males were tested. Overall screening rates varied widely across practices (human immunodeficiency virus 0% 29%; gonorrhea/Chlamydia 7%-29%). There was no difference in screening rates among youth with and without time alone. CONCLUSION: STI testing for adolescents is being conducted in this primary care urban population, especially for sexually active females. However, clinicians in this setting are not screening females consistently enough and rarely screen males. We were unable to test our hypothesis that provision of time alone was associated with a higher rate of STI testing. Site differences suggest substantial variation in clinician practices that should be addressed in quality improvement interventions. PMID- 23804804 TI - Ecstacy-associated hyponatremia: why are women at risk? PMID- 23804805 TI - A case of localized AL amyloidosis of the sigmoid colon with lymphocytes exhibiting a premalignant status. PMID- 23804806 TI - Estimated disability-adjusted life year (DALY) in Japan in GLOBOCAN 2008. PMID- 23804807 TI - The role of Bruton's tyrosine kinase in the development and BCR/TLR-dependent activation of AM14 rheumatoid factor B cells. AB - The protein kinase Btk has been implicated in the development, differentiation, and activation of B cells through its role in the BCR and TLR signaling cascades. These receptors and in particular, the BCR and either TLR7 or TLR9 also play a critical role in the activation of autoreactive B cells by RNA- or DNA-associated autoantigens. To explore the role of Btk in the development of autoreactive B cells, as well as their responses to nucleic acid-associated autoantigens, we have now compared Btk-sufficient and Btk-deficient mice that express a prototypic RF BCR encoded by H- and L-chain sdTgs. These B cells bind autologous IgG2a with low affinity and only proliferate in response to IgG2a ICs that incorporate DNA or RNA. We found that Btk-sufficient RF(+) B cells mature into naive FO B cells, all of which express the Tg BCR, despite circulating levels of IgG2a. By contrast, a significant proportion of Btk-deficient RF(+) B cells acquires a MZ or MZ precursor phenotype. Remarkably, despite the complete inability of RF(+) Xid/y B cells to respond to F(ab')2 anti-IgM, RF(+) Xid/y B cells could respond well to autoantigen-associated ICs. These data reveal unique features of the signaling cascades responsible for the activation of autoreactive B cells. PMID- 23804809 TI - Inhibition of pre-B cell colony-enhancing factor (PBEF/NAMPT/visfatin) decreases the ability of human neutrophils to generate reactive oxidants but does not impair bacterial killing. AB - NAMPT, also known as PBEF and visfatin, can act extracellularly as a cytokine like molecule or intracellularly as a NAMPT, regulating NAD biosynthesis in the NAD salvage pathway. Inhibitors of NAMPT have anti-inflammatory and anticancer activity and are finding use as therapeutic agents. In view of the importance of NAD metabolism in neutrophil function, we determined the effects of NAMPT inhibition on a variety of neutrophil functions associated with their role in host protection against infections. Incubation of human neutrophils with the NAMPT inhibitor APO866 decreased neutrophil NAD(P)/H levels in a dose- and time dependent manner but without a concomitant change in cell viability. NAMPT inhibition did not affect the expression of a number of cell-surface receptors involved in adhesion and opsono-phagocytosis, but the respiratory burst was decreased significantly. Whereas opsono-phagocytosis of Staphylococcus aureus was unaffected by NAMPT inhibition, intraphagosomal oxidant production was decreased. However, the killing efficiency of neutrophils was unaffected. These data indicate that therapeutic NAMPT inhibition is unlikely to have deleterious effects on host protection against infections, in spite of this ability to down regulate neutrophil respiratory burst activity significantly. PMID- 23804808 TI - Human beta-defensin 3 induces STAT1 phosphorylation, tyrosine phosphatase activity, and cytokine synthesis in T cells. AB - The AMP hBD-3 stimulates numerous immune effector functions in myeloid cells and keratinocytes, predominantly through the MAPK signaling cascade. In contrast, hBD 3 was reported to neutralize the activation of T cells by antagonizing MAPK signaling initiated by SDF-1alpha through CXCR4. With the use of complementary proteomic and immunochemical approaches, we investigated possible stimulatory effects of hBD-3 on T cells and demonstrate that hBD-3 induces STAT1 tyrosine phosphorylation within 5 min yet is unable to induce MAPK activation. Inclusion of a PTPase inhibitor increased hBD-3-induced phosphorylation dramatically, suggesting that hBD-3 also stimulates PTPase activity concurrently. The increase in PTPase activity was confirmed by demonstrating that hBD-3 suppresses IFN-gamma induced STAT1 tyrosine phosphorylation but not STAT1 serine and ERK1/2 threonine phosphorylation and stimulates the translocation of SHP-2 into the nucleus within 15 min. The signaling pathways initiated by hBD-3 may lead to the observed enhancement of distinct T cell effector functions during TCR activation, such as the increase in IL-2 and IL-10, but not IFN-gamma secretion. Thus, hBD-3 initiates distinct lineage-specific signaling cascades in various cells involved in host defense and induces a concurrent tyrosine kinase and tyrosine phosphatase signaling cascade that may activate simultaneously the targeted T cells and inhibit their response to other immune mediators. Furthermore, these results suggest that this evolutionarily conserved peptide, which exhibits a broad spectrum of antimicrobial and immunomodulatory activities, serves to integrate innate and adaptive immunity. PMID- 23804811 TI - On being multidisciplinary: a tribute to a teacher. PMID- 23804812 TI - Why I believe the hybrid norwood is inferior to the norwood/sano procedure. PMID- 23804810 TI - LDL particle core enrichment in cholesteryl oleate increases proteoglycan binding and promotes atherosclerosis. AB - Several studies in humans and animals suggest that LDL particle core enrichment in cholesteryl oleate (CO) is associated with increased atherosclerosis. Diet enrichment with MUFAs enhances LDL CO content. Steroyl O-acyltransferase 2 (SOAT2) is the enzyme that catalyzes the synthesis of much of the CO found in LDL, and gene deletion of SOAT2 minimizes CO in LDL and protects against atherosclerosis. The purpose of this study was to test the hypothesis that the increased atherosclerosis associated with LDL core enrichment in CO results from an increased affinity of the LDL particle for arterial proteoglycans. ApoB-100 only Ldlr(-/-) mice with and without Soat2 gene deletions were fed diets enriched in either cis-MUFA or n-3 PUFA, and LDL particles were isolated. LDL:proteogylcan binding was measured using surface plasmon resonance. Particles with higher CO content consistently bound with higher affinity to human biglycan and the amount of binding was shown to be proportional to the extent of atherosclerosis of the LDL donor mice. The data strongly support the thesis that atherosclerosis was induced through enhanced proteoglycan binding of LDL resulting from LDL core CO enrichment. PMID- 23804814 TI - Pregnancy in patients with tetralogy of fallot: outcome and management. AB - The objective was to evaluate pregnancy outcome in women with tetralogy of Fallot, including impact of corrective cardiac surgery on pregnancy outcome in a tertiary care referral hospital. The study was a retrospective analysis of maternal and perinatal outcome in all women with tetralogy of Fallot treated in a cardio-obstetric unit during 1996-2008. Ten women had 21 pregnancies. Of the 10 women, 7 with uncorrected tetralogy of Fallot had 16 pregnancies. Obstetric and cardiac complications were more frequent in the uncorrected group (70% vs 40% and 40% vs nil, respectively). The frequency of spontaneous abortion and preterm birth was greater in the uncorrected group (37.5% vs nil and 25% vs nil, respectively). The percentage of babies who were small for gestational age was 40% in the uncorrected group and 20% in the corrected group. Tetralogy of Fallot carries substantial risk to mother and fetus. Surgical correction is associated with improved maternal and perinatal outcome. These patients need detailed prepregnancy evaluation and should be under joint supervision of an obstetrician, a cardiologist, a congenital cardiac surgeon, and an anesthetist. PMID- 23804813 TI - Surgical treatment of transposition of great arteries with ventricular septal defect and left ventricular outflow tract obstruction: midterm results. AB - Our purpose was to evaluate our single-center experience with the treatment of transposition of the great arteries (TGA) with ventricular septal defect (VSD) and left ventricular outflow tract obstruction (LVOTO). Between 1992 and 2009, 42 patients were operated on. Twenty-three patients underwent the Rastelli operation, 8 patients underwent arterial switch operation (ASO) with associated LVOTO procedures, 4 patients underwent the reparation a l'etage ventriculaire (REV) procedure, 3 patients underwent the Bex/Nikaidoh (BN) procedure, and the Fontan operation was performed in 4 patients. The median age at final operation was 20.7 months (range, 0.3-234). The overall survival rate was 97% (1 early death), with a median follow-up of 8.2 years. There were no differences in survival among the surgical groups. Event-free survival was 100%, 84%, 59%, and 24% at 1, 5, 10, and 15 years of follow-up, respectively, with it being worse in the Rastelli group (P < .0348). The last echocardiography showed good function of the systemic ventricle in all patients; LVOTO pressure gradient greater than 30 mm Hg was observed in 2 patients (5%), and right ventricular outflow tract obstruction (RVOTO) pressure gradient >30 mm Hg was observed in 12 patients (31%). All patients are in sinus rhythm, and 74% of them are without medication. All surgical approaches are safe and show excellent midterm functional outcome. ASO is the best option if the LVOTO is resectable. Intraventricular rerouting (Rastelli or REV) is the method of choice in the majority of patients, but Rastelli has a significant reintervention rate. The BN operation has the potential to minimize utilization of the Fontan operation, which was used in the past if the intracardiac anatomy was unfavorable. PMID- 23804815 TI - Pregnancy in patients with tetralogy of fallot: invited commentary. PMID- 23804816 TI - Mitral annular growth in children following early mechanical mitral valve replacement. AB - Irreparable mitral pathology may lead to early mitral valve replacement (MVR) in children. Often, a small mechanical prosthesis (<23 mm) is required, raising concerns about annular growth in patients who may eventually require subsequent mitral valve re-replacement (MVRR). The aim of this study was to evaluate interval mitral annular growth in this cohort. Between January 1972 and December 2006, 164 children underwent MVR with a mechanical prosthesis; 110 of these children (median age, 4 years; range, 7 days to 14 years) received a small mechanical prosthesis (<23 mm). The most common diagnoses were congenital mitral stenosis (10%), regurgitation (46%), and left atrioventricular valve dysfunction after previous atrioventricular septal defect repair (44%). The cohort was analyzed for age, body surface area (BSA), prosthesis size, and Z score at the time of MVR and MVRR. At the time of MVR, 78 patients had a BSA of 0.77 +/- 0.06 m(2), had an annular size of 24 +/- 0.62 mm (Z score, 2.91 +/- 0.23), and ultimately did not require MVRR. Another cohort, who eventually did require MVRR (n = 24), had an initial BSA at the time of MVR of 0.62 +/- 0.05 m(2) (P = NS vs MVR only) and an annular size of 20 +/- 0.49 mm (Z score, 1.85 +/- 0.22) (P = .008 vs MVR only). In the interval between MVR and MVRR (7.8 +/- 1.1 years), BSA increased to 1.12 +/- 0.07 m(2), and annulus size increased to 24 +/- 0.47 mm (Z score, 1.80 +/- 0.28). These data suggest growth of the mitral annulus following MVR with a small mechanical prosthesis, as evidenced by an unchanged Z score in the setting of normal interval increase in BSA. Additionally, there was a statistically significant difference in initial Z scores between the cohorts requiring MVRR and those who have not needed re-replacement, suggesting that the feasibility of placement of a slightly larger prosthesis may be associated with a decreased need for MVRR. PMID- 23804817 TI - Surgical treatment of severe complications caused by transcatheter closure of ventricular septal defects. AB - The objective was to report the surgical results following failed transcatheter intervention for closure of ventricular septal defects (VSDs). This study is a retrospective analysis of patients (n = 9) from Xijing Hospital (Xi'an, China) with failed transcatheter intervention for VSDs who subsequently underwent open heart surgery. Five patients experienced complications during transcatheter intervention, including third-degree atrioventricular block (III degrees AVB) (n = 2), aortic incompetence (n = 2), or tricuspid incompetence (n = 1). The devices were immediately removed in the catheterization laboratory followed by open heart surgery to repair VSDs. Four patients experienced complications after transcatheter intervention; one patient's device was displaced into the right ventricle, and 3 patients had III degrees AVB. These patients underwent surgery to retrieve the devices and to repair VSDs. All cardiac surgery was performed under general anesthesia and under cardiopulmonary bypass. Postoperatively, all patients recovered uneventfully with no deaths or complications. The patients with III degrees AVB after device implantation recovered sinus rhythm postoperatively, and tricuspid apparatus injuries were surgically repaired with valvuloplasty. Transcatheter interventional VSD closure is safe and effective, but only under the conditions of strict patient selection, proper technique, and device application. Once severe complications are observed and diagnosed, devices should be retrieved immediately, and open heart surgery should be performed to avoid further injury. PMID- 23804818 TI - Transcatheter closure of ventricular septal defects: invited commentary. PMID- 23804819 TI - Hard choices for high-risk patients with critical left ventricular outflow obstruction: contemporary comparison of hybrid versus surgical strategy. AB - Surgical management of high-risk newborns with critical left ventricular outflow tract obstruction (LVOTO) involves difficult decision making and complex procedures associated with significant morbidity and mortality. We sought to compare the outcomes of the hybrid and surgical strategies for the management of neonates with critical LVOTO considered at high risk in a contemporary nonrandomized cohort. This is a retrospective review of all patients undergoing management of critical LVOTO between January 2001 and December 2008. High-risk conditions included prematurity, low birth weight, and genetic or associated cardiac and noncardiac pathology. Analysis was performed based on intention to treat. Primary and secondary outcomes were operative and 6-month mortality. The cohort included 55 patients (21 hybrid and 34 surgical [31 Norwood, 3 biventricular repair]). The cohort had a median age of 4 (range, 1-62) days, mean weight of 2.7 +/- 0.5 kg, and Aristotle comprehensive score of 18.6 +/- 2.9. Low birth weight (P = .0007), prematurity (P = .004), and organ dysfunction (P = .04) were risk factors for operative death. Six-month mortality was associated with need for reintervention (P = .017) in the surgical group and history of organ dysfunction (P = .02) or aortic atresia (P = .03) in the hybrid group. Logistic regression identified low birth weight (P = .05; odds ratio [OR], 5.6 [0.9 34.6]), organ dysfunction (P = .05; OR, 4.7 [0.9-22.5]), and non-hypoplastic left heart syndrome (HLHS) diagnosis (P = .03; OR, 0.06 [0.005-0.93]) as predictors of mortality for the entire cohort. No differences in operative and 6-month mortality were detected between management strategies. Although initial surgical insult is lessened by the hybrid palliation, important interstage mortality and ongoing morbidity result in similar 6-month survival with either strategy. Patient-related factors have a larger influence on outcome than the management strategy chosen. PMID- 23804820 TI - Interpreting congenital heart disease outcomes: what do available metrics really tell us? AB - As interest in measuring the cost and quality of health care has increased, congenital cardiac surgery has increasingly been scrutinized. To accurately assess the performance of one's own congenital cardiac program and to interpret data presented by outside entities, an understanding of the available metrics and their limitations is essential. Our ability to assess quality in congenital cardiac surgery is constrained by the data and evidence available. Evaluating the surgical patient in the context of all patients with congenital cardiac disease will help determine the effectiveness of a program's broader approach. Tracking of long-term outcomes, including morbidity, mortality, neurological status, and functional status will help focus attention on the results and the timeline that matter most to patients and their families. Defining structural and process measures that affect outcome not only may improve the results of congenital cardiac surgery but may lead to improvement in other patient populations that share hospital resources. PMID- 23804821 TI - Management of complete atrioventricular canal defect with aortic arch obstruction: an unresolved debate. AB - Patients with complete atrioventricular canal defect and aortic arch obstruction represent a particular challenge for management. The incidence is rare, so surgical experience is limited. A reasonable treatment option for newborns and young infants with competent atrioventricular valves is the staged approach, with the arch obstruction repaired first, followed at an appropriate interval by repair of the complete atrioventricular canal defect. If there is a significant degree of atrioventricular valve regurgitation, the primary single-stage correction of both aortic arch obstruction and the intracardiac malformation should be undertaken, irrespective of age. It remains to be seen whether this surgical strategy can be adopted for the entire spectrum of atrioventricular canal defect associated with arch obstruction. PMID- 23804822 TI - The walter sisulu paediatric cardiac centre for Africa: proceedings of the 2010 symposium. AB - The symposium's first session was embryological, with emphasis on changing concepts in the development of the heart; double outlet right atrium and isolation of the right subclavian artery provided interesting illustrations. Focus was subsequently directed at management of pulmonary atresia with MAPCAs, hypoplastic left heart syndrome, the primary arterial switch operation in the first 10 weeks of life, Ebstein's anomaly and several others. PMID- 23804823 TI - Surgical management of unusual cardiac tumors in infants and children. AB - While most primary tumors of the heart are histologically benign, they are significant space-occupying lesions with serious functional implications for the heart and lungs. Herein, we highlight our experience with the surgical management of selected cardiac tumors in the pediatric population between 2008 and 2010. (1) Intrapericardial teratomas in the fetus can produce fatal tamponade from compression by the attendant pericardial effusion, and a critical life-saving maneuver preoperatively is to drain the effusion prenatally, followed by an expeditious resection after birth. (2) Rhabdomyomas, the most common of the pediatric cardiac tumors, can be intracavitary, large, and associated with the mitral subvalvular apparatus. (3) Cardiac fibromas should be aggressively resected or at least debulked, especially given their propensity for dysrrhythmias. The key to success is as complete a resection as possible, but not at the expense of other normal structures. (4) Complex nonobstructive hypertrophic myopathy can be thought of as a type of neoplastic overgrowth, and aggressive resection of even midcavitary obstructive lesions should be considered as a viable alternative to primary transplantation. PMID- 23804824 TI - Advances in cardiopulmonary bypass and extracorporeal membrane oxygenation for the neonate and infant. AB - There have been numerous advances in all of the associated subspecialty areas necessary for successful congenital cardiac surgery over the last 2 decades. Within the operating room itself, advances have occurred in instrumentation, prosthetics and biomaterials, surgical optics including loupes, and fiberoptic lighting. However, some of the most important advances have been in the techniques and hardware of cardiopulmonary bypass, the use of extracorporeal membrane oxygenation support in the intensive care unit, and the refinement of strategies to optimize neurodevelopmental outcomes. PMID- 23804825 TI - Minimally invasive options for failing homografts in the pulmonary position. AB - Homograft implantation in the pulmonary position is usually part of initial repair in congenital heart defects with dysplasia or atresia of the pulmonary valve and at the time of the Ross operation. As part of reoperations, homografts are mainly required after nonvalved right ventricular outflow tract procedures. Due to an annual increase of homograft dysfunction, replacement is inevitable. Recently, percutaneous catheter-based valve implantations gain increasing acceptance. Even transventricular pulmonary valve implantation has been reported. Prior to decision making for any surgical or interventional therapy, the right ventricular outflow tract morphology together with additional pathologies need to be assessed. With the development of new prostheses and delivery modes, the demand for conventional surgery will further decrease. PMID- 23804826 TI - Pulmonary artery banding: when is the use of a telemetrically adjustable device indicated? AB - Proponents of a telemetrically adjustable pulmonary artery band (PAB) device have cited simplified postoperative management and shortened length of stay as advantages associated with that technology. This report concerns a recent experience with both conventional pulmonary artery banding (conv-PAB) and the telemetrically adjustable PAB FloWatch (FW-PAB). From January 2005 through December 2008, 19 consecutive infants underwent either conv-PAB (8 patients, mean age 3.5 months, mean weight 4.1 kg) or FW-PAB (11 patients, mean age 2.6 months, mean weight 3.1 kg). Indications for PAB were left ventricular retraining (1 patient in FW-PAB), palliation prior to biventricular repair (7 patients in conv PAB and 10 in FW-PAB group), and staged univentricular repair (1 patient in conv PAB). In-hospital mortality was 0%. In the FW-PAB group, 1 FloWatch device was removed because of hemodynamic compromise related to the bulk of the device. There were no major complications in the conv-PAB group and no differences between groups with respect to postoperative ventilation time or length of stay in the intensive care unit or in hospital. In the FW-PAB group, a mean of 3.1 +/- 1.7 regulations per patient were undertaken. Of the regulations, 85% (29/34) were adjustments to tighten the device, and 15% (5/34) were to loosen it. During follow-up, 8 patients underwent intracardiac repair and pulmonary artery debanding: 4 in the conv-PAB group and 4 in the FW-PAB group. The course of patients in both groups after PAB were similar. Major differences in length of stay and resource utilization were not apparent. PMID- 23804827 TI - Global challenges in education and training for congenital heart surgery: the second aldo R. Castaneda lecture (2009). PMID- 23804828 TI - Prenatal diagnosis and neonatal surgical management of a giant proximal right coronary artery to right ventricular fistula. AB - We report a case of prenatal diagnosis and early neonatal surgical repair of a large proximal right coronary artery to right ventricular fistula. The surgical findings and technical details of the reparative operation are discussed in the context of the differential diagnosis, which, in addition to coronary-cameral fistula, also includes aortoventricular tunnel and ruptured sinus of Valsalva aneurysm. Timely and appropriate diagnosis and surgical management resulted in preserved patency of the right coronary artery and restoration of normal right ventricular function. PMID- 23804829 TI - Risks of extracorporeal membrane oxygenation in patients with coronary artery anomalies. AB - Extracorporeal membrane oxygenation is widely used to support and rest the heart before or following repair of congenital cardiac lesions in children. The beneficial effects of extracorporeal membrane oxygenation for the failing myocardium are undisputed. It is often an automatic choice whenever the heart seems incapable of supporting the circulation. However, its use may prove detrimental in patients with coronary anomalies, as illustrated by the case reports presented here. PMID- 23804830 TI - Anomalous origin of the right coronary artery from the pulmonary artery with aortopulmonary window. AB - This report describes a rare case of anomalous origin of the right coronary artery from the pulmonary artery associated with a large aortopulmonary window in a 2-month-old boy. The right coronary artery was exposed to systemic pressure and carried fairly well-oxygenated blood to the myocardium. Closure of the aortopulmonary window alone could have caused acute myocardial ischemia. The purpose of this case report is to describe successful diagnosis and management of anomalous origin of the right coronary artery associated with an aortopulmonary window. The pathological findings and the physiological effects, clinical importance, and method of correction used are discussed. PMID- 23804831 TI - Successful Coil Embolization of a Large Ascending Aortic Pseudoaneurysm Following Explantation of the EXCOR Pediatric Ventricular Assist Device in a Patient With Acute Fulminant Myocarditis. AB - Mechanical ventricular assistance has become a reliable tool for the support of children and infants with heart failure. The devices have shown efficacy both as a bridge to transplantation and as a bridge to recovery. The potential complications that may occur with long-term support have not been fully described. This article reports the occurrence of a large pseudoaneurysm associated with the ascending aorta following explantation of the EXCOR Pediatric ventricular assist device. A management strategy for this potentially lethal complication is described. PMID- 23804832 TI - Bilateral pulmonary artery banding. PMID- 23804833 TI - Sabiston & Spencer Surgery of the Chest, 8th ed. PMID- 23804834 TI - Erratum. PMID- 23804835 TI - Quality of care at the end of life. PMID- 23804836 TI - Assessing trustworthiness of personal aides. AB - BACKGROUND: Smaller family size has increased the need for assistance from personal aides. Respite care provided by personal aides reduces depressive symptoms and improves intergenerational relations and overall well-being of family members and patients. Yet, little is known about how family members evaluate personal aides prior to and during the employment period. METHODS: Qualitative semistructured interviews were conducted face-to-face with 10 families providing home-based care. Family members' ages ranged from 43 to 70 years. Patients' ages ranged from 67 to 86 years. Interviews were audio-recorded and transcribed verbatim. Data were coded and themes were identified. RESULTS: Family members emphasized the importance of personal aides. Other concerns included protection of their loved ones against risks from dishonest, unethical, or incompetent personal aides and unsafe, uncomfortable caregiving contexts. After family members hired a personal aide they presumed to be trustworthy, monitoring was a nearly endless task in seeking assurance that their initial assessment was accurate. CONCLUSIONS: Appropriate care, according to family members, went far beyond actions required to competently administer medicines, assist with activities of daily living, or maintain a watchful presence in the home. While positive experiences with personal aides added to the quality of life for both family members and patients when trustworthiness was established, quite the opposite was found when trust was violated. Personal relations, interpersonal communication skills, and affection between the aide and the patient were found to be much more important in determining trustworthiness than were standard caregiving skills. PMID- 23804837 TI - Provision of psychosocial care for cancer patients: service delivery in urban and rural settings. AB - Although common, psychosocial distress is frequently under diagnosed and untreated in the US health care system. Previous research shows that cancer patients have unmet psychosocial needs, and provision of psychosocial care frequently falls to primary care providers who may lack the resources to adequately deal with complex psychosocial issues. We conducted 25 in-depth key informant interviews with health care professionals working within medical facilities that provide care to cancer patients. Cancer care centers included in the sample were located within both rural and urban communities in a midwestern state, and included providers of both inpatient and outpatient services. Interview questions addressed the assessment of psychosocial needs, availability of psychosocial care, perceptions of the effectiveness of psychosocial services, and perceptions of organizational processes to manage psychosocial needs among their patients. Respondents were also queried regarding recommendations for improving psychosocial care for patients with cancer. Assessment of psychosocial need in most settings was often subjective, not performed, or completed without access to an accepted standardized assessment tool, and clinical pathways to direct psychosocial care were often lacking. Because of the lack of systematic assessment, access to psychosocial care was frequently dependent on the subjective judgment of busy clinicians. This study shows the clear need for organizational and practice redesign initiatives in both rural and urban settings to improve the delivery of psychosocial services to cancer patients. A number of possible system improvements were identified, including the use of allied health providers, standardized screening, and information technology to increase the ease and efficiency of psychosocial assessment. PMID- 23804838 TI - Gender and Medical Leadership: Student Perceptions and Implications for Developing Future Leaders in Primary and Secondary Care--a Pilot Study. AB - OBJECTIVE: To explore perceptions of leadership in undergraduate medical students. DESIGN: A quantitative pilot study; anonymous online survey. All undergraduates were invited to participate from one UK medical school; 469 students participated. The survey used Likert scales and open and closed questions. RESULTS: Lack of self-confidence and perceptions of women leaders were issues for undergraduates. A significant number of male undergraduates rated women less able to perform 10 of 12 attributes of leadership. Furthermore, male undergraduates showed greater ambition towards future leadership, with 42.2% males compared to 21.7% females strongly agreeing that they saw themselves in a position of leadership in the future. Networking and tradition were also seen as barriers to females gaining the highest office in the student medical society. The importance of embedding leadership in the curriculum was highlighted by both genders. CONCLUSIONS Barriers to progression still need to be investigated and removed especially because women are expected to comprise the majority of the medical workforce by 2017. There needs to be greater emphasis on mentoring and role models at the undergraduate level and beyond and more awareness of leadership in curricula at all levels. These changes should ultimately improve confidence and change the perception of women in the medical workforce. PMID- 23804839 TI - Variation in Excessive Fetal Growth across Levels of Prenatal Care among Women with Gestational Diabetes. AB - OBJECTIVE: Examine the association between prenatal care and excessive fetal growth outcomes among mothers with gestational diabetes mellitus (GDM). METHODS: We conducted a retrospective analysis of 2004-2007 singleton live births to South Carolina women, limited to those for whom both birth certificate and hospital discharge data were available (N = 179 957). Gestational diabetes mellitus was identified from birth certificate and/or hospital discharge claims. Measures of excessive fetal growth were large for gestational age (90th and 95th percentiles) and macrosomia (birth weight > 4500 g). The Adequacy of Prenatal Care Utilization index was used to measure prenatal care. RESULTS: Gestational diabetes mellitus was recorded for 6.9% of women in the study population. Women with GDM were more likely than other women to have an infant with excessive fetal growth, regardless of the level of prenatal care; however, there was a significant interaction between GDM status and levels of prenatal care. All women with GDM had increased odds for large infant outcomes. However, those receiving inadequate prenatal care were markedly more likely to experience excessive fetal growth outcomes (odds ratio = 1.38, confidence interval = 1.15-1.66) than women also with GDM and intermediate/adequate prenatal care. Similar patterns were noted for large for gestational age (95th) and macrosomia (total birth weight >= 4500 g). CONCLUSIONS: Observed associations suggest a link between inadequate prenatal care and a higher risk for excessive fetal growth among women with GDM. Further research is needed to clarify the nature of the association and suggest ways to get high-risk women into care sooner. PMID- 23804840 TI - Memory Impairment and Executive Dysfunction are Associated with Inadequately Controlled Diabetes in Older Adults. AB - OBJECTIVE: To assess the cross-sectional relationship of glycemic control to memory impairment and executive dysfunction in older adults with diabetes treated at an urban primary care center. PARTICIPANTS AND METHODS: As part of a primary care-based cognitive screening program, we identified adults age 65 or older with a diagnosis of diabetes. Glycosylated hemoglobin level (HbA1c) was used to define diabetes as controlled (HbA1c <7) or inadequately controlled(HbA1c >= 7). Episodic memory was measured by quartile of free recall scores on the Free and Cued Selective Reminding Test. Executive function was measured using an ordinal composite score derived from animal fluency and months backward. These were the main predictors of diabetic control. RESULTS: The 169 participants with diabetes had a median age of 74. The sample was 38% African American and 42% Latino. One hundred four (61%) had inadequately controlled diabetes. Memory impairment and executive dysfunction were independent predictors of diabetic control after adjusting for age and education. Binary logistic regression models indicated that the odds of inadequately controlled diabetes was higher for patients in the worst quartile of memory functioning compared to patients in higher quartiles of memory functioning (odds ratio = 6.4; 95% confidence interval: 2.3, 17.6). Any level of executive dysfunction increased the odds of inadequately controlled diabetes compared to patients in the best quintile of executive functioning (odds ratio = 3.6; 95% confidence interval: 1.58, 8.35). CONCLUSIONS: Memory impairment and executive dysfunction were associated with inadequately controlled diabetes. Though causal inferences are not robust in a cross-sectional study, we suggest that cognitive dysfunction may interfere with diabetes management and that inadequate diabetic control may contribute to cognitive dysfunction. PMID- 23804841 TI - Enhancing quality of primary care using an ambulatory ICU to achieve a patient- centered medical home. AB - RESEARCH OBJECTIVE: The Patient-Centered Medical Home (PCMH) has been advocated as a model to address the lack of coordination and continuity in the health system. However, implementation in practice has been slow and incompletely described. STUDY DESIGN: Patients referred into the program received intensive nurse follow-up focused on medication adherence, care coordination, and education. Patients graduate from the program when treatment goals are met. POPULATION STUDIED: The first 100 patients enrolled into the PCMH focused program of a primary care clinic in an urban, academic medical center. The main outcome measures are goal adherence and emergency room use. PRINCIPAL FINDINGS: Ninety percent of enrollees met the health goals set for them at enrollment. During their enrollment, 31.6% of patients with diabetes reduced and maintained their blood glucose readings; 24.6% of patients with hypertension reduced and maintained their blood pressure readings. Emergency department use in the time period following enrollment dropped 46.7%. CONCLUSIONS: The ambulatory intensive care unit program showed an improvement in health outcomes and health care use.This program also helps to move the practice toward PCMH by centralizing care through a primary care provider, enhancing access to care, and by focusing on the patient holistically through rapport with a nurse. IMPLICATIONS FOR POLICY, DELIVERY, OR PRACTICE: This care delivery method drives the clinic closer to the PCMH and toward the Accountable Care Organization (ACO) model. PMID- 23804842 TI - Cancer screening delivery in persistent poverty rural counties. AB - BACKGROUND: Rural populations are diagnosed with cancer at different rate and stages than nonrural populations, and race/ethnicity as well as the area-level income exacerbates the differences. The purpose of this analysis was to explore cancer screening rates across persistent poverty rural counties, with emphasis on nonwhite populations. METHODS: The 2008 Behavioral Risk Factor Surveillance System was used, combined with data from the Area Resource File (analytic n = 309 937 unweighted, 196 344 347 weighted). Unadjusted analysis estimated screening rates for breast, cervical, and colorectal cancer. Multivariate analysis estimated the odds of screening, controlling for individual and county-level effects. RESULTS: Rural residents, particularly those in persistent poverty counties, were less likely to be screened than urban residents. More African Americans in persistent poverty rural counties reported not having mammography screening (18.3%) compared to 15.9% of urban African Americans. Hispanics had low screening rates across all service types. Multivariate analysis continued to find disparities in screening rates, after controlling for individual and county-level factors. African Americans in persistent poverty rural counties were more likely to be screened for both breast cancer (odds ratio, 1.44; 95% confidence interval, 1.12-1.85) and cervical cancer (1.46; 1.07-1.99) when compared with urban whites. CONCLUSIONS: Disparities in cancer screening rates exist across not only race/ethnicity but also county type. These disparities cannot be fully explained by either individual or county-level effects. Programs have been successful in improving screening rates for African American women and should be expanded to target other vulnerable women as well as other services such as colorectal cancer screening. PMID- 23804843 TI - After-hours care in suburban Canada: influencing emergency department utilization. AB - OBJECTIVE: To determine if operation of an outpatient "after-hours" clinic (AHC) was associated with a reduction in local emergency department (ED) visits. STUDY SETTING: Leduc, Alberta, Canada is a city of approximately 20 000 people. There is one hospital ED and a single AHC. Information on AHC and ED visits was collected from January 2005 to February 2008. STUDY DESIGN: This was an observational before-and-after study of monthly ED visit frequency, stratified by patient illness severity. DATA COLLECTION: We collected patient visits per month to the ED before and after AHC implementation. Twenty-eight months of ED patient visit information were collected (14 months of pre-AHC; 14 months of post-AHC). A Wilcoxon signed-rank test was used to test the statistical strength of difference in ED visits, matched by month, before and after the AHC became operational. RESULTS: An average of 261.2 (standard deviation [SD], 47.7) patient visits per month were made to the AHC. There was a mean reduction of 36.7 (standard error of mean [SEM], 9.6; P = .009) total patient visits per month and 49.3 (SEM, 5.6; P = .001) fewer semiurgent patient visits per month to the Leduc ED during AHC operating hours. CONCLUSIONS: There was a consistently observable and statistically significant reduction in total patients visiting the ED subsequent to AHC operation. Stratified analysis indicated that this was due to fewer semiurgent patients seeking medical care at the local ED. PMID- 23804844 TI - A review of diagnostic process and postdiagnostic support for people with dementia in rural areas. AB - PURPOSE: Early diagnosis of dementia allows the affected individuals to make plans, and helps services to identify and act on need. Previous work has suggested that obtaining an early diagnosis in rural areas can be difficult. This paper discusses diagnosis and postdiagnostic support for people with dementia, with a focus on service delivery in rural areas. METHODS: A review of published English language literature 1999 to 2011 identified in Medline, PsycINFO, PubMed, Cochrane Library, and ScienceDirect. RESULTS: Primary care services play a key role in accessing services in many health care systems. The role of primary care staff, and in particular general practitioners, is greatest in rural communities where specialist service access is often reduced. Despite this, rural staff often report limited training on supporting people with dementia. Postdiagnostic services can be more difficult to access in rural areas, and informal caregivers in rural areas can be more reluctant to seek such services. Transport difficulties and distance from specialist services can act as a barrier to service use. Memory services have been offered in both rural and urban areas. CONCLUSIONS: Addressing stigma, supporting staff, and signposting access are important in all areas, but seem to be particularly important in rural areas. Training and support for general staff in rural areas can be improved. Memory services provide one way of delivering services in rural areas. Service planners should take negative perceptions of dementia, barriers to access, and training of generalist service providers into account when designing dementia services in rural areas. PMID- 23804845 TI - The importance of primary care psychiatry: an Australian perspective with global implications. AB - This paper provides a review of the importance of primary care psychiatry within an Australian context. The aims of this review are: (1) to emphasize the integral role of mental health in overall health and well-being, (2) to elucidate the factors that make the provision of primary care psychiatry essential, and (3) to review the impact of the Australian government's mental health policy initiatives on the mental health of the Australian population as well as on the practice of primary care psychiatry. From this review, it is evident that the discipline of psychiatry is integral to the overall health of the community. Furthermore, it is apparent that primary care psychiatry has a large and pivotal role to play in the prevention, treatment, and early detection of mental disorders in Australia and worldwide. The article concludes with some simple, actionable recommendations for the practice of primary care psychiatry. PMID- 23804847 TI - A pilot study to increase fruit and vegetable intake in pregnant latina women. AB - Previous studies have suggested that women have low dietary intake of fruits and vegetables. This study's objective was to test the effectiveness of a novel nutrition intervention (education about prenatal flavor learning) on increasing fruit and vegetable intake in a group of primarily Latina women at an urban prenatal clinic. METHODS: The Harvard Service Food Frequency Questionnaire (HSFFQ) was administered to 2 groups at the same clinic at 2 time points for each group. The first group was a nonintervention, comparison group. The second (intervention) group received specific information about how a pregnant woman's food choices can influence subsequent solid food preferences of her infant, with encouragement given to increase fruit and vegetable choices. The HSFFQ was administered pre- and post-intervention for this group. RESULTS: Combined fruit and vegetable intake declined from the administration of Q#1 to Q#2 in both the comparison (n = 28) and intervention (n = 31) groups. The decline was primarily the result of a decrease in vegetable intake, but it was not statistically significant. In the comparison group, only 23.3-36.6% of women were eating adequate daily servings of vegetables, and in the intervention group 32.3%-38.7%. In both the comparison and intervention groups, over 74% of the women were eating adequate daily servings of fruit at both time points. CONCLUSIONS: In this Latina population of pregnant women, there was no difference in fruit and vegetable intake after receiving education about prenatal flavor learning. These findings suggest that education alone may not be sufficient to change health behaviors. PMID- 23804846 TI - Advancing genetic testing for deafness with genomic technology. AB - BACKGROUND: Non-syndromic hearing loss (NSHL) is the most common sensory impairment in humans. Until recently its extreme genetic heterogeneity precluded comprehensive genetic testing. Using a platform that couples targeted genomic enrichment (TGE) and massively parallel sequencing (MPS) to sequence all exons of all genes implicated in NSHL, we tested 100 persons with presumed genetic NSHL and in so doing established sequencing requirements for maximum sensitivity and defined MPS quality score metrics that obviate Sanger validation of variants. METHODS: We examined DNA from 100 sequentially collected probands with presumed genetic NSHL without exclusions due to inheritance, previous genetic testing, or type of hearing loss. We performed TGE using post-capture multiplexing in variable pool sizes followed by Illumina sequencing. We developed a local Galaxy installation on a high performance computing cluster for bioinformatics analysis. RESULTS: To obtain maximum variant sensitivity with this platform 3.2-6.3 million total mapped sequencing reads per sample were required. Quality score analysis showed that Sanger validation was not required for 95% of variants. Our overall diagnostic rate was 42%, but this varied by clinical features from 0% for persons with asymmetric hearing loss to 56% for persons with bilateral autosomal recessive NSHL. CONCLUSIONS: These findings will direct the use of TGE and MPS strategies for genetic diagnosis for NSHL. Our diagnostic rate highlights the need for further research on genetic deafness focused on novel gene identification and an improved understanding of the role of non-exonic mutations. The unsolved families we have identified provide a valuable resource to address these areas. PMID- 23804848 TI - Prescribing information therapy: opportunity for improved physician-patient communication and patient health literacy. AB - BACKGROUND: Recently, experts have included information therapy (Ix) as a method for increasing clinician-patient communication, patient adherence, patient understanding of diagnosis and treatment options, and reduction in hospitalizations. METHODS: This study, a secondary, retrospective analysis of survey data, independently examined participating patient perceptions of an Ix program between two Mid-western employers. Surveys were administered through the online platform from January 1, 2006 through December 31, 2009 for Employer 1 (N = 4105) and from June 1, 2007 through December 31, 2009 for Employer 2 (N = 8123). RESULTS: Preliminary findings indicate the majority of patients were adherent to recommended treatment(s) and highly rated their physician's performance. Additionally, patients indicated that their physician's access to their questionnaire responses motivated them to improve their health literacy and change their health behaviors. Secondary data analysis indicated a positive relationship between prescribed Ix and self-reported health literacy. CONCLUSION: As Web-based Ix increases in frequency, the evaluation of patient and clinician communication is important and should be expanded to increase the benefits for both patients and clinicians. PMID- 23804849 TI - The impact of primary care dual-management on quality of care. AB - BACKGROUND: Discontinuity is common in US healthcare. Patients access multiple systems of care and in the nation's largest integrated healthcare system, Veteran's Administration (VA) patients frequently use non-VA primary care providers. The impact of this "dual-management" on quality is unknown. The authors' objective was to identify dual-management and associations with markers of care quality for hypertension and associated conditions. METHODS: Data was collected via surveys and chart reviews of primary care patients with hypertension from six VA clinics in Iowa and Minnesota. Clinical measures abstracted included the following: goal blood pressure (BP) and use of guideline concordant therapy, low-density lipoprotein (LDL) cholesterol, hemoglobin A1C, and body mass index (BMI). Dual-management data was obtained through self-report. RESULTS: Of 189 subjects (mean age = 66), 36% were dual-managed by non-VA providers. There was no difference in hypertension quality of care measures by dual-management status. A total of 51% were at BP goal and 58% were on guideline concordant therapy. Dual-managed patients were more likely to use thiazide diuretics (43% vs 29%; P = .03) and angiotensin receptor blockers (13% vs 3%; P < .01), but less likely to use angiotensin-converting enzyme inhibitors (43% vs 61%; P = .02). There was no difference in LDL cholesterol (97.1 mg/dl vs 100.1 mg/dl; P = .55), hemoglobin A1C (7% vs 6%; P = .74), or BMI (29.8 vs 30.9; P = .40) for dual-managed versus VA managed patients, respectively. CONCLUSIONS: Although dual-management may decrease continuity, VA/private sector dual management did not impact quality of care, though some medication differences were observed. With the high prevalence of dual-management, future work should further address quality and evaluate redundancy of services. PMID- 23804850 TI - Activity limitations and healthcare access as correlates of frequent mental distress in adults 65 years and older: a behavioral risk factor surveillance study--2008. AB - OBJECTIVES: Poor mental health is a major source of distress, disability, and social burden in older adults. The objective of this study was to determine if activity limitation and healthcare access are associated with frequent mental distress (FMD) in adults 65 years and older. METHODS: Of the 123 427 study participants aged 65 years or older, 120 445 participants responded to the Behavioral Risk Factors Surveillance System (BRFSS) survey question on number of mentally unhealthy days. Participants who reported having 14 or more mentally unhealthy days during the past 30 days were considered as having FMD. Activity limitation, avoidance of medical care due to cost, and availability of personal doctor were examined for their association with FMD in multivariable logistic regression analysis. Age, sex, race/ethnicity, marital and employment status, emotional support, and life satisfaction were included as potential confounders. RESULTS: The prevalence of FMD in this study population was 6.5% (95% CI = 6.3 6.8) with estimates significantly greater among women (7.2%, 95% CI = 6.9-7.6) as compared to men (5.5%, 95% CI = 5.1-6.0). The odds of FMD were more than 2-fold elevated for those who reported activity limitations due to physical, mental, or emotional problems (adjusted OR = 2.59, 95% CI = 2.33-2.87), and among those who reported health care cost as a barrier to see a doctor (adjusted OR = 2.14, 95% CI = 1.75-2.61). There was no significant relationship between availability of personal doctor and FMD observed in the study. CONCLUSIONS: The findings of this study showed that activity limitation and cost of medical care are associated with FMD in the US elderly population. PMID- 23804851 TI - Very mild dementia and medical comorbidity independently predict health care use in the elderly. AB - OBJECTIVE: To determine whether dementia status and medical burden were independent predictors of emergency department (ED) visits and hospitalizations in older patients from an urban geriatric practice participating in a primary care based cognitive screening program. PARTICIPANTS AND METHODS: A comprehensive chart review was conducted for 300 African American and Caucasian patients, including 46 with prevalent dementia and 28 with incident dementia using the Cumulative Illness Burden Scale. Hospital-based claims data was used to retrieve ED visits and hospital admissions for 5 years following baseline assessment. RESULTS: Patients with dementia had a 49% higher rate of ED visits (IRR = 1.49; 95% CI = 1.06, 2.09) and an 83% higher risk of death than patients without dementia (HR = 1.83; 95% CI = 3.07, 0.03). Dementia status predicted hospital admissions after adjustment for medical burden (IRR = 1.37; 95% CI = 0.99, 1.89). For each one point increase in medical burden, there was an 11% increase in ED visits (IRR = 1.11; 95% CI = 1.06, 1.16), a 13% increase in hospital admissions (IRR = 1.13; 95% CI = 1.09, 1.17), and an 11% higher risk of death (HR = 1.11; 95% CI = 1.04, 1.17). Age did not predict utilization. CONCLUSION: Dementia status and medical burden were independent predictors of ED visits and death in patients with clinically diagnosed dementia followed from the early stage of disease. PMID- 23804852 TI - Attitudes, practices, and barriers to adolescent suicide and mental health screening: a survey of pennsylvania primary care providers. AB - OBJECTIVE: To determine primary care providers' rates of screening for suicide and mental health problems in adolescents and the factors that promote or discourage this practice. PATIENTS AND METHODS: Overall, 671 medical professionals (ie, pediatricians, family physicians, nurse practitioners, physician assistants) completed an electronic survey. The 53 items focused on (1) attitudes, knowledge, and comfort with general psychosocial and suicide screening and (2) current practices and barriers regarding screening and referrals to behavioral health services. RESULTS: Forty percent had a patient attempt suicide in the past year, and 7.7% had 6 or more patients attempt suicide. At a well visit, 67% screened for mental health, and 35.2% screened for suicide risk. Most (61.1%) primary care providers rarely screened for suicide or only when it was indicated. Only 14.2% of primary care providers often used a standardized suicide screening tool. Factors associated with screening were being knowledgeable about suicide risk, being female, working in an urban setting, and having had a suicidal patient. Only 3.0% reported adequate compensation for these practices, and 44% agreed that primary care providers frequently use physical health billing codes for behavioral health services. Nearly 90% said parent involvement was needed if adolescents were to follow through with referrals to mental health services. Only 21% frequently heard back from the behavioral health providers after a referral was made. CONCLUSION: Policy that promotes mental health education for primary care providers, provides reimbursement for mental health screening, and encourages better service integration could increase suicide screening and save healthcare costs and patients' lives. PMID- 23804853 TI - Adolescents' use of the emergency department: does source of primary care make a difference? AB - BACKGROUND: Many of the 18 million emergency department visits by adolescents annually in the United States are for nonurgent problems that might be addressed in a primary care setting. METHODS: As part of a larger randomized controlled intervention, 1023 adolescents aged 12 to 21 years registering in an urban pediatric emergency department (PED) were tracked over the subsequent 365 days to record all visits to the PED. Adolescents identifying an adolescent medicine service (AMS) as the primary care source were compared with adolescents receiving primary care elsewhere in an integrated urban medical system (non-AMS) to determine how often after the index PED visit they revisited the PED, returned to primary care (PC), visited a subspecialist (SS), or were hospitalized. Mean values and odds ratios of each type of visit were compared between AMS and non AMS patients using multivariate logistic and ordinary least squares regressions to control for covariates. RESULTS: AMS patients (n = 124, 12%), compared to non AMS patients (n = 899, 88%), were more likely female (75% vs 48%, P < .001) and used public insurance (52% vs 40%, P = .017). In unadjusted comparisons, AMS and non-AMS patients did not differ in the probability of any return PED visit (46% vs 37%, P = .052) in the 365 days following the index PED visit but differed in the mean number of return PED visits (1.35 vs 0.93, P = .026). AMS patients were more likely to be hospitalized (15% vs 7%, P = .006) after the index PED visit and also had a greater mean number of hospitalizations (0.41 vs 0.19, P = .048). Multivariate analyses controlling for demographic variables, triage level of initial PED visit, and hospitalizations showed AMS patients returned to primary care after an index PED visit 24.6 days earlier than non-AMS patients (P = .026). CONCLUSIONS: This study demonstrates attending an AMS for primary care predicted earlier return to the primary care provider after an index PED visit. Elements of adolescent specialty care producing such outcomes are worthy of further study. PMID- 23804854 TI - Medical audit of the quality of diabetes care: is primary care more successful than hospitals? AB - OBJECTIVE: To assess the quality of diabetes care provided to patients attending primary care settings and hospitals in the State of Qatar. DESIGN: Observational cohort study. SETTING: The survey was carried out in primary health care centers and hospitals. SUBJECTS AND METHODS: The study was conducted from January 2010 to August 2010 among diabetic patients attending primary health care centers and hospitals. Among the patients participating, 575 were from hospitals and 1103 from primary health care centers. Face-to-face interviews were conducted using a structured questionnaire including sociodemographic, clinical, and satisfaction score of the patients. RESULTS: The mean age of the primary care diabetic patients was 46.1 +/- 15.1 years and 44.5 +/- 14.8 years for hospital patients (P = .03). There was a significant difference observed in terms of age group, gender, marital status, occupation, and consanguinity of the diabetic patients in both medical settings (P < .001). Overweight was less prevalent in primary care patients than in hospital diabetes mellitus patients (40.4% vs 46.4%). A significant variation was observed in the mean values of blood glucose (-0.76), HbA1C (-0.78), LDL (-0.01), albumin (-0.37), bilirubin (-0.76), and triglyceride (-0.01) in primary care patients compared to the mean values of the preceding year. Overall, complications were lower in primary care diabetic patients, and patients attending primary care were more satisfied with the diabetes care. CONCLUSION: The present study revealed that in general, primary health care provided a better quality of care to diabetic patients compared to that of hospitals. Also, primary care patients had a better satisfaction score towards diabetes care. PMID- 23804855 TI - Multiple chronic conditions and the aging of america: challenge for primary care physicians. AB - BACKGROUND: As the United States population ages, chronic conditions are becoming more prevalent and our healthcare system is faced with increasing costs. This aging population with increased multiple chronic conditions coupled with increased burden of disease will provide a challenge to primary care physicians to provide quality care that is cost-effective. Therefore, we examined national data to study the impact of chronic conditions, age and caregiving on lifestyle burden. METHODS: Cross-sectional data from the 2009 Behavioral Risk Factor Surveillance System were analyzed for the presence of 9 chronic health conditions, including angina/coronary heart disease (CHD), arthritis, asthma, cancer, diabetes, heart attack, hypertension, obesity, and stroke, and average number of chronic conditions among persons 50 years of age and older. Lifestyle burden, measured by activity limitation, required use of assistive devices, and/or serving in a caregiving capacity was measured and stratified by number of chronic conditions. RESULTS: All conditions except obesity and asthma increased with each age category. By age 70, the majority of adults had hypertension (60.7%) and arthritis (55.0%). Prevalence of activity limitations and use of assistive devices increased as did the numbers of chronic conditions. DISCUSSION: These findings point to a changing population of patients for primary care physicians that will require treatment of multiple chronic conditions as well as increased burden of disease. As this population grows, workloads for primary care physicians will increase and could likely lead to inefficient care and possibly inadequate payment for the required level of management. Therefore, the current challenge facing our healthcare system is to evaluate existing models of care for older patients and to develop new models that are cost-effective while at the same time providing fair reimbursement for increased management. PMID- 23804856 TI - Eating behavior and obesity in Canada: evidence from panel data. AB - BACKGROUND: Although a growing body of research has examined the association between food prices and the availability of fast food restaurants on weight outcomes, there is limited empirical evidence on the direct effect of eating behavior on body weight. OBJECTIVE: The effect of eating behavior on obesity prevalence among Canadians is examined. METHODS: A nationally representative sample from the Canadian National Population Health Survey (2000-2008) with 29 722 observations is used. Obesity prevalence is estimated by a linear probability model using cross-sectional and panel estimation methods. Separate regressions are estimated for males and females. RESULTS: Multivariate analyses suggest that eating behavior has a statistically significant effect on obesity prevalence. In particular, individuals who reported excellent, very good, and good eating behavior have a lower risk of obesity compared with those with fair or poor eating behavior. Although cross-sectional and panel data methods produce consistent results, the cross-sectional model overestimates the effect of eating behavior on the risk of obesity. This highlights the importance of controlling for unobserved individual factors that may affect how eating behavior is related to body weight. CONCLUSION: Evidence is found showing that eating behavior is an important determinant of obesity prevalence. The findings suggest that improving the eating behavior of individuals would help reduce excessive body weight and its induced health risks. PMID- 23804857 TI - Challenges of older patients' knowledge about warfarin therapy. AB - OBJECTIVE: To review the challenges of warfarin education for older patients (aged 65 years or older) in terms of knowledge, access to warfarin education, and education resources. METHODS: A quasi-systematic review of the literature was performed via electronic database searches (eg, Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, International Pharmaceutical Abstracts, Meditext, and Google Scholar) from 1990 to May 2011. RESULTS: The 62 articles reviewed found that improved patient knowledge results in better anticoagulation control. The review also found that between 50% and 80% of older patients have inadequate knowledge about the basic aspects of warfarin therapy (eg, action, benefits and risks, interactions with other drugs or foods, international normalized ratio management). Demographic factors, such as advancing age, lower family income, and limited health literacy, were found to inversely affect patients' warfarin knowledge, and access to warfarin education and information resources were often suboptimal in different practice settings. Finally, a number of educational strategies and resources that could be readily incorporated to improve the effectiveness of current warfarin education programs were extracted from the review. CONCLUSION: This comprehensive review highlights that education about warfarin in older patients is currently suboptimal and may in part contribute to poor therapeutic outcomes. This review article also acknowledges the need to identify, target, and develop educational strategies and resources to further improve older patients' knowledge about their warfarin therapy. PMID- 23804858 TI - Retrospective database research in pediatric cardiology and congenital heart surgery: an illustrative example of limitations and possible solutions. AB - BACKGROUND: Secondary use of data, whether from clinical information systems or registries, for carrying out clinical research in rare diseases is a common practice but is fraught with potential errors. We sought to elucidate some of the limitations of database research and describe possible solutions to overcome these limitations. METHODS: Using a disease model of a rare postsurgical outcome, we evaluated the ability of four different data sources to correctly identify patients who had that outcome both as individual databases and also when used in conjunction with each other. These results were compared with manual chart review. RESULTS: The sensitivity of the various databases to pick up a rare and specific outcome was poor (9.9%-37%), while the specificities were fairly good (91%-96.7%). By combining the databases, the sensitivity was increased to as much as 56.8% without a large decrease in the specificity (85.2%-91.6%). The electronic medical record (EMR) search engine had the highest sensitivity (96.9%) and a high specificity (89.3%) with a very high negative predictive value (99.4%). CONCLUSION: For rare and specific diseases or outcomes, a single data source search methodology can miss large numbers of patients and potentially bias study results. Combining overlapping databases can improve the ability to capture these rare diseases or outcomes. While chart review remains the most accurate way to obtain complete case capture, new tools like EMR search engines can facilitate the efficiency of this process without sacrificing search quality. PMID- 23804859 TI - Outcome after two-patch repair of complete common atrioventricular canal defects in patients weighing four kilograms or less. AB - BACKGROUND: Early repair of a complete common atrioventricular canal defect (CCAVCD) may benefit patients who exhibit congestive heart failure and failure to thrive. However, concern about increased risk and fragility of valve tissue has commonly led to delaying the surgical repair until the patients achieve a predetermined weight. We report our experience with a strategy of early repair independent of age or weight. METHODS: Between 2003 and 2009, 32 patients underwent two-patch repair of CCAVCD at our institution; 22 patients weighed between 2.5 and 4 kg (group #1) and 10 weighed more than 4 kg (group #2). Medical records and echocardiographic studies were reviewed to determine whether there was a difference in the incidence of mortality, rate of reintervention, and complications between the two groups. RESULTS: Operative mortality was 3.1% (1 of 32), with one additional death two years after repair, for an overall mortality of 6.25%. Median duration of mechanical ventilation, median hospital stay, and intropic score was similar between both groups. Freedom from valve reintervention was 91% in group #1 (20 of 22), and 89% in group #2 (8 of 9, p = 1.00). CONCLUSIONS: Complete common atrioventricular canal defect can be repaired safely and effectively in patients under 4 kg. Although mortality was not increased, smaller patients have a tendency for longer intensive care and hospital stay as well as a higher incidence of atrioventricular valve regurgitation. However, valve function improved during the period of follow-up and did not impact the freedom from reintervention. PMID- 23804860 TI - Palliative arterial switch operation in the context of multiple ventricular septal defects, potentially biventricular and univentricular hearts with malposed great arteries: a review of 15 cases. AB - BACKGROUND: This study is an examination of our unit's experience with palliative arterial switch in univentricular and potentially biventricular hearts with transposition of the great arteries (TGA). METHODS: These patients were divided into three groups based on their physiology. (a) Single ventricle physiology (n = 8), in which all the patients had univentricular hearts, TGA, and subaortic stenosis (SAS). (b) Borderline biventricular physiology (n = 4), in which the patients had TGA, ventricular septal defect (VSD), and hypoplastic right ventricle (RV). (c) Biventricular physiology (n = 3), in which the patients had TGA and multiple VSDs. RESULTS: In all, 12 (80%) patients survived. Seven of these have undergone second stage surgery (cavopulmonary shunt, n = 5; biventricular repair, n = 2). CONCLUSION: Palliative arterial switch is an alternative to Norwood procedure and modifications thereof for managing SAS in single ventricle with malposed great arteries. Palliative switch with adjunctive pulmonary artery band may be a temporizing measure in TGA with multiple VSDs, where the VSDs are judged to be inaccessible through the tricuspid valve or through either of the great arteries. It may also be utilized for TGA and hypoplastic RV instead of committing them to univentricular pathway and keeping the option of biventricular repair. PMID- 23804861 TI - Web-based survey of current trends in hemodynamic monitoring after congenital heart surgery. AB - Strategies for monitoring patients recovering after congenital heart surgery have evolved considerably as technology continues to progress. Monitoring techniques traditionally centered around the comprehensive physical examination have been replaced by a number of revolutionary technologies developed to objectively evaluate various components of the cardiovascular system. Despite scant evidence that these methodologies actually improve outcomes, some have been embraced by clinicians. We developed an Internet survey designed to describe current practices of clinicians who care for patients after congenital heart surgery. There were 162 respondents to our survey with the majority from the United States. The views of cardiologists, intensivists, those dual trained in both cardiology and critical care medicine, and surgeons are all robustly represented in the results. Serial lactate monitoring was the strategy that was utilized most often by respondents (94%), followed by multisite near-infrared spectrometry (NIRS, 67%). There were 78% who utilized the combination of serial lactate and NIRS monitoring. Serial lactate monitoring was the technique that was thought to best represent cardiovascular well-being after heart surgery (40%). The results of this survey suggest that despite the paucity of evidence that clinical outcomes of patients recovering after congenital heart surgery are improved by any of these monitoring techniques, there is almost universal acceptance to monitor patients with serial lactate monitoring, NIRS monitoring, or a combination of these techniques. PMID- 23804862 TI - Controlling oxygenation during initiation of cardiopulmonary bypass: can it improve immediate postoperative outcomes in cyanotic children undergoing cardiac surgery? A prospective randomized study. AB - OBJECTIVE: Cardiopulmonary bypass (CPB) initiated with high oxygen levels may expose cyanotic children to reoxygenation injury. The ideal method of initiation of bypass to prevent this phenomenon still remains largely unproven. This study tested the hypothesis that controlling oxygenation during initiation of CPB improves early postoperative outcomes. METHODS: Thirty-one cyanotic children were randomized to two treatment arms of the study. In group A (intervention), CPB was initiated with fraction of inspired oxygen (Fio 2) 0.21, and after one minute of full bypass, Fio 2 was increased at increments of 0.1 per minute to reach 0.6. In group B (hyperoxemic), CPB was initiated using Fio 2 >0.6. Aortic cross clamp time (minutes), CPB time (minutes), creatine phosphokinase-MB (CPK-MB) levels (U/L), lactate levels (mmol/L), duration of ventilator support (hours), inotropic support (hours), and intensive care unit (ICU) stay (hours) as well as hospital mortality were measured. RESULTS: Levels of CPK-MB (group A mean = 59.6 U/L, 95% confidence interval [CI]: 45.9-73.3; group B mean = 82.6 U/L, 95% CI: 66.1-99.1, P = .016) and ventilation time (group A median = 16.5 hours; interquartile range [IQR] = 11.25-23; group B median = 27.5 hours; IQR = 17-54, P = .045) were significantly lower in the intervention group. Other parameters showed no significant differences: CPB time (group A median = 71.5 minutes, IQR = 64-100; group B median = 95.5 minutes, IQR = 58-145, P = .71), cross clamp time (group A mean = 59.2 minutes, 95% CI: 47.6-70.8; group B mean = 66.57 minutes, 95% CI: 47.6-88.5, P =.57), lactate levels (mmol/L; group A median = 1.8, IQR = 1.48 2.59; group B median = 2.1, IQR = 1.29-2.62, P = 1), inotropic support (group A median = 47.5 hours, IQR = 36-73.75; group B median = 59.5 hours, IQR = 41.75 92.5, P = .27), ICU stay (group A median = 59.5 hours, IQR = 48.25-118.5; group B median = 85 hours, IQR = 47.75-137.50, P = .21), and mortality (group A n = 2, group B n = 2). CONCLUSION: A controlled oxygenation protocol was associated with significantly lower postoperative CPK-MB levels. Evaluation of other end points including ventilation times requires a study with larger sample size for validation. PMID- 23804863 TI - Invited commentary: surgical reoxygenation injury in myocardium of patients with cyanosis: how is it clinically important? PMID- 23804864 TI - Left ventricular and mitral valve function long after repair of left anomalous coronary artery from the pulmonary artery: recovery years after severe ischemia. AB - BACKGROUND: The study evaluates the long-term results of surgery for anomalous left coronary artery from the pulmonary artery (ALCAPA) with special attention on the left ventricular (LV) function and mitral regurgitation. METHODS: Twenty-one children underwent surgery for ALCAPA over 23 years (1987-2010). All patients underwent establishment of a two-coronary system, by direct reimplantation (n = 13) or by intrapulmonary tunnel technique (n = 8), with concomitant mitral valve repair in one. The follow-up echocardiograms were evaluated to assess LV function and mitral regurgitation. RESULTS: Five patients died. The age of the nonsurvivors was lower, 4.2 +/- 1.3 versus 22.7 +/- 29.4 months, P = .04. All nonsurvivors had moderate or severe mitral regurgitation preoperatively and higher LV diameter z score than the survivors: 11.8 (9-14.6) versus 4.6 (1.9 13.1), P = .01. At last follow-up, all survivors were asymptomatic; the diastolic LV diameter was normal, with z scores: 0.3 (0.1-1.9) versus 7 (1.9-14.6) preoperatively, P = .001, as was the LV ejection fraction: 66% (61%-78%) versus 38% (16%-70%) preoperatively, P = .001. Fifteen patients had moderate or severe mitral regurgitation at initial presentation and it eventually regressed to insignificant in all survivors (P = .001). No subsequent interventions on the coronary arteries or the mitral valve were needed. Four patients with intrapulmonary tunnel had mild suprapulmonary obstruction with Doppler peak gradients between 20 and 30 mm Hg. CONCLUSIONS: In our experience, establishment of a two-coronary circulation without mitral valve repair leads to normalization of LV dimension and systolic function and to improvement of mitral regurgitation in the surviving patients. Mortality is related to low age and to the associated higher degree of LV dysfunction. PMID- 23804865 TI - Invited commentary: management of anomalous origin of the left coronary artery from the pulmonary artery. PMID- 23804866 TI - Serum cardiac troponin T in asphyxiated term neonates delivered at two teaching hospitals in lagos, Nigeria. AB - BACKGROUND: Asphyxia is a leading cause of perinatal morbidity and mortality in the developing countries. All organs including the myocardium are vulnerable to ischemic injury in asphyxia. The aim of the current study was to assess myocardial injury in asphyxiated full-term neonates using their serum cardiac troponin T levels. METHODS: In all, 30 term asphyxiated neonates and 30 gestational age-, birth weight-, and sex-matched controls were studied. Asphyxia was defined by double criteria of low umbilical arterial blood pH <7.20 and low five-minutes Apgar score <=6, while the controls were term nonasphyxiated neonates with umbilical arterial blood pH >=7.20 and five minutes Apgar score >6. The umbilical arterial pH was done soon after delivery, while the serum cardiac troponin T was done within the first 4 to 24 hours of life. RESULTS: Participants and controls were similar in terms of mean gestational age, mode of delivery, gender, and birth weight (P = 1.0, .07, 1.0, and 1.0, respectively). Two thirds of the asphyxiated babies had elevated serum cardiac troponin T in the high risk range (> 0.1 ng/mL). On the contrary, none of the controls had serum cardiac troponin T in that range. Serum cardiac troponin T showed negative correlation with pH (r = -.75), five-minute Apgar score (r = -.74), and one-minute Apgar score (r = -0.70). CONCLUSION: The study identified perinatal asphyxia as a high risk factor for elevated serum cardiac troponin T and hence for myocardial cellular injury. PMID- 23804867 TI - Ventricular septation for double inlet left ventricle. AB - Ventricular septation is a biventricular repair for certain types of functionally univentricular hearts. Double inlet left ventricle (DILV) is one type of functionally univentricular heart which in certain instances is amenable to ventricular septation. Thirty-four patients underwent ventricular septation for DILV from 1971 to 2000. Hospital death occurred in seven and late death in two. Mean follow-up period was 15 years. Actuarial survival rate was 73.3% (24 patients) at 15 years, 73.3% (15 patients) at 20 years, 73.3% (five patients) at 25 years, and 73.3% (one patient) at 30 to 40 years. Ventricular septation is an alternative to Fontan operation for selected patients with single ventricle, DILV. PMID- 23804868 TI - Challenges in the management of patients with functionally univentricular heart in Turkey. AB - Management of patients with functionally univentricular heart encompasses a wide array of developments over the years in every country. This article describes our working group experiences and 30-year story of single ventricle surgery in Turkey. Diagnosis, surgical treatment, and medical treatment of this complex group of patients necessitate courageous and continuous team effort with multi institutional collaboration. PMID- 23804869 TI - Hematologic alterations in patients with functionally univentricular hearts. AB - Coagulation factor deficiencies may predispose patients with functionally univentricular hearts to bleeding tendencies preoperatively and perioperatively. Postoperatively, this is altered to a prothrombotic predisposition in these patients. Early and late thromboembolic events secondary to a prothrombotic state following univentricular repair contribute to significant morbidity after establishment of the Fontan circulation. Anticoagulation following univentricular repair is advocated but its benefits are controversial. PMID- 23804870 TI - Intensive care and perioperative management of neonates with functionally univentricular hearts. AB - Although mortality rates for patients with univentricular hearts continue to fall, the course in the intensive care unit is remarkable for significant morbidity and utilization of significant resources. Preoperative patient management focuses on balancing competing circulations, pulmonary and systemic, which exist in parallel rather than in series, as in the normal circulation. Postoperative patient management focuses on optimizing systemic output, respiratory status, and mitigating the effects of cardiopulmonary bypass. In this article, we review pre- and postoperative intensive care management in neonates with a univentricular heart. PMID- 23804871 TI - Plastic bronchitis in patients with fontan physiology: review of the literature and preliminary experience with fontan conversion and cardiac transplantation. AB - Plastic bronchitis is a rare, life-threatening condition characterized by the formation of mucofibrinous casts within the pulmonary bronchi. In patients with congenital heart disease, it is most frequently observed in single ventricular anatomies after Fontan palliation. The pathophysiology of plastic bronchitis remains unknown, and a consistently effective treatment strategy has yet to be identified. We report two cases of plastic bronchitis in patients with Fontan physiology. The first was treated with Fontan conversion and, despite encouraging short-term results, experienced recurrence of cast formation seven months postoperatively. The second underwent cardiac transplantation and has been free of bronchial casts for over one year. In addition, we explore the similarities between plastic bronchitis and protein-losing enteropathy, considering theories of their pathophysiologic mechanisms and reports of mutually effective treatment strategies. We propose that bronchial cast formation may result from the confluence of genetic makeup, inflammation, and the Fontan physiology and conclude that further investigation into therapies directed at these factors is merited. PMID- 23804872 TI - Modified technique for the implantation of berlin heart excor ventricular assist device in children. AB - The Berlin Heart Excor (BHE) assist device has become our standard mechanical support device for long-term support in children with heart failure. We report two useful surgical modifications for the implantation of the BHE in the pediatric population, improving ease of implantation as well as subsequent surgical procedures at the time of explantation or transplantation. The first modification entails the use of a polytetrafluoroethylene graft for cannulation via the innominate artery for arterial perfusion during cardiopulmonary bypass. This graft is preserved and reused for institution of bypass at the time of transplantation or explantation of the device after recovery. The second modification consists of an extension of the BHE arterial cannula using a length of knitted polyester graft. This allows for improved positioning of the arterial cannula in the ascending aorta or main pulmonary artery, facilitates vascular anastomosis, and improves hemostasis. PMID- 23804873 TI - Three pledget technique for closure of muscular ventricular septal defects. AB - We propose a modification of the simple, horizontal mattress, pledgetted suture technique for closing the small muscular ventricular septal defect (VSD) by interposing an oversized third pledget on the left ventricular (LV) aspect of the defect. PMID- 23804874 TI - Mycotic aneurysm complicating a covered stent implanted for coarctation of the aorta in a child. AB - A mycotic aneurysm associated with a covered stent in the thoracic aorta of a 12 year-old child was successfully managed by excision and replacement with aortic homograft. On follow-up, there was unobstructed flow through the homograft. This case highlights the need for high index of suspicion for mycotic aneurysm and prompt surgical intervention in children with coarctation of aorta who present with features of infective endocarditis. PMID- 23804875 TI - Right pulmonary artery to left atrial fistula: a rare presentation. AB - Right pulmonary artery to left atrial fistula is a rare congenital vascular anomaly which usually presents with cyanosis, clubbing, dyspnea, and signs and symptoms of a right to left shunt. Paradoxical embolism to the brain resulting in cerebral abscess formation and death is a rare and ominous complication that has been described. We describe an unusual presentation with abdominal pain resulting from splenic infarction. PMID- 23804876 TI - Anatomic biventricular repair in right isomerism with noncommitted ventricular septal defect. AB - Biventricular repair in right atrial isomerism is rarely feasible due to associated anomalies of venous connection, ventricular imbalance, nonroutabilty of the interventricular communication, a common atrioventricular junction, and inadequate pulmonary arterial branches. These patients are also often not ideal for univentricular repair due to some of the above associations. We describe a novel surgical technique that was utilized in such a patient for biventricular repair of a child with right atrial isomerism with total anomalous pulmonary venous connection, regurgitant common atrioventricular valve, hypoplastic left ventricle, nonroutable ventricular septal defect, and pulmonary stenosis. PMID- 23804877 TI - Aortopulmonary window with the absence of left pulmonary artery. AB - We report an unusual combination of an aortopulmonary window with the absence of intrapericardial left pulmonary artery. The morphogenesis of this condition is briefly discussed. PMID- 23804878 TI - Giant left atrial appendage aneurysm in a neonate. AB - Giant aneurysm of the left atrial appendage (LAA) is a rare condition typically presenting in adulthood. This case report describes the investigations and surgical management of a giant LAA aneurysm in a neonate, emphasizing the role of echocardiography and cardiovascular magnetic resonance imaging in preoperative evaluation as well as challenges in surgical repair of this defect. PMID- 23804879 TI - Unusual combination of hypoplastic left ventricle, atrioventricular septal defect with restrictive ventricular septal defect, and common arterial trunk. AB - We describe rare cases of common arterial trunk (truncus arteriosus communis) with unbalanced atrioventricular septal defect, left ventricular hypoplasia, and restrictive ventricular septal defect. The embryology, hemodynamics, and the clinical implications of this complex combination are discussed. PMID- 23804880 TI - The curious case of a button which led to the needle. AB - Foreign bodies in the heart are uncommon in children. These are often removed even if asymptomatic to prevent complications like erosion, embolization, bleeding, thrombosis, and endocarditis. We report the case of a one-and-a-half year-old child with a hypodermic needle in the heart which was found incidentally and removed successfully by surgery. PMID- 23804882 TI - Dexmedetomidine controls supraventricular tachycardia following cardiac surgery in a child. AB - Dexmedetomidine is an alpha2-adrenergic agonist which initially received US Food and Drug Administration (FDA) approval in the United States in 1999 for the sedation of adults during mechanical ventilation and then in 2009 for monitored anesthesia care. Although generally viewed as an adverse effect, bradycardia and the negative chronotropic effects may be beneficial in certain patient populations and have occasionally been used as a therapeutic maneuver. We present a case summary describing intraoperative and postoperative use of dexmedetomidine to treat and control supraventricular tachycardia in a 5-year-old boy undergoing surgical repair of a large atrial septal defect. The specific effects of dexmedetomidine on the cardiac conduction system are reviewed and previous reports of its use as a therapeutic agent for the treatment of perioperative tachyarrhythmias are discussed. PMID- 23804881 TI - Pentalogy of cantrell: surgical resection of a biventricular diverticulum. AB - Pentalogy of Cantrell is a rare diagnosis consisting of several midline defects of the sternum, abdominal wall, diaphragm, pericardium, and heart. One of the known features is ventricular diverticulum that can represent a technical challenge surgically. This is a follow-up case report of the successful simultaneous resection of a biventricular diverticulum and omphalocele repair after previous report of repair of complex intracardiac disease in the same patient. PMID- 23804883 TI - My back pages. PMID- 23804884 TI - Simple versus complex truncus arteriosus: neutralization of risk but with increased resource utilization. AB - This study examined simple versus complex forms of truncus arteriosus (TA) results in the current era with regard to mortality, reintervention, and resource utilization. From 1999 to 2008, 42 infants underwent primary repair of TA, including 22 simple forms of TA without associated anomalies and 20 complex forms with risk factors such as interrupted aortic arch (n = 8), coarctation (n = 1), significant truncal valve regurgitation (n = 6), discontinuous pulmonary arteries (n = 3), and truncal valve stenosis (n = 2). There were 4 early deaths (4/42, 9.5%), with no difference between simple TA (2/22, 9.1%) and complex TA (2/20, 10%). Early mortality decreased to 1 patient (1/23, 4%) in the most recent era: 2003-2008. Late mortality occurred in 4 (4/38, 10.5%). Reintervention was required in 12 patients, a median of 2 years postoperatively: for conduit reasons in 8 and combined conduit and truncal valve insufficiency in 4. Actuarial survival was 82% +/- 7% at 5 years and freedom from reintervention was 52% +/- 17% at 5 years, which are not different between complex and simple forms. Complex TA, age, and weight were not predictors on multivariable analysis for early or late death or reintervention. Complex TA had significantly longer (P < .05) median length of stay (17 vs 13 days) and intensive care unit intubation times (8 vs 5 days) versus simple TA. Complex TA does not have a higher operative or late mortality risk or increased risk of reintervention compared with simple TA. However, complex patients can be expected to have increased resource utilization as compared with simple forms of TA. PMID- 23804885 TI - Initial single-center experience with levosimendan infusion for perioperative management of univentricular heart with ductal-dependent systemic circulation. AB - The aim of this study was to evaluate the safety and the efficacy of levosimendan, a novel calcium sensitizer agent, on postoperative hemodynamic and metabolic parameters of neonates affected by single ventricle anatomy. Twenty consecutive neonates scheduled for the Norwood procedure with Blalock Taussig shunt were prospectively enrolled. All patients received an infusion of levosimendan at 0.1 MUg/kg/min commencing 24 hours before surgery, and the infusion was continued for 48 hours after surgery. No side effects (intolerance to the drug, hypotension, arrhythmias) were shown. A median inotropic score (IS) of 37 was necessary to maintain a mean arterial pressure between 45 and 50 mm Hg at intensive care unit (ICU) admission: IS was significantly reduced after 72 hours (P < .05). Brain natriuretic peptide values decreased significantly from 1210 to 459 pg/mL in 72 hours (P < .05). Median SvO2 increased significantly from 38% to 59% during the evaluated period (P < .05). Cerebral near-infrared spectroscopy values were close to 40% at ICU admission with a significant stable increase to 50% after 12 hours (P < .05). Median lactate level was 13 mmol/L at ICU admission but showed a trend to a rapid and significant decrease after 12 hours (P < .05). Median urine output was surprisingly elevated, always remaining between 5.2 and 6.2 mL/kg/h throughout the postoperative period. Survival rate was 85% at 30 days (17/20 patients) and 75% (15/20) at hospital discharge. Levosimendan infusion in a cohort of neonates with univentricular anatomy was safe and potentially beneficial on postoperative hemodynamic and metabolic parameters. PMID- 23804886 TI - Report from the international society for nomenclature of paediatric and congenital heart disease: creation of a visual encyclopedia illustrating the terms and definitions of the international pediatric and congenital cardiac code. AB - Tremendous progress has been made in the field of pediatric heart disease over the past 30 years. Although survival after heart surgery in children has improved dramatically, complications still occur, and optimization of outcomes for all patients remains a challenge. To improve outcomes, collaborative efforts are required and ultimately depend on the possibility of using a common language when discussing pediatric and congenital heart disease. Such a universal language has been developed and named the International Pediatric and Congenital Cardiac Code (IPCCC). To make the IPCCC more universally understood, efforts are under way to link the IPCCC to pictures and videos. The Archiving Working Group is an organization composed of leaders within the international pediatric cardiac medical community and part of the International Society for Nomenclature of Paediatric and Congenital Heart Disease (www.ipccc.net). Its purpose is to illustrate, with representative images of all types and formats, the pertinent aspects of cardiac diseases that affect neonates, infants, children, and adults with congenital heart disease, using the codes and definitions associated with the IPCCC as the organizational backbone. The Archiving Working Group certifies and links images and videos to the appropriate term and definition in the IPCCC. These images and videos are then displayed in an electronic format on the Internet. The purpose of this publication is to report the recent progress made by the Archiving Working Group in establishing an Internet-based, image encyclopedia that is based on the standards of the IPCCC. PMID- 23804887 TI - Building a culture of excellence in Boston and beyond. AB - There is mounting evidence that unhealthy work environments result in dissatisfied staff, breakdown in communication among disciplines, and poor patient outcomes. The American Association of Critical Care Nurses (AACN) Standards for Establishing and Sustaining Healthy Work Environments and the American College of Chest Physicians (ACCP) Patient-Focused Care project were developed as complementary initiatives to provide direction for improving patient care environments. Hospitalized pediatric patients benefit from interdisciplinary collaboration, teamwork, and clinical innovation that are not obstructed by disciplinary silos and rigid roles. AACN's 6 evidence-based standards are used as a framework to guide this discussion about cultures of excellence in pediatric cardiovascular programs through the lens of an experienced nurse administrator. Each standard interacts in a dynamic way to promote clinical and operational excellence for optimal patient outcomes. Evidence-based examples of contemporary interdisciplinary practice from pediatric cardiovascular centers are described for each of the standards. The 2010 results from the AACN Healthy Work Environment Survey for the cardiovascular program at Children's Hospital Boston are documented. The AACN standards are aligned as a foundation for assessment and improvement of pediatric professional practice environments. Implementation of the standards may be helpful in achieving a culture of excellence in pediatric cardiovascular centers. Monitoring the standards across programs and organizations may be accomplished through the AACN Healthy Work Environment Survey. PMID- 23804888 TI - Pediatric cardiovascular surgery in South america: current status and regional differences. AB - Very little information is available about the epidemiology of congenital heart disease in developing parts of the world, including South America. This article describes the incidence of congenital cardiac disease, the different treatment rates among countries, and future solutions for achieving improved coverage for the children with cardiac diseases in South America. An incidence of congenital cardiac disease of 8 per 1000 live births appears to be a fair approximation for the population of the world and also the population in South America. Nevertheless, a wide variation exists in the observed incidence of congenital cardiac disease in South American countries, which can be partly explained by inequalities in the access to diagnosis, differences in the diagnostic criteria, and true regional variations. It is estimated that 58,718 children are born yearly with congenital heart disease in South America. Brazil, Colombia, and Argentina have the highest number, followed by Peru, Venezuela, Chile, Ecuador, Bolivia, Paraguay, Uruguay, and Guyana. It is also estimated that in South America, 24,081 children per year with a new diagnosis of congenital cardiac disease do not receive any treatment. This paper provides strategies for improving the access to and quality of pediatric cardiac surgery in South America. PMID- 23804889 TI - Insights after 40 years of the fontan operation. AB - Fontan's visionary operation and its modifications over the ensuing decades have re-established nonturbulent flow and substantially reduced cyanosis for patients with severe hypoplasia of one ventricle. However, a long list of largely unexpected sequelae has emerged over the last 40 years. Although it is not difficult to understand how care providers could become discouraged, a number of myths have arisen, which we will attempt to dispel with real-world counterexamples as well as with lessons learned from other disciplines: evolutionary, developmental, and computational biology. We argue that distinctive biochemical abnormalities pointing to dysfunction in multiple organs, including the largest organ system in the body, the endothelium, occur long before grossly observable changes in cardiac imaging can be recognized. With a rational redesign of both our surveillance scheme and our wellness strategies, we hope that Fontan survivors and their families, as well as physicians, nurses, and therapists, will see why Fontan's principle remains just as vibrant today as it was in 1971. PMID- 23804890 TI - A history of pediatric tracheal surgery. AB - Tracheal stenosis in children is primarily caused by congenital complete cartilage tracheal rings. These infants present with severe respiratory distress early in life. The purpose of this review is to examine the history of surgical intervention for infants and children with congenital tracheal stenosis. Most of the significant advances in the surgical treatment of patients with congenital tracheal stenosis have occurred over the past 50 years. The highlights of the historical events include the first pulmonary artery sling repair (1953), tracheal resection (1958), cartilage tracheoplasty (1981), pericardial tracheoplasty (1982), slide tracheoplasty (1989), homograft tracheoplasty (1994), and tracheal autograft (1996). The results of surgical intervention on patients with congenital tracheal stenosis have steadily improved, particularly during the past 20 years. Most successful centers are using cardiopulmonary bypass, simultaneous repair of associated pulmonary artery sling and cardiac anomalies, and the current procedure of choice-slide tracheoplasty. During the past 50 years, significant advances have been made in the care of infants with congenital tracheal stenosis. The outlook for these children is currently quite good, and successful outcomes are particularly evident at institutions with a careful multidisciplinary approach to these patients. PMID- 23804891 TI - Normally and abnormally related great arteries: what have we learned? AB - The conus arteriosus or infundibulum was the site of the major cardiovascular evolutionary and developmental adaptation that made possible air-breathing and permanent land-living for vertebrates, including mammals such as ourselves. The subarterial conal free walls perform an embryonic aortic switch procedure by 35 to 44 days of age in utero, based on growth of the left-sided subpulmonary conal free wall and resorption of the right-sided subaortic conal free wall, i.e., complete right-left asymmetry in the development of the subarterial conal free walls. There is only one way of doing the developmental aortic aortic switch procedure right (one way in situs solitus, and its mirror-image in situs inversus), and there are many ways of doing it wrong, resulting in the conotruncal anomalies. The proximal or apical part of the conus arteriosus, the septal band, was the mother of the right ventricular sinus (the lung pump). The conus transformed the single (systemic) circulation of fish into our double (systemic and pulmonary) circulations. The right ventricle (RV) is only about 36% as old as the left ventricle (LV). Most congenital heart disease involves anomalies of the more recently developed RV, congenital heart disease being the most frequent anomaly in liveborn children - almost 1 percent (0.8%). PMID- 23804892 TI - Left ventricular pseudoaneurysm in children following subaortic muscular resection. AB - Left ventricular pseudoaneurysm is an extremely rare cardiac complication, especially in early childhood. This potentially catastrophic complication may develop following cardiac operations for left ventricular outflow tract obstruction. Surgical repair is indicated when the complication is detected. This article presents 2 cases of left ventricular pseudoaneurysm development following subaortic muscular resection. PMID- 23804893 TI - Emergency transmediastinal pneumonectomy for scimitar syndrome. AB - Repair of scimitar syndrome presenting in infancy involves either tunneling or reimplantation of the anomalous vein to the left atrium and may be fraught with serious complications such as thrombosis and secondary pulmonary infarction necessitating pneumonectomy. The authors present the case of a severely symptomatic infant with scimitar syndrome, managed initially with closure of an atrial septal defect in the hope of avoiding a repair with considerable risk of scimitar vein thrombosis and pulmonary infarction. Despite initial clinical improvement, subsequent rapid development of spontaneous massive emphysematous degeneration of the right lung necessitated emergency pneumonectomy, which was accomplished via the median sternotomy approach. PMID- 23804894 TI - Magnetic resonance angiography detection of vascular aneurysms in patients with kawasaki disease and coronary artery aneurysms. AB - Kawasaki disease is a systemic panvasculitis that causes coronary artery aneurysms in approximately 15% to 25% of untreated patients. Systemic vascular aneurysms may also occur in medium-sized arteries throughout the body and may lead to increased morbidity and mortality in patients with Kawasaki disease. We report a case of diffuse systemic aneurysm formation in a 2-year-old patient with Kawasaki disease with coronary artery aneurysms. Full-body magnetic resonance angiography (MRA) imaging was utilized both in the acute phase and again prior to cardiac catheterization performed at 6 months from the acute illness. The initial MRA detected aneurysmal dilatation of the common and internal iliac arteries bilaterally in the acute phase. Subsequent MRA performed prior to cardiac catheterization 6 months later demonstrated resolution of the iliac artery lesions. Full-body MRA may be useful in screening for associated systemic vascular aneurysms in patients with Kawasaki disease and associated coronary artery aneurysms. PMID- 23804895 TI - Atrial myxoma in 2 nigerian children: case reports and review of the literature. AB - Myxomas are the most common primary cardiac tumors in adults. They are more common in the third to sixth decades of life but infrequent in the pediatric age group. Among pediatric patients, the most often affected patients are teenagers. Their presentation is often enigmatic because of vague constitutional findings. The vague and unusual symptomatology of cardiac myxomas often has led to delayed diagnosis or misdiagnosis in children and adolescents. We, therefore, present 2 cases among Nigerian children below adolescent age and also with vague symptomatology. PMID- 23804896 TI - Interatrial communication with unusual caval venous anomalies. AB - We report a 3-year-old patient with a rare combination of a sinus venosus interatrial communication, anomalous drainage of the right superior pulmonary vein to the right atrium, persistent left superior caval vein, and interruption of the inferior caval vein. We discuss features of anatomical and technical interest. PMID- 23804897 TI - Simultaneous repair of supravalvar aortic and supravalvar pulmonary stenosis using the 3-patch technique. AB - Patients with Williams-Beuren syndrome may have bilateral outflow tract obstruction. We report a simultaneous repair of supravalvar aortic and supravalvar pulmonary stenosis using the 3-patch technique. PMID- 23804898 TI - Advantages of early primary repair of congenital heart disease. PMID- 23804899 TI - The natural and unnatural history of congenital heart disease. PMID- 23804900 TI - Comment on "our roots, our future". PMID- 23804901 TI - Reply to comment on "our roots, our future". PMID- 23804902 TI - Maximizing the value of single-center quality improvement reports. PMID- 23804903 TI - Using the UNOS/SRTR and PHTS Databases to Improve Quality in Pediatric Cardiac Transplantation. AB - Data collection and dissemination have been a part of the US transplant experience since its earliest days. As part of this process, the United Network for Organ Sharing (UNOS) has provided open access to its data. In addition, multiinstitutional groups such as the Pediatric Heart Transplant Study (PHTS) have collected data of particular interest to pediatric and congenital transplants. This wealth of data enables quality improvement along several pathways including individual program assessment and improvement and development of both structure and process measures for ongoing improvement. Extensive literature exists utilizing these data, but must be read critically, recognizing the limitations presented by missing variables (whether uncollected or collected but left blank), reproducibility, and small sample sizes among pediatric patients. However, despite these limitations, opportunity continues to exist to apply these data sets to ongoing questions of quality and optimize organ allocation and long-term survival among pediatric patients with heart failure. PMID- 23804904 TI - Thromboelastography in the assessment of bleeding following surgery for congenital heart disease. AB - BACKGROUND: Perioperative bleeding is common in pediatric cardiac surgery patients. Traditional laboratory tests do not adequately characterize coagulation derangements in patients with bleeding. We sought to establish preoperative thromboelastography parameters in children prior to cardiopulmonary bypass, to compare thromboelastography assessment with standard coagulation parameters postoperatively, and to assess thromboelastography in children with significant hemorrhage. METHODS: Sixty patients requiring cardiopulmonary bypass were enrolled in a prospective observational study of perioperative thromboelastography. Thromboelastography measures were obtained preoperatively, intraoperatively after protamine administration, upon admit to the intensive care unit, and when patients were treated for bleeding. Thromboelastography measures were not used for clinical care. Postoperative thromboelastography measurements were compared with the standard coagulation parameters. Intraoperative thromboelastography, postoperative thromboelastography, and clinical outcomes were compared among patients who did and did not have significant postoperative bleeding. RESULTS: Preoperative thromboelastography parameters were similar to other published normal values for pediatric patients. Transfusion recommendations based on thromboelastography measurements were significantly different from those based on the standard coagulation testing. Thromboelastography measures after initial protamine administration were significantly different in patients with postoperative bleeding. This difference was not present upon arrival to the intensive care unit. Patients with significant bleeding tended to cease bleeding when clinical interventions were in agreement with recommendations based on thromboelastography. CONCLUSIONS: Pediatric patients with significant postoperative bleeding after surgery are more likely to have abnormal thromboelastography early after cessation of cardiopulmonary bypass. Thromboelastography illustrates derangements in the coagulation system and may aid in the treatment of postoperative bleeding. PMID- 23804905 TI - The effects of multiple doses of glucocorticoids on the inflammatory response to cardiopulmonary bypass in children. AB - BACKGROUND: We previously demonstrated that a dose of glucocorticoids (GCs) administered prior to cardiopulmonary bypass (CPB) is effective at suppressing the inflammatory response to CPB and leads to an improved postoperative course. We evaluated whether an additional dose of GC administered eight hours prior to CPB would lead to further clinical benefit. METHODS: We conducted a prospective study in which patients were randomized to receive placebo or GC eight hours prior to CPB, in addition to a dose of GC administered following induction of anesthesia. We measured serum inflammatory mediator levels and postoperative clinical parameters. RESULTS: Thirty-one patients were included in the study. Eighteen patients received two doses of GC and 13 patients received a single does of GC. Complement C3a levels were significantly lower at 24 hours following surgery in those patients who received two doses of GC (3136 +/- 1650 vs 1779 +/- 1616 ng/mL, P = .04). There was no significant difference in tumor necrosis factor (TNF)-alpha or interleukin (IL)-6 levels at any time between groups. There was no significant difference in core body temperature or renal function (based on serum creatinine levels) between groups. There was no significant difference between groups in duration of mechanical ventilation (2.4 +/- 1.5 vs 3.6 +/- 3.7 days, two vs one dose, respectively, P = .33) or length of stay in the intensive care unit ([ICU]; 3.4 +/- 1.4 vs 4.9 +/- 3.6 days, 2 vs 1 dose, respectively, P = .15). CONCLUSION: While those patients who received two doses of GC prior to surgery had significantly less complement activation postoperatively, clinical outcomes did not differ between groups. We conclude that the practice of administering an additional dose of GC prior to CPB is not supported. However, a large randomized study is needed to conclusively discount the potential benefit of this strategy. PMID- 23804906 TI - Perventricular closure of muscular ventricular septal defects in infants with echocardiographic guidance only. AB - OBJECTIVE: To report our experience with perventricular closure of muscular (apical) ventricular septal defects (VSDs) in small infants, with echocardiographic guidance only, in a nonhybrid suite. METHODS: Eight infants with nine large muscular (apical) VSDs underwent perventricular device closure in a nonhybrid operating room, with transesophageal and epicardial echocardiography guidance, at a mean age and weight of 3.07 (0.3-7.28) months and 3.7 (2.5-6.2) kg, respectively. Five patients had multiple VSDs. Four had associated cardiac defects. RESULTS: Nine Amplatzer muscular VSD devices with a mean size of 10 (4 14) mm were deployed. Seven patients were discharged from the intensive care unit with a mean length of stay of 8.6 days. Four patients had minimal postprocedural residual shunt; no one had a residual shunt at six-month follow-up. Mid-term results are excellent. CONCLUSION: Perventricular closure is feasible under echocardiographic guidance only in small patients, even without hybrid suite. This may be a good approach for very symptomatic low-weight infants with apical VSD and may also be useful, in any center, at any time, and in any operating room, to treat an associated apical VSD, even unexpected. PMID- 23804907 TI - Muscular ventricular septal defects in small patients--invited commentary. PMID- 23804908 TI - Surgical Placement of Permanent Epicardial Pacing Systems in Very Low-Birth Weight Premature Neonates: A Review of Data From the Pediatric Cardiac Care Consortium (PCCC). AB - Few studies have characterized the surgical outcomes following epicardial pacemaker placement in very low-birth weight infants with congenital complete heart block. This study was undertaken to review the surgical experience with this patient population based on data from a large multi-institutional registry. METHODS: The Pediatric Cardiac Care Consortium (PCCC) multi-institutional database was retrospectively reviewed to identify premature, low-birth weight neonates that underwent surgical placement of an epicardial pacing system for heart block. We reviewed 179 patients with birth weights less than 1.5 kg that underwent a major operative procedure. Of these, 10 patients underwent surgical placement of an epicardial pacing system for heart block. Patients had heart block in otherwise structurally normal hearts (n = 6) or heart block associated with complex structural congenital cardiac anomalies (n = 4). RESULTS: There were no deaths directly related to the surgical placement of the epicardial pacing system. There were no immediate complications with either lead or generator placement. One generator pocket was revised three months following placement. Survival to discharge was 60%. The four deaths occurred at a mean of 11 days (range 1-45 days) following the procedure. CONCLUSIONS: Neonates born with prematurity and congenital heart block represent a challenging subset of patients with significant mortality. Generator pocket breakdown and infection have been considered barriers to optimal short- and long-term outcomes. Among cases in the PCCC, there were no deaths or major complications that could be attributed to permanent epicardial pacemaker placement. These data suggest that an aggressive surgical strategy may be justified. PMID- 23804909 TI - Apical Left Ventriculotomy is Safe in Infants and Young Children Requiring Cardiac Surgery. AB - OBJECTIVES: Incisions in the left ventricle have previously been associated with increased mortality and morbidity, particularly in infants. In order to determine whether this assumption is still true in the current era, we reviewed our recent experience with apical left ventriculotomy in neonates and infants. METHODS: The records of five consecutive patients requiring a left ventriculotomy between 2007 and 2010 were reviewed. Weight and age ranged from 2.6 to 16 kilograms and 5 days to 2 years. The diagnoses were three multiple ventricular septal defects, one rhabdomyoma, and one apical aneurysm. The primary end point was left ventricular ejection fraction, with other end points being intensive care unit length of stay, time to extubation, inotrope requirement, arrhythmias, and mitral valve function. RESULTS: There were no early or late deaths. Although lower than their preoperative values, early postoperative ejection fractions were greater than 50% in all patients. Two patients required no inotropes, and 3 required only minimal support. Hospital length of stay was 9 +/- 7 days for multiple ventricular septal defect patients, with intensive care unit stays of 2 to 5 days. There were no postoperative arrhythmias requiring pharmacological therapy, and one patient had a significant reduction in mitral insufficiency postoperatively. CONCLUSIONS: Based on our experience, we believe that an apical left ventriculotomy does not significantly impair left ventricular function even in small infants, and is not associated with significant morbidity, based on short-term follow-up. Although the long-term effects are still unknown, early results suggest that a left ventriculotomy may safely be used when alternative approaches are inadequate for complex cardiac defects. PMID- 23804910 TI - Prevention of sternal wound infection in pediatric cardiac surgery: a protocolized approach. AB - BACKGROUND: Sternal wound infections (SWIs) are a costly complication for children after cardiac surgery, increasing morbidity, mortality, and financial cost. There are no pediatric guidelines to reduce the incidence of SWI in this vulnerable population. METHODS: A quality improvement, multidisciplinary team was formed, and a protocol to prevent SWI was developed. A prospective review of patients who underwent pediatric cardiac surgery was conducted over a two-year period to follow adherence to the protocol and incidence of SWI. The Centers for Disease Control definitions for surgical site infections were used to determine the depth and presence of infection. RESULTS: Three hundred and eight children <18 years of age had sternotomies during the study period. There was a reduction in all SWI between the first and second years of the study (odds ratio [OR] = 0.35; confidence interval [CI] 95% 0.12-1.01; P = .059). Delayed sternal closure (DSC) was associated with increased risk of SWI (OR = 5.4; CI 95% 2.13-14.9; P <= .001). Institution of a protocol in patients with DSC was associated with decreased infections during the second year (first year: n = 7 (14%), second year: n = 2 (4%), P = .14). CONCLUSIONS: Institution of a protocol was associated with a decreased number of infections in children. A multicenter study of a bundled protocol approach to SWI prevention is needed. Children with DSC had a significantly higher risk of developing a wound infection. Initiating strategies to reduce SWI with a focus on children with DSC may result in improved overall infection rates. PMID- 23804911 TI - Bleeding and thrombotic emergencies in pediatric cardiac intensive care: unchecked balances. AB - Children in the cardiac intensive care unit (CICU) with congenital or acquired heart disease are at risk for hematologic complications, both hemorrhage and thrombosis. The overall incidence of hematologic complications in the CICU is unknown, but risk factors and target groups have been identified where the essential physiologic balance between bleeding and clotting has been disrupted. Although the best management of life-threatening bleeding and clotting is prevention, the cardiac intensivist is often faced with managing life-threatening hematologic events involving patients from within the unit or those who present from outside. Part I of this review deals with the propensity of children with congenital and acquired heart disease to complications of both bleeding and clotting, and includes discussions of perioperative bleeding, thromboses in single-ventricle patients, clotting of Blalock-Taussig shunts and thrombotic complications of mechanical valves. Part II deals with the subject of stroke in children with heart disease. Part III reviews monitoring the effectiveness of anticoagulation and thrombolysis in the CICU. Currently available diagnostics modalities, medications and management strategies are reviewed and future directions discussed. PMID- 23804912 TI - The role of tricuspid valve surgery in the late management of tetralogy of fallot: collective review. AB - While surgical repair of tetralogy of Fallot (TOF) is generally associated with good early outcomes, late complications affect long-term survival and may require reoperation. Pulmonary regurgitation (PR) and tricuspid regurgitation (TR) may increase the risk of arrhythmias, reduced cardiac function, and sudden death. Tricuspid valve function can be compromised secondarily in the setting of PR or directly as a result of injury or alteration of the valve related to the original TOF repair. This article reviews the etiologic mechanisms, pathophysiological implications, and surgical interventions for TR. Effective management following TOF repair requires consideration of TR to optimize late outcomes. PMID- 23804913 TI - Management of pulmonary arterial supply dependent on a coronary arterial fistula in a patient with tetralogy of fallot with pulmonary atresia. AB - In this report, we describe the surgical management of a patient with tetralogy of Fallot and pulmonary atresia, in whom a fistula from the anterior interventricular coronary artery was the predominant source of arterial supply to both the lungs. PMID- 23804914 TI - Double aortic arch and aortopulmonary window: an uncommon presentation in a newborn. AB - We describe a rare association of aortopulmonary window and double aortic arch in a 1.7-kg newborn who presented with severe respiratory distress. A staged surgical approach was used because of the size of the patient and significant comorbidity. This approach resulted in excellent outcome. PMID- 23804915 TI - Normal Drainage, Abnormal Connection: Partial Anomalous Pulmonary Venous Connection and Sinus Venosus Atrial Septal Defect With a Net Right-to-Left Shunt. AB - A seven-month-old girl with partial anomalous pulmonary venous connection and atrial septal defect underwent cardiac magnetic resonance for further evaluation. Anatomical images and flow quantification confirmed the diagnosis and demonstrated a commitment of the superior vena cava to the left atrium, resulting in a right-to-left shunt and pulmonary/systemic blood flow ratio of 0.85. The findings were confirmed during surgery. PMID- 23804916 TI - Successful simultaneous correction of complex congenital tracheal stenosis and tetralogy of fallot. AB - Congenital tracheal stenosis is frequently associated with heart malformations. Simultaneous correction of both anomalies has been advocated by several authors. We describe our experience with a premature neonate with congenital tracheal stenosis and tetralogy of Fallot. The anomalies were corrected during the same surgical procedure with the aid of extracorporeal circulation. The implications of the operative and postoperative courses, concerning both the cardiac anomaly and the tracheal anomaly are discussed. PMID- 23804917 TI - A case of complete repair of type-B atrioventricular canal defect and cor triatriatum. AB - The association of atrioventricular canal defect and cor triatriatum sinister is very rare and only a few anecdotal reports of successful surgical repair and outcome have been reported. We report a case of Rastelli type-B atrioventricular canal defect with cor triatriatum which was successfully repaired. PMID- 23804918 TI - Surgical repair of tetralogy of fallot at age 83. AB - Tetralogy of Fallot (TOF) is a cyanotic congenital heart defect typically diagnosed in infancy and treated with early surgical correction. We report a patient with TOF diagnosed at age 78. Successful surgical repair was performed at age 83, the oldest reported age of surgical correction of this condition. Despite a complicated surgical and postoperative course, the patient is doing well almost four years later. PMID- 23804919 TI - Totally anomalous pulmonary venous connection draining through an intrapulmonary vertical vein. AB - We report a two-year-old patient with isomerism of the right atrial appendages, a functionally univentricular heart, and associated totally anomalous pulmonary venous connection. The unusual finding was an intrapulmonary course of the vertical vein. We discuss the anatomical findings, management, and outcome. PMID- 23804920 TI - Left ventricular aneurysm in a four-year-old child: a diagnostic challenge. AB - We describe spontaneous rupture of a congenital left ventricular (LV) aneurysm with subsequent tamponade and cardiac arrest in a 4-year-old male with staphylococcal septicemia. Emergency resuscitation, thoracotomy, and oversewing were successfully undertaken in the pediatric intensive care unit. There was complete cardiovascular recovery without adverse neurodevelopmental sequelae. This article details the difficulties in determining the etiology of ventricular aneurysms but highlights the importance of attempting to do so, particularly in distinguishing between congenital and acquired forms. Congenital aneurysms are usually a stable pathology; mycotic aneurysms are not and should be managed emergently, as survival after rupture is rare. PMID- 23804921 TI - Conservative management of iatrogenic esophageal perforation during neonatal cardiac surgery. AB - Esophageal perforation is a rare, but life threatening, entity in children. The most common iatrogenic causes include nasogastric tube insertion, stricture dilation, or endotracheal intubation. Recently, transesophageal echocardiography (TEE) has been increasingly used in pediatric cardiac surgery to assess cardiac function and structural abnormalities. The safety of TEE in children is still controversial and complications such as airway obstruction, hemodynamic compromise, and esophageal injury have been reported. We recently experienced a case of esophageal perforation caused by TEE probe insertion during neonatal cardiac surgery; two weeks of conservative management resulted in complete resolution of the injury. PMID- 23804922 TI - Spontaneous Resolution of Residual Mitral Regurgitation in Patient With ALCAPA on ECMO. AB - We describe a case of revascularization for anomalous left coronary artery from the pulmonary artery (ALCAPA) with severe left ventricular (LV) dysfunction and severe mitral regurgitation (MR). Extracorporeal membrane oxygenation (ECMO), later successfully converted to an indigenous left ventricular assist device (LVAD) functionally resulted in the spontaneous resolution of MR and satisfactory recovery of LV function. PMID- 23804923 TI - Cor triatriatum sinister in a newborn with transposition of the great arteries. PMID- 23804924 TI - Giant thrombus in right atrium and pulmonary artery in an adult patient with fontan surgery. PMID- 23804926 TI - Coming together in cape town in 2013. PMID- 23804927 TI - Judge a book by its cover, please. PMID- 23804928 TI - The anatomy of transposition. AB - The basic morphology of transposition of the great arteries is described, together with a discussion of anatomic variables of surgical significance including the spectrum of variation of coronary artery anatomy and associated lesions. PMID- 23804929 TI - Transposition of the great arteries: lessons learned about patterns of practice and outcomes from the congenital heart surgery database of the society of thoracic surgeons. AB - The Society of Thoracic Surgeons (STS) Congenital Heart Surgery Database contains data about 3258 patients with the diagnosis of transposition of the great arteries (TGA) who underwent surgery during the 4-year time interval from July 1, 2005 to June 30, 2009, inclusive. This cohort includes 2918 patients with concordant atrioventricular connections and discordant ventriculoarterial connections and 341 patients with congenitally corrected TGA (discordant atrioventricular connections and discordant ventriculoarterial connections). The 4 most common operations were the following: (1) arterial switch operation (ASO) for TGA with intact ventricular septum (n = 1196), (2) ASO with ventricular septal defect (VSD) repair for TGA with VSD (n = 420), (3) ASO with VSD repair and aortic arch repair for TGA with VSD and hypoplastic arch (n = 55), and (4) Rastelli operation for TGA with VSD and left ventricular outflow tract obstruction (n = 49). Detailed preoperative, intraoperative, and postoperative data were obtained about patients who underwent these 4 operations. Median age at surgery (days) was as follows: ASO: 6.0; ASO with VSD repair: 7.0; ASO with VSD repair and aortic arch repair: 7.0; and Rastelli: 309.0. Mean age at surgery (days) was as follows: ASO: 22.9; ASO with VSD repair: 24.8; ASO with VSD repair and aortic arch repair: 14.4; and Rastelli: 721.8. Discharge mortality was as follows: ASO: 2.2%; ASO with VSD repair: 5.5%; ASO with VSD repair and aortic arch repair: 7.3%; and Rastelli: 0%. Median length of stay (days) was as follows: ASO: 11.0; ASO with VSD repair: 11.0; ASO with VSD repair and aortic arch repair: 18.0; and Rastelli: 7.0. The sternum was left open in the following: ASO: 24.8%; ASO with VSD repair: 29.5%; ASO with VSD repair and aortic arch repair: 40.0%; and Rastelli: 6.1%. This review of data from the STS Congenital Heart Surgery Database allows for unique documentation of patterns of practice and outcomes. From this review, we learned that although surgery for TGA is often complex and may be associated with morbidity, most patients survive without major complications. PMID- 23804930 TI - Late arrhythmias after surgery for transposition of the great arteries. AB - The evolution of surgical techniques for transposition of the great arteries (TGA) provides a moving target for the assessment of late arrhythmias. Imposed on varying anatomical substrates are progressive surgical interventions, each with its own set of sequelae. Analysis of the risk of arrhythmia development requires division into which arrhythmia is present, for which form of transposition, undergoing what type of surgery, and in which surgical era. For purposes of this review, available data on d-TGA undergoing Senning repairs, Mustard repairs, and arterial switch repairs and congenitally corrected TGA undergoing double switch repairs are reviewed. PMID- 23804931 TI - Late complications following the arterial switch operation. AB - The arterial switch operation has been the principal treatment for transposition of the great arteries and its variants for the last 25 years. Early mortality has decreased significantly over time, but long-term complications include pulmonary artery stenosis, coronary artery obstruction, neoaortic valvar insufficiency, arrhythmia, and aortic arch obstruction. This article provides an overview of the history, anatomic patterns, surgical results, and possible operative solutions discussed in the literature for patients with transposition of the great arteries who undergo arterial switch operations that result in late complications. Published journal articles were identified through PubMed literature search. The authors selected 72 articles for analysis. It is concluded that modifications can be made to the arterial switch operation in an effort to meet the challenges presented by late complications. PMID- 23804932 TI - Anatomy of discordant atrioventricular connections. AB - The term discordant atrioventricular connections refers to the situation in which the ventricles are connected inappropriately to the atrial chambers. In most instances, the connections of the great arteries are also abnormal, with the aorta and the pulmonary trunk arising from morphologically inappropriate ventricles. This combination results in the presence of so-called congenitally corrected transposition. Double-outlet right ventricle is occasionally present, while concordant ventriculoarterial connections may be seen rarely. Most such hearts have a range of additional abnormalities, including ventricular septal defects; outflow tract obstruction, usually of the morphologically left ventricle; anomalies of the morphologically tricuspid valve; and a highly abnormal location of the specialized atrioventricular conduction axis. Some examples exhibit bizarre abnormalities of ventricular relationships and topology, including criss-cross atrioventricular connections and superoinferior ventricular relations. In describing the anatomy of these malformations, it is important to use a step-by-step segmental approach to the documentation of the connections and associated defects in each case and to avoid potentially confusing shorthand terms. PMID- 23804933 TI - Echocardiography for discordant atrioventricular connections. AB - An understanding of the nomenclature of discordant atrioventricular connections is necessary to understand the corresponding anatomy and hence physiology of this rare, and complex heart defect. Echocardiography is an important imaging modality for the diagnosis of discordant atrioventricular connections. The morphology of the atria, ventricles and great arteries can be determined by echocardiography. A precise and organized segmental approach to the echocardiographic examination can establish the diagnosis and associated abnormalities. Such an approach is essential for the initial diagnosis, to help guide medical and surgical intervention, and evaluate the corresponding response to intervention in these patients. PMID- 23804934 TI - The natural history of congenitally corrected transposition of the great arteries. AB - The natural history of congenitally corrected transposition of the great arteries is of clinical/surgical importance once the fetus is born without heart block or signs of heart failure. Without significant tricuspid valve malformation, associated defects such as ventricular septal defect and left ventricular outflow obstruction can be repaired surgically. The mortality and long-term outcome appear to be linked strongly with the severity of tricuspid valve regurgitation. Some patients with an intact ventricular septum and no right ventricular dysfunction will live long lives without detection, and some women will successfully complete pregnancy. PMID- 23804935 TI - Congenitally Corrected Transposition of Great Arteries: Surgical Options for the Failing Right Ventricle and/or Severe Tricuspid Regurgitation. AB - In patients with congenitally corrected transposition of the great arteries, the main concern has been the long-term performance of the morphologic right ventricle in association with tricuspid valve regurgitation when it remains as the systemic ventricle. Deterioration in ventricular function can occur slowly over many years, even without associated cardiac anomalies or previous surgical interventions. This review summarizes the authors' experience and provides a thorough review of the literature addressing the management of the failing systemic right ventricle as well as the tricuspid valve regurgitation with congenitally corrected transposition. This includes different surgical options, the authors' preferred management algorithm, and the late outcome. PMID- 23804936 TI - The impact of shunt type on palliative outcomes in neonates and infants with diminished pulmonary blood flow. AB - We analyzed early and intermediate outcomes in cyanotic neonates (n = 43) and infants (n = 26) requiring palliation with either a modified Blalock-Taussig shunt (MBT) or a central aortopulmonary shunt (CAP). Between 1995 and 2009, 69 consecutive patients underwent an MBT (n = 42) or CAP (n = 27) for tetralogy of Fallot (n = 21), pulmonary atresia (n = 25), severe pulmonary valve stenosis (n = 22), and 2-stage repair of transposition of the great arteries (n = 1). The groups were similar with regard to age, weight, pulmonary artery diameter, and preoperative saturations. Postoperative mortality was 3 after CAP (11.1%) versus 1 after MBT (2.4%; P = .0203). Shunt size/weight index was comparable for both groups. MBTs had shorter surgical times (P = .002), required less inotropes (inotropic index, 103 +/- 18 vs 889 +/- 199; P = .0069), less blood product transfusions (P = .01), and had shorter duration of ventilation (P = .026) and intensive care unit (ICU) stay (P = .042). Children with MBTs had higher saturations at hospital discharge (P = .018). Prior to complete repair, 2 patients with a CAP and 10 patients after an MBT needed pulmonary artery dilation or stent implantation (P = .23). At the time of complete repair and shunt takedown, 3 MBT patients needed surgical patch augmentation of the pulmonary artery. The MBT is a safer and more expeditious operation and more frequently avoids cardiopulmonary bypass. Patients require less inotropes, blood products, and ICU time but may require more interventional therapy to treat pulmonary artery stenosis in the interval to complete repair. Surgical treatment of shunt related pulmonary artery distortion may be addressed at the time of complete repair. PMID- 23804937 TI - Optimal normative pediatric cardiac structure dimensions for clinical use. AB - Cardiac structure size influences surgical decision making in pediatric cardiac surgery. Lack of universally adopted normative cardiac structure dimensions may confound decision making. A review of the relevant literature contained in 2 large databases was performed with a view to determine the optimal normative cardiac structure dimensions for clinical use. The current article initially discusses technical issues related to cardiac structure measurement and measurement normalization. It then describes the literature search strategy and examines the quality of published data in subjects below 19 years of age. The optimal normative dimension data set is then recommended. PMID- 23804938 TI - Impact of shunt type on growth of pulmonary arteries after norwood stage I procedure: current best available evidence. AB - The past decade has seen a substantial improvement in the outcome following surgical palliation for hypoplastic left heart syndrome. This has been attributed to modifications in the surgical as well as postoperative management strategies. One such modification is the reemergence of the right ventricle to pulmonary artery (RV-PA) shunt as an alternative to the modified Blalock-Taussig (mBT) shunt as the source of pulmonary blood flow. The RV-PA shunt has been shown to improve the immediate surgical outcome compared with the classic Norwood procedure with an mBT shunt. Despite the several reported advantages, the impact of the RV-PA shunt on growth of the pulmonary arteries and incidence of late development of central PA stenosis remains unclear. This systematic review evaluates the current best available evidence to address this issue and concludes that the evidence from retrospective studies and only available randomized controlled trial (RCT) is conflicting. The retrospective studies predominantly suggest that the Norwood procedure with RV-PA shunt may have favorable effects on the development of the pulmonary arteries due to even distribution of pulmonary blood flow with greater distal left pulmonary artery growth, resulting in more balanced distal branch pulmonary artery size albeit with a greater degree of central pulmonary artery hypoplasia needing surgical attention. On the contrary, the RCT reports that the overall size of the pulmonary artery on angiography before the stage II procedure was smaller in the RV-PA shunt group than in the mBT shunt group, with no information available on incidence of central pulmonary hypoplasia. PMID- 23804939 TI - Ascites in adult patients with cyanotic congenital heart disease. AB - Hematologic, neurologic, renal, and rheumatic complications in patients with cyanotic congenital heart disease are well known. However, the effects of this condition on the liver are poorly described. Between April 2005 and April 2010, 25 adults with cyanotic congenital heart disease were studied to determine clinical history, liver ultrasonographic data, and liver histological presentation. Twenty-five patients, with a median age of 28.7 +/- 8.3 years and a basal tissue hemoglobin oxygen saturation of 83.3% +/- 6.8%, were studied. Liver ultrasonographic examination showed abnormalities in 10 of 20 patients (50%): 6 patients (30%) had hepatomegaly, 2 patients (10%) heterogeneous parenchyma echo pattern, and 2 patients (10%) increased portal echogenicity. Ascites was found in 7 patients (28%): 4 patients had refractory ascites and 3 patients anasarca. Patients with anasarca responded well to oral and intravenous furosemide, but those with isolated ascites did not. No data to indicate severe ventricular dysfunction or severe valve regurgitation were seen. In patients with refractory ascites who had therapeutic paracentesis, serum-ascites albumin gradient in ascites was greater than 1.1 g/dL. No significant association was found between patients with or without ascites when laboratory data and New York Heart Association functional class were compared. Liver biopsy was performed in 6 patients (24%). The most remarkable liver histological finding, in those with refractory ascites, was the existence of periportal fibrosis associated with sinusoidal dilatation. Periportal liver fibrosis associated with congestive heart failure, sepsis, or a long-term Fontan procedure can trigger refractory ascites formation. PMID- 23804940 TI - Development of pediatric cardiology in latin america: accomplishments and remaining challenges. AB - Until the first quarter of the 20th century, most physicians were more than happy to differentiate congenital heart lesions from rheumatic heart disease, which then was rampant. As early as 1932, Dr Rodolfo Kreutzer, from Buenos Aires, Argentina, was already involved in the study of congenital heart defects. He started off assessing children with a stethoscope and with Einthoven electrocardiography equipment. The cardiac unit at the Buenos Aires Children's Hospital was created in 1936. It established the onset of pediatric cardiology in Argentina and fueled its development in South America. Nearly at the same time, Agustin Castellanos from Cuba also became a pioneer in the assessment of congenital heart disease. He described the clinical applications of intravenous angiocardiography in 1937. Meanwhile in Mexico, Dr Ignacio Chavez founded the National Institute of Cardiology in 1944 in Mexico City. It was the first center in the world to be exclusively devoted to cardiology. From this center, Victor Rubio and Hugo Limon performed the first therapeutic cardiac catheterization in 1953. Meanwhile, Professor Euriclydes Zerbini from Sao Paulo, Brazil, built the largest and most important school of cardiac surgeons in South America. In Santiago, Chile, the Calvo Makenna Hospital was the center where Helmut Jaegger operated on the first infant with extracorporeal circulation in Latin America in 1956. The patient was a 1-month-old baby, with complete transposition of the great arteries, who underwent an Albert procedure. Currently, there are many fully equipped centers all over the region, capable of dealing with most lesions and of providing excellent medical, interventional, and surgical treatment. Outcomes have improved substantially over the last 20 years. These achievements have gone beyond our pioneers' dreams. However, many neonates and young infants die prior to surgery because referral centers are overburdened and have long surgical waiting lists. Clearly, we still have to mastermind and establish sustainable public health policies to overcome these challenges. PMID- 23804941 TI - Microemboli detection and classification during pediatric cardiopulmonary bypass. AB - Microemboli may be a cause of postoperative neurological morbidity. Improved detection of microemboli may lead to better strategies to minimize embolization and improve neurological outcomes. Transcranial Doppler may have limited sensitivity for very small microemboli. The Emboli Detection and Classification (EDAC) Quantifier offers increased sensitivity (10 MUm) and potentially improved capability for microemboli monitoring. EDAC was used to measure microemboli in the cardiopulmonary bypass circuit during 33 pediatric heart operations. More microemboli were detected in the venous than the arterial line (median, 11,830 vs 1298). Venous microemboli tended to be larger in size than arterial microemboli (>40 MUm; 59% vs 7%). Increased venous and arterial microemboli were seen at the onset of bypass; increased venous microemboli were also seen with clamp removal. Thousands of microemboli <40 MUm are transmitted to pediatric patients during heart surgery. Initiation of bypass may be a key offender and may result from air in the venous line. Although the significance of microemboli remains unknown, increased awareness may lead to improved techniques to minimize microemboli, with improvement in neurological outcomes. PMID- 23804942 TI - Final thoughts. PMID- 23804943 TI - Pulmonary Arteriovenous Malformations in Heterotaxy Syndrome: The Case for Early, Direct Hepatic Vein-to-Azygos Vein Connection. AB - We report a surgical approach using hepatic vein-to-azygos vein connection without cardiopulmonary bypass or deep hypothermic circulatory arrest in a patient with heterotaxy syndrome and interrupted inferior vena cava with persistence of pulmonary arteriovenous malformations (PAVMs) after previous Fontan completion. We advocate early performance of hepatic vein-to-azygos vein connection following the Kawashima operation for heterotaxy with functionally univentricular heart and interrupted inferior vena cava. We review the physiology of heterotaxy syndrome with congenital heart disease and justify our approach in the context of a review of previous surgical strategies used in this patient population. PMID- 23804944 TI - A silent patent ductus arteriosus: a culprit or an innocent bystander? AB - A 4-mm patent ductus arteriosus (PDA) was serendipitously diagnosed during intraoperative transesophageal echocardiography for a noncardiac procedure in an obese adult patient with a history of decreased exercise tolerance and dyspnea, despite a negative preoperative transthoracic examination. This uncommon event poses questions regarding the relevance of this finding to the differential diagnosis of dyspnea in an obese adult with a negative transthoracic echocardiography study, given the unknown prevalence of this pathology and the absence of consensus regarding the clinical management. PMID- 23804945 TI - Norwood-sano operation using a stentless pulmonary valved conduit. AB - The Sano modification of Norwood's operation has the potential to generate an excess volume load on the single right ventricle as a consequence of diastolic reversal of flow through the conduit. This article describes the use of a new, small, biological conduit with a porcine valve inside. This new conduit has been used in modified Norwood procedures. It is interposed between the right ventricle and the confluence of the pulmonary arteries. The use of a valved conduit should prevent the retrograde diastolic blood flow observed with use of nonvalved conduits and may improve postoperative hemodynamics. The use of a new stentless valved conduit in 3 recent Norwood procedures is reported herein. PMID- 23804946 TI - Critical pulmonary stenosis: challenges following surgical correction. AB - A 20-day-old girl was diagnosed with critical pulmonary valvular stenosis with patent ductus arteriosus (PDA). She underwent surgical pulmonary valvotomy and infundibular resection. A trial snaring of the PDA resulted in significant systemic desaturation, and the PDA was left undivided. A continuous infusion of prostaglandin was used to keep the PDA open for the next 8 days. The PDA acted as a "natural systemic-to-pulmonary shunt" to provide pulmonary blood flow until right ventricular compliance and function improved. The various causes of persistent desaturation following pulmonary valvotomy are discussed. PMID- 23804947 TI - Abstracts from Cardiology 2011, 15th Annual Update on Pediatric and Congenital Cardiovascular Disease: Bringing Interdisciplinary Evidence-based Practice to the Patient, February 2 - 6, 2011; Scottsdale, Arizona, USA. PMID- 23804948 TI - Subsidence in two uncemented femoral stems: an in vitro study. AB - Many aspects of the performance of different implant designs remain as open questions in total hip arthroplasty. Despite the increased survivorship of each hip replacement, the amount of bone removed during surgery remains an important factor because of the potential need for revision surgery. Given that a smaller implant will have less surface area over which to transfer load, constructs that preserve more bone stock may be susceptible to mechanical complications related to the fixation of the implant in the femur. To assess mechanical fixation, this study compared the fiber metal taper and Mayo conservative hip stems in subsidence, frontal plane rotation and failure load. After dual-energy x-ray absorptiometry scans, pairs of cadaveric femurs received implants of each type and were loaded for 10,000 cycles. The subsidence and rotation were measured. Finally, specimens were loaded to failure. The subsidence and rotation after cyclic loading were -0.73 mm and 0.1 degrees , respectively, for the Mayo implants and -0.87 and 0.52 degrees , respectively, for the fiber metal taper implants, but no significant differences between implant types were found. There was also no significant relationship to bone mineral density. A power analysis revealed that 914 specimens would have been required to achieve a power of 0.8. PMID- 23804949 TI - Determination of remodeling parameters for a strain-adaptive finite element model of the distal ulna. AB - Strain energy-based adaptive material models are used to predict bone resorption resulting from stress shielding induced by prosthetic joint implants. Generally, such models are governed by two key parameters: a homeostatic strain-energy state (K) and a threshold deviation from this state required to initiate bone reformation (s). A refinement procedure has been performed to estimate these parameters in the femur and glenoid; this study investigates the specific influences of these parameters on resulting density distributions in the distal ulna. A finite element model of a human ulna was created using micro-computed tomography (uCT) data, initialized to a homogeneous density distribution, and subjected to approximate in vivo loading. Values for K and s were tested, and the resulting steady-state density distribution compared with values derived from uCT images. The sensitivity of these parameters to initial conditions was examined by altering the initial homogeneous density value. The refined model parameters selected were then applied to six additional human ulnae to determine their performance across individuals. Model accuracy using the refined parameters was found to be comparable with that found in previous studies of the glenoid and femur, and gross bone structures, such as the cortical shell and medullary canal, were reproduced. The model was found to be insensitive to initial conditions; however, a fair degree of variation was observed between the six specimens. This work represents an important contribution to the study of changes in load transfer in the distal ulna following the implementation of commercial orthopedic implants. PMID- 23804950 TI - Effect of lubricants on friction in laboratory tests of a total disc replacement device. AB - Some designs of total disc replacement devices have articulating bearing surfaces, and these devices are tested in vitro with a lubricant of diluted calf serum. It is believed that the lubricant found in total disc replacement devices in vivo is interstitial fluid that may have properties between that in Ringer's solution and diluted calf serum. To investigate the effect of lubricants, a set of friction tests were performed on a generic model of a metal against metal ball and-socket total disc replacement device. Two devices were tested: one with a ball radius of 10 mm and other with a ball radius of 16 mm; each device had a radial clearance of 0.015 mm. A spine simulator was used to measure frictional torque for each device in axial rotation, flexion-extension and lateral bending at frequencies of 0.25-2 Hz, under 1200 N axial load. Each device was tested with two different lubricants: a solution of new born calf serum diluted with deionised water and Ringer's solution. The results showed that the frictional torque generated between the bearing surfaces was significantly higher in Ringer's solution than in diluted calf serum. The use of Ringer's solution as a lubricant provides a stringent test condition to detect possible problems. Diluted calf serum is more likely to provide an environment closer to that in vivo. However, the precise properties of the fluid lubricating a total disc replacement device are not known; hence, tests using diluted calf serum may not necessarily give the same results as those obtained in vivo. PMID- 23804951 TI - Fracture risk and initial fixation of a cementless glenoid implant: the effect of numbers and types of screws. AB - The initial fixation of an anatomical cementless glenoid component, provided by different numbers and types of screws, and the risk of bone fracture were evaluated by estimating the bone-implant interface micromotions and the principal strains around the prosthesis. Four different fixation configurations using locking or compression screws were tested. Estimation of the micromotions at the bone-implant interface was performed both experimentally, using an in vitro model, and computationally, using a numerical model. Principal bone strains were estimated using the numerical model. Subject variability was included by modelling two different bone qualities (healthy and rheumatoid bone). For the fixation configurations that used two screws, experimental and modelling results found that the micromotions at the bone-implant interface did not change with screw type. However, screw type had a significant effect on fixation when only one screw was used; in this case, a locking screw resulted in less micromotion at the bone-implant interface compared with the compression screw. Bone strains were predicted by the numerical model, and strains were found to be independent of the screw type; however, the predicted strain levels calculated in rheumatoid bone were larger than the strain levels that may cause bone damage for most considered arm positions. Predicted bone strain in healthy bone did not reach this level. While proper initial component fixation that allows biological fixation can be achieved by using additional screws, the risk of bone failure around the screws must be considered, especially in cases of weak bone. PMID- 23804952 TI - Analysis of the compressive behaviour of the three-dimensional printed porous titanium for dental implants using a modified cellular solid model. AB - A set of cylindrical porous titanium test samples were produced using the three dimensional printing and sintering method with samples sintered at 900 degrees C, 1000 degrees C, 1100 degrees C, 1200 degrees C or 1300 degrees C. Following compression testing, it was apparent that the stress-strain curves were similar in shape to the curves that represent cellular solids. This is despite a relative density twice as high as what is considered the threshold for defining a cellular solid. As final sintering temperature increased, the compressive behaviour developed from being elastic-brittle to elastic-plastic and while Young's modulus remained fairly constant in the region of 1.5 GPa, there was a corresponding increase in 0.2% proof stress of approximately 40-80 MPa. The cellular solid model consists of two equations that predict Young's modulus and yield or proof stress. By fitting to experimental data and consideration of porous morphology, appropriate changes to the geometry constants allow modification of the current models to predict with better accuracy the behaviour of porous materials with higher relative densities (lower porosity). PMID- 23804953 TI - Comparison on intracochlear disturbances between drilling a manual and robotic cochleostomy. AB - During cochlear implantation, hearing preservation is a concern. Minimizing disturbances to the cochlea and protection of the underlying endosteal membrane during the formation of a cochleostomy are considered important factors. The robotic micro-drill system tested in this article is the first example of an autonomous surgical drill successfully producing a cochleostomy, which keeps the underlying endosteal membrane intact. This study compares induced disturbances within the cochlea during formation of cochleostomy using the robotic micro-drill with that of conventional manual drilling. The disturbance of the endosteal membrane is measured using a Microscope Scanning Vibrometer at a third window, produced in the cochlea. Results show that the highest velocity amplitude measured was associated with manual drilling technique. The robotic micro-drill technique produced only about 1% of the peak velocity amplitude seen in manual drilling and exhibited much more uniform behaviour, while keeping the underlying membrane intact. The technique applied when using the robotic drill could be a major step in reducing the trauma to the cochlea, by reducing disturbance levels. PMID- 23804954 TI - Changes in dynamic medial tibiofemoral contact mechanics and kinematics after injury of the anterior cruciate ligament: a cadaveric model. AB - The effects of tears of the anterior cruciate ligament on knee kinematics and contact mechanics during dynamic everyday activities, such as gait, remains unclear. The objective of this study was to characterize anterior cruciate ligament-deficient knee contact mechanics and kinematics during simulated gait. Nine human cadaveric knees were each augmented with a sensor capable of measuring dynamic normal contact stresses on the tibial plateau, mounted on a load controlled simulator, and subjected to physiological, multidirectional, dynamic loads to mimic gait. Using a mixed model with random knee identifiers, confidence intervals were constructed for contact stress before and after anterior cruciate ligament transection at two points in the gait cycle at which axial force peaked (14% and 45% of the gait cycle). Kinematic and contact mechanics changes after anterior cruciate ligament transection were highly variable across knees. Nonetheless, a statistically significant increase in contact stress in the posterior-central aspect of the medial tibial plateau at 45% of the gait cycle was identified, the location of which corresponds to the location of degenerative changes that are frequently found in patients with chronic anterior cruciate ligament injury. The variability in the contact stress in other regions of the medial plateau at 45% of the gait cycle was partly explained by the variations in osseous geometry across the nine knees tested. At 14% of gait, there was no significant change in peak contact stress after anterior cruciate ligament transection in any of the four quadrants, and none of the possible explanatory variables showed statistical significance. Understanding the variable effect of anterior cruciate ligament injury on contact mechanics based on geometric differences in osseous anatomy is of paramount clinical importance and may be invaluable to select the best reconstruction techniques and counsel patients on their individual risk of subsequent chondral degeneration. PMID- 23804955 TI - Comparison between FEBio and Abaqus for biphasic contact problems. AB - Articular cartilage plays an important role in the function of diarthrodial joints. Computational methods have been used to study the biphasic mechanics of cartilage, and Abaqus has been one of the most widely used commercial software packages for this purpose. A newly developed open-source finite element solver, FEBio, has been developed specifically for biomechanical applications. The aim of this study was to undertake a direct comparison between FEBio and Abaqus for some practical contact problems involving cartilage. Three model types, representing a porous flat-ended indentation test, a spherical-ended indentation test, and a conceptual natural joint contact model, were compared. In addition, a parameter sensitivity study was also performed for the spherical-ended indentation test to investigate the effects of changes in the input material properties on the model outputs, using both FEBio and Abaqus. Excellent agreement was found between FEBio and Abaqus for all of the model types and across the range of material properties that were investigated. PMID- 23804956 TI - A retrospective comparison of blood transfusion requirements during cardiopulmonary bypass with two different small adult oxygenators. AB - A low haematocrit during cardiopulmonary bypass (CPB) is associated with adverse outcomes and often results in homologous blood transfusions. Oxygenators with improved venous reservoir designs aid in reducing the priming volume. Recently, we changed our small adult oxygenator model from the D905 EOS oxygenator (Dideco, Mirandola, Italy) to the Capiox FX1540 (Terumo Corporation, Tokyo, Japan). We conducted a retrospective study of 42 patents to evaluate the impact of the Capiox FX 1540 on blood transfusion requirements in small patients (body surface area (BSA) up to 1.8 m(2)). The D905 EOS group had a lower minimum intraoperative haematocrit than the FX1540 group (20 +/- 3 v 22 +/- 4, p = 0.029) with 73% of the patients receiving intraoperative blood transfusions compared with 30% in the FX 1540 group (p = 0.012). Patients in the D905 EOS group received one blood transfusion more during CPB than the FX 1540 patients (p = 0.002). The haematocrits at the end of CPB and in the early postoperative period were identical in both groups. The postoperative ventilation time, length of stay in the intensive care unit and postoperative chest drain bleeding were similar in both groups. In conclusion, the Capiox FX1540 was effective in reducing intraoperative packed red cell transfusions. PMID- 23804957 TI - One for all: social power increases self-anchoring of traits, attitudes, and emotions. AB - We argue that powerful people tend to engage in social projection. Specifically, they self-anchor: They use the self as a reference point when judging others' internal states. In Study 1, which used a reaction-time paradigm, powerful people used their own traits as a reference when assessing the traits of group members, classifying group descriptors more quickly if they had previously reported that those terms described themselves. Study 2, which used a classic false-consensus paradigm, showed that powerful people believed that their group-related attitudes were shared by group members. Study 3 showed that more-powerful people relied more on their own state affect when judging other people's ambiguous emotional expressions. These results support our argument that power fosters self anchoring, because powerful individuals are often called on to act as the representative face of their groups, and the association between power and representation prompts the heuristic use of the self to infer group properties. PMID- 23804958 TI - Does the "why" tell us the "when"? AB - Traditional approaches to human causal reasoning assume that the perception of temporal order informs judgments of causal structure. In this article, we present two experiments in which people followed the opposite inferential route: Perceptual judgments of temporal order were instead influenced by causal beliefs. By letting participants freely interact with a software-based "physics world," we induced stable causal beliefs that subsequently determined participants' reported temporal order of events, even when this led to a reversal of the objective temporal order. We argue that for short timescales, even when temporal-resolution capabilities suffice, the perception of temporal order is distorted to fit existing causal beliefs. PMID- 23804959 TI - "The way I am is the way you ought to be": perceiving one's relational status as unchangeable motivates normative idealization of that status. AB - People often become evangelists for their own lifestyles. When it comes to relational status, people are rarely content to simply say "being single works for me" or "being in a relationship suits my disposition." Results from four studies suggested that this tendency to view one's own relational status as the universal ideal emerges in part from a desire to rationalize one's own relational status. Building on existing evidence that people are motivated to rationalize circumstances they perceive as likely to persist, we predicted that participants' perceptions of the stability of their own relational status would lead them to rationalize that status. In Studies 1 and 2, we found evidence for an association between perceptions of stability and idealizations and ruled out an alternative explanation. In Studies 3 and 4, we found evidence of the effect of stability on people's judgments of same- and different-status others in contexts in which relational status should carry little objective weight. PMID- 23804960 TI - A brief intervention to promote conflict reappraisal preserves marital quality over time. AB - Marital quality is a major contributor to happiness and health. Unfortunately, marital quality normatively declines over time. We tested whether a novel 21-min intervention designed to foster the reappraisal of marital conflicts could preserve marital quality in a sample of 120 couples enrolled in an intensive 2 year study. Half of the couples were randomly assigned to receive the reappraisal intervention in Year 2 (following no intervention in Year 1); half were not. Both groups exhibited declines in marital quality over Year 1. This decline continued in Year 2 among couples in the control condition, but it was eliminated among couples in the reappraisal condition. This effect of the reappraisal intervention on marital quality over time was mediated through reductions in conflict-related distress over time. This study illustrates the potential of brief, theory-based, social-psychological interventions to preserve the quality of intimate relationships over time. PMID- 23804961 TI - Teaching young children a theory of nutrition: conceptual change and the potential for increased vegetable consumption. AB - In two experiments, we used a novel approach to educating young children about nutrition. Instead of teaching simple facts, we provided a rich conceptual framework that helped children understand the need to eat a variety of healthy foods. Using the insight that children's knowledge can be organized into coherent belief systems, or intuitive theories, we (a) analyzed the incipient knowledge that guides young children's reasoning about the food-body relationship, (b) identified the prerequisites that children need to conceptualize food as a source of nutrition, and (c) devised a strategy for teaching young children a coherent theory of food as a source of diverse nutrients. In these two experiments, we showed that children can learn and generalize this conceptual framework. Moreover, this learning led children to eat more vegetables at snack time. Our findings demonstrate that young children can benefit from an intervention that capitalizes on their developing intuitive theories about nutrition. PMID- 23804962 TI - The medial prefrontal cortex and the emergence of self-conscious emotion in adolescence. AB - In the present study, we examined the relationship between developmental modulation of socioaffective brain systems and adolescents' preoccupation with social evaluation. Child, adolescent, and adult participants viewed cues indicating that a camera was alternately off, warming up, or projecting their image to a peer during the acquisition of behavioral-, autonomic-, and neural response (functional MRI) data. Believing that a peer was actively watching them was sufficient to induce self-conscious emotion that rose in magnitude from childhood to adolescence and partially subsided into adulthood. Autonomic arousal was uniquely heightened in adolescents. These behavioral patterns were paralleled by emergent engagement of the medial prefrontal cortex (MPFC) and striatum-MPFC connectivity during adolescence, which are thought to promote motivated social behavior in adolescence. These findings demonstrate that adolescents' self consciousness is related to age-dependent sensitivity of brain systems critical to socioaffective processes. Further, unique interactions between the MPFC and striatum may provide a mechanism by which social-evaluation contexts influence adolescent behavior. PMID- 23804963 TI - Asymptomatic 50% to 75% internal carotid artery stenosis in 288 patients: risk factors for disease progression and ipsilateral neurological symptoms. AB - INTRODUCTION: This study identified characteristics of patients with moderate internal carotid artery stenosis that are at increased risk for disease progression. METHODS: Patients with asymptomatic moderate internal carotid disease correlating to 50% to 75% diameter reduction were followed for 3 years. Progression to greater than 75% diameter reduction or presentation with focal neurological symptoms was documented. Descriptive statistics and chi(2) testing provided statistical analysis. RESULTS: During follow-up, 26 (9%) developed symptoms or had an asymptomatic increase in diameter reduction to >75%. The rate of disease progression and/or development of symptoms was 5.5% at 12 months and increased to 7.2% by 24 months. Comorbidities with the highest associated event incidences were coronary artery disease (8.1%), hyperlipidemia (7.3%), and hypertension (6.7%). CONCLUSION: Male patients with coronary artery disease, hyperlipidemia, and hypertension are at increased risk and are candidates for frequent screening and/or early intervention. PMID- 23804964 TI - The role of endografts in the management of type B aortic dissections. AB - Type B aortic dissection is a rare, but deadly, disease process. Advances in endovascular therapy have provided alternative means for the management of aortic dissection. This comprehensive review examines the incidence, pathophysiology, presentation, diagnosis, risk factors, and management of type B aortic dissection, with an emphasis on endovascular intervention. Additionally, this review provides current information regarding the procedural outcomes, complications, mortality, and overall survival of endovascular versus conventional management of type B aortic dissections. PMID- 23804965 TI - Smoking behavior and sociodemographic differences among young people: further evidence from southern Sweden based on public health survey data. AB - AIMS: Tobacco-smoking behaviours of young people between the age of 18 and 25 years are less understood than those of middle-aged people. The aim of this study is to contribute to improved knowledge of some of the factors that are associated with smoking and cessation among young people. METHODS: We use the most recently available public health survey data from the southern region of Skane in Sweden to analyze these factors. The survey is a cross-sectional study with a total sample size of 28,198 individuals with 2801 in the age category of interest. We apply statistical measures of association between smoking and gender and also model the relationship between smoking and smoking cessation and the role of a set of sociodemographic determinants by means of logistic regression to estimate odds ratios. RESULTS: The findings include significant differences between the younger age group and the older group with respect to the odds of smoking and method of cessation. We also find differences between young women and men with regard to smoking prevalence, intensity and cessation methods. In particular, young women attempt to quit smoking by means of unassisted methods to a significantly higher extent than do young men. CONCLUSIONS: There are significant differences between young people and older individuals with respect to a range of smoking behaviours. There are also strong gender effects within the group of young people. Policy development and anti-smoking interventions need to take such differences into consideration for improved effectiveness. PMID- 23804966 TI - Life course socioeconomic position and mortality: a population register-based study from Sweden. AB - AIMS: Adverse social circumstances during one's life course have been related to an increased risk of mortality. This article extends the literature by focusing on adversity at each phase of, and cumulatively at midlife in the Swedish population. METHODS: Data on socioeconomic indicators from 1970, 1980 and 1990 were linked to death registrations from 2000 to 2009. Relative indices of inequalities were computed for socioeconomic indicators, in order to measure the cumulative impact of inequality on mortality. RESULTS: A significant cumulative effect of being in the worst-off socioeconomic groups was found. For men, almost all indicators had a significant independent impact on risk of death. Among women, significant independent impacts were found for education in 1990 and for socioeconomic index in the 2 census years of 1970 and 1980. CONCLUSIONS: Being disadvantaged during a longer period in midlife has a significant negative impact on health. Policies targeted to reduce health inequality should focus on every stage of the midlife course. PMID- 23804967 TI - Sociodemographic characteristics and attitudes of men buying sex in Finland. AB - AIM: To study the sociodemographic characteristics and attitudes associated with buying sex among Finnish men residing in different areas of Finland. METHODS: A population-based questionnaire survey among 18-74-year-old Finns in 1999 with a response rate among men of 38%. The data on 575 men were analysed with descriptive statistics and logistic regression. RESULTS: The overall proportion of men ever having bought sex was 14%. Men who at the time of the survey were in the age group 30-39, aged 50 or over, with 13-15 years of educational study, entrepreneurs, and with high income, were more likely to have ever bought sex. Being married and living with a partner at the time of the study lowered the odds of ever having bought sex. The differences between the groups were mostly the same in all residential areas, though the strength and statistical significance varied. The exception was the association with education, which occurred only in small towns. The effect of attitudes to buying sex was strong and did not differ by area of residence. CONCLUSIONS: Many men with different sociodemographic characteristics reported having bought sex. There was no noticeable variation in the sociodemographic characteristics and attitudes of men having bought sex by the area of residence. More current research is needed on the motives and health consciousness of men buying sex. PMID- 23804968 TI - Addressing missing covariates for the regression analysis of competing risks: Prognostic modelling for triaging patients diagnosed with prostate cancer. AB - Competing risks arise in medical research when subjects are exposed to various types or causes of death. Data from large cohort studies usually exhibit subsets of regressors that are missing for some study subjects. Furthermore, such studies often give rise to censored data. In this article, a carefully formulated likelihood-based technique for the regression analysis of right-censored competing risks data when two of the covariates are discrete and partially missing is developed. The approach envisaged here comprises two models: one describes the covariate effects on both long-term incidence and conditional latencies for each cause of death, whilst the other deals with the observation process by which the covariates are missing. The former is formulated with a well established mixture model and the latter is characterised by copula-based bivariate probability functions for both the missing covariates and the missing data mechanism. The resulting formulation lends itself to the empirical assessment of non-ignorability by performing sensitivity analyses using models with and without a non-ignorable component. The methods are illustrated on a 20 year follow-up involving a prostate cancer cohort from the National Cancer Institutes Surveillance, Epidemiology, and End Results program. PMID- 23804969 TI - On analyzing ordinal data when responses and covariates are both missing at random. AB - In many occasions, particularly in biomedical studies, data are unavailable for some responses and covariates. This leads to biased inference in the analysis when a substantial proportion of responses or a covariate or both are missing. Except a few situations, methods for missing data have earlier been considered either for missing response or for missing covariates, but comparatively little attention has been directed to account for both missing responses and missing covariates, which is partly attributable to complexity in modeling and computation. This seems to be important as the precise impact of substantial missing data depends on the association between two missing data processes as well. The real difficulty arises when the responses are ordinal by nature. We develop a joint model to take into account simultaneously the association between the ordinal response variable and covariates and also that between the missing data indicators. Such a complex model has been analyzed here by using the Markov chain Monte Carlo approach and also by the Monte Carlo relative likelihood approach. Their performance on estimating the model parameters in finite samples have been looked into. We illustrate the application of these two methods using data from an orthodontic study. Analysis of such data provides some interesting information on human habit. PMID- 23804971 TI - On meetings of the minds. PMID- 23804970 TI - Statistical methods for multivariate meta-analysis of diagnostic tests: An overview and tutorial. AB - In this article, we present an overview and tutorial of statistical methods for meta-analysis of diagnostic tests under two scenarios: (1) when the reference test can be considered a gold standard and (2) when the reference test cannot be considered a gold standard. In the first scenario, we first review the conventional summary receiver operating characteristics approach and a bivariate approach using linear mixed models. Both approaches require direct calculations of study-specific sensitivities and specificities. We next discuss the hierarchical summary receiver operating characteristics curve approach for jointly modeling positivity criteria and accuracy parameters, and the bivariate generalized linear mixed models for jointly modeling sensitivities and specificities. We further discuss the trivariate generalized linear mixed models for jointly modeling prevalence, sensitivities and specificities, which allows us to assess the correlations among the three parameters. These approaches are based on the exact binomial distribution and thus do not require an ad hoc continuity correction. Lastly, we discuss a latent class random effects model for meta analysis of diagnostic tests when the reference test itself is imperfect for the second scenario. A number of case studies with detailed annotated SAS code in MIXED and NLMIXED procedures are presented to facilitate the implementation of these approaches. PMID- 23804972 TI - Addressing a global challenge. PMID- 23804973 TI - Presidential Address: Accomplishments and Challenges Ahead for CongenitalHeart Surgery. PMID- 23804974 TI - Pentalogy of Cantrell: Forty-two Years of Experience in the Hospital Infantil de Mexico Federico Gomez. AB - Pentalogy of Cantrell is a rare disease. Approximately 185 cases have been reported around the world. The authors performed a retrospective study that reviewed the clinical files and pathological samples of 22 cases of pentalogy of Cantrell treated at the Hospital Infantil de Mexico Federico Gomez. Thirteen patients had ectopia cordis associated with pentalogy of Cantrell (group I), and there were 9 cases without ectopia cordis (group II). In group I, the following types of congenital heart disease were found: single ventricle (4), double-outlet right ventricle (4), ventricular septal defect (3), aortic coarctation (1), and atrial septal defect (1). In group II, the following types of congenital heart disease were found: double-outlet right ventricle (3), double-inlet left ventricle (2), ventricular septal defect (2), tetralogy of Fallot (1), and hypoplastic right ventricle syndrome (1). Nine cases had a ventricular diverticulum (40%). Ten patients (45%) had some other congenital anomaly associated with pentalogy of Cantrell. Thirteen patients underwent surgery (59%), which included cardiac surgery in 10 cases (45%). Sixteen patients died (73%): 11 from group I and 5 from group II (P < .05). Little more than 50 years since it was first described, pentalogy of Cantrell remains a disease with high mortality, especially in patients with associated ectopia cordis. PMID- 23804975 TI - Teamwork and program organization in developing countries. AB - Establishment of congenital heart surgery programs in developing countries is often impeded by competition among providers for scarce resources and opportunities. To avoid this problem, the authors have sought to focus program development on a domestic medical team that includes a visiting North American surgeon. A leadership group was formed consisting of a domestic cardiologist and surgeon, the visiting surgeon, and leading local benefactors. Surgery was initiated beginning with closed cases, and the volume and complexity were gradually increased. The team was mentored by the visiting surgeon, and full medical brigades visited periodically. All members of the leadership group interacted with local health care providers, missionary groups, and visiting medical teams from international organizations, aiming to develop a single congenital heart surgery center. Over a period of 3 years, 185 children have been operated on and the team has progressed to do more complex open and closed cases. Overall mortality is 6.5%. Actively working with the program are 3 of the 5 local pediatric cardiologists, 2 of 4 pediatric intensivists, the only pediatric perfusionist, and the only active pediatric heart surgeon. Three additional international organizations currently participate in program development. Fundraising by the domestic nonprofit organization has increased approximately 20 fold in 5 years, and the program has been evaluated and approved by the government-based health insurance program. Focusing program development around a domestic leadership team allows coordination of patient referrals and resources, which contributes to excellent patient care and program sustainability. PMID- 23804976 TI - Sustainable knowledge transfer in pediatric cardiac surgery: a team approach to shared learning. AB - The study assesses the impact of a program using a model of knowledge transfer on the long-term development of a pediatric cardiac service in Lithuania. A team from the United Kingdom evaluated Lithuanian pediatric cardiac services and provided support in areas targeted for improvement. The total number of infant operations performed in Lithuania from 1990 to 2008, together with in-hospital mortality rates, was broken down into 3 time periods and analyzed to estimate the efficacy of the program: (1) 1990-1998, before the program; (2) 1999-2002, during the program; (3) 2003-2008, following the end of the program. Lithuanian results in children older than 1 year were comparable with other European centers. However, only 315 infant and neonatal cardiac procedures were performed between 1990 and 1998, and there was an in-hospital mortality of 34.2%. Between 1999 and 2002, the UK team performed 23 highly complex demonstration procedures (in hospital mortality, 13%). During the same period the Lithuanian team performed 305 additional operations in neonates and infants, and in-hospital mortality decreased to 18.7%. From 2003 to 2008 results continued to improve-559 infant operations were performed, with in-hospital mortality of 11.3% (P < .0001). Knowledge transfer has led to substantial and sustainable long-term improvement in the results of infant cardiac surgery in Lithuania. Demonstrating techniques and care on a limited number of more complex cases is an efficient way of transferring knowledge and skills to the developing pediatric cardiac centers. PMID- 23804977 TI - An alternative technique for rechanneling of sinus venosus atrial septal defect with partial anomalous pulmonary venous connection using autogenous right atrial appendage. AB - We report a new technique for closure of sinus venosus atrial septal defect with high partial anomalous pulmonary venous connection. This technique consisted of preservation of the atriocaval junction, advancement of the posterior rim of the atrial septal defect anterosuperiorly and enlargement of the superior caval vein using right atrial appendage. We found this to be a convenient technique and recommend it for correction of this anomaly. PMID- 23804978 TI - Late primary arterial switch for transposition of the great arteries with intact ventricular septum in an african population. AB - The arterial switch operation (ASO) is the optimal management of transposition of the great arteries with intact ventricular septum (TGA-IVS) within the first 3 weeks of life; beyond this age optimal treatment is debatable. The authors adopted a strategy of primary ASO for TGA-IVS in the first 10 weeks of life regardless of left ventricular (LV) status. This report reviews the early outcomes with this management approach. Between August 2006 and December 2009, 22 patients with TGA-IVS underwent the primary ASO. Sixteen of them were less than 21 days old (early switch group) and 6 were between 31 and 66 days old (late switch group). A review of their hospital records was performed to determine outcomes in the 2 groups. Operative variables and postoperative outcomes were recorded. There was 1 hospital death in the early switch group (6.3%) but none in the late group (0%). Temporary mechanical circulatory support was required in 1 patient (6.3%) in the early switch group and in 2 of the 6 (33.3%) in the late switch group. One late death of undetermined cause occurred in the late switch group 8 weeks after discharge. No significant difference could be demonstrated between the 2 groups in terms of operative variables and the measured postoperative outcomes. It is concluded that the age limit for the primary ASO can be extended to at least 10 weeks; temporary mechanical circulatory support may be required as a rescue. PMID- 23804979 TI - Application of Computer Modeling in Systemic VAD Support of Failing Fontan Physiology. AB - Although the Fontan procedure has been enormously successful in palliation of single-ventricle patients, many seem to experience progressive failure of the Fontan circulation over time. Ventricular assist devices (VADs) have developed into stable platforms for long-term support of adult patients with heart failure. Given the success of axial flow devices, it was hypothesized that the technology could provide clinical benefit to failing Fontan patients. The aim of this study was to use a computer model to evaluate VAD support in failing Fontan physiology. A computer model of Fontan circulation with heart failure was developed and the HeartMate II (HM II) (Thoratec Corp) axial flow ventricular assist device was connected to this model in a systemic configuration to examine its impact. Cardiac catheterization data from 7 patients (8 catheterization studies) with failing Fontan physiology were applied to this model to evaluate the impact of using the HM II in this manner. When the HM II was used in a systemic configuration at 8000 rpm, there was a 35% decrease in the systemic venous pressure in the Fontan circuit and a 63% decrease in pulmonary capillary wedge pressure with a resultant 41% increase in CI. The model also predicted patient specific parameters where the VAD may not benefit the patient, such as fixed elevated pulmonary vascular resistance, low systemic ventricular end-diastolic pressure, and high unresponsive systemic vascular resistance. These data suggest a potential benefit from application of axial flow VAD technology in the management of failing Fontan physiology. Clinical correlation will allow for refinement of this model as a predictive tool in discerning which patients may benefit from placement of a VAD and what issues must be addressed prior to implanting the device. PMID- 23804980 TI - Results of balloon atrial septostomy as preparation for surgical correction in transposition of great arteries. AB - Balloon atrial septostomy (BAS) is a palliative procedure performed in the preoperative management of patients with transposition of great arteries (TGA), to improve the mixing of blood between the 2 systems. This report describes experience at the Clinica Cardiovascular Santa Maria in Medellin, Colombia. Between 2002 and 2010, 22 patients with TGA underwent BAS. Patient age at the time of the procedure was 21 days on average; 68% of patients were male. Average weight was 2.96 kg and interatrial gradient was between 4 and 12 mm Hg. The average systemic oxygen saturation at the beginning of the procedure was 60%, with a final saturation of 90%. Z5 atrioseptostomy balloons were used in 18 patients (81%), using Rashkind technique; Tyshak balloon catheters were used in 3 patients (13%) with the Shrivastava technique; and static high-pressure peripheral angioplasty balloons were used in 3 patients (13%). Two patients underwent BAS with 2 types of balloons. Although there were no complications clearly attributable to the procedure, 14% of patients had evidence of focal brain injury on the postoperative magnetic resonance image. Six patients died (27%), 5 of them because of postoperative complications and 1 because of infectious complications at another institution. All postoperative deaths occurred before 2006. The BAS is a safe technique for preoperative stabilization of patients with TGA. PMID- 23804981 TI - Echocardiography in heterotaxy syndrome. AB - The important anatomic aspects of heterotaxy syndrome can be diagnosed by Doppler echocardiography in the newborn and infant. An organized approach and an understanding of asplenia (right atrial isomerism) and polysplenia (left atrial isomerism) are integral to the echocardiographic study. Detailed and precise depiction of the anatomy is the mainstay for staging subsequent medical and surgical management. PMID- 23804982 TI - Challenges of univentricular physiology in heterotaxy. AB - Patients with heterotaxy syndrome exhibit an extensive constellation of congenital cardiac malformations, making these patients a challenging group to manage surgically. Many of these patients' hearts do not lend themselves to separation of the pulmonary and systemic circulations except by some modification of the Fontan procedure. Palliative procedures early in life are directed at creating a satisfactory balance of pulmonary and systemic blood flow and at the same time ensuring unobstructed pulmonary venous return. Early conversion from parallel pulmonary and systemic circulations to superior cavopulmonary connections is important, to reduce volume work of the systemic ventricle. Heterotaxy patients are generally considered a high-risk population with respect to eventual Fontan procedure. It is important to appreciate the unique and variable anatomy of the sinus node and conduction system and the potential for occult pulmonary venous obstruction, atrioventricular valve regurgitation, and recurrent cyanosis, which may be related to the development of pulmonary arteriovenous malformations. PMID- 23804983 TI - Surgical management of the neonate with heterotaxy and long-term outcomes of heterotaxy. AB - A review of the many challenges facing the neonate with heterotaxy has identified total anomalous pulmonary venous connection, atrioventricular valve abnormalities, pulmonary atresia, and arrhythmias including heart block as particular risk factors for the child who will pursue a single-ventricle pathway. Experience varies widely between different centers as to the percentage of patients who are suitable for biventricular repair, ranging from less than 20% to greater than 50%. Biventricular repair may only require simple baffling of anomalous systemic or pulmonary veins or may involve complex intraventricular baffle repair of double-outlet right ventricle with common atrioventricular valve. The long-term complications of heterotaxy include accelerated development of pulmonary arteriovenous malformations after the Kawashima procedure, high mortality and morbidity for the Fontan procedure (although improving results have been reported more recently), and the development of late arrhythmias. Extracardiac problems include a high risk of volvulus if malrotation is present, suggesting the need for an elective Ladd procedure. The presence of associated ciliary dyskinesia appears to be associated with an increased risk of postoperative morbidity, particularly ventilator dependence and other respiratory complications. The child with heterotaxy faces many challenges that are often underappreciated by both caregivers and families. PMID- 23804984 TI - The conduction system in heterotaxy. AB - Cardiac malformations associated with the syndrome of atriovisceral heterotaxy are among the most complex forms of congenital heart disease. Accordingly, the disposition of the specialized conduction tissue (the conduction system) is also variable and complex in these particular anomalies. The location of the conduction system and the degree of abnormalities of the conduction system correlate with the severity and location of the associated structural cardiac anomalies. PMID- 23804985 TI - Heterotaxy: lessons learned about patterns of practice and outcomes from the congenital heart surgery database of the society of thoracic surgeons. AB - According to The International Society for Nomenclature of Pediatric and Congenital Heart Disease (ISNPCHD), "Heterotaxy is synonymous with 'visceral heterotaxy' and 'heterotaxy syndrome'. Heterotaxy is defined as an abnormality where the internal thoraco-abdominal organs demonstrate abnormal arrangement across the left-right axis of the body. By convention, heterotaxy does not include patients with either the expected usual or normal arrangement of the internal organs along the left-right axis, also known as 'situs solitus', or patients with complete mirror-imaged arrangement of the internal organs along the left-right axis also known as 'situs inversus'." or patients with complete mirror image arrangement of the internal organs along the left-right axis, also known as situs inversus. The purpose of this article is to review the data about heterotaxy in the Society of Thoracic Surgeons (STS) Congenital Heart Surgery Database. The investigators examined all index operations in the STS Congenital Heart Surgery Database over 12 years from January 1, 1998 to December 31, 2009, inclusive. This analysis resulted in a cohort of 77 153 total index operations. Of these, 1505 operations (1.95%) were performed in patients with heterotaxy. Of the 1505 index operations performed in patients with heterotaxy, 1144 were in patients with asplenia and 361 were in patients with polysplenia. In every STS EACTS Congenital Heart Surgery Mortality Category, discharge mortality is higher in patients with heterotaxy compared with patients without heterotaxy (EACTS = European Association for Cardio-Thoracic Surgery). Discharge mortality after systemic to pulmonary artery shunt is 6.6% in a cohort of all single-ventricle patients except those with heterotaxy, whereas it is 10.8% in single-ventricle patients with heterotaxy. Discharge mortality after Fontan is 1.8% in a cohort of all single-ventricle patients except those with heterotaxy, whereas it is 4.2% in single-ventricle patients with heterotaxy. The STS Congenital Heart Surgery Database is largest congenital heart surgery database in North America. This review of data from the STS Congenital Heart Surgery Database allows for unique documentation of practice patterns and outcomes. From this analysis, it is clear that heterotaxy is a challenging problem with increased discharge mortality in most subgroups. PMID- 23804986 TI - Restoration of transposed great arteries to nature. AB - Surgical correction of transposition of the great arteries was proposed by many in the past half-century and was claimed as the anatomical correction, but the treatment of choice was ever changing. The current technique usually includes the Lecompte maneuver to bring the pulmonary bifurcation in front of the aorta. Although the ventricular-arterial connection is corrected, it is not "normal." This review describes an innovative technique to reconstruct the great arteries in spiral fashion, which is the natural relationship of the aorta and pulmonary artery. The surgical principles of nature and even distribution using autologous tissues are emphasized. The structural and functional studies of the spiral great arteries in the last 2 decades are also presented. PMID- 23804987 TI - Pediatric cardiopulmonary bypass: does perfusion mode matter? AB - This current review describes how components of the cardiopulmonary bypass (CPB) circuit are selected and examines the benefits of pulsatile perfusion for use during CPB. Pulsatile flow generates significantly greater surplus hemodynamic energy (SHE) than nonpulsatile flow; higher SHE values have been associated with better microcirculation perfusion, lower rates of systemic inflammatory response, and better vital organ protection. Pulsatile perfusion may have a positive effect on clinical outcomes, play a role in preserving homeostasis, and help to decrease morbidity associated with CPB. PMID- 23804988 TI - Development of pediatric and congenital heart surgery in latin america: accomplishments and remaining challenges. AB - In the last 70 years, congenital heart surgery has dramatically evolved, and Latin America has completed this journey with unique regional features. Since the first ligation of a patent arterial duct by Enrique Finochietto in 1941 in Buenos Aires, the development of congenital heart surgery was deeply influenced by funding restrictions and scarcity of technology. However, the determined work of cardiovascular surgery pioneers as Hugo Filipozzi, Euriclides Zerbini, and Adib Jatene in Brazil; Helmut Jaeger in Chile; Hugo Baz and Clemente Robles in Mexico; Alberto Bejarano in Colombia; and Mario Brea and Fernando Tricerri in Argentina made cardiac surgery with cardiopulmonary bypass available by the late 1950s. In the following five decades new generations of cardiovascular surgeons received the legacy of these outstanding leaders and made several important contributions to the field in tetralogy of Fallot, transposition of the great arteries, tricuspid atresia, single ventricle, truncus arteriosus, heart transplantation, and many others. Many centers in Latin America routinely perform congenital heart disease surgery with excellent results, covering the entire spectrum from the newborn to the adult congenital heart patient. The most important challenge that remains is to provide access to care to all children with congenital heart disease in Latin America, since currently only 42% of them receive surgical treatment. PMID- 23804989 TI - Bilateral Ductus Arteriosus With Isolated Right Pulmonary Artery: Long-term Results With Interposition Pulmonary Allograft. AB - Bilateral patent ductus arteriosus and isolated right pulmonary artery (RPA) is a rare anomaly often interpreted as congenital absence of the RPA. Recognized early, continuity between the main pulmonary artery and distal RPA can be established and long-term sequelae avoided. We report 2 patients who underwent neonatal repair using a nonvalved pulmonary artery allograft conduit placed anterior to the aorta to establish continuity between the main pulmonary artery and RPA. Both patients continue to do well 10 and 15 years postoperatively with good growth of the distal RPA and good exercise tolerance. This approach offers good long-term palliation. PMID- 23804990 TI - Twin atrioventricular nodes connecting to sling of conduction tissue in congenitally corrected transposition associated with straddling tricuspid valve. AB - This report describes a case of reentrant supraventricular tachycardia relating to "twin" atrioventricular nodes in a 6-year-old female patient with congenitally corrected transposition of the great arteries associated with straddling tricuspid valve. Straddling and overriding of the tricuspid valve literally or by definition indicate malalignment of the inlet part of the ventricular septum and atrial septum by an abnormally large ventriculoatrial septal angle. Therefore, anterior atrioventricular conduction tissues are expected in this setting; however, the present report describes an exception to the rule that combination of straddling tricuspid valve is unlikely to be associated with twin atrioventricular nodes/sling. The patient underwent successful ablation of one atrioventricular node, eliminating the tachycardia, and subsequently Fontan-type palliation. PMID- 23804991 TI - Delayed arterial switch operation for d-transposition of the great arteries and glucocorticoid remediable aldosteronism. AB - The Jatene arterial switch operation (ASO) for dextro-transposition of the great arteries is ideally performed within the first 2 weeks of life. Clinical circumstances, however, may dictate a delayed ASO and left ventricle "retraining" prior to the procedure. Glucocorticoid remediable aldosteronism (GRA) accounts for 0.5% to 1% of primary aldosteronism. It presents as severe hypertension in infants and children, with poor response to standard antihypertensive medications. To the authors' knowledge, this is the first reported case of GRA in the context of transposition physiology. The management of GRA and a rationale for delayed ASO are discussed. PMID- 23804992 TI - Two-stage repair of truncus arteriosus associated with interrupted aortic arch in critically ill patients. AB - This report describes 2 newborns with truncus arteriosus associated with an interrupted aortic arch who underwent a 2-stage repair due to poor preoperative condition. A repair of the interrupted aortic arch and ventricular-to-pulmonary artery conduit with a 6-mm Gore-Tex tube was performed as a first stage. Closure of a ventricular septal defect and placement of a right ventricular-to-pulmonary artery homograft conduit were performed electively at 8 months of age. PMID- 23804993 TI - Intrapericardial teratoma in neonates: a surgical emergency. AB - Primary cardiac tumors are very rare, with a reported incidence of 0.15% to 0.2% in autopsy series. They can be life threatening because of myocardial compression and ventricular dysfunction. Once diagnosed during pregnancy, the clinical condition of the baby is monitored because of the risk of rupture of the tumor capsule. The authors report a rare case of a neonate who presented with respiratory and cardiac compromise due to cardiac tamponade necessitating emergency exploration of the pericardium and excision of tumor. A well encapsulated tumor measuring around 5 cm and bigger than the heart was completely excised. This was diagnosed to be an immature teratoma. Follow-up echocardiogram was normal, and on serial monitoring, alpha-fetoprotein was within normal limits. The baby was discharged home with no complications. Intrapericardial teratoma in neonates is a surgical emergency if presented with significant pericardial effusion. It can be a challenge if diagnosed in utero with rupture before the viability of pregnancy. A multidisciplinary team approach is necessary to manage such situations. Complete excision is necessary because of its association with tissues of malignant potential. PMID- 23804994 TI - Right aortic arch with aberrant left subclavian artery and anomalous origin of right pulmonary artery from ascending aorta. AB - The authors report a case of a neonate that was operated on with the diagnosis of right aortic arch and aberrant left subclavian artery and anomalous origin of right pulmonary artery from ascending aorta. Computed tomography (CT) scan suggested double aortic arch and cardiac catheterization suggested anomalous origin of right pulmonary artery from ascending aorta versus aorto-pulmonary window. The final diagnosis was made at the operation. There was a right aortic arch and aberrant left subclavian artery and persistent ductus arteriosus. Surgical repair consisted of section of the ductus arteriosus and reimplantation of the right pulmonary artery in the main pulmonary artery. PMID- 23804995 TI - Enhancing our view of the doubly committed ventricular septal defect. AB - A case of a doubly committed ventricular septal defect is presented that highlights the value of 3-dimensional echocardiography in the preoperative planning of surgical closure. PMID- 23804996 TI - A modified approach to component separation using biologic graft as a load sharing onlay reinforcement for the repair of complex ventral hernia. AB - BACKGROUND: Components separation has been proposed as a means to close large ventral hernia without undue tension. We report a modification on open components separation that allows for the incorporation of onlaid noncrosslinked porcine acellular dermal matrix (Strattice, LifeCell Corp, Branchburg, NJ) as a load sharing structure. METHODS: This was a retrospective case series including all cases using Strattice from July 2008 through December 2009. Data evaluated included patient demographics, comorbidities associated with risk of recurrence, hernia grade, and postoperative complications. The primary outcomes were hernia recurrence and surgical site occurrences. RESULTS: There were 58 patients; 60.8% presented with a recurrent incisional hernia. Average length of follow-up was 384 days. There were 4 hernia recurrences (7.9%). Complications included surgical site infection (20.7%), seroma (15.5%), and hematoma (5%) requiring intervention. Four deaths occurred in the series due to causes unrelated to the hernia repair, only 1 within 30 days of operation. CONCLUSIONS: This series demonstrates that components separation reinforced with noncrosslinked porcine acellular dermal matrix onlay is an efficacious, single-stage repair with a low rate of recurrence and surgical site occurrences. PMID- 23804997 TI - Quantitative chemical analysis of surgical smoke generated during laparoscopic surgery with a vessel-sealing device. AB - BACKGROUND: Exposure to surgical smoke in the operation room has been a long standing concern. Smoke generated by the interaction between lasers or electrocautery devices with biological tissue contains several toxic and carcinogenic substances, but only a few studies so far have provided quantitative data necessary for risk assessment. METHODS: With laser and Fourier-transform infrared spectroscopy, we investigated the chemical composition of smoke produced with a vessel-sealing device in an anoxic environment during laparoscopic surgery. RESULTS: Harmless concentrations of methane (<34 ppm), ethane (<2 ppm), and ethylene (<10 ppm) were detected. Traces of carbon monoxide (<3.2 ppm) and of the anesthetic sevoflurane (<450 ppm) were also found. CONCLUSIONS. Gas leaking or gas being released from the pneumoperitoneum could therefore increase pollution by waste anesthetic gas in the operating room. Most toxic compounds found in earlier studies remained undetected. Adverse health effects for operating room personnel due to some of those substances (e.g., toluene, styrene, xylene) can be excluded, assuming no significant losses or changes in the chemical composition of the samples occurred between our sampling and measurements. PMID- 23804998 TI - A new technique for laparoscopic splenectomy and azygoportal disconnection. AB - BACKGROUND: Laparoscopic splenectomy and azygoportal disconnection (LSD) using many different surgical techniques has become increasingly popular for treatment of cirrhotic patients with bleeding portal hypertension and secondary hypersplenism. Surgical procedures with the least possible impairment are consistently expected by both surgeons and patients. Here, we report a clinical cohort of 10 patients who underwent LSD with a new technique and present the advantages of less impairment during performance of this new technique. METHODS: A cohort of 10 cirrhotic patients with bleeding portal hypertension and secondary hypersplenism treated with LSD were studied. During the procedure, an electromechanical morcellator allowed for easy extraction of the entire massive splenic tissue without a cumbersome intracorporeal bag, enlarged incision, or hand-assisted incision. Various perioperative data were recorded. RESULTS: LSD was successful in all patients. There was no conversion to open operations or significant perioperative complications. The operative time was 288.0 +/- 53.9 minutes, the spleen removal time was 39.3 +/- 15.1 minutes, and blood loss was 240.0 +/- 217.1 mL. CONCLUSIONS: This new technique involving the use of an electromechanical morcellator provides expedient recovery and minimal postoperative pain and scarring. LSD with this technique is a feasible, effective, and safe surgical procedure, and embodies all the benefits of minimally invasive surgery for cirrhotic patients with bleeding portal hypertension and hypersplenism. PMID- 23804999 TI - Susceptibility of BALB/c-nu/nu mice and BALB/c mice to equine herpesvirus 9 infection. AB - This study aimed to clarify the timing and infectivity of equine herpesvirus 9 (EHV-9) infection in BALB/c-nu/nu mice and their immunocompetent counterpart (BALB/c). Following intranasal inoculation with 10(5) PFU of EHV-9, specimens from 8 mice per group were collected at different times postinoculation (PI) and assessed using histopathology, immunohistochemistry for viral antigen, and quantitative real-time polymerase chain reaction for ORF30 gene expression. In BALB/c-nu/nu mice, EHV-9 antigen was abundant in olfactory epithelia of all inoculated animals, and in the olfactory bulb of 1 animal. In contrast, only 1 BALB/c mouse per time point had rhinitis, with mild to moderate immunopositivity starting from 12 to 48 h PI, followed by a gradual virus clearance at 72 h PI. Statistically, significant differences were noted in the immunohistochemistry reactions between the 2 mouse strains, indicating that BALB/c-nu/nu is more susceptible to infection. Relative expression levels of ORF30 gene in olfactory epithelia were significantly different between the 2 groups, with the exception of 12 h PI, when BALB/c-nu/nu animals showed dramatic increases in ORF30 gene expression level until 48 h PI, followed by a decline in expression level until the end of experiment. In contrast, the expression level in brains showed no differences between mouse strain except at 96 h PI. In both strains, the highest messenger RNA expression was detected at 48 h PI, followed by a decline in BALB/c mice, proving a rapid clearance of virus in BALB/c and a gradual slowing down of the increased expression levels in BALB/c-nu/nu. PMID- 23805000 TI - Multiparameter behavioral analyses provide insights to mechanisms of cyanide resistance in Caenorhabditis elegans. AB - Environmental toxicants influence development, behavior, and ultimately survival. The nematode Caenorhabditis elegans has proven to be an exceptionally powerful model for toxicological studies. Here, we develop novel technologies to describe the effects of cyanide toxicity with high spatiotemporal resolution. Importantly, we use these methods to examine the genetic underpinnings of cyanide resistance. Caenorhabditis elegans that lack the EGL-9 oxygen sensing enzyme have been shown to be resistant to hydrogen cyanide (HCN) gas produced by the pathogen Pseudomonas aeruginosa PAO1. We demonstrate that the cyanide resistance exhibited by egl-9 mutants is completely dependent on the HIF-1 hypoxia-inducible factor and is mediated by the cysl-2 cysteine synthase, which likely functions in metabolic pathways that inactivate cyanide. Further, the expression of cysl-2 correlates with the degree of cyanide resistance exhibited in each genetic background. We find that each mutant exhibits similar relative resistance to HCN gas on plates or to aqueous potassium cyanide in microfluidic chambers. The design of the microfluidic devices, in combination with real-time imaging, addresses a series of challenges presented by mutant phenotypes and by the chemical nature of the toxicant. The microfluidic assay produces a set of behavioral parameters with increased resolution that describe cyanide toxicity and resistance in C. elegans, and this is particularly useful in analyzing subtle phenotypes. These multiparameter analyses of C. elegans behavior hold great potential as a means to monitor the effects of toxicants or chemical interventions in real time and to study the biological networks that underpin toxicant resistance. PMID- 23805002 TI - A Rapid Method for Determining the Oxidative Stability of Oils Suitable for Breeder Size Samples. AB - A method utilizing thin-layer chromatography with a flame ionization detector (TLC-FID) was developed for assessing the stability of breeder's oil seed samples based on the formation of polar compounds. The results showed a linear relationship between peroxide value (PV) and the content of polar material in the oxidized oil. Oil samples oxidized very readily on chromarods, even at low temperature, which is a particular advantage for antioxidant screening. At 45 degrees C, the oil oxidation rate was relatively low, but the relationship between the content of polar material and reaction time was linear. At 65 degrees C, if the content of polar material was below 50 %, the above relationship was still linear. At different temperatures, the action of tocopherol appeared to vary slightly. For example, at 65 degrees C, the oxidative stability of the oil sample was determined by the content of tocopherol, especially gamma-tocopherol. At 45 and 55 degrees C, the oxidative stability was determined by both the content of tocopherol and polyunsaturated fatty acids. Of the tocopherol isomers, gamma-tocopherol exhibited the highest antioxidant potency, consistent with the published literature. These results suggest that chromarods provide good media for monitoring oil oxidation for antioxidant screening. A particular advantage is the use of very small oil samples, usually 1-2 MUL, and the ability to analyze multiple samples at the same time. PMID- 23805003 TI - Frames and comparators: How might a debate on synthetic biology evolve? AB - A stimulated early public debate is frequently advocated when introducing an emerging technology like synthetic biology (SB). To debate a still quite abstract technology, participants functionally need a frame that determines which arguments are legitimate and which issues are relevant. Often, such frames are based on previous debates over other novel technologies. Three technologies currently provide frames for discussing SB: (green) biotechnology, nanotechnology and information technology. In the biotechnology debate, risk has long been emphasised over economic benefits. More recently, nanotechnology has been referred to mostly in terms of benefits, while risks tended to be an issue for scientific discourses. This has frequently been related to the many outreach activities around nanotechnology. Information technology, finally, has retained the image of being 'cool' and useful on a personal level. The technology itself is taken for granted and only the consequences of particular applications have been up for discussion. Upstream engagement exercises in SB will have to consider the comparator chosen more diligently, because it might influence the debate on SB 'out there' in the long run. PMID- 23805001 TI - Mapping acute systemic effects of inhaled particulate matter and ozone: multiorgan gene expression and glucocorticoid activity. AB - Recent epidemiological studies have demonstrated associations between air pollution and adverse effects that extend beyond respiratory and cardiovascular disease, including low birth weight, appendicitis, stroke, and neurological/neurobehavioural outcomes (e.g., neurodegenerative disease, cognitive decline, depression, and suicide). To gain insight into mechanisms underlying such effects, we mapped gene profiles in the lungs, heart, liver, kidney, spleen, cerebral hemisphere, and pituitary of male Fischer-344 rats immediately and 24h after a 4-h exposure by inhalation to particulate matter (0, 5, and 50mg/m(3) EHC-93 urban particles) and ozone (0, 0.4, and 0.8 ppm). Pollutant exposure provoked differential expression of genes involved in a number of pathways, including antioxidant response, xenobiotic metabolism, inflammatory signalling, and endothelial dysfunction. The mRNA profiles, while exhibiting some interorgan and pollutant-specific differences, were remarkably similar across organs for a set of genes, including increased expression of redox/glucocorticoid sensitive genes and decreased expression of inflammatory genes, suggesting a possible hormonal effect. Pollutant exposure increased plasma levels of adrenocorticotropic hormone and the glucocorticoid corticosterone, confirming activation of the hypothalamic-pituitary-adrenal axis, and there was a corresponding increase in markers of glucocorticoid activity. Although effects were transient and presumably represent an adaptive response to acute exposure in these healthy animals, chronic activation and inappropriate regulation of the hypothalamic-pituitary-adrenal axis are associated with adverse neurobehavioral, metabolic, immune, developmental, and cardiovascular effects. The experimental data are consistent with epidemiological associations of air pollutants with extrapulmonary health outcomes and suggest a mechanism through which such health effects may be induced. PMID- 23805004 TI - Anionic lanthanide complexes with 3-methyl-1-phenyl-4-formylpyrazole-5-one and hydroxonium as counter ion. AB - A series of [H3O]+[LnL4]-.nH2O complexes (n = 1-3, Ln = Nd, (1), Sm (2), Eu (3), Tb (4); HL = 3-methyl-1-phenyl-4-formylpyrazole-5-one) were synthesized and characterized. The structures of the SmIII and EuIII complexes were investigated by X-ray diffraction. The isostructutal crystalls 2 and 3 consist the tetrakis [LnL4]- anions which are linked by H-bonding with the hydroxonium counter-ion and water molecules. The lanthanide ion is situated in the center of distorted tetragonal antiprism formed by eight oxygen atoms of 4-formyl-5 hydroxypyrazolonate anions. The TbIII and SmIII complexes show strong luminescence in solid state, whereas the EuIII and NdIII complexes show low luminescence activity. PMID- 23805005 TI - Synthesis and characterisation of cobalt, nickel and copper complexes with tripodal 4N ligands as novel catalysts for the homogeneous partial oxidation of alkanes. AB - Four new compounds of the general formula [M(L)(CH3COO)][PF6], where L is a tetradentate tripodal ligand such as tris[2-(dimethylamino)ethyl]amine (L1) or (2 aminoethyl)bis(2-pyridylmethyl)amine (L2) and M is Co(II), Ni(II) or Cu(II), have been prepared employing a simple two-step synthesis. The compounds have been characterised by elemental analysis, mass spectroscopy, IR spectroscopy and X-ray diffraction. The catalytic properties of the derivatives containing the aliphatic ligand L1 have been investigated in particular toward the oxidation of cyclohexane and adamantane in the presence of the sacrificial oxidant m-CPBA (meta-chloroperbenzoic acid). Good TONs and selectivity have been determined for the cobalt and nickel compounds. PMID- 23805006 TI - Projecting and Monitoring the Life Course of the Marijuana/Blunts Generation. AB - Since the 1990s, marijuana has been the drug of choice among American youths, especially those that tend to sustain arrests. Previous birth cohorts had greater use of crack, powder cocaine, or heroin. This paper summarizes prior research that strongly suggests drug eras tend to follow a regular course. These insights then serve as the basis for projecting trends in marijuana use both for the general population nationwide and for Manhattan arrestees. To the extent that current trends persist, the prospects for the "Marijuana/Blunts Generation" (born 1970 and later) may be relatively good. These young persons may successfully avoid "hard drugs" as well as the attendant health, social, and legal problems for their entire life, but they may experience higher levels of smoking-related ailments. The conclusion presents issues for continued drug surveillance and ethnographic research to more accurately understand the Marijuana/Blunts Era and to provide an indicator of future changes as they occur. PMID- 23805007 TI - A microfluidic system to study the cytotoxic effect of drugs: the combined effect of celecoxib and 5-fluorouracil on normal and cancer cells. AB - We have investigated the response of normal and cancer cells to exposure a combination of celecoxib (Celbx) and 5-fluorouracil (5-FU) using a lab-on-a-chip microfluidic device. Specifically, we have tested the cytotoxic effect of Celbx on normal mouse embryo cells (Balb/c 3T3) and human lung carcinoma cells (A549). The single drugs or their combinations were adjusted to five different concentrations using a concentration gradient generator (CGG) in a single step. The results suggest that Celbx can enhanced the anticancer activity of 5-FU by stronger inhibition of cancer cell growth. We also show that the A549 cancer cells are more sensitive to Celbx than the Balb/c 3T3 normal cells. The results obtained with the microfluidic system were compared to those obtained with a macroscale in vitro cell culture method. In our opinion, the microfluidic system represents a unique approach for an evaluation of cellular response to multidrug exposure that also is more simple than respective microwell plate assays. Figure? PMID- 23805008 TI - Approaches to Iodinated Derivatives of Vanillin and Isovanillin. PMID- 23805009 TI - Microwave-assisted Heck Synthesis of Substituted 2,4-Diaminopyrimidine-based Antibiotics. PMID- 23805010 TI - Surface morphology, optical properties and conductivity changes of poly(3,4 ethylenedioxythiophene):poly(styrenesulfonate) by using additives. AB - The optical properties and electrical conductivity of highly conducting poly(3,4 ethylenedioxythiophene) (PEDOT) doped with poly(styrenesulfonate) (PSS) are reported as a function of the processing additive conditions. The addition of dimethyl sulfoxide (DMSO) increases the conductivity and modifies the dielectric response as observed from the ellipsometric studies. Also the surface roughness and morphology change with the composition of PEDOT:PSS:DMSO and film deposition conditions. The real part of the dielectric function becomes negative in highly conducting samples, indicating the presence of delocalized charge carriers. The real and imaginary parts of the refractive index were determined as a function of wavelength. The results are consistent with the increase in conductivity upon the addition of DMSO. PMID- 23805011 TI - PARENTHOOD AND CRIME: THE ROLE OF WANTEDNESS, RELATIONSHIPS WITH PARTNERS, AND SES. AB - PURPOSE: Parenthood may play a pivotal role in the criminal desistance process, but few studies have examined the conditions under which becoming a mother or father is most likely to lead to reductions in criminal behavior. METHODS: The current longitudinal study draws on four waves of adolescent and young adult interview data (N = 1,066) and HLM regression models to examine the impact of parenthood on criminal trajectories, as well as the degree to which the prosocial potential of parenthood is modified by socioeconomic factors, the nature of the relationship between the biological parents, and pregnancy wantedness. The analysis also draws on narrative life history accounts elicited from a subset of these respondents (N = 22). RESULTS: SES and the wantedness of the pregnancy condition the relationship between parenthood and criminal involvement, however some gender differences emerged. Status of the relationship (married or cohabiting and single) was in general not a strong predictor. CONCLUSIONS: Highly disadvantaged young men and women are not as likely as more advantaged young adults to evidence lower levels of criminal behavior after becoming parents, however wanted pregnancies may reduce female involvement in crime regardless of socioeconomic status. In-depth qualitative data further elucidate the conditional nature of the parenthood-crime relationship. PMID- 23805012 TI - Natural organic matter and iron export from the Tanner Moor, Austria. AB - Samples from a pristine raised peat bog runoff in Austria, the Tannermoor creek, were analysed for their iron linked to natural organic matter (NOM) content. Dissolved organic carbon < 0.45 MUm (DOC) was 41-64 mg L-1, iron 4.4-5.5 mg L-1. Samples were analysed applying asymmetric field flow fractionation (AsFlFFF) coupled to UV-vis absorption, fluorescence and inductively coupled plasma mass spectrometry (ICP-MS). The samples showed an iron peak associated with the NOM peak, one sample exhibiting a second peak of iron independent from the NOM peak. As highland peat bogs with similar climatic conditions and vegetation to the Tanner Moor are found throughout the world, including areas adjacent to the sea, we examined the behaviour of NOM and iron in samples brought to euhaline (350/00) conditions with artificial sea salt. The enhanced ionic strength reduced NOM by 53% and iron by 82%. Size exclusion chromatography (SEC) of the samples at sea like salinity revealed two major fractions of NOM associated with different iron concentrations. The larger one, eluting sharply after the upper exclusion limits of 4000-5000 g mol-1, seems to be most important for iron chelating. The results outline the global importance of sub-mountainous and mountainous raised peat bogs as a source of iron chelators to the marine environment at sites where such peat bogs release their run-offs into the sea. PMID- 23805013 TI - Static vs. mobile sink: The influence of basic parameters on energy efficiency in wireless sensor networks. AB - Over the last decade a large number of routing protocols has been designed for achieving energy efficiency in data collecting wireless sensor networks. The drawbacks of using a static sink are well known. It has been argued in the literature that a mobile sink may improve the energy dissipation compared to a static one. Some authors focus on minimizing Emax, the maximum energy dissipation of any single node in the network, while others aim at minimizing Ebar, the average energy dissipation over all nodes. In our paper we take a more holistic view, considering both Emax and Ebar. The main contribution of this paper is to provide a simulation-based analysis of the energy efficiency of WSNs with static and mobile sinks. The focus is on two important configuration parameters: mobility path of the sink and duty cycling value of the nodes. On the one hand, it is well known that in the case of a mobile sink with fixed trajectory the choice of the mobility path influences energy efficiency. On the other hand, in some types of applications sensor nodes spend a rather large fraction of their total lifetime in idle mode, and therefore higher energy efficiency can be achieved by using the concept of reduced duty cycles. In particular, we quantitatively analyze the influence of duty cycling and the mobility radius of the sink as well as their interrelationship in terms of energy consumption for a well-defined model scenario. The analysis starts from general load considerations and is refined into a geometrical model. This model is validated by simulations which are more realistic in terms of duty cycling than previous work. It is illustrated that over all possible configuration scenarios in terms of duty cycle and mobility radius of the sink the energy dissipation in the WSN can vary up to a factor of nine in terms of Emax and up to a factor of 17 in terms of Ebar. It turns out that in general the choice of the duty cycle value is more important for achieving energy efficiency than the choice of the mobility radius of the sink. Moreover, for small values of the duty cycle, a static sink turns out to be optimal in terms of both Emax and Ebar. For larger values of the duty cycle, a mobile sink has advantages over a static sink, especially in terms of Emax. These insights into the basic interrelationship between duty cycle value and mobility radius of a mobile sink are relevant for energy efficient operation of homogeneous WSNs beyond our model scenario. PMID- 23805014 TI - Post-Normal Science in Practice at the Netherlands Environmental Assessment Agency. AB - About a decade ago, the Netherlands Environmental Assessment Agency (PBL) unwittingly embarked on a transition from a technocratic model of science advising to the paradigm of "post-normal science" (PNS). In response to a scandal around uncertainty management in 1999, a Guidance for "Uncertainty Assessment and Communication" was developed with advice from the initiators of the PNS concept and was introduced in 2003. This was followed in 2007 by a "Stakeholder Participation" Guidance. In this article, the authors provide a combined insider/outsider perspective on the transition process. The authors assess the extent to which the PNS paradigm has delivered new approaches in the agency's practice and analyze two projects-on long-term options for Dutch sustainable development policy and for urban development policy-the latter in somewhat more detail. The authors identify several paradoxes PBL encounters when putting the PNS concept into practice. It is concluded that an openness to other styles of work than the technocratic model has become visible, but that the introduction of the PNS paradigm is still in its early stage. PMID- 23805016 TI - Smooth surfaces from bilinear patches: Discrete affine minimal surfaces. AB - Motivated by applications in freeform architecture, we study surfaces which are composed of smoothly joined bilinear patches. These surfaces turn out to be discrete versions of negatively curved affine minimal surfaces and share many properties with their classical smooth counterparts. We present computational design approaches and study special cases which should be interesting for the architectural application. PMID- 23805015 TI - YOUNG ADULT DATING RELATIONSHIPS AND THE MANAGEMENT OF SEXUAL RISK. AB - Young adult involvement in sexual behavior typically occurs within a relationship context, but we know little about the ways in which specific features of romantic relationships influence sexual decision-making. Prior work on sexual risk taking focuses attention on health issues rather than relationship dynamics. We draw on data from the Toledo Adolescent Relationships Study (TARS) (n = 475) to examine the association between qualities and dynamics of current/most recent romantic relationships such as communication and emotional processes, conflict, demographic asymmetries, and duration and the management of sexual risk. We conceptualize 'risk management' as encompassing multiple domains, including (1) questioning the partner about previous sexual behaviors/risks, (2) using condoms consistently, and (3) maintaining sexual exclusivity within the relationship. We identify distinct patterns of risk management among dating young adults and find that specific qualities and dynamics of these relationships are linked to variations in risk management. Results from this paper suggest the need to consider relational dynamics in efforts to target and influence young adult sexual risk-taking and reduce STIs, including HIV. PMID- 23805017 TI - Lexicalisation and de-lexicalisation processes in sign languages: Comparing depicting constructions and viewpoint gestures. AB - In this paper, we compare so-called "classifier" constructions in signed languages (which we refer to as "depicting constructions") with comparable iconic gestures produced by non-signers. We show clear correspondences between entity constructions and observer viewpoint gestures on the one hand, and handling constructions and character viewpoint gestures on the other. Such correspondences help account for both lexicalisation and de-lexicalisation processes in signed languages and how these processes are influenced by viewpoint. Understanding these processes is crucial when coding and annotating natural sign language data. PMID- 23805018 TI - Variation in handshape and orientation in British Sign Language: The case of the '1' hand configuration. AB - This paper investigates phonological variation in British Sign Language (BSL) signs produced with a '1' hand configuration in citation form. Multivariate analyses of 2084 tokens reveals that handshape variation in these signs is constrained by linguistic factors (e.g., the preceding and following phonological environment, grammatical category, indexicality, lexical frequency). The only significant social factor was region. For the subset of signs where orientation was also investigated, only grammatical function was important (the surrounding phonological environment and social factors were not significant). The implications for an understanding of pointing signs in signed languages are discussed. PMID- 23805019 TI - Late Pleistocene climate change and landscape dynamics in the Eastern Alps: the inner-alpine Unterangerberg record (Austria). AB - Drill cores from the inner-alpine valley terrace of Unterangerberg, located in the Eastern Alps of Austria, offer first insights into a Pleistocene sedimentary record that was not accessible so far. The succession comprises diamict, gravel, sand, lignite and thick, fine grained sediments. Additionally, cataclastic deposits originating from two paleo-landslide events are present. Multi-proxy analyses including sedimentological and palynological investigations as well as radiocarbon and luminescence data record the onset of the last glacial period (Wurmian) at Unterangerberg at ~120-110 ka. This first time period, correlated to the MIS 5d, was characterised by strong fluvial aggradation under cold climatic conditions, with only sparse vegetation cover. Furthermore, two large and quasi synchronous landslide events occurred during this time interval. No record of the first Early Wurmian interstadial (MIS 5c) is preserved. During the second Early Wurmian interstadial (MIS 5a), the local vegetation was characterised by a boreal forest dominated by Picea, with few thermophilous elements. The subsequent collapse of the vegetation is recorded by sediments dated to ~70-60 ka (i.e. MIS 4), with very low pollen concentrations and the potential presence of permafrost. Climatic conditions improved again between ~55 and 45 ka (MIS 3) and cold-adapted trees re-appeared during interstadials, forming an open forest vegetation. MIS 3 stadials were shorter and less severe than the MIS 4 at Unterangerberg, and vegetation during these cold phases was mainly composed of shrubs, herbs and grasses, similar to what is known from today's alpine timberline. The Unterangerberg record ended at ~45 ka and/or was truncated by ice during the Last Glacial Maximum. PMID- 23805020 TI - Analysis of the width-[Formula: see text] non-adjacent form in conjunction with hyperelliptic curve cryptography and with lattices. AB - In this work the number of occurrences of a fixed non-zero digit in the width [Formula: see text] non-adjacent forms of all elements of a lattice in some region (e.g. a ball) is analysed. As bases, expanding endomorphisms with eigenvalues of the same absolute value are allowed. Applications of the main result are on numeral systems with an algebraic integer as base. Those come from efficient scalar multiplication methods (Frobenius-and-add methods) in hyperelliptic curves cryptography, and the result is needed for analysing the running time of such algorithms. The counting result itself is an asymptotic formula, where its main term coincides with the full block length analysis. In its second order term a periodic fluctuation is exhibited. The proof follows Delange's method. PMID- 23805021 TI - Inference regarding multiple structural changes in linear models with endogenous regressors. AB - This paper considers the linear model with endogenous regressors and multiple changes in the parameters at unknown times. It is shown that minimization of a Generalized Method of Moments criterion yields inconsistent estimators of the break fractions, but minimization of the Two Stage Least Squares (2SLS) criterion yields consistent estimators of these parameters. We develop a methodology for estimation and inference of the parameters of the model based on 2SLS. The analysis covers the cases where the reduced form is either stable or unstable. The methodology is illustrated via an application to the New Keynesian Phillips Curve for the US. PMID- 23805022 TI - Ratio-based estimators for a change point in persistence. AB - We study estimation of the date of change in persistence, from [Formula: see text] to [Formula: see text] or vice versa. Contrary to statements in the original papers, our analytical results establish that the ratio-based break point estimators of Kim [Kim, J.Y., 2000. Detection of change in persistence of a linear time series. Journal of Econometrics 95, 97-116], Kim et al. [Kim, J.Y., Belaire-Franch, J., Badillo Amador, R., 2002. Corringendum to "Detection of change in persistence of a linear time series". Journal of Econometrics 109, 389 392] and Busetti and Taylor [Busetti, F., Taylor, A.M.R., 2004. Tests of stationarity against a change in persistence. Journal of Econometrics 123, 33-66] are inconsistent when a mean (or other deterministic component) is estimated for the process. In such cases, the estimators converge to random variables with upper bound given by the true break date when persistence changes from [Formula: see text] to [Formula: see text]. A Monte Carlo study confirms the large sample downward bias and also finds substantial biases in moderate sized samples, partly due to properties at the end points of the search interval. PMID- 23805023 TI - Planning policy, sustainability and housebuilder practices: The move into (and out of?) the redevelopment of previously developed land. AB - This paper explores the transformations of the housebuilding industry under the policy requirement to build on previously developed land (PDL). This requirement was a key lever in promoting the sustainable urban development agenda of UK governments from the early 1990s to 2010 and has survived albeit somewhat relaxed and permutated in the latest National Planning Policy Framework (NPPF). The paper therefore looks at the way in which the policy push towards densification and mixed use affected housebuilders' business strategy and practices and their ability to cope with the 2007 downturn of the housing market and its aftermath. It also points out the eventual feedback of some of these practices into planning policy. Following the gradual shift of British urban policy focus towards sustainability which started in the early 1990s, new configurations of actors, new skills, strategies and approaches to managing risk emerged in property development and housebuilding. There were at least two ways in which housebuilders could have responded to the requirements of developing long term mixed use high density projects on PDL. One way was to develop new products and to employ practices and combinations of practices involving phasing, a flexible approach to planning applications and innovative production methods. Alternatively, they could approach PDL development as a temporary turn of policy or view mixed use high density schemes as a niche market to be explored without drastically overhauling the business model of the entire firm. These transformations of the UK housebuilding sector were unfolding during a long period of buoyancy in the housing market which came to an end in 2007. Very little is known both about how housebuilder strategies and production practices evolved during the boom years as well as about how these firms coped with the effects of the 2007 market downturn. The paper draws on published data (company annual reports, government statistics) and primary material (stakeholder interviews, planning applications, unpublished project specific information) to explore two different approaches that two major housebuilders (the Berkeley Group and George Wimpey - now Taylor Wimpey) followed during the boom years in response to the changing requirements, risks and uncertainties embedded in the residential development process. The recent turmoil in the property markets acted as an 'acid test' to business models and practices and not all firms survived it. What is more, the UK government is now embedding some of those business practices into policy, thus completing one loop in a co-evolving feedback spiral between planning policy and business strategy. PMID- 23805025 TI - Marginal methods for clustered longitudinal binary data with incomplete covariates. AB - Many analyses for incomplete longitudinal data are directed to examining the impact of covariates on the marginal mean responses. We consider the setting in which longitudinal responses are collected from individuals nested within clusters. We discuss methods for assessing covariate effects on the mean and association parameters when covariates are incompletely observed. Weighted first and second order estimating equations are constructed to obtain consistent estimates of mean and association parameters when covariates are missing at random. Empirical studies demonstrate that estimators from the proposed method have negligible finite sample biases in moderate samples. An application to the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) demonstrates the utility of the proposed method. PMID- 23805024 TI - Preliminary study of kaonic deuterium X-rays by the SIDDHARTA experiment at DAPhiNE. AB - The study of the [Formula: see text] system at very low energies plays a key role for the understanding of the strong interaction between hadrons in the strangeness sector. At the DAPhiNE electron-positron collider of Laboratori Nazionali di Frascati we studied kaonic atoms with [Formula: see text] and [Formula: see text], taking advantage of the low-energy charged kaons from Phi mesons decaying nearly at rest. The SIDDHARTA experiment used X-ray spectroscopy of the kaonic atoms to determine the transition yields and the strong interaction induced shift and width of the lowest experimentally accessible level (1s for H and D and 2p for He). Shift and width are connected to the real and imaginary part of the scattering length. To disentangle the isospin dependent scattering lengths of the antikaon-nucleon interaction, measurements of [Formula: see text] and of [Formula: see text] are needed. We report here on an exploratory deuterium measurement, from which a limit for the yield of the K-series transitions was derived: [Formula: see text] and [Formula: see text] (CL 90%). Also, the upcoming SIDDHARTA-2 kaonic deuterium experiment is introduced. PMID- 23805026 TI - On conjugate families and Jeffreys priors for von Mises-Fisher distributions. AB - This paper discusses characteristics of standard conjugate priors and their induced posteriors in Bayesian inference for von Mises-Fisher distributions, using either the canonical natural exponential family or the more commonly employed polar coordinate parameterizations. We analyze when standard conjugate priors as well as posteriors are proper, and investigate the Jeffreys prior for the von Mises-Fisher family. Finally, we characterize the proper distributions in the standard conjugate family of the (matrix-valued) von Mises-Fisher distributions on Stiefel manifolds. PMID- 23805027 TI - Finance is good for the poor but it depends where you live. AB - I examine whether or not the incomes of the poor systematically grow with average incomes, and whether financial development enhances the incomes of the poorest quintile. Following the methodology of Dollar and Kraay (2002), I find, once extending Dollar and Kraay's data, their findings are robust to the Lucas critique and economic growth is important for poverty reduction universally. However, in comparison to other authors' work I show financial development aids the incomes of the poor in certain regions, whilst it may be detrimental in others. This proposes evidence against a "one size fits all" model adding a further contribution to the literature on financial development and poverty. PMID- 23805029 TI - A survey of urban climate change experiments in 100 cities. AB - Cities are key sites where climate change is being addressed. Previous research has largely overlooked the multiplicity of climate change responses emerging outside formal contexts of decision-making and led by actors other than municipal governments. Moreover, existing research has largely focused on case studies of climate change mitigation in developed economies. The objective of this paper is to uncover the heterogeneous mix of actors, settings, governance arrangements and technologies involved in the governance of climate change in cities in different parts of the world. The paper focuses on urban climate change governance as a process of experimentation. Climate change experiments are presented here as interventions to try out new ideas and methods in the context of future uncertainties. They serve to understand how interventions work in practice, in new contexts where they are thought of as innovative. To study experimentation, the paper presents evidence from the analysis of a database of 627 urban climate change experiments in a sample of 100 global cities. The analysis suggests that, since 2005, experimentation is a feature of urban responses to climate change across different world regions and multiple sectors. Although experimentation does not appear to be related to particular kinds of urban economic and social conditions, some of its core features are visible. For example, experimentation tends to focus on energy. Also, both social and technical forms of experimentation are visible, but technical experimentation is more common in urban infrastructure systems. While municipal governments have a critical role in climate change experimentation, they often act alongside other actors and in a variety of forms of partnership. These findings point at experimentation as a key tool to open up new political spaces for governing climate change in the city. PMID- 23805028 TI - Effects of variety and nutrient availability on the acrylamide-forming potential of rye grain. AB - Acrylamide is a probable human carcinogen that forms in plant-derived foods when free asparagine and reducing sugars react at high temperatures. The identification of rye varieties with low acrylamide-forming potential or agronomic conditions that produce raw material with low acrylamide precursor concentrations would reduce the acrylamide formed in baked rye foods without the need for additives or potentially costly changes to processes. This work compared five commercial rye varieties grown under a range of fertilisation regimes to investigate the effects of genotype and nutrient (nitrogen and sulphur) availability on the accumulation of acrylamide precursors. A strong correlation was established between the free asparagine concentration of grain and the acrylamide formed upon heating. The five rye varieties accumulated different concentrations of free asparagine in the grain, indicating that there is genetic control of this trait and that variety selection could be useful in reducing acrylamide levels in rye products. High levels of nitrogen fertilisation were found to increase the accumulation of free asparagine, showing that excessive nitrogen application should be avoided in order not to exacerbate the problem of acrylamide formation. This effect of nitrogen was mitigated in two of the varieties by the application of sulphur. PMID- 23805030 TI - Algorithmic requirements for swarm intelligence in differently coupled collective systems. AB - Swarm systems are based on intermediate connectivity between individuals and dynamic neighborhoods. In natural swarms self-organizing principles bring their agents to that favorable level of connectivity. They serve as interesting sources of inspiration for control algorithms in swarm robotics on the one hand, and in modular robotics on the other hand. In this paper we demonstrate and compare a set of bio-inspired algorithms that are used to control the collective behavior of swarms and modular systems: BEECLUST, AHHS (hormone controllers), FGRN (fractal genetic regulatory networks), and VE (virtual embryogenesis). We demonstrate how such bio-inspired control paradigms bring their host systems to a level of intermediate connectivity, what delivers sufficient robustness to these systems for collective decentralized control. In parallel, these algorithms allow sufficient volatility of shared information within these systems to help preventing local optima and deadlock situations, this way keeping those systems flexible and adaptive in dynamic non-deterministic environments. PMID- 23805031 TI - 'This place isn't worth the left boot of one of our boys': Geopolitics, militarism and memoirs of the Afghanistan war. AB - This paper argues for the continued significance of the text as a source and focus in critical geopolitical inquiry. It establishes the utility of the military memoir in explorations of popular contemporary geopolitical imaginaries, and considers the memoir as a vector of militarism. The paper examines the memoirs written by military personnel about service in Afghanistan with the British armed forces, specifically about deployments to Helmand province between 2006 and 2012. The paper explores how Afghanistan is scripted through these texts, focussing on the explanations for deployment articulated by their authors, on the representations they contain and promote about other combatants and about civilian non-combatants, and the constitution and expression of danger in the spaces and places of military action which these texts construct and convey. The paper then turns to consider how a reading of the military memoir with reference to the genre of testimonio might extend and inform our understanding and use of these texts as a source for exploring popular geopolitics and militarism. PMID- 23805032 TI - Diabetes-associated dry eye syndrome in a new humanized transgenic model of type 1 diabetes. AB - PURPOSE: Patients with Type 1 Diabetes (T1D) are at high risk of developing lacrimal gland dysfunction. We have developed a new model of human T1D using double-transgenic mice carrying HLA-DQ8 diabetes-susceptibility haplotype instead of mouse MHC-class II and expressing the human beta cell autoantigen Glutamic Acid Decarboxylase in pancreatic beta cells. We report here the development of dry eye syndrome (DES) after diabetes induction in our humanized transgenic model. METHODS: Double-transgenic mice were immunized with DNA encoding human GAD65, either naked or in adenoviral vectors, to induce T1D. Mice monitored for development of diabetes developed lacrimal gland dysfunction. RESULTS: Animals developed lacrimal gland disease (classically associated with diabetes in Non Obese Diabetic [NOD] mice and with T1D in humans) as they developed glucose intolerance and diabetes. Animals manifested obvious clinical signs of dry eye syndrome (DES), from corneal erosions to severe keratitis. Histological studies of peri-bulbar areas revealed lymphocytic infiltration of glandular structures. Indeed, infiltrative lesions were observed in lacrimal/Harderian glands within weeks following development of glucose intolerance. Lesions ranged from focal lymphocytic infiltration to complete acinar destruction. We observed a correlation between the severity of the pancreatic infiltration and the severity of the ocular disease. CONCLUSIONS: Our results demonstrate development of DES in association with antigen-specific insulitis and diabetes following immunization with clinically relevant human autoantigen concomitantly expressed in pancreatic beta cells of diabetes-susceptible mice. As in the NOD mouse model and as in human T1D, our animals developed diabetes-associated DES. This specific finding stresses the relevance of our model for studying these human diseases. We believe our model will facilitate studies to prevent/treat diabetes-associated DES as well as human diabetes. PMID- 23805034 TI - Co-occurrence of m.1555A>G and m.11778G>A mitochondrial DNA mutations in two Indian families with strikingly different clinical penetrance of Leber hereditary optic neuropathy. AB - BACKGROUND: Mitochondrial DNA (mtDNA) mutations are known to cause Leber hereditary optic neuropathy (LHON). However, the co-occurrence of double pathogenic mutations with different pathological significance in pedigrees is a rare event. METHODS: Detailed clinical investigation and complete mtDNA sequencing analysis was performed for two Indian families with LHON. The haplogroup was constructed based on evolutionarily important mtDNA variants. RESULTS: We observed the existence of double pathogenic mutations (m.11778G>A and m.1555A>G) in two Indian LHON families, who are from different haplogroup backgrounds (M5a and U2e1), with different clinical penetrance of the disease (visual impairment). The m.11778G>A mutation in the MT-ND4 gene is associated primarily with LHON; whereas, m.1555A>G in the 12S rRNA gene has been reported with aminoglycoside-induced non-syndromic hearing loss. CONCLUSIONS: The absence of hearing abnormality and widely varying clinical expression of LHON suggest additional nuclear modifier genes, environmental factors, and population heterogeneity might play an important role in the expression of visual impairment in these families. PMID- 23805033 TI - Disease-associated mutations in CNGB3 promote cytotoxicity in photoreceptor derived cells. AB - PURPOSE: To determine if achromatopsia associated F525N and T383fsX mutations in the CNGB3 subunit of cone photoreceptor cyclic nucleotide-gated (CNG) channels increases susceptibility to cell death in photoreceptor-derived cells. METHODS: Photoreceptor-derived 661W cells were transfected with cDNA encoding wild-type (WT) CNGA3 subunits plus WT or mutant CNGB3 subunits, and incubated with the membrane-permeable CNG channel activators 8-(4-chlorophenylthio) guanosine 3',5' cyclic monophosphate (CPT-cGMP) or CPT-adenosine 3',5'-cyclic monophosphate (CPT cAMP). Cell viability under these conditions was determined by measuring lactate dehydrogenase release. Channel ligand sensitivity was calibrated by patch-clamp recording after expression of WT or mutant channels in Xenopus oocytes. RESULTS: Coexpression of CNGA3 with CNGB3 subunits containing F525N or T383fsX mutations produced channels exhibiting increased apparent affinity for CPT-cGMP compared to WT channels. Consistent with these effects, cytotoxicity in the presence of 0.1 MUM CPT-cGMP was enhanced relative to WT channels, and the increase in cell death was more pronounced for the mutation with the largest gain-of-function effect on channel gating, F525N. Increased susceptibility to cell death was prevented by application of the CNG channel blocker L-cis-diltiazem. Increased cytotoxicity was also found to be dependent on the presence of extracellular calcium. CONCLUSIONS: These results indicate a connection between disease-associated mutations in cone CNG channel subunits, altered CNG channel-activation properties, and photoreceptor cytotoxicity. The rescue of cell viability via CNG channel block or removal of extracellular calcium suggests that cytotoxicity in this model depends on calcium entry through hyperactive CNG channels. PMID- 23805035 TI - The effect of postmortem time on the RNA quality of human ocular tissues. AB - PURPOSE: Profiling gene expression in human ocular tissues provides invaluable information for understanding ocular biology and investigating numerous ocular diseases. Accurate measurement of gene expression requires high-quality RNA, which often is a challenge with postmortem ocular tissues. METHODS: We examined the effect of various death to preservation (DP) times on the RNA quality of ten different ocular tissues. We used 16 eyes from eight different human donors. The eyes were preserved immediately in RNAlater or preserved after initial storage at 4 degrees C to create a range of DP times from 2 to 48 h. Ten ocular tissues were dissected from each eye. After total RNA was extracted from each dissected ocular tissue, the RNA integrity number (RIN) was determined using an Agilent Bioanalyzer. RESULTS: The RIN values from corneal and trabecular meshwork tissues were significantly (p<0.05) higher than those from the ciliary body at an earlier DP time (<6 h), but were not different among all tissues after 8 h. Interestingly, the RIN values from non-vascularized tissues were significantly (p=0.0002) higher than those from vascularized ocular tissues at early DP times (<6 h). The RIN value from the cornea was significantly (p<0.05) higher at short DP times compared to longer DP times. The RIN values from corneal tissues were significantly correlated to DP time according to regression analysis (p<0.05). CONCLUSIONS: In this study, we determined RNA quality from postmortem ocular tissues with various DP times. Our results emphasize the need for rapid preservation and processing of postmortem human donor eye tissues, especially for vascularized ocular tissues. PMID- 23805036 TI - The effects of small interfering RNA-targeting tissue factor on an in vitro model of neovascularization. AB - PURPOSE: Tissue factor (TF) plays an important role in neovascularization (NV). This study aimed to determine whether small interfering RNA-targeting TF (TF siRNA) could knock down TF expression and inhibit cell proliferation, cell migration, and tube formation in an in vitro model of NV. METHODS: Lipopolysaccharide (LPS) was used to stimulate human umbilical vein endothelial cell (HUVEC) lines to express TF and mimic certain phenotypes of NV in vitro. HUVECs were transfected with TF-siRNAs and control siRNAs using Lipofectamine(TM) 2000. The inhibitory effect of the siRNAs on the expression of TF mRNA and protein was evaluated by quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) and western blot analysis. The effects on the cell viability, migration, and tube formation of siRNA-treated cells were examined by MTT assay, wound-healing assay, and Matrigel-induced capillary tube formation. RESULTS: Lipopolysaccharide treatment increased the expression of TF. TF-siRNAs effectively knocked down TF expression, with the most efficient TF-siRNA reducing 78.9% of TF expression. TF protein was also notably curtailed by TF-siRNA. The MTT and wound-healing assays showed that the TF-siRNA substantially inhibited the proliferation and migration of HUVECs. Tube formation was decreased by 47.4% and 59.4% in cells treated with the TF-siRNA and vascular endothelial growth factor siRNA, respectively, compared with the blank control. CONCLUSIONS: TF-siRNA can knockdown TF expression and inhibit cell proliferation, migration, and tube formation in vitro. TF-siRNA may provide a novel therapeutic candidate for NV related diseases. PMID- 23805037 TI - Ethyl pyruvate treatment mitigates oxidative stress damage in cultured trabecular meshwork cells. AB - PURPOSE: Oxidative stress plays a key role in the pathophysiology of glaucoma. This study was designed to assess ethyl pyruvate (EP) as a novel antioxidative agent in cultured human trabecular meshwork (hTM) cells. METHODS: Primary hTM cells were cultured on collagen matrices. Tolerance to EP was assessed at various concentrations using fluorescent vital dyes (live/dead) and metabolic (1-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays. After the candidate doses were identified, cells received either preincubation with EP before hydrogen peroxide stressing or pre- and coincubation with EP before and during stressing. Live/dead and metabolic activity assays were used to quantify oxidative damage. RESULTS: Cultured hTM cells were well tolerant of EP concentrations at or below 10 mM while higher doses showed significant levels of cytotoxicity. In the peroxide stress assays, samples that received pre- and cotreatment with all concentrations of EP showed significantly increased cell survival and maintenance of metabolic activity. However, samples that received only pretreatment did not show a significant increase in survival rates and lost nearly all metabolic activity after peroxide-induced stressing. CONCLUSIONS: This work suggests that EP is a potent antioxidant that is well tolerated by hTM cells; however, EP's potential as a therapeutic agent for glaucoma is limited by its inability to enhance endogenous antioxidant capacity. A continuous drug delivery system may be needed to realize the full therapeutic potential of EP for treatment of glaucoma. PMID- 23805038 TI - Cre-mediated recombination efficiency and transgene expression patterns of three retinal bipolar cell-expressing Cre transgenic mouse lines. AB - PURPOSE: Retinal bipolar cells, comprising multiple types, play an essential role in segregating visual information into multiple parallel pathways in the retina. The ability to manipulate gene expression in specific bipolar cell type(s) in the retina is important for understanding the molecular basis of their normal physiological functions and diseases/disorders. The Cre/LoxP recombination system has become an important tool for allowing gene manipulation in vivo, especially with the increasing availability of cell- and tissue-specific Cre transgenic mouse lines. Detailed in vivo examination of the Cre/LoxP recombination efficiency and the transgene expression patterns for cell- and tissue-specific Cre transgenic mouse lines is essential for evaluating their utility. In this study, we investigated the Cre-mediated recombination efficiency and transgene expression patterns of retinal bipolar cell-expressing Cre transgenic lines by crossing with a Cre reporter mouse line and through Cre-dependent recombinant adeno-associated virus (rAAV) vector-mediated transgene delivery. METHODS: Three retinal bipolar cell-expressing Cre-transgenic mouse lines, 5-HTR2a-cre, Pcp2 cre, and Chx10-cre, were crossed with a strong Cre reporter mouse line that expresses a red fluorescent protein variant, tdTomato. rAAV2 vectors carrying a double-floxed inverted open-reading frame sequence encoding channelrhodopsin-2 mCherry (ChR2-mCherry) driven by a ubiquitous neuronal EF1alpha or a ubiquitous CMV promoter with a rAAV2 capsid mutation (Y444F) were injected into the intravitreal space of the eyes. Immunohistochemistry using retinal bipolar cell type-specific markers was performed to examine Cre-mediated recombination efficiency and the transgene expression patterns in bipolar cells in retinal whole mounts and vertical sections. RESULTS: For the 5-HTR2a-cre and Pcp2-cre mouse lines, the expression pattern of the Cre-mediated recombination by crossing the reporter line largely resembled the expression pattern of Cre. The bipolar cells showing Cre-mediated recombination in the 5-HTR2a-cre line and the Pcp2-cre line were predominantly type 4 cone bipolar cells and rod bipolar cells, respectively. For the Chx10-cre mouse line, the expression pattern of the Cre mediated recombination by crossing the reporter line was different from that of Cre. The Cre-mediated transgene expression in retinal bipolar cells in the Chx10 cre line was not observed by crossing with the reporter mouse line but through Cre-dependent rAAV vector delivery. A rAAV2 vector with the combination of a CMV promoter and the Y444F capsid mutation achieved Cre-dependent transgene expression in retinal bipolar cells. CONCLUSIONS: The retinal bipolar cell expressing Cre-transgenic lines and the Cre-dependent rAAV vector reported in this study could be valuable tools for gene targeting and manipulation in retinal bipolar cells in mice. PMID- 23805039 TI - Ocular fibroblast types differ in their mRNA profiles--implications for fibrosis prevention after aqueous shunt implantation. AB - PURPOSE: For an aqueous shunt draining from the anterior chamber into the choroidal space, fibroblasts from the choroidea and/or the sclera are most likely responsible for a fibrotic response around the outflow region of such a shunt. The prevention of fibrosis should extend the operating life of the shunt. A detailed characterization of fibroblasts derived from choroidea and sclera should provide information about whether a fibrosis reaction can be inhibited by cell type-specific agents. METHODS: We generated mRNA profiles of fibroblasts from the choroidea, sclera, and Tenon's space by gene array hybridization to provide a basis on which to search for potential pharmacological targets for fibrosis prevention. Hybridization data were analyzed by the Rosetta Resolver system and Limma to obtain mRNA profiles of the three fibroblast types. RESULTS: The three fibroblast types investigated shared fibroblast-specific gene expression patterns concerning extracellular matrix proteins as collagens and fibronectin, but also showed distinct mRNA patterns. CONCLUSIONS: Individual mRNA species overexpressed in one of the fibroblast types might serve as markers for the identification of the fibroblast type in histological analyses. Future in-depth analyses of the gene expression patterns might help identify pharmacological targets for fibrosis prevention. PMID- 23805040 TI - Oxidative stress response signaling pathways in trabecular meshwork cells and their effects on cell viability. AB - PURPOSE: To clarify the primary oxidative stress response signaling pathways in trabecular meshwork (TM) cells and their effects on cell viability. METHODS: Porcine TM cells were treated with 600 MUM or 800 MUM H2O2, and their time dependent morphologic changes were observed. Phosphorylation of protein kinase B (Akt), extracellular regulated kinase (ERK)1/2, p38, and c-Jun NH2-terminal kinase (JNK) was evaluated by western blot analysis. The intracellular localization of NFkappaB was evaluated by western blot analysis. One-hour pretreatments with LY294002, U0126, and SB203580, with the inhibitors of PI3K, ERK1/2, and p38, respectively, were conducted to evaluate the roles of these molecules in the cellular reaction against H2O2. Cell viability was assessed using propidium iodide and anticleaved caspase-3 antibody. RESULTS: TM cells treated with 600 MUM H2O2 showed morphologic changes at 2 h that were partially recovered at 8 h after treatment. TM cells treated with 800 MUM H2O2 did not recover, and the viability was significantly decreased. Both doses of H2O2 activated Akt, ERK1/2, and p38 in TM cells at 20 min after treatment, but not JNK or NFkB until 1 h after treatment. Inhibitors of PI3K, ERK1/2, and p38 suppressed recovery from the morphologic changes induced by 600 MUM H2O2. Of these three inhibitors, the PI3K and ERK1/2 inhibitors decreased TM cell viability under oxidative stress. CONCLUSIONS: In TM cells, the PI3K-Akt, ERK, and p38 signaling pathways are primary oxidative stress response pathways involved in the mechanism of recovery from cellular morphologic changes induced by H2O2 treatment accompanied by actin cytoskeletal changes. PMID- 23805041 TI - Quantitative analysis of SOD2, ALDH1A1 and MGST1 messenger ribonucleic acid in anterior lens epithelium of patients with pseudoexfoliation syndrome. AB - PURPOSE: The aim of the study was to investigate the expression of selected genes encoding enzymes involved in the antioxidant defense system (superoxide dismutase 2, SOD2; aldehyde dehydrogenase 1, ALDH1A1; microsomal glutathione S-transferase 1, MGST1) in fragments of anterior lens capsules of patients with pseudoexfoliation syndrome (PEX). The specificity and sensitivity of these molecular markers for PEX development were also assessed. METHODS: The study group consisted of 20 patients (9 women and 11 men) with diagnosed PEX and cataract. The control group included 23 patients (8 women and 15 men) who needed cataract surgery but did not have PEX. Quantification of SOD2, ALDH1A1, and MGST1 messenger ribonucleic acid (mRNA) was performed with quantitative real-time PCR. RESULTS: SOD2, ALDH1A1, and MGST1 mRNAs were detected in all studied samples. The examined genes had statistically significant higher expression in the group of patients with PEX than in the control group (SOD2, p=0.0015; ALDH1A1, p=0.0001; MGST1, p=0.0001, Mann-Whitney U test). The areas under the curve (AUC) of SOD2, MGST1, and ALDH1A1 were 0.766, 0.818, and 0.957, respectively. CONCLUSIONS: Differential expression of SOD2, ALDH1A1, and MGST1 genes in the anterior lens capsules of patients with PEX suggest that diseased tissue appears to respond to the previously reported oxidative stress. A possible role of ALDH1A1 mRNA level as a risk factor or marker for PEX needs further confirmation. PMID- 23805042 TI - Identification of a novel mutation in the PRCD gene causing autosomal recessive retinitis pigmentosa in a Turkish family. AB - PURPOSE: Progressive rod-cone degeneration (PRCD) is a canine form of autosomal recessive photoreceptor degeneration and serves as an animal model for human retinitis pigmentosa (RP). To date, only two RP-causing mutations of the PRCD gene have been reported in humans. We found a novel mutation in PRCD (c.52C>T, p.R18X) in three siblings affected by RP and present detailed morphologic and functional parameters. METHODS: A complete ophthalmological examination was performed including psychophysical tests (best-corrected visual acuity, Lanthony Panel D-15 color vision test, and visual field) and electrophysiology (ganzfeld and multifocal electroretinogram). Additionally, color and infrared fundus photography, autofluorescence, and spectral domain optical coherence tomography recordings were performed. Genomic DNA of the three affected individuals was analyzed with high-throughput sequencing for all RP-related genes in a diagnostic set-up. RESULTS: We identified a novel homozygous mutation in PRCD (c.52C>T, p.R18X) with diagnostic high-throughput panel sequencing. All three patients showed an advanced stage of retinitis pigmentosa with reduced visual acuity (mean: 20/80), small residual visual fields (mean for target III4e: 1134.35 deg2), and non-detectable electrophysiological responses. Myopia, posterior subcapsular cataract, bone spicule-like pigmentation, and attenuated arterioles were typical findings. Interestingly, bull's eye maculopathy due to patchy retinal pigment epithelium atrophy was also present in all patients. The mean central retinal thickness observed in optical coherence tomography was 148 um. CONCLUSIONS: The identification of a third mutation in PRCD confirms its role in the pathogenesis of RP. Clinical findings were in line with the morphological changes observed in previous studies. Bull's eye maculopathy seems to be a hallmark of RP due to mutations in the PRCD gene. PMID- 23805043 TI - Protein expression, biochemical pharmacology of signal transduction, and relation to intraocular pressure modulation by bradykinin B2 receptors in ciliary muscle. AB - PURPOSE: To examine the bradykinin (BK) B2-receptor system in human and monkey ciliary muscle (CM) using immunohistochemical techniques, and to pharmacologically characterize the associated biochemical signal transduction systems in human CM (h-CM) cells. BK-induced modulation of intraocular pressure (IOP) in pigmented Dutch-Belt rabbits and cynomolgus monkeys was also studied. METHODS: Previously published procedures were used throughout these studies. RESULTS: The human and monkey ciliary bodies expressed high levels of B2-receptor protein immunoreactivity. Various kinins differentially stimulated [Ca2+](i) mobilization in primary h-CM cells (BK EC50=2.4+/-0.2 nM > Hyp3,beta-(2-thienyl) Ala5,Tyr(Me)8-((r))-Arg9-BK (RMP-7) > Des-Arg9-BK EC50=4.2 uM [n=3-6]), and this was blocked by B2-selective antagonists, HOE-140 (IC50=1.4+/-0.1 nM) and WIN 63448 (IC50=174 nM). A phospholipase C inhibitor (U73122; 10-30 uM) and ethylene glycol tetraacetic acid (1-2 mM) abolished the BK-induced [Ca2+](i) mobilization. Total prostaglandin (primarily PGE2) secretion stimulated by BK and other kinins in h-CM cells was attenuated by the cyclooxygenase inhibitors bromfenac and flurbiprofen, and by the B2-antagonists. BK and RMP-7 (100 nM) induced a twofold increase in extracellular signal-regulated kinase-1/2 phosphorylation, and BK (0.1-1 uM; at 24 h) caused a 1.4-3.1-fold increase in promatrix metalloproteinases-1-3 release. Topical ocular BK (100 ug) failed to alter IOP in cynomolgus monkeys. However, intravitreal injection of 50 ug of BK, but not Des Arg9-BK, lowered IOP in rabbit eyes (22.9+/-7.3% and 37.0+/-5.6% at 5 h and 8 h post-injection; n=7-10). CONCLUSIONS: These studies have provided evidence of a functional endogenously expressed B2-receptor system in the CM that appears to be involved in modulating IOP. PMID- 23805045 TI - Statistical Considerations in the Design of Biosimilar Cancer Clinical Trials. AB - When the patent of an innovative (brand-name) small-molecule drug expires, generic copies of the innovative drug may be marketed if their therapeutic equivalence to the innovative drug has been shown. The small-molecule drugs are considered therapeutically equivalent and can be used interchangeably if two drugs are shown to be pharmaceutically equivalent with identical active substance and bioequivalent with comparable pharmacokinetics in a crossover clinical trial. However, the therapeutic equivalence paradigm cannot be applied to biosimilars since the active ingredients of biosimilars are huge molecules with complex and heterogeneous structures, and these molecules are difficult to replicate in every detail. The European Medicine Agency (EMEA) has introduced a regulatory biosimilar pathway which mandates clinical trials to show therapeutic equivalence. In this paper, we discuss statistical considerations in the design and analysis of biosimilar cancer clinical trials. PMID- 23805046 TI - A new genus for a rare African vespertilionid bat: insights from South Sudan. AB - A new genus is proposed for the strikingly patterned African vespertilionid "Glauconycteris" superba Hayman, 1939 on the basis of cranial and external morphological comparisons. A review of the attributes of a newly collected specimen from South Sudan (a new country record) and other museum specimens of "Glauconycteris" superba suggests that "Glauconycteris" superba is markedly distinct ecomorphologically from other species classified in Glauconycteris and is likely the sister taxon to Glauconycteris sensu stricto. The recent capture of this rarely collected but widespread bat highlights the need for continued research in tropical sub-Saharan Africa and in particular, for more work in western South Sudan, which has received very little scientific attention. New country records for Glauconycteris cf. poensis (South Sudan) and Glauconycteris curryae (Gabon) are also reported. PMID- 23805044 TI - RIT2, a neuron-specific small guanosine triphosphatase, is expressed in retinal neuronal cells and its promoter is modulated by the POU4 transcription factors. AB - PURPOSE: Ras-like without CAAX 2 (RIT2), a member of the Ras superfamily of small guanosine triphosphatases, is involved in regulating neuronal function. RIT2 is a unique member of the Ras family in that RIT2 is preferentially expressed in various neurons, including retinal neurons. The mechanisms that regulate RIT2 expression in neurons were studied. METHODS: Reverse transcription-quantitative PCR (RT-qPCR), immunohistochemistry, western blotting, bioinformatic prediction, electrophoretic mobility shift assay (EMSA), and cell transfection methods were used. RESULTS: With immunohistochemistry of the mouse retina, RIT2 protein was detected in the ganglion cell layer (GCL), inner plexiform layer, inner nuclear layer, and outer plexiform layer, with the strongest staining in the GCL and the inner plexiform layer. RT-qPCR combined with laser capture microdissection detected Rit2 messenger RNA in the GCL and the inner nuclear layer. Western blot analysis showed a large increase in the RIT2 protein in the retina during maturation from newborn to adult. Transient transfection identified the 1.3 kb upstream region of human RIT2 as capable of driving expression in neuronal cell lines. Based on the known expression pattern and biological activity, we hypothesized that POU4 family factors might modulate RIT2 expression in retinal ganglion cells (RGCs). Bioinformatic analyses predicted six POU4 factor-binding sites within the 1.3 kb human RIT2 promoter region. EMSA analyses showed binding of POU4 proteins to three of the six predicted sites. Cotransfection with expression vectors demonstrated that POU4 proteins can indeed modulate the human RIT2 promoter, and that ISL1, a LIM homeodomain factor, can further modulate the activity of the POU4 factors. CONCLUSIONS: These studies confirm the expression of RIT2 in retinal neuronal cells, including RGCs, begin to reveal the mechanisms responsible for neuronal expression of RIT2, and suggest a role for the POU4 family factors in modulating RIT2 expression in RGCs. PMID- 23805047 TI - A new species of Stenoloba Staudinger, 1892 from China (Lepidoptera, Noctuidae, Bryophilinae). AB - A new species of Stenoloba from the olivacea species group, Stenoloba solaris, sp. n. (Lepidoptera, Noctuidae), is described from Yunnan, China. Illustrations of the male holotype and its genitalia are provided. A diagnostic comparison is made with Stenoloba albistriata Kononenko & Ronkay, 2000, Stenoloba olivacea (Wileman, 1914), and Stenoloba benedeki Ronkay, 2001 (Fig. 4). PMID- 23805048 TI - First records of the genera Histeromerus Wesmael (Hymenoptera, Braconidae, Histeromerinae) and Ecclitura Kokujev (Hymenoptera, Braconidae, Euphorinae) in Italy. AB - Braconid genera Histeromerus Wesmael, 1838 from subfamily Histeromerinae and Ecclitura Kokujev, 1902 from subfamily Euphorinae are recorded in the fauna of Italy for the first time. The discussions about taxonomic position, morphological characters and composition of these genera as well as the redescriptions of the genus and species of Ecclitura primoris Kokujev are given. PMID- 23805049 TI - Review of the genus Agria (Diptera, Sarcophagidae) from China. AB - Agria mihalyii (Rohdendorf and Verves, 1978) is recorded from China for the first time, and both sexes are thoroughly documented using a combination of illustrations, photographs and scanning electron microscopy images. The generic affiliation is corroborated from an expanded definition of genus Agria Robineau Desvoidy, 1830, and a key to males of the two known species from China is provided. The distribution of coeloconic sensilla on the male pre- and postgonite are shown to possess significant diagnostic and phylogenetic information in this genus. PMID- 23805050 TI - Two common and problematic leucochrysine species - Leucochrysa (Leucochrysa) varia (Schneider) and L. (L.) pretiosa (Banks) (Neuroptera, Chrysopidae): redescriptions and synonymies. AB - We dedicate this article to the memory of Sergio de Freitas, FCAV-UNESP, Jaboticabal, Sao Paulo, Brazil (deceased, 2012). He was an active and enthusiastic Neuropterist and the cherished mentor and friend of Francisco Sosa. Leucochrysa McLachlan is the largest genus in the Chrysopidae, yet it has received relatively little taxonomic attention. We treat two problematic and common Leucochrysa species - Leucochrysa (Leucochrysa) varia (Schneider, 1851) and Leucochrysa (Leucochrysa) pretiosa (Banks, 1910). Both are highly variable in coloration and were described before the systematic importance of chrysopid genitalia was recognized. Recent studies show that these species occur within a large complex of cryptic species and that they have accumulated a number of taxonomic problems. We identify new synonymies for each of the species-for Leucochrysa (Leucochrysa) varia: Leucochrysa (Leucochrysa) ampla (Walker, 1853), Leucochrysa internata (Walker, 1853), and Leucochrysa (Leucochrysa) walkerina Navas, 1913; for Leucochrysa (Leucochrysa) pretiosa: Leucochrysa (Leucochrysa) erminea Banks, 1946. The synonymy of Leucochrysa delicata Navas, 1925 with Leucochrysa (Leucochrysa) pretiosa is stabilized by the designation of a neotype. The following species, which were previously synonymized with Leucochrysa (Leucochrysa) varia or Leucochrysa (Leucochrysa) pretiosa, are reinstated as valid: Leucochrysa (Leucochrysa) phaeocephala Navas, 1929, Leucochrysa (Leucochrysa) angrandi (Navas, 1911), and Leucochrysa (Leucochrysa) variata (Navas, 1913). To help stabilize Leucochrysa taxonomy, lectotypes are designated for Allochrysa pretiosa and Allochrysa variata. Finally, Leucochrysa vegana Navas, 1917 is considered a nomen dubium. PMID- 23805051 TI - The Flora of Chad: a checklist and brief analysis. AB - A checklist of the flora of Chad has been compiled by the authors, based on literature, on-line data-bases, herbarium collections and land surveys (1998 2011). It counts 2,460 records, i.e. 2,288 species (including 128 autonyms), 83 subspecies, 81 varieties, 8 forms, while all the previous available information reported 1,600 species. They belong to 151 Families, with 48.7% of the taxa belonging to the 6 largest families, i.e. Poaceae (14.6%), Fabaceae (13.6%), Cyperaceae (7.0%), Asteraceae (6.2 %), Malvaceae (3.9%) and Rubiaceae (3.4%). A total number or 2,173 species (88.3%) are native to Chad, including 55 (2.2%) endemic species, while 274 (11.0%) are alien to Chad, and 13 (0.5%) are considered cryptogenic, i.e. of uncertain status. It represents a considerable update on previous knowledge on the alien flora of Chad that counted for 131 taxa (5.3%). There are 657 therophytes (26.7%), 546 phanerophytes (22.2%), 378 hemicryptophytes (15.4%), 256 chamaephytes (10.4%), 160 geophytes (6.5%), 107 helophytes (4.3%), 104 hydrophytes (4.2%). A total of 252 taxa (10.2) may have different life forms (e.g. terophytes or chamaephytes). PMID- 23805052 TI - The typification of Cordia flavescens Aubl., the transfer of Firensia Scop. from Cordia L. (Cordiaceae, Boraginales) to the synonymy of Ocotea Aubl. (Lauraceae), and the identity of the species of Firensia. AB - Firensia Scop. was based on Cordia flavescens Aubl., a species described and illustrated from a mixed collection that Scopoli never transferred to Firensia. The genus included three additional species formally named by Rafinesque. Currently the four species are placed in three different families and none retained the epithet accepted by Scopoli or given by Rafinesque for reason of priority. A lectotype is designated for Cordia flavescens that places Firensia in the synonymy of Ocotea (Lauraceae). PMID- 23805053 TI - How many taxa can be recognized within the complex Tillandsia capillaris (Bromeliaceae, Tillandsioideae)? Analysis of the available classifications using a multivariate approach. AB - Tillandsia capillaris Ruiz & Pav., which belongs to the subgenus Diaphoranthema is distributed in Ecuador, Peru, Bolivia, northern and central Argentina, and Chile, and includes forms that are difficult to circumscribe, thus considered to form a complex. The entities of this complex are predominantly small-sized epiphytes, adapted to xeric environments. The most widely used classification defines 5 forms for this complex based on few morphological reproductive traits: Tillandsia capillaris Ruiz & Pav. f. capillaris, Tillandsia capillaris f. incana (Mez) L.B. Sm., Tillandsia capillaris f. cordobensis (Hieron.) L.B. Sm., Tillandsia capillaris f. hieronymi (Mez) L.B. Sm. and Tillandsia capillaris f. virescens (Ruiz & Pav.) L.B. Sm. In this study, 35 floral and vegetative characters were analyzed with a multivariate approach in order to assess and discuss different proposals for classification of the Tillandsia capillaris complex, which presents morphotypes that co-occur in central and northern Argentina. To accomplish this, data of quantitative and categorical morphological characters of flowers and leaves were collected from herbarium specimens and field collections and were analyzed with statistical multivariate techniques. The results suggest that the last classification for the complex seems more comprehensive and three taxa were delimited: Tillandsia capillaris (=Tillandsia capillaris f. incana-hieronymi), Tillandsia virescens s. str. (=Tillandsia capillaris f. cordobensis) and Tillandsia virescens s. l. (=Tillandsia capillaris f. virescens). While Tillandsia capillaris and Tillandsia virescens s. str. co occur, Tillandsia virescens s. l. is restricted to altitudes above 2000 m in Argentina. Characters previously used for taxa delimitation showed continuous variation and therefore were not useful. New diagnostic characters are proposed and a key is provided for delimiting these three taxa within the complex. PMID- 23805054 TI - A reassessment of Anthurium species with palmately divided leaves, and a reinterpretation of Anthurium section Dactylophyllium (Araceae). AB - A reappraisal is made of the Anthurium Schott species with palmately divided leaves with 3 or more segments free to the base (i.e. palmatisect leaves), previously recognized as section Dactylophyllium Schott (Engler), as well as those species with 5 or more segments united at the base (i.e. palmatifid leaves), formerly placed in section Schizoplacium Schott (Engler). New molecular data indicates that several species (Anthurium pedatum (Kunth) Schott, Anthurium pedatoradiatum Schott, and possibly, Anthurium podophyllum (Schltdl. & Cham.) Kunth) should be excluded from section Schizoplacium, and other species previously placed in that section cannot be separated from section Dactylophyllium. Thus, Anthurium section Schizoplacium is here synonymized within section Dactylophyllium and type species are designated for both groups. This paper also provides an updated description of section Dactylophyllium as here emended, listing the 24 accepted taxa now included (20 species and 4 varieties or subspecies), along with their geographic distributions. PMID- 23805055 TI - Perceptions and experiences of environmental health risks among new mothers: a qualitative study in Ontario, Canada. AB - There is a growing awareness and concern in contemporary societies about potential health impacts of environmental contaminants on children. Mothers are traditionally more involved than other family members in managing family health and household decisions and thus targeted by public health campaigns to minimise risks. However little is known about how new mothers perceive and experience environmental health risks to their children. In 2010, we undertook a parallel case study using qualitative, in-depth interviews with new mothers and focus groups with public health key informants in two Public Health Units in Ontario Province, Canada. We found that the concern about environmental hazards among participants ranged from having no concerns to actively incorporating prevention into daily life. Overall, there was a common perception among participants that many risks, particularly in the indoor environment, were controllable and therefore of little concern. But environmental risks that originate outside the home were viewed as less controllable and more threatening. In response to such threats, mothers invoked coping strategies such as relying on the capacity of children's bodies to adapt. Regardless of the strategies adopted, actions (or inactions) were contingent upon active information seeking. We also found an optimistic bias in which new mothers reported that other children were at greater risk despite similar environmental circumstances. The findings suggest that risk communication experts must attend to the social and environmental contexts of risk and coping when designing strategies around risk reducing behaviours. PMID- 23805056 TI - HEAVY MARIJUANA USE AMONG GAY AND BISEXUAL MALE EMERGING ADULTS LIVING WITH HIV/AIDS. PMID- 23805057 TI - An undergraduate laboratory exercise to study sensory inhibition. AB - Sensory inhibition was first described by von Bekesy as a process in which excitation of a field of sensory neurons leads to the reduction of activity of surrounding neurons and thus promotes contrast enhancement of the excited field. In the context of somatosensory cortex, the cortical neurons excited by touch or vibration will suppress excitation of neurons from surrounding receptive fields. USING TACTILE STIMULATORS BOTH DESIGNED AND FABRICATED AT THE UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL, WE CONDUCTED TWO SIMPLE EXPERIMENTS IN WHICH SENSORY INHIBITION PLAYS A ROLE IN INFORMATION PROCESSING: a unilateral study in which stimuli are delivered to the digits of one hand, and a bilateral study in which stimuli are delivered to the digits of both hands. In the unilateral study, we demonstrated that threshold detection on the third digit (D3) is impacted by conditioning stimuli delivered to adjacent digits 2 (D2) and digits 4 (D4). In the bilateral study, we delivered different conditions of bilateral stimulation in order to investigate the impact that conditioning stimulation of the right hand had on amplitude discriminative capacity of the left hand. The results demonstrated that conditioning stimulation on the right hand had a significant impact on the discriminative capacity of the left hand, and this alteration in discriminative capacity was consistent with previous animal studies in which somatosensory cortical responses evoked by stimulus conditions of unilateral vs. bilateral stimulation were compared. At the conclusion of this exercise, students will appreciate the fundamentals of sensory inhibition as well as the logistics of obtaining and analyzing data from human subjects. This study is designed to help students prepare for studying other facets of sensory processing by providing a firm foundation in the experimental methods and procedures. PMID- 23805058 TI - Da vinci coding? Using renaissance artists' depictions of the brain to engage student interest in neuroanatomy. AB - This report describes a pair of brief, interactive classroom exercises utilizing Renaissance artists' depictions of the brain to help increase student interest in learning basic neuroanatomy. Undergraduate students provided anonymous quantitative evaluations of both exercises. The feedback data suggest that students found both exercises engaging. The data also suggest that the first exercise increased student interest in learning more about neuroanatomy in general, while the second provided useful practice in identifying major neuroanatomical structures. Overall, the data suggest that these exercises may be a useful addition to courses that introduce or review neuroanatomical concepts. PMID- 23805059 TI - Using chick forebrain neurons to model neurodegeneration and protection in an undergraduate neuroscience laboratory course. AB - Since 2009 at Boston College, we have been offering a Research in Neuroscience course using cultured neurons in an in vitro model of stroke. The students work in groups to learn how to perform sterile animal cell culture and run several basic bioassays to assess cell viability. They are then tasked with analyzing the scientific literature in an attempt to identify and predict the intracellular pathways involved in neuronal death, and identify dietary antioxidant compounds that may provide protection based on their known effects in other cells. After each group constructs a hypothesis pertaining to the potential neuroprotection, we purchase one compound per group and the students test their hypotheses using a commonly performed viability assay. The groups generate quantitative data and perform basic statistics on that data to analyze it for statistical significance. Finally, the groups compile their data and other elements of their research experience into a poster for our departmental research celebration at the end of the spring semester. PMID- 23805060 TI - Preparing new minds and communicating innovations in undergraduate neuroscience education: welcoming change in many forms. PMID- 23805061 TI - Assessing the planning and implementation strategies for the ICD-10-CM/PCS coding transition in Alabama hospitals. AB - Health information management (HIM) professionals play a significant role in transitioning from ICD-9-CM to ICD-10-CM/PCS. ICD-10-CM/PCS coding will impact many operational aspects of healthcare facilities, such as physicians' documentation in health records, coders' process for review of clinical information, the billing process, and the payers' reimbursement to the healthcare facilities. This article examines the level of readiness and planning for ICD-10 CM/PCS implementation among hospitals in Alabama, identifies training methods/approaches to be used by the hospitals, and discusses the challenges to the ICD-10-CM/PCS coding transition. A 16-question survey was distributed to 116 Alabama hospital HIM directors in December 2011 with follow-up through February 2012. Fifty-three percent of respondent hospitals began the planning process in 2011, and most facilities were halfway or less than halfway to completion of specific implementation tasks. Hospital coders will be or are being trained using in-house training, through seminars/webinars, or by consultants. The impact of ICD-10-CM/PCS implementation can be minimized by training coders in advance, hiring new coders, and adjusting coders' productivity measures. Three major challenges to the transition were identified: the need to interact with physicians and other providers more often to obtain information needed to code in ICD-10-CM/PCS systems, education and training of coders and other ICD-10-CM/PCS users, and dependence on vendors for major technology upgrades for ICD-10-CM/PCS systems. Survey results provide beneficial information for HIM professionals and other users of coded data to assist in establishing sound practice standards for ICD-10-CM/PCS coding implementation. Adequate planning and preparation will be essential to the successful implementation of ICD-10-CM/PCS. PMID- 23805062 TI - Evaluating the usability of a free electronic health record for training. AB - The United States will need to train a large workforce of skilled health information technology (HIT) professionals in order to meet the US government's goal of universal electronic health records (EHRs) for all patients and widespread health information exchange. The Health Information Technology for Economic and Clinical Health (HITECH) Act established several HIT workforce educational programs to accomplish this goal. Recent studies have shown that EHR usability is a significant concern of physicians and is a potential obstacle to EHR adoption. It is important to have a highly usable EHR to train both clinicians and students. In this article, we report a qualitative-quantitative usability analysis of a web-based EHR for training health informatics and health information management students. PMID- 23805064 TI - ICD-9 to ICD-10: evolution, revolution, and current debates in the United States. AB - The International Statistical Classification of Diseases and Related Health Problems (ICD) has undergone a long evolution from its initial inception in the late 18th century. Today, ICD is the internationally recognized classification that helps clinicians, policy makers, and patients to navigate, understand, and compare healthcare systems and services. Currently in the United States, hot debates surround the transition from the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) to the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM). This article presents an analysis of the views of the proponents and opponents of the upcoming change. We also briefly present and analyze the quality of the most frequently cited scientific evidence that underpins the recent debates focusing on two major issues: ICD-10-CM implementation costs and revenue gains and the projected clinical data quality improvement. We conclude with policy and research suggestions for healthcare stakeholders. PMID- 23805063 TI - Exploring patient satisfaction before and after electronic health record (EHR) implementation: the Kuwait experience. AB - Patient satisfaction has gained the focal position in well-planned healthcare delivery systems. The objective of this study was to investigate patient satisfaction with the quality of services provided before and after the implementation of electronic health records (EHRs) at Primary Health Care Centers (PHCCs) in Kuwait. A self-developed questionnaire was used. A random sampling was used to select 700 subjects. The response rate was 74 percent. The majority of participants (67 percent) were 19 to 34 years of age. Of the participants, 63 percent were female and 92 percent were Kuwaiti nationals. Before EHR implementation, respondents' disagreement regarding the doctor's carefulness in conducting the examination, uses of medical terminology, explanations for medication given, and time given for a patient was more than 30 percent. Disagreement regarding the rest of the questions related to the patient/physician relationship after EHR implementation was also higher (25 percent to 39 percent). PMID- 23805065 TI - Investigation of physicians' attitudes concerning the implementation of international classification systems of diseases as a precondition for evidence based policy making. AB - This study investigated the main factors affecting physicians' attitudes toward the implementation of international classification systems of diseases. A cross sectional study was carried out during September 2010. The sample consisted of 158 physicians older than 24 years who were working in a public hospital and a private hospital in central Greece. A questionnaire was drawn up based on the relevant literature. Results indicated that younger physicians and those who worked in the public hospital were most familiar with classification systems. Female physicians and specialists with more than 10 years of experience (since qualifying as a specialist) were not particularly familiar with these systems (58 percent and 56 percent, respectively). Both having a master's degree and attending conferences or seminars had a remarkable impact on knowledge of these systems. Almost all physicians (98 percent) holding a master's degree or a PhD believed that these systems contribute to the compilation of valid statistical data. The majority of physicians would like to use these systems in the future, as long as they are provided with the appropriate training. PMID- 23805066 TI - Tele-ICU: efficacy and cost-effectiveness of remotely managing critical care. AB - Tele-ICU is the use of an off-site command center in which a critical care team (intensivists and critical care nurses) is connected with patients in distant ICUs to exchange health information through real-time audio, visual, and electronic means. The aim of this study is to review the available literature related to the efficacy and cost-effectiveness of tele-ICU applications and to study the possible barriers to broader adoption. While the available studies draw conclusions on cost based on mortality and length of stay, actual costs were not reported. Another problem with the studies is the lack of consistent measurement, reporting, and adjustment for patient severity. From the data available, tele-ICU seems to be a promising path, especially in the United States, where there is a limited number of board-certified intensivists. PMID- 23805067 TI - HIM: changing across the nation and the world. PMID- 23805068 TI - Subcultural evolution and illicit drug use. AB - This article articulates a subcultural basis to the evolving popularity for different illicit drugs primarily based on empirical research in the United States, especially among inner-city populations. From this perspective, drug use emerges from a dialectic between drug subcultures with individual identity development. The prevailing culture and subcultures affect drugs' popularity by imparting significance to their use. Innovations, historical events, and individual choices can cause subcultures to emerge and change over time. This subcultural view provides insight into the widespread use of licit drug, the dynamics of drug eras (or epidemics), the formation of drug generations, and the apparent "gateway" phenomenon. PMID- 23805070 TI - Neurotrophic effects of neudesin in the central nervous system. AB - Neudesin (neuron-derived neurotrophic factor; NENF) was identified as a neurotrophic factor that is involved in neuronal differentiation and survival. It is abundantly expressed in the central nervous system, and its neurotrophic activity is exerted via the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways. Neudesin is also an anorexigenic factor that suppresses food intake in the hypothalamus. It is a member of the membrane-associated progesterone receptor (MAPR) family and shares key structural motifs with the cytochrome b5-like heme/steroid-binding domain. Progesterone receptor membrane component 1 (PGRMC1), the first to be discovered among the MAPR family, binds progesterone to induce "rapid non-genomic effects" in biological responses that are unrelated to the nuclear progesterone receptors (PRs). Hence, neudesin may also be involved in the rapid non-genomic actions of progesterone. In this review, we summarize the identification, structure, and activity of neudesin in the central nervous system, and present an essential overview of the current understanding of its physiological roles and the prospect of elucidating its non-genomic progesterone effects. PMID- 23805069 TI - Perinatal complications and schizophrenia: involvement of the immune system. AB - The neurodevelopmental hypothesis of schizophrenia suggests that, at least in part, events occurring within the intrauterine or perinatal environment at critical times of brain development underlies emergence of the psychosis observed during adulthood, and brain pathologies that are hypothesized to be from birth. All potential risks stimulate activation of the immune system, and are suggested to act in parallel with an underlying genetic liability, such that an imperfect regulation of the genome mediates these prenatal or early postnatal environmental effects. Epidemiologically based animal models looking at environment and with genes have provided us with a wealth of knowledge in the understanding of the pathophysiology of schizophrenia, and give us the best possibility for interventions and treatments for schizophrenia. PMID- 23805072 TI - From pattern separation to mood regulation: multiple roles for developmental signals in the adult dentate gyrus. PMID- 23805071 TI - Biomarker investigations related to pathophysiological pathways in schizophrenia and psychosis. AB - Post-mortem brain investigations of schizophrenia have generated swathes of data in the last few decades implicating candidate genes and protein. However, the relation of these findings to peripheral biomarker indicators and symptomatology remain to be elucidated. While biomarkers for disease do not have to be involved with underlying pathophysiology and may be largely indicative of diagnosis or prognosis, the ideal may be a biomarker that is involved in underlying disease processes and which is therefore more likely to change with progression of the illness as well as potentially being more responsive to treatment. One of the main difficulties in conducting biomarker investigations for major psychiatric disorders is the relative inconsistency in clinical diagnoses between disorders such as bipolar and schizophrenia. This has led some researchers to investigate biomarkers associated with core symptoms of these disorders, such as psychosis. The aim of this review is to evaluate the contribution of post-mortem brain investigations to elucidating the pathophysiology pathways involved in schizophrenia and psychosis, with an emphasis on major neurotransmitter systems that have been implicated. This data will then be compared to functional neuroimaging findings as well as findings from blood based gene expression investigations in schizophrenia in order to highlight the relative overlap in pathological processes between these different modalities used to elucidate pathogenesis of schizophrenia. In addition we will cover some recent and exciting findings demonstrating microRNA (miRNA) dysregulation in both the blood and the brain in patients with schizophrenia. These changes are pertinent to the topic due to their known role in post-transcriptional modification of gene expression with the potential to contribute or underlie gene expression changes observed in schizophrenia. Finally, we will discuss how post-mortem studies may aid future biomarker investigations. PMID- 23805073 TI - Canonical Wnt signaling protects hippocampal neurons from Abeta oligomers: role of non-canonical Wnt-5a/Ca(2+) in mitochondrial dynamics. AB - Alzheimer's disease (AD) is the most common type of age-related dementia. The disease is characterized by a progressive loss of cognitive abilities, severe neurodegeneration, synaptic loss and mitochondrial dysfunction. The Wnt signaling pathway participates in the development of the central nervous system and growing evidence indicates that Wnts also regulate the function of the adult nervous system. We report here, that indirect activation of canonical Wnt/beta-catenin signaling using Bromoindirubin-30-Oxime (6-BIO), an inhibitor of glycogen synthase kinase-3beta, protects hippocampal neurons from amyloid-beta (Abeta) oligomers with the concomitant blockade of neuronal apoptosis. More importantly, activation with Wnt-5a, a non-canonical Wnt ligand, results in the modulation of mitochondrial dynamics, preventing the changes induced by Abeta oligomers (Abetao) in mitochondrial fission-fusion dynamics and modulates Bcl-2 increases induced by oligomers. The canonical Wnt-3a ligand neither the secreted Frizzled Related Protein (sFRP), a Wnt scavenger, did not prevent these effects. In contrast, some of the Abeta oligomer effects were blocked by Ryanodine. We conclude that canonical Wnt/beta-catenin signaling controls neuronal survival, and that non-canonical Wnt/Ca(2+)signaling modulates mitochondrial dysfunction. Since mitochondrial dysfunction is present in neurodegenerative diseases, the therapeutic possibilities of the activation of Wnt signaling are evident. PMID- 23805075 TI - Layer-specific high-frequency action potential spiking in the prefrontal cortex of awake rats. AB - Cortical pyramidal neurons show irregular in vivo action potential (AP) spiking with high-frequency bursts occurring on sparse background activity. Somatic APs can backpropagate from soma into basal and apical dendrites and locally generate dendritic calcium spikes. The critical AP frequency for generation of such dendritic calcium spikes can be very different depending on cell type or brain area involved. Previously, it was shown in vitro that calcium electrogenesis can be induced in L(ayer) 5 pyramidal neurons of prefrontal cortex (PFC). It remains an open question whether somatic burst spiking and the resulting dendritic calcium electrogenesis also occur in morphologically more compact L2/3 pyramidal neurons. Furthermore, it is not known whether critical frequencies that trigger dendritic calcium electrogenesis occur in PFC under awake conditions in vivo. Here, we addressed these issues and found that pyramidal neurons in both PFC L2/3 and L5 in awake rats spike APs in short bursts but with different probabilities. The critical frequency (CF) for calcium electrogenesis in vitro was layer specific and lower in L5 neurons compared to L2/3. Taking the in vitro CF as a predictive measure for dendritic electrogenesis during in vivo spontaneous activity, supracritical bursts in vivo were observed in a larger fraction of L5 neurons compared to L2/3 neurons but with similar incidence within these subpopulations. Together, these results show that in PFC of awake rats, AP spiking occurs at frequencies that are relevant for dendritic calcium electrogenesis and suggest that in awake rat PFC, dendritic calcium electrogenesis may be involved in neuronal computation. PMID- 23805074 TI - A quantitative theory of the functions of the hippocampal CA3 network in memory. AB - A quantitative computational theory of the operation of the hippocampal CA3 system as an autoassociation or attractor network used in episodic memory system is described. In this theory, the CA3 system operates as a single attractor or autoassociation network to enable rapid, one-trial, associations between any spatial location (place in rodents, or spatial view in primates) and an object or reward, and to provide for completion of the whole memory during recall from any part. The theory is extended to associations between time and object or reward to implement temporal order memory, also important in episodic memory. The dentate gyrus (DG) performs pattern separation by competitive learning to produce sparse representations suitable for setting up new representations in CA3 during learning, producing for example neurons with place-like fields from entorhinal cortex grid cells. The dentate granule cells produce by the very small number of mossy fiber (MF) connections to CA3 a randomizing pattern separation effect important during learning but not recall that separates out the patterns represented by CA3 firing to be very different from each other, which is optimal for an unstructured episodic memory system in which each memory must be kept distinct from other memories. The direct perforant path (pp) input to CA3 is quantitatively appropriate to provide the cue for recall in CA3, but not for learning. Tests of the theory including hippocampal subregion analyses and hippocampal NMDA receptor knockouts are described, and support the theory. PMID- 23805076 TI - Wnt signaling in the regulation of adult hippocampal neurogenesis. AB - In the adult brain new neurons are continuously generated mainly in two regions, the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) in the hippocampal dentate gyrus. In the SGZ, radial neural stem cells (NSCs) give rise to granule cells that integrate into the hippocampal circuitry and are relevant for the plasticity of the hippocampus. Loss of neurogenesis impairs learning and memory, suggesting that this process is important for adult hippocampal function. Adult neurogenesis is tightly regulated by multiple signaling pathways, including the canonical Wnt/beta-catenin pathway. This pathway plays important roles during the development of neuronal circuits and in the adult brain it modulates synaptic transmission and plasticity. Here, we review current knowledge on the regulation of adult hippocampal neurogenesis by the Wnt/beta-catenin signaling cascade and the potential mechanisms involved in this regulation. Also we discuss the evidence supporting that the canonical Wnt pathway is part of the signaling mechanisms involved in the regulation of neurogenesis in different physiological conditions. Finally, some unsolved questions regarding the Wnt-mediated regulation of neurogenesis are discussed. PMID- 23805077 TI - Structural plasticity of GABAergic axons is regulated by network activity and GABAA receptor activation. AB - Coordinated changes at excitatory and inhibitory synapses are essential for normal brain development and function. It is well established that excitatory neurons undergo structural changes, but our knowledge about inhibitory structural plasticity is rather scarce. Here we present a quantitative analysis of the dynamics of GABAergic boutons in the dendritic region of the hippocampal CA1 area using time-lapse two-photon imaging in organotypic hippocampal cultures from GAD65-GFP mice. We show that ~20% of inhibitory boutons are not stable. They are appearing, disappearing and reappearing at specific locations along the inhibitory axon and reflect immature or incomplete synapses. Furthermore, we observed that persistent boutons show large volume fluctuations over several hours, suggesting that presynaptic content of inhibitory synapses is not constant. Our data show that inhibitory boutons are highly dynamic structures and suggest that inhibitory axons are continuously probing potential locations for inhibitory synapse formation by redistributing presynaptic material along the axon. In addition, we found that neuronal activity affects the exploratory dynamics of inhibitory axons. Blocking network activity rapidly reduces the number of transient boutons, whereas enhancing activity reduces the number of persistent inhibitory boutons, possibly reflecting enhanced competition between boutons along the axon. The latter effect requires signaling through GABAA receptors. We propose that activity-dependent regulation of bouton dynamics contributes to inhibitory synaptic plasticity. PMID- 23805079 TI - The secondary loss of gyrencephaly as an example of evolutionary phenotypical reversal. AB - Gyrencephaly (the folding of the surface of the neocortex) is a mammalian specific trait present in almost all mammalian orders. Despite the widespread appearance of the trait, little is known about the mechanism of its genesis or its adaptive significance. Still, most of the hypotheses proposed concentrated on the pattern of connectivity of mature neurons as main components of gyri formation. Recent work on embryonic neurogenesis in several species of mammals revealed different progenitor and stem cells and their neurogenic potential as having important roles in the process of gyrification. Studies in the field of comparative neurogenesis revealed that gyrencephaly is an evolutionarily labile trait, and that some species underwent a secondary loss of a convoluted brain surface and thus reverted to a more ancient form, a less folded brain surface (lissencephaly). This phenotypic reversion provides an excellent system for understanding the phenomenon of secondary loss. In this review, we will outline the theory behind secondary loss and, as specific examples, present species that have undergone this transition with respect to neocortical folding. We will also discuss different possible pathways for obtaining (or losing) gyri. Finally, we will explore the potential adaptive consequence of gyrencephaly relative to lissencephaly and vice versa. PMID- 23805080 TI - Cellular and molecular basis of cerebellar development. AB - Historically, the molecular and cellular mechanisms of cerebellar development were investigated through structural descriptions and studying spontaneous mutations in animal models and humans. Advances in experimental embryology, genetic engineering, and neuroimaging techniques render today the possibility to approach the analysis of molecular mechanisms underlying histogenesis and morphogenesis of the cerebellum by experimental designs. Several genes and molecules were identified to be involved in the cerebellar plate regionalization, specification, and differentiation of cerebellar neurons, as well as the establishment of cellular migratory routes and the subsequent neuronal connectivity. Indeed, pattern formation of the cerebellum requires the adequate orchestration of both key morphogenetic signals, arising from distinct brain regions, and local expression of specific transcription factors. Thus, the present review wants to revisit and discuss these morphogenetic and molecular mechanisms taking place during cerebellar development in order to understand causal processes regulating cerebellar cytoarchitecture, its highly topographically ordered circuitry and its role in brain function. PMID- 23805083 TI - Subnetwork selection in deep cortical layers is mediated by beta-oscillation dependent firing. PMID- 23805082 TI - Laminar firing and membrane dynamics in four visual areas exposed to two objects moving to occlusion. AB - It is not known how visual cortical neurons react to several moving objects and how their firing to the motion of one object is affected by neurons firing to another moving object. Here we combine imaging of voltage sensitive dye (VSD) signals, reflecting the population membrane potential from ferret visual areas 17, 18, 19, and 21, with laminar recordings of multiunit activity, (MUA), when two bars moved toward each other in the visual field, occluded one another, and continued on in opposite directions. Two zones of peak MUA, mapping the bars' motion, moved toward each other along the area 17/18 border, which in the ferret maps the vertical meridian of the field of view. This was reflected also in the VSD signal, at both the 17/18 border as well as at the 19/21 border with a short delay. After some 125 ms at the area 19/21 border, the VSD signal increased and became elongated in the direction of motion in front of both of the moving representations. This was directly followed by the phase of the signal reversing and travelling back from the 19/21 border toward the 17/18 border, seemingly without respect for retinotopic boundaries, where it arrived at 150 ms after stimulus onset. At this point the VSD signal in front of the moving bar representations along the 17/18 border also increased and became elongated in the direction of object motion; the signal now being the linear sum of what has been observed in response to single moving bars. When the neuronal populations representing the bars were some 600 MUm apart on the cortex, the dye signal and laminar MUA decreased strongly, with the MUA scaling to that of a single bar during occlusion. Despite a short rebound of the dye signal and MUA, the MUA after the occlusion was significantly depressed. The interactions between the neuronal populations mapping the bars' position, and the neurons in between these populations were, apart from 19/21 to 17/18 interaction, mainly lateral horizontal; first excitatory and inducing firing at the site of future occlusion, then inhibitory just prior to occlusion. After occlusion the neurons that had fired already to the first bar showed delayed and prolonged inhibition in response to the second bar. Thus, the interactions that were particular to the occlusion condition in these experiments were local and inhibitory at short cortical range, and delayed and inhibitory after the occlusion when the bars moved further apart. PMID- 23805081 TI - Novel space alters theta and gamma synchrony across the longitudinal axis of the hippocampus. AB - Hippocampal theta (6-10 Hz) and gamma (25-50 Hz and 65-100 Hz) local field potentials (LFPs) reflect the dynamic synchronization evoked by inputs impinging upon hippocampal neurons. Novel experience is known to engage hippocampal physiology and promote successful encoding. Does novelty synchronize or desynchronize theta and/or gamma frequency inputs across the septotemporal (long) axis of the hippocampus (HPC)? The present study tested the hypothesis that a novel spatial environment would alter theta power and coherence across the long axis. We compared theta and gamma LFP signals at individual (power) and millimeter distant electrode pairs (coherence) within the dentate gyrus (DG) and CA1 region while rats navigated a runway (1) in a familiar environment, (2) with a modified path in the same environment and (3) in a novel space. Locomotion in novel space was related to increases in theta and gamma power at most CA1 and DG sites. The increase in theta and gamma power was concurrent with an increase in theta and gamma coherence across the long axis of CA1; however, there was a significant decrease in theta coherence across the long axis of the DG. These findings illustrate significant shifts in the synchrony of entorhinal, CA3 and/or neuromodulatory afferents conveying novel spatial information to the dendritic fields of CA1 and DG targets across the long axis of the HPC. This shift suggests that the entire theta/gamma-related input to the CA1 network, and likely output, receives and conveys a more coherent message in response to novel sensory experience. Such may contribute to the successful encoding of novel sensory experience. PMID- 23805085 TI - Salsolinol and ethanol-derived excitation of dopamine mesolimbic neurons: new insights. PMID- 23805086 TI - Reduction of pain sensitivity after somatosensory therapy in adults with cerebral palsy. AB - OBJECTIVE: Pain and deficits in somatosensory processing seem to play a relevant role in cerebral palsy (CP). Rehabilitation techniques based on neuroplasticity mechanisms may induce powerful changes in the organization of the primary somatosensory cortex and have been proved to reduce levels of pain and discomfort in neurological pathologies. However, little is known about the efficacy of such interventions for pain sensitivity in CP individuals. METHODS: Adults with CP participated in the study and were randomly assigned to the intervention (n = 17) or the control group (n = 20). The intervention group received a somatosensory therapy including four types of exercises (touch, proprioception, vibration, and stereognosis). All participants were asked to continue their standardized motor therapy during the study period. Several somatosensory (pain and touch thresholds, stereognosis, proprioception, texture recognition) and motor parameters (fine motor skills) were assessed before, immediately after and 3 months after the therapy (follow-up). RESULTS: Participants of the intervention group showed a significant reduction on pain sensitivity after treatment and at follow-up after 3 months, whereas participants in the control group displayed increasing pain sensitivity over time. No improvements were found on touch sensitivity, proprioception, texture recognition, or fine motor skills. CONCLUSION: Data suggest the possibility that somatosensory therapy was effective in eliciting changes in central somatosensory processing. This hypothesis may have implications for future neuromodulatory treatment of pain complaints in children and adults with CP. PMID- 23805087 TI - Extensive neurological recovery from a complete spinal cord injury: a case report and hypothesis on the role of cortical plasticity. AB - Neurological recovery in patients with severe spinal cord injury (SCI) is extremely rare. We have identified a patient with chronic cervical traumatic SCI, who suffered a complete loss of motor and sensory function below the injury for 6 weeks after the injury, but experienced a progressive neurological recovery that continued for 17 years. The extent of the patient's recovery from the severe trauma-induced paralysis is rare and remarkable. A detailed study of this patient using diffusion tensor imaging (DTI), magnetization transfer imaging (MTI), and resting state fMRI (rs-fMRI) revealed structural and functional changes in the central nervous system that may be associated with the neurological recovery. Sixty-two percent cervical cord white matter atrophy was observed. DTI-derived quantities, more sensitive to axons, demonstrated focal changes, while MTI derived quantity, more sensitive to myelin, showed a diffuse change. No significant cortical structural changes were observed, while rs-fMRI revealed increased brain functional connectivity between sensorimotor and visual networks. The study provides comprehensive description of the structural and functional changes in the patient using advanced MR imaging technique. This multimodal MR imaging study also shows the potential of rs-fMRI to measure the extent of cortical plasticity. PMID- 23805089 TI - Misophonia: physiological investigations and case descriptions. AB - Misophonia is a relatively unexplored chronic condition in which a person experiences autonomic arousal (analogous to an involuntary "fight-or-flight" response) to certain innocuous or repetitive sounds such as chewing, pen clicking, and lip smacking. Misophonics report anxiety, panic, and rage when exposed to trigger sounds, compromising their ability to complete everyday tasks and engage in healthy and normal social interactions. Across two experiments, we measured behavioral and physiological characteristics of the condition. Interviews (Experiment 1) with misophonics showed that the most problematic sounds are generally related to other people's behavior (pen clicking, chewing sounds). Misophonics are however not bothered when they produce these "trigger" sounds themselves, and some report mimicry as a coping strategy. Next, (Experiment 2) we tested the hypothesis that misophonics' subjective experiences evoke an anomalous physiological response to certain auditory stimuli. Misophonic individuals showed heightened ratings and skin conductance responses (SCRs) to auditory, but not visual stimuli, relative to a group of typically developed controls, supporting this general viewpoint and indicating that misophonia is a disorder that produces distinct autonomic effects not seen in typically developed individuals. PMID- 23805088 TI - Deep impact: unintended consequences of journal rank. AB - Most researchers acknowledge an intrinsic hierarchy in the scholarly journals ("journal rank") that they submit their work to, and adjust not only their submission but also their reading strategies accordingly. On the other hand, much has been written about the negative effects of institutionalizing journal rank as an impact measure. So far, contributions to the debate concerning the limitations of journal rank as a scientific impact assessment tool have either lacked data, or relied on only a few studies. In this review, we present the most recent and pertinent data on the consequences of our current scholarly communication system with respect to various measures of scientific quality (such as utility/citations, methodological soundness, expert ratings or retractions). These data corroborate previous hypotheses: using journal rank as an assessment tool is bad scientific practice. Moreover, the data lead us to argue that any journal rank (not only the currently-favored Impact Factor) would have this negative impact. Therefore, we suggest that abandoning journals altogether, in favor of a library-based scholarly communication system, will ultimately be necessary. This new system will use modern information technology to vastly improve the filter, sort and discovery functions of the current journal system. PMID- 23805090 TI - Focal dystonia in musicians: linking motor symptoms to somatosensory dysfunction. AB - Musician's dystonia (MD) is a neurological motor disorder characterized by involuntary contractions of those muscles involved in the play of a musical instrument. It is task-specific and initially only impairs the voluntary control of highly practiced musical motor skills. MD can lead to a severe decrement in a musician's ability to perform. While the etiology and the neurological pathomechanism of the disease remain unknown, it is known that MD like others forms of focal dystonia is associated with somatosensory deficits, specifically a decreased precision of tactile and proprioceptive perception. The sensory component of the disease becomes also evident by the patients' use of "sensory tricks" such as touching dystonic muscles to alleviate motor symptoms. The central premise of this paper is that the motor symptoms of MD have a somatosensory origin and are not fully explained as a problem of motor execution. We outline how altered proprioceptive feedback ultimately leads to a loss of voluntary motor control and propose two scenarios that explain why sensory tricks are effective. They are effective, because the sensorimotor system either recruits neural resources normally involved in tactile-proprioceptive (sensory) integration, or utilizes a fully functioning motor efference copy mechanism to align experienced with expected sensory feedback. We argue that an enhanced understanding of how a primary sensory deficit interacts with mechanisms of sensorimotor integration in MD provides helpful insights for the design of more effective behavioral therapies. PMID- 23805091 TI - Mom feels what her child feels: thermal signatures of vicarious autonomic response while watching children in a stressful situation. AB - Maternal attunement with an infant's emotional states is thought to represent a distinctive feature of the human primary bond. It implies the mother's ability of empathizing with her child in order to fulfil the child's needs in an immediate and appropriate manner. Thus, it is particularly involved in stressful situations. By assuming that maternal attunement embodies a direct sharing of physiological responses with the child, we compared the autonomic response of mothers observing their own distressed child with those of other women observing an unknown child involved in an ecological distressful condition (mishap paradigm). The hypothesis was that the adult's response was more attuned with the child's response in the former group than in the latter group. The autonomic response was non-invasively evaluated through the recording of the thermal facial imprints by means of thermal infrared (IR) imaging. Nine mother-child dyads and 9 woman-unknown child dyads were studied. We found marked similarities between the facial temperature dynamics of women and children along the experimental procedure, thus providing evidence for a direct emotional sharing within the adult-child dyad. The evidence for common dynamics in the time course of the temperatures was assessed through correlation analysis and, nevertheless, resulted stronger in the mother-child dyads than in the other women-child dyads. In addition, temporal analysis showed a faster response in mothers than in other women, thus confirming our study hypothesis. Besides confirming the extraordinary capability of IR imaging to preserve ecological context in the study of social or non-verbal interactions, these results suggest that maternity appears to potentiate the emotional attunement with the child. Although based on preliminary results, this study opens new perspectives in the study of the factors modulating vicarious socio-emotional processes. PMID- 23805093 TI - Repeated measurements of cerebral blood flow in the left superior temporal gyrus reveal tonic hyperactivity in patients with auditory verbal hallucinations: a possible trait marker. AB - BACKGROUND: The left superior temporal gyrus (STG) has been suggested to play a key role in auditory verbal hallucinations (AVH) in patients with schizophrenia. METHODS: Eleven medicated subjects with schizophrenia and medication-resistant AVH and 19 healthy controls underwent perfusion magnetic resonance (MR) imaging with arterial spin labeling (ASL). Three additional repeated measurements were conducted in the patients. Patients underwent a treatment with transcranial magnetic stimulation (TMS) between the first 2 measurements. The main outcome measure was the pooled cerebral blood flow (CBF), which consisted of the regional CBF measurement in the left STG and the global CBF measurement in the whole brain. RESULTS: Regional CBF in the left STG in patients was significantly higher compared to controls (p < 0.0001) and to the global CBF in patients (p < 0.004) at baseline. Regional CBF in the left STG remained significantly increased compared to the global CBF in patients across time (p < 0.0007), and it remained increased in patients after TMS compared to the baseline CBF in controls (p < 0.0001). After TMS, PANSS (p = 0.003) and PSYRATS (p = 0.01) scores decreased significantly in patients. CONCLUSIONS: This study demonstrated tonically increased regional CBF in the left STG in patients with schizophrenia and auditory hallucinations despite a decrease in symptoms after TMS. These findings were consistent with what has previously been termed a trait marker of AVH in schizophrenia. PMID- 23805094 TI - Thorough specification of the neurophysiologic processes underlying behavior and of their manifestation in EEG - demonstration with the go/no-go task. AB - In this work we demonstrate the principles of a systematic modeling approach of the neurophysiologic processes underlying a behavioral function. The modeling is based upon a flexible simulation tool, which enables parametric specification of the underlying neurophysiologic characteristics. While the impact of selecting specific parameters is of interest, in this work we focus on the insights, which emerge from rather accepted assumptions regarding neuronal representation. We show that harnessing of even such simple assumptions enables the derivation of significant insights regarding the nature of the neurophysiologic processes underlying behavior. We demonstrate our approach in some detail by modeling the behavioral go/no-go task. We further demonstrate the practical significance of this simplified modeling approach in interpreting experimental data - the manifestation of these processes in the EEG and ERP literature of normal and abnormal (ADHD) function, as well as with comprehensive relevant ERP data analysis. In-fact we show that from the model-based spatiotemporal segregation of the processes, it is possible to derive simple and yet effective and theory-based EEG markers differentiating normal and ADHD subjects. We summarize by claiming that the neurophysiologic processes modeled for the go/no-go task are part of a limited set of neurophysiologic processes which underlie, in a variety of combinations, any behavioral function with measurable operational definition. Such neurophysiologic processes could be sampled directly from EEG on the basis of model-based spatiotemporal segregation. PMID- 23805092 TI - Social modulation of decision-making: a cross-species review. AB - Taking decisions plays a pivotal role in daily life and comprises a complex process of assessing and weighing short-term and long-term costs and benefits of competing actions. Decision-making has been shown to be affected by factors such as sex, age, genotype, and personality. Importantly, also the social environment affects decisions, both via social interactions (e.g., social learning, cooperation and competition) and social stress effects. Although everyone is aware of this social modulating role on daily life decisions, this has thus far only scarcely been investigated in human and animal studies. Furthermore, neuroscientific studies rarely discuss social influence on decision-making from a functional perspective such as done in behavioral ecology studies. Therefore, the first aim of this article is to review the available data of the influence of the social context on decision-making both from a causal and functional perspective, drawing on animal and human studies. Also, there is currently still a gap between decision-making in real life where influences of the social environment are extensive, and decision-making as measured in the laboratory, which is often done without any (deliberate) social influences. However, methods are being developed to bridge this gap. Therefore, the second aim of this review is to discuss these methods and ways in which this gap can be increasingly narrowed. We end this review by formulating future research questions. PMID- 23805095 TI - Sensorimotor incongruence and body perception: an experimental investigation. AB - OBJECTIVES: Several studies have shown that mirrored arm or leg movements can induce altered body sensations. This includes the alleviation of chronic pain using congruent mirror feedback and the induction of abnormal sensation in healthy participants using incongruent mirror feedback. Prior research has identified neuronal and conceptual mechanisms of these phenomena. With the rising application of behavior-based methods for pain relief, a structured investigation of these reported effects seems necessary. METHODS: We investigated a mirror setup that included congruent and incongruent hand and arm movements in 113 healthy participants and assessed the occurrence and intensity of unusual physical experiences such as pain, the sensation of missing or additional limbs, or changes in weight or temperature. A wooden surface instead of a mirror condition served as control. RESULTS: As reported earlier, mirrored movements led to a variety of subjective reactions in both the congruent and incongruent movement condition, with the sensation of possessing a third limb being significantly more intense and frequent in the incongruent mirror condition. Reports of illusory pain were not more frequent during mirrored than during non mirrored movements. CONCLUSION: These results suggest that, while all mirrored hand movements induce abnormal body perceptions, the experience of an extra limb is most pronounced in the incongruent mirror movement condition. The frequent sensation of having a third arm may be related to brain processes designed to integrate input from several senses in a meaningful manner. Painful sensations are not more frequent or intense when a mirror is present. PMID- 23805096 TI - Plasticity in the Visual System is Associated with Prosthesis Use in Phantom Limb Pain. AB - The experience of strong phantom limb pain (PLP) in arm amputees was previously shown to be associated with structural neural plasticity in parts of the cortex that belong to dorsal and ventral visual streams. It has been speculated that this plasticity results from the extensive use of a functional prosthesis which is associated with increased visual feedback to control the artificial hand. To test this hypothesis, we reanalyzed data of cortical volumes of 21 upper limb amputees and tested the association between the amount of use of the hand prosthesis and cortical volume plasticity. On the behavioral level, we found no relation between PLP and the amount of prosthesis use for the whole patient group. However, by subdividing the patient group into patients with strong PLP and those with low to medium PLP, stronger pain was significantly associated with less prosthesis use whereas the group with low PLP did not show such an association. Most plasticity of cortical volume was identified within the dorsal stream. The more the patients that suffered from strong PLP used their prosthesis, the smaller was the volume of their posterior parietal cortex. Our data indicate a relationship between prosthesis use and cortical plasticity of the visual stream. This plasticity might present a brain adaptation process to new movement and coordination patterns needed to guide an artificial hand. PMID- 23805097 TI - Long-Term Effects of Serial Anodal tDCS on Motion Perception in Subjects with Occipital Stroke Measured in the Unaffected Visual Hemifield. AB - Transcranial direct current stimulation (tDCS) is a novel neuromodulatory tool that has seen early transition to clinical trials, although the high variability of these findings necessitates further studies in clinically relevant populations. The majority of evidence into effects of repeated tDCS is based on research in the human motor system, but it is unclear whether the long-term effects of serial tDCS are motor-specific or transferable to other brain areas. This study aimed to examine whether serial anodal tDCS over the visual cortex can exogenously induce long-term neuroplastic changes in the visual cortex. However, when the visual cortex is affected by a cortical lesion, up-regulated endogenous neuroplastic adaptation processes may alter the susceptibility to tDCS. To this end, motion perception was investigated in the unaffected hemifield of subjects with unilateral visual cortex lesions. Twelve subjects with occipital ischemic lesions participated in a within-subject, sham-controlled, double-blind study. MRI-registered sham or anodal tDCS (1.5 mA, 20 min) was applied on five consecutive days over the visual cortex. Motion perception was tested before and after stimulation sessions and at 14- and 28-day follow-up. After a 16-day interval an identical study block with the other stimulation condition (anodal or sham tDCS) followed. Serial anodal tDCS over the visual cortex resulted in an improvement in motion perception, a function attributed to MT/V5. This effect was still measurable at 14- and 28-day follow-up measurements. Thus, this may represent evidence for long-term tDCS-induced plasticity and has implications for the design of studies examining the time course of tDCS effects in both the visual and motor systems. PMID- 23805098 TI - The Quest for EEG Power Band Correlation with ICA Derived fMRI Resting State Networks. AB - The neuronal underpinnings of blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) resting state networks (RSNs) are still unclear. To investigate the underlying mechanisms, specifically the relation to the electrophysiological signal, we used simultaneous recordings of electroencephalography (EEG) and fMRI during eyes open resting state (RS). Earlier studies using the EEG signal as independent variable show inconclusive results, possibly due to variability in the temporal correlations between RSNs and power in the low EEG frequency bands, as recently reported (Goncalves et al., 2006, 2008; Meyer et al., 2013). In this study we use three different methods including one that uses RSN timelines as independent variable to explore the temporal relationship of RSNs and EEG frequency power in eyes open RS in detail. The results of these three distinct analysis approaches support the hypothesis that the correlation between low EEG frequency power and BOLD RSNs is instable over time, at least in eyes open RS. PMID- 23805099 TI - A musculoskeletal model of human locomotion driven by a low dimensional set of impulsive excitation primitives. AB - Human locomotion has been described as being generated by an impulsive (burst like) excitation of groups of musculotendon units, with timing dependent on the biomechanical goal of the task. Despite this view being supported by many experimental observations on specific locomotion tasks, it is still unknown if the same impulsive controller (i.e., a low-dimensional set of time-delayed excitastion primitives) can be used as input drive for large musculoskeletal models across different human locomotion tasks. For this purpose, we extracted, with non-negative matrix factorization, five non-negative factors from a large sample of muscle electromyograms in two healthy subjects during four motor tasks. These included walking, running, sidestepping, and crossover cutting maneuvers. The extracted non-negative factors were then averaged and parameterized to obtain task-generic Gaussian-shaped impulsive excitation curves or primitives. These were used to drive a subject-specific musculoskeletal model of the human lower extremity. Results showed that the same set of five impulsive excitation primitives could be used to predict the dynamics of 34 musculotendon units and the resulting hip, knee and ankle joint moments (i.e., NRMSE = 0.18 +/- 0.08, and R (2) = 0.73 +/- 0.22 across all tasks and subjects) without substantial loss of accuracy with respect to using experimental electromyograms (i.e., NRMSE = 0.16 +/- 0.07, and R (2) = 0.78 +/- 0.18 across all tasks and subjects). Results support the hypothesis that biomechanically different motor tasks might share similar neuromuscular control strategies. This might have implications in neurorehabilitation technologies such as human-machine interfaces for the torque driven, proportional control of powered prostheses and orthoses. In this, device control commands (i.e., predicted joint torque) could be derived without direct experimental data but relying on simple parameterized Gaussian-shaped curves, thus decreasing the input drive complexity and the number of needed sensors. PMID- 23805100 TI - Manganese neurotoxicity: new perspectives from behavioral, neuroimaging, and neuropathological studies in humans and non-human primates. AB - Manganese (Mn) is an essential metal and has important physiological functions for human health. However, exposure to excess levels of Mn in occupational settings or from environmental sources has been associated with a neurological syndrome comprising cognitive deficits, neuropsychological abnormalities and parkinsonism. Historically, studies on the effects of Mn in humans and experimental animals have been concerned with effects on the basal ganglia and the dopaminergic system as it relates to movement abnormalities. However, emerging studies are beginning to provide significant evidence of Mn effects on cortical structures and cognitive function at lower levels than previously recognized. This review advances new knowledge of putative mechanisms by which exposure to excess levels of Mn alters neurobiological systems and produces neurological deficits not only in the basal ganglia but also in the cerebral cortex. The emerging evidence suggests that working memory is significantly affected by chronic Mn exposure and this may be mediated by alterations in brain structures associated with the working memory network including the caudate nucleus in the striatum, frontal cortex and parietal cortex. Dysregulation of the dopaminergic system may play an important role in both the movement abnormalities as well as the neuropsychiatric and cognitive function deficits that have been described in humans and non-human primates exposed to Mn. PMID- 23805102 TI - Polyphenols from the mangosteen (Garcinia mangostana) fruit for breast and prostate cancer. AB - The mangosteen (Garcinia mangostana) is a tropical fruit native to Southeast Asia and has long been reported to contain multiple health promoting properties. This fruit is an abundant source of xanthones, a class of polyphenolic compounds with a distinctive tricyclic aromatic ring system and is largely responsible for its biological activities including anti-cancer activity. Herein we describe the anti cancer activity and mechanisms of mangosteen polyphenolic xanthones including alpha-Mangostin against breast cancer and prostate cancer. So far, extracts and individual xanthones have been found to induce apoptosis and inhibit proliferation on cancer cells in vitro and in vivo. Based on the reported findings there is clear evidence that these polyphenols target multiple signaling pathways involved in cell cycle modulation and apoptosis. Further work is required to understand its potential for health promotion and potential drug discovery for prostate and breast cancer chemoprevention. PMID- 23805103 TI - Repurposing phosphodiesterase-5 inhibitors as chemoadjuvants. PMID- 23805101 TI - Is it time for a new paradigm for systemic cancer treatment? Lessons from a century of cancer chemotherapy. AB - U.S. SEER (Surveillance Epidemiology and End Results) data for age-adjusted mortality rates for all cancers combined for all races show only a modest overall 13% decline over the past 35 years. Moreover, the greatest contributor to cancer mortality is treatment-resistant metastatic disease. The accepted therapeutic paradigm for the past half-century for the treatment of advanced cancers has involved the use of systemic chemotherapy drugs cytotoxic for cycling cells (both normal and malignant) during DNA synthesis and/or mitosis. The failure of this therapeutic modality to achieve high-level, consistent rates of disease-free survival for some of the most common cancers, including tumors of the lung, colon breast, brain, melanoma, and others is the focus of this paper. A retrospective assessment of critical milestones in cancer chemotherapy indicates that most successful therapeutic regimens use cytotoxic cell cycle inhibitors in combined, maximum tolerated, dose-dense acute treatment regimens originally developed to treat acute lymphoblastic leukemia and some lymphomas. Early clinical successes in this area led to their wholesale application to the treatment of solid tumor malignancies that, unfortunately, has not produced consistent, long-term high cure rates for many common cancers. Important differences in therapeutic sensitivity of leukemias/lymphomas versus solid tumors can be explained by key biological differences that define the treatment-resistant solid tumor phenotype. A review of these clinical outcome data in the context of recent developments in our understanding of drug resistance mechanisms characteristic of solid tumors suggests the need for a new paradigm for the treatment of chemotherapy-resistant cancers. In contrast to reductionist approaches, the systemic approach targets both microenvironmental and systemic factors that drive and sustain tumor progression. These systemic factors include dysregulated inflammatory and oxidation pathways shown to be directly implicated in the development and maintenance of the cancer phenotype. The paradigm stresses the importance of a combined preventive/therapeutic approach involving adjuvant chemotherapies that incorporate anti-inflammatory and anti-oxidant therapeutics. PMID- 23805104 TI - Deficiency of Nox2 prevents angiotensin II-induced inward remodeling in cerebral arterioles. AB - Angiotensin II is an important determinant of inward remodeling in cerebral arterioles. Many of the vascular effects of angiotensin II are mediated by reactive oxygen species (ROS) generated from homologs of NADPH oxidase with Nox2 predominating in small arteries and arterioles. Therefore, we tested the hypothesis that superoxide generated by Nox2 plays a role in angiotensin II induced cerebral arteriolar remodeling. We examined Nox2-deficient and wild-type (WT) mice in which a pressor or a non-pressor dose of angiotensin II (1000 or 200 ng/kg/day) or saline was infused for 4 weeks via osmotic minipumps. Systolic arterial pressure was measured by a tail-cuff method. Pressure and diameter of cerebral arterioles were measured through an open cranial window in anesthetized mice. Cross-sectional area (by histology) and superoxide level (by hydroethidine staining) of cerebral arterioles were determined ex vivo. The pressor, but not the non-pressor, dose of angiotensin II significantly increased systolic arterial pressure in both WT and Nox2-deficient mice. Both doses of angiotensin II increased superoxide levels and significantly reduced external diameter in maximally dilated cerebral arterioles in WT mice. Increased superoxide and inward remodeling were prevented in Nox2-deficient mice. Moreover, only the pressor dose of AngII increased cross-sectional area of arteriolar wall in WT mice and was prevented in Nox2-deficient mice. In conclusion, superoxide derived from Nox2 containing NADPH oxidase plays an important role in angiotensin II-mediated inward remodeling in cerebral arterioles. This effect appears to be independent of pressure and different from that of hypertrophy. PMID- 23805105 TI - Abnormal Ca(2+) homeostasis, atrial arrhythmogenesis, and sinus node dysfunction in murine hearts modeling RyR2 modification. AB - Ryanodine receptor type 2 (RyR2) mutations are implicated in catecholaminergic polymorphic ventricular tachycardia (CPVT) thought to result from altered myocyte Ca(2+) homeostasis reflecting inappropriate "leakiness" of RyR2-Ca(2+) release channels arising from increases in their basal activity, alterations in their phosphorylation, or defective interactions with other molecules or ions. The latter include calstabin, calsequestrin-2, Mg(2+), and extraluminal or intraluminal Ca(2+). Recent clinical studies additionally associate RyR2 abnormalities with atrial arrhythmias including atrial tachycardia (AT), fibrillation (AF), and standstill, and sinus node dysfunction (SND). Some RyR2 mutations associated with CPVT in mouse models also show such arrhythmias that similarly correlate with altered Ca(2+) homeostasis. Some examples show evidence for increased Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) phosphorylation of RyR2. A homozygotic RyR2-P2328S variant demonstrates potential arrhythmic substrate resulting from reduced conduction velocity (CV) in addition to delayed afterdepolarizations (DADs) and ectopic action potential (AP) firing. Finally, one model with an increased RyR2 activity in the sino-atrial node (SAN) shows decreased automaticity in the presence of Ca(2+)-dependent decreases in I Ca, L and diastolic sarcoplasmic reticular (SR) Ca(2+) depletion. PMID- 23805106 TI - Characterization of N-terminally mutated cardiac Na(+) channels associated with long QT syndrome 3 and Brugada syndrome. AB - Mutations in SCN5A, the gene encoding the cardiac voltage-gated Na(+) channel hNav1.5, can result in life-threatening arrhythmias including long QT syndrome 3 (LQT3) and Brugada syndrome (BrS). Numerous mutant hNav1.5 channels have been characterized upon heterologous expression and patch-clamp recordings during the last decade. These studies revealed functionally important regions in hNav1.5 and provided insight into gain-of-function or loss-of-function channel defects underlying LQT3 or BrS, respectively. The N-terminal region of hNav1.5, however, has not yet been investigated in detail, although several mutations were reported in the literature. In the present study we investigated three mutant channels, previously associated with LQT3 (G9V, R18W, V125L), and six mutant channels, associated with BrS (R18Q, R27H, G35S, V95I, R104Q, K126E). We applied both the two-microelectrode voltage clamp technique, using cRNA-injected Xenopus oocytes, and the whole-cell patch clamp technique using transfected HEK293 cells. Surprisingly, four out of the nine mutations did not affect channel properties. Gain-of-function, as typically observed in LQT3 mutant channels, was observed only in R18W and V125L, whereas loss-of-function, frequently found in BrS mutants, was found only in R27H, R104Q, and K126E. Our results indicate that the hNav1.5 N-terminus plays an important role for channel kinetics and stability. At the same time, we suggest that additional mechanisms, as e.g., disturbed interactions of the Na(+) channel N-terminus with other proteins, contribute to severe clinical phenotypes. PMID- 23805107 TI - Executive functioning in schizophrenia. AB - The executive function (EF) is a set of abilities, which allows us to invoke voluntary control of our behavioral responses. These functions enable human beings to develop and carry out plans, make up analogies, obey social rules, solve problems, adapt to unexpected circumstances, do many tasks simultaneously, and locate episodes in time and place. EF includes divided attention and sustained attention, working memory (WM), set-shifting, flexibility, planning, and the regulation of goal directed behavior and can be defined as a brain function underlying the human faculty to act or think not only in reaction to external events but also in relation with internal goals and states. EF is mostly associated with dorsolateral prefrontal cortex (PFC). Besides EF, PFC is involved in self-regulation of behavior, i.e., the ability to regulate behavior according to internal goals and constraints, particularly in less structured situations. Self-regulation of behavior is subtended by ventral medial/orbital PFC. Impairment of EF is one of the most commonly observed deficits in schizophrenia through the various disease stages. Impairment in tasks measuring conceptualization, planning, cognitive flexibility, verbal fluency, ability to solve complex problems, and WM occur in schizophrenia. Disorders detected by executive tests are consistent with evidence from functional neuroimaging, which have shown PFC dysfunction in patients while performing these kinds of tasks. Schizophrenics also exhibit deficit in odor identifying, decision-making, and self-regulation of behavior suggesting dysfunction of the orbital PFC. However, impairment in executive tests is explained by dysfunction of prefronto-striato thalamic, prefronto-parietal, and prefronto-temporal neural networks mainly. Disorders in EFs may be considered central facts with respect to schizophrenia and it has been suggested that negative symptoms may be explained by that executive dysfunction. PMID- 23805108 TI - PTSD and DNA Methylation in Select Immune Function Gene Promoter Regions: A Repeated Measures Case-Control Study of U.S. Military Service Members. AB - BACKGROUND: The underlying molecular mechanisms of PTSD are largely unknown. Distinct expression signatures for PTSD have been found, in particular for immune activation transcripts. DNA methylation may be significant in the pathophysiology of PTSD, since the process is intrinsically linked to gene expression. We evaluated temporal changes in DNA methylation in select promoter regions of immune system-related genes in U.S. military service members with a PTSD diagnosis, pre- and post-diagnosis, and in controls. METHODS: Cases (n = 75) had a post-deployment diagnosis of PTSD in their medical record. Controls (n = 75) were randomly selected service members with no PTSD diagnosis. DNA was extracted from pre- and post-deployment sera. DNA methylation (%5-mC) was quantified at specific CpG sites in promoter regions of insulin-like growth factor 2 (IGF2), long non-coding RNA transcript H19, interleukin-8 (IL8), IL16, and IL18 via pyrosequencing. We used multivariate analysis of variance and generalized linear models to calculate adjusted means (adjusted for age, gender, and race) to make temporal comparisons of %5-mC for cases (pre- to post-deployment) versus controls (pre- to post-deployment). RESULTS: There were significant differences in the change of %5-mC pre- to post-deployment between cases and controls for H19 (cases: +0.57%, controls: -1.97%; p = 0.04) and IL18 (cases: +1.39%, controls: 3.83%; p = 0.01). For H19 the difference was driven by a significant reduction in %5-mC among controls; for IL18 the difference was driven by both a reduction in %5-mC among controls and an increase in %5-mC among cases. Stratified analyses revealed more pronounced differences in the adjusted means of pre-post H19 and IL18 methylation differences for cases versus controls among older service members, males, service members of white race, and those with shorter deployments (6-12 months). CONCLUSION: In the study of deployed personnel, those who did not develop PTSD had reduced %5-mC levels of H19 and IL18 after deployment, while those who did develop PTSD had increased levels of IL18. Additionally, pre deployment the people who later became cases had lower levels of IL18 %5-mC compared with controls. These findings are preliminary and should be investigated in larger studies. PMID- 23805110 TI - Audio-visual onset differences are used to determine syllable identity for ambiguous audio-visual stimulus pairs. AB - Content and temporal cues have been shown to interact during audio-visual (AV) speech identification. Typically, the most reliable unimodal cue is used more strongly to identify specific speech features; however, visual cues are only used if the AV stimuli are presented within a certain temporal window of integration (TWI). This suggests that temporal cues denote whether unimodal stimuli belong together, that is, whether they should be integrated. It is not known whether temporal cues also provide information about the identity of a syllable. Since spoken syllables have naturally varying AV onset asynchronies, we hypothesize that for suboptimal AV cues presented within the TWI, information about the natural AV onset differences can aid in speech identification. To test this, we presented low-intensity auditory syllables concurrently with visual speech signals, and varied the stimulus onset asynchronies (SOA) of the AV pair, while participants were instructed to identify the auditory syllables. We revealed that specific speech features (e.g., voicing) were identified by relying primarily on one modality (e.g., auditory). Additionally, we showed a wide window in which visual information influenced auditory perception, that seemed even wider for congruent stimulus pairs. Finally, we found a specific response pattern across the SOA range for syllables that were not reliably identified by the unimodal cues, which we explained as the result of the use of natural onset differences between AV speech signals. This indicates that temporal cues not only provide information about the temporal integration of AV stimuli, but additionally convey information about the identity of AV pairs. These results provide a detailed behavioral basis for further neuro-imaging and stimulation studies to unravel the neurofunctional mechanisms of the audio-visual-temporal interplay within speech perception. PMID- 23805112 TI - "Seeing" and "feeling" architecture: how bodily self-consciousness alters architectonic experience and affects the perception of interiors. AB - Over the centuries architectural theory evolved several notions of embodiment, proposing in the nineteenth and twentieth century that architectonic experience is related to physiological responses of the observer. Recent advances in the cognitive neuroscience of embodiment (or bodily self-consciousness) enable empirical studies of architectonic embodiment. Here, we investigated how architecture modulates bodily self-consciousness by adapting a video-based virtual reality (VR) setup previously used to investigate visuo-tactile mechanisms of bodily self-consciousness. While standing in two different interiors, participants were filmed from behind and watched their own virtual body online on a head-mounted display (HMD). Visuo-tactile strokes were applied in synchronous or asynchronous mode to the participants and their virtual body. Two interiors were simulated in the laboratory by placing the sidewalls either far or near from the participants, generating a large and narrow room. We tested if bodily self-consciousness was differently modulated when participants were exposed to both rooms and whether these changes depend on visuo-tactile stimulation. We measured illusory touch, self-identification, and performed length estimations. Our data show that synchronous stroking of the physical and the virtual body induces illusory touch and self-identification with the virtual body, independent of room-size. Moreover, in the narrow room we observed weak feelings of illusory touch with the sidewalls and of approaching walls. These subjective changes were complemented by a stroking-dependent modulation of length estimation only in the narrow room with participants judging the room-size more accurately during conditions of illusory self-identification. We discuss our findings and previous notions of architectonic embodiment in the context of the cognitive neuroscience of bodily self-consciousness and propose an empirical framework grounded in architecture, cognitive neuroscience, and VR. PMID- 23805111 TI - Social cognition in a case of amnesia with neurodevelopmental mechanisms. AB - Episodic-autobiographical memory (EAM) is considered to emerge gradually in concert with the development of other cognitive abilities (such as executive functions, personal semantic knowledge, emotional knowledge, theory of mind (ToM) functions, language, and working memory). On the brain level its emergence is accompanied by structural and functional reorganization of different components of the so-called EAM network. This network includes the hippocampal formation, which is viewed as being vital for the acquisition of memories of personal events for long-term storage. Developmental studies have emphasized socio-cultural linguistic mechanisms that may be unique to the development of EAM. Furthermore it was hypothesized that one of the main functions of EAM is the social one. In the research field, the link between EAM and social cognition remains however debated. Herein we aim to bring new insights into the relation between EAM and social information processing (including social cognition) by describing a young adult patient with amnesia with neurodevelopmental mechanisms due to perinatal complications accompanied by hypoxia. The patient was investigated medically, psychiatrically, and with neuropsychological and neuroimaging methods. Structural high resolution magnetic resonance imaging revealed significant bilateral hippocampal atrophy as well as indices for degeneration in the amygdalae, basal ganglia, and thalamus, when a less conservative threshold was applied. In addition to extensive memory investigations and testing other (non-social) cognitive functions, we employed a broad range of tests that assessed social information processing (social perception, social cognition, social regulation). Our results point to both preserved (empathy, core ToM functions, visual affect selection, and discrimination, affective prosody discrimination) and impaired domains of social information processing (incongruent affective prosody processing, complex social judgments). They support proposals for a role of the hippocampal formation in processing more complex social information that likely requires multimodal relational handling. PMID- 23805113 TI - Handwriting measures as reflectors of executive functions among adults with Developmental Coordination Disorders (DCD). AB - Planning ahead and organizational abilities in time and space are ingredients of high-level cognitive functions labeled as 'Executive Functions' (EF) required for daily activities such as writing or home management. EF deficits are considered a possible underlying brain mechanism involved in Developmental Coordination Disorders (DCD). THE AIM: of the study was to compare the handwriting process measures and the planning and organizational abilities in space and time of students with DCD with those of matched controls and to find whether handwriting measures can predict daily planning and organizational abilities among students with DCD. METHOD: 30 students diagnosed with DCD, between the ages of 24-41, and 30 age- and gender-matched controls participated in the study. They filled out the Handwriting Proficiency Screening Questionnaire (HPSQ) and the Adult Developmental Co-ordination Disorders Checklist (ADC). Furthermore, they copied a paragraph on a digitizer that is part of a computerized system Computerised Penmanship Evaluation Toll (ComPET). RESULTS: Significant group differences were found for the HPSQ subscales scores as well as for the temporal and spatial measures of the paragraph copy task. Significant group differences were also found for the planning and organizational abilities in space and time as reflected through the ADC subscales. Significant medium correlations were found in both groups between the mean HPSQ time subscale and the ADC-B subscale mean score (r = 0.50/0.58, p < 0.05). Series of regression analyses indicated that two handwriting performance measures (mean HPSQ time subscale and mean stroke duration) predicted 19% of planning and organizational abilities as reflected through daily functions (ADC-B) [F (3, 54) = 38.37, beta = 0.40, p < 0.0001]. CONCLUSION: The results support previous evidence about EF deficits as an underlying brain mechanism involved in motor coordination disorders, their significance as related to theoretical models of handwriting and daily function among DCD will be examined. PMID- 23805109 TI - Interindividual Variability in Stress Susceptibility: A Role for Epigenetic Mechanisms in PTSD. AB - Post-traumatic stress disorder (PTSD) is a psychiatric condition characterized by intrusive and persistent memories of a psychologically traumatic event that leads to significant functional and social impairment in affected individuals. The molecular bases underlying persistent outcomes of a transient traumatic event have remained elusive for many years, but recent studies in rodents have implicated epigenetic modifications of chromatin structure and DNA methylation as fundamental mechanisms for the induction and stabilization of fear memory. In addition to mediating adaptations to traumatic events that ultimately cause PTSD, epigenetic mechanisms are also involved in establishing individual differences in PTSD risk and resilience by mediating long-lasting effects of genes and early environment on adult function and behavior. In this review, we discuss the current evidence for epigenetic regulation of PTSD in human studies and in animal models and comment on ways in which these models can be expanded. In addition, we identify key outstanding questions in the study of epigenetic mechanisms of PTSD in the context of rapidly evolving technologies that are constantly updating and adjusting our understanding of epigenetic modifications and their functional roles. Finally, we discuss the potential application of epigenetic approaches in identifying markers of risk and resilience that can be utilized to promote early intervention and develop therapeutic strategies to combat PTSD after symptom onset. PMID- 23805115 TI - Feeling backwards? How temporal order in speech affects the time course of vocal emotion recognition. AB - Recent studies suggest that the time course for recognizing vocal expressions of basic emotion in speech varies significantly by emotion type, implying that listeners uncover acoustic evidence about emotions at different rates in speech (e.g., fear is recognized most quickly whereas happiness and disgust are recognized relatively slowly; Pell and Kotz, 2011). To investigate whether vocal emotion recognition is largely dictated by the amount of time listeners are exposed to speech or the position of critical emotional cues in the utterance, 40 English participants judged the meaning of emotionally-inflected pseudo utterances presented in a gating paradigm, where utterances were gated as a function of their syllable structure in segments of increasing duration from the end of the utterance (i.e., gated syllable-by-syllable from the offset rather than the onset of the stimulus). Accuracy for detecting six target emotions in each gate condition and the mean identification point for each emotion in milliseconds were analyzed and compared to results from Pell and Kotz (2011). We again found significant emotion-specific differences in the time needed to accurately recognize emotions from speech prosody, and new evidence that utterance-final syllables tended to facilitate listeners' accuracy in many conditions when compared to utterance-initial syllables. The time needed to recognize fear, anger, sadness, and neutral from speech cues was not influenced by how utterances were gated, although happiness and disgust were recognized significantly faster when listeners heard the end of utterances first. Our data provide new clues about the relative time course for recognizing vocally expressed emotions within the 400-1200 ms time window, while highlighting that emotion recognition from prosody can be shaped by the temporal properties of speech. PMID- 23805114 TI - Ongoing egocentric spatial processing during learning of non-spatial information results in temporal-parietal activity during retrieval. AB - Deficits in amnesic patients suggest that spatial cognition and episodic memory are intimately related. Among the different types of spatial processing, the allocentric, relying on the hippocampal formation, and the egocentric-updated, relying on parieto-temporal connections have both been considered to functionally underlie episodic memory encoding and retrieval. We explore the cerebral correlates underlying the episodic retrieval of words previously learnt outside the magnet while performing different spatial processes, allocentric and egocentric-updated. Subsequently and during fMRI, participants performed an episodic word recognition task. Data processing revealed that the correct recognition of words learnt in egocentric-updated condition enhanced activity of the medial and lateral parietal, as well as temporal cortices. No additional regions were activated in the present study by retrieving words learnt in allocentric condition. This study sheds new light on the functional links between episodic memory and spatial processing: The temporo-parietal network is confirmed to be crucial in episodic memory in healthy participants and could be linked to the egocentric-updated process. PMID- 23805116 TI - Knowing too little or too much: the effects of familiarity with a co-performer's part on interpersonal coordination in musical ensembles. AB - Expert ensemble musicians produce exquisitely coordinated sounds, but rehearsal is typically required to do so. Ensemble coordination may thus be influenced by the degree to which individuals are familiar with each other's parts. Such familiarity may affect the ability to predict and synchronize with co-performers' actions. Internal models related to action simulation and anticipatory musical imagery may be affected by knowledge of (1) the musical structure of a co performer's part (e.g., in terms of its rhythm and phrase structure) and/or (2) the co-performer's idiosyncratic playing style (e.g., expressive micro-timing variations). The current study investigated the effects of familiarity on interpersonal coordination in piano duos. Skilled pianists were required to play several duets with different partners. One condition included duets for which co performers had previously practiced both parts, while another condition included duets for which each performer had practiced only their own part. Each piece was recorded six times without joint rehearsal or visual contact to examine the effects of increasing familiarity. Interpersonal coordination was quantified by measuring asynchronies between pianists' keystroke timing and the correlation of their body (head and torso) movements, which were recorded with a motion capture system. The results suggest that familiarity with a co-performer's part, in the absence of familiarity with their playing style, engenders predictions about micro-timing variations that are based instead upon one's own playing style, leading to a mismatch between predictions and actual events at short timescales. Predictions at longer timescales-that is, those related to musical measures and phrases, and reflected in head movements and body sway-are, however, facilitated by familiarity with the structure of a co-performer's part. These findings point to a dissociation between interpersonal coordination at the level of keystrokes and body movements. PMID- 23805117 TI - The importance of being relevant: modulation of magnitude representations. AB - The current study aims to answer two main questions. First, is there a difference between the representations of the numerical and the physical properties of visually presented numbers? Second, can the relevancy of the dimension change its representation? In a numerical Stroop task, participants were asked to indicate either the physically or the numerically larger value of two digits. The ratio between the physical sizes and the numerical values changed orthogonally from 0.1 (the largest difference) to 0.8. Reaction times (RT) were plotted as a function of both physical and numerical ratios. Trend analysis revealed that while the numerical dimension followed Weber's law regardless of task demands, the physical ratio deviated from linearity. Our results suggest that discrete and continuous magnitudes are represented by different yet interactive systems rather than by a shared representation. PMID- 23805118 TI - Is data cleaning and the testing of assumptions relevant in the 21st century? PMID- 23805119 TI - Speech vs. singing: infants choose happier sounds. AB - Infants prefer speech to non-vocal sounds and to non-human vocalizations, and they prefer happy-sounding speech to neutral speech. They also exhibit an interest in singing, but there is little knowledge of their relative interest in speech and singing. The present study explored infants' attention to unfamiliar audio samples of speech and singing. In Experiment 1, infants 4-13 months of age were exposed to happy-sounding infant-directed speech vs. hummed lullabies by the same woman. They listened significantly longer to the speech, which had considerably greater acoustic variability and expressiveness, than to the lullabies. In Experiment 2, infants of comparable age who heard the lyrics of a Turkish children's song spoken vs. sung in a joyful/happy manner did not exhibit differential listening. Infants in Experiment 3 heard the happily sung lyrics of the Turkish children's song vs. a version that was spoken in an adult-directed or affectively neutral manner. They listened significantly longer to the sung version. Overall, happy voice quality rather than vocal mode (speech or singing) was the principal contributor to infant attention, regardless of age. PMID- 23805120 TI - General Commentary: Rethinking the role of animals in human well-being. PMID- 23805121 TI - Magnitude processing in non-symbolic stimuli. AB - Dot arrays are often used to study basic numerical skills across cultures, species and development. Researchers investigate the ability of subjects to discriminate between dot arrays, as a function of the ratio or distance between their numerosities. Such studies have contributed significantly to the number sense theory (i.e., that humans are born with the ability to process numerosities, and share this ability with various species)-possibly the most influential theory in numerical cognition literature today. However, a dot array contains, in addition to numerosity, continuous properties such as the total surface area of the dots, their density, etc. These properties are highly correlated with numerosity and therefore might influence participants' performance. Different ways in which different studies choose to deal with this confound sometimes lead to contradicting results, and in our opinion, do not completely eliminate the confound. In this work, we review these studies and suggest several possible reasons for the contradictions in the literature. We also suggest that studying continuous properties, instead of just trying to control them, may contribute to unraveling the building blocks of numerical abilities. PMID- 23805122 TI - Face puzzle-two new video-based tasks for measuring explicit and implicit aspects of facial emotion recognition. AB - Recognizing others' emotional states is crucial for effective social interaction. While most facial emotion recognition tasks use explicit prompts that trigger consciously controlled processing, emotional faces are almost exclusively processed implicitly in real life. Recent attempts in social cognition suggest a dual process perspective, whereby explicit and implicit processes largely operate independently. However, due to differences in methodology the direct comparison of implicit and explicit social cognition has remained a challenge. Here, we introduce a new tool to comparably measure implicit and explicit processing aspects comprising basic and complex emotions in facial expressions. We developed two video-based tasks with similar answer formats to assess performance in respective facial emotion recognition processes: Face Puzzle, implicit and explicit. To assess the tasks' sensitivity to atypical social cognition and to infer interrelationship patterns between explicit and implicit processes in typical and atypical development, we included healthy adults (NT, n = 24) and adults with autism spectrum disorder (ASD, n = 24). Item analyses yielded good reliability of the new tasks. Group-specific results indicated sensitivity to subtle social impairments in high-functioning ASD. Correlation analyses with established implicit and explicit socio-cognitive measures were further in favor of the tasks' external validity. Between group comparisons provide first hints of differential relations between implicit and explicit aspects of facial emotion recognition processes in healthy compared to ASD participants. In addition, an increased magnitude of between group differences in the implicit task was found for a speed-accuracy composite measure. The new Face Puzzle tool thus provides two new tasks to separately assess explicit and implicit social functioning, for instance, to measure subtle impairments as well as potential improvements due to social cognitive interventions. PMID- 23805123 TI - Dancing in the dark: no role for consciousness in action control. PMID- 23805124 TI - Limitations of Current GABA Agonists in Neonatal Seizures: Toward GABA Modulation Via the Targeting of Neuronal Cl(-) Transport. AB - Neonatal intensive care has advanced rapidly in the last 40 years, with dramatic decreases in mortality and morbidity; however, for neonatal seizures, neither therapies nor outcomes have changed significantly. Basic and clinical studies indicate that seizures in neonates have long-term neurodevelopmental and psychiatric consequences, highlighting the need for novel pharmacotherapeutics. First-line treatments targeting GABAA receptors, like barbiturates and benzodiazepines, are limited in their efficacy and carry significant risks to the developing brain. Here, we review the use of current GABA agonist therapies for neonatal seizures and suggest other treatment strategies given recent developments in the understanding of disease pathogenesis. One promising avenue is the indirect manipulation of the GABAergic system, via the modulation of neuronal Cl(-) gradients, by targeting the cation-Cl(-) cotransporters (NKCC1 and KCC2) or their regulatory signaling molecules. This strategy might yield a novel class of more efficacious anti-epileptics with fewer side effects by specifically addressing disease pathophysiology. Moreover, this strategy may have ramifications for other adult seizure syndromes in which GABA receptor-mediated depolarizations play a pathogenic role, such as temporal lobe epilepsy. PMID- 23805126 TI - "Sightblind": perceptual deficits in the "intact" visual field. AB - Unilateral visual cortex lesions caused by stroke or trauma lead to blindness in contralateral visual field - a condition called homonymous hemianopia. Although the visual field area processed by the uninjured hemisphere is thought to be "intact," it also exhibits marked perceptual deficits in contrast sensitivity, processing speed, and contour integration. Such patients are "sightblind" - their blindness reaches far beyond the primary scotoma. Studies showing perceptual deficits in patients' intact fields are reviewed and implications of these findings are discussed. It is concluded that consequences of partial blindness are greater than previously thought, since perceptual deficits in the "intact" field likely contribute to subjective vision loss in patients with visual field defect. This has important implications for vision diagnosis and rehabilitation. PMID- 23805127 TI - Implication of Human UGT2B7, 2B15, and 2B17 in 19-Norandrosterone Metabolism. AB - Nandrolone (19-nortestosterone) is an anabolic androgenic steroid commonly abused for doping purposes. Nandrolone is mainly metabolized in the liver into 19 norandrosterone prior to glucuronidation and excretion through urine over an extended period of time. Several UGTs (i.e., UGT2B7, UGT2B15, and UGT2B17) are thought to be the major enzymes responsible for conjugation of androgens in human. An in vitro study using recombinant enzymes expressed in insect cells showed that UGT1A4 and UGT2B7 are the two main enzymes responsible of 19 norandrosterone glucuronidation. However, the identity of the enzyme involved in nandrolone metabolism in vivo together with their relative contribution and regulation remain unknown. Inhibition assays using human liver microsomes (HLM) incubated with 19-norandrosterone and selective inhibitors confirmed that UGT2B7 and UGT2B15 are involved in 19-norandrosterone glucuronidation, since the presence of the specific UGT2B7 and UGT2B15 inhibitors gemfibrozil and valproic acid inhibited the 19-norandrosterone glucuronidation by 35 and 45%, respectively. HLM were genotyped for UGT2B15 D85Y, UGT2B7 H268Y, and the UGT2B17 deletion polymorphism. The glucuronidation activity on 19-norandrosterone was significantly higher in UGT2B15 DD than in the other UGT2B15 genotypes (p < 0.05). Moreover, human liver cancer HepG2 cells were exposed to androgens to determine if the transcriptional activity of the genes of interest was affected. Only UGT2B7 mRNA expression was significantly increased (1.8-folds) after incubation with nandrolone decanoate. These results show that the UGT2B7 and UGT2B15 are involved in 19-norandrosterone glucuronidation and that the UGT2B15 polymorphism (D85Y) is the only UGT genetic variation that influences the glucuronidation activity. This could partly explain the inter-individual variation in 19-norandrosterone excretion. PMID- 23805125 TI - Amyloid-beta Peptides and Tau Protein as Biomarkers in Cerebrospinal and Interstitial Fluid Following Traumatic Brain Injury: A Review of Experimental and Clinical Studies. AB - Traumatic brain injury (TBI) survivors frequently suffer from life-long deficits in cognitive functions and a reduced quality of life. Axonal injury, observed in many severe TBI patients, results in accumulation of amyloid precursor protein (APP). Post-injury enzymatic cleavage of APP can generate amyloid-beta (Abeta) peptides, a hallmark finding in Alzheimer's disease (AD). At autopsy, brains of AD and a subset of TBI victims display some similarities including accumulation of Abeta peptides and neurofibrillary tangles of hyperphosphorylated tau proteins. Most epidemiological evidence suggests a link between TBI and AD, implying that TBI has neurodegenerative sequelae. Abeta peptides and tau may be used as biomarkers in interstitial fluid (ISF) using cerebral microdialysis and/or cerebrospinal fluid (CSF) following clinical TBI. In the present review, the available clinical and experimental literature on Abeta peptides and tau as potential biomarkers following TBI is comprehensively analyzed. Elevated CSF and ISF tau protein levels have been observed following severe TBI and suggested to correlate with clinical outcome. Although Abeta peptides are produced by normal neuronal metabolism, high levels of long and/or fibrillary Abeta peptides may be neurotoxic. Increased CSF and/or ISF Abeta levels post-injury may be related to neuronal activity and/or the presence of axonal injury. The heterogeneity of animal models, clinical cohorts, analytical techniques, and the complexity of TBI in the available studies make the clinical value of tau and Abeta as biomarkers uncertain at present. Additionally, the link between early post-injury changes in tau and Abeta peptides and the future risk of developing AD remains unclear. Future studies using methods such as rapid biomarker sampling combined with enhanced analytical techniques and/or novel pharmacological tools could provide additional information on the importance of Abeta peptides and tau protein in both the acute pathophysiology and long-term consequences of TBI. PMID- 23805128 TI - Immune Regulation in T1D and T2D: Prospective Role of Foxp3+ Treg Cells in Disease Pathogenesis and Treatment. AB - There is increasing evidence that dysregulated immune responses play key roles in the pathogenesis and complications of type 1 but also type 2 diabetes. Indeed, chronic inflammation and autoimmunity, which are salient features of type 1 diabetes, are now believed to actively contribute to the pathogenesis of type 2 diabetes. The accumulation of activated innate and adaptive immune cells in various metabolic tissues results in the release of inflammatory mediators, which promote insulin resistance and beta-cell damage. Moreover, these dysregulated immune responses can also mutually influence the prevalence of both type 1 and 2 diabetes. In this review article, we discuss the central role of immune responses in the patho-physiology and complications of type 1 and 2 diabetes, and provide evidence that regulation of these responses, particularly through the action of regulatory T cells, may be a possible therapeutic avenue for the treatment of these disease and their respective complications. PMID- 23805131 TI - Microbial communities associated with ferromanganese nodules and the surrounding sediments. AB - The formation and maintenance of deep-sea ferromanganese/polymetallic nodules still remains a mystery 140 years after their discovery. The wealth of rare metals concentrated in these nodules has spurred global interest in exploring the mining potential of these resources. The prevailing theory of abiotic formation has been called into question and the role of microbial metabolisms in nodule development is now an area of active research. To understand the community structure of microbes associated with nodules and their surrounding sediment, we performed targeted sequencing of the V4 hypervariable region of the 16S rRNA gene from three nodules collected from the central South Pacific. Results have shown that the microbial communities of the nodules are significantly distinct from the communities in the surrounding sediments, and that the interiors of the nodules harbor communities different from the exterior. This suggests not only differences in potential metabolisms between the nodule and sediment communities, but also differences in the dominant metabolisms of interior and exterior communities. We identified several operational taxonomic units (OTUs) unique to both the nodule and sediment environments. The identified OTUs were assigned putative taxonomic identifications, including two OTUs only found associated with the nodules, which were assigned to the alpha-Proteobacteria. Finally, we explored the diversity of the most assigned taxonomic group, the Thaumarchaea MG 1, which revealed novel OTUs compared to previous research from the region and suggests a potential role as a source of fixed carbon for ammonia oxidizing archaea in the environment. PMID- 23805129 TI - Platelet granule exocytosis: a comparison with chromaffin cells. AB - The rapid secretion of bioactive amines from chromaffin cells constitutes an important component of the fight or flight response of mammals to stress. Platelets respond to stresses within the vasculature by rapidly secreting cargo at sites of injury, inflammation, or infection. Although chromaffin cells derive from the neural crest and platelets from bone marrow megakaryocytes, both have evolved a heterogeneous assemblage of granule types and a mechanism for efficient release. This article will provide an overview of granule formation and exocytosis in platelets with an emphasis on areas in which the study of chromaffin cells has influenced that of platelets and on similarities between the two secretory systems. Commonalities include the use of transporters to concentrate bioactive amines and other cargos into granules, the role of cytoskeletal remodeling in granule exocytosis, and the use of granules to provide membrane for cytoplasmic projections. The SNAREs and SNARE accessory proteins used by each cell type will also be considered. Finally, we will discuss the newly appreciated role of dynamin family proteins in regulated fusion pore formation. This evaluation of the comparative cell biology of regulated exocytosis in platelets and chromaffin cells demonstrates a convergence of mechanisms between two disparate cell types both tasked with responding rapidly to physiological stimuli. PMID- 23805130 TI - Genetic variability and evolutionary dynamics of viruses of the family Closteroviridae. AB - RNA viruses have a great potential for genetic variation, rapid evolution and adaptation. Characterization of the genetic variation of viral populations provides relevant information on the processes involved in virus evolution and epidemiology and it is crucial for designing reliable diagnostic tools and developing efficient and durable disease control strategies. Here we performed an updated analysis of sequences available in Genbank and reviewed present knowledge on the genetic variability and evolutionary processes of viruses of the family Closteroviridae. Several factors have shaped the genetic structure and diversity of closteroviruses. (I) A strong negative selection seems to be responsible for the high genetic stability in space and time for some viruses. (2) Long distance migration, probably by human transport of infected propagative plant material, have caused that genetically similar virus isolates are found in distant geographical regions. (3) Recombination between divergent sequence variants have generated new genotypes and plays an important role for the evolution of some viruses of the family Closteroviridae. (4) Interaction between virus strains or between different viruses in mixed infections may alter accumulation of certain strains. (5) Host change or virus transmission by insect vectors induced changes in the viral population structure due to positive selection of sequence variants with higher fitness for host-virus or vector-virus interaction (adaptation) or by genetic drift due to random selection of sequence variants during the population bottleneck associated to the transmission process. PMID- 23805132 TI - Biogeographical characterization of Saccharomyces cerevisiae wine yeast by molecular methods. AB - Biogeography is the descriptive and explanatory study of spatial patterns and processes involved in the distribution of biodiversity. Without biogeography, it would be difficult to study the diversity of microorganisms because there would be no way to visualize patterns in variation. Saccharomyces cerevisiae, "the wine yeast," is the most important species involved in alcoholic fermentation, and in vineyard ecosystems, it follows the principle of "everything is everywhere." Agricultural practices such as farming (organic versus conventional) and floor management systems have selected different populations within this species that are phylogenetically distinct. In fact, recent ecological and geographic studies highlighted that unique strains are associated with particular grape varieties in specific geographical locations. These studies also highlighted that significant diversity and regional character, or 'terroir,' have been introduced into the winemaking process via this association. This diversity of wild strains preserves typicity, the high quality, and the unique flavor of wines. Recently, different molecular methods were developed to study population dynamics of S. cerevisiae strains in both vineyards and wineries. In this review, we will provide an update on the current molecular methods used to reveal the geographical distribution of S. cerevisiae wine yeast. PMID- 23805133 TI - The dual role of candida glabrata drug:H+ antiporter CgAqr1 (ORF CAGL0J09944g) in antifungal drug and acetic acid resistance. AB - Opportunistic Candida species often have to cope with inhibitory concentrations of acetic acid, in the acidic environment of the vaginal mucosa. Given that the ability of these yeast species to tolerate stress induced by weak acids and antifungal drugs appears to be a key factor in their persistence and virulence, it is crucial to understand the underlying mechanisms. In this study, the drug:H(+) antiporter CgAqr1 (ORF CAGL0J09944g), from Candida glabrata, was identified as a determinant of resistance to acetic acid, and also to the antifungal agents flucytosine and, less significantly, clotrimazole. These antifungals were found to act synergistically with acetic acid against this pathogen. The action of CgAqr1 in this phenomenon was analyzed. Using a green fluorescent protein fusion, CgAqr1 was found to localize to the plasma membrane and to membrane vesicles when expressed in C. glabrata or, heterologously, in Saccharomyces cerevisiae. Given its ability to complement the susceptibility phenotype of its S. cerevisiae homolog, ScAqr1, CgAqr1 was proposed to play a similar role in mediating the extrusion of chemical compounds. Significantly, the expression of this gene was found to reduce the intracellular accumulation of (3)H-flucytosine and, to a moderate extent, of (3)H-clotrimazole, consistent with a direct role in antifungal drug efflux. Interestingly, no effect of CgAQR1 deletion could be found on the intracellular accumulation of (14)C-acetic acid, suggesting that its role in acetic acid resistance may be indirect, presumably through the transport of a still unidentified physiological substrate. Although neither of the tested chemicals induces changes in CgAQR1 expression, pre exposure to flucytosine or clotrimazole was found to make C. glabrata cells more sensitive to acetic acid stress. Results from this study show that CgAqr1 is an antifungal drug resistance determinant and raise the hypothesis that it may play a role in C. glabrata persistent colonization and multidrug resistance. PMID- 23805134 TI - Fractionation of sulfur isotopes by Desulfovibrio vulgaris mutants lacking hydrogenases or type I tetraheme cytochrome c 3. AB - The sulfur isotope effect produced by sulfate reducing microbes is commonly used to trace biogeochemical cycles of sulfur and carbon in aquatic and sedimentary environments. To test the contribution of intracellular coupling between carbon and sulfur metabolisms to the overall magnitude of the sulfur isotope effect, this study compared sulfur isotope fractionations by mutants of Desulfovibrio vulgaris Hildenborough. We tested mutant strains lacking one or two periplasmic (Hyd, Hyn-1, Hyn-2, and Hys) or cytoplasmic hydrogenases (Ech and CooL), and a mutant lacking type I tetraheme cytochrome (TpI-c 3). In batch culture, wild-type D. vulgaris and its hydrogenase mutants had comparable growth kinetics and produced the same sulfur isotope effects. This is consistent with the reported redundancy of hydrogenases in D. vulgaris. However, the TpI-c 3 mutant (DeltacycA) exhibited slower growth and sulfate reduction rates in batch culture, and produced more H2 and an approximately 50% larger sulfur isotope effect, compared to the wild type. The magnitude of sulfur isotope fractionation in the CycA deletion strain, thus, increased due to the disrupted coupling of the carbon oxidation and sulfate reduction pathways. In continuous culture, wild-type D. vulgaris and the CycA mutant produced similar sulfur isotope effects, underscoring the influence of environmental conditions on the relative contribution of hydrogen cycling to the electron transport. The large sulfur isotope effects associated with the non-ideal stoichiometry of sulfate reduction in this study imply that simultaneous fermentation and sulfate reduction may be responsible for some of the large naturally-occurring sulfur isotope effects. Overall, mutant strains provide a powerful tool to test the effect of specific redox proteins and pathways on sulfur isotope fractionation. PMID- 23805135 TI - Genomic analysis of ERVWE2 locus in patients with multiple sclerosis: absence of genetic association but potential role of human endogenous retrovirus type W elements in molecular mimicry with myelin antigen. AB - Human endogenous retroviruses (HERVs) arise from ancient infections of the host germline cells by exogenous retroviruses, constituting 8% of the human genome. Elevated level of envelope transcripts from HERVs-W has been detected in CSF, plasma and brain tissues from patients with Multiple Sclerosis (MS), most of them from Xq22.3, 15q21.3, and 6q21 chromosomes. However, since the locus Xq22.3 (ERVWE2) lack the 5' LTR promoter and the putative protein should be truncated due to a stop codon, we investigated the ERVWE2 genomic loci from 84 individuals, including MS patients with active HERV-W expression detected in PBMC. In addition, an automated search for promoter sequences in 20 kb nearby region of ERVWE2 reference sequence was performed. Several putative binding sites for cellular cofactors and enhancers were found, suggesting that transcription may occur via alternative promoters. However, ERVWE2 DNA sequencing of MS and healthy individuals revealed that all of them harbor a stop codon at site 39, undermining the expression of a full-length protein. Finally, since plaque formation in central nervous system (CNS) of MS patients is attributed to immunological mechanisms triggered by autoimmune attack against myelin, we also investigated the level of similarity between envelope protein and myelin oligodendrocyte glycoprotein (MOG). Comparison of the MOG to the envelope identified five retroviral regions similar to the Ig-like domain of MOG. Interestingly, one of them includes T and B cell epitopes, capable to induce T effector functions and circulating Abs in rats. In sum, although no DNA substitutions that would link ERVWE2 to the MS pathogeny was found, the similarity between the envelope protein to MOG extends the idea that ERVEW2 may be involved on the immunopathogenesis of MS, maybe facilitating the MOG recognizing by the immune system. Although awaiting experimental evidences, the data presented here may expand the scope of the endogenous retroviruses involvement on MS pathogenesis. PMID- 23805137 TI - Extracellular chromatin traps interconnect cell biology, microbiology, and immunology. PMID- 23805136 TI - Food and human gut as reservoirs of transferable antibiotic resistance encoding genes. AB - The increase and spread of antibiotic resistance (AR) over the past decade in human pathogens has become a worldwide health concern. Recent genomic and metagenomic studies in humans, animals, in food and in the environment have led to the discovery of a huge reservoir of AR genes called the resistome that could be mobilized and transferred from these sources to human pathogens. AR is a natural phenomenon developed by bacteria to protect antibiotic-producing bacteria from their own products and also to increase their survival in highly competitive microbial environments. Although antibiotics are used extensively in humans and animals, there is also considerable usage of antibiotics in agriculture, especially in animal feeds and aquaculture. The aim of this review is to give an overview of the sources of AR and the use of antibiotics in these reservoirs as selectors for emergence of AR bacteria in humans via the food chain. PMID- 23805138 TI - IL-15 Fosters Age-Driven Regulatory T Cell Accrual in the Face of Declining IL-2 Levels. AB - We and others have shown that regulatory T cells (Treg) accumulate dramatically with age in both humans and mice. Such Treg accrual contributes to age-related immunosenescence as they reduce the response to tumors and parasite infection. While we reported earlier that aged Treg have decreased expression of the pro apoptotic molecule Bim and germline deletion of Bim promoted earlier accumulation of Treg, it remains unclear whether the effects of Bim are: (i) Treg intrinsic and (ii) dominant to other BH3-only pro-apoptotic molecules. Further, the mechanism(s) controlling Bim expression in aged Treg remain unclear. Here we show that Treg-specific loss of Bim is sufficient to drive Treg accrual with age and that additional loss of the downstream apoptotic effectors Bax and Bak did not exacerbate Treg accumulation. Further, our results demonstrate that a subpopulation of Treg expands with age and is characterized by lower expression of CD25 (IL-2Ralpha) and Bim. Mechanistically, we found that IL-2 levels decline with age and likely explain the emergence of CD25(lo)Bim(lo) Treg because Treg in IL-2(-/-) mice are almost entirely comprised of CD25(lo)Bim(lo) cells, and IL-2 neutralization increases CD25(lo)Bim(lo) Treg in both young and middle-aged mice. Interestingly, the Treg population in aged mice had increased expression of CD122 (IL-2/IL-15Rbeta) and neutralization or genetic loss of IL-15 led to less Treg accrual with age. Further, the decreased Treg accrual in middle-aged IL-15(-/-) mice was restored by the additional loss of Bim (IL-15(-/-)Bim(-/-)). Together, our data show that aging favors the accrual of CD25(lo) Treg whose homeostasis is supported by IL-15 as IL-2 levels become limiting. These data have implications for manipulating Treg to improve immune responses in the elderly. PMID- 23805139 TI - Lessons to be Learned from Natural Control of HIV - Future Directions, Therapeutic, and Preventive Implications. AB - Accumulating data generated from persons who naturally control HIV without the need for antiretroviral treatment has led to significant insights into the possible mechanisms of durable control of AIDS virus infection. At the center of this control is the HIV-specific CD8 T cell response, and the basis for this CD8 mediated control is gradually being revealed. Genome wide association studies coupled with HLA sequence data implicate the nature of the HLA-viral peptide interaction as the major genetic factor modulating durable control of HIV, but host genetic factors account for only around 20% of the variability in control. Other factors including specific functional characteristics of the TCR clonotypes generated in vivo, targeting of vulnerable regions of the virus that lead to fitness impairing mutations, immune exhaustion, and host restriction factors that limit HIV replication all have been shown to additionally contribute to control. Moreover, emerging data indicate that the CD8(+) T cell response may be critical for attempts to purge virus infected cells following activation of the latent reservoir, and thus lessons learned from elite controllers (ECs) are likely to impact the eradication agenda. On-going efforts are also needed to understand and address the role of immune activation in disease progression, as it becomes increasingly clear that durable immune control in ECs comes at a cost. Taken together, the research achievements in the attempt to unlock the mechanisms behind natural control of HIV will continue to be an important source of insights and ideas in the continuous search after an effective HIV vaccine, and for the attempts to achieve a sterilizing or functional cure in HIV positive patients with progressive infection. PMID- 23805140 TI - The role of regulatory T cells in the biology of graft versus host disease. AB - Graft versus host disease (GVHD) is the major complication of allogeneic hematopoietic stem cell transplantation. GVHD is characterized by an imbalance between the effector and regulatory arms of the immune system which results in the over production of inflammatory cytokines. Moreover, there is a persistent reduction in the number of regulatory T (Treg) cells which limits the ability of the immune system to re-calibrate this proinflammatory environment. Treg cells are comprised of both natural and induced populations which have unique ontological and developmental characteristics that impact how they function within the context of immune regulation. In this review, we summarize pre clinical data derived from experimental murine models that have examined the role of both natural and induced Treg cells in the biology of GVHD. We also review the clinical studies which have begun to employ Treg cells as a form of adoptive cellular therapy for the prevention of GVHD in human transplant recipients. PMID- 23805142 TI - The Avalanche is Coming ... And Just Now It's Starting to Snow. PMID- 23805141 TI - Weft, warp, and weave: the intricate tapestry of calcium channels regulating T lymphocyte function. AB - Calcium (Ca(2+)) is a universal second messenger important for T lymphocyte homeostasis, activation, proliferation, differentiation, and apoptosis. The events surrounding Ca(2+) mobilization in lymphocytes are tightly regulated and involve the coordination of diverse ion channels, membrane receptors, and signaling molecules. A mechanism termed store-operated Ca(2+) entry (SOCE), causes depletion of endoplasmic reticulum (ER) Ca(2+) stores following T cell receptor (TCR) engagement and triggers a sustained influx of extracellular Ca(2+) through Ca(2+) release-activated Ca(2+) (CRAC) channels in the plasma membrane. The ER Ca(2+) sensing molecule, stromal interaction molecule 1 (STIM1), and a pore-forming plasma membrane protein, ORAI1, have been identified as important mediators of SOCE. Here, we review the role of several additional families of Ca(2+) channels expressed on the plasma membrane of T cells that likely contribute to Ca(2+) influx following TCR engagement, particularly highlighting an important role for voltage-dependent Ca(2+) channels (CaV) in T lymphocyte biology. PMID- 23805143 TI - An improved strategy to recover large fragments of functional human neutrophil extracellular traps. AB - Netosis is a recently described neutrophil function that leads to the release of neutrophil extracellular traps (NETs) in response to various stimuli. NETs are filaments of decondensed chromatin associated with granular proteins. In addition to their role against microorganisms, NETs have been implicated in autoimmunity, thrombosis, and tissue injury. Access to a standardized source of isolated NETs is needed to better analyze the roles of NETs. The aim of this study was to develop a procedure yielding soluble, well-characterized NET preparations from fresh human neutrophils. The calcium ionophore A23187 was chosen to induce netosis, and the restriction enzyme AluI was used to prepare large NET fragments. DNA and proteins were detected by electrophoresis and specific labeling. Some NET proteins [histone 3, lactoferrin (LF)] were quantified by western blotting, and double-stranded DNA (dsDNA) was quantified by immunofluorescence. Co-existence of dsDNA and neutrophil proteins confirmed the quality of the NET preparations. Their biological activity was checked by measuring elastase (ELA) activity and bacterial killing against various strains. Interindividual differences in histone 3, LF, ELA, and dsDNA relative contents were observed in isolated NETs. However, the reproducibility of NET preparation and characterization was validated, suggesting that this interindividual variability was rather related to donor variation than to technical bias. This standardized protocol is suitable for producing, isolating, and quantifying functional NETs that could serve as a tool for studying NET effects on immune cells and tissues. PMID- 23805144 TI - Increased Peptide Contacts Govern High Affinity Binding of a Modified TCR Whilst Maintaining a Native pMHC Docking Mode. AB - Natural T cell receptors (TCRs) generally bind to their cognate pMHC molecules with weak affinity and fast kinetics, limiting their use as therapeutic agents. Using phage display, we have engineered a high affinity version of the A6 wild type TCR (A6wt), specific for the human leukocyte antigen (HLA-A(*)0201) complexed with human T cell lymphotropic virus type 111-19 peptide (A2-Tax). Mutations in just 4 residues in the CDR3beta loop region of the A6wt TCR were selected that improved binding to A2-Tax by nearly 1000-fold. Biophysical measurements of this mutant TCR (A6c134) demonstrated that the enhanced binding was derived through favorable enthalpy and a slower off-rate. The structure of the free A6c134 TCR and the A6c134/A2-Tax complex revealed a native binding mode, similar to the A6wt/A2-Tax complex. However, concordant with the more favorable binding enthalpy, the A6c134 TCR made increased contacts with the Tax peptide compared with the A6wt/A2-Tax complex, demonstrating a peptide-focused mechanism for the enhanced affinity that directly involved the mutated residues in the A6c134 TCR CDR3beta loop. This peptide-focused enhanced TCR binding may represent an important approach for developing antigen specific high affinity TCR reagents for use in T cell based therapies. PMID- 23805145 TI - Late Embryogenesis Abundant (LEA) proteins in legumes. AB - Plants are exposed to different external conditions that affect growth, development, and productivity. Water deficit is one of these adverse conditions caused by drought, salinity, and extreme temperatures. Plants have developed different responses to prevent, ameliorate or repair the damage inflicted by these stressful environments. One of these responses is the activation of a set of genes encoding a group of hydrophilic proteins that typically accumulate to high levels during seed dehydration, at the last stage of embryogenesis, hence named Late Embryogenesis Abundant (LEA) proteins. LEA proteins also accumulate in response to water limitation in vegetative tissues, and have been classified in seven groups based on their amino acid sequence similarity and on the presence of distinctive conserved motifs. These proteins are widely distributed in the plant kingdom, from ferns to angiosperms, suggesting a relevant role in the plant response to this unfavorable environmental condition. In this review, we analyzed the LEA proteins from those legumes whose complete genomes have been sequenced such as Phaseolus vulgaris, Glycine max, Medicago truncatula, Lotus japonicus, Cajanus cajan, and Cicer arietinum. Considering their distinctive motifs, LEA proteins from the different groups were identified, and their sequence analysis allowed the recognition of novel legume specific motifs. Moreover, we compile their transcript accumulation patterns based on publicly available data. In spite of the limited information on these proteins in legumes, the analysis and data compiled here confirm the high correlation between their accumulation and water deficit, reinforcing their functional relevance under this detrimental conditions. PMID- 23805146 TI - Deciphering the hormonal signalling network behind the systemic resistance induced by Trichoderma harzianum in tomato. AB - Root colonization by selected Trichoderma isolates can activate in the plant a systemic defense response that is effective against a broad-spectrum of plant pathogens. Diverse plant hormones play pivotal roles in the regulation of the defense signaling network that leads to the induction of systemic resistance triggered by beneficial organisms [induced systemic resistance (ISR)]. Among them, jasmonic acid (JA) and ethylene (ET) signaling pathways are generally essential for ISR. However, Trichoderma ISR (TISR) is believed to involve a wider variety of signaling routes, interconnected in a complex network of cross communicating hormone pathways. Using tomato as a model, an integrative analysis of the main mechanisms involved in the systemic resistance induced by Trichoderma harzianum against the necrotrophic leaf pathogen Botrytis cinerea was performed. Root colonization by T. harzianum rendered the leaves more resistant to B. cinerea independently of major effects on plant nutrition. The analysis of disease development in shoots of tomato mutant lines impaired in the synthesis of the key defense-related hormones JA, ET, salicylic acid (SA), and abscisic acid (ABA), and the peptide prosystemin (PS) evidenced the requirement of intact JA, SA, and ABA signaling pathways for a functional TISR. Expression analysis of several hormone-related marker genes point to the role of priming for enhanced JA dependent defense responses upon pathogen infection. Together, our results indicate that although TISR induced in tomato against necrotrophs is mainly based on boosted JA-dependent responses, the pathways regulated by the plant hormones SA- and ABA are also required for successful TISR development. PMID- 23805147 TI - A re-sequencing based assessment of genomic heterogeneity and fast neutron induced deletions in a common bean cultivar. AB - A small fast neutron (FN) mutant population has been established from Phaseolus vulgaris cv. Red Hawk. We leveraged the available P. vulgaris genome sequence and high throughput next generation DNA sequencing to examine the genomic structure of five P. vulgaris cv. Red Hawk FN mutants with striking visual phenotypes. Analysis of these genomes identified three classes of structural variation (SV); between cultivar variation, natural variation within the FN mutant population, and FN induced mutagenesis. Our analyses focused on the latter two classes. We identified 23 large deletions (>40 bp) common to multiple individuals, illustrating residual heterogeneity and regions of SV within the common bean cv. Red Hawk. An additional 18 large deletions were identified in individual mutant plants. These deletions, ranging in size from 40 bp to 43,000 bp, are potentially the result of FN mutagenesis. Six of the 18 deletions lie near or within gene coding regions, identifying potential candidate genes causing the mutant phenotype. PMID- 23805148 TI - Proteomic comparison of basal endosperm in maize miniature1 mutant and its wild type Mn1. AB - Developing endosperm in maize seed is a major site for biosynthesis and storage of starch and proteins, and of immense economic importance for its role in food, feed and biofuel production. The basal part of endosperm performs a major role in solute, water and nutrition acquisition from mother plant to sustain these functions. The miniature1 (mn1) mutation is a loss-of-function mutation of the Mn1-encoded cell wall invertase that is entirely expressed in the basal endosperm and is essential for many of the metabolic and signaling functions associated with metabolically released hexose sugars in developing endosperm. Here we report a comparative proteomic study between Mn1 and mn1 basal endosperm to better understand basis of pleiotropic effects on many diverse traits in the mutant. Specifically, we used iTRAQ based quantitative proteomics combined with Gene Ontology (GO) and bioinformatics to understand functional basis of the proteomic information. A total of 2518 proteins were identified from soluble and cell wall associated protein (CWAP) fractions; of these 131 proteins were observed to be differentially expressed in the two genotypes. The main functional groups of proteins that were significantly different were those involved in the carbohydrate metabolic and catabolic process, and cell homeostasis. The study constitutes the first proteomic analysis of basal endosperm cell layers in relation to endosperm growth and development in maize. PMID- 23805150 TI - EXO modifies sucrose and trehalose responses and connects the extracellular carbon status to growth. AB - Plants have the capacity to adapt growth to changing environmental conditions. This implies the modulation of metabolism according to the availability of carbon (C). Particular interest in the response to the C availability is based on the increasing atmospheric levels of CO2. Several regulatory pathways that link the C status to growth have emerged. The extracellular EXO protein is essential for cell expansion and promotes shoot and root growth. Homologous proteins were identified in evolutionarily distant green plants. We show here that the EXO protein connects growth with C responses. The exo mutant displayed altered responses to exogenous sucrose supplemented to the growth medium. Impaired growth of the mutant in synthetic medium was associated with the accumulation of starch and anthocyanins, altered expression of sugar-responsive genes, and increased abscisic acid levels. Thus, EXO modulates several responses related to the C availability. Growth retardation on medium supplemented with 2-deoxy-glucose, mannose, and palatinose was similar to the wild type. Trehalose feeding stimulated root growth and shoot biomass production of exo plants whereas it inhibited growth of the wild type. The phenotypic features of the exo mutant suggest that apoplastic processes coordinate growth and C responses. PMID- 23805149 TI - Fluorescent protein tagging as a tool to define the subcellular distribution of proteins in plants. AB - Fluorescent protein (FP) tagging approaches are widely used to determine the subcellular location of plant proteins. Here we give a brief overview of FP approaches, highlight potential technical problems, and discuss what to consider when designing FP/protein fusion constructs and performing transformation assays. We analyze published FP tagging data sets along with data from proteomics studies collated in SUBA3, a subcellular location database for Arabidopsis proteins, and assess the reliability of these data sets by comparing them. We also outline the limitations of the FP tagging approach for defining protein location and investigate multiple localization claims by FP tagging. We conclude that the collation of localization datasets in databases like SUBA3 is helpful for revealing discrepancies in location attributions by different techniques and/or by different research groups. PMID- 23805151 TI - Are sucrose transporter expression profiles linked with patterns of biomass partitioning in Sorghum phenotypes? AB - Sorghum bicolor is a genetically diverse C4 monocotyledonous species, encompassing varieties capable of producing high grain yields as well as sweet types which accumulate soluble sugars (predominantly sucrose) within their stems to high concentrations. Sucrose produced in leaves (sources) enters the phloem and is transported to regions of growth and storage (sinks). It is likely that sucrose transporter (SUT) proteins play pivotal roles in phloem loading and the delivery of sucrose to growth and storage sinks in all Sorghum ecotypes. Six SUTs are present in the published Sorghum genome, based on the BTx623 grain cultivar. Homologues of these SUTs were cloned and sequenced from the sweet cultivar Rio, and compared with the publically available genome information. SbSUT5 possessed nine amino acid sequence differences between the two varieties. Two of the remaining five SUTs exhibited single variations in their amino acid sequences (SbSUT1 and SbSUT2) whilst the rest shared identical sequences. Complementation of a mutant Saccharomyces yeast strain (SEY6210), unable to grow upon sucrose as the sole carbon source, demonstrated that the Sorghum SUTs were capable of transporting sucrose. SbSUT1, SbSUT4, and SbSUT6 were highly expressed in mature leaf tissues and hence may contribute to phloem loading. In contrast, SbSUT2 and SbSUT5 were expressed most strongly in sinks consistent with a possible role of facilitating sucrose import into stem storage pools and developing inflorescences. PMID- 23805152 TI - The DNA damage response in mammalian oocytes. AB - DNA damage is one of the most common insults that challenge all cells. To cope, an elaborate molecular and cellular response has evolved to sense, respond to and correct the damage. This allows the maintenance of DNA fidelity essential for normal cell viability and the prevention of genomic instability that can lead to tumor formation. In the context of oocytes, the impact of DNA damage is not one of tumor formation but of the maintenance of fertility. Mammalian oocytes are particularly vulnerable to DNA damage because physiologically they may lie dormant in the ovary for many years (>40 in humans) until they receive the stimulus to grow and acquire the competence to become fertilized. The implication of this is that in some organisms, such as humans, oocytes face the danger of cumulative genetic damage for decades. Thus, the ability to detect and repair DNA damage is essential to maintain the supply of oocytes necessary for reproduction. Therefore, failure to confront DNA damage in oocytes could cause serious anomalies in the embryo that may be propagated in the form of mutations to the next generation allowing the appearance of hereditary disease. Despite the potential impact of DNA damage on reproductive capacity and genetic fidelity of embryos, the mechanisms available to the oocyte for monitoring and repairing such insults have remained largely unexplored until recently. Here, we review the different aspects of the response to DNA damage in mammalian oocytes. Specifically, we address the oocyte DNA damage response from embryonic life to adulthood and throughout oocyte development. PMID- 23805153 TI - Extracellular circulating viral microRNAs: current knowledge and perspectives. AB - MicroRNAs (miRNAs) are small non-coding RNAs responsible of post-transcriptional regulation of gene expression through interaction with messenger RNAs (mRNAs). They are involved in important biological processes and are often dysregulated in a variety of diseases, including cancer and infections. Viruses also encode their own sets of miRNAs, which they use to control the expression of either the host's genes and/or their own. In the past few years evidence of the presence of cellular miRNAs in extracellular human body fluids such as serum, plasma, saliva, and urine has accumulated. They have been found either cofractionate with the Argonaute2 protein or in membrane-bound vesicles such as exosomes. Although little is known about the role of circulating miRNAs, it has been demonstrated that miRNAs secreted by virus-infected cells are transferred to and act in uninfected recipient cells. In this work we summarize the current knowledge on viral circulating miRNAs and provide a few examples of computational prediction of their function. PMID- 23805154 TI - Circulating inflamma-miRs in aging and age-related diseases. AB - Evidence on circulating microRNAs (miRNAs) is indisputably opening a new era in systemic and tissue-specific biomarker research, highlighting new inter-cellular and inter-organ communication mechanisms. Circulating miRNAs might be active messengers eliciting a systemic response as well as non-specific "by-products" of cell activity and even of cell death; in either case they have the potential to be clinically relevant biomarkers for a number of physiopathological processes, including inflammatory responses and inflammation-related conditions. A large amount of evidence indicates that miRNAs can exert two opposite roles, activating as well as inhibiting inflammatory pathways. The inhibitory action probably relates to the need for activating anti-inflammatory mechanisms to counter potent proinflammatory signals, like the nuclear factor kappaB (NF-kappaB) pathway, to prevent cell and tissue destruction. MiRNA-based anti-inflammatory mechanisms may acquire a crucial role during aging, where a chronic, low-level proinflammatory status is likely sustained by the cell senescence secretome and by progressive activation of immune cells over time. This process entails age-related changes, especially in extremely old age, in those circulating miRNAs that are capable of modulating the inflammatory status (inflamma-miRs). Interestingly, a number of such circulating miRNAs seem to be promising biomarkers for the major age-related diseases that share a common chronic, low-level proinflammatory status, such as cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), Alzheimer Disease (AD), rheumatoid arthritis (RA), and cancers. PMID- 23805155 TI - Virological Response and Muscular Adverse Events during Long-Term Clevudine Therapy in Chronic Hepatitis B Patients. AB - BACKGROUND: Recently, several reports issued clevudine induced myopathy in the long term use. OBJECTIVES: The aim of this study was to investigate antiviral effects and adverse events of clevudine monotherapy in patients with chronic hepatitis B (CHB). PATIENTS AND METHODS: The subjects were 110 treatment-naive CHB patients. They were treated with 30 mg clevudine/day for more than six months. Virological and biochemical tests, including that for serum creatine kinase (CK), were monitored at baseline and at 3-month intervals during treatment period. RESULTS: In HBeAg-positive patients, the cumulative rates of virological response were 74.0 %, 68.5 %, and 67.3 % after one, two, and three years of clevudine treatment, respectively. Cumulative rates of HBeAg loss or seroconversion were 17.8 %, 30 %, and 31.5 % after one, two and, three years of clevudine treatment, respectively. In HBeAg-negative patients, the cumulative rates of virological response were 97.3 %, 100 %, and 94.6 %, respectively. Virological breakthrough occurred in 27 patients. The rtM204I mutation in HBV polymerase was predominantly detected. Muscular adverse events were observed in 15 patients. All patients with myopathy recovered after the cessation of clevudine monotherapy. Fluctuations in CK level during the clevudine treatment period were frequently observed irrespective of development of myopathy. Multiple episodes of CK elevation were significantly related to the development of myopathy. CONCLUSIONS: Long-term clevudine monotherapy is effective for suppression of serum HBV DNA level and normalization of serum alanine amino transaminase levels, but associated with occurrence of rtM204I mutation. Clevudine-induced muscular adverse events are not uncommon, although they are totally reversible after cessation of the treatment. Muscular adverse events and serum CK level should be carefully monitored during long-term treatment with clevudine. PMID- 23805157 TI - Is There any Difference Between the Glomerular Filtration Rate of Patients With Chronic Hepatitis B and C and Patients With Cirrhosis? AB - BACKGROUND: Renal dysfunction is a major determinant of the Model of End-stage Liver Disease (MELD) score. The implementation of the MELD score has shifted allocation of livers to patients with renal dysfunction. OBJECTIVES: The aim of our study was the assessment of estimated Glomerular Filtration Rate (eGFR) by the Modification of Diet in Renal Disease 4 (MDRD4) method in patients with HBV chronic hepatitis, HCV chronic hepatitis, and cirrhosis (CH) caused by these viruses to detect any differences in renal function among these diseases. PATIENTS AND METHODS: We performed a cross-sectional analysis of all consecutive patients with HBV chronic hepatitis, HCV chronic hepatitis, and cirrhosis caused by these viruses hospitalized during a 4 year period in the Gastroenterology and Hepatology department of the Emergency County Hospital Timisoara, Romania. The eGFR was assessed by the MDRD4 method. Statistical analysis (unpaired t-test, ANOVA, Chi Square test) was performed using OpenEpi 2.3.1. RESULTS: HBV chronic hepatitis, HCV chronic hepatitis, and cirrhosis secondary to these viruses were associated with a reduction of the GFR. The eGFR was higher in patients with HBV chronic hepatitis than in patients with HCV chronic hepatitis (P < 0.001). Patients with cirrhosis secondary to HBV infection had a higher eGFR than patients with cirrhosis secondary to HCV (P = 0.01). The eGFR of patients with HCV chronic hepatitis was higher than the eGFR of patients with cirrhosis due to this virus (P < 0.001). CONCLUSIONS: Functional renal impairment in diseases caused by HCV was more important than in diseases caused by HBV. The eGFR was statistically lower in cirrhosis secondary to HCV than in HCV chronic hepatitis. PMID- 23805156 TI - Prophylactic Lamivudine to Improve the Outcome of Breast Cancer Patients With HBsAg Positive During Chemotherapy: A Meta-Analysis. AB - CONTEXT: Raising the chemotherapy-induced HBV reactivation is parallel to the increment of chemotherapy treatments in breast cancer patients. This meta analysis aims to evaluate the efficacy of prophylactic use of lamivudine in breast cancer patients with HBsAg positive during chemotherapy. EVIDENCE ACQUISITION: MEDLINE, Pubmed, Ovid and Embase were used to search for clinical studies comparing with or without prophylactic use of lamivudine for HBV reactivation in breast cancer patients receiving chemotherapy. Outcomes of interest were the rate of HBV reactivation, incidence of hepatitis and incidence of hepatitis attributable to HBV reactivation, severity of hepatitis and severity of hepatitis attributable to HBV reactivation, the rate of chemotherapy disruption, and the rate of chemotherapy disruption attributable to HBV reactivation, overall mortality, and mortality attributable to HBV reactivation. RESULTS: Four studies with 285 patients were included in this meta-analysis. The rate of HBV reactivation, incidence of hepatitis and incidence of hepatitis related to HBV reactivation were reduced by use of prophylactic lamivudine compared to control group. Pooled Odds Ratios (ORs) were 0.09 (95% confidence intervals [CI] 0.03-0.26; P < 0.0001), 0.23 (95% CI 0.06-0.92; P = 0.04), and 0.10 (95% CI 0.03-0.32; P < 0.0001) respectively. There was a reduction in chemotherapy disruption related to HBV reactivation by use of prophylactic lamivudine (pooled OR = 0.11; 95% CI 0.02-0.58; P = 0.01). Chemotherapy disruption, overall mortality, and mortality attributable to HBV reactivation were not significantly different between two groups. Pooled ORs were 0.42 (95% CI 0.11-1.58; P = 0.20), 0.37 (95% CI 0.07-2.04; P = 0.25), and 0.25 (95% CI 0.01 6.82; P = 0.41) respectively. Lamivudine was well-tolerated, and no additional toxicity was observed. CONCLUSIONS: Use of prophylactic lamivudine may have positive effect on the outcome of breast cancer patients with HBsAg positive during chemotherapy. PMID- 23805159 TI - Hepatocellular carcinoma in two patients with autoimmune hepatitis, a single center experience and review of the literature. PMID- 23805158 TI - Association Between ABCB1 (MDR1) Gene Polymorphism and Unresponsiveness Combined Therapy in Chronic Hepatitis C virus. AB - BACKGROUND: To treat viral infection of chronic hepatitis C (CHC) is a main strategy to prevent progression of liver disease, and cancer. Some patients with CHC have failed to respond to the common antiviral therapy in different populations. OBJECTIVES: In the current study it was aimed to find out the possible role of multiple drug resistance gene1 (MDR1) in non-responder patients with CHC infection in Turkish population. PATIENTS AND METHODS: Peripheral blood EDTA samples were used for total genomic DNA isolation. In total of 55 patients with chronic hepatitis C and positive results for genotype 1 [31 male (56.4%), 24 female (43.6%) and mean age-min-max; 56.9 +/- 9.66 (39-71)]; 19 responder (34.5%), 21 non responder (38.2%), and 15 recurrence (27.3%) were included in the presented results. Functional MDR1 gene was genotyped by multiplex PCR-based reverse-hybridization Strip Assay method, and some samples were confirmed by direct sequencing. RESULTS: Our results indicate that MDR1 gene polymorphism is strongly associated with non-responder patients and those with recurrent chronic hepatitis C during conventional drug therapy when compared to the responder patients. Homozygous of the TT genotype for MDR1 exon 26 polymorphism was at 2.0 fold higher risk of non-responder than patients with CC and CT. CONCLUSIONS: The homozygous MDR1 3435TT genotype which encodes the xenobiotic transporter P glycoprotein may be associated with a poor antiviral response in HCV chronicity during conventional therapy, and large-scale studies are needed to validate this association. PMID- 23805160 TI - Norjizak injection: a critical risk for transmitting blood-borne infectious diseases. PMID- 23805161 TI - Maintenance therapy with opium tincture for injecting drug users; implications for prevention from viral infections. PMID- 23805162 TI - Search in the literature for viral hepatitis and hepatocellular carcinoma in iran. PMID- 23805164 TI - Self-reported low physical function is associated with diabetes mellitus and insulin resistance in HIV-positive and HIV-negative men. AB - AIM: To investigate the association between self-reported physical function (as a surrogate for physical activity) and diabetes mellitus (DM) and insulin resistance (IR) among HIV-positive and -negative men. METHOD: A total of 384 HIV negative and 274 HIV-positive men from the Pitt Men's Study contributed data. DM was defined by fasting serum glucose levels. IR was calculated using the homeostasis model assessment. The Physical Functioning 10 Scale from the Short Form-36 Health Survey measured physical function. Multivariate logistic regression assessed the independent association between physical function and DM and IR. RESULTS: Physical function, older age and Black race were associated with DM in multivariate analyses. Physical function/HIV interaction, older age, higher body mass index, HIV infection and Black race were associated with IR in multivariate analyses. CONCLUSION: Self-reported low physical function is associated with DM and IR in HIV-negative and -positive men. PMID- 23805163 TI - Low physical function as a risk factor for incident diabetes mellitus and insulin resistance. AB - Data from 1790 HIV-infected and uninfected men in the Multicenter AIDS Cohort Study (MACS) were analyzed to evaluate relationships between physical function, incident diabetes mellitus (DM) and insulin resistance among HIV-infected and uninfected men. DM was defined in two ways, using less stringent and more stringent criteria. The 10-item Physical Functioning Scale from the Short Form-36 Health Survey measured baseline physical function. Cumulative DM incidence was highest among HIV-uninfected and HIV-infected men with low physical function. Physical function was a risk factor for DM in HIV-uninfected men and remained so after controlling for BMI, DM family history and race. Among HIV-infected men, physical function was an independent risk factor for DM using the less stringent diabetes definition. This study supports our previous findings that low physical function is an important risk factor for DM in the MACS cohort. PMID- 23805165 TI - A mixed-methods study into ballet for people living with Parkinson's. AB - Background: Parkinson's is a neurological disease that is physically debilitating and can be socially isolating. Dance is growing in popularity for people with Parkinson's and claims have been made for its benefits. The paper details a mixed methods study that examined a 12-week dance project for people with Parkinson's, led by English National Ballet. Methods: The effects on balance, stability and posture were measured through the Fullerton Advanced Balance Scale and a plumb line analysis. The value of participation and movement quality were interpreted through ethnographic methods, grounded theory and Effort analysis. Results: Triangulation of results indicates that people were highly motivated, with 100% adherence, and valued the classes as an important part of their lives. Additionally, results indicated an improvement in balance and stability, although not in posture. Conclusions: Dancing may offer benefit to people with Parkinson's through its intellectual, artistic, social and physical aspects. The paper suggests that a range of research methods is fundamental to capture the importance of multifaceted activity, such as dance, to those with Parkinson's. PMID- 23805166 TI - Music as a method of coping with cancer: A qualitative study among cancer patients in Sweden. AB - Background: This study investigated patients' understanding of the role of music in coping and in influencing their well-being. Methods: A qualitative study was conducted based on semi-structured interviews with 17 cancer patients. Participants were chosen from a group of patients who had listened to or played music as a means of coping with their illness. Results: The study shows the importance of considering the roles that different kinds of music play in coping with cancer. The music of nature, healing music, religious music and cheerful music each have different benefits for patients. Conclusions: A patient's situation and his or her individual characteristics determine the types of music that can act as a useful or harmful coping strategy. Therefore, it is essential to investigate the types of individual characteristics that can make listening to different kinds of music a helpful or harmful coping method. PMID- 23805168 TI - Targeting Underglycosylated MUC1 for the Selective Capture of Highly Metastatic Breast Cancer Cells Under Flow. AB - The underglycosylated form of the MUC1 glycoprotein, uMUC1, has been identified as a ligand for both E-selectin and ICAM-1 and can play multiple potential roles during rolling and firm adhesion events in the metastatic cascade. Using flow cytometry and confocal microscopy, the T47D and ZR-75-1 cell lines were verified to highly express uMUC1, however it was found that only ZR-75-1 cells expressed the E-selectin binding moiety sialyl Lewis x (sLex). Furthermore, perfusing T47D cells through E-selectin coated microtubes resulted in fast rolling velocities and low numbers of interacting cells and blocking uMUC1 with the SM3 antibody had no effect. ZR-75-1 cells, on the other hand, were highly dependent on the E selectin:uMUC1 interaction as exemplified by significant increases in cell rolling velocities and decreases in the number of interacting cells when blocking with SM3 or when uMUC1 expression was knocked down via siRNA transfection. Whereas uMUC1 interactions with E-selectin supported cell rolling, P-selectin: uMUC1 interactions exclusively facilitated cell tethering, while L-selectin surfaces supported no cell adhesive interactions. These experimental observations are consistent with molecular dynamics simulations of uMUC1 bound to E-, P-, and L-selectin where the degree of residue contact correlated with the differential adhesion of uMUC1 to each selectin. Finally, an E-selectin and SM3 combined surface coating captured approximately 30% of the total number of interacting cancer cells comparable to the number of adhered cells when utilizing E-selectin and ICAM-1 combined surfaces. The E-selectin/SM3 surface strategy offers a viable method to selectively capture cancer cells from whole blood samples. PMID- 23805167 TI - The role of exercise in facilitating basal ganglia function in Parkinson's disease. AB - Epidemiological and clinical studies have suggested that exercise is beneficial for patients with Parkinson's disease (PD). Through research in normal (noninjured) animals, neuroscientists have begun to understand the mechanisms in the brain by which behavioral training and exercise facilitates improvement in motor behavior through modulation of neuronal function and structure, called experience-dependent neuroplasticity. Recent studies are beginning to reveal molecules and downstream signaling pathways that are regulated during exercise and motor learning in animal models of PD and that are important in driving protective and/or adaptive changes in neuronal connections of the basal ganglia and related circuitry. These molecules include the neurotransmitters dopamine and glutamate (and their respective receptors) as well as neurotrophic factors (brain derived neurotrophic factor). In parallel, human exercise studies have been important in revealing 'proof of concept' including examining the types and parameters of exercise that are important for behavioral/functional improvements and brain changes; the feasibility of incorporating and maintaining an exercise program in individuals with motor disability; and, importantly, the translation and investigation of exercise effects observed in animal studies to exercise effects on brain and behavior in individuals with PD. In this article we highlight findings from both animal and human exercise studies that provide insight into brain changes of the basal ganglia and its related circuitry and that support potentially key parameters of exercise that may lead to long-term benefit and disease modification in PD. In addition, we discuss the current and future impact on patient care and point out gaps in our knowledge where continuing research is needed. Elucidation of exercise parameters important in driving neuroplasticity, as well as the accompanying mechanisms that underlie experience-dependent neuroplasticity may also provide insights towards new therapeutic targets, including neurorestorative and/or neuroprotective agents, for individuals with PD and related neurodegenerative disorders. PMID- 23805169 TI - Heparan Sulfate Regrowth Profiles Under Laminar Shear Flow Following Enzymatic Degradation. AB - The local hemodynamic shear stress waveforms present in an artery dictate the endothelial cell phenotype. The observed decrease of the apical glycocalyx layer on the endothelium in atheroprone regions of the circulation suggests that the glycocalyx may have a central role in determining atherosclerotic plaque formation. However, the kinetics for the cells' ability to adapt its glycocalyx to the environment have not been quantitatively resolved. Here we report that the heparan sulfate component of the glycocalyx of HUVECs increases by 1.4-fold following the onset of high shear stress, compared to static cultured cells, with a time constant of 19 h. Cell morphology experiments show that 12 h are required for the cells to elongate, but only after 36 h have the cells reached maximal alignment to the flow vector. Our findings demonstrate that following enzymatic degradation, heparan sulfate is restored to the cell surface within 12 h under flow whereas the time required is 20 h under static conditions. We also propose a model describing the contribution of endocytosis and exocytosis to apical heparan sulfate expression. The change in HS regrowth kinetics from static to high-shear EC phenotype implies a differential in the rate of endocytic and exocytic membrane turnover. PMID- 23805170 TI - Changes in mammary caveolin-1 signaling pathways are associated with breast cancer risk in rats exposed to estradiol in utero or during prepuberty. AB - Developmental stage of rat mammary gland at the time of estrogen exposure determines whether the exposure increases or reduces later breast cancer risk. For example, in utero exposure to 17beta-estradiol (E2) increases, whereas prepubertal exposure to this hormone decreases susceptibility of developing carcinogen-induced mammary tumors. E2 mediates its actions by interacting with caveolin-1 (CAV1), a putative tumor suppressor gene in breast cancer. Mammary tissues from 2-month-old rats exposed to E2 in utero contained decreased levels of CAV1, whereas prepubertal E2 exposure increased the levels, when compared to vehicle controls. Low CAV1 expression was associated with increased cell proliferation and estrogen receptor alpha expression, and reduced apoptosis in the mammary glands of rats exposed to E2 in utero. In contrast, high CAV1 expression correlated with reduced cell proliferation and cyclin D1 and phospho Akt levels, and increased apoptosis in the mammary glands of rats exposed to E2 during prepuberty. In support of the role of CAV1 as a negative regulator of a variety of pro-growth signaling proteins, we detected decreased levels of Src and ErbB2 in rats exposed to E2 during prepuberty. Thus, estrogen exposure during mammary gland development affects the expression and function of CAV1 in a manner consistent with observed changes in susceptibility to mammary tumorigenesis. PMID- 23805171 TI - ApoStream(TM), a new dielectrophoretic device for antibody independent isolation and recovery of viable cancer cells from blood. AB - Isolation and enumeration of circulating tumor cells (CTCs) are used to monitor metastatic disease progression and guide cancer therapy. However, currently available technologies are limited to cells expressing specific cell surface markers, such as epithelial cell adhesion molecule (EpCAM) or have limited specificity because they are based on cell size alone. We developed a device, ApoStream(TM) that overcomes these limitations by exploiting differences in the biophysical characteristics between cancer cells and normal, healthy blood cells to capture CTCs using dielectrophoretic technology in a microfluidic flow chamber. Further, the system overcomes throughput limitations by operating in continuous mode for efficient isolation and enrichment of CTCs from blood. The performance of the device was optimized using a design of experiment approach for key operating parameters such as frequency, voltage and flow rates, and buffer formulations. Cell spiking studies were conducted using SKOV3 or MDA-MB-231 cell lines that have a high and low expression level of EpCAM, respectively, to demonstrate linearity and precision of recovery independent of EpCAM receptor levels. The average recovery of SKOV3 and MDA-MB-231 cancer cells spiked into approximately 12 * 10(6) peripheral blood mononuclear cells obtained from 7.5 ml normal human donor blood was 75.4% +/- 3.1% (n = 12) and 71.2% +/- 1.6% (n = 6), respectively. The intra-day and inter-day precision coefficients of variation of the device were both less than 3%. Linear regression analysis yielded a correlation coefficient (R(2)) of more than 0.99 for a spiking range of 4-2600 cells. The viability of MDA-MB-231 cancer cells captured with ApoStream was greater than 97.1% and there was no difference in cell growth up to 7 days in culture compared to controls. The ApoStream device demonstrated high precision and linearity of recovery of viable cancer cells independent of their EpCAM expression level. Isolation and enrichment of viable cancer cells from ApoStream enables molecular characterization of CTCs from a wide range of cancer types. PMID- 23805172 TI - SEMIPARAMETRIC ZERO-INFLATED MODELING IN MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA). AB - We analyze the Agatston score of coronary artery calcium (CAC) from the Multi Ethnic Study of Atherosclerosis (MESA) using semi-parametric zero-inflated modeling approach, where the observed CAC scores from this cohort consist of high frequency of zeroes and continuously distributed positive values. Both partially constrained and unconstrained models are considered to investigate the underlying biological processes of CAC development from zero to positive, and from small amount to large amount. Different from existing studies, a model selection procedure based on likelihood cross-validation is adopted to identify the optimal model, which is justified by comparative Monte Carlo studies. A shrinkaged version of cubic regression spline is used for model estimation and variable selection simultaneously. When applying the proposed methods to the MESA data analysis, we show that the two biological mechanisms influencing the initiation of CAC and the magnitude of CAC when it is positive are better characterized by an unconstrained zero-inflated normal model. Our results are significantly different from those in published studies, and may provide further insights into the biological mechanisms underlying CAC development in human. This highly flexible statistical framework can be applied to zero-inflated data analyses in other areas. PMID- 23805173 TI - Acute Myocardial Infarction and Pulmonary Diseases Result in Two Different Degradation Profiles of Elastin as Quantified by Two Novel ELISAs. AB - BACKGROUND: Elastin is a signature protein of the arteries and lungs, thus it was hypothesized that elastin is subject to enzymatic degradation during cardiovascular and pulmonary diseases. The aim was to investigate if different fragments of the same protein entail different information associated to two different diseases and if these fragments have the potential of being diagnostic biomarkers. METHODS: Monoclonal antibodies were raised against an identified fragment (the ELM-2 neoepitope) generated at the amino acid position '552 in elastin by matrix metalloproteinase (MMP) -9/-12. A newly identified ELM neoepitope was generated by the same proteases but at amino acid position '441. The distribution of ELM-2 and ELM, in human arterial plaques and fibrotic lung tissues were investigated by immunohistochemistry. A competitive ELISA for ELM-2 was developed. The clinical relevance of the ELM and ELM-2 ELISAs was evaluated in patients with acute myocardial infarction (AMI), no AMI, high coronary calcium, or low coronary calcium. The serological release of ELM-2 in patients with chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis (IPF) was compared to controls. RESULTS: ELM and ELM-2 neoepitopes were both localized in diseased carotid arteries and fibrotic lungs. In the cardiovascular cohort, ELM-2 levels were 66% higher in serum from AMI patients compared to patients with no AMI (p<0.01). Levels of ELM were not significantly increased in these patients and no correlation was observed between ELM-2 and ELM. ELM-2 was not elevated in the COPD and IPF patients and was not correlated to ELM. ELM was shown to be correlated with smoking habits (p<0.01). CONCLUSIONS: The ELM-2 neoepitope was related to AMI whereas the ELM neoepitope was related to pulmonary diseases. These results indicate that elastin neoepitopes generated by the same proteases but at different amino acid sites provide different tissue related information depending on the disease in question. PMID- 23805174 TI - Comparison of Dynamic and Liver-Specific Gadoxetic Acid Contrast-Enhanced MRI versus Apparent Diffusion Coefficients. AB - BACKGROUND: Hepatic lesions often present diagnostic connundrums with conventional MR techniques. Hepatobiliary phase contrast-enhanced imaging with gadoxetic acid can aid in the characterization of such lesions. However, quantitative measures describing late-phase enhancement must be assessed relative to their accuracy of hepatic lesion classification. PURPOSE: To compare quantitative parameters in gadoxetic acid contrast-enhanced dynamic and hepatobiliary phase imaging versus apparent diffusion coefficients in hepatic lesion characterization. MATERIAL AND METHODS: 57 patients with focal hepatic lesions on gadoxetic acid MR were included. Lesion enhancement at standard post contrast time points and in the hepatobiliary phase (HB; 15 and 25 minutes post contrast) was assessed via calculation of contrast (CR) and enhancement ratios (ER). Apparent diffusion coefficient (ADC) values were also obtained. Values for these parameters were compared among lesions and ROC analyses performed. RESULTS: HB enhancement was greatest with FNH and adenomas. HB ER parameters but not HB CR could distinguish HCC from benign entities (0.9 ER ROC AUC versus 0.5 CR ROC AUC). There was no statistically significant difference found between the 15 and 25 minutes HB time points in detection of any lesion (p>0.4). ADC values were statistically significantly higher with hemangiomas (p<0.05) without greater accuracy in lesion detection relative to HB phase parameters. CONCLUSION: Hepatobiliary phase gadoxetic acid contrast-enhanced MR characterizes focal hepatic lesions more accurately than ADC and conventional dynamic post-contrast time point enhancement parameters. ER values are generally superior to CR. No discernible benefit of 25 minute versus 15 minute delayed imaging is demonstrated. PMID- 23805175 TI - Determinants of the Changes in Glycemic Control with Exercise Training in Type 2 Diabetes: A Randomized Trial. AB - AIMS: To assess the determinants of exercise training-induced improvements in glucose control (HbA1C) including changes in serum total adiponectin and FFA concentrations, and skeletal muscle peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) protein content. METHODS: A sub-cohort (n = 35; 48% men; 74% Caucasian) from the HART-D study undertaking muscle biopsies before and after 9 months of aerobic (AT), resistance (RT), or combination training (ATRT). RESULTS: Changes in HbA1C were associated with changes in adiponectin (r = -0.45, P = 0.007). Participants diagnosed with type 2 diabetes for a longer duration had the largest increase in PGC-1alpha (r = 0.44, P = 0.008). Statistical modeling examining changes in HbA1C suggested that male sex (P = 0.05), non-Caucasian ethnicity (P = 0.02), duration of type 2 diabetes (r = 0.40; P<0.002) and changes in FFA (r = 0.36; P<0.004), adiponectin (r = -0.26; P<0.03), and PGC-1alpha (r = -0.28; P = 0.02) explain ~65% of the variability in the changes in HbA1C. CONCLUSIONS: Decreases in HbA1C after 9 months of exercise were associated with shorter duration of diabetes, lowering of serum FFA concentrations, increasing serum adiponectin concentrations and increasing skeletal muscle PGC-1alpha protein expression. TRIAL REGISTRATION: ClinicalTrials.gov NCT00458133. PMID- 23805176 TI - Cost-Effectiveness of a Community Pharmacist-Led Sleep Apnea Screening Program - A Markov Model. AB - BACKGROUND: Despite the high prevalence and major public health ramifications, obstructive sleep apnea syndrome (OSAS) remains underdiagnosed. In many developed countries, because community pharmacists (CP) are easily accessible, they have been developing additional clinical services that integrate the services of and collaborate with other healthcare providers (general practitioners (GPs), nurses, etc.). Alternative strategies for primary care screening programs for OSAS involving the CP are discussed. OBJECTIVE: To estimate the quality of life, costs, and cost-effectiveness of three screening strategies among patients who are at risk of having moderate to severe OSAS in primary care. DESIGN: Markov decision model. DATA SOURCES: Published data. TARGET POPULATION: Hypothetical cohort of 50-year-old male patients with symptoms highly evocative of OSAS. TIME HORIZON: The 5 years after initial evaluation for OSAS. PERSPECTIVE: Societal. INTERVENTIONS: Screening strategy with CP (CP-GP collaboration), screening strategy without CP (GP alone) and no screening. OUTCOMES MEASURES: Quality of life, survival and costs for each screening strategy. RESULTS OF BASE-CASE ANALYSIS: Under almost all modeled conditions, the involvement of CPs in OSAS screening was cost effective. The maximal incremental cost for "screening strategy with CP" was about 455? per QALY gained. RESULTS OF SENSITIVITY ANALYSIS: Our results were robust but primarily sensitive to the treatment costs by continuous positive airway pressure, and the costs of untreated OSAS. The probabilistic sensitivity analysis showed that the "screening strategy with CP" was dominant in 80% of cases. It was more effective and less costly in 47% of cases, and within the cost-effective range (maximum incremental cost effectiveness ratio at ?6186.67/QALY) in 33% of cases. CONCLUSIONS: CP involvement in OSAS screening is a cost-effective strategy. This proposal is consistent with the trend in Europe and the United States to extend the practices and responsibilities of the pharmacist in primary care. PMID- 23805178 TI - Phrasal Paraphrase Based Question Reformulation for Archived Question Retrieval. AB - Lexical gap in cQA search, resulted by the variability of languages, has been recognized as an important and widespread phenomenon. To address the problem, this paper presents a question reformulation scheme to enhance the question retrieval model by fully exploring the intelligence of paraphrase in phrase level. It compensates for the existing paraphrasing research in a suitable granularity, which either falls into fine-grained lexical-level or coarse-grained sentence-level. Given a question in natural language, our scheme first detects the involved key-phrases by jointly integrating the corpus-dependent knowledge and question-aware cues. Next, it automatically extracts the paraphrases for each identified key-phrase utilizing multiple online translation engines, and then selects the most relevant reformulations from a large group of question rewrites, which is formed by full permutation and combination of the generated paraphrases. Extensive evaluations on a real world data set demonstrate that our model is able to characterize the complex questions and achieves promising performance as compared to the state-of-the-art methods. PMID- 23805177 TI - The Prognostic Role of Ezrin Immunoexpression in Osteosarcoma: A Meta-Analysis of Published Data. AB - BACKGROUND: The significance of ezrin immunoexpression and prognosis for osteosarcoma is still controversial. The aim was to provide a meta-analysis for ezrin immunoexpression and prognostic features of osteosarcoma patients. METHODS: A detailed search was made in MEDLINE, EMBASE and the Web of Knowledge for relevant original articles published in English; methodological quality of the included studies was also assessed. Two reviewers extracted data independently. Studies were pooled and summary hazard ratios (HRs) and odds ratio (ORs) with corresponding confidence intervals (CIs) were calculated. RESULTS: Final analysis of 318 patients from 5 eligible studies was performed. Combined HR of ezrin immunohistochemical staining suggested that positive immunoexpression had an unfavorable impact on osteosarcoma patients' overall survival (n = 223 in 4 studies; HR = 4.79; 95% CI: 1.50-15.30; P = 0.008) but not on event-free survival (n = 202 in 3 studies; HR = 1.59; 95% CI: 0.61-4.15; P = 0. 0.342). Combined OR of ezrin immunohistochemical staining indicated that positive immunoexpression was associated with recurrence (n = 134 in 2 studies; OR = 3.79; 95% CI: 1.49 9.64; P = 0.005) but not with serum ALP level (n = 160 in 2 studies; OR = 2.16; 95% CI: 0.09-52.50; P = 0.637) and histological response to neoadjuvant chemotherapy(n = 260 in 4 studies; OR = 0.87; 95% CI: 0.37-2.03; P = 0.740). CONCLUSIONS: The results of this meta-analysis suggest that ezrin positive immunoexpression confers a higher risk of recurrence and a worse survival in osteosarcoma patients. Large prospective studies are needed to provide solid data to investigate the precise prognostic significance of ezrin. PMID- 23805180 TI - Occult and Overt HBV Co-Infections Independently Predict Postoperative Prognosis in HCV-Associated Hepatocellular Carcinoma. AB - OBJECTIVE AND BACKGROUND: The roles of chronic hepatitis B virus (HBV) co infection (CI) in carcinogenesis of hepatitis C virus (HCV)-associated hepatocellular carcinoma (HCC) remained controversial. To gain new insights into this issue, we investigated the postoperative prognostic value of HBVCI in HCV associated HCC. METHODS: A study cohort of 115 liver tissues obtained from the noncancerous parts of surgically removed HCV-associated HCCs were subjected to virological analysis in a tertiary care setting. Assayed factors included clinicopathological variables, tissue amounts of viral genomes, genotypic characterization of viruses, as well as the presence of overt (serum HBsAg positive) or occult (serum HBsAg negative but tissue HBV-DNA positive) HBVCI. Cox proportional hazard model was used to estimate postoperative survivals. RESULTS: Of the 115 patients, overt and occult HBVCIs were detected in 35 and 16 patients, respectively. Multivariate analysis revealed that tumor size >3 cm (adjusted hazard ratio (AHR), 2.079 [95% confidence interval, 1.149~3.761]), alpha fetoprotein >8 ng/mL (AHR, 5.976 [2.007~17.794]) albumin <4 g/dL(AHR, 2.539 [1.399~4.606]), ALT >50 U/L (AHR,1.086 [1.006~1.172]), presence of occult HBVCI (AHR, 2.708 [1.317~5.566]), and absence of overt HBVCI (AHR, 2.216 [1.15~4.269]) were independently associated with unfavorable disease-free survival. Patients with occult HBVCI had a shorter disease-free (P = 0.002), a shorter overall survival (P = 0.026), a higher bilirubin level (P = 0.003) and a higher prevalence of precore G1896A mutation (P = 0.006) compared with those with overt HBVCI. CONCLUSION: Occult and overt HBVCI served as independent predictors for postoperative survival in HCV-associated HCC. PMID- 23805181 TI - Synchrotron Reveals Early Triassic Odd Couple: Injured Amphibian and Aestivating Therapsid Share Burrow. AB - Fossorialism is a beneficial adaptation for brooding, predator avoidance and protection from extreme climate. The abundance of fossilised burrow casts from the Early Triassic of southern Africa is viewed as a behavioural response by many tetrapods to the harsh conditions following the Permo-Triassic mass-extinction event. However, scarcity of vertebrate remains associated with these burrows leaves many ecological questions unanswered. Synchrotron scanning of a lithified burrow cast from the Early Triassic of the Karoo unveiled a unique mixed-species association: an injured temnospondyl amphibian (Broomistega) that sheltered in a burrow occupied by an aestivating therapsid (Thrinaxodon). The discovery of this rare rhinesuchid represents the first occurrence in the fossil record of a temnospondyl in a burrow. The amphibian skeleton shows signs of a crushing trauma with partially healed fractures on several consecutive ribs. The presence of a relatively large intruder in what is interpreted to be a Thrinaxodon burrow implies that the therapsid tolerated the amphibian's presence. Among possible explanations for such unlikely cohabitation, Thrinaxodon aestivation is most plausible, an interpretation supported by the numerous Thrinaxodon specimens fossilised in curled-up postures. Recent advances in synchrotron imaging have enabled visualization of the contents of burrow casts, thus providing a novel tool to elucidate not only anatomy but also ecology and biology of ancient tetrapods. PMID- 23805179 TI - A Genome-Wide Association Study Suggests Novel Loci Associated with a Schizophrenia-Related Brain-Based Phenotype. AB - Patients with schizophrenia and their siblings typically show subtle changes of brain structures, such as a reduction of hippocampal volume. Hippocampal volume is heritable, may explain a variety of cognitive symptoms of schizophrenia and is thus considered an intermediate phenotype for this mental illness. The aim of our analyses was to identify single-nucleotide polymorphisms (SNP) related to hippocampal volume without making prior assumptions about possible candidate genes. In this study, we combined genetics, imaging and neuropsychological data obtained from the Mind Clinical Imaging Consortium study of schizophrenia (n = 328). A total of 743,591 SNPs were tested for association with hippocampal volume in a genome-wide association study. Gene expression profiles of human hippocampal tissue were investigated for gene regions of significantly associated SNPs. None of the genetic markers reached genome-wide significance. However, six highly correlated SNPs (rs4808611, rs35686037, rs12982178, rs1042178, rs10406920, rs8170) on chromosome 19p13.11, located within or in close proximity to the genes NR2F6, USHBP1, and BABAM1, as well as four SNPs in three other genomic regions (chromosome 1, 2 and 10) had p-values between 6.75*10(-6) and 8.3*10(-7). Using existing data of a very recently published GWAS of hippocampal volume and additional data of a multicentre study in a large cohort of adolescents of European ancestry, we found supporting evidence for our results. Furthermore, allelic differences in rs4808611 and rs8170 were highly associated with differential mRNA expression in the cis-acting region. Associations with memory functioning indicate a possible functional importance of the identified risk variants. Our findings provide new insights into the genetic architecture of a brain structure closely linked to schizophrenia. In silico replication, mRNA expression and cognitive data provide additional support for the relevance of our findings. Identification of causal variants and their functional effects may unveil yet unknown players in the neurodevelopment and the pathogenesis of neuropsychiatric disorders. PMID- 23805182 TI - Oligomerization of Peptides LVEALYL and RGFFYT and Their Binding Affinity to Insulin. AB - Recently it has been proposed a model for fibrils of human insulin in which the fibril growth proceeds via stacking LVEALYL (fragment 11-17 from chain B of insulin) into pairs of tightly interdigitated [Formula: see text]-sheets. The experiments have also shown that LVEALYL has high propensity to self-assembly and binding to insulin. This necessitates study of oligomerization of LVEALYL and its binding affinity to full-length insulin. Using the all-atom simulations with Gromos96 43a1 force field and explicit water it is shown that LVEALYL can aggregate. Theoretical estimation of the binding free energy of LVEALYL to insulin by the molecular mechanic Poisson-Boltzmann surface area method reveals its strong binding affinity to chain B, implying that, in agreement with the experiments, LVEALYL can affect insulin aggregation via binding mechanism. We predict that, similar to LVEALYL, peptide RGFFYT (fragment B22-27) can self assemble and bind to insulin modulating its fibril growth process. The binding affinity of RGFFYT is shown to be comparable with that of LVEALYL. PMID- 23805183 TI - Is Pain Intensity Really That Important to Assess in Chronic Pain Patients? A Study Based on the Swedish Quality Registry for Pain Rehabilitation (SQRP). AB - BACKGROUND: Incorporating the patient's view on care and treatment has become increasingly important for health care. Patients describe the variety of consequences of their chronic pain conditions as significant pain intensity, depression, and anxiety. We hypothesised that intensities of common symptoms in chronic pain conditions carry important information that can be used to identify clinically relevant subgroups. This study has three aims: 1) to determine the importance of different symptoms with respect to participation and ill-health; 2) to identify subgroups based on data concerning important symptoms; and 3) to determine the secondary consequences for the identified subgroups with respect to participation and health factors. METHODS AND SUBJECTS: This study is based on a cohort of patients referred to a multidisciplinary pain centre at a university hospital (n = 4645, participation rate 88%) in Sweden. The patients answered a number of questionnaires concerning symptoms, participation, and health aspects as a part of the Swedish Quality Registry for Pain Rehabilitation (SQRP). RESULTS: Common symptoms (such as pain intensity, depression, and anxiety) in patients with chronic pain showed great variability across subjects and 60% of the cohort had normal values with respect to depressive and anxiety symptoms. Pain intensity more than psychological symptoms showed stronger relationships with participation and health. It was possible to identify subgroups based on pain intensity, depression, and anxiety. With respect to participation and health, high depressive symptomatology had greater negative consequences than high anxiety. CONCLUSIONS: Common symptoms (such as pain intensity and depressive and anxiety symptoms) in chronic pain conditions carry important information that can be used to identify clinically relevant subgroups. PMID- 23805184 TI - Aberrant Pregnancy Adaptations in the Peripheral Immune Response in Type 1 Diabetes: A Rat Model. AB - INTRODUCTION: Despite tight glycemic control, pregnancy complication rate in type 1 diabetes patients is higher than in normal pregnancy. Other etiological factors may be responsible for the development of adverse pregnancy outcome. Acceptance of the semi-allogeneic fetus is accompanied by adaptations in the maternal immune response. Maladaptations of the immune-response has been shown to contribute to pregnancy complications. We hypothesized that type 1 diabetes, as an autoimmune disease, may be associated with maladaptations of the immune-response to pregnancy, possibly resulting in pregnancy complications. METHODS: We studied pregnancy outcome and pregnancy-induced immunological adaptations in a normoglycemic rat-model of type 1 diabetes, i.e. biobreeding diabetes-prone rats (BBDP; 5 non-pregnant rats, 7 pregnant day 10 rats and 6 pregnant day 18 rats) , versus non-diabetic control rats (i.e. congenic non-diabetic biobreeding diabetes resistant (BBDR; 6 non-pregnant rats, 6 pregnant day 10 rats and 6 pregnant day 18 rats) and Wistar-rats (6 non-pregnant, 6 pregnant day 10 rats and 5 pregnant day 18 rats)). RESULTS: We observed reduced litter size, lower fetal weight of viable fetuses and increased numbers of resorptions versus control rats. These complications are accompanied by various differences in the immune-response between BBDP and control rats in both pregnant and non-pregnant animals. The immune-response in non-pregnant BBDP-rats was characterized by decreased percentages of lymphocytes, increased percentages of effector T-cells, regulatory T-cells and natural killer cells, an increased Th1/Th2-ratio and activated monocytes versus Wistar and BBDR-rats. Furthermore, pregnancy-induced adaptations in BBDP-rats coincided with an increased Th1/Th2-ratio, a decreased mean fluorescence intensity CD161a/NKR-P1b ratio and no further activation of monocytes versus non-diabetic control rats. CONCLUSION: This study suggests that even in the face of strict normoglycemia, pregnancy complications still occur in type 1 diabetic pregnancies. This adverse pregnancy outcome may be related to the aberrant immunological adaptations to pregnancy in diabetic rats. PMID- 23805185 TI - Allele and Haplotype Diversity of 26 X-STR Loci in Four Nationality Populations from China. AB - BACKGROUND: Haplotype analysis of closely associated markers has proven to be a powerful tool in kinship analysis, especially when short tandem repeats (STR) fail to resolve uncertainty in relationship analysis. STR located on the X chromosome show stronger linkage disequilibrium compared with autosomal STR. So, it is necessary to estimate the haplotype frequencies directly from population studies as linkage disequilibrium is population-specific. METHODOLOGY AND FINDINGS: Twenty-six X-STR loci including six clusters of linked markers DXS6807 DXS8378-DXS9902(Xp22), DXS7132-DXS10079-DXS10074-DXS10075-DXS981 (Xq12), DXS6801 DXS6809-DXS6789-DXS6799(Xq21), DXS7424-DXS101-DXS7133(Xq22), DXS6804 GATA172D05(Xq23), DXS8377-DXS7423 (Xq28) and the loci DXS6800, DXS6803, DXS9898, GATA165B12, DXS6854, HPRTB and GATA31E08 were typed in four nationality (Han, Uigur, Kazakh and Mongol) samples from China (n = 1522, 876 males and 646 females). Allele and haplotype frequency as well as linkage disequilibrium data for kinship calculation were observed. The allele frequency distribution among different populations was compared. A total of 5-20 alleles for each locus were observed and altogether 289 alleles for all the selected loci were found. Allele frequency distribution for most X-STR loci is different in different populations. A total of 876 male samples were investigated by haplotype analysis and for linkage disequilibrium. A total of 89, 703, 335, 147, 39 and 63 haplotypes were observed. Haplotype diversity was 0.9584, 0.9994, 0.9935, 0.9736, 0.9427 and 0.9571 for cluster I, II, III, IV, V and VI, respectively. Eighty-two percent of the haplotype of cluster IIwas found only once. And 94% of the haplotype of cluster III show a frequency of <1%. CONCLUSIONS: These results indicate that allele frequency distribution for most X-STR loci is population-specific and haplotypes of six clusters provide a powerful tool for kinship testing and relationship investigation. So it is necessary to obtain allele frequency and haplotypes data of the linked loci for forensic application. PMID- 23805186 TI - Low-Grade Albuminuria Is Associated with Metabolic Syndrome and Its Components in Middle-Aged and Elderly Chinese Population. AB - BACKGROUND: Micro-albuminuria has been well established as one of the risk factors of metabolic syndrome (MetS). However, the association of MetS and its components with low-grade albuminuria among those with normal urinary albumin excretion has not been clearly elucidated in Chinese population. METHODOLOGY AND FINDINGS: A cross-sectional study was conducted among 9,579 participants with normal urinary albumin excretion, who were recruited from Jia Ding District, Shanghai, China. The single-void first morning urine sample was collected for urinary albumin and creatinine measurements, and urinary albumin-to-creatinine ratio (UACR) was calculated as urinary albumin divided by creatinine. Low-grade albuminuria was classified as sex-specific upper UACR quartile in this population. MetS was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria. The prevalence of MetS and its components increased across the UACR quartiles (all P trend <0.01). A multivariable adjusted logistic regression analysis revealed that the prevalence of MetS was gradually elevated according to the UACR quartiles (adjusted odds ratios [ORs] were 1.14, 1.24 and 1.59 for UACR quartiles 2, 3 and 4, compared with the lowest quartile; P trend<0.0001). In the further stratified logistic regression analyses, the associations between low-grade albuminuria and MetS were significant in both sex strata (male and female), both age strata (<60 and >=60 years), both body mass index strata (<24 and >=24 kg/m(2)), and both diabetes strata (yes and no). Compared to the lowest UACR quartile, the participants in the highest quartile of UACR had the highest prevalence of central obesity (OR = 1.43; 95%CI = 1.25-1.63), high blood pressure (OR = 1.64; 95%CI = 1.43-1.87), hyperglycemia (OR = 1.52; 95%CI = 1.30-1.78) and high triglycerides (OR = 1.19; 95%CI = 1.04-1.37). CONCLUSIONS AND SIGNIFICANCE: Low-grade albuminuria was significantly associated with the increasing prevalence of MetS and its components in the middle-aged and elderly Chinese population with normal urinary albumin excretion. PMID- 23805187 TI - Refinement of Imaging Predictors of Recurrent Events following Transient Ischemic Attack and Minor Stroke. AB - BACKGROUND: TIA and minor stroke have a high risk of recurrent stroke. Abnormalities on CT/CTA and MRI predict recurrent events in TIA and minor stroke. However there are many other imaging abnormalities that could potentially predict outcome that have not been assessed in this population. Also the definition of recurrent events used includes deterioration due to stroke progression or recurrent stroke and whether imaging is either of these is not known. AIMS: To improve upon the clinical, CT/CTA and MRI parameters that predict recurrent events after TIA and minor stroke by assessing further imaging parameters. Secondary aim was to explore predictors of stroke progression versus recurrent stroke. METHODS: 510 consecutive TIA and minor stroke patients had CT/CTA and most had MRI. Primary outcome was recurrent events (stroke progression or recurrent stroke) within 90 days. Further imaging parameters were assessed for prediction of recurrent events (combined outcome of stroke progression and recurrent stroke). We also explored predictors of symptom progression versus recurrence individually. RESULTS: 36 recurrent events (36/510, 7.1% (95% CI: 5.0 9.6)) including 19 progression and 17 recurrent strokes. On CT/CTA: white matter disease, prior stroke, aortic arch focal plaque>=4 mm, or intraluminal thrombus did not predict recurrent events (progression or recurrent stroke). On MRI: white matter disease, prior stroke, and microbleeds did not predict recurrent events. Parameters predicting the individual outcome of symptom progression included: ongoing symptoms at initial assessment, symptom fluctuation, intracranial occlusion, intracranial occlusion or stenosis, and the CT/CTA metric. No parameter was strongly predictive of a distinct recurrent stroke. CONCLUSIONS: There was no imaging parameter that could improve upon our original CT/CTA or MRI metrics to predict the combined outcome of stroke progression or a recurrent stroke after TIA and minor stroke. We are better at using imaging to predict stroke progression rather than recurrent stroke. PMID- 23805188 TI - Vitamin D (25OHD) Serum Seasonality in the United States. AB - BACKGROUND: Vitamin D is an important micronutrient for health. Hypovitaminosis D is thought to play a role in the seasonality of a number of diseases and adverse health conditions. To refine hypotheses about the links between vitamin D and seasonal diseases, good estimates of the cyclicality of serum vitamin D are necessary. OBJECTIVES: The objective of this study is to describe quantitatively the cyclicality of 25-hydroxyvitamin D (25OHD) in the United States. We provide a statistical analysis with weekly time resolution, in comparison to the quarterly (winter/spring/summer/fall) estimates already in the literature. METHODS: We analyzed time series data on 25OHD, spanning 287 consecutive weeks. The pooled data set comes from 3.44 million serum samples from the United States. We statistically analyzed the proportion of sera that were vitamin D sufficient, defined as 25OHD [Formula: see text] ng/mL, as a function of date. RESULTS: In the United States, serum 25OHD follows a lagged pattern relative to the astronomical seasons, peaking in late summer (August) and troughing in late winter (February). Airmass, which is a function of solar altitude, fits the 25OHD data very well when lagged by 8 weeks. CONCLUSIONS: Serum vitamin D levels can be modeled as a function of date, working through a double-log transformation of minimal solar airmass (easily calculated from solar altitude, retrievable from an online solar altitude/azimuth table). PMID- 23805189 TI - Crawling at High Speeds: Steady Level Locomotion in the Spider Cupiennius salei Global Kinematics and Implications for Centre of Mass Dynamics. AB - Spiders are an old yet very successful predatory group of arthropods. Their locomotor system differs from those of most other arthropods by the lack of extensor muscles in two major leg joints. Though specific functional characteristics can be expected regarding the locomotion dynamics of spiders, this aspect of movement physiology has been only scarcely examined so far. This study presents extensive analyses of a large dataset concerning global kinematics and the implications for dynamics of adult female specimens of the large Central American spider Cupiennius salei (Keyserling). The experiments covered the entire speed-range of straight runs at constant speeds. The analyses revealed specific characteristics of velocity dependent changes in the movements of the individual legs, as well as in the translational and rotational degrees of freedom of both the centre of mass and the body. In contrast to many other fast moving arthropods, C. salei avoid vertical fluctuations of their centre of mass during fast locomotion. Accordingly, aerial phases were not observed here. This behaviour is most likely a consequence of optimising energy expenditure with regard to the specific requirements of spiders' leg anatomy. A strong synchronisation of two alternating sets of legs appears to play only a minor role in the locomotion of large spiders. Reduced frequency and low centre of mass amplitudes as well as low angular changes of the body axes, in turn, seems to be the result of relatively low leg coordination. PMID- 23805190 TI - First Insight into Exploration and Cognition in Wild Caught and Domesticated Sea Bass (Dicentrarchus labrax) in a Maze. AB - European sea bass aquaculture is so recent that very little is known on the effects of the early steps of its domestication. Behavioural parameters are sensitive indicators of the domestication process since they are generally impacted as soon as the first generation. The present work compared wild-caught and domesticated sea bass juvenile swimming activity, exploration and ability to learn to discriminate between two 2-D objects associated to a simple spatial task that enabled the tested individual to visually interact with an unfamiliar congener (the reward) located behind a transparent wall at the end of one of the two arms of a maze. Ten fish from each origin were individually tested 3 times in a row during 3 days (9 trials in total). Fish were placed in a start box closed by a transparent wall located in front of two 2-D objects. Fish were filmed during 10 min after the removal of the start box wall. Different swimming variables including angular velocity, total distance travelled and velocity mean, were analyzed from videos as well as the time spent in each of 6 virtual zones including the reward zone near the congener (Cong) and the zone opposite to the reward zone (OpCong). Two learning criteria were chosen: the number of successful turns and time to reach Cong. Behavioural differences were found between domesticated and wild fish. Angular velocity was higher in wild fish while the distance travelled and the velocity mean were higher in domesticated ones. Wild and domesticated fish spent most of the time in Cong and in OpCong. No differences were seen in learning ability between wild and domesticated fish. However, our findings for learning require confirmation by further studies with larger numbers of learning sessions and experiments designed to minimise stress. This study therefore demonstrated an impact of domestication on swimming behaviour but not on spatial learning. PMID- 23805191 TI - Drug Promiscuity in PDB: Protein Binding Site Similarity Is Key. AB - Drug repositioning applies established drugs to new disease indications with increasing success. A pre-requisite for drug repurposing is drug promiscuity (polypharmacology) - a drug's ability to bind to several targets. There is a long standing debate on the reasons for drug promiscuity. Based on large compound screens, hydrophobicity and molecular weight have been suggested as key reasons. However, the results are sometimes contradictory and leave space for further analysis. Protein structures offer a structural dimension to explain promiscuity: Can a drug bind multiple targets because the drug is flexible or because the targets are structurally similar or even share similar binding sites? We present a systematic study of drug promiscuity based on structural data of PDB target proteins with a set of 164 promiscuous drugs. We show that there is no correlation between the degree of promiscuity and ligand properties such as hydrophobicity or molecular weight but a weak correlation to conformational flexibility. However, we do find a correlation between promiscuity and structural similarity as well as binding site similarity of protein targets. In particular, 71% of the drugs have at least two targets with similar binding sites. In order to overcome issues in detection of remotely similar binding sites, we employed a score for binding site similarity: LigandRMSD measures the similarity of the aligned ligands and uncovers remote local similarities in proteins. It can be applied to arbitrary structural binding site alignments. Three representative examples, namely the anti-cancer drug methotrexate, the natural product quercetin and the anti-diabetic drug acarbose are discussed in detail. Our findings suggest that global structural and binding site similarity play a more important role to explain the observed drug promiscuity in the PDB than physicochemical drug properties like hydrophobicity or molecular weight. Additionally, we find ligand flexibility to have a minor influence. PMID- 23805192 TI - Improved Analysis of Long-Term Monitoring Data Demonstrates Marked Regional Declines of Bat Populations in the Eastern United States. AB - Bats are diverse and ecologically important, but are also subject to a suite of severe threats. Evidence for localized bat mortality from these threats is well documented in some cases, but long-term changes in regional populations of bats remain poorly understood. Bat hibernation surveys provide an opportunity to improve understanding, but analysis is complicated by bats' cryptic nature, non conformity of count data to assumptions of traditional statistical methods, and observation heterogeneities such as variation in survey timing. We used generalized additive mixed models (GAMMs) to account for these complicating factors and to evaluate long-term, regional population trajectories of bats. We focused on four hibernating bat species - little brown myotis (Myotis lucifugus), tri-colored bat (Perimyotis subflavus), Indiana myotis (M. sodalis), and northern myotis (M. septentrionalis) - in a four-state region of the eastern United States during 1999-2011. Our results, from counts of nearly 1.2 million bats, suggest that cumulative declines in regional relative abundance by 2011 from peak levels were 71% (with 95% confidence interval of +/-11%) in M. lucifugus, 34% (+/-38%) in P. subflavus, 30% (+/-26%) in M. sodalis, and 31% (+/-18%) in M. septentrionalis. The M. lucifugus population fluctuated until 2004 before persistently declining, and the populations of the other three species declined persistently throughout the study period. Population trajectories suggest declines likely resulted from the combined effect of multiple threats, and indicate a need for enhanced conservation efforts. They provide strong support for a change in the IUCN Red List conservation status in M. lucifugus from Least Concern to Endangered within the study area, and are suggestive of a need to change the conservation status of the other species. Our modeling approach provided estimates of uncertainty, accommodated non-linearities, and controlled for observation heterogeneities, and thus has wide applicability for evaluating population trajectories in other wildlife species. PMID- 23805193 TI - The Attenuated Brucella abortus Strain 19 Invades, Persists in, and Activates Human Dendritic Cells, and Induces the Secretion of IL-12p70 but Not IL-23. AB - BACKGROUND: Bacterial vectors have been proposed as novel vaccine strategies to induce strong cellular immunity. Attenuated strains of Brucella abortus comprise promising vector candidates since they have the potential to induce strong CD4(+) and CD8(+) T-cell mediated immune responses in the absence of excessive inflammation as observed with other Gram-negative bacteria. However, some Brucella strains interfere with the maturation of dendritic cells (DCs), which is essential for antigen-specific T-cell priming. In the present study, we investigated the interaction of human monocyte-derived DCs with the smooth attenuated B. abortus strain (S) 19, which has previously been employed successfully to vaccinate cattle. METHODOLOGY/PRINCIPAL FINDINGS: We first looked into the potential of S19 to hamper the cytokine-induced maturation of DCs; however, infected cells expressed CD25, CD40, CD80, and CD86 to a comparable extent as uninfected, cytokine-matured DCs. Furthermore, S19 activated DCs in the absence of exogeneous stimuli, enhanced the expression of HLA-ABC and HLA-DR, and was able to persist intracellularly without causing cytotoxicity. Thus, DCs provide a cellular niche for persisting brucellae in vivo as a permanent source of antigen. S19-infected DCs produced IL-12/23p40, IL-12p70, and IL-10, but not IL-23. While heat-killed bacteria also activated DCs, soluble mediators were not involved in S19-induced activation of human DCs. HEK 293 transfectants revealed cellular activation by S19 primarily through engagement of Toll-like receptor (TLR)2. CONCLUSIONS/SIGNIFICANCE: Thus, as an immunological prerequisite for vaccine efficacy, B. abortus S19 potently infects and potently activates (most likely via TLR2) human DCs to produce Th1-promoting cytokines. PMID- 23805194 TI - Neural Crest Cells Isolated from the Bone Marrow of Transgenic Mice Express JCV T Antigen. AB - JC virus (JCV), a common human polyomavirus, is the etiological agent of the demyelinating disease, progressive multifocal leukoencephalopathy (PML). In addition to its role in PML, studies have demonstrated the transforming ability of the JCV early protein, T-antigen, and its association with some human cancers. JCV infection occurs in childhood and latent virus is thought to be maintained within the bone marrow, which harbors cells of hematopoietic and non hematopoietic lineages. Here we show that non-hematopoietic mesenchymal stem cells (MSCs) isolated from the bone marrow of JCV T-antigen transgenic mice give rise to JCV T-antigen positive cells when cultured under neural conditions. JCV T antigen positive cells exhibited neural crest characteristics and demonstrated p75, SOX-10 and nestin positivity. When cultured in conditions typical for mesenchymal cells, a population of T-antigen negative cells, which did not express neural crest markers arose from the MSCs. JCV T-antigen positive cells could be cultured long-term while maintaining their neural crest characteristics. When these cells were induced to differentiate into neural crest derivatives, JCV T-antigen was downregulated in cells differentiating into bone and maintained in glial cells expressing GFAP and S100. We conclude that JCV T-antigen can be stably expressed within a fraction of bone marrow cells differentiating along the neural crest/glial lineage when cultured in vitro. These findings identify a cell population within the bone marrow permissible for JCV early gene expression suggesting the possibility that these cells could support persistent viral infection and thus provide clues toward understanding the role of the bone marrow in JCV latency and reactivation. Further, our data provides an excellent experimental model system for studying the cell-type specificity of JCV T-antigen expression, the role of bone marrow-derived stem cells in the pathogenesis of JCV related diseases and the opportunities for the use of this model in development of therapeutic strategies. PMID- 23805195 TI - Spatiotemporal Phylogenetic Analysis and Molecular Characterisation of Infectious Bursal Disease Viruses Based on the VP2 Hyper-Variable Region. AB - BACKGROUND: Infectious bursal disease is a highly contagious and acute viral disease caused by the infectious bursal disease virus (IBDV); it affects all major poultry producing areas of the world. The current study was designed to rigorously measure the global phylogeographic dynamics of IBDV strains to gain insight into viral population expansion as well as the emergence, spread and pattern of the geographical structure of very virulent IBDV (vvIBDV) strains. METHODOLOGY/PRINCIPAL FINDINGS: Sequences of the hyper-variable region of the VP2 (HVR-VP2) gene from IBDV strains isolated from diverse geographic locations were obtained from the GenBank database; Cuban sequences were obtained in the current work. All sequences were analysed by Bayesian phylogeographic analysis, implemented in the Bayesian Evolutionary Analysis Sampling Trees (BEAST), Bayesian Tip-association Significance testing (BaTS) and Spatial Phylogenetic Reconstruction of Evolutionary Dynamics (SPREAD) software packages. Selection pressure on the HVR-VP2 was also assessed. The phylogeographic association-trait analysis showed that viruses sampled from individual countries tend to cluster together, suggesting a geographic pattern for IBDV strains. Spatial analysis from this study revealed that strains carrying sequences that were linked to increased virulence of IBDV appeared in Iran in 1981 and spread to Western Europe (Belgium) in 1987, Africa (Egypt) around 1990, East Asia (China and Japan) in 1993, the Caribbean Region (Cuba) by 1995 and South America (Brazil) around 2000. Selection pressure analysis showed that several codons in the HVR-VP2 region were under purifying selection. CONCLUSIONS/SIGNIFICANCE: To our knowledge, this work is the first study applying the Bayesian phylogeographic reconstruction approach to analyse the emergence and spread of vvIBDV strains worldwide. PMID- 23805196 TI - An Evaluation of Methods for Inferring Boolean Networks from Time-Series Data. AB - Regulatory networks play a central role in cellular behavior and decision making. Learning these regulatory networks is a major task in biology, and devising computational methods and mathematical models for this task is a major endeavor in bioinformatics. Boolean networks have been used extensively for modeling regulatory networks. In this model, the state of each gene can be either 'on' or 'off' and that next-state of a gene is updated, synchronously or asynchronously, according to a Boolean rule that is applied to the current-state of the entire system. Inferring a Boolean network from a set of experimental data entails two main steps: first, the experimental time-series data are discretized into Boolean trajectories, and then, a Boolean network is learned from these Boolean trajectories. In this paper, we consider three methods for data discretization, including a new one we propose, and three methods for learning Boolean networks, and study the performance of all possible nine combinations on four regulatory systems of varying dynamics complexities. We find that employing the right combination of methods for data discretization and network learning results in Boolean networks that capture the dynamics well and provide predictive power. Our findings are in contrast to a recent survey that placed Boolean networks on the low end of the "faithfulness to biological reality" and "ability to model dynamics" spectra. Further, contrary to the common argument in favor of Boolean networks, we find that a relatively large number of time points in the time series data is required to learn good Boolean networks for certain data sets. Last but not least, while methods have been proposed for inferring Boolean networks, as discussed above, missing still are publicly available implementations thereof. Here, we make our implementation of the methods available publicly in open source at http://bioinfo.cs.rice.edu/. PMID- 23805197 TI - Genotype-Phenotype Correlation of 2q37 Deletions Including NPPC Gene Associated with Skeletal Malformations. AB - Coordinated bone growth is controlled by numerous mechanisms which are only partially understood because of the involvement of many hormones and local regulators. The C-type Natriuretic Peptide (CNP), encoded by NPPC gene located on chromosome 2q37.1, is a molecule that regulates endochondral ossification of the cartilaginous growth plate and influences longitudinal bone growth. Two independent studies have described three patients with a Marfan-like phenotype presenting a de novo balanced translocation involving the same chromosomal region 2q37.1 and overexpression of NPPC. We report on two partially overlapping interstitial 2q37 deletions identified by array CGH. The two patients showed opposite phenotypes characterized by short stature and skeletal overgrowth, respectively. The patient with short stature presented a 2q37 deletion causing the loss of one copy of the NPPC gene and the truncation of the DIS3L2 gene with normal CNP plasma concentration. The deletion identified in the patient with a Marfan-like phenotype interrupted the DIS3L2 gene without involving the NPPC gene. In addition, a strongly elevated CNP plasma concentration was found in this patient. A possible role of NPPC as causative of the two opposite phenotypes is discussed in this study. PMID- 23805198 TI - Protection of Vascular Endothelial Growth Factor to Brain Edema Following Intracerebral Hemorrhage and Its Involved Mechanisms: Effect of Aquaporin-4. AB - Vascular endothelial growth factor (VEGF) has protective effects on many neurological diseases. However, whether VEGF acts on brain edema following intracerebral hemorrhage (ICH) is largely unknown. Our previous study has shown aquaporin-4 (AQP4) plays an important role in brain edema elimination following ICH. Meanwhile, there is close relationship between VEGF and AQP4. In this study, we aimed to test effects of VEGF on brain edema following ICH and examine whether they were AQP4 dependent. Recombinant human VEGF165 (rhVEGF165) was injected intracerebroventricularly 1 d after ICH induced by microinjecting autologous whole blood into striatum. We detected perihemotomal AQP4 protein expression, then examined the effects of rhVEGF165 on perihemotomal brain edema at 1 d, 3 d, and 7 d after injection in wild type (AQP4(+/+)) and AQP4 knock-out (AQP4(-/-)) mice. Furthermore, we assessed the possible signal transduction pathways activated by VEGF to regulate AQP4 expression via astrocyte cultures. We found perihemotomal AQP4 protein expression was highly increased by rhVEGF165. RhVEGF165 alleviated perihemotomal brain edema in AQP4(+/+) mice at each time point, but had no effect on AQP4(-/-) mice. Perihemotomal EB extravasation was increased by rhVEGF165 in AQP4(-/-) mice, but not AQP4(+/+) mice. RhVEGF165 reduced neurological deficits and increased Nissl's staining cells surrounding hemotoma in both types of mice and these effects were related to AQP4. RhVEGF165 up-regulated phospharylation of C-Jun amino-terminal kinase (p-JNK) and extracellular signal-regulated kinase (p-ERK) and AQP4 protein in cultured astrocytes. The latter was inhibited by JNK and ERK inhibitors. In conclusion, VEGF reduces neurological deficits, brain edema, and neuronal death surrounding hemotoma but has no influence on BBB permeability. These effects are closely related to AQP4 up-regulation, possibly through activating JNK and ERK pathways. The current study may present new insights to treatment of brain edema following ICH. PMID- 23805199 TI - Resolution of Conflicting Signals at the Single-Cell Level in the Regulation of Cyanobacterial Photosynthesis and Nitrogen Fixation. AB - Unicellular, diazotrophic cyanobacteria temporally separate dinitrogen (N2) fixation and photosynthesis to prevent inactivation of the nitrogenase by oxygen. This temporal segregation is regulated by a circadian clock with oscillating activities of N2 fixation in the dark and photosynthesis in the light. On the population level, this separation is not always complete, since the two processes can overlap during transitions from dark to light. How do single cells avoid inactivation of nitrogenase during these periods? One possibility is that phenotypic heterogeneity in populations leads to segregation of the two processes. Here, we measured N2 fixation and photosynthesis of individual cells using nanometer-scale secondary ion mass spectrometry (nanoSIMS) to assess both processes in a culture of the unicellular, diazotrophic cyanobacterium Crocosphaera watsonii during a dark-light and a continuous light phase. We compared single-cell rates with bulk rates and gene expression profiles. During the regular dark and light phases, C. watsonii exhibited the temporal segregation of N2 fixation and photosynthesis commonly observed. However, N2 fixation and photosynthesis were concurrently measurable at the population level during the subjective dark phase in which cells were kept in the light rather than returned to the expected dark phase. At the single-cell level, though, cells discriminated against either one of the two processes. Cells that showed high levels of photosynthesis had low nitrogen fixing activities, and vice versa. These results suggest that, under ambiguous environmental signals, single cells discriminate against either photosynthesis or nitrogen fixation, and thereby might reduce costs associated with running incompatible processes in the same cell. PMID- 23805200 TI - Functional Integration of the Conserved Domains of Shoc2 Scaffold. AB - Shoc2 is a positive regulator of signaling to extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). Shoc2 is also proposed to interact with RAS and Raf-1 in order to accelerate ERK1/2 activity. To understand the mechanisms by which Shoc2 regulates ERK1/2 activation by the epidermal growth factor receptor (EGFR), we dissected the role of Shoc2 structural domains in binding to its signaling partners and its role in regulating ERK1/2 activity. Shoc2 is comprised of two main domains: the 21 leucine rich repeats (LRRs) core and the N-terminal non-LRR domain. We demonstrated that the N-terminal domain mediates Shoc2 binding to both M-Ras and Raf-1, while the C-terminal part of Shoc2 contains a late endosomal targeting motif. We found that M-Ras binding to Shoc2 is independent of its GTPase activity. While overexpression of Shoc2 did not change kinetics of ERK1/2 activity, both the N-terminal and the LRR-core domain were able to rescue ERK1/2 activity in cells depleted of Shoc2, suggesting that these Shoc2 domains are involved in modulating ERK1/2 activity. PMID- 23805201 TI - c-Abl Kinase Is a Regulator of alphavbeta3 Integrin Mediated Melanoma A375 Cell Migration. AB - Integrins are heterodimeric transmembrane receptors that physically link the extracellular matrix (ECM) to the intracellular actin cytoskeleton, and are also signaling molecules that transduce signals bi-directionally across the plasma membrane. Integrin regulation is essential for tumor cell migration in response to growth factors. c-Abl kinase is a nonreceptor tyrosine kinase and is critical for signaling transduction from various receptors. Here we show that c-Abl kinase is involved in A375 cell migration mediated by alphavbeta3 integrin in response to PDGF stimulation. c-Abl kinase colocalizes with alphavbeta3 integrin dynamically and affects alphavbeta3 integrin affinity by regulating its cluster. The interaction between c-Abl kinase and alphavbeta3 integrin was dependent on the activity of c-Abl kinase induced by PDGF stimulation, but was not dependent on the binding of alphavbeta3 integrin with its ligands, suggesting that c-Abl kinase is not involved in the outside-in signaling of alphavbeta3 integrin. Talin head domain was required for the interaction between c-Abl kinase and alphavbeta3 integrin, and the SH3 domain of c-Abl kinase was involved in its interaction with talin and alphavbeta3 integrin. Taken together, we have uncovered a novel and critical role of c-Abl kinase in alphavbeta3 integrin mediated melanoma cell migration. PMID- 23805203 TI - Optimization of Multiple Pathogen Detection Using the TaqMan Array Card: Application for a Population-Based Study of Neonatal Infection. AB - Identification of etiology remains a significant challenge in the diagnosis of infectious diseases, particularly in resource-poor settings. Viral, bacterial, and fungal pathogens, as well as parasites, play a role for many syndromes, and optimizing a single diagnostic system to detect a range of pathogens is challenging. The TaqMan Array Card (TAC) is a multiple-pathogen detection method that has previously been identified as a valuable technique for determining etiology of infections and holds promise for expanded use in clinical microbiology laboratories and surveillance studies. We selected TAC for use in the Aetiology of Neonatal Infection in South Asia (ANISA) study for identifying etiologies of severe disease in neonates in Bangladesh, India, and Pakistan. Here we report optimization of TAC to improve pathogen detection and overcome technical challenges associated with use of this technology in a large-scale surveillance study. Specifically, we increased the number of assay replicates, implemented a more robust RT-qPCR enzyme formulation, and adopted a more efficient method for extraction of total nucleic acid from blood specimens. We also report the development and analytical validation of ten new assays for use in the ANISA study. Based on these data, we revised the study-specific TACs for detection of 22 pathogens in NP/OP swabs and 12 pathogens in blood specimens as well as two control reactions (internal positive control and human nucleic acid control) for each specimen type. The cumulative improvements realized through these optimization studies will benefit ANISA and perhaps other studies utilizing multiple-pathogen detection approaches. These lessons may also contribute to the expansion of TAC technology to the clinical setting. PMID- 23805204 TI - Molecular Genetic Diversity of Major Indian Rice Cultivars over Decadal Periods. AB - Genetic diversity in representative sets of high yielding varieties of rice released in India between 1970 and 2010 was studied at molecular level employing hypervariable microsatellite markers. Of 64 rice SSR primer pairs studied, 52 showed polymorphism, when screened in 100 rice genotypes. A total of 184 alleles was identified averaging 3.63 alleles per locus. Cluster analysis clearly grouped the 100 genotypes into their respective decadal periods i.e., 1970s, 1980s, 1990s and 2000s. The trend of diversity over the decadal periods estimated based on the number of alleles (Na), allelic richness (Rs), Nei's genetic diversity index (He), observed heterozygosity (Ho) and polymorphism information content (PIC) revealed increase of diversity over the periods in year of releasewise and longevitywise classification of rice varieties. Analysis of molecular variance (AMOVA) suggested more variation in within the decadal periods than among the decades. Pairwise comparison of population differentiation (Fst) among decadal periods showed significant difference between all the pairs except a few. Analysis of trends of appearing and disappearing alleles over decadal periods showed an increase in the appearance of alleles and decrease in disappearance in both the categories of varieties. It was obvious from the present findings, that genetic diversity was progressively on the rise in the varieties released during the decadal periods, between 1970s and 2000s. PMID- 23805202 TI - Optical Coherence Tomography Reveals Distinct Patterns of Retinal Damage in Neuromyelitis Optica and Multiple Sclerosis. AB - BACKGROUND: Neuromyelitis optica (NMO) and relapsing-remitting multiple sclerosis (RRMS) are difficult to differentiate solely on clinical grounds. Optical coherence tomography (OCT) studies investigating retinal changes in both diseases focused primarily on the retinal nerve fiber layer (RNFL) while rare data are available on deeper intra-retinal layers. OBJECTIVE: To detect different patterns of intra-retinal layer alterations in patients with NMO spectrum disorders (NMOSD) and RRMS with focus on the influence of a previous optic neuritis (ON). METHODS: We applied spectral-domain OCT in eyes of NMOSD patients and compared them to matched RRMS patients and healthy controls (HC). Semi-automatic intra retinal layer segmentation was used to quantify intra-retinal layer thicknesses. In a subgroup low contrast visual acuity (LCVA) was assessed. RESULTS: NMOSD-, MS and HC-groups, each comprising 17 subjects, were included in analysis. RNFL thickness was more severely reduced in NMOSD compared to MS following ON. In MS ON eyes, RNFL thinning showed a clear temporal preponderance, whereas in NMOSD-ON eyes RNFL was more evenly reduced, resulting in a significantly lower ratio of the nasal versus temporal RNFL thickness. In comparison to HC, ganglion cell layer thickness was stronger reduced in NMOSD-ON than in MS-ON, accompanied by a more severe impairment of LCVA. The inner nuclear layer and the outer retinal layers were thicker in NMOSD-ON patients compared to NMOSD without ON and HC eyes while these differences were primarily driven by microcystic macular edema. CONCLUSION: Our study supports previous findings that ON in NMOSD leads to more pronounced retinal thinning and visual function impairment than in RRMS. The different retinal damage patterns in NMOSD versus RRMS support the current notion of distinct pathomechanisms of both conditions. However, OCT is still insufficient to help with the clinically relevant differentiation of both conditions in an individual patient. PMID- 23805205 TI - Myocardial Ablation of G Protein-Coupled Receptor Kinase 2 (GRK2) Decreases Ischemia/Reperfusion Injury through an Anti-Intrinsic Apoptotic Pathway. AB - Studies from our lab have shown that decreasing myocardial G protein-coupled receptor kinase 2 (GRK2) activity and expression can prevent heart failure progression after myocardial infarction. Since GRK2 appears to also act as a pro death kinase in myocytes, we investigated the effect of cardiomyocyte-specific GRK2 ablation on the acute response to cardiac ischemia/reperfusion (I/R) injury. To do this we utilized two independent lines of GRK2 knockout (KO) mice where the GRK2 gene was deleted in only cardiomyocytes either constitutively at birth or in an inducible manner that occurred in adult mice prior to I/R. These GRK2 KO mice and appropriate control mice were subjected to a sham procedure or 30 min of myocardial ischemia via coronary artery ligation followed by 24 hrs reperfusion. Echocardiography and hemodynamic measurements showed significantly improved post I/R cardiac function in both GRK2 KO lines, which correlated with smaller infarct sizes in GRK2 KO mice compared to controls. Moreover, there was significantly less TUNEL positive myocytes, less caspase-3, and -9 but not caspase-8 activities in GRK2 KO mice compared to control mice after I/R injury. Of note, we found that lowering cardiac GRK2 expression was associated with significantly lower cytosolic cytochrome C levels in both lines of GRK2 KO mice after I/R compared to corresponding control animals. Mechanistically, the anti-apoptotic effects of lowering GRK2 expression were accompanied by increased levels of Bcl-2, Bcl-xl, and increased activation of Akt after I/R injury. These findings were reproduced in vitro in cultured cardiomyocytes and GRK2 mRNA silencing. Therefore, lowering GRK2 expression in cardiomyocytes limits I/R-induced injury and improves post ischemia recovery by decreasing myocyte apoptosis at least partially via Akt/Bcl 2 mediated mitochondrial protection and implicates mitochondrial-dependent actions, solidifying GRK2 as a pro-death kinase in the heart. PMID- 23805206 TI - The Guinea Pig as a Model for Sporadic Alzheimer's Disease (AD): The Impact of Cholesterol Intake on Expression of AD-Related Genes. AB - We investigated the guinea pig, Cavia porcellus, as a model for Alzheimer's disease (AD), both in terms of the conservation of genes involved in AD and the regulatory responses of these to a known AD risk factor - high cholesterol intake. Unlike rats and mice, guinea pigs possess an Abeta peptide sequence identical to human Abeta. Consistent with the commonality between cardiovascular and AD risk factors in humans, we saw that a high cholesterol diet leads to up regulation of BACE1 (beta-secretase) transcription and down-regulation of ADAM10 (alpha-secretase) transcription which should increase release of Abeta from APP. Significantly, guinea pigs possess isoforms of AD-related genes found in humans but not present in mice or rats. For example, we discovered that the truncated PS2V isoform of human PSEN2, that is found at raised levels in AD brains and that increases gamma-secretase activity and Abeta synthesis, is not uniquely human or aberrant as previously believed. We show that PS2V formation is up-regulated by hypoxia and a high-cholesterol diet while, consistent with observations in humans, Abeta concentrations are raised in some brain regions but not others. Also like humans, but unlike mice, the guinea pig gene encoding tau, MAPT, encodes isoforms with both three and four microtubule binding domains, and cholesterol alters the ratio of these isoforms. We conclude that AD-related genes are highly conserved and more similar to human than the rat or mouse. Guinea pigs represent a superior rodent model for analysis of the impact of dietary factors such as cholesterol on the regulation of AD-related genes. PMID- 23805207 TI - Two Distinct Categories of Focal Deletions in Cancer Genomes. AB - One of the key questions about genomic alterations in cancer is whether they are functional in the sense of contributing to the selective advantage of tumor cells. The frequency with which an alteration occurs might reflect its ability to increase cancer cell growth, or alternatively, enhanced instability of a locus may increase the frequency with which it is found to be aberrant in tumors, regardless of oncogenic impact. Here we've addressed this on a genome-wide scale for cancer-associated focal deletions, which are known to pinpoint both tumor suppressor genes (tumor suppressors) and unstable loci. Based on DNA copy number analysis of over one-thousand human cancers representing ten different tumor types, we observed five loci with focal deletion frequencies above 5%, including the A2BP1 gene at 16p13.3 and the MACROD2 gene at 20p12.1. However, neither RNA expression nor functional studies support a tumor suppressor role for either gene. Further analyses suggest instead that these are sites of increased genomic instability and that they resemble common fragile sites (CFS). Genome-wide analysis revealed properties of CFS-like recurrent deletions that distinguish them from deletions affecting tumor suppressor genes, including their isolation at specific loci away from other genomic deletion sites, a considerably smaller deletion size, and dispersal throughout the affected locus rather than assembly at a common site of overlap. Additionally, CFS-like deletions have less impact on gene expression and are enriched in cell lines compared to primary tumors. We show that loci affected by CFS-like deletions are often distinct from known common fragile sites. Indeed, we find that each tumor tissue type has its own spectrum of CFS-like deletions, and that colon cancers have many more CFS-like deletions than other tumor types. We present simple rules that can pinpoint focal deletions that are not CFS-like and more likely to affect functional tumor suppressors. PMID- 23805208 TI - Comparative Transcriptome Analysis of Adipose Tissues Reveals that ECM-Receptor Interaction Is Involved in the Depot-Specific Adipogenesis in Cattle. AB - Adipocytes mainly function as energy storage and endocrine cells. Adipose tissues showed the biological and genetic difference based on their depots. The difference of adipocytes between depots might be influenced by the inherent genetic programing for adipogenesis. We used RNA-seq technique to investigate the transcriptomes in 3 adipose tissues of omental (O), subcutaneous (S) and intramuscular (I) fats in cattle. Sequence reads were obtained from Illumina HiSeq2000 and mapped to the bovine genome using Tophat2. Differentially expressed genes (DEG) between adipose tissues were detected by EdgeR. We identified 5797, 2156, and 5455 DEGs in the comparison between OI, OS, and IS respectively and also found 5657 DEGs in the comparison between the intramuscular and the combined omental and subcutaneous fats (C) (FDR<0.01). Depot specifically up- and down- regulated DEGs were 853 in S, 48 in I, and 979 in O. The numbers of DEGs and functional annotation studies suggested that I had the different genetic profile compared to other two adipose tissues. In I, DEGs involved in the developmental process (eg. EGR2, FAS, and KLF7) were up-regulated and those in the immune system process were down-regulated. Many DEGs from the adipose tissues were enriched in the various GO terms of developmental process and KEGG pathway analysis showed that the ECM-receptor interaction was one of commonly enriched pathways in all of the 3 adipose tissues and also functioned as a sub-pathway of other enriched pathways. However, genes involved in the ECM-receptor interaction were differentially regulated depending on the depots. Collagens, main ECM constituents, were significantly up-regulated in S and integrins, transmembrane receptors, were up-regulated in I. Different laminins were up-regulated in the different depots. This comparative transcriptome analysis of three adipose tissues suggested that the interactions between ECM components and transmembrane receptors of fat cells depend on the depot specific adipogenesis. PMID- 23805209 TI - HIV Infection among Young People in Northwest Tanzania: The Role of Biological, Behavioural and Socio-Demographic Risk Factors. AB - BACKGROUND: Young people are at high risk of HIV and developing appropriate prevention programmes requires an understanding of the risk factors for HIV in this age group. We investigated factors associated with HIV among participants aged 15-30 years in a 2007-8 cross-sectional survey nested within a community randomised trial of the MEMA kwa Vijana intervention in 20 rural communities in northwest Tanzania. METHODS: We analysed data for 7259(53%) males and 6476(47%) females. Using a proximate-determinant conceptual framework and conditional logistic regression, we obtained sex-specific Odds Ratios (ORs) for the association of HIV infection with socio-demographic, knowledge, behavioural and biological factors. RESULTS: HSV-2 infection was strongly associated with HIV infection (females: adjOR 4.4, 95%CI 3.2-6.1; males: adjOR 4.2, 95%CI 2.8-6.2). Several socio-demographic factors (such as age, marital status and mobility), behavioural factors (condom use, number and type of sexual partnerships) and biological factors (blood transfusion, lifetime pregnancies, genital ulcers, Neisseria gonorrhoeae) were also associated with HIV infection. Among females, lifetime sexual partners (linear trend, p<0.001), >=2 partners in the past year (adjOR 2.0, 95%CI 1.4-2.8), >=2 new partners in the past year (adjOR 1.9 95%CI 1.2, 3.3) and concurrent partners in the past year (adjOR 1.6 95%CI 1.1, 2.4) were all associated with HIV infection. CONCLUSIONS: Efforts must be intensified to find effective interventions to reduce HSV-2. Effective behavioural interventions focusing on reducing the number of sexual partnerships and risk behaviour within partnerships are also needed. An increase in risky sexual behaviour may occur following marriage dissolution or when a young woman travels outside of her community and interventions addressing the needs of these subgroups of vulnerable women may be important. TRIAL REGISTRATION: ClinicalTrial.gov NCT00248469. PMID- 23805211 TI - The Socioeconomic and Institutional Determinants of Participation in India's Health Insurance Scheme for the Poor. AB - The Rashtriya Swasthya Bima Yojana (RSBY), which was introduced in 2008 in India, is a social health insurance scheme that aims to improve healthcare access and provide financial risk protection to the poor. In this study, we analyse the determinants of participation and enrolment in the scheme at the level of districts. We used official data on RSBY enrolment, socioeconomic data from the District Level Household Survey 2007-2008, and additional state-level information on fiscal health, political affiliation, and quality of governance. Results from multivariate probit and OLS analyses suggest that political and institutional factors are among the strongest determinants explaining the variation in participation and enrolment in RSBY. In particular, districts in state governments that are politically affiliated with the opposition or neutral parties at the centre are more likely to participate in RSBY, and have higher levels of enrolment. Districts in states with a lower quality of governance, a pre-existing state-level health insurance scheme, or with a lower level of fiscal deficit as compared to GDP, are significantly less likely to participate, or have lower enrolment rates. Among socioeconomic factors, we find some evidence of weak or imprecise targeting. Districts with a higher share of socioeconomically backward castes are less likely to participate, and their enrolment rates are also lower. Finally, districts with more non-poor households may be more likely to participate, although with lower enrolment rates. PMID- 23805210 TI - The GDNF System Is Altered in Diverticular Disease - Implications for Pathogenesis. AB - BACKGROUND & AIMS: Absence of glial cell line-derived neurotrophic factor (GDNF) leads to intestinal aganglionosis. We recently demonstrated that patients with diverticular disease (DD) exhibit hypoganglionosis suggesting neurotrophic factor deprivation. Thus, we screened mRNA expression pattern of the GDNF system in DD and examined the effects of GDNF on cultured enteric neurons. METHODS: Colonic specimens obtained from patients with DD (n = 21) and controls (n = 20) were assessed for mRNA expression levels of the GDNF system (GDNF, GDNF receptors GFRalpha1 and RET). To identify the tissue source of GDNF and its receptors, laser-microdissected (LMD) samples of human myenteric ganglia and intestinal muscle layers were analyzed separately by qPCR. Furthermore, the effects of GDNF treatment on cultured enteric neurons (receptor expression, neuronal differentiation and plasticity) were monitored. RESULTS: mRNA expression of GDNF and its receptors was significantly down-regulated in the muscularis propria of patients with DD. LMD samples revealed high expression of GDNF in circular and longitudinal muscle layers, whereas GDNF receptors were also expressed in myenteric ganglia. GDNF treatment of cultured enteric neurons increased mRNA expression of its receptors and promoted neuronal differentiation and plasticity revealed by synaptophysin mRNA and protein expression. CONCLUSIONS: Our results suggest that the GDNF system is compromised in DD. In vitro studies demonstrate that GDNF enhances expression of its receptors and promotes enteric neuronal differentiation and plasticity. Since patients with DD exhibit hypoganglionosis, we propose that the observed enteric neuronal loss in DD may be due to lacking neurotrophic support mediated by the GDNF system. PMID- 23805212 TI - Lack of Structural Variation but Extensive Length Polymorphisms and Heteroplasmic Length Variations in the Mitochondrial DNA Control Region of Highly Inbred Crested Ibis, Nipponia nippon. AB - The animal mitochondrial DNA (mtDNA) length polymorphism and heteroplasmy are accepted to be universal. Here we report the lack of structural variation but the presence of length polymorphism as well as heteroplasmy in mtDNA control region of an endangered avian species - the Crested Ibis (Nipponia nippon). The complete control region was directly sequenced while the distribution pattern and inheritance of the length variations were examined using both direct sequencing and genotyping of the PCR fragments from captive birds with pedigrees, wild birds and a historical specimen. Our results demonstrated that there was no structural variation in the control region, however, different numbers of short tandem repeats with an identical motif of CA3CA2CA3 at the 3'-end of the control region determined the length polymorphisms among and heteroplasmy within individual birds. There were one to three predominant fragments in every bird; nevertheless multiple minor fragments coexist in all birds. These extremely high polymorphisms were suggested to have derived from the 'replication slippage' of a perfect microsatellite evolution following the step-wise mutational model. The patterns of heteroplasmy were found to be shifted between generations and among siblings but rather stable between blood and feather samples. This study provides the first evidence of a very extensive mtDNA length polymorphism and heteroplasmy in the highly inbred Crested Ibis which carries an mtDNA genome lack of structural genetic diversity. The analysis of pedigreed samples also sheds light on the transmission of mtDNA length heteroplasmy in birds following the genetic bottleneck theory. Further research focusing on the generation and transmission of particular mtDNA heteroplasmy patterns in single germ line of Crested Ibis is encouraged by this study. PMID- 23805213 TI - Human H3N2 Influenza Viruses Isolated from 1968 To 2012 Show Varying Preference for Receptor Substructures with No Apparent Consequences for Disease or Spread. AB - It is generally accepted that human influenza viruses bind glycans containing sialic acid linked alpha2-6 to the next sugar, that avian influenza viruses bind glycans containing the alpha2-3 linkage, and that mutations that change the binding specificity might change the host tropism. We noted that human H3N2 viruses showed dramatic differences in their binding specificity, and so we embarked on a study of representative human H3N2 influenza viruses, isolated from 1968 to 2012, that had been isolated and minimally passaged only in mammalian cells, never in eggs. The 45 viruses were grown in MDCK cells, purified, fluorescently labeled and screened on the Consortium for Functional Glycomics Glycan Array. Viruses isolated in the same season have similar binding specificity profiles but the profiles show marked year-to-year variation. None of the 610 glycans on the array (166 sialylated glycans) bound to all viruses; the closest was Neu5Acalpha2-6(Galbeta1-4GlcNAc)3 in either a linear or biantennary form, that bound 42 of the 45 viruses. The earliest human H3N2 viruses preferentially bound short, branched sialylated glycans while recent viruses bind better to long polylactosamine chains terminating in sialic acid. Viruses isolated in 1996, 2006, 2010 and 2012 bind glycans with alpha2-3 linked sialic acid; for 2006, 2010 and 2012 viruses this binding was inhibited by oseltamivir, indicating binding of alpha2-3 sialylated glycans by neuraminidase. More significantly, oseltamivir inhibited virus entry of 2010 and 2012 viruses into MDCK cells. All of these viruses were representative of epidemic strains that spread around the world, so all could infect and transmit between humans with high efficiency. We conclude that the year-to-year variation in receptor binding specificity is a consequence of amino acid sequence changes driven by antigenic drift, and that viruses with quite different binding specificity and avidity are equally fit to infect and transmit in the human population. PMID- 23805215 TI - Keywords and Co-Occurrence Patterns in the Voynich Manuscript: An Information Theoretic Analysis. AB - The Voynich manuscript has remained so far as a mystery for linguists and cryptologists. While the text written on medieval parchment -using an unknown script system- shows basic statistical patterns that bear resemblance to those from real languages, there are features that suggested to some researches that the manuscript was a forgery intended as a hoax. Here we analyse the long-range structure of the manuscript using methods from information theory. We show that the Voynich manuscript presents a complex organization in the distribution of words that is compatible with those found in real language sequences. We are also able to extract some of the most significant semantic word-networks in the text. These results together with some previously known statistical features of the Voynich manuscript, give support to the presence of a genuine message inside the book. PMID- 23805214 TI - Serum Fucosylated Haptoglobin as a Novel Diagnostic Biomarker for Predicting Hepatocyte Ballooning and Nonalcoholic Steatohepatitis. AB - Nonalcoholic fatty liver disease (NAFLD) is a growing medical problem around the world. NAFLD patients with nonalcoholic steatohepatitis (NASH) can develop cirrhosis and hepatocellular carcinoma. The ability to distinguish NASH from simple steatosis would be of great clinical significance. Ballooning hepatocytes are characteristic of typical pathological NASH; here, the polarized secretion of proteins is disrupted due to destruction of the cytoskeleton. We previously reported that fucosylated glycoproteins are secreted into bile, but not into sera in normal liver. Therefore, we hypothesized that the fucosylation-based sorting machinery would be disrupted in ballooning hepatocytes, and serum fucosylated glycoproteins would increase in NASH patients. To confirm our hypothesis, we evaluated serum fucosylated haptoglobin (Fuc-Hpt) levels in biopsy-proven NAFLD patients (n = 126) using a lectin-antibody ELISA kit. Fuc-Hpt levels were significantly increased in NASH patients compared with non-NASH (NAFLD patients without NASH) patients. Interestingly, Fuc-Hpt levels showed a significant stepwise increase with increasing hepatocyte ballooning scores. Multiple logistic regression analysis showed that Fuc-Hpt levels were independent and significant determinants of the presence of ballooning hepatocytes. Moreover, Fuc-Hpt levels were useful in monitoring liver fibrosis staging. Next, to investigate the significance of serum Fuc-Hpt in a larger population, we measured Fuc-Hpt levels in ultrasound-diagnosed NAFLD subjects (n = 870) who received a medical health checkup. To evaluate NAFLD disease severity, we used the FIB-4 index (based on age, serum AST and ALT levels, and platelet counts). Fuc-Hpt levels increased stepwise with increasing FIB-4 index. CONCLUSION: Measurement of serum Fuc-Hpt levels can distinguish NASH from non-NASH patients, and predict the presence of ballooning hepatocytes in NAFLD patients with sufficient accuracy. These results support the potential usefulness of measuring Fuc-Hpt levels in clinical practice. PMID- 23805216 TI - Gonadotropin-Releasing Hormone Analog Cotreatment for the Preservation of Ovarian Function during Gonadotoxic Chemotherapy for Breast Cancer: A Meta-Analysis. AB - OBJECTIVE: To determine by meta-analysis whether gonadotropin-releasing hormone analog (GnRHa) cotreatment accompanying chemotherapy for breast cancer protects ovarian function. METHODS: Randomized controlled trials (RCTs) comparing GnRH cotreatment with chemotherapy alone in premenopausal women were collected by electronic and manual searches of Pubmed, MEDLINE (OVID), CENTRAL (The Coehrane Central Register of Controlled Trials), CBM, CNKI, VIP and Wanfang data bases. All the data was analyzed by Stata 11.2. RESULTS: Seven studies with a total of 677 participants met the inclusion criteria. The outcome of meta-analysis implied that, compared with adjuvant chemotherapy alone, the number of patients with resumption of spontaneous menstruation was statistically greater in the GnRH cotreatment patients (OR 2.83; 95% CI, 1.52-5.25). CONCLUSIONS: Evidence from RCTs suggests a potential benefit of GnRH cotreatment with chemotherapy in premenopausal women, producing higher rates of spontaneous resumption of menses. PMID- 23805217 TI - Lignin Induces ES Cells to Differentiate into Neuroectodermal Cells through Mediation of the Wnt Signaling Pathway. AB - Embryonic stem cells (ES cells) are characterized by their pluripotency and infinite proliferation potential. Ever since ES cells were first established in 1981, there have been a growing number of studies aimed at clinical applications of ES cells. In recent years, various types of differentiation inducement systems using ES cells have been established. Further studies have been conducted to utilize differentiation inducement systems in the field of regenerative medicine. For cellular treatments using stem cells including ES cells, differentiation induction should be performed in a sufficient manner to obtain the intended cell lineages. Lignin is a high-molecular amorphous material that forms plants together with cellulose and hemicelluloses, in which phenylpropane fundamental units are complexly condensed. Lignin derivatives have been shown to have several bioactive functions. In spite of these findings, few studies have focused on the effects of lignin on stem cells. Our study aimed to develop a novel technology using lignin to effectively induce ES cells to differentiate into neuroectodermal cells including ocular cells and neural cells. Since lignin can be produced at a relatively low cost in large volumes, its utilization is expected for more convenient differentiation induction technologies and in the field of regenerative medicine in the future. PMID- 23805218 TI - Direct Interaction of Selenoprotein R with Clusterin and Its Possible Role in Alzheimer's Disease. AB - Selenoprotein R (SelR) plays an important role in maintaining intracellular redox balance by reducing the R-form of methionine sulfoxide to methionine. As SelR is highly expressed in brain and closely related to Alzheimer's disease (AD), its biological functions in human brain become a research focus. In this paper, the selenocysteine-coding TGA of SelR gene was mutated to cysteine-coding TGC and used to screen the human fetal brain cDNA library with a yeast two-hybrid system. Our results demonstrated that SelR interacts with clusterin (Clu), a chaperone protein. This protein interaction was further verified by fluorescence resonance energy transfer (FRET), coimmunoprecipitation (co-IP), and pull-down assays. The interacting domain of Clu was determined by co-IP to be a dynamic, molten globule structure spanning amino acids 315 to 381 with an amphipathic-helix. The interacting domain of SelR was investigated by gene manipulation, ligand replacement, protein over-expression, and enzyme activity measurement to be a tetrahedral complex consisting of a zinc ion binding with four Cys residues. Study on the mutual effect of SelR and Clu showed synergic property between the two proteins. Cell transfection with SelR gene increased the expression of Clu, while cell transfection with Clu promoted the enzyme activity of SelR. Co overexpression of SelR and Clu in N2aSW cells, an AD model cell line, significantly decreased the level of intracellular reactive oxygen species. Furthermore, FRET and co-IP assays demonstrated that Clu interacted with beta amyloid peptide, a pathological protein of AD, which suggested a potential effect of SelR and Abeta with the aid of Clu. The interaction between SelR and Clu provides a novel avenue for further study on the mechanism of SelR in AD prevention. PMID- 23805220 TI - Cationic and PEGylated Amphiphilic Cyclodextrins: Co-Formulation Opportunities for Neuronal Sirna Delivery. AB - Optimising non-viral vectors for neuronal siRNA delivery presents a significant challenge. Here, we investigate a co-formulation, consisting of two amphiphilic cyclodextrins (CDs), one cationic and the other PEGylated, which were blended together for siRNA delivery to a neuronal cell culture model. Co-formulated CD siRNA complexes were characterised in terms of size, charge and morphology. Stability in salt and serum was also examined. Uptake was determined by flow cytometry and toxicity was measured by MTT assay. Knockdown of a luciferase reporter gene was used as a measure of gene silencing efficiency. Incorporation of a PEGylated CD in the formulation had significant effects on the physical and biological properties of CD.siRNA complexes. Co-formulated complexes exhibited a lower surface charge and greater stability in a high salt environment. However, the inclusion of the PEGylated CD also dramatically reduced gene silencing efficiency due to its effects on neuronal uptake. The co-formulation strategy for cationic and PEGylated CDs improved the stability of the CD.siRNA delivery systems, although knockdown efficiency was impaired. Future work will focus on the addition of targeting ligands to the co-formulated complexes to restore transfection capabilities. PMID- 23805219 TI - The Effect of a Physical Activity Program on the Total Number of Primary Care Visits in Inactive Patients: A 15-Month Randomized Controlled Trial. AB - BACKGROUND: Effective promotion of exercise could result in substantial savings in healthcare cost expenses in terms of direct medical costs, such as the number of medical appointments. However, this is hampered by our limited knowledge of how to achieve sustained increases in physical activity. OBJECTIVES: To assess the effectiveness of a Primary Health Care (PHC) based physical activity program in reducing the total number of visits to the healthcare center among inactive patients, over a 15-month period. RESEARCH DESIGN: Randomized controlled trial. SUBJECTS: Three hundred and sixty-two (n = 362) inactive patients suffering from at least one chronic condition were included. One hundred and eighty-three patients (n = 183; mean (SD); 68.3 (8.8) years; 118 women) were randomly allocated to the physical activity program (IG). One hundred and seventy-nine patients (n = 179; 67.2 (9.1) years; 106 women) were allocated to the control group (CG). The IG went through a three-month standardized physical activity program led by physical activity specialists and linked to community resources. MEASURES: The total number of medical appointments to the PHC, during twelve months before and after the program, was registered. Self-reported health status (SF-12 version 2) was assessed at baseline (month 0), at the end of the intervention (month 3), and at 12 months follow-up after the end of the intervention (month 15). RESULTS: The IG had a significantly reduced number of visits during the 12 months after the intervention: 14.8 (8.5). The CG remained about the same: 18.2 (11.1) (P = .002). CONCLUSIONS: Our findings indicate that a 3-month physical activity program linked to community resources is a short duration, effective and sustainable intervention in inactive patients to decrease rates of PHC visits. TRIAL REGISTRATION: ClinicalTrials.gov NCT00714831. PMID- 23805221 TI - Influence of Nutrient Stress on the Relationships between PAM Measurements and Carbon Incorporation in Four Phytoplankton Species. AB - Two methods of measuring primary production, modulated fluorimetry (PAM) and the traditional carbon incorporation method ((13)C), were compared in four phytoplankton species, two diatoms (Pseudo-nitzschia pungens and Asterionellopsis glacialis), and two dinoflagellates (Heterocapsa sp and Karenia mikimotoi), under N (nitrogen), P (phosphorus) and Si (silicon) limited semi-continuous culture. N and Si-limited cultures showed relatively high quantum efficiency of the PSII (Fv/Fm) values, confirming that Fv/Fm is not a good proxy for nutrient stress in balanced systems, whereas P limitation had a drastic effect on many physiological parameters. In all species, the physiological capacity of phytoplankton cells to acclimate to nutrient limitations led to changes in the cellular biochemical composition and the structure of the photosynthetic apparatus. The observed physiological responses were species and nutrient specific. The values of the chlorophyll-specific absorption cross section (a*) increased with nutrient limitation due to package effect, while the carbon/Chl a ratio was higher under N and P limitations. In diatoms, Si limitation did not affect photosynthesis confirming the uncoupling between Si and carbon metabolisms. In all four species and under all treatments, significant relationships were found between photosynthetic activities, ETR(Chl) (electron transport rate) and P(Chl) (carbon fixation rate) estimated using PAM measurements and (13)C incorporation, showing that the fluorescence technique can reliably be used to estimate carbon fixation by phytoplankton. The relationship between ETR(Chl) and P(Chl) can be described by the shape and the slope of the curve (PhiC.e). Linear relationships were found for dinoflagellates and P. pungens under all treatments. A decrease in PhiC.e was observed under N and P limitation probably due to structural damage to the photosynthetic apparatus. A. glacialis showed a logarithmic relationship in N and P limited conditions, due to the alternative electron flow which takes place to optimise photosynthetic performances under high light and/or nutrient stress. PMID- 23805222 TI - The Influence of Hepatitis B Viral Load and Pre-S Deletion Mutations on Post Operative Recurrence of Hepatocellular Carcinoma and the Tertiary Preventive Effects by Anti-Viral Therapy. AB - BACKGROUND: Whether or not hepatitis B virus (HBV) genotypes, mutations, and viral loads determine outcomes for patients with HBV-induced hepatocellular carcinoma (HCC) remains controversial. AIMS: To study the influence of HBV viral factors on prognoses for patients with HBV-induced HCC after resection surgery and investigate if antiviral therapy could counteract the adverse effects of viral factors. METHODS: A total of 333 HBV-related HCC patients who underwent tumor resection were enrolled retrospectively. Serum HBV DNA levels, mutations, anti-viral therapy, and other clinical variables were analyzed for their association with post-operative recurrence. RESULTS: After a median follow-up of 45.9 months, 208 patients had HCC recurrence after resection. The 5-year overall survival and recurrence-free survival rates were 55.4% and 35.3%, respectively. Multivariate analysis showed indocyanine green retention rate at 15 minutes >10%, gamma-glutamyltransferase (GGT) level >60 U/L, macroscopic and microscopic venous invasion, and the absence of anti-viral therapy were significant risk factors for recurrence. Anti-viral therapy could decrease recurrence in patients with early stage HCC, but the effect was less apparent in those with the Barcelona-Clinic Liver Cancer stage C HCC. For patients without antiviral therapy after resection, serum HBV DNA levels >10(6) copies/mL, GGT >60 U/L, and macroscopic and microscopic venous invasion were significant risk factors predicting recurrence. Among the 216 patients without anti-viral therapy but with complete HBV surface gene mapping data, 73 were with pre-S deletion mutants. Among patients with higher serum HBV DNA levels, those with pre-S deletion had significantly higher rates of recurrence. Moreover, multivariate analysis showed multi-nodularity, macroscopic venous invasion, cirrhosis, advanced tumor cell differentiation, and pre-S deletion were significant risk factors predictive of recurrence. CONCLUSIONS: Ongoing HBV viral replication and pre-S deletion are crucial for determining post-operative tumor recurrence. Anti-viral therapy can help reduce recurrence and improve prognosis, especially for those with early stage HCC. PMID- 23805223 TI - PUMA Cooperates with p21 to Regulate Mammary Epithelial Morphogenesis and Epithelial-To-Mesenchymal Transition. AB - Lumen formation is essential for mammary morphogenesis and requires proliferative suppression and apoptotic clearance of the inner cells within developing acini. Previously, we showed that knockdown of p53 or p73 leads to aberrant mammary acinus formation accompanied with decreased expression of p53 family targets PUMA and p21, suggesting that PUMA, an inducer of apoptosis, and p21, an inducer of cell cycle arrest, directly regulate mammary morphogenesis. To address this, we generated multiple MCF10A cell lines in which PUMA, p21, or both were stably knocked down. We found that morphogenesis of MCF10A cells was altered modestly by knockdown of either PUMA or p21 alone but markedly by knockdown of both PUMA and p21. Moreover, we found that knockdown of PUMA and p21 leads to loss of E cadherin expression along with increased expression of epithelial-to-mesenchymal transition (EMT) markers. Interestingly, we found that knockdown of DeltaNp73, which antagonizes the ability of wide-type p53 and TA isoform of p73 to regulate PUMA and p21, mitigates the abnormal morphogenesis and EMT induced by knockdown of PUMA or p21. Together, our data suggest that PUMA cooperates with p21 to regulate normal acinus formation and EMT. PMID- 23805225 TI - High Resolution Typing by Whole Genome Mapping Enables Discrimination of LA-MRSA (CC398) Strains and Identification of Transmission Events. AB - After its emergence in 2003, a livestock-associated (LA-)MRSA clade (CC398) has caused an impressive increase in the number of isolates submitted for the Dutch national MRSA surveillance and now comprises 40% of all isolates. The currently used molecular typing techniques have limited discriminatory power for this MRSA clade, which hampers studies on the origin and transmission routes. Recently, a new molecular analysis technique named whole genome mapping was introduced. This method creates high-resolution, ordered whole genome restriction maps that may have potential for strain typing. In this study, we assessed and validated the capability of whole genome mapping to differentiate LA-MRSA isolates. Multiple validation experiments showed that whole genome mapping produced highly reproducible results. Assessment of the technique on two well-documented MRSA outbreaks showed that whole genome mapping was able to confirm one outbreak, but revealed major differences between the maps of a second, indicating that not all isolates belonged to this outbreak. Whole genome mapping of LA-MRSA isolates that were epidemiologically unlinked provided a much higher discriminatory power than spa-typing or MLVA. In contrast, maps created from LA-MRSA isolates obtained during a proven LA-MRSA outbreak were nearly indistinguishable showing that transmission of LA-MRSA can be detected by whole genome mapping. Finally, whole genome maps of LA-MRSA isolates originating from two unrelated veterinarians and their household members showed that veterinarians may carry and transmit different LA-MRSA strains at the same time. No such conclusions could be drawn based spa-typing and MLVA. Although PFGE seems to be suitable for molecular typing of LA-MRSA, WGM provides a much higher discriminatory power. Furthermore, whole genome mapping can provide a comparison with other maps within 2 days after the bacterial culture is received, making it suitable to investigate transmission events and outbreaks caused by LA-MRSA. PMID- 23805224 TI - Herpes Zoster Risk Reduction through Exposure to Chickenpox Patients: A Systematic Multidisciplinary Review. AB - Varicella-zoster virus (VZV) causes chickenpox and may subsequently reactivate to cause herpes zoster later in life. The exogenous boosting hypothesis states that re-exposure to circulating VZV can inhibit VZV reactivation and consequently also herpes zoster in VZV-immune individuals. Using this hypothesis, mathematical models predicted widespread chickenpox vaccination to increase herpes zoster incidence over more than 30 years. Some countries have postponed universal chickenpox vaccination, at least partially based on this prediction. After a systematic search and selection procedure, we analyzed different types of exogenous boosting studies. We graded 13 observational studies on herpes zoster incidence after widespread chickenpox vaccination, 4 longitudinal studies on VZV immunity after re-exposure, 9 epidemiological risk factor studies, 7 mathematical modeling studies as well as 7 other studies. We conclude that exogenous boosting exists, although not for all persons, nor in all situations. Its magnitude is yet to be determined adequately in any study field. PMID- 23805226 TI - Topological Strata of Weighted Complex Networks. AB - The statistical mechanical approach to complex networks is the dominant paradigm in describing natural and societal complex systems. The study of network properties, and their implications on dynamical processes, mostly focus on locally defined quantities of nodes and edges, such as node degrees, edge weights and -more recently- correlations between neighboring nodes. However, statistical methods quickly become cumbersome when dealing with many-body properties and do not capture the precise mesoscopic structure of complex networks. Here we introduce a novel method, based on persistent homology, to detect particular non local structures, akin to weighted holes within the link-weight network fabric, which are invisible to existing methods. Their properties divide weighted networks in two broad classes: one is characterized by small hierarchically nested holes, while the second displays larger and longer living inhomogeneities. These classes cannot be reduced to known local or quasilocal network properties, because of the intrinsic non-locality of homological properties, and thus yield a new classification built on high order coordination patterns. Our results show that topology can provide novel insights relevant for many-body interactions in social and spatial networks. Moreover, this new method creates the first bridge between network theory and algebraic topology, which will allow to import the toolset of algebraic methods to complex systems. PMID- 23805227 TI - Recruitment of Perisomatic Inhibition during Spontaneous Hippocampal Activity In Vitro. AB - It was recently shown that perisomatic GABAergic inhibitory postsynaptic potentials (IPSPs) originating from basket and chandelier cells can be recorded as population IPSPs from the hippocampal pyramidal layer using extracellular electrodes (eIPSPs). Taking advantage of this approach, we have investigated the recruitment of perisomatic inhibition during spontaneous hippocampal activity in vitro. Combining intracellular and extracellular recordings from pyramidal cells and interneurons, we confirm that inhibitory signals generated by basket cells can be recorded extracellularly, but our results suggest that, during spontaneous activity, eIPSPs are mostly confined to the CA3 rather than CA1 region. CA3 eIPSPs produced the powerful time-locked inhibition of multi-unit activity expected from perisomatic inhibition. Analysis of the temporal dynamics of spike discharges relative to eIPSPs suggests significant but moderate recruitment of excitatory and inhibitory neurons within the CA3 network on a 10 ms time scale, within which neurons recruit each other through recurrent collaterals and trigger powerful feedback inhibition. Such quantified parameters of neuronal interactions in the hippocampal network may serve as a basis for future characterisation of pathological conditions potentially affecting the interactions between excitation and inhibition in this circuit. PMID- 23805229 TI - Diet Segregation between Cohabiting Builder and Inquiline Termite Species. AB - How do termite inquilines manage to cohabit termitaria along with the termite builder species? With this in mind, we analysed one of the several strategies that inquilines could use to circumvent conflicts with their hosts, namely, the use of distinct diets. We inspected overlapping patterns for the diets of several cohabiting Neotropical termite species, as inferred from carbon and nitrogen isotopic signatures for termite individuals. Cohabitant communities from distinct termitaria presented overlapping diet spaces, indicating that they exploited similar diets at the regional scale. When such communities were split into their components, full diet segregation could be observed between builders and inquilines, at regional (environment-wide) and local (termitarium) scales. Additionally, diet segregation among inquilines themselves was also observed in the vast majority of inspected termitaria. Inquiline species distribution among termitaria was not random. Environmental-wide diet similarity, coupled with local diet segregation and deterministic inquiline distribution, could denounce interactions for feeding resources. However, inquilines and builders not sharing the same termitarium, and thus not subject to potential conflicts, still exhibited distinct diets. Moreover, the areas of the builder's diet space and that of its inquilines did not correlate negatively. Accordingly, the diet areas of builders which hosted inquilines were in average as large as the areas of builders hosting no inquilines. Such results indicate the possibility that dietary partitioning by these cohabiting termites was not majorly driven by current interactive constraints. Rather, it seems to be a result of traits previously fixed in the evolutionary past of cohabitants. PMID- 23805228 TI - Soluble CD26/Dipeptidyl Peptidase IV Enhances the Transcription of IL-6 and TNF alpha in THP-1 Cells and Monocytes. AB - CD26 is a 110-kDa multifunctional molecule having dipeptidyl peptidase IV (DPPIV) enzyme activity and is present on the surface of human T cells. Soluble CD26 (sCD26) exists in human blood and enhances the proliferation of peripheral T lymphocytes induced by tetanus toxoid (TT). The mechanisms by which CD26 enhances the activation of T cells and monocytes remain to be fully elucidated. In this study, we compared the stimulation of THP-1 cells and isolated human monocytes with a combination of recombinant sCD26 and lipopolysaccharide (LPS) and the stimulation of these cells with LPS alone. We found that addition of sCD26 increased TNF-alpha and IL-6 mRNA and protein expression and enhanced ERK1/2 levels in the cytosol as well as c-Fos, NF-kappaB p50, NF-kappaB p65, and CUX1 levels in the nuclei of these cells. On the other hand, the selective DPPIV inhibitor sitagliptin inhibited the increase in TNF-alpha mRNA and protein expression as well as the increase in ERK, c-Fos, NF-kappaB p50, NF-kappaB p65, and CUX1 levels. However, it did not inhibit the increase in IL-6 mRNA and protein expression. We then demonstrated that sCD26 enhanced binding of transcription factors to the TNF- and IL-6 promoters and used reporter assays to demonstrate that transcription factor binding enhanced promoter activity. Once again, we observed differential activities at the TNF- and IL-6 promoters. Finally, we demonstrated that CUX-1 overexpression enhanced TNF- production on sCD26/LPS stimulation, while CUX-1 depletion had no effect. Neither CUX-1 overexpression nor CUX-1 depletion had an effect on IL-6 stimulation. These results are discussed in the context of a model that describes the mechanisms by which stimulation of monocytic cells by sCD26 and LPS leads to elevation of TNF- and IL-6 expression. CUX-1 is identified as a new transcription factor that differently regulates the activities of the TNF- and IL-6 promoters. PMID- 23805231 TI - Self-Help for Depression via E-mail: A Randomised Controlled Trial of Effects on Depression and Self-Help Behaviour. AB - BACKGROUND: Self-help or self-management strategies are commonly used to deal with depression, but not all are thought to be helpful. A previous study found that sub-threshold depression symptoms were improved by an e-mail intervention that encouraged the use of evidence-based self-help strategies. AIM: To investigate whether these e-mails were effective for adults with a range of depression symptomatology including major depression. METHOD: The study was a parallel-group randomised controlled trial. Adult participants with any level of depressive symptoms were recruited over the internet from the United Kingdom, Australia, Canada, Ireland, New Zealand and the United States. Participants were randomised to receive a series of e-mails either promoting the use of evidence based self-help strategies or containing depression information as a control. E mails were sent automatically twice a week for six weeks. Depression symptoms were assessed with the self-rated Patient Health Questionnaire depression scale (PHQ-9). RESULTS: 1736 participants with a wide range of symptom severity were recruited and assigned to active (n = 862) and control (n = 874) groups. However, there was a significant attrition rate, with 66.9% lost to follow-up at post intervention. Both groups showed large improvements in depression symptoms overall, with no significant difference in improvement at the end of the study (mean difference in improvement 0.35 points, 95% CI: -0.57 to 1.28, d = 0.11, 95% CI: -0.06 to 0.27), although there was a small effect at the study mid-point. Results were similar for the sub-group of participants with major depression. The active group showed small to moderate improvements in self-help behaviour (d = 0.40, 95% CI: 0.23 to 0.56). CONCLUSIONS: These results suggest that the e-mails were able to increase participants' use of evidence-based self-help, but that this did not improve depression more than an attention control. CLINICALTRIALSGOV: NCT01399502. PMID- 23805230 TI - Mutant Native Outer Membrane Vesicles Combined with a Serogroup A Polysaccharide Conjugate Vaccine for Prevention of Meningococcal Epidemics in Africa. AB - BACKGROUND: The meningococcal serogroup A (MenA) polysaccharide conjugate vaccine used in Sub-Saharan Africa does not prevent disease caused by MenW or MenX strains, which also cause epidemics in the region. We investigated the vaccine potential of native outer membrane vesicles with over-expressed factor H-binding protein (NOMV-fHbp), which targeted antigens in African meningococcal strains, and was combined with a MenA polysaccharide conjugate vaccine. METHODOLOGY/PRINCIPAL FINDINGS: The NOMV-fHbp vaccine was prepared from a mutant African MenW strain with PorA P1.5,2, attenuated endotoxin (DeltaLpxL1), deleted capsular genes, and over-expressed fHbp in variant group 1. The NOMV-fHbp was adsorbed with Al(OH)3 and used to reconstitute a lyophilized MenA conjugate vaccine, which normally is reconstituted with liquid MenC, Y and W conjugates in a meningococcal quadrivalent conjugate vaccine (MCV4-CRM, Novartis). Mice immunized with the NOMV-fHbp vaccine alone developed serum bactericidal (human complement) activity against 13 of 15 African MenA strains tested; 10 of 10 African MenX strains, 7 of 7 African MenW strains, and 6 of 6 genetically diverse MenB strains with fHbp variant group 1 (including 1 strain from The Gambia). The combination NOMV-fHbp/MenA conjugate vaccine elicited high serum bactericidal titers against the two MenA strains tested that were resistant to bactericidal antibodies elicited by the NOMV-fHbp alone; the combination elicited higher titers against the MenA and MenW strains than those elicited by a control MCV4 CRM vaccine (P<0.05); and high titers against MenX and MenB strains. For most strains, the titers elicited by a control NOMV-fHbp knock out vaccine were <1?10 except when the strain PorA matched the vaccine (titers >1?000). CONCLUSION/SIGNIFICANCE: The NOMV-fHbp/MenA conjugate vaccine provided similar or higher coverage against MenA and MenW strains than a quadrivalent meningococcal conjugate vaccine, and extended protection against MenX strains responsible for epidemics in Africa, and MenB strains with fHbp in variant group 1. PMID- 23805232 TI - A Simple and Computationally Efficient Approach to Multifactor Dimensionality Reduction Analysis of Gene-Gene Interactions for Quantitative Traits. AB - We present an extension of the two-class multifactor dimensionality reduction (MDR) algorithm that enables detection and characterization of epistatic SNP-SNP interactions in the context of a quantitative trait. The proposed Quantitative MDR (QMDR) method handles continuous data by modifying MDR's constructive induction algorithm to use a T-test. QMDR replaces the balanced accuracy metric with a T-test statistic as the score to determine the best interaction model. We used a simulation to identify the empirical distribution of QMDR's testing score. We then applied QMDR to genetic data from the ongoing prospective Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. PMID- 23805234 TI - Aerobic Capacity, Activity Levels and Daily Energy Expenditure in Male and Female Adolescents of the Kenyan Nandi Sub-Group. AB - The relative importance of genetic and socio-cultural influences contributing to the success of east Africans in endurance athletics remains unknown in part because the pre-training phenotype of this population remains incompletely assessed. Here cardiopulmonary fitness, physical activity levels, distance travelled to school and daily energy expenditure in 15 habitually active male (13.9+/-1.6 years) and 15 habitually active female (13.9+/-1.2) adolescents from a rural Nandi primary school are assessed. Aerobic capacity ([Formula: see text]) was evaluated during two maximal discontinuous incremental exercise tests; physical activity using accelerometry combined with a global positioning system; and energy expenditure using the doubly labelled water method. The [Formula: see text] of the male and female adolescents were 73.9+/-5.7 ml(.) kg(-1.) min(-1) and 61.5+/-6.3 ml(.) kg(-1.) min(-1), respectively. Total time spent in sedentary, light, moderate and vigorous physical activities per day was 406+/-63 min (50% of total monitored time), 244+/-56 min (30%), 75+/-18 min (9%) and 82+/ 30 min (10%). Average total daily distance travelled to and from school was 7.5+/ 3.0 km (0.8-13.4 km). Mean daily energy expenditure, activity-induced energy expenditure and physical activity level was 12.2+/-3.4 MJ(.) day(-1), 5.4+/-3.0 MJ(.) day(-1) and 2.2+/-0.6. 70.6% of the variation in [Formula: see text] was explained by sex (partial R(2) = 54.7%) and body mass index (partial R(2) = 15.9%). Energy expenditure and physical activity variables did not predict variation in [Formula: see text] once sex had been accounted for. The highly active and energy-demanding lifestyle of rural Kenyan adolescents may account for their exceptional aerobic fitness and collectively prime them for later training and athletic success. PMID- 23805233 TI - Neurochemical Changes in the Mouse Hippocampus Underlying the Antidepressant Effect of Genetic Deletion of P2X7 Receptors. AB - Recent investigations have revealed that the genetic deletion of P2X7 receptors (P2rx7) results in an antidepressant phenotype in mice. However, the link between the deficiency of P2rx7 and changes in behavior has not yet been explored. In the present study, we studied the effect of genetic deletion of P2rx7 on neurochemical changes in the hippocampus that might underlie the antidepressant phenotype. P2X7 receptor deficient mice (P2rx7-/-) displayed decreased immobility in the tail suspension test (TST) and an attenuated anhedonia response in the sucrose preference test (SPT) following bacterial endotoxin (LPS) challenge. The attenuated anhedonia was reproduced through systemic treatments with P2rx7 antagonists. The activation of P2rx7 resulted in the concentration-dependent release of [(3)H]glutamate in P2rx7+/+ but not P2rx7-/- mice, and the NR2B subunit mRNA and protein was upregulated in the hippocampus of P2rx7-/- mice. The brain-derived neurotrophic factor (BDNF) expression was higher in saline but not LPS-treated P2rx7-/- mice; the P2rx7 antagonist Brilliant blue G elevated and the P2rx7 agonist benzoylbenzoyl ATP (BzATP) reduced BDNF level. This effect was dependent on the activation of NMDA and non-NMDA receptors but not on Group I metabotropic glutamate receptors (mGluR1,5). An increased 5-bromo-2-deoxyuridine (BrdU) incorporation was also observed in the dentate gyrus derived from P2rx7-/- mice. Basal level of 5-HT was increased, whereas the 5HIAA/5-HT ratio was lower in the hippocampus of P2rx7-/- mice, which accompanied the increased uptake of [(3)H]5-HT and an elevated number of [(3)H]citalopram binding sites. The LPS induced elevation of 5-HT level was absent in P2rx7-/- mice. In conclusion there are several potential mechanisms for the antidepressant phenotype of P2rx7-/- mice, such as the absence of P2rx7-mediated glutamate release, elevated basal BDNF production, enhanced neurogenesis and increased 5-HT bioavailability in the hippocampus. PMID- 23805235 TI - The Applicability of TaqMan-Based Quantitative Real-Time PCR Assays for Detecting and Enumerating Cryptosporidium spp. Oocysts in the Environment. AB - Quantitative real-time polymerase chain reaction (qPCR) assays to detect Cryptosporidium oocysts in clinical samples are increasingly being used to diagnose human cryptosporidiosis, but a parallel approach for detecting and identifying Cryptosporidium oocyst contamination in surface water sources has yet to be established for current drinking water quality monitoring practices. It has been proposed that Cryptosporidium qPCR-based assays could be used as viable alternatives to current microscopic-based detection methods to quantify levels of oocysts in drinking water sources; however, data on specificity, analytical sensitivity, and the ability to accurately quantify low levels of oocysts are limited. The purpose of this study was to provide a comprehensive evaluation of TaqMan-based qPCR assays, which were developed for either clinical or environmental investigations, for detecting Cryptosporidium oocyst contamination in water. Ten different qPCR assays, six previously published and four developed in this study were analyzed for specificity and analytical sensitivity. Specificity varied between all ten assays, and in one particular assay, which targeted the Cryptosporidium 18S rRNA gene, successfully detected all Cryptosporidium spp. tested, but also cross-amplified T. gondii, fungi, algae, and dinoflagellates. When evaluating the analytical sensitivity of these qPCR assays, results showed that eight of the assays could reliably detect ten flow sorted oocysts in reagent water or environmental matrix. This study revealed that while a qPCR-based detection assay can be useful for detecting and differentiating different Cryptosporidium species in environmental samples, it cannot accurately measure low levels of oocysts that are typically found in drinking water sources. PMID- 23805236 TI - Features of Variable Number of Tandem Repeats in Yersinia pestis and the Development of a Hierarchical Genotyping Scheme. AB - BACKGROUND: Variable number of tandem repeats (VNTRs) that are widely distributed in the genome of Yersinia pestis proved to be useful markers for the genotyping and source-tracing of this notorious pathogen. In this study, we probed into the features of VNTRs in the Y. pestis genome and developed a simple hierarchical genotyping system based on optimized VNTR loci. METHODOLOGY/PRINCIPAL FINDINGS: Capillary electrophoresis was used in this study for multi-locus VNTR analysis (MLVA) in 956 Y. pestis strains. The general features and genetic diversities of 88 VNTR loci in Y. pestis were analyzed with BioNumerics, and a "14+12" loci based hierarchical genotyping system, which is compatible with single nucleotide polymorphism-based phylogenic analysis, was established. CONCLUSIONS/SIGNIFICANCE: Appropriate selection of target loci reduces the impact of homoplasies caused by the rapid mutation rates of VNTR loci. The optimized "14+12" loci are highly discriminative in genotyping and source-tracing Y. pestis for molecular epidemiological or microbial forensic investigations with less time and lower cost. An MLVA genotyping datasets of representative strains will improve future research on the source-tracing and microevolution of Y. pestis. PMID- 23805237 TI - Interleukin-10 -592C/A, -819C/T and -1082A/G Polymorphisms with Risk of Type 2 Diabetes Mellitus: A HuGE Review and Meta-analysis. AB - BACKGROUND: Several studies have been conducted in recent years to evaluate the risk of type 2 diabetes mellitus (T2DM) and polymorphisms of interleukin (IL)-10. However, the results remain conflicting rather than conclusive. This meta analysis aimed to summarize the current evidence from case-control studies that evaluated this association. METHODS: We carried out a search in Medline, EMBASE, and the Chinese National Knowledge Infrastructure (CNKI) database for relevant studies. Data were extracted using a standardized form and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the strength of the association. RESULTS: 10 studies were included in our meta-analysis and systemic review. Our meta-analysis indicated that IL-10 -1082A/G polymorphism was associated with the risk of T2DM (GA vs. AA: OR = 1.21, 95% CI = 1.03-1.14; GA/GG vs. AA: OR = 1.22, 95% CI = 1.05-1.41), whereas there was no association between IL-10 -592C/A (CC/CA vs. AA: OR = 1.07, 95% CI = 0.59-1.93) or -819C/T (CC/CT vs. TT: OR = 0.93, 95% CI = 0.49-1.75) polymorphism and T2DM risk was found in our study. CONCLUSIONS: This meta-analysis provides strong evidence that IL-10 1082A/G polymorphism associated with risk of T2DM. However, no association of the IL-10 -592C/A or -819C/T polymorphism with T2DM risk was found. Additional well designed large studies were required for the validation of our results. PMID- 23805238 TI - High Fat Diet Induces Liver Steatosis and Early Dysregulation of Iron Metabolism in Rats. AB - This paper is dedicated to the memory of our wonderful colleague Professor Alfredo Colonna, who passed away the same day of its acceptance. Fatty liver accumulation, inflammatory process and insulin resistance appear to be crucial in non-alcoholic fatty liver disease (NAFLD), nevertheless emerging findings pointed an important role also for iron overload. Here, we investigate the molecular mechanisms of hepatic iron metabolism in the onset of steatosis to understand whether its impairment could be an early event of liver inflammatory injury. Rats were fed with control diet or high fat diet (HFD) for 5 or 8 weeks, after which liver morphology, serum lipid profile, transaminases levels and hepatic iron content (HIC), were evaluated. In liver of HFD fed animals an increased time dependent activity of iron regulatory protein 1 (IRP1) was evidenced, associated with the increase in transferrin receptor-1 (TfR1) expression and ferritin down regulation. Moreover, ferroportin (FPN-1), the main protein involved in iron export, was down-regulated accordingly with hepcidin increase. These findings were indicative of an increased iron content into hepatocytes, which leads to an increase of harmful free-iron also related to the reduction of hepatic ferritin content. The progressive inflammatory damage was evidenced by the increase of hepatic TNF-alpha, IL-6 and leptin, in parallel to increased iron content and oxidative stress. The major finding that emerged of this study is the impairment of iron homeostasis in the ongoing and sustaining of liver steatosis, suggesting a strong link between iron metabolism unbalance, inflammatory damage and progression of disease. PMID- 23805239 TI - A Molecular Predictor Reassesses Classification of Human Grade II/III Gliomas. AB - Diffuse gliomas are incurable brain tumors divided in 3 WHO grades (II; III; IV) based on histological criteria. Grade II/III gliomas are clinically very heterogeneous and their prognosis somewhat unpredictable, preventing definition of appropriate treatment. On a cohort of 65 grade II/III glioma patients, a QPCR based approach allowed selection of a biologically relevant gene list from which a gene signature significantly correlated to overall survival was extracted. This signature clustered the training cohort into two classes of low and high risk of progression and death, and similarly clustered two external independent test cohorts of 104 and 73 grade II/III patients. A 22-gene class predictor of the training clusters optimally distinguished poor from good prognosis patients (median survival of 13-20 months versus over 6 years) in the validation cohorts. This classification was stronger at predicting outcome than the WHO grade II/III classification (P<=2.8E-10 versus 0.018). When compared to other prognosis factors (histological subtype and genetic abnormalities) in a multivariate analysis, the 22-gene predictor remained significantly associated with overall survival. Early prediction of high risk patients (3% of WHO grade II), and low risk patients (29% of WHO grade III) in clinical routine will allow the development of more appropriate follow-up and treatments. PMID- 23805240 TI - Circulating microRNAs as a Fingerprint for Liver Cirrhosis. AB - BACKGROUND: Sensitive and specific detection of liver cirrhosis is an urgent need for optimal individualized management of disease activity. Substantial studies have identified circulation miRNAs as biomarkers for diverse diseases including chronic liver diseases. In this study, we investigated the plasma miRNA signature to serve as a potential diagnostic biomarker for silent liver cirrhosis. METHODS: A genome-wide miRNA microarray was first performed in 80 plasma specimens. Six candidate miRNAs were selected and then trained in CHB-related cirrhosis and controls by qPCR. A classifier, miR-106b and miR-181b, was validated finally in two independent cohorts including CHB-related silent cirrhosis and controls, as well as non-CHB-related cirrhosis and controls as validation sets, respectively. RESULTS: A profile of 2 miRNAs (miR-106b and miR-181b) was identified as liver cirrhosis biomarkers irrespective of etiology. The classifier constructed by the two miRNAs provided a high diagnostic accuracy for cirrhosis (AUC = 0.882 for CHB related cirrhosis in the training set, 0.774 for CHB-related silent cirrhosis in one validation set, and 0.915 for non-CHB-related cirrhosis in another validation set). CONCLUSION: Our study demonstrated that the combined detection of miR-106b and miR-181b has a considerable clinical value to diagnose patients with liver cirrhosis, especially those at early stage. PMID- 23805241 TI - CpG-Oligodeoxynucleotide Treatment Protects against Ionizing Radiation-Induced Intestine Injury. AB - BACKGROUND: the bone marrow and the intestine are the major sites of ionizing radiation (IR)-induced injury. Our previous study demonstrated that CpG oligodeoxynucleotide (ODN) treatment mitigated IR-induced bone marrow injury, but its effect on the intestine is not known. In this study, we sought to determine if CpG-ODN have protective effect on IR-induced intestine injury, and if so, to determine the mechanism of its effect. METHODS AND FINDINGS: Mice were treated with CpG-ODN after IR. The body weight and survival were daily monitored for 30 days consecutively after exposure. The number of surviving intestinal crypt was assessed by the microcolony survival assay. The number and the distribution of proliferating cell in crypt were evaluated by TUNEL assay and BrdU assay. The expression of Bcl-2, Bax and caspase-3 in crypt were analyzed by Immunohistochemistry assay. The findings showed that the treatment for irradiated mice with CpG-ODN diminished body weight loss, improved 30 days survival, enhanced intestinal crypts survival and maintained proliferating cell population and regeneration in crypt. The reason might involve that CpG-ODN up-regulated the expression of Bcl-2 protein and down-regulated the expression of Bax protein and caspase-3 protein. CONCLUSION: CpG-ODN was effective in protection of IR-induced intestine injury by enhancing intestinal crypts survival and maintaining proliferating cell population and regeneration in crypt. The mechanism might be that CpG-ODN inhibits proliferating cell apoptosis through regulating the expression of apoptosis-related protein, such as Bax, Bcl-2 and caspase-3. PMID- 23805242 TI - The Prognostic Value of p16 Hypermethylation in Cancer: A Meta-Analysis. AB - BACKGROUND: The prognostic value of p16 promoter hypermethylation in cancers has been evaluated for several years while the results remain controversial. We thus performed a systematic review and meta-analysis of studies assessing the impact of p16 methylation on overall survival (OS) and disease-free survival (DFS) to clarify this issue. METHODS: We searched Pubmed, Embase and ISI web of knowledge to identify studies on the prognostic impact of p16 hypermethylation in cancers. A total of 6589 patients from 45 eligible studies were included in the analysis. Pooled hazard ratios (HRs) with 95% confidence interval (95% CI) were calculated to estimate the effect using random-effects model. RESULTS: The analysis indicated that p16 hypermethylation had significant association with poor OS of non-small cell lung cancer (NSCLC) (HR 1.74, 95% CI: 1.36-2.22) and colorectal cancer (CRC) (HR 1.80; 95% CI 1.27-2.55). Moreover, the significant correlation was present between p16 hypermethylation and DFS of NSCLC (HR 2.04, 95% CI: 1.19 3.50) and head and neck cancer (HR 2.24, 95% CI: 1.35-3.73). Additionally, in the analysis of the studies following REMARK guidelines more rigorously, p16 hypermethylation had unfavorable impact on OS of NSCLC (HR 1.79, 95% CI: 1.35 2.39) and CRC (HR 1.96, 1.16-3.34), and on DFS of NSCLC (HR 2.12, 95% CI: 1.21 3.72) and head and neck cancer (HR 2.24, 95% CI: 1.35-3.73). CONCLUSIONS: p16 hypermethylation might be a predictive factor of poor prognosis in some surgically treated cancers, particularly in NSCLC. PMID- 23805244 TI - Real-Time Localization of Moving Dipole Sources for Tracking Multiple Free Swimming Weakly Electric Fish. AB - In order to survive, animals must quickly and accurately locate prey, predators, and conspecifics using the signals they generate. The signal source location can be estimated using multiple detectors and the inverse relationship between the received signal intensity (RSI) and the distance, but difficulty of the source localization increases if there is an additional dependence on the orientation of a signal source. In such cases, the signal source could be approximated as an ideal dipole for simplification. Based on a theoretical model, the RSI can be directly predicted from a known dipole location; but estimating a dipole location from RSIs has no direct analytical solution. Here, we propose an efficient solution to the dipole localization problem by using a lookup table (LUT) to store RSIs predicted by our theoretically derived dipole model at many possible dipole positions and orientations. For a given set of RSIs measured at multiple detectors, our algorithm found a dipole location having the closest matching normalized RSIs from the LUT, and further refined the location at higher resolution. Studying the natural behavior of weakly electric fish (WEF) requires efficiently computing their location and the temporal pattern of their electric signals over extended periods. Our dipole localization method was successfully applied to track single or multiple freely swimming WEF in shallow water in real time, as each fish could be closely approximated by an ideal current dipole in two dimensions. Our optimized search algorithm found the animal's positions, orientations, and tail-bending angles quickly and accurately under various conditions, without the need for calibrating individual-specific parameters. Our dipole localization method is directly applicable to studying the role of active sensing during spatial navigation, or social interactions between multiple WEF. Furthermore, our method could be extended to other application areas involving dipole source localization. PMID- 23805243 TI - Diversity of Microbial Communities in Production and Injection Waters of Algerian Oilfields Revealed by 16S rRNA Gene Amplicon 454 Pyrosequencing. AB - The microorganisms inhabiting many petroleum reservoirs are multi-extremophiles capable of surviving in environments with high temperature, pressure and salinity. Their activity influences oil quality and they are an important reservoir of enzymes of industrial interest. To study these microbial assemblages and to assess any modifications that may be caused by industrial practices, the bacterial and archaeal communities in waters from four Algerian oilfields were described and compared. Three different types of samples were analyzed: production waters from flooded wells, production waters from non-flooded wells and injection waters used for flooding (water-bearing formations). Microbial communities of production and injection waters appeared to be significantly different. From a quantitative point of view, injection waters harbored roughly ten times more microbial cells than production waters. Bacteria dominated in injection waters, while Archaea dominated in production waters. Statistical analysis based on the relative abundance and bacterial community composition (BCC) revealed significant differences between production and injection waters at both OTUs0.03 and phylum level. However, no significant difference was found between production waters from flooded and non-flooded wells, suggesting that most of the microorganisms introduced by the injection waters were unable to survive in the production waters. Furthermore, a Venn diagram generated to compare the BCC of production and injection waters of one flooded well revealed only 4% of shared bacterial OTUs. Phylogenetic analysis of bacterial sequences indicated that Alpha-, Beta- and Gammaproteobacteria were the main classes in most of the water samples. Archaeal sequences were only obtained from production wells and each well had a unique archaeal community composition, mainly belonging to Methanobacteria, Methanomicrobia, Thermoprotei and Halobacteria classes. Many of the bacterial genera retrieved had already been reported as degraders of complex organic molecules and pollutants. Nevertheless, a large number of unclassified bacterial and archaeal sequences were found in the analyzed samples, indicating that subsurface waters in oilfields could harbor new and still-non described microbial species. PMID- 23805245 TI - The Effect of Z-Ligustilide on the Mobility of Human Glioblastoma T98G Cells. AB - Z-ligustilide (LIG), an essential oil extract from Radix Angelica sinensis, has broad pharmaceutical applications in treating cardio-vascular diseases and ischemic brain injury. Recently, LIG has been connected to Glioblastoma multiforme (GBM) because of its structural similarity to 3-n-alkyphthalide (NBP), which is specifically cytotoxic to GBM cells. Hence, we investigated LIG's effect on GBM T98G cells. The study shows that LIG can significantly reduce T98G cells' migration in a dose-dependent manner. Furthermore, the attenuation of cellular mobility can be linked to the activity of the Rho GTPases (RhoA, Rac1 and Cdc42), the three critical molecular switches governing cytoskeleton remodeling; thus, regulating cell migration. LIG significantly reduces the expression of RhoA and affects in a milder manner the expression of Cdc42 and Rac1. PMID- 23805246 TI - Semi-Automated Detection of Cerebral Microbleeds on 3.0 T MR Images. AB - Cerebral microbleeds are associated with vascular disease and dementia. They can be detected on MRI and receive increasing attention. Visual rating is the current standard for microbleed detection, but is rater dependent, has limited reproducibility, modest sensitivity, and can be time-consuming. The goal of the current study is to present a tool for semi-automated detection of microbleeds that can assist human raters in the rating procedure. The radial symmetry transform is originally a technique to highlight circular-shaped objects in two dimensional images. In the current study, the three-dimensional radial symmetry transform was adapted to detect spherical microbleeds in a series of 72 patients from our hospital, for whom a ground truth visual rating was made by four raters. Potential microbleeds were automatically identified on T2*-weighted 3.0 T MRI scans and the results were visually checked to identify microbleeds. Final ratings of the radial symmetry transform were compared to human ratings. After implementing and optimizing the radial symmetry transform, the method achieved a high sensitivity, while maintaining a modest number of false positives. Depending on the settings, sensitivities ranged from 65%-84% compared to the ground truth rating. Rating of the processed images required 1-2 minutes per participant, in which 20-96 false positive locations per participant were censored. Sensitivities of individual raters ranged from 39%-86% compared to the ground truth and required 5-10 minutes per participant per rater. The sensitivities that were achieved by the radial symmetry transform are similar to those of individual experienced human raters, demonstrating its feasibility and usefulness for semi automated microbleed detection. PMID- 23805247 TI - Treatment of Glucocorticoids Inhibited Early Immune Responses and Impaired Cardiac Repair in Adult Zebrafish. AB - Myocardial injury, such as myocardial infarction (MI), can lead to drastic heart damage. Zebrafish have the extraordinary ability to regenerate their heart after a severe injury. Upon ventricle resection, fibrin clots seal the wound and serve as a matrix for recruiting myeloid-derived phagocytes. Accumulated neutrophils and macrophages not only reduce the risk of infection but also secrete cytokines and growth factors to promote tissue repair. However, the underlying cellular and molecular mechanisms for how immune responses are regulated during the early stages of cardiac repair are still unclear. We investigated the role and programming of early immune responses during zebrafish heart regeneration. We found that zebrafish treated with an anti-inflammatory glucocorticoid had significantly reduced heart regenerative capacities, consistent with findings in other higher vertebrates. Moreover, inhibiting the inflammatory response led to excessive collagen deposition. A microarray approach was used to assess the differential expression profiles between zebrafish hearts with normal or impaired healing. Combining cytokine profiling and immune-staining, our data revealed that impaired heart regeneration could be due to reduced phagocyte recruitment, leading to diminished angiogenesis and cell proliferation post-cardiac injury. Despite their robust regenerative ability, our study revealed that glucocorticoid treatment could effectively hinder cardiac repair in adult zebrafish by interfering with the inflammatory response. Our findings may help to clarify the initiation of cardiac repair, which could be used to develop a therapeutic intervention that may enhance cardiac repair in humans to compensate for the loss of cardiomyocytes after an MI. PMID- 23805248 TI - Prioritized Detection of Personally Familiar Faces. AB - We investigated whether personally familiar faces are preferentially processed in conditions of reduced attentional resources and in the absence of conscious awareness. In the first experiment, we used Rapid Serial Visual Presentation (RSVP) to test the susceptibility of familiar faces and faces of strangers to the attentional blink. In the second experiment, we used continuous flash interocular suppression to render stimuli invisible and measured face detection time for personally familiar faces as compared to faces of strangers. In both experiments we found an advantage for detection of personally familiar faces as compared to faces of strangers. Our data suggest that the identity of faces is processed with reduced attentional resources and even in the absence of awareness. Our results show that this facilitated processing of familiar faces cannot be attributed to detection of low-level visual features and that a learned unique configuration of facial features can influence preconscious perceptual processing. PMID- 23805249 TI - Effects of Global Warming on Predatory Bugs Supported by Data Across Geographic and Seasonal Climatic Gradients. AB - Global warming may affect species abundance and distribution, as well as temperature-dependent morphometric traits. In this study, we first used historical data to document changes in Orius (Heteroptera: Anthocoridae) species assemblage and individual morphometric traits over the past seven decades in Israel. We then tested whether these changes could have been temperature driven by searching for similar patterns across seasonal and geographic climatic gradients in a present survey. The historical records indicated a shift in the relative abundance of dominant Orius species; the relative abundance of O. albidipennis, a desert-adapted species, increased while that of O. laevigatus decreased in recent decades by 6 and 10-15 folds, respectively. These shifts coincided with an overall increase of up to 2.1 degrees C in mean daily temperatures over the last 25 years in Israel. Similar trends were found in contemporary data across two other climatic gradients, seasonal and geographic; O. albidipennis dominated Orius assemblages under warm conditions. Finally, specimens collected in the present survey were significantly smaller than those from the 1980's, corresponding to significantly smaller individuals collected now during warmer than colder seasons. Taken together, results provide strong support to the hypothesis that temperature is the most likely driver of the observed shifts in species composition and body sizes because (1) historical changes in both species assemblage and body size were associated with rising temperatures in the study region over the last few decades; and (2) similar changes were observed as a result of contemporary drivers that are associated with temperature. PMID- 23805250 TI - Human but Not Laboratory Borna Disease Virus Inhibits Proliferation and Induces Apoptosis in Human Oligodendrocytes In Vitro. AB - Borna disease virus (BDV) is a neurotropic virus that produces neuropsychiatric dysfunction in a wide range of warm-blooded species. Several studies have associated BDV with human psychiatric illness, but the findings remain controversial. Although oligodendrocytes are a major glial component of brain white matter and play a pivotal role in neuronal cell function, BDV's effects on human oligodendrocytes have not been clarified. Here, the effects of two BDV strains, Hu-H1 (isolated from a bipolar patient) and Strain V (a laboratory strain), on the proliferation and apoptosis of human oligodendrocytes were investigated. Three experimental cell lines were constructed: Hu-H1-infected oligodendroglioma (Hu-H1) cells, Strain V-infected oligodendroglioma (Strain V) cells, and non-infected oligodendroglioma (control) cells. BDV infection was assayed by BDV nucleoprotein (p40) immunofluorescence, cell proliferation was assayed by Cell Counting Kit-8 (CCK8), and cell cycle phases and apoptosis were assayed by flow cytometry. Expressions of the apoptosis-related proteins Bax and Bcl-2 were measured by Western blotting. p40 expression was confirmed in Hu-H1 and Strain V on and after day three post-infection. Strain V cells showed significantly greater cellular proliferation than Hu-H1 cells on and after day three post-infection. In Hu-H1 cells, Bax and Bcl-2 expression were significantly increased and decreased, respectively, on and after day three post-infection. In contrast, in Strain V cells, Bax and Bcl-2 expression were significantly decreased and increased, respectively, on and after day three post-infection. In conclusion, Hu-H1 inhibits cellular proliferation and promotes apoptosis in human oligodendrocytes via Bax upregulation and Bcl-2 downregulation. In contrast, Strain V promotes cellular proliferation and inhibits apoptosis in human oligodendrocytes via Bax downregulation and Bcl-2 upregulation. The effects of the Hu-H1 strain (isolated from a bipolar patient) are opposite from those of Strain V (a laboratory strain), thereby providing a proof of authenticity for both. PMID- 23805251 TI - Comparative Anatomy of the Bony Labyrinth (Inner Ear) of Placental Mammals. AB - BACKGROUND: Variation is a naturally occurring phenomenon that is observable at all levels of morphology, from anatomical variations of DNA molecules to gross variations between whole organisms. The structure of the otic region is no exception. The present paper documents the broad morphological diversity exhibited by the inner ear region of placental mammals using digital endocasts constructed from high-resolution X-ray computed tomography (CT). Descriptions cover the major placental clades, and linear, angular, and volumetric dimensions are reported. PRINCIPAL FINDINGS: The size of the labyrinth is correlated to the overall body mass of individuals, such that large bodied mammals have absolutely larger labyrinths. The ratio between the average arc radius of curvature of the three semicircular canals and body mass of aquatic species is substantially lower than the ratios of related terrestrial taxa, and the volume percentage of the vestibular apparatus of aquatic mammals tends to be less than that calculated for terrestrial species. Aspects of the bony labyrinth are phylogenetically informative, including vestibular reduction in Cetacea, a tall cochlear spiral in caviomorph rodents, a low position of the plane of the lateral semicircular canal compared to the posterior canal in Cetacea and Carnivora, and a low cochlear aspect ratio in Primatomorpha. SIGNIFICANCE: The morphological descriptions that are presented add a broad baseline of anatomy of the inner ear across many placental mammal clades, for many of which the structure of the bony labyrinth is largely unknown. The data included here complement the growing body of literature on the physiological and phylogenetic significance of bony labyrinth structures in mammals, and they serve as a source of data for future studies on the evolution and function of the vertebrate ear. PMID- 23805252 TI - Excess Cardiovascular Risk Burden in Jamaican Women Does Not Influence Predicted 10-Year CVD Risk Profiles of Jamaica Adults: An Analysis of the 2007/08 Jamaica Health and Lifestyle Survey. AB - BACKGROUND: Black Caribbean women have a higher burden of cardiovascular disease (CVD) risk factors than their male counterparts. Whether this results in a difference in incident cardiovascular events is unknown. The aim of this study was to estimate the 10 year World Health Organization/International Society for Hypertension (WHO/ISH) CVD risk score for Jamaica and explore the effect of sex as well as obesity, physical activity and socioeconomic status on these estimates. METHODS AND FINDINGS: Data from 40-74 year old participants in the 2007/08 Jamaica Health and Lifestyle Survey were used. Trained interviewers administered questionnaires and measured anthropometrics, blood pressure, fasting glucose and cholesterol. Education and occupation were used to assess socioeconomic status. The Americas B tables were used to estimate the WHO/ISH 10 year CVD risk scores for the population. Weighted prevalence estimates were calculated. Data from 1,432 (450 men, 982 women) participants were analysed, after excluding those with self-reported heart attack and stroke. The women had a higher prevalence of diabetes (19%W;12%M), hypertension (49%W;47%M), hypercholesterolemia (25%W;11%M), obesity (46%W;15%M) and physical inactivity (59%W;29%M). More men smoked (6%W;31%M). There was good agreement between the 10 year cardiovascular risk estimates whether or not cholesterol measurements were utilized for calculation (kappa -0.61). While 90% had a 10 year WHO/ISH CVD risk of less than 10%, approximately 2% of the population or 14,000 persons had a 10 year WHO/ISH CVD risk of >=30%. As expected CVD risk increased with age but there was no sex difference in CVD risk distribution despite women having a greater risk factor burden. Women with low socioeconomic status had the most adverse CVD risk profile. CONCLUSION: Despite women having a higher prevalence of CVD risk factors there was no sex difference in 10-year WHO/ISH CVD risk in Jamaican adults. PMID- 23805253 TI - Lifelong Physical Activity Prevents Aging-Associated Insulin Resistance in Human Skeletal Muscle Myotubes via Increased Glucose Transporter Expression. AB - Both aging and physical inactivity are associated with increased development of insulin resistance whereas physical activity has been shown to promote increased insulin sensitivity. Here we investigated the effects of physical activity level on aging-associated insulin resistance in myotubes derived from human skeletal muscle satellite cells. Satellite cells were obtained from young (22 yrs) normally active or middle-aged (56.6 yrs) individuals who were either lifelong sedentary or lifelong active. Both middle-aged sedentary and middle-aged active myotubes had increased p21 and myosin heavy chain protein expression. Interestingly MHCIIa was increased only in myotubes from middle-aged active individuals. Middle-aged sedentary cells had intact insulin-stimulated Akt phosphorylation however, the same cell showed ablated insulin-stimulated glucose uptake and GLUT4 translocation to the plasma membrane. On the other hand, middle aged active cells retained both insulin-stimulated increases in glucose uptake and GLUT4 translocation to the plasma membrane. Middle-aged active cells also had significantly higher mRNA expression of GLUT1 and GLUT4 compared to middle-aged sedentary cells, and significantly higher GLUT4 protein. It is likely that physical activity induces a number of stable adaptations, including increased GLUT4 expression that are retained in cells ex vivo and protect, or delay the onset of middle-aged-associated insulin resistance. Additionally, a sedentary lifestyle has an impact on the metabolism of human myotubes during aging and may contribute to aging-associated insulin resistance through impaired GLUT4 localization. PMID- 23805254 TI - In Planta Biocontrol of Pectobacterium atrosepticum by Rhodococcus erythropolis Involves Silencing of Pathogen Communication by the Rhodococcal Gamma-Lactone Catabolic Pathway. AB - The virulence of numerous Gram-negative bacteria is under the control of a quorum sensing process based on synthesis and perception of N-acyl homoserine lactones. Rhodococcus erythropolis, a Gram-positive bacterium, has recently been proposed as a biocontrol agent for plant protection against soft-rot bacteria, including Pectobacterium. Here, we show that the gamma-lactone catabolic pathway of R. erythropolis disrupts Pectobacterium communication and prevents plant soft-rot. We report the first characterization and demonstration of N-acyl homoserine lactone quenching in planta. In particular, we describe the transcription of the R. erythropolis lactonase gene, encoding the key enzyme of this pathway, and the subsequent lactone breakdown. The role of this catabolic pathway in biocontrol activity was confirmed by deletion of the lactonase gene from R. erythropolis and also its heterologous expression in Escherichia coli. The gamma-lactone catabolic pathway is induced by pathogen communication rather than by pathogen invasion. This is thus a novel and unusual biocontrol pathway, differing from those previously described as protecting plants from phytopathogens. These findings also suggest the existence of an additional pathway contributing to plant protection. PMID- 23805256 TI - Complex Effects of Ecosystem Engineer Loss on Benthic Ecosystem Response to Detrital Macroalgae. AB - Ecosystem engineers change abiotic conditions, community assembly and ecosystem functioning. Consequently, their loss may modify thresholds of ecosystem response to disturbance and undermine ecosystem stability. This study investigates how loss of the bioturbating lugworm Arenicola marina modifies the response to macroalgal detrital enrichment of sediment biogeochemical properties, microphytobenthos and macrofauna assemblages. A field manipulative experiment was done on an intertidal sandflat (Oosterschelde estuary, The Netherlands). Lugworms were deliberately excluded from 1* m sediment plots and different amounts of detrital Ulva (0, 200 or 600 g Wet Weight) were added twice. Sediment biogeochemistry changes were evaluated through benthic respiration, sediment organic carbon content and porewater inorganic carbon as well as detrital macroalgae remaining in the sediment one month after enrichment. Microalgal biomass and macrofauna composition were measured at the same time. Macroalgal carbon mineralization and transfer to the benthic consumers were also investigated during decomposition at low enrichment level (200 g WW). The interaction between lugworm exclusion and detrital enrichment did not modify sediment organic carbon or benthic respiration. Weak but significant changes were instead found for porewater inorganic carbon and microalgal biomass. Lugworm exclusion caused an increase of porewater carbon and a decrease of microalgal biomass, while detrital enrichment drove these values back to values typical of lugworm-dominated sediments. Lugworm exclusion also decreased the amount of macroalgae remaining into the sediment and accelerated detrital carbon mineralization and CO2 release to the water column. Eventually, the interaction between lugworm exclusion and detrital enrichment affected macrofauna abundance and diversity, which collapsed at high level of enrichment only when the lugworms were present. This study reveals that in nature the role of this ecosystem engineer may be variable and sometimes have no or even negative effects on stability, conversely to what it should be expected based on current research knowledge. PMID- 23805255 TI - Elevation of Eosinophil-Derived Neurotoxin in Plasma of the Subjects with Aspirin Exacerbated Respiratory Disease: A Possible Peripheral Blood Protein Biomarker. AB - Aspirin-exacerbated respiratory disease (AERD) remains widely underdiagnosed in asthmatics, primarily due to insufficient awareness of the relationship between aspirin ingestion and asthma exacerbation. The identification of aspirin hypersensitivity is therefore essential to avoid serious aspirin complications. The goal of the study was to develop plasma biomarkers to predict AERD. We identified differentially expressed genes in peripheral blood mononuclear cells (PBMC) between subjects with AERD and those with aspirin-tolerant asthma (ATA). The genes were matched with the secreted protein database (http://spd.cbi.pku.edu.cn/) to select candidate proteins in the plasma. Plasma levels of the candidate proteins were then measured in AERD (n = 40) and ATA (n = 40) subjects using an enzyme-linked immunosorbent assay (ELISA). Target genes were validated as AERD biomarkers using an ROC curve analysis. From 175 differentially expressed genes (p-value <0.0001) that were queried to the secreted protein database, 11 secreted proteins were retrieved. The gene expression patterns were predicted as elevated for 7 genes and decreased for 4 genes in AERD as compared with ATA subjects. Among these genes, significantly higher levels of plasma eosinophil-derived neurotoxin (RNASE2) were observed in AERD as compared with ATA subjects (70(14.62~311.92) ug/ml vs. 12(2.55~272.84) ug/ml, p-value <0.0003). Based on the ROC curve analysis, the AUC was 0.74 (p value = 0.0001, asymptotic 95% confidence interval [lower bound: 0.62, upper bound: 0.83]) with 95% sensitivity, 60% specificity, and a cut-off value of 27.15 ug/ml. Eosinophil-derived neurotoxin represents a novel biomarker to distinguish AERD from ATA. PMID- 23805257 TI - A Practical Approach Based on Analytic Deformable Algorithm for Scenic Image Registration. AB - BACKGROUND: Image registration is to produce an entire scene by aligning all the acquired image sequences. A registration algorithm is necessary to tolerance as much as possible for intensity and geometric variation among images. However, captured image views of real scene usually produce unexpected distortions. They are generally derived from the optic characteristics of image sensors or caused by the specific scenes and objects. METHODS AND FINDINGS: An analytic registration algorithm considering the deformation is proposed for scenic image applications in this study. After extracting important features by the wavelet based edge correlation method, an analytic registration approach is then proposed to achieve deformable and accurate matching of point sets. Finally, the registration accuracy is further refined to obtain subpixel precision by a feature-based Levenberg-Marquardt (FLM) method. It converges evidently faster than most other methods because of its feature-based characteristic. CONCLUSIONS: We validate the performance of proposed method by testing with synthetic and real image sequences acquired by a hand-held digital still camera (DSC) and in comparison with an optical flow-based motion technique in terms of the squared sum of intensity differences (SSD) and correlation coefficient (CC). The results indicate that the proposed method is satisfactory in the registration accuracy and quality of DSC images. PMID- 23805258 TI - Plant Kinesin-Like Calmodulin Binding Protein Employs Its Regulatory Domain for Dimerization. AB - Kinesin-like calmodulin binding protein (KCBP), a Kinesin-14 family motor protein, is involved in the structural organization of microtubules during mitosis and trichome morphogenesis in plants. The molecular mechanism of microtubule bundling by KCBP remains unknown. KCBP binding to microtubules is regulated by Ca(2+)-binding proteins that recognize its C-terminal regulatory domain. In this work, we have discovered a new function of the regulatory domain. We present a crystal structure of an Arabidopsis KCBP fragment showing that the C terminal regulatory domain forms a dimerization interface for KCBP. This dimerization site is distinct from the dimerization interface within the N terminal domain. Side chains of hydrophobic residues of the calmodulin binding helix of the regulatory domain form the C-terminal dimerization interface. Biochemical experiments show that another segment of the regulatory domain located beyond the dimerization interface, its negatively charged coil, is unexpectedly and absolutely required to stabilize the dimers. The strong microtubule bundling properties of KCBP are unaffected by deletion of the C terminal regulatory domain. The slow minus-end directed motility of KCBP is also unchanged in vitro. Although the C-terminal domain is not essential for microtubule bundling, we suggest that KCBP may use its two independent dimerization interfaces to support different types of bundled microtubule structures in cells. Two distinct dimerization sites may provide a mechanism for microtubule rearrangement in response to Ca(2+) signaling since Ca(2+)- binding proteins can disengage KCBP dimers dependent on its C-terminal dimerization interface. PMID- 23805259 TI - Structural Insights into Clostridium perfringens Delta Toxin Pore Formation. AB - Clostridium perfringens Delta toxin is one of the three hemolysin-like proteins produced by C. perfringens type C and possibly type B strains. One of the others, NetB, has been shown to be the major cause of Avian Nectrotic Enteritis, which following the reduction in use of antibiotics as growth promoters, has become an emerging disease of industrial poultry. Delta toxin itself is cytotoxic to the wide range of human and animal macrophages and platelets that present GM2 ganglioside on their membranes. It has sequence similarity with Staphylococcus aureus beta-pore forming toxins and is expected to heptamerize and form pores in the lipid bilayer of host cell membranes. Nevertheless, its exact mode of action remains undetermined. Here we report the 2.4 A crystal structure of monomeric Delta toxin. The superposition of this structure with the structure of the phospholipid-bound F component of S. aureus leucocidin (LukF) revealed that the glycerol molecules bound to Delta toxin and the phospholipids in LukF are accommodated in the same hydrophobic clefts, corresponding to where the toxin is expected to latch onto the membrane, though the binding sites show significant differences. From structure-based sequence alignment with the known structure of staphylococcal alpha-hemolysin, a model of the Delta toxin pore form has been built. Using electron microscopy, we have validated our model and characterized the Delta toxin pore on liposomes. These results highlight both similarities and differences in the mechanism of Delta toxin (and by extension NetB) cytotoxicity from that of the staphylococcal pore-forming toxins. PMID- 23805260 TI - Prediction and Analysis of Post-Translational Pyruvoyl Residue Modification Sites from Internal Serines in Proteins. AB - Most of pyruvoyl-dependent proteins observed in prokaryotes and eukaryotes are critical regulatory enzymes, which are primary targets of inhibitors for anti cancer and anti-parasitic therapy. These proteins undergo an autocatalytic, intramolecular self-cleavage reaction in which a covalently bound pyruvoyl group is generated on a conserved serine residue. Traditional detections of the modified serine sites are performed by experimental approaches, which are often labor-intensive and time-consuming. In this study, we initiated in an attempt for the computational predictions of such serine sites with Feature Selection based on a Random Forest. Since only a small number of experimentally verified pyruvoyl modified proteins are collected in the protein database at its current version, we only used a small dataset in this study. After removing proteins with sequence identities >60%, a non-redundant dataset was generated and was used, which contained only 46 proteins, with one pyruvoyl serine site for each protein. Several types of features were considered in our method including PSSM conservation scores, disorders, secondary structures, solvent accessibilities, amino acid factors and amino acid occurrence frequencies. As a result, a pretty good performance was achieved in our dataset. The best 100.00% accuracy and 1.0000 MCC value were obtained from the training dataset, and 93.75% accuracy and 0.8441 MCC value from the testing dataset. The optimal feature set contained 9 features. Analysis of the optimal feature set indicated the important roles of some specific features in determining the pyruvoyl-group-serine sites, which were consistent with several results of earlier experimental studies. These selected features may shed some light on the in-depth understanding of the mechanism of the post-translational self-maturation process, providing guidelines for experimental validation. Future work should be made as more pyruvoyl-modified proteins are found and the method should be evaluated on larger datasets. At last, the predicting software can be downloaded from http://www.nkbiox.com/sub/pyrupred/index.html. PMID- 23805261 TI - Relationship between Chronic Short Sleep Duration and Childhood Body Mass Index: A School-Based Cross-Sectional Study. AB - OBJECTIVE: To assess relationship between obesity and chronic shorter sleep duration in children and to determine if lack of sleep represents an independent determinant of childhood Body Mass Index. METHODS: This cross-sectional study was conducted in all children enrolled in the fifth class (approximately 10 years of age) of all public primary schools in Catanzaro (Southern Italy). The overall response rate was 62% resulting in 542 participating children. Parents completed a questionnaire with information on their demographics and socio-economic characteristics, their health status, characteristics of their child birth and health status. The sleeping habits were investigated in the 3 months preceding the consultation and parents were asked to indicate hours of bedtime and wake-up of their children. Multivariate linear regression analysis was performed to examine the association between child BMI and chronic lack of sleep. RESULTS: 36.7% of the children surveyed were overweight or obese. A quarter of children did not routinely play sports and many of them spent more than an hour a day watching TV (60.7%) and using videogames or computer (51.1%). Widespread dietary habits were inadequate, especially concerning vegetables and fruit intake with more than 95% of children who consumed insufficient amounts. The average duration of sleep was equal to 9.4 (SD = +/-0.6) hours, and the short-sleepers accounted for 38.9% of the total sample. The results of multivariate analysis showed a significant 0.77 Kg/m(2) increase of BMI for children classified as short compared to normal sleepers (95%CI = 0.16-1.38, p = 0.01). CONCLUSIONS: Chronic lack of sleep appears to be associated to higher BMI even in middle childhood and strongly suggests that public health strategies, focused on promoting healthy lifestyles should include an innovative approach to ensure an adequate duration of sleep at night especially in children, alongside more traditional approaches. PMID- 23805262 TI - Comparison of Barium and Arsenic Concentrations in Well Drinking Water and in Human Body Samples and a Novel Remediation System for These Elements in Well Drinking Water. AB - Health risk for well drinking water is a worldwide problem. Our recent studies showed increased toxicity by exposure to barium alone (<=700 ug/L) and coexposure to barium (137 ug/L) and arsenic (225 ug/L). The present edition of WHO health based guidelines for drinking water revised in 2011 has maintained the values of arsenic (10 ug/L) and barium (700 ug/L), but not elements such as manganese, iron and zinc. Nevertheless, there have been very few studies on barium in drinking water and human samples. This study showed significant correlations between levels of arsenic and barium, but not its homologous elements (magnesium, calcium and strontium), in urine, toenail and hair samples obtained from residents of Jessore, Bangladesh. Significant correlation between levels of arsenic and barium in well drinking water and levels in human urine, toenail and hair samples were also observed. Based on these results, a high-performance and low-cost adsorbent composed of a hydrotalcite-like compound for barium and arsenic was developed. The adsorbent reduced levels of barium and arsenic from well water in Bangladesh and Vietnam to <7 ug/L within 1 min. Thus, we have showed levels of arsenic and barium in humans and propose a novel remediation system. PMID- 23805263 TI - A Global Trend towards the Loss of Evolutionarily Unique Species in Mangrove Ecosystems. AB - The mangrove biome stands out as a distinct forest type at the interface between terrestrial, estuarine, and near-shore marine ecosystems. However, mangrove species are increasingly threatened and experiencing range contraction across the globe that requires urgent conservation action. Here, we assess the spatial distribution of mangrove species richness and evolutionary diversity, and evaluate potential predictors of global declines and risk of extinction. We found that human pressure, measured as the number of different uses associated with mangroves, correlated strongly, but negatively, with extinction probability, whereas species ages were the best predictor of global decline, explaining 15% of variation in extinction risk. Although the majority of mangrove species are categorised by the IUCN as Least Concern, our finding that the more threatened species also tend to be those that are more evolutionarily unique is of concern because their extinction would result in a greater loss of phylogenetic diversity. Finally, we identified biogeographic regions that are relatively species-poor but rich in evolutionary history, and suggest these regions deserve greater conservation priority. Our study provides phylogenetic information that is important for developing a unified management plan for mangrove ecosystems worldwide. PMID- 23805264 TI - Intramyocardial Injection of Pig Pluripotent Stem Cells Improves Left Ventricular Function and Perfusion: A Study in a Porcine Model of Acute Myocardial Infarction. AB - Induced pluripotent stem (iPS) cells have the potential to differentiate to various types of cardiovascular cells to repair an injured heart. The potential therapeutic benefits of iPS cell based treatment have been established in small animal models of myocardial infarction (MI). We hypothesize that porcine iPS (piPS) cell transplantation may be an effective treatment for MI. After a 90 minute occlusion of the left anterior descending artery in a porcine model, undifferentiated piPS cells or PBS were injected into the ischemic myocardium. Cardiac function, myocardial perfusion and cell differentiation were investigated. One week after piPS cell delivery, global left ventricular ejection fraction (LVEF) significantly decreased in both the iPS group and the PBS group compared to the Sham group (p<0.05, respectively). Six weeks after piPS cell delivery, LVEF of the iPS group significantly improved compared to the PBS group (56.68% vs. 50.93%, p = 0.04) but was still lower than the Sham group. Likewise, the piPS cell transplantation improved the regional perfusion compared to the PBS injection (19.67% vs. 13.67%, p = 0.02). The infarct area was significantly smaller in the iPS group than the PBS group (12.04% vs. 15.98% p = 0.01). PiPS cells engrafted into the myocardium can differentiate into vessel cells, which result in increased formation of new vessels in the infarcted heart. Direct intramyocardial injection of piPS cells can decrease infarct size and improve left ventricular function and perfusion for an immunosuppressed porcine AMI model. PMID- 23805265 TI - Evaluating the Effectiveness of France's Indoor Smoke-Free Law 1 Year and 5 Years after Implementation: Findings from the ITC France Survey. AB - France implemented a comprehensive smoke-free law in two phases: Phase 1 (February 2007) banned smoking in workplaces, shopping centres, airports, train stations, hospitals, and schools; Phase 2 (January 2008) banned smoking in hospitality venues (bars, restaurants, hotels, casinos, nightclubs). This paper evaluates France's smoke-free law based on the International Tobacco Control Policy Evaluation Project in France (the ITC France Project), which conducted a cohort survey of approximately 1,500 smokers and 500 non-smokers before the implementation of the laws (Wave 1) and two waves after the implementation (Waves 2 and 3). Results show that the smoke-free law led to a very significant and near total elimination of observed smoking in key venues such as bars (from 94-97% to 4%) and restaurants (from 60-71% to 2-3%) at Wave 2, which was sustained four years later (6-8% in bars; 1-2% in restaurants). The reduction in self-reported smoking by smoking respondents was nearly identical to the effects shown in observed smoking. Observed smoking in workplaces declined significantly after the law (from 41-48% to 18-20%), which continued to decline at Wave 3 (to 14-15%). Support for the smoke-free laws increased significantly after their implementation and continued to increase at Wave 3 (p<.001 among smokers for bars and restaurants; p<.001 among smokers and p = .003 for non-smokers for workplaces). The findings demonstrate that smoke-free policies that are implemented in ways consistent with the Guidelines for Article 8 of the WHO Framework Convention on Tobacco Control (WHO FCTC) lead to substantial and sustained reductions in indoor smoking while also leading to high levels of support by the public. Moreover, contrary to arguments by opponents of smoke-free laws, smoking in the home did not increase after the law was implemented and prevalence of smoke-free homes among smokers increased from 23.2% before the law to 37.2% 5 years after the law. PMID- 23805266 TI - Simultaneous Detection of Fenitrothion and Chlorpyrifos-Methyl with a Photonic Suspension Array. AB - A technique was developed for simultaneous detection of fenitrothion (FNT) and chlorpyrifos-methyl (CLT) using a photonic suspension array based on silica colloidal crystal beads (SCCBs). The SCCBs were encoded with the characteristic reflection peak originating from the stop-band of colloidal crystal. This approach avoids the bleaching, fading or potential interference seen when encoding by fluorescence. SCCBs with a nanopatterned surface had increased biomolecule binding capacity and improved stability. Under optimal conditions, the proposed suspension array allowed simultaneous detection of the selected pesticides in the ranges of 0.25 to 1024 ng/mL and 0.40 to 735.37 ng/mL, with the limits of detection (LODs) of 0.25 and 0.40 ng/mL, respectively. The suspension array was specific and had no significant cross-reactivity with other chemicals. The mean recoveries in tests in which samples were spiked with target standards were 82.35% to 109.90% with a standard deviation within 9.93% for CLT and 81.64% to 108.10% with a standard deviation within 8.82% for FNT. The proposed method shows a potentially powerful capability for fast quantitative analysis of pesticide residues. PMID- 23805267 TI - Germline Mutations in the Polyposis-Associated Genes BMPR1A, SMAD4, PTEN, MUTYH and GREM1 Are Not Common in Individuals with Serrated Polyposis Syndrome. AB - BACKGROUND: Recent reports have observed that individuals with serrated polyps, some of whom meet the clinical diagnostic criteria for Serrated Polyposis Syndrome (SPS), are among those who carry germline mutations in genes associated with polyposis syndromes including; (1) genes known to underlie hamartomatous polyposes (SMAD4, BMPR1A, and PTEN), (2) MUTYH-associated polyposis and (3) GREM1 in Hereditary Mixed Polyposis Syndrome (HMPS). The aim of this study was to characterise individuals fulfilling the current WHO criteria for SPS for germline mutations in these polyposis-associated genes. METHODS: A total of 65 individuals with SPS (fulfilling WHO criteria 1 or 3), were recruited to the Genetics of Serrated Neoplasia study between 2000 and 2012, through multiple Genetics or Family Cancer Clinics within Australia, or from the New Zealand Familial Gastrointestinal Cancer Service. Individuals with SPS were tested for coding mutations and large deletions in the PTEN, SMAD4, and BMPR1A genes, for the MUTYH variants in exons 7 (Y179C) and 13 (G396D), and for the duplication upstream of GREM1. RESULTS: We found no variants that were likely to be deleterious germline mutations in the SPS cases in the PTEN, SMAD4, and BMPR1A genes. A novel variant in intron 2 (c.164+223T>C) of PTEN was identified in one individual and was predicted by in silico analysis to have no functional consequences. One further individual with SPS was found to be mono-allelic for the MUTYH G396D mutation. No individuals carried the recently reported duplication within GREM1. CONCLUSIONS: Genes involved in the gastrointestinal hamartomatous polyposis, Hereditary Mixed Polyposis Syndrome and MUTYH-associated polyposis syndromes are not commonly altered in individuals with SPS. PMID- 23805268 TI - Calcium Antagonists Use and Its Association with Lower Urinary Tract Symptoms: A Cross-Sectional Study. AB - BACKGROUND: Lower urinary tract symptoms (LUTS) have been reported amongst the side effects of calcium antagonists (CA). CAs act on the bladder by affecting the ability of the detrusor muscle to create enough contractile force to overcome obstruction to normal voiding. We aimed to determine the relationship between CA use and LUTS in general medical inpatients. METHODS AND FINDINGS: In this cross sectional study we recruited 278 medical inpatients (including 85 CA users) aged >=40 (72.1+/-13.7) years. LUTS was assessed using the International Prostate Symptoms Score (IPSS) questionnaire. A Logistic regression model using a 'backwards-elimination' strategy was used to identify variables associated with LUTS and for calculating the adjusted odds ratios and the 95% confidence intervals (CI). After adjusting for other risk factors and drugs, patients on amlodipine/nifedipine and diltiazem/verapamil (compared to non-users) were more likely to suffer from severe LUTS [Males: 12.45(CI: 1.57-98.63) and Females: 7.75(CI: 0.94-63.94)] and moderate-to-severe LUTS [Males: 17.43(CI: 2.26-134.39) and Females: 47.8(CI: 6.22-367.37)]. Patients on felodipine/lercanidipine were less likely to suffer from either severe or moderate-to-severe LUTS. Further, 19 (22.4%) CA-users were on treatment for LUTS compared to 18 (9.3%) of the non users group, p = 0.003. Both male and female CA-users were three times more likely to be on alpha-blockers than non-users, p<0.001. CA-users were more likely to have undergone urinary tract-related surgery (Males: two times, p = 0.07 and females: nine times, p = 0.029). The study was limited by the fact that a causal relationship could not be established between CA use and LUTS. CONCLUSIONS: Our results demonstrate an association between CA use and an increasing severity of LUTS. They also demonstrate that CA-users are more likely to have medical or surgical treatment for LUTS. However, these CA's effects on LUTS vary, and the use of highly vascular selective agents does not appear to pose significant risk. PMID- 23805269 TI - Lability of the pAA Virulence Plasmid in Escherichia coli O104:H4: Implications for Virulence in Humans. AB - BACKGROUND: Escherichia coli O104:H4 that caused the large German outbreak in 2011 is a highly virulent hybrid of enterohemorrhagic (EHEC) and enteroaggregative (EAEC) E. coli. The strain displays "stacked-brick" aggregative adherence to human intestinal epithelial cells mediated by aggregative adherence fimbriae I (AAF/I) encoded on the pAA plasmid. The AAF/I-mediated augmented intestinal adherence might facilitate systemic absorption of Shiga toxin, the major virulence factor of EHEC, presumably enhancing virulence of the outbreak strain. However, the stability of pAA in the outbreak strain is unknown. We therefore tested outbreak isolates for pAA, monitored pAA loss during infection, and determined the impact of pAA loss on adherence and clinical outcome of infection. METHODOLOGY/PRINCIPAL FINDINGS: E. coli O104:H4 outbreak isolates from 170 patients (128 with hemolytic uremic syndrome [HUS] and 42 with diarrhea without HUS) were tested for pAA using polymerase chain reaction and plasmid profiling. pAA-harboring bacteria in stool samples were quantified using colony blot hybridization, and adherence to HCT-8 cells was determined. Isolates from 12 (7.1%) patients lacked pAA. Analyses of sequential stool samples demonstrated that the percentages of pAA-positive populations in the initial stools were significantly higher than those in the follow-up stools collected two to eight days later in disease (P<=0.01). This indicates a rapid loss of pAA during infections of humans. The pAA loss was associated with loss of the aggregative adherence phenotype and significantly reduced correlation with HUS (P = 0.001). CONCLUSIONS/SIGNIFICANCE: The pAA plasmid can be lost by E. coli O104:H4 outbreak strain in the human gut in the course of disease. pAA loss might attenuate virulence and diminish the ability to cause HUS. The pAA instability has clinical, diagnostic, epidemiologic, and evolutionary implications. PMID- 23805270 TI - Variability of Stepping during a Virtual Reality Paradigm in Parkinson's Disease Patients with and without Freezing of Gait. AB - BACKGROUND: Freezing of gait is a common and debilitating symptom affecting many patients with advanced Parkinson's disease. Although the pathophysiology of freezing of gait is not fully understood, a number of observations regarding the pattern of gait in patients with this symptom have been made. Increased 'Stride Time Variability' has been one of the most robust of these features. In this study we sought to identify whether patients with freezing of gait demonstrated similar fluctuations in their stepping rhythm whilst performing a seated virtual reality gait task that has recently been used to demonstrate the neural correlate of the freezing phenomenon. METHODS: Seventeen patients with freezing and eleven non-freezers performed the virtual reality task twice, once whilst 'On' their regular Parkinsonian medication and once in their practically defined 'Off' state. RESULTS: All patients displayed greater step time variability during their 'Off' state assessment compared to when medicated. Additionally, in the 'Off' state, patients with freezing of gait had greater step time variability compared to non-freezers. The five steps leading up to a freezing episode in the virtual reality environment showed a significant increase in step time variability although the final three steps preceding the freeze were not characterized by a progressive shortening of latency. CONCLUSIONS: The results of this study suggest that characteristic features of gait disturbance observed in patients with freezing of gait can also be demonstrated with a virtual reality paradigm. These findings suggest that virtual reality may offer the potential to further explore the freezing phenomenon in Parkinson's disease. PMID- 23805271 TI - Compensatory Role of Inositol 5-Phosphatase INPP5B to OCRL in Primary Cilia Formation in Oculocerebrorenal Syndrome of Lowe. AB - Inositol phosphatases are important regulators of cell signaling, polarity, and vesicular trafficking. Mutations in OCRL, an inositol polyphosphate 5 phosphatase, result in Oculocerebrorenal syndrome of Lowe, an X-linked recessive disorder that presents with congenital cataracts, glaucoma, renal dysfunction and mental retardation. INPP5B is a paralog of OCRL and shares similar structural domains. The roles of OCRL and INPP5B in the development of cataracts and glaucoma are not understood. Using ocular tissues, this study finds low levels of INPP5B present in human trabecular meshwork but high levels in murine trabecular meshwork. In contrast, OCRL is localized in the trabecular meshwork and Schlemm's canal endothelial cells in both human and murine eyes. In cultured human retinal pigmented epithelial cells, INPP5B was observed in the primary cilia. A functional role for INPP5B is revealed by defects in cilia formation in cells with silenced expression of INPP5B. This is further supported by the defective cilia formation in zebrafish Kupffer's vesicles and in cilia-dependent melanosome transport assays in inpp5b morphants. Taken together, this study indicates that OCRL and INPP5B are differentially expressed in the human and murine eyes, and play compensatory roles in cilia development. PMID- 23805272 TI - Comparison of Genomic and Epigenomic Expression in Monozygotic Twins Discordant for Rett Syndrome. AB - Monozygotic (identical) twins have been widely used in genetic studies to determine the relative contributions of heredity and the environment in human diseases. Discordance in disease manifestation between affected monozygotic twins has been attributed to either environmental factors or different patterns of X chromosome inactivation (XCI). However, recent studies have identified genetic and epigenetic differences between monozygotic twins, thereby challenging the accepted experimental model for distinguishing the effects of nature and nurture. Here, we report the genomic and epigenomic sequences in skin fibroblasts of a discordant monozygotic twin pair with Rett syndrome, an X-linked neurodevelopmental disorder characterized by autistic features, epileptic seizures, gait ataxia and stereotypical hand movements. The twins shared the same de novo mutation in exon 4 of the MECP2 gene (G269AfsX288), which was paternal in origin and occurred during spermatogenesis. The XCI patterns in the twins did not differ in lymphocytes, skin fibroblasts, and hair cells (which originate from ectoderm as does neuronal tissue). No reproducible differences were detected between the twins in single nucleotide polymorphisms (SNPs), insertion-deletion polymorphisms (indels), or copy number variations. Differences in DNA methylation between the twins were detected in fibroblasts in the upstream regions of genes involved in brain function and skeletal tissues such as Mohawk Homeobox (MKX), Brain-type Creatine Kinase (CKB), and FYN Tyrosine Kinase Protooncogene (FYN). The level of methylation in these upstream regions was inversely correlated with the level of gene expression. Thus, differences in DNA methylation patterns likely underlie the discordance in Rett phenotypes between the twins. PMID- 23805273 TI - Gene Deficiency in Activating Fcgamma Receptors Influences the Macrophage Phenotypic Balance and Reduces Atherosclerosis in Mice. AB - Immunity contributes to arterial inflammation during atherosclerosis. Oxidized low-density lipoproteins induce an autoimmune response characterized by specific antibodies and immune complexes in atherosclerotic patients. We hypothesize that specific Fcgamma receptors for IgG constant region participate in atherogenesis by regulating the inflammatory state of lesional macrophages. In vivo we examined the role of activating Fcgamma receptors in atherosclerosis progression using bone marrow transplantation from mice deficient in gamma-chain (the common signaling subunit of activating Fcgamma receptors) to hyperlipidemic mice. Hematopoietic deficiency of Fcgamma receptors significantly reduced atherosclerotic lesion size, which was associated with decreased number of macrophages and T lymphocytes, and increased T regulatory cell function. Lesions of Fcgamma receptor deficient mice exhibited increased plaque stability, as evidenced by higher collagen and smooth muscle cell content and decreased apoptosis. These effects were independent of changes in serum lipids and antibody response to oxidized low-density lipoproteins. Activating Fcgamma receptor deficiency reduced pro-inflammatory gene expression, nuclear factor-kappaB activity, and M1 macrophages at the lesion site, while increasing anti inflammatory genes and M2 macrophages. The decreased inflammation in the lesions was mirrored by a reduced number of classical inflammatory monocytes in blood. In vitro, lack of activating Fcgamma receptors attenuated foam cell formation, oxidative stress and pro-inflammatory gene expression, and increased M2 associated genes in murine macrophages. Our study demonstrates that activating Fcgamma receptors influence the macrophage phenotypic balance in the artery wall of atherosclerotic mice and suggests that modulation of Fcgamma receptor-mediated inflammatory responses could effectively suppress atherosclerosis. PMID- 23805274 TI - CD8(+) T Cells Are Required For Glatiramer Acetate Therapy in Autoimmune Demyelinating Disease. AB - The exact mechanism of glatiramer acetate (GA, Copaxone(r)), an FDA-approved immunomodulatory therapy for multiple sclerosis (MS), remains unclear after decades of research. Previously, we have shown that GA therapy of MS induces CD8(+) T cell responses that can potentially suppress pathogenic CD4(+) T cell responses. Using a murine model of MS, experimental autoimmune encephalomyelitis (EAE), we now demonstrate that CD8(+) T cells are necessary in mediating the therapeutic effects of GA. Further, adoptive transfer of GA-induced CD8(+) T cells resulted in amelioration of EAE, establishing a role as a viable immunotherapy in demyelinating disease. Generation of these cells required indoleamine-2,3-dioxygenase (IDO), while suppressive function depended on non classical MHC class I, IFN-gamma, and perforin expression. GA-induced regulatory myeloid cells, previously shown to activate CD4(+) regulatory T cells in an antigen-independent manner, required CD8(+) T cells for disease suppression in vivo. These studies demonstrate an essential role for CD8(+) T cells in GA therapy and identify their potential as an adoptive immunotherapeutic agent. PMID- 23805275 TI - On the Temperature Behavior of Pulse Propagation and Relaxation in Worms, Nerves and Gels. AB - The effect of temperature on pulse propagation in biological systems has been an important field of research. Environmental temperature not only affects a host of physiological processes e.g. in poikilotherms but also provides an experimental means to investigate the thermodynamic phenomenology of nerves and muscle. In the present work, the temperature dependence of blood vessel pulsation velocity and frequency was studied in the annelid Lumbriculus variegatus. The pulse velocity was found to vary linearily between 0 degrees C and 30 degrees C. In contrast, the pulse frequency increased non-linearly in the same temperature range. A heat block ultimately resulted in complete cessation of vessel pulsations at 37.2+/ 2.7 degrees C (lowest: 33 degrees C, highest: 43 degrees C). However, quick cooling of the animal led to restoration of regularly propagating pulses. This experimentally observed phenomenology of pulse propagation and frequency is interpreted without any assumptions about molecules in the excitable membrane (e.g. ion channels) or their temperature-dependent behaviour. By following Einstein's approach to thermodynamics and diffusion, a relation between relaxation time tau and compressibility kappa of the excitable medium is derived that can be tested experimentally (for kappaT ~ kappaS). Without fitting parameters this theory predicts the temperature dependence of the limiting (i.e. highest) pulse frequency in good agreement with experimental data. The thermodynamic approach presented herein is neither limited to temperature nor to worms nor to living systems. It describes the coupling between pulse propagation and relaxation equally well in nerves and gels. The inherent consistency and universality of the concept underline its potential to explain the dependence of pulse propagation and relaxation on any thermodynamic observable. PMID- 23805276 TI - Asthma Heredity, Cord Blood IgE and Asthma-Related Symptoms and Medication in Adulthood: A Long-Term Follow-Up in a Swedish Birth Cohort. AB - Cord blood IgE has previously been studied as a possible predictor of asthma and allergic diseases. Results from different studies have been contradictory, and most have focused on high-risk infants and early infancy. Few studies have followed their study population into adulthood. This study assessed whether cord blood IgE levels and a family history of asthma were associated with, and could predict, asthma medication and allergy-related respiratory symptoms in adults. A follow-up was carried out in a Swedish birth cohort comprising 1,701 consecutively born children. In all, 1,661 individuals could be linked to the Swedish Prescribed Drug Register and the Medical Birth Register, and 1,227 responded to a postal questionnaire. Cord blood IgE and family history of asthma were correlated with reported respiratory symptoms and dispensed asthma medication at 32-34 years. Elevated cord blood IgE was associated with a two- to threefold increased risk of pollen-induced respiratory symptoms and dispensed anti-inflammatory asthma medication. Similarly, a family history of asthma was associated with an increased risk of pollen-induced respiratory symptoms and anti inflammatory medication. However, only 8% of the individuals with elevated cord blood IgE or a family history of asthma in infancy could be linked to current dispensation of anti-inflammatory asthma medication at follow-up. In all, 49 out of 60 individuals with dispensed anti-inflammatory asthma medication at 32-34 years of age had not been reported having asthma at previous check-ups of the cohort during childhood. Among those, only 5% with elevated cord blood IgE and 6% with a family history of asthma in infancy could be linked to current dispensation of anti-inflammatory asthma medication as adults. Elevated cord blood IgE and a positive family history of asthma were associated with reported respiratory symptoms and dispensed asthma medication in adulthood, but their predictive power was poor in this long-time follow-up. PMID- 23805277 TI - The Impact of Full-Length, Trimeric and Globular Adiponectin on Lipolysis in Subcutaneous and Visceral Adipocytes of Obese and Non-Obese Women. AB - Contribution of individual adiponectin isoforms to lipolysis regulation remains unknown. We investigated the impact of full-length, trimeric and globular adiponectin isoforms on spontaneous lipolysis in subcutaneous abdominal (SCAAT) and visceral adipose tissues (VAT) of obese and non-obese subjects. Furthermore, we explored the role of AMPK (5'-AMP-activated protein kinase) in adiponectin dependent lipolysis regulation and expression of adiponectin receptors type 1 and 2 (AdipoR1 and AdipoR2) in SCAAT and VAT. Primary adipocytes isolated from SCAAT and VAT of obese and non-obese women were incubated with 20 ug/ml of: A) full length adiponectin (physiological mixture of all adiponectin isoforms), B) trimeric adiponectin isoform or C) globular adiponectin isoform. Glycerol released into media was used as a marker of lipolysis. While full-length adiponectin inhibited lipolysis by 22% in non-obese SCAAT, globular isoform inhibited lipolysis by 27% in obese SCAAT. No effect of either isoform was detected in non-obese VAT, however trimeric isoform inhibited lipolysis by 21% in obese VAT (all p<0.05). Trimeric isoform induced Thr172 p-AMPK in differentiated preadipocytes from a non-obese donor, while globular isoform induced Ser79 p-ACC by 32% (p<0.05) and Ser565 p-HSL by 52% (p = 0.08) in differentiated preadipocytes from an obese donor. AdipoR2 expression was 17% and 37% higher than AdipoR1 in SCAAT of obese and non-obese groups and by 23% higher in VAT of obese subjects (all p<0.05). In conclusion, the anti-lipolytic effect of adiponectin isoforms is modified with obesity: while full-length adiponectin exerts anti lipolytic action in non-obese SCAAT, globular and trimeric isoforms show anti lipolytic activity in obese SCAAT and VAT, respectively. PMID- 23805278 TI - Rapid, Facile Detection of Heterodimer Partners for Target Human G-Protein Coupled Receptors Using a Modified Split-Ubiquitin Membrane Yeast Two-Hybrid System. AB - Potentially immeasurable heterodimer combinations of human G-protein-coupled receptors (GPCRs) result in a great deal of physiological diversity and provide a new opportunity for drug discovery. However, due to the existence of numerous combinations, the sets of GPCR dimers are almost entirely unknown and thus their dominant roles are still poorly understood. Thus, the identification of GPCR dimer pairs has been a major challenge. Here, we established a specialized method to screen potential heterodimer partners of human GPCRs based on the split ubiquitin membrane yeast two-hybrid system. We demonstrate that the mitogen activated protein kinase (MAPK) signal-independent method can detect ligand induced conformational changes and rapidly identify heterodimer partners for target GPCRs. Our data present the abilities to apply for the intermolecular mapping of interactions among GPCRs and to uncover potential GPCR targets for the development of new therapeutic agents. PMID- 23805280 TI - An Agent-Based Modeling Template for a Cohort of Veterans with Diabetic Retinopathy. AB - BACKGROUND: Agent-based models are valuable for examining systems where large numbers of discrete individuals interact with each other, or with some environment. Diabetic Veterans seeking eye care at a Veterans Administration hospital represent one such cohort. OBJECTIVE: The objective of this study was to develop an agent-based template to be used as a model for a patient with diabetic retinopathy (DR). This template may be replicated arbitrarily many times in order to generate a large cohort which is representative of a real-world population, upon which in-silico experimentation may be conducted. METHODS: Agent-based template development was performed in java-based computer simulation suite AnyLogic Professional 6.6. The model was informed by medical data abstracted from 535 patient records representing a retrospective cohort of current patients of the VA St. Louis Healthcare System Eye clinic. Logistic regression was performed to determine the predictors associated with advancing stages of DR. Predicted probabilities obtained from logistic regression were used to generate the stage of DR in the simulated cohort. RESULTS: The simulated cohort of DR patients exhibited no significant deviation from the test population of real-world patients in proportion of stage of DR, duration of diabetes mellitus (DM), or the other abstracted predictors. Simulated patients after 10 years were significantly more likely to exhibit proliferative DR (P<0.001). CONCLUSIONS: Agent-based modeling is an emerging platform, capable of simulating large cohorts of individuals based on manageable data abstraction efforts. The modeling method described may be useful in simulating many different conditions where course of disease is described in categorical stages. PMID- 23805279 TI - Identification of Host Kinase Genes Required for Influenza Virus Replication and the Regulatory Role of MicroRNAs. AB - Human protein kinases (HPKs) have profound effects on cellular responses. To better understand the role of HPKs and the signaling networks that influence influenza virus replication, a small interfering RNA (siRNA) screen of 720 HPKs was performed. From the screen, 17 HPKs (NPR2, MAP3K1, DYRK3, EPHA6, TPK1, PDK2, EXOSC10, NEK8, PLK4, SGK3, NEK3, PANK4, ITPKB, CDC2L5 (CDK13), CALM2, PKN3, and HK2) were validated as essential for A/WSN/33 influenza virus replication, and 6 HPKs (CDK13, HK2, NEK8, PANK4, PLK4 and SGK3) were identified as vital for both A/WSN/33 and A/New Caledonia/20/99 influenza virus replication. These HPKs were found to affect multiple host pathways and regulated by miRNAs induced during infection. Using a panel of miRNA agonists and antagonists, miR-149* was found to regulate NEK8 expression, miR-548d-3p was found to regulate MAPK1 transcript expression, and miRs -1228 and -138 to regulate CDK13 expression. Up-regulation of miR-34c induced PLK4 transcript and protein expression and enhanced influenza virus replication, while miR-34c inhibition reduced viral replication. These findings identify HPKs important for influenza viral replication and show the miRNAs that govern their expression. PMID- 23805281 TI - Optimizing Frozen Sample Preparation for Laser Microdissection: Assessment of CryoJane Tape-Transfer System(r). AB - Laser microdissection is an invaluable tool in medical research that facilitates collecting specific cell populations for molecular analysis. Diversity of research targets (e.g., cancerous and precancerous lesions in clinical and animal research, cell pellets, rodent embryos, etc.) and varied scientific objectives, however, present challenges toward establishing standard laser microdissection protocols. Sample preparation is crucial for quality RNA, DNA and protein retrieval, where it often determines the feasibility of a laser microdissection project. The majority of microdissection studies in clinical and animal model research are conducted on frozen tissues containing native nucleic acids, unmodified by fixation. However, the variable morphological quality of frozen sections from tissues containing fat, collagen or delicate cell structures can limit or prevent successful harvest of the desired cell population via laser dissection. The CryoJane Tape-Transfer System(r), a commercial device that improves cryosectioning outcomes on glass slides has been reported superior for slide preparation and isolation of high quality osteocyte RNA (frozen bone) during laser dissection. Considering the reported advantages of CryoJane for laser dissection on glass slides, we asked whether the system could also work with the plastic membrane slides used by UV laser based microdissection instruments, as these are better suited for collection of larger target areas. In an attempt to optimize laser microdissection slide preparation for tissues of different RNA stability and cryosectioning difficulty, we evaluated the CryoJane system for use with both glass (laser capture microdissection) and membrane (laser cutting microdissection) slides. We have established a sample preparation protocol for glass and membrane slides including manual coating of membrane slides with CryoJane solutions, cryosectioning, slide staining and dissection procedure, lysis and RNA extraction that facilitated efficient dissection and high quality RNA retrieval from CryoJane preparations. CryoJane technology therefore has the potential to facilitate standardization of laser microdissection slide preparation from frozen tissues. PMID- 23805282 TI - miReader: Discovering Novel miRNAs in Species without Sequenced Genome. AB - Along with computational approaches, NGS led technologies have caused a major impact upon the discoveries made in the area of miRNA biology, including novel miRNAs identification. However, to this date all microRNA discovery tools compulsorily depend upon the availability of reference or genomic sequences. Here, for the first time a novel approach, miReader, has been introduced which could discover novel miRNAs without any dependence upon genomic/reference sequences. The approach used NGS read data to build highly accurate miRNA models, molded through a Multi-boosting algorithm with Best-First Tree as its base classifier. It was comprehensively tested over large amount of experimental data from wide range of species including human, plants, nematode, zebrafish and fruit fly, performing consistently with >90% accuracy. Using the same tool over Illumina read data for Miscanthus, a plant whose genome is not sequenced; the study reported 21 novel mature miRNA duplex candidates. Considering the fact that miRNA discovery requires handling of high throughput data, the entire approach has been implemented in a standalone parallel architecture. This work is expected to cause a positive impact over the area of miRNA discovery in majority of species, where genomic sequence availability would not be a compulsion any more. PMID- 23805283 TI - Molecular Characterization of the Multiple Interactions of SpsD, a Surface Protein from Staphylococcus pseudintermedius, with Host Extracellular Matrix Proteins. AB - Staphylococcus pseudintermedius, a commensal and pathogen of dogs and occasionally of humans, expresses surface proteins potentially involved in host colonization and pathogenesis. Here, we describe the cloning and characterization of SpsD, a surface protein of S. pseudintermedius reported as interacting with extracellular matrix proteins and corneocytes. A ligand screen and Western immunoblotting revealed that the N-terminal A domain of SpsD bound fibrinogen, fibronectin, elastin and cytokeratin 10. SpsD also interfered with thrombin induced fibrinogen coagulation and blocked ADP-induced platelet aggregation. The binding site for SpsD was mapped to residues 395-411 in the fibrinogen gamma chain, while binding sites in fibronectin were localized to the N- and C-terminal regions. SpsD also bound to glycine- and serine-rich omega loops within the C terminal tail region of cytokeratin 10. Ligand binding studies using SpsD variants lacking the C-terminal segment or containing an amino-acid substitution in the putative ligand binding site provided insights into interaction mechanism of SpsD with the different ligands. Together these data demonstrate the multi ligand binding properties of SpsD and illustrate some interesting differences in the variety of ligands bound by SpsD and related proteins from S. aureus. PMID- 23805284 TI - Effect of Hypotensive Resuscitation with a Novel Combination of Fluids in a Rabbit Model of Uncontrolled Hemorrhagic Shock. AB - OBJECTIVE: The aim of this study was to compare the effects of hypotensive and normotensive resuscitation with a novel combination of fluids via lactate Ringer's solution (LRS), 6% hydroxyethyl starch 130/0.4 solution (HES), and 7.5% hypertonic saline solution (HSS) at early stage of uncontrolled hemorrhagic shock (UHS) before hemostasis. METHODS: New Zealand white rabbits (n = 32) underwent UHS by transecting the splenic parenchyma, followed by blood withdrawal via the femoral artery to target mean arterial pressure (MAP) of 40-45 mmHg. Animals were distributed randomly into 4 groups (n = 8): in group Sham, sham operation was performed; in group HS, UHS was untreated; in group HS-HR, UHS was treated by hypotensive resuscitation with HSS and LRS+HES (ratio of 2?1) to MAP of 50-55 mmHg; in group HS-NR, UHS was treated by normotensive resuscitation with HSS and LRS+HES (ratio of 2?1) to MAP of 75-80 mmHg. Outcomes of hemodynamics, inflammatory and oxidative response, and other metabolic variables were measured and the histopathological studies of heart, lung and kidney were performed at the end of resusucitation. RESULTS: Hypotensive resuscitation with the novel combination of fluids for UHS rabbits decreased blood loss, maintained better stabilization of hemodynamics, and resulted in relatively higher hematocrit and platelet count, superior outcomes of blood gas, and lower plasma lactate concentration. Besides, hypotensive resuscitation attenuated the inflammatory and oxidative response significantly in UHS rabbits. CONCLUSION: Hypotensive resuscitation with the novel combination of fluids via HSS and LRS+HES (ratio of 2?1) has an effective treatment at early stage of UHS before hemostasis. PMID- 23805285 TI - Inhibitory Effects of Salinomycin on Cell Survival, Colony Growth, Migration, and Invasion of Human Non-Small Cell Lung Cancer A549 and LNM35: Involvement of NAG 1. AB - A major challenge for oncologists and pharmacologists is to develop more potent and less toxic drugs that will decrease the tumor growth and improve the survival of lung cancer patients. Salinomycin is a polyether antibiotic used to kill gram positive bacteria including mycobacteria, protozoans such as plasmodium falciparum, and the parasites responsible for the poultry disease coccidiosis. This old agent is now a serious anti-cancer drug candidate that selectively inhibits the growth of cancer stem cells. We investigated the impact of salinomycin on survival, colony growth, migration and invasion of the differentiated human non-small cell lung cancer lines LNM35 and A549. Salinomycin caused concentration- and time-dependent reduction in viability of LNM35 and A549 cells through a caspase 3/7-associated cell death pathway. Similarly, salinomycin (2.5-5 uM for 7 days) significantly decreased the growth of LNM35 and A549 colonies in soft agar. Metastasis is the main cause of death related to lung cancer. In this context, salinomycin induced a time- and concentration-dependent inhibition of cell migration and invasion. We also demonstrated for the first time that salinomycin induced a marked increase in the expression of the pro apoptotic protein NAG-1 leading to the inhibition of lung cancer cell invasion but not cell survival. These findings identify salinomycin as a promising novel therapeutic agent for lung cancer. PMID- 23805286 TI - Substrate Channel Flexibility in Pseudomonas aeruginosa MurB Accommodates Two Distinct Substrates. AB - Biosynthesis of UDP-N-acetylmuramic acid in bacteria is a committed step towards peptidoglycan production. In an NADPH- and FAD-dependent reaction, the UDP-N acetylglucosamine-enolpyruvate reductase (MurB) reduces UDP-N-acetylglucosamine enolpyruvate to UDP-N-acetylmuramic acid. We determined the three-dimensional structures of the ternary complex of Pseudomonas aeruginosa MurB with FAD and NADP(+) in two crystal forms to resolutions of 2.2 and 2.1 A, respectively, to investigate the structural basis of the first half-reaction, hydride transfer from NADPH to FAD. The nicotinamide ring of NADP(+) stacks against the si face of the isoalloxazine ring of FAD, suggesting an unusual mode of hydride transfer to flavin. Comparison with the structure of the Escherichia coli MurB complex with UDP-N-acetylglucosamine-enolpyruvate shows that both substrates share the binding site located between two lobes of the substrate-binding domain III, consistent with a ping pong mechanism with sequential substrate binding. The nicotinamide and the enolpyruvyl moieties are strikingly well-aligned upon superimposition, both positioned for hydride transfer to and from FAD. However, flexibility of the substrate channel allows the non-reactive parts of the two substrates to bind in different conformations. A potassium ion in the active site may assist in substrate orientation and binding. These structural models should help in structure-aided drug design against MurB, which is essential for cell wall biogenesis and hence bacterial survival. PMID- 23805287 TI - The Expression of SIRT1 and DBC1 in Laryngeal and Hypopharyngeal Carcinomas. AB - RATIONALE AND OBJECTIVE: Sirtuin 1 (SIRT1) plays an important role in tumorigenesis and is increased in many human tumors. DBC1 is a negative regulator of SIRT1 via promotion of p53-mediated apoptosis. It is necessary to investigate the expression of SIRT1 and DBC1 in laryngeal and hypopharyngeal squamous cell carcinomas (LSCC and HSCC) and its correlation with available clinical parameters. METHODS: The mRNA levels of SIRT1 and DBC1 were measured in 54 paired LSCC or HSCC tumors and corresponding adjacent noncancerous mucosae using quantitative RT-PCR (qRT-PCR). The protein levels of SIRT1 and DBC1 were also evaluated in 120 cases of patients with LSCC or HSCC using immunohistochemical staining. The correlation between SIRT1 and DBC1 expression and clinical parameters was analyzed with Pearson chi-square test. RESULTS: qRT-PCR assay showed that, compared with the paired adjacent noncancerous mucosae, SIRT1 mRNA was significantly decreased in tumors. The immunohistochemical results indicated that the SIRT1 protein was also downregulated in tumors compared with noncancerous mucosae. Moreover, decreased SIRT1 was significantly correlated with the tumor clinical stage and lymph node metastasis. Additionally, DBC1 mRNA was significantly increased in tumors compared with noncancerous mucosae. The immunohistochemical results indicated that the DBC1 protein was downregulated in tumors, which is inconsistent with the results obtained by qRT-PCR. Finally, decreased DBC1 protein was significantly correlated with tumor differentiation, lymph node metastasis, and p53 expression. CONCLUSIONS: SIRT1 and DBC1 might be involved in the pathophysiology of laryngeal and hypopharyngeal squamous cell carcinomas and are associated with lymph node metastasis and p53 positive staining in LSCCs and HSCCs. PMID- 23805288 TI - ESR1 Gene Polymorphisms and Prostate Cancer Risk: A HuGE Review and Meta Analysis. AB - BACKGROUND: Many published data on the association between single nucleotide polymorphisms (SNPs) in the ESR1 gene and prostate cancer susceptibility are inconclusive. The aim of this Human Genome Epidemiology (HuGE) review and meta analysis is to derive a more precise estimation of this relationship. METHODS: A literature search of PubMed, Embase, Web of Science and Chinese Biomedical (CBM) databases was conducted from their inception through July 1st, 2012. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the strength of association. RESULTS: Twelve case-control studies were included with a total 2,165 prostate cancer cases and 3,361 healthy controls. When all the eligible studies were pooled into the meta-analysis, ESR1 PvuII (C>T) and XbaI (A>G) polymorphisms showed no association with the risk of prostate cancer. However, in the stratified analyses based on ethnicity and country, the results indicated that ESR1 PvuII (C>T) polymorphism was significantly associated with increased risk of prostate cancer among Asian populations, especially among Indian population; while ESR1 XbaI (A>G) polymorphism may significantly increase the risk of prostate cancer among American population. Furthermore, we also performed a pooled analysis for all eligible case-control studies to explore the role of codon 10 (T>C), codon 325 (C>G), codon 594 (G>A) and +261G>C polymorphisms in prostate cancer risk. Nevertheless, no significant associations between these polymorphisms and the risk of prostate cancer were observed. CONCLUSION: Results from the current meta-analysis indicate that ESR1 PvuII (C>T) polymorphism may be a risk factor for prostate cancer among Asian populations, especially among Indian population; while ESR1 XbaI (A>G) polymorphism may increase the risk of prostate cancer among American population. PMID- 23805289 TI - Human Mycobacterium tuberculosis CD8 T Cell Antigens/Epitopes Identified by a Proteomic Peptide Library. AB - Identification of CD8(+) T cell antigens/epitopes expressed by human pathogens with large genomes is especially challenging, yet necessary for vaccine development. Immunity to tuberculosis, a leading cause of mortality worldwide, requires CD8(+) T cell immunity, yet the repertoire of CD8 antigens/epitopes remains undefined. We used integrated computational and proteomic approaches to screen 10% of the Mycobacterium tuberculosis (Mtb) proteome for CD8 Mtb antigens. We designed a weighting schema based upon a Multiple Attribute Decision Making:framework to select 10% of the Mtb proteome with a high probability of containing CD8(+) T cell epitopes. We created a synthetic peptide library consisting of 15-mers overlapping by 11 aa. Using the interferon-gamma ELISPOT assay and Mtb-infected dendritic cells as antigen presenting cells, we screened Mtb-specific CD8(+) T cell clones restricted by classical MHC class I molecules (MHC class Ia molecules), that were isolated from Mtb-infected humans, against this library. Three novel CD8 antigens were unambiguously identified: the EsxJ family (Rv1038c, Rv1197, Rv3620c, Rv2347c, Rv1792), PE9 (Rv1088), and PE_PGRS42 (Rv2487c). The epitopes are B5701-restricted EsxJ24-34, B3905-restricted PE953 67, and B3514-restricted PE_PGRS4248-56, respectively. The utility of peptide libraries in identifying unknown epitopes recognized by classically restricted CD8(+) T cells was confirmed, which can be applied to other intracellular pathogens with large size genomes. In addition, we identified three novel Mtb epitopes/antigens that may be evaluated for inclusion in vaccines and/or diagnostics for tuberculosis. PMID- 23805291 TI - Non-Random Sibling Cannibalism in the Marine Gastropod Crepidula coquimbensis. AB - Sibling cannibalism is commonly observed in marine species. For instance, intrabrood cannibalism has been documented in marine gastropods with direct development, suggesting a relationship between embryo behavior and the evolution of life history strategies. However, there has been little effort to document the factors driving sibling cannibalism in marine species. The kin selection theory suggests that the level of relatedness plays an important role in cannibalism patterns. We examined Crepidula coquimbensis, a marine gastropod that broods and encloses its brooded offspring in capsules. Encapsulated embryos show sibling cannibalism and high levels of intracapsular multiple paternity. Given these features, cannibalistic behavior may be driven by kin-relatedness. To test this hypothesis, we constructed artificial aggregations of embryos to mimic three levels of relatedness: high, medium and low. For each category of aggregation, the cannibalism rate and benefits (i.e. size at hatching of surviving offspring) were estimated. In addition, at the end of embryo development, we performed parentage analyses to determine if cannibalism was associated with the relatedness between cannibal and victim embryos. Our results show that the intensity of sibling cannibalism increased in aggregations characterized by the lowest level of relatedness. There were important benefits of cannibalism in terms of hatching cannibal size. In addition, cannibalism between embryos was not random: the variation in reproductive success between males increased over the course of the experiment and the effective number of fathers decreased. Altogether, these results suggest that polyandry may play an important role in the evolution of sibling cannibalism in C. coquimbensis and that kin selection may operate during early embryonic stages in this species. PMID- 23805292 TI - Relationships between Long-Term Demography and Weather in a Sub-Arctic Population of Common Eider. AB - Effects of local weather on individuals and populations are key drivers of wildlife responses to climatic changes. However, studies often do not last long enough to identify weather conditions that influence demographic processes, or to capture rare but extreme weather events at appropriate scales. In Iceland, farmers collect nest down of wild common eider Somateria mollissima and many farmers count nests within colonies annually, which reflects annual variation in the number of breeding females. We collated these data for 17 colonies. Synchrony in breeding numbers was generally low between colonies. We evaluated 1) demographic relationships with weather in nesting colonies of common eider across Iceland during 1900-2007; and 2) impacts of episodic weather events (aberrantly cold seasons or years) on subsequent breeding numbers. Except for episodic events, breeding numbers within a colony generally had no relationship to local weather conditions in the preceding year. However, common eider are sexually mature at 2-3 years of age and we found a 3-year time lag between summer weather and breeding numbers for three colonies, indicating a positive effect of higher pressure, drier summers for one colony, and a negative effect of warmer, calmer summers for two colonies. These findings may represent weather effects on duckling production and subsequent recruitment. Weather effects were mostly limited to a few aberrant years causing reductions in breeding numbers, i.e. declines in several colonies followed severe winters (1918) and some years with high NAO (1992, 1995). In terms of life history, adult survival generally is high and stable and probably only markedly affected by inclement weather or aberrantly bad years. Conversely, breeding propensity of adults and duckling production probably do respond more to annual weather variations; i.e. unfavorable winter conditions for adults increase probability of death or skipped breeding, whereas favorable summers can promote boom years for recruitment. PMID- 23805290 TI - Differential Changes in Expression of Stress- and Metabolic-Related Neuropeptides in the Rat Hypothalamus during Morphine Dependence and Withdrawal. AB - Chronic morphine treatment and naloxone precipitated morphine withdrawal activates stress-related brain circuit and results in significant changes in food intake, body weight gain and energy metabolism. The present study aimed to reveal hypothalamic mechanisms underlying these effects. Adult male rats were made dependent on morphine by subcutaneous implantation of constant release drug pellets. Pair feeding revealed significantly smaller weight loss of morphine treated rats compared to placebo implanted animals whose food consumption was limited to that eaten by morphine implanted pairs. These results suggest reduced energy expenditure of morphine-treated animals. Chronic morphine exposure or pair feeding did not significantly affect hypothalamic expression of selected stress- and metabolic related neuropeptides - corticotropin-releasing hormone (CRH), urocortin 2 (UCN2) and proopiomelanocortin (POMC) compared to placebo implanted and pair fed animals. Naloxone precipitated morphine withdrawal resulted in a dramatic weight loss starting as early as 15-30 min after naloxone injection and increased adrenocorticotrophic hormone, prolactin and corticosterone plasma levels in morphine dependent rats. Using real-time quantitative PCR to monitor the time course of relative expression of neuropeptide mRNAs in the hypothalamus we found elevated CRH and UCN2 mRNA and dramatically reduced POMC expression. Neuropeptide Y (NPY) and arginine vasopressin (AVP) mRNA levels were transiently increased during opiate withdrawal. These data highlight that morphine withdrawal differentially affects expression of stress- and metabolic-related neuropeptides in the rat hypothalamus, while relative mRNA levels of these neuropeptides remain unchanged either in rats chronically treated with morphine or in their pair-fed controls. PMID- 23805293 TI - Toward Reproducible Computational Research: An Empirical Analysis of Data and Code Policy Adoption by Journals. AB - Journal policy on research data and code availability is an important part of the ongoing shift toward publishing reproducible computational science. This article extends the literature by studying journal data sharing policies by year (for both 2011 and 2012) for a referent set of 170 journals. We make a further contribution by evaluating code sharing policies, supplemental materials policies, and open access status for these 170 journals for each of 2011 and 2012. We build a predictive model of open data and code policy adoption as a function of impact factor and publisher and find higher impact journals more likely to have open data and code policies and scientific societies more likely to have open data and code policies than commercial publishers. We also find open data policies tend to lead open code policies, and we find no relationship between open data and code policies and either supplemental material policies or open access journal status. Of the journals in this study, 38% had a data policy, 22% had a code policy, and 66% had a supplemental materials policy as of June 2012. This reflects a striking one year increase of 16% in the number of data policies, a 30% increase in code policies, and a 7% increase in the number of supplemental materials policies. We introduce a new dataset to the community that categorizes data and code sharing, supplemental materials, and open access policies in 2011 and 2012 for these 170 journals. PMID- 23805295 TI - FoxO3a Serves as a Biomarker of Oxidative Stress in Human Lens Epithelial Cells under Conditions of Hyperglycemia. AB - BACKGROUND: Forkhead box 'O' transcription factors (FoxOs) are implicated in the pathogenesis of type2 diabetes and other metabolic diseases. Abnormal activity of FoxOs was reported in the glucose and insulin metabolism. Expression of FoxO proteins was reported in ocular tissues; however their function under hyperglycemic conditions was not examined. METHODS: Human lens epithelial cell line was used to study the function of FoxO proteins. Immunofluorescence, flow cytometry and Western blotting were employed to detect the FoxO proteins under the conditions of hyperglycemia. RESULTS: In this study we examined the role of FoxO3a in hyperglycemia-induced oxidative stress in human lens epithelial cells. FoxO3a protein expression was elevated in a dose- and time-dependent fashion after high glucose treatment. Anti-oxidant defense mechanisms of the lens epithelial cells were diminished as evidenced from loss of mitochondrial membrane integrity and lowered MnSOD after 72 h treatment with high glucose. Taken together, FoxO3a acts as a sensitive indicator of oxidative stress and cell homeostasis in human lens epithelial cells during diabetic conditions. CONCLUSION: FoxO3a is an early stress response protein to glucose toxicity in diabetic conditions. PMID- 23805294 TI - Endotoxin Exposure during Sensitization to Blomia tropicalis Allergens Shifts TH2 Immunity Towards a TH17-Mediated Airway Neutrophilic Inflammation: Role of TLR4 and TLR2. AB - Experimental evidence and epidemiological studies indicate that exposure to endotoxin lipopolysaccharide (eLPS) or other TLR agonists prevent asthma. We have previously shown in the OVA-model of asthma that eLPS administration during alum based allergen sensitization blocked the development of lung TH2 immune responses via MyD88 pathway and IL-12/IFN-gamma axis. In the present work we determined the effect of eLPS exposure during sensitization to a natural airborne allergen extract derived from the house dust mite Blomia tropicalis (Bt). Mice were subcutaneously sensitized with Bt allergens co-adsorbed onto alum with or without eLPS and challenged twice intranasally with Bt. Cellular and molecular parameters of allergic lung inflammation were evaluated 24 h after the last Bt challenge. Exposure to eLPS but not to ultrapure LPS (upLPS) preparation during sensitization to Bt allergens decreased the influx of eosinophils and increased the influx of neutrophils to the airways. Inhibition of airway eosinophilia was not observed in IFN-gammadeficient mice while airway neutrophilia was not observed in IL-17RA-deficient mice as well in mice lacking MyD88, CD14, TLR4 and, surprisingly, TLR2 molecules. Notably, exposure to a synthetic TLR2 agonist (PamCSK4) also induced airway neutrophilia that was dependent on TLR2 and TLR4 molecules. In the OVA model, exposure to eLPS or PamCSK4 suppressed OVA-induced airway inflammation. Our results suggest that B. tropicalis allergens engage TLR4 that potentiates TLR2 signaling. This dual TLR activation during sensitization results in airway neutrophilic inflammation associated with increased frequency of lung TH17 cells. Our work highlight the complex interplay between bacterial products, house dust mite allergens and TLR signaling in the induction of different phenotypes of airway inflammation. PMID- 23805297 TI - In Vivo 3D Meibography of the Human Eyelid Using Real Time Imaging Fourier-Domain OCT. AB - Recently, we reported obtaining tomograms of meibomian glands from healthy volunteers using commercial anterior segment optical coherence tomography (AS OCT), which is widely employed in clinics for examination of the anterior segment. However, we could not create 3D images of the meibomian glands, because the commercial OCT does not have a 3D reconstruction function. In this study we report the creation of 3D images of the meibomian glands by reconstructing the tomograms of these glands using high speed Fourier-Domain OCT (FD-OCT) developed in our laboratory. This research was jointly undertaken at the Department of Ophthalmology, Seoul St. Mary's Hospital (Seoul, Korea) and the Advanced Photonics Research Institute of Gwangju Institute of Science and Technology (Gwangju, Korea) with two healthy volunteers and seven patients with meibomian gland dysfunction. A real time imaging FD-OCT system based on a high-speed wavelength swept laser was developed that had a spectral bandwidth of 100 nm at the 1310 nm center wavelength. The axial resolution was 5 um and the lateral resolution was 13 um in air. Using this device, the meibomian glands of nine subjects were examined. A series of tomograms from the upper eyelid measuring 5 mm (from left to right, B-scan) * 2 mm (from upper part to lower part, C-scan) were collected. Three-D images of the meibomian glands were then reconstructed using 3D "data visualization, analysis, and modeling software". Established infrared meibography was also performed for comparison. The 3D images of healthy subjects clearly showed the meibomian glands, which looked similar to bunches of grapes. These results were consistent with previous infrared meibography results. The meibomian glands were parallel to each other, and the saccular acini were clearly visible. Here we report the successful production of 3D images of human meibomian glands by reconstructing tomograms of these glands with high speed FD OCT. PMID- 23805296 TI - Effects of Chronic D-Serine Elevation on Animal Models of Depression and Anxiety Related Behavior. AB - NMDA receptors are activated after binding of the agonist glutamate to the NR2 subunit along with a co-agonist, either L-glycine or D-serine, to the NR1 subunit. There is substantial evidence to suggest that D-serine is the most relevant co-agonist in forebrain regions and that alterations in D-serine levels contribute to psychiatric disorders. D-serine is produced through isomerization of L-serine by serine racemase (Srr), either in neurons or in astrocytes. It is released by astrocytes by an activity-dependent mechanism involving secretory vesicles. In the present study we generated transgenic mice (SrrTg) expressing serine racemase under a human GFAP promoter. These mice were biochemically and behaviorally analyzed using paradigms of anxiety, depression and cognition. Furthermore, we investigated the behavioral effects of long-term administration of D-serine added to the drinking water. Elevated brain D-serine levels in SrrTg mice resulted in specific behavioral phenotypes in the forced swim, novelty suppression of feeding and olfactory bulbectomy paradigms that are indicative of a reduced proneness towards depression-related behavior. Chronic dietary D-serine supplement mimics the depression-related behavioral phenotype observed in SrrTg mice. Our results suggest that D-serine supplementation may improve mood disorders. PMID- 23805298 TI - Comparative Network Analysis of Preterm vs. Full-Term Infant-Mother Interactions. AB - Several studies have reported that interactions of mothers with preterm infants show differential characteristics compared to that of mothers with full-term infants. Interaction of preterm dyads is often reported as less harmonious. However, observations and explanations concerning the underlying mechanisms are inconsistent. In this work 30 preterm and 42 full-term mother-infant dyads were observed at one year of age. Free play interactions were videotaped and coded using a micro-analytic coding system. The video records were coded at one second resolution and studied by a novel approach using network analysis tools. The advantage of our approach is that it reveals the patterns of behavioral transitions in the interactions. We found that the most frequent behavioral transitions are the same in the two groups. However, we have identified several high and lower frequency transitions which occur significantly more often in the preterm or full-term group. Our analysis also suggests that the variability of behavioral transitions is significantly higher in the preterm group. This higher variability is mostly resulted from the diversity of transitions involving non harmonious behaviors. We have identified a maladaptive pattern in the maternal behavior in the preterm group, involving intrusiveness and disengagement. Application of the approach reported in this paper to longitudinal data could elucidate whether these maladaptive maternal behavioral changes place the infant at risk for later emotional, cognitive and behavioral disturbance. PMID- 23805299 TI - To Dash or to Dawdle: Verb-Associated Speed of Motion Influences Eye Movements during Spoken Sentence Comprehension. AB - In describing motion events verbs of manner provide information about the speed of agents or objects in those events. We used eye tracking to investigate how inferences about this verb-associated speed of motion would influence the time course of attention to a visual scene that matched an event described in language. Eye movements were recorded as participants heard spoken sentences with verbs that implied a fast ("dash") or slow ("dawdle") movement of an agent towards a goal. These sentences were heard whilst participants concurrently looked at scenes depicting the agent and a path which led to the goal object. Our results indicate a mapping of events onto the visual scene consistent with participants mentally simulating the movement of the agent along the path towards the goal: when the verb implies a slow manner of motion, participants look more often and longer along the path to the goal; when the verb implies a fast manner of motion, participants tend to look earlier at the goal and less on the path. These results reveal that event comprehension in the presence of a visual world involves establishing and dynamically updating the locations of entities in response to linguistic descriptions of events. PMID- 23805300 TI - Identification and Validation of a Putative Polycomb Responsive Element in the Human Genome. AB - Epigenetic cellular memory mechanisms that involve polycomb and trithorax group of proteins are well conserved across metazoans. The cis-acting elements interacting with these proteins, however, are poorly understood in mammals. In a directed search we identified a potential polycomb responsive element with 25 repeats of YY1 binding motifthatwe designate PRE-PIK3C2B as it occurs in the first intron of human PIK3C2B gene. It down regulates reporter gene expression in HEK cells and the repression is dependent on polycomb group of proteins (PcG). We demonstrate that PRE-PIK3C2B interacts directly with YY1 in vitro and recruits PRC2 complex in vivo. The localization of PcG proteins including YY1 to PRE PIK3C2B in HEK cells is decreased on knock-down of either YY1 or SUZ12. Endogenous PRE-PIK3C2B shows bivalent marking having H3K27me3 and H3K4me3 for repressed and active state respectively. In transgenic Drosophila, PRE-PIK3C2B down regulates mini-white expression, exhibits variegation and pairing sensitive silencing (PSS), which has not been previously demonstrated for mammalian PRE. Taken together, our results strongly suggest that PRE-PIK3C2B functions as a site of interaction for polycomb proteins. PMID- 23805301 TI - What the Inbred Scandinavian Wolf Population Tells Us about the Nature of Conservation. AB - The genetic aspects of population health are critical, but frequently difficult to assess. Of concern has been the genetic constitution of Scandinavian wolves (Canis lupus), which represent an important case in conservation. We examined the incidence of different congenital anomalies for 171 Scandinavian wolves, including the immigrant founder female, born during a 32-year period between 1978 and 2010. The incidence of anomalies rose from 13% to 40% throughout the 32-year study period. Our ability to detect this increase was likely facilitated by having considered multiple kinds of anomaly. Many of the found anomalies are likely associated with inbreeding or some form of genetic deterioration. These observations have implications for understanding the conservation needs of Scandinavian wolves. Moreover, these observations and the history of managing Scandinavian wolves focus attention on a broader question, whether conservation is merely about avoiding extinction of remnant populations, or whether conservation also entails maintaining genetic aspects of population health. PMID- 23805302 TI - Exposure of Bifidobacterium longum subsp. infantis to Milk Oligosaccharides Increases Adhesion to Epithelial Cells and Induces a Substantial Transcriptional Response. AB - In this study, we tested the hypothesis that milk oligosaccharides may contribute not only to selective growth of bifidobacteria, but also to their specific adhesive ability. Human milk oligosaccharides (3'sialyllactose and 6'sialyllactose) and a commercial prebiotic (Beneo Orafti P95; oligofructose) were assayed for their ability to promote adhesion of Bifidobacterium longum subsp. infantis ATCC 15697 to HT-29 and Caco-2 human intestinal cells. Treatment with the commercial prebiotic or 3'sialyllactose did not enhance adhesion. However, treatment with 6'sialyllactose resulted in increased adhesion (4.7 fold), while treatment with a mixture of 3'- and 6'-sialyllactose substantially increased adhesion (9.8 fold) to HT-29 intestinal cells. Microarray analyses were subsequently employed to investigate the transcriptional response of B. longum subsp. infantis to the different oligosaccharide treatments. This data correlated strongly with the observed changes in adhesion to HT-29 cells. The combination of 3'- and 6'-sialyllactose resulted in the greatest response at the genetic level (both in diversity and magnitude) followed by 6'sialyllactose, and 3'sialyllactose alone. The microarray data was further validated by means of real time PCR. The current findings suggest that the increased adherence phenotype of Bifidobacterium longum subsp. infantis resulting from exposure to milk oligosaccharides is multi-faceted, involving transcription factors, chaperone proteins, adhesion-related proteins, and a glycoside hydrolase. This study gives additional insight into the role of milk oligosaccharides within the human intestine and the molecular mechanisms underpinning host-microbe interactions. PMID- 23805303 TI - Using a Dynamic Model to Consider Optimal Antiviral Stockpile Size in the Face of Pandemic Influenza Uncertainty. AB - BACKGROUND: The Canadian National Antiviral Stockpile (NAS) contains treatment for 17.5% of Canadians. This assumes no concurrent intervention strategies and no wastage due to non-influenza respiratory infections. A dynamic model can provide a mechanism to consider complex scenarios to support decisions regarding the optimal NAS size under uncertainty. METHODS: We developed a dynamic model for pandemic influenza in Canada that is structured by age and risk to calculate the demand for antivirals to treat persons with pandemic influenza under a wide-range of scenarios that incorporated transmission dynamics, disease severity, and intervention strategies. The anticipated per capita number of acute respiratory infections due to viruses other than influenza was estimated for the full pandemic period from surveys based on criteria to identify potential respiratory infections. RESULTS: Our results demonstrate that up to two thirds of the population could develop respiratory symptoms as a result of infection with a pandemic strain. In the case of perfect antiviral allocation, up to 39.8% of the population could request antiviral treatment. As transmission dynamics, severity and timing of the emergence of a novel influenza strain are unknown, the sensitivity analysis produced considerable variation in potential demand (median: 11%, IQR: 2-21%). If the next pandemic strain emerges in late spring or summer and a vaccine is available before the anticipated fall wave, the median prediction was reduced to 6% and IQR to 0.7-14%. Under the strategy of offering empirical treatment to all patients with influenza like symptoms who present for care, demand could increase to between 65 and 144%. CONCLUSIONS: The demand for antivirals during a pandemic is uncertain. Unless an accurate, timely and cost effective test is available to identify influenza cases, demand for antivirals from persons infected with other respiratory viruses will be substantial and have a significant impact on the NAS. PMID- 23805304 TI - Experimental Genetics of Plasmodium berghei NFU in the Apicoplast Iron-Sulfur Cluster Biogenesis Pathway. AB - Eukaryotic pathogens of the phylum Apicomplexa contain a non-photosynthetic plastid, termed apicoplast. Within this organelle distinct iron-sulfur [Fe-S] cluster proteins are likely central to biosynthesis pathways, including generation of isoprenoids and lipoic acid. Here, we targeted a nuclear-encoded component of the apicoplast [Fe-S] cluster biosynthesis pathway by experimental genetics in the murine malaria parasite Plasmodium berghei. We show that ablation of the gene encoding a nitrogen fixation factor U (NifU)-like domain containing protein (NFUapi) resulted in parasites that were able to complete the entire life cycle indicating redundant or non-essential functions. nfu (-) parasites displayed reduced merosome formation in vitro, suggesting that apicoplast NFUapi plays an auxiliary role in establishing a blood stage infection. NFUapi fused to a combined fluorescent protein-epitope tag delineates the Plasmodium apicoplast and was tested to revisit inhibition of liver stage development by azithromycin and fosmidomycin. We show that the branched apicoplast signal is entirely abolished by azithromycin treatment, while fosmidomycin had no effect on apicoplast morphology. In conclusion, our experimental genetics analysis supports specialized and/or redundant role(s) for NFUapi in the [Fe-S] cluster biosynthesis pathway in the apicoplast of a malarial parasite. PMID- 23805305 TI - The Organization of Collective Group Movements in Wild Barbary Macaques (Macaca sylvanus): Social Structure Drives Processes of Group Coordination in Macaques. AB - Social animals have to coordinate activities and collective movements to benefit from the advantages of group living. Animals in large groups maintain cohesion by self-organization processes whereas in smaller groups consensus decisions can be reached. Where consensus decisions are relevant leadership may emerge. Variation in the organization of collective movements has been linked to variation in female social tolerance among macaque species ranging from despotic to egalitarian. Here we investigated the processes underlying group movements in a wild macaque species characterized by a degree of social tolerance intermediate to previously studied congeneric species. We focused on processes before, during and after the departure of the first individual. To this end, we observed one group of wild Barbary macaques (Macaca sylvanus) in the Middle Atlas, Morocco using all-occurrence behaviour sampling of 199 collective movements. We found that initiators of a collective movement usually chose the direction in which more individuals displayed pre-departure behavior. Dominant individuals contributed to group movements more than subordinates, especially juveniles, measured as frequencies of successful initiations and pre-departure behaviour. Joining was determined by affiliative relationships and the number of individuals that already joined the movement (mimetism). Thus, in our study group partially shared consensus decisions mediated by selective mimetism seemed to be prevalent, overall supporting the suggestion that a species' social style affects the organization of group movements. As only the most tolerant species show equally shared consensus decisions whereas in others the decision is partially shared with a bias to dominant individuals the type of consensus decisions seems to follow a stepwise relation. Joining order may also follow a stepwise, however opposite, relationship, because dominance only determined joining in highly despotic, but not in intermediate and tolerant species. PMID- 23805306 TI - Indirect Transmission of Influenza A Virus between Pig Populations under Two Different Biosecurity Settings. AB - Respiratory disease due to influenza virus is common in both human and swine populations around the world with multiple transmission routes capable of transmitting influenza virus, including indirect routes. The objective of this study was to evaluate the role of fomites in influenza A virus (IAV) transmission between pig populations separated by two different biosecurity settings. Thirty five pigs were divided into four experimental groups: 10 pigs (1 replicate) were assigned to the infected group (I), 10 pigs (2 replicates of 5 pigs) were assigned to the low biosecurity sentinel group (LB), 10 pigs (2 replicates of 5 pigs) were assigned to the medium biosecurity sentinel group (MB), and 5 pigs (1 replicate) were assigned to the negative control group (NC). Eight of 10 pigs in the infected group were inoculated with IAV and 36 hours following inoculation, personnel movement events took place in order to move potentially infectious clothing and personal protective equipment (PPE) to sentinel pig rooms. Following contact with the infected group, personnel moved to the MB group after designated hygiene measures while personnel moved directly to the LB group. Nasal swabs and blood samples were collected from pigs to assess IAV infection status and fomites were sampled and tested via RRT-PCR. All experimentally inoculated pigs were infected with IAV and 11 of the 144 fomite samples collected following contact with infected pigs were low level positive for IAV genome. One replicate of each sentinel groups LB and MB became infected with IAV and all five pigs were infected over time. This study provides evidence that fomites can serve as an IAV transmission route from infected to sentinel pigs and highlights the need to focus on indirect routes as well as direct routes of transmission for IAV. PMID- 23805307 TI - BRCA1-Dependent Translational Regulation in Breast Cancer Cells. AB - BRCA1 (Breast Cancer 1) has been implicated in a number of cellular processes, including transcription regulation, DNA damage repair and protein ubiquitination. We previously demonstrated that BRCA1 interacts with PABP1 (Poly(A)-Binding Protein 1) and that BRCA1 modulates protein synthesis through this interaction. To identify the mRNAs that are translationally regulated by BRCA1, we used a microarray analysis of polysome-bound mRNAs in BRCA1-depleted and non-depleted MCF7 cells. Our findings show that BRCA1 modifies the translational efficiency of approximately 7% of the mRNAs expressed in these cells. Further analysis revealed that several processes contributing to cell surveillance such as cell cycle arrest, cell death, cellular growth and proliferation, DNA repair and gene expression, are largely enriched for the mRNAs whose translation is impacted by BRCA1. The BRCA1-dependent translation of these species of mRNAs therefore uncovers a novel mechanism through which BRCA1 exerts its onco-suppressive role. In addition, the BRCA1-dependent translation of mRNAs participating in unexpected functions such as cellular movement, nucleic acid metabolism or protein trafficking is indicative of novel functions for BRCA1. Finally, this study contributes to the identification of several markers associated with BRCA1 deficiency and to the discovery of new potential anti-neoplastic therapeutic targets. PMID- 23805308 TI - Brain 3-Mercaptopyruvate Sulfurtransferase (3MST): Cellular Localization and Downregulation after Acute Stroke. AB - 3-Mercaptopyruvate sulfurtransferase (3MST) is an important enzyme for the synthesis of hydrogen sulfide (H2S) in the brain. We present here data that indicate an exclusively localization of 3MST in astrocytes. Regional distribution of 3MST activities is even and unremarkable. Following permanent middle cerebral artery occlusion (pMCAO), 3MST was down-regulated in both the cortex and striatum, but not in the corpus collosum. It appears that the down-regulation of astrocytic 3MST persisted in the presence of astrocytic proliferation due to gliosis. Our observations indicate that 3MST is probably not responsible for the increased production of H2S following pMCAO. Therefore, cystathionine beta synthase (CBS), the alternative H2S producing enzyme in the CNS, remains as a more likely potential therapeutic target than 3MST in the treatment of acute stroke through inhibition of H2S production. PMID- 23805309 TI - Identification and Functional Characterisation of CRK12:CYC9, a Novel Cyclin Dependent Kinase (CDK)-Cyclin Complex in Trypanosoma brucei. AB - The protozoan parasite, Trypanosoma brucei, is spread by the tsetse fly and causes trypanosomiasis in humans and animals. Both the life cycle and cell cycle of the parasite are complex. Trypanosomes have eleven cdc2-related kinases (CRKs) and ten cyclins, an unusually large number for a single celled organism. To date, relatively little is known about the function of many of the CRKs and cyclins, and only CRK3 has previously been shown to be cyclin-dependent in vivo. Here we report the identification of a previously uncharacterised CRK:cyclin complex between CRK12 and the putative transcriptional cyclin, CYC9. CRK12:CYC9 interact to form an active protein kinase complex in procyclic and bloodstream T. brucei. Both CRK12 and CYC9 are essential for the proliferation of bloodstream trypanosomes in vitro, and we show that CRK12 is also essential for survival of T. brucei in a mouse model, providing genetic validation of CRK12:CYC9 as a novel drug target for trypanosomiasis. Further, functional characterisation of CRK12 and CYC9 using RNA interference reveals roles for these proteins in endocytosis and cytokinesis, respectively. PMID- 23805310 TI - Secretome Analysis of the Pine Wood Nematode Bursaphelenchus xylophilus Reveals the Tangled Roots of Parasitism and Its Potential for Molecular Mimicry. AB - Since it was first introduced into Asia from North America in the early 20(th) century, the pine wood nematode Bursaphelenchus xylophilus has caused the devastating forest disease called pine wilt. The emerging pathogen spread to parts of Europe and has since been found as the causal agent of pine wilt disease in Portugal and Spain. In 2011, the entire genome sequence of B. xylophilus was determined, and it allowed us to perform a more detailed analysis of B. xylophilus parasitism. Here, we identified 1,515 proteins secreted by B. xylophilus using a highly sensitive proteomics method combined with the available genomic sequence. The catalogue of secreted proteins contained proteins involved in nutrient uptake, migration, and evasion from host defenses. A comparative functional analysis of the secretome profiles among parasitic nematodes revealed a marked expansion of secreted peptidases and peptidase inhibitors in B. xylophilus via gene duplication and horizontal gene transfer from fungi and bacteria. Furthermore, we showed that B. xylophilus secreted the potential host mimicry proteins that closely resemble the host pine's proteins. These proteins could have been acquired by host-parasite co-evolution and might mimic the host defense systems in susceptible pine trees during infection. This study contributes to an understanding of their unique parasitism and its tangled roots, and provides new perspectives on the evolution of plant parasitism among nematodes. PMID- 23805311 TI - Metschnikowia Species Share a Pool of Diverse rRNA Genes Differing in Regions That Determine Hairpin-Loop Structures and Evolve by Reticulation. AB - Modern taxonomy of yeasts is mainly based on phylogenetic analysis of conserved DNA and protein sequences. By far the most frequently used sequences are those of the repeats of the chromosomal rDNA array. It is generally accepted that the rDNA repeats of a genome have identical sequences due to the phenomenon of sequence homogenisation and can thus be used for identification and barcoding of species. Here we show that the rDNA arrays of the type strains of Metschnikowia andauensis and M. fructicola are not homogenised. Both have arrays consisting of diverse repeats that differ from each other in the D1/D2 domains by up to 18 and 25 substitutions. The variable sites are concentrated in two regions that correspond to back-folding stretches of hairpin loops in the predicted secondary structure of the RNA molecules. The substitutions do not alter significantly the overall hairpin-loop structure due to wobble base pairing at sites of C-T transitions and compensatory mutations in the complementary strand of the hairpin stem. The phylogenetic and network analyses of the cloned sequences revealed that the repeats had not evolved in a vertical tree-like way but reticulation might have shaped the rDNA arrays of both strains. The neighbour-net analysis of all cloned sequences of the type strains and the database sequences of different strains further showed that these species share a continuous pool of diverse repeats that appear to evolve by reticulate evolution. PMID- 23805312 TI - Computational Model of Gab1/2-Dependent VEGFR2 Pathway to Akt Activation. AB - Vascular endothelial growth factor (VEGF) signal transduction is central to angiogenesis in development and in pathological conditions such as cancer, retinopathy and ischemic diseases. However, no detailed mass-action models of VEGF receptor signaling have been developed. We constructed and validated the first computational model of VEGFR2 trafficking and signaling, to study the opposing roles of Gab1 and Gab2 in regulation of Akt phosphorylation in VEGF stimulated endothelial cells. Trafficking parameters were optimized against 5 previously published in vitro experiments, and the model was validated against six independent published datasets. The model showed agreement at several key nodes, involving scaffolding proteins Gab1, Gab2 and their complexes with Shp2. VEGFR2 recruitment of Gab1 is greater in magnitude, slower, and more sustained than that of Gab2. As Gab2 binds VEGFR2 complexes more transiently than Gab1, VEGFR2 complexes can recycle and continue to participate in other signaling pathways. Correspondingly, the simulation results show a log-linear relationship between a decrease in Akt phosphorylation and Gab1 knockdown while a linear relationship was observed between an increase in Akt phosphorylation and Gab2 knockdown. Global sensitivity analysis demonstrated the importance of initial concentration ratios of antagonistic molecular species (Gab1/Gab2 and PI3K/Shp2) in determining Akt phosphorylation profiles. It also showed that kinetic parameters responsible for transient Gab2 binding affect the system at specific nodes. This model can be expanded to study multiple signaling contexts and receptor crosstalk and can form a basis for investigation of therapeutic approaches, such as tyrosine kinase inhibitors (TKIs), overexpression of key signaling proteins or knockdown experiments. PMID- 23805313 TI - Discrete Neural Correlates for the Recognition of Negative Emotions: Insights from Frontotemporal Dementia. AB - Patients with frontotemporal dementia have pervasive changes in emotion recognition and social cognition, yet the neural changes underlying these emotion processing deficits remain unclear. The multimodal system model of emotion proposes that basic emotions are dependent on distinct brain regions, which undergo significant pathological changes in frontotemporal dementia. As such, this syndrome may provide important insight into the impact of neural network degeneration upon the innate ability to recognise emotions. This study used voxel based morphometry to identify discrete neural correlates involved in the recognition of basic emotions (anger, disgust, fear, sadness, surprise and happiness) in frontotemporal dementia. Forty frontotemporal dementia patients (18 behavioural-variant, 11 semantic dementia, 11 progressive nonfluent aphasia) and 27 healthy controls were tested on two facial emotion recognition tasks: The Ekman 60 and Ekman Caricatures. Although each frontotemporal dementia group showed impaired recognition of negative emotions, distinct associations between emotion-specific task performance and changes in grey matter intensity emerged. Fear recognition was associated with the right amygdala; disgust recognition with the left insula; anger recognition with the left middle and superior temporal gyrus; and sadness recognition with the left subcallosal cingulate, indicating that discrete neural substrates are necessary for emotion recognition in frontotemporal dementia. The erosion of emotion-specific neural networks in neurodegenerative disorders may produce distinct profiles of performance that are relevant to understanding the neurobiological basis of emotion processing. PMID- 23805314 TI - Regulation of the Epithelial-Mesenchymal Transition by Claudin-3 and Claudin-4. AB - The mechanisms that control intracellular adhesion are central to the process of invasion and metastasis. Claudin-3 (CLDN3) and claudin-4 (CLDN4) are major structural molecules of the tight junctions that link epithelial cells. Our prior work has demonstrated that knockdown of the expression of either CLDN3 or CLDN4 produces marked changes in the phenotype of ovarian carcinoma cells including increases in growth rate in vivo, migration, invasion, metastasis, and drug resistance, similar to those produced by the epithelial-to-mesenchymal transition (EMT). We postulated that these changes may result from the ability of CLDN3 or CLDN4 to suppress EMT. In this study we found that knockdown of either CLDN3 or CLDN4 increased cell size and resulted in flattened morphology. While knockdown of CLDN3 or CLDN4 did not alter the expression of vimentin, it significantly down regulated the level of E-cadherin and up-regulated N-cadherin expression. Conversely, over-expression of CLDN3 or CLDN4 in a cell line that does not express endogenous CLDN3 or CLDN4 decreased N-cadherin expression. Re-expression of E-cadherin in the CLDN3 or CLDN4 knockdown cells reduced migration, invasion and tumor growth in vivo. Loss of either CLDN3 or CLDN4 resulted in activation of the PI3K pathway as evidenced by increased Akt phosphorylation, elevated cellular PIP3 content and PI3K activity as well as up-regulation of the mRNA and protein levels of the transcription factor Twist. Taken together, these findings suggest that CLDN3 and CLDN4 function to sustain an epithelial phenotype and that their loss promotes EMT. PMID- 23805315 TI - A Meta-Analysis of the Relationship between Cigarette Smoking and Incidence of Myelodysplastic Syndromes. AB - BACKGROUND: In recent years, epidemiologic studies have reported controversial results relating cigarette smoking to myelodysplastic syndromes (MDS) risk. A meta-analysis was performed to assess such potential relationship between cigarette smoking and incidence of MDS. METHODS: A search of literature published before October 2012 for observational studies evaluating the association between cigarette smoking and MDS, returned 123 articles and of these, 14 were selected for this study. The outcomes from these studies were calculated and reported as odds ratios (OR). Quality assessments were performed with the Newcastle-Ottawa Scale. Heterogeneity was evaluated by the I(2) index and source of heterogeneity was detected by sensitivity analyses. Finally, publication bias was assessed through visual inspection of funnel plots and Egger's test. RESULTS: The pooled OR of developing MDS in ever-smokers was 1.45 (95% CI, 1.25 to 1.68) versus non smokers. Current and former smokers had increased risks of MDS, with ORs of 1.81 (95% CI, 1.24 to 2.66) and 1.67 (95% CI, 1.42 to 1.96), respectively. In subset analyses, ever-smokers had increased risks of developing MDS if they were living in the United States, or in Europe, female in gender, had refractory anemia (RA)/RA with ringed sideroblasts (RARS) or RA with excess blasts (RAEB)/RAEB in transformation (RAEBt), respectively. Our results demonstrated that the association was stronger in individuals who smoked >=20 cigarettes/day (OR, 1.62; 95% CI, 1.03 to 2.55) versus those who smoked <20 cigarettes/day (OR, 1.36; 95% CI, 1.13 to 1.64). Moreover, individuals who smoked more than 20 pack-years had increased MDS risk (OR, 1.94; 95% CI, 1.29 to 2.92). CONCLUSION: Our outcomes show that smoking increases the risk of developing MDS in ever-smokers who are current or former smokers. We also demonstrate here that positive association between cigarette smoking and risk of MDS exists, and occurs in a dose-dependent manner. PMID- 23805316 TI - Effects of Endotoxin and Psychological Stress on Redox Physiology, Immunity and Feather Corticosterone in Greenfinches. AB - Assessment of costs accompanying activation of immune system and related neuroendocrine pathways is essential for understanding the selective forces operating on these systems. Here we attempted to detect such costs in terms of disruption to redox balance and interference between different immune system components in captive wild-caught greenfinches (Carduelis chloris). Study birds were subjected to an endotoxin-induced inflammatory challenge and temporary exposure to a psychological stressor (an image of a predator) in a 2*2 factorial experiment. Injection of bacterial endotoxin resulted in up-regulation of two markers of antioxidant protection - erythrocyte glutathione, and plasma oxygen radical absorbance (OXY). These findings suggest that inflammatory responses alter redox homeostasis. However, no effect on markers of oxidative damage to proteins or DNA in erythrocytes could be detected. We found no evidence that the endotoxin injection interfered with antibody production against Brucella abortus antigen or the intensity of chronic coccidiosis. The hypothesis of within-immune system trade-offs as a cost of immunity was thus not supported in our model system. We showed for the first time that administration of endotoxin can reduce the level of corticosterone deposited into feathers. This finding suggests a down regulation of the corticosterone secretion cascade due to an endotoxin-induced immune response, a phenomenon that has not been reported previously. Exposure to the predator image did not affect any of the measured physiological parameters. PMID- 23805317 TI - MiR-34a/c-Dependent PDGFR-alpha/beta Downregulation Inhibits Tumorigenesis and Enhances TRAIL-Induced Apoptosis in Lung Cancer. AB - Lung cancer is the leading cause of cancer mortality in the world today. Although some advances in lung cancer therapy have been made, patient survival is still poor. MicroRNAs (miRNAs) can act as oncogenes or tumor-suppressor genes in human malignancy. The miR-34 family consists of tumor-suppressive miRNAs, and its reduced expression has been reported in various cancers, including non-small cell lung cancer (NSCLC). In this study, we found that miR-34a and miR-34c target platelet-derived growth factor receptor alpha and beta (PDGFR-alpha and PDGFR beta), cell surface tyrosine kinase receptors that induce proliferation, migration and invasion in cancer. MiR-34a and miR-34c were downregulated in lung tumors compared to normal tissues. Moreover, we identified an inverse correlation between PDGFR-alpha/beta and miR-34a/c expression in lung tumor samples. Finally, miR-34a/c overexpression or downregulation of PDGFR-alpha/beta by siRNAs, strongly augmented the response to TNF-related apoptosis inducing ligand (TRAIL) while reducing migratory and invasive capacity of NSCLC cells. PMID- 23805318 TI - 2-phenylethynesulfonamide Prevents Induction of Pro-inflammatory Factors and Attenuates LPS-induced Liver Injury by Targeting NHE1-Hsp70 Complex in Mice. AB - The endotoxin-mediated production of pro-inflammatory cytokines plays an important role in the pathogenesis of liver disorders. Heat shock protein (Hsp70) overexpression has established functions in lipopolysaccharide (LPS)-mediated inflammatory response. However, little is known about the role of Hsp70 activity in LPS signaling. We hypothesized that inhibition of Hsp70 substrate binding activity can ameliorate LPS-induced liver injury by decreasing induction of pro inflammatory factors. In this study, C57/BL6 mice were injected intraperitoneally with LPS and 2-phenylethynesulfonamide (PES), an inhibitor of Hsp70 substrate binding activity. We found that i. PES prevented LPS-induced increase in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity, infiltration of inflammatory cells, and liver cell apoptosis; ii. PES reduced inducible nitric oxide synthase (iNOS) protein expression as well as serum nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) content in LPS-stimulated mice; iii. PES reduced the mRNA level of iNOS, TNF alpha, and IL-6 in LPS-stimulated liver. iiii. PES attenuated the degradation of inhibitor of kappaB-alpha (IkappaB-alpha) as well as the phosphorylation and nuclear translocation of nuclear factor-kappaB (NF-kappaB) in LPS-stimulated liver. Similar changes in the protein expression of inflammatory markers, IkappaB alpha degradation, and NF-kappaB phosphorylation and nuclear translocation were observed in RAW 264.7 cells. Further mechanistic studies revealed that PES remarkably reduced the elevation of [Ca(2+)]i and intracellular pH value (pHi) in LPS-stimulated RAW 264.7 cells. Furthermore, PES significantly reduced the increase in Na(+)/H(+) exchanger 1 (NHE1) association to Hsp70 in LPS-stimulated macrophages and liver, suggesting that NHE1-Hsp70 interaction is required for the involvement of NHE1 in the inflammation response. In conclusion, inhibition of Hsp70 substrate binding activity in vivo reduces the induction of pro inflammatory factors and prevents LPS-induced liver injury likely by disrupting NHE1-Hsp70 interaction which consequently reduces the activation of IkappaB-alpha NF-kappaB pathway in liver. PMID- 23805319 TI - Identification of a Broadly Cross-Reactive Epitope in the Inner Shell of the Norovirus Capsid. AB - Noroviruses are major pathogens associated with acute gastroenteritis. They are diverse viruses, with at least six genogroups (GI-GVI) and multiple genotypes defined by differences in the major capsid protein, VP1. This diversity has challenged the development of broadly cross-reactive vaccines as well as efficient detection methods. Here, we report the characterization of a broadly cross-reactive monoclonal antibody (MAb) raised against the capsid protein of a GII.3 norovirus strain. The MAb reacted with VLPs and denatured VP1 protein from GI, GII, GIV and GV noroviruses, and mapped to a linear epitope located in the inner shell domain. An alignment of all available VP1 sequences showed that the putative epitope (residues 52-56) is highly conserved across the genus Norovirus. This broadly cross-reactive MAb thus constitutes a valuable reagent for the diagnosis and study of these diverse viruses. PMID- 23805320 TI - Biochemical Characteristics and PrP(Sc) Distribution Pattern in the Brains of Cattle Experimentally Challenged with H-type and L-type Atypical BSE. AB - Besides the classical form of bovine spongiform encephalopathy (BSE) that has been known for almost three decades, two atypical forms designated H-type and L type BSE have recently been described. While the main diagnostic feature of these forms is the altered biochemical profile of the accumulated PrP(Sc), it was also observed in the initial analysis that L-type BSE displays a distribution pattern of the pathological prion protein (PrP(Sc)), which clearly differs from that observed in classical BSE (C-type). Most importantly, the obex region in the brainstem is not the region with the highest PrP(Sc) concentrations, but PrP(Sc) is spread more evenly throughout the entire brain. A similar distribution pattern has been revealed for H-type BSE by rapid test analysis. Based on these findings, we performed a more detailed Western blot study of the anatomical PrP(Sc) distribution pattern and the biochemical characteristics (molecular mass, glycoprofile as well as PK sensitivity) in ten different anatomical locations of the brain from cattle experimentally challenged with H- or L-type BSE, as compared to cattle challenged with C-type BSE. Results of this study revealed distinct differences in the PrP(Sc) deposition patterns between all three BSE forms, while the biochemical characteristics remained stable for each BSE type among all analysed brain areas. PMID- 23805322 TI - As Facts and Chats Go Online, What Is Important for Adolescents with Type 1 Diabetes? AB - BACKGROUND: Continued refinement of resources for patient information, education and support is needed. Considering the rapid development of new communication practices, the perspectives of young people themselves warrant more attention using a wide research focus. The purpose of this study was to understand information-seeking behaviours, Internet use and social networking online in adolescents with type 1 diabetes (T1DM). This applied to their everyday life, including the context of diabetes and their experiences and need of contact with T1DM peers. METHODOLOGY/PRINCIPAL FINDINGS: Twenty-four adolescents aged 10-17 years with T1DM were recruited from a county hospital in the south-east of Sweden. Qualitative data were obtained using eight focus groups, wherein each participant engaged in a 60-90 minute video/audio-recorded session. The focus group data were transcribed and analysed using qualitative content analysis. Some demographic and medical information was also collected. The three main categories that were identified; Aspects of Security, Updating, and Plainness and their sub categories gave significant information about how to enhance information retrieval and peer contacts related to T1DM. Regarding the persons' information seeking behaviour, Internet use, and use of social media some differences could be identified depending on gender and age. CONCLUSIONS/SIGNIFICANCE: Sensitivity and adaptation to users' needs and expectations seem crucial in the development of future online resources for adolescents with T1DM. To start with, this could mean applying a wider range of already existing information and communication technologies. Health practitioners need to focus on the areas of security of information and communication, frequency of updating, and simplicity of design less is more. PMID- 23805321 TI - Cryopreservation Causes Genetic and Epigenetic Changes in Zebrafish Genital Ridges. AB - Cryopreservation is an important tool routinely employed in Assisted Reproduction Technologies (ARTs) and germplasm banking. For several years, the assessment of global DNA fragmentation seemed to be enough to ensure the integrity of genetic material. However, cryopreservation can produce molecular alterations in key genes and transcripts undetectable by traditional assays, such modifications could interfere with normal embryo development. We used zebrafish as a model to study the effect of cryopreservation on key transcripts and genes. We employed an optimized cryopreservation protocol for genital ridges (GRs) containing primordial germ cells (PGCs) considered one of the best cell sources for gene banking. Our results indicated that cryopreservation produced a decrease in most of the zebrafish studied transcripts (cxcr4b, pou5f1, vasa and sox2) and upregulation of heat shock proteins (hsp70, hsp90). The observed downregulation could not always be explained by promoter hypermethylation (only the vasa promoter underwent clear hypermethylation). To corroborate this, we used human spermatozoa (transcriptionally inactive cells) obtaining a reduction in some transcripts (eIF2S1, and LHCGR). Our results also demonstrated that this effect was caused by freezing/thawing rather than exposure to cryoprotectants (CPAs). Finally, we employed real-time PCR (qPCR) technology to quantify the number of lesions produced by cryopreservation in the studied zebrafish genes, observing very different vulnerability to damage among them. All these data suggest that molecular alterations caused by cryopreservation should be studied in detail in order to ensure the total safety of the technique. PMID- 23805323 TI - Vitamin D Receptor Gene Expression and Function in a South African Population: Ethnicity, Vitamin D and FokI. AB - Polymorphisms of the vitamin D receptor gene (VDR) have been associated inconsistently with various diseases, across populations of diverse origin. The T(f) allele of the functional SNP FokI, in exon 2 of VDR, results in a longer vitamin D receptor protein (VDR) isoform, proposed to be less active. Genetic association of VDR with disease is likely confounded by ethnicity and environmental factors such as plasma 25(OH)D3 status. We hypothesized that VDR expression, VDR level and transactivation of target genes, CAMP and CYP24A1, depend on vitamin D, ethnicity and FokI genotype. Healthy volunteers participated in the study (African, n = 40 and White, n = 20). Plasma 25(OH)D3 levels were quantified by LC-MS and monocytes cultured, with or without 1,25(OH)2D3. Gene expression and protein level was quantified using qRT-PCR and flow cytometry, respectively. Mean plasma 25(OH)D3 status was normal and not significantly different between ethnicities. Neither 25(OH)D3 status nor 1,25(OH)2D3 supplementation significantly influenced expression or level of VDR. Africans had significantly higher mean VDR protein levels (P<0.050), nonetheless transactivated less CAMP expression than Whites. Genotyping the FokI polymorphism by pyrosequencing together with HapMap data, showed a significantly higher (P<0.050) frequency of the CC genotype in Africans than in Whites. FokI genotype, however, did not influence VDR expression or VDR level, but influenced overall transactivation of CAMP and 1,25(OH)2D3-elicited CYP24A1 induction; the latter, interacting with ethnicity. In conclusion, differential VDR expression relates to ethnicity, rather than 25(OH)D3 status and FokI genotype. Instead, VDR transactivation of CAMP is influenced by FokI genotype and, together with ethnicity, influence 1,25(OH)2D3-elicited CYP24A1 expression. Thus, the expression and role of VDR to transactivate target genes is determined not only by genetics, but also by ethnicity and environment involving complex interactions which may confound disease association. PMID- 23805325 TI - Development of eSSR-Markers in Setaria italica and Their Applicability in Studying Genetic Diversity, Cross-Transferability and Comparative Mapping in Millet and Non-Millet Species. AB - Foxtail millet (Setariaitalica L.) is a tractable experimental model crop for studying functional genomics of millets and bioenergy grasses. But the limited availability of genomic resources, particularly expressed sequence-based genic markers is significantly impeding its genetic improvement. Considering this, we attempted to develop EST-derived-SSR (eSSR) markers and utilize them in germplasm characterization, cross-genera transferability and in silico comparative mapping. From 66,027 foxtail millet EST sequences 24,828 non-redundant ESTs were deduced, representing ~16 Mb, which revealed 534 (~2%) eSSRs in 495 SSR containing ESTs at a frequency of 1/30 kb. A total of 447 pp were successfully designed, of which 327 were mapped physically onto nine chromosomes. About 106 selected primer pairs representing the foxtail millet genome showed high-level of cross-genera amplification at an average of ~88% in eight millets and four non-millet species. Broad range of genetic diversity (0.02-0.65) obtained in constructed phylogenetic tree using 40 eSSR markers demonstrated its utility in germplasm characterizations and phylogenetics. Comparative mapping of physically mapped eSSR markers showed considerable proportion of sequence-based orthology and syntenic relationship between foxtail millet chromosomes and sorghum (~68%), maize (~61%) and rice (~42%) chromosomes. Synteny analysis of eSSRs of foxtail millet, rice, maize and sorghum suggested the nested chromosome fusion frequently observed in grass genomes. Thus, for the first time we had generated large-scale eSSR markers in foxtail millet and demonstrated their utility in germplasm characterization, transferability, phylogenetics and comparative mapping studies in millets and bioenergy grass species. PMID- 23805324 TI - Healthy Neonates Possess a CD56-Negative NK Cell Population with Reduced Anti Viral Activity. AB - BACKGROUND: Neonatal Natural Killer (NK) cells show functional impairment and expansion of a CD56 negative population of uncertain significance. METHODS: NK cells were isolated from cord blood and from adult donors. NK subpopulations were identified as positive or negative for the expression of CD56 and characterized for expression of granzyme B and surface markers by multi-parameter flow cytometry. Cell function was assessed by viral suppression and cytokine production using autologous lymphocytes infected with HIV. Activating (NKp30, NKp46) and inhibitory (Siglec-7) markers in healthy infants and adults were compared with viremic HIV-infected adults. RESULTS: Cord blood contained increased frequencies of CD56 negative (CD56neg) NK cells with reduced expression of granzyme B and reduced production of IFNgamma and the CC-class chemokines RANTES, MIP1alpha and MIP1beta upon stimulation. Both CD56pos and CD56neg NK subpopulations showed impaired viral suppression in cord blood, with impairment most marked in the CD56neg subset. CD56neg NK cells from cord blood and HIV infected adults shared decreased inhibitory and activating receptor expression when compared with CD56pos cells. CONCLUSIONS: CD56neg NK cells are increased in number in normal infants and these effectors show reduced anti-viral activity. Like the expanded CD56neg population described in HIV-infected adults, these NK cells demonstrate functional impairments which may reflect inadequate development or activation. PMID- 23805326 TI - ScriptingRT: A Software Library for Collecting Response Latencies in Online Studies of Cognition. AB - ScriptingRT is a new open source tool to collect response latencies in online studies of human cognition. ScriptingRT studies run as Flash applets in enabled browsers. ScriptingRT provides the building blocks of response latency studies, which are then combined with generic Apache Flex programming. Six studies evaluate the performance of ScriptingRT empirically. Studies 1-3 use specialized hardware to measure variance of response time measurement and stimulus presentation timing. Studies 4-6 implement a Stroop paradigm and run it both online and in the laboratory, comparing ScriptingRT to other response latency software. Altogether, the studies show that Flash programs developed in ScriptingRT show a small lag and an increased variance in response latencies. However, this did not significantly influence measured effects: The Stroop effect was reliably replicated in all studies, and the found effects did not depend on the software used. We conclude that ScriptingRT can be used to test response latency effects online. PMID- 23805327 TI - DISSECT Method Using PNA-LNA Clamp Improves Detection of EGFR T790m Mutation. AB - Non-small cell lung cancer (NSCLC) patients treated with small molecule EGFR inhibitors, such as gefitinib, frequently develop drug resistance due to the presence of secondary mutations like the T790M mutation on EGFR exon 20. These mutations may originate from small subclonal populations in the primary tumor that become dominant later on during treatment. In order to detect these low level DNA variations in the primary tumor or to monitor their progress in plasma, it is important to apply reliable and sensitive mutation detection methods. Here, we combine two recently developed methodologies, Differential Strand Separation at Critical Temperature (DISSECT), with peptide nucleic acid-locked nucleic acid (PNA-LNA) polymerase chain reaction (PCR) for the detection of T790M EGFR mutation. DISSECT pre-enriches low-abundance T790M EGFR mutations from target DNA prior to implementing PNA-LNA PCR, a method that can detect 1 mutant allele in a background of 100-1000 wild type alleles. The combination of DISSECT and PNA-LNA PCR enables the detection of 1 mutant allele in a background of 10,000 wild type alleles. The combined DISSECT-PNA-LNA PCR methodology is amenable to adaptation for the sensitive detection of additional emerging resistance mutations in cancer. PMID- 23805328 TI - Intestine-Specific Mttp Deletion Increases the Severity of Experimental Colitis and Leads to Greater Tumor Burden in a Model of Colitis Associated Cancer. AB - BACKGROUND: Gut derived lipid factors have been implicated in systemic injury and inflammation but the precise pathways involved are unknown. In addition, dietary fat intake and obesity are independent risk factors for the development of colorectal cancer. Here we studied the severity of experimental colitis and the development of colitis associated cancer (CAC) in mice with an inducible block in chylomicron secretion and fat malabsorption, following intestine-specific deletion of microsomal triglyceride transfer protein (Mttp-IKO). METHODOLOGY/PRINCIPAL FINDINGS: Mttp-IKO mice exhibited more severe injury with ~90% mortality following dextran sodium sulfate (DSS) induced colitis, compared to <20% in controls. Intestinal permeability was increased in Mttp-IKO mice compared to controls, both at baseline and after DSS administration, in association with increased circulating levels of TNFalpha. DSS treatment increased colonic mRNA expression of IL-1beta and IL-17A as well as inflammasome expression in both genotypes, but the abundance of TNFalpha was selectively increased in DSS treated Mttp-IKO mice. There was a 2-fold increase in colonic tumor burden in Mttp-IKO mice following azoxymethane/DSS treatment, which was associated with increased colonic inflammation as well as alterations in cytokine expression. To examine the pathways by which alterations in fatty acid abundance might interact with cytokine signaling to regulate colonic epithelial growth, we used primary murine myofibroblasts to demonstrate that palmitate induced expression of amphiregulin and epiregulin and augmented the increase in both of these growth mediators when added to IL-1betaor to TNFalpha. CONCLUSIONS: These studies demonstrate that Mttp-IKO mice, despite absorbing virtually no dietary fat, exhibit augmented fatty acid dependent signaling that in turn exacerbates colonic injury and increases tumor formation. PMID- 23805329 TI - From Chemistry to Behavior. Molecular Structure and Bioactivity of Repellents against Ixodes ricinus Ticks. AB - Tick-borne zoonoses are considered as emerging diseases. Tick repellents represent an effective tool for reducing the risk of tick bite and pathogens transmission. Previous work demonstrated the repellent activity of the phenylpropanoid eugenol against Ixodes ricinus; here we investigate the relationship between molecular structure and repellency in a group of substances related to that compound. We report the biological activity of 18 compounds varying for the presence/number of several moieties, including hydroxyl and methoxy groups and carbon side-chain. Each compound was tested at different doses with a bioassay designed to measure repellency against individual tick nymphs. Both vapor pressure and chemical features of the tested compounds appeared to be related to repellency. In particular, the hydroxyl and methoxy groups as well as the side-chain on the benzene ring seem to play a role. These results are discussed in light of available data on chemical perception in ticks. In the course of the study new repellent compounds were identified; the biological activity of some of them (at least as effective as the "gold standard" repellent DEET) appears to be very promising from a practical point of view. PMID- 23805330 TI - Purification and Characterization of Biofilm-Associated EPS Exopolysaccharides from ESKAPE Organisms and Other Pathogens. AB - In bacterial biofilms, high molecular weight, secreted exopolysaccharides can serve as a scaffold to which additional carbohydrates, proteins, lipids, and nucleic acids adhere, forming the matrix of the developing biofilm. Here we report methods to extract and purify high molecular weight (>15 kDa) exopolysaccharides from biofilms of eight human pathogens, including species of Staphylcococcus, Klebsiella, Acinetobacter, Pseudomonas, and a toxigenic strain of Escherichia coli O157:H7. Glycosyl composition analysis indicated a high total mannose content across all strains with P. aeruginosa and A. baumannii exopolysaccharides comprised of 80-90% mannose, K. pneumoniae and S. epidermidis strains containing 40-50% mannose, and E. coli with ~10% mannose. Galactose and glucose were also present in all eight strains, usually as the second and third most abundant carbohydrates. N-acetyl-glucosamine and galacturonic acid were found in 6 of 8 strains, while arabinose, fucose, rhamnose, and xylose were found in 5 of 8 strains. For linkage analysis, 33 distinct residue-linkage combinations were detected with the most abundant being mannose-linked moieties, in line with the composition analysis. The exopolysaccharides of two P. aeruginosa strains analyzed were consistent with the Psl carbohydrate, but not Pel or alginate. The S. epidermidis strain had a composition rich in mannose and glucose, which is consistent with the previously described slime associated antigen (SAA) and the extracellular slime substance (ESS), respectively, but no polysaccharide intracellular adhesion (PIA) was detected. The high molecular weight exopolysaccharides from E. coli, K. pneumoniae, and A. baumannii appear to be novel, based on composition and/or ratio analysis of carbohydrates. PMID- 23805331 TI - A Single Nucleotide Polymorphism within the Interferon Gamma Receptor 2 Gene Perfectly Coincides with Polledness in Holstein Cattle. AB - Polledness is a high impact trait in modern milk and beef production to meet the demands of animal welfare and work safety. Previous studies have mapped the polled-locus to the proximal region of the bovine chromosome 1 (BTA1) and narrowed it down to approximately 1 Mb. Sequencing of the positional candidate genes within the 1 Mb polled region and whole genome sequencing of Holsteins revealed a single nucleotide polymorphism (SNP) AC000158: g.1390292G>A within intron 3 of the interferon gamma receptor 2 gene (IFNGR2) in perfect co segregation with polledness in Holsteins. This complete association was validated in 443 animals of the same breed. This SNP allows reliable genotyping of horned, heterozygous and homozygous polled Holsteins, even in animals that could not be resolved using the previously published haplotype for Holstein. PMID- 23805332 TI - An fMRI Study of Audiovisual Speech Perception Reveals Multisensory Interactions in Auditory Cortex. AB - Research on the neural basis of speech-reading implicates a network of auditory language regions involving inferior frontal cortex, premotor cortex and sites along superior temporal cortex. In audiovisual speech studies, neural activity is consistently reported in posterior superior temporal Sulcus (pSTS) and this site has been implicated in multimodal integration. Traditionally, multisensory interactions are considered high-level processing that engages heteromodal association cortices (such as STS). Recent work, however, challenges this notion and suggests that multisensory interactions may occur in low-level unimodal sensory cortices. While previous audiovisual speech studies demonstrate that high level multisensory interactions occur in pSTS, what remains unclear is how early in the processing hierarchy these multisensory interactions may occur. The goal of the present fMRI experiment is to investigate how visual speech can influence activity in auditory cortex above and beyond its response to auditory speech. In an audiovisual speech experiment, subjects were presented with auditory speech with and without congruent visual input. Holding the auditory stimulus constant across the experiment, we investigated how the addition of visual speech influences activity in auditory cortex. We demonstrate that congruent visual speech increases the activity in auditory cortex. PMID- 23805333 TI - Regulator of G-Protein Signalling-14 (RGS14) Regulates the Activation of alphaMbeta2 Integrin during Phagocytosis. AB - Integrin-mediated phagocytosis, an important physiological activity undertaken by professional phagocytes, requires bidirectional signalling to/from alphaMbeta2 integrin and involves Rap1 and Rho GTPases. The action of Rap1 and the cytoskeletal protein talin in activating alphaMbeta2 integrins, in a RIAM independent manner, has been previously shown to be critical during phagocytosis in mammalian phagocytes. However, the events downstream of Rap1 are not clearly understood. Our data demonstrate that one potential Rap1 effector, Regulator of G Protein Signalling-14 (RGS14), is involved in activating alphaMbeta2. Exogenous expression of RGS14 in COS-7 cells expressing alphaMbeta2 results in increased binding of C3bi-opsonised sheep red blood cells. Consistent with this, knock-down of RGS14 in J774.A1 macrophages results in decreased association with C3bi opsonised sheep red blood cells. Regulation of alphaMbeta2 function occurs through the R333 residue of the RGS14 Ras/Rap binding domain (RBD) and the F754 residue of beta2, residues previously shown to be involved in binding of H-Ras and talin1 head binding prior to alphaMbeta2 activation, respectively. Surprisingly, overexpression of talin2 or RAPL had no effect on alphaMbeta2 regulation. Our results establish for the first time a role for RGS14 in the mechanism of Rap1/talin1 activation of alphaMbeta2 during phagocytosis. PMID- 23805335 TI - Davies lends editorial expertise to follow-up issue on critical limb ischemia. PMID- 23805334 TI - Discovery and Characterization of a Novel Carlavirus Infecting Potatoes in China. AB - A new carlavirus, tentatively named Potato virus H (PVH), was found on potato plants with mild symptoms in Hohhot, Inner Mongolia Autonomous Region, China. PVH was confirmed by genome sequencing, serological reactions, electron microscopy, and host index assays. The PVH particles were filamentous and slightly curved, with a modal length of 570 nm. Complete RNA genomic sequences of two isolates of PVH were determined using reverse transcription-PCR (RT-PCR) and the 5' rapid amplification of cDNA ends (5' RACE) method. Sequence analysis revealed that PVH had the typical genomic organization of members of the genus Carlavirus, with a positive-sense single-stranded genome of 8410 nt. It shared coat protein (CP) and replicase amino acid sequence identities of 17.9-56.7% with those of reported carlaviruses. Phylogenetic analyses based on the protein-coding sequences of replicase and CP showed that PVH formed a distinct branch, which was related only distantly to other carlaviruses. Western blotting assays showed that PVH was not related serologically to other potato carlaviruses (Potato virus S, Potato virus M, and Potato latent virus). PVH systemically infected Nicotianaglutinosa but not Nicotiana tabacum, Nicotianabenthamiana, or Chenopodiumquinoa, which is in contrast with the other potato carlaviruses. These results support the classification of PVH as a novel species in the genus Carlavirus. Preliminary results also indicated that a cysteine-rich protein encoded by the smallest ORF located in the 3' proximal region of the genome suppressed local RNA silencing and enhanced the pathogenicity of the recombinant PVX. PMID- 23805336 TI - Bypass surgery in limb salvage: inflow procedures. AB - Proper management of lower-extremity inflow vessel disease is critical to the success of distal interventions. Aortobifemoral bypass is the most effective means of treating aortoiliac disease, but this invasive procedure is not always ideal for a patient population that often has diffuse vascular disease and multiple comorbidities. Technologic advances and increasing experience have fundamentally altered the management algorithm for lower-extremity vascular lesions, and endovascular options have become the first-line therapy for Trans Atlantic Inter-Society Guidelines (TASC) class A and B lesions. In fact, an endovascular first approach is being endorsed even for highly complex TASC C and even TASC D lesions. Other alternatives include minimally invasive (laparoscopic or robotic) options or extra-anatomic bypass procedures. Inadequate outflow can compromise any inflow procedure, but inflow treatment failures are the crux of all limb salvage in patients with lower-extremity vascular disease. PMID- 23805337 TI - Endovascular techniques in limb salvage: cutting, cryo, brachy, and drug-eluting balloons. AB - The complex pathophysiology response to injury of the lower-extremity arteries has prompted the development of several unique balloon technologies to overcome initial technical failures and short-term intimal hyperplasia. Cryoplasty alters the cellular and mechanical properties of the vessel wall during angioplasty. Cutting balloons incise the wall, preventing elastic recoil and allowing expansion of the lumen at a lower pressure, thus limiting barotrauma. Drug eluting balloons actively transfer inhibitory compounds to the wall during the initial therapy, while brachytherapy balloons allow for localized delivery of radiation to inhibit the proliferative response seen after angioplasty. These platforms provide unique means to enhance immediate and short-term results and also reduce stent usage in the lower extremity. PMID- 23805338 TI - Retrograde pedal/tibial artery access for treatment of infragenicular arterial occlusive disease. AB - Endovascular intervention has emerged as an accepted modality for treating patients with critical limb ischemia. However, this therapy poses multiple challenges to the interventionalist due to the presence of widespread multilevel disease, long and complex occlusive lesions, and the common involvement of the tibial vessels. Retrograde pedal/tibial access is a relatively new technique that allows the treatment of tibial occlusive lesions when conventional endovascular techniques fail. This article reviews the technical details and published data regarding this technique and evaluates its use in this difficult-to-treat patient population. PMID- 23805339 TI - Endovascular techniques in limb salvage: stents. AB - In patients with critical limb ischemia, the first-line approach for limb salvage has shifted over the past decade from bypass surgery to endovascular intervention. Stenting for the treatment of lower-extremity arterial occlusive disease is an important tool and continues to evolve, with new stent designs and technologies that have been developed to provide superior patency rates and limb salvage. In this article, we discuss the role of peripheral stenting in the treatment of patients with critical limb ischemia, including a review of the relevant current literature and the future directions of such interventions. PMID- 23805340 TI - Limb salvage in women. AB - The prevalence of peripheral arterial occlusive disease (PAD) in women and men is equal. Studies to date present conflicting data of gender effects on the risk factors, clinical presentation, and treatment outcomes. Clinical trials have often failed to analyze results by gender or to recruit sufficient women to enable such an analysis. This review summarizes the management and outcome of limb salvage therapy with a particular focus in women. PMID- 23805341 TI - Hybrid interventions in limb salvage. AB - Hybrid interventions have become an integral part of our strategy for limb salvage in patients with multilevel arterial occlusive disease. In this article, we describe the commonly used hybrid interventions and review their indications and outcomes. Iliac stenting and femoral endarterectomy are the two most frequently performed procedures in hybrid cases. Short- and long-term outcomes of hybrid interventions are at least comparable to conventional endovascular and surgical revascularization procedures. Hybrid revascularization offers the efficiency and convenience of a single-stage revascularization. PMID- 23805342 TI - Muscle flaps and their role in limb salvage. AB - Muscle flaps have proved to be a valuable and versatile tool in the surgical treatment of the severely compromised lower extremity. Utilized as both local pedicle flaps and free tissue transfers, muscles have been successfully employed to cover complex wounds, manage osteomyelitis, salvage infected vascular grafts, treat recalcitrant venous stasis ulcers, preserve amputation levels, and restore motion following compartment syndrome. Free flap pedicles have also been used in a flow-through fashion to create a distal arterial bypass. This article explores the multipurpose role of muscle flaps in limb salvage surgery and their beneficial physiologic characteristics in hostile wound environments. PMID- 23805343 TI - Spinal cord stimulation for chronic limb ischemia. AB - The treatment of chronic limb ischemia involves the restoration of pulsatile blood flow to the distal extremity. Some patients cannot be treated with endovascular means or with open surgery; some may have medical comorbidities that render them unfit for surgery, while others may have persistent ischemia or pain even in the face of previous attempts at reperfusion. In spinal cord stimulation (SCS), a device with electrodes is implanted in the epidural space to stimulate sensory fibers. This activates cell-signaling molecules that in turn cause the release of vasodilatory molecules, a decrease in vascular resistance, and relaxation of smooth muscle cells. SCS also suppresses sympathetic vasoconstriction and pain transmission. When patient selection is based on microcirculatory parameters, SCS therapy can significantly improve pain relief, halt the progression of ulcers, and potentially achieve limb salvage. PMID- 23805344 TI - Endovascular techniques in limb salvage: infrapopliteal angioplasty. AB - Critical limb ischemia (CLI) results from inadequate blood flow to supply and sustain the metabolic needs of resting muscle and tissue. Infragenicular atherosclerosis is the most common cause of CLI, and it is more likely to develop when multilevel or diffuse arterial disease coincides with compromised run-off to the foot. Reports of good technical and clinical outcomes have advanced the endovascular treatment options, which have gained a growing acceptance as the primary therapeutic strategy for CLI, especially in patients with significant risk factors for open surgical bypass. In fact, endovascular recanalization of below-the-knee arteries has proven to be feasible and safe, reduce the need for amputation, and improve wound healing. The distribution of various vascular territories or angiosomes in the foot has been recognized, and it appears advantageous to revascularize the artery supplying the territory directly associated with tissue loss. In addition, the targeted application and local delivery of drugs using drug-coated balloons (DCB) during angioplasty has the potential to improve patency rates compared to balloon angioplasty alone. PMID- 23805346 TI - Convocation speech presented at the American College of Cardiology 62nd Annual Scientific Session. PMID- 23805348 TI - Museum of TMH Multimodality Imaging Center. Left ventricular pseudoaneurysm. PMID- 23805345 TI - End-stage renal disease and limb salvage. AB - The prevalence of peripheral arterial disease and both traditional and nontraditional vascular risk factors are more common in patients with end-stage renal disease who are undergoing hemodialysis than the general population. Patients undergoing hemodialysis may also be at risk for peripheral arterial disease via nonvascular risk factors and the hemodialysis treatment itself. Unfortunately, because peripheral arterial disease and its risk factors in hemodialysis patients have not been thoroughly ascertained, evaluation of potential treatments has been limited. Given the high potential of morbidity and impaired quality-of-life related to peripheral arterial disease in patients with end-stage renal disease, additional studies are needed to evaluate both quality of life and potential screening for peripheral arterial disease, its risk factors, and treatments to identify areas for improvement in this vulnerable population. PMID- 23805351 TI - Avoiding burnout. PMID- 23805352 TI - Vanishing constriction. PMID- 23805353 TI - Synchronous resections of primary colorectal tumor and liver metastasis by laparoscopic approach. AB - Liver metastasis of colorectal cancer is common. Resection of solitary tumors of primary and metastatic colorectal cancer can have a favorable outcome. Open resection of primary colorectal tumor and liver metastasis in one operation or in separate operations is currently common practice. Reports have shown that synchronous resections do not jeopardize short or long-term surgical outcomes and that this is a safe and effective approach in open surgery. The development of laparoscopic colorectal surgery and laparoscopic hepatectomy has made a minimally invasive surgical approach to treating colorectal cancer with liver metastasis feasible. Synchronous resections of primary colorectal tumor and liver metastasis by laparoscopy have recently been reported. The efficacy and safety of laparoscopic colorectal resection and laparoscopic hepatectomy have been proven separately but synchronous resections by laparoscopy are in hot debate. As it has been shown that open resection of primary colorectal tumor and liver metastasis in one operation results in an equally good short-term outcome when compared with that done in separate operations, laparoscopic resection of the same in one single operation seems to be a good option. Recent evidence has shown that this new approach is a safe alternative with a shorter hospital stay. Large scale randomized controlled trials are needed to demonstrate the effectiveness of this minimally invasive approach. PMID- 23805354 TI - Management of hepatocellular carcinoma: Enlightening the gray zones. AB - Management of hepatocellular carcinoma (HCC) has been continuously evolving during recent years. HCC is a worldwide clinical and social issue and typically a complicates cirrhosis. The incidence of HCC is increasing, not only in the general population of patients with cirrhosis, but particularly in some subgroups of patients, like those with human immunodeficiency virus infection or thalassemia. Since a 3% annual HCC incidence has been estimated in cirrhosis, a bi-annual screening is generally suggested. The diagnostic criteria of HCC has recently had a dramatic evolution during recent years. HCC diagnosis is now made only on radiological criteria in the majority of the cases. In the context of cirrhosis, the universally accepted criteria for HCC diagnosis is contrast enhancement in arterial phase and washout in venous/late phase at imaging, the so called "typical pattern". However, recently updated guidelines slightly differ in diagnostic criteria. Apart from liver transplantation, the only cure of both HCC and underlying liver cirrhosis, all the other treatments have to match with higher rate of HCC recurrence. The latter can be classified into curative (resection and percutaneous ablation) and palliative treatments. The aim of this paper was to review the current knowledge on management of HCC and to enlighten the areas of uncertainty. PMID- 23805356 TI - Hepatocellular carcinoma in patients co-infected with hepatitis C virus and human immunodeficiency virus. AB - Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) share a common route of transmission so that about one third of HIV infected individuals show HCV co-infection. Highly active antiretroviral therapy has offered a longer and better life to infected patients. While has removed AIDS-related diseases from the list of most common causes of death their place has been taken by complications of HCV infection, such as cirrhosis, end stage liver disease and hepatocellular carcinoma (HCC). HIV/HCV co-infection requires complex management, especially when HCC is present. Co-infected patients with HCC undergo the same therapeutic protocol as their mono-infected counterparts, but special issues such as interaction between regimens, withdrawal of therapy and choice of immunosuppressive agents, demand a careful approach by specialists. All these issues are analyzed in this minireview. PMID- 23805357 TI - Normal vitamin D levels are associated with spontaneous hepatitis B surface antigen seroclearance. AB - AIM: To investigate a possible association between serum vitamin D levels and spontaneous hepatitis B surface antigen (HBsAg) seroclearance. METHODS: Fifty three patients diagnosed with chronic inactive hepatitis B and spontaneous HBsAg seroclearance were followed up in two Israeli liver units between 2007 and 2012. This retrospective study reviewed medical charts of all the patients, extracting demographic, serological and vitamin D rates in the serum, as well as medical conditions and current medical therapy. Spontaneous HBsAg seroclearance was defined as the loss of serum HBsAg indefinitely. Vitamin D levels were compared to all patients who underwent spontaneous HBsAg seroclearance. RESULTS: Out of the 53 patients who underwent hepatitis B antigen seroclearance, 44 patients (83%) had normal levels of 25-hydroxyvitamin vitamin D compared to 9 patients (17%) who had below normal levels. Multivariate analysis showed that age (> 35 years) OR = 1.7 (95%CI: 1.25-2.8, P = 0.05), serum vitamin D levels (> 20 ng/mL) OR = 2.6 (95%CI: 2.4-3.2, P = 0.02), hepatitis B e antigen negativity OR = 2.1 (95%CI: 2.2-3.1, P = 0.02), low viral load (hepatitis B virus DNA < 100 IU/mL) OR = 3 (95%CI: 2.6-4.2, P = 0.01) and duration of HBsAg seropositivity (> 8 years) OR = 1.6 (95%CI: 1.15-2.6, P = 0.04) were also associated with spontaneous HBsAg seroclearance. CONCLUSION: We found a strong correlation between normal vitamin D levels and spontaneous HBsAg seroclearance. PMID- 23805358 TI - Coadministration of telaprevir and transcatheter arterial chemoembolization in hepatitis C virus-associated hepatocellular carcinoma. AB - The use of direct-acting antiviral agents (e.g., telaprevir, boceprevir) has improved response rates in patients with hepatitis C virus (HCV) genotype 1 infections. Substantial number of drug-drug interactions are anticipated with the use of telaprevir, a cytochrome P450 3A and P-glycoprotein substrate and inhibitor. Herein we describe a patient with HCV-associated hepatocellular carcinoma treated simultaneously with a telaprevir-containing regimen and localized chemotherapy (transcatheter arterial chemoembolization) with doxorubicin. No clinically relevant interactions or adverse events developed while on antiviral therapy. PMID- 23805355 TI - Non-viral factors contributing to hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a major cause of cancer death worldwide, accounting for over half a million deaths per year. The geographic pattern of HCC incidence is parallel to exposure to viral etiologic factors. Its incidence is increasing, ranging between 3% and 9% annually depending on the geographical location, and variability in the incidence rates correspond closely to the prevalence and pattern of the primary etiologic factors. Chronic infections with hepatitis B viruses or hepatitis C viruses have both been recognized as human liver carcinogens with a combined attributable fraction of at least 75% of all HCC cases. Multiple non-viral factors have been implicated in the development of HCC. Increased body mass index and diabetes with subsequent development of non alcoholic steatohepatitis represent significant risk factors for HCC. Other non viral causes of HCC include iron overload syndromes, alcohol use, tobacco, oral contraceptive, aflatoxin, pesticides exposure and betel quid chewing, a prevalent habit in the developing world. Wilson disease, alpha-1 antitrypsin deficiency, Porphyrias, autoimmune hepatitis, Schistosoma japonicum associated with positive hepatitis B surface antigen, and thorotrast-ray are also contributing hepatocellualar carcinoma. In addition, primary biliary cirrhosis, congestive liver disease and family history of liver cancer increase the risk of HCC incident. In conclusion, clarification of relevant non-viral causes of HCC will help to focus clinicians on those risk factors that are modifiable. The multilevel preventative approach will hopefully lead to a reduction in incidence of non-viral HCC, and a decrease in the patient morbidity and mortality as well as the societal economic burden associated with HCC. PMID- 23805359 TI - Progressive multi-organ expression of immunoglobulin G4-related disease: A case report. AB - A 63-year-old Caucasian man presented with a cholestatic syndrome, renal failure and arthralgias. A laboratory examination revealed high immunoglobulin G (IgG) and IgG4 levels (5.95 g/L; normal range: 0.08-1.4 g/L), pointing to a diagnosis of systemic IgG4-related disease, with definite radiological evidence of biliary and pancreatic expression, and plausible renal, articular, salivary and lacrimal glands involvement. Due to the rarity of the condition, there are currently no random control trials to point to the optimal therapeutic approach. The patient has been on steroid therapy with the subsequent introduction of azathioprine, with a complete resolution of all symptoms, a rapid reduction to normalization of all blood tests, and a complete regression of the radiological picture. Our experience underlines the complexity of IgG4-related disease and its variable and sometimes progressive presentation, while pointing out the need for a careful and complete assessment for possible multi-organ involvement. PMID- 23805360 TI - Multiple focal nodular hyperplasias induced by oxaliplatin-based chemotherapy. AB - Focal nodular hyperplasia (FNH) is a benign condition that affects normal liver with low prevalence. Recently, the extensive use of oxaliplatin to treat patients with colorectal cancer has been reported to be associated with the development of different liver injuries, as well as focal liver lesions. The present work describes two patients with multiple bilateral focal liver lesions misdiagnosed as colorectal liver metastases, and treated with liver resection. The first patient had up to 15 small bilateral focal liver lesions, with magnetic resonance imaging consistent with colorectal liver metastases (CLM), and fluorodeoxyglucose (FDG)-positron emission tomography (PET) negative. The second patient had up to 5 small focal liver lesions, with computed tomography consistent with CLM, and FDG PET negative. They had parenchyma sparing liver surgery, with uneventful postoperative course. At the histology the diagnosis was multiple FNHs. The risks of oxaliplatin-based chemotherapy regimens in development of liver injuries, such as FNH, should not be further denied. The value of the modern multidisciplinary management of patients with colorectal cancer relies also on the precise estimation of the risk/benefit for each patient. PMID- 23805361 TI - Efficacy of a Culturally Based Parenting Intervention: Strengthening Open Communication Between Mexican-Heritage Parents and Adolescent Children. AB - This article presents the results of an initial efficacy trial of a parenting intervention, Familias: Preparando la Nueva Generacion (FPNG), used to strengthen parenting practices, specifically, open family communication. Using community based participatory research, including stakeholder involvement, the FPNG curriculum was developed, evaluated for feasibility, and revised to complement the classroom-based keepin' itREAL youth substance-use prevention program. FPNG focuses on family influences that characterize Mexican-heritage youth and families, including the impact of acculturation. The 9 middle schools were block randomized into 3 groups: parents and youth (PY), youth only (Y), and control (C) conditions. Parents of 7th grade youth (N = 393, 82.8% mothers) completed self report surveys at baseline and immediately following the intervention. Structural equation model analyses confirmed that PY parents reported significantly greater levels of open family communication at the follow-up compared with Y parents; C parents were not significantly different from Y parents at follow-up. The inclusion of parents in adolescent-focused preventive interventions might increase the effect size of an original and efficacious youth prevention intervention. PMID- 23805362 TI - Open versus laparoscopic right hemicolectomy in the elderly population. AB - AIM: To compare short term outcomes of elective laparoscopic and open right hemicolectomy (RH) in an elderly population. METHODS: All patients over the age of 70 undergoing elective RH at Ninewells Hospital and Perth Royal Infirmary between January 2006 and May 2011 were included in our analysis. Operative details, hospital length of stay, morbidity and mortality was collected by way of proforma from a dedicated prospective database. An extracorporeal anastomosis was performed routinely in the laparoscopic group. The primary endpoints for analysis were morbidity and mortality. Our secondary endpoints were operative duration, length of hospital stay and discharge destination. RESULTS: Two hundred and six patients were included in our analysis. One hundred and twenty-five patients underwent an open resection and 81 patients had a laparoscopic resection. The mean operating time was significantly longer in the laparoscopic group (139 +/- 36 min vs 197 +/- 53 min, P = 0.001). The mean length of hospital stay was similar in both groups (11.2 +/- 7.8 d vs 9.6 +/- 10.7 d, P = 0.28). The incidence of post-operative morbidities was 27% in the open group and 38% in the laparoscopic group (P = 0.12). Overall in-hospital mortality was 0.8% in open procedures vs 1% in laparoscopic. CONCLUSION: Laparoscopic RH was associated with a significantly longer operative time compared to open RH. In our study, laparoscopic RH was not associated with reduced post-operative morbidity or significantly shorter length of hospital stay. PMID- 23805363 TI - A rare cause of obstructive jaundice and gastric outlet obstruction. AB - Superior mesenteric artery syndrome is a rare cause of upper gastrointestinal obstruction, and is characterized by 3(rd) duodenal obstruction between the abdominal aorta and the superior mesenteric artery. Classical symptoms are postprandial epigastric pain, nausea, vomiting, and weight loss, or acute upper gastrointestinal obstruction. We herein describe an unusual presentation, with jaundice due to compression of the common bile duct by the gastric obstruction and dilated duodenum. PMID- 23805364 TI - A bizarre foreign body in the appendix: A case report. AB - Foreign bodies are rare causes of appendicitis and, in most cases, ingested foreign bodies pass through the alimentary tract asymptomatically. However, ingested foreign bodies may sometimes remain silent within the appendix for many years without an inflammatory response. Despite the fact that cases of foreign body-induced appendicitis have been documented, sharp and pointed objects are more likely to cause perforations and abscesses, and present more rapidly after ingestion. Various materials, such as needles and drill bits, as well as organic matter, such as seeds, have been implicated as causes of acute appendicitis. Clinical presentation can vary from hours to years. Blunt foreign bodies are more likely to remain dormant for longer periods and cause appendicitis through obstruction of the appendiceal lumen. We herein describe a patient presenting with a foreign body in his appendix which had been swallowed 15 years previously. The contrast between the large size of the foreign body, the long clinical history without symptoms and the total absence of any histological inflammation was notable. We suggest that an elective laparoscopic appendectomy should be offered to such patients as a possible management option. PMID- 23805365 TI - A black perforated esophagus treated with surgery: Report of a case. AB - A case of a perforated black esophagus treated with minimal invasive surgery is presented. A 68-year-old women underwent a right-sided hemihepatectomy and radio frequency ablation of two metastasis in the left liver lobe. Previous history revealed a hemicolectomy for an obstructive colon carcinoma with post-operative chemotherapy. Postoperatively she developed severe dyspnea due to a perforation of the esophagus with leakage to the pleural space. Video-assisted thoracoscopic surgery (VATS) to adequately drain the perforation was performed. Gastroscopy revealed a perforated black esophagus. The black esophagus, acute esophageal necrosis or Gurvits syndrome is a rare entity with an unknown aetiology which is likely to be multifactorial. The estimated mortality rate is high. To our knowledge, this is the first case published of early VATS used in a case of perforated black esophagus. PMID- 23805366 TI - Intrathoracic major duodenal papilla with transhiatal herniation of the pancreas and duodenum: A case report and review of the literature. AB - Transhiatal herniation of the pancreas is an extremely rare condition. In the published literature we found only eleven cases reported in the period of 1958 to 2011. A coincidental hiatal herniation of the duodenum is described in two cases only. To our knowledge, we report the first case with a hiatal herniation of the complete duodenum and proximal pancreas presenting an intrathoracic major duodenal papilla with consecutive intrahepatic and extrahepatic cholestasis. A 72 year-old Caucasian woman was admitted to our department with a hiatal hernia grade IV for further evaluation. According to our recommendation of surgical hernia repair soon after the diagnosis of a transhiatal herniation of the proximal pancreas and entire duodenum, we had to respect the declared intention of the patient for a conservative procedure. So we were forced to wait for surgical repair within an emergency situation complicated by a myocardial infarction and reduced general condition. We discuss the therapeutic decision making process and a complete literature review of this rare entity. PMID- 23805367 TI - Laparoscopic appendectomy for appendiceal mucocele in an 83 years old woman. AB - Mucocele of the appendix is an uncommon but potentially dangerous pathological entity that presents in a variety of ways. Therefore, optimal surgical therapy is controversial; while some authors adopt a simple appendectomy, others recommend extensive resection, such as right hemicolectomy. We report the case of an 83 years old woman who presented with cystic neoformation in the right iliac fossa that was preoperatively considered an appendiceal mass. We electively performed a laparoscopic resection that histological examination defined as a mucinous cystadenoma. No recurrence was observed in the follow-up period of 9 mo. PMID- 23805368 TI - Topical nitrate drip infusion using cystic duct tube for retained bile duct stone: A six patients case series. AB - A retained bile duct stone after operation for cholelithiasis still occurs and causes symptoms such as biliary colic and obstructive jaundice. An endoscopic retrograde cholangiopancreatography with endoscopic sphincterotomy (EST), followed by stone extraction, are usually an effective treatment for this condition. However, these procedures are associated with severe complications including pancreatitis, bleeding, and duodenal perforation. Nitrates such as glyceryl trinitrate (GTN) and isosorbide dinitrate (ISDN) are known to relax the sphincter of Oddi. In 6 cases in which a retained stone was detected following cholecystectomy, topical nitrate drip infusion via cystic duct tube (C-tube) was carried out. Retained stones of 2-3 mm diameter and no dilated common bile duct in 3 patients were removed by drip infusion of 50 mg GTN or 10 mg ISDN, which was the regular dose of intravenous injection. Three other cases failed, and EST in 2 cases and endoscopic biliary balloon dilatation in 1 case were performed. One patient developed an adverse event of nausea. Severe complications were not observed. We consider the topical nitrate drip infusion via C-tube to be old but safe, easy, and inexpensive procedure for retained bile duct stone following cholecystectomy, inasmuch as removal rate was about 50% in our cases. PMID- 23805369 TI - Computed tomography of Crohn's disease: The role of three dimensional technique. AB - Crohn's disease, a transmural inflammatory bowel disease, remains a difficult entity to diagnose clinically. Over the last decade, multidetector computed tomography (CT) has become the method of choice for non-invasive evaluation of the small bowel, and has proved to be of significant value in the diagnosis of Crohn's disease. Advancements in CT enterography protocol design, three dimensional (3-D) post-processing software, and CT scanner technology have allowed increasing accuracy in diagnosis, and the acquisition of studies at a much lower radiation dose. The cases in this review will illustrate that the use of 3-D technique, proper enterography protocol design, and a detailed understanding of the different manifestations of Crohn's disease are all critical in properly diagnosing the full range of possible complications in Crohn's patients. In particular, CT enterography has proven to be effective in identifying involvement of the small and large bowel (including active inflammation, stigmata of chronic inflammation, and Crohn's-related bowel neoplasia) by Crohn's disease, as well as the extra-enteric manifestations of the disease, including fistulae, sinus tracts, abscesses, and urologic/hepatobiliary/osseous complications. Moreover, the proper use of 3-D technique (including volume rendering and maximum intensity projection) as a routine component of enterography interpretation can play a vital role in improving diagnostic accuracy. PMID- 23805370 TI - Correlation analysis of dual-energy CT iodine maps with quantitative pulmonary perfusion MRI. AB - AIM: To correlate dual-energy computed tomography (DECT) pulmonary angiography derived iodine maps with parameter maps of quantitative pulmonary perfusion magnetic resonance imaging (MRI). METHODS: Eighteen patients with pulmonary perfusion defects detected on DECT derived iodine maps were included in this prospective study and additionally underwent time-resolved contrast-enhanced pulmonary MRI [dynamic contrast enhanced (DCE)-MRI]. DCE-MRI data were quantitatively analyzed using a pixel-by-pixel deconvolution analysis calculating regional pulmonary blood flow (PBF), pulmonary blood volume (PBV) and mean transit time (MTT) in visually normal lung parenchyma and perfusion defects. Perfusion parameters were correlated to mean attenuation values of normal lung and perfusion defects on DECT iodine maps. Two readers rated the concordance of perfusion defects in a visual analysis using a 5-point Likert-scale (1 = no correlation, 5 = excellent correlation). RESULTS: In visually normal pulmonary tissue mean DECT and MRI values were: 22.6 +/- 8.3 Hounsfield units (HU); PBF: 58.8 +/- 36.0 mL/100 mL per minute; PBV: 16.6 +/- 8.5 mL; MTT: 17.1 +/- 10.3 s. In areas with restricted perfusion mean DECT and MRI values were: 4.0 +/- 3.9 HU; PBF: 10.3 +/- 5.5 mL/100 mL per minute, PBV: 5 +/- 4 mL, MTT: 21.6 +/- 14.0 s. The differences between visually normal parenchyma and areas of restricted perfusion were statistically significant for PBF, PBV and DECT (P < 0.0001). No linear correlation was found between MRI perfusion parameters and attenuation values of DECT iodine maps (PBF: r = 0.35, P = 0.15; PBV: r = 0.34, P = 0.16; MTT: r = 0.41, P = 0.08). Visual analysis revealed a moderate correlation between perfusion defects on DECT iodine maps and the parameter maps of DCE-MRI (mean score 3.6, kappa 0.45). CONCLUSION: There is a moderate visual but not statistically significant correlation between DECT iodine maps and perfusion parameter maps of DCE-MRI. PMID- 23805371 TI - Chronic hepatitis B: Enlarged perihepatic lymph nodes correlated with hepatic histopathology. AB - AIM: To assess the value of enlarged perihepatic lymph nodes in determining hepatic histopathology for chronic hepatitis B (CHB) by magnetic resonance imaging (MRI). METHODS: Sixty-seven patients who were clinically and histologically diagnosed with CHB and 18 healthy subjects without history of liver disease underwent abdominal MRI. Histological diagnosis and hepatic inflammation (grade 0-4) and fibrosis (stage 0-4) were assessed by a simplified system for scoring in chronic viral hepatitis. The major imaging protocol included an axial breath-hold fat suppressed fast spoiled gradient echo T2 weighted imaging (T2WI), axial breath-trigger fat suppressed fast recovery fast spin echo T2WI, and axial and coronal fast imaging employing steady-state acquisition. Perihepatic lymph nodes larger than 5 mm in shortest diameter were noted. RESULTS: The numbers and size indexes of lymph nodes greater than 5 mm in shortest diameter in hepatic hilum suggested inflammatory activity for subjects with grade 2 or higher, with a high accuracy of diagnosis (the area under the curves > 0.9, P < 0.001). The numbers of lymph nodes were 2 or more with a sensitivity of 87.27%, a specificity of 90.00%, an accuracy of 88.24%, a positive predictive value of 94.12%, and a negative predictive value of 79.41% in patients with grade 2 or higher, and the size indexes were no less than 180 mm(2) with a sensitivity of 83.64%, a specificity of 100%, an accuracy of 89.41%, a positive predictive value of 100%, and a negative predictive value of 76.92%. The numbers and size indexes of lymph nodes were not correlated with hepatic fibrosis. The signal intensity indexes of lymph nodes were no significant correlation with histological grading or staging of liver. CONCLUSION: The numbers and size indexes of enlarged perihepatic lymph nodes for patients with CHB suggest inflammatory activity for subjects with grade 2 or higher. PMID- 23805372 TI - Incidental meandering right pulmonary vein, literature review and proposed nomenclature revision. AB - We report a case of an anomalous pulmonary vein on chest X-ray resembling a scimitar sign in an 80-year-old female undergoing investigation of syncope. Multislice computed tomography (CT) with multiplanar reformatting and maximum intensity projections demonstrated an aberrant right inferior pulmonary vein coursing inferomedially towards the diaphragm before turning superiorly and draining normally into the left atrium. The diagnosis of an incidental meandering right pulmonary vein was established. The case is used to review the literature on this rare pulmonary anomaly, including pathogenesis, its relationship with scimitar syndrome and scimitar variant, and diagnosis, with an emphasis on the role modern CT techniques can play in non-invasive diagnosis. A revision to the nomenclature of pulmonary vascular anomalies is proposed to help reduce confusion in the literature. PMID- 23805373 TI - Sonographic assessment of a suspected biloma: A case report and review of the literature. AB - A biloma is a rare disease characterized by an abnormal intra- or extrahepatic bile collection due to a traumatic or spontaneous rupture of the biliary system. Laboratory findings are nonspecific. The diagnosis is usually suspected on the basis of a typical history (right upper quadrant abdominal pain, chills, fever and recent abdominal trauma or surgery) and is confirmed by detection of typical radiologic features. We report the case of a patient with a history of previous cholecystectomy for lithiasis who presented with clinical symptoms and laboratory data suggestive of acute pancreatitis. Imaging studies also revealed the presence of a chronic and asymptomatic biloma, which could be mistaken for a pseudocyst. The atypical location and ultrasound findings suggested an alternative diagnosis. We therefore reviewed the known literature for bilomas, focusing on the role of ultrasonography, which can reveal some typical aspects, such as location and imaging features. We conclude that ultrasound plays a key role in the assessment of a suspected biloma in patients with appropriate history and clinical features and provides valuable diagnostic clues even in the absence of these. PMID- 23805374 TI - Occlusion of the anterior cerebral artery after head trauma. AB - Intracranial arterial occlusion is rarely encountered in association with head injury. Only six cases of traumatic occlusion of the anterior cerebral artery (ACA) have previously been reported. In this paper, the authors describe a case of a posttraumatic occlusion of ACA. A 35-year-old male presented to the emergency room with severe head injury. Computed tomography (CT) scan displayed diffuse brain swelling with multiple skull fractures. Follow up CT scan showed extensive cerebral infarction in the territory of ACA. The patient underwent CT angiography that demonstrated occlusion of the ACA by a fracture of the anterior fossa. He died after 3 d. ACA traumatic occlusion is a rare condition, with poor prognosis. In this case, fracture was responsible for dissection and direct obstruction of the artery. PMID- 23805375 TI - Management Strategies for Elderly Patients with Diffuse Large B-Cell Lymphoma. PMID- 23805376 TI - New Challenges in the Management of Diffuse Large B-Cell Lymphoma. PMID- 23805377 TI - Focal segmental glomerulosclerosis in association with neurofibromatosis type 1: a case report and proposed molecular pathways. AB - A 42-year-old Caucasian female with history of neurofibromatosis type 1 presented with nephrotic range proteinuria and focal segmental glomerulosclerosis (FSGS). On final dose of lisinopril 20 mg/day, protein-creatinine ratio declined to 0.33 within 10 months. We propose the hypothesis that development of FSGS in NF1 may be mediated by activation of mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) signaling pathways secondary to up regulation of ras proteins due to deficient neurofibromin. Since mTOR signaling pathway is partially mediated through angiotensin-II activation, angiotensin converting enzyme (ACE) inhibition may serve as an effective initial treatment beyond anti-proteinuric properties of ACE-inhibitors. PMID- 23805378 TI - CAMKII and calcineurin regulate the lifespan of Caenorhabditis elegans through the FOXO transcription factor DAF-16. AB - The insulin-like signaling pathway maintains a relatively short wild-type lifespan in Caenorhabditis elegans by phosphorylating and inactivating DAF-16, the ortholog of the FOXO transcription factors of mammalian cells. DAF-16 is phosphorylated by the AKT kinases, preventing its nuclear translocation. Calcineurin (PP2B phosphatase) also limits the lifespan of C. elegans, but the mechanism through which it does so is unknown. Herein, we show that TAX-6*CNB-1 and UNC-43, the C. elegans Calcineurin and Ca(2+)/calmodulin-dependent kinase type II (CAMKII) orthologs, respectively, also regulate lifespan through DAF-16. Moreover, UNC-43 regulates DAF-16 in response to various stress conditions, including starvation, heat or oxidative stress, and cooperatively contributes to lifespan regulation by insulin signaling. However, unlike insulin signaling, UNC 43 phosphorylates and activates DAF-16, thus promoting its nuclear localization. The phosphorylation of DAF-16 at S286 by UNC-43 is removed by TAX-6*CNB-1, leading to DAF-16 inactivation. Mammalian FOXO3 is also regulated by CAMKIIA and Calcineurin. DOI:http://dx.doi.org/10.7554/eLife.00518.001. PMID- 23805379 TI - Rigid firing sequences undermine spatial memory codes in a neurodegenerative mouse model. AB - Hippocampal neurons encode spatial memories by firing at specific locations. As the animal traverses a spatial trajectory, individual locations along the trajectory activate these neurons in a unique firing sequence, which yields a memory code representing the trajectory. How this type of memory code is altered in dementia-producing neurodegenerative disorders is unknown. Here we show that in transgenic rTg4510 mice, a model of tauopathies including Alzheimer's disease, hippocampal neurons did not fire at specific locations, yet displayed robust firing sequences as animals run along familiar or novel trajectories. The sequences seen on the trajectories also appeared during free exploration of open spaces. The spatially dissociated firing sequences suggest that hippocampal neurons in the transgenic mice are not primarily driven by external space but by internally generated brain activities. We propose that tau pathology and/or neurodegeneration renders hippocampal circuits overwhelmed by internal information and therefore prevents them from encoding spatial memories. DOI:http://dx.doi.org/10.7554/eLife.00647.001. PMID- 23805380 TI - Arabidopsis plants perform arithmetic division to prevent starvation at night. AB - Photosynthetic starch reserves that accumulate in Arabidopsis leaves during the day decrease approximately linearly with time at night to support metabolism and growth. We find that the rate of decrease is adjusted to accommodate variation in the time of onset of darkness and starch content, such that reserves last almost precisely until dawn. Generation of these dynamics therefore requires an arithmetic division computation between the starch content and expected time to dawn. We introduce two novel chemical kinetic models capable of implementing analog arithmetic division. Predictions from the models are successfully tested in plants perturbed by a night-time light period or by mutations in starch degradation pathways. Our experiments indicate which components of the starch degradation apparatus may be important for appropriate arithmetic division. Our results are potentially relevant for any biological system dependent on a food reserve for survival over a predictable time period. DOI:http://dx.doi.org/10.7554/eLife.00669.001. PMID- 23805381 TI - Dismantling the Papez circuit for memory in rats. AB - Over the last 50 years, anatomical models of memory have repeatedly highlighted the hippocampal inputs to the mammillary bodies via the postcommissural fornix. Such models downplay other projections to the mammillary bodies, leaving them largely ignored. The present study challenged this dominant view by removing, in rats, the two principal inputs reaching the mammillary bodies: the postcommissural fornix from the hippocampal formation and Gudden's ventral tegmental nucleus. The principal mammillary body output pathway, the mammillothalamic tract, was disconnected in a third group. Only mammillothalamic tract and Gudden's ventral tegmental nucleus lesions impaired behavioral tests of spatial working memory and, in particular, disrupted the use of extramaze spatial landmarks. The same lesions also produced widespread reductions in immediate early gene (c-fos) expression in a network of memory-related regions, not seen after postcommissural fornix lesions. These findings are inconsistent with previous models of mammillary body function (those dominated by hippocampal inputs) and herald a new understanding of why specific diencephalic structures are vital for memory. DOI:http://dx.doi.org/10.7554/eLife.00736.001. PMID- 23805384 TI - Introduction to volume 2, third issue. PMID- 23805382 TI - Evolutionary dynamics of cancer in response to targeted combination therapy. AB - In solid tumors, targeted treatments can lead to dramatic regressions, but responses are often short-lived because resistant cancer cells arise. The major strategy proposed for overcoming resistance is combination therapy. We present a mathematical model describing the evolutionary dynamics of lesions in response to treatment. We first studied 20 melanoma patients receiving vemurafenib. We then applied our model to an independent set of pancreatic, colorectal, and melanoma cancer patients with metastatic disease. We find that dual therapy results in long-term disease control for most patients, if there are no single mutations that cause cross-resistance to both drugs; in patients with large disease burden, triple therapy is needed. We also find that simultaneous therapy with two drugs is much more effective than sequential therapy. Our results provide realistic expectations for the efficacy of new drug combinations and inform the design of trials for new cancer therapeutics. DOI:http://dx.doi.org/10.7554/eLife.00747.001. PMID- 23805383 TI - Retrospective review of pectoralis major ruptures in rodeo steer wrestlers. AB - Background. Pectoralis major tendon ruptures have been reported in the literature as occupational injuries, accidental injuries, and sporting activities. Few cases have been reported with respect to rodeo activities. Purpose. To describe a series of PM tendon ruptures in professional steer wrestlers. Study Design. Case series, level of evidence, 4. Methods. A retrospective analysis of PM ruptures in a steer wrestling cohort was performed. Injury data between 1992 and 2008 were reviewed using medical records from the University of Calgary Sport Medicine Center. Results. Nine cases of pectoralis major ruptures in professional steer wrestlers were identified. Injuries occurred during the throwing phase of the steer or while breaking a fall. All athletes reported unexpected or abnormal behavior of the steer that contributed to the mechanism of injury. Seven cases were surgically repaired, while two cases opted for nonsurgical intervention. Eight cases reported successful return to competition following the injury. Conclusion. Steer wrestlers represent a unique cohort of PM rupture case studies. Steer wrestling is a demanding sport that involves throwing maneuvers that may predispose the muscle to rupture. All cases demonstrated good functional outcomes regardless of surgical or non-surgical treatment. PMID- 23805385 TI - Benchmarking and quality-screening colonoscopy. PMID- 23805386 TI - The water exchange method and difficult colonoscopy. PMID- 23805387 TI - Indigocarmine added to the water exchange method enhances adenoma detection - a RCT. AB - PURPOSE: Chromoendoscopy with dye spray and the water method both increase adenoma detection. HYPOTHESIS: Adding indigocarmine to the water method will enhance further the effectiveness of the latter in adenoma detection. METHODS: Screening colonoscopy was performed with the water method (control) or with 0.008% indigocarmine added (study) by two endoscopists. Randomization was based on computer-generated codes contained in blocks of pre-arranged opaque sealed envelopes. High resolution colonoscopes were used. Upon insertion into the rectum, air was suctioned. With the air pump turned off, water was infused using a blunt needle adaptor connected to the scope channel and a foot pump to facilitate scope insertion until the cecum was reached. Residual stool causing cloudiness was suctioned followed by infusion of clear or colored water (water exchange) to facilitate scope passage with minimal distention of the colonic lumen. Upon seeing the appendix opening under water, water was suctioned and air was insufflated to facilitate inspection on scope withdrawal. STATISTICS: Sample size calculation revealed 168 patients (84/group) needed to be randomized. Study was IRB-approved and registered (NCT01383265). RESULTS: There were no significant differences in mean age, gender distribution, BMI, and family history of colon cancer. Cecal intubation success rate was 100% in both groups. The overall adenoma detection rate was 44% (water only) versus 62% (water with indigocarmine), respectively (p=0.03). One cancer was detected in each group. CONCLUSION: In a RCT, indigocarmine at 0.008% concentration, added to the water method, significantly enhanced further the effectiveness of the latter in detecting adenomas. PMID- 23805388 TI - Chromocolonoscopy for colorectal cancer screening: Dive into the Big Blue. PMID- 23805389 TI - A new method for screening and surveillance colonoscopy: Combined water-exchange and cap-assisted colonoscopy. AB - BACKGROUND & AIMS: Colonoscopy plays an important and central role in current colorectal cancer screening and prevention programs, but it is an imperfect tool. Adjunct techniques may help improve the performance of colonoscopy to increase the detection of polyps with neoplastic potential. This study investigates the novel approach of combined water-exchange and cap-assisted colonoscopy (WCC) and its impact on adenoma detection. METHODS: A single-center single-colonoscopist consecutive group observational study to compare WCC with conventional air insufflation colonoscopy was performed. Data were collected from 50 consecutive patients undergoing outpatient colorectal cancer screening or polyp surveillance with WCC. Adenoma detection rates (ADR) and adenomas detected per colonoscopy (APC) were compared to a control group of 101 consecutive patients examined with conventional air colonoscopy during the immediate prior period. RESULTS: Cecal intubation was achieved in all patients. As an emerging and alternative quality metric for colonoscopy, APC was significantly higher in the WCC group (3.08 vs. 1.50, p=0.0021). The conventional quality metric, overall ADR, was higher in the WCC group compared to the air colonoscopy group (70.0% vs. 59.4%, p=0.22). This difference was not statistically significant, likely due to a type II error. CONCLUSION: The observational data suggest APC is a more sensitive indicator of quality colonoscopy than ADR. WCC shows promise as a novel technique that merges two simple adjunct methods to help improve the performance of colonoscopy. The data suggest larger, prospective studies are necessary to determine the true impact of water-exchange combined with cap-assisted maneuvers. PMID- 23805390 TI - Best of both worlds - combining water-exchange and cap assisted colonoscopy. PMID- 23805392 TI - Can old dogs learn new tricks? PMID- 23805391 TI - The water exchange method for colonoscopy-effect of coaching. AB - The growing popularity of water immersion is supported by its long history as an adjunct to air insufflation; after facilitating colonoscope passage, the infused water is conveniently removed during withdrawal. Water exchange, a modification of water immersion to minimize discomfort in scheduled unsedated patients in the U.S. is new. Even though it may be superior in reducing pain and increasing adenoma detection, the paradigm shift to complete exclusion of air during insertion necessitates removal of infused water containing residual feces, a step often perceived as laborious and time-consuming. The nuances are the efficient steps to remove infused water predominantly during insertion to maintain minimal distension and deliver salvage cleansing. Mastery of the novel maneuvers with practice returns insertion time towards baseline. In this observational study the impact of direct verbal coaching on the primary outcome of intention-to-treat cecal intubation was assessed. The results showed that 14 of 19 (74%) experienced colonoscopists achieved 100% intention-to-treat cecal intubation. Initiation of the examination with water exchange did not preclude completion when conversion to the more familiar air insufflation method was deemed necessary to achieve cecal intubation (total 98%). The overall intention-to-treat cecal intubation rate was 88%, 90% in male and 87% in female. Only 2.7% of bowel preparation was rated as poor during withdrawal. The mean volume of water infused and cecal intubation time was 1558 ml and 18 min, respectively. Direct coaching appears to facilitate understanding of the nuances of the water exchange method. Studies of individual learning curves are necessary. PMID- 23805393 TI - Water exchange method for colonoscopy: learning curve of an experienced colonoscopist in a U.S. community practice setting. AB - BACKGROUND: Water exchange colonoscopy has been reported to reduce examination discomfort and to provide salvage cleansing in unsedated or minimally sedated patients. The prolonged insertion time and perceived difficulty of insertion associated with water exchange have been cited as a barrier to its widespread use. AIM: To assess the feasibility of learning and using the water exchange method of colonoscopy in a U.S. community practice setting. SETTING: Quality improvement program in nonacademic community endoscopy centers. SUBJECTS: Patients undergoing sedated diagnostic, surveillance, or screening colonoscopy. METHODS: After direct coaching by a knowledgeable trainer, an experienced colonoscopist initiated colonoscopy using the water method. Whenever >5 min elapsed without advancing the colonoscope, conversion to air insufflation was made to ensure timely completion of the examination. PRIMARY OUTCOME: Water Method Intention-to-treat (ITT) cecal intubation rate (CIR). RESULTS: Female patients had a significantly higher rate of past abdominal surgery and a significantly lower ITTCIR. The ITTCIR showed a progressive increase over time in both males and females to 85-90%. Mean insertion time was maintained at 9 to 10 min. The overall CIR was 99%. CONCLUSION: Use of water exchange did not preclude cecal intubation upon conversion to usual air insufflation in sedated patients examined by an experienced colonoscopist. With practice ITTCIR increased over time in both male and female patients. Larger volumes of water exchanged were associated with higher ITTCIR and better quality scores of bowel preparation. The data suggest that learning water exchange by a busy colonoscopist in a community practice setting is feasible and outcomes conform to accepted quality standards. PMID- 23805394 TI - Re-learning colonoscopy: just a matter of time. PMID- 23805395 TI - Interim report of a randomized cross-over study comparing clinical performance of novice trainee endoscopists using conventional air insufflation versus warm water infusion colonoscopy. AB - BACKGROUND: The applicability of water method colonoscopy in trainee education is not known. AIM: To compare the water method vs. usual air method in teaching novice trainee colonoscopy. METHOD: An IRB approved prospective randomized cross over study (NCT01482546) in a university setting with diverse patient population. DESIGN: Three first year GI fellows consented to participate in the study. Trainees were randomized to learn with either usual air method or the water method in performing colonoscopy with a dedicated endoscopy attending during their weekly outpatient endoscopy clinics for the initial six months of training and then cross-over to the other method for the remaining six months. PATIENTS: Patients undergoing screening, surveillance or diagnostic colonoscopy. RESULTS: The interim data revealed no significant difference in age, gender, and body mass index (BMI). Trainees rated the water method colonoscopy as significantly easier to learn compared to the air method (p=0.007). CONCLUSIONS: The interim data demonstrate positive effects of using the water method in training novice endoscopists who reported a significant ease of learning colonoscopy using this method. Training programs could consider joining us in evaluating the use of warm water infusion in colonoscopy education. PMID- 23805396 TI - Is colonoscopy best learned underwater? PMID- 23805397 TI - Magnetic endoscope imaging (ScopeGuide) elucidates the mechanism of action of the pain-alleviating impact of water exchange colonoscopy - attenuation of loop formation. AB - BACKGROUND: The explanation why water exchange colonoscopy produces a significant reduction of pain during colonoscopy is unknown. A recent editorial recommended use of magnetic endoscope imaging (MEI) to elucidate the explanation. OBJECTIVE: In unselected patients to show that MEI documents less frequent loop formation when water exchange is used. DESIGN: Observational, performance improvement. SETTING: Veterans Affairs outpatient endoscopy. PATIENTS: Routine colonoscopy cases. INTERVENTIONS: Colonoscopy using air or water exchange method was performed as previously described. The MEI equipment (ScopeGuide, Olympus) with built-in magnetic sensors displays the configuration of the colonoscope inside the patient. During sedated colonoscopy the endoscopist was blinded to the ScopeGuide images which were recorded and subsequently reviewed. MAIN OUTCOME MEASURES: Loop formation based on a visual guide provided by Olympus. RESULTS: There were 41 and 32 cases in the water exchange and air group, respectively. The sigmoid N loop was most common, followed by the sigmoid alpha loop, and exaggeration of scope curvature at the splenic flexure/transverse colon. Of these, 20/32 vs. 9/41 patients (p=0.0007) had sigmoid looping, and 17/32 vs. 9/41 patients (p=0.0007) had sigmoid/splenic looping when the scope tip was in the transverse colon, in the air and water exchange group, respectively. LIMITATIONS: Colonoscopy method was not blinded and non randomized. CONCLUSION: MEI data objectively demonstrated significantly fewer loops during water exchange colonoscopy, elucidating its mechanism of pain alleviation - attenuation of loop formation. Since MEI feedback enhances cecal intubation by trainees, the role of MEI combined water exchange in speeding up trainee learning curves deserves further evaluations. PMID- 23805399 TI - In this issue of Adipocyte. PMID- 23805398 TI - Review of Gardasil. AB - Human papillomavirus (HPV) is necessary for the development of cervical cancer. Cervical cancer is the second most common cancer in women worldwide but 80% occurs in developing countries, not countries with Pap screening programs. Pap screening programs in industrialized countries have reduced the incidence of cervical cancer to 4-8/100,000 women. HPV vaccines may be a promising strategy for cervical cancer in women without access to screening programs. In industrialized countries, the benefit of HPV vaccines focuses on individual abnormal Pap test reduction not cancer prevention. The focus of this review is to cover the side effects of Gardasil in perspective with the limited population benefit cervical cancer reduction in countries with organized Pap screening programs. In addition, information about Gardasil benefits, risks and unknowns for individual patient decision making for vaccination is presented. Gardasil offers protection against CIN 2+ lesions caused by HPV 16/18 and against genital warts caused by HPV 6/11 for at least 5 years. Combining Gardasil with repeated cytology screenings may reduce the proportion of abnormal cytology screens and hence reduce the associated morbidity with the subsequent colposcopies and excisional procedures. PMID- 23805400 TI - The TLR family protein RP105/MD-1 complex: A new player in obesity and adipose tissue inflammation. AB - The radioprotective 105 (RP105)/MD-1 complex is a member of the Toll-like receptor (TLR) family of proteins. We have previously reported that this complex cooperates with the essential lipopolysaccharide (LPS) receptor TLR4/MD-2 complex and plays a crucial role in LPS responses by B cells. Recent evidences suggest that TLRs can also recognize endogenous ligands and promote non-infectious chronic inflammation. For instance, TLR4/MD-2 can be ligated by adipose tissue derived saturated free fatty acids (FAs) and induce adipose tissue inflammation and insulin resistance. Recently, we reported that RP105 knockout (KO) or MD-1 KO mice have less high-fat diet (HFD)-induced obesity, adipose tissue inflammation and insulin resistance than wild-type (WT) or TLR4 KO mice. As RP105/MD-1 is not involved in recognition of palmitic and stearic acids, which are endogenous ligands for TLR4/MD-2, we conclude that RP105/MD-1 is itself a key regulator of diet-induced chronic inflammation in adipose tissue, obesity and insulin resistance that appears to be independent of the TLR4-dependent pathway. In this mini-review, we will highlight the significance of the RP105/MD-1 complex in adipose tissue inflammation and discuss implications for human diseases. PMID- 23805401 TI - A three-party alliance in solid tumors: Adipocytes, macrophages and vascular endothelial cells. AB - In tumors, cross talk between malignant and non-malignant cells (stroma) influences tumor growth, angiogenesis and metastasis. Stromal cells in tumors typically include vascular cells, fibroblasts and a heterogeneous population of inflammatory cells. Adipocytes may also be present. Adipose tissue is perhaps the least studied stromal cell "compartment" despite the fact that some tumors, particularly breast tumors, grow in close proximity to or physically interact with adipocytes. Apart from adipocytes and numerous blood vessels, adipose tissue harbors macrophages, which increase in proportion to adipose tissue mass. While circulating or bone marrow-derived macrophages play a well-defined role in tumor growth, it is less understood how resident adipose tissue-associated macrophages contribute to tumor progression. Here, we will review the role of adipose tissue in tumor growth and angiogenesis with emphasis on the specific functions of adipose tissue macrophages in these processes. PMID- 23805402 TI - Metabolic impact of sex chromosomes. AB - Obesity and associated metabolic diseases are sexually dimorphic. To provide better diagnosis and treatment for both sexes, it is of interest to identify the factors that underlie male/female differences in obesity. Traditionally, sexual dimorphism has been attributed to effects of gonadal hormones, which influence numerous metabolic processes. However, the XX/XY sex chromosome complement is an additional factor that may play a role. Recent data using the four core genotypes mouse model have revealed that sex chromosome complement-independently from gonadal sex-plays a role in adiposity, feeding behavior, fatty liver and glucose homeostasis. Potential mechanisms for the effects of sex chromosome complement include differential gene dosage from X chromosome genes that escape inactivation, and distinct genomic imprints on X chromosomes inherited from maternal or paternal parents. Here we review recent data in mice and humans concerning the potential impact of sex chromosome complement on obesity and metabolic disease. PMID- 23805403 TI - Perilipin 1 moves between the fat droplet and the endoplasmic reticulum. AB - Perilipin 1, unlike the other perilipins, is thought to be restricted to the fat droplet. We reassessed its cellular distribution using the fat droplet marker CGI 58 in OP9 and 3T3-L1 adipocyte lines and in brown adipose tissue (BAT). As expected, we found perilipin 1 in the fat droplet-enriched floating fraction from centrifuged adipocyte or BAT homogenates. However, about half of perilipin 1 was suspended in the cytosol/infranate or pelleted with cellular membranes. In these fractionations, most of the fat droplet-associated protein CGI-58 was in the floating fraction. In BAT and OP9 adipocytes about a third of perilipin 1 pellets, compared with a much smaller fraction of CGI-58. Co-imaging perilipin 1 and smooth endoplasmic reticulum (ER) markers reveals both ER and fat droplet associated perilipin 1 in OP9 adipocytes. Consistent with these observations, perilipin 1 overexpressed in COS7 cells mostly fractionates with cellular membranes and imaging shows it on the ER. In 3T3-L1 adipocytes almost half of perilipin 1 floats, half is suspended as infranate and small amounts pellet. Finally, driving rapid fat droplet synthesis in OP9 adipocytes increases the intensity of perilipin 1 on fat droplets, while decreasing non-fat droplet immunolabeling. Confirming the morphological findings, fractionation shows perilipin 1 moving from the pelleted to the floated fractions. In conclusion, this study documents an expanded intracellular distribution for perilipin 1 and its movement from ER to fat droplet during lipid synthesis. PMID- 23805404 TI - Adipose-derived stem cell fate is predicted by cellular mechanical properties. AB - Adipose-derived stem cells (ASCs) show great promise for tissue engineering applications and cell-based therapies because of their multipotency, relative abundance and immunosuppressive properties. However, ASCs must be isolated from heterogeneous cell populations present in adipose tissue. In this brief report, we provide a concise summary of the history and use of cellular mechanical properties as novel, label-free biomarkers to predict the differentiation potential of ASCs toward adipogenic, osteogenic and chondrogenic lineages. Additionally, we have found that passage number influences the mechanical properties of ASCs along with a discussion of potential environmental factors that could affect these properties. Altogether, this report provides evidence for the reliability of cellular mechanical properties as biomarkers for ASC differentiation potential and outlines how they can be used to sort ASCs with lineage-specific preferences for particular applications. PMID- 23805405 TI - Increasing muscle mass to improve metabolism. AB - Skeletal muscle insulin resistance is a predictor of the development of type 2 diabetes and maintenance of adequate muscle glucose disposal in muscle may help to prevent diabetes. Lipodystrophy is a type of diabetes caused by a reduction of white adipose tissue and the adipokine leptin. Lipidemia, insulin resistance and hyperphagia develop as a consequence. In a recent study, we showed that increasing skeletal muscle mass by inhibiting signaling of myostatin, a transforming growth factor beta (TGFbeta) family member that negatively regulates muscle growth, prevents the development of diabetes in a mouse model of lipodystrophy. Muscle-specific myostatin inhibition also prevented hyperphagia suggesting muscle may regulate food intake. Here we discuss these results in the context of strategies to increase muscle insulin sensitivity as well as new findings about the effects of myostatin and other TGFbeta family members on similar metabolic processes. PMID- 23805406 TI - CCR5: A novel player in the adipose tissue inflammation and insulin resistance? AB - Adipose tissue macrophage (ATM) accumulation through C-C motif chemokine receptor 2 (CCR2) and its ligand monocyte chemoattractant protein-1 (MCP-1) is considered pivotal in the development of insulin resistance. However, our new study has demonstrated that CCR5, a different CC chemokine receptor, plays an important role in the ATM recruitment and activation and subsequent development of insulin resistance (see the recent article in Diabetes). Although recent human studies have shown upregulation of the expression of not only MCP-1-CCR2 but also other CC chemokines and their receptors in the visceral fat of obese individuals, it is not known if CCR5 is involved in ATM recruitment and insulin resistance. This article has shown several new important observations. First, expression of CCR5 and its ligands is significantly increased and is equal to that of CCR2 and its ligands in the white adipose tissue (WAT) of obese mice, particularly in the macrophage fraction. Second, fluorescence-activated cell sorter analysis clearly demonstrates a robust increase in accumulation of CCR5(+) ATMs in response to a high fat (HF) diet. Third, and most important, two distinct models, both Ccr5 (-/ ) mice and chimeric mice lacking CCR5 only in myeloid cells, are protected from insulin resistance and diabetes through reduction in ATM accumulation. Finally, it is interesting that an alternatively activated, M2-dominant shift in ATM is induced in obese Ccr5 (-/-) mice. Taken together, these data indicate that CCR5 is a novel link between obesity, adipose tissue inflammation, and insulin resistance. PMID- 23805407 TI - Heart hormones fueling a fire in fat. AB - Our view of how adipose tissue metabolism is regulated recently experienced a change in focus and breadth, meaning that some of the key controlling factors were not fully in the picture. The catecholamines of the sympathetic nervous system are well-known activators of beta-adrenergic receptors in adipocytes to increase lipolysis. They also drive energy expenditure in brown adipose tissue and, importantly, the "browning" of cells in white adipose depots. However, this is clearly not the whole story. In earlier work, we established a pathway from beta-adrenergic receptors to p38 MAP kinase to drive the transcription of brown adipocyte genes and respiratory uncoupling. Now we recently discovered that cardiac natriuretic peptides (NPs) stimulate a similar "browning" of human and mouse adipocytes. NPs activate the guanylyl cyclase coupled NP receptor A and activation of protein kinase G. Importantly, this pathway also depends upon p38 MAPK. These two pathways work together, additively increasing expression of brown adipocyte marker genes, as well as reflexively controlling each other's components. We discuss these findings and how the control of body fat by these cardiac hormones, in conjunction with the sympathetic nervous system, has implications for obesity as well as cardiovascular disease, including hypertension and heart failure. PMID- 23805408 TI - New insights into adipose tissue VEGF-A actions in the control of obesity and insulin resistance. AB - Vascular endothelial growth factor A (VEGF-A) is classically viewed as a key factor in angiogenesis and tissue remodeling. However, recent evidence suggests a potential role of this growth factor in the control of energy metabolism and adipose tissue function. In this regard, we and others have described the effects of the up and downregulation of VEGF-A in adipose tissue on the control of energy homeostasis. VEGF-A overexpression protects against diet-induced obesity and insulin resistance. The observation that VEGF-A overexpression leads to an increase in brown adipose tissue (BAT) thermogenesis and also promotes a "BAT like" phenotype in white adipose tissue depots is of particular relevance for the understanding of the mechanisms underlying obesity development. In addition, VEGF A may not only have pro-inflammatory but also anti-inflammatory properties, with a chemotactic activity specific for M2 anti-inflammatory macrophages. This new scientific evidence highlights the importance that VEGF-A actions on metabolism could have on the design of new treatments for obesity, insulin resistance and obesity-related disorders. PMID- 23805409 TI - Sirtuin-1 is a nutrient-dependent modulator of inflammation. AB - Inflammation accompanies obesity and its comorbidities-type 2 diabetes, non alcoholic fatty liver disease and atherosclerosis, among others-and may contribute to their pathogenesis. Yet the cellular machinery that links nutrient sensing to inflammation remains incompletely characterized. The protein deacetylase sirtuin-1 (SirT1) is activated by energy depletion and plays a critical role in the mammalian response to fasting. More recently it has been implicated in the repression of inflammation. SirT1 mRNA and protein expression are suppressed in obese rodent and human white adipose tissue, while experimental reduction of SirT1 in adipocytes and macrophages causes low-grade inflammation that mimics that observed in obesity. Thus suppression of SirT1 during overnutrition may be critical to the development of obesity-associated inflammation. This effect is attributable to multiple actions of SirT1, including direct deacetylation of NFkappaB and chromatin remodeling at inflammatory gene promoters. In this work, we report that SirT1 is also suppressed by diet-induced obesity in macrophages, which are key contributors to the ontogeny of metabolic inflammation. Thus, SirT1 may be a common mechanism by which cells sense nutrient status and modulate inflammatory signaling networks in accordance with organismal energy availability. PMID- 23805410 TI - Hippocampal cellular loss after brief hypotension. AB - Brief episodes of hypotension have been shown to cause acute brain damage in animal models. We used a rat hemorrhagic shock model to assess functional outcome and to measure the relative neuronal damage at 1, 4 and 14 days post-injury (3 min of hypotension). All rats underwent a neurological assessment including motor abilities, sensory system evaluation and retrograde memory at post-hypotensive insult. Brains were harvested and stained for Fluorojade C and Nissl. Stereology was used to analyze Fluorojade C and Nissl stained brain sections to quantitatively detect neuronal damage after the hypotensive insult. Statistical analysis was performed using Graphpad Prism 5 with the Bonferroni test at a 95% confidence interval after ANOVA. A Mixed Effect Model was used for the passive avoidance evaluation. Stereologically counted fluorojade positive cells in the hippocampus revealed significant differences in neuronal cell injury between control rats and rats that received 3 min of hypotension one day after insult. Quantification of Nissl positive neuronal cells showed a significant decrease in the number hippocampal cells at day 14. No changes in frontal cortical cells were evident at any time, no significative changes in neurological assessments as well. Our observations show that brief periods of hemorrhage-induced hypotension actually result in neuronal cell damage in Sprague-Dawley rats even if the extent of neuronal damage that was incurred was not significant enough to cause changes in motor or sensory behavior. PMID- 23805411 TI - Elevation of plasma basic fibroblast growth factor after nocturnal hypoxic events in patients with obstructive sleep apnea syndrome. AB - Obstructive sleep apnea syndrome (OSAS) is associated with recurrent nocturnal hypoxia during sleep; this hypoxia has been implicated in the pathogenesis of cardiovascular complication. However, a useful soluble factor that is sensitively correlated with OSAS severity for the diagnosis remains unidentified. We hypothesized that systemic levels of basic fibroblast growth factor (bFGF), a hypoxia-induced cytokine, were affected by nocturnal hypoxemia in OSAS patients, and we assessed whether the degree of change in the plasma bFGF concentrations before and after nocturnal hypoxia is correlated with the severity of OSAS. Thirty subjects who had suspected OSAS and had been investigated by nocturnal polysomnography (PSG) were enrolled. Plasma bFGF and vascular endothelial growth factor (VEGF) concentrations the night before PSG and the next morning were measured by sandwich enzyme-linked immunosorbent assay. Correlations between the changes in these factors and hypoxia-associated parameters for OSAS severity were analyzed. Patients with OSAS had significantly elevated levels of plasma bFGF but not VEGF and hemoglobin after rising. The degree of change in bFGF concentrations after nocturnal apnea episodes was significantly correlated with diagnostic parameters for OSAS severity. The change in plasma bFGF levels is associated with the degree of hypoxic state in OSAS patients, implying that bFGF might be a useful soluble factor for evaluating OSAS severity. PMID- 23805412 TI - Nutrition research in the first decade of 21(st) century in Iran: the necessity of road Map. AB - Due to important role of nutrition research in understanding of relevant health subjects and lack of periodic situation analysis of nutrition articles in Iran, this study was conducted to assess nutrition publications in two time intervals of 2001-2005 and 2006-2010 in Farsi scientific journals. A title to title search was performed in all medical, basic science, agricultural and veterinary journals in a 10-year period. All the article titles were placed in techniques, foods, nutritional biochemistry and physiology, nutrition and health, and clinical nutrition subject headings based on Nutrition Abstracts and Reviews Series A (NARA) database. The publication type and the study design were also determined. Statistical analysis was carried out by chi square to test temporal changes. There were 2127 Farsi publications. The original articles consisted 98.1% of the articles. Interventional and survey articles composed 28.1% and 20.8% of the publication types, respectively. Researchers were mostly interested in descriptive articles. Regarding subject, nutrition and health, and clinical nutrition were of the first and second time period interests, respectively. In comparison between the two time periods, regarding subject heading, the proportion of nutrition and health publications showed a significant decline; while, the proportion of clinical nutrition publication showed a remarkable rise. The publication type, subject and study design of the article do not follow coordinated planning and policy making. Therefore, these researches are not efficient enough to solve nutritional problems in our community properly. Planning of the research priorities in the field of food and nutrition with the agreement and participation of all stakeholders is a necessity. PMID- 23805413 TI - Notch Signaling is Associated with ALDH Activity and an Aggressive Metastatic Phenotype in Murine Osteosarcoma Cells. AB - Osteosarcoma (OS) is the most common primary malignancy of bone, and pulmonary metastatic disease accounts for nearly all mortality. However, little is known about the biochemical signaling alterations that drive the progression of metastatic disease. Two murine OS cell populations, K7M2 and K12, are clonally related but differ significantly in their metastatic phenotypes and therefore represent excellent tools for studying metastatic OS molecular biology. K7M2 cells are highly metastatic, whereas K12 cells display limited metastatic potential. Here we report that the expression of Notch genes (Notch1, 2, 4) are up-regulated, including downstream targets Hes1 and Stat3, in the highly metastatic K7M2 cells compared to the less metastatic K12 cells, indicating that the Notch signaling pathway is more active in K7M2 cells. We have previously described that K7M2 cells exhibit higher levels of aldehyde dehydrogenase (ALDH) activity. Here we report that K7M2 cell ALDH activity is reduced with Notch inhibition, suggesting that ALDH activity may be regulated in part by the Notch pathway. Notch signaling is also associated with increased resistance to oxidative stress, migration, invasion, and VEGF expression in vitro. However, Notch inhibition did not significantly alter K7M2 cell proliferation. In conclusion, we provide evidence that Notch signaling is associated with ALDH activity and increased metastatic behavior in OS cells. Both Notch and ALDH are putative molecular targets for the treatment and prevention of OS metastasis. PMID- 23805414 TI - Immunosuppressive microenvironment in neuroblastoma. AB - According to the cancer immunoediting model, the interplay between tumor cells and the host immune system is crucial for the control of tumor growth. NB is a pediatric tumor that presents with metastatic disease at diagnosis in about 50% of the cases, the majority of which have poor prognosis. In this Review article, immune escape pathways adopted by human neuroblastoma (NB) cells are reviewed. These include intrinsic defects of tumor cells such impaired expression of the HLA class I related antigen processing machinery and functional alterations of the tumor microenvironment (TM) induced by NB cell-derived immunosuppressive molecules as MICA and HLA-G. Finally, examples of therapeutic interventions targeting the TM are discussed to emphasize the concept that successful cancer treatment may be achieved using this strategy. PMID- 23805416 TI - Re: podiatric "physicians and surgeons". PMID- 23805417 TI - Thoughts on the orthopedic guidelines and joint replacement registry. PMID- 23805418 TI - Patient education is key in sports medicine. PMID- 23805419 TI - Effect of anterior versus posterior in situ decompression on ulnar nerve subluxation. AB - We sought to determine the effect anterior versus posterior in situ decompression with 360 degrees external neurolysis on ulnar nerve subluxation. Ten cadaveric specimens were used, with anterior release performed on 5 specimens and posterior release the other 5 specimens. Each specimen was released for 4 cm centered over the cubital tunnel followed by 12 cm, 20 cm, and 20 cm with 360 degrees external neurolysis. After release, the elbow was brought through a range of motion from 0 degrees to 140 degrees of flexion. Compared with posterior release, anterior release demonstrated significantly more total subluxation of the ulnar nerve for all release types from 80 degrees to 120 degrees of flexion (P<.05). At 140 degrees of flexion, the 4-cm release, the 12-cm release, and the 20-cm release with 360 degrees external neurolysis also demonstrated significantly more total subluxation with anterior release (P<.05). Ulnar nerve subluxation was significantly lower with posterior release, compared with anterior release for limited and complete in situ decompression. PMID- 23805420 TI - Deep vein thrombosis and pulmonary embolism after spine surgery: incidence and patient risk factors. AB - Anticoagulation after spine surgery confers the unique risk of epidural hematoma. We sought to determine the incidence of and patient risk factors for deep vein thrombosis (DVT) and pulmonary embolism (PE) after spine surgery. We retrospectively reviewed the charts of 1485 patients who had spine surgery at a single tertiary-care center between 2002 and 2009. DVT and PE incidence were recorded along with pertinent patient history information. Univariate and multivariate analyses were performed on the data. VTE incidence was 1.1% (DVTs, 0.7%; PEs, 0.4%). Univariate analysis demonstrated that VTEs had 9 positive risk factors: active malignancy, prior DVT or PE, estrogen replacement therapy, discharge to a rehabilitation facility, hypertension, major depressive disorder, renal disease, congestive heart failure, and benign prostatic hyperplasia (P<.05). Multivariate analysis demonstrated 4 independent risk factors: prior DVT or PE, estrogen replacement therapy, discharge to a rehabilitation facility, and major depressive disorder (P>.05). Surgeons with an improved understanding of VTE after spine surgery can balance the risks and benefits of postoperative anticoagulation. PMID- 23805415 TI - Prospects for circumventing aminoglycoside kinase mediated antibiotic resistance. AB - Aminoglycosides are a class of antibiotics with a broad spectrum of antimicrobial activity. Unfortunately, resistance in clinical isolates is pervasive, rendering many aminoglycosides ineffective. The most widely disseminated means of resistance to this class of antibiotics is inactivation of the drug by aminoglycoside-modifying enzymes (AMEs). There are two principal strategies to overcoming the effects of AMEs. The first approach involves the design of novel aminoglycosides that can evade modification. Although this strategy has yielded a number of superior aminoglycoside variants, their efficacy cannot be sustained in the long term. The second approach entails the development of molecules that interfere with the mechanism of AMEs such that the activity of aminoglycosides is preserved. Although such a molecule has yet to enter clinical development, the search for AME inhibitors has been greatly facilitated by the wealth of structural information amassed in recent years. In particular, aminoglycoside phosphotransferases or kinases (APHs) have been studied extensively and crystal structures of a number of APHs with diverse regiospecificity and substrate specificity have been elucidated. In this review, we present a comprehensive overview of the available APH structures and recent progress in APH inhibitor development, with a focus on the structure-guided strategies. PMID- 23805421 TI - Nonfatal air embolism during shoulder arthroscopy. AB - An air embolism is a rare but potentially fatal complication of shoulder arthroscopy. In this article, we report the case of a patient who developed a nonfatal air embolism during shoulder arthroscopy for an acute bony Bankart lesion and a greater tuberosity avulsion fracture. The venous air embolism occurred immediately after the joint was insufflated with air for diagnostic air arthroscopy. The diagnosis was based on a drop in end-tidal carbon dioxide and blood pressure and presence of mill wheel (waterwheel) murmur over the right heart. Supportive treatment was initiated immediately. The patient recovered fully and had no further complications of air embolism. This patient's case emphasizes the importance of being aware that air embolisms can occur during shoulder arthroscopy performed for acute intra-articular fractures of the shoulder. Monitoring end tidal carbon dioxide can be very useful in early detection of air embolisms. PMID- 23805422 TI - Isolated sciatic nerve entrapment by ectopic bone after femoral head fracture dislocation. AB - Although posttraumatic pelvic heterotopic ossification (HO) after hip fracture dislocation is well established, and nerve encasement by HO may occur, the development of neurologic deficit is rare. A thorough history and adequate clinical suspicion are imperative in the workup of affected patients. Computed tomography and magnetic resonance imaging provide good visualization and assist in surgical planning. If symptoms persist and are recalcitrant to conservative management, surgical intervention with HO excision and nerve neurolysis can be performed with success. PMID- 23805423 TI - Open repair of retracted latissimus dorsi tendon avulsion. AB - Latissimus dorsi avulsion injuries are rarely reported in the literature and are managed with a variety of strategies. Primary anatomical repair of tendon to bone may offer athletes the best chance for successful return to sports. In this article, we describe a surgical technique for safely repairing an acute or chronic, retracted, avulsed latissimus tendon back to its insertion on the medial aspect of the bicipital groove of the proximal humerus. Using 1 low anterior axillary incision and 1 posterior axillary incision for tendon retrieval when retraction is more than 5 cm, this technique allows for direct anatomical repair of a retracted tendon to bone using 3 points of bony fixation supplemented by soft-tissue repair. The technique also minimizes the risks for neurovascular compromise and cosmetic deformity, while decreasing the risk for postinjury strength deficits. PMID- 23805424 TI - Wound hematoma after anterior cervical spine surgery: in vitro study of the pathophysiology of airway obstruction. AB - Airway obstruction by wound hematoma is a serious adverse event associated with anterior cervical spine surgery. Although intrinsic airway edema is the most plausible pathophysiologic mechanism of obstruction, we hypothesized that extrinsic compression of the trachea by a hematoma can result in airway occlusion at an angle to the sagittal plane. A silicone indenter and a servohydraulic test frame were used to apply pressure to the ventral neck of 7 human cadaveric specimens. Increasing pressure was applied in the anteroposterior (AP) and oblique planes until the trachea collapsed, as visualized with fluoroscopy. A paired t test was used to determine any statistically significant differences in maximum pressure or indenter displacement at tracheal occlusion between the 2 test modes. Mean (SD) pressure required to cause complete tracheal collapse was 227.9 (54.8) mm Hg in the AP test mode and 135.6 (73.4) mm Hg in the oblique test mode. The difference was statistically significant (P = .004). Indenter displacement was significantly higher in the AP mode than in the oblique mode (P = .031). The trachea can collapse from external force within a physiologic pressure range when pressure is applied in an oblique orientation. The mass effect of a wound hematoma appears to be a viable mechanism of airway occlusion. PMID- 23805425 TI - National Football League athletes' return to play after surgical reattachment of complete proximal hamstring ruptures. AB - Although hamstring strains are common among professional football players, proximal tendon avulsions are relatively rare. Surgical repair is recommended, but there is no evidence on professional football players return to play (RTP). We hypothesized that surgical reattachment of complete proximal hamstring ruptures in these athletes would enable successful RTP. Ten proximal hamstring avulsions were identified in 10 National Football League (NFL) players between 1990 and 2008. Participating team physicians retrospectively reviewed each player's training room and clinical records, operative notes, and imaging studies. The ruptures were identified and confirmed with magnetic resonance imaging. Of the 10 injuries, 9 had palpable defects. Each of the ruptures was managed with surgical fixation within 10 days of injury. All of the players reported full return of strength and attempted to resume play at the beginning of the following season, with 9 of the 10 actually returning to play. However, despite having no limitations related to the surgical repair, only 5 of the 10 athletes played in more than 1 game. Most NFL players who undergo acute surgical repair of complete proximal hamstring ruptures are able to RTP, but results are mixed regarding long-term participation. This finding may indicate that this injury is a marker for elite-level physical deterioration. PMID- 23805426 TI - Reply by authors. PMID- 23805427 TI - The write way. PMID- 23805428 TI - The central answer. Interview by Kristie Nybo. PMID- 23805429 TI - Primer design. PMID- 23805430 TI - Testing on animals. Editorial. PMID- 23805431 TI - EU: final ban on animal experiments for cosmetic ingredients implemented. PMID- 23805432 TI - ESC Congress 2012, Munchen, Germany, 25-29 August 2012. Abstracts. PMID- 23805441 TI - Additional techniques for diagnosing scabies. In reply. PMID- 23805442 TI - A sprouting business: farmers' markets can help local producers while giving low income communities more healthy food choices. PMID- 23805443 TI - Compounding interest: a tragedy caused by contaminated steroids turned the spotlight on compounding pharmacies. PMID- 23805444 TI - Bridging the health divide: community health workers are helping eliminate costly health inequalities. PMID- 23805445 TI - [Evolving views on the classification of stomach cancer]. PMID- 23805446 TI - [X-ray and emission-computed tomography in the diagnosis of lung cancer]. PMID- 23805447 TI - [Gene expression analysis and its clinical use in breast tumors]. PMID- 23805448 TI - [Morbidity, mortality and analysis of the effectiveness of the organization of oncology care for patients with esophageal cancer]. PMID- 23805449 TI - [Risk of malignant neoplasms in personnel of radio-hazardous industries (for example, at the Siberian Chemical Plant)]. PMID- 23805450 TI - [The role of spiral computed tomography in planning the surgical interventions for non-organ retroperitoneal tumors]. AB - The surgical operation is a principal and in most cases a solitary treatment for non-organ retroperitoneal tumors. High risk of recurrence, aptitude to large local extension dictates necessity of individual surgical plan. An equality of approach is excluded. Pre-operative specified diagnostics of tumor extension is extremely important. We present an experience of determination of such characteristics of non-organ retroperitoneal tumors, which influence the extent of surgery (multiple lesions, invasion of adjacent vessels and organs). PMID- 23805451 TI - [Combined use of 99mTc-MIBI scintigraphy and ultrasonography (US) in the diagnosis of axillary lymphatic metastasis in patients with breast cancer]. AB - We aimed to evaluate different imaging strategies for diagnosis of axillary LNMs in patients with primary breast cancer (BC). 168 consecutive patients with primary BC were included in the study. Functional imaging by scintigraphy (AxSc) with 99mTc-MIBI was performed in static and tomography modes 15 min after i/v injection. Focal areas of tracer accumulation in axial region were considered as sings of LNMs. Ultrasound (US) examination of axillary region was performed on 7.5 kH scanner. Nodes with diameter more than 1 cm were considered abnormal. All patients were operated with axial LN dissection and subsequent histological evaluation. Scintigraphic signs of LNMs revealed in 65 patients: 48--true positive, 17--false positive. Among 103 women with normal AxSc results 27 had LNMs and 76--uninvolved nodes. Sensitivity (Sen), Specificity (Sp) and Accuracy (Ac) of AxSc were as follows: 64%, 82% and 74%. Sonography diagnosed LNMs in 74 women: 56 were metastatic on histology while other 18--uninvolved. On the contrary, 19 of 94 US normal sized nodes were metastatic on histology. US had following values when used for diagnosis of axillary LNMs: Sen--75%, Sp--81%, Ac- 78%. When LNMs were diagnosed as the combination of concordantly abnormal US and AxSc examinations Sp reached 95%, Sen dropped down to 56% and Ac--to 77%. Another model was based on the assumption that LNMs must be diagnosed in all patients with abnormal US or AxSc examinations. According to this strategy Sen reached 83%, Sp--68% and Ac--74%. Thus, we found comparative accuracy of US and AxSc in diagnosis of axillary LNMs in patients with primary BC. Combination of both modalities can significantly improve sensitivity (83%) or specificity (95%) of final conclusion which is determined by established diagnostic strategy and criteria's that are used for BC diagnosis. PMID- 23805452 TI - [Diagnostic accuracy of mammography and mammoscintigraphy in multifocal breast cancer]. AB - The aim of the study was to compare accuracy of conventional mammography and mammoscintigraphy with the 99mTc-Technetril in the detection of multicentric (MC) breast cancer. A total of 135 women (mean age 52 years) with unilateral simple breast lesions at clinical examination underwent preoperative mammography and mammoscintigraphy. Data of diagnostic procedure were compared with histopathologic analysis in all cases. The present of MC breast cancer was proven in 11 of 135 cases (8%). Mammography detected only one of 11 multicentric cases, while mammoscintigraphy-9 of 11 cases. Mammography showed a 9.1% and 93.5% sensitivity and specificity rates for the detection of multicentric breast cancer, respectively. The overall sensitivity and specificity rates for the detection of the form were 81.8% and 91.1% for mammoscintigraphy, respectively. Confirmation of the distinction between two methods has been attained by Bayesian probability calculation. Mammoscintigraphy proved a more highly sensitive diagnostic method than mammography in the detection and preoperative assessment of MC breast cancer and may contribute to changing surgical management in some cases. PMID- 23805453 TI - [Antibodies against phospholipids in patients with normal pregnancy]. AB - We investigated the serum levels of IgG and IgM anticardiolipin (ACL), anti-beta 2-glycoprotein I (B2GPI), anti-phosphatidyl serine (PS), anti-prothrombin(PT), anti-annexin V (AnV) and anti-ethanolamine (Eth) antibodies using an ELISA method (Orgentec, Germany) in 16 females with normal pregnancy in the I, II and Ill trimester. We observed the following changes: 1. Elevation of the IgG u IgMACL, IgG PS, IgM Pr antibodies in the II and decreasing in the Ill trimester. 2. Decreasing of IgG u IgM B2GPI, IgG u IgM AnV, IgG Pr, IgG u IgM Eth antibodies in the II trimester, maintainante of the levels or more decreasing in the Ill trimester. 3. Increasing of lgM PS in the II and more increasing in the Ill trimester. All of these changes have no significant values (p > 0,05). In 10/16 we found extreme values of different antibodies, but all of them had normal delivery. PMID- 23805454 TI - [Gestational age of delivery in multiple gestation]. AB - OBJECTIVES: The aim of this research was to find out the average gestational age of delivery in multiple pregnancy and to compare the results with world trend. MATERIAL AND METHODS: Retrospective and prospective comparative analysis was used. The study covered 20 years from 1991 to 2011, included 71114 births, 1436 twins, 67 triplets and I quadruplets. RESULTS: The number of multiple pregnancies in 1991 was 64 and in 2011 was 118. The frequency of twins increased from 1.56% at the beginning of the observed period to 3.44% at the end of the period. The frequency of triplets went from 0.02% to 0.26%. We discovered that the number of twins increased more than twice and the number of triplets - 13 times. Average gestational age of delivery in twins was 35+5 w.g. and in triplets - 31 w.g. 1 min Apgar score in twins was 6.1 and 5-min Apgar score was 7.5. In triplets the results showed that 1-min Apgar score was 5.6 and the 5-min Apgar score was 7.0. At the beginning of the researched period in 1991, 62% of women had vaginal delivery and only 38% Ceasarean section. In 2011 the Ceasarean section was 84% and vaginal delivery only 16%. CONCLUSIONS: There is a significant increase in the frequency of multiple gestation, observed in twins as well as in triplets. The average gestational age of delivery is earlier compared to world tendencies. The received results of the newborns' health status in the early neonatal period are good. The predominance of Ceasarean section as a mode of delivery is similar to world trend. PMID- 23805455 TI - [Areas of risk for ureteral lesion during radical hysterectomy]. AB - INTRODUCTION: The close interrelations of the pelvic ureter with surrounding structures and organs are a prerequisite for complications during surgical interventions in the lesser pelvis. OBJECTIVE: Exploration and visualization of the areas of risk for lesion of pelvic ureter during minimally invasive radical hysterectomy. RESULTS: Based on our observations and the available literature, we identified the following areas and steps of the radical hysterectomy as risky: at the entrance in the lesser pelvis, upon ligation of the infundibulopelvic ligament; incision of the back leaf of broad ligament of the uterus; dissection of the pararectal space; ligation of the uterine artery; dissection of the fourth space and transection of the vesicouterine ligaments; transection of the sacrouterine ligaments; incision of the anterior vaginal wall. We registered one uretero-vaginal fistula in a total of 133 patients on the eighth postoperative day. The lesion was identified in area of the distal portion of ureter. CONCLUSION: Knowledge about the ureter location, its interrelations with surrounding structures, and its blood supply, combined with capable surgical techniques, would contribute to reduction of the incidence of complications. PMID- 23805456 TI - [Autofluorescence and endometriosis optical trap or new hope in dianosis of endometriosis?]. AB - Laparoscopic autofluorescence imaging of endometriosis is a new method to properly detect the disease. Autofluorescence in contrast to conventional white light laparoscopy enables us to visualize the entire extent of disease and to recognize extremely small or occult lesions. Autofluorescence imaging in fact reveals a world behind the world, a substantial new representation of endometriosis, which will have much impact on our future therapeutic strategies. PMID- 23805457 TI - [Frequency, severity and risk factors for bronchopulmonary dysplasia among very low birth weight premature infants admitted in the NICU of the University Obstetrics and Gynecology Hospital, Sofia]. AB - BACKGROUND: The progress in the perinatology improved the survival rate of the infants with extremely low birth weight and gestational age. Among the most immature of them the frequency of bronchopulmonary dysplasia (BPD) remains high.. The use of different diagnostic criteria for BPD makes comparing the results difficult. AIM: To evaluate the frequency of BPD by birth weight and gestational age according to the new diagnostic criteria, and to identify the risk factors for development the disease. METHODS: 563 very low birth weight infants (<1500 g) were admitted to NICU from 01.01.2008 to 30.06.2010. 485 survived more than 28 days and were included in this study. BPD was diagnosed if supplemental 02 for the first 28 days was necessary. 02-requirements at 36 gestational weeks (gw) determine the severity level. RESULTS: 26,8% from the infants were with supplemental 02 in the first 28 d of life, but only the half of them 13,6% were with 02 > 21% at 36 gw (the classical diagnostic criteria for BPD). 10,9% were with moderate BPD, 2,7% - with severe BPD. The frequency of BPD decreased progressively from almost 100% at 23 gw or birth weight < 600 g to single cases after the 31 gw and birth weight > 1200 g. Mild or moderate BPD was more likely if gestational age was > 27 gw. The need for ventilatory support increased from 1,5 (+2,8) days (no-BPD group) to 50,2 (+/-20,1) days (severe BPD), p<0.05. Significant postnatal risk factors for developing BPD were patent ductus arteriosus - diagnosed in 25,4%; pneumothorax - in 3% of the BPD infants, compared with 1,7% and 0,5% among the infants without BPD respectively, p<0. 05. Sepsis and pulmonary hemorrhage were found slightly more frequently in the BPD group too (p>0, 05). The use of antenatal steroids was found to be a protective factor - 45% of the BPD infants had received antenatal steroids compared with 55% of those without BPD (p=0.05). CONCLUSION: According to the new diagnostic criteria, the frequency of BPD was about 2 times higher compared to the classical definition. Main risk factors were found to be ELBW, ELGA; additional risk carried the need for prolonged ventilatory support, patent ductus arteriosus and air leak syndrome. PMID- 23805458 TI - [Problems and neonatal outcome of very low birth weight newborn infants after in vitro fertilization]. AB - The use of assisted reproduction technologies is undoubtedly successful in the treatment of sterility. However it sets up numerous of issues for the obstetricians and neonatologists. AIMS: To evaluate the incidence, the specific problems and the neonatal outcome of newborns with very low birth weight (VLBW) <1500 g born from pregnancies after in vitro fertilization (IVF). METHODS: The study enrolled all 563 VLBW infants admitted in the NICU of the "Maichin Dom" hospital from 01.01.2008 to 30.06.2010. 119 (21.1%) of them were conceived with assisted reproduction technology (IVF- group), and 444 (78.9%) were conceived naturally (control group). All infants were followed up till their discharge home or death. Poor outcome measures were in hospital neonatal death or morbidities with long term sequels: severe congenital malformations, bronchopulmonary dysplasia, severe brain injuries (intraventricular haemorrhages gr. Ill-IV periventricular leucomalacia), retinopathy of prematurity gr. Ill-V. RESULTS: There were no significant differences in terms of mean birth weight (BW) and gestational age (GA) between the groups (1170 g and 1173 g, 29,8 and 30,0 weeks of gestation respectively). Intrauterine growth retardation (BW of <10 percentile for GA) was observed in 42% in the IVF-group, versus 38.5% (NS) The frequency of the babies from multiple pregnancies was significantly higher in the IVF-group: 88.2% versus 27.5%, and the triplets were 48% versus only 0.9% in the control group. In the IVF-babies more active obstetric approach was carried out: caesarean section in 85% versus 57%, and completed antenatal corticosteroid course in 80% versus 41% in the control group. There were no significant differences of in hospital neonatal mortality rate - 14.3% in the IVF-group versus 14.9%; congenital malformations or severe morbidities at discharge - 22.7% versus 27.5%, discharged in good health - 63% versus 57.6%. CONCLUSIONS: The major problems of VLBW-newborns after IVF result from the higher incidence of multiple pregnancies with their corresponding risks. Nevertheless, strict pregnancy follow-up, more frequently use of antenatal steroids, cesarean delivery such as intensive neonatal resuscitation ensure a clinical outcome and prognosis which do not differ from the naturally conceived VLBW-newborns. PMID- 23805459 TI - [Intrahepatic cholestasis of pregnancy]. AB - The contemporary aspects of obstetric cholestasis including its etiology, pathogenesis, molecular basis, diagnosis, therapy and obstetric management are presented. The possible maternal and fetal complications are discussed too. PMID- 23805460 TI - [Clinical treatment in shorten cervix]. AB - Preterm birth (PrTB) remains a major cause of perinatal morbidity and mortality. This article reviews the various diagnostic methods (midtrimester Cervical Length measurement on Transvaginal ultrasonography, fFN) and interventions in the different patient groups and proposes some algorithms for management women with short cervix. PMID- 23805461 TI - [Newaspects of neonatal resuscitation guidelines and their practical application]. AB - In this article we discuss the changes in the guidelines for newborn resuscitation, 2010, the International Liaison Committee on Resuscitation and their practical application at national level. The Resuscitation algorithm is simplified, the assessment of the need for resuscitation and progression to the next stage are based on heart rate and respiration only, that makes it easy for routine use and staff training. Routine suctioning of airways is not more recommended, even if meconium stained amniotic fluid is available endotracheal aspiration remains controversial. The most important changes concern the use of oxygen - there are clear recommendations to start resuscitation with air in term and low oxygen concentrations in preterm infants, monitoring the SpO2, so that the targeted SpO2 values for the first minutes of life are not exceeded. Some other aspects of newborn resuscitation and their practical application on local basis are discussed too: delayed cord clamping, therapeutic hypothermia, staff training. Controversial remain questions concerning initial resuscitation of extremely low gestational age newborns, such as some ethical issues. PMID- 23805462 TI - [The role of adjuvant chemotherapy as a prognostic factor in patients with early stage of epithelian ovarian cancer (I - II stage)]. AB - The authors present and analyze the modem concepts of the role of adjuvant chemotherapy as a prognostic factor for patients with early epithelial ovarian cancer (st. I-II). They review, synthetize and summarize the information from studies and researches, published in the recent years, and concerning the subject. CONCLUSION: Adjuvant chemotherapy for early epithelial ovarian cancer improves overall survival of patients having tumors with grade 2 or 3, stagelC or grater and suboptimal surgical staging. PMID- 23805463 TI - [Vaginismus and our experience in treating this sexual problem]. AB - According to various statistics from 4.2 to 42% of women in reproductive age, complained of a mild or severe problems in sexual function. The study presents own data on treatment of vaginismus in 14 girls and young women aged 16 to 36 years who have turned from 2007 to 2012 to the Cabinet Children and adolescent gynaecology at the University Hospital "Maychin dom". A primary examination established a high and tenacious hymen in 7 (50%) patients. The patients demonstrated fear, but still allowed careful examination. At 3 girls (21.43%) a combined cause of complaints was found. They demonstrated fear of pain during coitus and reported bad memory of the first sexual attempts; they had high and tenacious hymen and were able to tolerate touching the vulva after much persusions. In 3 (21.43%) patients consequences of puritan education were registered. They did not allowed to touch the vulva despite the declaration that would allow such. In one patients (7.14%) a unstretchable vagina was found. She demonstrated dyspareunia (avoiding intercourse and having one failed marriage) but she tolerated penetration of her vagina of one phalanx. In all cases of vaginismus we performed educational lectures and artefitial defloration. PMID- 23805464 TI - [Case of atypical polypoid adenomyoma of the uterine cevix]. AB - Atypical polypoid adenomyoma (APA) is a rare benign polypoid tumor occuring in young reproductive age women. There are no specific clinical features of APA. Grossly the tumor presents as a small polypoid lession in the low uterin cavum segment and cervical canal, mimicring infiltative endocervical or endometrial carcinoma. Microscopicaly APA consists of irregular glands, as endometrial with mild cellular atypia and diffuse smooth-mussle stroma. We present a case of APA of the uterine cervix in a young woman in regard to the diagnostical and treatment obstacles usually accompaning this rare pathology. PMID- 23805465 TI - [Prognostic value of markers for proliferative activity and apoptotic regulation in laryngeal squamous cell carcinoma]. AB - Prognosis for patients with laryngeal squamous cell carcinoma depends on many factors, among which molecular biological markers receive ever increasing attention. The purpose of this study was to determine the prognostic value of the expression of the proteins p53 and bcl-2 and the proliferation markers Ki-67 and cyclin D1 in laryngeal squamous cell carcinoma. Biopsy specimens from 64 patients aged 34 to 77 years (mean age 56+1.2 years) with invasive laryngeal squamous cell carcinoma, who received combination therapy at the Medical Radiology Research Center, Russian Academy of Medical Sciences, were studied. The level of Ki-67 and the expression of cyclin D1, p53, and bcl-2 were compared with clinical and anatomic parameters (T stage, tumor grade, and the presence of regional metastases), using Student's t-test and fourfold table analysis (X2 or Fisher's exact test). Survival rates were analyzed by the Kaplan-Meier method; the significance of differences between survival curves was confirmed by Cox's F test. The value p0.05 was taken to be significant. Ki-67 is an important prognostic marker for the N status (p=0.03) and recurrence (p=0.04) and a marker for tumor grading (p<0.01). Cyclin D1 expression is associated with low overall and relapse-free survival rates (p=0.05 and 0.03, respectively). The prognostic marker for a recurrence is p53 (p=0.01) that is related to the N status at the trend level (p=0.08). The marker bcl-2 is associated with high overall survival (p=0.01) and N status at the trend level (p=0.08). PMID- 23805466 TI - [Ki-67 and matrix metalloproteinase-9 expression in the follicular cyst, keratocystic odontogenic tumor, and ameloblastoma]. AB - An immunohistochemical study using antibodies against Ki-67 protein was conducted, which characterized the proliferative activity of cells and matrix metalloproteinase-9 (MMP-9) in follicular cyst, variants of keratocystic odontogenic tumor (with a preponderance of hyperkeratosis and parakeratosis), and ameloblastoma. The marked proliferative activity of a parabasal cell layer (28.0+/-8.4%) was found in the keratocystic odontogenic tumor with a preponderance of parakeratosis; the proliferative activity of the peripheral layer of ameloblastoma cells was equal to 7.0+/-5.6%. The maximal matrix metalloproteinase-9 expression in the keratocystic odontogenic tumor with a predominance of hyperkeratosis was 1.1 +/-0.9 conventional units (CU) and that in the ameloblastoma was 1.9+/-1.3 CU versus 0.4+/-0.5 CU in the follicular cyst, keratocystic odontogenic tumor with a preponderance of hyperkeratosis. The values of Ki-67 and MMP-9 expression allow one to distinguish benign odontogenic cysts and tumors (follicular cyst and keratocystic odontogenic tumor with a predominance of hyperkeratosis) and odontogenic tumors characterized by an aggressive clinical course (keratocystic odontogenic tumor with a preponderance of parakeratosis and ameloblastoma). PMID- 23805467 TI - [On perinatal and infant mortality in the Arkhangelsk Region]. AB - Perinatal and infant mortality in the Arkhangelsk Region tends to decline. At the same time, the structure of perinatal mortality shows a significant increase in the proportion of congenital defects, among which multiple forms constitute a major portion. The most common causes of infant death are acute respiratory infections, congenital malformations, and sudden infant death syndrome. PMID- 23805468 TI - [Caspase-3 expression in the tissues of experimental melanoma and its metastases during matrix metalloproteinase-9 inhibition]. AB - The specific features of caspase-3 expression were studied in intact tissues and skin melanoma cells, by reducing the activity of matrix metalloproteinase-9 in vivo. Immunohistochemical examination revealed no significant changes in the expression of caspase-3 in the primary tumor cells. There were the greatest changes in the organs having metastastic melanomas (lung, liver, spleen) and significant differences between control and treatment groups (p<0.05), unlike cardiac and nephritic tissues where the similar distinctions were absent. PMID- 23805469 TI - Extraosseous osteosarcoma arising in recurrent ossifying fibromyxoid tumor of soft tissue: a case report. AB - We present a case of an osteosarcoma arising in ossifying fibromyxoid tumor. The patient was a 50-year-old man when an initial tumor was identified. It was a soft tissue mass in the left popliteal area, measuring 14x9 cm. The tumor was surgically removed. Histologically, the primary tumor had the appearance of a conventional ossifying fibromyxoid tumor, although there were cellular areas with pleomorphism and high mitotic rate. The neoplasm recurred 4 times over the next 8 years, involving underlying tissues, including skeletal muscle and bone. The recurrent lesions features areas of osteoid, which increased with each recurrence and in the fourth recurrence the tumor had an appearance of extraskeletal osteosarcoma lacking the ossifying fibromyxoid tumor. The tumor generalized that killed the patient with widespread metastatic disease. PMID- 23805470 TI - [Epithelioid hemangioendothelioma of the mediastinum]. AB - The paper describes a rare case of mediastinal epithelioid hemangioendothelioma characterized by a population of fusiform cells, metaplastic osteogenesis, and aggressive behavior. A 5.5x4-cm encapsulated mass was found in the anterior mediastinum of a 19-year-old female patient. A bone density tumor was sealed with lung tissue and it occluded the lumen of the left subclavian vein. Microscopically, the tumor was composed of foci of the so-called "blister cells" typical of epithelioid hemangioendothelioma, anastomosing chains of epithelioid cells in the microhyaline stroma, diffusely located bone trabeculae, and hemorrhagic stroma. Fusiform cells were present in considerable quantities. A moderate cellular and nuclear polymorphism occurred when mitotic figures were absent. Tumor cells expressed Flil, vimentin, CD31, and CD34. Multiple metastases were detected in the liver and lung. They had the similar morphology. PMID- 23805471 TI - [Histiocytic sarcoma of the stomach]. AB - The paper describes a case of gastric histiocytic sarcoma in a 70 year-old man, which was diagnosed from immunohistochemical examination of biopsy and surgical specimens. It gives the data available in the literature on the morphological features of this rare cancer and its diagnostic criteria. PMID- 23805472 TI - [Anti-glomerular basement membrane glomerulonephritis concurrent with membranous nephropathy]. AB - The paper describes a case of anti-glomerular basement membrane glomerulonephritis (anti-GBM GN) concurrent with membranous glomerulopathy (MGP) in a 25-year-old female patient. The diagnosis was established on the basis of clinical, laboratory, and pathomorphological data, including electron microscopic ones). The comprehensive analysis, including ultrastructural diagnosis, is shown to be important in identifying this rare combination of two nosological entities, anti-GBM GN and MGP, in the same patient. PMID- 23805473 TI - [Cytomegalovirus infection and pneumocystis pneumonia after coronary stenting and cardiac transplantation for acute myocardial infarction]. AB - The paper presents the clinical and anatomic data of combination treatment for acute myocardial infarction, by stenting the infarct-related artery, followed by cardiac transplantation, which have provided the optimal result of surgery and caused no severe rejection reaction. The immediate causes of death have been infectious complications (cytomegalovirus infection and pneumocystis pneumonia) developing in the presence of immunodeficiency state. The following diagnosis formulation is pathogenetically warranted: the underlying disease is "Secondary immunodeficiency due to immunosuppressive therapy" and infectious complications may be assigned to the individual rubric "Secondary disease" (i.e. occurring in immunodeficiency). PMID- 23805474 TI - [Algorithm for the differential diagnosis of precancerous and regenerative changes in the cervix uteri]. AB - Pretumoral changes in the epithelium of the cervix uteri include cervical intraepithelial neoplasia (CIN). CIN III should be differentiated with regenerative changes during epidermization of endocervicoses. Epidermization is proliferation of undifferentiated reserve cells that differentiate towards the squamous epithelium, by superseding the ectopic endocervical glandular epithelium. This process was called immature squamous metaplasia (ISM). The objective of the investigation was to define the significance of different morphological signs in the differential diagnosis of CIN III and ISM. One hundred and twelve cervical, CIN III, and immature squamous metaplasia biopsies were selected for examination. The selected cervical specimens were divided into 2 groups according to the presence or absence of p16 and CK17 expression. The p16+, CK17- cases were taken as true CIN III and the pl 6-, CK17+ as a regenerative process. The basis for this investigation is the signs included by O.K. Khmelnitsky into an algorithm for the differential diagnosis of epidermizing pseudoerosion and intraepithelial cancer of the cervix uteri. The algorithm was reconsidered to objectify. The investigation established great differences in the number of significant mitoses in the study groups. A clear trend was found for differences in the number of acanthotic strands. A new differential diagnostic algorithm for CIN III and ISM, which included the number of significant mitoses and acanthotic strands and p16 and CK17 expression, was proposed. PMID- 23805475 TI - [A FISH analysis in one day. Experience in evaluating HER2 gene status by means of a new HER2 IQFISH pharmdx kit]. AB - Determination of the HER2 status of tumor cells in stomach and breast cancer is a routine diagnostic method. Immunohistochemical study is sufficient for its evaluation in most cases. However, a specifying molecular genetic study using the FISH technique is performed when borderline results are obtained. The paper describes the new procedure IQFISH that allows the results to be obtained in one working day. PMID- 23805476 TI - [Gene amplification and coamplification in breast cancer: frequency and prognosis value]. AB - Numerical impairments in genes or some genome sites - gene amplifications or deletions - are one of the most frequent genetic mutations occurring in breast cancer. Gene amplifications in breast cancer, their frequency, prognostic value, and the possible role of these disorders in the identification of the subtypes of this heterogeneous disease are considered. PMID- 23805477 TI - [The fate of professor Ivan Fedorovich Klein (on the occasion of the 175th anniversary of his birth)]. PMID- 23805478 TI - [Davydovsky is a founder of a clinical anatomical area of Russian medicine (on the occasion of the 125th anniversary of his birth)]. PMID- 23805479 TI - [Cerebral toxoplasmosis in the pattern of secondary CNS involvements in HIV infected patients in the Russian federation: clinical and diagnostic features]. AB - The incidence of cerebral toxoplasmosis (CT) among all brain involvements was determined in patients with Stage 4B HIV infection (AIDS) in 2003-2009. Clinical and laboratory parameters were estimated in 156 patients to reveal diagnostic criteria. As a result, CT was shown to be a leading cause of neurologic diseases in patients with late-stage HIV infection (34.7% of cases of brain involvement). In 11.5%, it took place as a generalized process. CT concurrent with cytomegalovirus infection, tuberculosis, or other secondary lesions was frequently diagnosed. Of importance in the diagnosis of CT are magnetic resonance imaging results in addition to basic, clinical data that can assume this diagnosis. The high and moderate serum concentrations of T.gondii IgG are of diagnostic value, which may be used as an auxiliary method to verify the diagnosis. PMID- 23805480 TI - [Use of immunological and molecular biological methods to diagnose cerebral toxoplasmosis in HIV infection]. AB - Cerebral toxoplasmosis is one of the leading causes of neurologic diseases with high mortality rates in patients with HIV infection. Invasion was difficult to diagnose for a number of objective reasons. The objective of the investigation was to determine the clinical sensitivity of different laboratory techniques as both a single study and their various combinations to verify the diagnosis of cerebral toxoplasmosis in HIV-infected patients. Blood and cerebrospinal fluid were tested in 51 patients with Stage 4B HIV infection (AIDS) with the verified diagnosis of cerebral toxoplasmosis. Separate determination of specific antibodies of IgG, IgM, IgA and toxoplasma DNA in the blood and cerebrospinal fluid was shown to have an insufficient clinical sensitivity (37.3-68.6%). The benefits of various combinations of immunological and molecular biological assays enhancing the diagnostic efficiency up to 76.5-96.1% are demonstrated. PMID- 23805481 TI - [Relationships of the plague pathogen and vector from different parasitic systems]. AB - The specific features of interaction of the strains of the plague microbe of the main subspecies, which circulate in the area of natural foci of Mongolia and China, with Citellophilus tesquorum sungaris fleas, the major vector of the plague pathogen in a Transbaikalian natural focus, as well as with Xenopsylla cheopis ones, the classical vector, were revealed. Experiments used virulent Yersinia pestis strains, such as I-3230 isolated from C.tesquorum in Mongolia in 1998 and 2155 isolated from humans in Manchuria (China) in 1947. They established that ectoparasites from other parasitic systems could transmit these strains. At the same time, the Y.pestis strain 1-3230 far exceeded the strain 2155 in its ability to form conglomerates as lumps. It is possible that this fact reflects the adaptive peculiarity of the Y.pestis strain 1-3230 to remain long (during the cold period of a year) in the flea C.tesquorum sungaris that survives winters mainly in the imago stage. The strain 2155 was more active in forming proventricular blocks in the body of X.cheopis, the blocking period in the latter was 3-7 times shorter than that in C.tesquorum sungaris when infected with both strains. PMID- 23805482 TI - [The duration of preservation of plague pathogen strains with a different plasmid kit from a Central Caucasian high-altitude natural focus in the organism of citellophilus tesquorum fleas and the possibility of their transmission to laboratory animals]. AB - Two plasmid variants of the main subspecies of the plague microbe circulate in a Central Caucasian high-altitude natural focus of plague. The strains of one plasmid variant fully correspond to the main subspecies of the plague pathogen in their characteristics. Those of the other are auxotrophic for proline, weakly virulent to one or both species of laboratory animals. The mountain subspecies of Citellophilus tesquorum fleas excretes the greatest quantity of plague microbe strains so the investigation of whether unblocked fleas can transmit the plague microbe is of interest. PMID- 23805483 TI - [Role of endoparasites of fleas of wild rodents in plague enzootia]. AB - Laboratory studies of fleas for gregarines have established that it is the latter inhabiting the intestine and stomach of the fleas of wild rodents which are of much interest as protozoa, in whose organism, parasitic species of bacteria can survive. Penetration of plague bacteria into the endoplasm ofgregarines and their possible survival in the cysts may create an additional component in the chain of an epizootic process, which ensures its function, without involving the rodents at the nesting biocenotic level following the pattern: flea imagoes - nesting litter infected with gregarine spores, cysts - flea larvae - flea imagoes infected with cysts, with the plague pathogen emerging into a rodent population through the imago of blocked fleas. PMID- 23805484 TI - [Comparative activity of different groups of insecticides against permethrin resistant lice (anoplura: pediculidae)]. AB - The activity of insecticides (CK50, CK95 ) from different chemical classes against permethrin-resistant body and head lice was investigated. Having developed resistance to pyrethroids (permethrin, d-phenothrin, cypermethrin, and deltamethrin), the lice remain susceptible to organophosphorus compounds, phenylpyrazoles, neonicotinoids, and avermectins. The susceptibility of lice to the insecticides having a mechanism of action that is different from that of pyrethroids does not depend on the level of their resistance to permethrin. PMID- 23805485 TI - [The immune structure against q fever and tick-bite spotted fever group rickettsioses in the population and domestic animals of the Republic of Guinea]. AB - The circulation of the rickettsiae R.africae and C.brunetii, the causative agents of African tick-bite spotted fever and Q fever, was first ascertained throughout the territory of the Republic of Guinea. The immune stratum against R.africae among the population varied 1.1 to 25.4% or 10.6+/-0.7% on average and that among the livestock did 0.6 to 18.8% or 7.6+/-0.6% on average. The proportion of sera to C,brunettii in the population was in the rage from 0.8 to 10.5% or 2.4+/-0.3% on average; that in livestock was 3.2 to 18.7% or 8.0+/-0.6% on average. However, many aspects of the circulation of rickettsiae, the pathology and importance of these fevers in the structure of morbidity in Guinea remain still unclarified and call for further investigations, by applying the current laboratory diagnostic tests for rickettsiosial diseases. PMID- 23805486 TI - [Nematodes of humans in the Primorye Territory]. AB - Nematodes occupy the top in the general pattern of human parasitic diseases in the Primorye Territory. In the south of the Far East, there are a total of 28 nematode species that can parasitize man. However, the authors have identified only 8 nematode-induced diseases, such as ascariasis, enterobiasis, toxocariasis, trichocephaliasis, anisakiasis, trichinosis, dirofilariasis, dioctophymosis. The latter has been found only once in the 1920s. According to official statistical data, the proportion of ascariasis and enterobiasis accounted for 43.8 and 53.5% of the total number of helminthiases, respectively. PMID- 23805487 TI - [Dirofilariasis in the Nizhny Novgorod Region]. AB - The paper presents the results of clinical, epidemiological, and epizootological analyses of local cases of human dirofilariasis in the Nizhny Novgorod Region, which suggest that natural and climatic changes, namely the abnormally hot summer in 2010-2011 and increasing migratory processes among human beings and animals, open up possibilities for forming foci ofdirofilariasis outside habitats of Dirofilaria repens. PMID- 23805488 TI - [Contamination of water objects with helminth eggs and protozoan cysts in the Minsk Region]. PMID- 23805489 TI - [Development of conditions for preparing specimens for the detection of blood parasites]. PMID- 23805490 TI - [The preparation and anticestodal activity of the compounds MCT-09 and MCT-11]. PMID- 23805491 TI - [Comparative analysis of the efficiency of methods for the diagnosis of cryptosporidiosis]. AB - The paper comparatively analyzes the efficiency of two methods for the diagnosis ofcryptosporidiosis: microscopy of Ziehl-Neelsen- or Romanovsky-Gimse-stained smears and immunofluorescence labeling using the diagnostic reagent kit Crypt-a Glo A400 BIOT (Cryptosporidium oocysts) (Stailab Co.) in fecal samples. The efficiency of the reagent kit Crypt-a-Glo A400 BIOT has been shown to be sufficiently high in diagnosing cryptosporidiosis. The authors propose to use the immunofluorescence labeling [a diagnostic reagent kit Crypt-a-Glo A400 BIOT (Cryptosporidium oocysts)] to increase the detection rate of persons suspected as having cryptosporidiosis who are invaded during comprehensive examination. PMID- 23805492 TI - [Evaluation of the efficiency of rapid tests in identifying malaria patients and parasite carriers in the Republic of Tajikistan]. AB - The sensitivity of a rapid test versus microscopy ofblood samples was studied while examining 8000 dwellers from the republic's endemic areas. The results of blood testing in the Kumsangir, Dangara, and Vakhdat districts showed agreement with those of blood microscopy. The result of rapid tests did not agree to that of blood microscopy only in one case in the Kabadiyan District. The findings suggest that tests (Care Start b Malaria HPR2/PLDH 2 line test (P.falciparum/P.vivax) COMBO GO161 Access Bio, Inc.) are rather effective and may be further used particularly in remote and Afghanistan-adjacent settlements, as well as among border-guards, in blood transfusion centers and emergency units. PMID- 23805493 TI - [Distribution of aedes (stegomyia) aegypti l. and aedes (stegomyia) albopictus skus. mosquitoes on the Black Sea coast of the Caucasus]. AB - There is evidence that in the Black Sea coastal area, Ae.albopictus mosquitoes are encountered everywhere from N. Afon to Dzhubga over a length of 250 km of the coast and Ae.aegypti ones are from N. Afon to Agoi, Tuapse District (215 km). The Ae.albopictus mosquitoes have extended 44 km in length and 600 m in height in the eastern part of the coast (Krasnaya Polyana). PMID- 23805494 TI - [Parasitic diseases in organ or tissue recipients]. PMID- 23805495 TI - [Development of professional competencies in sanitary and antiepidemic provision of the population in emergencies]. PMID- 23805496 TI - [The training of parasitologists in compliance with federal state standards]. PMID- 23805497 TI - How can I get my patients to say Yes! and prevent the dreaded No!? PMID- 23805498 TI - Why is estate planning such a mystery? PMID- 23805499 TI - Are you abandoning patients? PMID- 23805500 TI - What can I do for gummy smiles? PMID- 23805501 TI - Product review. Eye-Fi cards. PMID- 23805502 TI - How safe is acetaminophen? PMID- 23805503 TI - Is my practice vulnerable to cyber threats? PMID- 23805504 TI - Profile by Dr. Bill Scheerer. Sonia Gupta, DDS. PMID- 23805505 TI - R staff txtng @ wrk?? #@%&!! Have a clear policy about mobile phones, texting. PMID- 23805506 TI - [Association of adiponectin gene polymorphrism with metabolic syndrome in older Han adults from major cities in China]. AB - OBJECTIVE: To investigate the association of adiponectin gene rs2241766 (T45G) and rs15011299 (G276T) single nucleotide polymorphrism (SNP) with metabolic syndrome (MS) in older han adults from major cities in China. METHODS: A total of 907 older Han adults were selected from 18 major cities of the China National Nutrition and Health Survey in 2002. According to the MS definition proposed by International Diabetes Federation, the subjects were divided into MS and control groups. Plasma adiponectin and Genomic DNA was isolated from blood and insulin concentrations were measured. genotypes of rs2241766 and rs15011299 were identified by Taqman method. Association There was of genotypes of adiponectin gene SNPs with MS was analyzed. RESULTS: significant difference in the distribution of genotypes of rs15011299 SNP between the MS and control group. The T allele frequency of rs15011299 was significantly increased in MS group. For rs15011299 site, there were significant differences of BMI and adiponectin level among the subjects carried GG, GT or TT genotypes. The GG+GT carriers had lower BMI, waist circumference, insulin level and higher adiponectin level than those of TT carriers. For rs2241766 site, there were significant differences of BMI and diastolic blood pressure (DBP) among the subjects carried TT, TG or GG genotypes. The TT carriers had higher BMI, waist circumference and DBP than those of GG+GT carriers. The TT carriers in rsl5011299 had higher risk for MS than GG carriers (OR for TT v. s. GG=3.19; 95% CI 1.31-7.78). No association was found in rs2241766 with MS. CONCLUSION: The adiponectin gene rs15011299 polymorphrism may be associated with pathogenesis of MS in older Han adults. G-->T variance may be associated with an increased risk of MS and result in a decreased level of aiponectin and increments of waist circumference and BMI. PMID- 23805507 TI - [Relationship between the body mass index, waist circumference and lipids levels among adults in Shenzhen]. AB - OBJECTIVE: To study the relationship between the body mass index (BMI), waist circumference (WC) and lipids levels, dyslipidemia among adults. METHODS: Totally 12 communities from 8 districts were sampled through stratified randomized sampling, 75 households from each community were sampled by random sampling for questionnaire survey, physical examination and laboratory tests. RESULTS: Within different BMI categories, the triglyceride (TG) in higher BMI group were higher than in lower BMI group, and the high density lipoprotein-c (HDL-c) in higher BMI group were lower than in higher BMI group; Within different WC categories, the TG, total cholesterol (TC), low density lipoprotein-c (LDL-c) in higher WC group were higher than in lower WC group. With the increase of BMI/WC, the levels of TG, TC and LDL-c showed a rising trend (P<0.05), HDL-c showed a falling trend (P<0.05). With the increase of BMI, the odds ratios (ORs) of high TG, high TC, low HDL-c, high LDL-c and dyslipidemia showed a rising trend (P<0.05), and with the increase of WC, the ORs of high TG, high TC, high LDL-c and dyslipidemia showed a rising trend (P<0.05). There were positive partial correlations between BMI/WC and TG, TC, HDL-c, LDL-c. HDL-c had a higher correlation with BMI (P<0.05), TC had a higher correlation with WC (P<0.05). CONCLUSION: BMI and WC were independently associated with blood lipids levels, and high BMI and WC were the risk factors for dyslipidemia. PMID- 23805508 TI - [Vitamin A, vitamin E and beta-carotene nutritional status and antioxidase level analysis among tuberculosis patients]. AB - OBJECTIVE: To investigate vitamin A (VA), vitamin E (VE) and beta-carotene nutritional status and antioxidase level among tuberculosis patients. METHODS: Totally 70 tuberculosis patients were randomly selected as the experiment group from Tancheng Tuberculosis Control in 2010. And 70 matched normal persons were selected as the control group. Two groups of people were relative nutrition index test which include body mass index (BMI), hemoglobin (Hb), triglyceride (TG), total cholesterol ( TC) , high-density lipoprotein (HDL), superoxide dismutase (SOD), catalase (CAT), VA, VE and beta-carotene. RESULTS: BMI of the experiment group was 19.13, which was obviously lower than those of the control group which was 21.95 (P<0.05), but Hb of the experiment group was 128.36 g/L which was lower than those of the control group, not with significant statistic differences. For blood lipid level, TG, TC, HDL of the experiment group were 1.54, 4.47 and 1.21 mmol/L respectively, compared with corresponding indexes of the control group which were 1.63, 5.20, 1.30 mmol/L respectively, were all dramatic decline (P<0.05). Antioxidase level contrast between two groups showed that SOD and CAT of the experiment group were 78.20 and 5.24 U/ml respectively, and corresponding indexes of the control group were 83.27 and 9.99 U/ml respectively, so the former was significantly lower than the later (P<0.05); compared with the control group on vitamin level, VA, VE of the experiment group were 0.256 and 1.148 microg/ml respectively which were all lower than the control group which were 0.385 and 1.182 microg/ml (P<0.05), but beta-carotene of the experiment group was 0.048 microg/ml which was slightly lower than 0.051 microg/ml of the control group, not with significant statistic differences. CONCLUSION: Nutritional status among the tuberculosis patients is quite poor, especially antioxidase and VA, VE and beta carotene level are significantly lower than normal people. PMID- 23805510 TI - [Relationship between dietary behaviors and growth-development of 1-7 years old children from seven provinces in Chinese rural areas]. AB - OBJECTIVE: To explore the status of dietary behaviors of 1-7 years old children and its relationship with growth-development in Chinese rural areas and to provide 13,692 1-7 years old scientific evidences for corresponding intervention. METHODS: children from seven provinces in Chinese rural areas were randomly identified by multistage stratified cluster sampling. The ascertainment methods included face to face questionnaires and anthropometric measurements. Chi-square test and non-conditional logistic regression analysis were used to assess the relationship between dietary behaviors and growth-development. RESULTS: Among the respondents, 53.1% occasionally/never drank milk/soymilk, 48.1% ate snacks almost everyday, 22.5% were picky eaters, 7.3% were breakfast-skippers, 1.9% couldn't dine on time. Multivariate nonconditional logistic regression analysis showed that occasionally/never have breakfast, occasionally/never drink milk or soymilk, occasionally/never eat snacks were associated with stunting. Occasionally/never have breakfast or eat snacks were associated with underweight. The five dietary behaviors were not associated with wasting, overweight and obesity in our study. CONCLUSION: The incidence of children's poor dietary behaviors was relatively high in Chinese rural areas, which had a close association with children stunting and underweight. PMID- 23805509 TI - [Investigation of vitamin B1, vitamin B2 and niacin levels among children aged 0 3 years old in Chinese urban and rural areas]. AB - OBJECTIVE: To study the nutritional status and differences in vitamin B1, vitamin B2, and niacin of the urban/rural infants in Shandong Province, and to provide scientific basis for infants nutrition interventions. METHODS: 106 urban infants and 290 rural infants were selected from a city in Shandong Province. Forty milliliter urinary was collected from each one, which was adjusted to pH 4-5 with concentrated hydrochloric acid immediately. The concentration of thiamine, riboflavin and niacin in the urine was detected by fluorescence method. RESULTS: The insufficient percentages of vitamin B, vitamin B2 and niacin in urban infants were 1.9%, 8.0% and 9.1%, and that in rural infants were 4.5%, 56.7% and 27.1%. The median concentrations of vitamin B1 in urban and rural infants were 495.00 and 420.56 microg/g respectively, in which the 12-month and 24-month groups in urban were higher than that in rural (P<0.05). The medians of vitamin B2 content in urban and rural infants were 303.07 and 70.88 microg/g, and the content of vitamin B2 in urban infants was higher than that in rural infants in each group (P<0.05). The median concentrations of niacin content in urban and rural infants were 6.31 and 4.22 microg/g, and the niacin content of 6month-, 12 month-, 18 month- and 24 month- groups in urban infants were higher than that in rural infants (P<0.05). CONCLUSION: There were significant differences in vitamin B1, B2 and niacin content of infants between urban and rural areas, and the nutriture of urban infants was better than the rural infants. More improvement measures should be given to infants in rural areas for the high proportion of vitamin B, and niacin deficiency. PMID- 23805511 TI - [Effects of T-2 toxin of Fusarium on proliferation and apoptosis of human acute promyelocytic leukemia cell line HL60]. AB - OBJECTIVE: To study the effects of sesquiterpenes compounds T-2 toxin produced by Fusarium fungi on proliferation and apoptosis of acute promyelocytic leukemia cellline HL60. METHODS: HL60 cells were treated with T-2 toxin (0, 4, 8, 16 and 32 microg/ml) for 48 h, and then cells were harvested for the studies of growth inhibition with MTT, Cell morphology with Giemsa staining, apoptosis and the expression of Bax and Bcl-2 with flowcytometry (FCM) and Western blot. RESULTS: MTT results showed that T-2 toxin inhibited HL60 proliferation on dose-dependent. Morphological observation showed significant apoptotic morphological characteristics. FCM results showed that the apoptosis rates of HL60 cells in T-2 toxin treatment groups were higher than that in control, and positive dose-effect correlations could be found. FCM and Western blot results showed that the expression of Bax was increased while that of Bcl-2 was decreased in T-2 toxin treatment groups of HL60. CONCLUSION: The results suggested that T-2 toxin could inhibite proliferation and induce apoptosis of HL60 cells in vitro in a dose dependent manner. PMID- 23805512 TI - [Polyclonal antibody production and immunoassay development for detection of beta lactamase in milk]. AB - OBJECTIVE: To produce polyclonal antibody with affinity against several types of beta-lactamase and develop an indirect competitive ELISA for detection of beta lactamase in milk. METHODS: A mixture of beta-lactamase was used as immunogen for animal immunization to produce polyclonal antibody. After purification polyclonal produce animal immunization to characterization, the obtained antibody was employed to establish an ELISA method for beta-lactamase determination. RESULTS: The polyclonal antibody was acquired, with the concentration of 17.9-18.9 mg/ml in antiserum. The molecular weights were 55, 25 and 160 kD for heavy chain, light chain and the whole antibody, respectively. The developed ELISA method showed the LOD 0.2 ng/ml and the linear range of 0.2-200 ng/ml. The recoveries ranged from 80% to 115%, with RSD bellow 20%. CONCLUSION: With the polyclonal antibody, the proposed indirect competitive ELISA method was successfully applied to determine beta-lactamase in milk. PMID- 23805513 TI - [Study on no-fusion expression and purification of Glycine max dehydration responsive element-binding protein (GmDREB1) expressed in E. coli]. AB - OBJECTIVE: To obtain enough GmDREB1 protein comparable with native protein for further safety assessment of the protein. METHODS: The GmDREB1 gene was cloned into no-fusion expression vector pBV220 and the recombinant vector pBV220-GmDREB1 was obtained. The constructed vector was transformed into expression host E. coli DH5a. The protein expression was optimized by improving the codon, induced expression conditions and selecting the appropriate vector. The protein was obtained by cation exchange chromatography and gel filtration chromatography and identified by N-terminal amino acid sequencing, western blotting and activity determination. RESULTS: The soluble protein was expressed efficiently in E. coli DH5a containing the optimized target gene by 42 degrees C induction for 3 hours and the purified protein consistent with the native protein was obtained through the chromatography. CONCLUSION: The results of this study illustrated that the GmDREB1 protein could be acquired through prokaryotic host expression which had comparable N-terminal amino acid sequences, immunogenicity and biological activities with those of native GmDREB1 protein. PMID- 23805514 TI - [Isolation and purification of recombinant human lactoferrin (rhLF) from transgenic rice and its antibacterial activities]. AB - OBJECTIVE: To study the isolation and purification of recombinant human lactoferrin (rhLF) from transgenic rice, and to check its antibacterial activities. METHODS: After isolated rhLF from transgenic rice via saturated ammonium sulfate precipitation, then purified it through CM Sepharose FF-exchange chromatography and molecular sieve chromatography Sephadex G25. The inhibition effects under different concentrations of rhLF (0.25, 0.5, 1.0, 2.0, 4.0, and 5.0 mg/ml) against Salmonella typhimurium, Staphyloccocus aureus, Bacillus cereus, Listeria monocytogenes were observed, using broth microdilution method. RESULTS: The rhLF was obtained at a higher purity (about 90%) through successful isolation and purification. After Coomassie blue staining, Westernblot and mass spectrometer analysis, it was identified as the purpose protein with the molecular weight of approximately 79 kDa. The antibacterial experiments showed that 5 mg/ml and 4 mg/ml rhLF could inhibite Salmonella typhimurium and Staphylococcus aureus persistently, 2 mg/ml and 1 mg/ml rhLF showed a significant inhibitory effects in the later period; while 0.5 mg/ml or lower concentration, showed no inhibitory effects. As to Bacillus cereus, only 5 mg/ml and 4 mg/ml rhLF exhibited certain inhibitory effects within 18 hours. Listeria monocytogenes was inhibited within 18 hours just at 5 mg/ml rhLF. CONCLUSION: The rhLF could be successfully separated and purified from transgenic rice, and the purified protein still has significant antibacterial activities. PMID- 23805515 TI - [Effects of DiBP on the cAMP/PKA-CREB-BDNF signaling pathway of hippocampus in mice]. AB - OBJECTIVE: To explore the effects of diisobutyl phthalate (DiBP) on the cAMP/PKA CREB signaling pathway of hippocampus in mice. METHODS: Accommodating 30 KunMing mice to the animal house for 3 days, then dividing the mice into 5 groups according to their weights. That is, one control group and four experimental groups (I group, 50 mg/kg BW; II group, 250 mg/kg BW; Ill group, 500 mg/kg BW; IV group, 1000 mg/kg BW). The mice were fed with the corn oil in control group, and the other groups were fed with the related dose of DiBP mixture by gavages last for 8 weeks. At the end of experimental time, the mice were killed, and the tissue samples of hippocampus were taken immediately. The content of cAMP was determined by ELISA, and p-CREB, P-PKA C were measured by western blotting, while mRNA expressions including CREB, BDNF, c-fos and c-jun were checked by RT-PCR. RESULTS: The cAMP content and the p-PKA C protein of hippocampus in IV group was significantly less than control group (P<0.05) and compared with control group, the p-CREB protein of hippocampus in 1I group decreased (P<0.05), while the relative level of CREB, BDNF, c-fos and c-jun mRNA were down-regulated in all experimental groups. CONCLUSIONS: The abnormal changes of expression of the signal molecules composing the cAMP/PKA-CREB signaling pathway were observed in the hippocampus of DiBP exposure mice. This might be one of the possible mechanisms of DiBP induced cognitive impairment. PMID- 23805516 TI - [Interference of testosterone synthesis through HPGA and ERalpha pathway after 17beta-estradiol exposure to regulate spermatogenesis]. AB - OBJECTIVE: To evaluate the effects of 17beta-estradiol (E2) exposure on male reproductive endocrine system, and study the potential mechanism. METHODS: Male Wistar rats were gavaged with E2 (1.00, 0.50, 0.10, 0.01 mg.kg(-1).d(-1)) for 8 weeks, with corn oil as control. The testes weight and testicular organ coefficient and sperm parameter were examined. Serum levels of zinc and calcium were measured by atomic absorption spectrophotometry. Serum hormone concentrations were determined by RIA. The expression of testosterone synthetase mRNA were assessed by RT-PCR. The expression of estrogen and androgen receptor protein were detected by Western blot. RESULTS: Testis weight and testicular coefficient were significantly declined. Serum testosterone levels were significantly decreased. Serum estradiol levels showed a significant increase in a dose-related manner (P<0.01). Blood zinc had a significant decrease at 0.50 and 1.00 mg.kg(-1) d(-1) (P<0.01). Epididymal cauda sperm counts declined at 0.50 and 1.00 mg/kg (P<0.01). The expression of steroidogenic acute regulatory protein (StAR) and cytochrome cholesterol side-chain cleavage enzyme (P450scc) mRNA were decreased. The expression of ERa protein was increased, and AR protein was decreased. CONCLUSION: Exposure to E2 in puberty could interfere with the development of testis, The potential including testosterone biosynthesis and spermatogensis in adulthood. mechanism may be indirectly through disturbing the balance of HPGA, and directly through up-regulating the level of ERa protein consequently inhibiting testosterone synthetase. Blood zinc was involved in mediating spermatogensis by E2 exposure. PMID- 23805517 TI - [Effects of CdTe QDs on chromosome aberration of CHL cells in vitro]. AB - OBJECTIVE: To observed the chromosome oberration of CHL cells induced by CdTe QDs. METHODS: The chromosome oberration test of Chinese hamster lung (CHL) cell was conducted in CdTe QDs at the concentrations of 1.6, 3.2, 6.3, 12.6 and 25.2 microl/ml, under the metabolic (+S9) and non-metabolic (-S9) activation systems. RESULTS: The chromosome oberration rate of 12.6 and 25.2 microl/ml CdTe QDs groups were significantly higher than the control groups (P<0.01) Under the condition of metabolic activation. Main types of chromosomal aberrations was broken, fragmented and exchange. CONCLUSION: It was suggested that CdTe QDs could induce the effects of chromosome oberration under the metabolic activation systems (+S9). PMID- 23805518 TI - [Effect of Huperzine A on neural lesion of acute organophosphate poisoning in mice]. AB - OBJECTIVE: Effects of neurophathologic changes and expression of Glu and 60 nNOS were observed in acute isocarbophos and phoxim poisoning in mice. METHODS: KM male mice were randomly divided into three groups, which were control, non treated and Huperzine A (HupA)-treated groups. The control group was given tween 80. Nontreated group was given isocarbophos (14.7 mg/kg) or phoxim (1702 mg/kg). HupA-treated group was given HupA 2h before phoxim or isocarbophos. Twenty-four hours after exposure, the whole brain was removed and adjacent coronal sections was obtained. One part of sections were stained with toluidine blue. The part of sections were used to assessed the expression of Glu and nNOS in the cortex and hippocampal of brain by immunohistochemistry. RESULTS: Compared to control group, non-treated group was observed nissal body nembers reduced and dyeing light. The animals of HupA protective group were observed nissal body nembers reduced, but the lesional degree was lighter obviously than non-treated group. The statistically reduced of the expression of Glu (P<0.01), the elevation of nNOS (P<0.01), after Isocarbophos intoxication were observed. Compared to non-treated group, the significant elevation of Glu (P<0.01) and reduced of nNOS (P<0.01) was observed on HupA-treated groups. Whereas for phoxim treatment, no changes were observed. CONCLUSION: HupA have protective effect against glutamatergic systems disorder caused by Isocarbophos poisoning. Administration of HupA have no effects of the neurotransmitter changes induces by acute poisoning of phoxim. It is different for the toxic effect mechanism of the two organophosphate. PMID- 23805519 TI - [Screening of differentially expressed proteins in serum from subjects with Keshan disease by two-dimensional electrophoresis and mass and mass spectrometry]. AB - OBJECTIVE: To screen differentially expressed proteins in serum in patients with Keshan disease (KD), peripheral blood protein expression spectrum between subjects with Keshan disease and health controls were compared. METHODS: Differentially expressed protein spots were screened by two-dimensional gel electrophoresis (2-DE) between Keshan disease and health control subjects, and constitutive protein were identified by matrix assisted laser adsorption/ionization-time of flight mass spectrometry (MALDI-TOF-MS). RESULTS: 9 differentially expressed protein spots were showed in 2-DE images and 8 differentially expressed proteins were identified by MALDI-TOF-MS. In them, 3 up regulated proteins, mainly relatedd to lipid metabolism, apoptosis resistance, immunological regulation and 3 down-regulated proteins, involved to cellular iron ion homeostasis; 2 up-regulated proteins in serum in patients with KD versus controls from KD areas were detected, mainly associated with protease inhibition. CONCLUSIONS: Haptoglobin, serum albumin, alpha-l-antitrypsin, transferring and alpha2-heremans schmid glycoprotein may be considered as candidate biological indicators used for diagnosis or prognosis of KD. PMID- 23805520 TI - [Malnutrition status and influencing factors in children with migrant worker mother in poor areas in China]. AB - OBJECTIVE: To explore the malnutrition status and influencing factors in children with migrant worker mother in poor areas of 13 provinces. METHODS: Survey data was from the program of Public Health Emergency Response and Operation Mechanism Establish the monitoring and information system on nutrition and health and related risk factors in 0-5 children in 2009 which funded by China CDC. Multistage stratified random cluster sampling method used in the national survey was performed. The contents of the investigation included questionnaire survey, anthropometric measurement,biochemical tests and dietary survey. The subjects of the study were 2161 children no more than 18 months in the survey. Z-scores were calculated according to WHO growth standards (2006). Data processing and multiple factors analysis were finished by non condition logistic regression in software SAS 9.12. RESULTS: There were 9.3% children whose mother were migrant workers in the target population. The prevalence of stunting and underweight in children with migrant worker mother was 15.5% and 6.0% Excluding other influencing factors, the results suggested that low birth weight (OR=2.543, 95% CI 1.481 4.365), minority nationality (OR=1.661, 95% CI 1.274-2.165), mother is migrant worker (OR=1.602,95% CI 1.085-2.367), the nearest medical institution at a distance of >or=1 km (OR=1.308, 95% CI 1.008-1.696), and unsanitary toilet (OR=1.311, 95% CI 1.017-1.689) are the most important independent factors among 0 18 months young children. CONCLUSION: Malnutrition in children with migrant worker mother in poor areas should not be ignored. Enhance the monitoring and adopt comprehensive improvement are useful to improve the growth of children. PMID- 23805521 TI - [Total drinking water intake and sources of children and adolescent in one district of Shenzhen]. AB - OBJECTIVE: To describe total drinking water intake among primary and middle school students in one district of Shenzhen and to provide scientific evidence for adequate intakes of drinking water for different people in China. METHOD: A total of 816 students from three primary and middle schools of Shenzhen was selected using three-stage random sampling method. The information on amounts and types of daily drinking water was recorded by subjects for seven consecutive days using a 24 hours measurement. The amounts and types of daily drinking water among different ages and between boys and girls were analyzed. RESULTS: The average total drinking water of subjects was (1225+/-557) ml/d, and the consumption of total drinking water in boys ((1303+/-639) ml/d) was significantly higher than that in girls ((1134+/-478) ml/d, P<0.01). The consumption of total drinking water of secondary school students ((1389+/-541) ml/d) and high school student ((1318+/-641) ml/d) was no statistically difference, but was higher than primary school students ((1097+/-525) ml/d, P<0.01). The average plain water and beverages of the subjects was (818+/-541) ml/d and (407+/-294) ml/d respectively. CONCLUSION: Major of fluid intake comes from drinking water in children and adolescenct of Shenzhen. The knowledge of drinking water of primary school students is need to comprehensive enough. PMID- 23805522 TI - [Alcohol consumption and dyslipidemia risk: a case-control study in middle-aged men]. AB - OBJECTIVE: To explore the relationship between alcohol consumption and risk of dyslipidemia in middle-aged men. METHODS: Male patients of dyslipidemia (n=221) were chosen as the case group, while normal ones (n=233) as the contrast group. All study objects were aged 30-65 years old, came from in hospital or made physical examination at the Second Hospital of Shandong University from June 2011 to June 2012. Question test and physical examination were made for them. Single factor analysis and unconditional multi-factorial Logistic regression were performed to analyze the relationship between alcohol consumption and risk of dyslipidemia. RESULTS: Compared with the contrast group, the risk of dyslipidemia significantly increased with increasing average daily alcohol consumption, while ORs were 1. 52 (50 g/d). The similar thing happened on the risk of abnormal TG levels, while ORs were 1.98 (50 g/d). The results of unconditional multi-factorial Logistic regression analysis indicated that the average daily alcohol consumption (g/d)(OR=1.007, 95% CI 1.002-1.012) was a risk factor of dyslipidemia. CONCLUSION: Alcohol consumption may be a risk factor of dyslipidemia in middle aged men. PMID- 23805523 TI - [Studies of genetic polymorphism of CYP450 2E1 among the Tibetan populations in Qinghai Province and its effect on drinking behavior]. AB - OBJECTIVE: In order to explore the effect of genetic polymorphism of CYP450 2El among the Tibetan population in Qinghai and its relationship to drinking behavior. METHODS: By the self-reported questionnaires of 325 Tibetan male who contain 193 drinkers and 132 non-drinkers, we analyzed the relationship between drinking behavior and the genetic polymorphism of CYP450 2El by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. So does the 266 Han nationalism. RESULTS: Single variable analysis showed the drinking prevalence was related to occupation, educational status, economic income, marital status and smoking (P<0.05). There were no statistical significant differences of genotypes and alleles between male Tibetan and Han population (P>0.05). The three genotypes (cl/cl, cl/c2, c2/c2) and the two alleles (cl, c2) of CYP450 2El had statistical significant differences (P<0.05) between drinkers and non-drinkers in Tibetan population, and the drinkers had higher frequencies of cl/c2 genotype and c2 allele than that of the opposite group. Compared with safe drinkers, the frequency of c2 allele in the group of dangerous was higher. The related degree of drinking behavior and amount with c2 allele were 0.17 and 0.20. The multivariate statistical analysis showed that CYP450 2E1, incomes and smoking were independent. CONCLUSION: CYP450 2E1 is the mostly influence factor to drinking behavior in male Tibetan population. PMID- 23805524 TI - [Roles of glucose-6-phosphate dehydrogenase in obesity induced by high fat diet]. AB - OBJECTIVE: To explore the roles of glucose-6-phosphate dehydrogenase (G6PD) and its downstream NADPH oxidase (NOX) in obesity induced by high fat diet. METHODS: 40 male Wistar rats were randomly divided into a high fat diet group (30 rats) and a control group (10 rats) fed with rat chow. After six weeks, rats fed with high fat diet were screened out obesity-prone group and obesity-resistant group based on the gain of body weight, obesity-prone group and obesity-resistant group rats continued to be fed with high fat diet. Basic diet group served as normal control. All rats were killed after 13 weeks. Biochemical markers and G6PD activity were determined in adipose tissues. The expression of G6PD and the NOX subunit of P22 gene were detected using RT-PCR. RESULTS: Blood glucose levels were higher in obesity-prone group rats than those in control rats (P<0.05). Triglyceride levels and body fat contents were significantly higher in OP rats than that in obesity-resistant group rats (P<0.05). Insulin, insulin resistant index, body weight were significantly higher in obesity-prone group rats than that in control and obesity-resistant group rats (P<0.05). There was no significant difference between the control and obesity-resistant group rats. The activity and expression of G6PD in the obesity-prone group rats were lower than those in the control and obesity-resistant group rats (P<0.05). The expression of P22 subunit in the obesity-prone group rats was significantly higher than that in the control and obesity-resistant group rats (P<0.05), but there was no significant difference between the control and OR rats. CONCLUSION: G6PD and its downsream NAPDH oxidase may play an important role in the pathogenesis and development of obesity. PMID- 23805525 TI - [The study on the relationship between serum folic acid and vitamin B2 levels and esophageal cancer]. AB - OBJECTIVE: To study the relationship between serum folic acid and VB2 levels and esophageal cancer. METHOD: The enzyme-linked immunosorbent assay was used to observe the serum folic acid and vitamin B2 levels of the 1:1:1 paired of 106 groups, which include 106 cases of esophageal cancer, 106 cases of esophageal precancerous lesions and 106 cases of normal control group. RESULTS: The levels of folic acid and VB2 in serum of esophageal cancer group and esophageal precancerous lesions group were significantly lower than normal control group (P<0.05), the level of folic acid in serum of esophageal cancer group was significantly lower than esophageal precancerous lesions group (P<0.05), but the difference of the serum VB2 of esophageal cancer group and esophageal precancerous lesions group was not statistically significant (P>0.05). CONCLUSION: The folic acid and vitamin B2 deficiency has the relationship with the esophageal cancer occurrence and development. PMID- 23805526 TI - [Impact of oral vitamin D supplementation in early life on diabetic mice induced by streptozotocin]. AB - OBJECTIVE: To evaluate the effect of oral vitamin D supplementation in early life on blood glucose, insulin content, diabetes incidence, and histomorphology in pancreatic islet induced by streptozotocin. METHODS: Three-week-old C57BL/6 mice were given either control diet (American Institute of Nutrition [AIN]-93G), or three different dose of vitamin D-supplemented diet. Nine weeks after dietary intervention, C57BL/6 mice were treated with streptozotocin i.p. for 5 consecutive days. After injection of STZ, The fasting blood glucose and diabetes incidence was tested once a week. The insulin content, histomorphology in pancreatic islets was conducted at the end of experiments. RESULTS: (1) Vitamin D supplementation in early life can decrease the fasting blood glucose values induced by STZ, and the decreases effect of high dose vitamin D-supplemented group is the most significant (P<0.01). (2) Vitamin D supplementation in early life can prevent diabetes incidence, and the decreases effect of high dose vitamin D-supplemented group is the most significant, fully suppress the onset of diabetes about four weeks later after injected by STZ (P<0.01). (3) As compared to the control group, insulin content in medium and high dose vitamin D supplemented groups were significantly up-regulated after injection of STZ (P<0.05), and the effect of high dose vitamin D-supplemented group is the most significant. (4) The damage of pancreatic islets induced by STZ was clearly restored in medium and high dose vitamin D-supplemented groups, and effect of high dose vitamin D-supplemented group is the most significant. CONCLUSION: Oral vitamin D supplementation in early life can decrease the fasting blood glucose values, prevent diabetes incidence, up-regulate insulin content, restored the damage of pancreatic islets induced by STZ, and effects of high dose vitamin D supplementde group are all the most significant. PMID- 23805527 TI - [Effect of EGCG on the proliferation and invasion of human hepatoma HepG2 cells]. AB - OBJECTIVE: To investigate the effect and mechanism of EGCG on the proliferation and invasion of human hepatioma HepG2 cell. METHODS: Hepatioma HepG2 cell was treated with EGCG at different concentrations. The effect of EGCG on HepG2 proliferation was examined by CCK-8. The apoptosis of HepG2 treated with EGCG was observed by fluorescence microscopy and FCM via Annexin V-FITC/PI staining. The invasion of HepG2 was detected by Transwell assay. The expression of MMP-2 and VEGF was analyzed by ELISA. RESULTS: HepG2 proliferation was inhibited after treated with EGCG. The IC25 of 24 h and 48 h was 58.19 and 54.19 mg/L. The IC50 of 24 h and 48 h was 133.90 and 78.97 mg/L. The apoptosis of HepG2 was induced significantly after treated with 60 and 135 mg/L EGCG, and the number of cells crossing Matrigel membrane was (28.33+/-7.66) and 0 (P<0.05), and the inhibitory rate of invasion was 69.47% and 100%. The expression of MMP-2 and VEGF decreased significantly. CONCLUSION: EGCG suppressed the proliferation and invasion of HepG2 with the possible mechanism of inducing apoptosis and down-regulating the expression of MMP-2 and VEGF in HepG2. PMID- 23805528 TI - [Effect of ashitabe chalcones on the mRNA expression of PI3K and Akt in hepatocytes of rats with diabetes]. AB - OBJECTIVE: To study the effect of chalcones extracted from Angelica Keiskei (AC) on the mRNA expression of phosphatidy I inositol 3-kinase (PI3K) and serine threonine kinases (Akt) in hepatocytes of rats with diabetes. METHODS: The diabetes of rats was induced by streptozotocin with intraperitoeal injection as well as with high-fat diet feeding. The rats were randomly divided into 3 groups with 10 rats in each group,diabetic control group, high-dose AC group and low dose AC group. All the rats were fed with high-fat diet. 0, 30 and 10 mg/kg BW AC per day were given to high-dose AC, low-dose AC and the diabetic control groups,respectively. Another 10 normal rats fed with regular diet were used as the normal control group. After 4 weeks, serum insulin levels were evaluated by radioimmunoassay. The mRNA expression levels of PI3K and Akt were determined by reverse transcription polymerase chain reaction (RT-PCR). The phosphorylation levels of Akt in hepatocytes were detected by western blot. Blood glucose levels were measured by glucose oxidase method. RESULTS: Compared with rats in the diabetic control gruop, the levels of blood glucose and serum insulin in rats of high-dose AC gruop were decreased and the PI3K and AKT mRNA expression levels were increased. All the difference was statistically significant (P<0.05). CONCLUSION: AC may upregulate the mRNA expression levels of PI3K and Akt and improve insulin resistance of rats with diabetes. PMID- 23805529 TI - [Effect of wheat oligo-peptides on antioxidant function in aged mice]. AB - OBJECTIVE: To study the effect of wheat oligo-peptides on antioxidant function in vitro and in vivo. METHODS: Male KM aged mice were randomly divided into 4 groups according to the serum MDA level, i. e. the negative control group, low-dose group, middle-dose group and high-dose group (0, 500, 1000, 2000 mg/kg BW of wheat oligo-peptides). After a 30-day administration of wheat oligo-peptides, the content of serum MDA, activity of SOD, GSH-Px and T-AOC were determined. The reducing power, DPPH radical and hydroxyl radical scavenging activity were also determined to evaluate the antioxidant activity in vitro. RESULTS: The wheat oligo-peptides were found a good reducing power in vitro (R=0.97), scavenging activity of DPPH radical and hydroxyl radical (RDPPH.=0.90, R.OH=0.91). In vivo experiment, the activity of serum SOD and GSH-Px, and the serum T-AOC of all treated groups was significantly increased compared with negative control group (P<0.05). CONCLUSION: The results from this study showed that wheat oligo peptides have a good antioxidant activity both in vitro and in vivo. PMID- 23805530 TI - [Inhibition effects of black rice pericarp extracts on cell proliferation of PC-3 cells]. AB - OBJECTIVE: To observe the inhibitive effects of black rice pericarp extracts on cell proliferation of human prostate cancer cell PC-3 and to explore its effecting mechanism. METHODS: The black rice pericarp extract was used to treat the PC-3 cells. The inhibitory effect of black rice pericarp extract on cells proliferation of PC-3 was tested by MTT method. Cell apoptosis rates and cell cycle were measured by flow cytometric assay (FCM). Western blot was used to study the protein expression levels of p38, p-p38, JNK, p-JNK. RESULTS: A dose dependent and time-dependent proliferation inhibition of black rice pericarp extract was demonstrated in PC-3. The most prominent experiment condition was inhibitory concentration with 300microg/ml and treated for 72 h. The experiment result of flow cytometry analysis demonstrates that the apoptosis rate of PC-3 cells increased along with the increasing of black rice pericarp extract concentration, and a G1-S cell cycle arrest was induced in a dose-dependent manner. After PC-3 cell was treated with black rice pericarp extract for 72 h, the expressions of p-p38, p-JNK protein increased. CONCLUSION: Black rice pericarp extract could inhibit proliferation, change the cell cycle distributions and induce apoptosis in human prostatic cancer cell PC-3. Its inhibitory effect may be through promoting activation of the JNK, p38 signaling pathway. These results suggest that black rice pericarp extract maybe has an inhibitory effect on prostatic cancer. PMID- 23805531 TI - [Effect on the quality of corn oil in different cooking temperature and time]. AB - OBJECTIVE: To research the effect on fatty acid and oxidation products of corn oil under different temperature and time. METHODS: Corn oil was heated in 140 degrees C, 200 degrees C, 240 degrees C, after 60 s-300 s, then detected the fatty acid, POV and AV. RESULTS: Corn oil was heated in 240 degrees C, after 138 s, the corn oil started to fire, the contains of SFA rised from 14.18 g/100 g to 20.29 g/100 g, the contains of MUFA rised from 28. 30 g/100 g to 33. 33 g/100 g, the contains of PUFA reduced from 53. 13 g/100 g to 28.98 g/100 g, and tFA, POV, AV, TOV arrived to the highest value, they were 11.29 g/100 g, 108.9, 17.12 mmol/kg, 177.37 mmol/kg respectively. CONCLUSION: As the cooking time and the cooking temperature increased, the MUFA, tFA and the TV of the corn oil increased, on the contrary the PUFA reduced. PMID- 23805532 TI - [Study on melamine migration rules in products of tripolycyanamide for food packaging]. AB - OBJECTIVE: To study the migration rules of melamine in products of tripolycyanamide for food packaging. METHODS: With different stimulant solutions, temperatures exposure and long term use, the migration quantities of melamine in products of tripolycyanamide for food packaging into 3% acetic acid and 15% ethanol were measured by HPLC method. RESULTS: The amounts of melamine migrated to 3% acetic acid was higher than those to 15% ethanol. Higher temperatures more amounts of melamine of products of tripolycyanamide were migrated. With the higher temperature exposure was done, the amount of melamine migration reached maximum in lower number of repeated exposures. After 10 times of migration tests, melamine still can be migrated but the amount was not high. The single maximum migration amount was 0. 0851 mg/dm2, and the value was approximately 1/59 of the SML regulated by EU regulations. CONCLUSION: 3% acetic acid is the most serious solvent. The higher the temperature, the greater the migration, and melamine still migrate after repeated use. PMID- 23805533 TI - [The international intercalibration study on dioxins in foods, analysis of results, and the application in QA/QC]. AB - OBJECTIVE: To study the application of international intercalibration study in quality assurance and control (QA/QC) by the analysis of our laboratory' s results from interlaboratory comparison on dioxins in foods from 2005-2012. METHODS: Z-scores were used to appraise the results from the interlaboratory comparison on dioxins in foods organized by Norwegian Institute of Public Health, and analyze the determination of PCDD/Fs and dl-PCBs in various foods. RESULTS: The absolute values of z-score of concentrations of PCDD/Fs and dl-PCBs in almost all foods determined by our laboratory are were all less than 1, indicating excellent results. CONCLUSION: The international intercalibration study is a greatly effectively approach of QA/QC. Thus, qualified laboratories should be encouraged more involved in international comparison to improve the detection ability and the reliability of the results. PMID- 23805534 TI - [Detection of foodborne Salmonella typhimurium and Salmonella enteritidis by diplex real-time PCR using TaqMan probe]. AB - OBJECTIVE: To establish a method to detect Salmonella typhimurium (ST) and Salmonella enteritidis (SE) simultaneously with a dual real-time PCR assay using double-color fluorescent TaqMan probes. METHODS: The primers and probes were designed based on the conservative domain of STM4599 sequence of ST (GenBank: AERV01000023.1) and the specific sequence of SE ( GenBank: AF370707.1) respectively. The probes were labeled with reporter dye FAM for ST or VIC for SE at the 5' end. The dual real-time fluorescence PCR assay was set up and conditions were modified. RESULTS: The dual real-time fluorescence PCR method for ST and SE was developed successfully. ST and SE specific primers and probes amplified 16 SE and 15 ST strains, while other 28 different Sa serotypes and 17 negative control Proteus strains showed negative results. The amplification efficiency of ST and SE with the dual fluorescent PCR were all 94. 2% and R2 were 0. 998 and 0. 995 respectively, while the minimum detectable concentration reached 300 CFU/ml for ST and 260 CFU/ml for SE. The entire test can be completed within 31 hours. CONCLUSION: The method is highly specific, sensitive, and fast. The present study thus provides a rapid and effective method to detect ST and SE simultaneously from food samples. PMID- 23805535 TI - [Simultaneous determination of 11 polyphenols in ratafee by reversed-phase high performance liquid chromatography]. AB - OBJECTIVE: To develop a novel quantitative method for simultaneous analysis of 11 polyphenols in ratafee by reversed-phase high performance liquid chromatography. METHODS: The separation was performed on a Agilent Eclipse XDB C18 (4.6 mmx250 mm, 51 m) and the column temperature was set at 30 degrees C. The mobile phase was consisted of 0. 1% phosphoric acid (A) and methanol (B), with a linear gradient elution at a flow rate of I. 0 ml/min. The gradient program was as follow: 10% B isocratic (0-10 min), 10%-20% B liner (10-15 min), 20% B isocratic (15-25 min), 20%-60% B liner (25-65 min), 60% B isocratic (65-75 min). And detection wavelength was 210, 270, 320, 327 and 360 nm. RESULTS: The correlation coefficients of the 11 calibration curves were all higher than 0.9995. The scopes of the recovery rate was within the range of 85.1% to 112.0%, with RSDs no more than 2%. The limit of quantification (LOQ) and the detection limit (LOD) were 0.32-1.59 ng and 0.10-0.48 ng, respectively. CONCLUSION: The method is accurate and reliable, and can successfully analyze different ratafee samples from different sources. PMID- 23805536 TI - [Determination of 24 minerals in human milk by inductively coupled plasma mass spectrometry with microwave digestion]. AB - OBJECTIVE: To determine the levels of 24 minerals in human milk by inductively coupled plasma mass spectrometry with microwave digestion. METHODS: The samples were digested by microwave. The contents of minerals were determined by inductively coupled plasma mass spectrometry. The standard reference minerals of 1849a and 1568a from National Institute of Science and Technology were used for quality control. The accuracy and reproduability for this method were evaluated with mix standards and 1849a and 1568a standard reference materials. RESULTS: The ranges of the levels of sodium, magnesium, phosphorus, potassium, calcium, aluminum, chromium, arsenic, selenium, iron, zinc, manganese, copper, molybdenum, vanadium, cobalt, nickel, gallium, cadmium, silver, strontium, cesium, barium, lead in human milk was 34.97-415.83 mg/kg, 19.00-39.52 mg/kg, 102.13-274.53 mg/kg, 351.19-713.99 mg/kg, 180.08-349.64 mg/kg, 0.06-0.44 mg/kg, 0.9-7.37 microg/kg, 0.92-2.72 microg/kg, 0.20-21.15 microg/kg, 0.10-0.70 mg/kg, 0.56-3.25 mg/kg, 3.00-16.12 micro.g/kg, 62.16-591.69 microg/kg, 0.02-6.91 microg/kg, 5.99 13.70 microg/kg, 0.07-2.11 microg/kg, 0.77-209.26 microg/kg, 0.005-0.28 microg/kg, 0.02-0.23 microg/kg, 0.02-0.71 microg/kg, 36.89-132.26 microg/kg, 0.01 4.72 microg/kg, 0.83-28.16 microg/kg, 2.5-5.3 microg/kg, respectively. The levels of minerals in human milk in present study were consisted with other similar studies. CONCLUSION: The experiment examined the levels of minerals in human milk satisfactorily. The method has high accuracy and good reproducibility, which could be used for understanding the levels of minerals in human milk. PMID- 23805537 TI - [Determination of chromium in capsule by inductively coupled plasma-mass spectrometry]. AB - OBJECTIVE: To establish the method which determined the content of chromium(Cr) in capsule by inductively coupled plasma-mass spectrometry. METHODS: Pre digestion-microwave digestion procedures were applied to extract Cr from the capsules. The potentially interfering 40Ar12C+ and 37Cl16O+ at the chromium masses m/z 52 and 53 were reduced in intensity by approximately 2 orders of magnitude by using 0. 6 ml/min NH3 as reactive cell gas in the dynamic reaction cell (DRC) while a Rpq value of 0.55 was used. RESULTS: The correlation coefficient (r) of standard curve was 0.9996, and the detection limit of the method was 0.03 mg/kg, and the average recoveries for all determinations ranged from 86.5% to 107.8% with the related standard deviation below 5%. CONCLUSION: The method, which is of good precision and accuracy, is applicable to rapid and accurate determination of chromium content in capsule. PMID- 23805538 TI - [Determination of 15 kinds of pesticides in blood by gas chromatography-mass spectrometry]. AB - OBJECTIVE: To develop the method of gas chromatography-mass spectrometry (GC-MS) for simultaneous determination of 15 herbicides in blood. METHODS: 2ml of blood in vitro were sampled, concentrated and extracted with dichloromethane, reconstant with methanol agents of Gulonic acid lactone solution, and detected by GC-MS. RESULTS: Experimental results show that diazinon, atrazine, prometryn, methyl parathion, butachlor, bifenthrin at 4-80 microg/L, phorate, malathion, 2,4 D butyl ester, chlordane, fenpropathrin at 10-200 microg/L, alpha-endosulfan, beta-endosulfan, cyhalothrin at 20-400 microg/L, dimethoate at 40-800 microg/L, with good linear response. The correlation coefficient (r2) were between 0.998 1.000, respectively. The recovery of all analysts averaged between 56%-128% in blood samples. The detection limits of all compounds between 0.05 and 1.00 microg/L. The lower limit of quantification between 0.20 and 3.001 microg/L. CONCLUSION: The methods is apply to detect the content of analysts in blood samples. PMID- 23805539 TI - [Sequence-based typing for 61 Legionella pneumophila serogroup 1 isolates in Zhejiang Province]. AB - OBJECTIVE: To analyze the sequence characteristics of the serogroup 1 Legionella pneumophila (Lp1) strains isolated from the cooling tower water in Zhejiang province by sequence-based typing (SBT). METHODS: 61 strains of Lp1 isolated from cooling tower water in ten cities of Zhejiang Province from 2005 to 2011 were genotyped by SBT method. The nucleotide polymorphism of the sequencing results was analyzed by DnaSP 5.0, and the SBT results were cluster analyzed using SplitsTree and eBURST software. RESULTS: All 61 isolates of Lp1 were resolved into 11 STs, and 5 new STs were found in this study. The ST with the largest number of isolates was ST1 (n=50), and these ST-1 strains were found in 10 cities. The nucleotide polymorphism (Pi) of these seven housekeeping genes ranged from 0.01095 (mip) to 0.05355 (pilE). The STs of the Lpl isolates were clustered to four clonal complexes (CC), and ST-1, ST-149, ST-154 were the three main clonal complexes (CC). CONCLUSION: Genetic diversity was shown in the serogroup 1 Legionella pneumophila strains isolated from cooling tower water in Zhejiang province. PMID- 23805540 TI - Comparison of intranasal administration of xylazine, diazepam, and midazolam in budgerigars (Melopsittacus undulatus): clinical evaluation. AB - Effective sedation methods are important to facilitate safe handling for diagnostic and clinical procedures for small and often delicate birds such as budgerigars (Melopsittacus undulatus). The aim of this study was to directly compare the time of onset and duration of sedation produced by intranasal administration of xylazine, diazepam, or midazolam in budgerigars. Fifteen (seven male, eight female) clinically healthy mature budgerigars weighing 28.9 +/- 6.1 g were involved in the study Each bird was used three times in a randomized crossover study design with 7 days between treatments. Birds received xylazine (25.6 +/- 2.2 mg/kg), diazepam (13.6 +/- 1.1 mg/kg), or midazolam (13.2 +/- 1.3 mg/kg) intranasally (i.n.) using a micropipette. The onset time and dorsal recumbency duration time were measured and recorded. Sedation was produced in all birds after i.n. administration of xylazine, diazepam, and midazolam. Time to onset of sedation was significantly shorter after midazolam (1.3 +/- 0.44 min) compared with that after xylazine (2.6 +/- 0.89 min) and diazepam (2.8 +/- 0.88 min). Xylazine produced significantly longer duration of sedation (286.0 +/- 28.8 min) than that produced by diazepam (165.40 +/- 19.2 min) and midazolam (71.60 +/ 8.9 min). This study demonstrated that i.n. drug administration could provide fast and reliable sedation in budgerigars. Although i.n. midazolam or diazepam can provide adequate sedation for diagnostic and minor therapeutic procedures, xylazine at the dose used in this study is not recommended because the quality of sedation may be insufficient to perform a clinical procedure. PMID- 23805541 TI - Serum concentrations of vitamins and trace elements in clinically healthy greater flamingos (Phoeniconaias phoenicopterus rubeus) and lesser flamingos (Phoeniconaias minor). AB - Analysis of vitamins and trace elements has gained importance in avian medicine in recent years. It has become evident that interpretation should be based on species-specific reference intervals due to differences in intervals between species. This study was performed to evaluate the blood concentrations of vitamins A (retinol), B1 (thiamine), C (ascorbic acid), and E (alpha-tocopherol) and trace elements copper, selenium, and zinc for greater flamingos (Phoeniconaias (Phoenicopterus) rubeus) and lesser flamingos (Phoeniconaias minor). Reference intervals of vitamins and trace elements are presented for clinically healthy flamingos. Thirty-six clinically healthy greater flamingos, divided into male and female groups, and 14 healthy lesser flamingos were evaluated. There was no significant difference in the vitamin and trace element concentrations between male and female greater flamingos, but there was a statistically significant difference between greater flamingos and lesser flamingos for ascorbic acid, copper, and selenium. Blood concentration of ascorbic acid was greater (P < 0.001) in lesser flamingos (122.66 +/- 31.53 microM) than in male and female greater flamingos (40.53 +/- 13.83 and 30.44 +/- 11.43 microM, respectively). Blood concentrations of copper and selenium were greater (P < 0.001) in greater flamingos (copper: 5.57 +/- 1.3 microM for males, 5.65 +/- 1.53 microM for females; selenium: 2.74 +/- 0.43 microM for males, 2.54 +/- 0.7 microM for females) than lesser flamingos (copper: 2.45 +/- 1.96 microM; selenium: 0.45 +/- 0.29 microM). The mean +/- SD of vitamins A, B1, and E and zinc are reported as entire group (male and female greater flamingos and lesser flamingos): vitamin A, 1.54 +/- 0.45 micromM; thiamine, 0.49 +/- 0.07 jM; vitamin E, 31 +/- 9.8 micromol/L; and zinc, 29.52 +/- 6.49 microM. PMID- 23805542 TI - A DNA vaccine expressing ENV and GAG offers partial protection against reticuloendotheliosis virus in the prairie chicken (Tympanicus cupido). AB - Recurring infection of reticuloendotheliosis virus (REV), an avian oncogenic gammaretrovirus, has been a major obstacle in attempts to breed and release the endangered Attwater's prairie chicken (Tympanicus cupido attwateri). The aim of this study was to develop a DNA vaccine that protects the birds against REV infection. A plasmid was constructed expressing fusion proteins of REV envelope (env) and VP22 of Gallid herpesvirus 2 or REV gag and VP22. Birds vaccinated with these recombinant plasmids developed neutralizing antibodies; showed delayed replication of virus; and had significantly less infection of lymphocytes, specifically CD4+ lymphocytes. Although the vaccine did not prevent infection, it offered partial protection. Birds in field conditions and breeding facilities could potentially benefit from increased immunity when vaccinated. PMID- 23805543 TI - Anaerobic and aerobic bacteriology of the saliva and gingiva from 16 captive Komodo dragons (Varanus komodoensis): new implications for the "bacteria as venom" model. AB - It has been speculated that the oral flora of the Komodo dragon (Varanus komodoensis) exerts a lethal effect on its prey; yet, scant information about their specific oral flora bacteriology, especially anaerobes, exists. Consequently, the aerobic and anaerobic oral bacteriology of 16 captive Komodo dragons (10 adults and six neonates), aged 2-17 yr for adults and 7-10 days for neonates, from three U.S. zoos were studied. Saliva and gingival samples were collected by zoo personnel, inoculated into anaerobic transport media, and delivered by courier to a reference laboratory. Samples were cultured for aerobes and anaerobes. Strains were identified by standard methods and 16S rRNA gene sequencing when required. The oral flora consisted of 39 aerobic and 21 anaerobic species, with some variation by zoo. Adult dragons grew 128 isolates, including 37 aerobic gram-negative rods (one to eight per specimen), especially Enterobacteriaceae; 50 aerobic gram-positive bacteria (two to nine per specimen), especially Staphylococcus sciuri and Enterococcusfaecalis, present in eight of 10 and nine of 10 dragons, respectively; and 41 anaerobes (one to six per specimen), especially clostridia. All hatchlings grew aerobes but none grew anaerobes. No virulent species were isolated. As with other carnivores, captive Komodo oral flora is simply reflective of the gut and skin flora of their recent meals and environment and is unlikely to cause rapid fatal infection. PMID- 23805544 TI - Metabolic bone disease in juvenile koalas (Phascolartcos cinereus). AB - Due to climate restrictions in parts of North America and Europe, koalas (Phascolarctos cinereus) are housed indoors. Koala young (joeys) raised indoors are susceptible to the development of metabolic bone disease (MBD) due to a lack of exposure to natural ultraviolet light to themselves and their female parents (dams). In this retrospective study, radiographs from 27 koala joeys born at four zoos in North America and two zoos in Europe were evaluated for signs of MBD. Eight of the joeys were radiographically diagnosed with MBD and four additional joeys were considered suspect MBD cases; in two joeys absence or presence of MBD could not be determined. All joeys had mild to severe hip and shoulder dysplasia. There were significant associations between a lack of exposure to UV light and MBD development and between MBD and the degree of severity of hip and shoulder dysplasia. It is recommended to house breeding female koalas and their joeys outdoors whenever possible. PMID- 23805545 TI - Hematology and serum biochemistry of Sumatran rhinoceroses (Dicerorhinus sumatrensis) in a rainforest sanctuary in Way Kambas National Park, Indonesia. AB - There is a paucity of basic biological information for the Sumatran rhinoceros (Dicerorhinus sumatrensis). This information is fundamental to husbandry and management practices for captive animals and for support of in situ conservation efforts. Serial blood samples were collected over an 8-yr period to evaluate patterns in hematology and serum biochemistry values among five Sumatran rhinoceroses housed at the Sumatran Rhino Sanctuary in Way Kambas National Park, Lampung, Indonesia. Understanding the basis for variance in analytes both within and between subjects can allow use of more sensitive subject-based reference values, and is particularly suitable for small populations of endangered animals. Both intra- and intersubject variability was computed for each analyte and the associated index of individuality was determined. Previously published cutoff points for index of individuality indicate where population-based reference intervals can be used with confidence (index > 1.4) or with caution (0.6 < index < 1.4). Interrhino variability was small for the majority of analytes, with 12 of 19 analytes having an index of individuality greater than 1.4 and none having an index of individuality less than 0.6. With the high within-individual variability of most anayltes in the Sumatran rhinoceroses at the sanctuary, subject-based reference intervals offer little advantage over standard population-based reference intervals for monitoring the health of these endangered animals. Differences were noted (but not tested for statistical significance) in serum urea, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and cholesterol between young and old rhinoceroses, and in hematocrit, AST, alanine aminotransferase (ALT), LDH, and glucose between male and female rhinoceroses. Husbandry practices, animal management, nutrition and habitat factors may also impact hematology and biochemistry results, and these relationships deserve more careful investigation. This study represents the most comprehensive hematology and serum biochemistry comparison of Sumatran rhinoceroses held in natural rainforest conditions outside a traditional zoological setting. PMID- 23805546 TI - Blood mineral concentrations in manatees (Trichechus manatus latirostris and Trichechus manatus manatus). AB - Limited information is available regarding the role of minerals and heavy metals in the morbidity and mortality of manatees. Whole-blood and serum mineral concentrations were evaluated in apparently healthy, free-ranging Florida (Trichechus manatus latirostris, n = 31) and Belize (Trichechus manatus manatus, n = 14) manatees. Toxicologic statuses of the animals and of their environment had not been previously determined. Mean mineral whole-blood (WB) and serum values in Florida (FL) and Belize (BZ) manatees were determined, and evaluated for differences with respect to geographic location, relative age, and sex. Mean WB and serum silver, boron, cobalt, magnesium, molybdenum, and WB cadmium concentrations were significantly higher in BZ versus FL manatees (P < 0.05). Mean WB aluminum, calcium, manganese, sodium, phosphorus, vanadium, and serum zinc concentrations were significantly lower in BZ versus FL manatees. Adult manatees had significant and higher mean WB aluminum, manganese, sodium, antimony, vanadium, and serum manganese and zinc concentrations compared to juvenile animals. Significant and lower mean WB and serum silver, boron, cobalt, and serum copper and strontium concentrations were present in adults compared to juveniles (P < or = 0.05). Females had significant and higher mean WB nickel and serum barium compared to males (P < or = 0.05). Mean WB arsenic and zinc, and mean serum iron, magnesium, and zinc concentrations fell within toxic ranges reported for domestic species. Results reveal manatee blood mineral concentrations differ with location, age, and sex. Influence from diet, sediment, water, and anthropogenic sources on manatee mineral concentration warrant further investigation. PMID- 23805547 TI - Echocardiographic evaluation of clinically healthy Florida manatees (Trichechus manatus latirostris). AB - Antemortem studies pertaining to the manatee cardiovascular and cardiopulmonary systems are limited despite reports of cardiac disease in postmortem specimens. The objective of this project was to develop a technique for echocardiography in the Florida manatee (Trichechus manatus latirostris). Because of their unique anatomy, a ventral approach was employed by use of an echocardiography table designed specifically for this study. Fourteen clinically healthy, free-ranging and captive Florida manatees underwent echocardiography between the fall of 2011 and winter of 2012. Eight females and six males of various age categories were included in the study. Clear visualization of all valves and chambers was accomplished, and length and width measurements of the left atrium, peak aortic flow velocity, and ejection fraction percentage were calculated in most animals. Abnormalities observed during the study included atrioventricular regurgitation and severe right-atrial enlargement. Based on the results of this study, echocardiography in the Florida manatee is possible, which has both clinical and research implications in larger epidemiologic studies evaluating diseases of the cardiopulmonary and cardiovascular systems. PMID- 23805548 TI - Retrospective analysis of mortalities in elephant shrews (Macroscelididae) and tree shrews (Tupaiidae) at the Smithsonian National Zoological Park, USA. AB - Investigations into the cause of mortality and other important findings at necropsy were made into two families of small mammals at the Smithsonian National Zoological Park (SNZP; USA). Necropsy reports from 1976 through 2008 were reviewed for all elephant shrews in family Macroscelididae (n = 118) and all tree shrews in family Tupaiidae (n = 90) that lived for greater than 30 days at the SNZP. Causes of mortality were classified by body system and etiology to identify prevalent diseases and trends across demographics for each family. In elephant shrews, gastrointestinal disease (n = 18) and respiratory disease (n = 22) were important causes of mortality with an increased prevalence of pneumonia in adult males. Trauma was a common cause of mortality in tree shrews (n = 22). Cryptococcosis was an important cause of mortality in both families (n = 8 elephant shrews; n = 13 tree shrews). Bacterial infections, often systemic at time of mortality, were also common (n = 16 elephant shrews; n = 17 tree shrews). Arteriosclerosis was a common comorbid pathology noted at necropsy in certain populations, seen only in Elephantulus rufescens in the family Macroscelididae (n = 22) and in only males in the family Tupaiidae (n = 11). Gongylonemiasis was seen commonly in tree shrews (n = 15), as a comorbid finding, or in 5 cases directly leading to mortality. Awareness of the prevalence of these diseases can help guide prevention and intervention strategies. PMID- 23805549 TI - Quantitative computed tomography of the liver in juvenile green sea turtles (Chelonia mydas). AB - Quantitative computed tomography (QCT) is a highly sensitive, applicable technique for determining the x-ray attenuation of organs. This technique reveals great precision in the detection of alterations in the x-ray attenuation of hepatic parenchyma, although the lack of studies establishing normal values limits its application in wild animals. The objective of this study was to establish mean hepatic attenuation values in four healthy juvenile sea turtles (Chelonia mydas) using QCT. Helical computed tomography scans were performed and regions of interest selected in the liver after multi-planar reconstruction images were obtained. The mean attenuation value for the hepatic parenchyma in these four turtles was 60.09 +/- 5.3 standard deviation Hounsfield units. Determining normal x-ray attenuation values of the liver increases knowledge of the computed tomographic anatomy of this species and may be useful in the investigation of hepatic diseases. PMID- 23805550 TI - Estimation of normal tear production in free-living Eurasian black vultures (Aegypius monachus) and griffon vultures (Gyps fulvus) in Dadia National Park, Greece. AB - The aim of this study was to record the Schirmer tear test I (STT I) measurements in free-living vultures in order to estimate normal values. The Eurasian black vulture (Aegypius monachus), which breeds in the Mediterranean region and Asia, is listed as near threatened; it is also classified as vulnerable at the European level and endangered in Greece. The griffon vulture (Gyps fulvus), once widespread across the continent, has undergone a dramatic decline which has led to its extinction in many regions. Sixty-two animals were examined in total including 54 black vultures and 8 griffon vultures. The birds were classified into five age groups while four age groups were then combined into one large group: free-flying. STT I measurements and complete ophthalmic examinations were performed. Mean STT I value for black vultures was 10.9 +/- 3.3 mm/min (right eye, oculus dexter, OD) and 11.9 +/- 3.3 mm/min (left eye, oculus sinister, OS) and for griffon vultures was 6.4 +/- 1.8 mm/min OD and 6.5 +/- 1.8 mm/min OS. In both eyes, STT I values in black vultures were significantly higher than those recorded in griffon vultures. Intraspecific comparisons yielded a significant difference between eyes of black vultures but not between those of griffon vultures, with OS producing higher STT I readings than did OD. When STT I was compared between OD and OS for each age group separately, a statistically significant difference was detected in the immature and free-flying black vultures. In addition, black vulture hatchlings had a significantly higher tear production than did free-flying juveniles, immatures, subadults, and adults. STT I values in black vultures are similar to those reported in other Accipitriformes but are lower in griffon vultures. This difference is probably related to anatomic, evolutionary, and feeding factors and requires further investigation. PMID- 23805551 TI - The effects of hibernation and captivity on glucose metabolism and thyroid hormones in American black bear (Ursus americanus). AB - American black bears (Ursus americanus) have been shown to become transiently insulin resistant and hypothyroid during winter, but no studies have investigated these changes in long-term captive bears or in bears which remain awake year round. Wild, captive hibernating, and captive nonhibernating bears were evaluated at times corresponding to three of their major physiologic stages: fall (hyperphagic stage), winter (hibernation stage), and summer (normal activity stage). Combined insulin and glucose tolerance tests and thyroid hormone profiles were performed on all bears during each stage. All three groups of bears had evidence of insulin resistance during the winter, as compared to the summer or fall, based on glucose tolerance curves. Analysis of thyroid hormone concentration varied and distinct patterns or similarities were not apparent. While obesity in captive American black bears is multifactorial, the finding that, regardless of their ability to hibernate, captive bears retain similar physiology to their wild counterparts indicates that captive bears' complex physiologic changes need to be addressed in their management. PMID- 23805552 TI - Detection of antibodies against paramyxoviruses in tortoises. AB - Sera from a total of 202 tortoises from six countries and nine species were tested for antibodies against four different reptilian paramyxoviruses (ferlaviruses, ferlaVs) by hemagglutination inhibition (HI) test. The viruses used were a tortoise PMV (tPMV) and three squamatid PMV isolates, each belonging to a different subgroup of ferlaV within the genus Ferlavirus. HI tests revealed that antibodies against ferlaVs occurred regularly in the tested samples (5.5%). One and a half percent of the tested samples have measurable antibody titers against the group A isolate, 3% had antibodies against the group B isolate, and 1% had antibodies against the group C isolate. The significantly highest number of positive reactions was detected against the tortoise isolate (5%). Most of the animals that tested positive for one of the snake isolates also tested positive in HI assays with the tortoise isolate. Of the samples from different origins, the sera from Great Britain showed the highest percentage of positive tested animals (10.3%, n = 39), followed by those from Spain (10%, n = 10), while none of the samples from Madagascar or Italy scored positive. Since in most cases animals from one country came from the same collection, this does not represent the real prevalence of ferlaV in tortoises in these countries but rather indicates that ferlaVs occur in a number of different countries and tortoise species. PMID- 23805553 TI - Repeated exposure of goldfish (Carassius auratus) to tricaine methanesulfonate (MS-222). AB - Goldfish that have been repeatedly exposed to tricaine methanesulfonate (MS-222) require greater concentration of the drug to attain equivalent planes of anesthesia, but the mechanism for this increased anesthetic need is unknown. Minimum anesthetic concentration (MAC) is a commonly used method with which to compare anesthetics. It was hypothesized that fish exposed to MS-222 daily would have an increased MAC. It was also hypothesized that fish exposed daily to MS-222 would develop histomorphologic changes to their gills to explain the increasing demand. Forty-nine Serasa comet goldfish were enrolled and were divided into three populations (n = 15, n = 15, and n = 19). In trial 1, using an up-down method, MAC was determined daily after 4 min of exposure to MS-222 for which the starting concentration was 160 mg/L. In trial 2, MAC was determined following 2 min of exposure to MS-222 for which the starting concentration was 260 mg/L. In trial 3, four naive fish were euthanatized and gills collected for histology and electron microscopy (EM). The remaining fish were exposed to MS-222 daily for 4 wk. Four fish were euthanatized and their gills submitted for similar examination at 2 wk and 4 wk. MAC for fish exposed to MS-222 for 4 min increased from 120 to 160 mg/L. The regression line had a slope of 1.51 +/- 0.26 (R2 = 0.65; P < 0.0001). MAC for fish exposed to MS-222 for 2 min increased from 210 pmm to 220 mg/L; the regression line had a slope of 0.52 +/- 0.38 (R2 = 0.12; P = 0.2). Histologic and EM examination of gills did not show morphologic changes indicative of a reaction to MS-222. Goldfish in this study had an increased requirement for MS-222 following daily exposure for 4 min but not following daily exposure for 2 min at a higher concentration. The cause of this increased anesthetic need is not related to morphologic changes to the gills. PMID- 23805554 TI - Causes of morbidity and mortality in captive kori bustards (Ardeotis kori) in the United States. AB - The kori bustard (Ardeotis kori) is a popular avian resident of zoos and wild animal parks throughout North America and Europe. As this species' numbers continue to decline throughout its native African range, the need for its successful captive management becomes increasingly apparent. To this end, an understanding of the factors causing morbidity and mortality in the captive kori bustard population is critical. Here, the demographics, husbandry practices, and causes of morbidity and mortality of 94% of captive kori bustards (198 individuals) housed in zoos throughout the United States between 1988 and 2008 are described, and suggestions for captive management targets in this species are presented. The most common clinical and pathologic findings observed were lameness (48 cases), gastrointestinal parasitism (45 cases), and wing integumentary trauma (32 cases). Trauma was a very common cause of morbidity (135 cases) and was the most common cause of mortality (53 individuals, 40% of deceased animals). Considering the high prevalence of traumatic injury and death observed in this population, captive management of kori bustards should focus on developing strategies that minimize opportunity for injury. Priorities include preventing exposure to potentially hostile exhibit mates, decreasing stress associated with human interactions, and researching the effects of diet on skeletal development of young birds. PMID- 23805555 TI - Brevetoxin in blood, biological fluids, and tissues of sea turtles naturally exposed to Karenia brevis blooms in central west Florida. AB - In 2005 and 2006, the central west Florida coast experienced two intense Karenia brevis red tide events lasting from February 2005 through December 2005 and August 2006 through December 2006. Strandings of sea turtles were increased in the study area with 318 turtles (n = 174, 2005; n = 144, 2006) stranding between 1 January 2005 and 31 December 2006 compared to the 12-yr average of 43 +/- 23 turtles. Live turtles (n = 61) admitted for rehabilitation showed clinical signs including unresponsiveness, paresis, and circling. Testing of biological fluids and tissues for the presence of brevetoxin activity by enzyme-linked immunosorbent assay found toxin present in 93% (52 of 56) of live stranded sea turtles, and 98% (42 of 43) of dead stranded sea turtles tested. Serial plasma samples were taken from several live sea turtles during rehabilitation and toxin was cleared from the blood within 5-80 days postadmit depending upon the species tested. Among dead animals the highest brevetoxin levels were found in feces, stomach contents, and liver. The lack of significant pathological findings in the majority of animals necropsied supports toxin-related mortality. PMID- 23805556 TI - Variation in hematologic and serum biochemical values of belugas (Delphinapterus leucas) under managed care. AB - Blood analytes are critical for evaluating the general health of cetacean populations, so it is important to understand the intrinsic variability of hematology and serum chemistry values. Previous studies have reported data for follow-up periods of several years in managed and wild populations, but studies over long periods of time (> 20 yr) have not been reported. The study objective was to identify the influences of partitioning characteristics on hematology and serum chemistry analytes of apparently healthy managed beluga (Delphinapterus leucas). Blood values from 31 managed belugas, at three facilities, collected over 22 yr, were assessed for seasonal variation and aging trends, and evaluated for biologic variation among and within individuals. Linear mixed effects models assessed the relationship between the analytes and sex, age, season, facility location, ambient air temperature, and photoperiod. Sex differences in analytes and associations with increasing age were observed. Seasonal variation was observed for hemoglobin, hematocrit, mean corpuscular volume, monocytes, alkaline phosphatase, total bilirubin, cholesterol, and triglycerides. Facilities were associated with larger effects on analyte values compared to other covariates, whereas age, sex, and ambient temperature had smaller effects compared to facility and season. Present findings provide important baseline information for future health monitoring efforts. Interpretation of blood analytes and animal health in managed and wild populations over time is aided by having available typical levels for the species and reference intervals for the degree to which individual animals vary from the species average and from their own baseline levels during long-term monitoring. PMID- 23805557 TI - Persistent Giardia spp. and Trichuris spp. infection in maras (Dolichotis patagonum) at a zoo in Greece. AB - The mara (Dolichotis patagonum) is a species classified as "Near Threatened" by the International Union for Conservation of Nature. In the wild, it inhabits only Argentina, but it is also kept in zoos around the world. In order to investigate the endoparasites of the maras kept in the Attica Zoological Park, Greece, four fecal examinations were performed in a period of 4 yr (2008-2011) by standard parasitologic methods. Cysts of the protozoan parasite Giardia spp. and eggs of the nematode Trichuris spp. were found in all four examinations. The possible routes of infection of the maras and the importance of these parasites to other animals and to humans are discussed. PMID- 23805558 TI - Efficacy of treatment and long-term follow-up of Batrachochytrium dendrobatidis PCR-positive anurans following itraconazole bath treatment. AB - All anuran specimens in the Wildlife Conservation Society's collections testing positive for Batrachochytrium dendrobatidis (Bd) were treated with itraconazole and then studied after treatment to assess the long-term effects of itraconazole and the drug's effectiveness in eliminating Bd carriers. Twenty-four individuals and eight colonies of 11 different species (75 total specimens) tested positive for Bd via polymerase chain reaction (PCR) on multicollection survey. All positive individuals and colonies were treated with a 0.01% itraconazole bath solution and retested for Bd via one of two PCR methodologies within 14 days of treatment completion, and all were negative for Bd. A total of 64 animals received secondary follow-up PCR testing at the time of death, 6-8 mo, or 12-15 mo post-treatment. Fourteen animals (14/64, 21.9%) were PCR positive for Bd on second follow-up. The highest percentage positive at second recheck were green and-black poison dart frogs (Dendrobates auratus; 5/5 specimens, 100%), followed by red-eyed tree frogs (Agalychnis callidryas; 4/11, 36.4%), grey tree frogs (Hyla versicolor; 1/3, 33.3%), and green tree frogs (Hyla cinera; 3/11, 27.3%). Re-testing by PCR performed on 26/28 individuals that died during the study indicated 11/26 (42.3%) were positive (all via DNA extracted from formalin-fixed paraffin-embedded skin sections). However, there was no histologic evidence of chytridiomycosis in any of 27/28 individuals. The small number of deceased animals and effects of postmortem autolysis limited the ability to determine statistical trends in the pathology data, but none of the necropsied specimens showed evidence of itraconazole toxicity. Problems with itraconazole may be species dependent, and this report expands the list of species that can tolerate treatment. Although itraconazole is effective for clearance of most individuals infected with Bd, results of the study suggest that repeat itraconazole treatment and follow-up diagnostics may be required to ensure that subclinical infections are eliminated in amphibian collections. PMID- 23805559 TI - Serosurvey of leptospirosis in feral hogs (Sus scrofa) in Florida. AB - Leptospira is a global pathogen of emerging public health importance in both developing and industrialized nations and can infect almost all mammalian species, including humans. As suburbanization and the popularity of outdoor recreational activities increases, so do human-wildlife and companion animal wildlife interfaces. Florida offers a tropical climate favorable for outdoor activities and a semirural landscape that sustains an abundant feral hog population. Because no survey ofleptospirosis in feral hogs (Sus scrofa) in Florida has been published to our knowledge, we sought to establish preliminary seroprevalence ofleptospirosis exposure in feral hogs in Florida. Blood samples were collected opportunistically from 158 male and 166 female feral hogs taken at managed hunts and by permitted trappers in the northern, central, and southern regions of Florida. Samples were then analyzed using the microscopic agglutination test (MAT) for antibody titers to 20 Leptospira serovars representing 17 serogroups. A titer of > 1:100 was considered positive; 33% (107/324 total samples) were positive to at least one serovar, and 46% of those were positive to multiple serovars. Antibodies to L. interrogans serovar Bratislava strain Jez Bratislava (serogroup Australis) was the most common, with 18% (58/324) testing positive for antibodies. These initial data indicate that there is a significant possibility of feral hogs having a larger role in the complex etiology of leptospirosis in Florida than historically estimated and that further investigation is warranted. PMID- 23805560 TI - Intestinal and cloacal strictures in free-ranging and aquarium-maintained green sea turtles (Chelonia mydas). AB - Intestinal or cloacal strictures that resulted in intestinal obstruction were diagnosed in six green sea turtles (Chelonia mydas) from three rehabilitation facilities and two zoologic parks. The etiologies of the strictures were unknown in these cases. It is likely that anatomic adaptations of the gastrointestinal tract unique to the green sea turtle's herbivorous diet, paired with causes of reduced intestinal motility, may predispose the species to intestinal damage and subsequent obstructive intestinal disease. In aquarium-maintained green sea turtles, obesity, diet, reduced physical activity, chronic intestinal disease, and inappropriate or inadequate antibiotics might also be potential contributing factors. Clinical, radiographic, and hematologic abnormalities common among most of these sea turtles include the following: positive buoyancy; lethargy; inappetence; regurgitation; obstipation; dilated bowel and accumulation of oral contrast material; anemia; hypoglycemia; hypoalbuminemia; hypocalcemia; and elevated creatine kinase, aspartate aminotransferase, and blood urea nitrogen. Although these abnormalities are nonspecific with many possible contributing factors, intestinal disease, including strictures, should be considered a differential in green sea turtles that demonstrate all or a combination of these clinical findings. Although diagnostic imaging, including radiographs, computed tomography, or magnetic resonance imaging, are important in determining a cause for suspected gastrointestinal disease and identifying an anatomic location of obstruction, intestinal strictures were not successfully identified when using these imaging modalities. Lower gastrointestinal contrast radiography, paired with the use of oral contrast, was useful in identifying the suspected site of intestinal obstruction in two cases. Colonoscopy was instrumental in visually diagnosing intestinal stricture in one case. Therefore, lower gastrointestinal contrast radiography and colonoscopy should be considered in green turtles when gastrointestinal obstructions are suspected. Although partial strictures of the cloacal opening may be identified on gross examination and might be managed with appropriate medical treatment, surgical intervention or humane euthanasia are likely the only options for sea turtles once small or large intestinal strictures have formed. PMID- 23805561 TI - Findings of Devriesea agamarum associated infections in spiny-tailed lizards (Uromastyx sp.) in Croatia. AB - Actinobacteria are common agents that cause skin diseases in captive desert lizards, including the recently described Devriesea agamarum. To date, infections caused by D. agamarum, their symptoms, and treatment have been described only by the research group from Belgium that isolated the species in 2008. This article presents the symptoms that indicate the possibility of a D. agamarum-associated infection, such as scaly changes around the mouth in a juvenile lizard (Uromastyx ocelatta) and dermatitis in the form of skin scaling around the mouth and cloaca and over the dorsal part of the body in a group of four spiny-tailed lizards (Uromastyxgeyri). In two animals, swelling of the front limbs with the loss of some toes was also noted, a symptom not previously described with D. agamarum infections. Bacteriologic analysis of dermal lesion samples confirmed the presence of D. agamarum in all subjects. Treatment with ceftazidime was carried out, and the symptoms of dermatitis resolved, followed by negative bacteriologic findings. This is the first report, to our knowledge, that describes the diagnostics, detailed clinical picture with newly described symptoms, and treatment of lizards with D. agamarum-associated skin lesions that reside outside of Belgium. The results also confirm the effectiveness of the systemic administration of third-generation cephalosporin antibiotics in combination with local chlorhexidine in the treatment of D. agamarum infections. PMID- 23805562 TI - Scuticociliatid ciliate outbreak in Australian potbellied seahorse, Hippocampus abdominalis (Lesson, 1827): clinical signs, histopathologic findings, and treatment with metronidazole. AB - A severe outbreak of scuticociliatosis occurred in Australian pot-bellied seahorse, Hippocampus abdominalis (Lesson, 1872), kept at the Vancouver Aquarium Marine Science Centre (Vancouver, British Columbia, Canada). Clinical signs included anorexia, lethargy, irregular respiration, and death. Cytology and histopathology revealed a high number of histophagous ciliated protozoa within the tissues. The parasite, identified as Philasterides dicentrarchi, was observed in several internal organs that appeared edematous and hemorrhagic upon postmortem examination. Severe histopathologic lesions were reported in particular in the ovary, the kidney, and the intestine. This infection was successfully treated with metronidazole via bath therapy. No further evidence of this parasite was found in the treated fish. PMID- 23805563 TI - Benign gastric neuroendocrine tumors in three snow leopards (Panthera uncia). AB - Neuroendocrine tumors are relatively rare neoplasms arising from neuroendocrine cells that are distributed throughout the body and are predominant in the gastrointestinal tract. This report describes benign, well-differentiated gastric neuroendocrine tumors in three captive snow leopards (Panthera uncia). All tumors were well circumscribed, were within the gastric mucosa or submucosa, and had histologic and immunohistochemical features of neuroendocrine tumors. Histologic features included packeted cuboidal to columnar epithelial cells that were arranged in palisades or pseudorosettes and contained finely granular cellular cytoplasm with centrally placed, round nuclei. Cytoplasmic granules of neoplastic cells strongly expressed chromogranin A, variably expressed neuron-specific enolase, and did not express synaptophysin or gastrin. Each leopard died or was euthanatized for reasons unrelated to its tumor. PMID- 23805564 TI - Dehydration as an effective treatment for brevetoxicosis in loggerhead sea turtles (Caretta caretta). AB - Harmful algal blooms are known to cause morbidity and mortality to a large number of marine and estuarine organisms worldwide, including fish and marine mammals, birds, and turtles. The effects of these algal blooms on marine organisms are due to the various toxins produced by the different algal species. In southwest Florida, frequent blooms of the dinoflagellate Karenia brevis, which produces neurotoxins known as brevetoxins, cause widespread fish kills and affect many marine animals. In 2005-2007, numerous sea turtles of several species underwent treatment for brevetoxicosis at the Sea Turtle Rehabilitation Hospital. In green sea turtles, Chelonia mydas, and Kemp's ridley sea turtles, Lepidochelys kempii, symptoms associated with brevetoxicosis were limited to neurologic signs, such as the inability to control the head (head bobbing) and nervous twitching. For these turtles, treatment involved removing the turtles from the environment containing the toxins and providing short-term supportive care. In loggerhead sea turtles, Caretta caretta, symptoms were more generalized; thus, a similar approach was unsuccessful, as was routine treatment for general toxicosis. Loggerhead sea turtles had more extreme neurologic symptoms including coma, and other symptoms that included generalized edema, conjunctival edema, and cloacal or penile prolapse. Treatment of brevetoxicosis in loggerhead sea turtles required a therapeutic regimen that initially included dehydration and systemic antihistamine treatment followed by supportive care. PMID- 23805565 TI - Papillary cystadenocarcinoma of the mammary gland with metastases to the gastrointestinal tract in a Himalayan brown bear (Ursus arctos). AB - A 17-yr-old, multiparous female brown bear (Ursus arctos) bred in captivity at the Himalayan Nature Park, Kufri, Shimla, Himachal Pradesh, India, died after a short progressive illness of 2 wk duration. Clinically, the bear had dyspnea and was pyretic, inappetent, and lethargic. Within the right pectoral mammary gland was an 11-cm diameter, round, firm, subcutaneous mass. At postmortem examination, the mammary gland revealed a well-differentiated, multinodular infiltrative mass with multiple nonuniform cystic spaces. These cystic spaces were filled with watery, opaque white to yellow contents. Additionally, multifocal, nodular, ovoid intraluminal masses that extended transmurally from the mucosal surface to the serosa were detected in the duodenum and jejunum. Histopathologic examination revealed papillary cystadenocarcinoma of the mammary gland with metastases to the intestine, which has not been documented previously in Himalayan brown bears. PMID- 23805566 TI - Diagnosis and management of intestinal partial obstruction in a loggerhead turtle (Caretta caretta). AB - A loggerhead sea turtle (Caretta caretta) was suspected of ingesting rubber suction cups during rehabilitation following a cold-stun event. Survey radiographs were inconclusive. Computed tomography (CT) was performed to determine whether the objects had been ingested after traditional radiographs failed to resolve the material. The items were identified, and a partial obstruction was diagnosed. The case was managed with medical therapy using white petrolatum and light mineral oil administered to the turtle in fish for 3 wk. The CT exam was repeated 2 wk into the therapy. A persistent partial obstruction was identified; however, progression of the foreign objects through the intestinal tract was evident and continued medical mangement was deemed appropriate. The foreign bodies were passed with feces 26 days after ingestion. PMID- 23805568 TI - Diagnosis and treatment considerations in a case of malignant mesenchymoma in an African fur seal (Arctocephalus pusillus). AB - A 20-yr-old African fur seal (Arctocephalus pusillus) presented with a slowly growing mass located on the dorsum at the level of the last thoracic vertebrae. The mass was hard, 10 cm in diameter, and not adherent to the underlying tissues. Multiple biopsies were collected for histopathology and revealed extensive areas of necrosis, small nodules of malignant mesenchymal proliferation with areas of chondroid metaplasia, and atypical cells in vessel walls. The morphologic diagnosis was suggestive of malignant mesenchymal neoplasia originating from the vascular wall. The mass was removed 1 mo later due to ulceration and infection. Histologically, based on the World Health Organization's classification of neoplastic processes in domestic animals, the tumor was consistent with malignant mesenchymoma. The margins of resection revealed the presence of neoplastic cells. Based on these results, the particular species involved, the high local invasiveness, and the high metastatic index of this malignant tumor in domestic mammals and humans, the prognosis was poor. The animal died 6 mo later with metatastic disease. PMID- 23805569 TI - Mycobacteriosis, Mycobacterium chelonae, in a captive yellow stingray (Urobatis jamaicensis). AB - An adult yellow stingray (Urobatis jamaicensis) from a touch-tank exhibit developed a large abscess on the dorsal aspect of the calvarium and swollen soft tissue surrounding the left spiracle. A large amount of fluid exudate was drained from the abscess. Mycobacterium chelonae was diagnosed by cytology of the exudate and by polymerase chain reaction and sequencing. The animal was euthanized and disseminated mycobacteriosis was confirmed with histology. PMID- 23805567 TI - Successfully treated dermatomycosis in California sea lions (Zalophus californianus). AB - We describe clinical cases caused by Microsporum gypseum in two subadult male California sea lions (Zalophus californianus). Dermatomycosis is uncommonly reported in pinnipeds, including this species. In these cases, skin lesions were multifocal to coalescing, involved all flippers, and were most pronounced on the ventral surfaces of flippers. They were well-demarcated, depigmented, and covered with crusts. The definitive diagnosis was obtained through microscopic examination and fungal culture of skin scrapings. Oral terbinafine and topical enilconazole were used as treatments for 65 days, and complete recovery was subsequently achieved. California sea lion, dermatomycosis, Microsporum gypseum, terbinafine, enilconazole PMID- 23805570 TI - Environmental management procedures following fatal melioidosis in a captive chimpanzee (Pan troglodytes). AB - A 40-yr-old male captive chimpanzee (Pan troglodytes) presented with depression and anorexia for 7 days. The tentative diagnosis, following a physical examination under anesthesia, was pneumonia with sepsis. Despite antibiotic treatment and supportive care the chimpanzee died a week following presentation. Gross pathology confirmed severe purulent pneumonia and diffuse hepatosplenic abscesses. Detected in serum at the time of the initial examination, the melioidosis serum antibody titer was elevated (> 1:512). Soil samples were collected from three sites in the exhibit at three depths of 5, 15, and 30 cm. By direct and enrichment culture, positive cultures for Burkholderia pseudomallei were found at 5 and 15 cm in one site. The other two sites were positive by enrichment culture at the depth of 5 cm. To prevent disease in the remaining seven troop members, they were relocated to permit a soil treatment with calcium oxide. The exhibit remained empty for approximately 1 yr before the chimpanzees were returned. During that period, the soil in the exhibit area was again cultured as before and all samples were negative for B. pseudomallei. Following the soil treatment in the exhibit, all chimpanzees have remained free of clinical signs consistent with melioidosis. PMID- 23805571 TI - Serum vitamin D levels in free-ranging koalas (Phascolarctos cinereus). AB - Due to climatic conditions in Northern America and Europe, koalas (Phascolarctos cinereus) are often housed indoors. Koala joeys raised in these environments are susceptible to the development of metabolic bone disease due to a lack of exposure to solar ultraviolet radiation to themselves and their dam. As an initial step toward describing vitamin D sufficiency and adequately measuring responses to supplementation, vitamin D values were calculated by using serum collected from 20 free-ranging koalas on St. Bees Island, Queensland, Australia. Vitamin D values ranged from 8.1 to 30.4 pg/ml (18.4 +/- 5.5 pg/ml) for 1, 25 hydroxyvitamin D, and from 1 to 14 nM/L (7.4 +/- 3.0 nM/L) for 25-hydroxyvitamin D. These koala serum vitamin D values are unusually low when compared with eutherian mammals. Although this study was limited in numbers and in the geographically range of the koalas sampled, it does suggest that the koala's requirement for vitamin D is low. Therefore, supplementation to prevent disease may be relatively easy to achieve because low doses will likely meet requirements. Caution should be taken to avoid intoxication if supplementing vitamin D in koalas. PMID- 23805572 TI - Goats are a potential reservoir for the herpesvirus (MCFV-WTD), causing malignant catarrhal fever in deer. AB - In the recent investigation of malignant catarrhal fever in a red brocket deer (Mazama americana) from a Texas zoo, the viral DNA from the herpesvirus termed MCFV-WTD, which causes disease in white-tailed deer (Odocoileus virginianus), was detected. The epidemiology information revealed that the red brocket deer had been associated with a herd of pygmy goats (Capra hircus) at the zoo. MCFV-WTD DNA was also detected in one of these 12 goats that were malignant catarrhal fever viral antibody positive. The amplified herpesviral sequences from the affected deer and the MCFV-WTD-positive goat were identical, and matched the sequence in GenBank. Three of 123 DNA samples from various breeds of goats from different geographic locations in the United States were positive for MCFV-WTD DNA. The study shows that MCFV-WTD is capable of causing malignant catarrhal fever in other species of deer besides white-tailed deer and suggests that goats are a potential reservoir for the virus. PMID- 23805573 TI - Polycystic kidney disease in a European roe deer (Capreolus capreolus). AB - A severe case of polycystic nephropathy was seen in an adult European roe deer (Capreolus capreolus), culled in a German hunting district. The doe had bilaterally drastically enlarged kidneys, completely riddled with variably sized, fluid-filled cysts of up to 4 cm in diameter. Histopathologic and ultrastructural examination revealed disseminated formation of cysts with flattened epithelial cell linings in the entire renal parenchyma, as well as severe dilations of renal tubules, marked interstitial fibrosis, nephron atrophy, and chronic interstitial lymphoplasmacytic infiltrations in the intercystic kidney tissue. These morphologic findings most likely resemble the hallmarks of autosomal dominant polycystic disease in humans, and present the first detailed description of a case of polycystic kidney disease in a roe deer. PMID- 23805574 TI - Traumatic elbow luxation in a free-ranging hedgehog (Erinaceus europaeus): surgical management using circumferential suture prostheses. AB - A free-ranging adult female hedgehog (Erinaceus europaeus) was presented injured, presumably from vehicular trauma. Clinical and radiographic examination under general anesthesia revealed a lateral elbow luxation. Closed reduction was unsuccessful, so a surgical approach with circumferential suture prostheses was used to stabilize the elbow. Neither perioperative nor postoperative complications were recorded. The hedgehog regained good range of motion of the elbow and was fully able to run and to roll into a ball. PMID- 23805575 TI - Diagnosis and successful treatment of a lung abscess associated with Brucella species infection in a bottlenose dolphin (Tursiops truncatus). AB - This brief communication describes the clinical presentation, antemortem diagnosis, and successful treatment of a pulmonary abscess associated with a Brucella sp. in a 27-yr-old female bottlenose dolphin (Tursiops truncatus). Ultrasound revealed a 3-cm diameter hypoechoic mass deep to the pleural lining in the left lung field. Multiple ultrasound-guided fine-needle aspirates were performed and tested for bacterial and fungal etiology. All cultures were negative, but the infectious agent was identified by MicroSEQ analysis in two samples and confirmed with real-time polymerase chain reaction (PCR) amplification using known Brucella sp. primers. Amikacin was infused into the abscess and was followed by an oral doxycycline and rifampin protocol. Follow-up diagnostic imaging, including radiographs and computed tomography, revealed a resolved lesion with minimal mineralization within the affected lung fields. Brucellosis should be considered for pulmonary disease in dolphins, and personnel who interact with marine animals should use caution to prevent zoonotic brucellosis. PMID- 23805576 TI - Episodic syncope caused by ventricular flutter in a tiger (Panthera tigris). AB - A captive, 9-yr-old castrated male tiger (Panthera tigris) from an exotic cat sanctuary and rescue facility was observed to have three collapsing episodes within a 2-wk interval prior to being examined by veterinarians. No improvement in clinical signs was noted after empiric treatment with phenobarbital. During a more complete workup for epilepsy, ventricular flutter was observed on electrocardiogram (ECG). The arrhythmia resolved with a single intravenous bolus of lidocaine. Cardiac structure and function were unremarkable on echocardiogram and cardiac troponin I levels were within normal limits for domestic felids. No significant abnormalities were noted on abdominal ultrasound. Complete blood count and biochemistry panel were unremarkable, and heartworm antigen and Blastomyces urine antigen enzyme-linked immunosorbent assays were negative. Antiarrhythmic treatment with sotalol was initiated. On follow-up ECG performed 1 mo later, no significant arrhythmias were noted, and clinical signs have completely resolved. PMID- 23805577 TI - Persimmon phytobezoars in meerkats (Suricata suricatta). AB - Two meerkats (Suricata suricatta) died acutely and gastric bezoars were found at necropsy. Four of the eight remaining meerkats had bezoars identified radiographically. Surgical gastrotomies were performed and bezoars containing orange fibrous material were removed. Histologic examination of the bezoars and persimmon fruit from a tree in the exhibit revealed that the materials were identical. Tannins found in ripe persimmons are known to coagulate in the presence of gastric acid, and the resultant phytobezoars can lead to gastrointestinal obstructions. All four meerkats recovered uneventfully. The combination of interspecies aggression and a diet change may have led to consumption of persimmons produced by a tree in the exhibit. Persimmon phytobezoars are also seen in humans and horses. PMID- 23805578 TI - Cholangiocarcinoma of intrahepatic bile ducts with disseminated metastases in an African lion (Panthera leo). AB - A cholangiocarcinoma is reported in an 18-yr-old, female African lion (Panthera leo). The primary tumor consisted of multifocal to coalescing, hepatic, white yellow masses distributed throughout the liver lobes. Metastases were present in regional lymph nodes, peritoneal surface, and lungs. Histologically, the tumor was characterized by a tubular pattern with alcian- and periodic acid-Schiff positive secretory material in cystic spaces. The neoplastic cells were positive to broad-spectrum cytokeratins. Histochemical and immunohistochemical stains were consistent with bile duct carcinoma. Biliary tumors arising from the gallbladder have been reported in lions. However, to the authors' knowledge, this is the first case of intrahepatic bile duct carcinoma reported in an African lion. PMID- 23805579 TI - Oral fibrosarcoma in a black iguana (Ctenosaura pectinata). AB - A case of oral fibrosarcoma in a 13-yr-old male black iguana (Ctenosaura pectinata) is reported here. The iguana exhibited new tissue formation involving a large part of the maxilla and hard palate, which histologically and ultrastructurally corresponded to a primary fibrosarcoma of the oral cavity. Although there are reports of fibrosarcomas in other reptiles, such as snakes and crocodiles, no reports of this neoplasm in the oral cavity of an iguana were reported, which suggests that it is either infrequent or infrequently sampled for histological diagnosis. As an isolated case in an adult iguana living at a conservation center, it is likely that this diagnosis is associated with advanced age. The prognosis is considered unfavorable. PMID- 23805580 TI - Diagnosis and management of atypical hypoadrenocorticism in a variable flying fox (Pteropus hypomelanus). AB - A 19-yr-old intact female variable flying fox (Pteropus hypomelanus) presented with lethargy, behavior changes, and substantial weight loss. Initial clinical pathology revealed hypoglycemia and reduced ionized serum calcium, and imaging, including computed tomography, did not lead to a diagnosis. An adrenocorticotropic hormone (ACTH) stimulation test revealed baseline and post ACTH cortisol concentrations that were lower than reported normal baseline cortisol concentrations in this species. Treatment with prednisolone resolved the clinical signs and laboratory abnormalities. Repeated attempts to decrease the prednisolone dose caused recurrence of clinical signs and weight loss. Based on diagnostic test results and response to therapy, a diagnosis of atypical hypoadrenocorticism was made. PMID- 23805581 TI - Clinical challenge. Large and small ventral abdominal swellings in Panamanian golden frogs (Atelopus zeteki). PMID- 23805582 TI - Memorial Day: a call to service for PAs. PMID- 23805584 TI - Recalibrating to meet the nation's health care demands. PMID- 23805585 TI - Which drugs are indicated for upper GI bleeding? PMID- 23805586 TI - A worrisome thigh rash. PMID- 23805587 TI - Rethinking asthma education: a practical approach to improve treatment outcomes. AB - Many asthma-related hospitalizations are preventable with appropriate access to care as well as adherence to lifestyle modifications and medical treatment, yet as many as half of all patients with asthma fail to adhere to treatment as prescribed. Identifying the specific barriers affecting a patient and engaging with the patient in active planning to overcome adherence barriers is a practical strategy for achieving and sustaining adherence to long-term therapy. PMID- 23805588 TI - Shock: early recognition and resuscitation are key. AB - A life-threatening syndrome of circulatory failure, shock can be caused by loss of intravascular volume, obstruction of flow through the vascular compartment, or a generalized state of vasodilation. Early recognition and resuscitation are key to reducing patient mortality. PMID- 23805589 TI - Acute perilunate dislocation in a pediatric patient. AB - Lunate and perilunate dislocations are rare in children, but should be suspected in patients with significant wrist swelling and decreased range of motion after trauma or falls on an outstretched hand. PMID- 23805590 TI - An older man with gout and vision changes. AB - Digoxin is widely used to manage heart failure and atrial fibrillation, and requires careful patient monitoring to avoid toxicity. Vision disturbances are a specific indicator of toxicity and may be the initial sign. Treatment depends on the patient's clinical presentation. PMID- 23805591 TI - You cannot just treat the skin: primary care implications of psoriasis. PMID- 23805592 TI - Improving patient-centered care through advance care planning. AB - Advance care planning is crucial for patients confronting incurable, debilitating, or terminal disease. Discussing end-of-life issues can reduce overtreatment and undertreatment as defined by the patient, and improve satisfaction with care. PMID- 23805593 TI - Career patterns of physician assistants: a retrospective longitudinal study. AB - OBJECTIVES: A distinguishing characteristic of the physician assistant (PA) profession is career flexibility to move between specialties without further training or certification. The objectives of this study were to characterize the number and type of practice specialties and to explore attitudes towards career flexibility. METHODS: Practice patterns were examined using a survey of AAPA member and non-member graduates from the classes of 1978, 1988, and 1998. RESULTS: Overall, respondents (n = 1,703; 31%) reported practicing in an average of 1.95 specialty practices per decade over the course of their career (range, 1 18; SD, 1.40). Adjusted for the number of decades elapsed postgraduation, the 1978, 1988, and 1998 cohorts practiced in an average of 1.08 (SD, 0.71), 1.51 (SD, 1.02), and 2.41 (SD, 1.49) specialties per decade, respectively (P < 0.0001; all pair-wise comparisons significant, P < 0.001). CONCLUSIONS: Most PAs change specialties during their career, and this trait of the profession is highly valued. PMID- 23805594 TI - A physician assistant rheumatology fellowship. AB - A rheumatology postgraduate fellowship for physician assistants was inaugurated in 2004 as a pilot initiative to supplement shortages in rheumatologists. An administrative analysis documented that each PA trainee achieved a high level of rheumatology exposure and proficiency. Classes in immunology, rheumatology, and internal medicine augmented clinical training. Faculty and trainees considered PA postgraduate training in rheumatology worthwhile. PMID- 23805595 TI - Atrial septal defect. PMID- 23805596 TI - Sublingual immunotherapy for aeroallergen desensitization. PMID- 23805597 TI - A proper lady and a Wilde finding. PMID- 23805598 TI - Ear pain and fever. PMID- 23805599 TI - Hauntings: when the clinical mark is missed. PMID- 23805600 TI - The relationships between postpartum adaptation and postpartum depression symptoms of first pregnancy mothers in Taiwan. AB - BACKGROUND: Motherhood is a critical situation characterized by role conflicts. These conflicts between the roles of mother, worker, and wife are the norm in the postpartum period and may jeopardize a mother's well-being. The purpose of this study was to explore the relationships between postpartum adaptation and depression among new mothers who live in northern Taiwan. MATERIAL AND METHODS: A total of 186 first pregnancy mothers were recruited via convenience sampling methods and they completed mailed questionnaires between 1 week and 2 months after giving birth. Structured questionnaires including Demographic Inventory Scale, Postpartum Self-Evaluation Questionnaire, and Edinburgh Postnatal Depression Scale were used. RESULTS: Ninety-four (50.5%) women exhibited depressive symptoms (EPDS > 10) and 73 (39.2%) women needed to consult the doctor (EPDS > 12). The risk factors for postpartum depression symptoms included unplanned birth, low socioeconomic status, and part-time employment. The correlation between women's different aspects of postpartum adaptation and depression ranged was from low to medium. The best predictors of postpartum depression were confidence in their own competence of motherhood tasks, satisfaction with life circumstances, and partner participating in child care. These three subsets explained 44.8% of the total variance. CONCLUSION: This study shows that healthcare providers who work with primiparas during the first 2 months after giving birth should pay more attention to postpartum depression, keeping in mind associated risk factors. A new mother's confidence in her own abilities as a new mother may be particularly important in determining the likelihood of postpartum depression. PMID- 23805601 TI - Association of CD8 T cells with depression and anxiety in patients with liver cirrhosis. AB - OBJECTIVE: Depression and anxiety frequently co-occur in patients with. cirrhosis, but their underlying biological substrates are unclear. There is now evidence to suggest that depression is accompanied by signs of an immune response. This study investigated the correlation between depression/anxiety and T-lymphocyte subsets in liver cirrhosis patients. METHODS: A total of 59 patients (37 males and 22 females; aged between 26-81 years) with cirrhosis were enrolled in the study. Severity of depression and anxiety were assessed through the Hamilton depressive scale (HAMD, the 24-item version) and the Hamilton anxiety scale (HAMA). T-lymphocyte subsets (CD3, CD4, and CD8) in peripheral blood were determined by flow cytometry. The relationship between lymphocyte subsets and depression/anxiety scores was studied by correlation analysis. RESULTS: The mean total HAMD and HAMA scores for the 59 subjects were 12.8 +/- 10.4 (range = 0-46) and 7.0 +/- 5.7 (range = 0-26), respectively. Fourteen of 59 subjects (23.7%) had HAMD scores equal to or above 20, indicative of depression. The percentage of CD8, but not CD3 or CD4, in T-lymphocyte subsets was positively correlated with depression (HAMD) (r = 0.268, P = 0.043) and anxiety severity (HAMA) (r = 0.321, P = 0.013). After controlling for age and Child-Pugh scores, the correlations were still significant. CONCLUSION: Around one-fourth of cirrhosis patients may have depression, although depression is not related to cirrhosis severity. Our findings are the first to show that depression and anxiety may be associated with increased levels of CD8 in T-lymphocyte subsets in cirrhosis patients, suggesting that an imbalance of T-lymphocyte subsets may be a factor facilitating depression and anxiety in cirrhotic patients. Examination of CD8 T-lymphocytes may prove useful in assessing the potential relationship between depression, anxiety, immunity, and liver cirrhosis. PMID- 23805602 TI - Religion and beliefs about treating medically unexplained symptoms: a survey of primary care physicians and psychiatrists. AB - OBJECTIVE: Historical evidence and prior research suggest that psychiatry is biased against religion, and religious physicians are biased against the mental health professions. Here we examine whether religious and non-religious physicians differ in their treatment recommendations for a patient with medically unexplained symptoms. METHOD: We conducted a national survey of primary care physicians and psychiatrists. We presented a vignette of a patient with medically unexplained symptoms, and experimentally varied whether the patient was religiously observant. We asked whether physicians would recommend six interventions: antidepressant medication, in-office counseling, referral to a psychiatrist, referral to a psychologist or licensed counselor, participation in meaningful relationships and activities, and involvement in religious community. Predictors included the physician's specialty and the physician's attendance at religious services. RESULTS: The response rate was 63% (896 of 1427) primary care physicians and 64% (312 of 487) psychiatrists. We did not find evidence that religious physicians were less likely to recommend mental health resources, nor did we find evidence that psychiatrists were less likely to recommend religious involvement. Primary care physicians (but not psychiatrists) were more likely to recommend that the patient get more involved in their religious community when the patient was more religiously observant, and when the physician more frequently attended services. CONCLUSIONS: We did not find evidence that mental health professionals are biased against religion, nor that religious physicians are biased against mental health professionals. Historical tensions are potentially being replaced by collaboration. PMID- 23805603 TI - Comparison of consecutive periods of 1-, 2-, and 3-year mortality of geriatric inpatients with delirium, dementia, and depression in a consultation-liaison service. AB - OBJECTIVES: Dementia, depression, and delirium are the most prevalent psychiatric disorders in elderly medical inpatients and are all associated with higher mortality. The purpose of this study was to assess and compare consecutive periods of 1-, 2-, and 3-year mortality among elderly patients with dementia, depression, and delirium seen by a psychiatry consultation-liaison service in a general hospital. METHODS: We consecutively enrolled inpatients 65 years of age and older that were referred for psychiatric consultation (N = 614) from 2002 to 2006: 172 were diagnosed with delirium, 92 with dementia, and 165 with depression. The 1-, 2-, and 3-year mortality rates for the three groups of patients were compared by log-rank test. The Cox proportional hazard regression model was used to identify any possible factors associated with mortality during the study period. RESULTS: Only 1-year mortality in the delirium group was significantly higher than that in the depression group (p < 0.05), but there was no significant difference among the three groups in 2- and 3-year mortality. In terms of gender, higher mortality was identified only in depressed male patients. Furthermore, male, older age, and longer length of hospital stay, but not multiple physical comorbidities, were associated with higher mortality. CONCLUSION: Clinical physicians should give special attention to delirious patients within the first year after referral. Patients at risk for mortality should be closely followed and early intervention provided in an effort to decrease or delay mortality. PMID- 23805604 TI - Does a copycat effect exist in the emergency department? AB - OBJECTIVE: This study aimed to examine the copycat effect of a famous actress's suicide on suicide attempts visiting the emergency department (ED) in Korea. METHOD: We retrospectively reviewed the medical records of suicide attempt cases which had visited the EDs of two general hospitals. during the 6 months before and after a celebrity suicide. We obtained data pertaining to demographics, history of psychiatric illnesses and suicide attempts, method of the suicide attempts, discharge status, and follow-up compliance. RESULTS: We identified 319 cases during the study period, of which 158 cases occurred before the celebrity suicide, and 161 occurred after the event. Following the celebrity suicide, suicide attempts with the similar age and the same method as the celebrity's suicide (hanging), presence of psychiatric history, and use of intensive and multiple methods increased. We observed that suicide attempts with the similar age and the same method of hanging were consistent with a copycat effect. Despite a decrease of discharge against advice (DAA) after the celebrity's death from 67.7% to 59.6%, DAA was still high, and the follow-up compliance at outpatient clinics was less than 50%. CONCLUSIONS: A copycat effect was found in ED-visiting suicide attempts. Prevention of re-attempts should be initiated in the ED. A specific action guide should be established for suicide attempts in the ED, including cooperation between other hospitals, the community, and the media. PMID- 23805605 TI - Diagnostic criteria for major depressive disorder in cancer patients: a review. AB - OBJECTIVES: The lack of universal criteria makes diagnosing clinical depression in cancer patients a challenging task. We therefore review the current state of evidence regarding such diagnostic criteria for major depressive disorder in cancer patients. METHODS: We conducted a literature search for studies which compare two or more sets of diagnostic criteria for depression in cancer patients. The results were extracted and summarized. RESULTS: Three original studies were included in this review. One study supported the use of substitutive (Endicott) criteria. Another study showed the potential of an increased threshold approach and one had no conclusive findings. CONCLUSION: There was no standard reference test and precise definition of alternative criteria in these studies. There are no recognized diagnostic criteria for depression in cancer patients despite an apparent need for such criteria. PMID- 23805606 TI - The suicide rates in the Yunnan Province, a multi-ethnic province in southwestern China. AB - OBJECTIVE: Previous research has shown a high rate and a unique pattern of suicide in China. We aim to present the current suicide rates and patterns in the Yunnan province, a multi-ethnic region in Southwestern China. METHODS: This is a descriptive study based on the 3rd Chinese national mortality survey. We reported the suicide rates by sex, 5-year age group, region (urban or rural), and minority group from 2004 to 2005 in the Yunnan province. RESULTS: We estimated a mean annual suicide rate of 19.82 per 100,000 and a total of 8751 suicide deaths per year. Sex-specific rate estimates were 21.09 per 100,000 and 18.46 per 100,000 for males and females, respectively. The male/female ratio was 1.14. Region specific rate estimates were 20.60 per 100,000 and 19.18 per 100,000 for rural and urban regions, respectively. The rural-to-urban ratio was 1.07. Suicide accounted for 4.83% of all deaths in the Yunnan province and represented the fifth leading cause of death. In minority groups, the highest suicide rates were found in the Li su minority (50.75 per 100,000), the Jing po minority (36.38 per 100,000), the Meng gu minority (32.65 per 100,000) and the Miao minority (30.75 per 100,000). The lowest rates were found in the Hui minority (0.96 per 100,000) and the Ha ni minority (1.64 per 100,000). CONCLUSIONS: The suicide characteristics of this multi-ethnic region of China are different from those of the rest of China and the world, which indicates that the development of a special intervention strategy in multi-ethnic areas for suicide prevention is needed. PMID- 23805607 TI - [Distribution of alpha-tubulin in the structures of rat forebrain]. AB - The distribution of alpha-tubulin, the major protein of the microtubules, was studied using immunohistochemistry in the rat forebrain structures. The differential distribution of alpha-tubulin immunoreactivity was detected: high immunoreactivity was found in cingulate and pyriform cortex, olfactory tubercles and optic chiasm, while the weakest immunohistochemical staining was observed in caudatoputamen, superficial layers of septum, cingulum and areas around the third cerebral ventricle. Immunoreactivity in the nervous cells was distributed along perikaryon periphery and in the apical dendrite. It is suggested that the intensity of alpha-tubulin immunohistochemical reaction could reflect the functional state of the neurons. PMID- 23805608 TI - [Serotoninergic synapses on the ventral dendrite of the mauthner neuron (ultrastructural study with immunogold labeling)]. AB - Using immunogold labeling, excitatory serotoninergic synapses of both chemical and mixed types, were found on the ventral dendrite (VD) of goldfish Mauthner neuron (MN).They are characterized by the presence of several mitochondria in the bouton and by an obligatory desmosome-like contact (DLC) besides the active zone (AZ). Their AZs were commonly found to make contact with the unlabeled chemical crested synapses, which, in turn, directly interacted with VD. These synapses were practically devoid of mitochondria and had no DLCs, thus allowing to identify them as the inhibitory ones. This "two-level" organization of excitatory serotoninergic and inhibitory synapses appears to be related to the reciprocal mechanism of the regulation of MN functional activity by visual input. PMID- 23805609 TI - [Changes of hypothalamic ventromedial nucleus structure in rats of different age with experimental diabetes mellitus]. AB - This work describes morpho-functional organization of the hypothalamic ventromedial nucleus (VMN) in rats of different age with streptozotocin-induced diabetes mellitus (DM). On day 7 of experimental DM, the development of a stress reaction was observed in 3-month-old animals, which was characterized by the ultrastructural signs of increased functional activity of light neurosecretory cells (NSC) of the VMN. Meanwhile, NSC of the VMN of 24-month-old animals remained intact. These changes in the VMN of 3-month-old animals with DM mellitus are probably related to much higher levels of glucose. On day 28 of experimental DM, the decrease in NSC numbers in the VMN was observed in the animals of both age groups because of apoptosis and hydropic degeneration. Such changes were accompanied by the deterioration in NSC trophism due to the development of the initial stages of diabetic microangiopathy and destructive changes in glial cells. PMID- 23805610 TI - [Reactive microglial changes in rat neocortex and hippocampus after exposure to acute perinatal hypoxia]. AB - The dynamics of reactive changes of a population density of microglial cells and the reversibility of their phenotypic forms were studied in the brain of neonatal rats at different time intervals after 1 hr-long exposure to acute normobaric hypoxia in the pressure chamber at the second postnatal day. Different areas of the neocortex (frontal, motor, somatosensory and visual) and of the hippocampus (CAI, CA3, CA4 and fascia dentata) were examined 1 hr, 3 hrs, 1 and 5 days after exposure to hypoxia. Microglial cells were demonstrated using an immunocytochemical staining with the monoclonal antibodies against Iba- 1 antigen. The results have shown that the reaction of microglia to acute hypoxia in both the neocortex and the hippocampus of the new-borns developed simultaneously and synchronously with the augmentation of cell death. The increase of a population density of amoeboid form of microglial cells in the brain areas studied was recorded already after 1 hour as a result of their migration from the subventricular region and the areas adjacent to large vessels from where they practically disappeared. The number of amoeboid microglial cells in this area has recovered rather quickly (in 3 hrs). The population densify of microglial cells, especially of amoeboid forms, sharply increased with the augmentation of cell death and remained unchanged for about 5 days. PMID- 23805611 TI - [Immune reactivity of human lens structures in norm, age-related cortical and secondary opacification]. AB - Using immunohistochemical methods, the immune reactivity of human lens epithelium and fibers to NSE, S-100 protein, Vim, alpha-SMA and EMA was studied in 10 normal persons and in 25 patients with its age-related cortical and secondary cataract. It was demonstrated that in age-related cortical and secondary cataract lens epithelium and fibers became more reactive to antibodies against NSE, S-100 protein and Vim, but showed no immunopositivity to alpha-SMA and EMA. Thus, the data obtained suggest some common pathogenetic mechanisms of age-related cortical and secondary cataract development with the formation of Adamyuk-Elschnig pearls. PMID- 23805612 TI - [Structural organization of anterior corneal epithelium of the African ostrich eye]. AB - This investigation was aimed at the histological study of anterior corneal epithelium (ACE) of adult male ostrich Struthio camelus Linnaeus, 1758 (Struthioniformes). The total thickness of ACE was equal to 48.5+/-1.1 microm. The geometry of epithelial cells was investigated. The basal cells had columnar shape; their average height was equal to 21.4+/-1.8 microm, average width - to 5.94+/-0,45 microm, configuration index was 3.84+/-0,50. The intermediate cells were predominantly ellipsoidal in shape; their average height was equal to 6.2+/ 0.3 microm, average width - to 12.0+/-0.8 microm, configuration index was 0.54+/ 0,06. The superficial cells were squamous, their average height was equal to 3.8+/-0.3 microm, average width - to 22.4+/-1.7 microm, configuration index was 0.18+/-0.02. Index of flattening of epithelial cells of the superficial layer was 5.8+/-0.5. Negative correlation (r+/-m=-0,72+/-0,13) was detected between the height and the width of the epithelial cells. PMID- 23805613 TI - [Trabeculae of the sinus part of the heart interventricular septum in the fetal period of human development]. AB - In the series of 91 samples of human heart obtained from fetuses at develo pmental weeks 17-28 and formed without major defects and minor anomalies, the relief of the sinus part (SP) of the interventricular septum (IVS) was studied on the side of right ventricle (RV). Myocardial trabeculae carneae (MTC) were found in SP in 96.7% of the cases. MTC, associated with the IVS myocardium along their entire length (parietal MTC). were twice as frequent as bridge-like MTC. MTC were predominantly concentrated at the posterior corner of the RV; these were e xclusively bridge-like MTC. Most frequently, MTC were absent near the IVS membranous region. An individual anatomical variability of the relief of the RV in the fetal heart was demonstrated. Depending on the number, anatomical type and mutual position of the MIC, three variants of the SP relief were distinguished: hypertrabecular, hypotrabecular and intermediate. From week 17 to week 28 of the intrauterine life, the hearts of the fetuses may differ in the form of MTC, however their number and the anatomical type within a particular variant of the SP remained constant The existence of the parietal longitudinal MTC on the right side of the IVS SP is proposed to be one of the hallmarks of the anatomically "normal" (ordinarily formed) heart in the human fetuses. PMID- 23805614 TI - [Peculiarities of angiogenesis after the implantation of polyhydroxyalkanoate films with the adsorbed multipotent stromal stem cells of a bone marrow origin]. AB - The processes developing in various rat tissues after implantation of polymeric polyhydroxyalkanoate (PHA) film fragments with adsorbed autologous multipotent stromal (mesenchymal) cells of bone marrow origin (AMMSCBM), were studied by methods of light microscopy. After the implantation of PHA film with AMMSCBM, the number of blood vessels in the surrounding tissues was found to increase as a result of neoangiogenesis. In this case,AMMSCBM did not migrate and were not destroyed at the place of injection, but differentiated into the cells forming blood vessel structures. The processes of angiogenesis in the tissues around PHA implant, in turn, lead to development of a larger number of blood vessels in the granulations formed around the implanted foreign body, higher volume of granulations proper and subsequent development of a thicker capsule delimiting polymer implant. PMID- 23805615 TI - [Morphological peculiarities of interrelations of lymphoid nodules, lymphatic capillaries and lymphocyte migration in the wall of intestine and trachea]. AB - The objective of this study was to identify the peculiarities of lymphocyte migration in lymphoid nodules of the mucous membrane of the caecum and the trachea in autopsy material, obtained from 25 healthy individuals of various ages (from the newborns to the persons of 1st mature age). Also, the tendinous center of diaphragm was studied in 10 healthy rabbits. Using histological methods, the presence of two functionally different types of lymphatic capillaries in the wall of the caecum was demonstrated. The first group includes numerous lymphatic capillaries located around the base of the lymphoid nodules. A large number of lymphocytes in portions enter the lumen of the capillaries, in accordance with the intestinal wall contractions. The second group includes the rest of the lymphatic capillaries, draining the intestinal wall and the capillaries of the trachea, resorbing mainly the interstitial fluid. The migration of lymphocytes from the lymphoid nodules of the trachea was directed, mainly, towards the surrounding tissues. Using the lymphatic capillaries of the diaphragm as a model, it was demonstrated that during the migration of the cells through the endothelium, argyrophilic structures - the stigmata, were formed which disappeared after the passage of the cells. PMID- 23805616 TI - [Peculiarities of pre- and postnatal kidney development in vasopressin-deficient brattleboro rats]. AB - The objective of this study was to examine pre- and postnatal development of the kidney in vasopressin-deficient Brattleboro rats in comparison as compared to that in Wistar rats. Histological, histochemical and morphometric methods at light microscopic level were used. The study included 50 fetuses at gestational days 16 and 18, and 46 rat pups at postnatal days 5, 10, 20, and 30. It was found that nephrogenesis sequence in both rat strains was similar, however, Brattleboro embryos and infant rats were characterized by an accelerated growth of renal corpuscles and renal tubules. The results suggest that vasopressin has no direct effect on the formation of nephron structural elements, however it may participate in the regulation of hyaluronan biosynthesis in the renal medullary interstitial tissue involved in the mechanism of urine osmotic concentration. PMID- 23805617 TI - [Morphological characteristics of spermatogenesis in the offspring of female rats with chronic alcohol intoxication]. AB - Using general histological and morphometric methods, the peculiarities of spermatogenic epithelium were studied in the offspring of female rats with chronic alcohol intoxication, which was created before the onset of pregnancy by substitution of the drinking water by 15% solution of ethyl alcohol for the period of 3 months. Total number of animals was equal to 62 rat pups which were studied at postnatal days 15, 30 and 45, including 32 rats of the intact group (10 litters) and 30 pups of the experimental group (8 litters). It was found that in the offspring of female rats with chronic alcohol intoxication, the inhibition of the processes of spermatogenesis took place, as reflected by the reduction in the area of the convoluted seminiferous tubules (CST), decrease in the number of spermatogenic cells of the seminiferous layer, increase in the proportion of CST with desquamated epithelium and giant spermatogenic cells, as well as by the reduction of spermatogenic index, which reflects the average number of layers of spermatogenic cells in each CST. PMID- 23805618 TI - [Osteoplastic effectiveness of mineralized bone matrix]. AB - In the experiment conducted on 50 Wistar rats, the peculiarities of the reparative osteogenesis were studied using scanning electron microscopy, x-ray electron-probe microanalysis and histological techniques. Granulated mineralized bone matrix (MBM) obtained without thermal and demineralizing treatment, was implanted into the tibial defect. MBM was found to possess marked osteoinductive and osteoconductive properties. It induced a prolonged activation of reparative osteogenesis after the implantation, as well as deep bone tissue ingrowth into the implant, acceleration of organotypic remodeling of regenerated bone, intense angiogenesis and early restoration of the damaged PMID- 23805619 TI - [Mandibular bone tissue regeneration after the introduction of the implantation system performed on the basis of carbon composite material]. AB - The purpose of this study was to investigate the processes of regeneration of bone tissue after the introduction of new implant systems. In the experiment, performed on 10 male pigs of Landras breed aged 50-55 days and weighing 17-18.5 kg, the time course of histological changes was studied in the area of mandibular regeneration after the formation of tissue defect and the introduction of the implant of a proposed construction. Morphological analysis of the experimental results 90, 180 and 270 days after the operation demonstrated the process of reparative regeneration of damaged bone along implant-bone block boundaries. Bone repair proceeded through the stage of formation of the woven bone with its progressive substitution by the lamellar bone, with the maintenance of the shape, size and symmetry of the damaged organ. PMID- 23805620 TI - [Appearance of stellate smooth muscle cells in the rat brain after transitory focal ischemia]. AB - One of the poorly studied problems of the pathogenesis of the brain ischemic damage is the early reorganization of blood vessels in the zone of the transitory ischemia. The aim of the present study was to investigate the structural organization and cytochemical characteristics of smooth muscle cells (SMC) in the wall of the intracerebral blood vessels in 16 Wistar rats during the early postischemic period (48 hrs after a 30 minute-long ischemia). Examination of the lesioned hemisphere revealed the stellate cells, demonstrating positive reaction to alpha-smooth muscle actin, which seem to be a special population of structurally modified SMC, uncharacteristic to the intact brain of control animals (n=5). The functional role of these cells remains to be elucidated. PMID- 23805621 TI - [Hierarchically organized model of interconnected cellular and tissue mechanisms of calcium exchange between bone and blood]. AB - The objective of this study was to propose, on the basis of the results of authors' own research and literature data, the hierarchically organized model of the interrelation of morphological mechanisms with the participation of biochemical bases of Ca2+ exchange between bone and blood. It is shown that osteocytes control the activity of main known mechanism of skeleton architecture remodeling (osteoclast-osteoblast remodeling, modeling, osteocyte remodeling etc.), that is the destruction and formation of mineral matrix component, thus influencing calcium turnover between bone and blood. The hierarchical organization of the mechanisms of this exchange is established. The first level of Ca2+ metabolism corresponds to the borderline between bone and takes place without bone matrix disintegration by paracellular energy-free Ca2+ diffusion from blood to bone and transcellular energy-dependent Ca2+ transfer from bone to blood. At the second level, calcium exchanger takes place at the borderline between between bone matrix and extracellular fluid by osteocyte remodeling during resorption or formation of the matrix of lacunar-canalicular system walls. The third level includes the mechanisms of osteoclast-osteoblast remodeling acting at the borderline between bone and blood. The mass of rapidly exchanging calcium pool was calculated to reach 58,5 g, thus being 11 times higher than previously suggected. PMID- 23805622 TI - [Problems of organization of surgical care to the wounded in a modern armed conflict: surgical care to the walking wounded in armed conflicts (Report 2)]. AB - There are two triage groups of the walking wounded in a medical company of a brigade/special-purpose medical team: those returning to fighting role and those who have to be evacuated to level 3 echelon of care. The main purposes of surgical care of the walking wounded in the 3rd echelon of care are the following: diagnosis of injury pattern ruling out severe damages and separation of the independent category of the walking wounded. There is medical evacuation of the walking wounded from the 3rd echelon to the 4th echelon deployed in a combat zone. The walking wounded who needs less than 30 days of staying in hospital are evacuated to the garrison military hospitals and medical treatment facilities subordinated to a district military hospital. The wounded with the prolonged period of hospitalization (more than 30 days) are evacuated toward the district military hospital. Treatment of the walking wounded should be accomplished in the military district where the armed conflict goes on. PMID- 23805623 TI - [Experience, problems and prospects of development of the multipurpose outpatient institution in area system of medical supply of Moscow region]. AB - The article concerns the problems of development of ambulatory medical aid in Moscow and the regions of Moscow. The general conclusion is revealed from the broad modern experience of multi-field medical center. Moreover, the article demonstrates the performance of improvement in accordance with reorganization of public and military health service. PMID- 23805624 TI - [Structure of cytosolic membrane and chemical composition of red blood cells during the early period of wound damage according to scanning probe microscopy]. AB - With the help of scanning electronic and atomic force microscopy structure of red blood cell membranes of the system blood-groove and microcirculatory channels is studied. It is established, that in early stages of skin wounds in a peripheral blood circulation appear compressed red blood cells, losing water. As a result the basic mechanism of destruction of red blood cell membranes are interlayered shifts and stratification. In red blood cells of microvasculature, on the contrary, red blood cells in state of vacuolar degeneration are indentified. It creates preconditions for hydration and bullous deformations of membranes. Porous structures of membranes of both types erythrocytes are exposed to expansion. PMID- 23805625 TI - [Modern condition and prospects of improvement of the specialized medical care for acute bone marrow syndrome of radiation etiology]. AB - It is shown, that tactics of treatment of acute marrow failure of radiant etiology is based, first of all, on measures of supporting, replaceable and stimulating therapy. The modern means, used for prophylactic and treatment of infectious complications, are resulted. Opportunities and restrictions of transfusion of donor thrombocytes and granulocytes, erythrocytes and chilled plasma are described. Therapeutic efficiency of transplantation of a bone marrow, cells of embryonic liver and stem cells of peripheral or umbilical cord blood is analyzed. It is shown, that the greatest prospects in perfection of the specialized medical aid at acute radiation syndrome are connected to complex application of interleukin-1beta, interleukin-3, granulocyte or granulocyte/macrophage colony stimulated factor, thrombopoietin and others cytokines. PMID- 23805626 TI - [Endoscopic diagnosis of local chemical burn of mucous membranes of the stomach, induced with the purpose of simulation of gastric ulcer]. AB - With the purpose of improvement of diagnosis of induced gastric ulcer were examined 11 patients who took aggressive agents for simulation of gastric ulcer and 33 patients who took pseudo-aggressive agents. Observables, conduced diagnosis of local chemical burn of mucous coat of stomach during initial 6 days after taking aggressive agents. Stages of ulcerous process, resulting from local chemical burn of mucous coat of stomach, coressponds to real gactric ulcer. Gelatin capsule using as a container for delivery of aggressive agents, melts in stomach in 5-6 minutes after taking. Independent from body position, mucous coat of greater curvature of the stomach is damaged. It is impossible to simulate duodenal bulb ulcer using the gelatine capsule or ball made of breadcrumb. The last method of delivery of aggressive agent can damage the small intestine because of uncontrollability of the place of breaking the ball. PMID- 23805627 TI - [Delivery of healthcare to patients with infectious diseases during the pre hospital stage]. AB - In the field infectious military hospital work with double-triple overcharge. It leads to reduction of health care to patients, requires the additional hospital departments or evacuation of contagious patients to other hospitals. That is why the pre-hospital care is of prime importance. According to modem concept the number of interim stages is minimal--1 stage--on site of definition of contagious patients (isolator of medical station of military unit) and 2 stage--infectious military hospital. Main measures of health care to contagious patients during the pre-hospital stage are early active detection of patients or suspected of having infection, early clinical diagnosis, medical sorting, delivery of emergency care, treatment in isolators in case of delay of evacuation and evacuation in infectious military hospital. PMID- 23805628 TI - ["Diver's lung": features of respiratory system remodeling in Navy aquanauts in long-term period after deep saturation dives]. AB - It is established that after the termination of deep saturation dives reorganization of respiratory system at navy aquanauts proceeds. This remodeling is specific, atypical for natural age dynamics. PMID- 23805629 TI - [Medical research in the US Armed Forces. Part 4]. AB - The present article is the fourth part of the review dedicated to organization and management of medical research in the US Armed Forces. The first, second and the third parts were published in the previous issues of the journal. Specifically this article is dedicated to organization and management of medical research in the US Navy. It is shown that in the US Navy the fundamental and a part of applied investigations are conducted in the Office of Naval Research while more practical research is carried out at the Naval Medical Research Center. The latter includes the Naval Health Research Center, the Naval Submarine Medical Research Laboratory and seven Naval Medical Research Units which are successively presented. The particular research programs conducted in the above mentioned organizations are discussed. PMID- 23805630 TI - [Ussuriisk military hospital celebrates 130th anniversary]. AB - On the authority of the order issued by Military Department d.d. 13 September 1882 No 278 since 1 January 1883 in village Nikolskoe of Primorsk territory was established the local hospital with bed capacity--115 beds. In the following years this capacity was being increased. In 1914 hospital was renamed into Nikols Ussuriysk military hospital. This hospital took part in treatment-and-evacuation supply of wounded and ill soldiers during wars and armed conflicts. In 1982 Nikols-Ussuriysk military hospital awarded the Red Star. Employees of this hospital prepared and defended 25 doctoral and candidate's dissertations. In 2010 hospital was joined 301st District military clinical hospital and became it's branch. PMID- 23805631 TI - [Navy physician, poet, journalist ( the 80th anniversary of the birth of V.V.Belozerov)]. AB - There are biographical details about V. V. Belozyorov (16.02.1932-8.07.1999)- surgeon, talanted seascape poet, former editor-in-chef *Military-medical magazines (1978-1992), about his official and labour activity, poetic creativity and also about various employees of the magazine. PMID- 23805632 TI - [Anniversary of the medical department of the Federal Office for Safe Storage and Destruction of Chemical Weapons]. AB - The article is devoted to the process of formation and development of CW destruction management system and medical support of professional activities of personnel. Founders of Medical department of the Federal Directorate for Safe Storage and Destruction of Chemical Weapons are presented. Main principles and ways of working of medical department in specific conditions are covered. PMID- 23805633 TI - [Cardiac natriuretic peptides and hypertension: experimental study]. AB - The peculiarities of cardiac natriuretic peptide secretion have been investigated during ontogenesis using the hypertonic disease model in ISIAH rat line (with inherited stress induced arterial hypertension). The qualitative and quantitative ultrastructural investigations of right atrium myocardium revealed that the cardiac hormonal synthetic and secretory activities in ISIAH rats are higher as compared with normotensive even-aged rats from control group. Secretory hyperactivity of atrial myocytes in ISIAH rats during early ontogeny precedes the manifestations of hereditary hypertension. Natriuretic peptides present the hypotensive circuit of hemodynamic regulation during the whole ontogeny and the complementary chain in hypertension development. PMID- 23805634 TI - [Adaptive phenomenon of ischemic postconditioning of the heart. Perspectives of clinical use]. AB - Analysis of experimental data indicates that aging, metabolic syndrome may be serious obstacle against realization of cardioprotective effect of postconditioning. The moderate hypercholesterolemia, postinfarction cardiosclerosis and cardiac hypertrophy do not abolish protective effect of postconditioning in experimental animals. The issue whether diabetes mellitus and arterial hypertension affect an efficacy of postconditioning is a subject of discussion. Clinical investigations testify on cardioprotective impact of postconditioning in patients with acute myocardial infarction and cardiosurgery patients. At the same time, it is remained unclear when after coronary artery occlusion postconditioning exhibits cardioprotective effect. It is remained unknown how do affect aging, diabetes mellitus, metabolic syndrome, arterial hypertension, myocardial hypertrophy, cardiac postinfarction remodeling and efficacy postconditioning in clinical praxis. It is required a further clinical investigations turning the development pharmacological approaches to prophylaxis of reperfusion injury of the heart. PMID- 23805635 TI - [Cerebrolysin for acute ischemic stroke]. AB - The review discusses existing evidence of benefits and risks of cerebrolysin--a mixture of low-molecular-weight peptides and amino acids derived from pigs' brain tissue with proposed neuroprotective and neurotrophic properties, for acute ischemic stroke. The review presents results of systematic search and analysis of randomised clinical trials comparing cerebrolysin with placebo in patients with acute ischemic stroke. Only one trial was selected as meeting quality criteria. No difference in death and adverse events between cerebrolysin and placebo was established. The authors conclude about insufficiency of evidence to evaluate the effect of cerebrolysin on survival and dependency in people with acute ischemic stroke. PMID- 23805636 TI - [Peculiarities of cerebral structures functioning in adolescents with achondroplasia]. AB - Complex neurophysiological examination (rheoencephalography, electroencephalography) was carried out in 12 adolescents 12 to 18 years old in order to reveal the peculiarities of cerebral structures functioning in adolescents with achondroplasia. Some deviations from the normal values were found out: reduced blood filling of the brain vessels in the pools of a. carotis interna and a. vertebralis, rheoencephalographic signs of intracranial hypertension of mild degree and brain cycling characterized by moderate and significant amplitude increase, presence of pathological types (delta-, theta-) of the rhythmics and the reduction of the physiological ones (alpha-, beta-). At the same time the peculiarities of rheoencephalographic indices were observed while functional testings (hypercapnia, hyperoxia). Brain cycling differed from normal values by weaker response to the weight-bearing, mainly in alpha- and beta ranges. PMID- 23805637 TI - [Kynurenines in pathogenesis of endogenous psychiatric disorders]. AB - The essential amino acid tryptophan is metabolized on the methoxyindole pathway to serotonin, melatonin and 5-hydroxyindoleacetic acid and on the kynurenine pathway to kynurenine and related neuroactive metabolites, including 3 hydroxykynurenine, kynurenic acid, quinolinic acid and xanthurenic acid. Kynurenine and related metabolites play a significant role in the pathogenesis of major depressive disorder and schizophrenia. This paper is the review of literature data on the most modern state of this problem. PMID- 23805638 TI - [Efficiency of mildronate in rats of different age with experimental-induced myocardial ischemia]. AB - Under experimental myocardial ischemia in rats of 10 months treatment with mildronate resulted in essential changes in metabolism of cardiomyocites. This includes stimulation of aerobic and anaerobic ways of power supply of heart cells: activation of glycolysis, oxidative phosphorylation and oxidative pyruvate decarboxylation with restoration of adenosine triphosphate pool to intact rats level in myocardium, serum and erythrocytes with signs of stabilization of cardiomyocytes membranes and essential decrease of tissue hypoxia. Introduction of mildronate to old rats (24 months) with an experimental myocardium ischemia was accompanied by lesser expressed changes of metabolism: activation of glycolysis and oxidative pyruvate decarboxylation without stimulation of Crebs' cycle enzymes. This became sufficient for restoration of adenosine triphosphate pool in myocardium without change of its quantity in serum and erythrocytes with signs of stabilization of cardiomyocytes membranes and moderate reduction of tissue hypoxia degree. PMID- 23805639 TI - [Effects of a real and modeled microgravity influencing on some structural and metabolic parameters of skeletal muscles]. AB - The aim of present publication is summarization of experimental results on real and modeled effects of zero gravity on the impellent device of a man and other mammals. In particular, its effects on high-speed and power characteristics of skeletal muscles depending on their metabolic activity are analyzed. PMID- 23805640 TI - [The mechanisms of adaptation of the vascular bed to hemodynamic changes in portal hypertension]. AB - The data of the literature on the mechanisms of restructuring of vascular bed in response to hemodynamic changes due to portal hypertension. Despite the fact that these changes are compensatory-adaptive reaction to the deteriorating conditions of blood circulation, they contribute to its progression, promoting the development of serious complications, one of which was bleeding from esophageal varices. PMID- 23805641 TI - [Introduction into PPPM: experience of the past and tomorrow's reality]. AB - Health service today is on the verge of broad changes. The intensive practical application of the achievements of genomics, proteomics, metabolomics and bioinformatics has significantly deepened and continues to deepen our view of the pathological processes taking place at a level of biostructures. In the nearest future this progress will give medical practitioners the opportunity to focus on a subclinical stage of the disease, i.e. on the earliest stages of the pathological process. This will require the prediction of disease development risks, subclinical diagnostics with the precise staging of the pathological process, and, finally, the application as early as possible of targeted pharmacotherapeutic methods in order to prevent the manifestation of the disease or its progression into more severe stages. All these principles create the framework of a fundamentally new "3P" strategy in medicine: predictive, preventive and personalized medicine. PMID- 23805642 TI - [Proteomics as a fundamental tool for subclinical screening, tests verification and assessment of applied therapy]. AB - Proteomics is a science which studies proteins of the body, interactions of proteins and their biological functions. Today, it is an essential partner in establishing preclinical diagnosis protocols. In conjunction with other sciences such as genomics and bioinformatics it will be possible to diagnose diseases on the earliest stages before its clinical onset or to gain the dynamics of pathological processes in the body and response to drug therapy. This article discusses general aspects of proteomics as well as special ones on the basis of models of cardiac diseases and cancer. PMID- 23805643 TI - [Plastic closure of wounds and trophic ulcers in patients with diabetic foot syndrome by relief autoshred]. AB - This article describes the features of the surgical treatment of patients with diabetes mellitus complicated with diabetic foot syndrome. Results of autodermoplasty of acute and chronic skin damages with ripped and flat skin graft in 185 patients who were treated in the clinic of general surgery of I.Ya. Horbachevsky Ternopil State Medical University, Ukraine, in the period from 2007 to 2012 Using of this method leads to improved cosmetic and functional results in 81.7% of patients with reducing of treatment duration up to 12 days. PMID- 23805644 TI - [Comparative characteristic of Burkholderiae pseudomallei group]. AB - AIM: Comparative characteristic of diagnostic value of main cultural-biological characteristics of Burkholderiae pseudomallei group. MATERIALS AND METHODS: 59 strains of B. pseudomallei, 14 --B. mallei and 5--B. thailandensis were used in the study. Biochemical characteristics were studied by generally accepted methods, antigenic properties were evaluated in agglutination reaction and immunoelectrophoresis, virulence was determined by Dlm for laboratory animals, antibiotic sensitivity was verified by disc-diffusion method. RESULTS: Passaging of B. pseudomallei and B. mallei in mice results in increase of virulence, preservation of initial sensitivity to antibiotics, contraction of precipitogen specter. During therapy of experimental melioidosis in guinea pigs resistance to chemopreparations of various groups is formed. Varying degree of virulence and sensitivity to antibiotics of various B. thailandensis strains was established. Dependence of sensitivity on in vitro cultivation was not detected. CONCLUSION: Stability of diagnostically significant tests used for identification of Burkholderiae pseudomallei group was established. Relevance of attribute set expansion that facilitates their differentiation is justified. PMID- 23805645 TI - [Influence of plant extracts on the activity of cholera toxin of Vibrio cholerae]. AB - AIM: Study the activity of plant extracts against cholera toxin (CT) of Vibrio cholerae O1. MATERIALS AND METHODS: Antitoxic activity of plant extracts was determined by using enzyme immunoassay and CHO-K1 cell culture. RESULTS: 8 water extracts of plants were studied. Extracts of nut, tutsan, milfoil, basil do not have effect on CT activity in EIA or CHO-K1 cell culture. Celandine and rhubarb extracts do not reduce CT immunochemical activity but prevent elongation of CHO K1 cells. Oak and hop extracts suppress binding in EIA of cholera toxin and GM1 receptors and insignificantly reduce its activity in cell culture. CONCLUSION: Antitoxic activityofplant extracts against CT is perspective for the development of preparations possessing inhibition effect. PMID- 23805646 TI - [Epidemiologic diagnostic of nosocomial suppurative-septic infections of Pseudomonas etiology based on intraspecies typing of causative agent]. AB - AIM: Scientific justification of optimization of epidemiologic diagnostic of suppurative-septic infection (SSI) caused by Pseudomonas aeruginosa based on comparability of antibiotic sensitivity and beta-lactamase production. MATERIALS AND METHODS: Intraspecies typing of 37 P. aeruginosa strains isolated during microbiological monitoring of 106 patients and 131 objects of clinical environment of surgical and obstetrician hospitals by using a complex ofphenotypic and molecular-biological methods including determination of sensitivity to antibiotics by serial dilutions method and PCR-diagnostics with determination of TEM, SHV, CTX, OXA, MBL, VIM genes was performed. RESULTS: P. aeruginosa strains combined into groups by isolation location during studies turned out to be heterogeneous by sensitivity to antibiotics and beta-lactamase production that allowed to form subgroups of strains by focality attribute. Isolates recovered from different SSI foci had significant differences in minimal inhibitory concentration (MIC) reaching 1024 times. MIC parameter within subgroups did not exceed 8 - 16 consequent dilutions. CONCLUSION: Use of a complex of phenotypic and molecular-biologic methods of causative agent typing including determination of sensitivity to antibiotics by serial dilutions method and evaluation of beta-lactamase production allowed to establish a mechanism of development of SSI epidemic process caused by P. aeruginosa, detect origins and reservoirs of infection in hospital, modes and factors of transmission and reach maximum justification of epidemiologic control and prophylaxis measures of localization of foci of nosocomial infections of pseudomonas etiology. PMID- 23805647 TI - [Study of protective activity of Streptococcus pneumoniae protein-containing antigen complex in homologous system]. AB - AIM: Study protective activity of S. pneumoniae protein-containing antigen complex obtained from T3No.3 strain against infection by homologous pneumococcus strain. MATERIALS AND METHODS: S. pneumoniae T3No.3 (serotype 3) strain obtained from collection of pneumococcus strains of Mechnikov Research Institute of Vaccines and Sera was used in the study. S. pneumoniae protein-containing antigen complex was isolated by precipitation by 2 volumes of acetone of supernatant fraction of cultural medium used for pneumococcus cultivation. Molecular mass of proteins contained in S. pneumoniae antigen complex was determined by SDS electrophoresis in polyacrylamide gel. Protective activity of S. pneumoniae protein-containing antigen complex was studied in BALB/c line mice active protection experiments. Activity of mice immune sera obtained against whole-cell pneumococcus culture (T3No.3 strain) was determined in vitro by solid phase indirect EIA. RESULTS: The data obtained give evidence that the isolated protein containing antigen complex from S. pneumoniae T3No.3 strain effectively protects mice from consequent infection by a homologous S. pneumoniae strain. S. pneumoniae protein-containing antigen complex sorbed on solid phase at 5 microg dose was established by using EIA to interact with homologous mice immune sera. CONCLUSION: The results of the carried out studies allow to move to studies of cross-activity of S. pneumoniae protein-containing antigen complex isolated from T3No.3 strain. PMID- 23805648 TI - [Effect of strain-producer and cultivation medium on cross antigenic activity of Streptococcus pneumoniae water soluble antigens]. AB - AIM: Production of water soluble protein-containing antigens from various strains of S. pneumoniae during cultivation in complete and semi-synthetic culture media as well as selection of strains with cross antigenic activity. MATERIALS AND METHODS: S. pneumoniae 3, 6A, 6B, 14, 10A, 18A, 19A, 19F, 23F serotype strains were cultivated in brain-heart broth and semi-synthetic medium with addition of aminopeptide for 24 hours at 37 degrees C for the production of water soluble antigens. The antigens were obtained by a method of triple water extraction from acetone dried microbial cells. Chemical composition of preparations, electrophoresis mobility of protein-containing components of preparations and cross antigenic activity in gel immune diffusion reaction by using rabbit hyperimmune sera were studied. RESULTS: In studies of 10 pneumococcus strains from various serotypes a method of microbial cell inactivation by acetone was selected that allows to produce preparations with high protein content (25.5 - 53.1%). Electrophoretic separation of the preparations revealed difference in the preparations obtained from various pneumococcus strains in the layout of major protein lines in the 8 - 95 kDa range. The most virulent and immunogenic S. pneumoniae strain that during cultivation in semi-synthetic medium was characterized by intraspecies cross antigenic activity and in gel immune diffusion reacted with all the studied sera against 3, 14, 18C, 23F serotype strains was selected. CONCLUSION: The study resulted in the selection of a technologically simple method of production of pneumococcus antigens with high protein content and showed that only 1 of the studied preparations produced from a virulent strain with poorly expressed S. pneumoniae capsule during cultivation in semi-synthetic medium has the highest cross antigenic activity. PMID- 23805649 TI - [Laboratory diagnostics in evaluation of acute respiratory viral infection morbidity in 2010 - 2011 epidemic season]. AB - AIM: Study of etiological structure of ARVI and evaluation of acute respiratory virus infection morbidity in 2010 - 2011 epidemic season taking into account the data of laboratory diagnostics by method of polymerase chain reaction with hybridization-fluorescent detection. MATERIALS AND METHODS: By using reagent kits produced by Central Research Institute of Epidemiology for the detection of primary causative agents of influenza and ARVI 129 children and 94 adult patients monitored in an outpatient setting as well as 103 children hospitalized due to ARI were examined. RESULTS: Etiological structure of ARVI was studied; proportion of influenza and other actual causative agents of ARVI in monthly dynamics were established. During epidemic rise of influenza (January-March 2011) the proportion of influenza A viruses was 24% (peak in January--31%), the proportion of influenza B viruses--5%, rhinoviruses--9%, metapneumovirus was detected in 6% of cases, parainfluenza viruses (1 - 4 type) and adenovirses--4% each, coronaviruses--in 3%, respiratory syncytial virus--in 2%, bocavirus--in 1% of the studied samples. In influenza structure A/H1N1pdm2009 virus, its proportion was 70%, influenza virus B (26.9%), influenza virus A/H3N2 (2.6%) predominated. Indexes for monthly morbidity caused by each of the ARVI causative agents were calculated. CONCLUSION: The proposed approach allowed to evaluate ARVI morbidity taking into account laboratory-confirmed etiological factors. A 5 time increase in ARI morbidity in adults in February 2011 was shown to be mostly due to an increase in influenza A morbidity as well as involvement of influenza B virus, metapneumoviruses, coronaviruses, parainfluenza viruses and rhinoviruses into the epidemic process. Increase of morbidity of children by 1.4 times was also seen during activization of influenza viruses and metapneumovirus. The analysis of monitoring results allowed to prognose increase of respiratory-syncytial viral infection epidemic activity from September 2011 to February 2012. PMID- 23805650 TI - [Sporadic and group imported cases of hepatitis E in St. Petersburg]. AB - AIM: Carry out retrospective clinical-epidemiological analysis of sporadic and group cases of acute HE morbidity in St. Petersburg (2000 - 2012). MATERIALS AND METHODS; Medical histories of 11 patients with sporadic morbidity (9 males and 2 females, average age 36 +/- 18) and 13 patients involved in group HE morbidity were analyzed. Acute hepatitis E diagnosis was established based on common clinical-epidemiological criteria confirmed by results of biochemical study and data of objective examination. Hepatitis E etiological membership was confirmed by detection in patient blood sera of specific marker of infection--anti-HEV G and M classes with laboratory exclusion of hepatitis A, B and C. RESULTS: Study of epidemiological anamnesis of patients showed that 8 of them were migrants from countries with tropical and subtropical climate. 3 patients were residents of St. Petersburg. In the end of December 2011 and in January 2012 a group HE morbidity was registered among those who had arrived to study in St. Petersburg from India (Mumbai) in a group exceeding 200 individuals. Clinical characteristic of acute HE during sporadic and group morbidity is given. CONCLUSION: The presence of sporadic and group HE morbidity in St. Petersburg indicates the necessity to register these situation in organization of protection of the territory of Russia from endogenous HE. PMID- 23805651 TI - [Epidemiological well-being of population of Russia]. PMID- 23805652 TI - [Actual problems of hemorrhagic fever with renal syndrome]. AB - From 2000 to 2011 85 600 cases of hemorrhagic fever with renal syndrome (HFRS) were registered in Russian Federation. Epidemically active foci of HFRS infection are located generally in temperate latitudes of the European part and the Far East. In the Far East regions whose fraction of all the HFRS disease cases in Russia is around 2%, the causative agents of the infection are Hantaan, Amur, Seoul hantaviruses, the natural reservoir for those are striped field mouse, Korean field mouse and brown rat. In the European part of Russia the causative agent of the infection are Puumala hantavirus as well as 2 genetic subtypes of Dobrava virus, the main reservoirs of those in the nature are bank vole, striped field mouse and Black Sea field mouse, respectively. 9 strain of Puumala and 10 strains of Dobrava virus were isolated. Based on sequencing of Dobrava virus strains significant differences were detected between Dobrava virus strains isolated from Black Sea field mouse from Sochi and striped field mouse from Lipetsk Region. Cultural inactivated vaccine against HFRS was developed and completed preclinical trials. PMID- 23805653 TI - [Progress, problems and objectives in the field of vaccine prophylaxis of infectious diseases]. PMID- 23805654 TI - [Epidemiological situation and prophylaxis of zoonotic and natural-focal infectious diseases in Siberia and the Far East]. AB - Analysis of zoonotic and natural-focal infectious disease morbidity in 2009 - 2011 in Siberia and the Far East is presented, and a complex of measures aimed at their prophylaxis is proposed. Analysis is carried out based on the data received by Reference Center of Monitoring of Natural-Focal Infection Causative Agents and Regional Center of Monitoring of I-II Pathogenicity Group Causative Agents at the Irkutsk Research Institute of Plague Control from departments and Centers of Hygiene and Epidemiology of Siberian, Far Eastern, 3 subjects of Urals Federal District and 5 Stations of Plague Control of Federal Service for Control in the Sphere of Protection of Consumers' Rights and Well-Being of Humans. In the morbidity structure in this region "tick-borne" infections were established to predominate--69.4%, among bacterial--yersiniosis dominates. Deterioration of epizootic situation on rabies is observed in the Republics of Tuva and Buryatia. PMID- 23805655 TI - [Information technologies in epidemiological control of natural-focal infectious diseases]. AB - An approach to increase effectiveness of epidemiological control of Crimean hemorrhagic fever, West Nile fever and Astrakhan spotted fever by building a prognostic model of epidemic activity based on contemporary information technologies of spatial and intellectual data analysis was developed and tested. Personified data on 4505 laboratory confirmed cases of natural-focal infectious diseases registered in the Russian Federation and database on 1999 - 2011 climatic observations were processed. A model implementing prognosis of epidemiological situation intensity level as a function of a combination of factors, maps of density of epidemic manifestations were built. On a practical example high effectiveness of the approach to epidemiological analysis based on the use of contemporary analytical technologies for evaluation of temporal and spatial categories of epidemiological risk was demonstrated. PMID- 23805656 TI - [Molecular-epidemiological monitoring of enterovirus circulation in the Far East and Zabaikalye]. AB - 6 year molecular-biological monitoring of enteroviruses in the Far East and Zabaikalye was carried out. Nucleotide sequence of 125 strains was determined from 2006 to 2011. Molecular analysis was carried out in VP1 virus genome region. Phylogenetic interactions for ECHO-6, ECHO-30, ECHO-11, Coxsackie B-5 (CB-5), Coxsackie B-1 (CB-1) and Coxsackie A-9 (CA-9) were analyzed. Highly dynamic epidemiology was shown to be inherent for ECHO-6 and ECHO-30 viruses and is characterized by genetic heterogeneity and consequent change of virus variants. On the contrary a relative stability of circulating genotypes is intrinsic for CB 1, CB-5 and ECHO-11 enteroviruses. The results of molecular-biological studies indicate frequent introduction of new enterovirus variants from countries of Europe and Asia. PMID- 23805657 TI - [Molecular monitoring of non-polio enteroviruses in European territory of Russia in 2008 - 2011]. AB - As a result of 4 year monitoring the landscape of enteroviruses circulating in European territory of Russia was established to be presented by at least 50 serologic types. Phylogenetic analysis of ECHO30, ECHO9, Coxsackie A9, ECHO6 virus strains that had caused a seasonal increase of aseptic meningitis morbidity in 2008 - 2011 was carried out. PMID- 23805658 TI - [Epidemiology of viral hepatitis]. PMID- 23805659 TI - [Vaccine prophylaxis of varicella: tactics and perspectives]. PMID- 23805660 TI - [Actual problems of medical microbiology]. PMID- 23805661 TI - [Symbiotic interactions of microorganisms during infection]. AB - Symbiotic interactions of microorganisms during infection are reviewed. Infectious process is presented as a model system of associative symbiosis with 3 functional vectors of symbiont interactions. The principal attention is paid to microsymbiocenosis and estimation of its role during infection. Materials on population-communicative dialogue of microsymbionts are given, and their applied importance for medical-biological science is shown. Algorithm of microbial "self non self" recognition under the control of opposite (increase/ suppression) effect of dominant-associant microbe pair on principal physiological (growth and persistence) functions of microsymbionts is presented. PMID- 23805662 TI - [Actual problems of biosafety]. AB - Actual problems of biosafety are presented. Examination of biosafety as a subsystem of life safety of humans allows to attract methodical apparatus developed by taking into account general terms of safety theory applied to problems of ensuring biosafety. As an actual goal implementation of technologies of risk analysis in evaluation of potentially dangerous biological objects and territories of Russian Federation is determined. Analysis of legislation and normative-methodical documentation in the field of ensuring biological safety during work with pathogenic biological agents revealed a number of problems of technical, organizational and scientific nature. Proposals for their solution are given. PMID- 23805663 TI - [Problems of medical parasitology]. AB - Situation on parasitic disease in Russia remains complex. Reduction of parasitology personnel had a negative impact on the quality of epidemiological control in the field of parasitic diseases and resulted in a decrease of awareness of physicians of therapeutic-prophylaxis institutions. The situation was aggravated by a lack of anti-malaria preparations and insufficient specter of anti-helminthic drugs. Uncontrolled increase of the number of domestic and stray dogs in cities was the reason for increase of morbidity by helminthoses and zoonoses--toxocarosis and dirofilariasis. Emergence in the south of Krasnodar Region of effective carriers Aedes aegypti, Aedes albopictus became a serious threat to biological safety of the country. These mosquitos are effective carriers of causative agents of mosquito viral fevers: yellow, Dengue, Chikungunya et al. PMID- 23805664 TI - [Disinfectology and disinfection activity--basis of nonspecific prophylaxis of infectious diseases]. AB - The necessity of further development of disinfectology as a branch of science that studies regularities of nonspecific prophylaxis of infectious and parasitic diseases by impact on pathogenic biological objects and their carriers is justified. The importance and topicality of nonspecific prophylaxis of infectious diseases, the necessity to take into account significant factors that characterize epidemic process during selection and application of means and methods of nonspecific prophylaxis are specified. Data that are necessary to be taken into account during development of means, methods and technologies of disinfectologic prophylaxis of infectious and parasitic diseases are presented. PMID- 23805665 TI - [Epidemiological basis for disinfectologic prophylaxis of viral infections]. AB - Epidemiological justifications of disinfectologic prophylaxis of viral infections are given. Basic are data on survival of viruses on environmental objects, their resistance (sensitivity) to effect of chemical disinfection means and physical agents, mechanisms, routes and factors of infection transmission. Classification of viruses by resistance to chemical disinfection means as well as classification of disinfection means by virucidal activity is given. Methodical approaches to justification of selection of means and regiments of their application with the aim of prophylaxis of rotavirus, norovirus infection and atypical pneumonia are described. PMID- 23805666 TI - [Intestine infections, inflammation and autoimmunity. Lymphoid apparatus of intestine in interaction with intestine microflora]. AB - Topicality of interrelation between intestine infections, inflammation diseases of intestine and autoimmune processes is widely discussed in scientific literature of recent years. Thereby a review of literature on the designated aspect of the problem is dedicated to the analysis of interconnection between structural-functional features of lymphoid apparatus of intestine and its ability to react to antigen load from both commensal and pathogenic intestine microflora. During description of structure and functions of lymphoid formation of intestine a particular attention is paid to difference of subpopulation characteristics of lymphocytes and antigen-presenting cells composing intra-epithelial lymphocytes, elements ofimmune system lamina propria, Peyer's patches, mesenteric lymphatic nodes. The role of normal microflora and infectious agents in trigger mechanisms of reaction of immunocompetent cells is underscored; key aspects of cellular molecular mechanisms of mucous membrane immune system functions are discussed. PMID- 23805667 TI - [Membrane-bound proteases of ompT+ and ompT- Vibrio cholerae strains]. AB - AIM: Detection ofproteases in outer membranes (OM) of ompT+ and ompT- Vibrio cholerae strains of O1 and O139 serogroups. MATERIALS AND METHODS: Specific sterile preparations of OM were obtained by lysis of live V. cholerae cells by 4.5 M urea solution with subsequent differential centrifugation and treatment by nucleases. Extraction of OM proteins previously treated by sodium sarcosinate was carried out by Triton X-100 in the presence of EDTA. Protease and polypeptide spectra were studied in substrate and SDS electrophoresis. Sensitivity of proteases to inhibitors was determined in diffusion test in agarose gel containing substrate by using soy trypsin inhibitor (STI) and phenylmethylsulfonyl fluoride (PMSF). The presence of ompT was determined in PCR by using specific primers. RESULTS: According to PCR data 13 Vibrio cholerae O1 strains and 3 V. cholerae O139 strains isolated from clinical material as well as 22 V. cholerae O1 strains isolated from environmental objects contained ompT gene. 2 V. cholerae O1 human isolated strains, 9 V. cholerae O1 strains and 2 V. cholerae O139 strains isolated from the environment did not have ompT gene. By using SDS- and enzyme-electrophoresis in polyacrylamide gel quantitative and qualitative differences in composition of polypeptides and proteases of OM ompT+ and ompT- V. cholerae strains that hydrolyze gelatin, casein and protamine sulfate were detected. Inhibition of OM by STI and PMSF resulted in a decrease of their proteolytic activity. CONCLUSION: In preparations and extracts of ompT+ and ompT- V. cholerae OM up to 3 proteases some of which may be related to ompT-like were detected. PMID- 23805668 TI - [Optimization of Streptococcus equi subsp. zooepidemicus cultivation process- producer of hyaluronic acid]. AB - AIM: Selection of high-mucoid morphotype of Streptococcus equi subsp. zooepidemicus (Streptococcus zooepidemicus) and study of its morphological, physiological, biochemical and technological characteristics for providing increased secretion of hyaluronic acid (HA). MATERIALS AND METHODS: Submerged cultivation was performed in 100 ml glass flasks without baffles or in 1.5 or 10 1 laboratory bioreactors. LB and MRS media were used for cultivation. Mutagenesis was carried out by UV exposure with consequent selection of mucoid phenotype. HA was determined by carbazole method or after exhaustive acid hydrolysis by reaction of N-acetylglucosamine with Morgan-Elson reagent. Total hyaluronidase activity was evaluated by viscosimeter. Determination of cell and capsule size, ability to ferment carbohydrates and other microbiological, physiological and biochemical tests were performed by standard techniques. RESULTS: Instability of capsule phenotype of S. zooepidemicus B-8014 strain was revealed that is explained most probably by formation under certain conditions of bacterial hyaluronidase. This is confirmed by a reduction of HA concentration in cultural medium at pre- and stationary growth phases. Mucoid strain S. zooepidemicus KB-04 was obtained by mutagenesis with subsequent selection that is characterized by increased capsules. The strain was studied for HA formation. Optimization of growth medium composition, physical-chemical conditions and modes of cultivation allowed to significantly increase HA yield. CONCLUSION: The studies of morphologic, physiologic, biochemical and technological characteristics of the high-mucoid S. zooepidemicus KB-04 strain obtained by mutagenesis with consequent selection were performed, conditions of its cultivation and composition of growth mediu by carbon source and content of bivalent metal ions were optimized. PMID- 23805669 TI - [Dynamics of change of ureaplasma laboratory strain titers and quantity of their DNA in transport medium at varying temperature]. AB - AIM: Study of preservation dynamics of ureaplasma laboratory strain live cultures and their DNA in transport medium at varying temperature. MATERIALS AND METHODS: The study was carried out in laboratory strains Ureaplasma urealyticum serotype 8 and Ureaplasma parvum serotype 1. The quantity of live ureaplasmas was determined by method of tenfold dilutions in liquid medium. The growth of ureaplasmas was registered by changes in the color of the cultivation medium due to its alkalization by metabolism products and expressed in CCU/ml. DNA quantity in samples was determined by real time PCR performed by using Florocenosis micoplasmas-FL test system produced by ILS. RESULTS: Live ureaplasmas wer shown to be preserved in transport medium at 4 degrees C for 12 - 29 days, at 18 - 22 degrees C--for 9 - 20 days and at 37 degrees C--for only 2 days. In samples incubated at 37 degrees C the quantity of live ureaplasmas increased and then sharply decreased to 0, at lower temperature titers of the cells decreased smoothly. The quantity of ureaplasma DNA in the process of their incubation did not change significantly. CONCLUSION: Fundamental differences in the duration of survival of U. urealyticum strain and U. parvum strain in transport medium at varying temperature were not detected. Based on the studies performed a practical conclusion can be drawn that in cases of emergency when clinical material transportation is necessary its storage in transport medium for several days is acceptable. PMID- 23805670 TI - [Effect of low temperature plasma on various mycoplasma species]. AB - AIM: Study the influence of low temperature (cold) electrolyte plasma (CEP) on survivability of some mycoplasma strains growing in agar as well as mycoplasma that most frequently contaminate transplantable human cell lines of normal and malignant origin with the aim of decontamination. MATERIALS AND METHODS: Mycoplasma hominis, Mycoplasma arginini and Aholeplasma laidlawii grown in agar and mycoplasma that contaminated transplantable human cell lines of normal (MT4) and malignant (HeLa) origin. Plasma source--Plasmatom device that generates CEP at normal atmosphere pressure and environment temperature. Exposure to plasma was carried out with adherence to the same modes for all the variants of biological substrate. The duration of exposure was selected randomly from 15 to 300 seconds. RESULTS: A pronounced bactericidal effect of high doses of CEP on all the tested mycoplasma variants exposed immediately after seeding into agar was shown. However after a passage a residual number of survived colonies was registered. Passage of colonies exposed in grown state even to high doses of CEP also showed survival of a residual number of bacteria in all the tested mycoplasma species. Exposure of M. hominis immediately after seeding to low doses of CEP resulted in formation of unusual mini-colonies identical to those isolated from humans infected by the same mycoplasma. During microbiological seeding into agar of cultural fluid from 2 spontaneously contaminated strains of transplantable human cells and exposed to CEP growth ofmycoplasma was not detected. CONCLUSION: CEP has pronounced bactericidal properties on various mycoplasma strains growing in both agar and contaminating eukaryotic cells. However even at high doses of exposure to CEP an insignificant part of bacterial cells growing in agar still survives. This may indicate a high degree of heterogeneity and adaptation of mycoplasma subjected to even such hard exposure as cold plasma with plasma chemical mechanism of destruction of biological substrate. PMID- 23805671 TI - [Generalized mycoplasma infection in patients and carriers]. AB - AIM: Study of possibility of generalization of mycoplasma infection in patients with urogenital pathology. MATERIALS AND METHODS: Among the examined patients 5 males characterized by risky sexual behavior with pronounced symptoms of infection or without those were selected. Patients were examined by a complex of methods for the presence of mycoplasma infection by culture, PCR, DFA, PHA, AHR and by detection of specific immune complexes in blood sera. Scrapes from urogenital tract, blood sera samples, urine, saliva, prostatic fluid were materials for the study. RESULTS: In blood of all patients in ELISA antibodies against Mycoplasma hominis were detected; in PHA they were detected only in 2 individuals. In all the patients in blood CIC were detected including antigens and DNA of one or several mycoplasma species. Sperm of 3 individuals was infected by Ureaplasma spp., 2--M. genitalium. In saliva of 2 individuals M. hominis was detected, 3--U. urealyticum. CONCLUSION: In all the examined patients the infection was shown to have generalized character. This phenomenon presents itself as quite significant because mycoplasma may cause anti-apoptotic and oncogenic effect. PMID- 23805672 TI - [Chronic viral hepatitis in St.Petersburg]. AB - Morbidity data on chronic viral hepatitis including cirrhotic stages of disease and lethality indexes in St. Petersburg are provided. The necessity of isolation in ICD- 10 and statistical accounting of chronic viral hepatitis diagnosis with outcome into cirrhosis (cirrhotic stage) is shown. During use of viral etiology liver cirrhosis diagnosis the disease is registered in the structure of liver diseases which does not allow to have data on unfavorable outcomes of chronic viral hepatitis and for complete morbidity accounting. PMID- 23805673 TI - [Optimization of conditions of quantitative evaluation of argentine hemorrhagic fever causative agent]. AB - AIM: Optimization of conditions of quantitative evaluation of Argentine hemorrhagic fever causative agent. MATERIALS AND METHODS: Junin virus (XJ P37 strain) was obtained from National collection of viral hemorrhagic fever causative agents of the 1st pathogenicity group of the 33rd Central Research Testing Institute. Junin virus (XJ P37 strain) culture with biological activity of 5.2 lg PFUxm(-1) was used in the experiments. Vero B, 6619-1(D) and GMK-AH 1(D) were obtained from collection of cell culture of the Research Scientific Centre of the 33rd Central Research Testing Institute. Calculation of biological activity of Junin virus during titration in cell cultures was carried out by Kerber method with modification by I.P. Ashmarin. RESULTS: During incubation for 4 - 7 days after the infection of cell monolayer the determined biological activity was 4.4 - 6.4 lg PFUxml(-1); the size of the formed negative colonies- (1.5 +/- 0.5) mm. CONCLUSION: The conditions of quantitative evaluation of Argentine hemorrhagic fever were optimized by negative colonies method (using 5 - 7 day Vero B cell culture monolayer with staining of monolayer on day 5 of secondary incubation, recording of results at day 7 after the infection). PMID- 23805675 TI - [Induction and protective properties of antibodies against muramyl peptides of gram-negative bacteria]. AB - AIM: Characterize the role of humoral immune response in mechanisms of action of muramyl dipeptide immune stimulators. MATERIALS AND METHODS: Mice were immunized by a complex of muramyl peptides (CMP) obtained from Salmonella typhi peptidoglycan and consisting of 3 components: 1) N-acetyl-D-glucoasminyl-(beta1- > 4)-N-acetyl-D-muramoyl-L-alanyl-D-isoglutaminyl-meso-diaminopimelic acid (GMtri); 2) N-acetyl-D-glucosaminyl-(beta1- > 4)-N-acetyl-D-muramoyl-L-alanyl-D isoglutaminyl-meso-diaminopimeloyl-D-alanine (GMtetra) and 3) GMtetra dimer (diGMtetra), in which monomeric residues of GMtetra are linked by an amid bond between carboxyl group of terminal D-alanine of one of GMtetra residues and omega amino group of meso-diaminopimelic acid of the other GMtetra residue. RESULTS: Immunization resulted in a multifold increase of IgM, IgG1 and IgG2a titers against CMP. Antibodies were directed against the whole molecule of diGMtetra and did not recognize its fragments. Sera of mice immunized with CMP protected the mice from lethal infection with Gram-negative (S. typhimurium) but not Gram positive (Staphylococcus aureus) microorganisms. CONCLUSION: Induction of protective antibodies may present a novel mechanism of action of muramyl dipeptide immune stimulators. PMID- 23805674 TI - [State of collective immunity against poliomyelitis in some regions of Russia]. AB - AIM: Study the state of collective immunity against poliomyelitis in 7 regions of Russia in the last 3 years. MATERIALS AND METHODS: 2579 sera were studied for antibodies against poliomyelitis virus. Antibodies (AT) against 3 types of viruses were determined in neutralization reaction in RD cell culture, the state of collective immunity in the examined individuals was evaluated by the percent of individuals with AT against a type of poliovirus and geometric mean AT titer. The circulation of wild polioviruses was judged by the presence of strain specific AT against wild and vaccine viruses in the examined children (311 sera were studied). RESULTS: The indicators of collective immunity against poliomyelitis in both select examined regions and select age groups were generally high. The data obtained allow to make a conclusion that the quality of vaccine prophylaxis in the examined regions is good. Introduction of wild poliovirus type 1 from Tajikistan in 2010 caused disease in 7 residents of Russia whereas an epidemic that had affected more than 700 individuals emerged in Tajikistan. CONCLUSION: The studies carried out confirmed the necessity to continue qualitative poliomyelitis vaccine prophylaxis in the country despite the lack of circulation of wild polioviruses that can be introduced at any time. PMID- 23805676 TI - [Circulating immune complexes as a depot of conservation of mycoplasma cell components]. AB - AIM: Study the possibility of prolonged conservation in macroorganism of antigens, mycoplasma cell DNA and live pathogen cells as part of CIC against the background of persisting antigen biostructures. MATERIALS AND METHODS: Aggregate hemagglutination, direct immunofluorescence reactions and PCR method were used to determine antigens and DNA. Circulating immune complexes from blood sera samples were isolated by M. Digeon et al., mycoplasma isolation from CIC was carried out in SP-4 medium, species identity of the isolated mini-colonies was confirmed by real-time PCR method. RESULTS: In patients with urogenital and respiratory pathology the frequency of detection of Mycoplasma hominis, Ureaplasma urealyticum and Mycoplasma pneumoniae in free state was 63.3, 53.1 and 80.82% of cases, respectively. Specific CIC in patients with verified respiratory mycoplasmosis 1 month after the onset of the disease were registered in patients with severe course of the disease, bronchitis and diseases of upper respiratory tract--in 92.5, 74.7 and 25.7% of cases, respectively. In children, bronchial asthma patients the frequency of detection of antigens and DNA of M. pneumoniae cells in free state was 72.6 and 12.33%, as part of CIC--in 60.27 and 43.8% of cases, respectively. Antigens and DNA of M. hominis in blood of this group of patients were detected in 32.9 and 26.02%, as part of CIC--in 53.42 and 52.05% of cases, respectively. During repeated examination of 12 children after etiotropic therapy execution (generally in 1.5 - 6 months) in 75% of cases antigens of both M. pneumoniae and M. hominis were detected in free state and as part of CIC. DNA of cells of these mycoplasma species were detected in 20 and 33%, as part of CIC- in41.6 and 50% of cases, respectively. In 5 patients after 6 months (after 1 year in 1 case) mycoplasma antigens and DNA were identified in CIC or in blood sera. During cultivation of CIC components precipitated from 5 blood samples of patients of this group containing M. hominis DNA, culture of M. hominis mini colonies were isolated in 4 cases. CONCLUSION: The possibility of prolonged persistence of antigens, DNA and whole mycoplasma cells in both free state and as part of CIC in patients with respiratory and urogenital pathology was shown. CIC are thus a peculiar depot, a place of conservation of not only various mycoplasma cell components, but also live cells. PMID- 23805677 TI - [Comparative evaluation of effectiveness of traditional serologic and modified methods of herpes zoster laboratory diagnostics]. AB - AIM: Comparative evaluation of effectiveness of traditional serologic and modified diagnostic methods of disease arising due to varicella and herpes zoster virus (VZV) reactivation. MATERIALS AND METHODS: 2 groups of patients were examined. The main group consisted of 39 patients with manifest form of herpes zoster (HZ), control--20 healthy donors. Sex composition of the groups did not differ. Traditional method of serologic diagnostics included determination of anti-gE VZV IgG and anti-VZV IgG and anti-IgM in patient and donor blood sera by using EIA. Modified methods consisted of isolation in density gradient and cultivation for 48 hours of peripheral blood mononuclears (PBMC) in RPMI-1640 complete culture medium containing 10% of fetal bovine serum, 4 mM L-glutamin and gentamycin. Concentrations ofanti-VZV IgG and IgM were then determined in culture medium by using EIA. RESULTS: In all the examined HZ patients and healthy donors anti-VZV IgG were detected in blood. Only in 26 (67%) of 39 HZ patients anti-gE VZV IgG and anti-VZV IgM were determined in blood sera. Among donors false positive results for these markers were detected in 10% and 5% of cases, respectively. During simultaneous determination of anti-gE VZV IgG and anti-VZV IgM the specificity of the method increased to 100%, sensitivity of the diagnostic method based on simultaneous determination of anti-gE VZV IgG and anti VZV IgM was 59%. During analysis of spontaneous production of anti-VZV antibodies by PBMC in 38 (97.4%) of 39 patients anti-VZV IgG were determined in PBMC culture, anti-VZV IgM production was observed only in 4 patients. In control group false positive results of anti-VZV IgG and IgM production by PBMC was not detected by the modified method (100% specificity). At equal specificity level sensitivity of the modified method based on determination of spontaneous anti-VZV IgG production by PBMC culture was significantly higher than effectiveness of the traditional serologic diagnostics (97.4% and 59%, p < 0.0001). CONCLUSION: The data obtained allow to recommend during diagnostics of manifest and atypical VZV infection forms arising due to endogenous virus reactivation the new modified method of laboratory diagnostics of the disease as having higher sensitivity compared with traditional serologic method. PMID- 23805679 TI - [Experience of application of pneumococcus vaccines for studies of humoral immunity]. AB - AIM: Evaluate possible use of Pneumo-23 pneumococcus polysaccharide vaccine and Prevenar-7 conjugated vaccine in EIA as antigens for determination of IgG levels against capsule polysaccharides. MATERIALS AND METHODS: Solid phase EIA method with sorption on polystyrol of commercial vaccines Penumo-23 and Prevenar-7 was used in the study. Blood sera of 41 children before immunization and sera of 8 children before and after vaccination with Pneumo-23 and Prevenar-7 were analyzed. IgG level was determined in standard units (u.). RESULTS: Mean level of antibodies in groups of unimmunized children against antigens of both vaccines were in the range of 52.3-69.1 u. (p > 0.05). The number of children with diagnostically significant level of antibodies (114 - 120 u.) was 2.4% in the control group (1/41) when Pneumo-23 antigens were used and 7.3% (3/41) when Prevenar-7 antigens were used. After vaccination with Pneumo-23 the fraction of diagnostically significant level of antibodies against Pneumo-23 antigens was on average higher by 1.8 times than in pre-vaccination period in 62.5% of children, and against Prevenar-7 antigens - by 1.6 times higher in 75% of children. After immunization with Prevenar-7 vaccine the level of antibodies increased by 3-4 times against antigens of both vaccines and reached diagnostically significant in 100% of cases. CONCLUSION: Pneumo-23 and Prevenar-7 pneumococcal vaccines may be used as antigens for determination of antibodies against capsule polysaccharides of Streptococcus pneumoniae in EIA. Higher sensitivity of EIA based on Prevenar-7 allows to recommend this test for studies of postvaccination immunity in immunized with both conjugated and non-conjugated polysaccharide pneumococcal vaccines. PMID- 23805678 TI - [Helicobacter pylori population characteristic in patients with diseases of gastrointestinal tract]. AB - AIM: Study H. pylori strains circulating in St. Petersburg among patients with various gastrointestinal tract pathology as well as study of frequency of infection by H. pylori based on serological markers data among this group of patients. MATERIALS AND METHODS: By using serological method 162 individuals with various chronic diseases of stomach and duodenum were examined. The presence in blood serum of IgG against H. pylori bacterial antigen and IgG against its toxin- CagA was studied. 129 patients were examined bacteriologically, biopsy samples of stomach mucous membrane were studied. PCR in real time format was used for study of H. pylori strains (49) and biopsy samples (36) of stomach mucous membrane. RESULTS: The analysis performed showed that on the territory of St. Petersburg H. pylori strains containing cagA gene predominate (81.63% of the isolated strains). Genotyping of strains by vacA showed that s1m1 genotype was more frequent (in 57.14% of cases). The fraction of CagA positive strains in patients in St. Petersburg is maximum for stomach cancer (90.8%), whereas for peptic ulcer disease and gastritis it is 64.7% and 72.2%, respectively. In patients with stomach and duodenum pathology the parameters of seropositivity for H. pylori were significantly higher than in individuals without clinical manifestations of H. pylori infection (86.72% against 65.09%; p < 0.05). CONCLUSION: The data obtained on increase of fraction of CagA positive strains among H. pylori circulating in St. Petersburg determine the importance of conducting eradication H. pylori. PMID- 23805680 TI - [Intestine infections, inflammation and autoimmunity. Trigger and effector mechanisms of autoimmune disease development as an outcome of intestinal infections]. AB - Problem of interconnection of intestine infections, inflammatory intestine diseases and autoimmune illnesses in this article is examined from the position of their trigger and effector mechanisms. Among trigger mechanisms special attention is given to mechanisms by which the presence of pathogenic microbial causative agent in the organism is transformed into an autoimmune process. The phenomenon of antigen mimicry, carriage of superantigens by pathogenic agents, the role of cell apoptosis are accentuated. Autoimmune diseases are examined in the same way as genetically determined phenomenon with designation of main genes, polymorphism of which is involved in the development of this pathology. Among effector reactions accompanying the development of autoimmune process againstthe background of intestine infections the role of B1 lymphocytes, Th17 and Th1 are analyzed in more detail. Special attention is given to pathogenetic and protective role of natural killers which is recognized as relatively understudied. PMID- 23805681 TI - [Intestinal-brain axis. Neuronal and immune-inflammatory mechanisms of brain and intestine pathology]. AB - Mutually directed connections between intestine and brain are implemented by endocrine, neural and immune systems and nonspecific natural immunity. Intestine micro flora as an active participant of intestine-brain axis not only influences intestine functions but also stimulates the development of CNS in perinatal period and interacts with higher nervous centers causing depression and cognitive disorders in pathology. A special role belongs to intestine microglia. Apart from mechanic (protective) and trophic functions for intestine neurons, glia implements neurotransmitter, immunologic, barrier and motoric functions in the intestine. An interconnection between intestine barrier function and hematoencephalic barrier regulation exists. Chronic endotoxinemia as a result of intestine barrier dysfunction forms sustained inflammation state in periventricular zone of the brain with consequent destabilization of hematoencephalic barriers and spread oF inflammation to other parts of the brain resulting in neurodegradation development. PMID- 23805682 TI - [Virosphere and giruses]. AB - Novel findings and concepts in the field of virology particularly regarding virosphere and giruses--a group of large nuclear-cytoplasmic deoxyriboviruses are briefly summarized. In the context of novel understanding the major taxonomic features and virus pathogenicity including African swine plague are interpreted. PMID- 23805683 TI - [Development of the system for nanomaterials and nanotechnology safety in Russian Federation]. AB - The article discloses a system of guidelines establishing unified order of detection, identification of nanoparticles and nanomaterials, estimation of their safety, sanitary regulation, control and supervision in environmental objects and production of nanoindustry, evaluation and management of risk produced by nanoparticles and nanomaterials. Recent development of nanosafety system in Russian Federation serves the aim of balanced achievement of unconditional ensuring welfare of present and future human population together with promotion of advanced technologies promising lot of useful applications. PMID- 23805684 TI - [On the improvement of the legal support of the food safety in the conditions of trade and economic integration of states-members of the Customs union and the Russian Federation's accession to the WTO]. AB - In the article priority activities of The Federal Service for the Oversight of Consumer Protection and Welfare on improvement of standard legal support of safety of foodstuff and control of compliance of foodstuff to legislation requirements are reported. The main documents directed on harmonization of the international requirements with national ones and requirements of the Customs union on safety of foodstuff are submitted. Work within a framework of Russian Federation's accession to the WTO is described. And data on control of quality and safety of foodstuff are provided also. PMID- 23805685 TI - [Use of system of radiation and hygienic certification of territories for ensuring supervision of radiation safety of the population at the regional level]. AB - In article the experience of Department of Federal Service for Supervision of Consumer Rights Protection and Human Welfare in St. Petersburg, related with performing of radiation and hygienic certification of the organizations and territories is considered. The annual assessment of individual and collective risks of emergence of stochastic effects for the population and the personnel of radiation objects shows the significance of radiation and hygienic certification for hygienic justification of the measures directed on a decrease in radiation exposure of the population from technogenic, natural and medical sources of ionizing radiation. The long-term analysis of the structure and dynamics of annual individual and collective effective doses of radiation of the population within the framework of radiation and hygienic certification and the Universal state system for control and accounting for individual doses of radiation of citizens allows to estimate efficiency of address target programs for the solution of actual problems of radiation safety at the regional level. PMID- 23805686 TI - [The medical and sanitary passport of chemically hazardous facility and the surrounding area as the register of indicators of sanitary and epidemiologic safety of a state of health and habitat areas]. AB - Basic provisions of the medical and sanitary passport of chemically dangerous object and the territory adjoining to it are presented in article. Need of development of the medical and sanitary passport for systematization of sanitary and epidemiologic data with the purpose of a complex assessment of health of the population and the personnel working at chemically dangerous objects, harmful factors production and environment taking into account emissions of polluting substances of chemically dangerous objects is shown. PMID- 23805687 TI - [Physiological and hygienic assessment of perception of the information from electronic device for reading (reader)]. AB - A comparison of the legibility of the three different media: paper personal computer (LCD) and the e-reader in schoolchildren (12-14 years of age) was performed. Comprehensive assessment of the reading performance (speed of reading aloud, the number of errors in reading, and integral indicator of the degree of difficulty of visual task), its physiological value (according to data of EEG, EOG and ECG), and subjective preference of type of media by the schoolchildren showed that by the sum of signs e-reader occupies an intermediate position between printed text and the computer screen. The effect of increased emotional intensity of using e-reader (increased motivation), which is manifested in the preservation of the sympathetic nervous system activation after the reading, was obtained. The necessity of additional research has been shown. PMID- 23805688 TI - [A scientific providing for the system of hygienic optimization and anti-epidemic safety of rail ridership]. AB - The system of scientific and reasonable measures for hygienic and anti-epidemic providing of rail ridership is elaborated. The legal and methodical base for precautionary and current sanitary inspection in the field of hygiene and epidemiology of ridership has been created, standard and methodical documents have been introduced in practice of medical sanitary health services of the railroads and accepted to realization by the design, car-building and car-repair organizations. Sanitary and hygienic monitoring for rail ridership, including control for sanitary, hygienic and microbiological indices of the air environment of passenger and service premises of stations and passenger trains, and also control for indices of health of the workers providing ridership, with use of pre nosological symptoms of pathology is organized. Features of a bacterial aero plankton of passenger objects are revealed. The increase of indices of bacterial pollution of air in passenger objects during the summer-autumn periods of year in comparison with winter period is established. Direct relationship between levels of bacterial air pollution of passenger rooms of stations and integrated indices of anti-infectious stability of an organism of workers of the railway stations serving ridership, and also number of persons with the changed indices of the immune status is revealed. PMID- 23805689 TI - [The socio-hygienic monitoring as an integral system for health risk assessment and risk management at the regional level]. AB - The information and analytical framework for the introduction of health risk assessment and risk management methodologies in the Sverdlovsk Region is the system of socio-hygienic monitoring. Techniques of risk management that take into account the choice of most cost-effective and efficient actions for improvement of the sanitary and epidemiologic situation at the level of the region, municipality, or a business entity of the Russian Federation, have been developed and proposed. To assess the efficiency of planning and activities for health risk management common method approaches and economic methods of "cost-effectiveness" and "cost-benefit" analyses provided in method recommendations and introduced in the Russian Federation are applied. PMID- 23805690 TI - [The perspective directions of development of methodology of the analysis of risk in Russia]. AB - In the article the perspective directions of development of methodology of the analysis of risk in Russia with taking into account the last world achievements in this area and requirements to harmonization of a system for control of environment quality are considered. Main problem questions of the analysis of risk in relation to regulation of nature protection activity were emphasized to be related as well with insufficiency of legislative, standard and executive support for this direction of administrative activity as with the need of the solution of the methodical questions concerning new tendencies of justification and use of reference levels of chemicals, development of modern approaches to the specification of cancerogenic and not cancerogenic risks, including cumulative ones. PMID- 23805691 TI - [Issues of the support of the quality and safety of baby food]. AB - In article there are presented data on hypersensibility of children to the action of contaminants and caused by it the increased requirements to hygienic safety of products of baby food. Data on the main indices of safety, of such products, regulated by hygiene legislative requirements are provided. The system of hygienic expertise of baby food products, including the offered screening methods of studying of indices of quality and safety is considered. PMID- 23805692 TI - [Approaches to assessment of the alimentary load by nutrient additives]. AB - Methodological approaches to the assessment of alimentary load of nutritional supplements (ALNS) have been based. Description for the different models for assessment of ALNS according to the allowable daily intake and the use of hygienic regulations is presented. PMID- 23805693 TI - [Safety during the thermal disposal of medical waste containing PVC]. AB - In the article the issues of environmental, sanitary and hygienic safety of medical waste management are considered. Recently, for the treatment of certain types of medical waste thermal methods using small plants not equipped with a proper flue gas cleaning system are widely used. In this article the potential danger of supertoxicants generation when applying thermal methods of neutralization of medical waste that contains polyvinyl chloride (PVC) is justified by thermogravimetric and mass spectrometric studies. This research shows the necessity of introducing technologies of separate collection of PVC medical waste and its' thermal recycling in compliance with special requirements. PMID- 23805694 TI - [Atmospheric air pollution in an industrial city as the factor of non carcinogenic risk for health of communities]. AB - The paper deals with the results of the research on risk of exposure of atmospheric air pollution in a large industrial city to health of communities. The results of individual both immediate and chronic risk estimation for selectable city zones are presented. Regression ratios of various substances concentrations and disease incidence are revealed. On their basis the estimation of risk of additional disease incidence is carried out and taxonomic values characterizing the contribution of separate pollutants to risk of health of communities' disorder are obtained. PMID- 23805695 TI - [The study of health risk in short-term inhalation exposure in conditions of forest fires]. AB - The algorithm of studying of risk to population health due to short-term high atmospheric air pollution is presented. The algorithm was tested on a model example. The elevation of the content of a pool of carbon monoxide and the weighed particles in quantities above referential levels in the air are established to lead to increase in emergency medical aid appealability concerning diseases of respiratory and blood circulation organs. PMID- 23805696 TI - [Researches of the structure of solid household waste and assessment of their sanitary and epidemiologic danger]. AB - Compliance with hygiene requirements for the municipal solid waste (MSW) handling includes their composition control. The main methodological approaches to the MSW morphological composition study to assess their epidemiological risk are given. The main results of experimental waste composition analysis for a number of settlements are presented. These data were used for epidemiological risks estimation, measures for their minimization are suggested. PMID- 23805697 TI - [The significance of glucose positive coliform bacteria and potentially pathogenic bacteria as an indicator of epidemiological safety of tap water]. AB - Due to intensive anthropogenic pollution of water environment generally accepted indicators of epidemic security of water bodies--common bacteria (CB) and thermotolerant coliform bacteria (TCB) do not always permit to obtain an objective characterization of bacterial contamination of tap water. From the point of view of authors the integral index--glucose positive coliform bacteria most adequately reflect the sanitary-hygienic and epidemiological situation of water bodies. In monitoring for bacterial quality of tap water it is advisable to determine glucose positive coliform bacteria, that will provide the relevance of estimation of the epidemiological safety of water use. According to the method developed by the authors the calculation of the index of population risk of acute intestinal infections (AHI) occurrence in dependence on the quality of tap water in Azov and Tsimlyansk towns. PMID- 23805698 TI - [Self-estimation of health and mode of life of native minorities of the Yamal North]. AB - Preservation of health of native minorities of the Yamal North is the major medical and social problem. The purpose of research--a self-estimation of health of the native minorities of the district in relation with a way of life in modern social and economic and ecological conditions. "Bad" and "very bad" health has been revealed in 20.9% of persons. PMID- 23805699 TI - [Problem of congenital malformations in children in the region with an ambiguous ecological situation]. AB - The problem of birth defects in children in the Stavropol region is considered. The frequency and pattern of pathology is described on several sources of information. The environmental situation in the region has been analyzed, regional features of pathology and the territory of the region where excess of indices is noted have been revealed. PMID- 23805700 TI - [Risk factors negatively affecting on the formation of musculoskeletal system in children and adolescents in the present conditions]. AB - Identifying risk factors affecting the formation of the musculoskeletal system (MSS) in children and adolescents is considered by the author as a necessary condition for the implementation of prevention, timely diagnosis and adequate correction of the MSS disorders and diseases. Introduction in the educational process developed by the author for the first time a conceptual model of prevention and correction of the MSS disorders and diseases in schoolchildren allowed significantly reduce the prevalence of functional disorders and early forms of the MSS diseases in students of a number of comprehensive schools in Moscow by 50%. PMID- 23805701 TI - [Evaluation criteria of medical and ecological situation based on the method of sigma deviations]. AB - Comparative analysis of the existing criteria for assessment of health and environmental situation was produced. The approach to health assessment of the environmental situation, where sigma intervals are used as criteria of belonging population morbidity in certain administrative areas in the region to the background incidence rate was proposed. The suggested criteria will increase the objectivity of the assessment of environmental health situation in the environment and health monitoring and implementation of epidemiological research. PMID- 23805702 TI - [To a question on the impact of nanoparticles of metals present in the aquatic environment, on bacteria and continuous cell lines HEp-2 and BGM]. AB - Promising application of nanoparticles and nanomaterials is the creation of sanitary hygienic means of new generation used for disinfection of water and indoor surfaces of mass use, furniture, sanitary technical equipment by virtue of modifying traditional materials to bring them effective biocidal properties, and for the development of methods in vitro for assessment their toxicity In this paper the possibility of the use various forms of silver, copper and aluminum as disinfectant for bacterial test organisms in the aquatic environment and assess their toxicity on biological models of continuous culture of BGM cells (a stable line of African green monkey kidney cells) and HEp-2 (Human epithelial type 2 (HEp-2) cells, derived from a human laryngeal carcinoma) is considered. PMID- 23805703 TI - [Monitoring for contamination of food commodities and food products with toxic elements]. AB - The results of hygienic assessment of toxic elements in food produced locally. The estimation of the levels of foodborne contaminants (lead, cadmium, arsenic, copper, zinc, mercury) on the basis of data on average food consumption has been presented. That the traditional products of mass consumption (dairy products, vegetables) were shown to make most significant contribution to the overall burden of priority contaminants. Child population of Saratov region has a greater risk to health from the peroral route of toxic elements in food. PMID- 23805704 TI - [Monitoring the quality of groundwater exploited on the territory of the Republic of Mari El]. AB - Hygienic characteristics of ground water used for drinking water supply of the Republic of Mari El is presented in the article. The features of the quality of ground water in different areas of the country have been revealed, the causes of the deterioration of drinking water which can act as a risk to public health have been shown. PMID- 23805705 TI - [Algorithm for taking into account the average annual background of air pollution in the assessment of health risks]. AB - State Budgetary Educational Institution of Higher Professional Education "I.M. Sechenov First Moscow State Medical University" of the Ministry of Health care and Social Development, Moscow, Russian Federation. The assessment of health risks from air pollution with emissions from industrial facilities, without the average annual background of air pollution does not meet sanitary legislation. However Russian Federal Service for Hydrometeorology and Environmental Monitoring issues official certificates for a limited number of areas covered by the observations of the full program on the stationary points. Questions of accounting average background air pollution in the evaluation of health risks from exposure to emissions from industrial facilities are considered. PMID- 23805706 TI - [Modernization of production as criterion for reducing of sanitary protection zone]. AB - The complex hygienic assessment of a large enterprise of chemical profile as a source of the chemical and physical effects on the environment and human health has been given. Modernization of the production with the introduction of modern technologies, effective gas- powered dust collector units was found to permit to reduce emissions by 20%, diminish the levels of atmospheric air pollution to the normative values, health risks--to acceptable. According to the research after the reconstruction of the plant the possibility to move it from 1 to 2 danger class with reduction in size of sanitary protection zones in 2 times (from 1000 to 500 m). PMID- 23805707 TI - [New methodologicalapproaches to establishment the sizes of the sanitary protection zone and roadside clear zones of civil airports]. AB - This circumstance leads to considerable mistakes it creation of SPZ borders of the airports, in some cases it impedes development of the latters and causes objective difficulties for hygienic assessment of projects. In this article the results of studies on the creation and validation of two new domestic methods for the construction of impact zones of aircraft noise and dispersion of the concentrations of pollutants in assessing the negative impact of airports are considered. Both branch methods agreed upon with the Ministry of Transport have been harmonized with ICAO (International Civil Aviation Organization) requirements. The results of full-scale measurements have confirmed the possibilities of developed software for their implementation in the formation of a common SPZ border of an airport. PMID- 23805708 TI - [Systemic inflammation: theoretical and methodological approaches to description of general pathological process model. Part 2. Evolution aspects]. AB - Theoretical and methodological approaches to description of systemic inflammation as general pathological process are discussed. It is shown, that there is a need of integration of wide range of types of researches to develop a model of systemic inflammation. PMID- 23805709 TI - [The role of adiponectin in the pathogenesis of the metabolic syndrome and approach to therapy]. AB - In this adiponectin-focused review, the pathophysiological role and the potential therapeutic benefits of adiponectin in metabolic syndrome (MetS) are analysed. MetS is recognized as clusters several metabolic abnormalities and the leading cause of cardiovascular diseases. Insulin resistance (IR) is a key factor in the pathogenesis MetS. Adiponectin is the most abundant and adipose-specific adipokine. Adiponectin acts through the activation of AMP-activated protein kinase and peroxisome proliferator-activated receptor-alpha (PPARalpha) pathways. The wide distribution of adiponectin receptors in various organs and tissues suggests that adiponectin has pleiotropic effects on numerous physiological processes. Its well-known insulin-sensitizing, anti-inflammatory and antiatherosclerotic properties, accumulating evidence suggests that adiponectin may have cardioprotective properties. There is an evidence that adiponectin decreases systematic IR and generally predicts cardiovascular diseases. Recent therapeutic strategies have focused on the indirect upregulation of adiponectin through the administration of various therapeutic agents and/or lifestyle modifications. Weight loss, diet, lifestyle changes and/or medications including orlistat, sibutramine, rimonabant, increase level of adiponectin. Also insulin sensitizers, including thiazolidinediones, and lipid-lowering agents, including statins and fibrates, upregulate adiponectin and may improve IR. The wider use of new treatment approaches appears to signal of a new era in the management of cardiovascular diseases, diabetes mellitus and MetS. PMID- 23805710 TI - [Comparison of the effects of glutamate antibodies on neuronal activity of caspase 3 and memory impairment in rats induced by injection of Abeta(25-35) into the Meynert nuclei]. AB - In experiments on rats showed that intranasal administration of glutamate antibodies in a dose of 300 microg/kg after 1 h after bilateral injection of neurotoxic fragment of beta-amyloid protein (25-35)--Abeta(25-35)--into the Meynert nuclei restores learning ability in the test of passive avoidance on 3 and 14 days of the experiment. Antibodies to glutamate decrease significantly increasing caspase 3 activity, detected on Day 3 after injection of Abeta(25-35), in samples of the prefrontal cortex and hippocampus but not hypothalamus. Intranasal administration of gamma-globulin had no effect on the performance of violations of mnestic functions and caspase 3 activity. PMID- 23805711 TI - [Direct involvement of the glucose and Mg(2+)-ATP in the regulation of the GABAA coupled Cl-,H(CO3(-) -activated Mg(2+)-ATPase of the plasma membrane from rat brain in vitro experiences]. AB - Effect of the glucose and Mg(2+)-ATP on the coupled with CABA(A)-receptor Cl ,HCO3(-)-activated Mg(2+)-ATPase of the plasma membranes from rat brain involving from "basal" Mg(2+)-ATPase which it is activated by Cl-,HCO3(-) ions it was investigated. The glucose (1-10 mM) decreased the "basal" Mg(2+)-ATPase activity on 17% and completely eliminated the enzyme activation by 10 mM Cl(-)+2 mM HCO3( ) ions. The variety effect of the glucose and Mg(2+)-ATP on the activation of the '"basal" Mg(2+)-ATPase by variety concentrations of anions it was established. So it was found that in the presence Mg(2+)-ATP in the incubation medium > 1 mM the enzyme activation by 10 mM Cl- + 2 mM HCO ions not appear. However, in the presence of the glucose (10 mM) the inhibiting effect of the Mg(2+)-ATP on the enzyme is disappears and Cl-,HCO3(-)-ATPase activity is restored. While, in the presence of the high concentrations 40 mM Cl- + 8 mM HCO3(-) in the incubation medium the inhibiting effect of the glucose and Mg(2+)-ATP it was negligible ( 20%). It was conclusion about direct involvement of the glucose and Mg(2+)-ATP in the regulation of the coupled with CABA(A)-receptor Cl-,HCO3(-)-ATPase activity of the neuronal membrane under different concentration anions in the incubation medium. PMID- 23805712 TI - [Effect of damage integrity rat brain synaptic membranes on the functional activity GABA(A)-receptor/Cl(-)-ionophore complex in the CNC]. AB - Functional activity of the CGABA(A)-receptor/Cl(-) ionophore complex was investigated the muscimol-stimulated entry of the radioactive isotope 36Cl(-) in synaptoneurosomes in changing the structure and permeability of neuronal membranes. Integrity of the membranes was damaged by removal of Ca(+2) and Mg(+2) from the incubation medium and by the method of freezing-thawing synaptoneurosomes. In both cases, an increase in basal 36Cl(-) entry into synaptoneurosomes, indicating increased nonspecific permeability of neuronal membranes, and decreased activity the CABA(A)-receptor/Cl(-) ionophore complex. The conclusion about the relationship of processes damage neuronal membranes and reducing the inhibitory processes in the epileptic focus. PMID- 23805713 TI - [The response of cerebral blood flow and systemic arterial blood pressure to hypercapnia and hypocapnia in humans]. AB - In 11 healthy volunteers 21 +/- 3.7 years old was monitored cerebral blood flow (CBF) by transcranial Doppler (TCD) of middle cerebral artery and mean hemodynamic arterial blood pressure (MAP) by continuous non-invasive measurement "beat-to-beat" at normocapnia, hypercapnia and hypocapnia. Hypercapnia was creating by rebreathing, hypocapnia was creating by spontaneous hyperventilation. The partial pressure of CO2 in alveolar air (PetCO2) was monitored by capnograph, embedded in the TCD-analyzer. During hypercapnia the velocity of CBF and PetCO2 were significantly increased already at 10 s, which was considerably earlier than the increase in the MAP (30 s). During hypocapnia velocity CBF and PetCO2 were significantly decreased at 10 s, and MAP was not changed. We have installed the threshold PetCO2 42 (41; 44) mm Hg, below which amplification CBF occurs at a constant MAP and reflects the true cerebrovascular reactivity to CO2. PMID- 23805714 TI - [Study of hormone responsiveness of the adenylyl cyclase signaling system in erythrocyte membranes of patients with type 2 diabetes mellitus]. AB - Peptides of the insulin superfamily (insulin, insulin-like growth factor, relaxin), epidermal.growth factor (ECF) and biogenic amines (isoproterenol, adrenalin, noradrenalin, serotonin) stimulate the adenylyl cyclase signaling system (ACSS). In erythrocyte membranes from a control group of patients, the hormone activating affect on ACSS was potentiated in the presence of guanylylimidinodiphosphate (CppNHp). In erythrocyte membranes from patients of various severity of type 2 diabetes mellitus (DM2, early, medium and severe), the basal activity of AC was higher than in the control group and its responsiveness to hormones was different. It was reduced in patients with early and severe forms of DM2 both in the presence and absence of CppNHp. In patients with the medium severity of the disease, the stimulating effect of biogenic amines was not changed but there was no potentiating effect of CppNHp. The insulin superfamily peptides and ECF stimulated AC in the erythrocyte membranes of patients with the medium severity of DM2 to the same extent as in the control while, at the early and severe stages of the disease, the AC sensitivity to these hormones was significantly reduced. These data suggest that DM2 results in disturbances of the hormone stimulating properties of ACSS by insulin superfamily peptides, ECF and biogenic amines. In erythrocyte membranes, DM2 disturbs ACSS functions at the level of the catalytic component and its responsiveness to hormone action at the level of interactions between CG, and AC. PMID- 23805715 TI - [Morpho-biophysical research of erythrocytes of intact and vagotomized rats in various terms after the acute hemorrhage]. AB - The acute massive hemorrhage (35-37% of the blood volume) at rats is accompanied by changes of morphological (diameter, the area, polarizations, the form-factor, integrated and specific absorbency) and biophysical (a relief of a surface and microviscosity of a lipid phase of plasmolemma) characteristics of erythrocytes. Thus character and dynamics of response of erythron initially intact and vagotomized (14 days after operation) animals essentially differ: the former demonstrate significant changes in 3-10 h and 240 h and the latter--in 0.5 h and 96 h. PMID- 23805716 TI - [Biochemical aspects of the influence of antiorthostatic hypokinesia on the experimental peritonitis]. AB - Eighty white rats were divided into 4 groups: (1) vivarium control, (2) antiorthostatic hypokinesia (AH), (3) peritonitis alone, and (4) AH with peritonitis. Effects of AH were achieved by putting rats on a special stand for a period of 14 days, followed by the formation of peritonitis. After that biochemical parameters of blood samples have been investigated. Combination effects of microgravity and peritonitis is unidirectional and have mutual weights. As illustrated in some cases two-fold increase in the level of the studied parameters in comparison with the control and vivarium peritonitis. Comparative assessment of peritonitis severity revealed that simulated effects of microgravity turn the peritonitis into more complicated forms. PMID- 23805717 TI - [Dynamics of formation of bone tissue in rats under the influence of new xenotransplantat "Norian"]. AB - In experiments on rats CD comparative studies have been carried out which is the effect of osteoplastic material NORIAN CRS, the rate of bone regeneration after mandibular dental implants (titanium screw) and the combined effect of these processes NORIAN CRS protein and protein (Emdogein). Functionality and maturity of the newly formed bone tissue was evaluated by histological and biochemical methods. The results suggest that the use of osteoplastic material NORIAN CRS is the 120 days leading to almost complete regeneration of bone tissue. It was also found that the combined use of NORIAN CRS and protein Emdogein impractical because adding Emdogein not accelerate bone regenerative process, but in the early postoperative period may cause an inflammatory reaction. PMID- 23805718 TI - [Immunotropic and antihypoxant therapy of experimental drug-sensitive and drug resistant tuberculosis]. AB - The results of pre-clinical research of cycloferon, remaxol and runihol on the model of experimental generalized tuberculosis, caused by the MBT with a different spectrum of drug sensitivity are presented. A considerable increase of the curative effect of the therapy with the used of cycloferon and remaxol. There was manifested the strengthening of lung clearance from the office, reducing the prevalence of specific inflammation in the lungs of the index of lung damage, stimulation of sorption and destructive ability of peritoneal macrophages, inhibited in the course of development of experimental tuberculosis infection. Runihol has no impact on the effectiveness of chemotherapy in the absence of a stimulating influence on the phagocytic function of the peritoneal macrophages. PMID- 23805719 TI - [The natural triterpenoid miliacin prevents methotrexate-induced oxidative stress and normalizes the expression of genes encoding the cytochrome P-450 2E1 isoform and glutathione reductase in the liver]. AB - We studied the role of the natural triterpenoid miliacin (3-3-methoxy-Al8 oleanene) in the regulation of oxidative stress in the liver of (CBAxC57B1(6))F1 mice exposed to methotrexate. Miliacin attenuated methotrexate-induced lipid peroxidation as determined by an attenuation of thiobarbituric acid-reacting products in the liver. Furthermore, miliacin normalized the expression of genes encoding the 2e1 isoform of cytochrome P-450 and glutathione reductase that were dramatically dysregulated by methotrexate. These results established the role of miliacin in modulation of redox genes, thereby providing evidence for a new mechanism of organ protection by this triterpenoid. PMID- 23805720 TI - [Work with night shift as a factor dysregulation of autonomic nervous system of locomotive drivers]. AB - Work with night shift is an obligate necessity of modem industrial urban society. In developed countries in the work on the night shift use up to 20%. These categories of workers are definitely the locomotive drivers. The consequence of a regular work with night shifts is a violation of human circadian rhythms, which, through dysregulation of the autonomic nervous system, is reflected in a greater risk of disease and transport accidents. The need to find ways and criteria of preventive monitoring dysregulatory changes in the human body is an urgent and challenging issue in terms of the health of the working population, disease prevention, and transportation security. PMID- 23805721 TI - [Simulation of repeated local hemorrhagic stroke in rats]. AB - The processes of developed in CNS the complicated stroke and developments of fittings for their pharmaceutical therapy were developed and offering by standardized method of the experimental secondary stroke in rats, suitable for the use in sharp and chronic researches. Variant of repeated hemorrhagic stroke consist of autohemorrhagic right hemisphere stroke by the mechanical damage of brain tissue after 10-daily occlusion of right common carotid artery was studied. A model is comfortable for reproducing of the repeated standardized local damage of brain, is more adequate form of design of transient and chronic cerebrovascular pathology, than the independent use of local hemorrhage of autoblood in the brain of animals. The morphological description of model approaches the clinical variants of development and flow of sharp hemorrhagic stroke after a previous chronic cerebral insufficiency on an ischemic type. PMID- 23805722 TI - [Brain blood flow and cerebral insult. Part 2. Regulation of cerebral circulation]. AB - The data, concerning anatomy of brain vessels and the main parameters of cerebral blood flow, including vascular dilation (nitric oxide, prostacyclin, endothelial hyperpolarising factor, estrogen, calcitonin) and vascular contracting (thomboxan A2, endotolin) agents, as well the interaction between them have been scrutinized. Emphasized the leeding role of vascular endothelium and nitric oxide in the regulation of cerebral circulation. Analysis have been done of mechanisms of neuron/vascular conjugent, autoregulation of the brain blood flow, effects of functional loading (hyperoxia, hypoxia, hypercapnia, hypocapnia, acidosis) on the cerebral circulation, the different reactions between them in central and peripheral circulations, oxidant stress, inflammantion. Pointed the significance of these data for the pathogenic mechanisms and therapy of cerebral insult, others physiological and pathophysiologic process in the brain. PMID- 23805723 TI - [Coagulation and fibrinolytic activity of lymph in various pathological conditions (review of own and literature data)]. AB - The review presents information by the author and his collaborators, as well as literature data on the coagulation of lymph in blood loss, convulsive syndrome, trauma, crush syndrome, bums, injections of thrombin and heparin, an experimental thrombosis and other pathological conditions. It is shown that the coagulation of lymph in the development of pathological conditions in tissues may outpace changes observed in the blood. We present evidence that dissolution of fibrin clots in the lymph tissue if damaged, is many times faster than in the blood. PMID- 23805724 TI - [Interaction of native and modified low density lipoprotein with intimal cells in atherosclerotic lesion]. AB - In the present review we focus on the major cellular and molecular processes leading to the formation and accumulation of foamy cells: increased transmigration of monocytes into sub-endothelial sites of inflammation, activation of macrophages, modifications of lipoproteins, different types of uptake of native and associated lipoproteins (endocytosis, phagocytosis, and less investigated--patocytosis), as well as participation of different molecular systems in the reverse cholesterol transport in macrophages. Special attention is given to the recent data indicating that scavenger receptors participate not only in the uptake of modified lipoproteins, but also in the reverse cholesterol transport. In conclusion, we discuss most relevant open questions in our understanding of the mechanism and functional consequences of macrophage/lipoprotein interactions: which receptor systems are used for the recognition and internalisation of aggregated lipoproteins, what are the mechanisms of intracellular processing of associated lipoproteins, and how associated lipoproteins affect functional programming of macrophages. PMID- 23805725 TI - [The 'Ten-Camp' athlete in dentistry]. PMID- 23805726 TI - [Build-up restorations]. PMID- 23805727 TI - [Build-up restorations]. PMID- 23805728 TI - [Sarcopenia]. AB - Sarcopenia, the decrease in muscle mass and function, may lead to various negative health outcomes, including loss of physical performance and loss of the ability to perform the activities of daily living. The exact mechanisms of sarcopenia are not yet fully understood, but it is obvious that besides ageing, metabolic alterations, diseases, nutrition, and physical exercise play a major role. In the Netherlands, screening ofsarcopenia is not yet performed in daily practice. Evidence exists that training of muscle strength, whether or not combined with a dietary intervention, has a positive effect on the loss of muscle mass and function. PMID- 23805729 TI - [The dentist's role in the case of a suspected facial melanoma]. AB - A 78-year-old patient was referred by her dentist to the Department of Oral and Maxillofacial Surgery because of a number of grey-blue lesions on the inferior alveolar ridge and a number of skin lesions in the face. One of the skin lesions proved to be a melanoma, which was treated with a substantial excision and sentinel node procedure. A complete anamnesis and of both intraoral and extra oral investigation in the dental practice is very important. PMID- 23805730 TI - [Oral medicine 6. Ulcerations of the oral mucosa]. AB - An ulcer can be defined as a superficial defect of the skin or the mucosa, caused by tissue degeneration, and having little tendency to heal. With a careful review of the medical history and the findings of inspection of the oral cavity, including palpation of the ulcer, the dentist will in many cases be able to determine the diagnosis and also the treatment. There are, however, also ulcerations which require referral to a specialist, most often the oral and maxillofacial surgeon. PMID- 23805731 TI - [Dentistry and healthcare legislation 2. Differences of opinion concerning professional standards for oral healthcare]. AB - With respect to disciplinary and other complaints, it is apparent that they are often based on a difference of opinion concerning professional standards for oral healthcare. Relevant differences of opinion can arise between dentists, but also in the dentist-patient relationship. A large degree of the ambiguity which lies at the basis of such discussions could be removed by the use of clear clinical guidelines. Since these are still scarce in oral healthcare, a dentist will have to rely on adequate communication to avoid conflicts. A dentist must be aware of possible conflicts of interest and of the characteristic range of the professional standards for oral healthcare. Departing from that range at the request of a patient is not an option. PMID- 23805732 TI - [The preprosthetic treatment focusing on single- or multi-unit fixed dental prostheses]. AB - The preprosthetic treatment is a phase of the so-called patient-centred oral healthcare cycle. The goal of the preprosthetic treatment is the elimination of pathological conditions and of uncertainties and risks to the greatest extent possible. Teeth in a reduced occlusal system can be distinguished functionally as strategic, non-strategic, and undesirable. The most important objective of the preprosthetic treatment is to establish a positive prognosis for the strategic teeth. Specific aspects relevant to the preprosthetic treatment are: referral to a specialist, requesting a second opinion, inserting 1 or more oral implants, transitional treatments, and occlusal adjustments. Subsequently, the preprosthetic treatment is evaluated to assess whether healthy circumstances have been established for the intended treatment with single- or multi-unit fixed dental prostheses. PMID- 23805733 TI - [Implant-supported single- and multi-unit fixed dental prostheses in periodontally compromised patients]. AB - As a result of the introduction of oral implants, it is also possible to treat patients who have a reduced occlusal system with implant-supported fixed dental prostheses. Many publications report the successful application of implant supported single- and multi-unit fixed dental prostheses. However, it is questionable if implants are also successful in periodontally compromised patients. With respect to implant treatment, roughly 3 categories of periodontally compromised patients can be distinguished: patients who have not been treated for periodontitis, patients who have been treated for periodontitis and have stable periodontal health, and those who have been treated but have not achieved stable periodontal health. For the first group, periodontal treatment is required. Inserting implants is only indicated in cases showing steady improvement of post-operative periodontal health. The second category has no contraindication for inserting implants. For the third group, inserting implants is contraindicated absolutely. When treatment with oral implants is indicated, meticulous aftercare and a surgical treatment which enables adequate oral hygiene self-care are strict requirements. PMID- 23805734 TI - Preface. Lipids and membrane biophysics. PMID- 23805735 TI - Introductory lecture: basic quantities in model biomembranes. AB - One of the many aspects of membrane biophysics dealt with in this Faraday Discussion regards the material moduli that describe energies at a supramolecular level. This introductory lecture first critically reviews differences in reported numerical values of the bending modulus K(C), which is a central property for the biologically important flexibility of membranes. It is speculated that there may be a reason that the shape analysis method tends to give larger values of K(C) than the micromechanical manipulation method or the more recent X-ray method that agree very well with each other. Another theme of membrane biophysics is the use of simulations to provide exquisite detail of structures and processes. This lecture critically reviews the application of atomic level simulations to the quantitative structure of simple single component lipid bilayers and diagnostics are introduced to evaluate simulations. Another theme of this Faraday Discussion was lateral heterogeneity in biomembranes with many different lipids. Coarse grained simulations and analytical theories promise to synergistically enhance experimental studies when their interaction parameters are tuned to agree with experimental data, such as the slopes of experimental tie lines in ternary phase diagrams. Finally, attention is called to contributions that add relevant biological molecules to bilayers and to contributions that study the exciting shape changes and different non-bilayer structures with different lipids. PMID- 23805736 TI - Switchable domain partitioning and diffusion of DNA origami rods on membranes. AB - Recently, DNA origami became a powerful tool for custom-shaped functional biomolecules. In this paper, we present the first approach towards assembling amphipathic three-dimensional DNA origami nanostructures and assessing their dynamics on the surface of freestanding phospholipid membranes. Our nanostructures were stiff DNA origami rods comprising six DNA helices. They were functionalized with hydrophobic cholesteryl-ethylene glycol anchors and fluorescently labeled at defined positions. Having these tools in hand, we could demonstrate not only the capability of the amphipathic nanorods to coat membranes of various phospholipid compositions, but also their switchable liquid ordered/liquid-disordered partitioning on phase separated membranes. The observed translocation of our nanostructures between different domains was controlled by divalent ions. Moreover, selective fluorescent labeling enabled us to distinguish between the translational and rotational diffusion of our six helix bundles on the membranes by fluorescence correlation spectroscopy. The obtained data reveal how DNA origami can be employed as a valuable tool in membrane biophysics. PMID- 23805737 TI - The effect of cholesterol on the intrinsic rate of lipid flip-flop as measured by sum-frequency vibrational spectroscopy. AB - Cholesterol is a major constituent of biological membranes in mammalian cells. Experiments have shown that cholesterol influences the physical properties of the plasma membrane, such as lateral diffusion and phase equilibrium. In addition to controlling the 2-dimensional phase behaviour and mobility of lipids in membranes, cholesterol has also been implicated in the transbilayer diffusion of lipids across the bilayer. Sum-frequency vibrational spectroscopy (SFVS) is used to measure the intrinsic rate of lipid flip-flop for 1,2-distearoyl-sn-glycero-3 phosphocholine (DSPC) in the presence of cholesterol using planar supported lipid bilayer (PSLB) model membranes. Asymmetric PSLBs were prepared using the Langmuir Blodgett (LB) method by placing a perdeuterated lipid analogue in one leaflet of the PSLB. SFVS was used to directly measure the asymmetric distribution of DSPC within the membrane by measuring the decay in the CH3 vs intensity at 2875 cm(-1) with time and as a function of temperature. A complete kinetic analysis of DSPC flip-flop and the effect of cholesterol on the DSPC dynamics are presented. An analysis of the kinetic data in the framework of Eyring theory provides important insight into the transition state enthalpy (deltaH(double dagger)), entropy (deltaS(double dagger)) and free energy (deltaG(double dagger)) for this important biological process. In addition, the transmembrane migration of cholesterol molecules was also explored by SFVS. These combined studies are aimed at providing new insight in to the transbilayer migration of phospholipids and cholesterol in biological membranes and the effects cholesterol plays in membrane dynamics. PMID- 23805738 TI - Computer simulations of the phase separation in model membranes. AB - We used computer simulations to investigate the properties of model lipid membranes with coexisting phases. This is relevant for understanding lipid-lipid interactions underlying lateral organization in biological membranes. Molecular dynamics simulations with the MARTINI coarse-grained force field were employed to study lipid bilayers -40 nm in lateral dimension on a 20 micros time scale. The simulations retain near atomic-level detail and lipid chemical specificity, and allow formation of multiple domains of tens of nanometers in size. Using ternary lipid mixtures of saturated and unsaturated lipids and cholesterol, we reproduced the coexistence of the Lalpha/gel phases and the Lo/Ld phases. Phase transformation proceeded by either nucleation or spinodal decomposition. The properties of coexisting phases were characterized in detail, including partial lipid areas, composition, phase boundary and domain registry, based on Voronoi tessellation. We investigated variations of these properties with temperature and surface tension, and compared them to our recent simulations of lipid monolayers of the same size and composition. We found substantial overlap in bilayer and monolayer properties. Increasing the temperature in bilayers produced similar effects as increasing the surface tension in monolayers. This information can be used for interpreting experimental data on model membranes. PMID- 23805739 TI - STED microscopy detects and quantifies liquid phase separation in lipid membranes using a new far-red emitting fluorescent phosphoglycerolipid analogue. AB - We have developed a bright, photostable, and far-red emitting fluorescent phosphoglycerolipid analogue to probe diffusion characteristics of lipids in membranes. The lipid analogue consists of a saturated (C18) phosphoethanolamine and a hydrophilic far-red emitting fluorescent dye (KK114) that is tethered to the head group by a long polyethylenglycol linker. In contrast to reported far red emitting fluorescent lipid analogues, this one partitions predominantly into liquid ordered domains of phase-separated ternary bilayers. We performed fluorescence correlation spectroscopy with a super-resolution STED microscope (STED-FCS) to measure the lateral diffusion of the new lipid analogue in the liquid ordered (Lo) and disordered (Ld) phase. On a mica support, we observed micrometer large phases and found that the lipid analogue diffuses freely on all tested spatial scales (40-250 nm) in both the Ld and Lo phase with diffusion coefficients of 1.8 microm2 s(-1) and 0.7 microm2 s(-1) respectively. This indicates that the tight molecular packing of the Lo phase mainly slows down the diffusion rather than causing anomalous sub-diffusion. The same ternary mixture deposited on acid-cleaned glass forms Lo nanodomains of < 40 nm to 300 nm in diameter as only revealed by STED microscopy, which demonstrates the severe influence of interactions with the substrate on the sizes of domains in membranes. When averaging over different positions, STEd-FCS measurements on such glass supported membranes displayed anomalous sub-diffusion. This anomaly can be attributed to a transient partitioning of the lipid analogue into the nano domains, where diffusion is slowed down. Our results suggest that STED-FCS in combination with a Lo-partitioning fluorescent lipid analogue can directly probe the presence of Lo nano-domains, which in the future should allow the study of potential lipid rafts in live-cell membranes. PMID- 23805740 TI - Critical point fluctuations in supported lipid membranes. AB - In this paper, we demonstrate that it is possible to observe many aspects of critical phenomena in supported lipid bilayers using atomic force microscopy (AFM) with the aid of stable and precise temperature control. The regions of criticality were determined by accurately measuring and calculating phase diagrams for the 2 phase L(d)-L(o) region, and tracking how it moves with temperature, then increasing the sampling density around the estimated critical regions. Compositional fluctuations were observed above the critical temperature (T(c)) and characterised using a spatial correlation function. From this analysis, the phase transition was found to be most closely described by the 2D Ising model, showing it is a critical transition. Below T(c) roughening of the domain boundaries occurred due to the reduction in line tension close to the critical point. Smaller scale density fluctuations were also detected just below T(c). At T(c), we believe we have observed fluctuations on length scales greater than 10 microm. The region of critically fluctuating 10-100 nm nanodomains has been found to extend a considerable distance above T(c) to temperatures within the biological range, and seem to be an ideal candidate for the actual structure of lipid rafts in cell membranes. Although evidence for this idea has recently emerged, this is the first direct evidence for nanoscale domains in the critical region. PMID- 23805741 TI - Lipid phase behaviour under steady state conditions. AB - At the interface between two regions, for example the air-liquid interface of a lipid solution, there can arise non-equilibrium situations. The water chemical potential corresponding to the ambient RH will, in general, not match the water chemical potential of the solution, and the gradients in chemical potential cause diffusional flows. If the bulk water chemical potential is close to a phase transition, there is the possibility of forming an interfacial phase with structures qualitatively different from those found in the bulk. Based on a previous analysis of this phenomenon in two component systems (C. Aberg, E. Sparr, K. J. Edler and H. Wennerstrom, Langmuir, 2009, 25, 12177), we here analyse the henomenon for three-component systems. The relevant transport equations are erived, and explicit results are given for some limiting cases. Then the formalism s applied conceptually to four different aqueous lipid systems, which in addition to water and a phospholipid contain (i) octyl glucoside, (ii) urea, (iii) heavy water, and (iv) sodium cholate as the third component. These four cases are chosen to illustrate (i) a method to use a micelle former to transport lipid to the interface where a multi-lamellar structure can form; (ii) to use a co-solvent to inhibit the formation of a gel phase at the interface; (iii) a method to form pure phospholipid multi-lamellar structures at the interface; (iv) a method to form a sequence of phases in the interfacial region. These four cases all have the character of theoretically based conjectures and it remains to investigate experimentally whether or not the conditions can be realized in practice. PMID- 23805742 TI - Transient pearling and vesiculation of membrane tubes under osmotic gradients. AB - We report the experimental observation of osmotically induced transient pearling instabilities in vesicular membranes. Giant phospholipid vesicles subjected to negative osmotic gradient, which drives the influx of water in to the vesicular interior, produces transient cylindrical protrusions. These protrusions exhibit a remarkable pearling intermediate, which facilitates their subsequent retraction. The pearling front propagates from the distal free end of the protrusion toward the vesicular source and accompanies gradual shortening of the protrusion via pearl-pearl coalescence. Real-time introduction of a positive osmotic gradient, on the other hand, drives vigorous shape fluctuations, which in turn produce cylindrical, prolate- and pear-shaped intermediates presumably due to an increased vesicular area relative to the encapsulated volume. These intermediates transiently produce a pearled state prior to their fission. In both cases, the transient pearling state gives rise to an array of stable spherical daughter vesicles, which may be connected to one another by fine tethers not resolved in our experiments. These results may have implications for self-reproduction in primitive, protein-free, cells. PMID- 23805743 TI - Mode specific elastic constants for the gel, liquid-ordered, and liquid disordered phases of DPPC/DOPC/cholesterol model lipid bilayers. AB - Using microscopic molecular theory, we determine the bending and saddle-splay constants of three-component lipid bilayers. The membrane contains cholesterol, dipalmitoyl-phosphatidylcholine (DPPC) and dioleoylphosphatidylcholine (DOPC) and the predictions of the theory have been shown to qualitatively reproduce phase diagrams of giant unilamellar vesicles (GUVs) of the same three components. The bending and saddle-splay constants were calculated for the gel, liquid-ordered (lo) and liquid-disordered (ld) phases. By proper expansion of the free energy, the molecular theory enables us to determine the effects of the mode of membrane bending deformation on the value of the elastic constants for different phases. In particular, we refer to the ability of the molecules to arrange the composition between the two monolayers upon deformation. The bending and saddle splay constants obtained from the free energy expansion can be expressed in terms of moments of the local lateral pressures and their derivatives, all evaluated for a symmetric planar bilayer. The effect of blocked vs. free exchange of lipids across the two monolayers on the values of the bending constant is as high as 50 k(B)Tin the ld phase to as high as 200 k(B)T in the lo phase. These results show that one must strongly consider the mode of deformation in determining the mechanical properties of lipid bilayers. We discuss how the different contributions to the lateral pressures affect the values of the elastic constants, including the effects of the cholesterol concentration and temperature on the membrane elastic constants. We also calculate the equilibrium binding concentrations of lipid tail anchors as a function of membrane curvature by explicitly determining the chemical potential difference of species across a curved bilayer. Our results are in excellent agreement with recent experimental results. PMID- 23805744 TI - Tuning the aggregation behaviour of single-chain bolaphospholipids in aqueous suspension: from nanoparticles to nanofibres to lamellar phases. AB - The aggregation behaviour in aqueous suspensions of symmetrical bipolar phospholipids (bolalipids) composed of one long alkyl chain and two polar headgroups were studied as a function of their chemical structure, i.e. the length of their chain, the modification of the chain by introduction of hetero atoms, triple bonds, or phenyl rings, and the size of the headgroups. Three types of aggregate structures are formed by these bolalipids, namely helical nanofibres, micelle-like aggregates and lamellar sheets. The type of aggregate formed depends not only on the chemical structure, particularly the ratio of the cross-sectional area of the headgroup and the chain, but also on the presence of attractive interactions via hydrogen bonds or repulsive electrostatic interactions between the headgroups. PMID- 23805745 TI - Polycontinuous geometries for inverse lipid phases with more than two aqueous network domains. AB - Inverse bicontinuous cubic phases with two aqueous network domains separated by a smooth bilayer are firmly established as equilibrium phases in lipid/water systems. The purpose of this article is to highlight the generalisations of these bicontinuous geometries to polycontinuous geometries, which could be realised as lipid mesophases with three or more network-like aqueous domains separated by a branched bilayer. An analysis of structural homogeneity in terms of bilayer width variations reveals that ordered polycontinuous geometries are likely candidates for lipid mesophase structures, with similar chain packing characteristics to the inverse micellar phases (that once were believed not to exist due to high packing frustration). The average molecular shape required by global geometry to form these multi-network phases is quantified by the surfactant shape parameter, v/(al); we find that it adopts values close to those of the known lipid phases. We specifically analyse the 3etc(187 193) structure of hexagonal symmetry P6(3) /mcm with three aqueous domains, the 3dia(24 220) structure of cubic symmetry I43d composed of three distorted diamond networks, the cubic chiral 4srs(24 208) with cubic symmetry P4232 and the achiral 4srs(5 133) structure of symmetry P42/nbc, each consisting of four intergrown undistorted copies of the srs net (the same net as in the QII(G) gyroid phase). Structural homogeneity is analysed by a medial surface approach assuming that the headgroup interfaces are constant mean curvature surfaces. To facilitate future experimental identification, we provide simulated SAXS scattering patterns that, for the 4srs(24 208) and 3dia(24 220) structures, bear remarkable similarity to those of bicontinuous QII(G) gyroid and QII(D)-diamond phases, with comparable lattice parameters and only a single peak that cannot be indexed to the well-established structures. While polycontinuous lipid phases have, to date, not been reported, the likelihood of their formation is further indicated by the reported observation of a solid tricontinuous mesoporous silicate structure, termed IBN-9, which formed in the presence of surfactants [Han et al., Nat. Chem., 2009, 1, 123]. PMID- 23805746 TI - Physical properties of mixed bilayers containing lamellar and nonlamellar lipids: insights from coarse-grain molecular dynamics simulations. AB - A recently developed coarse-grain model is applied to simulate hydrated membranes containing the lamellar lipid DOPC and the nonlamellar lipid DOPE. In a first series of simulations, DOPC-water and DOPE-water systems are shown to form respectively bilayers and inverse hexagonal phases, in agreement with the well known behaviour observed experimentally. A second set of calculations is then run to investigate several fundamental physical features of mixed DOPC-DOPE bilayers at different relative compositions. In particular, a quantitative characterisation is obtained of the internal distributions (profiles) of lateral pressure and electrical potential. These two properties, very difficult to measure experimentally, are thought to underpin many key membrane phenomena, including nonspecific lipid-mediated mechanisms of protein regulation. The molecular origin of the distributions, and their dependence on changes in the DOPC: DOPE ratio, are explained through an analysis of separate contributions from individual interaction types and molecular groups. PMID- 23805747 TI - Spontaneous tubulation of membranes and vesicles reveals membrane tension generated by spontaneous curvature. AB - Recent experimental studies on supported lipid bilayers and giant vesicles have shown that uni-lamellar membrane systems can undergo spontaneous tubulation, i.e., can form membrane tubules or nanotubes without the application of external forces. In the case of supported lipid bilayers, the tube formation was induced by the adsorption of antimicrobial peptides. In the case of giant vesicles, spontaneous tubulation was observed after the polymer solution inside the vesicles underwent phase separation into two aqueous phases. Here, these processes are studied theoretically and shown to be driven by membrane tension generated by spontaneous curvature. The latter curvature is estimated for different types of adsorbing particles, such as ions, small molecules, and macromolecules, that differ in their size and in their adsorption kinetics. When the two sides of the membranes are exposed to two different concentrations of these particles, the membranes will acquire a spontaneous (or preferred) curvature. Particularly large spontaneous curvatures are induced by the adsorption of amphipathic peptides and BAR domain proteins. Another mechanism that induces spontaneous curvature is provided by different depletion layers in front of the two sides of the membranes. Irrespective of its molecular origin, a spontaneous curvature is predicted to generate a tension in weakly curved membranes, a 'spontaneous' tension that can vary over several orders of magnitudes and can be as high as 1 mJ m(-2). The concept of spontaneous tension is first used to explain the spontaneous tubulation of supported lipid bilayers when exposed to adsorbing particles. This tubulation process is energetically preferred when the spontaneous tension exceeds the adhesive strength of the underlying solid support. Furthermore, in the case of giant vesicles, the spontaneous tension can balance the osmotic pressure difference between the interior and exterior aqueous compartment. The vesicles are then able to form stable cylindrical nanotubes that protrude into the vesicle interior as observed recently for membranes in contact with two aqueous polymer phases. In these latter systems, the vesicle membranes are governed by two spontaneous tensions that can be directly measured since they are intimately related to the effective and intrinsic contact angles. PMID- 23805748 TI - Formation and analysis of topographical domains between lipid membranes tethered by DNA hybrids of different lengths. AB - We recently described a strategy to prepare DNA-tethered lipid membranes either to fixed DNA on a surface or to DNA displayed on a supported bilayer [Boxer et al., J. Struct. Biol., 2009, 168, 190; Boxer et al., Langmuir, 2011, 27, 5492]. With the latter system, the DNA hybrids are laterally mobile; when orthogonal sense-antisense pairs of different lengths are used, the DNA hybrids segregate by height and the tethered membrane deforms to accommodate the height difference. This architecture is particularly useful for modelling interactions between membranes mediated by molecular recognition and resembles cell-to-cell junctions. The length, affinity and population of the DNA hybrids between the membranes are completely controllable. Interesting patterns of height segregation are observed by fluorescence interference contrast microscopy. Diverse behavior is observed in the segregation and pattern forming process and possible mechanisms are discussed. This model system captures some of the essential physics of synapse formation and is a step towards understanding lipid membrane behaviour in cell-to cell junctions. PMID- 23805749 TI - Molecular view on protein sorting into liquid-ordered membrane domains mediated by gangliosides and lipid anchors. AB - We present results from coarse grain molecular dynamics simulations of mixed model membranes consisting of saturated and unsaturated lipids together with cholesterol, in which lipid-anchored membrane proteins are embedded. The membrane proteins studied are the peripherally bound H-Ras, N-Ras, and Hedgehog, and the transmembrane peptides WALP and LAT. We provide a molecular view on how the presence and nature of these lipid anchors affects partitioning of the proteins between liquid-ordered and liquid-disordered domains. In addition, we probed the role of the ganglioside lipid GM1 on the protein sorting, showing formation of GM1-protein nano-domains that act as shuttles between the differently ordered membrane regions. PMID- 23805750 TI - Gaussian curvature elasticity determined from global shape transformations and local stress distributions: a comparative study using the MARTINI model. AB - We calculate the Gaussian curvature modulus kappa of a systematically coarse grained (CG) one-component lipid membrane by applying the method recently proposed by Hu et al. [Biophys. J., 2012, 102, 1403] to the MARTINI representation of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC). We find the value kappa/kappa = -1.04 +/- 0.03 for the elastic ratio between the Gaussian and the mean curvature modulus and deduce kappa(m)/kappa(m) = -0.98 +/- 0.09 for the monolayer elastic ratio, where the latter is based on plausible assumptions for the distance z0 of the monolayer neutral surface from the bilayer midplane and the spontaneous lipid curvature K(0m). By also analyzing the lateral stress profile sigma0(z) of our system, two other lipid types and pertinent data from the literature, we show that determining K(0m) and kappa through the first and second moment of sigma0(z) gives rise to physically implausible values for these observables. This discrepancy, which we previously observed for a much simpler CG model, suggests that the moment conditions derived from simple continuum assumptions miss the effect of physically important correlations in the lipid bilayer. PMID- 23805751 TI - Elastic properties of polyunsaturated phosphatidylethanolamines influence rhodopsin function. AB - Membranes with a high content of polyunsaturated phosphatidylethanolamines (PE) facilitate formation of metarhodopsin-II (M(II)), the photointermediate of bovine rhodopsin that activates the G protein transducin. We determined whether M(II) formation is quantitatively linked to the elastic properties of PEs. Curvature elasticity of monolayers of the polyunsaturated lipids 18 : 0-22 : 6(n - 3)PE, 18 : 0-22 : 5(n)- 6PE and the model lipid 18 : 1(n - 9)-18 : 1,(n- 9)PE were investigated in the inverse hexagonal phase. All three lipids form lipid monolayers with rather low spontaneous radii of curvature of 26-28 angstroms. In membranes, all three PEs generate high negative curvature elastic stress that shifts the equilibrium of MI(I)/M(II) photointermediates of rhodopsin towards M(II) formation. PMID- 23805752 TI - Anomalous and normal diffusion of proteins and lipids in crowded lipid membranes. AB - Lateral diffusion plays a crucial role in numerous processes that take place in cell membranes, yet it is quite poorly understood in native membranes characterized by, e.g., domain formation and large concentration of proteins. In this article, we use atomistic and coarse-grained simulations to consider how packing of membranes and crowding with proteins affect the lateral dynamics of lipids and membrane proteins. We find that both packing and protein crowding have a profound effect on lateral diffusion, slowing it down. Anomalous diffusion is observed to be an inherent property in both protein-free and protein-rich membranes, and the time scales of anomalous diffusion and the exponent associated with anomalous diffusion are found to strongly depend on packing and crowding. Crowding with proteins also has a striking effect on the decay rate of dynamical correlations associated with lateral single-particle motion, as the transition from anomalous to normal diffusion is found to take place at macroscopic time scales: while in protein-poor conditions normal diffusion is typically observed in hundreds of nanoseconds, in protein-rich conditions the onset of normal diffusion is tens of microseconds, and in the most crowded systems as large as milliseconds. The computational challenge which results from these time scales is not easy to deal with, not even in coarse-grained simulations. We also briefly discuss the physical limits of protein motion. Our results suggest that protein concentration is anything but constant in the plane of cell membranes. Instead, it is strongly dependent on proteins' preference for aggregation. PMID- 23805754 TI - Cell cycle dependent changes in membrane stored curvature elastic energy: evidence from lipidomic studies. AB - One of the most developed theories of phospholipid homeostasis is the intrinsic curvature hypothesis, which, in broad terms, postulates that cells regulate their lipid composition so as to keep constant the membrane stored curvature elastic energy. The implication of this hypothesis is that lipid composition is determined by a ratio control function consisting of the weighted sum of concentrations of type II lipids in the numerator and the weighted sum of concentrations of Type 0 lipids in the denominator. In previous work we used a data-driven approach, based on lipidomic data from asynchronous cell cultures, to determine a criterion that allows the different lipid species to be assigned to the set of type 0 or of type II lipids, and hence construct a ratio control function that serves as a proxy for the lipid contribution to total membrane stored curvature elastic energy in vivo. Here we apply the curvature elastic energy proxy to the analysis of lipid composition data from synchronous HeLa cells as they traverse the cell cycle. Our analysis suggests HeLa cells modify their membrane stored elastic energy through the cell cycle. In S-phase type 0 lipids are the most abundant, whilst in G2 type II lipids are most abundant. Changes in our proxy for membrane stored elastic energy correlate with membrane curvature dependent processes in the HeLa cell around division, providing some insights into the interplay between the individual lipid and protein contributions to membrane free energy. PMID- 23805753 TI - Interactions of drugs and amphiphiles with membranes: modulation of lipid bilayer elastic properties by changes in acyl chain unsaturation and protonation. AB - Poly-unsaturated fatty acids (PUFAs) alter the function of many membrane proteins, whereas monounsatured fatty acids generally are inert. We previously showed that docosahexaenoic acid (DHA) at pH 7 decreases the bilayer stiffness, consistent with an amphiphile-induced increase in elasticity, but not with a negative change in curvature; oleic acid (OA) was inert (Bruno, Koeppe and Andersen, Proc. Natl. Acad. Sci., 2007, 104, 9638-9643). To further explore how PUFAs and other amphiphiles may alter lipid bilayer properties, and thus membrane protein function, we examined how changes in acyl chain unsaturation and head group charge and size alter bilayer properties, as sensed by bilayer-spanning gramicidin A (gA) channels of different lengths. Compared to DHA, the neutral DHA methyl ester has reduced effects on bilayer properties and 1-palmitoyl-2 docosahexaenoyl-phosphatidylcholine (PDPC) forms bilayers that are softer than dioleoylphosphatidylcholine (DOPC). The changes in channel function are larger for the short gA channels, indicating that changes in elasticity dominate over changes in curvature. We altered the fatty acid protonation by titration: docosahexaenoic acid (DHA) is more potent at pH 9 (relative to pH 7) and is inert at pH 4; OA, which was inert at pH 7, becomes a potent modifier of bilayer properties at pH 9. At both pH 7 and 9, DHA and OA produced larger changes in the lifetimes of the short gA channels, demonstrating that they increase lipid bilayer elasticity when deprotonated--though OA promotes the formation of inverted hexagonal phases at pH 7. The positively charged oleylamine (OAm), which has a small head-group and therefore should be a negative curvature promoter, inhibited gA channel function with similar reductions in the lifetimes of the short and long gA channels, indicating a curvature-dominated effect. Monitoring the single-channel conductance, we find that the negatively charged fatty acids increase the conductance by increasing the local negative charge around the channel, whereas the positively charged OAm has no effect. These results suggest that deprotonated fatty acids increase bilayer elasticity by reversibly adsorbing at the bilayer/solution interface. PMID- 23805755 TI - Impact of oxidized phospholipids on the structural and dynamic organization of phospholipid membranes: a combined DSC and solid state NMR study. AB - Membranes undergo severe changes under oxidative stress conditions due to the creation of oxidized phospholipid (OxPL) species, which possess molecular properties quite different from their parental lipid components. These OxPLs play crucial roles in various pathological disorders and their occurrence is involved in the onset of intrinsic apoptosis, a fundamental pathway in programmed mammalian cell death. However, the molecular mechanisms by which these lipids can exert their apoptotic action via their host membranes (e.g., altering membrane protein function) are poorly understood. Therefore, we studied the impact of OxPLs on the organization and biophysical properties of 1,2-dimyristoyl-sn glycero-3-phosphocholine (DMPC) based lipid membranes by differential scanning calorimetry (DSC) and solid state nuclear magnetic resonance (NMR) spectroscopy. Incorporation of defined OxPLs with either a carboxyl group (1-palmitoyl-2 azelaoyl-sn-glycero-3-phosphocholine (PazePC)) or aldehyde (1-palmitoyl (9'oxononanoyl)-sn-glycero-3-phosphocholine (PoxnoPC)) at their truncated sn-2 chain ends enabled us to reveal OxPL species-dependent differences. The calorimetric studies revealed significant effects of OxPLs on the thermotropic phase behavior of DMPC bilayers, especially at elevated levels where PazePC induced more pronounced effects than PoxnoPC. Temperature-dependent changes in the solid state 31P NMR spectra, which provided information of the lipid headgroup region in these mixed membrane systems, reflected this complex phase behavior. In the temperature region between 293 K (onset of the Lalpha-phase) and 298 K, two overlapping NMR spectra were visible which reflect the co-existence of two liquid-crystalline lamellar phases with presumably one reflecting OxPL-poor domains and the other OxPL-rich domains. Deconvolution of the DSC profiles also revealed these two partially overlapping thermal events. In addition, a third thermal, non-NMR-visible, event occurred at low temperatures, which can most likely be associated to a solid-phase mixing/demixing process of the OxPL containing membranes. The observed phase transitions were moved to higher temperatures in the presence of heavy water due its condensing effect, where additional wideline 2H-NMR studies revealed a complex hydration pattern in the presence of OxPLs. PMID- 23805756 TI - Materials characterization of the low temperature sensitive liposome (LTSL): effects of the lipid composition (lysolipid and DSPE-PEG2000) on the thermal transition and release of doxorubicin. AB - This paper describes how we have used material science, physical chemistry, and some luck, to design a new thermal-sensitive liposome (the low temperature sensitive liposome (LTSL)) that responds at clinically attainable hyperthermic temperatures releasing its drug in a matter of seconds as it passes through the microvasculature of a warmed tumor. The LTSL is composed of a judicial combination of three component lipids, each with a specific function and each affecting specific material properties, including a sharp thermal transition and a rapid on-set of membrane permeability to small ions, drugs and small dextran polymers. Experimentally, the paper describes how bilayer-concentration changes involving the lysolipid and the presence or absence of DSPE-PEG2000 affect both the lipid transition temperature and the drug release. While the inclusion of 4 mol% DSPE-PEG2000 raises the transition temperature peak (T(m)) by about 1 degrees C, the inclusion of 5.0, 9.7, 12.7 and 18.0 mol% MSPC slightly lowered this peak back to 41.7 degrees C, while not further broadening the peak breadth. As for drug release, in the absence of MSPC, the encapsulated doxorubicin-citrate is hardly released at all. Increasing the composition of MSPC in the lipid mixture (5.0, 7.4, 8.5 and 9.3 mol% MSPC) shows faster and faster initial doxorubicin release rates, with 8.5 and 9.3 mol% MSPC formulations giving 80% of encapsulated drug released in 4 and 3 min, respectively. The Thermodox formulation (9.7 mol% MSPC) gives 60% released in the first 20 s. The presence of PEG-lipid is found to be essential in order for the lysolipid-induced permeability to reach these very fast times. From drug and dextran release experiments, and estimates of the molecular and pore size, the conclusions are that: in order to induce lasting nanopores in lipid bilayers -10 nm diameter, they initially require the presence (from the solid phase structure) of grain boundary defects at the DPPC transition and the permeabilizing component(s) can either be a pore forming lysolipid/surfactant plus a PEG-lipid, or can be generated by a PEG-surfactant incorporated at -4-5 mol%. The final discussion is centered around the postulated defect structures that result in membrane leakage and the permeability of doxorubicin and H+ ions. PMID- 23805757 TI - Segregated ordered lipid phases and protein-promoted membrane cohesivity are required for pulmonary surfactant films to stabilize and protect the respiratory surface. AB - Pulmonary surfactant is a lipid-protein complex essential to stabilize alveoli, by forming surface active films able to reach and sustain very low surface tensions (< 2 mN m(-1)) during the film compression that occurs at end expiration. The particular lipid composition of surfactant, including a high proportion of dipalmitoylphosphatidylcholine (DPPC), induces segregation of fluid ordered and disordered phases in surfactant membranes and films at physiological temperatures. The segregation of DPPC-enriched ordered phase has been related with the ability of surfactant films to produce very low tensions, while the presence in surfactant of two specific hydrophobic polypeptides, SP-B and SP-C, is absolutely required to facilitate surfactant dynamics, including film formation and re-spreading during expansion at inspiration. In the present study, we have used X-ray scattering to analyze the structure of (1) whole native surfactant membranes purified from porcine lungs, (2) membranes reconstituted from the organic extract of surfactant containing the full lipid complement and the physiological proportion of SP-B and SP-C, and (3) membranes reconstituted from the lipid fraction of surfactant depleted of proteins. Small angle X-ray scattering data from whole surfactant or from membranes reconstituted from surfactant organic extract indicated the co-existence of two lamellar phases with different thicknesses. Such phase coexistence disappeared upon heating of the samples at temperatures above physiological values. When assessed in a captive bubble surfactometer, which mimics interfacial compression-expansion dynamics, the ability of surfactant films to produce very low tensions is only maintained at temperatures permitting the coexistence of the two lamellar phases. On the other hand, membranes reconstituted in the absence of proteins produced diffractograms indicative of the existence of a single dominant lamellar phase at all temperatures. These data suggest that SP-B and SP-C establish membrane membrane interactions coupling the stacks of different segregated phases. The low compressibility of surfactant films that leads to the maximal pressures (minimal tensions) is supported on one hand by the highly packed solid-like character of segregated DPPC-enriched domains and, on the other hand, by a high cohesivity of multilayered structures promoted by hydrophoblic surfactant proteins, in particular SP-B, at the more dynamic disordered membrane regions, in which SP-B selectively partitions. Cryo-electron microscopy has shown that SP-B induces formation of tight membrane-membrane contacts, a finding that supports our inference concerning the role of these surfactant proteins. PMID- 23805758 TI - Gibbs energy determinants of lipoprotein insertion into lipid membranes: the case study of Ras proteins. AB - In a combined chemical-biological and biophysical approach we explored the Gibbs (free) energy contributions to the membrane partitioning of lipidated proteins, and compared the theoretical predictions with recent experimental data on the membrane insertion of Ras proteins of various anchor systems into rationally designed model biomembrane systems. Various factors fostering or reducing the membrane partitioning properties are discussed, including hydrophobic effects, lipid chain mismatch, electrostatic interactions, membrane-mediated protein protein interactions, and terms that account for line tension effects between coexisting lipid domains, lipid sorting, and changes in the lateral organization of the lipid bilayer system. From these data, it is apparent that two membrane anchoring motifs are needed to facilitate firm membrane binding. For heterogeneous membranes, localization and sequestration at domain boundaries as well as formation of protein clusters and collective lateral organization via an effective lipid sorting mechanism provide complementary ways of inducing membrane nanodomains that could potentially operate as effective, high fidelity signalling platforms. PMID- 23805759 TI - Back to the future: mechanics and thermodynamics of lipid biomembranes. PMID- 23805760 TI - [Time for the Swedish Medical Association to reply in the health care debate]. PMID- 23805761 TI - [Surgical outcomes are not just about volume. Open result presentations are more important]. PMID- 23805762 TI - [Unknown public disease is becoming more prevalent]. PMID- 23805763 TI - [Early diagnosis can stop progression of the disease]. PMID- 23805764 TI - [Chronic kidney disease--a public health problem?]. PMID- 23805765 TI - [Time for new measurements in kidney disease diagnosis and follow-up]. PMID- 23805766 TI - [Prevention and protection in diabetic nephropathy]. PMID- 23805767 TI - [Treatment of hypertension in chronic kidney disease]. PMID- 23805768 TI - [Unclear on dose adjustment in renal impairment]. PMID- 23805769 TI - [Regional guidelines for preventative nephrology have been well received]. PMID- 23805770 TI - [Renal impairment and myocardial infarction--a combination of risks]. PMID- 23805771 TI - [Vascular calcification: a common but overlooked condition]. PMID- 23805772 TI - [Surrogacy is needed]. PMID- 23805773 TI - [No integration without health]. PMID- 23805774 TI - Hole transfer kinetics of DNA. AB - Not long after the discovery of the double-helical structure of DNA in 1952, researchers proposed that charge transfer along a one-dimensional pi-array of nucleobases might be possible. At the end of the 1990s researchers discovered that a positive charge (a hole) generated in DNA migrates more than 200 A along the structure, a discovery that ignited interest in the charge-transfer process in DNA. As a result, DNA became an interesting potential bottom-up material for constructing nanoelectronic sensors and devices because DNA can form various complex two-dimensional and three-dimensional structures, such as smiley faces and cubes. From the fundamental aspects of the hole transfer process, DNA is one of the most well-studied organic molecules with many reports on the synthesis of artificial nucleobase analogues. Thus, DNA offers a unique system to study how factors such as the HOMO energy and molecular flexibility affect hole transfer kinetics. Understanding the hole transfer mechanism requires a discussion of the hole transfer rate constants (kHT). This Account reviews the kHT values determined by our group and by Lewis and Wasielewski's group, obtained by a combination of the synthesis of modified DNA and time-resolved spectroscopy. DNA consists of G/C and A/T base pairs; the HOMO localizes on the purine bases G and A, and G has a lower oxidation potential and a higher energy HOMO. Typically, long-range hole transfer proceeded via sequential hole transfer between G/C's. The kinetics of this process in DNA sequences, including those with mismatches, is reproducible via kinetic modeling using the determined kHT for each hole transfer step between G/C's. We also determined the distance dependence parameter (beta), which describes the steepness of the exponential decrease of kHT. Because of this value, >0.6 A(-1) for hole transfer in DNA, DNA itself does not serve as a molecular wire. Interestingly, hole transfer proceeded exceptionally fast for some sequences in which G/C's are located close to each other, an observation that we cannot explain by a simple sequential hole transfer between G/C's but rather through hole delocalization over the nucleobases. To further investigate and refine the factors that affect kHT, we examined various artificial nucleobases. We clearly demonstrated that kHT depends strongly on the HOMO energy gap between the bases (DeltaHOMO), and that kHT can be increased with decreasing DeltaHOMO. We reduced DeltaHOMO between the two type of base pairs by replacing adenines (A's) with deazaadenines ((z)A's) or diaminopurines (D's) and showed that the hole transfer rate through the G/C and A/T mix sequence increased by more than 3 orders of magnitude. We also investigated how DNA flexibility affects kHT. Locked nucleic acid (LNA) modification, which makes DNA more rigid, lowered kHT by more than 2 orders of magnitude. On the other hand, 5-Me-2' deoxyzebularine (B) modification, which increases DNA flexibility, increased kHT by more than 1 order of magnitude. These new insights in hole transfer kinetics obtained from modified DNAs may aid in the design of new molecular-scale conducting materials. PMID- 23805775 TI - Targeting oxidative stress response by green tea polyphenols: clinical implications. AB - Green tea polyphenols, the most interesting constituent of green tea leaves, have been shown to have both pro-oxidant and antioxidant properties. Both pro-oxidant and antioxidant properties are expected to contribute to modulation of oxidative stress response under ideal optimal dosage regimens. Exposure to a low concentration of a pro-oxidant prior to exposure to oxidative stress induces the expression of genes that code for proteins that induce adaptation in a subsequent oxidative stress. On the other hand, exposure to an antioxidant concurrently with exposure to the oxidative stress affords protection through free radical scavenging or through other indirect antioxidant mechanisms. In any case, the optimal conditions that afford protection from oxidative stress should be defined for any substance with redox properties. Green tea polyphenols, being naturally occurring substances, seem to be an ideal option for the modulation of oxidative stress response. This paper reviews available data on the pro-oxidant and antioxidant properties of green tea polyphenols focusing on their potential on the modulation of oxidative stress response. PMID- 23805776 TI - Environmental conditions that influence the ability of humic acids to induce permeability in model biomembranes. AB - The interaction of humic acids (HAs) with 1-palmitoyl-2-oleoyl-Sn-glycero-3 phosphocholine (POPC) large unilamellar vesicle (LUV) model biomembrane system was studied by fluorescence spectroscopy. HAs from aquatic and terrestrial (including coal) sources were studied. The effects of HA concentration and temperature over environmentally relevant ranges of 0 to 20 mg C/L and 10 to 30 degrees C, respectively, were investigated. The dosage studies revealed that the aquatic Suwannee River humic acid (SRHA) causes an increased biomembrane perturbation (percent leakage of the fluorescent dye, Sulforhodamine B) over the entire studied concentration range. The two terrestrial HAs, namely Leonardite humic acid (LAHA) and Florida peat humic acid (FPHA), at concentrations above 5 mg C/L, show a decrease or a plateau effect attributable to the competition within the HA mixture and/or the formation of "partial aggregates". The temperature studies revealed that biomembrane perturbation increases with decreasing temperature for all three HAs. Kinetic studies showed that the membrane perturbation process is complex with both fast and slow absorption (sorption into the bilayer) components and that the slow component could be fitted by first order kinetics. A mechanism based on "lattice errors" within the POPC LUVs is put forward to explain the fast and slow components. A rationale behind the concentration and temperature findings is provided, and the environmental implications are discussed. PMID- 23805777 TI - Effect of venovenous extracorporeal membrane oxygenation on the heart in a healthy piglet model. AB - BACKGROUND: Cardiac function is important for patients treated by venovenous extracorporeal membrane oxygenation (VV ECMO), but data about the effect of VV ECMO on the heart in nonneonates is absent. We studied the effect of VV ECMO on cardiac performance, cardiomyocyte and mitochondria in an animal model. METHODS: Twelve farm piglets were randomly assigned into two groups: control group and ECMO group. In the ECMO group, ECMO cannulaes were placed and ECMO was instituted. Hemodynamics was recorded at baseline, 1 hour after induction, and every 4 hours thereafter, to assess the cardiac performance. All animals were monitored for 24 hours and were euthanized and myocardium was harvested. Myocardial histology, ultrastructure of cardiomyocyte and mitochondria were observed, and activities of mitochondrial complexes I-V were measured, to assess the effect to cardiomyocyte and mitochondria. RESULTS: Hemodynamics were stable in each group of animals throughout the experiment. Interstitial edema, disorderd and dissolved of focal myofilament, morphological deformations of mitochondria were observed in the ECMO group. The activities of mitochondrial complexes were decreased in the ECMO group, and complex I and IV reached significance. CONCLUSIONS: VV ECMO therapy is associated with changes of ultrastructure and function of cardiomyocyte and mitochondria, inducing myocardium injury. However, the injury was mild and had no effect on the cardiac performance for healthy piglets. PMID- 23805779 TI - Signaling pathway switch in breast cancer. AB - Next generation sequencing studies have drawn the general landscape of breast cancers and identified hundreds of new, actual therapeutic targets. Two major signaling pathways seem to be altered in a vast proportion of breast cancers. The PI3 kinase/AKT pathway is activated and the JUN/MAPK pathway is repressed. Via the regulation of the cell cycle this metabolic switch impacts on the balance between self-renewal, proliferation and differentiation of the tumor-initiating cells. PMID- 23805778 TI - Mice with different susceptibility to tick-borne encephalitis virus infection show selective neutralizing antibody response and inflammatory reaction in the central nervous system. AB - BACKGROUND: The clinical course of tick-borne encephalitis (TBE), a disease caused by TBE virus, ranges from asymptomatic or mild influenza-like infection to severe debilitating encephalitis or encephalomyelitis. Despite the medical importance of this disease, some crucial steps in the development of encephalitis remain poorly understood. In particular, the basis of the disease severity is largely unknown. METHODS: TBE virus growth, neutralizing antibody response, key cytokine and chemokine mRNA production and changes in mRNA levels of cell surface markers of immunocompetent cells in brain were measured in mice with different susceptibilities to TBE virus infection. RESULTS: An animal model of TBE based on BALB/c-c-STS/A (CcS/Dem) recombinant congenic mouse strains showing different severities of the infection in relation to the host genetic background was developed. After subcutaneous inoculation of TBE virus, BALB/c mice showed medium susceptibility to the infection, STS mice were resistant, and CcS-11 mice were highly susceptible. The resistant STS mice showed lower and delayed viremia, lower virus production in the brain and low cytokine/chemokine mRNA production, but had a strong neutralizing antibody response. The most sensitive strain (CcS 11) failed in production of neutralizing antibodies, but exhibited strong cytokine/chemokine mRNA production in the brain. After intracerebral inoculation, all mouse strains were sensitive to the infection and had similar virus production in the brain, but STS mice survived significantly longer than CcS-11 mice. These two strains also differed in the expression of key cytokines/chemokines, particularly interferon gamma-induced protein 10 (IP 10/CXCL10) and monocyte chemotactic protein-1 (MCP-1/CCL2) in the brain. CONCLUSIONS: Our data indicate that the genetic control is an important factor influencing the clinical course of TBE. High neutralizing antibody response might be crucial for preventing host fatality, but high expression of various cytokines/chemokines during TBE can mediate immunopathology and be associated with more severe course of the infection and increased fatality. PMID- 23805781 TI - Synchrotron-based microspectroscopic study on the effects of heat treatments on cotyledon tissues in yellow-type canola (Brassica) seeds. AB - Synchrotron-based infrared (IR) microspectroscopy is able to reveal structural features of biomaterials within intact tissue at both cellular and molecular levels. Heat-related treatments have been used to improve nutrient availability of canola seeds and meal. However, hitherto, there has been no study on the sensitivity and response of each layer in canola seeds to heat-related treatments. It is not known which layer (epiderm/mucllage, spermoderm, endosperm, or cotyledon) is the most sensitive to heat when heat treatment is applied to the seeds. Traditional wet chemical analysis is unable to answer such questions. The objective of this study is to use synchrotron IR microspectroscopy with multivariate molecular spectral analyses as a research tool to study heat treatment effects in a fast way on the structural changes in cotyledon tissues of yellow-type canola (Brassica) seeds among raw (treatment code "A"), wet heating (autoclaving at 121 degrees C for 60 min, treatment code "B"), and dry heating (dry roasting at 120 degrees C for 60 min, treatment code "C"). The hypothesis of this study was that different heat treatments have different heat penetration abilities on cotyledon tissues in yellow-type canola seeds. The multivariate analytical tools principal component analysis (PCA) and agglomerative hierarchal cluster analysis (AHCA) were applied to investigate variance and groupings within the spectral data set [whole spectral range of ca. 4000-650 cm(-1), spectral range of ca. 1300-900 cm(-1) (cellulose or saccarides), spectral range of ca. 1800-1500 cm(-1) (secondary structures of protein) and spectral range of ca. 1500 1300 cm(-1) (bending motion of methylene and methyl group; this change is consistent with the change in the range of ca. 3000-2800 cm(-1))]. The results showed that there were no clear cluster and groups formed in the cotyledon tissues among the three treatments (A, B, and C). There were no clear distinguished responses of the cotyledon tissues to different types of heat treatments using multivariate molecular spectral analyses. The results indicate that the cotyledon tissues might not be sufficiently penetrated by both heat treatments (autoclaving and dry roasting) under the specified conditions. A future study is needed to analyze individual functional group band intensity among the treatments using univariate molecular spectral analysis to confirm multivariate PCA and cluster analyses. PMID- 23805780 TI - Induction of chromosome instability and stomach cancer by altering the expression pattern of mitotic checkpoint genes in mice exposed to areca-nut. AB - BACKGROUND: There are strong indications for a causal association between areca nut consumption and cancers. In Meghalaya, India, the variety of areca-nut is used as raw and unprocessed form whose chemical composition and pharmacological actions have been reported. Yet we know little on the initial pathway involved in areca-nut associated carcinogenesis since it is difficult to assess its effects on genetic alterations without interference of other compounding factors. Therefore, present study was undertaken in mice to verify the ability of raw areca-nut (RAN) to induce cancer and to monitor the expression of certain genes involved in carcinogenesis. This study was not intended to isolate any active ingredients from the RAN and to look its action. METHODS: Three groups of mice (n = 25 in each) were taken and used at different time-points for different experimental analysis. The other three groups of mice (n = 15 in each) were considered for tumor induction studies. In each set, two groups were administered RAN-extract ad libitum in drinking water with or without lime. The expression of certain genes was assessed by conventional RT-PCR and immunoblotting. The mice were given the whole RAN-extract with and without lime in order to mimic the human consumption style of RAN. RESULTS: Histological preparation of stomach tissue revealed that RAN induced stomach cancer. A gradual increase in the frequency of precocious anaphase and aneuploid cells was observed in the bone marrow cells with a greater increment following RAN + lime administeration. Levels of p53, Bax, Securin and p65 in esophageal and stomach cells were elevated during early days of RAN exposure while those of different mitotic checkpoint proteins were downregulated. Apoptotic cell death was detected in non-cancerous stomach cells but not in tumor cells which showed overexpression of Bax and absence of PARP. CONCLUSION: Present study suggested (a) RAN induces stomach cancer, however, presence of lime promoted higher cell transformation and thereby developed cancer earlier, (b) perturbations in components of the chromosome segregation machinery could be involved in the initial process of carcinogenicity and (c) the importance of precocious anaphase as a screening marker for identification of mitotic checkpoint defects during early days. PMID- 23805782 TI - Enhanced cell-material interactions through the biofunctionalization of polymeric surfaces with engineered peptides. AB - Research on surface modification of polymeric materials to guide the cellular activity in biomaterials designed for tissue engineering applications has mostly focused on the use of natural extracellular matrix (ECM) proteins and short peptides, such as RGD. However, the use of engineered proteins can gather the advantages of these strategies and avoid the main drawbacks. In this study, recombinant engineered proteins called elastin-like recombinamers (ELRs) have been used to functionalize poly(lactic) acid (PLA) model surfaces. The structure of the ELRs has been designed to include the integrin ligand RGDS and the cross linking module VPGKG. Surface functionalization has been characterized and optimized by means of ELISA and atomic force microscopy (AFM). The results suggest that ELR functionalization creates a nonfouling canvas able to restrict unspecific adsorption of proteins. Moreover, AFM analysis reveals the conformation and disposition of ELRs on the surface. Biological performance of PLA surfaces functionalized with ELRs has been studied and compared with the use of short peptides. Cell response has been assessed for different functionalization conditions in the presence and absence of the bovine serum albumin (BSA) protein, which could interfere with the surface-cell interaction by adsorbing on the interface. Studies have shown that ELRs are able to elicit higher rates of cell attachment, stronger cell anchorages and faster levels of proliferation than peptides. This work has demonstrated that the use of engineered proteins is a more efficient strategy to guide the cellular activity than the use of short peptides, because they not only allow for better cell attachment and proliferation, but also can provide more complex properties such as the creation of nonfouling surfaces. PMID- 23805783 TI - Dynamic assessment of lung injury by ultrasound in a case with H7N9 influenza. AB - H7N9 influenza is a new emerging infection and has high mortality. Both chest radiography and computed tomography (CT) had some limitations in assessing such patients. We performed daily lung ultrasound in a patient with H7N9 influenza. Lung ultrasound and lung ultrasound score showed high consistency with CT and the progression of pneumonia. Ultrasound can be adjutant to chest radiography and CT in caring for patients with H7N9 influenza. PMID- 23805784 TI - Nanoparticle assemblies via coordination with a tetrakis(terpyridine) linker bearing a rigid tetrahedral core. AB - Controlling particle-particle interactions is a major challenge in achieving the programmable assembly of nanoparticles, which shows great potential for device fabrication and detection systems. We present here a simple chemical method that allows the formation of Pd nanoparticle assemblies using a tetrakis(terpyridine) linker with a rigid tetrahedral core. PMID- 23805785 TI - Tissue selective estrogen complex combinations with bazedoxifene/conjugated estrogens as a model. AB - The tissue selective estrogen complex (TSEC) pairs a selective estrogen receptor modulator (SERM) with one or more estrogens. Different TSECs are associated with distinct gene expression profiles in mammary gland and endometrial tissue according to the individual SERM and estrogen components. Few TSECs have been evaluated outside the laboratory. In preclinical trials, bazedoxifene (BZA) was distinct from other SERMs, with a neutral effect on mammary gland and endometrial tissue, and an antagonist effect on these tissues when combined with conjugated estrogens (CE). The only TSEC in an advanced stage of clinical development pairs BZA with CE. In large, randomized clinical trials, two doses, BZA 20 mg/CE 0.45 and 0.625 mg, reduced menopausal symptoms and prevented bone loss in postmenopausal women with a favorable safety profile on the breast, endometrium, and ovary, and with cardiovascular and venous thrombosis events similar to placebo. Improvements were seen in sleep, health-related quality of life, and treatment satisfaction. Compared with traditional, progestogen-containing hormone therapy, BZA/CE had higher rates of amenorrhea and reduced breast pain, with changes in breast density from baseline similar to placebo. Future TSECs identified in preclinical studies need to be tested in rigorous phase-3 clinical trials for effectiveness, safety and tolerability. PMID- 23805787 TI - Punctate inner choroidopathy and optic neuropathy: simultaneous presentation in a patient - a case report. AB - BACKGROUND: We present a case of a patient initially presenting with multifocal choroiditis (MFC) in one eye. She subsequently developed lesions most consistent with punctate inner choroidopathy (PIC) in the contralateral eye, followed by acute vision loss from retrobulbar optic neuropathy. Optic neuropathy has been well described in the setting of MFC. There is, however, only one report of its association with PIC. Punctate inner choroidopathy and MFC have many similarities, with visual loss generally resulting from choroidal neovascularization. In this case, the patient had significant visual loss from presumed retrobulbar optic neuropathy. FINDINGS: The patient responded well to immunomodulation with subsequent return of vision to baseline. CONCLUSIONS: Multifocal choroiditis and punctate inner choroidopathy may be a spectrum of the same disease with many overlapping presentations, including optic neuropathy. Good visual recovery and remission were attained with mycophenolate mofetil and systemic corticosteroid treatment. PMID- 23805786 TI - Acceleration of tuberculosis treatment by adjunctive therapy with verapamil as an efflux inhibitor. AB - RATIONALE: A major priority in tuberculosis (TB) is to reduce effective treatment times and emergence of resistance. Recent studies in macrophages and zebrafish show that inhibition of mycobacterial efflux pumps with verapamil reduces the bacterial drug tolerance and may enhance drug efficacy. OBJECTIVES: Using mice, a mammalian model known to predict human treatment responses, and selecting conservative human bioequivalent doses, we tested verapamil as an adjunctive drug together with standard TB chemotherapy. As verapamil is a substrate for CYP3A4, which is induced by rifampin, we evaluated the pharmacokinetic/pharmacodynamic relationships of verapamil and rifampin coadministration in mice. METHODS: Using doses that achieve human bioequivalent levels matched to those of standard verapamil, but lower than those of extended release verapamil, we evaluated the activity of verapamil added to standard chemotherapy in both C3HeB/FeJ (which produce necrotic granulomas) and the wild-type background C3H/HeJ mouse strains. Relapse rates were assessed after 16, 20, and 24 weeks of treatment in mice. MEASUREMENTS AND MAIN RESULTS: We determined that a dose adjustment of verapamil by 1.5-fold is required to compensate for concurrent use of rifampin during TB treatment. We found that standard TB chemotherapy plus verapamil accelerates bacterial clearance in C3HeB/FeJ mice with near sterilization, and significantly lowers relapse rates in just 4 months of treatment when compared with mice receiving standard therapy alone. CONCLUSIONS: These data demonstrate treatment shortening by verapamil adjunctive therapy in mice, and strongly support further study of verapamil and other efflux pump inhibitors in human TB. PMID- 23805788 TI - Cyclic compression and decompression of a lipid bilayer. AB - In this study, we measure transient thicknesses of a lipid bilayer during electrostatic compression and decompression and deduce non-equilibrium molecular interactions of the surfactants' tails within the layer. The bilayer under investigation (sorbitan monooleate) is single-tailed and self-assembles between a water drop and hafnium oxide in dodecane. We detect minute changes in bilayer thickness (~0.01 A/s) resulting from step changes in electrostatic pressure. The dynamic response of the bilayer consists of an elastic response followed by an inelastic dissipative behavior. We observe a distinct asymmetry between the inelastic responses: compression triggers a linear reduction in thickness over time, whereas decompression induces a logarithmic increase in thickness. PMID- 23805789 TI - Variant surface antigens of malaria parasites: functional and evolutionary insights from comparative gene family classification and analysis. AB - BACKGROUND: Plasmodium parasites, the causative agents of malaria, express many variant antigens on cell surfaces. Variant surface antigens (VSAs) are typically organized into large subtelomeric gene families that play critical roles in virulence and immune evasion. Many important aspects of VSA function and evolution remain obscure, impeding our understanding of virulence mechanisms and vaccine development. To gain further insights into VSA function and evolution, we comparatively classified and examined known VSA gene families across seven Plasmodium species. RESULTS: We identified a set of ultra-conserved orthologs within the largest Plasmodium gene family pir, which should be considered as high priority targets for experimental functional characterization and vaccine development. Furthermore, we predict a lipid-binding domain in erythrocyte surface-expressed PYST-A proteins, suggesting a role of this second largest rodent parasite gene family in host cholesterol salvage. Additionally, it was found that PfMC-2TM proteins carry a novel and putative functional domain named MC-TYR, which is conserved in other P. falciparum gene families and rodent parasites. Finally, we present new conclusive evidence that the major Plasmodium VSAs PfEMP1, SICAvar, and SURFIN are evolutionarily linked through a modular and structurally conserved intracellular domain. CONCLUSION: Our comparative analysis of Plasmodium VSA gene families revealed important functional and evolutionary insights, which can now serve as starting points for further experimental studies. PMID- 23805790 TI - Isolation of tick and mosquito-borne arboviruses from ticks sampled from livestock and wild animal hosts in Ijara District, Kenya. AB - Tick-borne viruses infect humans through the bite of infected ticks during opportunistic feeding or through crushing of ticks by hand and, in some instances, through contact with infected viremic animals. The Ijara District, an arid to semiarid region in northern Kenya, is home to a pastoralist community for whom livestock keeping is a way of life. Part of the Ijara District lies within the boundaries of a Kenya Wildlife Service-protected conservation area. Arbovirus activity among mosquitoes, animals, and humans is reported in the region, mainly because prevailing conditions necessitate that people continuously move their animals in search of pasture, bringing them in contact with ongoing arbovirus transmission cycles. To identify the tick-borne viruses circulating among these communities, we analyzed ticks sampled from diverse animal hosts. A total of 10,488 ticks were sampled from both wildlife and livestock hosts and processed in 1520 pools of up to eight ticks per pool. The sampled ticks were classified to species, processed for virus screening by cell culture using Vero cells and RT PCR (in the case of Hyalomma species), followed by amplicon sequencing. The tick species sampled included Rhipicephalus pulchellus (76.12%), Hyalomma truncatum (8.68%), Amblyomma gemma (5.00%), Amblyomma lepidum (4.34%), and others (5.86%). We isolated and identified Bunyamwera (44), Dugbe (5), Ndumu (2), Semliki forest (25), Thogoto (3), and West Nile (3) virus strains. This observation constitutes a previously unreported detection of mosquito-borne Semliki forest and Bunyamwera viruses in ticks, and association of West Nile virus with A. gemma and Rh. pulchellus ticks. These findings provide additional evidence on the potential role of ticks and associated animals in the circulation of diverse arboviruses in northeastern Kenya, including viruses previously known to be essentially mosquito borne. PMID- 23805791 TI - Rabies, canine distemper, and canine parvovirus exposure in large carnivore communities from two Zambian ecosystems. AB - Disease transmission within and among wild and domestic carnivores can have significant impacts on populations, particularly for threatened and endangered species. We used serology to evaluate potential exposure to rabies virus, canine distemper virus (CDV), and canine parvovirus (CPV) for populations of African lions (Panthera leo), African wild dogs (Lycaon pictus), and spotted hyenas (Crocuta crocuta) in Zambia's South Luangwa National Park (SLNP) and Liuwa Plain National Park (LPNP) as well as community lands bordering these areas. In addition, domestic dogs in the study region were evaluated for exposure to CDV and rabies. We provide the first comprehensive disease exposure data for these species in these ecosystems. Twenty-one lions, 20 hyenas, 13 wild dogs, and 38 domestic dogs were sampled across both regions from 2009 to 2011. Laboratory results show 10.5% of domestic dogs, 5.0% of hyenas, and 7.7% of wild dogs sampled were positive for CDV exposure. All lions were negative. Exposure to CPV was 10.0% and 4.8% for hyenas and lions, respectively. All wild dogs were negative, and domestic dogs were not tested due to insufficient serum samples. All species sampled were negative for rabies virus neutralizing antibodies except lions. Forty percent of lions tested positive for rabies virus neutralizing antibodies. Because these lions appeared clinically healthy, this finding is consistent with seroconversion following exposure to rabies antigen. To our knowledge, this finding represents the first ever documentation of rabies virus neutralizing antibodies consistent with rabies exposure that did not lead to clinical disease in free-ranging African lions from this region. With ever increasing human pressure on these ecosystems, understanding disease transmission dynamics is essential for proper management and conservation of these carnivore species. PMID- 23805792 TI - Tracing the geographic origin of beef in China on the basis of the combination of stable isotopes and multielement analysis. AB - The potential for classifying beef samples on the basis of their geographical origin was investigated by stable isotope and multielement analysis using samples from various provinces in China. C and N isotope composition and the concentrations of 23 elements of the defatted beef samples were determined. It was shown that as compared to the Tibet beef fed predominantly on C3 pasture, maize-fed beef produced in Shandong and Heilongjiang province gave rise to a significant difference in (13)C content. Significant differences were also observed in 18 elements among the defatted beef samples. Stable isotope data and multielement concentrations determined in the beef were subjected to multivariate analysis, including principal component analysis (PCA) and discriminant analysis (DA). Eight key variables were identified as providing maximum discrimination among samples. DA gave an overall correct classification rate of 100% and a cross validation rate of 100%. This research has proved that the geographical origin of beef in China can be identified by a combination of stable isotopes and multielement analysis. PMID- 23805793 TI - N-acetylcysteine amide, a thiol antioxidant, prevents bleomycin-induced toxicity in human alveolar basal epithelial cells (A549). AB - Bleomycin (BLM), a glycopeptide antibiotic from Streptomyces verticillus, is an effective antineoplastic drug. However, its clinical use is restricted due to the wide range of associated toxicities, especially pulmonary toxicity. Oxidative stress has been implicated as an important factor in the development of BLM induced pulmonary toxicity. Previous studies have indicated disruption of thiol redox status in lungs (lung epithelial cells) upon BLM treatment. Therefore, this study focused on (1) investigating the oxidative effects of BLM on lung epithelial cells (A549) and (2) elucidating whether a well-known thiol antioxidant, N-acetylcysteine amide (NACA), provides any protection against BLM induced toxicity. Oxidative stress parameters, such as glutathione (GSH), malondialdehyde (MDA), and antioxidant enzyme activities were altered upon BLM treatment. Loss of mitochondrial membrane potential (DeltaPsim), as assessed by fluorescence microscopy, indicated that cytotoxicity is possibly mediated through mitochondrial dysfunction. Pretreatment with NACA reversed the oxidative effects of BLM. NACA decreased the reactive oxygen species (ROS) and MDA levels and restored the intracellular GSH levels. Our data showed that BLM induced A549 cell death by a mechanism involving oxidative stress and mitochondrial dysfunction. NACA had a protective role against BLM-induced toxicity by inhibiting lipid peroxidation, scavenging ROS, and preserving intracellular GSH and DeltaPsim. NACA can potentially be developed into a promising adjunctive therapeutic option for patients undergoing chemotherapy with BLM. PMID- 23805794 TI - Gelling concept combining chitosan and alginate-proof of principle. AB - Biocompatible hydrogels are very interesting for applications in, e.g., tissue engineering and for immobilization of cells, such as calcium-alginate gels where the calcium ions form specific interactions with the guluronic acid units. We here report on a new gelling system of chitosan and alginate containing only mannuronic acid (poly-M), which are prepared using the following steps: (i) mixing at a pH well above 7 where the chitosan is mainly uncharged; (ii) controlled lowering of the pH by adding the slowly hydrolyzing d-glucono-delta lactone (GDL); (iii) formation of a homogeneous chitosan-alginate gel upon leaving the mixture at room temperature. Some properties of the new gelling system are demonstrated herein by adding controlled amounts of GDL to (i) a mixture of a polymeric and neutral-soluble chitosan with poly-M oligomers (MO) and (ii) a mixture of poly-M and neutral-soluble chitosan oligomers. The neutral solubility of the polymeric chitosan is achieved by selecting a polymeric chitosan with an intermediate degree of acetylation of 40%, while the neutral solubility of the fully de-N-acetylated chitosan oligomers (CO) is obtained by selecting oligomers with a chain length below 10. A proof of concept of the new gelling system is demonstrated by measuring the gel strengths of the polymeric chitosan-MO, and a poly-M-CO. The results show that the gel strength increases with decreasing the pH from neutral to 5, and that the gel strength decreases with increasing ionic strength, indicative of an ionic gel formation. Poly-M formed relatively strong gels with CO while an alginate highly enriched in Guluronic acid formed gels of very limited mechanical strength, suggesting the importance of the match in charge distances in the poly-M and chitosan, both with diequatorially linked sugar units in the (4)C1 conformation. PMID- 23805795 TI - Pb(II) binding to humic substances: an equilibrium and spectroscopic study. AB - The binding of Pb(II) to humic acids is studied through an approach combining equilibrium and spectroscopic measurements. The methods employed are potentiometric and fluorometric titrations, fluorescence excitation-emission matrices (EEM) and IR spectroscopy. Potentiometric titration curves are analyzed using the NICA equations and an electrostatic model treating the humic particles as an elastic polyelectrolyte network. EEMs are analyzed using parallel factor analysis, decomposing the signal in its independent components and finding their dependence on Pb(II) activity. Potentiometric results are consistent with bimodal affinity distributions for Pb(II) binding, whereas fluorometric titrations are explained by monomodal distributions. EEM analysis is consistent with three independent components in the humic fluorescence response, which are assigned to moieties with different degree of aromaticity. All three components show a similar quenching behavior upon Pb(II) binding, saturating at relatively low Pb(II) concentrations. This is attributed to metal ion induced aggregation of humic molecules, resulting in the interaction between the aromatic groups responsible for fluorescence; this is also consistent with IR spectroscopy results. The observed behavior is interpreted considering that initial metal binding (observed as strongly binding sites), correspond to bi- or multidentate complexation to carboxylate groups, including binding between groups of different humic molecules, promoting aggregation; further metal ions (observed as weakly binding sites) bind to single ligand groups. PMID- 23805796 TI - State variation in the cortisol awakening response. AB - The cortisol awakening response (CAR) is a much studied but poorly understood aspect of the circadian pattern of cortisol secretion. A Scopus search of "cortisol" and "awakening" reveals 666 publications in this area since 1997 when it was first identified by Pruessner and colleagues as a "reliable biomarker of adrenocortical activity". The primary focus of the majority of these studies is centered on its utility as a biomarker associated with a range of psychosocial, physical and mental health variables. Such studies typically examine differences in the CAR (studied on 1 or 2 days) between healthy participants and other comparator groups of interest. Fewer studies (25 in our estimation) have examined correlates of day-to-day variation in the CAR in healthy participants, informing its role and regulation within the healthy circadian pattern of cortisol secretion. This is the first review to examine these studies which, although limited in number, offer a relatively coherent emerging story about state factors that influence the CAR and the impact of the CAR on daily functioning. Greater understanding of these issues helps illuminate the utility of the CAR as a promising biomarker in psychophysiological and epidemiological research. The review also highlights areas that require greater clarification and points to potentially fruitful areas of further research. PMID- 23805798 TI - Pressure-induced switching between amorphization and crystallization in PbTe nanoparticles. AB - Combining in situ high-pressure X-ray scattering with transmission electron microscopy, we investigated the pressure-induced structural switches between the rock salt and amorphous phases as well as the associated mechanisms of their crystallization and growth in 6 nm PbTe nanocrystal. It was observed that rock salt PbTe nanocrystal started to become amorphous above 10 GPa and then underwent a low-to-high density amorphous phase transformation at pressures over 15 GPa. The low-density amorphous phase exhibited a structural memory of the rock salt phase, as manifested by a backward transformation to the rock salt phase via single nucleation inside each nanoparticle upon the release of pressure. In contrast, the high-density amorphous phase remained stable and could be preserved at ambient conditions. In addition, electron beam-induced heating could drive a recrystallization of the rock salt phase on the recovered amorphous nanoparticles. These studies provide significant insights into structural mechanisms for pressure-induced switching between amorphous and crystalline phases as well as their associated growth processes. PMID- 23805797 TI - Impact of moderate blast exposures on thrombin biomarkers assessed by calibrated automated thrombography in rats. AB - Severe blast exposures are frequently complicated with fatal intracranial hemorrhages. However, many more sustain low level blasts without tissue damage detectable by brain imaging. To investigate effects of nonlethal blast on thrombin-related biomarkers, rats were subjected to two different types of head directed blast: 1) moderate "composite" blast with strong head acceleration or 2) moderate primary blast, without head acceleration. Thrombin generation (TG) ex vivo after blast was studied by calibrated automated thrombography (CAT). In the same blood samples, we assessed maximal concentration of TG (TGmax), start time, peak time, mean time, and concentrations of protein markers for vascular/hemostatic dysfunctions: integrin alpha/beta, soluble endothelial selectin (sE-selectin), soluble intercellular cell adhesion molecule-1 (sICAM-1), and matrix metalloproteinases (MMP)-2, MMP-8, and MMP-13. Blast remarkably affected all TG indices. In animals exposed to "composite" blast, TGmax peaked at 6 h (~4.5-fold vs. control), sustained at day 1 (~3.8-fold increase), and declined to a 2-fold increase over control at day 7 post-blast. After primary blast, TGmax also rose to ~4.2-fold of control at 6 h, dropped to ~1.7-fold of control at day 1, and then exhibited a slight secondary increase at 2-fold of control at day 7. Other TG indices did not differ significantly between two types of blast exposure. The changes were also observed in other microvascular/inflammatory/hemostatic biomarkers. Integrin alpha/beta and sICAM-1 levels were elevated after both "composite" and primary blast at 6 h, 1 day, and 7 days. sE-selectin exhibited near normal levels after "composite" blast, but increased significantly at 7 days after primary blast; MMP-2, MMP-8, and MMP-13 slightly rose after "composite" blast and significantly increased (~2-4-fold) after primary blast. In summary, CAT may have a clinical diagnostic utility in combination with selected set of microvascular/inflammatory biomarkers in patients subjected to low/moderate level blast exposures. PMID- 23805799 TI - Prevalence of menopausal symptoms and their influence on adherence in women with breast cancer. AB - OBJECTIVES: The use of aromatase inhibitors for the adjuvant treatment of breast cancer may affect the quality of life of patients, as well as adherence to treatment. METHODS: Here we report the 2-year results of the 180 patients in the COMPAS study. This is the first randomized, controlled study reporting on menopausal symptoms under endocrine treatment with aromatase inhibitors in breast cancer patients, based on the Menopause Rating Scale. We analyzed the prevalence of menopausal symptoms as well as their associations with patient adherence. RESULTS: Baseline characteristics showed no significant differences among the control and the intervention groups. The majority of women experienced the symptoms at various severities. Overall, we found an increase in the prevalence of hot flushes, sleep disorders, bladder problems, dryness of the vagina as well as of joint and muscular discomfort between the 12- and 24-month visits. In compliant patients, all symptoms except for vaginal dryness improved between the 12- and 24-month visits while, in non-compliant women, hot flushes, irritability, dryness of the vagina as well as joint and muscular discomfort deteriorated. When comparing compliant and non-compliant patients, we found a significant difference only for anxiety (p = 0.028) in the 12-month analysis, as well as a large but non significant difference for heart discomfort (p = 0.089) in the 24-month visit. CONCLUSIONS: Our results indicate that the majority of women treated with aromatase inhibitors are experiencing menopausal symptoms at various severities. We showed that the mean symptom values in compliant patients improve with longer therapy duration. Furthermore, anxiety correlates with better compliance, while heart discomfort may lead to therapy discontinuation. PMID- 23805801 TI - The halogen bond in the design of functional supramolecular materials: recent advances. AB - Halogen bonding is an emerging noncovalent interaction for constructing supramolecular assemblies. Though similar to the more familiar hydrogen bonding, four primary differences between these two interactions make halogen bonding a unique tool for molecular recognition and the design of functional materials. First, halogen bonds tend to be much more directional than (single) hydrogen bonds. Second, the interaction strength scales with the polarizability of the bond-donor atom, a feature that researchers can tune through single-atom mutation. In addition, halogen bonds are hydrophobic whereas hydrogen bonds are hydrophilic. Lastly, the size of the bond-donor atom (halogen) is significantly larger than hydrogen. As a result, halogen bonding provides supramolecular chemists with design tools that cannot be easily met with other types of noncovalent interactions and opens up unprecedented possibilities in the design of smart functional materials. This Account highlights the recent advances in the design of halogen-bond-based functional materials. Each of the unique features of halogen bonding, directionality, tunable interaction strength, hydrophobicity, and large donor atom size, makes a difference. Taking advantage of the hydrophobicity, researchers have designed small-size ion transporters. The large halogen atom size provided a platform for constructing all-organic light-emitting crystals that efficiently generate triplet electrons and have a high phosphorescence quantum yield. The tunable interaction strengths provide tools for understanding light-induced macroscopic motions in photoresponsive azobenzene containing polymers, and the directionality renders halogen bonding useful in the design on functional supramolecular liquid crystals and gel-phase materials. Although halogen bond based functional materials design is still in its infancy, we foresee a bright future for this field. We expect that materials designed based on halogen bonding could lead to applications in biomimetics, optics/photonics, functional surfaces, and photoswitchable supramolecules. PMID- 23805802 TI - Estimating the effects of the Balanced Budget act of 1997 on the home health care use of the dually eligible: a natural experiments approach. AB - This research examines the use of home health agency services used by older adults after the implementation of changes to Medicare's payment scheme mandated by the Balanced Budget Act (BBA) of 1997. The objective of this study is to identify differential effects the BBA may have had on home health service use between dually eligible and Medicare-only beneficiaries. The results of this study suggest that although dually eligible and Medicare-only beneficiaries experienced a substantial decline in home health service use, the dually eligible had a relatively larger decline. Following the BBA, the dually eligible had more office-based physician visits but fewer inpatient hospital days, relative to the Medicare-only population. Finally, the author estimates cost savings to Medicare due to the BBA to be $1 billion in the 2 years following the legislation, whereas Medicaid programs shouldered a larger percentage of the home health service bill. PMID- 23805803 TI - Exploring attitudes regarding smokeless tobacco products for risk reduction. AB - Utilizing qualitative data analysis, this study focused on the attitudes, knowledge, and beliefs relating to smokeless tobacco (ST) as a reduced-risk cigarette substitute for smokers among focus groups from the general public and from the health profession. It revealed that there is a lack of awareness and understanding of ST products, which has a significant impact on overall perception of these products as acceptable substitutes. Regulatory actions regarding tobacco by the U.S. Food and Drug Administration should enhance consumers' access to accurate information about nicotine addiction and tobacco use. PMID- 23805804 TI - White slavery, whorehouse riots, venereal disease, and saving women: historical context of prostitution interventions and harm reduction in New York City during the Progressive Era. AB - Harm reduction and structural approaches to reduce HIV risk among sex workers face several barriers. One such barrier is based on moral arguments, and it has a rich historical context. This article examines the historical context of interventions with sex workers in New York City during the Progressive Era (1890 1920). Present at the time, though under a different name, the harm reduction approach was largely dismissed. These same moral underpinnings may be active today in driving interventions and policy toward those that are morally focused and away from those that focus on harm reduction and structural change. PMID- 23805805 TI - Prioritizing health and community food security through the farm bill. AB - Food security and health are complex interrelated issues. Individual characteristics exist within the physical and built environments. Title IV of the Food, Conservation, and Energy Act of 2008 is analyzed in terms of how it addresses systemic food insecurity and the opportunities the policy has for improving public health by increasing support for the availability of affordable local produce to low-income households. Structural changes need to occur for programs to be equitable, efficient, and effective. Interdisciplinary leadership within government agencies, school systems, social service agencies, health care agencies, and nonprofit networks is necessary to ensure food security and health for all Americans. Social work and public health practitioners have the opportunity to change the status quo, encourage community-level interventions, advocate for producers and consumers, and encourage more equitable distribution of food to create a healthier low-income population. PMID- 23805806 TI - Barriers to prostate cancer prevention and community recommended health education strategies in an urban African American community in Jackson, Mississippi. AB - This article describes the use of survey research in collaboration with the African American urban community of Georgetown, Jackson, Mississippi to identify and understand prostate cancer knowledge, resource utilization, and health education strategies considered most effective in reaching the community with prostate cancer prevention messages. The study revealed profound needs in disease identification and resources awareness and utilization. Barriers to utilization were identified by participants to include lack of self-efficacy, low self esteem, lack of trust in the health care system, limited knowledge of prostate pathology, and limited ability to pay. Participants' recommended strategies for reaching the community with prostate cancer education include traditional and nontraditional strategies. The list of recommendations exclude modern-day outlets such as handheld devices, Twitter, Facebook, blogs, wikis, and other Internet based outlets. The findings provide a road map for program development and an intervention research agenda custom-tailored to the Georgetown community of Jackson, Mississippi. PMID- 23805808 TI - Modeling adsorption properties on the basis of microscopic, molecular, and structural descriptors for nonpolar adsorbents. AB - We propose a method for analytically predicting single-component adsorption isotherms from molecular, microscopic and structural descriptors of the adsorbate adsorbent system and concepts of statistical thermodynamics. Expressions for Henry's constant and the heat of adsorption at zero coverage are derived. These functions depend on the pore size, pore shape, chemical composition, and density of the adsorbent material. They quantify the strength of the solid-fluid interaction, which governs the low-pressure part of the adsorption isotherm. For intermediate and high pressures, the fluid-fluid interactions must also be taken into account. Both solid-fluid and fluid-fluid interactions are combined within the framework of the Ruthven statistical model (RSM). The RSM thus constructs theoretical adsorption isotherms that are entirely based on microscopic molecular and structural descriptors. The theoretical results that we obtained are compared with experimental data for the adsorption of pure CO2 and CH4 on all-silica zeolites. The developed methodology allows for the estimation of the optimum properties of a nonpolar adsorbent for the adsorption of CO2 in cyclic adsorption processes. PMID- 23805809 TI - Periodontal status affects C-reactive protein and lipids in patients with stable heart disease from a tertiary care cardiovascular clinic. AB - BACKGROUND: There are scarce data on the impact of the periodontal condition in the control of biomarkers in patients with cardiovascular disease (CVD). The aim of this study is to assess whether periodontal inflammation and tissue breakdown are associated with C-reactive protein (CRP) and lipids in patients with stable heart disease. METHODS: This cross-sectional study included 93 patients with stable coronary artery disease (57 males; mean age: 63.5 +/- 9.8 years) who were in outpatient care for at least 6 months. After applying a structured questionnaire, periodontal examinations were performed by two calibrated periodontists in six sites per tooth at all teeth. Blood samples were collected from patients on the day of periodontal examination to determine levels of CRP, lipids, and glycated hemoglobin. Multiple linear regression models were fitted to evaluate the association among different periodontal and blood parameters controlling for sex, body mass index, glycated hemoglobin, use of oral hypoglycemic drugs, and smoking. RESULTS: Overall, the sample presented high levels of periodontal inflammation and tissue breakdown. Unadjusted mean concentrations of triglycerides (TGs), very-low-density lipoprotein cholesterol, and glucose were significantly higher in individuals with severe periodontitis. When multiple linear regression models were applied, number of teeth with clinical attachment loss >=6 mm and presence of severe periodontitis were significantly associated with higher CRP concentrations. Bleeding on probing was significantly associated with TGs, total cholesterol, and non-high-density lipoprotein cholesterol. CONCLUSION: In this sample of patients with stable CVD, current periodontal inflammation and tissue breakdown are associated with cardiovascular inflammatory markers, such as CRP and lipid profile. PMID- 23805810 TI - Evaluation of a variable-thread tapered implant in extraction sites with immediate temporization: a 3-year multicenter clinical study. AB - BACKGROUND: The purpose of this clinical study is to evaluate the radiographic bone remodeling, survival rate, and soft tissue health surrounding a variable thread tapered implant immediately placed in extraction sites. METHODS: Sixty implants were placed in 55 patients at six centers according to a predetermined protocol. All implants were placed in extraction sockets and were subjected to immediate temporization and function. Definitive prostheses (58 single crowns and one two-unit fixed bridge) were placed within the first year. Clinical and radiographic examinations were performed at implant placement and after 3, 6, 12, 24, and 36 months. Measurements of implant stability, papilla index, plaque, peri implant mucosa, and marginal bone levels were recorded at each visit. RESULTS: Thirty-five implants were evaluated at both implant insertion and 3-year follow up. Bone levels were observed at 6 months after surgery and yearly intervals thereafter and remained stable throughout the study. There was a slight decrease in mean bone level from -0.68 mm at implant insertion to -0.93 mm at the 6-month recall and then an increase of bone to -0.53 mm from the reference point at the 2 year follow-up (an average increase of 0.15 mm from implant insertion). Bone levels remained steady between the 2-year recall and the 3-year recall. Papilla scores increased significantly (P <0.001; Wilcoxon signed-rank test) from insertion to the 3-year follow-up, with most of the increase occurring during the first year. Patient assessments of function, esthetics, feel of implant, speech, and self-esteem also showed significant improvement over the course of the study. CONCLUSIONS: The results, over 36 months, indicate that the variable-thread tapered implant can be used safely and effectively under demanding conditions as an immediate postextraction tooth replacement. Bone remodeling remained stable with a slight increase, and patients expressed high levels of satisfaction with the restorative results over the course of the study. PMID- 23805811 TI - Evaluation of the host response in various models of induced periodontal disease in mice. AB - BACKGROUND: The aim of this study is to characterize and evaluate the host response caused by three different models of experimental periodontitis in mice. METHODS: C57BL/6 wild-type female mice were distributed into six experimental groups and sacrificed at 7, 15, and 30 days after the induction of periodontal disease: 1) group C: no treatment control group; 2) group L: periodontal disease induced by ligature; 3) group G-Pg: oral gavage with Porphyromonas gingivalis (Pg); 4) group G-PgFn: oral gavage with Fusobacterium nucleatum + Pg; 5) group I Pg: heat-killed Pg injected into the palatal mucosa between the molars; and 6) group I-V: phosphate-buffered saline injected into the palatal mucosa. The samples were used to analyze the immune-inflammatory process in the gingival tissue via descriptive histologic and real-time polymerase chain reaction analyses. The alveolar bone loss was evaluated using microcomputed tomography. The data were analyzed using the Kruskal-Wallis test, followed by a post hoc Dunn test and analysis of variance, followed by a Tukey test using a 5% significance level. RESULTS: Only the ligature model displayed significant alveolar bone loss in the initial period (7 days), which was maintained with time. The group injected with heat-killed Pg displayed significant alveolar bone loss starting from day 15, which continued to progress with time (P <0.05). A significant increase (P <0.05) in the gene expression of proinflammatory cytokines (interleukin-6 and -1beta) and proteins involved in osteoclastogenesis (receptor activator of nuclear factor-kappaB ligand and osteoprotegerin) was observed in the ligature group on day 7. CONCLUSION: The ligature and injection of heat killed Pg models were the most representative of periodontal disease in humans, whereas the oral gavage models were not effective at inducing the disease under the experimental conditions. PMID- 23805812 TI - The effect of alpha-tocopherol and selenium on human gingival fibroblasts and periodontal ligament fibroblasts in vitro. AB - BACKGROUND: The aim of the present study is to evaluate the effect of alpha tocopherol and selenium on gingival fibroblasts (GFs) and periodontal ligament fibroblasts (PDLFs) in terms of proliferation, basic fibroblast growth factor (bFGF) release, collagen type I synthesis, and wound healing. METHODS: Primary cultures of human GFs and PDLFs were isolated. Four test groups and a control group free of medication was formed. In group E, 60 MUM alpha-tocopherol was used, and in groups ES1, ES2, and ES3, the combination of 60 MUM alpha-tocopherol with 5 * 10(-9) M, 10 * 10(-9) M, and 50 * 10(-9) M selenium was used, respectively. Viability, proliferation, bFGF, and collagen type I synthesis from both cell types were evaluated at 24, 48, and 72 hours, and healing was compared on a new wound-healing model at 12, 24, 36, 48, and 72 hours. RESULTS: alpha Tocopherol alone significantly increased the healing rate of PDLFs at 12 hours and increased bFGF and collagen type I release from GFs and PDLFs at 24, 48, and 72 hours. The alpha-tocopherol/selenium combination significantly enhanced the proliferation rate of both cells at 48 hours, decreased the proliferation of PDLFs at 72 hours, and increased the healing rate of GFs at 12 hours and PDLFs at 12 and 48 hours. bFGF and collagen type I synthesis was also increased in both cell types at 24, 48, and 72 hours by alpha-tocopherol/selenium combination. CONCLUSION: alpha-Tocopherol and alpha-tocopherol/selenium combination is able to accelerate the proliferation rate and wound-healing process and increase the synthesis of bFGF and collagen type I from both GFs and PDLFs. PMID- 23805813 TI - Association of a common genetic factor, PTGER3, with outcome of periodontal therapy and preterm birth. AB - BACKGROUND: Clinical evidence suggests an association between preterm birth and periodontal disease. This study explores whether specific genetic polymorphisms are associated with success of periodontal therapy in pregnant women with periodontal disease and, further, whether any of these same polymorphisms are also associated with spontaneous preterm birth (sPTB). METHODS: One hundred sixty high-risk pregnant women (6 to 20 weeks of gestation) with periodontal disease (>= 3 sites with attachment loss >= 4 mm) were studied. All women received scaling and root planing plus oral hygiene instruction. Periodontal examinations were performed before treatment and 20 weeks later. Participants were classified according to two study outcomes: 1) success or failure of periodontal treatment; and 2) presence or absence of sPTB. Maternal DNA samples from mucosal swabs were characterized using a 1536-SNP (single-nucleotide polymorphism) custom polymerase chain reaction chip. A probabilistic model of each dichotomous outcome, derived using a stepwise Bayesian procedure, was compared to respective null hypotheses on the basis of Monte Carlo simulations and significance estimates obtained using three measures (z-test, Welch t-test, and probability convolution). The models were further confirmed by logistic regression analyses. RESULTS: The models revealed a significant relation between a specific polymorphism of prostaglandin E receptor 3 (a gene associated with inflammatory response) and both periodontal treatment failure (odds ratio 11.09, P <0.0002) and sPTB (odds ratio 6.89, P < 0.0032). CONCLUSIONS: These results demonstrate that the risk of unsuccessful periodontal treatment is associated with tag SNPs in specific genes that regulate the inflammatory response, one of which is also associated with sPTB. PMID- 23805814 TI - Antimicrobial action of minocycline microspheres versus 810-nm diode laser on human dental plaque microcosm biofilms. AB - BACKGROUND: The purpose of this study is to investigate the antimicrobial effects of minocycline hydrochloride microspheres versus infrared light at 810 nm from a diode laser on multispecies oral biofilms in vitro. These biofilms were grown from dental plaque inoculum (oral microcosms) and were obtained from six systemically healthy individuals with generalized chronic periodontitis. METHODS: Multispecies biofilms were derived using supra- and subgingival plaque samples from mesio-buccal aspects of premolars and molars exhibiting probing depths in the 4- to 5-mm range and 1- to 2-mm attachment loss. Biofilms were developed anaerobically on blood agar surfaces in 96-well plates using a growth medium of prereduced, anaerobically sterilized brain-heart infusion with 2% horse serum. Minocycline HCl 1 mg microspheres were applied on biofilms on days 2 and 5 of their development. Biofilms were also exposed on days 2 and 5 of their growth to 810-nm light for 30 seconds using a power of 0.8 W in a continuous-wave mode. The susceptibility of microorganisms to minocycline or infrared light was evaluated by a colony-forming assay and DNA probe analysis at different time points. RESULTS: At all time points of survival assessment, minocycline was more effective (>2 log10 colony-forming unit reduction) than light treatment (P <0.002). Microbial analysis did not reveal susceptibility of certain dental plaque pathogens to light, and it was not possible after treatment with minocycline due to lack of bacterial growth. CONCLUSION: The cumulative action of minocycline microspheres on multispecies oral biofilms in vitro led to enhanced killing of microorganisms, whereas a single exposure of light at 810 nm exhibited minimal and non-selective antimicrobial effects. PMID- 23805815 TI - Hypoxia regulates the proliferation and osteogenic differentiation of human periodontal ligament cells under cyclic tensile stress via mitogen-activated protein kinase pathways. AB - BACKGROUND: Previous studies have shown that periodontal ligament exists in a hypoxic microenvironment, especially under the condition of periodontitis or physical stress. The present study is designed to investigate the effects and mechanisms of hypoxia on regulating the proliferation and osteogenic differentiation of human periodontal ligament cells (hPDLCs) under cyclic tensile stress (CTS). METHODS: hPDLCs were cultured in 2% O2 (hypoxia) or 20% O2 (normoxia) and then subjected to a cyclic in-plane tensile deformation of 10% at 0.5 Hz. The following parameters were measured: 1) cell proliferation by flow cytometry; 2) cell ultrastructure by transmission electron microscopy; 3) expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and osteogenic relative factors (i.e., secreted phosphoprotein 1 [SPP1; also known as bone sialoprotein I/osteopontin], runt-related transcription factor 2 [RUNX2], and transcription factor Sp7 [SP7]) by real-time polymerase chain reaction and Western blot; and 4) involvement of mitogen-activated protein kinase (MAPK) signaling pathways by Western blot with specific inhibitor. RESULTS: Proliferation index in the hypoxia with CTS group was significantly higher than in other groups. Significant increases in HIF-1alpha, SPP1, RUNX2, and SP7 occurred in the presence of hypoxia for 24 hours. In addition, MAPK inhibitor (PD 98,059) significantly attenuated hypoxia and CTS-induced phosphor-ERK1/2 (extracellular regulated kinase 1/2), phosphor-JNK (c-jun N-terminal kinase), and phosphor-P38 expression. CONCLUSIONS: Hypoxia regulates CTS-responsive changes in proliferation and osteogenic differentiation of hPDLCs via MAPK pathways. Hypoxia treated hPDLCs may serve as an in vitro model to explore the molecular mechanisms of periodontitis. PMID- 23805816 TI - Resistin levels in gingival crevicular fluid of patients with chronic periodontitis and type 2 diabetes mellitus. AB - BACKGROUND: Resistin is associated with local and systemic inflammatory conditions with a direct correlation with type 2 diabetes mellitus (T2DM). The aim of this clinico-biochemical study is to estimate and compare the levels of resistin in the gingival crevicular fluid (GCF) in health, chronic periodontitis (CP), and T2DM. METHODS: Sixty patients (aged >35 years) who participated in this study were divided into four groups of 15 patients each: healthy individuals (group 1), patients with CP (group 2), patients with T2DM (group 3), and patients with T2DM and CP (group 4). The parameters assessed included plaque index (PI), gingival index (GI), probing depth (PD), periodontal index, body mass index, random blood sugar (RBS), and glycated hemoglobin (HbA1c). GCF (4 MUL) was collected and analyzed for resistin levels using an enzyme-linked immunosorbent assay. RESULTS: Resistin was detected in the GCF of all patients. A significant difference was observed in GCF resistin concentrations from group 1 versus group 2 (P = 0.0093), group 3 (P = 0.0341), and group 4 (P = 0.0002); in group 2 versus group 4 (P = 0.0032); and in group 3 versus group 4 (P = 0.0008). When all the samples were analyzed together, GCF resistin levels positively correlated with GI, PD, PI, RBS, and HbA1c and were predictable with PD and HbA1c. CONCLUSIONS: Resistin levels are increased in CP and T2DM. Hence, GCF resistin levels may be considered as a potential inflammatory marker for periodontitis with T2DM. PMID- 23805817 TI - Adipose-derived stem cells combined with inorganic bovine bone in calvarial bone healing in rats with type 2 diabetes. AB - BACKGROUND: Clinical studies have revealed that patients with type 2 diabetes mellitus (DM) have higher implant and bone grafting failure rates than the general population, likely owing to inferior bone healing. The authors sought to investigate whether adipose-derived stem cells (ASCs) combined with inorganic bovine bone improves bone repair in calvarial vertical critical-sized defects (CSDs) in rats with type 2 DM. METHODS: Bovine bone alone or seeded with 3 * 10(5), 3 * 10(6), or 3 * 10(7) ASCs/graft was randomly transplanted into calvarial CSDs in rats with DM induced by a high-fat diet with low-dose streptozotocin. Specimens were assayed using microcomputed tomography and histomorphometry at 4 and 8 weeks postimplantation. RESULTS: The histologic results showed an increase in new bone formation in the experimental groups compared with the control group. Both bone volume/total volume and trabecular thickness of newly formed bone within CSDs were the highest, and trabecular spacing was the lowest, in the 3 * 10(6) group at 8 weeks for the most favorable outcome. The results showed that the amount of new bone was greatest in the 3 * 10(6) group by 8 weeks. CONCLUSIONS: ASCs enhanced vertical bone regeneration in calvarial defects in rats with type 2 DM, when used in association with bovine bone scaffolds. The findings suggest that a combination of ASCs and bovine bone scaffolds could improve bone quantity in vertical bone defects. PMID- 23805818 TI - Motivational interviewing in improving oral health: a systematic review of randomized controlled trials. AB - BACKGROUND: The control and management of many oral health conditions highly depend on one's daily self-care practice and compliance to preventive and curative measures. Conventional (health) education (CE), focusing on disseminating information and giving normative advice, is insufficient to achieve sustained behavioral changes. A counseling approach, motivational interviewing (MI), is potentially useful in changing oral health behaviors. This systematic review aims to synthesize the evidence on the effectiveness of MI compared with CE in improving oral health. METHODS: Four databases (PubMed MEDLINE, Web of Science, Cochrane Library, and PsycINFO) were searched to identify randomized controlled trials that evaluated the effectiveness of MI compared with CE in changing oral health behaviors and improving oral health of dental patients and the public. The scientific quality of the studies was rated, and their key findings were qualitatively synthesized. RESULTS: The search yielded 221 potentially relevant papers, among which 20 papers (on 16 studies) met the eligibility criteria. The quality of the studies varied from 10 to 18 out of a highest possible score of 21. Concerning periodontal health, superior effect of MI on oral hygiene was found in five trials and was absent in two trials. Two trials targeting smoking cessation in adolescents failed to generate a positive effect. MI outperformed CE in improving at least one outcome in four studies on preventing early childhood caries, one study on adherence to dental appointments, and two studies on abstinence of illicit drugs and alcohol use to prevent the reoccurrence of facial injury. CONCLUSIONS: Reviewed randomized controlled trials showed varied success of MI in improving oral health. The potential of MI in dental health care, especially on improving periodontal health, remains controversial. Additional studies with methodologic rigor are needed for a better understanding of the roles of MI in dental practice. PMID- 23805820 TI - 1,2,3-triazoles: gas phase properties. AB - 1,2,3-Triazoles have come to the forefront as compounds of import in a vast number of applications. The fundamental properties of these species, however, remain largely unknown. Herein, the gas phase properties of 4-phenyl-1,2,3 triazole, benzotriazole, and a series of 1-phenylbenzotriazoles are described. Proton affinity and acidity values are computed and measured. Furthermore, ion molecule reactions and H/D exchange studies are used to ascertain tautomer prevalence for the 4-phenyl species. PMID- 23805819 TI - Periodontal fibroblasts modulate proliferation and osteogenic differentiation of embryonic stem cells through production of fibroblast growth factors. AB - BACKGROUND: Periodontal ligament fibroblasts (PLFs) maintain homeostasis of periodontal ligaments by producing paracrine factors that affect various functions of stem-like cells. It is hypothesized that PLFs induce proliferation and differentiation of stem cells more effectively than gingival fibroblasts (GFs) and skin fibroblasts (SFs). METHODS: PLFs and GFs were isolated from extracted teeth and cultured in the presence and absence of osteogenesis-inducing factors. Mouse embryonic stem (mES) cells and SFs were purchased commercially. mES cells were incubated with culture supernatants of these fibroblasts or cocultured directly with the cells. Proliferation and mineralization in mES cells were determined at various times of incubation. Immunostaining and polymerase chain reaction were performed. The activity of mitogen-activated protein kinase and alkaline phosphatase (ALP) was also measured. RESULTS: In cocultures, PLFs stimulated proliferation of mES cells more effectively than GFs or SFs. Similarly, the addition of culture supernatant of PLFs induced the most prominent proliferation of mES cells, and this was significantly inhibited by treatment with antibody against fibroblast growth factor (FGF)4 or the c-Jun N-terminal kinase inhibitor SP600125 (anthra[1,9-cd]pyrazol-6(2H)-one). Supplementation with culture supernatant from the fibroblasts induced osteogenic differentiation of mES cells in the order PLFs > GFs > SFs. These activities of PLFs were related to their potential to produce osteogenic markers, such as ALP and runt-related transcription factor-2 (Runx2), and to secrete FGF7. Pretreatment of mES cells with the extracellular signal-regulated kinase inhibitor PD98059 [2-(2-amino-3 methyoxyphenyl)-4H-1-benzopyran-4-one] or SP600125 clearly attenuated mineralization induced by culture supernatant of PLF with attendant decreases in mRNA levels of Runx2, bone sialoprotein, osteocalcin, and osteopontin. CONCLUSION: PLFs regulate the proliferation and osteogenic differentiation of mES cells more strongly than GFs and SFs via the secretion of FGF through a mechanism that involves mitogen-activated protein kinase-mediated signaling. PMID- 23805821 TI - Direct observation of large quantum interference effect in anthraquinone solid state junctions. AB - Quantum interference in cross-conjugated molecules embedded in solid-state devices was investigated by direct current-voltage and differential conductance transport measurements of anthraquinone (AQ)-based large area planar junctions. A thin film of AQ was grafted covalently on the junction base electrode by diazonium electroreduction, while the counter electrode was directly evaporated on top of the molecular layer. Our technique provides direct evidence of a large quantum interference effect in multiple CMOS compatible planar junctions. The quantum interference is manifested by a pronounced dip in the differential conductance close to zero voltage bias. The experimental signature is well developed at low temperature (4 K), showing a large amplitude dip with a minimum >2 orders of magnitude lower than the conductance at higher bias and is still clearly evident at room temperature. A temperature analysis of the conductance curves revealed that electron-phonon coupling is the principal decoherence mechanism causing large conductance oscillations at low temperature. PMID- 23805822 TI - Evaluation of CareStartTM malaria Pf/Pv combo test for Plasmodium falciparum and Plasmodium vivax malaria diagnosis in Butajira area, south-central Ethiopia. AB - Malaria is a major public health problem in Ethiopia. Plasmodium falciparum and Plasmodium vivax co-exist and malaria rapid diagnostic test (RDTs) is vital in rendering parasite-confirmed treatment especially in areas where microscopy from 2008 to 2010 is not available. CareStartTM Malaria Pf/Pv combo test was evaluated compared to microscopy in Butajira area, south-central Ethiopia. This RDT detects histidine-rich protein-2 (HRP2) found in P. falciparum, and Plasmodium enzyme lactate dehydrogenase (pLDH) for diagnosis of P. vivax. The standard for the reporting of diagnostic accuracy studies was complied. Among 2,394 participants enrolled, 10.9% (n=87) were Plasmodium infected (household survey) and 24.5% (n=392) health facility-based using microscopy. In the household surveys, the highest positivity was caused by P. vivax (83.9%, n=73), P. falciparum (15.0%, n=13), and the rest due to mixed infections of both (1.1%, n=1). In health facility, P. vivax caused 78.6% (n=308), P. falciparum caused 20.4% (n=80), and the rest caused by mixed infections 1.0% (n=4). RDT missed 9.1% (n=8) in household and 4.3% (n=17) in health facility-based surveys among Plasmodium positive confirmed by microscopy while 3.3% (n=24) in household and 17.2% (n=208) in health facility-based surveys were detected false positive. RDT showed agreement with microscopy in detecting 79 positives in household surveys (n=796) and 375 positives in health centre survey (n=1,598).RDT performance varied in both survey settings, lowest PPV (64.3%) for Plasmodium and P. falciparum (77.2%) in health centres; and Plasmodium (76.7%) and P. falciparum (87.5%) in household surveys. NPV was low in P. vivax in health centres (77.2%) and household (87.5%) surveys. Seasonally varying RDT precision of as low as 14.3% PPV (Dec. 2009), and 38.5% NPV (Nov. 2008) in health centre surveys; and 40-63.6% PPV was observed in household surveys. But the influence of age and parasite density on RDT performance was not ascertained. Establishing quality control of malaria RDT in the health system in areas with low endemic and where P. falciparum and P. vivax co-exist is recommendable. CareStartTM RDT might be employed for epidemiological studies that require interpreting the results cautiously. Future RDT field evaluation against microscopy should be PCR corrected. PMID- 23805823 TI - Sexual risk behaviour, marriage and ART: a study of HIV-positive people in Papua New Guinea. AB - BACKGROUND: The prevention of intimate partner transmission of HIV remains an important component of comprehensive HIV prevention strategies. In this paper we examine the sexual practices of people living with HIV on antiretroviral therapy (ART) in Papua New Guinea (PNG). METHOD: In 2008, a total of 374 HIV-positive people over the age of 16 and on ART for more than two weeks were recruited using a non-probability, convenience sampling methodology. This accounted for around 18% of adults on ART at the time. A further 36 people participated in semi structured interviews. All interviews were thematically analysed using NVivo qualitative data analysis software. RESULTS: Less than forty per cent (38%) of participants reported having had sexual intercourse in the six months prior to the survey. Marital status was by far the most important factor in determining sexual activity, but consistent condom use during vaginal intercourse with a regular partner was low. Only 46% reported consistent condom use during vaginal intercourse with a regular partner in the last six months, despite 77% of all participants reporting that consistent condom use can prevent HIV transmission. Consistent condom use was lowest amongst married couples and those in seroconcordant relationships. The vast majority (91.8%) of all participants with a regular heterosexual partner had disclosed their status to their partner. Qualitative data reinforced low rates of sexual activity and provided important insights into sexual abstinence and condom use. CONCLUSIONS: Considering the importance of intimate partner transmission of HIV, these results on the sexual practices of people with HIV on ART in PNG suggest that one-dimensional HIV prevention messages focussing solely on condom use fail to account for the current practices and needs of HIV-positive people, especially those who are married and know their partners' HIV status. PMID- 23805824 TI - Spatial analysis of air pollution and mortality in California. AB - RATIONALE: Although substantial scientific evidence suggests that chronic exposure to ambient air pollution contributes to premature mortality, uncertainties exist in the size and consistency of this association. Uncertainty may arise from inaccurate exposure assessment. OBJECTIVES: To assess the associations of three types of air pollutants (fine particulate matter, ozone [O3], and nitrogen dioxide [NO2]) with the risk of mortality in a large cohort of California adults using individualized exposure assessments. METHODS: For fine particulate matter and NO2, we used land use regression models to derive predicted individualized exposure at the home address. For O3, we estimated exposure with an inverse distance weighting interpolation. Standard and multilevel Cox survival models were used to assess the association between air pollution and mortality. MEASUREMENTS AND MAIN RESULTS: Data for 73,711 subjects who resided in California were abstracted from the American Cancer Society Cancer Prevention II Study cohort, with baseline ascertainment of individual characteristics in 1982 and follow-up of vital status through to 2000. Exposure data were derived from government monitors. Exposure to fine particulate matter, O3, and NO2 was positively associated with ischemic heart disease mortality. NO2 (a marker for traffic pollution) and fine particulate matter were also associated with mortality from all causes combined. Only NO2 had significant positive association with lung cancer mortality. CONCLUSIONS: Using the first individualized exposure assignments in this important cohort, we found positive associations of fine particulate matter, O3, and NO2 with mortality. The positive associations of NO2 suggest that traffic pollution relates to premature death. PMID- 23805825 TI - Psoriasis vulgaris and familial cancer risk- a population-based study. AB - BACKGROUND: Follow-up studies of psoriasis patients indicate an increased risk in the occurrence of malignancies at different sites of origin. Population stratification and/or complicated interpretation of evidence on the risk of cancer (due to the small number of patients included in most series) lead to inconsistent data. Herein we investigated the risk of occurrence of malignancies at different sites of origin in a series of 517 psoriasis patients and their 1st degree relatives. METHODS: We evaluated the tumour spectrum as well as the age of the patient at diagnosis of cancers in psoriasis families along with the observed and expected frequencies of malignancies. The distribution of 17 common mutations/polymorphisms in 10 known cancer susceptibility genes among psoriasis patients and 517 matched healthy controls were examined. No such study has been published to date. RESULTS: The statistical comparison of the observed and expected frequencies of cancers revealed a higher than expected occurrence of Hodgkin's lymphoma among males in psoriasis families when compared to the general population (OR=1.8, 95%CI 1.6-2.1, p=0.002). There was a non-significant tendency towards a younger age of onset and overrepresentation of laryngeal cancer and leukaemia in psoriasis families. We found no major differences in the distribution of cancer susceptibility mutations among our cases and the healthy controls. CONCLUSIONS: The results of our study suggest an increased risk of Hodgkin's lymphoma for male members of psoriasis families. Further studies are needed to confirm the findings and to evaluate whether or not the application of cancer surveillance protocols for Hodgkin's lymphoma, leukaemia and laryngeal cancer are justified in these families. PMID- 23805826 TI - Cultural and gender differences in emotion regulation: relation to depression. AB - In the last decade, studies have shown that the use of specific emotion regulation strategies contributes to an increased risk for depression. Past research, however, has overlooked potential cultural and gender differences in emotion regulation. The present study examined the relation between the use of emotion regulation strategies and depressive symptoms among college students in two different cultures (n=380 in Seoul, Korea; n=384 in Miami, USA). Koreans, compared with American students, reported more frequent use of brooding, whereas Americans reported more anger suppression than Koreans. Women were more likely than men to use both types of rumination (i.e., reflective pondering and brooding) and anger suppression in both countries, but these gender differences disappeared once levels of depressive symptoms were controlled for. In addition, the association between the use of reappraisal and depressive symptoms was significantly stronger in the Korean compared to the US sample. In contrast, the association between anger suppression and depressive symptoms was significantly stronger in the American compared to the Korean sample. These findings highlight the importance of considering the role of culture in emotion regulation. PMID- 23805827 TI - Development of a simple, fast, and accurate method for the direct quantification of selective estrogen receptor modulators using stable isotope dilution mass spectrometry. AB - A rapid analytical procedure was developed to quantify major selective estrogen receptor modulators (SERMs) simultaneously using stable isotope dilution mass spectrometry (SID-LCMS). Two novel isotopically labeled (SIL) analogues of natural SERMs, genistein and daidzein, were synthesized using a H/D exchange reaction mechanism. Computational chemistry coupled with MS and NMR data confirmed the site and mechanism of deuteration. The SIL analogues, which were mono- and dideutero substituted at the ortho positions, exhibited minimal deuterium isotope effects and were stable under the employed sample preparation protocol and MS analysis. An isotopic overlap correction was successfully employed to improve the accuracy and precision of the analytical method. The developed method, which was found to be sensitive, selective, precise and accurate, could be a valuable tool for research focused on determining the bioavailability of individual SERMs. PMID- 23805828 TI - Brimonidine protects against loss of Thy-1 promoter activation following optic nerve crush. AB - BACKGROUND: The loss of RGCs expressing Thy-1 after optic nerve injury has an initial phase of rapid decline followed by a longer phase with slower reduction rate. This study used longitudinal retinal imaging of mice expressing cyan fluorescent protein under control of the Thy-1 promoter (Thy1-CFP mice) to determine how the alpha2-adrenergic agonist brimonidine influences loss of Thy1 promoter activation. METHODS: Baseline images of the fluorescent retinal neurons in 30 Thy1-CFP mice were obtained using a modified confocal scanning laser ophthalmoscope. Next, brimonidine (100 ug/kg, IP) was administered either one time immediately after optic nerve crush, or immediately after optic nerve crush and then every 2 days for four weeks. A control group received a single saline injection immediately after optic nerve crush. All animals were imaged weekly for four weeks after optic nerve crush. Loss of fluorescent retinal neurons within specific retinal areas was determined by counting. RESULTS: At one week after optic nerve crush, the proportion of fluorescent retinal neurons retaining fluorescence was 44+/-7% of baseline in control mice, 51+/-6% after one brimonidine treatment, and 55+/-6% after brimonidine treatment every other day (P<0.05 for both brimonidine treatment groups compared to the control group). Subsequently, the number of fluorescent retinal neurons in the group that received one treatment differed insignificantly from the control group. In contrast, the number of fluorescent retinal neurons in the group that received repeated brimonidine treatments was greater than the control group by 28% at two weeks after crush and by 32% at three weeks after crush (P<0.05 at both time points). Rate analysis showed that brimonidine slowed the initial rate of fluorescent cell decline in the animals that received multiple treatments (P<0.05). Differences in the rate of loss among the treatment groups were insignificant after the second week. CONCLUSION: Repeated brimonidine treatments protect against loss of fluorescence within fluorescent retinal neurons of Thy1 CFP mice after optic nerve crush. As most of fluorescent retinal neurons in this system are RGCs, these findings indicate that repeated brimonidine treatments may protect RGC health following optic nerve crush. PMID- 23805829 TI - Purification methods: a way to treat severe acute inflammation related to sepsis? AB - After numerous negative randomized trials testing drugs for severe sepsis and/or septic shock, the blood purification approach remains one possibility. Many techniques have been proposed, having in common the goal to eliminate blood and/or plasma factors, supposed to play a negative role in outcomes. Among these, high dose of hemofiltration, high volume hemofiltration, high permeability hemofiltration and specific or non-specific hemoperfusion or hemoadsorption have been proposed. Until now, a poor level of proof has been published, questioning the pertinence of such a strategy. To have a chance to succeed, immune monitoring has to be performed to select suitable patients regarding their immune status, the intensity of inflammation and their cellular function. Because of the potential interaction with mediators and cell capture, Rimmele and colleagues published the results obtained with an in vitro set up, testing different adsorption cartridges in comparison to hemofiltration. They nicely confirmed the complex impact on mediator levels and cell capture and phenotype. This is certainly a more systematic approach to better understand the action of such adsorbing cartridges, which has to be developed. PMID- 23805830 TI - Zedoary oil (Ezhu You) inhibits proliferation of AGS cells. AB - BACKGROUND: Zedoary (Curcumae Rhizoma, Ezhu), a Chinese medicinal herb, has been reported to show anticancer activity. This study aims to investigate the effect of zedoary oil (Ezhu You) on the proliferation of AGS cells which is one gastric cancer cell line. METHODS: The main ingredients of the herb were detected by GC MS for herbal quality control. Cell viability was measured by MTT assay and cell proliferation was investigated by immunocytochemical staining for proliferating cell nuclear antigen (PCNA) protein. In addition, the cell cycle distributions were detected by flow cytometry with propidium iodine (PI) staining and the apoptosis rates were evaluated by flow cytometry with annexin V/PI double staining. The morphological changes associated with apoptosis were observed by Hoechst 33342/PI double-staining. Protein expression was determined by western blot analysis. RESULTS: The main ingredients of the herb, including curzerene (26.45%), eucalyptol (12.04%), curcumol (9.04%), pyridine (7.97%), germacrone (7.89%), beta-elemene (7.36%), tau-elemene (4.11%) and 28 other ingredients, including curdione, were consistent with the chemical profiles of zedoary. Zedoary oil significantly decreased the cell viability of AGS cells (P < 0.01) and MGC 803 cells (P < 0.01), and the inhibitory effects were attenuated by elevated concentrations of FBS. At high concentrations (>=90 MUg/mL), zedoary oil killed GES-1 cells. At low concentrations (<=60 MUg/mL), zedoary oil was less inhibitory toward normal gastric epithelial cells than gastric cancer cell lines. In AGS cells, zedoary oil inhibited cell proliferation in a dose- and time dependent manner, with decreased PCNA protein expression in the zedoary oil treated cells, and arrested the cell cycle at S, G2/M and G0/G1 stages after treatment for 6-48 h. At concentrations of 30, 60 and 90 MUg/mL, which resulted in significant inhibition of proliferation and cell cycle arrest, zedoary oil induced cell apoptosis. In addition, Hoechst 33342/PI double-staining confirmed the morphological characteristics of cell apoptosis at 24 h. Zedoary oil upregulated the ratio of Bax/Bcl-2 protein expression (P < 0.01). CONCLUSIONS: Zedoary oil inhibited AGS cell proliferation through cell cycle arrest and cell apoptosis promotion, which were related to Bax/Bcl-2 protein expression. PMID- 23805831 TI - When everyone is an orphan: against adopting a U.S.-styled orphan drug policy in Canada. AB - Putting aside whether diseases that affect only small numbers of people ("rare diseases") should be prioritized over diseases that are otherwise orphaned, in this article I argue that a new approach to rare, orphan diseases is needed. The current model, first signaled by the United States' Orphan Drug Act and subsequently emulated by several other jurisdictions, relies on a set of open ended criteria and market-based incentives in order to define and encourage drug therapies for rare, orphan diseases. Given a) the biopharmaceutical industries' growing interest in orphan diseases, b) progress in the sphere of personalized medicines enabling more and more common diseases to be reclassified as rare, and c) empirical evidence suggesting that the most orphan drugs target only a limited, lucrative subset of rare diseases, I argue that Canada, which recently announced plans to develop its own "orphan drug framework" should not follow the United States' orphan drug model. PMID- 23805832 TI - Reliability of reviewer ratings in the manuscript peer review process: an opportunity for improvement. AB - Accountability to authors and readers cannot exist without proper peer review practices. Thus, the information a journal seeks from its peer reviewers and how it makes use of this information is paramount. Disagreement amongst peer reviewers can be considerable, resulting in very diverse comments to authors. Incorporating a clear scoring system for key concrete items and requiring referees to provide justification for scores may ensure that reviewers contribute in a consistently fair and effective manner. This article evaluates information collected from reviewers and proposes an example of a system that aims to improve accountability, while having the potential to make it easier for reviewers to perform a more objective review. PMID- 23805833 TI - Letter to the editor: Orphan papers and ghostwriting: the case against the ICMJE. PMID- 23805834 TI - Lack of association between ESR1 gene polymorphisms and premature ovarian failure in Serbian women. AB - OBJECTIVE: It has previously been reported that estrogen receptor-alpha (ERalpha) gene (ESR1: estrogen receptor 1) polymorphisms are associated with premature ovarian failure (POF). The aim of this study was to investigate whether these genetic polymorphisms of ESR1 are associated with POF in Serbian women. METHODS: A series of 197 POF cases matched with 547 fertile controls was recruited by the Institute for Endocrinology, Diabetes and Metabolic Disorders of Serbia between 2007 and 2010. Genomic DNA was extracted from saliva using Oragene(r) DNA sample collection kits. Two single-nucleotide polymorphisms (SNPs), PvuII and XbaI, in ESR1 were genotyped by dynamic allele-specific hybridization. Haplotype analyses were performed with the restriction fragment length polymorphism method. SNP and haplotype effects were analyzed by logistic regression models. RESULTS: No significant difference was found in the distribution of ESR1 PvuII and XbaI polymorphisms or haplotypes between the POF and control groups. CONCLUSION: The two ESR1 SNPs, PvuII and XbaI, are not commonly associated with POF in Serbian women and may not contribute to the genetic basis of the condition. PMID- 23805835 TI - Self-assembly based plasmonic arrays tuned by atomic layer deposition for extreme visible light absorption. AB - Achieving complete absorption of visible light with a minimal amount of material is highly desirable for many applications, including solar energy conversion to fuel and electricity, where benefits in conversion efficiency and economy can be obtained. On a fundamental level, it is of great interest to explore whether the ultimate limits in light absorption per unit volume can be achieved by capitalizing on the advances in metamaterial science and nanosynthesis. Here, we combine block copolymer lithography and atomic layer deposition to tune the effective optical properties of a plasmonic array at the atomic scale. Critical coupling to the resulting nanocomposite layer is accomplished through guidance by a simple analytical model and measurements by spectroscopic ellipsometry. Thereby, a maximized absorption of light exceeding 99% is accomplished, of which up to about 93% occurs in a volume-equivalent thickness of gold of only 1.6 nm. This corresponds to a record effective absorption coefficient of 1.7 * 10(7) cm( 1) in the visible region, far exceeding those of solid metals, graphene, dye monolayers, and thin film solar cell materials. It is more than a factor of 2 higher than that previously obtained using a critically coupled dye J-aggregate, with a peak width exceeding the latter by 1 order of magnitude. These results thereby substantially push the limits for light harvesting in ultrathin, nanoengineered systems. PMID- 23805836 TI - Interplay of molecular hydrogelators and SDS affords responsive soft matter systems with tunable properties. AB - The gelation efficiency of low molecular weight bolaamphiphilic hydrogelators 1 and 2 is influenced by the presence of SDS micelles. Similarly, the critical micellar concentration value of SDS is reduced in the presence of the studied molecular hydrogelators. Rheological measurements indicate that the strength of the hydrogels can be modulated with SDS, the gels becoming weaker in the presence of micelles. This behavior has been rationalized with the help of NMR studies using diffusion measurements and NOE correlations. The results obtained clearly point to the formation of mixed micelles composed of SDS and the hydrogelators. In the case of 1, the gelator:SDS ratio in the mixed micelles has been estimated from solubility studies to be ca. 1:2.5. Electron microscopy reveals that when SDS is present, the morphology of the xerogels is modified in its appearance at the micrometer scale but fibers with diameter in the nanometer range are observed in all the cases. The interplay between the surfactant and the gelators provides with new possibilities for the modulation of both gel and micelle formation. Examples are shown to highlight the potential usefulness of this type of interconnected system. In one case the release of a gel entrapped dye is modulated by the presence of SDS and sodium chloride. In another example, an intricate system that responds to a temperature excursion by irreversible micelle disassembly is shown. PMID- 23805837 TI - Contribution of nucleosome binding preferences and co-occurring DNA sequences to transcription factor binding. AB - BACKGROUND: Chromatin plays a critical role in regulating transcription factors (TFs) binding to their canonical transcription factor binding sites (TFBS). Recent studies in vertebrates show that many TFs preferentially bind to genomic regions that are well bound by nucleosomes in vitro. Co-occurring secondary motifs sometimes correlated with functional TFBS. RESULTS: We used a logistic regression to evaluate how well the propensity for nucleosome binding and co occurrence of a secondary motif identify which canonical motifs are bound in vivo. We used ChIP-seq data for three transcription factors binding to their canonical motifs: c-Jun binding the AP-1 motif (TGA(C)/(G)TCA), GR (glucocorticoid receptor) binding the GR motif (G-ACA---(T)/(C)GT-C), and Hoxa2 (homeobox a2) binding the Pbx (Pre-B-cell leukemia homeobox) motif (TGATTGAT). For all canonical TFBS in the mouse genome, we calculated intrinsic nucleosome occupancy scores (INOS) for its surrounding 150-bps DNA and examined the relationship with in vivo TF binding. In mouse mammary 3134 cells, c-Jun and GR proteins preferentially bound regions calculated to be well-bound by nucleosomes in vitro with the canonical AP-1 and GR motifs themselves contributing to the high INOS. Functional GR motifs are enriched for AP-1 motifs if they are within a nucleosome-sized 150-bps region. GR and Hoxa2 also bind motifs with low INOS, perhaps indicating a different mechanism of action. CONCLUSION: Our analysis quantified the contribution of INOS and co-occurring sequence to the identification of functional canonical motifs in the genome. This analysis revealed an inherent competition between some TFs and nucleosomes for binding canonical TFBS. GR and c-Jun cooperate if they are within 150-bps. Binding of Hoxa2 and a fraction of GR to motifs with low INOS values suggesting they are not in competition with nucleosomes and may function using different mechanisms. PMID- 23805839 TI - An antioxidant role for catecholate siderophores in Salmonella. AB - Iron acquisition is an important aspect of the host-pathogen interaction. In the case of Salmonella it is established that catecholate siderophores are important for full virulence. In view of their very high affinity for ferric iron, functional studies of siderophores have been almost exclusively focused on their role in acquisition of iron from the host. In the present study, we investigated whether the siderophores (enterobactin and salmochelin) produced by Salmonella enterica sv. Typhimurium could act as antioxidants and protect from the oxidative stress encountered after macrophage invasion. Our results show that the ability to produce siderophores enhanced the survival of Salmonella in the macrophage mainly at the early stages of infection, coincident with the oxidative burst. Using siderophore biosynthetic and siderophore receptor mutants we demonstrated that salmochelin and enterobactin protect S. Typhimurium against ROS (reactive oxygen species) in vitro and that siderophores must be intracellular to confer full protection. We also investigated whether other chemically distinct siderophores (yersiniabactin and aerobactin) or the monomeric catechol 2,3 dihydroxybenzoate could provide protection against oxidative stress and found that only catecholate siderophores have this property. Collectively, the results of the present study identify additional functions for siderophores during host pathogen interactions. PMID- 23805838 TI - Exon skipping as a therapeutic strategy applied to an RYR1 mutation with pseudo exon inclusion causing a severe core myopathy. AB - Central core disease is a myopathy often arising from mutations in the type 1 ryanodine receptor (RYR1) gene, encoding the sarcoplasmic reticulum calcium release channel RyR1. No treatment is currently available for this disease. We studied the pathological situation of a severely affected child with two recessive mutations, which resulted in a massive reduction in the amount of RyR1. The paternal mutation induced the inclusion of a new in-frame pseudo-exon in RyR1 mRNA that resulted in the insertion of additional amino acids leading to the instability of the protein. We hypothesized that skipping this additional exon would be sufficient to restore RyR1 expression and to normalize calcium releases. We therefore developed U7-AON lentiviral vectors to force exon skipping on affected primary muscle cells. The efficiency of the exon skipping was evaluated at the mRNA level, at the protein level, and at the functional level using calcium imaging. In these affected cells, we observed a decreased inclusion of the pseudo-exon, an increased RyR1 protein expression, and a restoration of calcium releases of normal amplitude either upon direct RyR1 stimulation or in response to membrane depolarization. This study is the first demonstration of the potential of exon-skipping strategy for the therapy of central core disease, from the molecular to the functional level. PMID- 23805840 TI - Quantification of colloid retention and release by straining and energy minima in variably saturated porous media. AB - The prediction of colloid transport in unsaturated porous media in the presence of large energy barrier is hampered by scant information of the proportional retention by straining and attractive interactions at surface energy minima. This study aims to fill this gap by performing saturated and unsaturated column experiments in which colloid pulses were added at various ionic strengths (ISs) from 0.1 to 50 mM. Subsequent flushing with deionized water released colloids held at the secondary minimum. Next, destruction of the column freed colloids held by straining. Colloids not recovered at the end of the experiment were quantified as retained at the primary minimum. Results showed that net colloid retention increased with IS and was independent of saturation degree under identical IS and Darcian velocity. Attachment rates were greater in unsaturated columns, despite an over 3-fold increase in pore water velocity relative to saturated columns, because additional retention at the readily available air associated interfaces (e.g., the air-water-solid [AWS] interfaces) is highly efficient. Complementary visual data showed heavy retention at the AWS interfaces. Retention by secondary minima ranged between 8% and 46% as IS increased, and was greater for saturated conditions. Straining accounted for an average of 57% of the retained colloids with insignificant differences among the treatments. Finally, retention by primary minima ranged between 14% and 35% with increasing IS, and was greater for unsaturated conditions due to capillary pinning. PMID- 23805842 TI - Structure- and ligand-based drug design of novel p38-alpha MAPK inhibitors in the fight against the Alzheimer's disease. AB - Alzheimer's disease (AD) is characterized microscopically by the presence of amyloid plaques, which are accumulations of beta-amyloid protein inter-neurons, and neurofibrillary tangles formed predominantly by highly phosphorylated forms of the microtubule-associated protein, tau, which form tangled masses that consume neuronal cell body, possibly leading to neuronal dysfunction and ultimately death. p38alpha mitogen-activated protein kinase (MAPK) has been implicated in both events associated with AD, tau phosphorylation and inflammation. p38alpha MAPK pathway is activated by a dual phosphorylation at Thr180 and Tyr182 residues. Drug design of p38alpha MAPK inhibitors is mainly focused on small molecules that compete for Adenosine triphosphate in the catalytic site. Here, we used different approaches of structure- and ligand-based drug design and medicinal chemistry strategies based on a selected p38alpha MAPK structure deposited in the Protein Data Bank in complex with inhibitor, as well as others reported in literature. As a result of the virtual screening experiments performed here, as well as molecular dynamics, molecular interaction fields studies, shape and electrostatic similarities, activity and toxicity predictions, and pharmacokinetic and physicochemical properties, we have selected 13 compounds that meet the criteria of low or no toxicity potential, good pharmacotherapeutic profile, predicted activities, and calculated values comparable with those obtained for the reference compounds, while maintaining the main interactions observed for the most potent inhibitors. PMID- 23805843 TI - Targeting imported malaria through social networks: a potential strategy for malaria elimination in Swaziland. AB - BACKGROUND: Swaziland has made great progress towards its goal of malaria elimination by 2015. However, malaria importation from neighbouring high-endemic Mozambique through Swaziland's eastern border remains a major factor that could prevent elimination from being achieved. In order to reach elimination, Swaziland must rapidly identify and treat imported malaria cases before onward transmission occurs. METHODS: A nationwide formative assessment was conducted over eight weeks to determine if the imported cases of malaria identified by the Swaziland National Malaria Control Programme could be linked to broader social networks and to explore methods to access these networks. RESULTS: Using a structured format, interviews were carried out with malaria surveillance agents (6), health providers (10), previously identified imported malaria cases (19) and people belonging to the networks identified through these interviews (25). Most imported malaria cases were Mozambicans (63%, 12/19) making a living in Swaziland and sustaining their families in Mozambique. The majority of imported cases (73%, 14/19) were labourers and self-employed contractors who travelled frequently to Mozambique to visit their families and conduct business. Social networks of imported cases with similar travel patterns were identified through these interviews. Nearly all imported cases (89%, 17/19) were willing to share contact information to enable network members to be interviewed. Interviews of network members and key informants revealed common congregation points, such as the urban market places in Manzini and Malkerns, as well as certain bus stations, where people with similar travel patterns and malaria risk behaviours could be located and tested for malaria. CONCLUSION: This study demonstrated that imported cases of malaria belonged to networks of people with similar travel patterns. This study may provide novel methods for screening high-risk groups of travellers using both snowball sampling and time-location sampling of networks to identify and treat additional malaria cases. Implementation of a proactive screening programme of importation networks may help Swaziland halt transmission and achieve malaria elimination by 2015. PMID- 23805844 TI - A metallofullerene electron donor that powers an efficient spin flip in a linear electron donor-acceptor conjugate. AB - The dream target of artificial photosynthesis is the realization of long-lived radical ion pair states that power catalytic centers and, consequently, the production of solar fuels. Notably, magnetic field effects, especially internal magnetic field effects, are rarely employed in this context. Here, we report on a linear Lu3N@Ih-C80-PDI electron donor-acceptor conjugate, in which the presence of the Lu3N cluster exerts an appreciable electron nuclear hyperfine coupling on the charge transfer dynamics. As such, a fairly efficient radical ion pair intersystem crossing converts the initially formed singlet radical ion pair state, (1)[(Lu3N@Ih-C80)(*+)-PDI(*-)], to the corresponding triplet radical ion pair state, (3)[(Lu3N@Ih-C80)(*+)-PDI(*-)]. Most notably, the radical ion pair state lifetime of the latter is nearly 1000 times longer than that of the former. PMID- 23805845 TI - Experimental and computational exploration of ground and excited state properties of highly strained ruthenium terpyridine complexes. AB - Dissociative electron transfer reactions are prevalent in one-electron reduced aryl halides; however, calculations applied to charge-transfer excited states of metal complexes suggest that this reaction would be strongly endergonic unless attention is paid to specific structural details. In this current study, we explore the effect of introducing intramolecular strain into a series of halogenated ruthenium(II) polypyridyls. Parent [Ru(tpy)2](2+) (1) (tpy = 2,2':6',2"-terpyridine) is compared with two complexes, [Ru(6,6"-Br2 tpy)(tpy)](2+) (2) and [Ru(6,6"-Br2-tpy)2](2+) (3) (6,6"-Br2-tpy = 6,6"-dibromo tpy) that incorporate interligand van der Waals strain derived from the large halogen substituents. DFT calculations and the crystal structure of 3 show how this strain distorts the geometry of 3 as compared to 1. Time-dependent DFT calculations are used to explain the effect of this strain on electronic absorption spectra where, in particular, a transition observed in 3 is attenuated in 2 and absent in 1 and heralds interligand charge transfer mediated by the halogen substituent. Ultrafast transient absorption spectroscopy reveals coherent vibrational dynamics particularly in 3 but also in 2 that is interpreted as reflecting heavy-atom motion. Surprisingly, in spite of the additional strain, the excited-state lifetime of 3 is observed to be approximately a factor of 6 longer than 2. Constrained-DFT calculations show that while the excited behavior of 2 is similar to 1, the strain-induced geometric distortions in 3 cause a nesting of excited state triplet surfaces resulting in a longer excited state lifetime. This may afford the additional time needed to engage in photochemistry, and kinetic evidence is observed for the breaking of a C-Br bond in 3 and formation of a contact ion pair state. PMID- 23805847 TI - Death in the field: teaching paramedics to deliver effective death notifications using the educational intervention "GRIEV_ING". AB - INTRODUCTION: Emergency medical services (EMS) personnel are rarely trained in death notification despite frequently terminating resuscitation in the field. As research continues to validate guidelines for the termination of resuscitation (TOR) and reputable organizations such as NAEMSP lend support to such protocols, death notification in the field will continue to increase. We sought to test the hypothesis that a learning module, GRIEV_ING, which teaches a structured method for death notification, will improve the confidence, competency, and communication skills of EMS personnel in death notification. METHODS: The GRIEV_ING didactic session consisted of a 90-minute education session composed of a didactic lecture, small group breakout session, and role-plays. This was both preceded and followed by a 15-minute case role-play using trained standardized survivors. To assess performance we used a pre-post design with 3 quantitative measures: confidence, competency, and, communication. Paramedics from the local EMS agency participated in the education as a part of continuing education. Pre post differences were measured using a paired t-test and McNemar's test. RESULTS: Thirty EMS personnel consented and participated. Confidence and competency demonstrated statistically significant improvements: confidence (percent change in scores = 11.4%, p < 0.0001) and competency (percent change in scores = 13.9%, p = 0.0001). Communication skill scores were relatively unchanged in pre-post test analysis (percent change in scores = 0.4, p = 0.9). CONCLUSION: This study demonstrated that educating paramedics to use a structured communication model based on the GRIEV_ING mnemonic improved confidence and competence of EMS personnel delivering death notification. PMID- 23805846 TI - Alzheimer's amyloid-beta oligomers rescue cellular prion protein induced tau reduction via the Fyn pathway. AB - Amyloid-beta (Abeta) and tau are the pathogenic hallmarks in Alzheimer's disease (AD). Abeta oligomers are considered the actual toxic entities, and the toxicity relies on the presence of tau. Recently, Abeta oligomers have been shown to specifically interact with cellular prion protein (PrP(C)) where the role of PrP(C) in AD is still not fully understood. To investigate the downstream mechanism of PrP(C) and Abeta oligomer interaction and their possible relationships to tau, we examined tau expression in human neuroblastoma BE(2)-C cells transfected with murine PrP(C) and studied the effect under Abeta oligomer treatment. By Western blotting, we found that PrP(C) overexpression down regulated tau protein and Abeta oligomer binding alleviated the tau reduction induced by wild type but not M128V PrP(C), the high AD risk polymorphic allele in human prion gene. PrP(C) lacking the Abeta oligomer binding site was incapable of rescuing the level of tau reduction. Quantitative RT-PCR showed the PrP(C) effect was attributed to tau reduction at the transcription level. Treatment with Fyn pathway inhibitors, Fyn kinase inhibitor PP2 and MEK inhibitor U0126, reversed the PrP(C)-induced tau reduction and Abeta oligomer treatment modulated Fyn kinase activity. The results suggested Fyn pathway regulated Abeta-PrP(C)-tau signaling. Overall, our results demonstrated that PrP(C) down-regulated tau via the Fyn pathway and the effect can be regulated by Abeta oligomers. Our study facilitated the understanding of molecular mechanisms among PrP(C), tau, and Abeta oligomers. PMID- 23805848 TI - Synthesis of sulfonated oxindoles by potassium iodide catalyzed arylsulfonylation of activated alkenes with sulfonylhydrazides in water. AB - A catalytic system consisting of KI, 18-crown-6, and TBHP for arylsulfonylation of activated alkenes with sulfonylhydrazides as sulfonyl precursor is described. This protocol provides a practical and environmentally benign method for the construction of sulfonated oxindoles in water. PMID- 23805849 TI - Energy-pollution nexus for urban buildings. PMID- 23805850 TI - Food load manipulation ability shapes flight morphology in females of central place foraging Hymenoptera. AB - BACKGROUND: Ecological constraints related to foraging are expected to affect the evolution of morphological traits relevant to food capture, manipulation and transport. Females of central-place foraging Hymenoptera vary in their food load manipulation ability. Bees and social wasps modulate the amount of food taken per foraging trip (in terms of e.g. number of pollen grains or parts of prey), while solitary wasps carry exclusively entire prey items. We hypothesized that the foraging constraints acting on females of the latter species, imposed by the upper limit to the load size they are able to transport in flight, should promote the evolution of a greater load-lifting capacity and manoeuvrability, specifically in terms of greater flight muscle to body mass ratio and lower wing loading. RESULTS: Our comparative study of 28 species confirms that, accounting for shared ancestry, female flight muscle ratio was significantly higher and wing loading lower in species taking entire prey compared to those that are able to modulate load size. Body mass had no effect on flight muscle ratio, though it strongly and negatively co-varied with wing loading. Across species, flight muscle ratio and wing loading were negatively correlated, suggesting coevolution of these traits. CONCLUSIONS: Natural selection has led to the coevolution of resource load manipulation ability and morphological traits affecting flying ability with additional loads in females of central-place foraging Hymenoptera. Release from load-carrying constraints related to foraging, which took place with the evolution of food load manipulation ability, has selected against the maintenance of a powerful flight apparatus. This could be the case since investment in flight muscles may have to be traded against other life-history traits, such as reproductive investment. PMID- 23805852 TI - Rapid determination of silver in nanobased liquid dietary supplements using a portable X-ray fluorescence analyzer. AB - This paper reports a rapid and straightforward method for the quantitation of total Ag content in nanobased commercially available liquid dietary supplements using a portable X-ray fluorescence (pXRF) analyzer. Figures of merits were evaluated by analyzing a series of AgNO3 standards. This method was shown to have a detection limit of 3 ppm, a quantitation limit of 10 ppm, and a broad linear range from the detection limit to 10000 ppm (1%). Accurate detection and quantitation of Ag content in well-characterized Ag nanoparticle samples and in nanobased liquid dietary supplements were achieved with good correlation (i.e., percentage difference average values under 15%) between the total Ag concentration obtained by the pXRF analyzer and by inductively coupled plasma mass spectrometry (ICP-MS). Furthermore, accurate quantitation of Ag in the presence of high concentrations of potential spectral interferences was also demonstrated. PMID- 23805853 TI - Trend analysis of the pharmaceutical market in Iran; 1997-2010; policy implications for developing countries. AB - BACKGROUND: So far, no detailed study of the Iranian pharmaceutical market has been conducted, and only a few studies have analyzed medicine consumption and expenditure in Iran. Pharmaceutical market trend analysis remains one of the most useful instruments to evaluate the pharmaceutical systems efficiency. An increase in imports of medicines, and a simultaneous decrease in domestic production prompted us to investigate the pharmaceutical expenditure structure. On the other hand, analyzing statistics provides a suitable method to assess the outcomes of national pharmaceutical policies and regulations. METHODS: This is a descriptive and cross-sectional study which investigates the Iranian pharmaceutical market over a 13-year period (1997-2010). This study used the Iranian pharmaceutical statistical datasheet published by the Iranian Ministry of Health. Systematic searches of the relevant Persian and English research literature were made. In addition, official government documents were analyzed as sources of both data and detailed statements of policy. RESULTS: Analysis of the Iranian pharmaceutical market in the 13-year period shows that medicine consumption sales value growth has been 28.38% annually. Determination of domestic production and import reveals that 9.3% and 42.3% annual growth, respectively, have been experienced. CONCLUSIONS: The Iranian pharmaceutical market has undergone great growth in comparison with developing countries and the pharmerging group, and the market is expanding quickly while a major share goes to biotechnology drugs, which implies the need to commercialization activities in novel fields like pharmaceutical biotechnology. This market expansion has been in favor of imported medicine in sales terms, caused by the reinforcement of suspicious policies of policy makers that necessitates fundamental rearrangements. PMID- 23805851 TI - Alcoholism causes alveolar macrophage zinc deficiency and immune dysfunction. AB - RATIONALE: Alcohol use disorders cause oxidative stress in the lower airways and increase susceptibility to pneumonia and lung injury. Currently, no therapeutic options exist to mitigate the pulmonary consequences of alcoholism. OBJECTIVES: We recently determined in an animal model that alcohol ingestion impairs pulmonary zinc metabolism and causes alveolar macrophage immune dysfunction. The objective of this research is to determine the effects of alcoholism on zinc bioavailability and alveolar macrophage function in human subjects. METHODS: We recruited otherwise healthy alcoholics (n = 17) and matched control subjects (n = 17) who underwent bronchoscopy for isolation of alveolar macrophages, which were analyzed for intracellular zinc, phagocytic function, and surface expression of granulocyte-macrophage colony-stimulating factor receptor; all three of these indices are decreased in experimental models. MEASUREMENTS AND MAIN RESULTS: Alcoholic subjects had normal serum zinc, but significantly decreased alveolar macrophage intracellular zinc levels (adjusted means [SE], 718 [41] vs. 948 [25] RFU/cell; P < 0.0001); bacterial phagocytosis (adjusted means [SE], 1,027 [48] vs. 1,509 [76] RFU/cell; P < 0.0001); and expression of granulocyte-macrophage colony-stimulating factor receptor beta subunit (adjusted means [SE], 1,471 [42] vs. 2,114 [35] RFU/cell; P < 0.0001]. Treating alveolar macrophages with zinc acetate and glutathione in vitro increased intracellular zinc levels and improved their phagocytic function. CONCLUSIONS: These novel clinical findings provide evidence that alcohol abuse is associated with significant zinc deficiency and immune dysfunction within the alveolar space and suggest that dietary supplementation with zinc and glutathione precursors could enhance airway innate immunity and decrease the risk for pneumonia or lung injury in these vulnerable individuals. PMID- 23805854 TI - A conifer genome spruces up plant phylogenomics. AB - The Norway spruce genome provides key insights into the evolution of plant genomes, leading to testable new hypotheses about conifer, gymnosperm, and vascular plant evolution. PMID- 23805855 TI - Human freezing in response to affective films. AB - Human freezing has been objectively assessed using a passive picture viewing paradigm as an analog for threat. These results should be replicated for other stimuli in order to determine their stability and generalizability. Affective films are used frequently to elicit affective responses, but it is unknown whether they also elicit freezing-like defense responses. To test whether this is the case, 50 participants watched neutral, pleasant and unpleasant film fragments while standing on a stabilometric platform and wearing a polar band to assess heart rate. Freezing-like responses (indicated by overall reduced body sway and heart rate deceleration) were observed for the unpleasant film only. The unpleasant film also elicited early reduced body sway (1-2 s after stimulus onset). Heart rate and body sway were correlated during the unpleasant film only. The results suggest that ecologically valid stimuli like films are adequate stimuli in evoking defense responses. The results also underscore the importance of including time courses in human experimental research on defense reactions in order to delineate different stages in the defense response. PMID- 23805856 TI - Comparative nontargeted profiling of metabolic changes in tissues and biofluids in high-fat diet-fed Ossabaw pig. AB - Typical clinical biomarker analyses on urine and plasma samples from human dietary interventions do not provide adequate information about diet-induced metabolic changes taking place in tissues. The aim of this study was to show how a large-scale nontargeted metabolomic approach can be used to reveal metabolite groups for generating new hypotheses of obesity-related metabolic disturbances produced in an animal model. A large spectrum of metabolites in the semipolar region, including small water-soluble molecules like betaine and dihydroxyindole, and a wide range of bile acids as well as various lipid species were detected. The high-fat diet influenced metabolic homeostasis of Ossabaw pigs, especially the lipid metabolome, throughout all the analyzed sample types, including plasma, urine, bile, liver, pancreas, brain cortex, intestinal jejunum and proximal colon. However, even dramatic metabolic changes in tissues were not necessarily observed in plasma and urine. Metabolite profiling involving multiple sample types was shown to be a feasible method for the examination of a wide spectrum of metabolic species extending from small water-soluble metabolites to an array of bile acids and lipids, thus pointing to the pathways of metabolism affected by the dietary treatment. PMID- 23805857 TI - Monodisperse polymeric ionic liquid microgel beads with multiple chemically switchable functionalities. AB - We present simple, inexpensive microfluidics-based fabrication of highly monodisperse poly(ionic liquid) microgel beads with a multitude of functionalities that can be chemically switched in facile fashion by anion exchange and further enhanced by molecular inclusion. Specifically, we show how the exquisite control over bead size and shape enables extremely precise, quantitative measurements of anion- and solvent-induced volume transitions in these materials, a crucial feature driving several important applications. Next, by exchanging diverse anions into the synthesized microgel beads, we demonstrate stimuli responsiveness and a multitude of novel functionalities including redox response, controlled release of chemical payloads, magnetization, toxic metal removal from water, and robust, reversible pH sensing. These chemically switchable stimulus-responsive beads are envisioned to open up a vast array of potential applications in portable and preparative chemical analysis, separations and spatially addressed sensing. PMID- 23805858 TI - HHT diagnosis by Mid-infrared spectroscopy and artificial neural network analysis. AB - BACKGROUND: The vascular disorder Hereditary Hemorrhagic Telangiectasia (HHT) is in general an inherited disease caused by mutations in the TGF-beta/BMP receptors endoglin or ALK1 or in rare cases by mutations of the TGF-beta signal transducer protein Smad4 leading to the combined syndrome of juvenile polyposis and HHT. HHT is characterized by several clinical symptoms like spontaneous and recurrent epistaxis, multiple telangiectases at sites like lips, oral cavity, fingers, nose, and visceral lesions like gastrointestinal telangiectasia, pulmonary, hepatic, cerebral or spinal arteriovenous malformations. The disease shows an inter- and intra-family variability in penetrance as well as symptoms from mild to life threatening. Penetrance is also depending on age. Diagnosis of the disease is based on the presence of some of the listed symptoms or by genetic testing. HHT diagnosis is laborious, time consuming, costly and sometimes uncertain. Not all typical symptoms may be present, especially at a younger age, and genetic testing does not always identify the disease causing mutation. METHODS: Infrared (IR) spectroscopy was investigated as a potential alternative to the current diagnostic methods. IR-spectra were obtained by Fourier-transform Mid-IR spectroscopy from blood plasma from HHT patients and a healthy control group. Spectral data were mathematically processed and subsequently classified and analysed by artificial neural network (ANN) analyses and by visual analysis of scatter plots of the dominant principal components. RESULTS: The analyses showed that for HHT a disease specific IR-spectrum exists that is significantly different from the control group. Furthermore, at the current stage with the here used methods, HHT can be diagnosed by Mid-IR-spectroscopy in combination with ANN analysis with a sensitivity and specificity of at least 95%. Visual analysis of PCA scatter plots revealed an inter class variation of the HHT group. CONCLUSION: IR-spectroscopy in combination with ANN analysis can be considered to be a serious alternative diagnostic method compared to clinical and genetically based methods. Blood plasma is an ideal candidate for diagnostic purposes, it is inexpensive, easy to isolate and only minimal amounts are required. In addition, IR-spectroscopy measurement times are fast, less than one minute, and diagnosis is not based on interpretation of may be uncertain clinical data. And last but not least, the method is inexpensive. PMID- 23805860 TI - Radiation rate enhancement in subwavelength plasmonic ring nanocavities. AB - We demonstrate 25 times radiation rate and 2 times quantum efficiency enhancement of Er ions in metal-insulator-metal (MIM) ring nanocavities at room temperature. In particular, using time-resolved photoluminescence spectroscopy in partnership with full-vector numerical simulations based on the finite difference time domain (FDTD) method, we design, fabricate, and systematically investigate the photonic density of states, the quantum efficiency, and the 1.55 MUm radiation dynamics of cavities with varying nanoscale active regions. Our experimental findings demonstrate that the engineering of deep subwavelength gap plasmon modes leads to dramatic Purcell enhancement even at modest cavity Q factors. Finally, we discuss the possibility of achieving lasing due to the enhancement of stimulated emission rate achievable in ring nanocavities, and we provide a perspective for Si compatible plasmon-enhanced nanolasers. PMID- 23805859 TI - Investigating the safety and efficacy of naltrexone for anti-psychotic induced weight gain in severe mental illness: study protocol of a double-blind, randomized, placebo-controlled trial. AB - BACKGROUND: Obesity is a growing health problem leading to high rates of mortality and morbidity in patients with severe mental illness (SMI). The increased rate of obesity is largely attributed to antipsychotic use. The effect of antipsychotic medications on H1 and 5HT2 receptors has been associated with weight gain, but there is also a substantial amount of evidence showing that D2 receptor blockade may be responsible for weight gain by interacting with the dopamine-opioid system. Unfortunately, current available medications for weight loss have limited efficacy in this population. Naltrexone, an opioid receptor antagonist, may be a promising agent to reduce antipsychotic induced weight gain by decreasing food cravings. We aim to investigate the safety and efficacy of two doses of naltrexone (25 mg & 50 mg) versus placebo for weight and health risk reduction in overweight and obese individuals (BMI >= 28) with SMI, who gained weight while being treated with antipsychotics. METHODS AND DESIGN: One hundred and forty four patients will be recruited throughout the greater New Haven area. The participants will be randomized to naltrexone 25 mg/day, naltrexone 50 mg/day, or placebo in a 1:1:1 ratio. Participants will be on the study medication for 52 weeks, and assessed weekly for the first 4 weeks and bi-weekly thereafter. The primary outcome measurements are weight reduction and percentage achieving clinically significant weight loss (5% of total body weight). Waist circumference, body mass index, serum lipid profile, fasting glucose, and glycosylated hemoglobin are the secondary outcome measures. The effect of naltrexone on other outcome measurements such as schizophrenia symptoms, depression, dietary consumption, quality of life, cognitive functioning, physical activity, metabolism/inflammation markers, serum leptin, ghrelin, peptide YY, adinopectin, high sensitivity CRP, interleukin 6, interleukin-1B, interleukin-18, and tumor necrosis factor alpha (TNF-alpha) will be evaluated. The data will be analyzed by applying linear mixed effect models. DISCUSSION: This is the first large scale study investigating the safety and efficacy of naltrexone in antipsychotic induced weight gain; and hopefully, this may lead to a novel pharmacological option for management of this major health problem. TRIAL REGISTRATION: This trial is registered in http://www.clinicaltrials.gov as NCT01866098. PMID- 23805862 TI - One site fits all? A student ward as a learning practice for interprofessional development. AB - Interprofessional training wards (IPTWs), aiming to enhance interprofessional collaboration, have been implemented in medical education and evaluated over the last decade. The Faculty of Health Sciences, Linkoping University has, in collaboration with the local health provider, arranged such training wards since 1996, involving students from the medical, nursing, physiotherapy, and occupational therapy programs. Working together across professional boundaries is seen as a necessity in the future to achieve sustainable and safe healthcare. Therefore, educators need to arrange learning contexts which enhance students' interprofessional learning. This article shows aspects of how the arrangement of an IPTW can influence the students' collaboration and learning. Data from open ended questions from a questionnaire survey, during autumn term 2010 and spring term 2011 at an IPTW, was analyzed qualitatively using a theoretical framework of practice theory. The theoretical lens gave a picture of how architectures of the IPTW create a clash between the "expected" professional responsibilities and the "unexpected" responsibilities of caring work. Also revealed was how the proximity between students opens up contexts for negotiations and boundary work. The value of using a theoretical framework of professional learning in practice within the frames of healthcare education is discussed. PMID- 23805861 TI - The duration of gastrin treatment affects global gene expression and molecular responses involved in ER stress and anti-apoptosis. AB - BACKGROUND: How cells decipher the duration of an external signal into different transcriptional outcomes is poorly understood. The hormone gastrin can promote a variety of cellular responses including proliferation, differentiation, migration and anti-apoptosis. While gastrin in normal concentrations has important physiological functions in the gastrointestine, prolonged high levels of gastrin (hypergastrinemia) is related to pathophysiological processes. RESULTS: We have used genome-wide microarray time series analysis and molecular studies to identify genes that are affected by the duration of gastrin treatment in adenocarcinoma cells. Among 403 genes differentially regulated in transiently (gastrin removed after 1 h) versus sustained (gastrin present for 14 h) treated cells, 259 genes upregulated by sustained gastrin treatment compared to untreated controls were expressed at lower levels in the transient mode. The difference was subtle for early genes like Junb and c-Fos, but substantial for delayed and late genes. Inhibition of protein synthesis by cycloheximide was used to distinguish between primary and secondary gastrin regulated genes. The majority of gastrin upregulated genes lower expressed in transiently treated cells were primary genes induced independently of de novo protein synthesis. This indicates that the duration effect of gastrin treatment is mainly mediated via post-translational signalling events, while a smaller fraction of the differentially expressed genes are regulated downstream of primary transcriptional events. Indeed, sustained gastrin treatment specifically induced prolonged ERK1/2 activation and elevated levels of the AP-1 subunit protein JUNB. Enrichment analyses of the differentially expressed genes suggested that endoplasmic reticulum (ER) stress and survival is affected by the duration of gastrin treatment. Sustained treatment exerted an anti-apoptotic effect on serum starvation-induced apoptosis via a PKC-dependent mechanism. In accordance with this, only sustained treatment induced anti-apoptotic genes like Clu, Selm and Mcl1, while the pro-apoptotic gene Casp2 was more highly expressed in transiently treated cells. Knockdown studies showed that JUNB is involved in sustained gastrin induced expression of the UPR/ER stress related genes Atf4, Herpud1 and Chac1. CONCLUSION: The duration of gastrin treatment affects both intracellular signalling mechanisms and gene expression, and ERK1/2 and AP-1 seem to play a role in converting different durations of gastrin treatment into distinct cellular responses. PMID- 23805863 TI - Interprofessional collaboration may pay off: introducing a collaborative approach in an orthopaedic ward. AB - Fast-track hip and knee surgery focuses on optimising pain management, achieving early mobilisation and shortening the length of stay in hospital. These factors make interprofessional collaboration imperative. With the aim of further diminishing the length of stay for patients admitted to an orthopaedic ward for hip or knee replacement and with inspiration from an interprofessional training unit, a daily interprofessional meeting was introduced. At this interprofessional meeting, surgeons, nurses, occupational therapists and physiotherapists used a checklist in discussing barriers and focus areas for discharging hip and knee replacement patients and made joint decisions about which healthcare profession should handle a given task. This interprofessional collaboration was tested in a case control study comparing hospital length of stay in 75 patients treated before introduction of the daily interprofessional meeting with 88 patients treated after the introduction. The result was a significant reduction in the length of stay in hospital in total hip replacement patients (from a mean of 4.1 days (SD 2.1) to 2.7 days (SD 1.4), p < 0.05) but not in knee replacement patients (from a mean of 3.7 days (SD 1.9) to 3.1 days (SD 1.6), p = 0.33). So improving interprofessional collaboration by introducing an interprofessional daily meeting may reduce the length of stay in hospital for total hip replacement patients, but further studies are needed to explore the effect in knee replacement patients. PMID- 23805864 TI - Daily oral ketamine for the treatment of depression and anxiety in patients receiving hospice care: a 28-day open-label proof-of-concept trial. AB - BACKGROUND: Depression and anxiety are prevalent and undertreated in patients receiving hospice care. Standard antidepressants do not work rapidly or often enough to benefit most of these patients. Ketamine has many properties that make it an interesting candidate for rapidly treating depression and anxiety in patients receiving hospice care. To test this hypothesis, a 28-day, open-label, proof-of-concept trial of daily oral ketamine administration was conducted in order to evaluate the tolerability, potential efficacy, and time to potential efficacy in treating depression and anxiety in patients receiving hospice care. METHODS: In this open-label study, 14 subjects with symptoms of depression or depression mixed with anxiety warranting psychopharmacological intervention received daily oral doses of ketamine hydrochloride (0.5 mg/kg) over a 28-day period. The primary outcome measure was the Hospital Anxiety and Depression Scale (HADS), which was used to rate overall depression and anxiety symptoms at baseline, and on days 3, 7, 14, 21, and 28. RESULTS: Over the 28-day trial there was significant improvement in both depressive symptoms (F5,35=8.03, p=0.002, eta(2)=0.534) and symptoms of anxiety (F5,35=14.275, p<0.001, eta(2)=0.67) for the eight subjects that completed the trial. One hundred percent of subjects completing the trial responded to ketamine for both anxiety and depression. A significant response in depressive symptoms occurred by day 14 for depression (mean Delta=3.5, d=1.14, 95% CI=1.09-5.9, p=0.01) and day 3 for anxiety (mean Delta=2.4, d=0.67, 95% CI=1.0-3.7, p=0.004). These improvements remained significant through day 28 for both depression (mean Delta=4.0, d=1.34, 95% CI=2.3-5.9, p=0.001) and anxiety (mean Delta=6.09, d=1.34, 95% CI=3.6-8.6, p<0.001). Side effects were rare, the most common being diarrhea, trouble sleeping, and trouble sitting still. CONCLUSIONS: Patients who received daily oral ketamine experienced a robust antidepressant and anxiolytic response with few adverse events. The response rate for depression is similar to those found with IV ketamine; however, the time to response is more protracted. The findings of the potential efficacy of oral ketamine for depression and the response of anxiety symptoms are novel. Further investigation with randomized, controlled clinical trials is necessary to firmly establish the efficacy and safety of oral ketamine for the treatment of depression and anxiety in patients receiving hospice care or other subject populations. PMID- 23805866 TI - Structural basis for phosphorylation-triggered autophagic clearance of Salmonella. AB - Selective autophagy is mediated by the interaction of autophagy modifiers and autophagy receptors that also bind to ubiquitinated cargo. Optineurin is an autophagy receptor that plays a role in the clearance of cytosolic Salmonella. The interaction between receptors and modifiers is often relatively weak, with typical values for the dissociation constant in the low micromolar range. The interaction of optineurin with autophagy modifiers is even weaker, but can be significantly enhanced through phosphorylation by the TBK1 {TANK [TRAF (tumour necrosis-factor-receptor-associated factor)-associated nuclear factor kappaB activator]-binding kinase 1}. In the present study we describe the NMR and crystal structures of the autophagy modifier LC3B (microtubule-associated protein light chain 3 beta) in complex with the LC3 interaction region of optineurin either phosphorylated or bearing phospho-mimicking mutations. The structures show that the negative charge induced by phosphorylation is recognized by the side chains of Arg11 and Lys51 in LC3B. Further mutational analysis suggests that the replacement of the canonical tryptophan residue side chain of autophagy receptors with the smaller phenylalanine side chain in optineurin significantly weakens its interaction with the autophagy modifier LC3B. Through phosphorylation of serine residues directly N-terminally located to the phenylalanine residue, the affinity is increased to the level normally seen for receptor-modifier interactions. Phosphorylation, therefore, acts as a switch for optineurin-based selective autophagy. PMID- 23805865 TI - Association between obesity and calcium:phosphorus ratio in the habitual diets of adults in a city of Northeastern Brazil: an epidemiological study. AB - BACKGROUND: Low calcium:phosphorus ratios (Ca:P ratio) in habitual diet have been observed worldwide, and it has been shown to be harmful to the bone health of the population. However, no study associating this ratio with obesity was found. Thus, considering that the intake of calcium and phosphorus will generate a ratio between them, which may be associated with obesity, this research seeks at evaluating the relation between obesity and the Ca:P ratio in the habitual diet of adults. METHODS: Cross-sectional population-based epidemiological study with stratified and systematic sampling. The sample was composed of 506 adults, aged between 18 and 60 years, of both genders. Information on socioeconomic and demographic conditions was obtained through questionnaires completed during home visits, where anthropometric and dietary evaluations were also conducted. RESULTS: In the habitual diet consumed by the study subjects, a Ca:P ratio above the median of 0.57 reduced the risk of central obesity based on waist-to-height ratio (WHtR) (OR: 0.61; 95% CI: 0.41 - 0.92). Habitual dietary intake of calcium (OR: 0.65; 95% CI: 0.43 - 0.97) and dairy products (OR: 0.56; 95% CI: 0.37 - 0.84) above the median value (485.4 mg and 0.9 servings, respectively) was found to be a protective factor related to central obesity based on WHtR. CONCLUSIONS: Values above the median for the Ca:P ratio found in the habitual diet were negatively associated with central obesity based on WHtR. In addition, calcium and dairy consumption were negatively associated with central obesity based on WHtR. Therefore, higher Ca:P ratios contributed to a lower prevalence of central obesity. PMID- 23805867 TI - Water cluster confinement and methane adsorption in the hydrophobic cavities of a fluorinated metal-organic framework. AB - Water cluster formation and methane adsorption within a hydrophobic porous metal organic framework is studied by in situ vibrational spectroscopy, adsorption isotherms, and first-principle DFT calculations (using vdW-DF). Specifically, the formation and stability of H2O clusters in the hydrophobic cavities of a fluorinated metal-organic framework (FMOF-1) is examined. Although the isotherms of water show no measurable uptake (see Yang et al. J. Am. Chem. Soc. 2011 , 133 , 18094 ), the large dipole of the water internal modes makes it possible to detect low water concentrations using IR spectroscopy in pores in the vicinity of the surface of the solid framework. The results indicate that, even in the low pressure regime (100 mTorr to 3 Torr), water molecules preferentially occupy the large cavities, in which hydrogen bonding and wall hydrophobicity foster water cluster formation. We identify the formation of pentameric water clusters at pressures lower than 3 Torr and larger clusters beyond that pressure. The binding energy of the water species to the walls is negligible, as suggested by DFT computational findings and corroborated by IR absorption data. Consequently, intermolecular hydrogen bonding dominates, enhancing water cluster stability as the size of the cluster increases. The formation of water clusters with negligible perturbation from the host may allow a quantitative comparison with experimental environmental studies on larger clusters that are in low concentrations in the atmosphere. The stability of the water clusters was studied as a function of pressure reduction and in the presence of methane gas. Methane adsorption isotherms for activated FMOF-1 attained volumetric adsorption capacities ranging from 67 V(STP)/V at 288 K and 31 bar to 133 V(STP)/V at 173 K and 5 bar, with an isosteric heat of adsorption of ca. 14 kJ/mol in the high temperature range (288-318 K). Overall, the experimental and computational data suggest high preferential uptake for methane gas relative to water vapor within FMOF-1 pores with ease of desorption and high framework stability under operative temperature and moisture conditions. PMID- 23805868 TI - Heterogeneous mercury oxidation on au(111) from first principles. AB - Density functional theory (DFT) studies of mercury oxidation on Au(111) are conducted to determine the potential Hg oxidation mechanisms taking place on catalytic gold surfaces by using the Perdew and Wang approximation (PW91) described by a generalized gradient approximation (GGA). The Hg oxidation was examined via a Langmuir-Hinshelwood mechanism where each Hg(0) and Cl2 (or HCl) species is separately adsorbed on the gold surface and the bimolecular reaction occurs through the formation of bound HgCl and HgCl2. For this, the Climbing Image-Nudged Elastic Band (CI-NEB) method has been employed to calculate the activation energies of HgCl and HgCl2 formation pathways. In the three-step Hg oxidation mechanism (Hg -> HgCl -> HgCl2), the second Cl attachment step is endothermic which is the reaction rate-limiting step, while the first Cl attachment step is exothermic. This observation implies that Hg oxidation prefers a pathway in which HgCl and HgCl2 are formed, rather than a pathway directly oxidizing Hg to HgCl2. In the presence of H atoms due to HCl dissociation on the Au surface, the H atoms lower the activation energy for Hg oxidation by consuming the electron charge of Au atoms, thereby weakening the strength of interaction between Cl and the Au surface and lowering an energy required to detach Cl from the Au surface. This mechanism is in the absence of site competition on the Au surface. In addition, details of the electronic properties of these systems are discussed. PMID- 23805869 TI - The feasibility of nurse practitioner-performed, telementored lung telesonography with remote physician guidance - 'a remote virtual mentor'. AB - BACKGROUND: Point-of-care ultrasound (POC-US) use is increasingly common as equipment costs decrease and availability increases. Despite the utility of POC US in trained hands, there are many situations wherein patients could benefit from the added safety of POC-US guidance, yet trained users are unavailable. We therefore hypothesized that currently available and economic 'off-the-shelf' technologies could facilitate remote mentoring of a nurse practitioner (NP) to assess for recurrent pneumothoraces (PTXs) after chest tube removal. METHODS: The simple remote telementored ultrasound system consisted of a handheld ultrasound machine, head-mounted video camera, microphone, and software on a laptop computer. The video output of the handheld ultrasound machine and a macroscopic view of the NP's hands were displayed to a remote trauma surgeon mentor. The mentor instructed the NP on probe position and US machine settings and provided real-time guidance and image interpretation via encrypted video conferencing software using an Internet service provider. Thirteen pleural exams after chest tube removal were conducted. RESULTS: Thirteen patients (26 lung fields) were examined. The remote exam was possible in all cases with good connectivity including one trans-Atlantic interpretation. Compared to the subsequent upright chest radiograph, there were 4 true-positive remotely diagnosed PTXs, 2 false negative diagnoses, and 20 true-negative diagnoses for 66% sensitivity, 100% specificity, and 92% accuracy for remotely guided chest examination. CONCLUSIONS: Remotely guiding a NP to perform thoracic ultrasound examinations after tube thoracostomy removal can be simply and effectively performed over encrypted commercial software using low-cost hardware. As informatics constantly improves, mentored remote examinations may further empower clinical care providers in austere settings. PMID- 23805870 TI - Photo-crosslinked poly(ethylene glycol)-b-poly(epsilon-caprolactone) nanoparticles for controllable paclitaxel release. AB - Novel biodegradable core-crosslinked nanoparticles (CNPs) consisting of methoxy poly(ethylene glycol)-block-poly(epsilon-caprolactone-co-gamma-cinnamoyloxy epsilon-caprolactone) (mPEG-b-P(CL-co-CCL)) were prepared and evaluated for paclitaxel (PTX) delivery. mPEG113-b-P(CL65.2-co-CCL10.1) had a higher drug loading efficiency (95%) compared to mPEG113-b-PCL93.1 (43%). The stability of NPs has been largely improved and PTX release was significantly inhibited by crosslinking via UV irradiation at lambda = 254 nm. MTT assays demonstrated that both blank non-crosslinked and crosslinked NPs showed low cytotoxicity to NCL H460 cells while PTX-loaded non-crosslinked and crosslinked NPs exhibited obvious cytotoxicity against NCL-H460 cells, and the cytotoxicity was both dose-dependent and time-dependent. Furthermore, after 48 h incubation the cell viability of PTX loaded crosslinked NPs was lower compared to that of PTX-loaded non-crosslinked NPs or free PTX. These properties indicated that CNPs prepared from mPEG-b-P(CL co-CCL) have great potentials as carriers for drug delivery. PMID- 23805871 TI - Paramedic myocardial infarction care with fibrinolytics: a process map and hazard analysis. AB - OBJECTIVES: Despite the supporting published evidence for prehospital fibrinolysis (PHF) for ST-elevation myocardial infarction (STEMI) patients by paramedics, the complexity of the process has not been rigorously explored in a stepwise approach. The objectives of this study were to (1) map the process of care that occurs during EMS management of STEMI with administration of PHF from 911 call to transfer of care to the emergency department and (2) to identify steps that could adversely affect patient safety or clinical outcome. METHODS: A Health Care Failure Mode and Effect Analysis was conducted. Steps were identified and organized into major call phases. Each step was categorized as a decision, technical skill, or task. The role required to perform each was identified: emergency medical dispatcher (EMD) or primary (PCP) or advanced care paramedic (ACP). The map was validated against a video-taped STEMI scenario. Once finalized, the steps with potential for risk to safety or outcome (hazard modes (HMs)) were identified. HMs were scored by study team consensus for probability to occur and likely severity of impact to the patient (minimum = 2, maximum = 16, >=8 considered high risk). RESULTS: The map consisted of 18 phases and 167 steps, of which 37 (22.2%) were decisions, 67 (40.1%) were technical skills, and 63 (37.7%) were tasks. Ten steps could be completed by an EMD (6.0%), 76 (45.5%) by a PCP, and 81 (48.5%) by an ACP. The phases with the most steps were initial treatment, n = 31 steps (18.0%), and reperfusion therapy, n = 30 steps (18.0%). Sixty-eight HMs were identified, mean score 4.54 (SD 2.32), five of which scored eight or above (7.3%). The highest scoring HMs were history-taking, obtaining 12 lead, and transmitting 12-lead (all scores = 12). The phases with the most HMs were initial treatment (n = 12 HMs) and reperfusion therapy (n = 12 HMs). CONCLUSIONS: In this mapping study of STEMI calls in which paramedics administer fibrinolytics, the process was found to be complex, containing many steps, but relatively few individual steps were highly hazardous to patient care or safety. This study has enabled specific actions to target the highest scoring hazard modes, in an effort to improve paramedic practice and patient safety for EMS STEMI patients. Key words: emergency medical services; myocardial infarction; fibrinolytic agents; ambulances; process map. PMID- 23805873 TI - Dehydration of isobutanol and the elimination of water from fuel alcohols. AB - Rate coefficients for the dehydration of isobutanol have been determined experimentally from comparative rate single pulse shock tube measurements and calculated via multistructural transition state theory (MS-TST). They are represented by the Arrhenius expression, k(isobutanol -> isobutene + H2O)(experimental) = 7.2 * 10(13) exp(-35300 K/T) s(-1). The theoretical work leads to the high pressure rate expression, k(isobutanol -> isobutene + H2O)(theory) = 3.5 * 10(13) exp(-35400 K/T) s(-1). Results are thus within a factor of 2 of each other. The experimental results cover the temperature range 1090-1240 K and pressure range 1.5-6 atm, with no discernible pressure effects. Analysis of these results, in combination with earlier single pulse shock tube work, made it possible to derive the governing factors that control the rate coefficients for alcohol dehydration in general. Alcohol dehydration rate constants depend on the location of the hydroxyl group (primary, secondary, and tertiary) and the number of available H-atoms adjacent to the OH group for water elimination. The position of the H-atoms in the hydrocarbon backbone appears to be unimportant except for highly substituted molecules. From these correlations, we have derived k(isopropanol -> propene + H2O) = 7.2 * 10(13) exp(-33000 K/T) s( 1). Comparison of experimental determination with theoretical calculations for this dehydration, and those for ethanol show deviations of the same magnitude as for isobutanol. Systematic differences between experiments and theoretical calculations are common. PMID- 23805872 TI - The first complete genome sequence of HCV-1a from Pakistan and a phylogenetic analysis with complete genomes from the rest of the world. AB - BACKGROUND: Here, we report the first patient derived hepatitis C virus (HCV) complete genome from Pakistan as is not available from this region of the world. FINDINGS: Comprehensive evolutionary and phylogenetic analyses were conducted. The comparison was made in order to identify evolutionary and molecular phylogenetic relationships among HCV strains belonging to genotype 1a. The evolutionary divergence analysis for nucleotide and amino acid sequences, conducted by equal input model, suggested that evolutionary nucleotide and amino acid distances showed that the HCV Pakistani strain was genetically far from Denmark strain (0.29400 nt, 0.819646 aa) and near to German strain (0.06557 nt, 0.139449 aa), respectively. CONCLUSION: The current study will help to understand phylogenetic relationship of circulating Pakistani isolates. PMID- 23805874 TI - Effect of oil droplets and their solid/liquid composition on the phase separation of protein-polysaccharide mixtures. AB - The phase separation of a model system consisting of sodium caseinate + xanthan +/- a low fraction (up to 3 wt %) of an oil-in-water emulsion was studied at room temperature (20-25 degrees C). The composition of the oil phase was either 100 wt % n-tetradecane (TD); 50% TD + 50% eicosane (EC) or 100% EC. The droplets in these three "emulsions" were therefore totally liquid, partially solid, and totally solid, respectively. In the presence of 22 mM CaCl2, the mixed TD+EC droplets were most effective at inhibiting phase separation, while the EC emulsions could not prevent phase separation at all. At 32 mM CaCl2 the emulsions tended to promote phase separation, possibly due to enhanced calcium ion-induced droplet aggregation. The apparent interfacial viscosity (etai) between two macroscopically separated phases was also measured. In the presence of the semisolid mixed droplets etai = 25 mN s m(-1), significantly higher than etai with the pure (liquid) TD droplets (15 mN s m(-1)) or with the pure solid EC droplets (12 mN s m(-1)) or in the absence of droplets (<3 mN s m(-1)). Confocal microscopy showed that the microstructure of the phase separating regions also depended upon the composition of the oil droplets, and it is tentatively suggested that the more marked effects of the mixed emulsion droplets were due to them forming a stronger network at the interface via partial coalescence. Control of the extent of interfacial aggregation of droplets is therefore possibly one way to influence the course of phase separation in biopolymer mixtures. PMID- 23805875 TI - IL-33-responsive innate lymphoid cells are an important source of IL-13 in chronic rhinosinusitis with nasal polyps. AB - RATIONALE: Chronic rhinosinusitis (CRS) without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP) are associated with Th1 and Th2 cytokine polarization, respectively; however, the pathophysiology of CRS remains unclear. The importance of innate lymphoid cells in Th2-mediated inflammatory disease has not been clearly defined. OBJECTIVES: The objective of this study was to investigate the role of the epithelial cell-derived cytokine IL-33 and IL-33-responsive innate lymphoid cells in the pathophysiology of CRS. METHODS: Relative gene expression was evaluated using quantitative real-time polymerase chain reaction. Innate lymphoid cells in inflamed ethmoid sinus mucosa from patients with CRSsNP and CRSwNP were characterized using flow cytometry. Cytokine production from lymphoid cells isolated from inflamed mucosa of patients with CRS was examined using ELISA and intracellular cytokine staining. MEASUREMENTS AND MAIN RESULTS: Elevated expression of ST2, the ligand-binding chain of the IL-33 receptor, was observed in inflamed sinonasal mucosa from CRSwNP compared with CRSsNP and healthy control subjects. An increased percentage of innate lymphoid cells was observed in inflamed sinonasal mucosa from CRSwNP compared with CRSsNP. ST2(+) innate lymphoid cells are a consistent source of IL-13 in response to IL-33 stimulation. Significant induction of IL-33 was observed in epithelial cells derived from patients with CRSwNP compared with patients with CRSsNP in response to stimulation with Aspergillus fumigatus extract. CONCLUSIONS: These data suggest a role for sinonasal epithelial cell-derived IL-33 and an IL-33-responsive innate lymphoid cell population in the pathophysiology of CRSwNP demonstrating the functional importance of innate lymphoid cells in Th2-mediated inflammatory disease. PMID- 23805877 TI - Immobilizing metal nanoparticles to metal-organic frameworks with size and location control for optimizing catalytic performance. AB - AuNi alloy nanoparticles were successfully immobilized to MIL-101 with size and location control for the first time by double solvents method (DSM) combined with a liquid-phase concentration-controlled reduction strategy. When an overwhelming reduction approach was employed, the uniform 3D distribution of the ultrafine AuNi nanoparticles (NPs) encapsulated in the pores of MIL-101 was achieved, as demonstrated by TEM and electron tomographic measurements, which brings light to new opportunities in the fabrication of ultrafine non-noble metal-based NPs throughout the interior pores of MOFs. The ultrafine AuNi alloy NPs inside the mesoporous MIL-101 exerted exceedingly high activity for hydrogen generation from the catalytic hydrolysis of ammonia borane. PMID- 23805876 TI - Gene regulatory networks in plants: learning causality from time and perturbation. AB - The goal of systems biology is to generate models for predicting how a system will react under untested conditions or in response to genetic perturbations. This paper discusses experimental and analytical approaches to deriving causal relationships in gene regulatory networks. PMID- 23805878 TI - Prevalence and consequences of subacute ruminal acidosis in German dairy herds. AB - BACKGROUND: The prevalence and the clinical consequences of subacute ruminal acidosis (SARA) in dairy cows are still poorly understood. In order to evaluate the prevalence of SARA, 26 German dairy farms were included in a field study. In each herd, between 11 and 14 lactating dairy cows were examined for their ruminal pH using rumenocentesis. Milk production data and farm management characteristics were recorded. Each farm was scored for lameness prevalence among lactating animals, and body condition score was recorded three times four to five weeks apart in all animals examined. Farms were grouped on basis of ruminal pH and compared for lameness, body condition, milk production parameters and style of management. Animals were grouped on basis of their measured ruminal pH and compared accordingly for milk production parameters and body condition score. RESULTS: Of 315 cows examined, 63 individuals (20%) exhibited a ruminal pH of <= 5.5 at time of rumenocentesis. Of 26 farms examined, eleven farms had three or more of their cows experiencing a ruminal pH of <= 5.5 and were classified as likely experiencing subacute ruminal acidosis. These farms tended to be bigger than the others and offered less lying space to the lactating cows. There was no clear tendency regarding lameness. Among individual cows, animals with a low ruminal pH of <= 5.5 were found to be in significantly poorer body condition than animals with higher pH values (p < 0,05). CONCLUSIONS: The study shows 11 out of 26 of herds likely experiencing SARA. Bigger herds tend to be at a higher risk for SARA, while individuals with low ruminal pH tend to be lower in body condition. The study points to the importance of management in preventing SARA. PMID- 23805879 TI - Deep-subwavelength plasmonic nanoresonators exploiting extreme coupling. AB - A metal-insulator-metal (MIM) waveguide is a canonical structure used in many functional plasmonic devices. Recently, research on nanoresonantors made from finite, that is, truncated, MIM waveguides attracted a considerable deal of interest motivated by the promise for many applications. However, most suggested nanoresonators do not reach a deep-subwavelength domain. With ordinary fabrication techniques the dielectric spacers usually remain fairly thick, that is, in the order of tens of nanometers. This prevents the wavevector of the guided surface plasmon polariton to strongly deviate from the light line. Here, we will show that the exploitation of an extreme coupling regime, which appears for only a few nanometers thick dielectric spacer, can lift this limitation. By taking advantage of atomic layer deposition we fabricated and characterized exemplarily deep-subwavelength perfect absorbers. Our results are fully supported by numerical simulations and analytical considerations. Our work provides impetus on many fields of nanoscience and will foster various applications in high-impact areas such as metamaterials, light harvesting, and sensing or the fabrication of quantum-plasmonic devices. PMID- 23805880 TI - The association between serum uric acid and diabetes mellitus is stronger in women. AB - OBJECTIVE: Previous studies have demonstrated an association between increased serum uric acid (SUA) levels and incident diabetes. Most clinical and epidemiological investigations, however, focused solely on male populations or did not analyze men and women separately. We assessed the association between SUA levels and diabetes incidence in a large cohort of apparently healthy men and women. METHODS: Data were retrospectively gathered from 9140 adults who participated in annual medical screening visits during 2000-2009. Mean follow-up time was 4.8 years, and the median age was 50 years. Laboratory test results, data from physical examinations, medical history, and lifestyle information were extracted. The main outcome measure was incident diabetes, defined as two consecutive fasting glucose tests higher than 125 mg/dL. Cox proportional-hazards multivariate models were applied for measuring hazard ratios (HRs) for diabetes according to continuous and categorical levels of uric acid. RESULTS: We identified 499 new cases of diabetes (total, 5.5%: men, 6.2%; women, 3.6%) during the follow-up period. The gender-specific HRs for diabetes, adjusted for age and a set of prespecified multiple risk and protective factors, were 1.57 for each 1 mg/dL increase in SUA (95% confidence interval [CI], 1.32-1.86) in women and 1.08 (95% CI, 0.99-1.17) in men; p for interaction of SUA by gender <0.001. CONCLUSION: SUA is independently associated with diabetes outcome, considerably more in women than in men. PMID- 23805882 TI - Thorium fluorides ThF, ThF2, ThF3, ThF4, ThF3(F2), and ThF5- characterized by infrared spectra in solid argon and electronic structure and vibrational frequency calculations. AB - Reactions of laser-ablated Th atoms with F2 produce ThF4 as the major product based on agreement with matrix spectra recorded of the vapor from the solid at 800-850 degrees C. Weaker higher-frequency bands at (567.2, 564.8), (575.9, 575.1), and (531.0, 528.4) cm(-1) in argon are assigned to ThF, ThF2 and ThF3, ThF3(F2) on the basis of their chemical behavior upon increasing reagent concentrations, annealing, and irradiation, the use of NF3, OF2, and HF as F-atom sources, and a comparison with frequencies calculated at the DFT/B3LYP and CCSD(T) levels with a large segmented + ECP basis set on Th and the aug-cc-pVTZ basis set on F. An additional broader band at 460 cm(-1) is assigned to the ThF5( ) anion. The trigonal-bipyramidal ThF5(-) anion (calculated electron detachment energy of 7.17 eV) increases at the expense of ThF3(F2) and F3(-) on full mercury arc irradiation. [ThF3(+)][F2(-)] is shown by calculations to be an ionic complex with a side-bound F2(-) subunit. This paper reports the first evidence for novel pentacoordinated thorium species including the unique [ThF3(+)][F2(-)] ionic radical-ion pair molecule and its electron-capture product, the very stable ThF5( ) anion. PMID- 23805881 TI - Social capital, health behaviours and health: a population-based associational study. AB - BACKGROUND: Social capital is associated with health behaviours and health. Our objective was to explore how different dimensions of social capital and health related behaviours are associated, and whether health behaviours mediate this association between social capital and self-rated health and psychological well being. METHODS: We used data from the Health 2000 Survey (n=8028) of the adult population in Finland. The response rate varied between 87% (interview) and 77% (the last self-administered questionnaire). Due to item non-response, missing values were replaced using multiple imputation. The associations between three dimensions of social capital (social support, social participation and networks, trust and reciprocity) and five health behaviours (smoking, alcohol use, physical activity, vegetable consumption, sleep) were examined by using logistic regression and controlling for age, gender, education, income and living arrangements. The possible mediating role of health behaviours in the association between social capital and self-rated health and psychological well-being was also analysed with a logistic regression model. RESULTS: Social participation and networks were associated with all of the health behaviours. High levels of trust and reciprocity were associated with non-smoking and adequate duration of sleep, and high levels of social support with adequate duration of sleep and daily consumption of vegetables. Social support and trust and reciprocity were independently associated with self-rated health and psychological well-being. Part of the association between social participation and networks and health was explained by physical activity. CONCLUSIONS: Irrespective of their social status, people with higher levels of social capital - especially in terms of social participation and networks - engage in healthier behaviours and feel healthier both physically and psychologically. PMID- 23805883 TI - Comparative evaluation of in vitro efficacy of colesevelam hydrochloride tablets. AB - CONTEXT: Colesevelam hydrochloride is used as an adjunct to diet and exercise to reduce elevated low-density lipoprotein (LDL) cholesterol in patients with primary hyperlipidemia as well as to improve glycemic control in patients with type 2 diabetes. This is likely to result in submission of abbreviated new drug applications (ANDA). OBJECTIVE: This study was conducted to compare the efficacy of two tablet products of colesevelam hydrochloride based on the in vitro binding of bile acid sodium salts of glycocholic acid (GC), glycochenodeoxycholic acid (GCDA) and taurodeoxycholic acid (TDCA). METHODS: Kinetic binding study was carried out with constant initial bile salt concentrations as a function of time. Equilibrium binding studies were conducted under conditions of constant incubation time and varying initial concentrations of bile acid sodium salts. The unbound concentration of bile salts was determined in the samples of these studies. Langmuir equation was utilized to calculate the binding constants k1 and k2. RESULTS: The amount of the three bile salts bound to both the products reached equilibrium at 3 h. The similarity factor (f2) was 99.5 based on the binding profile of total bile salts to the test and reference colesevelam tablets as a function of time. The 90% confidence interval for the test to reference ratio of k2 values were 96.06-112.07 which is within the acceptance criteria of 80-120%. CONCLUSION: It is concluded from the results that the test and reference tablets of colesevelam hydrochloride showed a similar in vitro binding profile and capacity to bile salts. PMID- 23805884 TI - Bifunctional silica nanoparticles for the exploration of biofilms of Pseudomonas aeruginosa. AB - Luminescent silica nanoparticles are frequently employed for biotechnology applications mainly because of their easy functionalization, photo-stability, and biocompatibility. Bifunctional silica nanoparticles (BSNPs) are described here as new efficient tools for investigating complex biological systems such as biofilms. Photoluminescence is brought about by the incorporation of a silylated ruthenium(II) complex. The surface properties of the silica particles were designed by reaction with amino-organosilanes, quaternary ammonium-organosilanes, carboxylate-organosilanes and hexamethyldisilazane. BSNPs were characterized extensively by DRIFT, (13)C and (29)Si solid state NMR, XPS, and photoluminescence. Zeta potential and contact angle measurements exhibited various surface properties (hydrophilic/hydrophobic balance and electric charge) according to the functional groups. Confocal laser scanning microscopy (CLSM) measurements showed that the spatial distribution of these nanoparticles inside a biofilm of Pseudomonas aeruginosa PAO1 depends more on their hydrophilic/hydrophobic characteristics than on their size. CLSM observations using two nanosized particles (25 and 68 nm) suggest that narrow diffusion paths exist through the extracellular polymeric substances matrix. PMID- 23805885 TI - Hierarchical level features based trainable segmentation for electron microscopy images. AB - BACKGROUND: The neuronal electron microscopy images segmentation is the basic and key step to efficiently build the 3D brain structure and connectivity for a better understanding of central neural system. However, due to the visual complex appearance of neuronal structures, it is challenging to automatically segment membranes from the EM images. METHODS: In this paper, we present a fast, efficient segmentation method for neuronal EM images that utilizes hierarchical level features based on supervised learning. Hierarchical level features are designed by combining pixel and superpixel information to describe the EM image. For pixels in a superpixel have similar characteristics, only part of them is automatically selected and used to reduce information redundancy. To each selected pixel, 34 dimensional features are extracted by traditional way. Each superpixel itself is viewed as a unit to extract 35 dimensional features with statistical method. Also, 3 dimensional context level features among multi superpixels are extracted. Above three kinds of features are combined as a feature vector, namely, hierarchical level features to use for segmentation. Random forest is used as classifier and is trained with hierarchical level features to perform segmentation. RESULTS: In small sample condition and with low dimensional features, the effectiveness of our method is verified on the data set of ISBI2012 EM Segmentation Challenge, and its rand error, warping error and pixel error attain to 0.106308715, 0.001200104 and 0.079132453, respectively. CONCLUSIONS: Comparing to pixel level or superpixel level features, hierarchical level features have better discrimination ability and the proposed method is promising for membrane segmentation. PMID- 23805887 TI - Synthesis of alpha,beta-unsaturated alpha'-haloketones through the chemoselective addition of halomethyllithiums to Weinreb amides. AB - A straightforward synthesis of variously functionalized alpha,beta-unsaturated alpha'-haloketones has been achieved through the chemoselective addition of halomethyllithium carbenoids to Weinreb amides at -78 degrees C. A comparative study employing the corresponding esters under the same reaction conditions pointed out that the instability of the tetrahedral intermediate formed from the latter is responsible for the observed formation of carbinols instead of the desired haloketones. PMID- 23805886 TI - Genetic variability of mutans streptococci revealed by wide whole-genome sequencing. AB - BACKGROUND: Mutans streptococci are a group of bacteria significantly contributing to tooth decay. Their genetic variability is however still not well understood. RESULTS: Genomes of 6 clinical S. mutans isolates of different origins, one isolate of S. sobrinus (DSM 20742) and one isolate of S. ratti (DSM 20564) were sequenced and comparatively analyzed. Genome alignment revealed a mosaic-like structure of genome arrangement. Genes related to pathogenicity are found to have high variations among the strains, whereas genes for oxidative stress resistance are well conserved, indicating the importance of this trait in the dental biofilm community. Analysis of genome-scale metabolic networks revealed significant differences in 42 pathways. A striking dissimilarity is the unique presence of two lactate oxidases in S. sobrinus DSM 20742, probably indicating an unusual capability of this strain in producing H2O2 and expanding its ecological niche. In addition, lactate oxidases may form with other enzymes a novel energetic pathway in S. sobrinus DSM 20742 that can remedy its deficiency in citrate utilization pathway.Using 67 S. mutans genomes currently available including the strains sequenced in this study, we estimates the theoretical core genome size of S. mutans, and performed modeling of S. mutans pan-genome by applying different fitting models. An "open" pan-genome was inferred. CONCLUSIONS: The comparative genome analyses revealed diversities in the mutans streptococci group, especially with respect to the virulence related genes and metabolic pathways. The results are helpful for better understanding the evolution and adaptive mechanisms of these oral pathogen microorganisms and for combating them. PMID- 23805888 TI - Secretome-based identification of TFPI2, a novel serum biomarker for detection of ovarian clear cell adenocarcinoma. AB - Of all of the epithelial ovarian cancers (EOC), clear cell adenocarcinoma (CCA) has the worst clinical prognosis. Furthermore, the conventional EOC biomarker CA125 is more often negative in CCA than in other subtypes of EOC. This study sought to discover a new diagnostic biomarker that would allow more reliable detection of CCA. Using mass spectrometry, we compared proteins in conditioned media from cell lines derived from CCA and other types of EOC. We identified 30 extracellular or released proteins specifically present in CCA-derived cell lines. Bioinformatics analyses identified a serine protease inhibitor, tissue factor pathway inhibitor 2 (TFPI2), as a potential biomarker for CCA. Real time RT-PCR and Western blot analyses revealed that TFPI2 was exclusively expressed in CCA-derived cell lines and tissues. For clinical validation, we measured levels of TFPI2 and CA125 in a set of sera from 30 healthy women, 30 patients with endometriosis, and 50 patients with CCA, using an automated enzyme-linked immunosorbent assay systems. Serum levels of TFPI2 were significantly elevated in CCA patients, even those with normal CA125 levels. In terms of area under the receiver operating characteristic curve (AUC), TFPI2 was superior to CA125 in discriminating CCA patients from healthy women (AUC 0.97 for TFPI2 versus AUC 0.80 for CA125), or from patients with endometriosis (AUC 0.93 for TFPI2 versus 0.80 for CA125). This is the first evidence for TFPI2 as a serum biomarker of CCA. We propose that this biomarker may be useful for detection of CCA and for monitoring the transformation from endometriosis into CCA. PMID- 23805889 TI - What do young people think makes their relationships good? Factors associated with assessments of dating relationships in South Africa. AB - Little is known about the factors and outcomes associated with young people's subjective relationship assessments. Understanding what young people think makes their relationships 'good' or 'bad' would give us insight into what is important to them in their relationships as well as their decision-making and behaviour within them. Self-report data from 757 girls (mean age = 17.09 years) and 642 boys (mean age = 17.23 years) were analysed using logistic regression. Relationship primacy was significantly associated with positive relationships for girls and boys. Among girls, partner education and open communication about sexual and reproductive health were additionally related to relationship assessments. Among boys, very little quarrelling was the only additional factor associated with positive relationship assessment. Although relationship assessment was not associated with depression or problem drinking for either girls or boys, drug use was less likely among both girls and boys who reported having a positive relationship. Boys in positive relationships were also more likely to have used a condom the last time they had sex with their main partner. Intervention programmes should equip teenagers with skills to develop and maintain positive relationships. PMID- 23805891 TI - Double trouble. PMID- 23805890 TI - The impact of prehospital continuous positive airway pressure on the rate of intubation and mortality from acute out-of-hospital respiratory emergencies. AB - BACKGROUND: Previous studies have demonstrated decreased rates of intubation and mortality with prehospital use of continuous positive airway pressure (CPAP). We sought to validate these findings in a larger observational study. METHODS: We conducted a before and after observational study of consecutive patients transported by emergency medical services (EMS) during the 12 months before and the 12 months following implementation of a prehospital CPAP protocol for acute respiratory distress. Included were all patients transported by EMS meeting preestablished criteria indicative of acute respiratory distress and CPAP use (patient's problem specified as cardiac, respiratory distress, respiratory disease, or congestive heart failure [CHF]; age >= 12 years; chest sounds documented as wheezes or rales; Glascow Coma Scale [GCS] >= 11; respiratory rate >= 24 breaths per minute; systolic blood pressure >= 90 mmHg; and oxygen saturation < 90%). Data were abstracted from ambulance call reports (ACRs) and hospital records. All cases in which "do not resuscitate" (DNR) was documented on the patient chart or ACR or whose in-hospital outcome (death or discharge) was unknown were excluded. RESULTS: In all, 442 patients met the above criteria. The mean (SD) age was 73.0 (13.9) years, and 51.5% were women. In-hospital mortality rates did not differ for these patients: 17/228 (7.5%) in the before group and 17/214 (7.9%) in the after group (p = 0.85). In-hospital intubation rates were similar for both groups (12.7 vs. 14.5%, p = 0.59). An analysis of the subgroup that had a hospital diagnosis of chronic obstructive pulmonary disease (COPD), CHF, or pulmonary edema (n = 273) showed mortality was somewhat lower in the before group (3/138, 2.2%) than in the after group (8/135, 5.9%) (p = 0.13). In hospital intubation rates were also similar for both groups in this subgroup analysis (11.6 vs. 9.6%, p = 0.61). CONCLUSION: In contrast to previous studies, we were unable to demonstrate a decrease in intubation or mortality related to the use of prehospital CPAP. Our findings may be specific to our EMS system but suggest that further large-scale, randomized, controlled trials may be warranted to firmly establish the benefit of prehospital CPAP. PMID- 23805892 TI - A novel interplay between the ubiquitin-proteasome system and serine proteases during Drosophila development. AB - The concentrations of the Drosophila proteasomal and extraproteasomal polyubiquitin receptors fluctuate in a developmentally regulated fashion. This fluctuation is generated by a previously unidentified proteolytic activity. In the present paper, we describe the purification, identification and characterization of this protease (endoproteinase I). Its expression increases sharply at the L1-L2 larval stages, remains high until the second half of the L3 stage, then declines dramatically. This sharp decrease coincides precisely with the increase of polyubiquitin receptor concentrations in late L3 larvae, which suggests a tight developmental co-regulation. RNAi-induced down-regulation of endoproteinase I results in pupal lethality. Interestingly, we found a cross-talk between the 26S proteasome and this larval protease: transgenic overexpression of the in vivo target of endoproteinase I, the C-terminal half of the proteasomal polyubiquitin receptor subunit p54/Rpn10 results in transcriptional down regulation of endoproteinase I and consequently a lower level of proteolytic elimination of the polyubiquitin receptors. Another larval protease, Jonah65A-IV, which degrades only unfolded proteins and exhibits similar cross-talk with the proteasome has also been purified and characterized. It may prevent the accumulation of polyubiquitylated proteins in larvae contrary to the low polyubiquitin receptor concentration. PMID- 23805893 TI - Cooperative roles of charge transfer and dispersion terms in hydrogen-bonded networks of (H2O)n, n = 6, 11, and 16. AB - The perturbation expansion based on the locally-projected molecular orbital (LPMO PT) was applied to the study of the hydrogen-bonded networks of water clusters with up to 16 molecules. Utilizing the local nature of the occupied and excited MOs on each monomer, the charge-transfer and dispersion terms are evaluated for every pair of molecules. The two terms are strongly correlated with each other for the hydrogen-bonded pairs. The strength of the hydrogen bonds in the clusters is further classified by the types of the hydrogen donor and acceptor water molecules. The relative energies evaluated with the LPMO PT among the isomers of (H2O)6, (H2O)11, and (H2O)16 agree very well with those obtained from CCSD(T) calculations with large basis sets. The binding energy of the LPMO PT is approximately free of the basis set superposition errors caused both by the orbital basis inconsistency and by the configuration basis inconsistency. PMID- 23805894 TI - Metal-organic-frameworks-derived general formation of hollow structures with high complexity. AB - Increasing the complexity of hollow structures, in terms of chemical composition and shell architecture, is highly desirable for both fundamental studies and realization of various functionalities. Starting with metal-organic frameworks (MOFs), we demonstrate a general approach toward the large-scale and facile synthesis of complex hollow microboxes via manipulation of the template-engaged reactions between the Prussian blue (PB) template and different alkaline substances. The reaction between PB microcubes with NaOH solution leads to the formation of Fe(OH)3 microboxes with controllable multishelled structure. In addition, PB microcubes will react with the conjugate bases of metal oxide based weak acids, generating multicompositional microboxes (Fe2O3/SnO2, Fe2O3/SiO2, Fe2O3/GeO2, Fe2O3/Al2O3, and Fe2O3/B2O3), which consist of uniformly dispersed oxides/hydroxides of iron and another designed element. Such complex hollow structures and atomically integrated multiple compositions might bring the usual physiochemical properties. As an example, we demonstrate that these complex hollow microboxes, especially the Fe2O3/SnO2 composite microboxes, exhibit remarkable electrochemical performance as anode materials for lithium ion batteries. PMID- 23805895 TI - Poly(azobenzene acrylate-co-fluorinated acrylate) spin-coated films: influence of the composition on the photo-controlled wettability. AB - The wetting properties of spin-coated films of copolymers based on azobenzene and fluorinated units have been investigated. The copolymers, denoted as poly(Azo-co AcRf6), have been synthesized by free-radical polymerization of different proportions of acrylate monomers bearing either an azobenzene group or a semifluorinated side chain. The UV-visible spectroscopy analysis of the different spin-coating films through a cycle of UV and visible light irradiation indicates the reversible trans-cis isomerization of azobenzene groups. Simultaneously, atomic force microscopy shows that surface roughness does not exceed 1 nm. Advancing and receding contact angles of water and diiodomethane have been measured before and after UV photoirradiation of the different surfaces. In particular, a decrease in the advancing contact angles has been observed upon trans-cis isomerization of azobenzene groups. Switching variations up to 50 degrees have been evidenced without any introduction of surface nanoroughness. Surface free-energy evaluations have been deduced from these measurements, including dispersive and polar components. The results show that, through surface composition and UV photoirradiation, a large range of surface free-energies can be obtained, from 7 to 46 mN.m(-1). PMID- 23805897 TI - Improved light harvesting and improved efficiency by insertion of an optical spacer (ZnO) in solution-processed small-molecule solar cells. AB - We demonstrate that the power conversion efficiency can be significantly improved in solution-processed small-molecule solar cells by tuning the thickness of the active layer and inserting an optical spacer (ZnO) between the active layer and the Al electrode. The enhancement in light absorption in the cell was measured with UV-vis absorption spectroscopy and by measurements of the photoinduced carriers generation rate. The ZnO layer used to improve the light-harvesting increases the charge collection efficiency, serves as a blocking layer for holes, and reduces the recombination rate. The combined optical and electrical improvements raise the power conversion efficiency of solution-processed small molecule solar cells to 8.9%, that is, comparable to that of polymer counterparts. PMID- 23805896 TI - The plant microbiome. AB - Plant genomes contribute to the structure and function of the plant microbiome, a key determinant of plant health and productivity. High-throughput technologies are revealing interactions between these complex communities and their hosts in unprecedented detail. PMID- 23805898 TI - Febrile neutropenia: significance of elaborated screening for respiratory viruses, and the comparison of different sampling methods, in neutropenic patients with hematological malignancies. AB - BACKGROUND: During febrile neutropenia in only 30 to 60 percent an infectious agent is identified. This diagnostic gap could hypothetically be reduced with the broad implementation of molecular detection techniques like PCR, which has revolutionized the detection of infectious diseases during the last two decades. FINDINGS: We performed a longitudinal prospective study (N = 81) of neutropenic patients to assess the role of respiratory viruses in neutropenic fever and to determine the clinical relevance of blind screening for these viruses. Respiratory viruses were recovered in 14% of the patients prior to neutropenia. In 13% of neutropenic patients without fever and in 19% of those with fever, a respiratory virus was detected. Comparing different sample types; nasal swabs performed significantly better (16/117 = 43%), than throat swabs (6/106 = 6%). Throat gurgles did not show significant differences from the latter sample types. CONCLUSIONS: Blind diagnostic screening for respiratory viruses before or during neutropenia is not useful. Nasal swabs are sensitive and practical option for screening on respiratory viruses. PMID- 23805901 TI - Green and facile synthesis of water-soluble Cu-In-S/ZnS core/shell quantum dots. AB - Water-soluble Cu-In-S/ZnS core/shell quantum dots with a photoluminescence quantum yield up to 38% and an emission peak tunable from 543 to 625 nm have been successfully synthesized. All of the synthetic procedures were conducted in an aqueous solution at 95 degrees C under open-air conditions. L-Glutathione and sodium citrate were used as the dual stabilizing agents to balance the reactivity between copper and indium ions. PMID- 23805902 TI - Evaluation of dihydroisocoumarins produced by the endophytic fungus Arthrinium state of Apiospora montagnei against Schistosoma mansoni. AB - Fractionation of extracts from the fermentation broth of the endophytic fungus Arthrinium state of Apiospora montagnei resulted in the isolation of the major secondary metabolites, R-(-)-mellein (1) and cis-(3R,4R)-4-hydroxymellein (2). The chemical structures of compounds were determined by spectroscopic analyses. The isolated compounds were tested in vitro to determine their activity against Schistosoma mansoni adult worms. Compounds 1 and 2 caused death of 100% of parasites at 200 and 50 MUg mL(-1), respectively. Ultrastructural analysis suggested that the tegument can be a target of compound 1. PMID- 23805900 TI - Associations of cardiorespiratory fitness, physical activity, and obesity with metabolic syndrome in Hong Kong Chinese midlife women. AB - BACKGROUND: Several studies have simultaneously examined physical activity (PA) and cardiorespiratory fitness (CRF) with metabolic syndrome (MS). However, the independent roles of both PA and CRF with MS are less firmly established. The combined contributions of PA and CRF with MS are less studied, particularly among Chinese women. There is uncertainty over the extent to which metabolically healthy but overweight/obese individuals have a higher CRF level. METHODS: The sample included 184 Chinese women aged 55 to 69 years with available metabolic data and lifestyle factors. PA was assessed by self-reported questionnaire; CRF was assessed by maximal oxygen consumption (VO2max) during a symptom-limited maximal exercise test on a cycle ergometer. Metabolically healthy/abnormal was defined on the basis of absence or presence of MS. Overweight was defined as a body mass index (BMI) of >= 23 kg/m2 and obese was defined as a BMI of >= 25 kg/m2. RESULTS: The prevalence of MS was 21.7%. PA was inversely associated with the prevalence of MS after adjustment for age, BMI, and dietary total calories intake, but the association was eliminated after further adjustment for CRF. CRF was inversely associated with the prevalence of MS independent of age, BMI, and dietary total calories intake, and the association remained significant after further adjustment for PA. In the PA and CRF combined analysis, compared with those in the lowest tertile of PA (inactive) and lowest tertile of CRF (unfit), the OR (95%CI) of having MS was 0.31 (0.09-1.06) for subjects in the higher tertiles (2nd-3rd) of PA (active) but were unfit, 0.23 (0.06-0.88) for subjects who were inactive but in the higher tertiles (2nd-3rd) of CRF (fit), and 0.14 (0.04-0.45) for subjects who were active and fit. Metabolically healthy but overweight/obese subjects had a higher CRF level than their metabolically abnormal and overweight/obese peers. However, the difference did not reach statistically significance. CONCLUSIONS: CRF has greater association with the prevalence of MS compared with PA in Chinese midlife women. The interrelationships between CRF, obesity, and MS needs further study. PMID- 23805899 TI - Physical and cognitive performance of patients with acute lung injury 1 year after initial trophic versus full enteral feeding. EDEN trial follow-up. AB - RATIONALE: We hypothesized that providing patients with acute lung injury two different protein/calorie nutritional strategies in the intensive care unit may affect longer-term physical and cognitive performance. OBJECTIVES: To assess physical and cognitive performance 6 and 12 months after acute lung injury, and to evaluate the effect of trophic versus full enteral feeding, provided for the first 6 days of mechanical ventilation, on 6-minute-walk distance, cognitive impairment, and secondary outcomes. METHODS: A prospective, longitudinal ancillary study of the ARDS Network EDEN trial evaluating 174 consecutive survivors from 5 of 12 centers. Blinded assessments of patients' arm anthropometrics, strength, pulmonary function, 6-minute-walk distance, and cognitive status (executive function, language, memory, verbal reasoning/concept formation, and attention) were performed. MEASUREMENTS AND MAIN RESULTS: At 6 and 12 months, respectively, the mean (SD) percent predicted for 6-minute-walk distance was 64% (22%) and 66% (25%) (P = 0.011 for difference between assessments), and 36 and 25% of survivors had cognitive impairment (P = 0.001). Patients performed below predicted values for secondary physical tests with small improvement from 6 to 12 months. There was no significant effect of initial trophic versus full feeding for the first 6 days after randomization on survivors' percent predicted for 6-minute-walk distance, cognitive impairment status, and all secondary outcomes. CONCLUSIONS: EDEN trial survivors performed below predicted values for physical and cognitive performance at 6 and 12 months, with some improvement over time. Initial trophic versus full enteral feeding for the first 6 days after randomization did not affect physical and cognitive performance. PMID- 23805904 TI - 18-Fluorodeoxyglucose positron emission tomography/computed tomography for assessment of response to brentuximab vedotin treatment in relapsed and refractory Hodgkin lymphoma. AB - Brentuximab vedotin has emerged as a possible treatment option in patients suffering from relapsed and refractory Hodgkin lymphoma (HL). We investigated the role of 18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for monitoring treatment response to brentuximab vedotin in patients with relapsed and refractory HL. Twelve consecutive, heavily pretreated patients with relapsed and refractory HL treated with brentuximab vedotin were available for analysis. FDG-PET/CT studies were performed early during treatment after a median of 3 cycles (range, 2-5 cycles), and were analyzed visually using a 5 point scale (5PS) and quantitatively using the maximum standardized uptake value (SUV(max)) and the three-dimensional (3D) isocontour at 50% of the maximum pixel value (SUV(50)) in the hottest single lesion. The median follow-up in our study cohort was 16 months (range, 5-30 months). The median progression-free survival (PFS) was 12.5 months and PFS at 12 months was 58%. Patients treated with brentuximab vedotin and negative interim FDG-PET/CT assessed by visual or quantitative analysis demonstrated a significantly prolonged PFS compared to patients with positive interim FDG-PET/CT. The 1-year PFS was 100% in patients with negative interim FDG-PET/CT assessed by visual analysis, whereas patients with positive interim FDG-PET/CT had a worse outcome with a 1-year PFS of 38% (p = 0.033). The 1-year PFS was 75% in patients with negative interim FDG-PET/CT assessed by quantitative analysis using the SUV(50), whereas patients with positive interim FDG-PET/CT had a worse outcome with a 1-year PFS of 25% (p = 0.017) Interim FDG-PET/CT might be a suitable diagnostic approach to predict response to brentuximab vedotin in relapsed and refractory HL. PMID- 23805906 TI - Biosimilars: the paradox of sharing the same pharmacological action without full chemical identity. AB - The use of biotech medicines is increasing, with consequent mounting expenses for National Health Systems (NHSs). Biosimilars should be considered an opportunity to improve access to care. On the other side, the general public might suspect to receive low-quality medicines to save money. Actually, no drugs with a lesser degree of pharmaceutical quality with respect to existing alternatives can be authorized on the ground of a lower price. Biosimilars can be authorized only if their quality is of the same level as that of the originator. There is no chemical identity between biosimilars and the originators: any differences in quality attributes must be justified and shown not to impact on the safety and efficacy of the biosimilar by scientific investigations including pre-approval nonclinical and/or clinical studies. The biosimilar safety profile may be different from the originator or change over time for the same product. Hence caveats limiting the widespread use of biosimilars yet exist and should be solved by education on the main biological issues of biotech medicines, and on continuous update of the rules set up by the Regulatory Authorities to assess biosimilarity and to monitor post-approval safety. PMID- 23805903 TI - Genomic clustering and co-regulation of transcriptional networks in the pathogenic fungus Fusarium graminearum. AB - BACKGROUND: Genes for the production of a broad range of fungal secondary metabolites are frequently colinear. The prevalence of such gene clusters was systematically examined across the genome of the cereal pathogen Fusarium graminearum. The topological structure of transcriptional networks was also examined to investigate control mechanisms for mycotoxin biosynthesis and other processes. RESULTS: The genes associated with transcriptional processes were identified, and the genomic location of transcription-associated proteins (TAPs) analyzed in conjunction with the locations of genes exhibiting similar expression patterns. Highly conserved TAPs reside in regions of chromosomes with very low or no recombination, contrasting with putative regulator genes. Co-expression group profiles were used to define positionally clustered genes and a number of members of these clusters encode proteins participating in secondary metabolism. Gene expression profiles suggest there is an abundance of condition-specific transcriptional regulation. Analysis of the promoter regions of co-expressed genes showed enrichment for conserved DNA-sequence motifs. Potential global transcription factors recognising these motifs contain distinct sets of DNA binding domains (DBDs) from those present in local regulators. CONCLUSIONS: Proteins associated with basal transcriptional functions are encoded by genes enriched in regions of the genome with low recombination. Systematic searches revealed dispersed and compact clusters of co-expressed genes, often containing a transcription factor, and typically containing genes involved in biosynthetic pathways. Transcriptional networks exhibit a layered structure in which the position in the hierarchy of a regulator is closely linked to the DBD structural class. PMID- 23805905 TI - Inflammation and impaired endothelium-dependant vasodilatation in non obese women with gestational diabetes mellitus: preliminary results. AB - BACKGROUND: To evaluate whether abnormal endothelial function, a common finding in gestational diabetes mellitus (GDM) pregnancies, can be explained by inflammatory cytokines. METHODS: Forearm skin blood flow (FSBF), into response to acetylcholine (Ach) (endothelium-dependent vasodilatation), were measured in 24 pregnant control subjects and 28 gestational diabetes mellitus (GDM) women, in the third trimester of gestation. A fasting glycemic and lipidic panel was obtained, and inflammatory cytokines (TNF-alpha and IL-6) and adiponectin were also determined. RESULTS: FSBF is significantly reduced in GDM group compared with control subjects (344.59 +/- 57.791 vs.176.38 +/- 108.52, P < 0.05). Among all subjects, FSBF showed a strong negative correlation with TNF-alpha and IL-6 (r = -0.426, P < 0.0001 and r = -0.564, P < 0.0001, respectively) and positive correlation with adiponectin (r = 0.468, P < 0.0001). CONCLUSIONS: Endothelial function, an early marker of macrovascular disease, is present in non-obese pregnancies complicated by GDM. This alteration seems to be directly related to inflammatory status, which may represent a patho-physiological link between GDM and type 2 diabetes and, later on, metabolic syndrome. PMID- 23805907 TI - Cyclodehydration of N-(aminoalkyl)benzamides under mild conditions with a Hendrickson reagent analogue. AB - Methods for the cyclodehydration of N-(aminoalkyl)benzamides are few and employ harsh reaction conditions. We have found that the easily prepared phosphonium anhydrides 1 (Hendrickson reagent) or 2 can be used for cyclodehydration of N (aminoalkyl)benzamides under very mild conditions (room temperature) to produce five-, six-, and seven-membered cyclic amidines. Good yields are obtained by employing a temporary trityl group protection strategy. Cyclic analogue 2 can be used when the product cyclic amidine is organic-soluble, thus producing water soluble byproducts. PMID- 23805908 TI - Tamoxifen inhibits macrophage FABP4 expression through the combined effects of the GR and PPARgamma pathways. AB - Macrophage adipocyte fatty acid-binding protein (FABP4) plays an important role in foam cell formation and development of atherosclerosis. Tamoxifen inhibits this disease process. In the present study, we determined whether the anti atherogenic property of tamoxifen was related to its inhibition of macrophage FABP4 expression. We initially observed that tamoxifen inhibited macrophage/foam cell formation, but the inhibition was attenuated when FABP4 expression was selectively inhibited by siRNA.We then observed that tamoxifen and 4 hydroxytamoxifen inhibited FABP4 protein expression in primary macrophages isolated from both the male and female wild-type mice, suggesting that the inhibition is sex-independent. Tamoxifen and 4-hydroxytamoxifen inhibited macrophage FABP4 protein expression induced either by activation of GR (glucocorticoid receptor) or PPARgamma (peroxisome-proliferator-activated receptor gamma). Associated with the decreased protein expression, Fabp4 mRNA expression and promoter activity were also inhibited by tamoxifen and 4 hydroxytamoxifen, indicating transcriptional regulation. Analysis of promoter activity and EMSA/ChIP assays indicated that tamoxifen and 4-hydroxytamoxifen activated the nGRE (negative glucocorticoid regulatory element), but inhibited the PPRE (PPARgamma regulatory element) in the Fabp4 gene. In vivo, administration of tamoxifen to ApoE (apolipoprotein E)-deficient (apoE-/-) mice on a high-fat diet decreased FABP4 expression in macrophages and adipose tissues as well as circulating FABP4 levels. Tamoxifen also inhibited FABP4 protein expression by human blood monocyte-derived macrophages. Taken together, the results of the present study show that tamoxifen inhibited FABP4 expression through the combined effects of GR and PPARgamma signalling pathways. Our findings suggest that the inhibition of macrophage FABP4 expression can be attributed to the antiatherogenic properties of tamoxifen. PMID- 23805909 TI - Adiabatic eigenfunction based approach to coherent transfer: application to the Fenna-Matthews-Olson (FMO) complex and the role of correlations in the efficiency of energy transfer. AB - We have recently suggested a method (Pallavi Bhattacharyya and K. L. Sebastian, Physical Review E 2013, 87, 062712) for the analysis of coherence in finite-level systems that are coupled to the surroundings and used it to study the process of energy transfer in the Fenna-Matthews-Olson (FMO) complex. The method makes use of adiabatic eigenstates of the Hamiltonian, with a subsequent transformation of the Hamiltonian into a form where the terms responsible for decoherence and population relaxation could be separated out at the lowest order. Thus one can account for decoherence nonperturbatively, and a Markovian type of master equation could be used for evaluating the population relaxation. In this paper, we apply this method to a two-level system as well as to a seven-level system. Comparisons with exact numerical results show that the method works quite well and is in good agreement with numerical calculations. The technique can be applied with ease to systems with larger numbers of levels as well. We also investigate how the presence of correlations among the bath degrees of freedom of the different bacteriochlorophyll a molecules of the FMO Complex affect the rate of energy transfer. Surprisingly, in the cases that we studied, our calculations suggest that the presence of anticorrelations, in contrast to correlations, make the excitation transfer more facile. PMID- 23805910 TI - Is the strength of direct antiglobulin test important for the duration of phototherapy? AB - The purpose of this study was to evaluate the relationship between the grades of positivity of the direct antiglobulin test (DAT) and their effects on the duration of phototherapy for neonatal jaundice. DAT reactions of blood samples were graded as (1+), (2+), (3+) and (4+). DAT was positive in 80 neonates who were exposed to phototherapy due to jaundice. Patients with positive DAT reactions are classified in the study as follows: 34 newborns were DAT (1+), 18 newborns were DAT (2+), 16 newborns were DAT (3+) and 12 newborns were DAT (4+). We found that higher grades of positivity of DAT are associated with extended duration of phototherapy (r = 0.436, p < 0.05). Additionally, DAT (4+) reactions are more predictive for a prolonged duration of phototherapy requirement than the other grades (p < 0.0001). PMID- 23805911 TI - The Kondrat'eva reaction in flow: direct access to annulated pyridines. AB - A continuous flow inverse-electron-demand Kondrat'eva reaction has been developed that provides direct access to cycloalka[c]pyridines from unactivated oxazoles and cycloalkenes. Annulated pyridines obtained by this one-step process are valuable scaffolds for medicinal chemistry. PMID- 23805912 TI - Growth hormone exacerbates diabetic renal damage in male but not female rats. AB - BACKGROUND: Human and animal studies support the idea that there are sex differences in the development of diabetic renal disease. Our lab and others have determined that in addition to Ang II (through the AT1R), growth hormone (GH) contributes to renal damage in models of renal failure; however, the impact of sex and GH on the mechanisms initiating diabetic renal disease is not known. This study examined the effect of sex and GH on parameters of renal damage in early, uncontrolled streptozotocin (STZ)-induced diabetes. METHODS: Adult male and female Sprague-Dawley rats were injected with vehicle (control), STZ, or STZ + GH and euthanized after 8 weeks. RESULTS: Mild but significant glomerulosclerosis (GS) and tubulointerstitial fibrosis (TIF) was observed in both kidneys from male and female diabetic rats, with GH significantly increasing GS and TIF by 30% and 25% in male rats, but not in female rats. STZ increased TGF-beta expression in both kidneys from male and female rats; however, while GH had no further effect on TGF-beta protein in diabetic females, GH increased TGF-beta protein in the male rat's kidneys by an additional 30%. This sex-specific increase in renal injury following GH treatment was marked by increased MCP-1 and CD-68+ cell density. STZ also reduced renal MMP-2 and MMP-9 protein expression in both kidneys from male and female rats, but additional decreases were only observed in GH-treated diabetic male rats. The sex differences were independent of AT1R activity. CONCLUSIONS: These studies indicate that GH affects renal injury in diabetes in a sex-specific manner and is associated with an increase in pro inflammatory mediators. PMID- 23805913 TI - High performance hydrogen storage from Be-BTB metal-organic framework at room temperature. AB - The metal-organic framework beryllium benzene tribenzoate (Be-BTB) has recently been reported to have one of the highest gravimetric hydrogen uptakes at room temperature. Storage at room temperature is one of the key requirements for the practical viability of hydrogen-powered vehicles. Be-BTB has an exceptional 298 K storage capacity of 2.3 wt % hydrogen. This result is surprising given that the low adsorption enthalpy of 5.5 kJ mol(-1). In this work, a combination of atomistic simulation and continuum modeling reveals that the beryllium rings contribute strongly to the hydrogen interaction with the framework. These simulations are extended with a thermodynamic energy optimization (TEO) model to compare the performance of Be-BTB to a compressed H2 tank and benchmark materials MOF-5 and MOF-177 in a MOF-based fuel cell. Our investigation shows that none of the MOF-filled tanks satisfy the United States Department of Energy (DOE) storage targets within the required operating temperatures and pressures. However, the Be BTB tank delivers the most energy per volume and mass compared to the other material-based storage tanks. The pore size and the framework mass are shown to be contributing factors responsible for the superior room temperature hydrogen adsorption of Be-BTB. PMID- 23805914 TI - Engineering chiral polyoxometalate hybrid metal-organic frameworks for asymmetric dihydroxylation of olefins. AB - Chiral metal-organic frameworks (MOFs) with porous and tunable natures have made them feasible for performing a variety of chemical reactions as heterogeneous asymmetric catalysts. By incorporating the oxidation catalyst [BW12O40](5-) and the chiral group, L- or D-pyrrolidin-2-ylimidazole (PYI), into one single framework, the two enantiomorphs Ni-PYI1 and Ni-PYI2 were obtained via self assembly, respectively. The channels of Ni-PYIs were enlarged through a guest exchange reaction to remove the cationic chiral templates and were well modulated with hydrophilic/hydrophobic properties to allow molecules of both H2O2 and olefin ingress and egress. The coexistence of both the chiral directors and the oxidants within a confined space provided a special environment for the formation of reaction intermediates in a stereoselective fashion with high selectivity. The resulting MOF acted as an amphipathic catalyst to prompt the asymmetric dihydroxylation of aryl olefins with excellent stereoselectivity. PMID- 23805915 TI - Neonatal brain abnormalities and memory and learning outcomes at 7 years in children born very preterm. AB - Using prospective longitudinal data from 198 very preterm and 70 full term children, this study characterised the memory and learning abilities of very preterm children at 7 years of age in both verbal and visual domains. The relationship between the extent of brain abnormalities on neonatal magnetic resonance imaging (MRI) and memory and learning outcomes at 7 years of age in very preterm children was also investigated. Neonatal MRI scans were qualitatively assessed for global, white-matter, cortical grey-matter, deep grey matter, and cerebellar abnormalities. Very preterm children performed less well on measures of immediate memory, working memory, long-term memory, and learning compared with term-born controls. Neonatal brain abnormalities, and in particular deep grey-matter abnormality, were associated with poorer memory and learning performance at 7 years in very preterm children. Findings support the importance of cerebral neonatal pathology for predicting later memory and learning function. PMID- 23805917 TI - Biofuel and energy crops: high-yield Saccharinae take center stage in the post genomics era. AB - The Saccharinae, especially sugarcane, Miscanthus and sorghum, present remarkable characteristics for bioenergy production. Biotechnology of these plants will be important for a sustainable feedstock supply. Herein, we review knowledge useful for their improvement and synergies gained by their parallel study. PMID- 23805918 TI - The relational dynamics of hegemonic masculinity among South African men and women in the context of HIV. AB - In South Africa, the frequent positioning of men's sexual behaviours as a prime driver of the HIV epidemic has generated much interest in men's sexuality. However, the relational nature of dominant male norms that exacerbate the risk of HIV transmission is inadequately understood. This study used sexual biographies to explore how men and women negotiate gendered norms and how this affects their sexual and reproductive health (SRH). A total of 50 sexual-history interviews and 10 focus group discussions were conducted with men, and 25 sexual-history interviews with women, with participants sampled from three age categories (ages 18-24, 25-55 and 55+years), a range of cultural and racial backgrounds and urban and rural sites across five provinces in South Africa. The narratives illustrate that men and women's SRH is largely dependent on the type and quality of their relationships. Men's sexuality was regularly depicted as being detached from intimacy and uncontrollable, which was premised as being opposite from and/or superior to women's sexuality and could justify men's high-risk sexual behaviours. Yet many participants also supported gender equitable relationships and endorsed accountable and healthy SRH behaviours. The narratives reveal that HIV-risky dominant male norms should be addressed relationally for the sake of better SRH outcomes. PMID- 23805916 TI - Isolation and genetic characterization of human coronavirus NL63 in primary human renal proximal tubular epithelial cells obtained from a commercial supplier, and confirmation of its replication in two different types of human primary kidney cells. AB - BACKGROUND: Cryopreserved primary human renal proximal tubule epithelial cells (RPTEC) were obtained from a commercial supplier for studies of Simian virus 40 (SV40). Within twelve hrs after cell cultures were initiated, cytoplasmic vacuoles appeared in many of the RPTEC. The RPTEC henceforth deteriorated rapidly. Since SV40 induces the formation of cytoplasmic vacuoles, this batch of RPTEC was rejected for the SV40 study. Nevertheless, we sought the likely cause(s) of the deterioration of the RPTEC as part of our technology development efforts. METHODS: Adventitious viruses in the RPTEC were isolated and/or detected and identified by isolation in various indicator cell lines, observation of cytopathology, an immunoflurorescence assay, electron microscopy, PCR, and sequencing. RESULTS: Cytomegalovirus (CMV) was detected in some RPTEC by cytology, an immunofluorescence assay, and PCR. Human Herpesvirus 6B was detected by PCR of DNA extracted from the RPTEC, but was not isolated. Human coronavirus NL63 was isolated and identified by RT-PCR and sequencing, and its replication in a fresh batch of RPTEC and another type of primary human kidney cells was confirmed. CONCLUSIONS: At least 3 different adventitious viruses were present in the batch of contaminated RPTEC. Whereas we are unable to determine whether the original RPTEC were pre-infected prior to their separation from other kidney cells, or had gotten contaminated with HCoV-NL63 from an ill laboratory worker during their preparation for commercial sale, our findings are a reminder that human-derived biologicals should always be considered as potential sources of infectious agents. Importantly, HCoV-NL63 replicates to high titers in some primary human kidney cells. PMID- 23805919 TI - Assessing the utility of infrared spectroscopy as a structural diagnostic tool for beta-sheets in self-assembling aromatic peptide amphiphiles. AB - beta-Sheets are a commonly found structural motif in self-assembling aromatic peptide amphiphiles, and their characteristic "amide I" infrared (IR) absorption bands are routinely used to support the formation of supramolecular structure. In this paper, we assess the utility of IR spectroscopy as a structural diagnostic tool for this class of self-assembling systems. Using 9-fluorene methyloxycarbonyl dialanine (Fmoc-AA) and the analogous 9-fluorene-methylcarbonyl dialanine (Fmc-AA) as examples, we show that the origin of the band around 1680 1695 cm(-1) in Fourier transform infrared (FTIR) spectra, which was previously assigned to an antiparallel beta-sheet conformation, is in fact absorption of the stacked carbamate group in Fmoc-peptides. IR spectra from (13)C-labeled samples support our conclusions. In addition, DFT frequency calculations on small stacks of aromatic peptides help to rationalize these results in terms of the individual vibrational modes. PMID- 23805921 TI - Chondroblastoma of the distal femur resected through a small fenestra via computed tomography navigation and endoscopy: a case report. AB - INTRODUCTION: Chondroblastoma is a benign bone tumor with a relatively high incidence in older children and adolescents during the period of active epiphyseal growth. It is generally regarded as a benign neoplasm, but sometimes it grows aggressively or recurs. To prevent recurrence, complete curettage is important; however, such an approach can be extremely difficult to perform precisely when the chondroblastoma arises deep in the epiphysis. In our patient's case, we used a computed tomography-based navigation system with registration technique involving skin marker fiduciaries and endoscopic curettage of the lesion. CASE PRESENTATION: A 16-year-old Japanese girl presented to our facility with left knee joint pain, which started nine months before her initial examination. Computed tomography and magnetic resonance imaging studies of the left knee showed a radiolucent lesion with marginal sclerosis and lobular homogeneous hypo-intensity and hyper-intensity signals in the distal epiphysis of the left femoral epiphysis, carried through to the growth plate. To prevent recurrence of chondroblastoma and growth disturbance, we used a computed tomography-based navigation system with registration technique involving skin marker fiduciaries and endoscopic curettage of the lesion. Wide excision with total removal of the chondroblastoma in the distal femur often requires large exposure with associated drawbacks, where a wide excision near the growth plate can potentially lead to growth disturbance. Therefore, in an accessible location in the distal femur, endoscopic excision of chondroblastoma under navigation system guidance can be performed with minimal operative damage. CONCLUSIONS: In the setting of a benign intra-osseous lesion infiltrating the growth plate, arthroscopic retrieval or excision under a computed tomography-based navigation system should be considered before proceeding with open surgery. PMID- 23805920 TI - Enriched environment and masticatory activity rehabilitation recover spatial memory decline in aged mice. AB - BACKGROUND: To measure the impact of masticatory reduction on learning and memory, previous studies have produced experimental masticatory reduction by modified diet or molar removal. Here we induced spatial learning impairment in mice by reducing masticatory activity and then tested the effect of a combination of environmental enrichment and masticatory rehabilitation in recovering spatial learning at adulthood and in later life. For 6 months (6M) or 18 months (18M), we fed three groups of mice from postnatal day 21 respectively with a hard diet (HD) of pellets; pellets followed by a powdered, soft diet (HD/SD, divided into equal periods); or pellets followed by powder, followed by pellets again (HD/SD/HD, divided into equal periods). To mimic sedentary or active lifestyles, half of the animals from each group were raised from weaning in standard cages (impoverished environment; IE) and the other half in enriched cages (enriched environment; EE). To evaluate spatial learning, we used the Morris water maze. RESULTS: IE6M-HD/SD mice showed lower learning rates compared with control (IE6M-HD) or masticatory rehabilitated (IE6MHD/SD/HD) animals. Similarly, EE-HD/SD mice independent of age showed lower performance than controls (EE-HD) or rehabilitated mice (EE HD/SD/HD). However, combined rehabilitation and EE in aged mice improved learning rate up to control levels. Learning rates did not correlate with swim speed. CONCLUSIONS: Reduction in masticatory activity imposed on mice previously fed a hard diet (HD/SD) impaired spatial learning in the Morris water maze. In adults, masticatory rehabilitation recovered spatial abilities in both sedentary and active mice, and rehabilitation of masticatory activity combined with EE recovered these losses in aged mice. PMID- 23805922 TI - From the editor: How can psychiatric nurses respond to the global pandemic of sex trafficking? PMID- 23805923 TI - Learned resourcefulness, danger in intimate partner relationships, and mental health symptoms of depression and PTSD in abused women. AB - The study investigated the relationships among learned resourcefulness, dangerousness in abusive relationships, and symptoms of depression and post traumatic stress disorder (PTSD) in a sample of abused sheltered women. A cross sectional descriptive research design was utilized and 42 women met criteria for participation. Data were collected over a ten-month period from June 2010 to March 2011 using the following instruments: (1) demographic data collection form, (2) Self-Control Schedule (SCS), (3) Danger Assessment (DA), (4) Index of Spouse Abuse (ISA), (5) Beck Depression Inventory, Second Edition (BDI-II), and (6) Posttraumatic Stress Diagnostic Scale (PDS). Results indicated that 74% of the sample reported symptoms of depression and 67% met criteria for PTSD. In addition, there was 62% comorbidity between depression and PTSD. High levels of danger and low levels of resourcefulness were associated with increased symptoms of depression and PTSD. Further research is necessary, but results of the study suggest that resourcefulness may be an important consideration for abused women in reducing the impact of violence and abuse on mental health issues. PMID- 23805924 TI - Intimate partner violence and the meaning of love. AB - Despite physical, emotional, verbal, and sexual abuse from their partner, many women remain in an abusive relationship, often proclaiming to love the one who is hurting them. Nineteen females who had experienced intimate partner violence were interviewed and asked to share their experiences and describe their meaning of love. An analysis of the transcripts was done using qualitative content analysis. With this approach, the contents of the verbal data were summarized and arranged in three major categories: (1) What love is not; (2) Attributes of a loving relationship; and (3) Attachment to the relationship. The findings demonstrate a woman's clear recognition of being in an abusive relationship, yearning to be truly loved, but often finding herself unable to detach from the relationship. PMID- 23805925 TI - "A feeling of connectedness": perspectives on a gentle yoga intervention for women with major depression. AB - Major depressive disorder (MDD) is one of the most common and debilitating health conditions in women in the United States and worldwide. Many women with MDD seek out complementary therapies for their depressive symptoms, either as an adjunct or alternative to the usual care. The purpose of this study is to understand the experiences of women who participated in a yoga intervention for their depression. The findings from this interpretive phenomenological study are derived from interviews with and daily logs by 12 women with MDD who took part in an 8-week gentle yoga intervention as part of a larger parent randomized, controlled trial. Results show that the women's experience of depression involved stress, ruminations, and isolation. In addition, their experiences of yoga were that it served as a self-care technique for the stress and ruminative aspects of depression and that it served as a relational technique, facilitating connectedness and shared experiences in a safe environment. Future long-term research is warranted to evaluate these concepts as potential mechanisms for the effects of yoga for depression. PMID- 23805926 TI - Barriers to treatment engagement for depression among Latinas. AB - In spite of successful treatment options for depression, the majority of Americans with severe depression do not receive treatment. Latinos are even less likely to engage in treatment than non-Hispanic Whites. The purpose of this study is to explore barriers to treatment engagement and, more specifically, how childhood adversity and gender-based violence (GBV) contribute to a lack of perceived support for treatment engagement. Experiences of GBV and childhood adversity can call into question deeply held family, cultural, and religious values, and affect the perceived quality of the therapeutic relationship and attitudes about depression treatment. A qualitative descriptive methodology was used to understand the experiences of a sample of 12 Latinas who were part of a diabetes prevention study (n = 67) and had been referred for treatment because of elevated symptoms of depression. Results indicate that the often-cited barriers to mental health care (i.e., language barriers, economic considerations, and lack of illness recognition) did not serve as deterrents for Latinas in this study. Participants recognized that they were depressed and agreed with the assessment of depression. However, none of the women followed up on the recommendation to seek care. What has emerged from this study is how cultural values, such as familismo and marianismo, and the lack of responsiveness from family and religious leaders in the context of exposure to GBV and childhood adversity created significant barriers to treatment engagement. This study highlights the need for nurses to screen for these exposures and to engage in shared decision making about treatment. PMID- 23805927 TI - Benefits of immediate EMDR vs. eclectic therapy intervention for victims of physical violence and accidents at the workplace: a pilot study. AB - This study focuses on 34 victims of aggression at the workplace, less than 48 hours following the incident of aggression. We compared victims who received an EMDR emergency protocol (URG-EMDR; n = 19) that we developed with those who received a method of intervention called eclectic therapy (n = 15). The results show that URG-EMDR therapy, provided within 48 hours, resulted in a greater decrease in perceived stress and a lower PCL-S score than eclectic therapy did. The scores were lower in both groups after 24 hours, and after 3 months, the drop was significantly greater among the victims treated with the URG-EMDR protocol; none of the EMDR-treated patients exhibited symptoms of posttraumatic stress. PMID- 23805928 TI - Resourcefulness training for grandmothers: feasibility and acceptability of two methods. AB - Grandmothers raising grandchildren may benefit from interventions to minimize stress and promote mental health. This pilot intervention trial with 40 grandmothers examined the acceptability and feasibility of resourcefulness training (RT) using expressive writing (EW) or verbal disclosure (VD). Grandmothers in RT-EW reported challenges with the daily journaling, facing reality, and not using names; those in RT-VD listed daily recording, sharing feelings, and device failures as challenges. Word counts were greater with VD than EW, but EW was used more frequently than VD. However, both EW and VD were found acceptable and feasible for practicing RT skills in grandmothers raising grandchildren and warrant further evaluation. PMID- 23805929 TI - Access to physical health care for people with serious mental illness: a nursing perspective and a human rights perspective-common ground? AB - Relative to the general population, people with serious mental illness (SMI) experience elevated risks of physical disease and illness and live shorter lives. A human rights perspective argues that people with serious mental illness have a right to equal access to physical health care. Nurses in mental health services can contribute to improving the availability and accessibility of physical health care. This study, involving focus group interviews with nurses in a large regional and rural mental health care district of Queensland, Australia, revealed significant problems in access to physical health care for service users. The current article reports on our exploratory analysis of nurses' views and perceptions to identify (1) orientation of nurses to human rights, and (2) access of consumers with SMI to general practitioner services. It was rare for nurses to raise the topic of human rights, and when raised, it was not as a strategy for improving access to physical health care services that they felt consumers with SMI greatly needed. Two main themes were identified as causes of poor access: clinical barriers to physical care and attitudinal barriers to physical care. In light of these results, the authors explore a human rights perspective on access and how this provides an inclusive lobbying umbrella under which nurses and other groups can pursue access to physical health services that are adequate, accessible, and non-discriminatory. The article then discusses the implications for these findings for the value of human rights as a perspective and means of increasing physical health of people with SMI. PMID- 23805930 TI - "At wits' end!": perspectives of Hispanic caregivers of a family member with schizophrenia. AB - The purpose of this qualitative exploratory study was to explore the perspectives of Hispanic caregivers as they provide the day-to-day care for their family member with schizophrenia. Interviews were conducted by a promotora (a Spanish speaking trained community health worker) with ten Hispanic caregivers at a large community center in a southwest border city over a six month period. Sixty interviews were audio recorded, translated into English, transcribed, and then interpreted using content analysis. One main overarching perspective emerged: "at wits' end." The following four supportive themes emerged: feeling marginalized, seeking answers, relying on God, and lacking support. PMID- 23805931 TI - Mental health learning needs assessment: competency-based instrument for best practice. AB - A learning needs assessment focused on psychiatric/mental health nursing competency development is a central component of nursing education in specialty mental health nursing practice. The provision of education for mental health nursing relies on the underlying assumption that the learning needs of experienced mental health nurses have been assessed and educational programs implemented to address educational needs for competency in professional practice. Few professional learning needs assessments have been developed to identify learning needs in mental health nursing practice. The majority of available professional learning needs assessments focus on medical nursing practice applications rather than the psychosocial aspects of a mental health assessment. The mental health field addresses very different assessment criteria such as knowledge of suicide assessment and therapeutic interventions. The purpose of this article is to present and describe the process of developing a learning needs assessment focused on competency development for the specialty practice of mental health nursing that addresses and resolves complex learning needs. PMID- 23805933 TI - AIDS 2012: epidemiology, resources, and control. PMID- 23805934 TI - Coercion and the corruption of care in mental health nursing: lessons from a case study. PMID- 23805936 TI - Phenolic antioxidants from Rosa soulieana flowers. AB - Rosa soulieana has been widely used in traditional medicine to treat cardiovascular disorders. In this study, antioxidant activity-guided fractionation and purification of the methanol extract from the flowers of R. soulieana has led to the isolation of nine phenolic antioxidants, which were identified as catechin (1), tiliroside (2), astragalin (3), isoquercitrin (4), nicotiflorin (5), eugenol 4-O-beta-d-(6'-O-galloyl) glucoside (6), michehedyosides D (7), citrusin C (8) and strictinin (9), respectively. Among them, compounds 5-9 were reported from the genus Rosa for the first time. All the compounds were also assayed by in vitro ABTS [2,2'-azinobis(3 ethylbenzothiazoline-6-sulphonic acid) diammonium salt] radical cation scavenging activity. Among these bioactive isolates (1-9), compounds 1, 6, 7 and 9 exhibited strong scavenging activity in ABTS (SC50 = 10.17, 7.38, 8.60, 4.72 MUmol/L, respectively) compared with the positive control l-ascorbic acid (SC50 = 15.97 MUmol/L). PMID- 23805937 TI - Diastereoselective [2 + 2] photocycloaddition of cyclohexenone derivative with olefins in supercritical carbon dioxide. AB - We performed diastereoselective [2 + 2] photocycloaddition of the cyclohexenone derivative with olefins in supercritical carbon dioxide (scCO2). A dramatic enhancement of conversion was observed at around critical density when ethylene gas was employed as a coupling partner. Furthermore, we elucidated that the pressure dependence of the diastereomeric excess (de) was discontinuous at critical density owing to the difference of substrate solubility between near critical carbon dioxide (ncCO2) and scCO2; both the reaction conversion and de values obtained were lower than those in conventional organic solvent. On the contrary, when cyclopentene (liquid) was utilized as a coupling partner, moderate conversion was always observed irrespective of CO2 pressure, because the substrate could be dissolved in cyclopentene. Furthermore, we could accomplish de enhancement in scCO2, in particular around critical density, compared to that in organic solvent. This highly selective photoreaction is due to the unique solvent property of scCO2, which is called the clustering effect. PMID- 23805935 TI - Anti-platelet-activating factor, antibacterial, and antiradical activities of lipids extract from silver carp brain. AB - BACKGROUND: Epidemiological studies have verified the protective role of fish lipids in cardiovascular diseases. However, the effects of fish lipids on health boost remain undefined. Large amounts of by-products, such as fish brain which contains high level of lipids, are produced with silver carp processing. Fish brain is rich in bioactive lipids which are overwhelmingly effective in preventing cardiovascular diseases. The aim of this study was to elucidate the pharmacological activities of silver carp brain lipids against diseases by inhibiting platelet-activating factor (PAF), suppressing bacterial growth and scavenging free radicals. METHODS: Total lipids (TL) were extracted from silver carp brain and separated into polar lipids (PL) and neutral lipids (NL). The capabilities of the lipid fractions in aggregating washed rabbit platelet or in inhibiting PAF-induced platelet aggregation were tested. Their antibacterial and antiradical activities were studied as well. RESULTS: The lipid fractions exhibited strong inhibitory activities, and the activity of TL was mainly attributed to NL. TL exhibited antibacterial activity towards Staphylococcus aureus, while NL managed to fight against S. aureus and Escherichia coli. PL excelled TL and NL in simultaneously suppressing the growths of Shigella dysenteriae and Salmonella typhi besides those of S. aureus and E. coli. The scavenging effect of PL on 2,2-diphenyl-1-picrylhydrazyl radical was considerably higher than those of TL and NL. CONCLUSION: The present study may help to explain the protective role of fish lipids against diseases and may be responsible for the effectiveness of fish brain in benefiting health. PMID- 23805938 TI - Electronic spectroscopy of diatomic VC. AB - Resonant two-photon ionization spectroscopy has been applied to diatomic VC, providing the first optical spectrum of this molecule. The ground state is determined to be a (2)Delta3/2 state that arises from the 1sigma(2)1pi(4)2sigma(2)1delta(1) configuration. The r0" ground-state bond length is 1.6167(3) A. The manifold of excited vibronic states in the visible portion of the spectrum is quite dense, but two possible vibrational progressions have been identified. It is noted that VC joins CrC, NbC, and MoC as species in which the metal ns-based 3sigma orbital is unoccupied, resulting in large dipole moments in the ground states of these molecules. In the corresponding 5d metal carbides, however, the 3sigma orbital is occupied, leading to different ground electronic states of the 5d congeners, TaC and WC. PMID- 23805939 TI - Alcohol drinking among college students: college responsibility for personal troubles. AB - BACKGROUND: One young adult in two has entered university education in Western countries. Many of these young students will be exposed, during this transitional period, to substantial changes in living arrangements, socialisation groups, and social activities. This kind of transition is often associated with risky behaviour such as excessive alcohol consumption. So far, however, there is little evidence about the social determinants of alcohol consumption among college students. We set out to explore how college environmental factors shape college students' drinking behaviour. METHODS: In May 2010 a web questionnaire was sent to all bachelor and master students registered with an important Belgian university; 7,015 students participated (participation = 39%). The survey looked at drinking behaviour, social involvement, college environmental factors, drinking norms, and positive drinking consequences. RESULTS: On average each student had 1.7 drinks a day and 2.8 episodes of abusive drinking a month. We found that the more a student was exposed to college environmental factors, the greater the risk of heavy, frequent, and abusive drinking. Alcohol consumption increased for students living on campus, living in a dormitory with a higher number of room-mates, and having been in the University for a long spell. Most such environmental factors were explained by social involvement, such as participation to the student folklore, pre-partying, and normative expectations. CONCLUSIONS: Educational and college authorities need to acknowledge universities' responsibility in relation to their students' drinking behaviour and to commit themselves to support an environment of responsible drinking. PMID- 23805940 TI - Tuning reactivity of diphenylpropynone derivatives with metal-associated amyloid beta species via structural modifications. AB - A diphenylpropynone derivative, DPP2, has been recently demonstrated to target metal-associated amyloid-beta (metal-Abeta) species implicated in Alzheimer's disease (AD). DPP2 was shown to interact with metal-Abeta species and subsequently control Abeta aggregation (reactivity) in vitro; however, its cytotoxicity has limited further biological applications. In order to improve reactivity toward Abeta species and lower cytotoxicity, along with gaining an understanding of a structure-reactivity-cytotoxicity relationship, we designed, prepared, and characterized a series of small molecules (C1/C2, P1/P2, and PA1/PA2) as structurally modified DPP2 analogues. A similar metal binding site to that of DPP2 was contained in these compounds while their structures were varied to afford different interactions and reactivities with metal ions, Abeta species, and metal-Abeta species. Distinct reactivities of our chemical family toward in vitro Abeta aggregation in the absence and presence of metal ions were observed. Among our chemical series, the compound (C2) with a relatively rigid backbone and a dimethylamino group was observed to noticeably regulate both metal-free and metal-mediated Abeta aggregation to different extents. Using our compounds, cell viability was significantly improved, compared to that with DPP2. Lastly, modifications on the DPP framework maintained the structural properties for potential blood-brain barrier (BBB) permeability. Overall, our studies demonstrated that structural variations adjacent to the metal binding site of DPP2 could govern different metal binding properties, interactions with Abeta and metal-Abeta species, reactivity toward metal-free and metal-induced Abeta aggregation, and cytotoxicity of the compounds, establishing a structure reactivity-cytotoxicity relationship. This information could help gain insight into structural optimization for developing nontoxic chemical reagents toward targeting metal-Abeta species and modulating their reactivity in biological systems. PMID- 23805942 TI - The preclinical profile of crizotinib for the treatment of non-small-cell lung cancer and other neoplastic disorders. AB - INTRODUCTION: The critical role of the activity of the nucleophosmin- anaplastic lymphoma kinase (NPM-ALK) fusion protein in anaplastic large-cell lymphoma prompted drug discovery programs directed against ALK. Drug discovery efforts increased after finding that about 4% of non-small-cell lung cancers (NSCLCs) possess an EML4-ALK fusion protein. AREAS COVERED: The author provides a review of the development of crizotinib, an orally effective c-Met and ALK protein kinase inhibitor. The article highlights its beginning with the X-ray crystallographic structure of a lead compound (PHA-0665752) bound to the active site of the kinase domain of c-Met. EXPERT OPINION: Studies of patients with EML4 ALK-positive NSCLC showed that crizotinib was clinically effective and led to its approval in August 2011. The use of lipophilic efficiency played a crucial role in the development of crizotinib from a lead c-Met inhibitor. The use of X-ray crystal structures from lead compounds, bound to their targets, is increasing in the drug discovery process owing to its effectiveness. That the drug also inhibits ALK and ALK-fusion proteins was serendipitous, however. The discovery of the EML4-ALK fusion protein in some NSCLC patients has led to the testing and rapid approval of the compound. PMID- 23805943 TI - Transmission of methicillin-sensitive Staphylococcus aureus to a preterm infant through breast milk. AB - Contrary to traditional belief, breast milk is not a sterile fluid, even in healthy women. Breast milk may contain pathogenic bacteria that could cause serious infections especially in premature infants. There is no recommendation to evaluate breast milk routinely for pathogenic bacteria. However discontinuation of breastfeeding is not recommended even the mother had mastitis, because it is believed this will not pose a risk to infant. This is the report of a premature infant born at the 32nd gestational week who was readmitted to neonatal intensive care unit with late-onset Staphylococcus aureus sepsis. While searching for the transmission route of the infection, the breast milk was assessed. Although the mother did not have any symptoms of breast inflammation, S. aureus isolates, genetically 99% similar to those from the infant blood samples, were documented in the breast milk. CONCLUSION: Breast milk may contain pathogenic bacteria, even when expressed, stored and transported properly. When evaluating the source of a S. aureus infection in preterm infants, breast milk might be the source of the infection, even if the mother has no sign of mastitis. PMID- 23805944 TI - Early administration of oropharyngeal colostrum to extremely low birth weight infants. AB - BACKGROUND: Human milk reduces morbidities in extremely low birth weight (ELBW) infants. However, clinical instability often precludes ELBW infants from receiving early enteral feeds. This study compared clinical outcomes before and after implementing an oropharyngeal colostrum (COL) protocol in a cohort of inborn (born at our facility) ELBW infants. STUDY DESIGN: This is a retrospective cohort study of inborn ELBW infants admitted to the Duke Intensive Care Nursery from January 2007 to September 2011. In November 2010, we initiated a COL protocol for infants not enterally fed whose mothers were providing breastmilk. Infants received 0.1 mL of fresh COL to each cheek every 4 hours for 5 days beginning in the first 48 postnatal hours. We assessed demographics, diagnoses, feeding history, and mortality and for the presence of medical necrotizing enterocolitis (NEC), surgical NEC, and spontaneous perforation. Between-group comparisons were made using Fisher's exact test or Wilcoxon rank sum testing where appropriate. RESULTS: Of the 369 infants included, 280 (76%) were born prior to the COL protocol (Pre-COL Cohort [PCC]), and 89 (24%) were born after (COL Cohort [CC]). Mortality and the percentage of infants with surgical NEC and spontaneous perforations were statistically similar between the groups. The CC weighed an average (interquartile range) of 1,666 (1,399, 1,940) g at 36 weeks versus 1,380 (1,190, 1,650) g for the PCC (p<0.001). In a multivariable analysis with birth weight as a covariable, weight at 36 weeks was significantly greater (37 g; p<0.01). CONCLUSIONS: Initiating oropharyngeal COL in ELBW infants in the first 2 postnatal days appears feasible and safe and may be nutritionally beneficial. Further research is needed to determine if early COL administration reduces neonatal morbidity and mortality. PMID- 23805946 TI - Plant genomics: from weed to wheat. AB - A report on the first 'Plant Genomics Congress' meeting, held in London, UK, 12 13 May 2013. PMID- 23805945 TI - Inhibition of hepatitis B virus (HBV) gene expression and replication by HBx gene silencing in a hydrodynamic injection mouse model with a new clone of HBV genotype B. AB - BACKGROUND: It has been suggested that different hepatitis B virus (HBV) genotypes may have distinct virological characteristics that correlate with clinical outcomes during antiviral therapy and the natural course of infection. Hydrodynamic injection (HI) of HBV in the mouse model is a useful tool for study of HBV replication in vivo. However, only HBV genotype A has been used for studies with HI. METHODS: We constructed 3 replication-competent clones containing 1.1, 1.2 and 1.3 fold overlength of a HBV genotype B genome and tested them both in vitro and in vivo. Moreover, A HBV genotype B clone based on the pAAV-MCS vector was constructed with the 1.3 fold HBV genome, resulting in the plasmid pAAV-HBV1.3B and tested by HI in C57BL/6 mice. Application of siRNA against HBx gene was tested in HBV genotype B HI mouse model. RESULTS: The 1.3 fold HBV clone showed higher replication and gene expression than the 1.1 and 1.2 fold HBV clones. Compared with pAAV-HBV1.2 (genotype A), the mice HI with pAAV HBV1.3B showed higher HBsAg and HBeAg expression as well as HBV DNA replication level but a higher clearance rate. Application of two plasmids pSB-HBxi285 and pSR-HBxi285 expressing a small/short interfering RNA (siRNA) to the HBx gene in HBV genotype B HI mouse model, leading to an inhibition of HBV gene expression and replication. However, HBV gene expression may resume in some mice despite an initial delay, suggesting that transient suppression of HBV replication by siRNA may be insufficient to prevent viral spread, particularly if the gene silencing is not highly effective. CONCLUSIONS: Taken together, the HI mouse model with a HBV genotype B genome was successfully established and showed different characteristics in vivo compared with the genotype A genome. The effectiveness of gene silencing against HBx gene determines whether HBV replication may be sustainably inhibited by siRNA in vivo. PMID- 23805947 TI - 'Sometimes it's fun to play with them first': girls and boys talking about sexual harassment in Caribbean schools. AB - This paper discusses findings from a qualitative study conducted in four government secondary schools in the Caribbean state of Antigua and Barbuda on students' experiences at school in relation to sexuality. Both girls and boys experienced a range of anxieties and confusions in relation to sexuality, whilst also seeing (hetero)sexual attraction as an exciting part of schooling. Sexual harassment of girls emerged as a widespread and serious (as well as 'normalised') occurrence in all the schools studied. However, the data also showed that girls were far from passive. Instead, girls demonstrated complex and contradictory responses to boys' behaviour due to their own investments in being desirable within discourses of hetero-femininity, as well as the pleasure they gained from their relationships. Both genders would clearly benefit from opportunities to discuss their needs, beliefs and desires regarding sexuality and relationships. PMID- 23805948 TI - The shielding function of task rules in the context of task switching. AB - There is increasing evidence that task rules help shield the response against distractor interference. Here, the authors investigate the cognitive mechanisms underlying this assumed shielding function of task rules and how it is adjusted to changing task demands. In two experiments, participants switched between a noun categorization and an adjective categorization task. Target words were superimposed on distractor pictures. These pictures were always irrelevant and depicted either objects also used as target words in the noun task (noun distractors) or objects that were not part of the noun target-set but could be categorized according to the noun task (noun-related distractors). Results show that (a) on task repetitions shielding prevents interference from any distractors associated with a competing task; this is indicated by the lack of interference on adjective task repetitions; and (b) shielding is reduced on task switches. In the noun task, this reduction resulted in attenuated interference by noun-related distractors. In the adjective task, spatial distractors did not interfere despite the reduction. This result suggests that shielding is supported by a processing advantage for task-related information and not by distractor suppression. PMID- 23805949 TI - Effective pi-extension of carbazole-based thiaporphyrins by peripheral phenylethynyl substituents. AB - Several tetrakis(phenylethynyl)- and (phenylethynylphenylethynyl)-substituted carbazole-based thiaporphyrins were synthesized. These pi-extended porphyrins display remarkably intensified and red-shifted absorption bands in the NIR region up to 1126 nm due to perturbation by the phenylethynyl substituents. PMID- 23805951 TI - Instability of liquid Cu films on a SiO2 substrate. AB - We study the instability of nanometric Cu thin films on SiO2 substrates. The metal is melted by means of laser pulses for some tens of nanoseconds, and during the liquid lifetime, the free surface destabilizes, leading to the formation of holes at first and then in later stages of the instability to metal drops on the substrate. By analyzing the Fourier transforms of the SEM (scanning electron microscope) images obtained at different stages of the metal film evolution, we determine the emerging length scales at relevant stages of the instability development. The results are then discussed within the framework of a long-wave model. We find that the results may differ whether early or final stages of the instability are considered. On the basis of the interpretation of the experimental results, we discuss the influence of the parameters describing the interaction of the liquid metal with the solid substrate. By considering both the dependence of dominant length scales on the film thickness and the measured contact angle, we isolate a model which predicts well the trends found in the experimental data. PMID- 23805950 TI - Climate change and health in Israel: adaptation policies for extreme weather events. AB - Climatic changes have increased the world-wide frequency of extreme weather events such as heat waves, cold spells, floods, storms and droughts. These extreme events potentially affect the health status of millions of people, increasing disease and death. Since mitigation of climate change is a long and complex process, emphasis has recently been placed on the measures required for adaptation. Although the principles underlying these measures are universal, preparedness plans and policies need to be tailored to local conditions. In this paper, we conducted a review of the literature on the possible health consequences of extreme weather events in Israel, where the conditions are characteristic of the Mediterranean region. Strong evidence indicates that the frequency and duration of several types of extreme weather events are increasing in the Mediterranean Basin, including Israel. We examined the public health policy implications for adaptation to climate change in the region, and proposed public health adaptation policy options. Preparedness for the public health impact of increased extreme weather events is still relatively limited and clear public health policies are urgently needed. These include improved early warning and monitoring systems, preparedness of the health system, educational programs and the living environment. Regional collaboration should be a priority. PMID- 23805952 TI - Is androgen production in association with immune system activation potential evidence for existence of a functional adrenal/ovarian autoimmune system in women? AB - BACKGROUND: Low functional ovarian reserve (FOR) is at all ages associated with low testosterone (T) levels. Causes are, however, unknown. We, therefore, investigate whether androgens with low FOR are associated with non-specific immune system activation. METHODS: 322 infertile women with low and normal FOR (controls) were assessed with a broadly based immune profile, which in previous studies has proven effective in differentiating infertile patients with and without immune system activation. Patients were either immune-positive (greater than or equal to one positive tested parameter) or immune negative (no positive test). 135 suffered from prematurely diminished FOR (POA/OPOI; < age 38), 155 from physiologic diminished FOR due to age (DOR; > age 40), and 32 were controls (< age 38 with normal age-specific FOR). Prevalence of immune-positive vs. negative was assessed in all 3 patient groups. RESULTS: Women with immune abnormalities, overall, demonstrated higher total T (TT, P = 0.004) and free T (FT, P < 0.001) levels than those without. The three clinical and two immunologic defined patient groups demonstrated significant statistical interaction in mean TT (P = 0.008), with mean TT and FT in women with positive immune findings being significantly higher in control than in POA/OPOI and physiologic DOR patients (all 4 differences P < 0.001). No such differences between the three groups were seen in women without immune abnormalities. CONCLUSIONS: In this study we used a definition of immune-positivity, which favors sensitivity over specificity, resulting in significant numbers of false-positives but likely only few false negatives. The study allows suggesting the possibility of an immune system derived androgen-production factor (APF), which maintains normal androgen levels but is deficient in women with low FOR and immune system inactivity. Existence of such an APF would suggest the presence of a still unknown functional adrenal autoimmune system. PMID- 23805953 TI - An unusual case of metastasis of a pulmonary undifferentiated pleomorphic sarcoma to the right ventricle: a case report. AB - INTRODUCTION: Undifferentiated pleomorphic sarcoma is defined as a pleomorphic high-grade sarcoma whose line of differentiation cannot be determined. These tumors constitute less than 5% of all sarcomas in adults. Cardiac neoplasms are rare, and most are metastatic in origin. More than one-third of cardiac metastases originate from lung cancer. Symptoms of cardiac neoplasms usually appear late in the course of the disease and are often ignored because of the more severe effects of the primary malignancy or its therapy. We present the case of a patient with undifferentiated pleomorphic sarcoma of the lung presenting with symptomatic right-heart failure secondary to cardiac metastasis. The purpose of this report is to present this unusual case. CASE PRESENTATION: Our patient was a 59-year-old Chinese woman with symptomatic metastasis of an undifferentiated pleomorphic sarcoma of the lung to the right ventricle. She had a history of a stage IV, pulmonary, undifferentiated pleomorphic sarcoma that had been successfully treated with chemotherapy and radiotherapy 4 years ago. A complete response was obtained, and she was in remission until the cardiac metastasis. She underwent surgical excision of the cardiac mass because it caused dyspnea and posed a high risk of sudden death, pulmonary embolism or tricuspid obstruction. Histopathological and immunohistochemical examinations of the surgical specimen established the diagnosis of undifferentiated pleomorphic sarcoma and confirmed that the cardiac tumor was a metastasis from the lung. CONCLUSIONS: In patients who have known metastatic neoplasms and present with cardiac manifestations, whether detected during history taking or physical examination, the clinician should be alert to the possibility of cardiac metastases. In patients with cardiac metastases, the therapeutic alternatives are limited to palliative treatment of symptoms and chemotherapy. In some patients, surgery can be used to relieve symptoms. We have reported the first case of symptomatic cardiac metastases from an undifferentiated pleomorphic sarcoma of the lung. Our patient underwent surgical resection, and her symptoms improved significantly. This case is unique because it is the only reported case of undifferentiated pleomorphic sarcoma of the lung which metastasized to the heart, and in which symptomatic improvement was effectively obtained with surgical resection. PMID- 23805954 TI - In-group bias in residency selection. AB - BACKGROUND: More than half of all Canadian medical graduates match to residency programs within the same university as their medical school. Here we describe two studies designed to explore whether there is partiality for internal applicants in the resident selection process. METHODS: We first performed an observational study in which we compared the ratings of 14 'internal' and 89 'external' applicants to the University of Calgary Internal Medicine Training Program by resident and faculty raters. Following this we then asked residents to rate anonymous application packages in which we manipulated applicants' affiliation to our training program. RESULTS: In our first study, we found that residents rated internal applicants significantly higher for both application packages (mean (SD)) rating for internal versus external applicants (4.86 (0.36) vs. 4.36 (0.57), d = 1.05, p = 0.002) and interviews (4.93 (0.27) vs. 4.36 (0.7), d = 1.07, p = 0.003). There was no difference in the faculty ratings of internal and external applicants. In our second study, we found that residents rated applicants with an affiliation to our program - either attending the local medical school or having completed an elective - higher than applicants with no affiliation to our program. CONCLUSIONS: Our finding support in-group bias during resident selection, possibly due to the interdependent relationship between residents and students. Considering the career implications of residency matching, we feel that further studies are needed to identify and mitigate sources of bias in the residency application process. PMID- 23805955 TI - Validity of self-reported height and weight among adolescents: the importance of reporting capability. AB - BACKGROUND: This study proposes a new approach for investigating bias in self reported data on height and weight among adolescents by studying the relevance of participants' self-reported response capability. The objectives were 1) to estimate the prevalence of students with high and low self-reported response capability for weight and height in a self-administrated questionnaire survey among 11-15 year old Danish adolescents, 2) to estimate the proportion of missing values on self-reported height and weight in relation to capability for reporting height and weight, and 3) to investigate the extent to which adolescents' response capability is of importance for the accuracy and precision of self reported height and weight. Also, the study investigated the impact of students' response capability on estimating prevalence rates of overweight. METHODS: Data was collected by a school-based cross-sectional questionnaire survey among students aged 11-15 years in 13 schools in Aarhus, Denmark, response rate =89%, n = 2100. Response capability was based on students' reports of perceived ability to report weight/height and weighing/height measuring history. Direct measures of height and weight were collected by school health nurses. RESULTS: One third of the students had low response capability for weight and height, respectively, and every second student had low response capability for BMI. The proportion of missing values on self-reported weight and height was significantly higher among students who were not weighed and height measured recently and among students who reported low recall ability. Among both boys and girls the precision of self reported height and weight tended to be lower than among students with low response capability. Low response capability was related to BMI (z-score) and overweight prevalence among girls. These findings were due to a larger systematic underestimation of weight among girls who were not weighed recently (-1.02 kg, p < 0.0001) and among girls with low recall ability for weight (-0.99 kg, p = 0.0024). CONCLUSION: This study indicates that response capability may be relevant for the accuracy of girls' self-reported measurements of weight and height. Consequently, by integrating items on response capability in survey instruments, participants with low capability can be identified. Similar analyses based on other and less selected populations are recommended. PMID- 23805956 TI - Talking about sex after cancer: a discourse analytic study of health care professional accounts of sexual communication with patients. AB - There is consistent evidence that health care professionals (hcps) are not addressing the sexual information and support needs of people with cancer. Thirty eight Australian hcps across a range of professions working in cancer care were interviewed, to examine constructions of sexuality post-cancer, the subject positions adopted in relation to sexual communication, and the ways in which discourses and subject positions shape information provision and communication about sexuality. Participants constructed sexual changes post-cancer in physical, psychological and relational terms, and positioned such changes as having the potential to significantly impact on patient and partner well-being. This was associated with widespread adoption of a discourse of psychosocial support, which legitimated discussion of sexual changes within a clinical consultation, to alleviate distress, dispel myths and facilitate renegotiation of sexual practices. However, this did not necessarily translate into patient-centred practice outcomes, with the majority of participants positioning personal, patient-centred and situational factors as barriers to the discussion of sex within many clinical consultations. This included: absence of knowledge, confidence and comfort; positioning sex as irrelevant or inappropriate for some people; and limitations of the clinical context. In contrast, those who did routinely discuss sexuality adopted a subject position of agency, responsibility and confidence. PMID- 23805957 TI - Synthesis and biological properties of novel brefeldin A analogues. AB - New brefeldin A (1) analogues were obtained by introducing a variety of substituents at C15. Most of the analogues exhibited significant biological activity. (15R)-Trifluoromethyl-nor-brefeldin A (3), (15R)-vinyl-nor-brefeldin A (5), their epimers 4 and 6 as well as (15S)-ethyl-nor-brefeldin A (2) were prepared from the key building blocks 12 or 24 by Julia-Kocienski olefination with tetrazolyl sulfones and subsequent macrolactonization. The vinyl derivative 5 allowed analogues to be synthesized by hydroboration and Suzuki-Miyaura coupling. The following biological properties were assessed: (a) inhibition of cell growth of human cancer cells (NCI), (b) induction of morphological changes of the Golgi apparatus of plant and mammalian cells, and (c) influence on the replication of the enterovirus CVB3. Furthermore, conformational aspects were studied by X-ray crystal structure analysis and molecular mechanics calculations, including docking of the analogues into the brefeldin A binding site of an Arf1/Sec7-complex. PMID- 23805958 TI - The pediatrician's role in the diagnosis and management of food allergy. AB - CME EDUCATIONAL OBJECTIVES 1. Recognize the signs and symptoms of food allergy versus food intolerance. 2. Review currently available diagnostic testing modalities for food allergy and their applicability in the pediatric outpatient setting. 3. Review appropriate management practices for pediatricians, including prescription of medications, counseling of families, and referrals to keep children safe. Food allergy is a rapidly increasing and potentially life threatening health concern in the United States. Given the ubiquity of food in our society and the absence of a cure, it is crucial that families receive proper guidance and medication to keep children safe. The pediatrician plays a key role to this end as he or she is often the first, and sometimes the only physician, these children can access. Accordingly, pediatricians must be equipped to recognize, manage, and evaluate food allergies over time while preventing unnecessary avoidance. This review provides practical translation of guidelines into recommended practices that are most pertinent to pediatricians. PMID- 23805959 TI - Establishing the safety of influenza vaccine in egg-allergic individuals. AB - CME EDUCATIONAL OBJECTIVES 1. Understand that trivalent influenza vaccine is safe for patients with egg allergy, including patients with severe egg allergy. 2. Understand that egg-allergic patients no longer require any special precautions to safely receive trivalent influenza vaccine. 3. Recognize that the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices advises that most egg-allergic patients can now receive trivalent influenza vaccine from their primary care physician. Trivalent influenza vaccine is grown in chick embryos and contains residual egg protein (ovalbumin). Historically, trivalent influenza vaccine (TIV) has been contraindicated in egg-allergic individuals (EAI) and the vaccine was withheld in many of these individuals due to the ovalbumin. However, protocols were developed that allowed EAIs to safely receive TIV, including stepwise desensitization, vaccine skin testing, and use of low ovalbumin containing vaccine. In the past 3 years, several groups have systematically disproven that EAI are at any increased risk for an allergic reaction than the general population and withholding TIV is not necessary. To date, approximately 4,315 patients have safely received 4,872 total doses of TIV, including 656 EAI with severe egg allergy (including anaphylaxis to egg) who safely received 740 doses of TIV. Thus, it is as safe to provide TIV to EAI as providing it to a non-EAI. This article will trace the evolution of this practice. PMID- 23805960 TI - Practical management of eosinophilic esophagitis. AB - CME EDUCATIONAL OBJECTIVES 1. Determine the clinical presentation and diagnostic criteria for eosinophilic esophagitis in children. 2. Discuss the three major treatment strategies for eosinophilic esophagitis. 3. Provide key strategies for practical identification and management of eosinophilic esophagitis in children and adolescents. Eosinophilic esophagitis (EoE) is a recently discovered disease that affects patients worldwide. The conceptual definition of EoE is a chronic, immune/antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. As a chronic, antigen-mediated disease causing eosinophilic inflammation in the esophagus, EoE symptoms are similar to gastroesophageal reflux disease (GERD) and it results in significant morbidity. PMID- 23805961 TI - Manifestations, diagnosis, and management of food protein-induced enterocolitis syndrome. AB - CME EDUCATIONAL OBJECTIVES 1. Recognize manifestations, diagnosis, and management of food protein-induced enterocolitis syndrome (FPIES) in an outpatient setting. 2. Assess nutritional needs and provide anticipatory guidance for dietary management. 3. Recognize the indications of when to refer for assessment of resolution of FPIES using physician-supervised food challenges. Food protein induced enterocolitis syndrome (FPIES) is an under-recognized non-immunoglobulin E (IgE)-mediated gastrointestinal food allergy affecting primarily infants and toddlers. An abnormal response to food antigen resulting in local inflammation is thought to lead to increased intestinal permeability and fluid shift. The primary features of acute FPIES are repetitive, projectile vomiting, lethargy, pallor, diarrhea, and dehydration. Chronic FPIES is typically seen in young infants with continued exposure to cow's milk or soy-based formula. Biomarkers are lacking and patients may undergo extensive workups for their symptoms, which often leads to a delay in diagnosis and puts infants at risk for feeding difficulties, nutritional deficiencies, and failure to thrive. This review will provide a guide in how to recognize the clinical features of and manage FPIES. PMID- 23805962 TI - The impact of food allergies on quality of life. AB - CME EDUCATIONAL OBJECTIVES 1. Recognize and appreciate the impact of food allergies on psychosocial health. 2. List the factors that have been shown to negatively affect health-related quality of life. 3. Understand how physicians can directly help to improve a child's quality of life while living with food allergies. Food allergy is a serious problem affecting a growing number of children worldwide. There is a large body of evidence supporting the detrimental effects that food allergy can have on a child's quality of life. With validated tools, we can identify these children and focus on how to protect, guide, and help them to live a safe life. Recent research articulates how food allergies impact health-related quality of life (HRQL). There are studies reported from the child's perspective, as well as studies reported from the parent's perspective. With the development of validated disease and age-specific questionnaires, researchers can reliably gather data on the psychological aspect of children with food allergies. The purpose of this article is to provide a review of the literature examining the psycho-social impact of food allergies on children. This article was designed to outline suggestions to help physicians care for the whole child - both mind and body. PMID- 23805963 TI - The antibiotic crisis. PMID- 23805965 TI - Behavioral and developmental screening advice from ABCD states' experience. PMID- 23805966 TI - A 10-month-old girl with prolonged diarrhea and eye wandering. PMID- 23805967 TI - Management of a digital world: from felons to fungus. PMID- 23805968 TI - A 7-year-old boy with abdominal pain, fever, and rash. PMID- 23805969 TI - Clinical, social, and family management of food allergies. PMID- 23805970 TI - Tularemia: epidemiology, diagnosis, and treatment. PMID- 23805971 TI - The use of epinephrine in acute allergic reaction to food. PMID- 23805972 TI - A conversation with Robert H. Lustig, MD, MSL. Interview by Stanford T Shulman. PMID- 23805973 TI - CRISPR interference: a structural perspective. AB - CRISPR (cluster of regularly interspaced palindromic repeats) is a prokaryotic adaptive defence system, providing immunity against mobile genetic elements such as viruses. Genomically encoded crRNA (CRISPR RNA) is used by Cas (CRISPR associated) proteins to target and subsequently degrade nucleic acids of invading entities in a sequence-dependent manner. The process is known as 'interference'. In the present review we cover recent progress on the structural biology of the CRISPR/Cas system, focusing on the Cas proteins and complexes that catalyse crRNA biogenesis and interference. Structural studies have helped in the elucidation of key mechanisms, including the recognition and cleavage of crRNA by the Cas6 and Cas5 proteins, where remarkable diversity at the level of both substrate recognition and catalysis has become apparent. The RNA-binding RAMP (repeat associated mysterious protein) domain is present in the Cas5, Cas6, Cas7 and Cmr3 protein families and RAMP-like domains are found in Cas2 and Cas10. Structural analysis has also revealed an evolutionary link between the small subunits of the type I and type III-B interference complexes. Future studies of the interference complexes and their constituent components will transform our understanding of the system. PMID- 23805975 TI - Is there a simple way to reliable simulations of infrared spectra of organic compounds? AB - To assess the ability of the quantum-chemical computations to reproduce the experimental relative intensities in the infrared (IR) spectra of both the gas- and condensed-phase systems, the hybrid DFT functional B3LYP has been applied to simulation of IR spectra for species containing from three to twelve first- or second-row atoms, both in the gas phase and in CCl4 solutions. The results demonstrate that B3LYP, combined with the highly compact double-zeta basis set 6 31+G* and "scaled quantum mechanics" techniques, offers excellent quantitative performance in the calculations of relative IR intensities and frequencies (nu <= 2200 cm(-1)) for the bands of vibrations of medium-size isolated molecules, whereas it produces unsatisfactory results for the solutions of the same species. Neither larger basis sets nor implicit treatment of the media effects improve the agreement of the simulated spectra with the condensed-phase experiment. At the same time, some preliminary results suggest that explicit modeling of media effects could offer better quality of the IR spectral simulations for the condensed-phase systems. PMID- 23805976 TI - Diboran(4)yl platinum(II) complexes. AB - The platinum diboran(4)yl complexes 1-3 have been prepared by the selective oxidative addition of one B-Hal bond in aryl-substituted diboranes(4) Hal2B2Ar2 (Hal = Cl, Ar = mes, dur; Hal = I, Ar = mes). Because of the electron deficiency of the remote B2 atom, all species show a rare dative Pt-B bonding interaction, whose magnitude is strongly dependent on the nature of the halide substituent. PMID- 23805977 TI - Thermodynamic and kinetic study of cleavage of the N-O bond of N-oxides by a vanadium(III) complex: enhanced oxygen atom transfer reaction rates for adducts of nitrous oxide and mesityl nitrile oxide. AB - Thermodynamic, kinetic, and computational studies are reported for oxygen atom transfer (OAT) to the complex V(N[t-Bu]Ar)3 (Ar = 3,5-C6H3Me2, 1) from compounds containing N-O bonds with a range of BDEs spanning nearly 100 kcal mol(-1): PhNO (108) > SIPr/MesCNO (75) > PyO (63) > IPr/N2O (62) > MesCNO (53) > N2O (40) > dbabhNO (10) (Mes = mesityl; SIPr = 1,3-bis(diisopropyl)phenylimidazolin-2 ylidene; Py = pyridine; IPr = 1,3-bis(diisopropyl)phenylimidazol-2-ylidene; dbabh = 2,3:5,6-dibenzo-7-azabicyclo[2.2.1]hepta-2,5-diene). Stopped flow kinetic studies of the OAT reactions show a range of kinetic behavior influenced by both the mode and strength of coordination of the O donor and its ease of atom transfer. Four categories of kinetic behavior are observed depending upon the magnitudes of the rate constants involved: (I) dinuclear OAT following an overall third order rate law (N2O); (II) formation of stable oxidant-bound complexes followed by OAT in a separate step (PyO and PhNO); (III) transient formation and decay of metastable oxidant-bound intermediates on the same time scale as OAT (SIPr/MesCNO and IPr/N2O); (IV) steady-state kinetics in which no detectable intermediates are observed (dbabhNO and MesCNO). Thermochemical studies of OAT to 1 show that the V-O bond in O=V(N[t-Bu]Ar)3 is strong (BDE = 154 +/- 3 kcal mol( 1)) compared with all the N-O bonds cleaved. In contrast, measurement of the N-O bond in dbabhNO show it to be especially weak (BDE = 10 +/- 3 kcal mol(-1)) and that dissociation of dbabhNO to anthracene, N2, and a (3)O atom is thermodynamically favorable at room temperature. Comparison of the OAT of adducts of N2O and MesCNO to the bulky complex 1 show a faster rate than in the case of free N2O or MesCNO despite increased steric hindrance of the adducts. PMID- 23805974 TI - Brown adipose tissue: development, metabolism and beyond. AB - Obesity represents a major risk factor for the development of several of our most common medical conditions, including Type 2 diabetes, dyslipidaemia, non alcoholic fatty liver, cardiovascular disease and even some cancers. Although increased fat mass is the main feature of obesity, not all fat depots are created equal. Adipocytes found in white adipose tissue contain a single large lipid droplet and play well-known roles in energy storage. By contrast, brown adipose tissue is specialized for thermogenic energy expenditure. Owing to its significant capacity to dissipate energy and regulate triacylglycerol (triglyceride) and glucose metabolism, and its demonstrated presence in adult humans, brown fat could be a potential target for the treatment of obesity and metabolic syndrome. Undoubtedly, fundamental knowledge about the formation of brown fat and regulation of its activity is imperatively needed to make such therapeutics possible. In the present review, we integrate the recent advancements on the regulation of brown fat formation and activity by developmental and hormonal signals in relation to its metabolic function. PMID- 23805978 TI - Detecting insomnia in patients with low back pain: accuracy of four self-report sleep measures. AB - BACKGROUND: Although insomnia is common in patients with low back pain (LBP), it is unknown whether commonly used self-report sleep measures are sufficiently accurate to screen for insomnia in the LBP population. This study investigated the discriminatory properties of the Pittsburgh Sleep Quality Index (Pittsburgh questionnaire), Insomnia Severity Index (Insomnia index), Epworth Sleepiness Scale (Epworth scale) and the sleep item of the Roland and Morris Disability Questionnaire (Roland item) to detect insomnia in patients with LBP by comparing their accuracy to detect insomnia to a sleep diary. The study also aimed to determine the clinical optimal cut-off scores of the questionnaires to detect insomnia in the LBP population. METHODS: Seventy nine patients with LBP completed the four self-reported questionnaires and a sleep diary for 7 consecutive nights. The accuracy of the questionnaires was evaluated using Receiver Operator Characteristic (ROC) curves with the Area Under the Curve (AUC) used to examine each test's accuracy to discriminate participants with insomnia from those without insomnia. RESULTS: The Pittsburgh questionnaire and Insomnia index had moderate accuracy to detect insomnia (AUC = 0.79, 95% CI = 0.68 to 0.87 and AUC = 0.78, 95% CI = 0.67 to 0.86 respectively), whereas the Epworth scale and the Roland item were not found to be accurate discriminators (AUC = 0.53, 95% CI = 0. 41 to 0.64 and AUC = 0.64, 95% CI = 0.53 to 0.75 respectively). The cut-off score of > 6 for the Pittsburgh questionnaire and the cut-off point of > 14 for the Insomnia index provided optimal sensitivity and specificity for the detection of insomnia. CONCLUSIONS: The Pittsburgh questionnaire and Insomnia index had similar ability to screen for insomnia in patients with low back pain. PMID- 23805979 TI - Aerobic training and angiogenesis activation in patients with stable chronic heart failure: a preliminary report. AB - The pathophysiology of chronic heart failure (CHF) involves multiple hystologic and molecular alterations. To determine the effects of physical training on circulating endothelial progenitor cells (EPCs), angiogenesis (angiogenin, angiopoietin-1 and -2, VEGF, Tie-2, SDF-1alpha) and inflammation (IL-6, CRP), we compared data obtained from 11 CHF pts before and after 3 months aerobic exercise training, to those from 10 non trained CHF pts (CHF-C group, age 64 + 2 years, NYHA 2). At the end of the study, EPCs count and AP-2 serum levels significantly increased in the CHF-TR group. These preliminary data suggest a significant effect of even a short program of physical training on angiogenic activation and endothelial dysfunction. PMID- 23805980 TI - MDR1 mRNA expression and MDR1 gene variants as predictors of response to chemotherapy in patients with acute myeloid leukaemia: a meta-analysis. AB - Data from 30 pharmacogenomic studies that investigated MDR1 mRNA expression or gene variants (C3435T, G2677TA, C1236T) and response to therapy in acute myeloid leukaemia (AML) were synthesized. Anthracycline-based regimens were mainly used. MDR1 mRNA overexpression was associated with poor response to therapy [odds ratio (OR) = 2.49 95% confidence interval (CI) 1.38-4.50]. The gene variants were not associated with response to treatment; the generalized ORs, a genetic model-free approach, for the variants C3435T, G2677TA and C1236T were ORG = 0.86 (95% CI 0.55-1.37), ORG = 0.97 (95% CI 0.58-1.64) and ORG = 1.17 (95% CI 0.75--1.83), respectively. There is indication that MDR1 mRNA expression may be considered as a potential marker for response to chemotherapy in AML patients. PMID- 23805981 TI - Turning over a new leaf in plant genomics. PMID- 23805982 TI - Twin pregnancy in patients with a uterine anomaly. AB - OBJECTIVE: In singleton pregnancies, a uterine anomaly is a known risk factor for preterm birth and fetal growth restriction. Data on outcomes of twin pregnancies with uterine anomalies is limited to case reports. The objective of this study was to compare outcomes in twin pregnancies based on the presence or not of a uterine anomaly. METHODS: This was a retrospective cohort of twin pregnancies managed by a single maternal-fetal medicine practice from 2005 to 2012. Patients with monoamniotic twins and twin-twin transfusion syndrome were excluded. Pregnancy outcomes were compared between patients with and without a uterine anomaly. Nonparametric tests (Fisher's exact test, Mann-Whitney U) were used for analysis. A p value of <= 0.05 was considered significant. RESULTS: Five hundred and fifty-six twin pregnancies were included, 17 (3.1%) of whom had a known uterine anomaly (nine septate uterus, three bicornuate, three arcuate, one unicornuate and one didelphys). Patients with a uterine anomaly had significantly worse outcomes, including cerclage, preterm birth and lower median birth weights. Birth weight less than the 10th or 5th percentile for gestational age was not more common in patients with a uterine anomaly, nor was there an increase in birth weight discordancy. CONCLUSION: In patients with twin pregnancies, the presence of a uterine anomaly is associated with an increased risk of cerclage, preterm birth and lower birth weights, but not fetal growth restriction. PMID- 23805983 TI - Chlorotropy of 1-chlorobenzimidazole. AB - The chlorotropy observed by NMR in this study occurred by the rapid intermolecular transfer of a chloro group between 1-chlorobenzimidazole and benzimidazole in CCl4/CH3OH/K2CO3 solution. PMID- 23805984 TI - Reactive nitrogen and oxygen species in anticoagulated blood of healthy sheep. AB - BACKGROUND: Little or no study has been done to compare the indices of 'nitrosative' and 'oxidative' stresses, especially in terms of correlation and the possible differential effects of the chelating agents. OBJECTIVE: This preliminary study investigated possible correlations between the indices of reactive nitrogen species (RNS) and reactive oxygen species (ROS) in blood, effect of anticoagulated-blood tubes, and impact of blood-clotting pathways. METHODS: Thirty blood samples from sheep were collected into ethylenediamine tetraacetic acid (EDTA) and citrate tubes at the Berrima Veterinary Laboratory using their standard protocol. Nitrosative and oxidative stress indices were then measured and correlation analyses performed. RESULTS: The ROS and RNS indices were weakly correlated (r > 0.2; p < 0.05) with each other from the EDTA sample, but not from citrated blood. None of the nitrosative or oxidative stress biomarkers was significantly associated with changes in the prothrombin time. The activated partial thromboplastin time showed statistically significant association with some oxidative stress indices (catalase and malondialdehyde), but with none of the nitrosative stress indices. Further, all measured parameters were higher in EDTA than in citrate blood (p < 0.0001). CONCLUSION: The choice of anticoagulated blood tube could affect the measures of nitrosative stress indices and may impact on the potential correlations between nitrosative versus oxidative stress biomarkers. Perhaps the suggestion that EDTA is better than citrate for hematological anticoagulant studies should be considered for nitrosative and oxidative stress studies. PMID- 23805985 TI - Ultrarapid generation of femtoliter microfluidic droplets for single-molecule counting immunoassays. AB - We report a microfluidic droplet-based approach enabling the measurement of chemical reactions of individual enzyme molecules and its application to a single molecule-counting immunoassay. A microfluidic device is used to generate and manipulate <10 fL droplets at rates of up to 1.3 * 10(6) per second, about 2 orders of magnitude faster than has previously been reported. The femtodroplets produced with this device can be used to encapsulate single biomolecular complexes tagged with a reporter enzyme; their small volume enables the fluorescent product of a single enzyme molecule to be detected within 10 min of on-chip incubation. Our prototype system is validated by detection of a biomarker for prostate cancer in buffer, down to a concentration of 46 fM. This work demonstrates a highly flexible and sensitive diagnostic platform that exploits extremely high-speed generation of monodisperse femtoliter droplets for the counting of individual analyte molecules. PMID- 23805986 TI - A novel solvent-free approach to imidazole containing nitrogen-bridgehead heterocycles. AB - A very simple domino reaction under solvent-free conditions of various pyridine like heterocycles with 1,2-diaza-1,3-dienes produces in good yields imidazo[1,2 a]pyridines, imidazo[1,2-a]quinolines, and imidazo[2,1-a]isoquinolines. The advantage of this one-pot transformation lies in the use of simple pyridine-like compounds without prefunctionalization of the starting heterocycles. PMID- 23805987 TI - Proton transfer in nucleobases is mediated by water. AB - Water plays a central role in chemistry and biology by mediating the interactions between molecules, altering energy levels of solvated species, modifying potential energy profiles along reaction coordinates, and facilitating efficient proton transport through ion channels and interfaces. This study investigates proton transfer in a model system comprising dry and microhydrated clusters of nucleobases. With mass spectrometry and tunable vacuum ultraviolet synchrotron radiation, we show that water shuts down ionization-induced proton transfer between nucleobases, which is very efficient in dry clusters. Instead, a new pathway opens up in which protonated nucleobases are generated by proton transfer from the ionized water molecule and elimination of a hydroxyl radical. Electronic structure calculations reveal that the shape of the potential energy profile along the proton transfer coordinate depends strongly on the character of the molecular orbital from which the electron is removed; i.e., the proton transfer from water to nucleobases is barrierless when an ionized state localized on water is accessed. The computed energetics of proton transfer is in excellent agreement with the experimental appearance energies. Possible adiabatic passage on the ground electronic state of the ionized system, though energetically accessible at lower energies, is not efficient. Thus, proton transfer is controlled electronically, by the character of the ionized state, rather than statistically, by simple energy considerations. PMID- 23805989 TI - Recurrent knee arthritis diagnosed as juvenile idiopathic arthritis with a 10 year asymptomatic period after arthroscopic synovectomy: a case report. AB - INTRODUCTION: Juvenile idiopathic arthritis is a chronic inflammatory disease associated with arthritis of unknown etiology that begins before the age of 16 and persists for longer than 6 weeks. The frequency of recurrence after arthroscopic synovectomy in patients with oligoarthritis juvenile idiopathic arthritis was reported to be lower than that in patients with polyarthritis. However, recurrence in cases of oligoarthritis after arthroscopic knee synovectomy was shown to be 67% in one recent study and, furthermore, a shorter period free from recurrence was also reported after synovectomy. Here we report a child who suffered recurrent knee arthritis with a 10-year asymptomatic period after arthroscopic synovectomy. CASE PRESENTATION: A 12-year-old Japanese girl presented with normal birth and developmental history. At the age of 2 years she experienced joint swelling in both knees. Her symptoms continued and arthroscopic synovectomy was eventually performed. During the operation, rice bodies and thickening of the synovial membrane were observed; however, no definitive diagnosis was made. After a 10-year asymptomatic period, knee joint swelling recurred on one side without any cause. Arthroscopic synovectomy was beneficial in reducing the symptoms and in diagnosis. CONCLUSIONS: Children who suffer prolonged joint swelling have a risk of juvenile idiopathic arthritis. Even if the symptoms heal and no definite diagnosis is made at the first treatment, informed consent is needed to make the patients understand the future risk of recurrent arthritis after even lengthy asymptomatic periods. PMID- 23805988 TI - Insulin receptor membrane retention by a traceable chimeric mutant. AB - BACKGROUND: The insulin receptor (IR) regulates glucose homeostasis, cell growth and differentiation. It has been hypothesized that the specific signaling characteristics of IR are in part determined by ligand-receptor complexes localization. Downstream signaling could be triggered from the plasma membrane or from endosomes. Regulation of activated receptor's internalization has been proposed as the mechanism responsible for the differential isoform and ligand specific signaling. RESULTS: We generated a traceable IR chimera that allows the labeling of the receptor at the cell surface. This mutant binds insulin but fails to get activated and internalized. However, the mutant heterodimerizes with wild type IR inhibiting its auto-phosphorylation and blocking its internalization. IR membrane retention attenuates AP-1 transcriptional activation favoring Akt activation. CONCLUSIONS: These results suggest that the mutant acts as a selective dominant negative blocking IR internalization-mediated signaling. PMID- 23805990 TI - Utility of the multivariate approach in predicting beta-thalassemia intermedia or beta-thalassemia major types In Iranian patients. AB - Recently, five genetic modifiers [beta-globin mutations, coinheritance of alpha thalassemia (alpha-thal), XmnI polymorphism and single nucleotide polymorphisms (SNPs) in the BCL11A and HBS1L-MYB loci] were used to predict the beta-thal major (beta-TM) or beta-thal intermedia (beta-TI) types in 106 French patients with 83.2% accuracy. The dichotomous grouping was based on the age when the patient received his/her first transfusion (4 years). Here, a similar study was conducted in a cohort of 306 Iranian beta-thal patients having distinct beta-globin mutations and minor allele frequencies of key SNPs in these loci. Multivariate regression analyses and a simple scoring system were used to predict the beta TM/beta-TI types using three scenarios: 1) when considering only the severe beta TM and the mild beta-TI cases, 2) using clinical parameters for beta-thal typing, and 3) using age at first transfusion as the basis for classification. Using these scenarios, the beta-thal types could be correctly predicted in 77.6, 75.5 and 68.0% of cases, respectively. PMID- 23805991 TI - Comparison of oral and intravenous fluid therapy in newborns with hypernatremic dehydration. AB - OBJECTIVE: To evaluate the efficacy and complications of oral and intravenous fluid therapy in newborns with hypernatremic dehydration. METHODS: A total of 75 term and near-term (>35 weeks) neonates with hypernatremic dehydration (Na >= 150 mmol/L) were included in this retrospective study. The patients were divided into two groups according to therapy approach for rehydration (breast milk-oral formula and intravenous fluid). The decline in sodium concentration (<0.5 mmol/L/h was regarded as safe drop) and complications were analyzed. RESULTS: The mean gestational age, birth weight and age at admission were 38.9 +/- 1.4(36-42) weeks, 3341 +/- 504 (2500-4500) gram and 4.3 +/- 2.6 (1-17) day, respectively. Fever (61.8%) and jaundice (39.4%) were the most common presenting signs. Forty four (58.6%) of the infants were treated with breast milk and/or oral formula (group 1) and 31 (41.4%) of the infants were treated with IV fluid (group 2). In group 1 and group 2, respectively, mean % weight loss, 5 and 7.5; median serum sodium at admission, 153 and 152 mmol/L; median change in sodium at 12 hours, 7 and 11 mmol/L; and median change in sodium at 24 hours, 10 and 15 mmol/L. The decline in sodium concentration was more safely in group 1 than group 2 at both 12 and 24 hours of rehydration. One patient had convulsion associated with cerebral edema in group 2. Otherwise no complication was observed in both groups. CONCLUSION: Enteral route for fluid replacement may be safe and effective and may be an alternative to intravenous fluid therapy in newborns with hypernatremic dehydration when clinical situation is stable. PMID- 23805992 TI - In situ study of atomic structure transformations of Pt-Ni nanoparticle catalysts during electrochemical potential cycling. AB - When exposed to corrosive anodic electrochemical environments, Pt alloy nanoparticles (NPs) undergo selective dissolution of the less noble component, resulting in catalytically active bimetallic Pt-rich core-shell structures. Structural evolution of PtNi6 and PtNi3 NP catalysts during their electrochemical activation and catalysis was studied by in situ anomalous small-angle X-ray scattering to obtain insight in element-specific particle size evolution and time resolved insight in the intraparticle structure evolution. Ex situ high-energy X ray diffraction coupled with pair distribution function analysis was employed to obtain detailed information on the atomic-scale ordering, particle phases, structural coherence lengths, and particle segregation. Our studies reveal a spontaneous electrochemically induced formation of PtNi particles of ordered Au3Cu-type alloy structures from disordered alloy phases (solid solutions) concomitant with surface Ni dissolution, which is coupled to spontaneous residual Ni metal segregation during the activation of PtNi6. Pt-enriched core-shell structures were not formed using the studied Ni-rich nanoparticle precursors. In contrast, disordered PtNi3 alloy nanoparticles lose Ni more rapidly, forming Pt enriched core-shell structures with superior catalytic activity. Our X-ray scattering results are confirmed by STEM/EELS results on similar nanoparticles. PMID- 23805993 TI - Synthesis of chromone, quinolone, and benzoxazinone sulfonamide nucleosides as conformationally constrained inhibitors of adenylating enzymes required for siderophore biosynthesis. AB - MbtA catalyzes the first committed step of mycobactin biosynthesis in Mycobacterium tuberculosis (Mtb) and is responsible for the incorporation of salicylic acid into the mycobactin siderophores. 5'-O-[N (Salicyl)sulfamoyl]adenosine (Sal-AMS) is an extremely potent nucleoside inhibitor of MbtA that possesses excellent activity against whole-cell Mtb but suffers from poor bioavailability. In an effort to improve the bioavailability, we have designed four conformationally constrained analogues of Sal-AMS that remove two rotatable bonds and the ionized sulfamate group on the basis of computational and structural studies. Herein we describe the synthesis, biochemical, and microbiological evaluation of chromone-, quinolone-, and benzoxazinone-3-sulfonamide derivatives of Sal-AMS. We developed new chemistry to assemble these three heterocycles from common beta-ketosulfonamide intermediates. The synthesis of the chromone- and quinolone-3-sulfonamide intermediates features formylation of a beta-ketosulfonamide employing dimethylformamide dimethyl acetal to afford an enaminone that can react intramolecularly with a phenol or intermolecularly with a primary amine via addition-elimination reaction(s). The benzoxazinone-3-sulfonamide was prepared by nitrosation of a beta-ketosulfonamide followed by intramolecular nucleophilic aromatic substitution. Mitsunobu coupling of these bicyclic sulfonamides with a protected adenosine derivative followed by global deprotection provides a concise synthesis of the respective inhibitors. PMID- 23805995 TI - Xanthone glycoside constituents of Swertia kouitchensis with alpha-glucosidase inhibitory activity. AB - Ten new xanthone glycosides, kouitchensides A-J (1-10), and 11 known analogues were isolated from an n-butanol fraction of Swertia kouitchensis. The structures of these glycosides were determined on the basis of extensive spectroscopic data interpretation and comparison with data reported in the literature. In an in vitro test, compounds 2, 4, 5, 6, 11, 12, and 13 (IC50 values in the range 126 to 451 MUM) displayed more potent inhibitory effects against alpha-glucosidase activity than the positive control, acarbose (IC50 value of 627 MUM). PMID- 23805994 TI - The ARIQUELI study: potentiation of quetiapine in bipolar I nonresponders with lithium versus aripiprazole. AB - BACKGROUND: The treatment of bipolar disorder (BD) remains a challenge due to the complexity of the disease. Current guidelines represent an effort to assist clinicians in routine practice but have several limitations, particularly concerning long-term treatment. The ARIQUELI (efficacy and tolerability of the combination of lithium or aripiprazole in young bipolar non or partial responders to quetiapine monotherapy) study aims to evaluate two different augmentation strategies for quetiapine nonresponders or partial responders in acute and maintenance phases of BD treatment. METHODS/DESIGN: The ARIQUELI study is a single-site, parallel-group, randomized, outcome assessor-blinded trial. BD I patients according to the DSM-IV-TR, in depressive, manic/hypomanic or mixed episode, aged 18 to 40 years, are eligible. After diagnostic assessments, patients initiated treatment in phase I with quetiapine. Nonresponders or partial responders after 8 weeks are allocated into one of two groups, potentiated with either lithium (0.5 to 0.8 mEq/l) or aripiprazole (10 or 15 mg). Patients will be followed up for 8 weeks in phase I (acute treatment), 6 months in phase II (continuation treatment) and 12 months in phase III (maintenance treatment). Outcome assessors are blinded to the treatment. The primary outcome is the evaluation of changes in mean scores on the CGI-BP-M between baseline and the endpoint at the end of each study phase. DISCUSSION: The ARIQUELI study is currently in progress, with patients undergoing acute treatment (phase I), potentiation (phase II) and maintenance (phase III). The study will be extended until January 2015. Trials comparing lithium and aripiprazole with potentiate treatment in young BD I nonresponders to quetiapine in monotherapy can provide relevant information on the safety of these drugs in clinical practice. Long-term treatment is an issue of great importance and should be evaluated further through more in-depth studies given that BD is a chronic disease. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01710163. PMID- 23805996 TI - Hexagonal-diamond-like gold lattices, Ba and (Au,T)3 interstitials, and delocalized bonding in a family of intermetallic phases Ba2Au6(Au,T)3 (T = Zn, Cd, Ga, In, or Sn). AB - Au-rich polar intermetallics exhibit a wide variety of structural motifs, and this hexagonal-diamond-like gold host is unprecedented. The series Ba2Au6(Au,T)3 (T = Zn, Cd, Ga, In, or Sn), synthesized through fusion of the elements at 700 800 degrees C followed by annealing at 400-500 degrees C, occur in space group R3[overline]c (a ~ 8.6-8.9 A, c ~ 21.9-22.6 A, and Z = 6). Their remarkable structure, generated by just three independent atoms, features a hexagonal diamond-like gold superstructure in which tunnels along the 3-fold axes are systematically filled by interstitial Ba atoms (blue) and triangles of disordered (Au,T)3 atoms (green) in 2:1 proportions. The Au/Zn mixing in the latter spans ~34 to 87% Zn, whereas the Au/Sn result is virtually invariant compositionally. Complementary bonding between the gold lattice and the disordered (Au,T)3 units is substantial and very regular. Bonding and charge density analyses indicate delocalized bonding within the gold host and the (Au,T)3 triangular units, and moderately polarized bonding between Ba and the electronegative framework. The new structure can also be viewed empirically as the result of an atom-by-triad [i.e., Ba by (Au,T)3 triangle] topological substitution in a BaAu2 (AlB2-type) superstructure. PMID- 23805997 TI - Israel is failing to protect its citizens from secondhand smoke: underestimating public support. AB - Rather than clearly and unequivocally requiring 100% smokefree workplaces and public places (including restaurants, bars and other entertainment venues), Israeli law contains several elements that parallel the tobacco companies' "accommodation" program, which is designed to maintain the social acceptability of smoking and protect industry profits. Rather than 100% smokefree workplaces, smoking is permitted in private offices despite the fact that it then wafts throughout the building. Bars and pubs are allowed to set aside a quarter of their space for smokers, as long as it is in a separate room, and this explains the dangerous levels of secondhand smoke air pollution in Israeli bars and pubs. The weaknesses in the current Israeli laws are sending Israeli citizens to the hospital for secondhand smoke-induced heart attacks, asthma and other diseases. The Israeli government needs to catch up with the rest of the developed world and enact and implement a strong smokefree law.This is a commentary on http://www.ijhpr.org/content/2/1/20/. PMID- 23805998 TI - GP perspectives of irritable bowel syndrome--an accepted illness, but management deviates from guidelines: a qualitative study. AB - BACKGROUND: The estimated prevalence of irritable bowel syndrome (IBS) is 10%. Up to one third of patients develop chronic symptoms, which impact on everyday functioning and psychological wellbeing. Guidelines suggest an increased role for primary care in the management of patients with IBS, and referral for psychological interventions. Literature reports dissatisfaction and frustration experienced by both patients with IBS and healthcare professionals. The aim of this study was to explore the perspectives of general practitioners (GPs) in relation to the diagnosis and management of IBS and their views on the potential use of a risk assessment tool to aid management decisions for patients with IBS in primary care. METHODS: This was a qualitative study using face-to-face semi structured interviews with GPs in North West England. Interviews were fully transcribed and data analyzed using constant comparison across interviews. Tensions between GP accounts and the NICE guideline for the management of IBS were highlighted. RESULTS: GPs described IBS as a diagnosis of exclusion and the process as tentative and iterative, with delay in adding a Read code to the patient record until they were confident of the diagnosis. Whilst GPs accepted there was a link between IBS and psychological symptoms they suggested that the majority of patients could be managed within primary care without referral for psychological interventions, in conflict with the NICE guideline. They did not feel that a risk assessment tool for patients with IBS would be helpful. CONCLUSIONS: This study highlights the tensions between evidence recognizing the need to identify patients whose symptoms may become chronic and offer pro-active care, including referral for psychological therapies, and the perspectives of GPs managing patients in every-day clinical practice. The reluctance of GPs to refer patients for evidence-based psychological treatments may have implications for commissioning services and patient care. PMID- 23805999 TI - Does the think-aloud protocol reflect thinking? Exploring functional neuroimaging differences with thinking (answering multiple choice questions) versus thinking aloud. AB - BACKGROUND: Whether the think-aloud protocol is a valid measure of thinking remains uncertain. Therefore, we used functional magnetic resonance imaging (fMRI) to investigate potential functional neuroanatomic differences between thinking (answering multiple-choice questions in real time) versus thinking aloud (on review of items). METHODS: Board-certified internal medicine physicians underwent formal think-aloud training. Next, they answered validated multiple choice questions in an fMRI scanner while both answering (thinking) and thinking aloud about the questions, and we compared fMRI images obtained during both periods. RESULTS: Seventeen physicians (15 men and 2 women) participated in the study. Mean physician age was 39.5 + 7 (range: 32-51 years). The mean number of correct responses was 18.5/32 questions (range: 15-25). Statistically significant differences were found between answering (thinking) and thinking aloud in the following regions: motor cortex, bilateral prefrontal cortex, bilateral cerebellum, and the basal ganglia (p < 0.01). DISCUSSION: We identified significant differences between answering and thinking aloud within the motor cortex, prefrontal cortex, cerebellum, and basal ganglia. These differences were by degree (more focal activation in these areas with thinking aloud as opposed to answering). Prefrontal cortex and cerebellum activity was attributable to working memory. Basal ganglia activity was attributed to the reward of answering a question. The identified neuroimaging differences between answering and thinking aloud were expected based on existing theory and research in other fields. These findings add evidence to the notion that the think-aloud protocol is a reasonable measure of thinking. PMID- 23806000 TI - Relationships among circadian typology, psychological symptoms, and sensation seeking. AB - Recently, attention has been focused on the relationship among circadian typology, psychiatric symptoms, and personality traits. This study analyzes the influence of circadian typology on psychological distress, and the sensation seeking personality trait. Five hundred seventeen college students (173 males), aged 17 to 30, answered the Composite Scale of Morningness (CSM), the General Health Questionnaire 28-item version (GHQ-28), and the Sensation Seeking Scale-V (SSS-V). The evening-type subjects in our sample scored higher than the neither- and morning- type in the GHQ-28 total score, as well as in the four subscales that composed it (Psychosomatic Symptoms, Anxiety and Insomnia, Social Dysfunction, and Severe Depression) (p<0.02 in all cases). The evening-type subjects also had a larger proportion of psychiatric cases than the other two circadian typologies (p<0.0001 in all cases). Moreover, the evening-type subjects obtained higher scores in the SSS-V total score and in the subscales of Disinhibition and Boredom Susceptibility (p<0.001 in all cases). A positive correlation was observed between the GHQ-28 and the SSS-V total scores in the total sample, but only for the evening-type group (r=0.217; p<0.027). In the evening group, several relations were also found between the subscales of the GHQ 28 and the subscales of the SSS-V (r>0.206; p<0.036). All these data point to a relationship between evening-type subjects and the level of psychological distress and the sensation-seeking personality trait. They also suggest that eveningness could be related to developing psychological distress and personality traits that could, in turn, be related to developing other problems, such as drug consumption. PMID- 23806001 TI - Template-directed fluorogenic oligonucleotide ligation using "click" chemistry: detection of single nucleotide polymorphism in the human p53 tumor suppressor gene. AB - A novel nonfluorescent alkyne-modified coumarin phosphoramidite was synthesized and successfully incorporated into oligonucleotides, which were then used in highly efficient DNA interstrand cross-linking and ligation reactions via "click" chemistry. The template-directed fluorogenic ligation "click" chemistry reaction was used for single nucleotide polymorphism analysis, where the target DNA catalyzes the ligation of two nonfluorescent probes to generate a fluorescent product. The upstream oligonucleotide probe is a nonfluorescent alkyne-modified coumarin and the downstream probe is an azide-modified oligonucleotide. When bound to a fully complementary template, the oligonucleotides ligated to produce a fluorescent product with a fluorophore at the ligation point. Wild-type and mutant p53 alleles were used to demonstrate that template-directed fluorogenic oligonucleotide ligation is sequence-specific and is capable of single nucleotide discrimination under mild conditions, even without the removal of unreacted probes. PMID- 23806002 TI - A novel type of highly effective nonionic gemini alkyl O-glucoside surfactants: a versatile strategy of design. AB - A novel type of highly effective gemini alkyl glucosides has been rationally designed and synthesized. The gemini surfactants have been readily prepared by glycosylation of the gemini alkyl chains that are synthesized with regioselective ring-opening of ethylene glycol epoxides by the alkyl alcohols. The new gemini alkyl glucosides exhibit significantly better surface activity than the known results. Then rheological, DLS, and TEM studies have revealed the intriguing self assembly behavior of the novel gemini surfactants. This study has proved the effectiveness of the design of gemini alkyl glucosides which is modular, extendable, and synthetically simple. The new gemini surfactants have great potential as nano carriers in drug and gene delivery. PMID- 23806003 TI - Our genomes today: time to be clear. PMID- 23806005 TI - People are more likely to be insincere when they are more likely to accidentally tell the truth. AB - Although people lie often, and mostly for self-serving reasons, they do not lie as much as they could. The "fudge factor" hypothesis suggests that one reason for people not to lie is that they do not wish to self-identify as liars. Accordingly, self-serving lies should be more likely when they are less obvious to the liars themselves. Here we show that the likelihood of self-serving lies increases with the probability of accidentally telling the truth. Players in our game could transmit sincere or insincere recommendations to their competitors. In line with the fudge factor hypothesis, players lied when their beliefs were based on flimsy evidence and did not lie when their beliefs were based on solid evidence. This is the first demonstration of a new moral hypocrisy paradox: People are more likely to be insincere when they are more likely to accidentally tell the truth. PMID- 23806006 TI - Cyclic alpha,beta-tetrapeptoids: sequence-dependent cyclization and conformational preference. AB - The presence of at least one N-Calpha branched side chain is crucial for successful cyclization of alpha,beta-tetrapeptoids. The ctct amide sequence revealed in the crystal structure of the 14-membered cyclotetrapeptoid 8 is also the most populated conformation in solution and is reminiscent of the predominant amide arrangement of the 12-membered cyclic tetrapeptides (CTPs). PMID- 23806004 TI - Immunomodulatory activity of polysaccharides isolated from Clerodendrum splendens: beneficial effects in experimental autoimmune encephalomyelitis. AB - BACKGROUND: Extracts of leaves from Clerodendrum have been used for centuries to treat a variety of medicinal problems in tropical Africa. However, little is known about the high-molecular weight active components conferring therapeutic properties to these extracts. METHODS: Polysaccharides from the leaves of Clerodendrum splendens were extracted and fractionated by ion exchange and size exclusion chromatography. Molecular weight determination, sugar analysis, degree of methyl esterification, and other chemical characterization of the fractions were performed. Immunomodulatory activity of the fractions was evaluated by determining their ability to induce monocyte/macrophage nitric oxide (NO), cytokine production, and mitogen-activated protein kinase (MAPK) phosphorylation. Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice, and severity of EAE was monitored in mice treated with intraperitoneal (i.p.) injections of the most active polysaccharide fraction. Lymph nodes (LN) and spleen were harvested, and levels of cytokines in supernatants from LN cells and splenocytes challenged with myelin oligodendrocyte glycoprotein peptide were determined. RESULTS: Fractions containing type II arabinogalactan had potent immunomodulatory activity. Specifically, the high-molecular weight sub-fraction CSP-AU1 (average of 38.5 kDa) induced NO and cytokine [interleukin (IL)-1alpha, 1beta, -6, -10, tumor necrosis factor (TNF; designated previously as TNF-alpha), and granulocyte macrophage-colony stimulating factor (GM-CSF)] production by human peripheral blood mononuclear cells (PBMCs) and monocyte/macrophages. CSP AU1-induced secretion of TNF was prevented by Toll-like receptor 4 (TLR4) antagonist LPS-RS, indicating a role for TLR4 signaling. Treatment with CSP-AU1 also induced phosphorylation of a number of MAPKs in human PBMC and activated AP 1/NF-kappaB. In vivo treatment of mice with CSP-AU1 and CSP-NU1 resulted in increased serum IL-6, IL-10, TNF, monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1alpha/CCL3, and MIP-1beta/CCL4. CSP-AU1 treatment of mice with EAE (50 mg/kg, i.p., daily, 13 days) resulted in significantly reduced disease severity in this experimental model of multiple sclerosis. Levels of IL-13, TNF, interferon (IFN)-gamma, IL-17, and GM-CSF were also significantly decreased, whereas transforming growth factor (TGF)-beta was increased in LN cells from CSP-AU1-treated EAE mice. CONCLUSIONS: Polysaccharide CSP-AU1 is a potent natural innate immunomodulator with a broad spectrum of agonist activity in vitro and immunosupressive properties after chronic administration in vivo. PMID- 23806007 TI - Prognostic significance of beta-human chorionic gonadotropin and PAX8 expression in anaplastic thyroid carcinoma. AB - BACKGROUND: Anaplastic thyroid carcinoma (ATC) is a rare, aggressive malignancy with a median survival of five months. Multimodality treatment is associated with some improvement in survival, but patients are only infrequently curable. Although beta-hCG secretion has been reported in many neoplasms, it has never been described in ATC. The objectives of this study were to report a case of beta hCG-secreting ATC and to study the expression and significance of beta-hCG and PAX8 in an institutional cohort of ATC. METHODS: The sentinel case was characterized and then immunohistochemistry was performed for beta-hCG and PAX8 on 30 ATC patients. Clinical follow-up was obtained by chart review. RESULTS: The sentinel patient with beta-hCG-secreting ATC had a dramatic response to chemotherapy and radiation. After surgical excision of residual disease, the patient developed a regional recurrence of differentiated thyroid carcinoma at 18 months. However, she is now, 30 months after initial therapy, with no evidence of disease and no detectable serum beta-hCG or thyroglobulin. Five of the 30 (17%) total ATCs were positive for beta-hCG and 18 (60%) for PAX8. Outcomes for the beta-hCG-positive cases were not significantly different from those for negative ones. However, none of the other four beta-hCG-positive ATC patients received treatment with either chemotherapy or radiation. Interestingly, PAX8 positivity correlated with statistically significantly better overall survival (p=0.019). CONCLUSIONS: beta-hCG is expressed in a minority of ATCs. Although only a single case in the study had diffuse immunohistochemical expression, the response it showed to aggressive multimodality therapy and the resulting favorable outcome suggest that beta-hCG-positive ATC may be a unique tumor subtype, or possibly even a unique entity. PAX8 is a useful marker of ATC and may be helpful in the differential diagnosis with other malignant neoplasms. PMID- 23806009 TI - Chemodynamics of soft charged nanoparticles in aquatic media: fundamental concepts. AB - A framework is presented for understanding the reactivity of nanoparticulate reactants with ions and small molecules. Without loss of generality, the formalism is developed for the case of nanoparticles in contact with environmentally relevant metal ions. In addition to reactive sites, nanoparticles generally carry indifferent electric charge distributed over either their surface (hard particles) or volume (soft particles). The ensuing structure and composition of the electric double layer formed within and/or outside the nanoparticulate reactants substantially govern the dynamics of their association and dissociation with ions in aquatic media. A defining feature of permeable nanoparticles is that their charges and reactive sites are spatially confined inside a particle body with an inner medium whose properties may be substantially different from those of the bulk solution. Consequently, the chemodynamic properties of nanoparticulate complexants may differ significantly from those of simple molecular ligands that are homogeneously dispersed in solution. The various physicochemical processes underlying the dynamic reactivity of nanoparticles toward metal ions are here identified, with a focus on the key role played by conductive-diffusion of both metal ions and nanoparticles, the partitioning of ions within the reactive nanoparticulate volume, and the dynamics of the local association/dissociation processes with the reactive sites. The nature of the rate-limiting step in the overall formation/dissociation of the nanoparticulate complexes is shown to depend on the size of the nanoparticle, its charge density, and the ionic strength of the bulk medium. The consequences of these features are further elaborated within the context of dynamics of metal partitioning at a macroscopic consuming biological interphase in the presence of metal complexing nanoparticles. PMID- 23806008 TI - Characterising food environment exposure at home, at work, and along commuting journeys using data on adults in the UK. AB - BACKGROUND: Socio-ecological models of behaviour suggest that dietary behaviours are potentially shaped by exposure to the food environment ('foodscape'). Research on associations between the foodscape and diet and health has largely focussed on foodscapes around the home, despite recognition that non-home environments are likely to be important in a more complete assessment of foodscape exposure. This paper characterises and describes foodscape exposure of different types, at home, at work, and along commuting routes for a sample of working adults in Cambridgeshire, UK. METHODS: Home and work locations, and transport habits for 2,696 adults aged 29-60 were drawn from the Fenland Study, UK. Food outlet locations were obtained from local councils and classified by type - we focus on convenience stores, restaurants, supermarkets and takeaway food outlets. Density of and proximity to food outlets was characterised at home and work. Commuting routes were modelled based on the shortest street network distance between home and work, with exposure (counts of food outlets) that accounted for travel mode and frequency. We describe these three domains of food environment exposure using descriptive and inferential statistics. RESULTS: For all types of food outlet, we found very different foodscapes around homes and workplaces (with overall outlet exposure at work 125% higher), as well as a potentially substantial exposure contribution from commuting routes. On average, work and commuting environments each contributed to foodscape exposure at least equally to residential neighbourhoods, which only accounted for roughly 30% of total exposure. Furthermore, for participants with highest overall exposure to takeaway food outlets, workplaces accounted for most of the exposure. Levels of relative exposure between home, work and commuting environments were poorly correlated. CONCLUSIONS: Relying solely on residential neighbourhood characterisation greatly underestimated total foodscape exposure in this sample, with levels of home exposure unrelated to levels of away from home exposure. Such mis-estimation is likely to be expressed in analyses as attenuated parameter estimates, suggesting a minimal 'environmental' contribution to outcomes of interest. Future work should aim to assess exposure more completely through characterising environments beyond the residential neighbourhood, where behaviours related to food consumption are likely to occur. PMID- 23806010 TI - Divergent synthesis of 4-epi-fagomine, 3,4-dihydroxypipecolic acid, and a dihydroxyindolizidine and their beta-galactosidase inhibitory and immunomodulatory activities. AB - A divergent asymmetric synthesis of the titled iminosugars has been formulated starting from a chiral homoallyl alcohol as the versatile intermediate. The homoallyl alcohol was prepared by a highly diastereoselective Barbier reaction on a d-glucose-derived aldehyde. The protection of its hydroxyl function followed by reductive ozonolysis of the olefin and a subsequent one-pot three-step protocol involving a Staudinger reaction, reductive amination, and benzyloxy carbonyl protection yielded an important bicyclic furanopiperidine derivative. This was converted to the target compounds by following standard reactions. Among the synthesized compounds, 4-epi-fagomine (2b) was the best beta-galactosidase inhibitor, and it also prevented LPS-mediated activation of Raw 264.7 macrophage cells. Its congener, 3,4-dihydroxypipecolic acid (4b) also showed similar trends in its cytokine- and enzyme-inhibitory properties at a low concentration (10 MUM) but was proinflammatory at higher concentrations. The bicyclic compound dihydroxyindolizidine (21) reduced the proinflammatory cytokine (IL-1beta and TNF alpha) levels in the LPS-activated Raw 264.7 cells without showing any enzyme inhibition activity. PMID- 23806011 TI - Two complex associations of an HBD mutation and a rare alpha hemoglobinopathy. AB - We present two case reports in which an HBD mutation is present with a rare alpha hemoglobinopathy that substantially complicates the associated phenotype. In the first case, a new delta-globin variant, Hb A2-Pierre-Benite [delta83(EF7)Gly >Arg; HBD: c.250G>C] is associated with Hb Groene Hart [alpha119(H2)Pro->Ser (alpha1); HBA1: c.358C>T], an alpha-thalassemic variant. In the second case, a delta(+)-thalassemic variant, delta4(A1)Thr->Ile; HBD: c.14C>T, is associated with a newly described deletion of the hypersensitive site 40 (HS-40) region on the alpha-globin gene cluster. In both patients, a delta-globin mutation was suspected because of an abnormally low Hb A2 level, whereas the alpha hemoglobinopathy was sought to explain the slight microcytosis and hypochromia presented by the probands. PMID- 23806012 TI - Hyperbaric oxygen therapy for primary sternal osteomyelitis: a case report. AB - INTRODUCTION: Primary osteomyelitis of the sternum is a rare condition, which accounts for 0.3% of all cases of osteomyelitis reported in the literature. The diagnosis requires a high degree of suspicion and confirmation by percutaneous biopsy. The treatment consists of resection of the periosteum and affected bone. Despite reports of successful conservative treatment using antibiotics alone, early surgical intervention plus bacterial control is the definitive treatment; it reduces morbidity, and is the most cost-effective approach for the patient. We report a case of primary osteomyelitis surgically treated with debridement and antibiotics, followed by hyperbaric oxygen therapy. CASE PRESENTATION: A 39-year old Brazilian man without a significant medical history presented with primary osteomyelitis. After a normal chest radiograph and normal laboratory test results, he was treated with 2 weeks of nonsteroidal anti-inflammatory drugs. One month later a presumptive diagnosis of Tietze syndrome was made and he was prescribed prednisolone (60mg/day) for 3 weeks. The following month he presented to our service with swelling, redness, and warmth in the area between his left third and fourth ribs. Subsequent magnetic resonance imaging revealed a large collection of liquid (8.8*6.8*20.2cm) in his chest wall, between the body and the manubrium of the sternum. An area of soft, friable tissue with a large amount of pus was found in his sternum during surgical debridement. Subsequent treatment consisted of antibiotic therapy using metronidazole and cefotaxime plus hyperbaric oxygen therapy. On postoperative day 10 the incision was sutured. The patient was discharged on postoperative day 15 on a regimen of oral ciprofloxacin, and completed hyperbaric oxygen therapy as an out-patient. CONCLUSIONS: The satisfying outcome of this patient reflects the quick action to promote surgical debridement and use of antibiotics, which are both recommended treatments. The closure of the wound in 10 days after debridement suggests that the hyperbaric oxygen therapy might have indirectly, but not conclusively, aided in the premature closure of the wound, avoiding a longer healing by second intention or muscle flap rotation closure. PMID- 23806014 TI - Bioactive compounds from the roots of Strophioblachia fimbricalyx. AB - Eight new compounds, fimbricalyxs B-D (1-3), fimbricalyxanhydrides A and B (4, 5), and fimbricalyxlactones A-C (6-8), together with three known compounds, trigonostemone (9), 3,6,9-trimethoxyphenanthropolone (10), and fimbricalyx A (11), were isolated from the roots of Strophioblachia fimbricalyx. The structures of the new compounds were elucidated on the basis of their spectroscopic data and, in the case of compounds 2, 4, and 7, confirmed by single-crystal X-ray crystallographic analysis. Compounds 1-4 and 8 were evaluated for their cytotoxicity (KB, MCF7, and NCI-H187 cancer cells) and antiplasmodial activity (Plasmodium falciparum, K1 multidrug-resistant strain). Fimbricalyx B (1) exhibited potent antiplasmodial activity with an IC50 value of 0.019 MUM, while 4 was cytotoxic toward NCI-H187 cancer cells and showed antiplasmodial activities with IC50 values of 5.7 and 3.9 MUM, respectively. In addition, the X-ray structure of 10 and the antiplasmodial activity of 11 are reported herein for the first time. PMID- 23806013 TI - Interreality for the management and training of psychological stress: study protocol for a randomized controlled trial. AB - BACKGROUND: Psychological stress occurs when an individual perceives that environmental demands tax or exceed his or her adaptive capacity. Its association with severe health and emotional diseases, points out the necessity to find new efficient strategies to treat it. Moreover, psychological stress is a very personal problem and requires training focused on the specific needs of individuals. To overcome the above limitations, the INTERSTRESS project suggests the adoption of a new paradigm for e-health--Interreality--that integrates contextualized assessment and treatment within a hybrid environment, bridging the physical and the virtual worlds. According to this premise, the aim of this study is to investigate the advantages of using advanced technologies, in combination with cognitive behavioral therapy (CBT), based on a protocol for reducing psychological stress. METHODS/DESIGN: The study is designed as a randomized controlled trial. It includes three groups of approximately 50 subjects each who suffer from psychological stress: (1) the experimental group, (2) the control group, (3) the waiting list group. Participants included in the experimental group will receive a treatment based on cognitive behavioral techniques combined with virtual reality, biofeedback and mobile phone, while the control group will receive traditional stress management CBT-based training, without the use of new technologies. The wait-list group will be reassessed and compared with the two other groups five weeks after the initial evaluation. After the reassessment, the wait-list patients will randomly receive one of the two other treatments. Psychometric and physiological outcomes will serve as quantitative dependent variables, while subjective reports of participants will be used as the qualitative dependent variable. DISCUSSION: What we would like to show with the present trial is that bridging virtual experiences, used to learn coping skills and emotional regulation, with real experiences using advanced technologies (virtual reality, advanced sensors and smartphones) is a feasible way to address actual limitations of existing protocols for psychological stress. TRIAL REGISTRATION: http://clinicaltrials.gov/ct2/show/NCT01683617. PMID- 23806015 TI - Multiscale analysis of changes in an anisotropic collagen gel structure by culturing osteoblasts. AB - Mimicking the complicated anisotropic structures of a native tissue is extremely important in tissue engineering. In a previous study, we developed an anisotropic collagen gel scaffold (ACGS) having a hierarchical structure and a properties gradient. In this study, our objective was to see how cells remodel the scaffolds through the cells-ACGS interaction. For this purpose, we cultured osteoblastic cells on ACGS, which we regarded as a model system for the cells-extracellular matrix (cell-ECM) interaction. Changes in the ACGS-cell composites structure by cell-ECM interactions was investigated from a macroscopic level to a microscopic level. Osteoblastic cells were also cultured on an isotropic collagen gel (ICGS) as a control. During the cultivation, mechanical stimuli were applied to collagen cell composites for adequate matrix remodeling. Confocal laser scanning microscope (CLSM) was used to observe macroscopic changes in the ACGS-cell composite structure by osteoblastic cells. Small-angle X-ray scattering (SAXS) measurements were performed to characterize microscopic structural changes in the composites. Macroscopic observations using CLSM revealed that osteoblastic cells remained only in the diluted phase in ACGS and they collected collagen fibrils or formed a toroidal structure, depending on the depth from the ACGS surface in the tubular diluted phase. The cells were uniformly distributed in ICGS. SAXS analysis suggests that collagen fibrils were remodeled by osteoblastic cells, and this remodeling process would be affected by the structure difference between ACGS and ICGS. These results suggest that we directly regulate cell-ECM interaction by the unique anisotropic and hierarchical structure of ACGS. The cell-gel composite presented in this study would promise an efficient scaffold material in tissue engineering. PMID- 23806016 TI - Structural transitions in nanoparticle assemblies governed by competing nanoscale forces. AB - Assembly of nanoscale materials from nanoparticle (NP) building blocks relies on our understanding of multiple nanoscale forces acting between NPs. These forces may compete with each other and yield distinct stimuli-responsive self-assembled nanostructures. Here, we report structural transitions between linear chains and globular assemblies of charged, polymer-stabilized gold NPs, which are governed by the competition of repulsive electrostatic forces and attractive poor solvency/hydrophobic forces. We propose a simple quantitative model and show that these transitions can be controlled by the quality of solvent, addition of a salt, and variation of the molecular weight of the polymer ligands. PMID- 23806017 TI - Use of behavioral economics and social psychology to improve treatment of acute respiratory infections (BEARI): rationale and design of a cluster randomized controlled trial [1RC4AG039115-01]--study protocol and baseline practice and provider characteristics. AB - BACKGROUND: Inappropriate antibiotic prescribing for nonbacterial infections leads to increases in the costs of care, antibiotic resistance among bacteria, and adverse drug events. Acute respiratory infections (ARIs) are the most common reason for inappropriate antibiotic use. Most prior efforts to decrease inappropriate antibiotic prescribing for ARIs (e.g., educational or informational interventions) have relied on the implicit assumption that clinicians inappropriately prescribe antibiotics because they are unaware of guideline recommendations for ARIs. If lack of guideline awareness is not the reason for inappropriate prescribing, educational interventions may have limited impact on prescribing rates. Instead, interventions that apply social psychological and behavioral economic principles may be more effective in deterring inappropriate antibiotic prescribing for ARIs by well-informed clinicians. METHODS/DESIGN: The Application of Behavioral Economics to Improve the Treatment of Acute Respiratory Infections (BEARI) Trial is a multisite, cluster-randomized controlled trial with practice as the unit of randomization. The primary aim is to test the ability of three interventions based on behavioral economic principles to reduce the rate of inappropriate antibiotic prescribing for ARIs. We randomized practices in a 2 * 2 * 2 factorial design to receive up to three interventions for non-antibiotic appropriate diagnoses: 1) Accountable Justifications: When prescribing an antibiotic for an ARI, clinicians are prompted to record an explicit justification that appears in the patient electronic health record; 2) Suggested Alternatives: Through computerized clinical decision support, clinicians prescribing an antibiotic for an ARI receive a list of non-antibiotic treatment choices (including prescription options) prior to completing the antibiotic prescription; and 3) Peer Comparison: Each provider's rate of inappropriate antibiotic prescribing relative to top-performing peers is reported back to the provider periodically by email. We enrolled 269 clinicians (practicing attending physicians or advanced practice nurses) in 49 participating clinic sites and collected baseline data. The primary outcome is the antibiotic prescribing rate for office visits with non-antibiotic-appropriate ARI diagnoses. Secondary outcomes will examine antibiotic prescribing more broadly. The 18-month intervention period will be followed by a one year follow-up period to measure persistence of effects after interventions cease. DISCUSSION: The ongoing BEARI Trial will evaluate the effectiveness of behavioral economic strategies in reducing inappropriate prescribing of antibiotics. TRIALS REGISTRATION: ClinicalTrials.gov: NCT01454947. PMID- 23806019 TI - Effect of hOGG1 over-expression on cisplatin resistance in esophageal squamous carcinoma cells. AB - PURPOSE: Human 8-oxoguanine DNA glycosylase (hOGG1) is an ubiquitous protein. It initiates the DNA base excision repair (BER) pathway to repair the 8-oxoguanine lesion. This may be associated with chemotherapeutics. In this article, the effect of hOGG1 over-expression on cisplatin resistance in esophageal squamous cell carcinoma (ESCC) EC9706 and ET13 cells was investigated. METHODS: Recombinant adenovirus pAd/CMV/V5-DEST-hogg1 and control adenovirus pAd/CMV/5 GW/lacZ were constructed and transferred into EC9706 and ET13 cells, respectively. The protein expression and localization were determined by Western blot and by immunofluorescence assay. The cell growth viability was determined by 3-(4,5-dimethylthiazol-2yl)-2,5 diphe-nyltetrazolium bromide (MTT) assay and clonogenic survival assay. The apoptotic cells were detected by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) staining and flow cytometry. The oxidative DNA damage (8-Hydroxyguanine [8-oxoG] DNA level) was semi-quantified by immunohistochemistry assay. RESULTS: The over-expression of hOGG1 protein was mainly in the nucleus in hOGG1 cells. After exposure to a common chemotherapeutic agent cisplatin, hOGG1 over-expression cells exhibited longer survival ability, lower cell apoptosis, and less 8-oxoG oxidative damage, compared with vector-treated cells and no-treated cells (p<0.05). CONCLUSION: BER pathway to repair 8-oxoG lesion may be associated with ESCC sensitivity to cisplatin, and over-expression of hOGG1 in the nucleus can repair more 8-oxoG oxidative damage. The findings implied that over-expression of hOGG1 can protect ESCC cells from cisplatin-induced apoptosis and prolong cancer cell survival time. Modulation of DNA damage repair activity in the nucleus or in the mitochondria may lead to a different approach regarding cisplatin-induced resistance to chemotherapy. PMID- 23806018 TI - The emergence of top-down proteomics in clinical research. AB - Proteomic technology has advanced steadily since the development of 'soft ionization' techniques for mass-spectrometry-based molecular identification more than two decades ago. Now, the large-scale analysis of proteins (proteomics) is a mainstay of biological research and clinical translation, with researchers seeking molecular diagnostics, as well as protein-based markers for personalized medicine. Proteomic strategies using the protease trypsin (known as bottom-up proteomics) were the first to be developed and optimized and form the dominant approach at present. However, researchers are now beginning to understand the limitations of bottom-up techniques, namely the inability to characterize and quantify intact protein molecules from a complex mixture of digested peptides. To overcome these limitations, several laboratories are taking a whole-protein-based approach, in which intact protein molecules are the analytical targets for characterization and quantification. We discuss these top-down techniques and how they have been applied to clinical research and are likely to be applied in the near future. Given the recent improvements in mass-spectrometry-based proteomics and stronger cooperation between researchers, clinicians and statisticians, both peptide-based (bottom-up) strategies and whole-protein-based (top-down) strategies are set to complement each other and help researchers and clinicians better understand and detect complex disease phenotypes. PMID- 23806020 TI - Role of goserelin in combination with endocrine therapy for the treatment of advanced breast cancer in premenopausal women positive for hormone receptor: a retrospective matched case-control study. AB - OBJECTIVE: This research was to investigate the role of goserelin in combination with endocrine therapy for the treatment of advanced breast cancer in premenopausal women positive for hormone receptors. METHODS: We retrospectively analyzed 40 patients as the treatment group with advanced breast cancer who, were positive for hormone receptors, received goserelin in combination with endocrine therapy and 40 patients as the control group received endocrine therapy alone, matched for age, gender, receptor status, and tumor stage. RESULTS: The median period of follow-up was 38.9 months. The response status at 6 months, the overall clinical benefit rate was 87.5% and 70.0% in the treatment group and control group, respectively. The mean progression-free survival (PFS) in the treatment group and control group was 27.9 and 16.9 months, respectively. The 1-, 2-, and 3 year PFS rates were 87.5%, 66.2%, and 49.7%, respectively, in the treatment group and 59.2%, 38.8%, and 35.3%, respectively, in the control group (p=0.076). The 1 , 2-, and 3-year overall survival (OS) rates were 100%, 87.2%, and 76.6%, respectively, in the treatment group and 90.0%, 74.2%, and 55.8%, respectively, in the control group (p=0.048). For the treatment group with age <40 years, PFS (p=0.036) and OS (p=0.014) were significantly longer than the control group, but it was no effect on the prognosis with the patients aged >=40 years. Continued use of goserelin after disease progress again in the median survival time was significantly longer than nonusers (28.2 months vs. 7.0 months), and there is the potential benefit of OS (p=0.070). CONCLUSIONS: For premenopausal hormone receptor-positive advanced breast cancer, goserelin-combined endocrine therapy can be used for those <40 years, the standard endocrine treatment for patients, we recommend continued use of goserelin for patients with disease progress again. PMID- 23806022 TI - Private health insurance policies in Israel: a report on the 2012 Dead Sea Conference. AB - The private health insurance (commercial and supplementary health insurance) sector has undergone a revolutionary transformation in recent years, both in the number of individuals who own private plans, and in the financial scope of these plans. With these developments in the background, leaders of the Israeli healthcare system convened in December 2012 at the Dead Sea for a discussion on "Private healthcare insurance plans in Israel: Developments, concerns, and directions for a solution". This meeting report summarizes the main issues discussed at the conference. PMID- 23806021 TI - Preliminary study of the biodegradation and the correlation between in vitro and in vivo release of (32)P-chromic phosphate-poly(L-lactide) seeds. AB - OBJECTIVE: To investigate the drug release kinetic of (32)P-chromic phosphate poly(L-lactide) ((32)P-CP-PLLA). METHODS: (32)P-CP-PLLA were placed into physiological saline and H22 solid tumor mass, respectively. The weight loss rate and radioactivity release rate were evaluated. The release of the microparticles was evaluated using fitting curves. The correlation of the release of the microparticles between physiological saline and H22 solid tumor mass was analyzed. RESULTS: Close correlation was noted in the release of the microparticles between physiological saline and H22 solid tumor mass. The Weibull equation showed the best fitting of (32)P-CP-PLLA in physiological saline. CONCLUSIONS: The Weibull equation could be used for the predictive release of microparticles in vitro. The parameters obtained from the drug release kinetics could be used to estimate the dose of radiopharmaceuticals within the tumors and the surrounding tissues. PMID- 23806023 TI - Primary headaches, attention deficit disorder and learning disabilities in children and adolescents. AB - BACKGROUND: Primary headaches and Learning difficulties are both common in the pediatric population. The goal of our study was to assess the prevalence of learning disabilities and attention deficit disorder in children and adolescents with migraine and tension type headaches. METHODS: Retrospective review of medical records of children and adolescents who presented with headache to the outpatient pediatric neurology clinics of Bnai-Zion Medical Center and Meyer Children's Hospital, Haifa, during the years 2009-2010. Demographics, Headache type, attention deficit disorder (ADHD), learning disabilities and academic achievements were assessed. RESULTS: 243 patients met the inclusion criteria and were assessed: 135 (55.6%) females and 108 (44.4%) males. 44% were diagnosed with migraine (35.8% of the males, 64.2% of the females, p = 0.04), 47.7% were diagnosed with tension type headache (50.4% of the males, 49.6% of the females). Among patients presenting with headache for the first time, 24% were formerly diagnosed with learning disabilities and 28% were diagnosed with attention deficit disorder (ADHD). ADHD was more prevalent among patients with tension type headache when compared with patients with migraine (36.5% vs. 19.8%, p = 0.006). Poor to average school academic performance was more prevalent among children with tension type headache, whereas good to excellent academic performance was more prevalent among those with migraine. CONCLUSIONS: Learning disabilities and ADHD are more common in children and adolescents who are referred for neurological assessment due to primary headaches than is described in the general pediatric population. There is an association between headache diagnosis and school achievements. PMID- 23806024 TI - Alleviation of kidney damage induced by unilateral ureter obstruction in rats by Rhodiola rosea. AB - PURPOSE: To evaluate the efficacy of Rhodiola rosea extract in terms of alleviating the renal damage induced by unilateral ureter obstruction (UUO) in rats. MATERIAL AND METHODS: Thirty Wistar albino male rats were divided into five groups: (I) Control, (II) UUO 7 days, (III) UUO 7 days+extract,(IV) UUO 14 days, and (V) UUO 14 days+extract. Seven or 14 days after the initiation of the experimental procedure, the left kidneys of rats in all five groups were removed for histological examination, and their blood was drawn for biochemical measurements. RESULT: Median malondialdehyde (MDA) and glutathione peroxidase (GPx) levels were, respectively, 39.4 (5.04) nmol/mL and 25.8 (8.01) nmol/minute/mL in group I, 77.9 (12.38) nmol/mL and 5.8 (1.95) nmol/minute/mL in group II, 48.7 (12.1) nmol/mL and 9.1 (2.3) nmol/minute/mL in group III, 58.5 (23.83) nmol/mL and 8.4 (2.1) nmol/minute/mL in group IV, and 44.8 (4.97) nmol/mL and 13.8 (3.73) nmol/minute/mL in group V. There was a statistically significant difference among the groups in terms of MDA and GPx levels (p<0.05 for both). The median numbers of apoptotic cells were 1 (1), 8 (2.25), 3 (1.25), 23.5 (9), and 7 (I) in groups I, II, III, IV, and V, respectively. There was a statistically siginificant difference among the groups in terms of apoptotic cell number (p<0.05). CONCLUSION: R. rosea extract was shown to alleviate the renal damage induced by UUO through its antioxidant effects. The mechanism by which R. rosea extract causes these effects merits further investigation. PMID- 23806025 TI - Large-area 3D chiral plasmonic structures. AB - We manufacture large-area plasmonic structures featuring 3-dimensional chirality by colloidal nanohole lithography. By varying the polar rotating speed of the samples during gold evaporation, we can fabricate spiral-type ramp nanostructures. The optical properties show chiroptical resonances in the 100 to 400 THz frequency region (750 to 3000 nm), with circular dichroism values of up to 13%. Our method offers a simple low-cost manufacturing method of cm(2)-sized chiral plasmonic templates for chiroptical applications such as stereochemical enantiomer sensors. PMID- 23806026 TI - Transcriptional responses of human aortic endothelial cells to nanoconstructs used in biomedical applications. AB - Understanding the potential toxicities of manufactured nanoconstructs used for drug delivery and biomedical applications may help improve their safety. We sought to determine if surface-modified silica nanoparticles and poly(amido amine) dendrimers elicit genotoxic responses on vascular endothelial cells. The nanoconstructs utilized in this study had a distinct geometry (spheres vs worms) and surface charge, which were used to evaluate the contributions of these parameters to any potential adverse effects of these materials. Time-dependent cytotoxicity was found for surfaced-functionalized but geometrically distinct silica materials, while amine-terminated dendrimers displayed time-independent cytotoxicity and carboxylated dendrimers were nontoxic in our assays. Transcriptomic evaluation of human aortic endothelial cell (HAEC) responses indicated time-dependent gene induction following silica exposure, consisting of cell cycle gene repression and pro-inflammatory gene induction. However, the dendrimers did not induce genomic toxicity, despite displaying general cytotoxicity. PMID- 23806028 TI - The confidence of speech-language pathology students regarding communicating with people with aphasia. AB - BACKGROUND: Aphasia is an acquired language disorder that can present a significant barrier to patient involvement in healthcare decisions. Speech language pathologists (SLPs) are viewed as experts in the field of communication. However, many SLP students do not receive practical training in techniques to communicate with people with aphasia (PWA) until they encounter PWA during clinical education placements. METHODS: This study investigated the confidence and knowledge of SLP students in communicating with PWA prior to clinical placements using a customised questionnaire. Confidence in communicating with people with aphasia was assessed using a 100-point visual analogue scale. Linear, and logistic, regressions were used to examine the association between confidence and age, as well as confidence and course type (graduate-entry masters or undergraduate), respectively. Knowledge of strategies to assist communication with PWA was examined by asking respondents to list specific strategies that could assist communication with PWA. RESULTS: SLP students were not confident with the prospect of communicating with PWA; reporting a median 29-points (inter quartile range 17-47) on the visual analogue confidence scale. Only, four (8.2%) of respondents rated their confidence greater than 55 (out of 100). Regression analyses indicated no relationship existed between confidence and students' age (p = 0.31, r-squared = 0.02), or confidence and course type (p = 0.22, pseudo r squared = 0.03). Students displayed limited knowledge about communication strategies. Thematic analysis of strategies revealed four overarching themes; Physical, Verbal Communication, Visual Information and Environmental Changes. While most students identified potential use of resources (such as images and written information), fewer students identified strategies to alter their verbal communication (such as reduced speech rate). CONCLUSIONS: SLP students who had received aphasia related theoretical coursework, but not commenced clinical placements with PWA, were not confident in their ability to communicate with PWA. Students may benefit from an educational intervention or curriculum modification to incorporate practical training in effective strategies to communicate with PWA, before they encounter PWA in clinical settings. Ensuring students have confidence and knowledge of potential communication strategies to assist communication with PWA may allow them to focus their learning experiences in more specific clinical domains, such as clinical reasoning, rather than building foundation interpersonal communication skills. PMID- 23806029 TI - Incidental identification of a thyroid hormone receptor beta (THRB) gene variant in a family with autoimmune thyroid disease. AB - BACKGROUND: Resistance to thyroid hormone (RTH) is a rare condition usually diagnosed in patients with classic thyroid function tests (TFTs) of elevated thyroid hormone levels with nonsuppressed TSH. The presence of autoimmune thyroid disease (AITD) can confound the clinical diagnosis of RTH. A family was evaluated because several members had elevated TSH and normal or low serum T4 concentrations with AITD. While these individuals were initially reported to have RTH, they were found to have a normal thyroid hormone receptor beta (THRB) gene sequence, and three other asymptomatic family members were found to harbor the variant TRbeta G339S. METHODS: The THRB gene was sequenced in 19 members of a large Mexican/Aztec family. In vitro expression of the mutant TRbeta protein was performed, as well as computer modeling of the variant compared to known mutations in the flanking codons. RESULTS: Investigation of an individual with AITD who was incorrectly diagnosed with RTH led to the fortuitous discovery of a THRB gene variant (G339S) in the proposita's father, paternal aunt, and cousin. This variant was not detected in analysis of 124 unrelated alleles. All individuals harboring G339S had normal TFTs. Normal in vitro expression and function of G339S and molecular modeling predicted that this variant would not have an effect on the hypothalamic-pituitary-thyroid axis as determined by thyroid hormone binding in vitro and thyroid function tests in vivo, despite profound effects seen in mutations in the adjacent codons 338 and 340. CONCLUSION: We report an individual with normal TFTs and AITD harboring a novel THRB gene variant. In addition to illustrating the importance of accurate diagnosis of thyroid disease so that proper treatment and counseling can be given, TRbeta codon 339 is not essential for normal TRbeta function. PMID- 23806030 TI - Synthesis of 2'-deoxy-9-deaza nucleosides using Heck methodology. AB - During the synthesis of a series of 2'-deoxy-9-deaza nucleosides using Heck methodology, the necessity for a pyrrole protecting group was discovered. The results of this brief study revealed that the benzyloxymethyl (BOM) group proved optimal, and Heck coupling using Jeffery conditions increased the coupling yield significantly. The results are reported herein. PMID- 23806031 TI - Light-induced magnetostructural anomalies in a polymer chain complex of Cu(hfac)2 with tert-butylpyrazolylnitroxides. AB - We report the study of light-induced magnetostructural anomalies in a polymer chain complex of Cu(hfac)2 (hfac = hexafluoroacetylacetonate) with an unusual acyclic tert-butylpyrazolylnitroxide radical (Ltert(Me)) using EPR. This complex ([Cu(hfac)2Ltert(Me)]n) belongs to the family of thermo- and photoswitchable molecular magnets "breathing crystals". Compared to previously studied breathing crystals with nitronyl nitroxides, [Cu(hfac)2Ltert(Me)]n shows much weaker absorption bands in the visible spectral region and therefore is superior for optical manipulation of the spin states. Illumination with light (lambda ~ 540 nm) at cryogenic temperatures leads to formation of a metastable weakly coupled spin state, which relaxes to the ground strongly coupled spin state on a time scale of hours. These phenomena are in many aspects similar to the light-induced excited spin state trapping (LIESST) well-known for spin-crossover compounds. Remarkably, the photoinduced spin state in [Cu(hfac)2Ltert(Me)]n is metastable at temperatures up to TLIESST ~ 60 K, which is a significant improvement compared to that of previously studied breathing crystals with nitronyl nitroxides (TLIESST ~ 20 K). We describe LIESST-like behavior observed in [Cu(hfac)2Ltert(Me)]n and discuss possible reasons for the increased stability of the photoinduced spin state. PMID- 23806033 TI - Amelioration of superoxide dismutase on ventilator-induced lung injury by suppressing leukocyte in the lungs and systemic circulation. AB - Superoxide dismutase (SOD) is a free radical scavenger and a broad-spectrum antioxidant. Its anti-inflammatory and immunomodulatory effects have recently been noted. We studied the effects of this antioxidant on lung damage, oxidative stress, and inflammation in a model of ventilator-induced lung injury (VILI), using 8- to 12-wk-old Sprange-Dawley rats (n = 40). Animals were randomized and evenly divided into two experimental groups, low tidal volume (V(T)) ventilation (V(T) = 9 ml/kg) and high V(T) ventilation (V(T) = 28 ml/kg). Each group was evenly divided into two subgroups: ten animals were treated with superoxide dismutase (SOD; 10,000 U/kg i.v., 2 h prior to the ventilation) and the rests were treated with vehicle. Lung injury was evaluated by histological examination, and cells counts of red blood cells (RBC) and white blood cells (WBC) in the alveoli and the septal wall thickness in lung tissues and serum lactate dehydrogenase (LDH). The lung permeability was assessed by the wet-to-dry weight ratio (W/D), lung weight to body weight ratio (LW/BW) and protein concentration in broncholavage fluid (BALF). Levels of oxidative stress and lipid peroxidation in the lungs were evaluated by tissue malondialdehyde (MDA) and methylguanidine (MG) in BALF, respectively. SOD pretreatment significantly decreased WBC counts in systemic circulation and in alveoli, and effectively attenuated high V(T) ventilation induced lung injury by reducing hyaline membrane development, septal wall thickness, lung W/D and LW/BW and serum LDH in relation to those of the control. In addition, lung tissues MDA and MG in BALF were also notably reduced. PMID- 23806032 TI - CARbon DIoxide for the treatment of Febrile seizures: rationale, feasibility, and design of the CARDIF-study. AB - BACKGROUND: 2-8% of all children aged between 6 months and 5 years have febrile seizures. Often these seizures cease spontaneously, however depending on different national guidelines, 20-40% of the patients would need therapeutic intervention. For seizures longer than 3-5 minutes application of rectal diazepam, buccal midazolam or sublingual lorazepam is recommended. Benzodiazepines may be ineffective in some patients or cause prolonged sedation and fatigue. Preclinical investigations in a rat model provided evidence that febrile seizures may be triggered by respiratory alkalosis, which was subsequently confirmed by a retrospective clinical observation. Further, individual therapeutic interventions demonstrated that a pCO2-elevation via re breathing or inhalation of 5% CO2 instantly stopped the febrile seizures. Here, we present the protocol for an interventional clinical trial to test the hypothesis that the application of 5% CO2 is effective and safe to suppress febrile seizures in children. METHODS: The CARDIF (CARbon DIoxide against Febrile seizures) trial is a monocentric, prospective, double-blind, placebo-controlled, randomized study. A total of 288 patients with a life history of at least one febrile seizure will be randomized to receive either carbogen (5% CO2 plus 95% O2) or placebo (100% O2). As recurrences of febrile seizures mainly occur at home, the study medication will be administered by the parents through a low pressure can fitted with a respiratory mask. The primary outcome measure is the efficacy of carbogen to interrupt febrile seizures. As secondary outcome parameters we assess safety, practicability to use the can, quality of life, contentedness, anxiousness and mobility of the parents. PROSPECT: The CARDIF trial has the potential to develop a new therapy for the suppression of febrile seizures by redressing the normal physiological state. This would offer an alternative to the currently suggested treatment with benzodiazepines. This study is an example of academic translational research from the study of animal physiology to a new therapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01370044. PMID- 23806034 TI - Altitude training improves glycemic control. AB - Under altitude hypoxia condition, energy reliance on anaerobic glycolysis increases to compensate the shortfall caused by reduced fatty acid oxidation. Short-term moderate altitude exposure plus endurance physical activity has been found to improve glucose tolerance (not fasting glucose) in humans, which is associated with the improvement in the whole-body insulin sensitivity. However, most of people cannot accommodate high altitude exposure above 4500 M due to acute mountain sickness and insulin resistance. There is a wide variation among individuals in response to the altitude challenge. In particular, the improvement in glucose tolerance and insulin sensitivity by prolonged altitude hiking activity was not apparent in those individuals with low baseline dehydroepiandrosterone sulfate (DHEA-S) concentration. In rats, exercise training recovery under prolonged hypoxia exposure (14-15% oxygen, 8 h per day for 6 weeks) can also improve insulin sensitivity, secondary to an effective suppression of adiposity. After prolonged hypoxia training, obese abnormality in upregulated baseline levels of AMP-activated protein kinase (AMPK) and AS160 phosphorylation in skeletal muscle can be reversed. In humans, moderate hypoxia increases postprandial blood distribution towards skeletal muscle during a training recovery. This physiological response plays a role in the redistribution of fuel storage among important energy storage sites and may explain its potent effect on the favorable change in body composition. CONCLUSION: Altitude training can exert strong impact on our metabolic system, and has the potential to be designed as a non-pharmacological or recreational intervention regimen for correcting metabolic syndromes. PMID- 23806035 TI - The influences of reserpine and imipramine on the 5-HT2 receptor binding site and its coupled second messenger in rat cerebral cortex. AB - An investigation on the molecular mechanism of depression state, less attention was focused on changes at the intracellular messenger level. In this study the effects of reserpine, a monoamine depletor, and imipramine, an antidepressant, on serotonin-2 (5-HT2) receptor binding and its second messenger system of rat cerebral cortex were studied. The level of inositol 4-monophosphate (IP1) accumulation elicited by 100 microM 5-HT via activation of the 5-HT2 receptor on cerebral cortical slices at twelve hours after a single dose of reserpine (2 mg/kg, i.p.) was significantly higher in treated rats, when compared to that of saline-treated rats; this significant level lasted for at least four days. The level of IP1 accumulation in rat cerebral cortical slices elicited by 100 microM serotonin was higher in the group pretreated with reserpine (0.25 mg/kg/day) sub chronically for seven days than the group pretreated with normal saline. In the receptor binding study, the maximum binding (B(max)) of 5-HT2 receptor binding was increased, when compared to the corresponding controls; whereas, the dissociation equilibrium constant (K(d)) value of the 5-HT2 receptor was found unchanged in the reserpine treated group. Increases in the sensitivity of phosphoinositol (PI) turnover coupled with the 5-HT2 receptor were also found in the long-term (21 days) low dose (0.1 mg/kg/day) administration of reserpine. However, a long-term administration of imipramine (10 mg/kg/day) reduced the function of the PI turnover coupled with the 5-HT2 receptor. Results obtained from the combined use of reserpine and imipramine demonstrated that this combination was able to antagonize the super-sensitivity of the second messenger responses in 5-HT2 receptor induced by long-term treatment with reserpine. Long term treatment with reserpine but not imipramine also caused an increase in the B(max) of the 5-HT2 receptor. This up-regulation of the 5-HT2 receptor by reserpine could be antagonized by imipramine, if a combined treatment was employed. However, this combination of imipramine with an additional phospholipid liposome did not enhance or decrease the imipramine's effect on the 5-HT2 receptor, or on its coupled second messenger level. In summary, reserpine induced up-regulation of the postsynaptic monoamine receptor and its coupled second messenger responses (such as IP1 formation). Imipramine was capable of antagonizing these same events in a depression animal model with reserpine. This study demonstrated the dynamic changes and adaptability of the receptor system, followed by changes in PI turnover. The results provide an explanation at the molecular level for the bases of depression and the role of antidepressant drugs effects on those pathological linking elements. PMID- 23806036 TI - Implication of cerebral dopamine-beta hydroxylase for cardiovascular and mood regulation in rats. AB - The essentiality of the role of norepinephrine (NE) in the central nervous system has recently been reconsidered. NE exerts many effects and mediates a number of functions in living organisms. Dopamine-beta-hydroxylase (DBH) is the crucial enzyme for NE and epinephrine biosynthesis. Removal of this enzyme causes deficient NE at sympathetic terminals characterized by orthostatic hypotension in humans. The hypothesis tested in this study was that NE deficiency in the central nervous system caused autonomic failure in cardiovascular regulation. The immunotoxin anti-DBH-saporin (DSAP) was used to examine the putative role of cerebral NE. Male Sprague-Dawley rats were injected, intracerebroventricularly (icv), with DSAP and cardiovascular reactivity, as well as behavioral variables in the open-field locomotion test (OLT), sucrose intake test (SIT) and forced swim test (FST), were monitored for changes. The results indicated that treatment with DSAP caused significant reductions in spontaneous blood pressure (BP) and heart rate (HR), and a decrease in the rearing position on the OLT, in the same group of rats. In addition, a significant increase in mobility with low concurrent immobility frequencies was observed on the FST. However, there was no variation on the SIT. In conclusion, a deficiency in the cerebral DBH might dysregulate the autonomic outflows and, thus, leads to lower BP and HR. However, there was no mood change such as despair or anhedonia observed in the experiments. PMID- 23806037 TI - Diminished contractile responses of isolated conduit arteries in two rat models of hypertension. AB - Hypertension is accompanied by thickening of arteries, resulting in marked changes in their passive and active mechanical properties. The aim of this study was to demonstrate that the large conduit arteries from hypertensive individuals may not exhibit enhanced contractions in vitro, as is often claimed. Mechanical responses to vasoconstrictor stimuli were measured under isometric conditions using ring arterial segments isolated from spontaneously hypertensive rats, N(omega)-nitro-L-arginine methyl ester (L-NAME)-treated Wistar rats, and untreated Wistar rats serving as normotensive control. We found that thoracic aortas from both types of hypertensive rats had a greater sensitivity but diminished maximal developed tension in response to noradrenaline, when compared with that from normotensive rats. In superior mesenteric arteries, the sensitivity to noradrenaline was similar in all examined rat groups but in L-NAME treated rats, these arteries exhibited decreased active force when stimulated with high noradrenaline concentrations, or with 100 mM KCl. These results indicate that hypertension leads to specific biomechanical alterations in diverse arterial types which are reflected in different modifications in their contractile properties. PMID- 23806038 TI - Effects of conditioning with sevoflurane before reperfusion on hippocampal ischemic injury and insulin-like growth factor-1 expression in rats. AB - Sevoflurane pre-conditioning before ischemia can reduce ischemia-reperfusion injuries in cardiac, pulmonary and cerebral tissues. It is uncertain whether sevoflurane conditioning before reperfusion has similar protective effects on neuronal injuries. In this study, we explored the effect of sevoflurane conditioning (at concentrations of 1.5%, 2.4% or 3.0%) on the morphology and molecular mechanisms of the hippocampal CA1 region in male Sprague-Dawley rats subjected to global cerebral ischemia. We determined the pathological results by hematoxylin and eosin (H&E) staining and examined the mRNA levels of insulin-like growth factor-1 (IGF-1) and protein levels of p-JNK1/2 and p-Akt1 in the hippocampus at 24 h, 48 h and 72 h after global cerebral ischemia-reperfusion. Our data showed that O2 post-conditioning and lower dose (1.5%) of sevoflurane did not ameliorate ischemia-induced CA1 injury. However, higher doses of 2.4% and 3.0% sevoflurane post-conditioning alleviated the CA1 injury and enhanced the expression levels of IGF-1 mRNA. Furthermore, sevoflurane post-conditioning inhibited the activations of p-JNK1/2 and enhanced activation of p-Akt1. In conclusion, these results suggest that post-conditioning with sevoflurane at 2.4% and 3.0% ameliorates global cerebral ischemia induced hippocampal CA1 injury by up-regulating the expression of IGF-1 mRNA followed by the activation of p-Akt1 and inhibition of the activation of p-JNK1/2. PMID- 23806039 TI - Biomimetic reagents for the selective free radical and acid-base chemistry of glycans: application to glycan structure determination by mass spectrometry. AB - Nature excels at breaking down glycans into their components, typically via enzymatic acid-base catalysis to achieve selective cleavage of the glycosidic bond. Noting the importance of proton transfer in the active site of many of these enzymes, we describe a sequestered proton reagent for acid-catalyzed glycan sequencing (PRAGS) that derivatizes the reducing terminus of glycans with a pyridine moiety possessing moderate proton affinity. Gas-phase collisional activation of PRAGS-derivatized glycans predominately generates C1-O glycosidic bond cleavages retaining the charge on the reducing terminus. The resulting systematic PRAGS-directed deconstruction of the glycan can be analyzed to extract glycan composition and sequence. Glycans are also highly susceptible to dissociation by free radicals, mainly reactive oxygen species, which inspired our development of a free radical activated glycan sequencing (FRAGS) reagent, which combines a free radical precursor with a pyridine moiety that can be coupled to the reducing terminus of target glycans. Collisional activation of FRAGS derivatized glycans generates a free radical that reacts to yield abundant cross ring cleavages, glycosidic bond cleavages, and combinations of these types of cleavages with retention of charge at the reducing terminus. Branched sites are identified with the FRAGS reagent by the specific fragmentation patterns that are observed only at these locations. Mechanisms of dissociation as well as application of the reagents for both linear and highly branched glycan structure analysis are investigated and discussed. The approach developed here for glycan structure analysis offers unique advantages compared to earlier studies employing mass spectrometry for this purpose. PMID- 23806040 TI - Amnion protective cesarean section--method for gentle delivery of preterm and/or VLBW neonates. AB - More than 50 percent of preterm neonates below 28 gestational weeks in our institution are delivered by cesarean section (CS). AIM: To present advantages of less used method of delivery of premature and/or very low birth weight (VLBW) neonates by Amnion Protective Cesarean Section (APCS) when indicated and to review our experience with the method. It can be used in all deliveries by CS with unruptured amniotic membranes, at all gestational ages. MATERIALS AND METHODS: Including criteria were singleton pregnancies, gestation of 26 to 35 weeks and birth body weight between 700 to 1500 g. According to the criteria, during the studied period 10 neonates were delivered by APCS. We compared the outcomes of APCS neonates with ones delivered by coventional CS who matched them in mentioned criteria. RESULTS: Compared to CS cases, APCS neonates had statistically significant better first minute AS. Stay in NICU was shorter for APCS neonates but not statistically significant. From our experience APCS neonates had clinically better appearance (less bruises and hematomas). CONCLUSION: APCS is promising method for delivery of preterm and/or VLBW neonates when indicated, although prospective studies are needed in order to prove its effectiveness compared to conventional CS. PMID- 23806041 TI - Coinheritance of a novel mutation on the HBA1 gene: c.187delG (p.W62fsX66) [codon 62 (-G) (alpha1)] with the alpha212 patchwork allele and Hb S [beta6(A3)Glu->Val, GAG>GTG; HBB: c.20A>T]. AB - We describe a novel frameshift mutation on the HBA1 gene (c.187delG), causative of alpha-thalassemia (alpha-thal) in a Black Cuban family with multiple sequence variants in the HBA genes and the Hb S [beta6(A3)Glu->Val, GAG>GTG; HBB: c.20A>T] mutation. The deletion of the first base of codon 62 resulted in a frameshift at amino acid 62 with a putative premature termination codon (PTC) at amino acid 66 on the same exon (p.W62fsX66), which most likely triggers nonsense mediated decay of the resulting mRNA. This study also presents the first report of the alpha212 patchwork allele in Latin America and the description of two new sequence variants in the HBA2 region (c.-614G>A in the promoter region and c.95+39 C>T on the first intron). PMID- 23806042 TI - Multi-disciplinary management for patients with oligometastases to the brain: results of a 5 year cohort study. AB - BACKGROUND: The incidence of oligometastases to the brain in good performance status patients is increasing due to improvements in systemic therapy and MRI screening, but specific management pathways are often lacking. METHODS: We established a multi-disciplinary brain metastases clinic with specific referral guidelines and standard follow-up for good prognosis patients with the view that improving the process of care may improve outcomes. We evaluated patient demographic and outcome data for patients first seen between February 2007 and November 2011. RESULTS: The clinic was feasible to run and referrals were appropriate. 87% of patients referred received a localised therapy during their treatment course. 114 patients were seen and patient numbers increased during the 5 years that the clinic has been running as relationships between clinicians were developed. Median follow-up for those still alive was 23.1 months (6.1-79.1 months). Primary treatments were: surgery alone 52%, surgery plus whole brain radiotherapy (WBRT) 9%, radiosurgery 14%, WBRT alone 23%, supportive care 2%. 43% received subsequent treatment for brain metastases. 25%, 11% and 15% respectively developed local neurological progression only, new brain metastases only or both. Median overall survival following brain metastases diagnosis was 16.0 months (range 1-79.1 months). Breast (32%) and NSCLC (26%) were the most common primary tumours with median survivals of 26 and 16.9 months respectively (HR 0.6, p=0.07). Overall one year survival was 55% and two year survival 31.5%. 85 patients died of whom 37 (44%) had a neurological death. CONCLUSION: Careful patient selection and multi-disciplinary management identifies a subset of patients with oligometastatic brain disease who benefit from aggressive local treatment. A dedicated joint neurosurgical/ neuro-oncology clinic for such patients is feasible and effective. It also offers the opportunity to better define management strategies and further research in this field. Consideration should be given to defining specific management pathways for these patients within general oncology practice. PMID- 23806043 TI - Potentially hazardous waste produced at home. AB - BACKGROUND: The purpose of this study was to identify the sources of waste generation household consisting of biological material and to investigate the knowledge presented by those responsible for the generation of waste in the home environment on the potential health risk human and environmental. METHOD: It is a quantitative survey performed in Parque Capuava, Santo Andre (SP). The questionnaire was administered by the community employers and nursing students during the consultation with nursing supervision through interview question/answer. The exclusion criteria were patients who were not in the area served by the Basic Health Unit which covers the area of Pq Capuava. The sample was consisted of 99 persons and the data collection a questionnaire was used. RESULTS: We observed that 63.3% of people said to use disposables, with the majority (58.7%) of these use the public collection as the final destination of these materials. It was reported that 73.7% of those surveyed reported having knowledge about the risk of disease transmission. Public awareness of the importance of proper packaging and disposal of potentially hazardous household waste may contribute significantly to the preservation of human and environmental health and this procedure can be performed and supervised by professional nurses. CONCLUSION: We suggest implementation of workshops for community health workers and the general population in order to enhance their knowledge about the storage and disposal of potentially infectious waste generated at home, thereby reducing the potential risk of disease transmission by improper management. PMID- 23806045 TI - Genetic parts to a preventive medicine whole. AB - Integration of clinical evaluations and whole-genome sequence data from eight individuals in a recent study demonstrates that genetic and clinical information can be combined and applied to preventive medicine. Statistical and graphical tools were developed to assess and visualize the genetic risk of common chronic conditions and to show the changes in disease risk that result from monitoring clinical symptoms over time. This approach provides a direction to consider in the adoption of genetic information in health care, but, like all provocative scientific articles, it raises as many questions as it answers. PLEASE SEE RELATED RESEARCH: http://genomemedicine.com/content/5/6/58. PMID- 23806044 TI - Blue light regulated two-component systems: enzymatic and functional analyses of light-oxygen-voltage (LOV)-histidine kinases and downstream response regulators. AB - Light is an essential environmental cue for diverse organisms. Many prokaryotic blue light photoreceptors use light, oxygen, voltage (LOV) sensory domains to control the activities of diverse output domains, including histidine kinases (HK). Upon activation, these proteins autophosphorylate a histidine residue before subsequently transferring the phosphate to an aspartate residue in the receiver domain of a cognate response regulator (RR). Such phosphorylation activates the output domain of the RR, leading to changes in gene expression, protein-protein interactions, or enzymatic activities. Here, we focus on one such light sensing LOV-HK from the marine bacterium Erythrobacter litoralis HTCC2594 (EL368), seeking to understand how kinase activity and subsequent downstream effects are regulated by light. We found that photoactivation of EL368 led to a significant enhancement in the incorporation of phosphate within the HK domain. Further enzymatic studies showed that the LOV domain affected both the LOV-HK turnover rate (kcat) and Km in a light-dependent manner. Using in vitro phosphotransfer profiling, we identified two target RRs for EL368 and two additional LOV-HKs (EL346 and EL362) encoded within the host genome. The two RRs include a PhyR-type transcriptional regulator (EL_PhyR) and a receiver-only protein (EL_LovR), reminiscent of stress-triggered systems in other bacteria. Taken together, our data provide a biochemical foundation for this light regulated signaling module of sensors, effectors, and regulators that control bacterial responses to environmental conditions. PMID- 23806046 TI - Changes in anterior and posterior corneal parameters in patients with keratoconus after intrastromal corneal-ring segment implantation. AB - PURPOSE: To compare changes in the anterior and the posterior corneal parameters and the anterior chamber depth (ACD) measured by a rotating Scheimpflug camera and scanning-slit topography before and after intrastromal corneal ring segment (ICRS) implantation. METHODS: Twenty-five eyes of 21 keratoconus patients who had Intacs (Addition Technology, Sunnyvale, CA) ICRS implantation were included. The anterior segment parameters of the participants were measured before and 3 months after Intacs ICRS implantation with a rotating Scheimpflug camera and scanning slit topography. Outcome measures included uncorrected (UDVA) and corrected (CDVA) distance visual acuities, refraction and corneal topography. RESULTS: The UDVA improved in 21 eyes (84%) and CDVA in 18 eyes (72%). The anterior average keratometry decreased from 51.80 D preoperatively to 49.59 D postoperatively (p < 0.001) using the rotating Scheimpflug camera and Sim K decreased from 51.21 to 47.44 D using the scanning-slit topography. The posterior average keratometry decreased from -8.03 D preoperatively to -8.42 D postoperatively (p < 0.001) using the rotating Scheimpflug camera. ACD decreased from 3.44 to 3.32 mm (p < 0.001) and from 3.28 to 3.19 mm (p < 0.001) using the rotating Scheimpflug camera and scanning-slit topography, respectively. CONCLUSIONS: The implantation of Intacs segments induced corneal flattening of the anterior surface and corneal steepening of the posterior surface. Both anterior corneal flattening and posterior corneal steepening contributed to the decrease in the keratometric power. PMID- 23806047 TI - Long-term associations between serum lipids and panretinal photocoagulation in type 1 diabetes. AB - AIMS: To examine the predictive value of serum lipids on the need for panretinal photocoagulation (PRP) treatment in a long-term follow-up of a cohort of Danish type 1 diabetic patients. METHODS: A total of 243 type 1 diabetic patients were included from a population-based cohort. Of these, 25 patients (10.3%) were excluded due to proliferative diabetic retinopathy (PDR) at baseline. The remaining 218 patients were followed from January 1993 to November 2006. Serum levels of lipids were collected at baseline. PRP treatment was considered as indicative of PDR during follow-up, and the date of PRP was documented from the Danish National Patients Registry. RESULTS: At baseline, the median age and duration of diabetes were 45.9 years (range 23.9-78.4 years) and 30 years (range 20-72 years), respectively. In the crude analysis, serum triglyceride was associated with incident PRP. However, after adjustments for baseline age, sex, duration of diabetes and HbA1c, this was no longer statistically significant, although a clear trend was found (hazard ratio 1.40, 95% confidence interval 0.97 2.03, p = 0.07, for each 1 mmol/L increase in serum triglyceride). Total cholesterol, HDL cholesterol and LDL cholesterol were not associated with a higher risk of incident PRP. CONCLUSIONS: In a 13-year follow-up of a population based cohort of long-term type 1 diabetic patients, there was a trend of an association between serum triglyceride and subsequent need of PRP treatment, which was used as a surrogate endpoint of PDR. This identifies triglycerides as a potential risk factor of PDR in type 1 diabetes. PMID- 23806050 TI - Growth of half-meter long carbon nanotubes based on Schulz-Flory distribution. AB - The Schulz-Flory distribution is a mathematical function that describes the relative ratios of polymers of different length after a polymerization process, based on their relative probabilities of occurrence. Carbon nanotubes (CNTs) are big carbon molecules which have a very high length-to-diameter ratio, somewhat similar to polymer molecules. Large amounts of ultralong CNTs have not been obtained although they are highly desired. Here, we report that the Schulz-Flory distribution can be applied to describe the relative ratios of CNTs of different lengths produced with a floating chemical vapor deposition process, based on catalyst activity/deactivation probability. With the optimized processing parameters, we successfully synthesized 550-mm-long CNTs, for which the catalyst deactivation probability of a single growth step was ultralow. Our finding bridges the Schulz-Flory distribution and the synthesis of one-dimensional nanomaterials for the first time, and sheds new light on the rational design of process toward controlled production of nanotubes/nanowires. PMID- 23806049 TI - Pure bipolar plasma vaporization of the prostate: the Zurich experience. AB - INTRODUCTION AND OBJECTIVES: Bipolar plasma vaporization (BPV) has been introduced as an alternative to transurethral resection of the prostate (TURP). Promising short-term results, but inferior mid-term results compared to TURP have been reported following first-generation bipolar electrovaporization. Outcome data following second-generation BPV are still scarce. The aim of this investigation was to evaluate the intra- and postoperative outcomes of contemporary BPV in a center with long-standing expertise on laser vaporization of the prostate. METHODS: A consecutive series of 83 patients undergoing BPV in a tertiary referral center was prospectively evaluated. The investigated outcome parameters included the maximum flow rate (Qmax), postvoid residual volume, International Prostate Symptom Score (IPSS)/quality of life (Qol), and prostate specific antigen (PSA) tests. Follow-up investigations took place after 6 weeks, 6 months, and 12 months. The Wilcoxon signed-rank test was used to compare pre- and post-treatment parameters. RESULTS: The median (range) preoperative prostate volume was 41 mL (17-111 mL). The preoperative IPSS, Qol, Qmax, and residual volume were 16 (2-35), 4 (0-6), 10.1 mL/s (3-29.3 mL/s), and 87 mL (0-1000 mL), respectively. One third of the patients were undergoing platelet aggregation inhibition (PAI). No intraoperative complications occurred. Postoperatively, 13 patients (15.7%) had to be recatheterized. Three patients (3.6%) had clot retention and 28 patients (34%) reported any grade of dysuria. After 6 weeks, all outcome parameters improved significantly and remained improved over the 12-month observation period [IPSS: 3 (0-2); Qol: 1 (0-4); Qmax: 17.2 mL/s (3.2-56 mL/s); residual volume 11 mL (0-190 mL)]. The PSA reduction was 60% at study conclusion. Three patients (3.6%) developed a urethral stricture and four patients (4.8%) bladder neck sclerosis. Re-resections were not necessary. CONCLUSIONS: Contemporary BPV is a safe and efficacious treatment option even for patients undergoing PAI. Early urinary retention and temporary dysuria seem to be specific side effects of the treatment. Bleeding complications are rare. Long-term follow up is needed to confirm these promising short-term results. PMID- 23806051 TI - Clinical significance in COPD patients followed in a real practice. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an important public health issue in many countries which is estimated to become the fifth cause of disability and the third cause of mortality in the world within 2020.The objective of this study was to identify the clinical characteristics in the real clinical practice of a sample of patients with COPD followed in a pulmonology clinic. METHODS: The initial sample contained 207 subjects with respiratory claims that searched for specialized treatment and initiated regular monitoring between 2004 and 2009 in a private clinic localized in Cascavel, in the state of Parana, Brazil. Demographic data (weight, height, body mass index - BMI), history of comorbidities, use of respiratory and non respiratory drugs were also registered. RESULTS: The main cause related to the development of COPD was current or prior smoking (92.0%); the most frequently reported symptom was dyspnea (95.0%), followed by cough (86.1%), wheezing (69.4%) and sputum production (40.0%). During the follow up, 51 patients developed the need for oxygen therapy (28.3%). In 96 patients, there were periods of acute exacerbation, resulting in 37 hospitalizations. In addition to COPD, a significant number of comorbidities were identified, being cardiovascular disease and neurological disorders the most prevalent ones. CONCLUSIONS: Based on the data collected, we could outline the profile of patients with COPD, showing characteristics of an elderly population, with multiple comorbidities, suggesting a health related quality of life lower than expected. PMID- 23806052 TI - Re-evaluation of the pathogenic roles of nonstructural protein 1 and its antibodies during dengue virus infection. AB - Dengue virus (DENV) infection can cause life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Vascular leakage and abnormal hemorrhage are the two major pathogenic changes found in these patients. From previous studies, it is known that both antibodies and cytokines induced in response to DENV infection are involved in the immunopathogenesis of DHF/DSS. However, the role of viral factors during DENV infection remains unclear. Nonstructural protein 1 (NS1), which is secreted in the sera of patients, is a useful diagnostic marker for acute DENV infection. Nevertheless, the roles of NS1 and its antibodies in the pathogenesis of DHF/DSS are unclear. The focus of this review is to evaluate the possible contributions of NS1 and the antibodies it induces to vascular leakage and abnormal hemorrhage during DENV infection, which may provide clues to better understanding the pathogenesis of DHF/DSS. PMID- 23806053 TI - Developing a complex intervention for the outpatient management of incidentally diagnosed pulmonary embolism in cancer patients. AB - BACKGROUND: Most patients with pulmonary embolism (PE) spend 5-7 days in hospital even though only 4.5% will develop serious complications during this time. In particular, the group of patients with incidentally diagnosed PE (i-PE) includes many patients with low risk features potentially ideal for outpatient management; however the evidence for their optimal management is lacking hence relative practices may vary considerably. We describe the development process, components, links and function of a nurse-led service for the management of patients with i PE, developed in accordance to the UK Medical Research Council complex intervention guidance. METHODS: Phase 0 (Theoretical underpinning): The Pulmonary Embolism Severity Index (PESI) was selected for patient risk assessment and the American Society of Clinical Oncology (ASCO) guideline for the management of PE in cancer patients (2007) was selected as quality measure. Historical registry and audit data from our centre regarding i-PE incidence and management for the period between 2006 and 2009 illustrating the then current practices were reviewed. Phase 1 (Modelling): Modelling of the pathway included the following: a) Identification of training needs, planning and implementation of training schemes and development of transferable competencies and training materials. b) Mapping patient pathways and flow and c) Production of key documentation and Standard Operating Procedures for the delivery of the service. RESULTS: Phase 2 (Implementation and testing of the intervention): During the initial 12 months of implementation, remedial action was taken to address identified deficiencies regarding patient referral to the pathway, compliance with treatment protocol, patient follow up, selection challenges from the use of PESI in cancer patients and challenges regarding the "first-pass" identification of i-PE. CONCLUSION: We have developed and piloted a complex intervention to manage cancer patients with incidental PE in an outpatient setting. Adherence to evidence- based care, improvement of communication between professionals and patients, and improved quality of data is demonstrated. PMID- 23806054 TI - Genetic and neural bases for species-specific behavior in Drosophila species. AB - Behavioral changes in evolution have attracted the attention of many evolutionary biologists. Closely related species, or even individuals from different populations within a species, often exhibit remarkably different behaviors. Such behavioral diversification has been implicated as a cause of speciation in some cases, yet the mechanisms that produce and maintain these changes remain largely unknown. Drosophila melanogaster, an outstanding model organism with which to explore the causal link among the gene, neural circuitry, and behavior, provides an excellent entry point for a comparative approach to the origin of behavioral diversification with a single-gene and single-cell resolution. Here we survey studies that attempted to reveal the mechanistic bases for behavioral changes potentially associated with speciation, and we discuss the successfully identified candidate genes or neurons involved in such events. Although evolutionary developmental biology (evo-devo), a field devoted to the developmental and molecular basis of phenotypic diversity, has mostly been focused on morphological traits, the extension of this evo-devo approach to behavioral diversity will provide a comprehensive understanding of the genome environment interactions underlying adaptive evolution. PMID- 23806055 TI - Structure determination using the method of continuous variation: lithium phenolates solvated by protic and dipolar aprotic ligands. AB - The method of continuous variation (MCV) was used in conjunction with (6)Li NMR spectroscopy to characterize four lithium phenolates solvated by a range of solvents, including N,N,N',N'-tetramethylethylenediamine, Et2O, pyridine, protic amines, alcohols, and highly dipolar aprotic solvents. Dimers, trimers, and tetramers were observed, depending on the precise lithium phenolate-solvent combinations. Competition experiments (solvent swaps) provide insights into the relative propensities toward mixed solvation. PMID- 23806056 TI - Concomitant BRAF(V600E) mutation and RET/PTC rearrangement is a frequent occurrence in papillary thyroid carcinoma. AB - BACKGROUND: The tyrosine kinase receptors/RAS/RAF/MAPK cascade is a site of mutational events associated with thyroid carcinogenesis. Some studies suggest the reciprocal exclusion of different oncogenes in the mitogen-activated protein kinase cascade, whereas others suggest that BRAF mutations and RET rearrangements can simultaneously occur in sporadic cases. The aim of this study was to determine the prevalence of concomitant BRAF(V600E) mutation and RET/PTC rearrangements in the same tumor and its association with some clinicopathological features. METHODS: The percentage of mutant BRAF alleles and the presence of RET/PTC rearrangements were determined by means of pyrosequencing and Southern blot analysis of reverse transcription polymerase chain reaction products in a series of 72 conventional papillary thyroid carcinomas (PTCs). Then, the associations between clinicopathological characteristics and mutation status were assessed. RESULTS: BRAF(V600E) alleles were present in 32 out of 72 PTCs (44.4%) in the range of 5.1-44.7% of total BRAF alleles. RET/PTC was present in 26 tumors (36.1%). Concomitant subclonal BRAF and RET/PTC were demonstrated in 14 PTCs (19.4%), and none of the oncogenes was detected in 22 tumors (30.5%). Only BRAF(V600E) was associated with a more advanced tumor staging. CONCLUSIONS: The present study demonstrates that concomitant BRAF mutation and RET/PTC rearrangement is a frequent event in PTC. PMID- 23806057 TI - The effect of hepatitis C treatment response on medical costs: a longitudinal analysis in an integrated care setting. AB - BACKGROUND: Studies suggest that chronic hepatitis C patients who achieve sustained virologic response (SVR) have lower risks of liver-related morbidity and mortality. Given the substantial costs and complexity of hepatitis C virus (HCV) antiviral treatment, post-treatment benefits are important to understand. OBJECTIVE: To determine whether health care costs and utilization for up to 5 years after treatment differed between patients who achieved SVR and those who did not. METHODS: Kaiser Permanente Medical Care Program patients receiving HCV treatment with pegylated interferon and ribavirin (Peg-IFN/RBV) from 2002 to 2007 were retrospectively analyzed, excluding those with human immunodeficiency virus (HIV) or chronic hepatitis B. Health care utilization and costs for up to 5 years after treatment completion were derived from electronic records. We compared mean annual cost and overall post-treatment costs (standardized to year-2007 dollars), and yearly utilization counts between the SVR and non-SVR groups, adjusting for pretreatment costs, age, sex, baseline cirrhosis, and race using gamma and Poisson regression models. RESULTS: The 1,924 patients eligible for inclusion were a mean age of 50 years; 63% male; 58% white, non-Hispanic; 62% with genotype 1; and 48% who had achieved SVR. The mean duration of post-treatment time was 3 years, and patients without SVR incurred significantly higher health care costs than patients with SVR. For each post-treatment year, total adjusted costs were significantly higher in the non-SVR group than in the SVR group, with rate ratios (RRs) and 95% CIs ranging from 1.26 (95% CI, 1.13-1.40) to 1.64 (95% CI, 1.38 1.96), driven mostly by hospital and outpatient pharmacy costs. When all post treatment years were considered collectively, the non-SVR group had significantly higher costs overall (RR=1.41; 95% CI, 1.17-1.69) and in each category of costs. The adjusted difference in yearly total mean costs was $2,648 (95% CI, 737 4,560). In post-treatment years 2-5, adjusted liver-specific laboratory test rates were 1.8 to 2.3 times higher in the non-SVR group than in the SVR group (each year, P less than 0.001). During post-treatment years 1-5, adjusted yearly liver-related hospitalization rates were up to 2.45 times higher (95% CI, 1.56 3.85), and medicine/GI clinic visit rates were up to 1.39 times higher (95% CI, 1.23-1.54) in the non-SVR group compared with the SVR group. CONCLUSION: Health care utilization and costs after HCV antiviral therapy with Peg-IFN/RBV, particularly for liver-related tests, outpatient drugs, and hospitalizations, were significantly lower for patients who achieved SVR than for those without SVR. Our observations are consistent with the potentially lower risk of severe liver disease among patients with SVR. PMID- 23806058 TI - Antiviral regimen complexity index as an independent predictor of sustained virologic response in patients with chronic hepatitis C. AB - BACKGROUND: Hepatitis C virus (HCV) infection affects more than 170 million people worldwide, and one-third of them have human immunodeficiency virus (HIV) coinfection. Multiple studies have been conducted in order to identify the factors that may explain different responses to treatment among patients. However, the reasons why HIV-HCV coinfected patients have lower responses to treatment are not clear. In addition, no studies have evaluated the influence of the complexity of the therapeutic regimen for hepatitis C infection on clinical outcomes. OBJECTIVES: To (a) investigate the influence of the antiviral regimen complexity in the sustained viral response (SVR) in patients with chronic hepatitis and (b) adapt a method of quantifying complexity of an antiretroviral regimen for patients infected with HCV. METHODS: A single center, retrospective study was conducted in HCV and HIV-HCV coinfected patients. We selected patients treated with interferon alfa-2a plus ribavirin between January 2005 and December 2010. Patients with severe psychiatric disorders, those included in a clinical trial, and those known to be nonadherent to treatment were excluded. The dependent variable was the sustained virologic response and the independent variables were sex, age, race, stage fibrosis (F) >=2, presence or absence of cirrhosis, low hepatitis C baseline viral load (defined as <=800,000 IU), viral genotype, rapid virological response (RVR), serum gamma-glutamyltransferase (GGT) levels, ratio of alanine aminotransferase to aspartate aminotransferase (ALT/AST), serum cholesterol level, presence or absence of diabetes mellitus, and antiviral regimen complexity index. The latter variable included drugs for HCV and HIV infection, but no medication for other comorbidities. To evaluate the complexity of antiviral treatment we performed an adaptation of the system developed by Martin et al. (2007) in HIV patients. The factors determining the complexity of treatment were the number of medications, dosing schedules, administration methods, special instructions, and required preparations associated with antiviral regimens. Sample size was estimated by the Freeman equation. To determine the independent variables associated with SVR, we performed an univariate logistic regression and subsequently a multivariate analysis with those variables that demonstrated a statistically significant difference in the univariate analysis. RESULTS: A total of 156 patients was included (76% men, mean age 44 years) of whom 45% were HIV-HCV coinfected. 75% were genotypes 1 or 4. The univariate analysis variables-genotypes 2 and 3 (OR=3.10; CI [1.38-6.95]; P=0.006); HIV-HCV coinfection (OR=0.36; CI [0.19 0.69]); presence of cirrhosis (OR=0.27; CI [0.10-0.73]; P=0,01); F>=2 (OR=0.44; CI [0.23-0.84]; P=0.01); low baseline viral load (OR= 2.05; CI [1.01-4.17]; P=0.048); RVR (OR=17,60; CI [6.84-45.30]; P less than 0.001); complexity index (OR=0.71; CI [0.58-0.87]; P=0.001), showed statistically significant relationships with SVR. Complexity index (OR=0.67; CI [0.52-0.87]; P=0.002) and RVR (OR=20.04; CI [7.33-54.85]; P less than 0.001) were independent predictors of SVR in multivariate analysis. The reliability of the multivariate analysis was checked with the Hosmer and Lemeshow test (P=0.079). CONCLUSIONS: The medication regimen complexity may be a crucial factor to achieve therapeutic success when treating patients for hepatitis C. The adaptation of this index in patients with HCV provides an objective value of the antiviral regimen complexity and could help us to identify patients in clinical practice who require multidisciplinary attention. Simplification of the antiretroviral regimen might result in a greater response to treatment for hepatitis C. PMID- 23806059 TI - A qualitative study examining HIV antiretroviral adherence counseling and support in community pharmacies. AB - BACKGROUND: Observational studies suggest that HIV-focused pharmacies can improve antiretroviral therapy (ART) refill adherence, but there is a lack of clear documentation about the kind and variability of adherence interventions that are conducted. OBJECTIVE: To use qualitative research methods to obtain an in-depth understanding of how ART adherence support and counseling is provided in human immunodeficiency virus (HIV)-focused community pharmacies. To determine relevant facilitators and barriers around adherence support from both patient's and pharmacist's perspectives. METHODS: A qualitative research study of patients who patronized and pharmacists who were employed at HIV-focused pharmacies in the San Francisco Bay Area was conducted. Participants were recruited using flyers at HIV clinics and community-based organizations and using blurbs in newsletters. Transcripts were analyzed using grounded theory methods to determine emergent themes in the data. RESULTS: 19 eligible patients with a self-reported diagnosis of HIV, who were taking their current ART regimen for at least 3 months, and who obtained their ART from a community pharmacy in the San Francisco Bay Area were included; 9 pharmacists who were employed at 9 different pharmacy locations frequented by participants were interviewed. Emergent themes included descriptions of pharmacy adherence counseling and support, roles and responsibilities regarding medication adherence, barriers to providing adherence support, and feeling connected as a facilitator to adherence support relationships. CONCLUSION: Pharmacists provide diverse types of ART adherence support and are uniquely positioned to help clients manage their medications. Additional training on developing relationships with patients and advertising their adherence services may further the role of community pharmacists in supporting antiretroviral adherence. PMID- 23806060 TI - Medical costs associated with use of systemic therapy in adults with colorectal cancer. AB - BACKGROUND: New cytotoxic agents and regimens, as well as immunotherapeutics, have recently been introduced for treatment of colorectal cancer (CRC). OBJECTIVE: To identify the patient-related and clinical and treatment-related factors associated with higher total health care expenditures in newly diagnosed patients with CRC who are receiving systemic therapy (biologic or chemotherapy) from a commercially insured population. METHODS: A longitudinal, retrospective analysis was employed to estimate costs and determinants of CRC treatment in a U.S. claims database for health care services used by commercial patients aged 18 to 64 years, who were diagnosed with CRC between January 1, 2005, and June 30, 2009. Generalized linear regression modeling was used to estimate the influence of demographic, clinical, and treatment factors on medical expenditures. RESULTS: Among the 5,160 patients newly diagnosed with CRC, 99.6% of patients had chemotherapy; 32.6% had biologics; and 85.6% had other pharmaceuticals (excluding the chemotherapy and biologics of interest). The average annualized per patient cost of CRC treatment was $97,400 and consisted of chemotherapy ($17,500), biologics ($30,400), other pharmaceuticals ($2,300), inpatient treatment ($26,300), and outpatient treatment ($42,900). From first line only, first and second lines only, and third+ lines, the cost per patient was $70,500, $100,100, and $152,900, respectively. After adjusting for health care inflation, the average treatment cost of CRC patients increased by 73% from 2005 to 2009. Adjusted analyses showed that the higher medical cost for CRC patients was associated with use of new regimens, metastasis, comorbidities, surgery, radiation, insurance plan, age, sex, and region. CONCLUSION: The health care cost of CRC treatment is increasing significantly over time, which is most likely caused by the use of new regimens, higher chances of surgery and radiation, and occurrence of various comorbidities and metastatic diseases due to increasing survival time. PMID- 23806061 TI - Identifying patient characteristics associated with high schizophrenia-related direct medical costs in community-dwelling patients. AB - BACKGROUND: Schizophrenia is a chronic, debilitating disease that affects approximately 1% of the U.S. population and has disproportionately high costs. Several factors, including age, gender, insurance status, and comorbid conditions, have been hypothesized to be associated with schizophrenia-?related costs. OBJECTIVE: To identify demographic and clinical characteristics of community-dwelling schizophrenia patients experiencing high schizophrenia-related direct medical costs. METHODS: Community-dwelling patients with a diagnosis for schizophrenic disorder (ICD-9-CM code 295) and other nonorganic psychoses (ICD-9 CM code 298) were identified from the 2005-2008 Medical Expenditure Panel Survey (MEPS). Schizophrenia-related direct medical costs were calculated for (a) inpatient hospitalizations; (b) prescription medications; and (c) outpatient, office-based physician, emergency room, and home health care visits. Using Andersen's Behavorial Model of Health Services Use and the literature, factors that could potentially affect schizophrenia-related direct medical costs were identified. Based on the distribution of their mean annual costs, patients were classified into high- and low-cost groups. Logistic regression was used to determine the likelihood of high-cost group membership based on age, sex, race, insurance status, marital status, region of residence, family income as a percentage of poverty line, number of medical comorbidities, number of mental health-related comorbidities, patient-perceived general health status, patient perceived mental health status, and year of inclusion in MEPS. In addition, a generalized linear model (GLM) regression (gamma distribution with a log-link function) was used to evaluate the relationships between the independent variables and total schizophrenia-related direct medical costs as a continuous variable. RESULTS: From the MEPS database, we identified 317 patients with schizophrenia who represented 2.75 million noninstitutionalized, community dwelling schizophrenia patients in the United States between 2005 and 2008. The logistic regression procedure showed that older patients (OR=0.933, 95% CI=0.902 0.966) and patients with a spouse (OR=0.150, 95% CI=0.041-0.555) were less likely to be in the high-cost group, while those who reported having "poor" perceived general health status (OR=15.548, 95% CI=1.278-189.127) were more likely to be in the high-cost group. The GLM regression procedure showed that younger patients (compared with older patients), African Americans (compared with Caucasions), patients with private insurance (compared with the uninsured), and those living in the northeastern United States (compared with those living in the southern United States) had higher schizophrenia-related direct medical costs. CONCLUSION: Identification of factors associated with a high-cost population may help decision makers in managed care, government, and other organizations allocate resources more efficiently and health care providers manage patients more effectively through assignment of these patients to case managers and appropriate monitoring and treatment. PMID- 23806062 TI - Influence of coadministration of antithrombotic medicines, warfarin, and NSAIDs on heparin safety: data from a prospective observational study. AB - BACKGROUND: Utilization of heparins has been increasing in the last decade, thus, in-depth analysis is needed to assess heparins safety monitoring patterns, incidence rates of adverse drug reactions (ADR), and frequency of coadministration with other medicines. OBJECTIVE: To investigate the safety monitoring of heparin in hospitals and the influence of coadministration of nonsteroidal anti-inflammatory drugs (NSAIDs), antithrombotic medicines, and warfarin on heparin safety. METHODS: We reviewed hospital records of 339 patients who had orders for heparin or low molecular weight heparin from May 2009 to May 2010. IBM SPSS Statistics version 18.0 was used to perform statistical analysis. RESULTS: Dalteparin (n=238, 70.21%) was the most frequently prescribed ?heparin. The most frequent indications given were for prophylaxis of venous thrombosis (n=135, 39.82%) and treatment of unstable coronary artery disease and myocardial infarction (n=166, 48.97%). ADRs were reported for 75 patients (22.12%), including coagulation abnormalities in 25 patients (7.37%), renal dysfunctions in 24 patients (7.08%), and thrombocytopenia in 10 patients (2.95%). 256 patients (75.52%) had relative contraindications. ADRs were associated with the previously reported relative contraindications (Spearman's rank correlation coefficient [rS] = 0.261, Pearson's chi-squared test [chi2]= 45.5, P less than 0.0005) and with prolonged treatment with heparins (rS=0.279 and chi2=74.7, P less than 0.0005). ADRs were not related to heparin use but indicated increased risk for negative treatment outcomes. Coadministration of heparin with warfarin, acetylsalicylic acid, clopidogrel, ketorolac, and NSAIDs was associated with the increased risk of adverse drug reactions. The relationship was low but statistically significant. The strongest relationship was with coadministration of aspirin (rS=0.283, chi2=21.42, P less than 0.0005), while the coadministration of NSAIDs showed only a very weak relationship to the development of ADRs (rS=0.133, chi2=21.01, P less than 0.0005). For the development of thrombocytopenia, the strongest risk was calculated for coadministration of warfarin (rS=0.248, chi2=28.14, P less than 0.0005), while coadministration of medicines from the list did not have a relationship with the risk of thrombocytosis. CONCLUSIONS: Safety monitoring of heparin orders is essential, especially for patients with relative contraindications during long term treatment and in case of coadministration of oral anticoagulants, platelet inhibitors, and NSAIDs. PMID- 23806064 TI - Catalyst-controlled divergent C-H functionalization of unsymmetrical 2-aryl cyclic 1,3-dicarbonyl compounds with alkynes and alkenes. AB - Achieving site-selective, switchable C-H functionalizations of substrates that contain several different types of reactive C-H bonds is an attractive objective to enable the generation of different products from the same starting materials. Herein, we demonstrate the divergent C-H functionalization of unsymmetrical 2 aryl cyclic 1,3-dicarbonyl compounds that contain two distinct, nonadjacent sites for initial C-H functionalization, where product selectivity is achieved through catalyst control. By use of a palladium-N-heterocyclic carbene complex as the precatalyst, these substrates undergo oxidative annulation with alkynes to provide spiroindenes exclusively. In contrast, a ruthenium-based catalyst system gives benzopyrans as the major products. Examples of divergent, oxidative C-H alkenylations of the same substrates are also provided. PMID- 23806063 TI - Legionnaires' disease case-finding algorithm, attack rates, and risk factors during a residential outbreak among older adults: an environmental and cohort study. AB - BACKGROUND: During a Legionnaires' disease (LD) outbreak, combined epidemiological and environmental investigations were conducted to identify prevention recommendations for facilities where elderly residents live independently but have an increased risk of legionellosis. METHODS: Survey responses (n = 143) were used to calculate attack rates and describe transmission routes by estimating relative risk (RR) and 95% confidence intervals (95% CI). Potable water collected from five apartments of LD patients and three randomly selected apartments of residents without LD (n = 103 samples) was cultured for Legionella. RESULTS: Eight confirmed LD cases occurred among 171 residents (attack rate = 4.7%); two visitors also developed LD. One case was fatal. The average age of patients was 70 years (range: 62-77). LD risk was lower among residents who reported tub bathing instead of showering (RR = 0.13, 95% CI: 0.02 1.09, P = 0.03). Two respiratory cultures were characterized as L. pneumophila serogroup 1, monoclonal antibody type Knoxville (1,2,3), sequence type 222. An indistinguishable strain was detected in 31 (74%) of 42 potable water samples. CONCLUSIONS: Managers of elderly-housing facilities and local public health officials should consider developing a Legionella prevention plan. When Legionella colonization of potable water is detected in these facilities, remediation is indicated to protect residents at higher risk. If LD occurs among residents, exposure reduction, heightened awareness, and clinical surveillance activities should be coordinated among stakeholders. For prompt diagnosis and effective treatment, clinicians should recognize the increased risk and atypical presentation of LD in older adults. PMID- 23806065 TI - Fractionated stereotactic radiotherapy for 136 patients with locally residual nasopharyngeal carcinoma. AB - BACKGROUND: To evaluate the efficacy and toxicity of fractionated stereotactic radiotherapy (FSRT) in patients with residual nasopharyngeal carcinoma (NPC). METHODS: From January 2000 to December 2009, 136 NPC patients with residual lesions after primary radiotherapy (RT) were treated by FSRT. The total dose of primary RT was 68.0-78.0 Gy (median, 70.0 Gy). The median time from the primary RT to FSRT was 24.5 days. Tumor volumes for FSRT ranged from 0.60 to 77.13 cm3 (median, 13.45 cm3). The total FSRT doses were 8.0-32.0Gy (median, 19.5 Gy) with 2.0-10.0 Gy per fraction. RESULTS: Five-year local failure-free survival (LFFS), freedom from distant metastasis (FFDM), overall survival (OS), and disease free survival (DFS) rates for all patients were 92.5%, 77.0%, 76.2%, and 73.6%, respectively. No statistical significant differences were found in LFFS, DFS and OS in patients with stage I/II versus stage III/ IV diseases. Nineteen patients exhibited late toxicity. T stage at diagnosis was a significant prognostic factor for OS and DFS. Age was a prognostic factor for OS. CONCLUSION: FSRT after external beam radiotherapy provides excellent local control for patients with residual NPC. The incidence of severe late toxicity is low and acceptable. Further investigation of optimal fractionation regimens will facilitate reduction of long-term complications. PMID- 23806066 TI - Dissecting the EGFR-PI3K-AKT pathway in oral cancer highlights the role of the EGFR variant III and its clinical relevance. AB - BACKGROUND: Dysregulated epidermal growth factor receptor (EGFR)-phosphoinositide 3-kinase (PI3K)-AKT signaling is considered pivotal for oral cancer, and the pathway is a potential candidate for therapeutic targeting. RESULTS: A total of 108 archival samples which were from surgically resected oral cancer were examined. Immunohistochemical staining showed the protein expression of membranous wild-type EGFR and cytoplasmic phosphorylated AKT was detected in 63.9% and 86.9% of the specimens, respectively. In 49.1% of the samples, no phosphatase and tensin homolog (PTEN) expression was detected. With regard to the EGFR variant III (EGFRvIII), 75.0% of the samples showed positive expression for moderate to severe staining, 31.5% of which had high expression levels. Real-time polymerase chain reaction assays for gene copy number assessment of PIK3CA revealed that 24.8% of the samples had alterations, and of EGFR showed that 49.0% had amplification. Direct sequencing of PIK3CA gene showed 2.3% of the samples had a hotspot point mutation. Statistical assessment showed the expression of the EGFRvIII correlated with the T classification and TNM stage. The Kaplan-Meier analyses for patient survival showed that the individual status of phosphorylated AKT and EGFRvIII led to significant differences in survival outcome. The multivariate analysis indicated that phosphorylated AKT, EGFRvIII expression and disease stage were patient survival determinants. CONCLUSIONS: Aberrations in the EGFR-PI3K-AKT pathway were frequently found in oral cancers. EGFRvIII and phosphorylated AKT were predictors for the patient survival and clinical outcome. PMID- 23806067 TI - Molecular epidemiological survey of hemoglobinopathies in the Wuxi region of Jiangsu Province, eastern China. AB - In order to determine the prevalence and molecular characterization of hemoglobinopathies in the Wuxi region of Jiangsu Province in the People's Republic of China (PRC), a total of 10,297 healthy people selected from a regional hospital were screened. Hemoglobin (Hb) electrophoresis, complete blood cell (CBC) count, polymerase chain reaction (PCR), DNA sequencing, reverse dot blot and multiplex ligation-dependent probe amplification (MLPA) were used to detect Hb variants, thalassemias and hereditary persistence of fetal Hb (HPFH). Two thousand and twenty-one adult subjects were screened for thalassemia, five cases were identified as alpha-thalassemia (alpha-thal) carriers including three cases of the -alpha(3.7) (rightward) deletion, one case of the - -(SEA) deletion and one case of beta-thal [IVS-II-654 (C>T), (HBB: c.316-197C>T)]. The incidence of Hb variants, thalassemia and HPFH/deltabeta-thal were 0.136% (14/10,297), 0.25% (5/2021) and 0.0001% (1/10,297), respectively. Eight genotypes of Hb variants were found, including Hb E [beta26(B8)Glu->Lys, GAG>AAG; HBB: c.79G>A], Hb J-Bangkok [beta56(D7)Gly->Asp (GGC>GAC); HBB; c.170G>A], Hb G-Coushatta [beta22(4)Glu->Ala (GAA>GCA); HBB: c.68A>C], Hb Queens [alpha34(B15)Leu->Arg (CTG>CGG) (alpha2 or alpha1); HBA2: c.104T>G (or HBA1)], Hb I [alpha16(A14)Lys >Glu, AAG>GAG (alpha1); HBA1: c.49A>G], Hb Beijing [alpha16(A14)Lys->Asn (AAG>AAC or AAT) (alpha2 or alpha1); HBA2: c.51G>C (or HBA1) or 51G>T (or HBA1)], Hb Ube-2 [alpha68(E17)Asn->Asp (AAC>GAC) (alpha2 or alpha1); HBA2: c.205A>G (or HBA1)] and Hb G-Taipei [beta22(B4)Glu->Gly (GAA>GGA); HBB: c.68A>G]. A Sicilian deltabeta(0) thal, identified for the first time in Asia, was also found in this survey. PMID- 23806068 TI - Rupatadine for the treatment of urticaria. AB - INTRODUCTION: Rupatadine fumarate is a second-generation antihistamine provided with a potent, long-lasting and balanced in vivo dual platelet-activating factor (PAF) and histamine antagonist activity and it uniquely combines both activities at a high level of potency. Rupatadine has a rapid onset of action and a long lasting effect, so a once-daily dosing is permitted, moreover is well tolerated by young adults and the elders. Rupatadine does not present the side effects of first-generation H1-antihistamines, such as somnolence, fatigue, headache, impaired memory and learning, sedation, increased appetite, dry mouth, dry eyes, visual disturbances, constipation, urinary retention and erectile dysfunction. AREAS COVERED: This study evaluates the effectiveness and safety of rupatadine in chronic urticaria (CU) and acquired cold urticaria (ACU), through a systematic review of the literature. EXPERT OPINION: Patients affected by urticaria are often discouraged because frequently their disease does not recognize a cause and it is unresponsive to treatments. Patients can control their symptoms assuming second-generation H1-antihistamines, such as rupatadine. Several randomized, double-blind, placebo-controlled trials testify effectiveness and safety of rupatadine in CU and ACU. However, further clinical trials to evaluate the efficacy of rupatadine in different urticaria subtypes and to test the safety of doses higher than 20 mg are encouraged. PMID- 23806069 TI - Obesity genomics: assessing the transferability of susceptibility loci across diverse populations. AB - The prevalence of obesity has nearly doubled worldwide over the past three decades, but substantial differences exist between nations. Although these differences are partly due to the degree of westernization, genetic factors also contribute. To date, little is known about whether the same genes contribute to obesity-susceptibility in populations of different ancestry. We review the transferability of obesity-susceptibility loci (identified by genome-wide association studies) using both single nucleotide polymorphism (SNP) and locus wide comparisons. SNPs in FTO and near MC4R, obesity-susceptibility loci first identified in Europeans, replicate widely across other ancestries. SNP-to-SNP comparisons suggest that more than half of the 36 body mass index-associated loci are shared across European and East Asian ancestry populations, whereas locus wide analyses suggest that the transferability might be even more extensive. Furthermore, by taking advantage of differences in haplotype structure, populations of different ancestries can help to narrow down loci, thereby pinpointing causal genes for functional follow-up. Larger-scale genetic association studies in ancestrally diverse populations will be needed for in depth and locus-wide analyses aimed at determining, with greater confidence, the transferability of loci and allowing fine-mapping. Understanding similarities and differences in genetic susceptibility across populations of diverse ancestries might eventually contribute to a more targeted prevention and customized treatment of obesity. PMID- 23806070 TI - The role of SOX9 transcription factor in pancreatic and duodenal development. AB - Progenitor expansion during development is a highly regulated process dictating the final organ size, while expansion of specific progenitor populators can adjust the final cellular composition of the organ. Understanding factors involved in these pathways is required to develop cell-based therapies such as beta-cell transplantation for conditions such as diabetes mellitus. One versatile factor controlling both processes as well as a network of other proteins involved in pancreatic and duodenal development is the transcription factor SOX9. This review will focus on a comparison of SOX9 function during progenitor expansion and differentiation in the developing pancreas and duodenum with specific focus on endocrine development. During human pancreatic development, SOX9 functions in a dose-dependent manner to regulate epithelial progenitor expansion and endocrine differentiation. SOX9 expression is eventually limited to a subset of ductal and centroacinar cells, hypothesized to be the pancreatic stem cell compartment. Similarly, during duodenal development, SOX9 is expressed in most early epithelial progenitors and becomes gradually restricted to proliferative progenitors in the lower crypts, as well as mature Paneth and enteroendocrine cells indicating some differences in functional roles. However, in both developmental contexts, SOX9 is involved in pathways responsible for cellular proliferation and differentiation, such as Notch and Wnt. With its adaptable and central function in progenitor control, SOX9 represents an attractive target for manipulation for in vitro progenitor expansion and differentiation meriting further investigation. PMID- 23806071 TI - Cytotoxic polyketide derivatives from the South China Sea sponge Plakortis simplex. AB - Five new polyketides, plakortoxides A (1) and B (2), simplextones C (3) and D (4), and plakorsin D (5), together with six known analogues (6-11) were isolated from the South China Sea sponge Plakortis simplex. Their structures were identified by spectroscopic and chemical methods, including NMR, MS, and IR. Experimental and calculated ECD spectra and the modified Mosher's method were used to determine the absolute configurations. Structurally, both plakortoxides A and B feature a butenolide coupled to an epoxide moiety, while simplextones C and D consist of gamma-butyrolactone and cyclopentane moieties, and plakorsin D is a furan acetic acid polyketide. The cytotoxic activities of the isolates were tested, and compounds 8, 10, and 11 showed potent cytotoxicity against both K562 and HeLa tumor cell lines with IC50 values ranging from 0.8 to 5.3 MUM. Compound 3 showed significant inhibitory activity against c-Met kinase. PMID- 23806072 TI - Alstoniaphyllines A-C, unusual nitrogenous derivatives from the bark of Alstonia macrophylla. AB - Chemical investigation of an alkaloidal extract of Alstonia macrophylla bark led to the isolation and identification of two new nitrogenous derivatives, alstoniaphyllines A (1) and B (2), a new indole alkaloid, alstoniaphylline C (4), and eight known alkaloids (3, 5-11). Alstonisine (9) exhibited antiplasmodial activity against Plasmodium falciparum, with an IC50 of 7.6 MUM. PMID- 23806073 TI - Associations of parental control of feeding with eating in the absence of hunger and food sneaking, hiding, and hoarding. AB - BACKGROUND: Overweight children as young as 5 years old exhibit disturbances in eating behaviors. METHODS: Using follow-up data from 419 participants in High Five for Kids, a randomized controlled trial of overweight children, the prevalence of (1) eating in the absence of hunger and (2) food sneaking, hiding, and hoarding was estimated and cross-sectional associations of parental control of feeding and these behaviors were examined using covariate-adjusted logistic regression models. RESULTS: At follow-up, mean [standard deviation (SD)] age of the children was 7.1 (1.2) years; 49% were female; 16% were healthy weight, 35% were overweight, and 49% were obese. On the basis of parental report, 16.5% of children were eating in the absence of hunger and 27.2% were sneaking, hiding, or hoarding food; 57.5% of parents endorsed parental control of feeding. In adjusted models, children exposed to parental control of feeding were more likely to eat in the absence of hunger [odds ratio (OR) 3.37, 95% confidence interval (CI) 1.66, 6.86], but not to sneak, hide, or hoard food (OR 1.43, 95% CI 0.87, 2.36). CONCLUSIONS: Disturbances in eating behaviors are common among overweight children. Future research should be dedicated to identifying strategies that normalize eating behaviors and prevent excess weight gain among overweight children. PMID- 23806074 TI - Efavirenz stimulates HIV-1 reverse transcriptase RNase H activity by a mechanism involving increased substrate binding and secondary cleavage activity. AB - Efavirenz is a non-nucleoside reverse transcriptase inhibitor used for treating HIV/AIDS. We found that polymerization activity of a reverse transcriptase (RT) with the E478Q mutation that inactivates the RNase H catalytic site is much more sensitive to efavirenz than wild-type RT, indicating that a functional RNase H attenuates the effectiveness of efavirenz. Moreover, efavirenz actually stimulated wild-type RNase H binding and catalytic functions, indicating another link between efavirenz action and RNase H function. During reverse transcription in vivo, the RT that is extending the DNA primer also periodically cleaves the genomic RNA. The RNase H makes primary template cuts ~18 nucleotides from the growing DNA 3'-end, and when the RT pauses synthesis, it shifts to make secondary cuts ~9 nucleotides from the DNA 3'-end. After synthesis, RTs return to bind the remaining template RNA segments at their 5'-ends and make primary and secondary cuts, 18 and 9 nucleotides in, respectively. We found that efavirenz stimulates both 3'- and 5'-directed RNase H activity. Use of specific substrates revealed a particular acceleration of secondary cuts. Efavirenz specifically promoted binding of the RT to RNase H substrates, suggesting that it stabilizes the shifting of RTs to make the secondary cuts. We further showed that efavirenz similarly stimulates the RNase H of an RT from a patient-derived virus that is highly resistant and grows more rapidly in the presence of low concentrations of efavirenz. We suggest that for efavirenz-resistant RTs, stimulated RNase H activity contributes to increased viral fitness. PMID- 23806075 TI - Analog neuromorphic module based on carbon nanotube synapses. AB - We report an analog neuromorphic module composed of p-type carbon nanotube (CNT) synapses and an integrate-and-fire (I&F) circuit. The CNT synapse has a field effect transistor structure with a random CNT network as its channel and an aluminum oxide dielectric layer implanted with indium ions as its gate. A positive voltage pulse (spike) applied on the gate attracts electrons into the defect sites of the gate dielectric layer, and the trapped electrons are gradually released after the pulse is removed. The electrons modify the hole concentration and induce a dynamic postsynaptic current in the CNT channel. Multiple input spikes induce excitatory or inhibitory postsynaptic currents via excitatory or inhibitory CNT synapses, which flow toward an I&F circuit to trigger output spikes. The dynamic transfer function between the input and output spikes of the neuromorphic module is analyzed. The module could potentially be scaled up to emulate biological neural networks and their functions. PMID- 23806076 TI - Control of hypertension in the critically ill: a pathophysiological approach. AB - Severe acute arterial hypertension can be associated with significant morbidity and mortality. After excluding a reversible etiology, choice of therapeutic intervention should be based on evaluation of a number of factors, such as age, comorbidities, and other ongoing therapies. A rational pathophysiological approach should then be applied that integrates the effects of the drug on blood volume, vascular tone, and other determinants of cardiac output. Vasodilators, calcium channel blockers, and beta-blocking agents can all decrease arterial pressure but by totally different modes of action, which may be appropriate or contraindicated in individual patients. There is no preferred agent for all situations, although some drugs may have a more attractive profile than others, with rapid onset action, short half-life, and fewer adverse reactions. In this review, we focus on the main mechanisms underlying severe hypertension in the critically ill and how using a pathophysiological approach can help the intensivist decide on treatment options. PMID- 23806077 TI - Stiffness memory of EA.hy926 endothelial cells in response to chronic hyperglycemia. AB - BACKGROUND: Glycemic memory of endothelial cells is an effect of long-lasting hyperglycemia and is a cause of various diabetics complications, that arises despite of the treatment targeted towards returning low glucose level in blood system. On the other hand, endothelial dysfunction, which is believed to be a main cause of cardiovascular complications, is exhibited in the changes of mechanical properties of cells. Although formation of the glycemic memory was widely investigated, its impact on the mechanical properties of endothelial cells has not been studied yet. METHODS: In this study, nanoindentaion with a tip of an atomic force microscope was used to probe the long-term changes (through 26 passages, c.a. 80 days) in mechanical properties of EA.hy926 endothelial cells cultured in hyperglycemic conditions. As a complementary method, alterations in the structure of actin cytoskeleton were visualized by fluorescent staining of F actin. RESULTS: We observed a gradual stiffening of the cells up to 20th passage for cells cultured in high glucose (25 mM). Fluorescence imaging has revealed that this behavior resulted from systematic remodeling of the actin cytoskeleton. In further passages, a drop in stiffness had occurred. The most interesting finding was recorded for cells transferred after 14 passages from high glucose to normal glucose conditions (5mM). After the transfer, the initial drop in stiffness was followed by a return of the cell stiffness to the value previously observed for cells cultured constantly in high glucose CONCLUSIONS: Our results indicate that glycemic memory causes irreversible changes in stiffness of endothelial cells. The formation of the observed "stiffness memory" could be important in the context of vascular complications which develop despite the normalization of the glucose level. PMID- 23806078 TI - A multi-national report on methods for institutional credentialing for spine radiosurgery. AB - BACKGROUND: Stereotactic body radiotherapy and radiosurgery are rapidly emerging treatment options for both malignant and benign spine tumors. Proper institutional credentialing by physicians and medical physicists as well as other personnel is important for the safe and effective adoption of spine radiosurgery. This article describes the methods for institutional credentialing for spine radiosurgery at seven highly experienced international institutions. METHODS: All institutions (n = 7) are members of the Elekta Spine Radiosurgery Research Consortium and have a dedicated research and clinical focus on image-guided spine radiosurgery. A questionnaire consisting of 24 items covering various aspects of institutional credentialing for spine radiosurgery was completed by all seven institutions. RESULTS: Close agreement was observed in most aspects of spine radiosurgery credentialing at each institution. A formal credentialing process was believed to be important for the implementation of a new spine radiosurgery program, for patient safety and clinical outcomes. One institution has a written policy specific for spine radiosurgery credentialing, but all have an undocumented credentialing system in place. All institutions rely upon an in house proctoring system for the training of both physicians and medical physicists. Four institutions require physicians and medical physicists to attend corporate sponsored training. Two of these 4 institutions also require attendance at a non-corporate sponsored academic society radiosurgery course. Corporate as well as non-corporate sponsored training were believed to be complimentary and both important for training. In 5 centers, all cases must be reviewed at a multidisciplinary conference prior to radiosurgery treatment. At 3 centers, neurosurgeons are not required to be involved in all cases if there is no evidence for instability or spinal cord compression. Backup physicians and physicists are required at only 1 institution, but all institutions have more than one specialist trained to perform spine radiosurgery. All centers believed that credentialing should also be device specific, and all believed that professional societies should formulate guidelines for institutions on the requirements for spine radiosurgery credentialing. Finally, in 4 institutions radiation therapists were required to attend corporate-sponsored device specific training for credentialing, and in only 1 institution were radiation therapists required to also attend academic society training for credentialing. CONCLUSIONS: This study represents the first multi-national report of the current practice of institutional credentialing for spine radiosurgery. Key methodologies for safe implementation and credentialing of spine radiosurgery have been identified. There is strong agreement among experienced centers that credentialing is an important component of the safe and effective implementation of a spine radiosurgery program. PMID- 23806079 TI - L1cam promotes tumor progression and metastasis and is an independent unfavorable prognostic factor in gastric cancer. AB - BACKGROUND: Previous reports have demonstrated that L1cam is aberrantly expressed in various tumors. The potential role of L1cam in the progression and metastasis of gastric cancer is still not clear and needs exploring. METHODS: Expression of L1cam was evaluated in gastric cancer tissues and cell lines by immunohistochemistry and Western blot. The relationship between L1cam expression and clinicopathological characteristics was analyzed. The effects of L1cam on cell proliferation, migration and invasion were investigated in gastric cancer cell lines both in vitro and in vivo. The impact of L1cam on PI3K/Akt pathway was also evaluated. RESULTS: L1cam was overexpressed in gastric cancer tissues and cell lines. L1cam expression was correlated with aggressive tumor phenotype and poor overall survival in gastric cancer patients. Ectopic expression of L1cam in gastric cell lines significantly promoted cell proliferation, migration and invasion whereas knockdown of L1cam inhibited cell proliferation, migration and invasion in vitro as well as tumorigenesis and metastasis in vivo. The low level of phosphorylated Akt in HGC27 cells was up-regulated after ectopic expression of L1cam, whereas the high level of phosphorylated Akt in SGC7901 cells was suppressed by knockdown of L1cam. Moreover, the migration and invasion promoted by L1cam overexpression in gastric cancer cells could be abolished by either application of LY294002 (a phosphoinositide-3-kinase inhibitor) or knockdown of endogenous Akt by small interfering RNA. CONCLUSIONS: Our study demonstrated that L1cam, overexpressed in gastric cancer and associated with poor prognosis, plays an important role in the progression and metastasis of gastric cancer. PMID- 23806080 TI - The effect of microvascular obstruction and intramyocardial hemorrhage on contractile recovery in reperfused myocardial infarction: insights from cardiovascular magnetic resonance. AB - BACKGROUND: Following acute myocardial infarction (AMI), microvascular obstruction (MO) and intramyocardial hemorrhage (IMH) adversely affect left ventricular remodeling and prognosis independently of infarct size. Whether this is due to infarct zone remodeling, changes in remote myocardium or other factors is unknown. We investigated the role of MO and IMH in recovery of contractility in infarct and remote myocardium. METHODS: Thirty-nine patients underwent cardiovascular magnetic resonance (CMR) with T2-weighted and T2* imaging, late gadolinium enhancement (LGE) and myocardial tagging at 2, 7, 30 and 90 days following primary percutaneous coronary intervention for AMI. Circumferential strain in infarct and remote zones was stratified by presence of MO and IMH. RESULTS: Overall, infarct zone strain recovered with time (p < 0.001). In the presence of MO with IMH and without IMH, epicardial strain recovered (p = 0.03, p < 0.01 respectively), but mid-myocardial or endocardial strain did not (mid myocardium: p = 0.05, p = 0.12; endocardium: p = 0.27, p = 0.05, respectively). By day 90, infarcts with MO had more attenuated strain in all myocardial layers compared to infarcts without MO (p < 0.01); those with IMH were attenuated further (p < 0.01). Remote myocardial strain was similar across groups at all time-points (p > 0.2). Infarct transmural extent did not correlate with strain (p > 0.05 at each time point). In multivariable logistic regression, MO and IMH were the only significant independent predictors of attenuated 90-day infarct zone strain (p = 0.004, p = 0.011, respectively). CONCLUSIONS: Strain improves within the infarct zone overall following reperfusion with or without MO or IMH. Mid myocardial and endocardial infarct contractility is diminished in the presence of MO, and further in the presence of IMH. MO and IMH are greater independent predictors of infarct zone contractile recovery than infarct volume or transmural extent. PMID- 23806081 TI - The role of uPAR in epithelial-mesenchymal transition in small airway epithelium of patients with chronic obstructive pulmonary disease. AB - BACKGROUND: Epithelial-mesenchymal transition (EMT) plays a crucial role in small airway fibrosis of patients with chronic obstructive pulmonary disease (COPD). Increasing evidence suggests that the urokinase plasminogen activator receptor (uPAR) is involved in the pathogenesis of COPD. Increased uPAR expression has been implicated in the promotion of EMT in numerous cancers; however the role of uPAR in EMT in small airway epithelial cells of patients with COPD remains unclear. In this study, we investigated the degree of EMT and uPAR expression in lung epithelium of COPD patients, and verified the effect of uPAR on cigarette smoke extract (CSE)-induced EMT in vitro. METHODS: The expression of EMT biomarkers and uPAR was assessed in lung epithelium specimens from non-smokers (n = 25), smokers (n = 25) and non-smokers with COPD (n = 10) and smokers with COPD (n = 18). The role of uPAR on CSE-induced EMT in human small airway epithelial cells (HSAEpiCs) was assessed by silencing uPAR expression in vitro. RESULTS: Markers of active EMT and uPAR expression were significantly increased in the small airway epithelium of patients with COPD compared with controls. We also observed a significant correlation between uPAR and vimentin expression in the small airway epithelium. In vitro, CSE-induced EMT in HSAEpiCs was associated with high expression of uPAR, and targeted silencing of uPAR using shRNA inhibited CSE-induced EMT. Finally, we demonstrate that the PI3K/Akt signaling pathway is required for uPAR-mediated EMT in HSAEpiCs. CONCLUSIONS: A uPAR dependent signaling pathway is required for CSE-induced EMT, which contributes to small airway fibrosis in COPD. We propose that increased uPAR expression in the small airway epithelium of patients with COPD participates in an active EMT process. PMID- 23806083 TI - Tales of telemedicine: I met my doctor on television. PMID- 23806082 TI - Teleconsultations in public primary care units of the city of belo horizonte, Brazil: profile of patients and physicians. AB - OBJECTIVE: The aim of this study is to report patient and physician profiles of those who used the teleconsultation system in the primary care health units of a health district in the city of Belo Horizonte, MG, Brazil. MATERIALS AND METHODS: Data were collected from the telehealth attendance records of nine Primary Health Units (Unidade Basica de Saude [UBS] in Portuguese) and from interviews carried out with the referring physicians. The criteria for inclusion required that data come from users seen by means of telehealth in the period between December 2004 and August 2010 and from the practitioners who saw them. The following were excluded: physicians who were not working in the UBS when the data were collected and a physician who did not agree to take part in the study. RESULTS: Two hundred sixty-three teleconsultations were analyzed, and 20 referring physicians were interviewed. The offline method was the most common. The physicians were predominantly female and had graduated over 11 years ago. The patients were predominantly adult women. After teleconsultation, a prescription was not necessary for 9.8% of patients. When required, 83.2% of the medication was available in the UBS. In 68.3% of cases, additional tests were required. The incorporation of these technologies prevented the physical referral of patients in 64.2% of cases. CONCLUSIONS: Telehealth resources can help to improve the provision of primary healthcare, reducing the number of physically referred patients. The number of teleconsultations is still small, and there is a need to encourage physicians to use the system. PMID- 23806084 TI - Latanoprost/timolol fixed combination for the treatment of glaucoma. AB - INTRODUCTION: Glaucoma is a multifactorial optic neuropathy that can lead to progressive and irreversible loss of vision. Today there are > 60 million glaucoma patients worldwide, and this figure is rising due to aging. The aim of glaucoma therapy is to maintain the patient's visual function and quality of life by means of intraocular pressure (IOP) reduction, which currently constitutes the only evidence-based approach. AREAS COVERED: Briefly discussed are selected, recent evidence on antiglaucoma fixed combinations. Then the efficacy and safety of the latanoprost/timolol fixed combination is comprehensively reviewed. EXPERT OPINION: The latanoprost/timolol fixed combination can be a helpful stepwise therapeutic option in patients whose IOP is insufficiently controlled with monotherapy options. Future research is needed to better delineate the role and value of this medication in glaucoma therapy. PMID- 23806085 TI - Comparison between beta-thalassemia minor and normal individuals using the Wechsler Adult Intelligence Scale. AB - The present study aimed at investigating and comparing patients suffering from beta-thalassemia (beta-thal) minor with normal individuals in regard to their performances in the short version of the Wechsler Adult Intelligence Scale (WAIS) test. Patients with beta-thal minor are carriers of beta-thal genes. They have mild microcytic and hypochromic anemia and are usually asymptomatic. In this cross-sectional study, a total of 60 individuals were divided into two equal groups of beta-thal minor and normal subjects; they were then studied by the WAIS subscales. The mean performance scores of the normal group in the subtests of arithmetic and vocabulary (p <0.01) and picture completion (p <0.05) were higher than those of the thalassemia group. The mean performance score and ability of the normal group on the verbal scale was higher in comparison to the thalassemia group (p <0.05), while on the non verbal scale, there was no significant difference between the two groups. It can be concluded that beta-thal minor negatively influences verbal fluency, reasoning and conceptualization, and sequencing tasks, perceptual skill, prediction of social situations and abstract thinking. PMID- 23806086 TI - Exome sequencing resolves apparent incidental findings and reveals further complexity of SH3TC2 variant alleles causing Charcot-Marie-Tooth neuropathy. AB - BACKGROUND: The debate regarding the relative merits of whole genome sequencing (WGS) versus exome sequencing (ES) centers around comparative cost, average depth of coverage for each interrogated base, and their relative efficiency in the identification of medically actionable variants from the myriad of variants identified by each approach. Nevertheless, few genomes have been subjected to both WGS and ES, using multiple next generation sequencing platforms. In addition, no personal genome has been so extensively analyzed using DNA derived from peripheral blood as opposed to DNA from transformed cell lines that may either accumulate mutations during propagation or clonally expand mosaic variants during cell transformation and propagation. METHODS: We investigated a genome that was studied previously by SOLiD chemistry using both ES and WGS, and now perform six independent ES assays (Illumina GAII (x2), Illumina HiSeq (x2), Life Technologies' Personal Genome Machine (PGM) and Proton), and one additional WGS (Illumina HiSeq). RESULTS: We compared the variants identified by the different methods and provide insights into the differences among variants identified between ES runs in the same technology platform and among different sequencing technologies. We resolved the true genotypes of medically actionable variants identified in the proband through orthogonal experimental approaches. Furthermore, ES identified an additional SH3TC2 variant (p.M1?) that likely contributes to the phenotype in the proband. CONCLUSIONS: ES identified additional medically actionable variant calls and helped resolve ambiguous single nucleotide variants (SNV) documenting the power of increased depth of coverage of the captured targeted regions. Comparative analyses of WGS and ES reveal that pseudogenes and segmental duplications may explain some instances of apparent disease mutations in unaffected individuals. PMID- 23806087 TI - Effects of bisphenol s exposure on endocrine functions and reproduction of zebrafish. AB - While bisphenol S (BPS) has been frequently detected both in environment and biota, limited information is available on their effects of endocrine system. In the present study, adult zebrafish pairs were exposed to 0.5, 5, and 50 MUg/L of BPS for 21 d, and the effects on reproduction, sex steroid hormones, and transcription of the genes belonging to the hypothalamic-pituitary-gonad (HPG) axis were investigated. The adverse effects on performances of F1 generation were further examined with or without subsequent exposure to BPS. Egg production and the gonadosomatic index in female fish were significantly decreased at >=0.5 MUg/L BPS. Plasma concentrations of 17beta-estradiol were significantly increased in both male and female fish. In male fish, however, significant decreases of testosterone concentration were observed along with up-regulation of cyp19a and down-regulation of cyp17 and 17betahsd transcripts. Parental exposure to BPS resulted in delayed and lesser rates of hatching even when they were hatched in clean water. Continuous BPS exposure in the F1 embryos resulted in worse hatchability and increased malformation rates compared to those without BPS exposure. Our observations showed that exposure to low level BPS could affect the feedback regulatory circuits of HPG axis and impair the development of offspring. PMID- 23806088 TI - Incidence and predictors of tuberculosis among adult people living with human immunodeficiency virus at the University of Gondar Referral Hospital, Northwest Ethiopia. AB - BACKGROUND: Tuberculosis (TB) is the leading killer of people living with HIV (PLHIV). Many of these deaths occur in developing countries. This study aimed at determining the incidence and predictors of tuberculosis among PLHIV. METHODS: A five year retrospective follow up study was conducted among adult PLHIV. The Cox proportional hazards model was used to identify predictors. RESULTS: A total of 470 patients were followed and produced 1724.13 Person-Years (PY) of observation, and 136 new TB cases occurred during the follow up period. The overall incidence density of TB was 7.88 per 100 PY. It was high (95.9/100PY) in the first year of enrolment. The cumulative proportion of TB- free survivals was 79% and 67% at the end of the first and fifth years, respectively. Baseline WHO clinical stage III (AHR = 2.88, 95% CI = 1.53-5.43), WHO clinical stage IV (AHR = 3.82, 95% CI = 1.86-7.85), CD4 count <50 cell/ul (AHR = 2.13, 95% CI = 1.28-3.53) and ambulatory or bed ridden functional status (AHR = 1.64, 95%CI = 1.13-2.38) were predictors of time to TB occurrence. CONCLUSIONS: TB incidence rate among PLHIV, especially in the first year of enrollment was high. Advanced WHO clinical stage, limited functional status, and low CD4 count (<50 cell cell/ul) were found to be the independent predictors of TB occurrence. Early care seeking and initiation of HAART to improve the CD4 count and functional status are important to reduce the risk of TB infection. PMID- 23806089 TI - Strong-ion gap approach in patients with cardiogenic shock following ST-elevation myocardial infarction. AB - OBJECTIVE: Assess if acid-base evaluation by Stewart's approach had a clinical role in cardiogenic shock (CS) following ST-elevation myocardial infarction (STEMI). SETTING: There are three widely used approaches to investigate metabolic acidosis: base excess (BE), anion gap (AG) and the Stewart's approach or strong ion gap (SIG). Available studies suggest the usefulness of SIG in sepsis and trauma. No data are so far available in CS. MEASUREMENTS AND RESULTS: We enrolled 63 consecutive patients with CS following STEMI submitted to Percutaneous Coronary Intervention (PCI). On admission, the APACHE II (Acute physiology and chronic health evaluation II) score and HOMA (Homeostasis model assessment) index were assessed together with glomerular filtration rate (eGFR), quantitative BE, AG, lactate values and 12 h lactate clearance. Non-survivors showed a higher incidence of PCI failure, higher APACHE II score, lower LVEF, lower eGFR, lower 12 h lactate clearance; a higher admission lactate and more negative BE. No difference was detectable in AG and SIG. Only 3 patients exhibited pathological values of SIG (>= 2) and only 1 of these patients died. CONCLUSIONS: According to our data the SIG approach does not seem to add further information to usual parameters in acid-base evaluation or early risk stratification in CS patients. PMID- 23806090 TI - Complete light annihilation in an ultrathin layer of gold nanoparticles. AB - We experimentally demonstrate that an incident light beam can be completely annihilated in a single layer of randomly distributed, widely spaced gold nanoparticle antennas. Under certain conditions, each antenna dissipates more than 10 times the number of photons that enter its geometric cross-sectional area. The underlying physics can be understood in terms of a critical coupling to localized plasmons in the nanoparticles or, equivalently, in terms of destructive optical Fano interference and so-called coherent absorption. PMID- 23806092 TI - Stromal-cell and cancer-cell exosomes leading the metastatic exodus for the promised niche. AB - Exosomes are thought to play an important role in metastasis. Luga and colleagues have described the production of exosomes by stromal cells such as cancer associated fibroblasts that are taken up by breast cancer cells and are then loaded with Wnt 11, which is associated with stimulation of the invasiveness and metastasis of the breast cancer cells. Previous studies have shown that exosomes produced by breast cancer cells are taken up by stromal fibroblasts and other stromal cells, suggesting that exosomes are agents of cross-talk between cancer and stromal cells to stimulate metastasis. Imaging of exosomes by labeling with fluorescent proteins will enlighten the process by which exosomes enhance metastasis, including premetastatic niche formation. PMID- 23806093 TI - Rationalized DNA sequencing-based protocol for genotyping patients receiving coumarin therapy. AB - During the last decade genetic factors affecting coumarin therapy have been extensively investigated. The most important genes appear to be CYP2C9 and VKORC1, and different studies have shown that DNA testing can dramatically improve the safety and effectiveness of the therapy. However, the implementation of pharmacogenetic testing in everyday practice is still not a reality. Facilities and ability to get results before the start of therapy are very important. The implementation of specific methodology and equipment for particular type of diagnostics can represent a serious, even impossible, financial hurdle to overcome (especially in developing countries). For this reason, the use of every tool that contributes to rationalization of the existing methods can be a considerable asset. Therefore, we set the goal to rationalize our current DNA sequencing based protocol for analysis of the VKORC1 c.-1639G> A, CYP2C9*2 and CYP2C9*3 variant alleles, in order to obtain shorter and easier procedure. Simplification of the protocol was achieved by setting up multiplex PCR and omitting DNA extraction. This rationalization of the existing DNA sequencing based procedure allows getting results in 12 hours. The new protocol was tested on 118 samples. Obtained results have shown full accordance to those obtained with previous, non-modified protocol. Therefore, given the circumstances, we consider that protocol for pharmocogenetic testing should be made more accessible - both to doctors and patients. It is one of the prerequisites in order to make genotyping prior to the therapy common practice. PMID- 23806094 TI - Randomized trial of tailored skin cancer prevention for children: the Project SCAPE family study. AB - This study evaluated a tailored intervention to promote sun protection in parents and their children, hypothesizing that the tailored intervention would lead to improved skin cancer prevention behaviors compared to generic materials. Families were recruited through schools and community centers and were included if there was 1 child in Grades 1-3 at moderate to high risk for skin cancer. Participants were randomized into one of two intervention groups: a tailored intervention, in which they received personalized skin cancer education through the mail; or a control group who received generic skin cancer information materials. Before and after intervention, parents completed questionnaires about their and their children's skin cancer risk and prevention knowledge and behaviors. Parents also completed 4-day sun exposure and protection diaries for their child and themselves. Tailored group participants demonstrated significantly greater positive changes in prevention behavior after the intervention, including children's use of sunscreen, shirts, and hats, and parents' use of shade, and skin examinations. Effect sizes were small and perceived benefits and social norms mediated intervention effects. Findings from this study support the efficacy of focusing tailored communications to families in order to change skin cancer prevention practices in young children. PMID- 23806095 TI - The role of IL-6 in the radiation response of prostate cancer. AB - BACKGROUND: Hormone-resistant (HR) prostate cancers are highly aggressive and respond poorly to treatment. IL-6/STAT3 signaling has been identified to link with the transition of HR and aggressive tumor behavior. The role of IL-6 in the radiation response of prostate cancer was investigated in the present study. MATERIAL AND METHODS: The murine prostate cancer cell line (TRAMP-C1) and the hormone-resistant cell sub-line, TRAMP-HR, were used to assess the radiation response using in vitro clonogenic assays and tumor growth delay in vivo. Biological changes following irradiation were investigated by means of experimental manipulation of IL-6 signaling. Correlations among IL-6 levels, tumor regrowth, angiogenesis and myeloid-derived suppressor cell (MDSC) recruitment were examined in an animal model. RESULTS: HR prostate cancer cells had a higher expression of IL-6 and more activated STAT3, compared to TRAMP-C1 cells. HR prostate cancer cells had a greater capacity to scavenge reactive oxygen species, suffered less apoptosis, and subsequently were more likely to survive after irradiation. Moreover, IL-6 expression was positively linked to irradiation and radiation resistance. IL-6 inhibition enhanced the radiation sensitivity of prostate cancer, which was associated with increased p53, RT induced ROS and oxidative DNA damage. Furthermore, when mice were irradiated with a sub-lethal dose, inhibition of IL-6 protein expression attenuated angiogenesis, MDSC recruitment, and decreased tumor regrowth. CONCLUSION: These data demonstrate that IL-6 is important in the biological sequelae following irradiation. Therefore, treatment with concurrent IL-6 inhibition is a potential therapeutic strategy for increasing the radiation response of prostate cancer. PMID- 23806096 TI - Vitamin C further improves the protective effect of GLP-1 on the ischemia reperfusion-like effect induced by hyperglycemia post-hypoglycemia in type 1 diabetes. AB - BACKGROUND: It has been reported that hyperglycemia following hypoglycemia produces an ischemia-reperfusion-like effect in type 1 diabetes. In this study the possibility that GLP-1 has a protective effect on this phenomenon has been tested. METHODS: 15 type 1 diabetic patients underwent to five experiments: a period of two hours of hypoglycemia followed by two hours of normo-glycemia or hyperglycemia with the concomitant infusion of GLP-1 or vitamin C or both. At baseline, after 2 and 4 hours, glycemia, plasma nitrotyrosine, plasma 8-iso prostaglandin F2alpha, sCAM-1a, IL-6 and flow mediated vasodilation were measured. RESULTS: After 2 h of hypoglycemia, flow mediated vasodilation significantly decreased, while sICAM-1, 8-iso-PGF2a, nitrotyrosine and IL-6 significantly increased. While recovering with normoglycemia was accompanied by a significant improvement of endothelial dysfunction, oxidative stress and inflammation, a period of hyperglycemia after hypoglycemia worsens all these parameters. These effects were counterbalanced by GLP-1 and better by vitamin C, while the simultaneous infusion of both almost completely abolished the effect of hyperglycemia post hypoglycemia. CONCLUSIONS: This study shows that GLP-1 infusion, during induced hyperglycemia post hypoglycemia, reduces the generation of oxidative stress and inflammation, improving the endothelial dysfunction, in type 1 diabetes. Furthermore, the data support that vitamin C and GLP-1 may have an additive protective effect in such condition. PMID- 23806097 TI - Whole genome sequencing in support of wellness and health maintenance. AB - BACKGROUND: Whole genome sequencing is poised to revolutionize personalized medicine, providing the capacity to classify individuals into risk categories for a wide range of diseases. Here we begin to explore how whole genome sequencing (WGS) might be incorporated alongside traditional clinical evaluation as a part of preventive medicine. The present study illustrates novel approaches for integrating genotypic and clinical information for assessment of generalized health risks and to assist individuals in the promotion of wellness and maintenance of good health. METHODS: Whole genome sequences and longitudinal clinical profiles are described for eight middle-aged Caucasian participants (four men and four women) from the Center for Health Discovery and Well Being (CHDWB) at Emory University in Atlanta. We report multivariate genotypic risk assessments derived from common variants reported by genome-wide association studies (GWAS), as well as clinical measures in the domains of immune, metabolic, cardiovascular, musculoskeletal, respiratory, and mental health. RESULTS: Polygenic risk is assessed for each participant for over 100 diseases and reported relative to baseline population prevalence. Two approaches for combining clinical and genetic profiles for the purposes of health assessment are then presented. First we propose conditioning individual disease risk assessments on observed clinical status for type 2 diabetes, coronary artery disease, hypertriglyceridemia and hypertension, and obesity. An approximate 2:1 ratio of concordance between genetic prediction and observed sub-clinical disease is observed. Subsequently, we show how more holistic combination of genetic, clinical and family history data can be achieved by visualizing risk in eight sub classes of disease. Having identified where their profiles are broadly concordant or discordant, an individual can focus on individual clinical results or genotypes as they develop personalized health action plans in consultation with a health partner or coach. CONCLUSION: The CHDWB will facilitate longitudinal evaluation of wellness-focused medical care based on comprehensive self-knowledge of medical risks. PMID- 23806098 TI - MCOIN: a novel heuristic for determining transcription factor binding site motif width. AB - BACKGROUND: In transcription factor binding site discovery, the true width of the motif to be discovered is generally not known a priori. The ability to compute the most likely width of a motif is therefore a highly desirable property for motif discovery algorithms. However, this is a challenging computational problem as a result of changing model dimensionality at changing motif widths. The complexity of the problem is increased as the discovered model at the true motif width need not be the most statistically significant in a set of candidate motif models. Further, the core motif discovery algorithm used cannot guarantee to return the best possible result at each candidate width. RESULTS: We present MCOIN, a novel heuristic for automatically determining transcription factor binding site motif width, based on motif containment and information content. Using realistic synthetic data and previously characterised prokaryotic data, we show that MCOIN outperforms the current most popular method (E-value of the resulting multiple alignment) as a predictor of motif width, based on mean absolute error. MCOIN is also shown to choose models which better match known sites at higher levels of motif conservation, based on ROC analysis. CONCLUSIONS: We demonstrate the performance of MCOIN as part of a deterministic motif discovery algorithm and conclude that MCOIN outperforms current methods for determining motif width. PMID- 23806099 TI - Fragment screening by weak affinity chromatography: comparison with established techniques for screening against HSP90. AB - The increasing use of fragment-based lead discovery (FBLD) in industry as well as in academia creates a high demand for sensitive and reliable methods to detect the binding of fragments to act as starting points in drug discovery programs. Nuclear magnetic resonance (NMR), surface plasmon resonance (SPR), and X-ray crystallography are well-established methods for fragment finding, and thermal shift and fluorescence polarization (FP) assays are used to a lesser extent. Weak affinity chromatography (WAC) was recently introduced as a new technology for fragment screening. The study presented here compares screening of 111 fragments against the ATPase domain of HSP90 by all of these methods, with isothermal titration calorimetry (ITC) used to confirm the most potent hits. The study demonstrates that WAC is comparable to the established methods of ligand-based NMR and SPR as a hit-id method, with hit correlations of 88% and 83%, respectively. The stability of HSP90 WAC columns was also evaluated and found to give 90% reproducibility even after 207 days of storage. A good correlation was obtained between the various technologies, validating WAC as an effective technology for fragment screening. PMID- 23806101 TI - Retained organic solutes, patient characteristics and all-cause and cardiovascular mortality in hemodialysis: results from the retained organic solutes and clinical outcomes (ROSCO) investigators. AB - BACKGROUND: Multiple solutes are retained in uremia, but it is currently unclear which solutes are toxic. Small studies suggest that protein-bound solutes, such as p-cresol sulfate and indoxyl sulfate and intracellular solutes, such as methylamine (MMA) and dimethylamine (DMA), may be toxic. Our objective was to test whether elevated levels of these solutes were associated with mortality. METHODS: We conducted a prospective cohort study in 521 U.S. incident hemodialysis patients to evaluate associations between these solutes and all cause and cardiovascular mortality. P-cresol sulfate, indoxyl sulfate, MMA and DMA levels were measured from frozen plasma samples obtained 2 to 6 months after initiation of dialysis. Mortality data was available through 2004 using the National Death Index. RESULTS: Elevated (greater than the population median) p cresol sulfate, MMA or DMA levels were not associated with all-cause or cardiovascular mortality. Elevated indoxyl sulfate levels were associated with all-cause mortality but not cardiovascular mortality (hazard ratio 1.30 (95% confidence interval 1.01, 1.69) p-value 0.043). CONCLUSIONS: In this cohort of 521 incident hemodialysis patients, only elevated indoxyl sulfate levels were associated with all-cause mortality. Further research is needed to identify causes of the toxicity of uremia to provide better care for patients with kidney disease. PMID- 23806102 TI - Analysis of protein-RNA complexes involving a RNA recognition motif engineered to bind hairpins with seven- and eight-nucleotide loops. AB - U1A binds U1hpII, a hairpin RNA with a 10-nucleotide loop. A U1A mutant (DeltaK50DeltaM51) binds U1hpII-derived hairpins with shorter loops, making it an interesting scaffold for engineering or evolving proteins that bind similarly sized disease-related hairpin RNAs. However, a more detailed understanding of complexes involving DeltaK50DeltaM51 is likely a prerequisite to generating such proteins. Toward this end, we measured mutational effects for complexes involving U1A DeltaK50DeltaM51 and U1hpII-derived hairpin RNAs with seven- or eight nucleotide loops and identified contacts that are critical to the stabilization of these complexes. Our data provide valuable insight into sequence-selective recognition of seven- or eight-nucleotide loop hairpins by an engineered RNA binding protein. PMID- 23806100 TI - Human embryonic and induced pluripotent stem cells express TRAIL receptors and can be sensitized to TRAIL-induced apoptosis. AB - Death ligands and their tumor necrosis factor receptor (TNFR) family receptors are the best-characterized and most efficient inducers of apoptotic signaling in somatic cells. In this study, we analyzed whether these prototypic activators of apoptosis are also expressed and able to be activated in human pluripotent stem cells. We examined human embryonic stem cells (hESC) and human-induced pluripotent stem cells (hiPSC) and found that both cell types express primarily TNF-related apoptosis-inducing ligand (TRAIL) receptors and TNFR1, but very low levels of Fas/CD95. We also found that although hESC and hiPSC contain all the proteins required for efficient induction and progression of extrinsic apoptotic signaling, they are resistant to TRAIL-induced apoptosis. However, both hESC and hiPSC can be sensitized to TRAIL-induced apoptosis by co-treatment with protein synthesis inhibitors such as the anti-leukemia drug homoharringtonine (HHT). HHT treatment led to suppression of cellular FLICE inhibitory protein (cFLIP) and Mcl 1 expression and, in combination with TRAIL, enhanced processing of caspase-8 and full activation of caspase-3. cFLIP likely represents an important regulatory node, as its shRNA-mediated down-regulation significantly sensitized hESC to TRAIL-induced apoptosis. Thus, we provide the first evidence that, irrespective of their origin, human pluripotent stem cells express canonical components of the extrinsic apoptotic system and on stress can activate death receptor-mediated apoptosis. PMID- 23806103 TI - Strategies for stabilization of electrodeposited metal particles in electropolymerized films for H2O oxidation and H+ reduction. AB - Metal particles were electrodeposited on a variety of conducting substrates, and their electrocatalytic activity toward H2O oxidation to O2 and H(+) reduction to H2 was evaluated. Co, Ni, Cu, Pd, Ag, and Pt were all electrodeposited on fluorine-doped tin oxide (FTO) electrodes. Particularly active were Pd and Pt for H(+) reduction and Co and Ag for H2O oxidation. When cycled reductively in 0.1 M HClO4, FTO electrodes derivatized with Pt and Pd reached current densities for hydrogen evolution of 18.3 and 13.2 mA/cm(2), respectively, at -0.6 V vs normal hydrogen electrode (NHE). FTO electrodes with electrodeposited Co or Ag were cycled oxidatively in H2O buffered to pH 7 with phosphate buffer. Current densities of 10.5 and 8.70 mA/cm(2), respectively, were reached at +1.8 V vs NHE with H2O oxidation onsets at +1.3 and +1.4 V, respectively. The impacts on catalytic stability and performance of electrodeposited metals in/on an electrically conductive polymer support were also investigated. Films of poly [Fe(vbpy)3](PF6)2 (vbpy is 4-methyl-4'-vinyl-2,2'-bipyridine) were generated on FTO by reductive electropolymerization. Significant improvements to the long-term stability of electrodeposited Ag and Pt particles were observed in the poly [Fe(vbpy)3](PF6)2 support. Films of poly-[M(vbpy)3](PF6)2 with M = Co(II) or Cu(II) were also prepared and evaluated as electrocatalysts for H2O oxidation. Films containing Co(II) reached current densities of 6.0 mA/cm(2) at +1.8 V vs NHE in H2O. PMID- 23806104 TI - Influence of cyclic dimer formation on the phase behavior of carboxylic acids. II. Cross-associating systems. AB - The doubly bonded dimer association scheme (DBD) proposed by Sear and Jackson is extended to mixtures exhibiting both self- and cross-associations. The PC-SAFT equation of state is combined with the new DBD association contribution to describe the vapor-liquid equilibria of binary mixtures of carboxylic acids + associating compounds (water, alcohols, and carboxylic acids). The effect of doubly bonded dimers on the phase behavior in such systems is less important than in mixtures of carboxylic acids with nonassociating compounds, due to the cross associations that compete with the formation of DBDs. Nevertheless, a clear improvement in the description of vapor-liquid coexistence curves is achieved over the classical 2B association model, particularly for the dew point curves. PMID- 23806105 TI - Fate of arsenic during microbial reduction of biogenic versus Abiogenic As Fe(III)-mineral coprecipitates. AB - Fe(III) (oxyhydr)oxide minerals exhibit a high sorption affinity for arsenic (As) and the reductive dissolution of As-bearing Fe(III) (oxyhydr)oxides is considered to be the primary mechanism for As release into groundwater. To date, research has focused on the reactivity of abiogenic Fe(III) (oxyhydr)oxides, yet in nature biogenic Fe(III) (oxyhydr)oxides, precipitated by Fe(II)-oxidizing bacteria are also present. These biominerals contain cell-derived organic matter (CDOM), leading to different properties than their abiogenic counterparts. Here, we follow Fe mineralogy and As mobility during the reduction of As-loaded biogenic and abiogenic Fe(III) minerals by Shewanella oneidensis MR-1. We found that microbial reduction of As(III)-bearing biogenic Fe(III) (oxyhydr)oxides released more As than reduction of abiogenic Fe(III) (oxyhydr)oxides. In contrast, As was immobilized more effectively during reduction of As(V)-loaded biogenic than abiogenic Fe(III) (oxyhydr)oxides during secondary Fe mineral formation. During sterile incubation of minerals and after microbial Fe(III) reduction stopped, As(V) was mobilized from biogenic Fe(III) (oxyhydr)oxides probably by sorption competition with phosphate and CDOM. Our data show that the presence of CDOM significantly influences As mobility during reduction of Fe(III) minerals and we suggest that it is essential to consider both biogenic and abiogenic Fe(III) (oxyhydr)oxides to further understand the environmental fate of As. PMID- 23806106 TI - A comparative in vitro evaluation of self-assembled PTX-PLA and PTX-MPEG-PLA nanoparticles. AB - We present a dialysis technique to direct the self-assembly of paclitaxel (PTX) loaded nanoparticles (NPs) using methoxypolyethylene glycol-poly(d,l-lactide) (MPEG-PLA) and PLA, respectively. The composition, morphology, particle size and zeta potential, drug loading content, and drug encapsulation efficiency of both PTX-PLA NPs and PTX-MPEG-PLA NPs were characterized by X-ray diffraction, Fourier transform infrared spectroscopy, transmission electron microscopy, dynamic light scattering, electrophoretic light scattering, and high-performance liquid chromatography. The passive targeting effect and in vitro cell viability of the PTX-MPEG-PLA NPs on HeLa cells were demonstrated by comparative cellular uptake and MTT assay of the PTX-PLA NPs. The results showed that the PTX-MPEG-PLA NPs and PTX-PLA NPs presented a hydrodynamic particle size of 179.5 and 441.9 nm, with a polydispersity index of 0.172 and 0.189, a zeta potential of -24.3 and 42.0 mV, drug encapsulation efficiency of 18.3% and 20.0%, and drug-loaded content of 1.83% and 2.00%, respectively. The PTX-MPEG-PLA NPs presented faster release rate with minor initial burst compared to the PTX-PLA NPs. The PTX-MPEG PLA NPs presented superior cell cytotoxicity and excellent cellular uptake compared to the PTX-PLA NPs. These results suggested that the PTX-MPEG-PLA NPs presented more desirable characteristics for sustained drug delivery compared to PTX-PLA NPs. PMID- 23806107 TI - Gene set analysis using variance component tests. AB - BACKGROUND: Gene set analyses have become increasingly important in genomic research, as many complex diseases are contributed jointly by alterations of numerous genes. Genes often coordinate together as a functional repertoire, e.g., a biological pathway/network and are highly correlated. However, most of the existing gene set analysis methods do not fully account for the correlation among the genes. Here we propose to tackle this important feature of a gene set to improve statistical power in gene set analyses. RESULTS: We propose to model the effects of an independent variable, e.g., exposure/biological status (yes/no), on multiple gene expression values in a gene set using a multivariate linear regression model, where the correlation among the genes is explicitly modeled using a working covariance matrix. We develop TEGS (Test for the Effect of a Gene Set), a variance component test for the gene set effects by assuming a common distribution for regression coefficients in multivariate linear regression models, and calculate the p-values using permutation and a scaled chi-square approximation. We show using simulations that type I error is protected under different choices of working covariance matrices and power is improved as the working covariance approaches the true covariance. The global test is a special case of TEGS when correlation among genes in a gene set is ignored. Using both simulation data and a published diabetes dataset, we show that our test outperforms the commonly used approaches, the global test and gene set enrichment analysis (GSEA). CONCLUSION: We develop a gene set analyses method (TEGS) under the multivariate regression framework, which directly models the interdependence of the expression values in a gene set using a working covariance. TEGS outperforms two widely used methods, GSEA and global test in both simulation and a diabetes microarray data. PMID- 23806108 TI - Let-7b expression determines response to chemotherapy through the regulation of cyclin D1 in glioblastoma. AB - BACKGROUND: Glioblastoma is the most common type of primary brain tumors. Cisplatin is a commonly used chemotherapeutic agent for Glioblastoma patients. Despite a consistent rate of initial responses, cisplatin treatment often develops chemoresistance, leading to therapeutic failure. Cellular resistance to cisplatin is of great concern and understanding the molecular mechanisms is an utter need. METHODS: Glioblastoma cell line U251 cells were exposed to increasing doses of cisplatin for 6 months to establish cisplatin-resistant cell line U251R. The differential miRNA expression profiles in U251 and U251R cell lines were identified by microarray analysis and confirmed by Q-PCR. MiRNA mimics were transfected into U251R cells, and cellular response to cisplatin-induced apoptosis and cell cycle distribution were examined by FACS analysis. RESULTS: U251R cells showed 3.1-fold increase in cisplatin resistance compared to its parental U251 cells. Microarray analysis identified Let-7b and other miRNAs significantly down-regulated in U251R cells compared to U251 cells. Transfection of Let-7b mimics greatly re-sensitized U251R cells to cisplatin, while transfection of other miRNAs has no effect or slightly effect. Cyclin D1 is predicted as a target of Let-7b through bioinformatics analysis. Over-expression of Let-7b mimics suppressed cyclin D1 protein expression and inhibited cyclin D1 3'-UTR luciferase activity. Knockdown of cyclin D1 expression significantly increased cisplatin-induced G1 arrest and apoptosis. CONCLUSIONS: Collectively, our results indicated that cisplatin treatment leads to Let-7b suppression, which in turn up-regulates cyclin D1 expression. Let-7b may serve as a marker of cisplatin resistance, and can enhance the therapeutic benefit of cisplatin in glioblastoma cells. PMID- 23806109 TI - Peptaibols, tetramic acid derivatives, isocoumarins, and sesquiterpenes from a Bionectria sp. (MSX 47401). AB - An extract of the filamentous fungus Bionectria sp. (MSX 47401) showed both promising cytotoxic activity (>90% inhibition of H460 cell growth at 20 MUg/mL) and antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). A bioactivity-directed fractionation study yielded one new peptaibol (1) and one new tetramic acid derivative (2), and the fungus biosynthesized diverse secondary metabolites with mannose-derived units. Five known compounds were also isolated: clonostachin (3), virgineone (4), virgineone aglycone (5), AGI-7 (6), and 5,6-dihydroxybisabolol (7). Compounds 5 and 7 have not been described previously from natural sources. Compound 1 represents the second member of the peptaibol structural class that contains an ester-linked sugar alcohol (mannitol) instead of an amide-linked amino alcohol, and peptaibols and tetramic acid derivatives have not been isolated previously from the same fungus. The structures of the new compounds were elucidated primarily by high-field NMR (950 and 700 MHz), HRESIMS/MS, and chemical degradations (Marfey's analysis). All compounds (except 6) were examined for antibacterial and antifungal activities. Compounds 2, 4, and 5 showed antimicrobial activity against S. aureus and several MRSA isolates. PMID- 23806110 TI - Caesalpins A-H, bioactive cassane-type diterpenes from the seeds of Caesalpinia minax. AB - Eight new cassane-type diterpenes, caesalpins A-H (1-8), were isolated from the ethyl acetate extract of Caesalpinia minax. Compound 1 displayed significant antiproliferative activity against HepG-2 (IC50 4.7 MUM) and MCF-7 (IC50 2.1 MUM) cells, and compounds 2 and 4 exhibited selective cytotoxic activities against MCF 7 (IC50 7.9 MUM) and AGS (IC50 6.5 MUM) cells. PMID- 23806111 TI - Potential of lichen secondary metabolites against Plasmodium liver stage parasites with FAS-II as the potential target. AB - Chemicals targeting the liver stage (LS) of the malaria parasite are useful for causal prophylaxis of malaria. In this study, four lichen metabolites, evernic acid (1), vulpic acid (2), psoromic acid (3), and (+)-usnic acid (4), were evaluated against LS parasites of Plasmodium berghei. Inhibition of P. falciparum blood stage (BS) parasites was also assessed to determine stage specificity. Compound 4 displayed the highest LS activity and stage specificity (LS IC50 value 2.3 MUM, BS IC50 value 47.3 MUM). The compounds 1-3 inhibited one or more enzymes (PfFabI, PfFabG, and PfFabZ) from the plasmodial fatty acid biosynthesis (FAS-II) pathway, a potential drug target for LS activity. To determine species specificity and to clarify the mechanism of reported antibacterial effects, 1-4 were also evaluated against FabI homologues and whole cells of various pathogens (S. aureus, E. coli, M. tuberculosis). Molecular modeling studies suggest that lichen acids act indirectly via binding to allosteric sites on the protein surface of the FAS-II enzymes. Potential toxicity of compounds was assessed in human hepatocyte and cancer cells (in vitro) as well as in a zebrafish model (in vivo). This study indicates the therapeutic and prophylactic potential of lichen metabolites as antibacterial and antiplasmodial agents. PMID- 23806112 TI - Asperterrestide A, a cytotoxic cyclic tetrapeptide from the marine-derived fungus Aspergillus terreus SCSGAF0162. AB - A new cytotoxic and antiviral cyclic tetrapeptide, asperterrestide A (1), a new alkaloid, terremide C (2), and a new aromatic butenolide, aspernolide E (3), together with 10 known compounds were isolated from the fermentation broth of the marine-derived fungus Aspergillus terreus SCSGAF0162. Their structures were elucidated by spectroscopic analysis, and the absolute configuration of 1 was determined by the Mosher ester technique and analysis of the acid hydrolysates using a chiral-phase HPLC column. Compound 1 contains a rare 3-OH-N-CH3-Phe residue and showed cytotoxicity against U937 and MOLT4 human carcinoma cell lines and inhibitory effects on influenza virus strains H1N1 and H3N2. PMID- 23806113 TI - Biodegradation of profenofos by Bacillus subtilis isolated from grapevines (Vitis vinifera). AB - The biodegradation of profenofos, an organophosphorus insecticide, by four Bacillus subtilis strains, namely, DR-39, CS-126, TL-171, and TS-204, isolated from grapevines or grape rhizosphere was studied in liquid culture, on grape berries, and in vineyard soil. Each of the four B. subtilis strains enhanced the degradation of profenofos in all three matrices. Degradation rate constants were best obtained by first + first-order kinetics module. In nutrient broth spiked with 5 MUg/mL profenofos, inoculation with B. subtilis strains DR-39, CS-126, TL 171, and TS-204 reduced the half-life (DT50) of profenofos to 4.03, 3.57, 2.87, and 2.53 days, respectively, from the DT50 = 12.90 days observed in the uninoculated control. In Thompson Seedless grapes sprayed with profenofos at a field dose of 1250 mL ai/ha, the DT50 values were 1.07, 1.00, 2.13, and 2.20 days in grapes inoculated with B. subtilis strains DR-39, CS-126, TL-171, and TS-204, respectively, as compared to 2.20 days in uninoculated grapes. These four B. subtilis strains also enhanced the degradation of profenofos in autoclaved soil (DT50 = 5.93, 7.47, 6.00, and 4.37 days) and in nonautoclaved soil (DT50 = 0.87, 2.00, 2.07, and 2.43 days) amended with 5 MUg/g profenofos from the half-lives of 17.37 and 14.37 days in respective uninoculated soils. Growth dynamic studies indicated that all four B. subtilis strains were able to establish and proliferate on berries and soil equally well in the presence or absence of profenofos. Degradation product 4-bromo-2-chlorophenol was identified by GC-MS. Strain DR-39 was most effective in the natural environments of grape and soil. PMID- 23806114 TI - Pre-natal and perinatal factors affecting body mass index in pre-pubertal Polish children. AB - BACKGROUND: An increased prevalence of body mass deficit among children has been reported in developing countries, including Eastern European states which have undergone political transformation. However, there are few studies evaluating risk factors for body mass deficit in schoolchildren and adolescents. AIM: To assess selected familial, pre-natal and early life factors in terms of risk associated with the prevalence of body mass deficit in children aged 7-10 years. SUBJECTS AND METHODS: Logistic regression models based on 812 records for children aged 7-10 years were applied for the evaluation of familial, pre-natal and perinatal risk factors affecting the height-to-weight ratio. RESULTS: The risk of underweight in 7-10-year-old children is significantly higher for girls (OR = 1.70) and for children whose mothers reported a traumatic experience during pregnancy (OR = 2.77). The effect of reported stress during pregnancy differed as regards the child's sex. Mother's trauma increased the risk of body weight deficit only in boys (OR = 2.74), while in girls it significantly decreased this risk (OR = 0.35). Low birth weight significantly increased the risk of underweight only in boys (OR = 2.99) and mother's occupational activity decreased the risk of underweight only in girls (OR = 0.57). CONCLUSION: Low birth weight and mother's trauma during pregnancy are risk factors for underweight in Polish schoolchildren, particularly in boys. PMID- 23806115 TI - Nuchal translucency and cardiac abnormalities in euploid singleton pregnancies. AB - OBJECTIVE: To investigate different cut-off levels of nuchal translucency (NT) to predict abnormal cardiac findings (ACF) in second trimester ultrasound examination and confirmed postnatal congenital heart defects (CHD) in euploid pregnancies. METHODS: A retrospective analysis was performed on singleton pregnancies examined in our ultrasound units from 2006 to 2011. Fetuses with an abnormal karyotype were excluded. Different cut-off levels of NT thickness were analyzed to evaluate its performance to detect the ACF on second trimester ultrasound (2nd US) examination and also the CHD detected in neonatal follow-up evaluation of ACF cases. RESULTS: Of the 12,840 cases, a total number of 8541 euploid pregnancies were included in the study. Thirty-three had ACFs detected by 2nd US (3.86/1000). The mean NT thickness was found to be higher in fetuses with ACFs (p < 0.0001). Of 33 ACFs, 17 (52%, 1.99/1000) had major CHDs in neonatal follow-up. The area under the ROC curves for NT thickness to predict ACFs and CHDs were 0.67 and 0.65, respectively. CONCLUSIONS: Higher NT thickness is associated with higher risk of ACF. NT is a weak predictor of ACF and major CHD; however, fetuses with an unexplained increase in NT measurement should be referred for further cardiac investigations. PMID- 23806116 TI - Hb Papanui [alpha99(G8)Lys->Arg; HBA2: c.299A>G]: a novel silent substitution interfering in Hb A1c determination. AB - We report a novel hemoglobin (Hb) mutation [Hb Papanui [alpha99(G8)Lys->Arg; HBA2: c.299A>G] that was identified in an individual with an inappropriately low Hb A1c value of 2.8% when using an ion exchange method. Although occurring at a well conserved site, the conservative substitution was not associated with any adverse clinical features. PMID- 23806121 TI - Polymyxin derivatives: a patent evaluation (WO2012168820). AB - The patent application WO201268820 claims a new class of polymyxin derivatives with potent antibacterial activity, especially toward Gram-negative pathogens. Compared to parent polymyxin B (PMB), the new derivatives have more potent antibacterial activity, as well as reduced cytotoxicity against human renal cells. PMID- 23806117 TI - Clinical review: Respiratory failure in HIV-infected patients--a changing picture. AB - Respiratory failure in HIV-infected patients is a relatively common presentation to ICU. The debate on ICU treatment of HIV-infected patients goes on despite an overall decline in mortality amongst these patients since the AIDS epidemic. Many intensive care physicians feel that ICU treatment of critically ill HIV patients is likely to be futile. This is mainly due to the unfavourable outcome of HIV patients with Pneumocystis jirovecii pneumonia who need mechanical ventilation. However, the changing spectrum of respiratory illness in HIV-infected patients and improved outcome from critical illness remain under-recognised. Also, the awareness of certain factors that can affect their outcome remains low. As there are important ethical and practical implications for intensive care clinicians while making decisions to provide ICU support to HIV-infected patients, a review of literature was undertaken. It is notable that the respiratory illnesses that are not directly related to underlying HIV disease are now commonly encountered in the highly active antiretroviral therapy (HAART) era. The overall incidence of P. jirovecii as a cause of respiratory failure has declined since the AIDS epidemic and sepsis including bacterial pneumonia has emerged as a frequent cause of hospital and ICU admission amongst HIV patients. The improved overall outcome of HIV patients needing ICU admission is related to advancement in general ICU care, including adoption of improved ventilation strategies. An awareness of respiratory illnesses in HIV-infected patients along with an appropriate diagnostic and treatment strategy may obviate the need for invasive ventilation and improve outcome further. HIV-infected patients presenting with respiratory failure will benefit from early admission to critical care for treatment and support. There is evidence to suggest that continuing or starting HAART in critically ill HIV patients is beneficial and hence should be considered after multidisciplinary discussion. As a very high percentage (up to 40%) of HIV patients are not known to be HIV infected at the time of ICU admission, the clinicians should keep a low threshold for requesting HIV testing for patients with recurrent pneumonia. PMID- 23806122 TI - Pictorial representation of attachment: measuring the parent-fetus relationship in expectant mothers and fathers. AB - BACKGROUND: Over the past decades, attachment research has predominantly focused on the attachment relationship that infants develop with their parents or that adults had with their own parents. Far less is known about the development of feelings of attachment in parents towards their children. The present study examined a) whether a simple non-verbal (i.e., pictorial) measure of attachment (Pictorial Representation of Attachment Measure: PRAM) is a valid instrument to assess parental representations of the antenatal relationship with the fetus in expectant women and men and b) whether factors such as gender of the parent, parity, and age are systematically related to parental bonding during pregnancy. METHODS: At 26 weeks gestational age, 352 primi- or multiparous pregnant women and 268 partners from a community based sample filled in the PRAM and the M/PAAS (Maternal/Paternal Antenatal Attachment Scale, Condon, 1985/1993). RESULTS: Results show that the PRAM was significantly positively associated to a self report questionnaire of antenatal attachment in both expectant mothers and fathers. Age and parity were both found significantly related to M/PAAS and PRAM scores. CONCLUSIONS: The present findings provide support that the PRAM is as a valid, quick, and easy-to-administer instrument of parent-infant bonding. However, further research focusing on its capacity as a screening instrument (to identify parents with serious bonding problems) and its sensitivity to change (necessary for the use in evaluation of intervention studies) is needed, in order to prove its clinical value. PMID- 23806123 TI - Double left ventricular pacing following accidental malpositioning of the right ventricular electrode during implantation of a cardiac resynchronization therapy device. AB - Accidental malpositioning of a right ventricular (RV) electrode has not been previously reported in the context of cardiac resynchronization therapy (CRT).The case of a 75-year old male patient with dilative cardiomyopathy, left ventricular (LV) ejection fraction 23%, New York Heart Association functional heart failure status stage III, left bundle branch block (LBBB) with QRS width of 136 ms, and misplacement of the RV lead to the LV apex during implantation of a CRT defibrillator is described.Following unremarkable implantation, routine interrogation of the CRT device on the first day after the implantation revealed uneventful technical findings. The 12-lead surface electrocardiogram (ECG) showed biventricular stimulation featuring a narrow QRS complex with incomplete right bundle branch block (RBBB) and R>S in V1. The biplane postoperative chest X-ray was graded normal. On routine follow-up one month later, a transthoracic echocardiogram revealed an increased ejection fraction of 51% but the RV lead was placed in the LV apex. An additional transesophageal echocardiogram exhibited an Eustachian valve guiding the lead via the patent foramen ovale through the mitral valve into the LV apex. Operative revision was scheduled and the active fixation lead was uneventful removed from the LV. A new electrode was inserted and placed in the RV apex.Accidental malplacement of the RV electrode to the LV may be difficult to diagnose in the context of CRT patients as a stimulated biventricular ECG with incomplete RBBB appearance is expected in this situation. Careful analysis of lateral radiographic views during the operation is important to ensure correct lead positioning. As timely revision is the preferred procedure, early routine transthoracic echocardiography may be considered for detection of malplacement. PMID- 23806125 TI - Efficient isolation of bone marrow adipocyte progenitors by silica microbeads incubation. AB - Excessive bone marrow adipocytes (BMAs) formation is tightly associated with development of osteoporosis. Considering the high heterogeneity of bone marrow stromal cells (BMSCs), identification of bone marrow adipocyte progenitors (BMAPs) within heterogeneous BMSCs may provide better cellular models for research regarding osteoporosis development and therapy. However, currently there is no efficient method or specific surface makers that are available for BMAPs isolation. In the current study, we developed a novel BMAPs isolation method based on silica microbeads incubation and subsequent centrifugation in ficoll paque. The "Sca-1(+)CD73(-)CD90(-)CD105(+)" subpopulation selected by this method exhibited significantly stronger adipogenic potential than nonselected BMSCs in vitro and could homogeneously differentiate into mature adipocytes within 4 days. Moreover, these cells also highly expressed a series of adipogenesis-related genes even before differentiation. After long-term culture, however, BMAPs would gradually lose high adipogenic ability, but sorting CD105(+) cells from BMAPs in later passages was able to retrieve the highly adipogenic subpopulation. In conclusion, this study demonstrated that BMAPs subpopulation could be effectively isolated from heterogeneous BMSCs by a special silica microbeads incubation method and re-enriched by sorting CD105(+) cells. These findings offer convenient and repeatable approaches to obtain pure BMAPs for research regarding pathogenic mechanisms and therapeutics development of osteoporosis. PMID- 23806126 TI - Influence of hydrophobic micelle structure on crystallization of the photosynthetic RC-LH1-PufX complex from Rhodobacter blasticus. AB - Small angle X-ray scattering (SAXS) experiments are performed on two non-ionic surfactants, the dodecyl beta-maltoside (DDbetaM) and the propyl(bi)cyclohexyl alpha-maltoside (PCCalphaM), a maltoside derivative containing a rigid bicyclohexyl group as hydrophobic chain, in order to compare the influence of both hydrophobic moiety structure and anomeric form on micelle form factors and intermicellar interactions relevant for membrane protein crystallization. Density and refractive index measurements were performed in order to determine volumetric and optical properties of surfactants, essential for determination of micelle molar masses by both SAXS and SEC-MALLS. SAXS form factors were analyzed by Guinier approximation and inverse Fourier transformation, to obtain the radius of gyration (RG) and the pair distribution function (P(r)) of each surfactant. Form factor model fitting was also performed to describe the shape and the assembly of both surfactant micelles. Finally, second virial coefficients were measured at different percentages of polyethylene glycol 3350, in order to correlate surfactant intermicellar interactions and RC-LH1-PufX phase diagram. It is thus found that while size, shape, and dimensions of micelles are slightly similar for both surfactants, their molar mass and aggregation number differ significantly. PCCalphaM are more densely packed than DDbetaM, which reflects (1) an increase in van der Waals contacts between PCCalphaM hydrophobic chains in the micelle bulk and (2) a supplementary intermicellar attraction compared to DDbetaM. Finally addition of PEG, which induces a depletion attraction, decreases the solubility of the RC-LH1-PufX complex in PCCalphaM. PMID- 23806124 TI - Production of hydroxycinnamoyl anthranilates from glucose in Escherichia coli. AB - BACKGROUND: Oats contain hydroxycinnamoyl anthranilates, also named avenanthramides (Avn), which have beneficial health properties because of their antioxidant, anti-inflammatory, and antiproliferative effects. The microbial production of hydroxycinnamoyl anthranilates is an eco-friendly alternative to chemical synthesis or purification from plant sources. We recently demonstrated in yeast (Saccharomyces cerevisiae) that coexpression of 4-coumarate: CoA ligase (4CL) from Arabidopsis thaliana and hydroxycinnamoyl/benzoyl-CoA/anthranilate N hydroxycinnamoyl/benzoyltransferase (HCBT) from Dianthus caryophyllusenabled the biological production of several cinnamoyl anthranilates upon feeding with anthranilate and various cinnamates. Using engineering strategies to overproduce anthranilate and hydroxycinnamates, we describe here an entire pathway for the microbial synthesis of two Avns from glucose in Escherichia coli. RESULTS: We first showed that coexpression of HCBT and Nt4CL1 from tobacco in the E. coli anthranilate-accumulating strain W3110 trpD9923 allowed the production of Avn D [N-(4'-hydroxycinnamoyl)-anthranilic acid] and Avn F [N-(3',4' dihydroxycinnamoyl)-anthranilic acid] upon feeding with p-coumarate and caffeate, respectively. Moreover, additional expression in this strain of a tyrosine ammonia-lyase from Rhodotorula glutinis (RgTAL) led to the conversion of endogenous tyrosine into p-coumarate and resulted in the production of Avn D from glucose. Second, a 135-fold improvement in Avn D titer was achieved by boosting tyrosine production using two plasmids that express the eleven genes necessary for tyrosine synthesis from erythrose 4-phosphate and phosphoenolpyruvate. Finally, expression of either the p-coumarate 3-hydroxylase Sam5 from Saccharothrix espanensis or the hydroxylase complex HpaBC from E. coli resulted in the endogenous production of caffeate and biosynthesis of Avn F. CONCLUSION: We established a biosynthetic pathway for the microbial production of valuable hydroxycinnamoyl anthranilates from an inexpensive carbon source. The proposed pathway will serve as a platform for further engineering toward economical and sustainable bioproduction of these pharmaceuticals and other related aromatic compounds. PMID- 23806127 TI - Peptide-bridged assembly of hybrid nanomaterial and its application for caspase-3 detection. AB - Recent developments in the rational design and the controlled assembly of nanoscale building blocks have resulted in functional devices such as nano optoelectronics, novel contrast probes for molecular imaging, and nanosensors. In the present study, we designed and synthesized a hybrid nanomaterial consisting of [Ru(bpy)3](2+)-encapsulated silica nanoparticles (SiNPs) and gold nanoparticles (AuNPs) through peptide-bridged assembly in a controllable way. A peptide that contains recognition sequence DEVD specific for active caspase-3 cleavage was employed to bring SiNPs and AuNPs into close proximity through specific molecular recognition. A FRET system with SiNPs as energy donors and AuNPs as energy acceptors has been thus developed and applied for caspase-3 detection. A change in distance between the two building blocks resulted in a change in FRET efficiency, causing a ratiometric change in emission. Caspase-3 triggers the cleavage of the peptide links between the two nanoparticles and releases AuNPs from the nanohybrids, inducing the activation of SiNPs to the "ON" state. The fluorescence turn-on response is specific to caspase-3 and allows the detection of caspase-3 as low as 0.05 U mL(-1) (~6 pM). PMID- 23806128 TI - Effect of farming strategies on environmental impact of intensive dairy farms in Italy. AB - Agriculture and animal husbandry are important contributors to global emissions of greenhouse (GHG) and acidifying gases. Moreover, they contribute to water pollution and to consumption of non-renewable natural resources such as land and energy. The Life Cycle Assessment (LCA) methodology allows evaluation of the environmental impact of a process from the production of inputs to the final product and to assess simultaneously several environmental impact categories among which GHG emissions, acidification, eutrophication, land use and energy use. The main purpose of this study was to evaluate, using the LCA methodology, the environmental impact of milk production in a sample of 41 intensive Italian dairy farms and to identify, among different farming strategies, those associated with the best environmental performances. The functional unit was 1 kg Fat and Protein Corrected Milk (FPCM). Farms showed characteristics of high production intensity: FPCM, expressed as tonnes per hectare, was 30.8+/-15.1. Total GHG emission per kg FPCM at farm gate was 1.30+/-0.19 kg CO2 eq. The main contributors to climate change potential were emissions from barns and manure storage (50.1%) and emissions for production and transportation of purchased feeds (21.2%). Average emission of gases causing acidification to produce 1 kg FPCM was 19.7+/-3.6 g of SO2 eq. Eutrophication potential was 9.01+/-1.78 ${?rm PO}_{?rm 4}^{{?rm 3} -} {?rm eq}.$ per kg FPCM on average. Farms from this study needed on average 5.97+/-1.32 MJ per kg FPCM from non-renewable energy sources. Energy consumption was mainly due to off-farm activities (58%) associated with purchased factors. Land use was 1.51+/-0.25 m2 per kg FPCM. The farming strategy based on high conversion efficiency at animal level was identified as the most effective to mitigate the environmental impact per kg milk at farm gate, especially in terms of GHG production and non-renewable energy use per kg FPCM. PMID- 23806129 TI - Word stress processing in specific language impairment: auditory or representational deficits? AB - Word stress processing has repeatedly been reported to be affected in specific language impairment (SLI) with potential consequences for various aspects of language development. However, it still remains unresolved whether word stress impairments in SLI are due to deficits in basic auditory processing or to a degraded phonological representation or both. We addressed this question examining an unselected sample of 10 children with SLI and 11 typically developing (TD) children, aged about 8 years, with respect to their basic auditory processing (duration and skewness discrimination) and phonological representation of prosodic (word stress) and segmental (consonant) contrasts. Our results show lower performance of the SLI group compared to the TD group in all tasks. Crucially, two subgroups of children with SLI emerged from our analyses: While one group was impaired in basic auditory perception, particularly affecting duration discrimination, the other showed no significant auditory processing deficits but a representational impairment. PMID- 23806130 TI - The discrimination of intonational contours in Broca's aphasia. AB - The observation has been made that agrammatic speakers fail in the comprehension of various sentence types, and this behaviour has been attributed to diminished syntactic capabilities, under the unverified assumption that perception of intonation is intact. Here we re-examine this assumption experimentally with a language, Catalan, which allows for intonation to be the only variable over four sentence types (declaratives, yes-no questions, topicalisations and contrastive focus constructions). We conducted a discrimination task with 10 agrammatic and 10 age- and education-matched control subjects. The subjects were asked to decide whether sentence pairs were identical or not. The overall agrammatic performance was very accurate (89.1% versus 95.6% correct of the controls). The aphasic participants performed above chance in six out of seven conditions. The results indicate that agrammatic individuals succeeded in the task and that their perception of intonation is spared. We conclude that failure in comprehension in agrammatism cannot be attributed to prosodic disruption. PMID- 23806131 TI - An exploration of dichotic listening among adults who stutter. AB - A pilot investigation of dichotic listening of CV stimuli was undertaken using seven adults who stutter (AWS) and a comparison group of seven adults who do not stutter (AWNS). The aim of this research was to investigate whether AWS show a difference in the strength of the right ear advantage (REA) in both undirected and directed attention tasks when compared to AWNS. The undirected attention task involved manipulating the interaural intensity difference (IID) of the CV stimuli presented to each ear. The CV stimuli were presented with equal intensity for the directed attention task. The undirected attention results indicated that both AWS and AWNS have a REA for processing speech information, with a primary difference observed between groups in regard to the IID point at which a REA shifts to a LEA. This crossing-over point occurred earlier for AWS, indicating a stronger right hemisphere involvement for the processing of speech compared to AWNS. No differences were found between groups in the directed attention task. The differences and similarities observed in dichotic listening between the two groups are discussed in regard to hemispheric specialization in the processing of speech. PMID- 23806132 TI - The use and characteristics of elderspeak in Swedish geriatric institutions. AB - The aim of this study is to investigate the occurrence of elderspeak in a Swedish context and to describe its characteristics. Elderspeak refers to adjustments made in communication with elderly people; adjustments similar to those made in interaction with infants. Previous findings show that adjustments of communication are made within several linguistic domains, and are a part of the communicative environment of elderly people. Five people working in different forms of geriatric institutions participated in this study, and data consist of recordings of interactions between caregivers and residents (without dementia) and interactions between caregivers and colleagues. The recordings were transcribed and analyzed by means of perceptual, semantic and acoustic analyses. The findings demonstrate that caregivers, to a varying extent, adjusted their communication within several linguistic domains. The adjustments were mainly made within the prosodic domain, but there were also adjustments made within other language domains. PMID- 23806133 TI - Pursuing prosody interventions. AB - This paper provides an overview of evidence-based prosodic intervention strategies to facilitate clinicians' inclusion of prosody in their therapeutic planning and to encourage researchers' interest in prosody as an area of specialization. Four current evidence-based prosodic interventions are reviewed and answers to some important clinical questions are proposed. Additionally, the future direction of prosodic intervention research is discussed in recommendations about issues that are of concern to clinicians. The paper ends with a call for participation in an online collaboration at the Clinical Prosody blog at clinicalprosody.wordpress.com. PMID- 23806134 TI - Suboptimal evolutionary novel environments promote singular altered gravity responses of transcriptome during Drosophila metamorphosis. AB - BACKGROUND: Previous experiments have shown that the reduced gravity aboard the International Space Station (ISS) causes important alterations in Drosophila gene expression. These changes were shown to be intimately linked to environmental space-flight related constraints. RESULTS: Here, we use an array of different techniques for ground-based simulation of microgravity effects to assess the effect of suboptimal environmental conditions on the gene expression of Drosophila in reduced gravity. A global and integrative analysis, using "gene expression dynamics inspector" (GEDI) self-organizing maps, reveals different degrees in the responses of the transcriptome when using different environmental conditions or microgravity/hypergravity simulation devices. Although the genes that are affected are different in each simulation technique, we find that the same gene ontology groups, including at least one large multigene family related with behavior, stress response or organogenesis, are over represented in each case. CONCLUSIONS: These results suggest that the transcriptome as a whole can be finely tuned to gravity force. In optimum environmental conditions, the alteration of gravity has only mild effects on gene expression but when environmental conditions are far from optimal, the gene expression must be tuned greatly and effects become more robust, probably linked to the lack of experience of organisms exposed to evolutionary novel environments such as a gravitational free one. PMID- 23806136 TI - The anterior hippocampus supports a coarse, global environmental representation and the posterior hippocampus supports fine-grained, local environmental representations. AB - Representing an environment globally, in a coarse way, and locally, in a fine grained way, are two fundamental aspects of how our brain interprets the world that surrounds us. The neural correlates of these representations have not been explicated in humans. In this study we used fMRI to investigate these correlates and to explore a possible functional segregation in the hippocampus and parietal cortex. We hypothesized that processing a coarse, global environmental representation engages anterior parts of these regions, whereas processing fine grained, local environmental information engages posterior parts. Participants learned a virtual environment and then had to find their way during fMRI. After scanning, we assessed strategies used and representations stored. Activation in the hippocampal head (anterior) was related to the multiple distance and global direction judgments and to the use of a coarse, global environmental representation during navigation. Activation in the hippocampal tail (posterior) was related to both local and global direction judgments and to using strategies like number of turns. A structural shape analysis showed that the use of a coarse, global environmental representation was related to larger right hippocampal head volume and smaller right hippocampal tail volume. In the inferior parietal cortex, a similar functional segregation was observed, with global routes represented anteriorly and fine-grained route information such as number of turns represented posteriorly. In conclusion, moving from the anterior to the posterior hippocampus and inferior parietal cortex reflects a shift from processing coarse global environmental representations to processing fine grained, local environmental representations. PMID- 23806135 TI - Prevalence of drug resistance mutations and HIV type 1 subtypes in an HIV type 1 infected cohort in rural Tanzania. AB - The development of resistance mutations in drug-targeted HIV-1 genes compromises the success of antiretroviral therapy (ART) programs. Genotyping of these mutations enables adjusted therapeutic decisions both at the individual and population level. We investigated over time the prevalence of HIV-1 primary drug resistance mutations in treatment-naive patients and described the HIV-1 subtype distribution in a cohort in rural Tanzania at the beginning of the ART rollout in 2005-2007 and later in 2009. Viral RNA was analyzed in 387 baseline plasma samples from treatment-naive patients over a period of 5 years. The reverse transcriptase (RT) and protease genes were reversely transcribed, polymerase chain reaction (PCR) amplified, and directly sequenced to identify HIV-1 subtypes and single nucleotide polymorphisms associated with drug resistance (DR-SNPs). The prevalence of major DR-SNPs in 2005-2007 in the RT gene was determined: K103N (5.0%), Y181C (2.5%), M184V (2.5%), and G190A (1.7%), and M41L, K65KR, K70KR, and L74LV (0.8%). In samples from 2009 only K103N (3.3%), M184V, and T215FY (0.8%) were detected. Initial frequencies of subtypes C, A, D, and recombinants were 43%, 32%, 18%, and 7%, respectively. Later similar frequencies were found except for the recombinants, which were found twice as often (15%), highlighting the subtype diversity and a relatively stable subtype frequency in the area. DR-SNPs were found at initiation of the cohort despite very low previous ART use in the area. Statistically, frequencies of major mutations did not change significantly over the studied 5-year interval. These mutations could reflect primary resistances and may indicate a possible risk for treatment failure. PMID- 23806137 TI - Putting an "end" to the motor cortex representations of action words. AB - Language processing is an example of implicit learning of multiple statistical cues that provide probabilistic information regarding word structure and use. Much of the current debate about language embodiment is devoted to how action words are represented in the brain, with motor cortex activity evoked by these words assumed to selectively reflect conceptual content and/or its simulation. We investigated whether motor cortex activity evoked by manual action words (e.g., caress) might reflect sensitivity to probabilistic orthographic-phonological cues to grammatical category embedded within individual words. We first review neuroimaging data demonstrating that nonwords evoke activity much more reliably than action words along the entire motor strip, encompassing regions proposed to be action category specific. Using fMRI, we found that disyllabic words denoting manual actions evoked increased motor cortex activity compared with non-body-part related words (e.g., canyon), activity which overlaps that evoked by observing and executing hand movements. This result is typically interpreted in support of language embodiment. Crucially, we also found that disyllabic nonwords containing endings with probabilistic cues predictive of verb status (e.g., -eve) evoked increased activity compared with nonwords with endings predictive of noun status (e.g., -age) in the identical motor area. Thus, motor cortex responses to action words cannot be assumed to selectively reflect conceptual content and/or its simulation. Our results clearly demonstrate motor cortex activity reflects implicit processing of ortho-phonological statistical regularities that help to distinguish a word's grammatical class. PMID- 23806138 TI - Needle, knife, or device--which choice in an airway crisis? PMID- 23806140 TI - Understanding arsenate reaction kinetics with ferric hydroxides. AB - Understanding arsenic reactions with ferric hydroxides is important in understanding arsenic transport in the environment and in designing systems for removing arsenic from potable water. Many experimental studies have shown that the kinetics of arsenic adsorption on ferric hydroxides is biphasic, where a fraction of the arsenic adsorption occurs on a time scale of seconds while full equilibrium may require weeks to attain. This research employed density functional theory modeling in order to understand the mechanisms contributing to biphasic arsenic adsorption kinetics. The reaction energies and activation barriers for three modes of arsenate adsorption to ferric hydroxides were calculated. Gibbs free energies of reaction depended on the net charge of the complexes, which is a function of the system pH value. Physical adsorption of arsenate to ferric hydroxide proceeded with no activation barrier, with Gibbs free energies of reaction ranging from -21 to -58 kJ/mol. The highest Gibbs free energies of reaction for physical adsorption resulted from negative charge assisted hydrogen bonding between H atoms on the ferric hydroxide and O atoms in arsenate. The conversion of physically adsorbed arsenate into monodentate surface complexes had Gibbs free energies of activation ranging from 62 to 73 kJ/mol, and Gibbs free energies of reaction ranging from -23 to -38 kJ/mol. The conversion of monodentate surface complexes to bidentate, binuclear complexes had Gibbs free energies of activation ranging from 79 to 112 kJ/mol and Gibbs free energies of reaction ranging from -11 to -55 kJ/mol. For release of arsenate from uncharged bidentate complexes, energies of activation as high as 167 kJ/mol were encountered. Increasingly negative charges on the complexes lowered the activation barriers for desorption of arsenate, and in complexes with -2 charges, the highest activation barrier was 65 kJ/mol. This study shows that the slow kinetics associated with arsenic adsorption and desorption can be attributed to the high Gibbs free energies of activation for forming and breaking bonds with the ferric hydroxide. PMID- 23806141 TI - KLF1 gene mutations in Chinese adults with increased fetal hemoglobin. AB - We investigated the Kruppel-like factor 1 (KLF1) gene mutations in Chinese adults with increased Hb F levels (>1.5%) referred to our laboratory for thalassemia screening. Functionally effective KLF1 mutations were identified in five out of 140 samples with an elevated Hb F (1.9-11.4%). Only two different KLF1 mutations were detected. Functional KLF1 mutations were not identified in the matched cohort of 110 samples with normal Hb F values (<1.0%). The KLF1 mutations could be one of the causes of hereditary persistence of fetal hemoglobin (HPFH) in regions where thalassemias are common. PMID- 23806144 TI - Dietary changes during pregnancy and the postpartum period in Singaporean Chinese, Malay and Indian women: the GUSTO birth cohort study. AB - OBJECTIVE: To examine changes in food consumption during pregnancy and the postpartum period in women of major Asian ethnic groups. DESIGN: Using interviewer-administered questionnaires, we assessed changes in food consumption during pregnancy (26-28 weeks' gestation) and the postpartum period (3 weeks after delivery) as compared with the usual pre-pregnancy diet. SETTING: Singapore. SUBJECTS: Pregnant women (n 1027) of Chinese, Malay and Indian ethnicity (mean age 30.4 (SD 5.2) years) who participated in the Growing Up in Singapore Towards healthy Outcomes (GUSTO) study. RESULTS: During pregnancy, participants tended to increase their consumption of milk, fruit and vegetables and decrease their consumption of tea, coffee, soft drinks and seafood (all P < 0.001). Most participants reported adherence to traditional restrictions ('confinement') during the early postpartum period (Chinese: 94.8 %, Malay: 91.6 %, Indian: 79.6 %). During the postpartum period, participants tended to increase their consumption of fish and milk-based drinks and decrease their consumption of noodles, seafood, and chocolates and sweets (all P < 0.001). Ethnic differences in food consumption were pronounced during the postpartum period. For example, most Chinese participants (87.2 %) increased their ginger consumption during the postpartum period as compared with smaller percentages of Malays (31.8 %) and Indians (40.8 %; P for ethnic difference <0.001). Similar ethnic differences were observed for cooking wine/alcohol, herbs and spices, and herbal tea consumption. CONCLUSIONS: Marked changes in food consumption that reflect both modern dietary recommendations and the persistence of traditional beliefs were observed in Singaporean women during pregnancy and the postpartum period. Traditional beliefs should be considered in interventions to improve dietary intakes during these periods. PMID- 23806145 TI - Magnetic bead-based reverse colorimetric immunoassay strategy for sensing biomolecules. AB - A novel reverse colorimetric immunoassay (RCIA) strategy was for the first time designed and utilized for sensitive detection of low-abundance protein (prostate specific antigen, PSA, used in this case) in biological fluids by coupling highly catalytic efficient catalase with magnetic bead-based peroxidase mimics. To construct such a RCIA system, two nanostructures including magnetic beads and gold nanoparticles were first synthesized and functionalized with anti-PSA capture antibody and catalase/anti-PSA detection antibody, respectively. Thereafter, a specific sandwich-type immunoassay format was employed for determination of PSA by using functional gold nanoparticles as enzymatic bioreactors and anti-PSA-conjugated magnetic beads as a colorimetric developer. The carried catalase, followed by the sandwiched immunocomplex, partially consumed the added hydrogen peroxide in the detection solution, which slowed down the catalytic efficiency of magnetic bead-based peroxidase mimics toward TMB/H2O2, thereby weakening the visible color and decreasing the colorimetric density. Different from conventional colorimetric immunoassay, the RCIA method determined the residual hydrogen peroxide in the substrate after consumption. Under the optimal conditions, the developed RCIA exhibited a wide dynamic range of 0.05-20 ng mL(-1) toward PSA with a detection limit of 0.03 ng mL(-1) at the 3Sblank level. Intra- and interassay coefficients of variation were below 6.1% and 9.3%, respectively. Additionally, the methodology was further validated for the analysis of 12 PSA clinical serum specimens, giving results in good accordance with those obtained by the commercially available enzyme-linked immunosorbent assay (ELISA) method. PMID- 23806142 TI - The role of noninvasive and invasive diagnostic imaging techniques for detection of extra-cranial venous system anomalies and developmental variants. AB - The extra-cranial venous system is complex and not well studied in comparison to the peripheral venous system. A newly proposed vascular condition, named chronic cerebrospinal venous insufficiency (CCSVI), described initially in patients with multiple sclerosis (MS) has triggered intense interest in better understanding of the role of extra-cranial venous anomalies and developmental variants. So far, there is no established diagnostic imaging modality, non-invasive or invasive, that can serve as the "gold standard" for detection of these venous anomalies. However, consensus guidelines and standardized imaging protocols are emerging. Most likely, a multimodal imaging approach will ultimately be the most comprehensive means for screening, diagnostic and monitoring purposes. Further research is needed to determine the spectrum of extra-cranial venous pathology and to compare the imaging findings with pathological examinations. The ability to define and reliably detect noninvasively these anomalies is an essential step toward establishing their incidence and prevalence. The role for these anomalies in causing significant hemodynamic consequences for the intra-cranial venous drainage in MS patients and other neurologic disorders, and in aging, remains unproven. PMID- 23806146 TI - Food-animal related Staphylococcus aureus multidrug-resistant ST9 strains with toxin genes. AB - To determine whether methicillin-susceptible S. aureus (MSSA) and methicillin resistant Staphylococcus aureus (MRSA) are present in commercial pig farms and food products from supermarkets in China, we characterized S. aureus isolates from 250 samples associated with swine and animal-related food products in Shandong Province. The isolates were characterized by susceptibility testing, toxin gene detection, pulse-field gel electrophoresis (PFGE), multilocus sequence typing, and spa typing. MRSA were identified and typed by the staphylococcal cassette chromosome mec (SCCmec). The prevalence of S. aureus among all samples was 19.6% (49/250). MRSA and MSSA accounted for 16.7% (20/120) and 8.3% (10/120), respectively, of swine feces samples. Only MSSA was detected from swine carcass, pork, chicken, and raw milk, accounting for 15% (6/40), 10% (3/30), 20% (6/30), and 13.3% (4/30), respectively. The predominant MRSA clone was ST9-t899 SCCmecIVb/PFGE A (70.0%, 14/20). Among the MSSA isolates, ST9-t899/PFGE A was the most prevalent (27.6%), followed by ST15-t084 (17.2%), ST97-t2756 (10.3%), ST1 t127 (6.9%), and ST398-t899 (3.5%). Some lineages were found that are commonly detected in humans (e.g., ST1, ST5, ST7, ST59, ST88) or are human-specific (e.g., ST15). The toxin genes sec, seh, and enterotoxin gene cluster (egc) were significantly more prevalent among isolates of lineage ST9 (p<0.001) compared to other lineages, and the ST9 isolates were more resistant to erythromycin, clindamycin, ciprofloxacin, chloramphenicol, and gentamicin. The same lineage was identified from different sample types, indicating circulation of the related strains within the area of study. In conclusion, swine and food products of animal origin carried S. aureus, and the predominant ST9 clone possesses a multidrug-resistance profile and a high prevalence of sec, seh, and egc enterotoxin genes. PMID- 23806147 TI - Survival of Arcobacter butzleri during production and storage of artisan water buffalo mozzarella cheese. AB - Water buffalo mozzarella cheese (WBMC) is a fresh stretched cheese produced from whole chilled buffalo milk. Although pasteurization of milk and the use of defined starter cultures are recommended, traditional technology involving unpasteurized milk and natural whey cultures is still employed for WBMC production in Italy. The purpose of this study was to assess the behavior of Arcobacter butzleri during WBMC production and storage under different temperature conditions (5, 10, and 20 degrees C). Raw milk was experimentally inoculated with one reference strain and two isolates of A. butzleri, and the count was monitored during WBMC production and storage. The bacterial count of A. butzleri decreased during curd ripening (from 7.83 log colony-forming units (CFU)/g to 4.14 log CFU/g in about 4 h) and a further decrease (>4 log CFU/g) was observed at the end of curd stretching. During storage testing, A. butzleri was never detected by direct plating, whereas it was recovered from 12 of the total 162 WBMC until the end of storage testing by enrichment. The results revealed that A. butzleri is able to survive during WBMC production and storage at different temperature conditions. Consequently, traditional WBMC produced from raw milk could represent a potential source of Arcobacter infection for humans. PMID- 23806148 TI - Ornithine cyclodeaminase-based proline production by Corynebacterium glutamicum. AB - BACKGROUND: The soil bacterium Corynebacterium glutamicum, best known for its glutamate producing ability, is suitable as a producer of a variety of bioproducts. Glutamate is the precursor of the amino acid proline. Proline biosynthesis typically involves three enzymes and a spontaneous cyclisation reaction. Alternatively, proline can be synthesised from ornithine, an intermediate of arginine biosynthesis. The direct conversion of ornithine to proline is catalysed by ornithine cyclodeaminase. An ornithine overproducing platform strain with deletions of argR and argF (ORN1) has been employed for production of derived compounds such as putrescine. By heterologous expression of ocd this platform strain can be engineered further for proline production. RESULTS: Plasmid-based expression of ocd encoding the putative ornithine cyclodeaminase of C. glutamicum did not result in detectable proline accumulation in the culture medium. However, plasmid-based expression of ocd from Pseudomonas putida resulted in proline production with yields up to 0.31 +/- 0.01 g proline/g glucose. Overexpression of the gene encoding a feedback-alleviated N acetylglutamate kinase further increased proline production to 0.36 +/- 0.01 g/g. In addition, feedback-alleviation of N-acetylglutamate kinase entailed growth coupled production of proline and reduced the accumulation of by-products in the culture medium. CONCLUSIONS: The product spectrum of the platform strain C. glutamicum ORN1 was expanded to include the amino acid L-proline. Upon further development of the ornithine overproducing platform strain, industrial production of amino acids of the glutamate family and derived bioproducts such as diamines might become within reach. PMID- 23806149 TI - The potential impact of new generation molecular point-of-care tests on gonorrhoea and chlamydia in a setting of high endemic prevalence. AB - Background Despite the availability of testing and treatment, bacterial sexually transmissible infections (STIs) continue to occur at endemic levels in many remote Indigenous communities in Australia. New generation molecular point-of care (POC) tests have high sensitivity, comparable with conventional diagnostic tests, and have the potential to increase the impact of STI screening. METHODS: We developed mathematical models of gonorrhoea (Neisseria gonorrhoeae) and chlamydia (Chlamydia trachomatis) transmission in remote Indigenous communities in Australia to evaluate screening and treatment strategies that utilise POC tests. RESULTS: The introduction of POC testing with 95% sensitivity could reduce the prevalence of gonorrhoea and chlamydia from 7.1% and 11.9% to 5.7% and 8.9%, respectively, under baseline screening coverage of 44% per year. If screening coverage is increased to 60% per year, prevalence is predicted to be reduced to 3.6% and 6.7%, respectively, under conventional testing, and further reduced to 1.8% and 3.1% with the introduction of POC testing. Increasing screening coverage to 80% per year will result in a reduction in the prevalence of gonorrhoea and chlamydia to 0.6% and 1.5%, respectively, and the virtual elimination of both STIs if POC testing is introduced. CONCLUSIONS: Modelling suggests that molecular POC tests of high sensitivity have great promise as a public health strategy for controlling chlamydia and gonorrhoea. However, evaluation of the cost effectiveness of POC testing needs to be made before widespread implementation of this technology can be considered. PMID- 23806150 TI - Controversies in Dermatology: part IV. PMID- 23806151 TI - Seborrheic dermatitis: etiology, risk factors, and treatments: facts and controversies. AB - Seborrheic dermatitis (SD) is a common skin condition seen frequently in clinical practice. The use of varying terms such as sebopsoriasis, seborrheic dermatitis, seborrheic eczema, dandruff, and pityriasis capitis reflects the complex nature of this condition. Despite its frequency, much controversy remains regarding the pathogenesis of SD. This controversy extends to its classification in the spectrum of cutaneous diseases, having being classified as a form of dermatitis, a fungal disease, or an inflammatory disease, closely related with psoriasis. Some have postulated that SD is caused by Malassezia yeasts, based on the observation of their presence in affected skin and the therapeutic response to antifungal agents. Others have proposed that Malassezia is incidental to a primary inflammatory dermatosis that resulted in increased cell turnover, scaling, and inflammation in the epidermis, similar to psoriasis. The presence of host susceptibility factors, permitting the transition of M furfur to its pathogenic form, may be associated with immune response and inflammation. Metabolites produced by Malassezia species, including oleic acid, malssezin, and indole-3-carbaldehyde, have been implicated. SD also has been traditionally considered to be a form of dermatitis based on the presence of Malassezia in healthy skin, the absence the pathogenic mycelial form of Malassezia yeasts in SD, and its chronic course. As a result, proposed treatments vary, ranging from topical corticosteroids to topical antifungals and antimicrobial peptides. PMID- 23806152 TI - Behcet's syndrome: facts and controversies. AB - Behcet's syndrome is a systemic vasculitis of small and large vessels affecting both veins and arteries. Almost all patients with Behcet's syndrome have recurrent oral aphthae, followed by genital ulcers, variable skin lesions, such as erythema nodosum and papulopustuler lesions, arthritis, uveitis, thrombophlebitis, and gastrointestinal and central nervous system involvement. Recent epidemiologic works suggest that genetic factors are more important than environmental factors in its pathogenesis. European League Against Rheumatism guidelines were recently published for the treatment of Behcet's syndrome. Although these are quite useful for the management of mucocutaneous, eye, and joint involvement, treatment of vascular, neurological, and gastrointestinal involvement are still problematic as there are no controlled studies for these manifestations. This contribution addresses the epidemiology, mucocutaneous manifestations, diagnostic criteria, and evidence-based therapies, including biologic agents. PMID- 23806153 TI - Anogenital malignancies and premalignancies: facts and controversies. AB - Anogenital malignancies and premalignancies are an important personal/public health problem due to their effects on individuals' physical, mental, and sexual health. Also, due to their etiological association with human papillomavirus (HPV) infection, anogenital malignancies and premalignancies constitute an immense public health burden. In addition to HPV infection, immunosuppression, HIV infection, chronic dermatoses, such as lichen sclerosis, previous radiotherapy and chemotherapy treatments, and smoking, are the other important etiopathologic factors in the development of anogenital malignancies and premalignancies. The incidence of anal squamous cell carcinoma (SCC) has increased considerably in the past decade, mainly due to the growing number of cases in high-risk groups, such as men who have sex with men, immunosuppressed individuals, and patients with HIV infection. Also, an increase in vulvar intraepithelial neoplasia (VIN) and VIN-related invasive vulvar cancer has been noted in women younger than age 50 years due to its association with HPV infections over the past decade. SCC of the scrotum seems to be the first cancer linked to occupational exposure. Bowen's disease, Bowenoid papulosis, and erythroplasia of Queyrat are the most widely seen premalignancies of anogenital region and are all forms of squamous intraepithelial neoplasia. Histopathologically, these conditions share identical histologic features of SCC in situ, but their clinical features differ. Early diagnosis is vital to improve prognosis, especially in anogenital malignancies. Also, if a delay occurs in diagnosis, treatment options used will be associated with significant negative effects on the patient's psychological well-being and quality of life; hence, management of anogenital malignancies and premalignancies should be organized in a multidisciplinary fashion. PMID- 23806154 TI - Pemphigus: etiology, pathogenesis, and inducing or triggering factors: facts and controversies. AB - Pemphigus includes a group of autoimmune bullous diseases with intraepithelial lesions involving the skin and Malpighian mucous membranes. Pemphigus vulgaris (PV), the most frequent and representative form of the group, is a prototypical organ-specific human autoimmune disorder with a poor prognosis in the absence of medical treatment. The pathomechanism of PV hinges on autoantibodies damaging cell-cell cohesion and leading to cell-cell detachment (acantholysis) of the epidermis and Malpighian mucosae (mainly oral mucosa). A controversy exists about which subset of autoantibodies is primarily pathogenic: the desmoglein-reactive antibodies or those directed against the acetylcholine receptors of the keratinocyte membrane. The onset and course of PV depend on a variable interaction between predisposing and inducing factors. Genetic predisposition has a complex polygenic basis, involving multiple genetic loci; however, the genetic background alone ("the soil"), although essential, is not by itself sufficient to initiate the autoimmune mechanism, as proven by the reports of PV in only one of two monozygotic twins and in only two of three siblings with an identical PV prone haplotype. The intervention of inducing or triggering environmental factors ("the seed") seems to be crucial to set off the disease. The precipitating factors are many and various, most of them directly originating from the environment (eg, drug intake, viral infections, physical agents, contact allergens, diet), others being endogenous (eg, emotional stress, hormonal disorders) but somehow linked with the subject's lifestyle. As to certain drugs, their potential of provoking acantholysis may be implemented by their interfering with the keratinocyte membrane biochemistry (biochemical acantholysis) and/or with the immune balance (immunologic acantholysis). Viral infections, especially the herpetic ones, may trigger the outbreak of PV or simply complicate its clinical course. The precipitating effect might be due to interferons and other cytokines released by the host as a consequence of the viral attack, which overactivate the immune response. Inductions of PV by physical agents (ultraviolet or ionizing radiation, thermal or electrical burns, surgery and cosmetic procedures), contact allergens (in particular, organophosphate pesticides), dietary factors (eg, garlic, leek, onion, black pepper, red chili pepper, red wine, tea), and emotional stress are rare, but well-documented events. The possible intervention of the environment in the outbreak of PV has been overlooked in the past, but nowadays clinicians perceive it more frequently. The assumption that genetic factors alone are not sufficient to cause the outbreak of the disease, inevitably instills the idea that PV may not occur spontaneously, but always results from an interaction between an individual predisposing genetic background and environmental precipitating factors, often concealed or apparently harmless. PMID- 23806155 TI - Pemphigus: associations and management guidelines: facts and controversies. AB - Pemphigus, a prototypical organ-specific human autoimmune disease, may be associated with other immunity-related disorders, viral infections, and different types of tumors. Coexistence with immune diseases is fairly frequent and, for some of them (eg, myasthenia gravis, Basedow's disease, rheumatoid arthritis, or lupus erythematosus), common pathogenic mechanisms can be considered. The association with viral infections (mainly herpesvirus infections) raises the question of whether the virus triggers the outbreak of the disease or simply complicates its clinical course. Neoplastic proliferations coexisting with pemphigus have a different histogenesis and the pathogenic link may vary according to the associated tumor (thymoma, lymphoma, carcinoma, or sarcoma). A subset of pemphigus-neoplasia association is represented by Anhalt's paraneoplastic pemphigus, with peculiar clinical, histologic, and immunologic features characterizing it. Coexistence of pemphigus with Kaposi's sarcoma, albeit not frequent, offers an intriguing speculative interest. The cornerstone of management in pemphigus is the combination of systemic corticosteroids and immunosuppressants. The conventional treatment used in most cases is based on oral administration of deflazacort and azathioprine. In selected cases, mycophenolate mofetil is preferred to azathioprine. Severe forms of pemphigus require intravenous pulse therapy with dexamethasone (or methylprednisolone) and cyclophosphamide. In the recent years, the use of high-dose intravenous immunoglobulin therapy has gained several consents. Rituximab, a monoclonal anti CD 20 antibody, which affects both the humoral and cell-mediated responses, has proved to give a good clinical response, often paralleled by decrease of pathogenic autoantibodies. The combination with intravenous immunoglobulin offers the double advantage of better clinical results and a reduced incidence of infection. Interventional treatments, such as plasmapheresis and extracorporeal immunoadsorption, are aimed at patients with life-threatening forms of pemphigus and high levels of circulating autoantibodies, a circumstance where the medical therapy alone risks failing. Second-line treatments include gold salts (which we do not favor because of the acantholytic potential inherent in thiol structure) and the association of oral tetracyclines with nicotinamide, which is rather safe. Local treatments, supplementary to the systemic therapy, are aimed at preventing infections and stimulating reepithelialization of eroded areas. Innovative topical treatments are epidermal growth factor, nicotinamide gel, pimecrolimus, and a proteomics-derived desmoglein peptide. Pemphigus patients should be warned against over-indulging in unnecessary drug intake, prolonged exposure to ultraviolet rays, intense emotional stress, and too spiced or too hot foods. Cigarette smoking is not contraindicated in pemphigus patients because of the nicotine anti-acantholytic properties. PMID- 23806156 TI - Bullous pemphigoid: etiology, pathogenesis, and inducing factors: facts and controversies. AB - The term pemphigoids includes a group of autoimmune bullous diseases characterized by subepidermal blistering. Bullous pemphigoid (BP) is not only the most common disorder within the pemphigoid group, but also represents the most frequent autoimmune blistering disease in general. The onset and course of BP depend on a variable interaction between predisposing and inducing factors. HLA genes are the most significant genetic predisposition factor to autoimmunity mechanisms. Many studies show an association between HLA-DQbeta1*0301 and distinct clinical pemphigoid variants. Imbalance between autoreactive T helper (Th) and T regulatory cells, toll-like receptor activation, and Th17/IL-17 pathway are the three possible autoimmunity triggers underlying BP. The pathomechanism of BP hinges on an autoantibody response toward structural components of the hemidesmosome (BP180 and BP230). The binding of autoantibodies leads to complement activation, recruitment of inflammatory cells, and release of proteolytic enzymes. The inflammatory cascade also may be directly triggered by activation of Th17 cells with no intervention of autoantibodies. The intervention of inducing factors in BP can be identified in no more than 15% of patients. Facilitating factors in genetically predisposed individuals are various (drug intake, physical agents, and viral infections). Drugs may act as triggers by either modifying the immune response or altering the antigenic properties of the epidermal basement membrane. Cases of induction of BP by physical agents (eg, radiation therapy, ultraviolet radiation, thermal or electrical burns, surgical procedures, transplants) are rare, but well-documented events. A contributing role in inducing BP has been suggested for infections, in particular human herpes virus (HHV) infections (cytomegalovirus, Epstein-Barr virus, and HHV-6), but also hepatitis B and C viruses, Helicobacter pylori, and Toxoplasma gondii. Unlike pemphigus, no dietary triggers have been suspected of being involved in the induction of BP. In all patients who have a diagnosis of BP, an environmental agent as a potential cause should always be considered, because the prompt discontinuation of it might result in rapid improvement or even cure of the disease. PMID- 23806157 TI - RETRACTED: Bullous pemphigoid: associations and management guidelines: facts and controversies. AB - This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal).This article has been retracted at the request of the Editor following the discovery that the text overlaps significantly with sections of several articles that are cited in the reference section, including the following:Culton DA, Diaz LA. Treatment of subepidermal immunobullous diseases. Clin Dermatol 2012;30:95 102.Meurer M. Immunosuppressive therapy for autoimmune bullous diseases. Clin Dermatol 2012;30:78-83.Ljubojevic S, Lipozencic J. Autoimmune bullous diseases associations. Clin Dermatol 2012;30:17-33.Sehgal VN, Verma. Leflunomide: dermatologic perspective. J Dermatolog Treat 2013;24:89-95.Gurcan HM, Ahmed AR. Analysis of current data on the use of methotrexate in the treatment of pemphigus and pemphigoid. Br J Dermatol 2009;16:723-31.Chen YJ, Wu CY, Lin MW, et al. Comorbidity profiles among patients with bullous pemphigoid: a nationwide population-based study. Br J Dermatol 2011;165:593-9 PMID- 23806158 TI - Kaposi's sarcoma: etiology and pathogenesis, inducing factors, causal associations, and treatments: facts and controversies. AB - Kaposi's sarcoma (KS), an angioproliferative disorder, has a viral etiology and a multifactorial pathogenesis hinged on an immune dysfunction. The disease is multifocal, with a course ranging from indolent, with only skin manifestations to fulminant, with extensive visceral involvement. In the current view, all forms of KS have a common etiology in human herpesvirus (HHV)-8 infection, and the differences among them are due to the involvement of various cofactors. In fact, HHV-8 infection can be considered a necessary but not sufficient condition for the development of KS, because further factors (genetic, immunologic, and environmental) are required. The role of cofactors can be attributed to their ability to interact with HHV-8, to affect the immune system, or to act as vasoactive agents. In this contribution, a survey of the current state of knowledge on many and various factors involved in KS pathogenesis is carried out, in particular by highlighting the facts and controversies about the role of some drugs (quinine analogues and angiotensin-converting enzyme inhibitors) in the onset of the disease. Based on these assessments, it is possible to hypothesize that the role of cofactors in KS pathogenesis can move toward an effect either favoring or inhibiting the onset of the disease, depending on the presence of other agents modulating the pathogenesis itself, such as genetic predisposition, environmental factors, drug intake, or lymph flow disorders. It is possible that the same agents may act as either stimulating or inhibiting cofactors according to the patient's genetic background and variable interactions. Treatment guidelines for each form of KS are outlined, because a unique standard therapy for all of them cannot be considered due to KS heterogeneity. In most cases, therapeutic options, both local and systemic, should be tailored to the patient's peculiar clinical conditions. PMID- 23806159 TI - Role of infectious agents in cutaneous T-cell lymphoma: facts and controversies. AB - The etiology of cutaneous T-cell lymphoma (CTCL) remains unknown, with potential infectious causes having been explored. This contribution evaluates the evidence suggesting an infectious etiology and pathogenesis of the disease, characterizes the relationships between various specific pathogens and CTCL, and discusses some of the difficulties in establishing a causal link between infectious agents and CTCL carcinogenesis. Researchers have evaluated CTCL specimens for evidence of infection with a variety of agents, including human T-lymphotropic virus, Epstein Barr virus, human herpesvirus-8, and Staphylococcus aureus, although other pathogens also have been detected in CTCL. Although there is significant evidence implicating one or more infectious agents in CTCL, studies to date have not linked definitively any pathogen to disease development, and various studies have yielded conflicting results. PMID- 23806160 TI - Scleroderma: nomenclature, etiology, pathogenesis, prognosis, and treatments: facts and controversies. AB - Scleroderma refers to a heterogeneous group of autoimmune fibrosing disorders. The nomenclature of scleroderma has changed dramatically in recent years, with morphea (localized scleroderma), limited cutaneous systemic sclerosis, diffuse cutaneous systemic sclerosis, and systemic sclerosis sine scleroderma encompassing the currently accepted disease subtypes. Major advances have been made in the molecular studies of morphea and systemic sclerosis; however, their etiologies and pathogenesis remain incompletely understood. Although morphea and systemic sclerosis demonstrate activation of similar inflammatory and fibrotic pathways, important differences in signaling pathways and gene signatures indicate they are likely biologically distinct processes. Morphea can cause significant morbidity but does not affect mortality, whereas systemic sclerosis has the highest disease-specific mortality of all autoimmune connective tissue diseases. Treatment recommendations for morphea and systemic sclerosis are based on limited data and largely expert opinions. Current collaborative efforts in morphea and systemic sclerosis research will hopefully lead to better understanding of the etiology and pathogenesis of these rare and varied diseases and improved treatment options. PMID- 23806161 TI - Treatment regimens, protocols, dosage, and indications for UVA1 phototherapy: facts and controversies. AB - During the last three decades, ultraviolet A1 (UVA1) phototherapy has emerged as a specific phototherapeutic modality with distinct modes of action and some well established indications. Atopic dermatitis, localized scleroderma, and systemic lupus erythematosus seem to be the conditions with the best evidence regarding efficacy and safety of UVA1 phototherapy. Further indications for UVA1 include subacute prurigo, lichen sclerosus, dyshidrotic dermatitis, cutaneous T cell lymphoma, urticaria pigmentosa, and pityriasis rosea; nevertheless, there are some unknowns, uncertainties, and controversies concerning short- and long-term side effects, efficacy and dosage regimens of UVA1 phototherapy in some conditions. We describe and discuss treatment regimens, protocols, dosage, and indications for UVA1 phototherapy. PMID- 23806162 TI - Skin diseases associated with Malassezia yeasts: facts and controversies. AB - The implication of the yeast genus Malassezia in skin diseases has been characterized by controversy, since the first description of the fungal nature of pityriasis versicolor in 1846 by Eichstedt. This is underscored by the existence of Malassezia yeasts as commensal but also by their implication in diseases with distinct absence of inflammation despite the heavy fungal load (pityriasis versicolor) or with characteristic inflammation (eg, seborrheic dermatitis, atopic dermatitis, folliculitis, or psoriasis). The description of 14 Malassezia species and subsequent worldwide epidemiologic studies did not reveal pathogenic species but rather disease-associated subtypes within species. Emerging evidence demonstrates that the interaction of Malassezia yeasts with the skin is multifaceted and entails constituents of the fungal wall (melanin, lipid cover), enzymes (lipases, phospholipases), and metabolic products (indoles), as well as the cellular components of the epidermis (keratinocytes, dendritic cells, and melanocytes). Understanding the complexity of their interactions will highlight the controversies on the clinical presentation of Malassezia-associated diseases and unravel the complexity of skin homeostatic mechanisms. PMID- 23806163 TI - Phacomatosis pigmento-pigmentaria: should we add a new type of phacomatosis? Fact and controversies. AB - There are currently five types of recognized phacomatosis pigmentovascularis plus one more, phacomatosis pigmentokeratotica, making six types altogether. Should we stop here and consider the classification as being complete? Or, do we leave room to add more types or, alternatively, lump the ones we have together and shorten the list? We present our reasons for adding one or two new types of phacomatoses to the current classification, in full recognition that it is already complicated and somewhat cumbersome. We consider that the benefits of doing so outweigh any additional strain on the already complicated classification. We expect that this might not sit well with some of our colleagues, but we are prepared to do battle. PMID- 23806164 TI - Contact dermatitis: facts and controversies. AB - The history of contact dermatitis (CD) is inseparable from the history of the patch test, and the patch test is inseparable from the pioneer in the field, Josef Jadassohn (1860-1936). Despite the fact that we have been diagnosing, treating, and investigating the condition for more than 100 years, there are still many unsolved questions and controversies, which show no signs of coming to an end in the foreseeable future. This contribution reviews and highlights some of the disagreements and discrepancies associated with CD. For example: * What is the real sensitizer in balsam of Peru, one of the most common allergens, and what, if any, is the value of a low-balsam diet? * Is benzalkonium chloride, which has well-known and undisputed irritant properties, a contact allergen as well? * Is cocamidopropyl betaine (CABP) a common contact allergen and what is the actual sensitizer in CABP allergy the molecule itself, or impurities, or intermediaries in its synthesis? * How can the significant differences in the prevalence of sensitization of formaldehyde (FA, a common cause of contact allergy) between the United States (8%-9%) and Europe (2%-3%) be explained? * What is the relationship between formaldehyde releasers (FRs) allergy and an FA allergy? Should we recommend that FA-allergic patients also avoid FRs, and, if so, to what extent? * What is the true frequency of lanolin allergy? This issue remains enigmatic despite the expenditure of thousands of dollars and the innumerable hours spent investigating this subject. * What is the basis behind the so-called "lanolin paradox"? This label was coined in 1996 and is still a matter of controversy. * Is there such a thing as systemic CD from nickel, and, if so, to what extent? Is there a cross-reactivity or concomitant sensitization between nickel and cobalt?These are some of the controversial problems discussed. We have selected the ones that we consider to be of special interest and importance to the practicing dermatologist. PMID- 23806165 TI - Patch testing: facts and controversies. AB - The German dermatologist, Josef Jadassohn (1863-1936), first presented the results of his innovative patch-testing technique in 1895. The safety and efficacy of this diagnostic tool has stood the test of time and is still the gold standard for the diagnosis of allergic contact dermatitis (ACD). Since its discovery, much effort has been put into standardization and optimization of allergens, vehicles, and concentrations of patch-test materials; in procedures of its application; and in reading and scoring of test reactions--all contributing to the development of an accurate, reliable, and safe test with a high reproducibility of its results. Even this seemingly carved-in-stone practice, which has been used for nearly 120 years, has been questioned and challenged, engendering debates, disagreements, and controversies, which show no signs of coming to an end. Almost every step of the procedure has provoked discussions and controversies: PMID- 23806166 TI - Folk remedies for alopecia. PMID- 23806167 TI - Understanding the collapse mechanism in Langmuir monolayers through polarization modulation-infrared reflection absorption spectroscopy. AB - The collapse of films at the air-water interface is related to a type of 2D-to-3D transition that occurs when a Langmuir monolayer is compressed beyond its stability limit. Studies on this issue are extremely important because defects in ultrathin solid films can be better understood if the molecular mechanisms related to collapse processes are elucidated. This paper explores how the changes of vibration of specific groups of lipid molecules, as revealed by polarization modulation-infrared reflection absorption spectroscopy (PM-IRRAS), are affected by the monolayer collapse. Different mechanisms of collapse were studied, for those lipids that undergo constant-area collapse (such as stearic acid) and for those that undergo constant-pressure collapse (such as DPPC, DPPG, and DODAB). Lipid charges also affect the mechanism of collapse, as demonstrated for two oppositely charged lipids. PMID- 23806168 TI - Surgical treatment. PMID- 23806169 TI - Clinical review: Clinical management of new oral anticoagulants: a structured review with emphasis on the reversal of bleeding complications. AB - New oral anticoagulants, including dabigatran, rivaroxaban, and apixaban, have been recently approved for primary and secondary prophylaxis of thromboembolic conditions. However, there is no clear strategy for managing and reversing their anticoagulant effects. We aimed to summarize the available evidence for clinical management and reversal of bleeding associated with new oral anticoagulants. Using a systematic review approach, we aimed to identify studies describing reversal strategies for dabigatran, rivaroxaban, and apixaban. The search was conducted using Medline, EMBASE, HealthSTAR, and grey literature. We included laboratory and human studies. We included 23 studies reported in 37 out of 106 potentially relevant references. Four studies were conducted in humans and the rest were in vitro and in vivo studies. The majority of the studies evaluated the use of prothrombinase complex concentrate (PCC), either activated or inactivated, and recombinant activated factor VII (rFVIIa). Other interventions were also identified. Laboratory studies suggest that hemostatic parameters and bleeding might be partially or completely corrected by PCC for rivaroxaban better than dabigatran. Studies in humans suggest that PCC might reverse the effects of rivaroxaban better than dabigatran assessed by hemostatic tests. We were not able to locate studies evaluating the clinical efficacy of these agents. The best available evidence suggests that PCC (activated or inactivated) might be the best option for reversing new anticoagulants. Evidence for rFVIIa is less compelling. There might be differences in the efficacy of reversing agents for different anticoagulants. Studies assessing the clinical efficacy of these reversal agents are urgently needed. PMID- 23806171 TI - Investigation of modified graphene for energy storage applications. AB - Lithium-ion batteries (LIB) have been receiving extensive attention because of the high specific energy density for wide applications such as electronic vehicles, commercial mobile electronics, and military applications. In LIB, graphite is the most commonly used anode material; however, lithium-ion intercalation in graphite is limited, hindering the battery charge rate and capacity. To overcome this obstacle, nanostructured anode assembly has been extensively studied to increase the lithium-ion diffusion rate. Among these approaches, high specific surface area metal oxide nanowires connecting nanostructured carbon materials accumulation have shown propitious results for enhanced lithium intercalation. Recently, nanowire/graphene hybrids were developed for the enhancement of LIB performance; however, almost all previous efforts employed nanowires on graphene in a random fashion, which limited lithium ion diffusion rate. Therefore, we demonstrate a new approach by hydrothermally growing uniform nanowires on graphene aerogel to further improve the performance. This nanowire/graphene aerogel hybrid not only uses the high surface area of the graphene aerogel but also increases the specific surface area for electrode electrolyte interaction. Therefore, this new nanowire/graphene aerogel hybrid anode material could enhance the specific capacity and charge-discharge rate. Scanning electron microscopy (SEM) and X-ray diffraction (XRD) are used for materials characterization. Battery analyzer and potentio-galvanostat are used for measuring the electrical performance of the battery. The testing results show that nanowire graphene hybrid anode gives significantly improved performance compared to graphene anode. PMID- 23806170 TI - Constitutional CHEK2 mutations are infrequent in early-onset and familial breast/ovarian cancer patients from Pakistan. AB - BACKGROUND: Less than 20% of Pakistani women with early-onset or familial breast/ovarian cancer harbor germ line mutations in the high-penetrance genes BRCA1, BRCA2 and TP53. Thus, mutations in other genes confer genetic susceptibility to breast cancer, of which CHEK2 is a plausible candidate. CHEK2 encodes a checkpoint kinase, involved in response to DNA damage. METHODS: In the present study we assessed the prevalence of CHEK2 germ line mutations in 145 BRCA1/2-negative early-onset and familial breast/ovarian cancer patients from Pakistan (Group 1). Mutation analysis of the complete CHEK2 coding region was performed using denaturing high-performance liquid chromatography analysis, followed by DNA sequencing of variant fragments. RESULTS: Two potentially deleterious missense mutations, c.275C>G (p.P92R) and c.1216C>T, (p.R406C), were identified (1.4%). The c.275C>G mutation is novel and has not been described in other populations. It was detected in a 30-year-old breast cancer patient with a family history of breast and multiple other cancers. The c.1216C>T mutation was found in a 34-year-old ovarian cancer patient from a family with two breast cancer cases. Both mutations were not detected in 229 recently recruited BRCA1/2 negative high risk patients (Group 2). CONCLUSION: Our findings suggest that CHEK2 mutations may not contribute significantly to breast/ovarian cancer risk in Pakistani women. PMID- 23806172 TI - Target delivery of MYCN siRNA by folate-nanoliposomes delivery system in a metastatic neuroblastoma model. AB - BACKGROUND: Folate-nanoliposomes delivery system has emerged recently as a specific and safety delivery method and gradually used as the carrier of a variety kinds of drugs including compounds, plasmids and siRNAs. METHODS: In this study, we established a bone marrow and bone metastasis xenograft mouse model by injecting the LA-N-5 cell into the bone marrow cavity. Fluorescence microscopy, TUNEL Assay, Quantitative RT-PCR and western blot were conducted to analysis the distribution of folate-nanoliposomes entrapped MYCN (V-myc myelocytomatosis viral related oncogene) siRNA in mice and the relevant suppression effect. RESULTS: The folate-nanoliposomes entrapped MYCN siRNA can be specifically distributed in tumor tissues. Further study shows that folate-nanoliposomes entrapped MYCN siRNA lead to MYCN mRNA expression significantly down-regulated (>50%, and p < 0.05) compared with negative control siRNA treatment. MYCN protein expression was inhibited about 60% in vivo, thus induced tumor cell apoptosis markedly. CONCLUSION: This study point to a new way for treatment of metastatic neuroblastoma and could widen the application of folate-nanoliposomes delivery system in tumor therapy. PMID- 23806173 TI - Chronic inflammation role in the obesity-diabetes association: a case-cohort study. AB - BACKGROUND: Chronic inflammation is related to both obesity and diabetes. Our aim was to investigate to what extent this inflammation contributes to the association between obesity and diabetes. METHODS: Using a case-cohort design, we followed 567 middle-aged individuals who developed diabetes and 554 who did not over 9 years within the ARIC Study. Weighted Cox proportional hazards analyses permitted statistical inference to the entire cohort. RESULTS: Obese individuals (BMI>=30 kg/m2), compared to those with BMI<25 kg/m2, presented a large increased risk of developing diabetes (HR[obesity]=6.4, 95%CI 4.5-9.2), as did those in the highest (compared to the lowest) quartile of waist circumference (HR[waist]=8.3, 95%CI 5.6-12.3), in analyses adjusted for age, gender, ethnicity, study center, and parental history of diabetes. Notably, further adjustment for adiponectin and inflammation markers halved the magnitude of these associations (HR[obesity]=3.2, 95%CI 2.1-4.7; and HR[waist]=4.2, 95%CI 2.8-6.5). In similar modeling, attenuation obtained by adding fasting insulin, instead of these markers, was only slightly more pronounced HR[obesity]=2.7, 95%CI 1.7-4.1; and HR[waist]=3.6, 95%CI 2.3-5.8). CONCLUSIONS: The marked decrease in the obesity-diabetes association after taking into account inflammation markers and adipokines indicates their major role in the pathways leading to adult onset of diabetes in obese individuals. PMID- 23806174 TI - Sleep-dependent neurophysiological processes in implicit sequence learning. AB - Behavioral studies have cast doubts about the role that posttraining sleep may play in the consolidation of implicit sequence learning. Here, we used event related fMRI to test the hypothesis that sleep-dependent functional reorganization would take place in the underlying neural circuits even in the possible absence of obvious behavioral changes. Twenty-four healthy human adults were scanned at Day 1 and then at Day 4 during an implicit probabilistic serial RT task. They either slept normally (RS) or were sleep-deprived (SD) on the first posttraining night. Unknown to them, the sequential structure of the material was based on a probabilistic finite-state grammar, with 15% chance on each trial of replacing the rules-based grammatical (G) stimulus with a nongrammatical (NG) one. Results indicated a gradual differentiation across sessions between RTs (faster RTs for G than NG), together with NG-related BOLD responses reflecting sequence learning. Similar behavioral patterns were observed in RS and SD participants at Day 4, indicating time- but not sleep-dependent consolidation of performance. Notwithstanding, we observed at Day 4 in the RS group a diminished differentiation between G- and NG-related neurophysiological responses in a set of cortical and subcortical areas previously identified as being part of the network involved in implicit sequence learning and its offline processing during sleep, indicating a sleep-dependent processing of both regular and deviant stimuli. Our results suggest the sleep-dependent development of distinct neurophysiological processes subtending consolidation of implicit motor sequence learning, even in the absence of overt behavioral differences. PMID- 23806175 TI - Associations between basal cortisol levels and memory retrieval in healthy young individuals. AB - Cortisol is known to affect memory processes. On the one hand, stress-induced or pharmacologically induced elevations of cortisol levels enhance memory consolidation. On the other hand, such experimentally induced elevations of cortisol levels have been shown to impair memory retrieval. However, the effects of individual differences in basal cortisol levels on memory processes remain largely unknown. Here we tested whether individual differences in cortisol levels predict picture learning and recall in a large sample. A total of 1225 healthy young women and men viewed two different sets of emotional and neutral pictures on two consecutive days. Both sets were recalled after a short delay (10 min). On Day 2, the pictures seen on Day 1 were additionally recalled, resulting in a long delay (20 hr) recall condition. Cortisol levels were measured three times on Days 1 and 2 via saliva samples before encoding, between encoding and recall as well as after recall testing. We show that stronger decreases in cortisol levels during retrieval testing were associated with better recall performance of pictures, regardless of emotional valence of the pictures or length of the retention interval (i.e., 10 min vs. 20 hr). In contrast, average cortisol levels during retrieval were not related to picture recall. Remarkably during encoding, individual differences in average cortisol levels as well as changes in cortisol did not predict memory recall. Our results support previous findings indicating that higher cortisol levels during retrieval testing hinders recall of episodic memories and extend this view onto interindividual changes in basal cortisol levels. PMID- 23806176 TI - Neural correlates of visual versus abstract letter processing in Roman and Arabic scripts. AB - In alphabetic orthographies, letter identification is a critical process during the recognition of visually presented words. In the present experiment, we examined whether and when visual form influences letter processing in two very distinct alphabets (Roman and Arabic). Disentangling visual versus abstract letter representations was possible because letters in the Roman alphabet may look visually similar/dissimilar in lowercase and uppercase forms (e.g., c-C vs. r-R) and letters in the Arabic alphabet may look visually similar/dissimilar, depending on their position within a word (e.g., [Formula: see text] - [Formula: see text] vs. [Formula: see text] - [Formula: see text]). We employed a masked priming same-different matching task while ERPs were measured from individuals who had learned the two alphabets at an early age. Results revealed a prime target relatedness effect dependent on visual form in early components (P/N150) and a more abstract relatedness effect in a later component (P300). Importantly, the pattern of data was remarkably similar in the two alphabets. Thus, these data offer empirical support for a universal (i.e., across alphabets) hierarchical account of letter processing in which the time course of letter processing in different scripts follows a similar trajectory from visual features to visual form independent of abstract representations. PMID- 23806177 TI - Why bilateral damage is worse than unilateral damage to the brain. AB - Human and animal lesion studies have shown that behavior can be catastrophically impaired after bilateral lesions but that unilateral damage often produces little or no effect, even controlling for lesion extent. This pattern is found across many different sensory, motor, and memory domains. Despite these findings, there has been no systematic, computational explanation. We found that the same striking difference between unilateral and bilateral damage emerged in a distributed, recurrent attractor neural network. The difference persists in simple feedforward networks, where it can be understood in explicit quantitative terms. In essence, damage both distorts and reduces the magnitude of relevant activity in each hemisphere. Unilateral damage reduces the relative magnitude of the contribution to performance of the damaged side, allowing the intact side to dominate performance. In contrast, balanced bilateral damage distorts representations on both sides, which contribute equally, resulting in degraded performance. The model's ability to account for relevant patient data suggests that mechanisms similar to those in the model may operate in the brain. PMID- 23806178 TI - Hyaluronan up-regulates growth and invasion of trophoblasts in an autocrine manner via PI3K/AKT and MAPK/ERK1/2 pathways in early human pregnancy. AB - INTRODUCTION: As one of the key molecules in the extracellular matrix in human conceptus, hyaluronan (HA) has been receiving particular attention. Here, we have investigated the expression and regulation of different molecular weight HA on the biological behaviors of primary human trophoblasts during the first trimester of pregnancy. METHODS: The expression of HA and HA synthetase (HAS) by human first trimester trophoblasts was analyzed in placentae from normal pregnancy or miscarriage by immunochemistry and real-time RT-PCR, respectively. ELISA was used to measure the secretion of HA by primary trophoblasts. The effects of HA on the proliferation, apoptosis and invasiveness of trophoblasts were examined. We also investigated the signaling pathways involved in HA activation in human trophoblasts. RESULTS: The higher HAS2 expression and HA secretion were observed in normal villi than that of miscarriage, and the primary trophoblasts secreted HA continuously. High molecular weight HA (HMW-HA) and medium molecular weight HA (MMW-HA) promoted proliferation and invasiveness while inhibited apoptosis of trophoblasts. However, low molecular weight HA (LMW-HA) had no obvious effect on the growth or invasiveness of human trophoblasts. In addition, HMW-HA showed more efficiently than MMW-HA on the growth while MMW-HA displayed a more obvious effect on the invasiveness of trophoblasts than HMW-HA. HMW-HA activated PI3K/AKT and MAPK/ERK1/2 signaling pathways in trophoblasts. Blocking PI3K/AKT or MAPK/ERK1/2 signaling inhibited the HA-upregulated growth and invasiveness of human trophoblasts. CONCLUSION: Our results suggest that higher level and greater molecular mass of HA can promote trophoblast growth and invasion in an autocrine manner, which was beneficial to placentation and maintenance of human early pregnancy. PMID- 23806179 TI - Receptors for non-MHC ligands contribute to uterine natural killer cell activation during pregnancy in mice. AB - INTRODUCTION: Activated uterine natural killer (uNK) cells are abundant in early human and mouse decidual basalis. In mice, distinct uNK cell subsets support early endothelial tip cell induction, the pruning of new vessels and initiation of spiral arterial modification. While genetic studies indicate that NK/uNK cell activation via receptors recognizing Class I MHC-derived peptides promotes human pregnancy, roles for other activation receptors expressed by NK cells, such as the aryl hydrocarbon receptor (AHR) and natural cytotoxicity receptors (NCR) are undefined in human or mouse pregnancies. METHODS: Expression of AHR and NCR1 (ortholog of human NKp46) by gestation day (gd)10.5 mouse uNK cell subsets was measured by quantitative real-time RT-PCR. Early implantation sites from mice lacking expression of either receptor were examined histologically. RESULTS: Gd10.5 uNK cell subsets, separated by reactivity to Dolichos biflorus agglutinin lectin, differed in relative transcript abundance for Ahr and Ncr1. Quantitative histology revealed that, in comparison to C57BL/6 controls, implant sites from gd10.5 Ahr(-/-) and gd6.5-12.5 UkCa:B6.Ncr1(Gfp/Gfp) mice had normal uNK cell abundance but the uNK cells were smaller than normal and unable to trigger spiral arterial remodeling. Whole mount immunohistochemistry comparisons of viable, gd6.5-8.5 Ncr1(Gfp/Gfp) and C57BL/6 implant sites revealed deficits in implant site angiogenesis and conceptus growth in Ncr1(Gfp/Gfp). DISCUSSION: In mice, activation of AHR and of NCR1 by endogenous, as yet undefined ligands, contributes to uNK cell activation/maturation and angiogenic functions during early to mid-gestation pregnancy. MHC-independent activation of uNK cells also likely makes critical contributions to human pregnancy success. PMID- 23806180 TI - Council-supported condom vending machines: are they acceptable to rural communities? AB - BACKGROUND: Twenty-four hour access to condoms for young people living in rural Victoria is problematic for many reasons, including the fact that condom vending machines are often located in venues and places they cannot access. METHOD: We partnered with three rural councils to install condom vending machines in locations that provided improved access to condoms for local young people. Councils regularly checked the machines, refilled the condoms and retrieved the money. They also managed the maintenance of the machine and provided monthly data. RESULTS: In total, 1153 condoms were purchased over 12 months, with 924 (80%) obtained from male toilets and 69% (801 out of 1153) purchased in the second half of the study. Revenue of $2626.10 (AUD) was generated and no negative feedback from residents was received by any council nor was there any negative reporting by local media. Vandalism, tampering or damage occurred at all sites; however, only two significant episodes of damage required a machine to be sent away for repairs. CONCLUSIONS: Condom vending machines installed in rural towns in north-east Victoria are accessible to young people after business hours, are cost-effective for councils and have not generated any complaints from residents. The machines have not suffered unrepairable damage and were used more frequently as the study progressed. PMID- 23806182 TI - Fabrication of porous beta-Co(OH)2 architecture at room temperature: a high performance supercapacitor. AB - A facile, cost-effective, surfactant-free chemical route has been demonstrated for the fabrication of porous beta-Co(OH)2 hierarchical nanostructure in gram level simply by adopting cobalt acetate as a precursor salt and ethanolamine as a hydrolyzing agent at room temperature. A couple of different morphologies of beta Co(OH)2 have been distinctly identified by varying the mole ratio of the precursor and hydrolyzing agent. The cyclic voltammetry measurements on beta Co(OH)2 displayed significantly high capacitance. The specific capacitance obtained from charge-discharge measurements made at a discharge current of 1 A/g is 416 F/g for the Co(OH)2 sample obtained at room temperature. The charge discharge stability measurements indicate retention of specific capacitance about 93% after 500 continuous charge-discharge cycles at a current density of 1 A g( 1). The capacitive behavior of the other synthesized morphology was also accounted. The nanoflower-shaped porous beta-Co(OH)2 with a characteristic three dimensional architecture accompanied highest pore volume which made it promising electrode material for supercapacitor application. The porous nanostructures accompanied by high surface area facilitates the contact and transport of electrolyte, providing longer electron pathways and therefore giving rise to highest capacitance in nanoflower morphology. From a broad view, this study reveals a low-temperature synthetic route of beta-Co(OH)2 of various morphologies, qualifying it as supercapacitor electrode material. PMID- 23806181 TI - Deficiency of complement component 5 ameliorates glaucoma in DBA/2J mice. AB - BACKGROUND: Glaucoma is an age-related neurodegenerative disorder involving the loss of retinal ganglion cells (RGCs), which results in blindness. Studies in animal models have shown that activation of inflammatory processes occurs early in the disease. In particular, the complement cascade is activated very early in DBA/2J mice, a widely used mouse model of glaucoma. A comprehensive analysis of the role of the complement cascade in DBA/2J glaucoma has not been possible because DBA/2J mice are naturally deficient in complement component 5 (C5, also known as hemolytic complement, Hc), a key mediator of the downstream processes of the complement cascade, including the formation of the membrane attack complex. METHODS: To assess the role of C5 in DBA/2J glaucoma, we backcrossed a functional C5 gene from strain C57BL/6J to strain DBA/2J for at least 10 generations. The prevalence and severity of glaucoma was evaluated using ocular examinations, IOP measurements, and assessments of optic nerve damage and RGC degeneration. To understand how C5 affects glaucoma, C5 expression was assessed in the retinas and optic nerves of C5-sufficient DBA/2J mice, using immunofluorescence. RESULTS: C5 sufficient DBA/2J mice developed a more severe glaucoma at an earlier age than standard DBA/2J mice, which are therefore protected by C5 deficiency. Components of the membrane attack complex were found to be deposited at sites of axonal injury in the optic nerve head and associated with RGC soma in the retina. CONCLUSION: C5 plays an important role in glaucoma, with its deficiency lessening disease severity. These results highlight the importance of fully understanding the role of the complement cascade in neurodegenerative diseases. Inhibiting C5 may be beneficial as a therapy for human glaucoma. PMID- 23806183 TI - Correlation of aspiration results with aseptic loosening in total hip arthroplasty. AB - In the evaluation of patients with a persistently painful total hip arthroplasty establishing an accurate diagnosis is paramount in the selection of a successful treatment regimen. It is unknown whether synovial analysis might differentiate aseptic loosening from other causes of failure. A physiological basis exists to suggest that aseptic loosening might be a process of non-segmented leukocytes. The objective of this study was to determine if the synovial fluid differential cell count might aid in the diagnosis of aseptic loosening. A retrospective chart review of all patients who had undergone revision hip arthroplasty with pre operative or intra-operative aspiration results was performed. Aseptic loosening was defined as gross intraoperative movement in the absence of infection. From these results Relative-Operating Characteristic (ROC) curves were created, and sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. A diagnosis of aseptic loosening was established in 76 of the 253 hips. The ROC curves indicated that lymphocyte count does have utility in the diagnosis of aseptic loosening. If an aspirate has a combination of fewer than 2500 WBCs (sensitivity 93%, specificity 42%, NPV 94%, accuracy 57%) or more than 10% lymphocytes (sensitivity 86%, specificity 42%, NPV 87%, accuracy 55%) then the sensitivity for aseptic loosening is 96%, the specificity is 33%, the NPV is 95% and the accuracy is 52%. In patients with painful total hip arthroplasties in whom infection has been excluded, aspiration data can be a useful adjunct in the diagnosis of aseptic loosening. In aspirates with neither a WBC cell count of less than 2500 nor a lymphocyte cell count of greater than 10% aseptic loosening can be effectively "ruled out" as fewer than 5% of these patients will have aseptic loosening. While non-specific, aspirate differential can be useful to "rule-out" aseptic loosening with a sensitivity and negative predictive value well exceeding that of standard radiographs. PMID- 23806184 TI - Author reply: cement-in-cement revision for selected Vancouver type B1 femoral periprosthetic fractures: a biomechanical analysis. PMID- 23806185 TI - Patient-ventilator trigger dys-synchrony: a common phenomenon with important implications. AB - Patient-ventilator trigger dys-synchronies are common with the use of assisted forms of mechanical ventilatory support, including non-invasive mechanical ventilatory support (NIV). Future system designs need to address this in order to improve the effectiveness of NIV. PMID- 23806186 TI - Needs of the hidden homeless - no longer hidden: a pilot study. AB - OBJECTIVE: The purpose of this pilot study was to describe the health, housing and social service needs of the hidden homeless. It has been estimated that 80% of all people experiencing homelessness are hidden homeless, and because they remain 'hidden', resources are not allocated to provide this vulnerable population with support. STUDY DESIGN: This was a descriptive, case series research design. METHODS: Participants were recruited through agency referral and snowball sampling. Research ethics board (REB) approval was granted. Using descriptive statistics, information obtained from participant surveys was analysed using SPSS version 19. RESULTS: Thirty-four participants met the inclusion criteria and ranged from 15 to 69 years. Fifty percent of the participants reported first being homeless between 14 and 18 years of age. Participants had several comorbidities, including mental health challenges, dental and respiratory problems, and sleep disorders. Participants described several challenges with accessing adequate nutrition, and finding adequate transportation and finances, and did not list housing as a priority need. The most frequent barriers to accessing health and social services identified by participants included their personal challenges with addiction, lack of transportation, and the perceived stigma they experienced when they sought help from health and social service agencies. CONCLUSIONS: Findings from this study can contribute to the development of best practice guidelines and policies that specifically address the needs of this unique population. Improved allocation of resources and coordination of health and community services are cost-effective, and advance the overall health of the hidden homeless. PMID- 23806187 TI - What are the determinants of post-traumatic stress disorder: age, gender, ethnicity or other? Evidence from 2008 Wenchuan earthquake. AB - OBJECTIVE: To estimate the prevalence of post-traumatic stress disorder (PTSD) and assess determinants related to PTSD symptoms among adult earthquake survivors after the 2008 Wenchuan earthquake in China. STUDY DESIGN: Cross-sectional multicluster sample surveys with data collected from four counties. METHODS: Surveys were conducted separately in four counties in Sichuan Province, with a total of 2004 respondents. Beichuan County and Dujiangyan City were damaged more severely than Yaan County and Langzhong County during the earthquake. In total, 1890 households were represented, with a mean of 2.2 respondents per household. Data were collected using structured interviews, and the Harvard Trauma Questionnaire and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria were used to diagnose PTSD. RESULTS: The prevalence rates of suspected PTSD were 47.3% (n = 436) in heavily damaged areas and 10.4% (n = 93) in moderately damaged areas. The prevalence rates of PTSD symptoms among elderly, middle aged and young adults were 55.8%, 50.2% and 28.6% (P = 0.001), respectively, in heavily damaged areas. Older age, female gender, unmarried/divorced/widowed, ethnic minority, death of family member, no household income and damaged household were independent risk factors for PTSD symptoms in heavily damaged areas. CONCLUSION: Interventions designed to reduce PTSD among populations affected by the 2008 earthquake should focus on people without household incomes, those with damaged households and those who experienced the death of a family member. Effective, sustainable and culturally sensitive psychosocial interventions and mental health services are required, and attention should be directed to survivors who experienced the death of a family member, women and older adults following the devastating natural disaster. Governments should support income-generating activities and improve living conditions. Trained field personnel can assist with PTSD assessments and referrals, and existing rural healthcare services can be used to provide treatment for common psychiatric disorders. PMID- 23806188 TI - Tumor bed delineation for external beam accelerated partial breast irradiation: a systematic review. AB - In recent years, accelerated partial breast irradiation (APBI) has been considered an alternative to whole breast irradiation for patients undergoing breast-conserving therapy. APBI delivers higher doses of radiation in fewer fractions to the post-lumpectomy tumor bed with a 1-2 cm margin, targeting the area at the highest risk of local recurrence while sparing normal breast tissue. However, there are inherent challenges in defining accurate target volumes for APBI. Studies have shown that significant interobserver variation exists among radiation oncologists defining the lumpectomy cavity, which raises the question of how to improve the accuracy and consistency in the delineation of tumor bed volumes. The combination of standardized guidelines and surgical clips significantly improves an observer's ability in delineation, and it is the standard in multiple ongoing external-beam APBI trials. However, questions about the accuracy of the clips to mark the lumpectomy cavity remain, as clips only define a few points at the margin of the cavity. This paper reviews the techniques that have been developed so far to improve target delineation in APBI delivered by conformal external beam radiation therapy, including the use of standardized guidelines, surgical clips or fiducial markers, pre-operative computed tomography imaging, and additional imaging modalities, including magnetic resonance imaging, ultrasound imaging, and positron emission tomography/computed tomography. Alternatives to post-operative APBI, future directions, and clinical recommendations were also discussed. PMID- 23806189 TI - Relationship between previous history of Streptococcus uberis infection and response to a challenge model. AB - Streptococcus uberis is the most common cause of clinical mastitis at calving in pasture-based dairy cows. Results of experimental inoculations were compared with cows' previous history of infection to help define a model for susceptibility to Str. uberis mastitis. Cows used had either no apparent history of intramammary infection (IMI) by Str. uberis or other major mastitis pathogens throughout their productive lifetime ('apparently uninfected'; AUI), or had a confirmed history of Str. uberis IMI ('historically infected'; HI). Cows were exposed to Str. uberis in sequential steps: dipping of the teat end (DIP; n=53 cows); a teat canal inoculation (TCI; n=33 cows); and, finally, intramammary inoculation challenge (IC; n=7 cows). Only cows that remained free of infection at each step progressed to the next phase. Infection rates were similar between AUI or HI cows following the DIP (9 and 17% respectively), or the TCI (75 and 68% respectively). Physical and biochemical traits of cows were examined. Analysis of traits prior to inoculations implied that HI cows produced more milk fat, while AUI cows tended to have longer teat canals. Analysis of traits for cows that became infected following DIP, implied that there was a positive association with milk fat production and negative association with somatic cell count (SCC), while there was a positive association with the duration of p.m. milking, and negative association with SCC in those cows that became infected following TCI. Only AUI cows became infected following the IC inoculation. Similarity in response to experimental inoculation between the two groups suggests that the current dip or teat canal inoculation (using a 3-mm depth of inoculation) models are not good predictors of natural resistance to Str. uberis. However, a population of cows was identified that remained uninfected after DIP, TCI and IC, and may comprise a resistant phenotype. PMID- 23806191 TI - Markedly decreased antibody titers against hepatitis B in previously immunised children presenting with juvenile idiopathic arthritis. AB - OBJECTIVES: Hepatitis B is a vaccine preventable disease with intermediate endemicity in Greece. Patients with juvenile idiopathic arthritis (JIA) on immunomodulating therapy are prone to infection or reactivation of hepatitis B virus (HBV). The aim of this study is to define the immune status against HBV in children newly-diagnosed with JIA. METHODS: Case-control prospective study including 89 JIA patients and 89 controls matched for age and gender. Eighty-nine JIA patients were included in the study (22 males), with a mean age of 6.8 years. Sera were tested for hepatitis B surface antigen, hepatitis B core antibody, and anti-HBs. Patients with anti-HBs titers >=10 IU/L were considered immune. Data were analysed with SPSS 18.0 version. RESULTS: In the JIA group 55% were HBV immune (anti-HBs level >=10 IU/L) while in the control group 92% were immune against HBV (p<0.001). Antibody levels in the patient group were significantly lower compared to the control group. The mean concentration of anti-HBs levels in JIA patients was 18.3 IU/L versus 82.6 IU/L in the control group (p<0.001). CONCLUSIONS: Antibody titers against HBV in fully vaccinated JIA patients due to start treatment are significantly lower compared to matched healthy children in this study. Diagnosis of JIA and older age were associated with the absence of protective antibodies. Although there is no evidence to support the introduction of a booster HBV dose in healthy children who mount low antibody response following immunisation, further studies are required to address this question in patients with JIA. PMID- 23806192 TI - Student nurses' views on respect towards service users - an interpretative phenomenological study. AB - AIM: To explore student nurses' understanding and behaviours of respect towards patients in order to inform educational strategies to optimise respectful care. BACKGROUND: There is a causal relationship between the perception of being treated with respect and patient satisfaction. Concerns over standards of care prompted a commissioned report into the quality of nurse education in the United Kingdom. DESIGN: A hermeneutic phenomenological interview study was used to identify and interpret student nurses' behaviours and understanding of respect towards patients. SETTING: University health and social care faculty in the north west of England, United Kingdom. PARTICIPANTS: Eight third-year student nurses (adult branch), on different university sites, with practice placements across different healthcare trusts. METHODS: Interviews about their understanding of respect and their behavioural intentions of respect towards patients were recorded and transcribed, then analysed using interpretative phenomenological analysis (IPA) to produce themes from the data. FINDINGS: Three themes of relevance to nurse education were identified. Respect is a complex concept that is difficult to apply in practice. Students are not always aware of incongruence between their feelings of respect towards patients and their behaviours towards them. Role-modelling of respectful care is variable, and essential care is often learned from healthcare assistants. DISCUSSION: Awareness of emotional responses and their relationship to patient perceptions of respect should be facilitated in theory and practice. Rehearsal of the application of respect involving emotional labour, and reflection in and on the practice of respectful care, are needed to address student learning needs. The theory-practice gap in relation to respect, variation in professional practice and the under-recognised importance of healthcare assistants in student nurse education, are barriers to the learning of respect to patients. CONCLUSIONS: Interactive education experiences are important to develop self-awareness and insight into respectful care. Mentorship in practice should encourage reflection in and on the practice of respect towards patients. PMID- 23806193 TI - Exploring faculty health and wellbeing: creating a caring scholarly community. AB - BACKGROUND: Nursing educators worldwide are challenged to integrate the care of culturally diverse people into coursework to prepare a nursing workforce to deliver culturally congruent care (CCC). Care that recipients consider safe, satisfying, and beneficial is the essence of CCC. To effectively teach and role model such care for students, it is important for faculty to experience it at work. While substantive literature exists on promoting health, wellbeing, and a healthy work environment for nurses in practice, there is a limited focus on these topics for nursing faculty. PURPOSE: The purpose of this study was to discover care practices that helped faculty teach students to provide CCC. This article reports' findings related to the theme that care is essential for the health and wellbeing of general nursing faculty who prepare students to provide CCC. THEORETICAL FRAMEWORK AND METHOD: This qualitative ethnonursing research study, guided by the culture care theory, used open-ended interviews to discover care practices that enhanced faculty's ability to teach students to provide CCC. The study was conducted in two public university baccalaureate nursing programs in urban and rural settings in the Southeastern United States. Purposive sampling was used to recruit 27 tenured, tenured-track, and clinical nursing faculty. Interview data were analyzed using Leininger's four phases of ethnonursing data analysis. Qualitative criteria were used to ensure rigor and included participant confirmation of patterns and themes. FINDINGS AND DISCUSSION: Faculty health and wellbeing were described as embracing each other's cultural similarities and differences, caring for self, caring for others, offering respect, and engaging in mentoring/co-mentoring. Evidence-based recommendations to promote faculty health and wellbeing are presented. Creating a caring scholarly community that supports nursing faculty health and wellbeing provided essential support for faculty who prepared students, often through role modeling, to provide CCC. PMID- 23806194 TI - Predictors of attitude and intention to use knowledge management system among Korean nurses. AB - Knowledge sharing using Knowledge Management (KM) systems helps nurses to understand and acquire appropriate knowledge that influences the quality of healthcare service. The purpose of this study was to identify organizational and individual factors influencing attitude and intention to use KM systems among Korean nurses. A cross-sectional survey design was used to study a sample of 245 nurses employed at five hospitals in Seoul. A multiple hierarchical regression was used to examine predictors of nurses' attitude and intention to use. From an individual perspective, nurse's informatics competency was identified as a significant factor influencing attitudes toward knowledge management usage within adhocracy and clan cultures. However, from an organizational perspective, level of hospital information system was identified as a significant factor influencing KM system usage within adhocracy cultures. The findings of this study will be helpful in better understanding and assessing the impact of the factors affecting the implementation of nursing knowledge management systems and in further developing successful managerial strategies using knowledge resources in healthcare settings. PMID- 23806195 TI - Intramyocardial autologous cell engraftment in patients with ischaemic heart failure: a meta-analysis of randomised controlled trials. AB - BACKGROUND: Intramyocardial cellular delivery provides a promising therapeutic strategy for ischaemic cardiac dysfunction. However, individual studies have reported controversial results. METHODS: Relevant trials were identified by systematic search of MEDLINE, EMBASE, the Cochrane database, and CINAH database. Studies, which applied randomised design and compared intramyocardial cell injection with placebo or optimal medical therapy in patients with chronic ischaemic heart failure, were eligible. RESULTS: A total of 210 participants in five randomised controlled trials were included. The pooled analyses showed that cell therapy did not significantly improve left ventricular ejection fraction compared with the control (95% CI -0.35 to 0.31, p=0.91). Nevertheless, cell therapy provided a benefit in increasing 6-min walk distance (95% CI 21.09 m 142.62 m, p=0.008), improving MLHF score (95% CI -25.21 to -3.55, p=0.009), and lowering the incidence of NYHA functional class deterioration (95% CI 0.05-0.76, p=0.02). However, the novel procedure did not result in a significant reduction in all-cause mortality. Conversely, cell therapy did not significantly increase the risk of ventricular tachycardia or acute heart failure, however we were underpowered to evaluate these endpoints. CONCLUSIONS: Intramyocardial cell therapy was feasible in treating patients with ischaemic heart failure. PMID- 23806196 TI - Accuracy and clinical outcomes of computed tomography coronary angiography in the presence of a high coronary calcium score. AB - BACKGROUND: A high coronary calcium burden may adversely affect image quality of CT coronary angiography (CTCA). The ability to rule out clinically significant disease in this setting is uncertain. METHODS: We examined CTCA findings in patients with a calcium score of >600. Utilising a search of death notices, structured patient interview and medical records, downstream investigations, cardiovascular events, revascularisation and mortality were recorded. RESULTS: Sixty patients with a calcium score >600 had CTCA performed on the same day. Coronary disease findings were: mild 28%, moderate 33%, severe 32% and non diagnostic 7%. During a median 1.75-year follow-up, 31 (53%) of patients underwent further assessment for coronary disease, eight patients (13%) underwent revascularisation and there were two non-cardiovascular and one cardiovascular deaths. No patient with mild or moderate disease at CTCA had subsequently demonstrated ischaemia, was deemed to require PCI or suffered cardiac mortality. The negative predictive value of CTCA for subsequent PCI and all-cause mortality was 97% (100% for cardiac mortality only). The positive predictive value of CTCA for revascularisation or CV death was 42%. CONCLUSION: In patients with an elevated coronary calcium score, a negative CTCA implies an excellent short-term outcome and appears to exclude clinically significant coronary disease. PMID- 23806197 TI - Left ventricular volumes and systolic function after long-term right ventricular pacing may be predicted by paced QRS duration, but not pacing site. AB - BACKGROUND: Long-term right ventricular apical (RVA) pacing causes adverse left ventricular (LV) remodelling and clinical outcomes. METHODS: Forty-one patients (19 men, mean age 70.9+/-14.2, 23 right ventricular septal and 18 RVA pacing) underwent pacemaker implantation for atrioventricular block. LV volumes and left ventricular ejection fraction (LVEF) were assessed by echocardiography 39.3+/ 17.2 months after implantation. Predictors of left ventricular systolic volume (LVESV), left ventricular diastolic volume (LVEDV) and LVEF were analysed. RESULTS: No difference was found between RVA pacing and right ventricular septal pacing groups in LVESV (40.6+/-22.6 vs 33+/-14.4ml; p=0.199), LVEDV (88.2+/-31.2 vs 73.7+/-23.9ml; p=0.102) and LVEF (56.1+/-8.6 vs 56+/-6.6%; p=0.996). With multivariate stepwise regression, only pQRSd and renal impairment independently predicted LVESV (beta=0.522, 95% CI: 0.242-0.802; p=0.001 and beta=40.3, 95% CI: 17.6-62.9; p=0.001 respectively), LVEDV (beta=0.786, 95% CI: 0.338-1.235; p=0.001 and beta=42.8, 95% CI: 6.6-79; p=0.022 respectively) and LVEF (beta=-0.161, 95% CI: -0.283 to -0.04; p=0.011 and beta=-14.8, 95% CI: -24.6 to -5.0; p=0.004 respectively). CONCLUSIONS: pQRSd and renal impairment, but not pacing site or baseline LVEF, may be predictors for LV volumes and systolic function after long term RV pacing. pQRSd may be target for pacing site optimisation. PMID- 23806198 TI - DNA methylation analysis reveals distinct methylation signatures in pediatric germ cell tumors. AB - BACKGROUND: Aberrant DNA methylation is a prominent feature of many cancers, and may be especially relevant in germ cell tumors (GCTs) due to the extensive epigenetic reprogramming that occurs in the germ line during normal development. METHODS: We used the Illumina GoldenGate Cancer Methylation Panel to compare DNA methylation in the three main histologic subtypes of pediatric GCTs (germinoma, teratoma and yolk sac tumor (YST); N = 51) and used recursively partitioned mixture models (RPMM) to test associations between methylation pattern and tumor and demographic characteristics. We identified genes and pathways that were differentially methylated using generalized linear models and Ingenuity Pathway Analysis. We also measured global DNA methylation at LINE1 elements and evaluated methylation at selected imprinted loci using pyrosequencing. RESULTS: Methylation patterns differed by tumor histology, with 18/19 YSTs forming a distinct methylation class. Four pathways showed significant enrichment for YSTs, including a human embryonic stem cell pluripotency pathway. We identified 190 CpG loci with significant methylation differences in mature and immature teratomas (q < 0.05), including a number of CpGs in stem cell and pluripotency-related pathways. Both YST and germinoma showed significantly lower methylation at LINE1 elements compared with normal adjacent tissue while there was no difference between teratoma (mature and immature) and normal tissue. DNA methylation at imprinted loci differed significantly by tumor histology and location. CONCLUSION: Understanding methylation patterns may identify the developmental stage at which the GCT arose and the at-risk period when environmental exposures could be most harmful. Further, identification of relevant genetic pathways could lead to the development of new targets for therapy. PMID- 23806200 TI - Canine kobuviruses in diarrhoeic dogs in Italy. AB - Canine kobuviruses (CaKVs) are newly recognized picornaviruses recently detected in dogs in the US. By molecular analysis of the whole genome, CaKV that appeared genetically closest to the murine kobuvirus (MuKV) and to the human Aichi virus (AiV), may be classified in the Kobuvirus genus as new genotype (CaKV type 1) within the species Aichivirus A. To date, there are no information on the epidemiology of these novel viruses in other continents. In this study, by screening a collection of 256 dog fecal samples either from diarrhoeic or asymptomatic animals, CaKV was identified in six specimens with an overall prevalence of 2.34% (6/256). All the positive dogs presented diarrhea and were found to be infected by CaKV alone or in mixed infections with canine coronavirus (CCoV) and/or canine parvovirus type 2 (CPV-2). By molecular analysis of the partial 3D gene, all the strains detected displayed a close relatedness with the CaKVs recently identified in the US. This study provides evidence that CaKVs circulate in diarrhoeic dogs in Italy and are not geographically restricted to the North American continent, where they were first signaled. PMID- 23806201 TI - Impact of aging on antigen presentation cell function of dendritic cells. AB - Older people exhibit increased mortality to infections and cancer as compared to younger people, indicating that aging impairs immunity. Dendritic cells (DCs) are key for bridging the innate and adaptive arms of the immune system by priming antigen specific T cells. Discerning how aging impacts DC function to initiate adaptive immune responses is of great biomedical importance as this could lead to the development of novel therapeutics to enhance immunity with aging. This review details reports indicating that aging impairs the antigen presenting function of DCs but highlights other studies indicating preserved DC function with aging. How aging impacts antigen presentation by DCs is complex and without a clear unifying biological underpinning. PMID- 23806202 TI - Are we counting mitoses correctly? AB - The number of mitotic figures in a predefined area is essential in pathologic evaluation for most tumors. This information sometimes provides clues in differentiating neoplastic lesions from nonneoplastic ones and sometimes in defining and grading of the tumors as well as prognosticating expected lifetime of the patient. As a generally accepted concept, scanning a certain number of consecutive nonoverlapping areas that are rich in viable tumor cells is required. Invasion fronts or the periphery of the tumors is preferred for counting mitosis. The target area to be counted for mitotic activity for various tumors is standardized as the number of mitosis in an established number of high-power fields. However, suggested mitotic counts, which constitute the basis of these studies, were obtained via the old microscopes, which usually had narrower visual fields than the state-of-the-art microscopes. Because the visual fields of the present microscopes provide larger areas compared with the older ones, corrections in mitosis counting are needed to make them compatible with the criteria, which had been put forward in the original reference studies. PMID- 23806203 TI - Interfacial dead-layer effects in Hf-silicate films with Pt or RuO2 gates. AB - The interfacial dead-layer (DL) effects at the interfaces between Hf-silicate films and Pt or RuO2 gate metals are examined. The Si content in the Hf-silicate film was controlled to vary the dielectric constant (k). The DL effect was strongly dependent on the k value of the Hf-silicate layer, and was suppressed when the Si content was increased to ~80% (k ~ 6). This Si content also coincides with the Fermi level pinning-free composition. Therefore, the optimum high-k gate dielectric structure could be a higher-k layer HfO2 capped with a lower-k layer (k ~ 6) with minimum thickness (~1 nm) for the best dielectric performance. PMID- 23806204 TI - Organization of brain networks governed by long-range connections index autistic traits in the general population. AB - BACKGROUND: The dimensional approach to autism spectrum disorder (ASD) considers ASD as the extreme of a dimension traversing through the entire population. We explored the potential utility of electroencephalography (EEG) functional connectivity as a biomarker. We hypothesized that individual differences in autistic traits of typical subjects would involve a long-range connectivity diminution within the delta band. METHODS: Resting-state EEG functional connectivity was measured for 74 neurotypical subjects. All participants also provided a questionnaire (Social Responsiveness Scale, SRS) that was completed by an informant who knows the participant in social settings. We conducted multivariate regression between the SRS score and functional connectivity in all EEG frequency bands. We explored modulations of network graph metrics characterizing the optimality of a network using the SRS score. RESULTS: Our results show a decay in functional connectivity mainly within the delta and theta bands (the lower part of the EEG spectrum) associated with an increasing number of autistic traits. When inspecting the impact of autistic traits on the global organization of the functional network, we found that the optimal properties of the network are inversely related to the number of autistic traits, suggesting that the autistic dimension, throughout the entire population, modulates the efficiency of functional brain networks. CONCLUSIONS: EEG functional connectivity at low frequencies and its associated network properties may be associated with some autistic traits in the general population. PMID- 23806205 TI - Childhood-onset systemic lupus erythematosus in Croatia: demographic, clinical and laboratory features, and factors influencing time to diagnosis. AB - OBJECTIVES: Childhood-onset systemic lupus erythematosus (cSLE) presents with diverse clinical features and often with non-classical symptoms that may delay diagnosis and increase risk of morbidity and mortality. This paper aims to analyse incidence, and clinical and laboratory features of cSLE in Croatia between 1991 and 2010, and to identify factors influencing time to diagnosis. RESULTS: Medical records at three university-based tertiary care centres were analysed retrospectively for 81 children with cSLE (68 girls). Mean age at onset was 13.4+/-2.8 yr (interquartile range 3), and annual incidence varied from 1-15 per million at risk. The most frequent clinical and laboratory features were musculoskeletal symptoms (80%) and increased erythrocyte sedimentation rate (96%). The most frequent immunological laboratory findings were the presence of antibodies against histones (86%), double-stranded DNA (73%), and Sm protein (64%), as well as low levels of C3 complement (69%). Haematuria was present in 58% of children, proteinuria in 56%, and biopsy-confirmed lupus nephritis in 43%. Median time from symptom onset to diagnosis was 2 months (range 0-96). Time to diagnosis was inversely associated with ECLAM score (p<0.001), but it showed no association with age, gender, clinical features or distance from the nearest paediatric centre. CONCLUSIONS: This is the first large-scale, in-depth study of clinical and laboratory features of cSLE in Croatia. Among all demographic, laboratory and clinical features examined, ECLAM score alone was inversely associated with time to diagnosis. This highlights the need to improve detection of children with fewer symptoms early in the course of the disease, therefore serious consequences for prognosis could be avoided. PMID- 23806206 TI - Overmilking causes deterioration in teat-end condition of dairy cows in late lactation. AB - The objective of the study was to determine the effect of varying degrees of overmilking on teat-end hyperkeratosis, milk production variables and indicators of udder health during late lactation. This was examined by assessing the effect of four end-of-milking criteria on 181 spring-calving, mixed-age Holstein Friesian cows, at an average 217+/-24 d in milk, over a six-week period. The four treatments were: remove cluster once milk flow rate fell to 0.2 kg/min plus 5 s (Ovr0), plus 120 s (Ovr2), plus 300 s (Ovr5), and plus 540 s (Ovr9). Daily measurements included individual cow milk yield, milking duration, overmilking duration, maximum milk flow rate, milk flow rate at cluster removal and the number of cluster re-attachments. Individual cow bulk milk samples were collected weekly at AM and PM milkings to determine composition (fat, protein and lactose) and somatic cell count (SCC; AM only). Teat-end hyperkeratosis score was assessed at weeks 0, 3, 5 and 6. At week 6 mean teat-end hyperkeratosis score of the Ovr2 treatment was not greater than Ovr0, whilst Ovr5 was greater than Ovr2 and Ovr9 was greater than Ovr5 and Ovr2. Milk production, milking characteristics and SCC were not different between treatments, except milking duration and milk flow rate at cluster removal. However, higher teat-end hyperkeratosis scores may have a longer-term impact on indicators of udder health if teat-end condition reaches severe levels. Results indicate that to minimise changes in teat-end condition overmilking should be limited to 2 min, which has implications for milking management in large parlours not fitted with automatic cluster removers. PMID- 23806208 TI - Iridovirus-like viruses in erythrocytes of lacertids from Portugal. AB - Icosahedral nucleo-cytoplasmic large DNA viruses (NCLDV)-like viruses, which forminclusions in the erythrocyte cytoplasm of reptiles, were previously presented as candidates for a new genus of the Iridoviridae family. The present work describes the distribution of infected lizard hosts and ultrastructural characteristics of the viral inclusions of NCLDV-like viruses from Portugal and adjacent locations in Spain. Giemsa-stained blood smears of 235 Lacerta schreiberi from Portugal and Spain, 571 Lacerta monticola from the mountain Serra da Estrela (Portugal), 794 Podarcis hispanica from several localities in Portugal and Spain, and 25 Lacerta dugesii from Madeira Island, were studied. Infection in L. schreiberi was only found in mountain populations, up to 30% in Serra da Estrela and 9-11% elsewhere. It was absent in lizards from lowlands. Prevalence of infection among L. monticola in Serra da Estrela was 10%; infected lizards were found during March to July and October but not in August and September. Infection in P. hispanica was below 3.3%. Only one infected specimen of L. dugesii was identified by light microscopy. Ultrastructural examination of infected samples revealed that the inclusions are virus assembly sites of icosahedral cytoplasmic iridovirus-like virions. Virions from different host species have different ultrastructural features and probably represent different related viruses. PMID- 23806207 TI - Gender policies and advertising and marketing practices that affect women's health. AB - BACKGROUND: The three papers of this doctoral thesis are based on the social construction of reality through the analysis of communication relating to health issues. We have analysed the contents of parliamentary, institutional, and mass media to uncover whether their communications create, transmit, and perpetuate gender biases and/or stereotypes, which may have an impact on peoples' health, with a particular focus on women. OBJECTIVE: To analyse decision making and the creation of gender awareness policies and actions affecting women's health: (1) political debates about abortion, (2) gender awareness communication campaigns and educational actions, and (3) pharmaceutical advertising strategies. DESIGN: Quantitative and qualitative methods were employed, and the research included observational studies and systematic reviews. To apply a gender perspective, we used the level of gender observation proposed by S. Harding, which states that: (1) gender is the basis of social norms and (2) gender is one of the organisers of the social structure. RESULTS: Sixty percentage of the bills concerning abortion introduced in the Spanish Parliament were initiated and led by pro choice women's groups. Seventy-nine percent of institutional initiatives aimed at promoting equality awareness and were in the form of educational actions, while unconventional advertising accounted for 6 percent. Both initiatives focused on occupational equality, and very few actions addressed issues such as shared responsibility or public policy. With regard to pharmaceutical advertising, similar traditional male-female gender roles were used between 1975 and 2005. CONCLUSIONS: Gender sensitivity continues to be essential in changing the established gender system in Spanish institutions, which has a direct and indirect impact on health. Greater participation of women in public policy and decision-making are critical for womens' health, such as the issue of abortion. The predominance of women as the target group of institutional gender awareness campaigns proves that the gender perspective still lacks the promotion of shared responsibilities between men and women. There is a need for institutions that act as 'policy watchdogs' to control the gender biases in mass media and pharmaceutical marketing as well as to ensure the proper implementation and maintenance of Spanish equality laws. PMID- 23806209 TI - Diagnostic accuracy of circulating tumor cells detection in gastric cancer: systematic review and meta-analysis. AB - BACKGROUND: Circulating tumor cells (CTCs) detection has previously been used for diagnosing gastric cancer. However, the previous studies failed to make an agreement whether the detection of CTCs contributes to the diagnosis of gastric cancer. METHODS: A systematic review and meta-analysis was performed to evaluate the overall accuracy of CTCs detection for diagnosing gastric cancer. PubMed, Embase and the Wanfang database were searched in all languages published up to Oct 2012. The pooled sensitivity (SEN), specificity (SPE), positive and negative likelihood ratios (PLR and NLR, respectively), diagnostic odds ratio (DOR) and summary receiver operating characteristic (sROC) curve were calculated to evaluate the overall test performance. RESULTS: Twenty studies were included in this systematic review and meta-analysis. The diagnostic value of CTCs detection for the gastric cancer was calculated to evaluate the overall test performance. The summary estimates of The pooled sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratio were 0.42 (95% confidence interval (CI), 0.21-0.67), 0.99 (95% CI, 0.96-1.00), 58.2 (95% CI, 9.8-345.9), 0.58 (95% CI, 0.38-0.89), and 100 (95% CI, 15-663), respectively. The summary receiver operating characteristic curve was 0.97 (95% CI, 0.95-0.98). Deek's funnel plot asymmetry test found no evidence of study publication bias in the current study (P = 0.49). CONCLUSION: This systematic review suggests that CTCs detection alone cannot be recommended as a screening test for gastric cancer. However, it might be used as a noninvasive method for the confirmation of the gastric cancer diagnosis. PMID- 23806210 TI - Retinaldehyde dehydrogenase enzymes regulate colon enteric nervous system structure and function. AB - The enteric nervous system (ENS) forms from the neural crest-derived precursors that colonize the bowel before differentiating into a network of neurons and glia that control intestinal function. Retinoids are essential for normal ENS development, but the role of retinoic acid (RA) metabolism in development remains incompletely understood. Because RA is produced locally in the tissues where it acts by stimulating RAR and RXR receptors, RA signaling during development is absolutely dependent on the rate of RA synthesis and degradation. RA is produced by three different enzymes called retinaldehyde dehydrogenases (RALDH1, RALDH2 and RALDH3) that are all expressed in the developing bowel. To determine the relative importance of these enzymes for ENS development, we analyzed whole mount preparations of adult (8-12-week old) myenteric and submucosal plexus stained with NADPH diaphorase (neurons and neurites), anti-TuJ1 (neurons and neurites), anti-HuC/HuD (neurons), and anti-S100beta (glia) in an allelic series of mice with mutations in Raldh1, Raldh2, and Raldh3. We found that Raldh1-/-, Raldh2+/-, Raldh3+/- (R1(KO)R2(Het)R3(Het)) mutant mice had a reduced colon myenteric neuron density, reduced colon myenteric neuron to glia ratio, reduced colon submucosal neuron density, and increased colon myenteric fibers per neuron when compared to the wild type (WT; Raldh1WT, Raldh2WT, Raldh3WT) mice. These defects are unlikely to be due to defective ENS precursor migration since R1(KO)R2(Het)R3(KO) mice had increased enteric neuron progenitor migration into the distal colon compared to WT during development. RALDH mutant mice also have reduced contractility in the colon compared to WT mice. These data suggest that RALDH1, RALDH2 and RALDH3 each contribute to ENS development and function. PMID- 23806211 TI - Requirement for frzb and fzd7a in cranial neural crest convergence and extension mechanisms during zebrafish palate and jaw morphogenesis. AB - Regulation of convergence and extension by wnt-frizzled signaling is a common theme in embryogenesis. This study examines the functional requirements of frzb and fzd7a in convergence and extension mechanisms during craniofacial development. Using a morpholino knockdown approach, we found that frzb and fzd7a are dispensable for directed migration of the bilateral trabeculae, but necessary for the convergence and extension of the palatal elements, where the extension process is mediated by chondrocyte proliferation, morphologic change and intercalation. In contrast, frzb and fzd7a are required for convergence of the mandibular prominences, where knockdown of either frzb or fzd7a resulted in complete loss of lower jaw structures. Further, we found that bapx1 was specifically downregulated in the wnt9a/frzb/fzd7a morphants, while general neural crest markers were unaffected. In addition, expression of wnt9a and frzb was also absent in the edn-/- mutant. Notably, over-expression of bapx1 was sufficient to partially rescue mandibular elements in the wnt9a/frzb/fzd7a morphants, demonstrating genetic epistasis of bapx1 acting downstream of edn1 and wnt9a/frzb/fzd7a in lower jaw development. This study underscores the important role of wnt-frizzled signaling in convergence and extension in palate and craniofacial morphogenesis, distinct regulation of upper vs. lower jaw structures, and integration of wnt-frizzled with endothelin signaling to coordinate shaping of the facial form. PMID- 23806212 TI - Trichodermin induces cell apoptosis through mitochondrial dysfunction and endoplasmic reticulum stress in human chondrosarcoma cells. AB - Chondrosarcoma is the second most common primary bone tumor, and it responds poorly to both chemotherapy and radiation treatment. Nalanthamala psidii was described originally as Myxosporium in 1926. This is the first study to investigate the anti-tumor activity of trichodermin (trichothec-9-en-4-ol, 12,13 epoxy-, acetate), an endophytic fungal metabolite from N. psidii against human chondrosarcoma cells. We demonstrated that trichodermin induced cell apoptosis in human chondrosarcoma cell lines (JJ012 and SW1353 cells) instead of primary chondrocytes. In addition, trichodermin triggered endoplasmic reticulum (ER) stress protein levels of IRE1, p-PERK, GRP78, and GRP94, which were characterized by changes in cytosolic calcium levels. Furthermore, trichodermin induced the upregulation of Bax and Bid, the downregulation of Bcl-2, and the dysfunction of mitochondria, which released cytochrome c and activated caspase-3 in human chondrosarcoma. In addition, animal experiments illustrated reduced tumor volume, which led to an increased number of terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL)-positive cells and an increased level of cleaved PARP protein following trichodermin treatment. Together, this study demonstrates that trichodermin is a novel anti-tumor agent against human chondrosarcoma cells both in vitro and in vivo via mitochondrial dysfunction and ER stress. PMID- 23806213 TI - Topical efficacy of dimercapto-chelating agents against lewisite-induced skin lesions in SKH-1 hairless mice. AB - Lewisite is a potent chemical warfare arsenical vesicant that can cause severe skin lesions. Today, lewisite exposure remains possible during demilitarization of old ammunitions and as a result of deliberate use. Although its cutaneous toxicity is not fully elucidated, a specific antidote exists, the British anti lewisite (BAL, dimercaprol) but it is not without untoward effects. Analogs of BAL, less toxic, have been developed such as meso-2,3-dimercaptosuccinic acid (DMSA) and have been employed for the treatment of heavy metal poisoning. However, efficacy of DMSA against lewisite-induced skin lesions remains to be determined in comparison with BAL. We have thus evaluated in this study the therapeutic efficacy of BAL and DMSA in two administration modes against skin lesions induced by lewisite vapor on SKH-1 hairless mice. Our data demonstrate a strong protective efficacy of topical application of dimercapto-chelating agents in contrast to a subcutaneous administration 1h after lewisite exposure, with attenuation of wound size, necrosis and impairment of skin barrier function. The histological evaluation also confirms the efficacy of topical application by showing that treatments were effective in reversing lewisite-induced neutrophil infiltration. This protective effect was associated with an epidermal hyperplasia. However, for all the parameters studied, BAL was more effective than DMSA in reducing lewisite-induced skin injury. Together, these findings support the use of a topical form of dimercaprol-chelating agent against lewisite-induced skin lesion within the first hour after exposure to increase the therapeutic management and that BAL, despite its side-effects, should not be abandoned. PMID- 23806214 TI - One-dimensional surface-imprinted polymeric nanotubes for specific biorecognition by initiated chemical vapor deposition (iCVD). AB - Molecular imprinting is a powerful, generic, and cost-effective technique; however, challenges still remain related to the fabrication and development of these systems involving nonhomogeneous binding sites, insufficient template removing, incompatibility with aqueous media, low rebinding capacity, and slow mass transfer. The vapor-phase deposition of polymers is a unique technique because of the conformal nature of coating and offers new possibilities in a number of applications including sensors, microfluidics, coating, and bioaffinity platforms. Herein, we demonstrated a simple but versatile concept to generate one dimensional surface-imprinted polymeric nanotubes within anodic aluminum oxide (AAO) membranes based on initiated chemical vapor deposition (iCVD) technique for biorecognition of immunoglobulin G (IgG). It is reported that the fabricated surface-imprinted nanotubes showed high binding capacity and significant specific recognition ability toward target molecules compared with the nonimprinted forms. Given its simplicity and universality, the iCVD method can offer new possibilities in the field of molecular imprinting. PMID- 23806215 TI - Identification of virulence genes in the crucifer anthracnose fungus Colletotrichum higginsianum by insertional mutagenesis. AB - To investigate the molecular and genetic mechanisms underlying virulence of Colletotrichum higginsianum on Arabidopsis thaliana, a T-DNA insertion mutant library of C. higginsianum, the causal agent of crucifer anthracnose, was established using Agrobacterium tumefaciens-mediated transformation. Among 875 transformants tested for virulence on Arabidopsis, six mutants with altered virulence, including an appressorial melanin-deficient mutant T734, two mutants defective in penetration, T45 and B30, and three mutants, T679, T732 and T801, that cause hypersensitive reactions on host Arabidopsis, were obtained. Southern blot analysis indicated that the mutants T732 and T734 harbored single-site T-DNA integrations, while B30 harbored two T-DNA insertions. Border flanking sequences of T-DNAs from these mutants were recovered by inverse polymerase chain reaction (PCR) and thermal asymmetric interlaced PCR. Sequence analyses revealed that single T-DNA insertions in mutant T734 targeted the coding region of a gene with unknown function, and in mutant T732 targeted a gene encoding a copper amine oxidase. The two T-DNA insertion sites in mutant B30 were found in the coding region of a gene encoding an exosome component and in the upstream region of a DUF221-domain gene. None of these genes have previously been implicated in virulence of the phytopathogenic fungi. Among these avirulent mutants, T734 showed altered color in colony growth and produced melanin-deficient, albino appressoria. The T-DNA insert in T734 was detected in the coding region of a gene named C. higginsianum melanin-deficiency gene (Ch-MEL1), which is highly similar to a gene encoding a hypothetical protein in Colletotrichum gloeosporioides (GenBank ELA33048). To validate whether the Ch-MEL1 gene was associated with virulence of the mutant T734, a targeted gene disruption and complementation approach was used. The appressoria of ?Ch-mel1 null mutants were defective in melanization and failed to penetrate the host epidermal cells. When inoculated onto the wounded leaf tissues, the ?Ch-mel1 mutants grew on host tissues but failed to cause lesions beyond the wound site. In contrast, both the complement C?Ch-mel1-2 and the wild type produced melanized appressoria and caused necrosis on leaves of Arabidopsis. Ch-MEL1 is required for both appressorial melanin production in C. higginsianum and post-invasive growth in host tissues. Together with identification of other avirulent mutants and their associated genes, this study provides novel insights into molecular mechanisms underlying virulence of the hemibiotroph, C. higginsianum. PMID- 23806217 TI - Phosphorylation of neuronal nitric oxide synthase at Ser1412 in the dentate gyrus of rat brain after transient forebrain ischemia. AB - We previously demonstrated that calmodulin-dependent protein kinase IIalpha (CaM KIIalpha) phosphorylates nNOS at Ser(847) in the hippocampus after forebrain ischemia; this phosphorylation attenuates NOS activity and might contribute to resistance to post-ischemic damage. We also revealed that cyclic AMP-dependent protein kinase (PKA) could phosphorylate nNOS at Ser(1412)in vitro. In this study, we focused on chronological and topographical changes in the phosphorylation of nNOS at Ser(1412) after rat forebrain ischemia. The hippocampus and adjacent cortex were collected at different times, up to 24h, after 15min of forebrain ischemia. NOS was partially purified from crude samples using ADP agarose gel. Neuronal NOS, phosphorylated (p)-nNOS at Ser(1412), PKA, and p-PKA at Thr(197) were studied in the rat hippocampus and cortex using Western blot analysis and immunohistochemistry. Western blot analysis revealed that p-nNOS at Ser(1412) significantly increased between 1 and 6h after reperfusion in the hippocampus, but not in the cortex. PKA was cosedimented with nNOS by ADP agarose gel. Immunohistochemistry revealed that phosphorylation of nNOS at Ser(1412) and PKA at Thr(197) occurred in the subgranular layer of the dentate gyrus. Forebrain ischemia might thereby induce temporary activation of PKA at Thr(197), which then phosphorylates nNOS at Ser(1412) in the subgranular layer of the dentate gyrus. PMID- 23806216 TI - Cut-off levels of salivary beta2-microglobulin and sodium differentiating patients with Sjogren's syndrome from those without it and healthy controls. AB - OBJECTIVES: For the diagnosis of Sjogren's syndrome (SS), cut-off levels of beta2 microglobulin (beta2MG) and sodium (Na+) in unstimulated whole saliva have not yet been shown. We aimed to determine the cut-off levels of salivary beta2MG and Na+ which differentiate SS patients from non-SS patients and healthy controls. METHODS: Seventy-one patients of primary SS (pSS, 69 females/2 males, 60.0+/-16.8 years old), 50 of secondary SS (sSS, 49/1, 55.8+/-17.4), 54 of connective tissue diseases other than SS (non-SS-CTD, 43/11, 60.0+/-16.0), and 75 healthy volunteers (HC, 43/32, 50.7+/-15.6) were included. Unstimulated whole saliva were examined for levels of beta2MG, Na+, potassium (K+), and chloride (Cl-). Receiver operating characteristic curve analysis was carried out. RESULTS: beta2MG, Na+, and Cl- levels in the SS group (pSS and sSS) were significantly higher than those in the non-SS group (non-SS-CTD and HC). The salivary beta2MG level was 5.3+/-4.6 mg/L in pSS, 5.1+/-2.0 in sSS, 2.5+/-2.1 in non-SS-CTD, and 1.2+/-0.7 in HC, respectively. The Na+ level was 39.2+/-25.2 mEq/L, 36.4+/-26.1, 19.6+/-16.8, and 16.5+/-7.3, and the Cl- level was 51.1+/-25.0, 47.8+/-24.3, 32.1+/-16.6, and 27.0+/-7.9 in the same order. The K+ level in the SS group was significantly higher than that in HC. The optimal cut-off beta2 MG and Na+ levels that differentiate the SS group from the non-SS group were 2.3 mg/L and 23 mEq/L. CONCLUSIONS: Salivary beta2MG and Na+ levels are useful markers for differentiating SS patients from non-SS-CTD patients and HC. PMID- 23806218 TI - Ultrasonicated Enterococcus faecium SF68 enhances neutrophil free radical production and udder innate immunity of drying-off dairy cows. AB - Proper dry cow management is critical not only for subsequent milk production and fertility but also for mastitis control. A phenomenon of immunosuppression was commonly observed in transition cows, an example being the high susceptibility of the mammary gland during early the dry period to new infectious agents. Polymorphonuclear neutrophils (PMN) play important defence roles in the mammary gland of newly dried cows. One of the bactericidal mechanisms of PMN is through producing reactive oxygen species (ROS), which can be efficiently quantified by chemiluminescence (CL) assay. In the current study, the potential of intramammary application of a commercial Enterococcus faecium SF68 (SF68) product to enhance the local innate immunity of newly dried mammary glands was evaluated based on the CL assay. The preliminary experiments in vitro indicated virtual dose responsiveness of ROS generation from three different cell preparations, bovine blood PMN, bovine blood PMN pre-conditioned with cow milk, and the post diapedesis model somatic cells from cow milk, on their exposure to phorbol 12 myristate 13-acetate (PMA), viable SF68, and ultrasonicated SF68, but not dry heated SF68. Because ultrasonication treatment was found to profoundly enhance the immunogenicity of SF68 in vitro, in the following animal trial, single infusion of either 5 or 10*107 original cfu of ultrasonicated SF68 was randomly applied to the front quarters and phosphate-bufferedsaline (PBS) applied to the rear quarters of each of the four experimental cows on the first day of milk stasis. The results showed that within the first post-infusion week, ultrasonicated SF68 induced a faster and greater (P<0.05) recruitment of PMN into mammary lumen with no apparent local or systemic inflammatory sign. Meanwhile, ultrasonicated SF68 also induced a greater (P<0.05) ROS production in response to PMA challenge by in situ somatic cells of mammary secretion. Taken together, ultrasonicated SF68 modulated ROS generation of bovine neutrophils, and would be a potential enhancer of udder innate immunity in drying-off dairy cows. More thorough work is warranted. PMID- 23806220 TI - Clinical Neuropathology practice guide 4-2013: post-herpes simplex encephalitis: N-methyl-Daspartate receptor antibodies are part of the problem. AB - Classic herpes simplex virus encephalitis (HSVE) is an acute viral infection that usually follows a monophasic disease course; however some patients, mainly children, experience a relapse within weeks or months after the initial event. In a subset of these patients a viral reactivation is unlikely because the CSF PCR for HSV is negative, repeated MRI does not show new necrotic lesions, and the symptoms are refractory to antiviral therapy. These patients often develop choreoathetosis variably accompanied by behavioral changes and seizures, and a postinfectious immune-mechanism has been postulated. Recent studies demonstrated that 7% of patients with HSVE harbor NR1 N-methyl-D-aspartate receptor (NMDAR) IgG antibodies. Moreover, a child with post- HSVE choreoathetosis was found to have NMDAR antibodies; the patient did not improve with antiviral therapy but recovered after aggressive immunotherapy. Based on these findings, evidence is increasing that a subgroup of post-HSVE represents a separate disease entity, which in fact is anti-NMDAR encephalitis. Patients with relapsing HSVE or prolonged atypical symptoms, who have negative CSF PCR for HSV should routinely be tested for NMDAR IgG antibodies in CSF and serum. It is important to be aware of this differential diagnosis because patients respond to immunotherapy. PMID- 23806222 TI - Health care cost containment in Denmark and Norway: a question of relative professional status? AB - The demand for publicly subsidized health care services is insatiable, but the costs can be contained in different ways: formal rules can limit access to and the number of subsidized services, demand and supply can be regulated through the price mechanism, the relevant profession can contain the costs through state sanctioned self-regulation, and other professions can contain the costs (e.g. through referrals). The use of these cost containment measures varies between countries, depending on demand and supply factors, but the relative professional status of the health professions may help explain why different countries use cost containment measures differently for different services. This article compares cost containment measures in Denmark and Norway because these countries vary with regard to the professional status of the medical profession relative to other health care providers, while other relevant variables are approximately similar. The investigation is based on formal agreements and rules, historical documents, existing analyses and an analysis of 360 newspaper articles. It shows that high relative professional status seems to help professions to avoid user fees, steer clear of regulation from other professions and regulate the services produced by others. This implies that relative professional status should be taken into consideration in analyses of health care cost containment. PMID- 23806221 TI - Small cell glioblastoma or small cell carcinoma: a case report and review of the literature. AB - It is often easy to distinguish between primary brain tumors and metastases based on morphology alone. However, in some cases immunohistochemistry (IHC) is necessary to obtain a diagnosis, but, as the present case report illustrates, this is not always straightforward. A 75-year old man was admitted to the hospital with left-sided loss of motor function. A MRI revealed a 6 cm tumor in the right temporoparietal area. The histology was consistent with both glioblastoma multiforme (GBM) and small cell lung carcinoma (SCLC) but IHC was suggestive of a SCLC metastasis. PET-CT revealed no enhancement in the lung, so the tumor was treated as a GBM. Eight months after the primary diagnosis a new MRI revealed metastases in the spinal cord, but there was still no enhancement in the lungs. We reviewed the literature concerning markers used to differentiate between GBM and SCLC and found that most of these markers showed limited specificity. It is further discussed whether the case illustrates an example of spontaneous regression of primary SCLC or might be an example of a GMB metastasizing to the spinal cord. Although immunohistochemical markers are of great help in many situations, the case illustrates important limitations and the need for better diagnostic markers. PMID- 23806223 TI - Surface functionalization of nanostructured Fe2O3 polymorphs: from design to light-activated applications. AB - Nanostructured iron(III) oxide deposits are grown by chemical vapor deposition (CVD) at 400-500 degrees C on Si(100) substrates from Fe(hfa)2TMEDA (hfa = 1,1,1,5,5,5-hexafluoro-2,4-pentanedionate; TMEDA = N,N,N',N' tetramethylethylenediamine), yielding the selective formation of alpha-Fe2O3 or the scarcely studied epsilon-Fe2O3 polymorphs under suitably optimized preparative conditions. By using Ti(OPr(i))4 (OPr(i) = iso-propoxy) and water as atomic layer deposition (ALD) precursors, we subsequently functionalized the obtained materials at moderate temperatures (<300 degrees C) by an ultrathin titanomagnetite (Fe3-xTixO4) overlayer. An extensive multitechnique characterization, aimed at elucidating the system structure, morphology, composition and optical properties, evidenced that the photoactivated hydrophilic and photocatalytic behavior of the synthesized materials is dependent both on iron oxide phase composition and ALD surface modification. The proposed CVD/ALD hybrid synthetic approach candidates itself as a powerful tool for a variety of applications where semiconductor-based nanoarchitectures can benefit from the coupling with an ad hoc surface layer. PMID- 23806224 TI - Efficient boosting of the antiviral T cell response in B cell-depleted patients with autoimmune rheumatic diseases following influenza vaccination. AB - OBJECTIVES: Booster vaccination against 2009 H1N1 influenza virus was recommended for rheumatologic patients under immunosuppressive therapy during the 2009/2010 H1N1 pandemic. In this study we assessed whether B cell depletion with rituximab influences of the antiviral immune response in 2009 H1N1 influenza virus vaccinated patients. METHODS: Influenza virus-specific immune responses were analysed after the first and a booster vaccination with pandemrixTM in sixteen consecutive rituximab-treated patients with different rheumatic autoimmune disorders. Antibody titers were determined by a haemagglutination-inhibition assay and virus-specific T cell responses were evaluated by a flow cytometry based intracellular cytokine-secretion assay. Patients showing clinical symptoms of influenza infection were excluded from this study. RESULTS: Two out of seven patients with low (<10%) and four out of nine with normal (>10%) B cells developed significant antibody responses after the first vaccination. Booster vaccination led to an antibody response in one additional patient. After the first vaccination, virus-specific CD4+ and CD8+ T cell responses were significantly lower in patients with low B cells than in those with normal B cells. Of importance, the booster vaccination stimulated the antiviral T cell response only in patients with low B cells. CONCLUSIONS: In the absence of a significant effect of booster vaccinations against 2009 H1N1 influenza virus on the humoral immune response in B cell-depleted patients with autoimmune rheumatic diseases, enhanced antiviral T cell responses in patients with low B cells indicate that T cells, maybe, compensate for the impaired humoral immunity in these patients. PMID- 23806225 TI - Taxonomic comments on South American species of Philophthalmus Looss, 1899 (Trematoda: Philophthalmidae). PMID- 23806226 TI - Reply to the comment by H.A. Pinto and A.L. de Melo on "Taxonomic comments on South American species of Philophthalmus Loos, 1899 (Trematoda: Philophthalmidae)". PMID- 23806227 TI - Nano-based antileishmanial agents: a toxicological study on nanoparticles for future treatment of cutaneous leishmaniasis. AB - Cutaneous leishmaniasis (CL) is endemic in the tropical and subtropical countries. Antileishmanial drugs that are traditionally used for treatment of CL are mainly toxic, ineffective for some parasite isolates, and mostly expensive. Previous studies showed that some metal and metal oxide nanoparticles have antimicrobial activity. Moreover, the use of nanoparticles together with ultra violet (UV) and infra red (IR) light increases toxic effects of nanoparticles by generation of reactive oxygen species (ROSs) and heat, respectively. There is little information on antileishmanial activity of nanoparticles, alone or together with UV/IR. Thus, the purpose of this research was to study antileishmanial effects of some nanoparticles including silver nanoparticles (Ag NPs), gold nanoparticles (Au NPs), titanium dioxide nanoparticles (TiO2 NPs), zinc oxide nanoparticles (ZnO NPs), and magnesium oxide nanoparticles (MgO NPs) on Leishmania major parasites under UV, IR, and dark conditions. After 24h exposure to nanoparticles, different biological parameters such as cell viability, proliferation, infectivity, and infection index were investigated under UV/IR/dark conditions. In this study, the highest antileishmanial activity was seen for Ag NPs, followed by Au NPs, TiO2 NPs, ZnO NPs, and MgO NPs. Both UV and IR light increased antileishmanial properties of all nanoparticles. In spite of antileishmanial activity of nanoparticles under UV, IR, and dark conditions, these nanoparticles had high cytotoxicity on macrophages, which must be considered in future studies. The authors declare that the use of nanoparticles for treatment of CL may have both positive and negative consequences. PMID- 23806228 TI - Immunosuppression effects on airway mucociliary clearance: comparison between two triple therapies. AB - BACKGROUND: Tacrolimus and mycophenolate have now become the most widely used combination for maintenance immunosuppressive regimens after lung transplantation in comparison with cyclosporine and azathioprine. However, limited information is available with respect to their effects on cells, other than those from the immunologic compartment. We hypothesized that different triple therapies could have different effects on airway mucociliary clearance, playing an important role in respiratory infections observed after lung transplantation. METHODS: Ninety rats were assigned to three groups (n = 30 each): control = vehicle, therapy 1 = tacrolimus + mycophenolate + prednisone, and therapy 2 = cyclosporine + azathioprine + prednisone. After 7, 15, or 30 days of treatment by gavage, the animals were killed and the following parameters were studied: mucus transportability, ciliary beating frequency, mucociliary transport velocity, and neutral and acid mucus production. RESULTS: There was a significant decrease in ciliary beating frequency, mucociliary transport velocity, and neutral mucus production in all immunosuppressed animals; indeed, both therapies, mainly therapy 1, caused an increase in acid mucus production for as long as 15 days of treatment. CONCLUSIONS: Both triple therapies impaired airway mucociliary clearance of rats, but therapy 1 had a more deleterious effect. These data suggest that these undesirable effects can contribute to the high incidence of respiratory infections observed in patients undergoing lung transplantation. PMID- 23806229 TI - Short-course rapamycin treatment preserves airway epithelium and protects against bronchiolitis obliterans. AB - BACKGROUND: Damage to airway epithelium is closely related to the development of bronchiolitis obliterans (BO) in pulmonary transplantation. Rapamycin protects against BO development in a murine model, but its use in patients undergoing lung transplantation is limited by its side effects. We hypothesized that short-course rapamycin dosing could be used to prevent airway epithelium loss and protect against BO development in a murine model. METHODS: A total alloantigenic mismatch, murine, heterotopic tracheal transplant model of BO was used. Animals were treated with either rapamycin or dimethyl sulfoxide (controls) according to one of three treatment regimens: (1) days 1 through 14 after transplantation, (2) days 3 through 7 after transplantation, or (3) days 14 through 28 after transplantation. Epithelial loss was assessed by use of hematoxylin and eosin stains 14 and 28 days after transplantation. Tracheal luminal obliteration was assessed at 28 days. RESULTS: Early rapamycin treatment was protective against epithelial loss 14 days after transplantation in comparison with control animals (p < 0.001). Rapamycin treatment from days 1 to 14 was more effective at epithelial preservation (p = 0.002) and reducing luminal obliteration (p < 0.001) at 28 days than was rapamycin treatment from days 3 to 7. Late rapamycin treatment (days 14 to 28) allowed for recovery of the previously denuded epithelium at 28 days (92.5% epithelial loss to 35.6%) and a reduction in BO (p < 0.001). CONCLUSIONS: Short-course rapamycin treatment protects against airway epithelium loss and subsequent development of BO in a murine model. Because of its immunosuppressive and antifibrotic effects, rapamycin may prove to be the ideal medication to prevent chronic rejection and BO in patients undergoing lung transplantation. PMID- 23806230 TI - Enhanced characterization of ventricular performance after coarctation repair in neonates and young children. AB - BACKGROUND: Within the group of patients undergoing coarctectomy today, two subgroups can be identified: neonates with a critical coarctation and nonneonatal patients. We hypothesize that patients who have to undergo repair in the neonatal period will have more persistent impairment of ventricular performance postoperatively. Accordingly, we aimed to characterize biventricular performance after coarctectomy in neonatal and nonneonatal patients. METHODS: Children (aged 0 to 17 years) undergoing a coarctectomy were prospectively included and classified as neonatal (<1 month old) or nonneonatal patients. Age-matched controls were included for each measurement occasion. To evaluate left (LV) and right ventricular (RV) performance, fractional shortening, peak systolic (S') and early diastolic (E') tissue Doppler imaging velocities, and E/E' were assessed preoperatively, at discharge, and 1 year postoperatively (11.4 +/- 8.3 months). RESULTS: In neonatal (n = 18) and nonneonatal (n = 19) patients LV performance significantly improved within the first postoperative year. Yet 1 year postoperatively, LV S' was still lower in neonatal patients vs controls (4.8 +/- 1.1 vs 6.1 +/- 1.6 cm/s; p = 0.036), whereas comparable results were observed in nonneonatal patients and controls. One year postoperatively, LV diastolic performance was impaired in neonatal (LV E' 8.7 +/- 3.1 vs 13.2 +/- 3.9 cm/s, p = 0.005) and nonneonatal patients (LV E' 12.1 +/- 3.5 vs 15.1 +/- 2.4 cm/s, p = 0.008) vs controls. In RV performance variables, no differences were observed 1 year postoperatively between neonatal and nonneonatal patients and controls. CONCLUSIONS: In both subgroups, LV diastolic performance does not recover to normal values within the first postoperative year. However, LV systolic performance remains more persistently impaired in patients who have to undergo repair in the neonatal period vs nonneonatal repair. PMID- 23806231 TI - A dominant adenocarcinoma with multifocal ground glass lesions does not behave as advanced disease. AB - BACKGROUND: Invasive lung adenocarcinomas increasingly present with synchronous, multifocal, in situ lesions that appear as ground glass opacities (GGOs). The optimal approach in this circumstance (often nonsmokers) remains unclear. We evaluated a general strategy of anatomic resection of the dominant tumor (DT) and wedge resection of accessible ipsilateral GGOs. METHODS: This is a retrospective review of 39 patients with suspected multifocal in situ adenocarcinomas and 1 DT in a predominantly Caucasian population. Mean follow-up is 30.7 months. RESULTS: Forty-nine percent of patients had no or minimal smoking history; 21% were Asian. The resected DT was pathologically "bronchioloalveolar carcinoma" (26%), minimally invasive adenocarcinoma (5%), adenocarcinoma with bronchioloalveolar features (41%), or moderate well-differentiated adenocarcinoma (28%). The p stage of the DT was IA in 20, IB in 15, and IIA in 4, with mean diameter of 2.6 cm. Thirty-two patients (82%) underwent anatomic resection of the DT; 7 (18%) underwent wedge resection. The mean number of GGOs present initially was 2.7 (range, 1 to 7) with a 5.2-mm mean diameter. An unresected nodule increased in size during follow-up in only 9 patients (23%). The mean diameter growth among these was 3.2 mm, with mean doubling time of 49 months. New GGOs (range, 1 to 8) developed in 16 patients (41%), all of which remained at 7 mm or less. Distant metastasis developed in 2 patients (5.2%); only 1 patient has required intervention for progression of a GGO. The overall survival is 100%. CONCLUSIONS: Patients with limited, multifocal, in situ adenocarcinomas and a clinical N0 DT enjoy prolonged survival with generally anatomic resection of the DT and wedge resection of accessible GGOs. These patients should not be considered to harbor T4 or M1a disease. PMID- 23806232 TI - Importance of lymph node dissection in thymic carcinoma. AB - BACKGROUND: Lymph node dissection plays important role in oncologic surgery. We investigated outcomes of lymph node dissection in thymic carcinoma. METHODS: We retrospectively reviewed 37 patients, who underwent complete resection for thymic carcinoma. Patients were divided into four groups: no node dissection (Nx), 8; pathologic N0 by limited dissection (N0a), 13; pathologic N0 by extensive dissection (N0b), 10; and node metastasis (N1), 6. Outcomes of lymph node dissection were investigated. Disease-free survival (DFS) and freedom from recurrence of the four groups were compared. RESULTS: A total of 349 lymph nodes were dissected in 29 patients. Metastasis was confirmed in 19 nodes in 6 patients, with tumor invading adjacent organs. Anterior mediastinal lymph node metastasis was confirmed in 4 patients. Intrathoracic lymph node metastasis was confirmed in 3 patients at the right paratracheal lymph nodes. Recurrences were diagnosed in 11 patients (Nx, 2; N0a, 4; N0b, 1; N1, 4). The 5-year overall survival rate was 65.5%, DFS was 60.9%, and freedom from recurrence was 68.2%. DFS rates of the N0b subgroup were significantly better than in the N1 subgroup (90% vs 33.3%). DFS rates of the Nx and N0a subgroups were similar (75% vs 48.7%, p=0.98), and the prognoses of both groups were intermediate between the N0b and N1 groups. Analyses of freedom from recurrence proved identical results. CONCLUSIONS: Extensive lymph node dissection, meaning dissection of more than 10 lymph nodes, is required to predict prognosis accurately. Anterior mediastinal and right paratracheal lymph nodes should be dissected in thymic carcinoma. PMID- 23806233 TI - Growth of xenotransplanted leukemia cells is influenced by diet nutrients and is attenuated with 2-deoxyglucose. AB - We examined the effects of diet nutrients on xenotransplanted leukemia cells, THP 1 or NB4. THP-1 tumors showed more growth when fed with high fat diet, while NB4 tumors grew more with high carbohydrate diet. Then, administration of 2 deoxyglucose (a glycolysis inhibitor) showed a significant antitumor effect on both tumors: NB4 tumor showed large necrotic areas, while THP-1 tumor did not, but had augmented expression of enzymes for fatty acid oxidation. 2-Deoxyglucose inhibited the growth of NB4 by cell death because main energy producing pathway (glycolysis) was abolished, while 2-deoxyglucose slowed the growth of THP-1 by shifting energy metabolism to fatty acid beta-oxidation. PMID- 23806235 TI - "To switch or not to switch: that is the question"-more than 10% of ratio @ 3 months: how to treat chronic myeloid leukemia patients with this response? PMID- 23806234 TI - Live cell detection of chromosome 2 deletion and Sfpi1/PU1 loss in radiation induced mouse acute myeloid leukaemia. AB - The CBA/H mouse model of radiation-induced acute myeloid leukaemia (rAML) has been studied for decades to bring to light the molecular mechanisms associated with multistage carcinogenesis. A specific interstitial deletion of chromosome 2 found in a high proportion of rAML is recognised as the initiating event. The deletion leads to the loss of Sfpi, a gene essential for haematopoietic development. Its product, the transcription factor PU.1 acts as a tumour suppressor in this model. Although the deletion can be detected early following ionising radiation exposure by cytogenetic techniques, precise characterisation of the haematopoietic cells carrying the deletion and the study of their fate in vivo cannot be achieved. Here, using a genetically engineered C57BL/6 mouse model expressing the GFP fluorescent molecule under the control of the Sfpi1 promoter, which we have bred onto the rAML-susceptible CBA/H strain, we demonstrate that GFP expression did not interfere with X-ray induced leukaemia incidence and that GFP fluorescence in live leukaemic cells is a surrogate marker of radiation induced chromosome 2 deletions with or without point mutations on the remaining allele of the Sfpi1 gene. This study presents the first experimental evidence for the detection of this leukaemia initiating event in live leukemic cells. PMID- 23806236 TI - Expanding research to provide an evidence base for nutritional interventions for the management of inborn errors of metabolism. AB - A trans-National Institutes of Health initiative, Nutrition and Dietary Supplement Interventions for Inborn Errors of Metabolism (NDSI-IEM), was launched in 2010 to identify gaps in knowledge regarding the safety and utility of nutritional interventions for the management of inborn errors of metabolism (IEM) that need to be filled with evidence-based research. IEM include inherited biochemical disorders in which specific enzyme defects interfere with the normal metabolism of exogenous (dietary) or endogenous protein, carbohydrate, or fat. For some of these IEM, effective management depends primarily on nutritional interventions. Further research is needed to demonstrate the impact of nutritional interventions on individual health outcomes and on the psychosocial issues identified by patients and their families. A series of meetings and discussions were convened to explore the current United States' funding and regulatory infrastructure and the challenges to the conduct of research for nutritional interventions for the management of IEM. Although the research and regulatory infrastructure are well-established, a collaborative pathway that includes the professional and advocacy rare disease community and federal regulatory and research agencies will be needed to overcome current barriers. PMID- 23806237 TI - Molecular diagnostic testing for congenital disorders of glycosylation (CDG): detection rate for single gene testing and next generation sequencing panel testing. AB - Congenital disorders of glycosylation (CDG) are comprised of over 60 disorders with the majority of defects residing within the N-glycosylation pathway. Approximately 20% of patients do not survive beyond five years of age due to widespread organ dysfunction. A diagnosis of CDG is based on abnormal glycosylation of transferrin but this method cannot identify the specific gene defect. For many individuals diagnosed with CDG the gene defect remains unknown. To improve the molecular diagnosis of CDG we developed molecular testing for 25 CDG genes including single gene testing and next generation sequencing (NGS) panel testing. From March 2010 through November 2012, a total of 94 samples were referred for single gene testing and 68 samples were referred for NGS panel testing. Disease causing mutations were identified in 24 patients resulting in a molecular diagnosis rate of 14.8%. Coverage of the 24 CDG genes using panel testing and whole exome sequencing (WES) was compared and it was determined that many exons of these genes were not adequately covered using a WES approach and a panel approach may be the preferred first option for CDG patients. A collaborative effort between physicians, researchers and diagnostic laboratories will be very important as NGS testing using panels and exome becomes more widespread. This technology will ultimately improve the molecular diagnosis of patients with CDG in hard to solve cases. PMID- 23806238 TI - Hematopoietic stem cell transplantation with umbilical cord multipotent stromal cell infusion for the treatment of aplastic anemia--a single-center experience. AB - BACKGROUND AIMS: The purpose of this study was to observe the outcome of co transfusion of umbilical cord multipotent stromal cells (UC-MSC) and allogeneic hematopoietic stem cells in the treatment of heavily-transfused patients with severe aplastic anemia. METHODS: Of the 22 patients, eight cases received haploidentical hematopoietic stem cells from granulocyte colony-stimulating factor-primed bone marrow and peripheral blood grafts; the other patients received granulocyte colony-stimulating factor-mobilized peripheral blood grafts from human leukocyte antigen-matched related (six cases) and unrelated donors (eight cases). MSCs were intravenously infused at a mean dose of 1.2 * 10(6)/ kg (range, 0.27-2.5 * 10(6)/kg). Fludarabine-based conditioning was conducted, and graft-versus-host disease prophylaxis containing cyclosporine A, methotrexate and mycophenolate mofetil with or without addition of anti-CD25 monoclonal antibody was performed. Hematopoietic engraftment, the occurrence of graft-versus-host disease (GVHD) and infections and overall survival were documented. RESULTS: All patients had rapid engraftment; mean time for neutrophil and platelet recovery was 13.95 d and 20.27 d, respectively. No acute toxicity associated with UC-MSC transfusion was observed. Acute GVHD developed in seven cases (grade I-II), and none had development of chronic GVHD. Cytomegalovirus reactivation was observed in 11 cases. One patient died of pulmonary complication 6 months after transplantation. Twenty-one patients are currently alive, at a median follow-up of 15 months; they are transfusion-independent and reached full donor chimerism at the time of reporting. CONCLUSIONS: UC-MSC infusion might be an alternative option to promote hematopoietic engraftment and reduce the occurrence of GHVD in hematopoietic stem cell transplantation in the treatment of heavily transfused patients with severe aplastic anemia. PMID- 23806239 TI - Improvement of contusive spinal cord injury in rats by co-transplantation of gamma-aminobutyric acid-ergic cells and bone marrow stromal cells. AB - BACKGROUND AIMS: Cell therapy is considered a promising option for treatment of spinal cord injury (SCI). The purpose of this study is to use combined therapy of bone marrow stromal cells (BMSCs) and BMSC-derived gamma-aminobutyric acid (GABA)ergic inhibitory neurotransmitter cells (BDGCs) for the contusion model of SCI in rats. METHODS: BDGCs were prepared from BMSCs by pre-inducing them with beta-mercaptoethanol followed by retinoic acid and then inducing them by creatine. They were immunostained with BMSC, proneuronal, neural and GABA markers. The BDGCs were intraspinally transplanted into the contused rats, whereas the BMSCs were delivered intravenously. The animals were sacrificed after 12 weeks. RESULTS: The Basso, Beattie and Bresnahan test showed improvement in the animals with the combined therapy compared with the untreated animals, the animals treated with GABAergic cells only and the animals that received BMSCs. The immunohistochemistry analysis of the tissue sections prepared from the animals receiving the combined therapy showed that the transplanted cells were engrafted and integrated into the injured spinal cord; in addition, a significant reduction was seen in the cavitation. CONCLUSIONS: The study shows that the combination of GABAergic cells with BMSCs can improve SCI. PMID- 23806240 TI - Cost-effectiveness of pneumococcal conjugate vaccination in immunocompromised adults. AB - OBJECTIVE: Pneumococcal disease is a significant problem in immunocompromised persons, particularly in HIV-infected individuals. The CDC recently updated pneumococcal vaccination recommendations for immunocompromised adults, adding the 13-valent pneumococcal conjugate vaccine (PCV13) to the previously recommended 23 valent pneumococcal polysaccharide vaccine (PPSV23). This analysis estimates the cost-effectiveness of pneumococcal vaccination strategies in HIV-infected individuals and in the broader immunocompromised adult group. DESIGN: Markov model-based cost-effectiveness analysis. METHODS: The model considered immunocompromised persons aged 19-64 years and accounted for childhood PCV13 herd immunity; in a separate analysis, an HIV-infected subgroup was considered. PCV13 effectiveness was estimated by an expert panel; PPSV23 protection was modeled relative to PCV13 effectiveness. We assumed that both vaccines prevented invasive pneumococcal disease, but only PCV13 prevented nonbacteremic pneumonia. RESULTS: In all immunocompromised individuals, a single PCV13 cost $70,937 per quality adjusted life year (QALY) gained compared to no vaccination; current recommendations cost $136,724/QALY. In HIV patients, with a longer life expectancy (22.5 years), current recommendations cost $89,391/QALY compared to a single PCV13. Results were sensitive to variation of life expectancy and vaccine effectiveness. The prior recommendation was not favored in any scenario. CONCLUSIONS: One dose of PCV13 is more cost-effective for immunocompromised individuals than previous vaccination recommendations and may be more economically reasonable than current recommendations, depending on life expectancy and vaccine effectiveness in the immunocompromised. PMID- 23806241 TI - Cost-effectiveness of the prophylactic HPV vaccine: an application to the Netherlands taking non-cervical cancers and cross-protection into account. AB - Despite an effective screening programme, 600-700 women are still diagnosed with cervical cancer in the Netherlands each year. In 2009 a prophylactic vaccine against HPV-type 16 and 18 was implemented in the national immunisation programme to decrease the incidence of cervical cancer. There is evidence that infections with several oncogenic HPV types other than the vaccine types 16 and 18 are also prevented by vaccination, also known as cross-protection. Besides cervical cancer, HPV can also cause cancers at other sites such as the oropharynx, vulva, vagina and the anus/anal area. In this study we estimated the maximum health and economic benefits of vaccinating 12-year old girls against infection with HPV, taking cross-protection and non-cervical cancers into account. In the base-case, we found an incremental cost ratio (ICER) of ?5815 per quality adjusted life year (QALY). Robustness of this result was examined in sensitivity analysis. The ICER proved to be most sensitive to vaccine price, discounting rates, costs of cervical cancer and to variation in the disutility of cervical cancer. PMID- 23806242 TI - Factors associated with vaccination for hepatitis B, pertussis, seasonal and pandemic influenza among French general practitioners: a 2010 survey. AB - Our objectives were to describe the vaccine coverage (VC(1)) for some occupational vaccines (hepatitis B, pertussis, seasonal and pandemic influenza) among French General Practitioners (GPs(2)) and to study the factors associated with being vaccinated for each of these four diseases. We surveyed a representative national sample of 1431 self-employed GPs in France. Self-reported VC was 76.9% for 2009/10 seasonal influenza, 73.0% for hepatitis B, 63.9% for pertussis and 60.8% for A/H1N1 pandemic influenza. The factors associated with reporting being vaccinated were quite different from one vaccine to another. For some or all four vaccines, we found a significant positive association (p<0.05) with the following factors in the multivariate analysis: GP's male gender, high volume of activity, no particular mode of exercise (e.g. homoeopathy), no use of Internet at the practice, Continuing Medical Education sessions, discussing the benefits and risks of vaccination with the patients and performing prevention investigations for oneself (lipid profile). Being vaccinated for one vaccine also increased the VC for some or all three other studied vaccines. All these findings argue for public health campaigns using messages adapted to each vaccine. PMID- 23806243 TI - Self-report compared to electronic medical record across eight adult vaccines: do results vary by demographic factors? AB - Immunizations are crucial to the prevention of disease, thus, having an accurate measure of vaccination status for a population is an important guide in targeting prevention efforts. In order to comprehensively assess the validity of self reported adult vaccination status for the eight most common adult vaccines we conducted a survey of vaccination receipt and compared it to the electronic medical record (EMR), which was used as the criterion standard, in a population of community-dwelling patients in a large healthcare system. In addition, we assessed whether validity varied by demographic factors. The vaccines included: pneumococcal (PPSV), influenza (Flu), tetanus diphtheria (Td), tetanus diphtheria pertussis (Tdap), Human Papilloma Virus (HPV), hepatitis A (HepA), hepatitis B (HepB) and herpes zoster (shingles). Telephone surveys were conducted with 11,760 individuals, >=18, half with documented receipt of vaccination and half without. We measured sensitivity, specificity, positive and negative predictive value, net bias and over- and under-reporting of vaccination. Variation was found across vaccines, however, sensitivity and specificity did not vary substantially by either age or race/ethnicity. Sensitivity ranged between 63% for HepA to over 90% (tetanus, HPV, shingles and Flu). Hispanics were 2.7 times more likely to claim receipt of vaccination compared to whites. For PPSV and Flu those 65+ had low specificity compared to patients of younger ages while those in the youngest age group had lowest specificity for HepA and HepB. In addition to racial/ethnic differences, over-reporting was more frequent in those retired and those with household income less than $75,000. Accurate information for vaccination surveillance is important to estimate progress toward vaccination coverage goals and ensure appropriate policy decisions and allocation of resources for public health. It was clear from our findings that EMR and self-report do not always agree. Finding approaches to improve both EMR data capture and patient awareness would be beneficial. PMID- 23806244 TI - Trends in serotypes and sequence types among cases of invasive pneumococcal disease in Scotland, 1999-2010. AB - INTRODUCTION: The 7-valent pneumococcal conjugate vaccine (Prevenar((r)), Wyeth; PCV7) was introduced to the UK paediatric immunisation schedule in 2006. This study investigates trends in serotypes and multi locus sequence types (STs) among cases of invasive pneumococcal disease (IPD) in Scotland prior to, and following, the introduction of PCV7. METHODS: Scottish Invasive Pneumococcal Disease Enhanced Surveillance has records of all cases of IPD in Scotland since 1999. Cases diagnosed from blood or cerebrospinal fluid isolates until 2010 were analysed. Logistic and poisson regression modelling was used to assess trends prior to and following the introduction of PCV7. RESULTS: Prior to PCV7 use, on average 650 cases of IPD were reported each year; 12% occurred in those aged <5 years and 35% affected those aged over 65 years. Serotypes in PCV7 represented 47% of cases (68% in <5 year olds). The serotype and ST distribution was relatively stable with only serotype 1 and associated ST 306 showing an increasing trend. PCV7 introduction was associated with a 69% (95% CI: 50%, 80%) reduction in the incidence of IPD among those aged <5 years, a 57% (95% CI: 47%, 66%) reduction among those aged 5-64 years but no significant change among those aged 65 years and over where increases in non-PCV7 serotypes were observed. Serotypes which became more prevalent post-PCV7 are those which were associated with STs related to the PCV7 serotypes. CONCLUSIONS: Routine serotyping and sequence typing in Scotland allowed the assessment of the relationship between the capsule and the clones in the post vaccination era. Changes in the distribution of serotypes post PCV7 introduction appear to be driven by associations between serotypes and STs prior to PCV7 introduction. This has implications for the possible effects of the introduction of higher valency vaccines and could aid in predicting replacement serotypes in IPD. PMID- 23806245 TI - Proteins as T cell antigens: methods for high-throughput identification. AB - Vaccines are the most cost-effective means of preventing infectious diseases and have the potential to be used in a therapeutic capacity for the treatment of numerous chronic diseases and cancer. The majority of available vaccines function by eliciting antibodies that can neutralize toxins or opsonize the pathogen leading to elimination by professional phagocytes. However, there are many infectious and non-infectious diseases for which there are no available vaccines or the current antibody-mediated vaccines offer insufficient protection. There is emerging evidence that successful protection for these conditions requires the stimulation of T cell responses in addition to antibody. Genome/proteome-wide screening of pathogens to identify appropriate antibody targets for inclusion in vaccines has become widely used in recent years. However, the application of high throughput proteomic screening approaches to identify T cell antigens has substantially lagged behind, primarily due to the lack of methods to identify full protein targets of T cell immunity across a broad human population. In this review, we will discuss some of the significant advances that have been made in high-throughput identification of T cell antigens for the development of novel efficacious vaccines. PMID- 23806246 TI - Predicting laryngeal edema in intubated patients by portable intensive care unit ultrasound. AB - PURPOSE: The purpose of this study is to determine the diagnostic accuracy of portable ultrasound for detection of laryngeal edema (LE) in intubated patients. MATERIALS AND METHODS: We conducted a prospective, observational study from December 2010 to September 2011. We measured air column width differences (ACWD) in planned extubation patients admitted in intensive care unit by ultrasound. The primary outcome was the diagnostic accuracy of ACWD to predict the presence of LE. RESULTS: A total of 101 patients were enrolled. The prevalence of LE was 16.8%. Baseline characteristics were similar between intubated patients with and without LE. The mean difference of increasing of air column width in patients without LE was higher than in LE group (1.9 vs 1.08 mm, P<.001). The sensitivity and specificity at ACWD higher or equal to 1.6 mm were 0.706 and 0.702, respectively. The positive predictive value and negative predictive value were 0.324 and 0.922, respectively. The area under the receiver operating characteristic curve of laryngeal ultrasound was 0.823 (95% confidence interval, 0.698-0.947) and that of cuff leak test was 0.840 (95% confidence interval, 0.715 0.964). CONCLUSION: Portable intensive care unit ultrasound visualizing ACWD between predeflation and postdeflation cuff balloon is a promising objective tool, which aids in prediction of successful extubation regarding LE. PMID- 23806247 TI - Acute respiratory distress syndrome: underrecognition by clinicians. AB - BACKGROUND: Previous reports suggest that acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is underdiagnosed in both adult and pediatric clinical practice. Underrecognition of this condition may be a barrier to instituting a low tidal volume ventilation strategy. This study aimed to determine the accuracy of clinical diagnoses of ARDS in daily practice using the American European Consensus Conference (AECC) criteria as a criterion standard and to investigate whether clinical recognition of ARDS altered ventilator management. METHODS: This retrospective study included intensive care unit (ICU) patients who died and underwent postmortem examination. Two independent reviewers assigned each patient to those with ALI/ARDS or no ALI. For those who met AECC criteria for ARDS, all patient records were reviewed for the presence of a documented diagnosis of the condition. The accuracy of the clinicians in diagnosing ALI/ARDS was determined, and ventilator settings between the clinically "diagnosed" and "non-diagnosed" groups were compared. The diagnostic accuracy in predetermined subgroups (those with diffuse alveolar damage, with >=3 affected chest x-ray quadrants, with diagnosis>=3 days, with pulmonary vs extrapulmonary cause) was also examined. RESULTS: Of 98 consecutive ICU patients who died and underwent autopsy, 51 met the inclusion criteria. Sixteen of 51 patients (31.3%) who had ALI/ARDS according to the AECC criteria had this recorded in their clinical notes. Those with histologic evidence of ALI/ARDS (diffuse alveolar damage) and with a more severe chest x-ray pattern or who satisfied the criteria for a number of consecutive days were no more likely to have a clinical diagnosis of ALI/ARDS recorded. However, those with a pulmonary cause of ALI/ARDS were more likely to have a diagnosis recorded. Tidal volumes, positive end-expiratory pressure, and mean airway pressure were higher in those with a clinical diagnosis of ARDS. CONCLUSIONS: Acute respiratory distress syndrome is underrecognized by clinicians in ICU, and recognition does not result in lower tidal volume ventilation. Significant barriers remain to the recognition of ALI/ARDS and application of an evidence-based ventilator strategy. PMID- 23806248 TI - Use of second-line therapies for management of massive primary postpartum hemorrhage. AB - OBJECTIVE: To determine rates of use and success of second-line therapies for massive primary postpartum hemorrhage (PPH). METHODS: A retrospective cohort study was conducted among 91 women who gave birth at Kwong Wah Hospital, Hong Kong, between January 1, 2006, and December 31, 2011. Inclusion criteria were gestational age of at least 24 weeks and massive PPH (defined as blood loss >=1500 mL within 24 hours after birth). Second-line therapies assessed were uterine compression sutures, uterine artery embolization, and balloon tamponade after failure of uterine massage and uterotonic agents to stop bleeding. RESULTS: The rate of massive PPH was 2.65 per 1000 births. Second-line therapies were used among 42 women with PPH, equivalent to a rate of 1.23 per 1000 births. Only 21.4% of the women who received second-line therapies required rescue hysterectomy. A rising trend was observed for the use of second-line therapies, whereas the incidence of rescue hysterectomy and estimated blood loss were found to concomitantly decrease. CONCLUSION: Increasing use of second-line therapies among women with massive PPH was associated with a decreasing trend for rescue hysterectomy. Obstetricians should, therefore, consider all available interventions to stop PPH, including early use of second-line options. PMID- 23806249 TI - Recent parvovirus B19 infection in late pregnancy. PMID- 23806250 TI - A systematic review and thematic synthesis of qualitative studies on maternal emergency transport in low- and middle-income countries. AB - BACKGROUND: Most maternal deaths are preventable with emergency obstetric care; therefore, ensuring access is essential. There is little focused information on emergency transport of pregnant women. OBJECTIVES: The literature on emergency transport of pregnant women in low- and middle-income countries (LMICs) was systematically reviewed and synthesized to explore current practices, barriers, and facilitators for transport utilization. SEARCH STRATEGY: MEDLINE, EMBASE, BNI, Cochrane Library, CINAHL, African Index Medicus, ASSIA, QUALIDATA, RHL, and Science Citation Index (inception to April 2012) were searched without language restriction. SELECTION CRITERIA: Studies using qualitative methodology and reporting on emergency transportation in LMICs were included. DATA COLLECTION AND ANALYSIS: Thematic framework and synthesis through examination and translation of common elements were used to analyze and synthesize the data. MAIN RESULTS: Twenty-nine articles were included. Eight major themes were identified: time for transport; transport options; geography; local support; autonomy; culture; finance; and ergonomics. Key issues were transport availability; transport speed; terrain; meteorology; support; dependence for decision making; cultural issues; cost; and lack of safe, comfortable positioning during transport. CONCLUSION: Themes should be appreciated within local contexts to illuminate barriers and facilitators. Potential solutions include motorcycle ambulance programs, collaboration with taxi services, community education, subsidies, and vehicle maintenance. PMID- 23806251 TI - Wet-chemical synthesis and consolidation of stoichiometric bismuth telluride nanoparticles for improving the thermoelectric figure-of-merit. AB - Bismuth telluride nanoparticles (NPs) have been synthesized using a low temperature wet-chemical approach from bismuth(III) oleate and tri-n octylphosphine telluride. The size and shape of the NPs can be controlled by adjusting the temperature, reaction time, and nature of the surfactants and solvents. Aromatic hydrocarbons (toluene, xylenes) and ethers (phenyl- and benzyl ether) favor the formation of stoichiometric Bi2Te3 NPs of platelike morphology, whereas the presence of oleylamine and 1-dodecanethiol yields Bi-rich Bi2Te3 spherical NPs. XRD, IR, SEM, TEM, and SAED techniques have been used to characterize the obtained products. We show that the surfactants can be efficiently removed from the surface of the NPs using a two-step process employing nitrosonium tetrafluoroborate and hydrazine hydrate. The surfactant free NPs were further consolidated into high density pellets using cold-pressing and field-assisted sintering techniques. The sintered surfactant-free Bi2Te3 showed electrical and thermal properties comparable to Bi2Te3 materials processed through conventional solid state techniques, and greatly improved over other nanostructured Bi2Te3 materials synthesized by wet-chemical approaches. PMID- 23806252 TI - The protective effect of low-dose methotrexate on ischemia-reperfusion injury of the rabbit spinal cord. AB - Methotrexate was developed as a cytostatic agent, but at low doses, it has shown potent anti-inflammatory activity. Previous studies have demonstrated that the anti-inflammatory effects of methotrexate are primarily mediated by the release of adenosine. In this study, we hypothesized that low-dose methotrexate has protective effects in spinal cord ischemia-reperfusion injury. Rabbits were randomized into the following four groups of eight animals each: group 1 (control), group 2 (ischemia), group 3 (methylprednisolone) and group 4 (methotrexate). In the control group only a laparotomy was performed. In all the other groups, the spinal cord ischemia model was created by the occlusion of the aorta just caudal to the renal artery. Neurological evaluation was performed with the Tarlov scoring system. Levels of myeloperoxidase, malondialdehyde and catalase were analyzed, as were the activities of xanthine oxidase and caspase-3. Histopathological and ultrastructural evaluations were also performed. After ischemia-reperfusion injury, increases were found in the serum and tissue myeloperoxidase levels, tissue malondialdehyde levels, xanthine oxidase activity and caspase-3 activity. In contrast, both serum and tissue catalase levels were decreased. After the administration of a low-dose of methotrexate, decreases were observed in the serum and tissue myeloperoxidase levels, tissue malondialdehyde levels, xanthine oxidase activity and caspase-3 activity. In contrast, both the serum and tissue catalase levels were increased. Furthermore, low-dose methotrexate treatment showed improved results concerning the histopathological scores, the ultrastructural score and the Tarlov scores. Our results revealed that low-dose methotrexate exhibits meaningful neuroprotective activity following ischemia-reperfusion injury of the spinal cord. PMID- 23806253 TI - Retrograde popliteal approach for challenging occlusions of the femoral-popliteal arteries. AB - OBJECTIVE: Antegrade ipsilateral subintimal angioplasty for recanalization of the superficial femoral arteries (SFAs) has a failure rate of 10%-20%. We report our initial experiences performing recanalization of the SFA or popliteal artery (PA) in cases of failed antegrade angioplasty using a medial infracondylar retrograde popliteal approach with the patient supine. METHODS: Between February 2010 and December 2011, 19 patients with chronic total occlusion of the SFA and/or proximal PA (mean occlusion length, 20.5 +/- 5.54 cm) underwent transpopliteal procedures after failure of an antegrade procedure. Upon failure to re-enter the true lumen distal to the occlusion during initial antegrade recanalization with the patient supine, a medial retrograde popliteal access at the infracondylar plane was adopted, without turning the patient (with the leg in a 60 degrees external rotation and the knee in a gentle flexion). Puncture of the distal PA was guided fluoroscopically and a guidewire was inserted into the true lumen, after which retrograde recanalization proceeded in accordance with standard protocol. Once the occlusion was crossed from distal to proximal, the wire was advanced through a 6F sheath in the common femoral artery. The preferred approach for angioplasty and stenting was from the femoral artery. Hemostasis at the popliteal access was achieved by combined intraluminal balloon dilatation and manual compression (3-5 minutes). The mean follow-up period was 8.6 +/- 4.1 months and included measuring the ankle-brachial index and duplex ultrasound. RESULTS: Technical success (puncture of the PA and SFA recanalization) was achieved in all cases. All but one patient received stent implantation from the antegrade approach. Sheaths were used in five (26%) patients; four patients were treated with a 4F sheath and one with a 6F sheath. There was one (5.26%) major complication (a popliteal access site occlusion) and two (10.5%) minor complications (small hematomas in the popliteal region). The primary patency at 6 months was 84.2%. CONCLUSIONS: The medial infracondylar retrograde popliteal approach with the patient in the supine position can be considered safe and efficient for recanalization of the SFA or proximal PA after failure of an antegrade approach. PMID- 23806254 TI - Invited commentary. PMID- 23806255 TI - Progression of asymptomatic carotid stenosis despite optimal medical therapy. AB - BACKGROUND: Despite level 1 evidence in support of carotid endarterectomy vs medical therapy in selected asymptomatic patients, an alternative posture is that optimal medical therapy (OMT) has not been adequately studied and that such OMT has reduced stroke risk in asymptomatic patients to levels wherein carotid endarterectomy is no longer justified. The goal of this study was to determine the natural history of patients with asymptomatic moderate (50%-69%) carotid artery stenosis (AMCAS) in a contemporary cohort as a function of their associated medical therapy. METHODS: Patients with AMCAS determined by duplex ultrasound (DUS) from 2005-2006 were identified in our hospital database. Patients were included in the cohort if they had at least one additional DUS during the 6-year follow-up interval. Patient characteristics including medication history and lipid levels were collected. Patients were considered to have OMT if they were on aspirin and a statin with a low-density lipoprotein level that was always <100 mg/dL. Study end points included progression of carotid disease by DUS to severe stenosis (70%-100%), development of ipsilateral neurologic symptoms (INS) such as stroke or transient ischemic attack, and death. RESULTS: There were 900 carotid arteries in 794 patients in the study cohort. The average age was 72.5 years, 77.2% had hypertension, 59.6% had coronary artery disease, and 87.1% were on a statin throughout the study. The low-density lipoprotein cholesterol level was always normal (<100 mg/dL) in 37.8% and accordingly, 241 (30.3%) had OMT as defined above. The 5-year actuarial survival was 81.9% +/- 1.3% with no advantage seen with OMT. Multivariate analysis of survival showed statins were protective (hazard ratio [HR], 0.50; confidence interval [CI], 0.34-0.73; P = .0004). The 5-year freedom from plaque progression was 61.2% +/- 2.1% with no benefit from OMT vs the control group. Multivariate predictors of plaque progression were chronic kidney disease (HR, 2.1; CI, 1.2 3.7; P = .009), aspirin use (HR, 1.9; CI, 1.2-3.0; P = .01), and the use of calcium channel blockers (HR, 1.4; CI, 1.1-1.8; P = .007). There were 90 (11.3%) patients who developed INS during follow-up (58% of these were strokes), and the 5-year freedom from INS was 88.4% +/- 1.5%. Multivariate predictors of INS were diabetes (HR, 2.3; CI, 1.5-3.6; P = .0002) and warfarin use (HR, 1.9; CI, 1.2 2.9; P = .009); while statin use (HR, 0.37; CI, 0.22-0.65; P = .0005) was protective against symptom development. CONCLUSIONS: At the 5-year of follow-up, OMT failed to prevent carotid disease progression or development of ipsilateral symptoms in 45% of patients with AMCAS. PMID- 23806256 TI - Bronchial artery aneurysm. PMID- 23806257 TI - A completely aberrant aortic arch. PMID- 23806259 TI - The role of diameter versus volume as the best prognostic measurement of abdominal aortic aneurysms. AB - Accurate measurement of abdominal aortic aneurysms is necessary to predict rupture risk and, more recently, to follow aneurysm sac behavior following endovascular repair. Up until this point, aneurysm diameter has been the most common measurement utilized for these purposes. Although aneurysm diameter is predictive of rupture, accurate measurement is hindered by such factors as aortic tortuosity and interobserver variability, and it does not account for variations in morphology such as saccular aneurysms. Additionally, decreases in aneurysm diameter do not completely describe the somewhat complex remodeling seen following endovascular repair of aortic aneurysms. Measurement of aneurysm volume has the advantage of describing aneurysm morphology in a multidimensional fashion, but it has not been readily available or easily measured until recently. This has changed with the introduction of commercially available software tools that permit quicker and easier to perform volume measurements. Whether it is time for volume to replace, or compliment, diameter is the subject of the current debate. PMID- 23806258 TI - Simulation-based training to teach open abdominal aortic aneurysm repair to surgical residents requires dedicated faculty instruction. AB - OBJECTIVE: We assessed the impact of abdominal aortic aneurysm (AAA)-specific simulation training on resident performance in simulated open AAA repair (SOAAAR) and determined whether simulation training required dedicated faculty instruction. METHODS: We randomized 18 residents (postgraduate years 3-5) to an AAA simulation course consisting of two mandatory practice sessions proctored either by a surgical skills lab coordinator (Group A, n = 8) or by a vascular surgery faculty instructor (Group B, n = 10). All residents received a detailed manual and video demonstrating the technique of open AAA repair. Using a validated tool, vascular faculty who were blinded to resident identity, level of training, and randomization status graded SOAAAR performance via videos that were recorded before and after the course. RESULTS: Characteristics and baseline scores between Groups A and B were not different. Postcourse, there was a no significant improvement in performance in Group A. Group B performance was improved significantly from baseline with regard to task-specific checklist scores (44.1 +/- 6.3 vs 34.9 +/- .5; P = .02), global rating scores (28.4 +/- .6 vs 25.3 +/- 5.0; P = .049), and overall assessment of operative competence (P = .02). Time to complete SOAAAR improved in both groups (P = .02). Baseline performance varied significantly with year of training as measured by task specific checklist scores, global rating scores, final product analysis, time to complete repair, and overall operative competence. Improvement varied inversely with year of training (P < .05) and postcourse scores were equivalent for postgraduate year 3-5 residents. CONCLUSIONS: An AAA-specific simulation training course improved resident performance in simulated open AAA repair. Dedicated faculty instruction during the simulation training was required for significant improvement in resident performance. The impact of simulation training was greatest in more junior residents. Procedure-specific simulation training with dedicated faculty can be used to effectively teach simulated open AAA repair. PMID- 23806260 TI - Editors' commentary. PMID- 23806261 TI - Why glucocorticoid withdrawal may sometimes be as dangerous as the treatment itself. AB - Glucocorticoid therapy is widely used, but withdrawal from glucocorticoids comes with a potential life-threatening risk of adrenal insufficiency. Recent case reports document that adrenal crisis after glucocorticoid withdrawal remains a serious problem in clinical practice. Partly due to difficulties in inter-study comparison the true prevalence of glucocorticoid-induced adrenal insufficiency is unknown, but it might be somewhere between 46 and 100% 24h after glucocorticoid withdrawal, 26-49% after approximately one week, and some patients show prolonged suppression lasting months to years. Adrenal insufficiency might therefore be underdiagnosed in clinical practice. Clinical data do not permit accurate estimates of a lower limit of glucocorticoid dose and duration of treatment, where adrenal insufficiency will not occur. Due to individual variation, neither the glucocorticoid dose nor the duration of treatment can be used reliably to predict adrenal function after glucocorticoid withdrawal. Also the recovery rate of the adrenal glands shows individual variation, which may be why there is currently insufficient evidence to prove the efficacy and safety of different withdrawal regimens. Whether a patient with an insufficient response to an adrenal stimulating test develops clinically significant adrenal insufficiency depends on the presence of stress and resulting glucocorticoid demand and it is thus totally unpredictable and can change relative fast. Adrenal insufficiency should therefore always be taken seriously. Individual variation in hypothalamic pituitary-adrenal axis function might be due to differences in glucocorticoid sensitivity and might be genetic. Further awareness of the potential side effect of withdrawal of glucocorticoid and further research are urgently needed. PMID- 23806262 TI - Modified total thigh musculocutaneous flap: 'operation of last resort' for massive pressure ulcers. AB - Massive bilateral pressure ulcers of dependent areas may complicate spinal cord injuries. These may be life threatening to patients and challenging for reconstructive surgeons. In massive recurrent ulcers, local tissue is either inadequate or previously exhausted. The total thigh musculocutaneous flap is an operation of last resort; we present a new variation of this procedure and a case of life threatening pressure ulcers with underlying osteomyelitis. A paraplegic patient had recurrent, extensive, bilateral pressure areas with some preserved tissue bridges. The nature of the pressure areas and lack of local options in this patient required modification of previously described total thigh flaps. An extended total thigh flap was partially de-epithelialised to fill the extensive sacral defect and a tunnelled extension was fashioned to cover the contralateral trochanteric defect. The timing of surgery was determined by balancing pre operative nutritional optimisation against life-threatening drug resistance of infective organisms. The total thigh flap can close massive bilateral pressure ulcers. Modifications are presented which preserve viable local tissue and demonstrate the versatility of this technique. It remains a 'last-resort' salvage procedure. PMID- 23806263 TI - Clinical significance of carcinoembryonic antigen in peritoneal lavage from patients with gastric cancer. AB - BACKGROUND: Peritoneal carcinomatosis is the most common pattern of recurrence of gastric cancer, and it is important to identify patients at high risk for recurrence. Although the carcinoembryonic antigen level in peritoneal lavage (pCEA) was reported to be a useful biomarker to predict peritoneal recurrence in a small series, its clinical significance has not been fully validated. We evaluated the clinical significance of pCEA in a large cohort of patients with gastric cancer. METHODS: We prospectively analyzed the pCEA level in 597 patients with histologically proven gastric cancer who underwent laparotomy. RESULTS: A significant relationship was demonstrated between the value of pCEA and clinicopathologic features, such as the peritoneal lavage cytology, peritoneal metastasis, the depth of tumor invasion, and the lymph node metastasis. The cutoff value was set at 100 ng/g of protein, and 134 of the 462 patients who underwent curative surgery had positive pCEA findings. The overall and the intraperitoneal-recurrence-related survival of patients positive for pCEA were significantly poorer than those of pCEA-negative patients. When we analyzed the patients with pathologic stage I through III gastric cancers separately, the pCEA positive patients had poorer prognoses than the pCEA-negative patients who had stage III gastric cancer. In a univariate analysis, the tumor size, depth of tumor invasion, lymph node metastasis, histologic type, serum CEA (sCEA), and pCEA were found to affect the patients' outcomes, although a multivariate analysis found only the extent of lymph node metastasis to be an independent prognostic factor. CONCLUSION: The pCEA level is a useful biomarker to predict gastric cancer-related death. Moreover, the pCEA level may be useful to identify a cohort of patients with gastric cancer who need more intensive adjuvant chemotherapy to improve their prognoses. PMID- 23806265 TI - Psychometric characteristics of the Italian version of the revised Fibromyalgia Impact Questionnaire using classical test theory and Rasch analysis. AB - OBJECTIVES: The aim of this study was to perform a psychometric analysis of the Italian Fibromyalgia Impact Questionnaire Revised version (FIQR), using both classical test theory (CTT) and Rasch analysis (RA) in order to better analyse its construct validity and provide a rational basis for a possible improvement of its metric quality. METHODS: The study involved 503 patients with fibromyalgia (FM) (423 women and 80 men) with mean age of 51.3+/-10.1 years (range 19-74) and mean duration of symptoms of 11.1+/-8.7 years (range 1-30). All patients completed the Italian FIQR during their clinical visit. The translation and cultural adaptation process of the Italian FIQR followed the published guidelines and no local adjustments were made except for a slight adaptation of item 13 related to 'energy'. RESULTS: Factor Analysis revealed two salient dimensions: function (items 1-9) and symptoms (items 12-21). RA was thus performed on these two subscales. Rating scale diagnostics suggested collapsing the eleven rating categories of the scale into five. After combining these rating categories, RA showed that most items of each of the two subscales fitted the respective constructs to measure (MnSq 0.7-1.3). The reliability levels of the two subscales were higher than 0.80. CONCLUSIONS: This study provides psychometric evidence of the reliability, internal validity and two-dimensional structure of the FIQR in a FM population. Our results support the use of two separate subscales for 'function' and 'symptoms', and provide a useful starting point for further refinement of the scale. PMID- 23806264 TI - miR-335 and miR-363 regulation of neuroblastoma tumorigenesis and metastasis. AB - BACKGROUND: microRNA (miRNA) functions broadly as post-transcriptional regulators of gene expression, and disproportionate miRNAs can result in dysregulation of oncogenes in cancer cells. We have previously shown that gastrin-releasing peptide receptor (GRP-R) signaling regulates tumorigenicity of neuroblastoma cells. Herein, we sought to characterize miRNA profile in GRP-R silenced neuroblastoma cells, and to determine the role of miRNAs on tumorigenicity and metastatic potential. METHODS: Human neuroblastoma cell lines, BE(2)-C and SK-N SH, were used for our study. Stably transfected GRP-R silenced cells were assessed for miRNA profiles. Cells were transfected with miR-335, miR-363, or miR CON, a nontargeting control, and in vitro assays were performed. In vivo functions of miR-335 and miR-363 were also assessed in a spleen-liver metastasis murine model. RESULTS: GRP-R silencing significantly increased expression of miR 335 and miR-363 in BE(2)-C cells. Overexpression of miR-335 and miR-363 decreased tumorigenicity as measured by clonogenicity, anchorage-independent growth, and metastasis determined by cell invasion assay and liver metastasis in vivo. CONCLUSION: We report, for the first time, that GRP-R-mediated tumorigenicity and increased metastatic potential in neuroblastoma are regulated, in part, by miR 335 and miR-363. A better understanding of the anti-tumor functions of miRNAs could provide valuable insights to discerning molecular mechanisms responsible for neuroblastoma metastasis. PMID- 23806266 TI - The genetic architecture of 3'untranslated region of the MICA gene: polymorphisms and haplotypes. AB - In this study, the 3'untranslated region (3'UTR) of MHC class I chain-related gene A (MICA) were investigated in 104 healthy, unrelated Han individuals recruited from northern China, using PCR-sequencing method. Nine polymorphic sites were detected, which were in very strong linkage disequilibrium with each other .Seven different MICA 3'UTR alleles were identified, among which UTR1 predominated (0.6971),followed by UTR2 (0.2356). Twenty-one extended haplotypes incorporating the 3'UTR and MICA exons 2-5 were observed in this population. Phylogenetic analysis revealed the existence of two MICA lineages, each with multiple subsets. The 2 lineages were primarily linked to UTR1 and UTR2 in the 3'UTR, respectively. Ewens-Watterson homozygosity statistics at MICA coding and 3'UTR regions were consistent with neutral expectations. Our data provided for the first time the data of genetic variation in the 3'UTR of MICA gene in human populations. The findings are valuable for future studies of the mechanisms underlying MICA post-transcriptional regulation, and will inform studies of evolution of the MHC gene complex. PMID- 23806267 TI - Race and sex-based differences in cytokine immune responses to smallpox vaccine in healthy individuals. AB - We assessed the effects of sex, race and ethnicity on smallpox vaccine-induced immune responses in 1071 armed forces members after primary Dryvax((r)) smallpox vaccination, including 790 males and 281 females; 580 Caucasians, 217 African Americans, and 217 Hispanics. Analysis of vaccinia-specific cytokine responses revealed that Caucasians had higher total IFNgamma ELISPOT responses (median 57 spot-forming units/SFUs per 200,000 cells, p=0.01) and CD8(+)IFNgamma ELISPOT responses (12 SFUs, p<0.001) than African-Americans (51 and 4 SFUs, respectively) and Hispanics (47 and 8 SFUs, respectively). Similarly, Caucasians secreted higher levels of vaccinia-specific IL-2 (p=0.003) and IFNalpha (p<0.001) compared to other racial/ethnic groups. Males had higher total IFNgamma ELISPOT responses (median 55 SFUs) compared to females (41 SFUs, p<0.001). We observed statistically significant sex-related differences in the secretion of IL-2 (p<0.001), IL-1beta (p<0.001) and IL-10 (p=0.017). These data suggest that vaccinia-specific cytokine responses following primary smallpox vaccination are significantly influenced by race and sex of vaccinees. PMID- 23806268 TI - Haplotypes of the IL-1 gene cluster are associated with gastroesophageal reflux disease and Barrett's esophagus. AB - OBJECTIVES: Gastroesophageal reflux (GERD) is a one of the major public health problem that can lead to reflux esophagitis (RE), Barrett's esophagus (BE), and esophageal adenocarcinoma (EAC). The aim of our study was to determine the impact of IL-1 gene polymorphisms on the development of GERD, RE and BE. METHODS: Three hundred and thirty-three Czech patients with gastroesophageal reflux and 165 healthy controls were included in this case-control study. Four polymorphisms in the genes of the IL-1 cluster [IL-1A(-889C/T), IL-1B(-511C/T), IL-1B(+3953C/T), and IL-1RN(VNTR)] were analyzed. RESULTS: Significant differences were found in IL-1RN 1/2 genotype between patients with GERD/RE and controls and in IL-1B+3953 T allele between patients with BE and healthy subjects. In addition, complex analysis revealed differences in IL-1 haplotype frequencies between the groups. Specifically, the haplotype TCCL was significantly more frequent (p = 0.016) in GERD patients than in controls and the haplotype CCCL more frequent (p = 0.008) in RE patients than in controls. However, in patients with BE, frequency of haplotype TCTL was lower (p = 0.05) and haplotypes CTCL and TCCL were higher (p = 0.03 and p = 0.02) in comparison with the controls. CONCLUSIONS: Our results suggest that IL-1 haplotypes may be associated with susceptibility to GERD, RE and BE. PMID- 23806270 TI - Six-locus high resolution HLA haplotype frequencies derived from mixed-resolution DNA typing for the entire US donor registry. AB - We have calculated six-locus high resolution HLA A~C~B~DRB3/4/5~DRB1~DQB1 haplotype frequencies using all Be The Match((r)) Registry volunteer donors typed by DNA methods at recruitment. Mixed resolution HLA typing data was inputted to a modified expectation-maximization (EM) algorithm in the form of genotype lists generated by interpretation of primary genomic typing data to the IMGT/HLA v3.4.0 allele list. The full cohort consists of 6.59 million subjects categorized at a broad race level. Overall 25.8% of the individuals were typed at the C locus, and 5.2% typed at the DQB1 locus, while all individuals were typed for A, B, DRB1. We also present a subset of 2.90 million subjects with detailed race/ethnic information mapped to 21 population subgroups, 64.1% of which have primary DNA typing data across at least A, B, and DRB1 loci. Sample sizes at the detailed race level range from 1,242,890 for European Caucasian to 1,376 Alaskan Native or Aleut. Genetic distance measurements show high levels of HLA genetic divergence among the 21 detailed race categories, especially among the eight Asian-American populations. These haplotype frequencies will be used to improve match predictions for donor selection algorithms for hematopoietic stem cell transplantation and improve the accuracy in modeling registry match rates. PMID- 23806269 TI - An HLA-modified ovarian cancer cell line induced CTL responses specific to an epitope derived from claudin-1 presented by HLA-A*24:02 molecules. AB - In an attempt to induce cytotoxic T lymphocytes (CTLs) that react to ovarian cancer cells, we isolated a CTL clone that specifically recognizes claudin-1 in an HLA-A*24:02-restricted manner. Naive CD8(+) T lymphocytes were obtained from a healthy adult donor and stimulated twice in vitro with HLA-modified TOV21G cells that were originally derived from an ovarian clear-cell carcinoma line. The TOV21G modification involved RNAi-mediated gene silencing of intrinsic HLA molecules and lentiviral transduction of a synonymously mutated HLA-A*24:02. Then, cDNA library construction using mRNA extracted from the parental TOV21G cells and subsequent expression cloning were conducted. These experiments revealed that a CTL clone obtained from the bulk culture recognized a minimal epitope peptide RYEFGQALF, which was derived from an autoantigen claudin-1 presented by HLA-A*24:02 molecules. This clone exhibited cytolytic activities against three ovarian cancer cell lines and normal bronchial epithelial cells in an HLA-A*24:02-restricted manner. Our data indicate that HLA-modified cancer cells can be used as an artificial antigen-presenting cell to generate antigen specific CTLs in a manner restricted by an HLA allele of interest. PMID- 23806271 TI - Effects of aging on face identification and holistic face processing. AB - Several studies have shown that face identification accuracy is lower in older than younger adults. This effect of aging might be due to age differences in holistic processing, which is thought to be an important component of human face processing. Currently, however, there is conflicting evidence as to whether holistic face processing is impaired in older adults. The current study therefore re-examined this issue by measuring response accuracy in a 1-of-4 face identification task and the composite face effect (CFE), a common index of holistic processing, in older adults. Consistent with previous reports, we found that face identification accuracy was lower in older adults than in younger adults tested in the same task. We also found a significant CFE in older adults that was similar in magnitude to the CFE measured in younger subjects with the same task. Finally, we found that there was a significant positive correlation between the CFE and face identification accuracy. This last result differs from the results obtained in a previous study that used the same tasks and which found no evidence of an association between the CFE and face identification accuracy in younger adults. Furthermore, the age difference was found with subtraction-, regression-, and ratio-based estimates of the CFE. The current findings are consistent with previous claims that older adults rely more heavily on holistic processing to identify objects in conditions of limited processing resources. PMID- 23806272 TI - Effect of different contents of extruded linseed in the sow diet on piglet fatty acid composition and hepatic desaturase expression during the post-natal period. AB - n-3 polyunsaturated fatty acids (n-3 PUFA) contribute to the normal growth and development of numerous organs in the piglet. The fatty acid composition of piglet tissues is linked to the fatty acid composition of sow milk and, consequently, to the composition of sow diet during the gestation and lactation period. In this study, we investigated the impact of different contents of extruded linseed in the sow diet on the fatty acid composition and desaturase gene expression of piglets. Sows received a diet containing either sunflower oil (low 18:3n-3 with 18:3n-3 representing 3% of total fatty acids) or a mixture of extruded linseed and sunflower oil (medium 18:3n-3 with 9% of 18:3n-3) or extruded linseed (high 18:3n-3 with 27% of 18:3n-3) during gestation and lactation. Fatty acid composition was evaluated on sow milk and on different piglet tissues at days 0, 7, 14, 21 and 28. The postnatal evolution of delta5 (D5D) and delta6 (D6D) desaturase mRNA expression was also measured in the liver of low 18:3n-3 and high 18:3n-3 piglets. The milk of high 18:3n-3 sows had higher proportions of n-3PUFA than that of low 18:3n-3 and medium 18:3n-3 sows. Piglets suckling the high 18:3n-3 sows had greater proportions of 18:3n-3, 20:5n-3, 22:5n 3 and 22:6n-3 in the liver, and of 22:5n-3 and 22:6n-3 in the brain than low 18:3n-3 and medium 18:3n-3 piglets. D5D and D6D mRNA expressions in piglet liver were not affected by the maternal diet at any age. In conclusion, extruded linseed in the sow diet modifies the n-3PUFA status of piglets during the postnatal period. However, a minimal content of 18:3n-3 in the sow diet is necessary to increase the n-3PUFA level in piglet liver and brain. Moreover, modifications in the n-3PUFA fatty acid composition of piglet tissue seem linked to the availability of 18:3n-3 in maternal milk and not to desaturase enzyme expression. PMID- 23806274 TI - Computer-interpretable clinical guidelines: a methodological review. AB - Clinical practice guidelines (CPGs) aim to improve the quality of care, reduce unjustified practice variations and reduce healthcare costs. In order for them to be effective, clinical guidelines need to be integrated with the care flow and provide patient-specific advice when and where needed. Hence, their formalization as computer-interpretable guidelines (CIGs) makes it possible to develop CIG based decision-support systems (DSSs), which have a better chance of impacting clinician behavior than narrative guidelines. This paper reviews the literature on CIG-related methodologies since the inception of CIGs, while focusing and drawing themes for classifying CIG research from CIG-related publications in the Journal of Biomedical Informatics (JBI). The themes span the entire life-cycle of CIG development and include: knowledge acquisition and specification for improved CIG design, including (1) CIG modeling languages and (2) CIG acquisition and specification methodologies, (3) integration of CIGs with electronic health records (EHRs) and organizational workflow, (4) CIG validation and verification, (5) CIG execution engines and supportive tools, (6) exception handling in CIGs, (7) CIG maintenance, including analyzing clinician's compliance to CIG recommendations and CIG versioning and evolution, and finally (8) CIG sharing. I examine the temporal trends in CIG-related research and discuss additional themes that were not identified in JBI papers, including existing themes such as overcoming implementation barriers, modeling clinical goals, and temporal expressions, as well as futuristic themes, such as patient-centric CIGs and distributed CIGs. PMID- 23806273 TI - Extraction of social information from gait in schizophrenia. AB - BACKGROUND: The human face and body are rich sources of socio-emotional cues. Accurate recognition of these cues is central to adaptive social functioning. Past studies indicate that individuals with schizophrenia (SZ) show deficits in the perception of emotion from facial cues but the contribution of bodily cues to social perception in schizophrenia is undetermined. The present study examined the detection of social cues from human gait patterns presented by computer generated volumetric walking figures. METHOD: A total of 22 SZ and 20 age-matched healthy control participants (CO) viewed 1 s movies of a 'digital' walker's gait and subsequently made a forced-choice decision on the emotional state (angry or happy) or the gender of the walker presented at three intensity levels. Overall sensitivity to the social cues and bias were computed. For SZ, symptom severity was assessed. RESULTS: SZ were less sensitive than CO on both emotion and gender discrimination, regardless of intensity. While impaired overall, greater signal intensity did improve performance of SZ. Neither group differed in their response bias in either condition. The discrimination sensitivity of SZ was unrelated to their social functioning or symptoms but a bias toward perceiving gait as happy was associated with better social functioning. CONCLUSIONS: These results suggest that SZ are impaired in extracting social information from gait but SZ benefited from increased signal intensity of social cues. Inaccurate perception of social cues in others may hinder adequate preparation for social interactions. PMID- 23806275 TI - Sharing clinical decisions for multimorbidity case management using social network and open-source tools. AB - INTRODUCTION: Social networks applied through Web 2.0 tools have gained importance in health domain, because they produce improvements on the communication and coordination capabilities among health professionals. This is highly relevant for multimorbidity patients care because there is a large number of health professionals in charge of patient care, and this requires to obtain clinical consensus in their decisions. Our objective is to develop a tool for collaborative work among health professionals for multimorbidity patient care. We describe the architecture to incorporate decision support functionalities in a social network tool to enable the adoption of shared decisions among health professionals from different care levels. As part of the first stage of the project, this paper describes the results obtained in a pilot study about acceptance and use of the social network component in our healthcare setting. METHODS: At Virgen del Rocio University Hospital we have designed and developed the Shared Care Platform (SCP) to provide support in the continuity of care for multimorbidity patients. The SCP has two consecutively developed components: social network component, called Clinical Wall, and Clinical Decision Support (CDS) system. The Clinical Wall contains a record where health professionals are able to debate and define shared decisions. We conducted a pilot study to assess the use and acceptance of the SCP by healthcare professionals through questionnaire based on the theory of the Technology Acceptance Model. RESULTS: In March 2012 we released and deployed the SCP, but only with the social network component. The pilot project lasted 6 months in the hospital and 2 primary care centers. From March to September 2012 we created 16 records in the Clinical Wall, all with a high priority. A total of 10 professionals took part in the exchange of messages: 3 internists and 7 general practitioners generated 33 messages. 12 of the 16 record (75%) were answered by the destination health professionals. The professionals valued positively all the items in the questionnaire. As part of the SCP, opensource tools for CDS will be incorporated to provide recommendations for medication and problem interactions, as well as to calculate indexes or scales from validated questionnaires. They will receive the patient summary information provided by the regional Electronic Health Record system through a web service with the information defined according to the virtual Medical Record specification. CONCLUSIONS: Clinical Wall has been developed to allow communication and coordination between the healthcare professionals involved in multimorbidity patient care. Agreed decisions were about coordination for appointment changing, patient conditions, diagnosis tests, and prescription changes and renewal. The application of interoperability standards and open source software can bridge the gap between knowledge and clinical practice, while enabling interoperability and scalability. Open source with the social network encourages adoption and facilitates collaboration. Although the results obtained for use indicators are still not as high as it was expected, based on the promising results obtained in the acceptance questionnaire of SMP, we expect that the new CDS tools will increase the use by the health professionals. PMID- 23806277 TI - Cosmetic incision in boys for lower abdominal surgery. PMID- 23806276 TI - Single incisional approach for reconstruction of hypospadias and concomitant inguinal hernia. AB - OBJECTIVE: To demonstrate the feasibility, cosmetic outcome and therapeutic values of our single incisional approach in patients with both hypospadias and inguinal hernia (IH) in comparison with standard multiple incisional techniques. MATERIALS AND METHODS: Sixty hypospadias-IH repairs were performed from February 2005 to February 2012. These patients were divided into two groups according to their age and hypospadias location. They were then separated randomly into multiple incision (MIG) and single incision (SIG) groups. Early and late complications were taken into consideration. Postoperative pain, need for analgesics, operative time, hospital stay and cosmetic results were recorded for further evaluation. RESULTS: Patients were followed up at 6-month intervals for up to 2 years postoperatively. Early and late complication rates were approximately the same in the two groups. 73.3% of patients in MIG and 96.6% in SIG attained an excellent cosmetic result according to two external surgeons. There was no case with poor cosmetic outcome in either group. More analgesic consumption was demanded in MIG patients. CONCLUSION: This method of surgery is reproducible with better cosmetic outcome and a slightly shorter hospital stay. It could be a viable option in the management of children with hypospadias and concomitant IH. Negligible postoperative pain and short operative time are the other advantages. PMID- 23806278 TI - The effect of prophylactic treatment with Shohl's solution in children with cystinuria. AB - OBJECTIVE: To investigate the effect of prophylactic treatment with Shohl's solution on the rates of stone recurrence in paediatric patients with cystinuria. PATIENTS AND METHODS: Between June 2007 and October 2011, 185 patients aged 16 years and younger whose stones had been completely removed by percutaneous nephrolithotomy (PCNL) were assessed for metabolic risk factors. Seventeen (9%) patients with positive cyanide-nitroprusside tests (CNT) and cystine stones enrolled in this study, and a Shohl's solution was used for alkalinisation. The patients were followed up for a mean period of two years for stone recurrence. RESULTS: Of the patients, 10 (59%) were male, and 7 (41%) were female (p = 0.13). Twelve patients (70.5%) continued to receive medical prophylaxis regularly, whereas 5 (29.5%) patients did not. The mean pre-treatment and post-treatment urinary pH values were 5.8 +/- 0.5 (5-7) and 7.5 +/- 0.4 (6.5-8), respectively (p < 0.001). The pre-treatment and post-treatment specific gravities of the urine were 1021.5 +/- 5.4 (1010-1030) and 1006 +/- 2.3 (1004-1015), respectively (p < 0.001). The rates of recurrence were 16.6% among those who continued prophylaxis and 100% among those who did not receive prophylaxis (p = 0.001). The most common combination of metabolic anomalies was cystinuria and hypocitraturia (p < 0.001). CONCLUSIONS: This study demonstrated that detailed clinical and laboratory evaluations should be performed for all children with cystine stone disease, and, appropriate prophylactic treatment should be recommended to prevent the reformation of stones. PMID- 23806279 TI - Highly transparent carbon counter electrode prepared via an in situ carbonization method for bifacial dye-sensitized solar cells. AB - A facile in situ carbonization method was demonstrated to prepare the highly transparent carbon counter electrode (CE) with good mechanical stability for bifacial dye-sensitized solar cells (DSCs). The optical and electrochemical properties of carbon CEs were dramatically affected by the composition and concentration of the precursor. The well-optimized carbon CE exhibited high transparency and sufficient catalytic activity for I3(-) reduction. The bifacial DSC with obtained carbon CE achieved a high power conversion efficiency (PCE) of 5.04% under rear-side illumination, which approaches 85% that of front-side illumination (6.07%). Moreover, the device shows excellent stability as confirmed by the aging test. These promising results reveal the enormous potential of this transparent carbon CE in scaling up and commercialization of low cost and effective bifacial DSCs. PMID- 23806280 TI - Bone-derived mesenchymal stromal cells from HIV transgenic mice exhibit altered proliferation, differentiation capacity and paracrine functions along with impaired therapeutic potential in kidney injury. AB - Mesenchymal stem cells (MSCs) secrete paracrine factors that could be cytoprotective and serve roles in immunoregulation during tissue injury. Although MSCs express HIV receptors, and co-receptors, and are susceptible to HIV infection, whether HIV-1 may affect biological properties of MSCs needs more study. We evaluated cellular proliferation, differentiation and paracrine functions of MSCs isolated from compact bones of healthy control mice and Tg26 HIV-1 transgenic mice. The ability of MSCs to protect against cisplatin toxicity was studied in cultured renal tubular cells as well as in intact mice. We successfully isolated MSCs from healthy mice and Tg26 HIV-1 transgenic mice and found the latter expressed viral Nef, Vpu, NL4-3 and Vif genes. The proliferation and differentiation of Tg26 HIV-1 MSCs was inferior to MSCs from healthy mice. Moreover, transplantation of Tg26 HIV-1 MSCs less effectively improved outcomes compared with healthy MSCs in mice with acute kidney injury. Also, Tg26 HIV-1 MSCs secreted multiple cytokines, but at significantly lower levels than healthy MSCs, which resulted in failure of conditioned medium from these MSCs to protect cultured renal tubular cells from cisplatin toxicity. Therefore, HIV-1 had adverse biological effects on MSCs extending to their proliferation, differentiation, function, and therapeutic potential. These findings will help in advancing mechanistical insight in renal injury and repair in the setting of HIV 1 infection. PMID- 23806282 TI - Sp1 mediates microRNA-29c-regulated type I collagen production in renal tubular epithelial cells. AB - Specificity protein 1 (Sp1), a ubiquitously expressed transcription factor, plays a potential pathogenic role for fibrotic disease in many organs by regulating the expression of several fibrosis-related genes, however, its role in kidney fibrosis and the mechanisms regulating its expression remain incompletely clarified. Here, we found that Sp1 was markedly induced and closely correlated with interstitial type I collagen accumulation in kidney tubular epithelia from obstructive nephropathy. In vitro, both Sp1 and type I collagen expression were up-regulated in TGF-beta1-treated kidney tubular epithelial cells (NRK-52E), whereas knockdown of Sp1 largely abolished TGF-beta1-induced type I collagen production, suggesting that Sp1 induction is partially responsible for type I collagen expression. In addition, we found that miR-29c expression was remarkably reduced in either the tubular epithelial cells from kidney with UUO nephropathy or TGF-beta1-treated NRK-52E cells. Knockdown of miR-29c could sufficiently induce Sp1 and type I collagen expression, whereas ectopic expression of miR-29c largely abolished their expression stimulated by TGF-beta1 in NRK-52E cells. Furthermore, knockdown of Sp1 effectively hindered type I collagen induction stimulated by miR-29c down-regulation. Collectively, this study demonstrates that Sp1 acts as an essential mediator for miR-29c in regulating type I collagen production in tubular epithelial cells, which may provide a novel mechanistic insight about miR-29c in renal fibrosis. PMID- 23806283 TI - On some recent insights in Integral Biomathics. AB - This paper summarizes the results in Integral Biomathics obtained to this moment and provides an outlook for future research in the field. PMID- 23806281 TI - Toward single cell traction microscopy within 3D collagen matrices. AB - Mechanical interaction between the cell and its extracellular matrix (ECM) regulates cellular behaviors, including proliferation, differentiation, adhesion, and migration. Cells require the three-dimensional (3D) architectural support of the ECM to perform physiologically realistic functions. However, current understanding of cell-ECM and cell-cell mechanical interactions is largely derived from 2D cell traction force microscopy, in which cells are cultured on a flat substrate. 3D cell traction microscopy is emerging for mapping traction fields of single animal cells embedded in either synthetic or natively derived fibrous gels. We discuss here the development of 3D cell traction microscopy, its current limitations, and perspectives on the future of this technology. Emphasis is placed on strategies for applying 3D cell traction microscopy to individual tumor cell migration within collagen gels. PMID- 23806284 TI - Effects of interleukin-1 on cardiac fibroblast function: relevance to post myocardial infarction remodelling. AB - The cardiac fibroblast (CF) is a multifunctional and heterogeneous cell type that plays an essential role in regulating cardiac development, structure and function. Following myocardial infarction (MI), the myocardium undergoes complex structural remodelling in an attempt to repair the damaged tissue and overcome the loss of function induced by ischemia/reperfusion injury. Evidence is emerging that CF play critical roles in all stages of post-MI remodelling, including the initial inflammatory phase that is triggered in response to myocardial damage. CF are particularly responsive to the proinflammatory cytokine interleukin-1 (IL-1) whose levels are rapidly induced in the myocardium after MI. Studies from our laboratory in recent years have sought to evaluate the functional effects of IL-1 on human CF function and to determine the underlying molecular mechanisms. This review summarises these data and sets it in the context of post-MI cardiac remodelling, identifying the fibroblast as a potential therapeutic target for reducing adverse cardiac remodelling and its devastating consequences. PMID- 23806285 TI - Development and validation of a claims-based prediction model for COPD severity. AB - BACKGROUND: Administrative claims are an important data source for COPD research but lack a validated measure of patient COPD severity, which is an important determinant of treatment and outcomes. METHODS: Patients with >=1 diagnosis of COPD and spirometry results from 01/2004-05/2011 were identified from an electronic health records database linked to healthcare claims. Patients were classified into 3 COPD severity groups based on spirometry and Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines: GOLD-Unclassified, Mild/Moderate, and Severe/Very Severe. A multinomial logistic regression model was constructed using claims data from 3 months before and after (observation period) the most recent spirometry (index date) to categorize patient COPD severity. A random selection of 90% of patients in each severity level was selected to build the model, and the remaining 10% were used as a validation sample. Model predictions were evaluated for sensitivity, specificity, accuracy, and concordance. RESULTS: Among 2028 COPD patients who met sample selection criteria, 886, 683, and 459 patients were in the GOLD-Unclassified, Mild/Moderate, and Severe/Very Severe categories, respectively. The final model included age, sex, comorbidities (such as pulmonary fibrosis and diabetes), COPD related resource utilization (such as oxygen use), and all-cause healthcare utilization. In the validation sample, the model correctly predicted COPD severity for 62.7% of all patients (accuracy for predicting GOLD-Unclassified: 73.5%; Mild/Moderate: 70.6%; Severe/Very Severe: 81.4%) with kappa = 0.41. CONCLUSIONS: The prediction model was developed using clinically measured COPD severity to provide researchers an approach to classify patients using claims data when clinical measures are not available. PMID- 23806286 TI - Complex interventions that reduce urgent care use in COPD: a systematic review with meta-regression. AB - CONTEXT: Chronic obstructive pulmonary disease is common and accounts for considerable healthcare expenditure. A large proportion of this healthcare expenditure is attributable to the use of expensive urgent healthcare. The characteristics of interventions that reduce the use of urgent healthcare remain unclear. OBJECTIVE: To examine the characteristics of complex interventions intended to reduce the use of urgent and unscheduled healthcare among people with COPD. DATA SOURCES: Electronic searches of MEDLINE, EMBASE, PSYCINFO, CINAHL, the British Nursing Library and the Cochrane library, from inception to 25th January 2013 were conducted. These were supplemented by hand-searching bibliographies and citation tracing identified reviews and eligible studies. STUDY SELECTION: Studies were eligible for inclusion if they: i) included adults with chronic obstructive pulmonary disease, ii) assessed the efficacy of a complex intervention using randomised controlled trial design, and iii) included a measure of urgent healthcare utilisation at follow-up. DATA EXTRACTION: Data on the subjects recruited, trial methods used, the characteristics of complex interventions and the effects of the intervention on urgent healthcare utilisation were extracted from eligible studies. RESULTS: 32 independent studies were identified. Pooled effects indicated that interventions were associated with a 32% reduction in the use of urgent healthcare (OR = 0.68, 95% CI = 0.57, 0.80). When study effects were grouped according to the components of the interventions used, significant effects were seen for interventions that included general education (OR = 0.66, 95% CI = 0.55, 0.81), Exercise (OR = 0.60, 95% CI = 0.48, 0.76) and relaxation therapy (OR = 0.48, 95% CI = 0.33, 0.70). CONCLUSIONS: Use of urgent healthcare in patients with COPD was significantly reduced by complex interventions. Complex interventions among people with COPD may reduce the use of urgent care, particularly those including education, exercise and relaxation. PMID- 23806287 TI - Effect of ambulatory oxygen on exertional dyspnea in IPF patients without resting hypoxemia. AB - BACKGROUND AND OBJECTIVE: The effects of ambulatory oxygen for idiopathic pulmonary fibrosis (IPF) patients without resting hypoxemia have not been elucidated. The purpose of this study was to assess the effect of ambulatory oxygen on dyspnea in IPF patients without resting hypoxemia but with desaturation on exertion. METHODS: This was a double-blind, placebo-controlled, randomized crossover trial of ambulatory oxygen versus ambulatory air. Patients with IPF who had a partial pressure of arterial oxygen (PaO2) between 60 mm Hg and 80 mm Hg at rest, and desaturation of 88% or less in a room-air 6-min walk test were eligible. Patients underwent a standardized 6-min walk test and a 6-min free walk test under each ambulatory gas. Oxygen and air were provided at 4 L/min intranasally. Dyspnea was evaluated immediately, 1, and 2 min after the tests. RESULTS: Twenty patients (16 men), with a mean age of 73.5 (SD 4.1) years, % predicted forced vital capacity (FVC) of 71.0 (13.3) %, % predicted diffusion capacity for carbon monoxide (DLco) of 57.0 (13.3) %, and PaO2 of 72.5 (5.4) mm Hg were recruited. No significant differences in dyspnea were observed between ambulatory oxygen and air at each time point. However, some patients showed improvement in dyspnea with oxygen on an individual basis. CONCLUSIONS: Since oxygen provides no additional benefit over air in terms of exertional dyspnea for IPF patients without resting hypoxemia, routine prescription of ambulatory oxygen is not recommended. However, assessment on an individual basis is necessary. Trial registration. UMIN Clinical Trial Registry; No.:UMIN000005098; URL:http://www.umin.ac.jp/ctr/. PMID- 23806288 TI - The osteogenic differentiation of PDLSCs is mediated through MEK/ERK and p38 MAPK signalling under hypoxia. AB - PURPOSE: During orthodontic treatment and chronic periodontitis, the periodontal vasculature is severely impaired by overloaded mechanical force or chronic inflammation. This leads to the hypoxic milieu of the periodontal stem cell niche and ultimately affects periodontal tissue remodelling. However, the role of hypoxia in the regulation of periodontal ligament stem cell (PDLSC) behaviours still remains to be elucidated. The present study was aimed at investigating the effects of hypoxia on osteogenic differentiation, mineralisation and paracrine release of PDLSCs and further demonstrating the involvement of mitogen-activated protein kinase (MAPK) signalling in the process. METHODS: First, PDLSCs were isolated and characterised. Second, the effects of different periods of hypoxia on PDLSC osteogenic potential, mineralisation and paracrine release were investigated. Third, extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38 kinase activities under hypoxia were measured. Finally, specific MAPK inhibitors PD98059 and SB203580 were employed to investigate the involvement of two kinases in PDLSC osteogenesis under hypoxia. RESULTS: Immunocytochemical staining and multilineage differentiation assays verified that the isolated cells were PDLSCs. Cell viability, alkaline phosphatase (ALP) activity, messenger RNA (mRNA) and protein levels of runt-related transcription factor 2 (Runx2) and Sp7, mineralisation and prostaglandin E2 (PGE2) and vascular endothelial growth factor (VEGF) release were significantly increased by hypoxia. ERK1/2 and p38 were activated in different ways under hypoxia. Furthermore, hypoxia-stimulated transcription and expression of the above-mentioned osteogenic regulators were also reversed by PD98059 and SB203580 to different degrees. CONCLUSIONS: Exposure of PDLSCs to hypoxia affected their osteogenic potential, mineralisation and paracrine release, and the process involved mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) and p38 MAPK signalling. PMID- 23806289 TI - Dynamic transcriptomes of human myeloid leukemia cells. AB - To identify the mechanisms controlling chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) in humans, we analyzed genome-wide transcription dynamics in three myeloid leukemia cell lines (K562, HL-60, and THP1) using high throughput sequencing technology. Using KEGG analysis, we found that the ERK/MAPK, JAK-STAT and ErbB pathways promoted proliferation and metabolism in CML. However, in AML, differentiation and apoptosis blocking resulted in the accumulation of blast cells in marrow. In addition, each cell type had unique characteristics. K562 cells are an ideal model for studying erythroid differentiation and globin gene expression. The chemokine signaling pathway and Fc gamma R-mediated phagocytosis were markedly upregulated in HL-60 cells. In THP1 cells, highly expressed genes ensured strong phagocytosis by monocytes. Further, we provide a new insight into myeloid development. The abundant data sets and well-defined analysis methods will provide a resource and strategy for further investigation of myeloid leukemia. PMID- 23806290 TI - IgG4-related Mikulicz's disease: ultrasonography of the salivary and lacrimal glands for monitoring the efficacy of corticosteroid therapy. AB - OBJECTIVES: IgG4-related Mikulicz's disease (IgG4-MD) has been recently established as a subtype of IgG4-related diseases involving the salivary and lacrimal glands, and the diseased glands are characteristically and highly responsive to corticosteroid therapy. We retrospectively evaluated ultrasonography (US) of the salivary and lacrimal glands for monitoring the efficacy of corticosteroid treatment in patients with IgG4-MD. METHODS: US features of the salivary and lacrimal glands were assessed and compared with the serum IgG4 levels in 8 patients with IgG4-MD before and at various stages after initiation of oral corticosteroids. RESULTS: US features of the lacrimal and salivary glands of patients with IgG4-MD were characterised by multiple hypoechoic areas in enlarged glands. The submandibular glands were most frequently involved by the disease, and bilateral glands of the same type were similarly affected exhibiting the same hypoechoic pattern. Alleviations of abnormal gland architecture and size in response to corticosteroid therapy were effectively detected with US. The US findings of the involved glands were proportional to the serum IgG4 level before and during the corticosteroid therapy. CONCLUSIONS: US helps monitor the efficacy of corticosteroid treatment in patients with IgG4-MD. PMID- 23806291 TI - Surface enhanced Raman scattering (SERS) with biopolymer encapsulated silver nanosubstrates for rapid detection of foodborne pathogens. AB - A biopolymer encapsulated with silver nanoparticles was prepared using silver nitrate, polyvinyl alcohol (PVA) solution, and trisodium citrate. It was deposited on a mica sheet to use as SERS substrate. Fresh cultures of Salmonella Typhimurium, Escherichia coli, Staphylococcus aureus and Listeria innocua were washed from chicken rinse and suspended in 10 ml of sterile deionized water. Approximately 5 MUl of the bacterial suspensions was placed on the substrate individually and exposed to 785 nm HeNe laser excitation. SERS spectral data were recorded over the Raman shift between 400 and 1800 cm(-1) from 15 different spots on the substrate for each sample; and three replicates were done on each bacteria type. Principal component analysis (PCA) model was developed to classify foodborne bacteria types. PC1 identified 96% of the variation among the given bacteria specimen, and PC2 identified 3%, resulted in a total of 99% classification accuracy. Soft Independent Modeling of Class Analogies (SIMCA) of validation set gave an overall correct classification of 97%. Comparison of the SERS spectra of different types of gram-negative and gram-positive bacteria indicated that all of them have similar cell walls and cell membrane structures. Conversely, major differences were noted around the nucleic acid and amino acid structure information between 1200 cm(-1) and 1700 cm(-1) and at the finger print region between 400 cm(-1) and 700 cm(-1). Silver biopolymer nanoparticle substrate could be a promising SERS tool for pathogen detection. Also this study indicates that SERS technology could be used for reliable and rapid detection and classification of food borne pathogens. PMID- 23806292 TI - Number dissimilarities facilitate the comprehension of relative clauses in children with (Grammatical) Specific Language Impairment. AB - This study investigates whether number dissimilarities on subject and object DPs facilitate the comprehension of subject- and object-extracted centre-embedded relative clauses in children with Grammatical Specific Language Impairment (G SLI). We compared the performance of a group of English-speaking children with G SLI (mean age: 12;11) with that of two groups of younger typically developing (TD) children, matched on grammar and receptive vocabulary, respectively. All groups were more accurate on subject-extracted relative clauses than object extracted ones and, crucially, they all showed greater accuracy for sentences with dissimilar number features (i.e., one singular, one plural) on the head noun and the embedded DP. These findings are interpreted in the light of current psycholinguistic models of sentence comprehension in TD children and provide further insight into the linguistic nature of G-SLI. PMID- 23806293 TI - Effects of water restriction on growth performance, feed nutrient digestibility, carcass and meat traits of rabbits. AB - The study investigates the effects of a post-weaning water restriction on performance, nutrient digestibility, carcass traits and meat quality of 84-day old rabbits. A total of 1388 weaned rabbits (35 days) were randomly divided into two groups on the basis of BW and sex. The two groups were fed the same diets ad libitum both in the post-weaning (35 to 60 days) and fattening (61 to 84 days) periods. In the post-weaning period, one group (AL) also received drinking water ad libitum, whereas the other (WR) had a water restriction from 35 to 41 days 2 h/day; from 42 to 48 days 2.5 h/day; from 49 to 55 days 3 h/day; and from 56 to 60 days 4 h/day. During the fattening period, both groups had water-free access. Individual live weights and feed intake per cage were recorded weekly for 32 cages randomly chosen per group (64 rabbits) to calculate the BW gain, feed intake and feed conversion ratio (FCR). The apparent digestibility values of nutrients were measured using acid-insoluble ash. Carcass data were collected from 16 rabbits (8 males and 8 females) per group selected for similar final BW in both groups. Mortality from 35 to 60 days was higher in the AL group (10.1% v. 5.2%, for AL and WR, respectively, P < 0.0001). BW gain was higher for the AL group during both the post-weaning (+22.4%, P < 0.01) and the entire period (+7.5%, P < 0.05). Water restriction reduced feed intake both in the post-weaning (-17.4%, P < 0.0001) and in the entire period (-9.9%, P < 0.05). During the fattening period, FCR was lower for the WR group (5.15 v. 5.75 g/g, for WR and AL, respectively, P < 0.05). The apparent digestibilities of dry matter, organic matter, NDF, ADF and cellulose were greater in the restricted rabbits (+4.7%, +4.5%, +10.2%, +18.8% and +12.8%, P < 0.01, P < 0.01, P < 0.05, P < 0.01, P < 0.05, respectively). Perirenal and scapular fat percentages were higher in the AL rabbits (+30.7% and +116.6%, P < 0.01 and P < 0.001, respectively). Water restriction increased saturated fatty acids (C16:0, +12.9%, P < 0.05), lauroleic acid (C12:1, +75.0%, P < 0.01), n-3 polyunsaturated fatty acids (C20:5, +50.0%, P < 0.01 and C22:5, +16.6%, P < 0.05) and the n-3/n-6 ratio (+28.6%, P < 0.05). The applied water restriction between 35 and 60 days executed during the winter months improved the digestive health of rabbits, with no negative effects on carcass traits, or physical and chemical meat characteristics. However, from the animal welfare point of view, a water restriction can be criticized as a method to restrict feed intake. PMID- 23806295 TI - Emergence of a new recombinant Sydney 2012 norovirus variant in Denmark, 26 December 2012 to 22 March 2013. AB - We report here new recombinants between the norovirus II.4 Sydney 2012 and the II.4 New Orleans 2009 variants. This demonstrates that the II.4 Sydney 2012 variant is undergoing further diversification and suggests a potential for rapid evolution. We also provide primers, which allow the amplification and sequencing of both the current New Orleans 2009 and Sydney 2012 variants and the new II.4 New Orleans 2009/II.4 Sydney 2012 recombinants for more accurate surveillance and transmission tracking. PMID- 23806294 TI - Transient effects of 2,4-dichlorophenoxyacetic acid (2,4-D) exposure on some metabolic and free radical processes in goldfish white muscle. AB - This study aims to assess effects of 96 h goldfish exposure to 1, 10 and 100 mg/L of the herbicide, 2,4-dichlorophenoxyacetic acid (2,4-D), on metabolic indices and free radical process markers in white muscle of a commercial fish, the goldfish Carassius auratus L. Most oxidative stress markers and antioxidant enzymes were not affected at 2,4-D fish treatment. 2,4-D fish exposure induced the elevated levels of total (by 46% and 40%) and reduced (by 77% and 73%) glutathione in muscles of goldfish of 10 mg/L 2,4-D and recovery (after 100 mg/L of 2,4-D exposure) groups, respectively. However, in muscles of 100 mg/L 2,4-D exposed goldfish these parameters were depleted (by 47% and 64%). None of investigated parameters of protein and carbohydrate metabolisms changed in white muscles of 2,4-D exposed fish, with exception of lactate dehydrogenase activity, which was slightly (by 11-15%) elevated in muscles of goldfish exposed to 10-100 mg/L of 2,4-D, but also recovered. Thus, the short term exposure of goldfish to the selected concentrations of 2,4-D does not substantially affect their white muscle, suggesting the absence of any effect under the environmentally relevant concentrations. PMID- 23806296 TI - High prevalence of antibodies against Leptospira spp. in male Austrian adults: a cross-sectional survey, April to June 2009. AB - To assess the distribution of specific antibodies against Leptospira spp. in Austrian adults, we conducted an explorative nationwide cross-sectional serological study in 400 healthy individuals. Antibody titres against Leptospira spp. were determined in a microscopic agglutination test using a panel of 14 serovar cultures. Sera of 18 participants were excluded because the samples were unsuitable for testing; the remaining 382 participants comprised 166 professional soldiers and 216 civilians. Overall, 88 (23%) individuals tested positive in serological screening. The subjects' sera reacted most frequently with serovars Canicola (16.5%) and Hardjo (11.8%). Epidemiological information was obtained from a questionnaire: no correlation was found for area of residence, travel abroad, regular outdoor activities, occupational animal contact, or ownership of companion animals. The proportion of seropositive samples was significantly lower among professional soldiers (15.7%) than among civilians (28.7%) (p=0.003). Our data demonstrate serological evidence of a high rate of exposure to Leptospira spp. among the Austrian population. No increased risk of exposure to Leptospira spp. was detected in military personnel. PMID- 23806298 TI - Evidence-Based Medicine applied to the control of communicable disease incidents when evidence is scarce and the time is limited. AB - Control of acute communicable disease incidents demands rapid risk assessment, often with minimal peer-reviewed literature available but conducted in the public's view. This paper explores how methods of evidence-based medicine (EBM) can be applied in this scenario to improve decision making and risk communication. A working group with members from EBM organisations, public health institutions and the European Centre for Disease Prevention and Control used a six-stage framework for rapid risk assessments: preparation, risk detection/verification, risk assessment, development of advice, implementation, and evaluation. It concluded that data from observational studies, surveillance and modelling play a vital role in the evidence base. However, there is a need to further develop protocols and standards, to perform, report and register outbreak investigations more systematically and rigorously, and to allow rapid retrieval of the evidence in emergencies. Lack of evidence for risk assessment and advice (usual for new and emerging diseases) should be made explicit to policy makers and the public. Priorities are to improve templates for reporting and assessing the quality of case and outbreak reports, apply grading systems to evidence generated from field investigations, improve retrieval systems for incident reports internationally, and assess how to communicate uncertainties of scientific evidence more explicitly. PMID- 23806297 TI - Laboratory preparedness for detection and monitoring of Shiga toxin 2-producing Escherichia coli O104:H4 in Europe and response to the 2011 outbreak. AB - A hybrid strain of enteroaggregative and Shiga toxin 2-producing Escherichia coli (EAEC-STEC) serotype O104:H4 strain caused a large outbreak of haemolytic uraemic syndrome and bloody diarrhoea in 2011 in Europe. Two surveys were performed in the European Union (EU) and European Economic Area (EEA) countries to assess their laboratory capabilities to detect and characterise this previously uncommon STEC strain. Prior to the outbreak, 11 of the 32 countries in this survey had capacity at national reference laboratory (NRL) level for epidemic case confirmation according to the EU definition. During the outbreak, at primary diagnostic level, nine countries reported that clinical microbiology laboratories routinely used Shiga toxin detection assays suitable for diagnosis of infections with EAEC-STEC O104:H4, while 14 countries had NRL capacity to confirm epidemic cases. Six months after the outbreak, 22 countries reported NRL capacity to confirm such cases following initiatives taken by NRLs and the European Centre for Disease Prevention and Control (ECDC) Food- and Waterborne Disease and Zoonoses laboratory network. These data highlight the challenge of detection and confirmation of epidemic infections caused by atypical STEC strains and the benefits of coordinated EU laboratory networks to strengthen capabilities in response to a major outbreak. PMID- 23806299 TI - New methods for inducing the differentiation of amniotic-derived mesenchymal stem cells into motor neuron precursor cells. AB - Our study investigates the differentiation of amniotic-derived mesenchymal stem cells (ADMSCs) into motor neuron (MN) precursor cells induced by a combination of extracellular matrix (ECM) and multi-cell factors. Membrane-like ECM was made by an enzymatic and chemical extraction method and exhibited good biological compatibility. Cells in the experimental group (EG) were treated with ECM and multi-cell factors in a multi-step induction process, while the control group (CG) was treated similarly, except without ECM. In the EG, after induction, the cells formed processes that connected with neighboring cells to form a net that had directionality. In these cells, neuron-specific enolase (NSE) and synaptophysin (SYN) expression levels increased and glial fibrillary acidic protein (GFAP) expression decreased. The SYN expression in the EG cells was higher compared with those in the CG. In the CG, NSE expression increased, while the expression of Nestin and SYN did not change. These were several changes in the levels of other genes: ADMSCs at passage 1 expressed Nanog, SOX2, octamer binding transcription factor 4 (OCT4) and Nestin. In the EG, at the beginning of induction, the expression of Nanog decreased and that of SOX2 and Nestin increased. After 2 days, the cells expressed Nestin, OCT4 and SYNIII, and after 3 days, they expressed Olig2, OCT4, Nestin, SYNII and Islet1 (ISL1). Finally, at day 6, the cells expressed Nestin, SYNI, SYNIII, ISL-1, homeobox 9 (Hb9) and oligodendrocyte lineage transcription factor 2 (Olig2). In the CG, the cells never expressed SYNI, SYNII or Hb9. Our studies therefore demonstrate that the extracted ECM was capable of promoting the maturation of synapses. Human ADMSCs are composed of multiple cell subsets, including neural progenitor cells. The multi-step induction method used in this study causes human ADMSCs to differentiate into MN precursor cells. PMID- 23806300 TI - Important developments in OMFS anaesthesia. Re: what is new in maxillofacial anaesthesia? PMID- 23806301 TI - Protective effects of recombinant human brain natriuretic peptide against LPS Induced acute lung injury in dogs. AB - BACKGROUND: Acute lung injury (ALI) is a common component of systemic inflammatory disease without more effective treatments. However, recent studies have demonstrated that the recombinant human brain natriuretic peptide (rhBNP) has anti-inflammatory effects. Therefore, we found that rhBNP could prevent lipopolysaccharide (LPS)-induced acute lung injury in a dog model. METHODS: Dogs were injected with LPS and subjected to continuous intravenous infusion (CIV) of saline solution or rhBNP. We detected the protective effects of rhBNP by histological examination and determination of serum cytokine levels and lung myeloperoxidase (MPO) activity and malondialdehyde (MDA) activity. Histological examination indicated marked inflammation, edema and hemorrhage in lung tissue taken 12h after rhBNP treatment compared with tissue from dogs which received saline treatment after LPS injection. LPS injection induced cytokine (IL-6 and TNF-alpha) secretion and lung MPO and MDA activities, which were also attenuated by rhBNP treatment. RESULTS: Inductions of IL-6 and TNF-alpha were significantly attenuated in the L-rhBNP and the H-rhBNP groups. The ratios of the L-rhBNP group and H-rhBNP group were lower than that in the lung injury group. Furthermore, MPO and MDA activities were significantly lower in the H-rhBNP group compared to those in the LI group. CONCLUSION: Our data indicate that rhBNP treatment may exert protective effects and may be associated with adjusting endogenous antioxidant enzymes. Thus, rhBNP may be considered as a therapeutic agent for various clinical conditions involving lung injury by sepsis. PMID- 23806302 TI - Blocking transforming growth factor-beta signaling pathway augments antitumor effect of adoptive NK-92 cell therapy. AB - Natural killer (NK) cells hold great potential for improving the immunotherapy of cancer. However, existing data indicate that tumor cells can effectively escape NK cell-mediated apoptosis through immunosuppressive effect in the tumor microenvironment. Transforming growth factor-beta (TGF-beta) is a potent immunosuppressant. The present study was intended to develop a treatment strategy through adoptive transfer of TGF-beta insensitive NK-92 cells. To block TGF-beta signaling pathway, NK-92 cells were genetically modified with dominant negative TGF-beta type II receptor (DNTbetaRII) by optimizing electroporation using the Amaxa Nucleofector system. These genetically modified NK-92 cells were insensitive to TGF-beta and able to resist the suppressive effect of TGF-beta on Calu-6 lung cancer cells in vitro. To determine the antitumor activity in vivo, recipient mice were challenged with a single subcutaneous injection of Calu-6 cells. Adoptive transfer of TGF-beta insensitive NK-92 cells decreased tumor proliferation, reduced lung metastasis, produced more IFN-gamma, and increased the survival rate of nude mice bearing established Calu-6 cells. Hence, we have demonstrated that blocking transforming growth factor-beta signaling pathway in NK cells provides a novel therapeutic strategy and warrants further investigation. PMID- 23806303 TI - Key issues of daily life in adults with congenital heart disease. AB - Increasing survival rates of patients with congenital heart disease have resulted in a new and growing patient population of adults with operated congenital heart disease. Medical professionals face the specific medical needs of these patients but must also deal with their daily life issues. Adult patients with congenital heart disease report difficulties in several areas of daily life, such as sport, employment, insurability and travel or driving. Moreover, they must have a healthy lifestyle to prevent cardiovascular complications. All these issues can be addressed in a specific educational program. In this review, we discuss the different daily life issues of adults with congenital heart disease and the preventive measures that can be proposed to improve their quality of life. PMID- 23806304 TI - Anaemia to predict outcome in patients with acute coronary syndromes. AB - BACKGROUND: Owing to the heterogeneous population of patients with acute coronary syndromes (ACS), risk stratification with tools such as the GRACE risk score is recommended to guide therapeutic management and improve outcome. AIM: To evaluate whether anaemia refines the value of the GRACE risk model to predict midterm outcome after an ACS. METHODS: A prospective registry of 1064 ACS patients (63 +/ 14 years; 73% men; 57% ST-segment elevation myocardial infarction [MI]) was studied. Anaemia was defined as haemoglobin less than 13 mg/dL in men or less than 12 mg/dL in women. The primary endpoint was 6-month death or rehospitalization for MI. RESULTS: The primary endpoint was reached in 132 patients, including 68 deaths. Anaemia was associated with adverse clinical outcomes (hazard ratio 3.008, 95% confidence interval 2.137-4.234; P<0.0001) in univariate analysis and remained independently associated with outcome after adjustment for the Global Registry of Acute Coronary Events (GRACE) risk score (hazard ratio 2.870, 95% confidence interval 1.815-4.538; P<0.0001). Anaemia provided additional prognostic information to the GRACE score as demonstrated by a systematic improvement in global model fit and discrimination (c-statistic increasing from 0.633 [0.571;0.696] to 0.697 [0.638;0.755]). Subsequently, adding anaemia to the GRACE score led to reclassification of 595 patients into different risk categories; 16.5% patients at low risk (<= 5% risk of death or rehospitalization for MI) were upgraded to intermediate (>5-10%) or high risk (>10%); 79.5% patients at intermediate risk were reclassified as low (55%) or high risk (24%); and 45.5% patients at high risk were downgraded to intermediate risk. Overall, 174 patients were reclassified into a higher risk category (17.3%) and 421 into a lower risk category (41.9%). CONCLUSION: Anaemia provides independent additional prognostic information to the GRACE score. Combining anaemia with the GRACE score refines its predictive value, which often overestimates the risk. PMID- 23806305 TI - Very late effects of dual chamber pacing therapy for obstructive hypertrophic cardiomyopathy. AB - BACKGROUND: The very long-term effects of dual chamber pacing as a primary treatment for hypertrophic obstructive cardiomyopathy (HOCM) are poorly known and controversial. AIMS: To examine the intermediate- and long-term clinical and haemodynamic effects of permanent dual chamber pacing in patients presenting with HOCM. METHODS: Between 1991 and 2007, 51 patients (mean age 59 +/- 14 years) presenting with HOCM and New York Heart Association (NYHA) functional class >= II despite optimal medical therapy underwent implantation of DDD pacemakers with or without a defibrillator and were followed for 11.5 years (range 0.4-21.8 years). RESULTS: During follow-up, no patient underwent myectomy or septal alcohol ablation. NYHA functional class and other disease manifestations decreased significantly over 1-2 years of follow-up and remained stable thereafter. The left intraventricular (LV) gradient decreased by a mean of 78% over 1-2 years, reaching 89% at end of follow-up, along with disappearance of systolic anterior motion of the mitral valve. Mean LV ejection fraction decreased from a mean of 64 +/- 8% before pacing to 56 +/- 9% at end of follow-up (P=0.05), while LV end diastolic diameter did not change significantly. The 5- and 10-year actuarial survival rates were 90% and 65%, respectively. Among 22 deaths, 10 were due to cardiovascular and 12 to non-cardiovascular causes; two patients underwent cardiac transplantation after 8 and 13 years of DDD pacing, respectively. CONCLUSIONS: In this sample of patients with HOCM, DDD pacing alleviated symptoms and improved haemodynamic function over the very long term. The merits of this treatment should be revisited in a controlled trial. PMID- 23806306 TI - Retromolar foramen and canal: a comprehensive review on its anatomy and clinical applications. AB - The retromolar foramen (RMF) and retromolar canal (RMC) are the anatomical structures of the mandible located in retromolar fossa behind the third molar tooth. This foramen and canal contain neurovascular structures which provide accessory/additional innervation to the mandibular molars and the buccal area. These neurovascular contents of the canal gain more importance in medical and dental practice, because these elements are vulnerable to damage during placement of osteointegrated implants, endodontic treatment and sagittal split osteotomy surgeries and a detailed knowledge of this anatomical variation would be vital in understanding failed inferior alveolar nerve blockage, spread of infection and also metastasis. Although few studies have been conducted in the past showing the incidence and types in different population groups, a lacunae in comprehensive review of this structure is lacking. Though this variation posed challenging situations for the practicing surgeons, it has been quite neglected and the incidence of it is not well presented in all the textbooks. Hence, we made an attempt to provide a consolidated review regarding variations and clinical applications of the RMF and RMC. PMID- 23806307 TI - Meta-analysis of laparoscopy assisted distal gastrectomy and conventional open distal gastrectomy for EGC. AB - In recent decades, laparoscopy assisted distal gastrectomy (LADG) has been introduced to treat early gastric cancer (EGC). This study evaluated the safety and efficacy of laparoscopy assisted and conventional open distal gastrectomy for EGC. Comprehensive searches of PubMed, EmBase, Cochrane Controlled Trials Register and Chinese Biomedical Database (CBM) were performed. Included literature was evaluated using the Newcastle-Ottawa Scale. Original data were extracted, pooled odds ratio (OR) and 95% confidence intervals (CI) were calculated using RevMan 5.0. Eight RCTs of 734 patients were included in the study. Compared to CODG, LADG increases the operation time (weighted mean difference [WMD]: 63.35; 95% confidence interval [CI]: 57.96, 68.74; P<0.01), reduces intraoperative blood loss (WMD: -127.95; 95% CI: -147.97, -107.93; P<0.01), decreases number of harvested lymph nodes (WMD: -4.21; 95% CI: -6.10, 2.31; P<0.01), forwards oral intake time (WMD:-0.43; 95% CI: -0.61, -0.24; P<0.01), and shortens hospital stay(WMD: -1.29; 95% CI: -1.76, -0.83; P<0.01). There is no significant difference in postoperative complications(OR: 0.70; 95% CI: 0.46, 1.06; P=0.09). All these findings indicate that LADG for EGC is feasible and safe. PMID- 23806308 TI - Note from the editor in chief. PMID- 23806310 TI - Overview of integrative medicine in child and adolescent psychiatry. AB - Complementary and alternative medicine (CAM) defies simple definition, because the distinction between CAM and conventional medicine is largely arbitrary and fluid. Despite inconclusive data on the efficacy and safety of many CAM treatments in child and adolescent psychiatry, there are enough data on certain treatments to provide guidance to clinicians and researchers. CAM treatments, as adjunctive therapy or monotherapy, can be clinically beneficial and sensible. The low stigma and cost-competitiveness of many CAM psychiatric treatments are highly attractive to children and parents. Physicians need to be knowledgeable about CAM treatments to provide clinically valid informed consent for some conventional treatments. PMID- 23806309 TI - Load-dependent variations in knee kinematics measured with dynamic MRI. AB - Subtle changes in knee kinematics may substantially alter cartilage contact patterns and moment generating capacities of soft tissues. The objective of this study was to use dynamic magnetic resonance imaging (MRI) to measure the influence of the timing of quadriceps loading on in vivo tibiofemoral and patellofemoral kinematics. We tested the hypothesis that load-dependent changes in knee kinematics would alter both the finite helical axis of the tibiofemoral joint and the moment arm of the patellar tendon. Eight healthy young adults were positioned supine in a MRI-compatible device that could impose either elastic or inertial loads on the lower leg in response to cyclic knee flexion-extension. The elastic loading condition induced concentric quadriceps contractions with knee extension, while an inertial loading condition induced eccentric quadriceps contractions with knee flexion. Peak internal knee extension moments ranged from 23 to 33 N m, which is comparable to loadings seen in normal walking. We found that anterior tibia translation, superior patella glide, and anterior patella translation were reduced by an average of 5.1, 5.7 and 2.9 mm when quadriceps loading coincided with knee flexion rather than knee extension. These kinematic variations induced a distal shift in the finite helical axis of the tibiofemoral joint and a reduction in the patellar tendon moment arm. We conclude that it may be important to consider such load-dependent changes in knee kinematics when using models to ascertain soft tissue and cartilage loading during functional tasks such as gait. PMID- 23806311 TI - Attention-deficit/hyperactivity disorder: dietary and nutritional treatments. AB - Dozens of complementary and alternative treatments have been advocated for attention-deficit/hyperactivity disorder. Some verge into standard treatment of specific cases. Most do not have conclusive evidence of effectiveness or safety for attention-deficit/hyperactivity disorder, but some have enough evidence and are safe, easy, cheap, and sensible enough that individual patient trials can be justified. There is a need to flesh out the evidence base, which could be done cost effectively for supplements or off-label agents that are amenable to placebo control. PMID- 23806312 TI - Mood disorders in youth: exercise, light therapy, and pharmacologic complementary and integrative approaches. AB - The therapeutic value of physical exercise, bright light therapy and dawn simulation, and several pharmacologic treatments, including hypericum (St. John's wort), S-adenosylmethionine, and 5-hydroxytryptophan, are reviewed, with a focus on their use for treating major depressive disorder in children and adolescents and also for alleviating depressed mood in the general (nonclinical) population of youth. For each treatment discussed, all published randomized, double-blind, placebo-controlled trials are summarized, along with some additional selected studies. Nutritional psychopharmacology and several other approaches to treating depression will be presented in an upcoming volume in the Child and Adolescent Psychiatric Clinics of North America. PMID- 23806313 TI - Autism: biomedical complementary treatment approaches. AB - This article provides a conceptual overview for the use of biomedical complementary and alternative medicine (CAM) treatments for autism spectrum disorders. Pharmaceutical agents with published studies are briefly mentioned; but the focus of the article is on possible biomedical CAM treatments, the rationale for their use, and the current database of mostly preliminary studies regarding their safety and efficacy. Of the more than 50 treatments currently listed here and in use by eager families, 9 are reviewed in more detail because of their promise from preliminary research studies or because of public interest. PMID- 23806314 TI - Learning and cognitive disorders: multidiscipline treatment approaches. AB - This article provides a select review of treatments for addressing reading disorder, mathematics disorder, disorder of written expression, auditory processing disorder, and poor working memory. This information will be valuable to practitioners in determining the suitability of certain treatments for these various disorders and problems, which has direct implications for providing comprehensive, multidisciplinary treatment for youth. PMID- 23806315 TI - Paradigm shift: stages of physicians' entry into integrative practice. AB - Integrative medicine and psychiatry are more than areas of interest; they represent a clear philosophic paradigm with a wide range of beliefs that separate it from conventional care. A child psychiatrist will typically pass through a developmental trajectory as he or she begins to embrace this approach to patient care, which can be broken down into common stages that represent the incorporation and expression of a new philosophy. This article outlines those common stages of development, and also walks through the process of opening an integrative mental health clinic. PMID- 23806316 TI - Complementary and alternative medicine in child and adolescent psychiatry: legal considerations. AB - The rising popularity of complementary and alternative medicine (CAM) in child and adolescent psychiatry raises unique ethical and legal concerns for psychiatrists and other conventional health care providers. This article explores these concerns and provides clinical advice for promoting patient health and safety while minimizing the psychiatrist's risk. Although any departure from the conventional standard of care is a potential risk, the risk of malpractice liability for practicing integrative medicine in child and adolescent psychiatry is low. CAM is most safely recommended from a legal standpoint when there is some published evidence of safety and efficacy. PMID- 23806318 TI - CAM encompasses a vast range of types of treatments, systems of health care, and lifestyle philosophies. Preface. PMID- 23806317 TI - Building an evidence base in complementary and integrative healthcare for child and adolescent psychiatry. AB - Complementary and integrative strategies are widely used by families with children who have mental health diagnoses. The therapies used by these children include herbs, dietary supplements, massage, acupuncture, meditation, and naturopathy. The literature on efficacy of complementary and alternative approaches is of limited value, and studies are needed to test efficacy and safety. Interpretation of complementary and integrative health care studies for symptomatic management of mental health conditions is hampered by study design and methodological limitations. Well-designed, adequately powered, and suitably controlled clinical trials on promising complementary and integrative modalities are needed for children and adolescents with psychiatric conditions. PMID- 23806319 TI - Anti-oxidant activity of holo- and apo-c-phycocyanin and their protective effects on human erythrocytes. AB - This study was conducted to investigate the anti-oxidant activity of the recombinant apo-c-phycocyanin (c-PC) beta-subunit compared to native c-PC purified from Spirulina sp. The gene encoding the beta-subunit of c-PC was successfully cloned and expressed in Escherichia coli. The anti-oxidant capacities of recombinant apo-c-PC(beta) and native c-PC were evaluated by measuring their Trolox equivalent antioxidant capacities and examining their protective effects on erythrocytes from normal and homozygous haemoglobin E individuals against peroxyl radicals and hydrogen peroxide. The results demonstrated that the anti-oxidant capacities are native c-PC?Trolox>recombinant apo-c-PC(beta). Both anti-oxidant proteins can potentially protect erythrocytes from oxidative damage. Expression of c-PC in bacteria reduces the cost and time for protein production, and the recombinant protein could be further developed to obtain a more efficient protein for therapeutic purposes. PMID- 23806320 TI - Oral administration of chitin and chitosan prevents peanut-induced anaphylaxis in a murine food allergy model. AB - Peanut allergy is IgE-mediated type-I hypersensitivity, and T helper 2 cytokines are central to those pathogenesis. We investigated the effects of the administration of chitin and chitosan on peanut-induced hypersensitivities in mouse food allergy models. Chitin and chitosan protected mice against peanut induced anaphylaxis reactions, and the peanut-specific IgE production decreased by up to 47% with the administration of beta-chitosan. The levels of IL-5, IL-13, and IL-10 were significantly suppressed in all groups (alpha-chitin>=beta chitin>=beta-chitosan). These results suggested that the administration of chitin and chitosan from by-products of food processing are beneficial for the prevention of food allergies. PMID- 23806321 TI - Osteochondrosis in pigs diagnosed with computed tomography: heritabilities and genetic correlations to weight gain in specific age intervals. AB - The aim of this study was to develop a method for scoring osteochondrosis (OC) by using information from computed tomography (CT), as well as to estimate the heritability for OC scored by means of CT (OCwCT) of the medial and lateral condyles at the distal end of the humerus or the femur of the right and left leg and the sum of these scores (OCT). In addition, we were aiming at revealing the genetic relationship between OCwCT traits and growth in different periods (days from birth to 30 kg (D30), days from 30 to 50 kg (D30_50), days from 50 to 70 kg (D50_70), days from 70 to 90 kg (D70_90), days from 90 to 100 kg (D90_100) and days from birth to 100 kg (D100)). The OCwCT was assessed for 1449 boars, and growth data were collected for these 1449 boars and additional 3779 boars tested in the same time period. All boars were tested as part of the Norsvin Landrace boar test and in the same test station. Heritabilities for OCwCT on anatomical locations varied from 0.21 (s.e. = 0.08) on the medial condyle of the right humerus to 0.06 (s.e. = 0.06) on the lateral condyle of the left femur, whereas OCT exhibited the highest heritability (h2 = 0.31, s.e. = 0.09). Genetic correlations between OCT and OCwCT for the anatomical locations ranged from 0.94 (s.e. = 0.07) for OCT and OCwCT score for the medial condyle of the humerus right side to 0.26 (s.e. = 0.39) for OCT and the lateral condyle of the femur left side. Genetic correlations between D30 and OCT were medium high and unfavourable (r(g) = -0.74). As the boar gain weight, the relationship between growth rate- expressed as number of days spent growing from one interval to the next--and OCT decreased to 0.12 (s.e. = 0.19, i.e. not significantly different from zero) for the trait D90_100 kg. These changes of genetic correlation coefficients coincide with the maturing of the joint cartilage and skeletal structures. In this study, we demonstrate that CT could be used for selection against OC in breeding programmes in pigs and that the genetic correlations between growth periods and OC are decreasing over time. PMID- 23806322 TI - Kv7.1 isoform gradients in the heart: new potential approach to alter repolarization reserve. PMID- 23806323 TI - Modulated parasystole: still relevant after all these years! PMID- 23806324 TI - Cardiovascular implantable electronic device monitoring: is an ounce of prevention worth a pound of cure? PMID- 23806325 TI - Asymmetric dimethylarginine serum levels in non-diabetic ankylosing spondylitis patients undergoing TNF-alpha antagonist therapy. AB - OBJECTIVES: This paper aims to determine whether disease activity, systemic inflammation and metabolic syndrome are potential determinants of circulating asymmetric dimethylarginine (ADMA) in ankylosing spondylitis (AS) patients undergoing TNF-alpha antagonist-infliximab-therapy. METHODS: We investigated ADMA serum concentrations in a series of 30 non-diabetic AS patients without history of cardiovascular (CV) events that were treated with the TNF-alpha antagonist infliximab, immediately prior to an infliximab infusion. Correlations of ADMA serum levels with disease activity, systemic inflammation and metabolic syndrome were assessed. Also, potential changes in ADMA concentration following an infusion of the anti-TNF-alpha monoclonal antibody-infliximab were analysed. RESULTS: A higher concentrations of ADMA in men (p=0.012) and patients with hypertension was found (p=0.001). There was also a marginally positive correlation of ADMA serum levels with C-reactive protein levels (p=0.08). Moreover, a significant negative correlation between ADMA levels and total cholesterol and LDL-cholesterol was observed (p= 0.05). No differences in ADMA levels according to the specific clinical features of the disease were seen. A single infliximab infusion did not lead to significant changes in ADMA serum levels. CONCLUSIONS: In AS patients undergoing periodical treatment with the anti TNF-alpha monoclonal antibody-infliximab a link between some features of metabolic syndrome and ADMA concentrations was observed. PMID- 23806326 TI - Letter to the editor. PMID- 23806327 TI - Analyses of direct and indirect impacts of a positive list system on pharmaceutical R&D investments. AB - BACKGROUND: The South Korean government recently enacted a Positive List System (PLS) as a major change of the national formulary listing system and reimbursed prices for pharmaceutical products. Regardless of the primary goal of the PLS, its implementation might have spillover effects by influencing the pharmaceutical industry's research and development (R&D), potentially leading to a variety of responses by firms in relation to their R&D activities. OBJECTIVE: We investigated the spillover effect of the PLS on R&D investments of the pharmaceutical industry in Korea through both direct and indirect channels, examining the influence of the PLS on sales profit and cash flow. METHODS: Data from 9 years (5 before and 4 after PLS implementation) were drawn from the financial statements of firms whose stocks were exchanged in 2 official stock markets in Korea (526 firms) and additional pharmaceutical firms whose financial performance was officially audited by external reviewers (263 firms). Longitudinal analyses were conducted, using the panel nature of the data to control for permanent unobserved firm heterogeneity. RESULTS: Our results showed that the PLS was directly associated with R&D investments. In contrast, its indirect impacts stemming from the influence on sales profit and cash flow were minimal and statistically nonsignificant. The gross impact of the PLS on R&D investments increased moving further from the enactment year; R&D investments were reduced by 18.3% to 25.8% in 2009-2010 (compared with before PLS implementation) in the firm fixed-effects model. We also found that such negative direct and gross impacts of the PLS on R&D investments were significant only in firms without newly developed chemical entities. CONCLUSION: Considering the gross negative impact of the PLS on R&D investments of pharmaceutical firms and the heterogeneous response of these firms by the R&D activities, governmental efforts of cost-containment may need to consider the spillover impact of the PLS on pharmaceutical innovation. PMID- 23806328 TI - A novel method to value real options in health care: the case of a multicohort human papillomavirus vaccination strategy. AB - BACKGROUND: A large number of economic evaluations have already confirmed the cost-effectiveness of different human papillomavirus (HPV) vaccination strategies. Standard analyses might not capture the full economic value of novel vaccination programs because the cost-effectiveness paradigm fails to take into account the value of active management. Management decisions can be seen as real options, a term used to refer to the application of option pricing theory to the valuation of investments in nonfinancial assets in which much of the value is attributable to flexibility and learning over time. OBJECTIVE: The aim of this article was to discuss the potential advantages shown by using the payoff method in the valuation of the cost-effectiveness of competing HPV immunization programs. METHODS: This was the first study, to the best of our knowledge, to use the payoff method to determine the real option values of 4 different HPV vaccination strategies targeting female subjects aged 12, 15, 18, and 25 years. The payoff method derives the real option value from the triangular payoff distribution of the project's net present value, which is treated as a triangular fuzzy number. To inform the real option model, cost-effectiveness data were derived from an empirically calibrated Bayesian model designed to assess the cost effectiveness of a multicohort HPV vaccination strategy in the context of the current cervical cancer screening program in Italy. A net health benefit approach was used to calculate the expected fuzzy net present value for each of the 4 vaccination strategies evaluated. RESULTS: Costs per quality-adjusted life-year gained seemed to be related to the number of cohorts targeted: a single cohort of girls aged 12 years (?10,955 [95% CI, -1,021 to 28,212]) revealed the lowest cost among the 4 alternative strategies evaluated. The real option valuation challenged the cost-effectiveness dominance of a single cohort of 12-year-old girls. The simultaneous vaccination of 2 cohorts of girls aged 12 and 15 years yielded a real option value (?17,723) equivalent to that attributed to a single cohort of 12-year-old girls (?17,460). CONCLUSIONS: The payoff method showed distinctive advantages in the valuation of the cost-effectiveness of competing health care interventions, essentially determined by the replacement of the nonfuzzy numbers that are commonly used in cost-effectiveness analysis models, with fuzzy numbers as an input to inform the real option pricing method. The real option approach to value uncertainty makes policy making in health care an evolutionary process and creates a new "space" for decision-making choices. PMID- 23806329 TI - Central corneal thickness does not correlate with TonoLab-measured IOP in several mouse strains with single transgenic mutations of matricellular proteins. AB - Accurate and reliable measurement of intraocular pressure (IOP) is crucial in the study of glaucoma using the mouse model. The purpose of this study was to determine the relationship between TonoLab-measured IOP and central corneal thickness (CCT) in mouse strains with single gene mutations of matricellular proteins. Wild-type (WT) and transgenic mouse strains with single gene mutations (KO) of thrombospondin-1 (TSP-1), thrombospondin-2 (TSP-2), osteopontin (OPN), hevin, and secreted protein acidic rich in cysteine (SPARC) were imaged at six weeks using optical coherence tomography (Stratus, Zeiss) to determine CCT. IOP was measured between 11am and 3pm using TonoLab, one week later. For all measurements, mice were anesthetized using intraperitoneal injection ketamine:xylazine. CCT and IOP were measured in 583 mice (TSP-1 n = 71 and 41, TSP-2 n = 60 and 32, OPN n = 81 and 50, hevin n = 59 and 76, SPARC n = 54 and 59, WT and KO, respectively). Mean CCT was 5-6% lower in three KO strains-TSP-1, OPN, and SPARC-compared to their corresponding WT (p = 1.55 * 10(-7), 1.63 * 10(-11), and 1.91 * 10(-7), respectively). The mean IOP was 8.3%, 6.6%, and 15.1% lower in three KO strains-TSP-1, TSP-2, and SPARC-compared to corresponding WT (p = 2.11 * 10(-5), 2.93 * 10(-3), and 3.76 * 10(-9), respectively. Linear regression of IOP versus CCT yielded no statistically significant within-strain correlations for TSP-1 (p = 0.12 and 0.073), TSP-2 (p = 0.473 and 0.92), OPN (p = 0.212 and 0.916), Hevin (p = 0.746 and 0.257), and SPARC (p = 0.080 and 0.056), reported as p-values considering a null hypothesis of zero slope (WT and KO, respectively). Neither C57-derived strains (TSP-1 and OPN) nor 129-derived strains (TSP-2, hevin, SPARC) demonstrated a correlation between mean IOP and mean CCT across different strains (p = 0.75 and p = 0.53, respectively). Taken together, these results indicate that CCT is not required to interpret TonoLab IOP readings in the mice when CCT varies 10% about the mean. This does not exclude the possibility of an IOP-CCT correlation for CCT values outside this range or for inter-strain comparisons where the mean CCT differs more than 10%. PMID- 23806330 TI - Relaxation of porcine retinal arterioles exposed to hypercholesterolemia in vivo is modified by hepatic LDL-receptor deficiency and diabetes mellitus. AB - Metabolic disturbances in diabetes mellitus include changes in the type and concentration of lipids in the blood plasma which may contribute to the development of diabetic retinopathy. This disease is characterized by changes in retinal blood flow secondary to changes in the tone of retinal arterioles which is regulated by compounds such as adenosine, adenosine triphosphate (ATP), the glutamate agonist N-methyl-d-aspartate (NMDA) and prostaglandin E2 (PGE2). However, the relation between increased plasma low density lipoprotein (LDL) and tone regulation in retinal resistance vessels has not been studied in detail. Twelve male and nine female Yucatan minipigs overexpressing a gain-of-function mutant (D374Y) of the human gene PCSK9 that blocks LDL transport into the liver and twelve wild-type males were studied. The animals were fed a cholesterol rich diet from the age of 60 days, followed by induction of diabetes mellitus in twelve of the transgenic animals. The animals were sacrificed at a mean age of 51 weeks (range 26-60 weeks), followed by inspection and histological examination of retinal vessels, and examination of the changes in vascular tone induced by adenosine, ATP, NMDA and PGE2. In the transgenic pigs without diabetes mellitus ATP-induced relaxation was reduced in isolated arterioles, and a whitish infiltration in an arteriole was observed in 4/8 (50%) of the animals, whereas these changes were not found in the other groups. Histological examination of one of the infiltrations showed staining with Oil Red O representing foamy cells sub endothelially in the vascular wall indicating atheromatosis. Adenosine, ATP and PGE2 induced a significant concentration-dependent relaxation of retinal arterioles in all groups. The presence of perivascular retinal tissue had no effect on the relaxing effect of adenosine, but increased the relaxing effect of ATP and PGE2 in the two transgenic animal groups, whereas NMDA had no significant effect on vascular tone in any of the groups. Relaxation of porcine retinal arterioles exposed to hypercholesterolemia in vivo is modified by hepatic LDL receptor deficiency and diabetes mellitus. This suggests that transgenic animal models are suitable for studying the influence of systemic diseases on retinal vascular function. PMID- 23806331 TI - Prevalence and risk factors for Staphylococcus aureus colonization in individuals entering maximum-security prisons. AB - To assess the prevalence and risk factors for colonization with Staphylococcus aureus in inmates entering two maximum-security prisons in New York State, USA, inmates (N=830) were interviewed and anterior nares and oropharyngeal samples collected. Isolates were characterized using spa typing. Overall, 50.5% of women and 58.3% of men were colonized with S. aureus and 10.6% of women and 5.9% of men were colonized with MRSA at either or both body sites. Of MSSA isolates, the major subtypes were spa type 008 and 002. Overall, risk factors for S. aureus colonization varied by gender and were only found in women and included younger age, fair/poor self-reported general health, and longer length of prior incarceration. Prevalence of MRSA colonization was 8.2%, nearly 10 times greater than in the general population. Control of epidemic S. aureus in prisons should consider the constant introduction of strains by new inmates. PMID- 23806332 TI - Acidification activates ERp44--a molecular litmus test for protein assembly. AB - In this issue of Molecular Cell, Vavassori et al. (2013) show that a pH-induced conformational change in the quality control protein ERp44 allows retrieval of secretory proteins that contain free thiols via a disulfide linkage from postendoplasmic reticulum compartments to prevent their premature secretion. PMID- 23806333 TI - p53: the TRiC is knowing when to fold 'em. AB - In this issue, Trinidad et al. (2013) show that CCT/TRiC is a chaperone required for p53 folding, thus providing another layer of regulation of p53 function, with implications for cancer therapeutics targeting the p53 pathway. PMID- 23806334 TI - OTULIN restricts Met1-linked ubiquitination to control innate immune signaling. AB - Conjugation of Met1-linked polyubiquitin (Met1-Ub) by the linear ubiquitin chain assembly complex (LUBAC) is an important regulatory modification in innate immune signaling. So far, only few Met1-Ub substrates have been described, and the regulatory mechanisms have remained elusive. We recently identified that the ovarian tumor (OTU) family deubiquitinase OTULIN specifically disassembles Met1 Ub. Here, we report that OTULIN is critical for limiting Met1-Ub accumulation after nucleotide-oligomerization domain-containing protein 2 (NOD2) stimulation, and that OTULIN depletion augments signaling downstream of NOD2. Affinity purification of Met1-Ub followed by quantitative proteomics uncovered RIPK2 as the predominant NOD2-regulated substrate. Accordingly, Met1-Ub on RIPK2 was largely inhibited by overexpressing OTULIN and was increased by OTULIN depletion. Intriguingly, OTULIN-depleted cells spontaneously accumulated Met1-Ub on LUBAC components, and NOD2 or TNFR1 stimulation led to extensive Met1-Ub accumulation on receptor complex components. We propose that OTULIN restricts Met1-Ub formation after immune receptor stimulation to prevent unwarranted proinflammatory signaling. PMID- 23806335 TI - The ZFP-1(AF10)/DOT-1 complex opposes H2B ubiquitination to reduce Pol II transcription. AB - The inhibition of transcriptional elongation plays an important role in gene regulation in metazoans, including C. elegans. Here, we combine genomic and biochemical approaches to dissect a role of ZFP-1, the C. elegans AF10 homolog, in transcriptional control. We show that ZFP-1 and its interacting partner DOT 1.1 have a global role in negatively modulating the level of polymerase II (Pol II) transcription on essential widely expressed genes. Moreover, the ZFP-1/DOT 1.1 complex contributes to progressive Pol II pausing on essential genes during development and to rapid Pol II pausing during stress response. The slowing down of Pol II transcription by ZFP-1/DOT-1.1 is associated with an increase in H3K79 methylation and a decrease in H2B monoubiquitination, which promotes transcription. We propose a model wherein the recruitment of ZFP-1/DOT-1.1 and deposition of H3K79 methylation at highly expressed genes initiates a negative feedback mechanism for the modulation of their expression. PMID- 23806336 TI - FANCD2 activates transcription of TAp63 and suppresses tumorigenesis. AB - Fanconi anemia (FA) is a rare genetic disorder characterized by an increased susceptibility to squamous cell cancers. Fifteen FA genes are known, and the encoded proteins cooperate in a common DNA repair pathway. A critical step is the monoubiquitination of the FANCD2 protein, and cells from most FA patients are deficient in this step. How monoubiquitinated FANCD2 suppresses squamous cell cancers is unknown. Here we show that Fancd2-deficient mice are prone to Ras oncogene-driven skin carcinogenesis, while Usp1-deficient mice, expressing elevated cellular levels of Fancd2-Ub, are resistant to skin tumors. Moreover, Fancd2-Ub activates the transcription of the tumor suppressor TAp63, thereby promoting cellular senescence and blocking skin tumorigenesis. For FA patients, the reduction of FANCD2-Ub and TAp63 protein levels may account for their susceptibility to squamous cell neoplasia. Taken together, Usp1 inhibition may be a useful strategy for upregulating TAp63 and preventing or treating squamous cell cancers in the general non-FA population. PMID- 23806338 TI - Oxidative stress decreases uptake of neutral amino acids in a human placental cell line (BeWo cells). AB - Increased oxidative stress (OS) is implicated in the pathophysiology of several pregnancy disorders. We aimed to investigate the effect of tert butylhydroperoxide (TBHP)-induced OS upon the placental transport of the neutral amino acids L-methionine (L-Met) and L-alanine (L-Ala), by using a human trophoblast cell model (BeWo cells). TBHP reduced both total and Na(+) independent (14)C-L-Met intracellular steady-state accumulation over time (Amax), by reducing non-system L-mediated uptake - most probably system y(+) - while having no effect on system L. Moreover, TBHP reduced total (14)C-L-Ala Amax through an inhibition of system A. The effect of TBHP upon total, but not system A-mediated, (14)C-L-Ala uptake was dependent upon phosphoinositide 3-kinase (PI3K) and protein kinase C (PKC) activation, and was completely prevented by the polyphenol quercetin. In conclusion, a reduction in placental uptake of neutral amino acids may contribute to the deleterious effects of pregnancy disorders associated with OS. PMID- 23806337 TI - SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways. AB - Protein function is regulated by diverse posttranslational modifications. The mitochondrial sirtuin SIRT5 removes malonyl and succinyl moieties from target lysines. The spectrum of protein substrates subject to these modifications is unknown. We report systematic profiling of the mammalian succinylome, identifying 2,565 succinylation sites on 779 proteins. Most of these do not overlap with acetylation sites, suggesting differential regulation of succinylation and acetylation. Our analysis reveals potential impacts of lysine succinylation on enzymes involved in mitochondrial metabolism; e.g., amino acid degradation, the tricarboxylic acid cycle (TCA) cycle, and fatty acid metabolism. Lysine succinylation is also present on cytosolic and nuclear proteins; indeed, we show that a substantial fraction of SIRT5 is extramitochondrial. SIRT5 represses biochemical activity of, and cellular respiration through, two protein complexes identified in our analysis, pyruvate dehydrogenase complex and succinate dehydrogenase. Our data reveal widespread roles for lysine succinylation in regulating metabolism and potentially other cellular functions. PMID- 23806339 TI - Lesion edge preserved direct average strain estimation for ultrasound elasticity imaging. AB - Elasticity imaging techniques with built-in or regularization-based smoothing feature for ensuring strain continuity are not intelligent enough to prevent distortion or lesion edge blurring while smoothing. This paper proposes a novel approach with built-in lesion edge preservation technique for high quality direct average strain imaging. An edge detection scheme, typically used in diffusion filtering is modified here for lesion edge detection. Based on the extracted edge information, lesion edges are preserved by modifying the strain determining cost function in the direct-average-strain-estimation (DASE) method. The proposed algorithm demonstrates approximately 3.42-4.25 dB improvement in terms of edge mean-square-error (EMSE) than the other reported regularized or average strain estimation techniques in finite-element-modeling (FEM) simulation with almost no sacrifice in elastographic-signal-to-noise-ratio (SNRe) and elastographic contrast-to-noise-ratio (CNRe) metrics. The efficacy of the proposed algorithm is also tested for the experimental phantom data and in vivo breast data. The results reveal that the proposed method can generate a high quality strain image delineating the lesion edge more clearly than the other reported strain estimation techniques that have been designed to ensure strain continuity. The computational cost, however, is little higher for the proposed method than the simpler DASE and considerably higher than that of the 2D analytic minimization (AM2D) method. PMID- 23806340 TI - The inhibitory effect of proanthocyanidin on soluble and collagen-bound proteases. AB - OBJECTIVE: This study evaluated the inhibitory effect of proanthocyanidin (PA), a natural collagen cross-linker, on soluble and matrix-bound proteases, which are responsible for progressive degradation of exposed collagen fibrils within the hybrid layer and resin-dentine bond failure over time. METHODS: The inhibitory effects of PA (1%, 2%, 3%, 4.5% and 6%) on soluble recombinant matrix metalloproteinases (MMP-2, -8 and -9) and cysteine cathepsins (cathepsin B and K) were evaluated using MMP and cysteine cathepsins fluorometric assay kits. Chlorhexidine (CHX) was used as an inhibitor control. The effect of PA on endogenous matrix-bound proteases was examined by determining the change in dry mass of demineralized dentine beams and solubilized collagen peptides over 30 days. Two-way ANOVA and Tukey multiple comparison tests were used to analyze the effect of PA and proteases on the percentage inhibition of soluble proteases (alpha=0.05). Kruskal-Wallis one-way ANOVA and Dunn's multiple comparison tests were used to analyse the effect of PA on loss of dry mass and hydroxyproline content over time (alpha=0.05). RESULTS: Proanthocyanidin inactivated more than 90% of soluble recombinant MMP-2, -8 and -9 and around 75-90% of cysteine cathepsin B and K, which was significantly higher than CHX (P<0.05). The inhibition of endogenous proteases by PA increased in a dose-dependent manner. The loss of dry mass and hydroxyproline release in the medium over time was the lowest in dentine beams pretreated with PA+/ 5%), this study provides viable alternatives for estimating sex in Western Australian individuals with accuracy equivalent to established standards developed from foot bones. PMID- 23806342 TI - Applicability of Willems model for dental age estimations in Brazilian children. AB - Several studies described tooth development as a reliable pathway for age estimations. Depending on the considered life span, the dental age indicators vary. In children, combinations of developing teeth provide the best information about age. In sub adults third molar mineralization is almost exclusively considered. The aim of this study was, firstly, to verify the Willems model in a Brazilian sample. Secondly, to observe differences between the Willems model and a new developed Brazilian model. Thirdly, the information of permanent teeth (PM) and third molar (TM), development was combined for age estimation in children. A sample of 1357 panoramic radiographs of Brazilian males (M) and females (F), with age between 5 and 23 years was collected. The technique of Gleiser and Hunt modified by Kohler (1955) [34] was applied for third molar staging in the entire sample. The Demirjian staging technique was used on the mandibular left permanent teeth (except third molars) of all individuals from 5 to 15 years. Kappa and weighted Kappa statistics were performed to verify inter- and intra-observer reliabilities. Based on the obtained Demirjian scores the Willems model was verified. Next the data were split to develop a new Brazilian model based on the Willems method and to verify the established model. The accuracy in age prediction between the Willems model and the new Brazilian model was compared. Additionally, regression models including PM, TM and PM plus TM information were compared. The Kappa and weighted Kappa statistics revealed high agreement between observers (0.88 Kappa; 0.93 weighted Kappa). The differences between predicted and chronological age for the verified Willems model were expressed in mean errors of -0.17 and -0.38 year for F and M respectively. The differences in mean error between the new developed Brazilian model and the Willems model were 0.02 (F) and 0.20 (M) year. The regression models combining PT and TM information provided only in the age range between 14 and 15.99 years a small decrease in root mean squared error (0.2 year) in females. The new developed Brazilian model provided similar age predicting performances as the Willems et al. model. Added TM was only providing more accurate age estimations in the ages of 14 and 15 year in F. PMID- 23806343 TI - Syritta pipiens (Diptera: Syrphidae), a new species associated with human cadavers. AB - The analyses of necrophagous insects feeding on a corpse can be successfully used to estimate the minimum time since death. A minimum time frame is sometimes an underestimate, but it is actually the only method that can provide such information when decomposed remains are found at a crime scene. Many insects are known to be colonisers of a corpse, but because there is an endless spectrum of crime scene environments, the development data bases for necrophagous insects is incomplete. The two cases detailed in this paper show different entomological patterns due to the different environments (well and burial) and locations (south and central Italy) where the two cadavers were found. Common to both of these cases' was the discovery of the corpse in the same period of the year (January) and the presence of Syritta pipiens (Diptera: Syrphidae), a species that has never been associated with deceased humans. The ecological information concerning this insect was used in combination with the more typical entomofauna found on the corpse to provide a minimum post mortem interval. PMID- 23806344 TI - Massive gas embolism revealed by two consecutive postmortem computed-tomography examinations. AB - We present a case of unusual gas embolism in a 73-year-old man who was found in a state of cardiopulmonary arrest with an oxygen-supply tube connected to an intravenous catheter inserted into his median cubital vein. Postmortem computed tomography (PMCT) performed 27 h after death showed systemic gas distribution including intravascular gas, pneumothorax, pneumoperitoneum, pneumomediastinum, pneumoretroperitoneum and gastric emphysema. A second PMCT scan performed 116 h after death showed a marked decrease of air inside the body. The current case shows the importance of PMCT for visualization, quantification, and preservation of evidence for establishment of the cause of death in cases with suspected gas embolism. Our findings also indicate that performance of two PMCT examinations may be useful for differentiation of embolized gas from gas produced by putrefaction. PMID- 23806345 TI - Patterns of skeletal trauma in suicidal bridge jumpers: a retrospective study from the southeastern United States. AB - In the discovery of human remains from water environments, manner of death may not be immediately obvious to medicolegal investigators due to several factors, including lack of associated material evidence, nondescript contextual environment, or possible poor preservation of remains due to delayed recovery. The determination of patterns of skeletal trauma in suicidal bridge jumpers assists investigators in determining whether the manner of death was suicide versus non-suicide. This study reports on the patterns of skeletal trauma sustained in individuals who jumped from one of four large bridges in Charleston Harbor, South Carolina, and explores victim demographics, bridge height, position of the body upon impact, and velocity at impact on skeletal trauma for this suicide population. Data for all bridge jumpers were collected from coroner files spanning the years 1990-2011. Skeletal trauma is more heavily focused in the thorax/ribs (63%) and craniofacial (30%) regions. Fifty-six percent of jumpers sustained polytrauma. Comparative data on drowning victims, bodies recovered from boating/airplane accidents, and individuals who died by other suicidal means all show patterns of injury different than bridge jumpers. PMID- 23806346 TI - Gut metagenome and spondyloarthritis. PMID- 23806347 TI - Level of evidence of clinical spinal research and its correlation with journal impact factor. AB - BACKGROUND: Over the past two decades, there has been a growing recognition and emphasis on the practice of evidence-based medicine (EBM). The level of evidence (LOE) is used to classify clinical studies based on their quality and design. To compare the quality of scientific journals, the impact factor (IF) is the most widely used ranking measure. However, the calculation of IF is not directly dependent on the quality or LOE of clinical articles published in a journal. PURPOSE: The primary aim of this study was to evaluate the current LOE for clinical research in leading spinal journals and assess the relationship between LOE and IF. We hypothesized that most clinical research would provide level IV evidence, and that a positive correlation would exist between the proportion of high LOE articles and the journal IF. STUDY DESIGN: A systematic review of all the articles in five general spinal journals was undertaken during 2010. SAMPLE: All online articles in The Spine Journal, Spine, European Spine Journal, Journal of Neurosurgery: Spine, and Journal of Spinal Disorders and Techniques during 2010, as well as supplements were included. OUTCOME MEASURE: The LOE for each clinical study was assessed using guidelines produced by the Oxford Centre for Evidence-Based Medicine. METHODS: Two reviewers independently assessed all articles. RESULTS: Overall 703 articles were suitable for LOE grading. Of these, 4.7% provided level I evidence, 23.2% level II, 12.5% level III, and 59.6% level IV. There was a significant association between LOE and type of study (p<.001); articles on therapeutic studies had the largest proportion (71.8%) of level IV evidence. There was a strong positive correlation between the proportion of level I and II evidence and the journal impact factor (rho=0.9; 95% confidence interval 0.1 to 0.99; p=.037). CONCLUSION: Spinal surgery journals with a higher IF contain a larger proportion of studies with high LOE, however most clinical articles provide level IV evidence of which the highest proportion are therapeutic studies. Clinicians, researchers, and journal editors should work hand in hand to enhance evidence-based practice in spinal care. PMID- 23806348 TI - Unstable odontoid fracture: surgical strategy in a 22-case series, and literature review. AB - Surgical treatment of unstable odontoid fracture (type II OBAR or HTAL) has progressed, with a range of techniques, the specificities of which need to be known so as to determine their respective roles in the therapeutic arsenal now available. A retrospective study of 22 patients operated on in our center for odontoid fracture between 2005 and 2010 examined the operative techniques employed and analyzed results in the light of the literature, so as to construct an updated decision tree. Two populations could be distinguished: elderly victims of simple fall (mean age, 82.1 years), and younger victims of high-energy trauma (mean age, 42.6 years). Surgical techniques comprised: anterior odontoid screwing (n=14), transarticular C1-C2 screwing on the posterior Magerl (n=3) or anterior Vaccaro approach (n=1), Harms' posterior C1-C2 arthrodesis (n=3), and occipitocervical arthrodesis (n=3). The overall complications rate for the series was 28%, including one case of non-union, at a mean 11 months' follow-up. The risk/benefit ratio may be hard to assess in elderly patients. However, anterior screwing restores odontoid anatomy and is the technique of choice in first intention for reducible fracture. In second intention, transarticular C1 C2arthrodesis may be performed on an anterior or posterior approach, depending on local vertebral artery anatomy. Harms' posterior C1-C2 arthrodesis allows fixation of non-reduced fractures. Occipitocervical arthrodesis is a last resort, as the associated morbidity rate is higher. PMID- 23806349 TI - Relation between lower extremity alignment and proximal femur anatomy. Parameters during total hip arthroplasty. AB - BACKGROUND: Lower extremity alignment correlates with native femoral offset. Eventual impact of the change in femoral offset induced by total hip arthroplasty (THA) on lower extremity alignment has not been documented. HYPOTHESIS: THA significantly changes lower extremity alignment, and the change correlates with the change in femoral offset. MATERIALS AND METHODS: We conducted a prospective study of 200 patients with primary hip osteoarthritis or avascular femoral head necrosis who underwent cementless THA. Pre-operative computed-tomography templating was performed and the femoral component was then custom-manufactured to replicate the native femoral anatomy. Mean age was 58 years (range, 28-83 years). Before and at least two years after THA, two observers who were not involved in the surgical procedures used standing antero-posterior long-leg radiographs to determine the mechanical axis of the lower-limb (hip-knee-ankle [HKA] angle), femoral offset, neck-shaft angle (NSA), and lower-limb length discrepancy (LLLD). RESULTS: Mean values pre-operatively and at last follow-up were as follows: HKA angle, 179.2 degrees +/- 3.9 degrees (range, 170.5 degrees to 190.5 degrees ) and 177.7 degrees +/- 3.5 degrees (range, 173 degrees to 187 degrees ); LLLD, -0.7 mm (range, -30 mm to +25 mm) and +5.1 mm (range, -7 mm to +21 mm); NSA, 134 degrees +/- 7.5 degrees (range, 100 degrees to 124 degrees ) and 135 degrees +/- 4.2 degrees (range, 124 degrees to 146 degrees ); and femoral offset, 42 +/- 7.8 mm (range, 24 mm to 68 mm) and 49 +/- 7.5 mm (range, 33 mm to 70 mm). Although THA significantly altered lower-limb alignment, univariate and multivariate analyses showed no significant association between the change in HKA angle and the change in femoral offset. DISCUSSION: Lower-limb alignment was significantly affected by THA, although the HKA angle changes were small. The small impact of THA on HKA angle values may be ascribable to efforts aimed at replicating the native femoral offset during arthroplasty, as well as to the limited sample size and to potential measurement errors related to the small size of the changes. Our results suggest that, provided careful attention is directed to replicating the native femoral offset, THA in patients with limited pre-operative anatomical abnormalities may have no major impact on the biomechanical parameters of the ipsilateral knee. LEVEL OF EVIDENCE: Level III, prospective diagnostic study. PMID- 23806350 TI - Massive wrist prosthesis for giant cell tumour of the distal radius: a case report with a 3-year follow-up. AB - We report the case of a 72-year-old woman in whom a mega wrist prosthesis was used to reconstruct the distal radius after en-bloc resection of a giant cell tumour. Three years later, her pain score was 2/10 and motion ranges were 20 degrees of flexion, 70 degrees of extension, 70 degrees of pronation, 60 degrees of supination, 20 degrees of radial deviation, and 20 degrees of ulnar deviation. The QuickDASH score was 52.27/100 and the Enneking score was 83%. Radiographically, the prosthesis was well aligned, with no evidence of loosening but with dorsal subluxation of the ulnar head. The outcome in this patient, together with published data, indicate that mega prosthesis use is among the treatment options for distal radius reconstruction after en-bloc resection of a giant cell tumour, provided a biocompatible, bipolar, unconstrained prosthesis is used. PMID- 23806351 TI - Correlation and prediction of partition coefficient using nonrandom two-liquid segment activity coefficient model for solvent system selection in counter current chromatography separation. AB - Selection of a suitable solvent system is the first and foremost step for a successful counter-current chromatography (CCC) separation. In this paper, a thermodynamic model, nonrandom two-liquid segment activity coefficient model (NRTL-SAC) which uses four types of conceptual segments to describe the effective surface interactions for each solvent and solute molecule, was employed to correlate and predict the partition coefficients (K) of a given compound in a specific solvent system. Then a suitable solvent system was selected according to the predicted partition coefficients. Three solvent system families, heptane/methanol/water, heptane/ethyl acetate/methanol/water (Arizona) and hexane/ethyl acetate/methanol/water, and several solutes were selected to investigate the effectiveness of the NRTL-SAC model for predicting the partition coefficients. Comparison between experimental results and predicted results showed that the NRTL-SAC model is of potential for estimating the K value of a given compound. Also a practical separation case on magnolol and honokiol suggests the NRTL-SAC model is effective, reliable and practical for the purpose of predicting partition coefficients and selecting a suitable solvent system for CCC separation. PMID- 23806352 TI - Fluoroacetylation/fluoroethylesterification as a derivatization approach for gas chromatography-mass spectrometry in metabolomics: preliminary study of lymphohyperplastic diseases. AB - Metabolic fingerprinting in combination with gas chromatography and multivariate analysis is being extensively employed for the improved understanding of biological changes induced by endogenous or exogenous factors. Chemical derivatization increases the sensitivity and specificity of gas chromatography mass spectrometry (GC-MS) for polar or thermally labile biological compounds, which bear derivatizable groups. Thus, there is a constant demand for simple methods of derivatization and separation that satisfy the need for metabolite analysis, identifying as many chemical classes of compounds as possible. In this study, an optimized protocol of extraction and derivatization is established as a generally applicable method for the analysis of a wide range of classes of metabolites in urine, whole blood and saliva. Compounds of biological relevance bearing hydroxyl- carboxyl- and amino-groups are derivatized using single-step fluoroacetylation/fluoroethylesterification after proper optimization of the protocol. Subsequently, the developed derivatization procedure is engaged in finding blood metabolic biomarkers, induced by lymphohyperplastic disease, through the metabolomic fingerprinting approach, the multivariate modeling (hierarchical cluster analysis) and GC-MS. Our preliminary, GC-MS-based metabolomic fingerprinting study underlines the contribution of certain metabolites to the discrimination of patients with lymphohyperplastic diseases. PMID- 23806353 TI - Comments on "hydrodynamic and dispersion behavior in a non-porous silica monolith through fluid dynamic study of a computational mimic reconstructed from sub-micro tomographic scans". AB - We comment on a recently published paper by Loh and Vasudevan [J. Chromatogr. A 1274 (2013) 65], which reported the physical reconstruction of the bulk macropore space of an analytical silica monolith by X-ray computed microtomography and the subsequent computational fluid dynamics simulations of flow and mass transport in the reconstructed monolith model. Loh and Vasudevan claim that their combined reconstruction and simulation approach offers a significant reduction of computational expenses without significant loss in accuracy in characterizing the macropore space heterogeneity of the monolith and predicting its transport properties. We challenge their claim and question the validity and validation of their results by discussing the employed scanning resolution, the characterization of macropore space heterogeneities, the interpretation of the simulated dispersion data, as well as the comparison of computational expenses with previous work. PMID- 23806354 TI - A new silylation reagent dimethyl(3,3,3-trifluoropropyl)silyldiethylamine for the analysis of estrogenic compounds by gas chromatography-mass spectrometry. AB - In this study we applied DIMETRIS (dimethyl(3,3,3 trifluoropropyl)silyldiethylamine), a new silylating reagent, to derivative natural estrogens such as estrone (E1), 17beta-estradiol (E2) and estriol (E3), as well as the synthetic 17alpha-ethinylestradiol (EE2) and the non-steroid diethylstilbestrol (DES). Its derivatizing properties were compared with those of the commonly used mixture of BSTFA (N,O-bis(trimethylsilyl)trifluoroacetamide)+1% trimethylchlorosilane (TMCS) and with MTBSTFA (N-tert-butyldimethylsilyl-N methyltrifluoroacetamide). The use of DIMETRIS for the silylation all of them is reported for the first time. The nucleophilic properties of DIMETRIS were found to be superior to those of MTBSTFA, but slightly inferior to those of BSTFA. It was used to derivatize steroid (E1, E2, E3 and EE2) and non-steroid (DES) estrogens at 30 degrees C prior to GC/MS analysis. These DMTFPS-derivatives exhibited good separation (low retention times despite the high molecular masses) and ionization properties in GC/MS analyses (the highest relative response factors for DMTFPS-derivatives among those tested). However, DIMETRIS and MTBSTFA (which produce mono-O-silyl derivatives of EE2) should not be used for the simultaneous analysis of EE2 and E1. Only a mixture of BSTFA+1% TMCS in pyridine, which generates the fully derivatized EE2 product (stable in GC injector), permits the determination of these two estrogenic compounds during one GC-MS run. On the other hand, because DIMETRIS requires a lower derivatization temperature than BSTFA, it could be very useful for the derivatization of thermally unstable estrogenic compounds. In the next step of this study, the SPE-GC-MS method based on DIMETRIS derivatization for the analysis of DES, E2 and E3 in aqueous samples was evaluated and validated. The MQL values: 1.4, 1.6 and 1.5ngL(-1) for DES, E2 and E3, respectively, proved its suitability to determine target compounds in environmental samples. Finally, the proposed method was successfully applied to the analysis of selected estrogenic compounds in real seawater and wastewater samples in Poland. PMID- 23806355 TI - Preparation and characterization of alkyl methacrylate-based monolithic columns for capillary gas chromatography applications. AB - Gas chromatography (GC) is considered the least common application of both polymer and silica-based monolithic columns. This study describes the fabrication of alkyl methacrylate monolithic materials for use as stationary phases in capillary gas chromatography. Following the deactivation of the capillary surface with 3-(trimethoxysilyl)propyl methacrylate (TMSM), the monoliths were formed by the co-polymerization of either hexyl methacrylate (HMA) or lauryl methacrylate (LMA) with different percentage of ethylene glycol dimethacrylate (EDMA) in presence of an initiator (azobisisobutyronitrile, AIBN) and a mixture of porogens include 1-propanol, 1,4-butanediol and water. The monoliths were prepared in 500mm length capillaries possessing inner diameters of 250MUm. The efficiencies of the monolithic columns for low molecular weight compounds significantly improved as the percentage of crosslinker was increased, because of the greater proportion of pores less than 50nm. The columns containing lower percentages of crosslinker were able to rapidly separate a series of 8 alkane members in 0.7min, but the separation was less efficient for the light alkanes. Columns prepared with the lauryl methacrylate monomer yielded a different morphology for the monolith-interconnected channels. The channels were more branched, which increased the separation time, and unlike the other columns, allowed for temperature programming. PMID- 23806356 TI - Molecular basis of interactions between mitochondrial proteins and hydroxyapatite in the presence of Triton X-100, as revealed by proteomic and recombinant techniques. AB - Hydroxyapatite chromatography is a very important step in the purification of voltage-dependent anion channels (VDACs) and several members of solute carrier family 25 (Slc25) from isolated mitochondria. In the presence of Triton X-100, VDACs and Slc25 members present a peculiar property, i.e., a lack of interaction with hydroxyapatite, resulting in their presence in the flow-through fraction of hydroxyapatite chromatography. This property has allowed selective isolation of VDACs and Slc25 members from a mixture of total mitochondrial proteins. However, the reason why only these few proteins are selectively obtained in the presence of Triton X-100 from the flow-though fraction of hydroxyapatite chromatography has not yet been adequately understood. In this study, when we examined the protein species in the flow-through fractions by proteomic analysis, VDAC isoforms, Slc25 members, and some other membrane proteins were identified. All the mitochondrial proteins had in common high hydrophobicity over their entire protein sequences. When the proteins were fused to soluble proteins, the fused proteins showed affinity for hydroxyapatite even in the presence of Triton X-100. Based on these results, we discussed the molecular basis of the interactions between proteins and hydroxyapatite in the presence of Triton X-100. PMID- 23806357 TI - Polyacrylamide brush layer for hydrophilic interaction liquid chromatography of intact glycoproteins. AB - A chromatographic column of nonporous silica particles with a bonded phase of linear polyacrylamide chains is evaluated for hydrophilic interaction liquid chromatography (HILIC) of intact glycoproteins. The column is shown to retain glycoproteins significantly more strongly than non-glycoproteins. A particle diameter of 700nm gives two-fold higher resolution than does a 1.4MUm particle diameter, and the column efficiency is found to be mostly limited by packing heterogeneity. LCMS is able to resolve the five glycoforms of ribonuclease B and give high quality mass spectra, but there is loss of resolution of the isomers of glycoforms due to the lower amount of TFA. Compared to two leading commercial HILIC columns operated at 60 degrees C, the polyacrylamide column operated at 30 degrees C provided at least two-fold higher resolution for intact ribonuclease B, and showed peaks for glycoforms of prostate specific antigen, although not resolved. PMID- 23806358 TI - Micro extraction by packed sorbent coupled to liquid chromatography tandem mass spectrometry for the rapid and sensitive determination of cannabinoids in oral fluids. AB - The evaluation of oral fluids (OFs) levels is useful in proving drug consumption, particularly for monitoring abuse in workplaces and for the driving under the influence of drugs (DUIDs) programs. OF is a complex matrix and a small amount of sample is available, especially after cannabis smoking. This paper reports a method for the determination of cannabinoids and metabolites in OF: THC, 11 hydroxy-THC (OH-THC) and THC-COOH. Cannabidiol (CBD) and cannabinol (CBN) were also detected by LC-MS/MS. The OF pre-treatment was based on micro-extraction by packed sorbent (MEPS), a recently developed solid phase extraction technique which operates with small sample volumes: only 125MUL of sample was required, allowing the collection by simple expectoration. Analytes elution was achieved using 2*25MUL of 50mM NH4OH in methanol. A rapid and effective clean-up has been obtained with satisfactory recovery values and a negligible matrix effect. The LOQs ranged between 0.020ngmL(-1) for THC-COOH and 0.40ngmL(-1) for OH-THC. The chromatographic conditions obtained with a fused-core column allowed a good separation of the analytes in 6min only. The whole procedure has been validated according to SOFT/AAFS guidelines. PMID- 23806359 TI - Facile preparation of a stable and functionalizable hybrid monolith via ring opening polymerization for capillary liquid chromatography. AB - An organic-inorganic hybrid monolith was prepared by a single-step ring-opening polymerization of octaglycidyldimethylsilyl polyhedral oligomeric silsesquioxane (POSS) with poly(ethylenimine) (PEI). The obtained hybrid monoliths possessed high ordered 3D skeletal microstructure with dual retention mechanism that exhibits reversed-phase (RP) mechanism under polar mobile phase and hydrophilic interaction liquid chromatography (HILIC) retention mechanism under less polar mobile phase. The high column efficiencies of 110,000N/m can be achieved for separation of alkylbenzenes in capillary reversed-phase liquid chromatography (cLC). Due to the robust property of hybrid monolith and the rich primary and secondary amino groups on its surface, the resulting hybrid monolith was easily modified with gamma-gluconolactone and physically coated with cellulose tris(3,5 dimethylphenylcarbamate) (CDMPC), respectively. The former was successfully applied for HILIC separation of neutral, basic and acidic polar compounds as well as small peptides, and the latter for enantioseparation of racemates in cLC. The high column efficiencies were achieved in all of those separations. These results demonstrated that the hybrid monolith (POSS-PEI) possessed high stability and good surface tailorbility, potentially being applied for other research fields. PMID- 23806360 TI - Structural investigation of the proton-coupled secondary transporters. AB - Transmembrane proton gradients, known as Proton Motive Force (PMF), serve important physiological functions. In addition to driving ATP synthesis, PMF is harnessed by a large variety of secondary transporters to achieve 'uphill' translocation of specific substrates across the membrane. Proton-coupled secondary transporters, including both symporters and antiporters, are widely involved in nutrient uptake and metabolite expulsion, multidrug resistance, and the maintenance of electrolyte homeostasis. Structural studies have led to the identification of several new folds for proton co-transporters, and establish an important framework for the mechanistic understanding of proton-dependent substrate transport. This review focuses on recent advances in the structural elucidation of proton-coupled secondary transporters. PMID- 23806361 TI - Post-hatching ontogeny of intestinal proton-coupled folate transporter and reduced folate carrier in broiler chickens. AB - Folate transporters, including the reduced folate carrier and the proton-coupled folate transporter, encoded by Slc19a1 and Slc46a1 genes respectively, play important roles in the transport of folate across biological membranes given the hydrophilic nature of folates. Although a number of studies have demonstrated that these two transporters are regulated ontogenetically in mammals, little data are available on their developmental patterns of expression in poultry. The objective of this study was to investigate the expression patterns of Slc19a1 and Slc46a1 in jejunal and cecal tissue of broiler chickens during post-hatching development. Post-hatch male chicks (Ross * Ross) had free access to water and a soybean/wheat-based diet. Jejunal, cecal and blood samples were collected on day of-hatch but before feeding (D0), and on D2, D7, D14, D21 and D35 post-hatch (n = 8 at each time point), respectively. Plasma folate concentrations were low on the day of hatch and increased with maturation; by contrast, plasma homocysteine, a marker of folate status, was highest (P < 0.05) in the day-of-hatch birds and decreased thereafter. Increasing age reduced mRNA abundance of Slc19a1 (P < 0.05) in the jejunum and cecum. Abundance of Slc46a1 mRNA (P < 0.05) gradually decreased in the cecum with increasing age and that of Slc46a1 in the jejunum initially decreased and then increased to level similar to that of day-of-hatch. The study provides some initial data on ontogenetic regulation of Slc19a1 and Slc46a1 in the jejunum and cecum of the chicken and lays the ground work for future nutritional studies. Moreover, the expression of Slc19a1 and Slc46a1 transcripts in the cecum provides evidence of the potential for cecally derived folate to contribute to the folate status of the host. PMID- 23806362 TI - First evidence of protein G-binding protein in the most primitive vertebrate: serum lectin from lamprey (Lampetra japonica). AB - The intelectins, a recently identified subgroup of extracellular animal lectins, are glycan-binding receptors that recognize glycan epitopes on foreign pathogens in host systems. Here, we have described NPGBP (novel protein G-binding protein), a novel serum lectin found in the lamprey, Lampetra japonica. RT-PCR yielded a 1005 bp cDNA sequence from the lamprey liver encoding a 334 amino acid secretory protein with homology to mammalian and aquatic organism intelectins. Gene expression analyses showed that the NPGBP gene was expressed in the blood, intestines, kidney, heart, gill, liver, adipose tissue and gonads. NPGBP was isolated by protein G-conjugated agarose immunoprecipitation, and SDS-PAGE analyses showed that NPGBP migrated as a specific band (~35 and ~124 kDa under reducing and non-reducing conditions, respectively). These results suggested that NPGBP forms monomers and tetramers. NPGBP gene expression was induced by in vivo bacterial stimulation, and NPGBP showed different agglutination activities against pathogenic Gram-positive bacteria, Gram-negative bacteria and fungi. The induction of NPGBP suggested that it plays an important role in defense against microorganisms in the internal circulation system of the lamprey. When incubated with an unrelated antibody, the specific binding between NPGBP and protein G was competitively inhibited, indicating that NPGBP and the Fc region of Ig bind to the same site on protein G. We thus assume that the tertiary structure of NPGBP is similar to that of the Fc region of Ig. Additionally, NPGBP can effectively promote endothelial cell mitosis. These findings suggest that NPGBP plays a role in the immune defense against microorganisms, and this study represents one of the few examples of the characterization and functional analysis of an aquatic organism intelectin. PMID- 23806363 TI - Understanding facilitators and barriers to reengineering the clinical research enterprise in community-based practice settings. AB - Solutions are employed to support clinical research trial tasks in community based practice settings. Using the IT Implementation Framework (ITIF), an integrative framework intended to guide the synthesis of theoretical perspectives for planning multi-level interventions to enhance IT use, we sought to understand the barriers and facilitators to clinical research in community-based practice settings preliminary to implementing new informatics solutions for improving clinical research infrastructure. The studies were conducted in practices within the Columbia University Clinical Trials Network. A mixed-method approach, including surveys, interviews, time-motion studies, and observations was used. The data collected, which incorporates predisposing, enabling, and reinforcing factors in IT use, were analyzed according to each phase of ITIF. Themes identified in the first phase of ITIF were 1) processes and tools to support clinical trial research and 2) clinical research peripheral to patient care processes. Not all of the problems under these themes were found to be amenable to IT solutions. Using the multi-level orientation of the ITIF, we set forth strategies beyond IT solutions that can have an impact on reengineering clinical research tasks in practice-based settings. Developing strategies to target enabling and reinforcing factors, which focus on organizational factors, and the motivation of the practice at large to use IT solutions to integrate clinical research tasks with patient care processes, is most challenging. The ITIF should be used to consider both IT and non-IT solutions concurrently for reengineering of clinical research in community-based practice settings. PMID- 23806364 TI - Establishing catalytic activity on an artificial (betaalpha)8-barrel protein designed from identical half-barrels. AB - It has been postulated that the ubiquitous (betaalpha)8-barrel enzyme fold has evolved by duplication and fusion of an ancestral (betaalpha)4-half-barrel. We have previously reconstructed this process in the laboratory by fusing two copies of the C-terminal half-barrel HisF-C of imidazole glycerol phosphate synthase (HisF). The resulting construct HisF-CC was stepwise stabilized to Sym1 and Sym2, which are extremely robust but catalytically inert proteins. Here, we report on the generation of a circular permutant of Sym2 and the establishment of a sugar isomerization reaction on its scaffold. Our results demonstrate that duplication and mutagenesis of (betaalpha)4-half-barrels can readily lead to a stable and catalytically active (betaalpha)8-barrel enzyme. PMID- 23806365 TI - Total mismatch in anterior circulation stroke patients before thrombolysis. AB - BACKGROUND AND PURPOSE: Our aim was to estimate the prevalence of negative diffusion-weighted imaging (DWI) with total perfusion-diffusion mismatch in a large series of anterior circulation stroke patients treated with thrombolysis and to describe the characteristics of these patients. MATERIALS AND METHODS: From January 2006 to December 2010, a retrospective search was made for total perfusion-diffusion (PWI-DWI) mismatch patterns on pretreatment 1.5-T MRI scans of 166 consecutive thrombolyzed patients taken<4.5 h after onset of anterior stroke. A total mismatch profile corresponded to an absence of initial DWI signal changes with hypoperfusion (T(max)>6 s) on PWI. Clinical and MRI characteristics were compared between DWI+ and DWI- patients. RESULTS: Five (3%) patients had a normal initial DWI. All had stable substantial clinical deficits (NIHSS scores >= 6) and large perfusion abnormalities - in other words, 'total mismatch' - and infarcts in the acutely hypoperfused area on follow-up imaging. While DWI- and DWI+ patients did not significantly differ in any of the pretreatment imaging or clinical variables except for the extent of PWI-DWI mismatch, DWI- patients had lower NIHSS scores at 24 h, and were more likely to show early neurological improvement (Delta0-24 h NIHSS >= 8) and good outcomes (mRS <= 2) at the time of hospital discharge. CONCLUSION: Total mismatch i.e. failure of DWI to reveal any ischemic tissue despite a large perfusion defect, can be observed before thrombolysis even in stroke patients with stable substantial neurological deficits. However, this rare MRI profile is associated with a favorable outcome after thrombolysis. PMID- 23806366 TI - Relation between electrophysiological findings and diffusion weighted magnetic resonance imaging in ulnar neuropathy at the elbow. AB - AIM: As only a limited number of studies have used diffusion-weighted imaging (DWI) and conventional magnetic resonance imaging (MRI) in patients with ulnar neuropathy at the elbow (UNE), the present study aimed to investigate the diagnostic value of the non-invasive DWI technique in patients with UNE. METHODS: A total of 26 elbows in 19 healthy controls (age range: 22-56 years) with no symptoms and 24 elbows in 21 symptomatic patients (age range: 21-46 years) with cubital tunnel syndrome underwent DWI. The electrophysiological and clinical criteria for the diagnosis of UNE were examined. RESULTS: No pathological signal from the ulnar nerve was detected in the healthy controls, whereas there was an increase in signals on DWI in all patients with UNE. On T2-weighted (T2W) imaging, there was increased signal intensity in 20 elbows, while low signal intensity was observed in the remaining four. A positive correlation was found between disease duration and presence of hyperintensity (P=0.044, r=0.42) on T2W images. CONCLUSION: DWI can be used together with electrophysiological methods for the diagnosis of UNE. Furthermore, DWI might be preferred in some cases, as it is non-invasive compared with the electrophysiological method for UNE diagnosis. PMID- 23806367 TI - Up-regulation of Fas ligand expression by sirtuin 1 in both flow-restricted vessels and serum-stimulated vascular smooth muscle cells. AB - OBJECTIVE: To study the role of sirtuin 1 (SIRT1) in Fas ligand (FasL) expression regulation during vascular lesion formation and to elucidate the potential mechanisms. METHODS: SIRT1 and FasL protein levels were detected by Western blotting in either mouse arteries extract or the whole rat aortic vascular smooth muscle cell (VSMC) lysate. Smooth muscle cell (SMC)-specific human SIRT1 transgenic (Tg) C57BL/6 mice and their littermate wild-type (WT) controls underwent complete carotid artery ligation (ligation groups) or the ligation excluded operation (sham groups). The carotid arteries were collected 1 day after operation. Reverse transcription-polymerase chain reaction was performed to detect the mRNA levels of SIRT1 and FasL. Luciferase reporter assays were performed to detect the effect of WT-SIRT1, a dominant-negative form of SIRT1 (SIRT1H363Y), and GATA-6 on the promoter activity of FasL. Flow cytometry assay was applied to measure the hypodiploid DNA content of VSMC so as to monitor cellular apoptosis. RESULTS: SIRT1 was expressed in both rat aortic VSMCs and mouse arteries. Forced SIRT1 expression increased FasL expression both in injured mouse carotid arteries 1 day after ligation (P<0.001) and VSMCs treated with serum (P<0.05 at the transcriptional level, P<0.001 at the protein level). No notable apoptosis was observed. Furthermore, transcription factor GATA-6 increased the promoter activity of FasL (P<0.001). The induction of FasL promoter activity by GATA-6 was enhanced by WT-SIRT1 (P<0.001), while SIRT1H363Y significantly relieved the enhancing effect of WT-SIRT1 on GATA-6 (P<0.001). CONCLUSIONS: Overexpression of SIRT1 up-regulates FasL expression in both flow restricted mouse carotid arteries and serum-stimulated VSMCs. The transcription factor GATA-6 participates in the transcriptional regulation of FasL expression by SIRT1. PMID- 23806368 TI - Chinese herbal medicine in treatment of polyhydramnios:a meta-analysis and systematic review. AB - OBJECTIVE: To compare the efficacy of Chinese herbal medicine (therapy A) or Chinese herbal medicine plus indomethacin (therapy B) with that of indomethacin alone (therapy C) in treating polyhydramnios. METHODS: Literatures published up to April 2012 were retrieved from PubMed, Embase and Cochrane library, Chinese National Knowledge Infrastructure (CNKI), Chinese Scientific and Technological Periodical Database (VIP), Wangfang, and Traditional Chinese Medicine online. Two researchers collected data independently. The assessment of methodological quality was based on Cochrane handbook and the materials were analyzed with software RevMan 5.1.2. The outcome measure index was relative risk or difference of mean value (95% confidence interval). The following outcomes were evaluated (1) general clinical improvement rate; (2) maximum vertical pocket depth; (3) amniotic fluid index (AFI) value; (4) rate of fetal ductus arteriosus constriction; (5) incidence of adverse events. RESULTS: Based on the search strategy, 5 trails involving 1017 patients were finally included. Compared with therapy C, therapy A decreased the rate of fetal ductus arteriosus constriction (P<0.01). Therapy B was more effective than therapy C in general clinical improvement and decrease of AFI for polyhydramnios (P<0.01). No serious adverse events were reported in therapy A and therapy B. CONCLUSIONS: Compared with therapy C, therapy A and therapy B may appear to be more effective for polyhydramnios. However, the exact effect needs to be confirmed with well designed large-scale clinical trials. PMID- 23806369 TI - Lysine-specific demethylase 1 represses THP-1 monocyte-to-macrophage differentiation. AB - OBJECTIVE: To investigate the role of lysine-specific demethylase 1 (LSD1) in the process of THP-1 monocyte-to-macrophage differentiation. METHODS: Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blotting were performed to analyze the expression of LSD1 and interleukin-6 (IL-6) in THP 1 monocytes and THP-1-derived macrophages. Chromatin immunoprecipitation (ChIP) assay was applied to detect the occupancy of LSD1 and H3K4 methylation at IL-6 promoter during THP-1 monocyte-to-macrophage differentiation. IL-6 mRNA level and H3K4 methylation at IL-6 promoter were analyzed using qRT-PCR and ChIP assay in LSD1-knockdown THP-1 cells treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) for 0, 4, 8, 12, and 24 hours. Fluorescence activated flow cytometry was performed to reveal the percentage of macrophages differentiated from THP-1 monocytes. RESULTS: The expression of LSD1 reduced during THP-1 monocyte-to macrophage differentiation (P<0.01). LSD1 occupancy decreased and H3K4 methylation increased at IL-6 promoter during the differentiation. With knockdown of LSD1, H3K4 methylation at IL-6 promoter was found increased after TPA treatment at different times points (all P<0.05, except 24 hours). The percentage of macrophages increased significantly in the THP-1 cells with LSD1 knockdown (P<0.05). CONCLUSIONS: LSD1 is repressed during the monocyte-to-macrophage differentiation of THP-1 cells. Suppression of LSD1-mediated H3K4 demethylation may be required for THP-1 monocyte-to-macrophage differentiation. PMID- 23806370 TI - Physiological testosterone retards cardiomyocyte aging in Tfm mice via androgen receptor-independent pathway. AB - OBJECTIVE: To determine whether testosterone modulates markers of cardiomyocytes aging via its classic androgen receptor (AR)-dependent pathway or conversion to estradiol. METHODS: Male littermates and testicular feminized (Tfm) mice were randomly separated into 4 experimental groups littermate controls (n=8), Tfm mice (n=7), testosterone-treated Tfm mice (n=8), and Tfm mice treated with testosterone in combination with the aromatase inhibitor anastrazole (n=7). Cardiomyocytes were isolated from mouse left ventricles, the activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and the amount of malondialdehyde (MDA) were measured using colorimetry method, and expression of p16(INK4alpha) and retinoblastoma (Rb) proteins were detected by Western blotting. RESULTS: The SOD and GSH-Px enzyme activities of cardiomyocytes were decreased, and the MDA levels and the expression of p16(INK4alpha) and Rb proteins were increased in Tfm mice compared with control mice. An increase was observed in the activities of SOD and GSH-Px enzyme as well as a decrease in MDA levels and the expression of p16(INK4alpha) and Rb proteins in the testosterone treated Tfm mice. After co-treatment with anastrazole in Tfm mice, these improvement were partly inhibited. CONCLUSION: Physiological testosterone replacement can delay cardiomyocyte aging in Tfm mice, an effect that is independent of the AR pathway and in part conversion to estradiol. PMID- 23806371 TI - Blood lead levels during pregnancy and its influencing factors in Nanjing, China. AB - OBJECTIVE: To investigate the blood lead levels (BLLs) in the duration of pregnancy and 6-12 weeks after delivery, and analyze the influencing factors of BLLs in healthy pregnant women. METHODS: Pregnant women were recruited from September 2009 to February 2010 at the prenatal clinic in Nanjing Maternity and Child Health Care Hospital. Altogether 174 healthy pregnant women without pregnant or obstetric complications or abnormal pregnancy outcomes were enrolled as the gravida group, and 120 healthy non-pregnant women as the control group. BLLs during pregnancy were determined by flame atomic absorption spectroscopy. RESULTS: BLLs in all the three pregnancy trimesters and postpartum were 59.8+/ 24.3, 55.4+/-20.1, 55.9+/-19.7, and 67.6+/-17.4 MUg/L, respectively, and the mean BLL in control group was 67.5+/-21.3 MUg/L. BLLs during all the three trimesters were lower in the gravida group than in the control group (P=0.043, 0.021, and 0.028). Furthermore, occupations, nutrients supplementation, and time of house/apartment painted were associated with BLLs in pregnant women. Lead-related occupations, cosmetics use, and living in a house painted less than 1 year before are risk factors of high BLLs among pregnant women, while calcium, iron, zinc, and milk supplements are protective factors. CONCLUSION: Supplementing calcium, iron, zinc, and milk, or avoiding contact with risk factors may help people, especially pregnant women, to reduce lead exposure. PMID- 23806372 TI - Notice of retraction. PMID- 23806373 TI - Unsuspected gallbladder cancer during or after laparoscopic cholecystectomy. AB - OBJECTIVE: To summarize the clinical features and outcomes of unsupected gallbladder carcinoma ( UGC) detected during or after laparoscopic cholecystectomy. METHODS: Medical records of 8005 patients, who underwent laparoscopic cholecystectomy in Peking Union Medical College Hospital between June 1993 and June 2011, were reviewed. Patients that pathologically diagnosed as UGC were retrospectively studied in terms of clinical features, preoperative and postoperative diagnosis, surviving period, and complications. RESULTS: In the 8005 patients who received laparoscopic cholecystectomy, 36 (0.45%) were diagnosed as UGC during (25 patients) or after (11 patients) laparoscopic cholecystectomy. The gallbladder cancer was staged as T1 in 16 patients, T2 in 11 patients, and T3 in 9 patients. The 1-, 3-, and 5-year survival rates of all the patients were 88.9% (32/36), 63.9% (23/36), and 58.3% (21/36). The 5-year survival rates in T1 stage, T2 stage, and T3 stage patients were 100%, 75.0%, and 0.0%, respectively. CONCLUSIONS: The survival rate of UGC is associated with tumor stage, not with operation approaches. Laparoscopic cholecystectomy is appropriate for T1 patients. PMID- 23806374 TI - Standard versus extended pancreaticoduodenectomy in treating adenocarcinoma of the head of the pancreas. AB - OBJECTIVES: To compare the postoperative complications and survival of standard pancreatoduodenectomy (SPD) and extended pancreatoduodenectomy (EPD) in patients with resectable adenocarcinoma of the head of the pancreas. METHODS: Between January 1994 and December 2011, 165 patients with biopsy-proven adenocarcinoma of the pancreatic head were treated in West China Hospital, among whom 93 underwent SPD and 72 had EPD. Complications and survival after the surgery were analyzed retrospectively. RESULTS: The median operation time of the EPD group was longer compared with the SPD group (375 minutes vs.310 minutes, P<0.01), the volume of blood transfusion was larger (700 mL vs.400 mL, P<0.05), while the median hospital stay (13.5 days vs.12 days, P=0.79) and the total complication rates were comparable (34.7% vs.32.4%, P=0.93). The total recurrence rates of the SPD and EPD groups were not significantly different (52.7% vs. 43.1%, P=0.83). No significant differences were found between the SPD and EPD groups in 1-year (81.7% vs. 86.1%), 3-year (38.7% vs. 43.1%), 5-year (16.7% vs. 19.4%), and median survivals (19.8 months vs. 23.2 months, P= 0.52). CONCLUSION: The postoperative complications and survival donot differ significantly between SPD and EPD. PMID- 23806375 TI - Safety and efficacy of frameless stereotactic brain biopsy techniques. AB - OBJECTIVE: To explore the safety and efficacy of frameless stereotactic brain biopsy. METHODS: Diagnostic accuracy was calculated by comparing biopsy diagnosis with definitive pathology in 62 patients who underwent frameless stereotactic brain biopsy between January 2008 and December 2010 in Xiamen University Southeast Hospital. Preoperative characteristics and histological diagnosis were reviewed and then information was analysed to identify factors associated with the biopsy not yielding a diagnosis and complications. RESULTS: Diagnostic yield was 93.5%. No differences were found between pathological diagnosis and frozen pathological diagnosis. The most common lesions were astrocytic lesions, included 16 cases of low-grade glioma and 12 cases of malignant glioma. Remote hemorrhage, metastasis, and lymphoma were following in incidence. Multiple brain lesions were found in 17 cases (27.4%). Eleven cases were frontal lesions (17.7%), 8 were frontotemporal (12.9%), 6 were frontoparietal (9.7%), and 5 each were temporal, parietal, and parietotemporal lesions (8.1%). Postoperative complications occurred in 21.0% of the patients after biopsies, including 10 haemorrhages (16.1%) and 3 temporary neurological deficits (1 epilepsy, 1 headache, and 1 partial hemiparesis). No patient required operation for hematoma evacuation. CONCLUSION: Frameless stereotactic biopsy is an effective and safe technique for histologic diagnosis of brain lesions, particularly for multifocal and frontal lesions. PMID- 23806376 TI - Open surgical insertion of Tenkchoff straight catheter without guide wire. AB - OBJECTIVE: To compare the clinical outcomes of open surgical peritoneal dialysis catheter (PDC) insertion with guide wire and the outcomes of PDC insertion without guide wire. METHODS: Data of the patients receiving open surgical Tenkchoff straight catheter insertion in our department from January 2005 to January 2011 were retrospectively analyzed. The 117 patients in whom PDC insertion was conducted with the guidance of guide wire were enrolled into group A, and the 121 cases receiving PDC insertion without guide wire were enrolled into group B. The incidences of post-operative complications (catheter obstruction, catheter displacement, bloody dialysate, and dialysate leakage), catheter survival, and patient survival rates were compared between the 2 groups. RESULTS: The baseline characteristics (gender, age, body mass index, prothrombin time, activated partial thromboplastin time, platelet count, serum creatinine, follow-up time, primary diseases, and outcomes) of the 2 groups were comparable (all P>0.05). In post-operative complications, only the incidence of early bloody dialysate showed significant difference, being 16.2% in group A and 7.4% in group B (P=0.04). Catheter and patient survival rates were not significantly different between the two groups. Overweight patients showed a higher incidence of catheter obstruction compared with normal weight patients [16.0% (4/25) vs.3.3% (7/213), P=0.02], but no differences in post-operative complications were found among overweight patients between the 2 groups. CONCLUSIONS: Open surgical Tenkchoff straight catheter insertion without guide wire does not lead to higher risk of post-operative complications and catheter removal. It may be an alternative option when guide wire is not available. PMID- 23806377 TI - Characteristics of antisense non-coding RNA in the INK4 locus and its roles in disease. AB - With the development of genome-wide sequencing technology, 195 types of functional long non-coding RNAs (lncRNAs) have so far been found, and their cellular roles are gradually being revealed. Now lncRNAs have become a hotspot in the life science. These small molecules exist in almost all higher eukaryotes, and have very important regulatory roles in these organisms. This review briefly summarizes recent progress in researches on antisense non-coding RNA in the INK4 locus. PMID- 23806378 TI - Ureteral stent fragmentation:a case report and review of literature. PMID- 23806379 TI - Combination of rapamycin and imatinib in treating refractory chronic myeloid leukemia myeloid blast crisis:a case report(025B3;). PMID- 23806380 TI - Add life to years: psychosocial interventions for people with cognitive disorders. PMID- 23806381 TI - Ionic liquid crystals as alignment medium to measure residual dipolar couplings for carbohydrates. AB - Ionic liquids consisting of N-dodecyl-N-methyl pyrrolidinium bromide [C12MPB] in a mixture with D2O, decanol, and DMSO were for the first time found to give anisotropic molecular alignment in magnetic fields and are useful to measure residual dipolar couplings (RDCs) from polar analytes, for example, glucose. The system shows less quadrupolar splitting of the deuterated solvent signal compared with other liquid crystal systems and hence less undesired line broadening. PMID- 23806382 TI - Stent grafts for central venous occlusive disease in patients with ipsilateral hemodialysis access. AB - PURPOSE: To assess long-term outcomes of stent grafts in patients with symptomatic central venous stenoses and occlusions ipsilateral to hemodialysis grafts or fistulas. MATERIALS AND METHODS: The study included 52 of 55 consecutive patients with symptomatic stenoses of the central veins draining upper limb dialysis access grafts or fistulas treated with stent grafts. Indications for stent grafts were poor angioplasty results, rapid recurrence, or total occlusion. Endpoints were lesion patency and access patency following intervention. Mean follow-up was 25 months with a median of 24 months and 1.25 additional procedures per patient year. Patency rates were calculated using Kaplan-Meier analysis. RESULTS: All stent grafts were successfully deployed. The lesion patency rates at 6, 12, 24, and 36 months after intervention were 60%, 40%, 28%, and 28%. The access patency rates at 6, 12, 24, and 36 months after intervention were 96%, 94%, 85%, and 72%. There was one major complication and no minor complications. In 40 patients (77%), the internal jugular vein confluence was covered by the stent graft. In five patients, the dialysis circuits became occluded, with no clinical sequelae in four; one patient was lost to follow-up. The contralateral brachiocephalic vein was covered in three patients (6%), preventing contralateral access construction in one patient. CONCLUSIONS: Central vein stent graft placement in patients with hemodialysis access is associated with prolonged access patency. Coverage of major vein confluences, which occurred in 83% of the patients in this series, can compromise future access and should be avoided whenever possible by careful technique. PMID- 23806383 TI - The changing face of percutaneous image-guided biopsy: molecular profiling and genomic analysis in current practice. AB - Oncology is undergoing a revolutionary change. Image-guided biopsy is expected to play an increasingly important role in this radical transformation. Current concepts of disease and treatment are based on an established set of physical signs and symptoms and laboratory tests broken down by organ system. However, soon diseases will be categorized and treated based on much more specific and detailed molecular and genetic information. This transformation in how disease is categorized and treated will depend on the ability to harvest tissue from tumors and analyze it appropriately. PMID- 23806385 TI - Nebivolol attenuates prooxidant and profibrotic mechanisms involving TGF-beta and MMPs, and decreases vascular remodeling in renovascular hypertension. AB - Nebivolol and metoprolol are beta1-adrenergic receptor blockers with different properties. We hypothesized that nebivolol, but not metoprolol, could attenuate prooxidant and profibrotic mechanisms of hypertension and therefore protect against the vascular remodeling associated with hypertension. Hypertension was induced in male Wistar rats by clipping the left renal artery. Six weeks after surgery, hypertensive and sham rats were treated with nebivolol (10 mg kg(-1) day(-1)) or metoprolol (20 mg kg(-1) day(-1)) for 4 weeks. Systolic blood pressure was monitored weekly. Morphologic changes in the aortic wall were studied in hematoxylin/eosin and picrosirius red sections. Aortic NAD(P)H activity and superoxide production were evaluated by luminescence and dihydroethidium, respectively, and TBARS levels were measured in plasma. Aortic nitrotyrosine staining was evaluated to assess peroxynitrite formation. TGF-beta levels and p-ERK 1/2 expression were determined by immunofluorescence and Western blotting, respectively. Matrix metalloproteinase (MMP) activity and expression were determined by in situ zymography, gel zymography, Western blotting, and immunofluorescence, and TIMP-1 was assessed by immunohistochemistry. Both beta1 receptor antagonists exerted very similar antihypertensive effects. However, while metoprolol had no significant effects, nebivolol significantly attenuated vascular remodeling and collagen deposition associated with hypertension. Moreover, nebivolol, but not metoprolol, attenuated hypertension-induced increases in aortic NAD(P)H oxidase activity, superoxide production, TBARS concentrations, nitrotyrosine levels, TGF-beta upregulation, and MMP-2 and -9 expression/activity. No effects on p-ERK 1/2 and TIMP-1 expression were found. These results show for the first time that nebivolol, but not metoprolol, attenuates prooxidant and profibrotic mechanisms involving TGF-beta and MMP-2 and MMP-9, which promote vascular remodeling in hypertension. PMID- 23806384 TI - Antiplatelet effects of dietary nitrate in healthy volunteers: involvement of cGMP and influence of sex. AB - Ingestion of vegetables rich in inorganic nitrate has emerged as an effective method, via the formation of a nitrite intermediate, for acutely elevating vascular NO levels. As such a number of beneficial effects of dietary nitrate ingestion have been demonstrated including the suggestion that platelet reactivity is reduced. In this study we investigated whether inorganic nitrate supplementation might also reduce platelet reactivity in healthy volunteers and have determined the mechanisms involved in the effects seen. We conducted two randomised crossover studies each in 24 (12 of each sex) healthy subjects assessing the acute effects of dietary nitrate (250 ml beetroot juice) or potassium nitrate capsules (KNO3, 8 mmol) vs placebo control on platelet reactivity. Inorganic nitrate ingested either from a dietary source or via supplementation raised circulating nitrate and nitrite levels in both sexes and attenuated ex vivo platelet aggregation responses to ADP and, albeit to a lesser extent, collagen but not epinephrine in male but not female volunteers. These inhibitory effects were associated with a reduced platelet P-selectin expression and elevated platelet cGMP levels. In addition, we show that nitrite reduction to NO occurs at the level of the erythrocyte and not the platelet. In summary, our results demonstrate that inorganic nitrate ingestion, whether via the diet or through supplementation, causes a modest decrease in platelet reactivity in healthy males but not females. Our studies provide strong support for further clinical trials investigating the potential of dietary nitrate as an adjunct to current antiplatelet therapies to prevent atherothrombotic complications. Moreover, our observations highlight a previously unknown sexual dimorphism in platelet reactivity to NO and intimate a greater dependence of males on the NO soluble guanylate cyclase pathway in limiting thrombotic potential. PMID- 23806387 TI - Adenoviruses isolated from wild gorillas are closely related to human species C viruses. AB - We have isolated and cultured three distinct adenoviruses from wild gorillas. Phylogenetic analysis grouped the viruses with human adenovirus species C based on DNA polymerase, hexon, and E4ORF6 genes. The three wild gorilla adenoviruses clustered with the other species C captive gorilla adenoviruses, forming a branch separate from human and chimpanzee/bonobo adenoviruses. Animal sera to the three newly isolated viruses did not cross-neutralize, demonstrating serological distinctiveness. The human adenovirus 5 fiber knob blocked infection, suggesting use of the Coxsackie and Adenovirus Receptor. These viruses may provide viral vectors with properties distinct from chimpanzee adenovirus and human adenovirus vectors. PMID- 23806386 TI - BST-2/tetherin is overexpressed in mammary gland and tumor tissues in MMTV induced mammary cancer. AB - BST-2 restricts MMTV replication, but once infection has established, MMTV modulates BST-2 levels. MMTV-directed BST-2 modulation is tissue-specific and dependent on infection and neoplastic transformation status of cells. In the lymphoid compartment of infected mice, BST-2 expression is first upregulated and then significantly downregulated regardless of absence or presence of mammary tumors. However, in mammary gland tissues, upregulation of BST-2 expression is dependent on the presence of mammary tumors and tumor tissues themselves have high BST-2 levels. Elevated BST-2 expression in these tissues is not attributable to IFN since levels of IFNalpha and IFNgamma negatively correlate with BST-2. Importantly, soluble factors released by tumor cells suppress IFNalpha and IFNgamma but induce BST-2. These data suggest that overexpression of BST-2 in carcinoma tissues could not be attributed to IFNs but to a yet to be determined factor that upregulates BST-2 once oncogenesis is initiated. PMID- 23806389 TI - Editorial comment. PMID- 23806388 TI - Do nomograms designed to predict biochemical recurrence (BCR) do a better job of predicting more clinically relevant prostate cancer outcomes than BCR? A report from the SEARCH database group. AB - OBJECTIVE: To examine the ability of various postoperative nomograms to predict prostate cancer-specific mortality (PCSM) and to validate that they could predict aggressive biochemical recurrence (BCR). Prostate-specific antigen (PSA), grade, and stage are the classic triad used to predict BCR after radical prostatectomy (RP). Multiple nomograms use these to predict risk of BCR. A previous study showed that several nomograms could predict aggressive BCR (prostate-specific antigen doubling time [PSADT] <9 months) more accurately than BCR. However, it remains unknown if they can predict more definitive endpoints, such as PCSM. METHODS: We performed Cox analyses to examine the ability of 4 postoperative nomograms, the Duke Prostate Center (DPC) nomogram, the Kattan postoperative nomogram, the Johns Hopkins Hospital (JHH) nomogram, and the joint Center for Prostate Disease Research(CPDR)/Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) nomogram to predict BCR and PCSM among 1778 men in the Shared Equal Access Regional Cancer Hospital (SEARCH) database who underwent RP between 1990 and 2009. We also compared their ability to predict BCR and aggressive BCR in a subset of men. We calculated the c-index for each nomogram to determine its predictive accuracy for estimating actual outcomes. RESULTS: We found that each nomogram could predict aggressive BCR and PCSM in a statistically significant manner and that they all predicted PCSM more accurately than they predicted BCR (ie, with higher c-index values). CONCLUSION: Currently available nomograms used to predict BCR accurately predict PCSM and other more clinically relevant endpoints. Moreover, not only do they significantly predict PCSM, but do so with generally greater accuracy than BCR. PMID- 23806392 TI - Editorial comment. PMID- 23806391 TI - Screening rectal culture to identify fluoroquinolone-resistant organisms before transrectal prostate biopsy: do the culture results between office visit and biopsy correlate? AB - OBJECTIVE: To investigate the performance of screening rectal cultures obtained 2 weeks before transrectal prostate biopsy to detect fluoroquinolone-resistant organisms and again at transrectal prostate biopsy. MATERIALS AND METHODS: After institutional review board approval for observational study, we obtained a rectal culture on patients identified for a prostate biopsy but before antibiotic prophylaxis from September 12, 2011 to April 23, 2012. The specimen was cultured onto MacConkey agar with and without 1 MUg/mL ciprofloxacin. We then obtained a second rectal culture immediately before prostate biopsy after 24 hours of ciprofloxacin prophylaxis. All cultures were blinded to the practitioner until the end of the study. RESULTS: Of 108 patients enrolled, 58 patients had both rectal cultures for comparison. The median time duration between cultures was 14 (6-119) days. There were 54 of 58 concordant pairs (93%), which included 47 negative cultures and 7 positive cultures; 2 patients (3%) who were culture negative from the first screening culture became positive at biopsy. Sensitivity, specificity, negative, positive predictive values, and area under the operator curve were 95.9%, 77.8%, 95.9%, 77.8%, and 0.868, respectively. When Pseudomonas spp. are removed from the analysis, the area under the curve is increased to 0.927. CONCLUSION: Screening rectal cultures 2 weeks before prostate biopsy has favorable test performance, suggesting screening cultures give an accurate estimate of fluoroquinolone-resistant colonization. PMID- 23806394 TI - Oxidative stress negatively affects human sperm mitochondrial respiration. AB - OBJECTIVE: To correlate the level of oxidative stress in serum and seminal fluid and the level of sperm deoxyribonucleic acid (DNA) fragmentation with sperm mitochondrial respiratory efficiency. METHODS: Sperm mitochondrial respiratory activity was evaluated with a polarographic assay of oxygen consumption carried out in hypotonically treated sperm cells. A possible relationship between sperm mitochondrial respiratory efficiency, the level of oxidative stress, and the level of sperm DNA fragmentation was investigated. RESULTS: Sperm motility was positively correlated with mitochondrial respiration but negatively correlated with oxidative stress and DNA fragmentation. Interestingly, sperm mitochondrial respiratory activity was negatively affected by oxidative stress and DNA fragmentation. CONCLUSION: Our data indicate that sperm mitochondrial respiration is decreased in patients with high levels of reactive oxygen species by an uncoupling between electron transport and adenosine triphosphate synthesis. This reduction in mitochondrial functionality might be 1 of the reasons responsible for the decrease in spermatozoa motility. PMID- 23806395 TI - Does the use of a barbed polyglyconate absorbable suture have an impact on urethral anastomosis time, urethral stenosis rates, and cost effectiveness during robot-assisted radical prostatectomy? AB - OBJECTIVE: To evaluate the use of a single needle driver with the V-Loc (Covidien, Dublin, Ireland) running suture and compare this with the use of 2 needle drivers with polyglactin interrupted sutures (IS) in dividing the dorsal venous complex (DVC) and forming the urethrovesical anastomosis (UVA) during robot-assisted radical prostatectomy (RARP). MATERIALS AND METHODS: A prospective cohort study was performed to compare V-Loc (n = 40) with polyglactin (n = 40) sutures. Division of the dorsal venous complex and formation of the UVA during robot-assisted radical prostatectomy using V-Loc or polyglactin sutures were studied. Preoperative, intraoperative, and postoperative parameters were measured. RESULTS: V-Loc sutures were associated with a statistically significant reduction in mean dorsal vein suture time (3.15 minutes V-Loc vs 3.75 minutes IS, P = .02) and UVA anastomosis time (8.5 minutes V-Loc vs 11.5 minutes IS, P = .001). No significant difference was noted between operative time (121 minutes V Loc vs 130 minutes IS, P = .199), delayed healing rates (5% V-Loc vs 7.5% IS, P = .238), continence rate at 12 months (97.5% V-Loc vs 95% IS, P = .368), and urethral stenosis rates (2.5% V-Loc vs 2.5% IS, P = .347) in both groups. CONCLUSION: The use of a V-Loc running suture with a single needle driver is a feasible, reproducible, and economic technique with no significant difference in continence rates and urethral stenosis rates, compared with the use of a traditional interrupted suture. PMID- 23806396 TI - Zero ischemia robotic partial nephrectomy: sequential preplaced suture renorrhaphy technique. AB - OBJECTIVE: To describe a robotic partial nephrectomy (PN) technique that eliminates renal global ischemia while decreasing parenchymal bleeding. METHODS: Before tumor resection, a suture is placed through the parenchyma adjacent to the tumor and deep to the planned edge of resection. The tumor resection is begun between the tumor edge and the preplaced suture and continued along the excision margin until some bleeding is encountered. A second suture is placed into the already excised parenchyma. This is repeated until the mass is completely excised, while suturing the parenchyma simultaneously. RESULTS: Fourteen patients underwent this technique between April 2008 and January 2013 by a single surgeon. Median age was 66 years and 64.3% (N = 9) were men. Median body mass index (BMI) was 27.5 Kg/m(2). Median radius, endophytic, nearness to collecting system, anterior/posterior, and location (RENAL) nephrometry score was 6.5. Median tumor size excised off clamp was 2.2 cm. Three patients had multiple tumors; 2 having a warm ischemia time (WIT) of 14.5 and 15 minutes. Median estimated blood loss (EBL) was 192.5 mL. Median operative time was 160 minutes. There were no Clavien grade 3 or 4 complications. One patient had a postoperative ileus and 1 patient had a blood transfusion and deep vein thrombosis. One patient had a positive tumor parenchymal margin, but negative excisional bed margin. Median hospital stay was 3 days and median follow-up was 8.4 months. CONCLUSION: Sequential preplaced suture renorrhaphy technique is a safe and effective technique that may be useful in renal function preservation by limiting or eliminating WIT while aiding in maximizing nephron preservation, especially in those patients with solitary kidneys and multiple tumors. PMID- 23806397 TI - First experience of active surveillance before systemic target therapy in patients with metastatic renal cell carcinoma. AB - OBJECTIVE: To reveal the outcomes of initial active surveillance (AS), followed by deferred systemic target therapy, in a subpopulation of patients with indolent metastatic renal cell carcinoma (mRCC). METHODS: We retrospectively reviewed the clinical and pathologic data of patients with mRCC, who initially were monitored by planned AS before systemic therapy because of their preference and asymptomatic or slowly progressive disease, at our institution between 2000 and 2011. The primary outcome measures were progression-free survival (PFS) and overall survival (OS). RESULTS: Twenty-nine patients with a metastatic lesion at start of AS were eligible for this analysis. The median age at the start of AS was 69 years. Of these patients, 65% had recurrent disease and 35% were in stage IV. All patients had undergone nephrectomy and 86% had clear-cell carcinoma. No patients were categorized into a poor risk according to Memorial Sloan-Kettering Cancer Center (MSKCC) and Heng criteria. The median follow-up period was 35.4 months. Disease progression was observed in 72% of patients, but only 14% died during the follow-up period. The median PFS time was 26.1 months. After disease progression was observed, only 58% of these patients received treatment. The median OS had not been reached, but 12, 24, and 48 months OS rates were 96.4%, 88.7%, and 83.8%, respectively. CONCLUSION: PFS and OS of patients who underwent AS were acceptable. AS might be a reasonable approach, particularly for patients with prolonged, indolent course of the disease. Further observational studies with a larger sample size might be needed. PMID- 23806398 TI - Reply by the authors. PMID- 23806399 TI - Re: El-Assmy et al.: kidney stone size and Hounsfield units predict successful shockwave lithotripsy in children (Urology 2013;81:880-884). PMID- 23806400 TI - Re: Lee et al.: factors indicating renal injury in pediatric bilateral ureteropelvic-junction obstruction (Urology 2013;81:873-879). PMID- 23806401 TI - Reply by the authors. PMID- 23806402 TI - Re: Cumpanas et al.: intravesical prostatic protrusion can be a predicting factor for the treatment outcome in patients with lower urinary tract symptoms due to benign prostatic obstruction treated with tamsulosin (Urology 2013;81:859-863). PMID- 23806403 TI - Reply by the authors. PMID- 23806404 TI - Re: Isac et al.: endoscopic-guided versus fluoroscopic-guided renal access for percutaneous nephrolithotomy: a comparative analysis (Urology 2013;81:251-256). PMID- 23806405 TI - Reply by the authors. PMID- 23806406 TI - Analysis of erectile responses to imatinib in the rat. AB - OBJECTIVE: To investigate the erectile and cardiovascular responses to the tyrosine kinase inhibitor imatinib in the rat. MATERIALS AND METHODS: The effect of intracavernosal injection of imatinib on the intracavernosal pressure (ICP), ICP/mean arterial pressure (MAP) ratio, area under the curve, and duration of the increase in ICP and the effect of intravenous injection of imatinib on the MAP, cardiac output, and total peripheral resistance were investigated. The effect of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester on the responses to imatinib was investigated. RESULTS: Intracavernosal injection of imatinib produced significant dose-related increases in the ICP, ICP/MAP ratio, area under the curve, and duration of the increase in ICP and decreases in the MAP. The erectile responses to imatinib were rapid in onset and short in duration. The erectile responses to imatinib were not significantly altered by NG nitro-L-arginine methyl ester or cavernosal nerve crush injury, and imatinib was significantly less potent than the nitric oxide donor sodium nitroprusside in inducing erection. Intravenous injection of imatinib produced significant dose related decreases in the MAP without significantly changing the cardiac output, and imatinib was significantly less potent than sodium nitroprusside in decreasing the MAP. Systemic vascular resistance was decreased in a significant dose-related manner, and the vasodilator responses to imatinib were not altered by NG-nitro-L-arginine methyl ester. CONCLUSION: The present results have indicated that imatinib has significant erectile and systemic vasodilator activity in the rat that is not dependent on nitric oxide release. Another tyrosine kinase inhibitor, nilotinib, also increased the ICP and decreased the MAP in the rat. These data suggest that tyrosine kinases might play a constitutive role in maintaining penile tumescence and the baseline vasoconstrictor tone in the peripheral vascular bed. PMID- 23806408 TI - Prevention of torsion-induced testicular injury by Rhodiola rosea. AB - OBJECTIVE: To evaluate the efficacy of Rhodiola rosea (R. rose) extract in terms of preventing tissue injury induced by testicular torsion and subsequent ischemia/reperfusion (I/R). METHODS: Twenty-one Wistar albino male rats were divided into 3 groups: group 1 = control group, group 2 = I/R group, and group 3 = I/R + extract group. After 2 hours of ischemia and 4 hours of reperfusion, testes were removed and evaluated histologically by hematoxylin and eosin staining. Apoptosis in spermatogonial cells of seminiferous tubules was determined by transferase biotin-2'-deoxyuridine, 5'-triphosphate nick end labeling (TUNEL). To assess oxidative damage, serum malondialdehyde (MDA) and glutathione (GSH) levels were measured. RESULTS: Median MDA and GSH levels were, respectively, 12 +/- 3 pmol/mL and 24.8 +/- 3.8 MUM in group 1, 38 +/- 11 pmol/mL and 10.3 +/- 1.7 MUM in group 2, and 19 +/- 5 pmol/mL and 17.6 +/- 1.3 MUM in group 3 (P <.001 and P <.001, respectively). Median MDA levels, apoptotic cell density, and histopathologic scoring were significantly lower in groups 1 and 3 compared to group 2 (P <.017 for all). Median GSH levels were higher in groups 1 and 3 compared to group 2 (P <.017). CONCLUSION: R. rosea extract was shown to have partially preventive effects on testicular injury induced by torsion in this rat model. The mechanism by which R. rosea extract cause these effects merits further investigation. PMID- 23806407 TI - Alterations in deoxyribonucleic acid (DNA) methylation patterns of Calca, Timp3, Mmp2, and Igf2r are associated with chronic cystitis in a cyclophosphamide induced mouse model. AB - OBJECTIVE: To determine whether epigenetic changes occur during cyclophosphamide induced chronic bladder inflammation in mice. MATERIALS AND METHODS: Epigenetic changes play a role in the regulation of inflammatory genes in noncancer diseases such as asthma and chronic obstructive pulmonary disease. However, epigenetic (deoxyribonucleic acid [DNA] methylation) changes during chronic bladder inflammation have not been previously described. Chronic cystitis was induced in 3 groups of adult CD-1 male mice using multiple weight-based intraperitoneal cyclophosphamide injections during a 3-month period. Histopathologic and MethyLight assays were performed on specimens with chronic bladder inflammation at multiple points to monitor cystitis progression and DNA methylation changes compared with the control specimens. RESULTS: Histopathologic analysis showed the most extensive edema and urothelial sloughing at the 1-month point. MethyLight analyses revealed statistically significant changes in DNA methylation associated with the Calca, Timp3, Mmp2, and Igf2r genes in the chronic bladder injury model. The changes in DNA methylation associated with chronic cystitis were DNA hypomethylation of the Calca gene in the control tissue and DNA hypermethylation for the Calca, Timp3, Mmp2, and Igf2r genes compared with that in the control tissue. CONCLUSION: DNA methylation changes were noted in the Calca, Timp3, Mmp2, and Igf2r genes during chronic cystitis in a murine model. Epigenetic changes appear to play a role in the regulation of inflammatory bladder genes during chronic cystitis; however, additional studies are needed to elucidate the pathways associated with these genes. PMID- 23806409 TI - Male primary retroperitoneal mucinous cystadenoma. AB - Primary retroperitoneal mucinous cystadenoma of borderline malignancy is a rare disease, especially in male patients. Often these tumors are not incidentally found due to abdominal symptoms. We present the radiologic abdominal computed tomography scan, surgical, and pathologic images of this unique, rare condition in a male patient. Surgical treatment is recommended to establish diagnosis and treatment. PMID- 23806410 TI - Giant adrenal cavernous hemangioma: a rare abdominal mass. AB - An 84-year-old woman with left flank pain presented to our institution. Contrast enhanced computed tomography demonstrated a large spherical adrenal mass (diameter 13 cm) showing features of a benign lesion. Histologic examination revealed a giant adrenal hemangioma. Surgical resection was curative, with no recurrence at 2 years of follow-up. Surgery is usually recommended for symptomatic patients or in the case of a large lesion (>6 cm) because of the possibility of the coexistence of a malignancy or potential complications (ie, hemorrhage, rupture). PMID- 23806411 TI - Inguinoscrotal hernia of the ureter combined with renal pelvic carcinoma. AB - Inguinoscrotal herniation of the ureter is a rare finding, with the potential for serious surgical complications. Here we report an extremely rare case of inguinoscrotal hernia of the ureter combined with renal pelvic carcinoma. This 61 year-old man was diagnosed with right renal pelvic tumor, bilateral hydronephrosis with inguinoscrotal hernia of the right ureter, and left ureteral calculus. He was successfully treated with right nephroureterectomy, inguinoscrotal hernia repair, and left ureterolithotomy. Pathologic examinations revealed a high-grade transitional cell carcinoma. PMID- 23806412 TI - Compression therapy in 100 consecutive patients with venous leg ulcers. AB - OBJECTIVE: To evaluate compression therapy for venous leg ulcers in terms of adherence, acceptability, quality, and effectiveness. DESIGN OF STUDY: Prospective observational cohort study. SETTING: Vascular diseases outpatient clinic in Paris, France. SUBJECTS: One hundred consecutive patients with active or healed leg ulcers and chronic lower limb venous insufficiency stage C5 or C6 in the CEAP classification scheme. INTERVENTIONS: Compression systems applied in a community-based practice. MAIN OUTCOME MEASURES: A standardized form was used to collect: (1) data on patient adherence; (2) objective criteria evaluating the quality, effectiveness, and correct application of compression systems and; (3) patient education and perceptions about their compression therapy. RESULTS: Patient adherence with compression therapy was high (89%), even though it was often a source of discomfort. Only 10% of patients signaled no discomfort. Drawbacks reported by patients were excessive warmth (29%), pruritus (33%), unacceptably high cost (48%), and moderate to considerable difficulty putting on footwear (64%). In the 11% of patients who did not wear their compression system, reasons for nonadherence were inadequate comprehension of expected benefits (45.5%), pain related to compression (36.4%), difficulty applying the compression system (27.3%), and difficulty putting on footwear (27.3%). Application was correct in 51.7% of adherent patients; errors in the remaining patients included slippage, failure of the bandage to extend to just under the knee (55.8%), a tourniquet effect (21%), failure of bandaging starting at the base of the toes (37.2%), and failure to cover the heel (53.5%). Full edema control was achieved in 51.7% of adherent patients. Compression was adequate overall (worn, correctly applied, and effective) in 49% of adherent patients. The most common reasons for lack of effectiveness were inadequate pressure and errors in application. Lack of awareness of potential benefits and wearing modalities of compression therapy was noted in 56% of patients. CONCLUSION: Patients, nurses, and physicians have inadequate knowledge of the modalities of compression therapy and as a result they are not well respected. Educational programs are needed. PMID- 23806413 TI - Study of an ethylene oxide-terminated bent-core compound: synthesis and Langmuir Blodgett film structure. AB - Bent-core compounds have attracted interest due to their unusual supramolecular structures, uncommon physical properties such as ferro- and antiferroelectricity and potential applications in fields such as nonlinear optics. Their incorporation into nanostructured materials, however, needs to be improved in terms of accurate control of the packing and orientation of the molecules in practical structures. Here, we have synthesized a novel bent-core compound bearing a tetraethylene glycol (TEG) chain as the hydrophilic head group and studied its capacity to obtain monomolecular films by means of the Langmuir Blodgett technique. We developed a synthetic route to the material and studied its behavior in Langmuir and Langmuir-Blodgett films by means of a variety of characterization techniques, including a new model for the interpretation of UV Vis reflection spectra of bent-core compounds. We found that the new head group, while destroying the formation of bulk mesophases, stabilizes the formation of the monolayer at the air-water interface and allows core-core interactions to dominate film dynamics, thus providing a promising alternative to carboxylic acid head groups. PMID- 23806414 TI - Preparation of an imogolite/poly(acrylic acid) hybrid gel. AB - Many efforts in the field of hydrogels have been focused toward increasing the mechanical strength of the gel using inorganic materials. In this study, we synthesized a hydrogel that has excellent mechanical properties using surface modified inorganic nanofibers composed of imogolite (Al2SiO3(OH)4), which is a hydrated aluminum silicate that has a hollow tube structure. Gamma ray radiation generates peroxide radicals on the nanofibers (imogolite), resulting in an additive free hybrid hydrogel. Structural optimization was carried out by changing the composition of imogolite and poly(acrylic acid). Chemical bonding between the nanofiber and the polymer was simulated by a cluster model and characterized by wide area Raman spectroscopy. The results indicate that imogolite embedded in a polymer matrix can align along the direction of an elongational force, as confirmed by small angle X-ray scattering (SAXS). PMID- 23806415 TI - Influence of surface conductivity on the apparent zeta potential of TiO2 nanoparticles: application to the modeling of their aggregation kinetics. AB - Titanium dioxide nanoparticles (TiO2 NPs) are extensively used in consumer products. The release of these NPs into aquatic environments raises the question of their possible risks to the environment and human health. The magnitude of the threat may depend on whether TiO2 NPs are aggregated or dispersed. Currently, limited information is available on this subject. A new approach based on DLVO theory is proposed to describe aggregation kinetics of TiO2 NPs in aqueous dispersions. It has the advantage of using zeta potentials directly calculated by an electrostatic surface complexation model whose parameters are calibrated by ab initio calculations, crystallographic studies, potentiometric titration and electrophoretic mobility experiments. Indeed, the conversion of electrophoretic mobility measurements into zeta potentials is very complex for metal oxide nanoparticles. This is due to their very high surface electrical conductivity associated with the electromigration of counter and co-ions in their electrical double layer. Our model has only three adjustable parameters (the minimum separation distance between NPs, the Hamaker constant, and the effective interaction radius of the particle), and predicts very well the stability ratios of TiO2 NPs measured at different pH values and over a broad range of ionic strengths (KCl aqueous solution). We found an effective interaction radius that is significantly smaller than the radius of the aggregate and corresponds to the radius of surface crystallites or small clusters of surface crystallites formed during synthesis of primary particles. Our results confirm that DLVO theory is relevant to predict aggregation kinetics of TiO2 NPs if the double layer interaction energy is estimated accurately. PMID- 23806416 TI - Halloysite nanotubule clay for efficient water purification. AB - Halloysite clay has chemical structure similar to kaolinite but it is rolled in tubes with diameter of 50 nm and length of ca. 1000 nm. Halloysite exhibits higher adsorption capacity for both cationic and anionic dyes because it has negative SiO2 outermost and positive Al2O3 inner lumen surface; therefore, these clay nanotubes have efficient bivalent adsorbancy. An adsorption study using cationic Rhodamine 6G and anionic Chrome azurol S has shown approximately two times better dye removal for halloysite as compared to kaolin. Halloysite filters have been effectively regenerated up to 50 times by burning the adsorbed dyes. Overall removal efficiency of anionic Chrome azurol S exceeded 99.9% for 5th regeneration cycle of halloysite. Chrome azurol S adsorption capacity decreases with the increase of ionic strength, temperature and pH. For cationic Rhodamine 6G, higher ionic strength, temperature and initial solution concentration were favorable to enhanced adsorption with optimal pH 8. The equilibrium adsorption data were described by Langmuir and Freundlich isotherms. PMID- 23806417 TI - Predictive force model for haptic feedback in bone sawing. AB - Bone sawing simulators with force feedback represent a cost effective means of training orthopedic surgeons in various surgical procedures, such as total knee arthroplasty. To develop a machine with accurate haptic feedback, giving a sensation of both cutting force and rate of material removal, algorithms are required to forecast bone sawing forces based on user input. Presently, studies on forces generated while machining bone are not representative of the high cutting speeds and low depths of cut common to the bone sawing process. The objective of this research was to quantify sawing forces in cortical bone as a function of blade speed and depth of cut. A fixture was developed to simulate linear bone sawing over a range of speeds comparable to surgical reciprocating and oscillating (sagittal) bone saws. A single saw blade tooth was isolated and used to create a slotted cut in bovine cortical bone. Over a range in linear sawing speed from 1700 to 7000 mm/s, a t-test (alpha=0.05) revealed there was no statistically significant effect of blade speed on either cutting or thrust force. However, an increase in depth of cut from 2 to 10 MUm resulted in a 30% increase in thrust force, while cutting force remained constant. The increase in thrust force with depth of cut was relatively linear, R(2)=0.80. Using a two factor, two level design of experiments approach, regression equations were developed to relate sawing forces to changes in blade speed and depth of cut. These equations can be used to predict forces in a haptic feedback model. PMID- 23806418 TI - A comparison between flexible electrogoniometers, inclinometers and three dimensional video analysis system for recording neck movement. AB - This study compared neck range of movement recording using three different methods goniometers (EGM), inclinometers (INC) and a three-dimensional video analysis system (IMG) in simultaneous and synchronized data collection. Twelve females performed neck flexion-extension, lateral flexion, rotation and circumduction. The differences between EGM, INC, and IMG were calculated sample by sample. For flexion-extension movement, IMG underestimated the amplitude by 13%; moreover, EGM showed a crosstalk of about 20% for lateral flexion and rotation axes. In lateral flexion movement, all systems showed similar amplitude and the inter-system differences were moderate (4-7%). For rotation movement, EGM showed a high crosstalk (13%) for flexion-extension axis. During the circumduction movement, IMG underestimated the amplitude of flexion-extension movements by about 11%, and the inter-system differences were high (about 17%) except for INC-IMG regarding lateral flexion (7%) and EGM-INC regarding flexion extension (10%). For application in workplace, INC presents good results compared to IMG and EGM though INC cannot record rotation. EGM should be improved in order to reduce its crosstalk errors and allow recording of the full neck range of movement. Due to non-optimal positioning of the cameras for recording flexion extension, IMG underestimated the amplitude of these movements. PMID- 23806419 TI - Temperature prediction in high speed bone grinding using motor PWM signal. AB - This research explores the feasibility of using motor electrical feedback to estimate temperature rise during a surgical bone grinding procedure. High-speed bone grinding is often used during skull base neurosurgery to remove cranial bone and approach skull base tumors through the nasal corridor. Grinding-induced heat could propagate and potentially injure surrounding nerves and arteries, and therefore, predicting the temperature in the grinding region would benefit neurosurgeons during the operation. High-speed electric motors are controlled by pulse-width-modulation (PWM) to alter the current input and thus maintain the rotational speed. Assuming full mechanical to thermal power conversion in the grinding process, PWM can be used as feedback for heat generation and temperature prediction. In this study, the conversion model was established from experiments under a variety of grinding conditions and an inverse heat transfer method to determine heat flux. Given a constant rotational speed, the heat conversion was represented by a linear function, and could predict temperature from the experimental data with less than 20% errors. Such results support the advance of this technology for practical application. PMID- 23806420 TI - Antihyperglycemic effect of fraxetin on hepatic key enzymes of carbohydrate metabolism in streptozotocin-induced diabetic rats. AB - Epidemiological studies have demonstrated that the diabetes mellitus is a serious health burden for both governments and healthcare providers. The present study was hypothesized to evaluate the antihyperglycemic potential of fraxetin by determining the activities of key enzymes of carbohydrate metabolism in streptozotocin (STZ) - induced diabetic rats. Diabetes was induced in male albino Wistar rats by intraperitoneal administration of STZ (40 mg/kg b.w). Fraxetin was administered to diabetic rats intra gastrically at 20, 40, 80 mg/kg b.w for 30 days. The dose 80 mg/kg b.w, significantly reduced the levels of blood glucose and glycosylated hemoglobin (HbA1c) and increased plasma insulin level. The altered activities of the key enzymes of carbohydrate metabolism such as glucokinase, glucose-6-phosphate dehydrogenase, glucose-6-phosphatase, fructose 1,6-bisphosphatase and hepatic enzymes (aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP)) in the liver tissues of diabetic rats were significantly reverted to near normal levels by the administration of fraxetin. Further, fraxetin administration to diabetic rats improved body weight and hepatic glycogen content demonstrated its antihyperglycemic potential. The present findings suggest that fraxetin may be useful in the treatment of diabetes even though clinical studies to evaluate this possibility may be warranted. PMID- 23806421 TI - Regulation of ribosome biogenesis in maize embryonic axes during germination. AB - Ribosome biogenesis is a pre-requisite for cell growth and proliferation; it is however, a highly regulated process that consumes a great quantity of energy. It requires the coordinated production of rRNA, ribosomal proteins and non-ribosomal factors which participate in the processing and mobilization of the new ribosomes. Ribosome biogenesis has been studied in yeast and animals; however, there is little information about this process in plants. The objective of the present work was to study ribosome biogenesis in maize seeds during germination, a stage characterized for its fast growth, and the effect of insulin in this process. Insulin has been reported to accelerate germination and to induce seedling growth. It was observed that among the first events reactivated just after 3 h of imbibition are the rDNA transcription and the pre-rRNA processing and that insulin stimulates both of them (40-230%). The transcript of nucleolin, a protein which regulates rDNA transcription and pre-rRNA processing, is among the messages stored in quiescent dry seeds and it is mobilized into the polysomal fraction during the first hours of imbibition (6 h). In contrast, de novo ribosomal protein synthesis was low during the first hours of imbibition (3 and 6 h) increasing by 60 times in later stages (24 h). Insulin increased this synthesis (75%) at 24 h of imbibition; however, not all ribosomal proteins were similarly regulated. In this regard, an increase in RPS6 and RPL7 protein levels was observed, whereas RPL3 protein levels did not change even though its transcription was induced. Results show that ribosome biogenesis in the first stages of imbibition is carried out with newly synthesized rRNA and ribosomal proteins translated from stored mRNA. PMID- 23806422 TI - Membrane cholesterol and sphingomyelin, and ostreolysin A are obligatory for pore formation by a MACPF/CDC-like pore-forming protein, pleurotolysin B. AB - The mushroom Pleurotus ostreatus has been reported to produce the hemolytic proteins ostreolysin (OlyA), pleurotolysin A (PlyA) and pleurotolysin B (PlyB). The present study of the native and recombinant proteins dissects out their lipid binding characteristics and their roles in lipid binding and membrane permeabilization. Using lipid-binding studies, permeabilization of erythrocytes, large unilamellar vesicles of various lipid compositions, and electron microscopy, we show that OlyA, a PlyA homolog, preferentially binds to membranes rich in sterol and sphingomyelin, but it does not permeabilize them. The N terminally truncated Delta48PlyB corresponds to the mature and active form of native PlyB, and it has a membrane attack complex-perforin (MACPF) domain. Delta48PlyB spontaneously oligomerizes in solution, and binds weakly to various lipid membranes but is not able to perforate them. However, binding of Delta48PlyB to the cholesterol and sphingomyelin membranes, and consequently, their permeabilization is dramatically promoted in the presence of OlyA. On these membranes, Delta48PlyB and OlyA form predominantly 13-meric oligomers. These are rosette-like structures with a thickness of ~9 nm from the membrane surface, with 19.7 nm and 4.9 nm outer and inner diameters, respectively. When present on opposing vesicle membranes, these oligomers can dimerize and thus promote aggregation of vesicles. Based on the structural and functional characteristics of Delta48PlyB, we suggest that it shares some features with MACPF/cholesterol dependent cytolysin (CDC) proteins. OlyA is obligatory for the Delta48PlyB permeabilization of membranes rich in cholesterol and sphingomyelin. PMID- 23806423 TI - Enterococcal and streptococcal resistance to PC190723 and related compounds: molecular insights from a FtsZ mutational analysis. AB - New antibiotics with novel mechanisms of action are urgently needed to overcome the growing bacterial resistance problem faced by clinicians today. PC190723 and related compounds represent a promising new class of antibacterial compounds that target the essential bacterial cell division protein FtsZ. While this family of compounds exhibits potent antistaphylococcal activity, they have poor activity against enterococci and streptococci. The studies described herein are aimed at investigating the molecular basis of the enterococcal and streptococcal resistance to this family of compounds. We show that the poor activity of the compounds against enterococci and streptococci correlates with a correspondingly weak impact of the compounds on the self-polymerization of the FtsZ proteins from those bacteria. In addition, computational and mutational studies identify two key FtsZ residues (E34 and R308) as being important determinants of enterococcal and streptococcal resistance to the PC190723-type class of compounds. PMID- 23806424 TI - Mitochondrial retinal dystrophy associated with the m.3243A>G mutation. AB - OBJECTIVE: To describe the spectrum of retinal abnormalities associated with the m.3243A>G mutation in the mitochondrial MTTL1 gene and to analyze putative correlations among the severity of retinal abnormalities, disease severity in other organ systems, and heteroplasmy levels. DESIGN: Observational, cohort based, cross-sectional study. PARTICIPANTS: Twenty-nine patients carrying the m.3243A>G mutation. METHODS: Extensive clinical examinations, including visual acuity testing, indirect ophthalmoscopy, color fundus photography, fundus autofluorescence (FAF), high-resolution optical coherence tomography (OCT), and central visual field analysis. In selected patients, Goldmann perimetry, fluorescein angiography, full-field electroretinography (ERG) and electro oculography (EOG), and color vision testing were performed. Heteroplasmy levels of the m.3243A>G mutation were measured in leukocytes, urinary epithelial cells (UECs), and buccal mucosa. The Newcastle Mitochondrial Disease Adult Scale (NMDAS) score was measured for all patients. MAIN OUTCOME MEASURES: Age at onset, visual acuity, fundus appearance, FAF, OCT findings, systemic disease features, heteroplasmy levels, and NMDAS scores. RESULTS: Twenty-five of the 29 mutation carriers (86%) had retinal abnormalities that could be classified into 4 grades. Six patients (21%) had grade 1 retinal dystrophy with fine pigment abnormalities that were clearly visible with FAF and fluorescein angiography. Eleven patients (38%) had grade 2 abnormalities that were characterized by yellowish or mildly pigmented deposits in the early stage; in advanced grade 2, these pigment changes encompassed the entire macula and often encircled the optic disc. Six patients (21%) had grade 3 disease in which profound chorioretinal atrophy was present outside the fovea. Two patients (7%) with retinal abnormalities had grade 4 disease, in which the fovea was affected by atrophy, with marked loss of visual acuity. The grade of mitochondrial retinal dystrophy correlated significantly with both age (r = -0.483, P = 0.008) and visual acuity (r = -0.614, P < 0.001), whereas no correlation was observed with heteroplasmy level or overall disease involvement. CONCLUSIONS: Mitochondrial retinal dystrophy associated with the m.3243A>G mutation has specific characteristics that can be classified into 4 grades based on the findings on ophthalmoscopy, FAF, and OCT. However, because the maternal inheritance pattern can be masked and the systemic disease associations can be variable or even absent, the disease may be misdiagnosed. PMID- 23806425 TI - Adoption of electronic health records and preparations for demonstrating meaningful use: an American Academy of Ophthalmology survey. AB - OBJECTIVE: To assess the current state of electronic health record (EHR) use by ophthalmologists, including adoption rate, user satisfaction, functionality, benefits, barriers, and knowledge of meaningful use criteria. DESIGN: Population based, cross-sectional study. PARTICIPANTS: A total of 492 members of the American Academy of Ophthalmology (AAO). METHODS: A random sample of 1500 AAO members were selected on the basis of their practice location and solicited to participate in a study of EHR use, practice management, and image management system use. Participants completed the survey via the Internet, phone, or fax. The survey included questions about the adoption of EHRs, available functionality, benefits, barriers, satisfaction, and understanding of meaningful use criteria and health information technology concepts. MAIN OUTCOME MEASURES: Current adoption rate of EHRs, user satisfaction, benefits and barriers, and availability of EHR functionality. RESULTS: Overall, 32% of the practices surveyed had already implemented an EHR, 15% had implemented an EHR for some of their physicians or were in the process of implementation, and another 31% had plans to do so within 2 years. Among those with an EHR in their practice, 49% were satisfied or extremely satisfied with their system, 42% reported increased or stable overall productivity, 19% reported decreased or stable overall costs, and 55% would recommend an EHR to a fellow ophthalmologist. For those with an electronic image management system, only 15% had all devices integrated, 33% had images directly uploaded into their system, and 12% had electronic association of patient demographics with the image. CONCLUSIONS: The adoption of EHRs by ophthalmology practices more than doubled from 2007 to 2011. The satisfaction of ophthalmologists with their EHR and their perception of beneficial effects on productivity and costs were all lower in 2011 than in 2007. Knowledge about meaningful use is high, but the percentage of physicians actually receiving incentive payments is relatively low. Given the importance of imaging in ophthalmology, the shortcomings in current image management systems need to be addressed. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23806426 TI - Molecular characterization of five steroid receptors from pengze crucian carp and their expression profiles of juveniles in response to 17alpha-ethinylestradiol and 17alpha-methyltestosterone. AB - Pengze crucian carp (Carassius auratus var. pengze, Pcc), a triploid gynogenetic fish, was used in this study to investigate the cross-talk between EDCs and steroid receptors. The full-length cDNAs of five steroid receptors (esr1, er alpha2, esr2a, esr2b, ar) and partial cDNA of vtg B were isolated. The tissue distributions of these genes were analyzed in adult fish by qRT-PCR. Then the expression profiles of five steroid receptors (esrs and ar) and vtg B were detected in the juveniles exposed to 17alpha-ethinylestradiol (EE2, 0.1, 1 and 10ng/L) and 17alpha-methyltestosterone (MT, 50MUg/L) for 4weeks. The results demonstrated that esrs, ar, and vtg B were predominantly expressed in liver of adult fish. However, among these detected genes, esr1 and er alpha2 mRNAs are sensitive biomarkers in response to EE2 at 0.1, 1, and 10ng/L for 1 and 2weeks compared to esr2a, esr2b, ar, and vtg B in the juveniles of mono-female gynogenetic fish. Totally, the subtypes of esrs show biphasic responses to EE2 exposures for 4weeks, and most of the EE2 exposures at 0.1, 1, and 10ng/L for 1, 2, 3 and 4weeks did not induce the mRNA expressions of vtg B. However, 1-, 2-, and 4-week 50MUg/L MT all significantly stimulated vtg B transcripts. Further investigations are needed to elucidate the mechanism underlying the insensitivity or down-regulation of vtg B mRNA in response to EE2 in juvenile Pcc. PMID- 23806429 TI - President's message. Multitudo sapientium sanitas orbis. PMID- 23806427 TI - Summer in the country. PMID- 23806431 TI - First practice: family physicians initially locating in rural areas. AB - INTRODUCTION: This paper quantifies the proportion of family physicians in rural practice and, in particular, initial rural practice. It examines differences between graduates of Canadian and international medical schools. METHODS: The Canadian Medical Association postal code master file was used to determine the distribution in rural practice of Canadian and international medical school graduates for every other year from 2000 to 2011. The master file maps practice postal codes into a census metropolitan area or census agglomeration; physicians practising outside these areas are considered rural. Initial practices were estimated based on year of undergraduate medical degree. RESULTS: Two-thirds of family physicians practising rural medicine in 2011 were graduates of Canadian medical SCHOOLS. However, between 2000 and 2011, a greater proportion of international medical graduates were practising in rural areas than graduates of Canadian medical schools. International graduates were more likely to initially locate in a rural area, but the drop-off rate was greater among them than with graduates of Canadian medical schools. The proportion of international medical graduates setting up rural practices was decreased among more recent graduation cohorts. The proportion of Canadian medical school graduates initially practising in rural areas was steady. CONCLUSION: The results of this study suggest that graduates of international and Canadian medical schools treat rural practice differently. International graduates may decide on a rural location as a means to set up practice in Canada or fulfill a return-of-service obligation, whereas graduates of Canadian medical schools may make a conscious choice to practise in rural locations. Decreasing proportions of international medical graduates in rural practice may be a result of increased opportunities for Canadian postgraduate training and full licensure. PMID- 23806432 TI - Motor vehicle crashes among Canadian Aboriginal people: a review of the literature. AB - INTRODUCTION: Aboriginal people are substantially more likely to be injured or die in motor vehicle crashes (MVCs) than the general population. However, research examining MVCs among Canadian Aboriginal populations is limited. We examine trends and gaps in the Canadian literature and suggest priorities for future research. METHODS: We conducted a systematic review of the published and grey literature on MVCs involving Canadian Aboriginal people. We used the Haddon matrix of injury epidemiology and prevention to identify trends in crash-related risk factors. RESULTS: We reviewed 20 studies, which consisted of research at both national and provincial levels. We identified various risk factors related to human (e.g., male sex, substance use), vehicle and equipment (e.g., driving an older vehicle, driving a car [v. other types of vehicles]), and physical environment (e.g., occurring on-reserve, muddy and loose-gravel road conditions) variables. However, we did not find research that examined risk factors related to the social environment, such as perspectives related to MVCs. CONCLUSION: This review indicates that rates of death, hospital admission and injury related to MVCs are twice as high among Aboriginal populations than the general Canadian population, which highlights a major public health concern. Priorities for future research should include examination of the social environment, more rigorous methods and collaborative research in partnership with Aboriginal communities. PMID- 23806433 TI - Country cardiograms case 48. PMID- 23806434 TI - The occasional femoral line. PMID- 23806435 TI - Move over Sir William Osler! The ascent of rural and remote medicine in Canada. PMID- 23806437 TI - The functional -94 insertion/deletion ATTG polymorphism in the promoter region of NFKB1 gene increases the risk of sporadic colorectal cancer. AB - OBJECTIVE: To investigate the allele and genotype frequencies of NFKB1 -94 ins/del ATTG (rs28720239) polymorphism and to evaluate the association between the polymorphism and colorectal cancer (CRC) risk in Malaysian population. METHODS: Genomic DNA was extracted from the peripheral blood samples of 474 study subjects, which consisted of 237 histopathologically confirmed CRC patients and an equal number of cancer-free controls. The NFKB1 -94 ins/del ATTG (rs28720239) polymorphism was genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and confirmed by DNA sequencing. The association between the polymorphic genotypes and CRC risk was evaluated by deriving odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression analysis. RESULTS: The frequencies of wildtype (del/del), heterozygous (del/ins) and variant (ins/ins) genotypes in CRC patients were 31.7%, 53.6% and 14.8%, respectively, while those in cancer-free controls were 35.0%, 58.2% and 6.8%, respectively. The frequency of the variant genotype was significantly higher in cases compared to controls (P<0.01). Evaluation of the risk association of the polymorphic genotypes revealed that the variant genotype could contribute to a significantly increased risk of CRC (OR=2.42, 95% CI=1.24 4.73, P<0.01). CONCLUSIONS: The variant allele of NFKB1 -94 ins/del ATTG (rs28362491) polymorphism is associated with higher risk of sporadic CRC in Malaysian population. PMID- 23806438 TI - The effects of cardiovascular exercise on human memory: a review with meta analysis. AB - We reviewed the evidence for the use of cardiovascular exercise to improve memory and explored potential mechanisms. Data from 29 and 21 studies including acute and long-term cardiovascular interventions were retrieved. Meta-analyses revealed that acute exercise had moderate (SMD=0.26; 95% CI=0.03, 0.49; p=0.03; N=22) whereas long-term had small (SMD=0.15; 95% CI=0.02, 0.27; p=0.02; N=37) effects on short-term memory. In contrast, acute exercise showed moderate to large (SMD=0.52; 95% CI=0.28, 0.75; p<0.0001; N=20) whereas long-term exercise had insignificant effects (SMD=0.07; 95% CI=-0.13, 0.26; p=0.51; N=22) on long-term memory. We argue that acute and long-term cardiovascular exercise represent two distinct but complementary strategies to improve memory. Acute exercise improves memory in a time-dependent fashion by priming the molecular processes involved in the encoding and consolidation of newly acquired information. Long-term exercise, in contrast, has negligible effects on memory but provides the necessary stimuli to optimize the responses of the molecular machinery responsible for memory processing. Strategically combined, acute and long-term interventions could maximize the benefits of cardiovascular exercise on memory. PMID- 23806440 TI - Understanding smell--the olfactory stimulus problem. AB - The main problem with sensory processing is the difficulty in relating sensory input to physiological responses and perception. This is especially problematic at higher levels of processing, where complex cues elicit highly specific responses. In olfaction, this relationship is particularly obfuscated by the difficulty of characterizing stimulus statistics and perception. The core questions in olfaction are hence the so-called stimulus problem, which refers to the understanding of the stimulus, and the structure-activity and structure-odor relationships, which refer to the molecular basis of smell. It is widely accepted that the recognition of odorants by receptors is governed by the detection of physico-chemical properties and that the physical space is highly complex. Not surprisingly, ideas differ about how odor stimuli should be classified and about the very nature of information that the brain extracts from odors. Even though there are many measures for smell, there is none that accurately describes all aspects of it. Here, we summarize recent developments in the understanding of olfaction. We argue that an approach to olfactory function where information processing is emphasized could contribute to a high degree to our understanding of smell as a perceptual phenomenon emerging from neural computations. Further, we argue that combined analysis of the stimulus, biology, physiology, and behavior and perception can provide new insights into olfactory function. We hope that the reader can use this review as a competent guide and overview of research activities in olfactory physiology, psychophysics, computation, and psychology. We propose avenues for research, particularly in the systematic characterization of receptive fields and of perception. PMID- 23806441 TI - On the diagnostic utility of junction plakoglobin in arrhythmogenic right ventricular cardiomyopathy. PMID- 23806442 TI - Can some aspects of the epidemiology of elderly suicides be applied to dementia. PMID- 23806443 TI - Expression of unc5 family genes in zebrafish brain during embryonic development. AB - UNC5 family proteins are trans-membrane receptors which mediate both repulsion and attraction signals for the axonal growth cones. The UNC5 family proteins may also play critical roles in angiogenesis and carcinogenesis. Here we have determined the temporal and spatial expression patterns of unc5 gene family members (unc5a, unc5b, unc5c, unc5da and unc5db) by RT-PCR and in situ hybridization. RT-PCR results showed that all transcripts except unc5b were expressed maternally. While unc5b and unc5c transcript was detected at all time points between shield stage and 48h post fertilization (hpf), unc5a, unc5da and unc5db showed expression at 24hpf and later time points. In situ hybridization analysis revealed that unc5a, unc5da and unc5db transcripts were expressed in the telencephalon, parts of thalamus and hindbrain between 24 and 48hpf. The expression patterns of unc5a-unc5da and unc5a-unc5db in the telencephalon showed substantial overlap by fluorescent in situ hybridization. Unc5b showed expression in the eye region, epiphysis and thalamus. Unc5c showed expression in the roof plate, the hindbrain and the mouth region. Our results provide a starting point to uncovering roles of unc5 gene family in zebrafish forebrain development and axonal outgrowth or guidance. PMID- 23806444 TI - Serial fetal abdominal circumference measurements in predicting normal birth weight in gestational diabetes mellitus. AB - OBJECTIVES: To construct a clinical management matrix using serial fetal abdominal circumference measurements (ACMs) that will predict normal birth weight in pregnancies complicated by gestational diabetes (GDM) and reduce unnecessary ultrasound examination in women with GDM. STUDY DESIGN: Retrospective cohort study of 144 women with GDM in a specialist obstetric-diabetes clinic. Women with GDM who delivered singleton infants were identified from a clinical register. Regression analysis was used to identify associations between serial ACMs, maternal parameters and normal birth weight (birth weight between the 10th and 90th percentiles). Predictive clinical models were designed with the aim of identifying normal birth weight infants with the lowest number of fetal ultrasound scans. RESULTS: Compared to mothers of large-for-gestational-age (LGA) infants, mothers of normal weight infants had lower fasting glucose measurements at diagnosis (5.9 mmol/l+/-1.0 vs. 6.6 mmol/l+/-0.7, p<0.05), lower maternal weight at delivery (90 kg+/-17 vs. 96 kg+/-17, p<0.05), and a lower rate of prior LGA infants (31% vs. 60%, p<0.05). Maternal weight and a history of prior LGA delivery were identified as useful predictors of fetal birth weight in predictive models. Serial ACMs below the 50th, 75th and 90th percentiles could predict normal birth weight with 100%, 97% and 96% positive predictive value respectively when used in these risk factor based models. Two measurements sufficed in low risk pregnancies. CONCLUSION: Serial ACMs can predict normal birth weight in GDM. PMID- 23806439 TI - Exercise as a novel treatment for drug addiction: a neurobiological and stage dependent hypothesis. AB - Physical activity, and specifically exercise, has been suggested as a potential treatment for drug addiction. In this review, we discuss clinical and preclinical evidence for the efficacy of exercise at different phases of the addiction process. Potential neurobiological mechanisms are also discussed focusing on interactions with dopaminergic and glutamatergic signaling and chromatin remodeling in the reward pathway. While exercise generally produces an efficacious response, certain exercise conditions may be either ineffective or lead to detrimental effects depending on the level/type/timing of exercise exposure, the stage of addiction, the drug involved, and the subject population. During drug use initiation and withdrawal, its efficacy may be related to its ability to facilitate dopaminergic transmission, and once addiction develops, its efficacy may be related to its ability to normalize glutamatergic and dopaminergic signaling and reverse drug-induced changes in chromatin via epigenetic interactions with brain-derived neurotrophic factor (BDNF) in the reward pathway. We conclude with future directions, including the development of exercise-based interventions alone or as an adjunct to other strategies for treating drug addiction. PMID- 23806445 TI - Laparoscopic management of recurrent adnexal torsion in the second and third trimesters of pregnancy. PMID- 23806446 TI - Management of pregnancy with Thomsen's disease. PMID- 23806447 TI - Soluble fms-like tyrosine kinase-1 and soluble endoglin in HIV-associated preeclampsia. AB - OBJECTIVE: Preeclampsia is characterized by endothelial dysfunction combined with increased concentrations of sFlt1, which antagonizes the biological effects of VEGF and PlGF, and of sEng, which antagonizes TGFbeta1. This angiogenic imbalance may have a role in its etiology. This study evaluated the expression of VEGF, PlGF, sFlt1 and sEng amongst third trimester pregnancies in women with HIV associated pre-eclampsia. METHOD: Serum and placental tissue were obtained from 76 pregnancies in women who were normotensive and HIV negative (N-) or positive (N+), and in women who were pre-eclamptic and HIV negative (P-) or positive (P+). The serum and placental samples were quantitatively evaluated using ELISAs and RT PCR respectively. RESULTS: Placental sFlt1 expression differed significantly between the N- and P- groups (p=0.001). Similarly, sEng expression differed between the N- and P- groups (p=0.001). No significant effect was shown between HIV status and pregnancy. Serum sFlt1 (p=0.02) and sEng (p=0.001) were up regulated in the P- compared to the N- groups. Similarly, no significant effect was shown between HIV status and pregnancy. Both VEGF and PlGF did not differ significantly between groups. Notably, sEng expression was elevated in both placenta and serum, whilst placental sFlt1 differed from serum. A weak but significant correlation between serum and placental concentration for sFlt1, sEng and PlGF (r=0.26, p=0.031; r=0.42, p<0.001 and r=-0.3, p=0.014) was observed. CONCLUSIONS: This novel study demonstrates an up-regulation of serum sFlt1 and sEng in preeclamptic compared to normotensive groups irrespective of the HIV status of the pregnancy. This implicates a contributory role of sFlt1 and sEng in preeclampsia development. The serum reduction of sFlt1 and sEng within the HIV positive compared to HIV negative cohorts may imply a neutralization of the immune hyperreactivity of preeclampsia. PMID- 23806448 TI - A multicentre study of advanced abdominal pregnancy: a review of six cases in low resource settings. AB - Abdominal pregnancy has remained a big challenge worldwide especially in developing countries where there are limitations in diagnostic resources. The most important approach is to be vigilant for the unexpected as most patients present with no specific symptoms or clinical signs. It also poses great challenges in diagnosis and management, and is associated with a lot of morbidity and mortality. This series of six cases, each presenting in a peculiar way, typically illustrates these issues. The cases were managed in three different hospitals in the last 15 years. These series is aimed at highlighting the atypical presenting features of advanced abdominal pregnancy and the need for vigilance when there is suspicion of a case. It is also aimed at showing the difficulty of diagnosis and management of advanced abdominal pregnancy in low resource environment. PMID- 23806449 TI - Serum anti-Mullerian hormone levels in the main phenotypes of polycystic ovary syndrome. AB - OBJECTIVE: To characterize the difference in circulating anti-Mullerian hormone (AMH) levels between the main polycystic ovary syndrome (PCOS) phenotypic groups and evaluate the role of AMH in predicting the severity of PCOS. STUDY DESIGN: Cross-sectional, retrospective study. A total of 251 women were divided into four groups based on the main features of PCOS, as follows: Group 1 (polycystic ovarian morphology [PCOM]+/oligo-anovulation [OA]+/hyperandrogenism [HA]+), Group 2 (PCOM+/OA+/HA-), Group 3 (PCOM+/OA-/HA+), and Group 4 (PCOM-/OA+/HA+). AMH and other hormone levels were measured in serum. The main outcome was serum AMH concentrations in the main phenotypes of PCOS. RESULT(S): The mean serum AMH levels were 9.50+/-6.1 ng/mL in Group 1; 8.02+/-6.2 ng/mL in Group 2; 6.12+/-3.6 ng/mL in Group 3; and 3.06+/-2.4 ng/mL in Group 4. Circulating AMH levels in Group 1 (PCOM+/OA+/HA+) were three times higher than those in Group 4 (PCOM /OA+/HA+). CONCLUSIONS: The highest AMH levels were found in cases where all three main diagnostic criteria existed. AMH levels correlate best with PCOM. In addition, oligo-anovulation contributes to increased AMH levels. Hyperandrogenism criteria were found to have less influence on AMH levels. AMH levels seem to have a diagnostic role in determining the severity of PCOS. PMID- 23806450 TI - High-dose erythropoietin during cardiac resuscitation lessens postresuscitation myocardial stunning in swine. AB - We investigated the metabolic and functional myocardial effects of erythropoietin (EPO) administered during resuscitation from cardiac arrest using an open-chest pig model of ventricular fibrillation and resuscitation by extracorporeal circulation, after having reported in rats a reversal of postresuscitation myocardial dysfunction associated with activation of mitochondrial protective pathways. Ventricular fibrillation was induced in 16 male domestic pigs and left untreated for 8 minutes, after which extracorporeal circulation was started and maintained for 10 additional minutes, adjusting the extracorporeal flow to provide a coronary perfusion pressure of 10 mmHg. Defibrillation was accomplished and the extracorporeal flow was adjusted to secure a mean aortic pressure of 40 mmHg or greater during spontaneous circulation for up to 120 minutes. Pigs were randomized 1:1 to receive EPO (1200 U/kg) or 0.9% NaCl before starting extracorporeal circulation. Severe postresuscitation myocardial dysfunction developed in both groups. However, recovery of myocardial function-comparing baseline with 120 minutes postresuscitation-was better in pigs treated with EPO than NaCl, as shown for left ventricular ejection fraction (from 45 +/- 8% to 36 +/- 9% in EPO, not significant; and from 46 +/- 8% to 26 +/- 8% in NaCl, P < 0.001) and for peak systolic pressure/end-systolic volume (from 2.7 +/- 0.8 mmHg/mL to 2.4 +/- 0.7 mmHg/mL in EPO, not significant; and from 3.0 +/- 1.1 mmHg/mL to 1.8 +/- 0.6 mmHg/mL, P < 0.001 in NaCl). The EPO effect was associated with significantly higher myocardial O2 consumption (12 +/- 6 mL/min/unit of tissue vs 6 +/- 2 mL/min/unit of tissue, P < 0.017) without effects on myocardial lactate consumption. Thus, EPO administered during resuscitation from ventricular fibrillation lessened postresuscitation myocardial stunning-an effect that could be useful clinically to help promote postresuscitation hemodynamic stability. PMID- 23806451 TI - When to suspect and work up allergic bronchopulmonary aspergillosis. PMID- 23806452 TI - Mast cell activation syndromes. PMID- 23806453 TI - The mountain cedar model in clinical trials of seasonal allergic rhinoconjunctivitis. AB - BACKGROUND: Clinical trials of seasonal allergic rhinoconjunctivitis use the mountain cedar (Juniperus ashei) season as the predominate model. OBJECTIVE: To evaluate clinical trials of rhinoconjunctivitis using mountain cedar, to present analysis of pollen counts during 18 seasons, and to discuss the model. METHODS: The medical literature was searched for clinical trials performed using mountain cedar either in or out of season. Pollen counts were recorded and analyzed for the duration of 18 seasons. RESULTS: Thirty-eight trials were identified. Of these, 1 evaluated onset of allergy, 8 were immunotherapy trials, 28 were pharmaceutical clinical trials, and 1 studied symptoms elicited in a pollen challenge chamber trial. Many generic equivalency trials are unreported. In the 18 years of counts in the Texas Hill Country, a dependable and intense pollen density was present in every season. The combination of dependable seasons without confounding pollens, the large number of allergic patients, and the ability to concentrate resources in one geographic area has made mountain cedar allergy a mainstay for therapeutic trials for allergic rhinoconjunctivitis. CONCLUSION: Mountain cedar allergy presents a dependable and durable model of allergic rhinoconjunctivitis. PMID- 23806454 TI - Assessing proxy reports: agreement between children with asthma and their caregivers on quality of life. AB - BACKGROUND: Health-related quality of life (HRQOL) questionnaires are important tools to evaluate health status in children with asthma; however, children with asthma and their caregivers have shown only low to moderate agreement in their responses. OBJECTIVE: To analyze the agreement between children with asthma and their caregivers on HRQOL, specifically in the domains of activity limitation, emotional function, and overall quality of life (QOL). METHODS: We enrolled 79 pediatric patients (ages 5-17 years) with asthma (53 with acute asthma and 26 with refractory asthma) and their caregivers. Children completed the Pediatric Asthma Quality of Life Questionnaire, and caregivers completed the Pediatric Asthma Caregiver's Quality of Life Questionnaire (potential score, 1-7; higher scores indicate better QOL). We used paired t test to examine differences in child and caregiver responses, Pearson correlation to describe patterns of agreement, and multivariate analysis to evaluate the effect of sex, age, and ethnicity on differences in child and caregiver responses. RESULTS: Children with asthma and their caregivers reported similar scores and demonstrated moderate correlation in emotional function and overall QOL. Children reported a significantly better QOL than their caregivers in response to questions about activity limitation (mean score, 4.62 vs 3.49; P < .001). Male children were more likely to differ from their caregivers than females, especially in regard to activity limitation. CONCLUSION: Although caregivers of children with asthma can provide useful proxy information about QOL, their responses cannot be substituted for their children's reports regarding activity limitation. Clinicians and researchers should ask both children and their caregivers about asthma-specific QOL. PMID- 23806455 TI - Interpretation of food specific immunoglobulin E levels in the context of total IgE. AB - BACKGROUND: Food specific immunoglobulin E (IgE) (fsIgE) cut points are used in the evaluation of food allergies. Concomitant measurement of total IgE (tIgE) is traditionally not obtained. We anecdotally observed elevations in fsIgE mirroring tIgE increases, which may confound accurate interpretation. OBJECTIVE: To determine whether changes in tIgE were associated with fsIgE and whether predictions of fsIgE could be formulated based on tIgE. METHODS: We studied children younger than 18 years who had both tIgE and fsIgE (egg, n = 136; milk, n = 123; peanut, n = 201; soy, n = 55) obtained simultaneously on 1 or more occasion between January 2008 and February 2011. After institutional review board approval, natural log-transformed (ln) tIgE and fsIgE levels were analyzed using univariate and multivariate regression models to assess associations and predict fsIgE using tIgE and other covariates. RESULTS: Soy IgE levels were strongly correlated (rho = 0.85, P < .001), whereas egg, milk, and peanut IgE levels were substantially correlated (rho = 0.69, 0.69, and 0.66, respectively, P < .001) with tIgE. A 1-unit increase in ln(tIgE) was significantly correlated with unit increases in ln(egg IgE) (0.77), ln(milk IgE) (0.84), ln(peanut IgE) (0.87), and ln(soy IgE) (0.89) (P < .001). The ln(tIgE)-based univariate models could predict fsIgE in the validation data with strong (soy) and substantial (egg, milk, and peanut) predictive ability (P < .001). CONCLUSION: Our study found significant and parallel relationships between tIgE and fsIgE levels to egg, milk, peanut, and soy. It underscores the importance of examining fsIgE levels in context of tIgE while making diagnostic and management decisions in children with food allergies. PMID- 23806456 TI - Interaction between allergy and innate immunity: model for eosinophil regulation of epithelial cell interferon expression. AB - BACKGROUND: Eosinophils in asthmatic airways are associated with risk of exacerbations. The most common cause of asthma exacerbations is viral respiratory infections, particularly human rhinovirus (HRV). OBJECTIVE: To determine the mechanism by which eosinophils may influence virus-induced responses. METHODS: We used an in vitro coculture model of primary human eosinophils and the BEAS-2B epithelial cell line either stimulated with HRV1A infection or polyinosinic polycytidylic acid (poly[I:C]). The messenger RNA (mRNA) expression of interferon (IFN) beta1 and IFN-lambda1 was assessed by quantitative reverse-transcriptase polymerase chain reaction and the protein level of IFN- lambda1 by enzyme-linked immunosorbent assay. RESULTS: Both poly(I:C) and HRV1A infection induced BEAS-2B expression of IFN-beta1 and IFN-lambda1 mRNA. Coculture of eosinophils resulted in suppression of poly(I:C)-stimulated IFN-beta1 and IFN-lambda1 mRNA expression (2.5-fold and 3.6-fold less, respectively). Separation of cells did not block eosinophil regulatory activity. Coculture of eosinophils with HRV1A-infected BEAS 2B cells also suppressed IFN-beta1 and IFN-lambda1 mRNA (5.7-fold and 5.0-fold less, respectively) and reduced IFN-lambda1 protein secretion (1.6-fold decrease). This corresponded to a 34% increase in the quantity of HRV1A virus RNA on coculture with eosinophils. Recombinant transforming growth factor beta suppressed IFN-lambda1 from HRV1A-infected BEAS-2B cells. Coculture of eosinophils and BEAS-2B cells induced transforming growth factor beta secretion, which may mediate suppression of HRV-induced interferon expression. CONCLUSION: Eosinophils suppressed HRV-induced expression of interferons from epithelial cells, resulting in increased quantity of HRV. This represents one mechanism for interaction between allergic inflammation and innate immunity. PMID- 23806457 TI - Characterization of Cannabis sativa allergens. AB - BACKGROUND: Allergic sensitization to Cannabis sativa is rarely reported, but the increasing consumption of marijuana has resulted in an increase in the number of individuals who become sensitized. To date, little is known about the causal allergens associated with C sativa. OBJECTIVE: To characterize marijuana allergens in different components of the C sativa plant using serum IgE from marijuana sensitized patients. METHODS: Serum samples from 23 patients with a positive skin prick test result to a crude C sativa extract were evaluated. IgE reactivity was variable between patients and C sativa extracts. IgE reactivity to C sativa proteins in Western blots was heterogeneous and ranged from 10 to 70 kDa. Putative allergens derived from 2-dimensional gels were identified. RESULTS: Prominent IgE reactive bands included a 23-kDa oxygen-evolving enhancer protein 2 and a 50-kDa protein identified to be the photosynthetic enzyme ribulose-1,5 bisphosphate carboxylase/oxygenase. Additional proteins were identified in the proteomic analysis, including those from adenosine triphosphate synthase, glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate kinase, and luminal binding protein (heat shock protein 70), suggesting these proteins are potential allergens. Deglycosylation studies helped refine protein allergen identification and demonstrated significant IgE antibodies against plant oligosaccharides that could help explain cross-reactivity. CONCLUSION: Identification and characterization of allergens from C sativa may be helpful in further understanding allergic sensitization to this plant species. PMID- 23806458 TI - Effects of atopy and grass pollen season on histamine H4 receptor expression in human leukocytes. AB - BACKGROUND: The histamine H4 receptor (H4R) is a novel therapeutic target to treat allergic inflammation. OBJECTIVE: To profile messenger RNA (mRNA) expression of H4R isoforms in human cells and evaluate the effects of atopy and grass pollen season on H4R expression in peripheral blood leukocytes ex vivo. METHODS: H4R isoform expression was assayed by quantitative polymerase chain reaction in human airway and peripheral RNA. During low and high grass pollen seasons, leukocytes were isolated from venous blood and fractionated into peripheral blood mononuclear cells and polymorphonuclear cells (PMN). H4R expression was determined and related to atopy, defined by a level of specific IgE to Timothy grass pollen of >=0.35 kU(A)/L (n = 7 atopic patients and 9 controls). RESULTS: Expression of total and full length H4R was at the limit of detection but predominant in peripheral blood leukocytes, where truncated H4R was expressed exclusively (<=300-fold less). Suggestive evidence for total H4R in airway cells and brain indicated an expression <=260-fold lower than in peripheral blood mononuclear cells. Total H4R mRNA expression was unaffected by atopy or grass pollen season, but truncated H4R was significantly reduced during high grass pollen season in total leukocytes, independently of atopy (P < .01). CONCLUSION: H4R mRNA is predominantly expressed in peripheral blood leukocytes, and total H4R expression levels are unrelated to atopy or grass pollen season. Atopy-independent seasonal variation in truncated H4R expression might affect putative negative regulation of full length H4R during high grass pollen season. If verified, this should be considered during the design of drugs targeting H4R to treat allergic inflammation, particularly for seasonal allergic rhinitis. PMID- 23806459 TI - Ocular safety of fluticasone furoate nasal spray in patients with perennial allergic rhinitis: a 2-year study. AB - BACKGROUND: This is the first study, to our knowledge, to evaluate the ocular effects of an intranasal corticosteroid during 2 years of treatment for perennial allergic rhinitis (PAR). OBJECTIVE: To assess ocular safety in adult and adolescent patients 12 years and older with PAR after 2 years of continuous treatment with fluticasone furoate nasal spray (FFNS), 110 MUg once daily, and placebo. METHODS: This was a 2-year, randomized, double-blind, placebo-controlled study of once-daily FFNS, 110 ig, and placebo in 548 patients 12 years and older with PAR. The primary ocular safety end points were time to first occurrence of an event for the Lens Opacities Classification System, Version III (LOCS III), posterior subcapsular opacity (PSO) and time to first occurrence of an event for intraocular pressure (IOP). RESULTS: On the basis of survival analyses, the difference between the treatment groups for time to first occurrence of a LOCS III PSO and time to first occurrence of an IOP event was not statistically significant (P = .39 and P = .34, respectively). Changes from baseline in visual acuity, LOCS III PSO, cortical opacity, LOCS III nuclear opacity and nuclear color, IOP, and horizontal cup-to-disc similar between treatment groups. There were no ophthalmic-related adverse events of LOCS III PSO or IOP that led to early withdrawal. The most common drug-related adverse event was epistaxis (FFNS, 28%; placebo, 14%). CONCLUSION: These data neither support nor negate current recommendations for regular ophthalmic monitoring in patients treated with intranasal corticosteroids. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00682643. PMID- 23806460 TI - Subcutaneous immunoglobulin therapy given by subcutaneous rapid push vs infusion pump: a retrospective analysis. AB - BACKGROUND: Administration of subcutaneous immunoglobulin (SCIG) via rapid push, an alternative to infusion pump delivery, can offer heightened simplicity and convenience for patients with primary immunodeficiency disease (PIDD). OBJECTIVE: To assess dosing and administration patterns, serum IgG responses, safety, and tolerability of the subcutaneous (SC) rapid push technique. METHODS: A retrospective medical record review captured data on 173 patients with PIDD (1,140 follow-up visits) who self-administered SCIG (16% or 20%) via infusion pump or SC rapid push. RESULTS: Serum IgG levels increased from a mean (SD) trough of 903.8 (285.4) mg/dL during intravenous immunoglobulin use to a steady state mean (SD) of 1,121.6 (257.6) mg/dL on SCIG. Mean frequency of weekly SCIG administration was 2.3 days per week with pump and 2.8 days per week with SC rapid push. Mean serum IgG levels were higher among push vs pump users (1,164 vs 1,048 mg/dL). Mean (SD) SCIG volume administered per infusion site with SC rapid push was 15.0 (7.3) mL (maximum, 60.0 mL). Most patients using SC rapid push infused in 9 minutes or less; median pump infusion duration was 49 minutes. Use of 20% SCIG was associated with smaller mean weekly product volumes vs 16% SCIG (41.7 vs 51.0 mL) and fewer mean dosing days per week (2.0 vs 2.8 days). Adverse events, primarily local, were reported on fewer visits with SC rapid push (15.6%) than with infusion pump (20.7%). CONCLUSION: The SC rapid push technique is a safe, viable alternative to an infusion pump, seemingly preferred by patients and offering more rapid administration. PMID- 23806461 TI - Cost-effectiveness for acupuncture in seasonal allergic rhinitis: economic results of the ACUSAR trial. AB - BACKGROUND: Allergic rhinitis (AR) is a frequent allergic disorder with a significant economic effect on health care costs and productivity. OBJECTIVE: To assess the cost-effectiveness of acupuncture for patients with seasonal AR (SAR) in Germany. METHODS: The present analysis was part of the Acupuncture in Seasonal Allergic Rhinitis (ACUSAR) trial, a 3-arm randomized, controlled, multicenter trial in patients with SAR, comparing acupuncture plus rescue medication (RM), penetrating sham acupuncture plus RM, and a control group receiving RM alone. Measures for health economic analyses were costs and health-related quality of life. Incremental cost-effectiveness ratio was calculated for different scenarios on the duration of acupuncture effects and was expressed as costs per quality adjusted life-year gained. The study was conducted from society's and from a third-party payer's perspective. RESULTS: From 422 initially randomized patients, a total of 364 patients with complete data on costs and quality of life were included in the health economic evaluation. Patients receiving acupuncture or sham acupuncture caused higher costs than patients in the RM group. Patients in the acupuncture group gained significantly more quality-adjusted life-years compared with the RM group. Depending on different scenarios, the incremental cost-effectiveness ratio for acupuncture patients was between ?31,241 (approximately US $38.569) and ?118,889 (approximately US $146,777) from society's perspective and between ?20,807 (approximately US $25,688) and ?74,585 (approximately US $92.080) from a third-party payer's perspective. CONCLUSION: Acupuncture is an effective intervention that results in improved quality of life in patients with SAR. However, in times of limited resources for health care, acupuncture for AR may not be a cost-effective intervention. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00610584. PMID- 23806462 TI - Eosinophilic esophagitis to unsuspected rare food allergen. PMID- 23806463 TI - The nebulous diagnosis of type III hereditary angioedema. PMID- 23806464 TI - Persistent specific nasal reactivity to occupational allergens after removal from exposure. PMID- 23806465 TI - Estrogen-independent hereditary angioedema with normal C1 inhibitor function in a 10-year-old boy. PMID- 23806466 TI - Efficacy of American College of Allergy Asthma and Immunology symposia and workshops. PMID- 23806467 TI - Anaphylaxis to gold tequila. PMID- 23806468 TI - Mannose-binding lectin 2 gene polymorphisms affect serum mannose-binding lectin levels in adult asthmatics. PMID- 23806469 TI - Rapid desensitization to doxycycline. PMID- 23806470 TI - Hypersensitivity to nabumetone: cross reactivity with naproxen. PMID- 23806471 TI - Immunoglobulin G4-related disease presenting as an ethmoid and maxillary mass. PMID- 23806472 TI - Multifunctional acrylates as possible sensitizers in electrocardiogram electrode allergy. PMID- 23806473 TI - Comment on terminology, close-calls, and bracketology for allergy, asthma, and immunology. PMID- 23806474 TI - Allergen of the month--water birch. PMID- 23806475 TI - Reference ranges of PR duration and P-wave indices in individuals free of cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis (MESA). AB - In this brief report, we provide normal reference ranges for PR duration [unadjusted and heart rate adjusted] and P-wave indices [duration, amplitude and terminal force in V1] in individuals free of cardiovascular disease and its risk factors. We used automatically processed digital ECG data from 1252 US participants [mean age 59 (+/- 10) years, 738 women, 588 whites, 207 African Americans, 217 Hispanics, 240 Chinese] from the Multi-Ethnic Study of Atherosclerosis [MESA]. In multivariable adjusted linear regression models with PR and each P-wave variable as a separate outcome, significant age, sex and race differences in these markers were observed. Subsequently, we report reference ranges for abnormal [2nd and 98th percentiles], borderline abnormal [5th and 95th percentiles] and mean [SD] values of PR and P-wave indices stratified by age [middle age (45-64 years) and seniors (65-84 years)], sex [men and women] and race [whites, African Americans, Hispanics and Chinese]. PMID- 23806476 TI - Semi-mechanistic physiologically-based pharmacokinetic modeling of clinical glibenclamide pharmacokinetics and drug-drug-interactions. AB - We studied if the clinical pharmacokinetics and drug-drug interactions (DDIs) of the sulfonylurea-derivative glibenclamide can be simulated via a physiologically based pharmacokinetic modeling approach. To this end, a glibenclamide PBPK-model was build in Simcyp using in vitro physicochemical and biotransformation data of the drug, and was subsequently optimized using plasma disappearance data observed after i.v. administration. The model was validated against data observed after glibenclamide oral dosing, including DDIs. We found that glibenclamide pharmacokinetics could be adequately modeled if next to CYP metabolism an active hepatic uptake process was assumed. This hepatic uptake process was subsequently included in the model in a non-mechanistic manner. After an oral dose of 0.875 mg predicted Cmax and AUC were 39.7 (95% CI:37.0-42.7)ng/mL and 108 (95% CI: 96.9 120)ng/mLh, respectively, which is in line with observed values of 43.6 (95% CI: 37.7-49.5)ng/mL and 133 (95% CI: 107-159)ng/mLh. For a 1.75 mg oral dose, the predicted and observed values were 82.5 (95% CI:76.6-88.9)ng/mL vs 91.1 (95% CI: 67.9-115.9) for Cmax and 224 (95% CI: 202-248) vs 324 (95% CI: 197-451)ng/mLh for AUC, respectively. The model correctly predicted a decrease in exposure after rifampicin pre-treatment. An increase in glibenclamide exposure after clarithromycin co-treatment was predicted, but the magnitude of the effect was underestimated because part of this DDI is the result of an interaction at the transporter level. Finally, the effects of glibenclamide and fluconazol co administration were simulated. Our simulations indicated that co-administration of this potent CYP450 inhibitor will profoundly increase glibenclamide exposure, which is in line with clinical observations linking the glibenclamide-fluconazol combination to an increased risk of hypoglycemia. In conclusion, glibenclamide pharmacokinetics and its CYP-mediated DDIs can be simulated via PBPK-modeling. In addition, our data underline the relevance of modeling transporters on a full mechanistic level to further improve pharmacokinetic and DDI predictions of this sulfonylurea-derivative. PMID- 23806477 TI - Cognitive function is a risk for health literacy in older adults with diabetes. AB - AIMS: Cognitive impairment is common in older adults with diabetes, yet it is unclear to what extent cognitive function is associated with health literacy. We hypothesized that cognitive function, independent of education, is associated with health literacy. METHODS: The sample included 537 African American, American Indian, and White men and women 60 years or older. Measures of cognitive function included the Mini-Mental State Examination (MMSE), Verbal Fluency, Brief Attention, and Digit Span Backward tests. Health literacy was assessed using the S-TOFHLA. RESULTS: Cognitive function was associated with health literacy, independent of education and other important confounders. Every unit increase in the MMSE, Digit Span Backward, Verbal Fluency or Brief Attention was associated with a 20% (p<.001), 34% (p<.001), 5% (p<.01), and 16% (p<.01) increase in the odds of having adequate health literacy, respectively. CONCLUSIONS: These results suggest that cognitive function is associated with health literacy in older adults with diabetes. Because poor cognitive function may undermine health literacy, efforts to target older adults on improving health literacy should consider cognitive function as a risk factor. PMID- 23806478 TI - Left ventricular dysfunction and outcome at two-year follow-up in patients with type 2 diabetes: The DYDA study. AB - AIMS: Left ventricular dysfunction (LVD) in type 2 diabetes mellitus (DM) (DYDA) study is a prospective investigation enrolling 960 with DM without overt cardiac disease. At baseline, a high prevalence of LVD was detected by analysing midwall shortening. We report here the incidence of clinical events in DYDA patients after 2-year follow-up and the frequency of LVD detected at baseline and 2-year evaluation. METHODS: Systolic LVD was defined as midwall shortening <=15%, diastolic LVD as any condition different from "normal diastolic function" identified as E/A ratio on Doppler mitral flow between 0.75 and 1.5 and deceleration time of E wave >140 ms. Major outcome was a composite of major events, including all-causes death and hospital admissions. RESULTS: During the study period, any systolic/diastolic LVD was found in 616 of 699 patients (88.1%) in whom LVD function could be measured at baseline or at 2 years. Older age and high HbA1c predicted the occurrence of LVD. During the follow-up 15 patients died (1.6%), 3 for cardiovascular causes, 139 were hospitalized (14.5%, 43 of them for cardiovascular causes, 20 for a new cancer). CONCLUSIONS: During a 2-year follow up any LVD is detectable in a large majority of patients with DM without overt cardiac disease. Older age and higher HbA1c predict LVD. All-cause death or hospitalization occurred in 15% of patients, cardiovascular cause was uncommon. Independent predictors of events were older age, pathologic lipid profile, high HbA1c, claudicatio and repaglinide therapy. Echo-assessed LVD at baseline was not prognosticator of events. PMID- 23806479 TI - Severely obese people with diabetes experience impaired emotional well-being associated with socioeconomic disadvantage: results from diabetes MILES - Australia. AB - AIM: To examine the emotional well-being of severely obese Australians with type 2 diabetes, along with markers of social and economic disadvantage, using the Diabetes MILES - Australia dataset. METHODS: Diabetes MILES - Australia was a national survey of 3338 adults with diabetes that focused on psychosocial issues; 1795 had type 2 diabetes and reported BMI. We extracted data regarding depression (PHQ-9), anxiety (GAD-7), obesity- and diabetes-related comorbidities, and demographics. The severely obese group (SOG) (BMI >= 35; median BMI=41.6) constituted 530 (30%) of the type 2 diabetes respondents and was matched with 530 controls (CG) (BMI<35; median BMI=28.2). Within- and between-group trends were examined. RESULTS: The SOG had higher depression scores (median (IQR) 6.0 (3-12)) than CG (5.0 (2-10)); p<0.001, and were more likely to report moderate-severe depressive symptoms (37% versus 27%; p<0.001). The groups did not differ on anxiety. The SOG, compared with the CG, were more likely to live alone (21% versus 17%), receive a disability pension (21% versus 15%), earn <=$40.000/year (51% versus 41%; all p<0.05), and were less likely to be employed (46% versus 53%), university or higher educated (17% versus 26%), or have health insurance (50% versus 60%; all p <= 0.01). Moderate-severe depression was positively associated with cumulative stressors of severe obesity, socioeconomic disadvantage, and obesity- and diabetes-related comorbidity. CONCLUSIONS: Severely obese people living with type 2 diabetes have cumulative stressors related to health, disability, demographic and socioeconomic factors, and impaired emotional well-being. PMID- 23806480 TI - A hospital-based cross-sectional study to develop an estimation formula for 2-h post-challenge plasma glucose for screening impaired glucose tolerance. AB - AIMS: To create and validate an estimation formula for 2-h post-challenge plasma glucose (2-hPG) as an alternative to oral glucose tolerance test (OGTT) for impaired glucose tolerance (IGT) screening. METHODS: 380 Japanese subjects (57.6% males, aged 58.5 (14.0); mean (SD) years) undergoing OGTT were included in this hospital-based cross-sectional study mainly at Kyoto University Hospital between 2000 and 2011. We determined the main predictive variables of 2-hPG from clinical variables and separated the subjects randomly into two groups: a derivation group to construct an estimation formula of 2-hPG on the basis of predictive variables and a validation group to evaluate the accuracy of the formula. RESULTS: Fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) were highly correlated with 2-hPG measured by OGTT. Multiple linear regression analysis showed that estimated 2-hPG (e2-hPG) was calculated by the formula: e2-hPG = 1.66 * FPG (mmol/l) + 1.63 * HbA1c (%)-10.11 (R(2), coefficient of determination=60.2%). When the cut-off value was set to the diagnostic criteria of IGT, 7.8 mmol/l of e2-hPG, sensitivity, specificity, and negative predictive value (NPV) were 83.3%, 44.1%, and 74.3%, respectively. When the cut-off value was set lower (7.2 mmol/l), these values were 94.4%, 30.5%, and 85.7%, respectively. The area under the receiver operating characteristic (ROC) curve was 0.68. CONCLUSIONS: This high-sensitive estimation formula may be a useful alternative to OGTT for IGT screening. For the levels <= 7.2 mmol/l, this formula may also be useful in cross-sectional study to identify people whose glucose tolerance is normal. PMID- 23806481 TI - Insulin-deficient diabetes-induced bone microarchitecture alterations are associated with a decrease in the osteogenic potential of bone marrow progenitor cells: preventive effects of metformin. AB - AIMS: Diabetes mellitus is associated with metabolic bone disease and increased low-impact fractures. The insulin-sensitizer metformin possesses in vitro, in vivo and ex vivo osteogenic effects, although this has not been adequately studied in the context of diabetes. We evaluated the effect of insulin-deficient diabetes and/or metformin on bone microarchitecture, on osteogenic potential of bone marrow progenitor cells (BMPC) and possible mechanisms involved. METHODS: Partially insulin-deficient diabetes was induced in rats by nicotinamide/streptozotocin-injection, with or without oral metformin treatment. Femoral metaphysis micro-architecture, ex vivo osteogenic potential of BMPC, and BMPC expression of Runx-2, PPARgamma and receptor for advanced glycation endproducts (RAGE) were investigated. RESULTS: Histomorphometric analysis of diabetic femoral metaphysis demonstrated a slight decrease in trabecular area and a significant reduction in osteocyte density, growth plate height and TRAP (tartrate-resistant acid phosphatase) activity in the primary spongiosa. BMPC obtained from diabetic animals showed a reduction in Runx-2/PPARgamma ratio and in their osteogenic potential, and an increase in RAGE expression. Metformin treatment prevented the diabetes-induced alterations in bone micro-architecture and BMPC osteogenic potential. CONCLUSION: Partially insulin-deficient diabetes induces deleterious effects on long-bone micro-architecture that are associated with a decrease in BMPC osteogenic potential, which could be mediated by a decrease in their Runx-2/PPARgamma ratio and up-regulation of RAGE. These diabetes-induced alterations can be totally or partially prevented by oral administration of metformin. PMID- 23806482 TI - Early life permethrin treatment leads to long-term cardiotoxicity. AB - Environmental, nutritional or hormonal influences in early life may have long term effects changing homeostatic processes and physiological parameters in adulthood. NF-kB and Nrf2, two of the main transcription factors regulating genes involved in pro-inflammatory and antioxidant responses respectively, can be modified by various stimuli. NF-kB controls immediate early genes and is required for cardiomyocyte hypertrophic growth, while Nrf2 protects the heart from oxidative stress-induced cardiovascular complications. The aim of this study was to investigate the impact of early life permethrin treatment (1/50 of LD50, from 6th to 21st day of life) on the development of cardiotoxicity in 500-day-old rats. Nrf2 and NF-kB gene expression, calcium level and heart surface area were chosen as biomarkers of toxicity. Six candidate reference genes were first examined and GAPDH resulted the most stable one for RT-qPCR. The comparative expression analysis of the target genes showed 1.62-fold increase in Nrf2 mRNA level, while the NF-kB mRNA in treated rats was not significantly changed compared to control ones. A significant decrease in heart surface area was observed in treated rats (296.59 +/- 8.09, mm(2)) with respect to the control group (320.86 +/- 4.93, mm(2)). Finally, the intracellular calcium influx in heart of early life treated rats increased 4.33-fold compared to the control one. In conclusion, early life pesticide exposure to low doses of permethrin insecticide, has long-term consequences leading to cardiac hypotrophy, increased calcium and Nrf2 gene expression levels in old age. PMID- 23806483 TI - Toxicity testing with luminescent bacteria--characterization of an automated method for the combined assessment of acute and chronic effects. AB - The luminescent bacteria test according to EN ISO 11348 is frequently applied in (eco) toxicity testing and is applicable for a huge variety of environmental and industrial samples. A big disadvantage of this method is the very short exposure time, which is expressed in a low sensitivity in regard to substances with a delayed effect. Chronic effects, i.e. interference with cell growth, cannot be assessed with this conventional standard method. The goal of this research was to develop an automated testing system for long term toxicity towards the luminescent bacteria Vibrio fischeri by implementing microtitration-based instrumentation. The optimized method, hereinafter referred to as "kinetic luminescent bacteria test", can be described as a miniaturized combination of the conventional short-term luminescence inhibition test according to EN ISO 11348 and the Photobacterium phosphoreum growth inhibition test (DIN 38412-37). The validation procedure included the evaluation of six reference compounds (3,4 Dichloroaniline, 3,5-Dichlorophenol, Chloramphenicol, Streptomycin sulfate, Potassium dichromate, Zinc sulfate heptahydrate) and three different endpoints that are acute luminescence inhibition (acute LI) after 30 min, chronic luminescence inhibition (chronic LI) after 24h and growth inhibition (GI) after 14 h. The optimized method allows the assessment of acute and chronic effects within one test, by what a misinterpretation of the toxicity of substances with delayed bacterial toxicity can be prevented, without abandoning most of the advantages of the conventional short-term test. Therefore, the kinetic luminescent bacteria test is exceptional as an initial screening test for environmental samples or substances with unknown (eco) toxicological characteristics. PMID- 23806484 TI - Spatiotemporal evaluation of water quality incidents in Japan between 1996 and 2007. AB - We present a spatiotemporal evaluation of water quality incidents in Japan considering incident numbers, incident causes, pollutant categories, and pollution effects. Water pollution incidents in first-class river systems almost tripled to about 1487 in the 12 years from 1996 to 2007. In addition, oil makes up the largest proportion of pollutants nationwide (76.61%) and the major source of pollution for each region in Japan. Moreover, every category shows a growth trend, especially since 2005. The main cause of incidents was "Unknown" (43%), followed by "Poor working practice" (24%), and then by "Accident" (10%) and "Other" (10%). In Hokuriku, however, the main cause of incidents was "Poor working practice" (36%), which is greater than "Unknown" (30%). Finally, waterworks (approximately 60%) was the largest of four kinds of water supply infrastructure affected by pollution incidents, followed by simplified waterworks. The population affected by offensive odors and tastes peaked in 1990 and has been decreasing. Overall, the results show the characteristics of incidents from 1996 to 2007, with significant implications for adaptation measures, strategies and policies to reduce water quality incidents. PMID- 23806485 TI - Biodegradability of the antioxidant diaryl-p-phenylene diamine using a modified inherent biodegradation method at an environmentally relevant concentration. AB - The chemical product diaryl-p-phenylene diamine (DAPD), produced by The Goodyear Tire & Rubber Company as POLYSTAY 100 (CAS 68953-84-4), is employed as an antidegradant in polymers used in tires and industrial rubber products. Previous evaluations pertaining to the ecological fate of DAPD indicated a lack of biodegradative activity in aquatic media. In order to further pursue the biodegradation potential of DAPD, it was deemed necessary to enhance the sensitivity of the aquatic biodegradation assay through (a) employment of a radiotracer of the test substance, and (b) optimisation of conditions for achieving maximal solubilisation of test material in the aquatic media of the incubation vessels. Test vessels were prepared according to the OECD ready biodegradability test guidelines, with DAPD added on silica gel at concentrations of 10 or 100 MUg L(-1), together with a surfactant to aid solubilisation. After 63 d incubation up to 37% mineralisation was measured and up to 29% of the applied radioactivity was incorporated into cell biomass. Also, after 28 d no DAPD could be measured in solution by radio-TLC and HPLC-MS. These three results demonstrate that the antioxidant DAPD undergoes microbiologically mediated biodegradation and is highly unlikely to persist in the environment. PMID- 23806486 TI - The effect of EDDS and citrate on the uptake of lead in hydroponically grown Matthiola flavida. AB - Root and shoot lead concentrations and the impact of chelating agents on these were investigated in two populations of the novel metallophyte Matthiola flavida. Plants were exposed in hydroponics to Pb(NO3)2, supplied alone, or in combination with citric acid, or EDDS. When supplied at concentrations expected to bind about 95% of the Pb in a solution containing 1-MUM Pb (1000 MUM citrate or 3.1 MUM EDDS, respectively), the root and shoot Pb concentrations were dramatically lowered, in comparison with a 1-MUM free ionic Pb control exposure. A 1-mM EDDS+1 MUM Pb treatment decreased the plants' Pb concentrations further, even to undetectable levels in one population. At 100 MUM Pb in a 1-mM EDDS-amended solution the Pb concentration increased strongly in shoots, but barely in roots, in comparison with the 1-MUM Pb+1-mM EDDS treatment, without causing toxicity symptoms. Further increments of the Pb concentration in the 1-mM EDDS-amended solution, i.e. to 800 and 990 MUM, caused Pb hyperaccumulation, both in roots and in shoots, associated with a complete arrest of root growth and foliar necrosis. M. flavida seemed to be devoid of constitutive mechanisms for uptake of Pb citrate or Pb-EDDS complexes. Hyperaccumulation of Pb-EDDS occurred only at high exposure levels. Pb-EDDS was toxic, but is much less so than free Pb. Free EDDS did not seem to be toxic at the concentrations tested. PMID- 23806487 TI - Carbendazim dissipation in the biomixture of on-farm biopurification systems and its effect on microbial communities. AB - The impact of repeated carbendazim (CARB) applications on the extent of CARB dissipation, the microbial diversity, the community level physiological profile (CLPP), and the enzymatic activity within the biomixture of an on-farm biopurification system was evaluated. After three successive CARB applications, the CARB dissipation efficiency was high; the efficiency of dissipation was 87%, 94% and 96% after each application, respectively. Although microbial enzymatic activity was affected significantly by CARB application, it could recover after each CARB pulse. Likewise, the numbers of cultivable bacteria, fungi and actinomycetes (as measured in CFUs) were slightly affected by the addition of CARB, but the inhibitory effect of the pesticide application was temporary. Denaturing gradient gel electrophoresis (DGGE) and Biolog Ecoplate assays demonstrated that the microbial populations remained relatively stable over time when compared to the control. The results obtained herein therefore demonstrate the high dissipation capacity of this biomixture and highlight the microbiological robustness of this biological system. PMID- 23806488 TI - Immediate effects of active cranio-cervical flexion exercise versus passive mobilisation of the upper cervical spine on pain and performance on the cranio cervical flexion test. AB - This study compared the immediate effects of an assisted plus active cranio cervical flexion exercise (exercise group) versus a passive mobilisation plus assisted cranio-cervical flexion (mobilisation group) on performance of the cranio-cervical flexion test (CCFT), cervical range of motion (ROM) and pain in patients with chronic neck pain. Eighteen volunteers with chronic idiopathic neck pain participated in the study and were randomised to one of the two intervention groups. Current level of pain, cervical ROM and pain perceived during movement, pressure pain threshold (PPT) and surface electromyography (EMG) during performance of the CCFT were measured before and immediately after the intervention. A significant reduction in resting pain and PPT measured over cervical sites was observed immediately following both interventions, although a greater change was observed for the exercise group. No change in cervical ROM was observed after either intervention. Reduced sternocleidomastoid and anterior scalene EMG amplitude were observed during stages of the CCFT but only for the participants in the active exercise group. Although both active and passive interventions offered pain relief, only the exercise group improved on a task of motor function highlighting the importance of specific active treatment for improved motor control of the cervical spine. PMID- 23806489 TI - Perceptions of sitting posture among members of the community, both with and without non-specific chronic low back pain. AB - Physiotherapists perceive upright, lordotic sitting postures to be important in the management of non-specific chronic low back pain (NSCLBP). Little is known about the perceptions of the wider community about seated posture, despite this being an important consideration before attempting to change seated posture. This study investigated perceptions of the best and worst sitting postures among members of the community, both with (n = 120) and without (n = 235) NSCLBP. Participants with NSCLBP perceived posture to be more important (p < 0.001), and reported thinking about their posture significantly more frequently (p < 0.001), than those without NSCLBP. 54% of participants selected a "neutral" lordotic sitting posture as their best posture, which was more frequent than any other posture (p < 0.001). Sitting postures which were "straight", and were perceived to keep the head, neck and shoulders in good alignment were preferred. However, what people considered "straight" varied considerably. 78% selected a slumped sitting posture as their worst posture, which was more frequent than any other posture (p < 0.001). The choice of best and worst sitting postures was not significantly influenced by gender, the presence of NSCLBP, or measures of pain, disability or back pain beliefs. Interestingly, a very upright sitting posture was the second most popular selection as both the best (19%) and worst (15%) posture. Overall, lordotic lumbar postures were strongly favoured among members of the community, which is broadly in line with the previously reported perceptions of physiotherapists. PMID- 23806490 TI - Introduction: the changing landscape of prostate cancer. PMID- 23806492 TI - Molecular diagnosis of prostate cancer: are we up to age? AB - Prostate cancer (PCa), a highly heterogeneous disease, is the one of the leading cause of morbidity and mortality in the developed countries. Historically used biomarkers such as prostatic acid phosphatase (PAP), serum prostate-specific antigen (PSA), and its precursor have not stood the challenge of sensitivity and specificity. At present, there is need to re-evaluate the approach to diagnose and monitor PCa. To this end, molecular markers that can accurately identify men with PCa at an early stage, and those who would benefit from early therapeutic intervention, are the need of the hour. There has been unprecedented progress in the development of new PCa biomarkers through advancements in proteomics, tissue DNA and protein/RNA microarray, identification of microRNA, isolation of circulating tumor cells, and tumor immunohistochemistry. This review will examine the current status of prostate cancer biomarkers with emphasis on emerging biomarkers by evaluating their diagnostic and prognostic potentials. PMID- 23806493 TI - Prostate cancer chemoprevention. AB - Prostate cancer is a leading cause of morbidity and mortality in men and has significant treatment-associated complications. Prostate cancer chemoprevention has the potential to decrease the morbidity and mortality associated with this disease. Chemoprevention research to date has primarily focused on nutrients and 5 alpha-reductase inhibitors (5ARIs). A large randomized trial (SELECT) found no favorable effect of selenium or vitamin E on prostate cancer prevention. Two large randomized placebo controlled trials (the PCPT and REDUCE trials) have been published and have supported the role of 5ARIs in prostate cancer chemoprevention; however, these trials also have prompted concerns regarding the increase in high-grade disease seen with treatment and have not been approved by the US Food and Drug Administration (FDA) for chemoprevention. Conclusive evidence for the chemopreventive benefit of nutrients or vitamins is lacking, whereas the future role of 5ARIs remains to be clarified. PMID- 23806491 TI - Molecular pathogenesis and progression of prostate cancer. AB - Prostate cancer (PCa) is the most commonly diagnosed noncutaneous malignancy and second leading cause of cancer-related deaths in US males. Clinically, locally confined disease is treated surgically and/or with radiation therapy. Invasive disease, however, must be treated with pharmacological inhibitors of androgen receptor (AR) activity, since disease progression is fundamentally reliant on AR activation. However, despite initially effective treatment options, recurrent castration-resistant PCa (CRPC) often occurs due to aberrant reactivation of AR. Additionally, it is appreciated that many other signaling molecules, such as transcription factors, oncogenes, and tumor suppressors, are often perturbed and significantly contribute to PCa initiation and progression to incurable disease. Understanding the interplay between AR signaling and other signaling networks altered in PCa will advance therapeutic approaches. Overall, comprehension of the molecular composition promoting neoplastic growth and formation of CRPC is paramount for developing durable treatment options. PMID- 23806494 TI - Retropubic, laparoscopic, or robotic radical prostatectomy: is there any real difference? AB - The surgical management of localized prostate cancer has evolved over the last 20 years. The "gold standard" open radical prostatectomy (ORP) has been replaced largely by the robotic-assisted laparoscopic radical retropubic prostatectomy (RALP) as the most common surgical approach to treat localized prostate cancer. Pure laparoscopic radical prostatectomy (LRP), still performed by a limited number of surgeons, was more commonly utilized before the widespread availability of the robotically assisted technique. The general consensus based on the current literature is that RALP is associated with less blood loss and a shorter hospital stay but at a higher cost when compared to ORP. The literature continues to be conflicted concerning outcome measures such as impotence and urinary incontinence. Large series of long-term oncologic follow-up are not yet available; however, the data suggest that oncologic control is similar between RALP and ORP. Considerable disparities in measurement and reporting practices of perioperative outcomes continue to make direct comparisons difficult. Future prospective studies of perioperative outcomes should aim to use rigorous methodology and established criteria for standardized reporting. PMID- 23806495 TI - Pushing the limits of radiation therapy for prostate cancer: where do we go next? AB - There have been significant advancements in the quality and precision of radiation therapy (RT) for prostate cancer over the past two decades. The development and implementation of intensity-modulated radiation therapy has allowed for RT dose-escalation without parallel increases in treatment morbidity. Moreover, integration of androgen deprivation therapy with definitive RT has led to improvements in outcomes for certain subgroups of prostate cancer patients. In this review, we highlight several ongoing and developing technical advances that hold promise for further optimizing RT care, including proton beam therapy, inter and intra-fractional image-guided dose-delivery, methods for improved target volume definition, and development of techniques for safely performing hypofractionation and stereotactic body radiotherapy. We also discuss the importance of investigating the potential benefit of integrating novel systemic therapies with prostate RT to further improve outcomes for patients with locally advanced prostate cancer. PMID- 23806496 TI - Multimodality therapy for patients with high-risk prostate cancer: current status and future directions. AB - Prostate cancer is the most commonly diagnosed cancer and second most common cause of cancer death in American men. Although high-risk disease accounts for less than 15% of diagnoses, high-risk prostate cancer patients have a cancer specific mortality rate of 15% at 10 years. There is currently no consensus on the optimal management of high-risk disease because (1) there are different primary modalities available (ie, surgery, radiation), for which there are no randomized trials comparing efficacy; and (2) unstandardized timing of different therapies (ie, neoadjuvant v concurrent v adjuvant), which makes comparisons of efficacy problematic. Increased understanding into the mechanisms leading to the formation of advanced metastatic disease has spurred the development of agents to target these pathways. However, new questions regarding optimal management of disease arise with regard to the role of these therapies in combination with "conventional" primary modalities for earlier stage, high-risk prostate cancer patients. In this article, we review the transforming world of multimodality therapy in high-risk prostate cancer. PMID- 23806497 TI - The dilemma of a rising prostate-specific antigen level after local therapy: what are our options? AB - Prostate cancer is the most common solid tumor diagnosed in men in the United States and Western Europe. Primary treatment with radiation or surgery is largely successful at controlling localized disease. However, a significant number (up to one third of men) may develop biochemical recurrence (BR), defined as a rise in serum prostate-specific antigen (PSA) level. A general presumption is that BR will lead to overt progression in patients over subsequent years. There are a number of factors that a physician must consider when counseling and recommending treatment to a patient with a rising PSA. These include the following (1) various PSA-based definitions of BR; (2) source of PSA (ie, local or distant disease, residual benign prostate); (3) available modalities to treat the disease with the least morbidity; and (4) timing of therapy. In this article we review the current and future factors that clinicians should consider in the diagnosis and treatment of recurrent prostate cancer. PMID- 23806498 TI - Non-castrate metastatic prostate cancer: have the treatment options changed? AB - Over the past 7 decades androgen-deprivation therapy (ADT) has been the cornerstone of treatment for metastatic non-castrate prostate cancer (NCPC); however, the mechanisms to achieve this goal have evolved over time to include not only bilateral orchiectomy and estrogens, but also gonadotropin-releasing hormone (GnRH) agonists, antagonists, and the inclusion of androgen receptor (AR) blockade. Despite treatment with ADT, most men will progress to castrate resistant prostate cancer (CRPC). Over the last decade many new treatment options for CRPC have emerged. These new treatments also could have a meaningful role earlier in NCPC. In this review, we outline the biologic drivers of NCPC, review current standard therapy available for NCPC, and discuss the evolving role of new therapeutics in metastatic disease. PMID- 23806499 TI - Perspectives on immunotherapy in prostate cancer and solid tumors: where is the future? AB - The goals of any cancer therapy are to improve disease control, palliate pain and improve overall survival. We are fortunate to have in our cancer armamentarium two new immune-directed therapies which not only impact on disease control but also on overall survival. The first, sipuleucel-T, a cellular-based vaccine, was approved for prostate cancer and was shown to be safe with minimal toxicity. The second, ipilimumab, a monoclonal antibody directed to an immunologic checkpoint molecule, showed a survival benefit in patients with advanced melanoma. Benefit appeared to correlate in some cases with the development of autoimmune events, signaling that the immune system is in overdrive against the cancer. Where we are and where we will likely go are the topics to be discussed in this review. PMID- 23806500 TI - Chemotherapy and targeted therapies: are we making progress in castrate-resistant prostate cancer? AB - First-line therapy for men with metastatic or recurrent prostate cancer following definitive local therapy is medical or surgical castration. Though effective initially in most patients, the majority of tumors develop castration resistance, necessitating the addition of further therapy. The historic treatment paradigm of second-line androgen manipulation, followed by cytotoxic salvage chemotherapy, has changed in recent years with better understanding of mechanisms that lead to castration resistance. This review will outline the data supporting the use of targeted and chemotherapeutic agents for prostate cancer, review data leading to US Food and Drug Administration (FDA) approval of the newest agents abiraterone, enzalutamide, and cabazitaxel, as well as review ongoing studies of novel agents. PMID- 23806501 TI - Monitoring the clinical outcomes in advanced prostate cancer: what imaging modalities and other markers are reliable? AB - Effective patient care and efficient drug development require accurate tools to assess treatment effects. For metastatic castration-resistant prostate cancer (mCRPC), response biomarkers have historically been poorly reproducible, inaccurate, inconsistently applied, or only loosely associated with tangible clinical benefits such as survival. However, the field of response assessments for prostate cancer is maturing, in compliance with a rigorous process defined by analytic validation, clinical validation, and clinical qualification. For example, bone imaging with technetium-99m scintigraphy has historically been poorly used in prostate cancer clinical trials and routine patient care, and frequently has led to poor decision-making. However, contemporary clinical trial consensus criteria (Prostate Cancer Working Group 2 [PCWG2]) have standardized the definition of progression on bone scintigraphy and the clinical trials endpoint of radiographic progression-free survival (rPFS). A validated bone scan interpretation form captures the relevant data elements. rPFS and the forms have been undergoing prospective testing in multiple phase III studies. The first of these trials demonstrated a high degree of reproducibility and correlation with overall survival, and rPFS was used by the US Food and Drug Administration (FDA) for approval of abiraterone in chemotherapy-naive mCRPC. Circulating tumor cells (CTC) are another class of assays with significant promise as response-indicator biomarkers. CTC enumeration has undergone analytic validation and has been FDA cleared for monitoring patients with prostate cancer in conjunction with other clinical methods. It is not yet a surrogate for survival. Patient-reported outcomes (PROs) are direct indicators of patient benefit. The assays to measure PROs must undergo each of the steps of biomarker development, and are increasingly being standardized and used as clinical trial endpoints. In this review, we critically assess each of these classes of novel biomarkers--imaging, CTC, and PROs--in regard to the quality of data supporting their use to monitor clinical outcomes in advanced prostate cancer. PMID- 23806502 TI - Targeting epigenetics for the treatment of prostate cancer: recent progress and future directions. AB - Epigenetic aberrations contribute to prostate cancer carcinogenesis and disease progression. Efforts have been made to target DNA methyltransferase and histone deacetylases (HDACs) in prostate cancer and other solid tumors but have not had the success that was seen in the hematologic malignancies. Oral, less toxic, and more specific agents are being developed in solid tumors including prostate cancer. Combinations of epigenetic agents alone or with a targeted agent such as androgen receptor signaling inhibitors are promising approaches and will be discussed further. PMID- 23806503 TI - A 60-year-old Indian male with altered sensorium and extensive lymphoma of the scalp. PMID- 23806507 TI - [Vaccination status of family physicians in the Loire district, France]. AB - OBJECTIVES: We surveyed the vaccination status of family physicians (FP) in the Loire district (France) in 2010. SUBJECTS AND METHODS: A self-administered questionnaire was proposed to a panel of 460 FP; 288 (64%) answered. RESULTS: The vaccination coverage for Diphtheria-Tetanus-Polio in the previous 10 years, BCG, pertussis, seasonal influenza, A/H1N1 2009 influenza, and hepatitis B was 81, 74, 59, 73, 65, and 87% respectively. Sixty-four percent of FP reported they were vaccinated against measles and 49% against chicken pox; 76% were aware of vaccination recommendations for healthcare professionals but 41% wanted more information on the subject. The younger physicians were better vaccinated for Diphtheria-Tetanus-Polio, measles, hepatitis B, and influenza according to a multivariate analysis. CONCLUSIONS: The vaccinations of FP (knowledge, practice) must be improved, especially by yearly updates, continuous medical education, and medical follow-up of healthcare professionals. PMID- 23806508 TI - [Bacterial meningitis: factors related to the delay before appropriate antibiotic administration in the emergency department]. AB - OBJECTIVES: We had for aim to check the appropriateness of our practices according to French guidelines (17th consensus conference, SPILF 2008) and to identify variables associated with the delay before appropriate measures were implemented. METHODS: Our retrospective observational study (2009-2011) focused on acute bacterial meningitis (ABM) in adults. Data was collected on a standardized questionnaire from medical charts and nurse reports. RESULTS: We included 31 adults presenting with ABM; 29 (93.5%) received ceftriaxone or cefotaxime in the emergency department. Indications for corticosteroids and brain imaging complied with guidelines in respectively 71.0% and 83.9% of cases. The median delays (IQR) were: admission/lumbar puncture (LP), 2h43 [1h09-5h57]; admission/antimicrobials, 3h21 [1h34-5h11]. The indication of suspected ABM in the admission letter was associated with earlier LP (P=0.01), and was almost significantly associated also with faster initiation of adequate antibiotic therapy (P=0.05). CONCLUSIONS: Suspicion of ABM mentioned in the admission letter was associated to a better management in the emergency department. PMID- 23806509 TI - SR-NLM: a sinogram restoration induced non-local means image filtering for low dose computed tomography. AB - Radiation dose has raised significant concerns to patients and operators in modern X-ray computed tomography (CT) examinations. A simple and cost-effective means to perform a low-dose CT scan is to lower the milliampere-seconds (mAs) as low as reasonably achievable in data acquisition. However, the associated image quality with lower-mAs scans (or low-dose scans) will be unavoidably degraded due to the excessive data noise, if no adequate noise control is applied during image reconstruction. For image reconstruction with low-dose scans, sinogram restoration algorithms based on modeling the noise properties of measurement can produce an image with noise-induced artifact suppression, but they often suffer noticeable resolution loss. As an alternative technique, the noise-reduction algorithms via edge-preserving image filtering can yield an image without noticeable resolution loss, but they often do not completely eliminate the noise induced artifacts. With above observations, in this paper, we present a sinogram restoration induced non-local means (SR-NLM) image filtering algorithm to retain the CT image quality by fully considering the advantages of the sinogram restoration and image filtering algorithms in low-dose image reconstruction. Extensive experimental results show that the present SR-NLM algorithm outperforms the existing methods in terms of cross profile, noise reduction, contrast-to ratio measure, noise-resolution tradeoff and receiver operating characteristic (ROC) curves. PMID- 23806510 TI - Extractive bioconversion of cyclodextrins by Bacillus cereus cyclodextrin glycosyltransferase in aqueous two-phase system. AB - An extractive bioconversion with Bacillus cereus cyclodextrin glycosyltransferase (CGTase, EC 2.4.1.19) in aqueous two-phase system (ATPS) was investigated for the synthesis and recovery of cyclodextrins (CDs). Optimum condition for the extractive bioconversion of CDs was achieved in ATPS consisted of 7.7% (w/w) polyethylene glycol (PEG) 20,000 and 10.3% (w/w) dextran T500 with volume ratio (VR) of 4.0. Enzymatic conversion of starch occurred mainly in dextran-rich bottom phase whereas the product, CDs was transferred to top phase and a higher partition coefficient of CDs was achieved. Repetitive batch of CDs synthesis was employed by replenishment of the top phase components and addition of starch every 8h. An average total CDs concentration of 13.7 mg/mL, (4.77 mg/mLalpha-CD, 5.02 mg/mLbeta-CD and 3.91 mg/mLgamma-CD) was recovered in the top phase of PEG 20,000/dextran T500 ATPS. This study showed the effectiveness of ATPS application in extractive bioconversion of CDs synthesis with B. cereus CGTase. PMID- 23806512 TI - Molecular characterisation of the recovery process in the entomopathogenic nematode Heterorhabditis bacteriophora. AB - In Heterorhabditis bacteriophora, an insect-parasitic nematode, the third juvenile is the infective, developmentally arrested form. When it infects a suitable host, the infective juvenile recovers from developmental arrest and resumes growth and development. This process is called recovery and it is the first outcome of the host-parasite interaction. Recovery is also very important from a commercial point of view. To characterise the recovery in H. bacteriophora, we sought to identify genes involved in this process. A large scale bioassay for recovery was established and subtraction libraries of recovering infective juvenile from arrested infective juvenile transcripts were constructed at different time points. Most of the genes identified as differentially expressed between recovering and developmentally arrested infective juveniles belonged to metabolic pathways. Elevated expression levels of 23 selected genes during recovery were confirmed by quantitative PCR. For eight of these genes, transcription silencing in H. bacteriophora resulted in a significant decline in infective juvenile recovery rates, suggesting that these genes are critical to the recovery process. Two of the genes were associated with the insulin-like growth factor-1 (insulin/IGF-1) pathway, known to regulate dauer formation in the free-living nematode Caenorhabditis elegans, whereas the other six genes were associated with pathways not previously associated with recovery in nematodes. These results suggest that although little is known about parasitism-unique genes, the pathways regulating recovery in H. bacteriophora include those activated in C. elegans and those that might be unique to parasitic nematodes; the latter may be activated in response to host signals and enable the parasite to recognise its host. PMID- 23806511 TI - SAP modulates B cell functions in a genetic background-dependent manner. AB - Mutations affecting the SLAM-associated protein (SAP) are responsible for the X linked lympho-proliferative syndrome (XLP), a severe primary immunodeficiency syndrome with disease manifestations that include fatal mononucleosis, B cell lymphoma and dysgammaglobulinemia. It is well accepted that insufficient help by SAP-/- CD4+ T cells, in particular during the germinal center reaction, is a component of dysgammaglobulinemia in XLP patients and SAP-/- animals. It is however not well understood whether in XLP patients and SAP-/- mice B cell functions are affected, even though B cells themselves do not express SAP. Here we report that B cell intrinsic responses to haptenated protein antigens are impaired in SAP-/- mice and in Rag-/- mice into which B cells derived from SAP-/- mice together with wt CD4+ T cells had been transferred. This impaired B cells functions are in part depending on the genetic background of the SAP-/- mouse, which affects B cell homeostasis. Surprisingly, stimulation with an agonistic anti-CD40 causes strong in vivo and in vitro B cell responses in SAP-/- mice. Taken together, the data demonstrate that genetic factors play an important role in the SAP-related B cell functions. The finding that anti-CD40 can in part restore impaired B cell responses in SAP-/- mice, suggests potentially novel therapeutic interventions in subsets of XLP patients. PMID- 23806513 TI - Should we worry about post-rewarming hyperthermia? PMID- 23806514 TI - Protective and dysregulated T cell immunity in RSV infection. AB - Respiratory syncytial virus (RSV) is the most important cause of infantile bronchiolitis and a major pathogen in elderly and immunosuppressed persons. Although RSV shows limited antigenic diversity, repeated infections occur throughout life. Vaccine development has been delayed by poor immunogenicity, production issues and the fear of causing enhanced disease. T cells assist in viral clearance, but immune regulation serves to limit these responses and to prevent the exaggerated inflammatory response to RSV infection seen in children with bronchiolitis. Severe RSV disease can therefore be regarded as a dysregulated response to an otherwise trivial infection. Further insights into the role of T cells (including Th17) are needed to enable the rational design of safe, effective vaccines and novel treatments. PMID- 23806516 TI - Molecular analysis of Porcine Circovirus Type 2 strains from Uruguay: evidence for natural occurring recombination. AB - Porcine Circovirus Type 2 (PCV2) is a worldwide distributed virus and is considered an important emerging pathogen related to several distinct disease syndromes in pigs. Genomic structure consists of three major open reading frames (ORFs). ORF1 (rep gene) encodes replication-related proteins, ORF2 (cap gene) encodes the capsid protein and ORF3 encodes a protein putatively involved in virus-induced apoptosis. Based on cap gene sequences, PCV2 strains are classified into two main genotypes, PCV2a with five clusters (2A-2E) and PCV2b with three clusters (1A-1C). According to previous theoretical studies, PCV2 strains can eventually undergo intra and inter-genotype recombination, mainly within the rep gene. Ever since, several evidences of recombination in the field have been reported and confirmed this hypothesis. In South America, data regarding molecular characterization of PCV2 strains is still scant. Genotyping studies in the region have concluded that PCV2b is the predominant circulating genotype in the region and till now, no recombinant strains have ever been reported. In this work we thoroughly characterized at the molecular level Uruguayan PCV2 strains by extensive sequence data analysis. Moreover, recombination software tools were applied to explore and characterize eventual occurrence of natural recombination events. Two recombinant PCV2 strains were detected in this study, as a consequence of an inter-genotype recombination event between PCV2b-1A and PCV2a 2D, as the major and minor parent, respectively. According to recombination software analysis, in both cases the event occurred within the ORF1. Herein, extensive viral sequence dataset is provided, including the characterization of the first PCV2 recombinant strains ever reported in South America. Additionally, our results suggested a multi-centered source of PCV2 infection in Uruguay, which probably involved Brazilian and European origins. PMID- 23806515 TI - Advances in structure-based vaccine design. AB - Despite the tremendous successes of current vaccines, infectious diseases still take a heavy toll on the global population, and that provides strong rationale for broadening our vaccine development repertoire. Structural vaccinology, in which protein structure information is utilized to design immunogens, has promise to provide new vaccines against traditionally difficult targets. Crystal structures of antigens containing one or more protection epitopes, especially when in complex with a protective antibody, are the launching point for immunogen design. Integrating structure and sequence information for families of broadly neutralizing antibodies (bNAbs) has recently enabled the creation of germline targeting immunogens that bind and activate germline B-cells in order to initiate the elicitation of such antibodies. The contacts between antigen and neutralizing antibody define a structural epitope, and methods have been developed to transplant epitopes to scaffold proteins for structural stabilization, and to design minimized antigens that retain one or more key epitopes while eliminating other potentially distracting or unnecessary features. To develop vaccines that protect against antigenically variable pathogens, pioneering structure-based work demonstrated that multiple strain-specific epitopes could be engineered onto a single immunogen. We review these recent structural vaccinology efforts to engineer germline-targeting, epitope-specific, and/or broad coverage immunogens. PMID- 23806517 TI - Validated patient-reported outcome measure: a step forward to improve patient counselling before urethral reconstruction. PMID- 23806518 TI - Robot-assisted sacrocolpopexy for pelvic organ prolapse: surgical technique and outcomes at a single high-volume institution. AB - BACKGROUND: Pelvic organ prolapse (POP) represents a common female pelvic floor disorder that has a serious impact on quality of life. Several types of procedures with different surgical approaches have been described to correct these defects, but the optimal management is still debated. OBJECTIVE: To describe our surgical technique of robot-assisted sacrocolpopexy (RASC) for POP and to assess its safety and long-term outcomes. DESIGN, SETTING, AND PARTICIPANTS: A retrospective review of the medical records of 95 consecutive patients who underwent RASC for POP at our centre from April 2006 to December 2011 was performed. SURGICAL PROCEDURE: RASC with use of polypropylene meshes was performed in all cases using a standardised technique with the da Vinci Surgical System (Intuitive Surgical, Sunnyvale, CA, USA) in a four-arm configuration. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Clinical data were collected in a dedicated database. Intraoperative variables, postoperative complications, and outcomes of RASC were assessed. A descriptive statistical analysis was performed. RESULTS AND LIMITATIONS: Median operative time was 101 min. No conversion to open surgery was needed. One vaginal and two bladder injuries occurred and were repaired intraoperatively. Only one Clavien grade 3 postoperative complication was observed (bowel obstruction treated laparoscopically). At a median follow-up of 34 mo, persistent POP was observed in four cases (4.2%). One mesh erosion occurred and required robot-assisted removal of the mesh. Ten (10.5%) patients complained de novo urgency after RASC, which resolved in the first few weeks after surgery. No significant de novo bowel or sexual symptoms were reported. CONCLUSIONS: Our technique of RASC for correction of POP is safe and effective, with limited risk of complications and good long-term results in the treatment of all types of POP. The robotic surgical system facilitates precise and accurate placement of the meshes with short operative time, thereby favouring wider diffusion of minimally invasive treatment of POP. PATIENT SUMMARY: We studied the treatment of patients with vaginal prolapse by using a robot-assisted surgical technique to fix the vaginal wall with a synthetic mesh. This technique was found to be safe and effective, with limited risk of complications and good long-term results. PMID- 23806519 TI - Re: Rodolfo Montironi, Marina Scarpelli, Liang Cheng, et al. Immunoglobulin G4 related disease in genitourinary organs: an emerging fibroinflammatory entity often misdiagnosed preoperatively as cancer. PMID- 23806520 TI - A case of abiraterone acetate withdrawal. PMID- 23806521 TI - Clinically asymptomatic myocardial bridging in a child with familial subaortic stenosis. AB - Myocardial bridging is usually seen in the setting of hypertrophic cardiomyopathy or left ventricular hypertrophy. It is rarely reported in an asymptomatic patient with an otherwise structurally normal heart. Familial subaortic stenosis is also a rare entity, and its mode of inheritance is still unknown. Here, we described the case of a 13-year-old asymptomatic girl with a positive family history of sudden cardiac death and subaortic stenosis who was diagnosed with severe myocardial bridging concomitant with familial subaortic stenosis. PMID- 23806522 TI - Identification of a critical region in the Drosophila ryanodine receptor that confers sensitivity to diamide insecticides. AB - Anthranilic diamides, which include the new commercial insecticide, chlorantraniliprole, are an exciting new class of chemistry that target insect ryanodine receptors. These receptors regulate release of stored intracellular calcium and play a critical role in muscle contraction. As with insects, nematodes express ryanodine receptors and are sensitive to the plant alkaloid, ryanodine. However the plant parasitic nematode, Meloidogyne incognita, is insensitive to anthranilic diamides. Expression of a full-length Drosophila melanogaster ryanodine receptor in an insect cell line confers sensitivity to the receptor agents, caffeine and ryanodine along with nanomolar sensitivity to anthranilic diamides. Replacement of a 46 amino acid segment in a highly divergent region of the Drosophila C-terminus with that from Meloidogyne results in a functional RyR which lack sensitivity to diamide insecticides. These findings indicate that this region is critical to diamide sensitivity in insect ryanodine receptors. Furthermore, this region may contribute to our understanding of the differential selectivity diamides exhibit for insect over mammalian ryanodine receptors. PMID- 23806523 TI - Gould talking past Dawkins on the unit of selection issue. AB - My general aim is to clarify the foundational difference between Stephen Jay Gould and Richard Dawkins concerning what biological entities are the units of selection in the process of evolution by natural selection. First, I recapitulate Gould's central objection to Dawkins's view that genes are the exclusive units of selection. According to Gould, it is absurd for Dawkins to think that genes are the exclusive units of selection when, after all, genes are not the exclusive interactors: those agents directly engaged with, directly impacted by, environmental pressures. Second, I argue that Gould's objection still goes through even when we take into consideration Sterelny and Kitcher's defense of gene selectionism in their admirable paper "The Return of the Gene." Third, I propose a strategy for defending Dawkins that I believe obviates Gould's objection. Drawing upon Elisabeth Lloyd's careful taxonomy of the various understandings of the unit of selection at play in the philosophy of biology literature, my proposal involves realizing that Dawkins endorses a different understanding of the unit of selection than Gould holds him to, an understanding that does not require genes to be the exclusive interactors. PMID- 23806524 TI - Novel markers of squamous differentiation in the urinary bladder. AB - Urinary bladder squamous cell carcinoma and urothelial carcinoma with squamous differentiation are often high-grade and high-stage tumors that are thought to be associated with a poorer prognosis and response to therapy compared with urothelial carcinoma without divergent differentiation. Therefore, recognition of a squamous component is increasingly important in guiding prognosis and therapy. We investigated the expression of MAC387, desmoglein-3, and TRIM29 in pure squamous cell carcinoma and urothelial carcinoma with squamous differentiation to determine whether they have utility as diagnostic biomarkers for squamous differentiation. Eighty-four cases were retrieved from participating institutions including 51 pure urinary bladder squamous cell carcinomas and 33 urothelial carcinomas with squamous differentiation. MAC387, desmoglein-3, and TRIM29 antibodies demonstrated positive staining in pure squamous cell carcinoma in 51 (100%), 46 (90%), and 48 (93%) cases, respectively. Urothelial carcinoma with squamous differentiation showed reactivity for MAC387, desmoglein-3, and TRIM29 in the squamous component for 32 (97%), 26 (79%), and 32 (97%) cases, respectively. MAC387 demonstrated a sensitivity of 99% and a specificity of 70% for squamous differentiation, whereas desmoglein-3 yielded a sensitivity of 86% and a specificity of 91%. No urothelial component showed greater than 10% labeling for desmoglein-3. TRIM29 labeling showed a sensitivity of 95%, but a poorer specificity of 33%. In summary, MAC387 and desmoglein-3 are reliable diagnostic markers for supporting the morphologic impression of squamous differentiation in urinary bladder carcinoma. Desmoglein-3 shows high specificity, whereas TRIM29 was most likely to demonstrate labeling in areas without light microscopically recognizable squamous differentiation. PMID- 23806525 TI - Pathologic definition and number of lymphovascular emboli: impact on lymph node metastasis in endoscopically resected early gastric cancer. AB - Endoscopic submucosal dissection (ESD) is widely accepted as an appropriate treatment modality for early gastric cancer (EGC). Accepted indications for ESD are mostly based on the risk of lymph node (LN) metastasis in EGC. The presence of lymphovascular emboli (LVEs) is the most important risk factor for predicting LN metastasis, but the criteria for diagnosing LVEs are inconsistent and controversial. Here, we defined LVE as the presence of tumor cells within a space according to the following criteria: (1) red cells or lymphocytes surrounding the tumor cells, (2) an endothelial cell lining, and (3) attachment to the vascular wall. We reviewed a series of 102 patients with EGC who underwent gastrectomy after ESD, evaluated the definition of LVE, counted the number of LVEs in ESD specimens, and validated the significance of the definition and number of LVEs with regard to the presence of LN metastasis in gastrectomy specimens using receiver operating characteristic (ROC) curve analysis. Overall, 13 instances (12.7%) of LN metastasis were identified among 102 patients with EGC who underwent gastrectomy after ESD. The LN metastasis-positive group showed higher numbers of definite (4.46 +/- 2.45 versus 0.19 +/- 0.07), suspicious (3.15 +/- 0.76 versus 0.62 +/- 0.14), and probable (1.62 +/- 0.43 versus 0.43 +/- 0.10) LVEs in ESD specimens than the LN metastasis-negative group. In ROC analysis, the area under the ROC curve was 0.851 (95% confidence interval [CI], 0.711-0.991) for definite LVEs, compared with 0.82 (95% CI, 0.698-0.960) for suspicious LVEs and 0.72 (95% CI, 0.549-0.891) for probable LVEs. We recommend the use of strict LVE criteria to predict LN metastasis and determine the need for surgical intervention after ESD. PMID- 23806526 TI - Ossifying fibromyxoid tumor presenting EP400-PHF1 fusion gene. AB - Ossifying fibromyxoid tumor is a rare soft tissue tumor of borderline malignancy and uncertain differentiation. Recently, a novel fusion gene, EP400-PHF1, was discovered in ossifying fibromyxoid tumor; however, its relation to this type of tumor has been uncertain because the EP400-PHF1 fusion gene has been successfully detected in only 1 case. We present an ossifying fibromyxoid tumor case with the EP400-PHF1 fusion gene detected by reverse transcriptase polymerase chain reaction, along with compatible cytogenetic data showing a t(6;12)(p21;q24.3) translocation. Our results suggest that the EP400-PHF1 fusion gene is a reproducible finding in ossifying fibromyxoid tumor. PMID- 23806527 TI - Histologic prognostic factors associated with chromosomal imbalances in a contemporary series of 89 clear cell renal cell carcinomas. AB - Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cancer. The aim of this study was to define specific chromosomal imbalances in ccRCC that could be related to clinical or histologic prognostic factors. Tumors and karyotypes of 89 patients who underwent nephrectomy for ccRCC were analyzed from April 2009 to July 2012. The mean number of chromosomal aberrations was significantly higher (7.8; P < .05) in Fuhrman grade 4 (F4) than in F3 (4) and F2 (3.4) cases. The results were similar, considering separately the mean number of chromosomal losses and gains. The F4 cases had a distinct pattern with more frequent losses of chromosomes 9, 13, 14, 18, 21, 22, and Y and gains of chromosome 20. Necrosis was associated with losses of chromosomes 7, 9, 18, and 22; sarcomatoid component, losses of chromosomes 7, 9, and 14 and gains of 20; and T stage, losses of chromosomes 18 and Y. After multivariate analysis, renal fat invasion, renal vein emboli, and microscopic vascular invasion were, respectively, associated with losses of chromosomes 13 and Y, loss of chromosome 13, and loss of chromosome 14 and gains of chromosomes 7 and 20. F4 was independently associated with losses of chromosomes 9 and Y; sarcomatoid component, loss of chromosome 9 and gain of 20; necrosis, loss of chromosome 18; and T stage, loss of chromosome Y. These chromosomal imbalances can be detected routinely by karyotype or fluorescence in situ hybridization analyses to stratify patients for risk of progression. PMID- 23806528 TI - Extrapulmonary neuroendocrine small and large cell carcinomas: a review of controversial diagnostic and therapeutic issues. AB - Extrapulmonary neuroendocrine carcinoma (EPNEC) is a heterogeneous and rare group of high-grade neoplasms occurring in different organs. They usually share a poor prognosis, but diagnostic and therapeutic options still include several controversial issues, due to the rarity of this condition and to differences in architecture and cell size, being some cases pure small cell carcinomas, other pure large cell neuroendocrine carcinomas and some others combined/mixed neuroendocrine carcinomas with a conventional non-neuroendocrine carcinoma. In addition, the therapeutic strategy varies in different organs (surgery and/or chemotherapy and/or radiation therapy and/or targeted treatments), and clinicians and pathologists are asked to interact to reach an accurate classification of every single case, as well as the most appropriate selection of the treatment options, even considering different time points of each EPNEC natural history. This overview highlights controversial pathological and clinical issues and summarizes possible solutions to most of such EPNEC-related problems. PMID- 23806529 TI - Oncofetal protein IMP3: a new diagnostic biomarker for laryngeal carcinoma. AB - An accurate diagnosis of laryngeal squamous cell carcinoma (LSCC) is essential for patient management. The diagnosis of LSCC, especially in superficial biopsies, can present a diagnostic challenge for pathologists. The ability to diagnose LSCC would be greatly improved by the detection of a tumor-associated antigen. IMP3 is an oncofetal protein associated with aggressive and advanced tumors and is specifically expressed in malignant tumors but not found in benign tissues. The aim of this study was to determine the expression and diagnostic value of IMP3 in LSCC to determine whether it can serve as a diagnostic biomarker. A total of 238 cases (laryngectomy, n = 121; biopsy, n = 117) consisting of 11 laryngeal carcinoma in situ/severe dysplasia and 227 invasive LSCC were examined by immunohistochemistry for IMP3 expression. IMP3 showed strong cytoplasmic staining in 217 (92%) of 238 LSCCs regardless of histologic grade. In addition, 58 (89%) of 65 small biopsies (<=5 mm in greatest dimension) containing a minute amount of carcinoma were positive for IMP3. In contrast to malignant tumors, IMP3 expression was not found in any of the adjacent benign squamous epithelium (0/118 cases; 0%), mild or moderate dysplasia (0/139 cases; 0%), or pseudoepitheliomatous hyperplasia (0/99 cases; 0%). In summary, we are the first to describe that IMP3 is a highly sensitive and specific biomarker for LSCC. The expression of IMP3 in LSCC can be used as a positive biomarker to increase the level of confidence in establishing a definitive diagnosis of a malignancy in laryngeal biopsy. PMID- 23806530 TI - Significance of peribiliary oedema on computed tomography in diagnosis and severity assessment of acute cholangitis. AB - OBJECTIVES: To evaluate usefulness of peribiliary oedema on computed tomography (CT) in diagnosing acute cholangitis and assessing its severity. MATERIALS AND METHODS: Sixty patients (male 59%, mean age 67.3 years) who underwent endoscopic retrograde biliary drainage (ERBD) for suspected biliary obstruction within 6h after contrast-enhanced CT were evaluated. Two radiologists performed a consensus evaluation of CT for the presence of peribiliary oedema. Patients were divided into the cholangitis group and the non-cholangitis group based on clinical and ERBD findings, and CT results were compared between the two groups. In the cholangitis group, laboratory values and blood culture results were compared between those with and without peribiliary oedema. Chi-squared test was used for analyses. RESULTS: Of 60 enrolled patients, there were 46 patients in the cholangitis group and 14 patients in the non-cholangitis group. Peribiliary oedema was seen in 24/46 (52.2%) patients in the cholangitis group and 3/14 (23.3%) patients in the non-cholangitis group (p=0.043). In the cholangitis group, positive blood culture was seen in 12/24 (50%) patients with peribiliary oedema and 4/22 (18.1%) patients without it (p=0.03). CONCLUSIONS: Peribiliary oedema appears to be useful for diagnosis and severity assessment of acute cholangitis. PMID- 23806531 TI - Impact of liver cirrhosis on liver enhancement at Gd-EOB-DTPA enhanced MRI at 3 Tesla. AB - PURPOSE: The purpose of this study was to assess differences in enhancement effects of liver parenchyma between normal and cirrhotic livers on dynamic, Gd EOB-DTPA enhanced MRI at 3T. MATERIALS AND METHODS: 93 patients with normal (n=54) and cirrhotic liver (n=39; Child-Pugh class A, n=18; B, n=16; C, n=5) underwent contrast-enhanced MRI with liver specific contrast media at 3T. T1 weighted volume interpolated breath hold examination (VIBE) sequences with fat suppression were acquired before contrast injection, in the arterial phase (AP), in the late arterial phase (LAP), in the portal venous phase (PVP), and in the hepatobiliary phase (HBP) after 20 min. The relative enhancement (RE) of the signal intensity of the liver parenchyma was calculated for all phases. RESULTS: Mean RE was significantly different among all evaluated groups in the hepatobiliary phase and with increasing severity of liver cirrhosis, a decreasing, but still significant reduction of RE could be shown. Phase depending changes of RE for each group were observed. In case of non-cirrhotic liver or Child-Pugh Score A cirrhosis mean RE showed a significant increase between AP, LAP, PVP and HBP. For Child-Pugh B+C cirrhosis RE increased until PVP, however, there was no change in case of B cirrhosis (p=0.501) and significantly reduced in case of C cirrhosis (p=0.043) during HBP. CONCLUSION: RE of liver parenchyma is negatively affected by increased severity of liver cirrhosis, therefore diagnostic value of HBP could be limited in case of Child Pugh B+C cirrhosis. PMID- 23806532 TI - Honeycombing on CT; its definition, pathologic correlation, and future direction of its diagnosis. AB - Honeycombing on CT is the clue for the diagnosis of usual interstitial pneumonia (UIP) and its hallmark. According to the ATS-ERS-JRS-ALAT 2010 guideline, the patients with honeycombing on CT can be diagnosed as UIP without surgical biopsy. On CT scans, it is defined as clustered cystic airspaces, typically of comparable diameters of the order of 3-10mm, which are usually subpleural and have well defined walls. Pathologically, honeycombing consists of both collapsing of multiple fibrotic alveoli and dilation of alveolar duct and lumen Although the definition of honeycombing seems to be strict, recognition of honeycombing on CT is various among each observer Because typical honeycombing is frequently observed in the patients with UIP, we should judge clustered cysts as honeycombing when a diagnosis of UIP is suspected. PMID- 23806533 TI - Background 18F-FDG uptake in positron emission mammography (PEM): correlation with mammographic density and background parenchymal enhancement in breast MRI. AB - We aimed to determine whether background (18)F-FDG uptake in positron emission mammography (PEM) was related to mammographic density or background parenchymal enhancement in breast MRI. METHODS: We studied a total of 52 patients (mean age, 50.9 years, 26 premenopausal, 26 postmenopausal) with newly diagnosed breast cancer who underwent (18)F-FDG PEM (positron emission mammography), conventional mammography and breast MRI. The background mean (18)F-FDG uptake value on PEM was obtained by drawing a user-defined region of interest (ROI) in a normal area of the contralateral breast. We reviewed the mammography retrospectively for overall breast density of contralateral breast according to the four-point scale (grade 1 4) of the Breast Imaging Reporting and Data System (BI-RADS) classification. The background parenchymal enhancement of breast MRI was classified as minimal, mild, moderate, or marked. All imaging findings were interpreted by two readers in consensus without knowledge of image findings of other modalities. RESULTS: Multiple linear regression analysis revealed a significant correlation between background (18)F-FDG uptake on PEM and mammographic density after adjustment for age and menopausal status (P<0.01), but not between background (18)F-FDG uptake on PEM and background parenchymal enhancement on MRI. CONCLUSION: Background (18)F-FDG uptake on PEM significantly increases as mammographic density increases. Background parenchymal enhancement in breast MRI was not an independent predictor of the background (18)F-FDG uptake on PEM unlike mammographic density. PMID- 23806534 TI - Do you really know precise radiologic-pathologic correlation of usual interstitial pneumonia? AB - Although usual interstitial pneumonia (UIP) is the most common chronic interstitial pneumonia, understanding of pathologic backgrounds of CT findings has still not been enough. Since honeycombing on either scanning microgram or CT is essential for diagnosis of UIP in 2010 ATS-ERS-JRS-ALAT guide line, the role of radiologists has become much more important. We will summarize common and uncommon CT findings with radiologic-pathological correlation. PMID- 23806536 TI - Poetry is in the air: first multi-institutional results of the per-oral endoscopic myotomy procedure for achalasia. PMID- 23806535 TI - The development of a population-based automated screening procedure for PTSD in acutely injured hospitalized trauma survivors. AB - OBJECTIVE: This investigation aimed to advance posttraumatic stress disorder (PTSD) risk prediction among hospitalized injury survivors by developing a population-based automated screening tool derived from data elements available in the electronic medical record (EMR). METHOD: Potential EMR-derived PTSD risk factors with the greatest predictive utilities were identified for 878 randomly selected injured trauma survivors. Risk factors were assessed using logistic regression, sensitivity, specificity, predictive values and receiver operator characteristic (ROC) curve analyses. RESULTS: Ten EMR data elements contributed to the optimal PTSD risk prediction model including International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) PTSD diagnosis, other ICD-9-CM psychiatric diagnosis, other ICD-9-CM substance use diagnosis or positive blood alcohol on admission, tobacco use, female gender, non-White ethnicity, uninsured, public or veteran insurance status, E-code identified intentional injury, intensive care unit admission and EMR documentation of any prior trauma center visits. The 10-item automated screen demonstrated good area under the ROC curve (0.72), sensitivity (0.71) and specificity (0.66). CONCLUSIONS: Automated EMR screening can be used to efficiently and accurately triage injury survivors at risk for the development of PTSD. Automated EMR procedures could be combined with stepped care protocols to optimize the sustainable implementation of PTSD screening and intervention at trauma centers nationwide. PMID- 23806538 TI - Somatostatin, estrogen, and polycystic liver disease. PMID- 23806539 TI - An inactivated hepatitis C virus vaccine on the horizon? PMID- 23806540 TI - Garlic, silver bullets, and surveillance upper endoscopy for Barrett's esophagus. PMID- 23806541 TI - Gluten sensitivity: not celiac and not certain. PMID- 23806542 TI - Obesity heats up adipose tissue lymphocytes. PMID- 23806543 TI - Massive esophageal bleeding in an immunocompetent young man. PMID- 23806544 TI - A case of esophageal pseudomembranes. PMID- 23806545 TI - Hematemesis in a patient with diabetic ketoacidosis and chronic HCV infection. PMID- 23806546 TI - Dipstick proteinuria as a surrogate marker of long-term mortality after acute myocardial infarction. AB - BACKGROUND: Proteinuria and reduced estimated glomerular filtration rate (eGFR) are associated with an increased risk of mortality from acute myocardial infarction (AMI). However, it is unknown whether there is a difference in prognostic value for all-cause mortality between proteinuria and eGFR during post AMI. METHODS: A consecutive series of 101 patients admitted with AMI who received angioplasty were enrolled. Dipstick proteinuria and eGFR were assessed on admission: (i) the patients were divided into 2 groups according to the presence of proteinuria (proteinuria, n=25), or not (negative, n=76), (ii) the patients were divided into 2 groups according to lower eGFR (GFR<60mL/min/1.73m(2), n=31) or higher (GFR>60mL/min/1.73m(2), n=70). Clinical characteristics and 3-year all cause mortality estimated by Kaplan-Meier method were evaluated in each group. Additionally, a multivariate Cox proportional hazards model was applied to evaluate which factor was associated with all-cause mortality. RESULTS: Mean follow-up period was 914 days. Higher brain natriuretic peptide (BNP) levels were shown in the proteinuria and lower eGFR groups, respectively (proteinuria, 301+/ 324pg/mL; negative, 146+/-159pg/mL; p=0.02; lower eGFR, 294+/-305pg/mL; higher eGFR, 142+/-161pg/mL; p=0.02). Three-year all-cause mortality was higher in the proteinuria group than in the normal group (p<0.001) and in the lower eGFR group than in the higher group (p=0.006). In a Cox proportional hazards model, the presence of proteinuria [hazard ratio (95% confidence interval), 4.51 (1.07 18.96); p=0.04] was selected as one of the predictors for all-cause mortality. CONCLUSIONS: Dipstick proteinuria and lower eGFR in the early phase of AMI follow up were related to increased plasma BNP level during the sub-acute phase and long term adverse outcome. Dipstick proteinuria may be a prognostic marker for long term all-cause mortality. PMID- 23806547 TI - Heart rate: a global target for cardiovascular disease and therapy along the cardiovascular disease continuum. AB - Heart rate is a predictor of cardiovascular and all-cause mortality in the general population and in patients with cardiovascular disease. Increased resting heart rate multiplies risk and interferes at all stages of the cardiovascular disease continuum initiating from endothelial dysfunction and continuing via atherosclerotic lesion formation and plaque rupture to end-stage cardiovascular disease. As a therapeutic target, heart rate is accessible via numerous pharmacological interventions. The concept of selective heart rate reduction by the I(f) current inhibitor ivabradine provides an option to intervene effectively along the chain of events and to define the specific and prognostic role of heart rate for patients with coronary artery disease and heart failure. Future interventional studies will further clarify the significance of heart rate and targeted heart rate reduction for primary and secondary prevention in cardiovascular and cerebrovascular events. PMID- 23806548 TI - Propensity-matched lesion-based comparison of midterm outcomes of TAXUS Express and TAXUS Liberte stents for de novo native coronary stenosis. AB - BACKGROUND: We examined the implication of the revised platform of TAXUS Liberte (TAXUS-Lib; Boston Scientific, Natick, MA, USA) from TAXUS Express (TAXUS-Exp; Boston Scientific) stents, after stent placements in a daily practice environment, on midterm clinical and angiographic outcomes. METHODS AND RESULTS: By adjusting historically different baselines with propensity score matching analysis in 1358 de novo native coronary stenoses, the incidence of the clinical safety endpoint (700-day cardiac death, nonfatal recurrent myocardial infarction, and definite stent thrombosis) after placement of TAXUS-Lib (0.60%; mean follow up, 683+/-64 days) was not significantly different from that in the TAXUS-Exp group (1.20%; 677+/-96 days, p=0.182). Cardiac dysfunction (ejection fraction of left ventricle less than 40%) was the predictor of primary endpoint [odds ratio (OR), 17.8; 95% CI, 4.39-71.9; p<0.001]. In the baseline-adjusted angiographic followed-up lesions (n=443 in each arm), the incidence of secondary endpoint [binary in-stent restenosis: percent diameter stenosis (%DS) >50% at the follow up angiography] in the TAXUS-Lib group (11.3%) was not significantly different from that in the TAXUS-Exp group (13.5%, p=0.368). TAXUS-Exp was not the predictor of secondary endpoint (OR, 1.20; 95% CI, 0.77-1.85; p=0.424). CONCLUSIONS: The midterm clinical and angiographic outcomes after placement of the new TAXUS-Lib stent for de novo coronary stenosis in a daily practice environment were statistically equivalent compared to the former TAXUS-Exp. PMID- 23806549 TI - Prognostic importance of objective nutritional indexes in patients with chronic heart failure. AB - BACKGROUND: Although malnutrition indicates an unfavorable prognosis in some clinical settings, the association between nutritional indexes and outcomes for patients with chronic heart failure (CHF) is unclear. METHODS AND RESULTS: All the previously established objective nutritional indexes were evaluated. The controlling nutritional status score (CONUT), prognostic nutritional index (PNI), and geriatric nutritional risk index (GNRI) were determined for 388 consecutive patients with CHF (mean age 69.6+/-12.3 years). The prevalence of malnutrition in this cohort was 60-69%. Patients were followed prospectively, with the endpoints being death due to a cardiovascular event or re-hospitalization. There were 130 events, including 33 deaths and 97 re-hospitalizations, during a mean follow-up period of 28.4 months. Patients experiencing cardiovascular events showed impaired nutritional status, higher CONUT scores, lower PNI scores, and lower GNRI scores, compared with those who did not experience cardiovascular events. CONUT score [hazard ratio 40.9, 95% confidence interval (CI) 10.8-154.8], PNI score (hazard ratio 6.4, 95% CI 5.4-25.1), and GNRI score (hazard ratio 11.6, 95% CI 3.7-10.0) were independently associated with cardiovascular events. Kaplan Meier analysis showed that there was a significantly higher incidence of cardiovascular events in patients who were malnourished than in those who were not. CONCLUSION: Malnutrition was common in patients with CHF. Evaluation of nutritional status may provide additional prognostic information in patients with CHF. PMID- 23806550 TI - Low diastolic blood pressure was one of the independent predictors of ischemia like findings of electrocardiogram in patients who underwent coronary angiography. AB - BACKGROUND: The underlying cause of a high cardiovascular event rate in the population with low diastolic blood pressure (DBP) has not been fully elucidated. METHODS AND RESULTS: The relationship between DBP and ischemia-like findings on electrocardiography (ECG) was investigated in 187 patients who underwent coronary angiography. Patients with conditions affecting ECG (e.g. patients taking digitalis or those with old myocardial infarction, complete right bundle branch block, or hypokalemia) were excluded from the analyses. Ischemia-like ECG was defined as having one or more of the following: borderline Q wave [Minnesota code (MC) I 3], ST depression (MC IV 1-3), negative T wave (MC V 1-3), and complete left bundle branch block (MC VII 1). Based on this definition, 70 of 187 patients (37%) had ischemia-like ECG. Compared with the group without it, the group with ischemia-like ECG included more females (p<0.01), and had lower values of body mass index (p = 0.01), DBP (p<0.01), estimated glomerular filtration rate (p<0.01), left ventricular ejection fraction (LVEF; p<0.01), and higher values of age (p<0.01) and left ventricular mass index (LVMI; p<0.01). The severity of coronary artery disease did not differ between the groups. Receiver operating characteristics curve analysis revealed that 74.5 mmHg was the optimal cut-off point of DBP to predict ischemia-like ECG (area under curve, 0.63; 95% confidence interval, 0.55-0.71, p = 0.003). There were no significant relationships between systolic blood pressure and ischemia-like ECG. A multivariate analysis showed that female sex, low DBP (<= 74.5 mmHg), LVMI, and LVEF were the significant factors for the ischemia-like ECG. The odds ratio of low DBP was 2.53 (95% confidence interval, 1.19-5.40; p = 0.02). CONCLUSIONS: Low DBP was one of the significant predictors of the ischemia-like ECG in the present study. Myocardial ischemia may be a part of the cause of high cardiovascular morbidity in the population with low DBP. PMID- 23806552 TI - The inhibitory effect of a synthetic compound, (Z)-5-(2,4-dihydroxybenzylidene) thiazolidine-2,4-dione (MHY498), on nitric oxide-induced melanogenesis. AB - Nitric oxide (NO) and the NO/PKG signaling pathway play crucial roles in ultraviolet (UV)-induced melanogenesis, which is known to be related to the induction of tyrosinase. In an attempt to find a novel anti-melanogenic agent, we synthesized (Z)-5-(2,4-dihydroxybenzylidene)thiazolidine-2,4-dione (MHY498). The purpose of this study was to investigate the effect of MHY498 on NO levels and on the NO-mediated signaling pathway using an in vitro model of melanogenesis. MHY498 inhibited 200 MUM sodium nitroprusside (SNP, a NO donor)-induced NO generation, dose-dependently and suppressed tyrosinase activity and melanin synthesis induced by SNP in B16F10 melanoma cells. To investigate the effect of MHY498 on NO-mediated signaling pathway, guanosine cyclic 3',5'-monophosphate (cGMP) activities were measured using a cGMP EIA Kit and western blotting was performed to determine the effects of MHY498 on the gene expressions of tyrosinase and microphthalmia-associated transcription factor (MITF). The increased activity of cGMP by SNP was reduced dose-dependently by pretreatment with MHY498. Furthermore, MHY498 suppressed the expressions of tyrosinase and MITF stimulated by SNP. This study shows that enhancement of tyrosinase gene expression via the cGMP pathway is a probable primary mechanism of NO-induced melanogenesis and that the NO-mediated signaling pathway with the expression of MITF enhances melanogenesis. In addition, MHY498 was found to scavenge NO and to suppress the activity of the NO-mediated signaling pathway, and thus, to subsequently down-regulate tyrosinase expression and melanogenesis. This study suggests that MHY498 is a promising anti-melanogenic agent that targets the NO induced cGMP signaling pathway. PMID- 23806553 TI - Discovery of triazines as potent, selective and orally active PDE4 inhibitors. AB - Expanding on HTS hit 4 afforded a series of [1,3,5]triazine derivatives as novel PDE4 inhibitors. The SAR development and optimization process with the emphasis on ligand efficiency and physicochemical properties led to the discovery of compound 44 as a potent, selective and orally active PDE4 inhibitor. PMID- 23806554 TI - 3-Aryl-3-arylmethoxyazetidines. A new class of high affinity ligands for monoamine transporters. AB - A series of 3-aryl-3-arylmethoxy-azetidines were synthesized and evaluated for binding affinities at dopamine and serotonin transporters. The 3-aryl-3 arylmethoxyazetidines were generally SERT selective with the dichloro substituted congener 7c (Ki=1.0 nM) and the tetrachloro substituted derivative 7i (Ki=1.3 nM) possessing low nanomolar affinity for the SERT. The 3-(3,4-dichlorophenyl-3 phenylmethoxyazetidine (7g) exhibited moderate affinity at both DAT and SERT transporters and suggests that substitution of the aryl rings can be used to tune the mononamine transporter affinity. PMID- 23806555 TI - Development of stapled short helical peptides capable of inhibiting vitamin D receptor (VDR)-coactivator interactions. AB - We synthesized stapled helical leucine-based peptides (DPI-01-07) containing 2 aminoisobutyric acid and a covalent cross-linked unit as inhibitors of vitamin D receptor (VDR)-coactivator interactions. The effects of these peptides on the human VDR were examined in an inhibition assay based on the receptor cofactor assay system, and one of them, DPI-07, exhibited potent inhibitory activity (IC50: 3.2 MUM). PMID- 23806556 TI - Rational design and generation of recombinant control reagents for bispecific antibodies through CDR mutagenesis. AB - Developments in the field of bispecific antibodies have progressed rapidly in recent years, particularly in their potential role for the treatment of malignant disease. However, manufacturing stable molecules has proven to be costly and time consuming, which in turn has hampered certain aspects of preclinical evaluation including the unavailability of appropriate "negative" controls. Bispecific molecules (e.g., bispecific tandem scFv) exhibit two specificities, often against a tumor antigen as well as an immune-activation ligand such as CD3. While for IgG antibodies, isotype-matched controls are well accepted, when considering smaller antibody fragments it is not possible to adequately control for their biological activity through the use of archetypal isotypes, which differ dramatically in affinity, size, structure, and design. Here, we demonstrate a method for the rapid production of negative control tandem scFvs through complementarity determining region (CDR) mutagenesis, using a recently described bispecific T cell engager (BiTE) targeting a tumor-specific mutation of the epidermal growth factor receptor (EGFRvIII) as an example. Four independent control constructs were developed by this method through alteration of residues spanning individual CDR domains. Importantly, while target antigen affinity was completely impaired, CD3 binding affinity was conserved in each molecule. These results have a potential to enhance the sophistication by which bispecific antibodies can be evaluated in the preclinical setting and may have broader applications for an array of alternative antibody-derived therapeutic platforms. PMID- 23806557 TI - Genes involved in fatty acid metabolism: molecular characterization and hypothalamic mRNA response to energy status and neuropeptide Y treatment in the orange-spotted grouper Epinephelus coioides. AB - As in mammals, fatty acid (FA) metabolism plays diverse and vital roles in regulating food intake in fish. Multiple lines of evidence suggest that the effect of FA metabolism on food intake is linked to changes in the level of neuropeptide Y (NPY) in the hypothalamus of the rainbow trout. In mammals, the evidence suggests that FA metabolism regulates feeding via hypothalamic NPY. NPY is therefore considered an important factor that mediates the modulation of food intake by FA metabolism in vertebrates. The stimulatory effect of NPY on food intake is well known. However, to the best of our knowledge, the effect of NPY on FA metabolism in the hypothalamus has not been examined. In this study, we cloned the cDNA of four key enzymes involved in FA metabolism and assessed the effect of energy status and NPY on their mRNA expression in the hypothalamus of grouper. The full-length cDNAs of UCP2 and CPT1a and the partial coding sequence (CDS) of ACC1 and FAS were isolated from the grouper hypothalamus. These genes are expressed in the hypothalamus and during the organogenetic stage of embryogenesis. A feeding rhythm study showed that the hypothalamic expression level of NPY and CPT1a was highly correlated with feeding rhythm. Long-term fasting was found to significantly induce the hypothalamic mRNA expression of NPY, CPT1a and UCP2. An in vitro study demonstrated that NPY strongly stimulated CPT1a and UCP2 mRNA expression in a time- and dose-dependent manner. Collectively, these results suggest that these four genes related to FA metabolism may play a role in regulating food intake in grouper and, that NPY modulates FA metabolism in the grouper hypothalamus. This study showed, for the first time in vertebrates, the effect of NPY on the gene expression of FA metabolism-related enzymes. PMID- 23806558 TI - Inhibition of dehydroepiandosterone sulfate action in androgen-sensitive tissues by EM-1913, an inhibitor of steroid sulfatase. AB - Steroid sulfatase (STS) plays an important role in the formation of estrogens and androgens by allowing the conversion of inactive circulating sulfated steroids into active hormones. These steroids support the development and growth of a number of hormone-dependent cancers, including prostate cancer. Here, we tested a non-estrogenic and non-androgenic inhibitor of steroid STS, namely EM-1913, with special attention to its potential use in the treatment of prostate cancer. After determining the required dosage of dehydroepiandrosterone sulfate (DHEAS) needed to stimulate the ventral prostate and seminal vesicles in castrated rats, we measured that EM-1913 partially (26%) and almost entirely blocked (81%) the stimulating effect of DHEAS on ventral prostates and seminal vesicles, respectively. In addition, the homogenization of these two tissues allowed us to confirm that they were completely deprived of STS activity following a treatment with EM-1913. This effect is also reflected in blood, since the plasma level of DHEAS was increased in animals treated with EM-1913, whereas the levels of dehydroepiandrosterone (DHEA) and dihydrotestosterone (DHT), two DHEAS metabolites, meanwhile decreased. From these results, we concluded that STS inhibitor EM-1913 is a good candidate for additional preclinical studies. PMID- 23806560 TI - Differential expression of estrogen receptor beta isoforms in prostate cancer through interplay between transcriptional and translational regulation. AB - Estrogen receptor beta (ERbeta) and its isoforms have different putative functions and expression patterns in prostate cancer. Current studies on 5'-most exons, 0K and 0N, show that their respective promoters are actively involved in transcription. These data, however, do not explain why ERbeta isoforms are differentially expressed in normal and cancerous tissues, since 0K and 0N transcripts are detectable in clinical specimens. Various combinations of 5' untranslated exons, termed exon 0Xs, associate with promoter 0K only and exon 0Xs accommodate upstream open reading frames (uORFs) reducing protein expression. Moreover, ERbeta1, 2, and 5 are transcriptionally linked to promoter 0K; exon 0Xs are spliced only into ERbeta2 and ERbeta5 transcripts, suggesting that their expressions are regulated post-transcriptionally by exon 0Xs. This study reveals that expression of ERbeta1 is regulated primarily at the transcriptional level, whereas that of ERbeta2 and ERbeta5 is controlled by the interplay between transcriptional and post-transcriptional regulation. PMID- 23806561 TI - Hysteroscopic sterilization using a virtual reality simulator: assessment of learning curve. AB - STUDY OBJECTIVE: To assess the learning curve using a virtual reality simulator for hysteroscopic sterilization with the Essure method. DESIGN: Prospective multicenter study (Canadian Task Force classification II-2). SETTING: University and teaching hospital in the Netherlands. PARTICIPANTS: Thirty novices (medical students) and five experts (gynecologists who had performed >150 Essure sterilization procedures). INTERVENTIONS: All participants performed nine repetitions of bilateral Essure placement on the simulator. Novices returned after 2 weeks and performed a second series of five repetitions to assess retention of skills. Structured observations on performance using the Global Rating Scale and parameters derived from the simulator provided measurements for analysis. MEASUREMENTS AND MAIN RESULTS: The learning curve is represented by improvement per procedure. Two-way repeated-measures analysis of variance was used to analyze learning curves. Effect size (ES) was calculated to express the practical significance of the results (ES >= 0.50 indicates a large learning effect). For all parameters, significant improvements were found in novice performance within nine repetitions. Large learning effects were established for six of eight parameters (p < .001; ES, 0.50-0.96). Novices approached expert level within 9 to 14 repetitions. CONCLUSION: The learning curve established in this study endorses future implementation of the simulator in curricula on hysteroscopic skill acquisition for clinicians who are interested in learning this sterilization technique. PMID- 23806559 TI - Mutations in G protein-coupled receptors that impact receptor trafficking and reproductive function. AB - G protein coupled receptors (GPCRs) are a large superfamily of integral cell surface plasma membrane proteins that play key roles in transducing extracellular signals, including sensory stimuli, hormones, neurotransmitters, or paracrine factors into the intracellular environment through the activation of one or more heterotrimeric G proteins. Structural alterations provoked by mutations or variations in the genes coding for GPCRs may lead to misfolding, altered plasma membrane expression of the receptor protein and frequently to disease. A number of GPCRs regulate reproductive function at different levels; these receptors include the gonadotropin-releasing hormone receptor (GnRHR) and the gonadotropin receptors (follicle-stimulating hormone receptor and luteinizing hormone receptor), which regulate the function of the pituitary-gonadal axis. Loss-of function mutations in these receptors may lead to hypogonadotropic or hypergonadotropic hypogonadism, which encompass a broad spectrum of clinical phenotypes. In this review we describe mutations that provoke misfolding and failure of these receptors to traffick from the endoplasmic reticulum to the plasma membrane. We also discuss some aspects related to the therapeutic potential of some target-specific drugs that selectively bind to and rescue function of misfolded mutant GnRHR and gonadotropin receptors, and that represent potentially valuable strategies to treat diseases caused by inactivating mutations of these receptors. PMID- 23806562 TI - Using immunoproteomics to identify tumor-associated antigens (TAAs) as biomarkers in cancer immunodiagnosis. AB - Since intracellular proteins involved in carcinogenesis have been shown to provoke autoantibody responses, autoantibodies can be used as probes in immunoproteomics to isolate, identify, and characterize potential tumor associated antigens (TAAs). Once a TAA is identified, several approaches will be used to comprehensively characterize and validate the identified TAA/anti-TAA systems that are potential biomarkers in certain types of cancer. Our ultimate goal is to establish rigorous criteria for designation of an autoantibody to a TAA as a cancer biomarker, examine candidate TAAs for sensitivity and specificity of anti-TAA antibody response, and further develop customized TAA arrays that can be used to enhance anti-TAA antibody detection in cancer. This review will mainly focus on the recent advances in our studies using immunoproteomic approach to identify and characterize TAAs as biomarkers in cancer. PMID- 23806563 TI - Goodpasture's disease: a report of ten cases and a review of the literature. AB - This review is based on our experience with ten patients diagnosed with Goodpasture's disease (GD). Six of the patients presented with combined renal and pulmonary insufficiencies; in the remaining four patients the clinical findings were limited to renal involvement. Circulating anti-glomerular basement membrane (GBM) autoantibodies were detected at diagnosis in all patients. Two patients were double-positive for anti-GBM and anti-proteinase-3 neutrophil cytoplasmic antibodies (c-ANCA). Another patient was double positive for anti-GBM and anti myeloperoxidase cytoplasmic antibodies (p-ANCA). Four patients with rapidly progressive glomerulonephritis underwent hemodialysis: two of these patients died 6 and 8months after diagnosis, and the other two required maintenance dialysis. The remaining six patients were administered variable combinations of plasma exchange, corticosteroids, and immunosuppressive drugs, which resulted in a remarkable and progressive improvement in renal function and one-year renal survival in all of them. Building on these observations, we provide an update on this relatively rare, frequently severe, and sometimes lethal autoimmune disease of unknown etiology. GD patients typically present with rapidly progressive renal insufficiency and pulmonary hemorrhage. Involvement restricted to the kidneys alone, as in our series, is also seen. The unfailing immunological hallmark of the disease is the occurrence of circulating anti-GBM antibodies, whose titer is directly related to the clinical severity of GD. The antibodies are associated with serum ANCAs in 10% to almost 40% of GD patients, with double positivity indicative of a worse renal prognosis. The target antigen of anti-GBM antibodies is a component of the non-collagenous-1 (NC1) domain of the alpha3 chain of type IV collagen, alpha345NC1. The prevalent expression of this hexamer on the basement membrane of both the glomeruli and the pulmonary alveoli accounts for the frequently combined renal and pulmonary involvement. A strong positive association of GD with the HLA-DRB1*15:01 allele has been described, but the factor(s) responsible for the loss of self-tolerance to NC1 autoantigen has not yet been identified. A conformational change in the quaternary structure of the alpha345NC1 likely plays a crucial role in triggering an immune response and justifies the proposed description of GD as an autoimmune "conformeropathy." The function of autoreactive T-cells in GD is poorly defined but may involve a shift from TH2 to TH1 cytokine regulation, such that affinity maturation and the antigen specificity of the antibody response are enhanced. The timely diagnosis of GD and the adoption of a triple therapeutic regimen comprising plasmapheresis, corticosteroids, and immunosuppressive drugs have remarkably improved the previously dismal outcome of these patients, resulting in a one-year survival rate of 70-90%. PMID- 23806564 TI - WITHDRAWN: Abatacept as a first-line biological therapy. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.autrev.2013.06.008. The duplicate article has therefore been withdrawn. PMID- 23806565 TI - Systemic sclerosis and cryoglobulinemia: our experience with overlapping syndrome of scleroderma and severe cryoglobulinemic vasculitis and review of the literature. AB - OBJECTIVE: Systemic sclerosis (SSc) is an immune-mediated disorder characterized by multiple organ fibrotic alterations and diffuse microangiopathy. The SSc can be associated with other connective tissue diseases and less frequently with systemic vasculitides, including cryoglobulinemic vasculitis (CV). The aim of the present study was to investigate the prevalence of CV in a large series of SSc patients. METHODS: The presence of serum cryoglobulins was detected in 246 SSc patients (24 M and 222 F, age 61+/-13.5 SD years, disease duration 9.3+/-6.7 SD years); the observed clinico-serological findings, in particular the presence of SSc-CV overlapping syndrome, were carefully analyzed and compared with previous data reported in the literature. RESULTS: The presence of circulating cryoglobulins was found in 7/246 (2.8%) of SSc patients; namely, 2 subjects only trace amounts of cryoglobulins, while 5 (2%) showed mixed cryoglobulinemia (type II, IgG-IgMk), low C4, rheumatoid factor seropositivity, and hepatitis C virus infection. Among SSc patients with serum mixed cryoglobulins, 4 (1.6%) developed a clinically overt CV, while the other one was totally asymptomatic with regard to typical vasculitic manifestations. Patients with SSc-CV overlapping syndrome had limited cutaneous SSc with serum anticentromere antibodies, pulmonary hypertension, clinico-serological features of HCV-related CV, and non-healing skin ulcers of the lower limbs. In all cases, the diagnosis of SSc preceded the clinical onset of CV, from 3 to 17years. The treatment with rituximab was useful on skin ulcers of lower limb in 2/3 patients; however, the overall clinical outcome of the four SSc-CV patients was unusually severe: one with very severe skin ulcers complicated by gangrene required bilateral through-the knee amputation, the other three subjects died because of severe heart failure, and in two cases because of untreatable pulmonary hypertension. In the literature, the prevalence of mixed cryoglobulinemia in scleroderma patients is quite rare (range 0.3-2%); while, the association of SSc with clinically overt CV is only anecdotally described, always in the absence of HCV infection. CONCLUSION: The SSc-CV overlapping syndrome described here is characterized by markedly severe vascular manifestations responsible for very poor prognosis; these peculiar clinical manifestations suggest a synergic activity of typical scleroderma microangiopathy and cryoglobulinemic vasculitis. PMID- 23806566 TI - A rapid method for infectivity titration of Andes hantavirus using flow cytometry. AB - The focus assay is currently the most commonly used technique for hantavirus titer determination. This method requires an incubation time of between 5 and 11 days to allow the appearance of foci after several rounds of viral infection. The following work presents a rapid Andes virus (ANDV) titration assay, based on viral nucleocapsid protein (N) detection in infected cells by flow cytometry. To this end, an anti-N monoclonal antibody was used that was developed and characterized previously. ANDV N could be detected as early as 6 h post infection, while viral release was not observed until 24-48 h post-infection. Given that ANDV detection was performed during its first round of infection, a time reduction for titer determination was possible and provided results in only two days. The viral titer was calculated from the percentage of N positive cells and agreed with focus assay titers. Furthermore, the assay was applied to quantify the inhibition of ANDV cell entry by patient sera and by preventing endosome acidification. This novel hantavirus titration assay is a highly quantitative and sensitive tool that facilitates infectivity titration of virus stocks, rapid screening for antiviral drugs, and may be further used to detect and quantify infectious virus in human samples. PMID- 23806567 TI - Utility of the microculture method for Leishmania detection in non-invasive samples obtained from a blood bank. AB - In recent years, the role of donor blood has taken an important place in epidemiology of Leishmaniasis. According to the WHO, the numbers of patients considered as symptomatic are only 5-20% of individuals with asymptomatic leishmaniasis. In this study for detection of Leishmania infection in donor blood samples, 343 samples from the Capa Red Crescent Blood Center were obtained and primarily analyzed by microscopic and serological methods. Subsequently, the traditional culture (NNN), Immuno-chromatographic test (ICT) and Polymerase Chain Reaction (PCR) methods were applied to 21 samples which of them were found positive with at least one method. Buffy coat (BC) samples from 343 blood donors were analyzed: 15 (4.3%) were positive by a microculture method (MCM); and 4 (1.1%) by smear. The sera of these 343 samples included 9 (2.6%) determined positive by ELISA and 7 (2%) positive by IFAT. Thus, 21 of (6.1%) the 343 subjects studied by smear, MCM, IFAT and ELISA techniques were identified as positive for leishmaniasis at least one of the techniques and the sensitivity assessed. According to our data, the sensitivity of the methods are identified as MCM (71%), smear (19%), IFAT (33%), ELISA (42%), NNN (4%), PCR (14%) and ICT (4%). Thus, with this study for the first time, the sensitivity of a MCM was examined in blood donors by comparing MCM with the methods used in the diagnosis of leishmaniasis. As a result, MCM was found the most sensitive method for detection of Leishmania parasites in samples obtained from a blood bank. In addition, the presence of Leishmania parasites was detected in donor bloods in Istanbul, a non-endemic region of Turkey, and these results is a vital importance for the health of blood recipients. PMID- 23806568 TI - Novel genetic diversity within Anopheles punctimacula s.l.: phylogenetic discrepancy between the Barcode cytochrome c oxidase I (COI) gene and the rDNA second internal transcribed spacer (ITS2). AB - Anopheles punctimacula s.l. is a regional malaria vector in parts of Central America, but its role in transmission is controversial due to its unresolved taxonomic status. Two cryptic species, An. malefactor and An. calderoni, have been previously confused with this taxon, and evidence for further genetic differentiation has been proposed. In the present study we collected and morphologically identified adult female mosquitoes of An. punctimacula s.l. from 10 localities across Panama and one in Costa Rica. DNA sequences from three molecular regions, the three prime end of the mitochondrial cytochrome c oxidase I gene (3' COI), the Barcode region in the five prime end of the COI (5' COI), and the rDNA second internal transcribed spacer (ITS2) were used to test the hypothesis of new molecular lineages within An. punctimacula s.l. Phylogenetic analyses using the 3' COI depicted six highly supported molecular lineages (A-F), none of which was An. malefactor. In contrast, phylogenetic inference with the 5' COI demonstrated paraphyly. Tree topologies based on the combined COI regions and ITS2 sequence data supported the same six lineages as the 3' COI alone. As a whole this evidence suggests that An. punctimacula s.l. comprises two geographically isolated lineages, but it is not clear whether these are true species. The phylogenetic structure of the An. punctimacula cluster as well as that of other unknown lineages (C type I vs C type II; D vs E) appears to be driven by geographic partition, because members of these assemblages did not overlap spatially. We report An. malefactor for the first time in Costa Rica, but our data do not support the presence of An. calderoni in Panama. PMID- 23806569 TI - Efficacy of ivermectin and oxfendazole against Taenia solium cysticercosis and other parasitoses in naturally infected pigs. AB - Smallholder semi-confined pig production is a fast growing practice in sub Saharan Africa with an unfortunate outcome of high prevalence of Taenia solium cysticercosis and other parasitoses. The widely used anthelmintic for control of endo and ecto-parasites in pigs in the area is ivermectin at a recommended dose of 0.3mg/kg. This study was conducted to evaluate the efficacy and safety in pigs after subcutaneous injection of ivermectin (IVM, 0.3mg/kg) and orally administration of oxfendazole (OFZ, 30mg/kg) in treatment of porcine cysticercosis and other parasitoses in naturally infected pigs. A total of 61 pigs with T. solium cysticercosis (38 males and 23 females) as identified by tongue palpation with age ranging from 3 to 24 months were recruited. The pigs were stratified based on sex, age and number of cysts on the tongue and randomly allocated to IVM, OFZ and control groups. Three days before treatment and two weeks after treatment faecal samples and skin scrapings were taken to establish the burden of endo- and ectoparasites, respectively and the effect of the treatment. No adverse effect was observed in any of the treatment groups throughout the study period. Half of the pigs from each group were slaughtered at week four and the remaining half at week twelve post treatment. The IVM treatment group had no significant effect (p=0.224) on T. solium cysts viability in comparison to the control group. Significant effect on cysts viability was observed in the OFZ treated group (p<0.001) compared to IVM and control groups in all muscle tissues. Regarding to brain cysts, neither of the drugs was efficacious. Ivermectin and OFZ treatments significantly reduced (p<0.001) the faecal egg count of Ascaris suum, strongyles and Trichuris suis two weeks after treatment. At slaughter, Oesophagostomum dentatum, Ascarops strongylina and Physocephalus sexalatus were recovered from pigs in the IVM treated and in the control groups. Ivermectin was 100% effective in control of Sarcoptes scabiei. In conclusion, IVM at a single dose of 0.3mg/kg was efficacious against ectoparasites but did not effectively cure pigs from T. solium cysticercosis or nematodes. Oxfendazole, on the other hand, killed all nematodes and muscle cysts, but did not have any effect on ectoparasites. A combination of the two drugs would be a most useful treatment option for control of pig parasitoses in sub Saharan Africa. PMID- 23806570 TI - Vulvovaginitis and balanitis in patients with diabetes treated with dapagliflozin. AB - BACKGROUND: Vulvovaginitis, balanitis, and related genital infections are common in patients with type 2 diabetes. Glucosuria, which is an outcome of treatment with sodium glucose cotransporter 2 (SGLT2) inhibitors, is among the possible causes. Dapagliflozin, an SGLT2 inhibitor with demonstrated glycemic benefits in patients with diabetes, has been studied across a broad spectrum of patients. Analysis of multi-trial safety data may better define the relationship between glucosuria and genital infection. METHODS: Safety data were pooled from 12 randomized, placebo-controlled Phase 2b/3 trials to analyze the association of glucosuria with genital infection in patients with suboptimally controlled diabetes (HbA1c >6.5%-12%). Patients were randomized to receive dapagliflozin (2.5mg, 5mg, or 10mg) or placebo once daily, either as monotherapy or add-on to metformin, insulin, sulfonylurea, or thiazolidinedione for 12-24weeks. The incidence of clinical diagnoses and of events suggestive of genital infection was evaluated. RESULTS: The pooled safety data included 4545 patients: 3152 who received once-daily dapagliflozin (2.5mg [n=814], 5mg [n=1145], or 10mg [n=1193]) as monotherapy or add-on treatment, and 1393 placebo-treated patients. For dapagliflozin 2.5mg, 5mg, 10mg, and placebo, diagnosed infections were reported in 4.1%, 5.7%, 4.8%, and 0.9%, respectively. Most infections were mild or moderate and responded to standard antimicrobial treatment. Discontinuation due to these events was rare. No clear dose-response relationship between dapagliflozin and genital infection was demonstrated. CONCLUSIONS: Treatment with dapagliflozin 2.5mg, 5mg, or 10mg once daily is accompanied by an increased risk of vulvovaginitis or balanitis, related to the induction of glucosuria. Events were generally mild to moderate, clinically manageable, and rarely led to discontinuation of treatment. PMID- 23806571 TI - Posterior fossa surgery in octogenarians: special considerations. PMID- 23806572 TI - Implications of pathological vascular changes following radiosurgery for intracranial arteriovenous malformations. PMID- 23806573 TI - Zinc in depression: a meta-analysis. AB - BACKGROUND: Zinc is an essential micronutrient with diverse biological roles in cell growth, apoptosis and metabolism, and in the regulation of endocrine, immune, and neuronal functions implicated in the pathophysiology of depression. This study sought to quantitatively summarize the clinical data comparing peripheral blood zinc concentrations between depressed and nondepressed subjects. METHODS: PubMed, Cumulated Index to Nursing and Allied Health Literature, and PsycINFO were searched for original peer-reviewed studies (to June 2012) measuring zinc concentrations in serum or plasma from depressed subjects (identified by either screening or clinical criteria) and nondepressed control subjects. Mean (+/-SD) zinc concentrations were extracted, combined quantitatively in random-effects meta-analysis, and summarized as a weighted mean difference (WMD). RESULTS: Seventeen studies, measuring peripheral blood zinc concentrations in 1643 depressed and 804 control subjects, were included. Zinc concentrations were approximately -1.85 umol/L lower in depressed subjects than control subjects (95% confidence interval: [CI]: -2.51 to -1.19 umol/L, Z17 = 5.45, p < .00001). Heterogeneity was detected (chi(2)17 = 142.81, p < .00001, I(2) = 88%) and explored; in studies that quantified depressive symptoms, greater depression severity was associated with greater relative zinc deficiency (B = 1.503, t9 = -2.82, p = .026). Effect sizes were numerically larger in studies of inpatients (WMD -2.543, 95% CI: -3.522 to -1.564, Z9 = 5.09, p < .0001) versus community samples (WMD -.943, 95% CI: -1.563 to -.323, Z7 = 2.98, p = .003) and in studies of higher methodological quality (WMD -2.354, 95% CI: -2.901 to 1.807, Z7 = 8.43, p < .0001). CONCLUSIONS: Depression is associated with a lower concentration of zinc in peripheral blood. The pathophysiological relationships between zinc status and depression, and the potential benefits of zinc supplementation in depressed patients, warrant further investigation. PMID- 23806574 TI - Compulsivity and free will. PMID- 23806575 TI - A template approach to quality improvement activity: a primary care example. AB - INTRODUCTION: This paper demonstrates the use of a Quality Framework and Implementation Template to review processes for improving the quality and safety of opiate prescribing for chronic non-malignant pain (CNMP). Escalating use of prescription opiates for chronic pain is of national and international concern, with major implications for personal and public health as well as for patient safety and health service quality and safety. OBJECTIVES: This paper uses opiate prescribing for CNMP as a worked example to illustrate use of the Quality Framework for self-directed quality improvement in smaller specialist medical or community-based practices. METHODS: An Implementation Template, comprising a series of focussed questions derived from the Quality Framework, was applied to one specific quality improvement activity arising from clinical practice (opiate prescribing for CNMP). This helped the practice team understand current systems and processes, identify actual and potential problems, and find possible solutions to institute interventions for change. CONCLUSION: The template approach to quality activity is very applicable within smaller specialist or community health service settings, enabling such health services to focus on their own quality improvement activities and address topics of importance to the practice in a systematic and productive manner. PMID- 23806576 TI - Extraordinary level of hormone and number of ghrelin cells in the stomach and duodenum of an obese woman. AB - Obesity is a major metabolic disorder, in which ghrelin plays a significant role. The objective of this study was to characterize the morphology of ghrelin cells in the stomach and duodenum and the levels of ghrelin and leptin in the serum of a 52-year-old obese woman. Material for the study was obtained from the stomachs and duodenum, of obese and control women. Each subject had been treated at the Intensive Care Unit of the Clinical University Hospital in Bialystok, due to brain damage, due to primary cardiac arrest. After brain death was diagnosed and individual death was confirmed by doctors, stomach and duodenum samples were collected from each body. Paraffin sections were stained with hematoxylin and eosin and processed for immunolocalization of ghrelin. The density of ghrelin cells in each part of the gastrointestinal tract was estimated under a light microscope with a digital camera. Ghrelin-IR cells were also analyzed in terms of morphometric features such as length, width and area. The ghrelin and leptin concentrations in each blood sample were measured by ELISA. Immunohistochemical studies revealed a small number of ghrelin cells in the stomach and duodenum which did not reflect the high level of hormone. The obese woman had lower number of ghrelin cells in the stomach and duodenum and elevated ghrelin and leptin levels in serum. It can therefore be assumed that additional source of ghrelin and probably changes in activity of ghrelin o-acylotransferase, are responsible for the high concentration of ghrelin in the obese woman. PMID- 23806577 TI - Mortality in persons with mental disorders is substantially overestimated using inpatient psychiatric diagnoses. AB - Mental disorders are associated with premature mortality, and the magnitudes of risk have commonly been estimated using hospital data. However, psychiatric patients who are hospitalized have more severe illness and do not adequately represent mental disorders in the general population. We conducted a national cohort study using outpatient and inpatient diagnoses for the entire Swedish adult population (N = 7,253,516) to examine the extent to which mortality risks are overestimated using inpatient diagnoses only. Outcomes were all-cause and suicide mortality during 8 years of follow-up (2001-2008). There were 377,339 (5.2%) persons with any inpatient psychiatric diagnosis, vs. 680,596 (9.4%) with any inpatient or outpatient diagnosis, hence 44.6% of diagnoses were missed using inpatient data only. When including and accounting for prevalent psychiatric cases, all-cause mortality risk among persons with any mental disorder was overestimated by 15.3% using only inpatient diagnoses (adjusted hazard ratio [aHR], 5.89; 95% CI, 5.85-5.92) vs. both inpatient and outpatient diagnoses (aHR, 5.11; 95% CI, 5.08-5.14). Suicide risk was overestimated by 18.5% (aHRs, 23.91 vs. 20.18), but this varied widely by specific disorders, from 4.4% for substance use to 49.1% for anxiety disorders. The sole use of inpatient diagnoses resulted in even greater overestimation of all-cause or suicide mortality risks when prevalent cases were unidentified (~20-30%) or excluded (~25-40%). However, different methods for handling prevalent cases resulted in only modest variation in risk estimates when using both inpatient and outpatient diagnoses. These findings have important implications for the interpretation of hospital-based studies and the design of future studies. PMID- 23806578 TI - Latent subtypes of depression in a community sample of older adults: can depression clusters predict future depression trajectories? AB - Identifying sources of heterogeneity in late life depression remains an important focus of psychiatric investigation. Community samples are particularly informative since many older adults have clinically significant depressive symptoms but fail to meet criteria for major depression and older adults generally do not seek treatment for their depressive symptoms. The primary data used for these analyses were those collected in a community-based survey of over 3000 adults age 65 or older followed for up to ten years. Depressive symptoms were measured by the Center for Epidemiologic Studies-Depression scale (CES-D). Latent class analysis was used to identify clusters of participants based on their symptom profiles at baseline. Mixed models were used to examine trajectories of CES-D scores based on cluster assignment. A model with three unique clusters best fit the data. Cluster 1 (59%) had a low probability of any symptom endorsement. Cluster 2 (31%) endorsed as a group some negative affect and somatic symptoms but their endorsement of low positive affect did not differ from Cluster 1. Participants in Cluster 3 (10%) had a higher probability of endorsement of all symptoms compared to Clusters 1 and 2. The results did not appreciably differ when symptom severity was included. Cluster assignment was a significant predictor of change in CES-D score over the ten-year follow-up period, and the effects over time differed by sex. Depressive symptom profiles predict the longitudinal course of depression in a community sample of older adults, findings that are important especially in primary care settings. PMID- 23806579 TI - Phosphate levels as a possible state marker in panic disorder: preliminary study of a feasible laboratory measure for routine clinical practice. AB - OBJECTIVE: Low serum phosphate level is considered one of the metabolic adaptations to the respiratory alkalosis induced by hyperventilation associated with panic disorder. The aim of this study was to assess phosphatemia as a possible state marker for panic disorder. METHODS: Sixteen panic disorder patients underwent clinical assessment with a semi-structured interview, a set of rating scales and the self-rated State and Trait Anxiety Inventory (STAI), as well as extraction of venous blood samples at baseline and after 12 weeks of pharmacological treatment. Ten healthy volunteers of similar sex, age and educational level filled out the STAI and gave blood samples at baseline and 12 weeks later. RESULTS: The median (25th-75th percentiles) of phosphate levels (mg/dl) was 2.68 (2.22-3.18) among patients and 4.13 (3.74-4.70) among healthy volunteers respectively (P < 0.001). Seven (44%) patients and no healthy volunteers presented low serum phosphate (<2.50 mg/dl) at baseline; this patient abnormality was corrected in all cases after successful treatment. At baseline, the age-adjusted correlation between phosphate levels and state-anxiety was -0.66 (P < 0.001) among all 26 participants and -0.51 (P = 0.05) among the 16 panic disorder patients. CONCLUSIONS: Measurement of phosphate levels could be easily introduced into clinical practice as a possible marker for chronic hyperventilation in panic disorder, although further investigations with larger sample sizes are necessary to characterize panic disorder patients with low versus normal phosphate levels. PMID- 23806581 TI - Altered arginine metabolism in the hippocampus and prefrontal cortex of maternal immune activation rat offspring. AB - Altered arginine metabolism has been implicated in the pathogenesis of schizophrenia. The present study measured the levels of L-arginine and its downstream metabolites in the sub-regions of the hippocampus, prefrontal cortex and cerebellum in adult rats that had been exposed to maternal immune activation (MIA; a risk factor for schizophrenia). MIA significantly increased L-arginine, L ornithine and putrescine levels and decreased agmatine levels in the hippocampus and prefrontal cortex in a region-specific manner. Correlational analysis revealed a significant neurochemical-behavioural correlation. Cluster analyses showed that L-arginine and its main metabolites formed distinct groups, which changed as a function of MIA. These results demonstrate, for the first time, that MIA leads to altered arginine metabolism in the hippocampus and prefrontal cortex of the adult offspring. PMID- 23806580 TI - Impact of peripheral levels of chemokines, BDNF and oxidative markers on cognition in individuals with schizophrenia. AB - OBJECTIVE: To investigate possible differences in peripheral levels of chemokines, BDNF and oxidative markers between patients with Schizophrenia (SZ) and matched healthy controls, and investigate the correlation of these biomarkers with cognitive performance. METHODS: Thirty individuals with SZ and 27 healthy controls were included and the following plasmatic biomarkers' levels were determined according to manufacturers' instructions: BDNF, TBARS, protein carbonyl content (PCC) and the chemokines CXCL-10/IP-10, CXCL-8/IL-8, CCL-11, CCL 24/Eotaxin-2, CCL-2/MCP-1, CCL-3/MIP-1. Selected neuropsychological tasks were administered to assess verbal learning (Hopkins Verbal Learning Test), verbal fluency (FAS test), working memory (Visual Working Memory Task, Keep Track Task, Letter Memory Task), set shifting (Plus-minus task, Number-letter task), inhibition (Computerized Stroop Task, Semantic Generation Task) and complex executive function tasks (Tower of London and the shortened version of the WCST 64). RESULTS: Compared with the healthy control group, individuals with SZ presented significantly higher levels of BDNF and the chemokine CCL-11, and lower levels of TBARS and the chemokine CXCL-10/IP-10. When we examined only the SZ group, BDNF levels were positively correlated with semantic generation tasks. Working memory ability was negatively correlated with PCC. Regarding chemokines, CCL-11 was negatively correlated to performance in working memory test, and positively correlated with cognitive flexibility task. CXCL-8/IL-8 was positively correlated with verbal fluency. CCL-24/Eotaxin-2 was positively correlated with semantic generation ability and letter memory task. CONCLUSIONS: Our results indicate that cognitive performance in SZ is associated with mediators of neuroplasticity that can be measured peripherally. PMID- 23806582 TI - Persecutory ideation and a history of cannabis use. AB - BACKGROUND: Cannabis use is associated with the occurrence of psychotic experiences. However there are multiple distinct psychotic experiences, each likely to occur as quantitative traits in the general population. In this study we tested for an association of cannabis use with a dimensional assessment of persecutory ideation. METHOD: A total of 1714 individuals from the general population completed a dimensional measure of current persecutory ideation and reported on whether they had ever taken cannabis. RESULTS: Of all participants, 648 (38%) reported a history of cannabis use. These individuals reported significantly higher current levels of persecutory ideation. The amount of variance in paranoia scores explained was low. Individuals with a history of cannabis use had almost twice the odds of reporting any paranoid ideation in the past month compared with individuals who had never taken cannabis. CONCLUSIONS: Using a state of the art assessment, the study adds to findings of an association of persecutory ideation with cannabis use. PMID- 23806583 TI - Catatonia in DSM-5. AB - Although catatonia has historically been associated with schizophrenia and is listed as a subtype of the disorder, it can occur in patients with a primary mood disorder and in association with neurological diseases and other general medical conditions. Consequently, catatonia secondary to a general medical condition was included as a new condition and catatonia was added as an episode specifier of major mood disorders in DSM-IV. Different sets of criteria are utilized to diagnose catatonia in schizophrenia and primary mood disorders versus neurological/medical conditions in DSM-IV, however, and catatonia is a codable subtype of schizophrenia but a specifier for major mood disorders without coding. In part because of this discrepant treatment across the DSM-IV manual, catatonia is frequently not recognized by clinicians. Additionally, catatonia is known to occur in several conditions other than schizophrenia, major mood disorders, or secondary to a general medical condition. Four changes are therefore made in the treatment of catatonia in DSM-5. A single set of criteria will be utilized to diagnose catatonia across the diagnostic manual and catatonia will be a specifier for both schizophrenia and major mood disorders. Additionally, catatonia will also be a specifier for other psychotic disorders, including schizoaffective disorder, schizophreniform disorder, brief psychotic disorder, and substance induced psychotic disorder. A new residual category of catatonia not otherwise specified will be added to allow for the rapid diagnosis and specific treatment of catatonia in severely ill patients for whom the underlying diagnosis is not immediately available. These changes should improve the consistent recognition of catatonia across the range of psychiatric disorders and facilitate its specific treatment. PMID- 23806584 TI - Error bounds in diffusion tensor estimation using multiple-coil acquisition systems. AB - We extend the diffusion tensor (DT) signal model for multiple-coil acquisition systems. Considering the sum-of-squares reconstruction method, we compute the Cramer-Rao bound (CRB) assuming the widely accepted noncentral chi distribution. Within this framework, we assess the effect of noise in DT estimation and other measures derived from it, as a function of the number of acquisition coils, as well as other system parameters. We show the applications of CRB in many actual problems related to DT estimation: we compare different gradient field setup schemes proposed in the literature and show how the CRB can be used to choose a convenient one; we show that for fiber-type anisotropy tensors the ellipsoidal area ratio (EAR) can be estimated with less error than other scalar factors such as the fractional anisotropy (FA) or the relative anisotropy (RA), and that for this type of anisotropy tensors, increasing the number of coils is equivalent to increasing the signal-to-noise ratio, i.e., the information of the different coils can be regarded as independent. Also, we present results showing the CRB of several parameters for actual DT-MRI data. We conclude that the CRB is a valuable tool to optimal experiment design in DT-related studies. PMID- 23806585 TI - When aspiration fails: a study of its effect on mental disorder and suicide risk. AB - BACKGROUND: The Strain Theory of Suicide postulates that psychological strains usually precede suicide mental disorders including suicidal behavior. The four sources of strain are basically (1) differential value conflicts, (2) discrepancies between aspiration and reality, (3) relative deprivation, and (4) lack of coping skills. This paper focuses on the effect of perceived failed life aspiration on the individual's mental disorder and suicide risk. METHOD: Data for this study were from a large psychological autopsy study conducted in rural China, where 392 suicides and 416 community living controls were consecutively recruited. Two informants (a family member and a close friend) were interviewed for each suicide and each control. Major depression was assessed with HAM-D and the diagnosis of mental disorder was made with SCID. RESULTS: It was found that individuals having experienced failed aspiration were significantly more likely than those having not experienced a failed aspiration to be diagnosed with at least one disorder measured by the SCID and major depression measured by HAM-D, and to be a suicide victim, which is true of both suicides and controls. CONCLUSION: This study supports the hypothesis that the discrepancies between an individual's aspiration and the reality is likely to lead to mental disorder including major depression and suicidal behavior. Lowering a patient's unrealistic aspiration can be part of the of psychological strains reduction strategies in cognitive therapies by clinicians' and mental health professionals. PMID- 23806586 TI - Correlation of brain default mode network activation with bipolarity index in youth with mood disorders. AB - BACKGROUND: Major Depressive Disorder (MDD) and Bipolar Disorder (BD) can be difficult to differentiate, as both feature depressive episodes. Here we have utilized fMRI and a measure of trait bipolarity to examine resting-state functional connectivity of brain activation in the default mode network in youth with MDD and BD to isolate trait-specific patterns. METHODS: We collected resting state fMRI scans from thirty youth (15 MDD; 15 BD, Type 1). The Bipolarity Index (BI) was completed by each patient's treating psychiatrist. Independent components analysis was used to extract a default mode network component from each participant, and then multiple regression was used to identify correlations between bipolarity and network activation. RESULTS: Activation in putamen/claustrum/insula correlated positively with BI; activation in the postcentral gyrus/posterior cingulate gyrus correlated negatively with BI. These correlations did not appear to be driven by movement in the scanner, state depression, gender or lithium use. LIMITATIONS: There were group differences in state depression and sex that needed to be statistically covaried; differences in medication use existed between the groups; sample size was not large. CONCLUSIONS: The identification of the putamen/claustrum in our positive correlation may indicate a potential trait marker for the psychomotor activation unique to bipolar mania. The negative correlation in the postcentral gyrus/posterior cingulate suggests that this functional inactivation is more specific to MDD and is consistent with previous research. Ultimately, this approach may help to develop techniques to minimize the current clinical dilemma by facilitating the classification between BD and MDD. PMID- 23806587 TI - Hierarchical screening for multiple mental disorders. AB - BACKGROUND: There is a need for brief, accurate screening when assessing multiple mental disorders. Two-stage hierarchical screening, consisting of brief pre screening followed by a battery of disorder-specific scales for those who meet diagnostic criteria, may increase the efficiency of screening without sacrificing precision. This study tested whether more efficient screening could be gained using two-stage hierarchical screening than by administering multiple separate tests. METHOD: Two Australian adult samples (N=1990) with high rates of psychopathology were recruited using Facebook advertising to examine four methods of hierarchical screening for four mental disorders: major depressive disorder, generalised anxiety disorder, panic disorder and social phobia. RESULTS: Using K6 scores to determine whether full screening was required did not increase screening efficiency. However, pre-screening based on two decision tree approaches or item gating led to considerable reductions in the mean number of items presented per disorder screened, with estimated item reductions of up to 54%. The sensitivity of these hierarchical methods approached 100% relative to the full screening battery. LIMITATIONS: Further testing of the hierarchical screening approach based on clinical criteria and in other samples is warranted. CONCLUSIONS: The results demonstrate that a two-phase hierarchical approach to screening multiple mental disorders leads to considerable increases efficiency gains without reducing accuracy. Screening programs should take advantage of prescreeners based on gating items or decision trees to reduce the burden on respondents. PMID- 23806588 TI - The epidemiological modelling of dysthymia: application for the Global Burden of Disease Study 2010. AB - BACKGROUND: In order to capture the differences in burden between the subtypes of depression, the Global Burden of Disease 2010 Study for the first time estimated the burden of dysthymia and major depressive disorder separately from the previously used umbrella term 'unipolar depression'. A global summary of epidemiological parameters are necessary inputs in burden of disease calculations for 21 world regions, males and females and for the year 1990, 2005 and 2010. This paper reports findings from a systematic review of global epidemiological data and the subsequent development of an internally consistent epidemiological model of dysthymia. METHODS: A systematic search was conducted to identify data sources for the prevalence, incidence, remission and excess-mortality of dysthymia using Medline, PsycINFO and EMBASE electronic databases and grey literature. DisMod-MR, a Bayesian meta-regression tool, was used to check the epidemiological parameters for internal consistency and to predict estimates for world regions with no or few data. RESULTS: The systematic review identified 38 studies meeting inclusion criteria which provided 147 data points for 30 countries in 13 of 21 world regions. Prevalence increases in the early ages, peaking at around 50 years. Females have higher prevalence of dysthymia than males. Global pooled prevalence remained constant across time points at 1.55% (95%CI 1.50-1.60). There was very little regional variation in prevalence estimates. LIMITATIONS: There were eight GBD world regions for which we found no data for which DisMod-MR had to impute estimates. CONCLUSION: The addition of internally consistent epidemiological estimates by world region, age, sex and year for dysthymia contributed to a more comprehensive estimate of mental health burden in GBD 2010. PMID- 23806589 TI - Mimotope selection of blood group A antigen from a phage display 15-mer peptide library. AB - We select the peptide mimics of blood group A antigen by a monoclonal anti-A from a phage display 15-mer peptide library. Monoclonal anti-A was used in biopanning a phage display 15-mer peptide library. After four rounds of panning, ELISA was carried out to confirm the positive phage clones. The exogenous DNAs of the positive phages were sequenced and the corresponding amino acid sequences were deduced. Both the synthesized peptide and the phage clones were used to bind to anti-A in competitive ELISA. Erythrocyte agglutination inhibition tests were carried out to determine the mimic ability of the free synthesized peptide to the natural blood group A antigen. Computer softwares were used to simulate the interaction between the peptide and anti-A. After four rounds of biopanning, the eluted phage reached an enrichment of approximately 1600 times. Thirty-seven phage clones were chosen randomly and amplified. There were eleven clones that interacted specifically with anti-A in ELISA. DNA sequencing of the inserted oligonucleotide revealed that nine clones present a same peptide - TRWLVYFSRPYLVAT (named TRW) and each of the other two clones presented a different peptide. The synthesized free peptide TRW could inhibit the interaction of both phage displayed peptide and group A red blood cell with anti-A in competitive ELISA and hemagglutination inhibition test. Both the peptide TRW and the natural group A antigen were docked into a same cavity of anti-A in a computer simulation assay. The results indicate that peptide TRW can mimic blood group A antigen. It may be used as a proxy of natural blood group A antigen in clinical application. PMID- 23806591 TI - DNP and PhD options for perioperative nurses. PMID- 23806592 TI - Implementing AORN recommended practices for sterile technique. AB - Using sterile technique helps prevent the surgical environment from becoming contaminated and thus can help reduce the incidence of surgical site infection. The AORN "Recommended practices for sterile technique" provides guidance for setting up, maintaining, and monitoring a sterile field. Topics include the use of surgical attire and personal protective equipment; appropriate selection and evaluation of surgical gowns, gloves, and drape products for each procedure; use of sterile technique to don sterile gowns and gloves; appropriate methods for establishing and monitoring a sterile field; and techniques to ensure that items such as surgical instruments that may be contaminated are not used. Breaks in sterile technique should be corrected immediately unless the actions necessary would endanger the patient. If remedial actions must be delayed, they should be undertaken as soon as possible. Adhering to best practices for sterile technique requires remaining up to date with new approaches and incorporating these into quality initiatives. PMID- 23806593 TI - Immediate use steam sterilization: it's all about the process. AB - Proper reprocessing of surgical instrumentation assists in infection prevention efforts. Immediate use steam sterilization, previously known as flash sterilization, is an effective method of sterilization if it is performed according to manufacturers' validated instructions. Items that undergo immediate use steam sterilization are subject to the same cleaning and decontamination requirements that apply to preparing items for terminal sterilization, and manufacturers' instructions for use must be strictly followed. In 2009, The Joint Commission revised its position statement on flash sterilization and emphasized that three critical steps of reprocessing must be followed to ensure sterility (ie, cleaning and decontamination, sterilization, aseptic transfer) and that complete documentation must be available for each immediate use steam sterilization cycle so that the device is traceable to the patient if problems arise. PMID- 23806594 TI - Validation of the data elements for the health system domain of the PNDS. AB - This research study established the data elements for the health system domain in the Perioperative Nursing Data Set. A sample of AORN members were asked to confirm the clarity, necessity, measurability, and accuracy of each proposed data element. As a result of this study, the health system domain contains 114 data elements with definitions. When integrated into an electronic health record, data elements can be used to identify, compare, and evaluate the context in which patient care is delivered across settings. PMID- 23806595 TI - Whole-lung lavage for pediatric patients with pulmonary alveolar proteinosis. AB - Pulmonary alveolar proteinosis (PAP) is a chronic disorder of surfactant clearance from the alveoli. Its prevalence is rare, especially in the pediatric population. Although there is no cure for this condition, symptoms of PAP are managed most effectively through whole-lung lavage (WLL). Perioperative RNs caring for children with PAP undergoing WLL in the OR should implement patient interventions to maintain vital signs and normothermia and preserve skin integrity. Additionally, perioperative RNs often are responsible for assembling closed-drainage systems for WLL. Detailed procedural preference cards, targeted education sessions, and multidisciplinary collaboration are crucial for establishing a comprehensive plan of care for the pediatric patient with PAP undergoing WLL in the OR. PMID- 23806596 TI - Preparing for optimal outcomes: a live evacuation exercise. AB - Requirements for emergency preparation and training are a part of medical facility guidelines. At one pediatric level I trauma center with 525 beds and more than 12,000 employees, the perioperative teams received regular evacuation training but had never held a live evacuation exercise, so a team made up of perioperative and support personnel created a plan for a live evacuation exercise. The team evaluated the six key areas of evacuation planning: communication, resources and assets, security and safety, staff responsibilities, utilities management, and clinical and patient support activities. Lessons learned from the exercise included the need to include surgeons in evacuation plans, the need for improved communication between different perioperative departments, and the need for security personnel to assist in evacuations. PMID- 23806597 TI - Measure twice, cut once. PMID- 23806599 TI - Resuscitation errors: a shocking problem. PMID- 23806600 TI - Effect of blonanserin on methamphetamine-induced disruption of latent inhibition and c-Fos expression in rats. AB - To clarify the psychopharmacological profile of blonanserin, a novel antipsychotic, we examined its effect on the methamphetamine-induced disruption of latent inhibition (LI) and the neural activation related to this effect in rats. To evaluate the LI, we used a conditioned emotional response in which a tone (conditioned stimulus) was paired with a mild foot shock (unconditioned stimulus). This paradigm was presented to rats licking water. Methamphetamine induced (1.0mg/kg, i.p.) disruption of LI was significantly improved by the administration of a higher dose (3.0mg/kg, i.p.) of blonanserin and tended to be improved by 1.0-mg/kg blonanserin and 0.2-mg/kg haloperidol but not by a lower dose (0.3mg/kg) of blonanserin. Immunohistochemical examination showed blonanserin (3.0mg/kg, i.p.) increased c-Fos expression in the shell area but not in the core area of the nucleus accumbens while methamphetamine (3.0mg/kg, i.p.) produced the opposite expression pattern. Blonanserin also increased the number of c-Fos expressions in the central amygdala nucleus but not in the basolateral amygdala nucleus or the prefrontal cortex. Blonanserin ameliorates the methamphetamine-induced disruption of LI, as other antipsychotics do, and a neuronal activation and/or modulation of neurotransmission in the nucleus accumbens is related to the disruption of LI by methamphetamine and to its amelioration by blonanserin. PMID- 23806601 TI - Neural connectivity of the posterior body of the fornix in the human brain: diffusion tensor imaging study. AB - Little is known about the neural connectivity of the fornix in the human brain. In the current study, using diffusion tensor imaging, we attempted to investigate the neural connectivity of the posterior body of the fornix in the normal human brain. A total of 43 healthy subjects were recruited for this study. DTIs were acquired using a sensitivity-encoding head coil at 1.5T. For connectivity of the posterior body of the fornix, a seed region of interest was used on the posterior body of the fornix. Connectivity was defined as the incidence of connection between the posterior body of the fornix and any neural structure of the brain at the threshold of 5, 25, and 50 streamline. At the threshold of 5, 25, and 50, the posterior body of the fornix showed connectivity to the precentral gyrus (37%, 19%, and 15%), the postcentral gyrus (25%, 11.5%, and 7%), the posterior parietal cortex (16.5%, 5%, and 5%), the brainstem (12%, 4.5%, and 3.5%), the crus of the fornix (34%, 10.5%, and 7%), the contralateral splenium of the corpus callosum (12.5%, 5%, and 0%), and the ipsilateral splenium of the CC (69.8%%, 33.7%, and 23.3%), respectively. Findings of this study showed that the posterior body of the fornix had connectivity with the cerebral cortex, the brainstem, the fornical crus, and the contralateral splenium through the splenium of the corpus callosum in normal subjects. We believe that the results of this study would be helpful in investigation of the neural network related to memory and recovery mechanisms following fornical injury in the human brain. PMID- 23806602 TI - Reduced numbers of cortical GABA-immunoreactive neurons in the chronic D galactose treatment model of brain aging. AB - Chronic administration of d-galactose (d-gal) is widely used to mimic the process of brain aging; however, the neural mechanisms are still poorly understood. In this study, we investigated the effect of long-term d-gal treatment on the number of GABA-immunoreactive neurons in rat cerebral cortex and the behavioral correlates. After eight weeks of daily subcutaneous injection of d-gal (100mg/ml/kg), rats showed reduced exploratory activity and lower ambulation in the open field compared to controls. There was no significant reduction in total neurons in the cortex, but there was a marked decrease in the number of GABA immunoreactive neurons in all cortical layers of d-gal-treated rats. The ratio of GABA-immunoreactive neurons to total neurons was significantly lower in all cortical layers of d-gal-treated rats, with greatest reductions in output layers III (39.9% reduction), V (46.3%), and VI (48.4%). Our study provides the first evidence that chronic d-gal treatment may decrease cortical GABAergic neurotransmission, especially in cerebral output layers. The reduction in GABA immunoreactive cell number likely disrupts the intracortical excitatory/inhibitory balance and may contribute to the behavioral deficits observed in this aging model. PMID- 23806603 TI - Biological subtypes of triple-negative breast cancer are associated with distinct morphological changes and clinical behaviour. AB - Triple negative breast cancer (TNBC) is a heterogeneous group of tumours accounting for approximately 10-20% of all breast carcinomas. To identify biologically distinct subgroups of TNBC and to assess their clinical properties we examined a series of 142 consecutive patients all of which had received adjuvant cytotoxic chemotherapy using a comprehensive panel of immunostains. Hierarchical unsupervised cluster analysis based on the expression of 13 markers permitted separation of four distinct groups (basal A, basal B, basoluminal, luminal) with the main distinguishing features being cytokeratin (Ck5/6, Ck14, Ck19), EGFR, p53, p16, and Ki-67 expression. Clusters differed with respect to patient age, modified Bloom and Richardson grading, the presence of tumour necrosis, growth pattern and survival, both in uni- and multivariate analysis. Basal (A or B) tumours showed a substantially better outcome compared with basoluminal and luminal tumours. Our data underline the heterogeneity of TNBC and characterise potentially relevant biological subtypes. PMID- 23806604 TI - Can temperate insects take the heat? A case study of the physiological and behavioural responses in a common ant, Iridomyrmex purpureus (Formicidae), with potential climate change. AB - Insects in temperate regions are predicted to be at low risk of climate change relative to tropical species. However, these assumptions have generally been poorly examined in all regions, and such forecasting fails to account for microclimatic variation and behavioural optimisation. Here, we test how a population of the dominant ant species, Iridomyrmex purpureus, from temperate Australia responds to thermal stress. We show that ants regularly forage for short periods (minutes) at soil temperatures well above their upper thermal limits (upper lethal temperature = 45.8 +/- 1.3 degrees C; CT(max) = 46.1 degrees C) determined over slightly longer periods (hours) and do not show any signs of a classic thermal performance curve in voluntary locomotion across soil surface temperatures of 18.6-57 degrees C (equating to a body temperature of 24.5-43.1 degrees C). Although ants were present all year round, and dynamically altered several aspects of their thermal biology to cope with low temperatures and seasonal variation, temperature-dependence of running speed remained invariant and ants were unable to elevate high temperature tolerance using plastic responses. Measurements of microclimate temperature were higher than ant body temperatures during the hottest part of the day, but exhibited a stronger relationship with each other than air temperatures from the closest weather station. Generally close associations of ant activity and performance with microclimatic conditions, possibly to maximise foraging times, suggest I. purpureus displays highly opportunistic thermal responses and readily adjusts behaviour to cope with high trail temperatures. Increasing frequency or duration of high temperatures is therefore likely to result in an immediate reduction in foraging efficiency. In summary, these results suggest that (1) soil-dwelling temperate insect populations may be at higher risks of thermal stress with increased frequency or duration of high temperatures resulting from climate change than previously thought, however, behavioural cues may be able to compensate to some extent; and (2) indices of climate change-related thermal stress, warming tolerance and thermal safety margin, are strongly influenced by the scale of climate metrics employed. PMID- 23806605 TI - Differential distribution of glutamate- and GABA-gated chloride channels in the housefly Musca domestica. AB - l-Glutamic acid (glutamate) mediates fast inhibitory neurotransmission by affecting glutamate-gated chloride channels (GluCls) in invertebrates. The molecular function and pharmacological properties of GluCls have been well studied, but not much is known about their physiological role and localization in the insect body. The distribution of GluCls in the housefly (Musca domestica L.) was thus compared with the distribution of gamma-aminobutyric acid (GABA)-gated chloride channels (GABACls). Quantitative PCR and ligand-binding experiments indicate that the GluCl and GABACl transcripts and proteins are predominantly expressed in the adult head. Intense GluCl immunostaining was detected in the lamina, leg motor neurons, and legs of adult houseflies. The GABACl (Rdl) immunostaining was more widely distributed, and was found in the medulla, lobula, lobula plate, mushroom body, antennal lobe, and ellipsoid body. The present findings suggest that GluCls have physiological roles in different tissues than GABACls. PMID- 23806606 TI - Advances in multiplexed MRM-based protein biomarker quantitation toward clinical utility. AB - Accurate and rapid protein quantitation is essential for screening biomarkers for disease stratification and monitoring, and to validate the hundreds of putative markers in human biofluids, including blood plasma. An analytical method that utilizes stable isotope-labeled standard (SIS) peptides and selected/multiple reaction monitoring-mass spectrometry (SRM/MRM-MS) has emerged as a promising technique for determining protein concentrations. This targeted approach has analytical merit, but its true potential (in terms of sensitivity and multiplexing) has yet to be realized. Described herein is a method that extends the multiplexing ability of the MRM method to enable the quantitation 142 high-to moderate abundance proteins (from 31mg/mL to 44ng/mL) in undepleted and non enriched human plasma in a single run. The proteins have been reported to be associated to a wide variety of non-communicable diseases (NCDs), from cardiovascular disease (CVD) to diabetes. The concentrations of these proteins in human plasma are inferred from interference-free peptides functioning as molecular surrogates (2 peptides per protein, on average). A revised data analysis strategy, involving the linear regression equation of normal control plasma, has been instituted to enable the facile application to patient samples, as demonstrated in separate nutrigenomics and CVD studies. The exceptional robustness of the LC/MS platform and the quantitative method, as well as its high throughput, makes the assay suitable for application to patient samples for the verification of a condensed or complete protein panel. This article is part of a Special Issue entitled: Biomarkers: A Proteomic Challenge. PMID- 23806607 TI - Bile carcinoembryonic cell adhesion molecule 6 (CEAM6) as a biomarker of malignant biliary stenoses. AB - Differentiating malignant from nonmalignant biliary stenoses is challenging. This could be facilitated by the measurement of cancer biomarkers in bile. We aimed at (i) identifying new cancer biomarkers by comparative proteomic analysis of bile collected from patients with a malignant or benign biliary stenosis (exploratory phase) and (ii) verifying the accuracy of the newly identified potential biomarkers for discriminating malignant versus nonmalignant biliary stenoses in a larger group of patients (confirmation phase). Overall, 66 proteins were found overexpressed (ratio>1.5) in at least one cancer condition using proteomic analysis and 7 proteins were increased in all malignant/nonmalignant disease comparisons. Preliminary screening by immunoblot highlighted carcinoembryonic cell adhesion molecule 6 (CEAM6), a cell surface protein overexpressed in many human cancers, as an interesting candidate biomarker. ELISA subsequently confirmed CEAM6 as a potential bile biomarker for distinguishing malignant from benign biliary stenoses with a receiver operating characteristic (ROC) area under the curve (AUC) of 0.92 (specificity 83%, sensitivity 93%, positive predictive value 93%, and negative predictive value 83%). No significant difference in serum CEAM6 level was found between malignant and nonmalignant samples. Combining bile CEAM6 and serum CA19-9 in a panel further improved diagnostic accuracy for malignant stenoses (AUC 0.96, specificity 83%, sensitivity 97%, positive predictive value 93%, and negative predictive value 91%). CEAM6 measurement in bile could be clinically useful to discriminate between malignant and nonmalignant causes of biliary stenosis. This article is part of a Special Issue entitled: Biomarkers: A Proteomic Challenge. PMID- 23806608 TI - Mutation mapping of apolipoprotein A-I structure assisted with the putative cholesterol recognition regions. AB - Twenty-nine from 52 missense mutations in apoA-I gene are predicted to be deleterious by both SIFT and PolyPhen-2 algorithms. Among those, eight mutations with a prominent change in structure stability as modeled by the SDM tool for both lipid-free (Mei and Atkinson (2011) PDB ID: 3R2P) and HDL-bound (Wu et al. (2009) PDB ID: 3K2S) apoA-I, are referred as structural. The remaining mutations with a preferential location in a long intrinsically disordered region, predicted by the SPINE-D and DNdisorder tools, may influence the functional sites. Among structural mutations, five amyloidosis-only-related mutations, significant in a lipid-free structure, are located in 1-90 region. Six amyloidosis- and hypoalphalipoproteinemia-associated mutations, differently significant in two chains of lipid-bound apoA-I, are distributed among the N-domain. Six cholesterol recognition putative motifs (5 CRAC/1 CCM) in apoA-I structure are suggested to interact with cholesterol. Among those, the K40-W50 partially conserved CCM sequence with a putative recognition feature, predicted by the MoRF tool, may underlie cholesterol binding to lipid-free apoA-I, the binding triggering the disorder-to-order transition within MoRF. Thus, the impairment of helix formation and accelerated protein aggregation may underlie the amyloidogenic effect of W50R substitution. Also, D102H substitution in conserved CRAC2 V97-K106 sequence may be harmful in reverse cholesterol transport. With PDBe Motifs and Sites algorithm, cholesterol is a ligand for L101, F104 and W108 residues in HDL-bound apoA-I. The influence of specific mutation on apoA-I structure and mutated apolipoprotein switch between different pathologies is suggested to depend on the surrounding phase properties. PMID- 23806609 TI - Postural control and functional strength in patients with type 2 diabetes mellitus with and without peripheral neuropathy. AB - OBJECTIVE: To assess the influence of diabetic neuropathy (DN) on balance and functional strength in patients with diabetes mellitus type 2 (DM2). DESIGN: Cross-sectional study. SETTING: Diabetes outpatient unit. PARTICIPANTS: Adults (N=62; age range, 40-65y): 32 with DM2 (19 subjects without DN and 13 with DN) and 30 without DM2 (control group). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Upright balance, evaluated in 4 situations (fixed platform, unstable platform, with eyes open, with eyes closed), and functional strength, assessed with a five-times-sit-to-stand test, were analyzed using an electromagnetic system, with a sensor placed over C7 to allow maximum trunk displacements in the anterior-posterior and medial-lateral directions. The Berg Balance Scale and the Timed Up & Go test were also used. RESULTS: Subjects with DM2 had greater anterior-posterior displacement (P<.05) in the unstable platform with eyes closed condition compared with those without DM2, whereas no difference in medial lateral displacement was observed between these groups. A difference in time was observed in the five-times-sit-to-stand test (P<.05), with subjects in the control group performing the tasks faster than either group of subjects with DM2. Additionally, subjects in the control group showed a higher score in the Berg Balance Scale and performed the Timed Up & Go test in less time compared with subjects in other groups. CONCLUSIONS: Subjects with DM2, with or without DN, showed deficits in postural control and functional strength compared with healthy individuals of the same age group. PMID- 23806610 TI - Effects of Pilates exercises on health-related quality of life in individuals with juvenile idiopathic arthritis. AB - OBJECTIVE: To determine the effects of Pilates exercises on health-related quality of life (HRQOL) in individuals with juvenile idiopathic arthritis (JIA). DESIGN: Randomized, prospective, single-blind trial. SETTING: Outpatient clinic of pediatric rheumatology and the rehabilitation department. PARTICIPANTS: Children (N=50) with JIA according to the International League of Associations for Rheumatology criteria. INTERVENTIONS: Participants were randomly assigned into 2 groups. In group I (n=25), the participants were given a conventional exercise program for 6 months. Patients in group II (n=25) participated in a Pilates exercise program for 6 months. MAIN OUTCOME MEASURES: The primary outcome measure was HRQOL, as measured by the Pediatric Quality of Life Inventory version 4.0 (PedsQL 4.0). The secondary outcome measures provided an estimate of the clinical relevance of the primary outcome results and included joint pain intensity (according to a 10-cm visual analog scale), disability (according to the Childhood Health Assessment Questionnaire), joint status (using the Pediatric Escola Paulista de Medicina Range of Motion Scale), and the total PedsQL 4.0 score. RESULTS: All participants completed the study. The scores of the PedsQL 4.0 differed significantly between groups, indicating that Pilates exercises increased these scores when compared with the conventional exercise program. Group II participants showed significant improvements in the 10-cm visual analog scale-joint pain, Childhood Health Assessment Questionnaire, and Pediatric Escola Paulista de Medicina Range of Motion Scale. CONCLUSIONS: The use of Pilates exercises had a positive physical and psychosocial impact on HRQOL in individuals with JIA. Future multicenter studies with a follow-up beyond the period of treatment using more objective parameters will be useful to support the results of the present study. PMID- 23806611 TI - Sleep related beliefs and their association with alcohol relapse following residential alcohol detoxification treatment. AB - BACKGROUND: Alcohol dependence is known to impact upon sleep, and poor sleep has been shown to affect relapse rates following treatment for alcohol dependence. AIMS: The aim of this study was to investigate the association between sleep problems and relapse in dependent drinkers in an inpatient setting. This was done by studying sleep related cognitions in individuals undergoing medically assisted alcohol withdrawal. METHOD: Sleep and sleep-related cognitions data were collected for 71 individuals undergoing detoxification treatment. Sleep was measured using sleep diaries and actigraph motion monitors. Participants completed sleep-related cognition questionnaires and were subject to telephone follow-up interviews. The results were then used to predict relapse rates 4 weeks after discharge. RESULTS: Longer sleep onset latency recorded on the unit predicted relapse at 4 weeks. Higher dysfunctional beliefs about sleep were found to be associated with lower relapse rates. CONCLUSIONS: This study suggests that some dysfunctional beliefs about sleep may support recovery following discharge from treatment. The study further supports the need for tailored cognitive behavioural treatments for sleep difficulties in this population to reduce relapse rates. PMID- 23806612 TI - Oct4: the final frontier, differentiation defining pluripotency. AB - The transcription factor OCT4 is a cornerstone of pluripotency, and yet OCT4 has also been associated with differentiation in a number of contexts. Reporting in this issue of Developmental Cell, Frum et al. (2013) show that OCT4's major early activity in the blastocyst is to support primitive endoderm differentiation. PMID- 23806613 TI - Can't wait to myelinate. AB - Oligodendrocytes myelinate axons in the central nervous system (CNS). In this issue of Developmental Cell, Czopka et al. (2013) shed light on the temporal control of myelination by individual cells. They demonstrate that oligodendrocytes in vivo have only a brief time window to initiate myelination, which has important implications for CNS plasticity. PMID- 23806614 TI - Aggregating the message to control the cell cycle. AB - Localization of messenger RNAs (mRNAs) enables the precise regulation of protein expression in space and time. In this issue of Developmental Cell, Lee et al. (2013) report that the RNA-binding protein Whi3 spatially constrains a cyclin encoding mRNA in the cytoplasm of multinucleate cells, thus allowing independent cell-cycle control of individual nuclei. PMID- 23806615 TI - Argonaute regulation: two roads to the same destination. AB - Reporting recently in Nature and Nature Structural and Molecular Biology, Shen et al. (2013) and Smibert et al. (2013) uncover mechanisms for Argonaute (Ago) protein regulation. Smibert et al. find that microRNA availability controls Ago levels, and Shen et al. show that epidermal growth factor receptor-mediated Ago2 phosphorylation affects Ago loading. PMID- 23806616 TI - The extracellular domain of Notch2 increases its cell-surface abundance and ligand responsiveness during kidney development. AB - Notch2, but not Notch1, plays indispensable roles in kidney organogenesis, and Notch2 haploinsufficiency is associated with Alagille syndrome. We proposed that proximal nephron fates are regulated by a threshold that requires nearly all available free Notch intracellular domains (NICDs) but could not identify the mechanism that explains why Notch2 (N2) is more important than Notch1 (N1). By generating mice that swap their ICDs, we establish that the overall protein concentration, expression domain, or ICD amino acid composition does not account for the differential requirement of these receptors. Instead, we find that the N2 extracellular domain (NECD) increases Notch protein localization to the cell surface during kidney development and is cleaved more efficiently upon ligand binding. This context-specific asymmetry in NICD release efficiency is further enhanced by Fringe. Our results indicate that an elevated N1 surface level could compensate for the loss of N2 signal in specific cell contexts. PMID- 23806617 TI - Individual oligodendrocytes have only a few hours in which to generate new myelin sheaths in vivo. AB - The number of myelin sheaths made by individual oligodendrocytes regulates the extent of myelination, which profoundly affects central nervous system function. It remains unknown when, during their life, individual oligodendrocytes can regulate myelin sheath number in vivo. We show, using live imaging in zebrafish, that oligodendrocytes make new myelin sheaths during a period of just 5 hr, with regulation of sheath number after this time limited to occasional retractions. We also show that activation and reduction of Fyn kinase in oligodendrocytes increases and decreases sheath number per cell, respectively. Interestingly, these oligodendrocytes also generate their new myelin sheaths within the same period, despite having vastly different extents of myelination. Our data demonstrate a restricted time window relative to the lifetime of the individual oligodendrocyte, during which myelin sheath formation occurs and the number of sheaths is determined. PMID- 23806620 TI - Community event-based outreach screening for syphilis and other sexually transmissible infections among gay men in Sydney, Australia. AB - Objectives Increased testing frequency is a key strategy in syphilis control, but achieving regular testing is difficult. The objective of this study is to describe a sexually transmissible infection (STI) testing outreach program (the Testing Tent) at a gay community event. METHODS: Gay men attending the testing tent in 2010-11 completed a computer-assisted self-interview and were screened for STIs. Clinical, demographic, behavioural and diagnostic data were compared with gay men attending a clinic-based service during 2009. The Testing Tent was marketed on social media sites and data were extracted on the number of times the advertisements were viewed. Staffing, laboratory, marketing and venue hire expenses were calculated to estimate the cost of delivering the service. RESULTS: Ninety-eight men attended the Testing Tent. They were older (median age: 42 years v. 30 years; P<0.001), had more sex partners (median: five in 3 months v. two; P<0.001) and more likely to inject drugs (9% v. 4%; P=0.034) than the 1006 clinic attendees, but were more likely to have previously tested for STIs (81% v. 69%; P=0.028) and to always use condoms for anal sex (59% v. 43%; P=0.005). Five cases of STIs were detected; the diagnostic yield was not significantly different from that of the clinic. The cost of the Testing Tent was A$28?440. CONCLUSION: Nonclinical testing facilities are an acceptable option and are accessed by gay men requiring regular testing, and may be an important addition to traditional testing environments. PMID- 23806618 TI - Fuz mutant mice reveal shared mechanisms between ciliopathies and FGF-related syndromes. AB - Ciliopathies are a broad class of human disorders with craniofacial dysmorphology as a common feature. Among these is high arched palate, a condition that affects speech and quality of life. Using the ciliopathic Fuz mutant mouse, we find that high arched palate does not, as commonly suggested, arise from midface hypoplasia. Rather, increased neural crest expands the maxillary primordia. In Fuz mutants, this phenotype stems from dysregulated Gli processing, which in turn results in excessive craniofacial Fgf8 gene expression. Accordingly, genetic reduction of Fgf8 ameliorates the maxillary phenotypes. Similar phenotypes result from mutation of oral-facial-digital syndrome 1 (Ofd1), suggesting that aberrant transcription of Fgf8 is a common feature of ciliopathies. High arched palate is also a prevalent feature of fibroblast growth factor (FGF) hyperactivation syndromes. Thus, our findings elucidate the etiology for a common craniofacial anomaly and identify links between two classes of human disease: FGF hyperactivation syndromes and ciliopathies. PMID- 23806619 TI - The Drosophila nuclear lamina protein otefin is required for germline stem cell survival. AB - LEM domain (LEM-D) proteins are components of an extensive protein network that assembles beneath the inner nuclear envelope. Defects in LEM-D proteins cause tissue-restricted human diseases associated with altered stem cell homeostasis. Otefin (Ote) is a Drosophila LEM-D protein that is intrinsically required for female germline stem cell (GSC) maintenance. Previous studies linked Ote loss with transcriptional activation of the key differentiation gene bag-of-marbles (bam), leading to the model in which Ote tethers the bam gene to the nuclear periphery for gene silencing. Using genetic and phenotypic analyses of multiple ote(-/-) backgrounds, we obtained evidence that is inconsistent with this model. We show that bam repression is maintained in ote(-/-) GSCs and that germ cell loss persists in ote(-/-), bam(-/-) mutants, together demonstrating that GSC loss is independent of bam transcription. We show that the primary defect in ote(-/-) GSCs is a block of differentiation, which ultimately leads to germ cell death. PMID- 23806621 TI - Pharmacological disruption of mouse social approach behavior: relevance to negative symptoms of schizophrenia. AB - Social withdrawal is one of several negative symptoms of schizophrenia, all of which are poorly treated by current therapies. One challenge in developing agents with efficacy against negative symptoms is the lack of suitable preclinical models. The social approach test was used as the basis for developing an assay to test emerging therapies for negative symptoms. NMDA antagonists and dopamine agonists have been used extensively to produce or disrupt behaviors thought to be rodent correlates of positive and cognitive symptoms of schizophrenia. The aim of these studies was to determine whether sociability of mice in the 3-chamber social approach test could be disrupted and whether this paradigm could have utility in predicting efficacy against negative symptoms. The criteria for such a model were: a lack of response to antipsychotics and attenuation by agents such as the glycine agonist, d-cycloserine, which has been shown to possess clinical efficacy against negative symptoms. Administration of the NMDA antagonists MK 801, PCP, or ketamine did not disrupt sociability. In contrast, Grin1 hypomorph mice displayed a social deficit which was not reversed by atypical antipsychotics or d-serine. d-Amphetamine disrupted sociability without stimulating locomotor activity and its effect was not reversed by antipsychotics. The GABAA inverse agonist, FG-7142, reduced sociability and this was reversed by the GABAA antagonist, flumazenil and dcycloserine, but not by clozapine, or the GABAA benzodiazepine anxiolytic, alprazolam. Based on our criteria, the GABAA model warrants further evaluation to confirm that this paradigm has utility as a preclinical model for predicting efficacy against negative symptoms of schizophrenia. PMID- 23806622 TI - Induced sputum compared to bronchoalveolar lavage in young, non-expectorating cystic fibrosis children. AB - BACKGROUND: Induced sputum (IS) is feasible and safe in young CF children and is a readily accessible, non-invasive technique. However, it has not been compared to bronchoalveolar lavage (BAL), the gold standard for diagnosing lower airway infection. METHODS: We compared bacterial yield from IS and BAL in 11 non expectorating CF children, aged 3 to 7.4 years. IS samples were obtained in 10/11 cases. RESULTS: Eight out of ten had the same predominant bacteria cultured from IS and BAL: Pseudomonas aeruginosa and Stenotrophomonas maltophilia[1], Staphylococcus aureus[3], and upper respiratory tract flora [4]. In one, Serratia marcescens and Haemophilus parainfluenzae were cultured from IS alone, whereas in one, non-group B Haemophilus influenzae was cultured from BAL alone. CONCLUSIONS: As proof of principle, IS samples showed good bacteriologic correlation with BAL. Larger studies are recommended to confirm IS as a clinically valuable tool and measure for early intervention studies in young CF children. PMID- 23806623 TI - Relapses in recurrent depression 1 year after maintenance cognitive-behavioral therapy: the role of therapist adherence, competence, and the therapeutic alliance. AB - The prevention of relapse in recurrent depression is considered a central aim in cognitive-behavioral therapy, given the high risk of relapse. In this study, patients with recurrent major depressive disorder (currently remitted) received 16 sessions of Maintenance Cognitive-Behavioral Therapy (M-CBT) over a period of 8 months, in order to prevent relapse. Therapist adherence and competence, as well as the therapeutic alliance, were investigated as predictors for reducing the risk of recurrence in depression. Videotapes of 80 participants were analyzed in order to evaluate therapist adherence and competence. Additionally, the therapeutic alliance was assessed by questionnaire. No associations were found between therapist adherence or competence, and the risk of relapse 1 year after treatment. By contrast, the therapeutic alliance was a significant predictor of the time to relapse. Moreover, we found that the number of previous depressive episodes (>= 5 vs. <= 4) was a significant moderator variable. This indicates that the alliance-outcome relationship was particularly important when patients with five or more previous depressive episodes were taken into account, in comparison to patients with four or fewer episodes. For the psychotherapeutic treatment of recurrent depression and the prevention of relapse, sufficient attention should be paid to the therapeutic alliance. PMID- 23806624 TI - Association between plasma brain-derived neurotrophic factor levels and personality traits in healthy Japanese subjects. AB - Although depression has been associated with decreased brain-derived neurotrophic factor (BDNF) levels for specific personality traits, there is a little information regarding the association between peripheral BDNF levels and such traits. The sample consisted of 178 healthy Japanese subjects (age range, 37.4 +/ 11.5 years). All subjects filled out the Temperament and Character Inventory (TCI). Plasma BDNF levels were measured using the enzyme-linked immunosorbent assay. A simple regression analysis revealed that plasma BDNF levels were significantly correlated with harm avoidance (r=-0.177, p=0.018) and self directedness scores (r=0.165, p=0.028). Our findings suggest that plasma BDNF levels are associated with depression-related personality traits. PMID- 23806625 TI - Dietary patterns and anthropometric indices among Iranian women with major depressive disorder. AB - Major depression is a common mental disorder among women. A number of studies have demonstrated the association between some nutrients and food items with depression, but the studies on the association of dietary patterns with depression, especially in the Middle East, are rare. Further, the literature examining the relationship between anthropometric status and depression are inconsistent. In this study, 45 women with major depression and 90 patients with no mental disorder participated. We collected dietary intakes by a semi quantitative food frequency questionnaire, and measured anthropometric indices (weight, height, waist and hip circumferences). Using factor analysis, two major dietary patterns were extracted: Healthy and Unhealthy. After adjusting for confounders, individuals who gained higher scores in healthy dietary pattern, had 84% lower odds of major depression; while the odds of major depression in participants who gained higher scores in unhealthy dietary pattern showed no significant association. No significant association was found between anthropometric indices and major depression. These results suggest that the healthy dietary pattern is significantly associated with lower odds of major depression in adult women. Further researches are needed to confirm these findings. PMID- 23806626 TI - Prioritization of the cirrhotic patients entering intensive care unit for liver transplantation: Do we need to change the rules? PMID- 23806627 TI - Methylation and liver cancer. AB - Cancer evolution at all stages (including initiation, progression and invasion) is driven by both epigenetic abnormalities and genetic alterations. Epigenetics refer to any structural modification of genomic regions, which lead to modification in gene expression without alterations in DNA sequence. Progressive deregulation of epigenetic process is being increasingly recognized in liver carcinogenesis. This review will provide an overview of DNA methylation, one of the most commonly epigenetic events, which profoundly contributes to liver cancer initiation and progression. Furthermore, the recent advancements in the knowledge of epigenetic reprogramming underlying hepatic cancer stem cells will be highlighted. PMID- 23806628 TI - Small bowel obstruction secondary to transport aircraft: coincidence or reality? AB - Small bowel obstructions (SBO) are a leading cause of admission to general surgery, posing the problem of the aetiology and treatment based on the diagnosis. More than 300 patients were admitted for SBO in 2011 in our institution. In our clinical practice, we have had to care for patients with SBO immediately after air travel, all of whom had an antecedent of abdominal surgery by laparotomy. The finding of episodes of acute SBO immediately following a commercial flight has never been reported in the literature. We report the cases of four patients for whom we offer several pathophysiological hypotheses, and we publish the first dietary rules for people with a history of intraperitoneal surgery to adopt during a flight. PMID- 23806630 TI - Extraordinarily elevation of CA 19-9 due to H. pylori infection. PMID- 23806629 TI - Notch signalling beyond liver development: emerging concepts in liver repair and oncogenesis. AB - Notch signalling is an evolutionarily conserved intercellular pathway involved in many aspects of development and tissue renewal in several organs. The importance of Notch signalling in liver development and morphogenesis is well established. However, the post-natal role of Notch in liver repair/regeneration is only now beginning to be unveiled. Despite the simplicity of the pathway activation, a fine spatial-temporal regulation of Notch signalling is required to avoid pathologic effects. This review highlights recent advances in the field indicating that Notch signalling is involved in the reparative morphogenesis of the biliary tree and in liver carcinogenesis. Defective Notch signalling leads to impaired ability of the liver to repair liver damage, while excessive activation may be involved in liver cancer. Even though much remains to be understood about these mechanisms, including the cross-talk between Notch signalling and other liver morphogens, current evidence suggests that the modulation of the Notch pathway may represent a therapeutic target in chronic liver disease. PMID- 23806631 TI - Using electronic patient records in practice: a focused review of the evidence of risks to the clinical interaction. AB - Electronic patient records (EPRs) are increasingly being viewed as key to high quality chronic disease management, and have been advocated for epilepsy care. Whether EPRs can really deliver on their promise, however, remains a matter of debate. In this focused review, I highlight one set of risks associated with EPR use: risks to the interaction between health professional and patient. This review summarises a small body of evidence derived from studies that examined - in fine-grained detail - recordings of real consultations. These show that EPRs are often used in ways that prioritise the demands of the system over the needs of the patient. However, they also demonstrate that health professionals sometimes integrate EPRs in ways that enhance the clinical encounter. I argue that we not only need more of this kind of interaction-based research - as opposed to focusing on the single EPR user - but that the findings from these previous studies need to be acted upon. They indicate a need both for the design of EPRs and the training of EPR users to be sensitive to the impact of EPR use on the interaction between health professional and patient. PMID- 23806632 TI - Perceived trigger factors of seizures in persons with epilepsy. AB - PURPOSE: Little is known about the triggering factors (TFs) of seizures in persons with epilepsy (PWE). This study aimed to document the perception of PWE of factors that precipitated their seizures. MATERIALS AND METHODS: Data was obtained from 405 patients attending the Epilepsy Clinic at the All India Institute of Medical Sciences (AIIMS). This was analyzed using appropriate descriptive and inferential biostatistical methods. A Trigger Assessment Tool (TAT) was designed for this study. RESULTS: 89% of the participants reported at least one TF. Between one and ten TFs were endorsed. The most common TFs reported by the patients (in descending order) were found to be: Missing medication (40.9%), emotional stress (31.3%), sleep deprivation (19.7%), fatigue (15.3%), missing meals (9.1%), fever (6.4%), and smoking (6.4%). A significant association was seen among some of the commonly reported TFs (missing medication, sleep deprivation, emotional stress, and fatigue). CONCLUSION: TFs should be evaluated during the management of PWE. However, self perceived TF should be interpreted with caution and differentiated from actual TF. Future studies may consider empowering patients with avoidance strategies and self-control techniques done. PMID- 23806633 TI - Clinical risk factors for non-convulsive status epilepticus during emergent electroencephalogram. AB - PURPOSE: Emergent electroencephalograms (EmEEG) are performed to exclude non convulsive status epilepticus (NCSE) but are resource-intensive. Prior studies have identified a seizure or seizures in the acute setting preceding the EmEEG request as a risk factor of NCSE but few other consistent clinical risk factors have been identified. We aimed to identify clinical risk factors for NCSE in EmEEGs METHODS: We conducted a retrospective analysis of consecutive patients who underwent EmEEG to exclude NCSE over a 20-month period. One blinded investigator extracted clinical information from patient case records using a standardized form. Patients were grouped using EmEEG results into those with and without NCSE. We analyzed differences between these two groups. RESULTS: A total of 2333 EEGs were performed over the study period, 215 (9.3%) were EmEEGs ordered to exclude NCSE. 21 patients (9.8%) of the 215 patients were found to have NCSE. Three independent clinical risk factors for NCSE were identified--seizure(s) in the acute setting, ocular movements (nystagmus and/or gaze deviation) and ongoing CNS infection. The presence of seizure(s) in the acute setting showed the highest adjusted odds ratio (OR=8.8, 95% CI 2.0-39.4, p=0.005). In addition, prevalence of NCSE increased as more clinical risk factors were present. CONCLUSION: Seizures in the acute setting, ocular movements and ongoing CNS infection are associated with NCSE. By using these risk factors at the bedside, clinicians can prioritize patients for EmEEG, recognizing that risk of NCSE increases as more clinical risk factors are present. PMID- 23806634 TI - Severe adult-onset asthma: A distinct phenotype. AB - BACKGROUND: Some patients with adult-onset asthma have severe disease, whereas others have mild transient disease. It is currently unknown whether patients with severe adult-onset asthma represent a distinct clinical phenotype. OBJECTIVE: We sought to investigate whether disease severity in patients with adult-onset asthma is associated with specific phenotypic characteristics. METHODS: One hundred seventy-six patients with adult-onset asthma were recruited from 1 academic and 3 nonacademic outpatient clinics. Severe refractory asthma was defined according to international Innovative Medicines Initiative criteria, and mild-to-moderate persistent asthma was defined according to Global Initiative for Asthma criteria. Patients were characterized with respect to clinical, functional, and inflammatory parameters. Unpaired t tests and chi(2) tests were used for group comparisons; both univariate and multivariate logistic regression were used to determine factors associated with disease severity. RESULTS: Apart from the expected high symptom scores, poor quality of life, need for high intensity treatment, low lung function, and high exacerbation rate, patients with severe adult-onset asthma were more often nonatopic (52% vs 34%, P = .02) and had more nasal symptoms and nasal polyposis (54% vs 27%, P <= .001), higher exhaled nitric oxide levels (38 vs 27 ppb, P = .02) and blood neutrophil counts (5.3 vs 4.0 10(9)/L, P <= .001) and sputum eosinophilia (11.8% vs 0.8%, P <= .001). Multiple logistic regression analysis showed that increased blood neutrophil (odds ratio, 10.9; P = .002) and sputum eosinophil (odds ratio, 1.5; P = .005) counts were independently associated with severe adult-onset disease. CONCLUSION: The majority of patients with severe adult-onset asthma are nonatopic and have persistent eosinophilic airway inflammation. This suggests that severe adult onset asthma has a distinct underlying mechanism compared with milder disease. PMID- 23806635 TI - Long-term follow-up of oral immunotherapy for cow's milk allergy. PMID- 23806636 TI - Prenatal alcohol exposure and childhood atopic disease: a Mendelian randomization approach. AB - BACKGROUND: Alcohol consumption in western pregnant women is not uncommon and could be a risk factor for childhood atopic disease. However, reported alcohol intake may be unreliable, and associations are likely to be confounded. OBJECTIVE: We aimed to study the relation between prenatal alcohol exposure and atopic phenotypes in a large population-based birth cohort with the use of a Mendelian randomization approach to minimize bias and confounding. METHODS: In white mothers and children in the Avon Longitudinal Study of Parents and Children (ALSPAC) we first analyzed associations between reported maternal alcohol consumption during pregnancy and atopic outcomes in the offspring measured at 7 years of age (asthma, wheezing, hay fever, eczema, atopy, and total IgE). We then analyzed the relation of maternal alcohol dehydrogenase (ADH)1B genotype (rs1229984) with these outcomes (the A allele is associated with faster metabolism and reduced alcohol consumption and, among drinkers, would be expected to reduce fetal exposure to ethanol). RESULTS: After controlling for confounders, reported maternal drinking in late pregnancy was negatively associated with childhood asthma and hay fever (adjusted odds ratio [OR] per category increase in intake: 0.91 [95% CI, 0.82-1.01] and 0.87 [95% CI, 0.78-0.98], respectively). However, maternal ADH1B genotype was not associated with asthma comparing carriers of A allele with persons homozygous for G allele (OR, 0.98 [95% CI, 0.66 1.47]) or hay fever (OR, 1.11 [95% CI, 0.71-1.72]), nor with any other atopic outcome. CONCLUSION: We have found no evidence to suggest that prenatal alcohol exposure increases the risk of asthma or atopy in childhood. PMID- 23806639 TI - The impact of climate change on plant epigenomes. PMID- 23806638 TI - Fluoroquinolone susceptibility in Mycobacterium tuberculosis after pre-diagnosis exposure to older- versus newer-generation fluoroquinolones. AB - Fluoroquinolone exposure before tuberculosis (TB) diagnosis is common. We anticipated that exposure to older-generation fluoroquinolones is associated with greater fluoroquinolone MICs in Mycobacterium tuberculosis than exposure to newer agents. A nested case-control study was performed among newly diagnosed TB patients reported to the Tennessee Department of Health (January 2002-December 2009). Each fluoroquinolone-resistant case (n=25) was matched to two fluoroquinolone-susceptible controls (n=50). Ciprofloxacin and ofloxacin were classified as older-generation fluoroquinolones; levofloxacin, moxifloxacin and gatifloxacin were considered newer agents. There was no difference between median ofloxacin MIC for isolates from 9 patients exposed only to older fluoroquinolones, 25 exposed only to newer fluoroquinolones, 6 exposed to both and 35 fluoroquinolone-unexposed patients (Kruskal-Wallis, P=0.35). Using multivariate proportional odds logistic regression adjusting for age and sex, duration of exposure to newer fluoroquinolones was independently associated with higher MIC (OR=1.79, 95% CI 1.22-2.64), but duration of exposure to older fluoroquinolones was not (OR=0.94, 95% CI 0.50-1.78). Isolates from patients exposed only to newer fluoroquinolones tended to have mutations at gyrA codons 90, 91 or 94 more frequently than those exposed only to older fluoroquinolones (44% vs. 11%). We were surprised to find that duration of exposure to newer fluoroquinolones, but not older ones, was independently associated with higher ofloxacin MIC. This suggests that the mutant selection window lower boundary is likely to have clinical relevance; caution is warranted when newer fluoroquinolones are prescribed to patients with TB risk factors. PMID- 23806637 TI - Prominent role of IFN-gamma in patients with aspirin-exacerbated respiratory disease. AB - BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is distinguished from aspirin-tolerant asthma/chronic sinusitis in large part by an exuberant infiltration of eosinophils that are characterized by their overexpression of metabolic pathways that drive the constitutive and aspirin-induced secretion of cysteinyl leukotrienes (CysLTs). OBJECTIVE: We defined the inflammatory milieu that in part drives CysLT overproduction and, in particular, the role of IFN gamma in the differentiation of eosinophils. METHODS: Quantitative real-time PCR was performed for TH1 and TH2 signature cytokines on tissue from control subjects, patients with chronic hyperplastic eosinophilic sinusitis, and patients with AERD, and their cellular source was determined. The influence of IFN-gamma on maturation, differentiation, and functionality of eosinophils derived from hematopoietic stem cells was determined. RESULTS: Gene expression analysis revealed that tissue from both aspirin-tolerant subjects and patients with AERD display a TH2 cytokine signature; however, AERD was distinguished from chronic hyperplastic eosinophilic sinusitis by the prominent expression of IFN-gamma. Intracellular and immunohistochemical cytokine staining revealed that the major sources of these cytokines were the eosinophils themselves. IFN-gamma promoted the maturation of eosinophil progenitors, as measured by increased mRNA and surface expression of CCR3 and sialic acid-binding immunoglobulin-like lectin 8 (Siglec-8). Additionally, IFN-gamma increased the expression of genes involved in leukotriene synthesis that led to increased secretion of CysLTs. IFN-gamma matured eosinophil progenitors were also primed, as demonstrated by their enhanced degranulation. CONCLUSIONS: High IFN-gamma levels distinguish AERD from aspirin-tolerant asthma and underlie the robust constitutive and aspirin-induced secretion of CysLTs that characterize this disorder. PMID- 23806640 TI - Detection of non-coding RNA in bacteria and archaea using the DETR'PROK Galaxy pipeline. AB - RNA-seq experiments are now routinely used for the large scale sequencing of transcripts. In bacteria or archaea, such deep sequencing experiments typically produce 10-50 million fragments that cover most of the genome, including intergenic regions. In this context, the precise delineation of the non-coding elements is challenging. Non-coding elements include untranslated regions (UTRs) of mRNAs, independent small RNA genes (sRNAs) and transcripts produced from the antisense strand of genes (asRNA). Here we present a computational pipeline (DETR'PROK: detection of ncRNAs in prokaryotes) based on the Galaxy framework that takes as input a mapping of deep sequencing reads and performs successive steps of clustering, comparison with existing annotation and identification of transcribed non-coding fragments classified into putative 5' UTRs, sRNAs and asRNAs. We provide a step-by-step description of the protocol using real-life example data sets from Vibrio splendidus and Escherichia coli. PMID- 23806642 TI - Correlative two-photon and light sheet microscopy. AB - Information processing inside the central nervous system takes place on multiple scales in both space and time. A single imaging technique can reveal only a small part of this complex machinery. To obtain a more comprehensive view of brain functionality, complementary approaches should be combined into a correlative framework. Here, we describe a method to integrate data from in vivo two-photon fluorescence imaging and ex vivo light sheet microscopy, taking advantage of blood vessels as reference chart. We show how the apical dendritic arbor of a single cortical pyramidal neuron imaged in living thy1-GFP-M mice can be found in the large-scale brain reconstruction obtained with light sheet microscopy. Starting from the apical portion, the whole pyramidal neuron can then be segmented. The correlative approach presented here allows contextualizing within a three-dimensional anatomic framework the neurons whose dynamics have been observed with high detail in vivo. PMID- 23806641 TI - Preparation of developing Xenopus muscle for sarcomeric protein localization by high-resolution imaging. AB - Mutations in several sarcomeric proteins have been linked to various human myopathies. Therefore, having an in vivo developmental model available that develops quickly and efficiently is key for investigators to elucidate the critical steps, components and signaling pathways involved in building a myofibril; this is the pivotal foundation for deciphering disease mechanisms as well as the development of myopathy-related therapeutics. Although striated muscle cell culture studies have been extremely informative in providing clues to both the distribution and functions of sarcomeric proteins, myocytes in vivo develop in an irreproducible 3D environment. Xenopus laevis (frog) embryos are cost effective, compliant to protein level manipulations and develop relatively quickly (? a week) in a petri dish, thus providing a powerful system for de novo myofibrillogenesis studies. Although fluorophore-conjugated phalloidin labeling is the gold standard approach for investigating actin-thin filament architecture, it is well documented that phalloidin-labeling can be challenging and inconsistent within Xenopus embryos. Therefore we highlight several techniques that can be utilized to preserve both antibody and fluorophore-conjugated phalloidin labeling within Xenopus embryos for high-resolution fluorescence microscopy. PMID- 23806644 TI - Allergens of weed pollen: an overview on recombinant and natural molecules. AB - Weeds represent a botanically unrelated group of plants that usually lack commercial or aesthetical value. Pollen of allergenic weeds are able to trigger type I reactions in allergic patients and can be found in the plant families of Asteraceae, Amaranthaceae, Plantaginaceae, Urticaceae, and Euphorbiaceae. To date, 34 weed pollen allergens are listed in the IUIS allergen nomenclature database, which were physicochemically and immunologically characterized to varying degrees. Relevant allergens of weeds belong to the pectate lyase family, defensin-like family, Ole e 1-like family, non-specific lipid transfer protein 1 family and the pan-allergens profilin and polcalcins. This review provides an overview on weed pollen allergens primarily focusing on the molecular level. In particular, the characteristics and properties of purified recombinant allergens and hypoallergenic derivatives are described and their potential use in diagnosis and therapy of weed pollen allergy is discussed. PMID- 23806643 TI - Measuring protein interactions using Forster resonance energy transfer and fluorescence lifetime imaging microscopy. AB - The method of fluorescence lifetime imaging microscopy (FLIM) is a quantitative approach that can be used to detect Forster resonance energy transfer (FRET). The use of FLIM to measure the FRET that results from the interactions between proteins labeled with fluorescent proteins (FPs) inside living cells provides a non-invasive method for mapping interactomes. Here, the use of the phasor plot method to analyze frequency domain (FD) FLIM measurements is described, and measurements obtained from cells producing the 'FRET standard' fusion proteins are used to validate the FLIM system for FRET measurements. The FLIM FRET approach is then used to measure both homologous and heterologous protein-protein interactions (PPI) involving the CCAAT/enhancer-binding protein alpha (C/EBPalpha). C/EBPalpha is a transcription factor that controls cell differentiation, and localizes to heterochromatin where it interacts with the heterochromatin protein 1 alpha (HP1alpha). The FLIM-FRET method is used to quantify the homologous interactions between the FP-labeled basic leucine zipper (BZip) domain of C/EBPalpha. Then the heterologous interactions between the C/EBPa BZip domain and HP1a are quantified using the FRET-FLIM method. The results demonstrate that the basic region and leucine zipper (BZip) domain of C/EBPalpha is sufficient for the interaction with HP1alpha in regions of heterochromatin. PMID- 23806645 TI - A negative selection methodology using a microfluidic platform for the isolation and enumeration of circulating tumor cells. AB - Circulating tumor cells (CTCs) exist in the peripheral blood stream of metastatic cancer patients at rates of approximately 1 CTC per billion background cells. In order to capture and analyze this rare cell population, various techniques exist that range from antibody-based surface marker positive selection to methods that use physical properties of CTCs to negatively exclude background cells from a CTC population. However, methods to capture cells for functional downstream analyses are limited due to inaccessibility of the captured sample or labeling techniques that may be prohibitive to cell function. Here, we present a negative selection method that leverages a Microfluidic Cell Concentrator (MCC) to allow collection and analysis of this rare cell population without needing cell adhesion or other labeling techniques to keep the cells within the chamber. Because the MCC is designed to allow collection and analysis of non-adherent cell populations, multiple staining steps can be applied in parallel to a given CTC population without losing any of the population. The ability of the MCC for patient sample processing of CTCs for enumeration was demonstrated with five patient samples, revealing an average of 0.31 CTCs/mL. The technique was compared to a previously published method - the ELISPOT - that showed similar CTC levels among the five patient samples tested. Because the MCC method does not use positive selection, the method can be applied across a variety of tumor types with no changes to the process. PMID- 23806646 TI - Anchors aweigh: protein localization and transport mediated by transmembrane domains. AB - The transmembrane domains (TMDs) of integral membrane proteins have emerged as major determinants of intracellular localization and transport in the secretory and endocytic pathways. Unlike sorting signals in cytosolic domains, TMD sorting determinants are not conserved amino acid sequences but physical properties such as the length and hydrophilicity of the transmembrane span. The underlying sorting machinery is still poorly characterized, but several mechanisms have been proposed, including TMD recognition by transmembrane sorting receptors and partitioning into membrane lipid domains. Here we review the nature of TMD sorting determinants and how they may dictate transmembrane protein localization and transport. PMID- 23806647 TI - Plasma membrane signaling in HIV-1 infection. AB - Plasma membrane is a multifunctional structure that acts as the initial barrier against infection by intracellular pathogens. The productive HIV-1 infection depends upon the initial interaction of virus and host plasma membrane. Immune cells such as CD4+ T cells and macrophages contain essential cell surface receptors and molecules such as CD4, CXCR4, CCR5 and lipid raft components that facilitate HIV-1 entry. From plasma membrane HIV-1 activates signaling pathways that prepare the grounds for viral replication. Through viral proteins HIV-1 hijacks host plasma membrane receptors such as Fas, TNFRs and DR4/DR5, which results in immune evasion and apoptosis both in infected and uninfected bystander cells. These events are hallmark in HIV-1 pathogenesis that leads towards AIDS. The interplay between HIV-1 and plasma membrane signaling has much to offer in terms of viral fitness and pathogenicity, and a better understanding of this interplay may lead to development of new therapeutic approaches. This article is part of a Special Issue entitled: Viral Membrane Proteins - Channels for Cellular Networking. PMID- 23806648 TI - Peptide-induced membrane leakage by lysine derivatives of gramicidin A in liposomes, planar bilayers, and erythrocytes. AB - Introducing a charged group near the N-terminus of gramicidin A (gA) is supposed to suppress its ability to form ion channels by restricting its head-to-head dimerization. The present study dealt with the activity of [Lys1]gA, [Lys3]gA, [Glu1]gA, [Glu3]gA, [Lys2]gA, and [Lys5]gA in model membrane systems (planar lipid bilayers and liposomes) and erythrocytes. In contrast to the Glu substituted peptides, the lysine derivatives of gA caused non-specific liposomal leakage monitored by fluorescence dequenching of lipid vesicles loaded with carboxyfluorescein or other fluorescent dyes. Measurements of electrical current through a planar lipid membrane revealed formation of giant pores by Lys substituted analogs, which depended on the presence of solvent in the bilayer lipid membrane. The efficacy of unselective pore formation in liposomes depended on the position of the lysine residue in the amino acid sequence, increasing in the row: [Lys2]gA<[Lys5]gA<[Lys1]gA<[Lys3]gA. The similar series of potency was exhibited by the Lys-substituted gA analogs in facilitating erythrocyte hemolysis, whereas the Glu-substituted analogs showed negligible hemolytic activity. Oligomerization of the Lys-substituted peptides is suggested to be involved in the process of nonselective pore formation. PMID- 23806649 TI - Flexibility is a mechanical determinant of antimicrobial activity for amphipathic cationic alpha-helical antimicrobial peptides. AB - Antimicrobial peptides (AMPs) are recognized as the potential substitutions for common antibiotics. Flexibility has been demonstrated to be a dominant on antimicrobial activity of an AMP, similar to the structural parameters such as hydrophobicity and hydrophobic moment as well as positive charge. To better understand the effect of flexibility on antimicrobial activity, we herein examined seventy-eight peptides derived from nine different species. Defined as a weighted average of amino acid flexibility indices over whole residue chain of AMP, flexibility index was used to scale the peptide flexibility and indicated to be a reflection of mechanical properties such as tensile and flexural rigidities. The results demonstrated that flexibility index is relevant to but different from other structural properties, may enhance activity against Escherichia coli for stiff clustered peptides or reduce activity against E. coli for flexible clustered peptides, and its optimum occurs at about -0.5. This effect of flexibility on antimicrobial activity may be involved to the antimicrobial actions, such as stable peptide-bound leaflet formation and sequent stress concentration in target cell membrane, mechanically. The present results provide a new insight in understanding antimicrobial actions and may be useful in seeking for a new structure-activity relationship for cationic and amphipathic alpha helical peptides. PMID- 23806650 TI - Ascorbyl palmitate interaction with phospholipid monolayers: electrostatic and rheological preponderancy. AB - Ascorbyl palmitate (ASC16) is an anionic amphiphilic molecule of pharmacological interest due to its antioxidant properties. We found that ASC16 strongly interacted with model membranes. ASC16 penetrated phospholipid monolayers, with a cutoff near the theoretical surface pressure limit. The presence of a lipid film at the interface favored ASC16 insertion compared with a bare air/water surface. The adsorption and penetration time curves showed a biphasic behavior: the first rapid peak evidenced a fast adsorption of charged ASC16 molecules to the interface that promoted a lowering of surface pH, thus partially neutralizing and compacting the film. The second rise represented an approach to the equilibrium between the ASC16 molecules in the subphase and the surface monolayer, whose kinetics depended on the ionization state of the film. Based on the Langmuir dimiristoylphosphatidylcholine+ASC16 monolayer data, we estimated an ASC16 partition coefficient to dimiristoylphosphatidylcholine monolayers of 1.5*10(5) and a DeltaGp=-6.7kcal.mol(-1). The rheological properties of the host membrane were determinant for ASC16 penetration kinetics: a fluid membrane, as provided by cholesterol, disrupted the liquid-condensed ASC16-enriched domains and favored ASC16 penetration. Subphase pH conditions affected ASC16 aggregation in bulk: the smaller structures at acidic pHs showed a faster equilibrium with the surface film than large lamellar ones. Our results revealed that the ASC16 interaction with model membranes has a highly complex regulation. The polymorphism in the ASC16 bulk aggregation added complexity to the equilibrium between the surface and subphase form of ASC16, whose understanding may shed light on the pharmacological function of this drug. PMID- 23806651 TI - Importance of lipopolysaccharide aggregate disruption for the anti-endotoxic effects of heparin cofactor II peptides. AB - Lipid membrane and lipopolysaccharide (LPS) interactions were investigated for a series of amphiphilic and cationic peptides derived from human heparin cofactor II (HCII), using dual polarization interferometry, ellipsometry, circular dichroism (CD), cryoTEM, and z-potential measurements. Antimicrobial effects of these peptides were compared to their ability to disorder bacterial lipid membranes, while their capacity to block endotoxic effects of LPS was correlated to the binding of these peptides to LPS and its lipid A moiety, and to charge, secondary structure, and morphology of peptide/LPS complexes. While the peptide KYE28 (KYEITTIHNLFRKLTHRLFRRNFGYTLR) displayed potent antimicrobial and anti endotoxic effects, its truncated variants KYE21 (KYEITTIHNLFRKLTHRLFRR) and NLF20 (NLFRKLTHRLFRRNFGYTLR) provide some clues on structure-activity relations, since KYE21 retains both the antimicrobial and anti-endotoxic effects of KYE28 (although both attenuated), while NLF20 retains the antimicrobial but only a fraction of the anti-endotoxic effect, hence locating the anti-endotoxic effects of KYE28 to its N-terminus. The antimicrobial effect, on the other hand, is primarily located at the C-terminus of KYE28. While displaying quite different endotoxic effects, these peptides bind to a similar extent to both LPS and lipid A, and also induce comparable LPS scavenging on model eukaryotic membranes. In contrast, fragmentation and densification of LPS aggregates, in turn dependent on the secondary structure in the peptide/LPS aggregates, correlate to the anti endotoxic effect of these peptides, thus identifying peptide-induced packing transitions in LPS aggregates as key for anti-endotoxic functionality. This aspect therefore needs to be taken into account in the development of novel anti endotoxic peptide therapeutics. PMID- 23806652 TI - Laparoscopic repair of perforated peptic ulcer: patch versus simple closure. AB - BACKGROUND: Laparoscopic correction of perforated peptic ulcer (PPU) has become an accepted way of management. Patch omentoplasty stayed for decades the main method of repair. The goal of the present study was to evaluate whether laparoscopic simple repair of PPU is as safe as patch omentoplasty. METHODS: Since June 2005, 179 consecutive patients of PPU were treated by laparoscopic repair at our centers. We conducted a retrospective chart review in December 2012. Group I (patch group) included patients who were treated with standard patch omentoplasty. Group II (non-patch group) included patients who received simple repair without patch. RESULTS: From June 2007 to Dec. 2012, 179 consecutive patients of PPU who were treated by laparoscopic repair at our centers were enrolled in this multi-center retrospective study. 108 patients belong to patch group. While 71 patients were treated with laparoscopic simple repair. Operative time was significantly shorter in group II (non patch) (p = 0.01). No patient was converted to laparotomy. There was no difference in age, gender, ASA score, surgical risk (Boey's) score, and incidence of co-morbidities. Both groups were comparable in terms of hospital stay, time to resume oral intake, postoperative complications and surgical outcomes. CONCLUSION: Laparoscopic simple repair of PPU is a safe procedure compared with the traditional patch omentoplasty in presence of certain selection criteria. PMID- 23806653 TI - Disturbed sensory perception of changes in thermoalgesic stimuli in patients with small fiber neuropathies. AB - The assessment of functional deficits in small fibre neuropathies (SFN) requires using ancillary tests other than conventional neurophysiological techniques. One of the tests with most widespread use is thermal threshold determination, as part of quantitative sensory testing. Thermal thresholds typically reflect one point in the whole subjective experience elicited by a thermal stimulus. We reasoned that more information could be obtained by analyzing the subjective description of the ongoing sensation elicited by slow temperature changes (dynamic thermal testing, DTT). Twenty SFN patients and 20 healthy subjects were requested to describe, by using an electronic visual analog scale system, the sensation perceived when the temperature of a thermode was made to slowly change according to a predetermined pattern. The thermode was attached to the left ventral forearm or the distal third of the left leg and the stimulus was either a monophasic heat or cold stimuli that reached 120% of pain threshold and reversed to get back to baseline at a rate of 0.5 degrees C/s. Abnormalities seen in patients in comparison to healthy subjects were: (1) delayed perception of temperature changes, both at onset and at reversal, (2) longer duration of pain perception at peak temperature, and (3) absence of an overshoot sensation after reversal, ie, a transient perception of the opposite sensation before the temperature reached again baseline. The use of DTT increases the yield of thermal testing for clinical and physiological studies. It adds information that can be discriminant between healthy subjects and SFN patients and shows physiological details about the process of activation and inactivation of temperature receptors that may be abnormal in SFN. PMID- 23806654 TI - A tale of two RCTs: using randomized controlled trials to benchmark routine clinical (psychological) treatments for chronic pain. AB - This article reports the development of natural history and active treatment benchmarks for psychological treatments of chronic pain. The benchmarks were derived from randomized controlled trials (RCTs) reported in a published meta analysis. In two preliminary studies we surveyed small samples of active clinicians working in U.K. pain management programs. Study 1 assessed the fit between routine clinical treatment and the selected RCTs. In study 2 Delphi methodology was used to determine a set of outcome domains to be used in the development of benchmarks. In study 3 we extracted data from a set of RCTs where both pre- and post-treatment data were reported. Measures were allocated to 1 of 5 outcome domains (cognitive coping and appraisal, pain experience, pain behavior, emotional functioning, and physical functioning). Pre-treatment to post treatment effect sizes (Cohen's d) were computed and, where necessary, aggregated within trial so that each trial contributed a single estimate to outcome domain. Effect size (ES) benchmarks were computed for all trials and those trials with an explicit cognitive behavior therapy protocol. In no case did the ES estimates for the untreated control deviate from 0. The average ES across outcome domains for the treatment arms was approximately 0.35. These benchmarks may be used to assess the effectiveness of routine clinical treatments for chronic pain. The application of these data and the limitations of the study are discussed. PMID- 23806655 TI - Enhanced pain modulation among triathletes: a possible explanation for their exceptional capabilities. AB - Triathletes and ironman triathletes engage in an extremely intense sport that involves hours of considerable pain, as well as physical and psychological stress, every day. The basic pain modulation properties of these athletes has not been established and therefore it is not clear whether they present with unique features that enable them to engage in such efforts. The aim was to investigate the existence of possible alterations in pain perception and modulation of triathletes, as well as possible underlying factors. Participants were 19 triathletes and 17 non-athletes who underwent measurement of pain threshold, pain tolerance, suprathreshold perceived pain intensity, temporal summation of pain, and conditioned pain modulation (CPM). Participants also completed the fear of pain and the pain catastrophizing questionnaires, and rated the amount of perceived stress. Triathletes exhibited higher pain tolerance (P<.0001), lower pain ratings (P<.001), and lower fear of pain values (P<.05) than controls. The magnitude of CPM was significantly greater in triathletes (P<.05), and negatively correlated with fear of pain (P<.05) and with perceived mental stress during training and competition (P<.05). The results suggest that triathletes exhibit greater pain tolerance and more efficient pain modulation than controls, which may underlie their perseverance in extreme physical efforts and pain during training/competitions. This capability may be enhanced or mediated by psychological factors, enabling better coping with fear of pain and mental stress. PMID- 23806656 TI - Protein kinase A and phosphodiesterase-4D3 binding to coding polymorphisms of cardiac muscle anchoring protein (mAKAP). AB - Protein kinase A (PKA) substrate phosphorylation is facilitated through its co localization with its signaling partner by A-kinase anchoring proteins (AKAPs). mAKAP (muscle-selective AKAP) localizes PKA and its substrates such as phosphodiesterase-4D3 (PDE4D3), ryanodine receptor, and protein phosphatase 2A (PP2A) to the sarcoplasmic reticulum and perinuclear space. The genetic role of mAKAP, in modulating PKA/PDE4D3 molecular signaling during cardiac diseases, remains unclear. The purpose of this study was to examine the effects of naturally occurring mutations in human mAKAP on PKA and PDE4D3 signaling. We have recently identified potentially important human mAKAP coding non-synonymous polymorphisms located within or near key protein binding sites critical to beta adrenergic receptor signaling. Three mutations (P1400S, S2195F, and L717V) were cloned and transfected into a mammalian cell line for the purpose of comparing whether those substitutions disrupt mAKAP binding to PKA or PDE4D3. Immunoprecipitation study of mAKAP-P1400S, a mutation located in the mAKAP-PDE4D3 binding site, displayed a significant reduction in binding to PDE4D3, with no significant changes in PKA binding or PKA activity. Conversely, mAKAP-S2195F, a mutation located in mAKAP-PP2A binding site, showed significant increase in both binding propensity to PKA and PKA activity. Additionally, mAKAP-L717V, a mutation flanking the mAKAP-spectrin repeat domain, exhibited a significant increase in PKA binding compared to wild type, but there was no change in PKA activity. We also demonstrate specific binding of wild-type mAKAP to PDE4D3. Binding results were demonstrated using immunoprecipitation and confirmed with surface plasmon resonance (Biacore-2000); functional results were demonstrated using activity assays, Ca(2+) measurements, and Western blot. Comparative analysis of the binding responses of mutations to mAKAP could provide important information about how these mutations modulate signaling. PMID- 23806658 TI - Nucleotide-specific recognition of iron-responsive elements by iron regulatory protein 1. AB - IRP1 [iron regulatory protein (IRP) 1] is a bifunctional protein with mutually exclusive end-states. In one mode of operation, IRP1 binds iron-responsive element (IRE) stem-loops in messenger RNAs encoding proteins of iron metabolism to control their rate of translation. In its other mode, IRP1 serves as cytoplasmic aconitase to correlate iron availability with the energy and oxidative stress status of the cell. IRP1/IRE binding occurs through two separate interfaces, which together contribute about two-dozen hydrogen bonds. Five amino acids make base-specific contacts and are expected to contribute significantly to binding affinity and specificity of this protein:RNA interaction. In this mutagenesis study, each of the five base-specific amino acids was changed to alter binding at each site. Analysis of IRE binding affinity and translational repression activity of the resulting IRP1 mutants showed that four of the five contact points contribute uniquely to the overall binding affinity of the IRP1:IRE interaction, while one site was found to be unimportant. The stronger than-expected effect on binding affinity of mutations at Lys379 and Ser681, residues that make contact with the conserved nucleotides G16 and C8, respectively, identified them as particularly critical for providing specificity and stability to IRP1:IRE complex formation. We also show that even though the base-specific RNA-binding residues are not part of the aconitase active site, their substitutions can affect the aconitase activity of holo-IRP1, positively or negatively. PMID- 23806657 TI - Molecular architecture of the ankyrin SOCS box family of Cul5-dependent E3 ubiquitin ligases. AB - Multi-subunit Cullin-RING E3 ligases often use repeat domain proteins as substrate-specific adaptors. Structures of these macromolecular assemblies are determined for the F-box-containing leucine-rich repeat and WD40 repeat families, but not for the suppressor of cytokine signaling (SOCS)-box-containing ankyrin repeat proteins (ASB1-18), which assemble with Elongins B and C and Cul5. We determined the crystal structures of the ternary complex of ASB9-Elongin B/C as well as the interacting N-terminal domain of Cul5 and used structural comparisons to establish a model for the complete Cul5-based E3 ligase. The structures reveal a distinct architecture of the ASB9 complex that positions the ankyrin domain coaxial to the SOCS box-Elongin B/C complex and perpendicular to other repeat protein complexes. This alternative architecture appears favorable to present the ankyrin domain substrate-binding site to the E2-ubiquitin, while also providing spacing suitable for bulky ASB9 substrates, such as the creatine kinases. The presented Cul5 structure also differs from previous models and deviates from other Cullins via a rigid-body rotation between Cullin repeats. This work highlights the adaptability of repeat domain proteins as scaffolds in substrate recognition and lays the foundation for future structure-function studies of this important E3 family. PMID- 23806660 TI - Case report: lymphogranuloma venereum proctitis-from rapid screening to molecular confirmation of a masked sexually transmitted disease. AB - Proctitis caused by Chlamydia trachomatis L2b can manifest with very mild, nonspecific symptoms, and appropriate diagnostic evaluation is crucial. The case report demonstrates that rapid screening test, detection of specific antibodies in serum, and direct pathogen identification by PCR performed on tissue sample or rectal swab allow successful diagnosis of the still emerging sexually transmitted disease among homosexual patients. PMID- 23806661 TI - Evaluation of the Roche COBAS AmpliPrep/COBAS TaqMan HCV Test. AB - The performance of the Roche COBAS AmpliPrep/COBAS TaqMan HCV Test (CAP/CTM) was evaluated. The limit of detection was 9.5 IU/mL using the 3rd International Standard. Serial dilutions of each genotype demonstrated good reproducibility and linearity. Correlation with samples previously tested with the Roche Analyte Specific Reagent (ASR) was very good, with the CAP/CTM assay measuring 0.24 log IU/mL higher on average than ASR. Genotype inclusivity evaluated in the CAP/CTM, ASR, and Siemens Versant HCV RNA 3.0 Assay (bDNA) assay using a commercially available panel showed higher measurements than ASR or bDNA. The differences in observed CAP/CTM and ASR results for genotype 3 patient samples were significantly different (P < 0.05) from those for both genotype 1 and 2 samples. Common inhibitory substances had no more than a 0.25 log IU/mL affect. Overall, the automated CAP/CTM assay exhibits excellent sensitivity, reproducibility, and dynamic range. Its performance is compatible with its use in guiding therapy using direct acting antivirals such as boceprevir and telaprevir. PMID- 23806659 TI - Structure and function of palladin's actin binding domain. AB - Here, we report the NMR structure of the actin-binding domain contained in the cell adhesion protein palladin. Previously, we demonstrated that one of the immunoglobulin domains of palladin (Ig3) is both necessary and sufficient for direct filamentous actin binding in vitro. In this study, we identify two basic patches on opposite faces of Ig3 that are critical for actin binding and cross linking. Sedimentation equilibrium assays indicate that the Ig3 domain of palladin does not self-associate. These combined data are consistent with an actin cross-linking mechanism that involves concurrent attachment of two actin filaments by a single palladin molecule by an electrostatic mechanism. Palladin mutations that disrupt actin binding show altered cellular distributions and morphology of actin in cells, revealing a functional requirement for the interaction between palladin and actin in vivo. PMID- 23806662 TI - Evaluation of the correlation of caspofungin MICs and treatment outcome in murine infections by wild type strains of Candida parapsilosis. AB - We have evaluated the in vitro activity of caspofungin against 36 wild-type strains of Candida parapsilosis sensu stricto using 3 techniques: broth microdilution, disk diffusion, and the determination of minimal fungicidal concentration (MFC). The first 2 methods showed a good in vitro activity of caspofungin, but the MFCs were >=2 dilutions above their corresponding MICs. In a murine model of disseminated infection, we evaluated the efficacy of caspofungin at 5 mg/kg against 8 strains of C. parapsilosis representing different degrees of in vitro susceptibility (0.12-1 MUg/mL). All the isolates responded to treatment and (1->3)-beta-D-glucan levels were reduced in all the cases; however, the study revealed differences among isolates, since caspofungin reduced the tissue burden of mice infected with isolates with MICs <=0.5 MUg/mL but was less effective against those with MICs of 1 MUg/mL. PMID- 23806664 TI - A horizontally polarizing liquid trap enhances the tabanid-capturing efficiency of the classic canopy trap. AB - Host-seeking female tabanid flies, that need mammalian blood for the development of their eggs, can be captured by the classic canopy trap with an elevated shiny black sphere as a luring visual target. The design of more efficient tabanid traps is important for stock-breeders to control tabanids, since these blood sucking insects can cause severe problems for livestock, especially for horse- and cattle-keepers: reduced meat/milk production in cattle farms, horses cannot be ridden, decreased quality of hides due to biting scars. We show here that male and female tabanids can be caught by a novel, weather-proof liquid-filled black tray laid on the ground, because the strongly and horizontally polarized light reflected from the black liquid surface attracts water-seeking polarotactic tabanids. We performed field experiments to reveal the ideal elevation of the liquid trap and to compare the tabanid-capturing efficiency of three different traps: (1) the classic canopy trap, (2) the new polarization liquid trap, and (3) the combination of the two traps. In field tests, we showed that the combined trap captures 2.4-8.2 times more tabanids than the canopy trap alone. The reason for the larger efficiency of the combined trap is that it captures simultaneously the host-seeking female and the water-seeking male and female tabanids. We suggest supplementing the traditional canopy trap with the new liquid trap in order to enhance the tabanid-capturing efficiency. PMID- 23806663 TI - Role of PTEN in modulation of ADP-dependent signaling pathways in vascular endothelial cells. AB - ADP plays critical signaling roles in the vascular endothelium. ADP receptors are targeted by several cardiovascular drugs, yet the intracellular pathways modulated by ADP are incompletely understood. These studies have identified important roles for the phosphatase PTEN in ADP-dependent modulation of the endothelial isoform of nitric oxide synthase (eNOS) as well as of lipid and protein kinase pathways in endothelial cells. We find that ADP-promoted eNOS activation as well as phosphorylation of p38 MAPK are enhanced by siRNA-mediated PTEN knockdown. However, the increase in ADP-dependent eNOS activation promoted by PTEN knockdown is abrogated by siRNA-mediated knockdown of p38 MAPK. These findings indicate that PTEN tonically suppresses both p38 phosphorylation as well as ADP-stimulated eNOS activity. A key enzymatic activity of PTEN is its role as a lipid phosphatase, catalyzing the dephosphorylation of phosphoinositol-3,4,5 trisphosphate (PIP3) to phosphoinositol-4,5-bisphosphate (PIP2). We performed biochemical analyses of cellular phospholipids in endothelial cells to show that siRNA-mediated PTEN knockdown leads to a marked increase in PIP3. Because these complex lipids activate the small GTPase Rac1, we explored the role of PTEN in ADP-modulated Rac1 activation. We used a FRET biosensor for Rac1 to show that ADP dependent Rac1 activation is blocked by siRNA-mediated PTEN knockdown. We then exploited a FRET biosensor for PIP3 to show that the striking ADP-dependent increase in intracellular PIP3 is entirely blocked by PTEN knockdown. These studies identify a key role for PTEN in the modulation of lipid mediators involved in ADP receptor-regulated endothelial signaling pathways involving eNOS activation in vascular endothelial cells. PMID- 23806665 TI - Detection of HBoV DNA in idiopathic lung fibrosis, Cologne, Germany. AB - We report two confirmed cases of usual interstitial pneumonia (UIP) associated with infection of the human bocavirus (HBoV). In one case HBoV was identified in the bronchoalveolar lavage (BAL) during an acute exacerbation as well as post mortem in different tissues giving raise to the hypothesis that HBoV infections trigger UIP or could be a causative agent and be a systemic component in UIP. In the other case, the UIP was confirmed by radiological methods and HBoV was detected in the BAL during an acute exacerbation. Both cases give raise to the hypothesis that HBoV could be a causative agent of UIP or could contribute to its development and/or acute exacerbations. PMID- 23806666 TI - Improving molecular tools for global surveillance of measles virus. AB - BACKGROUND: The genetic characterization of wild-type measles viruses plays an important role in the description of viral transmission pathways and the verification of measles elimination. The 450 nucleotides that encode the carboxyl terminus of the nucleoprotein (N-450) are routinely sequenced for genotype analysis. OBJECTIVES: The objectives of this study were to develop improved primers and controls for RT-PCR reactions used for genotyping of measles samples and to develop a method to provide a convenient, safe, and inexpensive means to distribute measles RNA for RT-PCR assays and practice panels. STUDY DESIGN: A newly designed, genetically defined synthetic RNA and RNA isolated from cells infected with currently circulating genotypes were used to compare the sensitivity of primer pairs in RT-PCR and nested PCR. FTA(r) cards loaded with lysates of measles infected cells were tested for their ability to preserve viral RNA and destroy virus infectivity. RESULTS: A new primer pair, MeV216/MeV214, was able to amplify N-450 from viruses representing 10 currently circulating genotypes and a genotype A vaccine strain and demonstrated 100-fold increased sensitivity compared to the previously used primer set. A nested PCR assay further increased the sensitivity of detection from patient samples. A synthetic positive control RNA was developed that produced PCR products that are distinguishable by size from PCR products amplified from clinical samples. FTA(r) cards completely inactivated measles virus and stabilized RNA for at least six months. CONCLUSIONS: These improved molecular tools will advance molecular characterization of circulating measles viruses globally and provide enhanced quality control measures. PMID- 23806667 TI - Distribution of cytomegalovirus gN variants and associated clinical sequelae in infants. AB - BACKGROUND: Human cytomegalovirus (HCMV) is the most widespread cause of congenital infection. The effects of various viral strains and viral loads on the infection outcome have been under debate. OBJECTIVES: To determine the distribution of gN variants in HCMV strains isolated from children with congenital or postnatal infection and to establish the relationship between the viral genotype, the viral load, and the sequelae. STUDY DESIGN: The study population included congenitally HCMV-infected newborns and children with postnatal or unproven congenital HCMV infection. The genotyping was performed by RFLP analysis of PCR-amplified fragments, and the viral load was measured by quantitative real-time PCR. RESULTS: Our results demonstrated that the HCMV genotypes gN3b, gN4b, and gN4c were prevalent in the patients examined. There were no differences in the distributions of gN genotypes in the congenitally and postnatally infected children. Multiple HCMV strains were detected in both groups of children. A significant association between the HCMV gN4 genotype and the incidence of neurological disorders was observed (p=0.045). Our results suggest that the detection of the gN2 or the gN4 genotype may be indicative of serious manifestations in children. In contrast, the gN3b and the gN1 genotypes represent less pathogenic HCMV strains. The HCMV load in urine was significantly higher in children with congenital infection compared with children with postnatal infection. No correlation was found between the viral load and the genotype. CONCLUSION: Our results suggest that the gN genotype may be a virological marker of symptomatic HCMV infection in newborns. PMID- 23806668 TI - Temperature-salinity modeling for Ruwais coastal area in United Arab Emirates. AB - A three dimensional rectangular grid model is applied to resolve the temperature salinity dynamics of Ruwais, a segment of the UAE coast which is well known as dense water formation zone. The model employs a heat flux module and a turbulence closure scheme that facilitate realistic calculation of temperature-salinity dynamics. A field survey campaign is carried out to support the modeling study, involving measurements of tide, currents, temperature, and salinity. Investigation is done for two meteorologically extreme conditions, i.e. summer and winter. The model study showed that the western flux develops an anticlockwise circulation in the study area. The water industrial discharges elevated the temperature and salinity of the water near the southeastern shoreline. This water mass propagated towards north under the influence of gravity. PMID- 23806669 TI - Setting limits for acceptable change in sediment particle size composition: testing a new approach to managing marine aggregate dredging. AB - A baseline dataset from 2005 was used to identify the spatial distribution of macrofaunal assemblages across the eastern English Channel. The range of sediment composition found in association with each assemblage was used to define limits for acceptable change at ten licensed marine aggregate extraction areas. Sediment data acquired in 2010, 4 years after the onset of dredging, were used to assess whether conditions remained within the acceptable limits. Despite the observed changes in sediment composition, the composition of sediments in and around nine extraction areas remained within pre-defined acceptable limits. At the tenth site, some of the observed changes within the licence area were judged to have gone beyond the acceptable limits. Implications of the changes are discussed, and appropriate management measures identified. The approach taken in this study offers a simple, objective and cost-effective method for assessing the significance of change, and could simplify the existing monitoring regime. PMID- 23806670 TI - Temporal trends in dioxins (polychlorinated dibenzo-p-dioxin and dibenzofurans) and dioxin-like polychlorinated biphenyls in Baltic herring (Clupea harengus). AB - Polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and dioxin-like polychlorinated biphenyl (dl-PCBs) concentrations in Baltic herring (Clupea harengus) have been relatively stable since the mid to late 1990s. It is unclear why concentrations in Baltic herring are not following the observed decreases in other environmental matrices. Here, changes in long-term temporal trends in Baltic herring were examined. A number of biological variables were examined alongside the temporal trends to investigate whether fish biology e.g., growth (length, weight, age), lipid content, reproductive phase or fishing date may provide an explanation for the temporal trends observed. Significant (p<0.05) decreasing trends were observed for PCDD/F toxic equivalents (TEQPCDD/F) at three of the four sites (lipid weight (lw) and wet weight (ww), Swedish west coast lw only); however, other TEQ values e.g., TEQPCDD, TEQPCDF, TEQdl-PCB, TEQPCDD/F+dl PCB were inconsistent, decreasing at some sites but not others. In the most recent 10 years of data, fewer significant decreases were seen overall. Over the examined time period, significant decreases (Bothnian Bay, p<0.01, southern Baltic Proper, p<0.02) and increases (Swedish west coast, p<0.02) in lipid content, growth dilution or lack thereof, and significant changes in age were observed. However herring were not randomly selected which biases this result. Continual efforts to decrease PCDD/F and dl-PCB emissions and to locate/reduce hotspots are necessary, while bearing in mind that herring biology may be impeding faster decreases of these chemicals. PMID- 23806671 TI - Revisiting hydrocarbons source appraisal in sediments exposed to multiple inputs. AB - The aim of this work was to test the efficiency of statistical methods as compared to the traditional diagnostic ratios to improve hydrocarbon source identification in sediments subjected to multiple inputs. Hydrocarbon determination in Guanabara Bay sediments pointed out high degradation and ubiquitous petrogenic pollution through the presence of high unresolved complex mixture. Polycyclic aromatic hydrocarbon (PAHs) ratios suggested pervasive contamination derived from combustion in all sediments and failed discriminating samples despite the specificity of sources in different sampling sites. Principal component analysis (PCA) effectively distinguished the petrogenic imprint superimposed to the ubiquitous combustion contamination, since this technique reduces the influence of PAHs distribution which is common to all samples. PCA associated to multivariate linear regression (MLR) allowed a quantitative assessment of sources confirming predominance of the pervasive contaminant component superimposed to a generalized petrogenic imprint. The pervasive component derives from combustion contributions as well as from differential PAHs degradation. PMID- 23806672 TI - Spatial distribution of cadmium and lead in the sediments of the western Anzali wetlands on the coast of the Caspian Sea (Iran). AB - Spatial distribution patterns of total cadmium (Cd) and lead (Pb), their bioavailable fractions and total organic matter in sediment from Anzali wetlands are provided. Total sediment Pb was higher than Cd (34.95 versus 0.024 MUg/g dry weight). The geoaccumulation index indicated that the sediment was "uncontaminated", but some stations were categorized as "unpolluted" to "moderately polluted". Less than 0.01 of Pb existed in exchangeable and carbonate fractions. The sum of exchangeable and carbonate-bound fractions of Cd was 42%, suggesting that Cd poses high risk to the aquatic ecosystems. Total Cd and Pb exhibited positive relationships with total organic matter. Considering spatial distribution maps of total and bioavailable fractions of metals suggested that high concentrations of metals does not necessarily indicate high bioavailable fraction. The methodologies we used in this study can be in more effective management of aquatic ecosystems, as well as ecological risk assessment of metals, and remediation programs. PMID- 23806673 TI - Genomics in marine monitoring: new opportunities for assessing marine health status. AB - This viewpoint paper explores the potential of genomics technology to provide accurate, rapid, and cost efficient observations of the marine environment. The use of such approaches in next generation marine monitoring programs will help achieve the goals of marine legislation implemented world-wide. Genomic methods can yield faster results from monitoring, easier and more reliable taxonomic identification, as well as quicker and better assessment of the environmental status of marine waters. A summary of genomic methods that are ready or show high potential for integration into existing monitoring programs is provided (e.g. qPCR, SNP based methods, DNA barcoding, microarrays, metagenetics, metagenomics, transcriptomics). These approaches are mapped to existing indicators and descriptors and a series of case studies is presented to assess the cost and added value of these molecular techniques in comparison with traditional monitoring systems. Finally, guidelines and recommendations are suggested for how such methods can enter marine monitoring programs in a standardized manner. PMID- 23806674 TI - Characterisation of local immune responses induced by a novel nano-particle based carrier-adjuvant in sheep. AB - Most adjuvants require danger signals to promote immune responses against vaccine antigens. Our previous studies have characterised a powerful nano-particulate antigen delivery system, which by itself does not induce inflammation, and which further appears to induce substantial immune responses in mice and sheep without the requirement for added stimulators of toll like receptors or other pathogen recognition receptors. In the present study we dissect the nature of the early induction phase of the immune response stimulated by such a vaccine comprising 40 nm polystyrene nano-particles conjugated to the antigen. We analyse the kinetics of export from an individual draining lymph node from the sheep, of antibodies and cytokines as well as antigen responsive CD4 and CD8 T cells. Our results indicate that simple inert nano-bead based antigen delivery into the draining area of the lymph node is highly efficient at priming combined humoral and T cell antigen specific immunity without the need for added 'danger signals'. Furthermore this nano-bead adjuvant is a potent agent capable of promoting cross priming for CD8 T cell induction in sheep. Interestingly, using nano-beads, similarly to what has been observed with natural pathogen based lymph node stimulation, a phase of CD4 T cell priming and export preceded CD8 T cell induction, suggesting the engagement of natural priming processes and kinetics. PMID- 23806675 TI - Increased exposure to community-based education and 'below the line' social marketing results in increased fruit and vegetable consumption. AB - OBJECTIVE: To determine if localised programmes that are successful in engaging the community can add value to larger fruit and vegetable mass-media campaigns by evaluating the results of the Eat It To Beat It programme. DESIGN: The Eat It To Beat It programme is a multi-strategy intervention that uses community-based education and 'below the line' social marketing to increase fruit and vegetable consumption in parents. This programme was evaluated by a controlled before-and after study with repeat cross-sectional data collected via computer-assisted telephone interviews with 1403 parents before the intervention (2008) and 1401 following intervention delivery (2011). SETTING: The intervention area was the Hunter region and the control area was the New England region of New South Wales, Australia. SUBJECTS: Parents of primary school-aged children (Kindergarten to Year 6). RESULTS: The programme achieved improvements in knowledge of recommended intakes for fruit and vegetables and some positive changes in knowledge of serving size for vegetables. Exposure to the programme resulted in a net increase of 0.5 servings of fruit and vegetables daily for those who recalled the programme compared with those who did not (P = 0.004). Increased intake of fruit and vegetables was significantly associated with increasing exposure to programme strategies. CONCLUSIONS: The Eat It To Beat It programme demonstrates that an increase in consumption of fruit and vegetables can be achieved by programmes that build on the successes of larger mass-media and social-marketing campaigns.This suggests that funding for localised, community-based programmes should be increased. PMID- 23806676 TI - Measuring self-efficacy to use vaginal microbicides: the Microbicide Use Self Efficacy instrument. AB - Objectives To evaluate the psychometric properties of the Microbicide Use Self Efficacy (MUSE) instrument and to examine correlates of self-efficacy to use vaginal microbicides among a sample of racially and ethnically diverse women living in the north-eastern United States. METHODS: Exploratory and confirmatory factor analytic methods were used to explore and determine the dimensionality and psychometric properties of the MUSE instrument. Construct validity was assessed by examining the relationships of the MUSE instrument to key sexual behaviour, partner communication, relationship and psychosocial variables. RESULTS: Two dimensions of self-efficacy to use microbicides were psychometrically validated and identified as 'Adherence and Access' and 'Situational Challenges.' The two four-item subscales measuring Adherence and Access and Situational Challenges had reliability coefficients of 0.78 and 0.85, respectively. Correlates of the two measures were tested at a Bonferroni-adjusted alpha level of P=0.001, and 19 of 43 variables analysed were found to significantly relate to Adherence and Access, whereas 16 of 43 variables were significantly related to Situational Challenges. Of the 35 significant relationships, 32 were in the domains of partner communication, partner relationships, and behavioural and psychosocial variables. CONCLUSIONS: The MUSE instrument demonstrated strong internal validity, reliability and initial construct validity. The MUSE instrument can be a useful tool in capturing the multidimensional nature of self-efficacy to use microbicides among diverse populations of women. PMID- 23806677 TI - Crystal lattice tilting in prismatic calcite. AB - We analyzed the calcitic prismatic layers in Atrina rigida (Ar), Haliotis iris (Hi), Haliotis laevigata (HL), Haliotis rufescens (Hrf), Mytilus californianus (Mc), Pinctada fucata (Pf), Pinctada margaritifera (Pm) shells, and the aragonitic prismatic layer in the Nautilus pompilius (Np) shell. Dramatic structural differences were observed across species, with 100-MUm wide single crystalline prisms in Hi, HL and Hrf, 1-MUm wide needle-shaped calcite prisms in Mc, 1-MUm wide spherulitic aragonite prisms in Np, 20-MUm wide single-crystalline calcite prisms in Ar, and 20-MUm wide polycrystalline calcite prisms in Pf and Pm. The calcite prisms in Pf and Pm are subdivided into sub-prismatic domains of orientations, and within each of these domains the calcite crystal lattice tilts gradually over long distances, on the order of 100 MUm, with an angle spread of crystal orientation of 10-20 degrees . Furthermore, prisms in Pf and Pm are harder than in any other calcite prisms analyzed, their nanoparticles are smaller, and the angle spread is strongly correlated with hardness in all shells that form calcitic prismatic layers. One can hypothesize a causal relationship of these correlated parameters: greater angle spread may confer greater hardness and resistance to wear, thus providing Pf and Pm with a structural advantage in their environment. This is the first structure-property relationship thus far hypothesized in mollusk shell prisms. PMID- 23806678 TI - Web-based tools for finding optimal designs in biomedical studies. AB - Experimental costs are rising and applications of optimal design ideas are increasingly applied in many disciplines. However, the theory for constructing optimal designs can be esoteric and its implementation can be difficult. To help practitioners have easier access to optimal designs and better appreciate design issues, we present a web site at http://optimal-design.biostat.ucla.edu/optimal/ capable of generating different types of tailor-made optimal designs for popular models in the biological sciences. This site also evaluates various efficiencies of a user-specified design and so enables practitioners to appreciate robustness properties of the design before implementation. PMID- 23806679 TI - Adaptive network based on fuzzy inference system for equilibrated urea concentration prediction. AB - Post-dialysis urea rebound (PDUR) has been attributed mostly to redistribution of urea from different compartments, which is determined by variations in regional blood flows and transcellular urea mass transfer coefficients. PDUR occurs after 30-90min of short or standard hemodialysis (HD) sessions and after 60min in long 8-h HD sessions, which is inconvenient. This paper presents adaptive network based on fuzzy inference system (ANFIS) for predicting intradialytic (Cint) and post-dialysis urea concentrations (Cpost) in order to predict the equilibrated (Ceq) urea concentrations without any blood sampling from dialysis patients. The accuracy of the developed system was prospectively compared with other traditional methods for predicting equilibrated urea (Ceq), post dialysis urea rebound (PDUR) and equilibrated dialysis dose (eKt/V). This comparison is done based on root mean squares error (RMSE), normalized mean square error (NRMSE), and mean absolute percentage error (MAPE). The ANFIS predictor for Ceq achieved mean RMSE values of 0.3654 and 0.4920 for training and testing, respectively. The statistical analysis demonstrated that there is no statistically significant difference found between the predicted and the measured values. The percentage of MAE and RMSE for testing phase is 0.63% and 0.96%, respectively. PMID- 23806680 TI - A novel approach to speckle noise filtering based on Artificial Bee Colony algorithm: an ultrasound image application. AB - In this study a novel approach based on 2D FIR filters is presented for denoising digital images. In this approach the filter coefficients of 2D FIR filters were optimized using the Artificial Bee Colony (ABC) algorithm. To obtain the best filter design, the filter coefficients were tested with different numbers (3*3, 5*5, 7*7, 11*11) and connection types (cascade and parallel) during optimization. First, the speckle noise with variances of 1, 0.6, 0.8 and 0.2 respectively was added to the synthetic test image. Later, these noisy images were denoised with both the proposed approach and other well-known filter types such as Gaussian, mean and average filters. For image quality determination metrics such as mean square error (MSE), peak signal-to-noise ratio (PSNR) and signal-to-noise ratio (SNR) were used. Even in the case of noise having maximum variance (the most noisy), the proposed approach performed better than other filtering methods did on the noisy test images. In addition to test images, speckle noise with a variance of 1 was added to a fetal ultrasound image, and this noisy image was denoised with very high PSNR and SNR values. The performance of the proposed approach was also tested on several clinical ultrasound images such as those obtained from ovarian, abdomen and liver tissues. The results of this study showed that the 2D FIR filters designed based on ABC optimization can eliminate speckle noise quite well on noise added test images and intrinsically noisy ultrasound images. PMID- 23806681 TI - Building a new paradigm for the early recognition of behavioral variant frontotemporal dementia: Late Onset Frontal Lobe Syndrome study. AB - OBJECTIVE: To describe the aims and design of the ongoing Late Onset Frontal Lobe Syndrome study (LOF study), a study on the spectrum of neurodegenerative and psychiatric etiologies causing behavioral changes in later life, and on the role of magnetic resonance imaging (MRI), [(18)F]-fluorodeoxyglucose-positron emission tomography (FDG-PET), and cerebrospinal fluid (CSF) biomarkers in predicting and identifying the different underlying pathologies with a special focus on the behavioral variant of frontotemporal dementia. METHODS: The LOF study is an observational cross-sectional and prospective follow-up study. Patients aged 45 75 years with a frontal behavioral change consisting of apathy, disinhibition, or compulsive/stereotypical behavior were included (April 2011-2013). Patients underwent a multidisciplinary assessment by a neurologist and psychiatrist and MRI, CSF, and PET measurements at inclusion and after 2 years of follow-up. RESULTS: The diagnostic added value of MRI, PET, and CSF results and their predictive value will be measured after 2 years of follow-up. CONCLUSION: This is the first large-scale prospective follow-up study of patients with late-onset behavioral disorders. PMID- 23806682 TI - Loneliness among older veterans in the United States: results from the National Health and Resilience in Veterans Study. AB - OBJECTIVES: This study examined the current prevalence, and demographic, military, health, and psychosocial correlates of loneliness in a contemporary nationally representative sample of older U.S. veterans. METHODS: Two thousand twenty-five veterans aged 60 years and older participated in the National Health and Resilience in Veterans Study. Loneliness was assessed using a questionnaire adapted from the Revised UCLA Loneliness Scale. A broad range of demographic, military, health, and psychosocial variables was also assessed. RESULTS: 44% of veterans reported feeling lonely at least some of the time (10.4% reported often feeling lonely). Greater age, disability in activities of daily living, lifetime traumas, perceived stress, and current depressive and post-traumatic stress disorder symptoms were positively associated with loneliness, and being married/cohabitating, higher income, greater subjective cognitive functioning, social support, secure attachment, dispositional gratitude, and frequency of attending religious services were negatively associated with loneliness. The largest magnitude associations were observed for perceived social support, secure attachment style, and depressive symptoms. CONCLUSIONS: Loneliness is prevalent among older veterans in the United States, and associated with several health and psychosocial variables. These results suggest that multifactorial interventions that emphasize bolstering of social support and reduction of depressive symptoms may help mitigate loneliness in the rapidly growing population of older veterans. PMID- 23806683 TI - ERK1/2 regulates SIRT2 deacetylase activity. AB - SIRT2 is a mammalian member of the Sirtuin family of NAD-dependent protein deacetylases. The function of SIRT2 can be modulated by post-translational modification. However, the precise molecular signaling mechanisms of SIRT2 and extracellular signal-regulated kinase (ERK)1/2 have not been correlated. We investigated the potential regulation of SIRT2 function by ERK1/2. ERK activation by the over-expression of constitutively active MEK increased protein levels and enhanced the stability of SIRT2. In contrast, U0126, an inhibitor of mitogen activated kinase kinase, suppressed SIRT2 protein level. ERK1/2 interacted with SIRT2 exogenously and endogenously. Deacetylase activity of SIRT2 was up regulated in an ERK1/2-mediated manner. These results suggest that ERK1/2 regulates SIRT2 by increasing the protein levels, stability and activity of SIRT2. PMID- 23806684 TI - LOX-1, a bridge between GLP-1R and mitochondrial ROS generation in human vascular smooth muscle cells. AB - A growing body of evidence indicates that glucagon-like peptide-1 (GLP-1) agonists or dipeptidyl peptidase-4 (DPP-4) inhibitors play an important role in modulating oxidant stress in vascular beds. However, the underlying mechanism of this process remains unclear. In recent studies, we observed an increase in GLP-1 receptor (GLP-1R) expression in the aorta of LOX-1 knock-out mice. Since LOX-1 is a pivotal regulator of reactive oxygen species (ROS), we conducted studies to identify relationship between LOX-1, ROS and GLP-1 agonism or DPP-4 antagonism. We observed a sustained decrease in GLP-1R expression in human vascular smooth muscle cells (VSMCs) treated with ox-LDL. When VSMCs were treated with different concentration of liraglutide (a GLP-1 agonist) or NVPDPP728 (a DPP-4 inhibitor), expression of ROS decreased compared with ox-LDL alone treatment. To further prove that LOX-1 plays a pivotal role in ROS and GLP-1R expression, we treated VSMCs with LOX-1 antibody or transfected cells with human LOX-1 cDNA. The inhibitory effect of ox-LDL on GLP-1R expression was reversed with anti-LOX-1 antibody treatment, while the inhibitory effect of liraglutide and NVPDPP728 on ROS generation was attenuated when cells were transfected with LOX-1 cDNA. Our results suggest that LOX-1 may play a bridging role in GLP-1 activation and ROS interaction. PMID- 23806685 TI - Translational control of Nrf2 within the open reading frame. AB - Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) is a transcription factor that is essential for the regulation of an effective antioxidant and detoxifying response. The regulation of its activity can occur at transcription, translation and post-translational levels. Evidence suggests that under environmental stress conditions, new synthesis of Nrf2 is required - a process that is regulated by translational control and is not fully understood. Here we described the identification of a novel molecular process that under basal conditions strongly represses the translation of Nrf2 within the open reading frame (ORF). This mechanism is dependent on the mRNA sequence within the 3' portion of the ORF of Nrf2 but not in the encoded amino acid sequence. The Nrf2 translational repression can be reversed with the use of synonymous codon substitutions. This discovery suggests an additional layer of control to explain the reason for the low Nrf2 concentration under quiescent state. PMID- 23806686 TI - Screening-based discovery of the first novel ATP competitive inhibitors of the Staphylococcus aureus essential enzyme UMP kinase. AB - UMP kinase (PyrH) is an essential enzyme found only in bacteria, making it ideal as a target for the discovery of antibacterials. To identify inhibitors of PyrH, an assay employing Staphylococcus aureus PyrH coupled to pyruvate kinase/lactate dehydrogenase was developed and was used to perform a high throughput screen. A validated aminopyrimidine series was identified from screening. Kinetic characterization of this aminopyrimidine indicated it was a competitive inhibitor of ATP. We have shown that HTS can be used to identify potential leads for this novel target, the first ATP competitive inhibitor of PyrH reported. PMID- 23806687 TI - Perifosine inhibits lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF) alpha production via regulation multiple signaling pathways: new implication for Kawasaki disease (KD) treatment. AB - Kawasaki disease (KD) is a multisystem vasculitis of unknown etiology, with coronary artery aneurysms occurring in majority of untreated cases. Tumor necrosis factor (TNF)-alpha is the pleiotropic inflammatory cytokine elevated during the acute phase of KD, which induces damage to vascular endothelial cells to cause systemic vasculitis. We here investigated the potential role of perifosine, a novel Akt inhibitor, on TNFalpha expression in LPS-stimulated macrophages and in ex-vivo cultured peripheral blood mononuclear cells (PBMCs) of acute KD patients. Here, we found that perifosine inhibited LPS-induced TNFalpha expression and production in mouse macrophages (RAW 264.7 cells and bone marrow derived macrophages (BMDMs)). Meanwhile, perifosine administration down-regulated TNFalpha production in PBMCs isolated from acute KD patients. For the mechanism study, we found that perifosine significantly inhibited Akt and ERK/mitogen activated protein kinases (MAPK) signaling, while activating AMP-activated protein kinase (AMPK) signaling in both patients' PBMCs and LPS-stimulated macrophages. Interestingly, although perifosine is generally known as an Akt inhibitor, our data suggested that ERK inhibition and AMPK activation, but not Akt inactivation were possibly involved in perifosine-mediated inhibition against TNFalpha production in monocytes. In conclusion, our data suggested that perifosine significantly inhibited TNFalpha production via regulation multiple signaling pathways. The results of this study should have significant translational relevance in managing this devastating disease. PMID- 23806688 TI - Docosahexaenoic acid improves vascular function via up-regulation of SIRT1 expression in endothelial cells. AB - n-3-Polyunsaturated fatty acids (PUFAs) protect against myocardial infarction, arteriosclerosis and high blood pressure by stimulating endothelial nitric oxide synthase (eNOS) to increase nitric oxide (NO) production. However, the mechanism remains to be elucidated. This study investigated the role of SIRT1 in the protective effects of docosahexaenoic acid (DHA) in vascular endothelial cells. Exposure of human umbilical vein endothelial cells (HUVECs) to 0.3-30 MUM DHA did not affect cell viability, and DHA treatment dose-dependently increased SIRT1 expression. The DHA-mediated increase in SIRT1 expression induced eNOS deacetylation, increasing endothelial NO. However, inhibition of SIRT1 inhibited DHA-mediated increases in NO production. This effect was mediated via deacetylation of lysines 496 and 506 in the eNOS calmodulin-binding domain. The effects of DHA were also demonstrated in rat aortic rings, in which DHA treatment increased SIRT1 expression and bioavailable NO. Our results demonstrate that SIRT1 plays an important role in DHA-mediated increases in bioavailable NO via decreased eNOS acetylation. PMID- 23806689 TI - Store-operated calcium entry induced by activation of Gq-coupled alpha1B adrenergic receptor in human osteoblast. AB - Recent studies have revealed that the sympathetic nervous system is involved in bone metabolism. We previously reported that noradrenaline (NA) suppressed K(+) currents via Gi/o protein-coupled alpha1B-adrenergic receptor (alpha1B-AR) in human osteoblast SaM-1 cells. Additionally, it has been demonstrated that the intracellular Ca(2+) level ([Ca(2+)]i) was increased by NA via alpha1B-AR. In this study, we investigated the signal pathway of NA-induced [Ca(2+)]i elevation by using Ca(2+) fluorescence imaging in SaM-1 cells. NA-induced [Ca(2+)]i elevation was suppressed by pretreatment with a PLC inhibitor, U73122. This suggested that the [Ca(2+)]i elevation was mediated by Gq protein-coupled alpha1B AR. On the other hand, NA-induced [Ca(2+)]i elevation was completely abolished in Ca(2+)-free solution, which suggested that Ca(2+) influx is the predominant pathway of NA-induced [Ca(2+)]i elevation. Although the inhibition of K(+) channel by NA caused membrane depolarization, the [Ca(2+)]i elevation was not affected by voltage-dependent Ca(2+) channel blockers, nifedipine and mibefradil. Meanwhile, NA-induced [Ca(2+)]i elevation was abolished following activation of store-operated Ca(2+) channel by thapsigargin. Additionally, the [Ca(2+)]i elevation was suppressed by store-operated channel inhibitors, 2-APB, flufenamate, GdCl3 and LaCl3. These results suggest that Ca(2+) influx through store-operated Ca(2+) channels plays a critical role in the signal transduction pathway of Gq protein-coupled alpha1B-AR in human osteoblasts. PMID- 23806690 TI - Valine, the branched-chain amino acid, suppresses hepatitis C virus RNA replication but promotes infectious particle formation. AB - BACKGROUND & AIMS: Concentrations of the branched-chain amino acid (BCAA) in the serum of patients with liver cirrhosis correlate with their liver function. Oral administration of BCAA can ameliorate hypoalbuminemia and hepatic encephalopathy. In this study, we aim to clarify the role of BCAA in regulating the replication of the hepatitis C virus (HCV). METHODS: HCV sub-genomic replicon cells, genome length replicon cells, and cells infected with cell culture-infectious HCV (HCVcc) were cultured in media supplemented with various concentrations of BCAA, followed by evaluation of the replicon or HCV abundance. RESULTS: BCAA was capable of suppressing the HCV replicon in a dose-dependent manner and the effect was independent of the mTOR pathway. Of the three BCAAs, valine was identified as being responsible for suppressing the HCV replicon. Surprisingly, an abundance of HJ3-5(YH/QL), an HCVcc, in Huh7 cells was augmented by BCAA supplementation. In contrast, BCAA suppressed an abundance of HJ3-5(wild), an HCVcc that cannot assemble virus particle in Huh7 cells. Internal ribosome entry site of HCV was shown to be a target of BCAA. Single-cycle virus production assays using Huh7-25 cells, which lacked CD81 expression, revealed that BCAA, especially valine, promoted infectious virus particle formation with minimal effect on virus secretion. Thus, BCAA was found to have two opposing effects on HCV production: suppression of the HCV genome RNA replication and promotion of infectious virus formation. CONCLUSIONS: BCAA accelerates HCV production through promotion of infectious virus formation in infected cells despite its suppressive effect on HCV genome replication. PMID- 23806691 TI - Paclitaxel induces neurotoxicity through endoplasmic reticulum stress. AB - Due to chemotherapy, the majority of breast cancer patients survive, but frequently complain of chemotherapy-associated cognitive impairment. This phenomenon is termed "chemobrain" or "chemofog" in the literature. However, its mechanisms are unclear. The objective of this study was to investigate the mechanisms of paclitaxel (Px)-induced neurotoxicity, with a focus on endoplasmic reticulum (ER) stress. To investigate Px-induced neurotoxicity and ER stress induction, SK-N-SH cells were treated with 1, 10, 50, and 100 MUM Px for 24 h. Neurotoxicity was assessed using MTS viability assays, and ER stress was assessed by evaluating the expression of phosphorylated elF2alpha (phospho-eIF2alpha), C/EBP homologous protein (CHOP), and cleaved caspase 4 and caspase 3 (the active form of each caspase). Furthermore, to investigate whether immunoglobulin heavy chain binding protein (BiP) inducer X (BIX), which induces the molecular chaperone BiP, could attenuate Px-induced neurotoxicity, SK-N-SH cells were pre treated for 12 h with 3.5 MUM BIX before Px treatment. Neurotoxicity was observed in SK-N-SH cells treated with Px in a dose-dependent manner compared with vehicle control. Furthermore, phospho-eIF2alpha, CHOP, and activated caspase 4 and caspase 3 were significantly induced in Px-treated cells. In addition, pre treatment with BIX significantly attenuated the induction of CHOP and activated caspase 4 and caspase 3. The viability of BIX pre-treated cells prior to Px treatment was significantly increased compared with cells that were not treated with BIX. Our results suggest that Px induces neurotoxicity in part through activating the ER stress response. Our findings should contribute to novel approaches regarding the mechanism of Px-induced neurotoxicity, including chemobrain. PMID- 23806692 TI - Fatty acid amide hydrolase but not monoacyl glycerol lipase controls cell death induced by the endocannabinoid 2-arachidonoyl glycerol in hepatic cell populations. AB - The endogenous cannabinoids anandamide (N-arachidonoylethanolamide, AEA) and 2 arachidonoyl glycerol (2-AG) are upregulated during liver fibrogenesis and selectively induce cell death in hepatic stellate cells (HSCs), the major fibrogenic cells in the liver, but not in hepatocytes. In contrast to HSCs, hepatocytes highly express the AEA-degrading enzyme fatty acid amide hydrolase (FAAH) that protects them from AEA-induced injury. However, the role of the major 2-AG-degrading enzyme monoacylglycerol lipase (MGL) in 2-AG-induced hepatic cell death has not been investigated. In contrast to FAAH, MGL protein expression did not significantly differ in primary mouse hepatocytes and HSCs. Hepatocytes pretreated with selective MGL inhibitors were not sensitized towards 2-AG mediated death, indicating a minor role for MGL in the cellular resistance against 2-AG. Moreover, while adenoviral MGL overexpression failed to render HSCs resistant towards 2-AG, FAAH overexpression prevented 2-AG-induced death in HSCs. Accordingly, 2-AG caused cell death in hepatocytes pretreated with the FAAH inhibitor URB597, FAAH(-/-) hepatocytes, or hepatocytes depleted of the antioxidant glutathione (GSH). Moreover, 2-AG increased reactive oxygen species production in hepatocytes after FAAH inhibition, indicating that hepatocytes are more resistant to 2-AG treatment due to high GSH levels and FAAH expression. However, 2-AG was not significantly elevated in FAAH(-/-) mouse livers in contrast to AEA. Thus, FAAH exerts important protective actions against 2-AG induced cellular damage, even though it is not the major 2-AG degradation enzyme in vivo. In conclusion, FAAH-mediated resistance of hepatocytes against endocannabinoid-induced cell death may provide a new physiological concept allowing the specific targeting of HSCs in liver fibrosis. PMID- 23806693 TI - CDK-associated Cullin 1 promotes cell proliferation with activation of ERK1/2 in human lung cancer A549 cells. AB - Lung cancer is one of the most common causes of cancer-related death in the world, but the mechanisms remain unknown. In this study, we investigated the expression of CDK-associated Cullin 1 (CAC1) in lung cancer, the effect of CAC1 on the proliferation of human lung cancer A549 cells, and the activation of signaling pathways of mitogen-activated protein kinases (MAPKs). Results showed that CAC1 expression was higher levels in human lung carcinoma than normal lung tissue, and CAC1 siRNA reduced the proliferation of lung cancer A549 cells by decreasing cell activity and cell division in vitro. The proportion of cells treated with CAC1 siRNA increased in the G1 phase and decreased in the S and G2/M phase, indicative of G1 cell cycle arrest. Furthermore, the proportions of early/late apoptosis in lung cancer A549 cells were enhanced with CAC1 siRNA treatment. It was also found that activation of extracellular signal-regulated protein kinase (ERK) and p38 signaling pathways were involved in the proliferation of A549 cells. After CAC1 siRNA treatment, p-ERK1/2 levels decreased, and meanwhile p-p38 level increased, A549 cell proliferation increased when ERK1/2 signaling is activated by PMA. Our findings demonstrated that CAC1 promoted the proliferation of human lung cancer A549 cells with activation of ERK1/2 signaling pathways, suggesting a potential cure target for treatment of human lung cancer. PMID- 23806694 TI - The effect of multiple primer-template mismatches on quantitative PCR accuracy and development of a multi-primer set assay for accurate quantification of pcrA gene sequence variants. AB - Quantitative PCR (qPCR) is a critical tool for quantifying the abundance of specific organisms and the level or expression of target genes in medically and environmentally relevant systems. However, often the power of this tool has been limited because primer-template mismatches, due to sequence variations of targeted genes, can lead to inaccuracies in measured gene quantities, detection failures, and spurious conclusions. Currently available primer design guidelines for qPCR were developed for pure culture applications, and available primer design strategies for mixed cultures were developed for detection rather than accurate quantification. Furthermore, past studies examining the impact of mismatches have focused only on single mismatches while instances of multiple mismatches are common. There are currently no appropriate solutions to overcome the challenges posed by sequence variations. Here, we report results that provide a comprehensive, quantitative understanding of the impact of multiple primer template mismatches on qPCR accuracy and demonstrate a multi-primer set approach to accurately quantify a model gene pcrA (encoding perchlorate reductase) that has substantial sequence variation. Results showed that for multiple mismatches (up to 3 mismatches) in primer regions where mismatches were previously considered tolerable (middle and 5' end), quantification accuracies could be as low as ~0.1%. Furthermore, tests were run using a published pcrA primer set with mixtures of genomic DNA from strains known to harbor the target gene, and for some mixtures quantification accuracy was as low as ~0.8% or was non-detect. To overcome these limitations, a multiple primer set assay including minimal degeneracies was developed for pcrA genes. This assay resulted in nearly 100% accurate detection for all mixed microbial communities tested. The multi-primer set approach demonstrated herein can be broadly applied to other genes with known sequences. PMID- 23806695 TI - Shared rewarding overcomes defection traps in generalized volunteer's dilemmas. AB - For societies to produce or safeguard public goods, costly voluntary contributions are often required. From the perspective of each individual, however, it is advantageous not to volunteer such contributions, in the hope that other individuals will carry the associated costs. This conflict can be modeled as a volunteer's dilemma. To encourage rational individuals to make voluntary contributions, a government or other social organizations can offer rewards, to be shared among the volunteers. Here we apply such shared rewarding to the generalized N-person volunteer's dilemma, in which a threshold number of volunteers is required for producing the public good. By means of theoretical and numerical analyses, we show that without shared rewarding only two evolutionary outcomes are possible: full defection or coexistence of volunteers and non volunteers. We show that already small rewards destabilize full defection, stabilizing small fractions of volunteers instead. Furthermore, at these intermediate reward levels, we find a hysteresis effect such that increasing or decreasing group sizes can trigger different social outcomes. In particular, when group size is increased, the fraction of volunteers first increases gradually before jumping up abruptly; when group size is then decreased again, the fraction of volunteers not only remains high, but even continues to increase. As the shared reward is increased beyond a critical level, the bistablitity underlying this hysteresis effect vanishes altogether, and only a single social outcome remains, corresponding to considerable fractions of volunteers. We find that this critical level of shared rewarding is relatively small compared to the total cost of contributing to the public good. These results show that the introduction of shared rewarding is remarkably effective in overcoming defection traps in the generalized volunteer's dilemma. PMID- 23806696 TI - Modeling interleukin-2-based immunotherapy in AIDS pathogenesis. AB - In this paper, we sought to identify the CD4(+) T-cell dynamics in the course of HIV infection in response to continuous and intermittent intravenous courses of interleukin-2 (IL-2), the principal cytokine responsible for progression of CD4(+) T-lymphocytes from the G1 to the S phase of the cell cycle. Based on multivariate regression models, previous literature has concluded that the increase in survival of CD4(+) T-cell appears to be the critical mechanism leading to sustained CD4(+) T-cell levels in HIV-infected patients receiving intermittent IL-2 therapy. Underscored by comprehensive mathematical modeling, a major finding of the present work is related to the fact that, rather than due to any increase in survival of CD4(+) T-cells, the expressive, selective and sustained CD4(+) T-cell expansions following IL-2 administration may be related to the role of IL-2 in modulating the dynamics of Fas-dependent apoptotic pathways, such as activation-induced cell death (AICD) or HIV-specific apoptotic routes triggered by viral proteins. PMID- 23806697 TI - Hepatitis B virus among Saudi National Guard personnel: seroprevalence and risk of exposure. AB - BACKGROUND: Data on HBV prevalence among active military personnel in Saudi Arabia (SA) are lacking. In addition, the work-related risk of exposure is unclear. The objective of this study was to estimate the seroprevalence of HBV and the risk of HBV exposure among SA National Guard (SANG) soldiers. METHODS: A cross-sectional study was performed and included 400 male SANG soldiers working in Jeddah during January 2009. All soldiers completed a questionnaire to assess their risk of exposure and gave a blood sample to test for hepatitis serology markers. RESULTS: A total of 16 (4.0%) soldiers were positive for HbsAg, 53 (13.2%) were positive for anti-HBc, and 230 (57.5%) were positive for anti-HBs. None of the soldiers had acute HBV infection, but 15 (3.8%) were chronic HBV carriers. A total of 152 (38.0%) soldiers were susceptible to HBV infection, and 230 (57.5%) were immune to HBV infection, primarily (84.3%) due to HBV vaccination. Compared with those who were negative for anti-HBc (never exposed), soldiers who were positive for anti-HBc were more likely to be older, have a lower education level, have a higher income, have a longer service duration, have a household member with HBV disease, have undergone surgery, or have undergone endoscopy. In the multivariate logistic regression model, older age, presence of a household member with HBV disease and previous endoscopy were independent predictors of HBV exposure. CONCLUSION: We report a 4% prevalence of HBsAg in the Saudi military population. This HBV prevalence was higher than those in the general Saudi population and military populations from Western countries. Both work-related and community-related risk factors for exposure are suggested. PMID- 23806698 TI - Hepatitis B vaccination status among healthcare workers in a tertiary care hospital in Tripoli, Libya. AB - BACKGROUND: The prevalence of hepatitis B virus (HBV) among healthcare workers (HCWs) in hospitals in developing countries is high. However, the vaccination status of these workers and its relationship with occupational factors are not well documented. AIM: The aim of this study was to evaluate the susceptibility of HCWs to HBV infection in the representative Tripoli Central Hospital in Libya and prepare a practical guideline to protect HCWs from occupational exposure. METHOD: In this cross-sectional study, a questionnaire survey was administered to 2705 healthcare workers of a university hospital in Tripoli. The questionnaire included vaccination status. Compliance with preventive practices against HBV infection was also assessed. RESULT: The overall vaccination coverage (anti-HBs) was 78.1%. Furthermore, 82.6% of HCWs had received at least one dose of vaccine, but only 72% reported that they were fully vaccinated. The prevalence of hepatitis B surface antigen was 1.1%. The mean prevalence of hepatitis B core antibody (anti-HBc) was 17.3%. CONCLUSION: HCWs at hospitals are frequently exposed to blood-borne infections. Vaccines should be more readily available for Libyan HCWs, and current vaccination programs should be enforced. PMID- 23806699 TI - Unsafe injection practices in Hodeidah governorate, Yemen. AB - BACKGROUND: Unsafe injection practices are a major public health problem and can lead to the transmission of bloodborne pathogens, including hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV). METHODS: The present study was conducted to determine the nature and magnitude of unsafe injection practices in healthcare facilities in Hodeidah governorate, Yemen. The study was conducted in two hospitals and a representative sample of the governorate's health centers. A total of 1600 injections were observed in these facilities. RESULTS: This study revealed several unsafe practices, particularly the recapping of needles after use, which occurred in 61.1% and 36.8% of the observations in the hospitals and the health centers, respectively. CONCLUSION: This study showed that most healthcare workers (HCWs) followed the proper injection protocols but performed some procedures that exposed themselves and the community to the risk of needlestick injuries (NSIs) and bloodborne infections. PMID- 23806700 TI - Awareness of medical students in a medical college in Mangalore, Karnataka, India concerning infection prevention practices. AB - BACKGROUND: Healthcare-associated infections (HCAIs) are an important public health problem. It is estimated that approximately 1 out of every 20 hospitalized patients will contract an HCAI. The risk is substantial not only to patients but also to healthcare workers, who may contract deadly blood-borne infectious diseases. Hence, it is essential for healthcare professionals to have adequate knowledge regarding infection prevention practices (IPPs) to reduce the burden of these illnesses among patients seeking care. METHODS: This cross-sectional study was conducted among 268 medical students at Kasturba Medical College, Mangalore. Information regarding important IPPs such as hand hygiene (HH), needle-stick injuries (NSIs), and standard precautions (SPs) was collected using a semi structured questionnaire. The collected information was analyzed using SPSS v.11. Fisher's exact test was used to test the association between variables of interest. RESULTS: Overall, knowledge levels regarding HH were low in aspects such as healthcare workers' hands as sources of infection (40%) and the minimum time needed to apply hand rubs (45.7%), whereas knowledge levels were high in aspects such as indications for using HH. Regarding NSI prevention, knowledge levels were low in aspects such as activities with the highest NSI risk (56%). However, knowledge levels were high in relation to SPs. CONCLUSION: The knowledge levels regarding infection practices were not adequate among the participants, particularly in the case of hand hygiene methods. Other important aspects, such as needle-stick injuries and use of standard precautions, were better understood, although many aspects still require improvement. These findings suggest the need to consider strengthening the training related to IPPs as a separate entity in the existing curriculum. PMID- 23806701 TI - Knowledge of infection control practices among intensive care nurses in a tertiary care hospital. AB - BACKGROUND: The threat of hospital-acquired infections persists despite advances in the health care system. A lack of knowledge regarding infection control practices among health care workers decreases compliance with these practices. We conducted a study to assess the knowledge of infection control practices among nursing professionals at our hospital. METHODS: In total, 100 nurses in the intensive care units at our hospital were given a questionnaire with 40 multiple choice questions, including 10 questions each regarding hand hygiene, standard and transmission-based precautions, care bundles and general infection control practices. The responses were scored as percentages. RESULTS: The overall knowledge and awareness regarding different infection control practices were excellent (>90% positive responses) in 5% of the nursing professionals, good (80 90% positive responses) in 37%, average (70-80% positive responses) in 40% and below average (<70% positive responses) in 18%. CONCLUSION: The infection control knowledge among the nurses was fairly good; however, there is still a wide scope of improvement with regular educational programs and in-house training. PMID- 23806702 TI - Drug resistance in pulmonary tuberculosis in new and previously treated cases: experience from Turkey. AB - The emergence of drug resistance is a major problem for tuberculosis (TB) control. The aim of this study was to determine the rates of resistance against TB drugs in patients with pulmonary tuberculosis (PTB). Data from 387 patients with active PTB between the years of 1999 and 2004 from the Research and Education Hospital for Chest Diseases and Chest Surgery were evaluated retrospectively. The patients were categorized as new, re-treatment, extrapulmonary and chronic cases. The study group consisted of 268 (69%) new, 57 (14.7%) re-treatment, 49 (12.6%) extrapulmonary and 13 (3.3%) chronic TB cases. The rates of resistance to isoniazid (INH), rifampicin (R), ethambutol (E) and streptomycin (S) were calculated separately for each group. The resistance to any of the drugs was 7.8% in the new cases, 58.5% in the re-treatment cases and 100% in the chronic cases. The multidrug-resistance (MDR)-TB rates were found to be 2.16%, 11.3% and 92.3% among the new, re-treatment and chronic cases, respectively. These data are important as they reflect the drug resistance rates during the pre-notification time period in western Turkey. PMID- 23806703 TI - Emergence of coryneform bacteria as pathogens in nosocomial surgical site infections in a tertiary care hospital of North India. AB - PURPOSE: A prospective study was conducted to assess the role of coryneform bacteria in surgical site infections among obstetric and gynecological patients undergoing surgery. MATERIALS AND METHODS: The surgery was graded according to the degree of contamination, and surgical site infections (SSIs) were classified as superficial or deep. Pus samples were collected from SSIs according to rigorous aseptic precautions, and the quality of specimens was assessed by Q score. A detailed clinical and treatment history was elicited from all patients. The samples were processed using standard protocols. Coryneform bacteria were considered significant pathogens only if they fulfilled rigorous clinical and microbiological criteria. Antibiotic susceptibility testing was performed using the Kirby-Bauer method according to the CLSI guidelines. RESULTS: In total, 127 patients developed SSIs among 882 postoperative patients. Of these, 89 (70.1%) were culture positive: 40 (44.9%) were Gram-positive cocci, 27 (30.3%) were coryneform, and 22 (24.7%) were Gram-negative bacilli. All coryneform-infected patients had fever and post-operative wound dehiscence leading to a prolonged hospital stay. The most commonly isolated organism was Staphylococcus aureus (33.7%), followed by Corynebacterium amycolatum (11.2%), Escherichia coli (8.9%), Citrobacter spp. (7.8%) and coagulase-negative Staphylococci (6.7%). In our study, 45.5% were ESBL producers, 18.2% were Amp C producers, and 40% were MRSA. All the coryneform bacteria were multidrug resistant, and 51.8% of isolates were sensitive to only gatifloxacin and vancomycin. Symptomatic improvement was observed in all coryneform-infected patients after the administration of appropriate therapy. CONCLUSION: Coryneform bacteria appear to be emerging as significant nosocomial surgical site pathogens. The high level of multidrug resistance observed in coryneform bacteria in our study is cause for alarm. PMID- 23806704 TI - Preliminary data of the Surveillance of Surgical Site infections at Gaziantep University Hospital. AB - Surgical site infection (SSI) is a major surgical complication that leads to mortality, morbidity and socioeconomic losses. The objective of this study is to determine the rate of SSIs, the pathogens involved in the infections and the associated antimicrobial sensitivity patterns in the surgical clinics of our hospital. This study was conducted in all surgical departments of our hospital except ophthalmology. Patients (n = 1397) who had surgery for any reason and who stayed in the hospital for at least 48 h were enrolled in this study. The criteria issued by the Centers for Disease Control and Prevention was utilized in defining and diagnosing SSI. During the study, SSIs developed in 131 (9.4%) of 1397 patients. The development of a SSI resulted in an additional 12.8 days of hospital stay. Gram-negative microorganisms constituted 74.6% of the pathogens responsible for the SSIs. The most commonly isolated microorganisms were Escherichia coli (32.8%), Pseudomonas spp. (13.4%) and Enterococcus spp. (11.9%). Methicillin resistance in Staphylococcus aureus and coagulase-negative staphylococci was 83.3% and 100%, respectively. No vancomycin resistance was detected in the enterococci. The rates of extended spectrum beta lactamase production in E. coli and Klebsiella strains were 86.3% and 42.8%, respectively. SSI surveillance studies should be performed to decrease the rate of SSIs. PMID- 23806705 TI - The prevalence of oral Candida infections in periodontitis patients with type 2 diabetes mellitus. AB - OBJECTIVES: The purpose of this study was to determine the prevalence of Candida spp. in periodontitis patients with type 2 diabetes mellitus. METHODS: This cross sectional study included 42 diabetic patients with periodontitis (aged 21-70 years; 18 males and 24 females). Clinical measurements included probing pocket depth (PPD), clinical attachment level (CAL) and hemoglobin A1c (HbA1c) levels. Sub-gingival samples were collected from the mesio-buccal aspect of 3 teeth for fungal analysis. Candida species, including Candida albicans, Candida dubliniensis, Candida tropicalis and Candida glabrata, were identified using Gram staining, the germ tube test, CHROMagar, Staib agar and API 20C AUX. RESULTS: The overall prevalence of Candida in diabetic patients with periodontitis observed in our study was 52%. The most common spp. of Candida identified were C. albicans (38%), followed by C. dubliniensis (9.5%), C. tropicalis (4.7%) and C. glabrata (4.7%). Compared to females, male patients were characterized by increased levels of Candida infections. Our results also indicate that individuals over the age of 40 had increased levels of Candida infections compared to patients younger than 40. Candida infections were higher among subjects with elevated blood sugar levels (HbA1c>9) compared to individuals with well-controlled blood sugar levels (HbA1c<6). Patients with PPDs>=5 had an increased risk of Candida infection compared to patients with PPDs between 3 and 4. CONCLUSION: This study indicates that the frequency of C. albicans is higher than the frequencies of C. dubliniensis, C. tropicalis and C. glabrata in diabetic patients with periodontitis. Candida infections were observed at increased frequencies among subjects with high blood sugar levels and PPDs>=5. PMID- 23806706 TI - Episode of coexisting infections with multiple dengue virus serotypes in central Karnataka, India. AB - BACKGROUND: The co-circulation of multiple dengue virus serotypes has been reported in many parts of the world, including India; however, concurrent infection with more than one serotype of dengue virus in the same individual is rarely documented. METHOD: An outbreak of dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) occurred in and around Davangere, Karnataka, from June 2011 March 2012. This is the first report from India with a high percentage of concurrent infections with different dengue virus serotypes circulating during one outbreak. Acute phase sera from patients were tested for the presence of dengue virus RNA by RT-PCR. RESULTS: Of the 72 samples tested for dengue virus RNA, 42 (58.3%) were positive. All four dengue virus serotypes were found to be co-circulating in this outbreak, and DENV-2 was the predominant serotype. In addition, concurrent infection with more than one dengue virus serotype was identified in 18 (42.9%) dengue virus-positive samples. CONCLUSION: Our study showed that serotype DEN-2 was dominant in the positive dengue virus-infected samples; the other serotype present was DEN-3. This is the first report of concurrent infections with different dengue virus serotypes in this part of the world. PMID- 23806707 TI - Non-adherence to antiretroviral therapy in Yaounde: prevalence, determinants and the concordance of two screening criteria. AB - PURPOSE: To assess the prevalence and determinants of non-adherence to antiretroviral therapy (ART) as well as the concordance of two screening criteria in a major center for human immunodeficiency virus (HIV) treatment in Yaounde, Cameroon. METHODS: In 2011, we conducted a cross-sectional study involving a random sample of 889 adults (age > 18 years, 67.9% women) infected with HIV who were receiving chronic care at the Yaounde Jamot Hospital. Adherence was assessed via self-administered questionnaires using the Community Programs for Clinical Research on AIDS (CPCRA) index and the Center for Adherence Support Evaluation (CASE) index. RESULTS: The prevalence of non-adherence to ART was 22.5% based on the CPCRA index and 34.9% based on the CASE index, with a low agreement between the two indexes [kappa = 0.37 (95% confidence interval 0.31-0.44)]. Independent determinants of CPCRA-diagnosed non-adherence were as follows: being a remunerated employee [odds ratio (95% confidence interval): 1.61 (1.14-2.28)], Pentecostal Christianity [2.18 (1.25-3.80)], alcohol consumption [1.65 (1.16 2.34)] and non-adherence to cotrimoxazole prophylaxis [5.73 (3.92-8.38)]. The equivalents for CASE-diagnosed non-adherence were [1.59 (1.19-2.12)], [1.83 (1.36 2.47)], [1.70 (1.27-2.28)], respectively, in addition to association with changes to the ART regimen [1.61 (1.17-2.20)]. CONCLUSIONS: Non-adherence to ART remains high in this population. The careful evaluation of patients for the presence of determinants of non-adherence identified in this study may aid ART optimization. PMID- 23806708 TI - Social deficits in children with chronic tic disorders: phenomenology, clinical correlates and quality of life. AB - Youth with chronic tic disorders (CTD) experience social problems that have been associated with functional impairment and a diminished quality of life. Previous examinations have attributed social difficulties to either tic severity or the symptom severity of coexisting conditions, but have not directly explored performance deficits in social functioning. This report examined the presence and characteristics of social deficits in youth with CTD and explored the relationship between social deficits, social problems, and quality of life. Ninety-nine youth (8-17years) and their parents completed a battery of assessments to determine diagnoses, tic severity, severity of coexisting conditions, social responsiveness, and quality of life. Parents reported that youth with CTD had increased social deficits, with 19% reported to have severe social deficits. The magnitude of social deficits was more strongly associated with inattention, hyperactivity, and oppositionality than with tic severity. Social deficits predicted internalizing and social problems, and quality of life above and beyond tic severity. Social deficits partially mediated the relationship between tic severity and social problems, as well as tic severity and quality of life. Findings suggest that youth with CTD have social deficits, which are greater in the presence of attention-deficit hyperactivity disorder and obsessive compulsive disorder. These social deficits play an influential role in social problems and quality of life. Future research is needed to develop interventions to address social performance deficits among youth with CTD. PMID- 23806709 TI - Cognitive emotion regulation strategies contributing to resilience in patients with depression and/or anxiety disorders. AB - OBJECTIVE: Research suggests that resilience is associated with favorable treatment outcome in patients with depression and/or anxiety disorders. In this regard, the identification of specific characteristics related to resilience that could provide targets for resilience-enhancement interventions is needed. Since the type of cognitive coping strategies is a possible marker of resilience, we investigated adaptive and maladaptive cognitive emotion regulation strategies contributing to resilience in patients with depression and/or anxiety disorders. METHODS: A total of 230 outpatients with depression and anxiety disorders were consecutively recruited and completed the Cognitive Emotion Regulation Questionnaire, the Connor-Davidson Resilience Scale, the Beck Depression Inventory, and the State Anxiety Inventory. A linear regression model was used to determine which cognitive emotion regulation strategies predicted resilience after controlling for relevant covariates. Additionally, this model of resilience was compared with those of depression and anxiety symptoms. RESULTS: Adaptive strategies were more strongly correlated with resilience than maladaptive strategies. In the regression model, more use of refocus on planning and positive reappraisal as well as less use of rumination predicted high resilience after controlling for age, gender, marital status, depression, and anxiety. Among these strategies, refocus on planning was the common strategy contributing to resilience and depression. CONCLUSION: These results suggested that the cognitive emotion regulation strategies of refocus on planning, positive reappraisal, and less rumination contribute to resilience in patients with depression and anxiety disorders. It might provide potential targets for psychotherapeutic intervention to improve resilience in these patients. PMID- 23806710 TI - "Compensated hyperosmolarity" of cerebrospinal fluid and the development of hydrocephalus. AB - Acute osmolar loading of cerebrospinal fluid within one lateral ventricle of dogs was examined as a cause of water extraction from the bloodstream and an increase in intracranial pressure. We have shown that a certain amount of (3)H2O from the bloodstream enters osmotically loaded cerebrospinal fluid significantly faster, hence causing a significant increase in intracranial pressure. The noted phenomenon in which intracranial pressure still significantly increases, but in which the hyperosmolarity of the cerebrospinal fluid is no longer present, was named "compensated hyperosmolarity". In the case of the sub-chronic application of hyperosmolar solutions into cat ventricles, we observed an increase in cerebrospinal fluid volume and a more pronounced development of hydrocephalus in the area of application, but without significant increase in intracranial pressure and without blockage of cerebrospinal fluid pathways. These results support the newly proposed hypothesis of cerebrospinal fluid hydrodynamics and the ability to develop new strategies for the treatment of cerebrospinal fluid related diseases. PMID- 23806711 TI - Expression of exogenous LIN28 contributes to proliferation and survival of mouse primary cortical neurons in vitro. AB - LIN28, an RNA-binding protein, is known to be involved in the regulation of many cellular processes, such as embryonic stem cell proliferation, cell fate succession, developmental timing, and oncogenesis. In this study, we investigated the effect of constitutively expressing exogenous LIN28 on neuronal cell proliferation and viability in vitro. Plasmids containing LIN28-green fluorescent protein (GFP) or GFP were introduced into the embryonic mouse brains at E14.5 by in utero electroporation. Two days after electroporation, embryonic cortices were harvested and cultured. It was found that transfected cells stably overexpressed LIN28 in vitro. Viability curve from live cell imaging showed that the number of GFP-expressing cells decreased over time in line with naive primary cortical neurons. In contrast, the number of LIN28-GFP-overexpressing neurons initially increased and remained high at later time-points in culture than GFP-expressing cells. Double immunofluorescence showed that at an early time in culture, the number of Ki-67/GFP double-positive cells was higher in the LIN28-GFP group than that of controls. Moreover, there were significantly lower numbers of condensed nuclei/GFP- and cleaved caspase-3/GFP-positive cells in the LIN28-GFP groups compared to control GFP. Furthermore, it was confirmed that the LIN28-GFP expressing cells at days in vitro (DIV)13 were neuronal nuclei (NeuN)-positive mature neurons. Finally, the expression of insulin-like growth factor 2 (IGF-2) was induced in LIN28-expressing primary cortical neurons, which was not detected in controls. Taken together, our results indicate that the expression of exogenous LIN28 can promote the proliferation of neural progenitor cells and exert prosurvival effect on primary cortical neurons by inhibiting caspase dependent apoptosis, possibly via upregulation of IGF-2. PMID- 23806712 TI - Neonatal hypoxia-ischaemia disrupts descending neural inputs to dorsal raphe nuclei. AB - Neuronal losses have been shown to occur in the brainstem following a neonatal hypoxic-ischaemic (HI) insult. In particular serotonergic neurons, situated in the dorsal raphe nuclei, appear to be vulnerable to HI injury. Nonetheless the mechanisms contributing to losses of serotonergic neurons in the brainstem remain to be elucidated. One possible mechanism is that disruption of neural projections from damaged forebrain areas to dorsal raphe nuclei may play a role in the demise of serotonergic neurons. To test this, postnatal day 3 (P3) rat pups underwent unilateral common carotid artery ligation followed by hypoxia (6% O2 for 30 min). On P38 a retrograde tracer, fluorescent-coupled choleratoxin b, was deposited in the dorsal raphe dorsal (DR dorsal) nucleus or the dorsal raphe ventral (DR ventral) nucleus. Compared to control animals, P3 HI animals had significant losses of retrogradely labelled neurons in the medial prefrontal cortex, preoptic area and lateral habenula after tracer deposit in the DR dorsal nucleus. On the other hand, after tracer deposit in the DR ventral nucleus, we found significant reductions in numbers of retrogradely labelled neurons in the hypothalamus, preoptic area and medial amygdala in P3 HI animals compared to controls. Since losses of descending inputs are associated with decreases in serotonergic neurons in the brainstem raphe nuclei, we propose that disruption of certain descending neural inputs from the forebrain to the DR dorsal and the DR ventral nuclei may contribute to losses of serotonergic neurons after P3 HI. It is important to delineate the phenotypes of different neuronal networks affected by neonatal HI, and the mechanisms underpinning this damage, so that interventions can be devised to target and protect axons from the harmful effects of neonatal HI. PMID- 23806713 TI - Exogenous melatonin reproduces the effects of short day lengths on hippocampal function in male white-footed mice, Peromyscus leucopus. AB - Photoperiodism is a biological phenomenon, common among organisms living outside of the tropics, by which environmental day length is used to ascertain the time of year to engage in seasonally-appropriate adaptations. White-footed mice (Peromyscus leucopus) are small photoperiodic rodents which display a suite of adaptive winter responses to short day lengths mediated by the extended duration of nightly melatonin secretion. Exposure to short days alters hippocampal dendritic morphology, impairs spatial learning and memory, and impairs hippocampal long-term potentiation (LTP). To determine the role of melatonin in these photoperiod-induced alterations of behavioral, neuroanatomical, and neurophysiological processes in this species, we implanted male mice subcutaneously with melatonin or empty Silastic capsules and exposed them to long or short day lengths. After 10 weeks, mice were assessed for hippocampal LTP, tested for spatial learning and memory in the Barnes maze, and morphometric analysis of neurons in the hippocampus using Golgi staining. Extending the duration of melatonin exposure, by short-day exposure or via melatonin implants, impaired both Schaffer collateral LTP in the CA1 region of the hippocampus and spatial learning and memory, and altered neuronal morphology in all hippocampal regions. The current results demonstrate that chronic melatonin implants reproduce the effects of short days on the hippocampus and implicate melatonin signaling as a critical factor in day-length-induced changes in the structure and function of the hippocampus in a photoperiodic rodent. PMID- 23806714 TI - Neurological and cellular regulation of visceral hypersensitivity induced by chronic stress and colonic inflammation in rats. AB - The role of inflammation in inducing visceral hypersensitivity (VHS) in ulcerative colitis patients remains unknown. We tested the hypothesis that acute ulcerative colitis-like inflammation does not induce VHS. However, it sets up molecular conditions such that chronic stress following inflammation exaggerates single-unit afferent discharges to colorectal distension. We used dextran sodium sulfate (DSS) to induce ulcerative colitis-like inflammation and a 9-day heterotypic chronic stress protocol in rats. DSS upregulated Nav1.8 mRNA in colon responsive dorsal root ganglion (DRG) neurons, TRPV1 in colonic muscularis externae (ME) and BDNF in spinal cord without affecting the spike frequency in spinal afferents or VMR to CRD. By contrast, chronic stress did not induce inflammation but it downregulated Kv1.1 and Kv1.4 mRNA in DRG neurons, and upregulated TRPA1 and nerve growth factor in ME, which mediated the increase of spike frequency and VMR to CRD. Chronic stress following inflammation exacerbated spike frequency in spinal afferent neurons. TRPA1 antagonist suppressed the sensitization of afferent neurons. DSS-inflammation did not affect the composition or excitation thresholds of low-threshold and high-threshold fibers. Chronic stress following inflammation increased the percent composition of high threshold fibers and lowered the excitation threshold of both types of fibers. We conclude that not all types of inflammation induce VHS, whereas chronic stress induces VHS in the absence of inflammation. PMID- 23806715 TI - Tumor necrosis factor-alpha inhibits angiotensin II receptor type 1 expression in dorsal root ganglion neurons via beta-catenin signaling. AB - Both tumor necrosis factor (TNF)-alpha and the angiotensin (Ang) II/angiotensin II receptor type 1 (AT1) axis play important roles in neuropathic pain and nociception. In the present study, we explored the interaction between the two systems by examining the mutual effects between TNF-alpha and the Ang II/AT1 receptor axis in dorsal root ganglion (DRG) neurons. Rat DRG neurons were treated with TNF-alpha in different concentrations for different lengths of time in the presence or absence of transcription inhibitor actinomycin D, TNF receptor 1 (TNFR1) inhibitor SPD304, beta-catenin signaling inhibitor CCT031374, or different kinase inhibitors. TNF-alpha decreased the AT1 receptor mRNA level as well as the AT1a receptor promoter activity in a dose-dependent manner within 30 h, which led to dose-dependent inhibition of Ang II-binding AT1 receptor level on the cell membrane. Actinomycin D (1 mg/ml), SPD304 (50 MUM), p38 mitogen activated protein kinase (MAPK) inhibitor PD169316 (25 MUM), and CCT031374 (50 MUM) completely abolished the inhibitory effect of TNF-alpha on AT1 receptor expression. TNF-alpha dose-dependently increased soluble beta-catenin and phosphorylated GSK-3beta levels, which was blocked by SPD304 and PD169316. In DRG neurons treated with AT2 receptor agonist CGP421140, or Ang II with or without AT1 receptor antagonist losartan or AT2 receptor antagonist PD123319 for 30 h, we found that Ang II and Ang II+PD123319 significantly decreased TNF-alpha expression, whereas CPG421140 and Ang II+losartan increased TNF-alpha expression. In conclusion, we demonstrate that TNF-alpha inhibits AT1 receptor expression at the transcription level via TNFR1 in rat DRG neurons by increasing the soluble beta-catenin level through the p38 MAPK/GSK-3beta pathway. In addition, Ang II appears to inhibit and induce TNF-alpha expression via the AT1 receptor and the AT2 receptor in DRG neurons, respectively. This is the first evidence of crosstalk between TNF-alpha and the Ang II/AT receptor axis in DRG neurons. PMID- 23806716 TI - Deficient functional recovery after facial nerve crush in rats is associated with restricted rearrangements of synaptic terminals in the facial nucleus. AB - Crush injuries of peripheral nerves typically lead to axonotmesis, axonal damage without disruption of connective tissue sheaths. Generally, human patients and experimental animals recover well after axonotmesis and the favorable outcome has been attributed to precise axonal reinnervation of the original peripheral targets. Here we assessed functionally and morphologically the long-term consequences of facial nerve axonotmesis in rats. Expectedly, we found that 5 months after crush or cryogenic nerve lesion, the numbers of motoneurons with regenerated axons and their projection pattern into the main branches of the facial nerve were similar to those in control animals suggesting precise target reinnervation. Unexpectedly, however, we found that functional recovery, estimated by vibrissal motion analysis, was incomplete at 2 months after injury and did not improve thereafter. The maximum amplitude of whisking remained substantially, by more than 30% lower than control values even 5 months after axonotmesis. Morphological analyses showed that the facial motoneurons ipsilateral to injury were innervated by lower numbers of glutamatergic terminals (-15%) and cholinergic perisomatic boutons (-26%) compared with the contralateral non-injured motoneurons. The structural deficits were correlated with functional performance of individual animals and associated with microgliosis in the facial nucleus but not with polyinnervation of muscle fibers. These results support the idea that restricted CNS plasticity and insufficient afferent inputs to motoneurons may substantially contribute to functional deficits after facial nerve injuries, possibly including pathologic conditions in humans like axonotmesis in idiopathic facial nerve (Bell's) palsy. PMID- 23806717 TI - Same or different? ERP correlates of pretense and false belief reasoning in children. AB - Pretend play, emerging at about 18 months, and explicit false belief (FB) understanding, arising around 4 years, constitute two pivotal milestones in the development of a Theory of Mind since both involve the ability to separate real from non-real content. The developmental lag has evoked vivid discussion with respect to whether or not pretense (PT) involves a metarepresentational understanding similar to FB. However, in children PT and FB have not yet been contrasted on a neural level to reveal whether they are subserved by the same neurocognitive mechanism. Therefore, the present event-related potential (ERP) study compared PT to a FB and to a non-mental control condition in 6- to 8-year old children. Results revealed distinct ERP components for PT and FB. PT elicited a parietal P2, which was assumed to reflect the detection of incongruence, and a negative frontal slow wave (290-600 ms), which was associated with the identification of the intention underlying the pretend behavior. In contrast, FB evoked the characteristic positive fronto-central late slow wave (290-920 ms) that is supposed to indicate metarepresentation. Further, the broad distribution of the anterior slow-wave patterns associated with PT and FB reasoning was assumed to reflect the ongoing structural development and neural specialization of the respective areas, indicating the developmental progress in conceptualizing the mental domain. Given the differences in latency, polarity, and topography, PT and FB seem to rely on distinct neural substrates in children. The early negative frontal slow wave indicates that for PT reasoning children may use simple mentalizing processes such as intention processing, whereas the late positive slow-wave shows that for FB children may engage in metarepresentational processing. Therefore, the present findings seem to substantiate theoretical accounts postulating simple mentalistic reasoning for PT in children. PMID- 23806718 TI - Redox-sensitive synchronizing action of adenosine on transmitter release at the neuromuscular junction. AB - The kinetics of neurotransmitter release was recognized recently as an important contributor to synaptic efficiency. Since adenosine is the ubiquitous modulator of presynaptic release in peripheral and central synapses, in the current project we studied the action of this purine on the timing of acetylcholine quantal release from motor nerve terminals in the skeletal muscle. Using extracellular recording from frog neuromuscular junction we tested the action of adenosine on the latencies of single quantal events in the pro-oxidant and antioxidant conditions. We found that adenosine, in addition to previously known inhibitory action on release probability, also synchronized release by removing quantal events with long latencies. This action of adenosine on release timing was abolished by oxidants whereas in the presence of the antioxidant the synchronizing action of adenosine was further enhanced. Interestingly, unlike the timing of release, the inhibitory action of adenosine on release probability was redox-independent. Modulation of release timing by adenosine was mediated by purinergic A1 receptors as it was eliminated by the specific A1 antagonist 8 cyclopentyl-1,3-dipropylxanthine (DPCPX) and mimicked by the specific A1 agonist N(6)-cyclopentyl-adenosine. Consistent with data obtained from dispersion of single quantal events, adenosine also reduced the rise-time of multiquantal synaptic currents. The latter effect was reproduced in the model based on synchronizing effect of adenosine on release timing. Thus, adenosine which is generated at the neuromuscular junction from the breakdown of the co-transmitter ATP induces the synchronization of quantal events. The effect of adenosine on release timing should preserve the fidelity of synaptic transmission via "cost effective" use of less transmitter quanta. Our findings also revealed important crosstalk between purinergic and redox modulation of synaptic processes which could take place in the elderly or in neuromuscular diseases associated with oxidative stress like lateral amyotrophic sclerosis. PMID- 23806719 TI - The effects of music on brain functional networks: a network analysis. AB - The human brain can dynamically adapt to the changing surroundings. To explore this issue, we adopted graph theoretical tools to examine changes in electroencephalography (EEG) functional networks while listening to music. Three different excerpts of Chinese Guqin music were played to 16 non-musician subjects. For the main frequency intervals, synchronizations between all pair wise combinations of EEG electrodes were evaluated with phase lag index (PLI). Then, weighted connectivity networks were created and their organizations were characterized in terms of an average clustering coefficient and characteristic path length. We found an enhanced synchronization level in the alpha2 band during music listening. Music perception showed a decrease of both normalized clustering coefficient and path length in the alpha2 band. Moreover, differences in network measures were not observed between musical excerpts. These experimental results demonstrate an increase of functional connectivity as well as a more random network structure in the alpha2 band during music perception. The present study offers support for the effects of music on human brain functional networks with a trend toward a more efficient but less economical architecture. PMID- 23806720 TI - Hypothalamic and basal ganglia projections to the posterior thalamus: possible role in modulation of migraine headache and photophobia. AB - Migraine attacks are typically described as unilateral, throbbing pain that is usually accompanied by nausea, vomiting, and exaggerated sensitivities to light, noise and smell. The headache phase of a migraine attack is mediated by activation of the trigeminovascular pathway; a nociceptive pathway that originates in the meninges and carries pain signals through meningeal nociceptors to the spinal trigeminal nucleus and from there to the cortex through relay neurons in the thalamus. Recent studies in our lab have identified a population of trigeminovascular neurons in the posterior (Po) and lateral posterior (LP) thalamic nuclei that may be involved in the perception of whole-body allodynia (abnormal skin sensitivity) and photophobia (abnormal sensitivity to light) during migraine. The purpose of the current study was to identify sub-cortical areas that are in position to directly regulate the activity of these thalamic trigeminovascular neurons. Such process begins with anatomical mapping of neuronal projections to the posterior thalamus of the rat by performing discrete injections of the retrograde tracer Fluorogold into the Po/LP region. Such injections yielded retrogradely labeled neurons in the nucleus of the diagonal band of Broca, the dopaminergic cells group A11/A13, the ventromedial and ventral tuberomammillary nuclei of the hypothalamus. We also found that some of these neurons contain acetylcholine, dopamine, cholecystokinin and histamine, respectively. Accordingly, we speculate that these forebrain/hypothalamic projections to Po and LP may play a role in those migraine attacks triggered by disrupted sleep, skipping meals and emotional reactions. PMID- 23806721 TI - Neurodegeneration and inflammation in hippocampus in experimental autoimmune encephalomyelitis induced in rats by one--time administration of encephalitogenic T cells. AB - Cognitive dysfunction is relatively frequent in multiple sclerosis (MS) and it happens from the early stages of the disease. There is increasing evidence that the grey matter may be involved in autoimmune inflammation during relapses of MS. The purpose of this study was to evaluate if a single transfer of encephalitogenic T cells, mimicking a relapse of MS, may cause hippocampal damage and memory disturbances in rats. Lewis rats were injected with anti-MBP CD4+ T cells, that induced one-phase autoimmune encephalomyelitis (EAE) with full recovery from motor impairments at 10-15 days. The spatial learning and memory were tested by the Morris water maze test in control and EAE animals, 30 and 90 days post-induction (dpi). The neural injury and inflammation was investigated in the hippocampus by immunohistochemistry and quantitative analyses. There was a marked decrease in the number of CA1 and CA4 pyramidal neurons 5 dpi. The loss of neurons then aggravated till the 90 dpi. An increase in microglial and astroglial activation and in pro-inflammatory cytokines mRNA expression in the hippocampus, were present 30 and 90 dpi. Nerve growth factor and brain-derived neurotrophic factor mRNA levels were also significantly elevated. The water maze test, however, did not reveal memory deficits. The present data indicate that a single transfer of autoimmune T cells results in preserved inflammation and probable on going neuronal injury in the hippocampus, long after recovery from motor disturbances. These findings suggest that any relapse of the MS may start the neurodegenerative process in the hippocampus, which is not necessarily connected with memory deficits. PMID- 23806723 TI - ATP-ases of synaptic plasma membranes in striatum: enzymatic systems for synapses functionality by in vivo administration of L-acetylcarnitine in relation to Parkinson's Disease. AB - The maximum rate (Vmax) of some enzymatic activities related to energy consumption was evaluated in synaptic plasma membranes from rat brain striatum, the synaptic energy state being a crucial factor in neurodegenerative diseases etiopathogenesis. Two types of synaptic plasma membranes were isolated from rats subjected to in vivo treatment with L-acetylcarnitine at two different doses (30 and 60 mg * kg(-1) i.p., 28 days, 5 days/week). The following enzyme activities were evaluated: acetylcholinesterase (AChE); Na(+), K(+), Mg(2+)-ATP-ase; ouabain insensitive Mg(2+)-ATP-ase; Na(+), K(+)-ATP-ase; direct Mg(2+)-ATP-ase; Ca(2+), Mg(2+)-ATP-ase; and low- and high-affinity Ca(2+)-ATP-ase. In control (vehicle treated) animals, enzymatic activities are differently expressed in synaptic plasma membranes type I (SPM1) with respect to synaptic plasma membranes type II (SPM2), the evaluated enzymatic activities being higher in SPM2. Subchronic treatment with L-acetylcarnitine decreased AChE on SPM1 and SPM2 at the dose of 30 mg * kg(-1). Pharmacological treatment decreased ouabain insensitive Mg(2+) ATP-ase activity and high affinity Ca(2+)-ATP-ase activity at the doses of 30 and 60 mg * kg(-1) respectively on SPM1, while it decreased Na(+), K(+)-ATP-ase, direct Mg(2+)-ATP-ase and Ca(2+), Mg(2+)-ATP-ase activities at the dose of 30 mg * kg(-1) on SPM2. These results suggest that the sensitivity to drug treatment is different between these two populations of synaptic plasma membranes from the striatum, confirming the micro-heterogeneity of these subfractions, possessing different metabolic machinery with respect to energy consumption and utilization and the regional selective effect of L-acetylcarnitine on cerebral tissue, depending on the considered area. The drug potential effect at the synaptic level in Parkinson's Disease neuroprotection is also discussed with respect to acetylcholine and energy metabolism. PMID- 23806724 TI - Appropriate sample dilution for troponin I testing. PMID- 23806722 TI - Differential impact of a complex environment on positive affect in an animal model of individual differences in emotionality. AB - Anhedonia, or the inability to experience positive feelings is a hallmark of depression. However, few animal models have relied on decreased positive affect as an index of susceptibility to depression. Rats emit frequency-modulated ultrasonic vocalizations (USVs), designated as "positive" calls in the 50-kHz range. USVs have been associated with pharmacological activation of motivational reward circuits. Here we utilized selectively-bred rats differing in "emotionality" to ask whether there are associated differences in USVs. Rats bred based on locomotor response to novelty and classified as bred High Responders (bHRs) or bred Low Responders (bLRs) exhibit inborn differences in response to environmental cues, stress responsiveness, and depression-like behavior. These animals also exhibit differences in anxiety-like behavior, which are reversed by exposure to environmental complexity (EC). Finally, these animals exhibit unique profiles of responsiveness to rewarding stimuli accompanied with distinct patterns of dopamine regulation. We investigated whether acute and chronic environmental manipulations impacted USVs in bHRs and bLRs. We found that, relative to bLRs, bHRs emitted significantly more 50-kHz USVs. However, if a bLR is accompanied by another bLR, there is a significant increase in 50-kHZ USVs emitted by this phenotype. bHRs emitted increases in 50-kHZ UVSs upon first exposure to EC, whereas bLRs showed a similar increase only after repeated exposure. bLRs' increase in positive affect after chronic EC was coupled with significant positive correlations between corticosterone levels and c-fos mRNA in the accumbens. Conversely, a decline in the rate of positive calls in bHRs after chronic EC was associated with a negative correlation between corticosterone and accumbens c-fos mRNA. These studies demonstrate that inborn differences in emotionality interact with the environment to influence positive affect and underscore the potential interaction between glucocorticoids and the mesolimbic reward circuitry in modulating 50-kHz calls. PMID- 23806725 TI - Effect of Shenfu on inflammatory cytokine release and brain edema after prolonged cardiac arrest in the swine. AB - OBJECTIVE: Shenfu injection (SFI), a traditional Chinese formulation, has been confirmed to be protective against brain during ischemia and reperfusion injury. In this exploratory study, we investigated the action of SFI in regulating the inflammatory response and brain edema after cardiopulmonary resuscitation. METHODS: After 8 minutes of untreated ventricular fibrillation (VF), pigs in the cardiopulmonary resuscitation group (n = 24) received a central venous injection of either SFI (SFI group; 1.0 mL/kg), epinephrine (EP group; 0.02 mg/kg), or saline (SA group). Levels of porcine-specific tumor necrosis factor alpha and interleukin in sera were measured using enzyme-linked immunosorbent assay at 0.5, 1, 2, 4, 6, and 24 hours after return of spontaneous circulation (ROSC). Surviving pigs were killed 24 hours after ROSC, and the brains were removed for electron microscopy, Western blotting, and quantitative real-time polymerase chain reaction analysis. RESULTS: Compared with the EP and SA groups, SFI decreased the levels of tumor necrosis factor alpha and interleukin-6 in serum and the brain (P < .05) and decreased the expression of nuclear factor kappaB and aquaporin-4 messenger RNA in the brain (P < .05). Shenfu injection also inhibited the expression of nuclear factor kappaB, matrix metalloproteinase 9, and aquaporin-4 protein after ROSC (P < .05). Observation of brain tissue ultrastructure showed that injury was alleviated in the SFI group compared with the SA and EP groups. CONCLUSIONS: Our exploratory experiments demonstrated that SFI reduced cerebral damage in a porcine model of VF, which may be related to suppression of the inflammatory reaction and decreased brain edema after ROSC. PMID- 23806726 TI - Predictors of myocardial infarction after an acute coronary syndrome with clopidogrel and prasugrel. PMID- 23806727 TI - Complication after treatment for resistant supraventricular tachycardia: the Bezold-Jarisch reflex. AB - The Bezold-Jarisch reflex may become clinically relevant in times of profound relative hypovolemia. This results in uncoupled cardio inhibition leading to the triad of hypotension, bradycardia and vasodilation. PMID- 23806728 TI - Application of the Shock Index to the prediction of need for hemostasis intervention. AB - INTRODUCTION: The traditional method to identify hemorrhage after trauma has been vital signs-based. More recent attempts have used mathematical prediction models, but these are limited by the need for additional data including a Focused Assessment with Sonography for Trauma exam, or an arterial blood gas. Shock Index (SI) is the mathematical relationship of the heart rate divided by the systolic blood pressure; the cutoff of >0.9 has been associated with bleeding. METHODS: A total of 4292 trauma patients were identified in database over an 11 year period. Inclusion criteria included age >16 years and initial presentation to our trauma center. Patients were excluded for incomplete data, traumatic brain injury, or transfer leaving 4277 patients for analysis. Patients were further subdivided by age, and by mechanism of injury (blunt versus penetrating). Finally, patients were divided into bleeding versus nonbleeding, and the SI formula was applied to their initial hospital vital signs. RESULTS: Across our dataset, using the standard SI cutoff of >0.9 as the threshold for bleeding, the sensitivity is 54.5%, with a specificity of 93.6%. In the geriatric subanalysis, there was no difference for sensitivity between the age groups, but SI is more specific in the older patients. There was no difference in sensitivity using SI in blunt versus penetrating. Lowering the SI to >=0.8 increases the sensitivity to 76.1%, with a specificity of 87.4%. CONCLUSION: SI, at a lowered threshold of >=0.8, can be used to identify trauma patients that will require intervention for hemostasis. PMID- 23806729 TI - Contrast-enhanced ultrasonography to diagnose gallbladder perforation. AB - AIM: The purpose of this study was to evaluate contrast-enhanced ultrasonography (CEUS) as a modality for diagnosing perforation of the gallbladder (GB) and pericholecystic hepatic abscess. METHODS: This retrospective study comprised 6 patients with acute cholecystitis and GB perforation plus pericholecystic hepatic abscess who underwent conventional US and CEUS imaging. The following sonographic features were examined: GB contour, defect in the GB wall, and pericholecystic hepatic mass. The findings of conventional US and CEUS were compared. RESULTS: Conventional US revealed a defect in the GB wall in 2 patients and partially obscured GB wall in 4 patients. Pericholecystic masses were visualized as isohypoechoic masses in 3 and mixed cystic-solid masses in 3 patients. Contrast enhanced US revealed hyperenhancement of the GB wall during the early arterial phase, and a defect was seen in every patient. The pericholecystic masses showed heterogeneous enhancement with a honeycomb-like appearance during the arterial phase-interpreted abscesses. CONCLUSION: Contrast-enhanced US clearly visualized defects in the GB wall and pericholecystic abscesses in patients with GB perforation. The results indicate that CEUS is a useful modality for the diagnosis of GB perforation. PMID- 23806730 TI - Laryngeal fracture after coughing. AB - Nontraumatic laryngeal fractures are exceedingly rare disease entities. Only 3 prior instances have been described in the medical literature (Br Med J 1950;1:1052; Acta Otorrinolaringol Esp 2007;58:73-4; Otolaryngol Head Neck Surg 2012;147:801-2). We present a case of thyroid cartilage fracture and associated phlegmon formation after a vigorous coughing spell in a 47-year-old man. On presentation, the patient's symptoms included the triad of odynophagia, dysphagia, and dysphonia as well as diffuse swelling and tenderness over the thyroid cartilage. Computed tomography and magnetic resonance imaging revealed a mildly displaced anterior thyroid cartilage fracture as well as a phlegmon in the strap muscle compartment adjacent to the fracture (Figs. 1 and 2). Intravenous dexamethasone and antibiotics were initiated, and the patient was admitted to the medical intensive care unit. On fiberoptic examination with the flexible laryngoscope, the patient was found to have slightto-moderate watery edema of the right aryepiglottic fold and right greater than left arytenoid cartilages. After 48 hours, the patient's neck swelling and pain significantly improved. On hospital day 4, the patient was discharged with a course of oral antibiotics. One week later, the patient reported only mild odynophagia and persistent dysphonia. He otherwise felt well and was tolerating fluids and soft food without difficulty. A preexisting, congenital abnormality resulting in a focal weakness in the thyroid cartilage might predispose patients to nontraumatic fractures (Otolaryngol Head Neck Surg 2012;147:801-2). Patients in prior case reports of nontraumatic laryngeal fractures presented with similar symptoms (Table). The triad of odynophagia, dysphagia, and dysphonia after a severe coughing or sneezing episode should raise the clinician's suspicion of a thyroid cartilage fracture. PMID- 23806731 TI - The experience of sleep deprivation in intensive care patients: findings from a larger hermeneutic phenomenological study. AB - Sleep deprivation in critically ill patients has been well documented for more than 30 years. Despite the large body of literature, sleep deprivation remains a significant concern in critically ill patients in intensive care unit (ICU). This paper discusses sleep deprivation in critically ill patients as one of the main findings from a study that explored the lived experiences of critically ill patients in ICU with daily sedation interruption (DSI). Twelve participants aged between 20 and 76 years with an ICU stay ranging from three to 36 days were recruited from a 16 bed ICU in a large regional referral hospital in New South Wales (NSW), Australia. Participants were intubated, mechanically ventilated and subjected to daily sedation interruption during their critical illness in ICU. In depth face to face interviews with the participants were conducted at two weeks after discharge from ICU. A second interview was conducted with eight participants six to eleven months later. Interviews were audio taped and transcribed. Data were analysed thematically. "Longing for sleep" and "being tormented by nightmares" capture the experiences and concerns of some of the participants. The findings suggest a need for models of care that seek to support restful sleep and prevent or alleviate sleep deprivation and nightmares. These models of care need to promote both quality and quantity of sleep in and beyond ICU and identify patients suffering from sleep deprivation to make appropriate referrals for treatment and support. PMID- 23806732 TI - Evaluation of commercial resins for fructo-oligosaccharide separation. AB - Fructo-oligosaccharides (FOS) produced by fermentative processes are obtained in mixtures containing significant amounts of salts and other non-prebiotic sugars. A demineralisation process using a mixture of a cationic and an anionic resin was proposed. The separation of FOS from a mixture of fructose, glucose and sucrose was evaluated. Experiments were conducted with several commercial cationic exchange resins in calcium, sodium and potassium forms packed in preparative columns (7cm*2.2cm length*diameter). Resins in potassium form obtained the higher retention factor values for sugars when compared to the other ionic forms. However, when compared to calcium and sodium ones, resins in potassium cationic forms were shown to be the less efficient separating sugar mixtures. The resin with best separation performance was the Diaion UBK535Ca. A recovery yield of 92% (w/w) of FOS with 90% (w/w) of purity was obtained from batch experiments conducted in a single column loaded with the Diaion UBK535Ca resin at 25 degrees C. The temperature shown did not influence the separation performance significantly. By increasing the column length, the purity of FOS increased to 92% (w/w), however the recovery yield decreased to 88% (w/w). PMID- 23806733 TI - Cone-beam computed tomography incidental findings--a cause for worry? PMID- 23806734 TI - Evidence for the functional compartmentalization of the temporalis muscle: a 3 dimensional study of innervation. AB - PURPOSE: The temporalis muscle is commonly used for functional transfer. It is architecturally complex, but few studies have examined its intramuscular innervation and none has used 3-dimensional modeling techniques. Understanding neuromuscular compartmentalization may allow the design of local muscle transfers to minimize donor-site morbidity. The purpose of the present study was to document the intramuscular innervation patterns throughout the volume of the temporalis muscle and define functional units within the muscle. MATERIALS AND METHODS: In 10 formalin-embalmed cadaveric specimens, the foramen ovale was exposed and the branches of the mandibular nerve were identified. Each branch was digitized in short segments extramuscularly and intramuscularly. Three dimensional models were reconstructed from the digitized data using Maya software, and the innervation patterns were documented. RESULTS: The temporalis muscle was found to have superior and inferior parts that were further grouped by innervation into regions, with each receiving its innervation from 1 primary nerve. The nerves originated directly from the mandibular nerve, except in 3 specimens, where the posterior deep temporal nerve arose from the masseteric nerve. CONCLUSION: These results provide a detailed mapping of innervation patterns and suggest there are at least 5 functional compartments. Each of these has the capacity for selective activation, 3 of which have clinical value. These findings may allow for decreased donor-site morbidity and more functionally sophisticated designs in clinical practice. PMID- 23806735 TI - Transoral open reduction and fixation of mandibular condylar base and neck fractures in children and young teenagers--a beneficial treatment option? AB - PURPOSE: To evaluate the possible benefits of open surgery, endoscopically assisted reduction and fixation using a transoral route was used in a selected series of pediatric patients with displaced condylar base and neck fractures. PATIENTS AND METHODS: A cohort of 6 patients (1 male and 5 female; age range, 7 to 15 yr; mean, 13.4 yr) with displaced condylar base and neck fractures (n = 9) were included. Inclusion criteria were age younger than 16 years, fracture of the condylar base or neck, and displacement of the fracture by at least 45 degrees . Fractures were classified using conventional radiography, cone-beam computed tomography, or computed tomography. Patients underwent transoral endoscopically assisted open reduction and fixation using miniplate osteosynthesis. Postoperatively, patients were followed clinically and radiographically for 18 months. RESULTS: Complete follow-up varied from 18 to 35 months (median, 24.5 months). All patients showed normal occlusion and pain-free unrestricted function of the temporomandibular joint at 3, 6, 12, and 18 months postoperatively. There were no signs of incomplete remodeling or deformation of the condyles. CONCLUSION: Transoral endoscopically assisted surgical treatment of severely displaced condylar base and neck fractures in children and young teenagers offers a reliable solution to preclude the sequelae of closed treatment, such as altered morphology and functional disturbances, eliminates visible scars, and lowers the risk of facial nerve damage compared with open reduction using an extraoral approach. PMID- 23806736 TI - The effect of alpha-cyclodextrin on postprandial lipid and glycemic responses to a fat-containing meal. AB - OBJECTIVE: alpha-Cyclodextrin (alpha-CD), a soluble dietary fiber derived from corn, marketed under the trade name FBCx(r), has the potential to help individuals manage their weight and improve their lipid profiles. Initial studies in healthy overweight and/or obese diabetic individuals found that, in those consuming a normal to high fat diet over a 4 or 12 week period, alpha-CD use was associated with weight loss or maintenance and a reduction in triglyceride (TG) and cholesterol levels in hyperlipidemic individuals. Furthermore, alpha-CD use was associated with the positive effects of increasing insulin and leptin sensitivities. To date, the immediate post-prandial glucose and lipid responses to a fat-containing meal have not been reported. MATERIALS/METHOD: This double blinded placebo controlled cross-over trial examined the effect of 2 g of alpha CD taken immediately following consumption of a commercially prepared high-fat breakfast meal on the acute postprandial responses in healthy adults. RESULTS: The coincidental consumption of alpha-CD with a fat-containing meal was associated with a significant reduction in postprandial TG responses over time when compared to placebo. When incremental area under the curve was calculated, the area under the curve associated with alpha-CD consumption was significantly smaller than the Placebo area (0.30+/-1.07 mmol/L/3 h vs. 0.98+/-0.88 mmol/L/3 h, p<0.05). There were no significant changes in glucose or cholesterol levels. CONCLUSION: alpha-Cyclodextrin was shown to significantly lower acute postprandial blood triglyceride levels. PMID- 23806737 TI - Coexistence of Graves' disease, papillary thyroid carcinoma and unilateral benign struma ovarii: case report and review of the literature. AB - BACKGROUND: Struma ovarii is a rare cause of hyperthyroidism, while coexistence with Graves' disease has been scarcely reported. PATIENT FINDINGS: We report a patient with Graves' disease and unilateral benign functioning struma ovarii, accompanied by ascites, pleural effusion and elevated cancer antigen-125 (CA-125) levels. In subsequent thyroidectomy, incidental papillary thyroid carcinoma was also identified. The functionality of struma ovarii tissue in our patient was supported by the immunohistochemical identification of TSH receptors (TSHR), which may stimulate growth and thyroid hormone production in the presence of circulating TSHR stimulating antibodies (TSHR-Ab). REVIEW OF THE LITERATURE: A systematic review of reported cases of coexistent Graves' disease and struma ovarii was performed. CONCLUSIONS: The diagnosis of struma ovarii may be masked by Graves' disease and, therefore, be delayed for several years. Furthermore, ascites, pleural effusion and increased CA-125 may result from a benign struma ovarii. The presence of TSHR in the struma ovarii tissue along with their absence in the surrounding ovarian tissue indirectly suggests that struma ovarii is functional. It is unclear whether TSHR-Ab play a role in the development of thyroid carcinomas in such patients. PMID- 23806738 TI - What, not just salad and veg? Consumer testing of the eatwell week. AB - OBJECTIVE: To test the appeal of the eatwell week, a nutritionally balanced 7 d menu which satisfies nutritional guidelines of the Food Standards Agency in Scotland; determine the clarity and understanding of the main messages; and gather views on the usability and acceptability of the eatwell week resource format. DESIGN: Focus group discussions with consumers and health professionals. SETTING: Four locations across the UK. RESULTS: The eatwell week was considered realistic by consumers as it contained foods they recognised and already ate. A preconceived idea had been that there would be more fruit and vegetables and fewer 'treats'. Consumers found the recipes simple and lack of cooking skills was not an apparent barrier. However, the message of 'balance' was poorly understood. Consumers often lacked the knowledge to make informed substitutions in the week. Both the general public and some health professionals felt the menu contained too much carbohydrate. Health professionals felt it was unclear who the eatwell week was intended for and what purpose it served. CONCLUSIONS: Use of familiar foods and the provision of simple, easy-to-follow recipes have the potential to overcome some barriers to healthy eating encountered by the general public and encourage improvements in dietary intakes. The eatwell week shows promise as a resource to facilitate implementation of the principles of the eatwell plate and supports government priorities and policies for health. PMID- 23806739 TI - Interactions between ADIPOQ gene variants and dietary monounsaturated: saturated fatty acid ratio on serum lipid levels in Korean children. AB - BACKGROUND AND AIMS: Adiponectin plays important roles in the regulation of insulin action and metabolism of glucose and lipids. We investigated whether ADIPOQ genetic variants are associated with serum lipid levels in Korean children and whether those influences might be modulated by dietary factors such as dietary monounsaturated fatty acid to saturated fatty acid ratio (MUFA:SFA). METHOD AND RESULTS: The study included a population-based sample of 687 children aged 7-11 years in Gwacheon city, Kyunggi Province, Korea. Anthropometric and biochemical measurements and ADIPOQ genotype (-11377 C/G, +45 T/G, and +276 G/T) were determined. Dietary intake was estimated with a self reported 3-day food diary. The -11377 G allele carriers had significantly higher serum total cholesterol and LDL cholesterol compared to non-carriers. When dietary MUFA:SFA ratio was dichotomized (MUFA:SFA >= 1 or <1), the aggravating effects of the minor allele on serum total and LDL cholesterol were only present when the MUFA:SFA ratio was <1. Additionally, we observed that the ADIPOQ haplotype influenced serum total and LDL cholesterol levels. G-T-G haplotype carriers had higher total and LDL cholesterol levels than non-G-T-G carriers. The deleterious effect of ADIPOQ G-T-G haplotype to increase serum total and LDL cholesterol could be seen only when the MUFA:SFA ratio was <1. CONCLUSION: In this present study, we found interaction effects between ADIPOQ genetic variants and dietary MUFA:SFA ratio on serum lipid levels in Korean children. These results suggest that individual genetic information and dietary fatty acid intake information should be assessed together to achieve an effective outcome for reducing the atherogenic lipid profile. PMID- 23806740 TI - Lower incidence of macrovascular complications in patients on insulin glargine versus those on basal human insulins: a population-based cohort study in Italy. AB - BACKGROUND AND AIM: The aim of this study was to compare the use of insulin glargine and intermediate/long-acting human insulin (HI) in relation to the incidence of complications in diabetic patients. METHODS AND RESULTS: A population-based cohort study was conducted using administrative data from four local health authorities in the Abruzzo Region (900,000 inhabitants). Diabetic patients without macrovascular diseases and treated with either intermediate/long acting HI or glargine were followed for 3-years; the incidence of diabetic (macrovascular, microvascular and metabolic) complications was ascertained by hospital discharge claims and estimated using Cox proportional hazard models. Propensity score (PS) matching was also used to adjust for significant differences in the baseline characteristics between the two groups. RESULTS: Overall, 1921 diabetic patients were included: 744 intermediate/long-acting HI and 1177 glargine users. During the 3-year follow-up, 209 (28.1%) incident events of any diabetic complication occurred in the intermediate/long-acting HI and 159 (13.5%) in the glargine group. After adjustment for covariates, glargine users had an HR (95% CI) of 0.57 (0.44-0.74) for any diabetic complication and HRs of 0.61 (0.44-0.84), 0.58 (0.33-1.04) and 0.35 (0.18-0.70) for macrovascular, microvascular and metabolic complications, respectively, compared to intermediate/long-acting HI users. PS analyses supported these findings. CONCLUSIONS: The use of glargine is associated with a lower risk of macrovascular complications compared with traditional basal insulins. However, limitations inherent to the study design including the short length of observation and the lack of data on metabolic control or diabetes duration, do not allow us to consider this association as a proof of causality. PMID- 23806741 TI - Sub-labial packing: a novel method of stopping epistaxis from Little's area. AB - Epistaxis is frequently managed both by patients in the community and by health professionals. Many methods have been described in the literature about how to manage this condition. Epistaxis is usually due to anterior circulation bleeding at an area known as Kiesselbach's plexus (Little's area). Five vessels supply Little's area; one of these, the septal branch of the superior labial artery, can be compressed via an easy and novel technique, sub-labial packing. Sub-labial packing is a technique proposed as an adjunct to the standard 15 min ala nasi compression as a simple yet effective technique to stop epistaxis. We hereby report two cases of managing epistaxis from Little's area using sub-labial packing. PMID- 23806742 TI - Validation of the Mandarin version of the LittlEARS(r) Auditory Questionnaire. AB - OBJECTIVES: To evaluate the psychometric properties of the Mandarin version of the LittlEARS((r))Auditory Questionnaire and to compare the parameters with those of the original German version of the questionnaire. The results would indicate whether the Mandarin version of the questionnaire can be applied in Mandarin speaking children or not. METHODS: A "back-translation" method was used to translate and adapt the LittlEARS((r)) Auditory Questionnaire into Mandarin. A group of 157 Mandarin speaking parents of children below 24 months of age with normal hearing completed the LittlEARS((r)) Auditory Questionnaire. Various psychometric analyses (scale analysis and item analysis) were conducted and compared with the original German version. RESULTS: The following scale characteristics were found with the above sample: internal consistency: Cronbach's alpha = 0.945; reliability: split-half r = 0.914; predictive accuracy: Guttman's lambda = 0.882; correlation between overall score and age of the children: r = 0.841. Several parameters (correlation between age and item score, index of difficulty, discrimination coefficient) of each item were also calculated. The regression curve, which reflects the age-dependence of auditory behavior, was produced. All parameters above had no significant differences with the corresponding ones of the original German version. Standardized values (expected and minimum values) of the Mandarin LittlEARS((r)) Auditory Questionnaire were provided. CONCLUSION: The Mandarin version of the LittlEARS((r)) Auditory Questionnaire is reliable and valid as a sensitive tool to assess the development of auditory behavior in Mandarin speaking children up to 24 months of age. The Mandarin standardized values are helpful for clinicians to reach a preliminary judgment in children's hearing screening or for parents to monitor the auditory development of their hearing-impaired children. PMID- 23806743 TI - Differences in access to healthcare and utilisation of HIV and sexually transmissible infection services between men who have sex with men and men who have sex only with women: results of the 2006-10 National Survey of Family Growth in the United States. AB - Background Men who have sex with men (MSM) experience disparities in access to healthcare and have specific healthcare needs. METHODS: We analysed data from the 2006-10 National Survey of Family Growth (NSFG) to examine differences in access to healthcare and HIV and sexually transmissible infection (STI) related health services by MSM and non-MSM among men in the United States aged 15-44 years who have ever had sex. MSM and sexually active MSM were identified in the NSFG as men who had ever had oral or anal sex with another man, or who had sex in the past 12 months with another man, respectively. Access was measured by the type of health insurance, having a usual place for receiving healthcare and type of usual place. RESULTS: Of men aged 15-44 years who have ever had sex, there were no significant differences between MSM and non-MSM in the three access measures. MSM were more likely than non-MSM to receive HIV counselling (22.5% v. 8.3%) and STI testing (26.2% v. 15.6%) in the past 12 months, or to ever have had HIV testing (67.8% v. 44.6%). STI testing in the past 12 months was reported by 38.7% of sexually active MSM. CONCLUSION: Our findings show no significant differences in access to healthcare between MSM and non-MSM. MSM were more likely to receive HIV- and STI related preventive services than non-MSM. However, the low STI testing rate among MSM highlights the need for interventions to increase STI testing, and HIV and STI counselling for MSM. PMID- 23806744 TI - Horizontal and vertical eye movement metrics: what is important? AB - OBJECTIVE: To assist other eye movement investigators in the design and analysis of their studies. METHODS: We examined basic saccadic eye movements and smooth pursuit in the horizontal and vertical directions with video-oculography in a group of 145 healthy subjects between 19 and 82 years of age. RESULTS: Gender and education level did not influence eye movement metrics. With age, the latency of leftward and vertical pro- and antisaccades increased (p<0.001), velocity of upward prosaccades decreased (p<0.001), gain of rightward and upward prosaccades diminished (p<0.001), and the error rate of antisaccades increased (p<0.001). Prosaccades and antisaccades were influenced by the direction of the target, resulting in a right/left and up/down asymmetry. The skewness of the saccade velocity profile was stable throughout the lifespan, and within the range of saccades analyzed in the present study, correlated with amplitude and duration only for antisaccades (p<0.001). CONCLUSIONS: Some eye movement metrics must be separated by the direction of movement, others according to subject age, while others may be pooled. SIGNIFICANCE: This study provides important information for new oculomotor laboratories concerning the constitution of subject groups and the analysis of eye movement metrics. PMID- 23806745 TI - Presence of Ostertagia ostertagi antibodies in bulk tank milk from cattle herds in northern Spain. AB - The objective of this survey was to investigate the Ostertagia ostertagi infection status of cattle dairy herds from northern Spain through measurement of antibody concentration in the bulk tank milk (BTM). In addition, management and performance data were collected to determine possible relationships with BTM O. ostertagi antibody levels. BTM samples were collected in 118 dairy cattle farms from five northern Spain Autonomic Communities in the autumn of 2009 and spring of 2010. The O. ostertagi antibody levels in milk were determined using a commercial ELISA kit (Svanovir) and farm management information included type and farm size, production level, access to pasture, grazing regime and anthelmintic treatments. The overall mean optical density ratio (ODR) values of the two sampling times ranged from 0.60 (0.08-1.32) in autumn to 0.56 (0.05-1.24) in spring and no seasonal differences were detected. Herds with access to pasture showed significantly higher titers of O. ostertagi antibodies in milk (mean ODR=0.69-0.63) than in those without access (mean ODR=0.36-0.33). The association analyses showed significant correlations between the BTM O. ostertagi ODR and location (Navarra showed the highest ODR values), herd size (ODR decreased with increased herd size), milk production level (ODR negatively associated with milk yield), calves access to pasture (higher ODR when calves <12 months had access to pasture), outside access (no access low ODR, access high ODR) and grazing management (ODR increased proportionally to the percentage of time spent grazing each day). This study emphasizes that O. ostertagi-induced production losses should be considered on dairy farms in northern Spain. Additionally, putative risk-factors should be also considered for preventive measures. PMID- 23806746 TI - Alaria alata mesocercariae in wild boar (Sus scrofa, Linnaeus, 1758) in south regions of the Czech Republic. AB - From March 2012 to February 2013, 221 wild boar carcasses obtained from regular hunts in the Czech Republic were tested for Alaria alata mesocercariae using the Alaria-migration-technique. Most samples originated from South Moravia (173), and all 15 positive samples were found in this region, in particular in Tvrdonice (3/10) and Lanzhot (12/28), close to the site of the first description of this parasitic stage in wild boars in the territory of former CSSR. These hunting grounds are located between the rivers March and Thaya, and rich in floodplains. Among the 38 carcasses tested in this area, higher carcass weights were associated with higher frequency of positive carcasses (P<0.05). Overall frequency of positive carcasses was 15/221 (6.8%). In positive samples (adipose and glandular tissue and muscle), the median number of mesocercariae was 14.3 per 100 g (range 3-69). PMID- 23806747 TI - The association between Ostertagia ostertagi antibodies in bulk tank milk samples and parameters linked to cattle reproduction and mortality. AB - In Western Europe, gastrointestinal nematodes are widespread in dairy cattle. This study was carried out to evaluate the relationship between optical density ratio (ODR) measured on bulk tank milk with an indirect Ostertagia ostertagi ELISA and reproduction/mortality parameters. Data were collected between 2008 and 2010 from monitoring carried out on 1643 dairy herds (Normandy, Western France). ODR values of 3 samples from each farm taken from November 2008 to 2010 were averaged and then transformed into a categorical variable. Reproductive and mortality data were obtained from 1444 herds using cow records from government databases. Statistical analysis was carried out using ordinary logistic regression (OLR). The outcome variables were the case-control status of a herd for reproductive factors, age at first calving and inter-calving intervals, and mortality ratios of various age classes. The effect of the categorical ODR variable was studied and several potential confounder herd factors were used to improve the model fit. A significant relationship was found between high Ostertagia ODR levels and a late age at the first calving (>34.5 months) (odds ratio (OR)=1.94, p<0.001). No significant relationship was observed with OLR for inter-calving intervals although bivariate analysis showed that herds with high ODR levels had longer inter-calving intervals than herds with low ODR level (first inter-calving interval in herds with low vs. high ODR levels=412 days vs. 422 days, p<0.001; other inter-calving intervals=408 days vs. 413 days, p<0.01). A high ODR level was also associated with high mortality of calves between 0 and 30 days of life (mortality ratio>6%) (OR=1.43, p<0.05) and between 91 and 365 days (ratio>3%) (OR=1.72, p<0.01). No significant relationship was observed with multivariate approach for mortalities in other classes by age, but bivariate analysis showed that herds with high ODR level had higher mortalities than herds with low ODR levels (mortality between 31 and 90 days in herds with low vs. high ODR levels=1.89% vs. 2.91%, p<0.001; mortality after 365 days=1.67% vs. 2.93%, p<0.001). In conclusion, our results confirm the usefulness of ELISA as an indicator for production losses in dairy herds. This inexpensive tool could be advantageous, used to aid farmers and veterinarians to carry out appropriate control measures. PMID- 23806748 TI - June is the cruelest month. PMID- 23806749 TI - On the potential role of active DNA demethylation in establishing epigenetic states associated with neural plasticity and memory. AB - Dynamic variations in DNA methylation regulate neuronal gene expression in an experience-dependent manner. Although DNA methylation has been implicated in synaptic plasticity, learning and memory, active DNA demethylation is also induced by learning, which suggests that an interaction between the two processes is necessary for cognitive function. Active DNA demethylation is a complex process involving a variety of proteins and epigenetic regulatory enzymes, the understanding of which with respect to its role in the adult brain is in its infancy. We here provide an overview of the current understanding of active DNA demethylation, and describe how this process may establish persistent epigenetic states that are associated with neural plasticity and memory formation. PMID- 23806750 TI - Allostatic load and socioeconomic status in Polish adult men. AB - This study considers the relationship between a cumulative index of biological dysregulation (allostatic load) and several dimensions of socioeconomic status (SES) and lifestyle in adult Polish males. The extent to which lifestyle variables can explain SES variation in allostatic load was also evaluated. Participants were 3887 occupationally active men aged 25-60 years living in cities and villages in the Silesia region of Poland. The allostatic load indicator included eleven markers: % fat (adverse nutritional intake), systolic and diastolic blood pressures (cardiovascular activity), FEV1 (lung function), erythrocyte sedimentation rate (inflammatory processes), glucose and total cholesterol (cardiovascular disease risk), total plasma protein (stress haemoconcentration), bilirubin, creatinine clearance and alkaline phosphatase activity (hepatic and renal functions). A higher level of completed education, being married and residing in an urban area were associated with lower physiological dysregulation. The association between indicators of SES and allostatic load was not eliminated or attenuated when unhealthy lifestyle variables were included in the model. Smoking status and alcohol consumption played minimal roles in explaining the association between SES and allostatic load; physical activity, however, had a generally protective effect on allostatic load. PMID- 23806751 TI - The role of death-associated protein kinase (DAPK) in endothelial apoptosis under fluid shear stress. AB - Endothelial cells are the interface between hemodynamic fluid flow and vascular tissue contact. They actively translate physical and chemical stimuli into intracellular signaling cascades which in turn regulate cell function, and endothelial dysfunction leads to inflammation and diseased conditions. For example, atherosclerosis, a chronic vascular disease, favorably develops in regions of disturbed fluid flow and low shear stress. Apoptosis, or programmed cell death, must be properly regulated to maintain homeostasis in the vascular wall. The loss of apoptosis control, as seen in low shear stress regions, is implicated in various diseases such as atherosclerosis and cancer. Death associated protein kinase (DAPK) is a pro-apoptotic regulator for various cell types that is localized in the cell cytoskeleton and regulates changes in cytoplasm associated with apoptosis. Yet its role in endothelial cells remains unclear. Laminar shear stress inhibits cytokine, oxidative stress, and serum starvation induced endothelial apoptosis, while extended shearing elicit structural changes and cell alignment. We hypothesize that DAPK potentially plays a role in attenuating endothelial apoptosis in response to shear stress. We found that shear stress regulates DAPK expression and apoptotic activity in endothelial cells. In fact, shear stress alone induces DAPK and apoptosis, but has the opposite effect in the presence of apoptotic triggers such as tissue necrosis factor alpha (TNFalpha). This review summarizes mechanisms of endothelial mechanotransduction and apoptosis, and explores the potential of DAPK as a novel signaling pathway involved in mediating protective effects of shear stress on the vasculature. PMID- 23806752 TI - Disturbance of redox homeostasis by ornithine and homocitrulline in rat cerebellum: a possible mechanism of cerebellar dysfunction in HHH syndrome. AB - AIMS: Cerebellar ataxia is commonly observed in hyperornithinemia-hyperammonemia homocitrullinuria (HHH) syndrome, an inherited metabolic disorder biochemically characterized by ornithine (Orn), homocitrulline (Hcit) and ammonia accumulation. Since the pathophysiology of cerebellum damage in this disorder is still unknown, we investigated the effects of Hcit and Orn on important parameters of redox and energy homeostasis in cerebellum of young rats. MATERIAL AND METHODS: We determined thiobarbituric acid-reactive substance (TBA-RS) levels, carbonyl content, nitrate and nitrite production, hydrogen peroxide production, GSH concentrations, sulfhydryl content, as well as activities of respiratory chain complexes I-IV, creatine kinase, Na(+),K(+)-ATPase, aconitase and alpha ketoglutarate dehydrogenase. KEY FINDINGS: Orn and Hcit significantly increased TBA-RS levels (lipid oxidation), that was totally prevented by melatonin and reduced glutathione (GSH). We also found that nitrate and nitrite production was not altered by any of the metabolites, in contrast to hydrogen peroxide production which was significantly enhanced by Hcit. Furthermore, GSH concentrations were significantly reduced by Orn and Hcit and sulfhydryl content by Orn, implying an impairment of antioxidant defenses. As regards energy metabolism, Orn and Hcit provoked a significant reduction of aconitase activity, without altering the other parameters. Furthermore, Orn-elicited reduction of aconitase activity was totally prevented by GSH, indicating that the critical groups of this enzyme were susceptible to oxidation caused by this amino acid. SIGNIFICANCE: Taken together, our data indicate that redox homeostasis is disturbed by the major metabolites accumulating in HHH syndrome and that this mechanism may be implicated in the ataxia and cerebellar abnormalities observed in this disorder. PMID- 23806753 TI - Effect of transient vascular occlusion of the upper arm on motor evoked potentials during force exertion. AB - We previously observed that transient vascular occlusion in volunteers increased the estimation of force exertion with no change in peripheral nerves or muscles. We hypothesized that the primary factor responsible for the overestimation of force exertion during occlusion was the centrally generated motor command, as hypothesized by McCloskey et al. (1974) and McCloskey (1978, 1981). In the present study, we tested the hypothesis that transient vascular occlusion increases the excitability of the primary motor cortex (M1) during force exertion. Healthy human volunteers lay on a bed and squeezed a dynamometer in their right hand. Repetitive gripping forces were exerted at 20%, 40%, or 60% of maximum force, with or without transient (20s) vascular occlusion of the proximal portion of the right upper arm. During the task, single-pulse transcranial magnetic stimulation was applied to the contralateral M1 to induce motor evoked potentials (MEPs) in the flexor carpi ulnaris (FCU) muscle. The MEP amplitudes were enhanced with occlusion under all conditions, with the exception of 60% contraction. In contrast, no significant difference was observed between the MEP amplitudes obtained from the occluded or non-occluded, relaxed FCU muscle. These results suggest that transient vascular occlusion increases the excitability of M1 only during force exertion. PMID- 23806754 TI - Neurological and psychological applications of transcranial lasers and LEDs. AB - Transcranial brain stimulation with low-level light/laser therapy (LLLT) is the use of directional low-power and high-fluency monochromatic or quasimonochromatic light from lasers or LEDs in the red-to-near-infrared wavelengths to modulate a neurobiological function or induce a neurotherapeutic effect in a nondestructive and non-thermal manner. The mechanism of action of LLLT is based on photon energy absorption by cytochrome oxidase, the terminal enzyme in the mitochondrial respiratory chain. Cytochrome oxidase has a key role in neuronal physiology, as it serves as an interface between oxidative energy metabolism and cell survival signaling pathways. Cytochrome oxidase is an ideal target for cognitive enhancement, as its expression reflects the changes in metabolic capacity underlying higher-order brain functions. This review provides an update on new findings on the neurotherapeutic applications of LLLT. The photochemical mechanisms supporting its cognitive-enhancing and brain-stimulatory effects in animal models and humans are discussed. LLLT is a potential non-invasive treatment for cognitive impairment and other deficits associated with chronic neurological conditions, such as large vessel and lacunar hypoperfusion or neurodegeneration. Brain photobiomodulation with LLLT is paralleled by pharmacological effects of low-dose USP methylene blue, a non-photic electron donor with the ability to stimulate cytochrome oxidase activity, redox and free radical processes. Both interventions provide neuroprotection and cognitive enhancement by facilitating mitochondrial respiration, with hormetic dose response effects and brain region activational specificity. This evidence supports enhancement of mitochondrial respiratory function as a generalizable therapeutic principle relevant to highly adaptable systems that are exquisitely sensitive to energy availability such as the nervous system. PMID- 23806755 TI - Wandering abdominal pain due to a floating gallbladder. PMID- 23806756 TI - A multi-scale strategy for discovery of novel endogenous neuropeptides in the crustacean nervous system. AB - The conventional mass spectrometry (MS)-based strategy is often inadequate for the comprehensive characterization of various size neuropeptides without the assistance of genomic information. This study evaluated sequence coverage of different size neuropeptides in two crustacean species, blue crab Callinectes sapidus and Jonah crab Cancer borealis using conventional MS methodologies and revealed limitations to mid- and large-size peptide analysis. Herein we attempt to establish a multi-scale strategy for simultaneous and confident sequence elucidation of various sizes of peptides in the crustacean nervous system. Nine novel neuropeptides spanning a wide range of molecular weights (0.9-8.2kDa) were fully sequenced from a major neuroendocrine organ, the sinus gland of the spiny lobster Panulirus interruptus. These novel neuropeptides included seven allatostatin (A- and B-type) peptides, one crustacean hyperglycemic hormone precursor-related peptide, and one crustacean hyperglycemic hormone. Highly accurate multi-scale characterization of a collection of varied size neuropeptides was achieved by integrating traditional data-dependent tandem MS, improved bottom-up sequencing, multiple fragmentation technique-enabled top-down sequencing, chemical derivatization, and in silico homology search. Collectively, the ability to characterize a neuropeptidome with vastly differing molecule sizes from a neural tissue extract could find great utility in unraveling complex signaling peptide mixtures employed by other biological systems. BIOLOGICAL SIGNIFICANCE: Mass spectrometry (MS)-based neuropeptidomics aims to completely characterize the neuropeptides in a target organism as an important first step toward a better understanding of the structure and function of these complex signaling molecules. Although liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) with data-dependent acquisition is a powerful tool in peptidomic research, it often lacks the capability for de novo sequencing of mid size and large peptides due to inefficient fragmentation of peptides larger than 4kDa. This study describes a multi-scale strategy for complete and confident sequence elucidation of various sizes of neuropeptides in the crustacean nervous system. The aim is to fill a technical gap where the conventional strategy is inefficient for comprehensive characterization of a complex neuropeptidome without assistance of genomic information. Nine novel neuropeptides in a wide range of molecular weights (0.9-8.2kDa) were fully sequenced from a major neuroendocrine organ of the spiny lobster, P. interruptus. The resulting molecular information extracted from such multi-scale peptidomic analysis will greatly accelerate functional studies of these novel neuropeptides. PMID- 23806758 TI - Peptides with angiotensin I converting enzyme (ACE) inhibitory activity generated from porcine skeletal muscle proteins by the action of meat-borne Lactobacillus. AB - Angiotensin I converting enzyme (ACE) inhibitory activity of peptides derived from the hydrolysis of sarcoplasmic and myofibrillar porcine proteins by the action of Lactobacillus sakei CRL1862 and Lactobacillus curvatus CRL705 (whole cells+cell free extracts) was investigated at 30 degrees C for 36 h. The protein hydrolysates were subjected to RP-HPLC in order to fractionate the extracts for further evaluation of ACE inhibitory activity. Bioactive fractions were only found from the hydrolysis of sarcoplasmic proteins by both assayed lactobacilli strains. Identification of peptides contained in the bioactive fractions was carried out by tandem mass spectrometry using a nanoLC-ESI-QTOF instrument and the mascot search engine. From the four most active fractions obtained, a total of eighteen and fifty peptides were characterized from L. sakei CRL1862 and L. curvatus CRL705 protein hydrolysates, respectively. The sequence FISNHAY was generated by the proteolytic activity of the two lactobacilli species. Sequence similarity analyses between the peptides identified in this study and those previously identified as ACE inhibitory peptides and detailed in the BIOPEP database were outlined. Results suggest that meat-borne Lactobacillus were able to generate peptides with ACE inhibitory activity, highlighting their potential to be used in the development of functional fermented products. BIOLOGICAL SIGNIFICANCE: The results of this study would enable the obtention of porcine functional foods by applying lactic acid bacteria generating bioactive peptides. ACE inhibitory peptides obtained by the hydrolytic action of L. curvatus CRL705 and L. sakei CRL1862 on sarcoplasmic proteins were analyzed. Among them, the peptide FISNHAY exhibited the highest activity and its sequence has not yet been reported. PMID- 23806757 TI - Differential expression of proteins in naive and IL-2 stimulated primary human NK cells identified by global proteomic analysis. AB - Natural killer (NK) cells efficiently cytolyse tumors and virally infected cells. Despite the important role that interleukin (IL)-2 plays in stimulating the proliferation of NK cells and increasing NK cell activity, little is known about the alterations in the global NK cell proteome following IL-2 activation. To compare the proteomes of naive and IL-2-activated primary NK cells and identify key cellular pathways involved in IL-2 signaling, we isolated proteins from naive and IL-2-activated NK cells from healthy donors, the proteins were trypsinized and the resulting peptides were analyzed by 2D LC ESI-MS/MS followed by label free quantification. In total, more than 2000 proteins were identified from naive and IL-2-activated NK cells where 383 proteins were found to be differentially expressed following IL-2 activation. Functional annotation of IL-2 regulated proteins revealed potential targets for future investigation of IL-2 signaling in human primary NK cells. A pathway analysis was performed and revealed several pathways that were not previously known to be involved in IL-2 response, including ubiquitin proteasome pathway, integrin signaling pathway, platelet derived growth factor (PDGF) signaling pathway, epidermal growth factor receptor (EGFR) signaling pathway and Wnt signaling pathway. BIOLOGICAL SIGNIFICANCE: The development and functional activity of natural killer (NK) cells is regulated by interleukin (IL)-2 which stimulates the proliferation of NK cells and increases NK cell activity. With the development of IL-2-based immunotherapeutic strategies that rely on the IL-2-mediated activation of NK cells to target human cancers, it is important to understand the global molecular events triggered by IL-2 in human NK cells. The differentially expressed proteins in human primary NK cells following IL-2 activation identified in this study confirmed the activation of JAK-STAT signaling pathway and cell proliferation by IL-2 as expected, but also led to the discovery and identification of other factors that are potentially important in IL-2 signaling. These new factors warrant further investigation on their potential roles in modulating NK cell biology. The results from this study suggest that the activation of NK cells by IL-2 is a dynamic process through which proteins with various functions are regulated. Such findings will be important for the elucidation of molecular pathways involved in IL-2 signaling in NK cells and provide new targets for future studies in NK cell biology. PMID- 23806759 TI - Genome-wide identification and comparative expression analysis of NBS-LRR encoding genes upon Colletotrichum gloeosporioides infection in two ecotypes of Fragaria vesca. AB - Anthracnose caused by Colletotrichum spp. is one of the most destructive diseases of cultivated strawberry (Fragaria*ananassa Duchesne) worldwide. The correlation between NBS-LRR genes, the largest class of known resistance genes, and strawberry anthracnose resistance has been elusive. BLAST search in NCBI identified 94 FvNBSs in the diploid genome of strawberry Fragaria vesca, with 67 of the TIR-NBS-LRR type. At least 36 FvNBSs were expressed, with 25% being non coding genes. Two F. vesca ecotypes, HLJ and YW, showed great variations in both morphological and physiological responses upon C. gloeosporioides infection. qRT PCR revealed that 5 of the 12 leaf-expressed FvNBSs displaying opposite transcription responses to C. gloeosporioides infection in two ecotypes. These results showed that the transcriptional responses of several FvNBSs were involved in the ecotype-specific responses to C. gloeosporioides in F. vesca. These FvNBSs hold potential in characterizing molecular components and developing novel markers associated with anthracnose resistance in strawberry. PMID- 23806760 TI - Melanotic progonoma of temporal and occipital bones: A case report. AB - Melanotic progonoma is a rare tumor that primarily affects the maxilla of infants during the first year of life. Involvement in the skull is rare and can mimick other benign or malignant tumors affecting the infant's skull. The authors report a case of melanotic progonoma of right occipital and temporal bones in a 7 months' girl and discuss the histological features, immunohistochemistry study, differential diagnosis and management of this tumor. PMID- 23806762 TI - Eighteen cases of crowned dens syndrome: Presentation and diagnosis. AB - BACKGROUND AND PURPOSE: Crowned dens syndrome is an ill-known etiology of acute neck pain. METHODS: We carried out a retrospective study of 18 cases of patients with crowned dens syndrome, assessing clinical and radiological features. RESULTS: The results of our study are comparable to data from the literature. The clinical presentation of acute febrile neck pain, occipital headache and multidirectional stiff neck especially affects women aged over 60. No predisposing factor was recognized. However, a history of peripheral joint chondrocalcinosis may reinforce the diagnosis. In more than 50% of cases, laboratory tests showed a marked inflammatory syndrome. The diagnosis was obtained with cervical CT-scan focusing on the C1/C2 joint. This gold standard test was able to show a calcification of the cruciform ligament in connection with deposits of calcium pyrophosphate crystals in almost 80% of cases. Other imaging tests provided little information, including standard radiographs of the cervical spine. MRI can eliminate some differential diagnoses such as infections or neurological emergencies. Complications are infrequent. The standard treatment is based on anti-inflammatory drugs (NSAID, colchicine) or corticosteroids. These treatments are highly effective: a drammatic full recovery of cervical mobility may be observed within 48 hours. In over half of cases, a different diagnosis was initially made, responsible of unnecessary additional tests and treatment. CONCLUSION: A comprehensive consultation, a complete clinical examination and a precise analysis of the imaging will avoid certain investigations and rule out differential diagnoses. PMID- 23806761 TI - Distal middle cerebral artery aneurysm: A proposition of microsurgical management. AB - OBJECTIVES: Based on a cohort of patients treated on distal middle cerebral artery (MCA) aneurysm by microsurgical approach, the objectives were to assess the following: the postoperative functional outcome, study the causes of early neurological deterioration and to determine the predictive factors of favourable outcome. PATIENTS AND METHODS: From a neurovascular prospective database, this retrospective longitudinal study included all the patients treated for cerebral aneurysm located on the distal segment of the MCA over two decades (January 1990 December 2011). The patients were all treated by microsurgical clipping exclusion. Any aneurysm was associated to infectious angiopathy. Data were retrieved from the patient's medical charts. The outcome was analysed twice: during the immediate postoperative period and at 6 months according to the modified Rankin scale. The relative risk was estimated for each variable and the prognostic factors were assessed using a multivariate logistic regression model (P<0.05). RESULTS: Twenty-eight patients, mean age 40+/-13.3 years (median: 43 years; range 6-70 years) were divided into the ruptured group (n=20) and unruptured group (n=8). In the ruptured group, the initial clinical status was good (WFNS I-III) in 12 patients (60%) and poor in eight (40%) with an intracerebral haematoma (ICH) in 11 (55%). For both groups, the aneurysm location on the distal MCA decreased at a rate from 64.8% of the insular segment to 25% of the opercular then 10.7% to the cortical. During the hospital stay, neurological deterioration occurred in 16 patients (57.2%). The diagnosed causes were cerebral ischaemia in 10 (35.6%), initial ICH in three (10.7%), hydrocephalus in two (7.1%) and epilepsy in one (7.1%). At 6 months, a favourable outcome (mRS 0-2) was observed in 19 patients (68.1%), a definitive morbidity in seven (24.9%) and death in two (7.2%). Based on the prognostic factors, only the absence of immediate postoperative neurological deterioration was identified as significant for a favourable outcome. CONCLUSION: These rare cerebral aneurysms resulted in a high proportion of poor initial status related to a frequent ICH. Cerebral ischaemia was a major cause of the immediate neurological deterioration and the absence of immediate neurological deterioration was the single identified prognostic factor. PMID- 23806763 TI - Renal carcinoma relapse presenting as a peripheral nerve sheath tumor: A case report and brief review of the literature. AB - We report a rare case of renal carcinoma metastasis involving a lumbar nerve root. Metastases to nerve roots are rare occurrences, and to our knowledge, only six cases have been reported so far in the literature. The patient in this report presented with weakness in the right lower limb and intractable pain irradiating along the L5 dermatome. MRI findings revealed a right-sided L5 nerve root mass, suggestive of a schwannoma, involving the spinal ganglion and its extraforaminal region. Complete macroscopic resection of this mass was performed, and histopathologic analysis confirmed the lesion to be a metastasis of a renal clear cell carcinoma. Local radiotherapy was given and tyrosine kinase inhibitors administered. At 5 months, the patient was pain-free and his right limb weakness had completely resolved. A tumoral recurrence could be observed on the control MRI 5 months after surgery. This report presents the first case of a patient with a renal clear cell carcinoma metastasis to a L5 nerve root, as well as a brief review of previous cases of metastases to peripheral nerve roots. PMID- 23806764 TI - [Intracranial dural arteriovenous fistula with perimedullary venous drainage: Anatomical, clinical and therapeutic considerations about one case, and review of the literature]. AB - Intracranial dural arteriovenous fistulae with perimedullary venous drainage are unusual type of vascular brain malformations. Patients may present with a rapidly progressive ascending myelopathy associated with autonomic dysfunction, which can cause a misdiagnosis and delay the therapeutic management. These clinical signs must be quickly recognized to avoid a poor outcome. The authors report the case of a 60-year-old woman presenting with a progressive myelopathy due to a dural arteriovenous fistula with perimedullary venous drainage. The diagnosis was suspected on brain-spinal MRI and confirmed by brain arteriography visualizing the arteriovenous shunt in the middle segment of the superior petrous sinus. MRI showed edema in the medulla oblongata. The treatment was performed early by endovascular glue embolization of the arteriovenous shunt and of the origin of the vein. Brain arteriography and clinical follow-up, one month later, showed complete disappearance of the dural fistula and regression of clinical symptoms. MRI control showed the reduction of the brain stem edema. Because of the early pejorative prognosis of these kinds of fistulae, early diagnosis and treatment are needed. PMID- 23806765 TI - Ten misconceptions about antioxidants. AB - Oxidative damage is a common cellular event involved in numerous diseases and drug toxicities. Antioxidants prevent or delay oxidative damage, and therefore there has been extensive research into the discovery of natural and newly designed antioxidants. Initial excitement regarding the potential health benefits of antioxidants has diminished. Currently, it is even claimed that antioxidants increase mortality. The antioxidant pendulum appears to swing from healthy to toxic and from general panacea to insignificant ingredient. Owing to the polarity of views towards antioxidants, nutritional recommendation ranges from advice to increase antioxidant status in plasma to the notion that it is a useless measurement. Such views, lacking sufficient scientific support, lead to misconceptions, which in our opinion hinder the rational use of food supplements and impedes the design and development of new antioxidant drugs. As a result, good opportunities might easily be missed. PMID- 23806766 TI - Prevalence and severity of household food insecurity of First Nations people living in an on-reserve, sub-Arctic community within the Mushkegowuk Territory. AB - OBJECTIVE: To measure and describe the prevalence and severity of household food insecurity in a remote on-reserve First Nations community using the Household Food Security Survey Module (HFSSM) and to evaluate the perceived relevance of the HFSSM for this population. DESIGN: Household food security status was determined from the eighteen-item HFSSM following the classifications developed by Health Canada for the Canadian Community Health Survey, Cycle 2.2 Nutrition. One adult from each household in the community was invited to complete the HFSSM and to comment on its relevance as a tool to measure food security for First Nations communities. SETTING: Sub-Arctic Ontario, Canada. SUBJECTS: Households (n 64). RESULTS: Seventy per cent of households were food insecure, 17% severely and 53% moderately. The prevalence of food insecurity in households with children was 76%. Among respondents from homes rated as having severe food insecurity, all (100 %) reported worrying that food would run out, times when food didn't last and there wasn't money to buy more, and times when they couldn't afford to eat balanced meals. The majority of respondents felt the HFSSM did not capture an accurate picture of food security for their situation. Aspects missing from the HFSSM included the high cost of market food and the incorporation of traditional food practices. CONCLUSIONS: A high prevalence of household food insecurity was reported in this community. On-reserve remote First Nations communities may be more susceptible to food insecurity than off-reserve Aboriginal populations. Initiatives that promote food security for this vulnerable population are needed. PMID- 23806767 TI - Femoral trochlear dysplasia after patellar dislocation in rabbits. AB - BACKGROUND: The aim of this study was to investigate the effects of patellar dislocation on the development of the trochlear groove in rabbits. METHODS: Eighty knees from forty one-month-old white rabbits were divided into three groups (sham surgery, experimental, control). Lateral patellar dislocation was established in the experimental group and the effect on the development of the trochlear groove was compared with that in the sham surgery and control groups. Computed tomography (CT) scans were conducted to measure the angle, width and depth of the trochlear groove one month and six months after surgery. Gross specimen examination, cross-sectional anatomy and histological observation were conducted to investigate the anatomical configuration of the femoral trochlea and the changes in cartilage tissue of the trochlear groove at six months after surgery. RESULTS: At six months after surgery, CT scans showed a significant difference between the sham surgery group and the experimental group in the angle, width and depth of the trochlear groove. There were no significant differences between the sham surgery group and the control group. Gross specimen examination and cross-sectional anatomy indicated low lateral femoral trochlea and reduced height at the trochlear groove in the experimental group. The femoral trochlea was of normal appearance in the other two groups. Histological investigations showed that there were degenerative changes in the cartilage tissue of the femoral trochlea in the experimental group. CONCLUSIONS: Secondary femoral trochlear dysplasia may be caused by patellar dislocation in a normally developing femoral trochlea. Patellar dislocation may be one of the causes of femoral trochlear dysplasia. PMID- 23806769 TI - Characterization of glial fibrillary acidic protein (GFAP)-expressing hepatic stellate cells and myofibroblasts in thioacetamide (TAA)-induced rat liver injury. AB - Hepatic stellate cells (HSCs), which can express glial fibrillary acidic protein (GFAP) in normal rat livers, play important roles in hepatic fibrogenesis through the conversion into myofibroblasts (MFs). Cellular properties and possible derivation of GFAP-expressing MFs were investigated in thioacetamide (TAA) induced rat liver injury and subsequent fibrosis. Seven-week-old male F344 rats were injected with TAA (300mg/kg BW, once, intraperitoneally), and were examined on post single injection (PSI) days 1-10 by the single and double immunolabeling with MF and stem cell marker antibodies. After hepatocyte injury in the perivenular areas on PSI days 1 and 2, the fibrotic lesion consisting of MF developed at a peak on PSI day 3, and then recovered gradually by PSI day 10. MFs expressed GFAP, and also showed co-expressions such cytoskeletons (MF markers) as vimentin, desmin and alpha-SMA in varying degrees. Besides MFs co-expressing vimentin/desmin, desmin/alpha-SMA or alpha-SMA/vimentin, some GFAP positive MFs co-expressed with nestin or A3 (both, stem cell markers), and there were also MFs co-expressing nestin/A3. However, there were no GFAP positive MFs co-expressing RECA-1 (endothelial marker) or Thy-1 (immature mesenchymal cell marker). GFAP positive MFs showed the proliferating activity, but they did not undergo apoptosis. However, alpha-SMA positive MFs underwent apoptosis. These findings indicate that HSCs can proliferate and then convert into MFs with co-expressing various cytoskeletons for MF markers, and that the converted MFs may be derived partly from the stem cell lineage. Additionally, well-differentiated MFs expressing alpha-SMA may disappear by apoptosis for healing. These findings shed some light on the pathogenesis of chemically induced hepatic fibrosis. PMID- 23806768 TI - Clinical outcomes of bilateral single-stage unicompartmental knee arthroplasty. AB - BACKGROUND: Deciding whether to treat patients with bilateral arthritis with two stage or bilateral single-stage arthroplasties is a cause of considerable debate in orthopaedic surgery. METHODS: A total of 394 cemented Unicompartmental Knee Arthroplasties (UKA) were performed in this unit between 2006 and 2010. A retrospective review identified 38 patients (76 knees) who underwent bilateral Single-Stage Sequential UKA, performed by a single surgeon. RESULTS: The mean BMI was 29.8 and the majority of patients were ASA grade 2. The mean duration of follow-up was 30 months. The mean total tourniquet time was 83 min. The mean post operative haemoglobin was 11.8 and no patient required blood transfusion. The mean time to mobilisation was 18 h and the average length of stay was 3.5 days. This compares favourably with an institutional average length of stay of two days for a single UKA. There was a significant improvement in the mean pre- to post operative OKS (from 14 to 34, p<0.0001). One patient required operative fixation of a tibial plateau fracture after sustaining a mechanical fall two months following surgery. There were no other major complications, including thrombo embolic events or deep infections. Two patients required excision of a superficial suture granuloma. CONCLUSIONS: Bilateral Single-Stage Sequential UKAs provide significant improvement in patient function and can be performed safely with a low complication rate. Patients can benefit from a single hospital admission and anaesthetic whilst the shorter total in-patient stay reduces costs incurred by the hospital. LEVEL OF EVIDENCE: IV. PMID- 23806770 TI - Divergent effects of novel immunomodulatory agents and cyclophosphamide on the risk of engraftment syndrome after autologous peripheral blood stem cell transplantation for multiple myeloma. AB - Engraftment syndrome (ES) is an increasingly observed and occasionally fatal complication after autologous peripheral blood stem cell transplantation (PBSCT). In this study, we demonstrate that the incidence of ES is significantly increased in patients undergoing autologous PBSCT for multiple myeloma in comparison to patients with non-Hodgkin lymphoma or Hodgkin lymphoma. Multivariate analysis revealed that age > 60 (hazard ratio [HR], 1.71; 95% confidence interval [CI], 1.12 to 2.62; P = .013) and transplantation for multiple myeloma (HR, 2.80; 95% CI, 1.60 to 4.90; P = .0003) were associated with an increased risk of this complication. When stratified for myeloma patients only, age > 60 (HR, 1.80; 95% CI, 1.13 to 2.87; P = .013) and prior treatment with both lenalidomide and bortezomib (HR, 1.83; 95% CI, 1.11 to 3.04; P = .0001) were associated with an increased incidence of ES. Conversely, lack of exposure to cyclophosphamide from either chemomobilization or as a component of the pretransplantation therapeutic regimen increased the risk of this complication (HR, 3.05; 95% CI, 1.91 to 4.87; P <.0001). These studies demonstrate that the pretransplantation exposure of multiple myeloma patients to novel immunomodulatory agents and cyclophosphamide significantly affects the subsequent risk of developing ES. PMID- 23806771 TI - Adoptive transfer of umbilical cord blood-derived regulatory T cells and early viral reactivation. PMID- 23806772 TI - Mice engrafted with human fetal thymic tissue and hematopoietic stem cells develop pathology resembling chronic graft-versus-host disease. AB - Chronic graft-versus-host disease (cGVHD) is a significant roadblock to long-term hematopoietic stem cell (HSC) transplantation success. Effective treatments for cGVHD have been difficult to develop, in part because of a paucity of animal models that recapitulate the multiorgan pathologies observed in clinical cGVHD. Here we present an analysis of the pathology that occurs in immunodeficient mice engrafted with human fetal HSCs and implanted with fragments of human fetal thymus and liver. Starting at time points generally later than 100 days post transplantation, the mice developed signs of illness, including multiorgan cellular infiltrates containing human T cells, B cells, and macrophages; fibrosis in sites such as lungs and liver; and thickened skin with alopecia. Experimental manipulations that delayed or reduced the efficiency of the HSC engraftment did not affect the timing or progression of disease manifestations, suggesting that pathology in this model is driven more by factors associated with the engrafted human thymic organoid. Disease progression was typically accompanied by extensive fibrosis and degradation of the thymic organoid, and there was an inverse correlation of disease severity with the frequency of FoxP3(+) thymocytes. Hence, the human thymic tissue may contribute T cells with pathogenic potential, but the generation of regulatory T cells in the thymic organoid may help to control these cells before pathology resembling cGVHD eventually develops. This model thus provides a new system to investigate disease pathophysiology relating to human thymic events and to evaluate treatment strategies to combat multiorgan fibrotic pathology produced by human immune cells. PMID- 23806773 TI - Intermittent zoledronic Acid prevents bone loss in adults after allogeneic hematopoietic cell transplantation. AB - Bone mineral density (BMD) loss is common in survivors of allogeneic hematopoietic cell transplantation (alloHCT). We performed a multicenter, phase II, randomized open-label trial of intravenous zoledronic acid (ZA) to prevent BMD loss in adult recipients of alloHCT with osteopenia before HCT. The treatment group received ZA 4 mg intravenously within 28 days pre-HCT and at 3 and 6 months after HCT. Both treatment and control groups received calcium carbonate and vitamin D supplements. Of 61 patients, 32 were randomized to the ZA cohort and 29 to the control cohorts. More patients in the ZA group had an HCT comorbidity index high-risk score of >=3 (50% versus 21%, P < .01). Baseline BMD, T-scores, serum osteocalcin, bone alkaline phosphatase, and urine N-telopeptide (UNTX) levels were similar in both cohorts. Thirty patients were evaluable for outcomes (11 from the treatment and 19 from the control group). At 12 months, subjects in the treatment group had an improvement in BMD at the femoral neck (mean change, .018 for ZA group versus -.054 for controls; P = .04) and a significant decline in levels of UNTX (-56 for ZA group versus -9 for control; P = .04) compared with baseline. ZA was well tolerated and not associated with any cases of osteonecrosis of jaw or renal impairment. Lower survival observed in the ZA cohort was likely related to baseline imbalance in HCT-CI scores. Intermittent ZA is effective in preserving long-term bone health in adult alloHCT recipients at risk for osteoporosis. PMID- 23806774 TI - Aluminum(III) interferes with the structure and the activity of the peptidyl prolyl cis-trans isomerase (Pin1): a new mechanism contributing to the pathogenesis of Alzheimer's disease and cancers? AB - The enzyme peptidyl-prolyl cis-trans isomerase (Pin1) may play an important role in preventing the development of Alzheimer's disease (AD). The structural and functional stability of Pin1 is extremely important. Previously, we have determined the stability of Pin1 under stressed conditions, such as thermal treatment and acidic-pH. Considering that aluminum (Al(III)) is well known for its potential neurotoxicity in the pathogenesis of AD, we examined whether Al(III) affects the structure and function of Pin1, by means of a PPIase activity assay, intrinsic fluorescence, circular dichroism (CD) spectroscopy, FTIR, and differential scanning calorimetry (DSC). The intrinsic tryptophan fluorescence measurements mainly show that Al(III) may bind to the clusters nearby W11 and W34 in the WW domain of Pin1, quenching the intrinsic fluorescence of the two tryptophan residues, which possibly results in the decreased binding affinity of Pin1 to substrates. The secondary structural analysis as revealed by FTIR and CD measurements indicate that Al(III) induces the increase in beta-sheet and the decrease in alpha-helix in Pin1. Furthermore, the changes of the thermodynamic parameters for Pin1 as monitored by DSC confirm that the thermal stability of Pin1 significantly increases in the presence of Al(III). The Al(III)-induced structural changes of Pin1 result in a sharp decrease of the PPIase activity of Pin1. To some extent, our research is suggestive that Al(III) may inhibit the isomerization activity of Pin1 in vivo, which may contribute to the pathogenesis of AD. PMID- 23806776 TI - Increased hippocampal cell density and enhanced spatial memory in the valproic acid rat model of autism. AB - Autism is characterized by behavioral impairments in three main domains: social interaction; language, communication and imaginative play; and the range of interests and activities. However, neuronal processing studies have suggested that hyper-perception, hyper-attention, and enhanced memory, which may lie at the heart of most autistic symptoms. Pregnant Wistar rats were administered by either Valproic Acid (VPA, 500mg/kg) or Phosphate Buffer Saline (PBS) during fetal neural tube development on embryonic day 12.5. All offspring were subjected to various tests. The present study examined social interaction, repetitive behaviors, nociception and tactile threshold, anxiety as well as spatial memory. Histological analyses of cells in five regions of the hippocampus were done to determine neuronal density in both groups. A single intra-peritoneal injection of VPA to pregnant rats produced severe autistic-like symptoms in the offspring. The results showed significant behavioral impairments such as a lower tendency to initiate social interactions, enhanced stereotyped, repetitive behaviors, increased nociception threshold and anxiety at postnatal day (PND) 30 and PND 60. The Morris water maze learning paradigm revealed enhanced spatial memory at PND 60. Furthermore, histological analysis showed that the neuronal density in five separate regions of hippocampus (CA1, CA2, CA3, Dentate gyrus and Subiculum) were increased at PND 67. This work suggests that early embryonic exposure to VPA in rats provides a good model for several specific aspects of autism and should help to continue to explore pathophysiological and neuroanatomical hypotheses. This study provides further evidence to support the notion that spatial memory and hippocampal cell density are increased in this animal model of autism. PMID- 23806775 TI - The effects of rearing environment and chronic methylphenidate administration on behavior and dopamine receptors in adolescent rats. AB - Rearing young rodents in socially isolated or environmentally enriched conditions has been shown to affect numerous components of the dopamine system as well as behavior. Methylphenidate (MPH), a commonly used dopaminergic agent, may affect animals differently based on rearing environment. Here we examined the interaction between environment and chronic MPH treatment at clinically relevant doses, administered via osmotic minipump. Young Sprague Dawley rats (PND 21) were assigned to environmentally enriched, pair-housed, or socially isolated rearing conditions, and treated with either 0, 2, 4, or 8 mg/kg/day MPH for 3 weeks. At the end of the treatment period, animals were tested for locomotor activity and anxiety-like behavior. The densities of D1-like and D2-like receptors were measured in the striatum using in vitro receptor autoradiography. Locomotor activity and anxiety-like behavior were increased in isolated animals compared to pair-housed and enriched animals. The density of D1-like receptors was greater in isolated animals, but there were no differences between groups in D2-like receptor density. Finally, there were no effects of MPH administration on any reported measure. This study provides evidence for an effect of early rearing environment on the dopamine system and behavior, and also suggests that MPH administration may not have long-term consequences. PMID- 23806777 TI - Increased phosphorylation of mTOR is involved in remote ischemic preconditioning of hippocampus in mice. AB - Different signaling pathways are involved in tissue protection against ischemia reperfusion (IR) injury, among them mammalian target of rapamycin (mTOR) and related pathways have been examined in many recent studies. Present study evaluated the role of mTOR in remote ischemic preconditioning (RIPC) of hippocampus. Renal ischemia was induced (3 cycles of 5min occlusion and 5min reperfusion of unilateral renal artery) 24h before global brain ischemia (20min bilateral common carotid artery occlusion). Saline or rapamycin (mTOR inhibitor; 5mg/kg, i.p.) was injected 30min before RIPC. mTOR and phosphorylated mTOR (p mTOR) expression, superoxide dismutase (SOD) activity and retention trial of passive avoidance test were determined 24h after global ischemia. Apoptosis and neuronal cell density were assessed 72h after hippocampal ischemia. RIPC decreased apoptosis (p<0.05 vs. IR), improved memory (p<0.05 vs. IR), and augmented p-mTOR expression and SOD activity after hippocampal ischemia (p<0.05 vs. IR). Rapamycin abolished all protective effects of RIPC (p<0.05 vs. RIPC+IR) suggesting a role for mTOR in RIPC induced hippocampal protection. PMID- 23806778 TI - Effects of duration and timing of prenatal stress on hippocampal myelination and synaptophysin expression. AB - The relationship between prenatal stress (PS) exposure and neurodevelopmental deficits remains inconclusive, especially when assessing the role of PS duration and timing and sex-dependent effects. This study explored a sex-specific association between the duration and timing of exposure and the outcomes of PS induced neurotoxicity in hippocampal microstructure, synaptophysin expression, and neurobehavioral performance in rats. Pregnant rats were randomly assigned to control, PS-ML (exposed to prenatal restraint stress in the mid-to-late period of pregnancy), or PS-L (exposed in the late period of pregnancy) groups, and offspring in each group were divided into two subgroups by sex. Surface-righting reflex test, cliff avoidance test and Morris water maze test showed that neurodevelopmental levels were reduced in PS-treated pups but without significant sex differences. On postnatal day 22, hippocampal microstructure was examined by electron microscopy, and the expression of hippocampal synaptophysin was assessed by western blot. Abnormal ultrastructural appearance of hippocampal neurons and myelin sheaths, more degenerating neurons and higher G-ratios were found in young PS-ML and PS-L rats as well as reduced expression of hippocampal synaptophysin, although PS-ML pups were more greatly affected than PS-L, with males showing slightly greater impairments than females. These findings suggest that hippocampal hypo-myelination and decreased synaptophysin expression in neurodevelopment may be a duration and time-dependent effect of prenatal stress exposure, modified slightly by sex. PMID- 23806779 TI - Effect of sodium hydrosulphide after acute compression injury of spinal cord. AB - BACKGROUND: Early treatment of spinal cord white matter injury has been found beneficial. H2S, a neurotransmitter is neuroprotective at lower doses. PURPOSE: In the present study the effect of NaHS after clip compression injury of spinal cord white matter in vivo was studied. METHODS: The injury was induced in 8-10 weeks old Wistar rats by exposing the spinal cord at T8-T10 level by laminectomy and applying 35 g clip for 1 min. A dose of 50 uM NaHS was given intraperitoneally after 1h of injury. 0.5mm Spinal cord tissues were collected 8h after injury from both sides including epicenter and dorsal column was microdissected and used for further study. RESULTS: NaHS treatment decreases nitric oxide (NO) by 27% and lipid peroxide (LPO) by 18% as compared to injury, which are hallmark of attenuation in oxidative stress. Western blots shows significant changes in Myeloperoxidase (MPO) level went down by 10%. GSH contents increased 44% in treated group as compared to the injury group. NaHS treatment increased Nrf-2 expression 1.8 times. We found NaHS treatment reduced the GFAP expression 8%, there was no significant changes in NF-200 after treatment and no evident morphological changes with H and E staining. CONCLUSIONS: With the above data we conclude that NaHS at 50 uM dose at 1h after injury reduces the NO, LPO, GFAP and MPO level at injury site by increasing the expression of Nrf-2. We expect that a decrease in these parameters during acute phase of spinal cord injury would be helpful in neuroprotection and regeneration. PMID- 23806780 TI - Automated segmentation and fractal analysis of high-resolution non-invasive capillary perfusion maps of the human retina. AB - The retina provides a window to study the pathophysiology of cerebrovascular diseases. Pathological retinal microvascular changes may reflect microangiopathic processes in the brain. Recent advances in optical imaging techniques have enabled the imaging of the retinal microvasculature at the capillary level, and the generation of high-resolution, non-invasive capillary perfusion maps (nCPMs) with the Retinal Function Imager (RFI). However, the lack of quantitative analyses of the nCPMs may limit the wider application of the method in clinical research. The goal of this project was to demonstrate the feasibility of automated segmentation and fractal analysis of nCPMs. We took two nCPMs of each subject in a group of 6 healthy volunteers and used our segmentation algorithm to do the automated segmentation for monofractal and multifractal analyses. The monofractal dimension was 1.885+/-0.020, and the multifractal dimension was 1.876+/-0.010 (P=0.108). The coefficient of repeatability was 0.070 for monofractal analysis and 0.026 for multifractal analysis. This study demonstrated that the automatic segmentation of nCPMs is feasible for fractal analyses. Both monofractal and multifractal analyses yielded similar results. The quantitative analyses of microvasculature at the capillary level may open up a new era for studying microvascular diseases such as cerebral small vessel disease. PMID- 23806782 TI - Complexity analysis of the microcirculatory-blood-flow response following acupuncture stimulation. AB - Beat-to-beat cardiovascular variability analysis provides important information on the circulatory regulatory activities. Changes in the arterial pulse transmission or the opening condition of arteriolar openings might change the fluctuation pattern of the MBF supply, and thus change the complexity property therein. We performed complexity analysis of beat-to-beat laser Doppler flowmetry (LDF) signals to study the microcirculatory-blood-flow (MBF) response at the needled site (Hegu acupoint) following acupuncture stimulation (AS). LDF signals were measured in male healthy volunteers (n=29). Each experiment involved recording a 20-minute baseline-data sequence and two sets of effects data recorded 0-20 and 50-70min after stopping AS. Approximate-entropy (ApEn) analysis, which quantifies the unpredictability of fluctuations in a time series, was performed on each 20-minute beat-to-beat LDF data sequence. The present findings indicate that AS can not only improve the local blood supply but may also increase ApEn values and decrease MBF variability parameters. This was the first attempt to apply complexity analysis to LDF signals in order to elucidate microcirculatory responses following AS. The observed results are probably attributable to the contradictory effects on the MBF supply induced by AS, which might interfere with the microcirculatory regulatory activities so as to increase the complexity of LDF signals. The present findings could help to identify the mechanism underlying the effects of AS, might aid the development of an index for monitoring the induced microcirculatory regulatory responses, and thus provide an evidence-based connection between AS and modern physiology. PMID- 23806783 TI - Seventy years of Gastroenterology (1943-2013). PMID- 23806781 TI - Inflammatory cytokine-specific alterations in retinal endothelial cell function. AB - Diabetic retinopathy (DR) is recognized as a chronic low-grade inflammatory disease. Retinal microvascular cell dysfunction and loss play an important role in the pathogenesis of DR. However, the basic mechanisms underlying the development and progression of DR are poorly understood. Many recent studies indicate that increased production of inflammatory factors either systemically and/or locally, is strongly associated with vascular dysfunction during diabetes. Here we sought to determine the specific impact of different inflammatory mediators on retinal endothelial cell (EC) function. Inflammatory mediators TNF alpha and IL-1beta attenuated the migration and capillary morphogenesis of retinal EC. These dysfunctions were associated with an increased production of reactive oxygen species, expression of inducible nitric oxide synthase, and production of total nitrate/nitrite. Incubation of retinal EC with TNF-alpha and IL-1beta altered VE-cadherin localization, as well as the expression of other junctional proteins. In addition, TNF-alpha and IL-1beta also altered the production of various ECM proteins including osteopontin, collagen IV, and tenascin-C. Mechanistically, these changes were concomitant with the activation of the mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF kappaB) signaling pathways. In contrast, incubation of retinal EC with MCP-1 minimally affected their migratory, junctional, and ECM properties. Together our results indicate that the presence of inflammatory mediators in diabetes may have specific and significant impact on vascular cell function, and contribute to the pathogenesis of DR. PMID- 23806784 TI - Gastroenterology's editors-in-chief: historical and personal perspectives of their editorships. AB - Fourteen editors-in-chiefs have steered Gastroenterologyto success since its inception in 1943. Five (Alvarez, Ivy, Aaron, Grossman, and Donaldson) are no longer with us. Their personalities and editorships, along with those of Marvin Sleisenger, are presented by their admirers. Fordtran, Ockner, Goyal, LaRusso, Podolsky, Brenner, Rustgi, and Omary describe their own backgrounds, experiences, and personal reflections on serving as editor-in-chief of Gastroenterology. PMID- 23806785 TI - Beware of the patient with a glass eye and large liver. PMID- 23806786 TI - Soft tissue adhesion of polished versus glazed lithium disilicate ceramic for dental applications. AB - OBJECTIVE: Ceramics are widely used materials for prosthesis, especially in dental fields. Despite multiple biomedical applications, little is known about ceramic surface modifications and the resulting cell behavior at its contact. The aim of this study is to evaluate the biological response of polished versus glazed surface treatments on lithium disilicate dental ceramic. METHODS: We studied a lithium disilicate ceramic (IPS e.max((r)) Press, Ivoclar Vivadent) with 3 different surface treatments: raw surface treatment, hand polished surface treatment, and glazed surface treatment (control samples are Thermanox((r)), Nunc). In order to evaluate the possible modulation of cell response at the surface of ceramic, we compared polished versus glazed ceramics using an organotypic culture model of chicken epithelium. RESULTS: Our results show that the surface roughness is not modified as demonstrated by equivalent Ra measurements. On the contrary, the contact angle theta in water is very different between polished (84 degrees ) and glazed (33 degrees ) samples. The culture of epithelial tissues allowed a very precise assessment of histocompatibility of these interfaces and showed that polished samples increased cell adhesion and proliferation as compared to glazed samples. SIGNIFICANCE: Lithium disilicate polished ceramic provided better adhesion and proliferation than lithium disilicate glazed ceramic. Taken together, our results demonstrate for the first time, how it is possible to use simple surface modifications to finely modulate the adhesion of tissues. Our results will help dental surgeons to choose the most appropriate surface treatment for a specific clinical application, in particular for the ceramic implant collar. PMID- 23806787 TI - Co-exposure to lead increases the renal response to low levels of cadmium in metallurgy workers. AB - PURPOSE: Research on the effect of co-exposure to Cd and Pb on the kidney is scarce. The objective of the present study was to assess the effect of co exposure to these metals on biomarkers of early renal effect. METHODS: Cd in blood (Cd-B), Cd in urine (Cd-U), Pb in blood (Pb-B) and urinary renal biomarkers, i.e., microalbumin (MU-Alb), beta-2-microglobulin (beta2-MG), retinol binding protein (RBP), N-acetyl-beta-d-glucosaminidase (NAG), intestinal alkaline phosphatase (IAP) were measured in 122 metallurgic refinery workers examined in a cross-sectional survey. RESULTS AND CONCLUSIONS: The median Cd-B, Cd-U, Pb-B were: 0.8 MUg/l (IQR = 0.5, 1.2), 0.5 MUg/g creatinine (IQR = 0.3, 0.8) and 158.5 MUg/l (IQR = 111.0, 219.3), respectively. The impact of Cd-B on the urinary excretion of NAG and IAP was only evident among workers with Pb-B concentrations >= 75th percentile. The association between Cd-U and the renal markers NAG and RBP was also evidenced when Pb-B >= 75th percentile. No statistically significant interaction terms were observed for the associations between Cd-B or Cd-U and the other renal markers under study (i.e., MU-Alb and beta2-MG). Our findings indicate that Pb increases the impact of Cd exposure on early renal biomarkers. PMID- 23806788 TI - Tailing DNA aptamers with a functional protein by two-step enzymatic reaction. AB - An efficient, quantitative synthetic strategy for aptamer-enzyme conjugates was developed by using a two-step enzymatic reaction. Terminal deoxynucleotidyl transferase (TdT) was used to first incorporate a Z-Gln-Gly (QG) modified nucleotide which can act as a glutamine donor for a subsequent enzymatic reaction, to the 3'-OH of a DNA aptamer. Microbial transglutaminase (MTG) then catalyzed the cross-linking between the Z-QG modified aptamers and an enzyme tagged with an MTG-reactive lysine containing peptide. The use of a Z-QG modified dideoxynucleotide (Z-QG-ddUTP) or a deoxyuridine triphosphate (Z-QG-dUTP) in the TdT reaction enables the controlled introduction of a single or multiple MTG reactive residues. This leads to the preparation of enzyme-aptamer and (enzyme)n aptamer conjugates with different detection limits of thrombin, a model analyte, in a sandwich enzyme-linked aptamer assay (ELAA). Since the combination of two enzymatic reactions yields high site-specificity and requires only short peptide substrates, the methodology should be useful for the labeling of DNA/RNA aptamers with proteins. PMID- 23806789 TI - Age-related changes of forkhead transcription factor FOXO1 in the liver of senescence-accelerated mouse SAMP8. AB - SAMP8 exhibits accelerated aging and a short lifespan. Insulin-like growth factor 1 receptor (IGF-1R)/FOXO pathway is associated with aging. Phosphorylation of IGF 1R, Akt, and FOXO1 was found to be increased during aging in the liver of SAMR1 normal aging mice. However, significant decreases in the phosphorylation of IGF 1R and Akt were observed in the liver of SAMP8 during aging compared with that in SAMR1, whereas phosphorylation of FOXO1 was markedly increased with age in SAMP8. In addition, the protein level of FOXO1 was decreased with age in SAMP8. Protein phosphatase 2A (PP2A) directly dephosphorylates FOXO1. Significant reduction of PP2A activity was observed in the liver nucleus of SAMP8. These results suggest the possibility that the increased FOXO1 phosphorylation might occur by the decreased activity of PP2A, resulting in the decrease in the protein level of FOXO1 in SAMP8. Furthermore, FOXO1 regulates longevity and the expression of antioxidant enzymes such as Mn-SOD and catalase. The expression of Mn-SOD and catalase was significantly decreased in the liver of SAMP8. Therefore, it is possible that the elevation of phosphorylated FOXO1 level with age causes a short lifespan in SAMP8. PMID- 23806790 TI - Functional decline in older adults one year after hospitalization. AB - We studied the change in personal ability to perform the activities of daily living (P-ADL) one year after hospitalization (T2) of patients at least 65 years old at baseline (T1). The study included 363 (175 men) medical inpatients with age range 65-98 (mean 80.2, SD 7.5) years. Information was collected at baseline and at a 12 month follow-up using Lawton and Brody's physical self-maintenance scale (PSMS) (termed the P-ADL score), as the dependent variable, and the mini mental state examination (MMSE), the hospital anxiety and depression scale (HAD) and the WHOQOL-BREF questionnaire as independent variables. For the total sample, the mean P-ADL was significantly worsened from T1 to T2 (mean change 0.5, SD 2.8; p<0.01). In a fully adjusted linear regression analysis, worsened P-ADL from T1 to T2 was independently associated with cognitive impairment at T1, increasing cognitive impairment from T1 to T2, the tendency to fall between T1 and T2, increase in depressive symptoms from T1 to T2, poor physical QOL at T1 and change toward a poorer QOL from T1 to T2. In conclusion, worse P-ADL at T2 was, independently of age and baseline P-ADL, associated with impaired cognitive function and QOL related to physical ability at baseline, as well as worsening depression, cognition and QOL from T1 to T2. Our findings highlight the importance of applying results from screening measures of cognitive function and emotional health when planning care for older people after hospitalization. PMID- 23806791 TI - Developing and validating a Japanese version of the Assessment of Pain in Elderly People with Communication Impairment. AB - This study aimed to develop a Japanese version of the Assessment of Pain in Elderly People with Communication Impairment (PACSLAC-J) and evaluate the validity and reliability of the scale for use in older patients with dementia in Japan. All patients from 2 dementia wards at a geriatric hospital and 2 aged care facilities were asked to participate. Demographic data, medical prescriptions, Behavior Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD) score, and PACSLAC-J score were obtained from the patients or their medical charts. Researchers used the PACSLAC-J to assess pain behaviors while the patients walked or were transferred between a bed and a wheelchair. Intra-class correlation coefficients (ICC) for inter-rater and test-retest reliability, Cronbach's alpha, and correlations between PACSLAC-J score and other variables were examined. A total of 117 older patients participated. Dementia, including Alzheimer's disease (n=54) and/or vascular dementia (n=35), had been diagnosed in almost all of them. The ICC for inter-rater and test-retest reliability were 0.917 and 0.600, respectively. Internal consistency of the entire sample was 0.782. Patients who stated they were experienced pain during movement had higher scores than did patients who stated they had no pain during movement. PACSLAC-J total score was not associated with BEHAVE-AD score. Multiple regression analysis showed that total dependence on assistance during transfer (beta=0.32, p=0.001), and psychiatric medication prescription (beta=0.26, p=0.003) were independently associated with PACSLAC-J score. We found sufficient evidence of the validity and reliability of the PACSLAC-J. PMID- 23806792 TI - Potential roles of synonymous codon usage and tRNA concentration in hosts on the two initiation regions of foot-and-mouth disease virus RNA. AB - The open reading frame of foot-and-mouth disease virus (FMDV) contains two authentic initiation codons and the second initiation codon is often selected in high frequency. In the study, we analyzed the effects of the host-cell synonymous codon usage and the overall tRNA concentration in the hosts on the region flanked by the two initiation codons (termed as the region 1) and the same length starting from the second initiation codon (defined as the region 2). We find that low-usage codons of hosts are more selected in the region 1 than the region 2; no obvious usage bias of codon with high C/G content exists in the region 1, and the latter part (ranging from the 13th codon position to the 28th codon position) of the region 1 generally contains the codon sites with the generally lower tRNA concentration than the counterpart of the region 2. The low-usage codons of the hosts with high selection in the region 1 and the cluster codon position with low tRNA concentration in the region 1 may serve as potential factors in decreasing the translation rate of the region 1 caused by initiation from the first start codon of FMDV. PMID- 23806793 TI - Fibroblast growth factor receptor 1 (FGFR1) copy number is an independent prognostic factor in non-small cell lung cancer. AB - Fibroblast growth factor receptor 1 (FGFR1) is an oncogene that can potentially be targeted by tyrosine kinase inhibitors. We aimed to investigate the prevalence and prognostic significance of alterations in FGFR1 copy number in non-small cell lung cancer (NSCLC). FGFR1 status was evaluated by chromogenic silver in situ hybridisation (ISH) in tissue microarray sections from a retrospective cohort of 304 surgically resected NSCLCs and results were correlated with the clinicopathological features and overall survival. High FGFR1 gene copy number (amplification or high-level polysomy) was significantly more frequent in squamous cell carcinomas (SCC) (24.8%) and large cell carcinomas (LCC) (25%) compared to adenocarcinomas (11.3%) (p = 0.01 and p = 0.03 respectively). Among NSCLC there was no significant correlation between FGFR1-positive status and other clinicopathological features including age, gender, smoking history, tumour size, lymph node status, stage, grade, vascular, lymphatic or perineural invasion. FGFR1-positive patients showed a tendency to longer overall survival in univariate analysis (p = 0.14). Multivariate survival analysis using Cox regression model confirmed FGFR1-positive patients had a significant reduction in the risk of death compared to FGFR1-negative patients (HR 0.6; p = 0.02). High FGFR1 gene copy number is a common finding in SCC and LCC and is an independent favourable prognostic factor. PMID- 23806794 TI - Potentialities of aberrantly methylated circulating DNA for diagnostics and post treatment follow-up of lung cancer patients. AB - To date, aberrant DNA methylation has been shown to be one of the most common and early causes of malignant cell transformation and tumors of different localizations, including lung cancer. Cancer cell-specific methylated DNA has been found in the blood of cancer patients, indicating that cell-free DNA circulating in the blood (cirDNA) is a convenient tumor-associated DNA marker that can be used as a minimally invasive diagnostic test. In the current study, we investigated the methylation status in blood samples of 32 healthy donors and 60 lung cancer patients before and after treatment with neoadjuvant chemotherapy followed by total tumor resection. Using quantitative methylation-specific PCR, we found that the index of methylation (IM), calculated as IM = 100 * [copy number of methylated/(copy number of methylated + unmethylated gene)], for the RASSF1A and RARB2 genes in the cirDNA isolated from blood plasma and cell-surface bound cirDNA was elevated 2- to 3-fold in lung cancer patients compared with healthy donors. Random forest classification tree model based on these variables combined (RARB2 and RASSF1A IM in both plasma and cell-surface-bound cirDNA) lead to NSCLC patients' and healthy subjects' differentiation with 87% sensitivity and 75% specificity. An association of increased IM values with an advanced stage of non-small-cell lung cancer was found for RARB2 but not for RASSF1A. Chemotherapy and total tumor resection resulted in a significant decrease in the IM for RARB2 and RASSF1A, in both cirDNA fractions, comparable to the IM level of healthy subjects. Importantly, a rise in the IM for RARB2 was detected in patients within the follow-up period, which manifested in disease relapse at 9 months, confirmed with instrumental and pathologic methods. Our data indicate that quantitative analysis of the methylation status of the RARB2 and RASSF1A tumor suppressor genes in both cirDNA fractions is a useful tool for lung cancer diagnostics, evaluation of cancer treatment efficiency and post-treatment monitoring. PMID- 23806795 TI - Frequency of EGFR and KRAS mutations in patients with non small cell lung cancer by racial background: do disparities exist? AB - INTRODUCTION: Mutations in EGFR and KRAS can impact treatment decisions for patients with NSCLC. The incidence of these mutations varies, and it is unclear whether there is a decreased frequency among African Americans (AfAs). METHODS: We performed a retrospective chart review of 513 NSCLC patients undergoing EGFR and KRAS mutational analysis at the Hospital of the University of Pennsylvania between May 2008 and November 2011. Clinical and pathologic data were abstracted from the patients' electronic medical record. RESULTS: Of 497 patients with informative EGFR mutation analyses, the frequency of EGFR mutation was 13.9%. The frequency of EGFR mutations was associated with race (p < 0.001) and was lower in AfA patients compared to Caucasian (C) patients but did not reach statistical significance (4.8% vs. 13.7%, p = 0.06). Mean Charlson Comorbidity Index and number of cigarette pack years were significantly lower in patients with EGFR mutations (p = 0.01 and p < 0.001, respectively). Multivariable logistic regression analysis showed a significant association between race and EGFR mutation (p = 0.01), even after adjusting for smoking status (p < 0.001) and gender (p = 0.03). KRAS mutation (study frequency 28.1%) was not associated with race (p = 0.08; p=0.51 for Afa vs. C patients), but was more common among smokers (p < 0.001) and females (p = 0.01). CONCLUSIONS: Based on multivariable analysis, even after adjusting for smoking status and gender, we found that race was statistically significantly associated with EGFR mutation, but not KRAS mutational status. To the best of our knowledge, this is the largest single institution series to date evaluating racial differences in EGFR and KRAS mutational status among patients with NSCLC. PMID- 23806796 TI - Treatment of chronic deep vein thrombosis using ultrasound accelerated catheter directed thrombolysis. AB - OBJECTIVE: To evaluate the feasibility, efficacy and safety of ultrasound accelerated catheter-directed thrombolysis (UACDT) in the delayed treatment of lower extremity deep venous thrombosis (DVT). DESIGN: Twelve patients with unilateral iliofemoral or femoropopliteal DVT (mean symptom duration 92 +/- 44 days) were prospectively investigated. METHOD: UACDT was performed using recombinant human tissue plasminogen activator delivered using the EKOS EkoSonic system. Stents were deployed if indicated by post-procedure venography. Follow-up comprised weekly duplex ultrasound for 1 month and monthly thereafter. RESULTS: Successful thrombolysis occurred in 11/12 limbs (92%; complete 6/12, partial 5/12) after a mean infusion time of 26 +/- 7 hours. 2/12 patients required angioplasty and stent insertion. At a mean follow-up of 9 (6-15) months, 10/11 (91%) veins were patent whereas 1/11 re-occluded at 2 months (patient with protein-C deficiency). 2/11 limbs developed symptoms/signs of post-thrombotic syndrome and 3/11 had developed deep vein reflux (duplex ultrasound). 2/12 patients experienced peri-catheter bleeding but no major hemorrhage or symptomatic pulmonary embolism occurred. CONCLUSIONS: This preliminary evidence suggests that UACDT may be a safe and effective option for the delayed treatment of lower limb DVT. PMID- 23806797 TI - Physiological POSSUM as an indicator for long-term survival in vascular surgery. AB - OBJECTIVES: We investigated whether the POSSUM physiology score, originally designed as an indicator for 30-day mortality for comparative audit, could be used as an indicator of long-term survival in vascular surgery practice. METHODS: Data from 184 different vascular procedures conducted between 1989 and 2000, containing survival data for each patient of 10 years or longer, were analysed retrospectively. Parameters collected were the pre-operative physiological and the operative severity POSSUM score, gender, and type of procedure. Multivariate analyses were performed using Cox regression method and, on the basis of their physiological POSSUM score grouping, Kaplan-Meier analysis was performed for estimation of overall survival. RESULTS: Both an increase in physiological POSSUM score (hazard ratio [HR] 1.050, 95% confidence interval [CI] 1.031 to 1.070) and one of its components, age (HR 1.025, 95% CI 1.006 to 1.045; p = 0.009), were shown to be indicators of long-term all-cause mortality. The sample's mean physiological POSSUM score of 21 was then used as a cut-off point to categorise low and high-risk vascular surgery patients. Median survival in the low-risk group was 70 months (95% CI 56-86 months), whereas in the high-risk group this was 17 months (95% CI 3-31 months). CONCLUSION: The physiological POSSUM score, including patient age, is an indicator of long-term survival of patients with vascular disease. This may help in choosing the appropriate vascular intervention. PMID- 23806798 TI - Effect of odanacatib on bone turnover markers, bone density and geometry of the spine and hip of ovariectomized monkeys: a head-to-head comparison with alendronate. AB - Odanacatib (ODN) is a selective and reversible Cathepsin K (CatK) inhibitor currently being developed as a once weekly treatment for osteoporosis. Here, effects of ODN compared to alendronate (ALN) on bone turnover, DXA-based areal bone mineral density (aBMD), QCT-based volumetric BMD (vBMD) and geometric parameters were studied in ovariectomized (OVX) rhesus monkeys. Treatment was initiated 10 days after ovariectomy and continued for 20 months. The study consisted of four groups: L-ODN (2 mg/kg, daily p.o.), H-ODN (8/4 mg/kg daily p.o.), ALN (15 MUg/kg, twice weekly, s.c.), and VEH (vehicle, daily, p.o.). L-ODN and ALN doses were selected to approximate the clinical exposures of the ODN 50 mg and ALN 70-mg once-weekly, respectively. L-ODN and ALN effectively reduced bone resorption markers uNTx and sCTx compared to VEH. There was no additional efficacy with these markers achieved with H-ODN. Conversely, ODN displayed inversely dose-dependent reduction of bone formation markers, sP1NP and sBSAP, and L-ODN reduced formation to a lesser degree than ALN. At month 18 post-OVX, L ODN showed robust increases in lumbar spine aBMD (11.4%, p<0.001), spine trabecular vBMD (13.7%, p<0.001), femoral neck (FN) integral (int) vBMD (9.0%, p<0.001) and sub-trochanteric proximal femur (SubTrPF) int vBMD, (6.4%, p<0.001) compared to baseline. L-ODN significantly increased FN cortical thickness (Ct.Th) and cortical bone mineral content (Ct.BMC) by 22.5% (p<0.001) and 21.8% (p<0.001), respectively, and SubTrPF Ct.Th and Ct.BMC by 10.9% (p<0.001) and 11.3% (p<0.001) respectively. Compared to ALN, L-ODN significantly increased FN Ct. BMC by 8.7% (p<0.05), and SubTrPF Ct.Th by 7.6% (p<0.05) and Ct.BMC by 6.2% (p<0.05). H-ODN showed no additional efficacy compared to L-ODN in OVX-monkeys in prevention mode. Taken together, the results from this study have demonstrated that administration of ODN at levels which approximate clinical exposure in OVX monkeys had comparable efficacy to ALN in DXA-based aBMD and QCT-based vBMD. However, FN cortical mineral content clearly demonstrated superior efficacy of ODN versus ALN in this model of estrogen-deficient non-human primates. PMID- 23806800 TI - Use and effectiveness of quitlines for smokers with diabetes: cessation and weight outcomes, Washington State Tobacco Quit Line, 2008. AB - INTRODUCTION: Having diabetes and smoking increases the risk of morbidity and mortality. However, cessation-related weight gain, a common side effect during quitting, can further complicate diabetes. Evidence-based telephone quitlines can support quitting but have not been studied adequately in populations with chronic diseases such as diabetes. The purpose of this study was to evaluate the use and effectiveness of a tobacco quitline among tobacco users with diabetes. Cessation related weight concerns and weight gain were also assessed. METHODS: We administered a telephone-based follow-up survey to tobacco users with and without diabetes 7 months after their enrollment in a quitline. We collected and analyzed data on demographics, tobacco use, dieting, weight concern, quitting success (7- and 30-day point prevalence), and weight gain. We computed summary statistics for descriptive data, chi(2) and t tests for bivariate comparisons, and multivariable analyses to determine correlates of cessation. RESULTS: Tobacco users with diabetes used the quitline in a greater proportion than they were represented in the general population. Quit rates for those with and without diabetes did not differ significantly (24.3% vs 22.5%). No significant differences existed between groups for weight gain at follow-up, regardless of quit status. However, participants with diabetes reported more weight gain in previous quit attempts (34.2% vs 22.4% gained >20 lbs, P = .03). Weight concern was a significant correlate of continued smoking, regardless of diabetes status. CONCLUSIONS: Results suggest that quitlines are effective for participants with diabetes, but tailored interventions that address weight concerns during cessation are needed. PMID- 23806799 TI - E2F1 effects on osteoblast differentiation and mineralization are mediated through up-regulation of frizzled-1. AB - Frizzled homolog 1 (FZD1) is a transmembrane receptor that mediates Wnt signaling. The transcriptional regulation of FZD1 and the role of FZD1 in osteoblast biology are not well understood. We examined the role of E2F1 in FZD1 promoter activation and osteoblast differentiation and mineralization. A putative E2F1 binding site in the FZD1 promoter region was initially identified in silico and characterized further in Saos2 cells in vitro by chromatin immunoprecipitation (ChIP), electrophoretic mobility shift (EMSA) and promoter reporter assays. Over-expression of E2F1 transactivated the FZD1 promoter and increased endogenous FZD1 mRNA and protein levels in Saos2 cells. Over-expression of E2F1 in Saos2 cells up-regulated osteoblast differentiation markers alkaline phosphatase (ALP), type I collagen alpha (COL1A), and osteocalcin (OCN). Furthermore, E2F1 over-expression enhanced mineralization of differentiated Saos2 cells, whereas siRNA knockdown of FZD1 diminished the effects of E2F1 on osteoblast mineralization. The effects of E2F1 on FZD1 expression and osteoblast mineralization were further confirmed in normal human FOB osteoblasts. Taken together, our experiments demonstrate a role of E2F1 in osteoblast differentiation and mineralization and suggest that FZD1 is required, in part, for E2F1 regulation of osteoblast mineralization. PMID- 23806801 TI - Tools for identifying and prioritizing evidence-based obesity prevention strategies, Colorado. AB - Colorado's adult obesity rate has more than doubled since 1995, prompting its Department of Public Health and Environment to list obesity as its top prevention priority. To initiate comprehensive and effective action, the department used a well-known evidence-based public health framework developed by Brownson and others. This article describes the tools and process developed to conduct 2 of the 7 stages in this framework that challenge public health organizations: reviewing the literature and prioritizing effective strategies from that literature. Forty-five department staff participated in an intensive literature review training to identify physical activity and nutrition strategies that effectively address obesity and worked with external stakeholders to prioritize strategies for the state. Divided into 8 multidisciplinary teams organized by the setting where public health could exert leverage, they scanned the scientific literature to identify potential strategies to implement. These teams were trained to use standardized tools to critique findings, systematically abstract key information, and classify the evidence level for each of 58 identified strategies. Next, departmental subject matter experts and representatives from local public health and nonprofit health agencies selected and applied prioritization criteria to rank the 58 strategies. A team charter, group facilitation tools, and 2 web-based surveys were used in the prioritization stage. This process offered the staff a shared experience to gain hands-on practice completing literature reviews and selecting evidence-based strategies, thereby enhancing Colorado's obesity prevention efforts and improving public health capacity. Practitioners can use these tools and methodology to replicate this process for other health priorities. PMID- 23806802 TI - An update on tobacco control initiatives in comprehensive cancer control plans. AB - INTRODUCTION: Comprehensive cancer control (CCC) coalitions address tobacco use, the leading cause of preventable death in the United States, through formal plans to guide tobacco control activities and other cancer prevention strategies. Best Practices for Comprehensive Tobacco Control Programs (Best Practices) and The Guide to Community Preventive Services (The Community Guide) are used to assist with this effort. We examined CCC plans to determine the extent to which they followed the Centers for Disease Control and Prevention's (CDC's) tobacco control and funding recommendations. METHODS: We obtained 69 CCC plans, current as of August 1, 2011, to determine which CDC recommendations from Best Practices and The Community Guide were incorporated. Data were abstracted through a content review and key word search and then summarized across the plans with dichotomous indicators. Additionally, we analyzed plans for inclusion of tobacco control funding goals and strategies. RESULTS: CCC plans incorporated a mean 4.5 (standard deviation [SD], 2.1) of 5 recommendations from Best Practices and 5.2 (SD, 0.9) of 10 recommendations from The Community Guide. Two-thirds of plans (66.7%) addressed funding for tobacco control as a strategy or action item; 47.8% of those plans (31.9% of total) defined a specific, measurable funding goal. CONCLUSION: Although most CCC plans follow CDC-recommended tobacco control recommendations and funding levels, not all recommendations are addressed by every plan and certain recommendations are addressed in varying numbers of plans. Clearer prioritization of tobacco control recommendations by CDC may improve the extent to which they are followed and therefore maximize their public health benefit. PMID- 23806803 TI - Smoking behaviors and cessation interests among multiunit subsidized housing tenants, Columbus, Ohio, 2011. AB - INTRODUCTION: Cessation services have been recommended to complement smoke-free policies in subsidized multiunit housing, but little is known about smoking- and cessation-related characteristics among subsidized housing tenants. This study examined smoking behaviors and cessation-related interests in a population of subsidized housing tenants. METHODS: A face-to-face survey was conducted in August to October 2011 with a probability sample of private subsidized housing lease holders in Columbus, Ohio (N = 301, 64% response rate). RESULTS: Almost half (47.5%) of respondents were current smokers, including smokers of cigarettes or small cigars. Smokers were less likely than nonsmokers to have health insurance and more likely to be at risk for food insecurity. Among smokers, 20.3% did not smoke daily and 35.0% smoked 5 or fewer cigarettes per day. More than half (61.3%) purchased single cigarettes in the past month, with higher rates among nondaily smokers. Most smokers intended to quit within 6 months or less (60.1%) and were interested in using nicotine replacement therapy (NRT) (65.0%). Most respondents had Medicaid but only 30.4% knew Medicaid covered cessation medications. CONCLUSIONS: This population of subsidized housing tenants had high rates of smoking, including light smoking. Interest in NRT was high and access can be improved by increasing awareness of Medicaid coverage among clients and health care providers. However, more research is needed about scalable, evidence based cessation strategies for low-socioeconomic status and light smokers. Strategies to address environmental factors such as availability of single cigarettes should also be considered in parallel with smoke-free policies. PMID- 23806806 TI - Subacute bacterial endocarditis presenting as left upper quadrant abdominal pain. AB - Infective endocarditis is a microbial infection of the endocardial surface of the heart. Its symptoms and signs are varied, and include fever, heart murmur, peripheral embolism, and heart failure. The diagnosis of subacute bacterial endocarditis (SBE) is suggested by a history of an indolent process characterized by fever, fatigue, anorexia, and unexplained weight loss. These patients may have had an invasive procedure, such as dental work, or abused intravenous drugs prior to the diagnosis of SBE. Although uncommon, the patients may present with nonspecific symptoms caused by peripheral embolic events. Herein, we report a 25 year-old male diagnosed with SBE, who presented with the unusual symptom of sudden onset of left upper quadrant abdominal pain for 2 days. His clinical history is also discussed. PMID- 23806804 TI - Homeostatic plasticity at the Drosophila neuromuscular junction. AB - In biology, homeostasis refers to how cells maintain appropriate levels of activity. This concept underlies a balancing act in the nervous system. Synapses require flexibility (i.e. plasticity) to adjust to environmental challenges. Yet there must also exist regulatory mechanisms that constrain activity within appropriate physiological ranges. An abundance of evidence suggests that homeostatic regulation is critical in this regard. In recent years, important progress has been made toward identifying molecules and signaling processes required for homeostatic forms of neuroplasticity. The Drosophila melanogaster third instar larval neuromuscular junction (NMJ) has been an important experimental system in this effort. Drosophila neuroscientists combine genetics, pharmacology, electrophysiology, imaging, and a variety of molecular techniques to understand how homeostatic signaling mechanisms take shape at the synapse. At the NMJ, homeostatic signaling mechanisms couple retrograde (muscle-to-nerve) signaling with changes in presynaptic calcium influx, changes in the dynamics of the readily releasable vesicle pool, and ultimately, changes in presynaptic neurotransmitter release. Roles in these processes have been demonstrated for several molecules and signaling systems discussed here. This review focuses primarily on electrophysiological studies or data. In particular, attention is devoted to understanding what happens when NMJ function is challenged (usually through glutamate receptor inhibition) and the resulting homeostatic responses. A significant area of study not covered in this review, for the sake of simplicity, is the homeostatic control of synapse growth, which naturally, could also impinge upon synapse function in myriad ways. This article is part of the Special Issue entitled 'Homeostatic Synaptic Plasticity'. PMID- 23806807 TI - Progressive growth of arachnoid cysts with cauda equina syndrome after lumbar spine surgery. AB - Intradural arachnoid cysts are a rare cause of spinal cord compression. In symptomatic cases neuropathic pain, gait disturbance, and paraparesis or quadriparesis are often present. Postoperative arachnoid cysts have rarely been reported. We describe a 56-year-old male who developed progressively enlarging arachnoid cysts with cauda equina syndrome and vertebral body erosion after lumbar surgery. The clinical presentation of the patient, the possible mechanisms of cyst formation, and the management of the disease are discussed with regard to previous literature. PMID- 23806805 TI - The behavioral- and neuro-economic process of temporal discounting: A candidate behavioral marker of addiction. AB - Addiction science would benefit from the identification of a behavioral marker. A behavioral marker could reflect the projected clinical course of the disorder, function as a surrogate measure of clinical outcome, and/or may be related to biological components that underlie the disorder. In this paper we review relevant literature, made possible with the early and sustained support by NIDA, to determine whether temporal discounting, a neurobehavioral process derived from behavioral economics and further explored through neuroeconomics, may function as a behavioral marker. Our review suggests that temporal discounting 1) identifies individuals who are drug-dependent, 2) identifies those at risk of developing drug dependence, 3) acts as a gauge of addiction severity, 4) correlates with all stages of addiction development, 5) changes with effective treatment, and 6) may be related to the biological and genetic processes that underlie addiction. Thus, initial evidence supports temporal discounting as a candidate behavioral marker. Additional studies will be required in several areas for a more conclusive determination. Confirmation that temporal discounting functions as a behavioral marker for addiction could lead to 1) a screen for new treatments, 2) personalization of prevention and treatment interventions, and 3) the extension of temporal discounting as a behavioral marker for other etiologically similar disorders. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. PMID- 23806808 TI - Endoscopic vidian neurectomy assisted by power instrumentation and coblation. AB - Vidian neurectomy has been used to manage intractable vasomotor rhinitis for decades. After the introduction of endoscopic sinus surgery in the 1980s, transnasal endoscopic vidian neurectomy (EVN) was subsequently reported. The most common problem in performing EVN was excessive bleeding from the pterygopalatine fossa. The complexity and vascularity of the pterygopalatine fossa can cause bloody surgical fields and prevent complete neurectomy. In response to this surgical problem, a procedure was developed to use powered instrumentation and coblation during EVN. There were eight cases of EVNs (16 neurectomies) assisted by power instrumentation and coblation from December 2011 to May 2012. The average blood loss of these cases was 37.5 mL (range, 25-50 mL). The average surgical time of each neurectomy was 27.4 minutes (range, 20-35 minutes). No complications occurred in any of the eight cases. Very limited bleeding and less thermal damage were noted while achieving a complete neurectomy. PMID- 23806809 TI - Validation of circulating miRNA biomarkers for predicting lymph node metastasis in gastric cancer. AB - We validated candidate biomarkers using circulating miRNAs by analyzing serum miRNA concentrations from patients with gastric cancer (GC) to predict lymph node (LN) metastasis. In a pilot study, serum levels of miR-21, miR-27a, miR-106b, miR 146a, miR-148a, miR-223, and miR-433 were compared in 10 healthy donors, 16 LN positive patients with GC, and 15 LN-negative patients with GC. Then, we compared the level of three miRNAs (miR-21, miR-146a, and miR-148a) with the total of 79 GC patients with or without LN metastasis. In the pilot study, miR-21, miR-27a, miR-106b, miR-146a, miR-148a, and miR-223 concentrations from LN-positive patients with GC were significantly different from those of LN-negative patients with GC (P < 0.001, P = 0.003, P = 0.033, P < 0.001, P <0.001, and P = 0.017, respectively). In the validation study, levels of miR-21, miR-146a, and miR-148a increased as pN stage increased (P < 0.001, P = 0.001, and P < 0.001, respectively). Levels of the miRNAs were significantly different between pN0 and pN0 in the pT1 group (P = 0.013, P = 0.004, and P = 0.035, respectively) and among clinical stages (P = 0.001, P = 0.002, and P < 0.001, respectively). No differences in miRNA levels were observed by pT stage, Lauren's classification, sex, or age. Serum concentrations of miR-21, miR-146a, and miR-148a were closely associated with GC pN stage. These serum miRNA levels could be biomarker candidates to predict the presence of LN metastasis. PMID- 23806810 TI - Novel real-time polymerase chain reaction assay for simultaneous detection of recurrent fusion genes in acute myeloid leukemia. AB - The recent World Health Organization classification recognizes different subtypes of acute myeloid leukemia (AML) according to the presence of several recurrent genetic abnormalities. Detection of these abnormalities and other molecular changes is of increasing interest because it contributes to a refined diagnosis and prognostic assessment in AML and enables monitoring of minimal residual disease. These genetic abnormalities can be detected using single RT-PCR, although the screening is still labor intensive and costly. We have developed a novel real-time RT-PCR assay to simultaneously detect 15 AML-associated rearrangements that is a simple and easily applicable method for use in clinical diagnostic laboratories. This method showed 100% specificity and sensitivity (95% confidence interval, 91% to 100% and 92% to 100%, respectively). The procedure was validated in a series of 105 patients with AML. The method confirmed all translocations detected using standard cytogenetics and fluorescence in situ hybridization and some additional undetected rearrangements. Two patients demonstrated two molecular rearrangements simultaneously, with BCR-ABL1 implicated in both, in addition to RUNX1-MECOM in one patient and PML-RARA in another. In conclusion, this novel real-time RT-PCR assay for simultaneous detection of multiple AML-associated fusion genes is a versatile and sensitive method for reliable screening of recurrent rearrangements in AML. PMID- 23806811 TI - Profiling biopharmaceutical deciding properties of absorption of lansoprazole enteric-coated tablets using gastrointestinal simulation technology. AB - The aim of the present study was to correlate in vitro properties of drug formulation to its in vivo performance, and to elucidate the deciding properties of oral absorption. Gastrointestinal simulation technology (GST) was used to simulate the in vivo plasma concentration-time curve and was implemented by GastroPlusTM software. Lansoprazole, a typical BCS class II drug, was chosen as a model drug. Firstly, physicochemical and pharmacokinetic parameters of lansoprazole were determined or collected from literature to construct the model. Validation of the developed model was performed by comparison of the predicted and the experimental plasma concentration data. We found that the predicted curve was in a good agreement with the experimental data. Then, parameter sensitivity analysis (PSA) was performed to find the key parameters of oral absorption. The absorption was particularly sensitive to dose, solubility and particle size for lansoprazole enteric-coated tablets. With a single dose of 30 mg and the solubility of 0.04 mg/ml, the absorption was complete. A good absorption could be achieved with lansoprazole particle radius down to about 25 MUm. In summary, GST is a useful tool for profiling biopharmaceutical deciding properties of absorption of lansoprazole enteric-coated tablets and guiding the formulation optimization. PMID- 23806812 TI - Development of intravenous lipid emulsion of vinorelbine based on drug phospholipid complex technique. AB - In order to reduce the severe venous toxicity, we developed an intravenous lipid emulsion of vinorelbine and investigated its preclinical stability, toxicity and antitumor efficacy. Vinorelbine-phospholipid complex was prepared to enhance the lipophilicity of vinorelbine thus facilitating the encapsulation into lipid emulsion. After complexation more than 70% of vinorelbine was encapsulated into the oil phase. Meanwhile, the lipid emulsion showed good stability without drug leakage. Local irritation after injection of the lipid emulsion was investigated in rabbits and compared with Navelbine((r)) (the commercial product). The antitumor therapeutic efficacies were evaluated in tumor-bearing mouse models inoculated with A549 human lung cancer cells and BCAP-37 human breast cancer cells and compared as well. Results showed that the lipid emulsion significantly reduced the injection irritation compared with that of Navelbine((r)), while maintained the antitumor activity in A549 and BCAP-37 cells xenograft tumor mouse models. Taken together, lipid emulsion loaded with vinorelbine-phospholipid complex is a promising vinorelbine intravenous injection with reduced venous irritation. PMID- 23806813 TI - In vitro study of the cytotoxicity and antiproliferative effects of surfactants produced by Sphingobacterium detergens. AB - The application of biosurfactants in the biomedical field is growing due to their antimicrobial activity, low cytotoxicity and ability to induce apoptosis in cancer cells. In the light of this therapeutic potential, as well as possible applications in cosmetics or as drug vehicles in pharmaceutical products, a new biosurfactant produced by Sphingobacterium detergens was investigated for its haemolytic activity and cytotoxic and antiproliferative effects in different cell lines. Fraction A showed 100% haemolysis in rabbit erythrocytes, but in Fraction B the rate was only 83%. When comparing cytotoxicity values (IC50) of the two fractions in model fibroblast and keratinocyte cell cultures, Fraction B was less cytotoxic, showing lower values than the reference compound SDS, indicating low skin irritability. Finally, in non-differentiated intestinal Caco-2 cultures, Fractions A and B reduced cell proliferation and induced apoptosis by 44% and 75%, respectively. According to these results, biosurfactants produced by S. detergens have potential application in cosmetic and pharmaceutical formulations. PMID- 23806814 TI - Using machine learning for improving knowledge on antibacterial effect of bioactive glass. AB - The aim of this work was to find relationships between critical bioactive glass characteristics and their antibacterial behaviour using an artificial intelligence tool. A large dataset including ingredients and process variables of the bioactive glasses production, bacterial characteristics and microbiological experimental conditions was generated from literature and analyzed by neurofuzzy logic technology. Our findings allow an explanation on the variability in antibacterial behaviour found by different authors and to obtain general conclusions about critical parameters of bioactive glasses to be considered in order to achieve activity against some of the most common skin and implant surgery pathogens. PMID- 23806815 TI - A versatile drug delivery system using streptavidin-tagged pegylated liposomes and biotinylated biomaterials. AB - Here we have developed a versatile liposome-mediated drug delivery system (DDS) allowing a strong bridge between the streptavidin-tagged liposome (SAL) and biotin (Bi)-tagged biomaterials which has strong affinity to surface proteins expressed in restricted cell lineages. This DDS was effective and specific for many leukemia cells in vitro and in vivo. When examining 6 human leukemia cell lines using calcein-encapsulated SALs in combination with Bi-granulocyte colony stimulating factor (G-CSF), Bi-anti-CD33 monoclonal antibody (MAb) or Bi-anti-CD7 MAb, the fluorescent positive rate of each cell line was in almost proportion to degree of G-CSF receptor, CD33 or CD7 expression, respectively. More importantly, the binding ability was shown to be well maintained in a mouse xenograft model. Furthermore the cytosine arabinoside (AraC)-encapsulated SALs could kill the corresponding cells much more effectively in combination with Bi-biomaterials than free AraC, as expected. These findings strongly indicate that our SAL/Bi biomaterial system could allow various types of medical agents to be delivered reliably and stably to the cells targeted. PMID- 23806816 TI - The internalization of fluorescence-labeled PLA nanoparticles by macrophages. AB - Rhodamine B (RhB)-labeled PLA nanoparticles were prepared through surface grafting copolymerization of glycidyl methacrylate (GMA) onto PLA nanoparticles during the emulsion/evaporation process. RhB firstly interacts with sodium dodecyl sulfate (SDS) through electrostatic interaction to form hydrophobic complex (SDS-RhB). Due to the high-affinity of SDS-RhB with GMA, hydrophilic RhB can be successfully combined into PLA nanoparticles. The internalization of RhB labeled PLA nanoparticles by macrophages was investigated with fluorescence microscope technology. The effects of the PLA nanoparticle surface nature and size on the internalization were investigated. The results indicate that the PLA particles smaller than 200 nm can avoid the uptake of phagocytosis. The bigger PLA particles (300 nm) with polyethylene glycol (PEG) surface showed less internalization by macrophage compared with those with poly(ethylene oxide propylene oxide) copolymer (F127) or poly(vinyl alcohol) (PVA) surface. The "stealth" function of PEG on the PLA nanoparticles from internalization of macrophages due to the low protein adsorption is revealed by electrochemical impedance technology. PMID- 23806818 TI - Can a brief two-hour interdisciplinary communication skills training be successful in undergraduate medical education? AB - OBJECTIVE: To pilot-test feasibility, acceptance and learning-outcomes of a brief interdisciplinary communication skills training program in undergraduate medical education. METHODS: A two-hour interdisciplinary communication skills program with simulated patients was developed and pilot-tested with clinical students at Hamburg University. Five psychosocial specialties facilitated the training. Composite effects were measured qualitatively and quantitatively. RESULTS: Eighty students volunteered to participate in the pilot-program (intervention-group). Their evaluations of the program were very positive (1.1 on a six-point scale). Benefits were seen in feedback, increase of self-confidence, cross-disciplinary clinical and communication experience. Students who did not volunteer (n=206) served as the control-group. The intervention-group performed significantly better (p=0.023) in a primary care communication examination and female students performed better than males. Clinical teachers evaluated the pilot-training very positively with regard to learning-outcomes and feasibility. The positive results from the pilot-training led to implementation into the regular curriculum. CONCLUSIONS: A two-hour interdisciplinary communication skills training program is beneficial for medical students with regard to communication competencies, self-confidence and learning-outcomes. PRACTICE IMPLICATION: The training is feasible within given time-frames and limited staff resources. The high teaching load for small-group-training are split between five specialties. The concept might be an interesting option for other faculties. PMID- 23806817 TI - Satisfaction with information provided to Danish cancer patients: validation and survey results. AB - OBJECTIVES: To validate five items (CPWQ-inf) regarding satisfaction with information provided to cancer patients from health care staff, assess the prevalence of dissatisfaction with this information, and identify factors predicting dissatisfaction. METHODS: The questionnaire was validated by patient observer agreement and cognitive interviews. The prevalence of dissatisfaction was assessed in a cross-sectional sample of all cancer patients in contact with hospitals during the past year in three Danish counties. RESULTS: The validation showed that the CPWQ performed well. Between 3 and 23% of the 1490 participating patients were dissatisfied with each of the measured aspects of information. The highest level of dissatisfaction was reported regarding the guidance, support and help provided when the diagnosis was given. Younger patients were consistently more dissatisfied than older patients. CONCLUSIONS: The brief CPWQ performs well for survey purposes. The survey depicts the heterogeneous patient population encountered by hospital staff and showed that younger patients probably had higher expectations or a higher need for information and that those with more severe diagnoses/prognoses require extra care in providing information. PRACTICAL IMPLICATIONS: Four brief questions can efficiently assess information needs. With increasing demands for information, a wide range of innovative initiatives is needed. PMID- 23806819 TI - PR3-ANCA: a promising biomarker for ulcerative colitis with extensive disease. AB - BACKGROUND: We determined if PR3-ANCA is a biomarker that differentiates ulcerative colitis (UC) from Crohn's disease (CrD). METHODS: A total of 946 sera were tested, including 86 granulomatosis with polyangiitis (GPA) and 491 inflammatory bowel disease (IBD) patients (283 UC and 208 CrD), 264 pathological controls (various diseases) and 105 healthy individuals. All samples were tested for PR3-ANCA by ELISA (QUANTA Flash Lite(r), INOVA Diagnostics) and chemiluminescent immunoassays (CIA QUANTA Flash PR3). Conventional anti neutrophil cytoplasmic antibody (ANCA) indirect immunofluorescence assays (IIF) was performed with NOVA LiteTM (INOVA Diagnostics). RESULTS: PR3-ANCA by CIA were detected in 31.1% UC vs. 1.9% CrD sera (p=2.2E-16), and by ELISA in 6% UC and 0% CrD (p=0.0003). In GPA patients, PR3-ANCA were detected in 75.6% by CIA and 61.6% by ELISA (p<0.05). PR3-ANCA by CIA were more prevalent in E3-UC compared to E1/2 UC (p<0.05), and in patients with shorter disease duration (p<0.0001). PR3-ANCA showed similar sensitivity, but significantly higher specificity (p<0.05), compared to atypical pANCA by IIF. CONCLUSION: The novel PR3 CIA may prove helpful in the differentiation of CrD from UC, as well as in the identification of UC patients with more extensive disease. PMID- 23806820 TI - Rosuvastatin inhibits human airway smooth muscle cells mitogenic response to eicosanoid contractile agents. AB - BACKGROUND: The concept of permanent narrowing of the airways resulting from chronic inflammation and fibrosis is called remodeling and is a common feature of asthma and chronic obstructive pulmonary disease (COPD). The eicosanoid contractile agents thromboxane A(2) (TxA(2)) and cysteinyl-leukotriene D(4) (LTD(4)) are among the recognized mitogens for human airway smooth muscle (ASM) cells. Statins are known to possess anti-inflammatory and immunomodulatory properties that are independent on their cholesterol-lowering effects and may result in clinical lung benefits. Rosuvastatin is the last agent of the lipid lowering drugs to be introduced and experimental evidence indicates that it possess favorable pleiotropic effects in the cardiovascular and nervous systems. Yet, no data is available in the literature regarding its effects on human airway remodeling. The present study was aimed at examining the effect of rosuvastatin and the involvement of prenylated proteins in the response of human ASM cells to serum, epidermal growth factor (EGF) and eicosanoid contractile mitogens that activate TxA(2) prostanoid and LTD(4) receptors. METHODS: Cell growth was assessed by nuclear incorporation of [(3)H]thymidine in human ASM cells serum starved and then stimulated for 48 h in MEM plus 0.1% BSA containing mitogens in the absence and presence of modulators of the mevalonate and prenylation pathways. RESULTS: We found that rosuvastatin dose-dependently inhibited serum-, EGF-, the TxA(2) stable analog U46619-, and LTD(4)-induced human ASM cells growth. All these effects were prevented by pretreatment with mevalonate. Addition of the prenylation substrates farnesol and geranylgeraniol reversed the effect of rosuvastatin on EGF and U46619, respectively. Interestingly, only mevalonate showed restoration of cell growth following rosuvastatin treatment in LTD(4) and LTD(4) plus EGF treated cells, suggesting a possible involvement of both farnesylated and geranylgeranylated proteins in the cysteinyl-LT-induced cell growth. CONCLUSIONS: The hydrophilic statin rosuvastatin exerts direct effects on human ASM cells mitogenic response in vitro by inhibiting prenylation of signaling proteins, likely small G proteins. These findings are consistent with previous observed involvement of small GTPase signaling in EGF- and U46619 induced human airway proliferation and corroborate the recent interest in the potential clinical benefits of statins in asthma/COPD. PMID- 23806821 TI - CSE1L modulates Ras-induced cancer cell invasion: correlation of K-Ras mutation and CSE1L expression in colorectal cancer progression. AB - BACKGROUND: Ras plays an important role in colorectal cancer progression. CSE1L (chromosome segregation 1-like) gene maps to 20q13, a chromosomal region that correlates with colorectal cancer development. We investigated the association of CSE1L with Ras in colorectal cancer progression. METHODS: The effect of CSE1L on metastasis-stimulating activity of Ras was studied in an animal model with tumor cells expressing CSE1L-specific shRNA and v-H-Ras. CSE1L expression was evaluated by the immunohistochemical analysis of 127 surgically resected colorectal tumors. K-Ras mutations were analyzed by direct sequencing. RESULTS: CSE1L knockdown reduced Ras-induced metastasis of B16F10 melanoma cells in C57BL/6 mice. v-H-Ras expression altered the cellular trafficking of CSE1L and increased CSE1L secretion. Most colorectal tumors were positive for CSE1L staining (98.4%, 125 of 127). Colorectal tumors with K-Ras mutation or high cytoplasmic CSE1L expression were correlated with T status (depth of tumor penetration; P = .004), stage (P = .004), and lymph node metastasis (P = .019). CONCLUSIONS: CSE1L may be a target for treating Ras-associated tumors. Analysis of K-Ras mutation and CSE1L expression may provide valuable clinical and pathological information to aid in the determination of treatment options for colorectal cancer. PMID- 23806822 TI - The effects of Batroxobin on the intimal hyperplasia of graft veins. AB - BACKGROUND: To investigate the effects of Batroxobin (BX) on the intimal hyperplasia of graft veins. METHODS: Twenty dogs were evenly divided into 2 groups. The femoral veins were grafted into the femoral artery by microsurgery, and the experimental group was treated with BX (0.1 BU/kg/48 hours). The serum level of endothelin-1 (ET-1) was detected 2 weeks after operation. Computer image analysis system was performed to calculate the cross-sectional area of neointima and media in the vein grafts 8 weeks after operation. Immunohistochemistry method was performed to identify proliferating cell nuclear antigen (PCNA) and c-Myc. RESULTS: The experimental group had a lower level of serum ET-1 than the control group (P < .01), and both intimal hyperplasia and media thickness of graft veins were reduced by BX in comparison with the control group (P < .05). C-Myc expression was higher in the control group than in the experimental group (P < .01). The PCNA expression in the experimental group was significantly lower than the control group (P < .05). CONCLUSIONS: These findings suggested that BX could inhibit intimal hyperplasia through suppressing cell proliferation activity. PMID- 23806823 TI - Intraoperative digital specimen mammography: a significant improvement in operative efficiency. AB - BACKGROUND: The goal of this study was to determine the length of operative time and its effect on surgeon productivity with the use of intraoperative digital specimen mammography (IDSM) compared to standard specimen mammography (SSM). METHODS: A retrospective chart review was performed on 344 consecutive patients from a single breast surgeon from 2003 to 2010. Operative time was compared between procedures using SSM vs IDSM. Surgeon productivity was evaluated by the number of wire-localized excisions performed prior to and after implementation of IDSM. RESULTS: Two hundred thirty patients underwent SSM and 114 underwent IDSM. Average operative time in the SSM group was 78 minutes vs 68 minutes in the IDSM group (P < .0001). In the first 2 years after implementation of IDSM, the number of wire-localized excisions performed increased by 20%. CONCLUSIONS: Operative times were significantly shorter with the use of IDSM vs SSM, and this was associated with an increase in surgeon productivity. PMID- 23806824 TI - The impact of lymph node disease in extremity soft-tissue sarcomas: a population based analysis. AB - BACKGROUND: Because of the low incidence of regional lymph node metastasis, node positive soft-tissue sarcoma patients remain poorly characterized. Our objective was to assess regional lymph node metastasis in extremity sarcoma patients using a large population database. METHODS: The Surveillance, Epidemiology, and End Results database was queried for extremity sarcoma patients. Clinicopathologic data and outcomes were examined to evaluate the significance of regional lymph node metastasis. RESULTS: Of 7,159 patients without distant metastasis, 64 patients had identified regional lymph node metastasis (.9%). Regional lymph node metastasis was associated with younger age, tumor grade, size, invasion, and tumor subtype. Excluding distant metastasis, lymph node status was the strongest prognostic factor (hazards ratio = 5.1, P < .001). CONCLUSIONS: Isolated regional lymph node metastasis is rare in extremity sarcoma patients. However, in the absence of distant metastasis, lymph node status is the most important prognostic factor. The management of positive lymph nodes remains uncertain although diagnosing lymph node metastasis may identify early biologically aggressive disease. PMID- 23806825 TI - Procalcitonin ratio as a predictor of successful surgical treatment of severe necrotizing soft tissue infections. AB - BACKGROUND: Necrotizing soft tissue infections often are characterized by fulminant presentation and lethal outcomes. Besides critical care support and antibiotic therapy, aggressive surgical treatment is important for the therapy of necrotizing fasciitis. The aim of this study was to develop a procalcitonin (PCT) ratio indicating successful surgical intervention. METHODS: The study group consisted of 38 patients treated with clinical signs of sepsis caused by a necrotizing soft tissue infection. All patients received radical surgical treatment, and serum levels of PCT and C-reactive protein were monitored postoperatively. The ratio of day 1 to day 2 was calculated and correlated with the successful elimination of the infectious source and clinical recovery. RESULTS: An eradication of the infectious focus was successfully performed in 84% of patients, averaging 1.9 operations (range 1 to 6) to achieve an elimination of the infectious source. The PCT ratio was significantly higher in the group of patients with successful surgical intervention (1.665 vs .9, P < .001). A ratio higher than the calculated cutoff of 1.14 indicated successful surgical treatment with a sensitivity of 83.3% and a specificity of 71.4%. The positive predictive value was 75.8%, and the negative predictive value was 80.0%. CONCLUSIONS: The PCT ratio of postoperative day 1 to day 2 following major surgical procedures for necrotizing soft tissue infections represents a valuable clinical tool indicating successful surgical eradication of the infectious focus. PMID- 23806826 TI - Resource-efficient mobilization programs in the intensive care unit: who stands to win? AB - BACKGROUND: Functional outcomes can improve with early intensive care unit (ICU) mobilization programs but require additional resources. Details regarding resource allotment and methods to deliver therapy are lacking. We describe an effective team-based, resource-efficient mobility program (REMP). METHODS: Consecutive admissions (November 2009 to March 2010) underwent an evaluation by a physical therapist and participation in the REMP. Sitting balance (SB), transfer from bed to chair, and ambulation were assessed on the initial evaluation and compared with ICU and hospital discharge using the Functional Independence Measure scale. RESULTS: Twenty-eight patients entered the REMP, and 31 patients served as controls. There were no differences in baseline characteristics or initial Functional Independence Measure scores for ambulation or SB. Bed-to-chair evaluation was higher in the controls (P < .024). Both groups improved across the 3 time periods on all measures; however, more REMP patients had a significantly improved SB at ICU and hospital discharge. CONCLUSIONS: A team-based, resource efficient approach to early mobilization is feasible and effective in the ICU. PMID- 23806827 TI - Pylorus resection in partial pancreaticoduodenectomy: impact on delayed gastric emptying. AB - BACKGROUND: Partial pancreaticoduodenectomy (PD) is complicated by postoperative delayed gastric emptying (DGE) in up to 45% of patients. The aim of this study was to evaluate the impact of pylorus resection on DGE following PD. METHODS: Forty PD patients underwent pylorus resection with complete stomach preservation (prPD). They were compared with a pair-matched group of PD patients with pylorus preservation (ppPD) in a 1:1 ratio (age, sex, histopathology). The objectives were operative parameters, DGE incidence, morbidity, and length of hospital stay. RESULTS: DGE incidence was significantly lower after prPD (15.0% vs 42.5%; P = .0066). Operative parameters and surgical morbidity (other than DGE) were not different (27.5% prPD vs 30.0% ppPD). There was a trend toward a shorter hospital stay in the prPD group. CONCLUSIONS: Resection of the pylorus with stomach preservation significantly reduces the frequency of DGE after PD without showing any disadvantage when compared with standard ppPD. This finding could be of high relevance for the clinical practice in routine PD and should consequently be investigated in a large randomized multicenter trial to create further evidence. PMID- 23806829 TI - Stump closure of a thick pancreas using stapler closure increases pancreatic fistula after distal pancreatectomy. AB - BACKGROUND: The appropriate surgical stump closure after distal pancreatectomy (DP) is still controversial. This study investigated the benefits and risks of stapler closure during DP. METHODS: The risk factors of pancreatic fistulas were investigated in 122 DPs among 3 types of stump closure: hand-sewn suture (n = 32), bipolar scissors (n = 45), and stapler closure (n = 45). RESULTS: There was no significant difference in the incidence of pancreatic fistula between the 3 types of stump closure (hand-sewn suture [44%] vs bipolar scissors [37.7%] vs stapler closure [35.5%]). By using receiver operating characteristics curves, 12 mm was the best cutoff value of the thickness of the pancreas for pancreatic fistulas after DP using stapler closure. Three factors (ie, male sex, body mass index >25 kg/m(2), and stapler closure) were independent risk factors of pancreatic fistulas after DP with a pancreas thicker than 12 mm. CONCLUSIONS: A pancreas thicker than 12 mm significantly increased the incidence of pancreatic fistulas after DP using stapler closure. PMID- 23806828 TI - The use of the Hirsch index in benchmarking hepatic surgery research. AB - BACKGROUND: The Hirsch index (h-index) is recognized as an effective way to summarize an individual's scientific research output. However, a benchmark for evaluating surgeon scientists in the field of hepatic surgery is still not available. METHODS: A total of 3,251 authors who published between 1949 and 2011 were identified using the Scopus identification number. The h-index, the total number of cited document, the total number of citations, and the scientific age were calculated for each author using both Scopus and Google Scholar. RESULTS: The median h-index was 6 and the median scientific age, assessed with Google Scholar, was 19 years. The numbers of cited documents, numbers of citations, and h-indexes obtained from Scopus and Google Scholar showed good correlation with one another; however, the results from the 2 databases were modified in different ways by scientific age. By plotting scientific age against h-index percentiles an h-index growth chart for both Scopus database and Google Scholar was provided. CONCLUSIONS: This analysis provides a first benchmark to assess surgeon scientists' productivity in the field of liver surgery. PMID- 23806830 TI - Sex variability of fine-needle aspiration reliability in the diagnosis of malignancy in thyroid nodules >=4 cm. AB - BACKGROUND: The effect of sex on fine-needle aspiration (FNA) diagnosis of thyroid cancer remains unknown. This study determines the reliability of FNA when evaluating thyroid nodules >=4 cm in women and men. METHODS: Prospectively collected data of 1,068 patients who underwent FNA and thyroidectomy at a tertiary medical center were retrospectively reviewed. Data were stratified by sex and thyroid nodule size >=4 cm. RESULTS: The FNA false-negative rate for thyroid malignancy in women and men was 17% and 0%, respectively. FNA was less predictive of malignancy in women (odd ratio = 31.7; 95% confidence interval, 19.2 to 52.5; P < .0001) compared with men (odds ratio = 51.7; 95% confidence interval, 11.8 to 225.1; P < .0001) with thyroid nodules >=4 cm. CONCLUSIONS: For the diagnosis of malignancy in large thyroid nodules, FNA may be less reliable in women compared with men. This study advocates using a more aggressive approach that includes surgical resection for definitive diagnosis in women with thyroid nodules >=4 cm. PMID- 23806831 TI - Classification and individualization of used engine oils using elemental composition and discriminant analysis. AB - The six most common commercial automotive gasoline and diesel engine oils in the Republic of Korea, ZIC A, ZIC XQ RV/SUV, Kixx G1, Kixx RV, and the brand name products HD Premium gasoline and HD Premium diesel, were randomly used in nineteen different vehicles. Samples of seventy-six used engine oils, which were withdrawn from the sumps of those vehicles at different intervals, were analyzed using inductively coupled plasma-optical emission spectrometry (ICP-OES), and statistically compared. Two data analysis strategies were used to interpret and understand the elemental profiles in the multi-dimensional data. Macro (additive elements of Ca, Zn and P) and trace (wear metal elements of Ag, Al, Ba, Cd, Cr, Cu, Fe, Mg, Mo, Na, Ni, Pb and Sn) elements were used as potential markers to determine the brand of oil used and the engine type in which the oil was used, and to trace the individual vehicle for forensic purposes. The discriminant analysis statistical technique was applied, and its prediction ability was assessed. In this study, 92.1%, 82.9% and 92.1% of the cross-validated grouped cases correctly predicted the brand of oil, the engine type and the vehicle that was the source of the oil, respectively. PMID- 23806833 TI - Structure-activity-relationship studies on dihydrofuran-fused perhydrophenanthrenes as an anti-Alzheimer's disease agent. AB - As an extended study on development of anti-Alzheimer's disease agent, we newly synthesized various dihydrofuran-fused perhydrophenanthrenes via o-quinodimethane chemistry. This study revealed that the introduction of carbon side-chain on 8 position or removal of the acetal moiety on 3-position arose a cytotoxicity on rat cortical neurons. On the other hand, the ethereal or thio-ethereal substituent on 8-position enhanced the elongation effect on Abeta-damaged neurons. The necessity of the cyano group on 10b position was also proved in this structure-activity-relationship study. PMID- 23806832 TI - Cortisol at the emergency room rape visit as a predictor of PTSD and depression symptoms over time. AB - BACKGROUND: Dysregulation of the hypothalamic-pituitary-adrenal axis, typically reflected by alterations in cortisol responsivity, has been associated with exposure to traumatic events and the development of stress-related disorders such as posttraumatic stress disorder (PTSD) and depression. METHODS: Serum cortisol was measured at the time of a post sexual assault medical exam among a sample of 323 female victims of recent sexual assault. Analyses were conducted among 235 participants who provided data regarding history of previous assault as well as PTSD and depression symptoms during at least one of the three follow-ups. RESULTS: Growth curve models suggested that prior history of assault and serum cortisol were positively associated with the intercept and negatively associated with the slope of PTSD and depression symptoms after controlling for covariates. Prior history of assault and serum cortisol also interacted to predict the intercept and slope of PTSD and depression symptoms such that women with a prior history of assault and lower ER cortisol had higher initial symptoms that decreased at a slower rate relative to women without a prior history and those with higher ER cortisol. CONCLUSIONS: Prior history of assault was associated with diminished acute cortisol responsivity at the emergency room visit. Prior assault history and cortisol both independently and interactively predicted PTSD and depression symptoms at first follow-up and over the course a 6-month follow up. PMID- 23806834 TI - C-(alpha-d-Glucopyranosyl)-phenyldiazomethanes-irreversible inhibitors of alpha glucosidase. AB - Several C-(alpha-d-glucopyranosyl)-phenyldiazomethanes, with different substituent groups at the para-position of the phenyl ring, were prepared. The stabilities of these diazo compounds were investigated through NMR and UV monitoring. The para-cyano substituted diazo compound was found to be stable in neutral media (pH 7.0 buffer) and could be isolated. Inhibitory activity investigations indicated that this compound is an irreversible inhibitor against alpha-glucosidase from Saccharomyces cerevisiae. PMID- 23806835 TI - A one-pot enzymatic approach to the O-fluoroglucoside of N-methylanthranilate. AB - In connection with prospective (18)F-PET imaging studies, the potential for enzymatic synthesis of fluorine-labelled glycosides of small molecules was investigated. Approaches to the enzymatic synthesis of anomeric phosphates of d gluco-configured fluorosugars proved ineffective. In contrast, starting in the d galacto series and relying on the consecutive action of Escherichia coli galactokinase (GalK), galactose-1-phosphate uridylyltransferase (GalPUT), uridine 5'-diphosphogalactose 4-epimerase (GalE) and oat root glucosyltransferase (SAD10), a quick and effective synthesis of 6-deoxy-6-fluoro-d-glucosyl N methylanthranilate ester was achieved. PMID- 23806836 TI - Morphology and pathophysiology of target anatomical sites for ablation procedures in patients with atrial fibrillation. Part I: atrial structures (atrial myocardium and coronary sinus). AB - Experimental and clinical evidence suggests that the natural history of atrial fibrillation is characterised by increased structural remodelling, which may play a pivotal role in maintaining the arrhythmia and clinically favours progression from paroxysmal to persistent atrial fibrillation. In this setting, anti arrhythmic therapy gradually becomes inefficient, and this limitation has led to the introduction of new non-pharmacological interventions such as surgical or catheter ablation. At the same time, interest in the functional morphology and electrophysiological properties of the atria and their related anatomical structures has greatly increased. This article is the first of a two-part review whose main purpose is to describe the anatomical and functional details of some of the principal anatomical locations that are commonly targeted by ablative procedures to treat this supraventricular arrhythmia. In particular, this manuscript has dealt with the atrial structures (atrial myocardium and coronary sinus). General information on ablation procedures has also been provided. PMID- 23806837 TI - A request for an alliance in the battle for clean and safe hospital surfaces. PMID- 23806838 TI - Floor wars: the battle for 'clean' surfaces. PMID- 23806839 TI - Prevalence of latent tuberculosis infection among healthcare workers in China as detected by two interferon-gamma release assays. AB - Healthcare workers in China have a high risk of tuberculosis infection. This study measured the prevalence of latent tuberculosis infection in 210 healthcare workers in a chest hospital in Harbin using two interferon-gamma release assays (IGRAs) [QuantiFERON((r))-TB Gold In-Tube (QFT-GIT) and A.TB] and the tuberculin skin test. Results from the IGRAs had moderate agreement with positivity rates of 76.5% (QFT-GIT) and 65.7% (A.TB) but <50% of subjects returned for tuberculin skin test readings. Risk of infection increased with patient exposure. IGRAs may be more useful than tuberculin skin test in monitoring tuberculosis infections in high risk environments. PMID- 23806840 TI - The neural basis of implicit learning and memory: a review of neuropsychological and neuroimaging research. AB - Memory systems research has typically described the different types of long-term memory in the brain as either declarative versus non-declarative or implicit versus explicit. These descriptions reflect the difference between declarative, conscious, and explicit memory that is dependent on the medial temporal lobe (MTL) memory system, and all other expressions of learning and memory. The other type of memory is generally defined by an absence: either the lack of dependence on the MTL memory system (nondeclarative) or the lack of conscious awareness of the information acquired (implicit). However, definition by absence is inherently underspecified and leaves open questions of how this type of memory operates, its neural basis, and how it differs from explicit, declarative memory. Drawing on a variety of studies of implicit learning that have attempted to identify the neural correlates of implicit learning using functional neuroimaging and neuropsychology, a theory of implicit memory is presented that describes it as a form of general plasticity within processing networks that adaptively improve function via experience. Under this model, implicit memory will not appear as a single, coherent, alternative memory system but will instead be manifested as a principle of improvement from experience based on widespread mechanisms of cortical plasticity. The implications of this characterization for understanding the role of implicit learning in complex cognitive processes and the effects of interactions between types of memory will be discussed for examples within and outside the psychology laboratory. PMID- 23806841 TI - A video-based learning activity is effective for preparing physiotherapy students for practical examinations. AB - OBJECTIVES: To examine a video-based learning activity for engaging physiotherapy students in preparation for practical examinations and determine student performance outcomes. DESIGN: Multi-method employing qualitative and quantitative data collection procedures. SETTING: Tertiary education facility on the Gold Coast, Queensland, Australia. PARTICIPANTS: Physiotherapy students in their first year of a two-year graduate entry program. MAIN OUTCOME MEASURES: Questionnaire based surveys and focus groups were used to examine student perceptions and satisfaction. Surveys were analysed based on the frequency of responses to closed questions made on a 5-pont Likert scale, while a thematic analysis was performed on focus group transcripts. t-Tests were used to compare student awarded marks and examiner awarded marks and evaluate student performance. RESULTS: Sixty-two physiotherapy students participated in the study. Mean response rate for questionnaires was 93% and eight students (13%) participated in the focus group. Participants found the video resources effective to support their learning (98% positive) and rating the video examples to be an effective learning activity (96% positive). Themes emergent from focus group responses were around improved understanding, reduced performance anxiety, and enjoyment. Students were, however, critical of the predictable nature of the example performances. Students in the current cohort supported by the video-based preparation activity exhibited greater practical examination marks than those from the previous year who were unsupported by the activity (mean 81.6 SD 8.7 vs. mean 78.1 SD 9.0, p=0.01). CONCLUSION: A video-based learning activity was effective for preparing physiotherapy students for practical examinations and conferred benefits of reduced anxiety and improved performance. PMID- 23806842 TI - Human erythropoietin gene delivery for cardiac remodeling of myocardial infarction in rats. AB - Considerable efforts have been made to exploit cardioprotective drugs and gene delivery systems for myocardial infarction (MI). The promising cardioprotective effects of recombinant human erythropoietin (rHuEPO) protein in animal experiments have not been consistently reproduced in clinical human trials of acute MI; however, the mechanisms underlying the inconsistent discrepancies are not yet fully understood. We hypothesized that the plasmid human erythropoietin gene (phEPO) delivered by our bioreducible polymer might produce cardioprotective effects on post-infarct cardiac remodeling. We demonstrated that intramyocardial delivery of phEPO by an arginine-grafted poly(disulfide amine) (ABP) polymer in infarcted rats preserves cardiac geometry and systolic function. The reduced infarct size of phEPO/ABP delivery was followed by decrease in fibrosis, protection from cardiomyocyte loss, and down-regulation of apoptotic activity. In addition, the increased angiogenesis and decreased myofibroblast density in the border zone of the infarct support the beneficial effects of phEPO/ABP administration. Furthermore, phEPO/ABP delivery induced prominent suppression on Ang II and TGF-beta activity in all subdivisions of cardiac tissues except for the central zone of infarct. These results of phEPO gene therapy delivered by a bioreducible ABP polymer provide insight into the lack of phEPO gene therapy translation in the treatment of acute MI to human trials. PMID- 23806843 TI - The PhtL protein of Pseudomonas syringae pv. phaseolicola NPS3121 affects the expression of both phaseolotoxin cluster (Pht) and Non-Pht encoded genes. AB - Pseudomonas syringae pv. phaseolicola, the causal agent of halo blight disease in bean, produces a toxin known as phaseolotoxin, whose synthesis involves the products of some of the genes found within the Pht region. This region, considered a pathogenicity island, comprises 23 genes arranged in five transcriptional units: two single-gene units (argK, phtL) and three arranged as operons (phtA, phtD, phtM), most with unknown function. In P. syringae pv. phaseolicola, maximal expression of most of the genes encoded in the Pht region and the synthesis of phaseolotoxin require the product of the phtL gene, of unknown function but that has been proposed to have a regulatory role. In order to evaluate the role of phtL gene in P. syringae pv. phaseolicola, we performed a comparative transcriptional analysis with the wild type and a phtL(-) mutant strains using microarrays. The microarray data analysis showed that PhtL regulates the expression not only of genes within the Pht region, but also alters the expression of genomic genes outside it, indicating that this gene has been integrated into the regulatory machinery of the bacterium. The expression changes of many of those genes were confirmed by RT-PCR. This study also demonstrated the importance of the PhtL protein in the process of iron response, and suggests that the effect of PhtL on the expression of pathogenicity related, respiration and oxidative stress genes, observed in this study, appears to be indirect through its influence on the Fur protein expression. PMID- 23806844 TI - Classifying idiopathic inflammatory myopathies: comparing the performance of six existing criteria. AB - OBJECTIVES: Various criteria have been proposed to classify the inflammatory myositides (IIMs) polymyositis (PM) and dermatomyositis (DM). However, none have received universal acceptance. Our aim was to assess the performance of the main criteria used to classify IIM. Specialist consultant diagnosis was considered the gold standard. METHODS: Patients attending King's College Hospital (KCH) or Reggio Emilia Hospital (REH) since 1990 with a diagnosis of IIM or non inflammatory myopathy were identified, and their records and laboratory investigations retrospectively reviewed. Where the complete data required for the classification criteria or a final physician diagnosis was unavailable, patients were excluded. 52 patients with a specialist diagnosis of PM, DM, inclusion body myositis (IBM) or non-inflammatory myopathy were included. Agreement between specialist consultant diagnosis and classification criteria was measured using Cohen's kappa (kappa) statistics. Sensitivity and specificity were also calculated. RESULTS: The Dalakas (2003) criteria demonstrated substantial agreement with specialist diagnosis: kappa=0.69, sensitivity 77%, specificity 99%. The European Neuromuscular Centre criteria (ENMC) demonstrated fair agreement: kappa=0.49, sensitivity 71%, specificity 82%. Other criteria performed less well. In particular, the Bohan and Peter criteria demonstrated a specificity of only 29%. CONCLUSIONS: The criteria of Dalakas (2003) agreed best with specialist consultant diagnosis. The criteria of Bohan and Peter demonstrated very poor specificity. Prospective studies are required to develop improved classification criteria. PMID- 23806845 TI - Reply of the authors. PMID- 23806846 TI - Early luteal phase endocrine profile is affected by the mode of triggering final oocyte maturation and the luteal phase support used in recombinant follicle stimulating hormone-gonadotropin-releasing hormone antagonist in vitro fertilization cycles. AB - OBJECTIVE: To assess endocrine differences during early luteal phase according to mode of triggering final oocyte maturation with or without luteal phase support (LPS). DESIGN: A prospective randomized study. SETTING: University center for reproductive medicine. PATIENT(S): Four oocyte donors each underwent four consecutive cycles. INTERVENTION(S): To avoid interpatient variation, each donor underwent the same stimulation regimen. However, different modes of triggering final oocyte maturation and LPS were administered: A) 10,000 IU hCG and standard LPS; B) GnRH agonist (GnRHa; 0.2 mg triptorelin), and 35 hours later 1,500 IU hCG, and standard LPS; C) GnRH agonist (0.2 mg triptorelin) and standard LPS; and D) GnRH agonist (0.2 mg triptorelin) without LPS. MAIN OUTCOME MEASURE(S): Blood sampling was performed on the day of ovulation trigger, ovulation trigger + 1 day, and ovum pick-up + 5 days. Serum E2, FSH, LH, and P were measured. RESULT(S): The early luteal phase steroid levels following GnRHa trigger and modified luteal phase support (B) were similar to those seen after hCG trigger (A). However, significant differences were seen between groups A and B compared with C and D, as well as between groups C and D. CONCLUSION(S): Administration of a single bolus of GnRHa effectively induced LH and FSH surges in oocyte donors stimulated with recombinant FSH and cotreated with a GnRH antagonist. However, gonadotropin and steroid levels differed significantly according to the type of luteal phase support used after GnRHa trigger. EUROPEAN COMMUNITY CLINICAL TRIAL SYSTEM (EUDRACT) NUMBER: 2009-009429-26. PMID- 23806847 TI - Endometrial signaling pathways during ovarian stimulation for assisted reproduction technology. AB - OBJECTIVE: To determine the effects of different hormonal levels on endometrial biochemical development during ovulation induction for assisted reproduction technology (ART) cycles. DESIGN: Prospective controlled study. SETTING: University center. PATIENT(S): Nine women during a natural cycle (control) and 9 oocyte donors (treated) during an ART cycle. INTERVENTION(S): At the time consistent with day 3 embryo transfer (LH+5 in control, hCG+5 in treated), transvaginal ultrasound, endometrial biopsy, and blood sampling were performed. Real-time reverse-transcription polymerase chain reaction was used to measure mRNA levels for insulin receptor (InsR), type I IGF receptor (IGFRI), prolactin receptor (PRL-R), androgen receptor (AR), TSH receptor (TSHR), nuclear receptors for T3 and T4 (TRalpha1, TRalpha2, and TRbeta1), iodothyronine deiodinase (DIO2), and 1,25-dihydroxyvitamin D3 receptor (VDR) in the endometrial tissue. MAIN OUTCOME MEASURE(S): Biochemical endometrial development. RESULT(S): IGFRI mRNA levels were 69% lower in treated patients than in control subjects, 0.12 +/- 0.005 pg/MUg RNA versus 0.39 +/- 0.01 pg/MUg RNA. TSHR mRNA was 57% lower, 2.6 +/ 0.1 fg/MUg RNA versus 6.0 +/- 0.2 fg/MUg RNA. TRalpha1 and TRalpha2 mRNA did not change, but TRbeta1 mRNA levels were 63% higher. DIO2 mRNA was 63% lower, 1.2 +/- 0.07 pg/MUg RNA versus 3.2 +/- 0.2 pg/MUg RNA. InsR mRNA levels, despite being 68% lower in treated patients, did not reach significance, and PRL-R, AR, and VDR did not significantly change. CONCLUSION(S): Exposure of the endometrium to ovarian stimulation appears to influence insulin and thyroid hormone signaling pathways in the decidua at day 3 embryo transfer, whereas prolactin, androgen, and vitamin D pathways are uninfluenced. These findings echo the known delayed endometrial maturation during ovarian stimulation. PMID- 23806848 TI - Fertilization and embryo development with spermatozoa obtained from testicular sperm extraction into oocytes generated from human chorionic gonadotropin-primed in vitro maturation cycles. AB - OBJECTIVE: To evaluate the fertilization rate and embryo development resulting from intracytoplasmic sperm injection (ICSI) of spermatozoa retrieved by testicular sperm extraction (TESE) in hCG-primed in vitro maturation (IVM) cycles. DESIGN: Case-control study. SETTING: University teaching hospital. PATIENT(S): Twenty-four IVM cycles were performed in 21 patients (mean age, 32.3 +/- 2.4 years) with polycystic ovaries (PCO) whose partners were nonobstructive azoospermic. Twelve cycles where IVM oocytes were also retrieved were compared with a control group consisting of age-matched IVM cycles with ICSI using ejaculated spermatozoa (n = 12). INTERVENTION(S): In vitro maturation treatment with TESE sperm. MAIN OUTCOME MEASURE(S): Fertilization and embryo development between sibling oocytes matured in vivo and in vitro. RESULT(S): Eight singleton pregnancies and one twin pregnancy were obtained after ET (9/24, 37.5%). In the 12 IVM cycles where in vivo-matured oocytes were also obtained, the fertilization rate after TESE-ICSI was significantly higher in in vivo-matured oocytes than in sibling in vitro-matured oocytes (84.2% vs. 53.2%). The proportion of good quality embryos was also higher (63.5% vs. 40.2%). In the control group of cycles with ejaculated spermatozoa, there was no difference in fertilization rates between sibling oocytes matured in vivo and in vitro (84.6% vs. 79.6%). CONCLUSION(S): Our results suggest that IVM of immature oocytes combined with TESE-ICSI is an option for couples with PCO and azoospermia. However, there are lower fertilization and good quality embryo rates achieved when TESE-ICSI was done with in vitro-matured oocytes. Additional studies are necessary to determine the role of this treatment combination. PMID- 23806849 TI - Is universal application of blastocyst biopsy with comprehensive chromosome screening for embryo selection ready for prime time? PMID- 23806851 TI - Response to editorial entitled "Biomarkers of endometrial receptivity through a minimally invasive approach". PMID- 23806850 TI - A randomized trial comparing the endometrial effects of daily subcutaneous administration of 25 mg and 50 mg progesterone in aqueous preparation. AB - OBJECTIVE: To study the efficacy of a new P preparation in aqueous solution for subcutaneous injection for inducing the predecidual transformation of the endometrium. DESIGN: Prospective, single-blinded, randomized, parallel pilot trial. SETTING: University-affiliated clinical research center. PATIENT(S): Twenty-five regularly cycling female volunteers. INTERVENTION(S): Volunteers, aged 18-45 years, body mass index 19-25 kg/m(2), whose ovaries were suppressed with a GnRH agonist were estrogenized for 14 or 21 days with the use of transdermal systems delivering 0.1 mg/d E2. After confirming that the endometrial thickness was >7 mm, the women were randomized to 25 mg or 50 mg of subcutaneous P injections daily for 11 days, after which the endometrium was sampled with the use of a Pipelle device. The endometrial biopsies were evaluated by two independent pathologists. Adverse events and subjective tolerance were checked every day by the study investigator. MAIN OUTCOME MEASURE(S): Predecidual changes in endometrial biopsies obtained after 11 days of subcutaneous administration of P. RESULT(S): Of 24 biopsies performed (one dropout), 22 provided tissue for histologic analysis. Evidence of predecidual changes in the endometrial stroma was found in 100% of the cases, with no differences between the two studied doses. CONCLUSION(S): Both doses of the new aqueous P preparation available for subcutaneous administration demonstrated predecidual changes in 100% of the interpretable endometrial biopsies in total absence of endogenous P. This offers good prospect of efficacy in luteal phase support for the lowest dose tested, 25 mg/d, the physiologic amount produced daily by the ovary during the midluteal phase. CLINICAL TRIAL REGISTRATION NUMBER: NCT00377923. PMID- 23806852 TI - Low tolerance for complications. AB - Assisted reproductive techniques can lead to medical complications such as multiple pregnancy and ovarian hyperstimulation syndrome. A critical appraisal and strategies to reduce the occurrence of these complications are discussed in this manuscript. PMID- 23806853 TI - Colour of fat, and colour, fatty acid composition and sensory characteristics of muscle from heifers offered alternative forages to grass silage in a finishing ration. AB - The effect of type of silage offered to beef heifers during the finishing period on aspects of beef quality was determined. In two experiments, a diet based on grass silage (GS) was compared with a diet based on maize silage (MS) or whole crop wheat silage (WCW). Compared to the GS-based diet, increasing the amount of MS linearly increased fat whiteness while the increase in fat whiteness due to WCW was dependent on the stage of crop maturity at harvesting. There was no effect of diet on muscle colour or on muscle pH measured at 48h post-mortem, drip loss, taste panel traits after 14days ageing or shear force values at 2, 7 or 14days ageing. The alternative silages decreased the n-3 polyunsaturated fatty acid proportion and increased the linoleic:linolenic acid ratio in intramuscular lipid. It is concluded that type of silage affects fat colour and fatty acid composition of muscle but not the other muscle characteristics examined. PMID- 23806854 TI - Use of infrared ocular thermography to assess physiological conditions of pigs prior to slaughter and predict pork quality variation. AB - Infrared thermography (IRT) body temperature readings were taken in the ocular region of 258 pigs immediately before slaughter. Levels of lactate were measured in blood taken in the restrainer. Meat quality was assessed in the longissimus dorsi (LD), semimembranosus (SM), and adductor muscles. Ocular IRT (IROT) temperature was correlated with blood lactate levels (r=0.20; P=0.001), with pH taken 1hour postmortem (pH1: r=-0.18; P=0.03) and drip loss (r=0.20; P=0.02) in the LD muscle, and with pH1 in the SM muscle (r=-0.20; P=0.02). Potentially, IROT may be a useful tool to assess the physiological conditions of pigs at slaughter and predict the variation of important meat quality traits. However, the magnitude of the correlations is rather low, so a further development of image capture technique and further studies under more variable preslaughter conditions ensuring a larger pork quality variation are needed. PMID- 23806855 TI - Endocrinology of number of follicular waves per estrous cycle and contralateral or ipsilateral relationship between corpus luteum and preovulatory follicle in heifers. AB - A 3-d extension of the luteal phase occurs in interovulatory intervals (IOIs) with a contralateral relationship between the corpus luteum (CL) and preovulatory follicle with 3 follicular waves (Contra-3W group). Concentrations of FSH, progesterone, LH, and estradiol-17beta for the ipsilateral versus contralateral CL and/or follicle relationship and 2 versus 3 waves per IOI were studied in 14 heifers. Follicular waves and FSH surges were designated 1, 2, or 3, according to order of occurrence in the IOI. The day (day 0 = ovulation) of the FSH peak in surge 2 occurred earlier (P < 0.02) in 3-wave IOIs (day 6.3 +/- 0.5) than in 2 wave IOIs (day 8.5 +/- 0.5). Mean FSH was higher in 3-wave than in 2-wave IOI on 82% of the days in the IOI. Repeatability or individuality in FSH concentration was indicated by a correlation (r = 0.54, P < 0.04) in FSH concentrations between ovulations at the beginning and at the end of the IOI. Concentrations of LH and estradiol increased (P < 0.05) near the beginning of the luteolytic period in 2 wave IOI regardless of the CL and/or follicle relationship. In the Contra-3W group, LH and estradiol remained at basal concentrations concurrently with FSH surge 3 and extension of the luteal phase. The hypotheses were supported that FSH surge 2 occurs earlier in 3-wave IOIs than in 2-wave IOIs and that the development of 3-wave IOIs occurs in individuals with greater FSH concentrations. Extension of the luteal phase in the Contra-3W group was temporally associated with lower concentrations of LH and estradiol. PMID- 23806856 TI - Benthic community and biological trait composition in respect to artificial coastal defence structures: a study case in the northern Adriatic Sea. AB - Biological Traits Analysis (BTA) is a method for addressing ecological functioning based on traits exhibited by members of biological assemblages. This study explores and compares species and biological trait patterns on either side (landward and seaward) of coastal breakwater structures in northwestern Adriatic Sea (Italy), with the aim of giving insights and knowledge for management of sandy beach systems affected by coastal development. Eight ecological traits of 96 benthic species were considered. Taxon composition evidenced differences in benthic assemblages across time and exposure: landward and seaward communities shared less than 50% of the total number of species. BTA suggested a no management effect in the functioning of benthic assemblages. Dominant traits modalities were deposit-feeding, short life, small body size, short life span, iteroparity, gonocorism, with plankto-planktotrophic larvae. The results of BTA highlighted similarities and stability in trait composition contrary to species composition, suggesting a possible persistence in benthic functioning despite the occurrence of species replacements. To best of my knowledge, this study is one of the first attempts to investigate the effects of a management measure (submerged shore-parallel barriers with groynes) in a shallow marine system by means of BTA. PMID- 23806857 TI - Understanding the relationships between body esteem, risk for anorexia nervosa, and domain-dependent decision-making impulsivity in a college sample. AB - Impulsivity has been suggested to interact with low body esteem to elevate risk for anorexia nervosa. Discounting tasks are unique tools for examining impulsivity. Female college students (N=139) at varying levels of body esteem and risk for anorexia nervosa responded to discounting scenarios depicting opportunities to lose/gain weight and to worsen/improve complexion. Multiple regression analyses were used to examine the relationships between impulsivity and risk for anorexia nervosa and body esteem in four disorder-relevant decision making contexts. Results indicated that lower decision-making impulsivity predicted lower body esteem levels when the outcome of the task was framed as an opportunity to lose weight. It is suggested that greater self-control regarding weight-loss in women with low body esteem may be problematic, placing them at higher risk for eating- and weight-related problems. Results reiterate the need for continued attention to fostering healthy body esteem and weight-control patterns in women on college campuses. PMID- 23806858 TI - Percutaneous cryoablation for stage IV lung cancer: a retrospective analysis. AB - The aim of this study was to investigate the therapeutic effect of cryoablation treatment and palliative treatment in stage IV lung cancer. Fifty-four patients were enrolled into the study. Thirty-one patients received cryoablation treatment (including intra- and extrapulmonary tumors), and 23 patients had palliative treatment (no cryoablation). Both the safety of the procedure and overall survival (OS) for stage IV lung cancer were assessed during a 6.5 year follow-up period. The OS of patients in both groups and the effects of treatment timing and frequency were compared. The OS in the cryoablation group was significantly longer than in the palliative group (median OS: 14 months vs. 7 months, P = 0.0009). The OS of those who received delayed cryoablation treatment was longer than that observed for those who received timely treatment (median OS: 18.5 months vs. 10 months, P = 0.0485), but this was not observed in those who received palliative treatment (median OS: 7 months vs. 7.5 months, P = 0.9814). Multiple treatments played an important role in improving the OS of patients who received cryoablation treatment (median OS: 18 months vs. 14 months, P = 0.0376). There was a significant difference between cryoablation and palliative treatment, in terms of OS. In addition, multiple cryoablation treatments may have an advantage over single treatments. PMID- 23806859 TI - [Cardiac impairment after hanging attempt: a preliminary descriptive study]. AB - PURPOSE OF THE STUDY: Cardiomyopathy has sometimes been reported after suicide attempts by hanging. The objective of this retrospective observational study was to describe cardiac dysfunction occurring after hanging and its consequences on prognosis. PATIENTS AND METHODS: Fifteen patients admitted to the intensive care unit for hanging from 1997 to 2011 were included and divided into two groups according to presence or absence of cardiac arrest at initial presentation. Cardiac dysfunction was defined by the presence of clinical, biological, electrocardiographic or echocardiographic abnormalities. RESULTS: Cardiac impairment was diagnosed in nine patients over 15 (60%). Of the six patients with initial cardiac arrest, only one survived without severe neurological sequellae. Among the nine patients without cardiac arrest, eight survived and five patients (56%) had cardiac impairment, including two cases of echocardiographic aspect of Takotsubo complicated by pulmonary edema. Mortality in intensive care was significantly related to the severity of the initial neurological state assessed by the Glasgow Coma Score (OR=1.7; P=0.02), and the occurrence of cardiac arrest (OR=40; P=0.016). The presence of cardiac involvement, reversible after the acute phase in all surviving patients was not associated with increased mortality. CONCLUSION: In the aftermath of hanging, predictors of mortality are the presence of impaired consciousness or initial cardiac arrest, but not the occurrence of cardiac disease. PMID- 23806860 TI - [Transthoracic echocardiography in a heart institute in Abidjan (Ivory Coast): Indications and evaluation of the request appropriateness]. AB - OBJECTIVES: The aim of this study was to clarify the clinical situations motivating indications of transthoracic echocardiography (TTE) in a cardiology institute in Cote d'Ivoire and to assess the appropriateness of indications. PATIENTS AND METHODS: This is a prospective and observational study conducted over a period of 6 months. The 1733 enrolled were classified according to the indications and their relevance defined by the American College of Cardiology Foundation Appropriate Use Criteria Task Force, the American Society of Echocardiography and the American Heart Association (ACCF/ASE/AHA). RESULTS: In five cases (0.3%), indications were not listed in the document ACCF/ASE/AHA. The most common indication was the initial evaluation of hypertension (HTA) and suspicion of hypertensive heart disease (47.3%). All indications, the assessment in the context of hypertension represented 853 examinations (49.2%). Heart failure accounted for 5.3% of indications, but consisted of 302 applications (17.4%) when was associated hypertension with signs suggestive of heart failure. Requests were considered as appropriate in 95.3%, inappropriate in 3.2% and uncertain in 1.6%. In the group of inappropriate indications patients were significantly younger, and were examinations more often normal and less often absolutely abnormal. CONCLUSION: The profile of cardiovascular morbidity in our institution is dominated by the spectrum of hypertension and heart failure. Each indication must be balanced for the profitability of the ETT. PMID- 23806861 TI - [Caseous calcification of the mitral annulus, variable and revealing clinical picture, and the contribution of cardiac tomodensitometry to the diagnosis: report of two cases]. AB - Caseous calcification of the mitral annulus (CCMA) is a rare variant of mitral annular calcification and a common echocardiographic finding. CCMA discovery is mostly incidental, considered as benign tumor and may be unrelated to patient symptoms. Multimodality imaging may have an additional value for the diagnosis of CCMA. We report the cases of two CCMA revealed by acute pulmonary oedema and stroke, respectively. The aims of this presentation are: to illustrate the variety of cardiac symptoms that led to the diagnosis of CCMA; and to highlight the usefulness of thoracic multisliced computed tomography for the diagnosis of CCMA. PMID- 23806862 TI - [Cardiac tamponade and myocarditis in Churg-Strauss syndrome]. AB - INTRODUCTION: The successive occurrence of pericardial tamponade and myocarditis during a Churg-Strauss syndrome is exceptionally described. We report a patient in whom pericardial tamponade and myocarditis were the presenting manifestation of a Churg-Strauss syndrome. CASE REPORT: A 58-year-old woman was admitted because of alteration of the clinical status with eosinophilia. One month ago, she was hospitalized for a pericardial tamponade treated by pericardial drainage. Acute myocarditis was diagnosed on chest pain during the second hospitalization. The etiologic inquiry ended in the diagnosis of Churg-Strauss complicated with a double cardiac involvement. A good response of clinical and biological anomalies was obtained after corticosteroid and immunosuppressive treatment. CONCLUSION: Isolated or multiple involvements of cardiac tunics should lead to make diagnosis of systemic vasculitis. A complete initial assessment and a close observation of the patients followed for Churg-Strauss syndrome is imperative to detect a cardiac achievement and set up an early treatment. PMID- 23806863 TI - [Prehospital treatment with bivalirudin in acute myocardial infarction referred for primary angioplasty. About 152 consecutive patients study]. AB - OBJECTIVE OF THE STUDY: Bivalirudin, a direct thrombin inhibitor, demonstrated an improvement in the prognosis of acute coronary syndromes by a decrease in major bleeding complications. This observational study evaluated inhospital outcome of patients with acute myocardial infarction treated by prehospital bivalirudin before primary angioplasty. PATIENTS AND METHODS: We included, from June 2010 to June 2012, all patients with acute myocardial infarction receiving prehospital bivalirudin with bolus of 0.75mg/kg followed by an infusion of 1.75mg/kg per hour until the arrival in the catheterization laboratory. Bivalirudin was possibly continued after primary angioplasty. RESULTS: We included 152 patients aged 57.6+/-11.6 years. A prehospital 60mg loading dose of prasugrel was given in 77% of patients. Coronary angiography with radial access (77.6%) was performed before a successful angioplasty in 97.3% of cases. The bivalirudin infusion was continued after the procedure in 81.6% of patients. Inhospital outcome showed two deaths (1.3%) and two re-infarctions (1.3%) of which one was related to the single acute stent thrombosis (0.6%). Major bleeding complications were limited irrespective of the Gusto (0.6%), Timi (0.6%) or Horizons-MI (4.6%) classification. Bleeding complications rate was similar when bivalirudin was followed or not after primary angioplasty. CONCLUSION: The use of bivalirudin in the prehospital setting for primary angioplasty seems to be effective and safe about ischemic and bleeding complications during the inhospital outcome. PMID- 23806864 TI - [The coexistence of a para hisian accessory pathway and a complete atrioventricular block in a 32 years old patient]. AB - The present case report describes a 32-year-old patient with complete atrioventricular block coexisting with a permanent ventricular preexcitation. The patient ended up with pacemaker implantation without requiring ablation of accessory pathway. PMID- 23806865 TI - [Coronary artery fistulas, a current problem: Clinical and therapeutic considerations]. AB - The coronary fistula is a link between one or more of the coronary arteries and cardiac cavity or great vessel. The exact occurrence is unknown. The majority of these fistulas are congenital in origin. However, they may occasionally be detected after cardiac surgery. For a long time, fistulas are asymptomatic, especially if they are small; the frequency of the symptoms and especially the complications rise with age. The potential complications are: cardiac failure, endocarditis, endarteritis, atrial fibrillation, ventricular arrhythmias, rupture, and thrombosis. The main differential diagnosis is patent arterial duct, while other congenital arteriovenous shunts need to be excluded. Even though echocardiography Doppler can help to differentiate shunts, the coronary angiography remains the main diagnostic tool for the description of the anatomy. For a long time, the surgery was the only therapeutic means, up till now, percutaneous occlusion is the first line therapy of coronary fistulas and that the different devices can be tailored to meet different anatomic and functional characteristics. PMID- 23806866 TI - The root barks of Morus alba and the flavonoid constituents inhibit airway inflammation. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The root barks of Morus alba have been used in traditional medicine as an anti-inflammatory drug, especially for treating lung inflammatory disorders. AIM OF STUDY: To find new alternative agents against airway inflammation and to establish the scientific rationale of the herbal medicine in clinical use, the root barks of Morus alba and its flavonoid constituents were examined for the first time for their pharmacological activity against lung inflammation. MATERIALS AND METHODS: For in vivo evaluation, an animal model of lipopolysaccharide-induced airway inflammation in mice was used. An inhibitory action against the production of proinflammatory molecules in lung epithelial cells and lung macrophages was examined. RESULTS: Against lipopolysaccharide-induced airway inflammation, the ethanol extract of the root barks of Morus alba clearly inhibited bronchitis-like symptoms, as determined by TNF-alpha production, inflammatory cells infiltration and histological observation at 200-400mg/kg/day by oral administration. In addition, Morus alba and their major flavonoid constituents including kuwanone E, kuwanone G and norartocarpanone significantly inhibited IL-6 production in lung epithelial cells (A549) and NO production in lung macrophages (MH-S). CONCLUSIONS: Taken together, it is concluded that Morus alba and the major prenylated flavonoid constituents have a potential for new agents to control lung inflammation including bronchitis. PMID- 23806867 TI - Is aristolochic acid nephropathy a widespread problem in developing countries? A case study of Aristolochia indica L. in Bangladesh using an ethnobotanical phytochemical approach. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Species of Aristolochia are associated with aristolochic acid nephropathy (AAN), a renal interstitial fibrosis and upper urinary tract cancer (UUC). Aristolochic acid nephropathy has been reported in ten countries but its true incidence is unknown and most likely underestimated. By combining an ethnobotanical and phytochemical approach we provide evidence for the risk of AAN occurring in Bangladesh. More specifically, we assess the intra specific variation of aristolochic acid analogues in medicinally used Aristolochia indica samples from Bangladesh. MATERIALS AND METHODS: Ethnobotanical information was collected from 16 kavirajes (traditional healers) in different study locations in Bangladesh. Plant samples were obtained from native habitats, botanical gardens, herbal markets and pharmaceutical companies. The samples were extracted using 70% methanol and were analysed using LC-DAD-MS and (1)H-NMR. RESULTS: Roots as well as leaves are commonly used for symptoms such as snake bites and sexual problems. Among the informants knowledge about toxicity or side effects is very limited and Aristolochia indica is often administered in very high doses. Replacement of Aristolochia indica with other medicinal plants such as Rauvolfia serpentina (L.) Benth. ex Kurz was common. Aristolochia indica samples contained a variety of aristolochic acid analogues such as aristolochic acid I, aristolochic acid II, cepharadione A and related compounds. CONCLUSIONS: AAN cases are likely to occur in Bangladesh and more awareness needs to be raised about the health risks associated with the use of Aristolochia indica and other species of Aristolochia as herbal medicines. PMID- 23806868 TI - Glucocorticoid-induced skeletal muscle atrophy. AB - Many pathological states characterized by muscle atrophy (e.g., sepsis, cachexia, starvation, metabolic acidosis and severe insulinopenia) are associated with an increase in circulating glucocorticoids (GC) levels, suggesting that GC could trigger the muscle atrophy observed in these conditions. GC-induced muscle atrophy is characterized by fast-twitch, glycolytic muscles atrophy illustrated by decreased fiber cross-sectional area and reduced myofibrillar protein content. GC-induced muscle atrophy results from increased protein breakdown and decreased protein synthesis. Increased muscle proteolysis, in particular through the activation of the ubiquitin proteasome and the lysosomal systems, is considered to play a major role in the catabolic action of GC. The stimulation by GC of these two proteolytic systems is mediated through the increased expression of several Atrogenes ("genes involved in atrophy"), such as FOXO, Atrogin-1, and MuRF-1. The inhibitory effect of GC on muscle protein synthesis is thought to result mainly from the inhibition of the mTOR/S6 kinase 1 pathway. These changes in muscle protein turnover could be explained by changes in the muscle production of two growth factors, namely Insulin-like Growth Factor (IGF)-I, a muscle anabolic growth factor and Myostatin, a muscle catabolic growth factor. This review will discuss the recent progress made in the understanding of the mechanisms involved in GC-induced muscle atrophy and consider the implications of these advancements in the development of new therapeutic approaches for treating GC-induced myopathy. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. PMID- 23806869 TI - Podocyte energy metabolism and glomerular diseases. AB - Mitochondria are crucial organelles that produce and deliver adenosine triphosphate (ATP), by which all cellular processes are driven. Although the mechanisms that control mitochondrial biogenesis, function and dynamics are complex process and vary among different cell types, recent studies provided many new discoveries in this field. Podocyte injury is a crucial step in the development of a large number of glomerular diseases. Glomerular podocytes are unique cells with complex foot processes that cover the outer layer of the glomerular basement membrane, and are the principle cells composing filtration barriers of glomerular capillaries. Little is known on the modalities and the regulation of podocyte's energetics as well as the type of energy substrate primarily used for their activity, recent studies revealed that dysfunction of energy transduction in podocytes may underlie the podocyte injury associated with numerous glomerular diseases. We herein review and discuss the importance of a fine regulation of energy metabolism in podocytes for maintaining their cellular structure and related kidney function. In the future, understanding these mechanisms will open up new areas of treatment for glomerular diseases. PMID- 23806870 TI - Fanconi anemia complementation group A (FANCA) localizes to centrosomes and functions in the maintenance of centrosome integrity. AB - Fanconi anemia (FA) proteins are known to play roles in the cellular response to DNA interstrand cross-linking lesions; however, several reports have suggested that FA proteins play additional roles. To elucidate novel functions of FA proteins, we used yeast two-hybrid screening to identify binding partners of the Fanconi anemia complementation group A (FANCA) protein. The candidate proteins included never-in-mitosis-gene A (NIMA)-related kinase 2 (Nek2), which functions in the maintenance of centrosome integrity. The interaction of FANCA and Nek2 was confirmed in human embryonic kidney (HEK) 293T cells. Furthermore, FANCA interacted with gamma-tubulin and localized to centrosomes, most notably during the mitotic phase, confirming that FANCA is a centrosomal protein. Knockdown of FANCA increased the frequency of centrosomal abnormalities and enhanced the sensitivity of U2OS osteosarcoma cells to nocodazole, a microtubule-interfering agent. In vitro kinase assays indicated that Nek2 can phosphorylate FANCA at threonine-351 (T351), and analysis with a phospho-specific antibody confirmed that this phosphorylation occurred in response to nocodazole treatment. Furthermore, U2OS cells overexpressing the phosphorylation-defective T351A FANCA mutant showed numerical centrosomal abnormalities, aberrant mitotic arrest, and enhanced nocodazole sensitivity, implying that the Nek2-mediated T351 phosphorylation of FANCA is important for the maintenance of centrosomal integrity. Taken together, this study revealed that FANCA localizes to centrosomes and is required for the maintenance of centrosome integrity, possibly through its phosphorylation at T351 by Nek2. PMID- 23806871 TI - Simultaneous alcohol and marijuana use among U.S. high school seniors from 1976 to 2011: trends, reasons, and situations. AB - BACKGROUND: Simultaneous alcohol and marijuana (SAM) use raises significant concern due to the potential for additive or interactive psychopharmacological effects. However, no nationally representative studies are available that document prevalence, trends, or related factors in US youth SAM use. METHODS: Nationally representative cross-sectional samples of 12th grade students surveyed in the Monitoring the Future project from 1976 to 2011 provided data on SAM use. Analyses were conducted in 2012. RESULTS: In 2011, 23% of all U.S. high school seniors reported any SAM use. Among seniors reporting any past 12-month marijuana use, 62% reported any SAM use and 13% reported SAM use most or every time they used marijuana. SAM use consistently followed trends for past 30-day alcohol use over time. SAM use showed significant variation by psychosocial and demographic characteristics and was strongly associated with higher substance use levels, but occurred across the substance use spectrum. Certain reasons for alcohol or marijuana use (to increase effects of another drug; I'm hooked) and situations of alcohol or marijuana use (park/beach, car, party) were strongly associated with SAM use. CONCLUSIONS: A sizable proportion of US high school seniors reported SAM use, and it appeared to occur frequently in social use situations that could impact both the public as well as youth drug users. SAM use appears to be a complex behavior that is incidental to general substance use patterns as well as associated with (a) specific simultaneous reasons (or expectancies), and (b) heavy substance use and perceived dependence, especially on alcohol. PMID- 23806872 TI - Differences in self-reported and behavioral measures of impulsivity in recreational and dependent cocaine users. AB - BACKGROUND: Dependent cocaine users consistently display increased trait impulsivity on self-report questionnaires and less consistently exhibit elevated motor impulsivity in some behavioral tasks. However, trait and behavioral impulsivity measures have rarely been investigated in recreational users. Therefore, we examined self-reported trait and motor impulsivities in recreational and dependent cocaine users to clarify the role of impulse control in cocaine addiction and non-dependent cocaine use. METHODS: We investigated relatively pure recreational (n=68) and dependent (n=30) cocaine users, as well as psychostimulant-naive controls (n=68), with self-report questionnaires (Barratt Impulsiveness Scale 11; Temperament and Character Inventory) and behavioral tasks (Rapid Visual Information Processing Task; Stop-Signal Task). RESULTS: Compared with controls, recreational and dependent cocaine users displayed higher trait impulsivity and novelty seeking scores on self-report questionnaires. Trait impulsivity scores were strongly associated with an increased number of symptoms of depression and attention deficit hyperactivity disorder and correlated significantly with long-term cocaine intake parameters. By contrast, none of the behavioral motor impulsivity measures showed significant group effects or correlated with cocaine use parameters. The correlations among the self-report measures were high, but self-reports were scarcely correlated with behavioral task measures. CONCLUSIONS: These findings suggest that relatively pure cocaine users already display increased trait impulsivity at a recreational level of use. However, the results do not indicate any cocaine related elevation of behavioral impulsivity in terms of motor or response inhibition. In summary, our data imply that elevated trait impulsivity is not a specific feature of dependent cocaine use. PMID- 23806874 TI - Intravenous magnesium therapy in adult patients with an aneurysmal subarachnoid haemorrhage: a systematic review and meta-analysis. AB - BACKGROUND: The value of magnesium for the prevention of cerebral arterial vasospasm in patients with aneurysmal subarachnoid haemorrhage (SAH) is debatable. We performed a systematic review to collate the available evidence to evaluate the effects of intravenous magnesium for the prevention of cerebral arterial vasospasm. MATERIALS AND METHODS: An electronic search of MEDLINE (Ovid), ProQuest, CINAHL and the Cochrane Database of Systematic Reviews was undertaken up to 1st October 2012 for randomised controlled trials (RCTs) of intravenous magnesium for the prevention of vasospasm in adult patients with aneurysmal SAH. Primary outcome measures were risk of vasospasm, functional outcomes and mortality. Results are presented as risk ratios (RR) and 95% confidence intervals (CI). RESULTS: Nine of 38 trials were included in this review. Not all trials could be combined for analyses due to differences in reported outcomes and outcome definitions. Of the trials that could be combined we found a statistically significant reduction on the incidence of vasospasm with magnesium (RR 0.83; 95% CI 0.71, 0.98; P=0.03). No statistical difference for the last reported favourable functional outcome (RR 1.00; 95% CI 0.96, 1.05; P=0.84); or mortality (RR 0.95; 95% CI 0.77, 1.18; P=0.67) between magnesium treated and standard care/control groups was found. CONCLUSION: We identified a benefit in the role of magnesium to reduce the incidence of cerebral vasospasm in patients with an aneurysmal SAH. However no benefit was found regarding improved favourable functional outcome or a reduction of mortality. PMID- 23806873 TI - Methamphetamine dependent individuals show attenuated brain response to pleasant interoceptive stimuli. AB - BACKGROUND: Mechano-receptive C-fiber (MR-CF) stimulation via slow stroking of C fiber rich skin areas can be used to probe the relationship between reward and interoception. Individuals with substance use disorders show impaired reward processing, and dysfunctional interoceptive processing of MR-CF may contribute to this dysfunction. This study predicted that methamphetamine dependent (MD) individuals would exhibit altered responses to MR-CF stimulation in brain regions important for interoception. METHODS: Recently abstinent MD (n=25) and comparison (CTL, n=17) subjects received a pleasant interoceptive stimulus ("Soft Touch" consisting of a slow brush stroke) to the palm or forearm during functional magnetic resonance imaging. Subjects were provided with cues signaling stimulation to examine anticipatory and stimulus-related processing. Subjective responses were measured using visual analog scales (VAS). RESULTS: Groups were similar on behavioral performance and ratings of the interoceptive stimuli, yet MD exhibited lower anterior insula, dorsal striatum, and thalamus activation than CTL, across anticipation and soft touch conditions. The lower the anterior insula activation, the faster the reaction time across conditions in MD, whereas the opposite pattern was evident in CTL. Striatal activation in MD was greater than CTL during anticipation, but lower during soft touch. Greater striatal attenuation was associated with higher VAS pleasantness ratings of soft touch. CONCLUSIONS: MD expend fewer brain processing resources during soft touch, a form of positively-valenced interoceptive stimuli, in brain areas that are important for both interoception and reward. Future studies will ascertain if sustained abstinence from methamphetamine use can normalize aberrant neural interoceptive processing. PMID- 23806875 TI - Inflammatory pseudotumor of the endolymphatic sac: a case report. AB - The authors present a case of Endolymphatic Sac Inflammatory Pseudotumour treated at our institution and reviewed the relevant literature. This is a benign lesion which arises due to chronic inflammation. It has similar clinical and radiological features as endolymphatic sac tumors and is diagnosed through histopathological examination. To date, there have been over 200 case reports of ELSTs but only 2 case reports of endolymphatic sac pseudotumour. This report highlights the clinical presentation, radiological features, histological characteristics, treatment, and clinical outcomes of endolymphatic sac inflammatory pseudotumours and explores their likely etiology and discusses possible treatment options. Endolymphatic sac inflammatory pseudotumour may represent the end of a spectrum of immune-mediated inflammatory disease of the endolymphatic sac. Based on the experience of managing inflammatory pseudo tumours elsewhere in the body, there may be a role for high dose steroids in its management. PMID- 23806876 TI - The concurrent effects of strike pattern and ground-contact time on running economy. AB - OBJECTIVES: Running economy is a key determinant of endurance performance, and understanding the biomechanical factors that affect it is of great theoretical and applied interest. This study aimed to analyse how the ground-contact time and strike pattern used by competitive runners concurrently affect running economy. DESIGN: Cross-sectional. METHODS: Fourteen sub-elite male competitive distance runners completed a 6-min submaximal running trial at 14kmh(-1) on an outdoor track using their habitual strike pattern (n=7 rearfoot strikers: average age, 25.3 years old (SD=2.4); average weight, 64.7kg (SD=5.6); average height, 175.3cm (SD=5.2); n=7 midfoot strikers: average age, 25.0 years old (SD=2.8); average weight, 69.6kg (SD=4.0); average height, 180.1cm (SD=5.1). During the run, the oxygen uptake and ground-contact time were measured. RESULTS: Midfoot strikers showed a significantly shorter (p=0.015) mean contact time (0.228s (SD=0.009)) compared with rearfoot strikers (0.242s (SD=0.010)). Conversely, there was no significant difference (p>0.05) between the groups with respect to mean oxygen uptake (midfoot strikers: 48.4mlmin(-1)kg(-1) (SD=5.3); rearfoot strikers: 49.8mlmin(-1)kg(-1) (SD=6.4)). Linear modelling analysis showed that the effect of contact time on running economy was very similar in the two groups, with a 1ms longer contact time involving an approximately 0.51mlmin(-1)kg(-1) lower oxygen uptake. In contrast, when controlling for contact time, midfoot striking involved an approximately 8.7mlmin(-1)kg(-1) lower oxygen uptake compared with rearfoot striking. CONCLUSIONS: When adjusting the foot-ground contact biomechanics of a runner with the aim of maximising running economy, a trade-off between a midfoot strike and a long contact time must be pursued. PMID- 23806877 TI - Influence of strength training variables on strength gains in adults over 55 years-old: a meta-analysis of dose-response relationships. AB - OBJECTIVES: The importance of strength training to elderly individuals is well established. However, the dose-response relationship of the benefits of strength training in this population is unclear. The purpose of the study was to use meta analysis to investigate the dose-response of the effects of strength training in elderly individuals. DESIGN: Fifteen studies with a total of 84 effect-sizes were included. The analyses examined the dose-response relationships of the following training variables 'intensity', 'number of sets', 'weekly frequency', and 'training duration' on strength improvement. METHODS: The studies selected met the following inclusion criteria: (a) randomized controlled trials; (b) trained healthy subjects of both genders; (c) trained subjects aged 55 years or older; (d) strength increases were determined pre- and post-training; (e) use of similar strength evaluation techniques (strength determined by a repetition maximum test) and training routine (dynamic concentric-eccentric knee extension exercise to train the quadriceps muscle group). The effect-sizes were calculated using fixed and random effect models with the main effects determined by meta-regression. RESULTS: Many combinations of training variables resulted in strength increases. However meta-regression indicated only "training duration" had a significant dose response relationship to strength gains (p=0.001). Over durations of 8-52 weeks, longer training durations had a greater effect on strength gains compared to shorter duration protocols. CONCLUSIONS: Resistive training causes strength gains in elderly individuals, provided the training duration is sufficiently long, regardless of the combination of other training variables. PMID- 23806878 TI - The outbreak of avian influenza A (H7N9) in China: current status and future prospects. PMID- 23806879 TI - Stem cell-based therapy in neural repair. AB - Cell-based therapy could aid in alleviating symptoms or even reversing the progression of neurodegenerative diseases and nerve injuries. Fibroblast growth factor 1 (FGF1) has been shown to maintain the survival of neurons and induce neurite outgrowth. Accumulating evidence suggests that combination of FGF1 and cell-based therapy is promising for future therapeutic application. Neural stem cells (NSCs), with the characteristics of self-renewal and multipotency, can be isolated from embryonic stem cells, embryonic ectoderm, and developing or adult brain tissues. For NSC clinical application, several critical problems remain to be resolved: (1) the source of NSCs should be personalized; (2) the isolation methods and protocols of human NSCs should be standardized; (3) the clinical efficacy of NSC transplants must be evaluated in more adequate animal models; and (4) the mechanism of intrinsic brain repair needs to be better characterized. In addition, the ideal imaging technique for tracking NSCs would be safe and yield high temporal and spatial resolution, good sensitivity and specificity. Here, we discuss recent progress and future development of cell-based therapy, such as NSCs, induced pluripotent stem cells, and induced neurons, in neurodegenerative diseases and peripheral nerve injuries. PMID- 23806880 TI - Structure, function and regulation of the hsp90 machinery. AB - Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone which is essential in eukaryotes. It is required for the activation and stabilization of a wide variety of client proteins and many of them are involved in important cellular pathways. Since Hsp90 affects numerous physiological processes such as signal transduction, intracellular transport, and protein degradation, it became an interesting target for cancer therapy. Structurally, Hsp90 is a flexible dimeric protein composed of three different domains which adopt structurally distinct conformations. ATP binding triggers directionality in these conformational changes and leads to a more compact state. To achieve its function, Hsp90 works together with a large group of cofactors, termed co chaperones. Co-chaperones form defined binary or ternary complexes with Hsp90, which facilitate the maturation of client proteins. In addition, posttranslational modifications of Hsp90, such as phosphorylation and acetylation, provide another level of regulation. They influence the conformational cycle, co-chaperone interaction, and inter-domain communications. In this review, we discuss the recent progress made in understanding the Hsp90 machinery. PMID- 23806881 TI - G-protein-coupled receptors and their (Bio) chemical significance win 2012 Nobel Prize in Chemistry. AB - G-protein-coupled receptors (GPCRs) are seven transmembrane cell surface proteins specialized in cellular communication. These receptors represent a major gateway through which cells convert external cues into intracellular signals and respond with appropriate actions. While the effects of hormones, neurotransmitters, and drugs on cells, tissues, organs, and even whole organisms are well described, the molecular identity of the direct targets and the diverse signaling mechanisms of these biological ligands have been slow and hard to define. The Nobel Prize in Chemistry for the year 2012 acknowledges the importance of GPCRs in these processes, especially for the contribution of Profs Robert J. Lefkowitz and Brian K. Kobilka to the studies of GPCRs. In this brief review, the seminal works accomplished by the two GPCR pioneers are summarized and the (bio) chemical significance of GPCRs in health and disease is discussed. PMID- 23806882 TI - Comparison of sevoflurane versus propofol under auditory evoked potential monitoring in female patients undergoing breast surgery. AB - BACKGROUND: General anesthesia is used for most major surgeries, and the most common side effects include headache, nausea, vomiting, and sore throat. Major breast surgery is associated with a high incidence of postoperative nausea and vomiting (PONV). We compared the postoperative nausea and vomiting of propofol based total intravenous anesthesia (TIVA) and sevoflurane (SEVO) anesthesia under auditory evoked potential (AEP) monitoring in female patients undergoing breast surgery. METHODS: A total of 84 patients scheduled to undergo elective breast surgery from 1 to 4 h in duration from March 2011 to December 2011 were prospectively included in the study. All participants were randomly assigned to TIVA or SEVO group. The AEP index was maintained at 15-25. After completing the surgery, the duration of surgery, emergence time, and the side effects of PONV were recorded. RESULTS: Patient characteristics, intraoperative and postoperative data, and the amounts of intraoperative analgesic drugs used were not significantly different between the TIVA and SEVO groups. The incidence of PONV was significantly higher in the SEVO group than in the TIVA group (50% and 14.3%, respectively; p < 0.001), and the total cost was significantly lower in the TIVA group than in the SEVO group (648 +/- 185 and 850 +/- 197, respectively). CONCLUSION: We observed that when compared with sevoflurane, propofol given for the maintenance of general anesthesia improves the postoperative patient well being and reduces the incidence of PONV. Furthermore, total intravenous anesthesia with propofol resulted in significant cost reductions. PMID- 23806883 TI - Lower serum tropomyosin receptor kinase B levels in patients with schizophrenia. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) have previously been found to be reduced in the prefrontal cortex of patients with schizophrenia. In this study, we tried to investigate the protein levels of BDNF and TrkB from peripheral blood in the veins of individuals with schizophrenia and health controls. METHODS: From January 2008 to November 2010, we recruited 40 schizophrenic patients and 56 healthy controls. Serum BDNF and total TrkB protein levels were detected with enzyme-linked immunosorbent assay (ELISA) kits. Outliners of BDNF and TrkB were excluded initially. Analysis of covariance (ANCOVA) with age adjustment was used for group mean differences of different groups. RESULTS: After using the ANCOVA with age adjustment, the results of this work showed that BDNF presented no significant difference (F = 0.065, p = 0.800), but the serum TrkB protein level was significantly lower in schizophrenic patients than in healthy controls (F = 8.34, p = 0.005). CONCLUSION: Our findings showed a lower TrkB protein level in serum from schizophrenia patients compared with healthy controls, indicating that the signaling transmission of BDNF/TrkB may be affected in peripheral blood from individuals with schizophrenia. PMID- 23806884 TI - Plasma P-selectin predicts long-term cardiovascular events in hospitalized patients with suspected coronary artery disease and preserved left ventricular function: a 10-year follow-up study. AB - BACKGROUND: A variety of biomarkers have been investigated on their values to predict cardiovascular outcomes, such as high-sensitivity C-reactive protein (hs CRP), fibrinogen, troponin-I (TnI), and soluble P-selectin (sP-sel). By a design of head-to-head comparison, this study sought to figure out the long-term prognostic values of these parameters in patients hospitalized with suspected coronary artery disease. METHODS: A total of 170 patients hospitalized with suspected coronary artery disease were enrolled and followed up for an average of 10 years. sP-sel, hs-CRP, TnI, and fibrinogen levels were measured. During the follow-up period, cardiac events were recorded including cardiac death, non-fatal myocardial infarction, and acute coronary syndromes with hospitalization. RESULTS: For all 170 patients, with a median follow-up time of 9.86 +/- 3.87 years, no parameter was able to significantly predict the occurrence of cardiac events. In subgroup analysis, an sP-sel of >= 63.5 ng/ml significantly predicted the development of all composite cardiac events only in patients with a left ventricular ejection fraction > 50% (n = 94, p = 0.04). However, the levels of hs CRP, TnI, and fibrinogen did not have significant predictive values. Multivariate analysis also demonstrated the independent predictive value of sP-sel on all cardiac events (hazard ratio = 5.82, p = 0.02). All parameters, including sP-sel, could not demonstrate prognostic values in patients with a left ventricular ejection fraction <= 50% (n = 76). CONCLUSIONS: In this 10-year long-term follow up study, sP-sel was demonstrated to have prognostic values in predicting the cardiac events in patients with preserved left ventricular systolic function. PMID- 23806885 TI - Long-term Outcomes of Carotid Artery Stenting for Radiation-Associated Stenosis. AB - BACKGROUND: In Taiwan, the prevalence of head and neck cancer is relatively high. Because radiation-associated carotid stenosis is a significant risk factor for stroke, carotid artery stenting (CAS), instead of carotid endarterectomy, is indicated in patients with radiation-associated carotid stenosis. We sought to evaluate the effect of neck radiotherapy (XRT) on the long-term outcome of patients undergoing CAS. METHODS: From March 2001 to November 2011, 147 CAS procedures were performed on 129 patients (n = 43 for XRT, n = 86 for non-XRT). Mean follow-up was 42.7 +/- 20.5 months (median: 52 months; range: 1-60 months). Duplex velocity criterion for > 50% restenosis after CAS was defined as peak systolic velocity > 175 cm/s. Endpoints included 5-year freedom from mortality, ipsilateral recurrent stroke, and major adverse cardiovascular events (MACE). RESULTS: The mean age of XRT patients was significantly lesser than that of non XRT patients (61 +/- 8 vs. 71 +/- 8, p < 0.001). There was significantly less coronary artery disease and other cardiovascular co-morbidities in XRT patients. No significant differences were noted in the composite 30-day ipsilateral stroke/myocardial infarction/mortality (XRT: 8.6% vs. non-XRT: 6%, p > 0.05) and 5-year freedom from mortality, ipsilateral recurrent stroke, and MACE (p > 0.05) between the two groups. Intra-stent carotid restenosis > 50% was significantly higher in the XRT group on follow-up. CONCLUSION: Long-term outcomes of CAS for radiation-associated stenosis were not altered by a history of neck XRT, except for asymptomatic carotid restenosis. PMID- 23806886 TI - The issue of radiation-induced cardiovascular toxicity: preclinical highlights and perspectives on preventive strategies. PMID- 23806887 TI - Cone beam computed tomography: a new trend for craniofacial treatment planning. PMID- 23806888 TI - Decreased plasma nesfatin-1 levels in patients with acute myocardial infarction. AB - Nesfatin-1 is a novel anorexigenic hormone which has close relationship with diabetes, obese, anorexia nervosa, psychiatric disorders and neurogenic diseases. The aim of our study was to evaluate levels of plasma nesfatin-1 among patients presenting with coronary artery disease and the correlation between nesfatin-1 levels and other clinical parameters. Fasting plasma levels of nesfatin-1 were tested in 48 acute myocardial infarction (AMI) patients, 74 stable angina pectoris (SAP) patients and 34 control subjects. All of them were examined by coronary angiography. The severity of coronary atherosclerosis was assessed using the Gensini score. Plasma nesfatin-1 levels were significantly lower in AMI group than SAP group or control group (0.91+/-0.08 ng/mL vs. 0.98+/-0.19 ng/mL and 1.09+/-0.39 ng/mL, respectively, P<0.05). In AMI patients, plasma nesfatin-1 levels were negatively correlated with high-sensitivity C-reactive protein, neutrophil% or Gensini scores. Such information implies that lower nesfatin-1 concentration may play a very important role in the development of AMI. PMID- 23806889 TI - Traditional Chinese medicine for the treatment of primary dysmenorrhea: how do Yuanhu painkillers effectively treat dysmenorrhea? AB - AIM: To examine the efficacy of YuanHu painkillers (YHP) as a treatment for primary dysmenorrhea and to reveal YHP's principle formula. METHODS: A Wistar rat uterine contraction model was utilized in this study. Rats were given 0.698g/kg YHP, 0.07g/kg tetrahydropalmatine (THP; YHP's main component), 0.02g/kg imperatorin (IMP), or THP+IMP (0.07+0.02g/kg) as polypharmacy (PG) by gavage. H&E staining and histopathological examination of the uteri tissue samples were performed. We then detected superoxide dismutase (SOD) and malondialdehyde (MDA), nitric oxide (NO), as well as inducible nitric oxide synthase (iNOS), i-kappaB, nuclear factor-kappaB (NF-kappaB), and cyclooxygenase-2 (COX-2) indices. RESULTS: PG significantly inhibited the uterine contraction of the primary dysmenorrhea rat model (p<0.05), and was significantly different than single-agent therapy (p<0.05). Histopathological examination showed inflammation in the uteri of the control group which YHP and its main constitutes alleviated. THP significantly inhibited the contraction of isolated uteri caused by Ach, PGF2alpha and oxytocin in a concentration-dependent fashion. THP and IMP both significantly affected the levels of NO, activation of NF-kappaB, up-regulated the expression of i-kappaB and down-regulated the expression of both iNOS and COX-2. IMP obviously decreased the level of MDA and increased the activation of SOD (p<0.05). PG obviously improved all the parameters mentioned above (p<0.05). CONCLUSIONS: YHP exerted protective effects on primary dysmenorrhea in rats and remarkably alleviated the severity of experimental primary dysmenorrhea. The combined strategy proved to be more effective than either THP or IMP alone and may have synergistic effects in combination in primary dysmenorrhea. Mechanisms that might account for the beneficial effects include abating oxidative stress, inhibiting over-inflammatory reaction, and alleviating the contraction of isolated rat uteri by inhibiting the influx of extracellular Ca(2+). Broad potential for future clinical practice is foreseeable. PMID- 23806890 TI - Conserved microRNA miR-8 blocks activation of the Toll pathway by upregulating Serpin 27 transcripts. AB - microRNAs (miRNAs) play significant regulatory roles in gene expression at the post-transcriptional level. This includes modulating processes such as development, immunity, cancer, and host-pathogen interactions. It was recently shown that the phylogenetically deeply conserved miRNA, miR-8, plays a role in maintaining the homeostasis of immunity by suppressing the production of anti microbial peptides. In this study, we show that miR-8 from the insect Plutella xylostella positively regulates the transcript levels of the serine protease inhibitor Serpin 27, which has been shown to regulate activation of the Toll pathway and prophenoloxidase involved in the melanization response in insects. Interestingly, miR-8 is downregulated following parasitization by Diadegma semiclausum leading to significant declines in Serpin 27 transcript levels. This allows upregulation of antimicrobial peptides, such as gloverin, that are controlled by the Toll pathway and activation of proteolytic cascades essential for humoral immune responses to foreign invasion. PMID- 23806891 TI - Functional consequences of inadequate sleep in adolescents: a systematic review. AB - During adolescence, changes in sleep patterns due to biological and environmental factors are well documented. Later bedtimes and inadequate sleep, i.e., short and disrupted sleep patterns, insomnia and daytime sleepiness, have become increasingly common. Accumulating evidence suggests that sleep plays a crucial role in healthy adolescent development. This review systematically explores descriptive evidence, based on prospective and cross sectional investigations, indicating that inadequate sleep is associated with negative outcomes in several areas of health and functioning, including somatic and psychosocial health, school performance and risk taking behavior. Findings highlight the need for longitudinal investigations aimed at establishing the underpinnings of these associations and for developing and implementing interventions designed to achieve healthier and more balanced sleep patterns in the adolescent population. PMID- 23806892 TI - Community-acquired respiratory viral infections in lung transplant recipients. AB - PURPOSE OF REVIEW: Community-acquired respiratory virus (CARV) infections are a significant cause of morbidity and sometimes mortality in lung transplant recipients (LTRs); this review will focus on the most recent advances in this field. RECENT FINDINGS: Recent advancements in molecular diagnostics have resulted in the detection of higher rates of CARVs in LTRs. Persistence of rhinovirus has been implicated in the development of acute and chronic rejection, whereas the role of bocavirus remains uncertain. The data on the association of CARV infections with acute or chronic rejection remain less. A recent systematic review failed to show an association between CARV infections and acute or chronic rejection. Different routes of administration of antiviral medications, vaccines and newer promising antiviral medications are being evaluated to assess efficacy and safety. Similarly, newer strategies of vaccination may potentiate the immune response in these patients. SUMMARY: With current advanced investigating tools, the full impact of CARV infections in LTR is increasingly coming to realization. Research for novel effective treatments and improved responses to current and new vaccines is ongoing; they would provide great benefit in solving this complex and ever-evolving problem. PMID- 23806893 TI - Intestinal protozoan infections in the immunocompromised host. AB - PURPOSE OF REVIEW: Intestinal protozoa are becoming increasingly recognized as significant pathogens in immunocompromised hosts. However, pathogenesis of infection is still poorly understood, diagnostic tests remain insensitive, and management continues to pose a challenge. RECENT FINDINGS: Invasion by intestinal protozoa can be facilitated by impaired host T-cell immune response, although the exact pathogenesis at the cellular level is unclear. HIV-infected and transplant patients have been reported to have the highest risk for developing severe disease. Cryptosporidium is the most common parasite encountered in the immunocompromised host, followed by Cyclospora and Isospora. In recent years, Microsporidia and Blastocystis have also emerged as important players, due in part to improved molecular diagnostic assays. Effective drugs against these parasites in immunocompromised patients have not been reported in recent years. When possible, reducing the level of immunosuppression seems to be the most effective treatment strategy in combination with adjunctive antiparasitic therapy. SUMMARY: Despite that intestinal protozoan infections cause greater morbidity and mortality in the immunocompromised host, their pathogenesis in the setting of immunosuppression is poorly understood and efforts to develop new therapeutic agents are rather limited. Improving detection and identification of species or subtypes by PCR will result in improved management decisions and a better understanding of the epidemiology of intestinal protozoa. Favorable clinical outcomes can be achieved by early detection and effective treatment of the infection. Further research on key aspects of pathogenesis at the cellular level in humans is needed. PMID- 23806894 TI - Donor-derived filamentous fungal infections in solid organ transplant recipients. AB - PURPOSE OF REVIEW: Filamentous fungal infections due to rare opportunistic moulds can be transmitted with an allograft. However, epidemiologic and clinical characteristics of donor-derived filamentous fungal infections (DDFFIs) in transplant recipients are poorly understood. Hence, the aim of this article is to describe donor-related risk factors, clinical presentation, graft and recipient outcomes associated with DDFFIs. RECENT FINDINGS: To date, 23 cases of donor derived opportunistic filamentous fungal infections have been reported; a majority (91%) occurred in kidney transplant recipients. Aspergillus spp. was the most common organism (71%). Risk factors for DDFFIs include immunosuppressive state of the donor (transplant recipients serving as organ donors), near-drowning events, and transplant-tourism practices. DDFFIs manifested as vascular complications related to graft vasculature (65%), allograft dysfunction (43%) and unexplained febrile illness (39%) in the recipient. Rates of graft loss and overall mortality were 83 and 17%, respectively. SUMMARY: Donor-transmitted filamentous mycoses have a unique spectrum of illness and clinical settings under which transmission occurs. Prompt recognition, early surgical intervention and specific antifungal therapy are necessary for achieving optimal graft and recipient outcomes. PMID- 23806895 TI - Clostridium difficile infection among hematopoietic stem cell transplant recipients: beyond colitis. AB - PURPOSE OF REVIEW: To review the most recent data regarding the epidemiology, risks factors, and outcomes among hematopoietic stem cell transplant recipients with Clostridium difficile infection (CDI). RECENT FINDINGS: With the emergence of an epidemic strain of C. difficile known as NAP1 in the early 2000s, rates of this infection have escalated globally. Hematopoietic stem cell transplant recipients appear to be one of the most vulnerable populations for the development of CDI. Traditional risk factors for CDI including antimicrobial exposure and older age are likely only a piece of the overall risk profile, with recent study results also emphasizing other factors such as transplant type, conditioning regimen, and graft-versus-host disease (GVHD). The relationship between CDI and subsequent development of GVHD, particularly of the gastrointestinal tract, is of specific interest. A bidirectional relationship of association has been highlighted in a number of recent studies and underscores the need for further prospective studies to address the potential indirect effects of alloreactivity induced by CDI. SUMMARY: CDI has emerged as one of the most common infections in the early transplant period. Recent studies have begun to address the epidemiology of disease, risk factors for, and outcomes after infection in the stem cell transplant. However, more research is needed to unravel the observed relationship between CDI and GVHD. PMID- 23806896 TI - The intestinal microbiota and susceptibility to infection in immunocompromised patients. AB - PURPOSE OF REVIEW: Many infections of immunocompromised patients originate from the gastrointestinal tract. The pathogenesis of these infections often begins with alteration of the intestinal microbiota. Understanding the microbiota and how it can either cause or prevent infection is vital for the development of more effective prevention and treatment of these infections. This article reviews and discusses recent work providing insight into the intestinal microbiota of these at-risk immunocompromised patients. RECENT FINDINGS: Studies continue to support the premise that commensal bacteria, largely anaerobic, serve to maintain microbial stability and colonization resistance by preventing overgrowth or domination with more pathogenic bacteria, through interactions within the microbial community and with the host. In patients with immune suppression due to high-dose chemotherapy or hematopoietic stem cell transplantation, disruption of the microbiota through antibiotics as well as impairment of host immunity gives rise to perturbations favoring intestinal domination by pathogenic species, leading to increased bacterial translocation and susceptibility to systemic infection. SUMMARY: An understanding of the intestinal microbiota and the impact of antibiotics will help to guide our treatment of these gut-originating infections. PMID- 23806898 TI - Maximizing the impact of antimicrobial stewardship: the role of diagnostics, national and international efforts. AB - PURPOSE OF REVIEW: The decline in the development and approval of new antimicrobial agents, especially those with activity against multidrug-resistant Gram-negative bacteria, has arisen as one of the major public health threats of the 21st century. Antimicrobial stewardship has emerged as a key available means to attenuate this threat. Because of the immediacy of the crisis imposed by the dearth of new antimicrobial agents, this review aims to seek out innovative mechanisms that could complement existing programmes to maximize their effectiveness. RECENT FINDINGS: Provision of expedited microbiological identification and susceptibility profiles utilizing molecular diagnostic techniques are means that are showing promise in complementing existing stewardship interventions. Biomarkers such as procalcitonin that facilitate clinical decision-making processes in discriminating between noninfectious causes masquerading as sepsis can assist in withholding or earlier discontinuation of antimicrobial agents. Seasonal influenza and polyvalent pneumococcal vaccine have a role to play by preventing secondary bacterial infections. Electronic learning tools are a means of disseminating information rapidly and universally. Coordinated national and international stewardship efforts play an essential role in promotion, engaging the public, and ensuring provision of sufficient resources. SUMMARY: The safeguarding of antimicrobial agents for future generations is necessary, if we as a public do not wish to face a world without antibiotics. All potentially available resources must be recruited to order to protect antimicrobials. Robust methods of evaluating each of these interventions needs to be included from inception to evaluate which strategies are the most effective. PMID- 23806897 TI - The role of water in healthcare-associated infections. AB - PURPOSE OF REVIEW: The aim is to discuss the epidemiology of infections that arise from contaminated water in healthcare settings, including Legionnaires' disease, other Gram-negative pathogens, nontuberculous mycobacteria, and fungi. RECENT FINDINGS: Legionella can colonize a hospital water system and infect patients despite use of preventive disinfectants. Evidence-based measures are available for secondary prevention. Vulnerable patients can develop healthcare associated infections with waterborne organisms that are transmitted by colonization of plumbing systems, including sinks and their fixtures. Room humidifiers and decorative fountains have been implicated in serious outbreaks, and pose unwarranted risks in healthcare settings. SUMMARY: Design of hospital plumbing must be purposeful and thoughtful to avoid the features that foster growth and dissemination of Legionella and other pathogens. Exposure of patients who have central venous catheters and other invasive devices to tap water poses a risk for infection with waterborne pathogens. Healthcare facilities must conduct aggressive clinical surveillance for Legionnaires' disease and other waterborne infections in order to detect and remediate an outbreak promptly. Hand hygiene is the most important measure to prevent transmission of other Gram-negative waterborne pathogens in the healthcare setting. PMID- 23806899 TI - Vaccinations for healthcare personnel: update on influenza, hepatitis B, and pertussis. AB - PURPOSE OF REVIEW: Healthcare personnel (HCP) are at risk for exposure to and transmission of potentially life-threatening vaccine preventable diseases to patients and colleagues. The Centers for Disease Control and Advisory Committee on Immunization Practices (ACIP) recommend routine influenza immunization and maintenance of immunity to hepatitis B and pertussis, among others. In this article, we aim to review recently approved influenza vaccines, as well as address some of the issues regarding hepatitis B and pertussis vaccinations in HCP. RECENT FINDINGS: Several new formulations of influenza vaccines are now available, including quadrivalent vaccines and non-egg-based vaccines; their use in HCP requires further study. An alarming rise in pertussis rates has led to a revision of ACIP guidelines recommending vaccination for women during each pregnancy. Persistent lack of immunity to hepatitis B after vaccine series remains a problem for many HCP. SUMMARY: Inactivated trivalent influenza vaccines remain the safest and most widely studied influenza vaccinations for healthcare workers. A pertussis booster in the form of Tdap is now recommended for most HCP. More studies are needed regarding the issue of nonresponders in HCP who receive the three-dose hepatitis B vaccine series, as there are some promising strategies available that may boost immune responses. PMID- 23806900 TI - Deconstructing the infection control bundles for the containment of carbapenem resistant Enterobacteriaceae. AB - PURPOSE OF REVIEW: Rates of carbapenem-resistant Enterobacteriaceae (CRE), especially Klebsiella pneumoniae carbapenemase (KPC)-producing Gram-negatives, have increased worldwide. Infections caused by these organisms have been associated with a high mortality, which might be due in part to the limited availability of antibiotic options. Therefore, prevention of acquisition of these organisms is essential. This review summarizes published infection control interventions (bundles) that have been implemented for the control of outbreaks caused by KPC-producing organisms. RECENT FINDINGS: A total of 15 bundles of interventions aimed at controlling CRE outbreaks are presented. The interventions included combinations of increased compliance with hand hygiene and contact precautions, environmental cleaning, early identification of asymptomatic carriers, and physical separation of CRE-positive patients and their staff. Three bundles had staggered implementation of interventions with their later phase involving a combination of rectal surveillance cultures for identification of asymptomatic CRE carriers, cohorting of CRE-positive patients, and cohorting of the staff caring for CRE carriers. All three staggered bundles successfully decreased their CRE acquisition rates after implementation of their later phases. SUMMARY: Bundles combine multiple interventions targeting different levels of the transmission pathways and most include increased hand hygiene and contact precautions. However, bundles implemented in phases would seem to indicate that active surveillance cultures and the subsequent cohorting of patients and staff based on these results might be particularly beneficial for controlling horizontal transmission. PMID- 23806901 TI - Current world literature. Infections of the immunocompromised host. PMID- 23806904 TI - Impact and outcome of human acellular dermal matrix size for immediate and two stage breast reconstruction. AB - BACKGROUND: Following mastectomy, patients may choose to have breast reconstruction with autologous tissue or implants. Human acellular dermal matrix has been described as a tissue supplement where the implant is covered, without requiring further muscle elevation or dissection. The authors evaluated the impact of different matrix sizes. METHODS: Fifty-two patients (average age, 48.5 years) and 88 operated breasts were evaluated. The cohort was divided into two, depending on matrix size. In group A, a small matrix with a surface area of 48 or 96 cm was used. In group B, a larger matrix with either 128 or 160 cm was used. Intraoperative fill volumes, expansion procedure, and complications were analyzed. RESULTS: Size difference was significant (69.2 versus 135.5 cm). The calculated mean initial filling volume-to-excised pathology tissue weight ratio and the initial filling-to-final implant volume ratio were significant. Average number of fills to reach final expansion volume was 62.3 percent, or 4.7 times lower in group B. Seven complications were reported without any statistical difference between groups. CONCLUSIONS: This study suggests that using a larger human acellular dermal matrix in breast reconstruction offers a potential to increase the initial expander fill volume-to-breast pathology weight ratio and initial expander fill volume-to-final implant volume ratio. Larger matrices can reduce the number of subsequent expansions and may even decrease the risk of postoperative complications. This study also revealed that using a larger matrix is a safe method that does not increase complications. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 23806903 TI - Induction and reversal of myotonic dystrophy type 1 pre-mRNA splicing defects by small molecules. AB - The ability to control pre-mRNA splicing with small molecules could facilitate the development of therapeutics or cell-based circuits that control gene function. Myotonic dystrophy type 1 is caused by the dysregulation of alternative pre-mRNA splicing due to sequestration of muscleblind-like 1 protein (MBNL1) by expanded, non-coding r(CUG) repeats (r(CUG)(exp)). Here we report two small molecules that induce or ameliorate alternative splicing dysregulation. A thiophene-containing small molecule (1) inhibits the interaction of MBNL1 with its natural pre-mRNA substrates. Compound (2), a substituted naphthyridine, binds r(CUG)(exp) and displaces MBNL1. Structural models show that 1 binds MBNL1 in the Zn-finger domain and that 2 interacts with UU loops in r(CUG)(exp). This study provides a structural framework for small molecules that target MBNL1 by mimicking r(CUG)(exp) and shows that targeting MBNL1 causes dysregulation of alternative splicing, suggesting that MBNL1 is thus not a suitable therapeutic target for the treatment of myotonic dystrophy type 1. PMID- 23806905 TI - Discussion: impact and outcome of human acellular dermal matrix size for immediate and two-stage breast reconstruction. PMID- 23806906 TI - An analysis of the motivating and risk factors for conversion from implant-based to total autologous breast reconstruction. AB - BACKGROUND: Problems with implant-based breast reconstructions can lead to patient dissatisfaction and a request for total autologous reconstruction. This 12-year study aimed to determine the rate of conversion from implant-based to autologous reconstruction, to identify potential risk factors, compare the rate of conversion in implant-only and latissimus dorsi/implant reconstructions, and assess patient satisfaction following conversion. METHODS: Implant-based reconstructions performed between 2000 and 2008 were reviewed. The cohort was then followed prospectively until 2012. RESULTS: One hundred thirty-nine implant based reconstructions were performed in 118 patients. Sixty-nine patients underwent latissimus dorsi/implant (80 breasts) and 49 underwent implant-only reconstructions (59 breasts). Twenty-one underwent bilateral reconstructions following risk-reduction surgery. Sixteen percent (19 of 118) of patients and 14 percent of breasts (19 of 139) underwent conversion to autologous tissue. None of the 21 bilateral cases converted (hazard ratio, 4.6; p < 0.05). Median time to conversion was 64 months (range, 18 to 142 months). The main motivating factors for conversion included poor aesthetic result (36.8 percent), capsular contracture (31.6 percent), change in weight (21.1 percent), and implant infection/extrusion (10.5 percent). Implant-only reconstructions were more likely to convert (hazard ratio, 3.6; p < 0.05) and at an earlier stage (p < 0.05) than latissimus dorsi/implant reconstructions. Neither radiotherapy (p = 0.68) nor capsular contracture (p = 0.94) significantly increased the risk of conversion. The BREAST-Q demonstrated high patient satisfaction after conversion. CONCLUSIONS: Autologous tissue conversion offers a definitive means of improving the quality of the result, patient satisfaction, and quality of life in troublesome implant-based breast reconstructions. Latissimus dorsi coverage of implants and bilateral reconstructions appear to be protective. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 23806907 TI - Trends in autologous fat grafting to the breast: a national survey of the american society of plastic surgeons. AB - BACKGROUND: Autologous fat grafting has been gaining popularity in recent years, although there remains concern regarding the safety and efficacy of the practice for breast surgery. The purpose of this study was to determine national trends for fat grafting to the breast and to establish the frequency and specific techniques of the procedure to provide more supportive data. METHODS: A questionnaire was e-mailed to 2584 members of the American Society of Plastic Surgeons. Variables included prevalence and applications of fat grafting to the breast. Components of the fat graft protocol were also assessed. RESULTS: Four hundred fifty-six of the 2584 questionnaires were completed. Sixty-two percent of all respondents reported currently using fat grafting for reconstructive breast surgery and 28% of all respondents reported currently using the practice for aesthetic breast surgery. The most common reason cited by respondents for using fat grafting to the breast was as an adjunctive therapy to implant or flap surgery. CONCLUSIONS: Fat grafting to the breast is a common procedure most often used in reconstructive operations. The increasing prevalence of fat grafting to the breast indicates a need for collection of clinical data and supports the establishment of a national prospective registry to track outcomes after aesthetic and reconstructive applications. PMID- 23806908 TI - Surgical anatomy of the middle premasseter space and its application in sub-SMAS face lift surgery. AB - BACKGROUND: The premasseter space is a recognized, sub-superficial musculoaponeurotic system (SMAS) soft-tissue space overlying the lower masseter immediately anterior to the parotid. The performance, safety, and effectiveness of composite face lifts are enhanced when the space is used. This has drawn attention to the need for better understanding of the premasseter anatomy above the space. METHODS: The anatomy of the upper premasseter region was investigated in 20 fresh cadaver dissections as well as intraoperatively in hundreds of composite face lifts. RESULTS: A small, transverse, rectangular soft-tissue space overlies the upper masseter and was named the middle premasseter space. The space (transverse width, 25 to 28 mm; vertical width, 10 mm) is separated from the originally described (lower) premasseter space by a double membrane. It is a safe space between the upper and lower buccal trunks of the facial nerve, which are immediately outside the space and separated from it by the respective upper and lower boundary membranes. The parotid duct immediately beneath the floor of the space usually underlies the upper boundary membrane. CONCLUSIONS: The middle premasseter space is significant, as it is the center of the key anatomy immediately cephalad to the lower premasseter space. When used in composite face lifts, the space provides predictable sub-SMAS dissection between the buccal trunks of the facial nerve to the mobile area beyond the anterior border of the masseter where the SMAS overlies the buccal fat pad. PMID- 23806909 TI - A process for quantifying aesthetic and functional breast surgery: I. Quantifying optimal nipple position and vertical and horizontal skin excess for mastopexy and breast reduction. AB - BACKGROUND: This article defines a comprehensive process using quantified parameters for objective decision making, operative planning, technique selection, and outcomes analysis in mastopexy and breast reduction, and defines quantified parameters for nipple position and vertical and horizontal skin excess. Future submissions will detail application of the processes for skin envelope design and address composite, three-dimensional parenchyma modification options. METHODS: Breast base width was used to define a proportional, desired nipple-to-inframammary fold distance for optimal aesthetics. Vertical and horizontal skin excess were measured, documented, and used for technique selection and skin envelope design in mastopexy and breast reduction. This method was applied in 124 consecutive mastopexy and 122 consecutive breast reduction cases. Average follow-up was 4.6 years (range, 6 to 14 years). RESULTS: No changes were made to the basic algorithm of the defined process during the study period. No patient required nipple repositioning. Complications included excessive lower pole restretch (4 percent), periareolar scar hypertrophy (0.8 percent), hematoma (1.2 percent), and areola shape irregularities (1.6 percent). Delayed healing at the junction of vertical and horizontal scars occurred in two of 124 reduction patients (1.6 percent), neither of whom required revision. The overall reoperation rate was 6.5 percent (16 of 246). CONCLUSIONS: This study defines the first steps of a comprehensive process for using objectively defined parameters that surgeons can apply to skin envelope design for mastopexy and breast reduction. The method can be used in conjunction with, or in lieu of, other described methods to determine nipple position. PMID- 23806910 TI - Discussion: a process for quantifying aesthetic and functional breast surgery: I. Quantifying optimal nipple position and vertical and horizontal skin excess for mastopexy and breast reduction. PMID- 23806911 TI - The incidence of vitamin, mineral, herbal, and other supplement use in facial cosmetic patients. AB - BACKGROUND: Dietary supplement use is common in the United States. Some herbal supplements may cause coagulopathy, hypertension, or dry eyes. The goal of this study is to reveal the incidence of herbal supplement use in the cosmetic surgery population. METHODS: A retrospective chart review of 200 patients undergoing facial cosmetic surgery performed by a single surgeon was performed. Variables studied included patient age, sex, surgical procedure, herbal medication use, and intraoperative variables. Exclusion criteria were age younger than 15 years, noncosmetic procedures such as trauma, and incomplete preoperative medication form. Patients were subdivided into the supplement user group (herbal) and the supplement nonuser group (nonherbal). Statistical analysis included descriptive statistics, t test, and chi-square analysis. RESULTS: The incidence of supplement use was 49 percent in the 200 patients; 24.5 percent of patients used only vitamins or minerals, 2.5 percent of patients used only animal- and plant-based (nonvitamin/mineral) supplements, and 22 percent of patients used both types of supplements. In the herbal group, patients used an average of 2.8 supplements. The herbal and nonherbal groups differed significantly in sex (herbal, 89.8 percent female; nonherbal, 77.5 percent; p < 0.04) and age (herbal, 51.4 years; nonherbal, 38.5 years; p < 0.001). CONCLUSIONS: Herbal supplement use is prevalent in the facial cosmetic surgery population, especially in the older female population. Considering the potential ill effects of these products on surgery and recovery, awareness and careful documentation and prohibiting the patients from the consumption of these products will increase the safety and reduce the recovery following cosmetic procedures. PMID- 23806912 TI - Discussion: the incidence of vitamin, mineral, herbal, and other supplement use in facial cosmetic patients. PMID- 23806913 TI - Physicochemical decellularization of composite flexor tendon-bone interface grafts. AB - BACKGROUND: Extremity injuries involving tendon attachment to bone are difficult to address. Clinically, tendon-bone interface allografts must be decellularized to reduce immunogenicity. Composite grafts are difficult to decellularize because chemical agents cannot reach cells between tissues. In this study, the authors attempted to optimize tendon-bone interface graft decellularization. METHODS: Human flexor digitorum profundus tendons with attached distal phalanx were harvested from cadavers and divided into four groups. Group 1 (control) was untreated. Group 2 (chemical) was chemically treated with 5% peracetic acid, 0.1% ethylenediaminetetraacetic acid, and 0.1% sodium dodecyl sulfate. Group 3 (low power) underwent targeted ultrasonication for 3 minutes (22,274 J, 126W) followed by chemical decellularization. Group 4 (high-power) underwent targeted ultrasonication for 10 minutes (88,490 J, 155W) followed by chemical decellularization. Decellularization was assessed histologically with hematoxylin and eosin stain and stains for major histocompatibility complex I stains. Cell counts were performed. The ultimate tensile load of decellularized grafts (group 4) were compared with pair-matched untreated grafts (group 1). RESULTS: Average cell counts were 100 +/- 41, 27 +/- 10, 12 +/- 11, and 6 +/- 11 per high-power field for groups 1, 2, 3, and 4, respectively (p < 0.001). Decellularization using physical and chemical treatments (groups 3 and 4) resulted in substantial reduction of cells and major histocompatibility complex I molecules. There was no difference in ultimate tensile load between treated (group4) and untreated (group 1) samples (p > 0.5). CONCLUSIONS: Physicochemical decellularization of tendon bone interface grafts using targeted ultrasonication and chemical treatment resulted in near-complete reduction in cellularity and maintenance of tensile strength. In the future, these decellularized composite scaffolds may be used for reconstruction of tendon-bone injuries. PMID- 23806914 TI - A systematic review of the literature on the outcomes of treatment for recurrent and persistent carpal tunnel syndrome. AB - BACKGROUND: Recurrent and persistent carpal tunnel syndrome is an uncommon but potentially difficult surgical dilemma. Many surgical treatment options have been described in the literature without comparative data on outcome. METHODS: A systematic review on recurrent carpal tunnel syndrome was performed for all articles from 1946 to 2012 in MEDLINE, EMBASE, CENTRAL, and hand-searched reference lists from all identified articles. Twenty-three articles were screened and identified from the time period 1972 to 2012, representing two general treatment groups: decompression with flap interposition and repeated open decompression. A meta-analysis was then performed, generating forest and funnel plots of the data. RESULTS: In total, 294 patients from 14 studies in the flap arm of the meta-analysis had a weighted success rate of 86 percent (95 percent CI, 0.75 to 0.96), and 364 patients from nine studies in the nonflap arm had a weighted 75 percent success rate (95 percent CI, 0.66 to 0.84). Heterogeneity was statistically analyzed and revealed low heterogeneity with the I statistic. Forest plots were created and analyzed between subgroups, and chi-square analysis revealed a highly statistically significant difference (p = 0.001). The odds ratio of success in the nonflap group was 0.50 (95 percent CI, 0.33 to 0.75). CONCLUSIONS: Decompression with the use of vascularized flap coverage appears to have a higher success rate over simple repeated decompression. The relevance of these data is pertinent to all hand surgeons, as they could have an impact on treatment guidelines for this relatively uncommon but problematic condition, but further prospective study is needed. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 23806915 TI - Management of congenital radial longitudinal deficiency: controversies and current concepts. AB - SUMMARY: Radial longitudinal deficiency is a spectrum of upper extremity dysplasia and hypoplasia affecting the proximal arm and the radial aspect of the forearm, wrist, and hand. Often, the hand surgeon is the first to evaluate a patient with radial longitudinal deficiency and thus must be aware of its common associated syndromes. Specific evaluation, including clinical examination and laboratory testing, is necessary. At this time, there are many surgical approaches that can be used for treatment of radial longitudinal deficiency. The procedures should be specifically tailored to the patient and family to improve overall function and clinical outcome. PMID- 23806916 TI - Fat grafts supplemented with adipose-derived stromal cells in the rehabilitation of patients with craniofacial microsomia. AB - BACKGROUND: Although first reports of the clinical use of adipose-derived stromal cells suggest that this approach may be feasible and effective for soft-tissue augmentation, there is a lack of randomized, controlled clinical trials in the literature. Thus, this study aimed to investigate whether a faster protocol for isolation of adipose-derived stromal cells and their use in combination with fat tissue improve the long-term retention of the grafts in patients with craniofacial microsomia. METHODS: Patients with craniofacial microsomia (n = 14) were grafted either with supplementation of adipose-derived stromal cells (experimental group) or without supplementation of adipose-derived stromal cells (control group). The number of viable cells isolated before and after the supplementation of the grafts was calculated, and these cells were examined for mesenchymal cell surface markers using flow cytometry. Computed tomography was performed to assess both hemifaces preoperatively and at 6 months postoperatively. RESULTS: The average number of viable cells isolated before and after the supplementation of the grafts was 5.6 * 10 and 9.9 * 10 cells/ml of fat tissue (p = 0.015). Flow cytometric analysis revealed that the adipose-derived stromal cells were positive for mesenchymal cell markers (>95 percent for CD73 and CD105). Surviving fat volume at 6 months was 88 percent for the experimental group and 54 percent for the control group (p = 0.003). CONCLUSION: These results suggest that this strategy for isolation and supplementation of adipose-derived stromal cells is effective, safe, and superior to conventional lipoinjection for facial recontouring in patients with craniofacial microsomia. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 23806917 TI - Severe infectious complications following frontal sinus fracture: the impact of operative delay and perioperative antibiotic use. AB - BACKGROUND: The purpose of this study was to investigate whether a delay in operative management of frontal sinus fractures is associated with increased risk of serious infections. METHODS: Retrospective chart review was performed of 242 consecutive patients with surgically managed frontal sinus fractures who presented to the R Adams Cowley Shock Trauma Center between 1996 and 2011. Collected patient characteristics included demographics, surgical management, hospital course, and complications. All computed tomographic imaging was reviewed to evaluate involvement of the posterior table and nasofrontal outflow tract. Serious infections included meningitis, encephalitis, brain abscess, frontal sinus abscess, and osteomyelitis. Delayed operative interventions were defined as procedures performed more than 48 hours after admission. Adjusted relative risk estimates were obtained using multivariable regression. RESULTS: There were 14 serious infections (5.8 percent). All patients with serious infections had both involvement of the posterior table and nasofrontal outflow tract injury. The cumulative incidence of serious infection in these patients was 10.8 percent. After adjustments for confounding, multivariable regression showed that operative delay beyond 48 hours was independently associated with a 4.03-fold (p < 0.05) increased risk for serious infection; external cerebrospinal fluid drainage catheter use and local soft-tissue infection conferred a 4.09-fold (p < 0.05) and 5.10-fold (p < 0.001) increased risk, respectively. Antibiotic use beyond 48 hours postoperatively was not associated with fewer infections. CONCLUSIONS: Delay in operative management of frontal sinus fractures in patients requiring operative intervention is associated with an increased risk for serious infections. Continued antibiotic prophylaxis beyond the perioperative period provides little benefit in preventing serious infections. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II. PMID- 23806918 TI - Discussion: severe infectious complications following frontal sinus fracture: the impact of operative delay and perioperative antibiotic use. PMID- 23806919 TI - Prospective analysis of presurgical risk factors for outcomes in primary palatoplasty. AB - BACKGROUND: The authors present a single surgeon's series of primary palatoplasty over a 10-year period in order to determine which presurgical factors might influence postoperative fistula rate and speech outcome. METHODS: Data were prospectively acquired for all patients undergoing primary palatoplasty between January of 2000 and January of 2010. Standard demographic data were captured together with classification of cleft type and severity (as defined by palate length and cleft width). Outcome data were assessed in terms of fistula rate and the requirement for secondary speech surgery for velopharyngeal insufficiency. RESULTS: There were 485 primary procedures; 276 patients were male. Mean age at primary surgery was 20.4 months. Clefts were classified according to Kernahan and Stark (cleft palate, n = 260; cleft lip/palate, n = 225) and Veau class (I, n = 85; II, n = 175; III, n = 165; and IV, n = 60). Palate length was assessed according to Randall's classification (I, n = 81; II, n = 319; III, n = 58; IV, n = 2). Mean palate width was 7.7 mm (range, 0 to 19 mm). Cleft lip/palate was associated with wider mean cleft width and a higher incidence of shorter palates than cleft palate. Velopharyngeal insufficiency was more frequent in cleft lip/palate than in cleft palate. Male sex, greater cleft width, and shorter palate length were independent predictors of velopharyngeal insufficiency. CONCLUSIONS: Distributions of sex, cleft width, and palate length vary among the differing cleft types and may explain some of the variation in outcomes among centers and protocols. These data should be recorded to facilitate valid comparisons among future studies. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 23806920 TI - Repair of oronasal fistulae by interposition of multilayered amniotic membrane allograft. AB - BACKGROUND: Oronasal fistulas are a frequent complication after cleft palate surgery. Numerous repair methods have been described, but wound-healing problems occur often. The authors investigated, for the first time, the suitability of multilayered amniotic membrane allograft for fistula repair in a laboratory experiment (part A), a swine model (part B), and an initial patient series (part C). METHODS: In part A, one-, two-, and four-layer porcine and human amniotic membranes (n = 20 each) were fixed in a digital towing device and the force needed for rupture was determined. In part B, iatrogenic oronasal fistulas in 18 piglets were repaired with amniotic membrane allograft, autofetal amniotic membrane, or small intestinal submucosa (n = 6 each). Healing was evaluated by probing and visual inflammation control (no/moderate/strong) on postoperative days 3, 7, 10, and 76. Histological analysis was performed to visualize tissue architecture. In part C, four patients (two women and two men, ages 21 to 51 years) were treated with multilayered amniotic membrane allograft. RESULTS: In part A, forces needed for amniotic membrane rupture increased with additional layers (p < 0.001). Human amniotic membrane was stronger than porcine membrane (p < 0.001). In part B, fistula closure succeeded in all animals treated with amniotic membrane with less inflammation than in the small intestinal submucosa group. One fistula remained persistent in the small intestinal submucosa group. In part C, all fistulas healed completely without inflammation. CONCLUSIONS: Amniotic membrane is an easily available biomaterial and can be used successfully for oronasal fistula repair. The multilayer technique and protective plates should be utilized to prevent membrane ruptures. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 23806921 TI - Three-dimensional digital stereophotogrammetry: a reliable and valid technique for measuring scar surface area. AB - BACKGROUND: The surface area of scars is an important outcome parameter in scar assessment. It is often used to quantify the extent of scar features, such as pigmentation disturbances, hypertrophy, and contracture. Currently available techniques for measuring the surface area are known to be cumbersome or do not meet the basic clinimetric criteria (i.e., reliability and validity). Three dimensional stereophotogrammetry is a technique that may improve the quality of surface area measurements. The aim of this study was to investigate the reliability and validity of three-dimensional stereophotogrammetry for measuring scar surface area. METHODS: In a cross-sectional study, two independent clinicians photographed and measured 50 scar areas of 32 patients using a handheld stereographic camera, to assess reliability. Subsequently, using planimetry, the scar surface was traced on a transparent sheet (considered the accepted standard) to assess validity. RESULTS: Three-dimensional stereophotogrammetry showed good reliability, with an intraclass correlation coefficient of 0.99 and a coefficient of variation of 6.8 percent. To visualize the differences between the two observers, data were plotted and the limits of agreement were calculated at 0 +/- 0.19 * mean surface area. Also, excellent validity was found, with a concordance correlation coefficient of 0.99. CONCLUSION: This study showed that three-dimensional stereophotogrammetry is a reliable and valid tool for research purposes in the field of scar surface area measurements. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, I. PMID- 23806922 TI - Discussion: known preoperative deep venous thrombosis and/or pulmonary embolus: to flap or not to flap the severely injured extremity? PMID- 23806923 TI - Taking evidence-based plastic surgery to the next level: report of the second summit on evidence-based plastic surgery. PMID- 23806924 TI - The plastic surgeon as lecturer: speaking as well as we operate. AB - SUMMARY: This article provides information for the surgeon-educator on techniques for delivering effective lectures. The article provides insights into adult learning and how to motivate and educate through lectures. Delivery style and preparation are emphasized, and specific techniques for creating visual aids that complement a lecture are discussed. PMID- 23806925 TI - Discussion: the plastic surgeon as lecturer: speaking as well as we operate. PMID- 23806926 TI - Plastic and reconstructive surgery: becomes an official organ of the american society for reconstructive microsurgery. PMID- 23806927 TI - Facial topography: clinical anatomy of the face. PMID- 23806928 TI - Plastic reconstructive and aesthetic surgery: the essentials. PMID- 23806929 TI - Digital animation versus textbook in teaching plastic surgery techniques to novice learners. AB - BACKGROUND: The authors present a prospective, randomized, blinded trial comparing the educational efficacy of digital animation versus a textbook in teaching the Ivy loop technique to novice learners. METHODS: Medical student volunteers (n = 32) were anonymously videotaped as they fastened dental wire to the teeth of a skull model (preintervention analysis) and then were randomly assigned to one of two study groups. The animation and text groups (n = 16 each) were shown either a digital animation or textbook demonstrating the Ivy loop surgical technique. Volunteers were then videotaped as they performed the technique (postintervention analysis). Volunteers were then shown the educational material provided to the other study group and given a validated educational survey to compare the educational value of both materials. Preintervention and postintervention video recordings were graded using a validated surgical competency scale. Surgical performance grades, time to task completion, and educational survey scores were compared. RESULTS: Preintervention analysis performance scores did not significantly differ between the animation and text groups (10.7 [2.8] versus 11.1 [3.9]; p = 0.74), but postintervention analysis demonstrated significantly higher performance scores in the animation group (18.8 [2.9] versus 13.0 [3.5]; p < 0.001). Time to task completion was similar. The educational survey demonstrated significantly higher scores in the animation group. CONCLUSIONS: A prospective, randomized, blinded study comparing the educational efficacy of a surgical textbook to digital animation demonstrates that, in novice learners, digital animation is a more effective tool for learning the Ivy loop technique. Test takers found digital animation to be the superior educational medium. PMID- 23806930 TI - Involuntary movement during mastication in patients with long-term facial paralysis reanimated with a partial gracilis free neuromuscular flap innervated by the masseteric nerve. AB - BACKGROUND: Midface reanimation in patients with chronic facial paralysis is not always possible with an ipsilateral or contralateral facial nerve innervating a free neuromuscular tissue transfer. Alternate use of nonfacial nerves is occasionally indicated but may potentially result in inadvertent motions. The goal of this study was to objectively review videos of patients who underwent one stage reanimation with a gracilis muscle transfer innervated by the masseteric nerve for (1) inadvertent motion during eating, (2) characterization of masticatory patterns, and (3) social hindrance perceived by the patients during meals. METHODS: Between the years 2009 and 2012, 18 patients underwent midfacial reanimation with partial gracilis muscle transfer coapted to the masseter nerve for treatment of midfacial paralysis. Sixteen patients were videotaped in detail while eating. Involuntary midface movement on the reconstructed side and mastication patterns were assessed. In addition, 16 patients were surveyed as to whether involuntary motion constituted a problem in their daily lives. RESULTS: All 16 patients videotaped during mastication demonstrated involuntary motion on the reconstructed side while eating. Several unique masticatory patterns were noted as well. Only one of the 16 patients reported involuntary motion as a minor disturbance in daily life during meals. CONCLUSIONS: All patients with chronic facial paralysis who plan to undergo midface reanimation with a free tissue transfer innervated by the ipsilateral masseter nerve should be told that they would universally have involuntary animation during mastication. Most patients do not consider this a major drawback in their daily lives. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 23806931 TI - One-stage procedure using spinal accessory nerve (XI)-innervated free muscle for facial paralysis reconstruction. AB - BACKGROUND: For the treatment of facial paralysis, functioning free muscle transplantation has become accepted standard treatment. Choice of donor nerve and number of surgery stages, however, are still matters of great debate. METHODS: Between 2000 and 2011, 36 patients (out of 329; 11 percent) with 42 functioning free muscle transplantations were treated using spinal accessory nerve (XI) innervated muscle for facial reanimation as a one-stage procedure. Indications included bilateral or unilateral Mobius syndrome, severe postparetic facial synkinesis, and patient preference. Postoperative smile training was required to achieve spontaneous smile. For outcome assessment, patients were evaluated using multidisciplinary methods, including objective smile excursion score (range, 0 to 4), cortical adaptation stage (range, I to V), tickle test, and subjective patient questionnaire and satisfaction score (range, 1 to 5). RESULTS: Mean smile excursion score improved from 0.5 preoperatively to 3.4 postoperatively. Eighty three percent of patients were able to perform independent and even spontaneous smile after 1 year of follow-up. Ninety percent of patients had a mean satisfaction score of 3.4 out of 5. However, 50 percent expressed more concern with aesthetic appearance than functional status. There was no functional morbidity of the donor shoulder in daily life. CONCLUSIONS: The classic two-stage procedure is still the first choice for facial paralysis reconstruction. However, the effectiveness of XI-innervated free muscle for facial reanimation in a one stage procedure has proven it to be a good alternative treatment. It has become second in popularity for facial paralysis reconstruction in the authors' center. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 23806932 TI - Key textbooks in the development of modern american plastic surgery: the first half of the twentieth century. AB - BACKGROUND: A number of historical texts published during the first half of the twentieth century played a pivotal role in shaping and defining modern plastic surgery in the United States. METHODS: Blair's Surgery and Diseases of the Mouth and Jaws (1912), John Staige Davis's Plastic Surgery: Its Principles and Practice (1919), Gillies's Plastic Surgery of the Face (1920), Fomon's Surgery of Injury and Plastic Repair (1939), Ivy's Manual of Standard Practice of Plastic and Maxillofacial Surgery, Military Surgery Manuals (1943), Padgett and Stephenson's Plastic and Reconstructive Surgery (1948), and Kazanjian and Converse's The Surgical Treatment of Facial Injuries (1949) were reviewed. RESULTS: These texts were published at a time when plastic surgery was developing as a distinct specialty. Each work represents a different point in this evolution. All were not inclusive of all of plastic surgery, but all had a lasting impact. Four texts were based on clinical experience from World War I; one included experience from World War II; and two included experience from both. CONCLUSIONS: One text became a military surgical handbook in World Wars I and II, playing an important role in care for the wounded. History has demonstrated that times of war spark medical/surgical advancements, and these wars had a dramatic impact on the development of reconstructive plastic surgery. Each of these texts documented surgical advancements and provided an intellectual platform that helped shape and create the independent discipline of plastic surgery during peacetime. For many future leaders of plastic surgery, these books served as their introduction to this new field. PMID- 23806933 TI - Prospective randomized controlled trial: fibrin sealant reduces split skin graft donor-site pain. AB - BACKGROUND: Pain at split skin graft donor sites is common. Fibrin sealant has been demonstrated to reduce time to hemostasis at wound sites, and patients receiving this treatment were incidentally noted to report less pain. This study aimed to evaluate pain and incapacity in split skin graft donor sites treated with and without fibrin sealant. METHODS: Fifty patients requiring thigh donor site split skin grafts were prospectively randomized to receive either a self adhesive fabric dressing alone or fibrin sealant plus the self-adhesive fabric dressing as primary donor-site dressings. External secondary dressings were the same. Patients were blinded with regard to treatment group. Using visual analogue scales (scored 0 to 5), patients rated their donor-site pain and incapacity for 14 days postoperatively. Secondary endpoints were length of hospital stay and duration of requirement for dressings. RESULTS: Forty patients were included in the study analysis and completed self-reported pain and incapacity scores. Twenty received the fibrin sealant plus self-adhesive fabric dressing and 20 received the fabric dressing only (controls). Patients using the fibrin sealant plus the dressing reported significantly less pain (mean score, 0.42 versus 1.60, p < 0.001) and significantly less incapacity (mean score, 0.48 versus 1.71, p < 0.001). Patients allocated to the fibrin sealant group recorded shorter lengths of stay and faster time to discontinuation of dressing, though statistical significance was not achieved. CONCLUSION: Patients whose split skin graft donor sites were dressed with fibrin sealant plus self-adhesive fabric dressing experienced significantly less pain and incapacity than patients with self adhesive fabric dressings alone, allowing a more rapid return to normal activity. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 23806934 TI - A practical guide to free tissue transfer. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Evaluate a patient for a reconstructive microsurgery procedure. 2. Discuss the current literature with regard to perioperative patient care. 3. Describe the common microsurgical setup and operating room considerations and anastomotic techniques. 4. List postoperative monitoring, flap salvage, and complications. SUMMARY: The purpose of this article is to provide guidelines for maintenance of certification continuing medical education for microsurgical operations. It may be used as an aid in evaluation and management of the microsurgical patient. Interspersed with the maintenance of certification-oriented format is continuing medical education information regarding the current state of practice concerning multiple variables in specific procedures of reconstructive microsurgery. PMID- 23806935 TI - Medical specialty society-sponsored data registries: opportunities in plastic surgery. AB - SUMMARY: Clinical data registries are commonly used worldwide and are implemented for a variety of purposes ranging from physician or facility clinic logs for tracking patients, to collecting outcomes data, to measuring quality improvement or safety of medical devices. In the United States, the U.S. Food and Drug Administration has used data collected through registries to facilitate the drug and device regulatory process, for ongoing surveillance during the product life cycle, and for disease appraisals. Furthermore, the Centers for Medicare and Medicaid Services, in certain instances, bases registry participation and submitting data to registries as factors for reimbursement decisions. The purpose of this article is to discuss the use of clinical data registries; the role that medical specialty societies, in particular, the American Society of Plastic Surgeons and The Plastic Surgery Foundation, can have in the development and management of registries; and the opportunities for registry use in plastic surgery. As outcomes data are becoming essential measures of quality health care delivery, participation in registry development and centralized data collection has become a critical task for plastic surgery to engage in to proactively participate in the national quality and performance measurement agenda. PMID- 23806936 TI - The Ruth Graf technique: measurements do not support the efficacy of an inferior pedicle and pectoralis muscle loop in mammaplasty. PMID- 23806937 TI - Reply: the ruth graf technique: measurements do not support the efficacy of an inferior pedicle and pectoralis muscle loop in mammaplasty. PMID- 23806938 TI - Reduced incidence of breast cancer-related lymphedema following mastectomy and breast reconstruction versus mastectomy alone. PMID- 23806939 TI - Reply: reduced incidence of breast cancer-related lymphedema following mastectomy and breast reconstruction versus mastectomy alone. PMID- 23806940 TI - Pubic contouring in the male massive weight loss patient. PMID- 23806941 TI - Reply: pubic contouring in the male massive weight loss patient. PMID- 23806942 TI - Cephalic vein harvest for deep inferior epigastric perforator salvage: an aesthetic upper arm incision. PMID- 23806943 TI - The use of intercostal nerve blocks for implant-based breast surgery. PMID- 23806944 TI - Free flap breast reconstruction in the hypercoagulable patient with a concomitant bleeding diathesis. PMID- 23806945 TI - Flank bulge following retroperitoneal incisions: a myofascial flap repair that relieves pain and cosmetic Sequelae. PMID- 23806946 TI - The buttock crease adductor magnus peninsular perforator flap as another local flap option for repair of the ischial pressure sore transverse adductor magnus flap. PMID- 23806947 TI - The inaugural congress of the international society of plastic regenerative surgery. PMID- 23806948 TI - A multimedia approach for surgical training. PMID- 23806949 TI - The plastic and reconstructive surgery Facebook page: newfound treasure. PMID- 23806950 TI - The BREAST-V: a unifying predictive formula for volume assessment in small, medium, and large breasts. AB - BACKGROUND: Breast volume assessment enhances preoperative planning of both aesthetic and reconstructive procedures, helping the surgeon in the decision making process of shaping the breast. Numerous methods of breast size determination are currently reported but are limited by methodologic flaws and variable estimations. The authors aimed to develop a unifying predictive formula for volume assessment in small to large breasts based on anthropomorphic values. METHODS: Ten anthropomorphic breast measurements and direct volumes of 108 mastectomy specimens from 88 women were collected prospectively. The authors performed a multivariate regression to build the optimal model for development of the predictive formula. The final model was then internally validated. A previously published formula was used as a reference. RESULTS: Mean (+/-SD) breast weight was 527.9 +/- 227.6 g (range, 150 to 1250 g). After model selection, sternal notch-to-nipple, inframammary fold-to-nipple, and inframammary fold-to-fold projection distances emerged as the most important predictors. The resulting formula (the BREAST-V) showed an adjusted R of 0.73. The estimated expected absolute error on new breasts is 89.7 g (95 percent CI, 62.4 to 119.1 g) and the expected relative error is 18.4 percent (95 percent CI, 12.9 to 24.3 percent). Application of reference formula on the sample yielded worse predictions than those derived by the formula, showing an R of 0.55. CONCLUSIONS: The BREAST-V is a reliable tool for predicting small to large breast volumes accurately for use as a complementary device in surgeon evaluation. An app entitled BREAST-V for both iOS and Android devices is currently available for free download in the Apple App Store and Google Play Store. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, II. PMID- 23806951 TI - Incidence of surgical-site infection is not affected by method of immediate breast reconstruction. AB - BACKGROUND: To date, few large-scale studies have reported the incidence of surgical-site infection in women undergoing mastectomy with respect to the various methods of immediate breast reconstruction. This study assessed whether the reconstruction method was associated with the risk of surgical-site infection in these patients. METHODS: Using the National Surgical Quality Improvement Program database, 9230 female patients undergoing mastectomy with immediate reconstruction from 2005 to 2009 were identified. Reconstruction was classified as autologous, prosthetic, or hybrid. The primary outcome was the incidence of surgical-site infection within 30 days of operation. Univariate and multivariate analyses were performed to derive the unadjusted and adjusted risk of surgical site infection according to reconstruction method. RESULTS: The overall rate of surgical-site infection was 3.53 percent (95 percent CI, 3.15 to 3.94 percent), with individual rates of 3.33 percent (95 percent CI, 2.93 to 3.76 percent) for prosthetic reconstruction, 4.88 percent (95 percent CI, 3.48 to 6.11 percent) for autologous reconstruction, and 2.19 percent (95 percent CI, 0.88 to 4.45 percent) for hybrid reconstruction. The adjusted odds ratio of surgical-site infection was 1.14 (95 percent CI, 0.83 to 1.58; p = 0.42) for autologous versus prosthetic methods and 0.59 (95 percent CI, 0.27 to 1.27; p = 0.18) for hybrid versus prosthetic methods. CONCLUSIONS: Although the risk of surgical-site infection in patients undergoing immediate reconstruction is highest with autologous and lowest with hybrid methods of reconstruction, the difference in infection risk was not statistically significant after adjustment for confounding factors. Thus, all methods of reconstruction are viable options with regard to risk for surgical site infection. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 23806952 TI - Prospective comparative clinical evaluation of 784 consecutive cases of breast augmentation and vertical mammaplasty, performed individually and in combination. AB - BACKGROUND: Despite the growing popularity of breast lift surgery, no published study prospectively evaluates mastopexy and augmentation/mastopexy. Several investigators suggest an inordinate risk in combining augmentation and mastopexy, and recommend staging the surgery in some patients. However, no existing study includes the necessary individual and combined treatment cohorts to allow reliable comparisons of safety and efficacy. This study investigates the clinical outcomes and safety of these cosmetic breast procedures, whether performed individually or in combination. METHODS: This 10-year prospective study evaluated 759 consecutive women undergoing 784 consecutive cases of breast augmentation (n = 522), mastopexy (n = 57), augmentation/mastopexy (n = 146), reduction (n = 48), and reduction plus implants (n = 11). All patients were treated by the author using submuscular implant placement and vertical parenchymal resection with a medial pedicle and intraoperative determination of nipple positioning. A power analysis confirmed adequacy of the sample sizes. RESULTS: The complication rate was 36.3 percent for augmentation/mastopexy, 33.3 percent for mastopexy alone, and 17.6 percent for breast augmentation alone. Mammaplasties were complicated by persistent ptosis in 9.5 percent of patients. The revision rate after augmentation/mastopexy was 20.5 percent, compared with 24.6 percent for mastopexy and 10.7 percent for breast augmentation. CONCLUSIONS: Vertical mammaplasty may be used to correct ptosis in breasts of all sizes. Vertical augmentation/mastopexy provides complication and revision rates that are less than the calculated cumulative rates for the procedures performed separately. The combined procedure offers technical advantages and permits safe single-stage surgery using the vertical technique. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 23806953 TI - Discussion: prospective comparative clinical evaluation of 784 consecutive cases of breast augmentation and vertical mammaplasty, performed individually and in combination. PMID- 23806954 TI - Randomized controlled trial comparing health-related quality of life in patients undergoing vertical scar versus inverted T-shaped reduction mammaplasty. AB - BACKGROUND: There is controversy regarding the superiority of the vertical scar reduction technique versus the inverted T-shaped reduction technique for breast reduction surgery. METHODS: Two hundred fifty-five patients were randomized to either the vertical scar reduction or inverted T-shaped reduction technique immediately before surgery over a 5-year period. Patients completed the Health Utilities Index Mark 3, Short Form-36, Breast-Related Symptoms Questionnaire, and Multidimensional Body-Self Relations Questionnaire at 1 week preoperatively and 1, 6, and 12 months postoperatively. Data were treated according to intention-to treat principles. The primary outcome was the difference in the change in Health Utilities Index Mark 3 score from baseline to 12 months postoperatively between the two techniques. RESULTS: Patients undergoing either technique gained a statistically significant and clinically important improvement from baseline to 1 year postoperatively in the Health Utilities Index Mark 3 (vertical scar reduction, 0.81, 0.16 to 0.87, 0.19; inverted T-shaped reduction, 0.79, 0.20 to 0.89, 0.15) and the Breast-Related Symptoms Questionnaire (vertical scar reduction, 50.26, 12.98 to 95.59, 9.36; inverted T-shaped reduction, 50.06, 12.50 to 94.09, 9.86). No difference in mean change in scores from baseline to 12 months postoperatively was seen in any of the quality of life questionnaires between the techniques. CONCLUSIONS: There was a clinically important improvement between baseline and 1 year postoperatively in both groups in the Health Utilities Index Mark 3 and the Breast-Related Symptoms Questionnaire. The authors conclude that the techniques are similar when quality of life is the outcome of interest. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, I. PMID- 23806955 TI - Histone deacetylase inhibitor reduces hypertrophic scarring in a rabbit ear model. AB - BACKGROUND: Hypertrophic scars result from excessive collagen deposition at sites of healing dermal wounds and could be functionally and cosmetically problematic. The authors tested the ability of the histone deacetylase inhibitor trichostatin A to reduce hypertrophic scar formation in a rabbit ear model. METHODS: The authors have developed a reliable rabbit model that results in hypertrophic scarring. Four 1-cm, full-thickness, circular wounds were made on each ear. After the wounds reepithelialized, 0.02% trichostatin A was injected intradermally into the wounds in the treatment group. Expression of collagen I and fibronectin was detected by reverse transcription polymerase chain reaction and Western blot analysis at postoperative day 23. Scar hypertrophy was quantified by measurement of the scar elevation index at postoperative day 45. RESULTS: Compared with the control group, injection of trichostatin A led to much more normal-appearing scars in the rabbit ear. The scar elevation index at postoperative day 45 was significantly decreased after injection of trichostatin A compared with untreated scars. Furthermore, the authors confirmed the decreased expression of collagen I and fibronectin at postoperative day 23 (after the rabbits had been treated with trichostatin A for 1 week) in the treated scars compared with the control scars according to reverse transcription polymerase chain reaction and Western blot analysis. CONCLUSIONS: The introduction of trichostatin A can result in the decreased formation of hypertrophic scars in a rabbit ear model, which is corroborated by evidence of decreased collagen I and fibronectin synthesis. PMID- 23806956 TI - In vitro study of a novel oxysterol for osteogenic differentiation on rabbit bone marrow stromal cells. AB - BACKGROUND: Bone morphogenetic proteins (BMPs) are powerful osteoinductive growth factors but are associated with exorbitant costs and undesirable side effects. Oxysterols are biocompatible cholesterol oxidation products with osteoinductive properties that may represent an alternative to BMP. In this study, the authors examine the osteogenic potential and mechanisms of actions of oxysterol 49, a novel oxysterol analogue, in primary rabbit bone marrow stromal cells. METHODS: Bone marrow stromal cells were isolated from the iliac crests of New Zealand White rabbits and then treated with various concentrations of oxysterol 49 or BMP 2, either alone or in combination. Alkaline phosphatase activity and expression of osteocalcin and osteopontin were evaluated. The effect of treatment of cells with cyclopamine, a known hedgehog signaling pathway inhibitor, was also assessed. RESULTS: Alkaline phosphatase activity was increased in cells treated with 1 uM oxysterol 49 relative to cells treated with BMP-2. Expression of osteocalcin and osteopontin in cells treated with oxysterol 49 and BMP-2 was equivalent. Alkaline phosphatase activity was decreased with the addition of cyclopamine. Combined treatment with oxysterol 49 and BMP-2 resulted in additive increases in alkaline phosphatase activity and osteocalcin and osteopontin expression. CONCLUSIONS: Oxysterol 49 has osteoinductive properties that are similar to those of BMP-2 in rabbit bone marrow stromal cells. The mechanism of this activity is at least in part related to the hedgehog signaling pathway. The two growth factors demonstrate additive effects when used in combination. Further study is required to examine the potential role of oxysterol 49 as a complement or alternative to BMP-2 in bone tissue engineering. PMID- 23806957 TI - Validity and responsiveness of the DASH questionnaire as an outcome measure following ulnar nerve transposition for cubital tunnel syndrome. AB - BACKGROUND: This study sought to determine the validity and responsiveness of the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire in cubital tunnel syndrome. METHODS: Consecutive patients with cubital tunnel syndrome treated by anterior ulnar nerve transposition between September of 2009 and December of 2011 were reviewed retrospectively. Questionnaires were completed preoperatively and 1.5, 3, 6, and 12 months postoperatively. The relationship of the questionnaire to measures of pain, health status (Short Form-8), and pinch and grip strength was evaluated using Spearman's correlation coefficients. Responsiveness of the questionnaire was analyzed using Cohen's effect size, and was compared with responsiveness of the physical examination, pain, and Short Form-8 measures. RESULTS: The final cohort included 69 patients with isolated cubital tunnel syndrome and 39 with concurrent cubital and carpal tunnel syndrome. Questionnaire scores correlated as expected with other measures. Moderate to strong correlations were observed with pain visual analogue scale and Short Form-8 scores, and weak to moderate correlations were observed with pinch and grip strength. Effect sizes for the DASH questionnaire were small (<0.3) at 6 weeks and moderate (0.35 to 0.57) at 3, 6, and 12 months postoperatively in both groups. Pain visual analogue scale scores demonstrated large effect sizes (>0.8) at all postoperative time points, whereas Short Form-8 and pinch and grip strength were poorly responsive. CONCLUSION: The Disabilities of the Arm, Shoulder, and Hand questionnaire is a valid measure in cubital tunnel syndrome, and is moderately responsive to change beyond 3-month follow-up. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, II. PMID- 23806958 TI - Implant-based breast reconstruction using a titanium-coated polypropylene mesh (TiLOOP Bra): a multicenter study of 231 cases. AB - BACKGROUND: An alternative to implant-based breast reconstruction using acellular dermal matrix is the use of a titanium-coated polypropylene mesh. The mesh was approved for implant-based breast reconstruction in Europe in 2008, but only limited clinical data are available. METHODS: Two hundred seven patients (231 breasts) with skin-sparing/nipple-sparing or modified radical mastectomy and immediate or delayed implant-based breast reconstruction using titanium-coated polypropylene mesh were evaluated retrospectively. The primary endpoints were identification of patient-related and surgical factors that were predictive for an adverse outcome and the development of recommendations for patients eligible for implant-based breast reconstruction using the mesh. Complications were divided into major (need for additional surgery), minor (conservative treatment), and implant loss. Univariate and multivariate logistic regression analyses were performed to determine the influence of the patient- and procedure-related characteristics on postoperative complications and implant loss. RESULTS: No risk factors were observed for patient-associated complications. Major complications occurred in 13.4 percent, minor complications in 15.6 percent, and implant loss in 8.7 percent of patients. Univariate analysis revealed procedure-related risk factors for postoperative complications with a bilateral procedure (p = 0.013) or skin expansion before implant surgery (p = 0.043). Multivariate analysis confirmed these risk factors and revealed an increased risk for implant loss in patients with skin necrosis (p < 0.001) and capsule fibrosis (p < 0.001). CONCLUSIONS: This titanium-coated polypropylene mesh shows acceptable complication rates and can be a helpful device in implant-based breast reconstruction. The mesh should only be used in primary cases and, when adhering to the proposed indications, is a safe and convenient option in implant-based breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 23806959 TI - Parathyroid hormone therapy mollifies radiation-induced biomechanical degradation in murine distraction osteogenesis. AB - OBJECTIVE: Descriptions of mandibular distraction osteogenesis for tissue replacement after oncologic resection or for defects caused by osteoradionecrosis have been limited. Previous work demonstrated radiation decreases union formation, cellularity and mineral density in mandibular distraction osteogenesis. The authors posit that intermittent systemic administration of parathyroid hormone will serve as a stimulant to cellular function, reversing radiation-induced damage and enhancing bone regeneration. METHODS: Twenty male Lewis rats were randomly assigned to three groups: group 1 (radiation and distraction osteogenesis, n = 7) and group 2 (radiation, distraction osteogenesis, and parathyroid hormone, n = 5) received a human-equivalent dose of 35 Gy of radiation (human bioequivalent, 70 Gy) fractionated over 5 days. All groups, including group 3 (distraction osteogenesis, n = 8), underwent a left unilateral mandibular osteotomy with bilateral external fixator placement. Distraction osteogenesis was performed at a rate of 0.3 mm every 12 hours to reach a gap of 5.1 mm. Group 2 was injected with parathyroid hormone (60 ug/kg) subcutaneously daily for 3 weeks after the start of distraction osteogenesis. On postoperative day 40, all left hemimandibles were harvested. Biomechanical response parameters were generated. Statistical significance was considered at p <= 0.05. RESULTS: Parathyroid hormone-treated mandibles had significantly higher failure load and higher yield than did untreated mandibles. However, these values were still significantly lower than those of nonirradiated mandibles. CONCLUSIONS: The authors have successfully demonstrated the therapeutic efficacy of parathyroid hormone to stimulate and enhance bone regeneration in their irradiated murine mandibular model of distraction osteogenesis. Anabolic regimens of parathyroid hormone, a U.S. Food and Drug Administration-approved drug on formulary, significantly improve outcomes in a model of postoncologic craniofacial reconstruction. PMID- 23806961 TI - A new journal for challenges, trends and transformations in academic medicine today. PMID- 23806960 TI - Diacylglycerol lipase alpha manipulation reveals developmental roles for intercellular endocannabinoid signaling. AB - Endocannabinoids are small signaling lipids, with 2-arachidonoylglycerol (2-AG) implicated in modulating axonal growth and synaptic plasticity. The concept of short-range extracellular signaling by endocannabinoids is supported by the lack of trans-synaptic 2-AG signaling in mice lacking sn-1-diacylglycerol lipases (DAGLs), synthesizing 2-AG. Nevertheless, how far endocannabinoids can spread extracellularly to evoke physiological responses at CB1 cannabinoid receptors (CB1Rs) remains poorly understood. Here, we first show that cholinergic innervation of CA1 pyramidal cells of the hippocampus is sensitive to the genetic disruption of 2-AG signaling in DAGLalpha null mice. Next, we exploit a hybrid COS-7-cholinergic neuron co-culture system to demonstrate that heterologous DAGLalpha overexpression spherically excludes cholinergic growth cones from 2-AG rich extracellular environments, and minimizes cell-cell contact in vitro. CB1R mediated exclusion responses lasted 3 days, indicating sustained spherical 2-AG availability. Overall, these data suggest that extracellular 2-AG concentrations can be sufficient to activate CB1Rs along discrete spherical boundaries to modulate neuronal responsiveness. PMID- 23806962 TI - Comorbidity of mental and physical disorders: a main challenge to medicine in the 21st century. PMID- 23806963 TI - Professionalism in contemporary medicine: if it is an important academic issue, then surely it is a "hot" issue as well. AB - Professionalism has been a hot topic in medical education and in medicine in general. Professionalism in medicine embodies the relationship between medicine and society as it forms the basis of patient-physician relationships and the mutual expectations patients and physicians have of each other. Education on professionalism in medicine and professionalism in medical education are two important liasions. Increasing efforts have focused on fostering professionalism in medical education. Medical faculties have long taught the theoretical and technical aspects of medicine, but teaching professionalism in medicine and healing qualities has been a recent trend. The concept of professionalism has evolved over time by a process of exploration and reflection. It seems that medical professionalism has been changing from paternalism to partnership with patients and mutuality, from tribalism to collegiality, and from self-sacrifice to shared responsibility. There is still no consensus on how professionalism in medicine should be defined as and about the best methods for teaching medical professionalism. The aim of this "landscape" review is to promote the complete integration of a culture of professionalism into the educational and research body, including staff, faculty, residents and students. PMID- 23806964 TI - Secondary traumatisation and systemic traumatic stress. AB - Traditionally, research has been focused on the development of symptoms in direct trauma survivors. However, during the last two decades researchers and clinicians have started exploring the way individual traumatic stress exposure affects trauma victims' spouses, children and professional caregivers. Studying trauma within the family is a part of what is called systemic traumatology, a study of groups, institutions and other human systems that show stress reactions directly caused by a traumatic event or series of events. The effect of an individual's traumatic stress on family members and on persons in direct contact is conceptualized as secondary traumatisation. In its narrow sense, secondary traumatisation involves a transfer of nightmares, intrusive thoughts, flashbacks and other Posttraumatic Stress Disorder symptoms, which are typically experienced by individuals suffering from PTSD, onto their immediate surroundings. In its broader sense, the term refers to any kind of distress transfer from a trauma victim to their immediate surroundings, and includes a broad spectrum of distress manifestation along with that resembling Posttraumatic Stress Disorder. Beyond that, a family member's PTSD is potentially transferable to subsequent generations, interfering with the psychological development of children. PMID- 23806965 TI - Child- and family-centered care in the treatment of children - knowledge, attitudes, practice. AB - Despite the advances in medical technology, health care improvements have not always been accompanied by commensurate attention to the child's well-being. Psychological and emotional status of children during hospital treatment is often underestimated. Namely, certain kind of institutional negligence is frequently present in everyday practice in children's institutions. Many hospitals in Bosnia and Herzegovina (B&H) have become child-friendly during the implementation of the Project on Child-Friendly Hospitals supported by UNICEF and WHO. Apart from the introduction of child friendly environment, staff in hospitals was trained to provide a holistic approach. The program was closely linked to the Baby Friendly Hospital Initiative that supported breastfeeding. A few years thereafter, our focus is still on the physical treatment of sick children, whereas the attention to their anxieties, fears and suffering has failed. A more serious approach to this problem is needed and should begin at an educational level in medical school programs. Accordingly, our philosophy (mission) should change from a mechanical (techno-) medicine to holistic medicine. PMID- 23806966 TI - Private sector medicine-increasing excellence and viable alternative to state sector. PMID- 23806967 TI - The prevalence of metabolic syndrome in patient with posttraumatic stress disorder. AB - BACKGROUND: Although the connection between body and soul is written in the Bible, research papers haven't given much attention to it until the past few decades. Recently, both here and abroad, there have been more studies that investigate the prevalence of various somatic disorders in psychiatric patients, including metabolic syndrome. OBJECTIVE: The objective of this study was to establish the prevalence of metabolic syndrome and it's components in patients with posttraumatic stress disorder (PTSD). SUBJECTS AND METHODS: Metabolic syndrome and its components were investigated in 60 patients with chronic PTSD conditioned by the war and in 60 patients treated for somatic problems by their family physician in Mostar. RESULTS: The prevalence of metabolic syndrome was statistically significantly higher in patients with PTSD (48.3%) than in the control group (25%) (P=0.008) and the number of its individual components (test group 2.38+/-1.30 compared to control group 1.72+/-1.24) (P=0.005). PTSD patients diagnosed with metabolic syndrome had significantly more frequent hyperglycemia (P=0.010) and abdominal obesity (P=0.044) compared to the control group. CONCLUSION: The prevalence of metabolic syndrome increased in patients with PTSD compared to the control group. PMID- 23806968 TI - Association of erythrocyte sedimentation rate and fibrinogen concentration with metabolic syndrome in schizophrenic patients. AB - INTRODUCTION: Inflammation can be a process significant to the development of schizophrenia and metabolic disorders that are frequently found in patients suffering from schizophrenia. The aim of this study was to determine the values of erythrocyte sedimentation rate and fibrinogen concentration and to establish their possible association with MS and its components in schizophrenic patients. SUBJECTS AND METHODS: A cross-sectional study was conducted on 200 subjects who were divided into two groups. The study group consisted of schizophrenic patients from the University Clinical Hospital Mostar (n=100), while the control group consisted of healthy subjects who came for systematic medical examinations at the infirmary of the Health Center Mostar (n=100). The diagnosis of MS was made according to NCEP-ATP III criteria, and on that basis subjects from both groups were divided into two subgroups, one with and one without MS. Inflammatory indicators that were determinated were erythrocyte sedimentation rate and fibrinogen concentration. RESULTS: Statistically, MS was significantly more frequent in schizophrenic subjects (46.0%) compared to the control group (29.0%) (p=0.013). Schizophrenic subjects with MS had statistically higher sedimentation rate and fibrinogen concentration compared to the schizophrenic subjects without MS, as well as compared to the control subgroup without MS. The most significant correlations discovered were for the relation of sedimentation rate with systolic (r=0.41) and diastolic (r=0.34) blood pressures. CONCLUSION: Routine monitoring of erythrocyte sedimentation rate and fibrinogen concentration might have an important role in forecasting MS development and consequent adverse cardiovascular events which are the leading cause of mortality in schizophrenic patients. PMID- 23806969 TI - Analysis of psychopathological traits in psoriatic patients. AB - Psoriasis vulgaris is a multifactorial, heterogeneous disease that is associated with problems in skin image and feelings of shame and stigmatization. The aim of this study was to analyze psychopathological traits in patients with psoriasis and a comparative group. A total of 254 dermatological patients participated in the study: 124 patients with confirmed diagnoses of psoriasis vulgaris and 130 patients with melanocytic and non-melanocytic nevi on covered parts of the body. Psychometrically mensural and standardized instruments were used in the study: list of general data, appendix of disease data, Beck Depression Inventory test, State-Trait Anxiety Inventory, Measure of psychological stress and Eysenck's Personal Questionnaire. There is a significant statistical difference in the result of psychometric tests between the study groups. Patients with psoriasis have more severe symptoms of depression, more physical symptoms of anxiety and higher results on the anxiety scale as a state and as a trait p=0.000. Eysenck's personal questionnaire showed higher results on the psychoticism scale p=0.000 and lower results on the extraversion scale p=0.035 among psoriatic patients. PMID- 23806970 TI - PhD study "biomedicine and health" - perspective and experiences of the Faculty of Medicine University of Mostar. PMID- 23806971 TI - Comorbidity and multimorbidity in medicine today: challenges and opportunities for bringing separated branches of medicine closer to each other. AB - Comorbidity and multimorbidity represent one of the greatest chalenge to academic medicine. Many disorders are often comorbidly expressed in diverse combinations. In clinical practice comorbidity and multimorbidity are underrecognized, underdiagnosed, underestimated and undertreated. So that one can speak about comorbidity and multimorbidity anosognosia. Comorbidities and multimorbidities are indifferent to medical specializations, so the integrative and complementary medicine is an imperative in the both education and practice. Shifting the paradigm from vertical/mono-morbid interventions to comorbidity and multimorbidity approaches enhances effectiveness and efficiency of human resources utilization. Comorbidity and multimorbidity studies have been expected to be an impetus to research on the validity of current diagnostic systems as well as on establishing more effective and efficient treatment including individualized and personalized pharmacotherapy. PMID- 23806972 TI - Targeted delivery of miR-200c/DOC to inhibit cancer stem cells and cancer cells by the gelatinases-stimuli nanoparticles. AB - Cancer stem cells (CSCs) are recently discovered as vital obstacles for the successful cancer therapy. Emerging evidences suggest that miR-200c functions as an effective CSCs inhibitor and can restore sensitivity to microtubule-targeting drugs. In the present work, the intelligent gelatinases-stimuli nanoparticles (NPs) was set up to co-deliver miR-200c and docetaxel (DOC) to verify their synergetic effects on inhibition of CSCs and non-CSC cancer cells. After tumor cells were treated with miR-200c NPs, miR-200c and its targeted gene class III beta-tubulin (TUBB3)TUBB3 expression were evaluated. The effects of miR-200c/DOC NPs on tumor cell viability, migration and invasion as well as the expression of E-cadherin and CD44 were studied. The antitumor effects of miR-200c/DOC NPs were compared with DOC NPs in xenograft gastric cancer mice. Moreover, the residual tumors after treatment were subcutaneously seeded into nude mice to further investigate the effective maintenance of NPs. We found that the gelatinases stimuli NPs facilitated miR-200c into cells, achieving sustained miR-200c expression in tumor cells during 9 days. The miR-200c/DOC NPs significantly enhanced cytotoxicity of DOC, possibly by decreasing TUBB3 level, and reversing EMT. The miR-200c NPs achieved high levels of in vivo accumulation and long retention in gastric cancer xenografts after intravenous administration. The miR 200c/DOC NPs prominently suppressed in vivo tumor growth with elevated miR-200c and E-cadherin levels and down-regulated TUBB3 and CD44 expressions. When the residual tumors after miR-200c/DOC NPs treatment were re-transplanted into nude mice, the tumors demonstrated the slowest growth speed. The miR-200c/DOC NPs may provide a promising modality for co-delivery of nucleic acid and drugs to simultaneously inhibit CSCs and non-CSC cancer cells. PMID- 23806973 TI - Theoretical and experimental studies on isotachophoresis in multi-moving chelation boundary system formed with metal ions and EDTA. AB - In this paper, a general mode and theory of moving chelation boundary based isotachophoresis (MCB-based ITP), together with the concept of decisive metal ion (DMI) having the maximum complexation constant (lg Kmax) with the chelator, were developed from a multi-MCB (mMCB) system. The theoretical deductions were: (i) the reaction boundary velocities in the mMCB system at steady state were equal to each other, resulting in a novel MCB-based ITP separation of metal ions; (ii) the boundary directions and velocities in the system were controlled by the fluxes of chelator and DMI, rather than other metal ions; and (iii) a controllable stacking of metal ions could be simultaneously achieved in the developed system. To demonstrate the deductions, a series of experiments were conducted by using model chelator of EDTA and metal ions of Cu(II) and Co(II) due to characteristic colors of blue [Cu-EDTA](2-) and pink [Co-EDTA](2-) complexes. The experiments demonstrated the correctness of theoretical deductions, indicating the validity of the developed model and theory of ITP. These findings provide guidance for the development of MRB-based ITP separation and stacking of metal ions in biological sample matrix and heavy metal ions in environmental samples. PMID- 23806975 TI - Progress using Tc-99m radiopharmaceuticals for measuring high capacity sites and low density sites. AB - Technetium-99m (Tc-99m) has long been a mainstay in clinical nuclear medicine, primarily monitoring biological processes in the heart, kidney, liver, and brain. More recently, Tc-99m chelates have been used as the reporter in targeted nuclear medicine probes that monitor changes in specific protein expression products. The strengths remain the inexpensive source of Tc-99m from the Mo-99/Tc-99m generator, its rich chemistry, high-yield kit formulation, and its widespread availability. Hardware and software advances, such as OSEM reconstructions with scatter and attenuation corrections, have led to quantitation of the injected radioactivity in terms of kBq/cm. PMID- 23806974 TI - Age-dependent mitochondrial energy dynamics in the mice heart: role of superoxide dismutase-2. AB - The aging process alters cardiac physiology, decreases the number of cardiomyocytes and alters the energy metabolism. Mitochondrial dysfunction in aging is believed to cause these functional and phenotypic changes in the heart. Although precise understanding of alterations of mitochondrial respiration in aging is necessary to manage heart diseases in the elderly population conflicting data on the function of specific complex of electron transport chain of the heart mitochondria limits the intervention process. We have addressed these issues using the assay of mitochondrial coupling and electron flow to assess specific functional defects in mitochondria isolated from young or aged mice. Our results demonstrate that cardiac mitochondria from older mice utilize oxygen at a decreased rate via complex I, II or IV compared to younger mice. We further show that mitochondrial function decreases in young Sod2(+/-) mice heart compared to young wildtype mice. However, the mitochondrial function remains unchanged in older Sod2(+/-) mice heart compared to younger Sod2(+/-) mice heart. Further, the oxygen consumption remains similar in old wildtype mice and old Sod2(+/-) mice heart mitochondria. The expression and activity of Sod2 in young or old Sod2(+/-) mice heart remain unchanged. These data demonstrate that decreased oxygen utilization in older age could have resulted in decreased mitochondrial ROS mediated oxidative damage requiring less Sod2 for protection against mitochondrial oxidative stress in older wildtype or older Sod2(+/-) mice. PMID- 23806976 TI - Engineering in vitro microenvironments for cell based therapies and drug discovery. AB - Traditional ex vivo culture setups fail to imitate the native tissue niche, leading to cellular senescence, phenotypic drift, growth arrest and loss of stem cell multipotency. Growing evidence suggests that surface topography, substrate stiffness, mechanical stimulation, oxygen tension and localised density influence cellular functions and longevity, enhance tissue-specific extracellular matrix deposition and direct stem cell differentiation. In this review, we discuss how these cues will facilitate engineering of physiological in vitro microenvironments to enable clinical translation of cell based therapies and development of in vitro models for drug discovery applications. PMID- 23806977 TI - Physiological formation of fluorescent and conductive protein microfibers in live fibroblasts upon spontaneous uptake of biocompatible fluorophores. AB - We have recently reported initial results concerning an original approach to introduce additional properties into fibrillar proteins produced by live fibroblasts and extruded into the ECM. The key to such an approach was biocompatible, fluorescent and semiconducting synthetic molecules which penetrated spontaneously the cells and were progressively encompassed via non bonding interactions during the self-assembly process of the proteins, without altering cell viability and reproducibility. In this paper we demonstrate that the intracellular secretion of fluorescent microfibers can be generalized to living primary and immortalized human/mouse fibroblasts. By means of real-time single-cell confocal microscopy we show that the fluorescent microfibers, most of which display helical morphology, are generated by intracellular coding of the synthetic molecules. We also describe co-localization experiments on the fluorescent microfibers isolated from the cell milieu demonstrating that they are mainly made of type-I collagen. Finally, we report experimental data indicating that the embedded synthetic molecules cause the proteins not only to be fluorescent but also capable of electrical conductivity. PMID- 23806978 TI - Scanning probe microscopy: a visionary development. PMID- 23806979 TI - Measurements of uptake coefficients for heterogeneous loss of HO2 onto submicron inorganic salt aerosols. AB - Laboratory studies were conducted to investigate the kinetics of HO2 radical uptake onto submicron inorganic salt aerosols. HO2 reactive uptake coefficients were measured at room temperature using an aerosol flow tube and the Fluorescence Assay by Gas Expansion (FAGE) technique that allowed for measurements to be conducted under atmospherically relevant HO2 concentrations ([HO2] = 10(8) to 10(9) molecule cm(-3)). The uptake coefficient for HO2 uptake onto dry inorganic salt aerosols was consistently below the detection limit (gamma(HO2) < 0.004). The mass accommodation coefficient of HO2 radicals onto Cu(II)-doped (NH4)2SO4 aerosols was measured to be alpha(HO2) = 0.4 +/- 0.3 representing the kinetic upper limit to gamma. For aqueous (NH4)2SO4, NaCl and NH4NO3 aerosols not containing traces of transition metal ions, a range of gamma(HO2) = 0.003-0.02 was measured. These values were much lower than gamma values previously measured on aqueous (NH4)2SO4 and NaCl aerosols and also those typically used in atmospheric models (gamma(HO2) = 0.1-1.0). Evidence is presented showing that the HO2 uptake coefficients onto aqueous salt aerosol particles are dependent both on the exposure time to the aerosol and on the HO2 concentration used. PMID- 23806980 TI - Dysfunctions within limbic-motor networks in amyotrophic lateral sclerosis. AB - Previous studies have shown that affective symptoms are part of the clinical picture in amyotrophic lateral sclerosis (ALS), the most common motor neuron disorder in elderly people. Diffuse neurodegeneration of limbic regions (e.g., prefrontal cortex [PFC], amygdala) was demonstrated in ALS post-mortem, although the mechanisms of emotional dysregulation in ALS in vivo remain unclear. Using functional imaging, we assessed the brain responses to emotional faces in 11 cognitively unimpaired ALS patients and 12 healthy controls (HCs). We tested whether regional activities and connectivity patterns in the limbic system differed between ALS patients and HCs and whether the variability in clinical measures modulated the neuroimaging data. Relative to HCs, ALS patients displayed greater activation in a series of PFC areas and altered left amygdala-PFC connectivity. Anxiety modulated the right amygdala-PFC connectivity in HCs but not in ALS patients. Reduced right premotor cortex activity and altered left amygdala-supplementary motor area connectivity were associated with longer disease duration and greater disease severity, respectively. Our findings demonstrate dysfunctions of the limbic system in ALS patients at early stages of the disease, and extend our knowledge about the interplay between emotional brain areas and the regions traditionally implicated in motor control. PMID- 23806981 TI - Molecular biomarkers of resistance to anti-EGFR treatment in metastatic colorectal cancer, from classical to innovation. AB - BACKGROUND: Systematic dissection of the EGFR pathway was considered as the best way to identify putative markers of resistance to anti-EGFR therapies. This kind of approach leaves other, less known but by no means less important, putative mechanisms of resistance. We tried to shed some light on these mechanisms of resistance. MATERIALS AND METHODS: We performed a research through Pubmed database of all published articles highlighting mechanisms of resistance to Cetuximab and Panitumumab based therapies, published in 2000-2012 period. CONCLUSIONS: We reviewed the "classical" molecular factors, extensively analyzed as predictive factors for efficacy to anti-EGFR therapy, such as K-ras, B-raf, and PI3K-mTOR-Akt, focusing on their predictive or prognostic value and on the controversial aspects of the biomarker analysis for clinical practice. On the second part we will then move on to other less known molecular markers, for the future understanding of biological mechanisms underlying anti-EGFR therapy resistance, such as non-canonical heterodimer candidates, microRNA, IGF1-IGF1R, HGF-cMET and secondary mutations of EGFR. PMID- 23806982 TI - Immunomodulation as a therapeutic strategy in the treatment of multiple myeloma. AB - Growth and survival of multiple myeloma (MM) cells depend on intrinsic, cell autonomous parameters, such as the genetic lesions harboured by the MM cells, as well as extracellular, cell-non-autonomous factors, including the interaction between MM cells and bone-marrow stromal cells and the suppression of the host's anticancer immune responses. Thalidomide and the immunomodulatory agents lenalidomide and pomalidomide have pleiotropic effects on MM cells and their microenvironment, including promotion of direct mechanisms of MM-cell apoptosis, as well as indirect mechanisms mediated by perturbation of cell adhesion, modulation of cytokine production, and inhibition of tumor-associated angiogenesis. The immunomodulatory properties of these agents are mediated by effects on T-cell proliferation and function, stimulation of natural killer cells, and inhibition of regulatory T cells. Thalidomide and lenalidomide have established roles in the treatment of patients with newly diagnosed MM and those with relapsed/refractory disease. Pomalidomide is currently being evaluated in clinical trials, and preliminary clinical data suggest that it is active in patients with MM that is refractory to lenalidomide and bortezomib treatment. This article provides an overview of the current and potential future roles of immunomodulation in the management of MM, and how improved anticancer immune responses may improve treatment outcomes. PMID- 23806983 TI - Comparative study of laparoscopic versus open appendicectomy. AB - Comparative Study of Laparoscopic (LA) versus Open Appendicectomy (OA) as a Cross sectional hospital based study for evaluation of: Postoperative quality of life Postoperative painAmount of Narcotics/Analgesics usedHospital stayTime to full recovery BACKGROUND: This underdeveloped residuum of the caecum has no known function and is commonly termed as a 'vestigial' organ, yet diseases of the appendix loom large in surgical practice; and appendicitis continues to be the most common acute abdominal condition that requires immediate surgical treatment. STUDY DESIGN: Study to be carried out over a period of two months included patient diagnosed with appendicitis and admitted to surgery ward at Sir J.J. Group of Hospitals, Mumbai, India and St. George Hospital, Mumbai, India and willing to be enrolled in the study.Demographic data, clinical features, investigations, Technique, reintroduction of diet, postoperative pain, use of analgesia, hospital stay were documented and outcome recorded in a predesigned case record form. Return to normal activity and work was determined by questioning during postoperative clinic. RESULTS: Proved that laparoscopic procedures cause less post-operative pain than their conventional counterpartsAnalgesic requirement for post operative analgesia was significantly less in LA (mean 4 inj. doses) compared to the OA (mean 5.9 inj. doses) Hospital stay was less for LA (2.23 days) than OA (3.4 days) Full recovery on the basis of return to normal activity was earlier in LA (6.53 days) as compared to OA (8.7 days). CONCLUSION: LA holds a promising prospect and may replace OA in the near future as the method of choice for effective and qualitative clinical management of appendicitis in emergency and in elective set up. PMID- 23806984 TI - Role of 24 hour telephonic helpline in delivery of mental health services. AB - BACKGROUND: A large number of persons with psychiatric disorders are not seeking treatment due to various reasons, thus contributing to the huge treatment gap. One of the ways to bring these people into treatment is through telephonic helplines. MATERIALS AND METHODS: Following a large number of suicides in the city of Chandigarh in 2003, The department of Psychiatry, GMCH, Chandigarh was designated as nodal center for the prevention of suicide. A 24-hour suicide prevention helpline was set up as an immediate measure to help persons in crisis. Apart from providing telephonic counseling to persons in crisis, the helpline coordinated with police, media, schools, radio stations etc., to reduce the number of suicides in the city. RESULTS: Majority of the callers were males (65.93%), between 20 to 39 years old (56.34%), married (79.50%), had less than 12 years of formal education (60.68%), and were earning less than Rs. 5000/month (56.80%). 72.96% callers had contacted the mental health services for the first time. A significant number of persons (434, 13.26%) called the helpline for marital, academic, stress-related problems. Majority of the calls were received between 8 A.M. and 2 P.M. The number of suicides in the city of Chandigarh showed a decline in the following years since the helpline was set up. CONCLUSIONS: The telephonic helpline seems to be a very effective way of getting persons into contact with health services. They are cost-effective, the person can maintain his confidentiality and devoid of stigma. PMID- 23806985 TI - Anemia among adolescent girls in Shimla Hills of north India: does BMI and onset of menarche have a role? AB - BACKGROUND: Anemia is a global public health problem. Adolescents are vulnerable to iron deficiency because of increased iron requirements related to rapid growth. AIMS AND OBJECTIVES: To estimate the prevalence of anemia among adolescent girls and to study whether anemia is associated with body mass index and the attainment of menarche. MATERIALS AND METHODS: A cross-sectional descriptive survey was conducted in selected schools of Shimla district. One thousand five ninety-six (10-19 yrs old) school girls were included in the study. The study was conducted from June 2011 to May 2012 (1 year). Data analysis was done using SPSSS software version 18 for windows. RESULTS: Prevalence of anemia was found to be 21.4%. It was seen that among the anemic adolescent girls, 77.3% had mild anemia, 21.9% had moderate anemia, and 0.5% had severe anemia. BMI and onset of menarche had no significant effect on the prevalence of anemia. In bivariate logistic regression, age and urban residence were significantly related to anemia. CONCLUSION: We observed a low prevalence of anemia among adolescent girls. We recommend that adolescents be screened periodically for anemia and multi-sectoral, community-based approach be adopted to combat this serious public health issue. PMID- 23806986 TI - Biochemical changes in erythrocyte membrane in type 2 diabetes mellitus. AB - OBJECTIVE: This study aims to establish a link between the lipid composition of red blood cell membrane and serum to aid in the early diagnosis and treatment of patients with type 2 diabetes mellitus. MATERIALS AND METHODS: Diabetic subjects with and without dyslipidemia were selected along with healthy control subjects. Biochemical changes in serum and erythrocyte membrane were compared in study groups. RESULTS: The lipid composition of membrane was significantly altered with increased cholesterol:Phospholipid ratio and decreased Na + K + -ATPase of membrane upon comparison with control subjects. CONCLUSION: Increased hyperglycemia with altered serum lipid composition in diabetes mellitus causes glycation of membrane enzymes this along with oxidative stress leads to decrease in activity of Na + K + -ATPase and other changes in erythrocyte membrane. Significant findings of the study: As the lipid level increases there is increased lipid peroxidation and the membrane composition gets altered. PMID- 23806987 TI - MTRR A66G polymorphism among two caste groups of Uttar Pradesh (India). AB - OBJECTIVE: This study was aimed to evaluate the Methionine synthase reductase (MTRR) A66G mutation in Yadav and Scheduled Caste (SC) population of Uttar Pradesh. MATERIALS AND METHODS: Blood samples were collected from 100 subjects after taking informed written consent and PCR-RFLP method was used for the analysis of A66G mutation. After NdeI digestion, 66-bp amplicon of normal allele was cut into 22- and 44-bp long fragments, whereas mutant G allele was not digested. RESULTS: Frequencies of genotypes in Yadav population AA, AG, and GG were 12%, 60%, and 28%, respectively, and in SC population, genotypic frequencies were 12% (AA), 52% (AG), and 36% (GG). CONCLUSION: MTRR gene A66G mutation is found to be polymorphic in both the target populations with G allele frequencies being 0.58 for Yadav and 0.62 for Scheduled Caste. PMID- 23806988 TI - Lymphoedema - distichiasis syndrome with recurrent abortions. AB - Lymphoedema-distichiasis syndrome, a type of familial lymphoedema praecox, is a rare, primary lymphoedema of pubertal onset associated with distichiasis and other associations including congenital heart disease, ptosis, varicose veins, cleft palate, and spinal extradural cysts. We report a case of familial lymphoedema with associated distichiasis, atrial septal defect, varicose veins, and recurrent abortions in a 29-year-old female. PMID- 23806989 TI - Two interesting cases highlighting an oblivious specialty of psychoneuroendocrinology. AB - Psychoneuroendocrinology deals with the overlap disorders pertaining to three different specialties. Awareness about the somatic manifestations of psychiatric diseases and vice versa is a must for all the clinicians. The knowledge of this interlinked specialty is essential because of the obscure presentation of certain disorders. Our first case was treated as depressive disorder, whereas the diagnosis was hypogonadism with empty sella. Our second patient was managed as schizophrenia and the evaluation revealed bilateral basal ganglia calcification and a diagnosis of Fahr's disease. We report these cases for their unusual presentation and to highlight the importance of this emerging specialty. PMID- 23806990 TI - President's page: ACC strategic planning to improve value for patients and members. PMID- 23806991 TI - Body mass index, central obesity, and mortality among coronary disease subjects. PMID- 23806992 TI - Reply: To PMID 23290543. PMID- 23806993 TI - Pitfall of the meta-analysis regarding early repolarization pattern. PMID- 23806994 TI - Cerebral cavernous malformation: clinical report of two families with variable phenotype associated with KRIT1 mutation. AB - We report two families with a variable presentation in association with a KRIT1 mutation. The index patient in Family 1 was a 9-year old girl who presented with left hemi-dystonia and a cerebral cavernous malformation was identified in the right lentiform nucleus. The maternal grandmother presented with a spinal cavernoma, which was operated at 35-years of age. The mother presented with intractable temporal lobe epilepsy in childhood and underwent temporal lobe resection at 27-years of age. The second family has also presented variably with the youngest member of this family presenting with generalised tonic-clonic seizures at 18-months of age. We report both these families with variable presentation of an autosomal dominant condition and describe the phenotypic presentation in both these families in further detail and review the published literature on this condition. PMID- 23806995 TI - Acute paediatric paraplegia: a case series review. AB - Paediatric paraplegia resulting from spinal cord pathology of any cause is rare; hence prognostic information for children less than 16 years is limited. This case series review aims to ascertain all cases of paediatric paraplegia from 1997 to 2012 in the former Northern Region of England. METHODS: Children presenting with sudden paraplegia before the age of 16 years were multiply ascertained from databases in the regional paediatric neurology, neuroradiology, neuro-oncology and adult spinal injuries units. Data were obtained from retrospective case note review. RESULTS: A total of 44 cases (24 female) were identified. The incidence is estimated at 0.49 per 100,000 children under 16/year (95% confidence interval 0.41-0.57). Mean age of onset was 8.8 years and the most common aetiology was inflammatory. Twelve months post presentation, mortality was zero and a good outcome (defined as Gross Motor Function Classification System grades I or II) was seen in 66.6%. Motor outcome at 12 months was associated with the presence of bladder/bowel signs at presentation, previous viral illness and initial severity of paraplegia. Bladder signs at presentation were the strongest predictor of prognosis (OR for poor motor outcome 10.3). We were unable to demonstrate a relationship between aetiology and late outcome. CONCLUSION: Paediatric paraplegia is rare. Mortality rates are low and 66.6% have a good outcome with fully or nearly independent walking. Bladder signs are the strongest predictor of prognosis. PMID- 23806996 TI - Effects of selenium supplemented diets on growth and condition indexes in juvenile red swamp crayfish, Procambarus clarkii. AB - Effects of selenium diets (Se, 0.3 and 1.2mgkg(-1)) on juvenile red swamp crayfish Procambarus clarkii were observed for eight weeks. Growth, condition factors and Se levels in exoskeleton and hepatopancreas for both sexes and diets were evaluated at three endpoints. The specific growth rate (SGR) showed a faster, but not statistically significant growth in Se exposed specimens. Se levels were higher in exoskeleton and hepatopancreas of both Se exposed males and females, when compared to controls. The abdomen-total weight relationship (Tw/B) showed no significant differences between Se exposed and control groups. A constant decline of HI values was recorded in both Se exposed sexes and the same trend was observed in control males. Se exposed females evidenced lower HI after 4 and 8 weeks when compared to controls. Therefore, evident reductions of the health indicator values HI suggested that selenium can deplete the hepatopancreas energy reserves, mainly in juvenile male crayfish. PMID- 23806997 TI - In vitro toxic action potential of anti tuberculosis drugs and their combinations. AB - Tuberculosis (TB) is one of the leading infectious causes of death due to single infectious agent after HIV/AIDS. Rifampicin (RIF), Isoniazid (INH), Ethambutol (EMB), Pyrazinamide (PZA) and/or their combinations are extensively prescribed to treat TB. Despite several therapeutic implications, these drugs also produce several toxic effects at cellular level. MTT assay and Ames test were adopted in this study for the determination of cytotoxic and mutagenic potential of these anti-TB drugs. Among all tested drugs, cytotoxic potential of RIF was strongest with highly significant decline (p<0.001) in cell numbers at the concentration of 250MUg/ml with LC50 at 325MUg/ml, while significant decline (p<0.01) in cell count was observed in INH treated group at the concentration 500MUg/ml with LC50 at 1000MUg/ml. Moreover, combination RIPE demonstrated significant reduction (p<0.01) in cell number at the concentration of 25-500-500-500MUg/ml with LC50 at 60-1200-1200-1200MUg/ml. It is apparent from the data that almost all drugs represented identical mutagenic pattern i.e., more significant results were achieved in TA100 with metabolic activation (+S9). RIF proved to be highly mutagenic of all tested drugs with significant mutagenicity (p<0.01) at 0.0525MUg/plate against TA98 strain with S9. The combination RIPE exhibited highly significant mutagenic activity (p<0.01) at concentration 0.125-3-3 3MUg/plate without S9, while addition of S9 resulted in similar activity at lower doses, i.e., 0.0525-1-1-1MUg/plate. It was concluded from the data that all anti TB drugs possess significant cytotoxic and mutagenic potential, especially in combination, making TB patient more vulnerable to cytotoxic and mutagenic effects of anti-TB drugs, which could produce further health complications in TB patients. PMID- 23806998 TI - Immobilized capillary tyrosinase microreactor for inhibitor screening in natural extracts by capillary electrophoresis. AB - A method for creating an immobilized capillary tyrosinase (TRS) reactor based on a layer-by-layer (LBL) assembly for inhibitor screening is described. Tyrosinase was immobilized on the surface of fused-silica capillary via ionic binding technique with cationic polyelectrolyte hexadimethrine bromide (HDB). Then, HDB solution with the same plug length as the TRS was injected again into the capillary to cover the immobilized enzyme by forming HDB-TRS-HDB sandwich-like structure. Then, the substrate of l-tyrosine was introduced into the capillary and on-line enzyme inhibition study was performed by capillary electrophoresis (CE). The enzyme activity was determined by the quantification of peak area of the product of l-DOPA. Enzyme inhibition can be read out directly from the reduced peak area of the product in comparison with a reference electropherogram obtained in the absence of any inhibitor. The immobilized enzyme could withstand 25 consecutive assays by only losing 12% activity. A known TRS inhibitor, kojic acid was employed as a model compound for the validation of the inhibitor screening method. Finally, screening 19 natural extracts of traditional Chinese drugs was demonstrated. The results indicated that inhibition activity could be straightforwardly identified with the system. PMID- 23806999 TI - Selective determination of potential impurities in an active pharmaceutical ingredient using HPLC-SPE-HPLC. AB - The present paper describes the selective determination of two synthetic intermediates (2,4-dichloro-6,7-dimethoxyquinazoline (IMP-1) and its derivative (IMP-2) as potential impurities in the active pharmaceutical ingredient (API)-A using two-dimensional high-performance liquid chromatography (HPLC) hyphenated via on-line solid-phase extraction (SPE) (HPLC-SPE-HPLC). Two synthetic intermediates that are potential impurities in API-A were concentrated on-line on two Shimadzu MAYI-ODS SPE columns (10 mm*4.6 mm I.D.) after heartcutting in 1st dimension HPLC (1st HPLC) using a Shiseido CAPCELL PAK ACR C18 column (250 mm * 10.0 mm I.D.). Each analyte retained on these SPE columns was transferred to 2nd dimension HPLC (2nd HPLC) with a Shiseido CAPCELL PAK MG-II column (150 mm * 3.0 mm I.D.) for further separation and was subsequently detected with high sensitivity UV. The HPLC-SPE-HPLC system achieved a stepwise downsizing in HPLC. The method was validated and found to be accurate and precise with a linear range of 0.25-250 ppm of each intermediate in API-A with respect to a 500 MUL injection of 40 mg/mL of API-A in dimethyl sulfoxide. The method was successfully applied for the determination of these impurities in API batches, and the results demonstrated the usefulness of HPLC-SPE-HPLC for the selective determination of trace impurities in APIs. PMID- 23807000 TI - Chemical comparison of two dosage forms of Hemp Seed Pills by UHPLC-Q-ToF-MS/MS and multivariate statistical techniques. AB - Hemp seed soft gel capsule (HSSGC) is a modernised dosage form that is derived from a traditional Chinese patent medicine, Hemp Seed Pills (HSP). Two dosage forms claim the same therapeutic effects; however, their chemical components and chemical equivalency are unclear. In the present study, an ultra performance liquid chromatography coupled with time-of-flight mass spectrometry (UHPLC-ToF MS)-based chemical profiling approach was proposed to rapidly evaluate the chemical differences between HSP and HSSGC as model dosage forms. Samples of the two dosage forms were subjected to UHPLC-ToF-MS analysis. The datasets of retention time (TR) and mass-to-charge ratio (m/z) pairs, ion intensities and sample codes were processed with principal component analysis (PCA) and partial least squares discriminate analysis (PLS-DA) to holistically compare the difference between these two dosage form samples. A clear classification trend was observed in the score plot, and a loading bi-plot was generated in which the variables are correlated with the group and the samples that were observed. The important chemical components that caused differences among the samples were explored with a Variables Importance Projection (VIP) index. Using the proposed approach, global chemical differences were found between the two dosage forms and among samples of the same dosage form. The most important components that are related to the differences were identified and most of them were attributed to Fructus Aurantii Immaturus. It is suggested that this newly established approach could be used for pre-clinical trial chemical equivalence study or the quality evaluation of the traditional medicinal products with large variations in quality. PMID- 23807001 TI - Characterization of the components of meleumycin by liquid chromatography with photo-diode array detection and electrospray ionization tandem mass spectrometry. AB - Reversed-phase liquid chromatography coupled with photo-diode array (PDA) detection and electrospray ionization tandem mass spectrometry (ESI-MS/MS) was used to characterize the components of meleumycin, a 16-membered macrolide antibiotic produced by fermentation. In total 31 components were characterized in commercial samples, including 12 impurities that had never been reported before and 12 others that were partially characterized. The structures of these unknown compounds were deduced by comparison of their fragmentation patterns with those of known components. Their ultraviolet spectra and chromatographic behavior were used to confirm the proposed structures: e.g. lambdamax shift from 232 nm to 282 nm would indicate the presence of an alpha-, beta-, gamma-, delta-unsaturated ketone instead of a normal alpha-, beta-, gamma-, delta-unsaturated alcohol in the 16-membered ring of the examined components. Compared to other methods, this LC/MS(n) method is particularly advantageous to characterize minor components at trace levels in multi-components antibiotics, in terms of sensitivity and efficiency. PMID- 23807002 TI - Headspace solid-phase microextraction-gas chromatography-mass spectrometry characterization of propolis volatile compounds. AB - In this study, a novel and efficient method based on headspace solid-phase microextraction (HS-SPME), followed by gas chromatography-mass spectrometry (GC MS), was developed for the analysis of propolis volatile compounds. The HS-SPME procedure, whose experimental parameters were properly optimized, was carried out using a 100 MUm polydimethylsiloxane (PDMS) fiber. The GC-MS analyses were performed on a HP-5 MS cross-linked 5% diphenyl-95% dimethyl polysiloxane capillary column (30 m * 0.25 mm I.D., 1.00 MUm film thickness), under programmed temperature elution. Ninety-nine constituents were identified using this technique in the samples of raw propolis collected from different Italian regions. The main compounds detected include benzoic acid (0.87-30.13%) and its esters, such as benzyl benzoate (0.16-13.05%), benzyl salicylate (0.34-1.90%) and benzyl cinnamate (0.34-3.20%). Vanillin was detected in most of the samples analyzed in this study (0.07-5.44%). Another relevant class of volatile constituents is represented by sesquiterpene hydrocarbons, such as delta-cadinene (1.29-13.31%), gamma-cadinene (1.36-8.85%) and alpha-muurolene (0.78-6.59%), and oxygenated sesquiterpenes, such as beta-eudesmol (2.33-12.83%), T-cadinol (2.73 9.95%) and alpha-cadinol (4.84-9.74%). Regarding monoterpene hydrocarbons, they were found to be present at low level in the samples analyzed in this study, with the exception of one sample from Southern Italy, where alpha-pinene was the most abundant constituent (13.19%). The results obtained by HS-SPME-GC-MS were also compared with those of hydrodistillation (HD) coupled with GC-MS. The HS-SPME-GC MS method developed in this study allowed us to determine the chemical fingerprint of propolis volatile constituents, thus providing a new and reliable tool for the complete characterization of this biologically active apiary product. PMID- 23807003 TI - Anti-tumor effect of 4-Amino-2-Trifluoromethyl-Phenyl Retinate on human breast cancer MCF-7 cells via up-regulation of retinoid receptor-induced gene-1. AB - 4-Amino-2-Trifluoromethyl-Phenyl Retinate (ATPR) is one of the retinoid derivatives designed and synthesized in our team. In this paper, we explored the potential anti-tumor effects of ATPR in breast cancer. Here we found that ATPR showed remarkable anti-proliferative effects in a dose- and time-dependent manner, caused cell cycle arrest in the G0/G1 phase and significantly increased the expression of retinoid receptor-induced gene-1 (RRIG1). ATPR decreased the expression of phosphorylation-ERK (p-ERK) and increased the expression of estrogen receptor beta (ERbeta) and phosphorylation-p38 (p-p38). Following RRIG1 knockdown by RNAi interference, we found that the changes of ERbeta, p-ERK and p p38 induced by ATPR were both depressed. Our data suggest that ATPR could inhibit the proliferation and induce differentiation of MCF-7 cells via mediating the expression of RRIG1. PMID- 23807004 TI - Management of intra-Descemet membrane air bubble in big-bubble deep anterior lamellar keratoplasty. AB - PURPOSE: To report the recognition and management of intra-Descemet membrane air bubble (IDMA) as a complication of big-bubble deep anterior lamellar keratoplasty (DALK). METHODS: IDMA was present intraoperatively in 8 eyes after DALK. Indications for surgery were healed keratitis (n = 4), macular dystrophy (n = 2), and keratoconus (n = 2). The IDMA was present between the anterior banded layer and posterior nonbanded layer of Descemet membrane (DM). They were slid and displaced toward the peripheral cornea using 27-gauge cannula and punctured taking care that underlying DM was not ruptured. RESULTS: DM was bared in all eyes, and DALK was completed in 7 cases. One patient required conversion to penetrating keratoplasty because of macroperforation. No case had double anterior chamber. Mean follow-up was 13.9 +/- 4.1 months. A DM fold was noted in 1 eye. Seven cases had postoperative best-corrected visual acuity of 20/60 or better. CONCLUSIONS: Prompt recognition of the IDMA intraoperatively is required, which can be managed successfully. PMID- 23807005 TI - Topography-Based Keratoconus Regression. AB - PURPOSE: To report 3 cases of keratoconic patients who had progressive corneal topographic flattening during a 2-year follow-up period. METHODS: Case series. RESULTS: Three patients with bilateral keratoconus, each operated for advanced keratoconus in one of their eyes, were observed for possible progression of the disorder for a period of 2 years. During the 2-year follow-up period, topographic examination showed progressive corneal flattening in the nonoperated eye. Mean keratometry decreased in all patients, whereas topography showed significant flattening at the apex of the cone. Best-spectacle-corrected visual acuity increased in one of the patients, whereas the others had stable uncorrected and best-spectacle-corrected visual acuity during the follow-up period. All patients had positive family medical history for diabetes mellitus, but none of them was diabetic. CONCLUSIONS: This is the first report of topography-based keratoconus regression during a 2-year follow-up period. PMID- 23807006 TI - Impact of keratoconus, cross-linking and cross-linking combined with topography guided photorefractive keratectomy on self-reported quality of life: a 3-year update. PMID- 23807008 TI - A case of crocodile shagreen occurring in a 104-year-old age-mismatched lamellar corneal graft. PMID- 23807007 TI - Pre-Descemet corneal dystrophy and X-linked ichthyosis associated with deletion of Xp22.31 containing the STS gene. AB - PURPOSE: To report the association of X-linked ichthyosis and pre-Descemet corneal dystrophy with a deletion of the steroid sulfatase gene (STS) detected with microarray-based comparative genomic hybridization (aCGH). METHODS: A slit lamp biomicroscopic examination and cutaneous examination were performed, after which a saliva sample was collected as a source of genomic DNA. Polymerase chain reaction amplification of each of the 10 exons of STS was performed, as was aCGH on genomic DNA to detect copy number variation. RESULTS: The slit-lamp examination revealed punctate opacities in the posterior corneal stroma of each eye. The cutaneous examination demonstrated scaling and flaking skin of the arms and legs. Polymerase chain reaction amplification using primers designed to amplify each of the 10 exons of STS failed to produce any amplicons. Subsequently, aCGH performed on genomic DNA revealed a microdeletion in the Xp22.31 cytoband of approximately 1.7 megabases, containing STS. CONCLUSIONS: The identification of a microdeletion within Xp22.3 containing STS with aCGH in an individual with suspected pre-Descemet corneal dystrophy and X-linked ichthyosis demonstrates the clinical utility of copy number variation analysis in confirming a presumptive clinical diagnosis. PMID- 23807009 TI - Calcium hydroxyapatite crystals in the anterior chamber of the eye in a patient with renal hyperparathyroidism. AB - PURPOSE: To report a case of calcium hydroxyapatite crystals in the anterior chamber of a patient with renal hyperparathyroidism. METHODS: Case report. RESULTS: A 54-year-old man visited our clinic with mild ocular pain and decreased visual acuity in his left eye. A slit-lamp examination showed peripheral corneal band keratopathy and multiple white crystals in the anterior chamber. The patient had chronic renal failure and was on regular hemodialysis treatment for 12 years. He had previously undergone total parathyroidectomy because of secondary renal hyperparathyroidism. Aqueous humor analysis showed elevated phosphate levels. Multiple crystals were removed using a manual irrigation and aspiration cannula and were found to be calcium hydroxyapatite crystals on elemental analysis using energy dispersive x-ray spectroscopy. Ocular pain and visual acuity improved and corneal edema and ocular inflammation decreased after the surgery. CONCLUSIONS: Calcium hydroxyapatite crystals can form in the anterior chamber of the eye in a patient with renal hyperparathyroidism. PMID- 23807010 TI - The oral examination. PMID- 23807011 TI - Maintaining the certificate. PMID- 23807012 TI - Plastic & Reconstructive Surgery. Introduction. PMID- 23807013 TI - The American Board of Medical Specialties. PMID- 23807014 TI - Facing the challenges of subspecialization. PMID- 23807015 TI - A culture of ethics. PMID- 23807016 TI - Balancing the ledger. PMID- 23807017 TI - Governance and administration. PMID- 23807018 TI - The education of a resident. PMID- 23807019 TI - The written examination. PMID- 23807020 TI - Efficiencies of freshwater and estuarine constructed wetlands for phenolic endocrine disruptor removal in Taiwan. AB - We examined the distribution and removal efficiencies of phenolic endocrine disruptors (EDs), namely nonylphenol diethoxylates (NP2EO), nonylphenol monoethoxylates (NP1EO), nonylphenol (NP), and octylphenol (OP), in wastewater treated by estuarine and freshwater constructed wetland systems in Dapeng Bay National Scenic Area (DBNSA) and along the Dahan River in Taiwan. Water samples were taken bimonthly at 30 sites in three estuarine constructed wetlands (Datan, Pengcun and Linbian right bank (A and B)) in DBNSA, for eight sampling campaigns. The average removal efficiencies were in the range of 3.13-97.3% for wetlands in DBNSA. The highest average removal occurred in the east inlet to the outlet of the Tatan wetland. The most frequently detected compound was OP (57.7%), whose concentration was up to 1458.7 ng/L in DBNSA. NP was seen in only 20.5% of the samples. The temporal variation of EDs showed a decrease across seasons, where summer>spring>winter>autumn in these constructed wetlands. The removal efficiencies of EDs by estuarine wetlands, in decreasing order, were Datan>Pengcun>Linbian right bank in DBNSA. Water samples collected at 18 sites in three freshwater constructed wetlands (Daniaopi, Hsin-Hai I, and Hsin-Hai II) along the riparian area of Dahan River. NP2EO was the most abundant compound, with a concentration of up to 11,200 ng/L. Removal efficiencies ranged from 55% to 91% for NP1EO, NP2EO, and NP in Hsin-Hai I. The average removal potential of EDs in freshwater constructed wetlands, in decreasing order, was Hsin-Hai II>Daniaopi>Hsin-Hai I constructed wetlands. The lowest concentrations of the selected compounds were observed in the winter. The highest removal efficiency of the selected phenolic endocrine disruptors was achieved by Hsin-Hai I wetland. The calculated risk quotients used to evaluate the ecological risk were up to 30 times higher in the freshwater wetlands along Dahan River than in the estuarine (DBNSA) constructed wetlands, indicating that existing concentrations of these EDs in wetland systems pose a high ecological risk to aquatic organisms. The decreasing risk quotient from influent to effluent indicates that phenolic endocrine disruptors can be treated in these constructed wetlands. Our results of this research can serve as a preliminary understanding on the ED removal efficiencies in different types of constructed wetlands. PMID- 23807021 TI - Synthesis, characterization, and CO2 capture study of micro-nano carbonaceous composites. AB - The micro-nano carbonaceous composite activated carbon fiber/carbon nanotube (ACF/CNTs) was obtained by chemical vapor deposition technology with CNTs growth on the substrate ACF, and the composite was further modified by branched polyethyleneimine (PEI). The morphological features of the as-grown ACF/CNTs and PEI-modified samples were analyzed by scanning electron microscopy, transmission electron microscopy, X-ray diffraction, Fourier transform infrared spectroscopy and thermal gravimetric analysis respectively. Physical properties of the samples were recorded by conducting N2 adsorption/desorption at 77K. CO2 capture tests indicated that both the presence of CNTs and PEI increased the CO2 adsorption capacity, due to the unique hollow tubular structure of CNTs and poly amino groups of PEI. The CO2 adsorption capacities of ACF/CNTs and ACF/CNTs-PEI were tested to be 66.2 mg/g and 98.8 mg/g, respectively at 30 degrees C, which were much higher than that of unmodified ACF (42.4 mg/g). Increasing adsorption temperature up to 60 degrees C further promoted the CO2 adsorption capacity of ACF/CNTs-PEI (121.2 mg/g) due to the maximum equilibrium adsorption between the chemical and physical adsorption at this temperature. Cyclic CO2 adsorption tests via thermal desorption proved that ACF/CNTs-PEI had a good regenerability of 96.2%, suggesting this material is a promising CO2 adsorbent for practical applications. PMID- 23807022 TI - Contribution of tap water to chlorate and perchlorate intake: a market basket study. AB - The contributions of water to total levels of chlorate and perchlorate intake were determined using food and water samples from a market basket study from 10 locations in Japan between 2008 and 2009. Foods were categorized into 13 groups and analyzed along with tap water. The average total chlorate intake was 333 (min. 193-max. 486) MUg/day for samples cooked with tap water. The contribution of tap water to total chlorate intake was as high as 47%-58%, although total chlorate intake was less than 32% of the tolerable daily intake, 1500 MUg/day for body weight of 50 kg. For perchlorate, daily intake from water was 0.7 (0.1-4.4) MUg/day, which is not high compared to the average total intake of 14 (2.5-84) MUg/day, while the reference dose (RfD) is 35 MUg/day and the provisional maximum tolerable daily intake (PMTDI) is 500 MUg/day for body weight of 50 kg. The highest intake of perchlorate was 84 MUg/day, where concentrations in foods were high, but not in water. The contribution of water to total perchlorate intake ranged from 0.5% to 22%, while the ratio of highest daily intake to RfD was 240% and that to PMTDI was 17%. Eight baby formulas were also tested--total chlorate and perchlorate intakes were 147 (42-332) MUg/day and 1.11 (0.05-4.5) MUg/day, respectively, for an ingestion volume of 1 L/day if prepared with tap water. PMID- 23807024 TI - Non-engineered nanoparticles of C60. AB - We discovered that rubbing bulk solids of C60 between fingertips generates nanoparticles including the ones smaller than 20 nm. Considering the difficulties usually associated with nanoparticle production by pulverisation, formation of nanoparticles by such a mundane method is unprecedented and noteworthy. We also found that nanoparticles of C60 could be generated from bulk solids incidentally without deliberate engineering of any sort. Our findings imply that there exist highly unusual human exposure routes to nanoparticles of C60, and elucidating formation mechanisms of nanoparticles is crucial in assessing their environmental impacts. PMID- 23807023 TI - Differential effects of selective and non-selective nitric oxide synthase inhibitors on the blood perfusion of ischemia-reperfused myocardium in dogs. AB - BACKGROUND: Nitric oxide (NO) is protective for the cardiovascular system, and excessive NO exerts negative effects on the circulatory system. This study aimed to compare the effects of selective or non-selective NO synthase (NOS) inhibitors on blood flow perfusion of ischemia-reperfused myocardium. MATERIAL AND METHODS: Male mongrel dogs were randomly assigned to 4 groups: only ischemia-reperfusion (control), ischemia-reperfusion plus Nu-nitro-L-arginine methyl ester (NAME) treatment, ischemia-reperfusion plus aminoguanidine (AMD) treatment, and sham operation group. Myocardial contrast echocardiography (MCE) was performed. Blood samples were taken for measurement of NO. Background-subtracted peak videointensity (PVI) and PVI ratio in myocardium were measured. RESULTS: In the NAME-treated group, the PVI at 5 min reperfusion did not significantly differ from pre-LAD-occlusion, but declined to and retained at a level obviously lower than the pre-LAD-occlusion. In the AMD-treated group, the PVI at 5 min reperfusion was significantly higher than at pre-LAD-occlusion, and then restored to and remained at the pre-LAD-occlusion level. The changes of PVI ratios in the 3 groups were similar to PVI values. In the AMD-treated group, the curve width increased in the early reperfusion, but returned to the pre-LAD-occlusion level at 90 min reperfusion. The plasma NO concentration in the NAME-treated group greatly decreased and remained low during the whole period of reperfusion. In the AMD-treated group, there were only slight increases in NO concentrations during reperfusion. CONCLUSIONS: NAME totally inhibited NO production and attenuated myocardial blood flow perfusion. Aminoguanidine significantly relieved the increase in NO production and alleviated the congestion of reperfused myocardium. Selective inhibitors of iNOS might be useful in the management of certain diseases associated with ischemia-reperfusion. PMID- 23807025 TI - Sex ratio biases in termites provide evidence for kin selection. AB - Inclusive fitness theory, also known as kin selection theory, is the most general expansion of Darwin's natural selection theory. It is supported by female-biased investment by workers in the social Hymenoptera where relatedness to sisters is higher than to brothers because of haplodiploidy. However, a strong test of the theory has proven difficult in diploid social insects because they lack such relatedness asymmetry. Here we show that kin selection can result in sex ratio bias in eusocial diploids. Our model predicts that allocation will be biased towards the sex that contributes more of its genes to the next generation when sex-asymmetric inbreeding occurs. The prediction matches well with the empirical sex allocation of Reticulitermes termites where the colony king can be replaced by a queen's son. Our findings open broad new avenues to test inclusive fitness theory beyond the well-studied eusocial Hymenoptera. PMID- 23807026 TI - Quantitative trait locus mapping identifies REME2, a PPR-DYW protein required for editing of specific C targets in Arabidopsis mitochondria. AB - Targeted RNA editing by C-to-U alteration occurs at hundreds of sites in the mitochondrial transcriptome of flowering plants. By using natural variation and positional cloning on a population of Arabidopsis recombinant inbred lines between the ecotypes Col and Ler, we found that two of these occurrences involve the Arabidopsis PPR-DYW protein REME2 (Required for Efficiency of Mitochondrial Editing2). The analysis of a knockdown mutant along with silenced tissues confirms the specificity of REME2 for both sites located in mitochondrial ribosomal protein genes (rps3-1534 and rps4-175). The conservation level of both cis elements is relatively high, as is the amino acid conservation among flowering plants for both genes in that location, underlining the importance of these editing events and REME2. PMID- 23807027 TI - T-cell apoptosis induced by intratumoral activated hepatic stellate cells is associated with lung metastasis in hepatocellular carcinoma. AB - Profound T cell inhibitory activity of hepatic stellate cells (HSCs) in vitro has recently been described in hepatocellular carcinoma (HCC). In the present study, we investigated the immune inhibitory activity of HSCs in vivo in an orthotopic rat HCC model with lung metastasis. Rats (n=24) were randomly sacrificed on days 7, 14, 21 and 28 (n=4 each). Lung tissues were stained with hematoxylin and eosin. Liver sections were stained for immunofluorescence analysis. T-cell apoptosis was detected using double staining for terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). Staining revealed marked and continuous accumulation of alpha-smooth muscle actin with tumor progression after orthotopic tumor implantation in rat liver. T lymphocyte numbers gradually increased following tumor progression, and subset analysis revealed an increase in the distribution of liver CD8+ and CD4+ T cells. Double staining for CD3 and TUNEL demonstrated T-cell apoptosis. Apoptotic T cells were more frequent in the HCC livers compared to the normal livers, and were spatially associated with intratumoral activated HSCs (tHSCs), suggesting a direct interaction. T-cell apoptosis was more frequently induced in the co-cultures of activated splenic T cells(aT)/tHSCs compared to aT/quiescent (q) HSCs or qT/tHSCs. tHSCs were positively correlated with T-cell apoptosis, and the percentage of T-cells undergoing apoptosis was positively correlated with the number of lung metastasis nodules. T-cell apoptosis may be promoted via an interaction with tHSCs, suggesting that tHSCs regulate T cells and contribute to lung metastasis in HCC. PMID- 23807028 TI - Use of indwelling pleural catheters for cardiogenic pleural effusions. AB - BACKGROUND: Cardiogenic pleural effusions are rarely refractory to treatment of the underlying disease. Few options are available in these cases. Indwelling pleural catheter (IPC) insertion has been well described for the management of malignant pleural effusions. We present our experience with using IPCs for cardiogenic pleural effusion management. METHODS: We prospectively constructed a cohort of patients who underwent IPC insertion for cardiogenic pleural effusions. Patients were carefully selected, and the IPCs were inserted as a palliative measure or while awaiting cardiac transplantation. RESULTS: There were 43 IPCs inserted in 38 patients. Patients had significant dyspnea, with a mean baseline dyspnea index of 2.24 (95% CI, 1.53-2.94). There was significant improvement in dyspnea 2 weeks after IPC insertion, with a mean transitional dyspnea index of 6.19 (95% CI, 5.56-6.82). There was no occurrence of empyema. Pneumothorax, mostly ex vacuo, occurred in 11.6% of procedures but did not require further intervention. IPCs were removed in 18 patients (47.4%), and successful spontaneous pleurodesis occurred in 11 patients (29.0%) after a median of 66 days (interquartile range, 34-242 days). Patients who eventually had their catheters removed had better performance status (P = .008) and were less dyspneic (P = .005) at baseline and had longer survival (P < .0001). CONCLUSIONS: IPC insertion for cardiogenic pleural effusion is a feasible option in carefully selected patients. Further research is needed to confirm the results and to assess the impact of IPC insertion on the quality of life of these patients. PMID- 23807029 TI - Brace or no-brace after ACL graft? Four-year results of a prospective clinical trial. AB - PURPOSE: A controversial discussion is held on using stabilizing knee braces after anterior cruciate ligament (ACL) surgery. The current study investigated the influence of a stabilizing knee brace on results after ACL reconstruction using patellar tendon autografts. METHODS: A prospective randomized study was started including 64 patients divided into two equal groups and treated with or without a stabilizing knee brace for 6 weeks post-operatively. A follow-up examination 4 years after operation comprised IKDC 2000, KT1000 measurement, a visual analogue pain scale (VAS; scores 0-10) and radiographic evaluation. The t test for independent and paired samples and the Pearson's Chi-square test were used for statistical analysis (p < 0.05). The primary endpoint was the difference in IKDC classification. RESULTS: Eighty-one per cent of the patients were examined 4 years post-operatively. IKDC 2000 subjective (brace group 90.5 +/- 8.9, braceless group 93.2 +/- 6.1) and objective results (brace A 30%, B 56%, C 16%; braceless A 32%, B 48%, C 20%) and instrumental measurement of anteroposterior laxity with KT1000 (brace 0.6 +/- 2.4 mm, braceless 1.8 +/- 3.4 mm) showed no significant differences. VAS pain results were significantly better in the braceless group at 1.0 +/- 1.2 versus 1.9 +/- 1.4 under sports activity or heavy physical work (p = 0.015). There were no radiographic differences concerning osteoarthritic findings and tunnel widening between the groups. CONCLUSION: Post-operative treatment with a stabilizing knee brace after ACL replacement showed no advantage over treatment without a brace at 4-year follow up. The use of a knee-stabilizing brace after isolated ACL reconstruction with autologous patellar tendon graft is not recommended. LEVEL OF EVIDENCE: II. PMID- 23807030 TI - Systematic instruction of arthroscopic knot tying with the ArK Trainer: an objective evaluation tool. AB - PURPOSE: A Proficiency Formula was introduced as an objective self-evaluation method for evaluating basic arthroscopic knot tying in a laboratory setting. The correlation between the Proficiency Formula and gold standard pass/fail dichotomy was demonstrated, as well as with other popular evaluation tools--task-specific checklist (TSC) and global rating scale (GRS). METHOD: A step-by-step video tutorial was used to instruct 35 medical students on how to tie an arthroscopic Samsung Medical Center (SMC) knot secured by three half hitches. Participants were video recorded performing arthroscopic knot tying and assessed on their success tying an SMC knot, pass or fail, and through three outcome tools: the Proficiency Formula, GRS and the TSC. Independent samples t test was used to compare the GRS, TSC and Proficiency Formula scores, between those who were passed or failed by the evaluators. Correlation between the measurement scales was tested using Spearman's rho correlation coefficient. RESULTS: Participants received a mean proficiency score of 195 (140-249). The mean Proficiency score for those that passed was 323 (95 % CI 272-374), for those that failed, 87 (95 % CI 26-148, p < 0.001). We found strong linear correlation between the Proficiency Formula and GRS and TSE (0.83 and 0.78, respectively). CONCLUSION: The Proficiency Formula has high correlation with gold standard GRS and TSC measurements when used to assess arthroscopic knot tying skills on a model. It has the added advantage of being able to be self-assessed. PMID- 23807031 TI - VEGF expression is augmented by hypoxia-induced PGIS in human fibroblasts. AB - Prostacyclin synthase (PGIS or PTGIS) is an enzyme that catalyses the conversion of prostaglandin H2 (PGH2) to prostaglandin I2 (PGI2). PGI2 promotes cancer growth by activating peroxisome proliferator-activated receptor delta (PPARdelta), and increases the expression levels of the pro-angiogenic factor vascular endothelial growth factor (VEGF). We found that the expression of the PGIS gene was enhanced in WI-38, TIG-3-20 and HEL human lung fibroblast cells and two cancer cell lines (NB-1 and G361) under hypoxic conditions. The main localization of PGIS changed from the cytoplasm to the nucleus by hypoxia in WI 38 cells. The induced PGIS had an enzymatic activity since the intracellular level of 6-keto-prostaglandin, a useful marker of PGI2 biosynthesis in vivo, was increased with the increasing levels of PGIS. Expression of VEGF was increased in parallel with PGIS induction under hypoxic conditions. PGIS knockdown resulted in the decreased expression of VEGF mRNA. Since VEGF is a known PPARdelta target gene, we examined the effects of siRNAs targeting PPARdelta on the expression of VEGF under hypoxic conditions. Knockdown of PPARdelta suppressed the expression of VEGF under hypoxic conditions in WI-38 cells. These findings suggest that PGIS is induced by hypoxia and regulates the expression of VEGF in fibroblasts. Fibroblasts in the hypoxic area of tumors may have an important role in tumor growth and angiogenesis. PMID- 23807032 TI - Enhanced photodegradation of methyl orange with TiO2 nanoparticles using a triboelectric nanogenerator. AB - Methyl orange (MO) can be degraded by a photocatalytic process using TiO2 under UV irradiation. The photo-generated holes and electrons can migrate to the surface of TiO2 particles and serve as redox sources that react with adsorbed reactants, leading to the formation of superoxide radical anions, hydrogen peroxide and hydroxyl radicals involved in the oxidation of dye pollution. Here, we fabricated a polytetrafluoroethylene-Al based triboelectric nanogenerator (TENG) whose electric power output can be used for enhancing the photodegradation of MO with the presence of TiO2 nanoparticles, because the TENG generated electric field can effectively boost the separation and restrain the recombination of photo-generated electrons and holes. Due to the photoelectrical coupling, the degradation percentages of MO for 120 min with and without TENG assistance are 76% and 27%, respectively. The fabricated TENGs have potential applications in wastewater treatment, water splitting, and pollution degradation. PMID- 23807033 TI - Lipid profile and glycosylated hemoglobin status of gestational diabetic patients and healthy pregnant women. AB - AIM: Lipid profile and glycosylated hemoglobin level changes in gestational diabetes. The extent to which this alteration takes place is still not clearly documented. MATERIALS AND METHODS: To add a clear answer to this question, lipid profile parameters, and glycosylated hemoglobin status were determined in patients with gestational diabetes mellitus and compared to healthy pregnant women (controls). RESULTS: Fasting plasma glucose levels, plasma glucose levels 1 hour, and plasma glucose levels 2 hours after 75 gm oral glucose administration (oral glucose tolerance test) were significantly higher in patients with gestational diabetes as compared to controls. Glycosylated hemoglobin was significantly higher in gestational diabetes than in controls. It was observed that there was a significant increase in serum cholesterol and serum triglyceride level in cases with gestational diabetes when compared to healthy pregnant women. CONCLUSION: The results of our study suggest that abnormal glucose levels, glycosylated hemoglobin, serum cholesterol, and serum triglycerides play an important role in pathophysiology of gestational diabetes, and therefore, extensive studies are required. Early diagnosis of gestational diabetes will decrease adverse neonatal and maternal outcomes. PMID- 23807034 TI - Determination of insulin-like growth factor-I reference values using an immunoradiometric assay in a Brazilian adult population. AB - BACKGROUND: Serum levels of total insulin-like growth factor I (IGF-I) reflect endogenous growth hormone (GH) secretion in healthy adults, which makes it a good diagnostic marker for screening of GH-related disorders. Studies also have supported a possible relation between IGF-I levels and the risk and prognostic for some malignancies, besides a relation between IGF-I levels and mortality. OBJECTIVE: As the determination of the IGF-I normal values for local populations is strongly desired, the aim of this investigation was to determine reference values for IGF-I using an immunoradiometric assay (IRMA) in an adult Brazilian population of Rio de Janeiro city, since there is no other study using this methodology in Brazilian population, and that this method is widely used in Brazil and worldwide. MATERIALS AND METHODS: The study included samples of blood taken from 484 healthy subjects (251 men and 233 women) aged 18-70. The subjects agreed with this study, approved by the Ethical Committee of the Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti, Rio de Janeiro, Brazil. The samples were analyzed using a Diagnostic System Laboratories kit. For data analysis, age- and sex-specific figures were fitted after transformation of IGF-I values. RESULTS: In adulthood, a slow age-dependent decrease was found. There was no significant difference in IGF-I values between men and women. CONCLUSION: This study established age-specific IGF-I reference values, for a healthy Brazilian adult population, determined by a widely IGF-I, IRMA used currently in Brazil. PMID- 23807035 TI - The silent burden of anemia in school age children: a community based study in West Bengal. AB - BACKGROUND: Under nutrition and anemia are common co-morbidities in school age children. Due to transition in dietary habits in developing countries, a paradoxical finding of coexistence of anemia and normal/over nutrition is also a cause of concern. OBJECTIVE: > T o assess the nutritional status and prevalence of anemia among school age children (6 - 16 years) residing in rural and urban areas of a district of West Bengal and also to find out the association between weight status, measured as Body Mass Index(BMI) and anemia. MATERIALS AND METHODS: Age, height & weight were measured in 86 rural and 86 urban school age (6 -16 years) children in rural and urban field practice areas of Midnapore Medical College. Their blood was estimated for haemoglobin concentration. RESULTS: Overall prevalence of anemia was 80.2%, and not significantly different between the rural (83.7%) and urban (76.7%) participants and across the genders both in rural (86.4% versus 80.9%) and urban (85.7% versus 72.4%) areas. Thinness was observed to be higher in urban area (48.8% versus 41.9%). However, severe thinness was higher in rural area (18.5% versus 13.9%). Significantly, higher proportion of boys revealed severely low BMI compared to girls in both rural (33.3% versus 4.5%) and urban (17.2% versus 7.1%) areas with no significant differences between the prevalence of anemia across the grades of underweight and normal nutritional status. CONCLUSIONS: Poor nutritional status and anemia are still, taking heavy toll and new program strategies are needed, particularly those that improve the overall nutrition status of children. PMID- 23807036 TI - Vitamin A status and hematological values in sickle cell disorder cases. AB - BACKGROUND: Sickle cell anemia (SCA), which is an inherited blood disorder characterized primarily by chronic anemia and oxidative stress plays a major role in pathophysiology. OBJECTIVE: This study aims to evaluate vitamin A (serum retinol) status and hematological parameters in children with homozygous and heterozygous sickle cell disorders and compared with age- and sex-matched healthy controls. MATERIALS AND METHODS: A sample of 80 referred cases (37 sickle cell disorders and 43 normal cases) aged 2-40 years were included in the study. Hematological parameters were measured in cell counter and serum retinol by high performance liquid chromatography. RESULTS: The mean hemoglobin (Hb) and serum retinol were significantly lower among cases with sickle cell disease than in sickle cell trait and normal. Vitamin A deficiency (retinol < 20 MUg/dl) reported to be higher in homozygous cases (46.2%) as compared to either heterozygous (29.2%) or control (23.2%) groups. Serum retinol was correlated directly with Hb, RBC count, and hematocrit levels, and inversely with percentage of sickling among sickle cell disorder cases. CONCLUSION: The results indicate that deprived vitamin A status with inductive oxidative stress is mainly due to sickling and hemolysis in SCA cases. PMID- 23807037 TI - Health of children in Jamaica: the new health realities. AB - BACKGROUND: The World Health Organization developed a mathematical technique, which discount the life expectancy by the years spent in disability or morbidity. Health, therefore, must be more than morbidity as it expands to quality of life. It is within this framework that a study on childhood health in Jamaica is of vital importance. OBJECTIVES: To (1) expand the health literature in Jamaica and by extension the Caribbean, (2) understand the status of child health outside of mortality, (3) aid public health practitioners with research, upon which they are able to further improve the quality of life of children by adding quality to their lived years, (4) investigate the age at with children in Jamaica become influenced by chronic disease, it typology, and (5) evaluate the subjective wellbeing of children as is done for the general populace and elderly. MATERIALS AND METHODS: The current study extracted a sample of 8,373 and 2,104 children 0 14 years from two surveys. Descriptive statistics were used to analyze the socio demographic characteristics of the sample. Data were analyzed using Chi-square and analysis of variance and independent sample t-test. RESULTS: The current study found that a shift in health condition was noticed in 2007 over 2002. The number of children who had diarrhea fell by 84.2% in 2007 over 2002, and a similar reduction was observed for those with asthma (42.1% in 2002 and 19.7% in 2007). Another critical finding was that 1.2% of children, in 2007, had diabetes mellitus. CONCLUSION: Public health now has an epidemiological profile of health conditions of children and the demographic shifts, which are occurring, and this can be used for effective management and planning of the new health reality of the Jamaican child. PMID- 23807038 TI - A rare case of prostatic malignancy. AB - A 70-year-old male presented with refractory urinary retention 3 years back. He had undergone a prior trans urethral resection of prostate (TURP) 5 months back elsewhere. A revision TURP was done and the histopathology showed differentiated adenocarcinoma with cartilaginous and osseous metaplasia. Bone scan showed no evidence of metastasis. He underwent bilateral orchidectomy soon after. He presented with urinary retention 14 months later and underwent TURP. Hard prostatic tissue was resected and histopathology reports were same as previous report. Bone scan showed evidence of solitary metastasis in the second rib. MRI and CT scan showed re-growth. He had persisting lower urinary tract symptoms with hematuria. A palliative radiation was given which alleviated the urinary symptoms; patient refused radical cystoprostatectomy and currently is on conservative management. PMID- 23807039 TI - Unilateral lung hypoplasia: a rare cause of unilateral opaque hemithorax in chest X-ray in a young boy. AB - Congenital abnormalities of lung are very rare entity, and very often under or misdiagnosed by physicians. The present case, a 12-year boy, who was initially diagnosed as unilateral massive pleural effusion with collapse of lung, and after thorough investigation, including CT scan of thorax, fiber-optic bronchoscopy, and echocardiography, a final diagnosis of unilateral lung hypoplasia was made. So if a teenager present with a unilateral opaque hemithorax in chest X-ray, this entity may be a differential diagnosis. PMID- 23807040 TI - Noonan syndrome presenting with neurogenic intermittent claudication. PMID- 23807041 TI - Does the mean platelet volume have any importance in patients with acute pulmonary embolism? AB - AIM: To determine whether an association exists between a known marker of platelet activation, mean platelet volume (MPV), and the severity of acute pulmonary embolism (APE), and to test whether it can be used as prognostic indicator in patients with high-risk pulmonary embolism (PE). MATERIALS AND METHODS: The study included 209 consecutive patients with APE (106 male, 103 female, mean age 62.4 +/- 15.4 years) and 162 controls (86 male, 76 female) matched for age (60.5 +/- 14.3 years) and concomitant diseases. Contrast-enhanced spiral computerized tomography or ventilation-perfusion scintigraphy, echocardiography, and lower extremity venous Doppler ultrasound were performed on the patients with APE. D-dimer level, troponin, arterial blood gases, platelet count, and MPV were measured in serum. RESULTS: The MPV did not differ between the patients with APE and the controls (8.0 +/- 1.1 fL, 7.9 +/- 0.59 fL, p = 0.22). There were no significant differences in the value of MPV among the groups of patients with massive, submassive, and nonmassive PE (MPV: 8.3 +/- 0.9 fL, 8.1 +/- 1.0 fL, 7.9 +/- 1.1 fL, p = 0.08, respectively). The MPV was higher in non survivors than survivors (8.6 +/- 1.1 vs. 7.9 +/- 1.1 fL, p = 0.02). There was a statistically weak correlation between MPV and mean pulmonary arterial pressure (r = 0.25, p < 0.001) and also between MPV and right ventricle diameter (r = 0.11, p = 0.045). CONCLUSIONS: Our results suggest that a simple baseline determination of MPV at a single time point is not a reliable indicator to determine the severity of PE or for the diagnosis of APE, but it is possible that the MPV increases in nonsurvivors. PMID- 23807042 TI - Relationship between hepcidin and ferritin in haemodialysed patients. AB - BACKGROUND: Hepcidin is a key regulator of iron metabolism. It binds to ferroportin and causes the trapping of iron in cells, rendering it unavailable for erythropoiesis. The synthesis of hepcidin is upregulated by high iron stores and inflammation. Haemodialysed patients suffer from anaemia and impaired iron management, the cause of which is multifactorial. Our aim was to describe the relationship between hepcidin and other parameters of iron metabolism, erythropoiesis, and inflammation. PATIENTS, MATERIALS AND METHODS: Complete blood cell counts, hepcidin, parameters of iron metabolism, and inflammation were measured in samples from 164 dialysed patients and 37 control healthy volunteers. Patients were subdivided according to the time of dialysis session. RESULTS: According to the time of haemodialysis, iron levels showed an insignificant tendency for diurnal variability, whereas hepcidin levels were markedly different. Non-parametric correlations showed a weak, but statistically significant correlation between parameters of iron metabolism and inflammation in the entire group of patients. No correlation was found between hepcidin and other biochemical parameters in controls. Non-parametric correlations were also performed in the time subgroups of patients. CONCLUSION: It seems that the influence of inflammation on hepcidin levels in haemodialysed patients is not crucial and other factors (e.g. hepcidin retention) are involved. PMID- 23807043 TI - Economic burden of late presentation in HIV disease in Austria: a comparison of the initial costs imposed by advanced HIV disease vs. non-late presentation. AB - In addition to increasing the health risk to the individual patient, late diagnosis of HIV infection affects the costs of the medical care. Comprehensive data on the precise financial burden posed by late presentation are lacking. This retrospective analysis in Austria aimed to compare the marginal costs of initial care after diagnosis in patients presenting with advanced HIV disease vs. non late presenters. Treatment-naive late and non-late presenters were matched by age and risk group and were followed up for an average of 15 months. Using a marginal cost approach, the costs of medications, outpatient consultations, diagnostic interventions, and inpatient stays were compared. Cases had significantly higher viral load and lower CD4 cell counts. At first diagnosis, 45.8 % of cases had CDC stage A vs 85.2 % of controls. Late presenters had 70 % more outpatient consultations (p < 0.01) and three-fold higher total marginal costs ( 722,761 vs. 244,976). Cost per patient and month ranged from 600 to 17,108 for cases and from 102 to 26,958 for controls. Largest cost difference was noted for antiretroviral (ART) medication (monthly average 1,089 per case vs. 77 per control), accounting for 42 % of overall costs for cases compared to 10 % of total costs for the controls. Higher costs were also seen for hospitalizations, diagnostics, and non-ART-medication in cases. Late presentation places a significant economic burden on the Austrian healthcare system. Patients and society would benefit from effective screening programs to enable earlier diagnosis with more efficient linkage to care at least in the period immediately following diagnosis. PMID- 23807044 TI - CCN4 regulates vascular smooth muscle cell migration and proliferation. AB - The migration and proliferation of vascular smooth muscle cells (VSMCs) are essential elements during the development of atherosclerosis and restenosis. An increasing number of studies have reported that extracellular matrix (ECM) proteins, including the CCN protein family, play a significant role in VSMC migration and proliferation. CCN4 is a member of the CCN protein family, which controls cell development and survival in multiple systems of the body. Here, we sought to determine whether CCN4 is involved in VSMC migration and proliferation. We examined the effect of CCN4 using rat cultured VSMCs. In cultured VSMCs, CCN4 stimulated the adhesion and migration of VSMCs in a dose-dependent manner, and this effect was blocked by an antibody for integrin alpha5beta1. CCN4 expression was enhanced by the pro-inflammatory cytokine tumor necrosis factor alpha (TNF alpha). Furthermore, knockdown of CCN4 by siRNA significantly inhibited the VSMC proliferation. CCN4 also could up-regulate the expression level of marker proteins of the VSMCs phenotype. Taken together, these results suggest that CCN4 is involved in the migration and proliferation of VSMCs. Inhibition of CCN4 may provide a promising strategy for the prevention of restenosis after vascular interventions. PMID- 23807045 TI - Cell-cell communication via extracellular membrane vesicles and its role in the immune response. AB - The host immune response involves a variety of cell types, including specialized immune and non-immune cells. The delicate coordination among these cells via close communication is central for the proper operation of immune system. Cell cell communication is mediated by a complex network that includes soluble factors such as cytokines, chemokines, and metabolites exported from cells, as well as membrane-bound receptors and their ligands. Cell-cell communication is also mediated by membrane vesicles (e.g., exosomes, ectosomes), which are either shed by distant cells or exchanged by cells that are making direct contact. Intercellular communication via extracellular membrane vesicles has drawn much attention recently, as they have been shown to carry various biomolecules that modulate the activities of recipient cells. In this review, I will discuss current views on cell-cell communication via extra-cellular membrane vesicles, especially shedded membrane vesicles, and their effects on the control of the immune system. PMID- 23807046 TI - Transplantation of bone marrow stromal cells enhances nerve regeneration of the corticospinal tract and improves recovery of neurological functions in a collagenase-induced rat model of intracerebral hemorrhage. AB - The reorganization of brain structures after intracerebral hemorrhage (ICH) insult is crucial to functional outcome. Although the pattern of neuronal rewiring is well-documented after ischemic stroke, the study of brain plasticity after ICH has been focusing on the enhancement of dendritic complexity. Here we hypothesized that functional restoration after ICH involves brain reorganization which may be favorably modulated by stem cell transplantation. In this study, bone marrow stromal cells (BMSCs) were transplanted into the perilesional sites of collagenase-induced ICH in adult rats one day after ICH injury. Forelimb functional recovery was monitored with modified limb placing and vibrissae elicited forelimb placement tests. Anterograde and retrograde tracing were used to assess the reorganization of bilateral forelimb areas of the sensorimotor cortex. We found that in rats transplanted with BMSCs after ICH injury, axonal sprouting occurred in the contralateral caudal forelimb area of the cortex, and was significantly higher than in ICH rat models that received only the vehicle (P < 0.01). The number of positive neurons in the ipsilateral rostral forelimb area of the cortex of the BMSC group was 1.5-to 4.5-fold greater than in the vehicle group (P < 0.05). No difference was found between the BMSC and vehicle groups in hemispheric atrophy or labeled neurons in the ipsilateral caudal forelimb area (P = 0.193). Scores for improved functional behavior in the BMSC group were in accord with the results from histology. Neuronal plasticity of the denervated corticospinal tract at bilateral forelimb areas of the cortex in the collagenase induced ICH rat models was significantly enhanced by BMSC transplantation. BMSC transplantation may facilitate functional recovery after ICH injury. PMID- 23807047 TI - Bone morphogenetic protein 9 overexpression reduces osteosarcoma cell migration and invasion. AB - Transforming growth factor-beta (TGF-beta) is known to promote tumor migration and invasion. Bone morphogenetic proteins (BMPs) are members of the TGF-beta family expressed in a variety of human carcinoma cell lines. The role of bone morphogenetic protein 9 (BMP9), the most powerful osteogenic factor, in osteosarcoma (OS) progression has not been fully clarified. The expression of BMP9 and its receptors in OS cell lines was analyzed by RT-PCR. We found that BMP9 and its receptors were expressed in OS cell lines. We further investigated the influence of BMP9 on the biological behaviors of OS cells. BMP9 overexpression in the OS cell lines 143B and MG63 inhibited in vitro cell migration and invasion. We further investigated the expression of a panel of cancer-related genes and found that BMP9 overexpression increased the phosphorylation of Smad1/5/8 proteins, increased the expression of ID1, and reduced the expression and activity of matrix metalloproteinase 9 (MMP9) in OS cells. BMP9 silencing induced the opposite effects. We also found that BMP9 may not affect the chemokine (C-X-C motif) ligand 12 (CXCL12)/C-X-C chemokine receptor type 4 (CXCR4) axis to regulate the invasiveness and metastatic capacity of OS cells. Interestingly, CXCR4 was expressed in both 143B and MG63 cells, while CXCL12 was only detected in MG63 cells. Taken together, we hypothesize that BMP9 inhibits the migration and invasiveness of OS cells through a Smad-dependent pathway by downregulating the expression and activity of MMP9. PMID- 23807048 TI - Generation of demyelination models by targeted ablation of oligodendrocytes in the zebrafish CNS. AB - Demyelination is the pathological process by which myelin sheaths are lost from around axons, and is usually caused by a direct insult targeted at the oligodendrocytes in the vertebrate central nervous system (CNS). A demyelinated CNS is usually remyelinated by a population of oligodendrocyte progenitor cells, which are widely distributed throughout the adult CNS. However, myelin disruption and remyelination failure affect the normal function of the nervous system, causing human diseases such as multiple sclerosis. In spite of numerous studies aimed at understanding the remyelination process, many questions still remain unanswered. Therefore, to study remyelination mechanisms in vivo, a demyelination animal model was generated using a transgenic zebrafish system in which oligodendrocytes are conditionally ablated in the larval and adult CNS. In this transgenic system, bacterial nitroreductase enzyme (NTR), which converts the prodrug metronidazole (Mtz) into a cytotoxic DNA cross-linking agent, is expressed in oligodendrocyte lineage cells under the control of the mbp and sox10 promoter. Exposure of transgenic zebrafish to Mtz-containing media resulted in rapid ablation of oligodendrocytes and CNS demyelination within 48 h, but removal of Mtz medium led to efficient remyelination of the demyelinated CNS within 7 days. In addition, the demyelination and remyelination processes could be easily observed in living transgenic zebrafish by detecting the fluorescent protein, mCherry, indicating that this transgenic system can be used as a valuable animal model to study the remyelination process in vivo, and to conduct high-throughput primary screens for new drugs that facilitate remyelination. PMID- 23807049 TI - Kinetic spectrophotometric H-point standard addition method for the simultaneous determination of diloxanide furoate and metronidazole in binary mixtures and biological fluids. AB - Simple, reliable, and sensitive kinetic spectrophotometric method has been developed for the simultaneous determination of diloxanide furoate and metronidazole using H-point standard addition method (HPSAM). The method is based on the oxidation rate difference of diloxanide and metronidazole by potassium permanganate in basic medium. A green color has been developed and measured at 610 nm. Different experimental parameters were carefully optimized. The limiting logarithmic and the initial-rate methods were adopted for the construction of the calibration curve of each individual reaction with potassium permanganate. Under the optimum conditions, Beer's law was obeyed in the range of 1.0-20.0 and 5.0 25.0 MUg ml(-1) for diloxanide furoate and metronidazole, respectively. The detection limits were 0.22 MUg ml(-1) for diloxanide furoate and 0.83 MUg ml(-1) for metronidazole. Correlation coefficients of the regression equations were greater than 0.9970 in all cases. The precision of the method was satisfactory; the maximum value of relative standard deviation did not exceed 1.06% (n=5). The accuracy, expressed as recovery was between 99.4% and 101.4% with relative error of 0.12 and 0.14 for diloxanide furoate and metronidazole, respectively. The proposed method was successfully applied for the simultaneous determination of both drugs in pharmaceutical dosage forms and human urine samples and compared with alternative HPLC method. PMID- 23807050 TI - Using ATR-FT/IR to detect carbohydrate-related molecular structure features of carinata meal and their in situ residues of ruminal fermentation in comparison with canola meal. AB - There is no information on the co-products from carinata bio-fuel and bio-oil processing (carinata meal) in molecular structural profiles mainly related to carbohydrate biopolymers in relation to ruminant nutrition. Molecular analyses with Fourier transform infrared spectroscopy (FT/IR) technique with attenuated total reflectance (ATR) and chemometrics enable to detect structural features on a molecular basis. The objectives of this study were to: (1) determine carbohydrate conformation spectral features in original carinata meal, co products from bio-fuel/bio-oil processing; and (2) investigate differences in carbohydrate molecular composition and functional group spectral intensities after in situ ruminal fermentation at 0, 12, 24 and 48 h compared to canola meal as a reference. The molecular spectroscopic parameters of carbohydrate profiles detected were structural carbohydrates (STCHO, mainly associated with hemi cellulosic and cellulosic compounds; region and baseline ca. 1483-1184 cm(-1)), cellulosic compounds (CELC, region and baseline ca. 1304-1184 cm(-1)), total carbohydrates (CHO, region and baseline ca. 1193-889cm(-1)) as well as the spectral ratios calculated based on respective spectral intensity data. The results showed that the spectral profiles of carinata meal were significantly different from that of canola meal in CHO 2nd peak area (center at ca. 1091 cm( 1), region: 1102-1083 cm(-1)) and functional group peak intensity ratios such as STCHO 1st peak (ca. 1415 cm(-1)) to 2nd peak (ca. 1374 cm(-1)) height ratio, CHO 1st peak (ca. 1149 cm(-1)) to 3rd peak (ca. 1032 cm(-1)) height ratio, CELC to total CHO area ratio and STCHO to CELC area ratio, indicating that carinata meal may not in full accord with canola meal in carbohydrate utilization and availability in ruminants. Carbohydrate conformation and spectral features were changed by significant interaction of meal type and incubation time and almost all the spectral parameters were significantly decreased (P<0.05) during 48 h ruminal degradation in both carinata meal and canola meal. Although carinata meal differed from canola meal in some carbohydrate spectral parameters, multivariate results from agglomerative hierarchical cluster analysis and principal component analysis showed that both original and in situ residues of two meals were not fully distinguished from each other within carbohydrate spectral regions. It was concluded that carbohydrate structural conformation could be detected in carinata meal by using ATR-FT/IR techniques and further study is needed to explore more information on molecular spectral features of other functional group such as protein structure profile and their association with potential nutrient supply and availability of carinata meal in animals. PMID- 23807051 TI - MHV68 latency modulates the host immune response to influenza A virus. AB - Murine gammaherpesvirus 68 (MHV68) is a natural rodent pathogen that has been used as a model to study the pathogenesis of human gammaherpesviruses. Like other herpesviruses, MHV68 causes acute infection and establishes life-long latency in the host. Recently, it has been shown that mice latently infected with MHV68 have resistance to unrelated pathogens in secondary infection models. We therefore hypothesized that latent MHV68 infection could modulate the host response to influenza A virus. To test this hypothesis, mice were infected intranasally with influenza virus following the establishment of MHV68 latency. Mice latently infected with MHV68 showed significantly higher survival to influenza A virus infection than did PBS mock-infected mice. Latent MHV68 infection led to lower influenza viral loads and decreased inflammatory pathology in the lungs. Alveolar macrophages of mice latently infected with MHV68 showed activated status, and adoptive transfer of those activated macrophages into mice followed the infection with influenza A virus had significantly greater survival rates than control mice, suggesting that activated alveolar macrophages are a key mechanistic component in protection from secondary infections. PMID- 23807052 TI - Systemic administration of FC-77 dampens ischemia-reperfusion-induced acute lung injury in rats. AB - Systemic administration of perfluorocarbons (PFCs) reportedly attenuates acute lung injury induced by acid aspiration and phorbol myristate acetate. However, the effects of PFCs on ischemia-reperfusion (IR)-induced lung injury have not been investigated. Typical acute lung injury was induced in rats by 60 min of ischemia and 60 min of reperfusion in isolated and perfused rat lung model. Rat lungs were randomly assigned to receive PBS (control), 1 % FC-77, IR only, or IR with different doses of FC-77 (0.1 %, 0.5 %, or 1 %). Subsequently, bronchoalveolar lavage fluid (BALF), perfusate, and lung tissues were collected to evaluate the degree of lung injury. IR caused a significant increase in the following parameters: pulmonary arterial pressure, capillary filtration coefficient, lung weight gain, lung weight/body weight ratio, wet/dry lung weight ratio, and protein concentration in BALF. TNF-alpha and cytokine-induced neutrophil chemoattractant-1 concentrations in perfusate samples and MDA concentration and MPO activities in lung tissues were also significantly increased. Histopathology showed increased septal thickness and neutrophil infiltration in the lung tissues. Furthermore, NF-kappaB activity was significantly increased in the lungs. However, pretreatment with 1 % FC-77 prior to IR significantly attenuated the increases in these parameters. In conclusion, our results suggest that systemic FC-77 administration had a protective effect on IR-induced acute lung injury. These protective mechanisms may have been mediated by the inhibition of NF-kappaB activation and attenuation of subsequent inflammatory response. PMID- 23807053 TI - Setting the stage: Research to inform interventions, practice and policy to improve women veterans' health and health care. PMID- 23807054 TI - Improving health of veterans through research collaborations. PMID- 23807055 TI - Health services research on women veterans: a critical partner on the road to patient-centered care. PMID- 23807056 TI - Women's health during health care transformation. PMID- 23807057 TI - The VA Women's Health Practice-Based Research Network: amplifying women veterans' voices in VA research. PMID- 23807058 TI - Factors related to attrition from VA healthcare use: findings from the National Survey of Women Veterans. AB - BACKGROUND: While prior research characterizes women Veterans' barriers to accessing and using Veterans Health Administration (VA) care, there has been little attention to women who access VA and use services, but then discontinue use. Recent data suggest that among women Veterans, there is a 30 % attrition rate within 3 years of initial VA use. OBJECTIVES: To compare individual characteristics and perceptions about VA care between women Veteran VA attriters (those who discontinue use) and non-attriters (those who continue use), and to compare recent versus remote attriters. DESIGN: Cross-sectional, population-based 2008-2009 national telephone survey. PARTICIPANTS: Six hundred twenty-six attriters and 2,065 non-attriters who responded to the National Survey of Women Veterans. MAIN MEASURES: Population weighted demographic, military and health characteristics; perceptions about VA healthcare; length of time since last VA use; among attriters, reasons for no longer using VA care. KEY RESULTS: Fifty four percent of the weighted VA ever user population reported that they no longer use VA. Forty-five percent of attrition was within the past ten years. Attriters had better overall health (p = 0.007), higher income (p < 0.001), and were more likely to have health insurance (p < 0.001) compared with non-attriters. Attriters had less positive perceptions of VA than non-attriters, with attriters having lower ratings of VA quality and of gender-specific features of VA care (p < 0.001). Women Veterans who discontinued VA use since 2001 did not differ from those with more remote VA use on most measures of VA perceptions. Overall, among attriters, distance to VA sites of care and having alternate insurance coverage were the most common reasons for discontinuing VA use. CONCLUSIONS: We found high VA attrition despite recent advances in VA care for women Veterans. Women's attrition from VA could reduce the critical mass of women Veterans in VA and affect current system-wide efforts to provide high-quality care for women Veterans. An understanding of reasons for attrition can inform organizational efforts to re-engage women who have attrited, to retain current users, and potentially to attract new VA patients. PMID- 23807059 TI - Cardiovascular disease risk factors among women veterans at VA medical facilities. AB - BACKGROUND: Hypertension, hyperlipidemia, diabetes, and obesity in middle adulthood each elevate the long-term risk of cardiovascular disease (CVD). The prevalence of these conditions among women veterans is incompletely described. OBJECTIVE: To describe the prevalence of CVD risk factors among women veterans in middle adulthood. DESIGN: Serial cross-sectional studies of data from the Diabetes Epidemiologic Cohorts (DEpiC), a national, longitudinal data set including information on all patients in the Veterans Health Administration (VA). PARTICIPANTS: Women veterans (n = 255,891) and men veterans (n = 2,271,605) aged 35-64 receiving VA care in fiscal year (FY) 2010. MAIN MEASURES: Prevalence of CVD risk factors in FY2010 by age and, for those aged 45-54 years, by race, region, period of military service, priority status, and mental illness or substance abuse; prevalence by year from 2000 to 2010 in women veterans receiving VA care in both 2000 and 2010 who were free of the factor in 2000. KEY RESULTS: Hypertension, hyperlipidemia, and diabetes were common among women and men, although more so among men. Hypertension was present in 13 % of women aged 35-44 years, 28 % of women aged 45-54, and 42 % of women aged 55-64. Hyperlipidemia prevalence was similar. Diabetes affected 4 % of women aged 35-44, and increased more than four-fold in prevalence to 18 % by age 55-64. The prevalence of obesity increased from 14 % to 18 % with age among women and was similarly prevalent in men. The relative rate of having two or more CVD risk factors in women compared to men increased progressively with age, from 0.55 (35-44 years) to 0.71 (45-54) to 0.73 (55-64). Most of the women with a factor present in 2010 were first diagnosed with the condition in the 10 years between 2000 and 2010. CONCLUSIONS: CVD risk factors are common among women veterans aged 35-64. Future research should investigate which interventions would most effectively reduce risk in this population. PMID- 23807060 TI - Racial/ethnic differences in cardiovascular risk factors among women veterans. AB - BACKGROUND: Heart disease is the leading cause of death for women in the United States, accounting for 24.5 % of all deaths among women. Earlier research has demonstrated racial/ethnic differences in prevalence of cardiovascular (CVD) risk factors. OBJECTIVE: To empirically examine the prevalence of CVD risk factors among a national sample of women Veterans by race/ethnicity, providing the first portrait of women Veterans' cardiovascular care needs. DESIGN AND PARTICIPANTS: Cross-sectional, national population-based telephone survey of 3,611 women Veterans. MEASUREMENTS: Women Veterans were queried about presence of diabetes, hypertension, obesity, tobacco use and physical activity. Four racial/ethnic categories were created: Hispanic, Non-Hispanic White (White), Non-Hispanic Black (Black), and Other. Logistic regressions were conducted for each risk factor to test for racial/ethnic differences, controlling for age (under 40 vs. 40 and over). KEY RESULTS: Racial/ethnic differences in CVD risk factors persisted after adjusting for age. Black women Veterans were more likely to report a diagnosis of diabetes (OR: 2.58, 95 % CI: 1.07, 6.21) or hypertension (OR: 2.31, 95 % CI: 1.10, 4.83) and be obese (OR: 2.06, 95 % CI: 1.05, 3.91) than White women Veterans. Hispanic women Veterans were more likely than White women Veterans to report diabetes (OR: 4.20, 95 % CI: 1.15, 15.39) and daily smoking (OR: 3.38, 95 % CI: 1.01, 11.30), but less likely to report a hypertension diagnosis (OR 0.21, 95% CI: 0.07, 0.64) or to be obese (OR: 0.39, 95 % CI: 0.18, 0.81). CONCLUSIONS: Among women Veterans, CVD risks vary by race/ethnicity. Black women Veterans consistently face higher CVD risk compared to White women Veterans, while results are mixed for Hispanic women Veterans. PMID- 23807061 TI - Accounting for clinical action reduces estimates of gender disparities in lipid management for diabetic veterans. AB - BACKGROUND: Women with diabetes have higher low-density lipoprotein (LDL) levels than men, resulting in apparent disparities between genders on quality indicators tied to LDL thresholds. OBJECTIVE: To investigate whether gender disparities persist when accounting for clinical action with statins or cardiovascular risk. DESIGN: Retrospective cohort study. PARTICIPANTS: Veterans Health Administration patients (21,780 women and 646,429 men) aged 50-75 with diabetes. MAIN MEASURES: Threshold measure: LDL < 100 mg/dL; clinical action measure: LDL < 100 mg/dL; or LDL >= 100 mg/dL and the patient was prescribed a moderate or high-dose statin at the time of the test; or LDL >= 100 mg/dL and the patient received other appropriate clinical action within 90 days; adherence: continuous multiple interval measure of gaps in dispensed medication (CMG). KEY RESULTS: Women were much less likely to have LDL < 100 mg/dL than were men (55 % vs. 68 %). This disparity narrowed from 13 % to 6 % for passing the clinical action measure (79 % vs. 85 %). These gender differences persisted among those with ischemic heart disease (IHD). Women had a lower odds of passing the clinical action measure (odds ratio 0.68, 95 % confidence interval 0.66-0.71). Among those with IHD, the gender gap increased with age. Differences in pass rates were explained by women's higher LDL levels, but not by their slightly worse adherence (3 % higher CMG). CONCLUSIONS: Women and men veterans receive more similar quality of care for lipids in diabetes than previously indicated. Less reassuringly, the remaining gender differences appear to be as common in women at high cardiovascular risk as in those at low risk. Rather than focus on simply improving LDL levels in all women with diabetes, future efforts should ensure that patients with high cardiovascular risk are appropriately treated with statins when clinically indicated, feasible, and concordant with patient preferences. PMID- 23807062 TI - Military sexual trauma among homeless veterans. AB - BACKGROUND: Military sexual trauma (MST) is the Veteran Health Administration's (VHA) term for sexual assault and/or sexual harassment that occurs during military service. The experience of MST is associated with a variety of mental health conditions. Preliminary research suggests that MST may be associated with homelessness among female Veterans, although to date MST has not been examined in a national study of both female and male homeless Veterans. OBJECTIVE: To estimate the prevalence of MST, examine the association between MST and mental health conditions, and describe mental health utilization among homeless women and men. DESIGN AND PARTICIPANTS: National, cross-sectional study of 126,598 homeless Veterans who used VHA outpatient care in fiscal year 2010. MAIN MEASURES: All variables were obtained from VHA administrative databases, including MST screening status, ICD-9-CM codes to determine mental health diagnoses, and VHA utilization. KEY RESULTS: Of homeless Veterans in VHA, 39.7 % of females and 3.3 % of males experienced MST. Homeless Veterans who experienced MST demonstrated a significantly higher likelihood of almost all mental health conditions examined as compared to other homeless women and men, including depression, posttraumatic stress disorder, other anxiety disorders, substance use disorders, bipolar disorders, personality disorders, suicide, and, among men only, schizophrenia and psychotic disorders. Nearly all homeless Veterans had at least one mental health visit and Veterans who experienced MST utilized significantly more mental health visits compared to Veterans who did not experience MST. CONCLUSIONS: A substantial proportion of homeless Veterans using VHA services have experienced MST, and those who experienced MST had increased odds of mental health diagnoses. Homeless Veterans who had experienced MST had higher intensity of mental health care utilization and high rates of MST-related mental health care. This study highlights the importance of trauma-informed care among homeless Veterans and the success of VHA homeless programs in providing mental health care to homeless Veterans. PMID- 23807063 TI - Gender differences in prescribing among veterans diagnosed with posttraumatic stress disorder. AB - OBJECTIVE: The Department of Veterans Affairs (VA) and Department of Defense (DoD) issued a revised posttraumatic stress disorder (PTSD) Clinical Practice Guideline (CPG) in 2010 with specific pharmacotherapy recommendations for evidence-based quality care. The authors examined prescribing frequencies over an 11-year period prior to the release of the new guideline to determine gender differences in pharmacotherapy treatment in veterans with PTSD. METHOD: National administrative VA data from 1999 to 2009 were used to identify veterans with PTSD using ICD-9 codes extracted from inpatient discharges and outpatient clinic visits. Prescribing of antidepressants, antipsychotics and hypnotics was determined for each year using prescription drug files. RESULTS: Women were more likely than men to receive medication across all classes except prazosin where men had higher prescribing frequency. The proportion of women receiving either of the first-line pharmacotherapy treatments for PTSD, selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI), increased from 56.4 % in 1999 to 65.7 % in 2009, higher rates than seen in men (49.2 % to 58.3 %). Atypical antipsychotic prescriptions increased from 14.6 % to 26.3 % and nonbenzodiazepine hypnotics increased from 3.8 % to 16.9 % for women, higher frequencies than seen in men for both medications (OR = 1.31, 1.43 respectively). The most notable gender discrepancy was observed for benzodiazepines where prescriptions decreased for men (36.7 % in 1999 to 29.8 % in 2009) but steadily increased for women from 33.4 % to 38.3 %. CONCLUSION: A consistent pattern of increased prescribing of psychotropic medications among women with PTSD was seen compared to men. Prescribing frequency for benzodiazepines showed a marked gender difference with a steady increase for women despite guideline recommendations against use and a decrease for men. Common co-occurring disorders and sleep symptom management are important factors of PTSD pharmacotherapy and may contribute to gender differences seen in prescribing benzodiazepines in women but do not fully explain the apparent disparity. PMID- 23807064 TI - Self-reported stressors of National Guard women veterans before and after deployment: the relevance of interpersonal relationships. AB - BACKGROUND: With their rapidly expanding roles in the military, women service members experience significant stressors throughout their deployment experience. However, there are few studies that examine changes in women Veterans' stressors before and after deployment. OBJECTIVE: This study examines the types of stressors women Veterans report before deployment, immediately after deployment, 3 months after deployment, and 1 year post-deployment. DESIGN: Descriptive data on reported stressors was collected at four time points of a longitudinal study (HEROES Project). Open-ended responses from the Coping Response Inventory (CRI) were coded into six possible major stressor categories for analysis. PARTICIPANTS: Seventy-nine Army National Guard and Reserve female personnel deploying to Operation Enduring Freedom (OFF)/Operation Iraqi Freedom (OIF) were surveyed prior to deployment. Of these participants, 35 women completed Phase 2, 41 completed Phase 3, and 48 completed Phase 4 of the study. KEY RESULTS: We identified six major stressor categories: (1) interpersonal (i.e., issues with family and/or friends), (2) deployment-related and military-related, (3) health concerns, (4) death of a loved one, (5) daily needs (i.e., financial/housing/transportation concerns), and (6) employment or school-related concerns. At all time points, interpersonal issues were one of the most common type of stressor for this sample. Daily needs concerns increased from 3 months post-deployment to 1 year post-deployment. CONCLUSIONS: Interpersonal concerns are commonly reported by women Veterans both before and after their combat experience, suggesting that this is a time during which interpersonal support is especially critical. We discuss implications, which include the need for a more coordinated approach to women Veterans' health care (e.g., greater community based outreach), and the need for more and more accessible Veterans Affairs (VA) services to address the needs of female Veterans. PMID- 23807065 TI - Gender differences among veterans deployed in support of the wars in Afghanistan and Iraq. AB - BACKGROUND: The changing scope of women's roles in combat operations has led to growing interest in women's deployment experiences and post-deployment adjustment. OBJECTIVES: To quantify the gender-specific frequency of deployment stressors, including sexual and non-sexual harassment, lack of social support and combat exposure. To quantify gender-specific post-deployment mental health conditions and associations between deployment stressors and posttraumatic stress disorder (PTSD), to inform the care of Veterans returning from the current conflicts. DESIGN: National mail survey of OEF/OIF Veterans randomly sampled within gender, with women oversampled. SETTING: The community. PARTICIPANTS: In total, 1,207 female and 1,137 male Veterans from a roster of all Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) Veterans. Response rate was 48.6 %. MAIN MEASURES: Deployment stressors (including combat and harassment stress), PTSD, depression, anxiety and alcohol use, all measured via self-report. KEY RESULTS: Women were more likely to report sexual harassment (OR = 8.7, 95% CI: 6.9, 11) but less likely to report combat (OR = 0.62, 95 % CI: 0.50, 0.76). Women and men were equally likely to report symptoms consistent with probable PTSD (OR = 0.87, 95 % CI: 0.70, 1.1) and symptomatic anxiety (OR = 1.1, 9 5% CI: 0.86, 1.3). Women were more likely to report probable depression (OR = 1.3, 95 % CI: 1.1, 1.6) and less likely to report problematic alcohol use (OR = 0.59, 9 5% CI: 0.47, 0.72). With a five-point change in harassment stress, adjusted odds ratios for PTSD were 1.36 (95 % CI: 1.23, 1.52) for women and 1.38 (95 % CI: 1.19, 1.61) for men. The analogous associations between combat stress and PTSD were 1.31 (95 % CI: 1.24, 1.39) and 1.31 (95 % CI: 1.26, 1.36), respectively. CONCLUSIONS: Although there are important gender differences in deployment stressors-including women's increased risk of interpersonal stressors-and post deployment adjustment, there are also significant similarities. The post deployment adjustment of our nation's growing population of female Veterans seems comparable to that of our nation's male Veterans. PMID- 23807066 TI - The relationship between body mass index and mental health among Iraq and Afghanistan veterans. AB - BACKGROUND: Obesity is a growing public health concern and is becoming an epidemic among veterans in the post-deployment period. OBJECTIVE: To explore the relationship between body mass index (BMI) and posttraumatic stress disorder (PTSD) in a large cohort of Iraq and Afghanistan veterans, and to evaluate trajectories of change in BMI over 3 years. DESIGN: Retrospective, longitudinal cohort analysis of veterans' health records PARTICIPANTS: A total of 496,722 veterans (59,790 female and 436,932 male veterans) whose height and weight were recorded at the Department of Veterans Affairs (VA) healthcare system at least once after the end of their last deployment and whose first post-deployment outpatient encounter at the VA was at least 1 year prior to the end of the study period (December 31, 2011). MAIN MEASURES: BMI, mental health diagnoses. KEY RESULTS: Seventy-five percent of Iraq and Afghanistan veterans were either overweight or obese at baseline. Four trajectories were observed: "stable overweight" represented the largest class; followed by "stable obese;" "overweight/obese gaining;" and "obese losing." During the 3-year ascertainment period, those with PTSD and depression in particular were at the greatest risk of being either obese without weight loss or overweight or obese and continuing to gain weight. Adjustment for demographics and antipsychotic medication attenuated the relationship between BMI and certain mental health diagnoses. Although BMI trajectories were similar in men and women, some gender differences were observed. For example, the risk of being in the persistently obese class in men was highest for those with PTSD, whereas for women, the risk was highest among those with depression. CONCLUSIONS: The growing number of overweight or obese returning veterans is a concerning problem for clinicians who work with these patients. Successful intervention to reduce the prevalence of obesity will require integrated efforts from primary care and mental health to treat underlying mental health causes and assist with engagement in weight loss programs. PMID- 23807067 TI - Women veterans' healthcare delivery preferences and use by military service era: findings from the National Survey of Women Veterans. AB - BACKGROUND: The number of women Veterans (WVs) utilizing the Veterans Health Administration (VA) has doubled over the past decade, heightening the importance of understanding their healthcare delivery preferences and utilization patterns. Other studies have identified healthcare issues and behaviors of WVs in specific military service eras (e.g., Vietnam), but delivery preferences and utilization have not been examined within and across eras on a population basis. OBJECTIVE: To identify healthcare delivery preferences and healthcare use of WVs by military service era to inform program design and patient-centeredness. DESIGN AND PARTICIPANTS: Cross-sectional 2008-2009 survey of a nationally representative sample of 3,611 WVs, weighted to the population. MAIN MEASURES: Healthcare delivery preferences measured as importance of selected healthcare features; types of healthcare services and number of visits used; use of VA or non-VA; all by military service era. KEY RESULTS: Military service era differences were present in types of healthcare used, with World War II and Korea era WVs using more specialty care, and Vietnam era-to-present WVs using more women's health and mental health care. Operations Enduring Freedom, Iraqi Freedom, New Dawn (OEF/OIF/OND) WVs made more healthcare visits than WVs of earlier military eras. The greatest healthcare delivery concerns were location convenience for Vietnam and earlier WVs, and cost for Gulf War 1 and OEF/OIF/OND WVs. Co-located gynecology with general healthcare was also rated important by a sizable proportion of WVs from all military service eras. CONCLUSIONS: Our findings point to the importance of ensuring access to specialty services closer to home for WVs, which may require technology-supported care. Younger WVs' higher mental health care use reinforces the need for integration and coordination of primary care, reproductive health and mental health care. PMID- 23807069 TI - An inventory of VHA emergency departments' resources and processes for caring for women. AB - BACKGROUND: More women are using Veterans' Health Administration (VHA) Emergency Departments (EDs), yet VHA ED capacities to meet the needs of women are unknown. OBJECTIVE: We assessed VHA ED resources and processes for conditions specific to, or more common in, women Veterans. DESIGN/SUBJECTS: Cross-sectional questionnaire of the census of VHA ED directors MAIN MEASURES: Resources and processes in place for gynecologic, obstetric, sexual assault and mental health care, as well as patient privacy features, stratified by ED characteristics. KEY RESULTS: All 120 VHA EDs completed the questionnaire. Approximately nine out of ten EDs reported having gynecologic examination tables within their EDs, 24/7 access to specula, and Gonorrhea/Chlamydia DNA probes. All EDs reported 24/7 access to pregnancy testing. Fewer than two-fifths of EDs reported having radiologist review of pelvic ultrasound images available 24/7; one-third reported having emergent consultations from gynecologists available 24/7. Written transfer policies specific to gynecologic and obstetric emergencies were reported as available in fewer than half of EDs. Most EDs reported having emergency contraception 24/7; however, only approximately half reported having Rho(D) Immunoglobulin available 24/7. Templated triage notes and standing orders relevant to gynecologic conditions were reported as uncommon. Consistent with VHA policy, most EDs reported obtaining care for victims of sexual assault by transferring them to another institution. Most EDs reported having some access to private medical and mental health rooms. Resources and processes were found to be more available in EDs with more encounters by women, more ED staffed beds, and that were located in more complex facilities in metropolitan areas. CONCLUSIONS: Although most VHA EDs have resources and processes needed for delivering emergency care to women Veterans, some gaps exist. Studies in non-VA EDs are required for comparison. Creative solutions are needed to ensure that women presenting to VHA EDs receive efficient, timely, and consistently high-quality care. PMID- 23807068 TI - Sex disparities in overall burden of disease among HIV-infected individuals in the Veterans Affairs healthcare system. AB - BACKGROUND: Whether sex disparities exist in overall burden of disease among human immunodeficiency virus (HIV)-infected individuals in the Veterans Affairs healthcare system (VA) is unknown. OBJECTIVE: To determine whether sex differences exist in overall burden of disease after 1 year of combined antiretroviral therapy (ART) among HIV-infected individuals in VA. DESIGN: Retrospective cohort study. PARTICIPANTS: Among patients in the Veterans Aging Cohort Study Virtual Cohort (VACS-VC), all ART-naive HIV-infected Veterans who received VA-based HIV care between 1996 and 2009. MAIN MEASURES: Overall burden of disease was measured using the VACS Index, an index that incorporates HIV (e.g. CD4 cell count) and non-HIV biomarkers (e.g. hemoglobin) and is highly predictive of all-cause mortality. Possible scores range from 0 to 164, although scores typically range from 0 to 50 for 80 % of patients in VACS-VC. A higher score indicates greater burden of disease (each additional five points indicates approximately 20 % increased 5-year mortality risk). ART adherence was measured using pharmacy data. KEY RESULTS: Complete data were available for 227 women and 8,073 men. At ART initiation, compared with men, women were younger and more likely to be Black, less likely to have liver dysfunction, but more likely to have lower hemoglobin levels. Median VACS Index scores changed from ART initiation to 1 year after ART initiation: women's scores went from 41 to 28 for women (13 point improvement) and men's from 42 to 27 for men (15 point improvement). In multivariable regression, women had 3.6 point worse scores than men after 1 year on ART (p = 0.002); this difference decreased to 3.2 points after adjusting for adherence (p = 0.004). CONCLUSIONS: In VA, compared to men, women experienced less improvement in overall burden of disease after 1 year of HIV treatment. Further study is needed to elucidate the modifiable factors that may explain this disparity. PMID- 23807070 TI - VA location and structural factors associated with on-site availability of reproductive health services. AB - INTRODUCTION: With the increasing number of women Veterans enrolling in the Veterans Health Administration (VA), there is growing demand for reproductive health services. Little is known regarding the on-site availability of reproductive health services at VA and how this varies by site location and type. OBJECTIVE: To describe the on-site availability of hormonal contraception, intrauterine device (IUD) placement, infertility evaluation or treatment, and prenatal care by site location and type; the characteristics of sites providing these services; and to determine whether, within this context, site location and type is associated with on-site availability of these reproductive health services. METHODS: We used data from the 2007 Veterans Health Administration Survey of Women Veterans Health Programs and Practices, a national census of VA sites serving 300 or more women Veterans assessing practice structure and provision of care for women. Hierarchical models were used to test whether site location and type (metropolitan hospital-based clinic, non-metropolitan hospital based clinic, metropolitan community-based outpatient clinic [CBOC]) were associated with availability of IUD placement and infertility evaluation/treatment. Non-metropolitan CBOCs were excluded from this analysis (n = 2). RESULTS: Of 193 sites, 182 (94 %) offered on-site hormonal contraception, 97 (50 %) offered on-site IUD placement, 57 (30 %) offered on-site infertility evaluation/treatment, and 11 (6 %) offered on-site prenatal care. After adjustment, compared with metropolitan hospital based-clinics, metropolitan CBOCs were less likely to offer on-site IUD placement (OR 0.33; 95 % CI 0.14, 0.74). CONCLUSION: Compared with metropolitan hospital-based clinics, metropolitan CBOCs offer fewer specialized reproductive health services on-site. Additional research is needed regarding delivery of specialized reproductive health care services for women Veterans in CBOCs and clinics in non-metropolitan areas. PMID- 23807071 TI - Counseling of female veterans about risks of medication-induced birth defects. AB - BACKGROUND: Medications that may increase risk of birth defects if used during pregnancy or immediately preconception are dispensed to approximately half of female Veterans who fill prescriptions at a VA pharmacy. OBJECTIVE: To assess receipt of counseling about risk of medication-induced birth defects among female Veterans of reproductive age and to examine Veterans' confidence that their healthcare provider would counsel them about teratogenic risks. DESIGN AND PARTICIPANTS: Cross-sectional analysis of data provided by 286 female Veterans of Operation Iraqi Freedom and/or Operation Enduring Freedom who completed a mailed survey between July 2008 and October 2010. MAIN MEASURES: We examined associations between demographic, reproductive, and health service utilization variables and female Veterans' receipt of counseling and confidence that they would receive such counseling. KEY RESULTS: The response rate was 11 %; the large majority (89 %) of responding female Veterans reported use of a prescription medication in the last 12 months. Most (90 %) of the 286 female Veterans who reported medication use were confident that they would be told by their healthcare provider if a medication might cause a birth defect. However, only 24 % of women who received prescription medications reported they had been warned of teratogenic risks. Female Veterans who used medications that are known to be teratogenic were not more likely than women using other medications to report having been warned about risks of medication-induced birth defects, and fewer were confident that their health care providers would provide teratogenic risk counseling when needed. CONCLUSIONS: Female Veterans may not receive appropriate counseling when medications that can cause birth defects are prescribed. PMID- 23807072 TI - Sexual victimization, health status, and VA healthcare utilization among lesbian and bisexual OEF/OIF veterans. AB - BACKGROUND: Many lesbian and bisexual (LB) women veterans may have been targets of victimization in the military based on their gender and presumed sexual orientation, and yet little is known regarding the health or mental health of LB veterans, nor the degree to which they feel comfortable receiving care in the VA. OBJECTIVE: The purpose of this study was to examine the prevalence of mental health and gender-specific conditions, VA healthcare satisfaction and trauma exposure among LB veterans receiving VA care compared with heterosexually identified women veterans receiving. DESIGN: Prospective cohort study of Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) women veterans at two large VA facilities. PARTICIPANTS: Three hundred and sixty five women veterans that completed a baseline survey. Thirty-five veterans (9.6 %) identified as gay or lesbian (4.7 %), or bisexual (4.9 %). MAIN MEASURES: Measures included sexual orientation, military sexual trauma, mental and gender specific health diagnoses, and VA healthcare utilization and satisfaction. KEY RESULTS: LB OEF/OIF veterans were significantly more likely to have experienced both military and childhood sexual trauma than heterosexual women (MST: 31 % vs. 13 %, p < .001; childhood sexual trauma: 60 % vs. 36 %, p = .01), to be hazardous drinkers (32 % vs. 16 %, p = .03) and rate their current mental health as worse than before deployment (35 % vs. 16 %, p < .001). CONCLUSIONS: Many LB veterans have experienced sexual victimization, both within the military and as children, and struggle with substance abuse and poor mental health. Health care providers working with female Veterans should be aware of high rates of military sexual trauma and childhood abuse and refer women to appropriate VA treatment and support groups for sequelae of these experiences. Future research should focus on expanding this study to include a larger and more diverse sample of lesbian, gay, bisexual, and transgender veterans receiving care at VA facilities across the country. PMID- 23807073 TI - Incorporating lesbian and bisexual women into women veterans' health priorities. AB - Relative to the general population, lesbian and bisexual (LB) women are overrepresented in the military and are significantly more likely to have a history of military service compared to all adult women. Due to institutional policies and stigma associated with a gay or lesbian identity, very little empirical research has been done on this group of women veterans. Available data suggest that compared to heterosexual women veterans, LB women veterans are likely to experience heightened levels of prejudice and discrimination, victimization, including greater incidence of rape, as well as adverse health and substance use disorders. They are also likely to encounter a host of unique issues when accessing health care, including fears of insensitive care and difficulty disclosing sexual orientation to Veterans Health Administration (VHA) providers. Training of staff and providers, education efforts, outreach activities, and research on this subpopulation are critical to ensure equitable and high quality service delivery. PMID- 23807074 TI - Relevance of MPNST cell lines as models for NF1 associated-tumors. PMID- 23807075 TI - No association of neurotensin receptor 1 gene polymorphisms with coping styles in healthy Chinese-Han individuals. PMID- 23807076 TI - Impaired automatic and unconscious motor processes in Parkinson's disease. AB - While it is increasingly recognized that voluntary movements are produced by an interaction between conscious and unconscious processes, the role of the latter in Parkinson's disease has received little attention to date. Here, we administered a subliminal masked prime task to 15 Parkinson's disease patients and 15 age-matched healthy elderly subjects. Compatibility effects were examined by manipulating the direction of the arrows and the interstimuli interval. Analysis of the positive compatibility effect revealed performance differences between the most and the least affected hand in Parkinson's disease patients. Additionally, patients did not show the same tendency toward a negative compatibility effect as compared to elderly controls. These novel findings provide evidence supporting the role of basal ganglia circuits in controlling the balance between automatic motor response facilitation and inhibition. PMID- 23807077 TI - Evaluation of the effectiveness of HIV voluntary counseling and testing trainings for clinicians in the Odessa region of Ukraine. AB - In Ukraine, only 28 % of HIV-infected individuals are aware of their HIV status. Expansion of voluntary HIV counseling and testing (VCT) in primary and specialty health care settings holds promise for increasing the number of people who know their HIV status and can access care. To build capacity among health care providers to deliver VCT, we conducted two-day trainings on basic HIV knowledge and on VCT procedures in the Odessa region of Ukraine. The training program was developed by local trainers in collaboration with faculty from the US Southeast AIDS Training and Education Center and was delivered in the clinical settings where trainees worked (n = 392). We assessed training effectiveness in terms of change in knowledge among clinician trainees, comparing HIV specialists and nonspecialists and those working in urban and rural clinical settings. All else being equal, compared with their urban HIV-specialist peers, trainees who were rural nonspecialists demonstrated significantly greater increases in general HIV knowledge scores. This effort demonstrates that brief, on-site training programs support the expansion of VCT by increasing the knowledge and skills of rural nonspecialist clinicians to levels equal with urban HIV specialists. PMID- 23807080 TI - Bioinformatics analysis of H7N9 protein sequences. PMID- 23807078 TI - Structure of dual receptor binding to botulinum neurotoxin B. AB - Botulinum neurotoxins are highly toxic, and bind two receptors to achieve their high affinity and specificity for neurons. Here we present the first structure of a botulinum neurotoxin bound to both its receptors. We determine the 2.3-A structure of a ternary complex of botulinum neurotoxin type B bound to both its protein receptor synaptotagmin II and its ganglioside receptor GD1a. We show that there is no direct contact between the two receptors, and that the binding affinity towards synaptotagmin II is not influenced by the presence of GD1a. The interactions of botulinum neurotoxin type B with the sialic acid 5 moiety of GD1a are important for the ganglioside selectivity. The structure demonstrates that the protein receptor and the ganglioside receptor occupy nearby but separate binding sites, thus providing two independent anchoring points. PMID- 23807079 TI - Low immunogenicity predicted for emerging avian-origin H7N9: implication for influenza vaccine design. AB - A new avian-origin influenza virus emerged near Shanghai in February 2013, and by the beginning of May it had caused over 130 human infections and 36 deaths. Human to-human transmission of avian-origin H7N9 influenza A has been limited to a few family clusters, but the high mortality rate (27%) associated with human infection has raised concern about the potential for this virus to become a significant human pathogen. European, American, and Asian vaccine companies have already initiated the process of cloning H7 antigens such as hemagglutinin (HA) into standardized vaccine production vehicles. Unfortunately, previous H7 HA containing vaccines have been poorly immunogenic. We used well-established immunoinformatics tools to analyze the H7N9 protein sequences and compare their T cell epitope content to other circulating influenza A strains as a means of estimating the immunogenic potential of the new influenza antigen. We found that the HA proteins derived from closely related human-derived H7N9 strains contain fewer T cell epitopes than other recently circulating strains of influenza, and that conservation of T cell epitopes with other strains of influenza was very limited. Here, we provide a detailed accounting of the type and location of T cell epitopes contained in H7N9 and their conservation in other H7 and circulating (A/California/07/2009, A/Victoria/361/2011, and A/Texas/50/2012) influenza A strains. Based on this analysis, avian-origin H7N9 2013 appears to be a "stealth" virus, capable of evading human cellular and humoral immune response. Should H7N9 develop pandemic potential, this analysis predicts that novel strategies for improving vaccine immunogenicity for this unique low immunogenicity strain of avian-origin influenza will be urgently needed. PMID- 23807081 TI - Portrait: coincidences, convergences and opportunities. AB - Born in 1944, I grew up in a world in which polio was both a gripping fear and real threat. Then in a matter of a few years-polio was eradicated by a vaccine developed by Jonas Salk. Later I learned that Salk's efforts were built on pioneering work of many others, including John Enders, Thomas Weller and Frederick Robbins (Nobelists, 1954), and David Bodian, who pioneered studies of polio pathogenesis and immunity. Bodian became my teacher in medical school, and Robbins became a colleague. Later, Salk, Robbins and I shared a platform at an infectious diseases symposium, and I was privileged to speak at Robbins' retirement. But that gets ahead of my story. In January 1956, at age 12 y, I received my first of dose of the "Salk" vaccine. Other kids had pictures of athletes in their rooms; I had a picture of Jonas Salk. PMID- 23807083 TI - A novel amalgamation of 1,2,3-triazoles, piperidines and thieno pyridine rings and evaluation of their antifungal activity. AB - It is the first report of the novel amalgamation of 1,2,3-triazoles, piperidines, thieno pyridine rings and evaluation of their antifungal activity. The synthesized compounds showed interesting moderate to good antifungal activity, wherein they were able to discriminate between the two species Aspergillus flavus and Aspergillus niger of the same genus. In addition, the main highlight of this series is the sensitivity of the fungal strain Cryptococcus neoformans to the compounds having p-chlorobenzoyl (9h), methane sulfonyl (9i) and p-methylbenzene sulfonyl (9j) attached to the piperazine nitrogen. PMID- 23807084 TI - Curcumin enhances the lung cancer chemopreventive efficacy of phospho-sulindac by improving its pharmacokinetics. AB - Phospho-sulindac (PS) is a safe sulindac derivative with promising anticancer efficacy in colon cancer. We evaluated whether its combination with curcumin could enhance the efficacy in the treatment of lung cancer. Curcumin, the principal bioactive component in turmeric, has demonstrated versatile capabilities to modify the therapeutic efficacy of a wide range of anticancer agents. Here, we evaluated the effect of co-administration of curcumin on the anticancer activity of PS in a mouse xenograft model of human lung cancer. Curcumin enhanced the cellular uptake of PS in human lung and colon cancer cell lines. To assess the potential synergism between curcumin and PS in vivo, curcumin was suspended in 10% Tween-80 or formulated in micellar nanoparticles and given to mice by oral gavage prior to the administration of PS. Both formulations of curcumin significantly improved the pharmacokinetic profiles of PS, with the 10% Tween-80 suspension being much more effective than the nanoparticle formation. However, curcumin did not exhibit any significant modification of the metabolite profile of PS. Furthermore, in a mouse subcutaneous xenograft model of human lung cancer, PS (200 mg/kg) in combination with curcumin (500 mg/kg) suspended in 10% Tween-80 (51% inhibition, p<0.05) was significantly more efficacious than PS plus micelle curcumin (30%) or PS (25%) or curcumin alone (no effect). Consistent with the improved pharmacokinetics, the combination treatment group had higher levels of PS and its metabolites in the xenografts compared to PS alone. Our results show that curcumin substantially improves the pharmacokinetics of PS leading to synergistic inhibition of the growth of human lung cancer xenografts, representing a promising drug combination. PMID- 23807085 TI - Molecular basis for the regulation of hypoxia-inducible factor-1alpha levels by 2 deoxy-D-ribose. AB - The angiogenic factor, platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP), stimulates the chemotaxis of endothelial cells and confers resistance to apoptosis induced by hypoxia. 2-Deoxy-D-ribose, a degradation product of thymidine generated by TP enzymatic activity, inhibits the upregulation of hypoxia-inducible factor (HIF) 1alpha, BNIP3 and caspase-3 induced by hypoxia. In the present study, we investigated the molecular basis for the suppressive effect of 2-deoxy-D-ribose on the upregulation of HIF-1alpha. 2 Deoxy-D-ribose enhanced the interaction of HIF-1alpha and the von Hippel-Lindau (VHL) protein under hypoxic conditions. It did not affect the expression of HIF 1alpha, prolyl hydroxylase (PHD)1/2/3 and VHL mRNA under normoxic or hypoxic conditions, but enhanced the interaction of HIF-1alpha and PHD2 under hypoxic conditions. 2-Deoxy-D-ribose also increased the amount of hydroxy-HIF-1alpha in the presence of the proteasome inhibitor MG-132. The expression levels of TP are elevated in many types of malignant solid tumors and, thus, 2-deoxy-D-ribose generated by TP in these tumors may play an important role in tumor progression by preventing hypoxia-induced apoptosis. PMID- 23807086 TI - The deposition of Au-Pt core-shell nanoparticles on reduced graphene oxide and their catalytic activity. AB - Au-Pt core-shell nanoparticles have been synthesized on a reduced graphene oxide (RGO) surface by an under-potential deposition (UPD) redox replacement technique, which involves redox replacement of a copper UPD monolayer by PtCl42- that could be reduced and deposited simultaneously. Scanning electron microscopy (SEM) and electrochemical methods have been used to characterize the graphene decorated with Au-Pt core-shell nanoparticles. The electrochemical experiments show that the materials exhibit excellent catalytic activity towards the oxygen reduction reaction and the methanol oxidation reaction. It is believed that the high performance of this new catalyst is due to the ultrathin Pt shell on the Au nanoparticles surface and the oxygen-containing functional groups on the RGO surface. PMID- 23807087 TI - Free flap transplantation combined with skin grafting and vacuum sealing drainage for repair of circumferential or sub-circumferential soft-tissue wounds of the lower leg. AB - BACKGROUND: This study is aimed at evaluating the operation techniques and clinical significance of free flap transplantation combined with skin grafting and vacuum sealing drainage (VSD) in repairing severe traumatic extensive circumferential or semi-circumferential soft-tissue defects of the lower leg. MATERIAL AND METHODS: Thirty patients with severe lower leg injuries were treated by free flap transplantation combined with skin grafting and VSD from January 2008 to June 2011. The size of the wounds ranged from 23*8 cm to 44*28 cm and all affected more 70% of the low leg circumferential area. Wounds were complicated by exposure, necrosis, or infection of deep tissues. The wounds were first debrided and covered by VSD. When the condition of the wound had improved (5 to 7 days later), free flaps were harvested to reconstruct damaged tissue and skin grafts and VSD was used to cover granulation tissues around the transplanted flap. RESULTS: Granulation tissues developed and the area requiring flap cover decreased in all 30 patients after debridement and VSD. In 28 of 30 cases, the transplanted flaps grew well without complication. Peripheral necrosis was observed in only 2 cases, which required a second debridement and skin graft. Ten wound areas covered by grafts were left with scattered peripheral wounds, which healed with the help of 1 more skin graft or dressing change. Morphological appearance and functional recovery were satisfactory in all 30 cases. CONCLUSIONS: Initial debridement and the temporary VSD cover followed after several days by free flap transplantation combined with skin grafting and VSD protection is a reliable treatment regimen for traumatic large circumferential or sub-circumferential soft tissue wounds of the lower leg with deep tissue exposure. PMID- 23807089 TI - Feasibility of real-time selection of frequency tables in an acoustic simulation of a cochlear implant. AB - OBJECTIVES: Perception of spectrally degraded speech is particularly difficult when the signal is also distorted along the frequency axis. This might be particularly important for post-lingually deafened recipients of cochlear implants (CIs), who must adapt to a signal where there may be a mismatch between the frequencies of an input signal and the characteristic frequencies of the neurons stimulated by the CI. However, there is a lack of tools that can be used to identify whether an individual has adapted fully to a mismatch in the frequency-to-place relationship and if so, to find a frequency table that ameliorates any negative effects of an unadapted mismatch. The goal of the proposed investigation is to test the feasibility of whether real-time selection of frequency tables can be used to identify cases in which listeners have not fully adapted to a frequency mismatch. The assumption underlying this approach is that listeners who have not adapted to a frequency mismatch will select a frequency table that minimizes any such mismatches, even at the expense of reducing the information provided by this frequency table. DESIGN: Thirty-four normal-hearing adults listened to a noise-vocoded acoustic simulation of a CI and adjusted the frequency table in real time until they obtained a frequency table that sounded "most intelligible" to them. The use of an acoustic simulation was essential to this study because it allowed the authors to explicitly control the degree of frequency mismatch present in the simulation. None of the listeners had any previous experience with vocoded speech, in order to test the hypothesis that the real-time selection procedure could be used to identify cases in which a listener has not adapted to a frequency mismatch. After obtaining a self-selected table, the authors measured consonant nucleus consonant word-recognition scores with that self-selected table and two other frequency tables: a "frequency matched" table that matched the analysis filters with the noisebands of the noise vocoder simulation, and a "right information" table that is similar to that used in most CI speech processors, but in this simulation results in a frequency shift equivalent to 6.5 mm of cochlear space. RESULTS: Listeners tended to select a table that was very close to, but shifted slightly lower in frequency from the frequency-matched table. The real-time selection process took on average 2 to 3 min for each trial, and the between-trial variability was comparable with that previously observed with closely related procedures. The word-recognition scores with the self-selected table were clearly higher than with the right-information table and slightly higher than with the frequency-matched table. CONCLUSIONS: Real-time self-selection of frequency tables may be a viable tool for identifying listeners who have not adapted to a mismatch in the frequency-to-place relationship, and to find a frequency table that is more appropriate for them. Moreover, the small but significant improvements in word-recognition ability observed with the self-selected table suggest that these listeners based their selections on intelligibility rather than some other factor. The within-subject variability in the real-time selection procedure was comparable with that of a genetic algorithm, and the speed of the real-time procedure appeared to be faster than either a genetic algorithm or a simplex procedure. PMID- 23807088 TI - Aged skeletal muscle retains the ability to fully regenerate functional architecture. AB - While the general understanding of muscle regenerative capacity is that it declines with increasing age due to impairments in the number of muscle progenitor cells and interaction with their niche, studies vary in their model of choice, indices of myogenic repair, muscle of interest and duration of studies. We focused on the net outcome of regeneration, functional architecture, compared across three models of acute muscle injury to test the hypothesis that satellite cells maintain their capacity for effective myogenic regeneration with age. Muscle regeneration in extensor digitorum longus muscle (EDL) of young (3 mo old), old (22 mo-old) and senescent female mice (28 mo-old) was evaluated for architectural features, fiber number and central nucleation, weight, collagen and fat deposition. The 3 injury paradigms were: a myotoxin (notexin) which leaves the blood vessels and nerves intact, freezing (FI) that damages local muscle, nerve and blood vessels and denervation-devascularization (DD) which dissociates the nerves and blood vessels from the whole muscle. Histological analyses revealed successful architectural regeneration following notexin injury with negligible fibrosis and fully restored function, regardless of age. In comparison, the regenerative response to injuries that damaged the neurovascular supply (FI and DD) was less effective, but similar across the ages. The focus on net regenerative outcome demonstrated that old and senescent muscle has a robust capacity to regenerate functional architecture. PMID- 23807090 TI - Molecular heterogeneity of large-conductance calcium-activated potassium channels in canine intracardiac ganglia. AB - Large conductance calcium-activated potassium (BK) channels are widely expressed in the nervous system. We have recently shown that principal neurons from canine intracardiac ganglia (ICG) express a paxilline- and TEA-sensitive BK current, which increases neuronal excitability. In the present work, we further explore the molecular constituents of the BK current in canine ICG. We found that the beta1 and beta4 regulatory subunits are expressed in ICG. Single channel voltage dependence at different calcium concentrations suggested that association of the BKalpha with a particular beta subunit was not enough to explain the channel activity in this tissue. Indeed, we detected the presence of several splice variants of the BKalpha subunit. In conclusion, BK channels in canine ICG may result from the arrangement of different BKalpha splice variants, plus accessory beta subunits. The particular combinations expressed in canine IC neurons likely rule the excitatory role of BK current in this tissue. PMID- 23807091 TI - Cholesterol sensitivity of KIR2.1 depends on functional inter-links between the N and C termini. AB - In recent years, cholesterol has been emerging as a major regulator of ion channel function. We have previously shown that cholesterol suppresses Kir2 channels, a subfamily of constitutively active strongly rectifying K (+) channels. Furthermore, our earlier studies have shown that cholesterol sensitivity of Kir2 channels depends on a group of residues that form a belt-like structure around the cytosolic pore of the channel in proximity to the transmembrane domain. In this study, we focus on the contributions of different structural domains of Kir2 channels in the regulation of their cholesterol sensitivity. Focusing on the mildest mutation in the sensitivity belt, L222I, we show that the sensitivity of the channel to cholesterol can be restored by crosstalk between three distinct cytosolic regions: the C-terminal CD loop, the EF and GA loops of the C-terminus, and the betaA sheet of the N-terminus. Thus, in addition to the importance of residues that affect the cytosolic G-loop gate in the sensitivity of Kir2 channels to cholesterol, our data suggest an important role to the interactions at the interface between the channel's N- and C- termini that couple the intracellular domains of its four subunits during gating. PMID- 23807093 TI - Candy Wrapper for the Earth's inner core. AB - Recent global expansion of seismic data motivated a number of seismological studies of the Earth's inner core that proposed the existence of increasingly complex structure and anisotropy. In the meantime, new hypotheses of dynamic mechanisms have been put forward to interpret seismological results. Here, the nature of hemispherical dichotomy and anisotropy is re-investigated by bridging the observations of PKP(bc-df) differential travel-times with the iron bcc/hcp elastic properties computed from first-principles methods.The Candy Wrapper velocity model introduced here accounts for a dynamic picture of the inner core (i.e., the eastward drift of material), where different iron crystal shapes can be stabilized at the two hemispheres. We show that seismological data are best explained by a rather complicated, mosaic-like, structure of the inner core, where well-separated patches of different iron crystals compose the anisotropic western hemispherical region, and a conglomerate of almost indistinguishable iron phases builds-up the weakly anisotropic eastern side. PMID- 23807092 TI - Acid sensitive background potassium channels K2P3.1 and K2P9.1 undergo rapid dynamin-dependent endocytosis. AB - Acid-sensitive, two-pore domain potassium channels, K(2P)3.1 and K(2P)9.1, are implicated in cardiac and nervous tissue responses to hormones, neurotransmitters and drugs. K(2P)3.1 and K(2P)9.1 leak potassium from the cell at rest and directly impact membrane potential. Hence altering channel number on the cell surface drives changes in cellular electrical properties. The rate of K(2P)3.1 and K(2P)9.1 delivery to and recovery from the plasma membrane determines both channel number at the cell surface and potassium leak from cells. This study examines the endocytosis of K(2P)3.1 and K(2P)9.1. Plasma membrane biotinylation was used to follow the fate of internalized GFP-tagged rat K(2P)3.1 and K(2P)9.1 transiently expressed in HeLa cells. Confocal fluorescence images were analyzed using Imaris software, which revealed that both channels are endocytosed by a dynamin-dependent mechanism and over the course of 60 min, move progressively toward the nucleus. Endogenous endocytosis of human K(2P)3.1 and K(2P)9.1 was examined in the lung carcinoma cell line, A549. Endogenous channels are endocytosed over a similar time-scale to the channels expressed transiently in HeLa cells. These findings both validate the use of recombinant systems and identify an endogenous model system in which K(2P)3.1 and K(2P)9.1 trafficking can be further studied. PMID- 23807094 TI - Is it possible to identify exacerbations of mild to moderate COPD that do not require antibiotic treatment? AB - BACKGROUND: Anthonisen criteria are widely used to guide the use of antibiotics in exacerbations of COPD. We evaluated the best predictors of outcomes in exacerbations of mild to moderate COPD not treated with antibiotics. METHODS: We used data from 152 patients of the placebo arm of a randomized trial of amoxicillin/clavulanate for exacerbations of mild to moderate COPD. Clinical response in relation to Anthonisen criteria and point-of-care serum C-reactive protein (CRP) tests (cutoff, 40 mg/L) was assessed with multivariate logistic regression analysis. RESULTS: Clinical failure without antibiotics was 19.9% compared with 9.5% with amoxicillin/clavulanate (P = .022). The only factors significantly associated with an increased risk of failure without antibiotics were the increase in sputum purulence (OR, 6.1; 95% CI, 1.5-25.0; P = .005) and a CRP concentration >= 40 mg/L (OR, 13.4; 95% CI, 4.6-38.8; P < .001). When both factors were present, the probability of failure without antibiotics was 63.7%. The Anthonisen criteria showed an area under the curve of 0.708 (95% CI, 0.616 0.801) for predicting clinical outcome. With the addition of CRP level, the area under the curve rose significantly to 0.842 (95% CI, 0.76-0.924; P < .001). CONCLUSIONS: Among the Anthonisen criteria, only an increase in sputum purulence is a significant predictor of failure without antibiotics. The use of a point-of care CRP test significantly increases the predictive accuracy of failure. Both of these easy-to-obtain factors may help clinicians to identify patients with exacerbated mild to moderate COPD who can be safely treated without antibiotics in an ambulatory setting. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00495586; URL: www.clinicaltrials.gov. PMID- 23807095 TI - Quality in-training evaluation reports--does feedback drive faculty performance? AB - PURPOSE: Clinical faculty often complete in-training evaluation reports (ITERs) poorly. Faculty development (FD) strategies should address this problem. An FD workshop was shown to improve ITER quality, but few physicians attend traditional FD workshops. To reach more faculty, the authors developed an "at-home" FD program offering participants various types of feedback on their ITER quality based on the workshop content. Program impact is evaluated here. METHOD: Ninety eight participants from four medical schools, all clinical supervisors, were recruited in 2009-2010; 37 participants completed the study. These were randomized into five groups: a control group and four other groups with different feedback conditions. ITER quality was assessed by two raters using a validated tool: the completed clinical evaluation report rating (CCERR). Participants were given feedback on their ITER quality based on group assignment. Six months later, participants submitted new ITERs. These ITERs were assessed using the CCERR, and feedback was sent to participants on the basis of their group assignment. This process was repeated two more times, ending in 2012. RESULTS: CCERR scores from the participants in all feedback groups were collapsed (n=27) and compared with scores from the control group (n=10). Mean CCERR scores significantly increased over time for the feedback group but not the control group. CONCLUSIONS: The results suggest that faculty are able to improve ITER quality following a minimal "at-home" FD intervention. This also adds to the growing literature that has found success with improving the quality of trainee assessments following rater training. PMID- 23807096 TI - From Flexner to competencies: reflections on a decade and the journey ahead. AB - This article is a sequel to one published in 2002 only a few years after the initiation of the shift to competency-based medical education (CBME). The authors reflect on the major forces that have influenced the movement and tipped the balance toward widespread adoption of CBME in the United States, primarily in graduate medical education. These forces include regulatory bodies, international counterparts, and the general public. The authors highlight the most important lessons learned over the decade. These include (1) the need for standardization of language to develop a shared vision of the path ahead, (2) the power of direct observation in assessment, (3) the challenge of developing meaningful measures of performance, (4) desired outcomes as the starting point for curriculum development, (5) dependence on reflection in the development of expertise, (6) the need for exploiting the role of learners in their learning, and (7) competent clinical systems as the required learning environment for producing competent physicians.The authors speculate on why this most recent attempt to shift to CBME differs from previous aborted attempts. They conclude by explaining how the recent lessons learned inform the vision of what successful implementation of CBME would look like, and discussing the importance of milestones, entrustable professional activities, and an integrated, rather than a reductionist, approach to assessment of competence. The fundamental question at each step along the way in implementing CBME should be "How do we improve medical education to provide better care for patients?" PMID- 23807097 TI - How prevalent are potentially illegal questions during residency interviews? AB - PURPOSE: To study the prevalence of potentially illegal questions in residency interviews and to identify the impact of such questions on applicants' decisions to rank programs. METHOD: Using an Electronic Residency Application Service supported survey, the authors surveyed all applicants from U.S. medical schools to residency programs in five specialties (internal medicine, general surgery, orthopedic surgery, obstetrics-gynecology [OB/GYN], and emergency medicine) in 2006-2007. The survey included questions about the frequency with which respondents were asked about gender, age, marital status, couples matching, current children, intent to have children, ethnicity, religion, or sexual orientation, and the effect that such questions had on their decision to rank programs. RESULTS: Of 11,983 eligible applicants, 7,028 (58.6%) completed a survey. Of respondents, 4,557 (64.8%) reported that they were asked at least one potentially illegal question. Questions related to marital status (3,816; 54.3%) and whether the applicant currently had children (1,923; 27.4%) were most common. Regardless of specialty, women were more likely than men to receive questions about their gender, marital status, and family planning (P < .001). Among those respondents who indicated their specialty, those in OB/GYN (162/756; 21.4%) and general surgery (214/876; 24.4%) reported the highest prevalence of potentially illegal questions about gender. Being asked a potentially illegal question negatively affected how respondents ranked that program. CONCLUSIONS: Many residency applicants were asked potentially illegal questions. Developing a formal interview code of conduct targeting both applicants and programs may be necessary to address the potential flaws in the resident selection process. PMID- 23807098 TI - From rankings to mission. AB - Since the 1980s, school ranking systems have been a topic of discussion among leaders of higher education. Various ranking systems are based on inadequate data that fail to illustrate the complex nature and special contributions of the institutions they purport to rank, including U.S. medical schools, each of which contributes uniquely to meeting national health care needs. A study by Tancredi and colleagues in this issue of Academic Medicine illustrates the limitations of rankings specific to primary care training programs. This commentary discusses, first, how each school's mission and strengths, as well as the impact it has on the community it serves, are distinct, and, second, how these schools, which are each unique, are poorly represented by overly subjective ranking methodologies. Because academic leaders need data that are more objective to guide institutional development, the Association of American Medical Colleges (AAMC) has been developing tools to provide valid data that are applicable to each medical school. Specifically, the AAMC's Medical School Admissions Requirements and its Missions Management Tool each provide a comprehensive assessment of medical schools that leaders are using to drive institutional capacity building. This commentary affirms the importance of mission while challenging the leaders of medical schools, teaching hospitals, and universities to use reliable data to continually improve the quality of their training programs to improve the health of all. PMID- 23807099 TI - Teaching empathy to medical students: an updated, systematic review. AB - PURPOSE: Some research shows that empathy declines during medical school. The authors conducted an updated, systematic review of the literature on empathy enhancing educational interventions in undergraduate medical education. METHOD: The authors searched PubMed, EMBASE, PsycINFO, CINAHL, Scopus, and Web of Science (January 1, 2004 through March 19, 2012) using key words related to undergraduate medical education and empathy. They independently selected and reviewed all English-language articles that described an educational intervention designed to promote empathy in medical students, assessing the quality of the quantitative studies using the Medical Education Research Study Quality Instrument (MERSQI). RESULTS: The authors identified and reviewed the full texts of 18 articles (15 quantitative and 3 qualitative studies). Included interventions used one or more of the following-patient narrative and creative arts (n=7), writing (n=3), drama (n=1), communication skills training (n=4), problem-based learning (n=1), interprofessional skills training (n=1), patient interviews (n=4), experiential learning (n=2), and empathy-focused training (n=1). Fifteen articles reported significant increases in empathy. Mean effect size was 0.23. Mean MERSQI score was 10.13 (range 6.5-14). CONCLUSIONS: These findings suggest that educational interventions can be effective in maintaining and enhancing empathy in undergraduate medical students. In addition, they highlight the need for multicenter, randomized controlled trials, reporting long-term data to evaluate the longevity of intervention effects. Defining empathy remains problematic, and the authors call for conceptual clarity to aid future research. PMID- 23807100 TI - Expanding physician education in health care fraud and program integrity. AB - Program integrity (PI) spans the entire spectrum of improper payments from fraud to abuse, errors, and waste in the health care system. Few physicians will perpetrate fraud or abuse during their careers, but nearly all will contribute to the remaining spectrum of improper payments, making preventive education in this area vital. Despite the enormous impact that PI issues have on government sponsored and private insurance programs, physicians receive little formal education in this area. Physicians' lack of awareness of PI issues not only makes them more likely to submit inappropriate claims, generate orders that other providers and suppliers will use to submit inappropriate claims, and document improperly in the medical record but also more likely to become victims of fraud schemes themselves.In this article, the authors provide an overview of the current state of PI issues in general, and fraud in particular, as well as a description of the state of formal education for practicing physicians, residents, and fellows. Building on the lessons from pilot programs conducted by the Centers for Medicare and Medicaid Services and partner organizations, the authors then propose a model PI education curriculum to be implemented nationwide for physicians at all levels. They recommend that various stakeholder organizations take part in the development and implementation process to ensure that all perspectives are included. Educating physicians is an essential step in establishing a broader culture of compliance and improved integrity in the health care system, extending beyond Medicare and Medicaid. PMID- 23807101 TI - Summer in the country: changes in medical students' perceptions following an innovative rural community experience. AB - PURPOSE: The University of Missouri School of Medicine developed the Summer Community Program through which rising second-year medical students work alongside rural, community-based physician preceptors. This program is part of a comprehensive, longitudinal pipeline designed to increase student interest in rural practice. The authors describe the Summer Community Program, explain changes in students' perceptions of rural practice and rural lifestyle post program, and report participants' specialty choices and first practice locations. METHOD: The authors analyzed 229 participant responses (1996-2010) to pre- and postexperience questionnaires focused on perceptions of rural practice and lifestyle. The authors calculated the likelihood of participants matching into primary care compared with nonparticipants and analyzed participants' first practice locations. RESULTS: After the experience, participants' perceptions toward rural practice and lifestyle changed favorably, and 72% (n=208) reported more interest in rural practice. Compared with nonparticipants, summer participants were more likely to enter a primary care residency (relative risk [RR]=1.31; 95% confidence interval [CI]: 1.12-1.50) and twice as likely to choose specifically family medicine (RR=2.21; 95% CI: 1.68-2.88). Forty-six percent (n=78) of participants chose rural locations for their first practices. CONCLUSIONS: This program has positively influenced students' perceptions of rural practice and lifestyle and increased their interest in rural practice. Participants entered primary care and family medicine residencies at higher rates than nonparticipants, and nearly half started their medical practices in rural locations. Replicating this program may increase interest in rural medicine and address rural physician workforce needs. PMID- 23807102 TI - Sustaining quality improvement and patient safety training in graduate medical education: lessons from social theory. AB - PURPOSE: Despite an official mandate to incorporate formal quality improvement (QI) and patient safety (PS) training into graduate medical education, many QI/PS curricular efforts face implementation challenges and are not sustained. Educators are increasingly turning to sociocultural theories to address issues such as curricular uptake in medical education. The authors conducted a case study using Bourdieu's concepts of "field" and "habitus" to identify theoretically derived strategies that can promote sustained implementation of QI/PS curricula. METHOD: From October 2010 through May 2011, the authors conducted semistructured interviews with principal authors of studies included in a systematic review of QI/PS curricula and with key informants (identified by study participants) who did not publish on their QI/PS curricular efforts. The authors purposively sampled to theoretical saturation and analyzed data concurrently with iterative data gathering within Bourdieu's theoretical framework. RESULTS: The study included 16 participants representing six specialties in the United States and Canada. Data analysis revealed that academic physicians belong to, and compete for legitimate forms of capital within, two separate but related fields associated with QI/PScurricular implementation: the "academic field" and the "health care delivery field." Respondents used specific strategies toexploit and/or redefine the prevailingforms of legitimate capital in each field to encourage changes inacademic physicians' habitus that would legitimizeQI/PS. CONCLUSIONS: Situating study findings in a sociocultural theory enables articulation of concrete strategies that can legitimize QI/PS in the academic and health care delivery fields. These strategies can promote sustained QI/PS curricula in graduate medical education. PMID- 23807103 TI - Short-term stability and spread of the U.S. News & World Report primary care medical school rankings. AB - PURPOSE: The annual U.S. News & World Report (USN&WR) Primary Care Medical School (PCMS) ranking attracts considerable attention, but its measurement properties have not been published. The authors examined the short-term stability of the PCMS ranking and the PCMS score from which it derives, along with the short-term spread of schools' rankings. METHOD: The authors employed published data and methods to reconstruct the 2009-2012 PCMS scores and rankings. They used mixed effects models to assess the within-school, between-year reliability (short-term stability) of the PCMS score and ranking, yielding intraclass correlation coefficients (ICCs). They defined short-term spread as the median within-school range in ranking across the four-year study period. RESULTS: Reconstructed PCMS scores correlated highly with published scores all four years (Pearson correlations>=98.9%). Most schools' mean annual PCMS scores were tightly clustered near the center of the score distribution. ICCs for the PCMS score and ranking were, respectively, 94% and 90%. The median difference between the best and worst ranking over the study period was 4 for the 18 schools with an average annual ranking of 1 to 20, and 17 for the other 89 schools (P<.001, Kruskal Wallis test). CONCLUSIONS: The short-term stability of the USN&WR PCMS score and ranking were reasonably good. However, the short-term spread in PCMS rankings was large, particularly among schools with mean annual rankings below the top 20. The variability is greater than could be plausibly attributed to actual changes in training quality. These findings raise questions regarding the ranking's validity and usefulness. PMID- 23807105 TI - Satisfaction, motivation, and future of community preceptors: what are the current trends? AB - PURPOSE: To measure overall satisfaction of community-based preceptors, their anticipated likelihood of continuing to teach, professional satisfaction, influence of having students, motivation for teaching, satisfaction with professional practice, and satisfaction with and value of incentives, and to compare results with those of a similar 2005 statewide survey. METHOD: In 2011, the authors distributed a 25-item survey to all 2,359 community-based primary care preceptors (physicians, pharmacists, advanced practice nurses, physician assistants) served by the North Carolina Area Health Education Centers system's Offices of Regional Primary Care Education. The survey targeted the same items and pool of eligible respondents as did the North Carolina Area Health Education Center 2005 Preceptor Survey. RESULTS: Of 2,359 preceptors contacted, 1,278 (54.2%) completed questionnaires. The data from 2011 did not differ significantly from the 2005 data. In 2011, respondents were satisfied with precepting (91.7%), anticipated continuing to precept for the next five years (88.7%), and were satisfied overall with their professional life (93.7%). Intrinsic reasons (e.g., enjoyment of teaching) remained an important motivation for teaching students. Physicians reported significantly lower overall satisfaction with extrinsic incentives (e.g., monetary compensation) and felt more negativity about the influence of students on their practices. CONCLUSIONS: This study found that preceptors continue to be satisfied with teaching students. Intrinsic reasons remain an important motivation to precept, but monetary compensation may have increasing importance. Physicians responded more negatively than other health provider groups to several questions, suggesting that their needs might be better met by redesigned teaching models. PMID- 23807104 TI - Mastery learning for health professionals using technology-enhanced simulation: a systematic review and meta-analysis. AB - PURPOSE: Competency-based education requires individualization of instruction. Mastery learning, an instructional approach requiring learners to achieve a defined proficiency before proceeding to the next instructional objective, offers one approach to individualization. The authors sought to summarize the quantitative outcomes of mastery learning simulation-based medical education (SBME) in comparison with no intervention and nonmastery instruction, and to determine what features of mastery SBME make it effective. METHOD: The authors searched MEDLINE, EMBASE, CINAHL, ERIC, PsycINFO, Scopus, key journals, and previous review bibliographies through May 2011. They included original research in any language evaluating mastery SBME, in comparison with any intervention or no intervention, for practicing and student physicians, nurses, and other health professionals. Working in duplicate, they abstracted information on trainees, instructional design (interactivity, feedback, repetitions, and learning time), study design, and outcomes. RESULTS: They identified 82 studies evaluating mastery SBME. In comparison with no intervention, mastery SBME was associated with large effects on skills (41 studies; effect size [ES] 1.29 [95% confidence interval, 1.08-1.50]) and moderate effects on patient outcomes (11 studies; ES 0.73 [95% CI, 0.36-1.10]). In comparison with nonmastery SBME instruction, mastery learning was associated with large benefit in skills (3 studies; effect size 1.17 [95% CI, 0.29-2.05]) but required more time. Pretraining and additional practice improved outcomes but, again, took longer. Studies exploring enhanced feedback and self-regulated learning in the mastery model showed mixed results. CONCLUSIONS: Limited evidence suggests that mastery learning SBME is superior to nonmastery instruction but takes more time. PMID- 23807106 TI - Playing with curricular milestones in the educational sandbox: Q-sort results from an internal medicine educational collaborative. AB - PURPOSE: In competency-based medical education, the focus of assessment is on learner demonstration of predefined outcomes or competencies. One strategy being used in internal medicine (IM) is applying curricular milestones to assessment and reporting milestones to competence determination. The authors report a practical method for identifying sets of curricular milestones for assessment of a landmark, or a point where a resident can be entrusted with increased responsibility. METHOD: Thirteen IM residency programs joined in an educational collaborative to apply curricular milestones to training. The authors developed a game using Q-sort methodology to identify high-priority milestones for the landmark "Ready for indirect supervision in essential ambulatory care" (EsAMB). During May to December 2010, the programs'ambulatory faculty participated in the Q-sort game to prioritize 22 milestones for EsAMB. The authors analyzed the data to identify the top 8 milestones. RESULTS: In total, 149 faculty units (1-4 faculty each) participated. There was strong agreement on the top eight milestones; six had more than 92% agreement across programs, and five had 75% agreement across all faculty units. During the Q-sort game, faculty engaged in dynamic discussion about milestones and expressed interest in applying the game to other milestones and educational settings. CONCLUSIONS: The Q-sort game enabled diverse programs to prioritize curricular milestones with interprogram and interparticipant consistency. A Q-sort exercise is an engaging and playful way to address milestones in medical education and may provide a practical first step toward using milestones in the real-world educational setting. PMID- 23807107 TI - Introducing medical students to careers in medical education: the student track at an annual medical education conference. AB - Few avenues exist to familiarize medical students with careers as clinician educators, and the clinician-educator career pathway has not been well defined. In this article, the authors describe how they integrated a career-oriented student track into the 2011 Northeast Group on Educational Affairs (NEGEA) annual retreat to introduce students to careers in medical education. Annual education conferences are principal sources of educational scholarship, networking, collaboration, and information sharing; as such, they represent attractive venues for early exposure to the culture of medical education. The authors' goal in creating the NEGEA conference student track was to excite students about careers in medical education by providing them with an array of opportunities for active involvement in both student-specific and general conference activities.The authors draw from their experience to provide a guide for recruiting student participants to career-building student tracks. They also offer a guide for developing future student tracks, based on their experience and grounded in social cognitive career theory. Although their focus is on medical education, they believe these guides will be useful for educators planning a conference based student track in any field. PMID- 23807108 TI - Medical education and cognitive continuum theory: an alternative perspective on medical problem solving and clinical reasoning. AB - Recently, human reasoning, problem solving, and decision making have been viewed as products of two separate systems: "System 1," the unconscious, intuitive, or nonanalytic system, and "System 2," the conscious, analytic, or reflective system. This view has penetrated the medical education literature, yet the idea of two independent dichotomous cognitive systems is not entirely without problems.This article outlines the difficulties of this "two-system view" and presents an alternative, developed by K.R. Hammond and colleagues, called cognitive continuum theory (CCT). CCT is featured by three key assumptions. First, human reasoning, problem solving, and decision making can be arranged on a cognitive continuum, with pure intuition at one end, pure analysis at the other, and a large middle ground called "quasirationality." Second, the nature and requirements of the cognitive task, as perceived by the person performing the task, determine to a large extent whether a task will be approached more intuitively or more analytically. Third, for optimal task performance, this approach needs to match the cognitive properties and requirements of the task. Finally, the author makes a case that CCT is better able than a two-system view to describe medical problem solving and clinical reasoning and that it provides clear clues for how to organize training in clinical reasoning. PMID- 23807109 TI - Toward a common taxonomy of competency domains for the health professions and competencies for physicians. AB - Although health professions worldwide are shifting to competency-based education, no common taxonomy for domains of competence and specific competencies currently exists. In this article, the authors describe their work to (1) identify domains of competence that could accommodate any health care profession and (2) extract a common set of competencies for physicians from existing health professions' competency frameworks that would be robust enough to provide a single, relevant infrastructure for curricular resources in the Association of American Medical Colleges' (AAMC's) MedEdPORTAL and Curriculum Inventory and Reports (CIR) sites. The authors used the Accreditation Council for Graduate Medical Education (ACGME)/American Board of Medical Specialties six domains of competence and 36 competencies delineated by the ACGME as their foundational reference list. They added two domains described by other groups after the original six domains were introduced: Interprofessional Collaboration (4 competencies) and Personal and Professional Development (8 competencies). They compared the expanded reference list (48 competencies within eight domains) with 153 competency lists from across the medical education continuum, physician specialties and subspecialties, countries, and health care professions. Comparison analysis led them to add 13 "new" competencies and to conflate 6 competencies into 3 to eliminate redundancy. The AAMC will use the resulting "Reference List of General Physician Competencies" (58 competencies in eight domains) to categorize resources for MedEdPORTAL and CIR. The authors hope that researchers and educators within medicine and other health professions will consider using this reference list when applicable to move toward a common taxonomy of competencies. PMID- 23807110 TI - Rural track training based at a small regional campus: equivalency of training, residency choice, and practice location of graduates. AB - PURPOSE: Ten years of data for the rural-based Trover Campus (ULTC) were compared with data for the main campus of the University of Louisville School of Medicine to determine whether educational outcomes were equivalent and whether this method of optimizing the affinity model was effective in placing graduates in rural practice. METHOD: Demographic data and academic measures were compared for 1,391 graduates (60 from ULTC) for 2001-2010. A noninferiority model was developed to compare clinical experiences for each campus cohort. Residency match lists were examined for specialty choice. Graduates from 2001 to 2006 were matched to the American Medical Association Masterfile to determine practice site. RESULTS: ULTC students scored lower on United States Medical Licensing Examination (USMLE) Step 1 and Step 2 Clinical Skills (CK) but tended to close this gap after clinical training when compared with Louisville graduates. The noninferiority model indicates that ULTC students' scores were noninferior to Louisville students' on adjusted shelf exams for obstetrics-gynecology, pediatrics, and surgery, and Step 2 CK (P<.001). ULTC graduates were 4.5 times more likely to choose family medicine (P<.001) and over 6 times more likely to choose a nonmetropolitan area as a practice site (P=.001). CONCLUSIONS: These data support the value of a small regional rural clinical campus in optimizing the affinity model to place rural students into rural practice. The ULTC students showed equivalent adjusted test scores and slightly narrowed the gap in unadjusted USMLE scores compared with the main campus students. PMID- 23807111 TI - Setting quality and safety priorities in a target-rich environment: an academic medical center's challenge. AB - Hospitals are continually challenged to provide safer and higher-quality patient care despite resource constraints. With an ever-increasing range of quality and safety targets at the national, state, and local levels, prioritization is crucial in effective institutional quality goal setting and resource allocation.Organizational goal-setting theory is a performance improvement methodology with strong results across many industries. The authors describe a structured goal-setting process they have established at Massachusetts General Hospital for setting annual institutional quality and safety goals. Begun in 2008, this process has been conducted on an annual basis. Quality and safety data are gathered from many sources, both internal and external to the hospital. These data are collated and classified, and multiple approaches are used to identify the most pressing quality issues facing the institution. The conclusions are subject to stringent internal review, and then the top quality goals of the institution are chosen. Specific tactical initiatives and executive owners are assigned to each goal, and metrics are selected to track performance. A reporting tool based on these tactics and metrics is used to deliver progress updates to senior hospital leadership.The hospital has experienced excellent results and strong organizational buy-in using this effective, low-cost, and replicable goal setting process. It has led to improvements in structural, process, and outcomes aspects of quality. PMID- 23807112 TI - How do medical students navigate the interplay of explicit curricula, implicit curricula, and extracurricula to learn curricular objectives? AB - PURPOSE: Current focus in medical education on competencies and curricular objectives draws attention to boundaries rather than the openness inherent in the learning process. This qualitative study explored the tension between boundedness (mandated curricular objectives) and openness (variability in learning experience as students traverse the explicit, implicit, and extracurriculum) in the curriculum. METHOD: Following the revision and implementation of 10 curricular objectives for Columbia University College of Physicians and Surgeons, the authors interviewed 18 fourth-year medical students in spring 2011. For each objective, students indicated the relative influence of the explicit curriculum, implicit curriculum, and extracurriculum on their learning. Students were asked to think aloud and assign points as they made these judgments. Quantitative and qualitative data were analyzed to understand students' perceptions of learning across curricula and for each curricular objective. RESULTS: There was marked variability in students' learning experience. For two objectives, students perceived that learning occurred mainly in the explicit curriculum and consumed a disproportionate amount of study time. For two other objectives, students perceived that learning occurred mainly in the extracurriculum because opportunities to learn these objectives in the implicit and explicit curricula were sparse. For six objectives, students perceived that learning occurred mostly in the implicit curriculum, often through "watching" or interacting with peers. CONCLUSIONS: The findings can inform discussions about how to balance the boundedness of curricular mandates with the inherent openness of students' learning experiences. PMID- 23807113 TI - Discovery of novel tetrahydro-pyrazolo [4,3-c] pyridines for the treatment of neuropathic pain: synthesis and neuropharmacology. AB - We disclose the discovery of a novel series of tetrahydropyrido-pyrazoles that are potent inhibitors of tumour necrosis factor-alpha (TNF-alpha), nitric oxide and cannabinoid receptor subtype 1 (CB1). We report herein the synthesis and neuropharmacological screening results of the titled compounds in two acute pain and two neuropathic pain models in rodents. Particularly the analogue N-(4 bromophenyl)-3-tert-butyl-5-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-1 carboxamide (8a) exhibited pronounced acute antinociceptive efficacy, also being effective in chronic constriction injury (ED50 = 23.8 mg/kg) and partial sciatic nerve injury (ED50 = 29.0 mg/kg) models with CB1 receptor activity (IC50 = 49.6 nM) and inhibitory effect on TNF-alpha (86.4% inhibition at 100 mg/kg). These results suggest the importance of the development of this lead as multi-targeted treatment strategy for neuropathic pain. PMID- 23807114 TI - Exploring 4-substituted-2-thiazolylhydrazones from 2-, 3-, and 4-acetylpyridine as selective and reversible hMAO-B inhibitors. AB - A series of 4-substituted-2-thiazolylhydrazone derivatives have been synthesized and tested in vitro for their human monoamine oxidase (hMAO) A and B inhibitory activity. Our findings confirmed that the substitution at C4 of the thiazole ring was important to obtain highly potent and selective hMAO-B inhibitors with IC50 values in the nanomolar range. Moreover, these derivatives were endowed with a reversible mechanism of enzyme inhibition. Molecular modelling studies were performed to rationalize the recognition of all inhibitors with respect to hMAO-A and -B isoforms. PMID- 23807115 TI - First principles derived, transferable force fields for CO2 adsorption in Na exchanged cationic zeolites. AB - The development of accurate force fields is vital for predicting adsorption in porous materials. Previously, we introduced a first principles-based transferable force field for CO2 adsorption in siliceous zeolites (Fang et al., J. Phys. Chem. C, 2012, 116, 10692). In this study, we extend our approach to CO2 adsorption in cationic zeolites which possess more complex structures. Na-exchanged zeolites are chosen for demonstrating the approach. These methods account for several structural complexities including Al distribution, cation positions and cation mobility, all of which are important for predicting adsorption. The simulation results are validated with high-resolution experimental measurements of isotherms and microcalorimetric heats of adsorption on well-characterized materials. The choice of first-principles method has a significant influence on the ability of force fields to accurately describe CO2-zeolite interactions. The PBE-D2 derived force field, which performed well for CO2 adsorption in siliceous zeolites, does not do so for Na-exchanged zeolites; the PBE-D2 method overestimates CO2 adsorption energies on multi-cation sites that are common in cationic zeolites with low Si/Al ratios. In contrast, a force field derived from the DFT/CC method performed well. Agreement was obtained between simulation and experiment not only for LTA-4A on which the force field fitting is based, but for other two common adsorbents, NaX and NaY. PMID- 23807117 TI - Developing a public health policy-research nexus: an evaluation of Nurse Practitioner models in aged care. AB - A frustration often expressed by researchers and policy-makers in public health is an apparent mismatch between respective priorities and expectations for research. Academics bemoan an oversimplification of their work, a reticence for independent critique and the constant pressure to pursue evaluation funding. Meanwhile, policy-makers look for research reports written in plain language with clear application, which are attuned to current policy settings and produced quickly. In a context where there are calls in western nations for evidence based policy with stronger links to academic research, such a mismatch can present significant challenges to policy program evaluation. The purpose of this paper is to present one attempt to overcome these challenges. Specifically, the paper describes the development of a conceptual framework for a large-scale, multifaceted evaluation of an Australian Government health initiative to expand Nurse Practitioner models of practice in aged care service delivery. In doing so, the paper provides a brief review of key points for the facilitation of a strong research-policy nexus in public health evaluations, as well as describes how this particular evaluation embodies these key points. As such, the paper presents an evaluation approach which may be adopted and adapted by others undertaking public health policy program evaluations. PMID- 23807118 TI - Defining, illustrating and reflecting on logic analysis with an example from a professional development program. AB - Program designers and evaluators should make a point of testing the validity of a program's intervention theory before investing either in implementation or in any type of evaluation. In this context, logic analysis can be a particularly useful option, since it can be used to test the plausibility of a program's intervention theory using scientific knowledge. Professional development in public health is one field among several that would truly benefit from logic analysis, as it appears to be generally lacking in theorization and evaluation. This article presents the application of this analysis method to an innovative public health professional development program, the Health Promotion Laboratory. More specifically, this paper aims to (1) define the logic analysis approach and differentiate it from similar evaluative methods; (2) illustrate the application of this method by a concrete example (logic analysis of a professional development program); and (3) reflect on the requirements of each phase of logic analysis, as well as on the advantages and disadvantages of such an evaluation method. Using logic analysis to evaluate the Health Promotion Laboratory showed that, generally speaking, the program's intervention theory appeared to have been well designed. By testing and critically discussing logic analysis, this article also contributes to further improving and clarifying the method. PMID- 23807119 TI - Influence of human myasthenia gravis thymus on the differentiation of human cord blood stem cells in SCID mice. AB - The normal thymus contributes to T lymphocytes differentiation and induction of tolerance to self-antigens. Myasthenia gravis (MG) is characterized by abnormal thymic hyperplasia. To assess the potential influence of MG-thymus on the differentiation of T lymphocytes differentiation, we used the MG-thymus transplanted severe combined immunodeficiency (SCID) mice model to evaluate the human cord blood stem cells differentiation. Thymus fragments from MG patient and human cord blood stem cells were transplanted into SCID mice successively. SCID mice were observed to develop sustained human T lymphocytes and a functional anti tumor immune. The levels of various T cell subsets in SCID mice with MG-thymus were different from that of control group. Among that, the frequency of CD4(+)CD25(+) T cells was significant lower in SCID mice with MG-thymus. The deficiency of CD4(+)CD25(+) T cells seens to contribute to the pathogenesis of MG. PMID- 23807116 TI - Molecular pharmacology of store-operated CRAC channels. AB - Calcium influx through store-operated Ca(2+) release-activated Ca(2+) channels (CRAC channels) is a well-defined mechanism of generating cellular Ca(2+) elevations that regulates many functions including gene expression, exocytosis and cell proliferation. The identifications of the ER Ca(2+) sensing proteins, STIM1-2 and the CRAC channel proteins, Orai1-3, have led to improved understanding of the physiological roles and the activation mechanism of CRAC channels. Defects in CRAC channel function are associated with serious human diseases such as immunodeficiency and auto-immunity. In this review, we discuss several pharmacological modulators of CRAC channels, focusing specifically on the molecular mechanism of drug action and their utility in illuminating the mechanism of CRAC channel operation and their physiological roles in different cells. PMID- 23807120 TI - Vestibular-evoked myogenic potentials, clinical evaluation, and imaging findings in multiple sclerosis. AB - Vestibular-evoked myogenic potentials (VEMP), short-latency electromyographic responses elicited by acoustic stimuli, evaluate the function of vestibulocollic reflex and may give information about brainstem function. The aim of the present study is to evaluate the potential contribution of VEMP to the diagnosis of multiple sclerosis (MS). Fifty patients with MS and 30 healthy control subjects were included in this study. The frequency of VEMP p1-n1 and n2-p2 waves; mean p1, n1, n2, and p2 latency; and mean p1-n1 and n2-p2 amplitude were determined. The relation between clinical and imaging findings and VEMP parameters was evaluated. The p1-n1 and n2-p2 waves were more frequently absent in MS than in control subjects [p1-n1 wave absent: MS, 25 (25 %) ears; control, 6 (10 %) ears; P <= 0.02] [n2-p2 wave absent: MS, 44 (44 %) ears; control, 7 (12 %) ears; P <= 0.001]. The mean p1-n1 amplitude was lower in MS than in control subjects (MS, 19.1 +/- 7.2 MUV; control, 23.3 +/- 7.4 MUV; P <= 0.002). A total of 24/50 (48 %) MS patients had VEMP abnormalities (absent responses and/or prolonged latencies). VEMP abnormalities were more frequent in patients with than without vestibular symptoms (P <= 0.02) and with brainstem functional system score (FSS) >= 1 than FSS = 0 (P <= 0.02). In patients with MS, absence of p1-n1 wave was more frequent in patients with than without vestibular symptoms [absence of p1-n1 wave: vestibular symptoms, 9 (45 %) ears; no vestibular symptoms, 16 (20 %) ears; P <= 0.03] and patients with Expanded Disability Status Scale (EDSS) score >= 5.5 [absence of p1-n1 wave: EDSS >= 5.5, 7 (70 %) ears; EDSS <5.5, 18 (20 %) ears; P <= 0.001]. Abnormal VEMP may be noted in MS patients, especially those with vestibular symptoms and greater disability. The VEMP test may complement other studies for diagnosis and follow-up of patients with MS. PMID- 23807121 TI - Delay in presentation after acute ischemic stroke: the Careggi Hospital Stroke Registry. AB - Intravenous thrombolysis with recombinant tissue-type plasminogen activator is the approved treatment for acute ischemic stroke within 4.5 h from symptoms onset. Evidence suggests the earlier treatment was given, the greater the chance of a favorable outcome. We investigated if the delay in hospital presentation has been modified in the past 8 years. Acute ischemic strokes admitted to the Emergency Department of the Careggi Hospital, Florence from March 2004 to December 2012 were prospectively collected in the Careggi Hospital Stroke Registry. Proportion of patients presenting <= 2 h, 2-3.5, 3.5-6, and >6 h from symptom onset or with awakening stroke were compared. From March 2004 to December 2012, 3,856 patients with acute ischemic stroke arrived to the Careggi Emergency Department. During the period, 28.3 % of patients arrived <= 2 h from symptoms onset and 9.8 % between 2 and 3.5 h. The proportion of time-eligible patients is steady in the first years with a slight increase in 2011 and 2012. Early presentation is significantly associated with younger age, intracerebral hemorrhage, and stroke severity. In this study, about one-third of acute ischemic strokes arrived at the Emergency Department within the therapeutic time-window for intravenous thrombolysis. There is only a slight increase in early presentation through the period, mainly in the last 2 years. Additional efforts are required to impact deeply on the rates of time-eligible patients. PMID- 23807122 TI - Initial experiences of an enhanced recovery protocol in esophageal surgery. AB - BACKGROUND: A recent development in gastrointestinal surgery is the implementation of enhanced recovery after surgery (ERAS) programs. Evidence regarding the benefit of these programs in patients undergoing esophageal surgery is scarce. We investigated the feasibility and possible benefit of a perioperative ERAS program in patients undergoing esophagectomy for malignant disease. METHODS: The ERAS program was initiated in 2009. Patients who underwent esophagectomy and were treated according to the ERAS program were included. Items of ERAS included preoperative nutrition, early extubation, early removal of nasogastric tube, and early mobilization. Primary outcome parameters were hospital stay and the incidence of postoperative complications. Outcome parameters in the ERAS cohort were compared to a cohort of patients who underwent surgical resection in the year prior to the implementation of the ERAS protocol. A feasibility analysis was performed among a sample of ERAS patients to determine the number of achieved items per patient. RESULTS: Between 2008 and August 2010, 181 patients in our department underwent esophagectomy. Of these, 103 patients were included in the ERAS program (ERAS+ group) and were compared to 78 patients who had undergone an esophagectomy in 2008 (ERAS- group). Overall hospital stay was 14 days versus 15 days (ERAS+ and ERAS-, respectively; p = 0.013). There were no significant differences in the incidence of postoperative complications in either group. The percentage of achieved items varied between 42 and 93 % per item. CONCLUSIONS: The implementation of an ERAS program in esophageal surgery was feasible and resulted in a small but significant reduction in overall hospital stay, whereas overall morbidity was not affected. PMID- 23807123 TI - Discomfort and anxiety should never be considered surgical indications for hemangioma of the liver. PMID- 23807124 TI - Early oral feeding versus traditional postoperative care after abdominal emergency surgery: a randomized controlled trial. AB - BACKGROUND: Early oral feeding (EOF) has been demonstrated to be safe and beneficial after abdominal elective surgery. The aim of this randomized controlled trial is to assess the safety and benefits of EOF compared to traditional postoperative care (TPC) after abdominal emergency surgery. METHODS: Patients assigned to the EOF group commenced a soft diet within 24 h after surgery. In the TPC group, a liquid diet was commenced upon passage of flatus or stool and then advanced to soft food. The primary endpoint was the complication rate. Secondary endpoints were severity of complications, mortality, gastrointestinal leaks, surgical-site infection, reoperation, diet intolerance, time to first flatus and stool, amount of food intake, postoperative discomfort, hospital stay, weight loss at the 15th postoperative day and incisional hernias. RESULTS: A total of 295 patients assigned to EOF (n = 148) or TPC (n = 147) were analyzed. No significant differences were seen in the complications rates (EOF 45.3 % vs. TPC 37.4 %; p = 0.1). There was a significantly higher rate of vomiting with EOF (EOF 13.5 % vs. TPC 6.1 %; p = 0.03), with no differences in nasogastric tube reinsertion. EOF patients' food intake was proportionally lower for the first three meals than that of TPC patients (p < 0.01). Postoperative discomfort survey revealed more hunger in the TPC group (p < 0.01). There were no differences in postoperative ileus or length of hospital stay. CONCLUSIONS: EOF was safe after abdominal emergency surgery. EOF was associated with more vomiting (treated easily and without patient discomfort) and less hunger than with TPC. No other EOF-related benefits could be demonstrated during this trial. PMID- 23807125 TI - Characteristics and risk factors associated with permanent stomas after sphincter saving resection for rectal cancer. AB - BACKGROUND: The aim of the present study was to identify the risk factors and patient characteristics associated with permanent stomas after sphincter-saving resection for rectal cancer. METHOD: Between 2000 and 2007, 2,362 patients underwent sphincter-saving surgery [low anterior resection or ultra-low anterior resection (uLAR)] for rectal cancer. These patients were divided into two groups: 71 patients with permanent stomas and 2,291 patients without permanent stomas after rectal cancer surgery. RESULTS: Of the 71 permanent stomas (3 % of the patients), 34 (48 %) were ileostomies, 11 (15 %) were loop colostomies, 10 (14 %) were treated by Hartmann's operation, and 16 (23 %) were treated by abdominoperineal resection. Diverting stomas were created in 364 patients; 3 % (n = 11) of them could not be reversed due to anastomosis-related complications. Permanent stomas were constructed at a median of 20 months after sphincter-saving surgery for rectal cancer. The main causes of permanent stomas were local recurrence (n = 27), anastomotic leakage (n = 12), fistula (n = 9), and anastomosis site stricture (n = 7). The main causes of early permanent stomas (<1 year) were anastomosis-related complications, whereas for late permanent stomas (>=1 year), the main cause was local cancer recurrence. The independent risk factors for permanent stomas were local recurrence, postoperative pelvic sepsis, male gender of the patient, the uLAR operation type, and perioperative radiation therapy. CONCLUSIONS: In a high-volume surgical center, sphincter-saving surgery for rectal cancer is associated with a low incidence of permanent stoma. PMID- 23807126 TI - Interfacial characterization of Pluronic PE9400 at biocompatible (air-water and limonene-water) interfaces. AB - In this work, we provide an accurate characterization of non-ionic triblock copolymer Pluronic PE9400 at the air-water and limonene-water interfaces, comprising a systematic analysis of surface tension isotherms, dynamic curves, dilatational rheology and desorption profiles. The surface pressure isotherms display two different slopes of the Pi-c plot suggesting the existence of two adsorption regimes for PE9400 at both interfaces. Application of a theoretical model, which assumes the coexistence of different adsorbed states characterized by their molar areas, allows quantification of the conformational changes occurring at the adsorbed layer, indentifying differences between the conformations adopted at the air-water and the limonene-water interface. The presence of two maxima in the dilatational modulus vs. interfacial pressure importantly corroborates this conformational change from a 2D flat conformation to 3D brush one. Moreover, the dilatational response provides mechanical diferences between the interfacial layers formed at the two interfaces analyzed. Dynamic surface pressure data were transformed into a dimensionless form and fitted to another model which considers the influence of the reorganization process on the adsorption dynamics. Finally, the desorption profiles reveal that Pluronic PE9400 is irreversibly adsorbed at both interfaces regardless of the interfacial conformation and nature of the interface. The systematic characterization presented in this work provides important new findings on the interfacial properties of pluronics which can be applied in the rational development of new products, such as biocompatible limonene-based emulsions and/or microemulsions. PMID- 23807127 TI - Degradable behavior and bioactivity of micro-arc oxidized AZ91D Mg alloy with calcium phosphate/chitosan composite coating in m-SBF. AB - The degradation behavior of a MAO-AZ91D with a calcium phosphate/chitosan composite coating in the modified simulated human body fluid (m-SBF) was investigated by immersion experiments and electrochemical impedance spectroscopy. The compositions of the composite coating soaked in the m-SBF for different time intervals were studied by X-ray diffraction, Fourier transform infrared spectroscopy, Raman spectroscopy, thermo-gravimetric analysis and differential thermal analysis. The microstructures of the composite coating at different soaking stages were observed by using a scanning electron microscope. Results show that the as-prepared composite coating could slow down the corrosion rate of the AZ91D alloy and it demonstrated good bioactivity in the m-SBF. The coating's morphology changed from a flake-like one into a spherical-shaped one with the increase of immersion time in the m-SBF. PMID- 23807128 TI - Quantum simulation of low-temperature metallic liquid hydrogen. AB - The melting temperature of solid hydrogen drops with pressure above ~65 GPa, suggesting that a liquid state might exist at low temperatures. It has also been suggested that this low-temperature liquid state might be non-molecular and metallic, although evidence for such behaviour is lacking. Here we report results for hydrogen at high pressures using ab initio methods, which include a description of the quantum motion of the protons. We determine the melting temperature as a function of pressure and find an atomic solid phase from 500 to 800 GPa, which melts at <200 K. Beyond this and up to 1,200 GPa, a metallic atomic liquid is stable at temperatures as low as 50 K. The quantum motion of the protons is critical to the low melting temperature reported, as simulations with classical nuclei lead to considerably higher melting temperatures of ~300 K across the entire pressure range considered. PMID- 23807129 TI - From the editor. The science of quality improvement in health care. PMID- 23807130 TI - Seven propositions of the science of improvement: exploring foundations. AB - CONTEXT: The phrase "Science of Improvement" or "Improvement Science" is commonly used today by a range of people and professions to mean different things, creating confusion to those trying to learn about improvement. In this article, we briefly define the concepts of improvement and science, and review the history of the consideration of "improvement" as a science. METHODS: We trace key concepts and ideas in improvement to their philosophical and theoretical foundation with a focus on Deming's System of Profound Knowledge. We suggest that Deming's system has a firm association with many contemporary and historic philosophic and scientific debates and concepts. With reference to these debates and concepts, we identify 7 propositions that provide the scientific and philosophical foundation for the science of improvement. FINDINGS: A standard view of the science of improvement does not presently exist that is grounded in the philosophical and theoretical basis of the field. The 7 propositions outlined here demonstrate the value of examining the underpinnings of improvement. This is needed to both advance the field and minimize confusion about what the phrase "science of improvement" represents. We argue that advanced scientists of improvement are those who like Deming and Shewhart can integrate ideas, concepts, and models between scientific disciplines for the purpose of developing more robust improvement models, tools, and techniques with a focus on application and problem solving in real world contexts. CONCLUSIONS: The epistemological foundations and theoretical basis of the science of improvement and its reasoning methods need to be critically examined to ensure its continued development and relevance. If improvement efforts and projects in health care are to be characterized under the canon of science, then health care professionals engaged in quality improvement work would benefit from a standard set of core principles, a standard lexicon, and an understanding of the evolution of the science of improvement. PMID- 23807131 TI - Redefining payer-provider relationships in an era of pay for performance: a social capital perspective. AB - Pay for performance (P4P) has become a leading initiative for improving the quality of care in numerous countries around the world, most notably the United States and United Kingdom. However, the scientific evidence regarding the effectiveness of P4P for improving quality is quite thin. Applying a social capital perspective to the US experience with P4P, this article offers a conceptual analysis of the relationship between payers and providers relative to the prospect for improving the effectiveness of P4P as applied to quality of care. From this perspective, a key barrier to improving the effectiveness of P4P has been that payers and providers have not worked cooperatively in the design and implementation of these financial incentive programs. However, recent developments in the US health care system, namely, the formation of quality improvement collaboratives and global payment arrangements, are helping to redefine relationships between payers and providers that support innovative payment arrangements. These relationships are being redefined in ways that are in accordance with social capital concepts such as trust, commitment, and shared purpose. As such, the US experience offers lessons for improving the effectiveness of P4P in any context in which better cooperation between payers and providers is needed. PMID- 23807132 TI - Pay for performance improves quality across demographic groups. AB - OBJECTIVE: To evaluate quality and the effect of pay for performance among minority patient groups, during a pay-for-performance program in 22 primary care practice sites. METHODS: Data were collected on 26 standardized measures of care for 2 measurement cycles. Proportions of recommended care received across 5 composite quality domains were analyzed by demographic group. Regression models including significant covariates were constructed. Adjusted odds ratios (ORs) were derived to assess the effect of pay of performance within demographic groups. RESULTS: Improvements were observed from 2007 to 2009 for all patients in each of 5 composite quality domains of diabetes, coronary artery disease, heart failure, screening and prevention, and all care. With the exception of heart failure care for Hispanic/Latino and Spanish language-preferring patients, improvement was observed in all domains for African American/black race, Hispanic/Latino ethnicity, and Spanish language-preferred groups. Following adjustment for covariates, pay for performance was associated with significant improvement in all-patient diabetes care (adjusted OR = 1.15; [95% confidence interval [CI], 1.09-1.22), screening and prevention (adjusted OR = 1.55; 95% CI, 1.41-1.69), and all care (adjusted OR = 1.27; 95% CI, 1.20-1.35). Significant improvements were also observed within the minority demographic groups noted earlier. CONCLUSIONS: Pay-for-performance programs structured as additional incentive monies for providers improved care for all patients and among minority groups, in whom disparities have historically been observed. PMID- 23807133 TI - The use of six sigma in health care management: are we using it to its full potential? AB - Popular quality improvement tools such as Six Sigma (SS) claim to provide health care managers the opportunity to improve health care quality on the basis of sound methodology and data. However, it is unclear whether this quality improvement tool is being used correctly and improves health care quality. The authors conducted a comprehensive literature review to assess the correct use and implementation of SS and the empirical evidence demonstrating the relationship between SS and improved quality of care in health care organizations. The authors identified 310 articles on SS published in the last 15 years. However, only 55 were empirical peer-reviewed articles, 16 of which reported the correct use of SS. Only 7 of these articles included statistical analyses to test for significant changes in quality of care, and only 16 calculated defects per million opportunities or sigma level. This review demonstrates that there are significant gaps in the Six Sigma health care quality improvement literature and very weak evidence that Six Sigma is being used correctly to improve health care quality. PMID- 23807134 TI - Translating 10 lessons from lean six sigma project in paper-based training site to electronic health record-based primary care practice: challenges and opportunities. AB - Lean Six Sigma is a well-proven methodology to enhance the performance of any business, including health care. The strategy focuses on cutting out waste and variation from the processes to improve the value and efficiency of work. This article walks through the journey of "green belt" training using a Lean Six Sigma approach and the implementation of a process improvement project that focused on wait time for patients to be examined in an urban academic primary care clinic without requiring added resources. Experiences of the training and the project at an urban paper-based satellite clinic have informed the planning efforts of a data and performance team, including implementing a 15-minute nurse "pre-visit" at primary care sites of an accountable care organization. PMID- 23807135 TI - The governance of quality management in dutch health care: new developments and strategic challenges. AB - This article gives a brief sketch of quality management in Dutch health care. Our focus is upon the governance of guideline development and quality measurement. Governance is conceptualized as the structure and process of steering of quality management. The governance structure of guideline development in the Netherlands can be conceptualized as a network without central coordination. Much depends upon the self-initiative of stakeholders. A similar picture can be found in quality measurement. Special attention is given to the development of care standards for chronic disease. Care standards have a broader scope than guidelines and take an explicit patient perspective. They not only contain evidence-based and up-to-date guidelines for the care pathway but also contain standards for self-management. Furthermore, they comprise a set of indicators for measuring the quality of care of the entire pathway covered by the standard. The final part of the article discusses the mission, tasks and strategic challenges of the newly established National Health Care Institute (Zorginstituut Nederland), which is scheduled to be operative in 2013. PMID- 23807136 TI - Home enteral feeding: analysis and improvement of organizational models. AB - AIM: The purpose of this study was to analyze the organizational models of home enteral feeding used in 5 local health authorities (LHAs) in the Veneto region (Italy). By comparing these models with the main guidelines, the authors have attempted to determine the "minimum standards" to be adopted at an organizational level. MATERIALS AND METHODS: This 3-stage study analyzes procedures, precoded actions, and recordable processes. Stage 1: objectives were defined, work methods selected, and reference guidelines chosen. Stage 2: flowcharts were drafted to show the actions and work paths taken for the 5 LHAs. Stage 3: flowcharts were compared with data from the literature. RESULTS: The study shows that very different organizational models exist. For instance, by comparing organizational processes with the procedures prescribed by the guidelines, it can be seen that the mean percentages of actions taken by the 5 LHAs, for patients in both rest homes and nursing homes, rarely exceeds the threshold of 50% (on a scale from 0% to 100%). CONCLUSION: This study shows that home enteral feeding is neither optimized nor uniform in the 5 LHAs and that standardized methods are not used for clinical monitoring. PMID- 23807137 TI - Care bundle methodology reporting must be rigorous. PMID- 23807140 TI - Innovative approach to the design of low-cost Zr-based BMG composites with good glass formation. AB - The high manufacturing cost for metallic glasses hampers actual commercial applications of this class of fascinating materials. In this letter, the effect of oxygen impurity on the glass forming ability and tensile properties of Zr-BMG composites were studied. Our results have demonstrated that oxygen was absorbed and concentrated only in the precipitated beta-Zr phase, leading that the remainder molten metal retains good glass forming ability. The high oxygen concentration in the beta-Zr phase induces a significant solid-solution strengthening effect, this resulting in an enhanced strength of the BMG composites without sacrificing their overall ductility. Based on this alloying strategy, we have successfully developed the low-cost Zr-based BMG composites with excellent tensile properties and good glass forming ability, using the low grade industrial raw materials processed under industrial vacuum systems. This finding is expected to greatly cut down the manufacturing cost and greatly promote the commercial applications of the BMG composites. PMID- 23807141 TI - Microfluidic heart on a chip for higher throughput pharmacological studies. AB - We present the design of a higher throughput "heart on a chip" which utilizes a semi-automated fabrication technique to process sub millimeter sized thin film cantilevers of soft elastomers. Anisotropic cardiac microtissues which recapitulate the laminar architecture of the heart ventricle are engineered on these cantilevers. Deflection of these cantilevers, termed Muscular Thin Films (MTFs), during muscle contraction allows calculation of diastolic and systolic stresses generated by the engineered tissues. We also present the design of a reusable one channel fluidic microdevice completely built out of autoclavable materials which incorporates various features required for an optical cardiac contractility assay: metallic base which fits on a heating element for temperature control, transparent top for recording cantilever deformation and embedded electrodes for electrical field stimulation of the tissue. We employ the microdevice to test the positive inotropic effect of isoproterenol on cardiac contractility at dosages ranging from 1 nM to 100 MUM. The higher throughput fluidic heart on a chip has applications in testing of cardiac tissues built from rare or expensive cell sources and for integration with other organ mimics. These advances will help alleviate translational barriers for commercial adoption of these technologies by improving the throughput and reproducibility of readout, standardization of the platform and scalability of manufacture. PMID- 23807144 TI - Urogynecology digest: Presented by Mallika Anand. PMID- 23807142 TI - Assessment of pharmacists' job satisfaction and job related stress in Amman. AB - BACKGROUND: The myriad changes in pharmacy practice in Jordan have transformed the pharmacist's role to be more focused on the patient and his/her therapeutic needs than on just the traditional dispensing. This, in addition to other possible factors, is believed to have influenced pharmacists' job satisfaction and stress level in different practice settings in Jordan. OBJECTIVE: This study aimed to determine the level of job satisfaction and job related stress among pharmacists in Amman. Moreover, the main causes of dissatisfaction and stress related factors affecting pharmacists at their working positions were also explored. SETTING: The study was conducted in four pharmacy practice settings: independent and chain community pharmacies as well as private and public hospital pharmacies. METHODS: The study adopted the self-administered survey methodology technique using a pre-validated pre-piloted questionnaire. The questionnaire was adapted from one previously used in Northern Ireland. Data were entered into SAS database and analysed using descriptive statistics, Chi square and regression analysis. The significance level was set at P < 0.05. MAIN OUTCOME MEASURE: The level and factors affecting job satisfaction and job related stress as reported by participating pharmacists. RESULTS: A total of 235 registered pharmacists in Amman were involved. The pharmacists' job satisfaction was significantly affected by the type of pharmacy practice settings (P = 0.038), pharmacists' registration year (P = 0.048) and marital status (P = 0.023). Moreover, job related stress situations like patient care responsibility have been associated significantly with the type of pharmacy practice settings (P = 0.043) and pharmacists' registration year (P = 0.013). Other job stressors like long working hours, lack of advancement, promotion opportunities and poor physician pharmacists' relationship have also been reported by participants. CONCLUSION: The study concluded that community pharmacists in Amman are found to be less satisfied with their jobs than their hospital counterparts. Pharmacists' job satisfaction should be enhanced to improve pharmacists' motivation and competence. Consequently, this will improve their productivity and provision of pharmaceutical care. PMID- 23807143 TI - Ethnicity and variations of pelvic organ prolapse bother. AB - INTRODUCTION AND HYPOTHESIS: To determine if prolapse symptom severity and bother varies among non-Hispanic white, Hispanic, and Native American women with equivalent prolapse stages on physical examination. METHODS: This was a retrospective chart review of new patients seen in an academic urogynecology clinic from January 2007 to September 2011. Data were extracted from a standardized intake form, including patients' self-identified ethnicity. All patients underwent a Pelvic Organ Prolapse Quantification (POPQ) examination and completed the Pelvic Floor Distress Inventory-20 (PFDI-20) with its Pelvic Organ Prolapse Distress Inventory (POPDI) subscale. RESULTS: Five hundred and eighty eight new patients were identified with pelvic organ prolapse. Groups did not differ by age, prior prolapse, and/or incontinence surgery, or sexual activity. Based on POPDI scores, Hispanic and Native American women reported more bother compared with non-Hispanic white women with stage 2 prolapse (p < 0.01). Level of bother between Hispanic and Native American women with stage 2 prolapse (p = 0.56) was not different. In subjects with >= stage 3 prolapse, POPDI scores did not differ by ethnicity (p = 0.24). In multivariate stepwise regression analysis controlling for significant factors, Hispanic and Native American ethnicity contributed to higher POPDI scores, as did depression. CONCLUSIONS: Among women with stage 2 prolapse, both Hispanic and Native American women had a higher level of bother, as measured by the POPDI, compared with non-Hispanic white women. The level of symptom bother was not different between ethnicities in women with stage 3 prolapse or greater. Disease severity may overshadow ethnic differences at more advanced stages of prolapse. PMID- 23807145 TI - Cystocele repair with single-incision, trocarless mesh system. AB - INTRODUCTION AND HYPOTHESIS: The use of mesh at the time of anterior vaginal wall repair reduced the risk of recurrent anterior vaginal wall prolapse. The aim of our video is to demonstrate our dissection technique focusing on the main anatomical landmarks in the pelvis and present an overall safer system to correct pelvic floor prolapse. METHODS: The video demonstrates correction of cystocele with the EndoFast ReliantTM system (IBI Israel Biomedical Innovations, Caesarea Industrial Park South, Israel). The surgical technique is described. RESULTS: Twenty-nine patients were treated with the system. Mean follow-up was 10 (range, 6-30) months. At latest follow-up, favorable anatomical results were obtained for 26 of 29 patients (89.6 %); three patients presented stage 1 nonsymptomatic prolapse. Three cases (13 %) of de novo stress urinary incontinence (SUI) and two cases of de novo urgency (6.9 %) were diagnosed and treated. Postoperative voiding difficulties, dyspareunia, or pain were not observed. CONCLUSION: The operation with the trocarless system was found to be safe, easy to learn and implement, and have the potential for reducing intra- and postoperative complications, with very satisfactory functional and anatomical results. PMID- 23807146 TI - Stabilizing biocatalysts. AB - The area of biocatalysis itself is in rapid development, fueled by both an enhanced repertoire of protein engineering tools and an increasing list of solved problems. Biocatalysts, however, are delicate materials that hover close to the thermodynamic limit of stability. In many cases, they need to be stabilized to survive a range of challenges regarding temperature, pH value, salt type and concentration, co-solvents, as well as shear and surface forces. Biocatalysts may be delicate proteins, however, once stabilized, they are efficiently active enzymes. Kinetic stability must be achieved to a level satisfactory for large scale process application. Kinetic stability evokes resistance to degradation and maintained or increased catalytic efficiency of the enzyme in which the desired reaction is accomplished at an increased rate. However, beyond these limitations, stable biocatalysts can be operated at higher temperatures or co-solvent concentrations, with ensuing reduction in microbial contamination, better solubility, as well as in many cases more favorable equilibrium, and can serve as more effective templates for combinatorial and data-driven protein engineering. To increase thermodynamic and kinetic stability, immobilization, protein engineering, and medium engineering of biocatalysts are available, the main focus of this work. In the case of protein engineering, there are three main approaches to enhancing the stability of protein biocatalysts: (i) rational design, based on knowledge of the 3D-structure and the catalytic mechanism, (ii) combinatorial design, requiring a protocol to generate diversity at the genetic level, a large, often high throughput, screening capacity to distinguish 'hits' from 'misses', and (iii) data-driven design, fueled by the increased availability of nucleotide and amino acid sequences of equivalent functionality. PMID- 23807148 TI - Activation of the p38 MAPK/NF-kappaB pathway contributes to doxorubicin-induced inflammation and cytotoxicity in H9c2 cardiac cells. AB - A number of studies have demonstrated that inflammation plays a role in doxorubicin (DOX)-induced cardiotoxicity. However, the molecular mechanism by which DOX induces cardiac inflammation has yet to be fully elucidated. The present study aimed to investigate the role of the p38 mitogen-activated protein kinase (MAPK)/nuclear factor-kappaB (NF-kappaB) pathway in DOX-induced inflammation and cytotoxicity. The results of our study demonstrated that the exposure of H9c2 cardiac cells to DOX reduced cell viability and stimulated an inflammatory response, as demonstrated by an increase in the levels of interleukin-1beta (IL-1beta) and IL-6, as well as tumor necrosis factor-alpha (TNF-alpha) production. Notably, DOX exposure induced the overexpression of phosphorylated p38 MAPK and phosphorylation of the NF-kappaB p65 subunit, which was markedly inhibited by SB203580, a specific inhibitor of p38 MAPK. The inhibition of NF-kappaB by pyrrolidine dithiocarbamate (PDTC), a selective inhibitor of NF-kappaB, significantly ameliorated DOX-induced inflammation, leading to a decrease in the levels of IL-1beta and IL-6, as well as TNF-alpha production in H9c2 cells. The pretreatment of H9c2 cells with either SB203580 or PDTC before exposure to DOX significantly attenuated DOX-induced cytotoxicity. In conclusion, our study provides novel data demonstrating that the p38 MAPK/NF kappaB pathway is important in the induction of DOX-induced inflammation and cytotoxicity in H9c2 cardiac myocytes. PMID- 23807149 TI - Prophylaxis for acute scleral buckle infection using 0.25 % povidone-iodine ocular surface irrigation during surgery. AB - To investigate whether repeated washing of the ocular surface with 0.25 % povidone-iodine during scleral buckling surgery minimizes ocular surface bacterial contamination at completion of the procedure. A total of 489 consecutive eyes that underwent scleral buckling at a single institution were categorized into two groups according to the intraoperative ocular surface washing method used during two separate time periods--a group using physiological saline (saline group, 222 consecutive eyes) and a group using 0.25 % povidone iodine (PI group 267, consecutive eyes). In 37 eyes of each group, ocular surface fluids were sampled at the beginning of surgery and at completion of buckling, and subjected to bacteriological culture. Acute scleral buckle infection occurred in one patient, and was caused by Pseudomonas aeruginosa. The incidence of acute scleral buckle infection was 0.45 % (1/222 eyes) in the saline group, and 0 % in the PI group, with no significant difference (P = 0.4540). The bacterial detection rates in ocular surface fluid at the beginning of surgery were 5.4 % (2/37 eyes) using saline and 8.1 % (3/37 eyes) using povidone-iodine, with no significant difference (P = 0.6433). The rates at completion of buckling were 18.9 % (7/37 eyes) using saline and 0 % (0 eye) using povidone-iodine, with a significant difference (P = 0.0114). Repeated washing of the ocular surface with 0.25 % povidone-iodine during scleral buckling procedure reduced the ocular surface bacterial contamination rate to an extremely low level at completion of buckling, suggesting that this method is useful for the prevention of acute scleral buckle infection. PMID- 23807150 TI - Two cases of CHARGE syndrome with multiple congenital anomalies. AB - We report on two cases of bilateral chorioretinal colobomas with ocular anomalies in patients with CHARGE syndrome. In the first case, a female infant was born at 36 + 5 weeks gestation. At birth, the patient demonstrated a small left eye. Slit lamp examination revealed colobomas of both irises. Fundus examination showed both chorioretinal colobomas. Brain magnetic resonance imaging (MRI) showed left microphthalmia. Systemic evaluation revealed multiple congenital anomalies: benign external hydrocephalus, esophageal atresia with imperforate anus, atrial septal defect (ASD), ventricular septal defect, patent ductus arteriosis (PDA), and right mild hydronephrosis. In the second case, a male infant was born at 39 + 5 weeks gestation and demonstrated a dysmorphic appearance with an irregular left pupil and ptosis. Fundus examination of both eyes showed large chorioretinal colobomas involving the optic disc and posterior pole. The patient had multi organ anomalies: right facial palsy, a left short, wide ear with a small lobe, congenital heart defects, such as ASD and PDA, left renal atresia, seizure disorder, and micropenis. Both cases revealed multiple anomalies including nearly all major and minor criteria of CHARGE syndrome which could be life-threatening to neonates. Thus, all neonates with ocular colobomas should have fully and detailed systemic examinations checking all minor criteria and even occasional findings of CHARGE syndrome. PMID- 23807151 TI - Diagnostic odyssey of patients with myotonic dystrophy. AB - The onset and symptoms of the myotonic dystrophies are diverse, complicating their diagnoses and limiting a comprehensive approach to their clinical care. This report analyzes the diagnostic delay (time from onset of first symptom to diagnosis) in a large sample of myotonic dystrophy (DM) patients enrolled in the US National Registry [679 DM type 1 (DM1) and 135 DM type 2 (DM2) patients]. Age of onset averaged 34.0 +/- 14.1 years in DM2 patients compared to 26.1 +/- 13.2 years in DM1 (p < 0.0001). The most common initial symptom in DM2 patients was leg weakness (32.6 %) compared to grip myotonia in DM1 (38.3 %). Pain was reported as the first symptom in 11.1 % of DM2 and 3.0 % of DM1 patients (p < 0.0001). Reaching the correct diagnosis in DM2 took 14 years on average (double the time compared to DM1) and a significantly higher percentage of patients underwent extended workup including electromyography, muscle biopsies, and finally genetic testing. DM patients who were index cases experienced similar diagnostic delays to non-index cases of DM. Further evaluation of how to shorten these diagnostic delays and limit their impact on burdens of disease, family planning, and symptom management is needed. PMID- 23807152 TI - Validating a novel web-based method to capture disease progression outcomes in multiple sclerosis. AB - The Expanded Disability Status Scale (EDSS) is the current 'gold standard' for monitoring disease severity in multiple sclerosis (MS). The EDSS is a physician based assessment. A patient-related surrogate for the EDSS may be useful in remotely capturing information. Eighty-one patients (EDSS range 0-8) having EDSS as part of clinical trials were recruited. All patients carried out the web-based survey with minimal assistance. Full EDSS scores were available for 78 patients. The EDSS scores were compared to those generated by the online survey using analysis of variance, matched pair test, Pearson's coefficient, weighted kappa coefficient, and the intra-class correlation coefficient. The internet-based EDSS scores showed good correlation with the physician-measured assessment (Pearson's coefficient = 0.85). Weighted kappa for full agreement was 0.647. Full agreement was observed in 20 patients who had EDSS scores ranging from 0 to 6; many of those with 100 % agreement had scores of 5.5-6 (n = 8).The intra-class coefficient was 0.844 overall for all cases. Internet-based FS and EDSS show good agreement with physician-measured scores. Agreement was better in patients with higher scores. Overall patient satisfaction with the web-based assessment was high. An internet-based assessment tool is likely to prove an invaluable tool in the long-term monitoring in MS. PMID- 23807153 TI - Komagataella kurtzmanii sp. nov., a new sibling species of Komagataella (Pichia) pastoris based on multigene sequence analysis. AB - A novel methanol assimilating yeast species Komagataella kurtzmanii is described using the type strain VKPM Y-727 (=KBP Y-2878 = UCD-FST 76-20 = Starmer #75-208.2 = CBS 12817 = NRRL Y-63667) isolated by W.T. Starmer from a fir flux in the Catalina Mountains, Southern AZ, USA. The new species is registered in MycoBank under MB 803919. The species was differentiated by divergence in gene sequences for D1/D2 LSU rRNA, ITS1-5.8S-ITS2, RNA polymerase subunit I, translation elongation factor-1alpha and mitochondrial small subunit rRNA. K. kurtzmanii differs from its phenotypically similar sibling species Komagataella pastoris, Komagataella pseudopastoris, Komagataella phaffii, Komagataella populi and Komagataella ulmi by absence of growth at 35 degrees C and inability to assimilate trehalose. PMID- 23807154 TI - 'Sticky electrodes' for the detection of silver nanoparticles. AB - Detection and quantification of nanoparticles in environmental systems is a task that requires reliable and affordable analytical methods. Here an approach using a cysteine-modified 'sticky' glassy carbon electrode is presented. The electrode is immersed in a silver nanoparticle containing electrolyte and left in this suspension without an applied potential, i.e. under open circuit condition, for a variable amount of time. The amount of silver nanoparticles immobilized on the electrode within this sticking time is then determined by oxidative stripping, yielding the anodic charge and thus the amount of Ag nanoparticles sticking to the electrode surface. When using a cysteine-modified glassy carbon electrode, significant and reproducible amounts of silver nanoparticles stick to the surface, which is not the case for unmodified glassy carbon surfaces. Additionally, proof-of-concept experiments are performed on real seawater samples. These demonstrate that also under simulated environmental conditions an increased immobilization and hence improved detection of silver nanoparticles on cysteine-modified glassy carbon electrodes is achieved, while no inhibitive interference with this complex matrix is observed. PMID- 23807155 TI - Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of tenofovir alafenamide as 10-day monotherapy in HIV-1-positive adults. AB - OBJECTIVE: To evaluate the antiviral activity, safety, pharmacokinetics, and pharmacokinetics/pharmacodynamics of short-term monotherapy with tenofovir alafenamide (TAF), a next-generation tenofovir (TFV) prodrug. DESIGN: A phase 1b, randomized, partially blinded, active- and placebo-controlled, dose-ranging study. METHODS: Treatment-naive and experienced HIV-1-positive adults currently off antiretroviral therapy were randomized to receive 8, 25, or 40 mg TAF, 300 mg tenofovir disoproxil fumarate (TDF), or placebo, each once daily for 10 days. RESULTS: Thirty-eight subjects were enrolled. Baseline characteristics were similar across dose groups. Significant reductions in plasma HIV-1 RNA from baseline to day 11 were observed for all TAF dose groups compared with placebo (P < 0.01), with a median decrease of 1.08-1.73 log10 copies per milliliter, including a dose-response relationship for viral load decrease up to 25 mg. At steady state, 8, 25, and 40 mg TAF yielded mean TFV plasma exposures [area under the plasma concentration-time curve (AUCtau)] of 97%, 86%, and 79% lower, respectively, as compared with the TFV exposures observed with 300 mg TDF. For 25 and 40 mg TAF, the mean intracellular peripheral blood mononuclear cell tenofovir diphosphate AUCtau was ~7-fold and ~25-fold higher, relative to 300 mg TDF. CONCLUSIONS: Compared with 300 mg TDF, TAF demonstrated more potent antiviral activity, higher peripheral blood mononuclear cell intracellular tenofovir diphosphate levels, and lower plasma TFV exposures, at approximately 1/10th of the dose. This may translate into greater antiviral efficacy, a higher barrier to resistance, and an improved safety profile relative to TDF, supporting further investigation of TAF dosed once daily in HIV-infected patients. PMID- 23807156 TI - A randomized phase 3 study comparing once-daily elvitegravir with twice-daily raltegravir in treatment-experienced subjects with HIV-1 infection: 96-week results. AB - : This 96-week, double-blind, active-controlled, phase 3 study, randomized subjects to elvitegravir once daily or raltegravir twice daily with a fully active, ritonavir-boosted protease inhibitor plus a third agent. The proportion of subjects randomized to elvitegravir that achieved and maintained HIV-1 RNA < 50 copies/mL through week 96 was 47.6% (167/351) compared with 45.0% (158/351) for raltegravir with a treatment difference of 2.6% (95% confidence interval: 4.6% to 9.9%). Both regimens were well tolerated, with comparable rates of adverse events and laboratory abnormalities through week 96. Once-daily elvitegravir was noninferior to twice-daily raltegravir, showed durable long-term efficacy, and was well tolerated in HIV+ treatment-experienced patients. PMID- 23807158 TI - Safer conception options for HIV serodifferent couples in the United States: the experience of the National Perinatal HIV Hotline and Clinicians' Network. PMID- 23807157 TI - Noninferiority of a task-shifting HIV care and treatment model using peer counselors and nurses among Ugandan women initiated on ART: evidence from a randomized trial. AB - OBJECTIVE: To assess the noninferiority of a task-shifting HIV treatment model relying on peer counselors and nurses compared with a physician-centered model among HIV-1-positive women initiated on antiretroviral therapy (ART) at a prevention of mother-to-child transmission clinic in Mulago Hospital, Uganda. METHODS: HIV-1-infected ART eligible naive women were randomized to either nurse peer (intervention) or doctor-counselor (standard model) arm. The primary endpoint was virologic success defined attaining a viral load < 400 RNA copies per milliliter 6-12 months after ART initiation. Noninferiority was defined as the lower 95% confidence limit for the difference in proportions with virologic success being less than 10%. Secondary outcomes included immunologic success (mean CD4 count increase from baseline) and pill count. RESULTS: Data on 85 participants were analyzed (n = 45 in the intervention and n = 40 in the standard model). The proportion of participants with virologic success was similar in the standard and intervention models [91% versus 88% respectively; difference, 3%; 95% confidence interval (CI): -11% to 12%]. Probability of viral detection at 6 12 months' time point was similar in the 2 models (log-rank test P = 0.73). Immunologic and pill count indicators were also similar in the intervention and standard models, with mean CD4 increase of 217 versus 206 cells per microliter (difference, 11; 95% CI: -60 to 82 cells/MUL) and pill counts of 99.8% versus 99.7% (difference, 0.0; 95% CI: -5% to 5%) respectively. CONCLUSIONS: Nurses and peer counselors were not inferior in providing ART follow-up care to postpartum women, an approach that may help deliver treatment to many more HIV-infected people. PMID- 23807159 TI - Induction of apoptosis in MCF-7 cells by the hemagglutinin-neuraminidase glycoprotein of Newcastle disease virus Malaysian strain AF2240. AB - Newcastle disease virus (NDV) exerts its naturally occurring oncolysis possibly through the induction of apoptosis. We hypothesized that the binding of the virus to the cell via the hemagglutinin-neuraminidase (HN) glycoprotein may be sufficient to not only induce apoptosis but to induce a higher apoptosis level than the parental NDV AF2240 virus. NDV AF2240 induction of apoptosis in MCF-7 human breast cancer cells was analyzed and quantified. In addition, the complete HN gene of NDV strain AF2240 was amplified, sequenced and cloned into the pDisplay eukaryotic expression vector. HN gene expression was first detected at the cell surface membrane of the transfected MCF-7 cells. HN induction of apoptosis in transfected MCF-7 cells was analyzed and quantified. The expression of the HN gene alone was able to induce apoptosis in MCF-7 cells but it was a less potent apoptosis inducer compared to the parental NDV AF2240 strain. In conclusion, the NDV AF2240 strain is a more suitable antitumor candidate agent than its recombinant HN gene unless the latter is further improved by additional modifications. PMID- 23807160 TI - Paired related homoeobox 1, a new EMT inducer, is involved in metastasis and poor prognosis in colorectal cancer. AB - BACKGROUND: Paired related homoeobox 1 (PRRX1) has been identified as a new epithelial-mesenchymal transition (EMT) inducer in breast cancer. However, the function of PRRX1 in colorectal cancer (CRC) has not been elucidated. METHODS: We utilised ectopic PRRX1-expressing cell lines to analyse the function of PRRX1 in CRC. The clinical significance of PRRX1 was also examined on three independent CRC case sets. RESULTS: PRRX1 induced EMT and the stem-like phenotype in CRC cells. In contrast to studies of breast cancer, abundant expression of PRRX1 was significantly associated with metastasis and poor prognosis in CRC. CONCLUSION: PRRX1 is an indicator of metastasis and poor prognosis in CRC cases. Further investigation is required to uncover the signalling network regulating PRRX1. PMID- 23807162 TI - Reply: comment on 'estimating the asbestos-related lung cancer burden from mesothelioma mortality'. PMID- 23807161 TI - IRF-1 responsiveness to IFN-gamma predicts different cancer immune phenotypes. AB - BACKGROUND: Several lines of evidence suggest a dichotomy between immune active and quiescent cancers, with the former associated with a good prognostic phenotype and better responsiveness to immunotherapy. Central to such dichotomy is the master regulator of the acute inflammatory process interferon regulatory factor (IRF)-1. However, it remains unknown whether the responsiveness of IRF-1 to cytokines is able to differentiate cancer immune phenotypes. METHODS: IRF-1 activation was measured in 15 melanoma cell lines at basal level and after treatment with IFN-gamma, TNF-alpha and a combination of both. Microarray analysis was used to compare transcriptional patterns between cell lines characterised by high or low IRF-1 activation. RESULTS: We observed a strong positive correlation between IRF-1 activation at basal level and after IFN-gamma and TNF-alpha treatment. Microarray demonstrated that three cell lines with low and three with high IRF-1 inducible translocation scores differed in the expression of 597 transcripts. Functional interpretation analysis showed mTOR and Wnt/beta-cathenin as the top downregulated pathways in the cell lines with low inducible IRF-1 activation, suggesting that a low IRF-1 inducibility recapitulates a cancer phenotype already described in literature characterised by poor prognosis. CONCLUSION: Our findings support the central role of IRF-1 in influencing different tumour phenotypes. PMID- 23807163 TI - Mammaglobin B (SCGB2A1) is a novel tumour antigen highly differentially expressed in all major histological types of ovarian cancer: implications for ovarian cancer immunotherapy. AB - BACKGROUND: We studied the genetic fingerprints of ovarian cancer and validated the potential of Mammaglobin b (SCGB2A1), one of the top differentially expressed genes found in our analysis, as a novel ovarian tumour rejection antigen. METHODS: We profiled 70 ovarian carcinomas including 24 serous (OSPC), 15 clear cell (CC), 24 endometrioid (EAC) and 7 poorly differentiated tumours, and 14 normal human ovarian surface epithelial (HOSE) control cell lines using the Human HG-U133 Plus 2.0 chip (Affymetrix). Quantitative real-time PCR and immunohistochemistry staining techniques were used to validate microarray data at RNA and protein levels for SCGB2A1. Full-length human-recombinant SCGB2A1 was used to pulse monocyte-derived dendritic cells (DCs) to stimulate autologous SCGB2A1-specific cytotoxic T-lymphocyte (CTL) responses against chemo-naive and chemo-resistant autologous ovarian tumours. RESULTS: Gene expression profiling identified SCGB2A1 as a top differentially expressed gene in all histological ovarian cancer types tested. The CD8+ CTL populations generated against SCGB2A1 were able to consistently induce lysis of autologous primary (chemo-naive) and metastatic/recurrent (chemo-resistant) target tumour cells expressing SCGB2A1, whereas autologous HLA-identical noncancerous cells were not lysed. Cytotoxicity against autologous tumour cells was significantly inhibited by anti-HLA-class I (W6/32) monoclonal antibody. Intracellular cytokine expression measured by flow cytometry showed a striking type 1 cytokine profile (i.e., high IFN-gamma secretion) in SCGB2A1-specific CTLs. CONCLUSION: SCGB2A1 is a top differentially expressed gene in all major histological types of ovarian cancers and may represent a novel and attractive target for the immunotherapy of patients harbouring recurrent disease resistant to chemotherapy. PMID- 23807164 TI - Prognostic impact of family history in southern Chinese patients with undifferentiated nasopharyngeal carcinoma. AB - BACKGROUND: Family history of cancer is associated with developing nasopharyngeal carcinoma (NPC); however, the impact of it on survival among established NPC patients remains unknown. METHODS: We retrospectively analysed 1773 southern Chinese patients. Associations between a first-degree family history of NPC and overall survival (OS), locoregional relapse-free survival (LRFS) and distant metastasis-free survival (DMFS) were estimated by Cox regression. RESULTS: Among 1773 patients, 207 (11.7%) reported a first-degree family history of NPC. Compared with patients without a family history, the adjusted hazard ratios among those with it were 0.60 (95% confidence interval (CI), 0.37-0.98; P=0.040) for OS, 0.52 (95% CI, 0.24-1.12; P=0.096) for LRFS and 0.51 (95% CI, 0.27-0.97; P=0.040) for DMFS. There were trends for improving OS, LRFS and DMFS with increasing number of affected relatives (Ptrend: 0.050, 0.114 and 0.044, respectively). But no significant benefits of family history in second- or third degree relatives were observed. In subgroup analysis, we observed the effects of family history with restriction to male patients and those of advanced stage and treated with conventional radiotherapy and addition of chemotherapy. CONCLUSION: A first-degree family history of NPC is associated with improved survival of patients. PMID- 23807165 TI - Dysregulation of miR-106a and miR-591 confers paclitaxel resistance to ovarian cancer. AB - BACKGROUND: MicroRNAs are noncoding regulatory RNAs strongly implicated in carcinogenesis, cell survival, and chemosensitivity. Here, microRNAs associated with chemoresistance in ovarian carcinoma, the most lethal of gynaecological malignancies, were identified and their functional effects in chemoresistant ovarian cancer cells were assessed. METHODS: MicroRNA expression in paclitaxel (PTX)-resistant SKpac sublines was compared with that of the PTX-sensitive, parental SKOV3 ovarian cancer cell line using microarray and qRT-PCR. The function of differentially expressed microRNAs in chemoresistant ovarian cancer was further evaluated by apoptosis, cell proliferation, and migration assays. RESULTS: Upregulation of miR-106a and downregulation of miR-591 were associated with PTX resistance in ovarian cancer cells and human tumour samples. Transfection with anti-miR-106a or pre-miR-591 resensitized PTX-resistant SKpac cells to PTX by enhancing apoptosis (23 and 42% increase), and inhibited their cell migration (43 and 56% decrease) and proliferation (64 and 65% decrease). Furthermore, ZEB1 was identified as a novel target gene of miR-591, and BCL10 and caspase-7 were target genes of miR-106a, as identified by immunoblotting and luciferase assay. CONCLUSION: MiR-106a and miR-591 have important roles in conferring PTX resistance to ovarian cancer cells. Modulation of these microRNAs resensitizes PTX-resistant cancer cells by targeting BCL10, caspase-7, and ZEB1. PMID- 23807166 TI - Comment on 'estimating the asbestos-related lung cancer burden from mesothelioma mortality' - IARC and chrysotile risks. PMID- 23807167 TI - Sarcopenia and change in body composition following maximal androgen suppression with abiraterone in men with castration-resistant prostate cancer. AB - BACKGROUND: Standard medical castration reduces muscle mass. We sought to characterize body composition changes in men undergoing maximal androgen suppression with and without exogenous gluocorticoids. METHODS: Cross-sectional areas of total fat, visceral fat and muscle were measured on serial CT scans in a post-hoc analysis of patients treated in Phase I/II trials with abiraterone followed by abiraterone and dexamethasone 0.5 mg daily. Linear mixed regression models were used to account for variations in time-on-treatment and baseline body mass index (BMI). RESULTS: Fifty-five patients received a median of 7.5 months abiraterone followed by 5.4 months abiraterone and dexamethasone. Muscle loss was observed on single-agent abiraterone (maximal in patients with baseline BMI >30, 4.3%), but no further loss was observed after addition of dexamethasone. Loss of visceral fat was also observed on single-agent abiraterone, (baseline BMI >30 patients -19.6%). In contrast, addition of dexamethasone led to an increase in central visceral and total fat and BMI in all the patients. INTERPRETATION: Maximal androgen suppression was associated with loss of muscle and visceral fat. Addition of low dose dexamethasone resulted in significant increases in visceral and total fat. These changes could have important quality-of-life implications for men treated with abiraterone. PMID- 23807168 TI - Inducing apoptosis of cancer cells using small-molecule plant compounds that bind to GRP78. AB - BACKGROUND: Glucose regulated protein 78 (GRP78) functions as a sensor of endoplasmic reticulum (ER) stress. The aim of this study was to test the hypothesis that molecules that bind to GRP78 induce the unfolded protein response (UPR) and enhance cell death in combination with ER stress inducers. METHODS: Differential scanning calorimetry (DSC), measurement of cell death by flow cytometry and the induction of ER stress markers using western blotting. RESULTS: Epigallocatechin gallate (EGCG), a flavonoid component of Green Tea Camellia sinensis, and honokiol (HNK), a Magnolia grandiflora derivative, bind to unfolded conformations of the GRP78 ATPase domain. Epigallocatechin gallate and HNK induced death in six neuroectodermal tumour cell lines tested. Levels of death to HNK were twice that for EGCG; half-maximal effective doses were similar but EGCG sensitivity varied more widely between cell types. Honokiol induced ER stress and UPR as predicted from its ability to interact with GRP78, but EGCG was less effective. With respect to cell death, HNK had synergistic effects on melanoma and glioblastoma cells with the ER stress inducers fenretinide or bortezomib, but only additive (fenretinide) or inhibitory (bortezomib) effects on neuroblastoma cells. CONCLUSION: Honokiol induces apoptosis due to ER stress from an interaction with GRP78. The data are consistent with DSC results that suggest that HNK binds to GRP78 more effectively than EGCG. Therefore, HNK may warrant development as an antitumour drug. PMID- 23807169 TI - Limited role for surveillance PET-CT scanning in patients with diffuse large B cell lymphoma in complete metabolic remission following primary therapy. AB - BACKGROUND: The usefulness of positron emission tomography with computed tomography (PET-CT) in the surveillance of patients with diffuse large B-cell lymphoma (DLBCL) in complete metabolic remission after primary therapy is not well studied. METHODS: We performed a retrospective review of our database between 2002 and 2009 for patients with de novo DLBCL who underwent surveillance PET-CT after achieving complete metabolic response (CMR) following primary therapy. RESULTS: Four-hundred and fifty scans were performed in 116 patients, with a median follow-up of 53 (range 8-133) months from completion of therapy. Thirteen patients (11%) relapsed: seven were suspected clinically and six were subclinical (all within first 18 months). The positive predictive value in patients with international prognostic index (IPI) <3 was 56% compared with 80% in patients with IPI >=3. Including indeterminate scans, PET-CT retained high sensitivity 95% and specificity 97% for relapse. CONCLUSION: Positron emission tomography with computed tomography is not useful in patients for the majority of patients with diffuse large B-cell lymphoma in CMR after primary therapy, with the possible exception of patients with baseline IPI >=3 in the 18 months following completion of primary therapy. This issue could be addressed by a prospective clinical trial. PMID- 23807170 TI - Variation in reported experience of involvement in cancer treatment decision making: evidence from the National Cancer Patient Experience Survey. AB - BACKGROUND: Exploring variation in patients' experiences of involvement in treatment decision making can identify groups needing extra support, such as additional consultation time, when considering treatment options. METHODS: We analysed data from the 2010 English National Cancer Patient Experience Survey, a national survey of all patients attending hospitals in England for cancer treatment over a 3-month period, to examine how experience of involvement in decisions about treatment varied between patients with 38 different primary cancers using logistic regression. We analysed responses from 41 411 patients to a single question examining patient experience of involvement in treatment decision making. We calculated unadjusted odds ratios of reporting the most positive experience between patients of different sociodemographic and tumour characteristics and explored the effects of adjusting for age, gender, ethnicity, deprivation, cancer type and hospital of treatment. RESULTS: Of the 41 441 respondents, 29 776 (72%) reported positive experiences of decision-making involvement. Younger patients reported substantially less positive experiences of involvement in decision making (adjusted OR=0.49 16-24 vs 65-74; P<0.001), as did ethnic minorities (adjusted ORs=0.52, 0.62 and 0.73 for Black, Chinese and Asian vs White patients, respectively; P<0.001). Experience varied considerably between patients with different cancers ( e.g., OR=0.52 for anal and 1.37 for melanoma vs colon cancer; P<0.001), with ovarian, myeloma, bladder and rectal cancer patients reporting substantially worse experiences compared with other patients with gynaecological, haematological, urological and colorectal cancers, respectively. Clustering of different patient groups within hospitals with outlying performance report scores could not account for observed differences. CONCLUSION: Efforts to improve involvement in treatment decision making can focus on those who report the worst experience, in particular younger patients, ethnic minorities and patients with rectal, ovarian, multiple myeloma and bladder cancer. PMID- 23807171 TI - Development and validation of a prognostic model in patients with metastatic renal cell carcinoma treated with sunitinib: a European collaboration. AB - BACKGROUND: Accurate prediction of outcome for metastatic renal cell carcinoma (mRCC) patients receiving targeted therapy is essential. Most of the available models have been developed in patients treated with cytokines, while most of them are fairly complex, including at least five factors. We developed and externally validated a simple model for overall survival (OS) in mRCC. We also studied the recently validated International Database Consortium (IDC) model in our data sets. METHODS: The development cohort included 170 mRCC patients treated with sunitinib. The final prognostic model was selected by uni- and multivariate Cox regression analyses. Risk groups were defined by the number of risk factors and by the 25th and 75th percentiles of the model's prognostic index distribution. The model was validated using an independent data set of 266 mRCC patients (validation cohort) treated with the same agent. RESULTS: Eastern Co-operative Oncology Group (ECOG) performance status (PS), time from diagnosis of RCC and number of metastatic sites were included in the final model. Median OS of patients with 1, 2 and 3 risk factors were: 24.7, 12.8 and 5.9 months, respectively, whereas median OS was not reached for patients with 0 risk factors. Concordance (C) index for internal validation was 0.712, whereas C-index for external validation was 0.634, due to differences in survival especially in poor risk populations between the two cohorts. Predictive performance of the model was improved after recalibration. Application of the mRCC International Database Consortium (IDC) model resulted in a C-index of 0.574 in the development and 0.576 in the validation cohorts (lower than those recently reported for this model). Predictive ability was also improved after recalibration in this analysis. Risk stratification according to IDC model showed more similar outcomes across the development and validation cohorts compared with our model. CONCLUSION: Our model provides a simple prognostic tool in mRCC patients treated with a targeted agent. It had similar performance with the IDC model, which, however, produced more consistent survival results across the development and validation cohorts. The predictive ability of both models was lower than that suggested by internal validation (our model) or recent published data (IDC model), due to differences between observed and predicted survival among intermediate and poor-risk patients. Our results highlight the importance of external validation and the need for further refinement of existing prognostic models. PMID- 23807172 TI - Synergistic antitumour activity of sorafenib in combination with tetrandrine is mediated by reactive oxygen species (ROS)/Akt signaling. AB - BACKGROUND: Sorafenib is a potent inhibitor against Raf kinase and several receptor tyrosine kinases that has been approved for the clinical treatment of advanced renal and liver cancer. Combining sorafenib with other agents has been shown to improve its antitumour efficacy by not only reducing the toxic side effects but also preventing primary and acquired resistance to sorafenib. We have previously observed that tetrandrine exhibits potent antitumour effects in human hepatocellular carcinoma. In this study, we investigated the synergistic antitumour activity of sorafenib in combination with tetrandrine. METHODS: This was a two-part investigation that included the in vitro effects of sorafenib in combination with tetrandrine on cancer cells and the in vivo antitumour efficacy of this drug combination on tumour xenografts in nude mice. RESULTS: Combined treatment showed a good synergistic antitumour effect yet spared non-tumourigenic cells. The potential molecular mechanism may be mainly that it activated mitochondrial death pathway and induced caspase-dependent apoptosis in the cancer cells. Accumulation of intracellular reactive oxygen species (ROS) and subsequent activation of Akt may also be involved in apoptosis induction. CONCLUSION: The antitumour activity of sorafenib plus tetrandrine may be attributed to the induction of the intrinsic apoptosis pathway through ROS/Akt signaling. This finding provides a novel approach that may broaden the clinical application of sorafenib. PMID- 23807174 TI - A study of the transport and immobilisation mechanisms of human red blood cells in a paper-based blood typing device using confocal microscopy. AB - Recent research on the use of bioactive paper for human blood typing has led to the discovery of a new method for identifying the haemagglutination of red blood cells (RBCs). When a blood sample is introduced onto paper treated with the grouping antibodies, RBCs undergo haemagglutination with the corresponding grouping antibodies, forming agglutinated cell aggregates in the paper. A subsequent washing of the paper with saline buffer could not remove these aggregates from the paper; this phenomenon provides a new method for rapid, visual identification of the antibody-specific haemagglutination reactions and thus the determination of the blood type. This study aims to understand the mechanism of RBC immobilization inside the paper which follows haemagglutination reactions. Confocal microscopy is used to observe the morphology of the free and agglutinated RBCs that are labelled with FITC. Chromatographic elution patterns of both agglutinated and non-agglutinated RBCs are studied to gain insight into the transport behaviour of free RBCs and agglutinated aggregates. This work provides new information about RBC haemagglutination inside the fibre network of paper on a microscopic level, which is important for the future design of paper based blood typing devices with high sensitivity and assaying speed. PMID- 23807173 TI - Association between ERCC1 and XPA expression and polymorphisms and the response to cisplatin in testicular germ cell tumours. AB - BACKGROUND: Cisplatin cures over 80% of testicular germ cell tumours (TGCTs), and nucleotide-excision repair (NER) modifies the sensitivity to cisplatin. We explored the association between NER proteins and their polymorphisms with cisplatin sensitivity (CPS) and overall survival (OS) of patients with non seminomatous (ns)-TGCTs. METHODS: The expression of ERCC1 and XPA and the presence of gammaH2AX were evaluated in cancer cell lines and in fresh ns-TGCTs. The ERCC1 protein was also determined in ns-TGCTs. The differences between CPS and non-CPS cell lines and patients were analysed by Student's t- or chi(2) tests. The differences in OS were analysed using the log-rank test, and the hazard ratios (HRs) were calculated using the Cox model. RESULTS: High ERCC1 expression was observed in the non-CPS cells, and both ERCC1 and gammaH2AX expressions were augmented after cisplatin treatment. Increased ERCC1 expression was also identified in non-CPS patients. Neither polymorphism was associated with either CPS or OS. The presence of ERCC1 was associated with non-CPS (P=0.05) and adjusted in the prognosis groups. The HR in ERCC1-negative and non-CPS patients was >14.43, and in ERCC1-positive and non-CPS patients the HR was >11.86 (P<0.001). CONCLUSIONS: High levels of ERCC1 were associated with non-CPS, suggesting that ERCC1 could be used as a potential indicator of the response to cisplatin and prognosis in ns-TGCTs. PMID- 23807175 TI - Gender differences in creative thinking: behavioral and fMRI findings. AB - Gender differences in creativity have been widely studied in behavioral investigations, but this topic has rarely been the focus of neuroscientific research. The current paper presents follow-up analyses of a previous fMRI study (Abraham et al., Neuropsychologia 50(8):1906-1917, 2012b), in which behavioral and brain function during creative conceptual expansion as well as general divergent thinking were explored. Here, we focus on gender differences within the same sample. Conceptual expansion was assessed with the alternate uses task relative to the object location task, whereas divergent thinking was assessed in terms of responses across both the alternate uses and object location tasks relative to n-back working memory tasks. While men and women were indistinguishable in terms of behavioral performance across all tasks, the pattern of brain activity while engaged in the tasks in question was indicative of strategy differences between the genders. Brain areas related to semantic cognition, rule learning and decision making were preferentially engaged in men during conceptual expansion, whereas women displayed higher activity in regions related to speech processing and social perception. During divergent thinking, declarative memory related regions were strongly activated in men, while regions involved in theory of mind and self-referential processing were more engaged in women. The implications of gender differences in adopted strategies or cognitive style when faced with generative tasks are discussed. PMID- 23807176 TI - Assessing framing assumptions in quantitative health impact assessments: a housing intervention example. AB - Health impact assessment (HIA) is often used to determine ex ante the health impact of an environmental policy or an environmental intervention. Underpinning any HIA is the framing assumption, which defines the causal pathways mapping environmental exposures to health outcomes. The sensitivity of the HIA to the framing assumptions is often ignored. A novel method based on fuzzy cognitive map (FCM) is developed to quantify the framing assumptions in the assessment stage of a HIA, and is then applied to a housing intervention (tightening insulation) as a case-study. Framing assumptions of the case-study were identified through a literature search of Ovid Medline (1948-2011). The FCM approach was used to identify the key variables that have the most influence in a HIA. Changes in air tightness, ventilation, indoor air quality and mould/humidity have been identified as having the most influence on health. The FCM approach is widely applicable and can be used to inform the formulation of the framing assumptions in any quantitative HIA of environmental interventions. We argue that it is necessary to explore and quantify framing assumptions prior to conducting a detailed quantitative HIA during the assessment stage. PMID- 23807178 TI - Implications of prion polymorphisms. AB - The sequence of a host's prion protein (PrP) can affect that host's susceptibility to prion disease and is the primary basis for the species barrier to transmission. Yet within many species, polymorphisms of the prion protein gene (Prnp) exist, each of which can further affect susceptibility or influence incubation period, pathology and phenotype. As strains are defined by these features (incubation period, pathology, phenotype), polymorphisms may also lead to the preferential propagation or generation of certain strains. In our recent study of the mouse Prnp(a) and Prnp(b) polymorphisms (which produced the proteins PrP(a) and PrP(b), respectively), we found differences in aggregation tendency, strain adaptability and conformational variability. Comparing our in vitro data with that of in vivo studies, we found that differing incubation periods between Prnp(a) and Prnp(b) mice can primarily be explained on the basis of faster or more efficient aggregation of PrP(a). In addition, and more importantly, we found that the faithful propagation of strains in Prnp(b) mice can be explained by the ability of PrP(b) to adopt a wider range of conformations. This adaptability allows PrP(b) to successfully propagate the structural features of a seed. In contrast, Prnp(a) mice revert PrP(b) strains into PrP(a) -type strains, and overall they have a narrower distribution of incubation periods. This can be explained by PrP(a) having fewer preferred conformations. We propose that Prnp polymorphisms are one route by which certain prion strains may preferentially propagate. This has significant implications for prion disease, chronic wasting disease (CWD) in particular, as it is spreading through North America. Deer which are susceptible to CWD also carry polymorphisms which influence their susceptibility. If these polymorphisms also preferentially allow strain diversification and propagation, this may accelerate the crossing of species barriers and propagation of the disease up the food chain. PMID- 23807177 TI - Microbial content of household dust associated with exhaled NO in asthmatic children. AB - Exhaled nitric oxide (eNO) is increasingly used as a non-invasive measure of airway inflammation. Despite this, little information exists regarding the potential effects of indoor microbial components on eNO. We determined the influence of microbial contaminants in house dust and other indoor environmental characteristics on eNO levels in seven-year-olds with and without a physician diagnosis of asthma. The study included 158 children recruited from a birth cohort study, and 32 were physician-diagnosed as asthmatic. The relationship between eNO levels and exposures to home dust streptomycetes, endotoxin, and molds was investigated. Streptomycetes and endotoxin were analyzed both as loads and concentrations in separate models. Dog, cat, and dust mite allergens also were evaluated. In the multivariate exposure models, high streptomycetes loads and concentrations were significantly associated with a decrease in eNO levels in asthmatic (p<0.001) but not in healthy children. The presence of dog allergen, however, was associated with increased levels of eNO (p=0.001). Dust endotoxin was not significant. The relationship between eNO and indoor exposure to common outdoor molds was u-shaped. In non-asthmatic children, none of the exposure variables was significantly associated with eNO levels. To our knowledge, this is the first study demonstrating a significant association between microbial components in the indoor environment and eNO levels in asthmatic children. This study demonstrates the importance of simultaneously assessing multiple home exposures of asthmatic children to better understand opposing effects. Common components of the indoor Streptomyces community may beneficially influence airway inflammation. PMID- 23807179 TI - Effects of a three-year exposure to ambient ozone on biomass allocation in poplar using ethylenediurea. AB - We examined the effect of ambient ozone on visible foliar injury, growth and biomass in field-grown poplar cuttings of an Oxford clone sensitive to ozone (Populus maximoviczii Henry * berolinensis Dippel) irrigated with ethylenediurea (EDU) or water for three years. EDU is used as an ozone protectant for plants. Protective effects of EDU on ozone visible injury were found. As a result, poplar trees grown under EDU treatment increased leaves, lateral branches and root density in the third year, although no significant enhancement of stem height and diameter was found. Ambient ozone (AOT40, 24.6 ppm h; diurnal hourly average, 40.3 ppb) may finally reduce carbon gain by reducing the number of branches, and thus sites for leaf formation, in ozone-sensitive poplar trees under not-limiting conditions. PMID- 23807180 TI - Enhancement of phototoxicity of curcumin in human oral cancer cells using silica nanoparticles as delivery vehicle. AB - We report results on the use of organically modified silica nanoparticles (SiNp) as a vehicle for the delivery of curcumin in human oral cancer cells for improvement of uptake and phototoxicity. Nanoformulated drug (curcumin-SiNp complex) was prepared by postloading curcumin in SiNp, and the complex was soluble in aqueous solution. Cellular uptake studied by fluorescence microscopy and spectroscopy showed that curcumin accumulation was higher when cells were incubated with curcumin-SiNp complex as against free curcumin. Studies carried out on incubation time-dependent cytotoxicity, inhibition of NF-kappaB activity, suppression of NF-kappaB-regulated proteins involved in invasion (MMP-9), angiogenesis (VEGF), and inflammation (TNF-alpha) showed that curcumin-SiNp leads to significant improvement over free curcumin in dark as well as on exposure to light. PMID- 23807182 TI - Immediate corneal vitrectomy for posteriorly dislocated lens fragments during cataract surgery. PMID- 23807181 TI - Effects of temperature-dependent optical properties on the fluence rate and temperature of biological tissue during low-level laser therapy. AB - The effects of temperature-dependent optical properties on the change of fluence rate and temperature distribution within biological tissues during low-level laser therapy (LLLT) were investigated by experimental and numerical methods. The fluence rate and temperature within a porcine skin were measured in vitro using an optical fiber sensor and a thermocouple, respectively, while irradiating the sample with a continuous wave laser (IPG Laser GmbH, Burbach, Germany, 1,064 nm, 3.14 W/cm(2)). The absorption and reduced scattering coefficients of porcine skin were estimated using an inverse adding-doubling algorithm from the total reflectance and transmittance measured with a double-integrating sphere. It was shown that the reduced scattering coefficient of porcine skin decreased significantly as the skin temperature increased within the range of 26-40 degrees C. To incorporate the temperature dependency of tissue optical properties in the simulation, a mathematical model that adopted coupled equations for fluence rate and bioheat transfer was developed. It was shown that the predicted fluence rate and temperature by the proposed mathematical model agreed closely with the measured values of porcine skin. The calculation of human skin temperature using the developed model revealed that the skin temperature could be significantly underestimated if the temperature dependency of optical properties of human skin were ignored during LLLT simulation. PMID- 23807183 TI - Outcomes after combined 1.8-MM microincision cataract surgery and 23-gauge transconjunctival vitrectomy for posterior segment disease: a retrospective study. AB - PURPOSE: The aim of the study was to retrospectively review indications, intraoperative and postoperative complications, and outcomes of combined coaxial microincision cataract surgery and 23-gauge vitrectomy for posterior segment disease. METHODS: The outcomes and findings of surgery in 50 patients (50 eyes) who underwent coaxial microincision cataract surgery and foldable intraocular lens implantation combined with 23-gauge vitrectomy for a variety of indications between January 2010 and March 2012. RESULTS: No posterior capsule tear was observed during surgery. Intraoperatively, a retinal break was found in 9 eyes (18%), which were successfully treated with laser and/or cryotherapy. Corneal suture was done in 6 eyes (12%), 5 of them left and 1 right. Sclerotomy was sutured in 2 left and 2 right eyes, respectively, a total of 4 eyes (8%). In 1 case, 23-gauge vitrectomy was converted to 20-gauge vitrectomy. The postoperative intraocular pressure (millimeters of mercury, mean +/- standard deviation) was 16.7 +/- 9.8. Hypotony (intraocular pressure < 9 mmHg) occurred in 9 eyes (18%). In 1 eye (2%) posterior iris synechia were observed 2 weeks after surgery, and intraocular pressure was >40 mmHg. Intraocular pressure was normalized after Nd:YAG laser iridotomy. Fibrin reaction in the anterior chamber was observed in 1 eye (2%) Day 1 after surgery. Posterior capsule opacification, which required Nd:YAG laser capsulotomy, was observed in 11 eyes (22%) during the follow-up. CONCLUSION: Combined sutureless coaxial microincision cataract surgery and 23 gauge vitrectomy offers the advantages of both coaxial microincision cataract surgery (less wound leakage, good anterior chamber stability, and safety) and 23 gauge vitrectomy (decreased inflammation and faster rehabilitation after surgery). PMID- 23807184 TI - Combined intravitreal bevacizumab injection and zone I sparing laser photocoagulation in patients with zone I retinopathy of prematurity. AB - PURPOSE: To investigate the anatomical outcome of combined intravitreal bevacizumab injection and Zone I sparing laser ablation in patients with Type 1 retinopathy of prematurity in Zone I. METHODS: The medical records of consecutive 18 eyes of 10 infants, who underwent combined intravitreal bevacizumab (0.25 mg) injection and Zone I sparing laser ablation for the treatment of Type 1 retinopathy of prematurity in Zone I, were retrospectively reviewed. Laser photocoagulation was performed on the avascular retina anterior to the margin of Zone I extending to the ora serrata. Anatomical outcomes including progression to stage 4/5, macular changes, and vitreous organization were reviewed. RESULTS: The mean gestational age at birth and the birth weight of included patients were 24.0 weeks and 628 g, respectively. The timing of bevacizumab injection ranged from postmenstrual age 33(+2) to 35 weeks (mean, 34.3 weeks). Postmenstrual age at last follow-up ranged from 74(+6) to 107(+1) weeks (mean, 83.6 weeks). All 18 eyes demonstrated prompt regression of neovascular pathology and plus disease without recurrence. Previously avascular Zone I retina was vascularized in all eyes after the treatment. All eyes showed excellent anatomical outcome with intact macula, but one eye showed mild vitreous organization above the vascular/avascular junction. CONCLUSION: Combined intravitreal bevacizumab injection and Zone I sparing laser ablation for Type 1 retinopathy of prematurity in Zone I seem to be effective treatment options. Possible advantages include lower dose of anti-vascular endothelial growth factor, less recurrence than monotherapy, and preservation of central visual field. PMID- 23807185 TI - Corneal endothelial cell density after vitrectomy with silicone oil for complex retinal detachments. AB - PURPOSE: To evaluate the endothelial cell density changes in eyes with silicone oil tamponade after vitrectomy for complex rhegmatogenous retinal detachment. METHODS: A prospective controlled study with 81 eyes with complex rhegmatogenous retinal detachment undergoing vitrectomy and silicone oil tamponade. Fellow eyes that fulfilled specific inclusion criteria served as controls. Endothelial cell density (in cells per square millimeter), coefficient of variance (standard deviation per mean cell area * 100), percentage of hexagonal cells, and corneal thickness were documented preoperatively and compared with values obtained at 3, 6, and 12 months postoperatively. For the purpose of the study analysis, all study eyes were divided into 5 groups, according to their lens status during the follow-up. RESULTS: High endothelial cell density loss was found in Group 3, (eyes that underwent an additional phacoemulsification procedure) and Group 4 (eyes that underwent lens and/or intraocular lens removal during the follow-up) at 12 months with a mean cell loss of 19% and 39%, respectively (P < 0.001). CONCLUSION: An intact natural or artificial lens-iris diaphragm may provide a protective barrier against corneal endothelial cell damage from long-term silicone oil tamponade. PMID- 23807186 TI - Effect of combined cataract surgery and ranibizumab injection in postoperative macular edema in nonproliferative diabetic retinopathy. AB - PURPOSE: To evaluate whether intravitreal ranibizumab injection at cataract surgery prevents postoperative diabetic macular edema (PME) in patients with stable diabetic retinopathy without significant macular edema. METHODS: Eighty patients with cataract, stable diabetic retinopathy, and no significant macular edema were randomized to a sham group (cataract surgery only) or a group undergoing cataract surgery plus intraoperative ranibizumab injection. Best corrected visual acuities, central subfield thickness, and total macular volume were assessed at baseline and 1 week, 1, 3, and 6 months postoperatively by spectral domain optical coherence tomography. Clinically meaningful PME (central subfield thickness increase >60 MUm relative to baseline) was computed. RESULTS: The groups did not differ in baseline best-corrected visual acuity, central subfield thickness, and total macular volume. Compared with the ranibizumab injection group, the sham group had significantly larger central subfield thickness increases relative to baseline at 1 week and 1 month; larger total macular volume increases at all time points (P = 0.012, P = 0.005, P < 0.001, P < 0.001, P = 0.005, P = 0.017, respectively); higher PME frequency at 1 month (P = 0.019); and poorer best-corrected visual acuity improvement from baseline to 6 months after surgery (P = 0.046). CONCLUSION: In patients with stable diabetic retinopathy without significant macular edema, intravitreal ranibizumab injection at cataract surgery may prevent the postoperative worsening of macular edema and may improve the final visual outcome without affecting safety. PMID- 23807187 TI - Changing profile of organisms causing scleral buckle infections: a clinico microbiological case series. AB - PURPOSE: To study the microbiological spectrum and in vitro susceptibility of bacterial isolates from explanted scleral buckles and to correlate clinical presentation to the causative agent. METHOD: Medical records of patients who underwent buckle explantation from July 2007 to May 2012 were reviewed retrospectively. Clinical features and microbiological profile were noted and correlated. RESULTS: Twenty of 24 buckles (83.33%) from 24 patients grew 21 isolates. Isolates included 6 acid-fast bacilli (28.57%; atypical mycobacteria = 5, Nocardia asteroides = 1), 5 gram-positive bacilli (23.8%; Corynebacterium spp. = 4, Bacillus sp. = 1), 4 gram-positive cocci (19.0%; Staphylococcus spp. = 4), 2 gram-negative bacilli (9.5%; Pseudomonas aeruginosa = 2), and 4 fungi (19.0%; Aspergillus spp. = 3, Paecilomyces sp. = 1). Acid-fast bacilli and gram-negative bacilli were sensitive to amikacin and gram-positive bacilli and gram-positive cocci to vancomycin. Buckle exposure within 2 years of primary surgery tended to be noninfective (P = 0.06). Fungal or mycobacterial infections were more symptomatic than those with Corynebacterium species. Results of microscopic examination of conjunctival swab in 5 of 7 eyes (71.4%) were consistent with culture of conjunctival swab and explanted buckles. CONCLUSION: Clinical features and microscopic examination of conjunctival swab may give a lead toward the causative organism in suspected buckle infections. Based on these leads, vancomycin and amikacin may be used as the initial empirical therapy. PMID- 23807188 TI - Intravitreal anti-vascular endothelial growth factor for retinal angiomatous proliferation in treatment-naive eyes: long-term functional and anatomical results using a modified PrONTO-style regimen. AB - PURPOSE: To evaluate long-term outcome of intravitreal anti-vascular endothelial growth factor monotherapy in retinal angiomatous proliferation. METHODS: Twenty one treatment-naive eyes were included in this prospective, interventional case series. Treatment was three monthly injections of bevacizumab and/or ranibizumab with a modified PrONTO-style regimen. Best-corrected visual acuity (BCVA) was evaluated. The influence of baseline BCVA and pretreatment pigment epithelial detachment on BCVA outcome or retreatment were assessed by Pearson correlation analysis. RESULTS: Results were evaluated at 2 years and 3 years for 21 and 13 eyes, respectively. Mean baseline BCVA improved significantly from 44.5 (+/- 11.0) (20/32) to 51.1 (+/- 9.7) (20/24) and 50.8 (+/- 10.4) letters (20/24) at 2 and 3 years, respectively (P = 0.02 and P = 0.049). Pigment epithelial detachment correlated negatively with BCVA outcome (r = -0.65, P = 0.002 and r = -0.67, P = 0.01 at 2 years and 3 years, respectively) and was significantly associated with retreatment (r = 0.62, P = 0.003 and r = 0.87, P < 0.0001 at 2 years and 3 years, respectively). Complete occlusion of the lesion was obtained in 71% and 69% of eyes at 2 years and 3 years, respectively, with a mean of 9.4 injections at 3 years. CONCLUSION: Intravitreal anti-vascular endothelial growth factor monotherapy was a valid option for retinal angiomatous proliferation. Stable or improved visual acuity was obtained in 95% and 100% of eyes at 2 years and 3 years, respectively. PMID- 23807189 TI - Novel surgical technique for closure of large full-thickness macular holes. PMID- 23807190 TI - Role of optical coherence tomography in verifying the specificity of ultrasonography in detecting subtle subretinal fluid associated with small choroidal melanocytic tumors. AB - PURPOSE: To report the use of optical coherence tomography (OCT) in verifying the specificity of the ultrasonographic "apical double echo" sign in detecting subtle subretinal fluid (SRF) associated with small choroidal melanocytic tumors. METHODS: Retrospective review of consecutive patients demonstrating ultrasonographic "apical double echo," indicative of subtle SRF, who concurrently underwent OCT on initial evaluation of untreated small choroidal melanocytic tumors. Ultrasonography was performed with eyecubed version 3, ophthalmic ultrasound system (Ellex/Innovative Imaging, Inc, Adelaide, Australia) and OCT with spectral-domain OCT, Cirrus HD-OCT, model 4000 (Carl Zeiss; Meditec, Dublin, CA). Optical coherence tomographic images were examined to verify the presence of SRF and to identify other retinal pathology producing apical double echo in the absence of SRF. RESULTS: The study included 36 patients. With OCT, subtle SRF was present at tumor apex and/or margins in 20 patients (55%) and absent in 16 patients (45%). When SRF was present, it was detected at tumor apex only in 3 of 20 patients (14%), gravitated at the inferior margin only in 13 of 20 patients (64%), and at apex and inferior margin in 4 of 20 patients (22%). When SRF was absent, the retina over the tumor showed degenerative cystic changes in 10 of 16 patients (65%), retinal thickening in 4 of 16 patients (25%), and retinal pigment epithelium detachment in 2 of 16 patients (10%), accounting for the ultrasonographic apical double echo. CONCLUSION: Ultrasonography showed limited specificity for detecting subtle SRF related to small choroidal melanocytic tumors, with 45% of patients showing ultrasonographic apical double echo in the absence of SRF with OCT. The retinal changes that yielded false-positive results included retinal cystic degenerations, retinal thickening, and retinal pigment epithelium detachment. Optical coherence tomography is preferred to verify the presence of subtle SRF over small choroidal melanocytic tumors, provided that the inferior tumor margin is included in imaging. PMID- 23807191 TI - NetGestalt: integrating multidimensional omics data over biological networks. PMID- 23807192 TI - Data visualization: ambiguity as a fellow traveler. PMID- 23807193 TI - Another transistor-based revolution: on-chip qPCR. PMID- 23807194 TI - Building a better stop sign: understanding the signals that terminate transcription. PMID- 23807195 TI - Eavesdropping on PTM cross-talk through serial enrichment. PMID- 23807196 TI - Assessment of pathogenic bacteria using periodic actuation. AB - A new analytical platform for the assessment of pathogenic bacteria is presented. It is based on a robust technology which is able to amplify the signal to noise ratio providing fast and sensitive detection of target pathogenic bacteria. The system uses a custom made AC electrical impedance analyser to measure, using a lab on a chip platform, the oscillations of magnetically labelled analytes when applying a periodic magnetic field. The concentration of pathogenic Escherichia coli O157:H7 chosen as bacterial model was determined based on the amplitude of the electrical impedance oscillations at a selected AC frequency. The analytical platform provides a limit of detection of 10(2) cells ml(-1), has a fast analysis time, and is amenable for the detection of other target cells. The system has simple design suitable for portability and automated operation. PMID- 23807197 TI - Probing carrier lifetimes in photovoltaic materials using subsurface two-photon microscopy. AB - Accurately measuring the bulk minority carrier lifetime is one of the greatest challenges in evaluating photoactive materials used in photovoltaic cells. One photon time-resolved photoluminescence decay measurements are commonly used to measure lifetimes of direct bandgap materials. However, because the incident photons have energies higher than the bandgap of the semiconductor, most carriers are generated close to the surface, where surface defects cause inaccurate lifetime measurements. Here we show that two-photon absorption permits sub surface optical excitation, which allows us to decouple surface and bulk recombination processes even in unpassivated samples. Thus with two-photon microscopy we probe the bulk minority carrier lifetime of photovoltaic semiconductors. We demonstrate how the traditional one-photon technique can underestimate the bulk lifetime in a CdTe crystal by 10* and show that two-photon excitation more accurately measures the bulk lifetime. Finally, we generate multi dimensional spatial maps of optoelectronic properties in the bulk of these materials using two-photon excitation. PMID- 23807199 TI - A component of gamma-radiation-induced cell death in E. coli is programmed and interlinked with activation of caspase-3 and SOS response. AB - The current study deals with the molecular mechanism of radiation-induced cell death (RICD) in Escherichia coli. Irradiated E. coli cells displayed markers similar to those found in eukaryotic programmed cell death (PCD) such as caspase 3 activation and phosphatidylserine externalization. RICD was found to be suppressed upon pretreatment with sublethal concentrations of rifampicin or chloramphenicol, indicating the requirement of de novo gene expression. RICD was also found to be inhibited by cell permeable inhibitors of caspase-3 or poly (ADP ribose) polymerase, indicating the involvement of PCD during RICD in E. coli. Radiation-induced SOS response was alleviated as observed with decrease in LexA level and also reduced cell filamentation frequency in the presence of caspase inhibitor. Further, the inhibitor-mediated rescue was not observed in single-gene knockouts of umuC, umuD, recB and ruvA, the genes which are associated with SOS response. This implies a linkage between SOS response and PCD in radiation exposed E. coli cells. PMID- 23807198 TI - Corticospinal tract asymmetry and handedness in right- and left-handers by diffusion tensor tractography. AB - PURPOSE: Cerebral hemispheres represent both structural and functional asymmetry, which differs among right- and left-handers. The left hemisphere is specialised for language and task execution of the right hand in right-handers. We studied the corticospinal tract in right- and left-handers by diffusion tensor imaging and tractography. The present study aimed at revealing a morphological difference resulting from a region of interest (ROI) obtained by functional MRI (fMRI). METHODS: Twenty-five healthy participants (right-handed: 15, left-handed: 10) were enrolled in our assessment of morphological, functional and diffusion tensor MRI. Assessment of brain fibre reconstruction (tractography) was done using a deterministic algorithm. Fractional anisotropy (FA) and mean diffusivity (MD) were studied on the tractography traces of the reference slices. RESULTS: We observed a significant difference in number of leftward fibres based on laterality. The significant difference in regard to FA and MD was based on the slices obtained at different levels and the laterality index. We found left-hand asymmetry and right-hand asymmetry, respectively, for the MD and FA. CONCLUSIONS: Our study showed the presence of hemispheric asymmetry based on laterality index in right- and left-handers. These results are inconsistent with some studies and consistent with others. The reported difference in hemispheric asymmetry could be related to dexterity (manual skill). PMID- 23807200 TI - Reproducible fabrication of stable small nano Pt with high activity for sensor applications. AB - Pt nanoparticles with an average size of 2-3 nm in diameter were reproducibly synthesized by reduction of H2PtCl6 solution containing inositol hexaphosphate (IP6) as the stabilizing agent. Single crystals with Pt(111) faces of the resulting cubic nanoparticles were revealed by the electron diffraction pattern. The PtNPs-IP6 nanoparticles were used to modify an electrode as a nonenzymatic sensor for H2O2 detection, exhibiting a fast response and high sensitivity. A low detection limit of 2.0 * 10-7 M (S/N = 3) with two linear ranges between 2.4 * 10 7 and 1.3 * 10-3 M (R2 = 0.9987) and between 1.3 * 10-3 and 1.3 * 10-2 M (R2 = 0.9980) was achieved. The attractive electrochemical performance of PtNPs-IP6 enables it to be employed as a promising material for the development of Pt-based analytical systems and other applications. PMID- 23807201 TI - MTHFR C677T polymorphism, folate status and colon cancer risk in acromegalic patients. AB - BACKGROUND: Acromegalic patients have a higher risk of developing colorectal tumours (CRT). The common C677T polymorphism in methylenetetrahydrofolate reductase (MTHFR) gene is a well-documented CRT risk factor in the general population, but its role in acromegaly has never been examined. PURPOSE: We investigated the influence of MTHFR C677T polymorphism, folate status and other lifestyle, nutritional and disease-specific variables on CRT risk in acromegaly. METHODS: Clinical data were collected from 115 acromegalic patients (25 with active disease) who underwent a complete colonoscopy. C677T MTHFR genotype, homocysteine, vitamin B12, insulin growth factor and insulin levels, as well as metabolic variables were evaluated. RESULTS: Colorectal tumours were identified in 51 patients (3 adenocarcinomas). MTHFR C677T distribution was in the Hardy Weinberg equilibrium and similar in patients with or without CRT. There was a correlation between patients with TT genotype and CRT occurrence (Spearman's test: P = 0.03), with an Odds Ratio (OR) of 1.32 (95% CI 0.522-3.362, P NS). A folate-MTHFR genotype interaction on CRT risk was found (P = 0.037): in the lower folate subgroup, TT patients showed a 2.4 higher OR for CRT (95% CI 0.484-11.891; P NS) than C-allele carriers. Smoking (P = 0.007), increased HbA1c levels (P = 0.021), dyslipidaemia (P = 0.049), acromegaly control (P = 0.057), and folate MTHFR genotype interaction (P = 0.088) were associated with CRT at multivariate analysis. CONCLUSIONS: In this cohort of acromegalic patients, CRT risk is increased in 677TT MTHFR patients with low plasma folate levels. Smoking, high HbA1c levels, dyslipidaemia and disease activity were also associated with increased CRT risk. PMID- 23807202 TI - DSM-5 ASD moves forward into the past. AB - The fifth edition of the diagnostic and statistical manual of mental disorders (DSM-5) (APA in diagnostic and statistical manual of mental disorders, Author, Washington, 2013) has decided to merge the subtypes of pervasive developmental disorders into a single category of autism spectrum disorder (ASD) on the assumption that they cannot be reliably differentiated from one another. The purpose of this review is to analyze the basis of this assumption by examining the comparative studies between Asperger's disorder (AsD) and autistic disorder (AD), and between pervasive developmental disorder not otherwise specified (PDDNOS) and AD. In all, 125 studies compared AsD with AD. Of these, 30 studies concluded that AsD and AD were similar conditions while 95 studies found quantitative and qualitative differences between them. Likewise, 37 studies compared PDDNOS with AD. Nine of these concluded that PDDNOS did not differ significantly from AD while 28 reported quantitative and qualitative differences between them. Taken together, these findings do not support the conceptualization of AD, AsD and PDDNOS as a single category of ASD. Irrespective of the changes proposed by the DSM-5, future research and clinical practice will continue to find ways to meaningfully subtype the ASD. PMID- 23807203 TI - Childhood neurodevelopmental disorders and violent criminality: a sibling control study. AB - The longitudinal relationship between attention deficit hyperactivity disorder (ADHD) and violent criminality has been extensively documented, while long-term effects of autism spectrum disorders (ASDs), tic disorders (TDs), and obsessive compulsive disorder (OCD) on criminality have been scarcely studied. Using population-based registers of all child and adolescent mental health services in Stockholm, we identified 3,391 children, born 1984-1994, with neurodevelopmental disorders, and compared their risk for subsequent violent criminality with matched controls. Individuals with ADHD or TDs were at elevated risk of committing violent crimes, no such association could be seen for ASDs or OCD. ADHD and TDs are risk factors for subsequent violent criminality, while ASDs and OCD are not associated with violent criminality. PMID- 23807204 TI - Urbanicity and autism spectrum disorders. AB - The etiology of autism spectrum disorders (ASD) is for the majority of cases unknown and more studies of risk factors are needed. Geographic variation in ASD occurrence has been observed, and urban residence has been suggested to serve as a proxy for etiologic and identification factors in ASD. We examined the association between urbanicity level and ASD at birth and during childhood. The study used a Danish register-based cohort of more than 800,000 children of which nearly 4,000 children were diagnosed with ASD. We found a dose-response association with greater level of urbanicity and risk of ASD. This association was found for residence at birth as well as residence during childhood. Further, we found an increased risk of ASD in children who moved to a higher level of urbanicity after birth. Also, earlier age of ASD diagnosis in urban areas was observed. While we could not directly examine the specific reasons behind these associations, our results demonstrating particularly strong associations between ASD diagnosis and post-birth migration suggest the influence of identification related factors such as access to services might have a substantive role on the ASD differentials we observed. PMID- 23807205 TI - Brief report: concurrent validity of autism symptom severity measures. AB - The autism spectrum disorder (ASD) diagnostic classifications, according to the DSM-5, include a severity rating. Several screening and/or diagnostic measures, such as the autism diagnostic and observation schedule (ADOS), Childhood Autism Rating Scale (CARS) and social responsiveness scale (SRS) (teacher and parent versions), include an assessment of symptom severity. The purpose of this study was to examine whether symptom severity and/or diagnostic status of preschool aged children with ASD (N = 201) were similarly categorized on these measures. For half of the sample, children were similarly classified across the four measures, and scores on most measures were correlated, with the exception of the ADOS and SRS-P. While the ADOS, CARS, and SRS are reliable and valid measures, there is some disagreement between measures with regard to child classification and the categorization of autism symptom severity. PMID- 23807206 TI - RNA polymerase between lesion bypass and DNA repair. AB - DNA damage leads to heritable changes in the genome via DNA replication. However, as the DNA helix is the site of numerous other transactions, notably transcription, DNA damage can have diverse repercussions on cellular physiology. In particular, DNA lesions have distinct effects on the passage of transcribing RNA polymerases, from easy bypass to almost complete block of transcription elongation. The fate of the RNA polymerase positioned at a lesion is largely determined by whether the lesion is structurally subtle and can be accommodated and eventually bypassed, or bulky, structurally distorting and requiring remodeling/complete dissociation of the transcription elongation complex, excision, and repair. Here we review cellular responses to DNA damage that involve RNA polymerases with a focus on bacterial transcription-coupled nucleotide excision repair and lesion bypass via transcriptional mutagenesis. Emphasis is placed on the explosion of new structural information on RNA polymerases and relevant DNA repair factors and the mechanistic models derived from it. PMID- 23807208 TI - The nucleotide-binding proteins Nubp1 and Nubp2 are negative regulators of ciliogenesis. AB - Nucleotide-binding proteins Nubp1 and Nubp2 are MRP/MinD-type P-loop NTPases with sequence similarity to bacterial division site-determining proteins and are conserved, essential proteins throughout the Eukaryotes. They have been implicated, together with their interacting minus-end directed motor protein KIFC5A, in the regulation of centriole duplication in mammalian cells. Here we show that Nubp1 and Nubp2 are integral components of centrioles throughout the cell cycle, recruited independently of KIFC5A. We further demonstrate their localization at the basal body of the primary cilium in quiescent vertebrate cells or invertebrate sensory cilia, as well as in the motile cilia of mouse cells and in the flagella of Chlamydomonas. RNAi-mediated silencing of nubp-1 in C. elegans causes the formation of morphologically aberrant and additional cilia in sensory neurons. Correspondingly, downregulation of Nubp1 or Nubp2 in mouse quiescent NIH 3T3 cells markedly increases the number of ciliated cells, while knockdown of KIFC5A dramatically reduces ciliogenesis. Simultaneous double silencing of Nubp1 + KIFC5A restores the percentage of ciliated cells to control levels. We document the normal ciliary recruitment, during these silencing regimes, of basal body proteins critical for ciliogenesis, namely CP110, CEP290, cenexin, Chibby, AurA, Rab8, and BBS7. Interestingly, we uncover novel interactions of Nubp1 with several members of the CCT/TRiC molecular chaperone complex, which we find enriched at the basal body and recruited independently of the Nubps or KIFC5A. Our combined results for Nubp1, Nubp2, and KIFC5A and their striking effects on cilium formation suggest a central regulatory role for these proteins, likely involving CCT/TRiC chaperone activity, in ciliogenesis. PMID- 23807207 TI - alpha-Amylase: an enzyme specificity found in various families of glycoside hydrolases. AB - alpha-Amylase (EC 3.2.1.1) represents the best known amylolytic enzyme. It catalyzes the hydrolysis of alpha-1,4-glucosidic bonds in starch and related alpha-glucans. In general, the alpha-amylase is an enzyme with a broad substrate preference and product specificity. In the sequence-based classification system of all carbohydrate-active enzymes, it is one of the most frequently occurring glycoside hydrolases (GH). alpha-Amylase is the main representative of family GH13, but it is probably also present in the families GH57 and GH119, and possibly even in GH126. Family GH13, known generally as the main alpha-amylase family, forms clan GH-H together with families GH70 and GH77 that, however, contain no alpha-amylase. Within the family GH13, the alpha-amylase specificity is currently present in several subfamilies, such as GH13_1, 5, 6, 7, 15, 24, 27, 28, 36, 37, and, possibly in a few more that are not yet defined. The alpha amylases classified in family GH13 employ a reaction mechanism giving retention of configuration, share 4-7 conserved sequence regions (CSRs) and catalytic machinery, and adopt the (beta/alpha)8-barrel catalytic domain. Although the family GH57 alpha-amylases also employ the retaining reaction mechanism, they possess their own five CSRs and catalytic machinery, and adopt a (beta/alpha)7 barrel fold. These family GH57 attributes are likely to be characteristic of alpha-amylases from the family GH119, too. With regard to family GH126, confirmation of the unambiguous presence of the alpha-amylase specificity may need more biochemical investigation because of an obvious, but unexpected, homology with inverting beta-glucan-active hydrolases. PMID- 23807209 TI - Progesterone-induced blocking factor differentially regulates trophoblast and tumor invasion by altering matrix metalloproteinase activity. AB - Invasiveness is a common feature of trophoblast and tumors; however, while tumor invasion is uncontrolled, trophoblast invasion is strictly regulated. Both trophoblast and tumor cells express high levels of the immunomodulatory progesterone-induced blocking factor (PIBF), therefore, we aimed to test the possibility that PIBF might be involved in invasion. To this aim, we used PIBF silenced or PIBF-treated trophoblast (HTR8/Svneo, and primary trophoblast) and tumor (HT-1080, A549, HCT116, PC3) cell lines. Silencing of PIBF increased invasiveness as well as MMP-2,-9 secretion of HTR8/SVneo, and decreased those of HT-1080 cells. PIBF induced immediate STAT6 activation in both cell lines. Silencing of IL-4Ralpha abrogated all the above effects of PIBF, suggesting that invasion-related signaling by PIBF is initiated through the IL-4Ralpha/PIBF receptor complex. In HTR-8/SVneo, PIBF induced fast, but transient Akt and ERK phosphorylation, whereas in tumor cells, PIBF triggered sustained Akt, ERK, and late STAT3 activation. The late signaling events might be due to indirect action of PIBF. PIBF induced the expression of EGF and HB-EGF in HT-1080 cells. The STAT3-activating effect of PIBF was reduced in HB-EGF-deficient HT-1080 cells, suggesting that PIBF-induced HB-EGF contributes to late STAT3 activation. PIBF binds to the promoters of IL-6, EGF, and HB-EGF; however, the protein profile of the protein/DNA complex is different in the two cell lines. We conclude that in tumor cells, PIBF induces proteins, which activate invasion signaling, while based on our previous data-PIBF might control trophoblast invasion by suppressing proinvasive genes. PMID- 23807212 TI - Platypnoea-orthodeoxia syndrome after an acute ischemic stroke. PMID- 23807211 TI - Antitumoral effects of 9-cis retinoic acid in adrenocortical cancer. AB - The currently available medical treatment options of adrenocortical cancer (ACC) are limited. In our previous meta-analysis of adrenocortical tumor genomics data, ACC was associated with reduced retinoic acid production and retinoid X receptor mediated signaling. Our objective has been to study the potential antitumoral effects of 9-cis retinoic acid (9-cisRA) on the ACC cell line NCI-H295R and in a xenograft model. Cell proliferation, hormone secretion, and gene expression have been studied in the NCI-H295R cell line. A complex bioinformatics approach involving pathway and network analysis has been performed. Selected genes have been validated by real-time qRT-PCR. Athymic nude mice xenografted with NCI-H295R have been used in a pilot in vivo xenograft model. 9-cisRA significantly decreased cell viability and steroid hormone secretion in a concentration- and time-dependent manner in the NCI-H295R cell line. Four major molecular pathways have been identified by the analysis of gene expression data. Ten genes have been successfully validated involved in: (1) steroid hormone secretion (HSD3B1, HSD3B2), (2) retinoic acid signaling (ABCA1, ABCG1, HMGCR), (3) cell-cycle damage (GADD45A, CCNE2, UHRF1), and the (4) immune response (MAP2K6, IL1R2). 9-cisRA appears to directly regulate the cell cycle by network analysis. 9-cisRA also reduced tumor growth in the in vivo xenograft model. In conclusion, 9-cisRA might represent a promising new candidate in the treatment of hormone-secreting adrenal tumors and adrenocortical cancer. PMID- 23807213 TI - Congenital cystic eye in utero: novel prenatal magnetic resonance imaging findings. PMID- 23807214 TI - Identification of collagen-based materials in cultural heritage. AB - All stakeholders in cultural heritage share an interest in fabrication methods and material technology. Until now methods for analysis of organic materials, particularly proteins, have not been widely available to researchers at cultural institutions. This paper will describe an analytical method for the identification of collagen-based materials from soft tissue sources and show examples of its application to diverse museum objects. The method, peptide mass fingerprinting (PMF), uses enzymatic digestion of extracted proteins to produce a mixture of peptides. The mass spectrum of the mixture contains characteristic marker ions-a peptide mass fingerprint-which are compared to species-specific markers from references as the basis of identification. Preliminary results indicate that analysis of materials from aged samples, several different tissue types, and tanned or untanned materials yields comparable PMF results. Significantly, PMF is simple, rapid, sensitive and specific, has been implemented in a museum laboratory, and is being practiced successfully by non-specialists. PMID- 23807215 TI - Knockdown of FAK inhibits the invasion and metastasis of Tca-8113 cells in vitro. AB - Tongue cancer originating on the surface of the tongue is most commonly squamous cell carcinoma, which has a higher invasive ability and a lower survival rate compared with other forms of tongue cancer. Notably, tongue squamous cell carcinomas metastasize into lymph nodes at early stages. Focal adhesion kinase (FAK) is an important protein tyrosine kinase involved in invasion and metastasis of cancer cells. In the present study, the role of FAK in the invasion and metastasis of tongue cancer was evaluated and the underlying mechanisms involved in this process were explored. FAK knockdown was performed using shRNA in the tongue cancer cell line, Tca-8113, and the invasion and metastasis potentials were analyzed using wound healing and transwell assays, respectively. Cytoskeletal arrangement was detected by fluorescence using TRITC-conjugated phalloidin staining. The activity of matrix metalloproteinase (MMP)-2 and -9 was examined by gelatin zymography. Paxillin distribution was observed by immunofluorescence. The levels of E-cadherin, N-cadherin, MMP-2 and -9, and c-Jun N-terminal kinase (JNK) was detected by western blot analysis. Wound healing and transwell assays demonstrated that FAK knockdown inhibited the invasion and metastasis of Tca-8113 cells. Further analysis revealed that FAK knockdown caused the rearrangement of the cytoskeleton and decreased the activity of MMP-2 and -9. Immunofluorescence analysis revealed that downregulation of FAK induced the relocalization of paxillin. Paxillin accumulated as dots and patches at the cell membrane in control cells. By contrast, in FAK knockdown cells, paxillin was distributed homogeneously in the cytoplasm. Western blot analysis revealed that FAK knockdown inhibited epithelial-mesenchymal transition (EMT) and decreased levels of MMP-2 and -9, and p-JNK. Knockdown of FAK inhibits the invasion and metastasis of Tca-8113 by decreasing MMP-2 and -9 activities and led to the rearrangement of the cytoskeleton and inhibited the EMT. PMID- 23807216 TI - Measurement of testosterone in human sexuality research: methodological considerations. AB - Testosterone (T) and other androgens are incorporated into an increasingly wide array of human sexuality research, but there are a number of issues that can affect or confound research outcomes. This review addresses various methodological issues relevant to research design in human studies with T; unaddressed, these issues may introduce unwanted noise, error, or conceptual barriers to interpreting results. Topics covered are (1) social and demographic factors (gender and sex; sexual orientations and sexual diversity; social/familial connections and processes; social location variables), (2) biological rhythms (diurnal variation; seasonality; menstrual cycles; aging and menopause), (3) sample collection, handling, and storage (saliva vs. blood; sialogogues, saliva, and tubes; sampling frequency, timing, and context; shipping samples), (4) health, medical issues, and the body (hormonal contraceptives; medications and nicotine; health conditions and stress; body composition, weight, and exercise), and (5) incorporating multiple hormones. Detailing a comprehensive set of important issues and relevant empirical evidence, this review provides a starting point for best practices in human sexuality research with T and other androgens that may be especially useful for those new to hormone research. PMID- 23807210 TI - UCP2, a mitochondrial protein regulated at multiple levels. AB - An ever-increasing number of studies highlight the role of uncoupling protein 2 (UCP2) in a broad range of physiological and pathological processes. The knowledge of the molecular mechanisms of UCP2 regulation is becoming fundamental in both the comprehension of UCP2-related physiological events and the identification of novel therapeutic strategies based on UCP2 modulation. The study of UCP2 regulation is a fast-moving field. Recently, several research groups have made a great effort to thoroughly understand the various molecular mechanisms at the basis of UCP2 regulation. In this review, we describe novel findings concerning events that can occur in a concerted manner at various levels: Ucp2 gene mutation (single nucleotide polymorphisms), UCP2 mRNA and protein expression (transcriptional, translational, and protein turn-over regulation), UCP2 proton conductance (ligands and post-transcriptional modifications), and nutritional and pharmacological regulation of UCP2. PMID- 23807217 TI - Identification of cancer gene fusions based on advanced analysis of the human genome or transcriptome. AB - Many gene fusions have been recognized as important diagnostic and/or prognostic markers in human malignancies. In recent years, novel gene fusions have been identified in cases without prior knowledge of the genetic background. Accompanied by a powerful computational data analysis method, new genome-wide screening approaches were used to detect cryptic genomic aberrations. This review focused on advanced genomewide screening approaches in fusion gene identification, such as microarray-based approaches, next-generation sequencing, and NanoString nCounter gene expression system. The fundamental rationale and strategy for fusion gene identification using each biotech platform are also discussed. PMID- 23807218 TI - Mature neurons: equipped for survival. AB - Neurons completely transform how they regulate cell death over the course of their lifetimes. Developing neurons freely activate cell death pathways to fine tune the number of neurons that are needed during the precise formation of neural networks. However, the regulatory balance between life and death shifts as neurons mature beyond early development. Mature neurons promote survival at all costs by employing multiple, often redundant, strategies to prevent cell death by apoptosis. This dramatic shift from permitting cell death to ensuring cellular survival is critical, as these post-mitotic cells must provide neuronal circuitry for an organism's entire lifetime. Importantly, as many neurodegenerative diseases afflict adult neuronal populations, the survival mechanisms in mature neurons are likely to be either reversed or circumvented during neurodegeneration. Examining the adaptations for inhibiting apoptosis during neuronal maturation is key to comprehending not just how neurons survive long term, but may also provide insight for understanding how neuronal toxicity in various neurodegenerative diseases may ultimately lead to cell death. PMID- 23807219 TI - Gossypol and an HMT G9a inhibitor act in synergy to induce cell death in pancreatic cancer cells. AB - The histone methyltransferase G9a is overexpressed in a variety of cancer types, including pancreatic adenocarcinoma, and promotes tumor invasiveness and metastasis. We recently reported the discovery of BRD4770, a small-molecule inhibitor of G9a that induces senescence in PANC-1 cells. We observed that the cytotoxic effects of BRD4770 were dependent on genetic background, with cell lines lacking functional p53 being relatively resistant to compound treatment. To understand the mechanism of genetic selectivity, we used two complementary screening approaches to identify enhancers of BRD4770. The natural product and putative BH3 mimetic gossypol enhanced the cytotoxicity of BRD4770 in a synergistic manner in p53-mutant PANC-1 cells but not in immortalized non tumorigenic pancreatic cells. The combination of gossypol and BRD4770 increased LC3-II levels and the autophagosome number in PANC-1 cells, and the compound combination appears to act in a BNIP3 (B-cell lymphoma 2 19-kDa interacting protein)-dependent manner, suggesting that these compounds act together to induce autophagy-related cell death in pancreatic cancer cells. PMID- 23807220 TI - Human mesenchymal stem cell-replicative senescence and oxidative stress are closely linked to aneuploidy. AB - In most clinical trials, human mesenchymal stem cells (hMSCs) are expanded in vitro before implantation. The genetic stability of human stem cells is critical for their clinical use. However, the relationship between stem-cell expansion and genetic stability is poorly understood. Here, we demonstrate that within the normal expansion period, hMSC cultures show a high percentage of aneuploid cells that progressively increases until senescence. Despite this accumulation, we show that in a heterogeneous culture the senescence-prone hMSC subpopulation has a lower proliferation potential and a higher incidence of aneuploidy than the non senescent subpopulation. We further show that senescence is linked to a novel transcriptional signature that includes a set of genes implicated in ploidy control. Overexpression of the telomerase catalytic subunit (human telomerase reverse transcriptase, hTERT) inhibited senescence, markedly reducing the levels of aneuploidy and preventing the dysregulation of ploidy-controlling genes. hMSC replicative senescence was accompanied by an increase in oxygen consumption rate (OCR) and oxidative stress, but in long-term cultures that overexpress hTERT, these parameters were maintained at basal levels, comparable to unmodified hMSCs at initial passages. We therefore propose that hTERT contributes to genetic stability through its classical telomere maintenance function and also by reducing the levels of oxidative stress, possibly, by controlling mitochondrial physiology. Finally, we propose that aneuploidy is a relevant factor in the induction of senescence and should be assessed in hMSCs before their clinical use. PMID- 23807221 TI - Signal-dependent fra-2 regulation in skeletal muscle reserve and satellite cells. AB - Activator protein-1 (AP-1) is a ubiquitous transcription factor that paradoxically also has some tissue-specific functions. In skeletal muscle cells, we document that the AP-1 subunit, Fra-2, is expressed in the resident stem cells (Pax7-positive satellite cells) and also in the analogous undifferentiated 'reserve' cell population in myogenic cultures, but not in differentiated myofiber nuclei. Silencing of Fra-2 expression enhances the expression of differentiation markers such as muscle creatine kinase and myosin heavy chain, indicating a possible role of Fra-2 in undifferentiated myogenic progenitor cells. We observed that Fra-2 is a target of cytokine-mediated extracellular signal-regulated kinase-1/2 signaling in cultured muscle cells, and extensive mass spectrometry and mutational analysis identified S320 and T322 as regulators of Fra-2 protein stability. Interestingly, Fra-2 S320 phosphorylation occurs transiently in activated satellite cells and is extinguished in myogenin-positive differentiating cells. Thus, cytokine-mediated Fra-2 expression and stabilization is linked to regulation of myogenic progenitor cells having implications for the molecular regulation of adult muscle stem cells and skeletal muscle regeneration. PMID- 23807222 TI - Salinomycin induces cell death via inactivation of Stat3 and downregulation of Skp2. AB - Salinomycin has been shown to control breast cancer stem cells, although the mechanisms underlying its anticancer effects are not clear. Deregulation of cell cycle regulators play critical roles in tumorigenesis, and they have been considered as anticancer targets. In this study, we investigated salinomycin effect on cell cycle progression using OVCAR-8 ovarian cancer cell line and multidrug-resistant NCI/ADR-RES and DXR cell lines that are derived from OVCAR-8. Parental OVCAR-8 cells are sensitive to several anticancer drugs, but NCI/ADR-RES and DXR cells are resistant to several anticancer drugs. However, salinomycin caused cell growth inhibition and apoptosis via cell cycle arrest at G1 in all three cell lines. Salinomycin inhibited signal transducer and activator of transcription 3 (Stat3) activity and thus decreased expression of Stat3-target genes, including cyclin D1, Skp2, and survivin. Salinomycin induced degradation of Skp2 and thus accumulated p27Kip1. Knockdown of Skp2 further increased salinomycin-induced G1 arrest, but knockdown of p27Kip1 attenuated salinomycin effect on G1 arrest. Cdh1, an E3 ligase for Skp2, was shifted to nuclear fractions upon salinomycin treatment. Cdh1 knockdown by siRNA reversed salinomycin-induced Skp2 downregulation and p27Kip1 upregulation, indicating that salinomycin activates the APC(Cdh1)-Skp2-p27Kip1 pathway. Concomitantly, si-Cdh1 inhibited salinomycin-induced G1 arrest. Taken together, our data indicate that salinomycin induces cell cycle arrest and apoptosis via downregulation or inactivation of cell cycle-associated oncogenes, such as Stat3, cyclin D1, and Skp2, regardless of multidrug resistance. PMID- 23807223 TI - Dual role of chloroquine in liver ischemia reperfusion injury: reduction of liver damage in early phase, but aggravation in late phase. AB - The anti-malaria drug chloroquine is well known as autophagy inhibitor. Chloroquine has also been used as anti-inflammatory drugs to treat inflammatory diseases. We hypothesized that chloroquine could have a dual effect in liver ischemia/reperfusion (I/R) injury: chloroquine on the one hand could protect the liver against I/R injury via inhibition of inflammatory response, but on the other hand could aggravate liver I/R injury through inhibition of autophagy. Rats (n=6 per group) were pre-treated with chloroquine (60 mg/kg, i.p.) 1 h before warm ischemia, and they were continuously subjected to a daily chloroquine injection for up to 2 days. Rats were killed 0.5, 6, 24 and 48 h after reperfusion. At the early phase (i.e., 0-6 h after reperfusion), chloroquine treatment ameliorated liver I/R injury, as indicated by lower serum aminotransferase levels, lower hepatic inflammatory cytokines and fewer histopathologic changes. In contrast, chloroquine worsened liver injury at the late phase of reperfusion (i.e., 24-48 h after reperfusion). The mechanism of protective action of chloroquine appeared to involve its ability to modulate mitogen-activated protein kinase activation, reduce high-mobility group box 1 release and inflammatory cytokines production, whereas chloroquine worsened liver injury via inhibition of autophagy and induction of hepatic apoptosis at the late phase. In conclusion, chloroquine prevents ischemic liver damage at the early phase, but aggravates liver damage at the late phase in liver I/R injury. This dual role of chloroquine should be considered when using chloroquine as an inhibitor of inflammation or autophagy in I/R injury. PMID- 23807224 TI - MicroRNA-195 targets ADP-ribosylation factor-like protein 2 to induce apoptosis in human embryonic stem cell-derived neural progenitor cells. AB - Neural progenitor cells (NPCs) derived from human embryonic stem cells (hESCs) have great potential in cell therapy, drug screening and toxicity testing of neural degenerative diseases. However, the molecular regulation of their proliferation and apoptosis, which needs to be revealed before clinical application, is largely unknown. MicroRNA miR-195 is known to be expressed in the brain and is involved in a variety of proapoptosis or antiapoptosis processes in cancer cells. Here, we defined the proapoptotic role of miR-195 in NPCs derived from two independent hESC lines (human embryonic stem cell-derived neural progenitor cells, hESC-NPCs). Overexpression of miR-195 in hESC-NPCs induced extensive apoptotic cell death. Consistently, global transcriptional microarray analyses indicated that miR-195 primarily regulated genes associated with apoptosis in hESC-NPCs. Mechanistically, a small GTP-binding protein ADP ribosylation factor-like protein 2 (ARL2) was identified as a direct target of miR-195. Silencing ARL2 in hESC-NPCs provoked an apoptotic phenotype resembling that of miR-195 overexpression, revealing for the first time an essential role of ARL2 for the survival of human NPCs. Moreover, forced expression of ALR2 could abolish the cell number reduction caused by miR-195 overexpression. Interestingly, we found that paraquat, a neurotoxin, not only induced apoptosis but also increased miR-195 and reduced ARL2 expression in hESC-NPCs, indicating the possible involvement of miR-195 and ARL2 in neurotoxin-induced NPC apoptosis. Notably, inhibition of miR-195 family members could block neurotoxin-induced NPC apoptosis. Collectively, miR-195 regulates cell apoptosis in a context-dependent manner through directly targeting ARL2. The finding of the critical role of ARL2 for the survival of human NPCs and association of miR-195 and ARL2 with neurotoxin-induced apoptosis have important implications for understanding molecular mechanisms that control NPC survival and would facilitate our manipulation of the neurological pathogenesis. PMID- 23807225 TI - ATP citrate lyase knockdown impacts cancer stem cells in vitro. AB - ATP citrate lyase (ACL) knockdown (KD) causes tumor suppression and induces differentiation. We have previously reported that ACL KD reverses epithelial mesenchymal transition (EMT) in lung cancer cells. Because EMT is often associated with processes that induce stemness, we hypothesized that ACL KD impacts cancer stem cells. By assessing tumorsphere formation and expression of stem cell markers, we showed this to be the case in A549 cells, which harbor a Ras mutation, and in two other non-small-cell lung cancer cell lines, H1975 and H1650, driven by activating EGFR mutations. Inducible ACL KD had the same effect as stable ACL KD. Similar effects were noted in another well-characterized Ras induced mammary model system (HMLER). Moreover, treatment with hydroxycitrate phenocopied the effects of ACL KD, suggesting that the enzymatic activity of ACL was critical. Indeed, acetate treatment reversed the ACL KD phenotype. Having previously established that ACL KD impacts signaling through the phosphatidylinositol 3-kinase (PI3K) pathway, not the Ras-mitogen-activated protein kinase (MAPK) pathway, and that EMT can be reversed by PI3K inhibitors, we were surprised to find that stemness in these systems was maintained through Ras-MAPK signaling, and not via PI3K signaling. Snail is a downstream transcription factor impacted by Ras-MAPK signaling and known to promote EMT and stemness. We found that snail expression was reduced by ACL KD. In tumorigenic HMLER cells, ACL overexpression increased snail expression and stemness, both of which were reduced by ACL KD. Furthermore, ACL could not initiate either tumorigenesis or stemness by itself. ACL and snail proteins interacted and ACL expression regulated the transcriptional activity of snail. Finally, ACL KD counteracted stem cell characteristics induced in diverse cell systems driven by activation of pathways outside of Ras-MAPK signaling. Our findings unveil a novel aspect of ACL function, namely its impact on cancer stemness in a broad range of genetically diverse cell types. PMID- 23807226 TI - Hypericin-photodynamic therapy leads to interleukin-6 secretion by HepG2 cells and their apoptosis via recruitment of BH3 interacting-domain death agonist and caspases. AB - Photodynamic therapy (PDT) has emerged as a capable therapeutic modality for the treatment of cancer. PDT is a targeted cancer therapy that reportedly leads to tumor cell apoptosis and/or necrosis by facilitating the secretion of certain pro inflammatory cytokines and expression of multiple apoptotic mediators in the tumor microenvironment. In addition, PDT also triggers oxidative stress that directs tumor cell killing and activation of inflammatory responses. However, the cellular and molecular mechanisms underlying the role of PDT in facilitating tumor cell apoptosis remain ambiguous. Here, we investigated the ability of PDT in association with hypericin (HY) to induce tumor cell apoptosis by facilitating the induction of reactive oxygen species (ROS) and secretion of Th1/Th2/Th17 cytokines in human hepatocellular liver carcinoma cell line (HepG2) cells. To discover if any apoptotic mediators were implicated in the enhancement of cell death of HY-PDT-treated tumor cells, selected gene profiling in response to HY PDT treatment was implemented. Experimental results showed that interleukin (IL) 6 was significantly increased in all HY-PDT-treated cells, especially in 1 MUg/ml HY-PDT, resulting in cell death. In addition, quantitative real-time PCR analysis revealed that the expression of apoptotic genes, such as BH3-interacting-domain death agonist (BID), cytochrome complex (CYT-C) and caspases (CASP3, 6, 7, 8 and 9) was remarkably higher in HY-PDT-treated HepG2 cells than the untreated HepG2 cells, entailing that tumor destruction of immune-mediated cell death occurs only in PDT-treated tumor cells. Hence, we showed that HY-PDT treatment induces apoptosis in HepG2 cells by facilitating cytotoxic ROS, and potentially recruits IL-6 and apoptosis mediators, providing additional hints for the existence of alternative mechanisms of anti-tumor immunity in hepatocellular carcinoma, which contribute to long-term suppression of tumor growth following PDT. PMID- 23807227 TI - Inhibition of Rac1 promotes BMP-2-induced osteoblastic differentiation. AB - Small G proteins of the Rho family are pivotal regulators of several signaling networks. The Ras homolog family (Rho) and one of its targets, Rho-associated protein kinase (ROCK), participate in a wide variety of biological processes, including bone formation. A previous study has demonstrated that the ROCK inhibitor Y-27632 enhanced bone formation induced by recombinant human bone morphogenetic protein-2 (BMP-2) in vivo and in vitro. However, the effect of other Rho family members, such as Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division cycle 42 (Cdc42), on bone formation remains unknown. In this study, we investigated whether Rac1 also participates in BMP-2-induced osteogenesis. Expression of a dominant-negative mutant of Rac1 enhanced BMP-2 induced osteoblastic differentiation in C2C12 cells, whereas a constitutively active mutant of Rac1 attenuated that effect. Knockdown of T-lymphoma invasion and metastasis 1 (Tiam1), a Rac-specific guanine nucleotide exchange factor, enhanced BMP-2-induced alkaline phosphatase activity. Further, we demonstrated that BMP-2 stimulated Rac1 activity. These results indicate that the activation of Rac1 attenuates osteoblastic differentiation in C2C12 cells. PMID- 23807229 TI - Enzyme immobilisation: fundamentals and application. PMID- 23807228 TI - Repression of ATR pathway by miR-185 enhances radiation-induced apoptosis and proliferation inhibition. AB - Cellular responses to DNA damage induced by intrinsic and extrinsic genotoxic stresses are highly regulated by complex signaling pathways, such as activation of the phosphoinositide-3-kinase-like protein kinase family and their downstream genes. Disruption of these signaling pathways leads to genome instability and cell death, and thus may provide potential novel strategies for cancer therapy. Here, we find that the expression of a human microRNA (miRNA), hsa-miR-185, is downregulated in response to ionizing radiation. Elevation of miR-185 sensitizes renal cell carcinoma cells to X-rays both in vitro and in vivo. Bioinformatic analysis shows that the ATM- and Rad3-related (ATR) kinase, a master conductor of cellular responses to DNA damage and DNA replication stresses, is a target of miR 185. This prediction was validated by luciferase reporter and mutation assays. We also demonstrated that miR-185 negatively regulates ATR expression at post transcriptional level. miR-185 enhances radiation-induced apoptosis and inhibition of proliferation by repressing ATR pathway. In conclusion, our findings indicate a previously unreported regulatory mechanism for ATR expression mediated by miR-185 and shed light on the potential application of miRNAs both as direct cancer therapeutics and as tools to sensitize tumor cells to radiotherapy. PMID- 23807230 TI - Cancer risk in patients with cholelithiasis and after cholecystectomy: a nationwide cohort study. AB - BACKGROUND: This study examined the association of cholelithiasis post cholecystectomy with subsequent cancers and evaluated the risk of cancer in patients with both cholelithiasis and cholecystectomy. METHODS: The Taiwanese National Health Insurance Research Database was used to identify 15545 newly diagnosed cholelithiasis patients from 2000 to 2010, and 62180 frequency-matched non-cholelithiasis patients. A total of 5850 (37.6 %) with cholelithiasis patients received a cholecystectomy. The risk of developing cancer after cholecystectomy was measured using the Cox proportional-hazards model. RESULTS: The incidence of developing cancer in the cholelithiasis cohort was 1.52-fold higher than that in the comparison cohort (p < 0.001). Compared with patients aged 20-34 years, patients in older age groups had a higher risk of developing cancer. The hazard ratio (HR) for developing gallbladder, extrahepatic bile duct, pancreatic, liver, stomach, and colorectal cancer was 59.3, 10.7, 3.12, 1.90, 1.71, and 1.36-fold higher for patients with cholelithiasis, respectively. After a cholecystectomy, the HR for developing stomach and colorectal cancer was 1.81 fold and 1.56-fold, respectively. The incidence rate ratio was higher for the first 5 years and over 5 years (5.05 and 4.46, respectively) (95 % confidence interval 4.73-5.39 and 4.11-4.84, respectively) in proximal colon and stomach cancer patients with cholecystectomies. CONCLUSIONS: Cholelithiasis patients have a higher risk of gastrointestinal cancer, particularly of gallbladder and extrahepatic bile duct cancer. Post-cholecystectomy patients have a risk of colorectal and stomach cancer within the first 5 years and persisting after 5 years, respectively. This paper proposes strategies for preventing gastrointestinal cancer. PMID- 23807231 TI - A cytometric bead assay for sensitive DNA detection based on enzyme-free signal amplification of hybridization chain reaction. AB - A versatile flow cytometric bead assay (CBA) is developed for sensitive DNA detection by integrating the advantages of hybridization chain reaction (HCR) for enzyme-free signal amplification, flow cytometry for robust and rapid signal readout as well as magnetic beads (MBs) for facile separation. In this HCR-CBA, a biotinylated hairpin DNA (Bio-H1) is firstly immobilized on streptavidin functionalized MBs. Upon the addition of target DNA, each target would hybridize with one Bio-H1 to open its hairpin structure and subsequently initiate a cascade of hybridization events between two species of fluorescent DNA hairpin probes (H1*/H2*) to form a nicked double helical DNA structure, resulting in amplified accumulation of numerous fluorophores on the MBs. Finally, the fluorescent MBs are directly analyzed by flow cytometry. This technique enables quantitative analysis of the HCR products anchored on the MBs as a function of target DNA concentration, and analysis of each sample can be completed within few minutes. Therefore, the HCR-CBA approach provides a practical DNA assay with greatly improved sensitivity. The detection limit of a model DNA target is 0.5 pM (3sigma), which is about 3 orders of magnitude lower compared with traditional hybridization methods without HCR. Furthermore, the signal of complementary target can be clearly distinguished from that of single-base mismatched sequences, indicating the high specificity of the HCR-CBA. Moreover, this strategy is also successfully applied to the DNA analysis in complex biological samples, showing great potential in gene analysis and disease diagnosis in clinical samples. PMID- 23807232 TI - Stepwise reagent introduction-based droplet platform for multiplexed DNA sensing. AB - A stepwise reagent introduction (SRI)-based droplet platform is reported to apply in multiplexed DNA sensing via droplet imaging and manipulation techniques. The feature of SRI-based droplet platform is that the multiplexed DNA measurements are performed simultaneously without the need for expensive optical instruments. This is achieved by sequentially driving five different DNA probes labeled with carboxyfluorescein into the same chip channel to individually form droplet and fuse with target DNAs and graphene oxide droplets. Based on the variation of droplet color and fluorescence intensity, rapidly qualitative and quantitative DNA analysis are realized. The cooperation between SRI mode and droplet platform thus opens up the possibility of greatly simplified DNA sensing in high throughput format without complicated fluorescent labeling and chip design. PMID- 23807233 TI - A paper-based microbial fuel cell: instant battery for disposable diagnostic devices. AB - We present a microfabricated paper-based microbial fuel cell (MFC) generating a maximum power of 5.5 MUW/cm(2). The MFC features (1) a paper-based proton exchange membrane by infiltrating sulfonated sodium polystyrene sulfonate and (2) micro-fabricated paper chambers by patterning hydrophobic barriers of photoresist. Once inoculum and catholyte were added to the MFC, a current of 74 MUA was generated immediately. This paper-based MFC has the advantages of ease of use, low production cost, and high portability. The voltage produced was increased by 1.9 * when two MFC devices were stacked in series, while operating lifetime was significantly enhanced in parallel. PMID- 23807234 TI - A novel Au-nanoparticle biosensor for the rapid and simple detection of PSA using a sequence-specific peptide cleavage reaction. AB - PSA (prostate-specific antigen) is one of the most widely used proteins for the diagnosis of breast and prostate cancer. Of note, PSA displays enzymatic activity for the specific peptide sequence HSSKLQ, which it recognizes and cleaves. In this study, we developed a site-specific enzymatic-cleavage-reaction-based biosensor for the detection of PSA using fluorescein isothiocyanate (FITC)/peptide-conjugated gold (Au) nanoparticle complexes (FPANs). The FPANs do not initially fluoresce in the spectral region associated with the fluorophore, due to the quenching effect of the Au nanoparticles. When PSA was added to a solution containing the FPANs, PSA recognized and cleaved the specific sequence of the peptides attached to the Au nanoparticles. As a result, FITCs were separated from the Au nanoparticles and emitted strong fluorescence in their spectral region. Using this detection method, PSA was successfully detected as a function of concentration (10 pM-100 nM). This approach is superior to the immunoassay with respect to the performance of sensor, which is very rapid, simple, and one-step method for the detection of PSA and other protein markers can be measured for the early detection of several diseases. PMID- 23807235 TI - Stable label-free fluorescent sensing of biothiols based on ThT direct inducing conformation-specific G-quadruplex. AB - In this work, a new, label-free, turn-on fluorescent sensor for biothiols detection based on ThT direct inducing conformation-specific G-quadruplex is developed. The sensing approach is based on a conformational switch of oligonucleotide controlled by Hg(2+) and a commercially available water-soluble fluorescent dye, Thioflavin T (ThT). A noticeable fluorescence light-up in ThT on binding to the G-quadruplex grants the sensor excellent sensitivity. The specific quadruplex conformation induced directly by ThT and pronounced structural selectivity of ThT for G-quadruplexes could generate more stable luminescence and make sure high specificity in complex biological samples. The present assay allows for the selective determination of cysteine and glutathione in the range of 2.0 * 10(-8)-2.5 * 10(-6)M and 3.0 * 10(-8)-2.0 * 10(-6)M with a detection limit of 8.4 nM and 13.9 nM respectively. The diagnostic capability and potential in practical applications of this method have been demonstrated by detecting biothiols in human blood serum. PMID- 23807236 TI - Multi-component immunochromatographic assay for simultaneous detection of aflatoxin B1, ochratoxin A and zearalenone in agro-food. AB - Mycotoxins are highly toxic contaminants and have induced health threat to human and animals. Aflatoxin B1 (AFB1), ochratoxin A (OTA) and zearalenone (ZEA) commonly occur in food and feed. A multi-component immunochromatographic assay (ICA) was developed for rapid and simultaneous determination of these three mycotoxins in agro-food. The strategy was performed based on the competitive immunoreactions between antibody-colloidal gold nanoparticle conjugate probes and mycotoxins or mycotixin antigens. Each monoclonal antibody specially recognize its corresponding mycotoxin and antigen, and there was no cross reactivity in the assay. Three mycotixin antigens were immobilized as three test lines in the nitrocellulose membrane reaction zone, which enable the simultaneous detection in one single test. The visible ICA results were obtained in 20 min. The visual detection limits of this strip test for the AFB1, OTA and ZEA were 0.25 ng/mL, 0.5 ng/mL and 1 ng/mL, respectively. The assay was evaluated using spiked and naturally contaminated peanuts, maize and rice samples. The results were in accordance with those obtained using enzyme-linked immunosorbent assay. In summary, this developed ICA could provide an effective and rapid approach for onsite detection of multi-mycotoxin in agro-food samples without any expensive instrument. PMID- 23807237 TI - Intact emotion-cognition interaction in schizophrenia patients and first-degree relatives: evidence from an emotional antisaccade task. AB - Schizophrenia patients have deficits in cognitive control as well as in a number of emotional domains. The antisaccade task is a measure of cognitive control that requires the inhibition of a reflex-like eye movement to a peripheral stimulus. Antisaccade performance has been shown to be modulated by the emotional content of the peripheral stimuli, with emotional stimuli leading to higher error rates than neutral stimuli, reflecting an implicit emotion processing effect. The aim of the present study was to investigate the impact on antisaccade performance of threat-related emotional facial stimuli in schizophrenia patients, first-degree relatives of schizophrenia patients and healthy controls. Fifteen patients, 22 relatives and 26 controls, matched for gender, age and verbal intelligence, carried out an antisaccade task with pictures of faces displaying disgusted, fearful and neutral expressions as peripheral stimuli. We observed higher antisaccade error rates in schizophrenia patients compared to first-degree relatives and controls. Relatives and controls did not differ significantly from each other. Antisaccade error rate was influenced by the emotional nature of the stimuli: participants had higher antisaccade error rates in response to fearful faces compared to neutral and disgusted faces. As this emotional influence on cognitive control did not differ between groups we conclude that implicit processing of emotional faces is intact in patients with schizophrenia and those at risk for the illness. PMID- 23807238 TI - The relation between electroencephalogram asymmetry and attention biases to threat at baseline and under stress. AB - Electroencephalogram (EEG) asymmetry in the alpha frequency band has been implicated in emotion processing and broad approach-withdrawal motivation systems. Questions remain regarding the cognitive mechanisms that may help elucidate the observed links between EEG asymmetry and patterns of socioemotional functioning. The current study observed frontal EEG asymmetry patterns at rest and under social threat among young adults (N=45, M=21.1 years). Asymmetries were, in turn, associated with performance on an emotion-face dot-probe attention bias task. Attention biases to threat have been implicated as potential causal mechanisms in anxiety and social withdrawal. Frontal EEG asymmetry at baseline did not predict attention bias patterns to angry or happy faces. However, increases in right frontal alpha asymmetry from baseline to the stressful speech condition were associated with vigilance to angry faces and avoidance of happy faces. The findings may reflect individual differences in the pattern of response (approach or withdrawal) with the introduction of a mild stressor. Comparison analyses with frontal beta asymmetry and parietal alpha asymmetry did not find similar patterns. Thus, the data may reflect the unique role of frontal regions, particularly the dorsolateral prefrontal cortex, in cognitive control and threat detection, coupled with ruminative processes associated with alpha activity. PMID- 23807239 TI - Nicotine deprivation influences P300 markers of cognitive control. AB - Studies suggest that reduced cognitive control due to nicotine withdrawal may have a critical role in promoting tobacco use. The P3 family of event-related brain potential (ERP) components is thought to serve as markers of cognitive control processes. Unfortunately, existing research that examines the effects of nicotine deprivation on P3 amplitude has been marred by small sample sizes and other design limitations. The present study sought to determine the effects of nicotine deprivation on P3b and P3a amplitudes, which index task relevant target detection and orienting responses to novelty, respectively. A secondary aim was to examine self-reported trait cognitive control as a moderator of nicotine deprivation-induced reductions in P3b and P3a amplitudes. In all, 121 nicotine dependent smokers attended two experimental sessions following 12-h smoking/nicotine deprivation. In a counterbalanced manner, participants smoked nicotine cigarettes during one session and placebo cigarettes during the other session. Findings indicated that nicotine deprivation reduced P3b amplitude (p<0.00001) during a three-stimulus oddball task independent of trait cognitive control. In contrast, nicotine deprivation reduced P3a only among participants who scored lower on measures of trait cognitive control. Implications for conceptualizing risk for nicotine dependence, and its treatment, are discussed. PMID- 23807241 TI - A framework for testing and promoting expanded dissemination of promising preventive interventions that are being implemented in community settings. AB - Many evidence-based preventive interventions have been developed in recent years, but few are widely used. With the current focus on efficacy trials, widespread dissemination and implementation of evidence-based interventions are often afterthoughts. One potential strategy for reversing this trend is to find a promising program with a strong delivery vehicle in place and improve and test the program's efficacy through rigorous evaluation. If the program is supported by evidence, the dissemination vehicle is already in place and potentially can be expanded. This strategy has been used infrequently and has met with limited success to date, in part, because the field lacks a framework for guiding such research. To address this gap, we outline a framework for moving promising preventive interventions that are currently being implemented in community settings through a process of rigorous testing and, if needed, program modification in order to promote expanded dissemination. The framework is guided by RE-AIM (Reach, Efficacy/Effectiveness, Adoption, Implementation, and Maintenance) (Glasgow et al., Am J Publ Health 89:1322-1327, 1999), which focuses attention on external as well as internal validity in program tests, and is illustrated with examples. Challenges, such as responding to negative and null results, and opportunities inherent in the framework are discussed. PMID- 23807240 TI - Mood and memory deficits in a model of Gulf War illness are linked with reduced neurogenesis, partial neuron loss, and mild inflammation in the hippocampus. AB - Impairments in mood and cognitive function are the key brain abnormalities observed in Gulf war illness (GWI), a chronic multisymptom health problem afflicting ~25% of veterans who served in the Persian Gulf War-1. Although the precise cause of GWI is still unknown, combined exposure to a nerve gas prophylaxis drug pyridostigmine bromide (PB) and pesticides DEET and permethrin during the war has been proposed as one of the foremost causes of GWI. We investigated the effect of 4 weeks of exposure to Gulf war illness-related (GWIR) chemicals in the absence or presence of mild stress on mood and cognitive function, dentate gyrus neurogenesis, and neurons, microglia, and astrocytes in the hippocampus. Combined exposure to low doses of GWIR chemicals PB, DEET, and permethrin induced depressive- and anxiety-like behavior and spatial learning and memory dysfunction. Application of mild stress in the period of exposure to chemicals exacerbated the extent of mood and cognitive dysfunction. Furthermore, these behavioral impairments were associated with reduced hippocampal volume and multiple cellular alterations such as chronic reductions in neural stem cell activity and neurogenesis, partial loss of principal neurons, and mild inflammation comprising sporadic occurrence of activated microglia and significant hypertrophy of astrocytes. The results show the first evidence of an association between mood and cognitive dysfunction and hippocampal pathology epitomized by decreased neurogenesis, partial loss of principal neurons, and mild inflammation in a model of GWI. Hence, treatment strategies that are efficacious for enhancing neurogenesis and suppressing inflammation may be helpful for alleviation of mood and cognitive dysfunction observed in GWI. PMID- 23807242 TI - Arterial hypertension and cardiovascular risk in HIV-infected patients. AB - The dramatic change of the natural history of HIV-infected patients by highly active antiretroviral therapy (HAART) has exposed these patients to cardiovascular risk, including cardiovascular disease and hypertension. In HIV infected patients, the development of arterial hypertension, at least in the medium-long term is an established feature, although recognized predictors of its development have not been clearly identified. In addition, conflicting data regarding the influence of antiretroviral therapy (ART) are reported. The presence of a proinflammatory state and oxidative stress-mediated endothelial dysfunction seem, however, to play a pathophysiologic role. In this review, we examine and provide a comprehensive, literature based, consideration of the pathophysiologic aspects of hypertension in these patients. HIV-infected patients, independently of the presence of hypertension, remain at very high cardiovascular risk due to the presence of the same cardiovascular risk factors recognized for the general population with, in addition, the indirect influence of the ART, essentially via its effect on lipid metabolism. This review based on the evidence from the literature, concludes that the management of HIV-infected patients in terms of cardiovascular prevention emerges as a priority. The consideration of cardiovascular risk in these patients should receive the same emphasis given for the general population at high cardiovascular risk, including adequate blood pressure control according to international guidelines. PMID- 23807243 TI - Heme oxygenase 1 modulates thrombomodulin and endothelial protein C receptor levels to attenuate septic kidney injury. AB - This study investigated the effects of heme oxygenase 1 (HO-1) on thrombomodulin (TM) and endothelial protein C receptor (EPCR) expression in sepsis-induced kidney injury. The role of HO-1 was evaluated in a cecal ligation and puncture (CLP)-induced model. Wistar rats were randomly assigned into four groups: sham, CLP, CLP + hemin (an HO-1 inducer), CLP + ZnPP (zinc protoporphyrin IX, an HO-1 inhibitor), and CLP + bilirubin. Compared with the sham group, the CLP group exhibited significantly elevated plasma levels of cystatin C, creatinine, urea nitrogen (blood urea nitrogen), tumor necrosis factor alpha, interleukin 1beta, TM, and EPCR; lower plasma level of activated protein C, shorter prothrombin time and activated partial thromboplastin time; significantly increased microthrombus formation; and lower TM and EPCR mRNA and protein expression in the kidney. The administration of hemin lowered the plasma levels of cystatin C, creatinine, blood urea nitrogen, tumor necrosis factor alpha, interleukin 1beta, TM, and EPCR; elevated plasma level of activated protein C; prolonged prothrombin time and activated partial thromboplastin time; attenuated microthrombus formation; and upregulated the expression of TM and EPCR and mRNA levels of TM and EPCR in the kidney in the CLP + hemin group. In contrast, ZnPP had the opposite effects. The results indicated that the enhanced induction of HO-1 increased the expression of TM and EPCR in the kidney and exerted an anticoagulant effect, thereby attenuating kidney injury in septic rats. PMID- 23807244 TI - Inflammatory mechanisms in sepsis: elevated invariant natural killer T-cell numbers in mouse and their modulatory effect on macrophage function. AB - Invariant natural killer T cells (iNKT) cells are emerging as key mediators of innate immune cellular and inflammatory responses to sepsis and peritonitis. Invariant natural killer T cells mediate survival following murine septic shock. Macrophages are pivotal to survival following sepsis. Invariant natural killer T cells have been shown to modulate various mediators of the innate immune system, including macrophages. We demonstrate sepsis-inducing iNKT-cell exodus from the liver appearing in the peritoneal cavity, the source of the sepsis. This migration was affected by programmed death receptor 1. Programmed death receptor 1 is an inhibitory immune receptor, reported as ubiquitously expressed at low levels on iNKT cells. Programmed death receptor 1 has been associated with markers of human critical illness. Programmed death receptor 1-deficient iNKT cells failed to demonstrate similar migration. To the extent that iNKT cells affected peritoneal macrophage function, we assessed peritoneal macrophages' ability to phagocytose bacteria. Invariant natural killer T(-/-) mice displayed dysfunctional macrophage phagocytosis and altered peritoneal bacterial load. This dysfunction was reversed when peritoneal macrophages from iNKT(-/-) mice were cocultured with wild-type iNKT cells. Together, our results indicate that sepsis induces liver iNKT-cell exodus into the peritoneal cavity mediated by programmed death receptor 1, and these peritoneal iNKT cells appear critical to regulation of peritoneal macrophage phagocytic function. Invariant natural killer T cells offer therapeutic targets for modulating immune responses and detrimental effects of sepsis. PMID- 23807245 TI - Adoptive transfer of fibrocytes enhances splenic T-cell numbers and survival in septic peritonitis. AB - Fibrocytes are unique, fibroblast-like cells with diverse functions and the potential for immunomodulation, which prompted investigation of their previously unexplored role in sepsis. Specifically, the study goals were to determine if adoptive transfer of fibrocytes would affect outcome in sepsis and to define relevant immunopathologic changes associated with the outcomes. Initial in vitro studies demonstrated that naive T-cell proliferation was significantly increased in cocultures with tissue-derived fibrocytes as compared with culture either alone or with fibroblasts. In vivo, the adoptive transfer of fibrocytes at the time of cecal ligation and puncture significantly improved survival of mice compared with transfer of fibroblasts or saline. Septic mice had lower blood levels of interleukin 6 (IL-6) and markers of organ injury after fibrocyte transfer as well as a reduced bacterial burden. Locally, peritoneal lavage fluid yielded lower bacterial counts, lower IL-6, and reduced inflammatory cell counts when fibrocyte transfer was compared with saline. This was also accompanied by significant increases in splenic CD4(+) and CD8(+) T cells. In vitro stimulation of the splenic T cells demonstrated that, after cecal ligation and puncture and adoptive transfer, the percentages of both CD4(+) and CD8(+) T cells with intracellular interferon gamma were increased, whereas those with IL-4 remained similar between the groups. Therefore, it appears the adoptive transfer of fibrocytes improves sepsis survival, lowers bacterial burden, and promotes the proliferation of splenic T cells with a T(H)1 phenotype. These results confirm the immunomodulatory effects of exogenous, tissue-derived fibrocytes in sepsis and suggest their potential in cell therapy. PMID- 23807247 TI - Pulse pressure variation is comparable with central venous pressure to guide fluid resuscitation in experimental hemorrhagic shock with endotoxemia. AB - INTRODUCTION: Pulse pressure variation (PPV) has been proposed as a promising resuscitation goal, but its ability to predict fluid responsiveness has been questioned in various conditions. The purpose of this study was to assess the performance of PPV in predicting fluid responsiveness in experimental hemorrhagic shock with endotoxemia, while comparing it with goals determined by a conventional set of guidelines. METHODS: Twenty-seven pigs were submitted to acute hemorrhagic shock with intravenous infusion of endotoxin and randomized to three groups: (i) control; (ii) conventional treatment with crystalloids to achieve and maintain central venous pressure (CVP) 12 to 15 mmHg, mean arterial pressure of 65 mmHg or greater, and SvO2 (mixed venous oxygen saturation) of 65% or greater; (iii) treatment to achieve and maintain PPV of 13% or less. Parametric data were analyzed by two-way analysis of variance and Tukey test and differences in crystalloid volumes by t test. Predictive values of variables regarding fluid responsiveness were evaluated by receiver operating characteristic curves and multiple logistic regression. RESULTS: Both treatments produced satisfactory hemodynamic recovery, without statistical differences in fluid administration (P = 0.066), but conventional treatment induced higher CVP (P = 0.001). Areas under receiver operating characteristic curves were larger for CVP (0.77; 95% confidence interval, 0.68-0.86) and PPV (0.74; 95% confidence interval, 0.65-0.83), and these variables were further selected by multiple logistic regression as independent predictors of responsiveness. Optimal PPV cutoff was 15%, with false-positive results involving mean pulmonary arterial pressure of 27 mmHg or greater. CONCLUSIONS: Acute resuscitation guided by PPV was comparable with the strategy guided by CVP, mean arterial pressure, and SvO2. Central venous pressure and PPV were individually limited but independently predictive of fluid responsiveness. PMID- 23807246 TI - Fresh frozen plasma lessens pulmonary endothelial inflammation and hyperpermeability after hemorrhagic shock and is associated with loss of syndecan 1. AB - We have recently demonstrated that injured patients in hemorrhagic shock shed syndecan 1 and that the early use of fresh frozen plasma (FFP) in these patients is correlated with improved clinical outcomes. As the lungs are frequently injured after trauma, we hypothesized that hemorrhagic shock-induced shedding of syndecan 1 exposes the underlying pulmonary vascular endothelium to injury resulting in inflammation and hyperpermeability and that these effects would be mitigated by FFP. In vitro, pulmonary endothelial permeability, endothelial monolayer flux, transendothelial electrical resistance, and leukocyte-endothelial binding were measured in pulmonary endothelial cells after incubation with equal volumes of FFP or lactated Ringer's (LR). In vivo, using a coagulopathic mouse model of trauma and hemorrhagic shock, pulmonary hyperpermeability, neutrophil infiltration, and syndecan 1 expression and systemic shedding were assessed after 3 h of resuscitation with either 1* FFP or 3* LR and compared with shock alone and shams. In vitro, endothelial permeability and flux were decreased, transendothelial electrical resistance was increased, and leukocyte-endothelial binding was inhibited by FFP compared with LR-treated endothelial cells. In vivo, hemorrhagic shock was associated with systemic shedding of syndecan 1, which correlated with decreased pulmonary syndecan 1 and increased pulmonary vascular hyperpermeability and inflammation. Fresh frozen plasma resuscitation, compared with LR resuscitation, abrogated these injurious effects. After hemorrhagic shock, FFP resuscitation inhibits endothelial cell hyperpermeability and inflammation and restores pulmonary syndecan 1 expression. Modulation of pulmonary syndecan 1 expression may mechanistically contribute to the beneficial effects FFP. PMID- 23807248 TI - Inhibition of notch signaling protects mouse lung against zymosan-induced injury. AB - Notch signaling, a critical pathway in cell fate determination, is well known to be involved in immune and inflammatory reactions, whereas its role in acute lung injury (ALI) remains unclear. Here, we report that notch signal activity is upregulated in lung tissue harvested from an ALI mouse model (induced by zymosan). We showed that notch signal activity in lung tissue was increased 6 h after zymosan injection and peaked at 24 h. Inhibition of notch signaling by either pre- or post-zymosan treatment with N-[N-(3,5-difluorophenacetyl)-l alanyl]-(S)-phenylglycine t-butyl ester (DAPT) significantly reduced lung injury, characterized by improvement in lung histopathology, lung permeability (protein concentration in bronchoalveolar lavage fluid and lung wet-to-dry weight ratio), lung inflammation (bronchoalveolar lavage fluid cell count, lung myeloperoxidase, and tumor necrosis factor alpha), and also alleviated systemic inflammation and tissue damage, thus increasing the 7-day survival rate in zymosan-challenged mice. In conclusion, the role of notch signaling is functionally significant in the development of ALI. Inhibition of notch signaling by pretreatment or posttreatment with DAPT likely exerts its effects in part by mediating the expression of proinflammatory and anti-inflammatory cytokines and influencing tissue neutrophil recruitment. These results also imply that notch inhibitors may help attenuate local inflammatory lung damage. PMID- 23807249 TI - Left ventricular systolic function and systolic asynchrony in patients with septic shock and normal left ventricular ejection fraction. AB - Few studies were performed to investigate the association between tissue Doppler imaging parameters about left ventricular (LV) systolic function and LV systolic asynchrony and prognosis in patients with septic shock and normal LV ejection fraction (LVEF). This prospective study was performed from January 2010 to April 2012 in a medical intensive care unit. Fifty-one patients with septic shock and LVEF greater than or equal to 50% were analyzed. The clinical variables and transthoracic echocardiography data were obtained on admission. The mean value of the peak myocardial systolic velocity (Sm-mean) was measured in the four LV basal segments. Tissue Doppler imaging-based parameter (Ts-SD) was used to evaluate LV intraventricular asynchrony. The 28-day all-cause mortality was 43.1%. The nonsurvivors exhibited higher baseline heart rate and Sm-mean and lower mean arterial blood pressure and Ts-SD. A cutoff value of Sm-mean greater than or equal to 6.2 cm/s in identifying 28-day mortality was determined by the receiver operating characteristic curve analysis. The patients with Sm-mean greater than or equal to 6.2 cm/s or Ts-SD less than 33 ms had higher 28-day mortality. In the Cox multivariate analysis, Sm-mean, Ts-SD, and mean arterial blood pressure emerged as independent predictors for 28-day mortality. We concluded that LV systolic dysfunction and systolic asynchrony assessed by tissue Doppler imaging were associated with improved 28-day all-cause mortality in patients with septic shock and normal LVEF. PMID- 23807251 TI - Identifying key regulatory genes in the whole blood of septic patients to monitor underlying immune dysfunctions. AB - There is currently no reliable tool available to measure immune dysfunction in septic patients in the clinical setting. This proof-of-concept study assesses the potential of gene expression profiling of whole blood as a tool to monitor immune dysfunction in critically ill septic patients. Whole-blood samples were collected daily for up to 5 days from patients admitted to the intensive care unit with sepsis. RNA isolated from whole-blood samples was assayed on Illumina HT-12 gene expression microarrays consisting of 48,804 probes. Microarray analysis identified 3,677 genes as differentially expressed across 5 days between septic patients and healthy controls. Of the 3,677 genes, biological pathway analysis identified 86 genes significantly downregulated in the sepsis patients were present in pathways relating to immune response. These 86 genes correspond to known immune pathways implicated in sepsis, including lymphocyte depletion, reduced T-lymphocyte activation, and deficient antigen presentation. Furthermore, expression levels of these genes correlated with clinical severity, with a significantly greater degree of downregulation found in nonsurvivors compared with survivors. The results show that whole-blood gene expression analysis can capture systemic immune dysfunctions in septic patients. Our study provides an experimental basis to support further study on the use of a gene expression-based assay, to assess immunosuppression, and to guide immunotherapy in future clinical trials. PMID- 23807250 TI - Extracellular heat shock proteins: a new location, a new function. AB - The expression of heat shock proteins (HSPs) is a basic and well-conserved cellular response to an array of stresses. These proteins are involved in the repair of cellular damage induced by the stress, which is necessary for the salutary resolution from the insult. Moreover, they confer protection from subsequent insults, which has been coined stress tolerance. Because these proteins are expressed in subcellular compartments, it was thought that their function during stress conditions was circumscribed to the intracellular environment. However, it is now well established that HSPs can also be present outside cells where they appear to display a function different than the well understood chaperone role. Extracellular HSPs act as alert stress signals priming other cells, particularly of the immune system, to avoid the propagation of the insult and favor resolution. Because the majority of HSPs do not possess a secretory peptide signal, they are likely to be exported by a nonclassic secretory pathway. Different mechanisms have been proposed to explain the export of HSPs, including translocation across the plasma membrane and release associated with lipid vesicles, as well as the passive release after cell death by necrosis. Extracellular HSPs appear in various flavors, including membrane bound and membrane-free forms. All of these variants of extracellular HSPs suggest that their interactions with cells may be quite diverse, both in target cell types and the activation signaling pathways. This review addresses some of our current knowledge about the release and relevance of extracellular HSPs. PMID- 23807252 TI - The relationship between the success rate of empirical antifungal therapy with intravenous itraconazole and clinical parameters, including plasma levels of itraconazole, in immunocompromised patients receiving itraconazole oral solution as prophylaxis: a multicenter, prospective, open-label, observational study in Korea. AB - To identify the role of therapeutic drug monitoring of itraconazole (ITZ) in the setting of empirical antifungal therapy with intravenous (IV) ITZ, we performed a multicenter, prospective study in patients with hematological malignancies who had received antifungal prophylaxis with ITZ oral solution (OS). We evaluated the plasma levels of ITZ and hydroxy (OH) ITZ both before initiation of IV ITZ and on days 5-7 of IV ITZ. A total of 181 patients showed an overall success rate of 68.0 %. Prolonged baseline neutropenia and accompanying cardiovascular comorbidity were significantly associated with poor outcomes of the empirical antifungal therapy (P = 0.005 and P = 0.001, respectively). A significantly higher trough plasma level of OH ITZ per body weight was found in the patients who achieved success with empirical antifungal therapy (P = 0.036). There were no significant correlations between plasma concentrations of ITZ/OH ITZ (baseline or trough levels) and toxicities. Seven patients had a discontinuation of ITZ therapy due to toxicity. This study demonstrated that IV ITZ as empirical antifungal therapy was effective and therapeutic drug monitoring was helpful to estimate the outcome of empirical antifungal therapy in patients receiving antifungal prophylaxis with ITZ OS. To predict the outcome of empirical antifungal therapy with IV ITZ, we should evaluate baseline clinical characteristics and also perform the therapeutic drug monitoring of both ITZ and OH ITZ. PMID- 23807253 TI - Nephrolithiasis in patients exposed to deferasirox and desferioxamine: probably an age-linked event with different effects on some renal parameters. PMID- 23807254 TI - Cephalometric assessment of human fetal head specimens. AB - BACKGROUND: Past investigations of prenatal craniofacial growth have largely relied on histological sections. Few studies have taken measurements on three dimensional representations (3D reconstruction, 3D CT, postmortem) or varying depth levels (ultrasound), and we know of no craniofacial growth studies done on cleared-and-stained specimens of whole fetal heads. MATERIALS AND METHODS: This study comprised 14 human fetal head specimens cleared and stained with alizarin red and alcian blue. They had been stored in glycerol and represented weeks 8-12 of gestation, with crown-rump lengths ranging from 23-145 mm. These specimens were cephalometrically analyzed in norma frontalis and norma lateralis, which notably included the opportunity for side-to-side comparison. RESULTS: As the cranial membrane bones progressively approached each other, the orbits, maxilla, and mandible gradually grew wider. Likewise, the sagittal dimensions of the maxilla and mandible increased continuously and synchronically. We noted side-to side differences ranging from 2-5 mm. Another notable finding concerned the inclination of the maxilla relative to the cranial base, which increased more on the right than on the left side. CONCLUSION: This is the first investigation presenting side-to-side comparative measurements of human fetal head specimens. Such measurements are essential in the quest toward validating the findings of other imaging techniques such as CT or MRI and-most importantly-intrauterine sonography. PMID- 23807255 TI - Survey of oral health-related quality of life among skeletal malocclusion patients following orthodontic treatment and orthognathic surgery. AB - OBJECTIVES: The goal of this work was to conduct a survey of oral health-related quality of life (OHRQoL) among skeletal malocclusion patients who had undergone orthodontic treatment combined with orthognathic surgery. PATIENTS AND METHODS: The study included 28 patients who had undergone orthodontic therapy combined with orthognathic surgery (surgical repositioning osteotomy) to treat skeletal malocclusion. OHRQoL was assessed based on a 14-item German version of the Oral Health Impact Profile (OHIP-G14) and an additional questionnaire developed by the authors to evaluate aspects of quality of life specific to skeletal malocclusion patients. RESULTS: The mean OHIP-G14 score demonstrates that the malocclusion patients have a lower OHRQoL than the general population. The information collected via our skeletal malocclusion questionnaire correlates with the patients' perceived esthetic and functional outcomes of treatment as well as their psychological state and social interactions. Satisfaction with treatment outcomes and improved social interactions correlated with high OHRQoL scores. High OHRQoL scores significantly correlated with enhanced well-being and the intensification of social contacts. CONCLUSION: Our skeletal malocclusion questionnaire provides useful additional information on specific aspects of skeletal malocclusion patients, mapping in a detailed fashion aspects of function, esthetics, psychological condition, and social interactions. OHIP-G14 scores correlated negatively with OHRQoL. PMID- 23807256 TI - Digital 3D image of bimaxillary casts connected by a vestibular scan. AB - AIM: The task of three-dimensionally aligning digital images of scans taken from maxillary and mandibular casts can be accomplished by scanning an interocclusal record, but vestibular scanning is also an option. The present study addressed whether this latter technique is precise enough to be used in orthodontic practice. MATERIALS AND METHODS: A total of 10 pairs of casts representing different types of tooth and jaw malposition were scanned with a photo-optical scanner (Activity 102; Smart Optics, Bochum, Germany). After obtaining detailed single scans of each upper and lower jaw, each pair of casts was rigidly aligned with instant glue. Subsequently, three vestibular scans were taken and were then merged with the single-jaw scans to form virtual bimaxillary models. These virtual models were superimposed with each other and analyzed, using the structures of the mandible as constant and documenting the highest occlusal and vestibular deviations measured on each maxillary tooth or gingival region. Descriptive analysis and a mixed linear model were performed with SPSS and SAS. RESULTS: The greatest deviations between the virtual bimaxillary models averaged 37 +/- 28 MUm. No significant differences were seen between tooth sites along the dental arch, dentate versus edentulous sites, or occlusal versus vestibular surfaces. The mean of the greatest deviations between repeated scans were found to be 28 +/- 14 MUm (vestibular scans) and 15 +/- 8 MUm (single-jaw scans). CONCLUSION: The presented approach of generating bimaxillary study models in a virtual environment with the help of vestibular scans meets the precision requirements for use in orthodontics and can be employed in further studies. PMID- 23807257 TI - Maxillary reaction patterns identified by three-dimensional analysis of casts from infants with unilateral cleft lip and palate. AB - OBJECTIVES: In order to visualize and quantify the direction and extent of morphological upper-jaw changes in infants with unilateral cleft lip and palate (UCLP) during early orthodontic treatment, a three-dimensional method of cast analysis for routine application was developed. In the present investigation, this method was used to identify reaction patterns associated with specific cleft forms. MATERIALS AND METHODS: The study included a cast series reflecting the upper-jaw situations of 46 infants with complete (n=27) or incomplete (n=19) UCLP during week 1 and months 3, 6, and 12 of life. Three-dimensional datasets were acquired and visualized with scanning software (DigiModel(r); OrthoProof, The Netherlands). Following interactive identification of landmarks on the digitized surface relief, a defined set of representative linear parameters were three dimensionally measured. At the same time, the three-dimensional surfaces of one patient series were superimposed based on a defined reference plane. Morphometric differences were statistically analyzed. RESULTS: Thanks to the user-friendly software, all landmarks could be identified quickly and reproducibly, thus, allowing for simultaneous three-dimensional measurement of all defined parameters. The measured values revealed that significant morphometric differences were present in all three planes of space between the two patient groups. Patients with complete UCLP underwent significantly larger reductions in cleft width (p<0.001), and sagittal growth in the complete UCLP group exceeded sagittal growth in the incomplete UCLP group by almost 50% within the first year of life. CONCLUSION: Based on patients with incomplete versus complete UCLP, different reaction patterns were identified that depended not on apparent severities of malformation but on cleft forms. PMID- 23807259 TI - Development of temporomandibular disorders and posterior open bite in patients with mandibular advancement devices used in the treatment of obstructive sleep apnea. PMID- 23807258 TI - Shear bond strength of an experimental composite bracket. AB - OBJECTIVE: The in vitro shear bond strength of MZ100 brackets (an experimental composite bracket developed by the Dental Biomaterial Laboratory at Boston University) and the effect of different treatment methods on these brackets were evaluated. MATERIALS AND METHODS: As the bonding substrates, 80 Vitablocs(r) Mark II (Vident, Brea, CA, USA) were chosen. Three treatment methods were employed on 60 MZ100 bracket bases (20 brackets per treatment): silane coupling agent (Porcelain Primer; Ormco, Orange, CA, USA), sandblasting (Basic Professional Model Sandblaster; Renfert GmbH, Germany), and non-treatment. Two different orthodontic adhesives were also used: BluglooTM (Ormco, Orange, CA, USA) and EnlightTM (Ormco, Orange, CA, USA). Twenty metal brackets were used as controls. Shear bond strength tests were performed after sample preparation and bracket bonding. RESULTS: The mean shear bond strength of non-treated MZ100 brackets bonded with EnlightTM had the lowest value (7.9 MPa), while that of sandblasted MZ100 brackets bonded with BluglooTM showed the highest value (17.9 MPa). The mean shear bond strength of non-treated MZ100 brackets was significantly lower than that of the other groups (p<0.05). The mean shear bond strength of sandblasted MZ100 brackets bonded with BluglooTM was significantly higher than that of those bonded with EnlightTM (p<0.05). With the exception of the silane BluglooTM group, the treated MZ100 brackets demonstrated shear bond strengths that did not significantly differ from metal brackets. CONCLUSION: The use of sandblasting and silane coupling agent significantly increases the shear bond strength of the MZ100 brackets to values resembling those of metal brackets. PMID- 23807261 TI - A complete physical germanium-on-silicon quantum dot self-assembly process. AB - Achieving quantum dot self-assembly at precise pre-defined locations is of vital interest. In this work, a novel physical method for producing germanium quantum dots on silicon using nanoindentation to pre-define nucleation sites is described. Self-assembly of ordered ~10 nm height germanium quantum dot arrays on silicon substrates is achieved. Due to the inherent simplicity and elegance of the proposed method, the results describe an attractive technique to manufacture semiconductor quantum dot structures for future quantum electronic and photonic applications. PMID- 23807263 TI - Polyethyleneglycol crosslinked N-(2-hydroxyethyl)-polyethylenimine nanoparticles as efficient non-viral vectors for DNA and siRNA delivery in vitro and in vivo. AB - A series of electrostatically crosslinked nanoparticles, N-(2-hydroxyethyl) polyethylenimine-PEG600 (HePP), was prepared by allowing N-(2-hydroxyethyl) polyethylenimine (HeP) to interact with polyethyleneglycol (600) dicarboxylic acid (HOOC-PEG600-COOH, PEG600dc), they were then evaluated for their capability to transfect cells in vitro and in vivo. DLS studies revealed the size of the HePP nanoparticles in the range 106-170 nm, which efficiently condensed nucleic acids and provided sufficient protection against nuclease degradation. HePP-pDNA complexes exhibited a considerably higher transfection efficiency and cell viability in various mammalian cell lines, with HePP-3-pDNA displaying the highest gene expression, which outperformed HeP and the commercially available transfection reagent, LipofectamineTM. Also, HePP-3 mediated sequential delivery of GFP specific siRNA resulted in ~76% suppression of the target gene. Intravenous administration of HePP-3-pDNA complex to mice, followed by monitoring of the reporter gene analysis post 7d, revealed the highest gene expression occurred in the spleen. Together, these results advocate the potential of HePP nanoparticles as efficient vectors for gene delivery in vitro and in vivo. PMID- 23807262 TI - Protein pocket and ligand shape comparison and its application in virtual screening. AB - Understanding molecular recognition is one major requirement for drug discovery and design. Physicochemical and shape complementarity between two binding partners is the driving force during complex formation. In this study, the impact of shape within this process is analyzed. Protein binding pockets and co crystallized ligands are represented by normalized principal moments of inertia ratios (NPRs). The corresponding descriptor space is triangular, with its corners occupied by spherical, discoid, and elongated shapes. An analysis of a selected set of sc-PDB complexes suggests that pockets and bound ligands avoid spherical shapes, which are, however, prevalent in small unoccupied pockets. Furthermore, a direct shape comparison confirms previous studies that on average only one third of a pocket is filled by its bound ligand, supplemented by a 50 % subpocket coverage. In this study, we found that shape complementary is expressed by low pairwise shape distances in NPR space, short distances between the centers-of mass, and small deviations in the angle between the first principal ellipsoid axes. Furthermore, it is assessed how different binding pocket parameters are related to bioactivity and binding efficiency of the co-crystallized ligand. In addition, the performance of different shape and size parameters of pockets and ligands is evaluated in a virtual screening scenario performed on four representative targets. PMID- 23807264 TI - Lefty A protein inhibits TGF-beta1-mediated apoptosis in human renal tubular epithelial cells. AB - This study aimed to examine the effects of Lefty A protein on transforming growth factor-beta1 (TGF-beta1)-mediated apoptosis in human renal tubular epithelial cells (HK-2). HK-2 cells were transfected with the human Lefty gene to induce the secretion of endogenous Lefty A protein. Following exposure of the HK-2 cells to recombinant human TGF-beta1 (10 ng/ml), p-Smad2/3 protein levels were examined by western blot analysis, and cellular apoptosis was detected by flow cytometry 6, 12, 24 and 48 h following TGF-beta1 treatment. Coculture of renal tubular epithelial cells with TGF-beta1 resulted in a significant increase in p-Smad2/3 protein levels and the rate of cell apoptosis, which were attenuated by liposome mediated transfection with the Lefty gene. Lefty A protein was able to inhibit the TGF-beta1/Smad signaling pathway and markedly attenuate TGF-beta1-mediated apoptosis in human renal tubular epithelial cells. Taken together, these results indicated that the TGF-beta1/Smad signaling pathway most likely mediates apoptosis in renal tubular epithelial cells. In addition, Lefty A protein is capable of inhibiting the TGF-beta1/Smad pathway to reduce TGF-beta1/Smad mediated apoptosis in renal tubular epithelial cells. This study may provide novel insights into the prevention and treatment of urinary tract obstruction disease using Lefty A protein. PMID- 23807266 TI - Reconstruction of surface potential from Kelvin probe force microscopy images. AB - We present an algorithm for reconstructing a sample surface potential from its Kelvin probe force microscopy (KPFM) image. The measured KPFM image is a weighted average of the surface potential underneath the tip apex due to the long-range electrostatic forces. We model the KPFM measurement by a linear shift-invariant system where the impulse response is the point spread function (PSF). By calculating the PSF of the KPFM probe (tip+cantilever) and using the measured noise statistics, we deconvolve the measured KPFM image to obtain the surface potential of the sample.The reconstruction algorithm is applied to measurements of CdS-PbS nanorods measured in amplitude modulation KPFM (AM-KPFM) and to graphene layers measured in frequency modulation KPFM (FM-KPFM). We show that in the AM-KPFM measurements the averaging effect is substantial, whereas in the FM KPFM measurements the averaging effect is negligible. PMID- 23807265 TI - Epigenetic pathways and glioblastoma treatment. AB - Glioblastoma multiforme (GBM) is the most common malignant adult brain tumor. Standard GBM treatment includes maximal safe surgical resection with combination radiotherapy and adjuvant temozolomide (TMZ) chemotherapy. Alarmingly, patient survival at five-years is below 10%. This is in part due to the invasive behavior of the tumor and the resulting inability to resect greater than 98% of some tumors. In fact, recurrence after such treatment may be inevitable, even in cases where gross total resection is achieved. The Cancer Genome Atlas (TCGA) research network performed whole genome sequencing of GBM tumors and found that GBM recurrence is linked to epigenetic mechanisms and pathways. Central to these pathways are epigenetic enzymes, which have recently emerged as possible new drug targets for multiple cancers, including GBM. Here we review GBM treatment, and provide a systems approach to identifying epigenetic drivers of GBM tumor progression based on temporal modeling of putative GBM cells of origin. We also discuss advances in defining epigenetic mechanisms controlling GBM initiation and recurrence and the drug discovery considerations associated with targeting epigenetic enzymes for GBM treatment. PMID- 23807267 TI - Determination of volatile organic compounds in water samples using membrane-solid phase microextraction (M-SPME) (headspace version). AB - The results of a study on the use of membrane-solid phase microextraction (M SPME) for sampling volatile organic compounds (VOCs) from the headspace above the liquid medium are presented. The sampled VOCs were subsequently quantified by gas chromatography (GC). Two systems were compared in this study, i.e. a novel two phase sorption system (M-SPME), and a commercial fibre. Headspace sampling using SPME was optimized with respect to sample temperature, extraction time and the content of a salting-out agent (independently vs. each parameter). Under the optimized conditions, extraction with the M-SPME fibre yielded a limit of detection (LOD) of 0.011 ug L(-1). This value is comparable with LOD achieved with a commercial fibre under its own optimum conditions. However, using the M SPME sample preparation procedure developed in this work, a broad linear range from 0.5 to 100 ug L(-1) was obtained, while isolation with a commercial fibre resulted in a linear range up to ca. 25 ug L(-1) only. Finally, the suitability of the novel fibre for VOC determination was proved by conducting measurements on real samples. PMID- 23807269 TI - Rapid HIV self-testing: long in coming but opportunities beckon. AB - The recent approval by the United States Food and Drug Administration of a rapid HIV self-test marks a significant milestone in the evolution of HIV testing approaches. With nearly one in five people living with HIV in the United States still undiagnosed and an even higher proportion unaware of their infection globally, this decision reflects a new willingness to offer diverse options to get tested for HIV. Rapid self-testing offers several distinct opportunities to improve testing among those with undiagnosed HIV: to encourage testing among those who might not otherwise be tested, to increase the frequency of testing among persons at highest risk for new infection, and to facilitate mutual HIV testing with sex partners. To date, the path to regulatory approval has been long but instructive. The studies and clinical trials required for regulatory approval in the United States provide insight into the performance and potential implications of HIV self-tests as they become available for sale directly to consumers. Although some persistent reservations about self-testing for HIV remain, including the 'window period' of the current test kit, its cost, and its effectiveness for facilitating entry to medical care, others have been dispelled. Self-testing in resource-constrained settings is also promising, including self testing of health professionals. At present, although the impact has yet to be determined, availability of this new option might offer potential opportunities to improve HIV diagnosis and facilitate both treatment and prevention. PMID- 23807270 TI - Modulation of the complement system in monocytes contributes to tuberculosis associated immune reconstitution inflammatory syndrome. AB - OBJECTIVE: Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a common complication in HIV-TB co-infected patients receiving combined antiretroviral therapy (cART). This study investigated a putative contribution of monocytes to the development of TB-IRIS. DESIGN: A prospective study was designed to compare gene expression between patients who developed TB IRIS with matched non-TB-IRIS controls. METHODS: We performed a hypothesis generating transcriptome analysis on monocytes of HIV-TB co-infected patients. Identified pathways were subsequently analysed in patients' monocytes before and shortly after cART initiation, in a technically independent set-up (nCounter). Additionally, protein expression and enzymatic activities of specific factors were assessed at the systemic level. RESULTS: Pathway analysis of microarray datasets and focused gene expression study revealed that, even before initiation of cART, the complement system is dysregulated in HIV-TB co-infected patients who are predisposed to developing TB-IRIS. Detailed analysis revealed differences between TB-IRIS patients and matched non-TB-IRIS cases, at the level of the balance between the effector C1Q and the inhibitor C1-INH, both before and 2 weeks after cART initiation. These differences were mirrored by increases in the downstream pro-inflammatory complement factor C5 over the course of 2 weeks of cART. Our results suggest that inappropriate control of complement activation could be associated with the 'flaring up' of inflammation observed during TB IRIS. CONCLUSION: The current study reveals a contribution of monocytes and the complement system to TB-IRIS development. An intriguing possibility is that the development of TB-IRIS may depend partially on the relative balance between C1Q and C1-INH. PMID- 23807268 TI - Actin acting at the Golgi. AB - The organization, assembly and remodeling of the actin cytoskeleton provide force and tracks for a variety of (endo)membrane-associated events such as membrane trafficking. This review illustrates in different cellular models how actin and many of its numerous binding and regulatory proteins (actin and co-workers) participate in the structural organization of the Golgi apparatus and in trafficking-associated processes such as sorting, biogenesis and motion of Golgi derived transport carriers. PMID- 23807271 TI - High prevalence and incidence of high-grade anal intraepithelial neoplasia among young Thai men who have sex with men with and without HIV. AB - BACKGROUND: Men who have sex with men (MSM) are at elevated risk of having anal cancer. However, the prevalence and incidence among MSM of high-grade anal intraepithelial neoplasia (HGAIN), the putative precursor of anal cancer, is understudied, particularly in Asians. METHODS: A total of 123 HIV-positive and 123 HIV-negative MSM were enrolled at the Thai Red Cross AIDS Research Centre in Bangkok, Thailand, and followed for 12 months. Anal sample collection for human papillomavirus (HPV) genotyping and high-resolution anoscopy (HRA) with biopsies were performed at every visit. RESULTS: Mean age at enrollment was 28.9 years. HIV-positive MSM were more commonly infected with high-risk HPV types in the anus than HIV-negative MSM (57.5 vs. 36.6%; P = 0.001). The prevalence of HGAIN was 18.9% in HIV-positive and 11.4% in HIV-negative MSM (P = 0.1). The incidence of HGAIN at 12 months was 29% in HIV-positive and 8% in HIV-negative MSM (P = 0.001). The hazard ratios for incident HGAIN in multivariate models were 5.16 [95% confidence interval (CI) 1.89-14.08, P < 0.001] in MSM with persistent HPV 16 and/or 18 infection and 2.62 (95% CI 1.04-6.61, P = 0.042) in HIV-positive MSM. CONCLUSIONS: Approximately one-third of HIV-positive MSM developed incident HGAIN within 12 months. Given the relative increased prevalence of HIV among MSM worldwide, local HGAIN data are needed to guide practitioners, policy makers, and communities in planning for strategies to screen for and treat HGAIN in this population. PMID- 23807272 TI - Risk behavior among women enrolled in a randomized controlled efficacy trial of an adenoviral vector vaccine to prevent HIV acquisition. AB - OBJECTIVES: Report of risk behavior, HIV incidence, and pregnancy rates among women participating in the STEP study, which is a phase IIB trial of MRKAd5 HIV-1 gag/pol/nef vaccine in HIV-negative individuals who were at high risk of HIV-1. DESIGN: Prospective multicenter, double-blinded, placebo-controlled trial. METHODS: Women were from North American, and from Caribbean and South America (CSA) sites. Risk behavior was collected at screening and 6-month intervals. Differences in characteristics between groups were tested with chi-square, two sided Fisher's exact tests, and Wilcoxon rank-sum tests. Generalized estimating equation models were used to assess behavioral change. RESULTS: Among 1134 enrolled women, the median number of male partners was 18; 73.8% reported unprotected vaginal sex, 15.9% unprotected anal sex and 10.8% evidence of a sexually transmitted infection in the 6 months prior to baseline. With 3344 person-years of follow-up, there were 15 incident HIV infections: incidence rate was 0.45 per 100 person-years [95% confidence interval (CI) 0.25, 0.74]. Crack cocaine use in both regions [relative risk (RR) 2.4 (1.7, 3.3)] and in CSA, unprotected anal sex [RR 6.4 (3.8, 10.7)], and drug use [RR 4.1 (2.1, 8.0)] were baseline risk behaviors associated with HIV acquisition. There was a marked reduction in risk behaviors after study enrollment with some recurrence in unprotected vaginal sex. Of 963 nonsterilized women, 304 (31.6%) became pregnant. CONCLUSION: Crack cocaine use and unprotected anal sex are important risk criteria to identify high-risk women for HIV-efficacy trials. Pregnancy during the trial was a common occurrence and needs to be considered in trial planning for prevention trials in women. PMID- 23807273 TI - Dolutegravir in antiretroviral-naive adults with HIV-1: 96-week results from a randomized dose-ranging study. AB - OBJECTIVE: To evaluate the efficacy and safety/tolerability of dolutegravir (DTG, S/GSK1349572), a potent inhibitor of HIV integrase, through the full 96 weeks of the SPRING-1 study. DESIGN: ING112276 (SPRING-1) was a 96-week, randomized, partially blinded, phase IIb dose-ranging study. METHODS: Treatment-naive adults with HIV received DTG 10, 25, or 50 mg once daily or efavirenz (EFV) 600 mg once daily (control arm) combined with investigator-selected dual nucleos(t)ide reverse transcriptase inhibitor backbone regimen (tenofovir/emtricitabine or abacavir/lamivudine). The primary endpoint of the study was the proportion of participants with plasma HIV-1 RNA less than 50 copies/ml, based on time to loss of virologic response at 16 weeks (conducted for the purpose of phase III dose selection), with a planned analysis at 96 weeks. Safety and tolerability were also assessed. RESULTS: Of 208 participants randomized to treatment, 205 received study drug. At week 96, the proportion of participants achieving plasma HIV-1 RNA less than 50 copies/ml was 79, 78, and 88% for DTG 10, 25, and 50 mg, respectively, compared with 72% for EFV. The median increase from baseline in CD4 cells was 338 cells/MUl with DTG (all treatment groups combined) compared with 301 cells/MUl with EFV (P = 0.155). No clinically significant dose-related trends in adverse events were observed, and fewer participants who received DTG withdrew because of adverse events (3%) compared with EFV (10%). CONCLUSION: Throughout the 96 weeks of the SPRING-1 study, DTG demonstrated sustained efficacy and favorable safety/tolerability in treatment-naive individuals with HIV-1. PMID- 23807274 TI - HIV serostatus differs by catechol-O-methyltransferase Val158Met genotype. AB - OBJECTIVE: The Met allele of the catechol-O-methyltransferase (COMT) Val158Met polymorphism is associated with increased cortical dopamine and risk behaviors including illicit drug use and unprotected sex. Therefore, we examined whether or not the distribution of the Val158Met genotype differed between HIV-infected and HIV-uninfected women. DESIGN: Cross-sectional analysis using data from the Women's Interagency HIV Study (WIHS), the largest longitudinal cohort study of HIV in women. METHODS: We conducted an Armitage-Cochran test and logistic regression to compare genotype frequencies between 1848 HIV-infected and 612 HIV uninfected women in WIHS. RESULTS: The likelihood of carrying one or two Met alleles was greater in HIV-infected women (61%) compared to HIV-uninfected women (54%), Z = -3.60, P < 0.001. CONCLUSION: We report the novel finding of an association between the Val158Met genotype and HIV serostatus that may be mediated through the impact of dopamine function on propensity for risk-taking. PMID- 23807275 TI - The rapidly expanding CRF01_AE epidemic in China is driven by multiple lineages of HIV-1 viruses introduced in the 1990s. AB - OBJECTIVES: We sought to comprehensively analyze the origin, transmission patterns and sub-epidemic clusters of the HIV-1 CRF01_AE strains in China. METHODS: Available HIV-1 CRF01_AE samples indentified in national molecular epidemiologic surveys were used to generate near full-length genome (NFLG) sequences. The new and globally available CRF01_AE NFLG sequences were subjected to phylogenetic and Bayesian molecular clock analyses, and combined with epidemiologic data to elucidate the history of CRF01_AE transmission in China. RESULTS: We generated 75 new CRF01_AE NFLG sequences from various risk populations covering all major CRF01_AE epidemic regions in China. Seven distinct phylogenetic clusters of CRF01_AE were identified. Clusters 1, 2 and 3 were prevalent among heterosexuals and IDUs in southern and southwestern provinces. Clusters 4 and 5 were found primarily among MSM in major northern cities. Clusters 6 and 7 were only detected among heterosexuals in two southeast and southwest provinces. Molecular clock analysis indicated that all CRF01_AE clusters were introduced from Southeast Asia in the 1990s, coinciding with the peak of Thailand's HIV epidemic and the initiation of China's free overseas travel policy for their citizens, which started with Thailand as the first destination country. CONCLUSION: China's HIV-1 epidemic of sexual transmissions, was initiated by multilineages of CRF01_AE strains, in contrast to the mono lineage epidemic of B' strain in former plasma donors and IDUs. Our study underscores the difficulty in controlling HIV-1 sexual transmission compared with parenteral transmission. PMID- 23807276 TI - Endothelial activation biomarkers increase after HIV-1 acquisition: plasma vascular cell adhesion molecule-1 predicts disease progression. AB - OBJECTIVE: We aimed to determine whether endothelial activation biomarkers increase after HIV-1 acquisition, and whether biomarker levels measured in chronic infection would predict disease progression and death in HIV-1 seroconverters. DESIGN: HIV-1-seronegative Kenyan women were monitored monthly for seroconversion, and followed prospectively after HIV-1 acquisition. METHODS: Plasma levels of angiopoietin-1 and angiopoietin-2 (ANG-1, ANG-2) and soluble vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin were tested in stored samples from pre-infection, acute infection, and two chronic infection time points. We used nonparametric tests to compare biomarkers before and after HIV-1 acquisition, and Cox proportional hazards regression to analyze associations with disease progression (CD4 < 200 cells/MUl, stage IV disease, or antiretroviral therapy initiation) or death. RESULTS: Soluble ICAM-1 and VCAM-1 were elevated relative to baseline in all postinfection periods assessed (P < 0.0001). Soluble E-selectin and the ANG-2:ANG 1 ratio increased in acute infection (P = 0.0001), and ANG-1 decreased in chronic infection (P = 0.0004). Among 228 participants followed over 1028 person-years, 115 experienced disease progression or death. Plasma VCAM-1 levels measured during chronic infection were independently associated with time to HIV progression or death (adjusted hazard ratio 5.36, 95% confidence interval 1.99 14.44 per log10 increase), after adjustment for set point plasma viral load, age at infection, and soluble ICAM-1 levels. CONCLUSION: HIV-1 acquisition was associated with endothelial activation, with sustained elevations of soluble ICAM 1 and VCAM-1 postinfection. Soluble VCAM-1 may be an informative biomarker for predicting the risk of HIV-1 disease progression, morbidity, and mortality. PMID- 23807277 TI - GB virus C infection and B-cell, natural killer cell, and monocyte activation markers in HIV-infected individuals. AB - GB virus C (GBV-C), a pan-lymphotropic flavivirus capable of persistent infection, is associated with prolonged survival and reduced T-cell activation in HIV-infected patients. GBV-C was associated with reduced CD56brt/CD16- natural killer cell and monocyte activation, and a trend toward reduced B-cell activation by measuring cell surface activation markers or HIV entry coreceptors. The GBV-C association was independent of HIV viral load. Thus, GBV-C may influence non-T cell immune activation in individuals with HIV infection. PMID- 23807278 TI - Does the addition of magnesium to bupivacaine improve postoperative analgesia of ultrasound-guided thoracic paravertebral block in patients undergoing thoracic surgery? AB - PURPOSE: Magnesium is a plentiful intracellular cation that has been reported to possess analgesic effect. The present study was aimed to see whether addition of magnesium to bupivacaine in thoracic paravertebral block (TPVB) improved the analgesic effect after thoracic surgery. MATERIALS AND METHODS: Fifty adult patients undergoing elective open thoracic surgery were divided into two equal groups. Group I received 12 ml of 0.5 % bupivacaine plus 0.9 % saline (3 ml) whereas Group II received 12 ml of 0.5 % bupivacaine plus 150 mg magnesium sulphate (in 3 ml 0.9 % saline) for TPVB. The following parameters were assessed: onset, dermatomal levels and duration of sensory block, duration of analgesia, visual analogue scale (VAS) for pain, postoperative intravenous morphine consumption, pulmonary function tests (peak expiratory flow rate [PEFR], forced expiratory volume in 1 s [FEV1] and forced vital capacity [FVC]) before and 24 h after surgery, and complications from the drugs and technique. RESULTS: Group II patients showed a significantly longer sensory block duration (224.6 +/- 59.3 vs 160.1 +/- 55.2 min, P < 0.05), longer duration of analgesia (388.8 +/- 70.6 vs 222.2 +/- 61.6 min, P < 0.05), less VAS during the postoperative 48 h, less need for postoperative morphine (16.2 +/- 7.4 vs 29.5 +/- 11.1 mg, P < 0.05) and lower incidence of somnolence (0 [0 %] vs 5 [20 %], P < 0.05). Furthermore, postoperative pulmonary function tests (PEFR, FEV1 and FVC) were significantly better in Group II whereas there was no significant difference between both groups regarding the sensory block dermatomal level or hemodynamic data. CONCLUSION: Addition of magnesium to bupivacaine in TPVB improved the analgesic effect of bupivacaine in patients undergoing thoracic surgery. PMID- 23807279 TI - Enrichment of prostate cancer cells from blood cells with a hybrid dielectrophoresis and immunocapture microfluidic system. AB - The isolation of circulating tumor cells (CTCs) from cancer patient blood is a technical challenge that is often addressed by microfluidic approaches. Two of the most prominent techniques for rare cancer cell separation, immunocapture and dielectrophoresis (DEP), are currently limited by a performance tradeoff between high efficiency and high purity. The development of a platform capable of these two performance criteria can potentially be facilitated by incorporating both DEP and immunocapture. We present a hybrid DEP-immunocapture system to characterize how DEP controls the shear-dependent capture of a prostate cancer cell line, LNCaP, and the nonspecific adhesion of peripheral blood mononuclear cells (PBMCs). Characterization of cell adhesion with and without DEP effects was performed in a Hele-Shaw flow cell that was functionalized with the prostate specific monoclonal antibody, J591. In this model system designed to make nonspecific PBMC adhesion readily apparent, we demonstrate LNCaP enrichment from PBMCs by precisely tuning the applied AC electric field frequency to enhance immunocapture of LNCaPs and reduce nonspecific adhesion of PBMCs with positive and negative DEP, respectively. Our work shows that DEP and immunocapture techniques can work synergistically to improve cancer cell capture performance, and it informs the design of future hybrid DEP-immunocapture systems with improved CTC capture performance to facilitate research on cancer metastasis and drug therapies. PMID- 23807280 TI - Degradation of carotenoids in apricot (Prunus armeniaca L.) during drying process. AB - Carotenoids are natural compounds whose nutritional importance comes from the provitamin A activity of some of them and their protection against several serious human disorders. The degradation of carotenoids was investigated during apricot drying by microwave and convective hot-air at 60 and 70 degrees C. Seven carotenoids were identified: antheraxanthin, lutein, zeaxanthin, beta cryptoxanthin, 13-cis-beta-carotene, all-trans-beta-carotene and 9-cis-beta carotene; among these, all-trans-beta-carotene was found to be about 50 % of total carotenoids. First-order kinetic models were found to better describe all trans-beta-carotene reduction during drying, with a degradation rate constant (k1) that increased two folds when temperatures increased by 10 degrees C, in both methods. No differences were found in k1 between apricots dried by hot air at 70 degrees C (k1 = 0.0340 h(-1)) and by microwave at 60 degrees C. The evolution of total carotenoids (117.1 mg/kg on dry basis) during drying highlighted a wider decrease (about 50%) when microwave heating was employed, for both set temperatures. Antheraxantin was found to be the carotenoid most susceptible to heat, disappearing at 6 h during both trials with microwave as well as during convective hot-air at 70 degrees C. For this reason, antheraxanthin could be a useful marker for the evaluation of thermal damage due to the drying process. Also the degree of isomerization of all-trans-beta carotene could be a useful marker for the evaluation of the drying process. PMID- 23807281 TI - Perioperative management of patients who are receiving a novel oral anticoagulant. AB - The use of novel oral anticoagulants (NOACs) is increasing since these drugs are at least as efficacious and safe as vitamin K antagonists (VKAs) for the management of patients with non-valvular atrial fibrillation and venous thromboembolism. Compared with VKAs, NOACs have a faster onset and offset of action, a predictable and consistent pharmacokinetic profile, fewer drug interactions, and ease of use since anticoagulant monitoring is not required. Current perioperative management will be affected by these characteristics, with the potential to obviate the need for heparin bridging. This review aims to summarize the current evidence of perioperative thromboembolic and bleeding risk during anticoagulant interruption, which is derived predominantly from patients receiving VKA therapy, and early studies involving NOACs which mainly focus on patients who are receiving dabigatran. The role of heparin bridging is discussed. We also provide a practical approach for the perioperative management of patients who are receiving NOAC therapy. PMID- 23807282 TI - Further genetic and clinical insights of posterior polymorphous corneal dystrophy 3. AB - IMPORTANCE: Posterior polymorphous corneal dystrophy (PPCD) is a very rare disorder characterized by primary changes of the posterior corneal layers. Sequence variants in 3 genes are associated with the development of PPCD, including ZEB1 that is responsible for PPCD3. Evidence suggests at least 1 more gene remains to be identified. OBJECTIVE: To determine the molecular genetic cause of PPCD3. DESIGN: We performed extensive ophthalmological examination, including rotating Scheimpflug imaging technology and specular microscopy, and direct sequencing of the ZEB1 coding region. Comprehensive review of published PPCD3-causing variants was undertaken. SETTING: Ophthalmology department of a university hospital. PARTICIPANTS: Four Czech probands. MAIN OUTCOMES AND MEASURES: Results of ophthalmological examination and direct sequencing of the ZEB1 coding region. RESULTS: The following 2 novel frameshift mutations within ZEB1 were identified: c.2617dup in exon 8 in a 22-year-old woman, considered to be most likely de novo in origin, and c.698dup in exon 6 in a 20-year-old man. The first patient had mild changes consistent with PPCD and bilateral best corrected visual acuity of 1.00. The corneal phenotype of the patient in the second case was more severe, with best-corrected visual acuity of 0.40 OD and 0.05 OS. Corneas of both probands were abnormally steep (keratometry readings, flat >= 47.4 diopters [D] and steep >= 49.2 D) with increased pachymetry values but no pattern indicative of keratoconus. Specular microscopy in both patients revealed reduced endothelial cell density (range, 1055/mm2 to 1655/mm2). Both probands had a history of surgery for inguinal hernia; the male patient also reported hydrocele. CONCLUSIONS AND RELEVANCE: Nucleotide changes within the coding region of ZEB1 underlie the pathogenesis of PPCD in 4 of 23 Czech probands (17%). The cumulative de novo ZEB1 mutation rate is at least 14%. Possible involvement of ZEB1 sequence variants not readily identified by direct sequencing of coding regions needs to be further investigated. Our findings also have implications for patient counseling. PMID- 23807283 TI - [Restoration of knee extension with biceps femoris muscle transfer after resection of the quadriceps femoris muscle]. AB - OBJECTIVE: Improvement of gait and ability to stand by reconstruction of functional knee extension. INDICATIONS: Loss of function of the quadriceps femoris muscle due to tumour resection or traumatic damage of the muscle with loss of active knee extension. CONTRAINDICATIONS: Inadequate strength of the biceps femoris muscle. Recurrent tumour or ankylosis of the knee joint. SURGICAL TECHNIQUE: The tendon of the biceps femoris is dissected near the knee at the head of the fibula and is mobilized proximally. The underlying common peroneal nerve and the neurovascular supply of the biceps muscle must be spared. Through a ventral approach at the thigh the lateral intermuscular septum is opened and the biceps tendon is pulled through and sutured to the quadriceps tendon and periost of the patella. POSTOPERATIVE MANAGEMENT: The knee is immobilized in extension with a cast followed by a knee orthosis for 6 weeks, which is followed by intensive physiotherapy; however, the patient should not be forced to flex the knee extensively. The orthosis can be worn for another 3-4 weeks to stabilize the knee joint, while the muscles are intensively trained. RESULTS: Reliable reconstruction of functionally useful, active knee extension without an orthosis of a previously unstable knee joint in the sagittal plane, even if full extension is not to be expected. PMID- 23807284 TI - Weight gain in risperidone therapy: investigation of peripheral hypothalamic neurohormone levels in psychotic patients. AB - The use of antipsychotic drugs has started a new era in the treatment of psychotic disorders. Nevertheless, they cause complications in the long-term treatment, which is mainly weight gain. In this study, we investigated circulating levels of hypothalamic neuropeptides, which are related to appetite regulation, neuropeptide Y (NPY), alpha-melanocyte-stimulating hormone (alpha MSH), cocaine- and amphetamine-regulated transcript (CART), and leptin, in first attack psychotic patients who were treated with an atypical antipsychotic drug, risperidone, for 4 weeks. We used a case-control association design to compare the neuropeptides in the control group versus before and after treatment of the patient group. Samples were obtained from psychotic patients who were admitted to the Psychiatry Outpatient Clinics, Gulhane School of Medicine, Ankara, Turkey. When compared with the control group, NPY and alpha-MSH plasma levels of psychotic patients were severely reduced, and the CART levels were substantially increased when they were first diagnosed (before treatment). However, the patients' body mass index and circulating leptin levels were markedly high after the treatment. Circulating levels of those neurohormones were not significantly changed between before and after treatment of the patients. These data demonstrate that peripheral alpha-MSH and NPY, although reflecting only secretion from peripheral organs, nevertheless, may provide an insight into the patients sympathetic tone and also suggest change of their appetite regulation. alpha Melanocyte-stimulating hormone, NPY, and CART plasma levels may be used as a predictor of weight gain in the early treatment of the patients along with the leptin levels. PMID- 23807285 TI - Site-specific NMR mapping and time-resolved monitoring of serine and threonine phosphorylation in reconstituted kinase reactions and mammalian cell extracts. AB - We outline NMR protocols for site-specific mapping and time-resolved monitoring of protein phosphorylation reactions using purified kinases and mammalian cell extracts. These approaches are particularly amenable to intrinsically disordered proteins and unfolded, regulatory protein domains. We present examples for the 15N isotope-labeled N-terminal transactivation domain of human p53, which is either sequentially reacted with recombinant enzymes or directly added to mammalian cell extracts and phosphorylated by endogenous kinases. Phosphorylation reactions with purified enzymes are set up in minutes, whereas NMR samples in cell extracts are prepared within 1 h. Time-resolved NMR measurements are performed over minutes to hours depending on the activities of the probed kinases. Phosphorylation is quantitatively monitored with consecutive 2D 1H-15N band-selective optimized-flip-angle short-transient (SOFAST)-heteronuclear multiple-quantum (HMQC) NMR experiments, which provide atomic-resolution insights into the phosphorylation levels of individual substrate residues and time dependent changes thereof, thereby offering unique advantages over western blotting and mass spectrometry. PMID- 23807286 TI - Using transmission electron microscopy and 3View to determine collagen fibril size and three-dimensional organization. AB - Collagen fibrils are the major tensile element in vertebrate tissues, in which they occur as ordered bundles in the extracellular matrix. Abnormal fibril assembly and organization results in scarring, fibrosis, poor wound healing and connective tissue diseases. Transmission electron microscopy (TEM) is used to assess the formation of the fibrils, predominantly by measuring fibril diameter. Here we describe a protocol for measuring fibril diameter as well as fibril volume fraction, mean fibril length, fibril cross-sectional shape and fibril 3D organization, all of which are major determinants of tissue function. Serial section TEM (ssTEM) has been used to visualize fibril 3D organization in vivo. However, serial block face-scanning electron microscopy (SBF-SEM) has emerged as a time-efficient alternative to ssTEM. The protocol described below is suitable for preparing tissues for TEM and SBF-SEM (by 3View). We describe how to use 3View for studying collagen fibril organization in vivo and show how to find and track individual fibrils. The overall time scale is ~8 d from isolating the tissue to having a 3D image stack. PMID- 23807287 TI - Selective monitoring of ubiquitin signals with genetically encoded ubiquitin chain-specific sensors. AB - Despite intensive research, there is a distinct lack of methodology for visualizing endogenous ubiquitination in living cells. In this protocol, we describe how unique properties of ubiquitin (Ub)-binding domains (UBDs) can be used to selectively detect, visualize and inhibit Ub-dependent processes in mammalian cells. The procedure deals with designing and validating the binding selectivity of GFP-tagged K63- and linear-linked sensors (TAB2 NZF and NEMO UBAN, respectively) in vitro. We describe how these moieties can be used to inhibit tumor necrosis factor (TNF)-mediated NF-kappaB signaling and to detect ubiquitinated cytosolic Salmonella in living cells, emphasizing a more flexible use compared with chain-specific antibodies. These chain-specific sensors can be used to detect Ub-like or autophagy-related modifiers and, in combination with mass spectrometry, to identify new Ub targets. These Ub (-like) sensors can be designed, constructed and tested in ~2-3 weeks. PMID- 23807288 TI - Generation of iPS cells from normal and malignant hematopoietic cells. AB - Induced pluripotent stem cells (iPSCs) can be generated from various types of cells with transduction of defined transcription factors. In addition to regenerative medicine, iPSCs have been used for the study of pathogenesis of inherited genetic diseases. Here, we presented the examples of the establishment of iPSCs from hematopoietic cells or fibroblasts from hematological disease patients. Hematopoietic cells would be a good donor source for establishing iPSCs owing to the high reprogramming efficiency. iPSCs can be generated not only from normal cells, but also from several types of tumor cells. However it is not so easy, because iPSCs from hematological malignancies have been established only from myeloproliferative neoplasms including chronic myelogenous leukemia (CML) and JAK2-V617F mutation-positive polycythemia vera (PV). iPSC technology has great potential to promote oncology research based on patient samples. PMID- 23807290 TI - The reduction of carbon dioxide in iron biocatalyst catalytic hydrogenation reaction: a theoretical study. AB - The reaction mechanism of CO2 hydrogenation catalyzed by [FeH(PP3)]BF4 (PP3 = P(CH2CH2PPh2)3) had been investigated by DFT calculations. Our calculations indicated that the reduction of carbon dioxide could be carried out via two spin states, the high-spin (HS) triplet state and the low-spin (LS) singlet state. The minimum energy crossing points (MECPs) on the seam of two intersecting PESs (potential energy surfaces) were searched out. Some interesting phenomena, such as the open-loop phenomenon, and the O-rebound process, were demonstrated to be the important causes of the spin crossover. All these calculations gave us insight into the essence of the related experiment from the macro point of view, and helped to verify which spin states the related complexes pertinent were in. All of these researches would help advance the development of efficient and structurally tailorable CO2 hydrogenation catalysts. PMID- 23807289 TI - Endothelial activation and inflammation biomarkers in children and adolescents with sickle cell disease. AB - Sickle cell disease pathogenesis is a complex interplay of multiple factors associated with vascular endothelial activation, intense oxidative stress, and increased sickle cell adhesion. The aim of this study was to determine and compare three panels of plasma circulating biomarkers at 'steady state' and during veno-occlusive crises (VOC) in a cohort of children and adolescents with SCD and healthy controls. The following biomarkers were assessed: acute phase reactants, endothelial factors, and adhesion molecules. Forty-one SCD pediatric patients and 28 healthy children were enrolled. Patients at 'steady state' presented significantly elevated plasma levels of endothelin-1 (ET-1), soluble VCAM-1 (sVCAM-1), soluble P-selectin (sP-selectin), and d-dimers compared to the control group. ET-1, sP-selectin, platelet-derived growth factor (PDGF), von Willebrand factor (vWf), d-dimers, erythrocyte sedimentation rate (ESR), and C reactive protein (CRP) seems to represent additional, but not independent, prognostic markers of VOC crisis. Elevated plasma levels of sP-selectin, ET-1, and sVCAM-1 were associated with VOC frequency. The present study provides preliminary evidence of a possible association between these biomarkers and the endothelial activation at steady state and VOC in childhood SCD. Further prospective studies are required to confirm the potential independent prognostic value of these markers in different stages of pediatric SCD. PMID- 23807291 TI - An ex vivo study on immunohistochemical localization of MMP-7 and MMP-9 in temporomandibular joint discs with internal derangement. AB - Internal derangement (ID) is among the most common disorders of the temporomandibular joint (TMJ). Previous research by our group highlighted a correlation between apoptosis and TMJ ID. Metalloproteinases (MMP)-7 and -9 have been shown to play an important role in extracellular matrix ECM) homeostasis and, through it, in joint disc remodelling. The immunohistochemical expression of MMP-7 and -9 was investigated in discs from patients with TMJ ID and from healthy donors and compared with the degree of histological tissue degeneration. The collagen fibre arrangement in pathological discs exhibited varying degrees of disruption. New vessels were consistently detected; endothelial cells from these vessels were immunolabelled with both MMP-7 and MMP-9. More or less intense MMP-7 and MMP-9 immunolabelling was detected in the cytoplasm of disc cells from all patients. MMP-7 and MMP-9 immunostaining was significantly different between pathological and normal discs and correlated with the extent of histopathological degeneration. MMP-7 and MMP-9 upregulation in discs from patients with TMJ ID demonstrates their involvement in disc damage in this disorder. A greater understanding of these processes could help identify ways to curb MMP overproduction without affecting their tissue remodelling action. The design of specific inhibitors for these MMPs would not only help to gain insights into the biological roles of MMPs, but would also aid in developing therapeutic interventions for diseases associated with abnormal ECM degradation. PMID- 23807292 TI - Poly (ADP-ribose) polymerase 1 protein expression in normal and neoplastic prostatic tissue. AB - A genetic background has been implicated in the development of prostate cancer. Protein microarrays have enabled the identification of proteins, some of which associated with apoptosis, that may play a role in the development of such a tumor. Inhibition of apoptosis is a co-factor that contributes to the onset and progression of prostate cancer, though the molecular mechanisms are not entirely understood. Poly (ADP-ribose) polymerase 1 (PARP-1) gene is required for translocation of the apoptosis-inducing factor (AIF) from the mitochondria to the nucleus. Hence, it is involved in programmed cell death. Different PARP-1 gene expression has been observed in various tumors such as glioblastoma, lung, ovarian, endometrial, and skin cancers. We evaluated the expression of PARP-1 protein in prostatic cancer and normal prostate tissues by immunohistochemistry in 40 men with prostate cancer and in 37 normal men. Positive nuclear PARP-1 staining was found in all samples (normal prostate and prostate cancer tissues). No cytoplasmic staining was observed in any sample. PARP-1-positive cells resulted significantly higher in patients with prostate carcinoma compared with controls (P<0.001). PARP-1 over-expression in prostate cancer tissue compared with normal prostate suggests a greater activity of PARP-1 in these tumors. These findings suggest that PARP-1 expression in prostate cancer is an attempt to trigger apoptosis in this type of tumor similarly to what reported in other cancers. PMID- 23807293 TI - Stem cell populations in the heart and the role of Isl1 positive cells. AB - Cardiac progenitor cells are multipotent stem cells isolated from both embryonic and adult hearts in several species and are able to differentiate at least into smooth muscle cells, endothelial cells and cardiomyocytes. The embryonic origin of these cells has not yet been demonstrated, but it has been suggested that these cells may derive from the first and secondary heart fields and from the neural crest. In the last decade, two diffe-rent populations of cardiac progenitor or stem cells have been identified and isolated, i.e., the Islet1 positive (Isl1+) and c-Kit positive (c-Kit+)/Stem Cell Antigen-1 positive (Sca 1+) cells. Until 2012, these two populations have been considered two separate entities with different roles and a different origin, but new evidence now suggests a con-nection between the two populations and that the two populations may represent two subpopulations of a unique pool of cardiac stem cells, derived from a common immature primitive cell. To find a common consensus on this concept is very important in furthe-ring the application of stem cells to cardiac tissue engineering. PMID- 23807294 TI - Muscleblind-like1 undergoes ectopic relocation in the nuclei of skeletal muscles in myotonic dystrophy and sarcopenia. AB - Muscleblind-like 1 (MBNL1) is an alternative splicing factor involved in postnatal development of skeletal muscles and heart in humans and mice, and its deregulation is known to be pivotal in the onset and development of myotonic dystrophy (DM). In fact, in DM patients this protein is ectopically sequestered into intranuclear foci, thus compromising the regulation of the alternative splicing of several genes. However, despite the numerous biochemical and molecular studies, scarce attention has been paid to the intranuclear location of MBNL1 outside the foci, although previous data demonstrated that in DM patients various splicing and cleavage factors undergo an abnormal intranuclear distribution suggestive of impaired RNA processing. Interestingly, these nuclear alterations strongly remind those observed in sarcopenia i.e., the loss of muscle mass and function which physiologically occurs during ageing. On this basis, in the present investigation the ultrastructural localization of MBNL1 was analyzed in the myonuclei of skeletal muscles from healthy and DM patients as well as from adult and old (sarcopenic) mice, in the attempt to elucidate possible changes in its distribution and amount. Our data demonstrate that in both dystrophic and sarcopenic muscles MBNL1 undergoes intranuclear relocation, accumulating in its usual functional sites but also ectopically moving to domains which are usually devoid of this protein in healthy adults. This accumulation/delocalization could contribute to hamper the functionality of the whole splicing machinery, leading to a lower nuclear metabolic activity and, consequently, to a less efficient protein synthesis. Moreover, the similar nuclear alterations found in DM and sarcopenia may account for the similar muscle tissue features (myofibre atrophy, fibre size variability and centrally located nuclei), and, in general, for the aging-reminiscent phenotype observed in DM patients. PMID- 23807295 TI - Localization of peripheral autonomic neurons innervating the boar urinary bladder trigone and neurochemical features of the sympathetic component. AB - The urinary bladder trigone (UBT) is a limited area through which the majority of vessels and nerve fibers penetrate into the urinary bladder and where nerve fibers and intramural neurons are more concentrated. We localized the extramural post-ganglionic autonomic neurons supplying the porcine UBT by means of retrograde tracing (Fast Blue, FB). Moreover, we investigated the phenotype of sympathetic trunk ganglion (STG) and caudal mesenteric ganglion (CMG) neurons positive to FB (FB+) by coupling retrograde tracing and double-labeling immunofluorescence methods. A mean number of 1845.1+/-259.3 FB+ neurons were localized bilaterally in the L1-S3 STG, which appeared as small pericarya (465.6+/-82.7 um2) mainly localized along an edge of the ganglion. A large number (4287.5+/-1450.6) of small (476.1+/-103.9 um2) FB+ neurons were localized mainly along a border of both CMG. The largest number (4793.3+/-1990.8) of FB+ neurons was observed in the pelvic plexus (PP), where labeled neurons were often clustered within different microganglia and had smaller soma cross-sectional area (374.9+/-85.4 um2). STG and CMG FB+ neurons were immunoreactive (IR) for tyrosine hydroxylase (TH) (66+/-10.1% and 52.7+/-8.2%, respectively), dopamine beta hydroxylase (DbetaH) (62+/-6.2% and 52+/-6.2%, respectively), neuropeptide Y (NPY) (59+/-8.2% and 65.8+/-7.3%, respectively), calcitonin-gene-related peptide (CGRP) (24.1+/-3.3% and 22.1+/-3.3%, respectively), substance P (SP) (21.6+/-2.4% and 37.7+/-7.5%, respectively), vasoactive intestinal polypeptide (VIP) (18.9+/ 2.3% and 35.4+/-4.4%, respectively), neuronal nitric oxide synthase (nNOS) (15.3+/-2% and 32.9+/-7.7%, respectively), vesicular acetylcholine transporter (VAChT) (15+/-2% and 34.7+/-4.5%, respectively), leu-enkephalin (LENK) (14.3+/ 7.1% and 25.9+/-8.9%, respectively), and somatostatin (SOM) (12.4+/-3% and 31.8+/ 7.3%, respectively). UBT-projecting neurons were also surrounded by VAChT-, CGRP , LENK-, and nNOS-IR fibers. The possible role of these neurons and fibers in the neural pathways of the UBT is discussed. PMID- 23807296 TI - Immunoreactivity for thymosin beta 4 and thymosin beta 10 in the adult rat oro gastro-intestinal tract. AB - Thymosin beta 4 (Tbeta4) and thymosin beta 10 (Tbeta10) are two members of the beta-thymosin family, involved in multiple cellular activities in different organs in multiple animal species. Here we report the expression pattern of Tbeta4 and Tbeta10 in rat tissues, in the gut and in annexed glands. The two peptide were differently expressed: Tbeta4 was absent in salivary glands whereas Tbeta10 was expressed in parotid and in submandibular glands. Tbeta4 was mildly expressed in the tongue and in the oesophagus, where Tbeta10 was absent. A similar expression was found in the stomach, ileum and colon mucosa. In pancreas Tbeta4 reactivity was restricted to the Langerhans islet cells; Tbeta4 was also detected in the exocrine cells. Both peptide were not expressed in liver cells. When the rat expression pattern in rat organs was compared to reactivity for Tbeta4 and Tbeta10 in humans, marked differences were found. Our data clearly indicate a species-specific expression of Tbeta4 and Tbeta10, characterized by the actual unpredictability of the expression of these peptides in different cells and tissues. The common high expression of Tbeta4 in mast cells, both in humans and in rats, represents one of the few similarities between these two species. PMID- 23807297 TI - Immunolocalization of succinate dehydrogenase in the esophagus epithelium of domesticated mammals. AB - Using immunohistochemistry and transmission electron microscopy (TEM), the esophagus epithelia of seven domesticated mammals (horse, cattle, goat, pig, dog, laboratory rat, cat) of three nutrition groups (herbivorous, omnivorous, carnivorous) were studied to get first information about energy generation, as demonstrated by succinate dehydrogenase (SDH) activities. Distinct reaction intensities could be observed in all esophageal cell layers of the different species studied reflecting moderate to strong metabolic activities. The generally strong staining in the stratum basale indicated that new cells are continuously produced. The latter feature was confirmed by a thick, and in the horse generally highly active stratum spinosum. Only in the pig, reaction intensity variations occurred, obviously related to differences in physical feed quality or restricted feed allocation. The immunohistochemical results were corroborated by the presence of intact mitochondria in the esophageal cells of all species and nutrition types studied, except for the horse. Possible relationships between SDH reaction intensities and feed structure, mass or consistency are discussed. PMID- 23807298 TI - Stat3 and Socs3 expression patterns during murine placenta development. AB - Signal transducers and activators of transcription 3 (Stat3) has been identified as an important signal transducer in the invasive phenotype of the trophoblasts cells in in vitro studies. However, the in situ distribution and patterns of expression of this molecule in trophoblast cells during the development of the placenta are still under-elucidated. Mice uteri of gestational ages between 7 and 14 days of pregnancy (dop) were fixed in methacarn and processed with immunoperoxidase techniques for detection of Stat3 and its phosphorylation at serine (p-ser727) residues, as well as the suppressor of cytokine signaling 3 (Socs3) expression. Stat3 was observed at 7 through 9 dop in both the antimesometrial and mesometrial deciduas, while continued immunoreactivity between 10 and 13 dop was seen only in the mesometrial decidua. In the placenta, Stat3 was detected in the cytotrophoblast cells of labyrinth and giant trophoblast cells between 10 and 14 dop. Immunoreactivity for Stat3 was also seen in trophoblast cells surrounding the maternal blood vessels. On days 10 and 11 of pregnancy, p-ser727 was detectable in the mesometrial decidua and in giant trophoblasts, while during 12-14 dop in the spongiotrophoblast region. In addition, Socs3 was immunodetected in maternal and placental tissues, principally in the giant trophoblast cells during the whole period of the study. The present in situ study shows the distribution of Stat3, its serine activation and Socs3 in different maternal and fetal compartments during murine placental development, thus further supporting the idea that they play a role during physiological placentation in mice. PMID- 23807299 TI - Different immunohistochemical levels of Hsp60 and Hsp70 in a subset of brain tumors and putative role of Hsp60 in neuroepithelial tumorigenesis. AB - In this work we analysed, by immunohistochemistry, a series of brain tumors to detect the levels and cellular distribution of Hsp60 and Hsp70. We found that Hsp60 levels were significantly higher than those of Hsp70 in neuroepithelial tumors, while levels of both molecules were not significantly different from each other in meningeal neoplasms. In particular, Hsp60 immunopositivity was present mainly at the cytoplasmic level, while Hsp70 immunopositivity was found both in the cytoplasm and in the nucleus of tumor cells. The levels of these molecules in healthy control cells were always very low. Finally, Hsp60 and Hsp70 levels did not correlate with the different types (WHO grade) of neoplasm. Our results are partially in agreement with previous studies and suggest that Hsp60 is not increased by a passive phenomenon (e.g., due to the stress caused by the peritumor environment on cancer cells) but may be actively implicated in tumor progression, e.g. inhibiting tumor cell death or antitumor immune system response, as already postulated in vitro. We also briefly discuss the most recent publications on the extramitochondrial localization of Hsp60 in tumor cells and its role in tumor progression. PMID- 23807304 TI - Synapsin-1 and tau reciprocal O-GlcNAcylation and phosphorylation sites in mouse brain synaptosomes. AB - O-linked N-acetylglucosamine (O-GlcNAc) represents a key regulatory post translational modification (PTM) that is reversible and often reciprocal with phosphorylation of serine and threonine at the same or nearby residues. Although recent technical advances in O-GlcNAc site-mapping methods combined with mass spectrometry (MS) techniques have facilitated study of the fundamental roles of O GlcNAcylation in cellular processes, an efficient technique for examining the dynamic, reciprocal relationships between O-GlcNAcylation and phosphorylation is needed to provide greater insights into the regulatory functions of O GlcNAcylation. Here, we describe a strategy for selectively identifying both O GlcNAc- and phospho-modified sites. This strategy involves metal affinity separation of O-GlcNAcylated and phosphorylated peptides, beta-elimination of O GlcNAcyl or phosphoryl functional groups from the separated peptides followed by dithiothreitol (DTT) conjugation (BEMAD), affinity purification of DTT-conjugated peptides using thiol affinity chromatography, and identification of formerly O GlcNAcylated or phosphorylated peptides by MS. The combined metal affinity separation and BEMAD approach allows selective enrichment of O-GlcNAcylated peptides over phosphorylated counterparts. Using this approach with mouse brain synaptosomes, we identified the serine residue at 605 of the synapsin-1 peptide, 603QASQAGPGPR612, and the serine residue at 692 of the tau peptide, 688SPVVSGDTSPR698, which were found to be potential reciprocal O-GlcNAcylation and phosphorylation sites. These results demonstrate that our strategy enables mapping of the reciprocal site occupancy of O-GlcNAcylation and phosphorylation of proteins, which permits the assessment of cross-talk between these two PTMs and their regulatory roles. PMID- 23807305 TI - Icariside II induces apoptosis via inhibition of the EGFR pathways in A431 human epidermoid carcinoma cells. AB - Improvements in skin cancer treatment are likely to derive from novel agents targeting the molecular pathways that promote tumor cell growth and survival. Icariside II (IS) is a metabolite of icariin, which is derived from Herba Epimedii. The aim of the present study was to evaluate the antitumor effects of IS and to determine the mechanism of apoptosis in A431 human epidermoid carcinoma cells. A431 cells were treated with IS (0-100 uM) for 24 or 48 h and cell viability was detected using the WST-8 assay. Apoptosis was measured by the Annexin-V/propidium iodide (PI) flow cytometric assay. Western blot analysis was used to measure the expression of cleaved caspase-9, cleaved poly ADP ribose polymerase (PARP), phosphorylated signal transducer and activator of transcription 3 (P-STAT3), phosphorylated extracellular signal-regulated kinase (P-ERK), and P-AKT. A431 cells were also pretreated with IS (0-100 uM) 2 h prior to treatment with epidermal growth factor (EGF; 100 ng/ml) for 10 min. Phosphorylated EGF receptor (P-EGFR), P-STAT3, P-ERK and P-AKT were detected by western blot analysis. The results demonstrated that IS inhibited the cell viability of the A431 cells in a dose-dependent manner. Pretreatment with LY294002 [a phosphatidylinositol 3-kinase (PI3K) inhibitor], EGF (an EGFR agonist) and AG1478 (an EGFR inhibitor) partially reversed IS-induced decreases in cell viability. Treatment with 50 um IS resulted in an increased number of apoptotic cells mirrored by increases in cleaved caspase-9 and cleaved PARP. In addition, treatment with 50 uM IS significantly inhibited the activation of the Janus kinase (JAK)-STAT3 and mitogen-activated protein kinase (MAPK)-ERK pathways, but promoted the activation of the PI3K-AKT pathway. Furthermore, IS effectively inhibited the EGF-induced activation of the EGFR pathways. In conclusion, IS inhibited the cell viability of the A431 cells through the regulation of apoptosis. These effects were mediated, at least in part, by inhibiting the activation of the EGFR pathways. PMID- 23807306 TI - Interface studies of N2 plasma-treated ZnSnO nanowire transistors using low frequency noise measurements. AB - Due to the large surface-to-volume ratio of nanowires, the quality of nanowire insulator interfaces as well as the nanowire surface characteristics significantly influence the electrical characteristics of nanowire transistors (NWTs). To improve the electrical characteristics by doping or post-processing, it is important to evaluate the interface characteristics and stability of NWTs. In this study, we have synthesized ZnSnO (ZTO) nanowires using the chemical vapor deposition method, characterized the composition of ZTO nanowires using x-ray photoelectron spectroscopy, and fabricated ZTO NWTs. We have characterized the current-voltage characteristics and low-frequency noise of ZTO NWTs in order to investigate the effects of interface states on subthreshold slope (SS) and the noise before and after N2 plasma treatments. The as-fabricated device exhibited a SS of 0.29 V/dec and Hooge parameter of ~1.20 * 10(-2). Upon N2 plasma treatment with N2 gas flow rate of 40 sccm (20 sccm), the SS improved to 0.12 V/dec (0.21 V/dec) and the Hooge parameter decreased to ~4.99 * 10(-3) (8.14 * 10(-3)). The interface trap densities inferred from both SS and low-frequency noise decrease upon plasma treatment, with the highest flow rate yielding the smallest trap density. These results demonstrate that the N2 plasma treatment decreases the interface trap states and defects on ZTO nanowires, thereby enabling the fabrication of high-quality nanowire interfaces. PMID- 23807307 TI - Synthesis of boronate-silica hybrid affinity monolith via a one-pot process for specific capture of glycoproteins at neutral conditions. AB - In this study, a boronate-silica hybrid affinity monolith was prepared for specific capture of glycoproteins at neutral pH condition. The monolith was synthesized via a facile one-pot procedure in a stainless steel column by concurrently mixing hydrolyzed alkoxysilanes tetramethoxysilane and vinyltrimethoxysilane, organic monomer 3-acrylamidophenylboronic acid and initiator 2,2'-azobisisobutyronitrile together. The polycondensation of alkoxysilanes and copolymerization of organic monomer and vinyl-silica monolith were carried out successively by reacting at different temperatures. After optimizing the preparation conditions, the resulting hybrid affinity monolith was systematically characterized and exhibited excellent affinity to both cis-diol containing small molecules and glycoproteins at neutral and physiological pH, including adenosine, horseradish peroxidase, transferrin and ovalbumin. The binding capacity of ovalbumin on monolith was measured to be 2.5 mg g(-1) at pH 7.0. Furthermore, the hybrid affinity monolith was applied to the separation of transferrin from bovine serum sample at a physiological condition. Good repeatability was obtained and the relative standard deviations of retention time were 1.15 and 4.77 % (n = 5) for run-to-run and column-to-column, respectively. PMID- 23807308 TI - Asymmetric flow-field flow fractionation-multidetection coupling for assessing colloidal copper in drain waters from a Bordeaux wine-growing area. AB - The objective of this study was to show that on-line asymmetric flow-field flow fractionation (AFFFF)-multidetection coupling is useful for studying environmental colloids in a qualitative and quantitative way. The utility of the technique was illustrated by assessing the colloidal fraction of the copper that was extracted from the soil, transferred to an aqueous phase and then transported by drain waters in a wine-growing area. To determine the size and composition of the colloids, AFFFF was coupled to UV, multi-angle light scattering and inductively coupled plasma mass spectrometry detectors. Colloidal copper represents between 20 and 60% of the total copper in the sub 450 nm of drain waters. Copper is mainly associated with organic-rich colloids with a size below 10 nm. It is also found in organo-mineral populations (as clay or (oxy)hydroxides), with sizes ranging between 10 and 450 nm. PMID- 23807309 TI - Detection of tobacco-related biomarkers in urine samples by surface-enhanced Raman spectroscopy coupled with thin-layer chromatography. AB - The nicotine metabolites, cotinine and trans-3'-hydroxycotinine (3HC) are considered as superior biomarkers for identifying tobacco exposure. More importantly, the ratio of 3HC to cotinine is a good indicator to phenotype individuals for cytochrome P450 2A6 activity and to individualize pharmacotherapy for tobacco addiction. In this paper, a simple, robust and novel method based on surface-enhanced Raman spectroscopy coupled with thin-layer chromatography (TLC) was developed to directly quantify the biomarkers in human urine samples. This is the first time surface-enhanced Raman spectroscopy (SERS) was used to detect cotinine and 3HC in urine samples. The linear dynamic range for the detection of cotinine is from 40 nM to 8 MUM while that of 3HC is from 1 MUM to 15 MUM. The detection limits are 10 nM and 0.2 MUM for cotinine and 3HC, respectively. The proposed method was further validated by quantifying the concentration of both cotinine and 3HC in smokers' urine samples. This TLC-SERS method allows the direct detection of cotinine in the urine samples of both active and passive smokers and the detection of 3HC in smokers. PMID- 23807310 TI - C-reactive protein as a marker of complicated diverticulitis in patients on anti inflammatory medications. AB - BACKGROUND: Diverticulitis is a common indication for surgical emergency room admission, often leading to abdominal computed tomography (CT) scanning for both diagnosis and staging. C-reactive protein (CRP) has been identified as a useful biomarker of inflammation. Aspirin and corticosteroids are known to down-regulate CRP production. In this study, we evaluated the usefulness of CRP as a biomarker for complicated diverticulitis and specifically in patients on anti-inflammatory medications: aspirin and corticosteroids. METHODS: We analyzed the medical records of patients diagnosed at one medical center during a two-year period, with left-sided diverticulitis, according to clinical data and CT scan. Disease severity was assessed by the Hinchey score using the radiological findings detected by CT. RESULTS: A total of 295 patients were included in the study. Two hundred and forty-three (82 %) were classified with uncomplicated (Hinchey 1a) and 52 (18 %) with complicated disease (Hinchey > 1a). Mean CRP levels were 133.5 and 63.5 mg/ml for those with complicated and uncomplicated disease, respectively (p < 0.001), and 139 and 60 mg/ml, respectively (p < 0.001) in the subgroup of patients taking aspirin (n = 61). For 14 patients on corticosteroid treatment, the difference in mean CRP levels for complicated and uncomplicated disease was not statistically significant. CRP > 90 mg/ml had 88 % sensitivity and 75 % specificity for complicated disease. CONCLUSIONS: The CRP level distinguished between complicated and uncomplicated disease among left-sided diverticulitis patients including those taking aspirin, but not among those on corticosteroid treatment. PMID- 23807311 TI - In-vitro strength degradation of dental ceramics and novel PICN material by sharp indentation. AB - OBJECTIVES: To determine the flexural strength and subsequent strength degradation of a range of dental CAD/CAM ceramic materials and novel PICN (Polymer-Infiltrated-Ceramic-Network) materials by means of pre-damaging with Vickers indentations at various loads. METHODS: The materials tested included (Mark II, PICN test material 1 and 2, In-Ceram Alumina, VM 9, In-Ceram YZ; Vita Zahnfabrik, Bad Saeckingen, Germany) and (IPS e.max CAD, Ivoclar Vivadent, Schaan, Liechtenstein). Bending bars were cut and lapped with 15 um diamond suspension. Initial flexural strength (n=10) was determined in three-point bending. To evaluate the damage tolerance, Vickers indentations were placed on the bending bars (n=35) with varying loads (1.96-98.07 N). The indented bending bars were subsequently loaded to fracture in three-point-bending. In addition, the fracture toughness was determined by the indentation strength (IS) and the SEVNB technique (n=5). RESULTS: With increasing indentation loads the fracture strength of all materials tested decreased. The material with the highest fracture resistance to indentation induced damage, was the PICN test material 1 with an indentation load-flexural strength curve slope of 0.21. In-Ceram YZ exhibited the highest damage susceptibility with a slope of 0.4. The fracture toughness varied with the measurement technique and material in the range of 0.82 (VM 9) to 4.94 (In-Ceram YZ) MPa?m for the SEVNB method and 0.96 (VM 9) to 4.97 (In-Ceram YZ) MPa?m for the IS method respectively. SIGNIFICANCE: This study aims to indicate the likely clinical behavior by evaluating the damage tolerance and R curve behavior of dental ceramics by in-vitro strength degradation and fracture toughness measurements. PMID- 23807312 TI - [Ca2+] i-induced augmentation of the inward rectifier potassium current (IK1) in canine and human ventricular myocardium. AB - The inward rectifier K+ current (IK1) plays an important role in terminal repolarization and stabilization of the resting potential in cardiac cells. Although IK1 was shown to be sensitive to changes in intracellular Ca2+ concentration ([Ca2+]i), the nature of this Ca2+ sensitivity-in spite of its deep influence on action potential morphology-is controversial. Therefore, we aimed to investigate the effects of a nonadrenergic rise in [Ca2+]i on the amplitude of IK1 in canine and human ventricular myocardium and its consequences on cardiac repolarization. IK1, defined as the current inhibited by 10 MUM Ba2+, was significantly increased in isolated canine myocytes following a steady rise in [Ca2+]i. Enhanced IK1 was also observed when [Ca2+]i was not buffered by ethylene glycol tetraacetic acid, and [Ca2+]I transients were generated. This [Ca2+]i dependent augmentation of IK1 was largely attenuated after inhibition of CaMKII by 1 MUM KN-93. Elevation of [Ca2+]o in multicellular canine and human ventricular preparations resulted in shortening of action potentials and acceleration of terminal repolarization. High [Ca2+]o enhanced the action potential lengthening effect of the Ba(2+)-induced IK1 blockade and attenuated the prolongation of action potentials following a 0.3-MUM dofetilide-induced IKr blockade. Blockade of IKs by 0.5 MUM HMR-1556 had no significant effect on APD90 in either 2 mM or 4 mM [Ca2+]o. It is concluded that high [Ca2+]i leads to augmentation of the Ba2+-sensitive current in dogs and humans, regardless of the mechanism of the increase. This effect seems to be at least partially mediated by a CaMKII-dependent pathway and may provide an effective endogenous defense against cardiac arrhythmias induced by Ca2+ overload. PMID- 23807314 TI - Nanopore formation on the surface oxide of commercially pure titanium grade 4 using a pulsed anodization method in sulfuric acid. AB - Titanium and its alloys form a thin amorphous protective surface oxide when exposed to an oxygen environment. The properties of this oxide layer are thought to be responsible for titanium and its alloys biocompatibility, chemical inertness, and corrosion resistance. Surface oxide crystallinity and pore size are regarded to be two of the more important properties in establishing successful osseointegration. Anodization is an electrochemical method of surface modification used for colorization marking and improved bioactivity on orthopedic and dental titanium implants. Research on titanium anodization using sulphuric acid has been reported in the literature as being primarily conducted in molarity levels 3 M and less using either galvanostatic or potentiostatic methods. A wide range of pore diameters ranging from a few nanometers up to 10 MUm have been shown to form in sulfuric acid electrolytes using the potentiostatic and galvanostatic methods. Nano sized pores have been shown to be beneficial for bone cell attachment and proliferation. The purpose of the present research was to investigate oxide crystallinity and pore formation during titanium anodization using a pulsed DC waveform in a series of sulfuric acid electrolytes ranging from 0.5 to 12 M. Anodizing titanium in increasing sulfuric acid molarities showed a trend of increasing transformations of the amorphous natural forming oxide to the crystalline phases of anatase and rutile. The pulsed DC waveform was shown to produce pores with a size range from <=0.01 to 1 MUm(2). The pore size distributions produced may be beneficial for bone cell attachment and proliferation. PMID- 23807313 TI - Epigenetic marks in an adaptive water stress-responsive gene in tomato roots under normal and drought conditions. AB - Tolerance to water deficits was evolutionarily relevant to the conquest of land by primitive plants. In this context, epigenetic events may have played important roles in the establishment of drought stress responses. We decided to inspect epigenetic marks in the plant organ that is crucial in the sensing of drought stress: the root. Using tomato as a crop model plant, we detected the methylated epialleles of Asr2, a protein-coding gene widespread in the plant kingdom and thought to alleviate restricted water availability. We found 3 contexts (CG, CNG, and CNN) of methylated cytosines in the regulatory region of Solanum lycopersicum Asr2 but only one context (CG) in the gene body. To test the hypothesis of a link between epigenetics marks and the adaptation of plants to drought, we explored the cytosine methylation status of Asr2 in the root resulting from water-deficit stress conditions. We found that a brief exposure to simulated drought conditions caused the removal of methyl marks in the regulatory region at 77 of the 142 CNN sites. In addition, the study of histone modifications around this model gene in the roots revealed that the distal regulatory region was rich in H3K27me3 but that its abundance did not change as a consequence of stress. Additionally, under normal conditions, both the regulatory and coding regions contained the typically repressive H3K9me2 mark, which was lost after 30 min of water deprivation. As analogously conjectured for the paralogous gene Asr1, rapidly acquired new Asr2 epialleles in somatic cells due to desiccation might be stable enough and heritable through the germ line across generations, thereby efficiently contributing to constitutive, adaptive gene expression during the evolution of desiccation-tolerant populations or species. PMID- 23807315 TI - Production, characterisation, and cytocompatibility of porous titanium-based particulate scaffolds. AB - Despite its non-matching mechanical properties titanium remains the preferred metal implant material in orthopaedics. As a consequence in some cases stress shielding effect occurs, leading to implant loosening, osteopenia, and finally revision surgery. Porous metal scaffolds to allow easier specialised cells ingrowth with mechanical properties closer to the ones of bone can overcome this problem. This should improve healing processes, implant integration, and dynamic strength of implants retaining. Three Ti-6Al-4V materials were metal injection moulded and tailored porosities were effectively achieved. After microstructural and mechanical characterisation, two different primary cells of mesenchymal origin (human umbilical cord perivascular cells and human bone derived cells which revealed to be two pertinent models) as well as one cell line originated from primary osteogenic sarcoma, Saos-2, were bestowed to investigate cell material interaction on genomic and proteome levels. Biological examinations disclosed that no material has negative impact on early adhesion, proliferation or cell viability. An efficient cell ingrowth into material with an average porosity of 25-50 MUm was proved. PMID- 23807316 TI - Biological evaluation of polyvinyl alcohol hydrogel crosslinked by polyurethane chain for cartilage tissue engineering in rabbit model. AB - Polyvinyl alcohol (PVA) hydrogel chains were crosslinked by urethane pre-polymer (PPU) in order to fabricate a new substitute for cartilage lesions. The microscopy images showed that the cultured chondrocytes had spherical morphology on PVA-PPU sample after 4 weeks of isolation in vitro. The alcian blue and safranin O staining proved the presence of proteoglycan on the surface of PVA-PPU sample secreted by cultured chondrocytes. This was confirmed by the detection of sulfate ions in the wavelength dispersive X-ray (WDX) analysis. In addition, the expression of collagen type II and aggrecan were observed in chondrocytes cultured on PVA-PPU by RT-PCR. Moreover, the implantation of the PVA-PPU sample with autologous cultured chondrocytes revealed the formation of neocartilage tissue in a rabbit model during 12 weeks follow up. In conclusion, the results verified that isolated chondrocytes cultured on PVA-PPU retain their original phenotype and this composition can be considered as promising substrate for cartilage tissue engineering. PMID- 23807317 TI - A recyclable ruthenium(II) complex supported on magnetic nanoparticles: a regioselective catalyst for alkyne-azide cycloaddition. AB - A magnetically separable ruthenium catalyst was synthesized through immobilizing a pentamethylcyclopentadienyl ruthenium complex on iron oxide nanoparticles. The catalyst is highly active and selective for the synthesis of 1,5-disubstituted 1,2,3-trizoles via cycloaddition of alkynes and organic azides and can be recycled at least 5 times. PMID- 23807318 TI - Clinical and biological features at diagnosis in mitochondrial fatty acid beta oxidation defects: a French pediatric study from 187 patients. Complementary data. PMID- 23807320 TI - Phenotyping soybean plants transformed with rd29A:AtDREB1A for drought tolerance in the greenhouse and field. AB - The development of drought tolerant plants is a high priority because the area suffering from drought is expected to increase in the future due to global warming. One strategy for the development of drought tolerance is to genetically engineer plants with transcription factors (TFs) that regulate the expression of several genes related to abiotic stress defense responses. This work assessed the performance of soybean plants overexpressing the TF DREB1A under drought conditions in the field and in the greenhouse. Drought was simulated in the greenhouse by progressively drying the soil of pot cultures of the P58 and P1142 lines. In the field, the performance of the P58 line and of 09D-0077, a cross between the cultivars BR16 and P58, was evaluated under four different water regimes: irrigation, natural drought (no irrigation) and water stress created using rain-out shelters in the vegetative or reproductive stages. Although the dehydration-responsive element-binding protein (DREB) plants did not outperform the cultivar BR16 in terms of yield, some yield components were increased when drought was introduced during the vegetative stage, such as the number of seeds, the number of pods with seeds and the total number of pods. The greenhouse data suggest that the higher survival rates of DREB plants are because of lower water use due to lower transpiration rates under well watered conditions. Further studies are needed to better characterize the soil and atmospheric conditions under which these plants may outperform the non-transformed parental plants. PMID- 23807321 TI - A new method for producing transgenic birds via direct in vivo transfection of primordial germ cells. AB - Traditional methods of avian transgenesis involve complex manipulations involving either retroviral infection of blastoderms or the ex vivo manipulation of primordial germ cells (PGCs) followed by injection of the cells back into a recipient embryo. Unlike in mammalian systems, avian embryonic PGCs undergo a migration through the vasculature on their path to the gonad where they become the sperm or ova producing cells. In a development which simplifies the procedure of creating transgenic chickens we have shown that PGCs are directly transfectable in vivo using commonly available transfection reagents. We used Lipofectamine 2000 complexed with Tol2 transposon and transposase plasmids to stably transform PGCs in vivo generating transgenic offspring that express a reporter gene carried in the transposon. The process has been shown to be highly effective and as robust as the other methods used to create germ-line transgenic chickens while substantially reducing time, infrastructure and reagents required. The method described here defines a simple direct approach for transgenic chicken production, allowing researchers without extensive PGC culturing facilities or skills with retroviruses to produce transgenic chickens for wide-ranging applications in research, biotechnology and agriculture. PMID- 23807322 TI - Progression of lumbar spinal stenosis is influenced by polymorphism of thrombospondin 2 gene in the Korean population. AB - PURPOSE: The aim of this study is to determine the contribution of thrombospondin 2 (THBS2) polymorphisms to the development and progression of lumbar spinal stenosis (LSS) in the Korean population. METHODS: We studied 148 symptomatic patients with radiographically proven LSS and 157 volunteers with no history of back problems from our institution. Magnetic resonance images were obtained for all the patients and controls. Quantitative image evaluation for LSS was performed to evaluate the severity of LSS. All patients and controls were genotyped for THBS2 allele variations using a polymerase chain reaction-based technique. RESULTS: We found no causal single nucleotide polymorphism (SNPs) in THBS2 that were significantly associated with LSS. Two SNPs (rs6422747, rs6422748) were over-represented in controls [P = 0.042, odds ratio [OR] = 0.55 and P = 0.042, OR = 0.55, respectively]. Haplotype analysis showed that the ''AGAGACG'' haplotype (HAP4) and ''AAGGACG'' haplotype (HAP5) were over represented in severe LSS patients (P = 0.0147, OR = 2.02 and P = 0.0137, OR = 2.48, respectively). In addition, the ''AAAGGGG'' haplotype (HAP1) was over represented in controls (P = 0.0068, OR = 0.30). CONCLUSIONS: Although no SNPs in THBS2 were associated with LSS, haplotypes (HAP4 and HAP5) were significantly associated with progression of LSS in the Korean population, whereas another haplotype (HAP1) may play a protective role against LSS development. PMID- 23807324 TI - [Editorial]. PMID- 23807325 TI - [Effect of maternal education program on duration of hospitalization of the newborn and the mother after delivery]. PMID- 23807323 TI - Maintenance therapy with pemetrexed versus docetaxel after induction therapy with carboplatin and pemetrexed in chemotherapy-naive patients with advanced non squamous non-small-cell lung cancer: a randomized, phase II study. AB - PURPOSE: The optimal strategy for maintenance chemotherapy is controversial. We evaluated the efficacy and safety of continuation maintenance with pemetrexed and switch maintenance with docetaxel in advanced non-squamous non-small-cell lung cancer (NSCLC). METHODS: Chemotherapy-naive patients with non-squamous NSCLC were enrolled in this randomized phase II study. Patients who achieved disease control after four cycles of induction therapy with carboplatin (AUC 6) and pemetrexed (500 mg/m(2)) were randomized to maintenance therapy with pemetrexed (500 mg/m(2)) or docetaxel (60 mg/m(2)). The primary endpoint was survival without toxicity, defined as the time from the initiation of maintenance therapy to the first date of any grade 3/4 toxicity or death due to any cause. RESULTS: A total of eighty-five patients were enrolled in the induction phase, and 26 patients were assigned to the pemetrexed maintenance therapy and 25 patients were assigned to the docetaxel maintenance therapy. Survival without toxicity was significantly longer in the pemetrexed group (median 20.8 months, 95 % confidence interval (CI) 0.7-not estimable) than in the docetaxel group (median 0.5 months, 95 % CI 0.2 2.0, hazard ratio 0.36, 95 % CI 0.17-0.74). CONCLUSIONS: Continuation maintenance with pemetrexed may be a feasible treatment option for patients with non-squamous NSCLC who have achieved disease control after induction therapy with carboplatin and pemetrexed. Switch maintenance with docetaxel may also be efficacious but frequently causes severe hematologic toxicity. PMID- 23807326 TI - [Awareness about venous thromboembolic disease among residents and graduates in internal medicine]. PMID- 23807327 TI - [Low-dose all- retinoic acid in adults with acute promyelocytic leukemia]. PMID- 23807328 TI - [Progressive activation of brain areas induced by daily ingestion of a sweet snack]. PMID- 23807329 TI - [Screening program in Michoacan State for Retinopathy of prematurity]. PMID- 23807330 TI - [Positive surgical margins decrease cancer-specific survival of patients with prostate cancer treated with radical prostatectomy]. PMID- 23807331 TI - [In vitro assessment of UVA protection by sunscreens for prescription in Mexico]. PMID- 23807332 TI - [Sexual and reproductive health among adolescents in Mexico: evidence and proposals]. PMID- 23807333 TI - [Hemophilia]. PMID- 23807334 TI - [Type 2 diabetes mellitus and colorectal cancer: possible molecular mechanisms associated]. PMID- 23807335 TI - [Are xenoestrogens already impacting our human social structure?]. PMID- 23807336 TI - [Perioperative considerations in Parkinson's disease: pharmacologic implications]. PMID- 23807337 TI - [Epidemiology of bullous pemphigoid in 32 years]. PMID- 23807338 TI - [Humanism and medicine]. PMID- 23807339 TI - ["The mechanic's hands" sign: It's clinical implication]. PMID- 23807340 TI - [Constitutional thoughts on the Mexican General Health Council]. PMID- 23807341 TI - [Molecular diagnosis of Chagas disease]. PMID- 23807342 TI - [Eugenics and euthanasia: the life unworthy of life]. PMID- 23807343 TI - [The second expedition of Balmis: revolution and vaccine]. PMID- 23807344 TI - [Difficulties of the negotiation process of the Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the application of biology and medicine (and a call for its adhesion)]. PMID- 23807345 TI - Changes in biomechanical properties of the cornea and intraocular pressure after myopic laser in situ keratomileusis using a femtosecond laser for flap creation determined using ocular response analyzer and Goldmann applanation tonometry. AB - PURPOSE: To compare intraocular pressure (IOP) measurements before and after laser in situ keratomileusis (LASIK) using a femtosecond laser for flap creation, and to identify factors that may influence the preoperative and postoperative IOP, and the change in IOP after LASIK. METHODS: Forty eyes from 20 patients who underwent treatment for myopia using a femtosecond laser for flap creation were enrolled in this study. The IOP and corneal biomechanical markers were prospectively measured preoperatively and 1 month after LASIK with Goldmann applanation tonometry (GAT) and the ocular response analyzer (ORA). Manifest refraction spherical equivalent, central corneal thickness, ablation depth, and mean corneal curvature (K reading) were also recorded. RESULTS: After LASIK, there was a significant reduction in the IOP measurement with respect to the corneal-compensated intraocular pressure (IOPcc) (Delta=-0.67+/-2.07 mm Hg), Goldmann-correlated pressure (IOPg) (Delta=-3.92+/-2.19 mm Hg), and GAT (Delta= 2.6+/-2.51). Multiple regression analysis revealed that the corneal hysteresis (CH) and corneal resistance factor (CRF) are statistically significant predictors of IOPcc, IOPg, and GAT (P<0.000). In this analysis, the preoperative manifest refraction spherical equivalent, CH, and CRF were significant predictors of DeltaIOPcc (adjusted R2=0.401) and DeltaIOPg (adjusted R2=0.386). The preoperative SE and central corneal thickness significantly predicted DeltaGAT (adjusted R2=0.464). CONCLUSIONS: ORA provides a more complete measurement of IOP after LASIK with a femtosecond laser than GAT because ORA provides greater knowledge of the corneal biomechanics in terms of CH and CRF. PMID- 23807346 TI - Differences in ocular blood flow in glaucoma between patients of African and European descent. AB - PURPOSE: To investigate differences in ocular blood flow in individuals of African descent (AD) and European descent (ED) with open angle glaucoma (OAG). PATIENTS AND METHODS: A retrospective data analysis was performed on OAG patients of AD and ED who were previously examined for ocular blood flow within the Department of Ophthalmology at Indiana University School of Medicine. Data analysis included blood pressure, heart rate, visual fields, intraocular pressure, ocular perfusion pressure, and color Doppler imaging of retrobulbar vessels. Color Doppler imaging measurements were performed on ophthalmic, central retinal, and nasal and temporal short posterior ciliary arteries, with peak systolic (PSV) and end diastolic velocities (EDV) as well as the Pourcelot vascular resistive index calculated for each vessel. Two-sample t tests of unequal variance were performed with P values <0.05 considered statistically significant. RESULTS: OAG patients of AD had statistically significant lower retrobulbar blood flow values than patients of ED including lower ophthalmic artery PSV (P=0.0001), ophthalmic artery EDV (P=0.0008), central retinal artery PSV (P=0.01), temporal short posterior ciliary artery PSV (P=0.0037), and nasal short posterior ciliary artery PSV (P<0.0001). No significant differences were found in terms of intraocular pressure or visual field parameters. CONCLUSIONS: Significantly lower blood flow values were identified in all retrobulbar blood vessels in AD compared with ED OAG patients. These findings suggest that the contribution of ocular blood flow to the disease process may be different in AD compared with ED OAG patients. PMID- 23807347 TI - Efficacy of selective laser trabeculoplasty in phakic and pseudophakic eyes. AB - PURPOSE: To compare the efficacy of selective laser trabeculoplasty (SLT) in phakic and pseudophakic eyes in open-angle glaucoma and ocular hypertension. MATERIALS AND METHODS: Charts of 28 pseudophakic eyes and 60 phakic eyes that underwent 360-degree SLT were retrospectively reviewed. Patients were examined at 1, 3, 6, and 12 months. Treatment success was defined as >=20% intraocular pressure (IOP) reduction, with no additional medications, laser, or glaucoma surgery. Mean IOP change, mean percentage of IOP reduction, and success rates for phakic and pseudophakic eyes were compared. RESULTS: Mean percentage of IOP reduction post-SLT at 1-, 3-, 6-, and 12-month visits were 21.4%, 25.8%, 24.8%, and 23.7%, respectively, in the pseudophakic group and 22.8%, 25.0%, 25.7%, and 21.2%, respectively, in the phakic group. Success rates ranged between 60% and 64% in the pseudophakic group and between 58% and 73% in the phakic group. No statistically significant differences in IOP change, percentage of IOP reduction, and success rate were seen between the groups at any of the post-SLT visits (P>0.05). CONCLUSIONS: Application of 360-degree SLT seems to be an efficient and safe treatment option for the management of phakic and pseudophakic open-angle glaucoma and ocular hypertension. PMID- 23807348 TI - Projected cost comparison of Trabectome, iStent, and endoscopic cyclophotocoagulation versus glaucoma medication in the Ontario Health Insurance Plan. AB - PURPOSE: To compare the direct cost of treating glaucoma patients with Trabectome, iStent, and endoscopic cyclophotocoagulation (ECP) versus topical medications in Ontario, Canada. Costs are projected over a 6-year period, and presented on a per-patient level from the perspective of the Ontario Health Insurance Plan (OHIP). METHODS: The per-bottle cost of each medication was obtained from the 2011 Ontario Drug Benefit (ODB) formulary. A wastage adjustment fee was added to the cost, as was a pharmacy markup, and an ODB dispensing fee. Previously published medication prescription rates were used to determine the frequency with which each medication is prescribed. We estimated the overall cost by taking a weighted average of the cost of each class of glaucoma medications.The cost of each glaucoma device was determined by contacting local distributors. We then added the cost of disposables used during surgery (viscoelastic and keratome) to the cost of each procedure. Start-up costs for each device and surgeons' fees were excluded from the overall cost. RESULTS: At 6 years, treatment with the Trabectome offered a cumulative cost savings of $279.23, $1572.55, and $2424.71 per patient versus monodrug, bidrug, and tridrug therapy, respectively. A cumulative cost difference of -$20.77, $1272.55, and $2124.71 per patient were found when comparing iStent versus monodrug, bidrug, and tridrug therapy, respectively. Treatment with ECP yielded a cost savings of $779.23, $2072.55, and $2924.71 per patient versus monodrug, bidrug, and tridrug therapy, respectively. CONCLUSIONS: Over a projected period of 6 years, the Trabectome, iStent, and ECP may all offer a modest cost savings to OHIP versus the cost of glaucoma medication. Further analysis of direct and indirect costs to patients as well as quality of life assessments will help further delineate the role of these treatments in the glaucoma treatment paradigm. PMID- 23807349 TI - Comparison of dorzolamide/timolol versus brimonidine/timolol fixed combination therapy in the management of steroid-induced ocular hypertension. AB - PURPOSE: To compare the efficacy of fixed combinations of dorzolamide-timolol (FCDT) and brimonidine-timolol (FCBT) in patients with intraocular pressure (IOP) elevations after intravitreal triamcinolone acetonide (IVTA) injections. MATERIALS AND METHODS: This was a prospective, randomized, open-label study. Patients who received IVTA injections due to diffuse diabetic macular edema and who had an IOP of 24 mm Hg or higher after IVTA treatment were included. They were randomized to receive either FCBT or FCDT twice daily. Follow-up visits were scheduled on week 4 and 12 weeks after starting the study medication. At all follow-up visits, IOP was measured with Goldmann applanation tonometry. The primary outcome measure was mean IOP, the secondary outcome was reduction in mean IOP at 4 and 12 weeks compared with postinjection values. RESULTS: Sixty patients were randomized in 1:1 ratio. The FCBT and FCDT groups were similar in terms of age, sex, and preinjection IOP (P>0.05 for all). Mean postinjection IOP was 31.95+/-7.39 and 29.83+/-5.17 mm Hg in FCBT and FCDT groups, respectively (P=0.239). After 4 weeks, mean IOP was 17.05+/-3.61 mm Hg in FCBT and 18.93+/ 3.30 mm Hg in FCDT groups (P=0.063). After 12 weeks, mean IOP in the FCBT and FCDT study groups was 16.35+/-2.70 and 18.43+/-2.82 mm Hg, respectively (P=0.012). Both fixed combinations significantly reduced IOP in comparison with the postinjection values (P<0.05). Mean reduction in IOP after 4 weeks were 14.90+/-7.28 mm Hg in FCBT and 10.90+/-4.83 mm Hg in FCDT groups (P=0.024); after 12 weeks, these values were 15.60+/-7.77 and 11.40+/-5.89 mm Hg in FCBT and FCDT groups, respectively (P=0.035). CONCLUSIONS: Both FCBT and FCDT are effective in controlling IOP elevations after IVTA injections. The results of this study suggest that FCBT is superior to FCDT in reducing IOP and provides better IOP control after IVTA injections. PMID- 23807350 TI - Floppy eyelid syndrome as an indicator of the presence of glaucoma in patients with obstructive sleep apnea. AB - PURPOSE: The aim of the study was to investigate whether floppy eyelid syndrome (FES) could be an indicator of glaucoma in patients with obstructive sleep apnea (OSA). MATERIALS AND METHODS: A total of 152 patients were included: 75 patients with OSA and without FES; 52 patients with OSA and FES; and 25 non-OSA patients. The presence of FES was defined by easy upper eyelid eversion and tarsal papillary conjunctivitis. All the patients underwent a complete ophthalmologic examination to diagnose glaucoma; this included computerized perimetry and retinal fiber layer measurements with optical coherence tomography. RESULTS: The prevalence of glaucoma in OSA patients without FES was 5.33% (4/75). One patient had primary open-angle glaucoma and 3 had previously diagnosed glaucoma. The prevalence of glaucoma in OSA patients with FES was 23.07% (12/52). Six patients had normal-tension glaucoma, 5 had primary open-angle glaucoma and one patient had previously diagnosed glaucoma. None of the 25 patients without OSA had glaucoma. The difference in the prevalence of glaucoma between OSA patients without FES (5.3%) and OSA patients with FES (23.07%) was statistical significant (P=0.004). When adjustments were made for age and body mass index, this significance remained (P=0.04). CONCLUSIONS: These data suggest that FES may offer a useful way to identify individuals with a greater probability of having glaucoma in the OSA population. PMID- 23807351 TI - A study of the association between patterns of eye drop prescription and medication usage in glaucoma subjects. AB - PURPOSE: To investigate the association between patterns of eye drop prescription and medication usage in patients with glaucoma. PATIENTS AND METHODS: Sixty-seven Japanese patients with glaucoma who were prescribed topical antiglaucoma medications including a prostaglandin analogue bilaterally for >6 months at Nayoro City General Hospital, Nayoro, Japan, were included in the study. A self administered, 5-item patient questionnaire was administered to determine how patients routinely use medications, including the method of eye drop administration, number of eye drops per instillation, accuracy of eye drop placement, weekly frequency of eye drop application, and their awareness of local side effects. The number of prostaglandin analogue bottles prescribed monthly was compared in each factor. RESULTS: The mean patient age was 74.4+/-10.0 years (range, 52 to 95 y; 39 women, 28 men). The mean duration of glaucoma treatment was 4.2+/-3.2 years (range, 0.7 to 10.6 y). Patients who placed the eye drops outside the eye were prescribed significantly more bottles monthly (P=0.008). The other factors had no significant effect on the number of bottles prescribed monthly. CONCLUSIONS: Patients with glaucoma who used eye drops incorrectly were routinely prescribed additional bottles of eye drops. Ophthalmologists should determine whether patients who request an unusual number of eye drops are using the eye drops correctly. PMID- 23807352 TI - Comparison of visual recovery following ex-PRESS versus trabeculectomy: results of a prospective randomized controlled trial. AB - PURPOSE: To compare the rate of visual recovery after Ex-PRESS implantation versus standard trabeculectomy. PATIENTS AND METHODS: Subjects enrolled in a prospective randomized controlled trial comparing Ex-PRESS to trabeculectomy were analyzed for postoperative changes in visual acuity (VA). Risk factors for visual loss (split fixation, cup-disc ratio, intraocular pressure, visual field mean deviation, and hypotony) were evaluated. RESULTS: Sixty-four subjects were enrolled (33 Ex-PRESS, 31 trabeculectomy). There was no significant difference in mean logMAR VA between groups at baseline or any study visit. VA was significantly reduced up to week 2 following surgery in both the groups. However, by month 1, VA in the Ex-PRESS group was no longer significantly different from baseline (P=0.23) and remained nonsignificant at subsequent visits up to 6 months. In the trabeculectomy group, VA remained significantly lower than baseline at each study visit. At 6 months, 47% of the trabeculectomy eyes compared with 16% of the Ex-PRESS eyes had lost >=2 Snellen lines (P=0.01). Reasons for VA loss included cataract, central retinal vein occlusion, and diabetic retinopathy, however, in a significant number of cases no cause could be determined. None of the risk factors evaluated were associated with vision loss. CONCLUSIONS: Although there was no difference in mean VA between the Ex-PRESS and trabeculectomy groups at any time point, trabeculectomy eyes were more likely to lose >=2 Snellen lines. In addition, VA recovered faster in the Ex-PRESS group. PMID- 23807353 TI - Intraocular pressure outcomes after endophthalmitis associated with glaucoma surgery. AB - PURPOSE: To determine long-term intraocular pressure (IOP) outcomes and risk factors for failure of IOP control in patients with previous glaucoma surgery that was complicated with infectious endophthalmitis. PATIENTS AND METHODS: Retrospective case series of 12 patients with previous glaucoma surgery that presented with infectious endophthalmitis to the University Hospital, Newark, NJ between 1995 and 2006. IOP control failure was stratified into 2 groups: IOP of >=22 mm Hg and IOP >=16 mm Hg at 3 consecutive follow-up visits. A Kaplan-Meier survival analysis was used to determine failure rate and Cox proportional hazards model to analyze effects of pertinent variables on survival. P values <0.05 were considered statistically significant. RESULTS: Twelve patients that had previously undergone glaucoma surgery (8 trabeculectomies and 4 bleb revisions) and were complicated with infectious endophthalmitis were identified. Mean follow up time was 43.7 months (range, 10 to 98 mo). Of 12 patients, 9 (75%) failed, 2 (17%) consistently maintained IOP<22 mm Hg, and 1 (8%) maintained IOP<16 mm Hg during the follow-up period. Median survival time was 9.25 months. Age of the subject 65 years and older (P=0.0002) was associated with increased risk of IOP failure, whereas initial treatment selection with vitrectomy did not. Six patients required additional glaucoma surgery during the follow-up period. CONCLUSIONS: IOP control after resolution of endophthalmitis in patients with previous glaucoma surgery was maintained in only 25% of cases. Half the patients required additional glaucoma surgery. PMID- 23807354 TI - The effect of scleral spur identification methods on structural measurements by anterior segment optical coherence tomography. AB - PURPOSE: To assess methods for and variations in identifying the scleral spur (SS) position in anterior segment optical coherence tomography. METHODS: In images of 51 eyes (patients) with open and closed anterior chamber angles, we compared the success rate and the variability of 3 approaches for identifying the SS: the ciliary muscle (CM), bump, and Schwalbe line (SL) methods using mixed effects regression models. The effect of incremental variation in SS position on anterior chamber parameters using the Anterior Segment Analysis Program (ASAP) was analyzed in 8 images. Automated ASAP measurements were compared with manual ImageJ measurements in 46 images. RESULTS: The SS could be identified in 98% of images by each observer using the 3 methods in combination. The SL and CM approaches more successfully identified the SS (82% and 81% success, respectively) than the bump method (59%, P<0.001). The intraobserver, interobserver, and intermethod variabilities of the CM and bump methods were superior to those of the SL method. The SS was more likely to be identified in open angle than angle closure eyes (OR=2.26, P=0.03) and brown eyes were less likely than blue eyes (OR=0.36, P=0.04). Movement of SS position resulted in substantial differences in the angle parameters and iris concavity ratio, whereas iris area and volume were less affected. CONCLUSIONS: The CM method was the most successful and least variable method of SS marking, which was more difficult in narrow angle and brown eyes. Variability of SS placement had a large effect on angle parameters and iris concavity ratio. PMID- 23807355 TI - Coexistence and development of an open-angle glaucoma in eyes with superior segmental optic hypoplasia. AB - PURPOSE: Superior segmental optic hypoplasia (SSOH) is a congenital disorder that is expected not to progress. This study aimed to determine the prevalence and clinical characteristics of coexistent open-angle glaucoma (OAG) in patients with SSOH. PATIENTS AND METHODS: We retrospectively reviewed the records of 61 patients diagnosed with SSOH. The estimated prevalence and clinical characteristics of concomitant OAG among patients with SSOH were investigated. RESULTS: Of the 61 patients with SSOH, 12 patients presented with concomitant OAG (mean age, 44.8+/-19.2 y). Mean follow-up period was 84.9+/-50.9 months. Five patients (8.2%) were diagnosed with both high-tension glaucoma (HTG) and SSOH; 4 had HTG and SSOH in both the eyes; and the other had HTG only in the eye with SSOH. Seven patients (11.5%) were diagnosed with both normal-tension glaucoma (NTG) and SSOH. Two patients had NTG and SSOH in both eyes and 5 patients had unilateral NTG. The estimated prevalence of OAG in patients with SSOH was 19.7% (95% confidence interval, 9.7%-29.7%). CONCLUSIONS: Primary OAG, including HTG and NTG, could develop in eyes with SSOH, regarded as having a nonprogressive visual field defect. The estimated prevalence of OAG, including both NTG and HTG, might be relatively higher in the SSOH patients. Thus, continuous follow-up examinations of patients with SSOH are required. PMID- 23807356 TI - Pathologic investigation failure of trabeculotomy. AB - PURPOSE: To investigate the reason for failure of trabeculotomy using trabeculectomy (TLE) specimens involving the area of previous trabeculotomy. MATERIALS AND METHODS: Thirteen TLE specimens from 13 patients with open-angle glaucoma were processed for transmission electron microscopy and light microscopy, involving immunohistochemical staining of thrombomodulin, D2-40 (podoplanin), and CD34. RESULTS: All intraocular pressure after trabeculotomy decreased to normal and then returned to the same or a higher level compared with that before TLE. Eleven and 2 TLE specimens were taken from areas with no peripheral anterior synechia (PAS) and PAS areas, respectively. The 4 types of histologic change in the trabecular meshwork were observed: (1) persistence of a disconnected trabecular meshwork with swelling or degeneration at the cut edge; (2) fusion of the trabecular meshwork; (3) a membrane covering the innermost trabecular meshwork; and (4) pigmented cell invasion into the disconnected trabecular meshwork at the PAS site. Schlemm canal (SC) opening into the anterior chamber and SC occlusion were observed in 2 and 8 eyes, respectively. CONCLUSIONS: Opening of SC into the anterior chamber observed in the eyes with failed trabeculotomy suggested that the enhancement of conventional routes may not be important for the intraocular pressure-lowering effect. All 4 types of histologic change in the trabecular meshwork, as mentioned above, may reduce enhancement of the newly created unconventional routes by trabeculotomy. PMID- 23807357 TI - Diode laser cyclophotocoagulation for nanophthalmic chronic angle closure glaucoma. AB - PURPOSE: To retrospectively evaluate the results of diode laser cyclophotocoagulation (CPC) in patients with nanophthalmos. METHODS: The data on all bilaterally nanophthalmic patients who underwent diode laser CPC in our department between 2004 and 2012 were retrieved and evaluated. RESULTS: Four patients fulfilled study entry criteria. All 4 were females aged 58, 62, 68, and 74 years. The mean preoperative intraocular pressure of 46+/-5.7 mm Hg dropped to 16.2+/-1.5 mm Hg at the final follow-up visit (43.5+/-16 mo). Visual acuity did not change in 2 patients and slightly worsened in the other 2. Choroidal detachment was observed in all patients between 7 and 14 days after the procedure and lasted for 1 to 2 months, resolving spontaneously in 2 patients and following systemic steroid treatment in the other 2. CONCLUSIONS: Diode laser CPC was an effective treatment for patients with glaucoma secondary to nanophthalmos. PMID- 23807358 TI - Comparison of ocular biometry between eyes with chronic primary angle-closure glaucoma and their fellow eyes with primary angle-closure or primary angle closure suspect. AB - PURPOSE: To compare the eye with chronic primary angle-closure glaucoma (CPACG) with its fellow eye without glaucoma damage and to determine the biometric differences that may predispose to development of CPACG. METHODS: Consecutive patients diagnosed with CPACG in 1 eye and primary angle-closure (PAC)/primary angle-closure suspected (PACS) in the fellow eye were recruited. The biometric parameters of both the eyes were measured by A-scan ultrasonic biometry and ultrasound biomicroscopy. Comparisons of visual function, baseline intraocular pressure (IOP), and the biometric measurements were made. RESULTS: Forty-one patients were recruited. Eyes with CPACG had worse visual function, higher baseline IOP, and larger cup-to-disc ratio than their fellow eyes with PAC/PACS (P<0.001). Eyes with CPACG had shallower anterior chamber depths, smaller anterior chamber angles, thinner irises, and longer iris-ciliary process distances than their fellow eyes with PAC/PACS (P<0.05). There were no significant differences in terms of lens thicknesses, axial lengths, lens vault, and trabecular-ciliary process distances. CONCLUSIONS: Lens thickness, lens location, and axial length do not appear to play a significant role in the progression from PAC/PACS to CPACG. A thin and anterior iris bowing may be related to the progression from PAC/PACS to CPACG. PMID- 23807359 TI - How society should respond to the risk of vaccine rejection. AB - While vaccine acceptance remains high in general, fear of vaccines has grown dramatically in the past several years in many developed countries. In some communities, this fear has led to significantly increased rates of vaccine refusal which are associated with increases in illness and death from vaccine preventable diseases, and large economic costs for health care and society. Despite overwhelming evidence supporting the safety and benefits of vaccination, this fear has proven resistant to information campaigns, a phenomenon well explained by psychological research which has established that risk perception is subjective, a product of both the facts and how those facts feel. Given the innately emotional and instinctive nature of risk perception, and the risks to public health these perceptions produce, and consistent with well-established legal principles supporting government action to protect the common good, society has the right and responsibility to establish laws, regulations, and choice frameworks that discourage vaccine refusal. PMID- 23807360 TI - Reactogenicity and safety of a liquid human rotavirus vaccine (RIX4414) in healthy adults, children and infants in China: randomized, double-blind, placebo controlled Phase I studies. AB - We report the findings of three randomized, double-blind, placebo-controlled Phase I studies undertaken to support licensure of the liquid formulation of the human G1P[8] rotavirus (RV) vaccine (RIX4414; GlaxoSmithKline Biologicals SA) in China. Healthy adults aged 18-45 y (n=48) and children aged 2-6 y (n=50) received a single dose of the human RV vaccine or placebo. Healthy infants (n=50) aged 6 16 weeks at the time of first vaccination received two oral doses of the human RV vaccine or placebo according to a 0, 1 mo schedule. In infants, blood samples were collected prior to vaccination and one month post-dose 2 to assess anti-RV IgA antibody concentrations using ELISA. Stool samples were collected from all infants on the day of each vaccination, at 7 and 15 d after each vaccination and one month post-dose 2. Stool samples were analyzed by ELISA for detection of RV antigen to assess RV antigen excretion. The reactogenicity profile of the human RV vaccine was found to be comparable to that of placebo in all age groups studied. The anti-RV IgA antibody seroconversion rate in infants after two vaccine doses was 86.7% (95% CI: 59.5-98.3). Vaccine take in infants who received the liquid human RV vaccine was 86.7% (95% CI: 59.5-98.3). A Phase III efficacy study of the human RV vaccine in the infant population in China has now been completed (ROTA-075/NCT01171963). PMID- 23807362 TI - Association between microRNA polymorphisms and humoral immunity to hepatitis B vaccine. AB - To investigate whether selected single nucleotide polymorphisms (SNPs) in miR 146a, miR-196a2, miR-27a, miR-26a-1, miR-124 and miR-149 genes are associated with immune response to hepatitis B vaccine. The genotype and allele frequencies of SNPs were compared between the non-responders (n=77) and responders (n=207). The associations of the genotypes with antibody levels were assessed in the responders. Significant associations were observed between SNPs in miR-146a and miR-26a-1 genes and non-response to hepatitis B vaccine (p<0.05). In addition, SNPs in miR-146a and miR-27a genes were associated with variations in levels of antibodies to hepatitis B antigen. Thus, specific SNPs in microRNAs (miRNAs) genes may affect status of the hepatitis B vaccine induced protective humoral immune response. They also suggest that the three miRNAs play a role in modulating antibody responses to hepatitis B vaccine. PMID- 23807361 TI - Utilizing health information technology to improve vaccine communication and coverage. AB - Vaccination coverage is still below the Healthy People 2010 and 2020 goals. Technology use in the US is widespread by patients and providers including text message, email, internet, social media and electronic health records. Health information technology (IT) interventions can facilitate the rapid or real-time identification of children in need of vaccination and provide the foundation for vaccine-oriented parental communication or clinical alerts in a flexible and tailored manner. There has been a small but burgeoning field of work integrating IT into vaccination interventions including reminder/recall using non-traditional methods, clinical decision support for providers in the electronic health record, use of technology to affect work-flow and the use of social media. The aim of this review is to introduce and present current data regarding the effectiveness of a range of technology tools to promote vaccination, describe gaps in the literature and offer insights into future directions for research and intervention. PMID- 23807363 TI - Validity of medical record documented varicella-zoster virus among unvaccinated cohorts. AB - BACKGROUND: A varicella diagnosis or verification of disease history by any healthcare provider is currently accepted for determining evidence of immunity by the Advisory Committee on Immunization Practices (ACIP). OBJECTIVE: To examine the accuracy of medical record (MR) documented varicella history as a measure of varicella-zoster virus (VZV) immunity among unvaccinated individuals born after 1980. We also assessed methods to practically implement ACIP guidelines to verify varicella history using medical records. STUDY DESIGN: As part of a larger cross sectional study conducted at three Philadelphia clinics from 2004-2006, we recruited 536 unvaccinated patients aged 5-19 y (birth years: 1985-2001). Varicella history was obtained from three sources: parent/patient interview, any MR documentation (sick and well visits) and MR documentation of a sick visit for varicella. All participants were tested for VZV IgG. For each source and three age groups (5-9, 10-14, 15-19 y old), positive predictive value (PPV) was calculated. Specificity of varicella history was compared between different sources using McNemar's Chi-square. RESULTS: Among participants aged 5-9, 10-14 and 15-19 y the PPV for any MR documentation and sick visit diagnosis were 96% and 100%, 92% and 97%, and 99% and 100%, respectively. The specificity for sick visit documentation was higher than any MR documentation and patient/parent recall among all age groups; however, these differences were only statistically significant when comparing sick visit documentation to parent/patient recall for 10-14 y olds. CONCLUSION: Sick visit documentation of varicella in the MR is an accurate predictor of varicella seropositivity and useful for confirming disease history among unvaccinated persons (birth years: 1985-2001). This method is a practical way to verify varicella history using the ACIP guidelines. PMID- 23807364 TI - Acute immune thrombocytopenic purpura as adverse reaction to oral polio vaccine (OPV). AB - A case of acute immune thrombocytopenic purpura following oral polio vaccine (OPV) is reported. An 82-d-old infant developed purpura at the same day after the second dose of oral polio vaccine. Until the time of hospital admission, the male infant had been in good health and had not received any drugs, and the possible causes of this condition were excluded. His platelet count was 13*10(9)/L. Platelet-associated IgG was elevated, but the amount of megakaryocytes in bone marrow aspirates was within the normal range, suggesting immune mechanism associated thrombocytopenia. The infant recovered with the proper treatment within 30 d. Attention should be paid to OPV-associated thrombocytopenia, though it seems to be less frequent than after natural infections. PMID- 23807366 TI - Headspace volatile oxylipins of Eastern Himalayan moss Cyathophorella adiantum extracted by sample enrichment probe. AB - Cyathophorella adiantum (Griff.) M. Fleisch. (Division-Bryophyta, Family Daltoniaceae), an Eastern Himalayan moss was studied for the first time to identify the volatiles derived from cellular and membrane bound fatty acids. A high capacity sample enrichment probe (SEP) was used for extraction of headspace volatile (HSV) molecules followed by GC-MS analysis. Different short-chain oxylipins like alkenes, alkanes, saturated and unsaturated alcohols, saturated and unsaturated aldehydes, ketones were identified along with free and esterified fatty acids, cyclo compounds and some by-products of secondary metabolites. Fatty acid analysis of neutral lipids (NL) and phospholipids (PL) of this plant exhibits the predominance of C16 and C18 fatty acids. It also reveals some interesting information that might indicate the possible fatty acid precursors for volatile generation and their sources in this plant. PMID- 23807365 TI - Three dissimilar high fat diets differentially regulate lipid and glucose metabolism in obesity-resistant Slc:Wistar/ST rats. AB - Epidemiologic and ecologic studies suggest that dietary fat plays an important role in the development of obesity. Certain Wistar rat strains do not become obese when fed high-fat diets unlike others. In a preliminary study, we confirmed that Slc:Wistar/ST rats did not become obese when fed high-fat diets. The mechanisms governing the response of hepatic lipid-metabolizing enzymes to large quantities of dietary lipids consumed by obesity-resistant animals are unknown. The aim of the present study is to examine how obesity-resistant animals metabolize various types of high-fat diets and why they do not become obese. For this purpose, male Slc:Wistar/ST rats were fed a control low-fat diet (LS) or a high-fat diet containing fish oil (HF), soybean oil (HS), or lard (HL) for 4 weeks. We observed their phenotypes and determined lipid profiles in plasma and liver as well as mRNA expression levels in liver of genes related to lipid and glucose metabolism using DNA microarray and quantitative reverse transcriptase polymerase chain analyses. The body weights of all dietary groups were similar due to isocaloric intakes, whereas the weight of white adipose tissues in the LS group was significantly lower. The HF diet lowered plasma lipid levels by accelerated lipolysis in the peroxisomes and suppressed levels of very-low density lipoprotein (VLDL) secretion. The HS diet promoted hepatic lipid accumulation by suppressed lipolysis in the peroxisomes and normal levels of VLDL secretion. The lipid profiles of rats fed the LS or HL diet were similar. The HL diet accelerated lipid and glucose metabolism. PMID- 23807367 TI - Production and characterization of low molecular weight sophorolipid under fed batch culture. AB - The present study was designed for the production and optimization of the C12-C14 sophorolipid, using the yeast Candida bombicola ATCC-22214. The fermentation was carried under fed-batch culture conditions i.e., maintaining 15% coconut oil and 10% glucose as hydrophobic and hydrophilic carbon sources, respectively. A maximum yield 54.0 g/L (in 234 h) was achieved. A significant antimicrobial activity, surface activity, and emulsion ability were recorded. The native sophorolipid was found as enhancer of detergent efficacy of commercial detergent, tested on complex, smudge and oil contaminated clothes. Molecular weight of the C12 (605/623) and C14 (633/651) sophorolipids were determined by LC-MS which revealed it as diacetylated sophorolipid. This study is being important in terms of yield, which is better than the previously reported. PMID- 23807368 TI - Correlation between interleukin-23 receptor gene polymorphisms and risk of hepatitis B virus infection in patients. AB - There is an increasing amount of evidence supporting the hypothesis that the pathological stage from hepatitis to hepatocellular carcinoma (HCC) is a chronic inflammatory process. Interleukin-23 (IL-23) is an important mediator and modulator of inflammation. Specific polymorphisms in the genes encoding subunits of the IL-23 receptor (IL-23R) have been consistently observed to be associated with chronic immune-mediated diseases. In the current study, these variants were hypothesized to affect the risk of hepatitis B virus infection in patients. Three polymorphisms in the IL-23R gene (rs10889677, rs1884444 and rs11465817) were examined in 84 cases of chronic hepatitis B (HBV), 67 cases of HBV-related liver cirrhosis, 89 cases of HBV-related HCC and 94 healthy controls using the polymerase chain reaction (PCR)-restriction fragment length polymorphism method and DNA sequencing. The results revealed that subjects with the TG genotype of rs1884444 appeared to have higher susceptibility to HCC compared with the TT genotype (adjusted odds ratio (OR), 2.86; 95% confidence interval (CI), 1.39 5.85; P=0.00). The rs1884444 G allele was associated with a significantly increased risk of HCC compared with the T allele (adjusted OR, 1.58; 95% CI, 0.96 2.60; P=0.07). The rs11465817 and rs10889677 polymorphisms of the IL-23R gene were not observed as being relevant to liver disease. These observations indicate that the genetic variants in the IL-23R gene may contribute to HCC development. Additional studies with larger sample sizes must be conducted to confirm the current observations. PMID- 23807370 TI - A density functional theory study of the mechanisms of oxidation of ethylene by rhenium oxide complexes. AB - The oxo complexes of group VII B are of great interest for their potential toward epoxidation and dihydroxylation. In this work, the mechanisms of oxidation of ethylene by rhenium-oxo complexes of the type LReO3 (L = O(-), Cl, CH3, OCH3, Cp, NPH3) have been explored at the B3LYP/LACVP* level of theory. The activation barriers and reaction energies for the stepwise and concerted addition pathways involving multiple spin states have been computed. In the reaction of LReO3 (L = O(-), Cl, CH3, OCH3, Cp, NPH3) with ethylene, it was found that the concerted [3 + 2] addition pathway on the singlet potential energy surfaces leading to the formation of a dioxylate intermediate is favored over the [2 + 2] addition pathway leading to the formation of a metallaoxetane intermediate and its re arrangement to form the dioxylate. The activation barrier for the formation of the dioxylate on the singlet PES for the ligands studied is found to follow the order O(-) > CH3 > NPH3 > CH3O(-) > Cl(-) > Cp and the reaction energies follow the order CH3 > O(-) > NPH3 > CH3O(-) > Cl(-) > Cp. On the doublet PES, the [2 + 2] addition leading to the formation the metallaoxetane intermediate is favored over dioxylate formation for the ligands L = CH3, CH3O(-), Cl(-). The activation barriers for the formation of the metallaoxetane intermediate are found to increase for the ligands in the order CH3 < Cl(-) < CH3O(-) while the reaction energies follow the order Cl(-) < CH3O(-) < CH3. The subsequent re-arrangement of the metallaoxetane intermediate to the dioxylate is only feasible in the case of ReO3(OCH3). Of all the complexes studied, the best dioxylating catalyst is ReO3Cp (singlet surface); the best epoxidation catalyst is ReO3Cl (singlet surface); and the best metallaoxetane formation catalyst is ReO3(NPH3) (triplet surface). PMID- 23807369 TI - Relationship between responsiveness to erythropoiesis-stimulating agent and long term outcomes in chronic hemodialysis patients: a single-center cohort study. AB - BACKGROUND: Responsiveness to erythropoietin-stimulating agent (ESA) may be associated with mortality risk in hemodialysis (HD) patients. The aim of the present study was to assess the relationship between responsiveness to ESA and long-term outcome in chronic HD patients. METHODS: Patients on HD therapy for more than 6 months were enrolled in this cohort study. The first year was used to assess the longitudinal dialysis status of patients; the subsequent years were used to assess the time-dependent risk of all-cause mortality. Hazard ratios were estimated using a Cox proportional model for the association between ESA dose and hemoglobin (Hb) level and mortality, adjusting for potential confounders. The ESA resistance index (ERI) was determined as the weekly weight-adjusted dose of ESA divided by Hb concentration. Patients were divided into three groups by tertiles of ERI. RESULTS: Of the 320 subjects enrolled, 105 died during the follow-up period of 70.4 +/- 29.0 months. When subjects were stratified by epoetin dose and Hb level into four groups, those who had low Hb despite a high dose of epoetin were associated with the highest risk of mortality among the four groups (adjusted hazard ratio 1.86; 95 % confidence interval 1.25-2.75). These highest risk subjects had older age, lower body mass index, and lower serum levels of albumin, triglyceride, and transferring saturation. The impact of serum albumin and serum ferritin on mortality risk in an adjusted Cox proportional hazards model was in accordance with low Hb and higher ESA. There was no significant difference between the mortality risk and tertile of ERI. CONCLUSIONS: High ESA dose and low Hb level were associated with an increased risk of all-cause mortality. However, the responsiveness to ESA estimated by ERI was not related to mortality risk. These findings suggest that the responsiveness to ESA should be evaluated by different methods in HD patients. PMID- 23807372 TI - Asymmetric Ti-crossed Claisen condensation: application to concise asymmetric total synthesis of alternaric acid. AB - Asymmetric Ti-crossed Claisen condensation utilizing the dioxane-2,5-dione chiral template and its successful application to total synthesis of chiral alternaric acid are described. PMID- 23807373 TI - Deep sequencing discovery of novel and conserved microRNAs in wild type and a white-flesh mutant strawberry. AB - MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by base pairing to mRNA target sequences, and play crucial roles in plant development and stress responses. The knowledge on post-transcriptional regulation by miRNAs in strawberry is rather limited so far. In order to understand the role of miRNA in the molecular control during strawberry fruit development, small RNA libraries were constructed from fruits at the turning stage of strawberry cultivar 'Sachinoka' and its white-flesh mutant by using the Solexa platform. One hundred and twenty conserved miRNAs belonging to 27 miRNA families and 33 putative novel strawberry miRNAs were identified in both libraries. Their target genes were predicted using the Fragaria vesca genome. Nine of all miRNAs showed significant expression differences between two types of samples. Four miRNAs were up-regulated and five were down-regulated in white flesh mutant. The sequencing results were partially validated by quantitative RT PCR. Among them, the expression of miR399a shows the biggest change between the two samples. The prediction of its target gene showed that miR399 may play an important role in phosphate homeostasis of strawberry fruits. Furthermore, we deduce that the expression of miR399 has negative correlation with the content of sugars. PMID- 23807376 TI - The pycnometer challenge. PMID- 23807375 TI - Rivaroxaban for the treatment of pulmonary embolism. AB - With the advent of new oral anticoagulants (NOACs) for the treatment of deep-vein thrombosis (DVT) and/or pulmonary embolism (PE), a new era of oral anticoagulation for patients with venous thromboembolism (VTE) has begun. Rivaroxaban is the first NOAC to receive regulatory approval for the acute and continued treatment of DVT and PE, and for the secondary prevention of VTE. Here, the clinical trials of rivaroxaban in patients with VTE are reviewed, and the clinical use of rivaroxaban for patients with PE is discussed. Even though rivaroxaban will facilitate the therapeutic management of PE, its use in specific clinical situations needs further study. PMID- 23807377 TI - Solution to quality assurance challenge 11. PMID- 23807379 TI - Fabricating large-area metallic woodpile photonic crystals using stacking and rolling. AB - Stacking thin polymer films supporting metal nanowire gratings provides a simple route, demonstrated here, to producing large-area metallic woodpile structures with high throughput. Under appropriate conditions the grating films can spontaneously roll up, giving a rapid and controllable method of creating multilayers. The resulting three-dimensional (3D) wire structures are flexible and potentially stretchable. Since this process can be extended to include a wide variety of functional materials, it opens up the manufacture of many tailored 3D optical metamaterials. PMID- 23807378 TI - Novel therapies for hepatitis C - one pill fits all? AB - Almost 25 years after the hepatitis C virus (HCV) was identified, and following intense research and development efforts, a large number of direct-acting antiviral drugs are now beginning to reach patient care. Accordingly, the way in which care is delivered is evolving at a breath-taking pace. Here, we review the current and upcoming treatment options for HCV, describe the key challenges facing clinicians and drug developers and discuss how the landscape in the HCV arena will change over the coming years. PMID- 23807380 TI - Papillary carcinoma arising from thyroglossal duct cyst with thyroid and lateral neck metastasis. AB - INTRODUCTION: Thyroglossal duct carcinomas (TGDC) are rare, with approximately 274 reported cases since the first report in 1915. The prevalence of carcinomas in surgically removed thyroglossal duct cyst (TGD) is less than 1%. The usual recommended treatment for this condition is the Sistrunk operation, but controversies remain regarding the need for total or partial thyroidectomy. PRESENTATION OF CASE: A 28-year-old woman was admitted to our hospital with the symptoms of painless midline neck swelling and growing mass. A preoperative computed tomography (CT) showed a 4cm sized heterogeneous mass at the infrahyoid anterior neck. Ultrasonography of the neck additionally showed suspicious metastatic lymph node at right level VI, both level VI. The patient underwent a Sistrunk operation. The frozen section revealed papillary carcinoma arising from TGDC and also revealed metastatic papillary carcinoma in the right thyroid, at right level III and level VI. Total thyroidectomy, right modified radical neck dissection and central neck dissection were performed. The thyroid gland and TGD were confirmed papillary carcinoma. The dissected neck lymph nodes revealed metastatic papillary carcinoma. DISCUSSION: The usual recommended treatment for TGD is the Sistrunk procedure. There is controversy regarding whether total or partial thyroidectomy should be performed. CONCLUSION: Physicians should be aware of extended operation, including thyroidectomy and/or neck node dissection for TGDC with metastatic lesion of thyroid and neck node. PMID- 23807382 TI - Posterior lens nucleus displacement following intravitreal injection. PMID- 23807383 TI - Interactive binocular treatment (I-BiT) for amblyopia: results of a pilot study of 3D shutter glasses system. AB - PURPOSE: A computer-based interactive binocular treatment system (I-BiT) for amblyopia has been developed, which utilises commercially available 3D 'shutter glasses'. The purpose of this pilot study was to report the effect of treatment on visual acuity (VA) in children with amblyopia. METHODS: Thirty minutes of I BiT treatment was given once weekly for 6 weeks. Treatment sessions consisted of playing a computer game and watching a DVD through the I-BiT system. VA was assessed at baseline, mid-treatment, at the end of treatment, and at 4 weeks post treatment. Standard summary statistics and an exploratory one-way analysis of variance (ANOVA) were performed. RESULTS: Ten patients were enrolled with strabismic, anisometropic, or mixed amblyopia. The mean age was 5.4 years. Nine patients (90%) completed the full course of I-BiT treatment with a mean improvement of 0.18 (SD=0.143). Six out of nine patients (67%) who completed the treatment showed a clinically significant improvement of 0.125 LogMAR units or more at follow-up. The exploratory one-way ANOVA showed an overall effect over time (F=7.95, P=0.01). No adverse effects were reported. CONCLUSION: This small, uncontrolled study has shown VA gains with 3 hours of I-BiT treatment. Although it is recognised that this pilot study had significant limitations-it was unblinded, uncontrolled, and too small to permit formal statistical analysis these results suggest that further investigation of I-BiT treatment is worthwhile. PMID- 23807384 TI - Keratoglobus. AB - Keratoglobus is a rare noninflammatory corneal thinning disorder characterised by generalised thinning and globular protrusion of the cornea. It was first described as a separate clinical entity by Verrey in 1947. Both congenital and acquired forms have been shown to occur, and may be associated with various other ocular and systemic syndromes including the connective tissue disorders. Similarities have been found with other noninflammatory thinning disorders like keratoconus that has given rise to hypotheses about the aetiopathogenesis. However, the exact genetics and pathogenesis are still unclear. Clinical presentation is characterised by progressive diminution resulting from irregular corneal topography with increased corneal fragility due to extreme thinning. Conservative and surgical management for visual rehabilitation and improved tectonic stability have been described, but remains challenging. In the absence of a definitive standard procedure for management of this disorder, various surgical procedures have been attempted in order to overcome the difficulties. This article reviews the aetiological factors, differential diagnosis, histopathology, and management options of keratoglobus. PMID- 23807385 TI - Intra-lesional 5 fluorouracil for the management of recurrent pterygium. AB - AIM: Recurrence is the most common complication arising from pterygium surgery. The aim of this study was to investigate the effectiveness of 5 fluorouracil (5FU) in halting the recurrence of pterygium after surgical excision. METHODS: A retrospective review of patients treated for pterygium recurrence was carried out. Patients with recurrent (secondary) pterygium were treated with multiple weekly intra-lesional injections of 0.1-0.2 ml (2.5-5 mg) 5FU post-operatively depending on the size of the recurrence. The treatment was started within 1 month from the date of recurrence. The time from surgery to start of recurrence, previous treatment modalities, and number of recurrences were documented. The number of injections required to induce arrest of progression and/or regression of vascularity and fleshiness of the pterygium and any complications related to 5FU treatment were examined. RESULTS: Fifteen eyes from 14 patients with recurrent pterygium treated with intra-lesional 5FU injections were analysed. Three of the 15 eyes had undergone a secondary excision and 12 had undergone a primary excision. In all, 93.3% of patients showed regression of the fibrovascular tissue (thickness and vascularity) and arrest of progression following a dose of 0.1-0.2 ml (2.5-5 mg) 5FU. Twelve eyes required three injections or fewer, whereas one patient required eight injections. This beneficial effect was maintained over an average follow-up period of 17 months. No complications from 5FU were observed. CONCLUSION: The use of weekly intra lesional 5FU injections for the treatment of recurrent pterygium is safe and effective in limiting the progression and inducing the regression of recurrent pterygium. The number of injections can be tailored according to clinical need. PMID- 23807386 TI - Subconjunctival anaesthesia for intravitreal injections. PMID- 23807387 TI - Are generic topical prostanoids the way forward in the care of glaucoma patients? - No. PMID- 23807371 TI - Exploratory analysis of the effect of intravitreal ranibizumab or triamcinolone on worsening of diabetic retinopathy in a randomized clinical trial. AB - IMPORTANCE: The standard care for proliferative diabetic retinopathy (PDR) usually is panretinal photocoagulation, an inherently destructive treatment that can cause iatrogenic vision loss. Therefore, evaluating the effects of therapies for diabetic macular edema on development or worsening of PDR might lead to new therapies for PDR. OBJECTIVE: To evaluate the effects of intravitreal ranibizumab or triamcinolone acetonide, administered to treat diabetic macular edema, on worsening of diabetic retinopathy. DESIGN: Exploratory analysis was performed on worsening of retinopathy, defined as 1 or more of the following: (1) worsening from no PDR to PDR, (2) worsening of 2 or more severity levels on reading center assessment of fundus photographs in eyes without PDR at baseline, (3) having panretinal photocoagulation, (4) experiencing vitreous hemorrhage, or (5) undergoing vitrectomy for the treatment of PDR. SETTING: Community- and university-based ophthalmology practices. PARTICIPANTS: Individuals with central involved diabetic macular edema causing visual acuity impairment. INTERVENTIONS: Eyes were assigned randomly to sham with prompt focal/grid laser, 0.5 mg of intravitreal ranibizumab with prompt or deferred (>=24 weeks) laser, or 4 mg of intravitreal triamcinolone acetonide with prompt laser. MAIN OUTCOMES AND MEASURES: Three-year cumulative probabilities for retinopathy worsening. RESULTS: For eyes without PDR at baseline, the 3-year cumulative probabilities for retinopathy worsening (P value comparison with sham with prompt laser) were 23% using sham with prompt laser, 18% with ranibizumab with prompt laser (P = .25), 7% with ranibizumab with deferred laser (P = .001), and 37% with triamcinolone with prompt laser (P = .10). For eyes with PDR at baseline, the 3-year cumulative probabilities for retinopathy worsening were 40%, 21% (P = .05), 18% (P = .02), and 12% (P < .001), respectively. CONCLUSIONS AND RELEVANCE Intravitreal ranibizumab appears to be associated with a reduced risk of diabetic retinopathy worsening in eyes with or without PDR. Intravitreal triamcinolone also appears to be associated with a reduced risk of PDR worsening. These findings suggest that use of these drugs to prevent worsening of diabetic retinopathy may be feasible. Given the exploratory nature of these analyses, the risk of endophthalmitis following intravitreal injections, and the fact that intravitreal triamcinolone can cause cataract or glaucoma, use of these treatments to reduce the rates of worsening of retinopathy, with or without PDR, does not seem warranted at this time. PMID- 23807388 TI - Are generic topical prostanoids the way forward in the care of glaucoma patients? - Yes. PMID- 23807389 TI - Reply to Alexander et al (Subconjunctival anaesthesia for intravitreal injections). PMID- 23807390 TI - Partial alignment and measurement of residual dipolar couplings of proteins under high hydrostatic pressure. AB - High-pressure NMR spectroscopy has emerged as a complementary approach for investigating various structural and thermodynamic properties of macromolecules. Noticeably absent from the array of experimental restraints that have been employed to characterize protein structures at high hydrostatic pressure is the residual dipolar coupling, which requires the partial alignment of the macromolecule of interest. Here we examine five alignment media that are commonly used at ambient pressure for this purpose. We find that the spontaneous alignment of Pf1 phage, d(GpG) and a C12E5/n-hexnanol mixture in a magnetic field is preserved under high hydrostatic pressure. However, DMPC/DHPC bicelles and collagen gel are found to be unsuitable. Evidence is presented to demonstrate that pressure-induced structural changes can be identified using the residual dipolar coupling. PMID- 23807391 TI - PAIN with and without PAR: variants for third-spin assisted heteronuclear polarization transfer. AB - In this article, we describe third-spin assisted heteronuclear recoupling experiments, which play an increasingly important role in measuring long-range heteronuclear couplings, in particular (15)N-(13)C, in proteins. In the proton assisted insensitive nuclei cross polarization (PAIN-CP) experiment (de Paepe et al. in J Chem Phys 134:095101, 2011), heteronuclear polarization transfer is always accompanied by homonuclear transfer of the proton-assisted recoupling (PAR) type. We present a phase-alternating experiment that promotes heteronuclear (e.g. (15)N -> (13)C) polarization transfer while simultaneously minimizing homonuclear (e.g.(13)C -> (13)C) transfer (PAIN without PAR). This minimization of homonuclear polarization transfer is based on the principle of the resonant second-order transfer (RESORT) recoupling scheme where the passive proton spins are irradiated by a phase-alternating sequence and the modulation frequency is matched to an integer multiple of the spinning frequency. The similarities and differences between the PAIN-CP and this het-RESORT experiment are discussed here. PMID- 23807392 TI - Combinatory effect of fluconazole and FDA-approved drugs against Candida albicans. AB - Candida albicans is the primary cause of systemic candidiasis, which has a high mortality rate. Unfortunately, the number of antifungal drugs available for treatment of Candida infections is limited, and there is an urgent need for development of new drugs and alternative therapeutic options. We investigated the combinatory effect of fluconazole (FLCZ) and 640 FDA-approved drugs in vitro. Ten drugs enhanced and 77 drugs attenuated the antifungal activity of FLCZ. Other drugs did not appear to alter the antifungal activity of FLCZ, although 17 drugs displayed potency equivalent to or greater than that of FLCZ. The 10 FLCZ enhancing drugs included three inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA reductase, whose synergistic activity had been reported previously. However, the antifungal effects of 3 FLCZ enhancers-artesunate, carvedilol, and bortezomib were previously unknown. In addition, many drugs were found to attenuate the antifungal activity of FLCZ, including 17 cyclooxygenase (COX) inhibitors, 15 estrogen-related agents, vitamin A- and D-related compounds, antihypertensive drugs, and proton pump inhibitors. Although the clinical significance remains to be determined, analyses of molecular events responsible for synergy or antagonism could provide insight into more efficient use of existing antifungals and lead to novel therapies. PMID- 23807393 TI - Regulation of murine placentogenesis by the retroviral genes Syncytin-A, Syncytin B and Peg10. AB - The murine placenta has a trichorial structure with two multinucleated syncytiotrophoblast (SCT) layers representing a barrier between the maternal and fetal blood system. Genes of endogenous retroviruses and retrotransposon-derived paternally expressed genes (Peg), remnants of past infections and integrations in the genome, have essential functions in placentogenesis. Previous studies showed that the envelope genes Syncytin-A and Syncytin-B were essential for cell-cell fusion of the SCT. The goal of this study was to analyze the temporal localization and expression of nine genes throughout placental development from embryonic day (E)8.5 to E18.5 using in situ-hybridization and absolute RNA quantification. These included a comparison of previously characterized genes from the labyrinth Syncytin-A, Syncytin-B, Gcm1, the junctional zone PL-1, PL-2, Plf, Tpbpa with two further characterized genes Peg10 and Tpbpb. Syncytin-A and Syncytin-B RNA localized to SCT-I and SCT-II, respectively. Peg10 RNA localized to all extraembryonic tissues, specifically to the parietal and sinusoidal TGC of the labyrinth layer, which is in contact with SCT-I and the maternal blood. All three retroviral/retrotransposon-derived genes showed the highest expression at E16.5, but Peg10 with 188,917.1 molecules/ng cDNA was 208-fold and 106.8-fold higher expressed than Syncytin-A and Syncytin-B, respectively. Tpbpb localized to the junctional zone and showed the highest expression at E16.5 along with PL-2, Plf, Tpbpa, but not PL-1, which decreased in expression at E10.5. To investigate a role of Syncytin-A, Syncytin-B and Peg10 in cell-cell fusion, we established a cell culture system with fractionated primary trophoblasts from murine placentae. Culturing trophoblasts for up to 72h partly resembled trophoblast development in vivo according to the nine marker genes. Knockdown of Syncytin-A demonstrated a functional regulation of cell-cell fusion, where knockdown of Peg10 showed no involvement in cell fusion. Due to the expression of Peg10 in TGCs, we propose an essential functional role in the fetal-maternal blood system. PMID- 23807394 TI - Cervical spine instability in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is the most common inflammatory disease of the cervical spine (CS). After hands and feet, CS is the most commonly involved segment, being present in more than half of the patients with RA. Especially in the CS, RA may cause degeneration of ligaments, leading to laxity, instability and subluxation of the vertebral bodies. This is often asymptomatic or symptoms are erroneously attributed to peripheral manifestations. Otherwise, this may cause compression of spinal cord (SC) and medulla oblongata leading to severe neurologic deficits and even sudden death. Owing to its potentially debilitating and life-threatening sequelae, inevitable progression once neurologic deficits occur and the poor medical condition of afflicted patients, CS involvement remains a priority in the diagnosis and its treatment will remain a challenge. The surgical approach aims a solid fixation of the upper cervical spine, giving stability, preventing neurologic deterioration and injury to the SC, leading to improved neurologic function, vascular integrity and maintenance of sagittal balance. The recent advances in surgical techniques, complete understanding of the anatomy and precise preoperative evaluation led to safer and more effective procedures that have decreased complication rates. Based on the fact that when a patient becomes myelopathic the rate of long-term mortality increases and the chance of neurologic recovery decreases, many authors agree that early surgical intervention, before the onset of neurologic deficits, gives a more satisfactory outcome. However, the timing when a prophylactic stabilization should occur is poorly defined, and so, patients with radiographic instability but without evidence of neurologic deficit are still the most difficult to manage. PMID- 23807395 TI - Length of hospital stay with patient-dependent determination in bilateral scheduled staged total knee arthroplasty. AB - PURPOSE: The purpose of this study was to approach the length of hospital stay (LOS) by patient-dependent determination and evaluate the effect of contralateral total knee arthroplasty (TKA) on LOS in patients with bilateral osteoarthritis undergoing staged bilateral TKAs. METHODS: One hundred sixty TKAs in 80 patients with bilateral osteoarthritis were evaluated by retrospective review of their medical records. All patients had scheduled staged bilateral TKA. We investigated the length of hospital stay in each TKA and the postoperative day when patients could perform walking and climbing up and down the stairs with one cane independently. Range of motion in each knee was also evaluated in preoperatively and before discharge. The median interval between the first and second surgeries was 12 months. RESULTS: The first and second TKAs showed a median LOS of 37 and 35 days, respectively, with no significant difference (n.s.). The median number of days before independently walking and climbing up and down the stairs with one cane were 8 and 16 after the first TKA and 7 and 15 after the second TKA, respectively, without significant differences (n.s. for walking, n.s. for stairs). CONCLUSIONS: An initial TKA that results in good function might neither facilitate an earlier second rehabilitation nor decrease the LOS. Taking other factors such economics and local conditions that largely influence LOS into account, simultaneous bilateral TKAs might be an effective treatment for bilateral knee arthritis in properly selected patients in terms of decreasing the LOS. PMID- 23807396 TI - Single allograft medial collateral ligament and posterior oblique ligament reconstruction: a technique to improve valgus and rotational stability. AB - We present a novel and simple method for single hamstring allograft MCL and PMC reconstruction, which can improve both joint valgus and external rotational stability and maximize utilization of allograft. All patients received arthroscopic evaluation through inferomedial and inferolateral knee incisions to ascertain whether there were intra-articular injuries. An 8-cm-length longitudinal incision was made from 1 cm above adductor tubercle to 5-cm proximal medial tibia joint line. The anterior tibia insertion was defined as 15 mm lateral from the medial tibia edge and 45 mm below the medial tibia joint line. The posterior tibia insertion was defined as 15 mm lateral from the medial tibia edge and 20 mm below the medial tibia joint line. A 5- or 6-mm reamer was used to drill the tibia tunnel along with guide pin, and a 6 or 7 mm drill was used to drill the femur tunnel to a depth of 25 or 30 mm until the proximal adductor tubercle. The allograft was harvested from tibia and placed into the tunnel and fixed with absorbable interference screw. All patients performed active rehabilitation exercises after the operation periodically. PMID- 23807397 TI - Effects of acute and chronic electroconvulsive shocks on glycogen synthase kinase 3beta level and phosphorylation in mice. AB - OBJECTIVES: Glycogen synthase kinase 3beta (GSK-3beta) is recently proposed as a novel target in the treatment of mood disorders. Recent evidence has suggested that acute and chronic administration of antidepressants led to inhibition of GSK 3beta via phosphorylation of Serine9 residue. Acute electroconvulsive shock (ECS) has been reported to increase GSK-3beta phosphorylation transiently. In this study, the changes in the level of GSK-3beta and its phoshorylated form (phospho Ser9-GSK-3beta) following chronic ECS (cECS) were investigated in mice. METHODS: Mice were given daily ECS via bilateral corneal electrodes for 10 consecutive days in the chronic group and a single ECS in the acute group. Electrodes were applied without stimulation in corresponding sham groups. Immunoblotting for GSK 3beta and phospho-Ser9-GSK-3beta was performed with the frontal cortex and hippocampus samples, extracted 10 minutes after single ECS, and 24 hours after the last ECS in the chronic group. The optical densities of the bands obtained were compared between the active treatment and sham groups for each condition separately. RESULTS: The level of phospho-Ser9-GSK-3beta was not different following chronic ECS, but significantly higher following acute ECS, compared with the corresponding sham group, in the hippocampus and frontal cortex. The level of GSK-3beta was similar to sham following both acute and chronic ECS, in both regions. CONCLUSIONS: The transient increase in GSK-3beta phosphorylation observed following acute ECS in the mice hippocampus and frontal cortex was not found to persist 24 hours following chronic ECS. The mechanism of action of ECS does not seem to involve persistent change in the level and phosphorylation of GSK-3beta. PMID- 23807398 TI - Surgical strategy for aortoesophageal fistula in the endovascular era. AB - OBJECTIVE: Aortoesophageal fistula (AEF) is relatively rare and usually life threatening. Lots of strategies have so far been discussed for this entity including the role of endovascular repair. The aim of this study is to review our experiences and reconsider the surgical strategy for aortoesophageal fistula in the endovascular era. METHODS: This is a retrospective multicenter study. From 1995 to 2011, 10 aortoesophageal fistula cases were identified in four institutions. For all of these cases surgical procedures and results were retrieved from medical records. RESULTS: Six patients underwent open aortic repair and four patients underwent thoracic endovascular aortic repair (TEVAR) as a primary intervention. Three patients who underwent open aortic repair with esophagectomy and omental coverage in early phase, either as a primary intervention or performed after bridging TEVAR, showed 100 % 1-year survival. On the other hand, three patients with TEVAR alone did not survive more than 1 year without recurrence. One patient with bridging TEVAR underwent concomitant esophageal resection and conventional aortic graft replacement 2 days later, and simultaneous gastric tube reconstruction was performed with intact whole omentum covering the aortic prosthesis. This patient is doing well with no sign of infection at 1-year follow-up. CONCLUSION: For AEF, TEVAR as a primary approach is quite useful to stabilize the patients' condition. However, definitive aortic repair with omental coverage should be performed as early as possible as a next step. It may be one of the strategies for the treatment of AEF that concomitant esophageal resection and aortic graft replacement is performed with simultaneous gastric tube reconstruction with intact whole omentum after removing the stent graft, so far as the patient's physical condition permits. PMID- 23807399 TI - Hoarseness caused by arytenoid dislocation after surgery for lung cancer. AB - The patient was a 64-year-old woman with no history of laryngeal disorders. She underwent video-assisted right lower lobectomy and node dissection for lung cancer. Using a stylet while the patient was under general anesthesia, tracheal intubation with a 35-French gauge left-sided double-lumen endobronchial tube was successfully performed on the first attempt. The patient developed slight hoarseness on postoperative day 1, and we initially suspected recurrent laryngeal nerve paralysis caused by the surgery, which we elected to treat conservatively. However, because her hoarseness had not improved 4 months after surgery, we evaluated her vocal cords using laryngoscopy. This revealed severe dysfunction of the right vocal cord and arytenoid dislocation, which we treated through reduction using a balloon catheter. By 6 months, the patient's vocal cord mobility had improved. Arytenoid dislocation is a rare complication, but should be suspected when patients have right vocal fold paralysis after lung cancer surgery. PMID- 23807400 TI - [The German Standing Committee on Vaccination and its new methodological approach]. PMID- 23807401 TI - [Surveillance of antibiotic consumption : clarification of the "definition of data on the nature and extent of antibiotic consumption in hospitals according to S 23 paragraph 4 sentence 2 of the IfSG"]. AB - According to S 23 paragraph 4 of the German Infection Prevention Act (IfSG; July 2011), hospitals and clinics for ambulatory surgery are obliged to establish a continuous monitoring system of antibiotic consumption. This is aimed at contributing to an optimization of antibiotic prescription practices in order to confine the development and spread of resistant pathogens. The general requirements (restricted to hospitals) on the method and extent of data collection are provided by the national public health institution after discussion with representatives of various professional societies (Robert Koch Institut, Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 59, 2013). The article aims to clarify these specifications and to provide background details. In agreement with national and European surveillance systems, the Anatomical Therapeutic Chemical (ATC)/Defined Daily Dose (DDD) classification system recommended by the WHO should be used as reference standard. Antibiotic consumption should be expressed as the number of DDDs per 100 patient days and per 100 admissions. The categories of antimicrobials and hospital organizational units to be monitored and the time intervals in which analyses should be conducted are determined. Furthermore, various approaches of data assessment are described. PMID- 23807404 TI - [Recommendation for rotavirus vaccination standards for infants in Germany]. PMID- 23807405 TI - Background paper to the recommendation for routine rotavirus vaccination of infants in Germany. AB - Two rotavirus (RV) vaccines were introduced to the European market in 2006. To support the decision-making process of the German Standing Committee on Vaccination ("Standige Impfkommission", STIKO) regarding adoption of routine RV vaccination into the national vaccination schedule in Germany relevant scientific background was reviewed. According to STIKO's Standard Operating Procedures for the development of evidence-based vaccination recommendations, a set of key questions was addressed and systematic reviews were performed with a focus on the efficacy, effectiveness, impact and safety of RV vaccines. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was applied to assess the quality of available evidence. Data from 5 randomized controlled trials demonstrated a high efficacy of RV vaccines in preventing severe RV-associated gastroenteritis (91%) and hospitalization (92%) in settings comparable to Germany. Post-marketing observational studies confirmed these findings. In several countries, impact studies suggest that age groups not eligible for vaccination might also benefit from herd effects and demonstrated a decrease in the number of nosocomial RV infections after RV vaccine introduction. The vaccines were considered safe, except for a slightly increased risk of intussusception shortly after the first dose, corresponding to 1-2 additional cases per 100,000 infants vaccinated (relative risk =1.21, 95% confidence interval [CI] 0.68-2.14). RV case-fatality is extremely low in Germany. However, RV incidence among children aged <5 years is high (reported 8-14 cases per 1000 children annually), and of these almost half require hositalization. In view of the available evidence and expected benefits, STIKO recommends routine rotavirus vaccination of children under the age of 6 months with the main goal of preventing RV-associated hospitalizations in Germany, especially among infants and young children. PMID- 23807406 TI - [Report of the Central Ethics Committee for Stem Cell Research (ZES)]. PMID- 23807407 TI - [Vote of the National AIDS Advisory Council to the Federal Ministry of Health]. PMID- 23807408 TI - [Definition of data on the nature and extent of antibiotic consumption in hospitals by 23 paragraph 4 sentence 2 IfSG]. PMID- 23807409 TI - [Health assessment of materials and articles for food contact as part of the Food and Feed Code]. PMID- 23807410 TI - [The Genetic Engineering Commission Directive (Geko) according to the requirements for the implementation of prenatal risk clarification and to the extent of necessary quality assurance measures 23 para 2 No. 5 GenDG]. PMID- 23807411 TI - [The Genetic Engineering Commission (Geko) Directive for the assessment of genetic characteristics in terms of their significance after 15 paragraph 1 sentence 1 GenDG according to a deterioration in the health of the embryo or fetus during pregnancy or after birth 23 para 2 No. 1d GenDG ]. PMID- 23807412 TI - Rapid detection of Mycobacterium tuberculosis in clinical samples by multiplex polymerase chain reaction (mPCR). AB - Although the multi-copy and specific element IS6110 provides a good target for the detection of Mycobacterium tuberculosis complex by PCR techniques, the emergence of IS6110-negative strains suggested that false negative may occur if IS6110 alone is used as the target for detection. In this report, a multiplex polymerase chain reaction (mPCR) system was developed using primers derived from the insertion sequence IS6110 and an IS-like elements designated as B9 (GenBank accession no. U78639.1) to overcome the problem of detecting negative or low copy IS6110 containing strains of M. tuberculosis. The mPCR was evaluated using 346 clinical samples which included 283 sputum, 19 bronchial wash, 18 pleural fluid, 9 urine, 7 CSF, 6 pus, and 4 gastric lavage samples. Our results showed that the sensitivity (93.1 %) and specificity (89.6 %) of the mPCR system exceeds that of the conventional method of microscopy and culture. The mPCR assay provides an efficient strategy to detect and identify M. tuberculosis from clinical samples and enables prompt diagnosis when rapid identification of infecting mycobacteria is necessary. PMID- 23807413 TI - Characterization and applications of PVF film grafted with binary mixture of methacrylic acid and 4-vinyl pyridine by gamma radiations: effect of swift heavy ions. AB - Graft copolymerization of a binary mixture of methacrylic acid and 4-vinyl pyridine, onto poly (vinyl fluoride) film has been carried out by preirradiation method. Under optimum reaction conditions, maximum percentage of grafting, Pg, (92.10%) was obtained. Irradiation of the film by swift heavy ions, silicon and carbon, gave maximum Pg (77.50%) for Si(+8) irradiated film. Grafting of 4-VP onto PVF-g-poly (MAAc) films produced maximum Pg of 77.00%. FTIR, TGA, swelling ratio, ion and metal uptake studies were used for characterization. PMID- 23807414 TI - Synthesis, crystal structure and magnetic properties of dinuclear NiIILnIII complexes based on a flexible polydentate ligand. AB - The synthesis and characterization of three isomorphous complexes [NiII(L)LnIII(DBM)3] (Ln = Gd (1.2.5CH3CN.0.5H2O), Tb (2.2CH3CN.0.5MeOH), and Dy (3.2CH3CN.0.5MeOH.0.5H2O)) are reported (H2L = N,N'-dimethyl-N,N'-(2-hydroxy-3 methoxy-5-methylbenzyl)ethylenediamine, DBM- = anion of 1,3-diphenylpropane-1,3 dione). The flexible ligand L2- contains an N2O2-inner and an O4-outer coordination site. There are diphenoxo bridges between NiII and LnIII ions in these complexes. The remaining coordination sites are occupied by DBM- anions. Direct current (dc) magnetic susceptibility measurements indicate the presence of intramolecular ferromagnetic interactions in desolvated complexes 1-3. The magnetic coupling constant JNiGd in complex 1 is estimated to be 1.11 cm-1 (H = 2JNiGdSNiSGd). Alternating current (ac) magnetic susceptibility studies reveal that complexes 2 and 3 show frequency-dependent out-of-phase signals, which indicate that they exhibit SMM behavior. The energy barriers for complexes 2 and 3 under a 2 kOe applied direct current (dc) magnetic field are estimated from Arrhenius plots to be 14.4 and 11.3 K, respectively. PMID- 23807415 TI - Immunocytochemistry of GLUT2, uptake of fluorescent desnitroso-streptozotocin analogs and phosphorylation of D-glucose in INS-1E cells. AB - The non-invasive imaging of GLUT2-expressing cells remains a challenge. As streptozotocin, and similarly alloxan, may be transported into cells by GLUT2, the major aim of the present study was to assess the possible use of fluorescent desnitroso-streptozotocin analogs for in vitro labeling of GLUT2-expressing cells. INS-1E cells, human embryonic kidney (HEK) cells, rat isolated pancreatic islets, rat hepatic cells, rat exocrine pancreatic cells and tumoral insulin producing BRIN-BD11 cells were incubated in the presence of two distinct fluorescent desnitroso-streptozotocin analogs, probes A and B. The immunocytochemistry of GLUT2 in INS-1E cells and the phosphorylation of D-glucose by INS-1E cell homogenates were also examined. The uptake of probes A and B (12.0 uM) by INS-1E cells yielded apparent intracellular concentrations approximately one order of magnitude higher than the extracellular concentration. The two probes differed from one another by the absolute values for their respective uptake and time course, but not so by the pattern of their concentration dependency. Comparable results were recorded in HEK cells, rat isolated pancreatic islets and hepatocytes. Vastly different findings were recorded, however, in rat exocrine pancreatic cells, which do not express GLUT2. Moreover, an unusual concentration dependency for the uptake of each probe was observed in tumoral BRIN-BD11 cells. It is proposed that suitable fluorescent desnitroso streptozotocin analogs may be used to label GLUT2-expressing cells. PMID- 23807416 TI - Occurrence of Fusarium mycotoxin fumonisin B1 and B2 in animal feeds in Korea. AB - The objective of this study was to monitor the occurrence and levels of fumonisin B1 (FB1) and fumonisin B2 (FB2) in animal feeds distributed in South Korea in 2011. The contamination levels of FB1 and FB2 were investigated in 150 samples of compound feeds and in 40 samples of feed ingredients. The contamination rate of feed ingredients with FB1 and FB2 was 50 and 40%, respectively. FB2 was only found in samples contaminated with FB1. Of the compound feeds, 85% were contaminated by FB1 and 47% were contaminated by FB2. The highest contamination rate of FBs was observed in compound feeds for cattle (FB1: 100%; FB2: 80%), followed by poultry feed (FB1: 78%; FB2: 40%) and swine feed (FB1: 76%; FB2: 22%). The highest contamination level (14,600 ng/g) for FB1 were found in poultry broiler feed (early feeding period) samples, which had 82% contamination rate (9/11), and the highest level of FB2 (2,280 ng/g) was found in feed for fatting calves,which had a contamination rate of 100%. PMID- 23807418 TI - Roles of full-length and truncated neurokinin-1 receptors on tumor progression and distant metastasis in human breast cancer. AB - Substance P (SP) regulates various physiologic and pathophysiologic responses predominantly by acting through its primary receptor, the neurokinin-1 receptor (NK1R). There are two naturally occurring forms of NK1R: full-length NK1R-FL and truncated NK1R-Tr. SP-coupled NK1R can directly or indirectly regulate the proliferation and metastatic progression of many types of human cancer cells. However, the exact roles played by the two isoforms of NK1R in breast carcinogenesis still remain largely unclear. In the present study, we first examined the expression profile of total NK1Rs, NK1R-FL and NK1R-Tr in multiple breast cancer cell lines as well as in breast tumor samples. We found that total NK1Rs are present in normal, benign and breast tumor tissues; while, NK1R-FL expression are significantly decreased in tumor specimens, particularly in metastatic carcinomas. More interestingly, NK1R-FL is highly expressed in nontumorigenic HBL-100 breast cells, whereas MDA-MB-231, MCF-7 and T47D breast cancer cells express only NK1R-Tr. To further investigate potential implications of NK1R-FL and NK1R-Tr in the malignant phenotypes of breast cancer, we studied the impacts of ectopically overexpressed NK1R-FL and NK1R-Tr in MDA-MB-231 and HBL-100 cells, respectively. Our in vitro and in vivo data showed that NK1R-FL expression was inversely associated with proliferation, invasiveness and metastasis of MDA-MB-231 cells, but overexpression of NK1R-Tr was able to promote malignant transformation of HBL-100 cells and NK1R-Tr may contribute to tumor progression and promote distant metastasis in human breast cancer. A long-term treatment of NK1R antagonist ASN-1377642 exerted antitumor action in breast cancer cells with NK1R-Tr high expression. PMID- 23807419 TI - Bisphosphonates modulate vital functions of human osteoblasts and affect their interactions with breast cancer cells. AB - Bisphosphonates (BPs) are in clinical use for the treatment of breast cancer patients with bone metastases. Their anti-resorptive effect is mainly explained by inhibition of osteoclast activity, but recent evidence also points to a direct action of BPs on bone-forming osteoblasts. However, the mechanisms how BPs influence osteoblasts and their interactions with breast cancer cells are still poorly characterized. Human osteoblasts isolated from bone specimens were characterized in depth by their expression of osteogenic marker genes. The influence of the nitrogen-containing BPs zoledronate (Zol), ibandronate (Iban), and pamidronate (Pam) on molecular and cellular functions of osteoblasts was assessed focusing on cell proliferation and viability, apoptosis, cytokine secretion, and osteogenic-associated genes. Furthermore, effects of BPs on osteoblast-breast tumor cell interactions were examined in an established in vitro model system. The BPs Zol and Pam inhibited cell viability of osteoblasts. This effect was mediated by an induction of caspase-dependent apoptosis in osteoblasts. By interfering with the mevalonate pathway, Zol also reduces the proliferation of osteoblasts. The expression of phenotypic markers of osteogenic differentiation was altered by Zol and Pam. In addition, both BPs strongly influenced the secretion of the chemokine CCL2 by osteoblasts. Breast cancer cells also responded to Zol and Pam with a reduced cell adhesion to osteoblast derived extracellular matrix molecules and with a decreased migration in response to osteoblast-secreted factors. BPs revealed prominent effects on human osteoblasts. Zol and Pam as the most potent BPs affected not only the expression of osteogenic markers, osteoblast viability, and proliferation but also important osteoblast-tumor cell interactions. Changing the osteoblast metabolism by BPs modulates migration and adhesion of breast cancer cells as well. PMID- 23807417 TI - HuR is a post-transcriptional regulator of core metabolic enzymes in pancreatic cancer. AB - Cancer cell metabolism differs from normal cells, yet the regulatory mechanisms responsible for these differences are incompletely understood, particularly in response to acute changes in the tumor microenvironment. HuR, an RNA-binding protein, acts under acute stress to regulate core signaling pathways in cancer through post-transcriptional regulation of mRNA targets. We demonstrate that HuR regulates the metabolic phenotype in pancreatic cancer cells and is critical for survival under acute glucose deprivation. Using three pancreatic cancer cell line models, HuR-proficient cells demonstrated superior survival under glucose deprivation when compared with isogenic cells with siRNA-silencing of HuR expression (HuR-deficient cells). We found that HuR-proficient cells utilized less glucose, but produced greater lactate, as compared with HuR-deficient cells. Acute glucose deprivation was found to act as a potent stimulus for HuR translocation from the nucleus to the cytoplasm, where HuR stabilizes its mRNA targets. We performed a gene expression array on ribonucleoprotein immunoprecipitated mRNAs bound to HuR and identified 11 novel HuR target transcripts that encode enzymes central to glucose metabolism. Three (GPI, PRPS2 and IDH1) were selected for validation studies, and confirmed as bona fide HuR targets. These findings establish HuR as a critical regulator of pancreatic cancer cell metabolism and survival under acute glucose deprivation. Further explorations into HuR's role in cancer cell metabolism should uncover novel therapeutic targets that are critical for cancer cell survival in a metabolically compromised tumor microenvironment. PMID- 23807420 TI - Biomarker expression and St Gallen molecular subtype classification in primary tumours, synchronous lymph node metastases and asynchronous relapses in primary breast cancer patients with 10 years' follow-up. AB - Molecular profiles of asynchronous breast cancer metastases are of clinical relevance to individual patients' treatment, whereas the role of profiles in synchronous lymph node metastases is not defined. The present study aimed to assess individual biomarkers and molecular subtypes according to the St Gallen classification in primary breast tumours, synchronous lymph node metastases and asynchronous relapses and relate the results to 10-year breast cancer mortality (BCM). Tissue microarrays were constructed from archived tissue blocks of primary tumours (N = 524), synchronous lymph node metastases (N = 147) and asynchronous relapses (N = 36). The samples were evaluated by two independent pathologists according to oestrogen receptor (ER), progesterone receptor (PR), Ki67 and human epidermal growth factor receptor 2 (HER2) by immunohistochemistry and in situ hybridisation. The expression of biomarkers and molecular subtypes in the primary tumour was compared with that in the synchronous lymph node metastases and relapses, and related to 10-year BCM. Discordances were found between primary tumours and relapses (ER: p = 0.006, PR: p = 0.04, Ki67: p = 0.02, HER2: p = 0.02, St Gallen subtypes: p = 0.07) but not between primary tumours and metastatic lymph node. Prognostic information was gained by the molecular subtype classification in primary tumours and nodal metastases; triple negative subtype had the highest BCM compared with the luminal A subtype (primary tumours: HR 4.0; 95 % CI 2.0-8.2, p < 0.001, lymph node metastases: HR 3.5; 95 % CI 1.3-9.7, p = 0.02). When a shift in subtype inherence between primary tumour and metastatic lymph node was identified, the prognosis seemed to follow the subtype of the lymph node. Molecular profiles are not stable throughout tumour progression in breast cancer. Prognostic information for individual patients appears to be available from the analysis of biomarker expression in synchronous metastatic lymph nodes. The study supports biomarker analysis also in asynchronous relapses. PMID- 23807421 TI - In vitro study of oscillatory growth dynamics of Camellia pollen tubes in microfluidic environment. AB - A hallmark of tip-growing cells such as pollen tubes and fungal hyphae is their oscillatory growth dynamics. The multiple aspects of this behavior have been studied to identify the regulatory mechanisms that drive the growth in walled cells. However, the limited temporal and spatial resolution of data acquisition has hitherto prevented more detailed analysis of this growth behavior. To meet this challenge, we employed a microfluidic device that is able to trap pollen grains and to direct the growth of pollen tubes along microchannels filled with liquid growth medium. This enabled us to observe the growth behavior of Camellia pollen tubes without the use of the stabilizer agarose and without risking displacement of the cell during time lapse imaging. Using an acquisition interval of 0.5 s, we demonstrate the existence of primary and secondary peak frequencies in the growth dynamics. The effect of sucrose concentration on the growth dynamics was studied through the shift in these peak frequencies indicating the pollen tube's ability to modulate its growth activity. PMID- 23807422 TI - An automated method for retinal arteriovenous nicking quantification from color fundus images. AB - Retinal arteriovenous (AV) nicking is one of the prominent and significant microvascular abnormalities. It is characterized by the decrease in the venular caliber at both sides of an artery-vein crossing. Recent research suggests that retinal AV nicking is a strong predictor of eye diseases such as branch retinal vein occlusion and cardiovascular diseases such as stroke. In this study, we present a novel method for objective and quantitative AV nicking assessment. From the input retinal image, the vascular network is first extracted using the multiscale line detection method. The crossover point detection method is then performed to localize all AV crossing locations. At each detected crossover point, the four vessel segments, two associated with the artery and two associated with the vein, are identified and two venular segments are then recognized through the artery-vein classification method. The vessel widths along the two venular segments are measured and analyzed to compute the AV nicking severity of that crossover. The proposed method was validated on 47 high resolution retinal images obtained from two population-based studies. The experimental results indicate a strong correlation between the computed AV nicking values and the expert grading with a Spearman correlation coefficient of 0.70. Sensitivity was 77% and specificity was 92% (Kappa kappa = 0.70) when comparing AV nicking detected using the proposed method to that detected using a manual grading method, performed by trained photographic graders. PMID- 23807423 TI - Magnetic Resonance Imaging Duodenoscope. AB - A side-viewing duodenoscope capable of both optical and magnetic resonance imaging (MRI) is described. The instrument is constructed from MR-compatible materials and combines a coherent fiber bundle for optical imaging, an irrigation channel and a side-opening biopsy channel for the passage of catheter tools with a tip saddle coil for radio-frequency signal reception. The receiver coil is magnetically coupled to an internal pickup coil to provide intrinsic safety. Impedance matching is achieved using a mechanically variable mutual inductance, and active decoupling by PIN-diode switching. (1)H MRI of phantoms and ex vivo porcine liver specimens was carried out at 1.5 T. An MRI field-of-view appropriate for use during endoscopic retrograde cholangiopancreatography (ERCP) was obtained, with limited artefacts, and a signal-to-noise ratio advantage over a surface array coil was demonstrated. PMID- 23807424 TI - Multifractal texture estimation for detection and segmentation of brain tumors. AB - A stochastic model for characterizing tumor texture in brain magnetic resonance (MR) images is proposed. The efficacy of the model is demonstrated in patient independent brain tumor texture feature extraction and tumor segmentation in magnetic resonance images (MRIs). Due to complex appearance in MRI, brain tumor texture is formulated using a multiresolution-fractal model known as multifractional Brownian motion (mBm). Detailed mathematical derivation for mBm model and corresponding novel algorithm to extract spatially varying multifractal features are proposed. A multifractal feature-based brain tumor segmentation method is developed next. To evaluate efficacy, tumor segmentation performance using proposed multifractal feature is compared with that using Gabor-like multiscale texton feature. Furthermore, novel patient-independent tumor segmentation scheme is proposed by extending the well-known AdaBoost algorithm. The modification of AdaBoost algorithm involves assigning weights to component classifiers based on their ability to classify difficult samples and confidence in such classification. Experimental results for 14 patients with over 300 MRIs show the efficacy of the proposed technique in automatic segmentation of tumors in brain MRIs. Finally, comparison with other state-of-the art brain tumor segmentation works with publicly available low-grade glioma BRATS2012 dataset show that our segmentation results are more consistent and on the average outperforms these methods for the patients where ground truth is made available. PMID- 23807425 TI - A Molecular Communication System Model for Particulate Drug Delivery Systems. AB - The goal of a drug delivery system (DDS) is to convey a drug where the medication is needed, while, at the same time, preventing the drug from affecting other healthy parts of the body. Drugs composed of micro- or nano-sized particles (particulate DDS) that are able to cross barriers which prevent large particles from escaping the bloodstream are used in the most advanced solutions. Molecular communication (MC) is used as an abstraction of the propagation of drug particles in the body. MC is a new paradigm in communication research where the exchange of information is achieved through the propagation of molecules. Here, the transmitter is the drug injection, the receiver is the drug delivery, and the channel is realized by the transport of drug particles, thus enabling the analysis and design of a particulate DDS using communication tools. This is achieved by modeling the MC channel as two separate contributions, namely, the cardiovascular network model and the drug propagation network. The cardiovascular network model allows to analytically compute the blood velocity profile in every location of the cardiovascular system given the flow input by the heart. The drug propagation network model allows the analytical expression of the drug delivery rate at the targeted site given the drug injection rate. Numerical results are also presented to assess the flexibility and accuracy of the developed model. The study of novel optimization techniques for a more effective and less invasive drug delivery will be aided by this model, while paving the way for novel communication techniques for Intrabody communication networks. PMID- 23807426 TI - Unusual composition dependence of magnetic relaxation for Co(II)(1-x)Ni(II)(x) chain-based metal-organic frameworks. AB - A series of isomorphous 3D Co(II)(1-x)Ni(II)(x) MOFs based on ferromagnetic chains show SCM-type slow relaxation and the Co-rich system can exhibit a higher blocking temperature than both Co(II) and Ni(II) parent materials. PMID- 23807427 TI - In memoriam: Fernando Ortiz Monasterio, MD (1923-2012). PMID- 23807428 TI - Is there lattice contraction in multicomponent metal oxides? Case study for GdVO4:Eu3+ nanoparticles. AB - Metal oxide nanomaterials have been found to have great potential for diverse applications due to their unique relationships between structure and properties. Lattice expansion as particle size reduces was previously considered to be general for metal oxide nanomaterials. It is now a great challenge to see if lattice contraction could be induced by the size effect for metal oxide nanomaterials. ABO4 metal oxides (e.g., CaWO4, GdVO4, and CdWO4) are some of the most important functional materials with many applications, while such oxides at the nanoscale are never reported to show a lattice contraction. This work presents a first report on the variation from lattice expansion to lattice contraction by tuning the microstructures of GdVO4:Eu(3+) nanocrystals. A hydrothermal method was adopted to synthesize GdVO4:Eu(3+) nanocrystals, and then these nanoparticles were calcined at 600 degrees C in air. It is found that particle size reduction led to a lattice contraction for the calcined samples, which is in contrast to the lattice expansion observed for the hydrothermally synthesized counterparts or many other metal oxide nanomaterials. In addition, the lattice symmetry of the calcined samples remained almost a constant. The results indicate that the negative surface stress was eliminated by calcination treatment, leading to a homogeneous compression process in the lattice structure of the calcined GdVO4:Eu(3+) nanocrystals. Furthermore, Eu(3+) was taken as a structural probe and a luminescence center to study the local environments pertinent to these structural changes and to optimize the photoluminescence performance. PMID- 23807430 TI - Effect of a recombinant manganese superoxide dismutase on prevention of contrast induced acute kidney injury. AB - BACKGROUND: Contrast media (CM)-induced nephropathy (CIN) is an acute deterioration of renal function following administration of CM mediated to a large extent by the increased production of ROS within the kidney. Aim of this study was to evaluate whether a novel isoform of a recombinant Manganese SOD (rMnSOD) could provide an effective protection against CIN; this molecule shares the same ability of physiological SODs in scavenging reactive oxygen species (ROS) but, due to its peculiar properties, enters inside the cells after its administration. METHODS: We studied the effects rMnSOD on oxidative damage in a rat model of CIN in uninephrectomized rats, that were randomly assigned to 3 experimental Groups: Group CON, control rats treated with the vehicle of CM, Group HCM, rats treated with CM and Group SOD, rats treated with CM and rMnSOD. RESULTS: In normal rats, pretreatment with rMnSOD, reduced renal superoxide anion production, induced by the activation of NAPDH oxidase, by 84 % (p < 0.001). In rats of Group HCM, ROS production was almost doubled compared to rat of Group CON (p < 0.01) but returned to normal values in rats of Group SOD, where a significant increase of SOD activity was detected (+16 % vs HCM, p < 0.05). Administration of CM determined a striking fall of GFR in rats of Group HCM (-70 %, p < 0.001 vs CON), greatly blunted in Group SOD (-28 % vs CON, p < 0.01); this was associated with a lower presence of both tubular necrosis and intratubular casts in SOD-treated rats (both p < 0.01 vs Group HCM). CONCLUSIONS: Our data indicate that rMnSOD is able to reduce renal oxidative stress, thus preventing the reduction of GFR and the renal histologic damage that follows CM administration. PMID- 23807431 TI - Leaf-miners co-opt microorganisms to enhance their nutritional environment. AB - Organisms make the best of their mother's oviposition choices and utilize specific feeding options that meet energetic requirements and cope with environmental constraints. This is particularly true for leaf-miner insects that develop enclosed in the two epidermis layers of a single leaf for their entire larval life. Cytokinins (CKs) play a central role in plant physiology - including regulation of senescence and nutrient translocation - and, as such, can be the specific target of plant exploiters that manipulate plant primary metabolism. 'Green-islands' are striking examples of a CK-induced phenotype where green areas are induced by plant pathogens/insects in otherwise yellow senescent leaves. Here, we document how the leaf-miner caterpillar Phyllonorycter blancardella, working through an endosymbiotic bacteria, modifies phytohormonal profiles, not only on senescing (photosynthetically inactive) but also on normal (photosynthetically active) leaf tissues of its host plant (Malus domestica). This leaf physiological manipulation allows the insect to maintain sugar-rich green tissues and to create an enhanced nutritional microenvironment in an otherwise degenerating context. It also allows them to maintain a nutritional homeostasis even under distinct leaf environments. Our study also highlights that only larvae harboring bacterial symbionts contain significant amounts of CKs that are most likely not plant-derived. This suggests that insects are able to provide CKs to the plant through their symbiotic association, thus extending further the role of insect bacterial symbionts in plant-insect interactions. PMID- 23807432 TI - Different reactions of potato varieties to infection by potato leafroll virus, and associated responses by its vector, Myzus persicae (Sulzer). AB - Vector-dependent plant pathogens can alter their hosts such that vector behavior and pathogen spread are affected. For example, Potato leafroll virus (PLRV) induces changes in volatiles emitted by potato plants (Solanum tuberosum L.) that influence settling behavior by Myzus persicae, a principal vector of the virus. Prior work in this pathosystem has utilized a single potato variety, Russet Burbank, but as is true for other plant responses to biotic stresses, responses may differ among plant genotypes. To examine this, PLRV-induced changes in headspace volatile organic compounds (VOCs) and associated aphid responses to these VOCs were compared among four potato varieties (Chipeta, Desiree, IdaRose, and Russet Burbank). Total headspace VOCs differed among the varieties and were differentially induced by PLRV infection such that the effect of variety, infection, and their interaction was significant; two of the varieties had increased concentrations of headspace VOCs, and two did not. MANOVA for the effect of infection and variety on total VOCs and major VOC classes also was significant. A principal component analysis (PCA) partially separated the VOC profiles from the four varieties. Aphid arrestment differed in response to the VOCs of the four varieties, and was greater on those that were more readily infected by PLRV (Desiree and Russet Burbank) as compared with those that were less readily infected (Chipeta and IdaRose). Aphid responses were not clearly related to specific characteristics of blends, such that total VOCs and composition appear to contribute. The four varieties used in this study have distinct pedigrees representative of different cultivated forms of S. tuberosum. Although cultivated potato varieties have been subjected to genetic manipulation by humans, the differences in PLRV induced changes in VOCs nonetheless indicate the potential for complex effects of PLRV infection on host plant VOC emissions, and vector responses in managed, and natural systems. PMID- 23807433 TI - Bacteria associated with a tree-killing insect reduce concentrations of plant defense compounds. AB - Bark beetles encounter a diverse array of constitutive and rapidly induced terpenes when attempting to colonize living conifers. Concentrations of these compounds at entry sites can rapidly reach levels toxic to beetles, their brood, and fungal symbionts. Large numbers of beetles can overwhelm tree defenses via pheromone-mediated mass attacks, but the mechanisms are poorly understood. We show that bacteria associated with mountain pine beetles can metabolize monoterpenes and diterpene acids. The abilities of different symbionts to reduce concentrations of different terpenes appear complementary. Serratia reduced concentrations of all monoterpenes applied to media by 55-75 %, except for alpha pinene. Beetle-associated Rahnella reduced (-)- and (+)-alpha-pinene by 40 % and 45 %, respectively. Serratia and Brevundimonas reduced diterpene abietic acid levels by 100 % at low concentrations. However, high concentrations exhausted this ability, suggesting that opposing rates of bacterial metabolism and plant induction of terpenes are critical. The two major fungal symbionts of mountain pine beetle, Grosmannia clavigera and Ophiostoma montium were highly susceptible to abietic acid. Grosmannia clavigera did not reduce total monoterpene concentrations in lodgepole pine turpentine. We propose the ability of bark beetles to exert landscape-scale impacts may arise partly from micro-scale processes driven by bacterial symbionts. PMID- 23807435 TI - Lazer vaporization of vaginal intraepithelial neoplasia: a word of caution. PMID- 23807434 TI - Using choice experiments to understand household tradeoffs regarding pineapple production and environmental management in Costa Rica. AB - Choices among environmental management alternatives involve tradeoffs where, for example, the benefits of environmental protection may be offset by economic costs or welfare losses to individual agents. Understanding individual or household level preferences regarding these tradeoffs is not always straightforward, and it often requires an analysis of choices under alternative scenarios. A household survey was used to gather data for a choice experiment, where respondents were asked to choose among pairs of alternative management scenarios about pineapple production in Costa Rica. The experimental design consisted of six attributes that varied on between two and five attribute levels, and the experiment and accompanying survey were administered orally in Spanish. The results show that respondents are willing to make tradeoffs with respect to the management attributes in order to see an overall improvement in environmental quality. Respondents were willing to accept a moderate level of pesticide application, presumably in exchange for paying a lower cost or seeing a gain in another area, such as monitoring or soil conservation. Buffer zones were significant only in the case of large farms. The results have implications for policy decisions that aim to reflect public attitudes, particularly the aspects of pineapple production that matter most to people living near pineapple plantations. The study also highlights the effectiveness of the choice experiment approach in examining household preferences about environmental management in a rural development context. PMID- 23807436 TI - Cortical graph smoothing: a novel method for exploiting DWI-derived anatomical brain connectivity to improve EEG source estimation. AB - The electroencephalography source estimation problem consists of inferring cortical activation from measurements of electrical potential taken on the scalp surface. This inverse problem is intrinsically ill-posed. In particular the dimensionality of cortical sources greatly exceeds the number of electrode measurements, and source estimation requires regularization to obtain a unique solution. In this work, we introduce a novel regularization function called cortical graph smoothing, which exploits knowledge of anatomical connectivity available from diffusion-weighted imaging. Given a weighted graph description of the anatomical connectivity of the brain, cortical graph smoothing penalizes the weighted sum of squares of differences of cortical activity across the graph edges, thus encouraging solutions with consistent activation across anatomically connected regions. We explore the performance of the cortical graph smoothing source estimates for analysis of the event related potential for simple motor tasks, and compare against the commonly used minimum norm, weighted minimum norm, LORETA and sLORETA source estimation methods. Evaluated over a series of 18 subjects, the proposed cortical graph smoothing method shows superior localization accuracy compared to the minimum norm method, and greater relative peak intensity than the other comparison methods. PMID- 23807437 TI - Mesenteric vasculature-guided small bowel segmentation on 3-D CT. AB - Due to its importance and possible applications in visualization, tumor detection and preoperative planning, automatic small bowel segmentation is essential for computer-aided diagnosis of small bowel pathology. However, segmenting the small bowel directly on computed tomography (CT) scans is very difficult because of the low image contrast on CT scans and high tortuosity of the small bowel and its close proximity to other abdominal organs. Motivated by the intensity characteristics of abdominal CT images, the anatomic relationship between the mesenteric vasculature and the small bowel, and potential usefulness of the mesenteric vasculature for establishing the path of the small bowel, we propose a novel mesenteric vasculature map-guided method for small bowel segmentation on high-resolution CT angiography scans. The major mesenteric arteries are first segmented using a vessel tracing method based on multi-linear subspace vessel model and Bayesian inference. Second, multi-view, multi-scale vesselness enhancement filters are used to segment small vessels, and vessels directly or indirectly connecting to the superior mesenteric artery are classified as mesenteric vessels. Third, a mesenteric vasculature map is built by linking vessel bifurcation points, and the small bowel is segmented by employing the mesenteric vessel map and fuzzy connectness. The method was evaluated on 11 abdominal CT scans of patients suspected of having carcinoid tumors with manually labeled reference standard. The result, 82.5% volume overlap accuracy compared with the reference standard, shows it is feasible to segment the small bowel on CT scans using the mesenteric vasculature as a roadmap. PMID- 23807438 TI - Synthesis and antiproliferative activity of the heterobimetallic complexes [RuClCp(PPh3)-MU-dmoPTA-1kappaP:2kappa2N,N'-MCl2] (M = Co, Ni, Zn; dmoPTA = 3,7 dimethyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane). AB - The synthesis and characterization of three novel heterobimetallic derivatives of general formula [RuClCp(PPh3)-MU-dmoPTA-1kappaP:2kappa2N,N'-MCl2] (M = Co (1), Ni (2) and Zn (3), dmoPTA = 3,7-dimethyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane) are described. The sizes of their diffusing units are in agreement with the solid state structures of 2 and 3, supporting a similar solid-state structure for complex 1. The diamagnetic ruthenium-zinc derivative 3 was fully characterized in solution at 193 K by NMR. Electrochemical properties of the complexes were investigated by cyclic voltammetry, supporting the influence of the {MCl2} moiety on the electronic properties of the Ru-unit. For the three complexes the GI50 values were in the range 0.8-6.5 MUM and comparable to those of the standard anticancer drug cis-platin in the same cell lines. PMID- 23807440 TI - Image noise reduction via geometric multiscale ridgelet support vector transform and dictionary learning. AB - Advances in machine learning technology have made efficient image denoising possible. In this paper, we propose a new ridgelet support vector machine (RSVM) for image noise reduction. Multiscale ridgelet support vector filter (MRSVF) is first deduced from RSVM, to produce a multiscale, multidirection, undecimated, dyadic, aliasing, and shift-invariant geometric multiscale ridgelet support vector transform (GMRSVT). Then, multiscale dictionaries are learned from examples to reduce noises existed in GMRSVT coefficients. Compared with the available approaches, the proposed method has the following characteristics. The proposed MRSVF can extract the salient features associated with the linear singularities of images. Consequently, GMRSVT can well approximate edges, contours and textures in images, and avoid ringing effects suffered from sampling in the multiscale decomposition of images. Sparse coding is explored for noise reduction via the learned multiscale and overcomplete dictionaries. Some experiments are taken on natural images, and the results show the efficiency of the proposed method. PMID- 23807441 TI - Establishing point correspondence of 3D faces via sparse facial deformable model. AB - Establishing a dense vertex-to-vertex anthropometric correspondence between 3D faces is an important and fundamental problem in 3D face research, which can contribute to most applications of 3D faces. This paper proposes a sparse facial deformable model to automatically achieve this task. For an input 3D face, the basic idea is to generate a new 3D face that has the same mesh topology as a reference face and the highly similar shape to the input face, and whose vertices correspond to those of the reference face in an anthropometric sense. Two constraints: 1) the shape constraint and 2) correspondence constraint are modeled in our method to satisfy the three requirements. The shape constraint is solved by a novel face deformation approach in which a normal-ray scheme is integrated to the closest-vertex scheme to keep high-curvature shapes in deformation. The correspondence constraint is based on an assumption that if the vertices on 3D faces are corresponded, their shape signals lie on a manifold and each face signal can be represented sparsely by a few typical items in a dictionary. The dictionary can be well learnt and contains the distribution information of the corresponded vertices. The correspondence information can be conveyed to the sparse representation of the generated 3D face. Thus, a patch-based sparse representation is proposed as the correspondence constraint. By solving the correspondence constraint iteratively, the vertices of the generated face can be adjusted to correspondence positions gradually. At the early iteration steps, smaller sparsity thresholds are set that yield larger representation errors but better globally corresponded vertices. At the later steps, relatively larger sparsity thresholds are used to encode local shapes. By this method, the vertices in the new face approach the right positions progressively until the final global correspondence is reached. Our method is automatic, and the manual work is needed only in training procedure. The experimental results on a large-scale publicly available 3D face data set, BU-3DFE, demonstrate that our method achieves better performance than existing methods. PMID- 23807439 TI - Biogenesis, assembly, and export of viral messenger ribonucleoproteins in the influenza A virus infected cell. AB - The flow of genetic information from sites of transcription within the nucleus to the cytoplasmic translational machinery of eukaryotic cells is obstructed by a physical blockade, the nuclear double membrane, which must be overcome in order to adhere to the central dogma of molecular biology, DNA makes RNA makes protein. Advancement in the field of cellular and molecular biology has painted a detailed picture of the molecular mechanisms from transcription of genes to mRNAs and their processing that is closely coupled to export from the nucleus. The rules that govern delivering messenger transcripts from the nucleus must be obeyed by influenza A virus, a member of the Orthomyxoviridae that has adopted a nuclear replication cycle. The negative-sense genome of influenza A virus is segmented into eight individual viral ribonucleoprotein (vRNP) complexes containing the viral RNA-dependent RNA polymerase and single-stranded RNA encapsidated in viral nucleoprotein. Influenza A virus mRNAs fall into three major categories, intronless, intron-containing unspliced and spliced. During evolutionary history, influenza A virus has conceived a way of negotiating the passage of viral transcripts from the nucleus to cytoplasmic sites of protein synthesis. The major mRNA nuclear export NXF1 pathway is increasingly implicated in viral mRNA export and this review considers and discusses the current understanding of how influenza A virus exploits the host mRNA export pathway for replication. PMID- 23807442 TI - Generalizing the majority voting scheme to spatially constrained voting. AB - Generating ensembles from multiple individual classifiers is a popular approach to raise the accuracy of the decision. As a rule for decision making, majority voting is a usually applied model. In this paper, we generalize classical majority voting by incorporating probability terms pn,k to constrain the basic framework. These terms control whether a correct or false decision is made if k correct votes are present among the total number of n. This generalization is motivated by object detection problems, where the members of the ensemble are image processing algorithms giving their votes as pixels in the image domain. In this scenario, the terms pn,k can be specialized by a geometric constraint. Namely, the votes should fall inside a region matching the size and shape of the object to vote together. We give several theoretical results in this new model for both dependent and independent classifiers, whose individual accuracies may also differ. As a real world example, we present our ensemble-based system developed for the detection of the optic disc in retinal images. For this problem, experimental results are shown to demonstrate the characterization capability of this system. We also investigate how the generalized model can help us to improve an ensemble with extending it by adding a new algorithm. PMID- 23807443 TI - Context coding of depth map images under the piecewise-constant image model representation. AB - This paper introduces an efficient method for lossless compression of depth map images, using the representation of a depth image in terms of three entities: 1) the crack-edges; 2) the constant depth regions enclosed by them; and 3) the depth value over each region. The starting representation is identical with that used in a very efficient coder for palette images, the piecewise-constant image model coding, but the techniques used for coding the elements of the representation are more advanced and especially suitable for the type of redundancy present in depth images. Initially, the vertical and horizontal crack-edges separating the constant depth regions are transmitted by 2D context coding using optimally pruned context trees. Both the encoder and decoder can reconstruct the regions of constant depth from the transmitted crack-edge image. The depth value in a given region is encoded using the depth values of the neighboring regions already encoded, exploiting the natural smoothness of the depth variation, and the mutual exclusiveness of the values in neighboring regions. The encoding method is suitable for lossless compression of depth images, obtaining compression of about 10-65 times, and additionally can be used as the entropy coding stage for lossy depth compression. PMID- 23807444 TI - Variational stereo imaging of oceanic waves with statistical constraints. AB - An image processing observational technique for the stereoscopic reconstruction of the waveform of oceanic sea states is developed. The technique incorporates the enforcement of any given statistical wave law modeling the quasi-Gaussianity of oceanic waves observed in nature. The problem is posed in a variational optimization framework, where the desired waveform is obtained as the minimizer of a cost functional that combines image observations, smoothness priors and a weak statistical constraint. The minimizer is obtained by combining gradient descent and multigrid methods on the necessary optimality equations of the cost functional. Robust photometric error criteria and a spatial intensity compensation model are also developed to improve the performance of the presented image matching strategy. The weak statistical constraint is thoroughly evaluated in combination with other elements presented to reconstruct and enforce constraints on experimental stereo data, demonstrating the improvement in the estimation of the observed ocean surface. PMID- 23807445 TI - Shortest-path constraints for 3D multiobject semiautomatic segmentation via clustering and Graph Cut. AB - We derive shortest-path constraints from graph models of structure adjacency relations and introduce them in a joint centroidal Voronoi image clustering and Graph Cut multiobject semiautomatic segmentation framework. The vicinity prior model thus defined is a piecewise-constant model incurring multiple levels of penalization capturing the spatial configuration of structures in multiobject segmentation. Qualitative and quantitative analyses and comparison with a Potts prior-based approach and our previous contribution on synthetic, simulated, and real medical images show that the vicinity prior allows for the correct segmentation of distinct structures having identical intensity profiles and improves the precision of segmentation boundary placement while being fairly robust to clustering resolution. The clustering approach we take to simplify images prior to segmentation strikes a good balance between boundary adaptivity and cluster compactness criteria furthermore allowing to control the trade-off. Compared with a direct application of segmentation on voxels, the clustering step improves the overall runtime and memory footprint of the segmentation process up to an order of magnitude without compromising the quality of the result. PMID- 23807446 TI - Extracting dominant textures in real time with multi-scale hue-saturation intensity histograms. AB - It is very important to extract high quality texture features from images. This is, however, often laborious, because the randomness in the color distribution patterns for texture elements makes texture measurement very difficult, despite these elements having a very similar visual appearance. In this paper, we propose the use of multi-scale color histograms to measure the effect of color distribution patterns efficiently and without having to compute the actual patterns, which saves considerable effort. Meanwhile, the hue-saturation intensity color model is mainly adopted to take the advantage of human visual experiences in texture recognition. We discuss and validate the effectiveness and efficiency of our method by applying to various benchmarks. The results show that we can extract quality dominant textures automatically in real time, and faster by several orders of magnitude than existing methods. PMID- 23807447 TI - Face illumination manipulation using a single reference image by adaptive layer decomposition. AB - This paper proposes a novel image-based framework to manipulate the illumination of human face through adaptive layer decomposition. According to our framework, only a single reference image, without any knowledge of the 3D geometry or material information of the input face, is needed. To transfer the illumination effects of a reference face image to a normal lighting face, we first decompose the lightness layers of the reference and the input images into large-scale and detail layers through weighted least squares (WLS) filter with adaptive smoothing parameters according to the gradient values of the face images. The large-scale layer of the reference image is filtered with the guidance of the input image by guided filter with adaptive smoothing parameters according to the face structures. The relit result is obtained by replacing the largescale layer of the input image with that of the reference image. To normalize the illumination effects of a non-normal lighting face (i.e., face delighting), we introduce similar reflectance prior to the layer decomposition stage by WLS filter, which make the normalized result less affected by the high contrast light and shadow effects of the input face. Through these two procedures, we can change the illumination effects of a non-normal lighting face by first normalizing the illumination and then transferring the illumination of another reference face to it. We acquire convincing relit results of both face relighting and delighting on numerous input and reference face images with various illumination effects and genders. Comparisons with previous papers show that our framework is less affected by geometry differences and can preserve better the identification structure and skin color of the input face. PMID- 23807448 TI - Weighted color and texture sample selection for image matting. AB - Color sampling based matting methods find the best known samples for foreground and background colors of unknown pixels. Such methods do not perform well if there is an overlap in the color distribution of foreground and background regions because color cannot distinguish between these regions and hence, the selected samples cannot reliably estimate the matte. Furthermore, current sampling based matting methods choose samples that are located around the boundaries of foreground and background regions. In this paper, we overcome these two problems. First, we propose texture as a feature that can complement color to improve matting by discriminating between known regions with similar colors. The contribution of texture and color is automatically estimated by analyzing the content of the image. Second, we combine local sampling with a global sampling scheme that prevents true foreground or background samples to be missed during the sample collection stage. An objective function containing color and texture components is optimized to choose the best foreground and background pair among a set of candidate pairs. Experiments are carried out on a benchmark data set and an independent evaluation of the results shows that the proposed method is ranked first among all other image matting methods. PMID- 23807449 TI - The initial trauma center fluid management of penetrating injury: a systematic review. AB - BACKGROUND: Damage-control resuscitation is the prevailing trauma resuscitation technique that emphasizes early and aggressive transfusion with balanced ratios of red blood cells (RBCs), plasma (FFP), and platelets (Plt) while minimizing crystalloid resuscitation, which is a departure from Advanced Trauma Life Support (ATLS) guidelines. It is unclear whether the newer approach is superior to the approach recommended by ATLS. QUESTIONS/PURPOSES: With these recent changes pervading resuscitation protocols, we performed a systematic review to determine if the shift in trauma resuscitation from ATLS guidelines to damage control resuscitation has improved mortality in patients with penetrating injuries. METHODS: A systematic search of PubMed, the Cochrane Library, and the Current Controlled Trials Register was performed for studies comparing mortality in massively transfused penetrating trauma patients receiving either balanced ratios of blood transfusion per damage control resuscitation tenets or undergoing an alternate blood volume resuscitation strategy. Studies were deemed appropriate for inclusion if they had a Newcastle-Ottawa Scale score of 6 or greater as well as at least 30% penetrating trauma. Twenty studies that reported on a total of 12,154 patients were included. RESULTS: Transfusion ratios varied widely, with 1:1 and 1:2 ratios of FFP:RBC most often defined as high ratios for purposes of comparison with other low ratio groups. Fourteen of 20 studies found significantly lower 30-day mortality when higher transfusion ratios of FFP, RBC, and/or Plt were used; six of 20 studies found mortality to be similar between higher and lower transfusion ratios. CONCLUSIONS: Patients with penetrating injuries who require massive transfusion should be transfused early using balanced ratios of RBC, FFP, and Plt. Randomized, controlled trials are needed to determine optimal ratios for transfusion. PMID- 23807450 TI - Pancreatic tumor mass in a xenograft mouse model is decreased by treatment with therapeutic stem cells following introduction of therapeutic genes. AB - Pancreatic cancer is the fourth most common cause of cancer-related mortality. In the present study, we employed 2 types of therapeutic stem cells expressing cytosine deaminase (CD) with or without human interferon-beta (IFN-beta), HB1.F3.CD and HB1.F3.CD.IFN-beta cells, respectively, to selectively treat pancreatic cancer. The CD gene converts the non-toxic prodrug, 5-flurorocytosine (5-FC), into the toxic agent, 5-fluorouracil (5-FU). In addition, human IFN-beta is a potent cytokine that has antitumor effects. To generate a xenograft mouse model, PANC-1 cells (2x10(6)/mouse) cultured in DMEM containing 10% FBS were mixed with Matrigel and were subcutaneously injected into Balb/c nu/nu mice. In the migration assay, the stem cells expressing the CD or IFN-beta gene effectively migrated toward the pancreatic cancer cells, suggesting the presence of chemoattractant factors secreted by the pancreatic tumors. In the co-culture and MTT assay, antitumor activity of the therapeutic stem cells was observed in the presence of 5-FC was shown that the growth of PANC-1 cells was inhibited. Furthermore, these effects were confirmed in the xenograft mouse model bearing tumors originating from PANC-1 cells. Analyses by histological and fluorescence microscopy showed that treatment with the stem cells resulted in the inhibition of pancreatic cancer growth in the presence of 5-FC. Taken together, these results indicate that stem cells expressing the CD and/or IFN-beta gene can be used to effectively treat pancreatic cancer and reduce the side-effects associated with conventional therapies. PMID- 23807451 TI - [Primary treatment of tendon injuries of the hand]. AB - Tendon injuries of the hand are common and their treatment is surgically challenging. Precise knowledge of the anatomy of the extensor and flexor tendons in the hand is necessary to be able to perform a detailed clinical examination and to estimate adequately the extent of injury. Depending on the injury pattern, various conservative and surgical treatment options must be considered. Concerning the overall concept of the supply of tendon injuries of the hand, follow-up treatment is crucial to achieve an optimal functional outcome. It should be noted, however, that the results are influenced by the following: extent of the injury, mechanism, exact anatomical location, associated injuries, and finally the participation of the patient in the follow-up treatment. PMID- 23807452 TI - [Proctocolectomy in ulcerative colitis : is a multistep procedure in cases of immunosuppression advisable?]. AB - BACKGROUND: The coloproctomucosectomy (CPM) is the procedure of the choice for the surgical treatment of ulcerative colitis (UC). In cases with pronounced immunosuppression (IS), a 3-step (3S) procedure [i.e., subtotal colectomy and ileal pouch-anal anastomosis (IPAA) and finally ileostomy reconstruction] is often selected. Fewer perioperative complications can be expected compared to the 2-step (2S) procedure; however, an additional in-hospital stay and surgical intervention are necessary. The aim of the present study was to compare both approaches using the clinical outcome of our patients undergoing IPAA to determine efficacy of these two concepts. PATIENTS AND METHODS: From 1997-2010, a total of 225 patients were operated using a 2S or 3S IPAA procedure. Clinical outcomes were evaluated based on the number of surgical steps for the ileoanal pouch procedure and IPAA. The survey was performed within the scope of prospective study. RESULTS: Of the 225 patients with CPM, 66 were excluded due to a diagnosis other than UC (familial adenomatous polyposis, indeterminate colitis, Crohn's disease) and patients with permanent ILS procedures without the possibility or wish for an IPAA (n = 54). Included were 71 patients with 2S (w = 30, m = 41) and 34 patients with 3S procedures (w = 21, m = 13). Compared to the 2S procedure, the 3S procedure was shown to have shorter operation times (246 versus 296 min; p = 0.05), shorter hospital stays (15.5 versus 24.6 days; p = 0.05), shorter intensive care unit stays (3.3 versus 7.2 days; p = 0.05), and fewer major complications (5.9 % versus 22.5 %; p = 0.035). Patients with 3S procedures had a higher BMI (26.2 versus 23.1 kg/m2; p = 0.05) and fewer required IS (10 % vs. 62 %; p < 0.05). CONCLUSION: The decision for a 3S procedure in UC and pronounced IS is advisable and justified. Using a 3S procedure, immunosuppression and its influence on perioperative morbidity are thus reduced. The IPAA can be performed with shorter operation times, shorter hospital stays and fewer major complications. PMID- 23807453 TI - Contingent capture in cueing: the role of color search templates and cue-target color relations. AB - Visual search studies have shown that attention can be top-down biased to a specific target color, so that only items with this color or a similar color can capture attention. According to some theories of attention, colors from different categories (i.e., red, green, blue, yellow) are represented independently. However, other accounts have proposed that these are related--either because color is filtered through broad overlapping channels (4-channel view), or because colors are represented in one continuous feature space (e.g., CIE space) and search is governed by specific principles (e.g., linear separability between colors, or top-down tuning to relative colors). The present study tested these different views using a cueing experiment in which observers had to select one target color (e.g., red) and ignore two or four differently colored distractors that were presented prior to the target (cues). The results showed clear evidence for top-down contingent capture by colors, as a target-colored cue captured attention more strongly than differently colored cues. However, the results failed to support any of the proposed views that different color categories are related to one another by overlapping channels, linear separability, or relational guidance (N = 96). PMID- 23807454 TI - A bioinspired associative memory system based on enzymatic cascades. AB - A biomolecular system representing the first realization of associative memory based on enzymatic reactions in vitro has been designed. The system demonstrated "training" and "forgetting" features characteristic of memory in biological systems, but presently realized in simple biocatalytic cascades. PMID- 23807455 TI - Angiotensin II type 2 receptor (AT2R) is associated with increased tolerance of the hyperthyroid heart to ischemia-reperfusion. AB - BACKGROUND: Thyroid hormone induces cardiac hypertrophy and preconditions the myocardium against Ischemia/Reperfusion (I/R) injury. Type 2 Angiotensin II receptors (AT2R) are shown to be upregulated in cardiac hypertrophy observed in hyperthyroidism and this receptor has been reported to mediate cardioprotection against ischemic injury. METHODS: The aim of the present study was to evaluate the role of AT2R in the recovery of myocardium after I/R in isolated hearts from T3 treated rats. Male Wistar rats were treated with triiodothyronine (T3; 7 MUg/100 g BW/day, i.p.) in the presence or not of a specific AT2R blocker (PD123,319; 10 mg/Kg) for 14 days, while normal rats served as control. After treatment, isolated hearts were perfused in Langendorff mode; after 30 min of stabilization, hearts were subjected to 20 min of zero-flow global ischemia followed by 25 min, 35 min and 45 min of reperfusion. RESULTS: T3 treatment induced cardiac hypertrophy, which was not changed by PD treatment. Post-ischemic recovery of cardiac function was increased in T3-treated hearts after 35 min and 45 min of reperfusion as compared to control and the ischemic contracture was accelerated and intensified. AT2R blockade was able to return the evaluated functional parameters of cardiac performance (LVDP, +dP/dt(max) and -dP/dt(min)) to the control condition. Furthermore, AT2R blockade prevented the increase in AMPK expression levels induced by T3, suggesting its possible involvement in this process. CONCLUSION: AT2R plays a significant role in T3-induced cardioprotection. PMID- 23807456 TI - Discriminative methods for classification of asynchronous imaginary motor tasks from EEG data. AB - In this work, two methods based on statistical models that take into account the temporal changes in the electroencephalographic (EEG) signal are proposed for asynchronous brain-computer interfaces (BCI) based on imaginary motor tasks. Unlike the current approaches to asynchronous BCI systems that make use of windowed versions of the EEG data combined with static classifiers, the methods proposed here are based on discriminative models that allow sequential labeling of data. In particular, the two methods we propose for asynchronous BCI are based on conditional random fields (CRFs) and latent dynamic CRFs (LDCRFs), respectively. We describe how the asynchronous BCI problem can be posed as a classification problem based on CRFs or LDCRFs, by defining appropriate random variables and their relationships. CRF allows modeling the extrinsic dynamics of data, making it possible to model the transitions between classes, which in this context correspond to distinct tasks in an asynchronous BCI system. On the other hand, LDCRF goes beyond this approach by incorporating latent variables that permit modeling the intrinsic structure for each class and at the same time allows modeling extrinsic dynamics. We apply our proposed methods on the publicly available BCI competition III dataset V as well as a data set recorded in our laboratory. Results obtained are compared to the top algorithm in the BCI competition as well as to methods based on hierarchical hidden Markov models (HHMMs), hierarchical hidden CRF (HHCRF), neural networks based on particle swarm optimization (IPSONN) and to a recently proposed approach based on neural networks and fuzzy theory, the S-dFasArt. Our experimental analysis demonstrates the improvements provided by our proposed methods in terms of classification accuracy. PMID- 23807457 TI - Test-retest variability of various quantitative measures to characterize tracer uptake and/or tracer uptake heterogeneity in metastasized liver for patients with colorectal carcinoma. AB - PURPOSE: The aim of this study was to assess test-retest variability of various quantitative measures to characterize tracer uptake and/or tracer uptake heterogeneity. PROCEDURES: Two baseline whole-body 2-deoxy-2-[(18)F]fluoro-D glucose positron emission tomography/computed tomography (CT) scans were acquired in 29 subjects with colorectal carcinoma. Whole liver volumes of interest (VOI) were defined manually on CT. For each VOI, various quantitative measures were determined, e.g., skewness, kurtosis, and the area under a cumulative standardized uptake value-volume histogram (AUC). RESULTS: AUC showed a good reliability (intraclass correlation coefficients (ICC): 0.97) and low test-retest variability (10%). Most other quantitative parameters showed excellent agreement between test and retest values (ICC: 0.78-0.97) and low test-retest variability (<12%), except for kurtosis. Skewness also showed a higher test-retest variability (19%), but good ICC (0.96) and it correlated well with AUC (R (2): 0.90, all others: <0.76). CONCLUSION: This high reproducibility and reliability of AUC warrant further investigation of its use for quantification of tracer uptake heterogeneity. PMID- 23807458 TI - Fluorescence study of the membrane effects of aggregated lysozyme. AB - The last decade has seen unprecedented upsurge of interest in the structural and toxic properties of particular type of protein aggregates, amyloid fibrils, associated with a number of pathological states. In the present study fluorescence spectroscopy technique has been employed to gain further insight into the membrane-related mechanisms of amyloid toxicity. To this end, erythrocyte model system composed of liposomes and hemoglobin was subjected to the action of oligomeric and fibrillar lysozyme. Acrylamide quenching of lysozyme fluorescence showed that solvent accessibility of Trp62 and Trp108 increases upon the protein fibrillization. Resonance energy transfer measurements suggested the possibility of direct complexation between hemoglobin and aggregated lysozyme. Using the novel squaraine dye SQ-1 it was demonstrated that aggregated lysozyme is capable of inhibiting lipid peroxidation processes. Fluorescent probes pyrene, Prodan and diphenylhexatriene were employed to characterize the membrane modifying properties of hemoglobin and lysozyme. Both oligomeric and fibrillar forms of lysozyme were found to exert condensing influence on lipid bilayer structure, with the membrane effects of fibrils being less amenable to modulation by hemoglobin. PMID- 23807461 TI - Treatment of a hemodialysis patient with pulmonary calcification-associated progressive respiratory failure with sodium thiosulfate. PMID- 23807462 TI - Acquired oculomotor nerve paresis with cyclic spasms in a young woman, a rare subtype of neuromyotonia. AB - BACKGROUND: To report an unusual case of cyclic oculomotor nerve paresis and spasms, which developed 5 years following brain radiotherapy for cerebellar medulloblastoma. METHODS: Observational case report. RESULTS: The cyclic oculomotor nerve paresis and spasms resolved in our patient when treated with carbamazepine. However, because of severe photophobia and tearing, carbamazepine had to be discontinued leading to reappearance of the eye movement disorder. CONCLUSION: Cyclic oculomotor nerve paresis and spasms appear to be a delayed effect of radiotherapy and respond to carbamazepine therapy. It may be a rare form of ocular neuromyotonia. PMID- 23807463 TI - C-H bond activation by aluminum oxide cluster anions, an experimental and theoretical study. AB - Aluminum oxide cluster anions are produced by laser ablation and reacted with n butane in a fast flow reactor. A reflectron time-of-flight mass spectrometer is used to detect the cluster distribution before and after the reactions. Aluminum oxide clusters Al2O4,6- and Al3O7- can react with n-C4H10 to produce Al2O4,6H- and Al3O7-, respectively, while cluster Al3O6- reacts with n-C4H10 to produce both the Al3O6H- and Al3O6H2-. The theoretical calculations are performed to study the structures and bonding properties of clusters Al2O4,6- and Al3O6,7- as well as the reaction mechanism of Al2O4- + n-C4H10. The calculated results show that the mononuclear oxygen-centred radicals (O-) on Al2O4,6- and Al3O7-, and oxygen-centred biradical on Al3O6- are the active sites responsible for the observed hydrogen atom abstraction reactivity. Furthermore, mechanism investigation of the O- generation in Al3O7- upon O2 molecule adsorption on un reactive Al3O5- is performed by theoretical calculations. PMID- 23807465 TI - A right antenna for social behaviour in honeybees. AB - Sophisticated cognitive abilities have been documented in honeybees, possibly an aspect of their complex sociality. In vertebrates brain asymmetry enhances cognition and directional biases of brain function are a putative adaptation to social behaviour. Here we show that honeybees display a strong lateral preference to use their right antenna in social interactions. Dyads of bees tested using only their right antennae (RA) contacted after shorter latency and were significantly more likely to interact positively (proboscis extension) than were dyads of bees using only their left antennae (LA). The latter were more likely to interact negatively (C-responses) even though they were from the same hive. In dyads from different hives C-responses were higher in RA than LA dyads. Hence, RA controls social behaviour appropriate to context. Therefore, in invertebrates, as well as vertebrates, lateral biases in behaviour appear to be associated with requirements of social life. PMID- 23807466 TI - Model on cell movement, growth, differentiation and de-differentiation: reaction diffusion equation and wave propagation. AB - We construct a model for cell proliferation with differentiation into different cell types, allowing backward de-differentiation and cell movement. With different cell types labeled by state variables, the model can be formulated in terms of the associated transition probabilities between various states. The cell population densities can be described by coupled reaction-diffusion partial differential equations, allowing steady wavefront propagation solutions. The wavefront profile is calculated analytically for the simple pure growth case (2 states), and analytic expressions for the steady wavefront propagating speeds and population growth rates are obtained for the simpler cases of 2-, 3- and 4-states systems. These analytic results are verified by direct numerical solutions of the reaction-diffusion PDEs. Furthermore, in the absence of de-differentiation, it is found that, as the mobility and/or self-proliferation rate of the down-lineage descendant cells become sufficiently large, the propagation dynamics can switch from a steady propagating wavefront to the interesting situation of propagation of a faster wavefront with a slower waveback. For the case of a non-vanishing de differentiation probability, the cell growth rate and wavefront propagation speed are both enhanced, and the wavefront speeds can be obtained analytically and confirmed by numerical solution of the reaction-diffusion equations. PMID- 23807467 TI - Confinement effects on glass transition temperature, transition breadth, and linear expansivity: an ultraslow X-ray reflectivity study on supported ultrathin polystyrene films. AB - X-ray reflectivity measurements of the glass transition in thin polystyrene films supported on Si substrates were performed at slow cooling rates ranging from 0.62 to 0.01 ( degrees )C/min. At a cooling rate of 0.14 ( degrees )C/min, a depression in the glass transition temperature Tg was clearly observed with decreasing thickness. However, at a cooling rate of 0.62 ( degrees )C/min, only a slight decrease in Tg for a 12-nm-thick film was observed, while at an ultraslow cooling rate of 0.01 degrees C/min, a significant reduction in the Tg of ultrathin films (12 and 6 nm) was observed. As the thickness decreased, a broadening in the width of the glass transition, w, was found at higher cooling rates (0.62 degrees C/min and 0.14 degrees C/min), while narrowing of w was observed at ultraslow cooling rates of 0.01 degrees C/min and 0.04 degrees C/min. A narrow distribution of relaxation time in the ultrathin films indicates that most segments are able to relax under the ultraslow cooling process, thus showing an inherent reduction in the Tg of the confined thin polymer films. PMID- 23807468 TI - Chemotaxis migration and morphogenesis of living colonies. AB - Development of forms in living organisms is complex and fascinating. Morphogenetic theories that investigate these shapes range from discrete to continuous models, from the variational elasticity to time-dependent fluid approach. Here a mixture model is chosen to describe the mass transport in a morphogenetic gradient: it gives a mathematical description of a mixture involving several constituents in mechanical interactions. This model, which is highly flexible can incorporate many biological processes but also complex interactions between cells as well as between cells and their environment. We use this model to derive a free-boundary problem easier to handle analytically. We solve it in the simplest geometry: an infinite linear front advancing with a constant velocity. In all the cases investigated here as the 3 D diffusion, the increase of mitotic activity at the border, nonlinear laws for the uptake of morphogens or for the mobility coefficient, a planar front exists above a critical threshold for the mobility coefficient but it becomes unstable just above the threshold at long wavelengths due to the existence of a Goldstone mode. This explains why sparsely bacteria exhibit dendritic patterns experimentally in opposition to other colonies such as biofilms and epithelia which are more compact. In the most unstable situation, where all the laws: diffusion, chemotaxis driving and chemoattractant uptake are linear, we show also that the system can recover a dynamic stability. A second threshold for the mobility exists which has a lower value as the ratio between diffusion coefficients decreases. Within the framework of this model where the biomass is treated mainly as a viscous and diffusive fluid, we show that the multiplicity of independent parameters in real biologic experimental set-up may explain varieties of observed patterns. PMID- 23807469 TI - Elasticity of DNA and the effect of dendrimer binding. AB - Negatively charged DNA can be compacted by positively charged dendrimers and the degree of compaction is a delicate balance between the strength of the electrostatic interaction and the elasticity of DNA. We report various elastic properties of short double-stranded DNA (dsDNA) and the effect of dendrimer binding using fully atomistic molecular dynamics and numerical simulations. In equilibrium at room temperature, the contour length distribution P(L) and the end to-end distance distribution P(R) are nearly Gaussian, the former gives an estimate of the stretch modulus gamma1 of dsDNA in quantitative agreement with the literature value. The bend angle distribution P(theta) of the dsDNA also has a Gaussian form and allows to extract a persistence length, L(p) of 43nm. When the dsDNA is compacted by positively charged dendrimer, the stretch modulus stays invariant but the effective bending rigidity estimated from the end-to-end distance distribution decreases dramatically due to backbone charge neutralization of dsDNA by dendrimer. We support our observations with numerical solutions of the worm-like-chain (WLC) model as well as using non-equilibrium dsDNA stretching simulations. These results are helpful in understanding the dsDNA elasticity at short length scales as well as how the elasticity is modulated when dsDNA binds to a charged object such as a dendrimer or protein. PMID- 23807470 TI - Active matter. PMID- 23807471 TI - Torsional resonance mode atomic force microscopy in liquid with Lorentz force actuation. AB - In this work, we present a design based on Lorentz force induction to excite pure torsional resonances of different types of cantilevers in air as well as in water. To demonstrate the atomic force microscopy imaging capability, the phase modulation torsional resonance mode is employed to resolve fine features of purple membranes in a buffer solution. Most importantly, force-versus-distance curves using a relatively stiff cantilever can clearly detect the characteristic oscillatory profiles of hydration layers at a water-mica interface, indicating the high force sensitivity of the torsional mode. The high resonance frequencies and high quality-factors for the torsional mode may be of great potential for high-speed and high-sensitivity imaging in aqueous environment. PMID- 23807472 TI - The suborbicularis oculi fat (SOOF) and the fascial planes: has everything already been explained? AB - IMPORTANCE: During anatomic and surgical dissections, a connection was seen between the superficial layer of the deep temporal fascia and the prezygomatic area. These findings were in contrast to previous evaluations. This study defines this connection, which is important to understand from both surgical and anatomic standpoints. OBJECTIVE: To define the connection between the superficial layer of the deep temporal fascia and the prezygomatic area and demonstrate the presence of a deep fascial layer in the midface. DESIGN AND SETTING: Anatomical study performed at the Laboratoire d'Anatomie de la Faculte de Medecine de Nice, Sophia Antipolis, France; at the Centre du Don des Corps de l'Universite Paris Descartes, Paris, France; and at the Department of Experimental Medicine, Histology, and Embryology Unit of the University of Pavia, Pavia, Italy. Twenty four hemifaces of 14 white cadavers were dissected to define the relationship between deep temporal fascia and the midface. Four biopsy samples were harvested for histologic analysis. MAIN OUTCOMES AND MEASURES: Dissection of 24 hemifaces from the fresh cadavers revealed the following findings. There is a connection of the deep fascia of the temple (superficial layer of deep temporal fascia) to the midface that divides the fat deep to the orbicularis muscle into 2 layers. One layer of fat is the so-called suborbicularis oculi fat (SOOF), which is superficial to the deep fascia, and the other layer of fat (preperiosteal) is deep to the deep fascia and adherent to malar bone. These findings are in contrast to previous anatomical findings. RESULTS In 12 hemifaces, the superficial layer of the deep temporal fascia directly reached the prezygomatic area as a continuous fascial layer. In 16 hemifaces, the superficial sheet of the deep temporal fascia inserted at the level of the zygomatic and lateral orbital rim and continued as a deep fascial layer over the prezygomatic area. In all specimens, a deep fascial layer was present in the prezygomatic-infraorbital area. This deep fascial layer is adherent to the muscles of the infraorbital area, and it divided the fat located deep to the orbicularis oculi muscle into 2 layers: the SOOF and a deeper layer. Histologic examination of the biopsy samples confirmed these findings. CONCLUSIONS AND RELEVANCE: This study demonstrates the existence of a deep fascial layer in the midface. This fascia is connected to the superficial layer of the deep temporal fascia, and it divides the fat deep to the orbicularis oculi muscle into 2 layers. This new finding carries interesting implications related to the classic concept of the superficial musculoaponeurotic system. LEVEL OF EVIDENCE: NA. PMID- 23807473 TI - The effect of silica on polymorphic precipitation of calcium carbonate: an on line energy-dispersive X-ray diffraction (EDXRD) study. AB - Calcium carbonate is the most abundant biomineral and a compound of great industrial importance. Its precipitation from solution has been studied extensively and was often shown to proceed via distinct intermediate phases, which undergo sequential transformations before eventually yielding the stable crystalline polymorph, calcite. In the present work, we have investigated the crystallisation of calcium carbonate in a time-resolved and non-invasive manner by means of energy-dispersive X-ray diffraction (EDXRD) using synchrotron radiation. In particular, the role of silica as a soluble additive during the crystallisation process was examined. Measurements were carried out at different temperatures (20, 50 and 80 degrees C) and various silica concentrations. Experiments conducted in the absence of silica reflect the continuous conversion of kinetically formed metastable polymorphs (vaterite and aragonite) to calcite and allow for quantifying the progress of transformation. Addition of silica induced remarkable changes in the temporal evolution of polymorphic fractions existing in the system. Essentially, the formation of calcite was found to be accelerated at 20 degrees C, whereas marked retardation or complete inhibition of phase transitions was observed at higher temperatures. These findings are explained in terms of a competition between the promotional effect of silica on calcite growth rates and kinetic stabilisation of vaterite and aragonite due to adsorption (or precipitation) of silica on their surfaces, along with temperature dependent variations of silica condensation rates. Data collected at high silica concentrations indicate the presence of an amorphous phase over extended frames of time, suggesting that initially generated ACC particles are progressively stabilised by silica. Our results may have important implications for CaCO3 precipitation scenarios in both geochemical and industrial settings, where solution silicate is omnipresent, as well as for CO2 sequestration technologies. PMID- 23807474 TI - Remediation of soil co-contaminated with petroleum and heavy metals by the integration of electrokinetics and biostimulation. AB - Successful remediation of soil co-contaminated with high levels of organics and heavy metals is a challenging task, because that metal pollutants in soil can partially or completely suppress normal heterotrophic microbial activity and thus hamper biodegradation of organics. In this study, the benefits of integrating electrokinetic (EK) remediation with biodegradation for decontaminating soil co contaminated with crude oil and Pb were evaluated in laboratory-scale experiments lasting for 30 days. The treated soil contained 12,500 mg/kg of total petroleum hydrocarbons (TPH) and 450 mg/kg Pb. The amendments of EDTA and Tween 80, together with a regular refreshing of electrolyte showed the best performance to remediate this contaminated soil. An important function of EDTA-enhanced EK treatment was to eliminate heavy metal toxicity from the soil, thus activating microbial degradation of oil. Although Tween 80 reduced current, it could serve as a second substrate for enhancing microbial growth and biodegradation. It was found that oil biodegradation degree and microbial numbers increased toward the anode and cathode. Microbial metabolism was found to be beneficial to metal release from the soil matrix. Under the optimum conditions, the soil Pb and TPH removal percentages after 30 days of running reached 81.7% and 88.3%, respectively. After treatment, both the residual soil Pb and TPH concentrations met the requirement of the Chinese soil environmental quality standards. PMID- 23807475 TI - Trajectory of human movement during sit to stand: a new modeling approach based on movement decomposition and multi-phase cost function. AB - The purpose of this work is to develop a computational model to describe the task of sit to stand (STS). STS is an important movement skill which is frequently performed in human daily activities, but has rarely been studied from the perspective of optimization principles. In this study, we compared the recorded trajectories of STS with the trajectories generated by several conventional optimization-based models (i.e., minimum torque, minimum torque change and kinetic energy cost models) and also with the trajectories produced by a novel multi-phase cost model (MPCM). In the MPCM, we suggested that any complex task, such as STS, is decomposable into successive motion phases, so that each phase requires a distinct strategy to be performed. In this way, we proposed a multi phase cost function to describe the STS task. The results revealed that the conventional optimization-based models failed to correctly predict the invariable features of STS, such as hip flexion and ankle dorsiflexion movements. However, the MPCM not only predicted the general features of STS with a sufficient accuracy, but also showed a potential flexibility to distinguish between the movement strategies from one subject to the other. According to the results, it seems plausible to hypothesize that the central nervous system might apply different strategies when planning different phases of a complex task. The application areas of the proposed model could be generating optimized trajectories of STS for clinical applications (such as functional electrical stimulation) or providing clinical and engineering insights to develop more efficient rehabilitation devices and protocols. PMID- 23807476 TI - Attentional distraction, MU-suppression and empathic perspective-taking. AB - Social mirroring has been proposed to be an automatic process whereby an observer understands the intentions of others by using his/her motor system to simulate others' actions. Automaticity implies that if the observer's eyes are fixed on another person, the observer's mirror system will engage whether attention is focused on the other person or not. This proposal has not been fully tested, however. The current study therefore addressed whether MU-suppression, an electroencephalographic measure of putative mirror neuron activity, induced by observing the actions of others would be affected by attentional distraction. Participants performed two different distraction tasks while watching a video of a hand repeatedly touching the forefinger and thumb together. MU-suppression was compared across three different blocks: (1) video with no distraction, (2) video with mental imagery distraction and (3) video with word generation distraction. While the no distraction condition yielded the typical level of MU-suppression, the word generation distraction task eliminated any evidence of MU-suppression suggesting that simply fixating the eyes on an action without focusing attention is insufficient to induce MU-suppression. A secondary goal of the current experiment was to replicate correlational findings between MU-suppression and empathic perspective-taking. A counterintuitive, negative relationship between MU suppression and perspective-taking was replicated, and a theoretical model for explaining this relationship is offered. PMID- 23807477 TI - Anticipating the effects of visual gravity during simulated self-motion: estimates of time-to-passage along vertical and horizontal paths. AB - By simulating self-motion on a virtual rollercoaster, we investigated whether acceleration cued by the optic flow affected the estimate of time-to-passage (TTP) to a target. In particular, we studied the role of a visual acceleration (1 g = 9.8 m/s(2)) simulating the effects of gravity in the scene, by manipulating motion law (accelerated or decelerated at 1 g, constant speed) and motion orientation (vertical, horizontal). Thus, 1-g-accelerated motion in the downward direction or decelerated motion in the upward direction was congruent with the effects of visual gravity. We found that acceleration (positive or negative) is taken into account but is overestimated in module in the calculation of TTP, independently of orientation. In addition, participants signaled TTP earlier when the rollercoaster accelerated downward at 1 g (as during free fall), with respect to when the same acceleration occurred along the horizontal orientation. This time shift indicates an influence of the orientation relative to visual gravity on response timing that could be attributed to the anticipation of the effects of visual gravity on self-motion along the vertical, but not the horizontal orientation. Finally, precision in TTP estimates was higher during vertical fall than when traveling at constant speed along the vertical orientation, consistent with a higher noise in TTP estimates when the motion violates gravity constraints. PMID- 23807478 TI - Animation control of surface motion capture. AB - Surface motion capture (SurfCap) of actor performance from multiple view video provides reconstruction of the natural nonrigid deformation of skin and clothing. This paper introduces techniques for interactive animation control of SurfCap sequences which allow the flexibility in editing and interactive manipulation associated with existing tools for animation from skeletal motion capture (MoCap). Laplacian mesh editing is extended using a basis model learned from SurfCap sequences to constrain the surface shape to reproduce natural deformation. Three novel approaches for animation control of SurfCap sequences, which exploit the constrained Laplacian mesh editing, are introduced: 1) space time editing for interactive sequence manipulation; 2) skeleton-driven animation to achieve natural nonrigid surface deformation; and 3) hybrid combination of skeletal MoCap driven and SurfCap sequence to extend the range of movement. These approaches are combined with high-level parametric control of SurfCap sequences in a hybrid surface and skeleton-driven animation control framework to achieve natural surface deformation with an extended range of movement by exploiting existing MoCap archives. Evaluation of each approach and the integrated animation framework are presented on real SurfCap sequences for actors performing multiple motions with a variety of clothing styles. Results demonstrate that these techniques enable flexible control for interactive animation with the natural nonrigid surface dynamics of the captured performance and provide a powerful tool to extend current SurfCap databases by incorporating new motions from MoCap sequences. PMID- 23807479 TI - Principal component analysis by Lp-norm maximization. AB - This paper proposes several principal component analysis (PCA) methods based on Lp-norm optimization techniques. In doing so, the objective function is defined using the Lp-norm with an arbitrary p value, and the gradient of the objective function is computed on the basis of the fact that the number of training samples is finite. In the first part, an easier problem of extracting only one feature is dealt with. In this case, principal components are searched for either by a gradient ascent method or by a Lagrangian multiplier method. When more than one feature is needed, features can be extracted one by one greedily, based on the proposed method. Second, a more difficult problem is tackled that simultaneously extracts more than one feature. The proposed methods are shown to find a local optimal solution. In addition, they are easy to implement without significantly increasing computational complexity. Finally, the proposed methods are applied to several datasets with different values of p and their performances are compared with those of conventional PCA methods. PMID- 23807480 TI - Enhanced computer vision with Microsoft Kinect sensor: a review. AB - With the invention of the low-cost Microsoft Kinect sensor, high-resolution depth and visual (RGB) sensing has become available for widespread use. The complementary nature of the depth and visual information provided by the Kinect sensor opens up new opportunities to solve fundamental problems in computer vision. This paper presents a comprehensive review of recent Kinect-based computer vision algorithms and applications. The reviewed approaches are classified according to the type of vision problems that can be addressed or enhanced by means of the Kinect sensor. The covered topics include preprocessing, object tracking and recognition, human activity analysis, hand gesture analysis, and indoor 3-D mapping. For each category of methods, we outline their main algorithmic contributions and summarize their advantages/differences compared to their RGB counterparts. Finally, we give an overview of the challenges in this field and future research trends. This paper is expected to serve as a tutorial and source of references for Kinect-based computer vision researchers. PMID- 23807481 TI - Projection-based ensemble learning for ordinal regression. AB - The classification of patterns into naturally ordered labels is referred to as ordinal regression. This paper proposes an ensemble methodology specifically adapted to this type of problem, which is based on computing different classification tasks through the formulation of different order hypotheses. Every single model is trained in order to distinguish between one given class (k) and all the remaining ones, while grouping them in those classes with a rank lower than k , and those with a rank higher than k. Therefore, it can be considered as a reformulation of the well-known one-versus-all scheme. The base algorithm for the ensemble could be any threshold (or even probabilistic) method, such as the ones selected in this paper: kernel discriminant analysis, support vector machines and logistic regression (LR) (all reformulated to deal with ordinal regression problems). The method is seen to be competitive when compared with other state-of-the-art methodologies (both ordinal and nominal), by using six measures and a total of 15 ordinal datasets. Furthermore, an additional set of experiments is used to study the potential scalability and interpretability of the proposed method when using LR as base methodology for the ensemble. PMID- 23807482 TI - Lipopolysaccharides elicit an oxidative burst as a component of the innate immune system in the seagrass Thalassia testudinum. AB - This study represents the first report characterizing the biological effects of a lipopolysaccharide (LPS) immune modulator on a marine vascular plant. LPS was shown to serve as a strong elicitor of the early defense response in the subtropical seagrass Thalassia testudinum Banks ex Konig and was capable of inducing an oxidative burst identified at the single cell level. The formation of reactive oxygen species (ROS), detected by a redox-sensitive fluorescent probe and luminol-based chemiluminescence, included a diphenyleneiodonium sensitive response, suggesting the involvement of an NADPH oxidase. A 900 bp cDNA fragment coding for this enzyme was sequenced and found to encode a NAD binding pocket domain with extensive homology to the Arabidopsis thaliana rbohF (respiratory burst oxidase homolog) gene. The triggered release of ROS occurred at 20 min post elicitation and was dose-dependent, requiring a minimal threshold of 50 MUg/mL LPS. Pharmacological dissection of the early events preceding ROS emission indicated that the signal transduction chain of events involved extracellular alkalinization, G-proteins, phospholipase A2, as well as K(+), Ca(2+), and anion channels. Despite exclusively thriving in a marine environment, seagrasses contain ROS-generating machinery and signal transduction components that appear to be evolutionarily conserved with the well-characterized defense response systems found in terrestrial plants. PMID- 23807483 TI - Notch1 destabilizes the adherens junction complex through upregulation of the Snail family of E-cadherin repressors in non-small cell lung cancer. AB - One of the critical steps driving cancer cell migration and metastasis is the repression of cell adhesion molecules resulting in loss of cell-to-cell adhesion. Although interactions between Notch1 and components of the adherens junction complex have been suggested, little is known concerning the consequence of their interactions. In this study, we investigated the interaction between the Notch1 and the E-cadherin/beta-catenin complex, its effect on the expression of adherens junction complex components and its influence on non-small cell lung cancer (NSCLC) cell proliferation. With progression of lung neoplastic lesions in LSL K ras G12D mice, the expression of E-cadherin was inhibited whereas that of Notch1 was increased with frequent nuclear localization, suggesting an inverse relationship between E-cadherin and Notch1 expression with tumor progression. Transduction of the human Notch1 intracellular domain (N1ICD) into NSCLC cells inhibited expression of E-cadherin and beta-catenin and induced changes in the localization of adherens junction molecules. The loss of E-cadherin was mediated through upregulation of the Snail family of transcription factors, Snail and Slug. Experiments in which siRNA against E-cadherin was introduced into NSCLC cells revealed that N1ICD decreased the expression of beta-catenin in an E cadherin-independent manner, leading to inhibition of markers of Wnt/beta-catenin signaling activation. Despite inhibition of Wnt/beta-catenin signaling in the N1ICD-transduced cells, cells transduced with N1ICD showed no difference in cell cycle progression when compared with that of the control vector-transduced cells. In conclusion, Notch1 inhibited the expression of E-cadherin through upregulation of the Snail family of transcriptional factors, resulting in inhibition of expression of beta-catenin and destabilization of adherens junctions. PMID- 23807484 TI - Atorvastatin counteracts aberrant soft tissue mineralization in a mouse model of pseudoxanthoma elasticum (Abcc6-/-). AB - Pseudoxanthoma elasticum (PXE), a multisystem heritable disorder with aberrant mineralization of arterial blood vessels, is caused by mutations in the ABCC6 gene. Previous studies have suggested that carriers of the ABCC6 mutations, particularly of p.R1141X, are at increased risk for coronary artery disease. In this study, we used Abcc6 (tm1Jfk) knock-out mice to determine the serum lipid profiles and examine the effects of atorvastatin on the aberrant mineralization in this model of PXE. First, serum lipid profiles at 12 weeks of age, after overnight fasting, revealed a statistically significant increase in total cholesterol and triglyceride levels in Abcc6 (tm1Jfk) mice compared to their wild type littermates. Placing these mice at 4 weeks of age for 20 weeks on atorvastatin, either 0.01 % or 0.04 % of the diet (low statin and high statin groups, respectively), reduced the total triglyceride and cholesterol levels, which was accompanied with significantly reduced mineralization of the dermal sheath of vibrissae, a biomarker of the aberrant mineralization process in these mice. However, if the mice were placed on atorvastatin for 12 weeks at 12 weeks of age, at which time point significant mineralization had already taken place, no difference in the amount of mineralization was noted. These observations suggest that statins, particularly atorvastatin, can prevent, but not reverse, aberrant mineralization in this mouse model of PXE. For a clinical perspective, a survey of 1,747 patients with PXE was conducted regarding their present or past use of statins. The results indicated that about one third of all PXE patients are currently or have previously been on cholesterol-lowering drugs. Thus, a sizable number of patients with PXE could be subject to modulation of their mineralization processes by concomitant statin treatment. KEY MESSAGE: The Abcc6 (-/-) mice serve as a model system for PXE, an ectopic mineralization disorder Abcc6 (-/-) mice were shown to have elevated serum cholesterol and triglyceride levels Feeding of the Abcc6 (-/-) mice with atorvastatin prevented connective tissue mineralization A third of patients with PXE was found to be on cholesterol lowering therapy Atorvastatin may potentially be beneficial for patients with PXE. PMID- 23807485 TI - Inhibition of tissue factor pathway inhibitor increases the sensitivity of thrombin generation assay to procoagulant microvesicles. AB - Patients with cancer have a seven-fold to 10-fold increased risk of developing venous thromboembolism (VTE). Circulating microvesicles could be a predictive biomarker for VTE in cancer. Thrombin generation assay (TGA) is a useful technique to detect procoagulant activity of microvesicles. However, TGA suffers from a lack of sensitivity due to the presence of tissue factor pathway inhibitor (TFPI) in plasma. The aim of the study was to improve the sensitivity of TGA to tissue factor by limiting the interference of TFPI. Serial dilutions of MDA-MB231 cells were incubated for 45 min at 37 degrees C to generate microvesicles. Samples were then centrifuged and supernatants that contain microvesicles were used for TGA. Normal pooled plasma was incubated with inhibitor of TFPI or was diluted twice to decrease plasma level of TFPI. Lagtime was used as a surrogate marker of TGA to detect procoagulant activity of microvesicles. Inhibition of TFPI decreased twice the cell concentration needed for a significant reduction of lagtime and decreased 2.4-fold the intraassay variability. Plasma dilution had no impact on the TGA sensitivity when TGA was triggered by microvesicles derived from MDA-MB-231. Thrombin generation is a very sensitive method to study the procoagulant activity of tissue factor bearing microvesicles. The sensitivity can be increased by inhibition of TFPI with specific monoclonal antibody against its Kunitz domain I. A two times plasma dilution is an interesting cheaper alternative to study the procoagulant activity of microvesicles by TGA with a good sensitivity, especially when low plasma quantities are available. PMID- 23807486 TI - Antithrombin Rybnik: a new point mutation (nt 683 G>T) associated with type I antithrombin deficiency in a patient with venous thromboembolism and recurrent superficial venous thrombosis. PMID- 23807487 TI - [Tropheryma whipplei endocarditis]. AB - Whipple's disease is a rare infectious disease caused by the bacterium Tropheryma whipplei. Usually the course of the disease is characterized by fever, diarrhea, weight loss and polyarthritis. We report on a case with a 10-year course of the disease with endocarditis, myocarditis and involvement of the bone marrow but with negative histological results of the small intestine. PMID- 23807488 TI - Autohydrolysis of tropical agricultural residues by compressed liquid hot water pretreatment. AB - Pretreatment is an essential step in biorefineries for improving digestibility of recalcitrant agricultural feedstocks prior to enzymatic hydrolysis to composite sugars, which can be further converted to fuels and chemicals. In this study, autohydrolysis by compressed liquid hot water (LHW) pretreatment of various tropical agricultural residues including sugarcane bagasse (BG), rice straw (RS), corn stover (CS), and empty palm fruit bunch (EPFB) was investigated. It was found that LHW pretreatment at 200 degrees C for 5-20 min resulted in high levels of hemicellulose solubilization into the liquid phase and marked improvement on enzymatic digestibility of the solid cellulose-enriched residues. The maximal yields of glucose and pentose were 409.8-482.7 mg/g and 81.1-174.0 mg/g of pretreated substrates, respectively. Comparative analysis based on severity factor showed varying susceptibility of biomass to LHW in the order of BG> RS> CS> EPFB. Structural analysis revealed surface modification of the pretreated biomass along with an increase in crystallinity index. Overall, 75.7 82.3 % yield of glucose and 27.4-42.4 % yield of pentose from the dried native biomass was recovered in the pretreated solid residues, while 18.3-29.7 % of pentoses were recovered in the liquid phase with dehydration by-product concentration under the threshold for ethanologens. The results suggest the potential of LHW as an efficient pretreatment strategy for implementation in biorefineries operated using various seasonal agricultural feedstocks. PMID- 23807489 TI - Identification of amino acid residues responsible for the binding to anti-FLAGTM M2 antibody using a phage display combinatorial peptide library. AB - FLAG, a short hydrophilic peptide consisting of eight amino acids (DYKDDDDK), has been widely used as a fusion tag for the purification and detection of a wide variety of recombinant proteins. One of the monoclonal antibodies against this peptide, anti-FLAG M2, recognises a FLAG peptide sequence at the N terminus, Met N terminus, C terminus, or internal site of a fusion protein and has been extremely useful for the detection, identification, and purification of recombinant proteins. Nevertheless, detailed binding specificity of anti-FLAG M2 has yet to be determined. In the current study, a phage display combinatorial peptide library was used to determine that the motif DYKxxD encompasses the critical amino acid residues responsible for the binding of FLAG peptide to this antibody. This study demonstrates the utility of phage display technology and helps to elucidate the mode of action of this detection system. PMID- 23807491 TI - Do planar tetracoordinate tin complexes really exist? AB - New experimental and theoretical data show that the previously reported planar tetracoordinate Sn complexes [Sn(Ph2P(Se)N(Se)PPh2)2] (1-sq) and [Sn(iPr2P(Se)N(Se)PiPr2)2] (2-sq) were not isolated and rather confused with the selenium complexes [Se(Ph2P(Se)N(Se)PPh2)2] (3-sq) and [Se(iPr2P(Se)N(Se)PiPr2)2] (4-sq), respectively. PMID- 23807490 TI - Glioma microvesicles carry selectively packaged coding and non-coding RNAs which alter gene expression in recipient cells. AB - Interactions between glioma cells and their local environment are critical determinants of brain tumor growth, infiltration and neovascularisation. Communication with host cells and stroma via microvesicles represents one pathway by which tumors can modify their surroundings to achieve a tumor-permissive environment. Here we have taken an unbiased approach to identifying RNAs in glioma-derived microvesicles, and explored their potential to regulate gene expression in recipient cells. We find that glioma microvesicles are predominantly of exosomal origin and contain complex populations of coding and noncoding RNAs in proportions that are distinct from those in the cells from which they are derived. Microvesicles show a relative depletion in microRNA compared with their cells of origin, and are enriched in unusual or novel noncoding RNAs, most of which have no known function. Short-term exposure of brain microvascular endothelial cells to glioma microvesicles results in many gene expression changes in the endothelial cells, most of which cannot be explained by direct delivery of transcripts. Our data suggest that the scope of potential actions of tumor-derived microvesicles is much broader and more complex than previously supposed, and highlight a number of new classes of small RNA that remain to be characterized. PMID- 23807493 TI - Reaction of strongly electrophilic alkenylboranes with phosphanylalkynes: rare examples of intermolecular 1,1-alkenylboration reactions. AB - Simple alkenylbis(pentafluorophenyl)boranes undergo 1,1-alkenylboration with phosphanylacetylenes to give phosphane-borane Lewis pairs with a conjugated diene backbone. PMID- 23807494 TI - Family-centered care for military and veteran families affected by combat injury. AB - The US military community includes a population of mostly young families that reside in every state and the District of Columbia. Many reside on or near military installations, while other National Guard, Reserve, and Veteran families live in civilian communities and receive care from clinicians with limited experience in the treatment of military families. Though all military families may have vulnerabilities based upon their exposure to deployment-related experiences, those affected by combat injury have unique additional risks that must be understood and effectively managed by military, Veterans Affairs, and civilian practitioners. Combat injury can weaken interpersonal relationships, disrupt day-to-day schedules and activities, undermine the parental and interpersonal functions that support children's health and well-being, and disconnect families from military resources. Treatment of combat-injured service members must therefore include a family-centered strategy that lessens risk by promoting positive family adaptation to ongoing stressors. This article reviews the nature and epidemiology of combat injury, the known impact of injury and illness on military and civilian families, and effective strategies for maintaining family health while dealing with illness and injury. PMID- 23807495 TI - Ultrasound-guided perineural steroid injection to treat intractable pain due to sciatic nerve injury. AB - PURPOSE: Sciatic neuropathy is a rare but serious complication of cardiac surgery. Neuropathic pain following nerve injury can be severely debilitating and largely resistant to treatment. We present a case of this complication where ultrasound-guided perineural steroid injection at the site of the sciatic nerve injury provided excellent pain relief and facilitated subsequent rehabilitation. CLINICAL FEATURES: A 17-yr-old boy developed bilateral sciatic neuropathy after a nine-hour cardiac surgical procedure in the supine position, resulting in debilitating dysesthesia refractory to neuropathic pain therapies and leading to severe functional limitation. With magnetic resonance imaging of the lower extremities, the location of the lesion was determined to be from the level of the superior gemellus to the level of the quadratus femoris. An ultrasound-guided injection of triamcinolone 20 mg and lidocaine 40 mg around both sciatic nerves at the level of the lesion was administered two months after the surgery, and the pain score (rated on a scale 0-10) at rest decreased from 9-10 to 1 two weeks after the injection. CONCLUSIONS: There are a limited number of reports in the literature on sciatic nerve injuries associated with cardiac surgery. This case illustrates the efficacy of ultrasound-guided steroid injection around sciatic nerves at the level of superior gemellus in treating our patient's neuropathic pain. PMID- 23807496 TI - Empowering underserved populations through cancer prevention and early detection. AB - It is well documented that cancer is disproportionately distributed in racial/ethnic minority groups and medically underserved communities. In addition, cancer prevention and early detection represent the key defenses to combat cancer. The purpose of this article is to showcase the comprehensive health education and community outreach activities at the H. Lee Moffitt Cancer Center and Research Institute (Moffitt) designed to promote and increase access to and utilization of prevention and early detection services among underserved populations. One of Moffitt's most important conduits for cancer prevention and early detection among underserved populations is through its community education and outreach initiatives, in particular, the Moffitt Program for Outreach Wellness Education and Resources (M-POWER). M-POWER works to empower underserved populations to make positive health choices and increase screening behaviors through strengthening collaboration and partnerships, providing community-based health education/promotion, and increasing access to care. Effective, empowering, and culturally and linguistically competent health education and community outreach, is key to opening the often impenetrable doors of cancer prevention and early detection to this society's most vulnerable populations. PMID- 23807497 TI - Fibular hemimelia - diagnostic management, principles, and results of treatment. AB - The objective of this study is to present treatment of fibular hemimelia along with the complications, results, and an algorithm for treatment indications on the basis of authors' experience. A group of 31 patients was studied. In patients fulfilling the criteria for amputation, Syme's amputation should be performed. Elongation should be performed in case of type IA or IB fibular hemimelia, with a functional foot with more than three rays, leg shortening less than 5 cm at birth, and less than 10 cm at 9 years of life. The combination of epiphysiodesis with elongation produces the best outcome and is best accepted by the patients. PMID- 23807498 TI - A vacuolar processing enzyme RsVPE1 gene of radish is involved in floral bud abortion under heat stress. AB - Radish floral bud abortion (FBA) is an adverse biological phenomenon that occurs during reproduction. Although FBA is a frequent occurrence, its molecular mechanism remains unknown. A transcript-derived fragment (TDF72), which was obtained by cDNA amplified fragment length polymorphism (cDNA-AFLP), was up regulated in the aborted buds and exhibited 89% sequence homology with the AtgammaVPE gene. In this study, TDF72 was used to clarify the role of VPE in FBA by isolation of the VPE gene RsVPE1 from radish flower buds. The full-length genomic DNA was 2346 bp including nine exons and eight introns. The full-length cDNA was 1825 bp, containing a complete open reading frame (ORF) of 1470 bp, which encoded a predicted protein containing 489 amino acid residues, with a calculated molecular mass of 53.735 kDa. Expression analysis demonstrated that RsVPE1 was expressed in all tested organs of radish at different levels. Highest expression was detected in aborted flower buds, suggesting that RsVPE1 has a role in FBA. In order to analyze the role of RsVPE1 in FBA, RsVPE1 was overexpressed in transgenic Arabidopsis thaliana plants. Aborted flower buds appeared in transgenic plants subjected to heat stress. In addition, RsVPE1 expression in the transgenic plants reached a maximum when subjected to heat stress for 24 h and increased by 2.1-fold to 2.8-fold in three homozygous transgenic lines. These results indicated that RsVPE1 led to FBA when its expression levels exceeded a particular threshold, and provided evidence for the involvement of RsVPE1 in promoting FBA under heat stress. PMID- 23807499 TI - Kinetic model for signal binding to the Quorum sensing regulator LasR. AB - We propose a kinetic model for the activation of the las regulon in the opportunistic pathogen Pseudomonas aeruginosa. The model is based on in vitro data and accounts for the LasR dimerization and consecutive activation by binding of two OdDHL signal molecules. Experimentally, the production of the active LasR quorum-sensing regulator was studied in an Escherichia coli background as a function of signal molecule concentration. The functional activity of the regulator was monitored via a GFP reporter fusion to lasB expressed from the native lasB promoter. The new data shows that the active form of the LasR dimer binds two signal molecules cooperatively and that the timescale for reaching saturation is independent of the signal molecule concentration. This favors a picture where the dimerized regulator is protected against proteases and remains protected as it is activated through binding of two successive signal molecules. In absence of signal molecules, the dimerized regulator can dissociate and degrade through proteolytic turnover of the monomer. This resolves the apparent contradiction between our data and recent reports that the fully protected dimer is able to "degrade" when the induction of LasR ceases. PMID- 23807500 TI - A labile pool of IQGAP1 disassembles endothelial adherens junctions. AB - Adhesion molecules are known to play an important role in endothelial activation and angiogenesis. Here we determined the functional role of IQGAP1 in the regulation of endothelial adherens junctions. VE-cadherin is found to be associated with actin filaments and thus stable, but IQGAP1 at intercellular junctions is not bound to actin filaments and thus labile. Expression of GFP labeled VE-alpha-catenin is shown to increase the electrical resistance across HUVEC monolayers and diminishes endogenous labile IQGAP1 at the intercellular junctions. Knockdown of endogenous IQGAP1 enhances intercellular adhesion in HUVECs by increasing the association of VE-cadherin with P120 and beta-catenin. IQGAP1 knockdown also decreases the interaction of N-cadherin with P120 and beta catenin. Together, these results suggest that a labile pool of IQGAP1 at intercellular junctions disassembles adherens junctions and thus impairs endothelial cell-cell adhesion. PMID- 23807501 TI - Apoferritin modified magnetic particles as doxorubicin carriers for anticancer drug delivery. AB - Magnetic particle mediated transport in combination with nanomaterial based drug carrier has a great potential for targeted cancer therapy. In this study, doxorubicin encapsulation into the apoferritin and its conjugation with magnetic particles was investigated by capillary electrophoresis with laser-induced fluorescence detection (CE-LIF). The quantification of encapsulated doxorubicin was performed by fluorescence spectroscopy and compared to CE-LIF. Moreover, the significant enhancement of the doxorubicin signal was observed by addition of methanol into the sample solution. PMID- 23807502 TI - Towards the identification of new genes involved in ABA-dependent abiotic stresses using Arabidopsis suppressor mutants of abh1 hypersensitivity to ABA during seed germination. AB - Abscisic acid plays a pivotal role in the abiotic stress response in plants. Although great progress has been achieved explaining the complexity of the stress and ABA signaling cascade, there are still many questions to answer. Mutants are a valuable tool in the identification of new genes or new alleles of already known genes and in elucidating their role in signaling pathways. We applied a suppressor mutation approach in order to find new components of ABA and abiotic stress signaling in Arabidopsis. Using the abh1 (ABA hypersensitive 1) insertional mutant as a parental line for EMS mutagenesis, we selected several mutants with suppressed hypersensitivity to ABA during seed germination. Here, we present the response to ABA and a wide range of abiotic stresses during the seed germination and young seedling development of two suppressor mutants-soa2 (suppressor of abh1 hypersensitivity to ABA 2) and soa3 (suppressor of abh1 hypersensitivity to ABA 3). Generally, both mutants displayed a suppression of the hypersensitivity of abh1 to ABA, NaCl and mannitol during germination. Both mutants showed a higher level of tolerance than Columbia-0 (Col-0-the parental line of abh1) in high concentrations of glucose. Additionally, soa2 exhibited better root growth than Col-0 in the presence of high ABA concentrations. soa2 and soa3 were drought tolerant and both had about 50% fewer stomata per mm2 than the wild-type but the same number as their parental line-abh1. Taking into account that suppressor mutants had the same genetic background as their parental line-abh1, it was necessary to backcross abh1 with Landsberg erecta four times for the map-based cloning approach. Mapping populations, derived from the cross of abh1 in the Landsberg erecta background with each suppressor mutant, were created. Map based cloning in order to identify the suppressor genes is in progress. PMID- 23807503 TI - Cloning and functional characterization of c-Jun NH2-terminal kinase from the Mediterranean species of the Whitefly Bemisia tabaci complex. AB - c-Jun NH2-terminal kinase (JNK) signaling is a highly conserved pathway that controls gene transcription in response to a wide variety of biological and environmental stresses. In this study, a JNK from the invasive Mediterranean (MED) species of the whitefly Bemisia tabaci complex was cloned and characterized. The full-length JNK cDNA of MED consists of 1565 bp, with an 1176 bp open reading frame encoding 392 amino acids. Comparison of JNK amino acid sequences among different species showed that the sequences of JNKs are highly conserved. To reveal its biological function, the gene expression and functional activation of JNK were analyzed during various stress conditions. Quantitative RT PCR analysis showed that the relative expression level of JNK remained hardly unchanged when the insects were transferred from cotton (a suitable host plant) to tobacco (an unsuitable host plant), infected with bacteria and treated with high and low temperatures. However, the mRNA level of JNK significantly increased when treated with fungal pathogens. Furthermore, we found that the amount of phosphorylated JNK increased significantly after fungal infection, while there is no obvious change for phosphorylated p38 and ERK. Our results indicate that the whitefly JNK plays an important role in whitefly's immune responses to fungal infection. PMID- 23807504 TI - The functions and applications of RGD in tumor therapy and tissue engineering. AB - Arginine-Glycine-Aspartic (RGD), is the specific recognition site of integrins with theirs ligands, and regulates cell-cell and cell-extracellular matrix interactions. The RGD motif can be combined with integrins overexpressed on the tumor neovasculature and tumor cells with a certain affinity, becoming the new target for imaging agents, and drugs, and gene delivery for tumor treatment. Further, RGD as a biomimetic peptide can also promote cell adherence to the matrix, prevent cell apoptosis and accelerate new tissue regeneration. Functionalizing material surfaces with RGD can improve cell/biomaterial interactions, which facilitates the generation of tissue-engineered constructs. This paper reviews the main functions and advantages of RGD, describes the applications of RGD in imaging agents, drugs, gene delivery for tumor therapy, and highlights the role of RGD in promoting the development of tissue engineering (bone regeneration, cornea repair, artificial neovascularization) in recent years. PMID- 23807505 TI - Non-covalent synthesis of metal oxide nanoparticle-heparin hybrid systems: a new approach to bioactive nanoparticles. AB - Heparin has been conjugated to Fe3O4, Co3O4, and NiO nanoparticles (NPs) through electrostatic interactions, producing colloidal suspensions of hybrid metal oxide heparin NPs that are stable in water. Negative zeta potentials and retention of heparin's ability to capture toluidine blue indicate that heparin's negative charges are exposed on the surface of the coated NPs. IR results confirmed the formation of nanohybrids as did NMR experiments, which were also interpreted on the basis of toluidine blue tests. Transmission electron microscopy results revealed that the heparin coating does not modify the shape or dimension of the NPs. Dynamic light scattering and negative zeta potential measurements confirmed that heparin surface functionalisation is an effective strategy to prevent NP aggregation. PMID- 23807506 TI - miR-125b regulates the early steps of ESC differentiation through dies1 in a TGF independent manner. AB - Over the past few years, it has become evident that the distinctive pattern of miRNA expression seen in embryonic stem cells (ESCs) contributes to important signals in the choice of the cell fate. Thus, the identification of miRNAs and their targets, whose expression is linked to a specific step of differentiation, as well as the modulation of these miRNAs, may prove useful in the learning of how ESC potential is regulated. In this context, we have studied the expression profile of miRNAs during neural differentiation of ESCs. We have found that miR 125b is upregulated in the first steps of neural differentiation of ESCs. This miRNA targets the BMP4 co-receptor, Dies1, and, in turn, regulates the balance between BMP4 and Nodal/Activin signaling. The ectopic expression of miR-125b blocks ESC differentiation at the epiblast stage, and this arrest is rescued by restoring the expression of Dies1. Finally, opposite to miR-125a, whose expression is under the control of the BMP4, miR-125b is not directly regulated by Transforming Growth Factor beta (TGFbeta) signals. These results highlight a new important role of miR-125b in the regulation of the transition from ESCs to the epiblast stage and add a new level of control on TGFbeta signaling in ESCs. PMID- 23807507 TI - Voltammetry as a tool for characterization of CdTe quantum dots. AB - Electrochemical detection of quantum dots (QDs) has already been used in numerous applications. However, QDs have not been well characterized using voltammetry, with respect to their characterization and quantification. Therefore, the main aim was to characterize CdTe QDs using cyclic and differential pulse voltammetry. The obtained peaks were identified and the detection limit (3 S/N) was estimated down to 100 fg/mL. Based on the convincing results, a new method for how to study stability and quantify the dots was suggested. Thus, the approach was further utilized for the testing of QDs stability. PMID- 23807508 TI - p38beta, A novel regulatory target of Pokemon in hepatic cells. AB - Pokemon is an important proto-oncogene involved in various biological processes and cancer development, such as cell differentiation, tumorigenesis and metastasis. Pokemon is recognized as a transcription factor localized upstream of several oncogenes, regulating their expression. p38MAPKs act as key regulatory factors in cellular signaling pathways associated with inflammatory responses, cell proliferation, differentiation and survival. p38beta, a member of p38MAPK family, is closely correlated with tumorigenesis, but the mechanism of activation remains unclear. In this study, we found overexpression of Pokemon promoted the growth, migration and invasion of HepG2 cells. However, a p38 inhibitor SB202190 efficiently attenuated the promoting effect of Pokemon in the HepG2 cells. Targeted expression or silencing of Pokemon changed cellular p38beta protein level and phosphorylation of downstream ATF2 in the p38 signaling pathway. Both dual luciferase report assay and ChIP assay suggested that p38beta is a novel regulatory target of the transcription factor Pokemon and positively regulated by Pokemon in hepatic cells. PMID- 23807509 TI - Colorectal carcinogenesis: a cellular response to sustained risk environment. AB - The current models for colorectal cancer (CRC) are essentially linear in nature with a sequential progression from adenoma through to carcinoma. However, these views of CRC development do not explain the full body of published knowledge and tend to discount environmental influences. This paper proposes that CRC is a cellular response to prolonged exposure to cytotoxic agents (e.g., free ammonia) as key events within a sustained high-risk colonic luminal environment. This environment is low in substrate for the colonocytes (short chain fatty acids, SCFA) and consequently of higher pH with higher levels of free ammonia and decreased mucosal oxygen supply as a result of lower visceral blood flow. All of these lead to greater and prolonged exposure of the colonic epithelium to a cytotoxic agent with diminished aerobic energy availability. Normal colonocytes faced with this unfavourable environment can transform into CRC cells for survival through epigenetic reprogramming to express genes which increase mobility to allow migration and proliferation. Recent data with high protein diets confirm that genetic damage can be increased, consistent with greater CRC risk. However, this damage can be reversed by increasing SCFA supply by feeding fermentable fibre as resistant starch or arabinoxylan. High protein, low carbohydrate diets have been shown to alter the colonic environment with lower butyrate levels and apparently greater mucosal exposure to ammonia, consistent with our hypothesis. Evidence is drawn from in vivo and in vitro genomic and biochemical studies to frame experiments to test this proposition. PMID- 23807512 TI - Laser speckle contrast imaging: theoretical and practical limitations. AB - When laser light illuminates a diffuse object, it produces a random interference effect known as a speckle pattern. If there is movement in the object, the speckles fluctuate in intensity. These fluctuations can provide information about the movement. A simple way of accessing this information is to image the speckle pattern with an exposure time longer than the shortest speckle fluctuation time scale-the fluctuations cause a blurring of the speckle, leading to a reduction in the local speckle contrast. Thus, velocity distributions are coded as speckle contrast variations. The same information can be obtained by using the Doppler effect, but producing a two-dimensional Doppler map requires either scanning of the laser beam or imaging with a high-speed camera: laser speckle contrast imaging (LSCI) avoids the need to scan and can be performed with a normal CCD- or CMOS-camera. LSCI is used primarily to map flow systems, especially blood flow. The development of LSCI is reviewed and its limitations and problems are investigated. PMID- 23807510 TI - Regulation of miRNA expression by low-level laser therapy (LLLT) and photodynamic therapy (PDT). AB - Applications of laser therapy, including low-level laser therapy (LLLT), phototherapy and photodynamic therapy (PDT), have been proven to be beneficial and relatively less invasive therapeutic modalities for numerous diseases and disease conditions. Using specific types of laser irradiation, specific cellular activities can be induced. Because multiple cellular signaling cascades are simultaneously activated in cells exposed to lasers, understanding the molecular responses within cells will aid in the development of laser therapies. In order to understand in detail the molecular mechanisms of LLLT and PDT-related responses, it will be useful to characterize the specific expression of miRNAs and proteins. Such analyses will provide an important source for new applications of laser therapy, as well as for the development of individualized treatments. Although several miRNAs should be up- or down-regulated upon stimulation by LLLT, phototherapy and PDT, very few published studies address the effect of laser therapy on miRNA expression. In this review, we focus on LLLT, phototherapy and PDT as representative laser therapies and discuss the effects of these therapies on miRNA expression. PMID- 23807513 TI - Fast, exact, and non-destructive diagnoses of contact failures in nano-scale semiconductor device using conductive AFM. AB - We fabricated a novel in-line conductive atomic force microscopy (C-AFM), which can analyze the resistive failures and examine process variance with an exact positioning capability across the whole wafer scale in in-line DRAM fabrication process. Using this in-line C-AFM, we introduced a new, non-destructive diagnosis for resistive failure in mobile DRAM structures. Specially, we focused on the self-aligned contact (SAC) process, because the failure of the SAC process is one of the dominant factors that induces the degradation of yield performance, and is a physically invisible defect. We successfully suggested the accurate pass mark for resistive-failure screening in the fabrication of SAC structures and established that the cause of SAC failures is the bottom silicon oxide layer. Through the accurate pass mark for the SAC process configured by the in-line C AFM analyses, we secured a good potential method for preventing the yield loss caused by failures in DRAM fabrication. PMID- 23807511 TI - First insights into the large genome of Epimedium sagittatum (Sieb. et Zucc) Maxim, a Chinese Ttaditional medicinal plant. AB - Epimedium sagittatum (Sieb. et Zucc) Maxim is a member of the Berberidaceae family of basal eudicot plants, widely distributed and used as a traditional medicinal plant in China for therapeutic effects on many diseases with a long history. Recent data shows that E. sagittatum has a relatively large genome, with a haploid genome size of ~4496 Mbp, divided into a small number of only 12 diploid chromosomes (2n = 2x = 12). However, little is known about Epimedium genome structure and composition. Here we present the analysis of 691 kb of high quality genomic sequence derived from 672 randomly selected plasmid clones of E. sagittatum genomic DNA, representing ~0.0154% of the genome. The sampled sequences comprised at least 78.41% repetitive DNA elements and 2.51% confirmed annotated gene sequences, with a total GC% content of 39%. Retrotransposons represented the major class of transposable element (TE) repeats identified (65.37% of all TE repeats), particularly LTR (Long Terminal Repeat) retrotransposons (52.27% of all TE repeats). Chromosome analysis and Fluorescence in situ Hybridization of Gypsy-Ty3 retrotransposons were performed to survey the E. sagittatum genome at the cytological level. Our data provide the first insights into the composition and structure of the E. sagittatum genome, and will facilitate the functional genomic analysis of this valuable medicinal plant. PMID- 23807514 TI - Three-dimensional MRI-linac intra-fraction guidance using multiple orthogonal cine-MRI planes. AB - The introduction of integrated MRI-radiation therapy systems will offer live intra-fraction imaging. We propose a feasible low-latency multi-plane MRI-linac guidance strategy. In this work we demonstrate how interleaved acquired, orthogonal cine-MRI planes can be used for low-latency tracking of the 3D trajectory of a soft-tissue target structure. The proposed strategy relies on acquiring a pre-treatment 3D breath-hold scan, extracting a 3D target template and performing template matching between this 3D template and pairs of orthogonal 2D cine-MRI planes intersecting the target motion path. For a 60 s free-breathing series of orthogonal cine-MRI planes, we demonstrate that the method was capable of accurately tracking the respiration related 3D motion of the left kidney. Quantitative evaluation of the method using a dataset designed for this purpose revealed a translational error of 1.15 mm for a translation of 39.9 mm. We have demonstrated how interleaved acquired, orthogonal cine-MRI planes can be used for online tracking of soft-tissue target volumes. PMID- 23807515 TI - Possibilities and limits of mind-reading: a neurophilosophical perspective. AB - Access to other minds once presupposed other individuals' expressions and narrations. Today, several methods have been developed which can measure brain states relevant for assessments of mental states without 1st person overt external behavior or speech. Functional magnetic resonance imaging and trace conditioning are used clinically to identify patterns of activity in the brain that suggest the presence of consciousness in people suffering from severe consciousness disorders and methods to communicate cerebrally with patients who are motorically unable to communicate. The techniques are also used non clinically to access subjective awareness in adults and infants. In this article we inspect technical and theoretical limits on brain-machine interface access to other minds. We argue that these techniques hold promises of important medical breakthroughs, open up new vistas of communication, and of understanding the infant mind. Yet they also give rise to ethical concerns, notably misuse as a consequence of hypes and misinterpretations. PMID- 23807516 TI - Effects of glycemia on immediate complications following CABG. AB - OBJECTIVE: We investigated the relationship between postoperative glucose levels (days 1 through 3) and immediate outcomes in patients who underwent isolated coronary artery bypass grafting (CABG). METHODS: We conducted a retrospective study of 2,558 consecutive patients who had isolated CABG. Patients were stratified into 3 groups based on their pre-operative mortality risk (MR), using Society of Thoracic Surgeons' criteria. Average glucose levels for the first 3 days following surgery were determined. Glucose levels for each group were divided into quartiles and related to relevant outcomes. Odds ratios assessing changes in outcomes as functions of increased glucose exposure were determined for postoperative days 1, 2, and 3 and for postoperative days 1 and 2 and 1 through 3. RESULTS: The number of patients in each MR group (1 through 3; low, medium, and high) was 1,233, 852, and 473, respectively. Mean +/- SD quartile glucose levels for days 1 and 2 were 133 +/- 8.2, 150.4 +/- 4.7, 167.2 +/- 6.89, and 205.9 +/- 24.9 mg/dL. The proportion of patients with a glucose level <70 mg/dL was 6.4%, <60 mg/dL was 2.7%, and <50 mg/dL was 1.1%. The most consistent and significant correlations between glucose quartiles and outcomes were observed for MR group 1, and they were most significant for the first 2 days following surgery. Glycemic control was not correlated with mortality, but it was correlated with total complications. CONCLUSION: Hyperglycemia during the first two days after CABG adversely affected total complications in patients who were in the low and medium MR groups, but it did not significantly affect hospital mortality. PMID- 23807517 TI - The role of temozolomide in the treatment of a patient with a pure silent pituitary somatotroph carcinoma. AB - OBJECTIVE: To describe a case of a pure silent somatotroph pituitary carcinoma. METHODS: We describe a 54-year-old female with a clinically nonfunctioning pituitary macroadenoma diagnosed 15 years earlier. RESULTS: The patient underwent transsphenoidal surgery and no visible tumor remnant was observed for 6 years. A magnetic resonance imaging (MRI) detected the recurrence of a 1.2 * 1.5 cm macroadenoma. The patient was submitted to conventional radiotherapy (4500 cGy), and the tumor volume remained stable for 7 years. Then, an MRI revealed a slight increase in tumor size, and 2 years later, a subsequent MRI detected a very large, invasive pituitary mass. The patient was resubmitted to transsphenoidal surgery, and the histopathological examination showed diffuse positivity for growth hormone (GH). The nadir GH level during an oral glucose tolerance test was 0.06 ng/mL, and the pre- and postoperative insulin like growth factor type I (IGF I) levels were within the normal range. Abdominal, chest, brain, and spine MRI showed multiple small and hypervascular liver and bone lesions suggestive of metastases. Liver biopsy confirmed metastasis of GH-producing pituitary carcinoma. The patient has been treated with temozolomide and zoledronic acid for 7 months and with octreotide long-acting release (LAR) for 4 months. The primary tumor and metastases are stable. CONCLUSION: Despite being an extremely rare event, pituitary carcinoma may develop several years after the successful treatment of even a silent GH-producing pituitary adenoma, which suggests that close long-term follow-up is necessary. PMID- 23807518 TI - Determination of nadir growth hormone concentration cutoff in patients with acromegaly. AB - OBJECTIVE: The purpose of this study was to define an appropriate nadir growth hormone (nGH) cutoff for patients with acromegaly in remission using the Access Ultrasensitive human growth hormone (hGH) assay (Beckman Coulter, Brea, CA). METHODS: This cross-sectional study included 55 acromegalic subjects and 41 healthy adult volunteers. All subjects underwent oral glucose tolerance testing (OGTT) for growth hormones (GHs). An optimal cutoff for nGH for patients with active disease versus those in remission was determined using receiver-operating curve analysis. RESULTS: The nGH of 0.53 ng/mL revealed a sensitivity of 97% (95% confidence interval [CI], 83-100%) and a specificity of 100% (95% CI, 82-100%). All 22 patients with acromegaly in remission suppressed GH to <1 ng/mL, 20/22 (91%) suppressed to <0.4 ng/mL, and 19/22 (86%) of subjects suppressed to <0.3 ng/mL (the maximum nGH measured in our healthy volunteer group). CONCLUSION: When using the Access Ultrasensitive hGH assay for OGTT, a cutoff of 0.53 ng/mL was found to most accurately differentiate patients with acromegaly in remission from those with active disease. PMID- 23807519 TI - Glycemic control and diabetic dyslipidemia in adolescents with type 2 diabetes. AB - OBJECTIVE: The incidence of type 2 diabetes mellitus (T2DM) is increasing at an alarming rate, especially in ethnic minorities, and T2DM is associated with significant comorbidities. The primary objective of this study was to assess glycemic control and cardiovascular risk outcomes in children with T2DM at 1 year after diagnosis. We also assessed whether insulin treatment at onset of diabetes is beneficial for overall outcome in those with elevated glycated hemoglobin (HbA1C). METHODS: A retrospective electronic chart review of non-Hispanic white (NHW) and African American (AA) children with T2DM. RESULTS: A total of 86 patients (66.3% females, 79.1% AA, mean age, 13.8 +/- 2.4 years) with T2DM were included. Analyses of therapeutic outcome measures at the 1-year follow-up showed HbA1C >8% in 27.7% of patients, low-density-lipoprotein cholesterol (LDL-C) >130 mg/dL in 12.5%, non-high-density-lipoprotein cholesterol (non-HDL-C) >160 mg/dL in 15.6%, HDL-C <35 mg/dL in 25%, systolic hypertension (HTN) in 35.6%, and diastolic HTN in 6.8% of subjects. Among those started on insulin at initial diagnosis, there was significant improvement in glycemic outcomes (P<.0001 on insulin vs. P = .02 not on insulin) and dyslipidemia (total cholesterol [TC] [P = .001], LDL-C [P = .02], HDL-C [P = .01], non-HDL-C [P = .0002], and TC/HDL-C [P = .005]) compared with no significant change among those who did not receive insulin at diagnosis. CONCLUSION: Substantial numbers of children with T2DM do not achieve glycemic and cardiovascular therapeutic goals 1 year after diagnosis. Insulin therapy at diagnosis has significant beneficial effects on diabetic dyslipidemia in those with higher HbA1C. PMID- 23807520 TI - Liraglutide as additional treatment to insulin in obese patients with type 1 diabetes mellitus. AB - OBJECTIVE: Because approximately 40% of patients with type 1 diabetes have the metabolic syndrome, we tested the hypothesis that addition of liraglutide to insulin in obese patients with type 1 diabetes will result in an improvement in plasma glucose concentrations, a reduction in hemoglobin A1c (HbA1c), a fall in systolic blood pressure, and weight loss. METHODS: This is a retrospective analysis of data obtained from 27 obese patients with type 1 diabetes treated with liraglutide in addition to insulin. Patients were also treated for hypertension. Paired t tests were used to compare the changes in HbA1c, insulin doses, body weight, body mass index, 4-week mean blood glucose concentrations (28 day insulin pump mean blood glucose), blood pressure, and lipid parameters prior to and 180 +/- 14 days after liraglutide therapy. RESULTS: Mean glucose concentrations fell from 191 +/- 6 to 170 +/- 6 mg/dL (P = .002). HbA1c fell from 7.89 +/- 0.13% to 7.46 +/- 0.13% (P = .001), without an increase in frequency of hypoglycemia. Mean body weight fell from 96.20 +/- 3.68 kg to 91.56 +/- 3.78 kg (P<.0001). Daily total and bolus doses of insulin fell from 73 +/- 6 to 60 +/- 4 (P = .008) units and from 40 +/- 5 to 29 +/- 3 units (P = .011), respectively. Mean systolic blood pressure fell from 130 +/- 3 to 120 +/- 4 mm Hg (P = .020). CONCLUSION: Addition of liraglutide to insulin in obese patients with type 1 diabetes mellitus leads to improvements in glycemic control and HbA1c and to reductions in insulin dose, systolic blood pressure, and body weight. PMID- 23807521 TI - Impact of a hyperglycemic crises protocol. AB - OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of an adult hyperglycemic crises protocol based upon the 2009 American Diabetes Association (ADA) consensus statement. METHODS: We performed a retrospective review of patients treated before and after protocol implementation at a university teaching hospital. A total of 256 adult patients met the criteria for diabetic ketoacidosis (DKA) or hyperosmolar hyperglycemic state (HHS) and were treated with an insulin infusion between February 2011 and February 2012 (nonprotocol n = 143, protocol n = 113). Protocol efficacy was evaluated by assessing time to resolution of DKA or HHS, length of stay (LOS) in the intensive care unit (ICU), and LOS in the hospital. Protocol safety was evaluated by assessing the numbers of patients with hypoglycemic and hypokalemic events. RESULTS: Patients on the hyperglycemic crises protocol experienced a 9.2 hour (95% confidence interval (CI): 4.70-13.70; P<.001) decrease in time to resolution, with nonprotocol patients (n = 143) resolving in 22.78 hours and protocol patients (n = 113) resolving in 13.58 hours. There was no difference in safety outcomes, including the number of patients with moderate hypoglycemia (blood glucose <70 mg/dL), severe hypoglycemia (blood glucose <50 mg/dL), or hypokalemia (K+ <3.3 mmol/L). CONCLUSION: Implementation of a hyperglycemic crises protocol decreased times to resolution of DKA and HHS without increasing the rate of hypoglycemia or hypokalemia. PMID- 23807522 TI - Nicotine-substitute gum-induced milk alkali syndrome: a look at unexpected sources of calcium. AB - OBJECTIVE: This report describes a 64-year-old woman with recurrent hypercalcemia. Her laboratory evaluation was consistent with milk-alkali syndrome. It was eventually discovered that the source of the excessive calcium consumption was nicotine-replacement chewing gum and carbonated water. METHODS: An extensive literature search was performed to see if milk-alkali syndrome due to nicotine-replacement gum and carbonated water has been previously reported. RESULTS: No prior report describing the association of milk alkali syndrome with nicotine-replacement gum and carbonated water was found. CONCLUSION: We present a unique case of milk-alkali syndrome due to nicotine-replacement gum and carbonated water. It serves as a lesson to evaluate other sources besides calcium supplements as the cause of excessive calcium intake. PMID- 23807523 TI - Effects of amiodarone, thyroid hormones and CYP2C9 and VKORC1 polymorphisms on warfarin metabolism: a review of the literature. AB - OBJECTIVE: To review the literature regarding the interaction among amiodarone therapy, thyroid hormone levels, and warfarin metabolism. METHODS: A 73-year-old male with type 2 after describing an unusual case of amiodarone-induced thyrotoxicosis (AIT) who experienced a severe rise in international normalized ratio (INR) values after initiating warfarin therapy due to an unusual combination of excessive thyroid hormones, amiodarone therapy, and a genetic abnormality affecting warfarin metabolism. RESULTS: Genetic analysis revealed that the patient was CYP2C9*2 wild-type, CYP2C9*3/*3 homozygous mutant, and VKORC1*3/*3 homozygous mutant. A review of the literature revealed that both mutations can independently affect warfarin metabolism. In addition, amiodarone therapy and the presence of thyrotoxicosis per se can affect warfarin metabolism and reduce the dose needed to maintain INR in the therapeutic range. The association of the 2 genetic polymorphisms in a patient with AIT is extremely rare and strongly impairs warfarin metabolism, exposing the patient to a high risk of overtreatment. CONCLUSIONS: In patients with AIT, warfarin therapy should be gradually introduced, starting with a very low dose, because of the significant risk of warfarin overtreatment. Whether the genetic analysis of CYP2C9 and VKORC1 polymorphisms should be routinely performed in AIT patients remains conjectural. PMID- 23807524 TI - Hormone replacement therapy in children with hypogonadotropic hypogonadism: where do we stand? AB - OBJECTIVE: To characterize hormone replacement therapy in a cohort of adolescent males and females with hypogonadotropic hypogonadism (HH) with a focus on changes in management during the past 10 years. METHODS: Medical records of patients followed for HH during the past 10 years were reviewed. RESULTS: A total of 45 patients (22 female: 23 male) with HH were identified. The average age at HH diagnosis was 14.48 +/- 2.02 years in females and 14.89 +/- 1.64 years in males (P = .53). In females, the average age of pubertal induction was 14.53 +/- 1.86 years. Conjugated equine estrogen was used in 54.5%, transdermal estradiol in 41%, and oral estradiol in 4.5%. The average duration to cycling was 1.96 +/- 0.78 years. A progressive increase in the use of transdermal estradiol was noted over time, with 100% of females being started on this regimen since 2008. In males, the average age of induction was 15.22 +/- 1.41 years. All were started on intramuscular testosterone cypionate at various doses. The average duration to full adult replacement was 1.95 +/- 0.51 years. CONCLUSION: There is no current standard of care to guide pubertal induction in adolescents with HH. However, a significant increase in the use of transdermal estrogen was noted in females during the past 10 years. While much less variability in pubertal induction was seen in males, wide disparities in doses and escalation schedules were found. Prospective studies aimed at elucidating optimal strategies for sex steroid replacement in this pediatric population are badly needed. PMID- 23807525 TI - Risks and benefits of estrogen therapy for a male-to-female transsexual with a prothrombin gene mutation. AB - OBJECTIVE: We present the case of a male-to-female transsexual person in her 20s requesting hormone therapy in the setting of a history of a deep venous thrombosis and pulmonary embolus and carrying the prothrombin G20210A gene mutation. METHODS: We interviewed the patient and reviewed her medical records. We carefully weighed the risks and benefits of hormone therapy and took into account two important ethical principles: beneficence (to act in the patient's best interest) and nonmaleficence (to avoid harm). RESULTS: Our patient presented to an outside facility with weight loss, generalized weakness, right lower extremity swelling, and chest pain. She was diagnosed with a pulmonary embolus and extensive deep venous thrombus by computed tomography (CT) scan and Doppler ultrasound, respectively. She was found to carry the prothrombin G20210A gene mutation. She was treated with anticoagulation therapy for 12 months, which was restarted prior to beginning therapy with transdermal estrogen. CONCLUSION: While the exact risk of recurrent deep venous thrombosis and pulmonary embolus in our patient is unknown, we recommended that hormone therapy should only be given in conjunction with anticoagulation. We speculate that this strategy would allow the patient to experience the benefits to her overall well-being with hormone therapy while reducing the risks of venous thrombosis to acceptable levels. Prospective long-term follow-up of this patient is needed to verify the benefits and risk of the intervention chosen. PMID- 23807526 TI - Health care transition in young adults with type 1 diabetes: barriers to timely establishment of adult diabetes care. AB - OBJECTIVE: To examine barriers to health care transition reported by young adults with type 1 diabetes and associations between barriers and prolonged gaps between pediatric and adult diabetes care. METHODS: We surveyed young adults aged 22 to 30 years with type 1 diabetes about their transition experiences, including barriers to timely establishment of adult diabetes care. We evaluated relationships between barriers and gaps in care using multivariate logistic regression. RESULTS: The response rate was 53% (258 of 484 eligible subjects). Respondents (62% female) were 26.7 +/- 2.4 years old and transitioned to adult diabetes care at 19.5 +/- 2.9 years. Reported barriers included lack of specific adult provider referral name (47%) or contact information (27%), competing life priorities (43%), difficulty getting an appointment (41%), feeling upset about leaving pediatrics (24%), and insurance problems (10%). In multivariate analysis, barriers most strongly associated with gaps in care >6 months were lack of adult provider name (odds ratio [OR], 6.1; 95% confidence interval [CI], 3.0-12.7) or contact information (OR, 5.3; 95% CI, 2.0-13.9), competing life priorities (OR, 5.2; 95% CI, 2.7-10.3), and insurance problems (OR, 3.5; 95% CI, 1.2-10.3). Overall, respondents reporting >=1 moderate/major barrier (48%) had 4.7-fold greater adjusted odds of a gap in care >6 months (95% CI, 2.8-8.7). CONCLUSION: Significant barriers to transition, such as a lack of specific adult provider referrals, may be addressed with more robust preparation by pediatric providers and care coordination. Further study is needed to evaluate strategies to improve young adult self-care in the setting of competing life priorities. PMID- 23807527 TI - Iatrogenic Cushing syndrome in patients receiving inhaled budesonide and itraconazole or ritonavir: two cases and literature review. AB - OBJECTIVE: To present two cases of iatrogenic Cushing syndrome caused by the interaction of budesonide, an inhaled glucocorticoid, with ritonavir and itraconazole. METHODS: We present the clinical and biochemical data of two patients in whom diagnosis of Cushing syndrome was caused by this interaction. We also reviewed the pertinent literature and management options. RESULTS: A 71-year old man was treated with inhaled budesonide for a chronic obstructive pulmonary disease and itraconazole for a pulmonary aspergillosis. The patient rapidly developed a typical Cushing syndrome complicated by bilateral avascular necrosis of the femoral heads. Serum 8:00 AM cortisol concentrations were suppressed at 0.76 and 0.83 MUg/dL on two occasions. The patient died 4 days later of a massive myocardial infarction. The second case is a 46-year-old woman who was treated for several years with inhaled budesonide for asthma. She was put on ritonavir, a retroviral protease inhibitor, for the treatment of human immunodeficiency virus (HIV). In the following months, she developed typical signs of Cushing syndrome. Her morning serum cortisol concentration was 1.92 MUg/dL. A cosyntropin stimulation test showed values of serum cortisol of <1.10, 2.65, and 5.36 MUg/dL at 0, 30, and 60 minutes, respectively, confirming an adrenal insufficiency. Because the patient was unable to stop budesonide, she was advised to reduce the frequency of its administration and eventually taper the dose until cessation. CONCLUSION: Clinicians should be aware of the potential occurrence of iatrogenic Cushing syndrome and secondary adrenal insufficiency due to the association of inhaled corticosteroids with itraconazole or ritonavir. PMID- 23807528 TI - Efficacy and safety of adding pioglitazone or sitagliptin to patients with type 2 diabetes insufficiently controlled with metformin and a sulfonylurea. AB - OBJECTIVE: To evaluate the efficacy and safety of add-on pioglitazone versus sitagliptin in patients with type 2 diabetes inadequately controlled on metformin and a sulfonylurea (SU). METHODS: This 24-week, randomized, open-label study compared pioglitazone (30 mg daily, n = 59) and sitagliptin (100 mg daily, n = 60) in patients with inadequate glycemic control (glycosylated hemoglobin [HbA1c] >=7.0% to <11.0%) while receiving a stable dose of metformin (>=1,500 mg daily) and an SU (>=half-maximal dose). RESULTS: The mean changes in HbA1c from baseline was -0.94 +/- 0.12% with pioglitazone and -0.71 +/- 0.12% with sitagliptin, for a between-groups difference of -0.23 +/- 0.16% (P = .16). The mean change in fasting plasma glucose (FPG) were -35.7 +/- 4.0 mg/dL with pioglitazone and -22.8 +/- 4.0 mg/dL with sitagliptin, for a between-groups difference of -12.9 +/- 5.7 mg/dL (P = .02). Pioglitazone was associated with a significant decrease in high sensitive C-reactive protein (hs-CRP), but sitagliptin did not. The mean weight gain was higher in the pioglitazone group, with a between-group difference of 1.6 kg (P<.01). Overall adverse events (AEs) were similar in both groups. However, the incidence of edema was higher with pioglitazone, and the incidence of gastrointestinal AEs was higher with sitagliptin. CONCLUSION: Pioglitazone and sitagliptin achieved similar improvements in overall glycemic control in patients with type 2 diabetes inadequately controlled with metformin and an SU. However there were some differences in terms of FPG, hs-CRP, lipids, body-weight change, and AEs. PMID- 23807529 TI - Antiretroviral lipodystrophy of the forehead. PMID- 23807530 TI - AACE Comprehensive Diabetes Management Algorithm 2013. Endocrine Practice. PMID- 23807531 TI - Effects of different dosages of parathyroid hormone-related protein 1-34 on the bone metabolism of the ovariectomized rat model of osteoporosis. AB - Intermittent and low-dose parathyroid hormone (PTH) injection to stimulate bone formation has been used in the treatment of osteoporosis. The N-terminal fragment 1-34 of PTH is quite similar in structure and function to N-terminal PTH-related protein (PTHrP). PTH(1-34) and PTHrP also share a coreceptor, the PTH/PTHrP receptor. Therefore, some studies have suggested that PTHrP could effectively stimulate bone formation, similar to PTH. We used an ovariectomized (OVX) rat model of osteoporosis to study the effects of PTHrP(1-34) on bone metabolism by measuring bone mineral density (BMD), bone histomorphometrics, and biomechanical parameters. We found that subcutaneous injection of PTHrP(1-34) (40 or 80 MUg/kg body weight every day) in OVX rats increased lumbar and femoral BMD, improved bone biomechanical properties, enhanced bone strength, and promoted bone formation. We selected 40 MUg/kg as the preferred therapeutic dose of PTHrP(1-34) and investigated the effects of frequency of treatment (per 1, 2, 3, or 7 days) on bone metabolism in OVX rats. We found that injection of PTHrP(1-34) once per day or every other day significantly improved the BMD and strength of OVX rats. Serum calcium and phosphate levels in all treated rats did not vary significantly from control rats. Based on our results, intermittent low-dose PTHrP(1-34) injection promoted bone formation in OVX rats, suggesting a high potential for therapeutic use in osteoporosis patients. PMID- 23807532 TI - [New aspects of treatment of the severely injured. Report on the second annual conference of the Committee on Emergency Medicine, Intensive Care and Trauma Management (Sektion NIS)]. PMID- 23807533 TI - Fabrication of curled conducting polymer microfibrous arrays via a novel electrospinning method for stretchable strain sensors. AB - Stretchable strain sensors based on aligned microfibrous arrays of poly(3,4 ethylenedioxythiophene):poly(styrene sulfonate)-poly(vinyl pyrrolidone) (PEDOT:PSS-PVP) with curled architectures have been fabricated by a novel reciprocating-type electrospinning setup with a spinneret in straightforward simple harmonic motion. The incorporation of PEDOT:PSS into PVP is confirmed by Raman spectra, which improves the room-temperature conductivity of the composite fibers (1.6 * 10(-5) S cm(-1)). Owing to the curled architectures of the as-spun fibrous polymer arrays, the sensors can be stretched reversibly with a linear elastic response to strain up to 4%, which is three times higher than that from electrospun nonwoven mats. In addition, the stretchable strain sensor with a high repeatability and durability has a gauge factor of about 360. These results may be helpful for the fabrication of stretchable devices which have potential applications in some fields such as soft robotics, elastic semiconductors, and elastic solar cells. PMID- 23807534 TI - Does health promote economic growth? Portuguese case study: from dictatorship to full democracy. AB - This paper revisits the debate on health and economic growth (Deaton in J Econ Lit 51:113-158, 2003) focusing on the Portuguese case by testing the relationship between growth and health. We test Portuguese insights, using time series data from 1960 to 2005, taking into account different variables (life expectancy, labour, capital, infant mortality) and considering the years that included major events on the political scene, such as the dictatorship and a closed economy (1960-1974), a revolution (1974) and full democracy and an open economy (1975 2005), factors that influence major economic, cultural, social and politic indicators. Therefore the analysis is carried out adopting Lucas' (J Monet Econ 22(1):3-42, 1988) endogenous growth model that considers human capital as one factor of production, it adopts a VAR (vector autoregressive) model to test the causality between growth and health. Estimates based on the VAR seem to confirm that economic growth influences the health process, but health does not promote growth, during the period under study. PMID- 23807535 TI - The therapeutic effects of bone marrow-derived mesenchymal stem cells and simvastatin in a rat model of liver fibrosis. AB - Liver fibrosis is the excessive accumulation of extracellular matrix (ECM) proteins including collagen that occurs in most types of chronic liver diseases. Studies concerning the capacity of mesenchymal stem cells (MSCs) and simvasatain (SIMV) to repair fibrotic tissues through reducing inflammation, collagen deposition, are still controversial. This study aimed to investigate the therapeutic efficacy of bone marrow (BM)-derived MSCs and SIMV on carbon tetrachloride (CCl4)-induced liver fibrosis in rats. Rats were divided into: normal, CCl4, CCl4/MSCs, CCl4/SIMV, CCl4/MSCs/SIMV, and SIMV groups. BM-derived MSCs were detected by RT-PCR of CD29 and were then infused into the tail vein of female rats that received CCl4 injection to induce liver fibrosis. Sex determining region Y (SRY) gene on Y-chromosome gene was assessed by PCR to confirm homing of the male stem cells in liver tissue of the female recipients. Serum liver function tests, liver procollagens I and III, tissue inhibitors of metalloproteinase-1 (TIMP-1), endoglin, matrix metalloproteinase-1 (MMP-1) gene expressions, transforming growth factor-beta (TGF-beta1) immunostaining, and histopathologicl examination were performed. MSCs and SIMV decreased liver procollagens I and III, TIMP-1 and endoglin gene expressions, TGF-beta1 immunostaining, and serum liver function tests compared with the CCl4 group. MMP 1 expression was increased in the CCl4/MSCs group. Histopathological examination as well as fibrosis score supports the biochemical and molecular findings. It can be concluded that MSCs and SIMV were effective in the treatment of hepatic CCl4 induced fibrosis-rat model. Treatment with MSCs was superior to SIMV. This antifibrotic effect can be attributed to their effect on the MMPs/TIMPs balance which is central in fibrogenesis. PMID- 23807537 TI - Macrocycle synthesis by trimerization of boronic acids around a hexaol template, and recognition of polyols by resulting macrocyclic oligoboronic acids. AB - 2,6-Bis(alkenyloxy) substituted arylboronic acids can be cyclotrimerized with the help of a hexaol as a template. First, the boronic acids are assembled by boronic ester formation with hexahydroxy-bicyclo[2.2.2]octane. Next, the resulting triboronates are cyclized by ring-closing metathesis to yield trimacrocycles as diastereomeric E/Z mixtures. Catalytic hydrogenation yields a single saturated trimacrocycle. Cleavage of the boronic ester functions liberates the template and generates a macrocycle with three boronic acid functionalities in endo orientation. Due to this preorganization, macrocycles with boronic acids in endo positions are good receptors for polyols. The binding of carbohydrates such as fructose was compared with the uptake of the respective templates into macrocycles with two or three boronic acids in endo-orientation. PMID- 23807536 TI - Copy number variation of transposable elements in Triticum-Aegilops genus suggests evolutionary and revolutionary dynamics following allopolyploidization. AB - KEY MESSAGE: Here, we report on copy number variation of transposable elements and on the genome-specific proliferation in wheat. In addition, we report on revolutionary and evolutionary dynamics of transposons. Wheat is a valuable model for understanding the involvement of transposable elements (TEs) in speciation as wheat species (Triticum-Aegilops group) have diverged from a common ancestor, have undergone two events of speciation through allopolyploidy, and contain a very high fraction of TEs. However, an unbiased genome-wide examination of TE variation among these species has not been conducted. Our research utilized quantitative real time PCR to assess the relative copy numbers of 16 TE families in various Triticum and Aegilops species. We found (1) high variation and genome specificity of TEs in wheat species, suggesting they were active throughout the evolution of wheat, (2) neither Ae. searsii nor Ae. speltoides by themselves can be the only contributors of the B genome to wheat, and (3) nonadditive changes in TE quantities in polyploid wheat. This study indicates the apparent involvement of large TEs in creating genetic variation in revolutionary and evolutionary scales following allopolyploidization events, presumably assisting in the diploidization of homeologous chromosomes. PMID- 23807538 TI - A comparison of the EQ-5D-3L and ICECAP-O in an older post-acute patient population relative to the general population. AB - BACKGROUND: The measurement and valuation of quality of life forms a major component of economic evaluation in health care and is a major issue in health services research. However, differing approaches exist in the measurement and valuation of quality of life from a health economics perspective. While some instruments such as the EQ-5D-3L focus on health-related quality of life alone, others assess quality of life in broader terms, for example, the newly developed ICECAP-O. OBJECTIVE: The aim of this study was to utilize two generic preference based instruments, the EQ-5D-3L and the ICECAP-O, to measure and value the quality of life of older adult patients receiving post-acute care. An additional objective was to compare the values obtained by each instrument with those generated from two community-based general population samples. METHOD: Data were collected from a clinical patient population of older adults receiving post-acute outpatient rehabilitation or residential transition care and two Australian general population samples of individuals residing in the general community. The individual responses to the ICECAP-O and EQ-5D-3L instruments were scored using recently developed Australian general population algorithms. Empirical comparisons were made of the resulting patient and general population sample values for the total population and dis-aggregated according to age (65-79 and 80+ years) and gender. RESULTS: A total of 1,260 participants aged 65-99 years (n = 86 clinical patient sample, n = 385 EQ-5D-3L general population sample, n = 789 ICECAP-O general population sample) completed one or both of the EQ-5D-3L and ICECAP-O instruments. As expected, the patient group demonstrated lower quality of life than the general population sample as measured by both quality-of-life instruments. The difference in values between the patient and general population groups was found to be far more pronounced for the EQ-5D-3L than for the ICECAP O. The ICECAP-O was associated with a mean difference in values of 0.04 (patient group mean 0.753, SD 0.18; general population group mean 0.795, SD 0.17, respectively, p = 0.033). In contrast, the EQ-5D-3L was associated with a mean difference in values of 0.19 (patient group mean 0.595, SD 0.20; general population group mean 0.789, SD 0.02, respectively, p <= 0.001). CONCLUSIONS: The study findings illustrate the magnitude of the difference in patient and general population values according to the instrument utilized, and highlight the differences in both the theoretical underpinnings and valuation algorithms for the EQ-5D-3L and ICECAP-O instruments. Further empirical work is required in larger samples and alternative patient groups to investigate the generalizability of the findings presented here. PMID- 23807539 TI - A practical approach for calculating reliable cost estimates from observational data: application to cost analyses in maternal and child health. AB - BACKGROUND: Comparative effectiveness research (CER) and cost-effectiveness analysis are valuable tools for informing health policy and clinical care decisions. Despite the increased availability of rich observational databases with economic measures, few researchers have the skills needed to conduct valid and reliable cost analyses for CER. OBJECTIVE: The objectives of this paper are to (i) describe a practical approach for calculating cost estimates from hospital charges in discharge data using publicly available hospital cost reports, and (ii) assess the impact of using different methods for cost estimation in maternal and child health (MCH) studies by conducting economic analyses on gestational diabetes (GDM) and pre-pregnancy overweight/obesity. METHODS: In Florida, we have constructed a clinically enhanced, longitudinal, encounter-level MCH database covering over 2.3 million infants (and their mothers) born alive from 1998 to 2009. Using this as a template, we describe a detailed methodology to use publicly available data to calculate hospital-wide and department-specific cost to-charge ratios (CCRs), link them to the master database, and convert reported hospital charges to refined cost estimates. We then conduct an economic analysis as a case study on women by GDM and pre-pregnancy body mass index (BMI) status to compare the impact of using different methods on cost estimation. RESULTS: Over 60 % of inpatient charges for birth hospitalizations came from the nursery/labor/delivery units, which have very different cost-to-charge markups (CCR = 0.70) than the commonly substituted hospital average (CCR = 0.29). Using estimated mean, per-person maternal hospitalization costs for women with GDM as an example, unadjusted charges ($US14,696) grossly overestimated actual cost, compared with hospital-wide ($US3,498) and department-level ($US4,986) CCR adjustments. However, the refined cost estimation method, although more accurate, did not alter our conclusions that infant/maternal hospitalization costs were significantly higher for women with GDM than without, and for overweight/obese women than for those in a normal BMI range. CONCLUSIONS: Cost estimates, particularly among MCH-related services, vary considerably depending on the adjustment method. Our refined approach will be valuable to researchers interested in incorporating more valid estimates of cost into databases with linked hospital discharge files. PMID- 23807540 TI - Human erythropoietin increases the pro-angiogenic potential of A2780 ovarian adenocarcinoma cells under hypoxic conditions. AB - Erythropoietin (Epo) is a key regulator of erythroid cell proliferation, differentiation and apoptosis. In the form of the recombinant protein, it is widely used to treat various types of anemias, including that associated with cancer and with the myelosuppressive effects of chemotherapy, particularly platinum-based regimens. Our previous studies confirmed the presence of Epo receptors (EpoRs) in ovarian adenocarcinoma cell lines and demonstrated that long term Epo treatment of A2780 cells resulted in the development of a phenotype exhibiting both enhanced Epo signaling and increased paclitaxel resistance. In the present study, we carried out a series of experiments to analyze the pro angiogenic potential of Epo-treated A2780 and SKOV-3 cells. Our studies revealed that conditioned media of Epo-treated A2780 cells had a stimulative effect on human umbilical vein endothelial cells (HUVECs). This effect was only seen when A2780 cells were incubated under hypoxic conditions. Furthermore, Epo increased the secretion of interleukin (IL)-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, GM CSF and interferon-gamma by A2780 cells that grew in hypoxic conditions. In this regard, conditioned media of hypoxic and Epo-treated A2780 cells induced a significant phosphorylation of STAT-5 in HUVECs. Our results may have important implications for ovarian cancer patients receiving Epo. PMID- 23807542 TI - Homo- and heterobinuclear Cu2+ and Zn2+ complexes of abiotic cyclic hexaazapyridinocyclophanes as SOD mimics. AB - The new receptor 3,7,11,15,19,23-hexaaza-1(2,6)-pyridinacyclotetracosaphane (L1) containing a complete sequence of propylenic chains has been synthesised. The acid-base behaviour and Cu2+ and Zn2+ coordination have been analysed by potentiometric measurements in 0.15 M NaClO4 for L1 and for the related compounds 3,7,11,14,18,22-hexaaza-1(2,6)-pyridinacyclotricosaphane (L2), 3,7,10,13,16,20 hexaaza-1(2,6)-pyridinacycloheneicosaphane (L3) and 3,7,10,12,15,19-hexaaza 1(2,6)-pyridinacycloicosaphane (L4). The crystal structure of [(CuH4L2)(H2O)(ClO4)](ClO4)5.3H2O shows an interesting combination of a metal ion coordinated by the pyridine nitrogen atom and the adjacent amine groups of the chain, and a perchlorate anion sitting at the middle of the site defined by the remaining four protonated ammonium groups of L1. Paramagnetic NMR data suggest that imidazole coordinates to the Cu2+ ions as a bridging ligand in a wide pH range. SOD activity for Cu2+-Cu2+ and Cu2+-Zn2+ complexes with L1-L4 have been measured by NBT assays at pH 7.4, obtaining some of the lowest values so far reported for SOD mimics. SOD activity has also been checked by chemiluminescence assays using polymorphonuclear leukocytes (PMNLs). PMID- 23807541 TI - Changes of placental syndecan-1 expression in preeclampsia and HELLP syndrome. AB - Preeclampsia is characterized by maternal systemic anti-angiogenic and pro inflammatory states. Syndecan-1 is a cell surface proteoglycan expressed by the syncytiotrophoblast, which plays an important role in angiogenesis and resolution of inflammation. Our aim was to examine placental syndecan-1 expression in preeclampsia with or without hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. Placentas were obtained from women in the following groups: (1) late-onset preeclampsia (n = 8); (2) early-onset preeclampsia without (n = 7) and (3) with HELLP syndrome (n = 8); (4) preterm controls (n = 5); and (5) term controls (n = 9). Tissue microarrays (TMAs) were constructed from paraffin-embedded placentas. TMA slides were immunostained for syndecan-1 and evaluated using microscopy, virtual microscopy, and semi-automated image analysis. Maternal sera from patients with preeclampsia (n = 49) and controls (n = 32) were immunoassayed for syndecan-1. BeWo cells were treated with Forskolin or Latrunculin B or kept in ischemic conditions. SDC1 expression and syndecan-1 production were investigated with qRT-PCR, confocal microscopy, and immunoassays. Syndecan-1 was localized to the syncytiotrophoblast apical membrane in normal placentas. Syndecan-1 immunoscores were higher in late-onset preeclampsia (p = 0.0001) and early-onset preeclampsia with or without HELLP syndrome (p = 0.02 for both) than in controls. Maternal serum syndecan-1 concentration was lower in preeclampsia (median, 673 ng/ml; interquartile range, 459-1,161 ng/ml) than in controls (1,158 ng/ml; 622-1,480 ng/ml). SDC1 expression and syndecan-1 immunostainings in BeWo cells and syndecan-1 concentrations in supernatants increased during cell differentiation. Disruption of the actin cytoskeleton with Latrunculin B decreased syndecan-1 release, while ischemic conditions increased it. Syncytiotrophoblastic syndecan-1 expression depends on the differentiation of villous trophoblasts, and trophoblastic syndecan-1 release is decreased in preeclampsia and HELLP syndrome. This phenomenon may be related to the disturbed syncytiotrophoblastic cortical actin cytoskeleton and associated with maternal anti-angiogenic and pro-inflammatory states in these syndromes. PMID- 23807543 TI - Pyrosequencing analysis of EGFR and KRAS mutations in EUS and EBUS-derived cytologic samples of adenocarcinomas of the lung. AB - INTRODUCTION: Patients with stage IV non-small-cell lung cancer harboring an activating epidermal growth factor receptor (EGFR) mutation are eligible for treatment with EGFR tyrosine kinase inhibitors. With pyrosequencing, low frequency mutations may be detected more easily even in small diagnostic samples like endoscopic ultrasound-guided fine needle aspirations (EUS-FNA) and endobronchial ultrasound-guided transbronchial needle aspirations (EBUS-TBNA). The diagnostic performance of pyrosequencing in analyzing cytological specimens is compared with the routinely used high-resolution melting (HRM) and Sanger sequencing. METHODS: Patients diagnosed with adenocarcinoma of the lung were selected from a fine needle aspiration and transbronchial needle aspiration specimen database. If formalin-fixed paraffin-embedded tumor blocks were available, mutation analysis was performed for EGFR and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog genes using both pyrosequencing and HRM. When HRM showed abnormalities, Sanger sequencing was used. RESULTS: A total of 126 samples were available for mutation analysis. The analysis success rate for pyrosequencing and HRM were 97% and 93%, respectively. HRM failures were observed in fragmented DNA showing chains of 100 to 200 bp. A significant correlation between length of DNA fragments (100-300 bp versus 300-400 bp) and mean sample age (797 versus 317 days) was found (p < 0.0001), suggesting an influence of sample age on DNA quality. CONCLUSION: Pyrosequencing on cytological blocks, especially older tumor blocks, is feasible with a high diagnostic success rate. Failures in HRM were observed in DNA samples with short fragments related to longer storage times. PMID- 23807544 TI - "Not Just Right Experiences" in adolescents: phenomenology and associated characteristics. AB - Efforts to understand the nature of "Not Just Right Experiences" (NJREs) have expanded the scientific understanding of obsessive-compulsive (OC) behavior. Approximately 80% of unselected adults report experiencing NJREs and these experiences have been found to highly correlate with OC behavior. The purpose of this study was to assess NJREs in an unselected sample of adolescents (ages 14 17; N = 152), to compare their experience with adults (N = 237), and to assess the relation between NJREs and OC symptoms. Findings from questionnaires completed on the Internet were consistent with previous findings in adults, 81% of adolescents endorsed recently having an NJRE. Some reactions differed according to age: adults reported NJREs as more frequent and adolescents endorsed feeling more compelled to respond. Surprisingly, OC symptoms were not significantly related to NJREs in the adolescents. Implications, limitations, and future directions for the study of NJREs in youth are discussed. PMID- 23807545 TI - Interpreting the possible ecological role(s) of cyanotoxins: compounds for competitive advantage and/or physiological aide? AB - To date, most research on freshwater cyanotoxin(s) has focused on understanding the dynamics of toxin production and decomposition, as well as evaluating the environmental conditions that trigger toxin production, all with the objective of informing management strategies and options for risk reduction. Comparatively few research studies have considered how this information can be used to understand the broader ecological role of cyanotoxin(s), and the possible applications of this knowledge to the management of toxic blooms. This paper explores the ecological, toxicological, and genetic evidence for cyanotoxin production in natural environments. The possible evolutionary advantages of toxin production are grouped into two main themes: That of "competitive advantage" or "physiological aide". The first grouping illustrates how compounds produced by cyanobacteria may have originated from the need for a cellular defence mechanism, in response to grazing pressure and/or resource competition. The second grouping considers the contribution that secondary metabolites make to improved cellular physiology, through benefits to homeostasis, photosynthetic efficiencies, and accelerated growth rates. The discussion also includes other factors in the debate about possible evolutionary roles for toxins, such as different modes of exposures and effects on non-target (i.e., non-competitive) species. The paper demonstrates that complex and multiple factors are at play in driving evolutionary processes in aquatic environments. This information may provide a fresh perspective on managing toxic blooms, including the need to use a "systems approach" to understand how physico-chemical conditions, as well biological stressors, interact to trigger toxin production. PMID- 23807547 TI - Nepheliosyne B, a new polyacetylenic acid from the new caledonian marine sponge Niphates sp. AB - A new C47 polyoxygenated acetylenic acid, nepheliosyne B (2), along with the previously described nepheliosyne A (1), have been isolated from the New Caledonian marine sponge Niphates sp. Their structures have been elucidated on the basis of extensive spectroscopic analyses. These metabolites exhibited a moderate cytotoxicity against K562, U266, SKM1, and Kasumi cancer cell lines. PMID- 23807546 TI - Alternative sources of n-3 long-chain polyunsaturated fatty acids in marine microalgae. AB - The main source of n-3 long-chain polyunsaturated fatty acids (LC-PUFA) in human nutrition is currently seafood, especially oily fish. Nonetheless, due to cultural or individual preferences, convenience, geographic location, or awareness of risks associated to fatty fish consumption, the intake of fatty fish is far from supplying the recommended dietary levels. The end result observed in most western countries is not only a low supply of n-3 LC-PUFA, but also an unbalance towards the intake of n-6 fatty acids, resulting mostly from the consumption of vegetable oils. Awareness of the benefits of LC-PUFA in human health has led to the use of fish oils as food supplements. However, there is a need to explore alternatives sources of LC-PUFA, especially those of microbial origin. Microalgae species with potential to accumulate lipids in high amounts and to present elevated levels of n-3 LC-PUFA are known in marine phytoplankton. This review focuses on sources of n-3 LC-PUFA, namely eicosapentaenoic and docosahexaenoic acids, in marine microalgae, as alternatives to fish oils. Based on current literature, examples of marketed products and potentially new species for commercial exploitation are presented. PMID- 23807548 TI - Counteraction by nitric oxide synthase inhibitor of neurochemical alterations of dopaminergic system in 6-OHDA-lesioned rats under L-DOPA treatment. AB - Nitric oxide synthase inhibitors reduce L-3, (Del-Bel et al., Cell Mol Neurobiol 25(2):371-392, 2005) 4-dihydroxyphenylalanine (L-DOPA)-induced abnormal motor effects subsequent to depletion of dopaminergic neurons in rodents and non-human primates. The present study used quantitative high-performance liquid chromatography to analyze, for the first time, dopamine metabolism in striatum of rats in order to elucidate the mechanism of action of the nitric oxide synthase inhibitors. Adult male Wistar rats received unilateral microinjection of saline (sham) or 6-hydroxydopamine (6-OHDA-lesioned) in the medial forebrain bundle. Past 3 weeks, rats were treated during 21 days with L-DOPA/benserazide (30 mg/kg/7.5 mg/kg, respectively, daily). On the 22nd day rats received an intraperitoneal (i.p.) injection of either vehicle or 7-nitroindazole, a preferential neuronal nitric oxide synthase inhibitor before L-DOPA. Abnormal involuntary movements and rotarod test were assessed as behavioral correlate of motor responses. Lesion intensity was evaluated through tyrosine hydroxylase immunohystochemical reaction. Dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and an extent of dopamine striatal tissue levels/dopamine metabolism were measured in the striatum. Lesion with 6-OHDA decreased dopamine, DOPAC, and DOPAC/dopamine ratio in the lesioned striatum. L-DOPA treatment induced abnormal involuntary movements and increased DOPAC/dopamine ratio (nearly five times) in the lesioned striatum. L-DOPA-induced dyskinesia was mitigated by 7 nitroindazole, which also decreased dopamine turnover, dopamine and DOPAC levels. Our results revealed an almost two times increase in dopamine content in the non lesioned striatum of 6-OHDA-lesioned rats. Reduction of striatal DOPAC/dopamine ratio in dyskinetic rats may suggest an increase in the dopamine availability. Our data confirm contribution of nitrergic transmission in the pathogenesis of L DOPA-induced dyskinesia with potential utilization of nitric oxide synthase inhibitors for treatment. PMID- 23807550 TI - A new method to graft titania using Grignard reagents. AB - A new method to graft titania with organic groups has been developed. In contrast to common condensation based grafting methods, this method uses organometallic chemistry to bond organic groups directly at the surface. Thereby the introduction of hetero elements at the bonding interface is avoided. PMID- 23807549 TI - Deformable image registration for cone-beam CT guided transoral robotic base-of tongue surgery. AB - Transoral robotic surgery (TORS) offers a minimally invasive approach to resection of base-of-tongue tumors. However, precise localization of the surgical target and adjacent critical structures can be challenged by the highly deformed intraoperative setup. We propose a deformable registration method using intraoperative cone-beam computed tomography (CBCT) to accurately align preoperative CT or MR images with the intraoperative scene. The registration method combines a Gaussian mixture (GM) model followed by a variation of the Demons algorithm. First, following segmentation of the volume of interest (i.e. volume of the tongue extending to the hyoid), a GM model is applied to surface point clouds for rigid initialization (GM rigid) followed by nonrigid deformation (GM nonrigid). Second, the registration is refined using the Demons algorithm applied to distance map transforms of the (GM-registered) preoperative image and intraoperative CBCT. Performance was evaluated in repeat cadaver studies (25 image pairs) in terms of target registration error (TRE), entropy correlation coefficient (ECC) and normalized pointwise mutual information (NPMI). Retraction of the tongue in the TORS operative setup induced gross deformation >30 mm. The mean TRE following the GM rigid, GM nonrigid and Demons steps was 4.6, 2.1 and 1.7 mm, respectively. The respective ECC was 0.57, 0.70 and 0.73, and NPMI was 0.46, 0.57 and 0.60. Registration accuracy was best across the superior aspect of the tongue and in proximity to the hyoid (by virtue of GM registration of surface points on these structures). The Demons step refined registration primarily in deeper portions of the tongue further from the surface and hyoid bone. Since the method does not use image intensities directly, it is suitable to multi-modality registration of preoperative CT or MR with intraoperative CBCT. Extending the 3D image registration to the fusion of image and planning data in stereo-endoscopic video is anticipated to support safer, high-precision base-of-tongue robotic surgery. PMID- 23807552 TI - Three-dimensional computational analysis of optical coherence tomography images for the detection of soft tissue sarcomas. AB - We present a three-dimensional (3-D) computational method to detect soft tissue sarcomas with the goal of automatic surgical margin assessment based on optical coherence tomography (OCT) images. Three parameters are investigated and quantified from OCT images as the indicators for the tissue diagnosis including the signal attenuation (A-line slope), the standard deviation of the signal fluctuations (speckles), and the exponential decay coefficient of its spatial frequency spectrum. The detection of soft tissue sarcomas relies on the combination of these three parameters, which are related to the optical attenuation characteristics and the structural features of the tissue. Pilot experiments were performed on ex vivo human tissue samples with homogeneous pieces (both normal and abnormal) and tumor margins. Our results demonstrate the feasibility of this computational method in the differentiation of soft tissue sarcomas from normal tissues. The features of A-line-based detection and 3-D quantitative analysis yield promise for a computer-aided technique capable of accurately and automatically identifying resection margins of soft tissue sarcomas during surgical treatment. PMID- 23807553 TI - Microcirculation imaging based on full-range high-speed spectral domain correlation mapping optical coherence tomography. AB - Microcirculation imaging is a key parameter for studying the pathophysiological processes of various disease conditions, in both clinical and fundamental research. A full-range spectral-domain correlation mapping optical coherence tomography (cm-OCT) method to obtain a complex-conjugate-free, full-range depth resolved microcirculation map is presented. The proposed system is based on a high-speed spectrometer at 91 kHz with a modified scanning protocol to achieve higher acquisition speed to render cm-OCT images with high-speed and wide scan range. The mirror image elimination is based on linear phase modulation of B frames by introducing a slight off-set of the probe beam with respect to the lateral scanning fast mirror's pivot axis. An algorithm that exploits the Hilbert transform to obtain a complex-conjugate-free image in conjunction with the cm-OCT algorithm is used to obtain full-range imaging of microcirculation within tissue beds in vivo. The estimated sensitivity of the system was around 105 dB near the zero-delay line with ~20 dB roll-off from +/-0.5 to +/-3 mm imaging-depth position. The estimated axial and lateral resolutions are ~12 and ~30 MUm, respectively. A direct consequence of this complex conjugate artifact elimination is the enhanced flow imaging sensitivity for deep tissue imaging application by imaging through the most sensitive zero-delay line and doubling the imaging range. PMID- 23807554 TI - Relationship of metal enrichment with adverse biological effect in the Yangtze Estuary sediments: role of metal background values. AB - Exclusive pristine values of As, Cd, Cr, Cu, Fe, Mn, Pb, and Zn in the Yangtze Estuary are calculated using principal components analysis (PCA) to probe the relationship between degrees of metal enrichment and their adverse biological effects. The results show that obvious differences in the degrees of metal enrichment exist when the enrichment factors are analyzed with reference background values on global, national, and local scales. Based on the low variability of aluminum, the exclusive metal background values in the estuary are obtained with PCA and are more likely to reflect the pristine contents of the abovementioned metals in the Yangtze Estuary. For the six most common metals (As, Cd, Cr, Cu, Pb, and Zn), significant correlations exist between the enrichment factors and their adverse biological effects. Arsenic shows the highest potential to cause adverse effects despite its general lack of enrichment. However, Cd is the most conservative element and is not likely to cause biological effects in the estuary. PMID- 23807555 TI - Status of metal levels and their potential sources of contamination in Southeast Asian rivers. AB - To assess the concentration and status of metal contaminants in four major Southeast Asian river systems, water were collected from the Tonle Sap-Bassac Rivers (Cambodia), Citarum River (Indonesia), lower Chao Phraya River (Thailand), and Saigon River (Vietnam) in both dry and wet seasons. The target elements were Be, Al, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Se, Mo, Ag, Cd, Ba, Tl, and Pb and the concentrations exceeded the background metal concentrations by 1- to 88-fold. This distinctly indicates enrichment by human urban area activities. The results of a normalization technique used to distinguish natural from enriched metal concentrations confirmed contamination by Al, Cd, Co, Mn, Ni, Pb, and Zn. Cluster analysis revealed the probable source of metals contamination in most sampling sites on all rivers studied to be anthropogenic, including industrial, commercial, and residential activities. Stable lead isotopes analyses applied to track the sources and pathways of anthropogenic lead furthermore confirmed that anthropogenic sources of metal contaminated these rivers. Discharges of wastewater from both industrial and household activities were major contributors of Pb into the rivers. Non-point sources, especially road runoff and street dust, also contributed contamination from Pb and other metals. PMID- 23807556 TI - Fungicides transport in runoff from vineyard plot and catchment: contribution of non-target areas. AB - Surface runoff and erosion during the course of rainfall events are major processes of pesticides transport from agricultural land to aquatic ecosystem. These processes are generally evaluated either at the plot or the catchment scale. Here, we compared at both scales the transport and partitioning in runoff water of two widely used fungicides, i.e., kresoxim-methyl (KM) and cyazofamid (CY). The objective was to evaluate the relationship between fungicides runoff from the plot and from the vineyard catchment. The results show that seasonal exports for KM and CY at the catchment were larger than those obtained at the plot. This underlines that non-target areas within the catchment largely contribute to the overall load of runoff-associated fungicides. Estimations show that 85 and 62 % of the loads observed for KM and CY at the catchment outlet cannot be explained by the vineyard plots. However, the partitioning of KM and CY between three fractions, i.e., the suspended solids (>0.7 MUm) and two dissolved fractions (i.e., between 0.22 and 0.7 um and <0.22 um) in runoff water was similar at both scales. KM was predominantly detected below 0.22 MUm, whereas CY was mainly detected in the fraction between 0.22 and 0.7 MUm. Although KM and CY have similar physicochemical properties and are expected to behave similarly, our results show that their partitioning between two fractions of the dissolved phase differs largely. It is concluded that combined observations of pesticide runoff at both the catchment and the plot scales enable to evaluate the sources areas of pesticide off-site transport. PMID- 23807557 TI - The removal of arsenate from water using iron-modified diatomite (D-Fe): isotherm and column experiments. AB - Iron hydroxide supported onto porous diatomite (D-Fe) is a low-cost material with potential to remove arsenic from contaminated water due to its affinity for the arsenate ion. This affinity was tested under varying conditions of pH, contact time, iron content in D-Fe and the presence of competitive ions, silicate and phosphate. Batch and column experiments were conducted to derive adsorption isotherms and breakthrough behaviours (50 MUg L(-1)) for an initial concentration of 1,000 MUg L(-1). Maximum capacity at pH 4 and 17% iron was 18.12-40.82 mg of arsenic/g of D-Fe and at pH 4 and 10% iron was 18.48-29.07 mg of arsenic/g of D Fe. Adsorption decreased in the presence of phosphate and silicate ions. The difference in column adsorption behaviour between 10% and 17% iron was very pronounced, outweighing the impact of all other measured parameters. There was insufficient evidence of a correlation between iron content and arsenic content in isotherm experiments, suggesting that ion exchange is a negligible process occurring in arsenate adsorption using D-Fe nor is there co-precipitation of arsenate by rising iron content of the solute above saturation. PMID- 23807558 TI - Combining stable isotope (delta13C) of trace gases and aerobiological data to monitor the entry and dispersion of microorganisms in caves. AB - Altamira Cave (north of Spain) contains one of the world's most prominent Paleolithic rock art paintings, which are threatened by a massive microbial colonization of ceiling and walls. Previous studies revealed that exchange rates between the cave and the external atmosphere through the entrance door play a decisive role in the entry and transport of microorganisms (bacteria and fungi) and nutrients to the interior of the cave. A spatial-distributed sampling and measurement of carrier (CO2) and trace (CH4) gases and isotopic signal of CO2 (delta(13)C) inside the cave supports the existence of a second connection (active gas exchange processes) with the external atmosphere at or near the Well Hall, the innermost and deepest area of the cave. A parallel aerobiological study also showed that, in addition to the entrance door, there is another connection with the external atmosphere, which favors the transport and increases microorganism concentrations in the Well Hall. This double approach provides a more complete knowledge on cave ventilation and revealed the existence of unknown passageways in the cave, a fact that should be taken into account in future cave management. PMID- 23807559 TI - Comparison of bioavailable vanadium in alfalfa rhizosphere soil extracted by an improved BCR procedure and EDTA, HCl, and NaNO3 single extractions in a pot experiment with V-Cd treatments. AB - The BCR sequential extraction procedure was compared with EDTA, HCl, and NaNO3 single extractions for evaluating vanadium bioavailability in alfalfa rhizosphere soil. The amounts of vanadium extracted by these methods were in the following order: BCR (bioavailable V) > EDTA ~ HCl > NaNO3. Both correlation analysis and stepwise regression were adopted to illustrate the extractable vanadium between different reagents. The correlation coefficients between extracted vanadium and the vanadium contents in alfalfa roots were R NaNO3 = 0.948, R HCl = 0.902, R EDTA = 0.816, and R bioavailable V = 0.819. The stepwise multiple regression equation of the NaNO3 extraction was the most significant at a 95 % confidence interval. The influence of pH, total organic carbon, and cadmium content of soil to vanadium bioavailability were not definite. In summary, both the BCR sequential extraction and the single extraction methods were valid approaches for predicting vanadium bioavailability in alfalfa rhizosphere soil, especially the single extractions. PMID- 23807560 TI - Effectiveness of chemical amendments for stabilisation of lead and antimony in risk-based land management of soils of shooting ranges. AB - This study aims to examine the effectiveness of amendments for risk-based land management of shooting range soils and to explore the effectiveness of amendments applied to sites with differing soil physiochemical parameters. A series of amendments with differing mechanisms for stabilisation were applied to four shooting range soils and aged for 1 year. Chemical stabilisation was monitored by pore water extraction, toxicity characteristic leaching procedure (TCLP) and the physiologically based extraction test (PBET) over 1 year. The performance of amendments when applied in conditions reflecting field application did not match the performance in the batch studies. Pore water-extractable metals were not greatly affected by amendment addition. TCLP-extractable Pb was reduced significantly by amendments, particularly lime and magnesium oxide. Antimony leaching was reduced by red mud but mobilised by some of the other amendments. Bioaccessible Pb measured by PBET shows that bioaccessible Pb increased with time after an initial decrease due to the presence of metallic fragments in the soil. Amendments were able to reduce bioaccessible Pb by up to 50 %. Bioaccessible Sb was not readily reduced by soil amendments. Soil amendments were not equally effective across the four soils. PMID- 23807561 TI - Decontamination of polycyclic aromatic hydrocarbons and nonylphenol from sewage sludge using hydroxypropyl-beta-cyclodextrin and evaluation of the toxicity of leachates. AB - A decontamination technique based in cyclodextrin extraction has been developed to eliminate nonylphenol (NP) and 16 polycyclic aromatic hydrocarbons (PAHs; the US Environmental Protection Agency priority pollutants list) from sewage sludge. In a first step, PAHs and NP were characterised in six sludges to determine contamination levels according to limit values proposed by the European Union Sludge Directive draft. There were few variations in the total PAHs content with levels of 1.88 to 3.05 mg kg(-1). Three-ring PAHs predominated, but fluoranthene and pyrene were also present. None of the sludge exceeded the PAHs limit proposed by the European Union's draft Directive. On the contrary, NP content in four of the six sludges was over the recommended limits of 50 mg kg(-1) for NP ethoxylates. With the aim of obtaining NP values below the concentration limits proposed to use the sewage sludge as agricultural amendments, a preliminary study using hydroxypropyl-beta-cyclodextrin (HPBCD) extractions as a decontamination technique was carried out. About 90% of NP content was removed with only one extraction with HPBCD, whereas after three sequential extractions using an aqueous solution without HPBCD, the NP extraction percentage was less than 1%. Simultaneously, PAHs extraction percentages obtained with HPBCD were also much higher than when aqueous solution was used, especially in the case of two- and three-ring PAHs. Finally, the potential environmental hazard of HPBCD leachates to aquatic organisms (Daphnia magna) was tested. These results indicate that the treatment of sewage sludge with cyclodextrin could allow their safe use as fertiliser in agriculture. PMID- 23807562 TI - Alternative solid carbon source from dried attached-growth biomass for nitrogen removal enhancement in intermittently aerated moving bed sequencing batch reactor. AB - The feasibility of using dried attached-growth biomass from the polyurethane (PU) foam cubes as a solid carbon source to enhance the denitrification process in the intermittently aerated moving bed sequencing batch reactor (IA-MBSBR) during the treatment of low COD/N containing wastewater was investigated. By packing the IA MBSBR with 8% (v/v) of 8-mL PU foam cubes saturated with dried attached-growth biomass, total nitrogen removal efficiency of 80% could be achieved for 10 consecutive cycles of operation when the intermittent aeration strategy of consecutive 1 h of aeration followed by 2 h of non-aeration period during the REACT period of the IA-MBSBR was adopted. Negligible release of ammonium nitrogen (NH4(+)-N) and slow-release of COD from the dried biomass would ensure that the use of this solid carbon source would not further burden the treatment system. The slow-releasing COD was found to have no effect in promoting the assimilation process and would also allow the carbon source to be used for many cycles of operation. The 'carbon-spent' PU foam cubes could be reused by merely drying at 60 degrees C at the end of the operational mode. Thus, the dried attached-growth biomass formed on the PU foam cubes could be exploited as an alternative solid carbon source for the enhancement of denitrification process in the IA-MBSBR. PMID- 23807563 TI - Shisha smoking, nickel and chromium levels in Tunisia. PMID- 23807564 TI - PXR polymorphisms and their impact on pharmacokinetics/pharmacodynamics of repaglinide in healthy Chinese volunteers. AB - PURPOSE: CYP3A4 is the main isoform of cytochrome P450 oxidases involved in the metabolism of approximately 60 % drugs, and its expression level is highly variable in human subjects. CYP3A4 is regulated by many transcription factors, among which the pregnane X receptor/steroid and xenobiotic receptor (PXR/SXR, NR1I2) have been identified as the most critical. Genetic polymorphisms (such as SNPs) in PXR may affect the expression level of CYP3A4. Although numerous SNPs have been identified in PXR and have appeared to affect PXR function, their impact on the expression of CYP3A4 in human subjects has not been well studied. Thus, a clinical study in healthy Chinese subjects was conducted to investigate the impact of PXR polymorphisms on repaglinide (an endogenous marker for CYP3A4 activity) pharmacokinetics used alone or in combination with a PXR inducer, flucloxacillin. METHOD: Two SNPs, -298A>G and 11193T>C, were identified as the tag SNPs to represent the overall genetic polymorphic profile of PXR. To evaluate the potential functional change of these two SNPs, 24 healthy subjects were recruited in a pharmacokinetics/pharmacodynamics study of repaglinide with or without flucloxacillin. RESULTS: The pharmacokinetic parameters including AUC and T1/2 were significantly different among the PXR genotype groups. The SNPs of 298G/G and 11193C/C were found to be associated with a lower PXR activity resulting in reduction of CYP3A4 activity in vivo. After administration of flucloxacillin, a significant drug-drug interaction was observed. The clearance of repagnilide was significantly increased by concomitant flucloxacillin in a genotype dependent manner. The subjects with SNPs of -298G/G and 11193C/C appeared to be less sensitive to flucloxacillin. CONCLUSION: Our study results demonstrated for the first time the impact of genetic polymorphisms of PXR on the PK and PD of repaglinide, and showed that subjects with genotype of -298G/G and 11193C/C in PXR has a decreased elimination rate of 3A4/2C8. Furthermore, flucloxacillin was able to induce 3A4/2C8 expression mediated by PXR in a genotype dependent manner. PMID- 23807565 TI - A service-based evaluation of a therapist-supported online cognitive behavioral therapy program for depression. AB - BACKGROUND: Evidence suggests that Internet-delivered cognitive behavioral therapy (CBT) may be as effective as face-to-face delivery for depression, but attrition and engagement rates remain a challenge. OBJECTIVE: This service-based study aimed to evaluate an online, therapist-supported, CBT-based program for depression. The program was specifically designed to address engagement issues, most notably by integrating online therapist support and communication within the platform. METHODS: Participants were 80 adults who were registered university students. Participants used the modular online program over 8 weeks, supported by a therapist. Engagement information was gathered automatically by the online system, and analyzed for all participants. Severity of participants' self reported symptoms of depression were assessed preintervention and postintervention using the Beck Depression Inventory-II (BDI-II). Postintervention measures were completed by 53 participants. RESULTS: A high level of engagement was observed compared to a previous study within the same service, along with extensive use of a range of program features. A statistically significant (P<.001) decrease in self-reported depressive symptomatology from preintervention (mean BDI-II 25.47) to postintervention (mean BDI-II 15.53) with a large effect size (d=1.17) was also observed. CONCLUSIONS: The results indicate the potential of unintrusive and easily provided online support to enhance engagement with online interventions. The system described in the paper also illustrates how such online support can be tightly integrated with interactive online programs by using a range of design strategies intended to improve the user experience. PMID- 23807566 TI - p38gamma overexpression in gliomas and its role in proliferation and apoptosis. AB - The objective of this study was to confirm the biological role of p38gamma in human gliomas. The expression profiles of p38gamma and hTERT in human glioma samples were detected by Western Blot and immunohistochemistry. RNA interference was performed in U251 cells by p38gamma silencing. Cell proliferation and apoptosis were assayed by CCK-8 and flow cytometric analysis, and then RNA and protein expression levels were measured by real-time RT-PCR and Western Blot, respectively. Telomerase activity assays and Caspase-3,-9 activation assays were also conducted. The results showed p38gamma had a positive correlation with the glioma's malignancy grade and that the treatment of U251 cells with p38gamma siRNA inhibited proliferation and induced apoptosis. Correspondingly, hTERT expression and telomerase activity were down regulated and Caspase-3 and -9 activities were elevated. In conclusion, p38gamma may serve as an oncogenic factor promoting the growth and progression of gliomas and may become a useful therapeutic target. PMID- 23807567 TI - Nicotine dependence more strongly correlates with psychological distress in disadvantaged areas of Kazakhstan than Germany. AB - The aim of this study was to describe the association of current smoking and nicotine dependence with psychological distress in socially disadvantaged urban areas of Germany and Kazakhstan. Random samples of people living in disadvantaged areas of Berlin, Germany, and Almaty, Kazakhstan, were assessed using the General Health Questionnaire with 28 items and the Fagerstrom Test for Nicotine Dependence. The association of both current smoking and nicotine dependence with psychological distress was assessed for each sample using linear regression analyses and compared between the two samples calculating t-values for the comparison of B-coefficients. Current smoking was equally associated with psychological distress in both countries, whereas the association of nicotine dependence and psychological distress was only seen for the Kazakh sample and significantly stronger than for the German sample. The results could not be explained by social characteristics. Possibly due to the lack of outpatient community mental health services for the treatment of common mental disorders, nicotine dependence was associated with psychological distress in the disadvantaged area of Kazakhstan. PMID- 23807568 TI - Detection of coronary artery stenosis with sub-milliSievert radiation dose by prospectively ECG-triggered high-pitch spiral CT angiography and iterative reconstruction. AB - OBJECTIVES: To evaluate the diagnostic accuracy of sub-milliSievert (mSv) coronary CT angiography (cCTA) using prospectively ECG-triggered high-pitch spiral CT acquisition combined with iterative image reconstruction. METHODS: Forty consecutive patients (52.9 +/- 8.7 years; 30 men) underwent dual-source cCTA using prospectively ECG-triggered high-pitch spiral acquisition. The tube current-time product was set to 50 % of standard-of-care CT examinations. Images were reconstructed with sinogram-affirmed iterative reconstruction. Image quality was scored and diagnostic performance for detection of >=50 % stenosis was determined with catheter coronary angiography (CCA) as the reference standard. RESULTS: CT was successfully performed in all 40 patients. Of the 601 assessable coronary segments, 543 (90.3 %) had diagnostic image quality. Per-patient sensitivity for detection of >=50 % stenosis was 95.7 % [95 % confidence interval (CI), 76.0-99.8 %] and specificity was 94.1 % (95 % CI, 69.2-99.7 %). Per-vessel sensitivity was 89.5 % (95 % CI, 77.8-95.6 %) with 93.2 % specificity (95 % CI, 86.0-97.0 %). The area under the receiver-operating characteristic curve on per patient and per-vessel levels was 0.949 and 0.913. Mean effective dose was 0.58 +/- 0.17 mSv. Mean size-specific dose estimate was 3.14 +/- 1.15 mGy. CONCLUSIONS: High-pitch prospectively ECG-triggered cCTA combined with iterative image reconstruction provides high diagnostic accuracy with a radiation dose below 1 mSv for detection of coronary artery stenosis. KEY POINTS: * Cardiac CT with sub-milliSievert radiation dose is feasible in many patients * High-pitch spiral CT acquisition with iterative reconstruction detects coronary stenosis accurately. * Iterative reconstruction increases who can benefit from low radiation cardiac CT. PMID- 23807569 TI - Defining predictors for long progression-free survival after radioembolisation of hepatic metastases of neuroendocrine origin. AB - OBJECTIVES: To define predictive parameters of long progression-free survival (PFS) in patients undergoing radioembolisation of neuroendocrine liver metastases. METHODS: The following clinical and magnetic resonance imaging (MRI) parameters of 45 radioembolised patients (median age, 62 years; range, 43-75) were reviewed: age, gender, levels of chromogranin A and neuron-specific enolase (NSE), primary tumour site, Ki-67 proliferation index, hepatic tumour load, number of metastases, signal intensity characteristics, vascularisation, haemorrhagic and necrotic transformation and fluid-fluid levels. PFS was assessed according to RECIST 1.0. Statistical analysis included univariate Cox regression, Kaplan-Meier and multivariate regression. RESULTS: Median PFS was 727 days (95 % CI, 378-964). In the univariate regression analysis, hypovascular metastases progressed earlier (111 vs 727 days; P < 0.05). A Ki-67 <=2 % was associated with a longer PFS than a Ki-67 of 3-20 % or >20 % (911 vs 727 vs 210 days, respectively; P < 0.05). Low NSE predicted longer PFS (911 vs 378 days; P < 0.05). In the adjusted multivariate analysis, vascularisation (hypervascularisation vs. no hypervascularisation; P = 0.0009) and NSE level (low vs high; P = 0.0119) had the strongest influence on PFS. CONCLUSION: Response to radioembolisation in patients with neuroendocrine liver metastases can be predicted by the metastatic vascularisation pattern, the NSE level and the Ki-67. KEY POINTS: * Radioembolisation is an effective treatment in hepatic metastases of neuroendocrine origin. * Pre-therapeutic vascularisation patterns of metastases on MRI can predict long progression-free survival. * Assessment of pre therapeutic markers provides better therapy planning. PMID- 23807570 TI - Congenital anorectal atresia: MR imaging of late post-operative appearances in adult patients with anal incontinence. AB - OBJECTIVES: To describe the MR imaging findings in adults presenting with anal incontinence following pull-through perineoplasty for anorectal atresia. METHODS: 15 adults (12 male, 3 female; age 22-52 years) with anal incontinence following a prior perineal pull-through procedure as an infant for anorectal atresia were identified retrospectively. MR imaging was performed using either an endoanal coil or body coil. MR images were reviewed by three observers who noted whether pelvic floor and sphincter muscles were present and, if so, whether they were thinned or not. Data were tabulated and raw frequencies determined. RESULTS: Images were unavailable for one patient, leaving 14 for analysis. Anal stenosis prevented endoanal coil placement in 5. The pull-through was anatomically correct in 12 (86 %) patients but was misdirected in 2. Thinned muscle was seen in 11 (79 %) patients. External sphincter thinning was commonest (present in 10 patients), with levator plate thinning least common (present in 4 patients). Only one patient had thinning of all muscle groups. CONCLUSION: MR imaging may be used to determine the extent and quality of residual pelvic floor and anal sphincter muscle in adults who have functional disability following pull-through perineoplasty for anorectal agenesis. PMID- 23807571 TI - Twelve novel Atm mutations identified in Chinese ataxia telangiectasia patients. AB - Ataxia telangiectasia (A-T) is an autosomal recessive disease characterized mainly by progressive cerebellar ataxia, oculocutaneous telangiectasia, and immunodeficiency. This disease is caused by mutations of the ataxia telangiectasia mutated (Atm) gene. More than 500 Atm mutations that are responsible for A-T have been identified so far. However, there have been very few A-T cases reported in China, and only two Chinese A-T patients have undergone Atm gene analysis. In order to systemically investigate A-T in China and map their Atm mutation spectrum, we recruited eight Chinese A-T patients from six unrelated families nationwide. Using direct sequencing of genomic DNA and the multiplex ligation-dependent probe amplification, we identified twelve pathogenic Atm mutations, including one missense, four nonsense, five frameshift, one splicing, and one large genomic deletion. All the Atm mutations we identified were novel, and no homozygous mutation and founder-effect mutation were found. These results suggest that Atm mutations in Chinese populations are diverse and distinct largely from those in other ethnic areas. PMID- 23807572 TI - Acquisition of paclitaxel resistance via PI3K-dependent epithelial-mesenchymal transition in A2780 human ovarian cancer cells. AB - Epithelial ovarian cancer is a major cause of mortality among women with gynecological malignancies. Paclitaxel is commonly used for chemotherapy of ovarian cancer, yet its efficacy is limited by chemoresistance. Generally, drug resistance is associated with acquisition of the epithelial-mesenchymal transition (EMT) in cancer. The aim of the present study was to determine whether the EMT is involved in acquired resistance to paclitaxel in A2780 human ovarian cancer cells. Using the paclitaxel-resistant A2780/PTX cell line, we examined the cellular morphology, molecular changes, migration and proliferation consistent with the EMT. Furthermore, we found that inhibition of phosphatidylinositol 3 kinase (PI3K) activity reduced the proliferation and migration and restored their sensitivity to paclitaxel. Our study provides new insights into EMT-like phenotypic changes that are linked to paclitaxel resistance in A2780 cells. We believe that inhibition of the PI3K signaling pathway could provide a novel therapeutic approach to overcome chemoresistance and prevent metastasis during paclitaxel chemotherapy. PMID- 23807573 TI - Transcranial passive acoustic mapping with hemispherical sparse arrays using CT based skull-specific aberration corrections: a simulation study. AB - The feasibility of transcranial passive acoustic mapping with hemispherical sparse arrays (30 cm diameter, 16 to 1372 elements, 2.48 mm receiver diameter) using CT-based aberration corrections was investigated via numerical simulations. A multi-layered ray acoustic transcranial ultrasound propagation model based on CT-derived skull morphology was developed. By incorporating skull-specific aberration corrections into a conventional passive beamforming algorithm (Norton and Won 2000 IEEE Trans. Geosci. Remote Sens. 38 1337-43), simulated acoustic source fields representing the emissions from acoustically-stimulated microbubbles were spatially mapped through three digitized human skulls, with the transskull reconstructions closely matching the water-path control images. Image quality was quantified based on main lobe beamwidths, peak sidelobe ratio, and image signal-to-noise ratio. The effects on the resulting image quality of the source's emission frequency and location within the skull cavity, the array sparsity and element configuration, the receiver element sensitivity, and the specific skull morphology were all investigated. The system's resolution capabilities were also estimated for various degrees of array sparsity. Passive imaging of acoustic sources through an intact skull was shown possible with sparse hemispherical imaging arrays. This technique may be useful for the monitoring and control of transcranial focused ultrasound (FUS) treatments, particularly non-thermal, cavitation-mediated applications such as FUS-induced blood-brain barrier disruption or sonothrombolysis, for which no real-time monitoring techniques currently exist. PMID- 23807574 TI - Effects of combined elicitors on tanshinone metabolic profiling and SmCPS expression in Salvia miltiorrhiza hairy root cultures. AB - Tanshinones are abietane-type norditerpenoid quinone natural products found in a well-known traditional Chinese medicinal herb, Salvia miltiorrhiza Bunge. The copalyl diphosphate synthase of S. miltiorrhiza (SmCPS) is the key enzyme in the first step for transformation of geranylgeranyl diphosphate (GGPP) into miltiradiene, which has recently been identified as the precursor of tanshinones. Based on previous gene-to-metabolite network, this study examined the influences of various combined elicitors on the expression of SmCPS and production of tanshinones in S. miltiorrhiza hairy root cultures. Combined elicitors were composed of three classes of elicitors, a heavy metal ion (Ag+), a polysaccharide (yeast extract, YE), and a plant response-signalling compound (methyl jasmonate, MJ). YE + Ag+, Ag+ + MJ, YE + MJ, and YE + Ag+ + MJ were the combinations we tested. The effect of elicitors on the SmCPS expression level was detected by quantitative real-time PCR (qRT-PCR), and the tanshinones accumulation responses to elicitation were analysed by Ultra Performance Liquid Chromatography (UPLC) metabolite profiling. Of these combined elicitors, the expression of SmCPS was significantly enhanced by elicitation, especially at 24 h and 36 h. Of four tanshinones detected, the contents of cryptotanshinone and dihydrotanshinone I were enhanced by treatment with YE + Ag+, Ag+ + MJ, and YE + Ag+ + MJ. Our results indicate that appropriate combined elicitors can enhance tanshinones production in hairy root cultures. PMID- 23807575 TI - A new resveratrol trimer from the roots and stems of Vitis wenchowensis. AB - Phytochemical constituents of Vitis wenchowensis were investigated for the first time. A new resveratrol trimer, wenchowenol (1), was isolated from the roots and stems of Vitis wenchowensis along with four known stilbenoids 2-5. The structure and relative configuration of 1 were established on the basis of spectral evidence, especially HMBC and NOESY experiments. It showed potent antioxidant activity against DPPH (1,1-diphenyl-2-picrylhydrazyl) radical. PMID- 23807576 TI - Spectroscopic and theoretical studies of some 3-(4'-substituted phenylsulfanyl)-1 methyl-2-piperidones. AB - The analysis of the IR carbonyl bands of some 3-(4'-substituted phenylsulfanyl)-1 methyl-2-piperidones 1-6 bearing substituents: NO2 (compound 1), Br (compound 2), Cl (compound 3), H (compound 4) Me (compound 5) and OMe (compound 6) supported by B3LYP/6-31+G(d,p) and PCM calculations along with NBO analysis (for compound 4) and X-ray diffraction (for 2) indicated the existence of two stable conformations, i.e., axial (ax) and equatorial (eq), the former corresponding to the most stable and the least polar one in the gas phase calculations. The sum of the energy contributions of the orbital interactions (NBO analysis) and the electrostatic interactions correlate well with the populations and the nuCO frequencies of the ax and eq conformers found in the gas phase. Unusually, in solution of the non-polar solvents n-C6H14 and CCl4, the more intense higher IR carbonyl frequency can be ascribed to the ax conformer, while the less intense lower IR doublet component to the eq one. The same nuCO frequency trend also holds in polar solvents, that is nu(CO)(eq)< nu(CO)(ax). However, a reversal of the ax/eq intensity ratio occurs going from non-polar to polar solvents, with the ax conformer component that progressively decreases with respect to the eq one in CHCl3 and CH2Cl2, and is no longer detectable in the most polar solvent CH3CN. The PCM method applied to compound 4 supports these findings. In fact, it predicts the progressive increase of the eq/ax population ratio as the relative permittivity of the solvent increases. Moreover, it indicates that the computed nu(CO) frequencies of the ax and eq conformers do not change in the non-polar solvents n-C6H14 and CCl4, while the nu(CO) frequencies of the eq conformer become progressively lower than that of the ax one going from CHCl3 to CH2Cl2 and to CH3CN, in agreement with the experimental IR values. The analysis of the geometries of the ax and eq conformers shows that the carbonyl oxygen atom of the eq conformer is free for solvation, while the O[CO]...H[o-Ph] hydrogen bond that takes place in the ax conformer partially hinders the approach of the solvent molecules to the carbonyl oxygen atom. Therefore, the larger solvation that occurs in the carbonyl oxygen atom of the eq conformer is responsible for the observed and calculated decrease of the corresponding frequency. The X-ray single crystal analysis of 2 indicates that this compound adopts the most polar eq geometry in the solid. In fact, in order to obtain the largest energy gain, the molecules are arranged in the crystal in a helical fashion due to dipole moment coupling along with C-H...O and C-H...pi(Ph) hydrogen bonds. PMID- 23807577 TI - Facile and efficient syntheses of a series of N-benzyl and N-biphenylmethyl substituted imidazole derivatives based on (E)-urocanic acid, as angiotensin II AT1 receptor blockers. AB - In the present work, a facile and efficient route for the synthesis of a series of N-substituted imidazole derivatives is described. Docking studies have revealed that N-substituted imidazole derivatives based on (E)-urocanic acid may be potential antihypertensive leads. Therefore, new AT1 receptor blockers bearing either the benzyl or the biphenylmethyl moiety at the N-1 or N-3 position, either the (E)-acrylate or the propanoate fragment and their related acids at the C-4 position as well as a halogen atom at the C-5 position of the imidazole ring, were synthesized. The newly synthesized analogues were evaluated for binding to human AT1 receptor. The biological results showed that this class of molecules possesses moderate or no activity, thus not always confirming high docking scores. Nonetheless, important conclusions can be derived for their molecular basis of their mode of action and help medicinal chemists to design and synthesize more potent ones. An aliphatic group as in losartan seems to be important for enhancing binding affinity and activity. PMID- 23807578 TI - Synthesis, surface modification and characterisation of biocompatible magnetic iron oxide nanoparticles for biomedical applications. AB - Superparamagnetic iron oxide nanoparticles (MNPs) with appropriate surface chemistry exhibit many interesting properties that can be exploited in a variety of biomedical applications such as magnetic resonance imaging contrast enhancement, tissue repair, hyperthermia, drug delivery and in cell separation. These applications required that the MNPs such as iron oxide Fe3O4 magnetic nanoparticles (Fe3O4 MNPs) having high magnetization values and particle size smaller than 100 nm. This paper reports the experimental detail for preparation of monodisperse oleic acid (OA)-coated Fe3O4 MNPs by chemical co-precipitation method to determine the optimum pH, initial temperature and stirring speed in order to obtain the MNPs with small particle size and size distribution that is needed for biomedical applications. The obtained nanoparticles were characterized by Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), scanning electron microscopy (SEM), energy dispersive X-ray fluorescence spectrometry (EDXRF), thermogravimetric analysis (TGA), X-ray powder diffraction (XRD), and vibrating sample magnetometer (VSM). The results show that the particle size as well as the magnetization of the MNPs was very much dependent on pH, initial temperature of Fe2+ and Fe3+ solutions and steering speed. The monodisperse Fe3O4 MNPs coated with oleic acid with size of 7.8 +/- 1.9 nm were successfully prepared at optimum pH 11, initial temperature of 45 degrees C and at stirring rate of 800 rpm. FTIR and XRD data reveal that the oleic acid molecules were adsorbed on the magnetic nanoparticles by chemisorption. Analyses of TEM show the oleic acid provided the Fe3O4 particles with better dispersibility. The synthesized Fe3O4 nanoparticles exhibited superparamagnetic behavior and the saturation magnetization of the Fe3O4 nanoparticles increased with the particle size. PMID- 23807579 TI - Characterization of total phenolic constituents from the stems of Spatholobus suberectus using LC-DAD-MS(n) and their inhibitory effect on human neutrophil elastase activity. AB - Spatholobus suberectus Dunn, belonging to the legume family (Fabaceae), has been used as a Traditional Chinese Medicine for the treatment of anemia, menoxenia and rheumatism. A limited number of studies report that various types of flavonoids are the main characteristic constituents of this herb. We have now found that S. suberectus contains about 2% phenolic components and characterized the major phenolic components as homogeneous B-type procyanidin conjugates using a liquid chromatography with diode-array detection-ESI mass spectrometry (LC-DAD/ESI-MS) method. This is the first report on occurrence of most B-type procyanidins in this herb. Moreover, the total phenolics extract was assayed for inhibitory activity on human neutrophil elastase and its IC50 was found to be 1.33 MUg/mL. PMID- 23807580 TI - New 7-[4-(4-(un)substituted)piperazine-1-carbonyl]- piperazin-1-yl] derivatives of fluoroquinolone: synthesis and antimicrobial evaluation. AB - Fluoroquinolones have been a class of important synthetic antimicrobial agents broadly and effectively used in clinic for infectious diseases. In this study, the synthesis of a range of fluoroquinolone derivatives with 4-(carbopiperazin-1 yl)piperazinyl moieties at the C7 position and their inhibition of bacterial pathogens commonly disseminated in hospital environment were described. The results indicated that a 7-[4-(4-(benzoyl)carbopiperazin-1-yl)]piperazinyl derivative 5h and two 7-[4-(4- (benzenesulfonyl)carbopiperazin-1-yl)]piperazinyl derivatives 5k and 5l showed more promising growth inhibition of ciprofloxacin resistant P. aeruginosa (CRPA) with MIC values as low as 16 MUg/mL which is 16 fold more potent than ciprofloxacin, while most of other derivatives maintained potency against methicillin-resistant Staphylococcus aureus (MRSA). PMID- 23807581 TI - Synthesis and properties of T-shaped organic conjugates based on 3,6 diarylpyridazine-fused tetrathiafulvalene. AB - A facile synthetic approach to the pi-expanded tetrathiafulvalene derivatives is described. The Suzuki reaction of 3,6-dichloropyridazine-fused tetrathiafulvalenes with phenyl boronic acid or biphenyl boronic acid gave a series of novel T-shaped organic pi-conjugates. The electronic properties of the conjugates were studied experimentally by the combination of cyclic voltammetry and UV-vis spectroscopy. Their HOMO and LUMO energy levels are estimated to be about -5 eV and -3.2 eV, which are the air operating stability ranges in the p channel and n-channel field effect transistors, respectively. Only one conjugate bearing the longer alkyl chain (n = 1, R = n-C18H37) was verified to self assemble into lamellar structures in the mesogenic phase and the best measured charge carrier mobility of its thin-film devices was 4.5 * 10(-5) cm(2) V(-1) s( 1). PMID- 23807582 TI - [Surgical technique for pancreas transplantation]. AB - OBJECTIVE: The transplantation of a cadaveric donor pancreas represents a therapeutic option for the type 1 diabetic. A precondition is the proof of negative serum C-peptide after glucagon stimulation (< 0.02 ng/ml) as it is found in the typical patient with type 1 or a pancreoprive diabetes. The pancreas can be transplanted alone (PTA) or after a kidney (PAK), either following a preceding living related or cadaveric kidney transplantation. The majority of pancreata worldwide are transplanted simultaneously with a kidney (SPK) in stage 4 and 5 (eGFR < 29 ml/min) of chronic kidney disease. The beneficial effect of physiological glucose regulation on mortality, kidney failure and diabetic complications (cardiovascular, neuropathy, retinopathy) is well established. Patient survival rate at 1 year after transplantation is above 90 %, pancreas graft survival overall after 1 year is about 80 %. INDICATIONS: Type 1 diabetic patients with recurrent hypoglycemic episodes or major complications due to dysregulated glucose metabolism qualify for pancreas transplantation alone in case of a stable kidney function. Patients with chronic kidney disease stage 4 and 5 are candidates for SPK. PROCEDURE: Pancreatic transplantation into the right iliac fossa. CONCLUSION: Although technically demanding, pancreas transplantation is safely performable with a low periprocedural morbidity and mortality. Potential perioperative complications include inflammation, rejection or graft thrombosis. After a successful transplantation, long-term physiological glucose regulation can be achieved which results in a prolonged life expectancy and quality of life in type 1 diabetic patients. PMID- 23807583 TI - [Significance of emergency and complication management]. PMID- 23807584 TI - [What the surgeon needs to know about basic new concepts of inflammation and their therapeutic consequences: sanitation of inflammation is not a passive but rather an active process regulated by lipid mediators]. AB - The acute inflammatory response as a physiological programme that protects the organism against injurious pathogens is characterised by highly regulated actions of pro- and anti-inflammatory mediators. Intensive investigations during the last decades have led to the identification of these mediators and their complex interplay as well as the design and development of anti-inflammatory therapies. However, the resolution of acute inflammation has long been considered to be a passive process. In consequence, little was known about the mechanisms which guide acute inflammation either to complete resolution, repair of inflamed tissue and restoration of normal function or to a chronic inflammatory process characterised by persistent signs of inflammation, tissue damage and impaired function. Predominantly during the last decade the so-called specialised proresolving mediators (SPM) have been identified. These essential fatty acid derived mediators - lipoxins, resolvins, protectins, and maresins - terminate the acute inflammatory responses and stimulate their complete resolution. SPM possess both anti-inflammatory and proresolving activities in that they inhibit pro inflammatory cytokines, limit infiltration of neutrophils, enhance macrophage uptake, and finally stimulate their non-phlogistic activation and clearance of apoptotic neutrophils and microbial particles. It has been demonstrated in multiple animal models of human inflammatory diseases that, e.g., atherosclerosis, diabetes, and inflammatory bowel diseases are caused by a decreased synthesis and/or an impaired signal transduction of the proresolving mediators. Future studies are warranted to clarify whether these proresolving lipid mediators will participate in healing human inflammatory diseases and their complications. PMID- 23807585 TI - [Prof. Dr. Hartwig Bauer, former General Secretary of the German Society of Surgery from 2002 to 2012]. PMID- 23807586 TI - [Commen ont: Darius et al. Occupational health aspects in general (visceral) surgery - risk of infection through needle-stick injuries (what the surgeon should know) Zentralbl Chir 2013; 138 : 88-93]. PMID- 23807587 TI - [Response by the authors to a "Letter to the editor" concerning the article Zentralbl Chir 2013; 138 (1): 88-93]. PMID- 23807588 TI - [Thoracic surgery in the Zentralblatt fur Chirurgie]. PMID- 23807589 TI - [Biomedicine in thoracic surgery: state of the art]. AB - Biomedicine represents a new scientific field at the interface of human, molecular and cell biology and medicine. Comprising the diverse disciplines of stem cell research, tissue engineering and material sciences, biomedicine gives rise to new approaches in research and therapy for - to date - unmet medical issues. Biomedical research is currently conducted in many medical, especially surgical subspecialties, and a number of successful developments have already been brought to clinical application. Concerning thoracic surgery, biomedical approaches are pursued primarily for tissue and organ replacement of the upper airways, lung and thoracic wall. In spite of a comparatively small research foundation, five different concepts have been clinically implemented worldwide, due to a lack of established treatment options in the case of extensive disease of the greater airways. In this review, the clinical background and the tissue specific basics of tracheobronchial biomedicine are presented. PMID- 23807591 TI - [Pleural empyema - treatment strategies in light of etiology]. AB - The variety of strategies in the treatment of parapneumonic pleural empyema demonstrates the ambiguity for the method of choice. Parapneumonic pleural empyema has been classified into different stages and classes. While the American Thoracic Society (ATS) classification is based on the natural course of the disease, or according to the radiological, physical and biochemical characteristics respectively, the American College of Chest Physicians (ACCP) has categorized the patients with pleural empyema according to the risk of a poor outcome. The British Thoracic Society (BTS) developed a treatment algorithm based on a systematic review of peer-reviewed literature. With regard to this classification the management of parapneumonic and postoperative pleural empyema is based on the stage of the disease. Therapeutic strategies include chest tube alone, chest tube with fibrinolysis, thoracoscopic debridement and decortication in open or minimally invasive techniques, closed empyemectomy, or treatment with thoracomyoplasty, open window treatment or vacuum clothing with negative pressure. The different conservative and operative therapeutic possibilities determinate the central treatment function of thoracic surgery. PMID- 23807592 TI - Racial/Ethnic differences in Medicare experiences and immunization: the role of disease burden. AB - BACKGROUND: Although Medicare provides beneficiaries with primary access to the health care system, racial/ethnic disparities in health care experiences and preventive care are well documented in the Medicare population. OBJECTIVE: To investigate disease burden and its possible impact on racial/ethnic health disparities for measures of secondary and tertiary access to health care, such as access to health plan information, obtaining recommended care in a timely manner, and immunization. SUBJECTS: A total of 355,874 beneficiaries over the age of 64 years who responded to the 2008 Medicare Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey. METHODS: We fit a series of linear, case mix adjusted models predicting Medicare CAHPS measures of patient experience and immunization from race/ethnicity, a 0 to 6 count of disease burden, and their interaction. RESULTS: Disparities between non-Hispanic whites and other racial/ethnic groups are largest among beneficiaries with no major health conditions. Disparities between whites and other racial/ethnic groups on getting care quickly and immunization are mitigated at higher levels of disease burden. Disparities persist at higher levels of disease burden for getting information from one's health plan. DISCUSSION: Whites have better overall access to care than other beneficiaries with Medicare in the absence of major health conditions. Disparities in getting care quickly and immunizations are smaller among beneficiaries with greater disease burden, perhaps as a function of integration into the health care system gained through management of health issues. These results underscore the importance of outreach to minorities with low utilization and few or no major health conditions. PMID- 23807593 TI - Using administrative data to identify naturally occurring networks of physicians. AB - BACKGROUND: Physicians naturally form networks. Networks could form a rational basis for Accountable Care Organizations (ACOs) for defined populations of Medicare beneficiaries. OBJECTIVES: To use methods from network science to identify naturally occurring networks of physicians that might be best suited to becoming ACOs. RESEARCH DESIGN, SUBJECTS, AND MEASURES: Using nationally representative claims data from the Medicare program for CY 2006 on 51 hospital referral regions (HRRs), we used a network science-based community-detection algorithm to identify groups of physicians likely to have preestablished relationships. After assigning patients to networks based upon visits with a primary care physician, we examined the proportion of care delivered within communities and compared our results with potential ACOs organized around single hospitals. RESULTS: We studied 4,586,044 Medicare beneficiaries from 51 HRRs who were seen by 68,288 active physicians practicing in those HRRs. The median community-based network ACO had 150 physicians with 5928 ties, whereas the median hospital-based network ACO had 96 physicians with 3276 ties. Among patients assigned to networks via their primary care physicians, seventy-seven percent of physician visits occurred with physicians in the community-based networks as compared with 56% with physicians in the hospital-based networks; however, just 8% of specialist visits were to specialists within the hospital-based networks as compared with 60% of specialist visits within the community-based networks. Some markets seemed better suited to developing ACOs based on network communities than others. CONCLUSIONS: We present a novel approach to identifying groups of physicians that might readily function as ACOs. Organic networks identified and defined in this natural and systematic manner already have physicians who exhibit close working relationships, and who, importantly, keep the vast majority of care within the networks. PMID- 23807594 TI - Construction of a recombinant eukaryotic expression vector containing a leptin gene and its expression in HPMSCs. AB - Leptin gene fragments were amplified from human adipose tissue using reverse transcription polymerase chain reaction technology. The leptin gene was reconstructed in pIRES2-EGFP and transfected into human placenta-derived mesenchymal stem cells (HPMSCs) using a liposome-mediated method. Leptin mRNA and protein was detected in the transfected cells using RT-PCR and Western blot analysis, and the results showed that HPMSCs transfected with pIRES2-EGFP-leptin expressed significantly more leptin mRNA and protein than HPMSCs transfected with pIRES2-EGFP. EGFP expression was observed under a fluorescence microscope, and results showed the report gene to have been successfully transferred into the target cells. The biological activity of leptin and the cell proliferation activity of HPMSCs transfected with pIRES2-EGFP-leptin was detected using an MTT assay, which showed that leptin can promote the proliferation of HPMSCs. However, leptin in HPMSCs transfected with pIRES2-EGFP-leptin showed significantly more activity than HPMSCs transfected with pIRES2-EGFP. Identification of multipotency showed that HPMSCs transfected with pIRES2-EGFP-leptin maintained their multipotency. PMID- 23807595 TI - Transgene copy number comparison in recombinant mammalian cell lines: critical reflection of quantitative real-time PCR evaluation. AB - Nucleic acid quantification is a relevant issue for the characterization of mammalian recombinant cell lines and also for the registration of producer clones. Quantitative real-time PCR is a powerful tool to investigate nucleic acid levels but numerous different quantification strategies exist, which sometimes lead to misinterpretation of obtained qPCR data. In contrast to absolute quantification using amplicon- or plasmid standard curves, relative quantification strategies relate the gene of interest to an endogenous reference gene. The relative quantification methods also consider the amplification efficiency for the calculation of the gene copy number and thus more accurate results compared to absolute quantification methods are generated. In this study two recombinant Chinese hamster ovary cell lines were analysed for their transgene copy number using different relative quantification strategies. The individual calculation methods resulted in differences of relative gene copy numbers because efficiency calculations have strong impact on gene copy numbers. However, in context of comparing transgene copy numbers of two individual clones the influence of the calculation method is marginal. Therefore especially for the comparison of two cell lines with the identical transgene any of the relative qPCR methods was proven as powerful tool. PMID- 23807596 TI - Water exchange-minimizing DCE-MRI protocol to detect changes in tumor vascular parameters: effect of bevacizumab/paclitaxel combination therapy. AB - OBJECTIVE: The purpose of this study was to assess changes in the tumor microvasculature induced by combination antiangiogenic therapy in MCF-7 breast tumor mouse models, using a noninvasive DCE-MRI method that minimizes the effect of water exchange. MATERIALS AND METHODS: 3D quantitative DCE-MRI images were acquired with a heavily T1-weighted saturation recovery gradient echo sequence with a recovery delay of 20 ms. Tumor vascular volume (VV) and vascular permeability-surface area product (PS) were obtained through a linear regression of the albumin-Gd-DTPA-enhanced dynamic image intensity on MCF-7 breast tumor mouse models treated with combination bevacizumab/paclitaxel therapy. RESULTS: Measured tumor VV values were significantly higher than the values that have been reported previously using quantitative T1 mapping, and are in good agreement with micro-CT (computed tomography) results reported earlier from other tumor models. A trend of decreasing tumor PS was detected in the group of MCF-7 tumor bearing mice treated with the bevacizumab/paclitaxel combination regimen. CONCLUSION: VV and PS maps obtained by a heavily T1-weighted acquisition protocol revealed the large peripheral blood vessels as well as the permeable areas within the tumor. A 12-day/three-dose combination treatment of bevacizumab and paclitaxel resulted in delayed tumor growth and a trend of decreasing tumor vascular permeability surface area product. PMID- 23807597 TI - [Sonographic screening of basilar arteries reduces the risk of sudden infant death]. AB - Sudden infant death syndrome (SIDS) is the most frequent cause of death in the first year of life. The causes of SIDS remain unclear although multiple theories have been published in recent decades. However, some important risk factors associated with SIDS, such as prone sleeping have been validated. Over 85% of all SIDS victims were found in a prone position but it is unclear why the prone sleeping position is more dangerous than the supine sleeping position. A possible cause of SIDS is hypoperfusion of the brain stem during head rotation. Some infants show compression of the vertebral arteries at the craniocervical junction during head rotation, especially in the prone position and this may lead to a subsequent decrease of brain stem perfusion. If compression lasts for a longer time hypoperfusion of the brainstem and central apnea and bradycardia result, which can lead to SIDS. The decrease in brainstem perfusion occurs more often and is more pronounced in the prone position as the head is more rotated in the prone than in the supine position. Doppler sonographic flow measurements of the flow in the basilar artery through the open fontanel, allow the detection of patients at risk of position-dependent hypoperfusion of the brain. Flow measurements are obtained in a neutral position (head in midline) and during head rotation. In the vast majority of infants (98.7%) the flow in the basilar artery is independent of head rotation and body position. In rare cases (1.3%) flow velocities drop to below 50% of the initial value during head rotation. A pathological biphasic or even retrograde flow can be found during head rotation in only 0.3% of infants and these infants may have an increased risk for SIDS. To prevent SIDS head rotation which leads to an abnormal or pathological flow decrease during head rotation should be avoided. Additionally these infants should be monitored until blood flow in the basilar artery has returned to normal, which usually occurs during the first year of life. This approach reduced the incidence of SIDS in our patients from 1% to 0.040/00. PMID- 23807599 TI - Radiation oncology: a primer for medical students. AB - Radiation oncology requires a complex understanding of cancer biology, radiation physics, and clinical care. This paper equips the medical student to understand the fundamentals of radiation oncology, first with an introduction to cancer treatment and the use of radiation therapy. Considerations during radiation oncology consultations are discussed extensively with an emphasis on how to formulate an assessment and plan including which treatment modality to use. The treatment planning aspects of radiation oncology are then discussed with a brief introduction to how radiation works, followed by a detailed explanation of the nuances of simulation, including different imaging modalities, immobilization, and accounting for motion. The medical student is then instructed on how to participate in contouring, plan generation and evaluation, and the delivery of radiation on the machine. Lastly, potential adverse effects of radiation are discussed with a particular focus on the on-treatment patient. PMID- 23807598 TI - Do better-rated navigators improve patient satisfaction with cancer-related care? AB - Patient navigation has emerged as a promising strategy for addressing racial ethnic and socioeconomic disparities in cancer-related care. However, little is known about the impact of patients' perception of the quality of navigation on patient outcomes. We examined the impact of better-rated navigators on patients' satisfaction with cancer-related care. The sample included 1,593 adults (85.8% with abnormal cancer screening and 14.2% with confirmed cancer diagnosis) who received patient navigation. We defined better-rated navigators as those scoring above the first quartile of mean scores on the Patient Satisfaction with Interpersonal Relationship with Navigator scale. We defined patient satisfaction based on scores above or below the median of the Patient Satisfaction with Cancer Related Care (PSCC) scale. We controlled for patient and site characteristics using backward selection logistic regression analyses. Among patients with abnormal screening, having a better-rated navigator was associated with higher score on the PSCC (p < 0.05). After controlling for other bivariate predictors of satisfaction (e.g., age, race, income, and household size), navigation by better rated navigators was associated with a greater likelihood of having higher patient satisfaction [odds ratio (OR), 1.38; 95% confidence interval (CI), 1.05 1.82]. Similar findings between better-rated navigators and score on the PSCC were found for participants with diagnosed cancer (OR, 3.06; 95% CI, 1.56-6.0). Patients navigated by better-rated navigators reported higher satisfaction with their cancer-related care. PMID- 23807600 TI - Recent progress in generation of human surrogate beta cells. AB - PURPOSE OF REVIEW: This review evaluates recent progress in several approaches aimed at developing human surrogate beta cells, and identifies gaps that need to be filled for bringing them closer to clinical application. RECENT FINDINGS: Cells expanded in vitro from human cadaver donor beta cells under conditions causing dedifferentiation have been shown to undergo redifferentiation following inhibition of the Notch pathway. Efforts for differentiation of insulin-producing cells from human pluripotent stem cells have focused on isolation and expansion of intermediate-stage cells. The role of mesenchyme in expansion of pancreas progenitors has been emphasized by mouse cell ablation, and co-culture of human embryonic stem cell-derived definitive endoderm with mesenchyme. Incomplete removal of Polycomb-mediated repression of endocrine genes in embryonic stem cell derived insulin-producing cells generated in vitro has been suggested to be responsible for their immature phenotype. Induced pluripotent stem cells reprogrammed from beta cells have been shown to exhibit an enhanced differentiation capacity toward insulin-producing cells, compared with other pluripotent stem cells. A new approach for reprogramming non-beta into beta-like cells involving transcription factor gene ablation has been demonstrated in mouse enteroendocrine cells in vivo. SUMMARY: New insights into the stumbling blocks in expansion of human donor islet cells, differentiation of pluripotent stem cells, and reprogramming of non-beta cell types are shaping improved strategies, which are likely to bring us closer to the goal of generating abundant human surrogate beta cells. PMID- 23807601 TI - Intersection between genetic polymorphisms and immune deviation in type 1 diabetes. AB - PURPOSE OF REVIEW: Above 60 non-HLA genes have been associated with T1D, many of which are immune-related genes. One challenge following identification of these genes is finding causative connections between risk alleles and disease. Phenotypes linked to T1D-associated genetic variants are beginning to help us better understand the cellular and molecular mechanisms underlying T1D. RECENT FINDINGS: The list of immune-related genes with T1D-associated polymorphisms will be reviewed and cellular phenotypes correlating with these variants will be described highlighting recent finding from variants in the PTPN22 gene and genes encoding proteins in theIL-2/IL2R signaling pathway. SUMMARY: Building from extensive genome-wide association studies, we are discovering cellular and molecular phenotypes that may help unravel the underlying causes of T1D. PMID- 23807602 TI - Growth hormone and cancer: an update on progress. AB - PURPOSE OF REVIEW: Animals born with a deficiency in the cell surface receptor for growth hormone (GH) have a significantly reduced risk of developing cancer. Conversely, increased expression levels of GH and the GH receptor (GHR) are detectable in a variety of different human cancers. Here we discuss recent literature contributing to our understanding of the field. RECENT FINDINGS: In addition to animal evidence, studies of individuals with Laron syndrome suggest that congenital GHR deficiency may also protect humans against cancer. GH expression in certain malignancies is correlated with clinicohistopathological parameters and may contribute the therapeutic resistance. Other recent studies have identified novel aspects of the GH signal transduction pathway, including receptor crosstalk and the involvement of microRNA in endocrine regulation of GH. SUMMARY: Substantial evidence suggests the GH/insulin-like growth factor-1 axis initiates and promotes progression of cancer. However, important questions remain unanswered regarding the therapeutic utility of GH or GHR antagonism in cancer. Further clinical studies regarding the clinical association of GH expression with human malignancies and translational studies investigating GHR antagonism in animal models of human cancer are critical. PMID- 23807603 TI - Updates in growth hormone treatment and mortality. AB - PURPOSE OF REVIEW: To review the literature with regard to mortality in patients with hypopituitarism with a focus on the role of growth hormone (GH) deficiency and therapy. RECENT FINDINGS: Mortality is increased in hypopituitarism, particularly in female patients. In recent years mortality rates appear to be trending downwards towards that of the general population. Recent studies from retrospective or postmarketing surveillance studies have suggested that patients who receive GH therapy may not have increased mortality. Recent studies regarding mortality in paediatric patients treated with GH are conflicting and this area needs further study. SUMMARY: There are several important limitations of available data regarding mortality in hypopituitarism and even more so in the impact of GH therapy, which need to be taken into account when interpreting the available data. The data regarding mortality in patients treated with GH as children is an area of much debate and will need further studies to clarify, given the conflicting reports in recent studies. PMID- 23807604 TI - The role of combination medical therapy in acromegaly: hope for the nonresponsive patient. AB - PURPOSE OF REVIEW: This review focuses on combination drug treatment for acromegaly patients, including novel concepts and experimental therapies, with an emphasis on the author's personal experience. RECENT FINDINGS: A review of published clinical studies demonstrates that combination therapy; somatostatin receptor ligands and dopamine agonists, somatostatin receptor ligands and pegvisomant, or cabergoline and pegvisomant could provide significant additive biochemical control of acromegaly in patients inadequately controlled with conventional somatostatin receptor ligand therapy. SUMMARY: Advances in combination medical therapy have opened up new perspectives for acromegaly patients who are poorly, or nonresponsive to, presently available single drug therapies. PMID- 23807605 TI - Update in the medical therapy of Cushing's disease. AB - PURPOSE OF REVIEW: Recently developed agents treat Cushing's disease by inhibiting ACTH secretion from corticotrope tumors or antagonizing cortisol action. RECENT FINDINGS: The dopamine agonist cabergoline and the somatostatin agonist pasireotide target ACTH secretion. Each has low rates of normalization of urine-free cortisol (UFC), about 40% at doses of 1-7 mg weekly and 20% at doses of 600 or 900 MUg twice daily, respectively. Cabergoline, an oral agent, has a relatively benign side-effect profile, primarily asthenia. Small trials suggest that combination therapy with ketoconazole increases effectiveness. Pasireotide, a parenteral agent, is associated with types and rates of adverse events similar to those seen with other somatostatin agonists (diarrhea, nausea, cholelithiasis), except for glucose intolerance, which occurs more frequently (~75%). It may be most effective when UFC is less than two-fold normal. A few case reports suggest that pasireotide or cabergoline may control tumor size and ACTH secretion from macroadenomas. Retinoic acid must be evaluated further. The glucocorticoid antagonist mifepristone ameliorates glucose intolerance but may not normalize other Cushingoid features. SUMMARY: These novel approaches provide options for treatment of patients in whom surgery has failed or is not possible, and those who decline adrenalectomy or radiation therapy. PMID- 23807607 TI - Radiation-induced hypopituitarism. AB - PURPOSE OF REVIEW: Progressive and irreversible neuro-endocrine dysfunction following radiation-induced damage to the hypothalamic-pituitary (h-p) axis is the most common complication in cancer survivors with a history of cranial radiotherapy involving the h-p axis and in patients with a history of conventional or stereotactic pituitary radiotherapy for pituitary tumours. This review examines the controversy about the site and pathophysiology of radiation damage while providing an epidemiological perspective on the frequency and pattern of radiation-induced hypopituitarism. RECENT FINDINGS: Contrary to the previously held belief that h-p axis irradiation with doses less than 40 Gy result in a predominant hypothalamic damage with time-dependent secondary pituitary atrophy, recent evidence in survivors of nonpituitary brain tumours suggests that cranial radiation causes direct pituitary damage with compensatory increase in hypothalamic release activity. Sparing the hypothalamus from significant irradiation with sterteotactic radiotherapy for pituitary tumours does not appear to reduce the long-term risk of hypopituitarism. SUMMARY: Radiation-induced h-p dysfunction may occur in up to 80% of patients followed long term and is often associated with an adverse impact on growth, body image, skeletal health, fertility, sexual function and physical and psychological health. A detailed understanding of pathophysiological and epidemiological aspects of radiation-induced h-p axis dysfunction is important to provide targeted and reliable long-term surveillance to those at risk so that timely diagnosis and hormone-replacement therapy can be provided. PMID- 23807608 TI - Neuroendocrine consequences of traumatic brain injury. AB - PURPOSE OF REVIEW: This article attempts to summarize findings of recent publications addressing the prevalence, effects, and treatment of pituitary hormone deficiency following traumatic brain injury (TBI). RECENT FINDINGS: A number of recent studies of TBI victims offer larger samples and much longer follow-up times. However, the prevalence of pituitary hormone deficiency continues to vary widely, underscoring the influence of patient selection, differences in endocrine testing, and patient's comorbidities and age. Growth hormone deficiency (GHD) continues to be the most frequently detected type of pituitary dysfunction. Several reports show the influence of GHD on functional outcomes of TBI victims beyond what is predicted by trauma severity. Emerging data support the notion growth hormone (GH) replacement as a useful intervention to improve symptomatology and functional outcomes among adequately selected GH deficient patients recovering from TBI. SUMMARY: Pituitary dysfunction is prevalent following TBI. Pituitary dysfunction seems to influence functional outcomes in some patients recovering from brain injury. Adequately selected patients could benefit from hormonal replacement. PMID- 23807606 TI - Metabolic influences on neuroendocrine regulation of reproduction. AB - PURPOSE OF REVIEW: Reproduction is a tightly regulated function in which many mechanisms contribute to ensure the survival of the species. Among those, due to the elevated energy requirements of reproduction, metabolic factors exert a pivotal role in the control of hypothalamic-pituitary-gonadal axis. Although this control may occur at multiple levels of the axis, the majority of interactions between metabolic and reproductive systems take place in the hypothalamus. In this article, we present an overview of the state-of-the-art knowledge regarding the metabolic regulation of reproduction at the central level. We aim to identify the neuroanatomical location where both functions interconnect by discussing the likelihood of each component of the neuronal hierarchical network controlling gonadotropin-releasing hormone (GnRH) release to be first-order responders to metabolic cues, especially the peripheral metabolic signals leptin, insulin, and ghrelin. RECENT FINDINGS: Latest evidence suggests that the primary action of leptin, insulin, and ghrelin to regulate reproduction is located upstream of the main central elicitors of gonadotropin release, Kiss1 and GnRH neurons, and neuroanatomically separated from their metabolic action. SUMMARY: The study of the neuronal interactions between the mechanisms governing metabolism and reproduction offers the platform to overcome or treat a number of prevailing metabolic and/or reproductive conditions. PMID- 23807609 TI - Current world literature. Diabetes and the endocrine pancreas II. PMID- 23807611 TI - Geographic variation in the frequency of abdominal adiposity and metabolic syndrome in Italian adolescents with type 1 diabetes. PMID- 23807612 TI - Transient no reflow following primary percutaneous coronary intervention. AB - No reflow following primary percutaneous coronary intervention (PCI) is a serious complication in the treatment of acute myocardial infarction. No reflow in some patients is reversible (transient no reflow), whereas no reflow in others persists until the end of the procedure (persistent no reflow). The aim of this study was to identify clinical features of transient no reflow following primary PCI. Consecutive patients with no reflow (n = 123) were enrolled following primary PCI. Among them, 59 patients were in the transient group and 64 in the persistent group. We compared clinical features and hospital outcomes between the two groups. Multivariate logistic regression analysis was performed to identify the determinants of transient no reflow. The transient group had a lower rate of in-hospital cardiac death than the persistent group (0 vs. 6.4 %, relatively, P = 0.018). There was a trend for a shorter length of hospital stay in the transient group. Multivariate logistic regression analysis identified initial thrombolysis in myocardial infarction (TIMI) flow grade 3 (OR 6.239, 95 % CI 1.727-22.541, P = 0.005) and a higher estimated glomerular filtration rate (OR 1.204, 95 % CI 1.006 1.440, P = 0.042) as independent predictors of transient no reflow. Transient no reflow tended to be associated with TIMI thrombus grade <=3 (OR 2.879, 95 % CI 0.928-8.931, P = 0.067). In conclusion, initial TIMI flow grade 3 and preserved renal function were associated with recovery from no reflow. Initial angiographic finding such as TIMI flow or TIMI thrombus grade might be an important predictor of recovery from the no-reflow phenomenon. PMID- 23807614 TI - Variations in predicted risks in personal genome testing for common complex diseases. AB - PURPOSE: The promise of personalized genomics for common complex diseases depends, in part, on the ability to predict genetic risks on the basis of single nucleotide polymorphisms. We examined and compared the methods of three companies (23andMe, deCODEme, and Navigenics) that have offered direct-to-consumer personal genome testing. METHODS: We simulated genotype data for 100,000 individuals on the basis of published genotype frequencies and predicted disease risks using the methods of the companies. Predictive ability for six diseases was assessed by the AUC. RESULTS: AUC values differed among the diseases and among the companies. The highest values of the AUC were observed for age-related macular degeneration, celiac disease, and Crohn disease. The largest difference among the companies was found for celiac disease: the AUC was 0.73 for 23andMe and 0.82 for deCODEme. Predicted risks differed substantially among the companies as a result of differences in the sets of single nucleotide polymorphisms selected and the average population risks selected by the companies, and in the formulas used for the calculation of risks. CONCLUSION: Future efforts to design predictive models for the genomics of common complex diseases may benefit from understanding the strengths and limitations of the predictive algorithms designed by these early companies. PMID- 23807613 TI - Long-term incidence and prognostic factors of the progression of new coronary lesions in Japanese coronary artery disease patients after percutaneous coronary intervention. AB - Revascularization of an initially non-target site due to its progression as a new culprit lesion has emerged as a new therapeutic target of coronary artery disease (CAD) in the era of drug-eluting stents. Using the Shinken database, a single hospital-based cohort, we aimed to clarify the incidence and prognostic factors for progression of previously non-significant coronary portions after prior percutaneous coronary intervention (PCI) in Japanese CAD patients. We selected from the Shinken database a single-hospital-based cohort of Japanese patients (n = 15227) who visited the Cardiovascular Institute between 2004 and 2010 to undergo PCI. This study included 1,214 patients (median follow-up period, 1,032 +/- 704 days). Additional clinically driven PCI to treat previously non significant lesions was performed in 152 patients. The cumulative rate of new lesion PCI was 9.5 % at 1 year, 14.4 % at 3 years, and 17.6 % at 5 years. There was no difference in background clinical characteristics between patients with and without additional PCI. Prevalence of multi-vessel disease (MVD) (82 vs. 57 %, p < 0.001) and obesity (47 vs. 38 %, p = 0.028) were significantly higher and high-density lipoprotein cholesterol (HDL) level (51 +/- 15 vs. 47 +/- 12 mg/dl, p < 0.001) was significantly lower in patients with additional PCI than those without. Patients using insulin (6 vs. 3 %, p = 0.035) were more common in patients with additional PCI. Multivariate analysis showed that MVD, lower HDL, and insulin use were independent determinants of progression of new culprit coronary lesions. In conclusion, progression of new coronary lesions was common and new-lesion PCI continued to occur beyond 1 year after PCI without attenuation of their annual incidences up to 5 years. Greater coronary artery disease burden, low HDL, and insulin-dependent DM were independent predictors of progression of new culprit coronary lesions. PMID- 23807615 TI - Understanding of informed consent by parents of children enrolled in a genetic biobank. AB - PURPOSE: Prior research suggests that parents undervalue long-term risks associated with their children's participation in research studies. The primary aim of this study was to evaluate parental understanding of informed consent for a pediatric biobanking study. METHODS: The study population included parents who provided consent for their child to participate in a study examining the genetic etiology of congenital cardiovascular malformations. Informed consent understanding was measured by adapting the Quality of Informed Consent assessment to our study. We evaluated possible predictors of individual Quality of Informed Consent items using generalized estimating equations. RESULTS: A total of 252 individuals representing 188 families completed the study. The Quality of Informed Consent items best understood by parents included consent to participate in research, the main purpose of the study, and the possibility of no direct benefit. The items least understood by parents were those involving the indefinite storage of DNA, the possible risks of participation, and the fact that the study was not intended to treat their child's heart defect. Parent age and medical decision making by one versus both parents were frequent predictors of individual Quality of Informed Consent items. CONCLUSION: Parents overestimate personal benefit and underestimate the risks associated with their child's participation in a biobanking study.Genet Med 16 2, 141-148. PMID- 23807617 TI - Regional differences in disability retirement: explaining between-county differences in Finland. AB - OBJECTIVES: This study aimed to examine between-county differences in disability retirement due to main diagnosis groups and explain these differences by individual-level demographic and work-related factors and municipality-level characteristics. METHODS: A 20% random sample of the Finnish social insured population aged 25-62 years at the end of 2006 was followed for disability retirement until the end of 2011. Individual-level demographic and work-related covariates were derived from the registers of the Finnish Centre for Pensions and complemented by municipality-level covariates from the national SotkaNet databank. Standardized disability retirement rates were calculated and logistic regression analysis was used to examine between-county differences during the 5 year follow-up. RESULTS: In the county with the highest incidence, disability retirement was nearly twice as common as in the county with the lowest incidence. The between-county differences were larger in disability retirement due to cardiovascular and musculoskeletal diseases than other causes. Adjusting for demographic and work-related characteristics explained a third of the differences. Further adjustment for municipal characteristics explained up to 60% of the differences. However, in regions of Northern and Eastern Finland with the highest incidence of disability retirement, 20-30% excess incidence remained even after all adjustments. CONCLUSIONS: Large differences exist in disability retirement between Finnish counties. Disability retirement due to musculoskeletal diseases has the highest impact on the overall differences. Demographic structure and work-related characteristics but also municipality-level characteristics contribute to these differences. PMID- 23807616 TI - Researchers' views on return of incidental genomic research results: qualitative and quantitative findings. AB - PURPOSE: Comprehensive genomic analysis including exome and genome sequencing is increasingly being utilized in research studies, leading to the generation of incidental genetic findings. It is unclear how researchers plan to deal with incidental genetic findings. METHODS: We conducted a survey of the practices and attitudes of 234 members of the US genetic research community and performed qualitative semistructured interviews with 28 genomic researchers to understand their views and experiences with incidental genetic research findings. RESULTS: We found that 12% of the researchers had returned incidental genetic findings, and an additional 28% planned to do so. A large majority of researchers (95%) believe that incidental findings for highly penetrant disorders with immediate medical implications should be offered to research participants. However, there was no consensus on returning incidental results for other conditions varying in penetrance and medical actionability. Researchers raised concerns that the return of incidental findings would impose significant burdens on research and could potentially have deleterious effects on research participants if not performed well. Researchers identified assistance needed to enable effective, accurate return of incidental findings. CONCLUSION: The majority of the researchers believe that research participants should have the option to receive at least some incidental genetic research results. PMID- 23807618 TI - Role of CREB signaling in aging brain. AB - During aging, brain undergoes several changes which influence its function through alteration in the expression of genes. Some of these genes are regulated by estrogen which requires a host of coregulator proteins including CREB. In brain, CREB is expressed in different regions and regulates a wide range of functions such as cellular growth, proliferation and memory in response to a variety of intracellular signaling events including synaptic efficacy and long lasting changes in synaptic plasticity. In response to signals at the cell surface, CREB is phosphorylated in the nucleus by various protein kinases via secondary messengers such as cAMP and/or Ca+2 for regulating specific genes. Alterations in CREB signaling lead to cognitive deficits as observed in normal aging and neurodegenerative diseases. In brain, the expression of CREB changes with age, but its variation with sex is not known. So, in this review paper, we summarize recent findings indicating age and sex dependent expression of CREB and its interaction with estrogen receptor (ER)beta, and the role of CREB signaling in brain aging and diseases. Such understanding of CREB signaling through ER may help to design therapeutic strategies for age related cognitive deficits and neurodegenerative disorders. PMID- 23807620 TI - Persistent effects after trigeminal nerve proprioceptive stimulation by mandibular extension on rat blood pressure, heart rate and pial microcirculation. AB - The trigemino-cardiac reflex is a brainstem reflex known to lead to a decrement in heart rate and blood pressure, whereas few data have been collected about its effects on the cerebral hemodynamic. In this study we assess the in vivo effects of trigeminal nerve peripheral stimulation by mandibular extension on pial microcirculation and systemic arterial blood pressure in rats. Experiments were performed in male Wistar rats subjected to mandibular extension obtained inserting an ad hoc developed retractor between the dental arches. Mean arterial blood pressure and heart rate were recorded and the pial arterioles were visualized by fluorescence microscopy to measure the vessel diameters before (15 minutes) during (5-15 minutes) and after (80 minutes) mandibular extension. While in control rats (sham-operated rats) and in rats subjected to the dissection of the trigeminal peripheral branches mean arterial blood pressure, heart rate and pial microcirculation did not change during the whole observation period (110 minutes), in rats submitted to mandibular extension, mean arterial blood pressure, heart rate and arteriolar diameter significantly decreased during stimulation. Afterward mean arterial blood pressure remained reduced as well as heart rate, while arteriolar diameter significantly increased evidencing a vasodilatation persisting for the whole remaining observation time. Therefore, trigeminal nerve proprioceptive stimulation appears to trigger specific mechanisms regulating systemic arterial blood pressure and pial microcirculation. PMID- 23807619 TI - High volume microinfusion suppresses local astrocyte response within nucleus basalis of rat. AB - Our study investigates the impact of different volume sham control and excitotoxin microinfusions in vivo on local reactive astroglial response within rat nucleus basalis (NB). We followed the effects of unilateral 200, 100, and 50 nL of sham-control (phosphate buffer PBS) versus ibotenic acid (IBO) microinfusions, mechanical NB lesion (10 uL Hamylton syringe needle positioned into NB for 5 min), or physiological control (intact brain), on the local reactive astroglial response within the NB site, by immunoreactivity against glial fibrillary acidic protein (GFAP). NB lesions were identified by NADPHdiaphorase histochemistry. Local astrocytes responses within NB were suppressed by both high volume microinfusions, PBS and IBO (200 and 100 nL) versus mechanical lesion. Our study has proved, for the first time, the volume of microinfusion as critical for any selective pharmacological stimulation or lesion in vivo, and suggest the microinfusion volume less than 50nL as protective for physiological astroglial reactivity. PMID- 23807621 TI - Minimal changes of thyroid axis activity influence brain functions in young females affected by subclinical hypothyroidism. AB - There is evidence of an association between thyroid hormones (TH) alterations and mental dysfunctions related to procedural and working memory functions, but the physiological link between these domains is still under debate, also for the presence of age as a confounding factor. Thus, we investigated the TH tuning of cerebral functions in young females affected by the borderline condition of subclinical hypothyroidism (SH) and in euthyroid females of the same age. The experiment consisted in the characterization of the affective state and cognitive abilities of the subjects by means of specific neuropsychological questionnaires, and of brain activity (EEG) in resting state and during the passive viewing of emotional video-clips. We found that SH had i) increased anxiety for Physical Danger; ii) better scores for both Mental Control and no-working-memory-related functions; iii) association between anxiety for Physical Danger and fT4 levels. Thus, in young adults, SH increases inward attention and paradoxically improves some cognitive functions. In addition, self-assessed questionnaires showed that SH had a greater susceptibility to unpleasant emotional stimulation. As for EEG data, SH compared to controls showed: i) reduction of alpha activity and of gamma left lateralization in resting state; ii) increased, and lateralized to the right, beta2 activity during stimulations. Both results indicated that SH have higher levels of arousal and greater susceptibility to negative emotion than controls. In conclusion, our study indicates that minimal changes in TH levels produce subtle but well-defined mental changes, thus encouraging further studies for the prediction of pathology evolution. PMID- 23807622 TI - DNA interaction of CuII, NiII and ZnII functionalized salphen complexes: studies by linear dichroism, gel electrophoresis and PCR. AB - The interaction of salphen-type NiII, CuII and ZnII complexes with native DNA was investigated by exploiting linear dichroism experiments. The NiII complex behaves as a typical intercalator, binding strongly and stiffening and unwinding the DNA. The strength of the DNA interaction is slightly weaker for the copper complex and much weaker for the zinc complex. Plasmid-DNA gel electrophoresis experiments indicated that while CuII and ZnII complexes do not induce the unwinding of supercoiled DNA, the NiII complex has a nuclease activity without the addition of external agents. On the other hand, as shown in the PCR assays, we demonstrate that, at the used concentrations, only the CuII complex is able to inhibit the DNA amplification mediated by Taq DNA polymerase. In this paper we have also reported a detailed characterization of the three compounds including 2D-NMR and ESI-mass experiments and X-ray single crystal structure of the copper and nickel compounds. PMID- 23807623 TI - Left ventricular synchronicity in acromegaly. PMID- 23807624 TI - Surface plasmon delocalization in silver nanoparticle aggregates revealed by subdiffraction supercontinuum hot spots. AB - The plasmonic resonances of nanostructured silver films produce exceptional surface enhancement, enabling reproducible single-molecule Raman scattering measurements. Supporting a broad range of plasmonic resonances, these disordered systems are difficult to investigate with conventional far-field spectroscopy. Here, we use nonlinear excitation spectroscopy and polarization anisotropy of single optical hot spots of supercontinuum generation to track the transformation of these plasmon modes as the mesoscopic structure is tuned from a film of discrete nanoparticles to a semicontinuous layer of aggregated particles. We demonstrate how hot spot formation from diffractively-coupled nanoparticles with broad spectral resonances transitions to that from spatially delocalized surface plasmon excitations, exhibiting multiple excitation resonances as narrow as 13 meV. Photon-localization microscopy reveals that the delocalized plasmons are capable of focusing multiple narrow radiation bands over a broadband range to the same spatial region within 6 nm, underscoring the existence of novel plasmonic nanoresonators embedded in highly disordered systems. PMID- 23807625 TI - Species identification of Asini Corii Collas (donkey glue) by PCR amplification of cytochrome b gene. AB - Asini Corii Collas (ACC; donkey glue) is a crude drug used to promote hematopoiesis and arrest bleeding. Because adulteration of the drug with substances from other animals such as horses, cattle, and pigs has been found, we examined PCR methods based on the sequence of the cytochrome b gene for source species identification. Two strategies for extracting DNA from ACC were compared, and the ion-exchange resin procedure was revealed to be more suitable than the silica-based one. Using DNA extracted from ACC by the ion-exchange resin procedure, PCR methods for species-specific detection of donkey, horse, cattle, and pig substances were established. When these species-specific PCR methods were applied to ACC, amplicons were obtained only by the donkey-specific PCR. Cattle specific PCR detected as little as 0.1% admixture of cattle glue in the ACC. These results suggest that the species-specific PCR methods established in this study would be useful for simple and easy detection of adulteration of ACC. PMID- 23807626 TI - Synthesis of a phosphine imide bearing a hydrosilane moiety, and its water-driven reduction to a phosphine. AB - Organosilanes bearing a phosphine imide moiety were synthesized and crystallographically characterized. Reaction of the pentacoordinated hydrodiphenylsilyl derivative with water gave [2 (diphenylphosphino)phenyl]diphenylsilanol accompanied by both reduction of the phosphine imide moiety and hydrolytic oxidation of the Si-H moiety. PMID- 23807627 TI - Community treatment orders: state of the evidence. PMID- 23807628 TI - Antisocial Personality Disorder Subscale (Chinese Version) of the Structured Clinical Interview for the DSM-IV Axis II disorders: validation study in Cantonese-speaking Hong Kong Chinese. AB - OBJECTIVE. Antisocial personality disorder (ASPD) is a risk factor for violence and is associated with poor treatment response when it is a co-morbid condition with substance abuse. It is an under-recognised clinical entity in the local Hong Kong setting, for which there are only a few available Chinese-language diagnostic instruments. None has been tested for its psychometric properties in the Cantonese-speaking population in Hong Kong. This study therefore aimed to assess the reliability and validity of the Chinese version of the ASPD subscale of the Structured Clinical Interview for the DSM-IV Axis II Disorders (SCID-II) in Hong Kong Chinese. METHODS. This assessment tool was modified according to dialectal differences between Mainland China and Hong Kong. Inpatients in Castle Peak Hospital, Hong Kong, who were designated for priority follow-up based on their assessed propensity for violence and who fulfilled the inclusion criteria for the study, were recruited. To assess the level of agreement, best-estimate diagnosis made by a multidisciplinary team was compared with diagnostic status determined by the SCID-II ASPD subscale. The internal consistency, sensitivity, and specificity of the subscale were also calculated. RESULTS. The internal consistency of the subscale was acceptable at 0.79, whereas the test-retest reliability and inter-rater reliability showed an excellent and good agreement of 0.90 and 0.86, respectively. Best-estimate clinical diagnosis-SCID diagnosis agreement was acceptable at 0.76. The sensitivity, specificity, positive and negative predictive values were 0.91, 0.86, 0.83, and 0.93, respectively. CONCLUSION. The Chinese version of the SCID-II ASPD subscale is reliable and valid for diagnosing ASPD in a Cantonese-speaking clinical population. PMID- 23807629 TI - Positive aspects of caregiving and its correlates in caregivers of schizophrenia: a study from north India. AB - OBJECTIVE. To study the positive aspects of caregiving and its correlates in primary caregivers of patients with schizophrenia. METHODS. A total of 100 patients with schizophrenia and their primary caregivers were evaluated. Regarding the caregivers, their positive aspects of caregiving were assessed on the Scale for Positive Aspects of Caregiving Experience (SPACE). To examine the correlates of positive aspects of caregiving, they were also assessed on the Family Burden Interview (FBI) Schedule, the Involvement Evaluation Questionnaire (IEQ), coping checklist, the Social Support Questionnaire, the World Health Organization Quality of Life-BREF (Hindi version), the WHO Quality of Life Spirituality, Religiousness and Personal Beliefs Scale, as well as the General Health Questionnaire-12. The patients were assessed on the Positive and Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning Scale. RESULTS. On the SPACE, the highest mean score was seen in the domain of motivation for the caregiving role (2.7), followed by that of caregiver satisfaction (2.4) and caregiver gains (2.3). The mean score was least for the domain of self-esteem and social aspect of caring (1.9). The SPACE domain of caregiver satisfaction correlated negatively with many aspects of burden as assessed by FBI Schedule and coping as assessed by the coping checklist; whereas the self-esteem and social aspect of caring domain correlated positively with worrying-urging II domain and the total IEQ score. No significant correlations between the SPACE and socio demographics as well as most of the clinical variables were noted. Motivation for the caregiving had a positive correlation with the PANSS negative symptom scale. Multiple correlations were found between the SPACE and quality of life, suggesting that higher positive caregiving experience was associated with better quality of life in caregivers. CONCLUSION. Caregivers of patients with schizophrenia do enjoy positive aspects of caregiving while taking care of their ill relatives. In these caregivers, the positive aspects of caregiving were associated with better quality of life. PMID- 23807630 TI - Symptoms and aetiology of delirium: a comparison of elderly and adult patients. AB - OBJECTIVE. To compare the symptoms of delirium as assessed by the Delirium Rating Scale-Revised-98 (DRS-R-98) and associated aetiologies in adult and elderly patients seen in a consultation-liaison service. METHODS. A total of 321 consecutive patients with a DSM-IV-TR diagnosis of delirium were assessed on the DRS-R-98 and a study-specific aetiology checklist. RESULTS. Of the 321 patients, 245 (76%) aged 18 to 64 years formed the adult group, while 76 (24%) formed the elderly group (>= 65 years). The prevalence and severity of various symptoms of delirium as assessed using the DRS-R-98 were similar across the 2 groups, except for the adult group having statistically higher prevalence and severity scores for thought process abnormalities and lability of affect. For both groups and the whole sample, factor analysis yielded a 3-factor model for the phenomenology. In the 2 groups, the DRS-R-98 item loadings showed subtle differences across various factors. The 2 groups were similar for the mean number of aetiologies associated with delirium, the mean number being 3. However, the 2 groups differed with respect to hepatic derangement, substance intoxication, withdrawal, and postpartum causes being more common in the adult group, in contrast lung disease and cardiac abnormalities were more common in the elderly group. CONCLUSION. Adult and elderly patients with delirium are similar with respect to the distribution of various symptoms, motor subtypes, and associated aetiologies. PMID- 23807631 TI - Psychopathology, cognitive function, and social functioning of patients with schizophrenia. AB - OBJECTIVES. To explore the relationship between cognitive functions, social functioning, and psychopathology in schizophrenia. METHODS. Patients diagnosed with schizophrenia, according to the ICD-10 criteria, were enrolled from the Department of Psychiatry of 2 postgraduate hospitals in Kolkata, India. The Positive and Negative Syndrome Scale for Schizophrenia, Schizophrenia Research Foundation India-Social Functioning Index, and a cognitive test battery were administered. RESULTS. Regarding the 100 patients recruited into the study, 4 subtests (self-care, occupational role, social role, and family role) of the social functioning were found to be significantly correlated with cognitive functions. Cognitive function battery performance scores were more inversely correlated with negative symptoms than with positive symptoms. CONCLUSION. Positive and negative symptoms along with verbal fluency were able to predict social functioning. PMID- 23807632 TI - Prevalence of blood parasites in eastern versus Western house finches: are eastern birds resistant to infection? AB - The rapid spread of the bacterial disease, Mycoplasma gallisepticum (MG), throughout the introduced range of house finches (Carpodacus mexicanus) in eastern North America, compared to its slower spread through the native western range, has puzzled researchers and highlights the need to understand the relative differences in health state of finches from both populations. We conducted a light-microscope survey of hemoparasites in populations of finches from Arizona (within the western range) and from Alabama (within the eastern range), and compared our estimates of prevalence to published reports from house finches sampled in both ranges. Of the 33 Arizona birds examined, we recorded hematozoan infections in 16 (48.5%) individuals, compared to 1 infected Alabama bird out of 30 birds examined (3.3%). Based on independent surveys of seven western North American and five eastern North American populations of house finches the average prevalence of blood parasites in western populations is 38.8% (+/-17.9 SD), while the average prevalence within the eastern range is only 5.9% (+/-6.1 SD). The average rate of infection among all songbirds sampled in the east is 34.2% (+/ 4.8 SD). Thus, our surveys of wild birds as well as previously published observations point to eastern house finches having a much lower prevalence of blood parasite infections than their western counterparts. Combined with the fact that eastern finches also tend to have lower rates of avian pox infections than do western birds (based on a literature review), these observations suggest that eastern birds have either strong resistance to these infections or high susceptibility and associated mortality. PMID- 23807633 TI - The distribution of phthalate esters in indoor dust of Palermo (Italy). AB - In this work, phthalic acid esters (PAEs): dimethyl phthalate (DMP), diethyl phthalate (DEP), di-n-butyl phthalate, benzyl butyl phthalate, bis(2-ethylhexyl) phthalate, and di-n-octyl phthalate in indoor dust (used as passive sampler) were investigated. The settled dust samples were collected from thirteen indoor environments from Palermo city. A fast and simple method using Soxhlet and GC-MS analysis has been optimized to identify and quantify the phthalates. Total phthalates concentrations in indoor dusts ranged from 269 to 4,831 mg/kg d.w. (d.w. = dry weight). The data show a linear correlation between total PAEs concentration and a single compound content, with the exclusion of the two most volatile components (DMP and DEP) that are present in appreciable amounts only in two samples. These results suggest that most of the PAEs identified in the samples of settled dust originate from the same type of material. This evidence indicates that, in a specific indoor environment, generally is not present only one compound but a mixture having over time comparable percentages of PAEs. Consequently, for routine analyses of a specific indoor environment, only a smaller number of compounds could be determined to value the contamination of that environment. We also note differences in phthalate concentrations between buildings from different construction periods; the total concentration of PAEs was higher in ancient homes compared to those constructed later. This is due to a trend to reduce or remove certain hazardous compounds from building materials and consumer goods. A linear correlation between total PAEs concentration and age of the building was observed (R = 0.71). PMID- 23807635 TI - Hedgehog in the Drosophila testis niche: what does it do there? AB - Stem cell niche is a specialized microenvironment crucial to self-renewal. The testis in Drosophila contains two different types of stem cells, the germline stem cells and the somatic cyst stem cells that are sustained by their respective niche signals, thus is a good system for studying the interaction between the stem cells and their hosting niche. The JAK-STAT and BMP pathways are known to play critical roles in the self-renewal of different kinds of stem cells, but the roles of several other pathways have emerged recently in a complex signaling network in the testis niche. Reports of independent observations from three research groups have uncovered an important role of Hedgehog (Hh) in the Drosophila testis niche. In this review, we summarize these recent findings and discuss the interplay between the Hh signaling mechanisms and those of the JAK STAT and BMP pathways. We also discuss directions for further investigation. PMID- 23807636 TI - The Pontin series of recombinant alien translocations in bread wheat: single translocations integrating combinations of Bdv2, Lr19 and Sr25 disease-resistance genes from Thinopyrum intermedium and Th. ponticum. AB - Two bread wheat lines each with a translocation on chromosome 7DL from either Thinopyrum intermedium (TC5 and TC14) or Thinopyrum ponticum (T4m), were hybridized in a ph1b mutant background to enhance recombination between the two translocated chromosomal segments. The frequency of recombinants was high in lines derived from the larger and similar-sized translocations (TC5/T4m), but much lower when derived from different-sized translocations (TC14/T4m). Recombinant translocations contained combinations of resistance genes Bdv2, Lr19 and Sr25 conferring resistance to Barley yellow dwarf virus (BYDV), leaf rust and stem rust, respectively. Their genetic composition was identified using bioassays and molecular markers specific for the two progenitor Thinopyrum species. This set of 7DL Th. ponticum/intermedium recombinant translocations was termed the Pontin series. In addition to Thinopyrum markers, the size of the translocation was estimated with the aid of wheat markers mapped on each of the 7DL deletion bins. Bioassays for BYDV, leaf rust and stem rust were performed under greenhouse and field conditions. Once separated from ph1b background, the Pontin recombinant translocations were stable and showed normal inheritance in successive backcrosses. The reported Pontin translocations integrate important resistance genes in a single linkage block which will allow simultaneous selection of disease resistance. Combinations of Bdv2 + Lr19 or Lr19 + Sr25 in both long and short translocations, are available to date. The smaller Pontins, comprising only 20 % of the distal portion of 7DL, will be most attractive to breeders. PMID- 23807634 TI - Crystal structures and biochemical studies of human lysophosphatidic acid phosphatase type 6. AB - Lysophosphatidic acid (LPA) is an important bioactive phospholipid involved in cell signaling through Gprotein-coupled receptors pathways. It is also involved in balancing the lipid composition inside the cell, and modulates the function of lipid rafts as an intermediate in phospholipid metabolism. Because of its involvement in these important processes, LPA degradation needs to be regulated as precisely as its production. Lysophosphatidic acid phosphatase type 6 (ACP6) is an LPA-specific acid phosphatase that hydrolyzes LPA to monoacylglycerol (MAG) and phosphate. Here, we report three crystal structures of human ACP6 in complex with malonate, L-(+)-tartrate and tris, respectively. Our analyses revealed that ACP6 possesses a highly conserved Rossmann-foldlike body domain as well as a less conserved cap domain. The vast hydrophobic substrate-binding pocket, which is located between those two domains, is suitable for accommodating LPA, and its shape is different from that of other histidine acid phosphatases, a fact that is consistent with the observed difference in substrate preferences. Our analysis of the binding of three molecules in the active site reveals the involvement of six conserved and crucial residues in binding of the LPA phosphate group and its catalysis. The structure also indicates a water-supplying channel for substrate hydrolysis. Our structural data are consistent with the fact that the enzyme is active as a monomer. In combination with additional mutagenesis and enzyme activity studies, our structural data provide important insights into substrate recognition and the mechanism for catalytic activity of ACP6. PMID- 23807637 TI - Recurrent brachial artery embolism caused by a crutch-induced axillary artery aneurysm: report of a case. AB - We report a case of axillary artery aneurysm with brachial artery embolism in a 60-year-old man who had walked with the assistance of axillary crutches all of his life since poliomyelitis during infancy had left him with lower limb paralysis. We performed bypass grafting from the axillary to brachial artery with exclusion of the aneurysm. An axillary artery aneurysm is rare, but potentially lethal for the upper extremity; therefore, surgical treatment should be considered. PMID- 23807639 TI - Differentiating a large abdominal cystic lymphangioma from multicystic mesothelioma: report of a case. AB - We report a case of retroperitoneal cystic lymphangioma in a 30-year-old woman who presented with abdominal distention and pain. Imaging studies revealed a large, thin-walled multicystic mass occupying the whole abdomen. Based on a preoperative diagnosis of multicystic mesothelioma, we performed laparotomy, which revealed a tumor arising from the gastropancreatic ligament in the posterior wall of the omental bursa. We resected the tumor completely, without the adjacent viscera. The final pathological diagnosis was cystic lymphangioma, based on the immunohistochemical findings of positive CD31 and CD34 expression, the presence of smooth muscle confirmed by smooth muscle antigen and desmin, and negative calretinin, WT-1 and cytokeratins 5/6 expression. Multicystic mesotheliomas and cystic lymphangiomas are so similar in morphology that immunohistochemical staining should be fully utilized to differentiate them. PMID- 23807640 TI - Bone morphogenetic protein-2 gene controls tooth root development in coordination with formation of the periodontium. AB - Formation of the periodontium begins following onset of tooth-root formation in a coordinated manner after birth. Dental follicle progenitor cells are thought to form the cementum, alveolar bone and Sharpey's fibers of the periodontal ligament (PDL). However, little is known about the regulatory morphogens that control differentiation and function of these progenitor cells, as well as the progenitor cells involved in crown and root formation. We investigated the role of bone morphogenetic protein-2 (Bmp2) in these processes by the conditional removal of the Bmp2 gene using the Sp7-Cre-EGFP mouse model. Sp7-Cre-EGFP first becomes active at E18 in the first molar, with robust Cre activity at postnatal day 0 (P0), followed by Cre activity in the second molar, which occurs after P0. There is robust Cre activity in the periodontium and third molars by 2 weeks of age. When the Bmp2 gene is removed from Sp7(+) (Osterix(+)) cells, major defects are noted in root, cellular cementum and periodontium formation. First, there are major cell autonomous defects in root-odontoblast terminal differentiation. Second, there are major alterations in formation of the PDLs and cellular cementum, correlated with decreased nuclear factor IC (Nfic), periostin and alpha SMA(+) cells. Third, there is a failure to produce vascular endothelial growth factor A (VEGF-A) in the periodontium and the pulp leading to decreased formation of the microvascular and associated candidate stem cells in the Bmp2-cKO(Sp7-Cre EGFP). Fourth, ameloblast function and enamel formation are indirectly altered in the Bmp2-cKO(Sp7-Cre-EGFP). These data demonstrate that the Bmp2 gene has complex roles in postnatal tooth development and periodontium formation. PMID- 23807641 TI - Isolation and characterization of biliary epithelial and stromal cells from resected human cholangiocarcinoma: a novel in vitro model to study tumor-stroma interactions. AB - Cholangiocarcinoma (CCA) is a devastating malignancy arising from the bile ducts. Cancer-associated fibroblasts (CAFs) are key players in CCA invasiveness and in the generation of a desmoplastic reaction. The aim of the present study was to develop a novel model by which to study tumor-stroma interactions using primary cultures of human biliary epithelial cells (hBECs) and stromal cells (SCs) in CCA. hBECs and SCs, isolated from surgical resections (n=10), were semi-purified by centrifugation on a Percoll gradient; hBECs were further immunopurified. hBECs and SCs were characterized using epithelial [cytokeratin 7 (CK7) and CK19] and mesenchymal [vimentin (VMN), alpha-smooth muscle actin (alpha-SMA), CD68] cell markers. The purity of cultured cells was assessed by fluorescent immunocytochemistry. hBECs were HEA125/CK7/CK19-positive and VMN/alpha-SMA negative. SCs were VMN/alpha-SMA-positive and CK7/CK19-negative. CCA 2-D culture models have been described but they use long-standing CCA cell lines of various biliary tumor cell origins with stromal cells derived from non-cholangiocarcinoma tissues. Recently, a novel 3-D organotypic co-culture model of rat cholangiocarcinoma was described. In the present study, we obtained pure and stable primary cultures of hBECs and SCs from CCA surgical specimens. These cell cultures may provide a useful tool by which to study CCA tumor-stroma interactions. PMID- 23807642 TI - Cardiac valve calcification: an immutable pathologic finding in chronic kidney disease? AB - Although less frequent than vascular calcification, cardiac valve calcification (CVC) is a relevant clinical problem affecting about 2%-10% of adults from the general population aged 75 years and older, and is 5- to 10-fold more prevalent in individuals with impaired kidney function. An expanding body of evidence suggests that mineral metabolism abnormalities aside from traditional cardiovascular risk factors are involved in CVC pathogenesis. Nonetheless, very few studies have investigated whether mineral metabolism manipulation impacts CVC. In this issue of the Journal of Nephrology, it is reported that a combination of low-phosphate diet and sevelamer may reduce CVC. Though the observational nature of that study and the lack of a control group significantly limit the generalizability of these results, they fit in with the ongoing debate on the role of chronic kidney disease mineral bone metabolism (CKD-MBD) in the pathogenesis of vascular disease and suggest the importance of mineral metabolism control in patients with CKD. PMID- 23807643 TI - Management of hyperglycemia in patients with chronic kidney disease. AB - Diabetes currently accounts for approximately 45% of cases of end-stage renal failure in patients undergoing hemodialysis. Several observational studies have identified a positive correlation between measures of glycemic control and cardiovascular and microvascular benefits. Several randomized prospective studies have been conducted to quantify the impact of strict glycemic control on morbidity and mortality. These studies have consistently demonstrated an association between strict glycemic control and a reduction in microvascular events, but these results contrast with the lack of consistent results regarding macrovascular events. Treating diabetes has always been challenging. This challenge is increased in chronic kidney disease, due to changes in the pharmacokinetics and pharmacodynamics of insulin and most oral antidiabetic agents. The available pharmacotherapeutic arsenal for treating type 2 diabetes mellitus currently involves approximately 6 different pharmacological classes of oral antidiabetic agents and different modalities of insulin therapy. PMID- 23807644 TI - Fibromuscular dysplasia of renal arteries presenting with bilateral renal infarction in a young man. AB - Fibromuscular dysplasia (FMD) describes a group of conditions which cause nonatheromatous arterial stenoses, most commonly of the renal and carotid arteries, typically in young women. We report the case of a previously healthy 43 year-old white man presenting with acute bilateral flank pain. The pain was more severe on the left side. Initially treated for ureteral colic, he was transferred to the nephrology unit upon recognition of a rising serum creatinine. He was found to have FMD of bilateral renal arteries with resultant infarctions in both kidneys. He was treated with intravenous heparin and, then, warfarin at discharge. At a 16-month review, the patient remained pain-free with normal renal function and with antiplatelet and dual antihypertensive therapy. In conclusion, renal infarction complicating FMD is rare, with most cases involving causative cardiovascular risk factors, including coagulopathy, ischemic heart disease, atrial fibrillation or structural cardiac abnormalities, none of which was present in this case. What makes this case interesting are the clinically significant bilateral renal infarctions due to atypical asymmetric FMD in both kidneys in a young man. PMID- 23807645 TI - Diabetic nephropathy: new approaches for improving glycemic control and reducing risk. AB - Nephropathy is a common consequence of diabetes, with a high prevalence in patients with type 1 (15%-25%) and type 2 diabetes mellitus (T2DM; 30%-40%). Nephropathy is associated with a poor prognosis and high economic burden. The risk of developing nephropathy increases with the duration of diabetes, and early diagnosis and treatment of risk factors for nephropathy (e.g., tight control of glycemia and hypertension) can reduce the development and progression of diabetic nephropathy. Advances in our understanding of the mechanisms of renal complications associated with diabetes and the etiology of nephropathy have identified additional risk factors for nephropathy, and novel therapeutic options are being explored. This review discusses the pathophysiology of diabetic nephropathy and common risk factors. Furthermore, we discuss emerging treatments for T2DM that could potentially slow or prevent the progression of diabetic nephropathy. The use of incretin-based therapies, such as the dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) analogs, is growing in patients with T2DM, due to their efficacy and tolerability profiles. As renal safety is a key factor when choosing treatment options to manage patients with T2DM, drugs that are suitable for use in patients with varying degrees of renal impairment without a requirement for dose adjustment, such as the DPP-4 inhibitor linagliptin, are of particular use. The ongoing advances in T2DM therapy may allow optimization of glycemic control in a wide range of patients, thereby helping to reduce the increasing morbidity and mortality associated with diabetic nephropathy. PMID- 23807646 TI - NF-kappaB and systemic lupus erythematosus: examining the link. AB - Physicians should be knowledgeable regarding several aspects of autoimmune disorders, especially systemic lupus erythematosus (SLE), with which patients can present in their office with urticaria or vasculitis and which may masquerade as another condition. This paper reviews the link between NF-kappaB and SLE, including B-cell development, signaling and cytokines which play a crucial role in the pathogenesis of SLE and T-cell development, a key player in T-cell activation. The roles of dendritic cells, which can promote tolerance or immunity to antigens, of polymorphisms and of NF-kappaB, which are linked with SLE, are also discussed. The role of Toll-like receptors which are important in the pathogenesis of SLE and lupus nephritis is also discussed. PMID- 23807647 TI - Screening for transient ischemic attacks in hemodialysis patients. AB - BACKGROUND: Rapid recognition and management of transient ischemic attacks (TIAs) reduce incident strokes in the general population, but similar data are lacking in dialysis patients, who form a high-risk group for this pathology. We systematically screened hemodialysis patients for TIA to estimate its incidence and determine whether there was significant scope to reduce subsequent strokes by risk modification. METHODS: Patients established on hemodialysis at a satellite dialysis unit at our center were screened prospectively using weekly symptom questionnaires over a 12-month period. Following clinical review, patients who screened positive were urgently referred to a TIA clinic, and all stroke and TIA and stroke events were recorded. RESULTS: A total of 304 patients were screened over 2,594 total patient months of follow-up (1st November 2009 to 1st November 2010). Six strokes occurred, of which 5 were ischemic (a rate of 23.1/1,000 patient-years). No patients screened positive for a TIA, despite predicted rates of 4.2/1,000 patient-years (95% confidence interval, 1.4-9.7/1,000 patient years). One ischemic stroke was preceded by symptoms compatible with a TIA, although this was ascertained in retrospect and not during screening. CONCLUSIONS: Based on the first study of its kind to date, systematic screening for TIA has a low yield and cannot be relied on alone to identify patients at higher risk of cerebrovascular events. The confounding presence of symptoms attributable to uremia, neuropathy, hypotension and dysglycemia could reduce the sensitivity of established tests, with significant implications for the detection and treatment of TIA in dialysis. PMID- 23807648 TI - Neutrophil gelatinase-associated lipocalin in peritoneal dialysis reflects status of peritoneum. AB - BACKGROUND: Ultrafiltration failure and peritonitis are the most important limitations of peritoneal dialysis (PD). The aim of our study was to evaluate peritoneum damage through neutrophil gelatinase-associated lipocalin (NGAL), white blood cell (WBC) count and cancer antigen 125 (CA125). PATIENTS AND METHODS: Thirty patients with peritonitis and 30 patients undergoing continuous ambulatory peritoneal dialysis (CAPD) were studied for 12 months. In the peritonitis group, blood samples and peritoneal fluid (lp) were collected before the onset of peritonitis, at the onset of peritonitis (T1) and every day until its resolution. CAPD patients were divided into 3 groups according to the treatment received. Long-dwell effluents were collected for NGAL, WBC count and Ca125 assessment. RESULTS: In the peritonitis group, at time T1, NGAL levels were higher compared with baseline values. lpNGAL levels decreased at least 24 hours earlier than peritoneal WBC (lpWBC). At ROC analysis, lpNGAL was characterized by a very good diagnostic profile identifying treatment failure. In CAPD patients, the highest NGAL values were observed in the icodextrin group. An inverse correlation between lpNGAL, pKt/V and peritoneal ultrafiltration volume was also found. CONCLUSION: Mesothelial cells have an active role in the structural and functional alteration of the peritoneum during PD, and NGAL represents a valid biomarker for peritoneum evaluation. PMID- 23807649 TI - Invasive assessment of renal artery atherosclerotic disease and resistant hypertension before renal sympathetic denervation. AB - BACKGROUND: Renal sympathetic denervation (RSD) is emerging as a new therapeutic option for patients with severe hypertension refractory to medical therapy. The presence of a renal artery stenosis may be both a cause of secondary hypertension and a contraindication to RSD if a renal artery stent is implanted; therefore, the definition of the functional importance of a renal artery stenosis in a patient with refractory hypertension is crucial. METHODS: We describe the imaging and functional intravascular assessment of an angiographically severe stenosis of the renal artery in a patient with severe refractory hypertension, by means of intravascular ultrasound (IVUS), and measurement of the translesional pressure gradient with a pressure wire. RESULTS: Pressure wire examination excluded any severity of the stenosis, and IVUS showed the presence of a dissected plaque that resolved spontaneously after 3 months of intensive medical therapy and high-dose statin. Subsequently the patient was treated with RSD, achieving a significant effect on blood pressure control. CONCLUSIONS: Intravascular imaging and functional assessment of renal artery anatomy in patients with atherosclerotic disease may prove particularly suited to patients with refractory hypertension and multilevel vascular disease who are considered for endovascular therapies, either renal artery stenting or RSD. PMID- 23807650 TI - Progression of cardiac valve calcification and decline of renal function in CKD patients. AB - BACKGROUND: No study has evaluated the efficacy of non-calcium-containing phosphate binders in slowing progression of cardiac valve calcification or deterioration of kidney function in patients with chronic kidney disease not on dialysis. This study addressed these issues. METHODS: Outpatients (n = 170) with stage 3-4 chronic kidney disease and either mitral or aortic valve calcification were evaluated in this single-center, single-arm, prospective observational study. Patients received sevelamer hydrochloride (1,600 mg/day) for 1 year. Cardiac valve calcification progression was assessed by echocardiography, and decline of renal function by estimated glomerular filtration rate. Parathyroid hormone, FGF-23 and C-reactive protein (CRP) serum concentration and urinary phosphorus excretion were assayed. RESULTS: At the end of treatment with sevelamer (12th month), mitral valve calcification had decreased by 79.3% from baseline. At baseline, 69 patients had grade 1, 97 patients grade 2 and 4 patients grade 3 calcification scores; at the end of the study, 60 patients showed grade 1, and no mitral valve calcification was registered in the remaining patients. An aortic valve score of 1 was found in 32%, score of 2 in 58%, score of 3 in 9% and score of 4 in 1% of patients at baseline; at the end of the study, a score of 1 was found in 95% and a score of 2 in 5% of patients. Significant slowing down of renal function decline (p<0.001), reduction of FGF-23 and CRP concentration (p<0.0001) and phosphorus excretion (p<0.0001) were observed. CONCLUSIONS: One-year treatment with a non-calcium-containing phosphate binder may hamper the progression of cardiac valve calcification and slow the decline of renal function, as well as reduce serum concentration of FGF-23 and CRP and urinary phosphorus excretion. PMID- 23807652 TI - Eliminated risk of iodine contrast cancellation with multibin spectral CT. AB - This note compares the extent of contrast cancellation induced by iodinated contrast agents in energy integrating and photon counting multibin CT images. The contrast between a hypodense target and soft tissue is modeled for the two systems for a range of iodine concentrations and tube voltages. In energy integrating systems, we show that the contrast vanishes for low concentrations of iodine whereas the same effect is not seen in multibin systems. We conclude that it is the ability of multibin systems to apply weighting schemes post-acquisition that allows the operator to eliminate the risk of contrast cancellation between iodinated targets and the background. PMID- 23807654 TI - Pain control and chaplaincy in Aotearoa New Zealand. AB - This paper summarizes the results of 100 New Zealand health care chaplains with regard to their involvement in issues concerning pain control within the New Zealand health care context. Both quantitative (via survey) and qualitative methods (in-depth interviewing) were utilized. The findings of this study indicated that approximately 52 % of surveyed hospital chaplains had provided some form of pastoral intervention directly to patients and/or their families dealing with issues concerning pain and that approximately 30 % of hospital chaplains had assisted clinical staff with issues concerning pain. NZ chaplaincy personnel involved in pain-related issues utilized a number of pastoral interventions to assist patients, their families and clinical staff. Differences of involvement between professionally stipended hospital chaplains and their volunteer chaplaincy assistants are noted, as are the perspectives of interviewed chaplains about their pastoral interventions with issues relating to pain. Some implications of this study with respect to chaplaincy utility, training and collaboration with clinical staff are noted, as are comparisons with international findings. PMID- 23807653 TI - Small doses from artificial UV sources elucidate the photo-production of vitamin D. AB - To clarify the relation between UV exposure and vitamin D status, 201 volunteers wore personal electronic UV dosimeters during daylight hours, to record their UV exposure over a 10 week period when ambient UV levels were significantly less than the summer maxima. Blood samples to determine serum 25-hydroxyvitamin D3 [25(OH)D3] levels were taken at the end of week 4 and week 8. Participants were then given a single full-body exposure of approximately 2 SED from one of four artificial UV sources with different spectral outputs and a further blood sample taken at study completion, nominally week 10. The artificial UV exposure reversed the mean seasonal decline in 25(OH)D3. Increases in 25(OH)D3 from week 8 to week 10 were related to total UV exposure, including the ambient sun exposures. These exposures were weighted by the erythemal action spectrum and separately for three different action spectra for pre-vitamin D production. For the erythema weighting function, 25(OH)D3 increased 1.78 +/- 0.25 nmol per litre per SED, a value consistent with other studies. Any differences due to age, BMI, gender, and skin reflectance were not statistically significant. Ethnicity differences were the only significant factor, with Asians producing the least vitamin D, and Maori the most. There was no statistically significant improvement in consistency between sources for any of the three pre-vitamin weightings compared with that for erythema. Further work is needed to verify which vitamin D action spectrum is most appropriate. Nevertheless, these small doses of UV from artificial sources were helpful in quantifying the relationship between UV exposure and vitamin D status among the New Zealand population. PMID- 23807655 TI - Catalytic role of pre-adsorbed CO in platinum-based catalysts: the reduction of SO2 by CO on PtlAum(CO)n. AB - Using density functional theory, we have investigated the catalytic properties of bimetallic complex catalysts PtlAum(CO)n (l + m = 2, n = 1-3) in the reduction of SO2 by CO. Due to the strong coupling between the C-2p and metal 5d orbitals, pre adsorption of CO molecules on the PtlAum is found to be very effective in not only reducing the activation energy, but also preventing poisoning by sulfur. As result of the coupling, the metal 5d band is broadened and down-shifted, and charge is transferred from the CO molecules to the PtlAum. As SO2 is adsorbed on the catalyst, partial charge moves to the anti-sigma bonding orbitals between S and O in SO2, weakening the S-O bond strength. This effect is enhanced by pre adsorbing up to three CO molecules, therefore the S-O bonds become vulnerable. Our results revealed the mechanism of the excellent catalytic properties of the bimetallic complex catalysts. PMID- 23807651 TI - Multi-copper oxidases and human iron metabolism. AB - Multi-copper oxidases (MCOs) are a small group of enzymes that oxidize their substrate with the concomitant reduction of dioxygen to two water molecules. Generally, multi-copper oxidases are promiscuous with regards to their reducing substrates and are capable of performing various functions in different species. To date, three multi-copper oxidases have been detected in humans--ceruloplasmin, hephaestin and zyklopen. Each of these enzymes has a high specificity towards iron with the resulting ferroxidase activity being associated with ferroportin, the only known iron exporter protein in humans. Ferroportin exports iron as Fe(2+), but transferrin, the major iron transporter protein of blood, can bind only Fe(3+) effectively. Iron oxidation in enterocytes is mediated mainly by hephaestin thus allowing dietary iron to enter the bloodstream. Zyklopen is involved in iron efflux from placental trophoblasts during iron transfer from mother to fetus. Release of iron from the liver relies on ferroportin and the ferroxidase activity of ceruloplasmin which is found in blood in a soluble form. Ceruloplasmin, hephaestin and zyklopen show distinctive expression patterns and have unique mechanisms for regulating their expression. These features of human multi-copper ferroxidases can serve as a basis for the precise control of iron efflux in different tissues. In this manuscript, we review the biochemical and biological properties of the three human MCOs and discuss their potential roles in human iron homeostasis. PMID- 23807656 TI - Home-sampling as a tool in the context of Chlamydia trachomatis partner notification: a randomized controlled trial. PMID- 23807658 TI - Concentration polarization of ox-LDL activates autophagy and apoptosis via regulating LOX-1 expression. AB - Here we demonstrate that "concentration polarization" of ox-LDL enhances LOX-1 expression and ox-LDL uptake. It damages cell surface heparan sulfate proteoglycans (HSPG) and activates LOX-1 dependent autophagy and apoptosis. We also show that ox-LDL concentration polarization occurs on the surface of rabbit thoracic aorta and induces autophagy and apoptosis. In order to investigate the significance of swirling flow on LOX-1 expression, HSPG damage, autophagy and apoptosis in the arterial system, an ex vivo model of swirling flow was developed. We observed that swirling flow decreases relative wall concentration of ox-LDL, inhibits LOX-1 expression, protects HSPG from damage, and decreases both autophagy and apoptosis. Taken together, our data suggest that ox-LDL concentration polarization plays an important role in the localization of atherosclerotic lesions concomitant with LOX-1 dependent autophagy and apoptosis. These observations also suggest a novel mechanism by which swirling flow in the arterial system protects arterial wall from atherogenesis. PMID- 23807657 TI - Antimicrobial treatment of febrile neutropenia: pharmacokinetic-pharmacodynamic considerations. AB - Patients with cancer or hematologic diseases are particularly at risk of infection leading to high morbidity, mortality and costs. Extensive data show that optimization of the administration of antimicrobials according to their pharmacokinetic and pharmacodynamic parameters improves clinical outcome. Evidence is growing that when pharmacokinetic and pharmacodynamic parameters are used to target not only clinical cure but also eradication, the selection resistance is also contained. This is of particular importance in patients with neutropenia in whom increasing rates of drug-resistant Gram-negative bacteria have been reported, particularly Pseudomonas aeruginosa. Based on experimental and clinical studies, pharmacokinetic and pharmacodynamic parameters are discussed in this review for each antibiotic used in febrile neutropenia in order to help physicians improve dosing and optimization of antimicrobial agents. PMID- 23807659 TI - Does a combination of opisthorchiasis and ethyl alcohol consumption enhance early cholangiofibrosis, the risk of cholangiocarcinoma? AB - Combination of Opisthorchis viverrini infection and other factors could drive cholangiocarcinoma (CCA) development in Southeast Asia. However, other CCA factors are obscure. Alcohol consumption is well known in the risk for several cancers, but there is no report in CCA development. Therefore, the present study was to clarify whether drinking alcohol increases the liver pathology of Opisthorchis viverrini (OV) infection which may be the CCA risk. Experimental Syrian hamsters were divided into two groups: (1) infected with OV alone (OV); and (2) infected with OV plus administration of drinking alcohol (OV + ALC) for various lengths of time, i.e., 1, 2, 3, and 6 months. Hamster livers were collected for analysis of histopathological changes through hematoxylin and eosin, Sirius red, and immunohistostaining for proliferating cell nuclear antigen (PCNA) and cytokeratin 19 (CK19). Syrian hamster sera were used for liver function tests. Observed histopathological changes consisted primarily of aggregations of inflammatory cells surrounding the hepatic bile duct, especially at the hilar region, in both OV and OV + ALC groups; however, there was a difference in virulence. The OV + ALC group showed greater severity than the OV group. Moreover, in addition to aggregations of inflammatory cells, new bile duct formation (including hepatic cell death) was observed in subcapsular hepatic tissue. Bile duct proliferation, as determined by positive immunohistochemical staining for CK19 and PCNA, was correlated with the histopathology. Increased fibrosis was observed in subcapsular liver tissue. The present study suggests that alcohol consumption can exacerbate cholangiofibrosis, cholangitis, and lithiasis, which are risk factors for CCA. PMID- 23807660 TI - Risk of colorectal cancer in chronic kidney disease: a matched cohort study based on administrative data. AB - BACKGROUND: The risk of colorectal cancer (CRC) in chronic kidney disease (CKD) patients relative to the general population is unknown. The aim of this population-based study was to investigate the risk of CRC in patients with CKD. METHODS: The study cohort included patients aged >=18 years diagnosed with CKD between 2004 and 2005 (n = 15,975). The comparison cohort (n = 79,875) included five randomly selected age- and gender-matched controls for each patient in the study cohort. All the subjects were followed up from the date of cohort entry until they developed CRC or until the end of 2006. RESULTS: We identified 15,975 patients with a diagnosis of CKD who matched the inclusion criteria. A total of 460 patients developed CRC during the study period, of whom 116 were from the CKD cohort and 344 were from the comparison cohort. After adjusting for potential confounding factors, the CKD patients not undergoing dialysis were independently associated with a greater risk of CRC (hazard ratio, 1.79; 95% confidence interval [CI] 1.41-2.27). The overall incidence rate of CRC was 341 per 100,000 person-years for CKD patients not undergoing dialysis, compared to 174 per 100,000 person-years. The age-matched hazard ratio of CRC after excluding dialysis patients was 1.64 (95% CI 1.27-2.11) in patients 50 years and older, and 3.7 (95% CI 1.83-7.49) in patients younger than 50 years. CONCLUSIONS: This population-based cohort study indicated that CKD patients not requiring dialysis have an increased risk of CRC compared to the general population, independent of comorbidities. PMID- 23807661 TI - Prognostic value of early postoperative tumor marker response in gastric cancer. AB - BACKGROUND: The clinical usefulness of tumor markers as predictors of treatment outcome in patients with stomach cancer after radical gastrectomy has been poorly defined. The purpose of this study was to evaluate a comprehensive understanding of the impact of early postoperative tumor marker normalization on survival after gastrectomy. METHODS: Between January 2001 and December 2007, we enrolled 206 patients who had received radical gastrectomy as an initial treatment and had elevated carcinoembryonic antigen (CEA) (>5 ng/mL) or carbohydrate antigen (CA) 19-9 (>37 U/mL) levels. Early tumor marker response was defined as a normalization of preoperative CEA or CA19-9 values 1-2 months after gastrectomy. RESULTS: The mean patient age was 61 years (range 29-84 years), and 139 patients (67.5%) were male. Early tumor marker response was identified in 150 of 206 (72.8%) patients. Of the patients, 49 (23.8%), 41 (19.9%), and 116 (56.4%) were stages I, II, and III, respectively, according to the seventh edition of the American Joint Commission on Cancer (AJCC) staging system. Both disease-free survival (DFS) and overall survival (OS) were significantly longer in patients with tumor marker response compared with nonresponse (61.5 vs. 37.6 months; P = 0.010 and 71.3 vs. 50.9 months; P = 0.008, respectively). Multivariate analyses showed that high CA19-9 level, early tumor marker response, and tumor, node, metastasis classification system stage were independent predictors of DFS and OS (P < 0.05). CONCLUSIONS: Early CEA or CA19-9 normalization after radical gastrectomy is a strong prognostic factor for gastric cancer, especially in patients with high preoperative levels of tumor markers. PMID- 23807663 TI - [The ECG -- beyond the "big" issues]. PMID- 23807662 TI - SNAI1 protein expression is an independent negative prognosticator in muscle invasive bladder cancer. AB - BACKGROUND: The prognosis of muscle-invasive bladder cancer is poor. Molecular prognosticators have gained increasing attention for individualized therapeutic options because they can identify patients with different prognoses. METHODS: Tissue microarrays of formalin-fixed and paraffin-embedded tumor samples from 206 bladder cancer patients treated with cystectomy and chemotherapy were studied for SNAI1 protein expression by immunohistochemistry. SNAI1 expression was evaluated using an immunoreactive score (IRS). For statistical analysis, the patients were separated into two groups: those with tumor specimens negative for SNAI1 expression (IRS = 0), and the other positive for SNAI1 expression (IRS >=1). RESULTS: Tumor samples from 42 patients showed negative SNAI1 expression, whereas the nuclei of tumor cells from 164 patients showed detectable nuclear staining of SNAI1. A Kaplan-Meier analysis of the bladder cancer patients with negative SNAI1 expression showed significantly reduced disease-specific survival (DSS) and progression-free survival (PFS) compared to the patients with positive expression (p = 0.010 and 0.013). A multivariate Cox regression analysis (adjusted for gender, age, tumor stage, tumor grade, lymph node metastasis, chemotherapy, and histologic subtype) again showed a significant correlation between patients lacking SNAI1 expression and DSS (p = 0.005; relative risk 2.31; 95 % confidence interval 1.28-4.17) or PFS (p = 0.004; relative risk 2.20; 95 % confidence interval 1.29-3.78) compared to patients with positive SNAI1 staining. CONCLUSIONS: Loss of SNAI1 protein expression is an independent prognosticator for PFS and DSS in bladder cancer patients treated by radical cystectomy and adjuvant chemotherapy. Its prognostic value for neoadjuvant or adjuvant chemotherapy must be evaluated in further prospective randomized controlled trials. PMID- 23807664 TI - Controlled synthesis of ultrathin ZnO nanowires using micellar gold nanoparticles as catalyst templates. AB - We demonstrate a simple and effective approach to control the diameter of ultrathin ZnO nanowires with high aspect ratios and high densities over large areas. Diblock copolymer-based nanoparticle arrays exhibiting a high degree of hexagonal order and offering easy control of particle size (typically 1-10 nm) and interparticle spacing (25-150 nm) are utilized as nanocatalysts for the subsequent growth of semiconductor nanowires. The as-grown ZnO nanowires exhibit a single crystal hexagonal wurtzite structure and grow along the [0002] direction. Facetted catalyst particles were observed at the tip of the nanowires after synthesis, thus suggesting a catalyst-assisted vapor-solid-solid (VSS) rather than a vapor-liquid-solid (VLS) growth mechanism, the latter being frequently used in semiconductor nanowire production. Such a growth process allows us to easily prepare ultrathin ZnO nanowires with tunable diameters well below 10 nm by taking advantage of the inherent size control of the micellar method during deposition of the catalyst nanoparticles. Raman spectroscopy reveals a phonon confinement effect as the diameter of nanowires decreases. Photoluminescence spectra of these ultrathin nanowires indicate a blue shift of the free excitons and their phonon replicas by 37 meV induced by quantum confinement. PMID- 23807665 TI - Enzymatic production of Cilastatin intermediate via highly enantioselective hydrolysis of methyl (+/-)-2,2-dimethylcyclopropane carboxylate using newly isolated Rhodococcus sp. ECU1013. AB - (S)-(+)-2,2-Dimethylcyclopropane carboxylic acid [(S)-(+)-DMCPA] is a key chiral intermediate for production of Cilastatin, an excellent renal dehydropeptidase-I inhibitor. In this study, a new method for preparation of (S)-(+)-DMCPA with microbial esterases was investigated. A microbial screening program obtained six esterase-producing isolates that could display relatively high activities and enantioselectivities using racemic ethyl 2,2-dimethylcyclopropane carboxylate (DMCPE) as screening substrate, aiming at forming optically pure (S)-(+)-DMCPA. Further selection was carried out with substrates having different alcohol moieties, including methyl, ethyl, and 2-chloroethyl esters. Finally, one of these strains, numbered ECU1013, with high enantioselectivity toward the hydrolytic resolution of methyl 2,2-dimethylcyclopropane carboxylate (DMCPM), afforded the (S)-product in 92 % ee, and was later identified as Rhodococcus sp. According to our research, there were several active esterases to DMCPM in cells of Rhodococcus sp. ECU1013; however, (S)-preferential esterase was selectively enriched based on the time-dependent profile of esterases biosynthesis, thereby the enantiomeric excess of biotransformation product (ee p) was constantly increased, finally maintained at 95 % (S). To improve the yield, various organic solvents were employed for better dispersion of the hydrophobic substrate. As a result, (+/-)-DMCPM of up to 400 mM in the organic phase of isooctane was enantioselectively hydrolyzed into (S)-(+)-DMCPA, with an isolation yield of 38 % and a further increase of ee p to 99 %. PMID- 23807666 TI - A simple and rapid method to isolate purer M13 phage by isoelectric precipitation. AB - M13 virus (phage) has been extensively used in phage display technology and nanomaterial templating. Our research aimed to use M13 phage to template sulfur nanoparticles for making lithium ion batteries. Traditional methods for harvesting M13 phage from Escherichia coli employ polyethylene glycol (PEG)-based precipitation, and the yield is usually measured by plaque counting. With this method, PEG residue is present in the M13 phage pellet and is difficult to eliminate. To resolve this issue, a method based on isoelectric precipitation was introduced and tested. The isoelectric method resulted in the production of purer phage with a higher yield, compared to the traditional PEG-based method. There is no significant variation in infectivity of the phage prepared using isoelectric precipitation, and the dynamic light scattering data indirectly prove that the phage structure is not damaged by pH adjustment. To maximize phage production, a dry-weight yield curve of M13 phage for various culture times was produced. The yield curve is proportional to the growth curve of E. coli. On a 200-mL culture scale, 0.2 g L(-1) M13 phage (dry-weight) was produced by the isoelectric precipitation method. PMID- 23807667 TI - The citric acid production from raw glycerol by Yarrowia lipolytica yeast and its regulation. AB - The optimal cultivation conditions ensuring the maximal rate of citric acid (CA) biosynthesis by glycerol-grown mutant Yarrowia lipolytica NG40/UV7 were found to be as follows: growth limitation by inorganic nutrients (nitrogen, phosphorus, or sulfur), 28 degrees C, pH 5.0, dissolved oxygen concentration (pO2) of 50 % (of air saturation), and pulsed addition of glycerol from 20 to 80 g L-1 depending on the rate of medium titration. Under optimal conditions of fed-batch cultivation, in the medium with pure glycerol, strain Y. lipolytica NG40/UV7 produced 115 g L 1 of CA with the mass yield coefficient of 0.64 g g-1 and isocitric acid (ICA) amounted to 4.6 g L-1; in the medium with raw glycerol, CA production was 112 g L 1 with the mass yield coefficient of 0.90 g g-1 and ICA amounted to 5.3 g L-1. Based on the activities of enzymes involved in the initial stages of raw glycerol assimilation, the tricarboxylic acid cycle and the glyoxylate cycle, the mechanism of increased CA yield from glycerol-containing substrates in Y. lipolytica yeast was explained. PMID- 23807668 TI - Ectopic thyroid tissue in the adrenal gland. PMID- 23807670 TI - Synthesis, structural characterization and cis-trans isomerization of novel (salicylaldiminato)platinum(II) complexes. AB - The reaction of cis-[PtCl2(dmso)] with the salicylaldimine ligand, N-(2 hydroxybenzylidene)-2,6-di-isopropylaniline, LA in the presence of sodium acetate in methanol produced both cis- and trans-[PtClLA(dmso)], 1a and 1b. An analogous reaction for the less bulky ligand, N-(2-hydroxybenzylidene)aniline LB produced only cis-[PtClLB(dmso)], 2. The reactions of these dmso complexes with triphenylphosphine also yielded complexes with different geometries depending on the nature of the salicylaldiminato ligand. Thus the cis-trans isomerization of cis-[PtClLA(PPh3)] 3a was investigated both experimentally and computationally, and a tetrahedral transition state was detected in this process. A good agreement of the experimental activation parameters with those determined theoretically using DFT was obtained. LA was also reacted with [PtClMe(cod)] in methanol to yield the corresponding salicylaldiminato complex 6 in which the methyl group is cis to the imine nitrogen. X-ray crystal structures of some compounds obtained are reported. PMID- 23807669 TI - Prospective evaluation in 123 patients of strain ratio as provided by quantitative elastosonography and multiparametric ultrasound evaluation (ultrasound score) for the characterisation of thyroid nodules. AB - PURPOSE: This study was done to compare quantitative elastosonography and ultrasound analysis in the characterisation of thyroid nodules. MATERIALS AND METHODS: From July 2009 to September 2011, 123 patients with 147 thyroid nodules were included in our study. All patients enrolled had to undergo thyroidectomy because of nodular thyroid disease (goitre or nodules). After preliminary examination with conventional ultrasound (US) and colour Doppler US, the patients were examined with elastosonography, using high-level equipment (Toshiba Aplio XG) and quantitative software (Elasto-Q). Each lesion was characterised using an US score (echogenicity, borders, microcalcifications and colour Doppler pattern), and then by elastosonographic strain ratio. Each patient subsequently underwent thyroidectomy. Histological results were used as the gold standard. RESULTS: Histological examination demonstrated 89 benign and 58 malignant lesions. On average, the strain ratio value was 2.84+/-2.69 (range, 0.05-14.5; p=0.001). Sensitivity and specificity of the US score were about 56% and 72%, respectively, whereas those of the strain ratio were 93% and 89%, using a cut-off of 2 obtained with receiver operating characteristic (ROC) curve analysis. Elastosonography was more accurate than US and colour Doppler US in characterising thyroid nodules (p=0.002). CONCLUSIONS: Quantitative elastosonography is a useful diagnostic tool in the evaluation of thyroid lesions, and can be used to limit fine-needle aspiration cytology and improve the selection of patients for thyroidectomy. PMID- 23807671 TI - Prevalence of health risk behaviors and their associated factors among university students in Kyrgyzstan. AB - BACKGROUND: With the advancements in knowledge about health promotion, public health professionals have been seeking determinants of personal health behaviors. The purpose of this study was to assess the prevalence of health risk behaviors and its associated factors in a sample of Kyrgyz university students. METHODS: In a cross-sectional survey, health risk behaviors among a sample of randomly selected university students were assessed. The sample included 837 university students from health sciences undergraduate courses of the State Medical Academy in Kyrgyzstan. The students were 358 (42.8%) males and 479 (57.2%) females in the age range of 18-29 years (Median age=21.3 years, SD=1.5). RESULTS: On average, students engaged in 9.4 (SD=2.3) out of 23 health risk behavior practices (range, 3-18). Generally, there was a high rate of insufficient fruit and vegetable intake (86.4%), eating red meat at least once a day (62%), usually adding salt to meals (78.3%), skipping breakfast (50.5%), current tobacco use (49.7%) and two or more sexual partners in the past 12 months (46.1%) among men, and never using a condom with a primary partner in the past 3 months (90.9%) among women. Furthermore, 60.8% of the women were physically inactive. In bivariate analysis among men, the lack of perceived benefits was associated with health risk behavior. In multivariate analysis among women, poorer family background, being Russian, high personal constraints or stress, and better subjective health were associated with the health risk behavior index. CONCLUSIONS: Students had a high proportion of health risk behavior practices. Several high health risk practices were identified, including poor dietary behavior, physical inactivity, sexual risk behavior, and tobacco use. Gender specific predictors identified included sociodemographic characteristics and social and health variables, which can be utilized in health promotion programs. PMID- 23807672 TI - Elevated level of cell-free plasma DNA is associated with advanced-stage breast cancer and metastasis. PMID- 23807673 TI - Easy verification of clinical chemistry reference intervals. PMID- 23807674 TI - Lack of association between vitamin D receptor gene FokI and BsmI polymorphisms and prostate cancer risk: an updated meta-analysis involving 21,756 subjects. AB - The vitamin D receptor (VDR) is a crucial mediator for the cellular effects of vitamin D. The polymorphisms in the VDR gene have been hypothesized to alter the risk of prostate cancer. However, studies investigating the association between VDR polymorphisms (BsmI and FokI) and prostate cancer (PCa) risk report conflicting results , therefore, we conducted a meta-analysis to re-examine the controversy. Published literatures from PubMed, Embase, Google Scholar, and China National Knowledge Infrastructure (CNKI) were searched (updated to March 9, 2013). According to our inclusion criteria, studies that observed the association between VDR BsmI and FokI polymorphisms and PCa risk were included. The principal outcome measure was the odds ratio (OR) with 95 % confidence interval (CI) for PCa risk associated with VDR BsmI and FokI polymorphisms. Thirty-four studies involving 10,267 cases and 11,489 controls were recruited. Overall, we did not find evidence to support an association between any of the VDR polymorphisms and PCa risk. For BsmI, the pooled OR was 0.894 (95 % CI 0.773 to 1.034) for the Bb vs. bb genotypes, 1.002 (95 % CI 0.869 to 1.157) for the BB vs. bb genotypes, 0.922 (95 % CI 0.798 to 1.065) for the dominant model (BB/Bb vs. bb), and 1.018 (95 % CI 0.936 to 1.107) for the recessive model (BB vs. Bb/bb). ORs for the FokI polymorphisms were similar. The results suggest that the VDR BsmI and FokI polymorphisms are not related to PCa risk. Further large and well-designed studies are required to confirm this conclusion. PMID- 23807675 TI - Association between X-ray repair cross-complementation group 1 rs25487 polymorphism and pancreatic cancer risk. AB - Previous published studies suggested that genetic polymorphisms in DNA repair genes could modify the DNA repair capacity and could be associated with pancreatic cancer risk. However, previous studies on the association between X ray repair cross-complementation group 1 (XRCC1) rs25487 (Arg399Gln) polymorphism and pancreatic cancer risk reported inconsistent results. To obtain a more precise estimation of the association between XRCC1 rs25487 polymorphism and pancreatic cancer risk, we performed a meta-analysis of previous published studies by calculating the pooled odds ratio (OR) with a 95% confidence interval (95% CI). Eight individual studies with 5,542 subjects from six publications were finally included into this meta-analysis. The meta-analysis of total eight studies showed that there was no association between XRCC1 rs25487 polymorphism and pancreatic cancer risk in total population under all four genetic models (Gln versus Arg: OR = 1.10, 95% CI 0.95-1.28, P = 0.199; GlnGln versus ArgArg: OR = 1.15, 95% CI 0.93-1.41, P = 0.191; GlnGln/ArgGln versus ArgArg: OR = 1.10, 95% CI 0.97-1.25, P = 0.127; GlnGln versus ArgArg/ArgGln: OR = 1.12, 95% CI 0.92-1.36, P = 0.253). Subgroup analysis showed that there was no association between XRCC1 rs25487 polymorphism and pancreatic cancer risk in Caucasians, but XRCC1 rs25487 polymorphism was associated with pancreatic cancer risk in Asians (GlnGln/ArgGln versus ArgArg: OR = 1.24, 95% CI 1.01-1.53, P = 0.040). Therefore, the meta analysis suggests that XRCC1 rs25487 polymorphism is associated with pancreatic cancer risk in Asians. Further studies with more participants are needed to provide a more precise estimation on the association above. PMID- 23807676 TI - Serum 25-hydroxyvitamin D and breast cancer risk: a meta-analysis of prospective studies. AB - There were some case-control studies, nested case-control studies, and cohort studies with controversial results on the association between serum 25 hydroxyvitamin D [25(OH)D] and breast cancer risk. Case-control studies are prone to selection bias, which limit the strength and quality of the evidence. To overcome the shortcoming of the case-control studies, the meta-analysis of prospective studies including nested case-control studies and cohort studies was conducted. PubMed, Embase, and Web of Science databases were searched, and the last retrieval date was March 24, 2013. For the highest versus the lowest level of serum 25(OH)D, the relative risks (RRs) and its 95% confidence intervals (CIs) from each study were used to estimate summary RR and its 95% CI. Subgroup analyses by geographic region, menopausal status, and adjusted status of RR were also performed, respectively. A dose-response association between serum 25(OH)D concentration and breast cancer risk was assessed. Fourteen articles with 9,110 breast cancer cases and 16,244 controls were included in the meta-analysis. Overall, serum 25(OH)D levels were inversely significantly associated with breast cancer risk (RR = 0.845, 95% CI = 0.750-0.951). Inversely statistically significant associations were observed in North American studies, postmenopausal women, and studies with adjusted and unadjusted RR, respectively. No statistically significant associations were observed in European studies and premenopausal women, respectively. Dose-response analysis showed that every 10 ng/mL increment in serum 25(OH)D concentration was associated with a significant 3.2% reduction in breast cancer risk. This meta-analysis provides evidence of a significantly inverse association between serum 25(OH)D concentration and breast cancer risk. PMID- 23807678 TI - Clinical implications of cancer stem cell-like side population cells in human laryngeal cancer. AB - In this study, we try to detect and isolate the cancer stem cell-like side population cells (SP) from the laryngeal carcinoma cell line and primary laryngeal carcinoma and explore the clinical implications of SP cells in laryngeal carcinoma. The SP cells and non-side population cells (NSP) cells were sorted by Hoechst 33342 through FACS. The proliferation capacity, invasion ability, migration ability, and tumorigenic activity of the SP cells were evaluated. In addition, the association between the SP cells ratio and the prognostic factors of laryngeal cancer was analyzed. As a result, the percentage of the SP cells in Hep-2 cells was 5.1%. The SP cells depicted float colonies, but the NSP cells failed to generate the typical cell spheres. The clone formation ratios were 47.47 +/- 10.20% vs. 4.98 +/- 1.41% in the flat plates and 46.82 +/- 5.67% vs. 12.53 +/- 3.51% in the soft agar for SP and NSP cells (P = 0.01 and 0.01). The SP cells depicted a higher migrating potency than the NSP cells in both the transwell assay and scarification test (all P < 0.05). The matrigel invasion assay showed that the artificial basement membrane penetration rate of SP cells was 39.04 +/- 4.78%, which was higher than 25.16 +/- 4.63% of the NSP cells (P < 0.05). Only 10(3) SP cells were able to form tumors in mice, whereas 10(4) NSP cells failed to form tumors. The SP cells were correlated with the differentiation, lymph node metastasis, and clinical stage of the laryngeal cancers. In conclusion, SP cells may be a potential prognostic factor of laryngeal cancer. PMID- 23807677 TI - Association of peripheral CD4+ CXCR5+ T cells with chronic lymphocytic leukemia. AB - Accumulating evidences indicate that immune dysregulation plays a key role in both lymphomagenesis and patient outcome of chronic lymphocytic leukemia (CLL). Peripheral blood CD4+ CXCR5+ T cells, known as circulating follicular helper T cells (Tfh), can induce B cell activation and production of specific antibody responses. The aim of the study was to investigate changes of circulating Tfh in CLL. Tfh and it subtypes were tested by measuring CD4, CXCR5, CXCR3, and CCR6 in 72 CLL cases and 86 healthy controls using flow cytometry. Data showed that the percentage of Tfh in the peripheral CD4+ T cells was significantly increased in CLL (25.1%) than in controls (8.4%) (p < 0.001). Further analysis revealed that the upregulation of Tfh was contributed by Tfh-th2 subtype and Tfh-th17 subtype. Investigating staging of the cases demonstrated that the prevalence of Tfh was significantly elevated in cases with Binet stage C (37.3%) than those with stage A (20.1 %) or stage B (23.9 %). In addition, we analyzed Tfh in patients with immunoglobulin variable heavy chain (IGHV) gene mutational status. Results presented that Tfh-th17 subtype had clearly higher frequency in patients with IGHV mutation compared to the unmutated cases (p = 0.035). This study suggested the involvement of Tfh in the pathogenesis and progression of CLL, and provided a potential target for treating this disease. PMID- 23807679 TI - Contrast-enhanced ultrasonography for the diagnosis of small hepatocellular carcinoma: a meta-analysis and meta-regression analysis. AB - The aim of this study is to determine the diagnostic accuracy of contrast enhanced ultrasonography (CEUS) for diagnosis of small (<= 2 cm in diameter) hepatocellular carcinoma (HCC) through a meta-analysis of published studies. A comprehensive literature search of PubMed, Embase, Web of Science, and China BioMedicine databases was conducted on articles published before 1 March 2013. Data from selected studies were pooled to yield summary sensitivity, specificity, positive and negative likelihood ratio (LR), diagnostic odds ratio (DOR), and receiver operating characteristic (SROC) curve. Statistical analyses were performed using Meta-Disc version 1.4 and STATA version 12.0 softwares. Fifteen studies were included with a total of 908 cirrhotic patients with 1,032 small hepatic nodules. All lesions were histologically confirmed through liver biopsies after CEUS. The pooled sensitivity was 0.81 (95% CI = 0.78-0.85); the pooled specificity was 0.86 (95% CI = 0.82-0.89). The pooled positive LR was 5.90 (95% CI = 3.90-8.94); the pooled negative LR was 0.20 (95% CI = 0.14-0.29). The pooled DOR was 37.07 (95% CI = 24.79-55.44). The area under the SROC curve was 0.93 (SE = 0.01). Meta-regression analysis showed that the number of lesions may be a major source of heterogeneity. No publication bias was detected in this meta analysis. This meta-analysis indicates that CEUS is a useful diagnostic tool with high sensitivity and specificity for identifying small HCC. PMID- 23807680 TI - Expression of CHD1L in bladder cancer and its influence on prognosis and survival. AB - Chromodomain helicase/ATPase DNA-binding protein 1-like (CHD1L) is overexpressed and highly associated with poor prognosis in many malignancies. However, the role of CHD1L in bladder cancer (BC) has not been thoroughly elucidated. The aim of this study is to investigate the relationship of CHD1L expression with clinicopathological parameters and prognosis in BC. Immunohistochemistry was carried out to investigate the protein expression of CHD1L in 153 BC tissues and 87 adjacent noncancerous tissues. Our data found that CHD1L protein expression was significantly higher in BC tissues than in adjacent noncancerous tissues (P < 0.001). CHD1L overexpression was significantly correlated with histologic grade (P = 0.005) and tumor stage (P = 0.009). The Kaplan-Meier survival analysis revealed that survival time of patients with high CHD1L expression was significantly shorter than that with low CHD1L expression. Multivariate analysis further demonstrated that CHD1L was an independent prognostic factor for patients with BC. In conclusion, CHD1L is likely to be a valuable marker for carcinogenesis and progression of BC. It might be used as an important diagnostic and prognostic marker for BC patients. PMID- 23807681 TI - Mercuric chloride induced toxicity responses in the olfactory epithelium of Labeo rohita (Hamilton): a light and electron microscopy study. AB - Bioaccumulation of mercury and histomorphological changes in the olfactory epithelium of Labeo rohita were investigated after exposing the fish to two sublethal concentrations of HgCl2 (66 and 132 MUg/L) for 15 and 30 days. Mercury deposition increased in the tissue significantly (p < 0.05) with dose- and duration-dependent manner. Severe damage to the olfactory epithelium was evident. When fish exposed to 66 MUg/L for 15 days, the histology of olfactory epithelium exhibited that mucous cell proliferation was upregulated and cell size was significantly increased from the control. Similar trends were found in 30 days exposure in both treated groups. Histology showed that mercury induced degeneration of columnar sensory cells, supporting cells and ciliated non-sensory cells and induced basal cell proliferation. Basal cell hyperplasia led to form intraepithelial proliferative lesion, thickening of epithelium, basal lamina disruption and cyst formation. Scanning electron microscopy revealed that mercury exposure at 66 MUg/L caused clumping and loss of cilia, erosion in microridges on the supporting cells and proliferation of mucous cell opening. Complete degeneration of ciliated cells and cyst formation was observed in the fish when exposed to 132 MUg/L HgCl2. This result suggests that prolonged exposure to mercury might cause irreversible damage to the olfactory epithelium and impair the olfactory function of fish. PMID- 23807682 TI - Determination of levels of current drugs in hospital and urban wastewater. AB - A rapid, sensitive and highly specific HPLC-MS/MS method with direct on-line preparation was applied for the determination of 20 common pharmaceuticals in hospital and urban wastewater. Median drug concentrations were quite similar in the majority of samples, cerca 1 MUg L-1 ranging from 0.06 to 2.67 MUg L-1 in both water. Pharmaceutical hospital contribution, below 1 %, was negligible, as compared to the huge amount in the municipal plant flow. Due to only partial elimination in the plant, hundreds of kilograms of harmful waste per year are discharged in the River Seine. Therefore, to reduce potential human and environmental exposure, a topic of major concern, an efficient drug treatment procedure should be used at the municipal plant stage in order to reduce urban wastewater pollution. The HPLC-MS/MS method could be a very useful tool to optimize the pharmaceutical wastewater treatment process. PMID- 23807683 TI - Dissipation and residue of rotenone in cabbage and soil under field conditions. AB - Rotenone dissipation and terminal residue in cabbage and soil under field conditions were determined by high-performance liquid chromatography. The dissipation rates of rotenone were described using first-order kinetics. The half lives ranged from 0.89 to 1.55 days in cabbage and 1.98 to 2.76 days in soil. Prolonged pre-harvest interval times ensure that the cabbage is safe for consumption. Temperature and the physico-chemical properties of the soil were identified as the key factors affecting rotenone degradation in cabbage and soil under field conditions. PMID- 23807684 TI - The overexpression of BAMBI and its involvement in the growth and invasion of human osteosarcoma cells. AB - The pseudoreceptor BAMBI (bone morphogenetic protein and activin membrane-bound inhibitor), formerly known as NMA, is an inhibitor of the TGF-beta signaling pathway. BAMBI exhibits structural homology to TGF-betaRI but lacks an intracellular kinase domain. In most of the high-grade carcinomas, the degree of BAMBI expression is abnormally increased, which leads to the proliferation and metastasis of tumor cells. Recent studies have reported that BAMBI is involved in the Wnt-beta-catenin pathway that regulates the proliferation and metastasis of tumor cells. However, little is known about the role of BAMBI and beta-catenin in human osteosarcoma. Given the above background, we examined the role of BAMBI in the pathophysiology of osteosarcoma. Using immunohistochemical staining and western blot analysis, the degree of the expression of BAMBI and beta-catenin was significantly higher in osteosarcoma specimens compared with normal tissues. With the overexpression of BAMBI, mediated by adenovirus, the degree of invasion and migration was significantly increased and the proliferation of U2-OS osteosarcoma cells was stimulated. Transwell analysis showed that BAMBI increased the invasion of osteosarcoma cells and upregulated the secretion of matrix metalloproteinases (MMPs), which was demonstrated by gelatin zymography. Fluorescence-activated cell sorting (FACS) analysis showed a significant arrest in cell cycle progression at G0/G1 in osteosarcoma cells transfected with siRNA targeting BAMBI. With the overexpression of BAMBI, mediated by the adenovirus, however, there was a decrease in the number of cells at G0/G1. Consistent with the findings that cell growth was increased, BAMBI promoted the transition from G0/G1 to G2/M in the osteosarcoma cells. Our results suggest that BAMBI plays a key role in the pathogenesis and progression of osteosarcoma by regulating the expression of beta catenin and other signaling molecules via the pathways involved in the regulation of the cell cycle. This relationship between BAMBI and its involvement in the regulation of the cell cycle would provide a possibility that the BAMBI may be a new target for gene therapy. PMID- 23807685 TI - The Simplified Psoriasis Index (SPI): a practical tool for assessing psoriasis. AB - The Simplified Psoriasis Index (SPI) is a summary measure of psoriasis with separate components for current severity (SPI-s), psychosocial impact (SPI-p), and past history and interventions (SPI-i). It derives from the Salford Psoriasis Index but replaces Psoriasis Area and Severity Index (PASI) with a composite weighted severity score designed to reflect the impact of psoriasis affecting functionally or psychosocially important body sites. Two complementary versions are available, differing only in that current severity (SPI-s) is either professionally (proSPI-s) or patient self-assessed (saSPI-s). This study examined the criterion and construct validity and response distribution of proSPI-s, saSPI s, and SPI-p in 100 patients with plaque psoriasis. A further 50 patients were assessed for test-retest reliability of these three components. Interrater reliability of proSPI-s was assessed in 12 patients, each assessed by 12 assessors (144 assessments). There was close correlation between PASI and proSPI s (r=0.91); SPI-p was closely correlated with the Dermatology Life Quality Index (r=0.89). Strong intrarater (proSPI-s, saSPI-s, SPI-p, and SPI-i) and interrater (proSPI-s) reliability was demonstrated (all intraclass correlation coefficients >0.75). There were wide response distributions for all three components. We believe that both professional (proSPI) and self-assessed (saSPI) versions can readily be introduced into routine clinical practice. PMID- 23807686 TI - On the use of simple geometric descriptors provided by RGB-D sensors for re identification. AB - The re-identification problem has been commonly accomplished using appearance features based on salient points and color information. In this paper, we focus on the possibilities that simple geometric features obtained from depth images captured with RGB-D cameras may offer for the task, particularly working under severe illumination conditions. The results achieved for different sets of simple geometric features extracted in a top-view setup seem to provide useful descriptors for the re-identification task, which can be integrated in an ambient intelligent environment as part of a sensor network. PMID- 23807687 TI - D-MSR: a distributed network management scheme for real-time monitoring and process control applications in wireless industrial automation. AB - Current wireless technologies for industrial applications, such as WirelessHART and ISA100.11a, use a centralized management approach where a central network manager handles the requirements of the static network. However, such a centralized approach has several drawbacks. For example, it cannot cope with dynamicity/disturbance in large-scale networks in a real-time manner and it incurs a high communication overhead and latency for exchanging management traffic. In this paper, we therefore propose a distributed network management scheme, D-MSR. It enables the network devices to join the network, schedule their communications, establish end-to-end connections by reserving the communication resources for addressing real-time requirements, and cope with network dynamicity (e.g., node/edge failures) in a distributed manner. According to our knowledge, this is the first distributed management scheme based on IEEE 802.15.4e standard, which guides the nodes in different phases from joining until publishing their sensor data in the network. We demonstrate via simulation that D-MSR can address real-time and reliable communication as well as the high throughput requirements of industrial automation wireless networks, while also achieving higher efficiency in network management than WirelessHART, in terms of delay and overhead. PMID- 23807688 TI - ADVICE: a new approach for near-real-time monitoring of surface displacements in landslide hazard scenarios. AB - We present a new method for near-real-time monitoring of surface displacements due to landslide phenomena, namely ADVanced dIsplaCement monitoring system for Early warning (ADVICE). The procedure includes: (i) data acquisition and transfer protocols; (ii) data collection, filtering, and validation; (iii) data analysis and restitution through a set of dedicated software; (iv) recognition of displacement/velocity threshold, early warning messages via SMS and/or emails; (v) automatic publication of the results on a dedicated webpage. We show how the system evolved and the results obtained by applying ADVICE over three years into a real early warning scenario relevant to a large earthflow located in southern Italy. ADVICE has speed-up and facilitated the understanding of the landslide phenomenon, the communication of the monitoring results to the partners, and consequently the decision-making process in a critical scenario. Our work might have potential applications not only for landslide monitoring but also in other contexts, as monitoring of other geohazards and of complex infrastructures, as open-pit mines, buildings, dams, etc. PMID- 23807689 TI - Energy consumption and control response evaluations of AODV routing in WSANs for building-temperature control. AB - The main objective of this paper is to investigate the effects of routing protocols on wireless sensor and actuator networks (WSANs), focusing on the control system response and the energy consumption of nodes in a network. We demonstrate that routing algorithms designed without considering the relationship between communication and control cannot be appropriately used in wireless networked control applications. For this purpose, an ad-hoc on-demand distance vector (AODV) routing, an IEEE 802.15.4, and a building-temperature control system are employed for this exploration. The findings from our scenarios show that the AODV routing can select a path with a high traffic load for data transmission. It takes a long time before deciding to change a new route although it experiences the unsuccessful transmission of packets. As a result, the desirable control target cannot be achieved in time, and nodes consume more energy due to frequent packet collisions and retransmissions. Consequently, we propose a simple routing solution to alleviate these research problems by modifying the original AODV routing protocol. The delay-threshold is considered to avoid any congested connection during routing procedures. The simulation results demonstrate that our solution can be appropriately applied in WSANs. Both the energy consumption and the control system response are improved. PMID- 23807690 TI - Development of an enzyme-linked immunosorbent assay for dibutyl phthalate in liquor. AB - A monoclonal antibody specifically recognizing dibutyl phthalate (DBP) was prepared based on a hapten (di-n-butyl-4-aminophthalate). After optimizing various parameters such as concentrations of antibody, coating antigen and composition of the assay buffer, an inhibition curve was plotted with the 50% inhibition concentration value (IC50) 33.6 +/- 2.5 ng/mL. A low level of cross reactivity (<5%) was found for other phthalate esters. Recovery tests were conducted using liquor simulant (a mixture of water and ethanol) at two fortification levels (100 ng/mL and 300 ng/mL). The recovery rates ranged from 84.7% to 94.5% with a coefficient of variation between 7.1% and 12.8%. Nine liquor samples of different alcoholic strengths were detected using the proposed measure and confirmatory analysis was performed using liquid chromatography-mass spectroscopy (LC-MS). The detection results showed good consistency between the two measures and all the data above indicated that the proposed ELISA could be applied in DBP screening. PMID- 23807691 TI - Symmetry-defying iron pyrite (FeS2) nanocrystals through oriented attachment. AB - Iron pyrite (fool's gold, FeS2) is a promising earth abundant and environmentally benign semiconductor material that shows promise as a strong and broad absorber for photovoltaics and high energy density cathode material for batteries. However, controlling FeS2 nanocrystal formation (composition, size, shape, stoichiometry, etc.) and defect mitigation still remains a challenge. These problems represent significant limitations in the ability to control electrical, optical and electrochemical properties to exploit pyrite's full potential for sustainable energy applications. Here, we report a symmetry-defying oriented attachment FeS2 nanocrystal growth by examining the nanostructure evolution and recrystallization to uncover how the shape, size and defects of FeS2 nanocrystals changes during growth. It is demonstrated that a well-controlled reaction temperature and annealing time results in polycrystal-to-monocrystal formation and defect annihilation, which correlates with the performance of photoresponse devices. This knowledge opens up a new tactic to address pyrite's known defect problems. PMID- 23807692 TI - Technique for methyl methacrylate cranioplasty to optimize cosmetic outcome. AB - BACKGROUND: Cranioplasty aims to reconstruct skull defects from fractures, decompressive craniectomies, tumors, and congenital anomalies in a cosmetically acceptable manner. We present a technique in methyl methacrylate cranioplasty that gives excellent cosmetic results by maintaining patient's calvarial curvature. METHOD: Cranioplasty material is placed into a plastic bag and packed inside the defect. Wire mesh cut larger than the defect is held in position to take the exact skull curvature. Once solid, the implant is fixed in position using titanium plates and mini-screws. CONCLUSION: This is a simple, inexpensive method of achieving the most cosmetically desired cranioplasty results. PMID- 23807693 TI - Decentralising HIV treatment in lower- and middle-income countries. AB - BACKGROUND: Policy makers, health staff and communities recognise that health services in lower- and middle-income countries need to improve people's access to HIV treatment and retention to treatment programmes. One strategy is to move antiretroviral delivery from hospitals to more peripheral health facilities or even beyond health facilities. This could increase the number of people with access to care, improve health outcomes, and enhance retention in treatment programmes. On the other hand, providing care at less sophisticated levels in the health service or at community-level may decrease quality of care and result in worse health outcomes. To address these uncertainties, we summarised the research studies examining the risks and benefits of decentralising antiretroviral therapy service delivery. OBJECTIVES: To assess the effects of various models that decentralised HIV treatment and care to more basic levels in the health system for initiating and maintaining antiretroviral therapy. SEARCH METHODS: We conducted a comprehensive search to identify all relevant studies regardless of language or publication status (published, unpublished, in press, and in progress) from 1 January 1996 to 31 March 2013, and contacted relevant organisations and researchers. The search terms included 'decentralisation', 'down referral', 'delivery of health care', and 'health services accessibility'. SELECTION CRITERIA: Our inclusion criteria were controlled trials (randomised and non-randomised), controlled-before and after studies, and cohorts (prospective and retrospective) in which HIV-infected people were either initiated on antiretroviral therapy or maintained on therapy in a decentralised setting in lower- and middle-income countries. We define decentralisation as providing treatment at a more basic level in the health system to the comparator. DATA COLLECTION AND ANALYSIS: Two authors applied the inclusion criteria and extracted data independently. We designed a framework to describe different decentralisation strategies, and then grouped studies against these strategies. Data were pooled using random-effects meta-analysis. Because loss to follow up in HIV programmes is known to include some deaths, we used attrition as our primary outcome, defined as death plus loss to follow-up. We assessed evidence quality with GRADE methodology. MAIN RESULTS: Sixteen studies met the inclusion criteria, all but one were from Africa, comprising two cluster randomised trials and 14 cohort studies. Antiretroviral therapy started at a hospital and maintained at a health centre (partial decentralisation) probably reduces attrition (RR 0.46, 95% CI 0.29 to 0.71, 4 studies, 39 090 patients, moderate quality evidence). There may be fewer patients lost to care with this model (RR 0.55, 95% CI 0.45 to 0.69, low quality evidence).We are uncertain whether there is a difference in attrition for antiretroviral therapy started and maintained at a health centre (full decentralisation) compared to a hospital at 12 months (RR 0.70, 95% CI 0.47 to 1.02; four studies, 56 360 patients, very low quality evidence), but there are probably fewer patients lost to care with this model (RR 0.3, 95% CI 0.17 to 0.54, moderate quality evidence).When antiretroviral maintenance therapy is delivered at home by trained volunteers, there is probably no difference in attrition at 12 months (RR 0.95, 95% CI 0.62 to 1.46, two trials, 1453 patients, moderate quality evidence). AUTHORS' CONCLUSIONS: Decentralisation of HIV care aims to improve patient access and retention in care. Most data were from good quality cohort studies but confounding between site of treatment and outcomes cannot be excluded. Nevertheless, this review found that attrition appears to be lower in partial decentralisation models of treatment, where antiretrovirals were started at hospital and continued in the health centre; with antiretroviral drugs started and continued at health centres, no difference in attrition was detected, but there were fewer patients lost to care. For antiretroviral therapy provided at home by trained volunteers, no difference in outcomes were detected when compared to facility-based care. PMID- 23807694 TI - A competing risks approach for nonparametric estimation of transition probabilities in a non-Markov illness-death model. AB - Competing risks model time to first event and type of first event. An example from hospital epidemiology is the incidence of hospital-acquired infection, which has to account for hospital discharge of non-infected patients as a competing risk. An illness-death model would allow to further study hospital outcomes of infected patients. Such a model typically relies on a Markov assumption. However, it is conceivable that the future course of an infected patient does not only depend on the time since hospital admission and current infection status but also on the time since infection. We demonstrate how a modified competing risks model can be used for nonparametric estimation of transition probabilities when the Markov assumption is violated. PMID- 23807695 TI - Adopting nested case-control quota sampling designs for the evaluation of risk markers. AB - Two-phase study methods, in which more detailed or more expensive exposure information is only collected on a sample of individuals with events and a small proportion of other individuals, are expected to play a critical role in biomarker validation research. One major limitation of standard two-phase designs is that they are most conveniently employed with study cohorts in which information on longitudinal follow-up and other potential matching variables is electronically recorded. However for many practical situations, at the sampling stage such information may not be readily available for every potential candidates. Study eligibility needs to be verified by reviewing information from medical charts one by one. In this manuscript, we study in depth a novel study design commonly undertaken in practice that involves sampling until quotas of eligible cases and controls are identified. We propose semiparametric methods to calculate risk distributions and a wide variety of prediction indices when outcomes are censored failure times and data are collected under the quota sampling design. Consistency and asymptotic normality of our estimators are established using empirical process theory. Simulation results indicate that the proposed procedures perform well in finite samples. Application is made to the evaluation of a new risk model for predicting the onset of cardiovascular disease. PMID- 23807696 TI - Evaluating subject-level incremental values of new markers for risk classification rule. AB - Suppose that we need to classify a population of subjects into several well defined ordered risk categories for disease prevention or management with their "baseline" risk factors/markers. In this article, we present a systematic approach to identify subjects using their conventional risk factors/markers who would benefit from a new set of risk markers for more accurate classification. Specifically for each subgroup of individuals with the same conventional risk estimate, we present inference procedures for the reclassification and the corresponding correct re-categorization rates with the new markers. We then apply these new tools to analyze the data from the Cardiovascular Health Study sponsored by the US National Heart, Lung, and Blood Institute. We used Framingham risk factors plus the information of baseline anti-hypertensive drug usage to identify adult American women who may benefit from the measurement of a new blood biomarker, CRP, for better risk classification in order to intensify prevention of coronary heart disease for the subsequent 10 years. PMID- 23807697 TI - Curcumin inhibits the proliferation of airway smooth muscle cells in vitro and in vivo. AB - The inhibition of the proliferation of airway smooth muscle cells (ASMCs) is crucial for the prevention and treatment of asthma. Recent studies have revealed some important functions of curcumin; however, its effects on the proliferation of ASMCs in asthma remain unknown. Therefore, in this study, we performed in vitro and in vivo experiments to investigate the effects of curcumin on the proliferation of ASMCs in asthma. The thickness of the airway wall, the airway smooth muscle layer, the number of ASMCs and the expression of extracellular signal-regulated kinase (ERK) were significantly reduced in the curcumin-treated group as compared with the model group. Curcumin inhibited the cell proliferation induced by platelet-derived growth factor (PDGF) and decreased the PDGF-induced phosphorylation of ERK1/2 in the rat ASMCs. Moreover, the disruption of caveolae using methyl-beta-cyclodextrin (MbetaCD) attenuated the anti-proliferative effects of curcumin in the ASMCs, which suggests that caveolin is involved in this process. Curcumin upregulated the mRNA and protein expression of caveolin-1. The data presented in this study demonstrate that the proliferation of ASMCs is inhibited by curcumin in vitro and in vivo; curcumin exerts these effects by upregulating the expression of caveolin-1 and blocking the activation of the ERK pathway. PMID- 23807698 TI - Disability and psychiatric symptoms in hyperemesis gravidarum patients. AB - PURPOSE: Nausea and vomiting is an important health problem which adversely affects the daily routine and quality of life in pregnant women. The purpose of this study was to measure the level of change in the quality of life, depression and anxiety in hyperemesis gravidarum (HG) patients in relation to social demographic data and disease variables. METHODS: One hundred pregnant women hospitalized with the diagnosis of HG were included in the study. A total of 100 healthy pregnant women were also evaluated as the control group. All the patients in the study completed the socio-demographic data form, the Hospital Anxiety and Depression Scale (HADS-A and D) and Brief Disability Questionnaire (BDQ). RESULTS: The mean HADS-D subscale score was 7.09 +/-3.91 in HG patients and 5.73 +/- 3.32 in controls. The depression score in the HG patients were significantly higher than that of the control group (p = 0.009). The mean HADS-A subscale score was 7.73 +/- 3.86, which was significantly higher in HG patients compared to 6.70 +/- 3.31 in controls (p = 0.045). The mean BDQ score was 11.2 +/- 4.40 in HG patients and 8.5 +/- 3.31 in the control group of pregnant women, thus, significantly higher in the HG group as compared to controls (p < 0.0001). In the HADS-D, 52 patients in the HG group and 40 patients in the control group scored above the threshold value (p = 0.089). In the HADS-A, 28 patients in the HG group and 20 in the control group scored above the threshold value (p = 0.185). CONCLUSIONS: In patients with HG, a significant deterioration of physical and social health was encountered. HG disease is independent of any underlying psychiatric condition and adversely affects the quality of life of the sufferer. PMID- 23807699 TI - Obstetric outcomes and prognostic factors of lupus pregnancies. AB - PURPOSE: To determine maternal and fetal outcomes in pregnancies with Systemic Lupus Erythematosus (SLE), and to evaluate the prognostic factors that may affect obstetrical outcomes. METHODS: Sixty-five consecutive cases of SLE and pregnancy were included in this retrospective clinical study, performed in a university hospital which is also a reference center for SLE. Lupus pregnancies followed and delivered during the period from 2002 to 2011 in our department are evaluated. Obstetric outcomes and prognostic factors were main outcome measures. RESULTS: The mean patient age was 28.8 years and the nulliparity rate was 43.1%. Disease flare-up occurred in 7.7% of patients. Lupus anticoagulants, anticardiolipin IgG and IgM antibodies were positive in 27.6, 15.3 and 13.8% of patients, respectively. Mean gestational age at delivery was 36.6 +/- 4.2 and mean birth weight was 2,706 +/- 927 g. Stillbirth, fetal growth restriction, preeclampsia and preterm delivery rates were 4.6, 18.5, 9.2 and 27.6%, respectively. Cases with uterine artery Doppler abnormalities had significantly poorer obstetric outcomes. CONCLUSIONS: Multidisciplinary approach to the care of pregnant women with SLE is mandatory for good maternal and fetal outcomes. Uterine artery Doppler seems to be a good prognostic factor for adverse obstetric outcomes. PMID- 23807700 TI - Electronic properties of CuPc and H2Pc: an experimental and theoretical study. AB - Phthalocyanine (H2Pc) and its open-shell copper complex (CuPc) deposited on amorphous gold films have been studied by combining the outcomes of several synchrotron based spectroscopic tools (X-ray photoelectron spectroscopy, UV photoelectron spectroscopy and near-edge X-ray absorption fine structure, NEXAFS, spectroscopy) with those of density functional theory (DFT) calculations. The assignment of experimental evidence has been guided by the results of DFT numerical experiments carried out on isolated molecules. With specific reference to CuPc NEXAFS data collected at the N K-edge, they have been assigned by using the open-shell time-dependent DFT (TDDFT) in the framework of the zeroth order regular approximation (ZORA) scalar relativistic approach. The agreement between theory and experiment has been found to be satisfactory, thus indicating that the open-shell TDDFT (F. Wang and T. Ziegler, Mol. Phys., 2004, 102, 2585) may be used with some confidence to look into the X-ray absorption spectroscopy results pertinent to transition metal complexes. As far as the metal-ligand interaction is concerned, the combined use of NEXAFS spectroscopy and DFT outcomes ultimately testified the significant ionic contribution characterizing the bonding between the metal centre and the nitrogen atoms of the phthalocyanine coordinative pocket. PMID- 23807701 TI - Stepwise hydrogenation of an arylthiophosphinidene isocyanide complex to give tethered aldimine and aminocarbene functions. AB - The sequential addition of H+ and H- ions to [Mo2Cp2(MU-kappa2P,S:kappa1P,eta4 SPMes*)(CNtBu)(CO)2] (Mes* = 2,4,6-C6H2tBu3) completes a hydrocarbation or hydronitration of the uncoordinated C=C bond of the Mes* ring, yielding new ligands with thiophosphinidene and aldimine or aminocarbene functions tethered to a eta4-cyclohexadiene ring. The H- ion first attacks a Cp group to give a cyclopentadiene complex which evolves via a hydride intermediate. PMID- 23807703 TI - Unveiling the last missing link of the cardiolipin synthetic pathway in mitochondria. PMID- 23807702 TI - Significant changes in the intestinal environment after surgery in patients with colorectal cancer. AB - BACKGROUND: There have been very few detailed reports of the intestinal environment after surgical treatment for colorectal cancer (CRC). We analysed faecal microbiota, organic acids and pH to investigate the influence of colorectal surgery on the intestinal environment. METHODS: Faecal samples from 81 CRC patients were collected before the start of pre-operative preparation the day before surgery, as well as 7 days or more after surgery. Thirteen groups of intestinal microbiota, eight types of organic acids, and pH were measured using 16S rRNA-targeted reverse transcription-quantitative PCR, high-performance liquid chromatography and a pH meter, respectively. RESULTS: Total bacterial counts (10.3 +/- 0.6 vs. 9.4 +/- 1.2 log10 cells/g; p < 0.001) and the numbers of 6 groups of obligate anaerobes were significantly decreased after surgery. In contrast, the populations of Enterobacteriaceae, Enterococcus, Staphylococcus and Pseudomonas were significantly increased. Post-operatively, the concentration of total organic acids was lower (77.9 +/- 40.1 vs. 50.1 +/- 37.0 MUmol/g; p < 0.001) than the pre-operative concentration, and a significant reduction in short chain fatty acids (SCFAs) was observed. CONCLUSION: Significant changes in the intestinal environment, including marked decreases in obligate anaerobes, increases in pathogenic bacteria, and reductions in SCFAs, were detected after surgery for CRC. PMID- 23807704 TI - Reliability of in-hospital mortality as a quality indicator in clinical quality registries. A case study in an intensive care quality register. AB - OBJECTIVES: Errors in the registration or extraction of patient outcome data, such as in-hospital mortality, may lower the reliability of the quality indicator that uses this (partly) incorrect data. Our aim was to measure the reliability of in-hospital mortality registration in the Dutch National Intensive Care Evaluation (NICE) registry. METHODS: We linked data of the NICE registry with an insurance claims database, resulting in a list of discrepancies in in-hospital mortality. Eleven Intensive Care Units (ICUs) were visited where local data sources were investigated to find the true in-hospital mortality status of the discrepancies and to identify the causes of the data errors in the NICE registry. Original and corrected Standardized Mortality Ratios (SMRs) were calculated to determine if conclusions about quality of care changed compared to the national benchmark. RESULTS: In eleven ICUs, 23,855 records with 460 discrepancies were identified of which 255 discrepancies (1.1% of all linked records) were due to incorrect in-hospital mortality registration in the NICE registry. Two programming errors in computer software of six ICUs caused 78% of errors, the remainder was caused by manual transcription errors and failure to record patient outcomes. For one ICU the performance became concordant with the national benchmark after correction, instead of being better. CONCLUSIONS: The reliability of in-hospital mortality registration in the NICE registry was good. This was reflected by the low number of data errors and by the fact that conclusions about the quality of care were only affected for one ICU due to systematic data errors. We recommend that registries frequently verify the software used in the registration process, and compare mortality data with an external source to assure consistent quality of data. PMID- 23807705 TI - Imaging tumor response following liver-directed intra-arterial therapy. AB - Liver-directed intra-arterial therapies are palliative treatment options for patients with unresectable liver cancer; their use has also resulted in patients being downstaged leading to curative resection and transplantation. These intra arterial therapies include transarterial embolization, conventional transarterial chemoembolization (TACE), drug-eluting bead TACE and radioembolization. Assessment of imaging response following these liver-directed intra-arterial therapies is challenging but pivotal for patient management. Size measurements based on computed tomography or magnetic resonance imaging (MRI) have been traditionally used to assess tumor response to therapy. However, these anatomic changes lag behind functional changes and may require months to occur. Further, these intra-arterial therapies cause acute tumor necrosis, which may result in a paradoxical increase in tumor size on early follow-up imaging despite complete cell death or necrosis. This concept is unique comparing to changes seen following systemic chemotherapy. The recent development of functional imaging techniques including diffusion-weighted MRI (DW MRI) and positron emission tomography (PET) allow for early assessment of treatment response and even prediction of overall tumor response to intra-arterial therapies. Although the results of DW MRI and PET studies are promising, the impact of these imaging modalities to assess treatment response has been limited without standardized protocols. The aim of this review article is to delineate the best practice for assessing tumor response in patients with primary or secondary hepatic malignancies undergoing intra-arterial therapies. PMID- 23807706 TI - Distribution of voltage-dependent and intracellular Ca2+ channels in submucosal neurons from rat distal colon. AB - We recently observed a bradykinin-induced increase in the cytosolic Ca2+ concentration in submucosal neurons of rat colon, an increase inhibited by blockers of voltage-dependent Ca2+ (Ca(v)) channels. As the types of Ca(v) channels used by this part of the enteric nervous system are unknown, the expression of various Ca(v) subunits has been investigated in whole-mount submucosal preparations by immunohistochemistry. Submucosal neurons, identified by a neuronal marker (microtubule-associated protein 2), are immunoreactive for Ca(v)1.2, Ca(v)1.3 and Ca(v)2.2, expression being confirmed by reverse transcription plus the polymerase chain reaction. These data agree with previous observations that the inhibition of L- and N-type Ca2+ currents strongly inhibits the response to bradykinin. However, whole-cell patch-clamp experiments have revealed that bradykinin does not enhance Ca2+ inward currents under voltage clamp conditions. Consequently, bradykinin does not directly interact with Ca(v) channels. Instead, the kinin-induced Ca2+ influx is caused indirectly by the membrane depolarization evoked by this peptide. As intracellular Ca2+ channels on Ca(2+)-storing organelles can also contribute to Ca2+ signaling, their expression has been investigated by imaging experiments and immunohistochemistry. Inositol 1,4,5-trisphosphate (IP3) receptors (IP3R) have been functionally demonstrated in submucosal neurons loaded with the Ca(2+)-sensitive fluorescent dye, fura-2. Histamine, a typical agonist coupled to the phospholipase C pathway, induces an increase in the fura-2 signal ratio, which is suppressed by 2-aminophenylborate, a blocker of IP3 receptors. The expression of IP3R1 has been confirmed by immunohistochemistry. In contrast, ryanodine, tested over a wide concentration range, evokes no increase in the cytosolic Ca2+ concentration nor is there immunohistochemical evidence for the expression of ryanodine receptors in these neurons. Thus, rat submucosal neurons are equipped with various types of high voltage activated Ca(v) channels and with IP3 receptors for intracellular Ca2+ signaling. PMID- 23807707 TI - It's getting better all the time? Using secular trends to understand the impact of neurocritical care. PMID- 23807708 TI - Peripheral metabotropic glutamate receptor subtype 5 contributes to inflammation induced hypersensitivity of the rat temporomandibular joint. AB - Temporomandibular disorders (TMD) comprise an assortment of clinical conditions characterized by pain in the temporomandibular joint (TMJ). TMD patients have a variety of symptoms, including jaw movement disorder and TMJ pain. Metabotropic glutamate receptor subtype 5 (mGluR5) was reported to be involved in pain processing in several animal models of neuropathic and inflammatory pain. In this study, the head withdrawal threshold and mGluR5 expression were investigated in rats with complete Freund's adjuvant (CFA)-induced TMJ inflammatory pain. CFA injection into the TMJ significantly decreased the mechanical head withdrawal thresholds relative to vehicle injection, and the effects were blocked by pre injection of 2-methyl-6-(phenylethynyl)-pyridine (MPEP). mGluR5 expression in the trigeminal ganglion was predominantly increased in the CFA-injected group compared with the normal control group. Pretreatment with MPEP, a selective mGluR5 antagonist, reduced mGluR5 expression in the trigeminal ganglion compared with the CFA group, as measured by immunohistochemistry, western blotting, and RT PCR. Significant differences in the proportion or intensity of mGluR5 expression were found in animals with inflammation versus control animals at the examined time point. These findings indicate a role for peripheral mGluR5 in CFA-induced nociceptive behavior and TMJ inflammation. Peripheral application of mGluR5 antagonists could provide therapeutic benefits for inflammatory TMJ pain. PMID- 23807712 TI - Computational methodology to determine fluid related parameters of non regular three-dimensional scaffolds. AB - The application of three-dimensional (3D) biomaterials to facilitate the adhesion, proliferation, and differentiation of cells has been widely studied for tissue engineering purposes. The fabrication methods used to improve the mechanical response of the scaffold produce complex and non regular structures. Apart from the mechanical aspect, the fluid behavior in the inner part of the scaffold should also be considered. Parameters such as permeability (k) or wall shear stress (WSS) are important aspects in the provision of nutrients, the removal of metabolic waste products or the mechanically-induced differentiation of cells attached in the trabecular network of the scaffolds. Experimental measurements of these parameters are not available in all labs. However, fluid parameters should be known prior to other types of experiments. The present work compares an experimental study with a computational fluid dynamics (CFD) methodology to determine the related fluid parameters (k and WSS) of complex non regular poly(L-lactic acid) scaffolds based only on the treatment of microphotographic images obtained with a microCT (MUCT). The CFD analysis shows similar tendencies and results with low relative difference compared to those of the experimental study, for high flow rates. For low flow rates the accuracy of this prediction reduces. The correlation between the computational and experimental results validates the robustness of the proposed methodology. PMID- 23807710 TI - Histone deacetylases in herpesvirus replication and virus-stimulated host defense. AB - Emerging evidence highlights a critical role for protein acetylation during herpesvirus infection. As prominent modulators of protein acetylation, histone deacetylases (HDACs) are essential transcriptional and epigenetic regulators. Not surprisingly, viruses have evolved a wide array of mechanisms to subvert HDAC functions. Here, we review the mechanisms underlying HDAC regulation during herpesvirus infection. We next discuss the roles of acetylation in host defense against herpesvirus infection. Finally, we provide a perspective on the contribution of current mass spectrometry-based "omic" technologies to infectious disease research, offering a systems biology view of infection. PMID- 23807711 TI - Focal nodular hyperplasia and hepatic adenoma: current diagnosis and management. AB - Benign liver tumors are common lesions that can be classified into cystic and solid lesions. Cystic lesions are the most frequent; however, they rarely represent a diagnostic or therapeutic challenge. In contrast, solid lesions are more difficult to characterize and management remains controversial. The wide availability and use of advanced imaging modalities, including ultrasonography, computed tomography, and magnetic resonance imaging have led to increased identification of incidental liver masses. Although some of these incidentally discovered masses are malignant, most are benign and must be included in the differential diagnosis. In this article we review FNH and HA. Its etiology, biological behavior, diagnosis, and treatment will be highlighted. PMID- 23807713 TI - Prevalence of Th17 and Treg cells in gastric cancer patients and its correlation with clinical parameters. AB - Th17 cells and CD4+CD25+ regulatory T (Treg) cells have been reported to share reciprocal developmental pathways but exhibit opposite effects, and the balance between them controls inflammation and autoimmune diseases. However, information regarding Th17/Treg cells in cancer-bearing hosts is still limited. In the present study, we investigated the distribution of Th17 cells in relation to Treg cells in gastric cancer patients, and evaluated how the imbalance in Th17/Treg cells in gastric cancer correlates with clinical and pathological parameters. We observed that the accumulation of Th17 and Treg cells in the tumor microenvironment was gradually increased according to disease progression, leading to an imbalance in Th17/Treg cells in gastric cancer patients. TGF-beta and interleukin (IL)-6 present in the gastric cancer microenvironment promoted the differentiation and expansion of Th17 cells, and increased numbers of Th17 cells promoted tumor progression through promotion of inflammation by secretion of IL-17. Treg cells promoted tumor progression by helping cancer cells escape from host immunosurveillance by secreting TGF-beta, and a high level of TGF-beta in the tumor microenvironment promoted differentiation and expansion of Treg cells. In conclusion, the imbalance in Th17/Treg cells was involved in the development and progression of gastric cancer. A better understanding of the nature, regulation, and function of Th17 and Treg cells in tumor immunity may aid in the development of novel and effective immunotherapy for gastric cancer. PMID- 23807714 TI - The Building Blocks Collaborative: advancing a life course approach to health equity through multi-sector collaboration. AB - Too many children are born into poverty, often living in disinvested communities without adequate opportunities to be healthy and thrive. Two complementary frameworks-health equity and life course-propose new approaches to these challenges. Health equity strategies seek to improve community conditions that influence health. The life course perspective focuses on key developmental periods that can shift a person's trajectory over the life course, and highlights the importance of ensuring that children have supports in place that set them up for long-term success and health. Applying these frameworks, the Alameda County Public Health Department launched the Building Blocks Collaborative (BBC), a countywide multi-sector initiative to engage community partners in improving neighborhood conditions in low-income communities, with a focus on young children. A broad cross-section of stakeholders, called to action by the state of racial and economic inequities in children's health, came together to launch the BBC and develop a Bill of Rights that highlights the diverse factors that contribute to children's health. BBC partners then began working together to improve community conditions by learning and sharing ideas and strategies, and incubating new collaborative projects. Supportive health department leadership; dedicated staff; shared vision and ownership; a flexible partnership structure; and broad collective goals that build on partners' strengths and priorities have been critical to the growth of the BBC. Next steps include institutionalizing BBC projects into existing infrastructure, ongoing partner engagement, and continued project innovation-to achieve a common vision that all babies have the best start in life. PMID- 23807715 TI - Intimate partner violence and breastfeeding in Africa. AB - We examined the associations of maternal intimate partner violence (IPV) victimization with early initiation and exclusive breastfeeding in eight African countries. For mothers 15-49 years with an infant aged less than 6 months from national Demographic and Health Surveys since 2007 for Ghana (n = 173), Kenya (n = 449), Liberia (n = 313), Malawi (n = 397), Nigeria (n = 2007), Tanzania (n = 549), Zambia (n = 454), and Zimbabwe (n = 480), logistic regression was used to estimate the unadjusted and adjusted associations of lifetime maternal emotional, physical, and sexual IPV victimization with early initiation (less than 1 hour of birth) and exclusive breastfeeding in the prior 24 hours. Maternal lifetime IPV victimization often was adversely associated with optimal breastfeeding practices. Physical IPV in Zimbabwe (aOR 0.40, p = 0.002), sexual IPV in Zambia (aOR 0.42, p = 0.017), and emotional IPV in Kenya (aOR 0.54, p = 0.050) and Tanzania (aOR 0.57, p = 0.088) were associated with lower adjusted odds of early initiation. Sexual IPV in Liberia (aOR 0.09, p = 0.026), Ghana (aOR 0.17, p = 0.033), and Kenya (aOR 0.34, p = 0.085) were associated with lower adjusted odds of exclusive breastfeeding. Atypically, physical IPV in Tanzania (aOR 2.11, p = 0.042) and sexual IPV in Zambia (aOR 2.49, p = 0.025) were associated with higher adjusted odds of early initiation and exclusive breastfeeding, respectively. Across several settings, maternal IPV victimization may adversely influence breastfeeding practices. Longitudinal research of these relationships is warranted. Screening for IPV victimization and breastfeeding counseling in prenatal and postpartum care may mitigate the potential intergenerational effects of IPV. PMID- 23807716 TI - Characterization of health care provider attitudes toward parental involvement in neonatal resuscitation-related decision making in Mongolia. AB - The aim of this study was to characterize attitudes and practices among health care providers (HCPs) in Mongolia regarding parental involvement in neonatal resuscitation (NR)-related decisions. A voluntary, anonymous questionnaire was administered to 210 HCPs across 19 of 21 Mongolia provinces. Eligible HCPs included midwives, neonatologists, pediatricians, and obstetricians involved in neonatal-perinatal care in both rural and urban hospitals. A total of 210 pediatric HCPs were surveyed and 100 % completed all questions (response rate 100 %). Despite the absence of nation-wide guidelines, NR is uniformly performed at 32-weeks gestation across HCP professions and across rural/urban settings. Most HCPs (67 %) indicate that parents should be counseled about resuscitation, but only 9 % ask the parents if they want their extremely premature child resuscitated and only 17 % counsel the parents prior to birth of an at-risk infant. Most HCPs (72 %) prefer to unilaterally decide when to withdraw NR, and only 28 % indicated that both parents should be involved in the decision. Following a newborn's death, 75 % of all HCPs reported that they do explain the death to parents, although only 28 % reported receiving any training in parental grief counseling. For HCPs in Mongolia, a discrepancy exists between the perceived value of parental involvement and the actual practice of NR-related counseling. This report is a necessary first step toward understanding the factors that influence NR-related practices in Mongolia, and may serve as model for collecting these types of data in other low and middle income countries. PMID- 23807717 TI - Child health insurance coverage and household activity toward child development in four South American countries. AB - We evaluate the association between child health insurance coverage and household activities that enhance child development. We use micro-level data on a unique sample of 2,370 children from four South American countries. Data were collected by physicians via in-person interviews with the mothers. The regression models compare insured and uninsured children seen within the same pediatric care practice for routine well-child care and adjust for several demographic and socioeconomic characteristics. We also stratify these analyses by selective household demographic and socioeconomic characteristics and by country. We find that insurance coverage is associated with increasingly engaging the child in development-enhancing household activity in the total sample. This association significantly varies with ethnic ancestry and is more pronounced for children of Native or African ancestry. When stratifying by country, a significant positive association is observed for Argentina, with two other countries having positive but insignificant associations. The results suggest that insurance coverage is associated with enhanced household activity toward child development. However, other data and research are needed to estimate the causal relationship. PMID- 23807718 TI - Socioeconomic and geographical disparities in under-five and neonatal mortality in Uttar Pradesh, India. AB - As a part of the Millennium Development Goals, India seeks to substantially reduce its burden of childhood mortality. The success or failure of this goal may depend on outcomes within India's most populous state, Uttar Pradesh. This study examines the level of disparities in under-five and neonatal mortality across a range of equity markers within the state. Estimates of under-five and neonatal mortality rates were computed using five datasets, from three available sources: sample registration system, summary birth histories in surveys, and complete birth histories. Disparities were evaluated via comparisons of mortality rates by rural-urban location, ethnicity, wealth, and districts. While Uttar Pradesh has experienced declines in both rates of under-five (162-108 per 1,000 live births) and neonatal (76-49 per 1,000 live births) mortality, the rate of decline has been slow (averaging 2 % per annum). Mortality trends in rural and urban areas are showing signs of convergence, largely due to the much slower rate of change in urban areas. While the gap between rich and poor households has decreased in both urban and rural areas, trends suggest that differences in mortality will remain. Caste-related disparities remain high and show no signs of diminishing. Of concern are also the signs of stagnation in mortality amongst groups with greater ability to access services, such as the urban middle class. Notwithstanding the slow but steady reduction of absolute levels of childhood mortality within Uttar Pradesh, the distribution of the mortality by sub-state populations remains unequal. Future progress may require significant investment in quality of care provided to all sections of the community. PMID- 23807720 TI - Screening parents of high-risk infants for emotional distress: rationale and recommendations. AB - Having a baby hospitalized in a neonatal intensive care unit (NICU) is a potentially traumatic event for parents. This article summarizes research documenting heightened symptoms of depression and post-traumatic stress in these parents and reviews studies of the relationship of parental distress with impaired infant and child development. We describe an array of validated screening devices for depression and post-traumatic stress, along with research on risk factors for elevated scores. In making recommendations for screening both mothers and fathers for emotional distress in the NICU, we (a) present commentary on the pros and cons of screening, (b) propose a timetable for screening and (c) describe both supportive interventions for parents in the NICU and a variety of referral possibilities for parents most at risk. PMID- 23807721 TI - Pulmonary embolism, myocardial infarction, and ischemic stroke in lung cancer patients: results from a longitudinal study. AB - PURPOSE: In this cohort study, the rates of pulmonary embolism (PE), myocardial infarction (MI), and ischemic stroke (IS) before and after lung cancer (LC) diagnosis were compared to cancer-free controls. METHODS: Patients with LC during 2000-2007 were selected from PALGA, the Dutch Pathology Registry, and linked to the PHARMO medical record linkage system, including drug use and hospitalizations of 3 million inhabitants in the Netherlands. Included LC patients were matched 1:10 by age and gender to cancer-free controls. Hospitalizations for PE, MI, and IS were assessed in the 12 months before and after LC diagnosis. RESULTS: LC patients (N = 3,717) were six times more likely than cancer-free controls to have had a PE in the 12 months before diagnosis. After LC diagnosis, patients experienced an extremely increased risk of PE in the first 6 months (hazard ratio [HR] 16.8; 95 % confidence interval [CI] 7.6-36.8) compared with controls), which decreased to a five times increased risk (HR 5.1; 95 % CI 2.7-9.4) thereafter. However, there were less than two events per 100 person years during both time periods. LC patients receiving chemotherapy were eight times more likely to develop PE, whereas surgery increased the risk on PE three times. For MI and IS, no significant difference was observed compared with cancer-free controls before or after LC diagnosis. CONCLUSIONS: LC patients have a higher risk of developing PE compared with cancer-free controls, although the frequency of PE hospitalizations was low. Surgery and chemotherapy were associated with an increased risk of PE. PMID- 23807723 TI - Radical diffusion limits to photoinhibited superresolution lithography. AB - Photoinhibited superresolution (PInSR) lithography is a two-color, one-photon scheme that promises high throughput far-field patterning at deep subwavelength scales. The technique requires that active species are confined for some minimum time to the illuminated area where they are generated. We investigate here the extent to which this condition is met for published materials. Using spatial and temporal control of focused beams as well as fluorescence recovery after photobleaching (FRAP), we probe the dynamics of photoinhibition in the PInSR material system. Our results indicate fast out-diffusion of unreacted photoinhibitor from the submicron optical spot during the polymerization interval, resulting in uniform rather than structured inhibition. Published results are consistent with this mechanism, indicating that superresolved polymer confinement with PInSR has not yet been shown with structured inhibition. To address the issue, we propose modifications to the material and exposure to slow inhibitor out-diffusion and accelerate polymer gelation. PMID- 23807719 TI - Characteristics of extremely low-birth-weight infant survivors with unimpaired outcomes at 30 months of age. AB - OBJECTIVE: To evaluate characteristics of unimpaired outcome in extremely low birth-weight (ELBW) survivors. STUDY DESIGN: ELBW infants (n=714) with 30 months' assessments were analyzed. Logistic regression was used to develop a model for the binary outcome of unimpaired versus impaired outcome. RESULT: Thirty-three percent of infants had an unimpaired outcome. Seventeen percent of ELBW survivors had a Bayley II Mental Developmental Index score of >= 101 and 2% had a score of >= 116. Female gender, use of antenatal steroids (ANS), maternal education >= high school and the absence of major neonatal morbidities were independent predictors of unimpaired outcome. The likelihood of an unimpaired outcome in the presence of major neonatal morbidities was higher in infants exposed to ANS. CONCLUSION: The majority of unimpaired ELBW survivors had cognitive scores shifted toward the lower end of the normal distribution. Exposure to ANS was associated with higher likelihood of an unimpaired outcome in infants with major neonatal morbidities. PMID- 23807722 TI - Crofelemer: a review of its use in the management of non-infectious diarrhoea in adult patients with HIV/AIDS on antiretroviral therapy. AB - Crofelemer (Fulyzaq) is a botanical drug substance (oligomeric proanthocyanidin) extracted from the stem bark latex of the Croton lechleri tree. Crofelemer undergoes minimal systemic absorption following oral administration; it acts locally within the gastrointestinal (GI) tract by inhibiting the two principal chloride ion channels in the luminal membrane of enterocytes. Crofelemer is the first (and so far only) agent to be approved by the US FDA specifically for the symptomatic relief of non-infectious (i.e. secretory) diarrhoea in adult patients with HIV/AIDS on antiretroviral therapy (ART). This approval was based on findings from the ADVENT study, a large (n = 376 randomized patients), multicentre, phase III trial in which the recommended dosage of oral crofelemer (125 mg twice daily) significantly reduced secretory diarrhoea in HIV-positive individuals on ART compared with placebo, as assessed over a 4-week period. Crofelemer was generally well tolerated in ADVENT (which included a 5-month placebo-free extension phase) and a 48-week, open-label, phase III safety study; infections and GI disorders were the most frequently reported treatment-emergent adverse events (TEAEs) in patients receiving the drug. Of note, the overall incidence of TEAEs was similar in the crofelemer and placebo groups during the 4 week placebo-controlled phase of ADVENT. Treatment with crofelemer had no appreciable effect on immune parameters, such as HIV viral load and CD4+ cell counts. PMID- 23807724 TI - Overexpression of Bmi-1 contributes to the invasion and metastasis of hepatocellular carcinoma by increasing the expression of matrix metalloproteinase (MMP)-2, MMP-9 and vascular endothelial growth factor via the PTEN/PI3K/Akt pathway. AB - Hepatocellular carcinoma (HCC) is one of the most common malignant tumours and it carries a poor prognosis due to a high rate of recurrence or metastasis after surgery. Bmi-1 plays a significant role in the growth and metastasis of many solid tumours. However, the exact mechanisms underlying Bmi-1-mediated cell invasion and metastasis, especially in HCC, are not yet known. In the present study, we sought to evaluate the expression of Bmi-1 in HCC samples and its relationship with clinicopathological characteristics and prognostic value, we also investigated related mechanisms underlying Bmi-1-mediated cell invasion in HCC. Our results showed that Bmi-1 is upregulated in HCC tissues compared to matched non-cancer liver tissues; and its expression is positively associated with tumour size, metastasis, venous invasion and AJCC TNM stage, respectively; multivariate analysis showed that high expression of Bmi-1 was an independent prognostic factor for overall survival. In addition, the shRNA-mediated inhibition of Bmi-1 reduced the invasiveness of two HCC cell lines in vitro by upregulating phosphatase and the tensin homolog deleted on chromosome 10 (PTEN) expression, inhibiting the phosphatidylinositol 3-kinase (PI3K)/Akt signalling pathway and downregulating the expression and activities of matrix metalloproteinase (MMP)-2 and MMP-9 and vascular endothelial growth factor (VEGF). These data demonstrate that Bmi-1 plays a vital role in HCC invasion and that Bmi-1 is a potential therapeutic target for HCC. PMID- 23807725 TI - Fibrosing mediastinitis: an unusual cause of pulmonary symptoms. AB - Fibrosing mediastinitis (FM), also known as granulomatous or sclerosing mediastinitis, is an uncommon but serious cause of chest symptoms. Due to an infectious or inflammatory challenge, production of collagen occurs in the confined space of the mediastinum. Collagen formation leads to compression of vital structures, resulting in cough, chest pain and dyspnea. The majority of cases of FM occur as a result of prior exposure to Histoplasma capsulatum. The following is a case of a previously healthy young woman who presented with a 3 month history of cough, chest pain and trouble breathing, and was subsequently found to have fibrosing mediastinitis. Fibrosing mediastinitis should be considered in the differential diagnosis of cough, chest pain and dyspnea, primarily when findings such as increased venous pressure are present on physical exam and hilar abnormalities are seen on chest radiograph. Clinical presentation, diagnosis and management of fibrosing mediastinitis are discussed. PMID- 23807726 TI - Documenting quality improvement and patient safety efforts: the quality portfolio. A statement from the academic hospitalist taskforce. AB - Physicians increasingly investigate, work, and teach to improve the quality of care and safety of care delivery. The Society of General Internal Medicine Academic Hospitalist Task Force sought to develop a practical tool, the quality portfolio, to systematically document quality and safety achievements. The quality portfolio was vetted with internal and external stakeholders including national leaders in academic medicine. The portfolio was refined for implementation to include an outlined framework, detailed instructions for use and an example to guide users. The portfolio has eight categories including: (1) a faculty narrative, (2) leadership and administrative activities, (3) project activities, (4) education and curricula, (5) research and scholarship, (6) honors, awards, and recognition, (7) training and certification, and (8) an appendix. The authors offer this comprehensive, yet practical tool as a method to document quality and safety activities. It is relevant for physicians across disciplines and institutions and may be useful as a standalone document or as an adjunct to traditional promotion documents. As the Next Accreditation System is implemented, academic medical centers will require faculty who can teach and implement the systems-based practice requirements. The quality portfolio is a method to document quality improvement and safety activities. PMID- 23807727 TI - Environmental variables affecting the distribution of POPs on Mt. Meru, Tanzania. AB - Tanzania is an equatorial country characterized by warm temperatures, which should increase the volatilization of persistent organic pollutants (POPs), but this scenario could be different in mountainous areas like Mount Meru, a volcano situated in the East African Rift (Tz). We collected soil samples along an altitudinal transect upto 4577 m a.s.l., reporting the first data about POP contamination in this area (DDX, HCHs, HCB and PCBs). The DDX contamination pattern in Mt. Meru shows levels slightly higher than those of other remote places with a strong increase in the metabolites/DDT historical trend, which is different from DDX, PCBs, HCHs and particularly HCB as this shows very low contamination levels. Back trajectory analysis allowed a discussion about putative contamination sources, while analysis of the environmental features (climatic and pedological) allowed us to discriminate their relative importance. The distribution of POPs shows a strong correlation with soil organic matter and vegetation. SOM-normalization evidenced altitudinal dependence according to cold condensation for PCBs and HCHs, while DDX are present in larger amounts in the agricultural area at the volcano foot. OM-normalized concentrations suggested also a possible role of the OM composition on the POPs' distribution. PMID- 23807728 TI - Involvement of alpha7 nAChR signaling cascade in epigallocatechin gallate suppression of beta-amyloid-induced apoptotic cortical neuronal insults. AB - Excessive generation and accumulation of the beta-amyloid (Abeta) peptide in selectively vulnerable brain regions is a key pathogenic event in the Alzheimer's disease (AD), while epigallocatechin gallate (EGCG) is a very promising chemical to suppress a variety of Abeta-induced neurodegenerative disorders. However, the precise molecular mechanism of EGCG responsible for protection against neurotoxicity still remains elusive. To validate and further investigate the possible mechanism involved, we explored whether EGCG neuroprotection against neurotoxicity of Abeta is mediated through the alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) signaling cascade. It was shown in rat primary cortical neurons that short-term treatment with EGCG significantly attenuated the neurotoxicity of Abeta1-42, as demonstrated by increased cell viability, reduced number of apoptotic cells, decreased reactive oxygen species (ROS) generation, and downregulated caspase-3 levels after treatment with 25-MUM Abeta1-42. In addition, EGCG markedly strengthened activation of alpha7nAChR as well as its downstream pathway signaling molecules phosphatidylinositol 3-kinase (PI3K) and Akt, subsequently leading to suppression of Bcl-2 downregulation in Abeta-treated neurons. Conversely, administration of alpha7nAChR antagonist methyllycaconitine (MLA; 20 MUM) to neuronal cultures significantly attenuated the neuroprotection of EGCG against Abeta-induced neurototoxicity, thus presenting new evidence that the alpha7nAChR activity together with PI3K/Akt transduction signaling may contribute to the molecular mechanism underlying the neuroprotective effects of EGCG against Abeta-induced cell death. PMID- 23807729 TI - Long-term subjective outcomes of computer-assisted total knee arthroplasty. AB - PURPOSE: This study aimed to clarify the results of computer-assisted total knee arthroplasty (TKA) after ten years using patient-derived scores. METHODS: Thirty posterior-stabilised total knee prostheses implanted using a computed tomography free navigation system were compared with 30 matched total knee prostheses of the same type implanted using a conventional, manual technique. At an average of ten years after surgery, we investigated patient-reported outcomes using the Knee Society's new scoring system. The results of 27 patients (14 patients in the navigation group and 13 patients in the manual group) were assessed in this study. RESULTS: There was no significant difference between the navigation and manual groups for any section of the questionnaire, which consisted of symptoms, patient satisfaction, patient expectation, walking/standing, standard activities, advanced activities, and discretionary activities. CONCLUSION: After long-term follow-up, we found no subjective advantages of using a navigation system for patients who undergo TKA though the absolute number of patients was very small. Additional extensive studies are required to validate our result. PMID- 23807730 TI - Asymmetric division: a marker for cancer stem cells in early stage tumors? PMID- 23807731 TI - Measurement of accelerometry-based gait parameters in people with and without dementia in the field: a technical feasibility study. AB - BACKGROUND: Gait analyses are an important tool to diagnose diseases or to measure the rehabilitation process of patients. In this context, sensor-based systems, and especially accelerometers, gain in importance. They are able to improve objectiveness of gait analyses. In clinical settings, there is usually a supervisor who gives instructions to the patients, but this can have an influence on patients' gait. It is expected that this effect will be smaller in field studies. OBJECTIVE: Aim of this study was to capture and evaluate gait parameters measured by a single waist-mounted accelerometer during everyday life of subjects. METHODS: Due to missing ground-truth in unsupervised conditions, another external criterion had to be chosen. Subjects of two different groups were considered: patients with dementia (DEM) and active older people (ACT). These groups were chosen, because of the expected difference in gait. The idea was to quantify the expected difference of accelerometric-based gait parameters. Gait parameters were e.g. velocity, step frequency, compensation movements, and variance of the accelerometric signal. RESULTS: Ten subjects were measured in each group. The number of walking episodes captured was 1,187 (DEM) vs. 1,809 (ACT). The compensation and variance parameters showed an AUC value (Area Under the Curve) between 0.88 and 0.92. In contrast, velocity and step frequency performed poorly (AUC values of 0.51 and 0.55). It was possible to classify both groups using these parameters with an accuracy of 89.2%. CONCLUSION: The results showed a much higher amount of walking episodes in field studies compared to supervised clinical trials. The classification showed a high accuracy in distinguishing between both groups. PMID- 23807732 TI - Demethylzeylasteral exhibits dose-dependent inhibitory behaviour towards estradiol glucuronidation. AB - The disturbance of estradiol level might induce the occurence of some diseases, including cancer. Estradiol is mainly metabolized through the conjugation reactions, including the sulfation and glucuronidation reactions. The present study tried to evaluate the inhibition of estradiol glucuronidation by the major ingredients of Tripterygium wilfordii Hook F. demethylzeylasteral. Selective ion monitoring at negative ion mode ([M+ H-] = 447) was employed to monitor the two glucuronides of estradiol. The reaction rate was determined through comparison of peak area of these two glucuronides. Lineweaver-Burk plot and Dixon plot were utilized to determine the inhibition kinetic type, and the inhibition kinetic parameters (K i) were calculated using the second plot. Competitive inhibition of demethylzeylasteral towards the formation of two glucuronides of estradiol was demonstrated, and the K i values were calculated to be 453.3 and 110.9 MUM, respectively. All these results will remind us the risk of elevated serum concentrations of estradiol due to the inhibition of estradiol glucuronidation by demethylzeylasteral. PMID- 23807733 TI - 'I could never have learned this in a lecture': transformative learning in rural health education. AB - Health indicators for rural populations in Australia continue to lag behind those of urban populations and particularly for Indigenous populations who make up a large proportion of people living in rural and remote Australia. Preparation of health practitioners who are adequately prepared to face the 'messy swamps' of rural health practice is a growing challenge. This paper examines the process of learning among health science students from several health disciplines from five Western Australian universities during 'Country Week': a one-week intensive experiential interprofessional education program in rural Western Australia. The paper weaves together strands of transformative theory of learning with findings from staff and student reflections from Country Week to explore how facilitated learning in situ can work to produce practitioners better prepared for rural health practice. PMID- 23807734 TI - A test of genotypic variation in specificity of herbivore-induced responses in Solidago altissima L. (Asteraceae). AB - Plant-induced responses to multiple herbivores can mediate ecological interactions among herbivore species, thereby influencing herbivore community composition in nature. Several studies have indicated high specificity of induced responses to different herbivore species. In addition, there may be genetic variation for plant response specificity that can have significant ecological implications, by altering the competitive strength and hierarchical relationships among interacting herbivore species. However, few studies have examined whether plant populations harbor genetic variation for induction specificity. Using three distinct genotypes of Solidago altissima plants, we examined whether specialist herbivore species Dichomeris leuconotella, Microrhopala vittata, and Trirhabda virgata elicit specific induction responses from plants (specificity of elicitation), and whether induction differentially affects these herbivore species (specificity of effect). Results from bioassays and secondary metabolite analyses suggest that there is specificity of both elicitation and effect in the induced responses: D. leuconotella and M. vittata preferred and performed better on leaves damaged by conspecifics than heterospecifics, and induced qualitatively different secondary metabolite profiles. In contrast, T. virgata equally avoided but physiologically tolerated all types of damage. These patterns of specificity suggest that plant-induced responses mediate asymmetric competitive interactions between herbivore species, which potentially intensifies inter-specific relative to intra-specific competition. Plant genotypes widely differed in overall susceptibility to the herbivores and secondary metabolite production, yet we found no genotype-by-treatment interactions in insect performance, preference and plant secondary metabolite production. This lack of genetic variation for induction specificity suggests that competitive interactions between herbivore species on S. altissima are homogeneous across plant genotypes. PMID- 23807735 TI - What is Patient-Centered Care? A Typology of Models and Missions. AB - Recently adopted health care practices and policies describe themselves as "patient-centered care." The meaning of the term, however, remains contested and obscure. This paper offers a typology of "patient-centered care" models that aims to contribute to greater clarity about, continuing discussion of, and further advances in patient-centered care. The paper imposes an original analytic framework on extensive material covering mostly US health care and health policy topics over several decades. It finds that four models of patient-centered care emphasize: patients versus their parts; patients versus providers; patients/providers/states versus "the system"; and patients and providers as persons. Each type is distinguishable along three dimensions: epistemological orientations, practical accommodations, and policy tools. Based on this analysis, the paper recommends that four questions be asked of any proposal that claims to provide patient-centered care: Is this care a means to an end or an end in itself? Are patients here subjects or objects? Are patients here individuals or aggregates? How do we know what patients want and need? The typology reveals that models are neither entirely compatible nor entirely incompatible and may be usefully combined in certain practices and policies. In other instances, internal contradictions may jeopardize the realization of coherent patient-centered care. PMID- 23807737 TI - Inelastic scattering of OH radicals from organic liquids: isolating the thermal desorption channel. AB - Inelastic scattering of OH radicals from liquid surfaces has been investigated experimentally. An initially translationally and rotationally hot distribution of OH was generated by 193 nm photolysis of allyl alcohol. These radicals were scattered from an inert reference liquid, perfluorinated polyether (PFPE), and from the potentially reactive hydrocarbon liquids squalane (C30H62, 2,6,10,15,19,23-hexamethyltetracosane) and squalene (C30H50, trans 2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene). The scattered OH v = 0 products were detected by laser-induced fluorescence. Strong correlations were observed between the translational and rotational energies of the products. The high-N levels are translationally hot, consistent with a predominantly direct, impulsive scattering mechanism. Impulsive scattering also populates the lower-N levels, but a component of translationally relaxed OH, with thermal desorption characteristics, can also be seen clearly for all three liquids. More of this translationally and rotationally relaxed OH survives from squalane than from squalene. Realistic molecular dynamics simulations confirm that double-bond sites are accessible at the squalene surface. This supports the proposition that relaxed OH may be lost on squalene via an addition mechanism. PMID- 23807736 TI - Evaluating medico-legal decisional competency criteria. AB - In this paper I get clearer on the considerations that ought to inform the evaluation and development of medico-legal competency criteria-where this is taken to be a question regarding the abilities that ought to be needed for a patient to be found competent in medico-legal contexts. In the "Decisional Competency in Medico-Legal Contexts" section I explore how the question regarding the abilities that ought to be needed for decisional competence is to be interpreted. I begin by considering an interpretation that takes the question to be asking about the abilities needed to satisfy an idealized view of competent decision-making, according to which decisional competency is a matter of possessing those abilities or attributes that are needed to engage in good or effective or, perhaps, substantially autonomous or rational decision-making. The view has some plausibility-it accords with the way decisional competency is understood in a number of everyday contexts-but fails as an interpretation of the question regarding the abilities that should be needed for decisional competence in medico-legal contexts. Nevertheless, consideration of why it is mistaken suggests a more accurate interpretation and points the way in which the question regarding the evaluation of medico-legal competency criteria is to be answered. Building on other scholarly work in the area, I outline in the "Primary and Secondary Requirements" section several requirements that decisional competence criteria ought to satisfy. Then, in the "Applying the Framework" section, I say something about the extent to which medico-legal competency criteria, as well as some models of decisional competency proposed in the academic literature, fulfil those requirements. PMID- 23807738 TI - PDCD5 expression predicts a favorable outcome in patients with hepatocellular carcinoma. AB - Liver cancer in men is the fifth most frequently diagnosed cancer worldwide. Programmed cell death 5 (PDCD5) is an apoptosis related gene and plays an important role in the pathogenesis and development of cancer. In this study, we confirmed that the levels of PDCD5 mRNA and protein were lower in hepatocellular carcinoma (HCC) tissue compared to normal tissue. PDCD5 expression was significantly associated with HBV infection, tumor number, lymph node metastasis and the survival time of the patients with HCC. In addition, the serum levels of PDCD5 and AFP in the patients were significantly positively correlated. We also confirmed that upregulation of PDCD5 was able to inhibit cell proliferation and mobility, induce apoptosis and G1 arrest. Interestingly, PDCD5 also inhibited proteasome activity similarly to the proteosome inhibitor MG132. PDCD5 could be considered as a reliable marker of favorable prognosis of HCC patients. PMID- 23807739 TI - Ghrelin induces gastric cancer cell proliferation, migration, and invasion through GHS-R/NF-kappaB signaling pathway. AB - This study aims to investigate the roles of ghrelin signaling in human gastric carcinoma cell lines AGS and SGC7901. Effects of ghrelin signaling on CDK6, P53, NF-kappaB/P65 and MMP2 mRNA and/or protein expression were determined by real time PCR and western blot. MTT method and flow cytometry were performed to assess the gastric cancer cell proliferation. The SGC7901 cells overexpressing ghrelin were inoculated into nude mice to produce tumors which were measured later. The wound-healing assay and cell invasion assay were used to test the cell migration and invasive ability of gastric cancer. Ghrelin signaling promotes the oncogene CDK6 gene expression and represses the tumor suppressor gene P53 gene expression in gastric cancer. Ghrelin activates NF-kappaB/P65 signaling pathway through GHS R in gastric cancer. Ghrelin upregulates the metastasis factor MMP2 expression via GHS-R/NF-kappaB signaling pathway in gastric cancer cells and promotes tumor cells migration and invasion, suggesting that ghrelin signaling is a critical pathway in cancer metastasis. Ghrelin induces cell proliferation, migration and invasion via GHS-R/NF-kappaB signaling pathway in gastric cancer cells. Ghrelin treatment must be avoided for gastric cancer patients. PMID- 23807740 TI - Condurango-glycoside-A fraction of Gonolobus condurango induces DNA damage associated senescence and apoptosis via ROS-dependent p53 signalling pathway in HeLa cells. AB - Gonolobus condurango plant extract is used as an anticancer drug in some traditional systems of medicine including homeopathy, but it apparently lacks any scientific validation. Further, no detailed study is available to suggest whether condurango-glycoside-A (CGA), a major ingredient of condurango serves as a potent anticancer compound. Therefore, we investigated apoptosis-inducing ability of CGA against cervix carcinoma cells (HeLa). beta-galactosidase-activity and DNA damage were critically studied at different time points; while induced DNA-damage was observed at 9-12th hours, senescence of cells appeared at a later stage (18th hour after CGA treatment), implicating thereby a possible role of DNA damage in inducing pre-mature cell senescence. Concurrently, the number of cells undergoing apoptosis increased along with increase in reactive oxygen species (ROS) generation. Expression of p53 was also up-regulated, indicating that apoptosis could have been mediated through p53 pathway. DCHFDA (4',6-Diamidino-2 phenylindole dihydrochloride) assay, acridine orange/ethidium bromide staining and annexin V/PI assay results collectively confirmed that apoptosis was induced by increased ROS generation. Reduction in proliferation of cells was further evidenced by the cell cycle arrest at G0/G1 stage. Expression profiles of certain relevant genes and proteins like p53, Akt, Bcl-2, Bax, cytochrome c and caspase 3 also provided evidence of ROS mediated p53 up-regulation and further boost in Bax expression and followed by cytochrome c release and activation of caspase 3. Overall results suggest that CGA initiates ROS generation, promoting up regulation of p53 expression, thus resulting in apoptosis and pre-mature senescence associated with DNA damage. PMID- 23807741 TI - Occupational exposure to low doses of ionizing radiation and cataract development: a systematic literature review and perspectives on future studies. AB - Ionizing radiation is a well-known but little understood risk factor for lens opacities. Until recently, cataract development was considered to be a deterministic effect occurring at lens doses exceeding a threshold of 5-8 Gy. Substantial uncertainty about the level and the existence of a threshold subsists. The International Commission on Radiation Protection recently revised it to 0.5 Gy. Based on a systematic literature review of epidemiological studies on exposure to low levels of ionizing radiation and the occurrence of lens opacities, a list of criteria for new epidemiological studies was compiled, and a list of potential study populations was reviewed. Among 24 publications finally identified, six report analyses of acute exposures in atomic bomb survivors and Chernobyl liquidators, and the others report analyses of protracted exposures in occupationally, medically or accidentally exposed populations. Three studies investigated a dose threshold: in atomic bomb survivors, the best estimates were 1 Sv (95 % CI <0-0.8 Sv) regarding lensectomies; in survivors exposed as children, 0.6 Sv (90 % CI <0.0-1.2 Sv) for cortical cataract prevalence and 0.7 Sv (90 % CI 0.0-2.8 Sv) for posterior subcapsular cataract; and in Chernobyl liquidators, 0.34 Sv (95 % CI 0.19-0.68 Sv) for stage 1 cataract. Current studies are heterogeneous and inconclusive regarding the dose-response relationship. Protracted exposures and high lens doses occur in several occupational groups, for instance, in physicians performing fluoroscopy-guided interventional procedures, and in accidentally exposed populations. New studies with a good retrospective exposure assessment are feasible and should be initiated. PMID- 23807745 TI - Characterization of signal sequences determining the nuclear export of Newcastle disease virus matrix protein. AB - The Newcastle disease virus (NDV) matrix (M) protein has been demonstrated to be a nuclear-cytoplasmic trafficking protein. Previous studies have shown that the M protein localizes in the nucleus through a bipartite nuclear localization signal. Here, we report that the ability of the M protein to shuttle to the cytoplasm is mediated by three nuclear export signal sequences (NESs). Using leptomycin B (LMB), a specific inhibitor of CRM1, we found that the nuclear export of the three NESs was LMB insensitive and thus was CRM1 independent. In addition, inactivation of these NESs led to nuclear accumulation of the M protein. Our results highlight the significance of these NESs to the nuclear export of the NDV M protein. PMID- 23807743 TI - Genetic diversity and mutation of avian paramyxovirus serotype 1 (Newcastle disease virus) in wild birds and evidence for intercontinental spread. AB - Avian paramyxovirus serotype 1 (APMV-1), or Newcastle disease virus, is the causative agent of Newcastle disease, one of the most economically important diseases for poultry production worldwide and a cause of periodic epizootics in wild birds in North America. In this study, we examined the genetic diversity of APMV-1 isolated from migratory birds sampled in Alaska, Japan, and Russia and assessed the evidence for intercontinental virus spread using phylogenetic methods. Additionally, we predicted viral virulence using deduced amino acid residues for the fusion protein cleavage site and estimated mutation rates for the fusion gene of class I and class II migratory bird isolates. All 73 isolates sequenced as part of this study were most closely related to virus genotypes previously reported for wild birds; however, five class II genotype I isolates formed a monophyletic clade exhibiting previously unreported genetic diversity, which met criteria for the designation of a new sub-genotype. Phylogenetic analysis of wild-bird isolates provided evidence for intercontinental virus spread, specifically viral lineages of APMV-1 class II genotype I sub-genotypes Ib and Ic. This result supports migratory bird movement as a possible mechanism for the redistribution of APMV-1. None of the predicted deduced amino acid motifs for the fusion protein cleavage site of APMV-1 strains isolated from migratory birds in Alaska, Japan, and Russia were consistent with those of previously identified virulent viruses. These data therefore provide no support for these strains contributing to the emergence of avian pathogens. The estimated mutation rates for fusion genes of class I and class II wild-bird isolates were faster than those reported previously for non-virulent APMV-1 strains. Collectively, these findings provide new insight into the diversity, spread, and evolution of APMV-1 in wild birds. PMID- 23807744 TI - Genetic structure of rice black-streaked dwarf virus populations in China. AB - Rice black-streaked dwarf virus (RBSDV) is a double-stranded RNA (dsRNA) virus belonging to the genus Fijivirus in the family Reoviridae. The genome of RBSDV consists of ten dsRNA segments. Although RBSDV has caused significant economic losses to rice and maize production in the past few years in China, its molecular diversity and evolution remain largely unknown. To elucidate the factor(s) underlying the evolution of RBSDV, we determined segment 8 (S8; carrying ORF8 encoding the minor core capsid protein) sequences of 101 samples and segment 10 (S10; carrying ORF10 encoding the major capsid protein) sequences of 103 samples. The results show that both ORF8 and ORF10 are under negative selection. The S8 of three isolates and S10 of two isolates are recombinants. The RBSDV population in China can be classified into three groups according to S8 sequences or into two groups according to S10 sequences, irrespective of host or geographical origin. Of the RBSDV isolates with both S8 and S10 sequences available, 17 are between group reassortants and 30 are between-subgroup reassortants. The RBSDV subpopulations from different geographical regions and hosts show frequent gene flow within or between subpopulations. The RBSDV population from maize is in a state of expansion. In this study, no new emergent population was detected. Taken together, the results indicate that, in addition to recombination and negative selection, reassortment and gene flow are important factors that drive evolution of RBSDV in China. PMID- 23807746 TI - Complete genome sequence of a novel porcine parainfluenza virus 5 isolate in Korea. AB - A novel cytopathogenic paramyxovirus was isolated from a lung sample from a piglet, using continuous porcine alveolar macrophage cells. Morphologic and genetic studies indicated that this porcine virus (pPIV5) belongs to the species Parainfluenza 5 in the family Paramyxoviridae. We attempted to determine the complete nucleotide sequence of the first Korean pPIV5 isolate, designated KNU 11. The full-length genome of KNU-11 was found to be 15,246 nucleotides in length and consist of seven nonoverlapping genes (3'-N-V/P-M-F-SH-HN-L-5') predicted to encode eight proteins. The overall degree of nucleotide sequence identity was 98.7 % between KNU-11 and PIV5 (formerly simian virus 5, SV5), a prototype paramyxovirus, and the putative proteins had 74.4 to 99.2 % amino acid identity to those of PIV5. Phylogenetic analysis further demonstrated that the novel pPIV5 isolate is a member of the genus Rubulavirus of the subfamily Paramyxovirinae. The present study describes the identification and genomic characterization of a pPIV5 isolate in South Korea. PMID- 23807747 TI - Ultraselective and sensitive detection of xylene and toluene for monitoring indoor air pollution using Cr-doped NiO hierarchical nanostructures. AB - Ultraselective and sensitive detection of xylene and toluene with minimum interferences of other indoor air pollutants such as benzene, ethanol, and formaldehyde is achieved using NiO hierarchical nanostructures doped with Cr. Pure and 1.15-2.56 at% Cr-doped NiO flower-like hierarchical nanostructures assembled from nanosheets are prepared by a simple solvothermal reaction and their gas sensing characteristics toward o-xylene and toluene gases are investigated. The 1.15 at% Cr-doped NiO hierarchical nanostructures show high responses to 5 ppm of o-xylene and toluene (ratio of resistance to gas and air = 11.61 and 7.81, respectively) and negligible cross-responses to 5 ppm of benzene, formaldehyde, ethanol, hydrogen, and carbon monoxide. However, pure NiO nanostructures show low responses to 5 ppm of o-xylene and toluene (ratio of resistance to gas and air = 2.01 and 1.14, respectively) and no selectivity toward any specific gas is observed. Significant enhancement of the response and selectivity to o-xylene and toluene is attributed to the decrease in the hole concentration in NiO and the catalytic oxidation of methyl groups by Cr doping. PMID- 23807748 TI - Targeting fibroblast growth factors in cancer: the key is what not to block. PMID- 23807749 TI - Visceral pleural invasion does not affect recurrence or overall survival among patients with lung adenocarcinoma <= 2 cm: a proposal to reclassify T1 lung adenocarcinoma. AB - BACKGROUND: T1 (<= 3 cm) tumors with visceral pleural invasion (VPI) are upstaged to T2a (stage IB) in the TNM classification. We investigated the effect of VPI on the cumulative incidence of recurrence (CIR) and overall survival (OS) of lung adenocarcinoma (ADC) <= 2 cm (T1a) and 2 to 3 cm (T1b). METHODS: OS and CIR among patients with or without VPI were examined by tumor size (<= 2 and 2-3 cm) in 777 patients with node-negative lung ADC <= 3 cm who underwent resection. RESULTS: Among patients with tumors <= 2 cm, VPI was not associated with either increased CIR (P = .90) or decreased OS (P = .11). Among patients with tumors 2 to 3 cm in size, the presence of VPI was associated with increased CIR (P = .015) and decreased OS (P < .001), even after adjusting for histologic subtype. When stage I lung ADCs <= 3 cm were regrouped as either new stage IA (<= 2 cm with or without VPI, 2-3 cm without VPI) or new stage IB (2-3 cm with VPI), there was a statistically significant difference in 5-year CIR and OS between new stage IA and new stage IB tumors (CIR, 18% vs 40% [P = .004]; OS, 76% vs 51% [P < .001]). CONCLUSIONS: VPI stratifies prognosis in patients with lung ADC 2 to 3 cm but not in those with tumors <= 2 cm. Our proposed regrouping of a new stage IB better stratifies patients with poor prognosis, similar to published outcomes in patients with stage II disease, who may benefit from adjuvant chemotherapy. PMID- 23807750 TI - Biofunctional characteristics of in situ and invasive breast carcinoma. AB - PURPOSE: The increasing use of breast-conserving surgery makes it essential to identify biofunctional profiles responsible for the progression of in situ to invasive carcinomas to facilitate the detection of lesions that are most likely to relapse or progress and, thus, to be able to offer patients tailored treatment options. Our objective was to analyse and compare biofunctional profiles in ductal carcinomas in situ (DCIS) and invasive ductal carcinomas (IDC). We also aimed to identify markers in tumor and normal surrounding tissues that may be predictive of locoregional recurrence in patients with DCIS. METHODS: Biofunctional parameters including mitotic activity, estrogen receptor, progesterone receptor, microvessel density (MVD), c-kit and p27 expression were evaluated in 829 in situ and invasive carcinomas. The impact of the biomarker profiles of DCIS, IDC and normal surrounding tissues on loco-regional recurrence was analyzed. RESULTS: A progressive increase in cell proliferation and a concomitant decrease in steroid hormone receptor-positive lesions was observed during the transition from in situ to invasive carcinomas, as also within each subgroup as grade increased. Conversely, p27 expression and MVD dramatically decreased during the transition from in situ to invasive carcinomas. Finally, we found that a low c-kit expression was indicative of IDC relapse. CONCLUSIONS: Cell proliferation, hormonal and differentiation characteristics differed in DCIS with respect to IDC, and the main variation in the transition between the two histologic lesions was the decrease in p27 expression and MVD. PMID- 23807751 TI - Good practice guidelines for the use of statistical regression models in economic evaluations. AB - Decision-analytic models (DAMs) used to evaluate the cost effectiveness of interventions are pivotal sources of evidence used in economic evaluations. Parameter estimates used in the DAMs are often based on the results of a regression analysis, but there is little guidance relating to these. This study had two objectives. The first was to identify the frequency of use of regression models in economic evaluations, the parameters they inform, and the amount of information reported to describe and support the analyses. The second objective was to provide guidance to improve practice in this area, based on the review. The review concentrated on a random sample of economic evaluations submitted to the UK National Institute for Health and Clinical Excellence (NICE) as part of its technology appraisal process. Based on these findings, recommendations for good practice were drafted, together with a checklist for critiquing reporting standards in this area. Based on the results of this review, statistical regression models are in widespread use in DAMs used to support economic evaluations, yet reporting of basic information, such as the sample size used and measures of uncertainty, is limited. Recommendations were formed about how reporting standards could be improved to better meet the needs of decision makers. These recommendations are summarised in a checklist, which may be used by both those conducting regression analyses and those critiquing them, to identify what should be reported when using the results of a regression analysis within a DAM. PMID- 23807752 TI - Laparoscopic versus robot-assisted bilateral nerve-sparing radical prostatectomy: comparison of pentafecta rates for a single surgeon. AB - BACKGROUND: This study aimed to compare the pentafecta rates between laparoscopic radical prostatectomy (LRP) and robot-assisted radical prostatectomy (RALP) and to identify prognostic factors predicting the pentafecta for each technique. METHODS: This prospective comparative study enrolled 248 consecutive male patients 70 years of age or younger with clinically localized prostate cancer [PCa: age <= 70 years, prostate-specific antigen (PSA) <= 10 ng/ml, biopsy Gleason score <= 7] who were fully continent, potent, and candidates for bilateral nerve-sparing (BNS) LRP or RALP. The pentafecta rates between LRP and RALP were compared. A logistic regression model was created to evaluate independent factors for achieving pentafecta. RESULTS: In the final analysis, 91 LRP and 136 RALP patients were evaluated. The median follow-up period was 21 months for the 91 LRP patients and 18 months for the 136 RALP patients (p = 0.07). Of the 227 patients, 87 reached pentafecta [25 LRP patients (27.5 %) vs 62 RALP patients (45.6 %), p = 0.006]. Of the 140 patients who failed pentafecta, 90 (64.3 %) missed a single parameter. In these cases, erectile deficit was the leading cause of pentafecta failure, with a significant [corrected] difference between groups (80 % LRP cases that missed potency recovery [corrected] vs 53.3 % RALP, p = 0.007). Lower age, lower pathologic stage, and RALP are significantly associated with pentafecta as independent factors. For the pT3 disease, the two techniques did not differ significantly. CONCLUSIONS: Patients submitted to BNS RP have low possibilities of achieving pentafecta. Use of the robotic platform by a single surgeon significantly enhances the possibility of achieving pentafecta independently of age and pathologic stage. Potency was the most difficult outcome to reach after surgery, and it was the main factor leading to pentafecta failure. LRP and RALP provide equivalent pentafecta rates for the pT3 disease and similar "tetrafecta" outcomes when potency recovery is not included among the postoperative expectations of the patient. PMID- 23807753 TI - Long-term follow-up evaluation of revisional gastric bypass after failed adjustable gastric banding. AB - BACKGROUND: Disappointing long-term results, frequent band failure, and high rates of band-related complications increasingly necessitate revisional surgery after adjustable gastric banding. Laparoscopic conversion to gastric bypass has been recommended as the procedure of choice. This single-center retrospective study aimed to evaluate the long-term results of revisional gastric bypass after failed adjustable gastric banding. METHODS: The study included 108 consecutive patients who underwent laparoscopic conversion of gastric banding to gastric bypass from 2002 to 2012. Indications for surgery, operative data, weight development, morbidity, and mortality were analyzed. The median follow-up period was 3.4 years (maximum, 10 years). RESULTS: The most common indications for band removal were band migration, insufficient weight loss, and pouch dilation. The median interval between gastric banding and gastric bypass was 6.6 years. In 52 % of the cases, band removal and gastric bypass surgery were performed simultaneously as a single-stage laparoscopic procedure. The early postoperative morbidity rate was 10.2 %. The body mass index before gastric banding (43.3 kg/m(2)) decreased significantly to 37.9 kg/m(2) before gastric bypass and to 28.8 kg/m(2) 5 years after gastric bypass. CONCLUSIONS: This is the first report on the long-term outcome after conversion of failed adjustable gastric banding to gastric bypass. Findings have shown revisional gastric bypass to be a feasible bariatric procedure particularly for patients with insufficient weight loss that guarantees a constant and long-lasting weight loss. PMID- 23807755 TI - Minimally invasive esophagectomy versus open surgery: is there an advantage? PMID- 23807754 TI - Efficacy of endoscopic mucosal resection using a dual-channel endoscope compared with endoscopic submucosal dissection in the treatment of rectal neuroendocrine tumors. AB - BACKGROUND: Conventional endoscopic mucosal resection (EMR) for removing rectal neuroendocrine tumors (NETs) has a high risk of incomplete removal because of submucosal tumor involvement. EMR using a dual-channel endoscope (EMR-D) may be a safe and effective method for resection of polyps in the gastrointestinal tract. The efficacy of EMR-D in the treatment of rectal NET has not been evaluated thoroughly. METHODS: From January 2005 to September 2011, a total of 70 consecutive patients who received EMR-D or endoscopic submucosal dissection (ESD) to treat a rectal NET <16 mm in diameter were included to compare EMR-D with ESD for the treatment of rectal NETs. RESULTS: The EMR-D group contained 44 patients and the ESD group contained 26 patients. The endoscopic complete resection rate did not differ significantly between the EMR-D and ESD groups (100 % for each). The histological complete resection rate also did not differ significantly between groups (86.3 vs. 88.4 %). The procedure time was shorter for the EMR-D group than for the ESD group (9.75 +/- 7.11 vs. 22.38 +/- 7.56 min, P < 0.001). Minor bleeding occurred in 1 EMR-D patient and in 3 ESD patients (2.3 vs. 7.6 %). There was no perforation after EMR-D or ESD. CONCLUSIONS: Compared with ESD, EMR D is technically simple, minimally invasive, and safe for treating small rectal NETs contained within the submucosa. EMR-D can be considered an effective and safe resection method for rectal NETs <16 mm in diameter without metastasis. PMID- 23807756 TI - Zinc supplements for treating thalassaemia and sickle cell disease. AB - BACKGROUND: Haemoglobinopathies, inherited disorders of haemoglobin synthesis (thalassaemia) or structure (sickle cell disease), are responsible for significant morbidity and mortality throughout the world. The WHO estimates that, globally, 5% of adults are carriers of a haemoglobin condition, 2.9% are carriers of thalassaemia and 2.3% are carriers of sickle cell disease. Carriers are found worldwide as a result of migration of various ethnic groups to different regions of the world. Zinc is an easily available supplement and intervention programs have been carried out to prevent deficiency in people with thalassaemia or sickle cell anaemia. It is important to evaluate the role of zinc supplementation in the treatment of thalassaemia and sickle cell anaemia to reduce deaths due to complications. OBJECTIVES: To assess the effect of zinc supplementation in the treatment of thalassaemia and sickle cell disease. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Date of most recent search: 01 February 2013. SELECTION CRITERIA: Randomised, placebo-controlled trials of zinc supplements for treating thalassaemia or sickle cell disease administered at least once a week for at least a month. DATA COLLECTION AND ANALYSIS: Two review authors assessed the eligibility and risk of bias of the included trials, extracted and analysed data and wrote the review. We summarised results using risk ratios or rate ratios for dichotomous data and mean differences for continuous data. We combined trial results where appropriate. MAIN RESULTS: We identified nine trials for inclusion with all nine contributing outcome data. Two trials reported on people with thalassaemia (n = 152) and seven on sickle cell anaemia (n = 307).In people with thalassaemia, in one trial, the serum zinc level value showed no difference between the zinc supplemented group and the control group, mean difference 47.40 (95% confidence interval -12.95 to 107.99). Regarding anthropometry, in one trial, height velocity was significantly increased in patients who received zinc supplementation for one to seven years duration, mean difference 3.37 (95% confidence interval 2.36 to 4.38) (total number of participants = 26). In one trial, however, there was no difference in body mass index between treatment groups.Zinc acetate supplementation for three months (in one trial) and one year (in two trials) (total number of participants = 71) was noted to increase the serum zinc level significantly in patients with sickle cell anaemia, mean difference 14.90 (95% confidence interval 6.94 to 22.86) and 20.25 (95% confidence interval 11.73 to 28.77) respectively. There was no significant difference in haemoglobin level between intervention and control groups, at either three months (one trial) or one year (one trial), mean difference 0.06 (95% confidence interval -0.84 to 0.96) and mean difference -0.07 (95% confidence interval -1.40 to 1.26) respectively. Regarding anthropometry, one trial showed no significant changes in body mass index or weight after one year of zinc acetate supplementation. In patients with sickle cell disease, the total number of sickle cell crises at one year were significantly decreased in the zinc sulphate supplemented group as compared to controls, mean difference -2.83 (95% confidence interval -3.51 to -2.15) (total participants 130), but not in zinc acetate group, mean difference 1.54 (95% confidence interval -2.01 to 5.09) (total participants 22). In one trial at three months and another at one year, the total number of clinical infections were significantly decreased in the zinc supplemented group as compared to controls, mean difference 0.05 (95% confidence interval 0.01 - 0.43) (total number of participants = 36), and mean difference 7.64 (95% confidence interval -10.89 to -4.39) (total number of participants = 21) respectively. AUTHORS' CONCLUSIONS: According to the results, there is no evidence from randomised controlled trials to indicate any benefit of zinc supplementation with regards to serum zinc level in patients with thalassaemia. However, height velocity was noted to increase among those who received this intervention.There is mixed evidence on the benefit of using zinc supplementation in people with sickle cell disease. For instance, there is evidence that zinc supplementation for one year increased the serum zinc levels in patients with sickle cell disease. However, though serum zinc level was raised in patients receiving zinc supplementation, haemoglobin level and anthropometry measurements were not significantly different between groups. Evidence of benefit is seen with the reduction in the number of sickle cell crises among sickle cell patients who received one year of zinc sulphate supplementation and with the reduction in the total number of clinical infections among sickle cell patients who received zinc supplementation for both three months and for one year.The conclusion is based on the data from a small group of trials,which were generally of good quality, with a low risk of bias. The authors recommend that more trials on zinc supplementation in thalassaemia and sickle cell disease be conducted given that the literature has shown the benefits of zinc in these types of diseases. PMID- 23807757 TI - Unifying diseases from a genetic point of view: the example of the genetic theory of infectious diseases. AB - In the contemporary biomedical literature, every disease is considered genetic. This extension of the concept of genetic disease is usually interpreted either in a trivial or genocentrist sense, but it is never taken seriously as the expression of a genetic theory of disease. However, a group of French researchers defend the idea of a genetic theory of infectious diseases. By identifying four common genetic mechanisms (Mendelian predisposition to multiple infections, Mendelian predisposition to one infection, and major gene and polygenic predispositions), they attempt to unify infectious diseases from a genetic point of view. In this article, I analyze this explicit example of a genetic theory, which relies on mechanisms and is applied only to a specific category of diseases, what we call "a regional genetic theory." I have three aims: to prove that a genetic theory of disease can be devoid of genocentrism, to consider the possibility of a genetic theory applied to every disease, and to introduce two hypotheses about the form that such a genetic theory could take by distinguishing between a genetic theory of diseases and a genetic theory of Disease. Finally, I suggest that network medicine could be an interesting framework for a genetic theory of Disease. PMID- 23807758 TI - Acting together around childbirth. Abstracts of the Marce International Society International Biennial General Scientific Meeting. October 3-5, 2012. Paris France. PMID- 23807759 TI - Mutational landscape of adult ETP-ALL. PMID- 23807760 TI - Thinking one thing, saying another: the behavioral correlates of mind-wandering while reading aloud. AB - Although mind-wandering during silent reading is well documented, to date no research has investigated whether similar processes occur during reading aloud. In the present study, participants read a passage either silently or aloud while periodically being probed about mind-wandering. Although their comprehension accuracies were similar for both reading conditions, participants reported more mind-wandering while they were reading aloud. These episodes of mindless reading were associated with nearly normal prosody, but were nevertheless distinguished by subtle fluctuations in volume that were predictive of both overall comprehension accuracy and individual sentence comprehension. Together, these findings reveal that previously hidden within the common activity of reading aloud lies: (1) a demonstration of the remarkable automaticity of speech, (2) a situation that is surprisingly conducive to mind-wandering, (3) subtle vocal signatures of mind-wandering and comprehension accuracy, and (4) the promise of developing useful interventions to improve reading. PMID- 23807761 TI - Abrupt category shifts during real-time person perception. AB - Previous studies have suggested that real-time person perception relies on continuous competition, in which partially active categories smoothly compete over time. Here, two studies demonstrated the involvement of a different kind of competition. In Study 1, before participants selected the correct sex category for morphed faces, their mouse trajectories often exhibited a continuous attraction toward the incorrect category that increased with sex-category ambiguity, indicating continuous competition. On other trials, however, trajectories initially pursued the incorrect category and then abruptly redirected toward the correct category, suggesting early incorrect category activation that was rapidly reversed later in processing. These abrupt category reversals also increased with ambiguity. In Study 2, participants were presented with faces containing a sex-typical or sex-atypical hair cue, in a context in which the norm was either sex-typical targets (normative context) or sex-atypical targets (counternormative context). Sex-atypical targets induced greater competition in the normative context, but sex-typical targets induced greater competition in the counternormative context. Together, these results demonstrate that categorizing others involves both smooth competition and abrupt category shifts, and that these flexibly adapt to the social context. PMID- 23807762 TI - Chemotherapy for second-stage human African trypanosomiasis. AB - BACKGROUND: Human African trypanosomiasis, or sleeping sickness, is a painful and protracted disease affecting people in the poorest parts of Africa and is fatal without treatment. Few drugs are currently available for second-stage sleeping sickness, with considerable adverse events and variable efficacy. OBJECTIVES: To evaluate the effectiveness and safety of drugs for treating second-stage human African trypanosomiasis. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register (January 2013), CENTRAL (The Cochrane Library Issue 12 2012) , MEDLINE (1966 to January 2013), EMBASE (1974 to January 2013), LILACS (1982 to January 2013 ), BIOSIS (1926-January 2013), mRCT (January 2013) and reference lists. We contacted researchers working in the field and organizations. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials including adults and children with second-stage HAT, treated with anti trypanosomal drugs. DATA COLLECTION AND ANALYSIS: Two authors (VL and AK) extracted data and assessed methodological quality; a third author (JS) acted as an arbitrator. Included trials only reported dichotomous outcomes, and we present these as risk ratio (RR) with 95% confidence intervals (CI). MAIN RESULTS: Nine trials with 2577 participants, all with Trypansoma brucei gambiense HAT, were included. Seven trials tested currently available drugs: melarsoprol, eflornithine, nifurtimox, alone or in combination; one trial tested pentamidine, and one trial assessed the addition of prednisolone to melarsoprol. The frequency of death and number of adverse events were similar between patients treated with fixed 10-day regimens of melarsoprol or 26-days regimens. Melarsoprol monotherapy gave fewer relapses than pentamidine or nifurtimox, but resulted in more adverse events.Later trials evaluate nifurtimox combined with eflornithine (NECT), showing this gives few relapses and is well tolerated. It also has practical advantages in reducing the frequency and number of eflornithine slow infusions to twice a day, thus easing the burden on health personnel and patients. AUTHORS' CONCLUSIONS: Choice of therapy for second stage Gambiense HAT will continue to be determined by what is locally available, but eflornithine and NECT are likely to replace melarsoprol, with careful parasite resistance monitoring. We need research on reducing adverse effects of currently used drugs, testing different regimens, and experimental and clinical studies of new compounds, effective for both stages of the disease. PMID- 23807764 TI - Josephson junction on one edge of a two dimensional topological insulator affected by magnetic impurity. AB - The current-phase relation in a Josephson junction formed by putting two s-wave superconductors on the same edge of a two dimensional topological insulator is investigated. We consider the case in which the junction length is finite and magnetic impurity exists. The similarities and differences with respect to a conventional Josephson junction are discussed. Both the 2pi- and 4pi-period current-phase relations (I2pi(phi),I4pi(phi)) are studied. There is a sharp jump at phi = pi and phi = 2pi for I2pi and I4pi, respectively, in the clean junction. For I2pi, the sharp jump is robust against the impurity strength and distribution. However, for I4pi, an impurity makes the jump at phi = 2pi smooth. The critical (maximum) current Ic,2pi of I2pi is given and we find it will be increased by an asymmetrical distribution of the impurity. PMID- 23807763 TI - Cobinamide production of hydrogen in a homogeneous aqueous photochemical system, and assembly and photoreduction in a (betaalpha)8 protein. AB - Components of a protein-integrated, earth-abundant metal macrocycle catalyst, with the purpose of H2 production from aqueous protons under green conditions, are characterized. The cobalt-corrin complex, cobinamide, is demonstrated to produce H2 (4.4 +/- 1.8 * 10(-3) turnover number per hour) in a homogeneous, photosensitizer/sacrificial electron donor system in pure water at neutral pH. Turnover is proposed to be limited by the relatively low population of the gateway cobalt(III) hydride species. A heterolytic mechanism for H2 production from the cobalt(II) hydride is proposed. Two essential requirements for assembly of a functional protein-catalyst complex are demonstrated for interaction of cobinamide with the (betaalpha)8 TIM barrel protein, EutB, from the adenosylcobalamin-dependent ethanolamine ammonia lyase from Salmonella typhimurium: (1) high-affinity equilibrium binding of the cobinamide (dissociation constant 2.1 * 10(-7) M) and (2) in situ photoreduction of the cobinamide-protein complex to the Co(I) state. Molecular modeling of the cobinamide-EutB interaction shows that these features arise from specific hydrogen-bond and apolar interactions of the protein with the alkylamide substituents and the ring of the corrin, and accessibility of the binding site to the solution. The results establish cobinamide-EutB as a platform for design and engineering of a robust H2 production metallocatalyst that operates under green conditions and uses the advantages of the protein as a tunable medium and material support. PMID- 23807765 TI - Fixed- and random-effects meta-analytic structural equation modeling: examples and analyses in R. AB - Meta-analytic structural equation modeling (MASEM) combines the ideas of meta analysis and structural equation modeling for the purpose of synthesizing correlation or covariance matrices and fitting structural equation models on the pooled correlation or covariance matrix. Cheung and Chan (Psychological Methods 10:40-64, 2005b, Structural Equation Modeling 16:28-53, 2009) proposed a two stage structural equation modeling (TSSEM) approach to conducting MASEM that was based on a fixed-effects model by assuming that all studies have the same population correlation or covariance matrices. The main objective of this article is to extend the TSSEM approach to a random-effects model by the inclusion of study-specific random effects. Another objective is to demonstrate the procedures with two examples using the metaSEM package implemented in the R statistical environment. Issues related to and future directions for MASEM are discussed. PMID- 23807766 TI - A modular, computer-controlled system for olfactory stimulation in the MRI environment. AB - Although the cerebral networks involved in sensory perception are of general interest in neuroscience, registration of the effects of olfactory stimulation, especially in a magnetic resonance imaging (MRI) environment, presents particular problems and constraints. This article presents details of a reliable and portable system for olfactory stimulation that is modular in design and based on microcontroller technology. It has the following characteristics: (1) It is under software control; (2) the presentation of olfactory stimulation can be synchronized with respiration; (3) it can be manually controlled; and (4) it is fully compatible with an MRI environment. The principle underlying this system is to direct an odor to the subject's nostrils by switching airflow to different odor diffusers. The characteristics of this system were established using (1) ultraviolet (UV) spectroscopy, to measure its response time, and (2) gas chromatography, to measure the repeatability of odor presentation in terms of gas concentration. A response time of 200 +/- 25 ms was obtained for the system, and the standard deviations of the gas concentration delivered during stimulation ranged from 1.5% to 22%, depending on the odor, the airflow, and the dilution of the odor used. Since it is portable, controlled by software, and reliable, on the basis of the results we obtained, this system will lend itself to a wide range of applications in olfactory neuroscience. PMID- 23807767 TI - Tensile bond characteristics between composite resin and resin-modified glass ionomer restoratives used in the open-sandwich technique. AB - BACKGROUND: The clinical success of large class II resin-modified glass-ionomer cement/composite resin (RMGIC/CR) 'open-sandwich' restorations in permanent or primary molars may be influenced by certain bonding parameters. AIM: To examine in vitro the effect of placing/curing mode on the RMGIC/CR bond strength. DESIGN: Two restoratives, a CR (Z250), a RMGIC (Vitremer) and a bonding agent (Adper Single Bond 2), all of 3M ESPE, were used for preparing five groups of seven specimen sticks each. The bond between the two restorative materials at the stick centre was created in the three test groups by: (A) 1-step placing RMGIC in contact with CR, then photocuring; (B) 2-step RMGIC placing/curing, then CR placement/curing; (C) 3-step RMGIC placing/curing, bonding agent placing/curing, CR placing/curing. Control groups consisted of sticks made of CR alone (D, positive) and RMGIC alone (E, negative). The specimens were subjected to tensile stress measurements in an Instron dynamometer and examined by scanning electron microscope for type of failure. STATISTICS: Tensile bond strength, tensile strain and elastic modulus differences were examined with one-way ANOVA and Tukey test. RESULTS: Among experimental groups, Group C exhibited significantly higher tensile strength (MPa) means (A = 12.11 +/- 4.72, B = 15.69 +/- 5.18, C = 19.08 +/- 4.05) and significantly higher tensile strain (%) means (A = 0.50 +/- 0.11, B = 0.64 +/- 0.19, C = 0.98 +/- 0.24), compared to Group A, at p = 0.05. Group D had significantly higher tensile strength and strain than all other groups. No statistically significant differences were observed in the elastic modulus. The use of bonding agent (Group C) resulted in absence of adhesive failures as seen by SEM. CONCLUSION: The use of bonding agent improved the CR/RMGIC bond by tensile strength and strain tests. PMID- 23807768 TI - Behavioral problems in school-aged hearing-impaired children: the influence of sociodemographic, linguistic, and medical factors. AB - The purpose of this study was to examine several behavioral problems in school aged hearing-impaired children with hearing aids or cochlear implants, compared to normally hearing children. Additionally, we wanted to investigate which sociodemographic, linguistic, and medical factors contributed to the level of behavioral problems, to pinpoint where targeted interventions can take place. This large, retrospective study included a sample of 261 school-aged children (mean age = 11.8 years, SD = 1.6), that consisted of three age- and gender matched subgroups: 75 with hearing aids, 57 with cochlear implants, and 129 normally hearing controls. Self- and parent-reports concerning reactive and proactive aggression, delinquency, and symptoms of psychopathy, attention deficit hyperactivity disorder, oppositional defiant disorder, and conduct disorder were used. In addition, several language and intelligence tests were administered. Hearing-impaired children showed significantly more proactive aggression, symptoms of psychopathy, attention deficit hyperactivity disorder, oppositional defiant disorder, and conduct disorder than their normally hearing peers. More behavioral problems were associated with special schools for the deaf, sign ( supported) language, hearing aids (in contrast to cochlear implants), higher age, male gender, lower socioeconomic status, lower intelligence, and delayed language development. Hearing-impaired children face multiple problems regarding their behavior. The outcomes implicate that professionals should be aware of the higher risk of developing behavioral problems, in order to screen, detect, and treat in time. Furthermore, the associated risk and protective factors emphasize that clinicians must always consider the heterogeneity of the group of hearing impaired children, in order to help and support the individual patient. PMID- 23807769 TI - The clinical relevance of minor paroxysmal nocturnal hemoglobinuria clones in refractory cytopenia of childhood: a prospective study by EWOG-MDS. PMID- 23807771 TI - The electronic structure of organic-inorganic hybrid compounds: (NH4)2CuCl4, (CH3NH3)2CuCl4 and (C2H5NH3)2CuCl4. AB - Hybrid organic-inorganic compounds are an intriguing class of materials that have been experimentally studied over the past few years because of a potential broad range of applications. The electronic and magnetic properties of three organic inorganic hybrid compounds with compositions (NH4)2CuCl4, (CH3NH3)2CuCl4 and (C2H5NH3)2CuCl4 are investigated for the first time with density functional theory plus on-site Coulomb interaction. A strong Coulomb interaction on the copper causes a relatively weak exchange coupling within the layers of the octahedral network, in good agreement with experiment. The character of the exchange interaction (responsible for magnetic behavior) is analyzed. The calculations reveal that (C2H5NH3)2CuCl4 has the strongest Jahn-Teller (JT) distortion in comparison with the two other compounds. The easy axis of magnetization is investigated, showing a weak anisotropic interaction between inter-layer Cu(2+) ions in the (C2H5NH3)2CuCl4 structure. Orbital ordering is concluded from our partial density of states calculations: a cooperation of the JT distortion with an antiferro-distortive pattern. PMID- 23807770 TI - Small-molecule multi-targeted kinase inhibitor RGB-286638 triggers P53-dependent and -independent anti-multiple myeloma activity through inhibition of transcriptional CDKs. AB - Small-molecule multi-targeted cyclin-dependent kinase (CDK) inhibitors (CDKIs) are of particular interest due to their potent antitumor activity independent of p53 gene alterations. P53 deletion is associated with a very poor prognosis in multiple myeloma (MM). In this regard, we tested the anti-MM activity of RGB 286638, an indenopyrazole-derived CDKI with Ki-nanomolar activity against transcriptional CDKs. We examined RGB-286638's mode-of-action in MM cell lines with wild-type (wt)-p53 and those expressing mutant p53. RGB-286638 treatment resulted in MM cytotoxicity in vitro associated with inhibition of MM tumor growth and prolonged survival in vivo. RGB-286638 displayed caspase-dependent apoptosis in both wt-p53 and mutant-p53 cells that was closely associated with the downregulation of RNA polymerase II phosphorylation and inhibition of transcription. RGB-286638 triggered p53 accumulation via nucleolar stress and loss of Mdm2, accompanied by induction of p53 DNA-binding activity. In addition, RGB-286638 mediated p53-independent activity, which was confirmed by cytotoxicity in p53-knockdown and p53-mutant cells. We also demonstrated downregulation of oncogenic miR-19, miR-92a-1 and miR-21. Our data provide the rationale for the development of transcriptional CDKIs as therapeutic agents, which activate p53 in competent cells, while circumventing p53 deficiency through alternative p53 independent cell death mechanisms in p53-mutant/deleted cells. PMID- 23807772 TI - Proteinivorax tanatarense gen. nov., sp. nov., an anaerobic, haloalkaliphilic, proteolytic bacterium isolated from a decaying algal bloom, and proposal of Proteinivoraceae fam. nov. AB - Two strains of a novel anaerobic, protein- and nucleoside-utilizing bacterium, Z 910(T) and Z-810, were isolated. The strains were spore-forming, mainly nonmotile rods, exhibiting positive Gram reaction with Gram-positive cell wall structure. The strains were mesophilic and haloalkaliphilic. Cultures used proteins and proteinaceous substrates as carbon, nitrogen, and energy sources. Both strains used also ribonucleosides, cellobiose, pyruvate, and glycerol. Ribose and nucleobases did not support growth. The fermentation products from all utilized substrates were identical but varied in content and included straight and branched acids, as well as hydrogen and ammonia. When grown on tryptone, strain Z 910(T) was able to reduce fumarate, dimethyl sulfoxide, thiosulfate, and elemental sulfur. Neither nitrate nor sulfate was reduced. The DNA G + C content of strain Z-910(T) was 32.2 mol%. Phylogenetic analysis based on the 16S rRNA gene sequence similarity revealed that strains Z-910(T) and Z-810 represented a new branch within the order Clostridiales, with 90.2 % similarity to the nearest genus with a validly published name Anaerobranca gottschalkii DSM 13577(T). According to their physiological, chemotaxonomic, and phylogenetic properties, strains Z-910(T) and Z-810 represented a new genus and novel species, for which the name Proteinivorax tanatarense gen. nov., sp. nov. was proposed. Phylogenetic analysis showed that the genera Proteinivorax gen. nov. and Anaerobranca formed a separate cluster within the order Clostridiales. The family Proteinivoraceae fam. nov. comprising the genera Proteinivorax gen. nov. and Anaerobranca was therefore proposed within the order Clostridiales of the phylum Firmicutes with Proteinivorax as a type genus of the new family. PMID- 23807773 TI - Body image and cognitive restraint are risk factors for obesity in French adolescents. AB - The present study explored the links between cognitive restraint and body image in obese adolescents when compared with normal-weight adolescents according to sex. Body image was measured on the Body Esteem Scale and cognitive restraint by means of the Three-Factor Eating Questionnaire Revised 18-item version (TFEQ R18). Although the results did not reveal any significant correlation between overall scores on these two measures, subscale scores showed that the obese adolescents used cognitive restraint more than the normal-weight adolescents did as a strategy for regulating their diet and were less satisfied with their body image. The normal-weight adolescents' use of cognitive restraint was correlated with body-weight dissatisfaction. Despite these differences, the two populations shared several characteristics. All the adolescents were dissatisfied with the way they thought that others saw them. The loss of control was one of their major concerns, although in the obese adolescents, it went hand in hand with major emotional investment. The results suggest that these are the variables responsible for adolescents' eating habits, regardless of their weight. The most discriminating variable when crossed with weight was sex, with girls being less satisfied with their body image, especially when they were obese. PMID- 23807774 TI - MET overexpression assessed by new interpretation method predicts gene amplification and poor survival in advanced gastric carcinomas. AB - The establishment of better selection criteria for identifying sub-populations that may benefit from treatment is a key aspect of the development and success of targeted therapy. To investigate methods for assessing MET overexpression in gastric cancer, we conducted immunohistochemistry using a new anti-Total MET monoclonal antibody in a single-institution cohort of 495 patients. As antibody is directed against a membranous and/or cytoplasmic epitope, two interpretation methods were used: (1) membranous and cytoplasmic and (2) membranous alone. In selected 120 cases, copy number gain and mRNA expression levels were measured using quantitative real-time PCR. Further in situ hybridization confirmed the presence of MET gene amplification. Among the 495 gastric cancers, simultaneous membranous and cytoplasmic overexpression of MET was found in 108 cases (21.8%) and membranous alone overexpression was observed in 40 cases (8.1%). The highest correlation was observed in membranous and cytoplasmic staining of MET: MET expression scores correlated significantly with high MET mRNA levels (r=0.465, P<0.0001), increased copy number gain (r=0.393, P=0.000002) and amplification of MET gene. Moreover, patients with MET overexpression showed shorter overall survival (HR, 1.781; 95% CI, 1.324-2.395; P<0.001) and disease-free survival (HR, 1.765; 95% CI, 1.227-2.541; P=0.002) compared with patients without MET overexpression. However, membranous overexpression of MET did not highly correlate with mRNA level (r=0.274, P=0.002), copy number gain or survival (P>0.05). We developed highly correlating interpretation methods of MET immunohistochemistry in gastric carcinomas. MET overexpression is an independent prognostic factor and could be a potential target and predictor of benefit for targeted therapy with MET inhibitors. PMID- 23807775 TI - Searching for mammary analogue [corrected] secretory carcinoma of salivary gland among its mimics. AB - Mammary analog secretory carcinoma of salivary gland is a recently described entity with unique morphologic, clinical, and genetic characteristics, including the characteristic t(12;15)(p13;q25) with ETV6-NTRK3 translocation found in secretory carcinomas of the breast. Before their initial description, these salivary gland tumors were generally diagnosed as acinic cell carcinoma or adenocarcinoma. For the purpose of this study, all cases of salivary gland acinic cell carcinoma, cribriform cystadenocarcinoma, and adenocarcinoma, not otherwise specified (NOS), diagnosed over a 10-year period were retrieved from our surgical pathology files. There were a total of 11 cases diagnosed as acinic cell carcinoma, 10 cases of adenocarcinoma, NOS, and 6 cases of cribriform cystadenocarcinoma. All slides were reviewed by two pathologists (AP, CGF) and tumors that show morphologic features of mammary analog secretory carcinoma according to the recent literature were selected. This process narrowed down the initial number to six cases originally diagnosed as acinic cell carcinoma, three cases originally diagnosed as adenocarcinoma, NOS, and one case originally diagnosed as cribriform cystadenocarcinoma. The 10 cases were subjected to immunohistochemistry for S-100, mammaglobin, and ANO1, as well as fluorescence in situ hybridization analysis for t(12;15)(p13;q25) with ETV6-NTRK3 fusion rearrangement. The ETV6-NTRK3 gene rearrangement was detected in three tumors. These three tumors, initially diagnosed as acinic cell carcinomas, stained positive for S-100 and mammaglobin, and negative for ANO1 by immunohistochemistry. Two of the three patients were male (2/3). In summary, mammary analog secretory carcinoma is a newly described diagnostic entity that should be in the differential diagnosis of salivary gland tumors that morphologically mimic other neoplasms, mainly acinic cell carcinomas. They differ from conventional acinic cell tumors immunohistochemically and molecularly. Positivity for mammaglobin and S-100, and negativity for ANO1 are useful screening tools before confirmatory molecular studies. PMID- 23807776 TI - HER2 in situ hybridization in breast cancer: clinical implications of polysomy 17 and genetic heterogeneity. AB - Trastuzumab-containing therapy is a standard of care for patients with HER2+ breast cancer. HER2 status is routinely assigned using in situ hybridization to assess HER2 gene amplification, but interpretation of in situ hybridization results may be challenging in tumors with chromosome 17 polysomy or intratumoral genetic heterogeneity. Apparent chromosome 17 polysomy, defined by increased chromosome enumeration probe 17 (CEP17) signal number, is a common genetic aberration in breast cancer and represents an alternative mechanism for increasing HER2 copy number. Some studies have linked elevated CEP17 count ('polysomy') with adverse clinicopathologic features and HER2 overexpression, although there are numerous discrepancies in the literature. There is evidence that elevated CEP17 ('polysomy') count might account for trastuzumab response in tumors with normal HER2:CEP17 ratios. Nonetheless, recent studies establish that apparent 'polysomy' (CEP17 increase) is usually related to focal pericentromeric gains rather than true polysomy. Assigning HER2 status may also be complex where multiple cell subclones with distinct HER2 amplification characteristics coexist within the same tumor. Such genetic heterogeneity affects up to 40% of breast cancers when assessed according to a College of American Pathologists guideline, although other definitions have been proposed. Recent data have associated heterogeneity with unfavorable clinicopathologic variables and poor prognosis. Genetically heterogeneous tumors harboring HER2-amplified subclones have the potential to benefit from trastuzumab, but this has yet to be evaluated in clinical studies. In this review, we discuss the implications of apparent polysomy 17 and genetic heterogeneity for assigning HER2 status in clinical practice. Among our recommendations, we support the use of mean HER2 copy number rather than HER2:CEP17 ratio to define HER2 positivity in cases where coamplification of the centromere might mask HER2 amplification. We also highlight a need to harmonize in situ hybridization scoring methodology to support accurate HER2 status determination, particularly where there is evidence of heterogeneity. PMID- 23807777 TI - Reproducibility of histological cell type in high-grade endometrial carcinoma. AB - Subclassification of endometrial carcinoma according to histological type shows variable interobserver agreement. The aim of this study was to assess specifically the interobserver agreement of histological type in high-grade endometrial carcinomas, recorded by gynecological pathologists from five academic centers across Canada. In a secondary aim, the agreement of consensus diagnosis with immunohistochemical marker combinations was assessed including six routine (TP53, CDKN2A (p16), ER, PGR, Ki67, and VIM) and six experimental immunohistochemical markers (PTEN, ARID1A, CTNNB1, IGF2BP3, HNF1B, and TFF3). The paired interobserver agreement ranged from kappa 0.50 to 0.63 (median 0.58) and the intraobserver agreement from kappa 0.49 to 0.67 (median 0.61). Consensus about histological type based on morphological assessment was reached in 72% of high-grade endometrial carcinomas. A seven-marker immunohistochemical panel differentiated FIGO grade 3 endometrioid from serous carcinoma with a 100% concordance rate compared with the consensus diagnosis. More practically, a three marker panel including TP53, ER, and CDKN2A (p16) can aid in the differential diagnosis of FIGO grade 3 endometrioid from endometrial serous carcinoma. Our study demonstrates that the inter- and intraobserver reproducibility of histological type based on morphology alone are mostly moderate. Ancillary techniques such as immunohistochemical marker panels are likely needed to improve diagnostic reproducibility of histological types within high-grade endometrial carcinomas. PMID- 23807778 TI - Adult-onset mastocytosis in the skin is highly suggestive of systemic mastocytosis. AB - Adult-onset urticaria pigmentosa/mastocytosis in the skin almost always persists throughout life. The prevalence of systemic mastocytosis in such patients is not precisely known. Bone marrow biopsies from 59 patients with mastocytosis in the skin and all available skin biopsies (n=27) were subjected to a meticulous cytological, histological, immunohistochemical, and molecular analysis for the presence of WHO-defined diagnostic criteria for systemic mastocytosis: compact mast cell infiltrates (major criterion); atypical mast cell morphology, KIT D816V, abnormal expression of CD25 by mast cells, and serum tryptase levels >20 ng/ml (minor criteria). Systemic mastocytosis is diagnosed when the major diagnostic criterion plus one minor criterion or at least three minor criteria are fulfilled. Systemic mastocytosis was confirmed in 57 patients (97%) by the diagnosis of compact mast cell infiltrates plus at least one minor diagnostic criterion (n=42, 71%) or at least three minor diagnostic criteria (n=15, 25%). In two patients, only two minor diagnostic criteria were detectable, insufficient for the diagnosis of systemic mastocytosis. By the use of highly sensitive molecular methods, including the analysis of microdissected mast cells, KIT D816V was found in all 58 bone marrow biopsies investigated for it but only in 74% (20/27) of the skin biopsies. It is important to state that even in cases with insufficient diagnostic criteria for systemic mastocytosis, KIT D816V-positive mast cells were detected in the bone marrow. This study demonstrates, for the first time, that almost all patients with adult-onset mastocytosis in the skin, in fact, have systemic mastocytosis with cutaneous involvement. PMID- 23807779 TI - Expression of MUC2, MUC5AC, MUC5B, and MUC6 mucins in colorectal cancers and their association with the CpG island methylator phenotype. AB - Mucinous differentiation is associated with both CpG island methylator phenotype and microsatellite instability in colorectal cancer. The mucinous phenotype derives from abundant expression of the colonic goblet cell mucin, MUC2, and de novo expression of gastric foveolar mucin, MUC5AC. We, therefore, investigated the protein expression levels of MUC2 and MUC5AC, as well as MUC5B and MUC6, in molecular subtypes of colorectal cancer. Seven-hundred and twenty-two incident colorectal carcinomas occurring in 702 participants of the Melbourne Collaborative Cohort Study were characterized for methylator status, MLH1 methylation, somatic BRAF and KRAS mutations, microsatellite-instability status, MLH1, MSH2, MSH6, and PMS2 mismatch repair, and p53 protein expression, and their histopathology was reviewed. Protein expression levels of MUC2, MUC5AC, MUC5B, MUC6, and the putative mucin regulator CDX2 were compared with molecular and clinicopathological features of colorectal cancers using odds ratios and corresponding 95% confidence intervals. MUC2 overexpression (>25% positive tumor cells) was observed in 33% colorectal cancers, MUC5B expression in 53%, and de novo MUC5AC and MUC6 expression in 50% and 39%, respectively. Co-expression of two or more of the mucins was commonly observed. Expression of MUC2, MUC5AC and MUC6 was strongly associated with features associated with tumorigenesis via the serrated neoplasia pathway, including methylator positivity, somatic BRAF p.V600E mutation, and mismatch repair deficiency, as well as proximal location, poor differentiation, lymphocytic response, and increased T stage (all P<0.001). Overexpression was observed in tumors with and without mucinous differentiation. There were inverse associations between expression of all four mucins and p53 overexpression. CDX2 expression was inversely associated with MUC2, MUC5AC and MUC6 expression. Our results suggest that, in methylator-positive tumors, mucin genes on chromosome 11p15.5 region undergo increased expression via mechanisms other than direct regulation by CDX2. PMID- 23807780 TI - Diagnostic utility and limitations of glutamine synthetase and serum amyloid associated protein immunohistochemistry in the distinction of focal nodular hyperplasia and inflammatory hepatocellular adenoma. AB - Inflammatory hepatocellular adenoma can show overlapping histological features with focal nodular hyperplasia, including inflammation, fibrous stroma, and ductular reaction. Expression of serum amyloid-associated protein in inflammatory hepatocellular adenoma and map-like pattern of glutamine synthetase in focal nodular hyperplasia can be helpful in this distinction, but the pitfalls and limitations of these markers have not been established. Morphology and immunohistochemistry were analyzed in 54 inflammatory hepatocellular adenomas, 40 focal nodular hyperplasia, and 3 indeterminate lesions. Morphological analysis demonstrated that nodularity, fibrous stroma, dystrophic blood vessels, and ductular reaction were more common in focal nodular hyperplasia, while telangiectasia, hemorrhage, and steatosis were more common in inflammatory hepatocellular adenoma, but there was frequent overlap of morphological features. The majority of inflammatory hepatocellular adenomas demonstrated perivascular and/or patchy glutamine synthetase staining (73.6%), while the remaining cases had diffuse (7.5%), negative (3.8%), or patchy pattern of staining (15%) that showed subtle differences from the classic map-like staining pattern and was designated as pseudo map-like staining. Positive staining for serum amyloid associated protein was seen in the majority of inflammatory hepatocellular adenomas (92.6%) and in the minority of focal nodular hyperplasia (17.5%). The glutamine synthetase staining pattern was map-like in 90% of focal nodular hyperplasia cases, with the remaining 10% of cases showing pseudo map-like staining. Three cases were labeled as indeterminate and showed focal nodular hyperplasia-like morphology but lacked map-like glutamine synthetase staining pattern; these cases demonstrated a patchy pseudo map-like glutamine synthetase pattern along with the expression of serum amyloid-associated protein. Our results highlight the diagnostic errors that can be caused by variant patterns of staining with glutamine synthetase and serum amyloid-associated protein in inflammatory hepatocellular adenoma and focal nodular hyperplasia. PMID- 23807781 TI - Simulation of a hump structure in the optical scattering rate within a generalized Allen formalism and its application to copper oxide systems. AB - We propose a possible way to simulate a hump structure in the optical scattering rate. The optical scattering rate of correlated charge carriers can be defined within an extended Drude model formalism. When some electron- and hole-doped copper oxide systems are in spin density or charge density wave phases they show hump structures in their optical scattering rates. The hump structures have not yet been simulated or clearly understood. We are able to simulate the hump structure by using a peak followed by a dip feature in the normalized density of states within a generalized Allen formalism. We observe that reversing the order of the dip and peak gives completely different features in the optical scattering rate; a peak-dip (dip-peak) results in a hump (a valley) in the scattering rate. We also obtain the real parts of the optical conductivity and reflectance spectra from the simulated optical scattering rate and compare them with published experimental spectra. From these comparisons we conclude that the peak-dip order can give the hump structure that is observed experimentally in copper oxide systems. Finally we fit two published optical spectra with our new model and discuss our results and the possible origin of the dip or peak features in the normalized density of states. PMID- 23807782 TI - Cellular cardiomyoplasty: its past, present, and future. AB - Cellular cardiomyoplasty is a cell therapy using stem cells or progenitor cells for myocardial regeneration to improve cardiac function and mitigate heart failure. Since we first published cellular cardiomyoplasty in 1989, this procedure became the innovative method to treat damaged myocardium other than heart transplantation. A significant improvement in cardiac function, metabolism, and perfusion is generally observed in experimental and clinical studies, but the improvement is mild and incomplete. Although safety, feasibility, and efficacy have been well documented for the procedure, the beneficial mechanisms remain unclear and optimization of the procedure requires further study. This chapter briefly reviews the stem cells used for cellular cardiomyoplasty and their clinical outcomes with possible improvements in future studies. PMID- 23807783 TI - Skeletal muscle stem cells. AB - Skeletal muscle satellite cells (myoblasts) are the primary stem cells of skeletal muscle which contribute to growth, maintenance, and repair of the muscles. Satellite cells are the first stem cells used for cellular cardiomyoplasty more than 20 years ago. The isolation, culture, labeling, and identification of satellite cells are described in detail here. The implantation and outcomes of cellular cardiomyoplasty using satellite cells have been summarized in the previous chapter (Chapter 1). PMID- 23807784 TI - Bone marrow stem cells. AB - The "mesenchymal stem cells (MSCs)" are cells adherent in the bone marrow, which can be isolated to induce differentiation. In contrast to the "embryonic stem cells" whose goal is to develop a new organism, the "MSC adult stem cells" can participate in tissue growth and repair throughout postnatal life. Addition of 5 azacytidine to MSCs in vitro induces the gradual increase in cellular size and begins spontaneous beatings, thereafter differentiating into cardiomyocytes. The "Methods" and "Protocols" to induce structural and functional maturations of MSCs, thus to achieve "Cellular Cardiomyoplasty," are described. With appropriate media, differentiations of MSCs to various kinds of cells such as chondrocytes, osteocytes, and adipocytes are also achievable. PMID- 23807785 TI - Adipose tissue-derived mesenchymal stem cells: isolation, expansion, and characterization. AB - Over the last decade, cell therapy has emerged as a potentially new approach for the treatment of cardiovascular diseases. Among the wide range of cell types and sources, adipose-derived mesenchymal stem cells have shown promise, mainly due to its plasticity and remarkable paracrine-secretion capacity, largely demonstrated at the in vitro and in vivo levels. Furthermore, its accessibility and abundance, the low morbidity of the surgical procedure, its easy isolation, culture, and long-term passaging capacity added to its immunomodulatory properties that could allow its allogeneic transplantation, making it one of the most attractive candidates for clinical application. In this chapter, we will focus on the methodology for the isolation, expansion, phenotypical characterization, differentiation, and storage of the adipose-derived stem cells. PMID- 23807786 TI - Cardiac side population cells and Sca-1-positive cells. AB - Since the resident cardiac stem/progenitor cells were discovered, their ability to maintain the architecture and functional integrity of adult heart has been broadly explored. The methods for isolation and purification of the cardiac stem cells are crucial for the precise analysis of their developmental origin and intrinsic potential as tissue stem cells. Stem cell antigen-1 (Sca-1) is one of the useful cell surface markers to purify the cardiac progenitor cells. Another purification strategy is based on the high efflux ability of the dye, which is a common feature of tissue stem cells. These dye-extruding cells have been called side population cells because they locate in the side of dye-retaining cells after fluorescent cell sorting. In this chapter, we describe the methodology for the isolation of cardiac SP cells and Sca-1 positive cells. PMID- 23807787 TI - Two-step protocol for isolation and culture of cardiospheres. AB - Cardiac progenitor cells (CPC) are a unique pool of progenitor cells residing in the heart that play an important role in cardiac homeostasis and physiological cardiovascular cell turnover during acute myocardial infarction (MI). Transplanting CPC into the heart has shown promise in two recent clinical trials of cardiac repair (SCIPIO & CADUCEUS). CSCs were originally isolated directly from enzymatically digested hearts followed by cell sorting using stem cell markers. However, long exposure to enzymatic digestion can affect the integrity of stem cell markers on the cell surface and also compromise stem cell function. Here, we describe a two-step procedure in which a large number of intact cardiac progenitor cells can be purified from small amount of heart tissue. PMID- 23807788 TI - Generation of human iPSCs from human peripheral blood mononuclear cells using non integrative Sendai virus in chemically defined conditions. AB - Human-induced pluripotent stem cells (hiPSCs) have received enormous attention because of their ability to differentiate into multiple cell types that demonstrate the patient's original phenotype. The use of hiPSCs is particularly valuable to the study of cardiac biology, as human cardiomyocytes are difficult to isolate and culture and have a limited proliferative potential. By deriving iPSCs from patients with heart disease and subsequently differentiating these hiPSCs to cardiomyocytes, it is feasible to study cardiac biology in vitro and model cardiac diseases. While there are many different methods for deriving hiPSCs, clinical use of these hiPSCs will require derivation by methods that do not involve modification of the original genome (non-integrative) or incorporate xeno-derived products (such as bovine serum albumin) which may contain xeno agents. Ideally, this derivation would be carried out under chemically defined conditions to prevent lot-to-lot variability and enhance reproducibility. Additionally, derivation from cell types such as fibroblasts requires extended culture (4-6 weeks), greatly increasing the time required to progress from biopsy to hiPSC. Herein, we outline a method of culturing peripheral blood mononuclear cells (PBMCs) and reprogramming PBMCs into hiPSCs using a non-integrative Sendai virus. PMID- 23807789 TI - Identification of stem cells after transplantation. AB - The ability to identify the donor stem cells following transplantation into injured hearts is critical. This is particularly important in evaluating stem cell survival and lineage differentiation into mature cardiovascular cells. Several approaches have been employed for tracking the donor stem cells, including fluorescent dyes and fluorescent protein gene transfer. Here, we will induce a protocol using lentivirus-mediated green fluorescent protein (GFP) to monitor the fate of donor stem cells following transplantation. PMID- 23807790 TI - Methods to study the proliferation and differentiation of cardiac side population (CSP) cells. AB - Investigation of cardiac progenitor cell proliferation and differentiation is essential for both the basic understanding of progenitor cell biology as well as the development of cellular therapeutics for tissue regeneration. Herein, we describe techniques used for the analysis of CSP cell proliferation, cell cycle status, and cardiomyogenic differentiation. PMID- 23807791 TI - Immune responses after mesenchymal stem cell implantation. AB - Stem cell transplantation is a promising approach for improving cardiac function after severe myocardial damage for which use of autologous cells have been preferred to avoid immune rejection. Recently, however, rodent as well as human mesenchymal stromal cells (MSCs) have been reported to be uniquely immune tolerant, both in in vitro as well as in vivo transplant models. In this chapter, we summarize the current understanding of the underlying immunologic mechanisms, which can facilitate the use of such cells as "universal donor cells." PMID- 23807792 TI - Route of delivery, cell retention, and efficiency of polymeric microcapsules in cellular cardiomyoplasty. AB - Stem cell transplantation has been considered as a major breakthrough for treating ischemic heart disease. However, survival and retention of transplanted cells at the site of infarction remains tenuous. This chapter details a method of creating polymeric microcapsules for cell delivery, resulting in increased retention of transplanted cells at the target site, while achieving minimal mechanical trauma and cell loss. Simultaneously biocompatible and biodegradable, polymeric microcapsules have important implications in regenerative cell therapy. PMID- 23807793 TI - Angiogenic nanodelivery systems for myocardial therapy. AB - Despite outstanding progress in the area of cardiovascular diseases, significant challenges remain in designing efficient delivery systems for myocardial therapy. Nanotechnology provides the tools to explore such frontiers of biomedical science at cellular level and thus offers unique features for potential application in the field of cardiac therapy. This chapter focuses on the methodology, based on the work done in our lab, to prepare and investigate two kinds of biocompatible nanoparticles (NPs) that can be useful for sustained delivery of single or multiple angiogenic growth factors to damaged sites, such as in myocardially infarcted heart to promote myocardial angiogenesis and reduce scar area. PMID- 23807794 TI - Bio-hybrid tissue engineering for cellular cardiomyoplasty: future directions. AB - Cardiomyopathy induces geometric alteration of the ventricular cavity, which changes from a natural elliptical (conical) to a spherical shape. Ventricular chamber dilatation and spherical deformation are important causes of morbidity and mortality among patients with congestive heart failure. In addition, diastolic dysfunction is an important clinical problem in these cases because there is no medical or surgical specific treatment. Myocardial tissue engineering associating stem cells represent a new road and fresh hope for this heart failure population. PMID- 23807795 TI - Decellularized whole heart for bioartificial heart. AB - Whole-organ decellularization has opened the gates to the creation of 3D extracellular matrix (ECM) templates that mimic nature's design to a degree that as for today-is not reproducible with any synthetic materials. Here, we describe a whole-heart decellularization approach through software-controlled automated coronary perfusion with standard decellularization detergents, enabling us to create native ECM-derived 3D templates that preserve the basic anatomy, vascular network, and critical ECM characteristics of the native heart. Such a cardiac ECM platform directly derived from nature itself might help us to better understand and reproduce cardiac biology and may even lay the grounds for the construction of a bioartificial heart in the future. PMID- 23807797 TI - Clinical study using adipose-derived mesenchymal-like stem cells in acute myocardial infarction and heart failure. AB - Adipose tissue represents an abundant, accessible source of regenerative cells that can be easily obtained in sufficient amount for therapy. Adipose-derived regenerative cells (ADRC) are comprised of leukocytes, smooth muscles, endothelial cells, and mesenchymal stem cells. In contrast to bone-marrow-derived MSC, the abundance of adipose tissue in patients and the higher frequency per unit mass of regenerative cells allow for the isolation of cells in therapeutic meaningful amounts in less than 2h after donor tissue acquisition.Harvest of adipose tissue can thus follow primary PCI, allowing efficient treatment within 24h. This obviates the need for extensive cell culturing in GMP clean room facilities and makes ADSCs a promising and practical autologous cell source. In the following chapter, we will describe the liposuction procedure for stem cell harvest, two cell delivery techniques, and pressure/volume loop analysis for the follow-up of our patients enrolled in the clinical studies. PMID- 23807798 TI - Delocalized and localized states of eg electrons in half-doped manganites. AB - We have studied the magnetic behaviour of half-doped manganite Y0.5Ca0.5MnO3 in an extended range of temperatures by means of magnetic susceptibility, chi(T), and electron spin resonance (ESR) experiments. At high temperature the system crystallizes in an orthorhombic structure. The resistivity value, rho ? 0.05 Omega cm at 500 K, indicates a metallic behaviour, while the Curie-Weiss dependence of chi(T) and the thermal evolution of the ESR parameters are very well described by a model that considers a system conformed by localized Mn(4+) cores, [Formula: see text], and itinerant, eg, electrons. The strong coupling between t2g and eg electrons results in an enhanced Curie constant and an FM Curie-Weiss temperature that overcomes the AFM interactions between the [Formula: see text] cores. A transition to a more distorted phase is observed at T ~ 500 K and signatures of localization of the eg electrons appear in the chi(T) behaviour below 300 K. A new Curie-Weiss regime is observed, where the Curie-constant value is consistent with dimer formation. Based on mean-field calculations, the dimer formation is predicted as a function of the interaction strength between the t2g and eg electrons. PMID- 23807796 TI - Clinical trials of cardiac repair with adult bone marrow- derived cells. AB - The past decade has witnessed a marked increase in the number of clinical trials of cardiac repair with adult bone marrow cells (BMCs). These trials included patients with acute myocardial infarction (MI) as well as chronic ischemic heart disease (IHD) and utilized different types of BMCs with variable numbers, routes of administration, and timings after MI. Given these differences in methods, the outcomes from these trials have been often disparate and controversial. However, analysis of pooled data suggests that BMC injection enhances left ventricular function, reduces infarct scar size, and improves remodeling in patients with acute MI as well as chronic IHD. BMC therapy also improves clinical outcomes during follow-up without any increase in adverse effects. Although the underlying mechanisms of heart repair are difficult to elucidate in human studies, valuable insights may be gleaned from subgroup analysis of key variables. This information may be utilized to design future randomized controlled trials to carefully determine the long-term safety and benefits of BMC therapy. PMID- 23807799 TI - Malignant bladder pheochromocytoma with SDHB genetic mutation. AB - A 30-year-old man presented with micturition pain and was diagnosed with a submucosal tumor in the right wall of the bladder with metastasis to the right obturator lymph node. Transurethral resection led to a diagnosis of invasive malignant pheochromocytoma. Radical cystectomy, neobladder reconstruction and bilateral iliac lymph node dissection were performed. Genetic analysis revealed succinate dehydrogenase B-associated hereditary pheochromocytoma/paraganglioma syndrome. 10 months after the operation, he had no evidence of recurrence. PMID- 23807800 TI - Random site dilution properties of frustrated magnets on a hierarchical lattice. AB - We present a method to analyze the magnetic properties of frustrated Ising spin models on specific hierarchical lattices with random dilution. Disorder is induced by dilution and geometrical frustration rather than randomness in the internal couplings of the original Hamiltonian. The two-dimensional model presented here possesses a macroscopic entropy at zero temperature in the large size limit, very close to the Pauling estimate for spin-ice on the pyrochlore lattice, and a crossover towards a paramagnetic phase. The disorder due to dilution is taken into account by considering a replicated version of the recursion equations between partition functions at different lattice sizes. An analysis to first order in replica number allows a systematic reorganization of the disorder configurations, leading to a recurrence scheme. This method is numerically implemented to evaluate thermodynamical quantities such as specific heat and susceptibility in an external field. PMID- 23807801 TI - Endoscopic ultrasound combined with submucosal saline injection for differentiation of T1a and T1b esophageal squamous cell carcinoma: a novel technique. AB - Endoscopic ultrasound (EUS) is the optimum method for investigation of early esophageal squamous cell carcinoma (ESCC). However, it is difficult to substage early ESCC as T1a or T1b. The aim of this study was to improve the staging accuracy of early ESCC by using EUS combined with submucosal saline injection (SSI). The study enrolled 15 patients with suspected early ESCC who were examined by EUS and subsequently by SSI combined with EUS. The patients then underwent endoscopic or surgical resection within 10 days. The accuracy of EUS staging (alone or following SSI) was evaluated and compared with the pathological results postoperatively. No severe complications of the SSI arose. EUS plus SSI easily distinguished the mucosa from the lesion and the submucosa because of the low echoic saline-filled cushion in the submucosa. The accuracy of SSI combined with EUS for staging T1a or T1b was 86.7 %, which was better than that using EUS alone (60.0 %). PMID- 23807802 TI - Can mechanical balloon dissection be applied to cleave fibrotic submucosal tissues? A pilot study in a porcine model. AB - BACKGROUND AND STUDY AIMS: Removal of a lesion containing an ulcer scar is one of the most challenging applications of endoscopic submucosal dissection (ESD). The present study examined whether a novel balloon dissector could cleave fibrotic submucosal tissue beneath ulcer scars. METHODS: Six pigs were studied. Endoscopic mucosal resection (EMR) with ligation was performed at 7 or 8 sites in the stomach for each animal; 4 weeks later, 23 sites with a visible scar were selected for submucosal dissection. The procedure involved first creating a submucosal fluid cushion (SFC) by injecting either saline mixed with mesna or pure saline. A slender, compliant balloon with a diameter of 8, 13, or 18 mm was inserted into the SFC. The balloon was unfolded and thrust forward to cleave the fibrotic submucosa over approximately 5 cm. RESULTS: Fibrotic submucosa was dissected within 90 seconds in 17 of 23 attempts. Isolating the ulcer scar from the muscularis with the SFC prior to balloon dissection and using a thinner balloon catheter both ensured a better dissection. CONCLUSIONS: The fibrotic submucosa underlying post-EMR scars can be dissected with the novel balloon dissector, although the technique is less effective in cases with no sign of lifting. PMID- 23807804 TI - Guide wire-assisted cannulation for the prevention of post-ERCP pancreatitis: a systematic review and meta-analysis. AB - BACKGROUND AND STUDY AIMS: Cannulation techniques are recognized to be important in causing post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). However, considerable controversy exists about the usefulness of the guide wire-assisted cannulation technique for the prevention of PEP. This systematic review of randomized controlled trials (RCTs) aimed to compare the guide wire-assisted cannulation technique with the contrast-assisted cannulation technique. METHODS: CENTRAL, MEDLINE, EMBASE, CINAHL, and abstracts from Digestive Disease Week and the United European Gastroenterology Week were searched up to February 2012 for RCTs comparing the guide wire-assisted ERCP cannulation technique with the conventional contrast-assisted ERCP cannulation technique. The risk of bias was assessed, and outcomes were pooled by meta analysis (random-effects model). The primary outcome measure was PEP. Secondary outcome measures included severity of PEP, primary common bile duct (CBD) cannulation success, overall CBD cannulation success, precut sphincterotomy, and other ERCP-related complications. RESULTS: In total, 12 RCTs (3450 patients) were included. The guide wire-assisted cannulation technique significantly reduced PEP compared with the contrast-assisted cannulation technique (risk ratio [RR] 0.51, 95 % confidence interval [CI] 0.32 - 0.82). In addition, the guide wire-assisted cannulation technique was associated with greater primary cannulation success (RR 1.07, 95 %CI 1.00 - 1.15), fewer precut sphincterotomies (RR 0.75, 95 %CI 0.60 - 0.95), and no increase in other ERCP-related complications. Subgroup analyses indicated that this significant risk reduction in PEP with the guide wire assisted cannulation technique existed only in "non-crossover" trials (RR 0.22, 95 %CI 0.12 - 0.42). The results were robust in sensitivity analyses. CONCLUSION: Compared with the contrast-assisted cannulation technique, the guide wire assisted cannulation technique increases the primary cannulation rate and reduces the risk of PEP, and therefore appears to be the most appropriate first-line cannulation technique. PMID- 23807803 TI - Peroral video cholangioscopy to evaluate indeterminate bile duct lesions and preoperative mucosal cancerous extension: a prospective multicenter study. AB - BACKGROUND AND STUDY AIMS: Despite the development of peroral video cholangioscopy (PVCS), no prospective multicenter studies have been undertaken to investigate the diagnostic accuracy of PVCS in biliary tract diseases. Therefore, the aim of this study was to clarify the accuracy of PVCS in evaluating biliary tract lesions. PATIENTS AND METHODS: This study was a prospective multicenter study at five tertiary referral centers in Japan and included 87 eligible patients with biliary tract diseases who underwent PVCS. The study evaluated the ability of PVCS to diagnose indeterminate biliary tract diseases, detect mucosal cancerous extension preoperatively in extrahepatic bile duct cancers, and predict adverse events. RESULTS: The use of PVCS appearance alone correctly distinguished benign from malignant indeterminate biliary lesions in 92.1 % of patients whereas biopsy alone was accurate in 85.7 %. In extrahepatic bile duct cancer, mucosal cancer extended histologically at least 20 mm in 34.7 % (17/49) of patients. The accuracy rate of PVCS to evaluate the presence or absence of mucosal cancerous extension by endoscopic retrograde cholangiography (ERC) alone, ERC with PVCS, and ERC with PVCS + biopsy were 73.5 %, 83.7 %, and 92.9 %, respectively. Adverse events were seen in 6.9 % of PVCS patients, but no serious complications were observed. CONCLUSION: PVCS enhanced the accurate diagnosis of biliary tract lesions by providing excellent resolution in combination with biopsy. PMID- 23807805 TI - MAGNAMOSIS IV: magnetic compression anastomosis for minimally invasive colorectal surgery. AB - BACKGROUND AND STUDY AIMS: MAGNAMOSIS forms a compression anastomosis using self assembling magnetic rings that can be delivered via flexible endoscopy. The system has proven to be effective in full-thickness porcine small-bowel anastomoses. The aim of this study was to show the feasibility of the MAGNAMOSIS system in hybrid endoscopic colorectal surgery and to compare magnetic and conventional stapled anastomoses. METHODS: A total of 16 swine weighing 35 - 50 kg were used following animal ethical committee approval. The first animal was an acute model to establish the feasibility of the procedure. The subsequent 15 animals were survival models, 10 of which underwent side-to-side anastomoses (SSA) and 5 of which underwent end-to-side (ESA) procedures. Time to patency, surveillance endoscopy, burst pressure, compression force, and histology were assessed. Histology was compared with conventional stapled anastomoses. Magnetic compression forces were measured in various anastomosis configurations. RESULTS: Colorectal anastomoses were performed in all cases using a hybrid NOTES technique. The mean operating time was 71 minutes. Mean time to completion of the anastomosis was similar between the SSA and ESA groups. Burst pressure at 10 days was greater than 95 mmHg in both groups. One complication occurred in the ESA group. Compression force among various configurations of the magnetic rings was significantly different (P < 0.05). Inflammation and fibrosis were similar between magnetic SSA and conventional stapled anastomoses. CONCLUSION: MAGNAMOSIS was feasible in performing a hybrid NOTES colorectal anastomosis. It has the advantage over circular staplers of precise endoscopic delivery throughout the entire colon. SSA was reliable and effective. A minimum initial compression force of 4 N appears to be required for reliable magnetic anastomoses. PMID- 23807806 TI - Japanese multicenter experience of endoscopic necrosectomy for infected walled off pancreatic necrosis: The JENIPaN study. AB - BACKGROUND AND STUDY AIMS: Only a few large cohort studies have evaluated the efficacy and safety of endoscopic necrosectomy for infected walled-off pancreatic necrosis (WOPN). Therefore, a multicenter, large cohort study was conducted to evaluate the efficacy and safety of endoscopic necrosectomy and to examine the procedural details and follow-up after successful endoscopic necrosectomy. PATIENTS AND METHODS: A retrospective review was conducted in 16 leading Japanese institutions for patients who underwent endoscopic necrosectomy for infected WOPN between August 2005 and July 2011. The follow-up data were also reviewed to determine the long-term outcomes of the procedures. RESULTS: Of 57 patients, 43 (75 %) experienced successful resolution after a median of 5 sessions of endoscopic necrosectomy and 21 days of treatment. Complications occurred in 19 patients (33 %) during the treatment period. Six patients died (11 %): two due to multiple organ failure and one patient each from air embolism, splenic aneurysm, hemorrhage from a Mallory - Weiss tear, and an unknown cause. Of 43 patients with successful endoscopic necrosectomy, recurrent cavity formation was observed in three patients during a median follow-up period of 27 months. CONCLUSIONS: Endoscopic necrosectomy can be an effective technique for infected WOPN and requires a relatively short treatment period. However, serious complications can arise, including death. Therefore, patients should be carefully selected, and knowledgeable, skilled, and experienced operators should perform the procedure. Further research into safer technologies is required in order to reduce the associated morbidity and mortality. PMID- 23807807 TI - Long-range magnetic ordering in bulk Tb1-xMxMnO3 (M = Ca, Sr). AB - Substitution of Ca(2+) and Sr(2+) at the A-site of multiferroic TbMnO3 bulk results in an increased average ionic radius and ionic-size mismatch, and was found to reduce the orthorhombic distortion. Signatures of long-range ferromagnetic-like ordering at 78 K in Tb0.67Ca0.33MnO3 and at 87 K in Tb0.67Sr0.33MnO3 samples are clearly observed in both the dc and ac susceptibility data. A compensation temperature is also observed in Tb0.67Ca0.33MnO3, indicating the antiparallel alignment of Tb(3+) moments to the Mn(3+)-Mn(4+) moments. The canted antiferromagnetic ordering coexists with antiferromagnetic clusters, resulting in spin-glass-like behavior at low temperatures. An increased average ionic radius and ionic-size mismatch at the A site are determined to be critical factors in determining the magnetic properties of the hole-doped manganites. PMID- 23807808 TI - A rapid and simple chromatographic separation of diastereomers of silibinin and their oxidation to produce 2,3-dehydrosilybin enantiomers in an optically pure form. AB - Silybin A and B were separated from commercial silibinin using the preparative HPLC method. The described method is rapid and effective in obtaining gram-scale amounts of two diastereoisomers with minimal effort. In our approach, silibinin was dissolved in THF (solubility greater than 100 mg/mL), an alternative solvent to H2O or MeOH in which silibinin has a very low solubility (ca 0.05-1.5 mg/mL), and then separated into its two components using preparative RP-HPLC. By starting with purified diastereoisomers, it was possible to obtain the two enantiomers of 2,3-dehydrosilybin in good yields and optically pure using an efficient oxidation procedure. All of the purified products were fully characterised using NMR (1H, 13C), CD, [alpha](D), and ESI MS analyses. The purities of the products, which were evaluated using analytical HPLC, were greater than 98% in all cases. PMID- 23807810 TI - Alterations in sulfur amino acid metabolism in mice treated with silymarin: a novel mechanism of its action involved in enhancement of the antioxidant defense in liver. AB - It has been known that silymarin exhibits protective activity against oxidative liver injury induced by various hepatotoxicants, but the underlying mechanism of its beneficial action remains unclear. We determined the alterations in sulfur containing amino acid metabolism induced by silymarin in association with its effects on the antioxidant capacity of liver. Male mice were treated with silymarin (100 or 200 mg/kg, p. o.) every 12 h for a total of 3 doses, and sacrificed 6 h after the final dosing. The hepatic methionine level was increased, but the activity and protein expression of methionine adenosyltransferase were decreased by silymarin in a dose-dependent manner. S Adenosylmethionine or homocysteine concentration was not changed, whereas the sulfur-containing metabolites generated from homocysteine in the transsulfuration pathway including cystathionine, cysteine, and glutathione were increased significantly. Cystathionine beta-synthase was induced, but cysteine dioxygenase was downregulated, both of which would contribute to the elevation of cysteine and its product, glutathione, in liver. Oxygen radical scavenging capacity of liver cytosol against peroxyl radical and peroxynitrite was increased, and also hepatic lipid peroxidation was diminished in the silymarin-treated mice. Taken together, the results demonstrate that silymarin enhances hepatic glutathione generation by elevating cysteine availability via an increment in cysteine synthesis and an inhibition of its catabolism to taurine, which may subsequently contribute to the antioxidant defense of liver. PMID- 23807809 TI - Inhibitory activity of plant stilbenoids against nitric oxide production by lipopolysaccharide-activated microglia. AB - Microglia-driven inflammatory processes are thought to play an important role in ageing and several neurological disorders. Since consumption of a diet rich in polyphenols has been associated with anti-inflammatory and neuroprotective effects, we studied the effects of twenty-five stilbenoids isolated from Milicia excelsa, Morus alba, Gnetum africanum, and Vitis vinifera. These compounds were tested at 5 and 10 uM on BV-2 microglial cells stimulated with bacterial lipopolysaccharide. Ten stilbenoids reduced lipopolysaccharide-induced nitric oxide production at 5 and/or 10 uM. Two tetramers, E-vitisin A and E-vitisin B, were the most effective molecules. Moreover, they attenuated the expression of the inducible NO synthase protein and gene. PMID- 23807811 TI - Curcumin alters the pharmacokinetics of warfarin and clopidogrel in Wistar rats but has no effect on anticoagulation or antiplatelet aggregation. AB - This study examined the effects of curcumin on the pharmacokinetic and pharmacodynamic properties of warfarin and clopidogrel in Wistar rats. Results showed that oral administration of curcumin at 25 mg/kg, 50 mg/kg, and 100 mg/kg for 7 days had no substantial effects on the pharmacodynamics of warfarin and clopidogrel in this animal model. However, oral administration of 100 mg/kg curcumin for 7 days significantly increased the AUC0-infinity and Cmax of the two drugs (by * 1.6 and * 1.5, respectively, for warfarin, and * 1.61 and * 1.81, respectively, for clopidogrel carboxylic acid). However, compared to warfarin alone, different doses of curcumin combined with warfarin had no effects on the prothrombin time in rats. Similarly, a combination of curcumin and clopidogrel had no significant effect on the maximum platelet aggregation rate of rats compared with the use of clopidogrel alone. This work demonstrated that preadministration of 100 mg/kg curcumin affected the pharmacokinetics of warfarin and clopidogrel but had no effect on pharmacodynamic parameters such as anticoagulation rate and antiplatelet aggregation. PMID- 23807812 TI - Anti-apoptotic and neuroprotective effects of oxysophoridine on cerebral ischemia both in vivo and in vitro. AB - In this study, we investigated the neuroprotective effect of oxysophoridine on ischemia and ischemia-like insults. Protection by oxysophoridine was studied at the in vivo level using a model of middle cerebral artery occlusion in mice and at the in vitro level using primary rat hippocampal neuronal cultures exposed to oxygen-glucose deprivation, a model of ischemia-like injury. The behavioral test was performed by using the neurological scores. The infarction volume of brain was assessed in the brain slices stained with 2,3,5-triphenyl tetrazolium chloride. The neuron apoptosis was evaluated by Hoechst 33342 staining. The morphological change in the neurons was examined using a Transmission Electron Microscope (TEM or EM). To evaluate neuron apoptosis, caspase-3, -9, and - 8 activities were measured using assay kits with an ELISA reader. The Western blotting assay was used to evaluate the release of cytochrome c and expression of caspase-3, Bcl-2, and Bax proteins. The quantitative real-time PCR assay was used to evaluate the release of cytochrome c and the expression of caspase-3 mRNA. Oxysophoridine-treated groups (62.5, 125, 250 mg/kg) markedly reduced neurological deficit scores and infarct volumes. Treatment with oxysophoridine (5, 20, 80 umol/L) significantly attenuated neuronal damage, with evidence of decreased cell apoptosis and decreased cell morphologic impairment. Furthermore, treatment with oxysophoridine could effectively downregulate the expression of cytochrome c and caspase-3 in both mRNA and protein levels, and Bax in the protein level, and induce an increase of Bcl-2 in the protein level. The caspase 3, -9, and -8 activities were also inhibited. These findings suggested that oxysophoridine may be a potential neuroprotective agent for cerebral ischemia injury. PMID- 23807813 TI - Application of plant metabonomics in quality assessment for large-scale production of traditional Chinese medicine. AB - The curative effects of traditional Chinese medicines are principally based on the synergic effect of their multi-targeting, multi-ingredient preparations, in contrast to modern pharmacology and drug development that often focus on a single chemical entity. Therefore, the method employing a few markers or pharmacologically active constituents to assess the quality and authenticity of the complex preparations has a number of severe challenges. Metabonomics can provide an effective platform for complex sample analysis. It is also reported to be applied to the quality analysis of the traditional Chinese medicine. Metabonomics enables comprehensive assessment of complex traditional Chinese medicines or herbal remedies and sample classification of diverse biological statuses, origins, or qualities in samples, by means of chemometrics. Identification, processing, and pharmaceutical preparation are the main procedures in the large-scale production of Chinese medicinal preparations. Through complete scans, plants metabonomics addresses some of the shortfalls of single analyses and presents a considerable potential to become a sharp tool for traditional Chinese medicine quality assessment. PMID- 23807814 TI - Model-based registration of ex vivo and in vivo MRI of the prostate using elastography*. AB - Registration of histopathology to in vivo magnetic resonance imaging (MRI) of the prostate is an important task that can be used to optimize in vivo imaging for cancer detection. Such registration is challenging due to the change in volume and deformation of the prostate during excision and fixation. One approach towards this problem involves the use of an ex vivo MRI of the excised prostate specimen, followed by in vivo to ex vivo MRI registration of the prostate. We propose a novel registration method that uses a patient-specific biomechanical model acquired using magnetic resonance elastography to deform the in vivo volume and match it to the surface of the ex vivo specimen. The forces that drive the deformations are derived from a region-based energy, with the elastic potential used for regularization. The incorporation of elastography data into the registration framework allows inhomogeneous elasticity to be assigned to the in vivo volume. We show that such inhomogeneity improves the registration results by providing a physical regularization of the deformation map. The method is demonstrated and evaluated on six clinical cases. PMID- 23807816 TI - "Designer"-Surfactant-Enabled Cross-Couplings in Water at Room Temperature. AB - New methodologies are discussed that allow for several commonly used transition metal-catalyzed coupling reactions to be conducted within aqueous micellar nanoparticles at ambient temperatures. PMID- 23807818 TI - Deviations from Ideal Sublimation Vapor Pressure Behavior in Mixtures of Polycyclic Aromatic Compounds with Interacting Heteroatoms. AB - Despite the relatively small atomic fraction of a given heteroatom in a binary mixture of polycyclic aromatic compounds (PAC), the inclusion of heteroatomic substituted compounds can significantly impact mixture vapor pressure behavior over a wide range of temperatures. The vapor pressures of several binary PAC mixtures containing various heteroatoms show varying behavior, from practically ideal behavior following Raoult's law to significant deviations from ideality depending on the heteroatom(s) present in the mixture. Mixtures were synthesized using the quench-cool technique with equimolar amounts of two PAC, both containing heteroatoms such as aldehyde, carboxyl, nitrogen, and sulfur substituent groups. For some mixtures, deviation from ideality is inversely related to temperature, though in other cases we see deviations from ideality increasing with temperature, whereas some appear independent of temperature. Most commonly we see lower vapor pressures than predicted by Raoult's law, which indicates that the interacting heteroatoms prefer the solid mixture phase as opposed to the vapor phase. Although negative deviations predominate from Raoult's Law, the varying mixtures investigated show both higher and lower enthalpies and entropies of sublimation than predicted. In each mixture, a higher enthalpy of sublimation leads to higher entropy of sublimation than predicted, and vice versa. PMID- 23807817 TI - Chemically Specific Imaging Through Stimulated Raman Photoexcitation and Ultrasound Detection: Minireview. AB - A powerful combination of chemically specific Raman excitation and deep tissue ultrasound imaging holds the promise to attain spatially resolved distribution of chemical compounds inside the scattering medium. In this report, an attempt is made to evaluate the recent achievements and possible challenges with an eye on potential clinical applications. PMID- 23807820 TI - The Challenges of Writing Portable, Correct and High Performance Libraries for GPUs. AB - Graphics Processing Units (GPUs) are widely used to accelerate scientific applications. Many successes have been reported with speedups of two or three orders of magnitude over serial implementations of the same algorithms. These speedups typically pertain to a specific implementation with fixed parameters mapped to a specific hardware implementation. The implementations are not designed to be easily ported to other GPUs, even from the same manufacturer. When target hardware changes, the application must be re-optimized. In this paper we address a different problem. We aim to deliver working, efficient GPU code in a library that is downloaded and run by many different users. The issue is to deliver efficiency independent of the individual user parameters and without a priori knowledge of the hardware the user will employ. This problem requires a different set of tradeoffs than finding the best runtime for a single solution. Solutions must be adaptable to a range of different parameters both to solve users' problems and to make the best use of the target hardware. Another issue is the integration of GPUs into a Problem Solving Environment (PSE) where the use of a GPU is almost invisible from the perspective of the user. Ease of use and smooth interactions with the existing user interface are important to our approach. We illustrate our solution with the incorporation of GPU processing into the Scientific Computing Institute (SCI)Run Biomedical PSE developed at the University of Utah. SCIRun allows scientists to interactively construct many different types of biomedical simulations. We use this environment to demonstrate the effectiveness of the GPU by accelerating time consuming algorithms in the scientist's simulations. Specifically we target the linear solver module, including Conjugate Gradient, Jacobi and MinRes solvers for sparse matrices. PMID- 23807819 TI - Cationic dirhodium carboxylate-catalyzed synthesis of dihydropyrimidones from propargyl ureas. AB - Cationic Rh(II) complexes are able to catalyze the regioselective hydroamination of propargyl ureas in a 6-endo fashion. This transformation permits access to interesting substitution patterns of dihydropyrimidines which have found use as nucleotide exchange factor inhibitors. PMID- 23807821 TI - Perceptions of societal developmental hierarchies in Europe and beyond: A Bulgarian Perspective. AB - We examine how ordinary citizens in Bulgaria view the developmental levels of European countries and certain states outside of Europe. Our research is motivated by the understanding that scholars and policy makers have for centuries used developmental hierarchies to characterize countries and that this perception of differential development has shaped interactions among different groups, countries and regions. We expect that views of such developmental hierarchies and models have great potential for influencing demographic and family behavior and political and cultural identities of ordinary people. Using data from a 2009 survey in Bulgaria we document that developmental hierarchies are widely perceived in Bulgaria, but are distributed differentially by age, education, and degree of urbanization. We also consider internal mechanisms underlying this hierarchical understanding of development and how hierarchical understandings may be related to national identities. PMID- 23807822 TI - Estimating Intergenerational Persistence of Lifetime Earnings with Life Course Matching: Evidence from PSID. AB - Why do estimates of the intergenerational persistence in earnings vary so much for the United States? Recent research suggests that life-cycle bias may be a major factor (Haider and Solon 2006; Grawe 2006). In this paper we estimate the intergenerational correlation in lifetime earnings by using sons' and fathers' earnings at similar ages in order to account for lifecycle bias. Our estimate based on earnings measured at 35-44 for both fathers and sons is similar to that for the age range 45-54. PMID- 23807823 TI - Antimicrobial and antiurease activities of newly synthesized morpholine derivatives containing an azole nucleus. AB - 2-[6-(Morpholin-4-yl)pyridin-3-ylamino]acetohydrazide (4) was obtained starting from 6-morpholin-4-ylpyridin-3-amine (2) via the formation of ester (3) and then converted to the corresponding Schiff bases (5, 6) with the reaction with aromatic aldehydes. The carbothioamide (9), obtained from the reaction of hydrazide with phenylisothiocyanate, was converted to the corresponding 1,2,4 triazole (11) and 1,3,4-thiadiazole (12) derivatives by the treatment with NaOH or H2SO4, respectively. The cyclocondenzation of 9 with 4-chlorophenacyl bromide or ethyl bromoacetate produced the corresponding 1,3-thiazole (10) or 1,3 thiazolidine derivatives (13), respectively. Antimicrobial and antiurease activities of newly synthesized compounds were investigated. Some of them were found to be active on M. smegmatis, and they displayed activity toward C. albicans and S. cerevisiae in high concentration. Compound 10 proved to be the most potent showing an enzyme inhibition activity with an IC50 = 2.37 +/- 0.19 MUM. PMID- 23807825 TI - Pension Participation: Do Parents Transmit Time Preference? AB - A wide range of economic and health behaviors are influenced by individuals' attitudes toward the future - including investments in human capital, health capital and financial capital. Intergenerational correlations in such behaviors suggest an important role the family may play in transmitting time preferences to children. This article presents a model of parental investment in future-oriented capital, where parents shape their children's time preference rates. The research identifies a dual role for a parent's time preference rate in the process of shaping the offspring's attitude toward the future, and discusses paths through which parents may socialize children to be patient. The model's implications are studied by investigating the parent-child correlation in pension participation using data from the Panel Study of Income Dynamics. PMID- 23807824 TI - Non-imidazole histamine H3 ligands: part V. synthesis and preliminary pharmacological investigation of 1-[2-thiazol-4-yl- and 1-[2-thiazol-5-yl-(2 aminoethyl)]-4-n-propylpiperazine derivatives. AB - Series of 1-[2-thiazol-4-yl-(2-aminoethyl)]- and 1-[2-thiazol-5-yl-(2 aminoethyl)]-4-n-propylpiperazine derivatives have been prepared and in vitro tested as H3-receptor antagonists (the electrically evoked contraction of the guinea-pig jejunum). It appeared that by comparison of homologous pairs, the 1-[2 thiazol-5-yl-(2-aminoethyl)]-4-n-propylpiperazines (3a,b and 4a-d) have much higher potency than their analogous 1-[2-thiazol-4-yl-(2-aminoethyl)]-4-n propylpiperazines (2a-k). Based on the obtained results, we observed the 5 position of 2-methyl-2-R-aminoethyl substituents in the thiazole ring is favourable for histamine H3 receptor antagonist activity, whereas its presence in position 4 leads, almost in each case, to strong decrease of activity. PMID- 23807826 TI - Efficacy and safety of chondroitin sulfate/xanthan gum versus polyethylene glycol/propylene glycol/hydroxypropyl guar in patients with dry eye. AB - PURPOSE: To evaluate the efficacy and safety of two ophthalmic solutions in patients with mild to moderate dry eye. METHODS: We performed a prospective, 2 month-long, randomized, double-blind, single-center, parallel clinical trial to compare the efficacy and safety of two ophthalmic solutions for dry eye treatment. Patients were randomly assigned to one of the two treatment groups, study group or active-control group, and received one drop four times a day. The primary efficacy endpoint was to extend the tear film break-up time (TBUT) after 2 months of treatment. The Ocular Surface Disease Index (OSDI) was also evaluated. Safety measures were assessed by the presence of adverse events. RESULTS: A total of 28 patients with mild to moderate dry eye were included in the per protocol analysis. TBUT was similar between groups at baseline (chondroitin sulfate and xanthan gum [CS/XG] group, 5.2 +/- 2.3; Systane((r)) group, 4.7 +/- 2.6; P = 0.488), after 2 months of treatment, TBUT was still similar in both groups (CS/XG group, 6.1 +/- 2.5; Systane((r)) group, 7.3 +/- 2.5; P = 0.088). Baseline OSDI was similar between the groups (CS/XG group, 18.8 +/- 5.3; Systane((r)) group, 19.8 +/- 7.1; P = 0.810), but after 2 months of treatment, the OSDI was significantly lower in the CS/XG group (6.7 +/- 5.7 versus 10.8 +/- 6.4; P = 0.049). An adverse event was present in the CS/XG group, but it was not related to the treatment. CONCLUSIONS: In this population of patients with mild to moderate dry eye, treatment with CS/XG was as effective as treatment with Systane((r)) with regard to TBUT; nevertheless, treatment in the CS/XG group was more effective at diminishing OSDI. PMID- 23807827 TI - Visual field loss in schizophrenia: evaluation of magnocellular pathway dysfunction in schizophrenic patients and their parents. AB - PURPOSE: We sought to evaluate the visual pathway deficits in schizophrenic patients, compared with their parents and healthy controls, using Matrix frequency doubling technology (FDT) perimetry. Matrix FDT is an ophthalmic test used to detect visual field loss. METHOD: A total of 13 patients, 13 parents, and 12 healthy controls were enrolled in the study. Participants were subjected to Matrix FDT perimetry in a single test session. We analyzed the mean deviation for each eye and used a generalized estimated equation to evaluate differences among the groups and correct the dependency between the eyes. RESULTS: The global mean deviation (presented as the mean of both eyes) was significantly lower in the schizophrenic patients than in their parents or controls. Analysis of the general sensitivity of the fibers crossing the optic chiasm showed a difference between the groups (P = 0.006), indicating that the sensitivity of the fibers crossing the optic chiasm was lower than those which did not cross. But when we analyzed the specific groups, the difference between the fibers was not considerable. Comparison of the right and left hemispheres showed that general sensitivity was lower for the left hemisphere, but when we analyzed specific groups, the difference was not significant (P = 0.29). CONCLUSION: These findings are suggestive of a lower global sensitivity in schizophrenic patients and their parents compared with controls. This difference may be an endophenotype of schizophrenia. The present study adds to a growing body of research on early stage visual processing deficits in schizophrenia. PMID- 23807828 TI - A case of anterior ischemic optic neuropathy associated with uveitis. AB - INTRODUCTION: Here, we describe a patient who presented with anterior ischemic optic neuropathy (AION) and subsequently developed uveitis. CASE: A 69-year-old man was referred to our hospital and initially presented with best-corrected visual acuities (BCVA) of 20/40 (right eye) and 20/1000 (left eye) and relative afferent pupillary defect. Slit-lamp examination revealed no signs of ocular inflammation in either eye. Fundus examination revealed left-eye swelling and a pale superior optic disc, and Goldmann perimetry revealed left-eye inferior hemianopia. The patient was diagnosed with nonarteritic AION in the left eye. One week later, the patient returned to the hospital because of vision loss. The BCVA of the left eye was so poor that the patient could only count fingers. Slit-lamp examination revealed 1+ cells in the anterior chamber and the anterior vitreous in both eyes. Funduscopic examination revealed vasculitis and exudates in both eyes. The patient was diagnosed with bilateral panuveitis, and treatment with topical betamethasone was started. No other physical findings resulting from other autoimmune or infectious diseases were found. No additional treatments were administered, and optic disc edema in the left eye improved, and the retinal exudates disappeared in 3 months. The patient's BCVA improved after cataract surgery was performed. CONCLUSION: Panuveitis most likely manifests after the development of AION. PMID- 23807829 TI - Retrospective analysis of patients self-referred to comprehensive ophthalmology seeking second opinions. AB - Patients choose to seek a second opinion in matters related to their health for a variety of reasons, and the total cost associated with these second opinion visits is estimated to be billions of dollars annually. Understanding the reasons behind second opinion self-referrals is key to improving patient satisfaction and reducing redundancy in delivered health care. This study represents a retrospective analysis of the records from a single provider at the Massachusetts Eye and Ear Infirmary (MEEI) Comprehensive Ophthalmology Service in order to determine the various reasons that patients self-refer to an ophthalmology clinic seeking second opinions. A total of 174 patients presenting for a second opinion were identified over a one-year period. Patients presented for second opinions for two primary reasons: 60% presented in order to seek a confirmation of a diagnosis from an outside ophthalmologist (54%) or optometrist (6%), and 40% presented due to a previous adverse experience with an outside provider, such as perceived treatment failure (26%), poor bedside manner (3%), distrust of the provider (5%), and poor provider communication skills (7%). This study strives to reiterate that the reduction of adverse patient experiences through effective communication of expected treatment options and outcomes, with a realistic time course of therapy, could significantly improve patient satisfaction and reduce costly second opinion visits. PMID- 23807830 TI - FS200 femtosecond laser LASIK flap digital analysis parameter evaluation: comparing two different types of patient interface applanation cones. AB - PURPOSE: To evaluate the safety and efficacy of a novel LASIK flap patient interface (PI) cone with our reported digital analysis and compare for potential differences with the standard metal and glass PI in flap parameters when used with the Alcon/WaveLight FS200 femtosecond laser. PATIENTS AND METHODS: Thirty six consecutive LASIK patients (72 eyes) subjected to a bilateral femtosecond assisted LASIK procedure with the novel clear cone PI FS200 1505 were examined for flap diameter and flap thickness over the entire flap area via digital analysis performed on intraoperation image (flap diameter) and anterior-segment optical coherence tomography image (flap thickness). This group was compared with an age- and procedure-matched group B from our practice, in which the standard metal and glass PI was employed. RESULTS: Horizontal flap diameter for group A (clear cone) was 7.87 mm +/- 0.02 mm (range 7.89-7.84 mm) for 8.00 mm programmed, whereas for group B (metal and glass cone) was 7.85 mm +/- 0.04 mm (range 7.93 7.80 mm). Likewise, along the vertical line, flap diameter for group A was 7.84 mm +/- 0.02 mm (range 7.85-7.80 mm) and for group B was 7.83 mm +/- 0.03 mm (range 7.87-7.80 mm). Central flap thickness for group A was 113.29 MUm (+/-1.19 MUm) for 110 MUm planned, 122.1 MUm (+/-2.10 MUm) for 120 MUm planned, and 133.50 MUm (+/-0.71 MUm) for 130 MUm planned. Group B central flap thickness was, accordingly, 112.8 MUm (+/-1.25 MUm), 122.4 MUm (+/-2.15 MUm), and 132.50 MUm (+/ 0.90 MUm). The data evaluated (paired group comparisons) between group A and group B did not show statistically significant differences. CONCLUSION: This study indicates that two PIs in use with the FS200 femtosecond laser are safe and have highly reproducible and accurate flap parameter results, such as achieved diameter and flap thickness. The paired group comparisons between the two PIs' respective data do not show statistically significant differences. PMID- 23807832 TI - Visual field characteristics in neuromyelitis optica in absence of and after one episode of optic neuritis. AB - PURPOSE: Optic neuritis (ON) observed during neuromyelitis optica (NMO) is in most cases very severe and with poor prognosis. This study's objective was to analyze visual field (VF) abnormalities observed in the absence of ON and post-ON episode. METHODS: Twenty-seven cases of both NMO and multiple sclerosis (MS) were selected. Thorough ophthalmologic exam was performed at least 6 months post-ON attack. The VF was collected using the Humphrey 750 perimeter. We used the central threshold tests 24-2 with FASTPAC strategy. The abnormalities were categorized based on the Optic Neuritis Treatment Trial classification. RESULTS: After one ON, 40% of the NMO group's eyes showed total VF loss (P = 0.01), 21% showed abnormalities of neurologic aspect, and 27% showed fascicular abnormalities of which 12% were altitudinal. Given the total VF loss, the positive predictive value in favor of an NMO was 92.8% and the negative predictive value was 47.3%. CONCLUSION: Alterations of the VF during the NMO differ from those observed in the course of the MS. One ON, blinding from the first attack, must call to mind an NMO. The altitudinal deficits point to a vascular mechanism. PMID- 23807831 TI - Interventions for the treatment of uveitic macular edema: a systematic review and meta-analysis. AB - BACKGROUND: Uveitic macular edema is the major cause of reduced vision in eyes with uveitis. OBJECTIVES: To assess the effectiveness of interventions in the treatment of uveitic macular edema. SEARCH STRATEGY: Cochrane Central Register of Controlled Trials, Medline, and Embase. There were no language or data restrictions in the search for trials. The databases were last searched on December 1, 2011. Reference lists of included trials were searched. Archives of Ophthalmology, Ophthalmology, Retina, the British Journal of Ophthalmology, and the New England Journal of Medicine were searched for clinical trials and reviews. SELECTION CRITERIA: Participants of any age and sex with any type of uveitic macular edema were included. Early, chronic, refractory, or secondary uveitic macular edema were included. We included trials that compared any interventions of any dose and duration, including comparison with another treatment, sham treatment, or no treatment. DATA COLLECTION AND ANALYSIS: Best corrected visual acuity and central macular thickness were the primary outcome measures. Secondary outcome data including adverse effects were collected. CONCLUSION: More results from randomized controlled trials with long follow-up periods are needed for interventions for uveitic macular edema to assist in determining the overall long-term benefit of different treatments. The only intervention with sufficiently robust randomized controlled trials for a meta analysis was acetazolamide, which was shown to be ineffective in improving vision in eyes with uveitic macular edema, and is clinically now rarely used. Interventions showing promise in this disease include dexamethasone implants, immunomodulatory drugs and anti-vascular endothelial growth-factor agents. When macular edema has become refractory after multiple interventions, pars plana vitrectomy could be considered. The disease pathophysiology is uncertain and the course of disease unpredictable. As there are no clear guidelines from the literature, interventions should be tailored to the individual patient. PMID- 23807833 TI - Changes in axial length and choroidal thickness after intraocular pressure reduction resulting from trabeculectomy. AB - PURPOSE: To evaluate changes in axial length and choroidal thickness after trabeculectomy. PATIENTS AND METHODS: Fourteen patients under 80 years of age with glaucoma, were enrolled. The choroid was imaged using prototypical high penetration optic coherence tomography (OCT) and the thickness was measured. Axial length, choroidal thickness, and intraocular pressure (IOP) were measured bilaterally at 3 pm 1 day before and 6 days after trabeculectomy. The choroidal thickness was measured at the fovea and four other locations (2 mm superior, temporal, inferior, and nasal to the center of the optic nerve head). RESULTS: The IOP and axial length significantly decreased in eyes that underwent trabeculectomy (P < 0.0001 for the IOP; P < 0.001 for axial length comparisons). The mean choroidal thicknesses significantly increased in eyes that underwent trabeculectomy compared to preoperatively (P < 0.0001 for the fovea; P < 0.01 for four locations around the optic disc). The mean magnitude of change in IOP was correlated positively with the mean magnitude of change in axial length, but not correlated with the mean magnitude of change in choroidal thickness at the fovea that underwent trabeculectomy. The sum of the axial length and subfoveal choroidal thickness in eyes decreased significantly postoperatively (P < 0.05). CONCLUSION: The axial length shortened, the choroid thickened, and the sum of the axial length and subfoveal choroidal thickness decreased with IOP reduction early after trabeculectomy. PMID- 23807834 TI - Abrupt spontaneous suprachoroidal hemorrhage post-23-gauge vitrectomy during peritoneal dialysis. AB - Herein, we report a case of abrupt suprachoroidal hemorrhage (SCH) that developed during peritoneal dialysis in a patient with proliferative diabetic retinopathy. A 53-year-old female patient visited our clinic with blurred vision due to vitreous hemorrhage and proliferative diabetic retinopathy. Her medical history included diabetes, hypertension, chronic renal failure, and she had received scheduled peritoneal dialysis. No anticoagulant agents were used. We performed combined phacoemulsification with intraocular lens implantation and vitrectomy without any complications. Two hours later, the retina was stable and the intraocular pressure (IOP) was 11 mmHg. Four hours later, while receiving peritoneal dialysis, she abruptly developed ocular pain. Examination of her eye revealed an IOP of 38 mmHg and a SCH in the entire peripheral retina and posterior pole. At 12 hours after surgery (on the same day), the SCH was found to be further aggravated, and because a "kissing retina" was imminent, silicone oil was injected. An attempted fluid-air exchange failed because there was not enough space to fill with silicone oil due to aggravation of the SCH. Sclerotomies were performed to remove the SCH, and to create space for the silicone oil injection. Two months after surgery, the silicone oil was removed and her visual acuity was found to have improved to 20/40, but the patient died of pontine hemorrhage 1 month later. SCH can occur in vitrectomized eyes due to an increase in abdominal pressure during peritoneal dialysis, because chronic renal failure patients with diabetes and hypertension have structural vulnerabilities and vascular weaknesses due to arterial sclerosis in response to the increased blood pressure. PMID- 23807835 TI - Optical ray tracing-guided myopic laser in situ keratomileusis: 1-year clinical outcomes. AB - PURPOSE: To compare the safety, efficacy, and predictability of laser in situ keratomileusis treatments at 1 year postprocedure using a novel geometric ray tracing algorithm with outcomes of treatments using wavefront-optimized, wavefront-guided, and topography-guided ablation profiles of an excimer laser (WaveLight GmbH, Erlangen, Germany; Alcon Laboratories, Fort Worth, TX, USA). SETTING: Wellington Eye Clinic, Dublin, Ireland. DESIGN: Retrospective comparative case series. METHODS: Eyes having a preoperative myopic spherical equivalent refractive error >4.00 D and/or astigmatism between 2.00-6.00 D resulting in a spherical equivalent power greater than -4.00 D received laser in situ keratomileusis treatments using a ray tracing algorithm. Refractive outcomes were analyzed postoperatively at 6 and 12 months and were compared to outcomes of wavefront-optimized, wavefront-guided, and topography-guided treatments in eyes with the same pretreatment refractive range. RESULTS: Forty-seven eyes of 26 patients were treated using the ray tracing algorithm. At 12 months postprocedure, uncorrected visual acuity was better than the preoperative best corrected visual acuity in this group. The percentage of eyes achieving an uncorrected visual acuity or best-corrected visual acuity >=20/20 significantly exceeded the rates achieved in the wavefront-optimized and topography-guided groups. A greater percentage of eyes achieved an uncorrected visual acuity >=20/20 and >=20/16 in the wavefront-guided group, but no eyes in the wavefront guided group had an uncorrected visual acuity >=20/12.5 in comparison to 9.5% of eyes in the ray tracing group. CONCLUSION: This study provides further evidence of the safety, efficacy, and predictability of laser in situ keratomileusis outcomes using an optical ray tracing algorithm to treat moderate to high myopic astigmatism and shows that good results are sustained through 1 year. PMID- 23807836 TI - PEGylated interferon beta-1a in the treatment of multiple sclerosis - an update. AB - Current standard immunomodulatory therapy with interferons (IFNs) for relapsing remitting multiple sclerosis (MS) exhibits proven, but limited, efficacy and increased side effects due to the need of frequent application of the drug. Therefore, there is a need for more effective and tolerable drugs. Due to their small size, optimization of therapy with IFNs in MS by PEGylation is feasible. PEGylation of an IFN means that at least one molecule of polyethylene glycol (PEG) is covalently added. This modification is a standard procedure to increase the stability, solubility, half-life, and efficacy of a drug, and is applied in several drugs and diseases. Currently, a therapy regimen applying PEG-IFN beta-1a in MS is being developed to achieve an optimized relationship between therapy related side effects and pharmacokinetic/pharmacodynamic efficacy. Phase I studies demonstrated that subcutaneous PEG-IFN beta-1a at a dose of 125 MUg every 2 or 4 weeks might be at least as efficient and safe as the current standard therapy with IFN beta-1a. A global Phase III clinical study is investigating the efficacy of PEG-IFN beta-1a in terms of reduction of the relapse rate in relapsing-remitting MS patients. The latest primary safety and efficacy analysis after 1 year has revealed a favorable risk-benefit profile with no significant difference between dosing regimens. Compared to placebo, the annualized relapse rate was reduced by about one-third and new or newly enlarging T2 brain lesions were reduced by about one-third when dosing every 4 weeks or by two-thirds when dosing every 2 weeks. This presents a significant effect of the dosing interval, favoring administration every 2 weeks. Chronic administration of PEGylated proteins mostly at toxic concentrations causes vacuolation of renal epithelium in animals, which - along with the issue of occurrence of anti-PEG antibodies - has to be addressed by Phase IV studies. PMID- 23807837 TI - Preparation and evaluation of a multimodal minoxidil microemulsion versus minoxidil alone in the treatment of androgenic alopecia of mixed etiology: a pilot study. AB - BACKGROUND: The variable success of topical minoxidil in the treatment of androgenic alopecia has led to the hypothesis that other pathways could mediate this form of hair loss, including infection and/or microinflammation of the hair follicles. In this study, we prepared a multimodal microemulsion comprising minoxidil (a dihydrotestosterone antagonist), diclofenac (a nonsteroidal anti inflammatory agent), and tea tree oil (an anti-infective agent). We investigated the stability and physicochemical properties of this formulation, and its therapeutic efficacy compared with a formulation containing minoxidil alone in the treatment of androgenic alopecia. METHODS: We developed a multimodal oil/water (o/w) microemulsion, a formulation containing minoxidil alone, and another containing vehicle. A three-phase diagram was constructed to obtain the optimal concentrations of the selected oil, surfactant, and cosurfactant. Thirty two men aged 18-30 years were randomized to apply 1 mL of microemulsion containing the multimodal formulation (formulation A, n = 11), minoxidil alone (formulation B, n = 11) or placebo (formulation C, n = 10) twice daily to the affected area for 32 weeks. Efficacy was evaluated by mean hair count, thickness, and weight on the targeted area of the scalp. Global photographs were taken, changes in the area of scalp coverage were assessed by patients and external investigators, and the benefits and safety of the study medications were evaluated. The physical stability of formula A was examined after a shelf storage period of 24 months. RESULTS: Formulation A achieved a significantly superior response than formulations B and C in terms of mean hair count (P < 0.001), mean hair weight (P < 0.001), and mean hair thickness (P < 0.05). A patient self assessment questionnaire demonstrated that the multimodal minoxidil formulation significantly (P < 0.001) slowed hair loss, increased hair growth, and improved appearance, and showed no appreciable side effects, such as itching and/or inflammation of the scalp compared with the minoxidil alone and placebo formulations. These improvements were in agreement with the photographic assessments made by the investigators. Formula A was shown to be an o/w formulation with consistent pH, viscosity, specific gravity, and homogeneity, and was physically stable after 24 months of normal storage. CONCLUSION: A multimodal microemulsion comprising minoxidil, diclofenac, and tea tree oil was significantly superior to minoxidil alone and placebo in terms of stability, safety, and efficacy, and achieved an earlier response in the treatment of androgenic alopecia compared with minoxidil alone in this 32-week pilot study. PMID- 23807840 TI - Medication possession ratio: implications of using fixed and variable observation periods in assessing adherence with disease-modifying drugs in patients with multiple sclerosis. AB - BACKGROUND: The purpose of this study was to compare two methods of adherence calculation using administrative data for patients with multiple sclerosis (MS) who are prescribed disease-modifying drugs. METHODS: Pharmacy-billed disease modifying drug prescription claims were selected from the 2007-2008 LifeLinkTM Health Plan Claims Database. The index date was the first disease-modifying drug prescription claim. Two cohorts were created: all patients with a disease modifying drug claim in 2007 and a subset with continuous eligibility for 12 months post-index. Adherence was calculated across all disease-modifying drugs for 12 months post-index. Medication possession ratios (MPRs) with variable (start to end of therapy) and fixed (365 days) duration denominators were calculated. Variable MPR was calculated by summing days supply from the first to the last prescription (inclusive) divided by time between the last prescription date plus days supply and the first prescription date. Variable MPR was evaluated for all patients and the continuously eligible cohort. Fixed MPR used the same numerator but divided by 365 days of follow-up and evaluated only for the continuously eligible cohort. RESULTS: There were 3405 patients with MS and a disease-modifying drug claim in 2007 and 2145 in the continuously eligible cohort. Means for variable MPR ranged from 87.5% +/- 16.6% for the continuously eligible cohort to 90.5% +/- 16.0% for the 2007 cohort. The comparable value for fixed MPR was 78.0% +/- 28.2% for the continuously eligible cohort. Fixed MPR gave a consistently lower rate of adherence than variable MPR at an 80% adherence threshold. CONCLUSION: Different adherence measures can yield different outcomes, especially when using different eligibility criteria. These results demonstrate the importance of full disclosure of methods used for calculations and specification of the study population. PMID- 23807839 TI - Qualitative study of the quality of sleep in marginalized individuals living with HIV. AB - Sleep disturbances have been reported to be higher in human immunodeficiency virus (HIV)-infected individuals compared to the general population. Despite the consequences of poor quality of sleep (QOS), research regarding sleep disturbances in HIV infection is lacking and many questions regarding correlates of poor QOS, especially in marginalized populations, remain unanswered. We conducted one-on-one qualitative interviews with 14 marginalized HIV-infected individuals who reported poor QOS to examine self-reported correlates of sleep quality and explore the relationship between QOS and antiretroviral adherence. Findings suggest a complex and multidimensional impact of mental health issues, structural factors, and physical conditions on QOS of these individuals. Those reporting poor QOS as a barrier to antiretroviral adherence reported lower adherence due to falling asleep or feeling too tired to take medications in comparison to those who did not express this adherence barrier. These interviews underscore the importance of inquiries into a patient's QOS as an opportunity to discuss topics such as adherence, depression, suicidal ideation, and substance use. PMID- 23807838 TI - Osteoporosis - a current view of pharmacological prevention and treatment. AB - Postmenopausal osteoporosis is the most common bone disease, associated with low bone mineral density (BMD) and pathological fractures which lead to significant morbidity. It is defined clinically by a BMD of 2.5 standard deviations or more below the young female adult mean (T-score =-2.5). Osteoporosis was a huge global problem both socially and economically - in the UK alone, in 2011 L6 million per day was spent on treatment and social care of the 230,000 osteoporotic fracture patients - and therefore viable preventative and therapeutic approaches are key to managing this problem within the aging population of today. One of the main issues surrounding the potential of osteoporosis management is diagnosing patients at risk before they develop a fracture. We discuss the current and future possibilities for identifying susceptible patients, from fracture risk assessment to shape modeling and in relation to the high heritability of osteoporosis now that a plethora of genes have been associated with low BMD and osteoporotic fracture. This review highlights the current therapeutics in clinical use (including bisphosphonates, anti-RANKL [receptor activator of NF kappaB ligand], intermittent low dose parathyroid hormone, and strontium ranelate) and some of those in development (anti-sclerostin antibodies and cathepsin K inhibitors). By highlighting the intimate relationship between the activities of bone forming (osteoblasts) and bone-resorbing (osteoclasts) cells, we include an overview and comparison of the molecular mechanisms exploited in each therapy. PMID- 23807841 TI - Using tablet computers compared to interactive voice response to improve subject recruitment in osteoporosis pragmatic clinical trials: feasibility, satisfaction, and sample size. AB - INTRODUCTION: Pragmatic clinical trials (PCTs) provide large sample sizes and enhanced generalizability to assess therapeutic effectiveness, but efficient patient enrollment procedures are a challenge, especially for community physicians. Advances in technology may improve methods of patient recruitment and screening in PCTs. Our study looked at a tablet computer versus an integrated voice response system (IVRS) for patient recruitment and screening for an osteoporosis PCT in community physician offices. MATERIALS AND METHODS: We recruited women >= 65 years of age from community physician offices to answer screening questions for a hypothetical osteoporosis active comparator PCT using a tablet computer or IVRS. We assessed the feasibility of these technologies for patient recruitment as well as for patient, physician, and office staff satisfaction with the process. We also evaluated the implications of these novel recruitment processes in determining the number of primary care practices and screened patients needed to conduct the proposed trial. RESULTS: A total of 160 women (80% of those approached) agreed to complete the osteoporosis screening questions in ten family physicians' offices. Women using the tablet computer were able to complete all screening questions consistently and showed a nonsignificant trend towards greater ease of use and willingness to spend more time in their physician's office compared to those using IVRS. Using the proportion of women found to be eligible in this study (almost 20%) and other eligibility scenarios, we determined that between 240 and 670 community physician offices would be needed to recruit ample patients for our hypothetical study. CONCLUSION: We found good satisfaction and feasibility with a tablet computer interface for the recruitment and screening of patients for a hypothetical osteoporosis PCT in community office settings. In addition, we used this experience to estimate the number of research sites needed for such a study. PMID- 23807842 TI - Phenomenological perspectives on self-care in aging. AB - Self-care is a central concept in health care and may be considered as a means to maintain, restore, and improve one's health and well-being. When performed effectively, self-care contributes not only to human functioning but also to human structural integrity and human development (ie, to a dynamic and holistic state of health). Self-care as a clinical concept is relevant for health care professionals, and it should be meaningful to investigate it at a philosophical level and to further elaborate upon this concept. The aim of this article is to discuss and elaborate upon a phenomenological perspective on self-care in aging that is relevant for the health sciences. Self-care may be preliminarily regarded as a fundamental perspective for the conscious older individual, and as a way of being in the world with both the objective body and with the lived body. The lived body is the personal center of perception and the field of action, and it is also the center of self-care. The potentiality or ability for self-care activity and self-care activity itself are structures given to perception, with self-care ability as an integral part of the lived body. The actualization of self-care ability comes about through a certain meaning, which can be regarded as an important driving force. It is constituted by communication, a healthy lifestyle, and by building meaning and socializing. Successful self-care involves having contacts with the health care system, being conscious of a sound lifestyle, being physically and mentally active, being engaged, having social contacts with family and others, as well as being satisfied, positive, and being able to look forward. One fundamental cornerstone is serenity on behalf of the individual. Self-care can facilitate transitions, and it may also be an outcome of transitions. PMID- 23807843 TI - Nutritional self-care in two older Norwegian males: a case study. AB - BACKGROUND: Knowledge about how to support nutritional self-care in the vulnerable elderly living in their own homes is an important area for health care professionals. The aim of this case study was to evaluate the effects of nutritional intervention by comparing perceived health, sense of coherence, self care ability, and nutritional risk in two older home-dwelling individuals before, during, and after intervention and to describe their experiences of nutritional self-care before and after intervention. METHODS: A study circle was established to support nutritional self-care in two older home-dwelling individuals (>=65 years of age), who participated in three meetings arranged by health professionals over a period of six months. The effects of this study circle were evaluated using the Nutritional Form For the Elderly, the Self-care Ability Scale for the Elderly (SASE), the Appraisal of Self-care Agency scale, the Sense of Coherence (SOC) scale, and responses to a number of health-related questions. Qualitative interviews were performed before and after intervention to interpret the changes that occurred during intervention. RESULTS: A reduced risk of undernutrition was found for both participants. A higher total score on the SASE was obtained for one participant, along with a slightly stronger preference for self-care to maintain sufficient food intake, was evident. For the other participant, total score on the SASE decreased, but the SOC score improved after intervention. Decreased mobility was reported, but this did not influence his food intake. The study circle was an opportunity to express personal views and opinions about food intake and meals. CONCLUSION: An organized meeting place for dialogue between older home-dwelling individuals and health care professionals can stimulate the older person's engagement, consciousness, and learning about nutritional self-care, and thereby be of importance in reducing the risk of undernutrition. PMID- 23807844 TI - Evaluation of clinical pharmacist recommendations in the geriatric ward of a Belgian university hospital. AB - OBJECTIVE: To evaluate the type, acceptance rate, and clinical relevance of clinical pharmacist recommendations at the geriatric ward of the Ghent university hospital. METHODS: The clinical pharmacist evaluated drug use during a weekly 2 hour visit for a period of 4 months and, if needed, made recommendations to the prescribing physician. The recommendations were classified according to type, acceptance by the physician, prescribed medication, and underlying drug-related problem. Appropriateness of prescribing was assessed using the Medication Appropriateness Index (MAI) before and after the recommendations were made. Two clinical pharmacologists and two clinical pharmacists independently and retrospectively evaluated the clinical relevance of the recommendations and rated their own acceptance of them. RESULTS: The clinical pharmacist recommended 304 drug therapy changes for 100 patients taking a total of 1137 drugs. The most common underlying drug-related problems concerned incorrect dose, drug-drug interaction, and adverse drug reaction, which appeared most frequently for cardiovascular drugs, drugs for the central nervous system, and drugs for the gastrointestinal tract. The most common type of recommendation concerned adapting the dose, and stopping or changing a drug. In total, 59.7% of the recommendations were accepted by the treating physician. The acceptance rate by the evaluators ranged between 92.4% and 97.0%. The mean clinical relevance of the recommendations was assessed as possibly important (53.4%), possibly low relevance (38.1%), and possibly very important (4.2%). A low interrater agreement concerning clinical relevance between the evaluators was found: kappa values ranged between 0.15 and 0.25. Summated MAI scores significantly improved after the pharmacist recommendations, with mean values decreasing from 9.3 to 6.2 (P < 0.001). CONCLUSION: In this study, the clinical pharmacist identified a high number of potential drug-related problems in older patients; however, the acceptance of the pharmacotherapy recommendations by the treating physician was lower than by a panel of evaluators. This panel, however, rated most recommendations as possibly important and as possibly having low relevance, with low interrater reliability. As the appropriateness of prescribing seemed to improve with decreased MAI scores, clinical pharmacy services may contribute to the optimization of drug therapy in older inpatients. PMID- 23807846 TI - Synergistic effects of 5-aminolevulinic acid based photodynamic therapy and celecoxib via oxidative stress in human cholangiocarcinoma cells. AB - 5-Aminolevulinic acid (ALA)-based photodynamic therapy (PDT) has the potential to kill cancer cells via apoptotic or necrotic signals that are dependent on the generation of intracellular reactive oxygen species (ROS). Celecoxib is an anti inflammatory drug that induces intracellular ROS generation. We investigated whether the combined application of celecoxib and ALA-PDT improved the efficacy of PDT in human cholangiocarcinoma cells and in tumor bearing mice. In vitro, combined treatment of celecoxib and ALA-PDT increased phototoxicity and intracellular ROS levels after irradiation with 0.75 J/cm(2) when compared to ALA PDT alone. Even though ROS levels increased with 0.25 J/cm(2) of irradiation, it did not influence phototoxicity. When heme oxygenase-1, a defensive protein induced by oxidative stress, was inhibited in the combined treatment group, phototoxicity was increased at both 0.25 J/cm(2) and 0.75 J/cm(2) of irradiation. We identified the combined effect of ALA-PDT and celecoxib through the increase of oxidative stress such as ROS. In vivo, about 40% tumor growth inhibition was observed with combined application of ALA-PDT and celecoxib when compared to ALA PDT alone. The combined application of ALA-PDT and celecoxib could be an effective therapy for human cholangiocarcinoma. Moreover, use of a heme oxygenase 1 inhibitor with PDT could play an important role for management of various tumors involving oxidative stress. PMID- 23807847 TI - Non-ionic surfactant vesicles simultaneously enhance antitumor activity and reduce the toxicity of cantharidin. AB - OBJECTIVE: The objective of the present study was to prepare cantharidin entrapped non-ionic surfactant vesicles (CTD-NSVs) and evaluate their potential in enhancing the antitumor activities and reducing CTD's toxicity. METHODS AND RESULTS: CTD-NSVs were prepared by injection method. 3-(4,5-Dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide assay and flow cytometry analysis showed that CTD NSVs could significantly enhance in vitro toxicity against human breast cancer cell line MCF-7 and induce more significant cell-cycle arrest in G0/G1 phase. Moreover, Hoechst 33342 staining implicated that CTD-NSVs induced higher apoptotic rates in MCF-7 cells than free CTD solution. In vivo therapeutic efficacy was investigated in imprinting control region mice bearing mouse sarcoma S180. Mice treated with 1.0 mg/kg CTD-NSVs showed the most powerful antitumor activity, with an inhibition rate of 52.76%, which was significantly higher than that of cyclophosphamide (35 mg/kg, 40.23%) and the same concentration of free CTD (1.0 mg/kg, 31.05%). In addition, the acute toxicity and liver toxicity of CTD were also distinctly decreased via encapsulating into NSVs. CONCLUSION: Our results revealed that NSVs could be a promising delivery system for enhancing the antitumor activity and simultaneously reducing the toxicity of CTD. PMID- 23807848 TI - Movement disorder profile and treatment outcomes in a one-year study of patients with schizophrenia. AB - BACKGROUND: This study identified subgroups of patients with schizophrenia who differed on their movement disorder profile and compared their treatment outcomes. METHODS: Data from a randomized, open-label, one-year study of patients with schizophrenia who were treated with antipsychotics in usual clinical care settings were analyzed (n = 640). Five measures of movement disorder were incorporated into a single Movement Disorder Index (MDI). Subgroups that differed in their movement disorder profile over the one-year study period were compared on clinical and functional outcomes. RESULTS: THREE SUBGROUPS WERE IDENTIFIED: a worsening of MDI in 15% of patients, an improvement in 33%, and no change in 53%. Compared with the other two subgroups, the MDI-worsened subgroup had poorer symptom improvement measured by the Positive and Negative Syndrome Scale (PANSS) total score (mean changes of -11.0, -18.4, and -16.8 for the patients who had a worsening of MDI, no change, and an improvement, respectively), poorer symptom improvement on the PANSS positive and anxiety/depression subscale scores, worsening on the 36-Item Short Form Health Survey (SF-36) physical component summary score, and a higher rate of hospitalization (P < 0.05). CONCLUSION: Patients with schizophrenia who experience worsening of their MDI score appear to have poorer clinical and functional outcomes, suggesting that such worsening may be a marker of poorer prognosis. PMID- 23807849 TI - A randomized, 4-week double-blind placebo control study on the efficacy of donepezil augmentation of lithium for treatment of acute mania. AB - INTRODUCTION: A significant number of mania patients fail to respond to current pharmacotherapy, thereby there is need for novel augmentation strategies. The results of some early studies showed the effectiveness of cholinomimetics in the treatment of mania. One open case series suggested the efficacy of donepezil in the treatment of bipolar disorder. Our aim was to explore whether an oral cholinesterase inhibitor, donepezil, administered during a 4-week treatment period, would benefit patients with acute mania. METHODS: We conducted a 4-week double-blind, placebo-controlled trial of donepezil as an adjunctive treatment to lithium in patients with acute mania. Eligible subjects were randomly assigned to receive donepezil or placebo in addition to lithium. Donepezil was started at 5 mg/day, and increased to 10 mg/day in the first week. Patients were rated with the Young Mania Rating Scale (YMRS) and Brief Psychiatric Rating Scale (BPRS) at baseline, day 1, week 1, week 2, and week 4. RESULTS: Out of the 30 patients who were enrolled, 15 were on donepezil and 15 were on placebo. All patients completed the 4-week trial. On the first day, there was a difference of 1.97 units on the psychomotor symptoms scale of the YMRS in the donepezil group as compared to the placebo group (t = 2.39, P = 0.02). There was a difference of 0.57 units (t = 2.09, P = 0.04) in the speech item and a difference of 0.29 units in the sexual interest item (t = 2.11, P = 0.04) in the donepezil group as compared to the placebo group. The total YMRS difference on the first day approached the conventional significance level (1.97 units, t = 1.84, P = 0.07). Over the course of 4 weeks, we failed to find that donepezil produced any significant difference in the YMRS (6.71 units difference, t = -1.44, P = 0.16) or the BPRS scale (1.29 units difference, t = -0.33, P = 0.75) as compared to placebo. Ten subjects (66.67%) in both groups met the criteria for clinical response (Fisher's exact P = 1.00). Five subjects (33.33%) in the donepezil group met the criteria for clinical remission while nine subjects (60.00%) in the placebo group met the remission criteria (Fisher's exact P = 0.27). CONCLUSION: Use of the oral anticholinergic donepezil had some benefit in the augmentation of lithium treatment on the first day, but did not provide any significant benefits in the long-term. PMID- 23807850 TI - Elevated factor VIII level and stroke in patients without traditional risk factors associated with cardiovascular diseases. AB - INTRODUCTION: Hemostasis is affected by interactions between physiological processes, including those connected with the coagulation system, whose essence is converting fibrinogen into fibrin. The role of factor VIII (FVIII) consists in activating factor X, which directly participates in the generation of thrombin, which is able to produce stable fibrin, which in turn forms blood clots. There are divergent opinions regarding the significance of high levels of FVIII in stroke pathogenesis. AIM: The aim of our study was to evaluate FVIII activity in individuals with cryptogenic stroke in order to determine a potential relationship between it and cerebral ischemia. MATERIAL AND METHODS: NINE PATIENTS SUFFERING WITH STROKE WERE USED IN THIS STUDY: six women and three men aged 49-63 years. In all of the patients, the presence of known and potential risk factors for stroke had been excluded during previous diagnostic procedures. These patients accounted for 1.2% of the 719 people who suffered a stroke and were hospitalized in 2011 at the Stroke Unit. FVIII activity was examined in each of the nine qualified subjects within 1-2 months of the occurrence of stroke (the first test) and repeated (the second test) in five patients with abnormal results obtained from the first examination. RESULTS: Increased activity of FVIII was found in 5 out of 9 patients. In patients with abnormal results, elevated FVIII was found in follow-up examinations in the 8th-10th month following stroke. Hemodynamic abnormalities in carotid or cerebral artery (presence of thrombus) were found in 3 of the 5 patients with increased FVIII levels. In the first 24 hours following stroke the neurological state of patients with abnormal FVIII was worse than individuals with normal FVIII activity. The patients with abnormal FVIII levels were found to be more disabled in the examination of self-dependence on the 90th day after stroke. CONCLUSION: When searching for the causes of stroke, it is worth examining the coagulation system, including FVIII concentration, the abnormality of which may play a significant part in brain ischemia. More research is needed to determine the relationship between abnormal FVIII activity and stroke. PMID- 23807851 TI - Persistent middle cerebral artery occlusion associated with lower body temperature on admission. AB - BACKGROUND: Low body temperature is considered neuroprotective in ischemic stroke, yet some studies suggest that low body temperature may also inhibit clot lysis and recanalization. We hypothesized that low body temperature was associated with persistent proximal middle cerebral artery (MCA) occlusion in patients with acute ischemic stroke presenting with symptoms of proximal MCA occlusion, suggesting a possible detrimental effect of low body temperature on recanalization. METHODS: All patients with acute ischemic stroke admitted to our Stroke Unit between February 2006 and August 2012 were prospectively registered in a database. Computed tomography (CT) angiography was performed in patients admitted <6 hours after stroke onset. Based on presenting symptoms, patients were classified according to the Oxford Community Stroke Project classification (OCSP). Patients with symptomatic proximal MCA occlusion were compared to patients with total anterior circulation infarct (TACI) without MCA occlusion on CT angiography. RESULTS: During the study period, 384 patients with acute ischemic stroke were examined with CT angiography. A total of 79 patients had proximal MCA occlusion and 31 patients had TACI without MCA occlusion. Median admission body temperatures were lower in patients with MCA occlusion compared to patients without occlusion (36.3 degrees C versus 36.7 degrees C, P = 0.027). Admission body temperature <36.5 degrees C was independently associated with persistent MCA occlusion when adjusted for confounders in multivariate analyses (odds ratio 3.7, P = 0.007). CONCLUSION: Our study showed that low body temperature on admission was associated with persistent proximal MCA occlusion. These results may support a possible detrimental effect of low body temperature on clot lysis and recanalization. PMID- 23807854 TI - Approaches to the detection of recessive effects using next generation sequencing data from outbred populations. AB - Conventional methods to analyze genome-wide association studies and whole exome or whole genome sequencing studies would be prone to overlook variants which might exert a recessive effect on risk of disease, either as homozygotes or compound heterozygotes. It is plausible that such effects may be common even in outbred populations. An approach is described which is based on identifying a set of variants in a gene as being potentially of interest and then testing whether there is an excess of cases who are either homozygotes or complex heterozygotes for these variants. Methods based on departure from Hardy-Weinberg equilibrium are more powerful than those which compare cases to controls. However, linkage disequilibrium between variants can be difficult to deal with if phase is unknown. A simple approach for discarding variants apparently in strong linkage disequilibrium with others is proposed. The procedure is simple and quick to apply so can be used in the context of whole genome or exome sequencing studies and is implemented in the SCOREASSOC program. PMID- 23807853 TI - Measurement of exhaled alveolar nitrogen oxide in patients with lung cancer: a friend from the past still precious today. AB - Nitric oxide (NO) is a marker of airway inflammation and indirectly a general indicator of inflammation and oxidative stress. NO is a contributing factor in lung cancer at an early stage and also after chemotherapy treatment of lung cancer. We studied whether exhaled NO levels were altered by three cycles of chemotherapy at diagnosis and after chemotherapy, and whether, directly or indirectly, these changes were related to the course of disease. Also, a correlation of NO levels with other markers of inflammation was performed. We studied 42 patients diagnosed early: 26 men and 16 women with lung cancer. We analyzed blood tests for control of inflammatory markers, functional pulmonary tests, and alveolar exhaled NO. We recorded a decrease in exhaled NO after three cycles of chemotherapy in all patients, regardless of histological type and stage: there were 42 patients with mean 9.8 NO after three cycles (average 7.7). Also, a strong correlation appeared between NO measurements before and after chemotherapy and C-reactive protein (P < 0.05, r = 0.42, before) and (P < 0.045, r = 0.64, after). NO alveolar measurement as an indicator of airway inflammation indicates response to chemotherapy in lung cancer. Also, the inflammatory process in lung cancer was confirmed and indicated response to chemotherapy through an index that is sensitive to inflammatory disease of the airways. PMID- 23807852 TI - Statins in heart failure: do we need another trial? AB - Statins lower serum cholesterol and are employed for primary and secondary prevention of cardiovascular events. Clinical evidence from observational studies, retrospective data, and post hoc analyses of data from large statin trials in various cardiovascular conditions, as well as small scale randomized trials, suggest survival and other outcome benefits for heart failure. Two recent large randomized controlled trials, however, appear to suggest statins do not have beneficial effects in heart failure. In addition to lowering cholesterol, statins are believed to have many pleotropic effects which could possibly influence the pathophysiology of heart failure. Following the two large trials, evidence from recent studies appears to support the use of statins in heart failure. This review discusses the role of statins in the pathophysiology of heart failure, current evidence for statin use in heart failure, and suggests directions for future research. PMID- 23807855 TI - Medical technology as a key driver of rising health expenditure: disentangling the relationship. AB - Health care spending has risen steadily in most countries, becoming a concern for decision-makers worldwide. Commentators often point to new medical technology as the key driver for burgeoning expenditures. This paper critically appraises this conjecture, based on an analysis of the existing literature, with the aim of offering a more detailed and considered analysis of this relationship. Several databases were searched to identify relevant literature. Various categories of studies (eg, multivariate and cost-effectiveness analyses) were included to cover different perspectives, methodological approaches, and issues regarding the link between medical technology and costs. Selected articles were reviewed and relevant information was extracted into a standardized template and analyzed for key cross-cutting themes, ie, impact of technology on costs, factors influencing this relationship, and methodological challenges in measuring such linkages. A total of 86 studies were reviewed. The analysis suggests that the relationship between medical technology and spending is complex and often conflicting. Findings were frequently contingent on varying factors, such as the availability of other interventions, patient population, and the methodological approach employed. Moreover, the impact of technology on costs differed across technologies, in that some (eg, cancer drugs, invasive medical devices) had significant financial implications, while others were cost-neutral or cost saving. In light of these issues, we argue that decision-makers and other commentators should extend their focus beyond costs solely to include consideration of whether medical technology results in better value in health care and broader socioeconomic benefits. PMID- 23807856 TI - Neurological manifestations in children with Sanjad-Sakati syndrome. AB - BACKGROUND: Sanjad-Sakati syndrome (SSS), also known as hypoparathyroidism-mental retardation-dysmorphism syndrome, or HRD, is a rare disorder characterized by growth and developmental delay, and by mental retardation and dysmorphic features. OBJECTIVE: The objective of this study was to clarify the clinical and neurological features of SSS. PATIENTS: Twenty-four patients were included in the study. They were seen at two hospitals in Kuwait. METHODS: This was a retrospective study of patients with SSS who attended the pediatric endocrinology, genetic, and neurology clinics in the Aladan and Alfarawanya hospitals in Kuwait from September 2007 to September 2012. Clinical and radiological data were obtained from each patient's medical records. RESULTS: All 24 patients had the characteristic dysmorphic features and laboratory findings of SSS. Consanguinity was reported in 75% of parents. Neurological manifestations in the form of microcephaly, developmental delay, mental retardation, and seizures were reported in all patients. Computerized tomography scans and/or magnetic resonance imaging showed evidence of intracranial calcifications in 29.2% of patients. Two patients showed a thin corpus callosum, and one patient showed intraventricular hemorrhaging. CONCLUSION: Patients with SSS display a variety of dysmorphic features and neurological manifestations, including microcephaly, mental retardation, intracranial calcification, and epilepsy. PMID- 23807857 TI - Gastrointestinal morphological alterations in obese rats kept under hypercaloric diets. AB - Hypercaloric diets have been successfully used as experimental models of obesity. This work compared morphological characteristics of inferior gastrointestinal organs. The experiment lasted 10 weeks, during which the rats' food consumption, body weight, distance between the mouth and neck, distance between mouth and neck, distance between neck and tail, and abdominal circumference were evaluated weekly. After the sacrifice of the rats, 20 variables referring to inferior gastrointestinal morphology were assessed. The results comprised descriptive statistics of the data, analysis of main components, linear correlation, and t tests. Significant differences were found between the two groups for the variables of abdominal circumference, retroperitoneal fat, ratio between retroperitoneal fat/animal weight, stomach weight, ratio between animal weight/intestine weight and mesentery/animal weight, length of small intestine, length of large intestine, and lateral line of the cecum. The data allow us to state that a hypercaloric diet can be responsible an increase in fat in the abdominal cavity as well as gastrointestinal morphological alterations, principally in stomach development. PMID- 23807858 TI - Evaluation of coagulation parameters and liver enzymes among alcohol drinkers in Port Harcourt, Nigeria. AB - Alcohol is a major contributor to the global burden of disease, disability, and death in high, middle, and low-income countries. Harmful use of alcohol is one of the main factors contributing to premature deaths and avoidable disease burden worldwide and has a major impact on public health. The aim of this present cross sectional study was to investigate the effect of alcohol consumption on coagulation parameters and liver enzymes of subjects in Port Harcourt, Nigeria. Two hundred adults consisting of 120 alcohol dependent subjects and 80 age, gender-matched nondrinkers aged 25-65 years (mean age 45.25 +/- 11.50 years) were enrolled in this study. Of the 120 chronic alcohol drinkers, 37 were dependent on local dry gin, while 83 were dependent on other alcoholic beverages. The mean values of the liver enzymes, aspartate aminotransferase and gamma glutamyl transferase, were significantly higher (P = 0.002 and P = 0.02 respectively) among the chronic alcohol consumers compared with their nondrinker counterparts. Although the value of alanine aminotransferase was higher in the chronic drinkers, it did not reveal any significant difference (P = 0.11). The coagulation parameters, prothrombin time and activated partial thromboplastin time were investigated among chronic drinkers and nondrinkers. The mean value of prothrombin time and activated partial thromboplastin time was significantly higher in the chronic alcohol drinkers compared to the nondrinkers (P = 0.04 and P = 0.02 respectively). We observed a positive and significant correlation between values of liver enzymes, serum gamma glutamyl transferase and aspartate aminotransferase, and values of prothrombin time among alcohol consumers (r = 0.72 and r = 0.68 respectively). The implementation of policies to target harm reduction strategies among alcoholics is urgently needed, alongside the building of a strong base of public awareness and community support required for the continuity and sustainability of alcohol policies. There is also the need for the Nigerian government to enforce tighter regulations and restrictions on the production and distribution of alcoholic beverages to reduce harmful use, and protect young people and other vulnerable groups. PMID- 23807859 TI - Azilsartan/chlorthalidone combination therapy for blood pressure control. AB - BACKGROUND: Edarbyclor((r)) is a combined angiotensin receptor blocker (ARB) and thiazide-like diuretic (azilsartan and chlorthalidone), and was approved on December 20, 2011 by the US Food and Drug Administration (FDA) for hypertension management. OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, safety, tolerability, and role of azilsartan plus chlorthalidone for hypertension management. METHODS: Peer-reviewed clinical trials, review articles, and relevant treatment guidelines, were identified from the databases MEDLINE and Current Contents (both 1966 to February 15, 2013, inclusive) using search terms "azilsartan", "chlorthalidone", "pharmacology", "pharmacokinetics", "pharmacodynamics", "pharmacoeconomics", and "cost-effectiveness". The FDA website, as well as manufacturer prescribing information, was also reviewed to identify other relevant information. RESULTS: Azilsartan is a new ARB with high affinity for the angiotensin 1 receptor, approved by the FDA for hypertension management. Unlike other ARBs, azilsartan has no clinical data supporting improvement in cardiovascular outcomes, and is not approved for indications other than hypertension, which a select few other ARBs may be used for (eg, diabetic nephropathy and heart failure). Chlorthalidone is a longer acting thiazide-like diuretic that has been demonstrated to improve cardiovascular outcomes. Combination treatment with azilsartan/chlorthalidone is effective for reducing blood pressure. Compared to olmesartan/hydrochlorothiazide and azilsartan/hydrochlorothiazide combinations, azilsartan/chlorthalidone appears to be more efficacious for reducing blood pressure. CONCLUSIONS: Azilsartan/chlorthalidone can be considered an antihypertensive therapy option in patients for whom combination therapy is required (blood pressure >20 mmHg systolic or >10 mmHg diastolic above goal). Cost to patients and insurance coverage will probably determine whether azilsartan/chlorthalidone will be the most appropriate combination therapy for an individual patient. PMID- 23807860 TI - Long-acting nifedipine for hypertensive patients in the Middle East and Morocco: observations on efficacy and tolerability of monotherapy or combination therapy. AB - BACKGROUND: The Middle Eastern and North African region of developing countries is associated with poor rates of blood pressure (BP) control and antihypertensive prescribing patterns. This post hoc analysis of data from an international observational study aimed to investigate the efficacy and tolerability of long acting nifedipine (30 mg or 60 mg; monotherapy or in combination) in the Middle Eastern and Moroccan populations defined as having high cardiovascular risk. METHODS: This was a prospective, noninterventional, multicenter observational study. Observations from patients (aged >= 18 years) with treated or untreated hypertension from the Middle East (Jordan, Saudi Arabia, Kuwait, Lebanon, Qatar, United Arab Emirates, and Yemen) and Morocco are presented. Hypertension grade and cardiovascular risk were defined at baseline, and systolic/diastolic BP change was defined at post-baseline visits (<=3). Adverse events and ratings of therapy efficacy and patient/physician satisfaction were recorded. RESULTS: The study included 1466 patients from the Middle East and 524 from Morocco. Characteristics of the populations differed, with a more severe hypertension profile in Moroccan patients. Despite these differences, nifedipine reduced BP to a similar extent in each group, with efficacy dependent on cardiovascular risk factors such as hypertension grade and age. Few adverse drug reactions occurred and nifedipine was well-tolerated in both populations. Efficacy and satisfaction with therapy were rated highly. CONCLUSION: Good rates of BP control were observed with nifedipine in patients with moderate-to-severe hypertension and high added risk. Published data in these countries suggest poor antihypertensive prescribing patterns and BP control; these data confirm this trend and suggest that suboptimal dosing may be prevalent. PMID- 23807861 TI - Anti-VEGF agents in metastatic colorectal cancer (mCRC): are they all alike? AB - Bevacizumab is a monoclonal antibody that binds and neutralizes vascular endothelial growth factor (VEGF)-A, a key player in the angiogenesis pathway. Despite benefits of bevacizumab in cancer therapy, it is clear that the VEGF pathway is complex, involving multiple isoforms, receptors, and alternative ligands such as VEGF-B, and placental growth factor, which could enable escape from VEGF-A-targeted angiogenesis inhibition. Recently developed therapies have targeted other ligands in the VEGF pathway (eg, aflibercept, known as ziv aflibercept in the United States), VEGF receptors (eg, ramucirumab), and their tyrosine kinase signaling (ie, tyrosine kinase inhibitors). The goal of the current review was to identify comparative preclinical data for the currently available VEGF-targeted therapies. Sources were compiled using PubMed searches (2007 to 2012), using search terms including, but not limited to: "bevacizumab," "aflibercept," "ramucirumab," and "IMC-18F1." Two preclinical studies were identified that compared bevacizumab and the newer agent, aflibercept. These studies identified some important differences in binding and pharmacodynamic activity, although the potential clinical relevance of these findings is not known. Newer antiangiogenesis therapies should help further expand treatment options for colorectal and other cancers. Comparative preclinical data on these agents is currently lacking. PMID- 23807862 TI - Community attitude towards the reproductive rights and sexual life of people living with HIV/AIDS in Olorunda Local Government Area, Osogbo, Nigeria. AB - BACKGROUND: Globally, the Human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic remains a major public health problem. In most countries in sub-Saharan Africa, HIV/AIDS has already reversed the post independence developmental gains. PURPOSE: This study assessed community attitudes regarding the reproductive rights and sexual life of people living with HIV/AIDS (PLWHA) in Olorunda Local Government Area of Osun State, Southwestern Nigeria. DESIGN AND METHODS: In a community-based descriptive cross-sectional study, the sample size calculation was based on the assumption that 67% of the target population has a negative attitude regarding the reproductive rights of PLWHA; a confidence interval (CI) of 95% was used. A minimum sample size of 340 was obtained using the formula n = Z(2)pq/d(2). An anticipated 10% nonresponse rate was added to obtain a sample size of 374; a multistage sampling technique was utilized to select a total of 450 respondents. Data collected through a semistructured standardized and pretested questionnaire were analyzed using Statistical Package for Social Sciences software, version 15. RESULTS: The study revealed that 283 (66.6%) and 142 (33.4%) of respondents were urban and rural dwellers, respectively. Mean age of respondents was 28.7 years +/- 2.2 years. Four hundred and two (94.6%) respondents were aware of HIV/AIDS, and 88.7% had knowledge of at least six different modes of HIV/AIDS transmission. About 30.7% of respondents had discriminatory and stigmatizing attitudes towards PLWHA, and 50.9% and 44.8% had negative attitudes towards their sexual and reproductive rights, respectively. There were significant associations between gender, marital status, educational status, occupation, and residential area of respondents and their attitude towards the reproductive and sexual right of PLWHA (P < 0.05). CONCLUSION AND RECOMMENDATION: Discriminatory and stigmatizing attitudes to PLWHA found among respondents translated into a negative attitude regarding the reproductive and sexual rights of PLWHA. There is an urgent need to institute programs for raising community awareness about the rights of PLWHA, especially in rural areas, and to strengthen legislative provisions for protecting and preserving the reproductive rights of PLWHA. PMID- 23807863 TI - Some hemostatic parameters in women with obstetric hemorrhage in Sokoto, Nigeria. AB - Obstetric hemorrhage is the leading cause of maternal mortality and morbidity worldwide. This study was carried out to investigate the effect of obstetric hemorrhage on the prothrombin time (PT), activated partial thromboplastin time (APTT), and platelet count (PLC). Women with obstetric hemorrhage were divided into two categories, women with antepartum hemorrhage (APH) and those with postpartum hemorrhage (PPH). Pregnant women without hemorrhage were included as controls. Eighty-six pregnant women aged 18-45 years (mean age 36.25 +/- 10.50 years) were presented to the Obstetrics and Gynaecology Department of Maryam Abacha Women and Children Hospital in Sokoto Metropolis, Sokoto State, Nigeria with history of obstetric hemorrhage. Forty-three age-matched nonhemorrhaging parturient women were included as controls. The determination of PT and APTT was done by manual methods using commercially prepared Diagen reagent kits, whereas PLC was done by manual methods using a hemocytometer. The results of PT and APTT were significantly higher among women with APH (20.7 +/- 4.226 seconds and 46.04 +/- 8.689 seconds, respectively) and among women with PPH (23.17 +/- 2.708 seconds and 53.78 +/- 4.089 seconds, respectively) compared to normal pregnant women (15.85 +/- 0.8930 seconds and 36.225 +/- 5.010 seconds, respectively) (P = 0.0001). Similarly, the PLC was significantly higher among normal pregnant women compared to those with APH and PPH (291.425 +/- 75.980 * 10(9) compared to 154.83 +/- 47.019 * 10(9) and 136.43 +/- 43.894 * 10(9), respectively) (P = 0.0001). The PT and APTT of women who presented with PPH were significantly higher compared to those who presented with APH (23.17 +/- 2.708 seconds and 53.78 +/- 4.089 seconds versus 20.7 +/- 4.226 seconds and 46.04 +/- 8.689 seconds, respectively) (P = 0.02 and P = 0.04, respectively). The PLC was significantly higher among women who presented with APH compared to those who presented with PPH (P = 0.01). The PT and APTT values were higher in the third trimester among women with APH (24.38 +/- 2.33 seconds and 52.25 +/- 6.71 seconds, respectively), PPH (24.75 +/- 2.63 seconds and 58.25 +/- 2.53 seconds, respectively), and control women (16.00 +/- 0.82 seconds and 34.42 +/- 5.59 seconds, respectively) compared to those in first and second trimester. The PLC was significantly lower in the third trimester among APH, PPH, and normal pregnant women (131 +/- 23.02 * 10(9), 99 +/- 21.46 * 10(9), and 192.86 +/- 25.44 * 10(9), respectively). PT and APTT values correlated positively and significantly with trimester (r = 0.52 and 0.65, respectively; P = 0.01). The PLC of women with APH, PPH, and normal control women correlated negatively with trimester (r = -0.36, -0.54, and -0.28, respectively; P = 0.05). Obstetrics hemorrhage compounded the hemostatic status of pregnant women in Sokoto, Nigeria. There is need for the provision of rapid diagnosis of coagulopathy to guide the provision of best therapeutic management options. PMID- 23807864 TI - Depressive symptoms of midlife Latinas: effect of immigration and sociodemographic factors. AB - Immigrant Latinas may have different cultural attitudes toward menopause and aging, and may experience higher levels of distress associated with adaptation to their new environment. The purpose of this secondary analysis was to describe the frequency of depressive symptoms experienced by premenopausal Latinas (40-50 years of age) living in the United States and compare Latinas born in the US with immigrant Latinas on stress and sociodemographic factors that influence depressive symptom experience. Analysis was conducted on a subsample of 94 self identified Latinas who participated in a longitudinal study and completed the Center for Epidemiological Studies-Depression (CES-D) scale at enrollment and 6 months. Immigrant Latinas had a significantly higher CES-D (14.4 +/- 11.1) than US-born Latinas (10.0 +/- 7.9) and the difference remained at 6 months. There was no difference in age, body mass index (BMI), self-report of general health, or perceived stress. Higher BMI, work-related stress, and insufficient income for essential daily needs were associated with depressive symptom scores in immigrant Latinas. High BMI and less education were associated with depressive symptom scores in the US-born Latinas. PMID- 23807865 TI - Iron stores in regular blood donors in Lagos, Nigeria. AB - BACKGROUND: Apart from challenging the bone marrow to increase its red cell production, thereby producing more blood for the donor, regular blood donation has been shown to have several benefits, one of which is preventing accumulation of body iron which can cause free radical formation in the body. This study was carried out to assess body iron stores in regular blood donors. METHODS: A total of 52 regular (study) and 30 first-time (control) volunteer blood donors were studied prospectively. Twenty milliliters of venous blood was drawn from each subject, 5 mL of which was put into sodium ethylenediamine tetra-acetic acid specimen bottles for a full blood count, including red blood cell indices. The remaining sample was allowed to clot in a plain container, and the serum was then retrieved for serum ferritin, serum iron, and serum transferrin receptor measurement by enzyme-linked immunosorbent assay. RESULTS: Mean hemoglobin and packed cell volume in the study group (13.47 +/- 2.36 g/dL and 42.00 +/- 7.10, respectively, P = 0.303) were not significantly higher than in the control group (12.98 +/- 1.30 g/dL and 39.76 +/- 4.41, respectively, P = 0.119). Mean serum ferritin was 102.46 +/- 80.26 ng/mL in the control group and 41.46 +/- 40.33 ng/mL in the study group (P = 0.001). Mean serum ferritin for women in the study group (28.02 +/- 25.00 ng/mL) was significantly lower than for women in the control group (56.35 +/- 34.03 ng/mL, P = 0.014). Similarly, men in the study group had a lower mean serum ferritin (48.57 +/- 45.17 ng/mL) than men in the control group (145.49 +/- 87.74 ng/mL, P = 0.00). The mean serum transferrin receptor value was higher in the study group (1.56 +/- 0.88 MUg/mL) than in the control group (1.19 +/- 0.38 MUg/mL, P = 0.033). CONCLUSION: These findings suggest that hemoglobin concentration, packed cell volume, and serum iron levels are not significantly affected by regular blood donation and that regular blood donors appear to have reduced iron stores compared with controls. PMID- 23807866 TI - Engaging community to support HIV prevention research. AB - Actively engaging communities in effective partnerships is considered critical for ethically robust and locally relevant HIV prevention research. This can be challenging in developing countries that have little prior experience in this area. This paper summarizes processes and lessons learnt while setting up the Community Involvement Plan of National AIDS Research Institute, Pune, India. Formal partnerships were established with voluntary agencies. The focus was on using strategies adapted from participatory learning and action techniques. The community program was implemented through peer educators specifically identified from the communities where partner non-governmental organizations function. At the grass root level, peer educators imparted education to the common people about research studies and helped to implement community based recruitment and retention activities. The focus was on facilitating periodic interaction between the outreach workers of the research team and the peers and modifying the strategies till they were found locally implementable and appropriate. Through adequate time investment, mutually beneficial and respectful partnerships with community based organizations and grass root level workers, the community became actively involved in clinical research. The program helped in developing a sense of partnership among the peers for the research conducted by the research organization, widening the net of community education and identification of research participants. By building trust in the community and implementing research within an ethical framework, culturally sensitive matters were appropriately addressed. The community involvement process is long, laborious and ever-evolving. Effective community engagement requires institutional leadership support, adequate funding and commitment by researchers. It is possible to sustain such a model in a resource limited setting. PMID- 23807867 TI - Ligand-dependent luminescence of ultra-small Eu3+-doped NaYF4 nanoparticles. AB - Pure cubic phase ultra-small alpha-NaYF4:4 % Eu3+ colloidal nanoparticles were synthesized by thermal decomposition reaction using three various capping ligands, i.e., oleic acid, trioctylphosphine oxide, and hexadecylamine. To expose as many Eu3+ ions as possible to interactions with the surface-bounded ligands, the nanoparticles were fabricated to have the diameters below 10 nm. The geometrical structure and properties of surface ligands needed for qualitative estimation of their influence on spectroscopic features of the investigated Eu3+ doped nanoparticles were obtained from DFT quantum-chemical calculations. Significant changes of luminescence spectra shapes and luminescence lifetime values were observed upon changes in the local chemical environment. We show that the ratio R = 5D0 -> 7F1/5D0 -> 7F2 of the intensities of the forced electric dipole (J = 2) and magnetic dipole (J = 1) transitions in the synthesized Eu3+ doped nanoparticles is highly sensitive to the type of ligand present on the nanoparticle surface. Similarly, 5D0 luminescence lifetimes are found to be sensitive to the refractive index, and also to the dielectric constant of ligands used during the synthesis to coat nanoparticles surface. We argue that the photophysical and electro-optical properties of colloidal Eu3+ doped inorganic nanoparticles show hyper-sensitive response to the chemical surroundings in the close vicinity of the nanoparticle itself. The behavior of both steady-state luminescence and its kinetics demonstrates the potential suitability of the studied nanoparticles for constructing self-referencing optical nano-sensors. PMID- 23807868 TI - Sweet taste perception not altered after acute sleep deprivation in healthy young men. AB - BACKGROUND: We hypothesized that acutely sleep-deprived participants would rate ascending concentrations of sucrose as more intense and pleasant, than they would do after one night of normal sleep. Such a finding would offer a potential mechanism through which acute sleep loss could promote overeating in humans. METHOD: A total of 16 healthy normal-weight men participated in 2 conditions: sleep (permitted between 22:30 and 06:30 h) and total sleep deprivation (TSD) respectively. On the morning after regular sleep and TSD, circulating concentrations of ghrelin and glucose were measured. In addition, participants hunger level was assessed by means of visual analogue scales, both before and after a caloric preload. Finally, following the preload, participants rated both intensity and pleasantness of six orally presented yogurt probes with varying sucrose concentrations (2-29 %). RESULTS: Feelings of hunger were significantly more intense under both fasted and sated conditions when subjects were sleep deprived. In contrast, the change in hunger induced by the preload was similar between the sleep and TSD conditions. Plasma concentrations of ghrelin were significantly higher under conditions of TSD, whereas plasma glucose did not differ between the conditions. No effects were found either on sweet taste intensity or on pleasantness after TSD. CONCLUSION: One night of TSD increases morning plasma concentrations of the hunger-promoting hormone ghrelin in healthy young men. In contrast, sweet taste perception was not affected by nocturnal wakefulness. This suggests that an altered sweet taste perception is an unlikely mechanism by which TSD enhances food intake. PMID- 23807869 TI - The Challenge of Structural Control on the Nanoscale: Bottom-Up Self-Assembly of Nucleic Acids in 3D. AB - Control of the structure of matter has been a major challenge to humankind for its entire history. The finer the features that that we are able to engineer, the greater the level of control that we have. Here, we summarize progress made in the bottom-up control of structure that is based on the self-assembly of nucleic acids. Nucleic acids are unique among molecular systems in that their intermolecular interactions can be programmed, from the perspectives of both affinity and of structure. Structural DNA nanotechnology has been based on directing the cohesion of branched DNA motifs by the same cohesive interactions used by genetic engineers. As a result, multiply-connected objects, periodic and aperiodic arrays and nanomechanical devices have been produced by these systems. Current experiments are directed at using nucleic acid systems to scaffold the spatial assembly of other species. PMID- 23807870 TI - A Cross-Linguistic Study of Sound-Symbolism in Children's Verb Learning. AB - A long history of research has considered the role of iconicity in language and the existence and role of non-arbitrary properties in language and the use of language. Previous studies with Japanese-speaking children whose language defines a large grammatical class of words with clear sound symbolism suggest that iconicity properties in Japanese may aid early verb learning, and a recent extended work suggest that such early sensitivity is not limited to children whose language supports such word classes. The present study further considers the use of sounds symbolic words in verb learning context by conducting systematic cross-linguistic comparisons on early exposure to and effect of sound symbolism in verb mapping. Experiment 1 is an observational study of how English- and Japanese-speaking parents talk about verbs. More conventionalized symbolic words were found in Japanese-speaking parental input and more idiosyncratic use of sound symbolism in English-speaking parental input. Despite this different exposure of iconic forms to describe actions, the artificial verb learning task in Experiment 2 revealed that children in both language groups benefit from sound meaning correspondences for their verb learning. These results together confirm more extensive use of conventionalized sound-symbolism among Japanese-speakers, and also support a cross-linguistic consistency of the effect, which has documented in the recent work. The work also points to the potential value of understanding the contexts in which sound-meaning correspondences matter in language learning. PMID- 23807871 TI - The Impact of Cigarette Quitting during Pregnancy on Other Prenatal Health Behaviors. AB - Several economic studies have evaluated the effects of cigarette smoking and quitting on other health behaviors such as alcohol use and weight gain. However, there is little research that evaluates the effects of cigarette quitting during pregnancy on other health behaviors such as caloric intake, alcohol consumption, multivitamin use, and caffeine intake. In this paper, we evaluate these effects and employ a genetic variant that predicts cigarette quitting to aid in identification. We find some evidence that cigarette quitting during pregnancy may increase multivitamin use and caloric intake and reduce caffeine consumption. PMID- 23807872 TI - WebProtege: A Collaborative Ontology Editor and Knowledge Acquisition Tool for the Web. AB - In this paper, we present WebProtege-a lightweight ontology editor and knowledge acquisition tool for the Web. With the wide adoption of Web 2.0 platforms and the gradual adoption of ontologies and Semantic Web technologies in the real world, we need ontology-development tools that are better suited for the novel ways of interacting, constructing and consuming knowledge. Users today take Web-based content creation and online collaboration for granted. WebProtege integrates these features as part of the ontology development process itself. We tried to lower the entry barrier to ontology development by providing a tool that is accessible from any Web browser, has extensive support for collaboration, and a highly customizable and pluggable user interface that can be adapted to any level of user expertise. The declarative user interface enabled us to create custom knowledge-acquisition forms tailored for domain experts. We built WebProtege using the existing Protege infrastructure, which supports collaboration on the back end side, and the Google Web Toolkit for the front end. The generic and extensible infrastructure allowed us to easily deploy WebProtege in production settings for several projects. We present the main features of WebProtege and its architecture and describe briefly some of its uses for real-world projects. WebProtege is free and open source. An online demo is available at http://webprotege.stanford.edu. PMID- 23807873 TI - Beta-adrenergic signaling in the development and progression of pulmonary and pancreatic adenocarcinoma. AB - Small airway epithelial cells from, which most pulmonary adenocarcinomas (PACs) derive, and pancreatic duct epithelia, from which pancreatic ductal adenocarcinomas (PDACs) originate, share the ability to synthesize and release bicarbonate. This activity is stimulated in both cell types by the alpha7nicotinic acetylcholine receptor (alpha7nAChR)-mediated release of noradrenaline and adrenaline, which in turn activate beta-adrenergic receptor (beta-AR) signaling, leading to the cAMP-dependent release of bicarbonate. The same signaling pathway also stimulates a complex network of intracellular signaling cascades which regulate the proliferation, migration, angiogenesis and apoptosis of PAC and PDAC cells. The amino acid neurotransmitter gamma aminobutyric acid (GABA) serves as the physiological inhibitor of this cancer stimulating network by blocking the activation of adenylyl cyclase. This review summarizes experimental, epidemiological and clinical data that have identified risk factors for PAC and PDAC such as smoking, alcoholism, chronic non neoplastic diseases and their treatments as well as psychological stress and analyzes how these factors increase the cancer-stimulating effects of this regulatory cascade in PAC and PDAC. This analysis identifies the careful maintenance of balanced levels in stimulatory stress neurotransmitters and inhibitory GABA as a key factor for the prevention of PDAC and suggests the marker-guided use of beta blockers, GABA or GABA-B receptor agonists as well as psychotherapeutic or pharmacological stress reduction as important tools that may render currently ineffective cancer intervention of PAC and PDAC more successful. PMID- 23807875 TI - Effects of Methyl Substituents on the Activity and Enantioselectivity of Homobenzotetramisole-Based Catalysts in the Kinetic Resolution of Alcohols. AB - Substitution of the tetrahydropyrimidine ring in enantioselective acyl transfer catalyst homobenzotetramisole (HBTM) 6 with methyl groups exerts a dramatic influence on its performance in the kinetic resolution of secondary alcohols. Syn 3-Methyl analogue of HBTM (9a) has proved to be superior to the parent compound in terms of catalytic activity, enantioselectivity, and synthetic accessibility. PMID- 23807874 TI - Evaluation of blood pressure control using a new arterial stiffness parameter, cardio-ankle vascular index (CAVI). AB - Arterial stiffness has been known to be a surrogate marker of arteriosclerosis, and also of vascular function. Pulse wave velocity (PWV) had been the most popular index and was known to be a predictor of cardiovascular events. But, it depends on blood pressure at measuring time. To overcome this problem, cardio ankle vascular index (CAVI) is developed. CAVI is derived from stiffness parameter beta by Hayashi, and the equation of Bramwell-Hill, and is independent from blood pressure at a measuring time. Then, CAVI might reflect the proper change of arterial wall by antihypertensive agents. CAVI shows high value with aging and in many arteriosclerotic diseases and is also high in persons with main coronary risk factors. Furthermore, CAVI is decreased by an administration of alpha1 blocker, doxazosin for 2-4 hours, Those results suggested that CAVI reflected the arterial stiffness composed of organic components and of smooth muscle cell contracture. Angiotensin II receptor blocker, olmesartan decreased CAVI much more than that of calcium channel antagonist, amlodipine, even though the rates of decreased blood pressure were almost same. CAVI might differentiate the blood pressure-lowering agents from the point of the effects on proper arterial stiffness. This paper reviewed the principle and rationale of CAVI, and the possibilities of clinical applications, especially in the studies of hypertension. PMID- 23807876 TI - Cinchona alkaloid catalyzed enantioselective amination of alpha,beta-unsaturated ketones: an asymmetric approach to Delta2-pyrazolines. AB - Delta2-Pyrazolines are of significant medicinal and synthetic interest due to their therapeutic properties and utility in the synthesis of 1,3-diamines, yet few asymmetric methods exist to prepare them. An unprecedented highly enantioselective organocatalytic synthesis of 2-pyrazolines was achieved through an asymmetric conjugate addition catalyzed by 9-epi-amino cinchona alkaloids followed by deprotection-cyclization, which furnished chiral 2-pyrazolines in 46 78% yield and 59-91% ee. This bifunctional catalytic methodology thus provides easy access to considerable range of optically active 3,5-dialkyl 2-pyrazolines. PMID- 23807877 TI - Improved blood velocity measurements with a hybrid image filtering and iterative Radon transform algorithm. AB - Neural activity leads to hemodynamic changes which can be detected by functional magnetic resonance imaging (fMRI). The determination of blood flow changes in individual vessels is an important aspect of understanding these hemodynamic signals. Blood flow can be calculated from the measurements of vessel diameter and blood velocity. When using line-scan imaging, the movement of blood in the vessel leads to streaks in space-time images, where streak angle is a function of the blood velocity. A variety of methods have been proposed to determine blood velocity from such space-time image sequences. Of these, the Radon transform is relatively easy to implement and has fast data processing. However, the precision of the velocity measurements is dependent on the number of Radon transforms performed, which creates a trade-off between the processing speed and measurement precision. In addition, factors like image contrast, imaging depth, image acquisition speed, and movement artifacts especially in large mammals, can potentially lead to data acquisition that results in erroneous velocity measurements. Here we show that pre-processing the data with a Sobel filter and iterative application of Radon transforms address these issues and provide more accurate blood velocity measurements. Improved signal quality of the image as a result of Sobel filtering increases the accuracy and the iterative Radon transform offers both increased precision and an order of magnitude faster implementation of velocity measurements. This algorithm does not use a priori knowledge of angle information and therefore is sensitive to sudden changes in blood flow. It can be applied on any set of space-time images with red blood cell (RBC) streaks, commonly acquired through line-scan imaging or reconstructed from full-frame, time-lapse images of the vasculature. PMID- 23807878 TI - The role of MRI in diagnostic algorithm of cervicofacial vascular anomalies in children. AB - BACKGROUND: Vascular anomalies are usually diagnosed through their clinical picture and history. The purpose of this study was to assess the role of MR imaging in initial assessment of cervicofacial vascular anomalies in children. MATERIAL/METHODS: Twenty pediatric patients with vascular anomalies located in the cervicofacial region underwent MRI examination in our department. Images were evaluated for lesion detectability and its signal characteristics (on T1w, T2w images with fat suppression and contrast enhanced T1w sequences); the extent of the lesions and surrounding tissue involvement were also assessed. RESULTS: In the studied group MR images revealed all anomalies and provided information of their anatomic extent and invasion of surrounding anatomic structures. Nine hemangiomas and six venous malformations were found among studied patients. Two children had multiloculated lesions corresponding to lymphatic malformations. One examination visualized a lesion consisting mainly of dilated vascular channels with an apparent feeding artery, which was consistent with arteriovenous malformation. Two remaining lesions were mixed malformations. Nine patients had lesions limited to subcutaneous tissue. Two masses infiltrated bone structures. There was muscle involvement found in nine cases. CONCLUSIONS: MR imaging is a well-established method for detection and monitoring of vascular anomalies in children. With ultrasound used mostly for initial diagnosis and additional flow assessment, angiography viewed as an invasive therapeutic method and computed tomography used only in specific situations due to its high irradiation dose, magnetic resonance is the best imaging method used in differential diagnosis and topographical characterization of vascular malformations and tumors of cervicofacial area in pediatric patients. Noninvasively and without irradiation, it enables evaluation of the extent and characteristics of lesions and planning proper therapeutic strategy. PMID- 23807879 TI - Application of geometrical measurements in the assessment of vertebral strength. AB - BACKGROUND: The study was aimed at the development of parameters that could be used as predictors of vertebral strength. Proposed parameters describing vertebral geometry and/or shape can be established on the basis of routine spine roentgenograms, making roentgenography a novel tool for vertebral fracture risk assessment in the future. MATERIAL/METHODS: 20 human cadaveric L3 vertebrae were included in the study. Dual-energy X-ray absorptiometry (DXA) was used for an assessment of bone mineral density (BMD). Quantitative computed tomography (QCT) was performed to measure the volumetric bone density as the most reliable parameter in vertebral fracture risk assessment. Geometrical measurements were performed on the basis of high quality and high resolution computer tomography 3 dimensional images. Biomechanical tests were performed to measure vertebral strength. Two parameters were defined on the basis of extensive research: the ratio between vertebral base area and its height (A/H), and the ratio of vertebral coronal width to coronal height (W/H). Correlations between vertebral mechanical strength - its BMD, QCT density, A/H and W/H were calculated. RESULTS: The best correlation to bone durability was achieved for QCT density (r=0.882), while correlation strength for BMD (r=0.779) and A/H (r=-0.773) were comparable. W/H correlated better than BMD to mechanical strength (-0.788). CONCLUSIONS: Geometrical parameters of vertebrae potentially measured on spine radiograms could be used as predictors of vertebral durability. The calculated correlation coefficients suggest that one of the proposed parameters works better than the commonly used BMD. PMID- 23807880 TI - Bone age assessment using cephalometric photographs. AB - BACKGROUND: The assessment of bone age comprises the basic element of orthodontic diagnostics as it enables the recognition of deviations from normal growth, determines the choice of treatment, helps determine the appropriate moment to begin treatment, establish prognosis and plan a retention strategy. In order to make an assessment of skeletal maturity possible in a single examination, radiological methods were adopted. The following characteristics are evaluated on a radiograph: the appearance, size and shape of ossification centers, the width and the shape of growth cartilage and the degree of fusion between diaphyses and epiphyses. In order to assess the maturity of bones, hand-wrist radiographs were introduced in the second decade of the 20(th) century. Bone age assessment of bone age could also be made based on an analysis of a morphological maturity of cervical vertebrae utilizing cephalometric radiographs. OBJECTIVE: The objective of the study was to evaluate the correspondence between bone age assessments made from hand-wrist radiographs and those from cephalometric radiographs. MATERIAL/METHODS: In order to fulfill the objectives, hand-wrist radiographs as well as cephalometric radiographs of 30 patients (15 girls and 15 boys) between 10 and 17 years of age were collected. Bone age of hand, wrist and cervical spine was assessed. Bone age on hand-wrist radiographs was evaluated using the Bjork method, whereas cephalometric radiographs were analyzed by the Baccetti et al. method. RESULTS: A strong and statistically highly significant (r=0.98; p<0.00001) Pearson's correlation was found between bone age assessed from hand wrist radiographs using Bjork's method and bone age assessed from cephalometric radiographs using the method by Baccetti et al. CONCLUSIONS: The analysis of cervical vertebrae in cephalometric radiographs appears to be the most desirable method of bone age assessment. Performing the analysis on routinely taken cephalograms eliminates the need for additional exposure to X-ray radiation and shortens the duration of examination. PMID- 23807881 TI - Endovascular embolization of varicoceles using n-butyl cyanoacrylate (NBCA) glue. AB - BACKGROUND: Varicoceles are abnormally dilated veins within the pampiniform plexus. They are caused by reflux of blood in the internal spermatic vein. The incidence of varicoceles is approximately 10-15% of the adolescent male population. The etiology of varicoceles is probably multifactorial. The diagnosis is based on Doppler US. Treatment could be endovascular or surgical. The aim of the study was to describe and evaluate a novel method of endovascular embolization of varicoceles using n-butyl cyanoacrylate (NBCA) glue. MATERIAL/METHODS: 17 patients were subjected to endovascular treatment of varicoceles using NBCA. A 2.8 Fr microcatheter and a 1:1 mixture of NBCA and lipiodol were used for embolization of the spermatic vein. RESULTS: All 17 procedures were successful. There were no complications. DISCUSSION: Embolization of varicoceles using NBCA glue is efficient and safe for all patients. The method should be considered as a method of choice in all patients. Phlebography and Valsalva maneuver are crucial for technical success and avoidance of complications. CONCLUSIONS: Endovascular treatment of varicoceles using NBCA glue is very effective and safe. PMID- 23807882 TI - Experimental evaluation of ballistic hazards in imaging diagnostic center. AB - BACKGROUND: Serious hazards for human health and life and devices in close proximity to the magnetic resonance scanners (MRI scanners) include the effects of being hit by ferromagnetic objects attracted by static magnetic field (SMF) produced by scanner magnet - the so-called ballistic hazards classified among indirect electromagnetic hazards. International safety guidelines and technical literature specify different SMF threshold values regarding ballistic hazards - e.g. 3 mT (directive 2004/40/EC, EN 60601-2-33), and 30 mT (BMAS 2009, directive proposal 2011). Investigations presented in this article were performed in order to experimentally verify SMF threshold for ballistic hazards near MRI scanners used in Poland. MATERIAL/METHODS: Investigations were performed with the use of a laboratory source of SMF (0-30 mT) and MRI scanners of various types. The levels of SMF in which metal objects of various shapes and 0.4-500 g mass are moved by the field influence were investigated. The distance from the MRI scanners (0.2 3T) where hazards may occur were also investigated. RESULTS: Objects investigated under laboratory conditions were moved by SMF of 2.2-15 mT magnetic flux density when they were freely suspended, but were moved by the SMF of 5.6-22 mT when they were placed on a smooth surface. Investigated objects were moved in fields of 3.5 40 mT by MRI scanners. Distances from scanner magnet cover, where ballistic hazards might occur are: up to 0.5 m for 0.2-0.3T scanners; up to 1.3 m for 0.5T scanners; up to 2.0 m for 1.5T scanners and up to 2.5 m for 3T scanners (at the front and back of the magnet). CONCLUSIONS: It was shown that SMF of 3 mT magnetic flux density should be taken as the threshold for ballistic hazards. Such level is compatible with SMF limit value regarding occupational safety and health-protected areas/zones, where according to the Polish labor law the procedures of work environment inspection and prevention measures regarding indirect electromagnetic hazards should be applied. Presented results do not support the increase up to 30 mT of the SMF limit for protected area. PMID- 23807883 TI - Not at random location of atherosclerotic lesions in thoracic aorta and their prognostic significance in relation to the risk of cardiovascular events. AB - Thoracic aortic calcium deposits are frequently detected on tomography of the chest, and in other imaging modalities. Numerous studies indicated the correlation of hemodynamic parameters such as wall shear stress in relation to distribution aortic calcifications. This publication discusses similarities and differences of two distinct pathomechanisms of arterial calcifications: intimal associated with atherosclerosis and medial knows as Monckeberg's arteriosclerosis. This review also analyzes the frequent coexistence of aortic calcification and coronary artery disease in terms of risk of cardiovascular events. PMID- 23807884 TI - Diagnostic imaging of sacroiliac joints and the spine in the course of spondyloarthropathies. AB - Spondyloarthropathies belong to a group of rheumatic diseases, in which inflammatory changes affect mainly the sacroiliac joints, spine, peripheral joints, tendon, ligaments and capsule attachments (entheses). This group includes 6 entities: ankylosing spondylitis, arthritis associated with inflammatory bowel disease, reactive arthritis, undifferentiated spondyloarthropathy, psoriatic arthritis and juvenile spondyloarthropathy. In 2009, ASAS (Assessment in SpondyloArthritis international Society) association, published classification criteria for spondyloarthropathies, which propose standardization of clinical diagnostic approach in the case of sacroiliitis, spondylitis and arthritis. Radiological diagnosis of inflammatory changes of sacroiliac joints is based on a 4 step radiographic grading method from 1966. According to modified New York criteria, the diagnosis of ankylosing spondylitis is made based on the presence of advanced lesions, sacroiliitis of at least 2 grade bilaterally or 3-4 unilaterally. In case of other types of spondyloarthropathies diagnosis is made based on presence of at least grade 1 changes. In MRI, active inflammation of sacroiliac joints is indicated by the presence of subchondral bone marrow edema, synovitis, bursitis, or enthesitis. ASAS discusses only the classic form of axial spondyloarthropathies, which is ankylosing spondylitis. To quantify radiological inflammatory changes in the course of the disease, Stoke Ankylosing spondylitis classification Spinal Score (SASSS) is recommended. The signs of inflammation and scarrying of the spinal cord in the course of ankylosing spondylitis, present in MRI include: bone marrow edema, sclerosis, fat metaplasia, formation of syndesmophytes, and ankylosis. PMID- 23807885 TI - Giant congenital malformation of the perirectal plexus in computed tomography imaging - case report. AB - BACKGROUND: Congenital arteriovenous malformation (AVM) in the pelvic area is uncommon in males. CASE REPORT: The described case is of a giant lesion of this type that caused recurrent hemorrhaging in the lower part of the gastrointestinal tract. Preliminary diagnosis of vascular pathology was made on the basis of an endoscopic examination that revealed numerous pulsating protuberances of the rectal wall, in which blood flow was identified by means of transrectal ultrasonography. Complementing the diagnostics with a CT revealed a considerable extent of malformation, as well as its morphology and anatomical relations with the surrounding tissues. RESULTS: Following a two-year follow-up period, the malformation did not progress or demonstrate any intensification of clinical symptoms, therefore the patient continues to undergo conservative treatment. PMID- 23807886 TI - Autologous blood-clot embolisation of cavernosal artery pseudoaneurysm causing delayed high-flow priapism. AB - BACKGROUND: High-flow priapism is a rare condition characterized by a prolonged and painless erection. Since it may permanently impair erectile function, it must be managed and treated as soon as possible, in order to restore potency. The case we are presenting here was successfully treated by embolizing the penile artery using an autologous clot. CASE REPORT: A case of delayed painless high-flow priapism that occured after blunt straddle-type perineal trauma, that was persistent for more than 30 days is being presented. Doppler ultrasonographic examination of the cavernosal artery revealed a 1.5 cm-diameter pseudoaneurysm at the right cavernosal artery, together with a high-velocity shunt between the two cavernous arteries. Extravasation from the proximal sites of both of the cavernous arteries and a right cavernosal artery pseudoaneurysm was detected on angiography. The patient was successfully treated by embolization of the penile artery with an autologous clot in two sessions with a 3-day interval. CONCLUSIONS: This experience along with a survey of the literature made us conclude that embolization of cavernous artery by means of an autologous clot is a very effective procedure and a method of choice for treatment of high-flow priapism and for restoration of penile erectile function. What makes our case even more interesting and important, is the fact that priapism of one month's duration could well be treated by means of this method. PMID- 23807887 TI - Clinical and radiological pictures of two newborn babies with manifestations of chondrodysplasia punctata and review of available literature. AB - BACKGROUND: Chondrodysplasia punctata (CDP) is a rare, heterogeneous congenital skeletal dysplasia, characterized by punctate or dot-like calcium deposits in cartilage observed on neonatal radiograms. A number of inborn metabolic diseases are associated with CDP, including peroxisomal and cholesterol biosynthesis dysfunction and other inborn errors of metabolism such as: mucolipidosis type II, mucopolysacharidosis type III, GM1 gangliosidosis. CDP is also related to disruption of vitamin K-dependent metabolism, causing secondary effects on the embryo, as well as fetal alcohol syndrome (FAS), chromosomal abnormalities that include trisomies 18 and 21, Turner syndrome. CASE REPORT: This article presents clinical data and diagnostic imaging findings of two newborn babies with chondrodysplasia punctata. Children presented with skeletal and cartilage anomalies, dysmorphic facial feature, muscles tone abnormalities, skin changes and breathing difficulties. One of the patients demonstrated critical stenosis of spinal canal with anterior subluxation of C1 vertebra relative to C2. The aim of this article is to present cases and briefly describe current knowledge on etiopathogenesis as well as radiological and clinical symptoms of diseases coexisting with CDP. CONCLUSIONS: Radiological diagnostic imaging allows for visualization of punctate focal mineralization in bone epiphyses during neonatal age and infancy. Determining the etiology of chondrodysplasia punctata requires performing various basic as well as additional examinations, including genetic studies. PMID- 23807888 TI - Recommended immunization schedule for children and adolescents: the Korean Pediatric Society, 2013. AB - This article contains the recommended immunization schedule by the Committee on Infectious Diseases of the Korean Pediatric Society, updated in March 2013, when Haemophilus influenzae type b vaccine is now included in the National Immunization Program in Korea. It also includes catch-up immunization schedule for children and adolescents who are behind the recommended schedule. These schedules are a minor revision of the corresponding parts of Immunization Guideline, 7th edition, of the Korean Pediatric Society, released in 2012. Pediatricians should be aware of these schedules to provide adequate immunization to Korean children and adolescents. PMID- 23807889 TI - Pulmonary stenosis and pulmonary regurgitation: both ends of the spectrum in residual hemodynamic impairment after tetralogy of Fallot repair. AB - Repair of tetralogy of Fallot (TOF) has shown excellent outcomes. However it leaves varying degrees of residual hemodynamic impairment, with severe pulmonary stenosis (PS) and free pulmonary regurgitation (PR) at both ends of the spectrum. Since the 1980s, studies evaluating late outcomes after TOF repair revealed the adverse impacts of residual chronic PR on RV volume and function; thus, a turnaround of operational strategies has occurred from aggressive RV outflow tract (RVOT) reconstruction for complete relief of RVOT obstruction to conservative RVOT reconstruction for limiting PR. This transformation has raised the question of how much residual PS after conservative RVOT reconstruction is acceptable. Besides, as pulmonary valve replacement (PVR) increases in patients with RV deterioration from residual PR, there is concern regarding when it should be performed. Regarding residual PS, several studies revealed that PS in addition to PR was associated with less PR and a small RV volume. This suggests that PS combined with PR makes RV diastolic property to protect against dilatation through RV hypertrophy and supports conservative RVOT enlargement despite residual PS. Also, several studies have revealed the pre-PVR threshold of RV parameters for the normalization of RV volume and function after PVR, and based on these results, the indications for PVR have been revised. Although there is no established strategy, better understanding of RV mechanics, development of new surgical and interventional techniques, and evidence for the effect of PVR on RV reverse remodeling and its late outcome will aid us to optimize the management of TOF. PMID- 23807890 TI - The results of cardiopulmonary exercise test in healthy Korean children and adolescents: single center study. AB - PURPOSE: The cardiopulmonary exercise test (CPET) is an important clinical tool for evaluating exercise capacity and is frequently used to evaluate chronic conditions including congenital heart disease. However, data on the normal CPET values for Korean children and adolescents are lacking. The aim of this study was to provide reference data for CPET variables in children and adolescents. METHODS: From August 2006 to April 2009, 76 healthy children and adolescents underwent the CPET performed using the modified Bruce protocol. Here, we performed a medical record review to obtain data regarding patient' demographics, medical history, and clinical status. RESULTS: The peak oxygen uptake (VO2Peak) and metabolic equivalent (METMax) were higher in boys than girls. The respiratory minute volume (VE)/CO2 production (VCO2) slope did not significantly differ between boys and girls. The cardiopulmonary exercise test data did not significantly differ between the boys and girls in younger age group (age, 10 to 14 years). However, in older age group (age, 15 to 19 years), the boys had higher VO2Peak and METMax values and lower VE/VCO2 values than the girls. CONCLUSION: This study provides reference data for CPET variables in case of children and adolescents and will make it easier to use the CPET for clinical decision-making. PMID- 23807891 TI - Utility of a multiplex reverse transcriptase-polymerase chain reaction assay (HemaVision) in the evaluation of genetic abnormalities in Korean children with acute leukemia: a single institution study. AB - PURPOSE: In children with acute leukemia, bone marrow genetic abnormalities (GA) have prognostic significance, and may be the basis for minimal residual disease monitoring. Since April 2007, we have used a multiplex reverse transcriptase polymerase chain reaction tool (HemaVision) to detect of GA. METHODS: In this study, we reviewed the results of HemaVision screening in 270 children with acute leukemia, newly diagnosed at The Catholic University of Korea from April 2007 to December 2011, and compared the results with those of fluorescence in situ hybridization (FISH), and G-band karyotyping. RESULTS: Among the 270 children (153 males, 117 females), 187 acute lymphoblastic leukemia and 74 acute myeloid leukemia patients were identified. Overall, GA was detected in 230 patients (85.2%). HemaVision, FISH, and G-band karyotyping identified GA in 125 (46.3%), 126 (46.7%), and 215 patients (79.6%), respectively. TEL-AML1 (20.9%, 39/187) and AML1-ETO (27%, 20/74) were the most common GA in ALL and AML, respectively. Overall sensitivity of HemaVision was 98.4%, with false-negative results in 2 instances: 1 each for TEL-AML1 and MLL-AF4. An aggregate of diseasesspecific FISH showed 100% sensitivity in detection of GA covered by HemaVision for actual probes utilized. G-band karyotype revealed GA other than those covered by HemaVison screening in 133 patients (49.3%). Except for hyperdiplody and hypodiploidy, recurrent GA as defined by the World Health Organizationthat were not screened by HemaVision, were absent in the karyotype. CONCLUSION: HemaVision, supported by an aggregate of FISH tests for important translocations, may allow for accurate diagnosis of GA in Korean children with acute leukemia. PMID- 23807892 TI - Combined chemotherapy and intra-arterial chemotherapy of retinoblastoma. AB - PURPOSE: Retinoblastoma (RB) is the most common primary malignant intraocular tumor in children. Although systemic chemotherapy has been the primary treatment, intra-arterial chemotherapy (IAC) represents a new treatment option. Here, we performed alternate systemic chemotherapy and IAC and retrospectively reviewed the efficacy and safety of this approach. METHODS: Patients diagnosed with intraocular RB between January 2000 and December 2011 at Severance Children's Hospital, Yonsei University, were reviewed. Before February 2010, the primary treatment for RB was chemotherapy (non-IAC/CTX). Since February 2010, the primary treatment for RB has been IAC (IAC/CTX). External beam radiotherapy or high-dose chemotherapy were used as "last resort" treatments just prior to enucleation at the time of progression or recurrence during primary treatment. Enucleation-free survival (EFS) and progression-free survival were assessed. RESULTS: We examined 19 patients (median age, 11.9 months; range, 1.4 to 75.6 months) with a sum of 25 eyes, of which, 60.0% were at advanced Reese Ellsworth (RE) stages. The enucleation rate was 33.3% at early RE stages and 81.8% at advanced RE stages (P=0.028). At 36 months, EFS was significantly higher in the IAC/CTX group than in the non-IAC/CTX group (100% vs. 40.0%, P=0.016). All 5 patients treated with IAC achieved eye preservation, although most patients were at advanced RE stages (IV-V). CONCLUSION: Despite the limitation of a small sample size, our work shows that an alternative combined approach using IAC and CTX may be safe and effective for eye preservation in advanced RB. PMID- 23807893 TI - Severe dapsone hypersensitivity syndrome in a child. AB - Dapsone (4,4'-diaminodiphenylsulfone, DDS), a potent anti-inflammatory agent, is widely used in the treatment of leprosy and several chronic inflammatory skin diseases. Dapsone therapy rarely results in development of dapsone hypersensitivity syndrome, which is characterized by fever, hepatitis, generalized exfoliative dermatitis, and lymphadenopathy. Here, we describe the case of an 11-year-old Korean boy who initially presented with high fever, a morbilliform skin rash, generalized lymphadenopathy, hepatosplenomegaly, and leukopenia after 6 weeks of dapsone intake. Subsequently, he exhibited cholecystitis, gingivitis, colitis, sepsis, aseptic meningitis, disseminated intravascular coagulation, syndrome of inappropriate antidiuretic hormone secretion, pneumonia, pleural effusions, peritonitis, bronchiectatic changes, exfoliative dermatitis, and acute renal failure. After 2 months of supportive therapy, and prednisolone and antibiotic administration, most of the systemic symptoms resolved, with the exception of exfoliative dermatitis and erythema, which ameliorated over the following 4 months. Agranulocytosis, atypical lymphocytosis, aseptic meningitis, and bronchiectatic changes along with prolonged systemic symptoms with exfoliative dermatitis were the most peculiar features of the present case. PMID- 23807894 TI - A case of familial X-linked thrombocytopenia with a novel WAS gene mutation. AB - Wiskott-Aldrich syndrome (WAS) is an inherited X-linked disorder. The WAS gene is located on the X chromosome and undergoes mutations, which affect various domains of the WAS protein, resulting in recurrent infection, eczema, and thrombocytopenia. However, the clinical features and severity of the disease vary according to the type of mutations in the WAS gene. Here, we describe the case of a 4-year-old boy with a history of marked thrombocytopenia since birth, who presented with recurrent herpes simplex infection and late onset of eczema. Examination of his family history revealed that older brother, who died from intracranial hemorrhage, had chronic idiopathic thrombocytopenia. Therefore, we proceeded with genetic analysis and found a new deletion mutation in the WAS gene: c.858delC (p.ser287Leufs(*)21) as a hemizygous form. PMID- 23807895 TI - Retraction: Mammalian target of rapamycin inhibitors for treatment in tuberous sclerosis. PMID- 23807896 TI - Antibacterial Biomimetic Hybrid Films. AB - In this work, we present a novel method to prepare a hybrid coating based on dextran grafted to a substrate and embedded with silver nanoparticles (Ag NPs). First, the Ag NPs are synthesized in situ in the presence of oxidized dextran in solution. Second, the oxidized dextran is exposed to an amine functionalized surface resulting in the simultaneous grafting of dextran and the trapping of Ag NPs within the layer. The NP loading is controlled by the concentration of silver nitrate, which is 2 mM (DEX-Ag2) and 5 mM (DEX-Ag5). The dried film thickness increases with silver nitrate concentration from 2 nm for dextran to 7 nm and 12 nm for DEX-Ag2 and DEX-Ag5, respectively. The grafted dextran film displays features with a diameter and height of ~ 50 nm and 2 nm, respectively. For the DEX-Ag2 and DEX-Ag5, the dextran features as well as individual Ag NPs (~ 5 nm) and aggregates of Ag NPs are observed. Larger and more irregular aggregates are observed for DEX-Ag5. Overall, the Ag NPs are embedded in the dextran film as suggested by AFM and UVO studies. In terms of its antimicrobial activity, DEX-Ag2 resists bacterial adhesion to a greater extent than DEX-Ag5, which in turn is better than dextran and silicon. Because these antibacterial hybrid coatings can be grafted to a variety of surfaces, many biomedical applications can be envisioned, ranging from coating implants to catheters. PMID- 23807897 TI - Can behavioral treatments be enhanced by integrative neuromuscular training in the treatment of juvenile fibromyalgia? PMID- 23807898 TI - Microglia/macrophage-derived inflammatory mediators galectin-3 and quinolinic acid are elevated in cerebrospinal fluid from newborn infants after birth asphyxia. AB - Activation of microglia/macrophages is important in neonatal hypoxic-ischemic (HI) brain injury. Based on experimental studies, we identified macrophage/microglia-derived mediators with potential neurotoxic effects after neonatal HI and examined them in cerebrospinal fluid (CSF) from newborn infants after birth asphyxia. Galectin-3 is a novel inflammatory mediator produced by microglia/macrophages. Galectin-3 is chemotactic for inflammatory cells and activates nicotinamide adenine dinucleotide phosphate (NADPH) oxidase resulting in production and release of reactive oxygen species (ROS). Matrix metalloproteinase-9 (MMP-9) is a tissue-degrading protease expressed by activated microglia in the immature brain after HI. Both galectin-3 and MMP-9 contribute to brain injury in animal models for neonatal HI. Quinolinic acid (QUIN) is a neurotoxic N-methyl-D-aspartate (NMDA) receptor agonist also produced by activated microglia/macrophages. Galectin-3 and MMP-9 were measured by ELISA and QUIN by mass spectrometry. Asphyxiated infants (n=20) had higher levels of galectin-3 (mean (SEM) 2.64 (0.43) ng/mL) and QUIN (335.42 (58.9) nM) than controls (n=15) (1.36 (0.46) ng/mL and 116.56 (16.46) nM, respectively), p<0.05 and p<0.01. Infants with septic infections (n=10) did not differ from controls. Asphyxiated infants with abnormal outcome had higher levels of galectin-3 (3.96 (0.67) ng/mL) than those with normal outcome (1.76 (0.32) ng/mL), p=0.02, and the difference remained significant in the clinically relevant group of infants with moderate encephalopathy. MMP-9 was detected in few infants with no difference between groups. The potentially neurotoxic macrophage/microglia-derived mediators galectin-3 and QUIN are increased in CSF after birth asphyxia and could serve as markers and may contribute to injury. PMID- 23807900 TI - Electrochemical and Structural Study of a Chemically Dealloyed PtCu Oxygen Reduction Catalyst. AB - A carbon-supported, dealloyed platinum-copper (Pt-Cu) oxygen reduction catalyst was prepared using a multi-step synthetic procedure. Material produced at each step was characterized using high angle annular dark field scanning transmission electron microscopy (HAADF-STEM), electron energy loss spectroscopy (EELS) mapping, x-ray absorption spectroscopy (XAS), x-ray diffraction (XRD), and cyclic voltammetry (CV), and its oxygen reduction reaction (ORR) activity was measured by a thin-film rotating disk electrode (TF-RDE) technique. The initial synthetic step, a co-reduction of metal salts, produced a range of poorly crystalline Pt, Cu, and Pt-Cu alloy nanoparticles that nevertheless exhibited good ORR activity. Annealing this material alloyed the metals and increased particle size and crystallinity. TEM shows the annealed catalyst to include particles of various sizes, large (>25 nm), medium (12-25 nm), and small (<12 nm). Most of the small and medium-sized particles exhibited a partial or complete coreshell (Cu-rich core and Pt shell) structure with the smaller particles typically having more complete shells. The appearance of Pt shells after annealing indicates that they are formed by a thermal diffusion mechanism. Although the specific activity of the catalyst material was more than doubled by annealing, the concomitant decrease in Pt surface area resulted in a drop in its mass activity. Subsequent dealloying of the catalyst by acid treatment to partially remove the copper increased the Pt surface area by changing the morphology of the large and some medium particles to a "Swiss cheese" type structure having many voids. The smaller particles retained their core-shell structure. The specific activity of the catalyst material was little reduced by dealloying, but its mass activity was more than doubled due to the increase in surface area. The possible origins of these results are discussed in this report. PMID- 23807901 TI - Contrast ultrasound in hepatocellular carcinoma at a tertiary liver center: First Indian experience. AB - AIM: To assess the role of contrast enhanced ultrasonography in evaluation of hepatocellular carcinoma (HCC) at the first Indian tertiary liver center. METHODS: Retrospective analysis of contrast enhanced ultrasound (CEUS) examinations over 24 mo for diagnosis, surveillance, characterization and follow up of 50 patients in the context of HCC was performed. The source and indication of referrals, change in referral rate, accuracy and usefulness of CEUS in a tertiary liver center equipped with a 64 slice dual energy computer tomography (CT) and 3 tesla magnetic resonance imaging (MRI) were studied. Sonovue (BR1, Bracco, Italy, a second generation contrast agent) was used for contrast US studies. Contrast enhanced CT/MRI or both were performed in all patients. The findings were taken as a baseline reference and correlation was done with respect to contrast US. Contrast enhanced MRI was performed using hepatocyte specific gadobenate dimeglumine (Gd-BOPTA). Iomeron (400 mg; w/v) was used for dynamic CT examinations. RESULTS: About 20 (40%) of the examinations were referred from clinicians for characterization of a mass from previous imaging. About 15 (30%) were performed for surveillance in chronic liver disease; 5 (10%) examinations were performed for monitoring lesions after radiofrequency ablation (RFA); 3 (6%) were post trans-arterial chemo-embolization (TACE) assessments and 3 (6%) were patients with h/o iodinated contrast allergy. About 2 (4%) were performed on hemodynamically unstable patients in the intensive care with raised alpha fetoprotein and 2 (4%) patients were claustrophobic. The number of patients referred from clinicians steadily increased from 12 in the first 12 mo of the study to 38 in the last 12 mo. CEUS was able to diagnose 88% of positive cases of HCC as per reference standards. In the surveillance group, specificity was 53.3% vs 100% by CT/MRI. Post RFA and TACE specificity of lesion characterization by CEUS was 100% in single/large mass assessment, similar to CT/MRI. For non HCC lesions such as regenerative and dysplastic nodules, the specificity was 50% vs 90% by CT/MRI. The positive role of CEUS in imaging spectrum of HCC included a provisional urgent diagnosis of an incidentally detected mass. It further led to a decrease in time for further management. A confident diagnosis on CEUS was possible in cases of characterization of an indeterminate mass, in situations where the patient was unfit for CT/MRI, was allergic to iodinated contrast or had claustrophobia, etc. CEUS was also cost effective, radiation free and an easy modality for monitoring post RFA or TACE lesions. CONCLUSION: CEUS is a valuable augmentation to the practice of ultrasonography, and an irreplaceable modality for confounding cases and interpretation of indeterminate lesions in imaging of HCC. PMID- 23807899 TI - Nanoscale Drug Delivery and Hyperthermia: The Materials Design and Preclinical and Clinical Testing of Low Temperature-Sensitive Liposomes Used in Combination with Mild Hyperthermia in the Treatment of Local Cancer. AB - The overall objective of liposomal drug delivery is to selectively target drug delivery to diseased tissue, while minimizing drug delivery to critical normal tissues. The purpose of this review is to provide an overview of temperature sensitive liposomes in general and the Low Temperature-Sensitive Liposome (LTSL) in particular. We give a brief description of the material design of LTSL and highlight the likely mechanism behind temperature-triggered drug release. A complete review of the progress and results of the latest preclinical and clinical studies that demonstrate enhanced drug delivery with the combined treatment of hyperthermia and liposomes is provided as well as a clinical perspective on cancers that would benefit from hyperthermia as an adjuvant treatment for temperature-triggered chemotherapeutics. This review discusses the ideas, goals, and processes behind temperature-sensitive liposome development in the laboratory to the current use in preclinical and clinical settings. PMID- 23807902 TI - Can imaging patterns of neuroendocrine hepatic metastases predict response yttruim-90 radioembolotherapy? AB - AIM: To evaluate the response to treatment in patients with neuroendocrine tumor liver metastases following yttrium-90 ((90)Y) radioembolotherapy, as a function of image patterns at presentation for (90)Y radioembolotherapy. METHODS: The study cohort consisted of patients with hepatic metastatic neuroendocrine tumors treated with (90)Y at our institution during a two-year time period. Hepatic metastases were evaluated on a pre-therapy study assessing relative arterial enhancement compared to liver, lesion size, necrosis of the lesion, and associated tumor burden in the liver. We used six response criteria: Response Evaluation Criteria in Solid Tumors (RECIST) size, World Health Organization (WHO) size, European Association for the Study of the Liver (EASL) necrosis guidelines, Choi size, Choi necrosis and combination of Choi size and necrosis. RESULTS: About 65 lesions in 17 patients met study criteria and formed the cohort. Statistically significant response was found for lesions < 5 cm vs those >= 5 cm with RECIST (P = 0.04), WHO (P = 0.002) and combined Choi criteria (P = 0.02). Hyperenhancing lesions demonstrated greater response only with the Choi size criteria (P = 0.04). Lesions with <= 50% necrosis on the pre-scan had statistically significant greater response with the Choi necrosis criteria (P = 0.01). There was no statistical significance for response comparing lesions < 2 cm vs >= 2 cm or in comparing the degrees of tumor burden. CONCLUSION: Based on our findings in this study, it is suggested that initial imaging findings, as listed above, are not a good predictor of response to (90)Y radioembolization. PMID- 23807903 TI - Helical tomotherapy and systemic targeted therapies in solitary plasmacytoma: Pilot study. AB - AIM: To assess the feasibility of the combination of helical tomotherapy((r)) (HT) and a concurrent systemic targeted therapy in patients with solitary plasmacytoma (SP) with the aim to decrease toxicity while improving therapeutic efficacy. METHODS: Six patients with biologically, histologically, and radiologically confirmed SP were treated using HT and a systemic targeted treatment concomitantly. Total dose was 40 Gy/20 fractions. Four patients received 4 cycles of concurrent lenalidomide-dexamethasone combination and two patients were treated with concomitant bortezomib-dexamethasone. All toxicities were described using the Common Terminology Criteria for Adverse Effects v3.0. RESULTS: Five patients had a bone tumor and one patient had an isolated pancreatic mass. Five patients presented with pain, one had neurologic symptoms related to medullary compression, which was treated by an emergency surgery. Median age was 59.5 years (range, 50-74 years). All patients had initial positron emission tomography-computed tomographys, three patients had total body bone magnetic resonance imaging examination, and three patients had computed tomodensitometry scans. The toxicity profile was excellent with no higher than grade 1 toxicity. Four of the six patients experienced a partial radiological response, four had complete response on positions emission tomography and 5/6 patients experienced a complete relief of their symptoms 4 mo after treatment. At a median follow-up of 18 mo, 5/6 patients were controlled clinically, radiologically, and biologically. CONCLUSION: Using HT, we could deliver a highly conformal irradiation concurrently with a molecularly targeted therapy. This association yielded in a high response rate and a low toxicity. A prospective study with longer follow-up will help determining the true benefit of such strategy. PMID- 23807904 TI - UNEXPECTED PRESENCE OF SOLUTE-FREE ZONES AT METAL-WATER INTERFACES. AB - Solute-free zones, termed "exclusion zones" are routinely seen next to hydrophilic surfaces in aqueous solution. Here we report similar zones next to various metals. The largest, approximately 200 um in width, was found adjacent to zinc. Other reactive metals, including aluminum, tin, lead, and tungsten exhibited distinct but smaller exclusion zones, while precious metals such as platinum and gold did not produce any. Electrical potential measurements showed positive potentials within the exclusion zones, while pH measurements revealed an abundance of OH- groups in the aqueous regions beyond the exclusion zones. A correspondence was found between exclusion-zone size and the respective metal's position within the galvanic series. The presence of these interfacial exclusion zones is unexpected, and may shed new light on electrochemical processes taking place at metal interfaces. PMID- 23807905 TI - Effects of medium and temperature on cellular responses in the superficial zone of hypo-osmotically challenged articular cartilage. AB - Osmotic loading of articular cartilage has been used to study cell-tissue interactions and mechanisms in chondrocyte volume regulation in situ. Since cell volume changes are likely to affect cell's mechanotransduction, it is important to understand how environmental factors, such as composition of the immersion medium and temperature affect cell volume changes in situ in osmotically challenged articular cartilage. In this study, chondrocytes were imaged in situ with a confocal laser scanning microscope (CLSM) through cartilage surface before and 3 min and 120 min after a hypo-osmotic challenge. Samples were measured either in phosphate buffered saline (PBS, without glucose and Ca(2+)) or in Dulbecco's modified Eagle's medium (DMEM, with glucose and Ca(2+)), and at 21 degrees C or at 37 degrees C. In all groups, cell volumes increased shortly after the hypotonic challenge and then recovered back to the original volumes. At both observation time points, cell volume changes as a result of the osmotic challenge were similar in PBS and DMEM in both temperatures. Our results indicate that the initial chondrocyte swelling and volume recovery as a result of the hypo osmotic challenge of cartilage are not dependent on commonly used immersion media or temperature. PMID- 23807907 TI - Predictors of Colorectal Cancer Survival in Golestan, Iran: A Population-based Study. AB - OBJECTIVES: We aimed to investigate factors associated with colorectal cancer survival in Golestan, Iran. METHODS: We used a population based cancer registry to recruit study subjects. All patients registered since 2004 were contacted and data were collected using structured questionnaires and trained interviewers. All the existing evidences to determine the stage of the cancer were also collected. The time from first diagnosis to death was compared in patients according to their stage of cancer using the Kaplan-Meir method. A Cox proportional hazard model was built to examine their survival experience by taking into account other covariates. RESULTS: Out of a total of 345 subjects, 227 were traced. Median age of the subjects was 54 and more than 42% were under 50 years old. We found 132 deaths among these patients, 5 of which were non-colorectal related deaths. The median survival time for the entire cohort was 3.56 years. A borderline significant difference in survival experience was detected for ethnicity (log rank test, p=0.053). Using Cox proportional hazard modeling, only cancer stage remained significantly associated with time of death in the final model. CONCLUSIONS: Colorectal cancer occurs at a younger age among people living in Golestan province. A very young age at presentation and what appears to be a high proportion of patients presenting with late stage in this area suggest this population might benefit substantially from early diagnoses by introducing age adapted screening programs. PMID- 23807908 TI - Factors Associated with a Low-sodium Diet: The Fourth Korean National Health and Nutrition Examination Survey. AB - OBJECTIVES: The low-sodium diet is a known preventive factor for hypertension and cardiovascular disease. Factors associated with low-sodium diets should be identified to reduce sodium intake effectively. This study was conducted to identify factors correlated with a low-sodium diet. METHODS: This cross-sectional study analyzed data from a total of 14,539 Koreans aged 20 years or older, who participated in the Fourth (2007-2009) Korean National Health and Nutrition Examination Survey. A low-sodium diet was defined as having <=2,000 mg/day based on 24-hour recalls. Multiple logistic regression models were used to assess sex, age, education, number of family members, household income, occupation, alcohol drinking, total energy intake, frequency of eating out, and hypertension management status for their associations with low-sodium diets. RESULTS: Among all participants, only 13.9% (n=2,016) had low-sodium diets. In the multivariate analysis, 40-49 years of age, clerical work jobs, higher total energy intake, and frequent eating out were inversely associated with low-sodium diets. And female sex and living-alone were associated with low-sodium diets. Lower frequency of eating out was significantly associated with low-sodium diets, even after adjusting for total energy intake and other potential confounders. Adjusted odds ratios (95% confidence interval) for a low-sodium diet were 1.97 (1.49-2.61), 1.47 (1.13-1.91), 1.24 (0.96-1.61), and 1.00 (reference) in people who eat out <1 time/month, 1-3 times/month, 1-6 times/week, and >=1 time/day, respectively. CONCLUSIONS: Our study suggests that sex, age, number of family members, occupation, total energy intake, and lower frequency of eating out were associated with a low-sodium diet in Korean adults. PMID- 23807910 TI - A review method for UML requirements analysis model employing system-side prototyping. AB - User interface prototyping is an effective method for users to validate the requirements defined by analysts at an early stage of a software development. However, a user interface prototype system offers weak support for the analysts to verify the consistency of the specifications about internal aspects of a system such as business logic. As the result, the inconsistency causes a lot of rework costs because the inconsistency often makes the developers impossible to actualize the system based on the specifications. For verifying such consistency, functional prototyping is an effective method for the analysts, but it needs a lot of costs and more detailed specifications. In this paper, we propose a review method so that analysts can verify the consistency among several different kinds of diagrams in UML efficiently by employing system-side prototyping without the detailed model. The system-side prototype system does not have any functions to achieve business logic, but visualizes the results of the integration among the diagrams in UML as Web pages. The usefulness of our proposal was evaluated by applying our proposal into a development of Library Management System (LMS) for a laboratory. This development was conducted by a group. As the result, our proposal was useful for discovering the serious inconsistency caused by the misunderstanding among the members of the group. PMID- 23807909 TI - Novel Fe3+-Based 1H MRI beta-Galactosidase Reporter Molecules** AB - There is increasing interest in the development of reporter agents to reveal enzyme activity in vivo using small animal imaging. We have previously demonstrated the feasibility of detecting lacZ gene activity using the commercially available 3,4-cyclohexenoesculetin-beta-D-galactopyranoside (S GalTM) as a 1H MRI reporter. Specifically, beta-galactosidase (beta-gal) releases the aglycone, which forms an MR contrast-inducing paramagnetic precipitate in the presence of Fe3+. Contrast was primarily T2-weighted signal loss, but T1 effects were also observed. Since T1-contrast generally provides signal enhancement as opposed to loss, it appeared attractive to explore whether analogues could be generated with enhanced characteristics. We now report the design and successful synthesis of novel analogues together with characterization of 1H MRI contrast based on both T1 and T2 response to beta-gal activity in vitro for the lead agent. PMID- 23807906 TI - B Cell in Autoimmune Diseases. AB - The role of B cells in autoimmune diseases involves different cellular functions, including the well-established secretion of autoantibodies, autoantigen presentation and ensuing reciprocal interactions with T cells, secretion of inflammatory cytokines, and the generation of ectopic germinal centers. Through these mechanisms B cells are involved both in autoimmune diseases that are traditionally viewed as antibody mediated and also in autoimmune diseases that are commonly classified as T cell mediated. This new understanding of the role of B cells opened up novel therapeutic options for the treatment of autoimmune diseases. This paper includes an overview of the different functions of B cells in autoimmunity; the involvement of B cells in systemic lupus erythematosus, rheumatoid arthritis, and type 1 diabetes; and current B-cell-based therapeutic treatments. We conclude with a discussion of novel therapies aimed at the selective targeting of pathogenic B cells. PMID- 23807912 TI - Demand spillovers of smash-hit papers: evidence from the 'Male Organ Incident'. AB - ABSTRACT: This study explores the short-run spillover effects of popular research papers. We consider the publicity of 'Male Organ and Economic Growth: Does Size Matter?' as an exogenous shock to economics discussion paper demand, a natural experiment of a sort. In particular, we analyze how the very substantial visibility influenced the downloads of Helsinki Center of Economic Research discussion papers. Difference in differences and regression discontinuity analysis are conducted to elicit the spillover patterns. This study finds that the spillover effect to average economics paper demand is positive and statistically significant. It seems that hit papers increase the exposure of previously less downloaded papers. We find that part of the spillover effect could be attributable to Internet search engines' influence on browsing behavior. Conforming to expected patterns, papers residing on the same web page as the hit paper evidence very significant increases in downloads which also supports the spillover thesis. JEL CLASSIFICATION: A11, C21. MSC CLASSIFICATION: 97K80. PMID- 23807911 TI - The melanocyte photosensory system in the human skin. AB - The pigment cells form the largest population of neural crest cells to migrate into the epidermis and hair follicle along each dermatomic area from the neural folds. The melanopsin system responsible for photoentrainment, was isolated from the photosensitive dermal melanophores of frogs Xenopus laevis responding to light. Melanocytes form a photoresponsive network which reads the environmental seasonal variations in the light cycles in the same manner. The present work was undertaken to study the organization of this system by: I. Experimental assessment of photoresponse and II. Evidence of an organized system of photoreception in the skin. Melanocytes, in whole skin organ cultures and epidermal strips, from margin of vitiligo in G2 phase show prominent dendricity, and express pigment, biogenic amines and hormones on UV exposure. The photoresponse depends on the photosensitive enzymes NAT/HIOMT and dopaoxidase. Melanocytes interact with adjacent keratinocytes, dermal capillaries, and nerve endings. The melanocyte network reads the diurnal and seasonal photophase by the melatonin/serotonin switch like the pineal. Sleep disorders and winter depression are corrected by phototherapy utilising this mechanism. Melanocytes showing photoactivity, aplasia, hypoplasia and hyperplasia, and interactive keratinocytes occupy the trigeminal, brachial and lumbosacral dermatomes, zones of high embryonic induction, forming an ectodermal placodal system. Melanin units and hair follicles serve as photoreceptors. Migration of active melanocytes to defined areas is evident in pigment patterns in guinea pigs. This study identifies defined photoreceptor melanocyte/epidermal domains which read the seasonal photophase and control the sleep waking cycle in response to the environmental light. I. Whole skin organ cultures, and epidermal strips from margin of vitiligo in G2 phase are exposed to UV and IR to study sequential and dose response of marginal melanocytes, using histochemistry, immunohistochemistry to assess pigment, biogenic amines and hormones on UV exposure. II. Dermatomic Distributions: Detailed maps of melanocyte photoresponse in 356 biopsies, lesions in 297 vitiligo, 100 melanosis, 165 melanomas 142 leprosy and 442 basal cell/keratinocytes lesions were assessed for patterns of dermatomic distribution. Embryonal melanocyte migration along dermatomes was assessed in 285 guinea pigs from an inbred colony having black, brown and white patches. PMID- 23807913 TI - Oryzias melastigma - an effective substitute for exotic larvicidal fishes: enhancement of its reproductive potential by supplementary feeding. AB - A preliminary study was conducted on the efficacy of Oryzias melastigma in consuming mosquito larva so as to control mosquito and mosquito borne diseases, and enhancing its reproductive success using supplementary feed. Oryzias melastigma is a larvivore fish and widely distributed in the shallow water, wetlands of Gangetic plains and peninsular India. These studies indicate that O. melastigma is a prolific breeder and gregarious feeder of mosquito larvae. Increased reproduction by providing different supplementary feed, of which Ulothrix acted remarkably, may aid in wide spread use of this fish as a biological control measure against mosquitoes. One adult fish of any sex can consume 87.1% first instars mosquito larvae/day. So, early stages of mosquito larvae are effectively controlled, as compared to other successive stages. Ulothrix has considerable effect on egg production, successful hatching and regaining reproductive maturity of female in surprisingly quicker interval. PMID- 23807914 TI - Research of thermal sensor allocation and placement based on dual clustering for microprocessors. AB - Dynamic thermal management techniques employ a set of on-chip thermal sensors to measure runtime thermal behavior of microprocessors so as to prevent the on-set of high temperatures. Therefore, effective analysis of thermal behavior and determination of the best allocation and placement of thermal sensors directly impact the effectiveness of the dynamic thermal management mechanisms. In this paper, we propose systematic and effective techniques for determining the fewest number of thermal sensors and the optimal locations based on dual clustering to provide a high fidelity thermal monitoring. Initially, we utilize the dual clustering algorithm to devise method that can reduce the number of sensors to a great extent while satisfying an expected accuracy. Then we identify an optimal physical location for each sensor such that the sensor's attraction towards steep thermal gradient is maximized. Experimental results indicate the superiority of our techniques and confirm that our proposed methods are capable of creating a sensor distribution for a given microprocessor architecture using the number of thermal sensors of 2, 8, 15, 24, 35, depending on different expected hot spot temperature error accuracy of 5%, 4%, 3%, 2%, 1%, respectively. PMID- 23807915 TI - Euthanasia tactics: patterns of injustice and outrage. AB - Struggles over euthanasia can be examined in terms of tactics used by players on each side of the issue to reduce outrage from actions potentially perceived as unjust. From one perspective, the key injustice is euthanasia itself, especially when the person or relatives oppose death. From a different perspective, the key injustice is denial of euthanasia, seen as a person's right to die. Five types of methods are commonly used to reduce outrage from something potentially seen as unjust: covering up the action; devaluing the target; reinterpreting the action, including using lying, minimising consequences, blaming others and benign framing; using official channels to give an appearance of justice; and using intimidation. Case studies considered include the Nazi T4 programme, euthanasia in contemporary jurisdictions in which it is legal, and censorship of Exit International by the Australian government. By examining euthanasia struggles for evidence of the five types of tactics, it is possible to judge whether one or both sides use tactics characteristic of perpetrators of injustice. This analysis provides a framework for examining tactics used in controversial health issues. PMID- 23807916 TI - Identification, technological and safety characterization of Lactobacillus sakei and Lactobacillus curvatus isolated from Argentinean anchovies (Engraulis anchoita). AB - In this study, the identification and characterization of Lactobacillus previously isolated from fresh anchovies (Engraulis anchoita) are investigated. 16S rDNA partial sequencing assigned all the isolates to belong to the Lactobacillus sakei/curvatus group. Fourteen out of 15 isolates were identified as L. sakei by phenotypic traits: they exhibited catalase activity and fermented melibiose, although only 10 of them hydrolyzed arginine. These results were confirmed by multiplex PCR-based restriction enzyme analysis with HindIII and by restriction fragment length polymorphic (RFLP) analysis of the 16S-23S rDNA intergenic spacer region with TaqI. Among identified isolates, four L. sakei strains and the sole L. curvatus strain showing sensitivity to chloramphenicol, erythromycin and tetracycline and exhibiting high tolerance to NaCl (10-18%) were unable to produce neither dextran nor biogenic amines. Based on technological and safety features, L. sakei SACB704 and L. curvatus SACB03a naturally present in fresh anchovies may be promising strains for the development of a starter culture to accelerate and control the fermentation of salt fermented anchovy-based products. PMID- 23807917 TI - Neonatal diabetes caused by activating mutations in the sulphonylurea receptor. AB - Adenosine triphosphate (ATP)-sensitive potassium (KATP) channels in pancreatic beta-cells play a crucial role in insulin secretion and glucose homeostasis. These channels are composed of two subunits: a pore-forming subunit (Kir6.2) and a regulatory subunit (sulphonylurea receptor-1). Recent studies identified large number of gain of function mutations in the regulatory subunit of the channel which cause neonatal diabetes. Majority of mutations cause neonatal diabetes alone, however some lead to a severe form of neonatal diabetes with associated neurological complications. This review focuses on the functional effects of these mutations as well as the implications for treatment. PMID- 23807919 TI - The effects of green tea on obesity and type 2 diabetes. PMID- 23807918 TI - Chemokine systems link obesity to insulin resistance. AB - Obesity is a state of chronic low-grade systemic inflammation. This chronic inflammation is deeply involved in insulin resistance, which is the underlying condition of type 2 diabetes and metabolic syndrome. A significant advance in our understanding of obesity-associated inflammation and insulin resistance has been recognition of the critical role of adipose tissue macrophages (ATMs). Chemokines are small proteins that direct the trafficking of immune cells to sites of inflammation. In addition, chemokines activate the production and secretion of inflammatory cytokines through specific G protein-coupled receptors. ATM accumulation through C-C motif chemokine receptor 2 and its ligand monocyte chemoattractant protein-1 is considered pivotal in the development of insulin resistance. However, chemokine systems appear to exhibit a high degree of functional redundancy. Currently, more than 50 chemokines and 18 chemokine receptors exhibiting various physiological and pathological properties have been discovered. Therefore, additional, unidentified chemokine/chemokine receptor pathways that may play significant roles in ATM recruitment and insulin sensitivity remain to be fully identified. This review focuses on some of the latest findings on chemokine systems linking obesity to inflammation and subsequent development of insulin resistance. PMID- 23807920 TI - An In Vitro Model to Probe the Regulation of Adipocyte Differentiation under Hyperglycemia. AB - BACKGROUND: The aim of this study was an in vitro investigation of the effect of high glucose concentration on adipogenesis, as prolonged hyperglycemia alters adipocyte differentiation. METHODS: 3T3-L1 preadipocytes differentiated in the presence of varying concentrations of glucose (25, 45, 65, 85, and 105 mM) were assessed for adipogenesis using AdipoRed (Lonza) assay. Cell viability and proliferation were measured using MTT reduction and [(3)H] thymidine incorporation assay. The extent of glucose uptake and glycogen synthesis were measured using radiolabelled 2-deoxy-D-[1-(3)H] glucose and [(14)C]-UDP-glucose. The gene level expression was evaluated using reverse transcription-polymerase chain reaction and protein expression was studied using Western blot analysis. RESULTS: Glucose at 105 mM concentration was observed to inhibit adipogenesis through inhibition of CCAAT-enhancer-binding proteins, sterol regulatory element binding protein, peroxisome proliferator-activated receptor and adiponectin. High concentration of glucose induced stress by increasing levels of toll-like receptor 4, nuclear factor kappaB and tumor necrosis factor alpha thereby generating activated preadipocytes. These cells entered the state of hyperplasia through inhibition of p27 and proliferation was found to increase through activation of protein kinase B via phosphoinositide 3 kinase dependent pathway. This condition inhibited insulin signaling through decrease in insulin receptor beta. Although the glucose transporter 4 (GLUT4) protein remained unaltered with the glycogen synthesis inhibited, the cells were found to exhibit an increase in glucose uptake via GLUT1. CONCLUSION: Adipogenesis in the presence of 105 mM glucose leads to an uncontrolled proliferation of activated preadipocytes providing an insight towards understanding obesity. PMID- 23807921 TI - Safety and efficacy of modern insulin analogues. AB - BACKGROUND: A1chieve(r) was a noninterventional study evaluating the clinical safety and efficacy of biphasic insulin aspart 30, insulin detemir, and insulin aspart. METHODS: Korean type 2 diabetes patients who have not been treated with the study insulin or have started it within 4 weeks before enrollment were eligible for the study. The patient selection and the choice of regimen were at the discretion of the physician. The safety and efficacy information was collected from the subjects at baseline, week 12, and week 24. The number of serious adverse drug reactions (SADRs) was the primary endpoint. The changes of clinical diabetic markers at week 12 and/or at week 24 compared to baseline were the secondary endpoints. RESULTS: Out of 4,058 exposed patients, 3,003 completed the study. During the study period, three SADRs were reported in three patients (0.1%). No major hypoglycemic episodes were observed and the rate of minor hypoglycemic episodes marginally decreased during 24 weeks (from 2.77 to 2.42 events per patient-year). The overall quality of life score improved (from 66.7+/ 15.9 to 72.5+/-13.5) while the mean body weight was slightly increased (0.6+/-3.0 kg). The 24-week reductions in glycated hemoglobin, fasting plasma glucose and postprandial plasma glucose were 1.6%+/-2.2%, 2.5+/-4.7 mmol/L, and 4.0+/-6.4 mmol/L, respectively. CONCLUSION: The studied regimens showed improvements in glycemic control with low incidence of SADRs, including no incidence of major hypoglycemic episodes in Korean patients with type 2 diabetes. PMID- 23807922 TI - Corrected QT Interval Prolongation during Severe Hypoglycemia without Hypokalemia in Patients with Type 2 Diabetes. AB - BACKGROUND: To evaluate the effects of severe hypoglycemia without hypokalemia on the electrocardiogram in patients with type 2 diabetes in real-life conditions. METHODS: Electrocardiograms of adult type 2 diabetic patients during the episodes of severe hypoglycemia and the recovered stage were obtained and analysed between October 1, 2011 and May 31, 2012. Patients who maintained the normal serum sodium and potassium levels during the episodes of severe hypoglycemia were only selected as the subjects of this study. Severe hypoglycemia was defined, in this study, as the condition requiring active medical assistance such as administering carbohydrate when serum glucose level was less than 60 mg/dL. RESULTS: Nine type 2 diabetes patients (seven men, two women) were included in the study. The mean subject age was 73.2+/-7.7 years. The mean hemoglobin A1c level was 6.07%+/ 1.19%. The median duration of diabetes was 10 years (range, 3.5 to 30 years). Corrected QT (QTc) intervals were significantly increased during the episodes of severe hypoglycemia compared to the recovered stage (447.6+/-18.2 ms vs. 417.2+/ 30.6 ms; P<0.05). However, the morphology and the amplitude of the T waves were not changed and ST-segment elevation and/or depression were not found during the episodes of severe hypoglycemia. CONCLUSION: In this study, QTc interval prolongation during the episodes of severe hypoglycemia was observed without hypokalemia. Therefore, the distinct alterations in cardiac repolarization during the episodes of severe hypoglycemia may not be associated with hypokalemia. PMID- 23807923 TI - Effect of Green Tea Extract/Poly-gamma-Glutamic Acid Complex in Obese Type 2 Diabetic Mice. AB - BACKGROUND: The increasing prevalence of type 2 diabetes mellitus (T2DM) is associated with the rapid spread of obesity. Obesity induces insulin resistance, resulting in beta-cell dysfunction and thus T2DM. Green tea extract (GTE) has been known to prevent obesity and T2DM, but this effect is still being debated. Our previous results suggested that circulating green tea gallated catechins (GCs) hinders postprandial blood glucose lowering, regardless of reducing glucose and cholesterol absorption when GCs are present in the intestinal lumen. This study aimed to compare the effect of GTE with that of GTE coadministered with poly-gamma-glutamic acid (gamma-PGA), which is likely to inhibit the intestinal absorption of GCs. METHODS: The db/db mice and age-matched nondiabetic mice were provided with normal chow diet containing GTE (1%), gamma-PGA (0.1%), or GTE+gamma-PGA (1%:0.1%) for 4 weeks. RESULTS: In nondiabetic mice, none of the drugs showed any effects after 4 weeks. In db/db mice, however, weight gain and body fat gain were significantly reduced in the GTE+gamma-PGA group compared to nondrug-treated db/db control mice without the corresponding changes in food intake and appetite. Glucose intolerance was also ameliorated in the GTE+gamma PGA group. Histopathological analyses showed that GTE+gamma-PGA-treated db/db mice had a significantly reduced incidence of fatty liver and decreased pancreatic islet size. Neither GTE nor gamma-PGA treatment showed any significant results. CONCLUSION: These results suggest that GTE+gamma-PGA treatment than GTE or gamma-PGA alone may be a useful tool for preventing both obesity and obesity induced T2DM. PMID- 23807924 TI - Beneficial Effects of Omega-3 Fatty Acids on Low Density Lipoprotein Particle Size in Patients with Type 2 Diabetes Already under Statin Therapy. AB - Beyond statin therapy for reducing low density lipoprotein cholesterol (LDL-C), additional therapeutic strategies are required to achieve more optimal reduction in cardiovascular risk among diabetic patients with dyslipidemia. To evaluate the effects and the safety of combined treatment with omega-3 fatty acids and statin in dyslipidemic patients with type 2 diabetes, we conducted a randomized, open label study in Korea. Patients with persistent hypertriglyceridemia (>=200 mg/dL) while taking statin for at least 6 weeks were eligible. Fifty-one patients were randomized to receive either omega-3 fatty acid 4, 2 g, or no drug for 8 weeks while continuing statin therapy. After 8 weeks of treatment, the mean percentage change of low density lipoprotein (LDL) particle size and triglyceride (TG) level was greater in patients who were prescribed 4 g of omega-3 fatty acid with statin than in patients receiving statin monotherapy (2.8%+/-3.1% vs. 2.3%+/-3.6%, P=0.024; -41.0%+/-24.1% vs. -24.2%+/-31.9%, P=0.049). Coadministration of omega-3 fatty acids with statin increased LDL particle size and decreased TG level in dyslipidemic patients with type 2 diabetes. The therapy was well tolerated without significant adverse effects. PMID- 23807925 TI - Letter: efficacy and safety of biphasic insulin aspart 30/70 in type 2 diabetes suboptimally controlled on oral antidiabetic therapy in Korea: a multicenter, open-label, single-arm study (diabetes metab j 2013;37:117-24). PMID- 23807926 TI - Response: efficacy and safety of biphasic insulin aspart 30/70 in type 2 diabetes suboptimally controlled on oral antidiabetic therapy in Korea: a multicenter, open-label, single-arm study (diabetes metab j 2013;37:117-24). PMID- 23807928 TI - Patient radiation dose and protection from cone-beam computed tomography. AB - After over one decade development, cone beam computed tomography (CBCT) has been widely accepted for clinical application in almost every field of dentistry. Meanwhile, the radiation dose of CBCT to patient has also caused broad concern. According to the literature, the effective radiation doses of CBCTs in nowadays market fall into a considerably wide range that is from 19 uSv to 1073 uSv and closely related to the imaging detector, field of view, and voxel sizes used for scanning. To deeply understand the potential risk from CBCT, this report also reviewed the effective doses from literatures on intra-oral radiograph, panoramic radiograph, lateral and posteroanterior cephalometric radiograph, multi-slice CT, and so on. The protection effect of thyroid collar and leaded glasses were also reviewed. PMID- 23807929 TI - Position of the mental foramen in a Moroccan population: A radiographic study. AB - PURPOSE: This study was performed to determine the position of the mental foramen relative to the apices of the teeth based on panoramic radiographs in a Moroccan population. We also analyzed gender differences and the symmetry of location within individuals. MATERIALS AND METHODS: Seven hundred ninety-four panoramic radiographs were evaluated with regard to the location and symmetry of the mental foramina in male and female subjects. The results were analyzed using Pearson's chi(2) and Fisher's exact test. RESULTS: Of the 794 panoramic radiographs, 377 met the inclusion criteria for at least one side. The mental foramen was located just below the apex of the second premolar in 62.7% of the patients and between the first and second premolars in 30%. It was symmetrically located in 79%. No statistically significant differences were found between males and females in the position and symmetry of the mental foramen. CONCLUSION: The most common position for the mental foramen in this sample was in line with the second premolar. PMID- 23807930 TI - Effective dose from direct and indirect digital panoramic units. AB - PURPOSE: This study aimed to provide comparative measurements of the effective dose from direct and indirect digital panoramic units according to phantoms and exposure parameters. MATERIALS AND METHODS: Dose measurements were carried out using a head phantom representing an average man (175 cm tall, 73.5 kg male) and a limbless whole body phantom representing an average woman (155 cm tall, 50 kg female). Lithium fluoride thermoluminescent dosimeter (TLD) chips were used for the dosimeter. Two direct and 2 indirect digital panoramic units were evaluated in this study. Effective doses were derived using 2007 International Commission on Radiological Protection (ICRP) recommendations. RESULTS: The effective doses of the 4 digital panoramic units ranged between 8.9 uSv and 37.8 uSv. By using the head phantom, the effective doses from the direct digital panoramic units (37.8 uSv, 27.6 uSv) were higher than those from the indirect units (8.9 uSv, 15.9 uSv). The same panoramic unit showed the difference in effective doses according to the gender of the phantom, numbers and locations of TLDs, and kVp. CONCLUSION: To reasonably assess the radiation risk from various dental radiographic units, the effective doses should be obtained with the same numbers and locations of TLDs, and with standard hospital exposure. After that, it is necessary to survey the effective doses from various dental radiographic units according to the gender with the corresponding phantom. PMID- 23807931 TI - A cone-beam computed tomography evaluation of buccal bone thickness following maxillary expansion. AB - PURPOSE: This study was performed to determine the buccal alveolar bone thickness following rapid maxillary expansion (RME) using cone-beam computed tomography (CBCT). MATERIALS AND METHODS: Twenty-four individuals (15 females, 9 males; 13.9 years) that underwent RME therapy were included. Each patient had CBCT images available before (T1), after (T2), and 2 to 3 years after (T3) maxillary expansion therapy. Coronal multiplanar reconstruction images were used to measure the linear transverse dimensions, inclinations of teeth, and thickness of the buccal alveolar bone. One-way ANOVA analysis was used to compare the changes between the three times of imaging. Pairwise comparisons were made with the Bonferroni method. The level of significance was established at p<0.05. RESULTS: The mean changes between the points in time yielded significant differences for both molar and premolar transverse measurements between T1 and T2 (p<0.05) and between T1 and T3 (p<0.05). When evaluating the effect of maxillary expansion on the amount of buccal alveolar bone, a decrease between T1 and T2 and an increase between T2 and T3 were found in the buccal bone thickness of both the maxillary first premolars and maxillary first molars. However, these changes were not significant. Similar changes were observed for the angular measurements. CONCLUSION: RME resulted in non-significant reduction of buccal bone between T1 and T2. These changes were reversible in the long-term with no evident deleterious effects on the alveolar buccal bone. PMID- 23807932 TI - The relationship between radiological features and clinical manifestation and dental expenses of keratocystic odontogenic tumor. AB - PURPOSE: This study was performed to identify correlations between keratocystic odontogenic tumor (KCOT) data from CT sections, and data on the KCOT clinical manifestation and resulting dental expenses. MATERIALS AND METHODS: Following local Institutional Review Board (IRB) approval, a seven-years of retrospective study was performed regarding patients with KCOTs treated at the Seoul National University Dental Hospital. A total of 180 KCOT were included in this study. The following information was collected: age, gender, location and size of the lesion, radiological features, surgical treatment provided and dental expenses. RESULTS: There was no significant association between the size of the KCOT and age, gender, and presenting preoperative symptoms. In both jaws, it was unusual to find KCOTs under 10 mm. The correlation between the number of teeth removed and the size of the KCOT in the tooth bearing area was statistically significant in the mandible, whereas in the maxilla, no significant relationship was found. Dental expenses compared with the size of the KCOT were found to be significant in both jaws. CONCLUSION: The size of KCOT was associated with a significant increase in dental expenses for both jaws and the number of teeth removed from the mandible. These findings emphasize the importance of routine examinations and early detection of lesions, which in turn helps preserving anatomical structures and reducing dental expenses. PMID- 23807933 TI - Clinical usefulness of teleradiology in general dental practice. AB - PURPOSE: This study was performed to investigate the clinical usefulness of teleradiology in general dental practice. MATERIALS AND METHODS: Two hundred and seventy five cases were submitted for inquiry to the case presentation board of the website of The Korean Academy of Oral and Maxillofacial Radiology for a 5 year periods. The diagnosis results of those cases were analyzed according to the disease classification, the correlation with the patient's chief complaint, the necessity of additional examinations or treatments, the image modalities, and the number of dentists inquiring. RESULTS: Differential diagnoses of normal anatomic structures were the most frequently submitted cases, covering 15.6% of all cases. Among 275 cases, 164 cases required no additional treatments or examinations. Panoramic radiographs were the most frequently submitted images, accounting for 248 inquiries. The 275 cases were submitted by 96 dentists. Fifty-two dentists wrote one inquiry, and 44 inquired 2 or more times. The average inquiry number of the latter group was 5.0 cases. CONCLUSION: A teleradiology system in general dental practice could be helpful in the differential diagnosis of common lesions and reduce unnecessary costs. PMID- 23807934 TI - Comparison of panoramic radiography with cone beam CT in predicting the relationship of the mandibular third molar roots to the alveolar canal. AB - PURPOSE: Preoperative radiographic assessment of the mandibular third molars is essential to prevent inferior alveolar nerve damage during extraction. The purpose of this study was to assess the reliability of panoramic signs of association between the roots of teeth and the canal, and to compare the panoramic signs with cone beam computed tomography (CBCT) findings. MATERIALS AND METHODS: CBCT images of 132 impacted mandibular third molars were evaluated to determine the association of the root to the canal. The CBCT findings were compared with the corresponding panoramic images. Logistic regression analysis was used to define the diagnostic criteria of the panoramic images. RESULTS: AMONG THE PANORAMIC SIGNS, LOSS OF THE CORTICAL LINE WAS THE MOST FREQUENT RADIOGRAPHIC SIGN PREDICTING ASSOCIATION (SENSITIVITY: 79.31). Contact of the tooth with the canal was observed in all cases in which the loss of cortical line of the canal or darkening of the roots was found on the panoramic radiographs. CONCLUSION: Darkening of the roots and loss of the cortical line on panoramic radiographs might be highly suggestive of the risk of nerve injury. PMID- 23807935 TI - Adenomatoid odontogenic tumor of the mandible with unusual radiographic features: A case report. AB - Adenomatoid odontogenic tumor (AOT) usually presents as a unilocular, pericoronal radiolucency in the maxillary anterior region in adolescent females. Very few conditions occur in such a narrow age range and at such a restrictive site. Rarely, these tumors present with varied clinical features. A case of AOT of the mandible is reported with unusual features such as large size, multilocular appearance, and aggressive behavior. The role of radiology in diagnosis of atypical AOT is extremely important. The unique radiological manifestations of the lesion helped in the diagnosis, and it was managed conservatively with no evidence of recurrence. PMID- 23807936 TI - Eosinophilic granuloma in the anterior mandible mimicking radicular cyst. AB - Eosinophilic granuloma is a common expression of Langerhans cell histiocytosis and corresponds with typical bone lesions. The radiographic appearance of eosinophilic granuloma in the jaw is variable and not specific. It may resemble periodontitis, radicular cyst, or malignancies. The purpose of this report is to describe the characteristic radiographic features of eosinophilic granuloma of a 39-year-old male. The lesion in the anterior mandible was first diagnosed as radicular cyst because the radiographic findings were ovoid radiolucent lesion with well-defined border. However, careful interpretation revealed a non corticated border and floating tooth appearance that were the characteristic radiographic features for the differential diagnosis. Early clinical signs of eosinophilic granuloma can occur in the jaw and a bony destructive lesion might be mistaken for periodontitis or an odontogenic cystic lesion; therefore, careful interpretation of radiographs should be emphasized. PMID- 23807937 TI - Mandibular lateral incisor with four root canals: A unique case of double tooth diagnosed using multidetector computed tomography. AB - Double tooth is a dental anomaly consequent to fusion of two or more teeth or gemination of a single tooth. This report describes a unique case of double tooth in relation to a mandibular lateral incisor exhibiting the presence of four root canals. The role of conventional radiography and advanced three-dimensional imaging techniques in the better assessment of complex root canal systems and their aid in endodontic management has also been highlighted. PMID- 23807938 TI - A unique case of Turner syndrome accompanying prolactinoma and unexpected elongated styloid process: Clinical and cone-beam computed tomographic features. AB - Turner syndrome (TS) is one of the most common chromosomal abnormalities, with an estimated frequency among female live births of 1/2,000-3,000. The syndrome is characterized by the partial or complete absence of one X chromosome (45,X karyotype). We reported a unique case of a 40-year-old woman with TS accompanying unexpected elongated styloid process specific to Eagle syndrome (ES) and followed up-prolactinoma. The present article is the first report to define the cone-beam computed tomographic (CBCT) features of TS accompanying ES. Patients with TS carry various risks that make treatment more complicated; thus advanced imaging techniques for proper treatment and follow-up are extremely important. In the light of CBCT examination, craniofacial abnormalities specific to TS and accompanying syndromes such as the crowding of teeth especially in the maxillary anterior region caused by maxillary narrowness, micrognatic maxilla and mandible, relative mandibular retrusion, malocclusion, open-bite, and an elongated styloid process (length of 32.7 mm) on the right side were illustrated in detail. PMID- 23807939 TI - Bedaquiline for the treatment of pulmonary, multidrug-resistant tuberculosis in adults. AB - After AIDS, tuberculosis (TB) is the leading killer worldwide due to a single infectious agent. Recently, drug-resistant strains of Mycobacterium tuberculosis elicited even more severe versions of TB. Bedaquiline inhibits mycobacterial ATP synthase. It shows potent and selective activity in vitro against M. tuberculosis, and in vivo against murine models of TB. Bedaquiline can be combined with antituberculosis and antiretroviral agents. The product displays good oral absorption, has a long terminal half-life and is metabolized mainly by cytochrome P450 3A4. In a phase II clinical trial in patients with multidrug resistant TB, bedaquiline (combined with the standard five-drug, second-line TB regimen), showed a time to 50% culture negative conversion of 78 days, with 81.0% and 52.4% efficacy at weeks 24 and 104, respectively. Bedaquiline was generally safe and well tolerated. At the end of 2012, the U.S. Food and Drug Administration approved bedaquiline (Sirturo(r)) as part of a combination therapy to treat adults with multidrug-resistant TB. PMID- 23807940 TI - Canagliflozin for the treatment of type 2 diabetes. AB - Canagliflozin, an oral inhibitor of sodium/glucose cotransporter 2 (SGLT2) in the kidneys, leads to glucosuria and provides a unique mechanism to lower blood glucose levels in diabetes. It corrects a novel pathophysiological defect, has an insulin-independent action, reduces HbA1c by 0.5 to 1.1%, promotes weight loss, has a low incidence of hypoglycemia, complements the action of other antidiabetic agents, can be used at any stage of diabetes and appears to be safe in patients with compromised renal function. Due to side effects such as urinary tract and genital infections and decrease in blood pressure, proper patient selection for drug initiation and close monitoring will be important. Results of ongoing cardiovascular safety trials are important to determine the risk-benefit ratio. Canagliflozin is the first oral SGLT2 inhibitor approved in the U.S. market and it represents a promising approach for the treatment of diabetes in this era of increasing obesity. PMID- 23807941 TI - Dabrafenib in the treatment of advanced melanoma. AB - Advanced melanoma has long been a challenging malignancy to treat due to a relative paucity of efficacious therapeutic options. However, the identification of activating BRAF mutations in approximately 50% of patients with cutaneous melanoma has ushered in the era of targeted therapy for melanoma patients. Similar to the first-in-class selective serine/threonine-protein kinase B-raf inhibitor vemurafenib, dabrafenib is highly efficacious in melanoma patients with BRAF V600E mutations, with response rates of approximately 50% and progression free survival of 6 months. There is data to suggest that dabrafenib not only shows activity in V600E-mutated melanoma, but also in non-V600E BRAF-mutated disease such as V600K. There is also early data to suggest that dabrafenib is effective in controlling metastases in the brain. Combining dabrafenib with the selective mitogen-activated protein kinase kinase (MEK) inhibitor trametinib has been effective in improving both the progression-free survival and overall survival of melanoma patients over those patients treated with dabrafenib alone. Dabrafenib is still being evaluated in several clinical trials in melanoma as well as a variety of other solid tumors with BRAF mutations. The U.S. Food and Drug Administration has recently approved dabrafenib as a single agent for the treatment of unresectable or metastatic melanoma in adult patients with BRAF V600E mutation. PMID- 23807942 TI - Insulin degludec: a long-acting modern insulin analogue with a predictable pharmacokinetic/pharmacodynamic profile. AB - Insulin degludec is, like insulin detemir, a product of coupling of Des-B30 threonine insulin to fatty acid side chains. After injection, degludec self associates, precipitating in subcutaneous tissue. There is a continuous and highly predictable slow dissociation of insulin monomers from this depot; insulin levels rise immediately reaching tmax at 10-12 hours, followed by a slow decline with a t1/2 of 17-21 hours, roughly double the duration of action of insulin glargine. An important property of degludec not shared by glargine is miscibility with rapid-acting insulin. Although the effect of coadministered insulin aspart is somewhat blunted by coformulation with degludec, a preparation of 70% degludec and 30% aspart has predictable pharmacodynamics. Daily administration of degludec has glucose-lowering benefits not different from those of glargine, with purportedly less hypoglycemia. Although degludec is approved and marketed in Europe under the brand name Tresiba(r), the U.S. Food and Drug Administration, in a surprising development, challenged the assertion of lower tendency to hypoglycemia with degludec, and, more importantly, raised concerns that degludec may have a higher cardiovascular risk than glargine. Only a long-term study in a large patient population can resolve these questions. However, release of degludec for marketing to appropriate patients should proceed while awaiting the results of such a study. PMID- 23807943 TI - White paper: an outlook on U.S. biosimilar competition. AB - The pharmaceutical industry is experiencing change in ways it hasn't ever before. One topic at the center of all of these changes is the U.S. biosimilars market. This report will provide updates and changes associated with biosimilar regulations in the U.S. Additionally, the paper will identify requirements for success, and the likely early entrants in the U.S. market. PMID- 23807944 TI - A report from the 26th International Conference on Antiviral Research (May 11-15, San Francisco, California, USA). AB - As described in the following report, numerous research programs reported during this year's International Conference on Antiviral Research (ICAR) in San Francisco resulted in novel agents with antiviral activity against a number of viral pathogens, including programs aimed at compounds active against specific pathogens as well as broad preclinical research that identified compounds with putative activity against many virus families. As an example of the latter, a research program was reported that identified compounds with activity against HIV 1 and -2, herpes virus, influenza virus and Coxsackie virus (Dejmek, M. et al., Abst 35), while studies with Griffithsin, a red algae-derived protein with potent, broad antiviral activity against hepatitis C virus, coronavirus and Japanese encephalitis virus, among others, showed it also inhibited HIV, although only when the tight dimer structure is respected (Xue, J. et al., Abst 104). PMID- 23807945 TI - Melamine modified gold nanoprobe for "on-spot" colorimetric recognition of clonazepam from biological specimens. AB - Inexpensive, rapid, and reliable methods of detection are crucial to the control of toxicological investigations. Here we report a highly sensitive, selective and cost effective method for the detection of trace amounts of clonazepam based on gold nanoparticles (AuNPs) in the presence of melamine. Hydrogen bonding interactions between clonazepam and melamine resulted in the aggregation of AuNPs and a consequent color change of AuNPs from wine red to blue. The results showed that the absorption ratio (A636/A552) was linear for clonazepam concentrations in the range of 10 * 10(-8) to 1.0 * 10(-9) M (R(2) = 0.999). The detection limit was 8.9 * 10(-10) M (S/N = 3), which was much lower than that of most existing methods. Coexisting substances including alprazolam, diazepam, nitrazepam and lorazepam did not affect the determination of clonazepam. The sensor developed by this new approach could be used as a spot test and a good alternative means for on-site and real time screening of clonazepam. This proposed scheme was also supported by the use of real samples such as skeletal remains and blood to illustrate the applicability of the developed nanosensor by a series of experiments. PMID- 23807946 TI - Aptamer-directed lanthanide chelate self-assembly for rapid thrombin detection. AB - We report a sensitive assay method for homogeneous thrombin detection. The method is based on lanthanide chelate complementation, where the luminescent complex is split into two separate label moieties, which are intrinsically non-luminescent. A luminescent mixed chelate complex is formed only when the label moieties are brought into close proximity directed by two separate binding events of aptamers to the analyte. This results in high specificity in signal generation while time resolved fluorescence detection eliminates the short lifetime autofluorescence, which is inherent to many homogeneous assays and limits their applicability. The developed method is also very rapid as the maximum signal is obtained in just five minutes. Lanthanide chelate complementation can be applied for the detection of other proteins when two binders recognizing separate epitopes of the analyte are available. PMID- 23807947 TI - Get rub-on relief for arthritis joint pain. Anti-inflammatory medications applied to the skin as creams, gels, sprays, or patches work best for mild to moderate pain near the surface. PMID- 23807948 TI - January is not too late to benefit from a flu shot. PMID- 23807949 TI - On call. I heard that there is a new pneumonia shot. Is it better than the old one? PMID- 23807950 TI - On call. I have read several news reports that claim finasteride, which I take for my prostate problem, can cause permanent impotence. Should I be concerned? PMID- 23807951 TI - Blood pressure: what's food got to do with it? If you follow the basics, healthy eating can lower your blood pressure as much as a medication. But it takes work. PMID- 23807952 TI - On call. I have been experiencing strong muscle cramps that curl my fingers into a claw shape, which I can straighten only by using the other hand. How can I prevent this? PMID- 23807953 TI - On call. Does chelation therapy work for heart disease? I have a friend who swears it will help him avoid having a second heart attack. PMID- 23807954 TI - Do CT scans cause cancer? For older men the risk from diagnostic CT scans is relatively small. PMID- 23807955 TI - Active surveillance: an option for low-risk prostate cancer. For some men, the smartest move after diagnosis may be to delay treatment and carefully watch the progression of the cancer. PMID- 23807956 TI - Social engagement and healthy aging. A rich web of human relationships enhances your health and stimulates your mind and memory. PMID- 23807957 TI - Survey reveals state of heart health in America. PMID- 23807958 TI - Regular exercise extends life. PMID- 23807959 TI - Statins linked to leg pain but not weakness. PMID- 23807960 TI - Exercising improves walking speed for people with Parkinson's. PMID- 23807961 TI - Can estimated breastfeeding support breastfeeding in the nicu? PMID- 23807962 TI - Transitioning premature infants supine. PMID- 23807963 TI - First, do no harm: single-use/single-dose vials. PMID- 23807964 TI - Effect of intravenous paracetamol on postoperative morphine requirements for major noncardiac surgery. PMID- 23807965 TI - Docosahexaenoic and arachidonic acid levels in ELBW infants with prolonged exposure to intravenous lipids. PMID- 23807966 TI - Outbreak news. Poliomyelitis, Somalia and Kenya. PMID- 23807967 TI - Global Alliance for the Elimination of Blinding Trachoma by 2020. PMID- 23807968 TI - Nationwide rubella epidemic in Japan, 2013. PMID- 23807969 TI - The "Stop Transmission of Polio (STOP)" programme of the Global Polio Eradication Initiative, 1999-2013. PMID- 23807970 TI - Performance of acute flaccid paralysis (AFP) surveillance and incidence of poliomyelitis,2013. PMID- 23807971 TI - Monthly report on dracunculiasis cases, January-April 2013. PMID- 23807972 TI - Making a difference through colorectal cancer screening. PMID- 23807973 TI - [Biometry and assessment of the levator hiatus by three-dimensional pelvic floor ultrasound]. AB - Images of the levator hiatus in 40 nulliparous, 40 asymptomatic parous women and 40 women with pelvic organ prolapse were obtained by transperineal/translabial three-dimentional ultrasonography of the pelvic floor. Volumes were taken at rest and during squeezing. Recontructed images of the levator hiatus at the plane of minimal dimentions were obtained by off-line processing of the stored volumes. The transverse, the longitudinal diameter and the area of the levator hiatus were measured at rest and during squeezing in the three groups. Qualitative assessment of the shape and the symmetry of the levator hiatus at rest was made, too. The average hiatal dimentions (transverse, longitudinal diameter and hiatal area) measured at rest in the three groups were: 35.8 mm, 43.1 mm and 11.84 cm2 in the nulliparous; 43.6 mm, 47.1 mm and 15.1 cm2 in the asymptomatic parous women and 50.5 mm, 57.2 mm and 25.8 cm2 in women with pelvic organ prolapse. Nulliparous women achieved the greatest reduction of hiatal area during squeezing (by 21% average). In asymptomatic parous women the hiatal area reduction averaged 12% while in women with pelvic organ prolapse the average reduction was by 4% only. Levator injury was detected in 7.5% of the asymptomatic parous women and in 22.5% of the women with pelvic organ prolapse. Left-sided injuries predominated. Three dimentional ultrasound provides easy and high-quality imaging of the pubovisceral miscles for the objective assessment of the levator hiatus in static and dynamic conditions. PMID- 23807974 TI - [Lymph node metastases and disease-free survival in cervical cancer patients]. AB - OBJECTIVE: To establish the prognostic significance of lymph node metastases (LNM) in terms of disease-free survival and incidence rate and localization of relapses. MATERIAL AND METHODS: 296 patients with invasive cervical cancer FIGO staged: IB1-110; IB2-98 and IIB-86 had been operated on between 2002-2011. Patients age ranges from 27 to 84 years, average 48 years. Follow-up period was estimated from the date of registration until September 2011 or until the occurrance of relapse. (2-96, average 45 months). 294 patients were submitted to pelvic lymphadenectomy and paraaortic lymphadenectomy was optional. RESULTS: We presented the relationships between number of LNM, incidence rate of LNM, macro- and micro- LNM and incidence rate and localization of local and distant relapses. CONCLUSION: Lymph node macrometastases leads to significantly higher incidence rate of relapses outside true pelvis in comparison to lymph node micrometastases. PMID- 23807975 TI - [Operative treatment--prognostic factor in patients with ovarian cancer stage I II]. AB - OBJECTIVE: The authors present and analyze the modern concepts of the role of surgery as a prognostic factor for patients with early epithelial ovarian cancer (st. I-II). They review, synthetize and summarize the information from 15 studies, published in the recent years, and concerning the subject. CONCLUSION: Surgery treatment for early epithelial ovarian cancer is one of the most important prognostic factors. The appropriate surgical performance contributes either for complete staging or for optimal primary cytoreduction and strongly influence the development and outcome of disease. PMID- 23807976 TI - [Vaginal disbacteriosis--social and sexual risk factors]. AB - The vaginal microbe equilibrium could be impaired by different agents. Many of the risk factors can change the preventive mechanisms of the vagina and can lead to inflammation and disease. We even do not suppose about the role of most of them in impairing of vaginal microbe equilibrium. The exact understanding of those risk factors and mechanisms by which they disturb the vaginal microbe balance could reduce female morbidity of vaginal disbacteriosis and vaginal inflammations. The aim of this literature synopsis is to review some of the most frequent risk factors for vaginal disbacteriosis and about how they change vaginal micro-flora with dominant lactobacillus within it. The most informative and detailed articles on the theme which were found in the resent literature as well as in Medline for the period between 1990 and 2012 were selected. The risk agents for vaginal disbacteriosis are: endogenetic, social, sexual, infectious and iatrogenic. The social and sexual factors are the most frequent in our daily round. The intensity and the kind of sexual life, smoking, homosexual connections, vaginal douching and contraception methods are included in them. All these factors depend on us. Thus we hope that through their popularization and discussion will help to prevent the females' health. PMID- 23807977 TI - [Small for gestational age newborns--definition, etiology and neonatal treatment]. AB - Newborns with intrauterine hypotrophy are at particular risk group of neonates. Diagnosis based on an adequate estimated gestational age, compared with accurate anthropometric measurements after birth. Among children born with low birth weight (< 2500 g) stands in one particular group--those small for gestational age SGA (Small for Gestational Age-SGA), whose health problems are studied intensively in recent years. In Bulgaria children with low birth weight in recent years is about 10%, which is well above the European average indicator--6.2%. In 2001. created International Advisory Board, composed of 42 people leading experts in obstetrics, perinatal and neonatal medicine, pediatricians endocrinologists, pharmacologists and epidemiologists, with the following main tasks: the definition of small for gestational age children, diagnosis of SGA, SGA children growth and role of growth hormone in their treatment. Subsequent meetings of this committee discuss consensus on SGA infants who acquire their final form at a meeting in Prague in 2009 Small for gestational age (SGA, SGA), is described children whose body weight and/or height is lower than the average by more than 2 standard deviations (< - 2SD). Some authors use the boundary 3rd, 5th, or 10th percentile, but most believe that the use of indicators (< - 2SD) comprises the largest percentage of newborns with fetal growth disorders. Small for gestational age children are divided into: newborn weight retardation (SGAW), growth retardation (SGAL), matched up in weight and height (SGAWL). "Intrauterine growth retardation" (Intra-Uterine Growth Retardation (IUGR) are born with fetal growth retardation, documented at least two ultrasound scans, one of which in the 1st trimester Intrauterine hypotrophy is the second most common cause of perinatal death after prematurity. Hypotrophy is present in about 53% of premature and stillborn at 26% of full-term stillborn children. The incidence of asphyxia in SGA intrapartum is about 50%. Neonatal care includes effective primary resuscitation, treatment of existing and prevention of complications anticipated adaptation. These children are subject to follow-up for later risk of socially significant diseases in the adult. PMID- 23807978 TI - [Congenital cystic lung lesions--review of the literature with three clinical cases]. AB - Congenital cystic lung lesions are rare. Mainly affects the lower respiratory patishta.i are congenital cystic malformation and adematozna bronchopulmonary sequestration (BPS). The pathogenesis of the occurrence of these malformations is not clear but they have a common clinical course. In most cases, the anomaly is asymptomatic and occurs with infections of the lung during the first year of life. Currently congenital lung lesions were classified into five types and is considered by most authors. The anomaly is due to the abnormal proliferation of terminal bronchioles accompanied by inhibition of alveolar development between 7 17 weeks, obstructed airway dysplasia and metaplasia of normal lung tissue. Early diagnosis is vital in making a medical decision on how to treat CCAM. Associated with abnormalities of the urinary tract, cardiovascular system, gastrointestinal atresia, diaphragmatic hernia skeletal abnormalities. In pregnancies in which prenatal lung lesions weighs registered necessary series of ultrasound examinations to track finding and using the Doppler to assess how the blood supply of the fault. The clinical presentation of malformations is respiratory distress, respiratory infection, and dyspnea. The use of CT and MRA allows better visualization of the pulmonary lesions. With its combination with arteriography and bronchoscopy are used to differentiate CCAM and pulmonary sequestration. We present three cases with lung lesions were born in Neonatologia clinic at the University Hospital of Obstetrics and Gynecology "Maternity" Sofia for the period 2010-2012 three cases CCAMs type 1, operated by 5 meters after birth with a good final outcome without complications in the postoperative period and lack of pulmonary symptoms up to 1 year after birth. PMID- 23807979 TI - [Intrauterine hypotrophy and programming the health status. Late problems in newborns with intrauterine hypotrophy]. AB - In recent years, accumulating more and more evidence demonstrating the programming effects of intrauterine development on the subsequent health of the individual. Intrauterine fetal hypotrophy is a consequence of the wide range of pathological processes in different periods of pregnancy. It is the second leading cause of perinatal death after prematurity. Newborns from similar pathological pregnancies are often leaked premature baby and/or small for gestational age (SGA). Premature baby children have not only complicated and postnatal adaptation problems in the neonatal period, but many diseases occurring in later life: 1. Disorders in postnatal growth. 2. Neurological and intellectual consequences of IUH in term children (hyperactivity disorders attention, impaired fine motor skills, speech problems, risk of cerebral palsy). 3. Neurological and intellectual consequences of prematurity IUH (cognitive impairment in children with low birth weight, short stature at birth, and small head circumference for gestational age). 4. Metabolic syndrome (dyslipidemia, abdominal obesity, hypertension and high blood sugar). 5. Abnormal sexual development (hyperandrogenism, polycystic ovary syndrome in girls, reduced testicular size and lower testosterone levels in boys. 6. Other complications associated with intrauterine hypotrophy cardiovascular renal, pulmonary complications (BPD) disorders in vision, sensory neural hearing loss. PMID- 23807980 TI - [Placenta accreta--prenatal diagnosis, treatment]. AB - Placenta accreta is a potentially life threatening obstetric condition that requires a multidisciplinary management. Placenta praevia and previous Cesarean section are the two most important known risk factors for placenta accreta. This study presents two patients having both of the foremention risk factors diagnosed ultrasonographically with placenta accreta in the second trimester. Ultrasound findings considered suggestive of placenta accreta are: presence of placental lacunae (vascular spaces), loss of the hyperehoic uterine serosa-bladder wall interface, loss of the retroplacental hypoechoic clear space, hypervascularity of the interface between the uterine wall and the bladder wall/isthmico-cervical zone, presence of placenta praevia, either anterior or posterior, overlying the uterine scar. Both of the cases with suspected placenta accreta ended successfully by planned preterm Cesarean hysterectomy with the placenta left in situ. Placenta accreta is a significant cause of maternal morbidity and mortality and the most common reason for urgent postpartum hysterectomy. PMID- 23807981 TI - [The use of prostaglandin F2alpha (Prostin 15M) for terminationof second trimester pregnancy]. AB - The authors describe a case of terminating a second trimester pregnancy in 21 gestational weeks with use of Prostin 15 M. The patient come to the clinic in 21 gestational week with spontaneous rupture of the liquid amnii 72 hours ago, without any contractions and cervical dilatation. The foetus has breech presentation. From the ultrasound investment the fetal weight is measured to be around 380 grams and it has been confirmed that the liquid is less than normal. The woman refuse the use of Foley catheter. We induce the delivery with 10 E Oxytocin intravenously and with Cytotec by vaginal and per oral way (3 tablets equal to 600 micrograms) but there was no effect. There were no changes at the cervix and no contractions. Then we use 4 ampules of Prostin 15 M intramuscular through three hours and the pregnancy was successfully terminated. PMID- 23807982 TI - [Dysgerminoma of the ovary. Presentation of case report]. AB - Germ-cell tumors account for about 20% of all ovarian tumors and the dysgerminoma is the most common in this group. The treatment is surgical, followed by chemotherapy and radiotherapy in greater stage than IA. The aim of this article is to present a case report of 18-years-old patient with a left ovary dysgerminoma who had undergone a surgery--left-side ovariectomy. One year later when the patient was pregnant in 6 m.l., retroperitoneal recurrence was diagnosed by ultrasound examination. The patient has completed her pregnancy and delivered by caesarean section. Retroperitoneal recurrence of the same tumor, inoperable at this stage was histologically confirmed during the operation. The treatment continued with two courses of neoadjuvant chemotherapy followed by radical surgery with removal of the whole left kidney and the tumor. After that 2 courses of adjuvant chemotherapy were conducted, followed by prophylactic external beam radiotherapy for retroperitoneal lymph nodes. No data for local recurrences and distant metastases were found during the regular examinations, performed 2 years later. The treatment of dysgerminoma is discussed. This treatment must be complex one and should include radical surgery, chemotherapy and radiotherapy. PMID- 23807983 TI - [PrenaTest]. PMID- 23807984 TI - [Application of Gynofit in obsetrics]. AB - Childbirth can be a fantastic experience for the future mother, but it holds risks for mothers and newborns. Vaginal birth is a result of uterine contractions, minus elastic forces, minus friction force. The objective of this study is to evaluate labor duration, perineal outcomes and safety when applying Gynofit in second stage of labor. Study duration was four months, 120 women were included and randomized in four groups. Two doses of Gynofit were applicated (vaginal and perineal dose) and the duration of second stage of labor was read by electronic chronometer. Results divided by groups were shown, that appyling Gynofit during second stage of labor significantly reduces labor duration by 40% in primiparous and multiparous women. Gynofit protects pelvic floor and perineum, is safe, is easy to apply, shows no side effects on mother and child. PMID- 23807985 TI - HPV status after cold knife conization. AB - INTRODUCTION: The aim of this study was to determine whether HPV DNA test after cold knife conization is a predictive factor for CIN persistence or recurrence. The study also investigated whether HPV DNA test results should influence post cold knife excision surveillance. MATERIALS AND METHODS: A retrospective observation study was performed on 738 patients who underwent cold knife conization for CIN or microinvasive cervical cancer at the University Clinic of Obstetrics & Gynecology, Medical Faculty, Ss. Cyril and Methodius University, Skopje from 1st June 2007 to 1st June 2009. A total of 217 patients met the inclusion criteria and were with complete data. The follow-up HPV DNA testing was performed at 8 months after cold knife conization, after which the patients were followed-up every 4 months till 24 months postoperatively. RESULTS: HPV DNA testing after 8 months after conization showed that 44 patients were HPV DNA positive and 199 were HPV DNA negative. Recurrent cytological abnormalities were found in 26 of the 44 HPV DNA positive patients, and in 12 of the 199 HPV DNA negative patients. Analysis showed that a positive HPV DNA result was a risk factor for recurrent/persistent cervical intraepithelial neoplasia. CONCLUSION: HPV DNA testing 8 months after conization is important for predicting the risk of disease: persistence or recurrence. In addition, such testing can assist in designing patient management, since HPV DNA negative patients should undergo routine surveillance, while HPV DNA positive patients should undergo frequent and meticulous surveillance. PMID- 23807986 TI - [The unification of physical chemical and biological actions of spirits of glycerin and cholesterol in cell's absorption of fatty acids: the singularity of pathogenesis of "metabolic pandemics"]. AB - According to phylogenetic theory of pathology, atherosclerosis is a syndrome of deficiency of essential polyene fatty acids in cells. The unfavorable impact of environment and derangement of biological function of trophology (function of nutrition) results in failure of transfer in the structure of lipoproteins and their active absorption by cells and metabolism of lipids and fatty acids. All these processes were formed billions years in the past at the autocrine (cell) level, in paracrine cenosis of cells and at the level of organism. The apparent derangements of trophology "highlight" the regular and metabolic limitations (hidden "defects") which derange bioavailability of essential polyene fatty acids for cells by blocking cells' active absorption. The processes of metabolism of nonpolar ethers of fatty acids with spirits of glycerin and cholesterol are impacted too. The biological function of intelligence applied the biological modes can eliminate this derangement through development of theory of pathogenesis of atherosclerosis and its effective prevention. The normalization of biological function of trophology and brining to conformity with capacities of organism advanced in phylogenesis are the only effective mode of prevention. This approach will decrease at once the prevalence of all "metabolic pandemics" in population. The spirit cholesterol will continue to occupy a fitting position in diagnostics of atherosclerosis on a par with spirit glycerin with identification of triglycerides. Both spirits are of equal value as diagnostic tests to detect the failure of transfer in the structure of lipoproteins and active receptor absorption of fatty acids by cells. The article proposes to unify on the basis of pathogenesis all "metabolic pandemics", diabetes mellitus included, into the section of clinical medicine and name it "pathology of fatty acids". PMID- 23807987 TI - [The analysis of data of large study of cholesterol level in population: on the issue of reference values of cholesterol]. AB - The article deals with analysis of the results of large study of cholesterol level at the sampling of 52 075 patients. The median of values of common cholesterol exceeds 5.0 mmol/l in all groups of males older than 30-35 years and females older than 35-40 years. The percentage of patients with level of common cholesterol > or = 6.2 mmol/l consisted 40.15 in the age group of 40-69 years. The issue of presentation of the results of laboratory analysis of common cholesterol (reference values as compared with recommended values) is discussed. PMID- 23807988 TI - [The dynamics of cardio-specified marker troponin I (TN I) as a predictor of acute coronary syndrome under surgery of carotid endarterectomy]. AB - The article deals with the data of dynamics of troponin I as a main marker of damage of myocardium under reconstructive surgery of inner carotid artery. The sampling for randomized prospective clinical examination included 227 patients. It is proved that the indicator of troponin I during the carotid endarterectomy can be used as a marker to evaluate severity of ischemic heart disease and as a predictor of possible development of acute coronary syndrome. PMID- 23807989 TI - [The energetic metabolism in newborns in normal conditions and under development of disorders of adaptation in early postnatal period]. AB - The article deals with the prospective complex approach to laboratory analysis of energetic metabolism under states of newborns. The approach provides simultaneous detection of content of main energy substrates, activity of adenosinetriphosphatases and succinate dehydrogenases in umbilical blood, characterized by high sensitivity to hypoxia. PMID- 23807990 TI - [The content of apolipoproteins in blood M and parameters of lipid metabolism in population of North Polar regions and Southern regions of Caucasus]. AB - The study was carried out concerning the between content of apolipoproteins A and B in blood and lipid metabolism in population of North Polar regions and Southern regions of Caucasus. The differences of correlation relationships depending on concentration of apolipoproteins A and B in blood in population dwelling in territories climate geographic regions were detected. PMID- 23807991 TI - [The value of quantitative analysis of procalcitonine in diagnostics of septic complications in patients with autoimmune rheumatic diseases]. AB - The infections very often complicate the course of autoimmune rheumatic diseases. In diagnostic of septic complications in rheumatic patients the new biomarkers of infections can have a decisive importance. The procalciotonine test is one of them. The issue was to evaluate the diagnostic informativity of this test. The sample included 93 patients. The examination was applied to 65 patients with rheumatic diseases. Among them, 13 patients had bacterial infections. The group consisted of 33 patients with rheumatoid arthritis, 11 patients with systemic lupus erythematous, 6 patients with systemic angiitis, and 15 patients with other rheumatic diseases. The comparative group included 27 patients of cardio therapeutic profile and 8 of these patients had bacterial infections. The procalcitonine test was applied with quantitative electrochemiluminescent technique. In patients with rheumatoid arthritis the mean levels of procalciotonine test consisted 0.10 +/- 0.13 ng/ml; with systemic lupus erythematous--0.08 +/- 0.06 ng/ml; with systemic angiitis--0.22 +/- 0.2 ng/ml; with other rheumatic diseases--0.12 +/- 0.15 ng/ml; of cardio-therapeutic profile without infections--0.08 +/- 0.06 ng/vl/ With threshold of procalcitonine test higher than 0.5/ml the sensitivity to diagnostic of infections consisted of 58%, specificity--94% in the group with rheumatic diseases. The procalciotonine test in case of no infection process with values higher than 0.5 ng/ml was detected in three patients. The evaluation of dependence of sensitivity and specificity for procalciotonine test and C-reactive protein the area under curve of procalcitonine test was larger in patients with rheumatic diseases (0.85 against 0.79) and in patients of cardio-therapeutic profile (0.92 against 0.90). The quantitative procalcitonine test is the best technique to detect septic complications in rheumatic patients. PMID- 23807992 TI - [The 8-OH-2-desoxiguanosin marker of oxidizing modification of DNA in patients with diffused dermatitis]. AB - The level of 8-OH-2-desoxiguanosin in blood serum of patients with severe chronic dermatitis was analyzed. It is demonstrated that in comparison with healthy patients in examined group of patients this indicator is increased mainly in patients with atopic dermatitis (up to 62%) and least of all with psoriasis (up to 25%) and bullous dermatitis (up to 18%). The statistically reliable differences of this indicator from control values under endogenic intoxication and different degree of severity of disease are determined. The detection of level of 8-OH-2-desoxiguanosin in blood serum is an informative technique of analysis to increase quality of laboratory monitoring of oxidizing stress. PMID- 23807993 TI - [The actual aspects of evaluation of proliferation and apoptosis in clinical laboratory diagnostic: a review]. AB - The article deals with the issues of studying cell proliferation and apoptosis, relationship and conditionality of these two important physiologic processes. The main cytological markers of proliferation and apoptosis are analyzed, including the techniques of intravital non-invasive visualization of apoptosis. The value of these markers in clinical laboratory diagnostic and investigation is considered. The mechanisms of action of antineoplastic pharmaceuticals and issues of choosing the optimal scheme of treatment are analyzed. PMID- 23807994 TI - [The relationship of AB0- and rhesus-phenotypes of erythrocytes with expression of intra-operational hemolysis in cardio-surgical patients]. AB - The study sampling included patients with ischemic heart disease with mild (70 patients) and marked (36 patients) hemolysis after coronary artery bypass grafting under artificial blood circulation. During post-operation period the content of free hemoglobin in blood plasma, AB0- and rhesus-phenotype of erythrocytes were evaluated. It is established that in patients with marked intra operational hemolysis as compared with cases of mild hemolysis the phenotypes of erythrocytes B(III), AB(IV), ccDEE, ccDEe are found reliably more often and 0(I) phenotype is found reliably more rare. The risk factor of marked intra operational hemolysis is a verification of ccD(E/e)-phenotype of erythrocytes and in case of different rhesus-phenotypes--blood type B(III) or AB(IV). PMID- 23807995 TI - [Prohepsidin in diagnostic of iron deficiency in patients with chronic cardiac failure and anemia]. AB - The sample for examination included 52 patients with chronic cardiac failure and 26 patients with anemia amongst. The expected increase of production of prohepsidin against the background of increased serum concentrations of anti inflammatory cytokines was not detected. The tendency to decrease level of prohepsidin alongside with decrease of content of serum iron and ferritin in blood serum testified depletion of iron resources in organism. PMID- 23807996 TI - [The verification possibilities of immunochips under low content of antibodies to Core-antigen of virus of hepatitis C]. AB - The detection of antibodies to Core-antigen of virus of hepatitis C in test systems for solid-phase immune-enzyme analysis with low optical density can be a result not only of true availability of antibodies but an effect of nonspecific reaction of blood serum. The diagnostic possibilities of immunochips to be used in immune-enzyme analysis for verification of availability of markers of viral hepatitis C were investigated in conditions of low positive reaction of blood serum to core-antigen. It is established that immunochips and immunoblots have similar specificity concerning detection of antibodies to Core-antigen. At that, in immunochips antibodies to nonstructural antigens of virus of hepatitis C were additionally detected in more than 90% of samples. PMID- 23807997 TI - [The microbiocenosis of intestine and immune status of children of primary school age]. AB - The article deals with the study of species and quantitative structure of microbiocenosis of intestine and characteristics of immune status in children aged 8-10 years. In children with chronic tonsillitis pharyngitis and bronchitis and with diseases of gastro-intestinal tract (biliary dysfunction, chronic gastroduodenitis and gastritis) the microbe imbalance of various degree of manifestation was established which was prevailing in cases of children with pathology of gastrointestinal tract. The increase of quantity of opportunistic microflora induces the production of both immunoglobulins and cytotoxic lymphocytes and cells-natural killers. PMID- 23807998 TI - [The characteristic of biocenosis of urogenital tract in women]. AB - The article deals with the study of characteristics of biocenosis of urogenital tract in women of reproductive age with using of "Femoflor" test. The scrapings of posterolateral wall of vagina were analyzed using the technique of real-time polymerase chain reaction using the reagents "Femoflor". The complex evaluation of urogenital biota identified three main types of biocenosis of vagina: type I- normocenosis (n = 50 or 11.5%): type II--mild dysbiosis (n = 88 or 21%); type III -marked dysbiosis (n = 133 or 30.6%). In the structure of alterations of biocenosis of urogenital tract the main role play the anaerobic bacteria with involvement of candida, ureoplasma and mcoplasma. PMID- 23807999 TI - [The kit of reagents for polymerase chain reaction diagnostic of infections caused by B. pertussis, B. parapertussis and B. bronchiseptica]. AB - The effective treatment of whooping cough directly depends of early diagnostics. The polymerase chain reaction diagnostic is the most perspective diagnostic technique. The kit of reagents is developed to diagnose whooping cough, parapertussis and bronchosepticosis with polymerase chain reaction. The evaluation of its analytical characteristics was carried out. The sensitivity made 1 x 103 of genome equivalents per 1 ml of sample (the sorption technique of DNA extraction was applied) and 5 x 102 of genome equivalents per 1 ml (the precipitation technique of DNA extraction was used). The specificity of test in the framework of analyzed panel of strains and isolates of microorganisms made 100%. The diagnostic sensitivity of analysis exceeded the sensitivity of bacteriological analysis up to 20 times. The application of this kit of reagents permits to detect and to differentiate DNA of agent of whooping cough, parapertussis during one working day already at the beginning of catarrhal period of disease and up to 18th day from the moment of cough appearance. In perspective, this process creates an opportunity to apply timely the specific therapy. The specter of agents of acute respiratory diseases brining on acute prolonged cough in children who were directed to bacteriological analysis to confirm whooping cough is investigated. PMID- 23808000 TI - [The high content of palmitinic fatty acid in food as a major cause of increase of concentration of cholesterol and low density lipoproteins and atheromatous plaques of arteries' intima]. AB - The positioning of individual triglycerides of blood serum in palmitinic and oleic lipoproteins ofvery low density in the order ofincrease of the rate constant of their hydrolysis under action of post-heparin lipoprotein leads to the sequence as follows: palmitoil-palmitoil-palmitate-->palmitoil-palmitoil oleate-->palmitoil-oleil-palmitat-->oleil-palmitoil-palmitate-->oleil-palmitate palmitate-->oleil-oleil-palmitate-->oleil-oleil-oleate. The shift to the left and to the right is discerned with this spectrum of isoforms of triglycerides. The shift to the left into direction of palmitinicc triglycerides occurs in case of eating of animal food (i.e. beef andfoodstuf of fat saw milk) when the content of palmitinic saturated fatty acid supersedes 15% of fatty acids total and under the development of endogenic syndrome of insulin resistance. The content of low density lipoproteins cholesterol is high in blood The shift to the right with prevalence of oleinic triglycerides occurs in case of low content of beef and foodstuff of fat saw milk in food, fish eating, seafood and olive oil. The physiologic levels of carbohydrates in food and insulin function are present too. The shift to the right initiates the action of insulin, ometa-3 essential polyenic fatty acids, glytazones and fibrates. They increase the activity of delta9-stearil-KoA-desaturase-2 and the transformation of palmitine saturated fatty acid into mono unsaturated oleinic fatty acid. The shift to the left forms the palmitine alternative of metabolism of substrate to supply cells with energy. The shift to the right is a more effective oleinic alternative. PMID- 23808001 TI - [The dynamics of endogenic intoxication in patients with extensive burns]. AB - The sampling consisted of 22 patients with extensive burns with total affected area from 20% to 84% of body surface and with deep burns area from 10% to 40%. The suppurative complications in the form of sepsis were diagnosed in 10 and the transitory bacteremia in 12 victims. The total and effective concentration of albumin, the content of medium molecular peptides in dynamics at 1-3, 7, 14 and 21 days from the moment of trauma were detected to objectively evaluate the endogenic intoxication. The degree of intensity of endogenic intoxication was studied using such integral indicator as effective utilization factor In patients with extensive burns the endogenic intoxication was diagnosed on the basis of total and effective concentration of albumin and increase of content of medium molecular peptides. However the detection of endogenic intoxication of the basis of effective utilization factor is a more informative as compared with the analysis of these indicators separately and, hence, it promote the prescription of more appropriate disintoxication therapy its effectiveness evaluation including. PMID- 23808002 TI - [The detection of leptin and metabolic markers of insulin resistance in patients with myocardial infarction]. AB - The shortage of data concerning the character of changes of leptin concentration and its role information of insulin resistance under development of acute coronary events determined the appropriateness of the present study. The cardiac infarction patients with and without diabetes type II were examined. The identified hyperleptinemia, its relationship with basal and post-prandial hyperglycemia and with increase of C-peptide concentration and free fatty acids made possible to consider leptin both as one of the important components in the series of carbohydrate and lipid metabolism disorders and the additional marker of development of insulin resistance under cardiac infarction. These study results can be applied to patients with diabetes anamnesis and to patients without this concomitant pathology. The study results can be used as a foundation for new diagnostic and therapy tactics of metabolic disorders correction in patients with acute coronary vascular pathology. PMID- 23808003 TI - [The evaluation of changes in concentration of ghrelin, somatotropin, insulin like growth factor-1, insulin, leptin and thyroid hormones in mother and umbilical blood in case of physiologic pregnancy with normosomia and macrosomia of fetus]. AB - The sample of women with physiologic pregnancy consisting of 40 females with fetus normosomia and 8 females with fetus macrosomia were examined. The examination covered the evaluation of changes in concentration of ghrelin, somatotropin, insulin-like growth factor-I, insulin, leptin and thyroid hormones in mother and umbilical blood. In females with fetus macrosomia the changes in concentration of hormones regulating trophism, energy balance and anabolic processes in organisms of mother and fetus were detected PMID- 23808004 TI - [The test of benzamide derivative neuroleptics using the technique of thin-layer chromatography]. AB - The article presents the data concerning the application of technique of thin layer chromatography in the conditions of laboratory diagnostics to identify benzamide derivative neuroleptics (amisupride, sulpiride, tiapride) in derivate from human biologic fluids and tissues with the possibility to separate the analyzed tissues from soextractive tissues. PMID- 23808005 TI - [The relationship between concentrations of pepsinogens in blood serum and pathohystologic parameters of stomach adenomas and adenocarcinomas]. AB - The article demonstrates that in patients with adenomas of stomach the concentration of pepsinogen I in blood serum and the rate between pepsinogen I and pepsinogen II is decreased. In case of adenomas and adenocarcinomas of stomach the concentration of pepsinogen I and the rate between pepsinogen I and pepsinogen II are in inverse correlation relationship with indicators of proliferative activity of epithelial cells and tumor cells correspondingly. The threshold level was the rate between pepsinogen I and pepsinogen II can be used as criteria of intensity ofproliferative activity of epithelial cells of adenomas and cells of adenocarcinomas of stomach. PMID- 23808006 TI - [The diagnostic role of chemokines and their receptors in chronic hepatitis C]. AB - The chronic hepatitis C is characterized by the increase of inflammatory disorders and progression of fibrosis of liver The corresponding immunologic mechanisms of hepatic lesions are still undiscovered. The actual review presents the analysis of scientific publications and genuine research data concerning the role of chemokines in pathogenesis of chronic hepatitis C. The chemokines are small cationic proteins enhancing transit and precipitation of migrating cells (leucocytes mainly) in tissues and organs. The significant role of chemokines in tissue homeostasis, in case of inflammation, wound healing and cell proliferation is demonstrated. The particular kinds of chemokines are produced by different types of cells and impact target cells through their specific receptors. According the data of various studies, chemokines and chemokine receptors of CC families and CXC-families are involved in fibrosing processes and anti inflammatory activation of hepatic-biliary system under chronic hepatitis C. The diversity of producers and targets of chemokines in liver is very pronounced: hepatocytes, stellar cells, endothelium cells, macrophages (Kupffer cells), dendritic cells, lymphocytes and monocytes. The review considers pathogenesis of chronic hepatitis C from the standpoint of participation of chemokines and chemokine receptors at different stages of cellular transit. The most important cellpopulations involved into pathologic changes under chronic hepatitis C are characterized. The decrease of expression of such gens as CCR1, CCR2, CCR3, and CCR5 in blood leucocytes deserves additional studies to establish their diagnostic values as a marker of disorders of immune system in patients with chronic hepatitis C. PMID- 23808007 TI - [The interpretation of immunophenotyping results during diagnostics of lymphatic proliferative disease using immunophenotyping count]. AB - The article considers immune phenotyping heterogeneity of chronic lymphatic leukemia detected using basic diagnostic markers ofcell. The results of analysis of immune phenotypes of 108 patients with B-cell lymphatic proliferative diseases made it possible to establish that the atypical is related most rarely to indicators of expression of monotypic immunoglobulines and CD5 and most frequently to CD23, FMC7, CD22 and CS79b. During the present observation, the immune phenotyping count made up "3" or "2"points and the atypical alternative was registered among 10% of all examined patients with chronic lymphatic leukemia. It is demonstrated that patients with chronic lymphatic leukemia and with lower immune phenotyping count are characterized by major intensity of tumor substrate. PMID- 23808008 TI - [The diagnostic and prognostic value of increase of blood pro-inflammatory and anti-inflammatory cytokines in chronic lymphatic leukemia]. AB - The article presents the results of study of cytokine profile of blood of patients with B-cell lymphatic leukemia. It is established that at diferent stages of disease the regular characteristic of changes in cytokine status is the increase of concentration of interleukin 4 (IL=4) and tumor necrosis factor This fact can be considered as one of leading pathogenic factors leading to disturbances of intercellular interaction in lymphoid tissue and to development of systemic metabolic and functional disorders. The parallelism between progressing increase of concentration of interleukin 4 and a-tumor necrosis factor character of qualitative and quantitative alterations of cell structure of peripheral blood, severity of clinical manifestations of disease are established. The indicators of concentration of interleukin 4 and a-tumor necrosis factor in blood are the objective diagnostic and prognostic criteria ofpathology development. They can complement the classification attributes of staging of the course of chronic lymphatic leukemia. PMID- 23808009 TI - [The ability of diphtheria causative agent to form biofilm]. AB - The article deals with results of studying diphtheria causative agent capacities to form biofilm as one of mechanisms of persistence in human organism. The study object was strain of C.diphtheriae gravis tox+ obtained from nasopharynx of patient aged 19 in municipal hospital No 1 of town of Gukovo of Rostov oblast in 2011. The patient had diagnosis of "diphtheria of nasopharynx, typical filmy, localized, mild severity, even course". The control was implemented using the museum strain C.diphtheriae gravis tox+ No 665 from the L.A. Tarasevitch state research institute of standardization and biologic preparations control. It is established that diphtheria causative agent as an ability to form biofilm. The intensity of process of formation of exopolysaccharide is higher on glass that on plastic surfaces. The differences in degree of intensity of formation of biofilm are revealed between the strain circulation in population and museum strains C.diphtheriae gravis tox+. The vital capacity of biofilm forming microorganisms is related with adaptation possibilities of strains. PMID- 23808010 TI - [The development of complex technique of evaluation of virulence of parahemolytic vibrio]. AB - The article deals with results of studying parahemolytic vibrio separatedfrom different sources according their phenotype and genotype attributes associated with virulence. In certain cases the mismatch of results of Kanagava tests and polymerase chain reaction test of gene tdh was established. The need in virulence complex evaluation is substantiated. This complex has to include detection of hemolytic activity in Kanagava test and urease activity on the Kristensen medium and polymerase chain reaction detection of genes tdh and trh. The developed complex technique is described. The formula of pathogenic strains is established Three alternatives of virulent parahemolytic vibrio are given. The test-strains Vibrio parahaemolyticus are proposed as control in testing phenotype and genotype strains according virulence signs. PMID- 23808011 TI - [The metrological support of medical laboratory activity]. AB - The article discusses the methodological approaches in implementing of regulations of the Federal law FZ-102 "On the support of unity of measurements in the area of laboratory medicine "from the positions of GOSTK ISO 9001-2008 "The systems of quality management. Requirements" and GOST K ISO 15189-2009 "medical laboratories. The particular requirements to quality and competence". The application of GOSTK ISO 18113.1-5 "The medicine items for diagnostic in vitro. Information provided by manufacturer (marking)" neatly assigns the responsibility for support of metrological correctness of laboratory measurements. PMID- 23808012 TI - [The analysis of dosage inaccuracy and its minimization modes]. AB - The article deals with the analysis of factors impacting dosage inaccuracy and input of this inaccuracy into total inaccuracy of analysis. The total dosage inaccuracy includes both the value of inaccuracy mentioned in the technical passport of dosage device and inaccuracy values occurring at all stages of dosage during implementation of technique. The characteristics of dosage devices and their merits and shortcomings are taken into account. The article substantiates the choice of types of dosage devices to be implemented in the laboratory research. The modes of errors elimination and inaccuracy minimization were analyzed against the perfectly calibrated and totally corresponded to passport data device of air transfer dosage. PMID- 23808013 TI - [The ways of harmonization of clinical laboratory measurement techniques]. AB - The results of implementation of different clinical laboratory techniques are to be equal in clinically significant limits to be optimally applied in diagnostics of diseases and treatment of patients. When the results of laboratory tests are not standardized and harmonized for the very same clinical assay the results can be expressed by unmatched numbers. Unfortunately, in some handbooks the values are presented based on the results of application of specific laboratory techniques without considering possibility or likelihood of differences between various techniques. When this is a case, accumulation of data of diferent clinical research studies and working out of clinical handbooks on this basis will be inconsistent. Inadequate understanding of issue that the results of laboratory tests are not standardized and harmonized can lead to incorrect clinical, financial, managerial or technical decisions. The standardization of clinical laboratory techniques was applied to many measurands related to primary referent techniques (standard specimen of pure substance) or/and developed referent measurement techniques. However, harmonization of clinical laboratory techniques for those measurands which are not related any developed measurement techniques is quite problematic due to inadequate determination of measurand, its inadequate analytical specificity, insufficient attention to commutability of referent materials and poor systematic approach to harmonization. To overcome these issues an infrastructure is to be developed to support systematic approach to identification and prioritization of measurands which are to be harmonized on the basis of clinical importance and technical applicability. The management of technical implementation harmonization process for specific measurands. PMID- 23808014 TI - [The dynamics of C-reactive protein in the process of coronary artery bypass grafting in patients with ischemic heart disease]. AB - The article presents the assessment of prognostic value of perioperative level of C-reactive protein in the development of post-operative cardio-vascular complications in patients with ischemic heart disease and underwent coronary artery bypass grafting. The sample consisted of 99 patients with stable forms of ischemic heart disease and underwent the planned coronary artery bypass grafting. The average age of patients was 58 +/- 4.19 years. All patients were applied direct revascularization of myocardium in conditions of artificial blood circulation. The patients were divided on the groups depending on occurrence of post-operational cardio-vascular complications. The group I consisted of 42 patients with non-complicated post-operational period (42%). The group 2 consisted of 57 patients with cardio-vascular complications and included the subgroup of 24 patients with fibrillation of atriums developed in post operational period. The concentration of C-reactive protein was analyzed in blood serum one day before the operation and at first and seventh days after operation. The post-operative period after application of coronary artery bypass in conditions of ischemic heart disease is characterized by activation of inflammation reaction evaluated by concentration of C-reactive protein. The pre operation level of C-reactive protein can be used as prognostic marker of development of cardio-vascular complications, post-operative fibrillation of atriums after application of coronary artery bypass in particular PMID- 23808015 TI - [The metabolic syndrome and inflammation: actual issues of pathogenesis]. AB - The publications' review and intrinsic data testify that metabolic syndrome represents an extremely actual problem due to high prevalence and strong influence of its components at the risk of development of cardio-vascular complications. PMID- 23808016 TI - [The diagnostic value of analysis of laboratory markers of endothelium dysfunction under infection pathology in children]. AB - The article presents the publications' review considering the diagnostic value of dysfunction of endothelium. The almost ignored issue of dysfunction of endothelium under infection pathology in children is discussed. PMID- 23808017 TI - [The level of neopterin in blood serum in premature newborn in the process of their adaptation to postnatal life]. AB - The study had a purpose to evaluate the level of serum neopterin in the process of adaptation of healthy newborns to postnatal life. The dynamic clinical monitoring and comparative analysis was applied to determine the level of neopterin in serum of umbilical blood in 46 children and in peripheral blood of their mothers. The immune-enzyme analysis was implemented. It is established that in healthy newborn the content of neopteril reliably exceeds common normative indicator of adults i.e. less than 10 nmol/l. The increased level of neopterin in blood of newborns and their mothers reflects the total reaction of immune response to delivery process. The dependence is established between the level of neopterin and pathologic course of gestation period (acute respiratory viral disease, fetoplacental insufficiency) and morphologic functional maturity of child PMID- 23808018 TI - [The allergy diagnostic of brucellosis]. AB - The infectious allergy plays an important role in the pathogenesis of brucellosis. In the allergy diagnostic of toxoplasmosis the cell reactions in vivo are equally applied with the Burnet intradermal allergic test. In the present study the reaction of leukolysis was applied to detect the sensibilization of leucocytes in blood and saliva under brucellosis. The reaction is considered positive in case of occurrence of lysis of 15% and more of leucocytes after incubation with allergen. The percentage of lyzed leucocytes of blood and saliva makes 18.4 +/- 1.2 in case with brucellin, 16.8 +/- 0.75 in case of acute brucellosis and 26.6 +/- 1.12 in case of chronic brucellosis and 28.9 +/ 1.4 in case of negative results of reaction of leukolysis with control antigens (toxoplasmin and medium 199). The reaction of leukolysis can be applied in allergy diagnostic of brucellosis due to its higher informativity with leucocytes of blood and saliva. PMID- 23808019 TI - [The characteristics of production of cytokines in patients with tuberculosis of lungs]. AB - The sample of 36 patients with primarily diagnosed mostly infiltrative tuberculosis of lungs was used to investigate the characteristics of spontaneous and stimulated by specific antigens production of cytokines FNO-alpha, IFN-beta, IL-8 playing the most significant role in pathogenesis of tuberculosis. The production of FNO-alpha and IFN-gamma was analyzed in the culture of peripheral mononuclear cells using antigen M. bovis (BCG). The cytokines IFN-gamma and IL-8 were analyzed in the cultures of whole heparinized blood using antigens H37Rv and ESAT-6. The significant inhibition of stimulated by antigens production of FNO alpha and IFN-gamma in patients with severe, destructive and complicated forms of tuberculosis as compared with to patients with limited and favorably developing tuberculosis. The differences in production of lL-8 in patients with different degree of severity of tuberculosis process are not revealed. PMID- 23808020 TI - [The IgG subclasses in patients with inhibitory form of hemophilia infected and noninfected with viruses]. AB - The sample consisted of 102 patients with hemophilia infected and non-infected with hepatitis viruses. It is established that in case of inhibitory form of hemophilia concentration of IgG increases at the expense of subclass II and in case of non-inhibitory form of hemophilia valuable increase of concentration of IgG occurs at the expense of subclasses I, II and III under concomitant chronic hepatitis. No significant differences between these groups in levels of antibodies to factors VIII and IX is established. PMID- 23808021 TI - [The clinical immunologic characteristics of different variants of course of ulcer colitis]. AB - The study was carried out to determine clinical and immunologic predictors of unfavorable variant of course of ulcer colitis. The sample included 89 patients (48 females--53.9% and 41 males--46.1%) with ulcer colitis established on the basis of clinical, endoscopic and morphologic data. The age of patients was 18-79 years and mean age--42.49 +/- 1.61 years. The patients were divided on two groups depending on clinical course of disease: group 1 with favorable course and group 2 with unfavorable course. The group 2 included patients with frequently relapsing form of disease, patients with hormone-depended/hormone-resistant form of disease and patients with severe exacerbation ua ulcer colitis at the moment of examination. The groups were compared by gender and age. All patients underwent medical history and complaints acquisition and total clinical examination. The clinical and biochemical analysis of blood was made too. The severity of disease was established using the calculation of Trulove- Witts indicator The anti-neutrophil cytoplasmic antibodies of classes IgG and IgA were analyzed using indirect immunofluorescence (Euroimmun AG, Germany). The diagnostic anti-neutrophil cytoplasmic antibodies titer was established in 58 out of 87 of examined patients (66.6%). The antineutrophil cytoplasmic antibodies of class IgG was revealed in 42 patients and anti-neutrophil cytoplasmic antibodies of class IgA in 27 patients. The combination of both classes of anti-neutrophil cytoplasmic antibodies was established in 11 examined patients. In the group of favorable course of disease the diagnostic titer of anti-neutrophil cytoplasmic antibodies was revealed in 20 patients (51%). At the same time, in the subgroups with frequently relapsing, hormone-depended/hormone-resistant and severe forms of disease these antibodies were revealed with rate of 76, 77 and 86.3% correspondingly. Hence, the anti-neutrophil cytoplasmic antibodies can be used both in diagnostic of ulcer colitis and in prognosis of course of disease. PMID- 23808022 TI - [The application of monoclonal peroxidase conjugates to identify comma bacillus of serum groups 01 and 0139 in the reaction of dot-immune analysis]. AB - The source of monoclonal antibodies was chosen the cultural fluid of hybridoma producers deposited in the specialized collection of cell cultures of vertebrates (St. Petersburg) with numbers RKKK(P) 386D and RKKK(P) 674D. The specific immunoglobulin (Ig) from cultural fluid was concentrated by precipitation with saturated solution of ammonium sulfate. The scheme of obtaining monoclonal antibodies included activation of peroxidase, conjugation of activated peroxidase with Ig, removal of unbounded proteins, storage and control. The preservation of activity of conjugates was supported with BSA (10%) or glycerin (50%). The last on is preferable to be applied for this purpose. The test of monoclonal antibody 01 and monoclonal antibody-0139 of peroxidase conjugates with kit of strains of comma bacillus 01 and 0139 demonstrated their strict specificity because they interacted only with corresponding serum groups under absence of crossed reactions with representatives of geterologic microorganisms. The direct dot immune analysis is carried out during 1.5 hour and its sensitivity is within the limits 105-106. The application of diagnostic monoclonal peroxidase conjugates 01, 0139 in laboratory practice can promote the increase of specificity of serologic analysis of cholera and saving time-frame of its application. PMID- 23808023 TI - [About effectiveness and perspective of application of test of venereal disease research laboratory (VDRL) for diagnostic of neurosyphilis in the Russian Federation]. AB - The comparative evaluation of effectiveness of different nontreponema tests in analysis of cerebrospinal fluid. The liquor from 100 patients with syphilis was analyzed using Bordet-Gengou test, VDRL test and micro-precipitation reaction with cardiolipin antigen. The Bordet-Gengou test and VDRL test made in Russia or abroad are equally effective in analysis of positive samples of liquor and twice surpass the same capacity of micro-precipitation reaction with cardiolipin antigen in case of neurosyphilis with symptoms and thrice surpass in case of asymptomatic neurosyphilis. VDRL test is a simple standardized nontreponema reaction which can substitute labor-consuming non-unified liquorologic complex in laboratory diagnostic of neurosyphilis. The testing of liquor on the basis of micro-precipitation reaction with cardiolipin antigen is non-effective and results in false negative results in Bordet-Gengou and VDRL positive tests determining high risk of erroneous clinical considerations. PMID- 23808024 TI - [The experience of applying techniques of molecular genetics in identification of clinical strains Pseudomonas aeruginosa]. AB - The article presents comparative analysis of application of common bacteriologic and molecular techniques to identify P. aerugenosa. The genetic detection was applied using polymerase chain reaction with genus-specific and species-specific primers and amplification of conservative sites of gens 16S pRNA with successive identification of bacteria by sequenation. It is established that 95% (151) of strains correspond to species of P. aerugenosa detected in primary bacteriologic laboratories and only 8 strains were not blue pus bacillus. Most of strains were closely congenial species: 2 isolates belonged to Pseudomonas aeruginosa group, 3 isolates to Pseudomonas putida group, 2 strains to Comamonas species and 1 isolate to Stenotrophomonas maltophilia species. The effectiveness of cultural technique of laboratory diagnostic was demonstrated concerning infections conditioned by P. aerugenosa. This conclusion does not eliminate application of molecular genetic trechnologies in complicated arbitral cases of bacteriologic analysis during monitoring of nosocomial infections. PMID- 23808025 TI - [The development and implementation of polymerase chain reaction to detect in real-time operation mode yersinia pestis in field material]. AB - The article presents the results of development and practical implementation of system of polymerase chain reaction testing in real-time operation mode to detect agent of plague infield material. In laboratory conditions the system demonstrated good results and hence it was applied in conditions of field laboratory of epidemiologic team during planned epizootologic examination of Gorno-Altaisk hot spot of plague. The sampling consisted of more than 1400 objects. It was demonstrated that high sensitivity and specificity is immanent to proposed system. The adaptation of the system to the real time amplifier "Smart Cycler" (Cephid, USA) having some specific technical characteristics makes it possible to consider the proposed test-system as an effective sensitive and precise instrument for screening studies in the process of regular epizootologic examinations of hot spots of plague. PMID- 23808026 TI - [The application of external and internal control objects in case of using of polymerase chain reaction and reverse transcription of polymerase chain reaction]. AB - The external and internal control samples are used in case of polymerase chain reaction application to ensure validity of results. The external control samples are used to establish operability of reagents included into diagnostic kit. The internal control samples make it possible to check not only all the stages of reaction but also the process of amplification in each individual test tube with reaction mixture. PMID- 23808027 TI - [The disbiotic changes of intestines microflora in healthy people]. AB - The article presents the results of study of species and quantitative composition of intestinal flora in volunteer students aged 18-21 years. The disbiotic abnormality of different degrees was diagnosed in 75% of students. The associations of microorganisms, in case of normobiosis and disbacteriosis degree I included predominantly representatives of normoflora, in case of disbiotic abnormality II and III degrees included both representatives of normoflora and opportunistic pathogenic microorganisms. PMID- 23808028 TI - [The development of polymer immunoglobulin preparations to identify different serovars legionella pneumophilia in reaction of slide-agglutination]. AB - The article deals with the results of study targeted to develop polymer diagnostic preparation to identify epidemically significant serogroups Legionella pneumophilia. The preparation combines rate of record (1-5 min) of reaction of paragglutinining preparations with color visualization and demonstrative of reaction of volume agglomeration with polymer diagnosticums. The specially synthesized polymer microspheres were sensibilized with serums enriched with antibodies to lipopolysaccharide of corresponding serovar L. pneumophilia. The derived immunoglobulin diagnostic preparations detect agent of legionellesis in the reaction of slide-agglutination on glass during 1-5 min. The polymer diagnostic preparations provide positive reaction with culture of corresponding serovar and no reaction with other gomologic and geterologic agents of infectious diseases. PMID- 23808029 TI - [The directions and experiences of integration of clinical laboratory diagnostic and branch medicine]. AB - The article considers the actual issues of teaching laboratory medicine to students of medical faculty and to physicians getting trained in different programs of postgraduate education. The major models of interaction between clinical physicians and specialists of laboratory diagnostic are considered. The proposed model of teaching of laboratory medicine is developed in collaboration with clinical chairs and is based on the principle of "clinical laboratory council of physicians". The analysis of clinical cases of specific patients and clinical analytical critiques are in the basement of the given system. The algorithm of considering one of situation tasks used in teaching is presented as example. PMID- 23808030 TI - [The public health and medal science: modern challenges and means of overcoming]. AB - The article presents author's personal position concerning the possibilities and conditions of development and implementation of strategy of society and public policy in the area of health preservation and health promotion in present conditions and near future. PMID- 23808031 TI - [The mean duration of stay in hospital of patients with pathology of circulatory system in Russia and particular European countries]. AB - The comparative analysis of mean duration of stay in hospital of patients with pathology of circulatory system in the Russian Federation (form No 14 "The information about hospital activities in 2011") and particular European countries (data about main characteristics of functioning of hospitals in European countries from the information system "The Hospital morbidity Database (HMDB) January 2011") established the characteristics of structure of hospitalized patients of the mentioned class including differences in duration of stay of patients in hospital. The significant differentiation between countries exists concerning the indicators of mean duration of stay in hospital of patients with various diseases of circulatory system. At that, in the Russian Federation certain indicators of particular nosology forms are lower than corresponding indicators in foreign countries. This peculiarity is to be taken into account in organization of medical care of these patients in Russia national conditions. PMID- 23808032 TI - [The diseases of circulatory system in employees of railway transport]. AB - The article presents the epidemiologic and medical social aspects of diseases of circulatory system in employees of railway transport in 2000-2010 exemplified by Privolzhskiy railroad. The established tendencies in prevalence of pathology of cardio-vascular system in railroad workers makes the issues of practical implementation of priority of prevention in the organization of medical care to this group of patients to come to foreground. The main directions for complex prevention of diseases of circulatory system in employees of railway transport are presented. PMID- 23808033 TI - [The service of obstetrics in Riazan region]. AB - The article emphasizes that the major purposes of priority national project in health care field are increase of availability and quality of primary and high tech medical care, including period during pregnancy and delivery. The prevention and decrease of maternal, perinatal morbidity and mortality are among these priorities too. The reorganization of obstetrics service will promote rationale using of bed stock of obstetrics institutions including the optimal supply rationale structure, proper selection and regulation of flow for hospitalization and stages of medical care delivery. PMID- 23808034 TI - [The mortality because of conditions related to alcohol consumption]. AB - The article presents the systematization of data concerning alcohol-depended mortality as a occurrence with complicated structure. It is established that grouping of alcohol-depended mortality on isolated components is conditioned by different nature of unhealthy consumption of alcohol in the development of alcohol-depended conditions as a conditional and/or supporting factor. Among other causation factors article points out the input of pattern of alcohol consumption into the value of risk of development of alcohol-attributive conditions and two-way impact of unhealthy alcohol consumption at the risk of development of particular alcohol-attributive conditions. PMID- 23808035 TI - [The availability and quality of the ambulatory polyclinic care]. AB - The article deals with the results of the study of complex of medical demographic and social economic indicators of Nizhny Novgorod oblast during 1989-2010. The results are as follows. The policlinics' net reduced by 2.25 times, including by 10.6 times in rural area and by 12.6 times of ambulatories of community hospitals. The indicators of physicians' supply of oblast population decreased too especially in urban area. The annual number of visits to physicians per capita decreased by 1.36 times. The number of calls of out-patients to physicians of emergency medical care increased by 1.5 times. The morbidity with temporarily disability and primary registration as a disabled person decreased by 1.45 times, including able-bodied citizen by 1.54 times. In Nizhny Novgorod oblast, the rate of decrease of indicators of primary disability during 2006-2009 overpassed the corresponding federal indicators by 1.45 times. The population mortality increased by 1.43 times. The accessibility and quality of ambulatory polyclinic care significantly impacts on the levels of mortality and social security of population and can be used as an indicator of social risks in the region. PMID- 23808036 TI - [The means of development of dispanserization of pregnant women and puerperants]. AB - The article deals with the issues of dispensarization of pregnant women and puerperants as exemplified by Moscow oblast and certain maternity clinics in municipal districts of oblast. The article presents the results of sociological survey of obstetricians-gynecologists and pregnant women about issues of dispensarization. The organizational functional model is presented to develop the means of dispensarization of pregnant women and to increase its role in population health promotion. PMID- 23808037 TI - [The organization of scientific innovative laboratory complex of modern technologies]. AB - The article discusses the actual issues of scientific innovative activity during the realization of principles of private-public partnership. The experience of development of model of scientific innovative complex is presented The possibilities to implement research achievements and their application in the area of cell technologies, technologies of regenerative medicine, biochip technologies are demonstrated. The opportunities to provide high level of diagnostic and treatment in practical health care increase of accessibility and quality of medical care and population health promotion are discussed. PMID- 23808038 TI - [About the need of restructuration of medical care of older than able-bodied population]. AB - The article deals with the results of study of factual volumes of medical care according its main services provided to total population and to people older than able-bodied population in Nizhny Novgorod oblast. The study demonstrated that during last ten years, the character of organization and application of main volumes of medical care to people older than able-bodied population factually had no changes and does not correspond to the planned volumes of territorial program of public guarantees of free medical care. The increase of volume of emergency medical care in functioning of ambulance and emergency care service shortens possibilities of emergency medical care support and promote misallocation of financial resources. The level of medical care support of people older than able bodied population in day-and-night hospitals is high at the same time it is lower in nursing departments and out-patient clinics. To provide the accessibility and quality of medical services to people older than able-bodied population the restructuration of medical care is needed to increase the volume of hospital substituting types of medical care and to organize the service of specialized palliative care primarily for oncological patients. PMID- 23808039 TI - [The characteristics of medical technologies in emergency medical care hospital]. AB - The article analyzes the implementation of major 12 diagnostic and 17 treatment technologies applied during medical care of patients with 12 key nosology forms of diseases in departments of the emergency medical care hospital No 2 of Omsk. It is established that key groups of technologies in the implementation of diagnostic process are the laboratory clinical diagnostic analyses and common diagnostic activities at reception into hospital and corresponding departments. The percentage of this kind of activities is about 78.3% of all diagnostic technologies. During the realization of treatment process the priority technologies are common curative and rehabilitation activities, intensive therapy activities and clinical diagnostic monitoring activities. All of them consist 80.1% of all curative technologies. PMID- 23808040 TI - [The characteristics of organization of anti-leprosy activities in Russia]. AB - The article presents data about dynamics of primary morbidity of leprosy and total number of registered leprosy patients in Russia. The causes and factors inputting into decrease of morbidity and successful control and elimination of leprosy in our country. The tasks are presented concerning the development of practical anti-leprosy activities and determination of research studies and prospective of development of corresponding service and forms of international cooperation concerning leprosy. PMID- 23808041 TI - [The characteristic of stomatologic service manpower in Omsk region]. AB - The article considers the network and manpower characteristics of stomatologic service in Omsk oblast during 2006-3011. The results are presented concerning statistical analysis of dynamics of manpower size and staffing of specialists in stomatologic rooms (departments) in state (budget) health institutions. The differences are demonstrated concerning the accessibility of stomatologic care to residents of city and rural regions of oblast. PMID- 23808042 TI - [The organization of system of quality management in large multitype hospital]. AB - The article presents the characteristics and assessment of functioning of model of quality management in large multitype hospital. The results of work of the municipal hospital of Saint Venerable martyr Elizabeth of St Petersburg concerning the implementation of system of quality management in 2001-2011 of the foundation of principles of total quality management of medical service and principles of quality management according international standards ISO and their Russian analogues. PMID- 23808043 TI - [About making up for manpower resource of paramedical personnel]. AB - The article deals with the analysis of quality of training of paramedical personnel in the medical colleges of Kursk oblast during last ten years. It is established that during last decade the number of graduates of the Kursk medical college has a tendency to decrease. If in 2001 the college graduated 169 medical nurses, 44 feldshers, and 30 midwives (243 in total) then in 2011 graduated 121 medical nurses, 64 feldshers (185 in totals). The number of college entrants with 11th grade is decreasing against the background of increasing of number of college entrants with 9th grade. Basically, the educational institutions are completed with graduates of rural schools whose resources are limited. The graduates from urban schools have no intent to acquire the profession of medical nurse. Hence, in Kursk oblast under annual decrease of number of paramedical personnel concurrently decreases number of graduates of medical colleges. This situation makes quite problematic the making up of manpower resource both in nowadays and in near-term outlook. PMID- 23808044 TI - [The scientific school of RAMS academician Iu.P. Lisitsyn in the field of public health and medicine]. AB - The development of medical science is not possible without studying of becoming and development of its scientific schools. In the field of public health, health care and history of medicine a unique position occupies the scientific school of RAMS academician, professor Yu.P Lisitsyn. The mentioned scientific school made a significant input into becoming and development of various directions of research in history of medicine and health care. PMID- 23808045 TI - [The becoming of public medicine in the second half of XVIII-first half of XIX centuries. Report II. The development of public systems of training of medical manpower and charity provision to socially unprotected groups of population]. AB - The present report considers the history of becoming of concept of medical police in second half of XVIII century. This concept became one of the most important instruments of public management in Austria, France, Prussia and Russia. Two directions of activity of public authorities in the area of implementation of medical police are discussed i.e. control of frauds and development of public systems of training of medical manpower and charity provision to socially unprotected groups of population. The historiographical data is presented concerning the development of public systems of training of medical manpower, reform of university medical education, implementation of hospital reform. PMID- 23808046 TI - [Ivan Alekseevich Chernogorov--the professor-cardiologist of the Moscow Stomatologic Institute]. AB - The article presents the scientific biography of Ivan Alekseyevitch Tchernogorov, the prominent Moscow cardiologist, the disciple of D.D. Pletnyev and VF Zelenin. PMID- 23808047 TI - [The sanitary preventive direction of Zemstvo medicine of Ekaterinoslav Gubernia]. AB - The article analyzes, for the reason of archive and literary sources, the historic medical characteristics of formation of sanitary antiepidemic organization of Yekaterinoslav gubernia. The historic stages are established and the essence and basic principles of formation of preventive direction oa Zemstvo medicine are revealed. It is demonstrated that the achievements of sanitary organization of Yekaterinoslav Zemstvo became possible due to the efforts of progressive Zemstvo sanutary physicians who developed a comprehensive system of sanitary epidemiologic service, the most advanced in Ukraine. PMID- 23808048 TI - [G.I. Braun and organization of education of ophthalmology in the Moscow University]. AB - The article considers the characteristics of organization of process of education of ophthalmology at the medical faculty of Moscow University in the second half of XIX century PMID- 23808049 TI - [The importance of works of the G.Ye. Rhein commission for public health in Russia]. AB - The article analyses the history of development, functioning and historical importance of works of imperially established interdepartmental commission for revision of medical sanitary legislation (the G.Ye. Rhein commissions 1912-1916). The commission developed several progressive legislation projects which were not accepted by medical community of Russia. On the contrary, these proposals were implemented by Narkomzdrav of the Russian Soviet Federative Socialist Republic. PMID- 23808050 TI - [The stages of development of Ayurvedic medicine]. AB - The Ayurveda medicine as one the three traditional systems of healing developed during millennia at the Hindustan subcontinent (the ancient India). Nowadays, Ayurveda medicine is widely used in many countries. The present day researchers mark out and analyze several periods in its history. PMID- 23808051 TI - A matter of perspective: implementing information management initiatives. PMID- 23808052 TI - Room for computing on the healthcare cloud. PMID- 23808053 TI - Incident-to services: legitimate revenue source or compliance pitfall? PMID- 23808054 TI - Federally required compliance programs: where do we stand? PMID- 23808055 TI - Association creates sample HIPAA documents for members. PMID- 23808057 TI - Virtual conundrum: a member perspective on HIEs. PMID- 23808056 TI - Learning from your patients. PMID- 23808058 TI - Are you a meaningful IT user? PMID- 23808059 TI - Successful partnerships in practice: a payer perspective. PMID- 23808060 TI - Don't forget the other HIPAA when thinking about meaningful use. PMID- 23808061 TI - You know more than you think: one member's trek to healthcare management certification. PMID- 23808063 TI - From dough to bread: Bachrachs' generosity stands alone among scholarship providers. PMID- 23808062 TI - Three EHR-related coding errors to avoid. PMID- 23808064 TI - As you reach forward in your nursing career, reach back to guide others along the way. PMID- 23808065 TI - Thrill of learning. PMID- 23808066 TI - How has completing a nurse residency program helped your transition to nursing? PMID- 23808067 TI - How does ONS Congress help educate Dutch oncology nurses? PMID- 23808068 TI - What barriers do you face in educating nurses to provide evidence-based care? PMID- 23808069 TI - Building our future. PMID- 23808070 TI - What makes an oncology nurse a natural leader? PMID- 23808072 TI - The case of the suspicious sunburn. PMID- 23808071 TI - Increase emotional intelligence awareness during clinical rounds. PMID- 23808074 TI - Health policy changes open doors for oncology nurses in education and leadership. PMID- 23808073 TI - Oncology nurses are on the forefront at NCI's Cancer Information Service. PMID- 23808075 TI - Washington's Death With Dignity program is a rarely used success, according to new study. PMID- 23808076 TI - What will your job look like in 10 years? PMID- 23808077 TI - [Ethical aspects of compulsory care]. PMID- 23808079 TI - [Interns' R & D education must be better defined]. PMID- 23808078 TI - [Hypertension is the greatest threat to global health. Increases the risk of cardiovascular disease, dementia and kidney disease]. PMID- 23808080 TI - [Increase in serious infections due to group A streptococci]. PMID- 23808081 TI - [ST-doctors believe scientific courses should relate more to everyday practice]. PMID- 23808082 TI - [Patients with ischemic heart disease often suffers from diabetes]. PMID- 23808083 TI - [Diabetes mellitus possible differential diagnose to diaper dermatitis]. PMID- 23808084 TI - [Drug utilization review--a practical example from primary care]. PMID- 23808085 TI - [Do we need a physicians' promise as ethical support?]. PMID- 23808086 TI - ["Pass the knife on"--campaign for better surgical training for interns]. PMID- 23808087 TI - [Call: 883 dissertations in psychiatry in Sweden 1858-2012]. PMID- 23808088 TI - [When women's dissatisfaction was classified as a disease]. PMID- 23808089 TI - Arkansas plan getting national spotlight. PMID- 23808090 TI - Compassionate medical care efficiency: are they compatible. PMID- 23808091 TI - The "cost" of surgical training. PMID- 23808092 TI - Fighting prescription drug abuse in Arkansas. PMID- 23808093 TI - Arkansas prescription monitoring program implemented. PMID- 23808094 TI - Ehrlichiosis presenting with toxic shock-like syndrome and secondary hemophagocytic lymphohistiocytosis. AB - Human monocytotropic ehrlichios is a tick borne illness caused by Ehrlichia chaffeensis. Ehrlichiosis presenting with septic shock and severe azotemia is rare, and may be seen in immunocompromised individuals. We present a case of ehrlichia induced toxic shock like syndrome in a patient with rheumatoid arthritis on disease modifying agents. He also had oliguric renal failure requiring dialysis on presentation and later found to have Hemophagocytic Lymphohistiocytosis secondary to severe ehrlichia sepsis. PMID- 23808095 TI - Rare cause of hemolytic anemia. AB - Hemolysis is commonly seen in patients with mechanical heart valves and is secondary to destruction of red blood cells by mechanical action of artificial valve. It is very unusual after repair of native heart valve. Here we present a case of hemolytic anemia in association with mitral valve repair. PMID- 23808096 TI - Symposium: women and prenatal genetic testing in the 21st century. PMID- 23808097 TI - The changing landscape of carrier screening: expanding technology and options?. PMID- 23808098 TI - Opportunistic testing: the death of informed consent? AB - This Article focuses on one aspect of prenatal diagnosis: noninvasive prenatal diagnosis, particularly the detection of Trisomy 21 (Down Syndrome) through a simple test of maternal blood. Although I discuss issues salient to this particular test, I place it in the context of "opportunistic" testing generally. It is my view that opportunistic testing presents the most serious challenge to patient autonomy we are facing in the twenty-first century. In this Article, I will explain what I mean by opportunistic testing and consider three different examples of how it threatens informed consent: (1) Prostate-Specific Antigen (PSA) screening, (2) newborn screening, and (3) prenatal diagnosis of maternal blood tests for fetal anomalies. PMID- 23808099 TI - What does choice really mean? Prenatal testing, disability, and special education without illusions. PMID- 23808100 TI - Taxation without representation: the illegal IRS rule to expand tax credits under the PPACA. AB - The Patient Protection and Affordable Care Act (PPACA) provides tax credits and subsidies for the purchase of qualifying health insurance plans on state-run insurance exchanges. Contrary to expectations, many states are refusing or otherwise failing to create such exchanges. An Internal Revenue Service (IRS) rule purports to extend these tax credits and subsidies to the purchase of health insurance in federal exchanges created in states without exchanges of their own. This rule lacks statutory authority. The text, structure, and history of the Act show that tax credits and subsidies are not available in federally run exchanges. The IRS rule is contrary to congressional intent and cannot be justified on other legal grounds. Because tax credit eligibility can trigger penalties on employers and individuals, affected parties are likely to have standing to challenge the IRS rule in court. PMID- 23808101 TI - Health care and the illegal immigrant. AB - The question of whether illegal immigrants should be entitled to some form of health coverage in the United States sits at the intersection of two contentious debates: health reform and immigration reform. Proponents of extending coverage argue that the United States has a moral obligation to provide health care to all those within its borders. Conversely, those against doing so argue that immigrants illegally present in the country should not be entitled to public benefits. This Article seeks to chart a middle course between these extremes while answering two questions. First, does constitutional law mandate extending health coverage to illegal immigrants? Second, even if not legally mandated, are there compelling policy reasons for extending such coverage? This Article concludes that while health coverage for illegal immigrants is not required under prevailing constitutional norms, extending coverage as a matter of policy would serve the broader interests of the United States. Extending coverage would be beneficial as a matter of economics and public health, generating spillover benefits for all US citizens and those in the US healthcare and health insurance systems. PMID- 23808102 TI - The moral from Sorrell: educate, don't legislate. AB - This Article argues that in response to the United States Supreme Court's 2011 decision in Sorrell v. IMS Health Inc., state legislators should refrain from enacting prescription confidentiality laws and instead implement policies supporting academic detailing, a form of continuing medical education in which trained health professionals such as physicians, registered nurses, advanced practice nurses, and pharmacists provide evidence-based information about prescription drugs to prescribers. According to Sorrell, pharmaceutical companies may freely use physicians' prescribing data to better promote, or "detail," products to physicians without government interference. While pharmaceutical companies may profit from detailing drugs to physicians, detailing increases health care costs for patients and negatively affects patient health outcomes. These problems motivated Maine, New Hampshire, and Vermont to enact prescription confidentiality laws that banned the use of information about the prescribing habits of physicians to help market drugs to physicians. Recent state attempts to stop drug detailing to physicians have been found to violate the First Amendment. This Article provides a history and background on the pharmaceutical-detailing process and analyzes recent legal decisions relating to prescription confidentiality. It concludes that academic detailing is a viable solution to the negative effects of pharmaceutical detailing and is consistent with the First Amendment. PMID- 23808104 TI - Defining intellectual disability and establishing a standard of proof: suggestions for a national model standard. PMID- 23808103 TI - Safeguards for mentally disabled respondents in removal proceedings. PMID- 23808105 TI - Drafting a "sensible" conscience clause: a proposal for meaningful conscience protections for religious employers objecting to the mandated coverage of prescription contraceptives. PMID- 23808106 TI - [Prostate cancer in Luxembourg from 1982 to 2006. Incidence and mortality. Survival of a hospital cohort]. AB - Prostate cancer incidence has tripled in Luxembourg as in many other western countries. From 1982 to 2006, new cases increased from 80 to 309 per year, while the incidence (world stand.pop.) rose from 29.5 to 85 per 100 000 men. Since 1991 prostate cancer is the most frequent male cancer in Luxembourg, exceeding colo rectal, lung and stomach cancer. Prostate cancer deaths have diminished from 64 in 1982 to 45 in 2006. This represents less than 10% of male cancer related deaths; it represents the third most frequent cancer death, behind lung and colo rectal cancers. Annual mortality rate has decreased from 29 to 10 per 100 000 men during the same period, this difference between incidence and mortality is explained on the one hand by the widespread use of PSA since the 1990's and on the other hand by a better local control as well as a multidisciplinary approach of advanced disease. The increase of the incidence is particularly important in the 60 to 70 age group, while for men older than 70, the peak incidence was reached in 2002. A lowering of the age at diagnosis is confirmed by the 5-year age group analysis. The hospital cohort consists of 628 patients from the urological department of the Centre Hospitalier de Luxembourg diagnosed with prostate cancer between 1st January 1982 and 31st December 2006; follow-up ended 31st December 2011. During this period, age at diagnosis decreased from 71.5 to 68.9 years whereas the proportion of localized clinical stages increased from 44 to 70%. Median PSA dropped from 14.5 to 9 ng/ml. Furthermore the analysis of cancer specific mortality confirms the negative effects of an advanced clinical stage (10-year survival: 90% for localized disease, 60% for advanced disease) or a high PSA level at diagnosis (10-year survival: 97% if PSA < 4 ng/nl, 94% if 4 < PSA < 10, and 72% if PSA > 10 ng/ml), as well as a poor differentiation (60% 10 year survival compared to 90% for differentiated tumors). Kaplan-Meier curves show that long term surveillance is necessary as even tumors with a good initial prognosis may relapse after 10-12 years. PMID- 23808107 TI - [A few reflections and definitions on the subject of embryonic research]. AB - Tissue regeneration by embryonic stem cells (ESC) opens new applications for cellular therapy. ECS are used in endocrinology, rheumatology, cardiology, orthopaedics, dermatology and neurology. They come from supernumerary embryos given by their progenitors to science. The moral embryo status is the conflicting point and a hotly debated question. No ethical committee has given any valuable definition. Some countries have set time limits governing research with embryos, while others consider ECS as more akin to things or living beings such as animals. PMID- 23808109 TI - [Giant melanoma of the scalp: Case report]. AB - We present a case of giant melanoma of the scalp observed in our department. It is a rare but very aggressive pathology which is generally treated by radical surgery. We emphasize early diagnosis because a large extension of the tumor can lead to the need of a very extensive surgical resection. Prognosis is very severe despite adjuvant medical treatments. PMID- 23808108 TI - Lifestyle counseling in patients with carotid arteriosclerosis from Luxemburg should focus more on the reduction of sugar, sodium and saturated fat consumption. AB - BACKGROUND: Healthy diet and physical activity improve risk factors for cerebrovascular disease. It is unclear whether patients with carotid artery disease from Luxemburg meet common guideline criteria and whether systematic counseling has a sustained effect. METHODS: We assessed anthropometric data, eating habits and physical activity habits in 53 patients with carotid atherosclerosis at baseline, after 4 and 20 weeks, and advised them five times for 30 min to follow a modified Mediterranean diet and to perform moderate physical exercise at least during 30 min/day. RESULTS: The patients had a mildly increased BMI (mean 27.6, recommended below 25), they already ate enough vegetables and fruits (mean 485 g daily, recommended at least 400 g), they ate too much sugar (mean 74 g daily) and sodium (mean 2710 mg daily, recommended less than 1500), they consumed 13% of calories from saturated fatty acids (recommended less than 10%), and they already moved sufficiently (62 min daily of moderate and intense physical activity, recommended at least 30 min of moderate physical activity). Lifestyle counseling had a sustained effect on weight, reduction of global caloric intake, carbohydrate and cholesterol intake and on an increase in consumption of poly-unsaturated fatty acids, vegetables and fibres. There was no sustained effect on the consumption of sugar, sodium, and saturated fat. CONCLUSIONS: The reduction of sugar, sodium and saturated fat consumption should be stressed more in counselling of this patient group. PMID- 23808111 TI - Preventing the 'triple fail'. PMID- 23808110 TI - [Using arts therapies in psycho-oncology: evaluation of an exploratory study implemented in an out-patient setting]. AB - According to the state-of-the-art in health psychology and psycho-oncology, a cancerous disease, as well as the accompanying medical treatments, is a source ofintense emotional stress. As feelings of insecurity and anxiety are likely to induce negative effects on immune defences, those effects may overlap with the cancerous disease and complicate its evolution. As arts therapies tend to favour the imaginary and symbolic elaboration of the tensions of daily life, as well as the re appropriation of one's body and personal history, different artistic mediations may occupy an important function in the psychological follow-up of the patient. Following an exploratory study in a hospital, we carried out an action research in an out-patient setting during six moths. The arts therapeutic treatment comprehended alternatively drawing and writing sessions while listening to music, opening tracks for a thorough verbal elaboration. The evaluation was based on psychometric scales (HADS and MDBF), rating scales for the pictorial and literary production and a semi-structured interview. According to the results of the quantitative analyses, based on non parametric statistical procedures for small groups and non metric data, as well as to the qualitative content analyses, arts therapies could become a valuable treating measure within a multidisciplinary bio-psycho-social approach. PMID- 23808112 TI - DR underscores the importance of security. Regardless of the selected solution, experts agree the most important criteria for a disaster recovery (DR) back-up system is that it is secure. PMID- 23808113 TI - Flying solo isn't easy. Addressing the challenges of private practice. PMID- 23808114 TI - Humanizing healthcare with technology. Streamlining the clinical documentation process augments doctor/patient interaction. PMID- 23808115 TI - Turning words into action. End-to-end transcription is changing everything we thought we knew about creating clinical documentation. PMID- 23808116 TI - Imaging: taking its rightful place at the enterprise level. Image-enabling the EMR leads to increased productivity and efficiencies. PMID- 23808117 TI - Advancing RIS features while addressing MU. New business intelligence tools enable improved care and profitability. PMID- 23808118 TI - Benefiting from the changing nature of home visits. Utilizing home-visit programs to render more proactive care management. PMID- 23808119 TI - Play nice in healthcare. PMID- 23808120 TI - The convergence of mHealth and accountable care. PMID- 23808121 TI - Helping a self-developed EMR evolve. PMID- 23808123 TI - A tool for patient engagement. Interview by Gabriel Perna. PMID- 23808122 TI - Carle clinic targets infections with new surveillance software. Interview by Rajiv Leventhal. PMID- 23808125 TI - Patients of empathetic GPs have better outcomes. PMID- 23808124 TI - Ten worst interview behaviors. PMID- 23808126 TI - Diagnosis and management of autism in adults. AB - Autism affects 1.1% of the adult population. The spectrum of symptoms is wide; some individuals have above average intelligence and are fully independent, while others have limited independence because of a learning disability. Developmental delay is a core feature, and autism is usually diagnosed in childhood. High functioning individuals with autism, Asperger's syndrome, may remain undiagnosed until adulthood. Autism is a life-long condition characterised by problems in two core dimensions: difficulties with social communication and strongly repetitive behaviour, resistance to change or restricted interests.The history should identify early developmental and behavioural problems in different settings e.g. at home, in education or employment. Sensory and GI problems are very common, and should be asked about. The Autism-Spectrum Quotient (AQ-10) is a 10-item questionnaire for people with suspected autism. The advantage of using this in primary care is that it provides a time-efficient, structured way of ascertaining key symptoms and clearly signals those who should be referred for further assessment. Patients should be referred if autism is suspected clinically and a diagnosis of autism should be confirmed by a specialist multidisciplinary team. If a diagnosis of autism is made, clinicians should do a risk assessment and formulate risk and crisis management plans. These should include details of the roles and responsibilities of both the specialist team and primary care team in managing crisis situations. For adults with autism a group-based or an individual learning programme to improve social interaction is recommended. Adults with autism have high rates of unemployment, and employment programmes have been successfully used to support people PMID- 23808127 TI - Managing disruptive behaviour disorders in children. AB - The age at which individuals are most physically aggressive is 22 months. However, some children fail to inhibit this normal aggression and by the time they are three or four are showing signs of oppositional defiant disorder. In older children persistent antisocial behaviour is classified as conduct disorder. At any age, antisocial behaviour is on a continuum, and while the most severe 5% or so will meet diagnostic criteria, those falling short are often described as having conduct problems. Epidemiological follow-up surveys show that the risk of poor outcomes in antisocial children is very high. The causes are multiple but two sets of factors stand out. First, genetic predisposition. Even children adopted away from violent or criminal parents have three or four times the rate of antisocial behaviour and second, poor parenting. Watching and waiting is a reasonable strategy if the antisocial behaviour is not very severe. It is important to be vigilant for severe tantrums or aggression occurring almost every day, harsh, rough, or inconsistent parenting and coexistent ADHD. If severity is moderate, referral to an evidence-based parenting group would be a good first move. If this fails to make things better, or if the child or parent has a comorbid condition, referral to CAMHS is indicated. For older children, aged 10 to 17, there are effective interventions such as anger management CBT and parenting groups for adolescents. PMID- 23808128 TI - Intense nocturnal itching should raise suspicion of scabies. AB - Scabies is caused by infestation with a parasitic mite Sarcoptes scabiei var hominis. The itch and rash appear to be largely the result of a delayed (type IV) allergic reaction to the mite, its eggs and excreta. Scabies is spread by a mite transferring to the skin surface of an unaffected person, usually by skin to skin contact with an infested person, but occasionally via contaminated bed linen, clothes or towels. In crusted scabies, mites are also dispersed within shed scales, enabling the condition to be contracted from contaminated surfaces. Patients with classical scabies usually present with an itchy non-specific rash. Often, the history alone can be 0032-6518 virtually diagnostic. An intense itch, affecting all body regions except the head, typically worse at night, appearing to be out of proportion to the physical evidence, with a close contact also itching, should prompt serious consideration of scabies. The generalised hypersensitivity rash consists of erythematous macules and papules with excoriation. Close inspection will reveal burrows usually up to 1 cm in length. The pathognomic sign of scabies is the presence of burrows. The crusted variant of scabies may not be itchy. It is characterised by areas of dry, scaly, hyperkeratotic and crusted skin, particularly on the extremities. Referral to secondary care should be considered in the following cases: diagnostic doubt; patient under two months of age; lack of response to two ourses of different insecticides; crusted scabies; or history suggests a isk of sexually transmitted infection. Outbreaks of scabies in institutions should be referred to the local health protection services. PMID- 23808129 TI - Disorders of blood vessels. PMID- 23808131 TI - GPs can be key advocates for older patients. PMID- 23808130 TI - Two curious cases of coin in the alimentary canal. 1913. PMID- 23808132 TI - Green house: flexible, low-cost funding available. PMID- 23808133 TI - QAPI: weaving the old with the new. PMID- 23808134 TI - Top 50 largest nursing facility companies: 2013 continuum of services continues. PMID- 23808135 TI - Top 40 largest asstisted living companies: 2013 dementia care universal in assisted living. PMID- 23808136 TI - [The role of the extracellular polymer matrix in the stability of bacterial biofilms under extreme medium factors]. PMID- 23808137 TI - [The effect of Luteococcus japonicus subsp. Casei reactivating factor on the expression of SOS response genes]. PMID- 23808138 TI - [The influence of bacterial autoregulation molecules (homoserine lactones and alkyloxybenzoles) on oxidative metabolism of the natural immunity cellular effectors]. PMID- 23808139 TI - [Tyrosinases from Azospirillum free living strains]. PMID- 23808140 TI - [Nogalose methylation in the nogalamycin biosynthesis in Streptomyces nogales LV65 ]. PMID- 23808141 TI - [Isolation of the photosynthetizing purple bacteria Rhodobacter sphaeroides dissociants and the study of their molecular, physiological-biochemical and morphological characteristics ]. PMID- 23808142 TI - [Molecular-genetic characteristic of the alcohol yeasts Saccharomyces cerevisiae]. PMID- 23808143 TI - [Azotobacter vinelandii and Bacillus subtilis chemotaxis in the mixed culture ]. PMID- 23808144 TI - [Microorganisms from carbonate oil deposits in Romashkinskoe oil field and their biotechnological potential ]. PMID- 23808145 TI - [Reidentification of the chromosomal CUP1-translocations in wine yeasts Saccharomyces cerevisiae]. PMID- 23808146 TI - [Qualitative and quantitative evaluation of the acidophilic microbial cultured consortium with real time-PCR and clone library analysis]. PMID- 23808147 TI - [The study of the specific interaction between microbial cells with polyclonal antibodies by the transverse electric field resonator]. PMID- 23808148 TI - [Sulfate reduction, methane formation and oxidation in the surface sediments in Vislinskii and Kurshskii Bay in the Baltic sea]. PMID- 23808149 TI - [The influence of soil pollution on soil microbial consortium]. PMID- 23808150 TI - [Diversity in the bacterial genus Halomonadaceae in the Upper Kama salts mining region]. PMID- 23808151 TI - [Production and characterization of Methylomicrobium alcaliphilum 20Z knockout mutants, which has sucrose and ectoin synthesis defective genes]. PMID- 23808152 TI - [Caspase-2: what do we know today?]. AB - Apoptosis (programmed cell death) is essential machinery for multicellular organisms. Apoptosis plays an important role in cell differentiation, damaged cell elimination and immune system homeostasis. This review is focused on various mechanisms of signal transduction through caspase-2 which believed to be one of the most enigmatical protease involved in apoptosis. Caspase-2 is activated upon stimulation by such agents as genotoxic stress, death receptors ligation, ER stress, metabolic changes, etc. In addition, caspase-2 may act as a tumor suppressor and has been implicated in cell response to oxidative stress and neurodegenerative progression during ischemic brain damage. Thus, variety of signal pathways triggered by caspase-2 place this protease apart from other members of the family and suggests a prominent role in apoptosis. Here, we analyse different functions of this unique caspase and discuss possible applications of accumulated knowledge in advanced oncology and medicine. PMID- 23808153 TI - [Enzymatic control of homologous recombination in Escherichia coli cells and hyper-recombination]. AB - The RecA protein is a major enzyme of homologous recombination in bacterial cell. Forming a right-handed helical filament on ssDNA, it provides a homology search between two DNA molecules and homologous strand exchange. The RecA protein not only defends the cell from exposure to ionizing radiation and UV-irradiation, but also ensures the recombination process in the course of normal cell growth. A number of wild-type or mutant RecA proteins demonstrate increased recombinogenic properties in vitro and in vivo as compared with the wild-type RecA protein from Escherichia coli, which leads to hyper-recombination. The hyper-rec activity of RecA proteins during the recombination process in many depends on the filamentation dynamics on ssDNA and DNA-transferase properties. Changes in filamentation and DNA-transferase abilities of RecA protein may be the result of not only specific amino-acid substitutions, but also the functioning of the cell enzymatic apparatus, including such proteins as RecO, RecR, RecF, RecX, DinI, SSB, PsiB. To date, the function of each of these proteins is identified at the molecular level. However, the role of some of them in the cell metabolism remains to be seen. Increase in recombination in vivo is not always useful for a cell and faces various limitations. Moreover, in the bacterial cell some mechanisms are activated, that cause genomic reorganization, directed to suppress the expression of hyper-active RecA protein. The ways of hyper-active RecA protein regulation are very interesting, and they are studied in different model systems. PMID- 23808154 TI - [Identification of endogenous control genes for gene expression studies in peripheral blood of patients with coronary artery disease]. AB - The selection of stable endogenous control genes is critical for normalization of quantitative real-time PCR (qPCR) data. In this study, we aimed to identify a suitable set of control genes to be used as endogenous references for gene expression evaluation in human peripheral blood samples among coronary artery disease patients. The expression levels of 12 endogenous control genes procured from TATAA Biocenter (Goteborg, Sweden) were measured in five acute coronary syndrome patients and five chronic stable angina patients. Gene expression stability was analyzed using two different software applications i.e geNorm and NormFinder. Results suggested that beta-glucuronidase is the most stable endogenous control, followed by hypoxanthine-guanine phosphoribosyltransferase. The NormFinder analysis further confirmed that beta-glucuronidase and hypoxanthine-guanine phosphoribosyltransferase were on the first rank order with the most stable expression among endogenous control genes analyzed and 60S acidic ribosomal protein P0. Besides this, the expression levels of 18S rRNA were revealed to be highly variable between coronary heart disease patients. We thus recommend the use of beta-glucuronidase and hypoxanthine-guanine phosphoribosyltransferase as reference genes for accurate normalization of relative quantities of gene expression levels in coronary artery disease patients using qPCR. Also the use of 18S rRNA as a control gene should be avoided. PMID- 23808155 TI - [G4-quadruplexes and genome instability]. AB - A comparative analysis in silico of distribution of nucleotide sequences that predispose to formation of non-canonical DNA structure of G-quadruplexes, closely related with gene expression regulation and double strand DNA breaks, within vertebrata and yeast nuclear and mitochondrial genomes was carried out. Data on preferable localization of potential quadruplexes within non-coding sequences, their evolutionary conservation, and existing homology between them in mitochondrial and nuclear genomes were obtained. A possible interrelation between quadruplexes, Pif1 helicase and genomic instability is discussed. PMID- 23808156 TI - [IncP-7 plasmids' classification based on structural diversity of their basic replicons]. AB - The structural diversity of basic replicons and repB gene of the IncP-7 plasmids' collection was firstly assessed on the basis of PCR, restriction analysis and partial sequencing. It has been revealed that DNA fragment containing gene for UvrD-like helicase RepB is a part of all known P-7 replicons, but often serves as hot place for diverse IS-elements invasion. The first system of P-7 plasmids' classification has been worked out on the basis of determined repA-oriV-par WABC nucleotide divergency. Most degradation plasmids established to be belonging to large beta-subgroup, streptomycin resistance plasmid Rms148 (IncP-7 archetype)- to alpha-subgroup, carbazole degradation plasmid pCAR1 and NAH/SAL-plasmids from pY-line (Yamal oil deposits)--to gamma-subgroup and CAP-plasmid pBS270 with potentially reduced P-7 replicon--to delta-subgroup. It has been observed that the type of IncP-7 basic replicon molecular organization does not correlate with fixed phenotypic character in most cases, that is plasmids encoding different phenotypic markers could be members of the same P-7 subgroup. PMID- 23808157 TI - [The structure and polymorphism of the Pain-1 vacuolar invertase locus in Solanum species]. AB - Nucleotide sequences of Solanum vacuolar invertase Pain-1 gene from 17 representatives of five subgenera Potatoe, Solanum, Leptostemonum, Minon, Brevantherum have been obtained. Structure and polymorphism of Pain-1 have been characterized. The length of analyzed DNA fragment from 3'-end of III exon to 5' end of V exon, ranged from 603 to 977 bp, with a highly variable III intron, saturated numerous indels and SNPs. In the coding region for 27 Solanum accessions 80 SNPs have been detected. 34 SNPs caused amino acid changes. Several single SNPs and SNP sets are found to be specific for single species or taxonomic groups. Estimated genetic distances and reconstructed phylogenic trees showed concordance with previous classifications of the investigated species and showed the utility of the Pain-1 locus for taxonomic identification and Solanaceae phylogeny. PMID- 23808158 TI - [(-)-Epigallocatechin gallate regulates expression of apoptotic genes and protects cultured human lens epithelial cells under hyperglycemia]. AB - (-)-Epigallocatechin gallate (EGCG), the most abundant component in green tea, has a potent anti-apoptotic activity. The purpose of this study was to investigate the protective effects of EGCG and their molecular mechanisms on high glucose-induced apoptosis of human lens epithelial cells (HLEB-3). HLEB-3 cells were exposed to various concentrations of glucose and EGCG. Cell death was assessed by MTT assay and flow cytometry using annexin V and propidium iodide. The expression of the Bcl-2 family, c-fos, c-myc and p53 was measured by real time PCR. EGCG decreased the Bcl-2/Bax expression stimulated by a high glucose. Moreover, EGCG suppressed the high glucose-induced expression of c-fos, c-myc and p53. These findings suggest that EGCG protects HLEB-3 cells from high glucose induced apoptosis by regulating the gene expression of the Bcl-2 family, c-fos, c myc and p53. Thus, EGCG may have a potential protective effect against diabetic cataract formation. PMID- 23808159 TI - [Production and evaluation of immunologic characteristics of mzNLA-3, a non infectious HIV-1 clone with a large deletion in the pol sequence]. AB - Inactivation ofintegrase and reverse transcriptase can revoke the replication of HIV virions, and non-infectious HIV particles are desirable virus-like particle (VLP) vaccine candidates. Here, we produced inactive in replication HIV-1 particles fit for vaccine and virological purposes by introducing a mutation into the pol sequence. Proviral DNA (pNLA-3) was cut at two points in the pol region using the Bal I restriction enzyme and then religated. HEK 293T cells were transfected with the resultant plasmid (pmzNL4-3) to produce mutated virions. To confirm a production of VLPs and evaluate their biological activity the p24 load and syncytium formation (MT2 cells) were analyzed. The assay indicated that mzNL4 3 virions were assembled and contained functional envelope glycoproteins (ENV). In addition, mzNL4-3 virions were not able to infect MT2 and HEK 293T cells. Furthermore, the immunogenicity of VLPs was investigated in a mouse model. According to the data on vaccinated mice, the titer of ENV-specific antibodies rose rapidly after a boosting injection. Moreover, lymphoid cells extracted from these mice proliferated after exposure to the antigen. The mzNL4-3 virus particles possessed immunogenic antigens of HIV and can effectively trigger humoral and CD4 immune responses. Non-infectious mzNL4-3 virions may also be used in biomedical experiments to improve the biological safety conditions. Moreover, the mzNL4-3 seems to be a promising candidate for further HIV-1 vaccine investigations. PMID- 23808160 TI - [Comparing performance of "TB-BIOCHIP", "Xpert MTB/RIF" and "genotype MTBDRplus" assays for fast identification of mutations in the Mycobacterium tuberculosis complex in sputum from TB patients]. AB - The frequency of mutations causing drug resistance in MTB isolates were studied in the respiratory material obtained from TB-patients in the Moscow Region. In izoniazid-resistant isolates, the most prevalent mutation was found to be the Ser315Thr substitution in the katG gene (15.8%) whereas the most frequent mutations in multidrug-resistant isolates were Ser531Leu and Ser315Thr in the rpoB and katG genes (26.3%), or a combination of these two substitutions with a T15 mutation in the inhA gene (5.3%). We compared performance of three molecular assays--"TB-BIOCHIP" ("BIOCHIP-IMB", Ltd, Russia), Xpert MTB/RIF ("Cepheid", USA) and GenoType MTBDRplus ("Hain Life-science", Germany), with the efficiency of luminescent microscopy, and phenotypic drug-suscepibility testing in an automated system BACTEC MGIT 960 (Becton, Disckinson and Company, USA). Xpert MTB/RIF, TB BIOCHIP and GenoType MTBDRplus detected MTB in sputum in 92, 78 and 49% of all culture-positive cases, respectively. The agreement between standard cultural data and molecular DST results for Xpert MTB/RIF (resistance towards rifampicin), for TB-BIOCHIP and GenoType MTBDRplus (resistance towards rifampicin and izoniazid) amounted to 100, 97 and 100% respectively. Summing up, Xpert MTB/RIF was concluded to be the most efficient assay for primary detection of MTB, whereas the TB-BIOCHIP was shown to be the only molecular assay sensitive enough for simultaneous detection of MTB DNA and for revealing multidrug resistance in sputum (i.e. resistance to both first-line anti-TB drugs, rifampicin and izoniazid). PMID- 23808161 TI - [SFP1 controls translation termination in Saccharomyces cerevisiae via regulation of the Sup35p (eRF3) level]. AB - Translation termination in yeast performed by Sup45 (eRF1) and Sup35 (eRF3) proteins is a subject to complicated genetic control. Among the potential candidate genes that participate in regulation of translation termination is SFP1 encoding the global transcription factor Sfp1p. The data obtained earlier in our work indicate that SFP1 deletion causes a weak nonsense suppression mediated by a decrease in Sup35p amount. In this work, we performed a further study of mechanism by which SFP1 regulates translation termination efficiency. To this aim, effects of SFP1 overexpression on manifestation of SUP45 mutations, disturbing termination and causing nonsense suppression, and on Sup35p and Sup45p production were studied. It was shown that SFP1 overexpression causes a specific phenotypic change in mutants and increases the termination efficiency. Notably, the Sup45p amount in strains overexpressing SFP1 is not altered, while sup35p amount increases. Thus, we may state that SFP1 participates in the control of translation termination by means of regulation of Sup35p level. PMID- 23808162 TI - [Expression of FLT3-ITD oncogene confers mice progenitor B-cells BAF3 sensitivity to the ribonuclease binase cytotoxic action]. AB - Acute myeloid leukemia is the most common acute leukemia affecting adults, and its incidence increases with age. Along with chromosomal translocations in leukemic cells mutations in the genes of receptor tyrosine kinases KIT and FLT3 were found with a high frequency. Here we show that transgenic progenitor of B cells BAF3/FLT3-ITD are much more sensitive to the ribonuclease binase cytotoxic effects than the original BAF3 cells. The principal difference between BAF3/FLT3 ITD and the original BAF3 cells is the expression of FLT3-ITD oncogene, which leads to a change in the normal cell signaling pathways. Earlier, we described a similar effect for the cytotoxic action of binase on Kasumi-1 and FDC-P1-N822K cells, which express the activated KIT-N822K oncogene. Increased binase cytotoxicity toward the cells, expressing FLT3-ITD oncogene, suggests that, as in the case of FDC-P1 cells, transduced by KIT oncogene, the expression of an activated oncogene determines the sensitivity of cells to binase. PMID- 23808163 TI - [Correlation on a cellular level of gene transcriptional silencing and heterochromatin compartment dragging in case of PEV-producing eu-heterochromatin rearrangement in Drosophila melanogaster]. AB - Eu-heterochromatic rearrangements transfer genes into the heterochromatin and cause their variegated inactivation (PEV). Genes affected by PEV often demonstrate association with heterochromatic nuclear compartment (a distinct area composed of heterochromatin sequences like satellite DNA and enriched in specific chromatin proteins e.g. HP1). Here, we investigate the nuclear localization and the expression levels of the genes subjected to PEV caused by chromosome inversion, In(2)A4. We demonstrate that the degree of PEV-caused gene inactivation depends on a developmental stage, and the maximum of repression corresponds to the gene expression activation period. In the case of In(2)A4 rearrangement we detect the dragging of affected euchromatic region into heterochromatic nuclear compartment and the increase in HP1 occupancy in this region. We developed a protocol of simultaneous RNA-DNA-protein staining to demonstrate firstly in a single cell a strong correlation between transcriptional activity of affected gene and its distance from chromosome 2 satellite DNA. PMID- 23808164 TI - [Dimeric bisberzimidazoles: cytotoxicity and effects on DNA methylation in normal and cancer human cells]. AB - Cancer cells are characterized by the hypermethylation of promoter regions of tumor suppressor genes. DNA methyltransferase inhibitors cause re-activation of these genes that allows considering DNA methyltransferases as targets for anticancer therapy. As it was previously shown by us, dimeric bisbenzimidazoles, DB(n), differing in length of the oligomethylene linker between the two bisbenzimidazole fragments (n--number of methylene groups in linker) effectively inhibit the methylation of DNA duplexes by murine methyltransferase Dnmt3a. Here, the cytotoxicity of some of these compounds, their penetration into cells and influence on the methylation of genomic DNA in fetal lung fibroblasts line F-977 and cervical cancer cells HeLa have been studied. In the 0-60 microM concentration range, only the DB(11) displayed a significant toxic effect on the normal cells, whereas the effect of DB(n) investigated on the cancer cells was not significant. Interestingly, the DB(1) and DB(3) to a small extent stimulate the proliferation of HeLa and F-977 cells, respectively. DB(1) and DB(3) display ability to penetrate into the nucleus of HeLa and F-977 cells and accumulate in various parts of the nuclei. DB(11) is not able to penetrate into the nuclei of these cells. The incubation of F-977 cells with 26 microM of DB(1) or DB(3) led to a decrease of the methylation of 18S rRNA gene, which is located in the region of DB(1) and DB(3) accumulation. A similar effect produces the same concentration of DB (3) in the F-977 cells. However, the overall level of genomic DNA methylation was not changed. These data suggest that DB(n) can be directed to act on specific genes demethylation and in the future may selectively inhibit the proliferation of cancer cells. PMID- 23808166 TI - [Activation of immunoproteasome subunit genes transcription in mice monocytes infected with different strains of mycobacteria]. AB - Immunoproteasomal processing of mycobacterial antigens is necessary to control the infection and to protect the organism from development of active form of tuberculosis. Here we investigate the activation of immunoproteasome subunit genes transcription in peritoneal monocytes of C57Bl/6 mice infected with vaccine M. bovis BCG and virulent strain M. tuberculosis H37Rv. The level of transcription of LMP2, LMP7, MECL1 subunits didn't increase for one and two days after a single infection. Two rounds of infection with BCG strain M. bovis led to enhancement of the only LMP7 subunit gene transcription. However after subsequent infection of monocytes with vaccine followed by virulent strain infection the dramatic rise of all immunoproteasomal subunit genes transcription was observed. Activation of transcription of the gene coding the PA28alpha subunit of regulatory complex PA28 was observed only after a single infection of monocytes with strain M. bovis BCG. Thus, vaccination with strain M. bovis BCG promotes effective activation of immunoproteasomal genes in case of subsequent contact with virulent strain M. tuberculosis H37Rv. PMID- 23808165 TI - [Dynamics of methylation changes within functional groups of genes during breast cancer progression]. AB - For the first time in a comparative perspective the epigenetic status of the benign proliferative processes, breast cancer, and metastases to regional lymph nodes was studied using DNA methylation microarray "GoldenGate Cancer Panel I" ("Illumina", USA). The functional groups of differentially methylated genes were identified in each set of samples. The genes that regulate cell proliferation and mobility were methylated in samples with benign proliferative processes. An aberrant methylation of the genes responsible for cell differentiation and proliferation, as well as protein phosphorylation and cell mobility was observed in the samples with malignant phenotype. Differential methylation of the genes that regulate cell adhesion, the formation of anatomical structures, angiogenesis, immune response, signal transduction, and protein phosphorylation was found in the samples with metastases to regional lymph nodes in comparison with the morphologically unaltered breast epithelium. The tissues from the benign proliferative processes and metastases to regional lymph nodes were generally characterized by a relatively lower level of epigenetic variability in comparison with the tissues of the primary tumor. PMID- 23808167 TI - [Expression of genes involved in retinoic acid biosynthesis in human gastric cancer]. AB - All-trans-retinoic acid (ATRA) is the main biologically active metabolite of retinol (vitamin A) that is required for the regulation of such processes as embryogenesis, tissue differentiation, proliferation, and others. Multiple alcohol, retinol and retinaldehyde dehydrogenases (ADHs, RDHs and RALDHs) as well as aldo-keto reductases (AKRs) catalyze the biosynthesis of retinoic acid in humans. For many normal and neoplastic tissues, the key ATRA-synthesizing enzymes remain unknown. We identified ATRA-generating genes that are expressed in normal and malignant gastric tissues using the transcriptomic database analysis. Quantitative changes in the expression levels of these genes in gastric cancer were determined by semi-quantitative RT-PCR and real-time PCR. Significant decreases in the mRNA levels of genes encoding enzymes that catalyze the reversible oxidation/reduction of retinol and retinaldehyde (ADH4, ADH1B, ADH1C, RDHL, AKR1B10, AKR1B1, and RDH12), as well as the oxidation of retinaldehyde (RALDH1) were revealed in most of the tumor samples. The sharp reduction in the expression levels of genes encoding the key enzymes that convert retinol and retinaldehyde to retinoic acid could lead to a significant decrease in the content of ATRA--the transcriptional regulator of many genes, which in turn can lead to a dysregulation of cell proliferation/differentiation and initiate cancer development. PMID- 23808168 TI - [The C-terminus of transcription factor TnrA from Bacillus subtilis controls DNA binding domain activity but is not required for dimerization]. AB - The transcription factor ThrA, which belongs to the MerR transcription regulators, in Bacillus subtilis cells controls genes of nitrogen metabolism under conditions of nitrogen limitation. As all the DNA-binding proteins, it is present as a dimer in cells, but the dimerization site is still unknown. The multiple alignment of TnrA homologs from the other Bacilli allowed to identify the putative dimerization sites. Using the C-terminal truncated TnrA proteins it is established, that, in contrast to other MerR-proteins, the TnrA C-terminus does not participate in dimerization. The surface plasmon resonance has revealed that C-terminus truncations of TnrA do not inactivate its DNA-binding activity. By contrary, it increased an affinity to DNA, confirming that C-terminus controls the DNA-binding activity in a full-length TnrA. PMID- 23808169 TI - [The structure of the complexes of DNA with nonhistone chromosomal protein HMGB1 and the histone H1 in the presence of manganese ions. II. Vibrational circular dichroism spectroscopy]. AB - Complexes of DNA with nonhistone chromosomal protein HMGB1 and histone H1 in the presence of manganese ions were studied using absorption and circular dichroism spectroscopy in infrared region. It was shown that the approach provides good results for solutions containing large particles, which cause light scattering in UV region. It was also shown that the manganese ions are able to coordinate to the chemical groups of DNA as well as to the carboxylic amino acid residues of the protein HMGB1. The latter stimulates DNA condensation and slightly weakens DNA-protein interactions in the complex. PMID- 23808170 TI - [Computational methods for prediction of structure of membrane proteins using their amino acids sequences]. AB - The structure of membrane proteins is interesting because of their functional properties that are important to medicine and pharmacology. The feature and an organic property of polytopic membrane proteins is the repetition of transmembrane regions consisting of hydrophobic amino acids. The ordered repetition--periodicity--can be identified by the Fourier method, applied to a digital image of symbolic sequence of amino acids in a protein. In this work it was carried out for the 24 transmembrane proteins, for 14 of them successfully. If the repetition of transmembrane regions is ordered insufficiently--non periodic, then a different method is supposed to use for its detection--the method of multiple (4-5 times) averaging of function of hydrophobicity of the protein within a "window" with width 9-11 aa moved along the sequence. This new method was applied to the same 24 transmembrane proteins (for 19 of them successfully) and it was shown to be more suitable (than the Fourier method) for predicting of the secondary structure of such proteins and functional properties corresponding to it. PMID- 23808171 TI - [The new gene encoding TrfA-type replication initiator has been found on caprolactam/salicylate degradation plasmid pBS270]. AB - The mini-replicon of pseudomonads' caprolactam/salicylate degradation plasmid pBS270 (105 kb, contains incompatibility determinants of P-7 group) has been obtained and its nucleotide sequence has been determined. The new gene encoding TrfA-like replication initiator has been found on this replicon. Poor homology of this replication initiator with known proteins of TrfA-family allows us to classify obtained replicon as IncP-1-like. The pBS270mini reveals chimeric nature. PMID- 23808172 TI - [Morphological manifestations of systemic atherosclerosis found in fundus (experimental study)]. AB - Results of angiography and morphology of 32 eyes (16 chinchilla rabbits) with experimental atherosclerosis are presented. N.N. Anichkov and S.S. Khalatova experimental hypercholesterolemia model (1912) was used. The animals were divided into the following groups: initial and advanced atherosclerosis, control group, follow-up 3 and 6 months. After 3 months progressive reduction of perfused retinal vessels and early degenerative changes of neurons and photoreceptors were found. In 6 months these changes became more significant and generalized. Due to ongoing small vessel reduction blood flow went to the major vessels and changed its distribution followed by ischemia of adjacent retina. No changes in choriocapillary layer and retinal pigment epithelium were found in any of groups studied. PMID- 23808173 TI - [Clinical and molecular genetic analysis of hereditary optic neuropathies]. AB - DNA samples of 50 patients with optic neuropathy (ON) associated with congenital cataract were studied to find 3 major mt-DNA mutations (m.11778G>A, m.3460G>A, m.14484T>C), mutations in "hot" regions of OPA 1 gene (exons 8, 14, 15, 16, 18, 27, 28) and in the entire coding sequence of OPA3 gene for molecular genetic confirmation of diagnosis of hereditary Leber and autosomal dominant ON. Primary mutations of mtDNA responsible for hereditary Leber ON were found in 16 patients (32%). Pathogenic mutations of OPAl gene (c.869G>A and c. 2850delT) were identified in 2 patients (4%), these mutations were not found in the literature. OPA3 gene mutations were not revealed. PMID- 23808174 TI - [Ocular blood flow assessment in normal subjects and in patients with hyperglycemia based on the results of ultrasonic examination in experiment]. AB - Scheme of ocular blood flow in rats was developed and main blood flow parameters were studied using color Doppler mapping, energetic mapping and impulse Doppler ultrasonography. Features of ocular blood flow changes are revealed in experimental model of streptozotocin induced diabetes mellitus during 12 months of follow-up. Inferior ophthalmic artery showed the most significant changes. Decrease of all parameters of blood flow velocity was found in central retinal artery, central retinal vein and in posterior long ciliary arteries. Increase of resistance index was observed during the entire follow-up period. Revealed data show development of hemodynamic changes before clinical signs of retina damage ip rats with hyperglycemia. PMID- 23808175 TI - [Prevention of ostial obstruction after microendoscopic endonasal dacryocystorhinostomy]. AB - Ostial dilatator was created to prevent recurrence and improve efficacy of microendoscopic endonasal dacryocystorhinostomy. Proposed technique was for the first time used in 52 patients. Postoperative results were analyzed: recovery was achieved in 78% of cases, improvement - in 22%. In a control group (51 patients) we used conventional technique, recovery was achieved in 67% of patients and improvement in 28%, in 5% recurrence occurred. The use of ostial dilatator resulted in microendoscopic endonasal dacryocystorhinostomy efficacy improvement. PMID- 23808176 TI - [On a connection of early manifestations of angle closure glaucoma and development of posterior vitreous detachment]. AB - In author's opinion development of posterior vitreous detachment (PVD) is an involutional factor which participates in pathogenesis of primary angle closure glaucoma (PACG) in predisposed eyes. Initial increase of intraocular pressure in the eyes with narrow anterior chamber angle and predisposition to PACG is closely connected with the moment of PVD development, which can be detected with ultrasonography. The author supposes that ultrasonic examination of the posterior globe to detect PVD can be used as one of monitoring method in patients predisposed to PACG. PMID- 23808177 TI - [Rationale for distinguishing the lipogenic form of thyroid orbitopathy]. AB - Pathogenesis of lipogenic form of thyroid orbitopathy (TO) is presented. 172 patients with TO are presented, among them 47 males (93 orbits) and 125 females (250 orbits). Features of clinical manifestations of lipogenic form of TO are described. The results of CT of extraocular muscles (EOM) and orbital fat volume are studied in these patients and the density of EOM is assessed. PMID- 23808178 TI - [Features of clinical manifestations of the globe, adnexal and orbital sarcoidosis]. AB - 86 patients with verified diagnosis of sarcoidosis with globe, adnexa and orbit manifestations were observed. The age of the patients ranged from 21 to 43 years old (average 35,1+/-1,2 years), among them 25 males and 61 females with disease duration from 1 month till 12 years and 15 years follow-up. The study is based on different variants of globe, adnexal and orbital sarcoidosis. In our practice we observed sarcoidosis as a combination of several manifestations simultaneously. In 32 patients of 38 patients examined HLA-B-7, B-8, DR-2, DR-3, DR-15 were detected, that confirms genetic predisposition to sarcoidosis and determines the course of the disease. In 27 patients cellular and humoral immunity disbalance was found, that confirms the immune etiology of sarcoidosis as well. However the treatment of patients was pathogenic as the etiology of sarcoidosis is still unknown. PMID- 23808179 TI - [Implants in ophthalmology and potential of visual control]. AB - Results of complex ultrasonic examination in different time after socket reconstruction using biomaterial "Alloplant" are presented. Modified technique of primary socket reconstruction showed good cosmetic result. PMID- 23808180 TI - [Eyelid reconstruction after full-thickness resections in benign and malignant tumors]. AB - Full-thickness eyelid defect closure requires appropriate reconstruction, function recovery and acceptable cosmetic result. The aim of the study was to study the results of eyelid reconstruction after full-thickness resections in different benign and malignant tumors. 241 patients (63,5% females, 36,5% males) who underwent full-thickness resectioh of the lower or the upper eyelid due to tumor with primary defect closure were enrolled in the study. Eyelid resection was performed within visually clear tissue 2 mm away of the tumor border in benign and at least 3 mm in malignant lesions. Presented results of different techniques of eyelid reconstruction after full-thickness resections show good functional and cosmetic rehabilitation of patients and low complication rate. PMID- 23808181 TI - [Regularities of structural and functional visual system changes in patients with myopic refraction and presbyopia]. AB - Two age groups of 57 patients with noncomplicated low or moderate myopia were examined to reveal the regularities of structural and functional visual system changes in patients with myopic refraction and presbyopia. Characteristics of visual impression, anatomic and physiologic parameters were studied. Presbyopia development in patients with myopic refraction was found to occur on the background of significant changes in anatomic proportions and optic parameters of the eye, decrease of functional capability of visual system and development of abnormal functional system of visual perception. The key mechanisms of presbyopia development in myopia besides the accommodation decrease are pupil dysfunction and binocular interactions disintegration i. e. all the near vision reflex components. PMID- 23808182 TI - [Prevention of anterior lens capsule fibrosis after cataract extraction with intraocular lens implantation]. AB - Proposed technique provides prevention of formation of anterior lens capsule fibrous ring, capsule deformity and intraocular lens (IOL) dislocation in the late postoperative period when a minor additional intraoperative procedure is performed that is 4-6 penetrating radial incisions 0.5-1.0 mm long starting from capsulorhexis margin before nucleus removal or after IOL implantation into the capsule bag. PMID- 23808183 TI - [Metastatic choroidal carcinoma. Two clinical cases]. AB - Presented clinical cases show significance of up-to-date diagnostic techniques (fluorescence angiography and spectral domain optical coherence tomography) in confirmation of metastatic choroidal carcinoma diagnosis in one case and in contradiction in another and appropriate treatment prescription. PMID- 23808184 TI - [Glaucoma dynamics in patients who followed monitoring and treatment instructions and in those who didn't]. AB - Clinical course of different stages of primary open-angle glaucoma (POAG) is studied in 216 patients (432 eyes) who followed monitoring and treatment instructions during 13 years and in those who didn't. In patients who did not follow recommendations glaucoma progression was found in 99,4% of patients with initial disease, in 48,7% of cases with advanced stage and in 50% of patients with the end stage of the disease. Patients who followed recommendations of general ophthalmologists and glaucomatologists showed stable course of glaucoma process in 1 patient (0,6%) with initial stage, in 51,3% of patients with advanced stage and in 50% of patients with the end stage of the disease. PMID- 23808185 TI - [Antioxidant agents in neuroprotection treatment of glaucoma]. AB - Purpose was to study efficiency and safety of mexidol in combined therapy in patients with primary open-angle glaucoma (POAG). 94 patients (185 eyes) at the age of 18-75 years old with POAG I-III stages were divided into 3 groups: 50 patients received combined therapy of mexidol 100 mg and picamilon 150 mg, 22 patients received combined therapy of mexidol 300 mg and picamilon 150 mg, 22 patients received only picamilon 150 mg. All medicine was administered qd during 14 or 21 days. Examination included standard ophthalmologic methods, perimetry, electroretinography, retinal and optic nerve heard arterial blood flow. Improvement of visual acuity, perimetric, electrofisiological indicies and increased blood flow velocity of central retinal artery were registrated. Combined mexidol therapy allows improving results in treatment of patients with POAG. PMID- 23808186 TI - [Efficacy of vitamin mineral complex "Focus forte" in combined treatment of primary open-angle glaucoma and age-related macular degeneration]. AB - The efficacy of Focus forte is proved in patients with primary open-angle glaucoma (POAG) and age-related macular degeneration (AMD) in terms of improvement of functional retinal activity, oxygenation, metabolism normalization as well as morphometric retinal and optic nerve indices. Principles of evidence based pharmacotherapy in this study allow advising Focus forte in the treatment of patients with POAG and AMD. PMID- 23808187 TI - [Experimental models of human retinal degenerations: genetic models]. AB - Existing approaches in experimental animal modeling of human retinal degenerations, genetic models in particular, that allow to study the pathogenesis are reviewed. PMID- 23808188 TI - [Molecular genetic basis of age-related macular degeneration]. AB - Visual loss due to age-related macular degeneration (AMD) is caused by one or both forms of advanced disease: "wet" (neovascular) or "dry" (geographic atrophy). Immune system plays a central role in pathogenesis and progression of both AMD forms. Main genetic polymorphisms associated with risk of AMD development and progression were found to be genes that regulate inflammation especially in complement factor H gen (1q31 locus) and 10q26 locus (PLEKHAI/ARMS2/HTRA1). Association of response to treatment and genotype was shown in patients with AMD. Complete characterization of both common and rare alleles that influence AMD risk is necessary for accurate determination of individual genetic risk as well as identification of new targets for therapeutic intervention. PMID- 23808189 TI - [Review of monography of E.I. Oustinova "Ocular tuberculosis and similar diseases: manual for a physician"]. PMID- 23808190 TI - [Implantation of plastic and metal stents to biliary tract in obstructive jaundice in material of Surgery Department of 4th Military Clinical Hospital in Wroclaw]. AB - INTRODUCTION: A method of treatment for malignant bile duct strictures depends on early diagnosis, location and extent of tumor infiltration. Patients eligible for radical surgery should be operated. AIM OF THE STUDY: The authors used plastic and metal prostheses in the treatment of biliary tract cancer cholestasis. MATERIAL AND METHODS: Retrospective analysis was done in 2730 endoscopies performed in the Laboratory of the Department of Endoscopic Surgery, 4th Military Hospital in Wroclaw in 2008-2011. The authors analyzed 441 cases of prosthetic biliary cancer. RESULTS: 223 patients (51%) were treated for pancreatic head tumor, 98 pts (22%)--for papilla of Vater tumor, 85 pts (19%)--due to Klatskin tumor and 35 pts (8%)--due to tumor of the gallbladder. Plastic prostheses were inserted in 228 (65.4%) patients, self-expanding metal prostheses--in 21 patients (4.9%). Dilatation of the bile duct or the inserted prosthesis was performed in 48 (11.1%) pts. 27 patients (6.1%) had endoscopic treatment failure. 32 patients (7.3%) had following complications of biliary prosthesis: bleeding into the bile duct, into the digestive tract--4 cases (1%), the migration of the prosthesis--7 (1.6%), cholangitis--21 cases (4.7%). CONCLUSIONS: Palliative biliary stenting is a safe method that provides efficient drainage of bile. It shows a definitive advantage over percutaneous, biliary transhepatic drainage. PMID- 23808191 TI - Evaluation the reflection coefficient of polymeric membrane in concentration polarization conditions. AB - INTRODUCTION: The reflection coefficient of the membrane (sigma) is one of the basic parameters of the polymer membrane transport. Classical methods used to determine this parameter require intensive mixing of two solutions separated by a membrane to eliminate the effects of concentration polarization. In the real conditions, especially in biological systems, this requirement is challenging. Thus, concentration boundary layers, which are the essence of the phenomenon of concentration polarization, form on both sides of the membrane. PURPOSE: The main aim of this paper is to determine whether the value of reflection coefficient in a concentration polarization conditions depend on the concentration of solutions and hydrodynamic state of concentration boundary layers. MATERIALS AND METHODS: In this paper, we used the hemodialysis membrane of cellulose acetate (Nephrophan) and aqueous glucose solutions as the research materials. Formalism of nonequilibrium thermodynamics and Kedem-Katchalsky equations were our research tools. RESULTS: Derived mathematical equations describe the ratio of reflection coefficients in a concentration polarization conditions (sigmaS) and in terms of homogeneity of the solutions (sigma). This ratio was calculated for the configuration in which the membrane was oriented horizontally. It was shown that each of the curves has a biffurcation point. Above this point, the value of the reflection coefficients depended on the concentration of the solution, the configuration of the membrane system and the hydrodynamic concentration boundary layers. Below this point, the system did not distinguish the gravitational directions. CONCLUSION: on coefficient of the hemodialysis membrane in a concentration polarization condition (sigmaS) is dependent on both the solutions concentration and the hydrodynamic state of the concentration boundary layers. The value of this coefficient is the largest in the state of forced convection, lower--in natural convection state and the lowest in diffusive state. Obtained equations may be relevant to the interpretation of membrane transport processes in conditions where the assumption of homogeneity of the solution is difficult to implement PMID- 23808192 TI - Structural studies of polymer hydrogel and silicone hydrogel contact lenses by means of positron lifetime spectroscopy methods. AB - PURPOSE OF JOB: Currently, there isa need to increase comfort and visual acuity man. Simultaneously improving biocompatibility and minimizing the impact of the material on the physiology of the cornea is the primary driving force behind the evolution of materials used in the manufacture of contact lenses. Despite progressive development of modern materials science, there is still the problem of reducing the level of oxygen available to the cornea resulting in pathological changes in the cornea. Therefore, structural studies increases interesting in relating to the amorphous contact lenses polymeric materials. MATERIALS AND METHODS: The aim of this work is structural investigation of polymer hydrogel and silicone hydrogel contact lenses made in the technology of PC (Phosphoryl Choline). The study method was used positron lifetime spectroscopy PALS. RESULTS: As a result of the measurements obtained curve describing the dependence of the number of counts of acts of annihilation as a function of time. CONCLUSIONS: The study of PALS showed the existence of three components. Component tau1 is responsible for the annihilation of free positrons and the annihilation of electrons vacancy-type point defects. Component tau2 is associated with defects in the volume of grain boundaries formed, dislocations or clusters of vacancies. The results of calculations of mean values positron lifetime samples, showed longtime component tau3 in the spectrum of positron lifetime. Component tau3 is assigned to pick-off annihilation of ortho-positronium o-Ps trapping by free volume and providing information on the geometric parameters of the volume. PMID- 23808193 TI - [The effect of selected excipients on properties hydrogels on the basis Carbopol 934P]. AB - AIM OF THE STUDY. The study on the effect of absorption promotors on the properties of hydrogels prepared from Carbopol 934P basis containing 1% hydrocortisone. MATERIAL AND METHODS: MATERIALS: hydrocortysone, Carbopol 934P, propylene glycol-1,2 N,N-dimethylacetamide purified water to P Ph 9th Ed., ethanol 760 g/1, Tween 20. Dynamic viscosity test: was carried out using the Rheotest 2. The values of the shear stress and viscosity were calculated from measurements. Consistency test--TPA test was performed with Exponent Stable Micro Systems texture analyzer. Examination of pharmaceutical availability of hydrocortisone: The process of hydrocortysone release from hydrophilic base was carried out according to the method based on active substance diffusion through a semi-permeable membrane. Concentration of hydrocortysone according to Polish Pharmacopoeia 9th Ed. RESULTS: Rheological studies showed that the process is nonlinear. Tested gels shows thixotropic properties. The tension decreases with the increase in the percentage of excipients. Hardness tests showed that in comparison to the reference gel, pressure force increased in the presence of 1% of the excipients in the gel, and the reduction in the presence of 15% of the excipients. Gels are characterized with greater cohesiveness than the control preparation. The release process of the drug substance proceeds in accordance with first order kinetics. Increasing concentrations of used absorption promotors influenced on increase the number of hydrocortisone released from the hydrogels prepared on the basis of 3% Carbopol 934 F gel. CONCLUSIONS: 1. Tested gels are showing thixotropic propereties and are non-Newtonian systems. 2. The hardness and cohesiveness of the gels increases with increasing concentrations of the excipients. 3. The value of the constant release rate is increases in the presence of ethanol, Tween 20, and DMA. PMID- 23808194 TI - [The use of photodegradability of polyethylene in medicine. Own experiments]. AB - AIM OF THE STUDY: The introduction ofphotodegradable polymers raises doubts among the natural profession. Photodegradation is a process of destruction of polymer, that is the entirety of physical and chemical change within the plastic, leading to irreversible changes in structure and deterioration of processing parameters. The prospect of release of products of degradation, possessing unknown capabilities is unsettling, as is the possibility of accumulation of compounds that could potentially be toxic, mutagenic and allergenic. Despite this, the use of photodegradable polymers is unavoidable in some cases. The applicability of degradable materials is easily visible in agriculture, horticulture and fruit growing and medicine. The aim of the study is to asses the influence of selected additives over the process of accelerated aging of polyethylene. The aging was conducted in laboratory environment using lamps simulating the effect of natural sunlight in conditions similar to natural. MATERIAL AND METHODS: Preparation of polyethylene samples with sensitizers (TiO2-anatase, acacFe (II), acacFe (III)) added, aging of the sample in a UV chamber, estimating the surface changes in polyethylene after irradiation by measuring contact angle, spectroscopic analysis of polyethylene photodegradation, assessing endurance characteristics. The results of study show the highest degradation occurs if Ferrous (Iron (II)) acetylacetonate is used, with Ferric (Iron (III)) acetylacetonate showing slightly less effectiveness. TiO2-anatase indicates little influence over the process of degradation, on the contrary--a protective activity can be noticed, connected with white colour of this additive reflecting UV radiation. CONCLUSIONS: The results of the study clearly signify an interrelation between aging process and endurance characteristics of the material. The conducted analysis shows correlation between the number of carbonyl groups and endurance characteristics which, in turn, points to clear structural changes in polyethylene. PMID- 23808195 TI - Rosin: a naturally derived excipient in drug delivery systems. AB - Natural polymers are primarily attractive because they are biodegradable, inexpensive, and readily available. The most important benefit of natural polymers is that they are capable for chemical modifications. One such biopolymer, rosin, and its derivatives have been pharmaceutically evaluated as microencapsulating materials, film forming agent and as binding agent in formulation of tablets. They are also employed in formulation of chewing gum bases and cosmetics. This review article provides an overview of pharmaceutical use of rosin and its derivatives as excipient in dosage forms as well as novel drug delivery systems. PMID- 23808196 TI - [Analysis and working data of day hospital of district consultation-and diagnostic out-patient hospital]. AB - The article is devoted to organization and establishment, aims and capacity rates of day hospital of district consultion-and-diagnostic out-patient hospital. 7894 patients were treated in the day hospital during 2007-2011. Percent of patients treated in therapeutic department--65.3%, surgical department--16.7%, neurologic- 18%. Length of hospital stay in average is 9.3 days. It is shorter than the length of hospital stay in specialized departments of the hospital. Average cost of stay in day hospital is 380 rubles. The price of stay in day hospital is significantly lower cheaper than in hospital. Except cost cut of treatment and rehabilitation, payments of temporary and permanent disability are diminished due to reduction of treatment terms in case of achievement of therapeutic effect. Also bed capacity of hospital gets free. PMID- 23808197 TI - [Applicability of the problem of peptic ulcer in modern gastroenterology, military-and-medical and medical-and-social assessment]. AB - The round-up article is devoted to the history of gastroenterology. The authors deal with a subject of aetiology, pathogenesis and treatment of diseases associated with destruction of mucous coat of GI tract. The main criteria of military-and-medical and medical-and-social assessment used in evaluation of patients with different forms of peptic ulcer are performed. PMID- 23808198 TI - [Prognosis of the immediate period of an ischemic stroke]. AB - We investigated 342 patients with clinical outcome of a disease and 61 died patients with acute disease. With the help of the method of representative sample of patients with an ischemic stroke the clinical picture and data about tool methods of research are investigated. We received solving rules of forecasting of favorable and adverse outcomes ischemic stroke with use of the discriminative analysis. PMID- 23808199 TI - [Treatment of purulonecrotic forms of diabetic foot in multipurpose hospital unit]. AB - Results of treatment and inspection of 278 patients with purulonecrotic complications of diabetic foot, treated in septic surgery department of 3rd Central Military-Clinical Hospital n. a. A.A. Vishnevsky during 1999-2009 are analyzed. For patients with purulonecrotic forms of diabetic foot is necessary to perform complex therapy with participation of endocrinologist and angiosurgeon, in specialized departments with the necessary medical equipment and dressing means and having experience of treatment of patients with diabetic foot, characterized with heavy and long-lasting course of disease leading to amputations. At the same time, application of gelling dressing means, iodoforms with ferment drapes for local treatment allowed to lower a level of amputations from 17.1 to12.8%, and also to reduce stay of patients in a hospital to 8 days. PMID- 23808200 TI - [Minimally invasive method of treatment of severe organic dysphagia]. AB - Dysphagia occurs in the clinical picture of stenosing esophageal diseases as a first symptom, but shows an extensive-stage disease. The aim of the study was to examine the experiences of esophageal stents incurable patients and the formulation of indications and contraindications to their use. The study was conducted on 68 patients treated at the Department of General Surgery of the Kirov Medical Academy during 2007-2011 for cancer of the esophagus and gastric cardia, and 2 patients with benign esophageal strictures. The success of self expanding stents esophageal stenting was 100% (that is technically able to put a stent in all patients). Thus, the self-expanding esophageal stent wire stents--is the most effective method used to maintain patency of malignant esophageal narrowing in inoperable esophageal cancer patients in stage IV, and is the primary treatment of choice for patients with esophageal fistulas malignant. PMID- 23808201 TI - [Evaluation of risk factors for atrial fibrillation in patients with atrial flutter after radiofrequency ablation of cavotricuspid isthmus]. AB - The author researched risk factors for atrial fibrillation in 93 patients with atrial flutter after radiofrequency ablation of cavotricuspid isthmus. Effectiveness of radiofrequency ablation of the inferior isthmus was 93.5%. Before operation in 10% patients from the group of patients without atrial fibrillation, in postoperative period developed atrial fibrillation. Factors for this arrhythmia include elderly age, low contractility of the aortic ventricle of heart, dilation of the left atrium, chronicity and rate of arterial hypertension. In group of patients with atrial fibrillation in pre- and postoperative period this arrhythmia developed in 73.9% of patients. Risk factors for atrial fibrillation include elderly age, time duration of arrhythmic anamnesis and chronicity and rate of arterial hypertension. PMID- 23808202 TI - [Functional assessment of stress and resistance of the body of soldiers on the stages of an emergency service]. AB - Service in the armed forces takes place on the background of tension of different systems of the body and the level of stress depends on the stage of passage performance. The highest level of stress is voltage observed at the initial stage, which affects the general state of health of the soldier, his successful performance of professional duties and, consequently, reducing the overall resistance of the organism. The results obtained indicate a high "energy" cost of passing military performance. PMID- 23808203 TI - [Determination of divers' resistance to decompression gas formation]. AB - The aim of the study was to determine the correlation between the state of the individual functions of the organism and the intensity of decompression venous gas embolism after high air pressure exposure. The analysis of the guidelines defining the procedure of divers' medical examination was made and 320 divers were surveyed. Indices of the divers' central nervous and cardiovascular systems were measured before and after their immersion into a hyperbaric chamber. The study found that the conduct divers' on-resistance to unfavorable scuba dive should be provided by the military-medical commission, so the position of diving doctor should be put to it staff. It was revealed that the rate of simple visual motor reaction, measured before the diving can serve as an indicator of human resistance to decompression gassing. The formula for determining the stability of decompression gassing of men aged 20-30 years in terms of state of organism functions was proposed. PMID- 23808204 TI - [Medical research in the US Armed Forces. (Report 5). The US Air Force and Coast Guard]. AB - The present article is the last part of the review dedicated to organization and management of medical research in the US Armed Forces. The first through fourth parts were published in the previous issues of the journal. Specifically this article is dedicated to organization and management of medical research in the US Air Force and Coast Guard. It is shown that in the US Air Force the medical research is conducted in the Air Force Research Laboratory and in the US Coast Guard--in its Research and Development Center. The particular research programs conducted in the above mentioned units are discussed. PMID- 23808205 TI - [Clinical military hospital in 1892]. AB - The article is devoted to the circumstances of visit of Alexander III to Clinical hospital of Military-Medical Academy in 1892. It is detailed about the situation in hospital: direct care, instruction and economic aspects. Representations of imperial authority in Russia in XIX century with respect to military-medical institutions are characterized. "Episode 3Match 1892" is important for Military Medical Academy because in that day the put on hold reconstruction got a crucial impulse. PMID- 23808206 TI - [Organization of clinical care of North Fleet hospitals in XVIII century]. AB - Clinical care of national navy hospitals was normed from reception of patients till hospital discharge. After admission to the hospital, patient got competent medical care and corresponding attendance. But the situation changed in XVIII century, period of wars. In conditions of war time hospitals were overcrowded with patients and wounded. The number of patients went beyond the bedspace. Deficit of vacant beds was supplied with the help of additional beds; deficit of medical staff was supplied with the help of participation of another medial staff. Huge number of patients with different diseases, including contagious diseases, conduced communication of contagious diseases inside the hospital. Diagnostics and methods of treatment of these diseases were not enough researched. Taking into account results of statistical analysis of data about the number of fatality cases (peace time--4-10%, war time--20%), we can make a conclusion that clinical care of national navy hospitals was satisfying. PMID- 23808208 TI - [About improvement of outpatient dental health service for young serviceman]. AB - The article gives a detailed account of results of epidemiological survey of dental morbidity in young serviceman and different types of outpatient dental health service needs. Medical norms for dispensary supply with all types of outpatient dental health service for young servicemen are estimated. Suggestions for improvement of organizational and staff structure of dental office of medical company are formulated. PMID- 23808207 TI - [The flagship of the national naval medical science (on the 80th anniversary of establishment of the 1st Central Research Institute of the Defense Ministry of Russian Federation)]. AB - The article is devoted to the 80th anniversary of the formation of the naval medical science subunit, which is the part of the 1st Central Research Institute of the Defense Ministry of Russian Federation. In the 30th years of XX century, a group of naval doctors formulated the main directions of preventive naval medicine. For eight decades, several generations of medical scientists have developed and ensured implementation of regulatory requirements for habitability and ergonomics of Navy ships. At the present stage, this work focuses on promising directions of the development of the domestic military shipbuilding and the use of advanced and innovative biomedical technologies. PMID- 23808209 TI - [Medical-and-economic substantiation of rational antibacterial therapy for patients with pleural empyema in the conditions of military medical institutions]. AB - We have performed a post-hoc analysis of the results of using antibacterial therapy in patients with pleural empyema. The cost-effectiveness analysis of rational and empiric antibacterial therapies was performed. The cost effectiveness ratio for rational antibacterial therapy was lower than for empiric one (2889 and 4480 rubles for 1 treated patient correspondingly). The use of the rules of rational antibacterial therapy in practice leads to proved saving of economic costs. PMID- 23808210 TI - [Primary and secondary prevention of alcoholic liver cirrhosis]. AB - Alcohol--is the main causative factor of cirrhosis among the population in Russia. The primary prevention must be focused on exception of consumption of heavy doses of alcohol hepatitis and B vaccination. There are no healthy doses of alcohol. Secondary prevention means the use of the hepatoprotectors. List of hepatoprotectors and also amount of money spent to the purchase of these hepatoprotectors increase constantly. But, unfortunately, alongside with it, increases the mortality from hepatic disorders. Effectiveness of the most hepatoprotectors (such as Essential phospholipids, milk thistle) equals to the effectiveness of placebo. PMID- 23808211 TI - [Evaluation of muscle relaxant requirement for hospital anesthesia]. AB - The rationale for cost-effectiveness of modern muscle relaxants (MR) administration in general anesthesia was evaluated. New MRs are more expensive than traditionally used pipecuronium and succinylcholine. However, the old MRs are often required as a block reversion with anticholinesterase medicines at the end of surgery, the longer artificial lung ventilation and observation in patients during recovery in intensive care unit. It was found that the district military hospital had done an annual average of about 900 general anesthesia assisted with artificial ventilation and muscle relaxation. About 2% of all anesthesias accrue to short-term anesthesia, the 27% to medium-term and 71% to long-term. 81% of the medium-term anesthesia accrue small hospitals. According to cost/effectiveness the most optimal muscle relaxants administration scheme for short-term (up to 30 min) anesthesia was mivacurium, for the operation of medium duration (30-120 min)--rocuronium, for long-term (120 min)--pipecuronium. An electronic form of annual report, which allows to obtain the necessary data for calculation of annual muscle relaxants demand and costs both in hospital and in the whole of the armed forces quickly, was developed. PMID- 23808212 TI - [Antihypertensive therapy in the elderly patients with metabolic syndrome]. AB - The article is concerned with modern methods of assessment of arterial hypertension in patients with metabolic syndrome and characteristics of modern antihypertensive drugs and its combinations necessary for the elderly. The authors gave their own example of treatment of more than 2000 patients with arterial hypertension and metabolic syndrome. PMID- 23808213 TI - [Fatal course of virus-associated pneumonia in patient with influenza A(H1N1)]. AB - In 2009 pandemic caused by high-path fluenza A(H1N1), so called "swine" flu was registered in the world. Aphylaxis to this type of influenza lead to pandemic. The authors gave an example of fatal course of influenza A(H1N1)S-OIV in young patient with severe VA-pneumonia, acute respiratory distress syndrome, disseminated intravascular coagulation with progressive respiratory distress secondary to an metabolic syndrome. It led to patient's death. Patient was refractory to all modern methods of intensive therapy in conditions of multifield specialized medical and preventive treatment facility. PMID- 23808214 TI - [Balance of iron and copper in cadets of military school during physical exercise and next-day rest at different times of the year]. AB - According to examination, with the help of emission spectrum analysis method, of 24 cadets-athletes of different specialization it was determined that during physical exercise in summer and in winter loss of ferrum and copper with excrements exceeded the intake if these microelements with food. The next day rise of impaction of microelements and decrease of excretion. But despite the positive balance of ferrum and copper, spend of these microelements during physical exercise wasn't compensated for the day of rest. That is why there is a possibility of microelement deficit. PMID- 23808215 TI - [Organisation of scientific and research work of Navy medical service]. AB - The main issues of organization of scientific and research work of medical service in the North Fleet are considered in the present article. Analysis of some paragraphs of documents, regulating this work at army level is given. The authors give an example of successful experience of such work in the North Fleet, table some suggestions which allow to improve the administration of scientific and research work in the navy and also on the district scale. PMID- 23808216 TI - [Delivery of health care for military veterans abroad. The USA and Great Britain models]. AB - The present review is dedicated to organization and management of military veteran's health care system of the US and UK. It is shown that despite the differences in health care systems of both countries their veterans receive the stat-of-the-art medical service which is readily available and financially affordable. PMID- 23808217 TI - [First medical museum of Russia (150-anniversary of the Surgical museum of the Imperial Medical-Surgery Academy)]. AB - The opening in 1863 of the Surgical museum of the Imperial Medical-Surgical Academy was the sign of a new age in the development of medical science. It became the first medical museum in our country. It was the period when similar museums appeared in Europe and America. Thus all over the world were formed the first museums that amassed their collections, the later basis of modem medical museums. PMID- 23808218 TI - [70th anniversary of 111th Main Federal Center of medical and forensic examination of the Ministry of Defence of the Russian Federation]. AB - The article is devoted to 70th anniversary of the head state forensic expert institution of the Ministry of Defence of the Russian Federation--111th Main state center of medicolegal and criminalistic examination of the Ministry of Defence of the Russian Federation. Some information about historical aspects of functioning of the institution and its activity at the present stage and in conditions of the reform of the Armed Forces of the Russian Federation is given. PMID- 23808219 TI - [75 years safeguarding health of warriors of Saints-Petersburg (Leningrad) garrison]. AB - The article is devoted to the anniversary of Consultation-and-diagnostic outpatient hospital of 442nd District military clinical hospital in Saint Petersburg. This outpatient hospital was founded in on the 20th March 1938. Work of garrison outpatient hospital was especially difficult during the Great Patriotic War. Employees of this hospital heroically fulfilled their duties in conditions of severe blocade winter 1941-1942. The outpatient hospital was nominally garrison, in fact this hospital operated units of Leningrad front-line. In 1993 the garrison outpatient hospital was renamed as 104th Consultation-and diagnostic. The main branch of activity is health maintenance of participants in the rectification of the consequences of the accident at the Chernobyl Atomic Electric Power Station and veterans (case follow up) belonging to special risk subunits. Nowadays there are 30 treatment-and-diagnostic departments including staff military physician board. PMID- 23808220 TI - [Ischemic heart disease and arterial hypertention as risk factors of surgical treatment of patients with infrarenal segment of aortic aneurysm]. AB - A retrospective analysis of the data of 188 patients with the infrarenal segment of the aortic aneurysm (ISAA) showed, that ischemic heart disease and arterial hypertension were diagnosed practically in all patients--175 (93.0%) and 177 (94.1%) patients respectively. A decreased retractor function of the myocardium was noted in 88 (46.8%) of patients. According to the findings of echocardiography 134 (71.3%) patients had the arterial hypertension of third degree. For the assessment of the influence of the accompanying cardiac pathology on the results of planned surgical treatment and systematization of postoperative cardiac complications the classification, which was proposed by R. B. Rutherford et al. and modified by A. V. Pokrovsky et al. was used. The obtained data point at a direct proportional relationship between the degree of the initial cardiac status, frequency and severity of postoperative cardiac complications in patients after resection of ISAA in 1.6-2.3 times. PMID- 23808221 TI - [Genesis of great saphenous vein obliteration and its clinical manifestations after endovenous laser coagulation combined with crossectomy during the varicose vein treatment]. AB - An analysis of results of the endovenous laser coagulation combined with crossectomy was made in 170 patients with varicose veins of lower extremities (C(VI), C(II)-C(V)). Clinical and ultrasonic data were investigated during a period of 3-5 days (45 lower extremities) and followed up in 1-3 years after operation (194 lower extremities). Three years later the absence of reflux was observed in 95.9% of cases. In 51.1% of cases, 1-2 zones of parietal and segmental hemodynamical insignificant bloodstream were detected. A recanalization of the great saphenous vein along the whole length was revealed in 8 cases out of 194 (4.1%) patients. The bloodstream was provided by affluxes in the area of a shin and a wellhead afflux of the stump of the great suphenous vein. The ultrasonic picture of recanalization was similar to that observed in post thrombophlebitic occlusion. PMID- 23808222 TI - [The randomized study of efficiency of preoperative photodynamic]. AB - The authors made a prospective randomized comparison of results of preoperative photodynamic therapy (PhT) with chemotherapy, preoperative chemotherapy in initial unresectable central non-small cell lung cancer in stage III. The efficiency and safety of preoperative therapy were estimated as well as the possibility of subsequent surgical treatment. The research included patients in stage IIIA and IIIB of central non-small cell lung cancer with lesions of primary bronchi and lower section of the trachea, which initially were unresectable, but potentially the patients could be operated on after preoperative treatment. The photodynamic therapy was performed using chlorine E6 and the light of wave length 662 nm. Since January 2008 till December 2011,42 patients were included in the research, 21 patients were randomized in the group for photodynamic therapy and 21--in group without PhT. These groups were compared according to their sex, age, stage of the disease and histological findings. After nonadjuvant treatment the remissions were reached in 19 (90%) patients of the group with PhT and in 16 (76%) patients without PhT and all the patients were operated on. The explorative operations were made on 3 patients out of 16 operated on in the group without PhT (19%). In the group PhT 14 pneumonectomies and 5 lobectomies were perfomed opposite 10 pneumonectomies and 3 lobectomies in group without PhT. The degree of radicalism of resection appears to be reliably higher in the group PhT (RO-89%, R1-11% as against RO-54%, R1-46% in group without PhT), p = 0.038. The preoperative endobronchial PhT conducted with chemotherapy was characterized by efficiency and safety, allowed the surgical treatment and elevated the degree of radicalism of this treatment in selected patients, initially assessed as unresectable. PMID- 23808223 TI - [Prognostic value of interleukin-6 in various biological environments in generalized peritonitis]. AB - The author analyzed the results of surgical treatment of 60 patients with generalized peritonitis (GP). The level of interleukin-6 in blood, serum, urine and peritoneal exudates were followed up and the diagnostic significance of interleukin was comparatively studied. All patients were treated by conventional intensive postoperative therapy, without immune correction. The severity of GP was determined by Mannheim peritoneal index (MPI): 17 patients had MPI, 20 patients had MPI II-23 and MPI III. The study revealed that the degree of the changes of IL-6 in blood, urine and peritoneal exudates depended on the severity of patients according to MPI. An analysis of the data suggests that the comparative study of IL-6 in peritoneal exudates, blood, urine during the postoperative period in patients with GP is one of the objective criteria for the assessment of the immune system. Increasing the rates of peritoneal exudates in the postoperative period shows a continuation of the systemic inflammatory response. PMID- 23808224 TI - [The ways of improvement of direct results of surgery of patients with rectal cancer]. AB - The data of 1740 patients (during 20 years) with rectal cancer were analyzed. Planned operations were performed in 95.8% of patients. The adenocarcinoma was verified in all patients. Accompanying pathology was detected in 84.9% of patients and the pathology of cardiovascular system was more frequent (76.6%). Complicated course of tumourous process was revealed in 4.5% of patients (cases of bowel obstruction, the perifocal inflammation). The majority of patients had the II, III stage of the oncologic process. All operations were performed by conventional (open) way. The number of anterior resection of the rectum increased and the number of abdominoanal resection with bringing down reduced. The specific weight of sphincter preserving operations, which were completed by forming a colostomy decreased. The quantity of performed abdominoperineal extirpation was constant. PMID- 23808225 TI - [Immediate and five-year results of application of preoperative oily chemoembolization of rectal arteries in complex treatment of the loco-regional rectal cancer]. AB - The authors present immediate and five-year results of complex endovascular and surgical treatment of 8 patients with loco-regional rectal cancer. The immediate positive result was achieved by using the single-stage selective oily chemoembolization of the upper, middle and low rectal arteries. This leads to the resolution of colonic obstruction, decreased tumor size and made a positive effect on the mesorectum. In all cases radical surgeries were performed 48-72 hours after endovascular treatment. The general 5-year survival was 87.5% and the survival without relapse was 75% respectively after such variant of complex treatment. In all cases distant metastases were not detected. PMID- 23808226 TI - [Differential diagnostic strategy in obstructive jaundice]. AB - An analysis of effectiveness of diagnostic noninvasive and invasive measures for obstructive jaundice was made using clinical findings of 383 patients. The efficacy of these measures was assessed and limits were determined in relation to etiology of obstructive jaundice and the condition of extrahepatic bile ducts. The criteria of selection of diagnostic methods were detected on preoperative and intraoperative stages. The rational report of diagnostic strategy was formulated. PMID- 23808227 TI - [Injury of subclavian artery in severe trauma of the shoulder girdle and chest]. AB - The authors consider one of possible variants of surgical treatment of shoulder girdle trauma, which is accompanied by an injury of the main artery. It is based on the application of the principle of staged surgical treatment (damage control orthopedic). The well-timed sufficient diagnostics and treatment of bone-arterial trauma, coordinated work of several surgical teams, the appropriate postoperative management of patients with the using of postponed high-technology intervention allowed obtaining an optimal functional result for extremely severe multitrauma of the chest and limb. PMID- 23808228 TI - [Objective assessment of trauma severity in patients with spleen injuries]. AB - The work presents an analysis of condition severity of 139 casualties with isolated and combined spleen injuries on admission to a surgical hospital. The assessment of condition severity was made using the traditional gradation and score scale VPH-SP. The degree of the severity of combined trauma of the spleen was determined by the scales ISS. The investigation showed that the scale ISS and VPH-SP allowed objective measurement of the condition severity of patients with spleen trauma. The score assessment facilitated early detection of the severe category of the patients, determined the diagnostic algorithm and the well-timed medical aid. PMID- 23808229 TI - [Risk factors of gastroduodenal bleeding in patients with severe burns]. AB - An experience of treatment of 133 patients with severe bums was analyzed. Bleedings from the upper parts of the gastrointestinal tract were diagnosed in 16 patients in different terms since their admission to the hospital. At the moment of carrying out of the endoscopic research all bleedings were considered as taking place. Statistically significant risk factors of the development of gastroduodenal bleedings were considered to be an alcoholic intoxication at the moment of injury and insufficient fluid therapy during the pre-admission stage and young age of the patients. The antisecretory therapy showed that the detection of risk factors in question should be regarded as an indication to the reinforced regime of preventive measures for gastroduodenal injuries. PMID- 23808230 TI - [Influence of microbial wound dissemination and microcirculation on the results of skin engraftment]. AB - The indices of Doppler laser flowmetery are proposed to be used for determination of the readiness of a granulating wound for free autoplasty. An analysis of capillary blood flow in the groups under test showed the information value of indicators of microcirculation obtained by Doppler laser flowmetery for determination of the granulating wound condition before autotransplantation and prediction of the results of skin engraftment. It is stated, that the disorder of microcirculation has been developed against the background of progression of wound invasive infection. The obtained data can allow the development of an algorithm of treatment and the preparation of the patients to surgery, determination of the terms of operation, the development the strategy of postoperative management of the patients, which can reduce unfavorable results of operations. PMID- 23808231 TI - [Algorithm of diagnostics and surgery of trauma and degenerative diseases of cervical spine]. AB - A retrospective analysis of diagnostics and surgery in 240 patients was made. The vertebral spinal trauma took place in 168 patients (average age 31 +/- 5 years), degenerative dystrophic diseases of spine were in 72 patients (average age 52 +/- 7 years). The clinicodiagnostic complex included survey and functional radiography of the spine, magnetic resonance image and helical computer tomography of the spine with spondylometric measurements and color duplex scanning of the vertebral artery. Stabilization of the spine was performed in 137 (57%) cases. The variants were determined on the basis of predominate injury of 1 out of 3 supporting complexes. The rigid and dynamic methods and their combination were used for fixation of the spine. More favorable results were registered using dynamic fixation and the arthroplasty of intervertebral disks with nitinol constructions. An algorithm of radiodiagnostics and surgery methods were proposed. PMID- 23808232 TI - [Up-to-date approaches in treatment of hydatid disease of the liver in childhood]. AB - Sixty children (age 3-15 years) with hydatid disease of the liver were treated. The patients were divided into 2 equal groups (control and main groups).The hydatid disease of the liver was revealed in 22 (33.6%) patients, combined hydatid disease of the liver and lung were noted in 38 (66.4%) patients. The "capitonnage" of the residual cavity was applied in the control group and omentoplasty--in the main group. Chemotherapy with Nemazol (dose 10-15 mg/kg/day) was carried out. In order to reduce the negative influence of Nemazol on patients and to accelerate reparation processes of liver parenchyma Vobenzyme (2-3 pills/3 times/day) was applied. The number of complications was 23.2 % in the control group. The adhesive bowel obstruction was noted in 6.6% of patients, bleeding and jaundice in 3.3%, the residual cavity suppuration in 10%. Complications were registered in the main group in 6.6% of children (the adhesive bowel obstruction in 3.3%, preservation of the residual cavity after a year in 3.3%). The number of relapses in the control group was 6 (12%), there were no relapses in the main group. Thus the procedure of preoperative and postoperative chemotherapy allowed avoidance of the development of relapses of hydatid disease of the liver. Omentoplasty is the most rational method of treatment of residual cavity in surgery of hydatid disease of the liver in children. PMID- 23808233 TI - [Combined methods of treatment the congenital arterio-venous fistulas of peripheral vessels]. AB - A 10-year experience and results of combined methods of surgical treatment of arterio-venous fistulas of peripheral vessels in 50 patients were analyzed. The patients were systematized on the basis of existing classifications, clinical manifestations of the disease, methods of invasive (ultrasound dopplerography and duplex scanning) and invasive (angiography) examinations. According to many authors no one of conventional methods of surgical treatment of arterio-venous fistulas which are used singly can be effective and must not be recommended as the most optimal. Stepwise employing of traditional operations and endovascular techniques are the main conditions for preventive measures of ischemic disorders in the limbs. PMID- 23808234 TI - [Prevention of incompetence of sutures of intestinal anastomoses by the method of permanent intramesenteric blockade and lymphotropic therapy]. AB - The author considers results of inestigation for studying an efficiency of permanent intramesenteric (retroperitoneal) blockade and applying lymphotropic therapy for prevention of incompetence of sutures of intestinal anastomosis against the background of diffuse peritonitis and acute intestinal obstruction. An infusion was carried out 4-6 times a day with a special solution (novocain 0.5% (7 ml/kg/day); heparin (150 units/kg/days); proserin (0.03 mg/kg/day) and seftriakson (15 mg/kg/days)) in order to obtain the effect of permanent intramesenteric blockade and lymphotropic therapy. The solution is administered by droplet injection with the rate 100-120 drops a minute (80-120 ml per each infusion). Due to the application of the given method the frequency of cases of the incompetent sutures of intestinal anastomoses in patients of the main group decreased from 15.5% to 3.4% (X2 = 16.2; p < 0.001) as compared with the other patients. PMID- 23808235 TI - [Microsurgical autografting for reconstruction of head and neck oncological defects. An analysis of 60 cases]. AB - The authors analyzed results of the free flap transfer in surgery of head and neck. 60 operations were performed since October 2006 till May 2012. Indications for using them were reconstruction of the mucosa of the oral cavity and the pharynx in 48 cases, the extensive defects of skin and soft tissues of the head and neck in 12 cases. All cases except 2 had the initial reconstruction. First 18 operations were performed with the binocular loupes, followed by using operating microscope. During the operations 42 radial skin-fascia flaps, 10 anterolateral femoral flaps, 5 thoracodorsal flaps, 1 anteromedial femoral flap, 1 scapular skin bone flap and 1 jejunal flap were used. During the early postoperative period one of the patients died (postoperative lethality 1.7%). Necrosis of flaps took place in 6 cases (5 radial skin-fascia flaps, 1 thoracodorsal flap). The causes of failures were assessed as arterial thrombosis (1 case), venous thrombosis (2 cases), postoperative infection (1 case). The exact cause in 2 cases couldn't be determined. Thus, the total success in the given series of surgery was 88.9%. PMID- 23808236 TI - [Radical operations of inguinal hernias with the temporary translocation of inguinal nerves]. AB - This article presents the results of anatomic researches of the innervations of the inguinal area, performed for studying an arrangement of the main nerves of the inguinal area in relation to the operation access and the area of plasty of the posterior wall of the inguinal canal. The method of temporary translocation of inguinal nerves is developed for their preservation at radical operations of inguinal hernias. Long-term experience of surgical treatment of inguinal hernias with the temporary translocation of inguinal nerves is summarized. PMID- 23808237 TI - [The assesment of significance of the retroperitoneal lymph node dissection in proximity of metastatic tumor with main vessels in patients with germ cell testicular tumors]. AB - The therapeutic approach should be defined more exactly in proximity of residual retroperitoneal metastases of germ cell testicular tumor and main vessels (left after chemotherapy). The data of 29 (24%) patients were analyzed over a period of time since 2003 till 2011. The general survival was 82% in the group without lymph node dissection (17 patients) in median observation of 27.5 months. The proximity with main vessels was registered in half of the cases in the group of operated patients (12 people), a single vascular reconstruction was required. The general survival was 97% in median observation for 35 months. The involvement of main vessels of retroperitoneal space significantly complicated the retroperitoneal lymph node dissection, but didn't have negative prognostic value. PMID- 23808238 TI - [Results of combined treatment with intraoperative radial therapy of soft tissue sarcoma]. AB - The intraoperative radiation therapy (IORT) in combined therapy of soft tissue sarcoma in a single dose 10-20 Gy is the method, which can optimize the role of radiation therapy in treatment of this nosology. This method allows exact localization of the irradiation zone in the frames of "tumor bed", thereby minimizing the damage of normal tissues and critical organs. The aim of the study was the influence of IORT on the rate and structure of postoperative complications and long-term results of treatment in the group under study (n = 49) in comparison with the group of combined treatment without IORT (n = 57) and the group of surgical treatment. No statistically reliable difference in the rate of postoperative complications in groups (p = 0.57) was obtained and there was no influence on the structure of postoperative complications. At the same time the statistically reliable increase of general survival rates (p = 0.025) and the survival without relapse in the main group (p < 0.025) were obtained. Thus, the application of IORT in combined treatment of soft tissue sarcomas showed the satisfactory profile of "surgical safety", provided the reliable increase of general survival rates and rates without relapse. PMID- 23808239 TI - [Complicated laparoscopic hernioplasty]. PMID- 23808241 TI - [Resources of surgical treatment of diabetes mellitus type II]. PMID- 23808240 TI - [Efficacy of dermoplasty and the dermal equivalent in treatment of vast leg ulcers of mixed genesis]. AB - The most frequent causes of leg ulcers (90-95%) are chronic venous insufficiency (45-60%), obliterating atherosclerosis of the lower extremity arteries (10-20%), diabetes mellitus (15-25%) and their combinations (10-15%). The leg ulcers, specified as pyoderma gangrenosum, are the rare and severe pathology, which is very often misdiagnosed. The case history of a 58-year old female patient with vast leg ulcers of the both shanks is analyzed. The leg ulcers were caused by pyoderma gangrenosum and chronic venous insufficiency due to the varicose disease. Complete epithelization of both ulcers was achieved by means of dermoplasty combined using the dermal equivalent against the background of system immunosuppressive therapy. PMID- 23808242 TI - [Problem of selection of plastic material in reconstructive heart surgery]. PMID- 23808243 TI - [Efficiency assessment of preoperative preparatory programs in pediatric patients in dentistry]. AB - Research objective was to compare the efficiency of different preoperative preparatory programs which had been used for anxiety decrease in Pediatric patients before oral cavity sanation with general anaesthesia. Two preparatory programs were used. In the first program patients were informed about the treatment they were undergoing. Patients visited the operating unit and watched the videos about forthcoming procedure (group of Information Technologies (IT), n = 82). The second program included the tutorials (face mask use, acquaintance with equipment alarms etc.) in addition to Information Technologies (group of lnformation Technologies and tutorials (ITT) n = 83). Information Technologies and tutorials were not used in the control group (n = 86). Both used programs were effective. ITT program was the most effective. PMID- 23808244 TI - [Xenon and sevoflurane anti stress activity comparative assessment during elective anaesthesia in pediatric patients]. AB - Research objective was to compare Xenon and Sevoflurane anti stress activities during elective anaesthesia in Pediatric patients. MATERIAL AND METHODS: The results of anaesthesia in 42 patients in age from 1 to 18 years were analyzed. The clinical sings, BIS-index, Somatotropinum hormone and Cortisol levels in patient's blood were studied. RESULTS: Xenon and Sevoflurane provide sufficient level of sedation, analgesia and do not cause Somatotropinum hormone and Cortisol levels increase. CONCLUSION: Xenon and Sevoflurane have the same high anti stress activity However Xenon anaesthesia is characterized by more stable haemodynamics. PMID- 23808245 TI - [Anaesthetic maintenance with laryngeal mask for a laparoscopic surgery in pediatric patients]. AB - Research objective was to make a comparative assessment of haemodynamics, ventilation and oxygen status and perioperative complications during laparoscopic surgeries anaesthetic maintenance with intubation and laryngeal mask use in Pediatric patients. METHODS: A retrospective observational controlled study. STUDY TERMS: from 2000 to 2012. Two groups of Pediatric patients were recruited in the study: 127 patients for general anaesthesia with laryngeal mask and 86 patients for general anaesthesia with endotracheal tube. Laparoscopy duration was 51.3 +/- 14.4 minutes. LMA-classic laryngeal mask was used. Study results showed that laryngeal mask use provided haemodynamics stability adequate ventilation and oxygen status and shorter awakening time when compared with endotracheal tube use. CONCLUSION: General anaesthesia with laryngeal mask can be used for a short laparoscopic surgery in Pediatric patients without respiratory disorders and I-II classes due to ASA physical status classification. PMID- 23808246 TI - [Modern approach to the neuromuscular blocking agents use in pediatric patients]. AB - Myorelaxants use decrease trend appeared since the end of 80 years of the 20th century. The trend is connected with use of the new narcotic analgesics (Remifentanil), intravenous (Propofol) and inhalation (Sevoflurane) anaesthetics. These drugs are manageable and predictable, they have not many side effects and can suppress laryngeal-pharyngeal reflex during the tracheal intubation. Furthermore there are other factors such as succinylcholines use when fast intubation is needed, the wrong myorelaxant and dosage choice. Residual curarization and side effects risk increases due to these factors. As a result the patient's activation is delayed. Nevertheless myorelaxants use refusal impairs the tracheal intubation conditions, increases the arterial hypotension and heart failure risk especially in newborns and children with severe pathology. If myorelaxants is not used, comfortable conditions of surgical manipulations impossible without big analgesics and anaesthetics doses use. PMID- 23808247 TI - [Recombinant activated factor VII use for the bleeding implications prevention during central venous catheterization in pediatric patients with acute leucosis and thrombocytopenia]. AB - Research objective was to develop an algorithm of the recombinant activated Factor VII (rFVIIa) prophylactic use for the bleeding implications prevention during central venous catheterization in Pediatric patients with acute leucosis and thrombocytopenia. METHODS: 30 Pediatric patients with acute leucosis and thrombocytopenia received rFVIIa 30-120 microg kg(-1) before the internal jugular vein catheterization with ultrasound control. Comparative group 1 included 39 Pediatric patients without preventive haemostatic treatment; comparative group 2 included 30 patients received platelet concentrate. RESULTS: the first attempt catheterization numbers increased, the time of the catheterization was reduced, platelet aggregation was improved and the bleeding implications frequency was 6.6% in patients received rFVIIa before the internal jugular vein catheterization. 23.1%--in the comparative group 1; 26.7% in the comparative group 2. CONCLUSION: Ultrasound navigation and rFVIIa preventive use together improve internal jugular vein catheterization results. PMID- 23808248 TI - [Alveolar recruitment maneuvers oxygenation effects in newborns with infant respiratory distress syndrome]. AB - Infant respiratory distress syndrome (IRDS) is a most common neonatal critical condition which is accompanied by the hypoxemia increase and needs the use of the highly invasive respiratory support methods. Alveolar recruitment maneuver is a one of the most promising and pathogenetically grounded method. The method is widely used in adults. but its use in Pediatric patients requires evidence of the effectiveness. RESEARCH OBJECTIVE: To study alveolar recruitment maneuver use effectiveness in newborns with IRDS by the examining patient's clinical status and the nearest and long-term outcomes. METHODS: Alveolar recruitment maneuver was used in 45 newborns with IRDS accompanied by the hypoxemia (group 1). Retrospective analysis of conditions and outcomes in 19 newborns with IRDS, without use of alveolar recruitment maneuver, was conducted in 2009 (group 2). RESULTS: Alveolar recruitment maneuver improves ventilation and oxygenation in newborns with IRDS (paO2 53 torr in group 1 vs. 36 torr in group 2 and SpO2 95% vs. 90%). Alveolar recruitment maneuver use decreases the long term implications frequency in newborns with IRDS. CONCLUSION: Alveolar recruitment maneuver is highly effective in newborns with IRDS. Its use decreases implications frequency and improves long term outcomes. PMID- 23808249 TI - [Prognostic criteria of the premature infants weaning from mechanical ventilation during trigger ventilation]. AB - Modern mechanical ventilation modes do not prevent ventilator-associated lung injury therefore respiratory cessation must be stopped as soon as possible. However extubation recommendations absence makes difficulties in process of weaning the infants from the mechanical ventilation. RESEARCH OBJECTIVE: To assess the prognostic criteria of the extubating and weaning from mechanical ventilation in premature infants during trigger ventilation (PSV/PSV + VG). METHODS: 66 Pediatric patients were divided into two groups during the period of weaning from mechanical ventilation: PSV + PG ventilation mode was used in the group 1 (n = 33), and PSV in the group 2 (n = 33). Basic characteristics were same in both groups: gestational age 31.1 +/- 2.5 weeks, mass of body 1586.2 +/- 356.8 grams. Extubation was successful if reintubation was not needed during 48 hrs. RESULTS: 90% of successful extubations were done when the compliance was over 1.1 ml mbar(-1). Compliance decrease under 0.75 ml mbar(-1) was an adverse prognostic criterion of the weaning from mechanical ventilation and extubation. Index breathing rate/breathing volume (RVR) can be used as general criterion of the weaning from mechanical ventilation. Progressive RVR increase to 8 is an adverse prognostic criterion of PSV/ PSV + VG mode use during the period of weaning from mechanical ventilation. Parameters of mechanical ventilation which maintain acceptable gas composition of blood and SpO2 mast be considered before extubation. CONCLUSION: Positive dynamics and stabilization of compliance and resistance are essential criteria of the successful weaning from mechanical ventilation and extubation. RVR can be used as objective criterion of an extubation. PMID- 23808250 TI - [CPAP as a method of primary respiratory support in premature infants with acute respiratory distress syndrome]. AB - Recent years neonatologists attempt to support the premature infants breathing without the intubation and mechanical ventilation use. Resent studies and new modern equipment for noninvasive ventilation resume the interest in CPAP The article presents the review of the recent studies which investigated CPAP effectiveness as a method of primary respiratory support in premature infants with acute respiratory distress syndrome. Big attention was paid to the surfactant use and InSurE approach in the modern treatment of respiratory disorders according the latest data of evidence based medicine. PMID- 23808251 TI - [Sugammadex use experience in pediatric oncology]. AB - Sugamnmadex is a new type agent for reversal of neuromuscular blockade in any stage. There are foreign and home sugammadex use studies; however the information of sugammadex use in Pediatric patients is not enough. The article deals with study results of sugammadex use in Pediatric surgical oncology for the reversal of neuromuscular blockade by the agent rocuronium. 42 Pediatric patients in age from 2 to 17 years after elective oncology surgeries were recruited in the study. The speed and entirety of myorelaxation shifting as an evidence of sugammadex effectiveness were assessed by the accelerometer. PMID- 23808252 TI - [Dexmedetomidine: new opportunities in anesthesiology]. AB - Dexmedetomidine is a novel a,-agonist with unique characteristics. The review contains description of main pharmacological and physiological features of this drug. The experience of off-label using of dexmedetomidine in anesthesia is discussed in details. Authors consider that dexmedetomidine can improve anesthesia management in various clinical situations due to specific sedation profile similar to natural human sleep pattern. It can be helpful in neurosurgery in overweight patients or in patients with high cardiac risk as well as in pediatric practice. PMID- 23808253 TI - [Haemodynamics during kidney transplantation and general anaesthesia in combination with epidural block and without it in pediatric patients]. AB - RESEARCH OBJECTIVE: To compare haemodynamic effects of general anaesthesia in combination with epidural block and without it during kidney transplantation in Pediatric patients. METHODS: 61 Pediatric patients undergoing kidney transplantation were divided into two groups. General anaesthesia with sevoflurane, propofol, phentanilum and regional ropivacaine epidural block were used in the group 1. General anaesthesia was used only in the group 2. Haemodynamic parameters were assessed: Arterial blood pressure, stroke volume, central venous pressure and cardiac index. RESULTS: Both techniques of anaesthesia were adequate. CONCLUSION: regional ropivacaine epidural block and general anaesthesia combination provides more stable haemodynamic parameters than general anaesthesia single use. PMID- 23808254 TI - [Peripheral regional block role in orthopedics in pediatric patients with cerebral palsy]. AB - Haemodynamics of 58 Pediatric patients with cerebral palsy was studied during combined anaesthesia based on sevoflurane and peripheral nerve block. Sevoflurane and peripheral nerve block with infusion support 14-15 ml/kg/ hr provide stable cardiac output during orthopedic surgeries in Pediatric patients with cerebral palsy. Excessive arterial hypotension and total peripheral vascular resistance decrease were registered in older patients as results of more pronounced vascular effect of anaesthetics in patients with decreased adaptive-compensatory possibilities and insufficient infusion support. The proposed anaesthesia method provides adequate intraoperative analgesia, fast recovery and comfortable postoperative period. PMID- 23808255 TI - [Study of glutamine solution use efficiency in pediatric patients with heavy thermic burns and concomitant injuries in the intensive care unit]. AB - Comparing analysis of randomized study was conducted. 40 Pediatric patients (2-15 years old) with heavy thermic burns and concomitant injuries were recruited into the study to assess the glutamine solution intravenous use efficiency. Parenteral feeding and feeding with glutamine solution intravenous use were clinicaly and laboratory compared Duration of mechanical ventilation decreased in group of feeding with glutamine solution intravenous use. Preliminary results of the study recommend to include glutamine in the programs of parentreral feeding. PMID- 23808256 TI - [Clinical case of cesarean, combined with convexital giant meningioma resection in adolescent girl]. AB - The article deals with a case of successful surgical treatment of 16 years old patient with giant meningioma of right temporal, parietal and frontal lobes. Patient was on a 32 week of pregnancy and she had a Caesarean section before meningioma treatment. The article discusses the problems of anaesthesiological, surgical and obstetric tactics. PMID- 23808257 TI - [Clinical case of amyotrophic lateral sclerosis management and treatment in the non-core clinic]. AB - The article points out the problems of amyotrophic lateral sclerosis (ALS) diagnostics, management and treatment in the non-core clinic (oncological dispensary intensive care unit). There is no legislative base for medical and social protection of patients with ALS in Russia. Article stresses the need to attract the attention of Ministry of healthcare of Russia to this problem. PMID- 23808258 TI - [Combined anaesthesia for rhinoseptoplasty in pediatric patients]. AB - The article deals with efficiency and advantages analysis of Marcaine 0.25% and Epinephrine 1:200000 intraoperative uses as a supplementary analgesia for rhinoseptoplasty in Pediatric patients. PMID- 23808259 TI - [Simulator for epidural anaesthesia skill training with ultrasound control]. AB - The article deals with skills improving problem of epidural anaesthesia with ultrasound control. Methods of gelatin spinal column model making, use and its economical side are discussed in the article. PMID- 23808260 TI - [Factors affecting the recovery in the intensive care unit]. AB - Urgency of the problem is defined by economical, regulatory and legislative acts, regional social and moral factors. There is critical situation in Russian Pediatric Healthcare system. This situation is due to inadequate funding, high medical technologies inaccessibility for some Russian children, their adverse health state. The article presents a retrospective analysis of intensive therapy and resuscitation outcomes with technical equipment and work environment assessment in the intensive care unit of Tushinskaya city pediatric clinic for the period from 2007 to 2011. Anaesthetic and emergency care quality and safety depend on several factors: permanent equipment improvement, comprehensive analysis of every fatal case and full implementation of "Anti-epidemic (prophylactic) actions plan" and "Program of monitoring compliance with the sanitary norms". PMID- 23808261 TI - [Contemporary opinion about anticholinergics use in premedication]. AB - The article deals with the analysis of publications which discuss anticholinergics use in premedication. The article briefly says about the use history and characteristics of anticholinergics. In conclusion the article stresses the need to abandon the routine anticholinergics use. Intravenous anticholinergics application is preferable if there are indications for its use. New inhalation and intravenous anaesthetics promote to prescribe the anticholinergics individually PMID- 23808262 TI - [Postoperative analgesia after thoracoscopic surgeries in pediatric patients]. AB - Postoperative pain after thoracic surgeries is characterized by intensity and long duration. The intensity of pain can be moderate or strongly expressed, the duration various from one day to months and years either after thoracotomy (TT) or thoracoscopy (TS). Pain relief is one of the most important problems of postoperative period. Adequate analgesia, lung function and temperate sedation, ventilation must be provided against the general disease, surgical injury and one lung ventilation. TS is a less invasive method therefore pain syndrome is not very strong. There are several methods of postoperative analgesia in Pediatric patients; however the choice is limited by the patient's age. Postoperative analgesia in Pediatric patients can be provided by narcotic and nonnarcotic analgesics, neuraxial anesthesia: multimodal approach is widely used. Postoperative pain after TS needs adequate analgesia for implications prevention and to reduce the duration of hospital stay. PMID- 23808264 TI - [The resolution of the XXVII (90th) session of the RAMS]. PMID- 23808263 TI - [Modes of mechanical ventilation during transferring the patient to spontaneous breathing]. AB - Mechanical ventilation (MV) has become a general treatment in the intensive care unit in recent years. Mechanical ventilation is a resuscitation treatment; however MV causes many implications therefore it is to be finished as soon as the patient's condition begins improve. Modern transferring the patient to spontaneous breathing decreases implications number. Significant part of mechanical ventilation time (40%) is a time of weaning from mechanical ventilation. Weaning from MV is an economical, clinical and ethical problem. Many ventilation modes have introduced in clinical practice through the microprocessor technologies development. Supporting ventilation modes help to avoid some adverse effects of mechanical ventilation. The article deals with historical approaches development their advantages and limitations. PMID- 23808265 TI - [Publication activity of the Russian medicine in focus of national science policy: estimating the feasibility of policy targets]. AB - A comprehensive review of National research policy papers issued over the past 6 years was carried out. A set of problems concerning the quality of predicted values of some bibliometric indicators reflecting the level of research performance and publication activity that were declared in governmental documents was discussed. Basic metrics of scientific performance that should be required to achieve the goals declared in the recent governmental policy papers including President's Executive Order No 599 of May 7, 2012 (increasing the share of Russian researchers' publications in the total number of publications in international scientific journals indexed in the Web of Science up to 2.44% in 2015). Taking into account the current structure of modern global science in which papers in biomedical subjects make up for approximately one third of the total world scientific output, it becomes obvious how difficult is the governmental task set up to the researchers--to double the number of journal publications indexed in Web of Science in the short-term period of the nearest three years. The priorities and reasonable goal-oriented efforts to meet the targets are proposed in the paper. PMID- 23808266 TI - [Molecular and pharmacogenetic mechanisms of severe asthma]. AB - This review summarizes the results of studies to identify the dominant mechanisms of development and persistence of inflammation in severe asthma and results of pharmacogenetic studies of determination response to drugs. These mechanisms could potentially be used for diagnostic purposes and become the new targets of asthma therapy. Pharmacogenetic information will enable the use of a personalized approach to the asthma management which will adjust the therapy technology and increase the possibility of achieving disease control. PMID- 23808267 TI - [Nonthyroidal illness syndrome in acute bacterial endotoxicosis: pathogenesis and methods of correction]. AB - Nonthyroidal illness syndrome is characterized by alterations of thyroid status inpatients with severe nonthyroidal illness who are clinically euthyroid. Mechanisms of nonthyroidal illness syndrome are poorly understood and controversial. Our investigations on nonthyroidal illness syndrome in acute endotoxicosis revealed two principal mechanisms of its development. The peripheral mechanism is the first to develop and referred to disturbance of thyrocytes secretory cycle due to increase of thyroglobulin synthesis, endocytosis and decrease of its proteolytic cleavage. It manifests with drop of serum thyroxine, not triiodthyronine, and increase of serum thyroid stimulating hormone. The central mechanism is associated with hypothalamic-pituitary hypofunction developed simultaneously with systemic inflammatory response. Rate of supplementation of the peripheral mechanism with the central one accounts for different types of nonthyroidal illness syndrome with high, normal and low serum levels of thyroid stimulating hormone. Our research showed that thyroid hormone replacement in nonthyroidal illness syndrome could only suppress thyroid function. Unlike thyroid hormones administration of thyroid stimulating hormone restores thyroid hormone secretion in nonthyroidal illness syndrome, decreases endotoxinemia and secretion of proinflammatory cytokines and improves liver function. PMID- 23808268 TI - [Cell therapy of critical lower limb ischemia (problems and prospects)]. AB - Critical limb ischemia is a syndrome that combines several peripheral artery diseases with different ethiology and pathogenesis but with similar prognosis, high morbidity and mortality. Possibility of surgical and conservative treatment of critical limb ischemia almost completely exhausted. Some hopes have arisen due to progress in cell technology. The article provides a critical analysis of pathogenic prerequisites of stem/progenitor cells for the treatment of patients with a critical limb ischemia in detail the basic results of preclinical and clinical studies on the safety and efficacy of cell technology. Unsolved problems and prospects of practical application are also discussed. PMID- 23808269 TI - [Staged correction of spinal deformity in a patient with incontinentia pigmenti syndrome]. AB - Case presentation of staged surgical treatment of patients with spinal deformity in incontinentia pigmenti syndrome. As a result of surgical procedure proper sagittal balance of the body was restored. PMID- 23808270 TI - [The assessment of mechanical heart valves stenosis in adults after aortic valve replacement: the advantage of full-flow design of mechanical valve]. AB - The analysis of transprosthetic hemodynamics in adults after aortic valve replacement in the Bakoulev Center for Cardiovascular Surgery in 2007-2010 demonstrated the hemodynamic advantage of the concept of new full-flow mechanical aortic valve prosthesis "CorBeat". Having the same size of internal orifice and tissue annulus diameters, the values of transprosthetic parameters (peak and mean gradients, blood flow velocities) through "CorBeat" were close to physiological values of transvalvular native aortic parameters and had a tendency to be not dependent on the size of prosthesis (p = 0.63). In the article for the first time a morphometric database of geometric values of internal orifice area of normal native aortic valves in adults was used taking into account both the gender and the body surface area's of a patient. There was also used the standardized prosthesis size Z-score which represents the number of SDs by which the internal prosthesis area differs from the mean normal native aortic valve area for the patient's body surface area. The article emphasizes the need of the personal selection of the size and the type of prosthesis for any patient as well as the need for new design development of prosthetic heart valves. PMID- 23808271 TI - [Dental diseases prevention and treatment among foreign students from different regions of the world]. AB - 420 foreign first year students of Peoples' Friendship University of Russia from different regions of the world were examined for oral health status. The main dental indexes were analyzed and recommendations for dental diseases prevention and treatment were given for each region group. For students from Africa the leading direction is caries prevention. Students from Middle East and Latin America need in caries treatment and endodontic treatment. The main problem of students from Asia is periodontal diseases. PMID- 23808272 TI - [Regional ecological and social and economic aspects of morbidity of the teenage population residing in industrial centres]. AB - It is presented the characteristic changes of atmospheric air pollution and morbidity of adolescents aged 15-17years living in urban environments with different specificity of industrial enterprises for the 10-year period. We investigated the relationship dynamics of the indicators of the health of modern teenagers with socio-economic indicators of regional development. A predictive model for the regression rate of absolutely healthy adolescents (group health I) is worked out and set the share of influence on this indicator factors included in the regression model. PMID- 23808273 TI - [Studying of hepatoprotective properties of dry extract from apricot leaves on the model of liver lesion by tetrachloromethane]. AB - The results of the pharmacological investigation of the properties of apricot leaves dry extract are indicated in the article. It is proved that the extract belongs to the group of "relatively harmless" substances, exclusion of the ulcerogenic effect on the stomach, local irritating and allergenic effect on animals. It is found minimal reacting dose of the extract, which is 70 mg/kg of body weight. On the model of liver lesion by tetrachlormethane it is proved the antioxidant properties of the extract, which is manifested by the decreasing of the activity of oxidative processes and the resumption of the activity of the endogenous antioxidant system. At the studying of the bile formation and bile secretion functions in the conditions of the toxic tetrachlormethane lesion the hepatoprotective effect of the dosage form was confirmed, which was realized by the increasing of the speed of bile secretion and its volume. It is proved a positive effect of the extract on the detoxification function of the liver, that is confirmed by the reducing of the hexenal sleep in rats after toxicant exposure. PMID- 23808274 TI - [Biologically active substances of plant origin. Flavonols and flavones: prevalence, dietary sourses and consumption]. AB - Flavonoids are the most numerous group of natural polyphenolic compounds, the secondary metabolites of plants that may play an important role in human health protection. Flavonols and flavones constitute the main two classes of flavonoids, whose antioxidant properties and high biological activity have been proofed both in vitro and in vivo. This review summarizes data, concerning the structure, occurrence and content of the main flavonols (quercetin, kaempherol, myricetin, isorhamnetin) and flavones (apigenin, luteolin) in some most widely consumed foodstuffs, including vegetables, fruits, berries, nuts, beverages and other products of plant origin. The products with high content of these biologically active food compounds--the major dietary sources of them--are noted. Forms of flavonols and flavones more often distributed among edible plants are characterized and some of their known glycosides occurred in foods are enumerated. Some peculiarities, characteristic to flavonol sand flavones glycosilation (O- and/or C-glycosides formation) are described. The data for flavonol and flavone glycosides composition (profiles) of some commonly consumed commodities rich by these flavonoids (onions, cabbage, apples at al.) are shown. Information about levels of daily dietary intake of total and individual flavonols and flavones in several countries is presented. The questions about dietary habits and lifestyle factors and the contribution of certain foods to flavonols and flavones in daily dietary consumption values are also discussed. PMID- 23808275 TI - [About flavouring substances and flavouring preparations regulation in the field of manufacturing of flavourings and foodstuffs]. AB - In article are given substantiation for modification of contemporary list of biologically active substances with undesirable toxicological qualities (namely included in this list of menthofuran, methyleugenol (4-Allyl-1,2 dimethoxybenzene), teucrin A, capsaicin, estragol1 (-Allyl-4-methoxybenzene) and excluded from the list of quinine, santonin, berberin) and developing the list of plants--natural sources of flavourings substances. The new criteria of European Union for including into the relevant for using in/on foodstuff list of flavouring substances, which was published in the Comission Implementing Regulation (EU) No 872/2012 concerning flavourings, listed the 11 flavouring substances for which have been established indexes of foodstuffs in manufacturing, which there are could using and criteria of their safety (caffeine, theobromine, neohesperidin dihydrocalcone, rebaudioside A, d-camphor, three quinine salts (FL 14.011, FL 14.152 and FL 14.155), glycyrrhizic acid and its ammoniated form, ammonium chloride, discussed the possibility of using R- and S-isomers of flavouring substances and L- and D-forms of aminoacids for preparing of flavours, are discussed. Improving of the system of safety using of flavourings in Russian Federation, harmonized with demands of European Union and FAQ/WHO, are, at first, connected with the necessity of reevaluation of the list flavouring substances, which could be use in/on foodstuff, developing of list of the plants--natural sources of flavourings substances and preparations and regulations of using flavourings preparations which can include biologically active substances. PMID- 23808276 TI - [Rapid methods for the genus Salmonella bacteria detection in food and raw materials]. AB - The article considers sanitary and epidemiological aspects and the impact of Salmonella food poisoning in Russia and abroad. The main characteristics of the agent (Salmonella enterica subsp. Enteritidis) are summarized. The main sources of human Salmonella infection are products of poultry and livestock (poultry, eggs, dairy products, meat products, etc.). Standard methods of identifying the causative agent, rapid (alternative) methods of analysis of Salmonella using differential diagnostic medium (MSRV, Salmosyst, XLT4-agar, agar-Rambach et al.), rapid tests Singlepath-Salmonella and PCR (food proof Salmonella) in real time were stated. Rapid tests provide is a substantial (at 24-48 h) reducing the time to identify Salmonella. PMID- 23808277 TI - [Nutrition value of tropical and subtropical fruits]. AB - The article is devoted to the study of the chemical composition of tropical and subtropical fruit (avocado, papaya and mango), which are now in great numbers are on the appeared on the Russian market. Due to use technology tropical and subtropical fruits can be implemented in almost all areas and regions of the country. Relatively low cost makes these products quite popular among the people. In domestic scientific literature there are no systematic data describing the chemical composition of these tropical and subtropical fruits sold in the domestic market, while the information needed to calculate food and energy value of diets and culinary products derived from tropical and subtropical fruit. Avocado fruits are sources of insoluble dietary fiber content of which was equal to 12.2%, as well as minerals. The study of the fatty acid composition of lipids avocados showed high content of oleic acid fruit, which accounts for 53.2% of total fatty acids in these fruits. Which makes them a valuable source of unsaturated fatty acids. PMID- 23808278 TI - [Enrichment effect of vitamin-deficient diet of rats by polyunsaturated fatty acids omega-3 on vitamin biomarkers and antioxidant status]. AB - Using the model of combined vitamin deficiency based on 5-fold reduction of the amount of vitamin mixture in semi-synthetic diet and on vitamin E exclusion from the mixture, the influence of omega-3 polyunsaturated fatty acids (PUFA) on vitamin and antioxidant status has been investigated. The enrichment of rat diet with PUFA was achieved by replacing of sunflower oil (4.5% of the diet) on linseed oil. This substitute led to omega-3 PUFA elevation from 0.03 to 2.4 g per 100 g of food and PUFA and saturated fatty acids diet ratio increased from 1.3 to 1.9. The diet treatment with PUFA did not affect blood plasma retinol concentration and total vitamin A (retinol palmitate and retinol) rat liver content, while liver retinol significantly 1,5-fold elevated. Despite of preliminary equation of tocopherols content in vegetable oils (up to 60 IU per 100 g by adding dl-alpha-tocopherol to linseed oil) the consuming of linen oil deteriorated animal vitamin E supply. The liver alpha-tocopherol content significantly decreased by 14%, its blood plasma concentration insignificantly decreased by 26%, while the amount of beta - and gamma-tocopherol significantly increased in 5,4-fold. At the same deprivation of vitamin D in the diet of rats treated with linseed oil 25(OH)D blood plasma concentration was 1,3-fold higher compared with the animals treated with sunflower oil, but the difference did not reach significance reliable. In this case, this index had significant differences from that of the receiving adequate diet rats in control group, having 2-fold higher concentration of vitamin D transport form in blood plasma. PUFA enrichment of the combined vitamin-deficit diet did not affect liver level of vitamin C, vitamin B1 and vitamin B2. Contrary to the assumptions, the enrichment with PUFA of vitamin-deficient diet did not lead to a further increase of liver MDA level and a decrease of liver ascorbic acid content, which is typical for animals in combined vitamin deficiency. The deterioration of vitamin E status at enriched with PUFA vitamin-deficient diet requires the additional intake of this vitamin for maintaining of vitamin E sufficiency. PMID- 23808279 TI - [Influence of dietotherapy on body composition in patients with obesity and diabetes mellitus type 2]. AB - The aim of the study was to evaluate indexes of body composition in patients with obesity and diabetes mellitus type 2 during the application of a standard hypocaloric diet. MATERIAL AND METHODS: in study were included 290 patients aged of 49 +/- 13 years. Patients were divided in two groups: 1) patients with obesity (n = 145), and 2) patients with obesity and diabetes mellitus type 2 (n = 145). Within 2 weeks, all patients received standard hypocaloric diet (1500 kcal/day). Dynamics of anthropometric parameters and indices of body composition with using of bioimpedance analyzer "Inbody 720" were investigated for all patients before and after 2 weeks of dietary intervention. RESULTS: During the diet there was a positive dynamics of the anthropometric parameters, which showed the reduce of body weight and body BMI in patients of first group: from 116.9 +/- 1.8 kg to 110.9 +/- 1.7 kg (p < 0.001) and from 42.1 +/- 0.6 kg/m2 to 39.8 +/- 0.6 kg/m2 (p < 0.001), while in the second group--from 112.2 +/- 1.8 do106, mass index 6 +/- 1.6 kg (p < 0.001) and from 41.6 +/- 0.6 kg/m2 to 39.4 +/- 0.5 kg/m2 (p < 0.001), respectively, without statistically significant differences between groups. Reducing the amount of fat in first group was on average 5.6 kg; and in second- an average of 3.7 kg (p < 0.001). Changes of other components of body composition also were observed in patients: the area of visceral fat in obese patients decreased from 224.9 +/- 4.5 cm2 up to 209.4 +/- 4.7 cm2 (p < 0.001) in patients with type 2 diabetes--from 237.6 +/- 4.2 cm3 up to 226.8 +/- 4.3 cm3 (p < 0.001). Study showed that controlled reduction of a diet caloric value can significantly decrease body weight in patients with obesity and diabetes mellitus type 2, mainly due to the fat component, and allow to reduce the risk of cardio-vascular diseases and metabolic disturbance. PMID- 23808280 TI - [Features to improve health care in "dietology" profile in Voronezh Region]. AB - Recent years, restructuring of the health care to the population, including a complex of measures to improve the human resources policy in health, spurring the practice of the disciplines to public health care, turning, organizing 3-tier health care system, including the profile "nutrition" is carried out in Voronezh region. Analysis of security by dietitians, dietary nurses and hi-tech medical equipment is carried out. Set of measures to developing interaction between health care institutions (accordingly Health Ministry order N 474 from 24.06.2010) was worked up. Implementation of order of medical care in "Dietology" profile, high-quality dietitians work at all stages of 3-tier system of organization of medical care will make an unconditional contribution to the overall development strategy of the national health care. PMID- 23808281 TI - [Contemporary dietotherapy of the irritable bowel syndrome]. AB - Irritable bowel syndrome (IBS) is the most prevalent functional disease of the gastrointestinal tract. This highly prevalent condition is best diagnosed by assessing the constellation of symptoms with which patients present to their physicians. Because some critics have previously questioned whether irritable bowel syndrome and other functional gastrointestinal disorders truly exist because they do not have defining structural features, the Rome Foundation fostered the use of symptom-based criteria for universal use. In most cases treatment is reduced to symptomatic therapy because a lot of unknown in pathogenesis by irritable bowel syndrome. Irritable bowel syndrome leads to decrease of quality of life of the patients and could be one of the reasons of patients' disability. Food is believed by patients promotes symptoms and the diet or avoiding specific food can reduce symptoms. Possible role of different food and microbiota in the pathophysiology of irritable bowel syndrome, as well as the data from randomized, controlled clinical trials dedicated to the effects of diet in irritable bowel syndrome are summarized and discussed in this review. The efficacy of the diet, enriched by fiber, prebiotics, probiotics, peppermint oil, curcumin and vitamin B6 in irritable bowel syndrome patients was shown in numerous studies. In some studies restriction in consumption of fermented carbohydrates, coffee and alcohol, as well as diet with elimination IgG-sensed food was also shown to be effective in irritable bowel syndrome. Food intolerances, defined as non-toxic non-immune adverse reactions to food, include reactions to bioactive chemicals in foods and metabolic reactions to poorly absorbed dietary carbohydrates. New dietary approaches like polyunsaturated fatty acids intake correction and the low tryptophan intake are discussed. PMID- 23808282 TI - [Analysis of interrelation between lifestyle, diet and anthropometrical characteristics and health of persons, working in the conditions of especially harmful production]. AB - OBJECTIVE: To estimate the relationship between lifestyle, anthropometrical characteristics, nutrition and health of persons working with sources of ionizing radiation. MATERIALS AND METHODS: 158 persons, selected by sampling method in compliance with the representation were examined. Nutritional status was assessed by frequency method. Anthropometrical measurements were performed under standard conditions with the use of scales and stadiometer with subsequent calculation of body mass index (BMI), and a tape to measure circumference of waist and hips. The level of physical activity was assessed based on a survey of time spent by respondents on the various types of physical activity on weekdays and weekends. Questionnaires included special sections that characterize the socio-demographic and economic characteristics, health status, habits, and occupations by physical culture and sport. The data were processed by the computer program SPSS-18. RESULTS: The prevalence of overweight and obesity at the age of 40 years was 70%. Also we was found that 98.7% of respondents have a low and very low energy expenditure. The actual nutrition of the surveyed contingent includes elements that are risk factors for cardiovascular disease, diabetes and other metabolic disorders. PMID- 23808283 TI - [Content of mineral elements in the diet of students of physical education faculty]. AB - Research of the diet of students of the Faculty of Physical Education found discrepancy of caloric content and correlation of macro- and micronutrients to physiological norms accompanied by a deficiency of some mineral elements. Thus, this research found discrepancy of a diet in caloric content and correlation of macro- and micronutrients to physiological norms. Calorie deficiency in both groups is caused for lack of all macro- and micronutrients, but mostly for lack of carbohydrates with an average glycemic index, fruit, and vegetables that have prebiotic properties and mineral-rich elements. Deficiency in the diet of young men 9.6% of the total protein and 23.5% of carbohydrates was accompanied for lack 15.5% of calcium. In the group of girls the results showed a decrease of the required amounts of calcium, magnesium and iron of 36.4; 7.5 and 1.5% respectively, which was displayed against a background of reducing the consumption of the total protein 25.1 and 36.0% of carbohydrates. As a result, basic nutrition of students practicing sports requires rationalization and adjustment. To improve the biological value of the diet it is advisable for students to use daily dairy products and other sources of animal protein in their diets. It is also necessary to introduce fruit and vegetables as a source of dietary fibers and mineral elements. Created in both groups deficiency of calcium and biologically high-grade proteins of animal origin can be eliminated by various dairy products in which calcium and phosphorus are in easily digestible form and in a balanced quantity. Despite the considerable amount of calcium in many foods (meat, bread, cereals, vegetables) calcium is assimilated with difficulty from these products. The exception is the calcium of milk, curd, cheese and other dairy products. The ration between calcium and phosphorus in milk is 1:1-1.4:1. For example, taking 0.5 liters of milk provides 600 mg of assimilable calcium intake. PMID- 23808284 TI - [Myocardial infarction morbidity and mortality in the Russian Federation in 2000 2011]. AB - AIM: To study trends in myocardial infarction (MI) morbidity and mortality in the Russian Federation in 2000 to 2011. MATERIALS AND METHODS: The 2000-2011 official statistical data of the Federal State Statistics Service and the Ministry of Health of Russia were used to analyze MI morbidity and mortality rates among urban and rural populations. Sex- and age-specific mortality rates were estimated. The number of IM morbidity cases and deaths were analyzed in absolute values and per 100,000 population (rates). The causes of MI morbidity and mortality were coded according to the International Classification of Diseases, Tenth Revision. RESULTS: According to the official statistical data, there is a small proportion of MI mortality in the structure of coronary heart disease mortality with a relatively stable incidence of MI and a low variability in its cases. MI death rates are much higher in males, particularly in able-bodied ones. Recently there have been an increasing number of deaths from MI among females in old age groups. Mortality from recurrent MI is recorded to show a 33.7% increase from 2000 to 2011. In-hospital mortality remains high (15-16%), with its high rates (40.4%) within 24 hours of admission to hospital. CONCLUSION: To more completely and objectively estimate MI morbidity and mortality rates and treatment quality in patients with this disease in the Russian Federation, it is expedient to conduct epidemiological surveys and to comparatively analyze the results of monitoring the regional vascular centers, the data of the Federal Acute Coronary Syndrome Registry, and the results of the auditing the vascular centers by the specialists of the Russian Cardiology Research-and-Production Complex. PMID- 23808285 TI - [How to validate the symptoms of pulmonary thromboembolism: how diagnostic scales help]. AB - AIM: To detect the most important clinical symptoms suggesting pulmonary thromboembolism (PTE) and to determine the diagnostic value of the scales used to estimate the likelihood of its occurrence. MATERIALS AND METHODS: The prospective study included 130 patients admitted to hospital with a diagnosis of PTE and a referral for a surgery clinic. Scores of the likelihood of PTE were estimated using the Canada and Geneva scales in all the patients on admission. RESULTS: In all the patients with suspected PTE, the Canadian and revised Geneva scores averaged 4.2 +/- 0.48 and 6.21 +/- 0.5, respectively. These scores correspond to the intermediate clinical probability of PTE. In 96 patients whose diagnosis was verified by instrumental studies, the Canadian and Geneva scores were 4.41 +/- 0.57 and 6.17 +/- 0.63, respectively, which was also consistent with the intermediate clinical probability of PTE. In 34 patients, whose diagnosis of PTE was ruled out, the average scores did not virtually differ from those in the patients with the verified diagnosis and were 6.14 +/- 1.3 and 4.18 +/- 0.87, respectively. The area under characteristic curve for the Canadian scale was 0.428 and that for the Geneva scale was 0.512. With the use of a two-level interpretation system, a total of more than 6 Canadian scores and 10 Geneva scores suggested that there was a high probability of PTE. CONCLUSION: The investigation indicated the low value of integral systems for estimating the likelihood of PTE in the total population of patients with this disease. The authors recommend the two-level interpretation system, in which a total of more than 6 Canadian scores and 10 Geneva scores were identified with a high probability (up to 80%) of PTE. PMID- 23808286 TI - [Informative value of multislice spiral computed tomography in identifying myocardial perfusion defect in patients with acute myocardial infarction]. AB - AIM: To estimate the informative value of multislice spiral computed tomography (MSCT) in the diagnosis of myocardial infarction (MI). SUBJECTS AND METHODS: The study enrolled 171 patients with acute coronary syndrome (ACS), including 121 patients diagnosed with acute ST-segment elevation MI (STEMI), 19 with non-STEMI, and 31 with unstable angina. A comparison group consisted of 52 patients with stable coronary heart disease (CHD) and a control group comprised 17 patients without CHD. Intravenous contrast-enhanced MSCT was performed using a 64-spiral CT scanner. MSCT was carried out in the patients with ACS on days 3-5 of the onset of a pain attack and in the other patients electively. It was redone in 44 patients with acute MI (AMI) 6 months after a primary examination. RESULTS: Left ventricular (LV) perfusion defect was imaged in 94.3% of the patients with AMI and in 10% of those with unstable angina. LV contrast defects were undetectable in the patients from the stable CHD and control groups. The sensitivity, specificity, prognostic value of a positive result, negative prognostic value of a result, and accuracy of MSCT in the diagnosis of MI were 94.3, 97.1, 97.8, 92.5, and 96.70%, respectively. In the patients with STEMI, myocardial perfusion defect was larger and transmural perfusion defect was more common than in those with non-STEMI. Comparison of the values of myocardial perfusion defect size and myocardial density according to the data of primary and repeat MSCT revealed no statistically significant differences: 2.0 (0.50; 5.45) and 1,8 (0.35; 5.00) cm3 (p = 0.15); 41.7 +/- 10.2 and 46.1 +/- 12.2 HU, respectively (p = 0.07). CONCLUSION: Contrast-enhanced MSCT allows visual and quantitative assessments of myocardial perfusion defect in patients with ACS. Myocardial perfusion defect from MSCT data suggests previous MI with a high probability, but does not permit the determination of the duration of the disease. PMID- 23808287 TI - [Diagnostic capabilities of cardiac magnetic resonance imaging in patients with inflammatory cardiomyopathy: comparison of its results with endomyocardial biopsy data and clinical picture]. AB - AIM: To evaluate the diagnostic capabilities of cardiac magnetic resonance imaging (MRI) in patients with inflammatory cardiomyopathy (ICMP) and to compare its results with endomyocardial biopsy (EMB) data and clinical and laboratory parameters. SUBJECTS AND METHODS: Cardiac MRI was performed using the "Lake Louise Criteria" in 51 patients with ICMP and a 4.1 +/- 3.4-year history of chronic heart failure (CHF). EMB was carried out in 25 patients. Their clinical state was evaluated by the results of a 6-minute walk test and by a clinical assessment scale; N-terminal pro-brain natriuretic peptide levels were estimated. All the patients received the recommended therapy for CHF. RESULTS: Myocardial areas of delayed enhancement were found in 20 (39%) patients. Myocardial edema or early contrast enhancement was not recorded in any case. An immunohistological study revealed myocardial inflammation in 12 (48%) patients. Six patients with chronic myocarditis and 4 patients without myocarditis had delayed-phase contrast enhancement areas. There was a statistically significant correlation of the contrast-enhanced myocardial volume with the frequency of single and paired ventricular premature beats (r = 0.66; p = 0.002 and r = 0.54; p = 0.01). CONCLUSION; The patients with delayed enhancement are at high risk of ventricular tachycardia. The severity of CHF is uncorrelated with the contrast-enhanced myocardial volume. Delayed enhancement is unrelated to the activity of myocardial inflammation, as evidenced by the immunohistological study. PMID- 23808288 TI - [Comprehensive magnetic resonance imaging for breast cancer]. AB - AIM: To enhance the efficiency of diagnosis of breast tumors by comprehensive magnetic resonance imaging (MRI) involving dynamic contrast-enhanced magnetic resonance mammography (MRM) and magnetic resonance spectroscopy (MRS). SUBJECTS AND METHODS: Eighty-seven women aged 32 to 75 years with breast neoplasms were examined. MRM was performed on a Philips Achieva 3.0T TX scanner. The MRI protocol consisted of axial fat-suppressed T1- and T2-weighted spin-echo images and 8 postcontrast dynamic series. Changes in contrast-enhanced MRI of breast cancer (BC) were estimated by constructing the signal intensity-time curves. MRS was carried out using a PRESS sequence. RESULTS: Dynamic MRM determined type III signal intensity-time curve in 83.9% of the patients with BC and type II curve in 16.1% of those with breast malignancies and in 33.3% of those with breast fibroadenomas. Type I signal intensity-time curve was identified in 66.7% of the cases of fibroadenomas. Elevated choline concentrations in the malignancies were detected in 17.7% of cases. Their tumors were larger than 2 cm. The choline peak in the malignancies could not be revealed in the other cases, which was associated to the large voxel size exceeding the mass size. There was a drastic fall in the signal-to-noise ratio with smaller voxel sizes. Furthermore, higher choline levels were determined in 9.5% of the fibroadenoma cases. Comparison of MRS findings before and after contrast injection revealed the advantage of the latter, which is primarily attributed to the more accurate voxel position on the tumor than that during non-contrast-enhanced MRS. CONCLUSION: Dynamic intravenous contrast-enhanced MRM is an effective method for the differential diagnosis of breast masses. MRS cannot be included in the standard study protocol for women with breast masses for the present. PMID- 23808289 TI - [Thromboembolism of pulmonary artery branches from the right cardiac chambers]. AB - AIM: To reveal possible predictors of thrombosis in the right cardiac chambers and to build a mathematical model to estimate the probability of thrombi in them in patients with thromboembolism of the pulmonary artery branches. MATERIALS AND METHODS: The data of autopsy protocols and case histories were analyzed in'157 patients in whom the source of thromboembolism had been right cardiac chambers according to postmortem evidence. A logistic regression method was used to create a probability model. RESULTS: The findings were used to select 69 indicators- possible provokers of thrombosis and accordingly predictors of thrombi in the right cardiac chambers. A mathematical model--a formula to estimate the probability of thrombi in the right cardiac chambers--was made. It comprised 8 indicators: weight, height, pericardial fluid, right atrial dilatation, right ventricular wall thickness, a left or right ventricular apical scar, a concomitant inflammatory process, and concurrent diabetes mellitus. CONCLUSION; The application of the developed formula may assist in identifying a group of patients who have the highest probability of thrombi in the right cardiac chambers and accordingly must undergo a more in-depth examination. PMID- 23808290 TI - [Systemic vasculitides: diagnostic stages]. AB - AIM: To present systemic vasculitis (SV) diagnostic stages. SUBJECTS AND METHODS: Immunological and hemostatic parameters were determined, vascular scanning, histological and immunomorphological studies were performed in 360 patients. RESULTS: The main diagnostic searching stages were presented, which could reveal the key clinical signs of vasculitis and systemacy of the process, differentiate primary and secondary vasculitides, conduct clinical and instrumental studies, detect specific markers of vascular wall injury, perform a morphological study of biopsy specimens, identify the major pathogenic components of vascular bed lesion, define the possible etiology and form of vasculitis, and make a nosological diagnosis. CONCLUSION: The proposed diagnostic steps will be able to specify the nosological form of SV and the activity of the process and to define approaches to pathogenetic therapy. PMID- 23808291 TI - [The International Classification of Functioning, Disability, and Health in the practice of a sociomedical examination service for internal diseases]. AB - The paper gives the International Classification of Functioning, Disability, and Health (ICF), interactions between health changes, the personality and social factors of an individual with therapeutic diseases to define disability criteria and a scientific rationale for the necessity and scope of rehabilitative measures through public health and social protection organizations. PMID- 23808292 TI - [Genetic markers for trait anxiety as one of the risk factors for cardiovascular diseases (WHO-MONICA program, MONICA-psychosocial subprogram)]. AB - AIM: To determine an association between trait anxiety (TA) and variable number tandem repeat (VNTR) polymorphisms in the DRD4 and DAT genes, as well as the prevalence of TA and the risk of cardiovascular diseases (CVD) in 25- to 64-year old males with TA. SUBJECTS AND METHODS: A representative sample of 25 to 64-year old males (n = 2149) was examined within the framework of the WHO MONICA program, MONICA-psychosocial subprogram, in 1984, 1988, and 1994. All new-onset arterial hypertension (AH), myocardial infarction (MI), and stroke cases were registered throughout the follow-up study (1984-2008). Spielberger's test was used to estimate the level of TA. The Cox proportional regression model was applied to assess a relative risk. RESULTS: The high level of anxiety (HLA) was 50.9% in the open population of 25 to 64-year-old males. The DRD4 genotype 4/6 and DAT genotype 9/9 were significantly associated with HLA. The latter increased the risk for CVD: it was maximal for AH and stroke within the first five years and for MI within 10 years. CONCLUSION: HLA was significant in the Novosibirsk open population of 25 to 64-year-old males. It is substantially associated with certain VNTR polymorphisms in the DRD4 and DAT genes and considerably increases the risk of CVD. PMID- 23808293 TI - [Cardiorenal syndrome and prerenal azotemia in patients with acute hypertensive encephalopathy]. AB - AIM: To estimate changes in renal function in patients with acute hypertensive encephalopathy (AHE) during standard inpatient antihypertensive therapy. SUBJECTS AND METHODS: Patients were selected for the trial in the cardiology and admission units of a Perm hospital. The group included 60 patients with AHE. The patients received inpatient antihypertensive therapy for 10-14 days. Within the first 2 hours, enalaprilate 1.25 mg was intravenously injected, by monitoring blood pressure. After 6 hours, the patients were given enalaprilate tablets 20 mg b.i.d. plus hydrochlorothiazide 12.5 mg (Subgroup 1) or nifedipine 60 mg plus hydrochlorothiazide 12.5 mg (Subgroup 2). The laboratory parameters of kidney function were measured twice: on admission to and before discharge from hospital. Plasma creatinine and urea concentrations were estimated. Glomerular filtration rate (GFR) and urea/creatinine ratio were calculated. The patients were found to have proteinurea, low GFR, high plasma creatinine concentrations, and increased urea/creatinine ratio. RESULTS: Transient proteinuria was observed in 25% of the patients with AHE within the first 24 hours of the disease. The proportion of patients with lower GFR was unchanged during a 2-week treatment period (20 and 16%, respectively; p = 0.22). There was a rise in the proportion of patients with higher urea/creatinine ratio (83 and 95%, respectively; p = 0.006). CONCLUSION: The course of AHE is complicated by cardiorenal syndrome (CRS) with transient proteinuria and low GFR, as well as by prerenal azotemia (PRA). The number of patients with PRA increased after 2-week conventional inpatient antihypertensive therapy (enalaprilate + hydrochlorothiazide 12.5 mg or nifedipine + hydrochlorothiazide 12.5 mg). PMID- 23808294 TI - [Renal functional state in patients with myocardial infarction]. AB - AIM: To study renal dysfunction in patients with myocardial infarction (MI). SUBJECTS AND METHODS: 670 case histories of patients diagnosed with acute coronary syndrome, including 369 (55.8%) men and 292 (44.2%) women at the age of 33 to 85 years (mean age 64.8 +/- 11.7 years), were retrospectively studied. The authors considered comorbidities and analyzed complaints, history data, and the results of physical examinations, biochemical blood tests for plasma glucose, troponin, MB fractions of creatine phosphokinase and creatinine, and cholesterol in all the patients. Instrumental studies involved electro- and echocardiography. Glomerular filtration rate (GFR) was estimated using the MDRD formula. The patients were divided into groups according to GFR values: 1) > 90 ml/min/1.73 m2; 2) 60 to 89 ml/min/1.73 m2; 3) 30 to 59 ml/min/1.73 m2; 4) less than 30 ml/min/1.73 m2. RESULTS: Most patients were found to have a moderate or significant reduction in kidney function. Worsening renal function in patients with MI was associated with advanced patient age, the lower proportion of men in the patient structure, the higher prevalence of concomitant cardiovascular diseases, such as arterial hypertension, chronic heart failure, and prior MI, and diabetes mellitus. CONCLUSION: The findings suggest that kidney dysfunction is of essential value in developing the multiplicity of comorbidities in patients with MI. The wide introduction of a GFR calculating method in daily medical practice will be able to adequately and timely identify renal filtration function and to make a correction into a treatment regimen, thus decreasing the number of poor outcomes. PMID- 23808295 TI - [Intraosseous blocks in the treatment of symmetrical distal diabetic polyneuropathy]. AB - AIM: To evaluate the efficiency of intraosseous blocks (IOB) in the combination treatment of patients with painful diabetic symmetrical distal polyneuropathy (DSDP) of the lower limbs. SUBJECTS AND METHODS: Seventy-eight patients with painful DSDP were examined. Its diagnosis was verified by neurological examination, assessments of the data of the neuropathic pain diagnostic (DN4) questionnaire and electroneuromyography (ENMG). The pain syndrome was evaluated with a combined visual analogue scale (VAS). The degree of DSDP was estimated using the total symptoms score (TSS) and the neuropathy impairment scale-lower limbs (NIS-LL) scale. The Spielberger questionnaire was used to evaluate reactive and trait anxiety and the Beck inventory was employed to estimate the level of depression. A study group comprised 40 patients receiving IOB as part of the standard treatment. A control group consisted of 38 patients taking oral amitriptyline as a component of the standard treatment. Therapeutic effectiveness was evaluated, by changing the neurological status, trends in VAS, TSS, and NIS LL scores, and data of psychological questionnaires and ENMG before and after the course of therapy and 1, 3, and 6 months after treatment. RESULTS: IOB was found to be highly effective in pain syndrome, affective disorders, and other manifestations of DSDP; moreover, the therapeutic effect persisted within 6 months after treatment. PMID- 23808296 TI - [Determination of the scope of cerebral stroke and myocardial infarction rehabilitation in accordance with the International Classification of Functioning, Disability, and Health]. AB - AIM: To determine the scope of rehabilitation in the evaluation of activity limitations and participation restrictions in patients with cerebral stroke in accordance with the International Classification of Functioning, Disability, and Health (ICF) and to compare the findings with respective disorders in patients with myocardial infarction (MI) in the early recovery period during inpatient rehabilitation. SUBJECTS AND METHODS: Activity limitations and participation restrictions were assessed in accordance with the ICF approved by the WHO in 2001. Patients with stroke (Group 1) and those with MI (Group 2) were examined. In Groups 1 and 2, the mean age was 70.3 +/- 7.4 and 63.6 +/- 11.6 years, respectively. A 5-point activity and participation rating scale was used. RESULTS: The patients with stroke had the most difficulties (3-4 scores) in the following domains: mobility, learning, knowledge application, common tasks and demands, self-care. Most patients who had experienced MI were ascertained to have moderate (2 scores) impairments in mobility, solution of common tasks and demands, learning, and applying knowledge. Comparison of both groups established that the stroke patients had significantly more marked activity limitations and participation restrictions, which was associated with skill acquisition on learning and applying knowledge, with carrying out common tasks and demands, communication, mobility, self-care, interpersonal interactions and relationships. CONCLUSION: The ICF provides a more detailed evaluation of activity limitations and participation restrictions in patients with circulatory system diseases, which is of great importance in determining the scope of rehabilitation. The patients with stroke have been found to have more marked activity limitations and participation restrictions than those with MI. Therefore, they need a more scope of rehabilitation measures implemented by a rehabilitation team that includes a larger number of specialists. PMID- 23808297 TI - [Metabolic correction of dyslipidemia in patients with nonalcoholic fatty liver disease as a new therapy policy]. AB - AIM: To study the impact of infusion therapy with the metabolic modulator remaxol on lipid metabolic parameters and target organ (liver, kidney) function in metabolic syndrome (MS). SUBJECTS AND METHODS: The investigation enrolled 90 patients (54 men and 36 women) with primary nonalcoholic steatohepatitis that was associated with insulin-resistance and MS; their age was 21 to 77 years. Every day the study group patients (n = 50) took as a component of combination therapy the metabolic hepatoprotective modulator remaxol intravenously in a dropwise manner in a dose of 400 ml once daily; the comparison group patients (n = 40) received ademetionine 400 mg diluted in 400 ml of isotonic sodium chloride. The duration of infusion therapy was 11 days. RESULTS: Infusion therapy with remaxol caused a pronounced blood lipid composition-regulating effect, by reducing the level of major atherogenic lipids (total cholesterol, triglycerides) and improving liver function and renal nitrogen-excreting and filtration function in patients with Stage IV diabetic nephropathy in the presence of MS. CONCLUSION: Therapy with the metabolic hepatoprotective modulator remaxol ensures reliable metabolic control and multifactorial correction of risk factors of organ lesions in MS: cardio-, hepato-, and nephroprotection. PMID- 23808298 TI - [A possibility to interchange heart rate-slowing therapy with ivabradine and atenolol in patients with stable angina pectoris]. AB - AIM: To evaluate the efficiency and safety of an interchange of atenolol and ivabradine in patients who had stable angina pectoris without myocardial infarction in the history and left ventricular (LV) systolic dysfunction. SUBJECTS AND METHODS: The trial enrolled 31 patients less than 70 years of age who had sinus rhythm, functional classes II-I angina on exertion without clinical signs of LV systolic dysfunction. At the first stage, 15 patients were randomized to ivabradine with its dose titration during 2 weeks; the other 16 patients were to atenolol. At the second stage, 10 patients were switched from ivabradine used at Stage 1 to atenolol 100 mg/day, other 10 patients who were on atenolol were switched to ivabradine 15 mg/day, and 11 patients received combination therapy with ivabradine + atenolol in half doses. All the patients underwent treadmill exercise testing and applanation tonometry. RESULTS: Atenolol, unlike ivabradine, lowered brachial blood pressure and unchanged the central index of its increment, which was associated with LV systolic elongation. On the contrary, ivabradine decreased the central increment index and exerted no significant effect on the duration of LV systole. By comparatively lowering heart rate, ivabradine as well as atenolol reduced pulse wave propagation velocity. CONCLUSION: If ivabradine or atenolol is insufficiently effective or poorly tolerated, there may be an interchange of the drugs, as well as their combination in half doses without substantially affecting their therapeutic action in patients with stable angina pectoris without LV systolic dysfunction. PMID- 23808299 TI - [Current recommendations for the diagnosis of chronic pancreatitis in general clinical practice]. AB - The paper gives practical recommendations based on the provisions of a number of foreign national guidelines for the diagnosis of chronic pancreatitis (CP). There is virtually no evidence for Class I database for its diagnosis. Despite an inadequate scientific rationale, the review of these international guidelines has brought together the basic available data in the context of the current global standards for the diagnosis of CP. PMID- 23808300 TI - [Efficiency of using the anxiolytic adaptol in the combination therapy of arterial hypertension in women]. AB - AIM: To evaluate the effect of the anxiolytic adaptol on blood pressure (BP) level in its concurrent use with a fixed dose angiotensin-converting enzyme (ACE) inhibitor/diuretic combination on quality of life and on the correction of psychoautonomic disorders. SUBJECTS AND METHODS: The trial included women aged 40 60 years with the verified diagnosis of Stage 2B arterial hypertension (AH), risk 2, and a disease history of at least 5 years. A study group received a fixed dose ACE inhibitor/diuretic combination once daily and adaptol 500 mg twice daily for 2 months. A comparison group had only the fixed dose ACE inhibitor/diuretic combination once daily without adaptol. RESULTS: By the end of one-month therapy, a more pronounced statistically significant BP reduction was achieved in the study group receiving the ACE inhibitor/diuretic combination and adaptol than in the comparison group. The quality of life was improved in 6 of the 8 items in the study group and in 3 items in the comparison group. The total scores of psychoautonomic disorders decreased from 48.7 to 25.8 in the study group and from 47.8 to 38 in the comparison one. CONCLUSION: It is expedient to combine antihypertensive therapy and anxiolytics in female hypertensive patients with autonomic dystonic disorders. PMID- 23808301 TI - [Edemas in chronic lower extremity venous insufficiency: clinical manifestations, medical and surgical treatments]. AB - The review presents data on the causes and pathogenesis of lower extremity (LE) edemas with special emphasis on the edemas occurring in chronic LE venous insufficiency. It discusses the possibilities of noninvasive and surgical treatments for LE edemas in venous insufficiency. Particular attention is given to the possibilities of phlebotonic therapy. PMID- 23808302 TI - [Ghrelin and its role in health and disease]. AB - The paper provides a review of the present-day literature on the role of the hormone ghrelin discovered in 1999. PMID- 23808303 TI - [Anemia and gastrointestinal tract diseases]. AB - The paper considers the causes of iron- and cyanobalamin-deficiency anemias caused by gastrointestinal tract (GT) diseases, among which malabsorption along with loss of these nutrients through the GT is of great importance. The paper reflects the current views of the pathogenesis of deficiency anemias that develop in gluten-sensitive celiac disease and atrophic gastritis. Among the atrophic gastritides, there are two forms caused by autoimmune processes and long-term Helicobacter pylori persistence, whose treatment is an effective measure in refractory anemia. The paper gives the provisions of the Russian Gastroenterology Association Guidelines (2012) for the management of H. pylori infection, which are based on Maastricht IV consensus (2010). PMID- 23808304 TI - [A variety of extrahepatic manifestations of chronic viral hepatitis B and C: basic treatment principles]. AB - Chronic viral hepatitides B and C are systemic diseases with a great number of extrahepatic manifestations caused by different immune abnormalities due to viral replication in and outside the liver and to the direct pathological effects of viral particles. Many of them can be the only manifestation of the infection and come to the foreground in its clinical picture, by determining the prognosis of the disease. PMID- 23808306 TI - Effect of fullerene C60 on ATPase activity and superprecipitation of skeletal muscle actomyosin. AB - Creation of new biocompatible nanomaterials, which can exhibit the specific biological effects, is an important complex problem that requires the use of last accomplishments of biotechnology. The effect of pristine water-soluble fullerene C60 on ATPase activity and superprecipitation reaction of rabbit skeletal muscle natural actomyosin has been revealed, namely an increase of actomyosin superprecipitation and Mg2+, Ca(2+)- and K(+)-ATPase activity by fullerene was investigated. We conclude that this finding offers a real possibility for the regulation of contraction-relaxation of skeletal muscle with fullerene C60. PMID- 23808305 TI - [The calix[4]arene C-107 is highly effective supramolecular inhibitor of the Na+,K(+)-ATPase of plasma membranes]. AB - The inhibition of the Na+,K(+)-ATPase activity of the myometrium cell plasma membranes with calixarene C-107 (5,17-diamino(2-pyridyl) methylphosphono-11,23-di tret-butyl-26,28-dihydroxy-25,27-dipropoxycalix[4]arene) was investigated. It has been shown that calixarene C-107 reduced the Na+,K(+)-ATPase activity more efficiently than ouabain did, while it did not practically influence the "basal" Mg(2+)-ATPase activity of the same membrane. The magnitude of the cofficient of inhibition I0.5 was 33 +/- 4 nM, Hill coefficient was 0.38 +/- 0.06. The model calixarene C-150--the calixarene "scaffold" (26,28-dihydroxy-25,27 dipropoxycalix[4]arene), and the model compound M-3 (4-hydroxyaniline(2 pyridine)methylphosphonic acid)--a fragment of the calixarene C-107, had practically no influence on the enzymatic activity of Na+,K(+)-ATPase and Mg(2+) ATPase. We carried out the computer simulation of interaction of calixarenes C 107 and the mentioned model compound with ligand binding sites of the Na+,K(+) ATPase of plasma membrane and structure foundation of their intermolecular interaction was found out. The participation of hydrogen, hydrophobic, electrostatic and pi-pi (stacking) interaction between calixarene and enzyme aminoacid residues, some of which are located near the active center of Na+,K(+) ATPase, was discussed. PMID- 23808307 TI - [A new mannose-specific lectin from daylily (Hemerocallis fulva L.) rhizome: purification and properties]. AB - A new lectin was purified from the daylily (Hemerocallis fulva L.) with the yield of approximately 10 mg per kg of fresh plant rhizome. The purification procedure was based on application of the affinity chromathography on the column with yeast mannan and the ion-exchange chromatography on the column with DEAE-Toyopearl. The lectin possessed low affinity for alpha-methyl-D-mannopyranoside, D-fructose, D turanose and 2-acetamido-D-galactopyranose and hight affinity for the yeast mannan. The lectin bound with greatly less affinity for the mannose-containig glycoproteins, such as ovoalbumin, ovomucoid and horseradish peroxidase. According to the results of electrophoresis in 20% DSNa-PAGE, the lectin consists of subunits of 12 kDa molecular weight. According to the results of gel chromatography on the Toyopearl HW-55, the lectin's molecular weight is 48 kDa. It agglutinated rabbit erythrocytes very well, while rat and guinea-pig erythrocytes were agglutinated worse, and human erythrocytes were not agglutinated at all. Lectin's dialysis against 1% EDTA or heating to 60 degrees C for 60 min did not stop its hemagglutinating activity. PMID- 23808308 TI - [Effect of free and polymer carrier encapsulated doxorubicin towards HCT116 cells of human colorectal carcinoma]. AB - Development of novel nanoscale functionalized carriers is nowadays one of the most urgent problems in cancer treatment. The aim of our study was to compare the antineoplastic effect of free doxorubicin and its complex with a nanoscale polymeric carrier towards HTC116 colorectal carcinoma cells. It was established that application of the complex of poly(5-tret-butylperoxy)-5-methyl-1-hexene-3 in-co-glycydyl metacrylat)-graft-polyethyleneglycol (poly(VEP-GMA-PEG)-graft PEG), where VEP--5-tret-butylperoxy)-5-methyl-1-hexene-3-in; GMA--glycydyl metacrylat; graft-PEG--graft-polyethyleneglycol accordingly, functionalized with phosphatidylcholine for doxorubicin delivery increased 10 times the efficiency of cytotoxic action of this drug, as compared wich such efficiency in case of the action of free doxorubicin. The encapsulated form of doxorubicin caused more intensive cleavage of the reparation enzyme PARP and longer delay in G2/M cell cycle arrest, compared to such effects of free doxorubicin. The developed carrier itself is non-toxic to the used mammalian cells and does not cause impairment in their cell cycle. A deletion in both alleles of p53 gene did not affect the antineoplastic action of doxorubicin that was immobilized on the nanoscale carrier. Thus, p53-dependent signaling pathways are not involved in the cytotoxic action of doxorubicin-carrier complex. It is suggested that novel nanoscale polymeric carrier poly(VEP-GMA-PEG)-graft-PEG functionalized with phosphatidylcholine could be a promising carrier for targeted delivery of anticancer drugs. PMID- 23808309 TI - [Organ-specific antitoxic effects of N-stearoylethanolamine in male mice with Lewis carcinoma under doxorubicin intoxication]. AB - With the introduction of doxorubicin into mice with Lewis carcinoma in the heart and liver tissues and kidney the organ-antitoxic effects of N stearoilethanolamine (NSE) were found, which depended on its concentration. Administration of doxorubicin to male mice leads to an increase in the level of urea and creatinine, as well as activation of ALT in blood plasma. Introduction of NSE resulted in normalization of these parameters to the level of intact animals. In the heart tissue doxorubicin has multidirectional effects on the activity of antioxidant enzymes, in particular it decreases the activity of catalase and superoxide dismutase activity increases. Introduction of NSE normalizes these two indicators. It was found that tumor growth leads to an increase in the activity of glutathione peroxidase and superoxide dismutase. Introduction of NSE normalizes activity of these enzymes. Doxorubicin causes an increase in catalase activity in the kidney of mice with tumour, NSE prevented the increase in the activity of the above enzyme. The cancer process leads to increased levels of catalase activity in the liver of tumour-bearing mice, the introduction of NSE decreases the enzyme activity. PMID- 23808310 TI - [Physiological prion and activity of plasma membrane Na+,K(+)- and Ca(2+)-ATPase in the medulla oblongata cells of rats of different ages]. AB - Based on the results of immunohistochemical analysis of the rat medulla tissue the localization of physiological prion has been established. Specifically, in rats aged one month they are placed in the gray matter near the bodies of neurons and mikrohliocytes and in animals of six and thirty months--in olive kernel core and upward path bodies. Physiological prion is localized along the nerve processes and is absent in the neuron bodies. In the medulla oblongata of animals aged six months its amount is the highest compared to animals of other age. The activity of plasma membrane ATPases in this tissue decreases with age, the content of sodium and calcium ions increases, while that of potassium is almost unchanged. PMID- 23808311 TI - [Mechanism of hepatoprotective action of methionine and composition "Metovitan" against a background of antituberculosis drug administration to rats]. AB - Oral administration of antituberculosis drugs to rats for 60 days in doses that are equivalent to clinical ones, causes changes in mRNA levels expression of liver cytochrome P-450 isoforms CYP3A2, CYP2C23, CYP2E1 and pro- and antioxidant state. Experimental composition "Metovitan" given with anti-TB drugs provided a correction of these abnormalities, that is evidenced by modulation of the level of CYP3A2, CYP2C23, CYP2E1 gene expression and antioxidant activity, inhibition of lipid peroxidation. "Metovitan" normalizes the enzymatic activity and content of total billirubin in the blood serum, shows high hepatoprotective properties, exceeding the efficiency of methionine. PMID- 23808312 TI - [Stress-responsive systems in the rat pancreas upon long-term gastric hypochlorhydria and administration of multiprobiotic "Symbiter"]. AB - The intensity of free-radical processes upon long-term omeprazole-induced hypoacidity in the rat pancreas was investigated. Significant violation of oxidative-antioxidative balance in pancreatic tissue upon gastric hypochlorhydria was established: overproduction of superoxide anion, quantitative changes of lipid functional groups, increased level of lipid peroxidation products, augmentation of xanthine oxidase, superoxide dismutase and glutathione transferase activity, as well as depletion of catalase, glutathione peroxidase activity and reduced glutathione content. The inflected expression of Cckbr gene in the rat pancreas upon these conditions was also observed, thus suggesting an increased risk of pathological changes development in the gland. Abovementioned parameters were only partially restored to control values in the case of simultaneous administration of multiprobiotic "Symbiter" with omeprazole, thus indicating the ability of this preparation to efficiently counteract the development of oxidative damages in pancreatic tissues upon long-term hypoacidic conditions. PMID- 23808313 TI - [Peptide composition of extracts of cryopreserved pigs' and piglets' heart fragments]. AB - It is known that extracts of cryopreserved organ fragments of pigs and piglets stimulate the processes of reparative regeneration. Therefore, the study of the extracts is essential for understanding the mechanism of their biological effects. In this paper was studied the molecular mass distribution of peptides in the extracts of cryopreserved heart fragments of pigs' and piglets', i.e., the chromatograms of pigs' heart extracts show 3 picks, whilst piglets' heart extract show 6 picks. The peculiarity of pigs' heart extracts is the absence of peptides with molecular mass of 10,000 and more. The differences in the intensity of extracts fluorescence prove that the peptides in pigs' heart extracts contain greater amount of tryptophan residues accessible for solvent. The synchronous fluorescence spectra of extracts were obtained which allows the identification of extract without assessment of their components. Results shown in this research could be used for control and standardization of heart extracts peptide composition under investigation of their biological quality. PMID- 23808314 TI - [The composition of lipids and lipid peroxidation in the pancreas of quails exposed to nitrates and correction by the amaranth's seeds]. AB - Researches of features of lipid composition, functioning of the system of antioxidant defense, maintenance of lipid peroxidation products in the quail's pancreas on the early postnatal ontogenesis stages are conducted for actions of nitrates and feeding with amaranth's seeds in mixed fodder. The arrival of nitrates in the organism of quails results in the decline of general lipids maintenance and nonetherified fat acids in the pancreas. Using of amaranth's seeds in mixed fodder on the background of the nitrate loading results in the increase of activity of the enzimes system of antioxidant defence, the growth of general lipid level in the quail's pancreas. Thus in correlation with separate classes of lipid maintenance of cholesterol goes down for certain, whereas the maintenance of triacylglycerols and ethers of cholesterol rises. The results obtained in the researches show the ability of amaranth's seeds to avert oxidative stress in quail's pancreas under nitrates influence. PMID- 23808315 TI - Self-oscillatory dynamics of the metabolic process in a cell. AB - In this work, a mathematical model of self-oscillatory dynamics of the metabolism in a cell is studied. The full phase-parametric characteristics of variations of the form of attractors depending on the dissipation of a kinetic membrane potential are calculated. The bifurcations and the scenarios of the transitions "order-chaos", "chaos-order" and "order-order" are found. We constructed the projections of the multidimensional phase portraits of attractors, Poincare sections, and Poincare maps. The process of self-organization of regular attractors through the formation torus was investigated. The total spectra of Lyapunov exponents and the divergences characterizing a structural stability of the determined attractors are calculated. The results obtained demonstrate the possibility of the application of classical tools of nonlinear dynamics to the study of the self-organization and the appearance of a chaos in the metabolic process in a cells. PMID- 23808316 TI - [Biochemical changes in rats under the influence of cesium chloride]. AB - Cesium is lately accumulated actively in the environment, but its influence on human and animal organism is the least studied among heavy metals. It is shown that the action of cesium chloride in rats caused significant changes in blood chemistry, which are characterized by a decrease of total protein content, pH, an increase in the level of urea, creatinine, glucose and total hemoglobin. The results showed that potassium content in all the studied organs and tissues of poisoned rats decreases under the action of cesium chloride. Histological examination of the heart tissue in rats poisoned with cesium chloride indicates the onset of pathology of cardiovascular system. It was found out that use of the drug "Asparkam" reduces the negative effect of cesium chloride on the body of rats. PMID- 23808317 TI - [Laureates of the Palladin Prize of the National Academy of Sciences of Ukraine (1985-1986)]. PMID- 23808318 TI - [Significance of SBIRT and countermeasures for its dissemination]. AB - This article reviews the literatures on screening, brief intervention, and referral to treatment(SBIRT). SBIRT is an intervention model that identifies at risk alcohol users and then provides them a patient-centered intervention. This literatures include publications on advice, intervention, minimal intervention, brief intervention, screening and intervention, and SBIRT. SBIRT evaluation is important for the following reasons. SBIRT is one of the most clinically effective and cost-effective preventive services. SBIRT prevents the progress to alcohol dependence, avoids stigma, treats all spectrums of drinking behavior, is evaluated high by patients and their families, strengthens a positive therapeutic atmosphere in medical settings, and has different importance in different medical settings. Next, we present concrete evidence for the effectiveness of SBIRT. Many clinical trials have been conducted to evaluate the efficacy and cost effectiveness of SBIRT in primary care, emergency departments, and trauma centers. In addition, we summarize barriers to the dissemination of SBIRT. Of particular importance is the lack of necessary knowledge, skill, financial incentive, time, and structured systems for SBIRT. Therefore, medical treatment fees, recommendation of the medical society, concrete countermeasure, and education of medical staff are important factors related to the dissemination of SBIRT. Finally, we present the costs factors associated with implementing SBIRT for the introduction of medical treatment fees. PMID- 23808319 TI - [Antibiotic drug minocycline: a potential therapeutic drug for methamphetamine related disorders]. AB - Accumulating evidence suggests a role of inflammation in the pathophysiology of a number of neuropsychiatric diseases. The second generation antibiotic drug minocycline has potent neuroprotective and anti-inflammatory effects. We reported that minocycline could attenuate behavioral abnormalities and dopaminergic neurotoxicity in mice after administration of methamphetamine or 3,4 methylenedioxymethamphetamine (MDMA). Furthermore, we reported that minocycline was effective in the animal models of schizophrenia. Moreover, a double-blind, placebo-control, cross-over study showed that minocycline was effective in the rewarding effects in healthy human subjects. In this article, we would like to discuss minocycline as a potential therapeutic drug for methamphetamine-related disorders. PMID- 23808320 TI - [Research on the actual conditions of alcohol dependence, the harmful use of alcohol and the optimal treatment in gastroenterological inpatients]. AB - PURPOSE: The goal of the study was to examine the status, Stages of Change and motivation, alcohol dependence, and harmful use of alcohol in gastroenterological inpatients. METHODS: We interviewed 141 gastroenterological inpatients and analyzed their medical charts. The interviews used the Alcohol Use Disorders Identification Test (AUDIT), CAGE questionnaire and questions pertaining to drinking behavior, diagnosis, self-awareness of drinking/alcohol dependency, physician instructions regarding abstinence, and Stages of Change. The proportion of patients who screened positive was calculated based on the AUDIT, CAGE and International Classification of Diseases (ICD)-10 alcohol dependence/harmful use criteria. Alcohol dependence was defined as a score >or= 15 on the AUDIT, and harmful use as 8-14 on the AUDIT or meeting ICD-10 criteria for harmful use. Patients with alcohol dependence or harmful use comprised the hazardous drinking group. Common disorders in this group and in patients in a non-drinking group were compared by Fisher exact test. Stages of Change were also determined in the hazardous drinking group and factors regarding motivation and Stages of Change were analyzed using logistic regression analysis. RESULTS: Of the 141 patients, 18 (12.8%) scored >or= 15 on the AUDIT, 19 (13.5%) scored L 2 on the CAGE, and 48 (34%) scored >or= 8 on the AUDIT. Among those who met the ICD-10 criteria, 16.3% had alcohol dependence and 17.7% exhibited harmful use of alcohol. Significantly, common disorders in the hazardous drinking group included liver disease, colonic diverticulitis, gout/hyperuricemia, and pancreatitis. Of the alcohol-dependent patients, 52% were in the Preparation stage. After the Contemplation stage, instructions to abstain from alcohol were the most significant motivational factor. CONCLUSIONS: Many gastroenterological inpatients exhibited alcohol dependence and about half of these patients were able to prepare for behavioral changes related to drinking. Therefore, the gastroenterological ward may help in secondary prevention of alcohol dependence and harmful use. PMID- 23808321 TI - [Investigation into drinking problem of patients who visited a general hospital in central and northern Okinawa]. AB - In Japan, many problems related to alcohol are pointed out from before. We believe that there is a unique drinking culture in Okinawa, such as a large amount of alcohol. Therefore, we estimate many people in Okinawa have a drinking problem. We conducted a survey of patients who visited general hospital (medical or surgical or orthopedic) in 2007. The purpose of this study is to collect basic data for introducing alcoholics to specialized treatment as early as possible, detecting the person who drink large amounts of alcohol, performing early intervention for people who drink large amount of alcohol, and advancing cooperation with specialized medical agencies of alcohol. As a result, Among the patients who visited general hospital in Okinawa, many problem drinkers are concentrated in the young age. and they have strong fears of health. The possibility of early intervention with intervention techniques, such as brief intervention, has been suggested. PMID- 23808322 TI - [Topiramate treatment for decreasing alcohol consumption in alcoholics: a comparative study of responders and nonresponders]. AB - PURPOSE: The present study investigated the effectiveness of topiramate (TPM) treatment for decreasing alcohol consumption in alcoholics. MATERIALS AND METHODS: Alcoholics of outpatients, relapsed repeatedly, were included in this study. The study was conducted over 24 weeks. Subject characteristics (e.g., gender) and medical variables (e.g., age of onset) were recorded. Autistic features were determined using the Autism - Spectrum Quotient (>or=27 points). The average daily alcohol consumption was assessed at the start of the study and at 4, 12, and 24 weeks after its start. The five-step alcohol consumption scale of the Obsessive-Compulsive Drinking Scale (OCDS) was used. The extent of the change between the first assessment and subsequent assessment was considered the primary evaluation point. Responders were defined as subjects showing an improvement of at least two steps in the score. Patients not treated with TPM were retrospectively selected according to the same criteria on the basis of their medical records and were used as controls. The TPM group was further subdivided into responders and nonresponders. RESULTS: Of the 31 subjects who consented to TPM therapy, 11 stopped or discontinued TPM, and they were considered nonresponders. The average TPM maintenance dosage (standard deviation) was 62.9 (38.1) mg. Alcohol consumption scores significantly decreased at each assessment point in the study. The percentage of responders in the TPM group (n = 31) was significantly higher than that in the control group (n = 41) at the 24 week assessment point (45.2% vs. 19.5%, p=0.0193). A significant difference was observed between responders (n = 14) and nonresponders (n = 17) only in well educated and autistic subjects (50% vs. 5.9%, p = 0.0109). CONCLUSION: TPM decreased the amount of alcohol consumption in alcoholics. In addition, a correlation between autistic features and TPM treatment response was suggested. PMID- 23808324 TI - A natural product telomerase activator as part of a health maintenance program: metabolic and cardiovascular response. AB - A short average telomere length is associated with low telomerase activity and certain degenerative diseases. Studies in animals and with human cells confirm a causal mechanism for cell or tissue dysfunction triggered by critically short telomeres, suggesting that telomerase activation may be an approach to health maintenance. Previously, we reported on positive immune remodeling in humans taking a commercial health maintenance program, PattonProtocol-1, composed of TA 65(r) (a natural product-derived telomerase activator) and other dietary supplements. In over a 5-year period and an estimated 7000 person-years of use, no adverse events or effects have been attributed to TA-65 by physicians licensed to sell the product. Here we report on changes in metabolic markers measured at baseline (n=97-107 subjects) and every 3-6 months (n=27-59 subjects) during the first 12 months of study. Rates of change per year from baseline determined by a multi-level model were -3.72 mg/dL for fasting glucose (p=0.02), -1.32 mIU/mL for insulin (p=0.01), -13.2 and -11.8 mg/dL for total cholesterol and low-density lipoprotein cholesterol (LDL-C) (p=0.002, p=0.002, respectively), -17.3 and -4.2 mmHg for systolic and diastolic blood pressure (p=0.007 and 0.001, respectively), and -3.6 MUmole/L homocysteine (p=0.001). In a subset of individuals with bone mineral density (BMD) measured at baseline and 12 months, density increased 2.0% in the spine (p=0.003). We conclude that in addition to apparent positive immune remodeling, PattonProtocol-1 may improve markers of metabolic, bone, and cardiovascular health. PMID- 23808325 TI - Women's experience of induction of labor: a mixed methods study. AB - OBJECTIVE: To investigate women's experience of induction of labor. DESIGN: Mixed methods study. SETTING: English maternity units. SAMPLE: Women who gave birth in a two-week period in late 2009, excluding women aged less than 16 years and women whose baby had died. METHODS: This study involved secondary analysis of data from questionnaires relating to care in childbirth. Women's experience of induction of labor was compared with that of women who had spontaneous labor by analysis of responses to structured survey questions. Responses to open questions relating to induction were analysed qualitatively. MAIN OUTCOME MEASURES: Satisfaction with care, mode of delivery, experience of induction of labor. RESULTS: The response rate to the survey was 55.1% representing 5333 women, 20% of whom were induced. Nulliparous women, those with long-term health problems, or specific pregnancy related problems were significantly more likely to be induced. Women who were induced were generally less satisfied with aspects of their care and significantly less likely to have a normal delivery. In the qualitative analysis the main themes that emerged concerned delay, staff shortages, neglect, pain and anxiety in relation to getting the induction started and once it was underway; and in relation to failed induction, the main themes were plans not being followed, wasted effort and pain, and feeling let down and disappointed. CONCLUSIONS: Women having an induction were generally less satisfied with their care, suggesting the need for a focused service for these women to address their additional needs. PMID- 23808323 TI - Novel monodisperse PEGtide dendrons: design, fabrication, and evaluation of mannose receptor-mediated macrophage targeting. AB - Novel PEGtide dendrons of generations 1 through 5 (G1.0-5.0) containing alternating discrete poly(ethylene glycol) (dPEG) and amino acid/peptide moieties were designed and developed. To demonstrate their targeting utility as nanocarriers, PEGtide dendrons functionalized with mannose residues were developed and evaluated for macrophage targeting. PEGtide dendrons were synthesized using 9-fluorenylmethyloxycarbonyl (Fmoc) solid-phase peptide synthesis (SPPS) protocols. The N-alpha-Fmoc-N-epsilon-(5-carboxyfluorescein)-l lysine (Fmoc-Lys(5-FAM)-OH) and monodisperse Fmoc-dPEG6-OH were sequentially coupled to Fmoc-beta-Ala-resin to obtain the resin-bound intermediate Fmoc-dPEG6 Lys(5-FAM)-beta-Ala (1). G1.0 dendrons were obtained by sequentially coupling Fmoc-Lys(Fmoc)-OH, Fmoc-beta-Ala-OH, and Fmoc-dPEG6-OH to 1. Dendrons of higher generation, G2.0-5.0, were obtained by repeating the coupling cycles used for the synthesis of G1.0. Dendrons containing eight mannose residues (G3.0-mannose8) were developed for mannose receptor (MR) mediated macrophage targeting by conjugating alpha-d-mannopyranosylphenyl isothiocyanate to G3.0 dendrons. In the present study PEGtide dendrons up to G5.0 were synthesized. The molecular weights of the dendrons determined by MALDI-TOF were in agreement with calculated values. The hydrodynamic diameters measured using dynamic light scattering (DLS) ranged from 1 to 8 nm. Cell viability in the presence of G3.0 and G3.0-mannose8 was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and was found to be statistically indistinguishable from that of untreated cells. G3.0-mannose8 exhibited 12-fold higher uptake than unmodified G3.0 control dendrons in MR-expressing J774.E murine macrophage-like cells. Uptake was nearly completely inhibited in the presence of 10 mg/mL mannan, a mannose analogue and known MR substrate. Confocal microscopy studies demonstrated the presence of significant intracellular punctate fluorescence colocalized with a fluid endocytosis marker with little surface fluorescence in cells incubated with G3.0-mannose8. No significant cell-associated fluorescence was observed in cells incubated with G3.0 dendrons that did not contain the targeting ligand mannose. The current studies suggest that PEGtide dendrons could be useful as nanocarriers in drug delivery and imaging applications. PMID- 23808326 TI - Molecular characterization of the human T cell lymphotropic virus type 2 long terminal repeat region: A discussion about possible influences at viral gene expression. AB - This study aimed to identify nucleotide signatures in the promoter region of human T cell lymphotropic virus type 2 (HTLV-2) isolated from infected individuals from Salvador, Brazil and in sequences from the GenBank database. DNA samples from HTLV-2-infected individuals were submitted to nested polymerase chain reaction (PCR) and sequencing, and molecular analyses were performed using bioinformatics tools. The phylogeny of HTLV-2 strains isolated from patients from Salvador reveals that all sequences were subtype c. One hundred and fifty-one sequences from GenBank were selected, among which 30 belong to subtype a, 88 to subtype b, 32 to subtype c, and one to subtype d. Subtype-specific signatures were identified as well as mutations resulting in loss or gain of motifs important to transcription regulation. The subtypes a and b have two E box motifs, while subtypes c and d have only one. These polymorphisms may impact viral fitness and infection outcome and should be more closely investigated. PMID- 23808328 TI - Questioning the costs and benefits of non-invasive prenatal testing. AB - Prenatal testing for Down syndrome through the use of non-invasive prenatal testing (NIPT) has been increasingly implemented in clinical practice and a recent cost analysis suggests that NIPT is cost effective when compared to other screening modalities in high risk populations. However, this anaylsis makes many assumptions regarding uptake of testing and pregnancy termination, which cannot be applied to all populations in the United States. Additionally, this cost analysis, which hinges on fewer Down syndrome births, does not align with the goals of prenatal testing to support autonomous and value consistent decisions. NIPT is an expensive new technology and more careful analysis is needed to determine the impact of NIPT on outcomes and overall healthcare costs. PMID- 23808327 TI - Optimization of ligand and lipophilic efficiency to identify an in vivo active furano-pyrimidine Aurora kinase inhibitor. AB - Ligand efficiency (LE) and lipophilic efficiency (LipE) are two important indicators of "drug-likeness", which are dependent on the molecule's activity and physicochemical properties. We recently reported a furano-pyrimidine Aurora kinase inhibitor 4 (LE = 0.25; LipE = 1.75), with potent activity in vitro; however, 4 was inactive in vivo. On the basis of insights obtained from the X-ray co-crystal structure of the lead 4, various solubilizing functional groups were introduced to optimize both the activity and physicochemical properties. Emphasis was placed on identifying potential leads with improved activity as well as better LE and LipE by exercising tight control over the molecular weight and lipophilicity of the molecules. Rational optimization has led to the identification of Aurora kinase inhibitor 27 (IBPR001; LE = 0.26; LipE = 4.78), with improved in vitro potency and physicochemical properties, resulting in an in vivo active (HCT-116 colon cancer xenograft mouse model) anticancer agent. PMID- 23808329 TI - Cnidarian-microbe interactions and the origin of innate immunity in metazoans. AB - Most epithelia in animals are colonized by microbial communities. These resident microbes influence fitness and thus ecologically important traits of their hosts, ultimately forming a metaorganism consisting of a multicellular host and a community of associated microorganisms. Recent discoveries in the cnidarian Hydra show that components of the innate immune system as well as transcriptional regulators of stem cells are involved in maintaining homeostasis between animals and their resident microbiota. Here I argue that components of the innate immune system with its host-specific antimicrobial peptides and a rich repertoire of pattern recognition receptors evolved in early-branching metazoans because of the need to control the resident beneficial microbes, not because of invasive pathogens. I also propose a mutual intertwinement between the stem cell regulatory machinery of the host and the resident microbiota composition, such that disturbances in one trigger a restructuring and resetting of the other. PMID- 23808330 TI - On the biological success of viruses. AB - Are viruses more biologically successful than cellular life? Here we examine many ways of gauging biological success, including numerical abundance, environmental tolerance, type biodiversity, reproductive potential, and widespread impact on other organisms. We especially focus on successful ability to evolutionarily adapt in the face of environmental change. Viruses are often challenged by dynamic environments, such as host immune function and evolved resistance as well as abiotic fluctuations in temperature, moisture, and other stressors that reduce virion stability. Despite these challenges, our experimental evolution studies show that viruses can often readily adapt, and novel virus emergence in humans and other hosts is increasingly problematic. We additionally consider whether viruses are advantaged in evolvability-the capacity to evolve-and in avoidance of extinction. On the basis of these different ways of gauging biological success, we conclude that viruses are the most successful inhabitants of the biosphere. PMID- 23808332 TI - Tip growth in filamentous fungi: a road trip to the apex. AB - Fungal hyphae extend by apical growth. This process involves the polarized traffic of secretory vesicles to the Spitzenkorper (SPK) and their subsequent distribution to specific domains of the plasma membrane, where they fuse to provide all the enzymes and material needed for cell wall expansion. Endocytic recycling and localized translation of specific mRNAs play an important role in hyphal apical growth. The traffic of vesicular carriers from synthesis sites to their destinations is coordinated by the combined action of coats, tethers, Rab GTPases, motors, and SNAREs in a mechanism that is just beginning to be understood. Only recently has it been confirmed that the different-sized vesicles present at the SPK contain distinct cell wall biosynthetic activities and are distributed in a stratified manner. PMID- 23808333 TI - Plant cell wall deconstruction by ascomycete fungi. AB - Plant biomass degradation by fungi requires a diverse set of secreted enzymes and significantly contributes to the global carbon cycle. Recent advances in genomic and systems-level studies have begun to reveal how filamentous ascomycete species exploit carbon sources in different habitats. These studies have laid the groundwork for unraveling new enzymatic strategies for deconstructing the plant cell wall, including the discovery of polysaccharide monooxygenases that enhance the activity of cellulases. The identification of genes encoding proteins lacking functional annotation, but that are coregulated with cellulolytic genes, suggests functions associated with plant biomass degradation remain to be elucidated. Recent research shows that signaling cascades mediating cellulolytic responses often act in a light-dependent manner and show crosstalk with other metabolic pathways. In this review, we cover plant biomass degradation, from sensing, to transmission and modulation of signals, to activation of transcription factors and gene induction, to enzyme complement and function. PMID- 23808331 TI - Prions and the potential transmissibility of protein misfolding diseases. AB - Prions, or infectious proteins, represent a major frontier in the study of infectious agents. The prions responsible for mammalian transmissible spongiform encephalopathies (TSEs) are due primarily to infectious self-propagation of misfolded prion proteins. TSE prion structures remain ill-defined, other than being highly structured, self-propagating, and often fibrillar protein multimers with the capacity to seed, or template, the conversion of their normal monomeric precursors into a pathogenic form. Purified TSE prions usually take the form of amyloid fibrils, which are self-seeding ultrastructures common to many serious protein misfolding diseases such as Alzheimer's, Parkinson's, Huntington's and Lou Gehrig's (amytrophic lateral sclerosis). Indeed, recent reports have now provided evidence of prion-like propagation of several misfolded proteins from cell to cell, if not from tissue to tissue or individual to individual. These findings raise concerns that various protein misfolding diseases might have spreading, prion-like etiologies that contribute to pathogenesis or prevalence. PMID- 23808334 TI - Archaea in biogeochemical cycles. AB - Archaea constitute a considerable fraction of the microbial biomass on Earth. Like Bacteria they have evolved a variety of energy metabolisms using organic and/or inorganic electron donors and acceptors, and many of them are able to fix carbon from inorganic sources. Archaea thus play crucial roles in the Earth's global geochemical cycles and influence greenhouse gas emissions. Methanogenesis and anaerobic methane oxidation are important steps in the carbon cycle; both are performed exclusively by anaerobic archaea. Oxidation of ammonia to nitrite is performed by Thaumarchaeota. They represent the only archaeal group that resides in large numbers in the global aerobic terrestrial and marine environments on Earth. Sulfur-dependent archaea are confined mostly to hot environments, but metal leaching by acidophiles and reduction of sulfate by anaerobic, nonthermophilic methane oxidizers have a potential impact on the environment. The metabolisms of a large number of archaea, in particular those dominating the subsurface, remain to be explored. PMID- 23808336 TI - Archaeal biofilms: the great unexplored. AB - Biofilms are currently viewed as the most common form in which microorganisms exist in nature. Bacterial biofilms play important roles in disease and industrial applications, and they have been studied in great detail. Although it is well accepted that archaea are not only the extremists they were thought to be as they occupy nearly every habitat where also bacteria are found, it is surprising how little molecular details are known about archaeal biofilm formation. Therefore, we aim to highlight the available information and indicate open questions in this field. PMID- 23808335 TI - Biological consequences and advantages of asymmetric bacterial growth. AB - Asymmetries in cell growth and division occur in eukaryotes and prokaryotes alike. Even seemingly simple and morphologically symmetric cell division processes belie inherent underlying asymmetries in the composition of the resulting daughter cells. We consider the types of asymmetry that arise in various bacterial cell growth and division processes, which include both conditionally activated mechanisms and constitutive, hardwired aspects of bacterial life histories. Although asymmetry disposes some cells to the deleterious effects of aging, it may also benefit populations by efficiently purging accumulated damage and rejuvenating newborn cells. Asymmetries may also generate phenotypic variation required for successful exploitation of variable environments, even when extrinsic changes outpace the capacity of cells to sense and respond to challenges. We propose specific experimental approaches to further develop our understanding of the prevalence and the ultimate importance of asymmetric bacterial growth. PMID- 23808337 TI - Molecular bacteria-fungi interactions: effects on environment, food, and medicine. AB - This review focuses on bacteria-fungi interactions mediated by secondary metabolites that occur in the environment and have implications for medicine and biotechnology. Bipartite interactions that affect agriculture as well as relationships involving additional partners (plants and animals) are discussed. The advantages of microbial interplay for food production and the risks regarding food safety are presented. Furthermore, recent developments in decoding the impact of bacteria-fungi interactions on infection processes and their implications for human health are highlighted. In addition, this reviews aims to demonstrate how the understanding of complex microbial interactions found in nature can be exploited for the discovery of new therapeutics. PMID- 23808338 TI - Hypoxia and gene expression in eukaryotic microbes. AB - The response of eukaryotic microbes to low-oxygen (hypoxic) conditions is strongly regulated at the level of transcription. Comparative analysis shows that some of the transcriptional regulators (such as the sterol regulatory element binding proteins, or SREBPs) are of ancient origin and probably regulate sterol synthesis in most eukaryotic microbes. However, in some fungi SREBPs have been replaced by a zinc-finger transcription factor (Upc2). Nuclear localization of fungal SREBPs is determined by regulated proteolysis, either by site-specific proteases or by an E3 ligase complex and the proteasome. The exact mechanisms of oxygen sensing are not fully characterized but involve responding to low levels of heme and/or sterols and possibly to levels of nitric oxide and reactive oxygen species. Changes in central carbon metabolism (glycolysis and respiration) are a core hypoxic response in some, but not all, fungal species. Adaptation to hypoxia is an important virulence characteristic of pathogenic fungi. PMID- 23808339 TI - Structure and operation of bacterial tripartite pumps. AB - In bacteria such as Pseudomonas aeruginosa and Escherichia coli, tripartite membrane machineries, or pumps, determine the efflux of small noxious molecules, such as detergents, heavy metals, and antibiotics, and the export of large proteins including toxins. They are therefore influential in bacterial survival, particularly during infections caused by multidrug-resistant pathogens. In these tripartite pumps an inner membrane transporter, typically an ATPase or proton antiporter, binds and translocates export or efflux substrates. In cooperation with a periplasmic adaptor protein it recruits and opens a TolC family cell exit duct, which is anchored in the outer membrane and projects across the periplasmic space between inner and outer membranes. Assembled tripartite pumps thus span the entire bacterial cell envelope. We review the atomic structures of each of the three pump components and discuss how these have allowed high-resolution views of tripartite pump assembly, operation, and possible inhibition. PMID- 23808340 TI - The algal past and parasite present of the apicoplast. AB - Plasmodium and Toxoplasma are genera of apicomplexan parasites that infect millions of people each year. The former causes malaria, and the latter causes neurotropic infections associated with a weakened or developing immune system. These parasites harbor a peculiar organelle, the apicoplast. The apicoplast is the product of an ancient endosymbiosis between a heterotrophic and a photosynthetic protist. We explore the cellular and molecular mechanisms that enabled a stable union of two previously independent organisms. These include the exchange of metabolites, transfer of genes, transport of proteins, and overall coordination of biogenesis and proliferation. These mechanisms are still active today and can be exploited to treat parasite infection. They were shaped by the dramatic changes that occurred in the evolution of the phylum Apicomplexa- including the gain and loss of photosynthesis, adaptation to symbiosis and parasitism, and the explosion of animal diversity-that ultimately provided an aquatic alga access to every biotope on this planet. PMID- 23808341 TI - Plasmodium nesting: remaking the erythrocyte from the inside out. AB - One of the most fascinating and remarkable features of Plasmodium parasites, which cause malaria, is their choice of erythrocytes as the principal host cells in which to reside during infection of a vertebrate host. Parasites completely renovate the terminally differentiated cells, which lack most of the normal organelles and functions of other cells, such as a nucleus and the machinery to express and transport proteins to subcellular locations. Erythrocyte remodeling begins immediately after invasion by the Plasmodium parasite, by expression and export of many hundreds of proteins that assemble into molecular machinery in the host cell that permit protein trafficking, harvesting of nutrients, and mechanisms to evade host immune responses. In this review, we discuss recent studies on erythrocyte remodeling, including mechanisms of protein export as well as the identity, functions, and subcellular locations of key exported proteins. PMID- 23808342 TI - Comment on "experimental energy barriers to transporting anions through nanofiltration membranes". PMID- 23808343 TI - Withdrawn: Supramolecular Evolution of Protein Organization. AB - Protein associations, whether transient or long-lasting, determine cellular processes and enable the cooperative and regulated functionalities characteristic of complex organisms. From a broad physical perspective, soluble natural proteins represent a unique kind of solute prone to associate but not to precipitate. Thus, discrete reproducible associations define the protein supramolecular organization. The evolutionary forces that enable and promote this complexity are the subject matter of this review. The central problem addressed involves the paradoxical constructive role of random genetic drift, typically mildly deleterious, in fostering interactome complexity. By introducing biophysical insights in molecular evolution, we are able to identify the adaptive and nonadaptive elements that define the protein association propensity. We emphasize the mechanistic importance of population size and selection inefficiency in creating an evolutionary niche to promote interactome complexity. Finally, we describe the fitness catastrophes that result from the prevailing evolutionary strategy. Expected final online publication date for the Annual Review of Genetics Volume 47 is November 23, 2013. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates. PMID- 23808344 TI - The RNA chaperone Hfq regulates expression of fimbrial-related genes and virulence of Salmonella enterica serovar Enteritidis. AB - Salmonella Enteritidis is an intracellular pathogen that causes enteritis and systemic disease in humans and other animals. The RNA chaperone protein Hfq mediates the binding of small noncoding RNAs to target mRNA and assists in post transcriptional gene regulation in bacteria. In this study, we constructed an hfq deletion mutant in S. Enteritidis SE50336 and analyzed the expression of major fimbrial subunits sefA, bcfA, fimA, safA, stbA, sthA, csgA, csgD, and pegA using quantitative real-time PCR. The gene expression of sefA increased about 14-fold in the hfq mutant, as compared with its expression in the wild-type strain. The expression of fimA and pegA did not change significantly, while the expression of the other fimbrial genes was significantly down-regulated in the hfq mutant. The ability of SE50336Deltahfq adhering to Caco-2 cells was also reduced as compared with wild-type adherence. The virulence of the hfq mutant was significantly reduced in a 1-day-old chicken model of S. Enteritidis disease, as determined by quantifying the lethal dose 50% of the bacterial strains. We conclude that Hfq critically contributes to S. Enteritidis virulence, likely partially affected by regulating fimbrial gene expression. PMID- 23808345 TI - Perceptions of campus climate by sexual minorities. AB - Previous research has indicated that students who identify as lesbian, gay, bisexual, or transgender (LGBT) often have negative experiences on university campuses due to their sexual orientation or gender identity. Direct and indirect experiences contribute to an overall perception of the campus climate. This study used an online survey to assess students' perceptions of campus climate, their experiences confronting bias, support of family members and friends, and whether they had considered leaving campus. Multiple regression analysis indicated that perceptions of poorer campus climate were predicted by greater unfair treatment by instructors, more impact from anti-lesbian, gay, bisexual, transgender, or queer (LGBTQ) bias on friends' and families' emotional support, and having hidden one's LGBT identity from other students. Cluster analyses revealed four groups of participants distinguished by openness about their sexual orientation and negative experiences, with one group appearing to be at risk for poor retention. Results are discussed in terms of the needs of LGBTQ students on campus. PMID- 23808346 TI - Same-sex relationships in Yoruba culture and orature. AB - It is widely believed that lesbianism and homosexuality are foreign concepts and colonial imports to Sub-Saharan Africa. This popular view is not unconnected with hegemonic heterosexual orientation of the society. The pitfall of heterosexual orientation, which hinges on politics of sexual representation, is worth an academic investigation. Therefore, this study seeks to close the analytical gap by examining Yoruba oral literature, which is regarded as the repertoire of their traditional and cultural beliefs and nuances, to unravel the subject of lesbianism and homosexuality from a sociological approach. Drawing on interviews and oral literature, this article examines the vital ideas of lesbianism and gay culture among the Yoruba people of southwestern Nigeria. This article argues that the preconceived obscenity of lesbianism and homosexuality among the Yoruba hinges on the culture of silence within the cultural milieu of the people. The study concludes that the representation of lesbianism and gay in diverse oral literature, as the repertoire of people's experiences and worldview, rubberstamped its presence and practices in the Yoruba society. PMID- 23808347 TI - On being gay in Barbados: "Bullers" and "Battyboys" and their HIV risk in a societal context of stigma. AB - Limited research exists about gay men in the Caribbean region. A qualitative study was conducted to characterize gay men in Barbados, their HIV risk, and the impact of stigma on their lives. The 2 main groups of gay men ("bougies" and "ghetto") reflect social class and level of "outness" in broader society. Homophobia, stigma, and buggery (sodomy) laws increase their HIV vulnerability. The need for anti-discrimination legislation and tools for self-development were identified for gay men to realize their strengths, develop their self-worth, and protect themselves from HIV. PMID- 23808348 TI - Sexual orientation microaggressions and the experience of sexual minorities. AB - This qualitative study sought to confirm and expand on previous research on sexual orientation microaggressions--subtle discrimination in the form of verbal, behavioral, and environmental slights and indignities as defined by Sue (2010). The study had two primary research questions: Does the data from the sample validate Sue's (2010) typology of sexual orientation microaggressions? Beyond Sue's (2010) typology, are other themes/types of sexual orientation microaggressions present in the data? Using a focus group methodology, data was collected from a sample of self-identified non-heterosexual college students (N=12). Data analysis confirmed five previously identified themes from Sue's (2010) typology (Endorsement of Heteronormative Culture, Sinfulness, Homophobia, Heterosexist Language/Terminology, and Oversexualization) and demonstrated two new themes (Undersexualization and Microaggressions as Humor). The implications of sexual orientation microaggressions, along with limitations and future research directions, are discussed. PMID- 23808349 TI - Gender effect and prejudice: when a salient female norm moderates male negative attitudes toward homosexuals. AB - Men generally express more negative attitudes than women toward homosexuals. This study aims to determine if social norms saliency can rely on this "gender effect" and influence attitudes toward homosexuals. Gender characteristics (attitudes and lexical markers) concerning homosexuality were identified in Study 1 and used to construct male- (i.e., promoting a prejudice-related norm) and female-marked (i.e., promoting an anti-prejudice-related norm) messages. Social norms saliency was primed using these messages (Studies 2 and 3) and the participant's immediate context (Study 3). Results show that promoting a prejudiced norm eases expression of males' negative attitudes toward homosexuals, whereas the promotion of an anti prejudice norm inhibits their attitudes. Theoretical elaborations and potential applications for promotion of tolerance are discussed. PMID- 23808350 TI - Heterosexual students' experiences in sexual orientation intergroup dialogue courses. AB - Heterosexism contributes to an unsafe campus climate for lesbian, gay, and bisexual (LGB) college students. Intergroup dialogue courses about sexual orientation seek to build awareness, cross-group relationships, and commitment to social action to address anti-LGB prejudice and discrimination. Although dialogue courses are growing in popularity, few courses address sexual orientation. To advance knowledge of these dialogues, this qualitative study explores heterosexual students' motivations and expectations, challenges, and learning outcomes related to their participation in intergroup dialogue courses on sexual orientation. Core themes include desire to learn about the LGB community, concerns about offending classmates, anxiety around LGB stigma, conflict with classmates around controversial topics, affirming LGB people, and learning about heterosexism, privilege, and intersectionality of identity. Implications for intergroup dialogue pedagogy and research are discussed. PMID- 23808352 TI - Fabrication of an efficient BaTaO2N photoanode harvesting a wide range of visible light for water splitting. AB - Photoanodes made from BaTaO2N that can harvest visible light up to 660 nm wavelength were fabricated on Ti substrates for achieving efficient water splitting. Both pre-treatment of BaTaO2N particles with an H2 stream and post necking treatment with TaCl5 effectively increased the photocurrent due to the decreased electrical resistance in the porous BaTaO2N photoanode. A combination of pre-loading of CoO(x) on the BaTaO2N particles and post-loading of RhO(x) significantly improved both the photocurrent and stability under visible light irradiation, along with an obvious negative shift (ca. 300 mV) of the onset potential for water oxidation, while sole loading resulted in a lower photocurrent or insufficient stability. The IPCE value was estimated to be ca. 10% at 1.2 V vs RHE under 600 nm, which is the highest among photoanode materials that can harvest light beyond 600 nm for water oxidation. Photoelectrochemical water splitting into H2 and O2 under visible light was demonstrated using RhO(x)/CoO(x)/BaTaO2N/Ti photoanodes under an externally applied bias larger than 0.7 V to a Pt counter electrode. PMID- 23808353 TI - UV photodissociation of pyrroles: symmetry and substituent effects. AB - H (Rydberg) atom photofragment translational spectroscopy and ab initio electronic structure calculations are used to explore ways in which ring substituents affect the photofragmentation dynamics of gas phase pyrroles. S1 <- S0 (sigma* <- pi) excitation in bare pyrrole is electric dipole forbidden but gains transition probability by vibronic mixing with higher electronic states. The S1 state is dissociative with respect to N-H bond extension, and the resulting pyrrolyl radicals are formed in a limited number of (nontotally symmetric) vibrational levels (Cronin et al. Phys. Chem. Chem. Phys. 2004, 6, 5031-5041). Introducing sigma-perturbing groups (e.g., an ethyl group in the 2 position or methyl groups in the 2- and 4-positions) lowers the molecular symmetry (to C(s)), renders the S1-S0 transition (weakly) allowed, and causes some reduction in N-H bond strength; the radical products are again formed in a select subset of the many possible vibrational levels but all involve in-plane (a') ring-breathing motions as expected (by Franck-Condon arguments) given the changes in equilibrium geometry upon sigma* <- pi excitation. The effects of pi perturbers are explored computationally only. Relative to bare pyrrole, introducing an electron donating group like methoxy (at the 3- or, particularly, the 2-position) is calculated to cause a ~10% reduction in N-H bond strength, while CN substitution (in either position) is predicted to cause a substantial (~3000 cm(-1)) increase in the S1-S0 energy separation but only a modest (~2%) increase in N-H bond strength. PMID- 23808354 TI - Changes in some blood parameters and production performance of old laying hens due to growth hormone and testosterone injection. AB - The experiment was designed to study the changes in some blood parameters and production performance of old laying hens after injection of different doses of growth hormone (GH) and testosterone (Ts). A total of 160 old laying hens (HyLine W-36) at 73 weeks of age were weighed individually and randomly allocated to four treatments with four replicates and 10 birds in each replicate in a completely randomized design. Growth hormone and Ts hormones were injected subcutaneously. Treatment groups were as follows: treatment 1: injection of 100 MUl distiled water (control group), treatment 2: injection of 500 MUg Ts/kg live-weight + 50 MUgGH/kg live-weight, treatment 3: injection of 500 MUgTs/kg live-weight + 100 MUgGH/kg live-weight and treatment 4: injection of 500 MUgTs/kg live-weight + 150 MUgGH/kg live-weight. Plasma levels of oestradiol, T4 , LDL, HDL and cholesterol significantly increased in treatment 3 in relation to the control group. All injected hens showed significantly higher levels of glucose in relation to control group. The results showed the positive effects of GH and Ts administration on production performance and blood parameters which are associated with egg production potentiality and in turn may improve reproductivity (egg production) in old laying hens. The positive results of the study may be useful in animal selection and breeding programmes. PMID- 23808356 TI - Clinical outcomes of endoscopic submucosal dissection for early gastric cancer in patients with chronic kidney disease. AB - BACKGROUND AND AIM: Endoscopic submucosal dissection (ESD) is a widely accepted treatment for early gastric cancer (EGC), and the number of ESD performed for EGC in patients with chronic kidney disease (CKD) is increasing. Although patients undergoing hemodialysis tend to bleed and are at high risk for cardiovascular disease, the effectiveness and safety of ESD for EGC in patients with CKD in particular have not been established. The aim of this study was to evaluate the effectiveness and potential adverse effects of ESD for EGC in patients with CKD undergoing hemodialysis. METHODS: Sixty-three consecutive CKD patients in whom 79 EGCs were treated by ESD between October 2004 and January 2012; 15 of the 63 patients were hemodialysis patients. Complete en bloc resection rate and ESD related complications in hemodialysis patients versus non-hemodialysis patients were evaluated. RESULTS: The complete en bloc resection rate was 100% (15/15) in the hemodialysis patients and 87.5% (56/64) in the non-hemodialysis patients, respectively. The post-ESD bleeding rate was 33% (5/15) and 9% (6/64), respectively (P < 0.05). Perforation occurred only in non-hemodialysis patients; the incidence was 5% (3/64). Two ESD-related deaths occurred among hemodialysis patients (13%, 2/15); femoral artery infarction triggered post-ESD bleeding in one of these two patients, and alveolar hemorrhage occurred in the other. CONCLUSION: Hemodialysis poses a risk of post-ESD bleeding. We must understand this risk and provide countermeasures for post-ESD bleeding in hemodialysis patients. PMID- 23808357 TI - Theory of mind and epilepsy: what clinical implications? AB - PURPOSE: Epilepsy can impair theory of mind (ToM), but the clinical significance of such a deficit is unknown. This study evaluated the influence of selective ToM deficits on self-appraisal, coping, and quality of life (QoL) in patients with focal epilepsy. METHODS: Data were collected from 66 patients with temporal or frontal lobe epilepsy, and from 42 healthy controls. The Faux Pas Task (FPT), Multiple Ability Self-report Questionnaire (MASQ), Coping Responses Inventory Adult (CRI-Adult), and World Health Organization QoL 100 (WHOQoL 100) evaluated ToM, self-rated cognitive abilities, coping to stressful events, and QoL. Different tests and inventories assessed other cognitive functions, depression, and anxiety. KEY FINDINGS: Patients were impaired in the recognition and comprehension of social faux pas. The FPT scores contributed to predict the MASQ, CRI-Adult, and WHOQoL overall scores; the comprehension of others' mental states and interactions score exerted a prominent influence. SIGNIFICANCE: In patients with focal epilepsy, selective ToM deficits may have clinical implications, with specific influence on self-appraisal, coping, and overall QoL. ToM evaluation may contribute in explaining some psychobehavioral difficulties and to plan nonpharmacological treatment. PMID- 23808355 TI - Systemic and cerebral exposure to and pharmacokinetics of flavonols and terpene lactones after dosing standardized Ginkgo biloba leaf extracts to rats via different routes of administration. AB - BACKGROUND AND PURPOSE: Flavonols and terpene lactones are putatively responsible for the properties of Ginkgo biloba leaf extracts that relate to prevention and treatment of cardiovascular disease and cerebral insufficiency. Here, we characterized rat systemic and cerebral exposure to these ginkgo compounds after dosing, as well as the compounds' pharmacokinetics. EXPERIMENTAL APPROACH: Rats received single or multiple doses of ShuXueNing injection (prepared from GBE50 for intravenous administration) or GBE50 (a standardized extract of G. biloba leaves for oral administration). Brain delivery of the ginkgo compounds was assessed with microdialysis. Various rat samples were analysed using liquid chromatography/mass spectrometry. KEY RESULTS: Slow terminal elimination features of the flavonols counterbalanced the influence of poor oral bioavailability on their systemic exposure levels, which also resulted in significant accumulation of the compounds in plasma during the subchronic treatment with ShuXueNing injection and GBE50. Unlike the flavonols, the terpene lactones had poor enterohepatic circulation due to their rapid renal excretion and unknown metabolism. The flavonol glycosides occurred as major forms in plasma after dosing with ShuXueNing injection, while the flavonol aglycone conjugates were predominant in plasma after dosing with GBE50. Cerebral exposure was negligible for the flavonols and low for the terpene lactones. CONCLUSION AND IMPLICATIONS: Unlike the significant systemic exposure levels, the levels of cerebral exposure to the flavonols and terpene lactones are low. The elimination kinetic differences between the two classes of ginkgo compounds influence their relative systemic exposure levels. The information gained is relevant to linking ginkgo administration to the medicinal effects. PMID- 23808358 TI - Factors predisposing to wrong blood in tube incidents: a year's experience in the North East of England. AB - INTRODUCTION: Wrong blood in tube (WBIT) describes a transfusion sample collected from one patient but labelled with the identification details of a different patient. These incidents have the potential to result in catastrophic harm to patients. In 2011, the Serious Hazards of Transfusion (SHOT) organisation received 469 reports of WBIT across the UK. WHAT THIS STUDY ADDS: This was a prospective study of WBIT which collected information not only on the frequency of WBIT but also risk factors. METHOD: All hospitals in the North East region of England submitted details of known WBITs during a 12-month period starting from July 2011, including the time of day and location where samples were taken, the job title and competency of the sample taker, and how the WBIT was identified. Where possible, the sampler was interviewed to determine reasons for the WBIT. RESULTS: There were 48 WBITs, giving a corrected incidence of 1 : 2717 repeat transfusion samples. Doctors were responsible for 24 of 45 WBITs where the identity of the sampler was known. The rate as a proportion of samples was highest in medicine and paediatric specialties. The commonest risk factor for WBIT was labelling away from the bedside (44%). CONCLUSIONS: These findings support, and add to, the data collected by SHOT. If our figures are representative of the whole of the UK, then over 1160 WBITs will occur each year, justifying SHOT's concerns that WBITs are under reported. Interventions are needed to ensure labelling of transfusion samples is always carried out at the patient's side. PMID- 23808359 TI - Sleep disturbance and affective comorbidity among episodic migraineurs. AB - BACKGROUND: Disturbances in sleep are common among migraineurs, particularly those with frequent (ie, chronic) migraine. Examination of specific types of sleep disturbance and behaviors among episodic migraineurs, however, has not been sufficiently explored. Further, few studies have investigated whether sleep disturbance is attributable to comorbid affective symptomatology. OBJECTIVES: The present case-control study sought to (1) assess sleep quality, daytime sleepiness, and sleep hygiene among a large sample of episodic migraineurs; (2) quantify relations between sleep disturbance and headache-related variables; and (3) determine if these relations remain after accounting for comorbid depression and anxiety. METHODS: Two hundred ninety-two undergraduate students (69.9% female, mean age = 19.19, standard deviation [SD] = 3.21 years) completed measures of sleep quality, daytime sleepiness, and sleep hygiene along with well validated measures of depression and anxiety symptomatology. Those screening positive for migraine were subsequently administered a structured diagnostic interview to verify diagnosis of migraine consistent with the International Classification of Headache Disorders, 2nd edition. Episodic migraineurs and non migraine controls were compared on the sleep disturbance variables, and among those with migraine, relations with headache frequency, severity, and disability were quantified with linear regression analyses. RESULTS: Seventy-eight (26.7%) participants met International Classification of Headache Disorders, 2nd edition criteria for episodic migraine. Compared with participants without migraine, episodic migraineurs reported poorer sleep quality (mean = 8.90 [SD = 3.39] vs 6.63 [SD = 3.02], P < .0001), with 85.9% reporting clinically significant poor sleep quality (vs 62.0% of controls). Poor sleep quality was significantly associated with headache frequency and headache-related disability, accounting for proportions of variance (14.8% in frequency and 18.2% in disability, both P <= .001) similar to those attributable to depression and anxiety. These relationships remained significant after controlling for these affective symptoms, in which sleep quality accounted for 5.3% and 5.8% of unique variance in frequency and disability, respectively (P < .05). By comparison, daytime sleepiness and poor sleep hygiene were not consistently associated with migraine or migraine-related variables. CONCLUSIONS: Consistent with prior studies on chronic migraine, poor sleep quality is uniquely associated with episodic migraine, and this relationship is not solely attributable to comorbid psychiatric symptomatology. Sleep quality should be preferentially assessed (vs sleepiness and sleep hygiene) when subjective self-report measures of insomnia are used in clinical headache settings. Future studies should supplement these findings by evaluating the efficacy of interventions that specifically target sleep quality and insomnia (eg, stimulus control, sleep restriction) among episodic migraineurs. PMID- 23808360 TI - The use of solar radiation by the photosynthetic bacterium, Rhodopseudomonas palustris: model simulation of conditions found in a shallow pond or a flatbed reactor. AB - Photosynthetic bacteria are attractive for biotechnology because they produce no oxygen and so H2 -production is not inhibited by oxygen as occurs in oxygenic photoorganisms. Rhodopseudomonas palustris and Afifella marina containing BChl a can use irradiances from violet near-UV (VNUV) to orange (350-650 nm) light and near-infrared (NIR) light (762-870 nm). Blue diode-based pulse amplitude modulation technology was used to measure their photosynthetic electron transport rate (ETR). ETR vs Irradiance curves fitted the waiting-in-line model--ETR = (ETRmax * E/Eopt) * exp (1 - E/Eopt). The equation was integrated over pond depth to calculate ETR of Afifella and Rhodopseudomonas in a pond up to 30 cm deep (A376, 1 cm = 0.1). Afifella saturates at low irradiances and so photoinhibition results in very low photosynthesis in a pond. Rhodopseudomonas saturates at ~15% sunlight and shows photoinhibition in the surface layers of the pond. Total ETR is ~335 MUmol (e(-)) m(-2) s(-1) in NUV + photosynthetically active radiation light (350-700 nm). Daily ETR curves saturate at low irradiances and have a square-wave shape: ~11-13 mol (e(-)) m(-2) day(-1) (350-700 nm). Up to 20-24% of daily 350-700 nm irradiance can be converted into ETR. NIR is absorbed by water and so competes with the bacterial RC-2 photosystem for photons. PMID- 23808361 TI - Supramaximal intermittent running performance in relation to age and locomotor profile in highly-trained young soccer players. AB - The aim of the study was to examine supramaximal intermittent running performance in highly-trained young soccer players, with regard to age and locomotor profile. Twenty-seven Under 14, 19 U16 and 16 U18 highly-trained soccer players performed an incremental intermittent running test (30-15 Intermittent Fitness Test) to assess supramaximal intermittent running performance (VIFT), an incremental running test to estimate maximal aerobic speed (VVam-Eval) and a 40-m sprint to estimate maximal sprinting speed (MSS). U16 and U18 presented very likely greater VIFT (19.2 +/- 0.9, 19.7 +/- 1.0 vs. 17.4 +/- 0.9 km . h(-1)) and VVam-Eval (16.2 +/- 0.9, 16.7 +/- 1.0 vs. 14.6 +/- 0.9 km . h(-1)) than U14, while there was no clear difference between U16 and U18. MSS (25.1 +/- 1.6, 29.3 +/- 1.6 and 31.0 +/ 1.1 km . h(-1) for U14, U16 and U18) was very likely different between all groups. When data were pooled together, VIFT was very largely correlated with VVam-Eval and MSS (overall r =0.89, partial r = 0.74 and 0.29, respectively). Within-age group correlations showed that the older the players, the greater the magnitude of the correlations between VIFT and VVam-Eval (r = 0.67, 0.73 and 0.87). In conclusion, the major predictors of VIFT were, in order of importance, VVam-Eval and MSS; however, the older the players, the greater the correlations with VVam-Eval. PMID- 23808362 TI - Pharmacokinetics of drugs in spontaneously or secondary hypertensive rats. AB - 1. Spontaneously hypertensive rats (SHRs) and deoxycorticosterone acetate-salt induced hypertensive rats (DOCA-salt rats) have been developed as animal models for human essential (idiopathic or primary) and secondary hypertensions, respectively. 2. In order to identify pharmacokinetic changes (mainly non-renal clearance, CLNR) in 16-week-old SHRs due to hereditary characteristics and/or neither the hypertensive state itself, we reviewed the pharmacokinetics of drugs in 6- (blood pressure within a normotensive range) and 16-week-old SHRs and 16 week-old DOCA-salt rats compared with respective control rats. 3. We reviewed changes in CLNRs of drugs which are primarily metabolized via hepatic microsomal cytochrome P 450 enzymes (CYPs) based mainly on data from hypertensive rats, and present the data in terms of changes in in vitro hepatic intrinsic clearance (CLint), free fraction in plasma (fp) and hepatic blood flow rate (QH) depending on the hepatic excretion ratios of drugs. In general, changes in the CLNRs of drugs in this category were well-explained by the above-described factors. 4. We also reviewed and discussed the mechanism of urinary excretion of drugs (i.e. glomerular filtration and active renal secretion or reabsorption) in hypertensive rats. PMID- 23808364 TI - Azurocidin levels in maternal serum in the first trimester can predict preterm prelabor rupture of membranes. AB - OBJECTIVE: To determine the possible association between azurocidin in maternal serum in the first trimester of pregnancy and subsequent spontaneous preterm labor, preterm prelabor rupture of membranes, and iatrogenic preterm delivery. METHODS: Women who underwent first trimester screening for chromosomal abnormalities between January and November 2011 were included in the study, and a sample of maternal serum was obtained. In total, 1905 women were followed-up through the local record system, and 13 women with spontaneous preterm labor, 17 women with preterm prelabor rupture of membranes (PPROM), and 16 women with iatrogenic preterm delivery were identified. Twenty-two women with uncomplicated pregnancies who delivered at term were selected as controls. Maternal serum azurocidin levels in women were determined using ELISA. RESULT: Women with PPROM had lower azurocidin levels (median 0.91 ng/mL, range 0.2-2.07) than women who delivered at term (median 1.63 ng/mL, range 0.4-10.98; p = 0.02). No differences in azurocidin levels between women with labor at term and those with either spontaneous preterm labor (median 1.46 ng/mL, range 0.19-2.59; p = 0.42) or iatrogenic preterm delivery (median 1.60 ng/mL, range 0.66-7.96; p = 0.27) were found. CONCLUSIONS: Low levels of azurocidin in maternal serum in the first trimester were associated with subsequent PPROM. PMID- 23808363 TI - Peptidoglycan recognition protein 1 promotes house dust mite-induced airway inflammation in mice. AB - Peptidoglycan recognition protein (Pglyrp) 1 is a pattern-recognition protein that mediates antibacterial host defense. Because we had previously shown that Pglyrp1 expression is increased in the lungs of house dust mite (HDM)-challenged mice, we hypothesized that it might modulate the pathogenesis of asthma. Wild type and Pglyrp1(-/-) mice on a BALB/c background received intranasal HDM or saline, 5 days/week for 3 weeks. HDM-challenged Pglyrp1(-/-) mice showed decreases in bronchoalveolar lavage fluid eosinophils and lymphocytes, serum IgE, and mucous cell metaplasia, whereas airway hyperresponsiveness was not changed when compared with wild-type mice. T helper type 2 (Th2) cytokines were reduced in the lungs of HDM-challenged Pglyrp1(-/-) mice, which reflected a decreased number of CD4(+) Th2 cells. There was also a reduction in C-C chemokines in bronchoalveolar lavage fluid and lung homogenates from HDM-challenged Pglyrp1(-/ ) mice. Furthermore, secretion of CCL17, CCL22, and CCL24 by alveolar macrophages from HDM-challenged Pglyrp1(-/-) mice was markedly reduced. As both inflammatory cells and airway epithelial cells express Pglyrp1, bone marrow transplantation was performed to generate chimeric mice and assess which cell type promotes HDM induced airway inflammation. Chimeric mice lacking Pglyrp1 on hematopoietic cells, not structural cells, showed a reduction in HDM-induced eosinophilic and lymphocytic airway inflammation. We conclude that Pglyrp1 expressed by hematopoietic cells, such as alveolar macrophages, mediates HDM-induced airway inflammation by up-regulating the production of C-C chemokines that recruit eosinophils and Th2 cells to the lung. This identifies a new family of innate immune response proteins that promotes HDM-induced airway inflammation in asthma. PMID- 23808365 TI - Genetic interaction networks: toward an understanding of heritability. AB - Understanding the relationship between the genotypes and phenotypes of individuals is key for identifying genetic variants responsible for disease and developing successful therapeutic strategies. Mapping the phenotypic effects of individual genetic variants and their combinations in human populations presents numerous practical and statistical challenges. However, model organisms, such as the budding yeast Saccharomyces cerevisiae, provide an incredible set of molecular tools and advanced technologies that should be able to efficiently perform this task. In particular, large-scale genetic interaction screens in yeast and other model systems have revealed common properties of genetic interaction networks, many of which appear to be maintained over extensive evolutionary distances. Indeed, despite relatively low conservation of individual genes and their pairwise interactions, the overall topology of genetic interaction networks and the connections between broad biological processes may be similar in most organisms. Taking advantage of these general principles should provide a fundamental basis for mapping and predicting genetic interaction networks in humans. PMID- 23808366 TI - Genetic analysis of hypoxia tolerance and susceptibility in Drosophila and humans. AB - Oxygen is essential for metazoans' life on earth. Oxygen deprivation, or hypoxia, contributes significantly to the pathophysiology of many human diseases. A better understanding of the fundamental molecular and genetic basis for adaptation to low-oxygen environments will help us develop therapeutic strategies to prevent or treat diseases that have hypoxia as a major part of their pathogenesis. Different cells and organisms have evolved different ways to cope with this life threatening challenge, and the molecular and genetic mechanisms remain largely unknown. The current revolution of genomic technology has advanced our understanding of the genetic basis of many diseases and conditions, including hypoxia tolerance and susceptibility. In this review, we highlight the progress made in understanding the molecular responses to hypoxia in an animal model organism (Drosophila melanogaster) and genetic adaptation to high-altitude hypoxia in humans. PMID- 23808367 TI - The past, present and future of minimally invasive therapy in urology: a review and speculative outlook. AB - INTRODUCTION: Twenty-five years of SMIT represents an important date. In this article we want to elaborate the development of minimally invasive surgery in urology during the last three decades and try to look 25 years ahead. MATERIAL AND METHODS: As classical scenarios to demonstrate the changes which have revolutionized surgical treatment in urology, we have selected the management of urolithiasis, renal tumour, and localized prostate cancer. This was based on personal experience and a review of the recent literature on MIS in Urology on a MEDLINE/PUBMED research. For the outlook to the future, we have taken the expertise of two senior urologists, middle-aged experts, and upcoming junior fellows, respectively. RESULTS: Management of urolithiasis has been revolutionized with the introduction of non-invasive extracorporeal shock wave lithotripsy (ESWL) and minimally invasive endourology in the mid-eighties of the last century obviating open surgery. This trend has been continued with perfection and miniaturization of endourologic armamentarium rather than significantly improving ESWL. The main goal is now to get rid of the stone in one session rather in multiple non-invasive treatment sessions. Stone treatment 25 years from today will be individualized by genetic screening of stone formers, using improved ESWL-devices for small stones and transuretereal or percutaneous stone retrieval for larger and multiple stones. Management of renal tumours has also changed significantly over the last 25 years. In 1988, open radical nephrectomy was the only therapeutic option for renal masses. Nowadays, tumour size determines the choice of treatment. Tumours >4 cm are usually treated by laparoscopic nephrectomy, smaller tumours, however, can be treated either by open, laparoscopic or robot-assisted partial nephrectomy. For patients with high co-morbidity focal tumour ablation or even active surveillance represents a viable option. In 25 years, imaging of tumours will further support early diagnosis, but will also be able to determine the pathohistological pattern of the tumour to decide whether the patient requires removal, ablation or active surveillance. Management of localized prostate cancer underwent significant changes as well. 25 years ago open retropubic nerve-sparing radical prostatectomy was introduced as the optimal option for effective treatment of the cancer providing minimal side-effects. Basically, the same operation is performed today, but with robot-assisted laparoscopic techniques providing 7-DOF instruments, 3D vision and tenfold magnification and enabling the surgeon to work in a sitting position at the console. In 25 years, prostate cancer may be managed in most cases by focal therapy and/or genetically targeting therapy. Only a few patients may still require robot-assisted removal of the entire gland. DISCUSSION: There has been a dramatic change in the management of the most frequent urologic diseases almost completely replacing open surgery by minimally invasive techniques. This was promoted by technical realisation of physical principles (shock waves, optical resolution, master-slave system) used outside of medicine. The future of medicine may lie in translational approaches individualizing the management based on genetic information and focalizing the treatment by further improvement of imaging technology. PMID- 23808368 TI - Reduced port laparoscopic splenectomy using a newly developed multichannel port: a pilot study. AB - BACKGROUND: The authors introduce the dual-incision laparoscopic splenectomy (DILS) technique using a specially designed multichannel trocar and report on the surgical outcomes and operative cost of DILS compared with conventional laparoscopic splenectomy (CLS). MATERIAL AND METHODS: The medical records of 53 patients who underwent a laparoscopic splenectomy using CLS with four trocars and DILS at our institution were analyzed. RESULTS: There was no statistical difference in operative time between the two groups and the intraoperative transfusion rate of red blood cell substitution was not different between the two groups. In terms of postoperative pain score, hospital stay, and overall complication rate, there were no differences between the two groups. Operative cost was significantly lower in the DILS group compared with the CLS group. CONCLUSIONS: DILS is a feasible and cost-effective modality of reduced port surgery in laparoscopic splenectomy. PMID- 23808369 TI - Usefulness of cone-beam computed tomography during balloon-occluded retrograde transvenous obliteration. AB - OBJECTIVE: The purpose of our investigation was to evaluate the usefulness of cone-beam computed tomography (CBCT) in balloon-occluded retrograde transvenous obliteration (B-RTO) for gastric varices. MATERIAL AND METHODS: Between December 2010 and March 2011, four patients underwent B-RTO for gastric varices that occurred after portal hypertension. In all, after insertion of sclerotic agents, CBCT was used to observe distribution of the sclerotic agent in the gastric varices and afferent gastric veins. Investigated was whether the entire gastric varices and afferent gastric veins were confirmed by retrograde venography performed when the sclerotic agent was infused and by CBCT obtained after insertion of the sclerotic agent. RESULTS: On CBCT obtained after insertion of the sclerotic agent, distribution of sclerotic agents in the gastric varices and afferent gastric veins was clearly visualized. On the other hand, retrograde venography was inferior in detecting the area of distribution of sclerotic agents and the afferent gastric veins. CONCLUSION: Application of CBCT is helpful to precisely evaluate the distribution of sclerotic agents in B-RTO. PMID- 23808370 TI - Lightweight polypropylene mesh fixation in laparoscopic incisional hernia repair. AB - INTRODUCTION: The choice of the mesh and fixation methods in laparoscopic incisional hernia repair is a crucial issue in preventing complications and recurrence. The authors report a series of 40 consecutive laparoscopic incisional hernia repairs, focusing on the use of lightweight polypropylene mesh and on the way of mesh fixation. MATERIAL AND METHODS: Forty laparoscopic incisional hernia repairs performed consecutively in 38 patients (16 males, 22 females) were retrospectively evaluated. Patients were divided into two groups depending on tacks used: Titanium tacks vs absorbable tacks. RESULTS: All patients received totally laparoscopic incisional hernia repair by the use of lightweight polypropylene mesh. No major post-operative complications were reported. Post operative pain (evaluated by VNS) was higher in Group A (titanium tacks, p < 0.05). No differences in follow-up as well as in recurrence incidence (one case in both groups, <6 months time interval) were reported. CONCLUSIONS: SecurestrapTM absorbable tacks are safe and effective and easy to use and did not increase the risk of mesh dislocation compared with non-absorbable tacks. The specific design well fits the lightweight polypropylene mesh PhysiomeshTM. Further evaluations in larger randomized studies are needed to confirm these preliminary data. PMID- 23808371 TI - Development of a novel controllable, multidirectional, reusable metallic port with a wide working space. AB - BACKGROUND: Endoscopic surgery is currently a standard procedure in many countries. Furthermore, conventional four-port laparoscopic cholecystectomy is developing into a single-port procedure. However, in many developing countries, disposable medical products are expensive and adequate medical waste disposable facilities are absent. Advanced medical treatments such as laparoscopic or single port surgeries are not readily available in many areas of developing countries, and there are often no other sterilization methods besides autoclaving. Moreover, existing reusable metallic ports are impractical and are thus not widely used. MATERIAL AND METHODS: We developed a novel controllable, multidirectional single port device that can be autoclaved, and with a wide working space, which was employed in five patients. RESULTS: In all patients, laparoscopic cholecystectomy was accomplished without complications. CONCLUSION: Our device facilitates single port surgery in areas of the world with limited sterilization methods and offers a novel alternative to conventional tools for creating a smaller incision, decrease postoperative pain, and improve cosmesis. This novel device can also lower the cost of medical treatment and offers a promising tool for major surgeries requiring a wide working space. PMID- 23808372 TI - Low-temperature combustion chemistry of n-butanol: principal oxidation pathways of hydroxybutyl radicals. AB - Reactions of hydroxybutyl radicals with O2 were investigated by a combination of quantum-chemical calculations and experimental measurements of product formation. In pulsed-photolytic Cl-initiated oxidation of n-butanol, the time-resolved and isomer-specific product concentrations were probed using multiplexed tunable synchrotron photoionization mass spectrometry (MPIMS). The interpretation of the experimental data is underpinned by potential energy surfaces for the reactions of O2 with the four hydroxybutyl isomers (1-hydroxybut-1-yl, 1-hydroxybut-2-yl, 4 hydroxybut-2-yl, and 4-hydroxybut-1-yl) calculated at the CBS-QB3 and RQCISD(T)/cc-pVinfinityZ//B3LYP/6-311++G(d,p) levels of theory. The observed product yields display substantial temperature dependence, arising from a competition among three fundamental pathways: (1) stabilization of hydroxybutylperoxy radicals, (2) bimolecular product formation in the hydroxybutyl + O2 reactions, and (3) decomposition of hydroxybutyl radicals. The 1-hydroxybut-1-yl + O2 reaction is dominated by direct HO2 elimination from the corresponding peroxy radical forming butanal as the stable coproduct. The chemistry of the other three hydroxybutylperoxy radical isomers mainly proceeds via alcohol-specific internal H-atom abstractions involving the H atom from either the -OH group or from the carbon attached to the -OH group. We observe evidence of the recently reported water elimination pathway (Welz et al. J. Phys. Chem. Lett. 2013, 4 (3), 350-354) from the 4-hydroxybut-2-yl + O2 reaction, supporting its importance in gamma-hydroxyalkyl + O2 reactions. Experiments using the 1,1-d2 and 4,4,4-d3 isotopologues of n-butanol suggest the presence of yet unexplored pathways to acetaldehyde. PMID- 23808373 TI - Deep eutectic solvent-assisted synthesis of biodegradable polyesters with antibacterial properties. AB - Bacterial infection related to the implantation of medical devices represents a serious clinical complication, with dramatic consequences for many patients. In past decades, numerous attempts have been made to develop materials with antibacterial and/or antifouling properties by the incorporation of antibiotic and/or antiseptic compounds. In this context, deep eutectic solvents (DESs) are acquiring increasing interest not only as efficient carriers of active principle ingredients (APIs) but also as assistant platforms for the synthesis of a wide repertoire of polymer-related materials. Herein, we have successfully prepared biodegradable poly(octanediol-co-citrate) polyesters with acquired antibacterial properties by the DES-assisted incorporation of quaternary ammonium or phosphonium salts into the polymer network. In the resulting polymers, the presence of these salts (i.e., choline chloride, tetraethylammonium bromide, hexadecyltrimethylammonium bromide, and methyltriphenylphosphonium bromide) inhibits bacterial growth in the early postimplantation steps, as tested in cultures of Escherichia coli on solid agar plates. Later, positive polymer cytocompatibility is expected to support cell colonization, as anticipated from in vitro preliminary studies with L929 fibroblasts. Finally, the attractive elastic properties of these polyesters permit matching those of soft tissues such as skin. For all of these reasons, we envisage the utility of some of these antibacterial, biocompatible, and biodegradable polyesters as potential candidates for the preparation of antimicrobial wound dressings. These results further emphasize the enormous versatility of DES-assisted synthesis for the incorporation, in the synthesis step, of a wide palette of APIs into polymeric networks suitable for biomedical applications. PMID- 23808374 TI - Response to comment on "experimental energy barriers to anions transporting through nanofiltration membranes". PMID- 23808375 TI - Synthesis, characterization, and electrochemical studies of PPh(3-n)(dipp)(n) (dipp = 2,6-diisopropylphenyl): steric and electronic effects on the chemical and electrochemical oxidation of a homologous series of triarylphosphines and the reactivities of the corresponding phosphoniumyl radical cations. AB - Activation barriers to the electrochemical oxidation for the series PPh3-n(dipp)n (dipp = 2,6-diisopropylphenyl) in CH2Cl2/Bu4NPF6 were measured using large amplitude FT ac voltammetry. Increasing substitution across this series, which offers the widest range of steric requirements across any analogous series of triarylphosphines reported to date, increases the energetic barrier to electron transfer; values of 18, 24, and 25 kJ mol(-1) were found for compounds with n = 1, 2, and 3, respectively. These values are significantly greater than those calculated for outer sphere activation barriers, with deviations between observed and calculated values increasing with the number of dipp ligands. This suggests that the steric congestion afforded by these bulky substituents imposes significant reorganizational energy on the electron transfer processes. This is the first investigation of the effect of sterics on the kinetics of heterogeneous electron transfer across a structurally homologous series. Increased alkyl substitution across the series also increases the chemical reversibility of the oxidations and decreases the oxidation peak potentials. As the compounds for which n = 1 and 2 are novel, the synthetic strategies employed in their preparation are described, along with their full spectroscopic, physical, and crystallographic characterization. Optimal synthesis when n = 1 is via a Grignard reagent, whereas when n = 2 an aryl copper reagent must be employed, as use of a Grignard results in reductive coupling. Chemical oxidation studies were performed to augment the electrochemical work; the O, S, and Se oxidation products for the parent triarylphosphines for which n = 1 and 2 were isolated and characterized. PMID- 23808376 TI - Match running performance fluctuations in elite soccer: indicative of fatigue, pacing or situational influences? AB - The aims of this study were to: (1) quantify match running performance in 5-min periods to determine if players fatigue or modulate high-intensity running according to a pacing strategy, and (2) examine factors impacting high-intensity running such as score line, match importance and the introduction of substitutes. All players were analysed using a computerised tracking system. Maintaining 'high' levels of activity in the first half resulted in a 12% reduction (P < 0.01) in the second half for high-intensity running (effect size [ES]: 0.8), while no changes were observed in 'moderate' and 'low' groups (ES: 0.0-0.2). The 'high' group covered less (P < 0.01) high-intensity running in the initial 10-min of the second versus first half (ES: 0.6-0.7), but this was not observed in 'moderate' and 'low' groups (ES: 0.2-0.4). After the most intense periods, players demonstrated an 8% drop in high-intensity running (P < 0.05) compared to the match average (ES: 0.2) and this persisted for 5-min before recovering. Players covered similar high-intensity running distances in matches with differing score lines but position-specific trends indicated central defenders covered 17% less (P < 0.01) and attackers 15% more high-intensity running during matches that were heavily won versus lost (ES: 0.9). High-intensity running distances were comparable in matches of differing importance, but between-half trends indicated that only declines (P < 0.01) occurred in the second half of critical matches (ES: 0.2). Substitutes covered 15% more (P < 0.01) high intensity running versus the same time period when completing a full match (ES: 0.5). The data demonstrate that high-intensity running in the second half is impacted by the activity of the first half and is reduced for 5-min after intense periods. High-intensity running is also influenced by score line and substitutions but not match importance. More research is warranted to establish if fluctuations in match running performance are primarily a consequence of fatigue, pacing or tactical and situational influences. PMID- 23808377 TI - Dravet syndrome: new potential genetic modifiers, imaging abnormalities, and ictal findings. AB - PURPOSE: Dravet syndrome is an autosomal dominant epileptic encephalopathy of childhood, which is caused mainly by SCN1A and PCHD19 mutations. Although Dravet syndrome is well recognized, the causes of acute encephalopathy are still elusive, and reported data on ictal electroencephalography (EEG) and structural brain abnormalities are scarce. METHODS: We studied 30 children who fulfilled the clinical criteria for Dravet syndrome. All patients were screened for SCN1A mutations and 25 for POLG mutations with bidirectional sequencing. Clinical data, including etiologic studies done as part of the clinical workup, were collected from hospital charts. Ictal video-EEG recordings and magnetic resonance (MR) images were reanalyzed by the authors. KEY FINDINGS: SCN1A mutations were found in 25 patients (83%). Two SCN1A mutation-negative patients had chromosomal translocations involving chromosomes 9 and X, and one had a mutation in PCDH19. Prolonged seizures were associated with acute encephalopathy in three SCN1A mutation-positive patients. One showed evidence of a significant hypoxic-ischemic event during status epilepticus. The other two demonstrated new persistent neurologic deficits postictally; they both carried heterozygous POLG variants (p.Trp748Ser or p.Gly517Val). Hippocampal sclerosis or loss of gray-white matter definition in the temporal lobe was observed in 7 of 18 patients who had MRI after age 3 years (39%). Motor seizures were recorded on video-EEG for 15 patients, of whom 12 were younger than 6 years at recording; 11 patients (73%) showed posterior onsets. SIGNIFICANCE: Our data imply that a heterozygous X;9 translocation and rare POLG variants may modify the clinical features of Dravet syndrome. The latter may increase susceptibility for acute encephalopathy. Temporal lobe abnormalities are common in patients imaged after 3 years of age. Focal seizures seem to localize predominantly in the posterior regions in young children with Dravet syndrome. PMID- 23808379 TI - Fetal biometry: does patient ethnicity matter? AB - OBJECTIVE: To determine if fetal biometry varies according to race. METHODS: We performed a retrospective chart review of prenatal ultrasounds completed in our Perinatal Center from January 2009 to December 2010. Singleton pregnancies 17 to 22.9 weeks were included. Pregnancies complicated by IUGR, fetal anomalies, chronic maternal diseases, or dated by an ultrasound after the first trimester were excluded. Biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), femur length (FL), and humerus length (HL) were compared between African Americans (AA), Caucasians, and Hispanics using ANOVA and Student t-test. RESULTS: Included were 1327 AA, 147 Caucasian, and 86 Hispanic subjects. The AC was significantly smaller in AA than Caucasians (p = 0.008). There was no difference between AA and Caucasians in BPD, HC, FL, or HL. There were no differences between Hispanics and either Caucasians or AA in any of the biometries evaluated. CONCLUSIONS: A single fetal growth curve is not applicable across all ethnicities. AA fetuses have smaller AC then Caucasian fetuses from 17 to 22.9 weeks, which is typically the period when anatomic surveys are performed. Because AC contributes heavily to estimated fetal weight calculations, physicians may be over estimating growth restriction in AA patients. Ethnicity-specific fetal growth curves are indicated to limit unnecessary follow up. PMID- 23808380 TI - Thermodynamically stable dispersions of quantum dots in a nematic liquid crystal. AB - Using transmittance electron microscopy, fluorescence and polarizing optical microscopy, optical spectroscopy, and fluorescent correlation spectroscopy, it was shown that CdSe/ZnS quantum dots coated with a specifically designed surfactant were readily dispersed in nematic liquid crystal (LC) to form stable colloids. The mixture of an alkyl phosphonate and a dendritic surfactant, where the constituent molecules contain promesogenic units, enabled the formation of thermodynamically stable colloids that were stable for at least 1 year. Stable colloids are formed due to minimization of the distortion of the LC ordering around the quantum dots. PMID- 23808378 TI - Functional pharmacology of H1 histamine receptors expressed in mouse preoptic/anterior hypothalamic neurons. AB - BACKGROUND AND PURPOSE: Histamine H1 receptors are highly expressed in hypothalamic neurons and mediate histaminergic modulation of several brain controlled physiological functions, such as sleep, feeding and thermoregulation. In spite of the fact that the mouse is used as an experimental model for studying histaminergic signalling, the pharmacological characteristics of mouse H1 receptors have not been studied. In particular, selective and potent H1 receptor agonists have not been identified. EXPERIMENTAL APPROACH: Ca(2+) imaging using fura-2 fluorescence signals and whole-cell patch-clamp recordings were carried out in mouse preoptic/anterior hypothalamic neurons in culture. KEY RESULTS: The H1 receptor antagonists mepyramine and trans-triprolidine potently antagonized the activation by histamine of these receptors with IC50 values of 0.02 and 0.2 MUM respectively. All H1 receptor agonists studied had relatively low potency at the H1 receptors expressed by these neurons. Methylhistaprodifen and 2-(3 trifluoromethylphenyl)histamine had full-agonist activity with potencies similar to that of histamine. In contrast, 2-pyridylethylamine and betahistine showed only partial agonist activity and lower potency than histamine. The histamine receptor agonist, 6-[2-(4-imidazolyl)ethylamino]-N-(4 trifluoromethylphenyl)heptanecarboxamide (HTMT) had no agonist activity at the H1 receptors H1 receptors expressed by mouse preoptic/anterior hypothalamic neurons but displayed antagonist activity. CONCLUSIONS AND IMPLICATIONS: Methylhistaprodifen and 2-(3-trifluoromethylphenyl)histamine were identified as full agonists of mouse H1 receptors. These results also indicated that histamine H1 receptors in mice exhibited a pharmacological profile in terms of agonism, significantly different from those of H1 receptors expressed in other species. PMID- 23808381 TI - Accommodative response under monocular and binocular conditions as a function of phoria in symptomatic and asymptomatic subjects. AB - BACKGROUND: The neurological linkage of vergence and accommodation is a factor which can affect accuracy of accommodation, is in turn associated with symptoms of near-related visual discomfort. The purpose of this study was to compare the accommodative response under monocular and binocular conditions in symptomatic and asymptomatic participants with different near phorias. METHODS: Seventy students at Zahedan University of Medical Sciences, Iran (mean age: 21.2 +/- 1.7 years; age range: 18 to 25 years) participated. The participants were divided into symptomatic and asymptomatic groups according to the convergence insufficiency symptom survey questionnaire score. The type and magnitude of the near dissociated phoria were determined using the prism neutralised cover test. The accommodative lag was measured by the 'monocular estimate method' (MEM) retinoscopy, at first under binocular and then monocular conditions. Testing distance was 40 cm. RESULTS: The accommodative lag in exophoric participants was lower under binocular conditions compared to monocular and in esophoric participants greater under binocular than under monocular conditions. The binocular accommodative response (AR) was greatest in participants with high exophoria at near vision and least in participants with esophoria at near vision (p < 0.001; one-way analysis of variance). The difference between binocular lag and monocular lag was significantly greater in symptomatic participants than in asymptomatic participants in both exophoria (p < 0.001) and esophoria (p = 0.009) (independent samples t-test). CONCLUSION: The near binocular accommodative response was related to near heterophoria. Higher levels of vergence accommodation, resulting in differences in lag under monocular and binocular conditions, may be a factor in near point asthenopia. PMID- 23808382 TI - Telomere length and telomerase activity in the context of menopause. AB - Telomere length is a marker of cell aging, since shorter telomeres and a higher rate of telomere shortening with time are associated with poorer health status and survival. Various factors may determine telomere length and the function of the telomere maintenance system, including the hereditary load and several modifiable variables such as diet and lifestyle. Telomere length and telomerase activity were investigated extensively in a variety of diseases, such as malignancies (i.e. breast and colon cancer), cardiovascular disease and its related metabolic risk factors, cognitive, mental and psychiatric conditions, and many others. Some evidence points at an association between longer endogenous estrogen exposure (length of reproductive years of life) and greater telomere length and lower telomerase activity. However, there is probably no correlation in regard to menopause per se or the use of hormone therapy. Changing the nutrition and implementing healthy lifestyles may improve the telomere/telomerase parameters in postmenopausal women, but better understanding of this system is still needed. PMID- 23808383 TI - Effect of feeding dried distillers' grains with solubles on milk yield and milk composition of cows in mid-lactation and digestibility in sheep. AB - We evaluated the effect of three sources of dried distillers' grains with solubles (DDGS) in diets of mid-lactating dairy cows on milk production and milk composition and on digestibility in sheep. DDGS from wheat, corn and barley (DDGS1 ), wheat and corn (DDGS2 ) and wheat (DDGS3 ) were studied and compared with a rapeseed meal (RSM). RSM and DDGS were characterized through in situ crude protein (CP) degradability. Nutrient digestibility was determined in sheep. Twenty-four multiparous cows were used in a 4 * 4 Latin square design with 28-day periods. Treatments included total mixed rations containing as primary protein sources RSM (control), DDGS1 (D1), DDGS2 (D2) or DDGS3 (D3). RSM contained less rapidly degradable CP (fraction a), more potentially degradable CP (fraction b) and more rumen undegradable CP (UDP) than the three DDGS. In vivo digestibility of RSM organic matter was similar to DDGS. Calculated net energy for lactation (NEL ) was lower for RSM (7.4 MJ/kg DM) than for DDGS, which averaged 7.7 MJ/kg DM. Cows' dry matter intake did not differ between diets (21.7 kg/day). Cows fed D1 yielded more milk than those fed D3 (31.7 vs. 30.4 kg/day); no differences were found between control and DDGS diets (31.3 vs. 31.1 kg/day). Energy corrected milk was similar among diets (31.2 kg/day). Diets affected neither milk fat concentration (4.0%) nor milk fat yield (1.24 kg/day). Milk protein yield of control (1.12 kg/day) was significantly higher than D3 (1.06 kg/day) but not different form D1 and D2 (1.08 kg/day each). Feeding DDGS significantly increased milk lactose concentration (4.91%) in relation to control (4.81%). DDGS can be a suitable feed in relation to RSM and can be fed up to 4 kg dry matter per day in rations of dairy cows in mid-lactation. However, high variation of protein and energy values of DDGS should be considered when included in diets of dairy cows. PMID- 23808385 TI - A simple and efficient protocol for the treatment of zebrafish colonies infected with parasitic nematodes. AB - Abstract Our zebrafish colony experienced a period of increased mortality rate of 6.5 times more deaths per month in a colony of over 13,000 zebrafish (Danio rerio), which developed over 3 months. We observed that before death, affected fish appeared emaciated, often with an abdominal bulge. We performed dissection on 18 fish that had this appearance and found in 15 that their gut was infected with a nematode that closely resembled Pseudocapillaria tomentosa. We devised a treatment protocol for this nematode infection, which involved addition of fenbendazole, a drug used to treat nematode infections in cattle and sheep, to the fish feed. Fenbendazole produced no severe side effects in the fish and several treatments have effectively eradicated the parasite from our colony. The mortality rate of our fish has decreased to a value of 0.7%/month (p<0.001, equal to that before the infection). We propose this protocol as an inexpensive alternative to having to rederive an entire colony from bleached eggs, and as a prophylactic measure used in quarantine facilities on a regular basis. PMID- 23808384 TI - Lysophosphatidic acid receptor-2 deficiency confers protection against bleomycin induced lung injury and fibrosis in mice. AB - Idiopathic pulmonary fibrosis is a devastating disease characterized by alveolar epithelial cell injury, the accumulation of fibroblasts/myofibroblasts, and the deposition of extracellular matrix proteins. Lysophosphatidic acid (LPA) signaling through its G protein-coupled receptors is critical for its various biological functions. Recently, LPA and LPA receptor 1 were implicated in lung fibrogenesis. However, the role of other LPA receptors in fibrosis remains unclear. Here, we use a bleomycin-induced pulmonary fibrosis model to investigate the roles of LPA2 in pulmonary fibrogenesis. In the present study, we found that LPA2 knockout (Lpar2(-/-)) mice were protected against bleomycin-induced lung injury, fibrosis, and mortality, compared with wild-type control mice. Furthermore, LPA2 deficiency attenuated the bleomycin-induced expression of fibronectin (FN), alpha-smooth muscle actin (alpha-SMA), and collagen in lung tissue, as well as levels of IL-6, transforming growth factor-beta (TGF-beta), and total protein in bronchoalveolar lavage fluid. In human lung fibroblasts, the knockdown of LPA2 attenuated the LPA-induced expression of TGF-beta1 and the differentiation of lung fibroblasts to myofibroblasts, resulting in the decreased expression of FN, alpha-SMA, and collagen, as well as decreased activation of extracellular regulated kinase 1/2, Akt, Smad3, and p38 mitogen-activated protein kinase. Moreover, the knockdown of LPA2 with small interfering RNA also mitigated the TGF-beta1-induced differentiation of lung fibroblasts. In addition, LPA2 deficiency significantly attenuated the bleomycin-induced apoptosis of alveolar and bronchial epithelial cells in the mouse lung. Together, our data indicate that the knockdown of LPA2 attenuated bleomycin-induced lung injury and pulmonary fibrosis, and this may be related to an inhibition of the LPA-induced expression of TGF-beta and the activation and differentiation of fibroblasts. PMID- 23808386 TI - Validating a screening tool for mental health and substance use risk in an Indigenous prison population. AB - INTRODUCTION AND AIMS: The Indigenous Risk Impact Screen (IRIS) is a validated culturally appropriate and widely used tool in the community for assessing substance use and mental disorder. This research aimed to assess the utility of this tool in an Indigenous prison population. DESIGN AND METHODS: The study used data collected from a cross-sectional study of mental health among Indigenous inmates in Queensland custodial centres (n = 395, 84% male). Participants were administered a modified version of the IRIS and International Classification of Diseases-10 diagnoses of substance use, depressive and anxiety disorders obtained using the Composite International Diagnostic Interview (CIDI). The concurrent validity of the modified IRIS was assessed against those of the CIDI. RESULTS: Three hundred and twelve people screened as high risk for a substance use disorder and 179 were high risk for mental problems. There were 73% of males and 88% of females diagnosed with a mental disorder. The IRIS was an effective screener for substance use disorders, with high sensitivity of 94% and low specificity of 33%. The screener was less effective in identifying depression (sensitivity 82%, specificity 59%) and anxiety (sensitivity 68%, specificity 60%). DISCUSSION: The IRIS is the first culturally appropriate screening instrument to be validated for the risk of drug and alcohol and mental disorder among Indigenous adults in custody. CONCLUSIONS: This study demonstrated that the IRIS is a valid tool for screening of alcohol and drug use risk among an incarcerated Indigenous population. The IRIS could offer an opportunity to improve the identification, treatment and health outcomes for incarcerated Indigenous adults. PMID- 23808387 TI - Hydrated alkali metal ions: spectroscopic evidence for clathrates. AB - The origin of enhanced abundances for some hydrated alkali metal ions, M(+)(H2O)n, where M = Cs, Rb, K, Na, and Li with between 17 and 21 water molecules attached was investigated with infrared photodissociation (IRPD) spectroscopy and by blackbody infrared radiative dissociation (BIRD) at 133 K. The abundances of clusters of Cs(+), Rb(+), and K(+) with 18 and 20 water molecules are anomalously high compared to the corresponding clusters of Na(+), and Li(+) with 20 water molecules has only a slightly enhanced abundance. BIRD results indicate that the anomalous abundance at n = 20 for the larger ions is due to the high stability of this cluster, and the significant instability of the next largest cluster, consistent with a stable core structure with 20 water molecules. IRPD spectra in the free-OH region (~3600-3800 cm(-1)) for Cs(+), Rb(+), and K(+) with 18 and 20 water molecules indicates that water molecules with a free-OH stretch accept two hydrogen bonds and donate one hydrogen bond (acceptor-acceptor-donor water) to other water molecules. No acceptor-donor (AD) bands are observed, consistent with clathrate structures for these ions. In contrast, the AD band is significant for Na(+), indicating that these clusters adopt different structures. Results for Li(+) indicate a contribution from clathrate structures at n = 20, but not at other cluster sizes. This analysis is supported by the relative intensities of bands in the hydrogen-bonding region for n = 20. PMID- 23808388 TI - Testing evolutionary models to explain the process of nucleotide substitution in gut bacterial 16S rRNA gene sequences. AB - The 16S rRNA gene has been widely used as a marker of gut bacterial diversity and phylogeny, yet we do not know the model of evolution that best explains the differences in its nucleotide composition within and among taxa. Over 46 000 good quality near-full-length 16S rRNA gene sequences from five bacterial phyla were obtained from the ribosomal database project (RDP) by study and, when possible, by within-study characteristics (e.g. anatomical region). Using alignments (RDPX and MUSCLE) of unique sequences, the FINDMODEL tool available at http://www.hiv.lanl.gov/ was utilized to find the model of character evolution (28 models were available) that best describes the input sequence data, based on the Akaike information criterion. The results showed variable levels of agreement (from 33% to 100%) in the chosen models between the RDP-based and the MUSCLE based alignments among the taxa. Moreover, subgroups of sequences (using either alignment method) from the same study were often explained by different models. Nonetheless, the different representatives of the gut microbiota were explained by different proportions of the available models. This is the first report using evolutionary models to explain the process of nucleotide substitution in gut bacterial 16S rRNA gene sequences. PMID- 23808389 TI - The terminal pathway of the complement system is activated in focal penetrating but not in mild diffuse traumatic brain injury. AB - The complement system plays an important role in the inflammatory response activated by many central nervous system disorders. However, its significance in traumatic diffuse traumatic axonal injury (TAI) is not fully known. Here we analyze the complement activity in two rat models of traumatic brain injury (TBI); a focal penetration injury (pen-TBI) and a rotational acceleration injury (rot-TBI) that leads to a mild TAI. We used in situ hybridization to examine the distribution of mRNA for C1q and C3 and immunohistochemistry to examine the presence of the C3 protein and C5b-9 complex at 1-5 days after injury. We found a time-dependent complement activity in both models. However, the responses caused by the two models were different. We detected C5b-9 surrounding the cavity in pen TBI, but C5b-9 was not found in the rot-TBI. Our findings suggest that the terminal complement pathway is progressed to the formation of the C5b-9 membrane attack complex only in the penetrating TBI but not in isolated TAI model. This indicates that the complement activation does not lead to membrane-damaging effects and a subsequent secondary axotomy in TAI by the terminal complex C5b-9. The role of complement activation in TAI is unclear, but might indicate an alternative function following rot-TBI, such as opsonizing the synapses for elimination. PMID- 23808390 TI - IL26 gene inactivation in Equidae. AB - Interleukin-26 (IL26) is a member of the IL10 cytokine family. The IL26 gene is located between two other well-known cytokines genes of this family encoding interferon-gamma (IFNG) and IL22 in an evolutionary conserved gene cluster. In contrast to humans and most other mammals, mice lack a functional Il26 gene. We analyzed the genome sequences of other vertebrates for the presence or absence of functional IL26 orthologs and found that the IL26 gene has also become inactivated in several equid species. We detected a one-base pair frameshift deletion in exon 2 of the IL26 gene in the domestic horse (Equus caballus), Przewalski horse (Equus przewalskii) and donkey (Equus asinus). The remnant IL26 gene in the horse is still transcribed and gives rise to at least five alternative transcripts. None of these transcripts share a conserved open reading frame with the human IL26 gene. A comparative analysis across diverse vertebrates revealed that the IL26 gene has also independently been inactivated in a few other mammals, including the African elephant and the European hedgehog. The IL26 gene thus appears to be highly variable, and the conserved open reading frame has been lost several times during mammalian evolution. PMID- 23808391 TI - Lutein administration to pregnant women with gestational diabetes mellitus is associated to a decrease of oxidative stress in newborns. AB - Oxidative stress (OS) is defined as an imbalance between pro- and antioxidant factors that can lead to cellular and tissue damage. Under condition of gestational diabetes, OS is exacerbated and can cause vascular dysfunction in the placenta, leading to fetal and perinatal complications. We investigated the oxidative status of diabetic pregnant women and of their babies. A group of those diabetic women received lutein, and another group did not receive anything. In order to verify a possible antioxidant function of lutein, we compared the OS values of the two groups. OS appeared lower in treated gravidas than in untreated ones; however, there was not a statistically significant difference between the two groups. As far as newborns are concerned, there was a significant difference of OS values between babies born to mothers treated with lutein and newborns to mothers untreated at 2 h of life. However, at 48 h, there was not a significant difference between the two groups. In conclusion, lutein administration during pregnancy significantly reduced neonatal OS at birth. Further studies are necessary to evaluate the effects of combined administration to mother and infants. PMID- 23808392 TI - Factors attributing to the failure of endometrial sampling in women with postmenopausal bleeding. AB - OBJECTIVE: To determine which doctor- and patient-related factors affect failure of outpatient endometrial sampling in women with postmenopausal bleeding, and to develop a multivariable prediction model to select women with a high probability of failed sampling. DESIGN: Prospective multicenter cohort study. SETTING: Three teaching hospitals in the Netherlands. POPULATION: Women presenting with postmenopausal bleeding with an indication for endometrial sampling. METHODS: Multivariable logistic regression was performed to evaluate the impact of doctor's training level and patient's characteristics on failure of sampling. MAIN OUTCOME MEASURES: Failure of endometrial sampling, classified as technical failure or insufficient tissue for diagnosis. RESULTS: In 74 (20.8%) of the 356 included women, sampling technically failed, and in 84 (29.8%) the amount of tissue was insufficient for diagnosis. Nulliparity [odds ratio (OR) 3.8, 95% confidence interval (CI) 1.8-7.9] and advanced age (OR 1.03 per year, 95% CI 1.00 1.06) were associated with technical failure. Advanced age was associated with insufficient sampling (OR 1.04 per year, 95% CI 1.01-1.07), and endometrial thickness >12 mm decreased the chance of insufficient sampling (OR 0.3, 95%CI 0.1 0.8). The prediction model for total failure had an area under the ROC curve of 0.64 (95% CI 0.58-0.70). CONCLUSIONS: In women with postmenopausal bleeding, the failure rate of endometrial sampling is relatively high and is associated with nulliparity and advanced age. Endometrial thickness >12 mm decreased the chance of failure. A multivariable prediction model for total failure based on patient characteristics has a moderate capacity to discriminate between women at high or low risk of failure. PMID- 23808393 TI - Parental HIV disclosure in Burkina Faso: experiences and challenges in the era of HAART. AB - Increasingly parents living with HIV will have to confront the dilemmas of concealing their lifelong treatment or disclosing to their children exposed to their daily treatment practices. However, limited data are available regarding parental HIV disclosure to children in Burkina Faso. Do parents on antiretroviral therapy disclose their HIV status to their children? What drives them? How do they proceed and how do children respond? We conducted in-depth interviews with 63 parents of children aged seven and above where the parents had been in treatment for more than 3 years in two major cities of Burkina Faso. Interviews addressed parental disclosure and the children's role in their parents' treatment. The rate of parental HIV status disclosure is as high as that of non disclosure. Factors associated with parental disclosure include female sex, parent's older age, parent's marital history and number of children. After adjustment, it appears that the only factor remaining associated with parental disclosure was the female gender of the parent. In most of the cases, children suspected, and among non-disclosers many believed their children already knew without formal disclosure. Age of the children and history of divorce or widowhood were associated with parental disclosure. Most parents believed children do not have the necessary emotional skills to understand or that they cannot keep a secret. However, parents who disclosed to their children did not experience blame nor was their secret revealed. Rather, children became treatment supporters. Challenges to parental HIV disclosure to children are neither essential nor specific since disclosure to adults is already difficult because of perceived risk of public disclosure and subsequent stigma. However, whether aware or not of their parents' HIV-positive status, children contribute positively to the care of parents living with HIV. Perceptions about children's vulnerability and will to protect them against stigma lead parents to delay disclosure and not to overwhelm them with their experience of living with HIV. Finally, without institutional counselling support, disclosure to children remains a challenge for both parents and children, which suggests a need for rethinking of current counselling practices. PMID- 23808394 TI - Cementation of colloidal particles on electrodes in a galvanic microreactor. AB - We have studied the processes leading to the cementation of colloidal particles during their autonomous assembly on corroding copper electrodes within a Cu-Au galvanic microreactor. We determined the onset of particle immobilization through particle tracking, monitored the dissolution of copper as well as the deposition of insoluble products of the corrosion reactions in situ, and showed that particle immobilization initiated after reaction products (RPs) began to deposit on the electrode substrate. We further demonstrated that the time and the extent of RP precipitation and thus the strength of the particle-substrate bond could be tuned by varying the amount of copper in the system and the microreactor pH. The ability to cement colloidal particles at locations undergoing corrosion illustrates that the studied colloidal assembly approach holds potential for applications in dynamic material property adaptation. PMID- 23808395 TI - Increased neocortical expression of the P2X7 receptor after status epilepticus and anticonvulsant effect of P2X7 receptor antagonist A-438079. AB - PURPOSE: ATP is an essential transmitter/cotransmitter in neuron function and pathophysiology and has recently emerged as a potential contributor to prolonged seizures (status epilepticus) through the activation of the purinergic ionotropic P2X7 receptor (P2X7R). Increased P2X7R expression has been reported in the hippocampus, and P2X7R antagonists reduced seizure-induced damage to this brain region. However, status epilepticus also produces damage to the neocortex. The present study was designed to characterize P2X7R in the neocortex and assess effects of P2X7R antagonists on cortical injury after status epilepticus. METHODS: Status epilepticus was induced in mice by intraamygdala microinjection of kainic acid. Specific P2X7R inhibitors were administered into the ventricle before seizure induction, and cortical electroencephalography and behavior was recorded to assess seizure severity. P2X7R expression was examined in neocortex up to 24 h after status epilepticus, in epileptic mice, and in resected neocortex from patients with pharmacoresistent temporal lobe epilepsy (TLE). In addition, the induction of P2X7R after status epilepticus was investigated using transgenic P2X7R reporter mice, which express enhanced green fluorescent protein under the control of the p2x7r promoter. KEY FINDINGS: Status epilepticus resulted in increased P2X7R protein levels in the neocortex of mice. Neocortical P2X7 receptor levels were also elevated in mice that developed epilepsy after status epilepticus and in resected neocortex from patients with pharmacoresistent TLE. Immunohistochemistry determined that neurons were the major cell population transcribing the P2X7R in the neocortex within the first 8 h after status epilepticus, whereas in epileptic mice, P2X7R up-regulation occurred in microglia as well as in neurons. Pretreatment of mice with the specific P2X7R inhibitor A 438079 reduced electrographic and clinical seizure severity during status epilepticus and reduced seizure-induced neuronal death in the neocortex. SIGNIFICANCE: Our findings identify neurons in the neocortex as an important site of P2X7R up-regulation after status epilepticus and in epilepsy, and provide support for the possible use of P2X7R antagonists for the treatment of status epilepticus and prevention of seizure-induced brain damage. PMID- 23808396 TI - Effect of fossil fuels on the parameters of CO2 capture. AB - The carbon dioxide capture is a more and more important issue in the design and operation of boilers and/or power stations because of increasing environmental considerations. Such processes, absorber desorber should be able to cope with flue gases from the use of different fossil primary energy sources, in order to guarantee a flexible, stable, and secure energy supply operation. The changing flue gases have significant influence on the optimal operation of the capture process, that is, where the required heating of the desorber is the minimal. Therefore special considerations are devoted to the proper design and control of such boiler and/or power stations equipped with CO2 capture process. PMID- 23808397 TI - In situ AFM imaging of Li-O2 electrochemical reaction on highly oriented pyrolytic graphite with ether-based electrolyte. AB - Understanding the lithium-oxygen (Li-O2) electrochemical reaction is of importance to improve reaction kinetics, efficiency, and mitigate parasitic reactions, which links to the strategy of enhanced Li-O2 battery performance. Many in situ and ex situ analyses have been reported to address chemical species of reduction intermediate and products, whereas details of the dynamic Li-O2 reaction have not as yet been fully unraveled. For this purpose, visual imaging can provide straightforward evidence, formation and decomposition of products, during the Li-O2 electrochemical reaction. Here, we present real-time and in situ views of the Li-O2 reaction using electrochemical atomic force microscopy (EC AFM). Details of the reaction process can be observed at nano-/micrometer scale on a highly oriented pyrolytic graphite (HOPG) electrode with lithium ion containing tetraglyme, representative of the carbon cathode and ether-based electrolyte extensively employed in the Li-O2 battery. Upon oxygen reduction reaction (ORR), rapid growth of nanoplates, having axial diameter of hundreds of nanometers, length of micrometers, and ~5 nm thickness, at a step edge of HOPG can be observed, which eventually forms a lithium peroxide (Li2O2) film. This Li2O2 film is decomposed during the oxygen evolution reaction (OER), for which the decomposition potential is related to a thickness. There is no evidence of byproduct analyzed by X-ray photoelectron spectroscopy (XPS) after first reduction and oxidation reaction. However, further cycles provide unintended products such as lithium carbonate (Li2CO3), lithium acetate, and fluorine related species with irregular morphology due to the degradation of HOPG electrode, tetraglyme, and lithium salt. These observations provide the first visualization of Li-O2 reaction process and morphological information of Li2O2, which can allow one to build strategies to prepare the optimum conditions for the Li-O2 battery. PMID- 23808398 TI - Cardosin A contains two vacuolar sorting signals using different vacuolar routes in tobacco epidermal cells. AB - Several vacuolar sorting determinants (VSDs) have been described for protein trafficking to the vacuoles in plant cells. Because of the variety in plant models, cell types and experimental approaches used to decipher vacuolar targeting processes, it is not clear whether the three well-known groups of VSDs identified so far exhaust all the targeting mechanisms, nor if they reflect certain protein types or families. The vacuolar targeting mechanisms of the aspartic proteinases family, for instance, are not yet fully understood. In previous studies, cardosin A has proven to be a good reporter for studying the vacuolar sorting of aspartic proteinases. We therefore propose to explore the roles of two different cardosin A domains, common to several aspartic proteinases [i.e. the plant-specific insert (PSI) and the C-terminal peptide VGFAEAA] in vacuolar sorting. Several truncated versions of the protein conjugated with fluorescent protein were made, with and without these putative sorting determinants. These domains were also tested independently, for their ability to sort other proteins, rather than cardosin A, to the vacuole. Fluorescent chimaeras were tracked in vivo, by confocal laser scanning microscopy, in Nicotiana tabacum cells. Results demonstrate that either the PSI or the C terminal was necessary and sufficient to direct fluorescent proteins to the vacuole, confirming that they are indeed vacuolar sorting determinants. Further analysis using blockage experiments of the secretory pathway revealed that these two VSDs mediate two different trafficking pathways. PMID- 23808399 TI - Barley metallothioneins differ in ontogenetic pattern and response to metals. AB - The barley genome encodes a family of 10 metallothioneins (MTs) that have not previously been subject to extensive gene expression profiling. We show here that expression of MT1a, MT2b1, MT2b2 and MT3 in barley leaves increased more than 50 fold during the first 10 d after germination. Concurrently, the root-specific gene MT1b1 was 1000-fold up-regulated. Immunolocalizations provided the first evidence for accumulation of MT1a and MT2a proteins in planta, with correlation to transcript levels. In developing grains, MT2a and MT4 expression increased 4- and 300-fold over a 28-day-period after pollination. However, among the MT grain transcripts MT2c was the most abundant, whereas MT4 was the least abundant. Excess Cu up-regulated three out of the six MTs expressed in leaves of young barley plants. In contrast, most MTs were down-regulated by excess Zn or Cd. Zn starvation led to up-regulation of MT1a, whereas Cu starvation up-regulated MT2a, which has two copper-responsive elements in the promoter. Arabidopsis lines constitutively overexpressing barley MT2a showed increased sensitivity to excess Cd and Zn but no Cu-induced response. We suggest that barley MTs are differentially involved in intracellular homeostasis of essential metal ions and that a subset of barley MTs is specifically involved in Cu detoxification. PMID- 23808400 TI - A dynamic system for delivering controlled bromine and chlorine vapor exposures to weanling swine skin. AB - CONTEXT: Assessing the hazards of accidental exposure to toxic industrial chemical (TIC) vapors and evaluating therapeutic compounds or treatment regimens require the development of appropriate animal models. OBJECTIVE: The objective of this project was to develop an exposure system for delivering controlled vapor concentrations of TICs to the skin of anesthetized weanling pigs. Injury levels targeted for study were superficial dermal (SD) and deep dermal (DD) skin lesions as defined histopathologically. MATERIALS AND METHODS: The exposure system was capable of simultaneously delivering chlorine or bromine vapor to four, 3-cm diameter exposure cups placed over skin between the axillary and inguinal areas of the ventral abdomen. Vapor concentrations were generated by mixing saturated bromine or chlorine vapor with either dried dilution air or nitrogen. RESULTS: Bromine exposure concentrations ranged from 6.5 * 10(-4) to 1.03 g/L, and exposure durations ranged from 1 to 45 min. A 7-min skin exposure to bromine vapors at 0.59 g/L was sufficient to produce SD injuries, while a 17-min exposure produced a DD injury. Chlorine exposure concentrations ranged from 1.0 to 2.9 g/L (saturated vapor concentration) for exposures ranging from 3 to 90 min. Saturated chlorine vapor challenges for up to 30 min did not induce significant dermal injuries, whereas saturated chlorine vapor with wetted material on the skin surface for 30-60 min induced SD injuries. DD chlorine injuries could not be induced with this system. CONCLUSION: The vapor exposure system described in this study provides a means for safely regulating, quantifying and delivering TIC vapors to the skin of weanling swine as a model to evaluate therapeutic treatments. PMID- 23808401 TI - Template for reporting results of biomarker testing of specimens from patients with non-small cell carcinoma of the lung. PMID- 23808402 TI - A multiplex technology platform for the rapid analysis of clinically actionable genetic alterations and validation for BRAF p.V600E detection in 1549 cytologic and histologic specimens. AB - CONTEXT: Current clinicopathologic assessment of malignant neoplastic diseases entails the analysis of specific genetic alterations that provide diagnostic, prognostic, or therapy-determining information. OBJECTIVE: To develop and validate a robust molecular method to detect clinically relevant mutations in various tissue types and anatomic pathology specimens. DESIGN: Genes of interest were amplified by multiplex polymerase chain reaction and sequence variants identified by liquid bead array cytometry. The BRAF assay was fully characterized by using plasmids and genomic DNA extracted from cell lines, metastatic colorectal cancer formalin-fixed, paraffin-embedded (FFPE) tissues, and thyroid nodule fine-needle aspirates. RESULTS: Qualitative multiplex assays for 22 different mutations in the BRAF, HRAS, KRAS, NRAS, or EGFR genes were established. The high signal-to-noise ratio of the technology enabled reproducible detection of BRAF c.1799T>A (p.V600E) at 0.5% mutant allele in 20 ng of genomic DNA. Precision studies with multiple operators and instruments showed very high repeatability and reproducibility with 100% (98.7%-100%) qualitative agreement among 292 individual measures in 38 runs. Evaluation of 1549 representative pathologic specimens in 2 laboratories relative to independent reference methods resulted in 99.0% (97.6%-99.6%) agreement for colorectal FFPE tissues (n = 416) and 98.9% (98.2%-99.4%) for thyroid fine-needle aspiration specimens (n = 1133) with an overall diagnostic odds ratio of 10 856 (2451-48 078). CONCLUSIONS: The multiplex assay system is a sensitive and reliable method to detect BRAF c.1799T>A mutation in colorectal and thyroid lesions. This optimized technology platform is suitable for the rapid analysis of clinically actionable genetic alterations in cytologic and histologic specimens. PMID- 23808403 TI - Template for reporting results of biomarker testing of specimens from patients with carcinoma of the colon and rectum. PMID- 23808404 TI - Introducing new College of American Pathologists reporting templates for cancer biomarkers. PMID- 23808405 TI - Determination of the minimum inhibitory concentration of Cryptococcus neoformans and Cryptococcus gattii against fluconazole by flow cytometry. AB - Recent studies have used flow cytometry (FCM) as an important alternative method to determine the antifungal susceptibility of yeasts compared to the broth microdilution Clinical and Laboratory Standards Institute (CLSI) reference procedure. We present a comparative study of the broth microdilution method and flow cytometry to assess the in vitro antifungal susceptibility of Cryptococcus neoformans (n = 16) and C. gattii (n = 24) to fluconazole. The minimum inhibitory concentration (MIC) assays by flow cytometry were defined as the lowest drug concentration that showed ~50% of the count of acridine orange negative cells compared to that of the growth control. Categorical classification showed all C. neoformans isolates were susceptible to fluconazole. Three isolates of C. gattii were susceptible dose-dependent and the remaining 21 isolates were classified as susceptible. MICs comparison of both methodologies demonstrated 100% categorical agreement of the results obtained for C. neoformans and C. gattii. The MICs obtained with the CLSI-approved method and flow cytometry were compared by the Spearman correlation test and a significant Pv = 0.001. The flow cytometric method has the advantage of analyzing a large and constant number of cells in less time, i.e., 9 h incubation for fluconazole using acridine orange versus 72 h for broth microdilution method. In conclusion, the two methods were comparable and flow cytometry method can expedite and improve the results of in vitro susceptibility tests of C. neoformans and C. gattii against fluconazole and also allows comparative studies in vitro/in vivo more rapidly, which along with clinical data, could assist in selecting the most appropriate treatment choice. PMID- 23808406 TI - Kininogen 1 and insulin-like growth factor binding protein 6: candidate serum biomarkers of proliferative vitreoretinopathy. AB - BACKGROUND: The aim was to validate whether kininogen 1 (KNG1) or insulin-like growth factor binding protein 6 (IGFBP-6) are serum biomarkers of proliferative vitreoretinopathy (PVR). METHODS: Samples from vitreous and corresponding serum samples were collected from patients with PVR. The donor vitreous samples and serum samples from healthy volunteers and volunteers who had undergone vitrectomies for other conditions were used as controls. The samples were subsequently analysed using Western blotting (WB) and enzyme-linked immunosorbent assay. RESULTS: The Western blotting outcomes indicated both IGFBP-6 and KNG1 could be specifically detected in the vitreous and serum samples of patients with PVR. The concentrations of KNG1 and IGFBP-6 were significantly higher in both vitreous and serum samples from patients with severe PVR than in the samples from patients with moderate PVR. The serum concentrations of KNG1 or IGFBP-6 had decreased by the post-vitrectomy examinations. The receiver operating characteristic (ROC) analyses when the concentrations of IGFBP-6 or KNG1 were greater than 181.4 pg/ml or 441.75 ng/ml, respectively, predicted severe PVR with both a sensitivity and specificity of over 70 per cent. When the concentrations of IGFBP-6 or KNG1 were greater than 98.5 pg/ml or 88.5 ng/ml, respectively, they predicted the PVR prognosis with both a sensitivity and specificity of 80 per cent. CONCLUSIONS: KNG1 and IGFBP-6 may be candidate serum biomarkers of PVR. PMID- 23808407 TI - Characterization of GFRalpha-1-positive and GFRalpha-1-negative spermatogonia in neonatal pig testis. AB - Type A spermatogonia, including spermatogonial stem cells, are primary cells that maintain spermatogenesis and produce spermatozoa. Many spermatogonial markers have been reported in rodents. However, few markers have been identified in pig spermatogonia. Despite the lack of information, it is necessary to separate pure spermatogonial cells from whole testicular cells to understand the mechanism of spermatogenic meiosis and to establish spermatogonial stem cells for further biotechnological studies. The purpose of this study was to identify glial cell derived neurotrophic factor receptor alpha-1 (GFRalpha-1) as a surface marker for early spermatogonia in neonatal pig testes. Histological analysis of 3-day-old pig testes revealed that type A spermatogonia, which lack heterochromatin, could be distinguished in neonatal pig testes. Immunohistochemistry of neonatal pig testes with GFRalpha-1 antibody identified that some of the spermatogonial cells expressed GFRalpha-1 on the cell membrane. Co-immunostaining with both GFRalpha-1 and protein gene product 9.5 (PGP 9.5) detected PGP 9.5 in all spermatogonia of neonatal pig testes, whereas GFRalpha-1 was not detected on the surface of some PGP 9.5-positive cells, indicating that some of the spermatogonial cells were PGP 9.5 positive and GFRalpha-1 negative. After immunomagnetic cell sorting using a GFRalpha-1 antibody, both GFRalpha-1-positive and GFRalpha-1-negative cells expressed PGP 9.5. Identifying the differential mRNA expression of both GFRalpha 1-positive and GFRalpha-1-negative cells using reverse transcription-polymerase chain reaction analysis revealed the expression of promyelocytic leukaemia zinc finger, octamer-binding protein 4 and homeobox transcription factor in both cell types. These results suggest that GFRalpha-1-positive and GFRalpha-1-negative spermatogonia exist in PGP 9.5-positive spermatogonia during the early stage of pig testes spermatogenesis, and that GFRalpha-1 can be used for sorting PGP 9.5 expressing spermatogonia. PMID- 23808408 TI - A model for drying control cosolvent selection for spin-coating uniformity: the thin film limit. AB - Striation defects in spin-coated thin films are a result of unfavorable capillary forces that develop due to the physical processes commonly involved in the spin coating technique. Solvent evaporation during spinning causes slight compositional changes in the coating during drying, and these changes lead to instability in the surface tension, which causes lateral motions of the drying fluid up to the point where it gels and freezes in the thickness variations. In an earlier publication, we looked at the case where evaporation happens fast enough that the compositional depletion is mostly a surface effect. In terms of the mass transport rate competition within the coating solution, that work covered the thick film limit of this instability problem. However, in many cases, the coatings are thin enough or diffusion of solvent within the coating is fast enough to require a different solvent mixing strategy, which is developed here. A simple perturbation analysis of surface roughness is developed, and evaporation is allowed in the thin film limit. The perturbation analysis allows for a simple rubric to be laid out for cosolvent additions that can reduce the Marangoni effect during the later stages of coating deposition and drying when the thin film limit applies. PMID- 23808409 TI - Variation in cesarean section rates is not related to maternal and neonatal outcomes. AB - OBJECTIVE: The aim of this study was to compare the rate of cesarean sections in 12 delivery units in Finland, and to assess possible associations between cesarean section rates and maternal and neonatal complications. DESIGN: Prospective multicenter cohort study. SETTING: The 12 largest delivery units in Finland. POPULATION: Total obstetric population between 1 January 2005 and 30 June 2005 (n = 19 764). METHODS: Prospectively collected data on 2496 cesarean sections and data derived from the Finnish Birth Register on all deliveries in these units were compared. Cesarean section rates and maternal complication rates were adjusted for known risk factors. MAIN OUTCOME MEASURES: Cesarean section rate, maternal complications related to cesarean section, and neonatal asphyxia. RESULTS: The cesarean section rates varied significantly between the hospitals (12.9-25.1%, p < 0.0001), as did the maternal complication rates related to cesarean section (13.0-36.5%, p < 0.0001). There was no relation between maternal complications and the cesarean section rate. The differences remained after adjusting for risk factors. Neonatal asphyxia rates varied between 0.14 and 2.8% (p < 0.0001) and were not related to the cesarean section rates. CONCLUSIONS: The rates of cesarean section, maternal complications and neonatal asphyxia vary markedly between different delivery units. Good maternal and neonatal outcomes can be achieved with cesarean section rates <15%. PMID- 23808410 TI - RpoS and oxidative stress conditions regulate succinyl-CoA: 3-ketoacid-coenzyme A transferase (SCOT) expression in Burkholderia pseudomallei. AB - Burkholderia pseudomallei, a pathogenic gram-negative bacterium, causes the severe human disease melioidosis. This organism can survive in eukaryotic host cells by escaping reactive oxygen species via the regulation of stress responsive sigma factors, including RpoS. In B. pseudomallei, RpoS has been reported to play a role in the oxidative stress response through enhanced activity of OxyR and catalase. In this study, the RpoS dependent oxidative stress responsive system was further characterized using comparative proteomic analysis. The proteomic profiles of wild-type B. pseudomallei following exposure to H2 O2 and between wild-type and the rpoS mutant strains were analyzed. Using stringent criteria, 13 oxidative responsive proteins, eight of which are regulated by RpoS, were identified with high confidence. It was observed that ScoA, a subunit of the SCOT enzyme not previously shown to be involved directly in the oxidative stress response, is significantly down-regulated after hydrogen peroxide treatment. ScoA and ScoB have been predicted to be organized in a single operon using computational methods: in this study it was confirmed by RT-PCR that these genes are indeed co-transcribed as a single mRNA. The present study is the first to report a role for RpoS in the down-regulation of SCOT expression in response to oxidative stress in B. pseudomallei. PMID- 23808411 TI - Role of aquaporin 1 in fetal fluid homeostasis. AB - INTRODUCTION: The homeostasis of maternal-fetal fluid exchange is critically important in pregnancy. We sought to investigate the function of aquaporin 1 (AQP1) during pregnancy by examining fluid compartments of AQP1 knockout (AQP1 KO) mice. METHODS: Homozygous pregnant AQP1 knockout (KO) mice and control pregnant wild type CD1 mice were sacrificed. Placenta and fetal membranes were examined by immunohistochemical staining for expression of AQP1. The total number of embryos, atrophic embryos, and fetal and placental weight was recorded in each subgroup. Amniotic fluid amount in each sac was measured and amniotic fluid composition was determined. Analysis of variance of factorial design and one factor analysis of variance were used for statistics. RESULTS: Immunohistochemistry performed on CD1, though not AQP1-KO, placenta revealed that AQP1 was expressed at the vascular endothelial cell, trophocyte, and amnion epithelial cell. In AQP1-KOs, the number of embryos decreased with advancing gestational age. Although the fetal weight of AQP1-KO mice was significantly lower than wild type, amniotic fluid amount was increased in AQP1-KO mice. The AQP1-KO placenta demonstrated increased degeneration with evidence of altered blood vessel structure and increased syncytiotrophoblast nodules. CONCLUSIONS: These findings demonstrate a critical role of AQP1 in placental and fetal growth and maternal-fetal fluid homeostasis. PMID- 23808412 TI - Perception of HIV/AIDS among the Igbo of Anambra State, Nigeria. AB - Perception is fundamental in the fight against stigmatization of people living with HIV/AIDS (PLHIV). Perception generally influences discriminatory attitudes towards PLHIV which exacerbates their problems and quickens the degeneration of the disease from HIV to AIDS. This study examined the Anambra people's perception and knowledge of HIV/AIDS with the goal of creating knowledge on these issues in order to design effective intervention programmes towards the reduction of social stigmatization associated with the pandemic. The study was carried out in Idemmili North and Oyi local government areas of Anambra State. Qualitative and quantitative methodologies were used to elicit information from respondents who were adult males and females of 18 years and above. The research instruments were questionnaires and in-depth interview schedule. Questionnaires were administered on 1000 respondents while 13 people were interviewed in-depth. Analysis of quantitative data were conducted by using the Statistical package for Social Sciences. Univariate analysis in the form of frequencies were conducted which generated the distribution of respondents across the research variables. Furthermore, multivariate analysis were conducted to test the hypotheses and sought for relationships among variables. The qualitative data were reported in themes based on the research objectives and were analysed jointly with the quantitative data. The findings were that majority of the respondents viewed HIV/AIDS as a disease that afflict immoral people and as a punishment from God. Only a handful of them saw the disease as a disease that could afflict anybody. Also, many of the respondents said that AIDS is real but showed a low level of knowledge. It was further indicated that there were significant relationships between educational level, sex, occupation, income influence perception and peoples' reactions to HIV positive status of a relative while there were no significant relationships between these variables and knowledge of HIV/AIDS. It was concluded that these negative perceptions were as a result of the people's low level of knowledge and cultural belief systems, which see a strange illness as punishment from God for disobedience. Furthermore, the fact that most of the socio-economic characteristics of the respondents had significant relationship with perception and reaction to HIV was an indication that most people in the study area had a uniform perception. It was also an indication that government HIV/AIDS awareness programmes were not effective. It was recommended that strategies for effective HIV educational programme should be sought and carried out in the study area. Effective intervention programme have the power to change behaviours and would likely change the people's negative perception and low level of knowledge of HIV/AIDS, thereby reducing stigmatization of people living with HIV/AIDS. PMID- 23808413 TI - Photoconversion mechanism of the second GAF domain of cyanobacteriochrome AnPixJ and the cofactor structure of its green-absorbing state. AB - Cyanobacteriochromes are members of the phytochrome superfamily. In contrast to classical phytochromes, these small photosensors display a considerable variability of electronic absorption maxima. We have studied the light-induced conversions of the second GAF domain of AnPixJ, AnPixJg2, a phycocyanobilin binding protein from the cyanobacterium Anabaena PCC 7120, using low-temperature resonance Raman spectroscopy combined with molecular dynamics simulations. AnPixJg2 is formed biosynthetically as a red-absorbing form (Pr) and can be photoconverted into a green-absorbing form (Pg). Forward and backward phototransformations involve the same reaction sequences and intermediates of similar cofactor structures as the corresponding processes in canonical phytochromes, including a transient cofactor deprotonation. Whereas the cofactor of the Pr state shows far-reaching similarities to the Pr states of classical phytochromes, the Pg form displays significant upshifts of the methine bridge stretching frequencies concomitant to the hypsochromically shifted absorption maximum. However, the cofactor in Pg is protonated and adopts a conformation very similar to the Pfr state of classical phytochromes. The spectral differences are probably related to an increased solvent accessibility of the chromophore which may reduce the pi-electron delocalization in the phycocyanobilin and thus raise the energies of the first electronic transition and the methine bridge stretching modes. Molecular dynamics simulations suggest that the Z -> E photoisomerization of the chromophore at the C-D methine bridge alters the interactions with the nearby Trp90 which in turn may act as a gate, allowing the influx of water molecules into the chromophore pocket. Such a mechanism of color tuning AnPixJg2 is unique among the cyanobacteriochromes studied so far. PMID- 23808414 TI - Targeted silencing of DNA-specific B cells combined with partial plasma cell depletion displays additive effects on delaying disease onset in lupus-prone mice. AB - Targeting autoreactive B lymphocytes at any stage of their differentiation could yield viable therapeutic strategies for treating autoimmunity. All currently used drugs, including the most recently introduced biological agents, lack target specificity. Selective silencing of double-stranded DNA-specific B cells in animals with spontaneous lupus has been achieved previously by the administration of a chimeric antibody molecule that cross-links their DNA-reactive B cell immunoglobulin receptors with inhibitory FcgammaIIb (CD32) receptors. However, long-lived plasmacytes are resistant to this chimeric antibody as well as to all conventional treatments. Bortezomib (a proteasome inhibitor) depletes most plasma cells and has been shown recently to suppress disease activity in lupus mice. We hypothesized that the co-administration of non-toxic doses of bortezomib, that partially purge long-lived plasma cells, together with an agent that selectively silences DNA-specific B cells, should have additive effects in an autoantibody mediated disease. Indeed, our data show that the simultaneous treatment of lupus prone MRL/lpr mice with suboptimal doses of bortezomib plus the chimeric antibody resulted in the prevention or the delayed appearance of the disease manifestations as well as in a prolonged survival. The effect of the combination therapy was significantly stronger than that of the respective monotherapies and was comparable to that observed after cyclophosphamide administration. PMID- 23808415 TI - Red blood cell transfusion practice in children: current status and areas for improvement? A study of the use of red blood cell transfusions in children and infants. AB - BACKGROUND: Patterns of red blood cell (RBC) transfusion are less well understood for children than adults. This study was undertaken to document current pediatric practice, to identify specific areas for improving patient care and safety. STUDY DESIGN AND METHODS: All UK hospitals were invited to participate. All children less than 18 years old admitted and receiving a RBC transfusion during a 3-month period in 2009 were eligible for inclusion. RESULTS: A total of 160 of 247 (65%) sites treating children or neonates responded; 119 provided data on 1302 pediatric patients transfused in nonneonatal wards. A total of 74% of patients received a single RBC transfusion during their admission. More than half (53%) of recipients had a hematologic or oncologic underlying diagnosis, and 33% were on general pediatric wards. The median pretransfusion hemoglobin (Hb) level was 7.9 g/dL (interquartile range [IQR], 6.9-9.4 g/dL), varying by location and diagnosis. The median volume prescribed was 15 mL/kg (IQR, 11.8-19.2 mL/kg). Prescribing by units instead of milliliters was recorded for 493 of 1264 (39%) of transfusions. For 734 of 1302 (56%) where Hb levels were available within 2 days between pre- and posttransfusion Hb, the median transfusion increment was 2.8 g/dL (IQR, 1.4-3.9 g/dL). CONCLUSION: This study of UK pediatric RBC transfusion practice has demonstrated significant variation in pretransfusion Hb, frequent prescribing in units rather than milliliters, and a high proportion of single transfusions during admissions. Future education and research should target transfusion triggers and prescription volumes for children in all clinical areas. PMID- 23808416 TI - Spatial periodic boundary condition for MODFLOW. AB - Small-scale hyporheic zone (HZ) models often use a spatial periodic boundary (SPB) pair to simulate an infinite repetition of bedforms. SPB's are common features of commercially available multiphysics modeling packages. MODFLOW's lack of this boundary type has precluded it from being effectively utilized in this area of HZ research. We present a method to implement the SPB in MODFLOW by development of the appropriate block-centered finite-difference expressions. The implementation is analogous to MODFLOW's general head boundary package. The difference is that the terms on the right hand side of the solution equations must be updated with each iteration. Consequently, models that implement the SPB converge best with solvers that perform both inner and outer iterations. The correct functioning of the SPB condition in MODFLOW is verified by two examples. This boundary condition allows users to build HZ-bedform models in MODFLOW, facilitating further research using related codes such as MT3DMS and PHT3D. PMID- 23808417 TI - Commentary: demystifying IBS mind-based therapies. PMID- 23808418 TI - Letter: international IBD practice guidelines. PMID- 23808419 TI - Letter: international IBD practice guidelines -- authors' reply. PMID- 23808421 TI - Molecular markers of biomass burning in arctic aerosols. AB - Biomass burning is one of the most important sources of organic matter in the atmosphere as it affects the absorption and scattering of solar radiation, creates cloud condensation nuclei and possibly influences ice and snow albedo. Here we created and validated an analytical method using HPLC/(-)-ESI-MS/MS to determine phenolic compounds (PCLCs): vanillic acid, isovanillic acid, homovanillic acid, syringic acid, syringaldehyde, ferulic acid, p-coumaric acid, and coniferyl aldehyde at trace levels in particulate matter. We analyzed eighteen high-volume air samples from Ny Alesund (Svalbard) collected during the boreal spring and summer of 2010. Biomass burning molecules including PCLCs (<0.49 MUm, mean atmospheric concentration 6 pg m(-3)), levoglucosan (0.004 to 0.682 ng m(-3)) and acrylamide (32 fg m(-3) to 166 fg m(-3)) were present in the sampled aerosols. Levoglucosan concentrations, an unambiguous cellulose combustion tracer, derived from 2010 Russian fires. PCLCs levels in the Ny Alesund atmosphere in different size fractions reflected both long-range transport linked to biomass burning and a terrigenous local source. PMID- 23808420 TI - Down-regulation of miR-301a suppresses pro-inflammatory cytokines in Toll-like receptor-triggered macrophages. AB - In many types of tumours, especially pancreatic adenocarcinoma, miR-301a is over expressed. This over-expression results in negative regulation of the target gene of miR-301a, the nuclear factor-kappaB (NF-kappaB) repressing factor (NKRF), increasing the activation of NF-kappaB and production of NF-kappaB-responsive pro inflammatory cytokines such as interleukin-8, interferon-beta, nitric oxide synthase 2A and cytochrome oxidase subunit 2 (COX-2). However, in immune cells, mechanisms that regulate miR-301a have not been reported. Similar to tumour cells, Toll-like receptor (TLR) -activated macrophages produce NF-kappaB responsive pro-inflammatory cytokines. Therefore, it is of considerable interest to determine whether miR-301a regulates the secretion of cytokines by immune cells. In the present study, we demonstrate that the expression of miR-301a was decreased in TLR-triggered macrophages. Through targeting NKRF, miR-301a affected the activity of NF-kappaB and the expression of pro-inflammatory genes downstream of NF-kappaB such as COX-2, prostaglandin E2 and interleukin-6. In addition, when lipopolysaccharide-treated macrophages were simultaneously stimulated with trichostatin A, an inhibitor of histone deacetylases, the expression of miR-301a increased, whereas NKRF and pro-inflammatory cytokine expression decreased. However, further investigation revealed that there was no correlation between the induction of miR-301a and the inhibitory effect of trichostatin A on lipopolysaccharide-induced gene expression in macrophages. In summary, our study indicates a new mechanism by which miR-301a regulates inflammatory cytokine expression in macrophages, which may clarify the regulatory role of microRNAs in immune-mediated inflammatory responses. PMID- 23808423 TI - Direct regulation of abiotic responses by the Arabidopsis circadian clock component PRR7. AB - Up to 30% of the plant transcriptome is circadian clock-regulated in different species; however, we still lack a good understanding of the mechanisms involved in these genome-wide oscillations in gene expression. Here, we show that PSEUDO RESPONSE REGULATOR 7 (PRR7), a central component of the Arabidopsis clock, is directly involved in the repression of master regulators of plant growth, light signaling and stress responses. The expression levels of most PRR7 target genes peak around dawn, in an antiphasic manner to PRR7 protein levels, and were repressed by PRR7. These findings indicate that PRR7 is important for cyclic gene expression by repressing the transcription of morning-expressed genes. In particular we found an enrichment of the genes involved in abiotic stress responses, and in accordance we observed that PRR7 is involved in the oxidative stress response and the regulation of stomata conductance. PMID- 23808424 TI - [Role of omega-3 fatty acids in cardiovascular disease prevention]. AB - Fatty acids, in addition to its known energy value and its structural function, have other beneficial properties. In particular, the polyunsaturated fatty acids omega-3 acting on the cardiovascular apparatus through many channels exerting a protective effect against cardiovascular risk. The benefits associated with the reduction in cardiac mortality and sudden death particular, are related to the incorporation of EPA and DHA in phospholipid membrane of cardiomyocytes. An index is established that relates the percentage of EPA + DHA of total fatty acids in erythrocytes and risk of death from cardiovascular disease may layering in different degrees. Therefore, the primary source of fatty fish w-3 PUFA, behaves like a reference food in cardiosaludables diets. PMID- 23808425 TI - [Functional properties and health benefits of lycopene]. AB - INTRODUCTION: Lycopene is a carotenoid, which is found mainly in tomatoes, retains its functional properties after processing, is not toxic and has antioxidant, anti-inflammatory and chemotherapeutics effects in cardiovascular or neurodegenerative diseases and in some cancers. However, it seems that its intake through the diet is inadequate. OBJECTIVE: The objective of this review is to highlight the properties of lycopene and provide recommendations to improve its health benefits. METHODS: We performed a literature review related to the topic through Pub Med database. RESULTS: The WHO and national governments promote through food guides the daily consumption of 400 g of fruits and vegetables because of their contain in antioxidants including lycopene. Lycopene intake widely varies, with an average consumption between 5 and 7 mg/day. Controversy arises from the ranger of figures between different studies and the fact that there is no recommended amount, precluding comparisons of national and international level and the establishment of policies and strategies to ensure its consumption. CONCLUSION: Lycopene intake can be seen as a preventive measure and non pharmacological therapy for different types of diseases, but the work of professionals in nutrition and health is required to increase its intake through food education and to propose daily intakes from results of scientific research. PMID- 23808426 TI - Effect of the use of probiotics in the treatment of children with atopic dermatitis; a literature review. AB - INTRODUCTION: Atopic dermatitis (AD) is a disease that mainly affects the pediatric population involving chronic and repetitive inflammatory skin manifestations. Its evolution is known as atopic march, which is characterized by the occurrence of respiratory and food allergies. AIM: To carry out a classical review of the state-of-theart scientific literature regarding the effect of probiotics on the treatment of children with AD. METHODS: Searches were conducted in Medline and Lilacs through the portals PubMed (http://www.ncbi.nlm. nih.gov/pubmed/) and SciELO (http://www.scielo.br). There was a selection of the available publications in the period from 2001 to 2011, using the keywords atopic dermatitis and probiotics (in English and in Portuguese). RESULTS: After applying the inclusion and exclusion criterias, we selected 12 case-control studies which were conducted in four European countries and Australia. The methodological quality of the studies was assessed according to the STROBE recommendations. Assessment of agreement among researches in classifying the quality of the articles showed excellent agreement (k = 1.00, 95%) with a total of 9 papers at B level. The majority of the studies (75%) indicated a beneficial biological effect of probiotics on AD, including protection against infections, enhancement of the immune response, inflammation reduction and changes in gut the flora. The remaining studies showed no beneficial effects according to the outcomes of interest. CONCLUSION: The majority of the studies in the scientific literature in this review showed improvements in some inflammatory parameters and in intestinal microbiota and not exactly, changes in clinical parameters. However, the biological effects observed in most of them suggest the possibility of benefits of the use of probiotics as an adjuvant in the treatment of AD. PMID- 23808427 TI - [Body image; literature review]. AB - INTRODUCTION: Nowadays, in developed countries there are standards of beauty based on pro-thin models, which are internalized by adolescents and young people especially in the case of women, assuming it as risk factor for developing changes in body image and perception. OBJECTIVE: To analyze the current state of research in relation to body image, the sociodemographic variables that influence it, the relationship between body composition, conducting diets, eating disorders, sports and intervention programs and prevention, and the body image. METHODS: It was searched in Medline, Isi Web of knowledge and Dialnet as well as a manual search among the references of selected studies and in different libraries. RESULTS AND DISCUSSION: A increased socio-cultural influence is associated with a greater perception of body fat, greater body image dissatisfaction and lower self assessment of overall fitness. This leads to a lot of teenagers and young adults to abuse to the restrictive diets and to suffer eating disorders. Numerous studies have analyzed the relationship between sports practice with body image disturbance; there are conflictive results. Moreover it is necessary to design objective tools to detect changes and enhance the design of prevention and intervention programs in order to avoid distortion of body image, especially in those age ranges where the population is more vulnerable to this phenomenon. CONCLUSIONS: The excessive current preoccupation about body image has resulted in the realization of diets and changes as eating disorders. There are other factors that influence body image and perception as the realization of physical exercise, although the results about the relationship between these factors are contradictory. Therefore, further work is needed on the issue by creating tools to detect changes and enhance the design of prevention and intervention programs. PMID- 23808428 TI - [Polyphenolic compounds and antioxidant capacity of typically consumed species in Mexico]. AB - Spices are aromatic plants that have been widely used in Mexico to preserve or seasoning different foods, but have also been used as herbal remedies to cure some diseases. These culinary and medicinal properties of spices have been attributed to several food components, including phytochemicals. Among them, polyphenolic compounds have been extensively studied for their effect against several chronic and degenerative diseases, probably due to their antioxidant activity. The study of the antioxidant capacity of Mexican spices may lead to new research on the potential benefits of these spices on human health. This paper analyzes the main studies on the potential beneficial effects of traditional Mexican spices on human health. PMID- 23808429 TI - Sugar-sweetened beverage intake before 6 years of age and weight or BMI status among older children; systematic review of prospective studies. AB - The purpose of this study was to conduct a systematic review of prospective studies that examined the association between sugar-sweetened beverage intake before 6y of age and later weight or BMI status among older children. An electronic literature search was conducted in the MEDLINE/PubMed, SciELO, and EBSCO databases of prospective studies published from 2001 to 2011. Seven studies were analyzed. The study population was from 72 to 10,904 children. Three studies showed a consistent association between SSB intake before 6 y of age and increased weight, BMI, or waist circumference later in childhood, one study showed a positive trend of consumption of SSB and childhood obesity and the OR for incidence of overweight by baseline beverage intake was 1.04, another study it was observed that an increase in total sugar intake and sugar from sweets and beverages in children 1-2 y of age and 7-9 y of age have a tendency to increase BMI, and two studies showed no association. In conclusion, although the trend of the reviews studies, indicate an association between sugar-sweetened beverage intake before 6 y of age and increased weight, BMI or waist circumference later in childhood, to date, the results are inconsistent, and the two studies with the higher number of children showed a positive association. PMID- 23808430 TI - Body composition changes during interventions to treat overweight and obesity in children and adolescents; a descriptive review. AB - Nutrition, physical activity and behavior-modifying techniques are widely applied components of interventions treating obesity. Our aim was to review available information on the short and long term effects of intervention treatment on body fat composition of overweight and obese children and adolescents and, to obtain a further understanding on how different body composition techniques detect longitudinal changes. In total, thirteen papers were included; seven included a multidisciplinary intervention component, five applied a combined dietary and physical activity intervention and one a physical activity intervention. Body composition techniques used included anthropometric indices, bioelectrical impedance analysis, and dual energy X-ray absorptiometry. Percentage of fat mass change was calculated in when possible. Findings suggested, no changes were observed in fat free mass after 16 weeks of nutritional intervention and the lowest decrease on fat mass percentage was obtained. However, the highest fat mass percentage with parallel increase in fat free mass, both assess by DXA was observed in a multi-component intervention applied for 20 weeks. In conclusion, more studies are needed to determine the best field body composition method to monitor changes during overweight treatment in children and adolescents. PMID- 23808431 TI - [Lipid profile analysis of two species of hake "merluccius capensis and merluccius paradoxus" and its contribution to cardiovascular disease prevention]. AB - INTRODUCTION: In recent years it has been shown that omega-3 PUFAs have multiple cardiovascular protective effects. Currently, fish is the main and most important source of Omega-3 fatty acids. OBJECTIVE: To analyze the fatty acid composition in two species of hake, its content of omega-3 fatty acids and study their contribution to the prevention of cardiovascular diseases. MATERIAL AND METHODS: We analyzed samples of two species of hake (Merluccius capensis and Merluccius paradoxus) in its natural state and frozen, cooked by microwave and boiled samples. We have studied the moisture content, lipid content and analysis, identification and composition of fatty acids. RESULTS: It was observed that the content of w-3 PUFA was higher than the w-6 PUFA. The omega-3 fatty acids DHA and EPA were the most representative of the omega-3 family, highlighting the DHA content in all samples analyzed. It has also demonstrated the safety of the cooking methods :microwave" and "boiling" as methods that ensure the integrity of the w-3 PUFA. CONCLUSION: Hake samples analyzed present an optimal lipid profile. Its content of w-3 PUFA and their properties, make hake fish is distinguished as hearthealthy diets reference. PMID- 23808432 TI - [Effects of preoperative weight loss with a very low calorie diet (VLCD) on weight loss after biliopancreatic diversion in patients with severe obesity]. AB - BACKGROUND: Weight loss before bariatric surgery, achieved by means of a very low calorie diet (VLCD) has been recently reported to be related to a lower rate of postoperative complications. However, it is controversial if preoperative weight loss after VLCD could improve postoperative weight loss. AIMS: To assess the effectiveness of a preoperative VLCD for 6 weeks in weight loss one year after bariatric surgery. To evaluate the changes obtained in anthropometric measures and biochemical parameters after VLCD. METHODS: Prospective uncontrolled study including severely obese patients undergoing biliopancreatic diversion in our Obesity Unit in 2008-2010. Patients included followed a VLCD providing 840 kcal and 60 g of protein (Optisource(r)). Descriptive data are presented as mean (standard deviation) and after checking a normal distribution is followed, they were analyzed by Student s T test, ANOVA or Pearson correlation. RESULTS: We evaluated 107 obese patients, 43.5 (10.2) years-old, 72% women, with initial weight 122.4 (18.6) Kg and BMI 46.8 (5.5) kg/m(2). 24.5% of them lost more than 10 % of initial weight and 73.5% more than 5% after following VLCD. Mean percentage of excess weight loss (% PSP) one year after surgery was 59.6 (13.4)%, and although it was higher for those patients losing more weight after VLCD, a significant correlation was not found: those who lost more than 5% showed %PSP 59.5 (13.8) % after twelve months and 68.4 (16.2) % of percentage of excess BMI loss (%PEIMC), vs 57,9 (13,1) % and 68.5 (16.6) % if they didn t lose that amount of weight. Those patients losing more than 10% achieved %PSP 63.3 (13.7) and %PEIMC 70.9 (14.7) vs 58.2 (14.0) y 67.7 (16.7) vs those not losing that amount. Significant correlations between preoperative loss with VLCD and %PSP or %PEIMC at 3,6,9 and 12 months were not found, and only %PSP 1 month after surgery correlated with %PSP after VLCD (r = 0.454, p = 0.003). CONCLUSIONS: Preoperative weight loss with VLCD in severely obese patients did not show to improve either %PSP or %PEIMC one year after bariatric surgery. PMID- 23808433 TI - Double blind randomized clinical trial controlled by placebo with a fos enriched cookie on saciety and cardiovascular risk factors in obese patients. AB - INTRODUCTION: It is essential to determine which snack foods are most affective for appetite control. The objective of the current study was to assess the responses of two different cookies on satiety and cardiovascular risk factors. MATERIAL AND METHODS: 38 patients were randomized: group I (FOS enriched cookie, n=19) and group II (control cookie, n=19). Previous and after 1 month , the subjects rated their feelings of satiety/hunger with a test meal of 5 cookies. RESULTS: After the test meal, the basal area under curve of the first hunger/satiety score was higher with satiety cookie than with control cookie, the data after 1 month of treatment was higher with satiety cookie than with control cookie, too. The score was higher than the fasting level for 20 minutes with satiety cookie and for 40 minutes with the same cookie, too. In satiety group, these scores (20 min and 40 min) were higher than control group before and after 1 month of treatment. The results were in the same way with the 100 mm 5-point visual satiety scale. Cardiovascular risk factors and dietary intake remained unchanged after dietary intervention. CONCLUSION: A FOS enriched cookie produced greater ratings of satiety than a control cookie, without effects on cardiovascular risk factors or dietary intakes. PMID- 23808434 TI - [Acceptance of handmade products containing nuts and fructooligosaccharides]. AB - INTRODUCTION: Prebiotic and food with functional properties are beneficial for consumers through prevention of many diseases. AIM: Verify the acceptance of handmade product (chocolate bar, soy sweet and sweet bread) formulated based on oil seeds (flaxseed, peanut and Brazil nut) and or fructooligosaccharides (FOS). METHODS: Four samples of each handmade product were prepared adding different concentrations of oil seed and FOS. The sensory evaluation was performed by a sample of 373 consumers; 126, 121 and 126 tasters of chocolate bar, soy sweet and sweet bread, respectively, using a hedonic scale of nine points. The results were submitted to analysis of variance (ANOVA) and Tukey's test. RESULTS AND DISCUSSION: Observing the trials averages, we inferred that samples of sweet bread with Brazil nut and/or FOS had the greater acceptance. However, all the samples are good market alternatives because they had presented averages between 6 and 9 points, and conferred accretion of omega-3 and omega-6 fatty acids, protein, fiber, antioxidant vitamins and minerals, as well as, phytochemicals, which plays an important role in health promotion. CONCLUSION: The handmade products formulated based on oil seeds and FOS had good acceptance and can improve the consumer dietary patterns. But, in order to prove the functionality of these products, new studies should be performed. PMID- 23808435 TI - Bioavailability of iron measurement in two nutrients multiple solutions by in vitro and in vivo;a comparative methodology between methods. AB - OBJECTIVES: The bioavailability of dietary iron present in a nutritional formulation may be evaluated by in vitro and in vivo methods since they provide for a cohesive line study and provided in the literature. The aim of this study was to evaluate the bioavailability of iron targeting a comparative analysis of two nutritional supplement formulations (A and B). METHODS: For this study were using in vitro and in vivo methods, both described in the literature for availability of iron in an enteral feeding after ingestion supplement nutrition with much nutrients. RESULTS: The results obtained by in vitro simulation of the human gastrointestinal tract were 0.70 +/- 0.02 and 0.80 +/- 0.01 % iron availability by formulations A and B. In vivo studies, as measured by the curves of serum iron in humans after ingestion of formulations allowed the calculation of coefficient of variation Delta < 0, indicating that there was a low absorption of iron. The bioavailability of iron as two multi-nutrients solutions obtained by in vitro and in vivo showed that there were comparisons of those methodologies used in this study. PMID- 23808436 TI - Iron (FeSo4) bioavailability in obese subjects submitted to bariatric surgery. AB - BACKGROUND: Iron bioavailability in obese subjects after the ingestion of a nutritional supplement was the aim of this work. METHODS: Fourteen persons were studied before and after bariatric surgery after the ingestion of a nutritional formulation containing 25 mg iron, 25 g fiber and 800 mg calcium. RESULTS: The following ferremia values (median and minimum--maximum) were obtained before and after bariatric surgery, respectively: Fasting, 105 (70 - 364) MUg/dL and 198 (38 - 617) MUg/dL; 1 hour, 103 (63 - 305) MUg/dL and 160 (11 - 207) MUg/dL; 2 hours, 103 (62 - 150) MUg/dL and 141 (10 - 412) MUg/dL; 3 hours. 97 (63 - 190) MUg/dL and 153 (6 - 270) MUg/dL; 4 hours, 91 (58 - 163) MUg/dL and 156 (40 - 251) MUg/dL (p>0.05), with no association of serum iron levels with time. There was a difference in total triglycerides (95 +/- 29 mg/dL and 60 +/- 10 mg/dL) which were correlated with a decrease in serum ferritin levels (r = 0,926, p = 0.008), UIBC (r = 0.910, p = 0.01), total cholesterol (r = 0,918, p = 0.01) and LDL-c fraction (r = 0.830, p = 0.04), with an increase in HDL-c fraction (r = 0,807, p = 0.05). CONCLUSION: Iron bioavailability in obese subjects was affected by the ingestion of the nutritional formulation containing calcium and fiber, a fact that may cause these patients to develop iron deficiency. PMID- 23808437 TI - Egg consumption and risk of type 2 diabetes in a Mediterranean cohort; the sun project. AB - INTRODUCTION AND AIM: The prevalence of diabetes is increasing at an alarming rate in nearly all countries. Some studies from non-Mediterranean populations suggest that higher egg consumption is associated with an increased risk of diabetes. The aim of our study was to prospectively assess the association between egg consumption and the incidence of type 2 diabetes in a large cohort of Spanish university graduates. METHODS: In this prospective cohort including 15,956 participants (mean age: 38.5 years) during 6.6 years (median), free of diabetes mellitus at baseline. Egg consumption was assessed at baseline through a semiquantitative food-frequency questionnaire repeatedly validated in Spain. Incident diabetes mellitus diagnosed by a doctor was assessed through biennial follow-up questionnaires and confirmed subsequently by medical reports or records, according to the American Diabetes Association criteria. Analyses were performed through multivariable non-conditional logistic regression. RESULTS: After adjustment for confounders, egg consumption was not associated with the development of diabetes mellitus, comparing the highest versus the lowest quartile of egg consumption (<4 eggs/week vs >1 egg/week): odds ratio = 0.7; 95% CI 0.3-1.7. CONCLUSION: Egg consumption was not associated with the development of diabetes mellitus in this Mediterranean cohort. PMID- 23808438 TI - Iron availability in an enteral feeding formulation by response surface methodology for mixtures. AB - BACKGROUND: The nutritional therapy with enteral diets has been getting specialized and those formulations to substitute the traditional diet for those patients who need to be fed by probe. This workis aim was to study the effect of the components of enteral diet formulation: fiber, calcium and medium-chain triglycerides, seeking optimize a formulation for the best dialysability of iron by Response Surface Methodology (RSM). METHODS: The ingredients used for the formulations of the diet were chosen according to the ones commercialized in the modules of a standard enteral diet, with which it was made an experimental diet and the applicability of the experimental limits. RESULTS: The found results in the model have shown that it depends on the proportion of the nutrients that were manipulated in the experimental design. When the level curve was obtained for the iron dialysable, it could be verified that the binary interaction fiber-calcium was the one that presented more synergism for the appraised formulation. Before the analyzed facts, the best formulation of enteral diet optimized for the dialysability of the iron was the proportion of 60% of fiber and 40% of calcium, showing to be the best formulation of the enteral diet for the availability of the iron. PMID- 23808439 TI - Effects on adolescents' lipid profile of a fitness-enhancing intervention in the school setting; the EDUFIT study. AB - OBJECTIVES: Observational studies have reported an association among physical activity, fitness and lipid profile in youth. The purpose of this study was to analyse the effect of a school-based intervention focused on increasing the number and intensity of Physical Education (PE) sessions a week, on adolescents' lipid profile. METHODS: A 4-month group-randomized controlled trial was conducted in 67 adolescents (12-14 years-old) from South-East Spain, 2007. Three school classes were randomly allocated into control group (CG), experimental group-1 (EG1) and experimental group-2 (EG2). The CG received the usual PE in Spain (2 sessions/week), the EG1 received 4 PE sessions/week, and the EG2 received 4 PE sessions/week of high intensity. The main study outcomes were fasting levels of total cholesterol, high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc) and triglycerides. All the analyses were adjusted for sex, sexual maturation, attendance and baseline value of the outcome studied. RESULTS: The intervention did not positively affect cardio-metabolic parameters except for LDLc, that was marginally yet significantly reduced in EG2 (-10.4 mg/dl), compared with the CG (+4.1 mg/dl) (p = 0.04); no differences were observed however for the LDLc/HDLc ratio. No significant effects were observed in EG1. DISCUSSION: Overall, a 4-month school-based physical activity intervention did not substantially influence lipid profile in adolescents. However, the results suggest that increasing both frequency and intensity of PE sessions had a modest effect on LDLc in youth. Future studies involving larger sample sizes and longer interventions should focus on the separate effects of volume and intensity of PE. PMID- 23808440 TI - Effects of the dietary amount and source of protein, resistance training and anabolic-androgenic steroids on body weight and lipid profile of rats. AB - INTRODUCTION: Dietary protein amount and source, hypertrophy resistance training (RT) and anabolicandrogenic steroids (AAS) may affect body weight and plasma and hepatic lipid profile. MATERIAL AND METHODS: 157 adult male Wistar rats were randomly distributed in 16 experimental groups resulting in: normal-protein (NP) or high-protein (HP) diets, whey or soy-protein diets, with or without RT and with or without AAS, for 3 months. RESULTS AND DISCUSSION: Final body weight was lower in the RT and AAS groups compared to sedentary and non- AAS groups, respectively (all, p<0.001). Plasma total cholesterol (TC) was lower for the HP compared to the NP diets, for the whey compared to the soy-protein diets and for the AAS compared to the non-AAS groups (all, p<0.001). Plasma HDL-cholesterol was higher in the RT groups (p<0.05) but lower for the AAS groups (p<0.001), the HP and the soy-protein diets (p<0.05). Plasma triglycerides (TAG) were lower for the HP diet (p<0.001), for the RT (p=0.002) and the non-AAS groups (p=0.001). Liver TC was lower for the NP (p<0.01), for the soyprotein (p<0.05) and for the AAS groups (p<0.001). Liver TAG were lower for the whey-protein diet (p<0.001), RT and non-AAS groups (both, p<0.05). Some interactions were found, such as the greater effect of AAS on reducing body weight of rats that performed RT or ingested a HP diet (all, p<0.05). HDL-cholesterol was higher when RT was combined with HP diets (p=0.010) or non-AAS and when HP diets were combined with non-AAS (both,p<0.001). Groups that combined RT with non-AAS administration obtained the lowest hepatic TAG (p<0.05). CONCLUSION: Among all the interventions tested, AAS was the factor that most negatively affected plasma and hepatic lipid profile, whereas HP diets and RT could benefit lipid profile, especially when combined. PMID- 23808441 TI - [Effectiveness of a program for treatment of overweight and nonmorbid obesity in primary healthcare and its influence lifestyle modification]. AB - BACKGROUND: Lifestyle intervention is fundamental for obesity treatment. The aim of this study was to evaluate the effects of a program focused on diet, exercise and psychological support on Lifestyle Modification in overweight and obese patients treated in Primary Health Care setting. METHODS: 60 patients with grade II overweight and non-morbid grade I-II obesity were included in this pilot clinical trial. Ages ranged from 18 to 50 years. They were provided with a program combining nutritional education, physical activity and psychological support. Subjects attended group sessions every 2 weeks. The main outcome measures at baseline and 6 months were body composition parameters (BMI, body fat percentage, waist circumference) and lifestyle intervention using the Questionnaire for the assessment of overweight and obesity related lifestyles at baseline and six months. This questionnaire yields an five dimensions: diet caloric intake (CC), healthy eating (AS), physical activity (EF), searching for psychological well-being eating (BP) and alcohol intake (CA). The higher score indicates better lifestyles for CC, AS, EF and worse for BP y CA. RESULTS: At the end of the intervention the program achieved improvements in Questionnaire related lifestyles subscales: CC (2,60 +/- 0,5 vs. 3,49 +/- 0,7, p<0,001), EF (2,19 +/- 0,9 vs. 3,17 +/- 1,0, p<0,001) and AS (3,04 +/- 0,4 vs. 3,43 +/- 0,4, p<0,05); CA (3,98 +/- 0,7 vs. 4,25 +/- 0,7, p<0,05) and BP (2,82 +/- 1,0 vs. 3,34 +/- 0,7, p<0,001) has got worse. CONCLUSION: The Program focused on balanced and moderate energy-restricted diets, increased physical activity and psychological support may improve the anthropometric parameters and the Lifestyle intervention in obese patients treated in a primary healthcare center. PMID- 23808442 TI - Basal energy expenditure measured by indirect calorimetry in patients with squamous cell carcinoma of the esophagus. AB - BACKGROUND: Determination of Basal Energy Expenditure (BEE) is essential for planning nutritional therapy in patients with esophageal cancer. AIMS: The objective of this study was to determine BEE through indirect calorimetry (IC) in patients with squamous cell carcinoma of the esophagus (SCC). METHODS: Cross sectional study involving 30 patients admitted with a diagnosis of SCC who underwent IC before starting cancer therapy. The BEE was evaluated using IC and also estimated by means of the Harris-Benedict Equation (HBE). Nutritional assessment was conducted using anthropometric parameters (body mass index, arm circumference, triceps skinfold thickness, arm muscle circumference, and weight loss), biochemical parameters (albumin, transferrin and C-reactive protein) and tetrapolar bioimpedance to assess body composition (fat free mass). Additionally, lung capacity was measured and clinical staging of the cancer established by the TNM method. RESULTS: The mean of the BEE for IC and Harris-Benedict Equation were 1421.8 +/- 348.2 kcal/day and 1310.6 +/- 215.1 kcal/day, respectively. No association was found between BEE measured by IC and clinical staging (p=0.255) or the Tiffeneau Index (p=0.946). There were no significant associations between BEE measured by IC and altered dosages of transferrin, albumin and C-reactive protein (p=0.364, 0.309 and 0.780 respectively). The factors most associated with BEE were BMI and fat free mass. CONCLUSION: The BEE of patients with SCC was underestimated when using the HBE, and the result overestimated when incorporating an injury factor with the HBE. Therefore, despite the practical difficulties of implementing IC, its use should be considered. PMID- 23808443 TI - [Longitudinal assessment of body composition by different methods as product of a integral intervention for treating obesity in Chilean children school]. AB - INTRODUCTION: In Chile, the main nutritional problem of children, is obesity. The alarming increase in childhood obesity, has generated an urgent need to develop prevention and treatment programs, unfortunately, the results have been disappointing because they have not achieved the expected impact on the nutritional status of the target population. For this it is necessary to use other strategies, such as incorporating exercise of muscle strength. OBJECTIVE: To determine the impact of an integral intervention (exercise, nutritional education and psychological support) in the body composition of obese school children after the intervention and post-intervention. METHODS: The sample consisted of 61 obese children (BMI = p 95) of both sex, between 8 and 13 years old, who participated in an integral intervention for treating childhood obesity in the short term (3 months) and medium term (12 months). Body composition was assessed by isotope dilution, plethysmography, radiographic absorptiometry and four-compartment model of Fuller. RESULTS: There was a significant increase over time in FFM (kg) by 4C in both sex, GC (%) by isotope dilution in boys was reduced in the post-intervention, while in girls decreased significantly over time and FFM (kg) by isotope dilution significantly increased in both sex. According to the magnitude and direction of change in time, there was only significant difference by sex in FFM (%) by isotope dilution, the increase was significantly higher in boys a result of the intervention (p = 0,000). CONCLUSIONS: An intervention that includes programmed exercise improves body composition. However, its effect is reversed in the medium term if training ceases. This reaffirms the need for sustainability of interventions over time. PMID- 23808444 TI - [Predict factors associated with malnutrition from patient generated subjective global assessment (PG-SGA) in head and neck cancer patients]. AB - INTRODUCTION: Patient Generated Subjective Global Assessment (PG-SGA) is a validated tool for nutrition evaluation in patients with cancer. AIM: The aim of our study was to estimate the prevalence of malnutrition in head and neck cancer patients at diagnosis and evaluate the independent prognostic factors for malnutrition from PG-SGA. MATERIAL AND METHODS: All outpatients attending at the Head and Neck Cancer Multidisciplinary Meeting for primary diagnosis, staging and treatment were evaluated by an oncology dietitian using the patient generated subjective global assessment (PG-SGA). Patients with recurrences or secondary tumours will be excluded. RESULTS: 64 patients were evaluated (55 men and 9 women) with an average age of 63 years and body mass index (BMI) of 25.3 kg/m(2) (SD +/- 5.18). After the nutritional assessment we observed that 43.8% of patients were malnourished or at risk of malnutrition. The most frequent symptom at diagnosis was dysphagia (48.4%) and anorexia (26.6%). From PG-SGA, the main prognostic factors (p<0,001) were the percentage of weight loss, serum albumin levels, BMI and the presence of dysphagia or/and anorexia prior diagnosis. CONCLUSIONS: Parameters as BMI, weight loss and low albumin levels at the time of diagnosis in head and neck cancer patients are independent predictors for malnutrition as well as the presence of anorexia or dysphagia.reaffirms the need for sustainability of interventions over time. PMID- 23808445 TI - Leptin regulates gonadotropins and steroid receptors in the rats ovary. AB - The leptin hormone is important to satiety and an important link between the nutritional status and reproductive processes. Owing to the contradictory effects of leptin on the ovary and the failure to clarify the precise mechanism by which leptin affects the ovary, our aim was to contribute to evaluation if leptin can directly regulate the gene expression of leptin itself and its receptors, and the expression of several genes related to the ovary function by a model of tissue culture. Ovaries from Wistar dams were used at 90 days of age and were submitted to medium with presence and absence of leptin. The results can demonstrate that leptin regulates gonadotropins and steroid receptors, which could suggest that the ovarian leptin role could be secondary to the changes in these receptors expression in rats. PMID- 23808446 TI - Routine supplementation does not warrant the nutritional status of vitamin d adequate after gastric bypass Roux-en-Y. AB - Bariatric surgery can lead to nutritional deficiencies, including those related to bone loss. The aim of this study was to evaluate serum concentrations of calcium, vitamin D and PTH in obese adults before and six months after gastric bypass surgery in Roux-en-Y (RYGB) and evaluate the doses of calcium and vitamin D supplementation after surgery. METHODS: Retrospective longitudinal study of adult patients of both sexes undergoing RYGB. We obtained data on weight, height, BMI and serum concentrations of 25-hydroxyvitamin D, ionized calcium and PTH. Following surgery, patients received dietary supplementation daily 500 mg calcium carbonate and 400 IU vitamin D. RESULTS: We studied 56 women and 27 men. Preoperative serum concentrations of vitamin D were inadequate in 45% of women and 37% of men, while in the postoperative period 91% of women and 85% of men had deficiency of this vitamin. No change in serum calcium was found before and after surgery. Serum PTH preoperatively remained adequate in 89% of individuals of both sexes. After surgery serum concentrations remained adequate and 89% women and 83% men evaluated. CONCLUSION: Obesity appears to be a risk factor for the development of vitamin D. The results show that supplementation routine postoperative was unable to treat and prevent vitamin D deficiency in obese adults undergoing RYGB. PMID- 23808447 TI - [Capacity analysis of health food choice by reference to consumers in two models of nutritional labeling; crossover study]. AB - INTRODUCTION: The aim of this study was to compare two models of nutrition labeling front-of-pack, in reference to the ability of consumers to choose a diet closer to nutritional recommendations. METHODS: Randomized crossover design in 32 adults (18-65 years) of both sexes. Participants were randomly exposed to two experimental conditions using nutritional traffic light system (S-SN) or monochrome system (SM). Participants had to choose options from a closed menu for five days on the basis of the experimental front-of-pack labelling. For each meal, three food options with different nutritional compositions were given to the participants. The total energy and fat, saturated fat, sugar and salt of the chosen options were calculated. RESULTS: No significant differences at baseline sociodemographic and anthropometric characteristics were shown between individuals regardless of the experimental condition in which they started. The subjects tended to choose a diet with a lower, but not significant energy content of 23.0 +/- 67.5 (P = 0.063) and a significantly lower sugar content of 3.5 +/- 9.2 g, P < 0.001 and 0.6 +/- 1 g, P < 0.003 for salt. CONCLUSIONS: Compared to the to the monochrome system, the multiple traffic-light system probably can help make food choices with less sugar and salt in a situation similar to the usual purchase in which there is a time limitation. PMID- 23808448 TI - [Association between overweight, glucocorticoids and metabolic syndrome in cancer patients under chemotherapy]. AB - Metabolic syndrome components like overweight, obesity, insulin resistance, and hyperglycemia are common findings in patients with cancer diagnosis under chemotherapy treatment. These factors have been associated with higher recurrence rates. This study associates Body Mass index, steroids treatment and tumor site with metabolic syndrome (MS) components in patients with cancer diagnosis under chemotherapy treatment. METHODS: In this retrospective study, files from patients under chemotherapy treatment treated in a university oncology center from 2008 to 2010 where reviewed. Anthropometric data and ATP III MS criteria were reviewed. RESULTS: 158 patients were included, 75.9% female. Most common tumors were breast, gastrointestinal and lung cancer. 56.3% presented =3 component of MS; 43.6% of patients received Dexametasone as part of chemotherapy treatment. Mean BMI was 25.3 kg/m(2). Breast cancer diagnosis was associated with presence of 3 or more components of metabolic syndrome. Glococorticoid treatment was not significantly associated with MS diagnosis. CONCLUSIONS: patients with IMC>25 presented 12.6 more risk of MS, independently of glucocorticoids treatment. Weight maintenance is important to reduce MS. PMID- 23808449 TI - Association between an inflammatory-nutritional index and nutritional status in cancer patients. AB - INTRODUCTION: Cachexia is a multifatorial syndrome characterized by loss of body weight, fat and muscle, increasing morbidity and mortality. The use of an index accounting for both serum albumin and C Reactive Protein levels could make early identification of cachexia easier. OBJECTIVE: To evaluate the variation of an inflammatory nutritional index related to nutritional status in cancer patients. METHODS: Cross sectional study including patients with gastrointestinal and lung cancer of a public chemotherapy service in Brazil. Serum albumin and C Reactive Protein were measured and the nutritional status was defined by Subjective Global Assessment. Statistical analyses were performed using Stata 9.2(TM). RESULTS: A total of 74 patients were evaluated, 58.1% of them were male, mean age 63.4 +/- 11.9 years old. Gastrointestinal cancer was the most prevalent type (71.6%). Only 13.7% of the patients were well nourished and 21.9% were severely malnourished. C Reactive Protein significantly increased according to nutritional status decline (p=0.03). When the albumin from patients with systemic inflammation was evaluated, there was no significant variation in relation to nutritional status (p=0.06). The Inflammatory Nutritional Index significantly varied in relation to nutritional status independent of the systemic inflammation (p=0.02). CONCLUSIONS: Inflammatory Nutritional Index can be an adjuvant way for biochemical nutritional assessment and follow up in cancer patients with systemic inflammation. PMID- 23808450 TI - Anthropometric traits, blood pressure, and dietary and physical exercise habits in health sciences students; the obesity observatory project. AB - BACKGROUND: Obesity and the metabolic syndrome affect a considerable segment of the population worldwide, including health professionals. In fact, several studies have reported that physicians tend to have more cardiovascular risk factors than their patients. The present cross-sectional study assessed whether the Health Sciences students had a healthier lifestyle, thus could have a more preventive attitude towards chronic diseases than the general population. MATERIALS AND METHODS: Students of the medical-biological areas were surveyed by answering a questionnaire about familiar cardiovascular risk factors, personal smoking, alcohol drinking, dietary and exercise habits. Blood pressure was also measured, along with weight, height, and abdominal circumference. RESULTS: 23.4% of the participants were overweight and 10% obese. Parental obesity was the most frequent risk factor, followed by social drinking and smoking. We found high consumption of animal derived foods, breakfast- like cereals, pastries, white bread and sweetened beverages; while low intake of fruit and vegetables were reported. More than half the sample reported to practice very little or no exercise at all. DISCUSSION AND CONCLUSIONS: We found similar or even higher rates of risk factors than the average population, that may eventually lead to the development of chronic cardiometabolic diseases. Thus we can infer that biomedical education is inefficient in inducing healthy lifestyles among biomedical students, which could have impact in their future practice as they will most probable become obese health-professionals, thus fail to effectively treat their own patients. PMID- 23808451 TI - Citrullinemia stimulation test in the evaluation of the intestinal function. AB - BACKGROUND: Citrullinemia is been reported as a quantitative parameter of the enterocyte mass and function. AIM: The objective of this research is to analyse the value of fasting and stimulated citrullinemias in the intestinal function evaluation. METHODS: A case-control study was undertaken, including 11 patients with short bowel syndrome, 13 patients submitted to malabsorptive bariatric surgery and 11 healthy controls. Plasma levels of amino acids were determined, before and after a stimulation test with oral Lglutamine, by ion exchange chromatography. RESULTS: Citrullinemia was inferior in short bowel patients (28,6 +/- 11,3 versus 35,5 +/- 11 in operated obese versus 32,2 +/- 6,6 MUmol/L in controls; n.s.) and lower than 25,5 MUmol/L in 54,5% of them (versus 16,7%; p = 0,041; accuracy = 74%; odds ratio = 3, 95%CI 1,2-7,6). DeltaCitrullinemia80 (relative variation of citrullinemia at the 80th minute of test) was lower in short bowel patients; its diagnostic accuracy was similar to baseline citrullinemia and also not significant. DeltaCitrullinemia80 revealed a high predictive capacity of a short bowel inferior or equal to 50 cm (auR.O.C. = 82,3%; 95%CI 61,7-102,8; p = 0,038). CONCLUSIONS: In short bowel syndrome context, citrullinemia stimulation test with oral L-glutamine is feasible and it may improve the predictive capacity of severity. Further investigation is required to determine its clinical relevance and applicability. PMID- 23808452 TI - [Salivary cortisol as a measure of stress during a nutrition education program in adolescents]. AB - OBJECTIVES: To analyse the stress level at different academic times, by measuring salivary cortisol and assessing the influence of the stress level on the effectiveness of a nutrition education program for adolescents. METHODS: Salivary cortisol of 42 compulsory secondary education students was determined (morning and evening) at the beginning of the course and in the time prior to final exams. A nutrition education program was developed during the course and food consumption data were collected by means of a food frequency questionnaire in both initial and final moments. In addition, the body mass index was determined. RESULTS: The initial morning cortisol level was lower with respect to the final morning level (P < 0.05), with higher levels in females (P < 0.05). In the final determination, the morning cortisol was also higher in girls (P < 0.01). There were no significant changes in body mass index. 23.8% of students referred fewer consumption of carbonated beverages after the intervention program, while 28.57% reported having breakfast before leaving home. A reduction in the consumption of fruit at the end of the study was observed. DISCUSSION: To properly assess whether the observed changes are related to the nutrition education program or with the stressful situation due to the proximity of the exams, which would imply an increase in the intake, more studies would be necessary at the different stages of the course. PMID- 23808453 TI - [Differences in magnitude of nutritional status in Chilean school children according to CDC and WHO 2005-2008 reference]. AB - INTRODUCTION: Further discussions are needed regarding the magnitude of nutritional problems diagnosed using CDC or WHO, against the existence of new biological or statistical definitions of obesity. OBJECTIVE: To compare the evolution of the prevalence of nutritional status among schoolchildren in first grade, from 2005 to 2008, according to CDC and WHO. METHODS: Retrospective cohort study, of 140.265 students of both sexes of first grade, evaluated from 2005- 2008, whose anthropometric data (weight and height), were obtained from annual registration system of school nutrition. To classify the nutritional status of children, CDC and WHO patterns were used. RESULTS: The mean BMI was slightly different and lower in girls than in boys, in 2005 and 2006. During 2007 and 2008 the average BMI in girls reached the observed in males. There was a higher prevalence of underweight according to WHO (p=0,03), with a tendency to decrease in the subsequent years. The prevalence of normality was greater according to the CDC criteria, with a reduction between 2005 and 2007 and an increase in 2008 (P < 0,001). There was a lower prevalence of overweight according to CDC criteria (P < 0,001), with an increase between 2005 and 2007, both CDC and WHO. The prevalence of obesity was lower according to the WHO criteria, and there were not statistically significant differences when comparing the CDC pattern. CONCLUSIONS: By comparing both patterns, CDC tends to overestimate the normal and underestimate the overweight, while obesity was not significant differences. PMID- 23808454 TI - Zinc in plasma and breast milk in adolescents and adults in pregnancy and pospartum: a cohort study in Uruguay. AB - OBJECTIVE: To assess if age is a risk factor for low zinc nutritional status in pregnancy, postpartum and in breast milk concentration, and the association between mother zinc plasma level with zinc milk concentration. DESIGN: Cohort study comparing adolescents with adult women, with < 14 weeks of gestation at first prenatal care. Socio demographic and plasma zinc data were collected at that moment and at postpartum time (4 + 1 month). Milk zinc concentrations were also measured at 4 th month postpartum. SETTING: Women were recruited from 16 public primary health care services in Uruguay Subjects: 151 adolescents and 161 adult women. RESULTS: Adolescent average plasma zinc at < 14 weeks of gestation was 84.4 +/- 3.6 ug /dl and did not differ significantly from that for adult women (85.2 +/- 13.6 ug/dl). Prevalence of hypozincemia was relatively low with but with no difference by age (14.6% in adolescents and 12.3% in adults). Zinc concentrations in breast milk were similar for adolescents, 1.24 mg. /L (CI 1.06 to 1.44) and adult women, 1.27 mg./L (CI .1.0-1.46). There was no correlation between plasma zinc and breast milk zinc concentrations in adults and a weak correlation in adolescents (- 0.27, P <0.05). CONCLUSIONS: Prevalence of hypozincemia in pregnancy was relatively low but similar in adolescents and adult women. Neither pregnancy nor age had negative consequences over postpartum plasma zinc, nor over breast milk zinc concentrations. No correlation was found between mother s plasma zinc and breast milk levels. PMID- 23808455 TI - A malfunctioning nasogastric feeding tube. AB - A critical point of nasogastric feeding tube placement, potentially resulting in an unsafe and/or non-effective operation of the device, is the monitoring of its proper placement into the stomach. A properly obtained and interpreted radiograph is currently recommended to confirm placement. We reported the case of a 68-year old demented woman referred for complicated dysphagia. A nasogastric tube was blindly inserted and its placement was confirmed by the radiologist. Enteral nutrition was initiated but the patient began to vomit immediately. After reviewing the radiograph it was understood that a gastric loop in the tube and its tip pointing upwards did not allow a safe infusion of the feeding formula. It is not enough having the radiologist reporting that a nasogastric feeding tube is placed in the stomach; the inclusion in the report of specific warnings on any potential cause of malfunctioning of the device should be considered. The presence of a gastric loop should be taken into account as a cause of potential malfunctioning. PMID- 23808456 TI - High-protein diets and renal status in rats. AB - INTRODUCTION: High-protein (HP) diets might affect renal status. We aimed to examine the effects of a HP diet on plasma, urinary and morphological renal parameters in rats. MATERIAL AND METHODS: Twenty Wistar rats were randomly distributed in 2 experimental groups with HP or normal-protein (NP) diets over 12 weeks. RESULTS AND DISCUSSION: Final body weight was a 10%lower in the HP group (p < 0.05) whereas we have not observed differences on food intake, carcass weight and muscle ashes content. No significant clear differences were observed on plasma parameters, whereas urinary citrate was an 88% lower in the HP group (p = 0.001) and urinary pH a 15% more acidic (p < 0.001). Kidney wet mass was ~22 heavier in the HP group (p < 0.001). Renal mesangium area was a 32% higher in the HP group (p < 0.01). Glomerular 1 and 2 were also ~30 higher in the HP diet (p < 0.01 and p < 0.05, respectively) and glomerular area a 13% higher (p < 0.01). CONCLUSION: High-protein diet promoted a worse renal profile, especially on urinary and morphological markers, which could increase the risk for developing renal diseases in the long time. PMID- 23808458 TI - Diagnostic medical home: a model for health and well-being. PMID- 23808457 TI - Napsin A staining in adrenal cortical neoplasms. PMID- 23808459 TI - Five top stories in anatomic pathology: stories from the faculty at UMass Medical School and UMass Memorial Medical Center, Worcester, Massachusetts. PMID- 23808460 TI - Clinical implications of current developments in genitourinary pathology. AB - CONTEXT: Several developments in genitourinary pathology are likely to change our understanding and management of some genitourinary cancers considerably. OBJECTIVE: To review 5 stories in genitourinary pathology: (1) fusion in the ETS (E26) gene family in prostatic adenocarcinoma; (2) insulin-like growth factor II messenger RNA-binding protein 3 (IMP3), an important prognostic biomarker for kidney and bladder cancers; (3) translocation renal cell carcinoma; (4) UroVysion fluorescence in situ hybridization test in urine cytology for detection of bladder cancer; and (5) the use of triple immunostaining for diagnosis of prostate cancer. DATA SOURCES: Literature review and authors' personal experiences. CONCLUSIONS: Many scientific findings have contributed recently to the understanding of the natural pathogenesis and progression of genitourinary cancers. This translational research helps in diagnosing, predicting, and potentially, treating genitourinary cancers. PMID- 23808461 TI - Five top stories in cytopathology. AB - CONTEXT: Cytology relies heavily on morphology to make diagnoses, and morphologic criteria have not changed much in recent years. The field is being shaped predominantly by new techniques for imaging and for acquiring and processing samples, advances in molecular diagnosis and therapeutics, and regulatory issues. OBJECTIVE: To review the importance of classical morphology in the future of cytopathology, to identify areas in which cytology is expanding or contracting in its scope, and to identify factors that are shaping the field. DATA SOURCES: Literature review. CONCLUSIONS: Five stories paint a picture in which classical cytomorphology will continue to have essential importance, both for diagnosis and for improving our understanding of cancer biology. New endoscopy and imaging techniques are replacing surgical biopsies with cytology samples. New molecularly targeted therapies offer a chance for cytology to play a major role, but they pose new challenges. New molecular tests have the potential to synergize with, but not replace, morphologic interpretation of thyroid fine-needle aspirations. Ultrasound-guided fine-needle aspiration performed by cytopathologists is opening a new field of "interventional cytopathology" with unique value. For the productive evolution of the field, it will be important for cytopathologists to play an active role in clinical trials that document the ability of cytology to achieve cost-effective health care outcomes. PMID- 23808462 TI - Accuracy and false-positive rate of the cytologic diagnosis of follicular cervicitis: observations from the College of American Pathologists Pap Educational Program. AB - CONTEXT: Follicular cervicitis is usually easily identifiable on Papanicolaou (Pap) tests; however, historically, follicular cervicitis is reported to lead to false-positive diagnoses of epithelial cell abnormalities. OBJECTIVES: To assess participant responses in the College of American Pathologists (CAP) Pap educational program (CAP-PAP) to determine the accuracy and false-positive rate of follicular cervicitis cases. Design.-We performed a retrospective review of 4914 participant responses for gynecologic cytology challenges with the reference diagnosis of follicular cervicitis during 11 years (2000-2010) from CAP-PAP. Reference diagnosis category, false-positive rates by participant type (laboratory, cytotechnologist, pathologist), and preparation type (conventional smears, ThinPrep) were analyzed. RESULTS: Of the total 4914 general category responses, 4368 (88.9%) were benign while 546 (11.1%) responses were epithelial cell abnormalities (false positives). Of benign responses, only 2026 (46.4%) were an exact match to follicular cervicitis. Adenocarcinoma and high-grade squamous intraepithelial lesion were the most common diagnoses chosen as a false-positive interpretation (42.3% and 20.1%, respectively). Participant type was significantly associated with false-positive interpretations (laboratory: 19.2%; cytotechnologist: 11.1%; pathologist: 7.9%; P < .001). ThinPrep was also significantly associated with false-positive results as compared to conventional smears (12.2% versus 3.6%; P < .001). CONCLUSIONS: In an interlaboratory comparison educational program, follicular cervicitis is difficult to interpret accurately and represents an important cause of false-positive responses. Follicular cervicitis may mimic adenocarcinoma or high-grade squamous intraepithelial lesion, particularly in liquid-based preparations. The diagnostic difficulty most likely arises from the lymphocytes being less conspicuous in the background as well as their tendency to aggregate in ThinPrep as compared to conventional smears. PMID- 23808463 TI - Laboratory performance in albumin and total protein measurement using a commutable specimen: results of a College of American Pathologists study. AB - CONTEXT: Discrepant results for serum constituents were observed among peer groups in the College of American Pathologists Comprehensive Chemistry Survey. OBJECTIVES: To assess the performance of serum albumin and total protein measurement procedures and to evaluate the commutability of the conventional survey specimens. DESIGN: A fresh frozen, off-the-clot serum sample was included along with 4 conventional survey specimens. The fresh frozen, off-the-clot serum sample was prepared in a manner expected to confer commutability with native clinical samples. RESULTS: For the fresh frozen, off-the-clot serum sample, the mean values for 17 peer-groups were -0.07 to 0.32 g/dL from the bromocresol green albumin designated comparison method, whereas 4 VITROS (Ortho Clinical Diagnostics, Rochester, New York) peer groups differed by -0.29 to -0.37 g/dL (15 of 21 differences [71%] had P < .001). For bromocresol purple albumin methods, the mean differences from the designated comparison method from 8 peer groups were 0.25 to 0.47 g/dL (all had P < .001). For total protein methods, 23 peer group mean values were -0.07 to 0.15 g/dL from the reference measurement procedure (12 of 24 [50%] had P < .001). The Beckman (Fullerton, California) Synchron LX20 had a bias of -0.30 g/dL (P <.001). The commutability of the conventional specimens was acceptable for 23 of 24 bromocresol green method material combinations (96%) and 13 of 16 bromocresol purple albumin method material combinations (81%). All (100%) of the 36 method-material combinations had acceptable commutability for total protein. CONCLUSIONS: One (2.2%) of the instrument systems (Synchron) using bromocresol green and none (0%) of the instrument systems using bromocresol purple had satisfactory total-error performance for albumin measurement. Differences in results between bromocresol green and bromocresol purple methods precluded using common reference intervals for interpreting results for serum albumin. Eight of 9 instrument systems (86.5%) had satisfactory total-error performance for total protein measurement. PMID- 23808464 TI - Screening for down syndrome in the United States: results of surveys in 2011 and 2012. AB - CONTEXT: Participants in a College of American Pathologists external proficiency testing program for first and second trimester Down syndrome screening. OBJECTIVES: To determine the number of women screened for Down syndrome in the United States, along with the type of test received and to compare those results to earlier surveys in 1988 and 1992. DESIGN: Questionnaires regarding the type and number of Down syndrome tests performed per month were completed by participants in early 2011 and again in early 2012. RESULTS: After accounting for some of the missing responses, data from up to 131 laboratories indicated that 67% (2 764 020 of 4 130 000) to 72% (2012: 2 963 592 of 4 130 000) of US pregnancies received prenatal screening for Down syndrome. Second trimester tests were most common (2012: 60%; 1 770 024 of 2 963 592), followed by integrated (2012: 21%; 627 876 of 2 963 592), and first trimester (2012: 19%; 565 692 of 2 963 592). The 6 largest laboratories tested 61% of screened pregnancies and offered the widest array of tests, while the smallest 32 tested 1% and almost always offered only second trimester tests. CONCLUSIONS: The current population estimate of 72% pregnancies screened annually is higher than estimates from 1988 (25%) and 1992 (50%). Available testing choices are also more varied, and all testing methods perform better than those methods available 10 years ago. Clinicians should ensure that women are offered tests that follow recommended best-practice testing protocols, and screening laboratories should assess whether patient needs are being met. PMID- 23808465 TI - Pathologic upgrade rates on subsequent excision when lobular carcinoma in situ is the primary diagnosis in the needle core biopsy with special attention to the radiographic target. AB - CONTEXT: Lobular carcinoma in situ (LCIS) as the primary pathologic diagnosis in a needle core biopsy is an infrequent finding, and the management of patients in this setting is controversial. OBJECTIVE: To determine the rate of pathologic upgrade (defined as the presence of a clinically more-significant lesion in the subsequent excision) in patients with a primary pathologic diagnosis of LCIS in the needle core biopsy. DESIGN: Patients with a primary diagnosis of LCIS in a needle core biopsy who underwent subsequent excision were identified. Core biopsies containing a concurrent high-risk lesion and cases with radiologic pathologic discordance were excluded. The presence of selected microscopic features in the needle core biopsy was correlated with pathologic upgrade. Microscopic findings were correlated with the radiographic target in the needle core biopsy. RESULTS: Sixty-one women with primary LCIS in their needle core biopsy showed a 10% pathologic upgrade rate. The percentage of cores involved by LCIS was significantly associated with pathologic upgrade (P= .04), whereas the remaining measured parameters were not. When LCIS represented the radiographic target, the pathologic upgrade rate was 18%, whereas when it was an incidental finding, the pathologic upgrade rate was 4%. CONCLUSIONS: It may be reasonable for patients with primary, yet incidental, LCIS on needle core biopsy to be managed in a nonsurgical fashion. Larger studies are needed to confirm our findings. PMID- 23808466 TI - Bone marrow examination for unexplained cytopenias reveals nonspecific findings in patients with collagen vascular disease. AB - CONTEXT: Collagen vascular diseases are frequently included in the differential diagnosis for unexplained cytopenias and often prompt a bone marrow biopsy in this patient population to exclude malignancy. Few large-scale studies have characterized the bone marrow morphology in patients with collagen vascular disease, and most are limited to systemic lupus erythematosus or rheumatoid arthritis. OBJECTIVE: To identify morphologic and immunohistochemical abnormalities specific to each of a wide range of collagen vascular disease cases. DESIGN: We examined 102 cases of collagen vascular disease and 38 controls and evaluated the complete blood count, peripheral blood morphology, bone marrow morphology, as well as immunohistochemical staining, for numerous cell lineages. RESULTS: Bone marrow findings, including abnormalities such as lymphoid aggregates, lipogranulomas, or abnormal localization of immature precursors, were not significantly different as compared to the control group. CONCLUSIONS: Bone marrow examination in patients with collagen vascular disease with cytopenias seldom provides new information. Caution should be exercised in interpreting morphologic findings suggestive of myelodysplasia since these are of a reactive nature in up to 27% of patients with collagen vascular disease. In a cost effective diagnostic strategy, successful utilization may favor postponing a bone marrow biopsy while a more standardized autoimmune diagnostic panel is being performed. PMID- 23808468 TI - Steatohepatitic hepatocellular carcinoma, a morphologic indicator of associated metabolic risk factors: a study from India. AB - CONTEXT: The common risk factors for hepatocellular carcinoma (HCC) include persistent viral infection with either hepatitis B or C virus, alcohol abuse, hemochromatosis, and metabolic syndrome. Steatohepatitic (SH) HCC has been recently recognized as a special morphologic variant of HCC associated with metabolic risk factors. OBJECTIVE: To assess the SH pattern in HCC cases of various etiologies in Indian patients and to further correlate this morphology with the presence of metabolic risk factors. DESIGN: A total of 101 cases of HCC with various etiologies in explanted livers from adults were included in the study. Morphologic examination was performed to identify SH lesions within the tumor and in the nontumorous liver parenchyma. Correlation of nontumor and tumor SH morphology with clinically identifiable metabolic risk factors and with non-SH type of HCC was performed. RESULTS: The SH variant of HCC was identified in 19 livers (18.8%). Most SH-HCC cases were associated with metabolic risk factors such as obesity, diabetes, hypertension, and hyperlipidemias. Comparison of SH HCC with non-SH-HCC was statistically significant in terms of presence of metabolic risk factors. CONCLUSIONS: Steatohepatitic morphology in HCC is frequent in nonalcoholic fatty liver disease-associated cirrhosis (P = .009) and is significantly associated with metabolic risk factors (P = .03). By recognizing SH pattern, one may predict associated metabolic diseases and determine the prognosis both in pretransplant and posttransplant patients. PMID- 23808467 TI - Prevalence of terminal duct lobular units and frequency of neoplastic involvement of the nipple in mastectomy. AB - CONTEXT: Breast cancer treatment has greatly evolved from radical mastectomy to more cosmetically acceptable and less-debilitating surgeries. Nipple-sparing mastectomy is increasingly done for both cancer treatment and risk reduction. The frequency of terminal duct lobular units (TDLUs) and occult neoplastic epithelial proliferation in grossly/clinically unremarkable nipples (GUNs) is not well investigated. OBJECTIVE: To describe frequency of TDLUs and occult and overt neoplastic nipple involvement. DESIGN: Nipples from 105 consecutive specimens (90 therapeutic, 15 prophylactic) were studied. Sixty-five nipples were entirely submitted to evaluate frequency of TDLUs; the rest had 1 vertical section submitted. RESULTS: Terminal duct lobular unit was seen in 17 GUNs (26%). Six had TDLU in the base, 6 had it in the papilla, and 5 in both. Four GUNs showed lobular carcinoma in situ (1), Paget disease (1), and pagetoid extension of underlying malignancy (2). Grossly/clinically abnormal nipples had Paget disease (2), lymphovascular invasion (2), invasive carcinoma (4), and pagetoid extension (5). Involved nipples were closer to tumor (mean, 1.1 versus 3.2 cm, P < .001), had larger underlying tumors (mean, 4.3 versus 2.6 cm, P = .03) and of higher grade (P = .04), and more often had lymph node metastases (91% versus 44%, P = .007). No pathologic abnormalities were found in prophylactic mastectomy nipples. CONCLUSIONS: Terminal duct lobular units were seen in 26% of nipples. They were frequently seen in the nipple papilla. Occult neoplastic epithelial proliferation was seen in 5% of grossly/clinically unremarkable therapeutic mastectomy nipples. Pagetoid extension was the dominant spread of underlying malignancy. Overall, the nipple was more often involved by larger and higher-grade tumors located closer to the nipple. All prophylactic mastectomies had unremarkable nipples. These findings should be considered while selecting patients for nipple-sparing mastectomy. PMID- 23808470 TI - Comparison between 1-needle technique versus 2-needle technique for bone marrow aspiration and biopsy procedures. AB - CONTEXT: Bone marrow examination is essential for diagnosis and staging of hematologic disorders. Traditionally, the bone marrow biopsy and aspirate are obtained with 2 needles at 2 separate sites. This approach is associated with significant discomfort, procedural time, and occasionally, morbidity. Although previous observations had suggested that a single-needle technique at one site is a simpler and less-painful procedure, there had been concern that the 1-needle technique may yield a suboptimal biopsy for diagnosis. OBJECTIVE: To conduct a systematic comparison of multiple parameters of bone marrow biopsy specimens obtained by the traditional 2-needle technique versus the 1-needle technique for bone marrow collection. DESIGN: We retrospectively evaluated 20 biopsy specimens obtained by each of the 2 mentioned techniques by comparing the morphologic quality of the biopsy, biopsy length, and biopsy cellularity. RESULTS: We found that the 1-needle technique yielded an adequate biopsy for diagnosis. The measured parameters of the samples obtained by the 1-needle versus 2-needle techniques were similar. CONCLUSION: This study suggests that the 1-needle technique may be preferred for bone marrow aspirate and biopsy. PMID- 23808469 TI - Direct thrombin inhibitors and factor xa inhibitors can influence the diluted prothrombin time used as the initial screen for lupus anticoagulant. AB - CONTEXT: Lupus anticoagulant (LA) is a heterogeneous group of antiphospholipid antibodies. Among others, diluted prothrombin time (dPT) is a sensitive screening test for LA; however, the interpretation of LA tests is difficult in patients treated with anticoagulants. The effect of different types of anticoagulants on the result of LA tests, particularly on dPT, has not been studied extensively. OBJECTIVE: To determine whether the direct thrombin inhibitors lepirudin and argatroban and the predominantly factor Xa inhibitors enoxaparin, danaparoid, and fondaparinux could interfere with LA screening based on dPT. DESIGN: Each drug was added to normal and LA-positive plasmas in clinically relevant concentrations. Each sample was tested for dPT. Samples with factor Xa inhibitors were investigated before and after addition of heparinase. Mixing and confirmatory tests for LA were not performed. RESULTS: In the presence of lepirudin or argatroban, dPT increased notably and the dPT ratio exceeded the cutoff value even at subtherapeutic concentrations resulting in false positivity. With increasing factor Xa inhibitor concentrations, a linear increase of dPT ratios and false-positive results were also demonstrated. Although heparinase could almost completely neutralize the anti-Xa effect of all investigated factor Xa inhibitors, dPT ratio returned to the basal level only in case of enoxaparin. CONCLUSIONS: Here we provide evidence that both the direct thrombin and indirect factor Xa inhibitors influence dPT assay for LA, causing false positivity. This should be considered when interpreting LA results during anticoagulant therapy. However, dPT seems to be a reliable test for LA screening under enoxaparin therapy after neutralization by heparinase. PMID- 23808471 TI - Prevalence and types of misrepresentation of publication record by pathology residency applicants. AB - CONTEXT: Publication misrepresentation among residency applicants has been demonstrated in various specialties. This study examines the prevalence of publication misrepresentation among US-trained and non-US-trained pathology residency applicants. OBJECTIVE: To determine the prevalence of publication misrepresentation in the pathology applicant pool at our institution, to compare the rates of misrepresentation among US-trained and non-US-trained applicants, and to compare results to published results from other medical specialties. DESIGN: All peer-reviewed journal articles reported on applications to our program in 2010 and 2011 were examined for veracity. Applications from current or past trainees and applications with unverifiable manuscripts were excluded. The type of misrepresentation and the country in which the applicant trained were recorded. RESULTS: Seven hundred applications were reviewed. Of 319 (46%) reported publications, 25 were from US graduates (8%) and 294 (92%) were from non US graduates. Eighty-six applications were excluded owing to unverifiable manuscripts. Publication misrepresentations were found in 42 (18%) of the remaining 233 applications. The most common misrepresentations were omission of authors (69%), nonauthorship (14%), and self-promotion on the author list (12%). A significantly higher percentage of foreign medical graduates listed publications (P < .001). The misrepresentation rate by foreign graduates (19%) did not differ significantly from that of US-trained graduates (13%) (P = .45). CONCLUSIONS: Publication misrepresentation was present among pathology residency applicants. Similar rates were seen among US and non-US applicants. Percentages of misrepresentation among applicants to our pathology program and applicants to other medical specialties (18% and 17%, respectively) were comparable. PMID- 23808473 TI - Extranodal rosai-dorfman disease associated with increased numbers of immunoglobulin g4 plasma cells involving the colon: case report with literature review. AB - A 49-year-old woman presented with fever, weight loss, night sweats, hematochezia, and acid reflux symptoms. Two large, firm cecal lesions were seen at colonoscopy, but multiple biopsies were inconclusive. The patient underwent a right hemicolectomy for a clinical diagnosis of colon cancer. Noncaseating granulomatous inflammation with background lymphocytes, plasma cells, and histiocytes exhibiting emperipolesis were identified. With these histologic features and immunoreactivity for S-100 protein and CD68, a diagnosis of Rosai Dorfman disease was rendered. Other areas had storiform fibrosis admixed with numerous immunoglobulin G4 (IgG4)-positive plasma cells. Although a few preliminary reports have noted an increased number of IgG4-positive plasma cells in Rosai-Dorfman disease, the relationship between these 2 conditions is unclear. To our knowledge, this is the first case report of a possible association of colonic Rosai-Dorfman disease with an increased number of IgG4-positive plasma cells. Reviews of colonic Rosai-Dorfman disease and IgG4-related sclerosis are presented to heighten awareness of this rare presentation. PMID- 23808472 TI - Current landscape and new paradigms of proficiency testing and external quality assessment for molecular genetics. AB - CONTEXT: Participation in proficiency testing (PT) or external quality assessment (EQA) programs allows the assessment and comparison of test performance among different clinical laboratories and technologies. In addition to the approximately 2300 tests for individual genetic disorders, recent advances in technology have enabled the development of clinical tests that quickly and economically analyze the entire human genome. New PT/EQA approaches are needed to ensure the continued quality of these complex tests. OBJECTIVES: To review the availability and scope of PT/EQA for molecular genetic testing for inherited conditions in Europe, Australasia, and the United States; to evaluate the successes and demonstrated value of available PT/EQA programs; and to examine the challenges to the provision of comprehensive PT/EQA posed by new laboratory practices and methodologies. DATA SOURCES: The available literature on this topic was reviewed and supplemented with personal experiences of several PT/EQA providers. CONCLUSIONS: Proficiency testing/EQA schemes are available for common genetic disorders tested in many clinical laboratories but are not available for most genetic tests offered by only one or a few laboratories. Provision of broad, method-based PT schemes, such as DNA sequencing, would allow assessment of many tests for which formal PT is not currently available. Participation in PT/EQA improves the quality of testing by identifying inaccuracies that laboratories can trace to errors in their testing processes. Areas of research and development to ensure that PT/EQA programs can meet the needs of new and evolving genetic tests and technologies are identified and discussed. PMID- 23808474 TI - Benign glomus tumor of the urinary bladder. AB - Glomus tumors are rare, mesenchymal neoplasms of adulthood, which occur in both the sexes with equal frequency. Most of these tumors are benign, but some cases with atypical/malignant behavior have been reported. They most often occur in the extremities, typically in the subungual region of the fingers, and rarely involve the internal organs. We report the case of a 63-year-old man who presented with hematuria. The cystoscopy showed a polypoid lesion of the anterior wall of the bladder, which was diagnosed on biopsy as a benign glomus tumor. To the best of our knowledge, this is the first case of benign glomus tumor of the bladder described in the literature. This report widens the spectrum of the differential diagnoses of bladder neoplasms. PMID- 23808475 TI - Adrenal schwannoma: a rare type of adrenal incidentaloma. AB - Adrenal schwannoma is a rare type of adrenal incidentaloma, an adrenal lesion found incidentally, usually on imaging or autopsy. Computed tomography and magnetic resonance imaging are tools used to evaluate adrenal lesions. The diagnosis of adrenal schwannoma, however, cannot be made on imaging alone. Surgical resection is the primary means of management of adrenal schwannomas, as it is not possible to distinguish the schwannoma from malignant entities simply based on imaging. Histopathologic features of adrenal schwannomas are similar to those of schwannomas found at other sites. Conventional schwannomas, consisting of alternating Antoni A and Antoni B areas as well as Verocay bodies, have distinct microscopic features and can be readily distinguished from other entities. Cellular schwannomas, on the other hand, consist only of intersecting fascicles of spindle cells or Antoni A areas, resulting in a wide differential diagnosis. Ancillary studies such as immunohistochemical analysis and electron microscopy can help to provide a specific diagnosis. PMID- 23808476 TI - Fertility after high-dose testosterone and intracytoplasmic sperm injection in a patient with androgen insensitivity syndrome with a previously unreported androgen receptor mutation. AB - We report on a case of a man with familial, X-linked, partial androgen insensitivity, in whom a new point mutation in the androgen receptor (AR) ligand binding domain (causing a valine-to-alanine substitution at codon 686) was identified. High-dose prolonged testosterone therapy resulted in marked progression in patient's appearance and great improvement in sperm count and characteristics. In combination with intracytoplasmic microinjection, treatment resulted in fertility. This is believed to be the first report of such a case. This case supports high-dose testosterone therapeutic trial in this condition. Furthermore, it underscores the possibility of achieving fertility with current endocrine and assisted reproduction modalities, making some of these X-linked AR mutations paternally transmissible. PMID- 23808477 TI - Antioxidant and hepatoprotective effects of silymarin phytosomes compared to milk thistle extract in CCl4 induced hepatotoxicity in rats. AB - Milk thistle extract is a well-known hepatoprotectant with low bioavailability (20-50%). The objective of the present study is to prepare and characterize silymarin phytosomes and to test the hepatoprotective effect of the phytosomes in CCl4 induced liver injury in rats compared to milk thistle extract. Phytosomes were prepared using lecithin from soybeans and from egg yolk. The prepared phytosomes were examined using scanning electron microscopy, transmission electron microscopy, differential scanning calorimetry, Fourier transform infrared spectroscopy and proton nuclear magnetic resonance spectroscopy (H(1)NMR). The loading efficiency was >85% in all phytosomal formulations. Formula P2 (with the molar ratio of soybean lecithin to silybin 1:1) and P4 (with the molar ratio of egg-yolk lecithin to silybin 0.25:1) exhibited significantly (p < 0.05) faster release than milk thistle extract. The in vivo study revealed that phytosomes significantly (p < 0.05) decreased glutamic pyruvic transaminase and super oxide dismutase activities compared to milk thistle extract. PMID- 23808478 TI - Round cell liposarcoma metastatic to the heart. AB - Myxoid liposarcoma is a soft tissue tumor in adults with rare cardiac involvement. We report a 50-year-old female with high grade round cell liposarcoma of the left knee with metastases to the right heart chambers. The tumor was located in the right atrium with extension to right ventricle. The Patient underwent radiotherapy after surgical resection and 12-month follow-up revealed no recurrent cardiac disease. PMID- 23808479 TI - Biotinylation of silicon and nickel surfaces and detection of streptavidin as biosensor. AB - The availability of metal mesh device sensors has been investigated using surface modified nickel mesh. Biotin was immobilized on the sensor surfaces consisting of silicon and nickel via a thiol-ene click reaction, known as the Michael addition reaction. Biotinylation on the maleimidated surface was confirmed by X-ray photoelectron spectroscopy. The binding of streptavidin to the biotinylated surfaces was evaluated using a quartz crystal microbalance and a metal mesh device sensor, with both techniques providing similar binding constant value. The recognition ability of the biotin immobilized using the thiol-maleimide method for streptavidin was comparable to that of biotin immobilized via several other methods. The adsorption of a biotin conjugate onto the streptavidin-immobilized surface via the biotin-streptavidin-biotin sandwich method was evaluated using a fluorescent microarray, with the results demonstrating that the biological activity of the streptavidin remained. PMID- 23808480 TI - Cooled storage of canine semen: in vitro effects of different concentrations of an antibiotic combination on growth of mollicutes. AB - The aim of this study was to examine effects of an antibiotic combination at different concentrations on growth of mycoplasma and ureaplasma during cooled storage of canine semen (n = 20). Semen aliquots were diluted with Tris-citric acid-fructose-egg yolk extender containing either 1.0 g/l streptomycin and 0.6 g/l benzylpenicillin (control) or a combination of gentamycin, tylosin, lincomycin and spectinomycin (GTLS-1: 0.25, 0.05, 0.15 and 0.3; GTLS-2: 0.5, 0.1, 0.3 and 0.6; GTLS-3: 1.0, 0.2, 0.6 and 1.2 g/l). Samples were assessed for motility and membrane integrity by computer-assisted sperm analysis immediately after dilution and at 24, 48 and 72 h of cooled storage. Morphologically, normal spermatozoa were determined, and bacterial culture was performed at 24 and 72 h. Mycoplasma spp. were detected in 14 of 20 ejaculates (70%) with severe growth in 12 samples. A reduction but not total elimination of mycoplasma growth occurred in all GTLS extenders with the most pronounced reduction in group GTLS-3 (control vs GTLS-1 and GTLS-2 p < 0.05, control vs GTLS-3 p < 0.001). Ureaplasmas were detected in four ejaculates, and growth was reduced to the same extent in GTLS and control extender. Progressive motility in all groups, total motility in groups GTLS 1-3 and percentage of membrane-intact spermatozoa in groups GTLS 2 and 3 decreased slightly (p < 0.05) over time. In conclusion, dilution of canine semen with GTLS extender has no major detrimental effects on spermatozoa during cooled storage. It reduced the growth but did not totally eliminate mycoplasmas and ureaplasmas from cooled-stored dog semen. PMID- 23808481 TI - Measuring electrostatic fields in both hydrogen-bonding and non-hydrogen-bonding environments using carbonyl vibrational probes. AB - Vibrational probes can provide a direct readout of the local electrostatic field in complex molecular environments, such as protein binding sites and enzyme active sites. This information provides an experimental method to explore the underlying physical causes of important biomolecular processes such as binding and catalysis. However, specific chemical interactions such as hydrogen bonds can have complicated effects on vibrational probes and confound simple electrostatic interpretations of their frequency shifts. We employ vibrational Stark spectroscopy along with infrared spectroscopy of carbonyl probes in different solvent environments and in ribonuclease S to understand the sensitivity of carbonyl frequencies to electrostatic fields, including those due to hydrogen bonds. Additionally, we carried out molecular dynamics simulations to calculate ensemble-averaged electric fields in solvents and in ribonuclease S and found excellent correlation between calculated fields and vibrational frequencies. These data enabled the construction of a robust field-frequency calibration curve for the C?O vibration. The present results suggest that carbonyl probes are capable of quantitatively assessing the electrostatics of hydrogen bonding, making them promising for future study of protein function. PMID- 23808482 TI - Halogenated graphenes: rapidly growing family of graphene derivatives. AB - Graphene derivatives containing covalently bound halogens (graphene halides) represent promising two-dimensional systems having interesting physical and chemical properties. The attachment of halogen atoms to sp(2) carbons changes the hybridization state to sp(3), which has a principal impact on electronic properties and local structure of the material. The fully fluorinated graphene derivative, fluorographene (graphene fluoride, C1F1), is the thinnest insulator and the only stable stoichiometric graphene halide (C1X1). In this review, we discuss structural properties, syntheses, chemistry, stabilities, and electronic properties of fluorographene and other partially fluorinated, chlorinated, and brominated graphenes. Remarkable optical, mechanical, vibrational, thermodynamic, and conductivity properties of graphene halides are also explored as well as the properties of rare structures including multilayered fluorinated graphenes, iodine-doped graphene, and mixed graphene halides. Finally, patterned halogenation is presented as an interesting approach for generating materials with applications in the field of graphene-based electronic devices. PMID- 23808485 TI - A conserved aromatic residue regulating photosensitivity in short-wavelength sensitive cone visual pigments. AB - Visual pigments have a conserved phenylalanine in transmembrane helix 5 located near the beta-ionone ring of the retinal chromophore. Site-directed mutants of this residue (F207) in a short-wavelength sensitive visual pigment (VCOP) were studied using UV-visible spectroscopy to investigate its role in photosensitivity and formation of the light-activated state. The side chain is important for pigment formation: VCOP(F207A), VCOP(F207L), VCOP(F207M), and VCOP(F207W) substitutions all bound 11-cis-retinal and formed a stable visual pigment, while VCOP(F207V), VCOP(F207S), VCOP(F207T), and VCOP(F207Y) substitutions do not. The extinction coefficients of all pigments are close, ranging between 35800 and 45600 M-1 cm-1. Remarkably, the mutants exhibit an up to 5-fold reduction in photosensitivity and also abnormal photobleaching behavior. One mutant, VCOP(F207A), forms an isomeric composition of the retinal chromophore after illumination comparable to that of wild-type VCOP yet does not release the all trans-retinal chromophore. These findings suggest that the conserved F207 residue is important for a normal photoactivation pathway, formation of the active conformation and the exit of all-trans-retinal from the chromophore-binding pocket. PMID- 23808486 TI - Implementation of an intraoperative blood transport and storage initiative and its effect on reducing red blood cell and plasma waste. AB - BACKGROUND: The national waste rate for hospital-issued blood products ranges from 0% to 6%, with operating room-responsible waste representing up to 70% of total hospital waste. A common reason for blood product waste is inadequate intraoperative storage. STUDY DESIGN AND METHODS: Our transfusion service database was used to quantify and categorize red blood cell (RBC) and fresh frozen plasma (FFP) units issued for intraoperative transfusion that were wasted over a 27-month period. Two cohorts were created: 1) before implementation of a blood transport and storage initiative (BTSI)-RBC and plasma waste January 1, 2011-May 31, 2012; 2) after implementation of BTSI-RBC and plasma waste June 1, 2012, to March 31, 2013. The BTSI replaced existing storage coolers (8-hr coolant life span with temperature range of 1-10 degrees C) with a cooler that had a coolant life span of 18 hours and a temperature range of 1 to 6 degrees C and included an improved educational cooler placard and an alert mechanism in the electronic health record. Monthly median RBC and plasma waste and its associated cost were the primary outcomes. RESULTS: An intraoperative BTSI significantly reduced median monthly RBC (1.3% vs. 0.07%) and FFP (0.4% vs. 0%) waste and its associated institutional cost. The majority of blood product waste was due to an unacceptable temperature of unused returned blood products. CONCLUSION: An intraoperative BTSI significantly reduced median monthly RBC and FFP waste. The cost to implement this initiative was small, resulting in a significant estimated return on investment that may be reproducible in institutions other than ours. PMID- 23808483 TI - The anti-aging factor alpha-klotho during human pregnancy and its expression in pregnancies complicated by small-for-gestational-age neonates and/or preeclampsia. AB - OBJECTIVE: alpha-klotho, a protein with anti-aging properties, has been involved in important biological processes, such as calcium/phosphate metabolism, resistance to oxidative stress, and nitric oxide production in the endothelium. Recent studies have suggested a role of alpha-klotho in endocrine regulation of mineral metabolism and postnatal growth in infants. Yet, the role of alpha-klotho during pregnancy remains largely unknown. The aim of this study was to determine whether maternal plasma concentration of alpha-klotho changes during pregnancy and evaluate its expression in pregnancies complicated by small for gestational age (SGA) and/or preeclampsia (PE). STUDY DESIGN: This cross-sectional study included patients in the following groups: (1) non pregnant women (n = 37); (2) uncomplicated pregnancy (n = 130); (3) PE without an SGA neonate (PE; n = 58); (4) PE with an SGA neonate (PE and SGA; n = 52); and (5) SGA neonate without PE (SGA; n = 52). Plasma concentrations of alpha-klotho were determined by ELISA. RESULTS: The median plasma alpha-klotho concentration was higher in pregnant than in non-pregnant women. Among women with an uncomplicated pregnancy, the median plasma concentration of alpha-klotho increased as a function of gestational age (Spearman Rho = 0.2; p = 0.006). The median (interquartile range) plasma concentration of alpha-klotho in women with PE and SGA [947.6 (762-2013) pg/mL] and SGA without PE [1000 (585-1567) pg/mL] were 21% and 17% lower than that observed in women with an uncomplicated pregnancy [1206.6 (894-2012) pg/mL], (p = 0.005 and p = 0.02), respectively. Additionally, there were no significant differences in the median plasma concentration of alpha-klotho between uncomplicated pregnancies and women with PE without an SGA neonate (p = 0.5). CONCLUSION: Maternal plasma concentration of alpha-klotho was higher during pregnancy than in a non-pregnant state. Moreover, the median maternal plasma concentration of alpha-klotho was lower in mothers who delivered an SGA neonate than in those with an uncomplicated pregnancy regardless of the presence or absence of PE. PMID- 23808488 TI - Stabbing headache as a sign of relapses in multiple sclerosis. PMID- 23808484 TI - Post-genome-wide association study challenges for lipid traits: describing age as a modifier of gene-lipid associations in the Population Architecture using Genomics and Epidemiology (PAGE) study. AB - Numerous common genetic variants that influence plasma high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride distributions have been identified via genome-wide association studies (GWAS). However, whether or not these associations are age-dependent has largely been overlooked. We conducted an association study and meta-analysis in more than 22,000 European Americans between 49 previously identified GWAS variants and the three lipid traits, stratified by age (males: <50 or >=50 years of age; females: pre- or postmenopausal). For each variant, a test of heterogeneity was performed between the two age strata and significant Phet values were used as evidence of age-specific genetic effects. We identified seven associations in females and eight in males that displayed suggestive heterogeneity by age (Phet < 0.05). The association between rs174547 (FADS1) and LDL-C in males displayed the most evidence for heterogeneity between age groups (Phet = 1.74E-03, I(2) = 89.8), with a significant association in older males (P = 1.39E-06) but not younger males (P = 0.99). However, none of the suggestive modifying effects survived adjustment for multiple testing, highlighting the challenges of identifying modifiers of modest SNP-trait associations despite large sample sizes. PMID- 23808487 TI - The social and gender context of HIV disclosure in sub-Saharan Africa: a review of policies and practices. AB - This paper reviews the legal and policy context of HIV disclosure in sub-Saharan Africa, as well as what is known about rates, consequences and social context of disclosure, with special attention to gender issues and the role of health services. Persistent rates of nondisclosure by those diagnosed with HIV raise difficult ethical, public health and human rights questions about how to protect the medical confidentiality, health and well-being of people living with HIV on the one hand, and how to protect partners and children from HIV transmission on the other. Both globally and within the sub-Saharan African region, a spate of recent laws, policies and programmes have tried to encourage or - in some cases - mandate HIV disclosure. These policies have generated ethical and policy debates. While there is consensus that the criminalization of transmission and nondisclosure undermines rights while serving little public health benefit, there is less clarity about the ethics of third party notification, especially in resource-constrained settings. Despite initiatives to encourage voluntary HIV disclosure and to increase partner testing in sub-Saharan Africa, health workers continue to grapple with difficult challenges in the face of nondisclosure, and often express a need for more guidance and support in this area. A large body of research indicates that gender issues are key to HIV disclosure in the region, and must be considered within policies and programmes. Taken as a whole, this evidence suggests a need for more attention to the challenges and dilemmas faced by both clients and providers in relation to HIV disclosure in this region and for continued efforts to consider the perspectives and rights of all those affected. PMID- 23808489 TI - 2-[(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4 (2-methylphenyl)octahydro-2H-isoindol-2-yl]-1,3-oxazol-4(5H)-one: a potent human NK1 receptor antagonist with multiple clearance pathways. AB - Hydroisoindoline 2 has been previously identified as a potent, brain-penetrant NK1 receptor antagonist with a long duration of action and improved profile of CYP3A4 inhibition and induction compared to aprepitant. However, compound 2 is predicted, based on data in preclinical species, to have a human half-life longer than 40 h and likely to have drug-drug-interactions (DDI), as 2 is a victim of CYP3A4 inhibition caused by its exclusive clearance pathway via CYP3A4 oxidation in humans. We now report 2-[(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5 bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H isoindol-2-yl]-1,3-oxazol-4(5H)-one (3) as a next generation NK1 antagonist that possesses an additional clearance pathway through glucuronidation in addition to that via CYP3A4 oxidation. Compound 3 has a much lower propensity for drug-drug interactions and a reduced estimated human half-life consistent with once daily dosing. In preclinical species, compound 3 has demonstrated potency, brain penetration, and a safety profile similar to 2, as well as excellent pharmacokinetics. PMID- 23808490 TI - Review article: the management of autoimmune hepatitis beyond consensus guidelines. AB - BACKGROUND: Consensus guidelines aid in the diagnosis and management of autoimmune hepatitis, but they are frequently based on low-quality clinical evidence, conflicting experiences and divergent opinions. Recommendations may be weak, discrepant or non-existent at critical decision points. AIMS: To identify the decision points where guidelines are weak or non-existent and review the evidence essential in the decision process. METHODS: Full-text articles published in English using the keyword 'autoimmune hepatitis' were identified by PubMed from 1972 to 2013. Personal experience and investigations in autoimmune hepatitis also identified important contributions. RESULTS: Seventy per cent of the guidelines developed by the American Association for the Study of Liver Diseases and 48% of those proposed by the British Society of Gastroenterology are based on low-quality evidence, conflicting experiences or divergent opinions. The key uncertainties in diagnosis relate to the timing of liver biopsy, recognising acute severe (fulminant) disease, interpreting coincidental nonclassical histological changes, accommodating atypical or deficient features in non-White patients, differentiating drug-induced from classical disease and identifying overlap syndromes. The key uncertainties in management relate to pre-treatment testing for thiopurine methyltransferase activity, treating asymptomatic mild disease, determining treatment end points, managing suboptimal responses, incorporating nonstandard medications as front-line and salvage agents, using azathioprine in pregnancy and instituting surveillance for hepatocellular carcinoma. CONCLUSIONS: Consensus guidelines are fraught with uncertainties in the diagnosis and management of autoimmune hepatitis. Each decision point must counterbalance the current available evidence and tailor the application of this evidence to the individual patient. PMID- 23808491 TI - Insights into Ru-based molecular water oxidation catalysts: electronic and noncovalent-interaction effects on their catalytic activities. AB - A series of Ru-bda water oxidation catalysts [Ru(bda)L2] (H2bda = 2,2'-bipyridine 6,6'-dicarboxylic acid; L = [HNEt3][3-SO3-pyridine], 1; 4-(EtOOC)-pyridine, 2; 4 bromopyridine, 3; pyridine, 4; 4-methoxypyridine, 5; 4-(Me2N)-pyridine, 6; 4 [Ph(CH2)3]-pyridine, 7) were synthesized with electron-donating/-withdrawing groups and hydrophilic/hydrophobic groups in the axial ligands. These complexes were characterized by (1)H NMR spectroscopy, high-resolution mass spectrometry, elemental analysis, and electrochemistry. In addition, complexes 1 and 6 were further identified by single crystal X-ray crystallography, revealing a highly distorted octahedral configuration of the Ru coordination sphere. All of these complexes are highly active toward Ce(IV)-driven (Ce(IV) = Ce(NH4)2(NO3)6) water oxidation with oxygen evolution rates up to 119 mols of O2 per mole of catalyst per second. Their structure-activity relationship was investigated. Electron withdrawing and noncovalent interactions (attraction) exhibit positive effect on the catalytic activity of Ru-bda catalysts. PMID- 23808496 TI - Do we have the capacity as a nation to come together around a good idea? PMID- 23808492 TI - A role for interleukin-17A in modulating intracellular survival of Mycobacterium bovis bacillus Calmette-Guerin in murine macrophages. AB - Interleukin 17A IL-17A is a crucial immunomodulator in various chronic immunological diseases including rheumatoid arthritis and inflammatory bowel disease. The cytokine has also been demonstrated to control the pathogenesis of the Mycobacterium tuberculosis by dysregulating production of cytokines and chemokines and promoting granuloma formation. Whether IL-17A regulates innate defence mechanisms of macrophages in response to mycobacterial infection remains to be elucidated. In the current report, we investigated the effects of IL-17A on modulating the intracellular survival of Mycobacterium bovis bacillus Calmette Guerin (BCG) in RAW264.7 murine macrophages. We observed that IL-17A pre treatment for 24 hr was able to synergistically enhance BCG-induced nitric oxide (NO) production and inducible nitric oxide synthase expression in dose- and time dependent manners. We further delineated the mechanisms involved in this synergistic reaction. IL-17A was found to specifically enhanced BCG-induced phosphorylation of Jun N-terminal kinase (JNK), but not of extracellular signal regulated kinase 1/2 and p38 mitogen-activated protein kinase. By using a specific JNK inhibitor (SP600125), we found that the production of NO in BCG infected macrophages was significantly suppressed. Taken together, we confirmed the involvement of the JNK pathway in IL-17A-enhanced NO production in BCG infected macrophages. We further demonstrated that IL-17A significantly enhanced the clearance of intracellular BCG by macrophages through an NO-dependent killing mechanism. In conclusion, our study revealed an anti-mycobacterial role of IL-17A through priming the macrophages to produce NO in response to mycobacterial infection. PMID- 23808497 TI - Transcending carrots and sticks: a review of self-determination theory. PMID- 23808498 TI - Zygomaticofacial foramen location accuracy and reliability in cone-beam computed tomography. AB - OBJECTIVE: This study aimed to evaluate the possibility of detecting the zygomaticofacial foramen (ZFF) in cone-beam computed tomography (CBCT). MATERIALS AND METHODS: This study evaluated ZFFs in 151 macerated skulls (302 zygomatic bones, ZBs) by physical inspection, in which the presence and diameters of the ZFFs were determined. These data were compared with the CBCT images of the skulls to determine the accuracy of CBCT in detecting ZFFs. The diameters were measured by insertion of steel wires with known thicknesses into the ZFFs. The CBCT images were acquired by an i-CAT Classic(r) (International Imaging Sciences, Hatfield, PA) connected to a workstation (Model ITOX Midtower Workstation; Imaging Sciences International(r)) with a 20-inch Eizo monitor. The images were generated in coronal, sagittal and axial slices to evaluate the best tomographic plane for ZFF visualization. RESULTS: The incidence of ZFF found by physical inspection was one foramen in 44% of ZBs (n = 133), two foramina in 28% (n = 86), three foramina in 8% (n = 24) and four foramina in 1% (n = 2). ZFF was absent in 19% (n = 57) of ZBs. The average diameter was 0.57 mm (+/- 0.27 mm). All foramina were observed in all tomography images. CONCLUSION: This preliminary study supports the conclusion that a CBCT scan has excellent accuracy in evaluating ZFFs. PMID- 23808499 TI - Influence of intermediate resin on the bond strength of light-curing composite resin to polymer substrate. AB - OBJECTIVES: The aim of this study was to examine the effect of intermediate resin (IMR) of different monomer compositions and viscosities on the shear bond strength between polymer substrate and light-curing composite. METHODS: The substrate used in the study was an autopolymerizing polymethyl methacrylate (PMMA) based polymer. The substrate was treated with the IMR for 3 min before application of light polymerizable particulate filler composite resin. The monomers of the IMR were either bisphenol-A-glycidyl dimethacrylate (BisGMA) and triethyleneglycol dimethacrylate (TEGDMA) or BisGMA and methyl methacrylate (MMA). The shear bond strength of the IMR treated substrate to the particulate filler composite was evaluated after storing the specimens dry and after thermocycling the specimens in water. Light microscope examination was accomplished to determine the swelled layer of the substrate. RESULTS: Significant differences were found between the shear bond strength values of the IMRs (p < 0.001). The bond strengths were generally higher in the BisGMA-MMA groups than in the BisGMA-TEGDMA groups. Two-way ANOVA revealed significant effects of type of IMR (p < 0.001) and thermocycling (p = 0.017) on the shear bond strength. No interaction was found between these variables (p > 0.05). CONCLUSIONS: The results suggest that the monomer composition and ratio of the IMRs used in the study influence the shear bond strength of the polymer substrate to the new resin. PMID- 23808500 TI - OsSUV3 dual helicase functions in salinity stress tolerance by maintaining photosynthesis and antioxidant machinery in rice (Oryza sativa L. cv. IR64). AB - To overcome the salinity-induced loss of crop yield, a salinity-tolerant trait is required. The SUV3 helicase is involved in the regulation of RNA surveillance and turnover in mitochondria, but the helicase activity of plant SUV3 and its role in abiotic stress tolerance have not been reported so far. Here we report that the Oryza sativa (rice) SUV3 protein exhibits DNA and RNA helicase, and ATPase activities. Furthermore, we report that SUV3 is induced in rice seedlings in response to high levels of salt. Its expression, driven by a constitutive cauliflower mosaic virus 35S promoter in IR64 transgenic rice plants, confers salinity tolerance. The T1 and T2 sense transgenic lines showed tolerance to high salinity and fully matured without any loss in yields. The T2 transgenic lines also showed tolerance to drought stress. These results suggest that the introduced trait is functional and stable in transgenic rice plants. The rice SUV3 sense transgenic lines showed lesser lipid peroxidation, electrolyte leakage and H2 O2 production, along with higher activities of antioxidant enzymes under salinity stress, as compared with wild type, vector control and antisense transgenic lines. These results suggest the existence of an efficient antioxidant defence system to cope with salinity-induced oxidative damage. Overall, this study reports that plant SUV3 exhibits DNA and RNA helicase and ATPase activities, and provides direct evidence of its function in imparting salinity stress tolerance without yield loss. The possible mechanism could be that OsSUV3 helicase functions in salinity stress tolerance by improving photosynthesis and antioxidant machinery in transgenic rice. PMID- 23808501 TI - The pursuit of oxygen euboxia. PMID- 23808502 TI - The easy option? PMID- 23808503 TI - High volume local infiltration analgesia compared to peripheral nerve block for hip and knee arthroplasty-what is the evidence? AB - Since being reported in 2008, high volume local infiltration analgesia (HVLIA) has rapidly gained popularity for patients undergoing hip and knee replacement. We undertook this review to investigate whether there was evidence for equivalence of HVLIA compared to peripheral nerve block techniques with respect to early postoperative analgesia and functional recovery, or for other outcomes such as cost and process efficiency, persistent postsurgical pain and arthroplasty revision rate. We found that despite the popularity of HVLIA, supporting evidence for its use is currently limited. HVLIA certainly provides postoperative analgesia, but it is not clear whether it is equivalent to contemporary peripheral nerve block techniques in terms of either analgesia or early or later functional outcome in the context of a modern, comprehensive enhanced recovery program. Nor is it possible to state whether HVLIA provides benefits in terms of persistent postsurgical pain or cost and process efficiency. Well designed trials directly comparing peripheral nerve block with a standardised HVLIA technique are urgently required. PMID- 23808504 TI - Acute respiratory distress syndrome: current concepts and future directions. AB - Acute respiratory distress syndrome is one of the leading causes of death in critically ill patients. Recent advances in supportive care have led to a moderate improvement in mortality. In particular, a much lower mortality rate than expected was evident in the severest category of patients (requiring extracorporeal membrane oxygenation) in Australia during the recent H1N1 pandemic. Though improvements in supportive care may have provided some benefit, there remains an absence of effective biological agents that are necessary to achieve further incremental reduction in mortality. This article will review the evidence available for current treatment strategies and discuss future research directions that may eventually improve outcomes in this important global disease. PMID- 23808505 TI - Bedside pleuroscopy in the management of undiagnosed exudative pleural effusion with acute respiratory failure. AB - Pleuroscopy is indicated in patients with acute respiratory failure due to an unresolved exudative pleural effusion but it may not be possible to move such patients to the operating theatre or endoscopy room for pleuroscopy due to their critical condition. We report our experience of using flexible bronchoscopy for pleuroscopy to diagnose pleural effusion in patients with acute respiratory failure at the bedside in the intensive care unit. Before pleuroscopy, patients were placed in the lateral decubitus position. We used bedside chest sonography to guide safe entry of the trocar. The skin was sterilised with povidone-iodine and local analgesia was with 2% lignocaine. Incisions were made using a knife with a width of 5 mm. A trocar 5.5 mm in diameter was inserted and a bronchoscope was inserted. The pleural cavity was inspected and biopsies were performed under direct vision in all suspected areas. A 16 Fr pigtail catheter was inserted for drainage after the pleuroscopy. Chest radiographs were routinely obtained after the procedure. In summary, this modified pleuroscopy technique can be performed at the bedside in an intensive care unit. PMID- 23808506 TI - Epidural versus continuous transversus abdominis plane catheter technique for postoperative analgesia after abdominal surgery. AB - Transversus abdominis plane block is an effective postoperative analgesic technique after abdominal surgery, but no study has compared continuous transversus abdominis plane block with continuous epidural analgesia. We designed a randomised controlled trial comparing these techniques for major abdominal surgery. Patients in the epidural group received a bolus of 8 to 15 ml of ropivacaine 0.2% and an infusion of 5 to 15 ml/hour and the transversus abdominis plane block group a bolus dose of 20 ml of ropivacaine 0.375% bilaterally and an infusion of 0.2% ropivacaine 8 ml/hour bilaterally, for three days. Both groups received paracetamol and patient controlled analgesia with fentanyl for three days. Primary outcomes were numerical rating scores for pain (rest and dynamic over 72 hours) and total fentanyl use; complications and satisfaction scores were also noted. The study was terminated early after 42 patients had been randomised (epidural n=19; transversus abdominis plane block n=22; one excluded). No differences were found in regards to point pain scores or scores over time, either immediately postoperatively or in surgical wards; total fentanyl requirement and Likert satisfaction scores were also similar in both groups. In this underpowered study we found comparable results between continuous transversus abdominis plane technique and epidural analgesia in regard to pain, analgesic use and satisfaction after abdominal surgery. To confirm this finding, randomised trials with larger numbers of participants are needed. PMID- 23808507 TI - Is comorbid status the best predictor of one-year mortality in patients with severe sepsis and sepsis with shock? AB - Understanding longer term outcomes in critically ill patients will assist treatment decisions, allocation of scarce resources and clinical research in that population. The aim of this study was to compare a well-validated means of determining comorbidity, the Charlson Comorbidity Score, to other verified risk stratification models in predicting one-year mortality and other outcomes in emergency department patients with severe sepsis and sepsis with shock. We conducted a planned subgroup analysis of a prospective observational study, the Critical Illness and Shock Study, in adult patients with sepsis meeting study criteria for critical illness. From emergency department arrival, patients were prospectively enrolled with data collected for a minimum of one year post enrolment. Scoring systems were derived from this data and compared using receiver-operating characteristic curves. One hundred and four patients were enrolled. The 28-day mortality was 18% and one-year mortality 40%. For predicting one-year mortality, the area under the receiver-operating characteristic curve for age-weighted Charlson Comorbidity Score (0.71, 95% confidence interval 0.61 to 0.81) was at least as good or superior to other scoring systems analysed. The intensive care unit admission rate was 45% and the median hospital length-of-stay was eight days. We conclude that in patients who present to the emergency department with severe sepsis or sepsis with shock, age-weighted Charlson Comorbidity Score is a predictor of one-year mortality that is simple to calculate and at least as accurate as other validated scoring systems. PMID- 23808508 TI - Does left ventricular tissue Doppler peak systolic velocity (Sm) reflect cardiac output in the critically ill? AB - Cardiac output (CO) is dependent on a number of factors, in particular, the systolic function of the heart. Tissue Doppler (TD) is a modality in echocardiography that measures myocardial velocity and is related to contractility. TD can therefore be used to measure the systolic function of the heart. This study sought to establish whether the systolic component of TD can be used to estimate CO in critically ill patients. Retrospective data was obtained from a total of 80 patients: 29 patients with a normal echocardiogram, and 51 intensive care unit patients; 28 septic and 23 with heart failure. The mean TD peak systolic velocity (Sm) was significantly lower in the heart failure patients (P <0.05) compared to both normal and septic group. The mean CO was significantly higher in septic patients when compared to heart failure patients. A mild to moderate positive correlation was found between Sm and CO in the heart failure group and with all patients combined (r2=0.19, P <0.001). Subsequent analysis of Sm versus stroke volume again showed a mild positive correlation in the heart failure group and combined results (r2=0.18, P <0.001). Sm was weakly correlated to heart rate only in the normal group but not in the combined cohort. Our data confirms a weak to moderate correlation between Sm and CO, probably resulting from a positive correlation of Sm and stroke volume. This correlation is not strong enough to support the use of an individual's Sm to estimate CO in intensive care patients. PMID- 23808509 TI - Chronic pain after caesarean delivery: an Australian cohort. AB - We investigated the incidence of and risk factors for persistent pain after caesarean delivery. Over a 12-month period, women having caesarean delivery were recruited prospectively at an Australian tertiary referral centre. Demographic, anaesthetic and surgical data were collected and at 24 hour follow-up, women were assessed for immediate postoperative pain and preoperative expectations of pain. Long-term telephone follow-up was conducted at two and 12 months postoperatively. Complete data were obtained from 426 of 469 women initially recruited (90.6%). The incidence of persistent pain at the abdominal wound at two months was 14.6% (n=62) but subsequently reduced to 4.2% (n=18) at 12 months. At two months, 33 patients (7.8%) experienced constant or daily pain. At 12 months, five patients (1.1%) continued to have constant or daily pain which was mild. There was no apparent increase in incidence of persistent pain associated with general versus regional anaesthesia (relative risk [RR] 0.89, 95% confidence interval [CI] 0.49 to 1.6); emergency vs elective procedure (RR 0.65, 95% CI 0.39 to 1.07); higher acute pain scores (RR 1.1, 95% CI 0.69 to 1.75); or history of previous caesarean delivery (RR 0.81, 95% CI 0.50 to 1.33). Persistent pain, usually of a mild nature, is reported by some women two months after their caesarean delivery, but by 12 months less than 1% of women had pain requiring analgesia or affecting mood or sleep. All declined a pain clinic review. Clinicians and patients can be reassured that caesarean delivery is unlikely to lead to severe persistent pain in the long-term. PMID- 23808510 TI - Effect of alkalinisation of lignocaine for propofol injection pain: a prospective, randomised, double-blind study. AB - The aim of this study was to determine whether pretreatment with alkalinised lignocaine reduced the incidence and severity of pain during propofol injection. This prospective, randomised, double-blind study included 300 adult, American Society of Anesthesiologists physcial status I to II patients undergoing elective surgery. Patients were randomly allocated to one of three groups: Group L received 0.05 ml/kg of 1% lignocaine (5 ml normal saline + 5 ml 2% lignocaine), Group A received 0.05 ml/kg alkalinised lignocaine (5 ml 2% lignocaine + 1 ml 8.4% NaHCO3 + 4 ml normal saline), and Group S, the control group, was given the same amount of normal saline (NaCl 0.9%). All drugs were given as a bolus over 20 seconds before propofol administration. A blinded researcher assessed the patient's pain level using a four-point scale. The pain score [median (range)] and the incidence of pain in Group A (6%) was significantly lower than in groups L (41%) and S (88%, P <0.001). In addition, the pain score and the incidence of pain were found to be significantly different between Group L and Group S (P <0.001). The incidence of moderate and severe pain were greater in Group S when compared with groups A and L (P <0.001). Intravenous pretreatment with alkalinised lignocaine appears to be effective in reducing the pain during propofol injection. PMID- 23808511 TI - Current oxygenation practice in ventilated patients-an observational cohort study. AB - Oxygen therapy is a mainstay of critical care medicine, yet its optimal therapeutic use has not been systematically evaluated. A detailed understanding of current practice in oxygen therapy in intensive care is required to enable future interventional studies. We aimed to describe current oxygenation practice in patients requiring >=48 hours of mechanical ventilation (MV) at an academic tertiary referral centre. We collected longitudinal arterial blood gas and hourly oxygenation data from intensive care unit charts in a consecutive cohort of 40 trauma, 41 medical and 20 surgical patients for their first seven MV days, analysed data for 14,063 MV hours, and derived time-weighted averages (TWA) of variables for each 24-hour interval on MV for all patients.The TWA-FiO2 was 0.42 (95% CI 0.41 to 0.44) and TWA-SpO2 was 97.1% (95% CI 96.8 to 97.4) for the first seven MV days. TWA-PaO2 was >80 mmHg on 80% of MV days. TWA-FiO2 of >=0.35 was used to achieve TWA-SpO2 >95% on 61% of MV days. Of 58 MV days with TWA-FiO2 >=0.60, TWA-SpO2 >=96% occurred on 28 (48%) days. Mean SpO2 and PaO2 in patients with severe acute lung injury (ALI) scores were higher than recommended targets. Wide variability in the mean SpO2 and PaO2 was observed in patients with comparable ALI scores. Inspired oxygen therapy in these MV patients was 'liberal', with PaO2 and SpO2 values generally above 80 mmHg and 96% respectively. An interventional study comparing current practice to more conservative targets (PaO2?60 to 65 mmHg and/or SpO2?90 to 92%) appears possible. PMID- 23808512 TI - Prediction of fluid responsiveness using dynamic preload indices in patients undergoing robot-assisted surgery with pneumoperitoneum in the Trendelenburg position. AB - We investigated the abilities of pulse pressure variation (PPV) and stroke volume variation (SVV) to predict fluid responsiveness during robot-assisted laparoscopic prostatectomy, requiring pneumoperitoneum and the Trendelenburg position. In 42 patients without cardiopulmonary disease, PPV and SVV were measured before and after administration of 500 ml colloid under pneumoperitoneum combined with the steep Trendelenburg position (35 degrees ). Fluid responsiveness was defined as a >=15% increase in stroke volume after the fluid loading measured using transoesophageal echocardiography. Of the 42 included patients, 22 were responders and 20 were non-responders. A PPV of >=9.5% identified responders with a sensitivity of 77.3% and a specificity of 90.0%, and a SVV of >=9.5% also identified responders with a sensitivity of 77.3% and a specificity of 75.0%. The area under receiver operating characteristic curves for PPV and SVV were 0.87 (P <0.001) and 0.81 (P=0.001), respectively. The findings suggest that both PPV and SVV could be useful predictors of fluid responsiveness in patients without cardiopulmonary disease undergoing robotic laparoscopic surgery with pneumoperitoneum in the Trendelenberg position. PMID- 23808513 TI - Asialoglycoprotein receptor scintigraphy with 99mTc-galactosyl human serum albumin (99mTc-GSA) as an early predictor of survival in acute liver failure. AB - This study evaluated the usefulness of asialoglycoprotein receptor scintigraphy with 99mTc-galactosyl human serum albumin (99mTc-GSA scintigraphy) as an early predictor for prognosis of acute liver failure. Forty-eight patients with acute liver failure and without a past history of chronic liver disease were enrolled. Patients were divided into survival and non-survival groups by 28-day mortality. 99mTc-GSA scintigraphy to detect uptake ratio of the heart at 15 minutes to that at three minutes (HH15) and uptake ratio of the liver at 15 minutes to the liver plus the heart at 15 minutes (LHL15), and measurements of serum total bilirubin, hepatocyte growth factor and prothrombin time were performed immediately after the diagnosis of acute liver failure. Areas under the receiver operating characteristic curves were used to compare the prognostic ability of total bilirubin, hepatocyte growth factor, prothrombin time, HH15 ratio, LHL15 ratio and the model for end-stage liver disease score. Clinical characteristics of patients in the survival group (n=20) and in the non-survival group (n=28) were not significantly different. HH15 and LHL15 uptake ratios in the survival group were 0.670 and 0.875, and they were significantly lower and higher than those in the non-survival group, respectively. All patients with LHL15 <0.760 died, and the area under the receiver operating characteristic curve for LHL15 were significantly larger than the areas under the receiver operating characteristic curves of serum variables and model for end-stage liver disease score. In summary, in patients with acute liver failure without chronic liver disease, HH15 and LHL15 of 99mTc-GSA scintigraphy are more useful variables in predicting prognosis than serum variables and model for end-stage liver disease score. PMID- 23808514 TI - Decontamination of ultrasound equipment used for peripheral ultrasound-guided regional anaesthesia. AB - Portable ultrasound machines are frequently used in operating theatres for peripheral single-shot nerve block procedures. This equipment must be decontaminated by reducing the microbial load to a sufficient level to reduce the risk of nosocomial infection. In our institution we use a simple three-step decontamination protocol utilising 70% isopropyl alcohol as chemical disinfectant. We performed a prospective, quality assurance study to assess the efficacy of this protocol, as it is unclear if this is suitable for disinfecting semi-critical equipment. The primary endpoint was presence of microbial contamination prior to re-use of equipment. Over a four-week period, 120 swabs were taken from multiple sites on our ultrasound machines and linear array transducers for microbial culture. Swabs were taken after decontamination and immediately prior to patient contact. Any pathogenic and environmental bacterial organisms were isolated and identified. No pathogenic organisms were grown from any of the collected swabs. In 85% (n=102) of cultures, no growth was detected. Of the remaining 15% (n=18), commensal organisms commonly found on skin, oral and environmental surfaces were isolated. Our results suggest that our decontamination protocol may be an effective, rapid and cost-effective method of cleaning ultrasound equipment used for peripheral invasive single-shot nerve blocks. Further guidance from national bodies is required to define appropriate cleaning protocols for these machines. PMID- 23808515 TI - Feasibility of anaesthetic provision for paediatric patients undergoing off-site intraoperative MRI-guided neurosurgery: the Singapore experience from 2009 to 2012. AB - The benefits of using intraoperative magnetic resonance imaging (iMRI) for neurosurgery have been recognised. However, iMRI facilities are not available in all hospitals. For example, in Singapore iMRI is currently available only at the Singapore General Hospital, an adult hospital without facilities for intensive care management of patients less than 12 years of age. KK Women's and Children's Hospital is a dedicated children's hospital situated 6.3 km away from this facility. In order to obtain iMRI services for our paediatric patients, transport to Singapore General Hospital is required, with return to our hospital for postoperative management. Since July 2009 we have managed nine paediatric patients in this manner: three children with arteriovenous malformations and six children with brain tumours. There was no morbidity or mortality that could be attributed to the transport of patients either to or from Singapore General Hospital. Our experience suggests that with adequate planning and preparation, providing anaesthetic care and transporting children for off-site iMRI-guided neurosurgery is feasible and safe for selected children. PMID- 23808516 TI - Critical airway obstruction by mediastinal masses in the intensive care unit. AB - Critical airway obstruction is a dreaded complication of a mediastinal mass. The acute management is difficult and catastrophic outcomes have been reported. A total of 19 patients, aged between 13 and 69 years, who had critical major airway obstruction due to mediastinal mass requiring mechanical ventilation were reviewed. Three patients had benign pathologies (retrosternal goitre, bronchogenic cyst, giant left atrium) and three had lymphoma. The remaining patients had advanced malignancies: metastatic mediastinal lymphadenopathy (n=6), thyroid carcinoma (n=1) and oesophageal carcinoma (n=6). Three patients underwent surgery, three received chemotherapy and 15 had airway stenting under deep intravenous sedation. Apart from one patient who had brain haemorrhage and nosocomial infection after cardiac surgery, all other patients were successfully weaned off ventilation within five days after the interventions to alleviate the major airway obstruction without major complications. All patients were discharged from hospital without supplemental oxygen. Patients who had benign pathologies and lymphoma (n=6, 32%) were still alive after a mean follow-up period of six years (range 3 to 10) and those with metastatic disease died after a mean survival period of 3.3 months (range 1 to 9). In summary, critical major airway obstruction is caused by a heterogeneous group of mediastinal pathologies, and the definitive treatment and long-term prognosis of these patients are highly dependent on the underlying aetiology. Combining various therapeutic modalities can lead to successful separation of these patients from mechanical ventilation within a short period of time. PMID- 23808517 TI - Frozen platelets for rural Australia-when, if not. PMID- 23808518 TI - Hidden implications: potential antiplatelet effects of adjuvant anaesthetic agents. PMID- 23808520 TI - Bilateral bispectral index monitoring of a post-hemispherotomy patient with Sturge-Weber syndrome. PMID- 23808519 TI - Dobutamine induced cardiogenic shock due to systolic anterior motion after mitral valve repair. PMID- 23808521 TI - Is it worth the weight? PMID- 23808522 TI - Inhaled iloprost plus levosimendan to decompensate right heart failure due to chronic thromboembolic pulmonary hypertension. PMID- 23808523 TI - Perfusion index changes during emergence from anaesthesia in children. PMID- 23808524 TI - A retrospective analysis of pathological changes of testicular tissue in normal adult rats. AB - Rat testicular model is widely used in experiments on andrology, pharmacology and reproductive toxicology. Generally, normal adult rat is considered to have normal testes. However, whether normal adult rats appeared abnormal testes have not been evaluated. The objective of this study was to evaluate the incidence of abnormal testes in normal adult Sprague Dawley (SD) rats and pathological changes in testicular tissues. Six hundred and sixteen adult male SD rats used in previous studies as controls were retrospectively analysed. Testicular tissues were stained with haematoxylin-eosin for observation of pathology. Among 616 rats, 14 rats had pathological testes, and the incidence of abnormal testis was 2.3%. In the 14 rats with abnormal testes, 10 rats were microrchidia (71.4%) and four rats showed normal testicular size. Testicular abnormality included complete interruption of spermatogenesis, partial germ cell arrest, progressive hypospermatogenesis, seminiferous epithelia vacuolation and inflammatory status. Bilateral testicular tissues had similar pathological changes in abnormal testes. The findings in this study demonstrate that the normal adult rats have abnormal testes. We should pay attention to the possibility of abnormal testes when using normal adult male rats for establishing a testicular model. PMID- 23808525 TI - An outlook on vascular hydrogen sulphide effects, signalling, and therapeutic potential. AB - Hydrogen sulphide (H(2)S) is the most recently discovered gasotransmitter. It is endogenously generated in mammalian vascular cells and attracts substantial interest by its function as physiological relevant signalling mediator, and by its dysfunction in metabolic diseases like obesity, type 2 diabetes and their associated complications. The purpose of this review is to highlight the novel findings on vascular H(2)S homeostasis, pathology-associated dysregulation, cell signalling, and therapeutic potential. The data bases searched were Medline and PubMed, from 2008 to 2012 (terms: hydrogen sulphide, sulfhydration). The new reports definitely assess the vasculoprotectant role of H(2)S in health, and its reduced biosynthesis/systemic levels in obesity, diabetes, atherosclerosis and hypertension. One of the mechanisms of H(2)S signalling discussed here is S sulfhydration of catalytic cysteine residue of PTP1B, a negative regulator of insulin and leptin signalling. Finally, the review critically evaluates the compounds able to regulate vascular H(2)S bioavailability, and with potential in therapeutic exploitation. PMID- 23808526 TI - Wound healing in the wild: stress, sociality and energetic costs affect wound healing in natural populations. AB - Ecoimmunologists strive to understand how ecology and evolution shape immunity in natural populations. To date, ecoimmunologists have sometimes struggled to find measures of immunity that can be easily performed in nonmodel systems. One exception is variation in rates of cutaneous wound healing, which is a functionally important, integrative measure of immunity that combines cell mediated, inflammatory and even some Th2-mediated processes. Here I review what is known about sources of variation in wound healing in wild populations, focusing on two key ecoimmunological questions: How and when does the stress response influence immune function? And how do energetic trade-offs alter immunity? The results indicate that stress and energetic costs can suppress wound healing, but the effects depend on individuals' social and abiotic environments. I also discuss methods to measure wound healing in natural populations and useful directions for future research. Because wound healing has functional significance to organisms, can be measured in diverse species and integrates several immune processes, this measure of immunity is an especially valuable member of the ecoimmunological toolkit. PMID- 23808527 TI - Should we pay the student? A randomised trial of financial incentives in medical education. AB - BACKGROUND: Financial incentives are effective in moderating physician and patient behaviour, but they have not been studied in the context of medical education. AIM: This study assessed whether financial incentives can motivate students to acquire electrocardiogram (ECG) interpretation skills. METHODS: Students enrolled for a cardio-respiratory teaching module (n = 121) were randomised to an intervention (financial incentive) or a control (book voucher raffle) condition. All students took three validated exams of ECG interpretation skills (at module entry, module exit and seven weeks later). Only the exit exam was financially incentivised in the intervention group. The primary outcome was the proportion of students who correctly identified >=60% of clinically important diagnoses in the exit exam. RESULTS: Financial incentives more than doubled the odds of correctly identifying >=60% of diagnoses in the exit exam (adjusted odds ratio 2.44, 95% confidence interval 1.05-5.67) and significantly increased student learning time. However, there was no significant effect on performance levels in the retention exam. CONCLUSIONS: Financial incentives increase reported learning time and examination results in the short-term. The lack of a sustained effect on performance suggests that financial incentives may foster a superficial or strategic rather than a deep approach to learning. PMID- 23808528 TI - Effect of polymers and media type on extending the dissolution of amorphous pioglitazone and inhibiting the recrystallization from a supersaturated state. AB - Amorphous forms of crystalline drug are widely utilized for bioavailability enhancement of low solubility drugs in the pharmaceutical industry. Polymers have been found to be effective crystallization inhibitors for amorphous forms in solid states during storage or in liquid states during dissolution process. The dissolution and crystallization behaviors of these amorphous forms in the presence or absence of polymers are still far from adequately understood especially in different dissolution environments. The objective of this study was to investigate the effects of polymers and media type on extending the dissolution of amorphous pioglitazone and inhibiting the recrystallization from a supersaturated state. Polyvinylpyrrolidone K30 (PVPK30), polyvinylpyrrolidone K90 (PVPK90), polyethylene glycol 6000 (PEG6000), polyethylene-polypropylene glycol 188 (F-68), hydroxypropylmethylcellulose (HPMC) and beta-cyclodextrin (beta-CD) were employed to understand these behaviors changes because these polymers were used widely. Three solutions including neutral water and phosphate buffer solutions (PBS, pH6.8 and pH7.4) were adopted as dissolution media to determine the behaviors changes comprehensively. In the presence of polymers, dissolution and solubility were extended to different degrees in three media. Polymers can delay the crystallization routes dependently of the medium type. Buffer salts in media reduced the dissolution and accelerated the crystallization process. Crystallization inhibition of these polymers was strongly dependent on the type and pH of media. HPMC displayed the strongest crystallization inhibition effects, resulting in the greatest degree of maintaining a supersaturated state that can sustain most effectively for biologically relevant timeframes. PMID- 23808529 TI - Influence of the aggregation of a carbazole thiophene cyanoacrylate sensitizer on sensitized photocurrents on ZnO single crystals. AB - Dye sensitization of zinc oxide single crystals by a carbazole thiophene cyanoacrylate (MK-2) sensitizer deposited from THF and mixtures of THF and water was investigated. AFM images show the formation of larger aggregates, with the maximum size of 20-30 nm from mixtures of THF and water, compared with 8-12 nm from pure THF. Sensitized photocurrent spectra were correlated with the morphological results from AFM imaging and indicate that aggregation in water results in less efficient sensitization of the ZnO substrate. The presence of the aggregation in solution due to water content was confirmed by absorbance and fluorescence spectroscopies. PMID- 23808530 TI - Semen collection and polymerase chain reaction-based sex determination of black headed and straw-necked ibis. AB - This study aimed to develop a polymerase chain reaction (PCR)-based sexing and effective semen collection methods for black-headed and straw-necked ibis species. However, most birds are not sexually dimorphic, that is, the sexes appear similar. Therefore, the gender should be determined before semen collection. DNA was extracted from the blood samples of 11 black-headed and 4 straw-necked ibis. The sex was determined after PCR amplification of the EE0.6 region of W-chromosome. The PCR products were separated using gel electrophoresis. A single band indicated the presence of the EE0.6 region and that the individual was a female, while no band indicated that the individual was a male. Further, the single bands from seven specimens were amplified. Semen collection was performed by massage or a combination of massage with electro ejaculation and was attempted during all four seasons. The semen was successfully collected in March from male straw-necked ibis using the massage method. Limited motility, viability and concentration of straw-necked ibis sperm were observed. The sperm length was 180 MUm and that of the nucleus was 30 MUm with acrosome located at the tip of the nucleus. Thus, the PCR-based sexing proved to be an accurate molecular sexing method for black-headed and straw-necked ibis. Furthermore, we successfully collected semen and observed the stained sperm nucleus and acrosome of the straw-necked ibis sperm. We propose that the use of this PCR methodology can be applied as a routine method for sex determination and semen collection in ibis species for future ecological research. However, considering our limited success, further studies on semen collection method are required. PMID- 23808531 TI - Intracaval resection of a partially obstructing intravascular hemangioma using deep hypothermic circulatory arrest. AB - We report a case of an obstructing hemangioma within the lumen of the inferior vena cava adjacent to the hepatic veins. The technique of resection and pathology are described. PMID- 23808532 TI - Direct catalytic anti-Markovnikov addition of carboxylic acids to alkenes. AB - A direct catalytic anti-Markovnikov addition of carboxylic acids to alkenes is reported. The catalyst system is comprised of the Fukuzumi acridinium photooxidant (1) and a substoichiometric quantity of a hydrogen-atom donor. Oxidizable olefins, such as styrenes, trisubstituted aliphatic alkenes, and enamides, can be employed along with a variety of carboxylic acids to afford the anti-Markovnikov addition adducts exclusively. A deuterium-labeling experiment lends insight to the potential mechanism. PMID- 23808533 TI - Temperature: the "ignored" factor at the NanoBio interface. AB - Upon incorporation of nanoparticles (NPs) into the body, they are exposed to biological fluids, and their interaction with the dissolved biomolecules leads to the formation of the so-called protein corona on the surface of the NPs. The composition of the corona plays a crucial role in the biological fate of the NPs. While the effects of various physicochemical parameters on the composition of the corona have been explored in depth, the role of temperature upon its formation has received much less attention. In this work, we have probed the effect of temperature on the protein composition on the surface of a set of NPs with various surface chemistries and electric charges. Our results indicate that the degree of protein coverage and the composition of the adsorbed proteins on the NPs' surface depend on the temperature at which the protein corona is formed. Also, the uptake of NPs is affected by the temperature. Temperature is, thus, an important parameter that needs to be carefully controlled in quantitative studies of bionano interactions. PMID- 23808534 TI - Lack of functional patency of the lamina terminalis after fenestration following clipping of anterior circulation aneurysms. AB - OBJECT: Fenestration of the lamina terminalis (FLT) during aneurysm surgery for subarachnoid hemorrhage can, in theory, improve CSF circulation from the lateral and third ventricles to the cortical subarachnoid space, which may, in turn, decrease the incidence of hydrocephalus and vasospasm. However, the actual effects of FLT on CSF circulation have been difficult to determine, due to confounding factors. In addition, it is unclear whether the lamina terminalis remains functionally patent when the brain resumes its normal position. The goal of this study was to assess the functional patency of the fenestrated lamina terminalis in patients who underwent surgery for ruptured aneurysms. METHODS: This prospective study included 15 patients who underwent surgical clipping of ruptured anterior circulation aneurysms, with FLT performed during surgery. On postoperative Day 1, the external ventricular drain of each patient was closed, and 1 ml of Omnipaque 300, an iodine based contrast agent, was injected intraventricularly, accompanied by cranial maneuvering designed to position the contrast agent adjacent to the lamina terminalis. Three to 5 minutes after cranial maneuvering, the flow of contrast agent into the basal cisterns was assessed with CT imaging. Flow was verified by an increase in Hounsfield units in a prespecified "region of interest" within the basal cisterns on the CT scan. This procedure was performed using a standardized protocol designed in consultation with the Department of Radiology and approved by the institutional review board. One patient who underwent endoscopic third ventriculostomy was recruited as a positive control to validate the technique, and 1 patient who underwent aneurysm clipping but not FLT was recruited as a negative control. RESULTS: Seventeen patients consented to study participation. In the 15 patients who underwent aneurysm clipping and FLT, and the negative control patient who underwent aneurysm clipping but not FLT, the contrast agent followed the normal ventricular pathway from the lateral ventricles into the fourth ventricle, and did not appear in the basal cisterns. In the positive control patient, the contrast agent robustly and immediately filled the basal cisterns. CONCLUSIONS: Fenestration of the lamina terminalis did not result in functional patency of the lamina terminalis when performed as part of surgical clipping for ruptured aneurysms. PMID- 23808535 TI - Dual antiplatelet therapy. PMID- 23808536 TI - Boron neutron capture therapy for recurrent high-grade meningiomas. AB - OBJECT: Similar to glioblastomas, high-grade meningiomas are difficult pathologies to control. In this study, the authors used boron neutron capture therapy (BNCT), a tumor-selective intensive particle radiation modality, to treat high-grade meningioma. METHODS: From June 2005 to September 2011, BNCT was applied 28 times in 20 cases of recurrent high-grade meningioma. All patients had previously undergone intensive treatments such as repetitive surgeries and multiple sessions of radiation therapy. Fluorine-18-labeled boronophenylalanine ((18)F-BPA) PET was performed before BNCT in 19 of the 20 cases; BPA is itself a therapeutic compound. Compound uptake, tumor shrinkage, long-term control rate including survival time, and failure pattern of the treated patients were all evaluated. RESULTS: Eighteen of 19 cases studied using (18)F-BPA PET showed good BPA uptake, with ratios of tumor to normal brain greater than 2.7. These ratios indicated the likely effects of BNCT prior to neutron irradiation. The original tumor sizes were between 4.3 cm(3) and 109 cm(3). A mean tumor volume reduction of 64.5% was obtained after BNCT within just 2 months. The median follow-up duration was 13 months. Six patients are still alive; at present, the median survival times after BNCT and diagnosis are 14.1 months (95% CI 8.6-40.4 months) and 45.7 months (95% CI 32.4-70.7 months), respectively. Clinical symptoms before BNCT, such as hemiparesis and facial pain, were improved after BNCT in symptomatic cases. Systemic metastasis, intracranial distant recurrence outside the radiation field, CSF dissemination, and local tumor progression were observed in 6, 7, 3, and 3 cases, respectively, during the clinical course. Apparent pseudoprogression was observed in at least 3 cases. Symptomatic radiation injuries occurred in 6 cases, and were controllable in all but 1 case. CONCLUSIONS: Boron neutron capture therapy may be especially effective in cases of high-grade meningioma. PMID- 23808538 TI - Arteriovenous malformations and radiosurgery. PMID- 23808537 TI - Risk of hemorrhagic complication associated with ventriculoperitoneal shunt placement in aneurysmal subarachnoid hemorrhage patients on dual antiplatelet therapy. AB - OBJECT: The use of an intracranial stent requires dual antiplatelet therapy to avoid in-stent thrombosis. In this study, the authors sought to investigate whether the use of dual antiplatelet therapy is a risk factor for hemorrhagic complications in patients undergoing permanent ventriculoperitoneal (VP) shunt for hydrocephalus following aneurysmal subarachnoid hemorrhage (aSAH). METHODS: Patients were given 325 mg acetylsalicylic acid and 600 mg clopidogrel during the coil/stent procedure, and they were maintained on dual antiplatelet therapy with acetylsalicylic acid 325 mg daily and clopidogrel 75 mg daily during hospitalization and for 6 weeks posttreatment. Patients underwent placement of VP shunt at a later time during initial hospitalization, usually between 7 and 21 days following aSAH. Postoperative CT scans obtained in each study patient were reviewed for hemorrhages related to placement of the VP shunt. RESULTS: A total of 206 patients were admitted to the University of Iowa Hospitals and Clinics with aSAH between July 2009 and October 2010. Thirty-seven of these patients were treated with a VP shunt for persistent hydrocephalus. Twelve patients (32%) had previously undergone stent-assisted coiling and were on dual antiplatelet therapy with acetylsalicylic acid and clopidogrel. The remaining 25 patients (68%) had undergone surgical clipping or aneurysm coiling and were not receiving antiplatelet therapy at the time of surgery. Four cases (10.8%) of new intracranial hemorrhages associated with VP shunt placement were observed. All 4 hemorrhages (33%) occurred in patients on dual antiplatelet therapy for stent assisted coiling. No new intracranial hemorrhages were observed in patients not receiving dual antiplatelet therapy. The difference in hemorrhagic complications between the 2 groups was statistically significant (4 [33%] of 12 vs 0 of 25, p = 0.0075]). All 4 hemorrhages occurred along the tract of the ventricular catheter. Only 1 hemorrhage (1 [8.3%] of 12) was clinically significant as it resulted in occlusion of the proximal shunt catheter and required revision of the VP shunt. The patient did not suffer any permanent morbidity related to the hemorrhage. The remaining 3 hemorrhages were not clinically significant. CONCLUSIONS: This small clinical series suggests that placement of a VP shunt in patients on dual antiplatelet therapy may be associated with an increased, but low, rate of symptomatic intracranial hemorrhage. It appears that in patients who are poor candidates for open surgical clipping and have aneurysms amenable to stent assisted coiling, the risk of symptomatic hemorrhage may be an acceptable trade off for avoiding risks associated with discontinuation of antiplatelet therapy. The authors' results are preliminary, however, and require confirmation in larger studies. PMID- 23808539 TI - Boot cAMP. PMID- 23808540 TI - Single-fraction radiosurgery of benign cavernous sinus meningiomas. AB - OBJECT: Stereotactic radiosurgery (SRS) is an important treatment option for patients with cavernous sinus meningiomas (CSM). To analyze factors associated with local tumor control and complications after single-fraction SRS, the authors reviewed cases involving patients treated with Gamma Knife SRS between 1990 and 2008. METHODS: Excluded were patients with WHO Grade II or III tumors, radiation induced tumors, multiple meningiomas, neurofibromatosis Type 2, and prior or concurrent radiotherapy. Five patients were lost to follow-up and 3 patients refused research authorization. The remaining 115 patients (29 men, 86 women) had either histologically confirmed WHO Grade I (n = 46, 40%) or presumed (n = 69, 60%) CSM. The median treatment volume was 9.3 cm(3) (range 1.3-42.2 cm(3)). The median margin dose was 16 Gy (range 12-20 Gy). The median follow-up after SRS was 89 months (range 12-251 months). Thirty-nine patients (34%) had 10 or more years of follow-up after SRS. RESULTS: Six patients (5%) had tumor progression (in field, n = 3; marginal, n = 3) at a median of 74 months (range 42-145 months) after SRS. The local tumor control rate was 99% at 5 years and 93% at 10 years after SRS. No analyzed factor was associated with local control after SRS. Fourteen patients (12%) had permanent complications at a median onset of 23 months (range 2-146 months) including trigeminal dysfunction (n = 9), diplopia (n = 2), ischemic stroke (n = 2), and hypopituitarism (n = 1). The 2-year, 5-year, and 10-year rates of complications were 7%, 10%, and 15%, respectively. Multivariate analysis found larger treatment volume (HR 1.1, 95% CI 1.02-1.2, p = 0.01) to be associated with complications after SRS. The complication rate for patients with a treatment volume of 9.3 cm(3) or less was 3% (2 of 58 cases) compared with 21% (12 of 57 cases) for patients with a treatment volume greater than 9.4 cm(3). CONCLUSIONS: Single-fraction SRS at the radiation doses used in this series provided durable tumor control for patients with benign CSM. Larger tumor volume remains the primary factor associated with complications after single-fraction SRS of benign CSM despite advancements in SRS technique. PMID- 23808541 TI - Expanding the clinical spectrum and allelic heterogeneity in van den Ende-Gupta syndrome. PMID- 23808542 TI - Variation at diabetes- and obesity-associated Loci may mirror neutral patterns of human population diversity and diabetes prevalence in India. AB - South Asian populations harbor a high degree of genetic diversity, due in part to demographic history. Two studies on genome-wide variation in Indian populations have shown that most Indian populations show varying degrees of admixture between ancestral north Indian and ancestral south Indian components. As a result of this structure, genetic variation in India appears to follow a geographic cline. Similarly, Indian populations seem to show detectable differences in diabetes and obesity prevalence between different geographic regions of the country. We tested the hypothesis that genetic variation at diabetes- and obesity-associated loci may be potentially related to different genetic ancestries. We genotyped 2977 individuals from 61 populations across India for 18 SNPs in genes implicated in T2D and obesity. We examined patterns of variation in allele frequency across different geographical gradients and considered state of origin and language affiliation. Our results show that most of the 18 SNPs show no significant correlation with latitude, the geographic cline reported in previous studies, or by language family. Exceptions include KCNQ1 with latitude and THADA and JAK1 with language, which suggests that genetic variation at previously ascertained diabetes-associated loci may only partly mirror geographic patterns of genome wide diversity in Indian populations. PMID- 23808543 TI - Mannuronan C-5 epimerases suited for tailoring of specific alginate structures obtained by high-throughput screening of an epimerase mutant library. AB - The polysaccharide alginate is produced by brown algae and some bacteria and is composed of the two monomers, beta-D-mannuronic acid (M) and alpha-L-guluronic acid (G). The distribution and composition of M/G are important for the chemical physical properties of alginate and result from the activity of a family of mannuronan C-5 epimerases that converts M to G in the initially synthesized polyM. Traditionally, G-rich alginates are commercially most interesting due to gelling and viscosifying properties. From a library of mutant epimerases we have isolated enzymes that introduce a high level of G-blocks in polyM more efficiently than the wild-type enzymes from Azotobacter vinelandii when employed for in vitro epimerization reactions. This was achieved by developing a high throughput screening method to discriminate between different alginate structures. Furthermore, genetic and biochemical analyses of the mutant enzymes have revealed structural features that are important for the differences in epimerization pattern found for the various epimerases. PMID- 23808545 TI - Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development. AB - Restoration of p53 activity by inhibition of the p53-MDM2 interaction has been considered an attractive approach for cancer treatment. However, the hydrophobic protein-protein interaction surface represents a significant challenge for the development of small-molecule inhibitors with desirable pharmacological profiles. RG7112 was the first small-molecule p53-MDM2 inhibitor in clinical development. Here, we report the discovery and characterization of a second generation clinical MDM2 inhibitor, RG7388, with superior potency and selectivity. PMID- 23808544 TI - Leukoreduction and ultraviolet treatment reduce both the magnitude and the duration of the HLA antibody response. AB - BACKGROUND: Both leukoreduction and ultraviolet (UV) light treatment of blood products have been shown to reduce the incidence of HLA antibody development in recipients, but the impact of these treatments on the magnitude and persistence of the antibody response is less clear. STUDY DESIGN AND METHODS: Longitudinal samples from 319 subjects taken from four different study cohorts were evaluated for HLA antibodies to determine the effects of leukoreduction and UV treatment on HLA antibody generation and persistence. RESULTS: Subjects receiving leukoreduced or UV-treated blood products were less likely to generate Class I HLA antibodies, and those receiving leukoreduced blood were also less likely to generate Class II HLA antibodies. Among those receiving nonleukoreduced blood, 55% developed Class I HLA antibodies and 51% developed Class II HLA antibodies compared with 28% (Class I) and 15% (Class II) for those receiving leukoreduced blood and 36% (Class I) and 54% (Class II) for those receiving UV-treated blood. Among alloimmunized subjects, leukoreduction resulted in a significant twofold reduction in the magnitude of Class I HLA antibodies, and UV treatment resulted in a significant threefold reduction in the magnitude of Class II HLA antibodies. Both treatments resulted in shorter persistence of Class I HLA antibodies. CONCLUSIONS: These data demonstrate that leukoreduction and UV treatment of blood products results not only in a reduction in the incidence of HLA antibody production, but also in lower and more transient HLA antibody levels among sensitized transfusion recipients. PMID- 23808546 TI - Enantioselective total syntheses of pygmaeocins B and C. AB - The first enantioselective total syntheses of pygmaeocins B and C have been accomplished using an efficient and highly diastereoselective intramolecular Heck cyclization for the construction of a quaternary stereogenic center and the functionalized A-ring of the natural products as the key step. PMID- 23808547 TI - Anticancer potency of platinum(II) complexes containing both chloride anion and chelated carboxylate as leaving groups. AB - Three platinum complexes with both a chloride anion and a chelated carboxylate as leaving groups were synthesized and spectrally characterized. In vitro cytotoxicity of complexes 1-3 was evaluated against human A549, HCT-116, MCF-7, and HepG-2 tumor cell lines. The results showed that all the compounds exhibited effective cytotoxicity against the tested cell lines, nearly comparable to those of cisplatin and oxaliplatin. Notably, the activity of complex 2 was about 2-fold better than that of oxaliplatin against the HCT-116 cell line. Flow cytometry analysis indicated that these complexes produced death of tumor cells through an apoptotic pathway. The DNA-binding properties of the platinum-based compounds were also studied by agarose gel electrophoresis. The kinetics study showed that the chloride anion departs from the Pt atom quickly, whereas the five and/or six membered ring formed by coordination of N,O-donors and the metal ion is opened a little more slowly by the rupture of a Pt-O bond, which helps us to further understand the mechanism of action of the newly synthesized complexes with biomolecules. Furthermore, the reaction rate constants of complexes 1-3 were roughly the same. PMID- 23808548 TI - Feasibility of point-of-care creatinine testing in community pharmacy to monitor drug therapy in ambulatory elderly patients. AB - WHAT IS KNOWN AND OBJECTIVE: It is often necessary to adjust drug therapy if renal function is impaired in elderly patients taking drugs for diabetes and/or cardiovascular disease that are cleared by the kidneys. Although clinical guidelines recommend regular monitoring of renal function in these patients, in practice adherence to these recommendations varies from 28% to 75%. To determine whether drug dosing is appropriate, pharmacists need have up-to-date information about patients' renal function. In this study, the feasibility of point-of-care creatinine testing (POCCT) in a community pharmacy was evaluated as part of monitoring the drug therapy of ambulatory elderly patients. METHODS: Elderly patients on maintenance therapy with renally excreted drugs for diabetes or cardiovascular disease were eligible for POCCT. After informed consent was obtained, POCCT was performed by trained personnel. A pharmacist assessed the clinical relevance of electronically generated drug alerts based on the patient's calculated renal function and the Dutch guidelines for adjusting drug dosage in patients with chronic kidney disease. If appropriate, the patient's general practitioner (GP) was consulted and adjustments to treatment were communicated to the patient. The feasibility of POCCT was evaluated by means of questionnaires completed by patients and healthcare professionals (GPs and pharmacists). RESULTS: Of 338 potentially eligible patients, 149 (44%) whose renal function was not known were asked, by letter, to participate in the study. Of these individuals, 46 (31%) gave their informed consent and underwent POCCT. Response rates for completing the patient and professional questionnaires were 87% and 100%, respectively. More than half of the patients who underwent POCCT had mild to-moderate renal impairment. On the basis of information provided by patients and healthcare professionals, POCCT would appear to be feasible in community pharmacies. WHAT IS NEW AND CONCLUSION: POCCT improves the management of drug therapy by community pharmacists and is feasible in daily practice. PMID- 23808549 TI - Candidate gene associations with withdrawn behavior. AB - BACKGROUND: Social withdrawal is a core neuropsychiatric phenomenon in developmental psychopathology. Its presence predicts psychopathology across many domains, including depression, psychosis, autism, anxiety, and suicide. Withdrawn behavior is highly heritable, persistent, and characteristically worsens without intervention. To date, few studies have successfully identified genetic associations with withdrawn behavior, despite the abundance of evidence of its heritability. This may be due to reliance of categorical over dimensional measures of the behaviorally inhibited phenotype. The aim of this study is to identify associations between known psychiatric candidate genes and a dimensionally derived measure of withdrawn behavior. METHODS: Genetic information was collected on 20 single-nucleotide polymorphisms (SNPs) from a custom-designed SNP chip and TAQMAN arrays of 4 variable number of tandem repeat (VNTR) genes for 551 individuals from 187 families. Linear mixed modeling was employed to examine the relationship between genotypes of interest and Child Behavior Checklist (CBCL) Withdrawn Behavior Subscale Score (WBS) while controlling for gender and age through multiple linear regressions. RESULTS: Withdrawn behavior was highly associated with polymorphism rs6314 of the serotonin receptor 2A (HTR2A) [p = .009, estimate = 0.310 (bootstrap 95% CI 0.155-0.448), bootstrap p = .001] and rs1800544 of the alpha 2-adrenergic (ADRA2A) [p = .001, estimate = -0.310 (bootstrap 95% CI -0.479 to -0.126), bootstrap p = .001] genes after correction for gender and age. The association between withdrawn behavior and ADRA2A was stronger for younger children. CONCLUSIONS: HTR2A and ADRA2A genes are associated with withdrawn behavior. This reinforces the role of catecholaminergic genes in the heritability of withdrawn behavior. PMID- 23808550 TI - Autonomic function in migraine patients: ictal and interictal pupillometry. AB - OBJECTIVE AND BACKGROUND: Pupillometric investigations into migraine have suggested that an autonomic disturbance is part of the pathogenesis of that condition. This observation is controversial, however, which may reflect that the putative sympathetic hypofunction is either subtle or transient. In this study, we assessed the sympathetic function of migraine patients and controls during both a symptom-free phase and a migraine attack, and challenged patients with apraclonidine to reveal small changes in autonomic function. METHODS: Infrared pupillometry was used to measure pupillometric parameters in 37 controls and 46 migraine patients in the interictal phase of disease. Fifteen migraine patients were also studied during a migraine attack. In addition, 26 controls and 18 migraine patients were tested interictally both with and without apraclonidine. Of these 18 migraine patients, seven were also tested with and without apraclonidine during a migraine attack. RESULTS: We found no significant differences between migraine patients and controls in the interictal phase. Additionally, no differences in pupil parameters were detected during the migraine attack. However, after administration of apraclonidine, migraine patients had a longer latency of the light reflex compared with controls. This increase in latency was more pronounced ictally (oculus dexter: P = .046, oculus sinister: P = .023) than interictally (oculus dexter: P = .075, oculus sinister: P = .021). CONCLUSIONS: We conclude that there is evidence for a subtle pupillary sympathetic hypofunction in migraine patients, observed as a prolonged latency to light reflex, which is revealed after the administration of apraclonidine. PMID- 23808551 TI - Transduction of the central nervous system after intracerebroventricular injection of adeno-associated viral vectors in neonatal and juvenile mice. AB - Several neurodevelopmental and neurodegenerative disorders affecting the central nervous system are potentially treatable via viral vector-mediated gene transfer. Adeno-associated viral (AAV) vectors have been used in clinical trials because of their desirable properties including a high degree of safety, efficacy, and stability. Major factors affecting tropism, expression level, and cell type specificity of AAV-mediated transgenes include encapsidation of different AAV serotypes, promoter selection, and the timing of vector administration. In this study, we evaluated the ability of single-stranded AAV2 vectors pseudotyped with viral capsids from serotype 9 (AAV2/9) to transduce the brain and target gene expression to specific cell types after intracerebroventricular injection into mice. Titer-matched AAV2/9 vectors encoding the enhanced green fluorescent protein (eGFP) reporter, driven by the cytomegalovirus (CMV) promoter, or the neuron-specific synapsin-1 promoter, were injected bilaterally into the lateral ventricles of C57/BL6 mice on postnatal day 5 (neonatal) or 21 (juvenile). Brain sections were analyzed 25 days after injection, using immunocytochemistry and confocal microscopy. eGFP immunohistochemistry after neonatal and juvenile administration of viral vectors revealed transduction throughout the brain including the striatum, hippocampus, cerebral cortex, and cerebellum, but with different patterns of cell-specific gene expression. eGFP expression was seen in astrocytes after treatment on postnatal day 5 with vectors carrying the CMV promoter, expanding the usefulness of AAVs for modeling and treating diseases involving glial cell pathology. In contrast, injection of AAV2/9-CMV-eGFP on postnatal day 21 resulted in preferential transduction of neurons. Administration of AAV2/9-eGFP with the synapsin-1 promoter on either postnatal day 5 or 21 resulted in widespread neuronal transduction. These results outline efficient methods and tools for gene delivery to the nervous system by direct, early postnatal administration of AAV vectors. Our findings highlight the importance of promoter selection and age of administration on the intensity, distribution, and cell type specificity of AAV transduction in the brain. PMID- 23808552 TI - Agminated pigmented matricoma: a case of a unique tumor with a multifocal appearance composed of neoplastic matrical cells with a significant component of melanocyte. AB - Matricoma is benign follicular neoplasm with the same constituent cells as pilomatricoma but with a different silhouette. Matricoma consists mostly of solid aggregations of matrical cells, as opposed to pilomatricoma, which is often a cystic lesion. We herein describe a case of agminated pigmented matricoma. A 27 year-old Japanese man visited our hospital complaining of three separate, pigmented, firm and sessile nodules on the back. Histopathologic examination revealed mostly solid aggregations of matrical and supramatrical cells located mainly within the dermis and the upper part of the subcutis. Shadow cells were present mostly within the aggregations. At higher magnifications, occasional indication of inner sheath differentiation, in addition to differentiation toward hair in the form of shadow cells, could be discerned in the center of the aggregations. The matrical and supramatrical cells within the aggregations were relatively uniform in size and shape, and contained several mitotic figures. Heavily pigmented melanocytes were present within the aggregations of matrical and supramatrical cells, and heavily pigmented melanophages were found in adjacent stroma. Pigmentation is a rare event in benign and malignant adnexal tumors, and to our knowledge, no similar case has been reported. PMID- 23808553 TI - Ameloblastomas: clinical-histopathological evaluation of 85 cases with emphasis on squamous metaplasia and keratinization aspects. AB - OBJECTIVES: Ameloblastoma is a benign odontogenic neoplasm with an origin reputed to reactivation of odontogenic structures. Histological classification is based on microscopic features and architectural distribution of neoplastic cells. The importance of squamous metaplasia and keratinization has been disputed in ameloblastomas. Clinical and histopathological aspects were evaluated of 85 ameloblastomas, with attention to keratinization and squamous metaplasia features. STUDY DESIGN: Clinical-demographical information of 85 ameloblastomas were gleaned from the medical records. Microscopic analysis of all cases was carried out with emphasis on keratinization aspects of each tumor. RESULTS: Most ameloblastomas (54.12%) were diagnosed in males with a mean age of 37 years. Fifty-six patients were Caucasians (65.88%) and the mandible was affected in 68 (89.4%) cases. Most cases analyzed presented areas of squamous metaplasia/keratinization. Recurrence was detected in 16 cases; this was not related to keratinization aspects of the tumor. CONCLUSIONS: Keratinization is a common feature in ameloblastomas with no impact in tumor behavior. PMID- 23808554 TI - Cover note. PMID- 23808555 TI - On the origin of the first Australian Medical Journal. AB - The Australian Medical Journal is important to Australian anaesthesia in that, as well as associated editorials, it recorded the first use of ether for surgical operations. Though it survived from 1 August 1846 until 1 October 1847, its first issue was surrounded with mystery, referring to an earlier publication. Proof of this earlier issue of April 1846 has been discovered though no copy remains extant. PMID- 23808556 TI - The role of Dr Isaac Aaron and the Australian Medical Journal in the dissemination of information about etherisation in the 1840s. AB - Isaac Aaron (1804 to 1877), an ambitious young medical practitioner, arrived in Sydney from Britain in 1838 and was registered by the New South Wales Medical Board the following year. After contributing to the Australian Medical Journal, established in August 1846 by William Baker, he became the editor in December and acquired it in May the following year. Dr Pugh became the most prolific local contributor to the journal but he and the editor had a somewhat 'prickly' relationship. Aaron was very critical of etherisation when the first news arrived in Australia, but Pugh chose Aaron's journal in which to report his initial and subsequent experience with the technique. Aaron repeatedly appealed for experimental evidence and rational decision-making to determine the place of etherisation in medical practice. Unfortunately for Australian medicine, Aaron had to suspend the publication of the journal in October 1847, lacking both time and the support of the profession necessary to maintain it. This created an unanticipated adverse outcome for Dr Pugh. PMID- 23808557 TI - Arthur Guedel's laryngeal plug. AB - The laryngeal plug is a little-known device developed by Arthur E. Guedel in the 1930s. The device was an alternative to the inflatable cuff used on tracheal tubes. Guedel did not publish a description of the laryngeal plug and the most detailed description of it was published by Gilbert Troup, an Australian anaesthetist. PMID- 23808558 TI - Overview of the introduction of neuromuscular monitoring to clinical anaesthesia. AB - Muscle relaxants were introduced into clinical practice in the early 1940s. From 1949, assessments were being made of the efficacy of various agents in awake volunteers, usually the researchers themselves. From the early to mid 1950s, while interest in using muscle relaxants was keen, concern emerged in the surgical literature that there was a higher mortality rate seen in patients receiving muscle relaxants. In fairness, the major article highlighted lack of randomisation, bias and confounding variables but this was largely regarded as showing a toxicity associated with muscle relaxants. By 1961 the matter had been settled that muscle relaxants were not toxic but required careful management and administration. Perhaps fortuitously, measurement of the degree of muscle relaxation was introduced to clinical practice with the use of nerve stimulation. These were measured responses to single twitch stimulus or tetanic stimulation. In 1970, train-of-four ratio was introduced, then in 1981 post-tetanic count, and in 1989 double burst stimulation. This article reviews the introduction of these techniques. PMID- 23808559 TI - Isosteric heats of gas and liquid adsorption. AB - The heat of adsorption is an indicator of the strength of the interaction between an adsorbate and a solid adsorbent. This parameter can be determined from the heat released in calorimetric experiments or from the analysis of adsorption isotherms at different temperatures. The latter, called isosteric heats of adsorption, are commonly used in the characterization of materials for gas- and liquid-phase adsorption. Although the equations for the determination of isosteric heats of adsorption from the gas phase are well-known, approximate equations are frequently used for liquid-phase adsorption. We present here the rigorous equations for determining the isosteric heats of gas- and liquid-phase adsorption and their relation to the commonly used approximate equations. These equations are used to compute the isosteric heats of liquid adsorption based on the adsorption isotherms obtained from simulations for two well-defined systems, one ideal and the other nonideal. The results of using the rigorous equations are compared with those from the approximate equations. The main conclusion is that the commonly used approximate equations provide reasonable, but not perfect, estimates of the isosteric heats of liquid adsorption using only the experimental adsorption isotherms. The more accurate rigorous equations require additional information, including the heat of vaporization and, for nonideal mixtures, the heat of mixing. PMID- 23808560 TI - Effect of semen collection methods on the quality of pre- and post-thawed Bali cattle (Bos javanicus) spermatozoa. AB - This study was conducted to evaluate the response of Bali bulls (Bos javanicus) to different semen collection methods and their effects on fresh and post-thawed semen quality. The collection methods employed were electro-ejaculation (EE), transrectal massage (RM) and RM followed by EE (RM + EE). A total of 25 untrained Bali bulls (age between 2 and 4 years old) were subjected to the different semen collection methods. Fresh semen samples from all the 25 bulls were evaluated for volume, pH, general motility, live/dead ratio and abnormality using the conventional method. For fresh and frozen samples collected by EE and RM from 10 bulls, computer-assisted semen analysis system was used for precise quantitative measurement of motility, velocity and forward progression. Accucell photometer was used to measure sperm concentration in all samples, regardless fresh and frozen. Semen samples were obtained 100% of the attempts using EE, 84% using RM and 96% using RM + EE. There were no differences among the collection methods for fresh semen quality characteristics, including motility, morphology and viability, but pH and volume were higher for EE than RM and RM + EE. Higher sperm concentration was observed in semen collected by RM than the other two methods. Different age groups (2-3 and >3-4 years old) of the bulls did not show significant differences in volume, pH, sperm concentration, percentages in motility, live/dead ratio and normal sperm morphology. The quality of semen for general and progressive motility, VAP, VSL and VCL and acrosomal integrity after thawing was higher for RM than EE. In conclusion, Bali bulls appeared to respond best to EE and the combination of RM + EE than RM, as a method of semen collection, with a shorter time of stimulation required. Differences in age of the Bali bulls did not affect the semen quality. PMID- 23808561 TI - Expression pattern of interferon-inducible transcriptional genes in neutrophils during bovine tuberculosis infection. AB - Mycobacterium bovis, the classical causative agent of bovine tuberculosis (BTB), infects animals of agricultural importance and other mammals, including humans. Neutrophils are one of the first lines of defense against all microbes and produce a diverse collection of antimicrobial molecules, which play an important role in the early control of tuberculosis progression. An interferon (IFN) inducible neutrophil-driven blood transcriptional signature that consisted of both IFN-gamma and type I IFN-alpha/beta signaling has been identified in human tuberculosis, supporting a role for neutrophils in the pathogenesis of tuberculosis disease. However, it is unknown whether bovine neutrophils play a similar role during M. bovis infection. Thus, we assessed the expression levels of ten IFN-inducible transcriptional genes in neutrophils from healthy cattle stimulated by M. bovis and neutrophils isolated from three groups of cattle of different infection status, and in addition, examined the changes in the expression of myeloperoxidase (MPO) and pentraxin-related protein pentraxin inducible protein (PTX3) genes during bovine tuberculosis infection. Our results demonstrated a specific expression pattern of IFN-inducible transcriptional genes and MPO and PTX3 genes in neutrophils during bovine tuberculosis infection. The observed expression pattern provides a potential diagnostic tool, which may have implications for vaccine and therapeutic development to combat the bovine tuberculosis epidemic. PMID- 23808562 TI - Imaging heterogeneity of membrane and storage lipids in transgenic Camelina sativa seeds with altered fatty acid profiles. AB - Engineering compositional changes in oilseeds is typically accomplished by introducing new enzymatic step(s) and/or by blocking or enhancing an existing enzymatic step(s) in a seed-specific manner. However, in practice, the amounts of lipid species that accumulate in seeds are often different from what one would predict from enzyme expression levels, and these incongruences may be rooted in an incomplete understanding of the regulation of seed lipid metabolism at the cellular/tissue level. Here we show by mass spectrometry imaging approaches that triacylglycerols and their phospholipid precursors are distributed differently within cotyledons and the hypocotyl/radicle axis in embryos of the oilseed crop Camelina sativa, indicating tissue-specific heterogeneity in triacylglycerol metabolism. Phosphatidylcholines and triacylglycerols enriched in linoleic acid (C18:2) were preferentially localized to the axis tissues, whereas lipid classes enriched in gadoleic acid (C20:1) were preferentially localized to the cotyledons. Manipulation of seed lipid compositions by heterologous over expression of an acyl-acyl carrier protein thioesterase, or by suppression of fatty acid desaturases and elongases, resulted in new overall seed storage lipid compositions with altered patterns of distribution of phospholipid and triacylglycerol in transgenic embryos. Our results reveal previously unknown differences in acyl lipid distribution in Camelina embryos, and suggest that this spatial heterogeneity may or may not be able to be changed effectively in transgenic seeds depending upon the targeted enzyme(s)/pathway(s). Further, these studies point to the importance of resolving the location of metabolites in addition to their quantities within plant tissues. PMID- 23808563 TI - Influence of clinical usage of GT and GTX files on cyclic fatigue resistance. AB - AIM: To compare static cyclic fatigue resistance of unused, unused and sterilized and clinically used conventional NiTi GT and M-Wire GTX files. METHODOLOGY: One hundred and sixty new files (80 GT and 80 GT series X) were divided into four control groups and four experimental groups (n = 20 each). Control groups were new unused files and new sterilized files. In the experimental groups, instruments were used in three (GT1 and GTX1 groups) or four molars (GT2 and GTX2 groups). Cyclic fatigue resistance was tested in stainless steel curved canals (60 degrees , r = 3 mm). Each file was rotated until fracture (300 rpm, 2 N cm torque). Time-to-fracture (s) was registered. Mean life, eta and beta parameters of their Weibull distributions were calculated. RESULTS: Unused and sterilized GTX files will last significantly longer than GT files with a probability of 75% and 65%, respectively; whilst mean life was significantly longer for GT than for GTX in used files with a probability of 68%. Sterilized GT files will last longer than unused files with a probability of 66%. In both brands, unused and sterilized files will last significantly longer than files used clinically with a probability higher than 98%. The probability that GT will last longer after being used in three rather than four molars was 62% (statistically significant) and 52% (not statistically significant) for GTX. CONCLUSIONS: GTX files had an extended cyclic fatigue life when compared with GT when they were unused or unused and sterilized, but GT were significantly more resistant to cyclic fatigue after clinical usage than GT series X files 3 mm from the tip. Sterilization of files enhanced the cyclic fatigue resistance of GT instruments. Clinical use of files diminished cyclic fatigue resistance. PMID- 23808564 TI - The training needs of general practitioners in the exploration of sexual health matters and providing sexual healthcare to lesbian, gay and bisexual patients. AB - BACKGROUND: General practitioners (GPs) have been identified as a key resource for people with sexual health concerns. However, research indicates that general practitioners feel unprepared to deal with sexual health, especially with lesbian, gay and bisexual (LGB) patients. AIM: To identify the training needs of general practitioners in the exploration of sexual health matters and providing sexual healthcare to lesbian, gay and bisexual patients. METHODS: Qualitative methodology using topic-guided interviews and focus groups with general practitioners and lesbian, gay, bisexual community members in Ireland. In addition, final year medical students at University College Cork completed a mixed-methods survey. RESULTS: General practitioner participants rarely broached sexual health topics, and were unaware of the sexual orientation of their patients or the specific health needs of lesbian, gay and bisexual patients. Participants identified numerous barriers to the discussion of sexual health. To overcome these barriers, respondents recommended better medical training using a variety of methods to increase awareness of sexual and LGB health issues. CONCLUSION: General practitioners in Ireland lack awareness of the unique health issues of lesbian, gay and bisexual patients and it is, therefore, essential that medical training programs develop better training curricula in sexual health and LGB health issues. PMID- 23808565 TI - Long-term survival following surgery for endomyocardial fibrosis. AB - We report a successful follow-up after 28 years of a woman with obliterative restrictive endomyocardial fibrosis (EMF) that underwent complete surgical decortication with simultaneous mitral and tricuspid bioprosthetic valve replacement in 1982 and underwent successful reoperation for the structural failure of biological prostheses after 25 years. PMID- 23808566 TI - Engineering an enantioselective amine oxidase for the synthesis of pharmaceutical building blocks and alkaloid natural products. AB - The development of cost-effective and sustainable catalytic methods for the production of enantiomerically pure chiral amines is a key challenge facing the pharmaceutical and fine chemical industries. This challenge is highlighted by the estimate that 40-45% of drug candidates contain a chiral amine, fueling a demand for broadly applicable synthetic methods that deliver target structures in high yield and enantiomeric excess. Herein we describe the development and application of a "toolbox" of monoamine oxidase variants from Aspergillus niger (MAO-N) which display remarkable substrate scope and tolerance for sterically demanding motifs, including a new variant, which exhibits high activity and enantioselectivity toward substrates containing the aminodiphenylmethane (benzhydrylamine) template. By combining rational structure-guided engineering with high-throughput screening, it has been possible to expand the substrate scope of MAO-N to accommodate amine substrates containing bulky aryl substituents. These engineered MAO-N biocatalysts have been applied in deracemization reactions for the efficient asymmetric synthesis of the generic active pharmaceutical ingredients Solifenacin and Levocetirizine as well as the natural products (R)-coniine, (R) eleagnine, and (R)-leptaflorine. We also report a novel MAO-N mediated asymmetric oxidative Pictet-Spengler approach to the synthesis of (R)-harmicine. PMID- 23808567 TI - Photothermoelectric p-n junction photodetector with intrinsic broadband polarimetry based on macroscopic carbon nanotube films. AB - Light polarization is used in the animal kingdom for communication, navigation, and enhanced scene interpretation and also plays an important role in astronomy, remote sensing, and military applications. To date, there have been few photodetector materials demonstrated to have direct polarization sensitivity, as is usually the case in nature. Here, we report the realization of a carbon-based broadband photodetector, where the polarimetry is intrinsic to the active photodetector material. The detector is based on p-n junctions formed between two macroscopic films of single-wall carbon nanotubes. A responsivity up to ~1 V/W was observed in these devices, with a broadband spectral response spanning the visible to the mid-infrared. This responsivity is about 35 times larger than previous devices without p-n junctions. A combination of experiment and theory is used to demonstrate the photothermoelectric origin of the responsivity and to discuss the performance attributes of such devices. PMID- 23808568 TI - Changes in functional visual acuity and ocular wavefront aberration after administration of eye ointment. AB - PURPOSE: To investigate the influence of an eye ointment on functional visual acuity (FVA) and ocular wavefront aberration. METHODS: In 11 healthy volunteers (6 men and 5 women), visual function parameters, such as FVA, visual maintenance ratios (VMR), and minimal visual acuity (minVA), were assessed by the FVA measurement system before and 2, 5, 10, 20, 30, 40, 50, 60, 90, 120, 180, and 240 min after administration of ofloxacin eye ointment. Ocular aberration was also measured, and the root mean square (RMS) of second-, third-, fourth-, and total higher-order aberrations was determined. The time course of changes in each parameter was statistically analyzed by using repeated-measures analysis of variance and the Dunnett post hoc test, and relationships between visual function and ocular aberration parameters were also analyzed by the Pearson correlation test. RESULTS: FVA, VMR, and minVA showed significant deteriorations at 2-, 5-, 10-, and 20 min after administration of eye ointment compared with the baseline values (P<0.05). All components of ocular wavefront aberration such as second-, third-, fourth-, and total higher-order RMS significantly increased at 2- and 5 min after the administration of eye ointment compared with the baseline values (P<0.05). In addition, deteriorations of these visual function parameters were significantly correlated with reduced blink numbers (Pearson's correlation coefficient; r=- 0.76, P=0.017 for FVA, r=0.79, P=0.013 for VMR, and r=-0.62, P=0.040 for minVA), and VMR was significantly related with changes in second order RMS (r=-0.60, P=0.049). CONCLUSIONS: Eye ointment significantly reduced visual function for at least 20 min. Especially, minVA was worse than 0.155 logMAR, which is legally required for driving, for 3 h after the administration. In addition, increases in lower-order aberration and low blink rates were associated with the degradation of visual function. PMID- 23808569 TI - Crouzon syndrome and Bent bone dysplasia associated with mutations at the same Tyr-381 residue in FGFR2 gene. PMID- 23808570 TI - Early stage alopecia areata is associated with inflammation in the upper dermis and damage to the hair follicle infundibulum. AB - BACKGROUND/OBJECTIVES: Alopecia areata (AA) is a non-scarring inflammatory hair loss disease. We investigated the early pathological changes of AA to identify possible factors participating in its pathogenesis. METHODS: Clinical, laboratory and pathological features of 87 AA patients were investigated. RESULTS: Anti nuclear antibody was found in 11 of 85 patients tested (13%), with a higher percentage in women (21%) than men (5%) (P = 0.026). In early AA lesions, inflammatory infiltration in the upper dermis and epithelial cell damage of the hair follicle infundibulum, just above the sebaceous gland, was observed. Liquefaction and disarrangement of peripheral infundibular epithelial cells coexisted with T-lymphocytic invasion and regression of the lower follicle. The latter findings positively correlated with the presence of eosinophils and perivascular mononuclear cell infiltration in the upper dermis. Eosinophilic infiltration was found in 35 patients (40%) and was positively correlated to elevated serum IgE levels (r = 0.21, P = 0.044), a more severe perivascular lymphocytic inflammation in the upper dermis (r = 0.24, P = 0.026), as well as a prominent swarm of bees-like peri-follicular infiltration (r = 0.41, P < 0.001). Mast cells were abundant in the upper dermis, especially around blood vessels, and positively correlated with eosinophil presence (r = 0.30, P = 0.027). CONCLUSION: Damage to the hair follicle infundibulum in the upper dermis might be an important component of early changes in AA lesions, possibly caused by lymphocyte cell infiltration in the same area. AA may involve damage of the upper hair follicle as well as the bulb, possibly involving hypersensitivity and autoimmunity. PMID- 23808571 TI - Patterned enzymatic degradation of poly(epsilon-caprolactone) by high-affinity microcontact printing and polymer pen lithography. AB - This paper reports deposition of Candida antarctica Lipase B (CALB) on relatively thick poly(epsilon-caprolactone) (PCL) films (300-500 nm) to create well-defined patterns using two different writing techniques: high-affinity microcontact (HA MUCL) and polymer pen (PPL) lithography. For both, an aqueous CALB ink is absorbed onto a polydimethylsiloxane (PDMS) writing implement (PDMS stamp or a PDMS pen tip), which is transferred to a spun-cast PCL film. HA-MUCL experiments demonstrated the importance of applied pressure to obtain high-resolution patterns since uniform contact is needed between raised 20 MUm parallel line regions of the PDMS stamp and the surface. AFM imaging shows pattern formation evolves gradually over incubation time only in areas stamped with CALB cutting through spherulites without apparent influence by grain boundaries. Strong binding of CALB to PCL is postulated as the mechanism by which lateral diffusion is limited. PPL enables formation of an arbitrary image by appropriate programming of the robot. The PDMS pen tips were coated with an aqueous CALB solution and then brought into contact with the PCL film to transfer CALB onto the surface. By repeating the ink transfer step multiple times where pen tips are brought into contact with the PCL film at a different locations, a pattern of dots is formed. After printing, patterns were developed at 37 degrees C and 95% RH. Over a 7-day period, CALB progressively etched the PCL down to the silicon wafer on which it was spun (350 nm) giving round holes with diameters about 10 MUm. AFM images show the formation of steep PCL walls indicating CALB degraded the PCL film in areas to which it was applied. This work demonstrates that high resolution patterns can be achieved without immobilizing the enzyme on the surface of polymeric stamps that limits the depth of features obtained as well as the throughput of the process. PMID- 23808572 TI - Preclinical safety evaluation of human platelets treated with antimicrobial peptides in severe combined immunodeficient mice. AB - BACKGROUND: Bacterial sepsis is a complication attributed to room temperature (RT)-stored platelets (PLTs) in transfusion medicine. Antimicrobial peptides (AMPs) are emerging as new therapeutic agents against microbes. We had previously demonstrated bactericidal activity of select synthetic AMPs against six types of bacteria in stored PLTs. In this report, we tested these AMPs for their potential antibody response and interference with the recovery and survival of human PLTs in an animal model. STUDY DESIGN AND METHODS: Two separate studies were conducted to evaluate the safety of the synthetic AMPs. 1) Two AMPs (PD3 and PD4), derived from thrombin-induced human PLT microbicidal protein, and four repeats of arginine-tryptophan (RW), containing two to five repeats (RW2-RW5), were tested in rabbits for potential antibody response. 2) RT-stored human PLTs treated for 2 hours with each of the six AMPs individually or with phosphate-buffered saline (PBS) alone were infused into severe combined immunodeficient (SCID) mice to evaluate their in vivo recovery and survival by flow cytometry. RESULTS: Except for PD3, which showed a weak immune response, all other peptides did not induce any detectable antibodies in rabbits. Furthermore, all six AMPs tested did not significantly affect the in vivo recovery and survival of human PLTs in SCID mice compared to PBS alone-treated PLTs. CONCLUSION: Preclinical evaluation studies reported here demonstrate that the selected AMPs used in the study did not adversely affect the human PLT recovery and survival in the SCID mouse model, suggesting further study of AMPs toward addressing the bacterial contamination of PLTs. PMID- 23808573 TI - Domino elimination/nucleophilic addition in the synthesis of chiral pyrrolidines. AB - Polyhydroxylated pyrrolidines have been synthesized in a one-pot procedure by the addition of an organometallic reagent to isoxazolidines obtained by a 1,3-dipolar cycloaddition between nitrones and vinylsulfones. This method highlights sulfone reactivity and provides an easy approach for the preparation of chiral pyrrolidines using cyclic imines as key intermediates. PMID- 23808574 TI - Prevalence of myopia-related retinal changes among 12-18 year old Hong Kong Chinese high myopes. AB - PURPOSE: To determine the prevalence and risk factors of myopia-related retinal changes in Hong Kong Chinese adolescents with high myopia. METHODS: A cross sectional study on Hong Kong Chinese teenage subjects with high myopia was conducted between January 2005 and June 2009. Subjects were recruited via newspaper advertisements, invitation letters to schools, leaflets and posters. Data collected included history related to myopia progression and retinal characteristics. RESULTS: In total, 120 subjects (61 boys and 59 girls) were recruited. The mean age was 14.8 +/- 1.6 years (range: 12-18 years). The mean SER of the eyes was -8.41 +/- 1.60 D. Ninety four of the 120 adolescents were found to have a retinal change of which 0.8% were sight-threatening, 2.5% were posterior pole changes, and 61.7% were peripheral retinal changes. The five most frequent retinal changes found were optic nerve crescents (52.5%), white-without pressure (51.7%), lattice degeneration (5.8%), microcystoid degeneration (5%) and pigmentary degeneration (4.2%). After adjusting for myopia over -8 D, age, gender, duration of myopia, family retinal history and intraocular pressure (IOP), binary logistic regressions showed that an axial length longer than 26.5 mm was a significant risk factor for peripheral retinal changes, optic nerve crescents and white-without-pressure. CONCLUSIONS: Peripheral retinal degenerative changes and optic nerve crescent were found in a significant proportion of high myopic teenage subjects. There is increased risk of retinal changes in eyes with an axial length >26.5 mm in 12-18 year-olds. PMID- 23808576 TI - One-pot construction of 3,3'-bisindolylmethanes through Bartoli indole synthesis. AB - A one-pot approach to 3,3'-bisindolylmethane derivatives from nitrobenzene derivatives through the Bartoli indole synthesis was developed, in which the acid used to quench the reaction markedly affected its outcome. Quenching the reaction with concd HCl produced 3,3'-bisindolylmethane in contrast to the formation of 7 substituted indole by quenching with NH4Cl. PMID- 23808575 TI - Maternal depression and co-occurring antisocial behaviour: testing maternal hostility and warmth as mediators of risk for offspring psychopathology. AB - BACKGROUND: Disruption in the parent-child relationship is a commonly hypothesized risk factor through which maternal depression may increase risk for offspring psychopathology. However, maternal depression is commonly accompanied by other psychopathology, including antisocial behaviour. Few studies have examined the role of co-occurring psychopathology in depressed mothers. Using a longitudinal study of offspring of mothers with recurrent depression, we aimed to test whether maternal warmth/hostility mediated links between maternal depression severity and child outcomes, and how far direct and indirect pathways were robust to controls for co-occurring maternal antisocial behaviour. METHODS: Mothers with a history of recurrent major depressive disorder and their adolescent offspring (9-17 years at baseline) were assessed three times between 2007 and 2010. Mothers completed questionnaires assessing their own depression severity and antisocial behaviour at Time 1 (T1). The parent-child relationship was assessed using parent rated questionnaire and interviewer-rated 5-min speech sample at Time 2 (T2). Offspring symptoms of depression and disruptive behaviours were assessed using the Child and Adolescent Psychiatric Assessment at Time 3 (T3). RESULTS: Maternal hostility and warmth, respectively, mediated the association between maternal depression severity and risk for offspring psychopathology. However, the effects were attenuated when maternal antisocial behaviour was included in the analysis. In tests of the full theoretical model, maternal antisocial behaviour predicted both maternal hostility and low warmth, maternal hostility predicted offspring disruptive behaviour disorder symptoms, but not depression, and maternal warmth was not associated with either child outcome. CONCLUSIONS: Parenting interventions aimed at reducing hostility may be beneficial for preventing or reducing adolescent disruptive behaviours in offspring of depressed mothers, especially when depressed mothers report co-occurring antisocial behaviour. PMID- 23808577 TI - New polymorph of Mo3S4 prepared using a high-pressure synthesis technique: crystal structure, electronic property, and band calculation. AB - A new polymorph of Mo3S4 was synthesized at 13 GPa and 1450 degrees C from a stoichiometric mixture of elements. It crystallizes in a triclinic unit cell (space group P1 (No. 2)) with cell constants of a = 6.364(2) A, b = 6.608(2) A, c = 6.809(2) A, alpha = 103.899(3) degrees , beta = 117.753(3) degrees , gamma = 103.958(3) degrees , and V = 224.25(13) A(3). The structure of Mo3S4 is composed of edge- and face-sharing MoS6 octahedra. It was closely related to the structure of MMo2S4 type compounds (M = V, Cr, Fe, and Co). Mo3S4 can be regarded as a derivative with M = Mo. The calculated density of 6.160 g/cm(3) was much larger than 5.191 g/cm(3) of famous polymorphic Mo6S8 (Chevrel phase). Mo3S4 was metallic and did not show any superconducting transition down to 2 K. The bond valence sums suggested that Mo3S4 can be classified in the class III-B of mixed valence compounds; all Mo ions have a similar nonintegral valence. Electronic structure calculations revealed that the conduction band of Mo3S4 contains much contribution of the relatively narrow Mo 4d bands as well as the bands composed of hybridized Mo4d-S3d orbitals. PMID- 23808578 TI - Evaluating migraineurs' preferences for migraine treatment outcomes using a choice experiment. AB - OBJECTIVE: The impact of migraines on patients is commonly divided between the level of impairment associated with headache symptoms (headache phase) and the quality-of-life effects immediately following the headache (post-headache phase). Evaluations of migraineurs' productivity losses and health-related quality of life have provided an understanding of the burden associated with the headache and post-headache symptoms, but do not quantify the relative importance of each phase from a patient perspective. In this study, we evaluated migraineurs' willingness to accept trade-offs among symptom severity in the headache and post headache phases, symptom duration in the headache and post-headache phases, and symptom-free time within a general-preference theoretic framework. METHODS: We administered a choice-format, conjoint-analysis survey, also called a discrete choice experiment, to a sample of migraineurs from a nationally representative online consumer panel. After inclusion and exclusion criteria were applied, 510 eligible subjects completed the survey. The survey elicited choices between pairs of migraine profiles describing symptom durations and symptom-free time for the headache and post-headache phase. RESULTS: Migraineurs in our study were strongly affected by the pain associated with the headache phase. However, experiencing difficulty with daily social and family activities in the post-headache phase also had a statistically significant impact on migraineurs' perceived level of well-being. Migraineurs reported that hypothetical treatments that limited the duration of headache symptoms without allowing them to resume their daily activities for 16 hours after a headache, on average, were less than half as good as treatments that limited both headache and post-headache symptoms. CONCLUSION: Our results suggest that treatments that relieve and shorten symptoms during the post-headache phase can offer significant benefits to migraineurs. PMID- 23808579 TI - Extracellular Hsp70 inhibits pro-inflammatory cytokine production by IL-10 driven down-regulation of C/EBPbeta and C/EBPdelta. AB - PURPOSE: Extracellular Hsp70 has anti-inflammatory potential, demonstrated in different models of inflammatory diseases. We investigated probable mechanisms used by Hsp70 to down-regulate pro-inflammatory cytokines. MATERIALS AND METHODS: We analysed cytokine mRNA levels in bone marrow-derived murine dendritic cells treated with Hsp70, lipopolysaccharide (LPS) and peptidoglycan (PGN) or OVA (an irrelevant protein control), hypothesising that this was mediated by C/EBPbeta and C/EBPdelta transcription factors. We also tested the involvement of TLR2, IL 10, ERK and STAT3, using genetically deficient mice and pharmacological inhibitors. RESULTS: C/EBPbeta and C/EBPdelta levels were inhibited in bone marrow derived dendritic cells (BMDCs) treated with Hsp70, and that correlated with inhibition of TNF-alpha, IFN-gamma and MCP-1. Such inhibition was not observed in TLR2 or IL-10 knockout mice, and was also abrogated upon pretreatment of cells with ERK and JAK2/STAT3 inhibitors. CONCLUSIONS: C/EBPbeta and C/EBPdelta transcription factors are inhibited by Hsp70 treatment, and their inhibition occurs via the TLR2-ERK-STAT3-IL-10 pathway in BMDCs, mediating the anti-inflammatory effects of Hsp70. PMID- 23808580 TI - Immunohistochemical expression of p16 in desmoplastic melanoma. AB - Desmoplastic melanoma can be difficult to distinguish from desmoplastic melanocytic nevi both clinically and histopathologically. Several attempts have been made to explore the use of ancillary studies to facilitate this distinction. Prior work has suggested that immunohistochemical expression of p16 could help distinguish sclerosing Spitz nevi from desmoplastic melanomas. We re-evaluated the expression of p16 in 22 desmoplastic melanomas (13 mixed and 9 pure desmoplastic tumors) and five desmoplastic melanocytic nevi (three desmoplastic Spitz nevi and two congenital melanocytic nevi with prominent dermal sclerosis). All desmoplastic melanocytic nevi were strongly immunoreactive for p16. Of the 22 desmoplastic melanomas, 6 tumors failed to label for p16, 10 were focally positive, but 6 tumors were diffusely immunoreactive. The latter finding is relevant, as it points to limitations in the diagnostic value of immunohistochemical staining for p16 for the diagnosis of desmoplastic melanocytic proliferations. Diffuse staining for p16 is not restricted to desmoplastic Spitz nevi but can also occur in a subset of desmoplastic melanomas, and this warrants caution in the use of this marker for diagnostic purposes. PMID- 23808581 TI - The impact of early recovery on long-term outcomes in a cohort of patients undergoing prolonged nonoperative treatment for lumbar disc herniation: clinical article. AB - OBJECT: The authors comprehensively studied the recovery of individual patients undergoing treatment for lumbar disc herniation. The primary goal was to gain insight into the variability of individual patient utility scores within a treatment cohort. The secondary goal was to determine how the rates and variability of patient recovery over time, represented by improvement in utility scores, affected long-term patient outcomes. METHODS: EuroQol Group-5 Dimension (EQ-5D) scores were obtained at baseline and at 2, 4, 8, 12, 26, 38, and 52 weeks for 93 patients treated under a prolonged conservative care protocol for lumbar disc herniation. Gaussian kernel densities were used to estimate the distribution of utility scores at each time point. Logistic regression and multistate Markov models were used to characterize individual patient improvement over time. Fisher exact tests were used to compare the distribution of EQ-5D domain scores. RESULTS: The distribution of utility scores was bimodal at 1 year and effectively sorted patients into a "higher" utility group (EQ-5D = 1; 43% of cohort) and a "lower" utility group (EQ-5D <= 0.86; 57% of cohort). Fisher exact tests revealed that pain/discomfort, mobility, and usual activities significantly differed between the 2 utility groups (p ? 0.001). The utility groups emerged at 8 weeks and were stable for the remainder of the treatment period. Using utility scores from 8 weeks, regression models predicted 1-year outcomes with 62% accuracy. CONCLUSIONS: This study is the first to comprehensively consider the utility recovery of individual patients within a treatment cohort for lumbar disc herniation. The results suggest that most utility is recovered during the early treatment period. Moreover, the findings suggest that initial improvement is critical to a patient's long-term outcome: patients who do not experience significant initial recovery appear unlikely to do so at a later time under the same treatment protocol. PMID- 23808582 TI - Combined S-1 and S-2 sacral alar-iliac screws as a salvage technique for pelvic fixation after pseudarthrosis and lumbosacropelvic instability: technical note. AB - Lumbosacropelvic pseudarthrosis after long spinal fusions for treatment of adult degenerative scoliosis remains a challenging condition. Moreover, although pelvic fixation with iliac screws is widely used in deformity surgery to provide a biomechanically strong distal anchor for long thoracolumbar constructs, there are very few options available after failed pelvic fixation with iliac screws. The authors conducted a retrospective review of the surgical charts and imaging findings of patients subjected to revision surgery for lumbosacropelvic pseudarthrosis from August 2011 to August 2012. This review identified 5 patients in whom a salvage technique combining both S-1 and S-2 sacral alar-iliac (SAI) screws had been performed. In this technical note, the authors present a detailed anatomical discussion and an appraisal of the sequential intraoperative steps of this new technique involving a combination of S-1 and S-2 SAI screws. The discussion is illustrated with a surgical case in which this technique was used to treat a patient with pseudarthrosis that had developed after fixation with classic iliac screws. In conclusion, although S-2 SAI screws have previously been reported as an interesting alternative to classic iliac wing screws, this report is the first on the use of combined S-1 and S-2 SAI screws for pelvic fixation as a salvage technique for lumbosacropelvic instability. According to the reported experience, this technique provides a biomechanically robust construct for definitive pelvic fixation during revision surgeries in the challenging scenarios of pseudarthrosis and instability of the lumbosacropelvic region. PMID- 23808583 TI - Epidural application of spinal instrumentation particulate wear debris: a comprehensive evaluation of neurotoxicity using an in vivo animal model. AB - OBJECT: The introduction and utilization of motion-preserving implant systems for spinal reconstruction served as the impetus for this basic scientific investigation. The effect of unintended wear particulate debris resulting from micromotion at spinal implant interconnections and bearing surfaces remains a clinical concern. Using an in vivo rabbit model, the current study quantified the neural and systemic histopathological responses following epidural application of 11 different types of medical-grade particulate wear debris produced from spinal instrumentation. METHODS: A total of 120 New Zealand White rabbits were equally randomized into 12 groups based on implant treatment: 1) sham (control), 2) stainless steel, 3) titanium alloy, 4) cobalt chromium alloy, 5) ultra-high molecular weight polyethylene (UHMWPe), 6) ceramic, 7) polytetrafluoroethylene, 8) polycarbonate urethane, 9) silicone, 10) polyethylene terephthalate, 11) polyester, and 12) polyetheretherketone. The surgical procedure consisted of a midline posterior approach followed by resection of the L-6 spinous process and L5-6 ligamentum flavum, permitting interlaminar exposure of the dural sac. Four milligrams of the appropriate treatment material (Groups 2-12) was then implanted onto the dura in a dry, sterile format. All particles (average size range 0.1-50 MUm in diameter) were verified to be endotoxin free prior to implantation. Five animals from each treatment group were sacrificed at 3 months and 5 were sacrificed at 6 months postoperatively. Postmortem analysis included epidural cultures and histopathological assessment of local and systemic tissue samples. Immunocytochemical analysis of the spinal cord and overlying epidural fibrosis quantified the extent of proinflammatory cytokines (tumor necrosis factor-alpha, tumor necrosis factor-beta, interleukin [IL]-1alpha, IL-1beta, and IL-6) and activated macrophages. RESULTS: Epidural cultures were negative for nearly all cases, and there was no evidence of particulate debris or significant histopathological changes in the systemic tissues. Gross histopathological examination demonstrated increased levels of epidural fibrosis in the experimental treatment groups compared with the control group. Histopathological evaluation of the epidural fibrous tissues showed evidence of a histiocytic reaction containing phagocytized inert particles and foci of local inflammatory reactions. At 3 months, immunohistochemical examination of the spinal cord and epidural tissues demonstrated upregulation of IL-6 in the groups in which metallic and UHMWPe debris were implanted (p < 0.05), while macrophage activity levels were greatest in the stainless-steel and UHMWPe groups (p < 0.05). By 6 months, the levels of activated cytokines and macrophages in nearly all experimental cases were downregulated and not significantly different from those of the operative controls (p > 0.05). The spinal cord had no evidence of lesions or neuropathology. However, multiple treatments in the metallic groups exhibited a mild, chronic macrophage response to particulate debris, which had diffused intrathecally. CONCLUSIONS: Epidural application of spinal instrumentation particulate wear debris elicits a chronic histiocytic reaction localized primarily within the epidural fibrosis. Particles have the capacity to diffuse intrathecally, eliciting a transient upregulation in macrophage/cytokine activity response within the epidural fibrosis. Overall, based on the time periods evaluated, there was no evidence of an acute neural or systemic histopathological response to the materials included in the current project. PMID- 23808584 TI - Applicability of the pediatric evaluation of disability inventory among Saudi children. AB - PURPOSE: To determine the cross-cultural applicability of the Pediatric Evaluation of Disability Inventory (PEDI) among Saudi children. METHODS: The PEDI score form was translated into Arabic then back translated to English. The Arabic translated PEDI was administered by specialized physical therapists to 52 nondisabled Saudi children (30 boys, 22 girls) aged between 1 and 7 years, from five schools. The sample was divided into age groups and the mean of each group score was compared to the US normative value using one sample t-test with a reference mean of 50. Consistency was tested using Cronbach's alpha and the influence of demographic factors was assessed using univariate analysis of variance. RESULTS: Data analysis showed lower scores from the Saudi children sample in both the Functional Skills scale and the Caregiver Assistance scale in some age groups compared to US PEDI reference values. Cronbach's alpha was found to be high to moderate, and no demographic factors were shown to have influenced the outcome, except PEDI scores differed significantly in children with working mothers compared to those with non-working mothers. CONCLUSION: Saudi children scored significantly lower than US PEDI reference values in some age groups. We highly attribute this to parental attitude and the more behaviour of Saudi mothers towards their children. The study also reinforces that children of working mothers are more independent, an encouraging finding for those mothers facing resistance and lack of support for their work. Implications for Rehabilitation Saudi children perform less than their U.S. peers, certifying the need for cultural norming of PEDI prior to its use among Saudi children. The surrounding environment and culture has remarkable influence on Saudi children neuro-development, as reflected by the delay from original PEDI reference values. While designing rehabilitation programs for disabled children, physical therapists must consider that mothers' attitude, home environment and local culture have an obvious impact on children's capability and performance in functional activity. Working mothers' children were more independent than nonworking mothers; hence, it is useful to consider this trait in the initial evaluation. PMID- 23808585 TI - Measuring quality in cancer care: overview of initiatives in selected countries. AB - To inform the Austrian National Cancer Plan on possible generic quality indicators that might be derived from routine data a systematic literature search in three databases, followed by extensive hand-searching to locate initiatives and their publications was carried out in spring 2011. Twenty-one initiatives that developed indicators for measuring quality of cancer care were identified: longer standing and decentralised initiatives are characteristics of the USA. The Canadian province of Ontario publishes the Cancer System Quality Index, centralised audit and peer review programmes are undertaken in the National Health Service in the UK. Methodologically sound cancer type-specific pilot projects in Belgium have been implemented, the Netherlands and Denmark are running national initiatives. Germany recently started quality measurement activities, too. Generic indicators often focus on end-of-life care, multidisciplinarity, advance care planning and documentation. Indicators measuring the quality of care during an entire episode of cancer are rare, as are those for less common cancers and for care in the outpatient setting. Access, equity and the patient's perspective are only beginning to be incorporated into indicators. After having identified a range of candidate indicators that can be implemented with routinely collected data alone, piloting them in Austria would be the next step to go. PMID- 23808586 TI - Participation of catalase in voluntary ethanol consumption in perinatally low level lead-exposed rats. AB - BACKGROUND: Environmental lead (Pb) exposure and alcohol abuse pose significant public health problems for our society. One of the proposed mechanisms of action of the developmental neurotoxicant Pb is related to its ability to affect antioxidant enzymes, including catalase (CAT). Ethanol's (EtOH) motivational effects are postulated to be mediated by the CAT-dependent acetaldehyde generated in the brain. The current study sought to investigate the role of this enzyme in the elevated EtOH intake previously reported in perinatally Pb-exposed rats. METHODS: Thirty-five-day-old male Wistar rats exposed to 220 ppm Pb during gestation and lactation were offered escalating EtOH solutions (2 to 10%) or water, 2 h/d for 28 days. Once baseline 10% EtOH intake was achieved, they were injected with (i) saline (SAL), (ii) 3-amino 1,2,4 triazole (aminotriazole [AT], a CAT inhibitor, 250 mg/kg intraperitoneally [i.p.], 5 hours before the last 8 EtOH intake sessions), or (iii) 3-nitropropionic acid (3NPA; a CAT activator, 20 mg/kg subcutaneously [s.c.], 45 minutes before the last 4 EtOH intake sessions). Rats were then sacrificed, blood collected, and brain regions harvested for CAT activity determination. Additional studies evaluated EtOH intake and CAT activity in response to 10 and 30 mg/kg 3NPA. Both 3NPA and AT were evaluated for striatal cytotoxicity. RESULTS: We observed that AT pretreatment blunted the increased EtOH intake, as well as the elevated CAT activity in blood, cerebellum, and hippocampus evidenced in the developmentally Pb-exposed rats that have consumed EtOH. Conversely, 20 mg/kg 3NPA further increased voluntary EtOH intake in these animals as compared with controls, concomitantly with a slight elevation in CAT activity both in blood and in the striatum, associated with no changes in striatal cytotoxicity. CONCLUSIONS: These results suggest a participation of CAT, and possibly acetaldehyde, in Pb-induced high EtOH intake, and open up new avenues to elucidate the mechanism that underlies the Pb and EtOH interaction. PMID- 23808587 TI - First impressions count: does FAIRness affect adaptation of clinical clerks in their first clinical placement? AB - BACKGROUND: FAIRness (Feedback, Activity, Individualisation, Relevance) teaching is a structured program, comprising series of classes in which student work is anonymised and reviewed by the whole class, as well as students receiving private feedback on their written work. The class work emphasises logic, structure and order in history and examination, with a diagnostic and management focus. AIM: The effect of FAIRness teaching methods on the adaptation of medical students entering their first clinical rotations was studied. METHODS: 18 students in FAIRness placements and 72 students in conventional placements, all in medical/surgical units in the same University teaching hospital were studied. They completed questionnaires relating to effectiveness and quality of clinical teaching. Some students additionally attended focus groups, at the start of placement to discuss their expectations, and after 3 weeks, to discuss their adaptation to the clinical learning environment. RESULTS: All students entering clinical placements had low expectations of their future teaching. Students in standard placements still expressed negative attitudes after 3 weeks, while students on FAIRness placements felt positive. Students in FAIRness placements scored significantly higher on questions related to feedback and review of student work. CONCLUSION: FAIRness teaching practices help students to adapt to their first clinical placements. PMID- 23808588 TI - Anomalous muscle band resulting in severe subaortic stenosis in an adult. AB - Abnormalities of the mitral valve are uncommon causes of subaortic stenosis. This paper describes an anomalous muscle band of the mitral valve causing severe subaortic stenosis. PMID- 23808589 TI - Crystal structure of a human prion protein fragment reveals a motif for oligomer formation. AB - The structural transition of the prion protein from alpha-helical- to beta-sheet rich underlies its conversion into infectious and disease-associated isoforms. Here we describe the crystal structure of a fragment from human prion protein consisting of the disulfide-bond-linked portions of helices 2 and 3. Instead of forming a pair-of-sheets steric zipper structure characteristic of amyloid fibers, this fragment crystallized into a beta-sheet-rich assembly of hexameric oligomers. This study reveals a never before observed structural motif for ordered protein aggregates and suggests a possible mechanism for self-propagation of misfolded conformations by such nonamyloid oligomers. PMID- 23808591 TI - Optimising outpatient efficiency - development of an innovative 'Did Not Attend' management approach. AB - OBJECTIVE: To examine non-attendance [or Did Not Attend (DNA)] rates in a community mental health follow-up outpatient clinic and evaluate a pragmatic initiative to reduce non-attendance. METHODS: Clinical audit of attendance across two community psychiatry outpatient clinics was used to establish DNA rates at baseline. Both clinics sought to reduce the DNA rate and were made aware of the outcome of the first cycle of audit. Clinic A (intervention clinic) introduced an innovative new management approach aimed at reducing DNAs, whilst Clinic B (control clinic) introduced no further systematic measures. The clinics were then re-audited to establish the impact of the changes. RESULTS: We found that the introduction of the new management approach in Clinic A was associated with reduced numbers of service users failing to attend for a clinic appointment (n = 1134, relative risk 0.59, 95% Confidence Interval (C.I.) 0.44-0.77, NNT = 12). No such difference was identified in Clinic B. CONCLUSIONS: Intervention to reduce the DNA rate is realistically achievable with minimal effort and modest additional cost. The actions required of clinicians are practicable, and can have a direct impact without large-scale organisational change. PMID- 23808590 TI - Dysregulation of macrophage activation profiles by engineered nanoparticles. AB - Although the potential human health impacts from exposure to engineered nanoparticles (ENPs) are uncertain, past epidemiological studies have established correlations between exposure to ambient air pollution particulates and the incidence of pneumonia and lung infections. Using amorphous silica and superparamagnetic iron oxide (SPIO) as model high production volume ENPs, we examined how macrophage activation by bacterial lipopolysaccharide (LPS) or the lung pathogen Streptococcus pneumoniae is altered by ENP pretreatment. Neither silica nor SPIO treatment elicited direct cytotoxic or pro-inflammatory effects in bone marrow-derived macrophages. However, pretreatment of macrophages with SPIO caused extensive reprogramming of nearly 500 genes regulated in response to LPS challenge, hallmarked by exaggerated activation of oxidative stress response pathways and suppressed activation of both pro- and anti-inflammatory pathways. Silica pretreatment altered regulation of only 67 genes, but there was strong correlation with gene sets affected by SPIO. Macrophages exposed to SPIO displayed a phenotype suggesting an impaired ability to transition from an M1 to M2-like activation state, characterized by suppressed IL-10 induction, enhanced TNFalpha production, and diminished phagocytic activity toward S. pneumoniae. Studies in macrophages deficient in scavenger receptor A (SR-A) showed SR-A participates in cell uptake of both the ENPs and S. pneumonia and co-regulates the anti-inflammatory IL-10 pathway. Thus, mechanisms for dysregulation of innate immunity exist by virtue that common receptor recognition pathways are used by some ENPs and pathogenic bacteria, although the extent of transcriptional reprogramming of macrophage function depends on the physicochemical properties of the ENP after internalization. Our results also illustrate that biological effects of ENPs may be indirectly manifested only after challenging normal cell function. Nanotoxicology screening strategies should therefore consider how exposure to these materials alters susceptibility to other environmental exposures. PMID- 23808593 TI - Recent advances in gastric floating drug delivery technology: a review. AB - Gastric floating drug delivery systems have been an avenue of considerable interest in terms of their immense potential for better pharmacotherapeutic interventions along with site-specific absorption. These buoyant systems significantly enhance the bioavailability and controlled delivery of several drug molecules. Scientific investigators have also carried out substantial research endeavours worldwide in order to design a more systematic and intellectual floating systems. The present manuscript is an attempt to highlight numerous recent advancements in the design of gastric floating drug delivery systems along with various available commercial preparations. Salient applications, characterization aspects and future perspectives of these multifarious systems have also been addressed. PMID- 23808592 TI - Expanding the phenotypic spectrum of ECEL1-related congenital contracture syndromes. AB - Using a combination of homozygosity mapping and whole-exome sequencing (WES), we identified a novel missense c.1819G>A mutation (G607S) in the endothelin converting enzyme-like 1 (ECEL1) gene in a consanguineous pedigree of Turkish origin presenting with a syndrome of camptodactyly, scoliosis, limited knee flexion, significant refractive errors and ophthalmoplegia. ECEL1 mutations were recently reported to cause recessive forms of distal arthrogryposis. This report expands on the molecular basis and the phenotypic spectrum of ECEL1-associated congenital contracture syndromes. PMID- 23808594 TI - Evaluation of the effect of nimodipine o.d. (extended release) vs nimodipine t.i.d. in the treatment of peripheral vertigo. AB - SUMMARY: Vertigo has a negative impact on quality of life; therefore, it is important to find an effective and convenient therapy that allows patients to continue their everyday tasks as soon as possible and to have a better quality of life. METHODS: There were two formulations used to assess the effectiveness in vertigo treatment from peripheral origin: nimodipine administrated three times daily (Nimotop(r)) 30 mg versus nimodipine AP administrated once daily (Tropocer(r)) 90 mg; both of them in a administrated in a prospective, randomized, double-blind, double dummy, multicenter and parallel-group study, where patients with peripheral vertigo defined as a score >=7 on the Vertigo Dizziness Differential Diagnosis Score were included. The patients were evaluated by vertigo severity index and vestibular disability index. RESULTS: In the AP nimodipine group (NAP), vertigo severity index was decreased by 50%: 24% of patients in 14 days, 41% in 4 weeks and 89% in 8 weeks. The vestibular disability index was decreased by 50%: 24% of patients in 15 days, 83% in 4 weeks and 92% of patients in 8 weeks. In the conventional nimodipine group (NC), rate of vertigo severity was decreased by 50%: 17% of patients in 14 days, 41% of patients in 4 weeks and 90% of patients in 8 weeks. The vestibular disability index was decreased by 50%: 15 days in 17% of patients, 53% in 4 weeks and 64% in 8 weeks, without difference between groups. CONCLUSIONS: both products were effective and well tolerated in the treatment of peripheral vertigo. PMID- 23808595 TI - Connecting with connexins. AB - We describe a case of an 18-year-old woman with congenital sensorineural deafness who presented to the dermatology clinic with asymptomatic thickening of the skin over the palmar aspect of her hands and feet. An examination revealed palmoplantar keratoderma of the palms and soles of the feet with no pseudoainhum. Her father wore a hearing aid and his deafness had been thought to be acquired. Mutation analysis of the connexin 26 gene revealed that she carried a paternally inherited mutation, p.Asp46Glu and a maternally inherited M34T variant. The p.Asp46Glu mutation has been described in a family exhibiting non-syndromic autosomal dominant deafness. Although the M34T variant has been described as a non-pathogenic variant or with a very mild phenotype only, its combination with the p.Asp46Glu mutation may account for her mild cutaneous phenotype with later clinical presentation. PMID- 23808596 TI - Parental stethoscope use for infant heart rate counting. PMID- 23808597 TI - A unified model for de novo design of elastin-like polypeptides with tunable inverse transition temperatures. AB - Elastin-like polypeptides (ELPs) are stimulus-responsive peptide polymers that exhibit inverse temperature phase transition behavior, causing an ELP to aggregate above its inverse transition temperature (T(t)). Although this property has been exploited in a variety of biotechnological applications, de novo design of ELPs that display a specific T(t) is not trivial because the T(t) of an ELP is a complex function of several variables, including its sequence, chain length, polypeptide concentration, and the type and concentration of cosolutes in solution. This paper provides a quantitative model that predicts the T(t) of a family of ELPs (Val-Pro-Gly-Xaa-Gly, where Xaa = Ala and/or Val) from their composition, chain length, and concentration in phosphate buffered saline. This model will enable de novo prediction of the amino acid sequence and chain length of ELPs that will display a predetermined T(t) in physiological buffer within a specified concentration regime, thereby greatly facilitating the design of new ELPs for applications in medicine and biotechnology. PMID- 23808598 TI - Intertwined network of Si/C nanocables and carbon nanotubes as lithium-ion battery anodes. AB - We demonstrate a new kind of Si-based anode architectures consisting of silicon nanowire/overlapped graphene sheet core-sheath nanocables (SiNW@G) intertwined with carbon nanotubes (CNTs). In such a hybrid structure, the CNTs, mechanically binding SiNW@G nanocables together, act as a buffer matrix to accommodate the volume change of SiNW@G, and overlapped graphene sheets (that is, G sheaths) effectively prevent the direct contact of silicon with the electrolyte during cycling, both of which enable the structural integrity and interfacial stabilization of such hybrid electrodes. Furthermore, the one-dimensional nature of both components affords the creation of a three-dimensional interpenetrating network of lithium ion and electron pathways in the resultant hybrids, thereby enabling efficient transport of both electrons and lithium ions upon charging/discharging. As a result, the hybrids exhibit much-improved lithium storage performance. PMID- 23808599 TI - Dissipative particle dynamics simulation of the phase behavior of T-shaped ternary amphiphiles possessing rodlike mesogens. AB - We employed dissipative particle dynamics simulations to explore the phase behavior of T-shaped ternary amphiphiles composed of rodlike cores connected by two incompatible end chains and side grafted segments. By fine-tuning the number of terminal and lateral beads, three phase diagrams for the model systems with different terminal chain lengths are constructed in terms of temperature and lateral chain length, which have some common features and mostly compare favorably with experimental studies with the exception a couple of new phases. It is worthwhile to highlight that the mixed cylindrical phase and the perforated layer phase, as the experimentally observed mesophases exclusive for facial amphiphilies, are found in simulations for the first time. Also, a novel gyroid structure is observed in series of T-shaped ternary amphiphiles for the first time. Furthermore, by evaluating the effective volume fraction of lateral chains, the phase sequence spanning from conventional smectic layer phase via perforated layer structures and polygonal cylindrical arrays to novel lamellar mesophase is established, which is not just qualitatively consistent with the related experimental findings but even the stability windows of some mesophases quantitatively correspond well to experimental results. The success of reproducing the in-plane ordering of rods in the lamellar phase as well as the generic phase diagram of such T-shaped ternary amphiphiles in great detail implies that our genetic model qualitatively captures many of the characteristics of the phase behavior of real T-shaped molecules and could serve as a satisfactory basis for further exploration of self-organization in other related soft matter systems. PMID- 23808600 TI - Asymmetric synthesis and catalytic activity of 3-methyl-beta-proline in enantioselective anti-Mannich-type reactions. AB - Enantiomerically pure 3-methyl-beta-proline was synthesized using an asymmetric phase-transfer-catalyzed alkylation of a cyanopropanoate to establish the all carbon stereogenic center. The catalytic activity of 3-methyl-beta-proline in the Mannich-type reaction between a glyoxylate imine and ketones/aldehydes was subsequently investigated. The catalyst was designed and found to be more soluble in nonpolar organic solvents relative to the unsubstituted beta-proline catalyst, and as a result allowed for added flexibility during optimization efforts. This work culminated in the development of a highly anti-diastereo- and enantioselective process employing low catalyst loading. PMID- 23808601 TI - Effects of cryopreservation on microbial-contaminated cord blood. AB - BACKGROUND: Cord blood units (CBUs) are associated with significant risk of exposure to microbial contamination during collection and processing; however, the survival of bacteria within a CBU is poorly understood. This study aimed to determine whether contaminating organisms in CBU survive the cryopreservation, frozen storage, and subsequent thawing conditions before infusion. STUDY DESIGN AND METHODS: A total of 134 CBUs rejected from banking due to known contamination were thawed and rescreened using blood culture bottles (BacT/ALERT, bioMerieux). An additional 61 fresh CBUs were deliberately spiked with a range of microbial organisms and evaluated both before freeze and after thaw. RESULTS: Microbial contaminants were detected after thaw in 63% of stored contaminated CBUs and 85% of spiked CBUs. Postthaw organism detection in spiked cord blood (CB) was higher in adult culture bottles (80%) than pediatric culture bottles (61%). Twenty percent of spiked organisms, particularly Bacillus subtilis, Escherichia coli, Clostridium sporogenes, and Propionibacterium acnes, were not detected in prefreeze samples but were detectable after thaw. CONCLUSIONS: This study demonstrates that the majority of contaminating organisms isolated in a prefreeze sample of CB have the ability to survive cryopreservation, frozen storage, and thawing. Further, CBUs reported as microbial free may contain microbial contamination, which could result in transplantation of contaminated CB and be potentially deleterious to a patient. PMID- 23808602 TI - Highly efficient synthesis of mixed 3,3'-bisindoles via Rh(II)-catalyzed three component reaction of 3-diazooxindoles with indoles and ethyl glyoxylate. AB - A series of mixed 3,3'-bisindoles were efficiently synthesized via a Rh2(OAc)4 catalyzed three-component reaction of 3-diazooxindoles with indoles and ethyl glyoxylate in high yields with excellent diastereoselectivities. The product easily underwent further synthetic transformations and could be potentially applied to the total synthesis of (+/-)-gliocladin C and related natural alkaloids. PMID- 23808603 TI - Cluster headache: potential options for medically refractory patients (when all else fails). AB - The most evidence exists for mixed anesthetic/steroid occipital nerve blocks (which are also useful in non-refractory patients), deep brain stimulation, sphenopalatine ganglion (SPG) blocks, SPG radiofrequency ablation, and SPG stimulation with the Autonomic Technologies, Inc (ATI) SPG Neurostimulator, the latter approved in the European Union and reimbursed in several countries. PMID- 23808604 TI - Lessons learned from the clinical development and market authorization of Glybera. PMID- 23808605 TI - Dissolving microneedles to obtain rapid local anesthetic effect of lidocaine at skin tissue. AB - Dissolving microneedles (DMs) were applied to lidocaine for local anesthesia of the skin. Three DM array chips were prepared where lidocaine was localized at the acral portion of DMs (type 1), loaded in whole DMs (type 2), and lidocaine was loaded both in whole DMs and the chip (type 3). DM chips were 15-mm diameter with 225 DMs, each 500-MUm long with a 300-MUm diameter base. The lidocaine contents were (type 1) 0.08 +/- 0.01 mg, (type 2) 0.22 +/- 0.01 mg and (type 3) 8.52 +/- 0.49 mg. Lidocaine was released from type 1 and 2 DM array chips within 10 min. Pharmacological activity of DMs were compared to lidocaine cream by the suppression of idiospasm of hair-removed rat skin. Type 1, 2 and 3 DMs showed faster onset time, 5 min, than lidocaine cream. Type 2 and 3 DMs showed stronger anti-idioplasmic activity than type 1 DMs. Pharmacokinetic study showed that tissue lidocaine levels, 62.8 +/- 3.6 (type 1), 89.1 +/- 9.9 (type 2) and 131.2 +/- 10.2(type 3) MUg/g wet weight at 5 min after the removal of DM were obtained higher than lidocaine cream, 26.2 +/- 12.5 MUg/g wet weight. Those results suggest the usefulness of type 2 DMs to obtain fast onset time for the local anesthesia in the skin. PMID- 23808606 TI - Effective classification of microRNA precursors using feature mining and AdaBoost algorithms. AB - MicroRNAs play important roles in most biological processes, including cell proliferation, tissue differentiation, and embryonic development, among others. They originate from precursor transcripts (pre-miRNAs), which contain phylogenetically conserved stem-loop structures. An important bioinformatics problem is to distinguish the pre-miRNAs from pseudo pre-miRNAs that have similar stem-loop structures. We present here a novel method for tackling this bioinformatics problem. Our method, named MirID, accepts an RNA sequence as input, and classifies the RNA sequence either as positive (i.e., a real pre miRNA) or as negative (i.e., a pseudo pre-miRNA). MirID employs a feature mining algorithm for finding combinations of features suitable for building pre-miRNA classification models. These models are implemented using support vector machines, which are combined to construct a classifier ensemble. The accuracy of the classifier ensemble is further enhanced by the utilization of an AdaBoost algorithm. When compared with two closely related tools on twelve species analyzed with these tools, MirID outperforms the existing tools on the majority of the twelve species. MirID was also tested on nine additional species, and the results showed high accuracies on the nine species. The MirID web server is fully operational and freely accessible at http://bioinformatics.njit.edu/MirID/ . Potential applications of this software in genomics and medicine are also discussed. PMID- 23808607 TI - Evaluation of normalization methods to pave the way towards large-scale LC-MS based metabolomics profiling experiments. AB - Combining liquid chromatography-mass spectrometry (LC-MS)-based metabolomics experiments that were collected over a long period of time remains problematic due to systematic variability between LC-MS measurements. Until now, most normalization methods for LC-MS data are model-driven, based on internal standards or intermediate quality control runs, where an external model is extrapolated to the dataset of interest. In the first part of this article, we evaluate several existing data-driven normalization approaches on LC-MS metabolomics experiments, which do not require the use of internal standards. According to variability measures, each normalization method performs relatively well, showing that the use of any normalization method will greatly improve data analysis originating from multiple experimental runs. In the second part, we apply cyclic-Loess normalization to a Leishmania sample. This normalization method allows the removal of systematic variability between two measurement blocks over time and maintains the differential metabolites. In conclusion, normalization allows for pooling datasets from different measurement blocks over time and increases the statistical power of the analysis, hence paving the way to increase the scale of LC-MS metabolomics experiments. From our investigation, we recommend data-driven normalization methods over model-driven normalization methods, if only a few internal standards were used. Moreover, data-driven normalization methods are the best option to normalize datasets from untargeted LC-MS experiments. PMID- 23808608 TI - Mastitis caused by Mycobacterium kansasii infection in a dog. AB - A 2-year, 7-month-old female Chihuahua was admitted for a mammary mass measuring one cm in diameter. The dog had a history of demodicosis for 4 months and showed signs of pseudopregnancy at the time of the visit. Cytologic examination of an aspirate of the mass revealed a large number of macrophages containing nonstaining bacterial rods, which were acid-fast in a Ziehl-Neelsen stain, suggesting mycobacterial infection. Histologic examination of the mass revealed a pyogranulomatous mastitis characterized by an infiltration with macrophages containing acid-fast bacteria. Mycobacterium kansasii was subsequently cultured and identified by PCR. Surgical excision of the mass resulted in the growth of other dermal masses, but antimycobacterial treatment with rifampin and clarithromycin resolved these masses within 1 month. Three months after discontinuation of the treatment, similar organisms were found in aspirates of the enlarged bilateral inguinal lymph nodes by cytologic examination. Despite antimycobacterial treatment for another 4 months, there was no improvement and demodicosis also recurred. The dog eventually died of lymphoma 5 months after the relapse of mycobacterial infection. Although M kansasii is considered an important pathogen for pulmonary and cutaneous disease in people, there is only one report in a dog with an infection in a pleural effusion. As both adult-onset demodicosis in dogs as well as mycobacterial infection in people have been associated with T-lymphocyte deficiency, the M kansasii infection in this dog may have been associated with a condition of immune compromise. PMID- 23808610 TI - Measuring and modeling hemoglobin aggregation below the freezing temperature. AB - Freezing of protein solutions is required for many applications such as storage, transport, or lyophilization; however, freezing has inherent risks for protein integrity. It is difficult to study protein stability below the freezing temperature because phase separation constrains solute concentration in solution. In this work, we developed an isochoric method to study protein aggregation in solutions at -5, -10, -15, and -20 degrees C. Lowering the temperature below the freezing point in a fixed volume prevents the aqueous solution from freezing, as pressure rises until equilibrium (P,T) is reached. Aggregation rates of bovine hemoglobin (BHb) increased at lower temperature (-20 degrees C) and higher BHb concentration. However, the addition of sucrose substantially decreased the aggregation rate and prevented aggregation when the concentration reached 300 g/L. The unfolding thermodynamics of BHb was studied using fluorescence, and the fraction of unfolded protein as a function of temperature was determined. A mathematical model was applied to describe BHb aggregation below the freezing temperature. This model was able to predict the aggregation curves for various storage temperatures and initial concentrations of BHb. The aggregation mechanism was revealed to be mediated by an unfolded state, followed by a fast growth of aggregates that readily precipitate. The aggregation kinetics increased for lower temperature because of the higher fraction of unfolded BHb closer to the cold denaturation temperature. Overall, the results obtained herein suggest that the isochoric method could provide a relatively simple approach to obtain fundamental thermodynamic information about the protein and the aggregation mechanism, thus providing a new approach to developing accelerated formulation studies below the freezing temperature. PMID- 23808609 TI - The educational impact of assessment: a comparison of DOPS and MCQs. AB - AIM: To evaluate the impact of two different assessment formats on the approaches to learning of final year veterinary students. The relationship between approach to learning and examination performance was also investigated. METHOD: An 18-item version of the Study Process Questionnaire (SPQ) was sent to 87 final year students. Each student responded to the questionnaire with regards to DOPS (Direct Observation of Procedural Skills) and a Multiple Choice Examination (MCQ). Semi-structured interviews were conducted with 16 of the respondents to gain a deeper insight into the students' perception of assessment. RESULTS: Students' adopted a deeper approach to learning for DOPS and a more surface approach with MCQs. There was a positive correlation between an achieving approach to learning and examination performance. Analysis of the qualitative data revealed that deep, surface and achieving approaches were reported by the students and seven major influences on their approaches to learning were identified: motivation, purpose, consequence, acceptability, feedback, time pressure and the individual difference of the students. CONCLUSIONS: The format of DOPS has a positive influence on approaches to learning. There is a conflict for students between preparing for final examinations and preparing for clinical practice. PMID- 23808611 TI - Elevated Activin A urine levels are predictors of intraventricular haemorrhage in preterm newborns. AB - AIM: Intraventricular haemorrhage (IVH) is the most common variety of cerebral haemorrhage and cause of neurological disabilities in preterm newborns. We evaluated the usefulness of urine Activin A concentrations for the early detection of perinatal IVH. METHODS: We conducted a case-control study on 100 preterm newborns (20 with IVH and 80 without IVH) in whom urine Activin A was measured at five predetermined time-points in the first 72 h after birth. IVH diagnosis and the extension of the lesion were performed by ultrasound scanning within the first 72 h and at 1 week after birth, respectively. RESULTS: Urine Activin A in infants who developed IVH was significantly higher than in controls at all monitoring time-points (p < 0.01 for all), increasing progressively from first urination to 24 h when it reached the highest peak (p < 0.001). At a cut off 0.08 ng/L, at the first void, Activin A sensitivity and specificity were 68.7% (CI: 41.3-89%) and 84.5% (CI: 75-91.5%). CONCLUSION: Activin A measurements in urine soon after birth can constitute a promising tool for identifying preterm infants at risk of IVH. PMID- 23808612 TI - Assessment of relationship between self-care and fatigue and loneliness in haemodialysis patients. AB - AIMS AND OBJECTIVES: To assess the level of fatigue, self-care abilities and level of loneliness in Turkish haemodialysis patients and to determine the relationship between the level of fatigue, self-care and loneliness. BACKGROUND: Dialysis patients experience difficulties such as deterioration in physical performance and self-care abilities, fatigue and social isolation due to the disease and the treatment. DESIGN: This is a descriptive study and was conducted at two dialysis treatment centres. METHODS: The sample included 325 haemodialysis patients. Patients were selected via convenience sampling. Criteria for inclusion of patients undergoing haemodialysis treatment were those who volunteered to take part in the study, who were literate and who were over 18 years of age. Data were gathered using Patient Information Form, Visual Analog Fatigue Scale, UCLA Loneliness Scale and Self-Care Ability Scale. RESULTS: Haemodialysis patients reported high level of fatigue, low level of self-care and moderate level of loneliness. The correlation values indicated that as the levels of loneliness and fatigue increased, the self-care abilities decreased. The self-care abilities of the female patients were worse. Patients over the age of 60 years, those with low education level or patients on a low income and those with other chronic diseases had higher levels of loneliness and fatigue, and lower level of self-care. CONCLUSIONS: In this study, the level of fatigue of haemodialysis patients was high, their self-care ability was very low and their level of perceived loneliness was moderate. Furthermore, fatigue negatively affects patients' self care; the higher the patients' level of fatigue was, the lower their level of self-care. RELEVANCE TO CLINICAL PRACTICE: In order for haemodialysis patients to manage their fatigue successfully, to improve their self-care abilities and to decrease their levels of loneliness and social isolation, nurses should provide physical, social and emotional support. PMID- 23808613 TI - Effects of Ginkgo biloba extract EGb 761 (r) in dementia with neuropsychiatric features: review of recently completed randomised, controlled trials. AB - OBJECTIVE: We review four randomised, controlled trials investigating the efficacy of Ginkgo biloba extract EGb 761((r)) in elderly patients with Alzheimer or vascular dementia with neuropsychiatric features. METHODS: Patients with a total score of 9-23 in the Syndrom-Kurz test (SKT) cognitive test battery (cognitive domain) and with a composite score 6 and greater in the Neuropsychiatric Inventory (NPI; behavioural domain) were included. Three trials compared 2 * 120 mg/day or 1 * 240 mg/day EGb 761((r)) to placebo while one used donepezil as an active control. The duration of randomised treatment was 22 or 24 weeks. RESULTS: One thousand, two hundred and ninety-four patients were analysed for efficacy. Patients treated with EGb 761((r)) showed improvements of cognitive performance and behavioural symptoms that were associated with advances in activities of daily living and a reduced burden to caregivers. Placebo-treated patients, on the other hand, showed only minimal improvements or signs of progression. In each placebo-controlled trial, EGb 761((r)) was significantly superior in all mentioned domains (p < 0.01). In the actively controlled trial, EGb 761((r)) and donezepil as well as a combination of both drugs had similar effects. CONCLUSIONS: The review supports the efficacy of EGb 761((r)) in age related dementia with neuropsychiatric features. The drug was safe and well tolerated. PMID- 23808614 TI - Among a sample of Iranian students, adult attention deficit hyperactivity disorder is related to childhood ADHD, but not to age, gender, socioeconomic status, or birth order--an exploratory study. AB - OBJECTIVE: The aim of the present study was to explore the prevalence of adult attention deficit hyperactivity disorder (ADHD) in young adult Iranian students and to examine gender, birth order, socioeconomic status (SES), and history of ADHD as potential predictors of adult ADHD. METHODS: A total of 387 young adult students (mean age: 19.6 years; 66.3% females) completed the Adult ADHD Self Report Scale-V1.1 symptom checklist to assess current symptoms of ADHD and the Wender Utah Rating Scale to assess symptoms of ADHD in childhood and adolescence. Experts' ratings were based on Wender-Reimherr Interview. RESULTS: Self-rated and expert-rated prevalence rates were 16.5% and 13.4%, respectively. Past symptoms of ADHD were correlated with current symptoms. Childhood ADHD, current hyperactivity, and disorganization predicted current ADHD. CONCLUSIONS: Among a sample of Iranian students, the prevalence rates of ADHD were higher than estimated rates worldwide. Data also show child ADHD to be associated with adult ADHD; gender, age, birth order, and SES did not seem to influence current symptomatology. PMID- 23808615 TI - The effects of acute treatment with paroxetine, amitriptyline, and placebo on the equilibrium function in healthy subjects: a double-blind crossover trial. AB - OBJECTIVE: Depression is common in old age, and is treatable with antidepressants. However, antidepressants use can increase the risk of falls. Thus, we assessed the effects of antidepressants on equilibrium function using posturography. METHODS: This study recruited 10 healthy male volunteers (35.3 +/- 3.7 years). In this double-blinded, three-way crossover trial, they received acute doses of 10 mg paroxetine, 25 mg amitriptyline, and placebo. They were administered posturography at baseline and 4-h postdosing. RESULTS: At 4-h postdosing, amitriptyline significantly decreased the locus length per unit area (L/A) and increased the envelope area compared with those at baseline. Meanwhile, the total length and the locus length per time (L/T) at 4-h postdosing of amitriptyline did not show significant differences from those at baseline. After paroxetine treatment, there were no significant differences in total length, L/T, L/A, and the envelope area between baseline and 4-h postdosing. CONCLUSION: An acute dose of amitriptyline significantly decreased L/A and increased the envelope area as markers of body sway. Evaluation of equilibrium function is important for preventing the potential risk of falls and body sway after taking antidepressants. PMID- 23808616 TI - Hypericum extract WS (r) 5570 for depression--an overview. AB - OBJECTIVE: WS((r)) 5570 is a Hypericum (St. John's wort) dry extract that is available as a medicinal product in coated tablets and has a marketing authorisation for the acute treatment of mild to moderate major depression in Germany. METHODS: This article summarizes the current state of knowledge regarding the clinical efficacy and safety of WS((r)) 5570. RESULTS: In randomised, double-blind, controlled clinical trials the antidepressant effect of the drug was superior to that of the placebo and at least comparable to that of paroxetine. The beneficial effect of WS((r)) 5570 is particularly pronounced with respect to the core symptoms of depression. There is evidence that the drug may also be effective in moderate to severe depression and in prophylactic continuation treatment after recovery from an acute episode. CONCLUSIONS: WS((r)) 5570 has a very favourable safety profile, with adverse event rates on one level with placebo and lower than that of synthetic antidepressants in randomised, controlled clinical trials. It may therefore also be an option for patients who do not tolerate other antidepressant drugs. Patients with polydrug treatment should nevertheless use the drug with caution, due to its potential for interactions. PMID- 23808617 TI - Ceiling and floor effects on the Rivermead Behavioural Memory Test in patients with alcohol-related memory disorders and healthy participants. AB - OBJECTIVE: The Rivermead Behavioural Memory Test (RBMT) is a widely used measure of everyday memory performance. In the most recent revision of this test (RBMT-3) some important changes have been made compared with the RBMT. This study examines whether this revision has improved the quality of the clinical classifications using this test, as well as the frequency of floor and ceiling performances that were prominent on some subtests of the RBMT, using a heterogeneous study sample. METHODS: Twenty-five healthy adults and 25 patients with alcohol-related memory impairment (including 15 Korsakoff patients) were examined using both the RBMT and the RBMT-3. The number of perfect scores and floor performances, as well as the percentage of individuals classified as impaired (< 5th percentile), were scored and compared. RESULTS: Administration of the RBMT-3 results in less participants performing at or near individual subtest's ceiling, and resulted in less floor performances. Moreover, the RBMT-3 misclassifies less healthy participants as impaired than the RBMT. CONCLUSIONS: The RBMT-3 is a substantial improvement over the original RBMT, as it reduces the problem of ceiling and floor performances and the number of misclassifications. However, more research is needed on the ecological validity of the RBMT-3. PMID- 23808618 TI - An orally administered lavandula oil preparation (Silexan) for anxiety disorder and related conditions: an evidence based review. AB - OBJECTIVE: Silexan is a lavender oil preparation in gelatine capsules containing 80 mg. We reviewed the clinical trials investigating the anxiolytic efficacy and tolerability of Silexan as well as its safety and potential for drug interactions. METHODS: Seven trials were included, among which four therapeutic trials had a treatment duration of 6 or 10 weeks. RESULTS: In patients with subsyndromal anxiety or generalised anxiety disorder (GAD) an anxiolytic effect of Silexan was evident after 2 weeks. Patients treated with Silexan showed Hamilton Anxiety Scale (HAMA) total score decreases between 10.4 +/- 7.1 and 12.0 +/- 7.2 points at Week 6 and between 11.8 +/- 7.7 and 16.0 +/- 8.3 points at Week 10. CONCLUSIONS: HAMA total score reductions between baseline and end of treatment were significantly superior to placebo in patients with subsyndromal anxiety and comparable to lorazepam in its starting dose in patients with GAD. Silexan had beneficial effects on typical co-morbidity symptoms of anxiety disorders, for example, disturbed sleep, somatic complaints, or decreased quality of life. Except for mild gastrointestinal symptoms, the drug was devoid of adverse effects and did not cause drug interactions or withdrawal symptoms at daily doses of 80 or 160 mg. PMID- 23808619 TI - Surgery for primary intrapericardial tumors in adults. AB - Primary intrapericardial tumors in adults, whether benign or malignant are rare. Surgical treatment for these tumors are reviewed together with their incidence, classification, clinical features, and diagnosis. PMID- 23808620 TI - One common structural feature of "words" in protein sequences and human texts. AB - Frequently discussed analogy between genetic and human texts is explored by comparison of alternation of polar and non-polar amino-acid residues in proteins and alternation of consonants and vowels in human texts. In human languages, the usage of possible combinations of consonants and vowels is influenced by pronounceability of the combinations. Similarly, oligopeptide composition of proteins is influenced by requirements of protein folding and stability. One special type of structure often present in proteins is amphipathic alpha-helices in which polar and non-polar amino acids alternate with the period 3.5 residues, not unlike alternation of consonants and vowels. In this study, we evaluated the contribution made by amphipathic alternations to the protein sequence texts (20 24%). Their proportion is lower than respective values for alternating words in human texts (57-89%). The proteomes (full sets of proteins for selected organisms) were transformed into ranked sequences of n-grams (words of length n), including periodical amphipathic structures. Similarly, human texts were transformed into sequences of alternating consonants and vowels. Analysis of the vocabularies shows that in both types of texts (human languages and proteins) the alternating words are dominant or highly preferred, thus, strengthening the analogy between these two types of texts. The contribution of amphipathic words in the upper parts of the ranked lists for 10 analyzed proteomes varies between 58 and 74%. In human texts respective values range between 90 and 100%. PMID- 23808621 TI - Self-induced gate dielectric for graphene field-effect transistor. AB - We report the electronic characteristics of an avant-garde graphene-field-effect transistor (G-FETs) based on ZnO microwire as top-gate electrode with self induced dielectric layer. Surface-adsorbed oxygen is wrapped up the ZnO microwire to provide high electrostatic gate-channel capacitance. This nonconventional device structure yields an on-current of 175 MUA, on/off current ratio of 55, and a device mobility exceeding 1630 cm(2)/(V s) for holes and 1240 cm(2)/(V s) for electrons at room temperature. Self-induced gate dielectric process prevents G FETs from impurity doping and defect formation in graphene lattice and facilitates the lithographic process. Performance degradation of G-FETs can be overcome by this avant-garde device structure. PMID- 23808624 TI - Ratiometric fluorescent probes for detection of intracellular singlet oxygen. AB - We have developed a series of molecular probes for the fluorescent detection of singlet dioxygen ((1)O2). The probes, based on asymmetrically substituted 1,3 diarylisobenzofurans, undergo the [2 + 4] cycloaddition reaction with (1)O2, producing ratiometric fluorescent responses. Two-photon fluorescence microscope experiments demonstrated the biological utility of the probes for the visualization of endogenous (1)O2 in macrophage cells. PMID- 23808622 TI - Childhood psychopathology in children of women with eating disorders: understanding risk mechanisms. AB - BACKGROUND: Very few studies have investigated psychopathology in children of mothers with eating disorders (ED). We aimed to determine the effect of maternal ED on childhood psychopathology in a large population-based cohort and investigate relevant risk pathways using structural equation modeling (SEM). METHODS: Data on emotional and behavioral problems at 31/2 years were obtained prospectively on 8,622 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). Children of exposed women who self-reported lifetime anorexia nervosa (AN, N = 193) or bulimia nervosa (BN, N = 158) in pregnancy were compared with children of unexposed women (N = 8,271) using linear and logistic regression models. SEM was used to determine best-fitting risk models by child gender. RESULTS: There was evidence that girls of AN women were more likely to have emotional, conduct, and hyperactivity disorders [Odds Ratio (OR): 1.7 (95% Confidence Intervals 1.0-3.0); OR: 2.2 (1.2-4.0); OR: 1.8 (1.1-3.1), respectively] and boys of AN women to have emotional disorders compared with unexposed [OR: 2.0(1.2-3.4)]. Girls of women with BN were more likely to show hyperactivity [OR: 1.7 (1.0-3.1)]; and boys to show emotional and conduct disorders compared with unexposed [OR: 2.2 (1.2-3.9); OR: 2.4 (1.4-4.2), respectively]. SEM models showed that pregnancy anxiety and depression mediated the effect of maternal ED on child psychopathology. CONCLUSIONS: Maternal ED are associated with different childhood psychopathology outcomes in boys and girls. Pregnancy anxiety and depression and active ED symptoms are important mediators of risk and are preventable; the direct effect of maternal lifetime ED was small. PMID- 23808625 TI - Sclerotic bodies beyond nephrogenic systemic fibrosis. AB - Sclerotic bodies are round to oval structures made up of collagen with entrapped elastic fibers, which may be sometimes ossified. These bodies may be found in skin biopsies from patients with nephrogenic systemic fibrosis (NSF), a disease linked to the use of gadolinium in radiologic procedures and chronic renal failure. Sclerotic bodies have not been reported in other diseases. Herein, we report sclerotic bodies as an incidental finding in a re-excision specimen of a squamous cell carcinoma (SCC) from the forearm of an 85-year-old man with chronic renal failure. The patient had had multiple SCC removed over time. Additional clinical history revealed patient having received gadolinium in 2003 and 2004, preceding his dialysis that began in 2009. All of his excision specimens revealed sclerotic bodies in 20 of 30 specimens from 2008. None of the 26 re-excision specimens prior to gadolinium exposure had these bodies. Our findings suggest that sclerotic bodies are the result of gadolinium exposure in patients with chronic renal insufficiency. Because the bodies were found near the re-excision scar, it may be that gadolinium or its metabolites activate fibroblasts in the setting of wound healing. The reasons why this patient did not develop NSF are unclear. PMID- 23808626 TI - Versatile three-dimensional virus-based template for dye-sensitized solar cells with improved electron transport and light harvesting. AB - By genetically encoding affinity for inorganic materials into the capsid proteins of the M13 bacteriophage, the virus can act as a template for the synthesis of nanomaterial composites for use in various device applications. Herein, the M13 bacteriophage is employed to build a multifunctional and three-dimensional scaffold capable of improving both electron collection and light harvesting in dye-sensitized solar cells (DSSCs). This has been accomplished by binding gold nanoparticles (AuNPs) to the virus proteins and encapsulating the AuNP-virus complexes in TiO2 to produce a plasmon-enhanced and nanowire (NW)-based photoanode. The NW morphology exhibits an improved electron diffusion length compared to traditional nanoparticle-based DSSCs, and the AuNPs increase the light absorption of the dye-molecules through the phenomenon of localized surface plasmon resonance. Consequently, we report a virus-templated and plasmon-enhanced DSSC with an efficiency of 8.46%, which is achieved through optimizing both the NW morphology and the concentration of AuNPs loaded into the solar cells. In addition, we propose a theoretical model that predicts the experimentally observed trends of plasmon enhancement. PMID- 23808627 TI - Accrual of non-melanoma skin cancer in renal-transplant recipients: experience of a Victorian tertiary referral institution. AB - BACKGROUND: Cutaneous carcinogenesis is increased in immunosuppressed organ transplant recipients (OTR). Tumour accrual is a useful measure for the rate of cutaneous carcinogenesis. There are few studies in tumour accrual rates in OTR in Australia. METHODS: This was a prospective study of renal transplant recipients in a single tertiary referral centre over 5 years (60 months). Outcome measures included tumour accrual, and numbers of skin cancers according to clinical risk factors (age, sex, anatomical location, skin phototype, duration of immunosuppression, history of graft rejection, acitretin use, occupational sun exposure and family history of skin cancer). RESULTS: A total of 142 patients were included in the study, with a median follow-up duration of 1.9 years. Of these patients, 53 (37%) developed a total of 341 invasive non-melanoma skin cancers (NMSC) (253 squamous cell carcinoma [SCC] and 88 basal cell carcinoma [BCC]) over the study period. Accrual for SCC and BCC were 0.89 SCC/patient per year and 0.31 BCC/patient per year, respectively. The overall NMSC accrual was 1.20 NMSC/patient per year. SCC accrual increased with the duration of immunosuppression. NMSC accrual increased with a history of graft rejection. CONCLUSIONS: The current study provides prospective, histologically verified and quantitative evidence for the increase of cutaneous carcinogenesis in renal transplant recipients in Victoria, Australia. PMID- 23808629 TI - Discordant CD34+ cell results in peripheral blood and hematopoietic progenitor cell-apheresis product: implications for clinical decisions and impact on patient treatment. AB - CASE REPORT: A 50-year-old male with T-cell lymphoma presented for autologous peripheral blood stem cell transplantation. After granulocyte-colony-stimulating factor (G-CSF) mobilization, his peripheral blood CD34+ cell count was 166 * 10(6) /L on the day before collection, which predicted a high yield of CD34+ cells in the apheresis product. The first two collections had yields much lower than expected, triggering an investigation and changes to the apheresis collection methods since mobilization appeared adequate from the peripheral CD34+ values. RESULTS: Changes to the apheresis collection variables and instrumentation did not improve the yields in the next three collections. The laboratory investigation demonstrated that there was an interfering substance in the patient's plasma that was causing falsely high peripheral blood CD34+ cell values and that the low CD34+ cell yields in the collections were consistent with the actual peripheral blood CD34+ cell value. Based on this finding and after discussion with the clinical service, the patient then received plerixafor to increase the number of circulating CD34+ cells before Collections 6 and 7. The patient went on to achieve the target CD34+ cell dose and subsequently underwent a successful autologous transplant with full hematopoietic engraftment. CONCLUSION: This case demonstrates the importance of timely and critical review of laboratory results in the context of the specific patient. This case exemplifies how diligent review of laboratory results and open communication among the various teams can positively affect patient outcomes. PMID- 23808628 TI - Circadian genes differentially affect tolerance to ethanol in Drosophila. AB - BACKGROUND: There is a strong relationship between circadian rhythms and ethanol (EtOH) responses. EtOH consumption has been shown to disrupt physiological and behavioral circadian rhythms in mammals (Alcohol Clin Exp Res 2005b, 29, 1550). The Drosophila central circadian pacemaker is composed of proteins encoded by the per, tim, cyc, and Clk genes. Using Drosophila mutant analysis, we asked whether these central components of the circadian clock make the equivalent contribution toward EtOH tolerance and whether rhythmicity itself is necessary for tolerance. METHODS: We tested flies carrying mutations in core clock genes for the capacity to acquire EtOH tolerance. Tolerance was assayed by comparing the sedation curves of populations during their first and second sedation. Animals that had acquired tolerance sedated more slowly. Movement was also monitored as the flies breathe the EtOH vapor to determine if other facets of the EtOH response were affected by the mutations. Gas chromatography was used to measure internal EtOH concentration. Constant light was used to nongenetically destabilize the PER and TIM proteins. RESULTS: A group of circadian mutations, all of which eliminate circadian rhythms, do not disrupt tolerance identically. Mutations in per, tim, and cyc completely block tolerance. However, a mutation in Clk does not interfere with tolerance. Constant light also disrupts the capacity to acquire tolerance. These lines did not differ in EtOH absorption. CONCLUSIONS: Mutations affecting different parts of the intracellular circadian clock can block the capacity to acquire rapid EtOH tolerance. However, the role of circadian genes in EtOH tolerance is independent of their role in producing circadian rhythmicity. The interference in the capacity to acquire EtOH tolerance by some circadian mutations is not merely a downstream effect of a nonfunctional circadian clock; instead, these circadian genes play an independent role in EtOH tolerance. PMID- 23808630 TI - Spontaneous low pressure, low CSF volume headaches: spontaneous CSF leaks. AB - Spontaneous intracranial hypotension typically results from spontaneous cerebrospinal fluid (CSF) leak, often at spine level and only rarely from skull base. Once considered rare, it is now diagnosed far more commonly than before and is recognized as an important cause of headaches. CSF leak leads to loss of CSF volume. Considering that the skull is a rigid noncollapsible container, loss of CSF volume is typically compensated by subdural fluid collections and by increase in intracranial venous blood which, in turn, causes pachymeningeal thickening, enlarged pituitary, and engorgement of cerebral venous sinuses on magnetic resonance imaging (MRI). Another consequence of CSF hypovolemia is sinking of the brain, with descent of the cerebellar tonsils and brainstem as well as crowding of the posterior fossa noted on head MRI. The clinical consequences of these changes include headaches that are often but not always orthostatic, nausea, occasional emesis, neck and interscapular pain, cochleovestibular manifestations, cranial nerve palsies, and several other manifestations attributed to pressure upon or stretching of the cranial nerves or brain or brainstem structures. CSF lymphocytic pleocytosis or increase in CSF protein concentration is not uncommon. CSF opening pressure is often low but can be within normal limits. Stigmata of disorders of connective tissue matrix are seen in some of the patients. An epidural blood patch, once or more, targeted or distant, at one site or bilevel, has emerged as the treatment of choice for those who have failed the conservative measures. Epidural injection of fibrin glue of both blood and fibrin glue can be considered in selected cases. Surgery to stop the leak is considered when the exact site of the leak has been determined by neurodiagnostic studies and when less invasive measures have failed. Subdural hematomas sometimes complicate the CSF leaks; a rebound intracranial hypertension after successful treatment of a leak is not rare. Cerebral venous sinus thrombosis as a complication is fortunately less common, and superficial siderosis and bibrachial amyotrophy are rare. Short-term recurrences are not uncommon, and long-term recurrences are not rare. PMID- 23808631 TI - Hypomagnesemia and proton-pump inhibitors. AB - INTRODUCTION: Proton pump inhibitors (PPIs) have been linked to clinically symptomatic hypomagnesemia. AREAS COVERED: We searched Medline database in all languages using 'proton-pump inhibitors, magnesium, hypomagnesemia and hypomagnesemic hypoparathyroidism' as search terms and other articles were identified through searches of the files of the authors and reference lists from relevant articles. All patients presented with hypomagnesemic hypoparathyroidism, however, they rarely had life-threatening conditions such as malignant ventricular arrhythmias associated with prolonged QT interval, tetany and generalized seizures. Hypomagnesemia was seen with different PPIs, which could suggest a class effect, and was refractory to Mg replacement until PPIs were stopped. Hypomagnesemia may recur after re-challenge with the same or a different PPI and is not clearly dose-related. Mechanisms are poorly understood but PPI induced hypochlorhydria does not seem involved. Carriers of TRPM6/7 mutations could be at risk. EXPERT OPINION: Although mechanism and incidence rate remain unclear, there seems little doubt that PPIs may cause hypomagnesemia. We should obtain blood Mg levels prior to initiation of PPIs when patients are expected to be on treatment for long period of time and in those with other potential causes of hypomagnesemia. Use of H2-blockers may be an appropriate alternative. PMID- 23808633 TI - Electrochemical technique and copper-promoted transformations: selective hydroxylation and amination of arylboronic acids. AB - An efficient and selective electrosynthesis of phenols and anilines from arylboronic acids in aqueous ammonia is achieved in an undivided cell. By simply changing the concentration of aqueous ammonia and the anode potential, good yields of phenols and anilines can be obtained chemoselectively with high reaction rates. We propose that anodic oxidation could have played an important role in these transformations. PMID- 23808634 TI - Short-term chamber exposure to low doses of two kinds of wood smoke does not induce systemic inflammation, coagulation or oxidative stress in healthy humans. AB - INTRODUCTION: Air pollution increases the risk of cardiovascular diseases. A proposed mechanism is that local airway inflammation leads to systemic inflammation, affecting coagulation and the long-term risk of atherosclerosis. One major source of air pollution is wood burning. Here we investigate whether exposure to two kinds of wood smoke, previously shown to cause airway effects, affects biomarkers of systemic inflammation, coagulation and lipid peroxidation. METHODS: Thirteen healthy adults were exposed to filtered air followed by two sessions of wood smoke for three hours, one week apart. One session used smoke from the start-up phase of the wood-burning cycle, and the other smoke from the burn-out phase. Mean particle mass concentrations were 295 ug/m3 and 146 ug/m3, and number concentrations were 140,000/cm3 and 100,000/cm3, respectively. Biomarkers were analyzed in samples of blood and urine taken before and several times after exposure. Results after wood smoke exposure were adjusted for exposure to filtered air. RESULTS: Markers of systemic inflammation and soluble adhesion molecules did not increase after wood smoke exposure. Effects on markers of coagulation were ambiguous, with minor decreases in fibrinogen and platelet counts and mixed results concerning the coagulation factors VII and VIII. Urinary F2-isoprostane, a consistent marker of in vivo lipid peroxidation, unexpectedly decreased after wood smoke exposure. CONCLUSIONS: The effects on biomarkers of inflammation, coagulation and lipid peroxidation do not indicate an increased risk of cardiovascular diseases in healthy adults by short-term exposure to wood smoke at these moderate doses, previously shown to cause airway effects. PMID- 23808635 TI - Exposure assessment of workers in printed electronics workplace. AB - Printed electronics uses converging technologies, such as printing, fine mechanics, nanotechnology, electronics and other new technologies. Consequently, printed electronics raises additional health and safety concerns to those experienced in the traditional printing industry. This study investigated two printed electronics workplaces based on a walk-through survey and personal and area sampling. All the printed electronics operations were conducted in a cleanroom. No indication of exposure to excess silver nanoparticles or carbon nanotubes (CNTs) was found. While the organic solvents were lower than current occupational exposure limits, there was a lack of engineering controls, such as local exhaust ventilation, correct enclosure and duct connections. There was also an insufficient quantity of personal protective equipment, and some organic solvents not described in the safety data sheets (SDSs) were detected in the air samples. Plus, the cleaning work, a major emissions operation, was not conducted within a hood, and the cleaning waste was not properly disposed of. Therefore, the present exposure assessment results from two printed electronics workplaces suggest that the printed electronics industry needs to take note of the occupational safety and health risks and hazards already established by the traditional printing industry, along with new risks and hazards originating from converging technologies such as nanotechnology. PMID- 23808637 TI - Subchronic toxicity and carcinogenicity studies of 1,2-dichloropropane inhalation to mice. AB - The subchronic toxicity and carcinogenicity of 1,2-dichloropropane (DCP) in male and female B6D2F1 mice exposed to DCP by inhalation for 13 weeks or for 2 years was investigated. The DCP concentrations used were 50, 100, 200, 300 or 400 ppm (v/v) in the 13-week study, and 32, 80 or 200 ppm (v/v) in the 2-year study. Thirteen weeks inhalation exposure of mice to DCP caused death in the mice exposed to 300 ppm and above, and was found to induce hemolytic anemia and lesions of the liver, forestomach and heart. Two years exposure to DCP significantly increased the combined incidence of bronchiolo-alveolar adenomas and carcinomas in females and marginally increased the incidence of Harderian gland adenomas in males. As non-neoplastic lesion, atrophy and respiratory metaplasia in the olfactory epithelium, and respiratory metaplasia in the submucosal gland of the nasal cavity were increased. Thus, two years inhalation exposure to DCP is carcinogenic in female mice and there is a marginal evidence of carcinogenicity in males. PMID- 23808636 TI - Glutathione (GSH) and the GSH synthesis gene Gclm modulate plasma redox and vascular responses to acute diesel exhaust inhalation in mice. AB - CONTEXT: Inhalation of fine particulate matter (PM2.5) is associated with acute pulmonary inflammation and impairments in cardiovascular function. In many regions, PM2.5 is largely derived from diesel exhaust (DE), and these pathophysiological effects may be due in part to oxidative stress resulting from DE inhalation. The antioxidant glutathione (GSH) is important in limiting oxidative stress-induced vascular dysfunction. The rate-limiting enzyme in GSH synthesis is glutamate cysteine ligase and polymorphisms in its catalytic and modifier subunits (GCLC and GCLM) have been shown to influence vascular function and risk of myocardial infarction in humans. OBJECTIVE: We hypothesized that compromised de novo synthesis of GSH in Gclm-/+ mice would result in increased sensitivity to DE-induced lung inflammation and vascular effects. MATERIALS AND METHODS: WT and Gclm-/+ mice were exposed to DE via inhalation (300 MUg/m3) for 6 h. Neutrophil influx into the lungs, plasma GSH redox potential, vascular reactivity of aortic rings and aortic nitric oxide (NO*) were measured. RESULTS: DE inhalation resulted in mild bronchoalveolar neutrophil influx in both genotypes. DE-induced effects on plasma GSH oxidation and acetylcholine (ACh) relaxation of aortic rings were only observed in Gclm-/+ mice. Contrary to our hypothesis, DE exposure enhanced ACh-induced relaxation of aortic rings in Gclm /+ mice. DISCUSSION AND CONCLUSION: THESE data support the hypothesis that genetic determinants of antioxidant capacity influence the biological effects of acute inhalation of DE. However, the acute effects of DE on the vasculature may be dependent on the location and types of vessels involved. Polymorphisms in GSH synthesis genes are common in humans and further investigations into these potential gene-environment interactions are warranted. PMID- 23808639 TI - Lamivudine-PEGylated chitosan: a novel effective nanosized antiretroviral agent. AB - Due to the fact that a definite treatment for AIDS disease has not been discovered so far, antiretroviral drugs are relatively significant in controlling the disease. In this study, Lamivudine- which is an old and effective anti-AIDS drug- was connected to PEGylated chitosan nanoparticle in order to produce a new and greater version of Lamivudine. First, physicochemical studies such as HNMR, FTIR spectroscopy and CHN analysis were performed to ensure the proper synthesis. Following that, Lamivudine-PEGylated Chitosan (LPC) drug was evaluated in terms of its inhibitory capability in producing HIV virions and its cytotoxicity in different doses. HIV virions were created by transfection of psPAX2, PmzNL4-3 and pMD2.G plasmids into HEK293T cell line. Also, assessment of the P24 amounts of cell supernatant was performed using ELISA method. Among the different doses of LPC drug (0.1, 1, 10 and 100MUM), it was found that 0.1MUM was the most effective and least toxic dose compared to Lamivudine in the same dose. Results of this study indicate that LPC drug has the ability to inhibit HIV virus replication in a more significant way in comparison to the old drug. Besides, the drug has a low cytotoxicity and is effective with a lower dose. PMID- 23808632 TI - Arsenic binding to proteins. PMID- 23808640 TI - Functional and esthetic outcome after bony lateral wall decompression with orbital rim removal and additional fat resection in graves' orbitopathy with regard to the configuration of the lateral canthal region. AB - PURPOSE: To investigate whether en bloc resection of the lateral orbital wall, including the orbital rim, during lateral wall decompression surgery in patients with Graves' orbitopathy (GO) potentially influences the esthetic and functional aspects of the lateral canthal region. METHODS: Lateral wall decompression was performed in 30 orbits of 18 patients using an upper lidcrease approach involving complete removal of the lateral orbital wall combined with additional orbital fat resection. Patients undergoing surgery before January 2010 were evaluated retrospectively for exophthalmos, vertical lid aperture, lagophthalmos and eye motility. Patients undergoing surgery after January 2010 were evaluated prospectively in addition for horizontal lid aperture, pupillary distance, lateral movement of the lateral canthus, and the disease-specific GO-QOL questionnaire, including subjective and objective assessments of the appearance of the lateral canthal region. RESULTS: A mean exophthalmos reduction of 3.0 mm was achieved, accompanied by a significant reduction in vertical lid aperture but without significant influence on horizontal eye movements. GO-QOL scores disclosed significant improvements with regard to both visual and psychosocial functioning. Although 3 out of 18 patients reported some temporal hollowing, this was confirmed objectively in only one patient. CONCLUSIONS: Our analysis did not demonstrate any impairment of lateral canthal stability or motility functions. Slight scar retraction was objectively confirmed in only one patient, allaying concerns about significant temporal hollowing. Given the good overall esthetic and functional results of this surgical technique, we advocate lateral wall decompression with resection of the orbital rim in GO patients with mild-to moderate exophthalmos. PMID- 23808641 TI - Fifth-order three-dimensional electronic spectroscopy using a pump-probe configuration. AB - We present the theoretical details and experimental demonstration of fifth-order three-dimensional (3D) electronic spectroscopy using a pump-probe beam geometry. This is achieved using a pulse shaper and appropriate phase cycling schemes. We show how 8-step and 27-step phase cycling schemes can measure purely absorptive 3D spectra as well as 3D spectra for the individual fifth-order processes that contribute to the purely absorptive spectrum. 3D spectra as a function of two separate controllable waiting time periods can be obtained. The peak shapes and positions of the peaks in the experimental measurement correspond well to theory. PMID- 23808642 TI - Reliability and concurrent validity of the Palliative Outcome Scale, the Rotterdam Symptom Checklist, and the Brief Pain Inventory. AB - BACKGROUND: Some domains of the questionnaires used to measure symptoms and quality of life (QOL) in patients with advanced cancer seem to measure similar dimensions or constructs, so it would be useful for clinicians to demonstrate the interchangeability of equivalent domains of the questionnaires in measuring the same constructs. OBJECTIVE: This study investigated the reliability and concurrent validity of the Palliative Outcome Scale (POS), the Rotterdam Symptom Checklist (RSCL), and the Brief Pain Inventory (BPI), used to measure symptom control in patients with advanced cancer. DESIGN: This was an evaluative study. SETTING/SUBJECTS: Subjects were patients with advanced cancer attended by Spanish primary care physicians. MEASUREMENTS: Secondary analysis was performed of 117 outpatients who completed the POS, BPI, and RSCL at two different times, with an interval of 7 to 10 days. Bland and Altman analyses and plot, repeatability coefficient, as well as Spearman correlations were carried out. RESULTS: There were 117 included patients. Mean age was 69.4 (11.5) years, gender was 60% male, 37.6% completed only elementary school, diagnoses were mainly digestive and lung cancer, with a low functional rate and presence of oncologic pain. First and second questionnaire rounds showed significant correlations and agreement. Agreement was shown between pain intensity of BPI and pain and physical scales of RSCL, and between physical symptoms of RSCL and of POS, with significant correlations in equivalent dimensions. CONCLUSION: BPI, POS, and RSCL have shown adequate reliability and moderate concurrent validity among them. PMID- 23808643 TI - "To be a phenomenal doctor you have to be the whole package": physicians' interpersonal behaviors during difficult conversations in pediatrics. AB - BACKGROUND: Delivery of bad news is a challenging task for physicians and other health care professionals. Several studies have assessed parental perceptions of the delivery of bad news, but none have focused on the role of physicians' interpersonal behaviors in the communication process. OBJECTIVE: The study's objective was to assess parental perceptions of physicians' interpersonal behaviors and their role in communication of bad news. DESIGN: The design was a cross-sectional qualitative interview study of 13 parents of patients hospitalized or previously hospitalized in the pediatric intensive care unit or oncology/bone marrow transplant unit at an academic children's hospital. RESULTS: Eleven interpersonal behaviors were identified as important by parents. The majority of parents identified empathy in physicians as critical. Availability, treating the child as an individual, and respecting the parent's knowledge of the child were mentioned by almost half of parents. Themes also considered important but by a smaller number of parents were allowing room for hope, the importance of body language, thoroughness, going beyond the call of duty, accountability, willingness to accept being questioned, and attention to the suffering of the child. CONCLUSIONS: To increase parental satisfaction and enhance the parent physician therapeutic partnership, we recommend that physicians consider attending to the 11 interpersonal behaviors described in this manuscript, and that educational programs pay particular attention to these behaviors when training health care providers in the communication of bad news. PMID- 23808644 TI - When a desired home death does not occur: the consequences of broken promises. AB - BACKGROUND: Evidence shows that most people prefer to die at home; however, the majority of expected deaths occur away from home. Although home deaths require family caregiver (FCG) commitment and care, we understand very little about their experiences in this context. AIM: The study's aim was to gain a better understanding of the experiences of FCGs when circumstances prevented a desired home death for a family member with advanced cancer. DESIGN: An interpretive description approach was used. Data collection involved semistructured interviews. Field notes and reflective journaling aided interpretive and analytical processes. SETTING/PARTICIPANTS: The study was conducted in western Canada and included 18 bereaved FCGs. RESULTS: FCGs were committed to the promises made to care for their family member at home until death. These promises were challenged by a lack of preparedness for caregiving, difficulty accessing professional support and information, and frustration with the inadequate help they received. The events that precipitated dying family members leaving their home for hospital or hospice were unexpected and often influenced by FCGs' lack of situation-specific knowledge and ability to cope with complex caregiving responsibilities. FCGs found it extremely challenging to reconcile with breaking their promise to care at home until death and many were unable to do so. CONCLUSIONS: FCGs' despair about not being able to keep their promise for a home death was related to complicated bereavement. Prospective studies of the experiences of FCGs who are aiming for home deaths are needed to identify both short- and long-term interventions to effectively support death at home. PMID- 23808645 TI - Highly fluorescent and specific molecular probing of (homo)cysteine or superoxide: biothiol detection confirmed in living neuronal cells. AB - Chemodosimetric action in detection of cysteine and homocysteine (310- and 290 fold) and superoxide inputs (336-fold increase) gives significant fluorescence intensity increases. Detection limits of 2.13 * 10(-5) M, 1.37 * 10(-5) M, and 2.71 * 10(-5) M, respectively, are biorelevant and are consistent with "OR" logic gating, demonstrated in intracellular biothiol detection in neuronal cells by way of novel fluorescein derivatization. As per our knowledge, this is the first example of a novel fluorescent probe based on the nucleophilic substitution reaction of biothiols and superoxide through ester cleavage. PMID- 23808646 TI - Role of tyrosine residue in methane activation at the dicopper site of particulate methane monooxygenase: a density functional theory study. AB - Methane hydroxylation at the dinuclear copper site of particulate methane monooxygenase (pMMO) is studied by using density functional theory calculations. The electronic, structural, and reactivity properties of a possible dinuclear copper species (MU-oxo)(MU-hydroxo)Cu(II)Cu(III) are discussed with respect to the C-H bond activation of methane. We propose that the tyrosine residue in the second coordination sphere of the dicopper site donates an H atom to the MU eta(2):eta(2)-peroxoCu(II)Cu(II) species and the resultant (MU-oxo)(MU hydroxo)Cu(II)Cu(III) species can hydroxylate methane. This species for methane hydroxylation is more favorable in reactivity than the bis(MU-oxo)Cu(III)Cu(III) species. The H-atom transfer or proton-coupled electron transfer from the tyrosine residue can reasonably induce the O-O bond dissociation of the MU eta(2):eta(2)-peroxoCu(II)Cu(II) species to form the reactive (MU-oxo)(MU hydroxo)Cu(II)Cu(III) species, which is expected to be an active species for the conversion of methane to methanol at the dicopper site of pMMO. The rate determining step for the methane hydroxylation is the C-H cleavage, which is in good agreement with experimental KIE values reported so far. PMID- 23808647 TI - Older people's views of quality of care: a randomised controlled study of continuum of care. AB - AIMS AND OBJECTIVES: To analyse frail older people's views of quality of care when receiving a comprehensive continuum of care intervention, compared with those of people receiving the usual care (control group). The intervention included early geriatric assessment, case management, interprofessional collaboration, support for relatives and organising of care-planning meetings in older people's own homes. BACKGROUND: Prior studies indicate that tailored/individualised care planning conducted by a case manager/coordinator often led to greater satisfaction with care planning among older people. However, there is no obvious evidence of any effects of continuum of care interventions on older people's views of quality of care. DESIGN: Randomised controlled study. METHODS: Items based on a validated questionnaire were used in face-to-face interviews to assess older people's views of quality of care at three, six and 12 months after baseline. RESULTS: Older people receiving a comprehensive continuum of care intervention perceived higher quality of care on items about care planning (p <= 0.005), compared with those receiving the usual care. In addition, they had increased knowledge of whom to contact about care/service, after three and 12 months (p < 0.03). CONCLUSIONS: The study gives evidence of the advantages of a combination of components such as organising care-planning meetings in older people's own homes, case management and interprofessional teamwork. RELEVANCE TO CLINICAL PRACTICE: The results have implications for policymakers, managers and professionals in the area of health and social care for older people to meet individual needs of frail older people. PMID- 23808648 TI - Managing end-of-life decisions in critical infants: a survey of neonatologists in Cordoba, Argentina. PMID- 23808650 TI - The ward round--patient experiences and barriers to participation. AB - BACKGROUND: Patients' participation is essential to their well-being and sense of coherence, as well as to their understanding of and adherence to prescribed treatments. Ward rounds serve as a forum for sharing information between patient and caregiver. The purpose of the ward round is to obtain information and plan medical and nursing care through staff-patient communication. AIM AND OBJECTIVE: The aim and objective of this study was to investigate patients' experiences during the ward round and their ability to participate in their care. METHODOLOGICAL DESIGN AND JUSTIFICATION: The study was qualitative and descriptive in design. Fourteen inpatients at a cardiovascular ward were interviewed. Qualitative content analysis was used for the analysis. ETHICAL ISSUES AND APPROVAL: The ethics of scientific work were adhered to. Each study participant gave his/her informed consent based on verbal and written information. The study was approved by the Research Ethics Committee at Uppsala University. RESULTS: The analysis revealed one theme and three subthemes related to patients' experiences of ward rounds. The main theme was handling of information from the daily ward round while waiting for private consultation. The subthemes were making the best of the short time spent on ward rounds; encountering traditional roles and taking comfort in staff competency; and being able to choose the degree to which one participates in the decision-making process. CONCLUSIONS: Several aspects of traditional ward round routines could be improved in regard to the two-way information exchange process between caregivers and patient. Patients' and caregivers' ability to communicate their goals and the environment in which the communication occurs are of great importance. The information provided by nurses is easier to understand than that provided by physicians. The atmosphere must be open; the patient should be treated with empathy by staff; and patients' right to participate must be acknowledged by all healthcare professionals involved. PMID- 23808651 TI - Decision-making bias in assessment: the effect of aggregating objective information and anecdote. AB - INTRODUCTION: Assessment decisions increasingly rely on synthesis of information from a variety of sources. It is known that aggregation of information to make decisions is open to a number of biases. The aim of this research was to investigate bias, accuracy and confidence of assessment decision making. METHODS: The participants were consultation skills assessors. A model for incremental information was developed with participants being shown results from purposefully selected, but authentic, data from the University's final summative 10-station Objective Structured Clinical Examination (OSCE). After each piece of information, participants gave a pass-fail decision and their confidence in that choice. Following the information from 10 OSCE stations the participants were given a discordant fictional anecdote and again participants gave a pass-fail decision and their confidence. RESULTS: When there is overwhelming evidence to support a pass or fail, participants were not as confident as the data would support. Participants were less confident to make a fail decision than a pass. Despite considerable evidence from multiple results some participants altered decisions based on isolated contradictory information from an anecdote. DISCUSSION: These findings are significant in understanding decision-making. Given equivalent levels of evidence, decision makers are less confident to fail than pass and less robust information can undermine more robust information. PMID- 23808652 TI - Characterization of the covalent binding of allyl isothiocyanate to beta lactoglobulin by fluorescence quenching, equilibrium measurement, and mass spectrometry. AB - Reversible binding of small compounds through hydrophobic interactions or hydrogen bonding to food proteins (e.g. milk proteins) is a thoroughly researched topic. In contrast, covalent interactions are not well characterized. Here, we report a rare form of positive-cooperativity-linear binding of allyl isothiocyanate with beta-lactoglobulin, resulting in the cleavage of a disulfide bond of the protein. We compared three methods (i.e. fluorescence quenching, equilibrium dialysis, and headspace-water equilibrium) to characterize the binding kinetics and investigated the molecular binding by mass spectrometry. The methodologies used were found to be comparable and reproducible in the presence of high and low ligand concentrations for fluorescence quenching and equilibrium based methods respectively. PMID- 23808649 TI - Gene-environment interactions in genome-wide association studies: current approaches and new directions. AB - BACKGROUND: Complex psychiatric traits have long been thought to be the result of a combination of genetic and environmental factors, and gene-environment interactions are thought to play a crucial role in behavioral phenotypes and the susceptibility and progression of psychiatric disorders. Candidate gene studies to investigate hypothesized gene-environment interactions are now fairly common in human genetic research, and with the shift toward genome-wide association studies, genome-wide gene-environment interaction studies are beginning to emerge. METHODS: We summarize the basic ideas behind gene-environment interaction, and provide an overview of possible study designs and traditional analysis methods in the context of genome-wide analysis. We then discuss novel approaches beyond the traditional strategy of analyzing the interaction between the environmental factor and each polymorphism individually. RESULTS: Two-step filtering approaches that reduce the number of polymorphisms tested for interactions can substantially increase the power of genome-wide gene-environment studies. New analytical methods including data-mining approaches, and gene-level and pathway-level analyses, also have the capacity to improve our understanding of how complex genetic and environmental factors interact to influence psychologic and psychiatric traits. Such methods, however, have not yet been utilized much in behavioral and mental health research. CONCLUSIONS: Although methods to investigate gene-environment interactions are available, there is a need for further development and extension of these methods to identify gene environment interactions in the context of genome-wide association studies. These novel approaches need to be applied in studies of psychology and psychiatry. PMID- 23808653 TI - Generalized erythroderma and palmoplantar hyperkeratosis in a patient receiving TNF-alpha antagonist therapy. PMID- 23808654 TI - Tetralogy of fallot, dextrocardia, and situs inversus associated with total anomalous pulmonary venous return. AB - We report a 3-year-old patient with tetralogy of Fallot (TOF), dextrocardia, situs inversus (SI), and total anomalous pulmonary venous return. This combination of anomalies is extremely unusual. The management is discussed and the literature is reviewed. PMID- 23808655 TI - Polyethylenimine-impregnated resin for high CO2 adsorption: an efficient adsorbent for CO2 capture from simulated flue gas and ambient air. AB - Polyethylenimine (PEI)-impregnated resins with high CO2 adsorption capacity were successfully prepared in this study. The nonpolar resin HP20 was suitable for PEI loading to achieve high CO2 adsorption, and the optimal PEI loading was 50 wt %. On the basis of the pore-size distribution of the resin before and after PEI modification, it can be found that mesopores of <43 nm were mainly responsible for PEI loading and pores in the range of 43-68 nm were probably favorable for CO2 diffusion. The adsorbed amount of CO2 on HP20/PEI-50 decreased with increasing adsorption temperature because of the dominant role of exothermic reaction of CO2 adsorption. The adsorption of CO2 on the adsorbent was very fast, and sorption equilibrium was achieved within 6 min at 75 degrees C. HP20/PEI-50 almost kept a stable adsorption capacity for CO2 at concentrations of 15 vol % and 400 ppm in the consecutive adsorption-desorption cycles, and its adsorption capacity was 181 mg/g from pure CO2 and 99.3 mg/g from 400 ppm CO2 at 25 degrees C, higher than all PEI-modified materials reported. The high volume-based amount of CO2 adsorbed on HP20/PEI-50 (96.0 mg/cm(3) at 25 degrees C and 84.5 mg/cm(3) at 75 degrees C for pure CO2) is beneficial to reducing the required volume of the adsorption bed for CO2 capture. This spherical and stable HP20/PEI-50 adsorbent with high and fast CO2 adsorption exhibits a very promising application in CO2 capture from flue gas and ambient air. PMID- 23808656 TI - Electrochemical determination of the glass transition temperature of thin polyelectrolyte brushes at solid-liquid interfaces by impedance spectroscopy. AB - Devising strategies to assess the glass transition temperature (Tg) of polyelectrolyte assemblies at solid-electrolyte interfaces is very important to understand and rationalize the temperature-dependent behavior of polyelectrolyte films in a wide range of settings. Despite the evolving perception of the importance of measuring Tg under aqueous conditions in thin film configurations, its straightforward measurement poses a challenging situation that still remains elusive in polymer and materials science. Here, we describe a new method based on electrochemical impedance spectroscopy (EIS) to estimate the glass transition temperature of planar polyelectrolyte brushes at solid-liquid interfaces. To measure Tg, the charge transfer resistance (Rct) of a redox probe diffusing through the polyelectrolyte brush was measured, and the temperature corresponding to the discontinuous change in Rct was identified as Tg. Furthermore, we demonstrate that impedance measurements not only facilitate the estimation of Tg but also enable a reliable evaluation of the transport properties of the polymeric interface, i.e., determination of diffusion coefficients, close to the thermal transition. We consider that this approach bridges the gap between electrochemistry and the traditional tools used in polymer science and offers new opportunities to characterize the thermal behavior of complex polymeric interfaces and macromolecular assemblies. PMID- 23808657 TI - Non-antibiotic properties of tetracyclines and their clinical application in dermatology. AB - Dermatologists have used tetracyclines since the 1950s to treat disorders that do not necessarily have an infectious aetiology. Their anti-inflammatory and anti collagenase properties contribute significantly to their success in treating diseases such as rosacea and acne. This article reviews the non-antibiotic properties of tetracyclines and their clinical application in dermatology. PMID- 23808658 TI - Epidermal stem cells manipulated by pDNA-VEGF165/CYD-PEI nanoparticles loaded gelatin/beta-TCP matrix as a therapeutic agent and gene delivery vehicle for wound healing. AB - The success of gene therapy largely relies on a safe and effective gene delivery system. The objective of this study is to design a highly efficient system for the transfection of epidermal stem cells (ESCs) and investigate the transfected ESCs (TESCs) as a therapeutic agent and gene delivery reservoir for wound treatment. As a nonviral vector, beta-cyclodextrin-linked polyethylenimines (CYD PEI) was synthesized by linking beta-cyclodextrin with polyethylenimines (600 Da). Gelatin scaffold incorporating beta-tricalcium phosphate (beta-TCP) was utilized as a substrate for the culture and transfection of ESCs. With the CYD PEI/pDNA-VEGF165 polyplexes incorporated gelatin/beta-TCP scaffold based 3D transfection system, prolonged VEGF expression with a higher level was obtained at day 7 in ESCs than those in two-dimensional plates. Topical application of the TESCs significantly accelerated the skin re-epithelization, dermal collagen synthesis, and hair follicle regeneration. It also exhibited a potential in scar inhibition by regulating the distribution of different types of collagen. In contrast to ESCs, an additive capacity in stimulating angiogenesis at the wound site was observed in the TESCs. The present study provides a basis for the TESCs as a promising therapeutic agent and gene delivery reservoir for wound therapy. PMID- 23808659 TI - Hospitable archean climates simulated by a general circulation model. AB - Evidence from ancient sediments indicates that liquid water and primitive life were present during the Archean despite the faint young Sun. To date, studies of Archean climate typically utilize simplified one-dimensional models that ignore clouds and ice. Here, we use an atmospheric general circulation model coupled to a mixed-layer ocean model to simulate the climate circa 2.8 billion years ago when the Sun was 20% dimmer than it is today. Surface properties are assumed to be equal to those of the present day, while ocean heat transport varies as a function of sea ice extent. Present climate is duplicated with 0.06 bar of CO2 or alternatively with 0.02 bar of CO2 and 0.001 bar of CH4. Hot Archean climates, as implied by some isotopic reconstructions of ancient marine cherts, are unattainable even in our warmest simulation having 0.2 bar of CO2 and 0.001 bar of CH4. However, cooler climates with significant polar ice, but still dominated by open ocean, can be maintained with modest greenhouse gas amounts, posing no contradiction with CO2 constraints deduced from paleosols or with practical limitations on CH4 due to the formation of optically thick organic hazes. Our results indicate that a weak version of the faint young Sun paradox, requiring only that some portion of the planet's surface maintain liquid water, may be resolved with moderate greenhouse gas inventories. Thus, hospitable late Archean climates are easily obtained in our climate model. PMID- 23808660 TI - Global ethanol-induced enhancements of monoaminergic neurotransmission: a meta analysis study. AB - BACKGROUND: Numerous studies use in vivo microdialysis as a quantification method for studying dynamical alterations of extracellular neurotransmitter concentrations in specific brain regions of various species following acute and chronic administration of ethanol (EtOH). A major focus of these investigations is the EtOH-induced effects on the neurochemistry of forebrain regions, particularly dose-dependent neuroadaptive changes of monoamine systems. METHODS: Here, we performed a meta-analysis on published data sets of in vivo microdialysis measurements to assess the concentration-dependent effects of EtOH on monoamine levels within 19 distinct brain regions in adult rats, which were identified as major components of a neurocircuitry for modeling drug effects. In total, data sets of 210 research articles (7,407 rats) were analyzed. RESULTS: The analysis of the basal values of noradrenaline, serotonin, and dopamine in those regions indicated hardly any dependencies on gender, strain, or state of consciousness. However, the acute administrations of EtOH (intraperitoneal 0.25 to 2.5 g/kg) appear to increase the level of monoamines globally and independent of the brain sites up to 270% of the basal concentrations. Moreover, a peak time average of approximately 40 minutes suggests an optimal time interval of maximal 240 minutes length to completely study the effects of different doses of EtOH within the framework of microdialysis experiments. The analysis further revealed a positive correlation between the magnitude of increase (peak % baseline) of local extracellular monoamine concentrations and the applied doses of EtOH, while the temporal occurrence of the EtOH-induced peaks in the concentrations (peak time) was mostly negatively correlated. CONCLUSIONS: Our results provide a universal database and framework for the optimal design of future in vivo microdialysis and in silico experiments in neurochemistry and pharmacology. PMID- 23808661 TI - Gold(I)-catalyzed benz[c]azepin-4-ol synthesis by intermolecular [5 + 2] cycloaddition. AB - A gold(I)-catalyzed intermolecular formal [2 + 5] cycloaddition for the preparation of benzofused N-heterocyclic azepine products is presented. A number of benz[c]azepin-4-ol products were readily prepared in one step from easily accessible phenylpropargyl acetals and benzaldimine substrates in the presence of a gold(I) catalyst. A direct one-pot procedure from the propargyl and the respective aldehyde and amine substrates was successful as well. The reaction to access the benzofused azepines could be rationalized by a cascade reaction, including a nucleophilic benzaldimine N-attack at a highly reactive phenylpropargyl-gold(I) carbenoid complex, generated from propargyl acetal. A subsequent deauration step promotes ring closure by 1,7-electrocyclization through an intramolecular Pictet-Spengler-type reaction with the aldiminium moiety. PMID- 23808662 TI - Successful cord blood transplantation after repeated transfusions of unmobilized neutrophils in addition to antifungal treatment in an infant with chronic granulomatous disease complicated by invasive pulmonary aspergillosis. AB - BACKGROUND: Chronic granulomatous disease (CGD) is a rare inherited primary immunodeficiency that affects phagocytic cells. CGD patients are susceptible to fungal infections, especially Aspergillus infections. The management of life threatening Aspergillus infections in CGD is particularly difficult because some infections cannot be eradicated with standard antifungal treatments and, hence, result in death. CASE REPORT: A 2-week-old girl developed invasive pulmonary aspergillosis, which rapidly progressed to respiratory failure. Liposomal amphotericin B, micafungin, and voriconazole were not effective. At the age of 2 months, she was diagnosed with p67phox-deficient CGD. In addition to antifungal treatment, the patient received 21 granulocyte transfusions (GTX), which were obtained from 300- or 400-mL whole blood samples from healthy random donors who were not treated with granulocyte-colony-stimulating factor or dexamethasone. The median neutrophil count of the GTX was 1.88 * 10(8) /kg body weight. Rituximab was administered to reduce alloimmunization to human leukocyte antigens (HLA) after the eighth GTX, resulting in their absence of anti-HLA before and after cord blood transplantation (CBT). A marked improvement in her invasive pulmonary aspergillosis was achieved, although the first CBT was rejected. Complete hematopoietic recovery was obtained after the second CBT. CONCLUSION: Repeated GTX containing relatively low doses of neutrophils might be able to control severe Aspergillus infections in infants with CGD. PMID- 23808663 TI - Continuous-flow stereoselective organocatalyzed Diels-Alder reactions in a chiral catalytic "homemade" HPLC column. AB - Continuous-flow organocatalyzed Diels-Alder reactions have been performed with excellent enantioselectivity for the first time in a chiral "homemade" HPLC column, packed with silica on which a MacMillan catalyst has been supported by a straightforward immobilization procedure. The versatility of the system was also proven by running with the same column continuous-flow stereoselective reactions with three different substrates, showing that the catalytic reactor may efficiently work in continuo for more than 150 h; the regeneration of the HPLC column was also demonstrated, allowing to further extend the activity of the reactor to more than 300 operating hours. PMID- 23808665 TI - Linear and nonlinear optical properties of tris-cyclometalated phenylpyridine Ir(III) complexes incorporating pi-conjugated substituents. AB - The synthesis, luminescence, and nonlinear optical properties of a new series of Ir(ppy)3 (ppy = 2-phenylpyridine) complexes incorporating pi-extended vinyl-aryl substituents at the para positions of their pyridine rings are reported. Appropriate substitution of the pyridyl rings allows the tuning of the luminescence properties and the second-order nonlinear optical response of this unusual family of three-dimensional chromophores. Theoretical calculations were performed to evaluate the dipole moments, to gain insight into the electronic structure, and to rationalize the observed optical properties of the investigated complexes. PMID- 23808664 TI - Bcr1 plays a central role in the regulation of opaque cell filamentation in Candida albicans. AB - The human fungal pathogen Candida albicans has at least two types of morphological transitions: white to opaque cell transitions and yeast to hyphal transitions. Opaque cells have historically not been known to undergo filamentation under standard filament-inducing conditions. Here we find that Bcr1 and its downstream regulators Cup9, Nrg1 and Czf1 and the cAMP-signalling pathway control opaque cell filamentation in C. albicans. We have shown that deletion of BCR1, CUP9, NRG1 and CZF1 results in opaque cell filamentation under standard culture conditions. Disruption of BCR1 in white cells has no obvious effect on hyphal growth, suggesting that Bcr1 is an opaque-specific regulator of filamentation under the conditions tested. Moreover, inactivation of the cAMP signalling pathway or disruption of its downstream transcriptional regulators, FLO8 and EFG1, strikingly attenuates filamentation in opaque cells of the bcr1/bcr1 mutant. Deletion of HGC1, a downstream gene of the cAMP-signalling pathway encoding G1 cyclin-related protein, completely blocks opaque cell filamentation induced by inactivation of BCR1. These results demonstrate that Bcr1 regulated opaque cell filamentation is dependent on the cAMP-signalling pathway. This study establishes a link between the white-opaque switch and the yeast-filamentous growth transition in C. albicans. PMID- 23808666 TI - Sex differences in the prevalence, symptoms, and associated features of migraine, probable migraine and other severe headache: results of the American Migraine Prevalence and Prevention (AMPP) Study. AB - BACKGROUND: The strikingly higher prevalence of migraine in females compared with males is one of the hallmarks of migraine. A large global body of evidence exists on the sex differences in the prevalence of migraine with female to male ratios ranging from 2:1 to 3:1 and peaking in midlife. Some data are available on sex differences in associated symptoms, headache-related disability and impairment, and healthcare resource utilization in migraine. Few data are available on corresponding sex differences in probable migraine (PM) and other severe headache (ie, nonmigraine-spectrum severe headache). Gaining a clear understanding of sex differences in a range of severe headache disorders may help differentiate the range of headache types. Herein, we compare sexes on prevalence and a range of clinical variables for migraine, PM, and other severe headache in a large sample from the US population. METHODS: This study analyzed data from the 2004 American Migraine Prevalence and Prevention Study. Total and demographic-stratified sex specific, prevalence estimates of headache subtypes (migraine, PM, and other severe headache) are reported. Log-binomial models are used to calculate sex specific adjusted prevalence ratios and 95% confidence intervals for each across demographic strata. A smoothed sex prevalence ratio (female to male) figure is presented for migraine and PM. RESULTS: One hundred sixty-two thousand seven hundred fifty-six individuals aged 12 and older responded to the 2004 American Migraine Prevalence and Prevention Study survey (64.9% response rate). Twenty eight thousand two hundred sixty-one (17.4%) reported "severe headache" in the preceding year (23.5% of females and 10.6% of males), 11.8% met International Classification of Headache Disorders-2 criteria for migraine (17.3% of females and 5.7% of males), 4.6% met criteria for PM (5.3% of females and 3.9% of males), and 1.0% were categorized with other severe headache (0.9% of females and 1.0% of males). Sex differences were observed in the prevalence of migraine and PM, but not for other severe headache. Adjusted female to male prevalence ratios ranged from 1.48 to 3.25 across the lifetime for migraine and from 1.22 to 1.53 for PM. Sex differences were also observed in associated symptomology, aura, headache related disability, healthcare resource utilization, and diagnosis for migraine and PM. Despite higher rates of migraine diagnosis by a healthcare professional, females with migraine were less likely than males to be using preventive pharmacologic treatment for headache. CONCLUSIONS: In this large, US population sample, both migraine and PM were more common among females, but a sex difference was not observed in the prevalence of other severe headache. The sex difference in migraine and PM held true across age and for most other sociodemographic variables with the exception of race for PM. Females with migraine and PM had higher rates of most migraine symptoms, aura, greater associated impairment, and higher healthcare resource utilization than males. Corresponding sex differences were not observed among individuals with other severe headache on the majority of these comparisons. Results suggest that PM is part of the migraine spectrum whereas other severe headache types are not. Results also substantiate existing literature on sex differences in primary headaches and extend results to additional headache types and related factors. PMID- 23808667 TI - Genital psoriasis among Indians: a prospective cross-sectional study. AB - There are limited epidemiological data on genital involvement in psoriasis. In this prospective study, 852 psoriasis patients were screened of whom 100 had genital psoriasis lesions, with a prevalence rate of 11.7%. The mean duration of genital involvement was 19.3 +/- 40.9 months. In 4% of the patients, genital psoriasis was the initial presentation of disease. The commonest site of genital involvement was the scrotum followed by glans and labia, corona and prepuce. There was no significant correlation between the severity of genital involvement and overall disease severity and body mass index. Morphologically, the commonest presentation was erythematous scaly plaques followed by thin non-scaly plaques and certain rare patterns such as pseudo-candidal balanitis, pseudo-circinate balanitis, annular psoriasis and pustular psoriasis. PMID- 23808669 TI - Association between intimate partner violence and preventive screening among women. AB - BACKGROUND: Intimate partner violence (IPV) is defined as physical, sexual, or psychological harm that can be perpetrated by a former/current spouse. IPV has been linked to adverse health outcomes and risky behaviors, and victims of IPV tend to need more healthcare overall than nonvictims of IPV. The purpose of this study was to determine the association between IPV and preventive screening among women. METHODS: The study used data from eight states/territories, which collected IPV information in the 2006 and 2007 Behavioral Risk Factor Surveillance System (n=30,182). IPV and preventive screening for HIV, cervical cancer, colorectal cancer, cholesterol, and breast cancer were determined by self report. Multivariable logistic regression models provided adjusted estimates of odds ratios (aOR) and 95% confidence intervals (CI). RESULTS: Approximately one in four women reported a history of lifetime IPV. Relative to those who did not report a history of IPV, IPV victims were twice as likely to have had an HIV test (aOR: 2.34; 95% CI: 2.06 to 2.66) or a breast exam (aOR: 1.76; 95% CI: 1.37 to 2.27). IPV victims are vigilant about certain screening practices related to sexual health (HIV testing) and passive screening (breast exam) compared to active screening. CONCLUSION: The strongest association between IPV and preventive screening was seen for HIV testing, which likely reflects the women's perceived risk for HIV infection. That these women are in contact with the healthcare system provides support for recommendations for widespread adoption of IPV screening and counseling. PMID- 23808668 TI - Performing Drug Safety Research During Pregnancy and Lactation: Biomedical HIV Prevention Research as a Template. AB - Evidence-based guidance regarding use of nearly all pharmaceuticals by pregnant and lactating women is limited. Models for performing research may assist in filling these knowledge gaps. Internationally, reproductive age women are at high risk of human immunodeficiency virus (HIV) acquisition. Susceptibility to HIV infection may be increased during pregnancy, and risk of maternal-child transmission is increased with incident HIV infection during pregnancy and lactation. A multidisciplinary meeting of experts was convened at the United States National Institutes of Health to consider paradigms for drug research in pregnancy and lactation applicable to HIV prevention. This report summarizes the meeting proceedings and describes a framework for research on candidate HIV prevention agent use during pregnancy and lactation that may also have broader applications to other pharmaceutical products. PMID- 23808670 TI - Structural glycobiology of heparinase II from Pedobacter heparinus. AB - The current work presents a conformational evaluation of heparinase II (hepII) from Pedobacter heparinus, employing molecular dynamics (MD) simulations, in order to characterize the main features of the enzyme dynamics, as well as the role of the glycan and metal components on the protein scaffold. Accordingly, four systems were simulated, encompassing nonglycosylated hepII without structural ions, nonglycosylated hepII with Zn(2+), nonglycosylated hepII with Ca(2+), and glycosylated hepII with Zn(2+). The obtained data suggest a role for Zn(2+) in modulating the protein flexibility at specific loop regions. Such flexibility pattern is not properly maintained in the absence of such structural ion or when the ion is replaced by Ca(2+). Still, semiempirical calculations suggest more favorable interactions with Zn(2+). These events correlate with the experimentally reported inhibitory effect of calcium over hepII. Additionally, the glycan chain seems able to promote an additional stabilization on hepII dynamics. Taken together, these results improve our understanding of the structural and dynamical features of hepII, as well as atomic-level comprehension of previous experimental data. PMID- 23808671 TI - Mathematical modeling of the growth and coarsening of ice particles in the context of high pressure shift freezing processes. AB - High pressure shift freezing (HPSF) has been proven more beneficial for ice crystal size and shape than traditional (at atmospheric pressure) freezing.1-3 A model for growth and coarsening of ice crystals inside a frozen food sample (either at atmospheric or high pressure) is developed, and some numerical experiments are given, with which the model is validated by using experimental data. To the best of our knowledge, this is the first model suited for freezing crystallization in the context of high pressure. PMID- 23808672 TI - An exploration of illness representations and treatment beliefs in heart failure. AB - AIMS AND OBJECTIVES: To explore the beliefs patients with heart failure hold about their illness and its treatment using the common-sense model of illness cognitions and behaviour as the theoretical framework. BACKGROUND: Heart failure is a disabling condition, which has a significant impact on individuals, their families and healthcare provision. The common-sense model provides a framework within which lay beliefs about illness and its treatment can be examined. Previous studies have reported a number of misconceptions in relation to the nature of and treatment for heart failure. Inaccurate beliefs are related to limited self-care and nonadherence to medication. DESIGN: A qualitative research design was used in which thematic analysis was used to interpret interview data. METHODS: Semi-structured interviews were carried out with twelve patients with chronic heart failure in a community setting in South East England. An interview schedule based on the dimensions of the common-sense model guided data collection. Data were analysed thematically using the framework method. RESULTS: A cluster of beliefs around a chronic illness with serious consequences was found. However, patients were unable to distinguish between symptoms of heart failure, effects of medication and emotional responses to the illness. The illness was attributed to external factors, especially stressful life events. There was a strong belief in the necessity of medication coupled with the belief that the illness and its symptoms could be controlled by medication. Concerns about drug interactions and side effects were prevalent. CONCLUSIONS: This study highlights the need for nurses to explore illness representations and treatment beliefs in heart failure. Misconceptions should be corrected to influence behaviour change. RELEVANCE TO CLINICAL PRACTICE: An understanding of illness representations and treatment beliefs should enable structured interventions to be developed, which improve clinical outcomes in this population. PMID- 23808673 TI - Comparison of virtual microscopy and glass slide microscopy among dermatology residents during a simulated in-training examination. AB - BACKGROUND: Virtual microscopy is increasingly being used in dermatopathology educational settings. OBJECTIVE: The objective is to evaluate diagnostic accuracy and attitudes between virtual microscopy and traditional glass slide microscopy among dermatology residents. METHODS: A 48-question dermatopathology examination was administered to 35 dermatology residents at three different dermatology residency training sites during the 2011-2012 academic year with half (n = 24) of the questions using the gold standard of glass slide microscopy and half (n = 24) using whole, scanned virtual slides. Correct number of questions using glass slides and virtual slides was evaluated. Participants were surveyed regarding previous experience with digital slide imaging; quality, ease of use, and speed of slide review; and overall microscopy preferences. RESULTS: Overall, diagnostic accuracy was better with glass slides than virtual slides (p = 0.01). However, no statistically significant difference was found in diagnostic accuracy of first year trainees (p > 0.99) or trainees with exposure to virtual microscopy greater than two times per month (p = 0.27). There was no overall personal preference for glass slide vs. virtual microscopy. LIMITATIONS: Different cases and questions were used for glass slides and virtual microscopy. CONCLUSIONS: Diagnostic accuracy with virtual microscopy is dependent on year of residency training and prior experience with virtual microscopy. PMID- 23808675 TI - Do pi-pi stacking interactions really play a role in the magnetic coupling mechanisms of [Cu2(MU2-CH3COO)2L2(H2O)2]n+ (L = heterocyclic base, n = 0, 2) complexes? An ab initio inspection. AB - The magnetic properties of two bis-acetate binuclear copper(II) complexes, namely [Cu2(MU2-CH3COO)2(bpydiol-H)2(H2O)2] (bpydiol-H = mono deprotonated 2,2' bipyridine-3,3'-diol) and [Cu2(MU2-CH3COO)2(phen)2(H2O)2](2+) (phen = 1,10 phenantroline), is revisited using ab initio wave function-based calculations (CASSCF, DDCI). Thanks to an analysis of the magnetic exchange coupling based on localized orbitals, it is shown that, unlike stated in the original work [C. Hou et al. Dalton Trans. 2008, 5970], pi-pi interactions do not contribute to the overall antiferromagnetism character of these complexes. PMID- 23808674 TI - Amplitude-integrated electroencephalography in male newborns <30 weeks' of gestation and unfavourable neurodevelopmental outcome at three years is less mature when compared to females. AB - AIM: To investigate gender-related differences in amplitude-integrated electroencephalography (aEEG) associated with neurodevelopmental outcome at 3 years. METHODS: Preterms born <30 weeks' gestational age between 2000 and 2002 were prospectively included. aEEGs obtained within the first 2 weeks of life were classified according to aEEG composite scores - including background pattern, sleep-wake cycling (SWC) and seizure activity. Neurodevelopmental outcome was assessed at 3 years of age. RESULTS: Neurodevelopmental outcome data was available for 148 of 264 eligible infants - 64 showed a normal outcome and 84 an impaired outcome. A logistic regression model revealed a significant independent influence of IVH, analgetic/sedative/anticonvulsant medication, gestational age and gender on aEEG composite scores. Odds ratios for having an abnormal aEEG composite score within the first 2 weeks of life for 'female sex', 'no IVH', 'no medication' and 'gestational age' were calculated. aEEG did not differ between males and females with normal outcomes. In patients with abnormal outcome, however, male preterms showed more burst-suppression patterns and less SWC when compared with female preterms. CONCLUSION: Being male with an abnormal outcome at 3 years of age is reflected by a less mature early aEEG when compared with the one of females. This association is independent of IVH and medication and was less evident with increasing gestational age. PMID- 23808676 TI - Essential components of an infection prevention program for outpatient hemodialysis centers. AB - Infections are a significant complication for dialysis patients. The CDC estimates that 37,000 central line-related bloodstream infections occurred in hemodialysis patients in 2008 and dialysis-associated outbreaks of hepatitis C continue to be reported. While established hospital-based infection prevention programs have existed since the 1970s, few dialysis facilities have an established in-center program, unless the dialysis facility is hospital associated. This review focuses on essential core components required for an effective infection prevention program, extrapolating from acute-care programs and building on current dialysis guidelines and recommendations. An effective infection prevention program requires infrastructure, including leaders who place infection prevention as a top priority, active involvement from a multidisciplinary team, surveillance of outcomes and processes with feedback, staff and patient education, and consistent use of evidence-based practices. The program must be integrated into the existing Quality Assessment and Performance Improvement program. Best practice recommendations for the prevention of infection, specific to dialysis, continue to evolve as the epidemiology of dialysis-associated infections is further researched and new evidence is gathered. A review of case studies illustrates that with an effective program in place, infection prevention becomes part of the culture, reduces infection risk, and improves patient safety. PMID- 23808677 TI - The RAMP-interacting Family B G protein-coupled receptors and their specific bioactive peptides. PMID- 23808678 TI - Exploring new CGRP family peptides and their receptors in vertebrates. AB - Vertebrates have expanded their habitats from aquatic to terrestrial environments, which has accompanied the evolution of cardiovascular and osmoregulatory hormones. Specifically, mammals have developed mechanisms to maintain high blood pressure and blood volume, while extant fishes have developed hypotensive and Na-extruding mechanisms to adapt to the marine environment where they underwent a vast diversification. The CGRP family is one of the hormone systems that decrease blood pressure and blood volume. Within the CGRP family of teleost fishes, we found that adrenomedullins (AMs) have diversified and five paralogs (AM1-5) form an independent subfamily. Based on this discovery in fishes, we found AM2 and AM5 in mammals. In mammalian species that have AM2 and/or AM5, the peptides assume greater importance in the case of pathophysiological disturbances in pressure and fluid balance such as hypertension and cardiac and renal failure. In addition, novel functions of AM peptides have been suggested by the discovery of AM2 and AM5 in mammals. Current research on the CGRP family is focused on the identification of new receptors for AM2/AM5 and the establishment of AM2 knockout mice, which will enable new developments in the basic and clinical research on this intriguing hormone family. Importantly, comparative fish studies can contribute to new developments in our understanding of the function of the AM peptides. PMID- 23808679 TI - Remote site intracranial haemorrhage: a clinical series of five patients with review of literature. AB - Post-operative haematoma is a well-known complication following the intracranial surgery, the surgical site itself being the most frequent and usually results from inadequate haemostasis. Remote site intracranial haemorrhage, that is, haemorrhage occurring at a distant site from the site of craniotomy, is relatively rare and may occasionally cause significant morbidity or even mortality. Authors report a clinical series of five patients who developed remote site haemorrhage following intracranial surgery. Out of 2500 cranial surgeries performed at the authors' institute in the year 2010, only five patients developed this complication (0.002%). One of these patients developed infratentorial haematoma following supratentorial surgery and one patient developed supratentorial haematoma following infratentorial surgery. All the patients were diagnosed by CT scan in the post-operative period. Four patients were operated and made a good recovery while one patient with cerebellar haematoma rapidly deteriorated and developed brain death and hence was not operated. The pertinent literature is reviewed regarding pathophysiology and management of this rare condition. PMID- 23808680 TI - Use of robot-guided stereotactic placement of intracerebral electrodes for investigation of focal epilepsy: initial experience in the UK. AB - We describe the operative technique and our preliminary experience with use of the Renishaw neuromate((r)) stereotactic robot to implant depth electrodes for investigation of focal epilepsy in the UK. Conventional electrocorticography involving a craniotomy and implantation of grids of electrodes directly onto the brain surface is invasive and carries a high risk of major complications such as acute subdural haematoma and infection. Robot-guided depth electrodes implantation for stereotactic electroencephalography is a less invasive technique that allows accurate implantation of multiple deep brain electrodes along predefined trajectories, and has not been associated with any major surgical complications in our initial experience. PMID- 23808681 TI - Quality of life, effort and disturbance perceived in noise: a comparison between employees with aided hearing impairment and normal hearing. AB - OBJECTIVES: The aims were to compare health-related quality of life (HRQOL) and hearing handicap between two groups of employees with normal hearing and aided hearing impairment (HI). HRQOL was also compared to a normative population. The second aim was to compare perceived effort (PE) and disturbance after completing a task in office noise between the two study groups. DESIGN: A Swedish version of the short form-36 (SF-36) and the hearing handicap inventory for adults (HHIA) was used to determine HRQOL and hearing handicap. The Borg-CR 10 scale was used to measure PE and disturbance. STUDY SAMPLE: Hearing impaired (n = 20) and normally hearing (n = 20) participants. The normative sample comprised of 597 matched respondents. RESULTS: Hearing-impaired employees report relatively good HRQOL in relation to the normative population, but significantly lower physical functioning and higher PE than their normally-hearing peers in noise. Results from the HHIA showed mild self-perceived hearing handicap. CONCLUSIONS: The current results demonstrate that physical health status can be negatively affected even at a mild-moderate severity of HI, and that a higher PE is reported from this group when performing a task in noise, despite the regular use of hearing aids. PMID- 23808682 TI - Detectability of newborn chirp-evoked ABR in the frequency domain at different stimulus rates. AB - OBJECTIVE: The present paper reports the results of a study on a group of newborns whose chirp-evoked auditory brainstem responses (ABR) were recorded at different repetition rates. The study was aimed at finding an optimum repetition rate for the chirp stimulus that facilitates a short response detection time in the frequency domain. DESIGN: Chirp-evoked ABR were recorded at six different stimulation rates between 20/s and 100/s. The stimulation level was 35 dB nHL. The mean harmonic related SNR was calculated, and the response detection time and rate were assessed using a detection algorithm. STUDY SAMPLE: A group of 80 sleeping and 27 awake newborns with normal hearing were included. RESULTS: The highest mean harmonic-related SNR in both groups was found at 60/s. The signal-to noise ratio (SNR) was significantly smaller for the awake newborns. A significantly shorter detection time can be achieved for both newborn groups at 60/s compared to the other rates tested. Response detection in the group of awake newborns profited more from the change to 60/s compared to the sleeping newborns. CONCLUSIONS: It can be expected that with this optimized stimulus paradigm a shorter test time and a higher specificity of the hearing screening can be reached. PMID- 23808683 TI - Recent advances in the chemistry of hydrogen trioxide (HOOOH). PMID- 23808684 TI - Difficulty giving feedback on underperformance undermines the educational value of multi-source feedback. AB - BACKGROUND: Multi-source feedback (MSF) was intended to provide both a summative and formative assessment of doctors' attitudes and behaviours. AIMS: To explore the influences of feedback quality and trainees' acceptance of the assessment on formative educational gains from MSF. METHODS: Semi-structured interviews were conducted with a convenience sample of eight dermatology trainees, from an insider researcher position, following two pilot interviews. Interviews were manually transcribed and coded to permit template analysis, a subtype of thematic analysis. RESULTS: The interview data indicated that MSF provides relatively little formative educational gains largely because of a paucity of constructive feedback on sub-optimal performance. This was due to difficulties encountered by raters giving developmental feedback, in particular, potential loss of anonymity, and by trainees selecting raters expected to give favourable comments. Dual use of MSF as a summative assessment in annual appraisals also inhibited educational gains by promotion of a 'tick box' mentality in which trainees' need to pass their assessment superseded their desire for self-improvement. CONCLUSIONS: A relative lack of developmental feedback limits the formative educational gains from MSF and could provide false reassurance that might reinforce negative behaviours. PMID- 23808685 TI - Matrix removal of labyrinthine fistulae by non-suction technique with intraoperative dexamethasone injection. AB - CONCLUSION: Matrix removal by a non-suction technique with intraoperative dexamethasone injection is a safe and effective management modality, regardless of fistula size. OBJECTIVE: Our goal was to evaluate the outcome of hearing treated by non-suction technique with intraoperative dexamethasone injection. METHODS: This was a retrospective chart review of 720 mastoidectomy cases for cholesteatoma, performed at our tertiary otolaryngologic care centers between 2005 and 2012. A total of 17 patients with a unilateral labyrinthine fistula were encountered. RESULTS: There was no recurrent cholesteatoma in any of the patients. In all cases, the matrix was removed by intraoperative dexamethasone injection with a bimanual non-suction technique, regardless of the fistula size. None of the patients showed deteriorated bone conduction (BC). Averaged BC was unchanged (n = 13) or improved (n = 4) in all patients and did not decrease by 10 dB more in any patient. The mean threshold of postoperative BC was significantly improved compared with preoperative mean threshold. Fistulae on the preoperative CT scans ranged from 1.41 to 7.12 mm and averaged 2.89 mm. There was no correlation between the fistula size and the postoperative BC level. Even with a large fistula, postoperative hearing preservation was possible with one-stage matrix removal. PMID- 23808686 TI - In vitro constitution of esophageal muscle tissue with endocyclic and exolongitudinal patterns. AB - Smooth muscle tissue is the main functional structure of the esophagus and comprises of the endocircular and exolongitudinal muscle layers. To construct a tissue engineered smooth muscle by mimicking the esophageal muscle tissue, we have designed a silicon wafer where a daughter mold was prepared using soft PDMS. The daughter mold was, in turn, casted with poly(ester urethane) (PU) solution to fabricate the tissue scaffolds. The casted PU scaffolds were available in two configurations. Prototype 1 (P1) have microchannels of 100 MUm width and discontinuous channel wall with gaps of 30 MUm at regular intervals. Prototype 2 (P2) have microchannels of 200 MUm width and continuous channel walls. The wall thickness and depth of the microchannels are 30 MUm. A tubular scaffold with micropattern P1 in the lumen and micropattern P2 on the exterior was fabricated with the aim of regenerating muscle tissue with endocircular and exolongitudinal muscle architecture. After grafting with natural silk fibroin (SF), the PU micropatterned scaffold demonstrated the ability to promote smooth muscle cell (SMC) growth and differentiation; differentiation is believed to contribute to maintain the contractile function of SMCs. Results from the preliminary in vivo test revealed that the tubular scaffold patterned with microchannels is capable of supporting esophageal muscle regeneration. PMID- 23808687 TI - T-wave morphology in a model of paced action potential duration alternans. PMID- 23808688 TI - Muscle development in the bamboo sole Heteromycteris japonicus with special reference to larval branchial levators. AB - Muscle development in the bamboo sole Heteromycteris japonicus was investigated, focusing primarily on the cranial muscles, using an improved whole mount immunohistochemical staining method with potassium hydroxide, hydrogen peroxide and trypsin. Larvae of H. japonicus had branchial levators, but not all of them were retained in adults, a condition also seen in the Japanese flounder Paralichthys olivaceus. In particular, larval branchial levators II and III disappeared during development, while I and IV remained to become the levator internus I and levator posterior, which were well-defined muscles in adults. In place of the atrophied muscles, levatores externi and levator internus II developed and regulated the branchial arches. The results showed that the muscle composition in the dorsal branchial arches changed to the adult form before metamorphosis in H. japonicus, as seen in P. olivaceus, and this transformation may be common to all members of that group. PMID- 23808689 TI - Geometric morphometrics as a tool for identifying emperor fish (Lethrinidae) larvae and juveniles. AB - The aim of this study was to evaluate the efficiency of geometric morphometrics for describing the body shape of fish larvae and juveniles, and identifying them to species, in comparison with traditional linear measurements. Species of emperor fishes (Perciformes: Lethrinidae, genus Lethrinus) were chosen as the model group, as the late larval and early juvenile stages in this genus are particularly difficult to identify. Forty-five individuals of different species of Lethrinus were collected from the south-western lagoon of New Caledonia between May 2005 and March 2006. The individuals were first identified to species by their partial cytochrome-b gene sequence. They were then morphologically characterized using eight linear measurements and 23 landmarks recorded on digital photographs. Except for a small proportion of individuals, geometric morphometrics gave better results to distinguish the different species than linear measurements. A 'leave one out' approach confirmed the nearly total discrimination of recently settled Lethrinus genivittatus and Lethrinus nebulosus, whereas traditional identification keys failed to distinguish them. Therefore, geometric morphometrics is a promising tool for identifying fish larvae and juveniles to species. An effective approach would require building image databases of voucher specimens associated with their DNA barcodes. These images could be downloaded by the operator and processed with the specimens to be identified. PMID- 23808690 TI - Five in situ observations of live oarfish Regalecus glesne (Regalecidae) by remotely operated vehicles in the oceanic waters of the northern Gulf of Mexico. AB - As part of the SERPENT Project, five observations of apparently healthy oarfish Regalecus glesne by remotely operated vehicles are reported from the northern Gulf of Mexico. Regalecus glesne were observed between 2008 and 2011 at depths from within the epipelagic and mesopelagic zones. These observations include the deepest verified record of R. glesne (463-492 m) and the first record of an arthropod ectoparasite (isopod). PMID- 23808691 TI - Diet and feeding selectivity of a benthivorous fish in streams: responses to the effects of urbanization. AB - This study evaluated the diet and feeding selectivity of the catfish Imparfinis mirini in streams with different degrees of urbanization and the effect of rainfall on the availability of prey. The diet was based especially on Chironomidae and Trichoptera. Significant spatial differences in diet were found between the streams; the diet of the fish was similar in the rural and peri-urban streams, and differed from that in the urban stream. Seasonality was an unimportant factor affecting the species' diet, which did not differ significantly between the rainy and dry periods in any of the streams. Fish from the urban stream fed more according to what was available in the environment, while fish from the peri-urban and rural streams showed higher degrees of selectivity. The results indicate that environmental conditions influenced the diet and prey selection of this species in response to the differences in diversity and abundance of the food organisms. They indicate that trophic studies of benthivorous fishes, such as I. mirini, may represent an alternative way to assess human effects on streams. PMID- 23808692 TI - Comparative morphology of pre-extrusion larvae, Sebastes mentella and Sebastes norvegicus (Pisces: Sebastidae) in Icelandic waters. AB - This study evaluated potential differences in morphology of unextruded larvae from Sebastes mentella and Sebastes norvegicus in Icelandic waters. Fifty-four larvae of each species were measured, and 18 measurements were recorded for each specimen (morphometric, meristic and pigmentation patterns). Pre-extrusion larvae of S. norvegicus were longer than those of S. mentella. Additionally, there were significant differences in morphometric, meristic and pigmentation characters between pre-extrusion larvae of these species. Pigmentation of S. mentella differed from that of S. norvegicus in several aspects. Dorsal and ventral body pigmentation tended to begin more posteriorly in S. mentella, therefore, the overall length of these pigmented areas tended to be longer in S. norvegicus. PMID- 23808693 TI - Review of the Acanthopagrus latus complex (Perciformes: Sparidae) with descriptions of three new species from the Indo-West Pacific Ocean. AB - Acanthopagrus latus, long considered a single valid Indo-West Pacific Ocean species, characterized by having yellow pelvic, anal and caudal fins, is reviewed and separated into A. latus (east Asian shelf) and Acanthopagrus longispinnis (Bengal Bay), and three new species: Acanthopagrus morrisoni sp. nov. (north western Australia), Acanthopagrus arabicus sp. nov. [Middle East (except for the Red Sea) to coasts of Iran and Pakistan, and western Indian coast] and Acanthopagrus sheim sp. nov. (The Gulf). Although A. latus as redefined considerably varies in morphology and colouration, it can be recognized as a discrete east Asian endemic, with the following nominal species being junior synonyms: Chrysophrys auripes, Chrysophrys xanthopoda, Chrysophrys rubroptera and Sparus chrysopterus. Chrysophrys novaecaledoniae, known only from the holotype (type locality: Noumea, New Caledonia), is a questionable junior synonym of A. latus, the lack of subsequent collections suggesting that the type locality is erroneous. Acanthopagrus longispinnis is differentiated from the other species in the complex by consistently having 12 dorsal-fin spines and a much larger second anal-fin spine, 21-26% (mean 23%) of standard length (LS ) (v. 14-24%, mean 18 21% in the other four species). Acanthopagrus morrisoni sp. nov. has the entire caudal fin yellow with a wide black posterior margin (persisting in preserved specimens) and consistently 3 1/2 scale rows between the fifth dorsal-fin spine base and the lateral line. Acanthopagrus sheim sp. nov. has the pelvic, anal and lower caudal fins vivid yellow, with two (rarely three) small black blotches on the lower inter-radial membranes between the spinous and soft dorsal-fin rays. Acanthopagrus arabicus sp. nov. consistently has 4 1/2 scale rows between the fifth dorsal-fin spine base and the lateral line, whereas A. latus always has black streaks proximally on the inter-radial membranes between the yellow anal fin rays. A neotype and lectotye, respectively, are designated for A. latus and A. longispinnis. The p-distance (net nucleotide substitutions per site) of partial mitochondrial 16s ribosomal RNA genes (538 bp) among the above species (except A. longispinnis) and three other congeners (Acanthopagrus berda, Acanthopagrus pacificus and Acanthopagrus bifasciatus) strongly indicates that each is a distinct species. A key is provided for the 20 species of Acanthopagrus currently known from the Indo-West Pacific Ocean. PMID- 23808694 TI - Can backcalculation models unravel complex larval growth histories in a tropical freshwater fish? AB - This experimental study compared the precision and accuracy of the biological intercept (BI), modified fry (MF) and time-varying growth (TVG) backcalculation models in estimating the early growth of the tropical freshwater purple-spotted gudgeon Mogurnda adspersa. Larvae were reared up to 41 days post hatching under two temperatures and four different feeding regimes. Food and temperature treatments induced complex growth profiles among fish, and although total length (LT ) and otolith radius were related under all conditions, some uncoupling was evident in the otolith-somatic-growth (OSG) relationship of fish subjected to periods of changing food availability. Furthermore, otolith growth was found to be significantly influenced by temperature, but not by food availability. Analysis of backcalculation residuals by linear mixed effects modelling revealed that BI and TVG were equally precise in predicting somatic growth, with the highest accuracy provided by TVG. The performance of all the three models declined as the OSG relationship weakened under low-food conditions, with maximum errors estimated to be 39, 60 and 36% of observed LT for the BI, MF and TVG models, respectively. The need for careful validation of backcalculation models is emphasized when examining fishes subjected to variable environmental conditions, and when exploring the differential influence of temperature and food on fish LT and otolith growth. PMID- 23808695 TI - Genetic divergence of a sympatric lake-resident-anadromous three-spined stickleback Gasterosteus aculeatus species pair. AB - The genetic relationship between sympatric, morphologically divergent populations of anadromous and lake-resident three-spined stickleback Gasterosteus aculeatus in the Jim Creek drainage of Cook Inlet, Alaska, was examined using microsatellite loci and mitochondrial d-loop sequence data. Resident samples differed substantially from sympatric anadromous samples in the Jim Creek drainage with the magnitude of the genetic divergence being similar to that between allopatric resident and anadromous populations in other areas. Resident samples were genetically similar within the Jim Creek drainage, as were the anadromous samples surveyed. Neighbour-joining and Structure cluster analysis grouped the samples into four genetic clusters by ecomorph (anadromous v. all resident) and geographic location of the resident samples (Jim Creek, Mat-Su and Kenai). There was no evidence of hybridization between resident and anadromous G. aculeatus in the Jim Creek drainage, which thus appear to be reproductively isolated. PMID- 23808696 TI - Comparative morphology of the egg cases of Asymbolus analis, Asymbolus rubiginosus and Figaro boardmani (Carcharhiniformes: Scyliorhinidae) from southern Queensland, Australia. AB - Descriptions of the egg cases of three catsharks, Asymbolus analis, Asymbolus rubiginosus and Figaro boardmani, are provided from 65 egg cases obtained from fishing surveys carried out on the continental shelf of southern Queensland, Australia. Egg cases of A. analis, A. rubiginosus and F. boardmani have the same basic morphology; they are typically vase-shaped, dorso-ventrally flattened and yellow and brown-tan in colour. The shape of the posterior border in terms of horn length and tendril thickness is the specific characteristic discriminating these three catsharks: enclosed horns in F. boardmani, short horns and tendrils in A. rubiginosus and long, coiled tendrils in A. analis. A non-parametric statistical approach was used as an exploratory tool for egg case identification in which six proportional measurements were sufficient to discriminate between species. Three egg cases of F. boardmani were recovered from the stomachs of three A. rubiginosus, which provided the first evidence of catshark-catshark predator-prey interaction. PMID- 23808697 TI - Comparative life histories of fishes in the genus Phallichthys (Pisces: Poeciliidae). AB - This study presents a description of the life histories of all four species of the genus Phallichthys, found primarily in the Atlantic slope of Central America (ranging from northern Panama to Mexico), based on a combination of data collected from preserved and living specimens. All species produced a single litter of offspring before developing another brood (i.e. no superfoetation). In the laboratory, the mean time interval between successive litters ranged from 24 to 48 days, further suggesting that they lack superfoetation. Embryos lose from 15 to 65% of their dry mass during development, meaning all or the large majority of resources required for development are provided prior to fertilization (lecithotrophy). All mature male size distributions were platykurtotic and appeared either bimodal or multimodal. Multimodal and skewed size distributions have been associated with genetic polymorphisms for size at maturity in other species of Poeciliidae. As the sister clade to Phallichthys includes genera in which all species have superfoetation (Neoheterandria and Poeciliopsis), these results suggest that their common ancestor with Phallichthys also had superfoetation and that the trait has been lost. PMID- 23808698 TI - Effects of intrinsic and extrinsic factors on the diet of Bathyraja macloviana, a benthophagous skate. AB - The effects of intrinsic (sex, maturity stage and body size) and extrinsic (depth and region) factors on the diet of Bathyraja macloviana, in the south-west Atlantic Ocean, were evaluated using a multiple-hypothesis modelling approach. Bathyraja macloviana fed mainly on polychaetes followed by amphipods, isopods and decapods. Effects of intrinsic and extrinsic factors on diet composition of this species were found. The consumption of polychaetes had a humped relationship with total length (L(T), and isopods and decapods increased with increasing L(T). Immature individuals preyed on amphipods more heavily than mature individuals. Furthermore, region and depth had an important effect on the consumption of isopods, decapods and amphipods. Such ontogenetic changes and spatial patterns may provide insights into understanding the regulatory mechanisms of marine communities. PMID- 23808699 TI - Diel vertical migration of adult Pacific cod Gadus macrocephalus in Alaska. AB - The diel vertical migration (DVM) of Pacific cod Gadus macrocephalus was examined using depth and temperature data from 250 recaptured archival tags deployed on G. macrocephalus in the eastern Bering Sea and in the Gulf of Alaska near Kodiak Island. DVM of two types, deeper during daytime (type I) and deeper during night time (type II), occurred frequently (15-40% of all days) in G. macrocephalus released at all sites. Most individuals displayed both diel types, with each type of behaviour lasting up to 58 contiguous days, and day and night depth differences averaging c. 8 m. Despite high among-individual variability, the occurrence of DVM varied significantly with the release site, season (i.e. day-of year) and bottom depth, with the trend in seasonal occurrence nearly opposite for type I compared to type II DVM. No significance could be attributed to G. macrocephalus fork length, sex or ambient (tag) temperature. Trends in the magnitude of G. macrocephalus depth change were observed, with increased movement often occurring during night-time, dawn and dusk, and at release sites where the bathymetry was more complex. Both type I and type II DVMs were attributed to foraging on prey species that also undergo DVM, and increased vertical movements of G. macrocephalus during crepuscular and night-time periods were attributed to more active foraging during dim-light conditions when G. macrocephalus can potentially exploit a sensory advantage over some of their prey. PMID- 23808700 TI - Low oxygen tolerance of different life stages of temperate freshwater fish species. AB - Data on low dissolved oxygen (DO2) tolerance of freshwater fish species of north western Europe were used to create species sensitivity distributions (SSD). Lowest observed effect concentrations (LOEC) and 100% lethal concentrations (LC100) data were collected from the scientific literature. Comparisons were made among life stages as well as between native and exotic species. In addition, lethal DO2 concentrations were compared to oxygen concentrations corresponding to maximum tolerable water temperatures of the same species. Fish eggs and embryos were the least tolerant. Juveniles had a significantly lower mean LOEC than adults, but there was no difference in mean LC100 between the two groups. The difference in lethal oxygen concentrations between adults and juveniles was largest for three salmonids, although it remains uncertain if this was a result of smoltification. There were no significant differences between native and exotic species; however, data on exotics are limited. DO2 concentrations converted from maximum tolerable water temperatures were 3.9 times higher than the measured lethal DO2 concentrations, which may reflect changes in respiration rates (Q10) and may also relate to the simplicity of the model used. PMID- 23808701 TI - Consistent behavioural traits and behavioural syndromes in pairs of the false clown anemonefish Amphiprion ocellaris. AB - Using the social clown anemonefish Amphiprion ocellaris, whether individuals exhibited consistency in activity levels, boldness and sociability in a paired context, and whether these three behavioural traits were positively correlated within a single behavioural syndrome, was investigated. The results highlight that consistent individual differences in behaviour are expressed in a social fish and suggest that consistent behavioural traits and behavioural syndromes could influence the structure and functioning of their societies. PMID- 23808702 TI - The relationship between emergence from spawning gravel and growth in farmed rainbow trout Oncorhynchus mykiss. AB - The relationship between the timing of emergence from spawning gravel and growth after emergence was investigated in farmed Oncorhynchus mykiss. A relationship between the time of emergence and growth became evident after 6 months of rearing, where individuals with an intermediate emergence time had grown larger compared with early and late emerging individuals. PMID- 23808703 TI - Behavioural cues of reproductive status in seahorses Hippocampus abdominalis. AB - A method is described to assess the reproductive status of male Hippocampus abdominalis on the basis of behavioural traits. The non-invasive nature of this technique minimizes handling stress and reduces sampling requirements for experimental work. It represents a useful tool to assist researchers in sample collection for studies of reproduction and development in viviparous syngnathids, which are emerging as important model species. PMID- 23808704 TI - Copper-catalyzed direct C-H trifluoromethylation of quinones. AB - An efficient and practical methodology has been developed to introduce the CF3 group onto quinones through Cu(I)-catalyzed direct C-H trifluoromethylation of quinones. PMID- 23808706 TI - Endometrial polyps associated with endometrial hyperplasia in an obese bonnet monkey (Macaca radiata): a case report. AB - BACKGROUND: A 10-year-old, female bonnet monkey (Macaca radiata) showed abnormal menstrual cycle length with heavy menstrual bleeding for 6-8 days. METHODS: Uterine ultrasound and histological examinations of endometrium by endometrial biopsy. RESULTS: An ultrasound examination of the uterine cavity showed presence of an enlarged polypoid mass. Further endometrial histology confirmed the presence of simple endometrial hyperplasia. CONCLUSIONS: We report for the first time that endometrial polyp is associated with endometrial hyperplasia in obese bonnet monkey. PMID- 23808705 TI - A surface-exposed neuraminidase affects complement resistance and virulence of the oral spirochaete Treponema denticola. AB - Neuraminidases (sialidases) catalyse the removal of terminal sialic acid from glycoconjugates. Bacterial pathogens often utilize neuraminidases to scavenge host sialic acid, which can be utilized either as a nutrient or as a decorating molecule to disguise themselves from host immune attacks. Herein, a putative neuraminidase (TDE0471) was identified in Treponema denticola, an oral spirochaete associated with human periodontitis. TDE0471 is a cell surface exposed exo-neuraminidase that removes sialic acid from human serum proteins; it is required for T.denticola to grow in a medium that mimics gingival crevice fluid, suggesting that the spirochaete may use sialic acid as a nutrient in vivo. TDE0471 protects T.denticola from serum killing by preventing the deposition of membrane attack complexes on the bacterial cell surface. Animal studies revealed that a TDE0471-deficient mutant is less virulent than its parental wild-type strain in BALB/C mice. However, it causes a level of tissue damage similar to the wild type in complement-deficient B6.129S4-C3(tm1) (Crr) /J mice albeit the damage caused by both bacterial strains is more severe in these transgenic mice. Based on these results, we propose that T.denticola has evolved a strategy to scavenge host sialic acid using its neuraminidase, which allows the spirochaete to acquire nutrients and evade complement killing. PMID- 23808708 TI - Is a potential Alzheimer's therapy already in use for other conditions? Can medications for hypertension, diabetes and acne help with the symptoms? AB - There is an urgent need to develop and evaluate more effective pharmacological treatments for Alzheimer's disease (AD). This editorial explores the avenue of drug repositioning and outlines a number of existing treatments that show great promise as therapies, in addition to discussing the potential for high-throughput drug discovery techniques in this important field. PMID- 23808707 TI - pH-evoked dural afferent signaling is mediated by ASIC3 and is sensitized by mast cell mediators. AB - BACKGROUND: Prior studies have shown that decreased meningeal pH activates dural afferents via opening of acid-sensing ion channels (ASICs), suggesting one pathophysiological mechanism for the generation of headaches. The studies described here further examined the ASIC subtype mediating pH-induced dural afferent activation and examined whether sensitization influences pH responses. OBJECTIVE: Given the potential importance of meningeal mast cells to headache, the goal of this study was to evaluate dural afferent responses to pH following sensitization with mast cell mediators. METHODS: Cutaneous allodynia was measured in rats following stimulation of the dura with decreased pH alone or in combination with mast cell mediators. Trigeminal ganglion neurons retrogradely labeled from the dura were stained with an ASIC3 antibody using immunohistochemistry. Current and action potentials evoked by changes in pH alone or in combination with mast cell mediators were measured in retrogradely labeled dural afferents using patch-clamp electrophysiology. RESULTS: pH-sensitive dural afferents generated currents in response to the ASIC3 activator 2-guanidine-4 methylquinazoline (GMQ), approximately 80% of these neurons express ASIC3 protein, and pH-evoked behavioral responses were inhibited by the ASIC3 blocker APETx2. Following exposure to mast cell mediators, dural afferents exhibited increased pH-evoked excitability, and cutaneous allodynia was observed at higher pH than with pH stimuli alone. CONCLUSIONS: These data indicate that the predominant ASIC subtype responding to decreased meningeal pH is ASIC3. Additionally, they demonstrate that in the presence of inflammation, dural afferents respond to even smaller decreases in pH providing further support for the ability of small pH changes within the meninges to initiate afferent input leading to headache. PMID- 23808709 TI - Bull's-eye pattern in miliaria rubra. PMID- 23808710 TI - Pterostilbene: Biomedical applications. AB - Resveratrol and its naturally dimethylated analog, pterostilbene, show similar biological activities. However, the higher in vivo bioavailability of pterostilbene represents a fundamental advantage. The main focus of this review is on biomedical applications of pterostilbene. The metabolism and pharmacokinetics of this stilbene in inflammatory dermatoses and photoprotection, cancer prevention and therapy, insulin sensitivity, blood glycemia and lipid levels, cardiovascular diseases, aging, and memory and cognition are addressed. Safety and toxicity, as well as recommendations for future research and biomedical uses, are discussed. This review includes comparisons between pterostilbene and other polyphenols, with particular emphasis on resveratrol. Potential benefits of using combinations of different polyphenols are considered. Based on present evidences we conclude that pterostilbene is an active phytonutrient and also a potential drug with multiple biomedical applications. PMID- 23808711 TI - Attitudes of emergency department patients about handover at the bedside. AB - AIMS AND OBJECTIVES: To explore patients' perspectives of bedside handover by nurses in the emergency department (ED). BACKGROUND: International guidelines promote standardisation in clinical handover. Poor handover can lead to adverse incidents and expose patients to harm. Studies have shown that nurses and patients have favourable opinions about handover that is conducted at the bedside in hospital wards; however, there is a lack of evidence for patients' perspective of nursing handover in the ED environment. DESIGN: Qualitative descriptive study. METHODS: Semi-structured interviews with 30 ED patients occurred within one hour of bedside handover. Data were analysed using thematic content analysis. RESULTS: Two main themes were identified in the data. First, patients perceive that participating in bedside handover enhances individual care. It provides the opportunity for patients to clarify discrepancies and to contribute further information during the handover process, and is valued by patients. Patients are reassured about the competence of nurses and continuum of care after hearing handover conversations. Second, maintaining privacy and confidentiality during bedside handover is important for patients. Preference was expressed for handover to be conducted in the ED cubicle area to protect privacy of patient information and for discretion to be used with sensitive or new information. CONCLUSIONS: Bedside handover is an acceptable method of performing handover for patients in the ED who value the opportunity to contribute and clarify information, and are reassured that their information is communicated in a private location. RELEVANCE TO CLINICAL PRACTICE: From the patients' perspective, nursing handover that is performed at the bedside enhances the quality and continuum of care and maintains privacy and confidentiality of information. Nurses should use discretion when dealing with sensitive or new patient information. PMID- 23808712 TI - NMR-based structure of anticancer drug mitoxantrone stacked with terminal base pair of DNA hexamer sequence d-(ATCGAT)2. AB - Mitoxantrone is a promising antitumor drug having considerably reduced cardiotoxicity as compared to anthracyclines. Its binding to deoxyhexanucleotides sequence d-(ATCGAT)2 has been studied by proton and phosphorous-31 nuclear magnetic resonance spectroscopy. The stoichiometry reveals that 1:1 and 2:1 mitoxantrone-d(ATCGAT)2 complexes are formed in solution. Significant upfield shifts in 6H/7H, 2H/3H, 11NH, and 12NH protons (~.5 ppm) of mitoxantrone and T6NH imino protons (~.3 ppm) are observed. The phosphorous resonances do not shift significantly indicating that the base pairs do not open at any nucleotide step along the sequence of hexamer. Several inter-molecular Nuclear Overhauser Enhancement connectivities between mitoxantrone and hexanucleotide protons indicate that mitoxantrone chromophore stacks with terminal A1-T6 base pair and side chains involving 12CH2, 12NH, and 14OH protons are in close proximity of A1, T2, A5, and T6 bases. Absorption and emission spectra show red shift in wavelength maxima, which is characteristic of stacking interaction. At higher mitoxantrone to nucleic acid ratios, electrostatic interactions are dominant. The 2:1 drug/DNA stoichiometric structure obtained by restrained Molecular Dynamics simulations shows considerable distortions in backbone torsional angles and helicoidal parameters although structural fluctuations in 25 ps analysis of trajectory are found to be negligible. Mitoxantrone binds as a monomer at either or both ends of hexamer externally with side chains interacting specifically with DNA. The findings are relevant to the understanding of pharmacological action of drug. PMID- 23808713 TI - Clinical outcome of sorafenib treatment in patients with advanced hepatocellular carcinoma refractory to hepatic arterial infusion chemotherapy. AB - BACKGROUND AND AIM: It has been reported about poor prognosis in patients with advanced hepatocellular carcinoma (HCC) refractory to hepatic arterial infusion chemotherapy (HAIC). We assessed the survival benefits of sorafenib therapy for advanced HCC in HAIC refractory patients. METHODS: The study subjects were 191 patients with advanced HCC who had been treated with HAIC. Sorafenib was used in 27 patients who finally failed to respond to HAIC (HAIC/sorafenib group). Clinical outcome was compared between HAIC/sorafenib and HAIC alone groups. RESULTS: There were no significant differences in clinical characteristics and response rate of HAIC between the two groups (response rate: 25.9%, HAIC/sorafenib group; 30.4%, HAIC alone group). The median survival time (MST) for all patients was 11.0 months. The survival rate was significantly higher in the HAIC/sorafenib group than HAIC alone group (MST 22.2 vs 8.7 months, P = 0.017). From administration sorafenib, the disease control rate was 51.8% with MST of 10.4 months. Among HAIC non-responders, the survival rate was significantly higher in the HAIC/sorafenib group than HAIC alone group. Multivariate analysis identified additional therapy with sorafenib as significant and independent determinant of overall survival in all patients and HAIC non responders. CONCLUSION: Additional therapy with sorafenib could probably improve the prognosis of HAIC refractory patients. PMID- 23808714 TI - State-to-state time-of-flight measurements of NO scattering from Au(111): direct observation of translation-to-vibration coupling in electronically nonadiabatic energy transfer. AB - Translational motion is believed to be a spectator degree of freedom in electronically nonadiabatic vibrational energy transfer between molecules and metal surfaces, but the experimental evidence available to support this view is limited. In this work, we have experimentally determined the translational inelasticity in collisions of NO molecules with a single-crystal Au(111) surface a system with strong electronic nonadiabaticity. State-to-state molecular beam surface scattering was combined with an IR-UV double resonance scheme to obtain high-resolution time-of-flight data. The measurements include vibrationally elastic collisions (v = 3->3, 2->2) as well as collisions where one or two quanta of molecular vibration are excited (2->3, 2->4) or de-excited (2->1, 3->2, 3->1). In addition, we have carried out comprehensive measurements of the effects of rotational excitation on the translational energy of the scattered molecules. We find that under all conditions of this work, the NO molecules lose a large fraction (~0.45) of their incidence translational energy to the surface. Those molecules that undergo vibrational excitation (relaxation) during the collision recoil slightly slower (faster) than vibrationally elastically scattered molecules. The amount of translational energy change depends on the surface temperature. The translation-to-rotation coupling, which is well-known for v = 0 >0 collisions, is found to be significantly weaker for vibrationally inelastic than elastic channels. Our results clearly show that the spectator view of the translational motion in electronically nonadiabatic vibrational energy transfer between NO and Au(111) is only approximately correct. PMID- 23808715 TI - Ethnography in qualitative educational research: AMEE Guide No. 80. AB - Ethnography is a type of qualitative research that gathers observations, interviews and documentary data to produce detailed and comprehensive accounts of different social phenomena. The use of ethnographic research in medical education has produced a number of insightful accounts into its role, functions and difficulties in the preparation of medical students for clinical practice. This AMEE Guide offers an introduction to ethnography - its history, its differing forms, its role in medical education and its practical application. Specifically, the Guide initially outlines the main characteristics of ethnography: describing its origins, outlining its varying forms and discussing its use of theory. It also explores the role, contribution and limitations of ethnographic work undertaken in a medical education context. In addition, the Guide goes on to offer a range of ideas, methods, tools and techniques needed to undertake an ethnographic study. In doing so it discusses its conceptual, methodological, ethical and practice challenges (e.g. demands of recording the complexity of social action, the unpredictability of data collection activities). Finally, the Guide provides a series of final thoughts and ideas for future engagement with ethnography in medical education. This Guide is aimed for those interested in understanding ethnography to develop their evaluative skills when reading such work. It is also aimed at those interested in considering the use of ethnographic methods in their own research work. PMID- 23808716 TI - A new statistical approach to predict bacteremia using electronic medical records. AB - BACKGROUND: Previous attempts to predict bacteremia have focused on selecting significant variables. However, these approaches have had limitations such as poor reproducibility in prediction accuracy and inconsistency in predictor selection. Here we propose a Bayesian approach to predict bacteremia based on the statistical distributions of clinical variables of previous patients, which has recently become possible through the adoption of electronic medical records. METHODS: In a derivation cohort, Bayesian prediction models were derived and their discriminative performance was compared with previous models under varying combinations of predictors. Then the Bayesian models were prospectively tested in a validation cohort. According to Bayesian probabilities of bacteremia, patients in both cohorts were grouped into bacteremia risk groups. RESULTS: Using the same prediction variables, the Bayesian predictions were more accurate than conventional rule-based predictions. Moreover, their better discriminative performance remained consistent despite variations in clinical variables. The receiver operating characteristic (ROC) area of the Bayesian model with 20 predictors was 0.70 +/- 0.007 in the derivation cohort and 0.70 +/- 0.018 in the validation cohort. The prevalence of bacteremia in groups I, II, and VI (grouped according to probability ratio) were 1.9%, 3.4%, and 20.0% in the derivation cohort, and 0.4%, 3.2%, and 18.4% in the validation cohort, respectively. The overall prevalence of bacteremia was 6.9% in both cohorts. CONCLUSIONS: In the present study, the Bayesian prediction model showed stable performance in predicting bacteremia and identifying risk groups, as the previous models did. The clinical significance of the Bayesian approach is expected to be demonstrated through a multicenter trial. PMID- 23808717 TI - Clinical significance of Staphylococcus aureus bacteriuria at a tertiary care hospital. AB - OBJECTIVES: Staphylococcus aureus bacteriuria has been associated with invasive S. aureus disease. The current project describes the clinical significance of S. aureus bacteriuria. METHODS: We conducted a retrospective chart review of patients who had S. aureus bacteriuria at the Michael E. DeBakey Veterans Affairs Medical Center, 2008-2010. RESULTS: A total of 326 patients were included. Invasive S. aureus disease was documented within 12 months of bacteriuria in 56 patients (22.3% of methicillin-resistant S. aureus (MRSA) cases and 8.4% of methicillin-sensitive S. aureus (MSSA), p = 0.002). Multiple logistic regression indicated that MRSA bacteriuria (odds ratio (OR) 2.91, p = 0.010), absence of symptoms suggestive of a urinary tract infection (UTI) (OR 3.21, p = 0.019), inpatient status (OR 4.72, p = 0.003), and receipt of antibiotics active against S. aureus (OR 6.41, p < 0.001) were significantly associated with the presence of invasive S. aureus disease. Seventy-seven patients (23.6%) died within 12 months of the documented S. aureus bacteriuria. Age (OR 1.02, p = 0.025), absence of pyuria (OR 2.00, p = 0.029), the presence of invasive S. aureus disease (OR 2.05, p = 0.033), and inpatient status (OR 3.62, p < 0.001) were significantly associated with death. CONCLUSIONS: S. aureus bacteriuria is associated with significant morbidity and mortality. Patients without UTI symptoms, those with MRSA bacteriuria, and those without pyuria were more to likely to have worse outcomes (invasive S. aureus disease or death). Obtaining blood cultures should be considered in these cases. PMID- 23808718 TI - Campylobacter infection after prosthetic joint surgery. AB - Few cases of Campylobacter prosthetic joint infection (PJI) have been reported so far. We describe the demographic characteristics, underlying conditions, clinical features, treatment, and outcome of 8 patients with Campylobacter PJI in our hospital. All strains were confirmed at the French National Reference Center for Campylobacter and Helicobacter. Seven patients were infected with C. fetus and 1 with C. jejuni. Most patients were elderly and immunocompromised. Four had bacteremia, one of these with a pacemaker endocarditis. All the patients received at least 3 months of antibiotic treatment and 6 were treated surgically. The outcome was favorable at 2 years of follow-up in all except for 1 patient. Campylobacter PJI cases are rare but likely to become more frequent. C. fetus bacteremia should motivate physicians to look for a secondary localization such as a Campylobacter PJI. PMID- 23808719 TI - Prevalence of Borrelia burgdorferi sensu stricto, Borrelia afzelii, Borrelia garinii, and Borrelia valaisiana in Ixodes ricinus ticks from the northwest of Norway. AB - OBJECTIVES: Over a 3-y period, Ixodes ricinus ticks were randomly collected to study the prevalence of 4 Borrelia species: B. burgdorferi sensu stricto, B. afzelii, B. garinii and B. valaisiana. While B. burgdorferi s. s., B. afzelii, and B. garinii have been associated with human borreliosis in Norway for several years, B. valaisiana was reported in a Norwegian tick for the first time in 2010. METHODS: A real-time polymerase chain reaction (qPCR) was developed as an easy-to use method, with high sensitivity and specificity, to detect and genospecies-type B. burgdorferi s. s., B. afzelii, B. garinii, and B. valaisiana in I. ricinus ticks. A combination of species-specific primers and TaqMan MGB probes labelled with fluorescents with different emission spectra, ensured a highly specific method with the potential to detect more than 1 genospecies in 1 run. Sequencing of the housekeeping gene recG from 48 Borrelia-positive samples was used to confirm specificity. Denaturing gradient gel electrophoresis profiling of tick borne bacteria was used to help optimize the assay sensitivity. RESULTS: The qPCR assay was applied to analyze 1808 I. ricinus ticks collected in the field, which resulted in an overall infection rate of 14.8%, 18.7%, and 14.3% in 2010, 2011, and 2012, respectively. The majority of the Borrelia-infected ticks were infected with B. afzelii. CONCLUSIONS: The overall infection rate is somewhat lower than that reported in the most recent study of the infection rate in southern Norway in 2010, and this study indicates that the infection rate varies from one year to another. PMID- 23808720 TI - Patients with non-tuberculous mycobacterial lung disease have elevated transforming growth factor-beta following ex vivo stimulation of blood with live Mycobacterium intracellulare. AB - We previously found that a subset of patients with pulmonary non-tuberculous mycobacterial (pNTM) disease were taller, leaner, and had a higher prevalence of pectus excavatum and scoliosis than uninfected controls. Additionally, whole blood of pNTM patients stimulated ex vivo with live Mycobacterium intracellulare produced significantly less interferon-gamma (IFNgamma) compared to that of uninfected controls. Since IFNgamma production can be suppressed by transforming growth factor-beta (TGFbeta), an immunosuppressive cytokine, we measured basal and M. intracellulare-stimulated blood levels of TGFbeta in a group of 20 pNTM patients and 20 uninfected controls. In contrast to the IFNgamma findings, we found that stimulated blood from pNTM patients produced significantly higher levels of TGFbeta compared to controls. Since pNTM patients frequently possess body features that overlap with Marfan syndrome (MFS), and increased TGFbeta expression is important in the pathogenesis of MFS, we posit that a yet-to-be identified syndrome related to MFS predisposes certain individuals to develop pNTM disease. PMID- 23808721 TI - Relapsing endocarditis caused by Enterococcus faecalis forming small colony variants. AB - Small colony variants (SCVs) are subpopulations of a bacterial strain that differ in morphology, growth rate, metabolism, and antibiotic sensitivity from the parent line. They are associated with chronic and difficult-to-treat infections. SCV endocarditis is very rare and usually associated with intracardiac devices. Herein, we report a case of endocarditis caused by SCV-forming Enterococcus faecalis that affected the native heart without any known predisposition. PMID- 23808722 TI - Early lumbar puncture in adult bacterial meningitis--rationale for revised guidelines. AB - Current international guidelines recommend cerebral computerized tomography (CT) before lumbar puncture (LP) in many adults with suspected acute bacterial meningitis (ABM), due to concern about LP-induced cerebral herniation. Despite guideline emphasis on early treatment based on symptoms, performing CT prior to LP implies a risk of delayed ABM treatment, which may be associated with a fatal outcome. Firm evidence for LP-induced herniation in adult ABM is absent and brain CT cannot discard herniation. Thus, the recommendation to perform CT before LP may contribute to an avoidable delay of LP and ABM treatment. The inappropriate use of the diagnostic treatment sequence of brain CT scan, followed by LP, followed by antibiotics and corticosteroids should be avoided in adults with suspected ABM by omitting needless contraindications for LP, thus eliminating an unnecessary fear of immediate LP. Revised Swedish guidelines regarding early LP are presented, and the background documentation and reasons for omitting impaired consciousness, new onset seizures, and immunocompromised state as contraindications to LP are discussed. PMID- 23808723 TI - When is coagulase-negative Staphylococcus bacteraemia clinically significant? AB - BACKGROUND: Coagulase-negative staphylococci (CoNS) are common contaminants in blood cultures (BC). A prospective study of patients with >= 2 blood culture sets and at least 1 positive CoNS BC was performed to develop an algorithm to assist in determining the clinical significance of CoNS bacteraemia. METHODS: A single reviewer examined the medical records of patients with CoNS bacteraemia (January June 2010). The determination of clinical significance was made according to CDC/NHSN (US Centers for Disease Control and Prevention/National Healthcare Safety Network) criteria. To explore risk factors associated with clinical significance, a multivariate analysis was performed. The performances of various algorithms were then compared. An algorithm to assist in determining clinical significance was developed. RESULTS: Two hundred and sixty-nine cases were included; 97 (36%) were considered clinically significant bacteraemia (CSB). Predictors of CSB in the multivariate analysis were: time to positivity < 16 h (odds ratio (OR) 4.540, 95% confidence interval (CI) 1.734-11.884), identification of Staphylococcus epidermidis (OR 4.273, 95% CI 2.124-5.593), central venous catheter (OR 4.932, 95% CI 2.467-9.858), > 2 CoNS-positive bottles from different BC sets (OR 1.957, 95% CI 1.401-2.733), and Charlson score >= 3 (OR 2.102, 95% CI 1.078-4.099). The algorithm with best sensitivity (62%) and specificity (93%) for determining clinical significance of CoNS included Charlson score >= 3, Pitt score >= 1, neutropenic patients, presence of central venous catheter, identification of S. epidermidis, and time to positivity < 16 h. The positive predictive value was 83% and the negative predictive value was 81% (likelihood ratio 8.87). CONCLUSION: The use of this algorithm could potentially reduce the misclassification of nosocomial bloodstream infections and inappropriate antibiotic treatment in patients for whom a positive CoNS does not represent a CSB. PMID- 23808724 TI - Early treatment of coronal synostosis with endoscopy-assisted craniectomy and postoperative cranial orthosis therapy: 16-year experience. AB - OBJECT: The objective of this study was to present the authors' 16-year experience treating coronal craniosynostosis in infants using endoscopy-assisted techniques and postoperative cranial orthoses. METHODS: A total of 128 synostosed coronal sutures in 115 patients were treated between 1996 and 2012 by endoscopically resecting a strip of bone containing the stenosed suture via a 2-3 cm incision made at the ipsilateral stephanion. Data were obtained from a prospective database. Following surgery, patients were fitted with custom cranial orthoses to help correct preoperative craniofacial deformities. All patients were followed closely with cranial anthropometric measurements and photographs. RESULTS: The estimated mean blood loss was 20 ml (range 5-120 ml) and the estimated mean strip size was 0.6 cm * 10.7 cm. The mean surgical duration was 55 minutes (range 22-150 minutes). One patient underwent an intraoperative blood transfusion and 1 had a postoperative blood transfusion, for a total transfusion rate of 1.7%. Ninety-seven percent of patients were discharged on the first postoperative day. There were no deaths. Vertical dystopia correction of more than 80% from baseline was obtained in almost two-thirds of patients, with 51% achieving 100% correction. Nasal and sagittal craniofacial deviation (vertex nasion-gnathion) correction greater than 80% was achieved in 80% of patients, with 77% achieving 100% correction. Supraorbital rim advancement of the ipsilateral eye was obtained in 98% of cases, with correction of frontal plagiocephaly the last deformity to achieve correction. CONCLUSIONS: Early treatment of coronal synostosis with endoscopy-assisted craniectomy and postoperative molding helmets leads to significant correction of craniofacial abnormalities, including vertical dystopia, nasal deviation, sagittal misalignment, and ipsilateral proptosis. This treatment method is associated with minimal trauma, blood loss, and transfusion rates, and typically only requires 1 overnight stay. This surgical approach is safe, effective, and associated with excellent results. PMID- 23808725 TI - Editorial: Cranial orthosis therapy. PMID- 23808726 TI - Staged bilateral far-lateral approach for bilateral cervicomedullary junction neurenteric cysts in a 10-year-old girl. AB - Neurenteric cysts are rare and benign lesions that consist of ectopic alimentary tissue residing in the central nervous system. They tend to occur most frequently in an intraspinal rather than intracranial location. Intracranial neurenteric cysts are a rare occurrence in the pediatric population. These lesions typically present as unilateral cystic structures in the lower cerebellopontine angle and craniocervical junction. To the authors' knowledge, there have been no reported cases of bilateral localization of intracranial neurenteric cysts. In this report, they present an unusual case of a 10-year-old girl who was found to have bilateral intracranial neurenteric cysts at the pontomedullary junction. The patient was successfully treated with staged, bilateral far-lateral transcondylar resection of the cysts. The authors also provide a brief overview of the literature describing intracranial neurenteric cysts in children. PMID- 23808727 TI - Validation and modification of a predictive model of postresection hydrocephalus in pediatric patients with posterior fossa tumors. AB - OBJECT: Postresection hydrocephalus is observed in approximately 30% of pediatric patients with posterior fossa tumors. However, which patients will develop postresection hydrocephalus is not known. The Canadian Preoperative Prediction Rule for Hydrocephalus (CPPRH) was developed in an attempt to identify this subset of patients, allowing for the optimization of their care. The authors sought to validate and critically appraise the CPPRH. METHODS: The authors conducted a retrospective chart review of 99 consecutive pediatric patients who presented between 2002 and 2010 with posterior fossa tumors and who subsequently underwent resection. The data were then analyzed using bivariate and multivariate analyses, and a modified CPPRH (mCPPRH) was applied. RESULTS: Seventy-six patients were evaluated. Four variables were found to be significant in predicting postresection hydrocephalus: age younger than 2 years, moderate/severe hydrocephalus, preoperative tumor diagnosis, and transependymal edema. The mCPPRH produced observed likelihood ratios of 0.737 (95% CI 0.526-1.032) and 4.688 (95% CI 1.421-15.463) for low- and high-risk groups, respectively. CONCLUSIONS: The mCPPRH utilizes readily obtainable and reliable preoperative variables that together stratify children with posterior fossa tumors into high- and low-risk categories for the development of postresection hydrocephalus. This new predictive model will aid patient counseling and tailor the intensity of postoperative clinical and radiographic monitoring for hydrocephalus, as well as provide evidence-based guidance for the use of prophylactic CSF diversion. PMID- 23808728 TI - Cerebellar seizures. AB - Epilepsy, especially with refractory seizures, is thought to arise only from cortical lesions or substrate. The authors report on 2 patients with refractory epilepsy and cerebellar lesions. Depth electrodes were placed within the cerebellar lesions in both patients, and intracranial electroencephalographic recordings showed seizure origin from the cerebellar lesions. One patient eventually attained seizure control with antiepileptic drugs. The other case involved a child with generalized myoclonic epilepsy associated with a pilocytic astrocytoma of the cerebellum. This patient obtained seizure control following gross-total resection of the tumor. PMID- 23808729 TI - United Kingdom 30-day mortality rates after surgery for pediatric central nervous system tumors. AB - OBJECT: In an increasing culture of medical accountability, 30-day operative mortality rates remain one of the most objective measurements reported for the surgical field. The authors report population-based 30-day postoperative mortality rates among children who had undergone CNS tumor surgery in the United Kingdom. METHODS: To determine overall 30-day operative mortality rates, the authors analyzed the National Registry of Childhood Tumors for CNS tumors for the period 2004-2007. The operative mortality rate for each tumor category was derived. In addition, comparison was made with the 30-day operative mortality rates after CNS tumor surgery reported in the contemporary literature. Finally, by use of a funnel plot, institutional performance for 30-day operative mortality was compared for all units across the United Kingdom. RESULTS: The overall 30-day operative mortality rate for children undergoing CNS tumor surgery in the United Kingdom during the study period was 2.7%. When only malignant CNS tumors were analyzed, the rate increased to 3.5%. One third of the deaths occurred after discharge from the hospital in which the surgery had been performed. The highest 30-day operative mortality rate (19%) was for patients with choroid plexus carcinomas. A total of 20 institutions performed CNS tumor surgery during the study period. Rates for all institutions fell within 2 SDs. No trend associating operative mortality rates and institutional volume was found. In comparison, review of the contemporary literature suggests that the postoperative mortality rate should be approximately 1%. CONCLUSIONS: The authors believe this to be the first report of national 30-day surgical mortality rates specifically for children with CNS tumors. The study raises questions about the 30-day mortality rate among children undergoing surgery for CNS tumors. International consensus should be reached on a minimum data set for outcomes and should include 30-day operative mortality rates. PMID- 23808730 TI - Designed fabrication of unique eccentric mesoporous silica nanocluster-based core shell nanostructures for pH-responsive drug delivery. AB - A novel and facile strategy using poly(acrylic acid) (PAA) as a nanoreactor and template has been proposed and applied for the first time to fabricate a novel and unique class of multifunctional eccentric Fe3O4@PAA/SiO2 core-shell nanoclusters (NCs) consisting of a single Fe3O4 nanoparticle (NP), PAA, and eccentric SiO2 NCs that are composed of a large number of small fluorescent SiO2 NPs. Interestingly, the resulting eccentric PAA shell around Fe3O4 NPs as a high water-absorbent polymer is like a "reservoir" to absorb and retain water molecules inside its net structure to confine the growth of small SiO2 NPs inside the PAA networks, resulting in the formation of an eccentric SiO2 NC with aggregated pores. The thicknesses of uniform and well-dispersed SiO2 NCs can also be precisely controlled by varying the amount of tetraethyl orthosilicate (TEOS). Importantly, the synthetic method has been confirmed to be universal and extended to other functional NPs with different compositions and shapes as eccentric cores. Furthermore, the as-prepared multifunctional eccentric Fe3O4@PAA/SiO2 core shell NCs combined fluorescence imaging, ultrahigh drug loading capacity (1.13 mg doxorubicin/mg eccentric NCs), and pH-responsive drug release into one were taken as an example to study the applications in simultaneous fluorescence imaging and pH responsive drug delivery into prostate cancer PC3M cells. PMID- 23808731 TI - Rosette-like structures in the spectrum of spitzoid tumors. AB - BACKGROUND: Spitz nevi demonstrate a diverse spectrum of morphologies. Recently, there have been two reported examples of Spitz nevi with rosette-like structures similar to Homer-Wright rosettes. Rosettes have also been described in melanomas and in a proliferative nodule arising in a congenital nevus. METHODS: A retrospective review of 104 cases of Spitz nevi and variants (n = 51), pigmented spindle cell nevi (n = 26), combined melanocytic nevi with features of Spitz (n = 8), atypical Spitz tumor (AST, n = 9), and spitzoid melanoma (n = 10). RESULTS: Rosette-like structures were present in 3 of the 104 cases (2.9%), including a compound Spitz nevus, a desmoplastic Spitz nevus, and an AST. All three cases demonstrated several foci of small nests of epithelioid cells with peripherally palisaded nuclei arranged around a central area of fibrillar eosinophilic cytoplasm. Immunohistochemical staining of the three spitzoid lesions demonstrated that the rosette-like structures express S100 protein, Melan-A, and neuron specific enolase (NSE) and lacked expression of neurofilament, glial fibrillary acidic protein and synaptophysin. CONCLUSIONS: While uncommon, rosette like structures can occur as a focal feature in Spitz nevi and AST. Rosette-like structures may represent a normal morphologic finding in Spitz nevi, and awareness of them may prevent misdiagnosis as a neural tumor or melanoma. PMID- 23808732 TI - Portion weights of food served in English schools: have they changed following the introduction of nutrient-based standards? AB - BACKGROUND: Mandatory food-based and nutrient-based standards for the food provided in English schools were introduced in 2008 (primary) and 2009 (secondary) and have had a positive impact on pupils' food choice and nutrient intake at school. There are no recommendations for portion sizes in England, although anecdotal evidence suggests that portions of food and drink sold in schools have decreased since the standards were introduced. METHODS: Data were collected from 136 primary and 80 secondary schools in 2009 and 2010/11, respectively. All food and drink items provided at lunchtime were weighed on five consecutive days at each school. The mean and median weight, SD, and 25th and 75th centile for each individual food were calculated. Data were compared with the results obtained from similar surveys in 2004 and 2005, as well as with portion size recommendations for Scottish schools. RESULTS: The proportion of food items that differed in weight since 2004/05 varied from 13% in primary schools to 29% in secondary schools. Changes in weight were equally likely to be positive or negative, with the exception of portions of fruit and vegetables, which had decreased. Primary schools were more likely to meet portion size recommendations than secondary schools. CONCLUSIONS: Of the items that were directly comparable over time, a limited number showed a significant change in portion size since the standards for school food were introduced. Portion weight recommendations are based on a balanced healthy diet, and pupils should eat all the components of meals offered by schools to meet dietary recommendations. PMID- 23808733 TI - [Not Available]. PMID- 23808734 TI - [The origins of the Czech Society of Cardiology and of Czech cardiology]. AB - The paper presents the origins of the Czech Society of Cardiology on the one hand, and the origins of Czech cardiology on the other. The Czech Society of Cardiology is the third oldest in the world (after the American and German Societies). It was founded in 1929 by Prof. Libensky. As early as in 1933, the Society organised the first international congress of cardiologists in Prague, which was attended by 200 doctors, out of which 50 were from abroad. The most participants came from France and Poland. Other participants came from England, Argentina, Belgium, the Netherlands, Italy, Romania, Spain and Switzerland. The worldwide importance of this congress is apparent from the fact that both the World Society of Cardiology and the European Society of Cardiology (EKS) were founded after World War II in the years 1950 and 1952, i.e. almost 20 years after the first international congress of cardiology in Prague. In 1964, the Fourth Congress of European Society of Cardiology was held in Prague with the participation of 1,500 specialists from 31 countries and chaired by Prof. Pavel Lukl, the later president of EKS (1964- 1968). The paper also presents the work of our specialists in WHO and the history of the international journal Cor et Vasa issued by the Avicenum publishing house in Prague in English and Russian in the years 1958- 1992. An important role in the development of our cardiology was played by certain departments and clinics. In 1951, the Institute for Cardiovascular Research (UCHOK) was founded in PrahaKrc, thanks to the initiative of MU Dr. Frantisek Kriegl, the Deputy Minister of Health. Its first director was Klement Weber, who published, as early as in 1929, a monograph on arrhythmias - 50 years earlier than arrhythmias started to be at the centre of attention of cardiologists. Klement Weber was one of the doctors of President T. G. Masaryk during his serious disease towards the end of his life. Jan Brod was the deputy of Klement Weber in the Institute and the chair of its Scientific Council. The Institute for Cardiovascular Research was the third institute for cardiovascular diseases in the world. The origins of Czech cardiology are documented in three most important areas - the treatment of hypertension, the development of cardiothoracic surgery and the development of treatment of acute myocardial infarction. Hradec Kralove became, thanks to Academician Bedrna, the first centre of cardiac surgery in this country. The development of hypertension treatment was stormy, thanks to the discovery of an effective pharmacotherapy, from the originally incurable malignant hypertension to the well curable benign hypertension. The effective treatment of acute infarction was based on the development of heart defibrillation enabling the establishment of coronary units, and later on the thrombolytic and antiplatelet therapies up to the contemporary PCI as the treatment of choice. During that time, AIM mortality decreased from the original 30% to the present 4- 5%. PMID- 23808735 TI - [Up to day trends in insulin therapy]. AB - Patients with type 2 diabetes mellitus have a double risk of development of cardiovascular diseases than patients without diabetes. Two thirds of patients with type 2 diabetes mellitus can die from heart attack or a cerebrovascular accident if it is not possible to influence these risks by procedures such as decreasing the blood pressure, cholesterol level, glycemia and to stop smoking. The recommendations of ADA/ EASD for therapy of type 2 diabetes mellitus emphasizes that the therapy should be conducted in such a manner as to decrease the risk of cardiovascular complications and undesirable effects, primarily hypoglycemic events. A whole line of clinical studies, e. g. DCCT EDIC, UKPDS have documented the importance of intensive insulin therapy for achievement of normoglycemia, decreasing risk of microangiopathic complications and in followup observation, also decreasing of cardiovascular risk. An ORIGIN study with insulin glargine documented the safety of therapy of longacting insulin analog and also reduction of development of new diabetes from prediabetes. Insulin therapy with respect to the positive outcomes of study with insulin analogs moved up to the second line in algorithm therapy, immediately after metformin therapy and change of life style. PMID- 23808736 TI - [Impact of aortic stiffness on central hemodynamics and cardiovascular system]. AB - Arterial stiffness increases as a result of degenerative processes accelerated by aging and many risk factors, namely arterial hypertension. Basic clinical examination reveals increased pulse pressure as its hemodynamic manifestation. The most serious consequence of increased vascular stiffness, which cannot be revealed by clinical examination, is a change of central hemodynamics leading to increased load of left ventricle, left ventricular hypertrophy, diastolic dysfunction and to overall increase of cardiovascular risk. This review aimed to point at some patophysiological mechanisms taking part in the development of vascular stiffness, vascular remodeling and hemodynamic consequences of these changes. This work also gives an overview of noninvasive examination methods and their characteristics enabling to evaluate the local, regional and systemic arterial stiffness and central pulse wave analysis and their meaning for central hemodynamics and heart workload. PMID- 23808737 TI - [Lipids and the size of lipoprotein particles in newly diagnosed and untreated patients with type 2 diabetes mellitus]. AB - Type 2 diabetes mellitus leads to the typical known form of dyslipidaemia among the patients. This dyslipiademia type re-presents prognostically important type of atherogenic dyslipiadaemia, that significantly increases the risk of atherothrombosis. Estimation of the size of lipoprotein particles with Lipoprint method among newly diagnosed, untreated patients with these patients have not been evaluated yet. Dyslipidaemia among patients with type 2 diabetes mellitus has its course and changes after the treatment. At the beginning i tis characterized by the significant increase of VLDL, large and middle size IDL lipoprotein particles, as well as by lowering of HDL particles. This lipoprotein profile has its own atherogenic potential. The course of the disease later leads to the change of dyslipidaemia, characterized by the increase of LDL levels (small dense particles), triglyceride levels and the persistence of the lower levels of HDLcholesterol. Hypolipidemic treatment leads to the significant lowering of cardiovascular risk, however despite treatment with statin or fibrate residual cardiovascular risk remains still very high. PMID- 23808738 TI - [Metabolic syndrome and prediabetic states]. AB - Metabolic syndrome is defined as cluster of independent risk factors of coronary heart disease and type 2 diabetes mellitus including prediabetic glucose metabolism disorders associated with insulin resistance as impaired fasting glucose, impaired glucose tolerance and/ or borderline increasing of glycosylated haemoglobin; central obesity, atherogenic dyslipidaemia with increasing of triglyceride levels and decreasing of high density lipoprotein levels and hypertension. In diagnosis of prediabetic states there are used fasting glycaemia, 2 hours glycaemia during oral glucose tolerant test and HbA1c level, which importance in diagnostic is discussed. In DM2 prevention there is important mainly physical activity at least 30 min daily. In the case of pharmacotherapy there was confirmed efficiency of metformin, which could be used in states with high risk of DM2 conversion and some antihypertensive drugs, mainly sartans. In the case of treatment of dyslipidaemia by statins there is moderate increased risk of DM2 in prediabetic states, but cardiovascular benefit from treatment some times exceeds this risk. PMID- 23808739 TI - [Resistant hypertension in the elderly]. AB - The issue of resistant hypertension is complex and from the clinical aspect very current, especially in the elderly. For the diagnosis of resistant hypertension in routine practice, ambulatory blood pressure monitoring is a proven method to distinguish it from the white coat hypertension. Fixed combinations of antihypertensive drugs helps to improve compliance not only in geriatric patients, but are also indicated in hypertensive patients with diabetes mellitus, metabolic syndrome, in patients with target organ damage, renal disease, coronary heart disease and post stroke conditions. Especially in the population of older hypertensive patients, listed diseases with polymorbidity are frequently present. PMID- 23808740 TI - [Epigenetic cancer drugs and their role in anticancer therapy]. AB - Epigenetic modification have been causally linked to cancer development and progression, and are potentially reversible by treatments with epigenetic cancer drugs. The aim of this review is to give an overview of the basic current knowledge on molecular mechanisms of epigenetic cancer drugs and their possible clinical use. Many of them are in in clinical trials. However only two demethylating agents ie. inhibitors of DNA methyltransferase (5- azacytidin and decitabin) are approved in the treatment of myelodysplastic syndrome and a few inhibitors of histonacetylase (vorinostat, romidepsin and panobinostat) are approved in the treatment of hematological malignancies, particularly in refractory or relapsed cutaneous T cell lymhoma. PMID- 23808741 TI - [The environmental estrogen bisphenol A and its effects on the human organism]. AB - Bisphenol A (BPA), i.e. an environmental estrogen, is one of the most common synthetic chemicals which enter the human body from plastic bottles, food packaging and dental materials. As many studies show, a longterm exposure to BPA is connected with a risk of developing various diseases and endocrine disorders. Exposure to BPA, particularly during development, increases the risk of breast carcinoma, obesity, diabetes mellitus type 2 as well as reproductive disorders. It also increases the risk of testes carcinoma and prostate carcinoma. Some isolated studies support also the relation between BPA and the risk of cardiovascular and autoimmune diseases. The effect of other xenoestrogens, such as polychlorinated biphenyls, phthalates, dioxins, as well as others, is similar or perhaps even stronger. For the time being, however, the exact pathophysiologic mechanisms of these relations are not quite clear and require further experimental, but especially human, studies. PMID- 23808742 TI - [Impact of pregnancy on pituitary disorders]. AB - In pregnancy, the volume of pituitary increases by multiplication of lactotopic and gonadotropic cells and developing placenta is the source of numerous hormones and enzymes that significantly affect and alter the function of the endocrine system. This naturally has an impact on the course of pituitary disorders and their treatment. The most common disorders of pituitary gland, which we can meet in pregnancy, are adenomas, particularly prolactinomas, and functionless adenomas. During pregnancy we avoid the treatment of microprolactinomas, but in macroprolactinomas where there is the risk of their enlargement by stimulation of placental estrogens, we administer preventively the dopaminergic agonists. Patients with acromegaly usually do not need the treatment during pregnancy, unless there is a danger to damage the visual pathway or heavy headaches occur. ACTH secreting adenomas (Cushings disease) in pregnancy are rare, they are difficult to diagnose but existing hypercortisolism is very dangerous to fetus and may damage even mother. Large functionless adenomas, unless treated before pregnancy, may damage the visual pathway. The volume of the enlarged pituitary gland in pregnancy and sometimes even of the functionless adenoma adenoma, may be reduced by cabergoline, so that the urgent neurosurgery in pregnancy is very rare. A typical disease that occurs primarily in pregnant women is autoimmune lymphocytic hypophysitis. Diagnosis is established on the basis of headaches and symptoms and signs of the deficits of adrenocorticotropic and thyreotropic function usually in the last third of pregnancy or in the first six months after birth, using a specific image in magnetic resonance. Treatment is limited to hormone replacement. It is also possible to meet pregnant women with deficient pituitary functions. In hypocortical women with exception of strains like as pregnancy vomiting, doses of hydrocortisone replacement usually do not change until birth. Childbirth, however, must be secured by increasing the doses of corticosteroids. Careful replacement of thyroid hormones in hypothyroid women is very important for the development of fetus. In women treated with growth hormone its administration during pregnancy may be omitted because the placental growth hormone takes over its function. Desmopressin dose for diabetes insipidus in pregnancy is unchanged - desmopressin is resistant to placental vasopressinases. However, their effects may cause manifestation of partial diabetes insipidus, which was compensated so far. PMID- 23808743 TI - [Differential diagnosis and treatment of hyponatremia]. AB - Hyponatremia is one of the most common metabolic disorders in clinical medicine. The value of Na+ in serum equalling 135 mmol/ l and lower is regarded as hyponatremia. Its clinical manifestations are the following: headaches, nausea, vomiting, seizures, numbness, coma and death. Hyponatremia caused by nonosmotic hypersecretion of vasopressin can be divided into: a) hypovolemic, b) normovolemic and c) hypervolemic. Hyponatremia which is not caused by the hypersecretion of vasopressin is the so called pseudohyponatremia, water intoxication, cerebral salt loss syndrome. Hypovolemic hyponatremia is caused by the loss of Na+ and fluid loss from the organism. It occurs, for example, after using thiazide diuretics, after recurrent diarrhoea, vomiting, after significant blood loss and other causes. Treatment of this disorder must focus on the producing cause and on the parenteral administration of 0.9% NaCl. Normovolemic hyponatremia can be with or without symptoms. Acute normovolemic hyponatremia is treated by the intravenous administration of 3% NaCl and with the simultaneous use of loop diuretics (20- 40 mg Furosemide/ 24 hrs) and restriction of fluid intake. In the case of chronic normovolemic hyponatremia, refractory to the previous treatment, caused by the inappropriate secretion of arginine vasopressin, it is recommended to use perorally its V2- receptor blocker, Tolvaptan. Hypervolemic hyponatremia occurs in the case of cardiovascular failure, with hepatic cirrhosis, nephrotic syndrome, renal failure, porphyric disease and other conditions. Symptoms occurring with it are swellings, ascites, distension of jugular veins and the presence of unaccented rales in the lungs, which can be detected during physical examination. For treatment it is recommended to restrict fluid intake and to administer NaCl as well as diuretic therapy. Recently it has been recommended to use Tolvaptan which increases excretion of free water (aquaresis), decreases osmolality in the urine, and leads to the increase in serum Na+. Apart from that, we present our three clinical laboratory observations in the paper: 1. Contrary to the data in the literature, after the Kosice Marathon (42.125 km) the serum concentration of Na+ in the runners increased (from 144.4 +/- 2.1 mmol/ l to 147 +/- 2.8 mmol/ l, p < 0.01) in spite of a significant reduction in the body weight (from 73.2 +/- 5.7 kg to 71.9 +/- 5.2 kg, p < 0.05), intensive perspiration and dehydration (blood haemoglobin before the run: 150.4 +/- 5.5 g/ l, after the run: 152.1 +/- 4.8 g/ l, p < 0.05). Apart from that, we detected a significant decrease in the fractional excretion of sodium (FENa) from 1.16 +/- 0.30% to 0.34 +/- 0.10%, p < 0.01. 2. One patient with chronic intermittent porphyria displayed the syndrome of inappropriate antidiuretic hormone secretion, which had been positively influenced by the restriction of fluid intake in the long term and by peroral administration of 1- 3 g NaCl/ 24 hrs. 3. In 15 haemodialysed patients with chronic renal failure, who displayed recurrent hypervolemic hyponatremia, we achieved, by means of adequate ultrafiltration and a dialysis solution containing Na+ 145 mmol/ l, the serum concentration of Na+ 142 mmol/ l at the end of haemodialysis. PMID- 23808744 TI - [Adherence and persistence with a focus on the treatment of hypertensive patients]. AB - Insufficient adherence of patients to treatment is a serious problem and it is monitored most frequently in hypertensive patients. The possibilities of increasing adherence to longterm treatment include mainly the motivation and education of patients, simple dosage regimes, telephone consultations and involving the patient in the treatment process (self monitoring), but it also means providing information about the consequences of failure to adhere to the treatment process. Other possibilities can include new dosage forms which increase the biological availability of medicines, reduce the variability of absorption, and thus allow for achieving their more stable levels. It is possible to take advantage of fixed combinations which can improve adherence. Some new dosage forms simplify the therapy for patients and make it more pleasant. One of the latest innovations is for example, orodispersible dosage forms, which have been recently introduced in the therapy of arterial hypertension. In order to improve the adherence of patients to hypertension treatment it is necessary to use all means available adjusted to the individual needs of patients. PMID- 23808745 TI - [Diuretics in monotherapy and in combination with other diuretics and nondiuretics in the treatment of hypertension]. AB - Diuretics belong to the basic group of medicines for the treatment of hypertension and heart failure. In the case of hypertension treatment, their main indication is higher age and isolated systolic hypertension. In the case of heart failure they are used for the treatment of swellings and shortness of breath. The most frequently prescribed group of diuretics is thiazides and similar products. In patients with renal insufficiency, loop diuretics are administered. In the case of hypertension, diuretics are mainly used in the combination treatment. The most frequently used diuretic in combination is again hydrochlorothiazide, which is combined with reninangiotensin system blockers. It is mainly the combination of an ACE inhibitor + indapamide that seems to be modern and promising, and it is, on the basis of large clinical trials, recommended also for diabetics (ADVANCE) or for secondary prevention following a cerebrovascular accident (PROGRESS) or for the elderly (HYVET). Also a combination of two diuretics is popular - mainly hydrochlorothiazide + amiloride. A combination of a betablocker and diuretic is less suitable. PMID- 23808746 TI - [Hypertension in patients with polycystic kidney disease - incidence, pathogenesis, prognosis, therapy]. AB - Hypertension is common in patients with autosomal dominant polycystic kidney disease (ADPKD) very early usually already in adolescence and its occurrence precedes the decrease of glomerular filtration rate. Expansion of renal cysts causing local renal ischemia and activation of the reninangiotensin system is believed to play a decisive role in its pathogenesis. Hypertension in ADPKD leads to early development of left ventricle hypertrophy and definitely contributes to the progression of chronic renal insufficiency. In ADPKD optimal control of blood pressure dramatically decreases the risk of left ventricle hypertrophy and contributes to its regression, but the beneficial effect of optimal compared to standard blood pressure control on the progression of chronic renal insufficiency has yet to be unequivocally demonstrated. Angiotensin converting enzyme inhibitors and/ or angiotensin receptor blockers are the drugs of choice in the treatment of hypertension in ADPKD. New drugs blocking the growth of renal cysts (e. g. inhibitors of V2 vasopressin antagonists) may have in ADPKD positive impact not only of the growth of the cysts and kidney volume, but also on the rate of loss of glomerular filtration rate. The influence of these drugs on the control of blood pressure, if any, remains uncertain. PMID- 23808747 TI - [Primary hyperaldosteronism: common cause of secondary hypertension with higher cardiovascular risk]. AB - Primary hyperaldosteronism (PH) is common cause of secondary hypertension with autonomous aldosterone overproduction by adrenal cortex with high plasma aldosterone, suppressed renin and high blood pressure. Patients with PH have compared to essential hypertension (EH) more frequent subclinical organ damage and higher cardiovascular risk (CV). Higher carotid IMT, arterial stiffness and microalbuminuria was found in PH. Early specific therapy of PH may lead to the regression of target organ damage and decrease of CV risk. Early diagnostic and therapeutic measures are very important due to high prevalence of PH. PMID- 23808748 TI - [Chronic obstructive pulmonary disease in the light of new guidelines - brief summary of phenotypically oriented guidelines for nonpulmonary physicians]. AB - INTRODUCTION: COPD is a global health and social problem. Morbidity and mortality increases in the Czech Republic. There are currently several global statements and strategies. METHODS: The Czech Pneumological and Phthisiological Society (CPFS) at the end of 2011 mandated the Section of bronchial obstruction in drafting national guidelines concerning the stable COPD. Subsequently, this document was discussed during the National Consensus Conference (COPD forum) in November 2012 and presented at series of local workshops and national conferences. National guidelines has been subject to a review and eventually posted on the website for another round of comments. DIAGNOSIS: A modern approach to COPD is a view of the patient through the pulmonary function, symptoms, exacerbation rates and the presence of specific phenotypes. CPFS identified six clinically relevant phenotypes: frequent exacerbators, COPD and asthma overlap, COPD and bronchiectasis overlap, emphysematic phenotype, bronchitic phenotype and phenotype of pulmonary cachexia. TREATMENT: TREATMENT recommendations can be divided into four elementary steps: the first step is the Elimination of all risks factors. The second one is the Standard therapy including in particular inhaled bronchodilators, pulmonary rehabilitation, and treatment of severe comorbidities. The third step is the Targeted therapy centered on clinical phenotypes of COPD. The final fourth step is the treatment of respiratory insufficiency and palliative care of the terminal COPD. CONCLUSION: The optimal treatment of COPD requires a personalized approach to the patient. PMID- 23808749 TI - [The effectiveness of anagrelide treatment in patients with Ph negative myeloproliferative diseases: influence on the incidence of thrombosis in the data from the Registry of patients with essential thrombocythemia and thrombocythemia associated with other myeloproliferative diseases treated with Thromboreductin(r) to the end of 2012]. AB - In the Czech Republic, anagrelide (Thromboreductin(r)) [29] is used according to the recommendations of the Czech Working Group on Myeloproliferative Disorders (CZEMP) for treatment of thrombocythemia associated with Ph negative myeloproliferative disorders (MPDs). The patient data are collected in the Registry of patients with essential thrombocythemia (ET) and thrombocythemia associated with other MPDs treated with Thromboreductin(r). At the end of 2012, the Registry contained data on 1,161 patients. Out of these, 1,159 patients with the dia-gnosis of a Ph negative MPD were evaluated. In 844 patients, precise WHO based dia-gnosis was known at start of therapy: 442 (52.4%) had ET, 108 (12.8%) had polycythaemia vera (PV) and 243 had primary myelofibrosis (PMF). The median age was 51 years at the time of diagnosis. At the time of the evaluation of the population, the median was 59 years. Every year, the proportion of patients newly treated with anagrelide as a firstline treatment in accordance with the CZEMP guidelines has been increasing. A growing proportion of patients has been treated with an additional cytoreducing drug, such as hydroxyurea and interferon. The majority of the patients received also an antiaggregant (or anticoagulant). More than a half of patients harbors the JAK2 mutation. A prompt decrease of platelet counts (as the response to Thromboreductin(r) treatment) was documented in most of the patients. After one year, 86.9% of patients had a full or partial response. In poorer responders, combination cytoreductive treatment was administered rather then the escalation of the Thromboreductin(r) dosage. There were 461 thrombotic manifestations in 363 patients and 61 haemorrhagic events in 57 patients recorded in the patients history. In the course of treatment (followup; F U), thrombosis was diagnosed only 179-times in 136 patients. There were more haemorrhagic events during F U: 109 events in 83 patients. Upon comparison of the number of events during F U to their numbers in history, we found a twofold decrease in arterial thrombosis, an almost twofold decrease in microvascular thrombosis and even a 6.6- fold decrease in venous thromboembolism events. Bleeding episodes increased 1.8-fold during F U. However, the vast majority of these hemorrhagic events were clinically insignificant. In conclusion, the treatment strategy according to the CZEMP guidelines incorporating anagrelide is highly effective in reducing the platelet counts, strongly prevents venous events, reduces arterial events, and leads to an increase of minor hemorrhages. PMID- 23808750 TI - Learning-induced modulations of the stimulus-preceding negativity. AB - The neural basis of feedback expectation, which is crucial in learning theory, has only been minimally studied. Stimulus-preceding negativity (SPN), an ERP component that appears prior to the presentation of feedback, has been proposed as being related to feedback expectation. The present study showed, for the first time, amplitude modulations of the SPN component during learning acquisition in a trial-by-trial associative learning task. The results indicate that SPN could be a plausible electrophysiological index of the cognitive processes engaged while expecting the appearance of relevant feedback during reinforcement learning. PMID- 23808751 TI - Biological nutrients removal from the supernatant originating from the anaerobic digestion of the organic fraction of municipal solid waste. AB - This study critically evaluates the biological processes and techniques applied to remove nitrogen and phosphorus from the anaerobic supernatant produced from the treatment of the organic fraction of municipal solid waste (OFMSW) and from its co-digestion with other biodegradable organic waste (BOW) streams. The wide application of anaerobic digestion for the treatment of several organic waste streams results in the production of high quantities of anaerobic effluents. Such effluents are characterized by high nutrient content, because organic and particulate nitrogen and phosphorus are hydrolyzed in the anaerobic digestion process. Consequently, adequate post-treatment is required in order to comply with the existing land application and discharge legislation in the European Union countries. This may include physicochemical and biological processes, with the latter being more advantageous due to their lower cost. Nitrogen removal is accomplished through the conventional nitrification/denitrification, nitritation/denitritation and the complete autotrophic nitrogen removal process; the latter is accomplished by nitritation coupled with the anoxic ammonium oxidation process. As anaerobic digestion effluents are characterized by low COD/TKN ratio, conventional denitrification/nitrification is not an attractive option; short-cut nitrogen removal processes are more promising. Both suspended and attached growth processes have been employed to treat the anaerobic supernatant. Specifically, the sequencing batch reactor, the membrane bioreactor, the conventional activated sludge and the moving bed biofilm reactor processes have been investigated. Physicochemical phosphorus removal via struvite precipitation has been extensively examined. Enhanced biological phosphorus removal from the anaerobic supernatant can take place through the sequencing anaerobic/aerobic process. More recently, denitrifying phosphorus removal via nitrite or nitrate has been explored. The removal of phosphorus from the anaerobic supernatant of OFMSW is an interesting research topic that has not yet been explored. At the moment, standardization in the design of facilities that treat anaerobic supernatant produced from the treatment of OFMSW is still under development. To move toward this direction, it is first necessary to assess the performance of alternative treatment options. It study concentrates existing data regarding the characteristics of the anaerobic supernatant produced from the treatment of OFMSW and from their co-digestion with other BOW. This provides data documenting the effect of the anaerobic digestion operating conditions on the supernatant quality and critically evaluates alternative options for the post treatment of the liquid fraction produced from the anaerobic digestion process. PMID- 23808752 TI - Difference in quality of life, fatigue and societal participation between living and deceased donor kidney transplant recipients. AB - Purpose of this study was to assess whether living (LD) and deceased donor (DD) kidney transplant recipients differ in health-related quality of life (HRQoL), fatigue and societal participation, depending on time since transplantation and after adjustment for clinical and demographic variables. A questionnaire study was performed among 309 LD and 226 DD recipients (response rate 74% and 61%) transplanted between 1997 and 2009. After adjustment for age, sex, and education, LD recipients transplanted less than or equal to five yr ago experienced better HRQoL than DD recipients on the domains' role limitations due to physical problems, general health perception, and on the physical component summary score (all p < 0.05) and a better societal participation (all subscales, p < 0.05). No differences were found in the mental health domains. The LD recipients also had better renal clearance than DD recipients (62.1 vs. 55.9 mL/min, p = 0.01). After additional adjustment for renal clearance, the differences in HRQoL and societal participation between LD and DD recipients remained. No differences were found in recipients transplanted more than five yr ago. We conclude that LD recipients on average have better HRQoL and societal participation than DD recipients, in the first years after transplantation. PMID- 23808753 TI - TWA regionality and ECG lead dependence. PMID- 23808754 TI - Retrospective chart review in a cohort of patients with urticarial dermatitis. AB - Urticarial dermatitis is a poorly understood skin condition while it seems to be much more common than the paucity of reports suggest. It manifests with severely pruritic papules and plaques that resemble eczematous and urticarial lesions morphologically. The key clues to diagnosis are the urticarial appearance and overlap with an eczematous reaction. Here, we present a series of 19 cases (13 women and six men) with urticarial dermatitis clinically and histologically. The patients' average age was 58 and most of the cases were idiopathic. Trunk and proximal extremities were the most common sites involved followed by the distal extremities. Poor response to potent topical corticosteroids and antihistamines was usual and many patients required oral prednisone or other immunosuppressant agents or phototherapy. PMID- 23808755 TI - Contrast-enhanced computed tomographic evaluation of the deep digital flexor tendon in the equine foot compared to macroscopic and histological findings in 23 limbs. AB - REASONS FOR PERFORMING THE STUDY: Distal deep digital flexor tendinopathy is an important cause of foot lameness in horses that is difficult to diagnose with radiography and ultrasonography. Magnetic resonance imaging is a well-accepted and validated technique for the identification of deep digital flexor tendon (DDFT) lesions, but has some practical and financial drawbacks. Contrast-enhanced computed tomography (CECT) has been proposed as a suitable alternative, but validation studies are currently lacking. OBJECTIVE: To assess the accuracy of CECT for the identification and characterisation of deep digital flexor tendinopathy. STUDY DESIGN: Descriptive study of CT, macroscopic and histological findings of the DDFT. METHODS: Plain and CECT scans were acquired of 23 limbs of 16 horses with clinical lameness localised to the foot. All horses had lesions of the DDFT that were identified and characterised with CT and CECT with respect to their anatomic location and extent. All horses underwent post mortem examination and gross abnormalities were described. Samples of the DDFT were taken at specific sites (lesion and nonlesion) for histological evaluation. Macroscopic and histological outcomes were compared with CECT findings. RESULTS: Of 67 sites in 23 DDFTs that were evaluated, 42 sites in 18 tendons had lesions on CECT images. These 42 sites also had lesions on macroscopic evaluation. There were 3 false negative and 3 false positive results identified on CECT. The sensitivity of CECT for diagnosing lesions of the DDFT in the equine foot was 93%. CONCLUSION: CECT is an effective adjunct to the more commonly used diagnostic techniques in equine foot pain. PMID- 23808756 TI - Prescription headache medication in OEF/OIF veterans: results from the Women Veterans Cohort Study. AB - OBJECTIVE: To examine differences in male and female veterans of Operations Enduring Freedom/Iraqi Freedom (OEF/OIF) period of service in taking prescription headache medication, and associations between taking prescription headache medication and mental health status, psychiatric symptoms, and rates of traumatic events. BACKGROUND: Headaches are common among active service members and are associated with impairment in quality of life. Little is known about headaches in OEF/OIF veterans. METHODS: Veterans participating in the Women Veterans Cohort Study responded to a cross-sectional survey to assess taking prescription headache medication, mental health status (Post Deployment Health Assessment), psychiatric symptoms (portions of the Brief Patient Health Questionnaire and the Posttraumatic Stress Disorder Checklist), and traumatic events (the Traumatic Life Events Questionnaire and queries regarding military trauma). Gender differences among taking prescription headache medication, health status, psychiatric symptoms, and traumatic events were examined. Regression analyses were used to examine the influence of gender on the associations between taking prescription headache medication and health status, psychiatric symptoms, and traumatic events. RESULTS: 139/551 (25.2%) participants reported taking prescription headache medication in the past year. A higher proportion of women veterans (29.1%) reported taking prescription medication for headache in the last year compared with men (19.7%). Taking prescription headache medication was associated with poorer perceived mental health status, higher anxiety and posttraumatic stress disorder symptoms, and higher rates of traumatic events. The association between prescription headache medication use and perceived mental health status, and with the association between prescription headache medication use and posttraumatic stress disorder symptoms, was stronger for men than for women. CONCLUSIONS: Among OEF/OIF veterans, the prevalence of clinically relevant headache is high, particularly among women veterans. Taking prescription headache medication is associated with poor mental health status, higher rates of psychiatric symptoms, and higher rates of traumatic events; however, these variables did not appear to meaningfully account for gender differences in prevalence of taking prescription headache medication. Future research should endeavor to identify factors that might account for the observed differences. PMID- 23808757 TI - Intraoperative frozen pathology during robot-assisted laparoscopic radical prostatectomy: can ALEXISTM trocar make it easy and fast? AB - OBJECTIVE: To describe the first series of robot-assisted laparoscopic radical prostatectomy (RALP) using the ALEXISTM trocar device when removal of the specimen is necessary for intraoperative frozen-section pathology. MATERIALS AND METHODS: Consecutive RALP using the ALEXIS were prospectively catalogue. Perioperative data, including preoperative oncologic diagnosis, operative time, estimated blood loss (EBL), size of incision for umbilical trocar, complications related to trocar, and length of hospital stay, were analyzed. RESULTS: One hundred twenty-eight patients were analyzed. The mean operative time was 216 minutes, mean time to trocar placement was 4 minutes, and mean EBL was 172 mL. The incision size for a trocar was 2-3 cm in 117 patients and 1 incisional hernia was observed. The mean hospital stay was 3 days and mean follow-up was 4 months. CONCLUSION: The ALEXIS trocar provides an easy and fast intraoperative removal of the specimen for frozen pathology during RALP, even for large prostates. Safe and cosmetic results with a low intraoperative complication rate are acquired with the wound retractor. PMID- 23808758 TI - Fertility and sexual function in female Hodgkin lymphoma survivors of reproductive age. AB - AIMS AND OBJECTIVES: To assess the perceived fertility status and to determine the association between perceived fertility status and sexual function, as reported by young female Hodgkin lymphoma survivors. BACKGROUND: Young female Hodgkin lymphoma survivors are at risk of infertility and impaired sexual function. However, little is known about their awareness of infertility and its association with sexual functioning. DESIGN: A descriptive questionnaire survey. METHODS: In this cross-sectional study, a survey was completed by female Hodgkin lymphoma survivors (< 40 years). Outcome measures included self-reported fertility status and sexual problems and the internationally validated Female Sexual Function Index. RESULTS: In total, 36 survivors were included (mean age 32 years, SD 4). Eighteen women (50%) thought themselves fertile. Eight survivors (22%) who perceived themselves as being infertile were more often treated with alkylator-based chemotherapy, and 63% reported sexual dysfunction. Ten survivors (28%) were not aware as to whether they were fertile or not; seven of these would like to have children. The reported fertility status was related to age and chemotherapy regimen. Regarding sexuality, 14 (39%) of the female Hodgkin lymphoma survivors reported one or more sexual problem and none reported recovery. Female sexual dysfunction according to the Female Sexual Function Index was reported by 11 (31%) survivors. CONCLUSION: Almost 30% of Hodgkin lymphoma survivors do not know whether they are fertile or not. Overall sexual dysfunction is common in Hodgkin lymphoma survivors and comparable to the general population. However, a lack of desire was significantly more often reported in female Hodgkin lymphoma survivors. RELEVANCE TO CLINICAL PRACTICE: To prevent assumed infertility and unintended childlessness by postponing parenthood in young female survivors, awareness of fertility status is needed. There is also a need to routinely assess sexual function and provide adequate interventions to improve arousal and lubrication problems. PMID- 23808759 TI - Liver fibrosis progression in chronic hepatitis B patients positive for hepatitis B e antigen: a prospective cohort study with paired transient elastography examination. AB - BACKGROUND AND AIM: Chronic hepatitis B patients in immune-reactive hepatitis B e antigen (HBeAg)-positive phase may have more rapid progression than those in immune-tolerant phase. We aimed to evaluate the risk of liver fibrosis progression in HBeAg-positive patients at different phases. METHODS: Two hundred forty-seven HBeAg-positive patients without advanced fibrosis at baseline underwent liver stiffness measurement (LSM) by transient elastography in 2006 2008 and again in 2010-2012. Liver fibrosis progression was defined as increase in LSM by 30% or more to levels suggestive of advanced fibrosis at the second assessment. RESULTS: At baseline, the mean age was 38 +/- 11 years, 58% were males, alanine aminotransferase (ALT) was 65 +/- 52 IU/L, hepatitis B virus DNA was 4.2 +/- 1.2 log IU/mL, and LSM was 6.3 +/- 2.1 kPa. At an interval of 42 +/- 6 months, 13 patients (5.2%) developed liver fibrosis progression, and 106 patients (42.9%) required antiviral therapy. None of the clinical parameters (e.g., gender, age, ALT, hepatitis B virus DNA, hepatitis B surface antigen level, etc.) was associated with liver fibrosis progression. Among 74 and 137 patients in immune-tolerant and immune-reactive phase, 4.1% and 6.6% had liver fibrosis progression, and 12.2% and 67.2% received antiviral therapy respectively (P = 0.45 and P < 0.001). Immune-tolerant patients with low-normal (< 0.5* upper limit of normal) or high-normal ALT (0.5-1* upper limit of normal) also had similar risk of liver fibrosis progression (5.7% vs. 2.6%; P = 0.49). CONCLUSIONS: Liver fibrosis progression is uncommon in HBeAg-positive patients. Patients in immune-reactive phase treated with antiviral therapy did not have increased risk of liver fibrosis progression. PMID- 23808761 TI - Medical students' deliberate practice of patient assessments. PMID- 23808760 TI - Multilayered electrospun scaffolds for tendon tissue engineering. AB - Full-thickness rotator cuff tears are one of the most common causes of shoulder pain in people over the age of 65. High retear rates and poor functional outcomes are common after surgical repair, and currently available extracellular matrix scaffold patches have limited abilities to enhance new tendon formation. In this regard, tissue-engineered scaffolds may provide a means to improve repair of rotator cuff tears. Electrospinning provides a versatile method for creating nanofibrous scaffolds with controlled architectures, but several challenges remain in its application to tissue engineering, such as cell infiltration through the full thickness of the scaffold as well as control of cell growth and differentiation. Previous studies have shown that ligament-derived extracellular matrix may enhance differentiation toward a tendon or ligament phenotype by human adipose stem cells (hASCs). In this study, we investigated the use of tendon derived extracellular matrix (TDM)-coated electrospun multilayered scaffolds compared to fibronectin (FN) or phosphate-buffered saline (PBS) coating for use in rotator cuff tendon tissue engineering. Multilayered poly(E-caprolactone) scaffolds were prepared by sequentially collecting electrospun layers onto the surface of a grounded saline solution into a single scaffold. Scaffolds were then coated with TDM, FN, or PBS and seeded with hASCs. Scaffolds were maintained without exogenous growth factors for 28 days in culture and evaluated for protein content (by immunofluorescence and biochemical assay), markers of tendon differentiation, and tensile mechanical properties. The collagen content was greatest by day 28 in TDM-scaffolds. Gene expression of type I collagen, decorin, and tenascin C increased over time, with no effect of scaffold coating. Sulfated glycosaminoglycan and dsDNA contents increased over time in culture, but there was no effect of scaffold coating. The Young's modulus did not change over time, but yield strain increased with time in culture. Histology demonstrated cell infiltration through the full thickness of all scaffolds and immunofluorescence demonstrated greater expression of type I, but not type III collagen through the full thickness of the scaffold in TDM-scaffolds compared to other treatment groups. Together, these data suggest that nonaligned multilayered electrospun scaffolds permit tenogenic differentiation by hASCs and that TDM may promote some aspects of this differentiation. PMID- 23808762 TI - Hood nebulization: effects of head direction and breathing mode on particle inhalability and deposition in a 7-month-old infant model. AB - BACKGROUND: Aerosol drug delivery to infants is a strong function of their behavior. Infants can be active during medication administration, changing head position or breathing mode. The objective was to evaluate the influence of the head direction and breathing mode on the hood drug delivery in a 7-month-old girl airway model by using an approach that couples imaging with computational fluid dynamics (CFD). Three head directions, i.e., face up, face side, and sitting (face front), and two breathing modes, i.e., oronasal and nasal breathing, were studied. METHODS: The face-airway model was developed from computed tomography scans of a 7-month-old girl. Respiratory airflows and particle transport were simulated with the low Reynolds number kappa-omega turbulence model and Lagrangian tracking approach. Three pharmaceutical aerosol sizes (1, 2.5, and 5 MUm) via hood nebulization were considered under quiet breathing conditions (5 L/min). RESULTS: Both head direction and breathing mode can noticeably affect aerosol inhalability and lung delivery efficiency. A maximum of 20% difference in inhalability is observed among the three head positions. Facial-ocular depositions are predominantly influenced by head position, but not breathing mode. The facial-ocular deposition rate with the face-up position is about threefold that with the sitting position for 5-MUm particles. Nasal breathing gives about 17.8% lower lung deposition and about 65% higher facial-ocular deposition than the oronasal breathing. CONCLUSION: The face-side position has less facial-ocular deposition than the face-up position, while still achieving similar lung delivery efficiency. Because aerosols deposited around the eyes may cause irritation to the eyes, the face-side position appears to be a better option than the face-up position for comfort and safety reasons. PMID- 23808763 TI - Patterns of cerebral amyloid angiopathy define histopathological phenotypes in Alzheimer's disease. AB - AIMS: Pathological heterogeneity of Abeta deposition in senile plaques (SP) and cerebral amyloid angiopathy (CAA) in Alzheimer's disease (AD) has been long noted. The aim of this study was to classify cases of AD according to their pattern of Abeta deposition, and to seek factors which might predict, or predispose towards, this heterogeneity. METHODS: The form, distribution and severity of Abeta deposition (as SP and/or CAA) was assessed semiquantitatively in immunostained sections of frontal, temporal and occipital cortex from 134 pathologically confirmed cases of AD. RESULTS: Four patterns of Abeta deposition were defined. Type 1 describes cases predominantly with SP, with or without CAA within leptomeningeal vessels alone. Type 2 describes cases where, along with many SP, CAA is present in both leptomeningeal and deeper penetrating arteries. Type 3 describes cases where capillary CAA is present along with SP and arterial CAA. Type 4 describes a predominantly vascular phenotype, where Abeta deposition is much more prevalent in and around blood vessels, than as SP. As would be anticipated from the group definitions, there were significant differences in the distribution and degree of CAA across the phenotype groups, although Abeta deposition as SP did not vary. There were no significant differences between phenotype groups with regard to age of onset, age at death, disease duration and brain weight, or disease presentation. Women were over-represented in the type 1 phenotype and men in type 2. Genetically, type 3 (capillary subtype) cases were strongly associated with possession of the APOE epsilon4 allele. CONCLUSIONS: This study offers an alternative method of pathologically classifying cases of AD. Further studies may derive additional genetic, environmental or clinical factors which associate with, or may be responsible for, these varying pathological presentations of AD. PMID- 23808764 TI - Radionuclide antibody-conjugates, a targeted therapy towards cancer. AB - Targeted alpha therapy (TAT) is an investigational procedure which utilises monoclonal antibodies (mAbs), peptide conjugates and/or other chemical compounds. These bio-vectors are able to transport a dose of alpha particles to destroy cancer cells. Radionuclide antibody-conjugates (RACs), labelled with beta emitters, have already been used in humans. More recently, TAT has been introduced to treat oncological diseases mainly leukaemia and lymphoma. Encouraging results have also been obtained in solid neoplasms with the administration of anti-tenascin. This chimeric antibody labelled with astatine 211 was delivered in patients with recurrent brain tumours into a surgically created cavity. Conversely, a clinical trial using a standard TAT approach to treat patients with metastatic melanoma, observed the shrinkage of the solid tumour mass. This response in melanoma may lead to an alternative mechanism for TAT, called tumour-antivascular- alpha-therapy (TAVAT), and forms the basis of a novel approach to the treatment of cancer disease states. In this paper, we will concentrate mainly on the application of TAT using antibodies. In particular, an investigation into the major general features connected with the use of alpha emitters in cancer therapy will be discussed. The prospective role of TAT with RACs will also be outlined briefly, especially focussing on the most important therapeutic strategies to date based on antibodies radiolabelled with beta emitters. PMID- 23808765 TI - Generator breakthrough and radionuclidic purification in automated synthesis of 68Ga-DOTANOC. AB - 68Ga labeled radiopharmaceuticals, like 68Ga-DOATNOC and other similar peptides, are gaining relevance in PET-CT, thanks to relatively easy local generator production, that do not requires an installed cyclotron. However, generator produced 68Ga is typically of suboptimal purity, mainly due to the breakthrough of the parent radionuclide 68Ge. Modern automated synthesis modules adopt both fractionation methods and purification methods in order to get rid of 68Ge breakthrough. Purification methods are mainly based on based on cationic prepurification even if anionic purification has been adopted as well. This work studies the efficacy of cationic prepurification using commercial STRATA-X-C, as well as distribution of the 68Ge contaminant during all steps of the synthesis of labeled peptides. Generator waste, STRATA-X-C purification cartridge, synthesis waste and the final product are quantitatively analyzed by means of high resolution gamma ray spectrometry. Our results show that current method of purification is highly effective; initial 68Ge breakthrough of the order of 1 kBq is decreased by a factor greater than 100, with removal of about 61% of the contaminant 68Ge in the first purification passage; this allow an efficient labeling, since removal of the remaining impurity happens during chelation in the reactor vessel. In conclusion, the synthesis with modular automated system resulted to reliably produce 68Ga-DOTANOC, with limited if any user intervention. 68Ge content in the final formulation results lower than 2x10(-7)%, avoiding unjustified patient irradiation due to radionuclidic impurities and satisfying quality prerequisites for radiopharmaceutical preparations. PMID- 23808766 TI - Determination of CK2 specificity and substrates by proteome-derived peptide libraries. AB - Understanding the specificity of kinases enables prediction of their substrates and uncovering kinase functions in signaling pathways. Traditionally synthesized peptide libraries are used to determine the kinase specificity. In this study, a proteomics-based method was developed to determine the specificity of kinase by taking the advantages of proteome-derived peptide libraries and quantitative proteomics. Proteome-derived peptide libraries were constructed by digesting proteins in total cell lysate followed with dephosphorylation of the resulting peptides. After incubating the peptide libraries with/without CK2 for in vitro kinase assay, stable isotopic labeling based quantitative phosphoproteomics was applied to distinguish the in vitro phosphosites generated by CK2. By using the above approach, 404 CK2 in vitro phosphosites were identified by 1D LC-MS/MS. Those sites allowed the statistic determination of the CK2 specificity. In addition to the easy construction of the proteome-derived peptide library, another significant advantage of this method over the method with synthesized peptide libraries is that the identified phosphosites could be directly mapped to proteins for the screening of putative kinase substrates. It was found that the confidence for substrate identification could be significantly improved by comparing the in vitro CK2 sites with the in vivo sites identified by phosphoproteomics analysis of the same cell lines. By applying this integrated strategy, 138 phosphosites from 105 putative CK2 substrates of high confidence were determined. PMID- 23808767 TI - Laser photobiomodulation as a potential multi-hallmark therapy for age-related macular degeneration. PMID- 23808768 TI - Enhanced hole carrier transport due to increased intermolecular contacts in small molecule based field effect transistors. AB - Small molecules and oligomers can be synthesized with very high purity and precise molecular weights, but they often do not form uniform thin films while processed from solution. Decreased intermolecular contacts between the small molecules are another disadvantage. To increase the intermolecular contacts in small molecules, we have chosen i-indigo, as one of the conjugated molecular units. The electron poor i-indigo has been connected with electron rich triphenylamine to synthesize a donor-acceptor-donor type small molecule. The propeller shaped triphenylamine helps to increase the solubility of the small molecule as well as isotropic charge transport. The intermolecular spacing between the molecules has been found to be low and did not vary as a function of thermal annealing. This implies that the intermolecular contacts between the small molecules are enhanced, and they do not vary as a function of thermal annealing. Organic field effect transistors (OFET) fabricated using a small molecule exhibited a hole carrier mobility (MU) of 0.3 cm(2)/(V s) before thermal annealing. A marginal increase in MU was observed upon thermal annealing at 150 degrees C, which has been attributed to changes in thin film morphology. The morphology of the thin films plays an important role in charge transport in addition to the intermolecular spacing that can be modulated with a judicious choice of the conjugated molecular unit. PMID- 23808769 TI - The p53 pathway induction is not primarily dependent on Ataxia Telangiectasia Mutated (ATM) gene activity after fludarabine treatment in chronic lymphocytic leukemia cells. AB - The prognostic role of ATM defects is well documented in chronic lymphocytic leukemia. However, the predictive value of ATM inactivation is much less understood, even in response to common drugs like fludarabine. It has been demonstrated that CLL cells having inactive ATM exhibit defective phosphorylation of its downstream targets after fludarabine treatment. We performed alternative analysis focusing on fludarabine-induced p53 accumulation and induction of p53 downstream genes after artificial ATM inhibition and, in parallel, using cells with endogenous ATM inactivation. We show that after 24h fludarabine exposure: (i) 5 out of 8 ATM-deficient samples (63%) normally accumulated p53 protein, and (ii) all analyzed ATM-deficient samples (n = 7) manifested clear induction of p21, PUMA, BAX, and GADD45 genes. In all experiments, doxorubicin was used as a confined ATM inductor and confirmed effective ATM inactivation. In conclusion, CLL cells lacking functional ATM appear to have normal response to fludarabine regarding the p53 pathway activation. PMID- 23808770 TI - Adult attachment style and cortisol responses across the day in older adults. AB - The association between cortisol and adult attachment style, an important indicator of social relationships, has been relatively unexplored. Previous research has examined adult attachment and acute cortisol responses to stress in the laboratory, but less is known about cortisol levels in everyday life. The present study examined adult romantic attachment style and cortisol responses across the day. Salivary cortisol was collected at six time points during the course of the day in 1,807 healthy men and women from a subsample of the Whitehall II cohort. Significant associations were found between attachment on cortisol across the day and slope of cortisol decline. The lowest cortisol output was associated with fearful attachment, with preoccupied attachment having the highest levels and a flatter cortisol profile. The results tentatively support the proposition that attachment style may contribute to HPA dysregulation. PMID- 23808771 TI - Development of a high-throughput screen and its use in the discovery of Streptococcus pneumoniae immunoglobulin A1 protease inhibitors. AB - Streptococcus pneumoniae relies on a number of virulence factors, including immunoglobulin A1 protease (IgA1P), a Zn(2+) metalloprotease produced on the extracellular surface of the bacteria, to promote pathogenic colonization. IgA1P exhibits a unique function, in that it catalyzes the proteolysis of human IgA1 at its hinge region to leave the bacterial cell surface masked by IgA1 Fab, enabling the bacteria to evade the host's immune system and adhere to host epithelial cells to promote colonization. Thus, S. pneumoniae IgA1P has emerged as a promising antibacterial target; however, the lack of an appropriate screening assay has limited the investigation of this metalloprotease virulence factor. Relying on electrostatics-mediated AuNP aggregation, we have designed a promising high-throughput colorimetric assay for IgA1P. By using this assay, we have uncovered inhibitors of the enzyme that should be useful in deciphering its role in pneumococcal colonization and virulence. PMID- 23808772 TI - The frequency of HHV-8 infection in otherwise healthy blood donors as well as renal allograft recipients living in Iran. AB - BACKGROUND: Different reports from Middle East countries demonstrated Kaposi's sarcoma (KS) in transplant population. This vascular malignancy occurs mostly among immunocompromised individuals. Human herpesvirus 8 (HHV-8) appears to be the causative factor for the development of this neoplasm. Transplant programs are concerned about the frequencies of HHV-8 infection either in general population or transplant patients. METHODS: The current study was conducted in two phases. Firstly, we detected antibodies against HHV-8 in 790 otherwise healthy blood donors. Secondly, a total of 125 kidney allograft recipients evaluated as being seropositive for HHV-8. We utilized enzyme immunoassay (EIA) for serologic studies. RESULTS: Among blood donors, the male to female ratio was 1.05 (405 vs. 385 ) while the mean age was 38.9 +/- 11.7 years. The serostatus of none of these blood donors were positive for HHV-8. Among kidney recipients, the male to female ratio was 1.9 (82 vs. 43). The mean age was 39.01 +/- 14.77 years. Two (1.6%) patients were seropositive for HHV-8. CONCLUSION: The prevalence of HHV-8 infection among Iranians is likely to be low. Yet, owing to the evidence of this infection among kidney allograft recipients and its probable role in developing post- transplantation KS (PT-KS), further studies appear to be required to keep the various aspects of this infection under close surveillance. PMID- 23808773 TI - The standardization of Victoria Stroop Color-Word Test among Iranian bilingual adolescents. AB - BACKGROUND: The Stroop Color-Word Test is a classic instrument for the assessment of selective attention and inhibition control and is a highly utilized instrument in research aspects of executive functions of the brain. The purpose of the present study was a preliminary standardization of Stroop test among Iranian bilingual adolescents. METHODS: In this study, 150 subjects, including three groups of adolescents (12 - 13, 14 - 15, and 16 - 17-year-olds) were randomly selected. Also, 30 subjects with attention-deficit hyperactivity disorder (ADHD) were selected for the study of differential validity. The instruments of this study were Victoria Stroop Color- Word Test and Strengths and Difficulties Questionnaire (SDQ). RESULTS: Correlation coeffecients by test-retest in Stroop test for reaction times of three cards and reaction time interference were 0.86, 0.86, 0.93, and 0.64; and for errors of three cards and error interference were 0.67, 0.37, 0.81, and 0.75 respectively. All of the corellations were significant. Differential validity by comparing ADHD and control group showed that there were significant differences among groups. The results of age effect in Stroop variables showed that there were significant differences between age groups in reaction time of all cards and error of the first and third cards; but sex did not show any significant effect on Stroop variables. CONCLUSION: The findings suggest that reaction time and error of almost all cards of Stroop test are reliable and also have a good differential validity to discriminate ADHD from healthy controls in Iranian bilingual adolescents. Based on our findings, age but not sex is influential on performance of Stroop test. PMID- 23808774 TI - Hepatitis B virus surface antigen (HBsAg) mutations are rare but clustered in immune epitopes in chronic carriers from Sistan-Balouchestan Province, Iran. AB - BACKGROUND: Hepatitis B virus (HBV) gene and protein variations have frequently been observed in chronic patients. The aims of this study were to determine the genotypes as well as the patterns of HBsAg variations in chronically-infected patients from the south-eastern part of Iran. METHODS: Twenty- one chronic inactive HBV carriers from Sistan-Balouchestan Province (an area with a low prevalence of HBV complications such as cirrhosis and hepatocellular carcinoma [HCC]) were enrolled. The surface genes were amplified, sequenced, and subsequently aligned using international and national Iranian database. RESULTS: All strains belonged to genotype D, subgenotype D1, and subtype ayw2. Of all 39 mutations occurred at 31 nucleotide positions, 15 (38.5%) were missense (amino acid altering) and 24 (61.5%) were silent (no amino acid changing). At the amino acid level, 15 substitutions occurred; 10 (66.67%) were distributed in different immune epitopes, five of which (33.33%) were in B cell epitopes; four (36.27%) were distributed in T helper epitopes, and one (6.67%) occurred inside CTL epitopes. CONCLUSION: A narrowly-focused immune pressure has been on the surface proteins, especially at the B cell level, led to the emergence of escape mutants in these patients that might be related to the pathogenicity of HBV chronic infection. Also, due to the negative selection imposed on HBV genome and the uniqueness of genotype D in this ethnic group, complications (cirrhosis and HCC) are lower than other published studies. PMID- 23808775 TI - Prediction of regulatory factor X1 binding sites in promoters of RNA-binding proteins genes in mouse brain. AB - BACKGROUND: There is an increasing interest in the role of regulatory factor X1 (RFX1) and RNA-binding proteins (RBPs) during neural development. However, there are few reports about their interaction. METHODS: We extracted RNA and performed reverse transcription polymerase chain reaction (RT-PCR) to identify RFX1 expression in imprinting control region (ICR) mouse tissues, analyzed RFX1 domains and motif consensus by comparing public databases on the Internet, tested the motif consensus with affinity-capture and western blotting experiments with mouse brain tissue, and predicted the binding sites of RFX1 in promoter regions of mouse RBPs genes. RESULTS: The expression of RFX1 was higher in embryonic brain compared to embryonic kidney, heart, and liver, and its expression level was relatively stable and higher in mouse embryonic brain than neonatal brain. RFX1 had several domains, including domain A as an activation domain, DBD as a DNA binding domain, domain B and C which played an important role in dimerization, and domain D as dimerization domain. RFX1 had three different profiles motif consensus RFX1M00281, RFX1M00280, and RFX1 (EF-C) M00626. There were 79 RFX1 binding sites at the promoters of 65 of 323 RBPs genes. CONCLUSION: RFX1 as regulatory factor will have putative important regulating role in the expression of RBPs genes during embryonic development of mouse brain. PMID- 23808776 TI - Acute pelvic pain: evaluation of 503 cases. AB - AIM: The aim of this study was to investigate the etiology according to the age groups (adolescent, reproductive, and perimenopausal / menopausal periods) of women who were admitted with complaints of acute pelvic pain (APP). MATERIALS AND METHODS: Data from 503 patients diagnosed with APP were evaluated retrospectively. The patients were divided into three groups according to their ages. The adolescent group consisted of patients who were 19 years of age and under (Group A), the reproductive age group consisted of patients who were between the ages of 20 and 44 years (Group B), and the perimenopausal / menopausal group consisted of patients who were at the age of 45 and above (Group C). The most common causes of APP among the three groups were investigated. RESULTS: The mean age was 29.9 +/- 6.01 years. Gynecologic factors were present in 469 cases, APP was nongynecologic in nature in 24 cases, while the cause was unknown in 10 cases. The patients were evaluated in terms of APP duration, accompanying symptoms, and pain localization. There were 36 cases in the adolescent group, 361 cases in the reproductive age group, and 72 cases in the perimenopausal / menopausal group. Adnexal pathologies were the most commonly observed APP factor in all three groups. CONCLUSION: APP was most commonly observed in the reproductive period, and adnexal pathologies and infections were etiologically prominent. Early and accurate diagnosis of APP will often enable more effective and conservative treatment methods for life-threatening pathologies. PMID- 23808778 TI - Long- term efficacy and safety of vanadium in the treatment of type 1 diabetes. AB - BACKGROUND: Vanadium compounds are able to reduce blood glucose in experimentally induced diabetic rats and type 2 diabetic patients, but data about their long- term safety and efficacy in diabetic patients are scarce. METHODS: Fourteen type 1 diabetic patients received oral vanadyl sulfate (50 - 100 mg TID) for a period of 30 months. Fasting blood sugar (FBS), lipid levels, hematologic, and biochemical parameters were measured before and periodically during the treatment. RESULTS: The daily doses of insulin decreased from 37.2 +/- 5.5 to 25.8 +/- 17.3 units/day and at the same time the mean FBS decreased from 238 +/- 71 to 152 +/- 42 mg/dL. Meanwhile, there was a decrease in plasma total cholesterol without any change in triglyceride level. No significant clinical or paraclinical side effects, with the exception for mild diarrhea at the beginning of treatment, were observed during 30 months therapy. CONCLUSION: Vanadium is effective and safe for long- term use in type 1 diabetic patients. PMID- 23808777 TI - Dietary glycemic index, glycemic load, and cardiovascular disease risk factors: Tehran Lipid and Glucose Study. AB - BACKGROUND: Data available on the effect of quality (glycemic index [GI]) and quantity (glycemic load [GL]) of carbohydrates on the risk factors of cardiovascular disease (CVD) are inconsistent. The objective of this study was to examine the association between dietary GI, GL, and CVD risk factors among Tehranian adults, the participants of the Tehran Lipid and Glucose Study. METHODS: This population- based cross-sectional study was conducted on 2457 subjects (46% men and 54% women), aged 19 to 84 years. Dietary GI and GL were measured using a validated 168- item semiquantitative food frequency questionnaire. Anthropometrics, blood pressure, fasting blood glucose, and lipid profiles were measured. RESULTS: The mean intakes of GI and GL were 68.3 and 244.8, respectively. Rice (26.6%) and bread (19.0%) were the major contributors to dietary GI and GL, respectively. Higher dietary GI and GL were associated with high intakes of carbohydrate, fiber, refined grain, fruits, simple sugar, snack, and desserts. After adjustment for lifestyle and dietary variables, a higher dietary GI was positively associated with triglycerides and high-density lipoprotein (HDL) cholesterol concentrations among obese subjects. Dietary GL was positively associated with fasting and 2-h blood glucose among nonobese subjects, after adjustment for confounders. CONCLUSION: Dietary GI and GL were associated with a few CVD risk factors, and body mass index levels may modulate these associations. PMID- 23808779 TI - A systematic review of magnesium therapy for treating attention deficit hyperactivity disorder. AB - There are contradictory reports about the association of magnesium and attention- deficit hyperactivity disorder (ADHD). Moreover, some studies reported that magnesium is effective for treating ADHD. This is the first systematic review evaluating the effectiveness of magnesium to treat patients with ADHD. The two databases of MEDLINE/ PubMedline and Google Scholar were electronically searched using the search items and considering inclusion and exclusion criteria. Out of the 37 titles, only six studies were experimental interventional studies. However, three of these studies were without any control group. The other three studies were controlled clinical trials. Nevertheless, none of the studies was a randomized double- blind controlled clinical trial. These studies supported that magnesium is effective for treating ADHD. Magnesium monotherapy studies were not found. There is no well- controlled clinical trial investigating the efficacy and safety of magnesium for treating ADHD. In addition, the safety of magnesium in ADHD is ignored. Therefore, until further strong evidences for its efficacy and safety are provided, magnesium is not recommended for treating ADHD. PMID- 23808780 TI - Natural course of thyroid disease profile in a population in nutrition transition: Tehran Thyroid Study. AB - BACKGROUND: There is a lack of data regarding the incidence rate, etiology, risk factors, and natural course of thyroid disorders and their relationship with cardiovascular disease and mortality in populations undergoing nutrition transition. Therefore, we aimed to assess the natural course of thyroid disease in Tehranians, a population in nutrition transition. METHODS AND DESIGN: Between March 1997 and December 2004, 5769 individuals, aged >= 20 years, were selected from district No.13 of Tehran and followed up every three years. Data on risk factors for cardiovascular disease such as diabetes, hyperlipidemia, smoking, obesity, hypertension, low levels of physical activity, and dietary habits were obtained at baseline and again every three years. Cardiovascular and mortality outcomes were assessed in detail. CONCLUSION: The results of this study will provide a better recognition regarding the incidence and risk factors of thyroid disorders and their relationship with cardiovascular outcomes and mortality in a community in nutrition transition. PMID- 23808781 TI - Hypocellular/lymphohistiocytic variant of Anaplastic Large Cell Lymphoma of lymph node, mimicking granulation tissue. AB - Anaplastic Large Cell Lymphoma (ALCL) is a subgroup of T/null cell non-Hodgkin lymphoma (NHL) in WHO classification. Lymphohistiocytic (LH) variant constitutes about 10% of all ALCLs and characterized by presence of abundant reactive histiocytes that can mask the neoplastic nature of the lesion, leading to misdiagnose as "reactive lymphadenopathy". Here we introduce a 16-year-old female patient, diagnosed as hypocellular LH variant ALCL with unusual histologic feature including granulation tissue- like appearance. We emphasize that in young patients with unusual- looking reactive lymphadenopathy, ALCL should be considered as one of differential diagnoses. A brief review of the nature of the lesion and differential diagnoses is also included. PMID- 23808782 TI - Oral hobnail hemangioma: a case report. AB - Hobnail hemangioma is a benign vascular lesion and intraoral of the lesions are relatively rare. Histopathologically, it shows distinctive biphasic pattern with vascular channels lined by endothelial cells showing characteristic "hobnail" cytomorphology. Since hobnail hemangioma shares similar clinical and histopathologic features with many other benign and malignant vascular tumors, accurate diagnosis is mandatory for proper treatment and prognosis. In the present study, emphasis was given to discuss the differential diagnosis and delineate the hobnail hemangioma from other vascular lesions. Further, immunohistochemical study was performed which showed strong immunopositivity for CD31 and factor VIII in all endothelial cells lining the vascular channels. CD34 was moderately immunopositive and vascular endothelial growth factor was negative. PMID- 23808783 TI - Heart-lung transplantation in Iran: a case report. AB - We report our initial experience with a heart-lung transplant operation performed on a 12- year- old girl with Eisenmenger syndrome at Masih Daneshvari Teaching Hospital in Tehran, in 2009. We also outline the operative indications, anesthetic management, and postoperative complications of heart-lung transplantation. We hope that this issue on transplantation may provide an encouraging prospect for patients with end-stage cardiopulmonary disorders in Iran. PMID- 23808784 TI - Cytologic findings of urogenital mesenteric cyst. AB - Mesenteric cysts are heterogeneous groups of lesions. Most of them are developmental cysts of lymphatic and enteric origin or cystic neoplasm such as mesothelioma or cystic teratoma. Urogenital cysts are a subcategory of developmental cysts of the mesentery. They are thought to arise from vestigial remnants of urogenital apparatus. These cysts may show evidence of mesonephric or metanephric differentiation. An 11 -year -old boy was presented with undescended testis. During preoperative work- up, an incidental cystic lesion was discovered which was attached to the ileum. Aspiration cytology of the cyst content revealed cuboidal to columnar cells; some of them were ciliated. Histologic examination showed a cyst with fibromuscular wall, lined by Mullerian type ciliated epithelium; so the diagnosis of urogenital mesenteric cyst of Mullerian type was made. Urogenital cysts are rare lesions, but they should be considered in differential diagnosis of any cystic lesion of the mesentery. Cytology could be a useful method for evaluation and revealing the nature of these cysts. PMID- 23808785 TI - Photoclinic. Giant cell tumor of tendon sheath in the subacromial space. PMID- 23808786 TI - Effects of neurofeedback versus stimulant medication in attention deficit/hyperactivity disorder: a randomized pilot study. AB - OBJECTIVE: The purpose of this pilot study was to compare the effects of 30 sessions of neurofeedback (NF) with stimulant medication on attention deficit/hyperactivity disorder (ADHD) patients. METHODS: Thirty-two medication naive ADHD patients, ages 7-16, from a neuropsychiatric clinic, were randomized to NF (n=16) or drug treatment (n=16). Other actions, such as parent management training, information, or support in school were given as needed, with no differences between the groups. All participants were assessed before treatment on two rating scales, each with parent and teacher forms. In addition, quantitative electroencephalogram (QEEG) and event-related potentials (ERPs), which included behavioral data from a go/no go test were administered. NF training took place in the clinic over a period of 7-11 months, and was followed by a repeat of the same assessment tools. The mean time interval between pre- and postassesment was not significantly different in the two groups. The 18 symptoms of ADHD (American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV)) were used as the primary outcome measure. RESULTS: Analysis of covariance revealed a significant difference between the groups at evaluation in favor of medication, with a large effect size. This picture was confirmed by other outcome measures. The QEEG spectral power in the theta and beta bands did not change in either group. In ERP, the P3 no go component increased significantly in 8 of 12 patients who had a clinically relevant medication effect, but did not increase in the medication nonresponders or the NF group. CONCLUSIONS: Our study supports effects for stimulants, but not for NF. Effects of NF may require thorough patient selection, frequent training sessions, a system for excluding nonresponders, and active transfer training. The P3 no go ERP component may be a marker for treatment response. PMID- 23808787 TI - Healthy Foods North improves diet among Inuit and Inuvialuit women of childbearing age in Arctic Canada. AB - BACKGROUND: Healthy Foods North (HFN) is a community-based intervention designed to promote a healthy diet and lifestyle of Inuit and Inuvialuit populations in Arctic Canada. The objective of the present study was to determine the effects of HFN on the nutrient intake of women of childbearing age. METHODS: Six communities in Nunavut (n = 3) and the Northwest Territories (n = 3) were selected for programme implementation; four received a 12-month intervention and two served as controls. Quantitative food frequency questionnaires were used to assess dietary intake at baseline and 1 year post-intervention. Among women participants aged 19 44 years (n = 136), 79 were exposed to the intervention and 57 were not. Mean daily energy and nutrient intake and density were determined. Dietary adequacy was assessed by comparing the women's daily nutrient intakes with dietary reference intakes (DRI). RESULTS: Main outcomes were the pre- to post intervention changes between intervention and control groups for energy and selected nutrient intakes, nutrient density and dietary adequacy. Among the participants, the intervention had a beneficial effect on vitamin A and D intake. The percentage of individuals with nutrient intakes below the DRI increased from pre- to post-intervention for vitamin A and D in the control group but only for vitamin A in the intervention group. The programme did not have a significant impact on calorie, sugar, or fat consumption. CONCLUSIONS: The HFN programme is effective in mitigating some of the negative impacts of the nutrition transition on dietary adequacy among Inuit and Inuvialuit women of childbearing age. PMID- 23808788 TI - Optimal use of acute headache medication: a qualitative examination of behaviors and barriers to their performance. AB - OBJECTIVE: This study aims to qualitatively examine the behaviors required to optimally use acute headache medication and the barriers to successful performance of these behaviors. BACKGROUND: The efficacy of drug treatment is partly determined by medication adherence. The adherence literature has focused almost exclusively on the behaviors required to optimally use medications that are taken on a fixed schedule, as opposed to medications taken on an as needed basis to treat acute episodes of symptoms, such as headaches. METHODS: Twenty-one people with headache and 15 health care providers participated in qualitative phenomenological interviews that were transcribed and coded by a multidisciplinary research team using phenomenological analysis. RESULTS: Interviews revealed 8 behaviors required to optimally use acute headache medication, including cross-episode behaviors that people with headache regularly perform to ensure optimal acute headache medication use, and episode-specific behaviors used to treat an individual headache episode. Interviews further revealed 9 barriers that hinder successful performance of these behaviors. CONCLUSIONS: Behaviors required to optimally use acute headache medication were numerous, often embedded in a larger chain of behaviors, and were susceptible to disruption by numerous barriers. PMID- 23808789 TI - Interaction between whole buttermilk and resveratrol. AB - The interaction between buttermilk and resveratrol (trans-3,5,4' trihydroxystilbene) was examined using fluorescence spectroscopy. Ultracentrifugation of buttermilk (10% total solids, TS)-resveratrol (100-1600 MUM) mixtures yielded three fractions comprising cream (14.79% w/w, 1.12% TS), milk serum (75.94% w/w, 5.56% TS), and a casein-rich precipitate (9.27% w/w, 2.94% TS). The majority of the added resveratrol was partitioned into the casein rich precipitate (50.5-56.8%), with lesser amounts in the milk serum (35.3-41.2%) and cream layer (7.9-8.7%), demonstrating that most of the resveratrol interacted with the proteins. The interaction of the milk proteins with resveratrol was investigated by measuring the quenching of protein intrinsic fluorescence. Complex formation was spontaneous and exothermic. The apparent binding constants between milk proteins in buttermilk and resveratrol were >= 2.47 * 10(4), 1.65 * 10(4), 1.11 * 10(4), and 0.72 * 10(4) M(-1), respectively, at 278, 288, 298, and 308 K. The increased aqueous solubility of resveratrol by complexation to whole buttermilk makes it useful as a food vehicle for carrying resveratrol. PMID- 23808790 TI - Hospice nurses' perspectives of spirituality. AB - AIMS AND OBJECTIVES: To explore Singapore hospice nurses' perspectives of spirituality and spiritual care. DESIGN: A descriptive, cross-sectional design was used. BACKGROUND: Spiritual care is integral to providing quality end-of-life care. However, patients often report that this aspect of care is lacking. Previous studies suggest that nurses' neglect of this aspect of care could be attributed to poor understanding of what spirituality is and what such care entails. This study aimed to explore Singapore hospice nurses' perspectives about spirituality and spiritual care. METHODS: A convenience sample of hospice nurses was recruited from the eight hospices in Singapore. The survey comprised two parts: the participant demographic details and the Spirituality Care-Giving Scale. This 35-item validated instrument measures participants' perspectives about spirituality and spiritual care. RESULTS: Sixty-six nurses participated (response rate of 65%). Overall, participants agreed with items in the Spiritual Care-Giving Scale related to Attributes of Spiritual Care; Spiritual Perspectives; Spiritual Care Attitudes; and Spiritual Care Values. Results from general linear model analysis showed statistically significant main effects between race, spiritual affiliation and type of hospice setting, with the total Spiritual Care-Giving Scale score and four-factor scores. CONCLUSIONS: Spirituality was perceived to be universal, holistic and existential in nature. Spiritual care was perceived to be relational and centred on respecting patients' differing faiths and beliefs. Participants highly regarded the importance of spiritual care in the care of patients at end-of-life. Factors that significantly affected participants' perspectives of spirituality and spiritual care included race, spiritual affiliation and hospice type. RELEVANCE TO CLINICAL PRACTICE: Study can clarify values and importance of spirituality and care concepts in end of-life care. Accordingly, spirituality and care issues can be incorporated in multi-disciplinary team discussions. Explicit guidelines regarding spiritual care and resources can be developed. PMID- 23808791 TI - Temporal trends in in vitro antimicrobial susceptibility patterns of bacteria isolated from foals with sepsis: 1979-2010. AB - REASONS FOR PERFORMING THE STUDY: Monitoring the development of antimicrobial resistance is important for the rational selection of appropriate antimicrobial drugs to initiate treatment of foals with sepsis. OBJECTIVES: To identify temporal trends in antimicrobial susceptibility patterns of bacteria isolated from foals with sepsis. STUDY DESIGN: Retrospective review of medical records. METHODS: Foals aged <30 days with a diagnosis of sepsis, confirmed by culture of bacteria, were included. Susceptibility data, expressed as minimum inhibitory concentrations (MICs) (MIC50 , MIC90 , MIC range) and percent of isolates that were susceptible to a particular antimicrobial drug, were compared for bacteria isolated from foals during 3 different time periods: 1979-1990, 1991-1997 and 1998-2010. The Cochran-Armitage trend test and the Jonckheere-Terpstra test were used for statistical analysis. RESULTS: A total of 1091 bacterial isolates were cultured from 588 foals. Enterobacteriaceae, Actinobacillus spp. and beta haemolytic Streptococcus spp. showed a decrease in percent of isolates susceptible to gentamicin over time. Enterobacteriaceae, Actinobacillus spp. and beta-haemolytic Streptococcus spp. showed an increase in MIC values for amikacin. Enterobacteriaceae showed a decrease in percent of isolates susceptible to ceftiofur. Enterococcus spp. and Pseudomonas spp. showed increased MIC values to ceftiofur. Enterobacteriaceae showed increased MIC values to ceftizoxime. Enterococcus spp. became more resistant to imipenem and showed increased MIC values to ticarcillin/clavulanic acid. In contrast, several trends in increased susceptibility were also seen. CONCLUSIONS: Based on these in vitro results, the combination of amikacin and ampicillin remains an appropriate choice for initiating treatment of sepsis in foals while awaiting culture and susceptibility test results, although increasing development of resistance to amikacin was demonstrated. The decrease in in vitro activity of ceftiofur against Enterobacteriaceae is of concern. Similarly, the development of resistance of Enterococcus spp. to imipenem is an important finding that warrants monitoring in the future. Judicious use of antimicrobials is therefore crucial. PMID- 23808792 TI - Down-regulation of apurinic/apyrimidinic endonuclease 1 (APE1) in spinal motor neurones under oxidative stress. AB - AIM: Apurinic/apyrimidinic endonuclease 1 (APE1) is an intermediate enzyme in base excision repair which is important for removing damaged nucleotides under normal and pathological conditions. Accumulation of damaged bases causes genome instability and jeopardizes cell survival. Our study is to examine APE1 regulation under oxidative stress in spinal motor neurones which are vulnerable to oxidative insult. METHODS: We challenged the motor neurone-like cell line NSC 34 with hydrogen peroxide and delineated APE1 function by applying various inhibitors. We also examined the expression of APE1 in spinal motor neurones after spinal root avulsion in adult rats. RESULTS: We showed that hydrogen peroxide induced APE1 down-regulation and cell death in a differentiated motor neurone-like cell line. Inhibiting the two functional domains of APE1, namely, DNA repair and redox domains potentiated hydrogen peroxide induced cell death. We further showed that p53 phosphorylation early after hydrogen peroxide treatment might contribute to the down-regulation of APE1. Our in vivo results similarly showed that APE1 was down-regulated after root avulsion injury in spinal motor neurones. Delay of motor neurone death suggested that APE1 might not cause immediate cell death but render motor neurones vulnerable to further oxidative insults. CONCLUSION: We conclude that spinal motor neurones down-regulate APE1 upon oxidative stress. This property renders motor neurones susceptible to continuous challenge of oxidative stress in pathological conditions. PMID- 23808793 TI - Fibronectin matrix mimetics promote full-thickness wound repair in diabetic mice. AB - During tissue repair, fibronectin is converted from a soluble, inactive form into biologically active extracellular matrix (ECM) fibrils through a cell-dependent process. ECM fibronectin promotes numerous cell processes that are critical to tissue repair and regulates the assembly of other proteins into the matrix. Nonhealing wounds show reduced levels of ECM fibronectin. To functionally mimic ECM fibronectin, a series of fibronectin matrix mimetics was developed by directly coupling the matricryptic, heparin-binding fragment of the first type III repeat of fibronectin (FNIII1H) to various sequences from the integrin binding domain (FNIII8-10). The recombinant proteins were produced as glutathione S-transferase (GST)-tagged fusion proteins for ease of production and purification. Full-thickness, excisional wounds were produced in genetically diabetic mice, and fibronectin matrix mimetics were applied directly to the wounds. A significant enhancement of wound closure was observed by day 9 in response to GST/III1H,8-10 versus GST-treated controls (73.9%+/-4.1% vs. 58.1%+/ 4.7% closure, respectively). Two weeks after injury, fibronectin matrix mimetic treated wounds had developed a multi-layered epithelium that completely covered the wound space. Furthermore, significant increases in granulation tissue thickness were observed in response to treatment with GST/III1H,8-10 (4.05+/-0.93 fold), GST/III1H,8,10 (2.91+/-0.49-fold), or GST/III1H,8(RGD) (3.55+/-0.59-fold) compared with GST controls, and was accompanied by dense collagen deposition, the presence of myofibroblasts, and functional vasculature. Thus, the recombinant fibronectin matrix analogs normalized the impairment in repair observed in this chronic wound model and may provide a new approach to accelerate the healing of diabetic wounds. PMID- 23808794 TI - Chronic hepatitis C infection is associated with insulin resistance and lipid profiles. AB - BACKGROUND AND AIM: Chronic hepatitis C virus (HCV) infection has been suggested to be associated with non-insulin-dependent diabetes mellitus and lipid profiles. This study aimed to investigate the possible relationships of insulin resistance (IR) and lipid profiles with chronic hepatitis C (CHC) patients in Taiwan. METHODS: We enrolled 160 hospital-based CHC patients with liver biopsy and the 480 controlled individuals without CHC and chronic hepatitis B from communities without known history of non-insulin-dependent diabetes mellitus. Fasting plasma glucose, total cholesterol, high-density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides (TGs), alanine aminotransferase, and serum insulin levels, and homeostasis model assessment (HOMA-IR) were tested. RESULTS: When comparing factors between CHC patients, and sex- and age-matched controls who had no HCV infection, patients with HCV infection had a significantly higher alanine aminotransferase level, fasting plasma glucose level, insulin level, and HOMA-IR (P < 0.001, P = 0.023, P = 0.017, and P = 0.011, respectively), and significantly lower TG level (P = 0.023), total cholesterol, and HDL-C and LDL-C levels (all P < 0.001) than 480 controls. In multivariate logistic regression analyses, a low total cholesterol, a low TGs, and a high HOMA-IR are independent factors significantly associated with chronic HCV infection. In the 160 CHC patients (41 patients with high HOMA IR [> 2.5]), a high body mass index, TGs, and HCV RNA level are independent factors significantly associated with high HOMA-IR in multivariate logistic analyses. CONCLUSIONS: Chronic HCV infection was associated with metabolic characteristics including IR and lipid profile. IR was also associated with virological characteristics. PMID- 23808795 TI - Chemical adsorption enhanced CO2 capture and photoreduction over a copper porphyrin based metal organic framework. AB - Effective CO2 capture and activation is a prerequisite step for highly efficient CO2 reduction. In this study, we reported a case of Cu(2+) in a porphyrin based MOF promoted enhanced photocatalytic CO2 conversion to methanol. Compared with the sample without Cu(2+), the methanol evolution rate was improved as high as 7 times. In situ FT-IR results suggested that CO2 chemical adsorption and activation over Cu(2+) played an important role in improving the conversion efficiency. PMID- 23808796 TI - Asthma control and concordance of opinions between patients and pulmonologists. AB - Patient-physician opinion concordance could play a key role in asthma control. There have been no studies evaluating this association in large samples of patients. OBJECTIVES: To determine opinion concordance between asthma patients and their pulmonologists on the impact of the disease and to correlate concordance to asthma control. METHODS: This was a cross-sectional multicentre study including 1160 patients and 300 pulmonologists. Patient-physician concordance rates were assessed by two semi-structured qualitative questionnaires: (1) impact of the disease and (2) treatment satisfaction. Subsequently, participating pulmonologists determined the concordance between their perceptions and their patient's. Sociodemographic and clinical data were recorded for all patients. RESULTS: In 53.6% of cases, asthma was controlled. The rate of patient-pulmonologist concordance on disease impact on patient daily life was 57%, with physicians underestimating the impact (compared to patients) in 26% of cases. Concordance on satisfaction with treatment was 56%, with physicians underestimating satisfaction in 26% of cases. Patient-physician discordance rates were significantly lower among patients with controlled asthma (29 and 32.1%) than those with poor control (73.7 and 73.1%). CONCLUSIONS: Patient-pulmonologist concordance on perceptions of disease impact is low, particularly in uncontrolled asthma. This poor concordance should be addressed in education programmes, particularly for patients with uncontrolled symptoms. PMID- 23808799 TI - The value of real-time clinician feedback during OSCEs. PMID- 23808798 TI - Prognostic impact of monocyte count at presentation in mantle cell lymphoma. AB - An increased number of circulating monocytes at presentation has recently been associated with shorter survival in Hodgkin lymphoma, follicular lymphoma and diffuse large B cell lymphoma. This study aimed to assess the prognostic impact of the absolute monocyte count (AMC) at diagnosis in mantle cell lymphoma (MCL). AMC at diagnosis was available in 97 MCL cases recorded in the databases of the Oncology Institute of Southern Switzerland in Bellinzona (Switzerland) and the Division of Haematology of the Amedeo Avogadro University of Eastern Piedmont in Novara (Italy). With a median follow up of 7 years, the 5-year overall survival was 29% for patients with AMC >0.50 * 10(9) /l and 62% for patients with AMC <=0.50 * 10(9) /l (P = 0.008). Elevated AMC and beta-2 microglobulin at diagnosis remained independent outcome predictors at multivariate analysis, controlling for the MCL International Prognostic Index (MIPI), and have been used to build a simple prognostic scoring system. In this relatively small and heterogeneous series an increased AMC identified poor-risk patients. Our results suggest that AMC together with the beta-2 microglobulin level might provide an inexpensive way to stratify MCL patient risk as a complement to the MIPI, which was confirmed to be a very powerful prognostic tool. PMID- 23808797 TI - The physical environment and child development: an international review. AB - A growing body of research in the United States and Western Europe documents significant effects of the physical environment (toxins, pollutants, noise, crowding, chaos, and housing, school and neighborhood quality) on children and adolescents' cognitive and socioemotional development. Much less is known about these relations in other contexts, particularly the global South. We thus briefly review the evidence for relations between child development and the physical environment in Western contexts, and discuss some of the known mechanisms behind these relations. We then provide a more extensive review of the research to date outside of Western contexts, with a specific emphasis on research in the global South. Where the research is limited, we highlight relevant data documenting the physical environment conditions experienced by children, and make recommendations for future work. In these recommendations, we highlight the limitations of employing research methodologies developed in Western contexts (Ferguson & Lee, 2013). Finally, we propose a holistic, multidisciplinary, and multilevel approach based on Bronfenbrenner's (1979) bioecological model to better understand and reduce the aversive effects of multiple environmental risk factors on the cognitive and socioemotional development of children across the globe. PMID- 23808800 TI - De novo malignancy post-liver transplantation: a single center, population controlled study. AB - BACKGROUND: With the growing numbers of liver transplant recipients, it is increasingly important to understand the risks of de novo malignancy after liver transplantation. AIM: To characterize the incidence of de novo malignancy after liver transplantation compared with a control non-transplant population. METHODS: We studied 534 Indiana state residents undergoing liver transplantation at our center between 1997 and 2004, followed through August 2010. The incidence and predictors of malignancy were determined. The standardized incidence ratio (SIR) of cancer in our cohort was compared with age-, gender-, and period-matched state population using the Indiana State Cancer Registry. RESULTS: After a mean follow up of 5.7 +/- 3.2 yr, 73 patients (13.7%) developed 80 cancers, with five- and 10 yr incidence rates of 11.7% and 24.8%, respectively. These included 24 (30%) skin, 16 (20%) hematologic, and 40 (50%) solid tumors. The most common solid cancers were aerodigestive. Compared with matched state population, liver transplant recipients had significantly higher incidence of all cancers (SIR: 3.1, 95% CI [Confidence interval]: 2.9-3.2), skin (melanoma) (SIR: 5.8, 95% CI: 4.7-7.0), hematologic (SIR: 7.1, 95% CI: 6.3-8.0), and solid (SIR: 2.7, 95% CI: 2.5-2.8) tumors. CONCLUSION: There is a significantly increased risk of de novo malignancies after liver transplantation, highlighting the need for surveillance strategies in this population. PMID- 23808801 TI - Accountable care organizations: benefits and barriers as perceived by Rural Health Clinic management. AB - INTRODUCTION: Rural Health Clinics (RHCs) have served the primary healthcare needs of the medically underserved in US rural areas for more than 30 years. As a new model of healthcare delivery, the Accountable Care Organization (ACO) offers potential opportunities for addressing the healthcare needs of rural populations, yet little is known about how the ACO model will meet the needs of RHCs. This article reports on the results of a survey, focus groups, and phone interviews with RHC management personnel on the subject of benefits of and barriers to RHC participation in ACOs. METHODS: Survey research, focus groups, and phone interviews were used to gather and analyze the opinions of RHCs' management about the benefits of and barriers to ACO participation. The study population consisted of all 2011 RHCs in Region 4 (Southeastern USA; as designated by the Department of Health and Human Services). California RHCs were used for comparison. Themes and concepts for the survey questionnaire were developed from recent literature. The survey data were analyzed in two stages: (1) analyses of the characteristics of the RHCs and their responses; and (2) bivariate analyses of several relationships using a variety of statistics including analysis of variance, Pearson's χ2 and likelihood χ2. Relationships were examined between the RHCs' willingness to join ACOs and the respondent clinic's classification (as provider-based or independent). In addition, willingness to join ACOs among Region 4 RHCs was compared with those in California. Finally, in order to gain a broader understanding of the results of the survey, focus groups and phone interviews were conducted with RHC personnel. RESULTS: It was found that the ACO model is generally unfamiliar to RHCs. Approximately 48% of the survey respondents reported having little knowledge of ACOs; the focus group participants and interviewees likewise reported a lack of knowledge. Among respondents who were knowledgeable about ACOs, the most frequently citied potential benefit of ACOs (58%) was improved patient quality of care, followed by a focus on the patient (54%). More than half of the respondents (53%) cited 'financing' as a deterrent to RHC participating in ACOs. Many (43%) reported that their clinic had inadequate capital to improve their information technology systems. Another 51% cited legal and regulatory barriers. CONCLUSIONS: While the ACO model was unfamiliar to many of the RHC study participants, many suggested that ACOs may promote the quality of health care for RHC patients and their communities. If, on the other hand, RHCs are not provided the necessary technical assistance or not valued as ACO partners, ACOs may not improve the services that RHCs provide. As the ACO model evolves, the authors will determine whether it will benefit RHCs and their patients, or how the ACO must be modified to accommodate the unique needs of RHCs. PMID- 23808802 TI - Glutathione reductase activity with an oxidized methylated glutathione analog. AB - The activity of glutathione reductase with an unnatural analog of oxidized glutathione was explored. The analog, L-gamma-glutamyl-2-methyl-L-cysteinyl glycine disulfide, places an additional methyl group on the alpha position of each of the central cysteine residues, which significantly increases steric bulk near the disulfide bond. Glutathione reductase was completely unable to catalyze the sulfur-sulfur bond reduction of the analog. Additionally, enzyme kinetics experiments indicated that the analog acts as a competitive inhibitor of glutathione reductase. Computational studies confirm that the methylated analog fits within the active site of the enzyme but its disulphide bond geometry is altered, preventing reduction by the enzyme. The substitution of (R)-2 methylcysteine in place of natural (R)-cysteine in peptides constitutes a new strategy for stabilizing disulphide bonds from enzyme-catalyzed degradation. PMID- 23808803 TI - 3D-QSAR CoMFA studies on sulfonamide inhibitors of the Rv3588c beta-carbonic anhydrase from Mycobacterium tuberculosis and design of not yet synthesized new molecules. AB - The human pathogen Mycobacterium tuberculosis contains three beta-carbonic anhydrases (CAs, EC 4.2.1.1) in its genome. Inhibition of some of these CAs was shown to modulate the growth of M. tuberculosis. 3D-QSAR Comparative molecular field analyses (CoMFA) were carried out on inhibitors of the enzyme Rv3588c (also denominated mtCA 2). A series of sulfonamides known to inhibit mtCA 2, including some diazenylbenzenesulfonamides, was considered in our study. The predictive ability of the model was assessed using a test set of seven compounds. The best model has demonstrated a good fit having predictive r(2) value of 0.93 and cross validated coefficient q(2) value as 0.88 in tripos CoMFA region. Our results indicate that the steric and electrostatic factors play a significant role in mtCA 2 inhibition for the investigated compounds. We proposed nine new not yet synthesized mtCA 2 inhibitors, all of them probably with significantly improved anti-Rv3588c inhibitory activity. PMID- 23808804 TI - Synthesis and characterization of a proton transfer salt between 2,6 pyridinedicarboxylic acid and 2-aminobenzothiazole, and its complexes and their inhibition studies on carbonic anhydrase isoenzymes. AB - A novel proton transfer compound (HABT)(+)(Hdipic)(-) (1) obtained from ABT and H2dipic and its metal complexes (2-5) have been prepared and characterized by spectroscopic techniques. Single crystal X-ray diffraction method has also been applied to 2 and 5. While complex 2 has a distorted octahedral conformation, 5 exhibits a distorted square pyramidal structure. The structures of 3 and 4 might be proposed as octahedral according to experimental data. All compounds were also evaluated for their in vitro inhibition effects on hCA I and II for their hydratase and esterase activities. Although there is no inhibition for hydratase activities, all compounds have inhibited the esterase activities of hCA I and II. The comparison of the inhibition studies of 1-5 to parent compounds indicates that 1-5 have superior inhibitory effects. The inhibition effects of 2-5 are also compared to inhibitory properties of the metal complexes of ABT and H2dipic, revealing an improved transfection profile. PMID- 23808805 TI - Carbonic anhydrase inhibitors. Phenols incorporating 2- or 3-pyridyl ethenylcarbonyl and tertiary amine moieties strongly inhibit Saccharomyces cerevisiae beta-carbonic anhydrase. AB - A series of phenols incorporating tertiary amine and trans-pyridylethenyl carbonyl moieties were assayed as inhibitors of the beta-carbonic anhydrase (CA, EC 4.2.1.1) from Saccharomyces cerevisiae, ScCA. One of these compounds was a low nanomolar ScCA inhibitor, whereas the remaining ones inhibited the enzyme with KIs in the range of 23.5-95.4 nM. The off-target human (h) isoforms hCA I and hCA II were much less inhibited by these phenols, with KIs in the range of 0.78-23.5 uM (hCA I) and 10.8-52.4 uM (hCA II). The model organism S. cerevisiae and this particular enzyme may be useful for detecting antifungals with a novel mechanism of action compared to the classical azole drugs to which significant drug resistance emerged. PMID- 23808806 TI - 4,5-Dihydro-1H-pyrazole: an indispensable scaffold. AB - Pyrazoles, categorized as nitrogen-containing heterocycles, are well known for their interminable participation in the field of perpetual research and development of therapeutical active agents. As a consequence pyrazoles became an inevitable core of numerous drugs having diverse activities. The broad spectrum of activities portrayed by the pyrazoles instigated the researchers to modify the pyrazole ring as 4,5-dihydro-1H-pyrazoles commonly known as 2-pyrazolines. The present review is a concerted effort to retrace compounds covered from 2009-till date which owe diverse biological activities to the 2-pyrazoline scaffold and also condenses the retro-synthetic approaches employed for their synthesis. This endeavor culminated in revelation that inhibitory potential varied when the substituents in particular N-substituents of 2-pyrazolines were altered. PMID- 23808807 TI - Label-free quantitative proteomic analysis of abscisic acid effect in early-stage soybean under flooding. AB - Flooding is a serious problem for soybean cultivation because it markedly reduces growth. To investigate the role of phytohormones in soybean under flooding stress, gel-free proteomic technique was used. When 2-day-old soybeans were flooded, the content of abscisic acid (ABA) did not decrease in the root, though its content decreased in untreated plant. When ABA was added during flooding treatment, survival ratio was improved compared with that of soybeans flooded without ABA. When 2-day-old soybeans were flooded with ABA, the abundance of proteins related to cell organization, vesicle transport and glycolysis decreased compared with those in root of soybeans flooded without ABA. Furthermore, the nuclear proteins were analyzed to identify the transcriptional regulation. The abundance of 34 nuclear proteins such as histone deacetylase and U2 small nuclear ribonucleoprotein increased by ABA supplementation under flooding; however, 35 nuclear proteins such as importin alpha, chromatin remodeling factor, zinc finger protein, transducin, and cell division 5 protein decreased. Of them, the mRNA expression levels of cell division cycle 5 protein, C2H2 zinc finger protein SERRATE, CCCH type zinc finger family protein, and transducin were significantly down-regulated under the ABA treatment. These results suggest that ABA might be involved in the enhancement of flooding tolerance of soybean through the control of energy conservation via glycolytic system and the regulation on zinc finger proteins, cell division cycle 5 protein and transducin. PMID- 23808808 TI - Advanced building energy management system demonstration for Department of Defense buildings. AB - This paper presents an advanced building energy management system (aBEMS) that employs advanced methods of whole-building performance monitoring combined with statistical methods of learning and data analysis to enable identification of both gradual and discrete performance erosion and faults. This system assimilated data collected from multiple sources, including blueprints, reduced-order models (ROM) and measurements, and employed advanced statistical learning algorithms to identify patterns of anomalies. The results were presented graphically in a manner understandable to facilities managers. A demonstration of aBEMS was conducted in buildings at Naval Station Great Lakes. The facility building management systems were extended to incorporate the energy diagnostics and analysis algorithms, producing systematic identification of more efficient operation strategies. At Naval Station Great Lakes, greater than 20% savings were demonstrated for building energy consumption by improving facility manager decision support to diagnose energy faults and prioritize alternative, energy efficient operation strategies. The paper concludes with recommendations for widespread aBEMS success. PMID- 23808809 TI - Noradrenaline-mediated inhibition of inflammatory cytokines is altered in macrophages from obese Zucker rats: effect of habitual exercise. AB - The obese Zucker rat (fa/fa) (ObZ) is a good animal model for Metabolic Syndrome (MS)-associated neuroendocrine and inflammatory disorders. The aim of the present investigation was to evaluate the effect of noradrenaline (NA) on the release of IL-1beta, IL-6 and TNFalpha by macrophages from ObZ, as well as the effect of habitual exercise (running, 5days/week for 35 min at 35cm/s for 14week); all of them using lean Zucker rats (Fa/fa) (LZ) as reference values. Cytokines were determined by ELISA in the supernatants of macrophages cultured for 24h (37 degrees C, 5% CO2 and 100% RH) in presence or absence of 10(-5)M NA. Both the spontaneous and NA-induced release of IL-1beta and IL-6 were higher in sedentary obese (ObSZ) rats than in healthy LZ rats (a significant lower spontaneous production of TNFalpha was also found in the ObSZ rats). While the NA-induced release of IL-1beta was higher in the exercised obese (ObTZ) rats, the NA-induced production of IL-6 was lower compared with ObSZ rats. In addition, NA has an inhibitory role on the release of IL-1beta and TNFalpha (with respect to the spontaneous release) in both lean and obese (sedentary and exercised) rats. However, NA inhibits the IL-6 production by macrophages from lean and exercised obese animals, but promotes IL-6 release in the sedentary obese rats. In conclusion, an altered inflammatory response of macrophages mediated by NA is underlying in MS, and this regulation is improved after regular exercise, particularly on IL-6. PMID- 23808810 TI - Fetal and early-postnatal developmental patterns of obese-genotype piglets exposed to prenatal programming by maternal over- and undernutrition. AB - The present study evaluated the effect of nutritional imbalances during pregnancy, either by excess or deficiency, on fertility and conceptus development in obese-genotype swine (Iberian pig). Twenty-five multiparous sows were fed, from mating to farrowing, with a standard diet fulfilling either 1.6 folds their daily maintenance requirements for pregnancy (overfed group, n = 12) or only the 50% of such requirements (underfed group, n = 13). Ten out of 12 overfed but only two out of 13 underfed sows became pregnant (P<0.005). Fetal development was determined in the pregnant females at Days 35, 50, 75 and 90 of pregnancy. The embryos from undernourished sows were smaller than the embryos from overfed females as early as at 35 days of pregnancy (P<0.05) and remained smaller until Day 90 of gestation. However, at the end of pregnancy, there were significant changes in the developmental patterns of fetuses. Thus, weight and size of the offspring from both nutritional treatments were finally similar at delivery; the same was found at weaning. There was thereafter a sex-related effect on the growth during the early-postnatal period, with male piglets of both nutritional origins being significantly heavier and more corpulent at weaning that their sisters (P<0.05). In conclusion, fetal growth conditioned by malnutrition from periconceptional stages is mainly regulated at the end of the pregnancy, so that ensure an adequate body-weight and size and, therefore, the survival of the offspring. Afterwards, the early-postnatal development of the offspring is affected by sex, independently from nutritional origin, with male piglets growing faster than females. PMID- 23808811 TI - Room temperature ionic liquids as useful overlayers for estimating food quality from their odor analysis by quartz crystal microbalance measurements. AB - An array of quartz crystals coated with different room-temperature ionic liquids (RTILs) is proposed for the analysis of flavors by quartz crystal microbalance (QCM) measurements. Seven RTILs were adopted as sensing layers, all containing imidazolium or phosphonium cations, differing from one another in the length and branching of alkyl groups and neutralized by different anions. The array was at first applied to the analysis of 31 volatile organic compounds (VOCs), such as alcohols, phenols, aldehydes, esters, ketones, acids, amines, hydrocarbons and terpenes, chosen as representative components of a wide variety of food flavors. Multivariate data analysis by the principal component analysis (PCA) approach of the set of the corresponding responses led to separated clusters for these different chemical categories. To further prove the good performance of the RTIL coated quartz crystal array as an "electronic nose", it was applied to the analysis of headspaces from cinnamon samples belonging to different botanical varieties ( Cinnamon zeylanicum and Cinnamon cassia ). PCA applied to responses recorded on different stocks of samples of both varieties showed that they could be fully discriminated. PMID- 23808812 TI - Shiftwork and sickness absence among police officers: the BCOPS study. AB - Shiftwork, regarded as a significant occupational stressor, has become increasingly prevalent across a wide range of occupations. The adverse health outcomes associated with shiftwork are well documented. Shiftwork is an integral part of law enforcement, a high-stress occupation with elevated risks of chronic disease and mortality. Sickness absence is an important source of productivity loss and may also serve as an indirect measure of workers' morbidity. Prior studies of shiftwork and sickness absenteeism have yielded varying results and the association has not been examined specifically among police officers. The objective of this study was to compare the incidence rate of sick leave (any, >=3 consecutive days) among day-, afternoon-, and night-shift workers in a cohort of police officers and also examine the role of lifestyle factors as potential moderators of the association. Participants (N=464) from the Buffalo Cardio Metabolic Occupational Police Stress (BCOPS) study examined between 2004 and 2009 were used. Daily work history records that included the shift schedule, number of hours worked, and occurrence of sick leave were available for up to 15 yrs starting in 1994 to the date of the BCOPS study examination for each officer. Poisson regression analysis for ungrouped data was used to estimate incidence rates (IRs) of sick leave by shift, and comparison of IRs across shifts were made by computing incidence rate ratios (IRRs) and their 95% confidence intervals (CIs). Sick leave occurred at a higher rate on the night shift (4.37 per 10,000 person-hours) compared with either day (1.55 per 10,000 person-hours) or afternoon (1.96 per 10,000 person-hours) shifts. The association between shiftwork and sickness absence depended on body mass index (BMI). For overweight individuals (BMI>=25 kg/m2), the covariate-adjusted incidence rate of sick leave (>=1 day) was twice as large for night-shift officers compared with those working on the day (IRR=2.29, 95% CI: 1.69-3.10) or afternoon (IRR=1.74, 95% CI: 1.29 2.34) shift. The IR of three or more consecutive days of sick leave was 1.7 times larger for those working on night shift (IRR=1.65, 95% CI: 1.17-2.31) and 1.5 times larger for those working on afternoon shift (IRR=1.50, 95% CI: 1.08-2.08) compared with day shiftworkers. For subjects with normal BMI (<25 kg/m2), the incidence rates of sick leave did not differ significantly across shifts. In conclusion, shiftwork is independently associated with sickness absence, with officers who work the night shift having elevated incidence of sick leave. In addition, overweight officers who work the night shift may be at additional risk for sickness absence. PMID- 23808813 TI - Fludarabine, cyclophosphamide and rituximab plus granulocyte macrophage colony stimulating factor as frontline treatment for patients with chronic lymphocytic leukemia. AB - Fludarabine, cyclophosphamide and rituximab (FCR), the standard of care for the frontline treatment of patients with chronic lymphocytic leukemia (CLL), is associated with a high rate of neutropenia and infectious complications. Granulocyte macrophage colony-stimulating factor (GM-CSF) reduces myelosuppression and can potentiate rituximab activity. We conducted a clinical trial combining GM-CSF with FCR for frontline treatment of 60 patients with CLL. Eighty-six percent completed all six courses and 18% discontinued GM-CSF for toxicity: grade 3-4 neutropenia was observed in 30% of cycles, and severe infections in 16% of cases. The overall response rate was 100%. Both median event free survival (EFS) and overall survival (OS) have not been reached. Longer EFS was associated with favorable cytogenetics. GM-CSF led to a lower frequency of infectious complications than in the historical FCR group, albeit similar EFS and OS. PMID- 23808814 TI - Rare occurrence of JAK3 mutations in natural killer cell neoplasms in Japan. PMID- 23808815 TI - Real-life patterns of use and effectiveness of bortezomib: the VESUVE cohort study. AB - In response to a regulatory request for real-life data on patterns of use and survival outcomes, 793 patients initiating bortezomib for multiple myeloma in France (May 2004-April 2006) were included in this observational study. Data were collected from medical files and patients were followed for 2 years, with vital status collected after 3 years. In total 779 patients were analyzed: 83.1% had immunoglobulin G (IgG) or IgA M-component, mean age was 65.7 years and 46.5% were female. Bortezomib was initiated as third-or-later line in 82.0%. For 75.9%, the starting dose was 1.3 mg/m(2); 42.6% had bortezomib alone, 54.0% with dexamethasone. The mean number of bortezomib cycles was 5.0. Three-year overall survival from bortezomib initiation was 31.4% (95% confidence interval, CI [28.1; 34.7]) and median overall survival was 19.6 months. Two-year progression-free survival was 12.0% (95% CI [9.8; 14.4]), and median progression-free survival was 7.2 months. Overall best response was 44.0%. Survival outcomes during real-life use of bortezomib were within the range of those reported in clinical trials. PMID- 23808816 TI - The evolution of the cardiac implantable electronic device connector. AB - Cardiac implantable electronic devices (CIEDs) play a vital role in the management of cardiac rhythm disturbances. The devices are comprised of two primary components: a generator and lead joined by a connector. Original pacemaker lead connectors were created de novo at the time of implantation or replacement and were very unreliable. With the development of new lead designs, creation of a standard connector configuration, the IS-1 connector became mandatory. Similar connector development also occurred with the advent of the implantable cardioverter defibrillator (ICD), resulting in creation of the high voltage standard: the DF-1 connector. Differing from a pacemaker lead, the ICD lead connector requires one IS-1 connector and one or two DF-1 connectors, resulting in a large cumbersome lead connector and generator header block. Recently, a revolutionary quad pole single plug connector standard has been approved for market release. These are the single-pin DF4 and IS4 lead connectors that carry low- and high-voltage poles or all low-voltage poles, respectively. These connectors, together with new labeling guidelines, have simplified operative procedures and reduced errors, when mating lead connectors into the generator's connector block. PMID- 23808817 TI - Patient satisfaction with nutrition services amongst cancer patients treated with autologous stem cell transplantation: a comparison of usual and extended care. AB - BACKGROUND: This study aimed to determine patient satisfaction with clinical nutrition services delivered by an accredited practicing dietitian amongst cancer patients treated with autologous stem cell transplantation that was provided with usual and extended care at 100 days post-transplantation. METHODS: Patients were randomised to receive usual nutrition care or extended nutrition care during the course of their stem cell transplantation. After hospital discharge, usual care patients received no further nutrition support, whereas extended care patients received telephone dietary counselling from the same dietitian for up to 100 days post-transplantation. The patient satisfaction with clinical nutrition service questionnaire was completed anonymously at 100 days post-transplantation. Group comparisons were made using independent t-tests. RESULTS: Thirty-seven patients consented to participate in the study (54% male; mean age 58.7 +/- 9.5 years; median body mass index 26.8 kg m(-2) , range 16.4-47.6 kg m(-2) ); 33 patients completed the study and 28 patients returned the questionnaire (response rate = 85%). All components of the questionnaire were rated highly by both groups; there was no significant difference between the groups (P > 0.05). Although not statistically significant, extended care patients who received at least three telephone calls rated a higher overall satisfaction compared to those who received less calls; this difference was clinically important (score difference = 0.56). CONCLUSIONS: Cancer patients treated with autologous stem cell transplantation were satisfied with usual and extended nutrition care. Extended care patients who received at least three telephone calls after hospital discharge were more satisfied than those with less frequent intervention. Further exploration regarding the frequency and intensity of nutrition service is required. PMID- 23808818 TI - Executive dysfunctions in migraine with and without aura: what is the role of white matter lesions? AB - OBJECTIVE/BACKGROUND: Executive dysfunctions and white matter lesions on magnetic resonance imaging have been reported in migraine. The aim of this study was to determine whether any correlation between these 2 variables exists. MATERIALS AND METHODS: Forty-four subjects affected by migraine with or without aura were compared with 16 healthy subjects. A battery of neuropsychological tests assessing executive functions was administered to all subjects. Number and total volume of white matter lesions were assessed in the whole brain and in the frontal lobe. RESULTS: The performances of both groups of migraineurs, with and without aura, were significantly worse when compared with controls on Boston Scanning Test. Moreover, we found lower performances compared with controls respectively on Frontal Assessment Battery in patients with migraine with aura and on Controlled Oral Word Association Test in patients with migraine without aura. Nineteen patients (43.2%) and one control subject (6.2%) had white matter lesions. We did not find any significant correlation between white matter lesions load and neuropsychological performances. CONCLUSIONS: On the basis of our results, white matter lesions load on magnetic resonance imaging do not seem to contribute to neuropsychological performances deficit in migraineurs. PMID- 23808819 TI - Temporal trends in prevalence of bacteria isolated from foals with sepsis: 1979 2010. AB - REASONS FOR PERFORMING STUDY: Sepsis is an important cause of death in foals. Knowledge of which pathogens are likely to be involved is important for selection of antimicrobial drugs for initial treatment. OBJECTIVES: To identify temporal trends in prevalence of bacteria isolated from foals with sepsis between 1979 and 2010. STUDY DESIGN: Retrospective review of medical records. METHODS: All foals <=30 days of age presented to the Veterinary Medical Teaching Hospital (VMTH) at the University of California, Davis between 1979 and 2010, with a diagnosis of sepsis confirmed by culture of bacteria from blood or internal organs (antemortem or at necropsy), were included in the study. Conventional microbiological methods were used to identify isolated organisms. The Cochran-Armitage trend test was used for statistical analysis. RESULTS: The percentage of Gram-positive isolates increased significantly over the years. The percentage Enterobacteriacea, and Klebsiella spp. in particular, decreased over time. Enterococcus spp. isolates were cultured more often in recent years. CONCLUSIONS: Whereas Gram-negative bacteria, particularly Enterobacteriaceae, remain the most common isolates from neonatal foals with sepsis, the prevalence of Gram-positive bacteria is increasing. This trend underlines the importance of including antimicrobial drugs active against both Gram-positive and Gram-negative bacteria in treatment protocols while awaiting the results of bacteriological culture and susceptibility tests. The increased prevalence of Enterococcus spp. is of concern because antimicrobial susceptibility patterns for enterococci are unpredictable and enterococci can also act as donors of antimicrobial resistance genes to other bacteria. PMID- 23808820 TI - Occlusal trauma accelerates attachment loss at the onset of experimental periodontitis in rats. AB - BACKGROUND AND OBJECTIVE: Occlusal trauma is an important factor that influences the progression of periodontitis, but it is unclear whether occlusal trauma influences periodontal destruction at the onset of periodontitis. We established an experimental periodontitis model with both site-specific loss of attachment and alveolar bone resorption. The purpose of the present study was to investigate the effects of occlusal trauma on periodontal destruction, particularly loss of attachment, at the onset of experimental periodontitis. MATERIAL AND METHODS: Sixty rats were used in the present study. Forty-eight rats immunized with lipopolysaccharide (LPS) intraperitoneally were divided into four groups. In the trauma (T) group, occlusal trauma was induced by placing an excessively high metal wire in the occlusal surface of the mandibular right first molar. In the inflammation (I) group, periodontal inflammation was induced by topical application of LPS into the palatal gingival sulcus of maxillary right first molars. In the trauma + inflammation (T+I) group, both trauma and periodontal inflammation were simultaneously induced. The PBS group was administered phosphate-buffered saline only. Another 12 nonimmunized rats (the n-(T+I) group) were treated as described for the T+I group. All rats were killed after 5 or 10 d, and their maxillary first molars with surrounding tissues were observed histopathologically. Loss of attachment and osteoclasts on the alveolar bone crest were investigated histopathologically. To detect immune complexes, immunohistological staining for C1qB was performed. Collagen fibers were also observed using the picrosirius red-polarization method. RESULTS: There were significant increases in loss of attachment and in the number of osteoclasts in the T+I group compared with the other groups. Moreover, widespread distribution of immune complexes was observed in the T + I group, and collagen fibers oriented from the root surface to the alveolar bone crest had partially disappeared in the T, T+I and n-(T+I) groups. CONCLUSION: When inflammation was combined with occlusal trauma, immune complexes were confirmed in more expanding areas than in the area of the I group without occlusal trauma, and loss of attachment at the onset of experimental periodontitis was increased. Damage of collagen fibers by occlusal trauma may elevate the permeability of the antigen through the tissue and result in expansion of the area of immune-complex formation and accelerating inflammatory reaction. The periodontal tissue destruction was thus greater in the T+I group than in the I group. PMID- 23808821 TI - A review of psychological dysfunction in asthma: affective, behavioral and cognitive factors. AB - BACKGROUND: The research on psychological dysfunction in asthma is extensive but heterogeneous. We undertook a narrative review about the effects of psychological dysfunction on asthma. METHODS: Electronic searches of MEDLINE, EMBASE, CINAHL and the Cochrane Library were conducted, supplemented by hand-searching bibliographies and seeking expert opinion. RESULTS: The impact of psychological factors on asthma can be classified according to dysfunction in the domains of affect, behavior and cognition. Affective or emotional disturbance may lead to poor asthma control by directly modulating disease activity. Maladaptive behaviors may occur in asthma patients. These include maladaptive breathing behaviors, such as impaired voluntary drive to breathe and dysfunctional breathing, as well as impaired asthma health behaviors, that is, a coordinated range of activities performed to maintain good disease control. Dysfunctional cognitions (thoughts and beliefs) about asthma and impaired cognitive processing of the perception of dyspnea are associated with poorly controlled disease and asthma deaths, respectively. The three domains of psychological dysfunction are often closely intertwined, leading to vicious circles. CONCLUSIONS: We have conceptualized psychological dysfunction in asthma using a framework consisting of affect, behavior and cognition. Their influences are intertwined and complex. Future research should focus on the formulation of a psychological assessment tool based on this framework and evaluating its efficacy in improving asthma outcomes. PMID- 23808823 TI - Crafting the leaders of tomorrow. PMID- 23808822 TI - Fibroblast growth factor receptor 1 gene amplification in pancreatic ductal adenocarcinoma. AB - AIMS: Pancreatic ductal adenocarcinomas (PDACs) are chemoresistant, resulting in extremely poor survival of patients; therefore, novel molecular targets, even in small subsets of genetically characterized tumours, are urgently needed. Tyrosine kinase receptor inhibitors (TKIs) are already in clinical use. The aims of this study were to examine the gene copy number and expression of fibroblast growth factor receptor 1 (FGFR1) in 155 patients with PDAC, and investigate the effects of the FGFR-specific inhibitor BGJ398 on FGFR1-amplified pancreatic tumour cells in vitro. METHODS AND RESULTS: Fluorescence in-situ hybridization (FISH) and immunohistochemical analysis of 155 PDACs were performed using tissue microarrays. Amplification of FGFR1 was found in 2.6% (4/155) of cases. Four per cent of tumours (5/125) were shown to express FGFR1 by immunohistochemistry. Sequence analysis demonstrated an activating KRAS mutation (exon 2) in all FGFR1 amplified cases. The FGFR1-amplified pancreatic carcinoma cell line PT45P1 showed high levels of FGFR1 mRNA and protein expression. Proliferation of this cell line can be inhibited using the FGFR1 inhibitor BGJ398. CONCLUSIONS: FGFR1 represents a potential new therapeutic target in a subset of patients harbouring FGFR1 amplified tumours. Identification of pancreatic cancers harbouring FGFR1 amplification may be important in preselecting patients and/or interpreting clinical studies using TKIs. PMID- 23808824 TI - Guggulsterone attenuates activation and survival of hepatic stellate cell by inhibiting nuclear factor kappa B activation and inducing apoptosis. AB - BACKGROUND AND AIM: Liver fibrosis is associated with the deposition of the extracellular matrix, and hepatic stellate cells (HSCs) are the major source of these matrix proteins. Guggulsterone has recently been shown to induce apoptosis in several cell lines. Thus, the aim of this study was to evaluate whether guggulsterone has antifibrotic activities by reducing the activation and survival of HSCs. METHODS: Apoptotic and fibrosis-related signaling pathways and nuclear factor kappa B (NF-kappaB) activity were explored in LX-2 cells, an immortalized human HSC line, and in a mice model of liver fibrosis. RESULTS: Guggulsterone suppressed LX-2 cell growth in a dose- and activation-dependent manner. This growth suppression was due to the induction of HSC apoptosis, which was mediated by the activation of c-Jun N-terminal kinase and mitochondrial apoptotic signaling. Additionally, guggulsterone regulated phosphorylation of Akt and adenosine monophosphate-activated protein kinase, which were subsequently proven responsible for the guggulsterone-induced HSC growth suppression. Guggulsterone inhibited NF-kappaB activation in LX-2 cells, which is one of the major mediators in HSC activation. Indeed, guggulsterone decreased collagen alpha1 synthesis and alpha-smooth muscle actin expression in these cells. Compared with the control mice or mice treated with a low dose of guggulsterone, high dose of guggulsterone significantly decreased the extent of collagen deposition and the percentage of activated HSCs undergoing apoptosis. CONCLUSIONS: These results demonstrate that guggulsterone suppressed HSC activation and survival by inhibiting NF-kappaB activation and inducing apoptosis. Therefore, guggulsterone may be useful as an antifibrotic agent in chronic liver diseases. PMID- 23808825 TI - Phenotypic characterization and outcome of paediatric patients affected with haemophagocytic syndrome of unknown genetic cause. PMID- 23808826 TI - Peri-operative hyperglycemia is associated with delayed graft function in deceased donor renal transplantation. AB - Increasing evidence indicates that recipient diabetes is a risk factor for delayed graft function (DGF) after renal transplant and that peri-operative hyperglycemia increases ischemia-reperfusion injury. To evaluate whether peri operative hyperglycemia as measured in the post-anesthesia care unit (PACU) after transplant is a risk factor for DGF, we retrospectively reviewed 976 adult recipients of deceased donor renal transplants between January 1, 1997 and December 1, 2004. Logistic regression was used to evaluate risk factors for DGF. In our final multivariate model, recipient blood glucose level in the PACU (odds ratio [OR] 1.10 per 25 unit increase, 95% confidence interval (CI) 1.14-2.46, p = 0.03) was a statistically significant predictor of DGF along with donor age (OR 1.02, 95% CI 1.01-1.03, p < 0.01), cold ischemia time (OR 1.04, 95% CI 1.02-1.07, p < 0.01), recipient male gender (OR 1.68, 95% CI 1.14-2.68, p = 0.01), and a panel-reactive antibody >30% (OR 1.92, 95% CI 1.20-3.05, p = 0.01). We conclude that recipient blood glucose measured in the PACU is associated with DGF and begs the question of whether improved peri-operative glucose control will decrease the incidence of DGF. PMID- 23808827 TI - Spectral library generating function for assessing spectrum-spectrum match significance. AB - Tandem mass spectrometry (MS/MS) continues to be the technology of choice for high-throughput analysis of complex proteomics samples. While MS/MS spectra are commonly identified by matching against a database of known protein sequences, the complementary approach of spectral library searching against collections of reference spectra consistently outperforms sequence-based searches by resulting in significantly more identified spectra. However, while spectral library searches benefit from the advance knowledge of the expected peptide fragmentation patterns recorded in library spectra, estimation of the statistical significance of spectrum-spectrum matches (SSMs) continues to be hindered by difficulties in finding an appropriate definition of "random" SSMs to use as a null model when estimating the significance of true SSMs. We propose to avoid this problem by changing the null hypothesis: instead of determining the probability of observing a high SSM score between randomly matched spectra, we estimate the probability of observing a low SSM score between replicate spectra of the same molecule. To this end, we explicitly model the variation in instrument measurements of MS/MS peak intensities and show how these models can be used to determine a theoretical distribution of SSM scores between reference and query spectra of the same molecule. While the proposed spectral library generating function (SLGF) approach can be used to calculate theoretical distributions for any additive SSM score (e.g., any dot product), we further show how it can be used to calculate the distribution of expected cosines between reference and query spectra. We developed a spectral library search tool, Tremolo, and demonstrate that this SLGF based search tool significantly outperforms current state-of-the-art spectral library search tools and provide a detailed discussion of the multiple reasons behind the observed differences in the sets of identified MS/MS spectra. PMID- 23808828 TI - Synergetic effect of SLN-curcumin and LDH-5-Fu on SMMC-7721 liver cancer cell line. AB - Curcumin and 5-Fluorouracil (5-Fu) have been reported to have anticancer potentials and show certain synergetic effect on some cancer cell lines. However, the poor bioavailability and rapid metabolism limited their medical application. In this study, we encapsulated curcumin with solid lipid nanoparticles (SLN), 5 Fu with Layered double hydroxides (LDHs) separately and tested its properties and anticancer potentials. SLN-curcumin and LDH-5-Fu were determined to be 100 and 60 nm by Transmission Electron Microscopy detection, and the loading efficiency were 28%+/-2.5% and 16.7%+/-1.8%, individually. Furthermore, SLN-curcumin and LDH-5-Fu showed a significantly synergetic effect on SMMC-7721 cell stronger than plain drugs together, of which the Idrug loaded nano-carriers was only 0.315. FACS analysis revealed that the combination of SLN-curcumin and LDH-5-Fu induced 80.1% apoptosis in SMMC-7721 cells, which were 1.7-folds of the sum of the two plain drug loaded carriers. The results demonstrated the significant synergetic anticancer potentials of nano-encapsulated curcumin and 5-Fu, which could be further explored for the treatment of other carcinoma. PMID- 23808829 TI - Halo-shaped flowing atmospheric pressure afterglow: a heavenly design for simplified sample introduction and improved ionization in ambient mass spectrometry. AB - The flowing atmospheric-pressure afterglow (FAPA) is a promising new source for atmospheric-pressure, ambient desorption/ionization mass spectrometry. However, problems exist with reproducible sample introduction into the FAPA source. To overcome this limitation, a new FAPA geometry has been developed in which concentric tubular electrodes are utilized to form a halo-shaped discharge; this geometry has been termed the halo-FAPA or h-FAPA. With this new geometry, it is still possible to achieve direct desorption and ionization from a surface; however, sample introduction through the inner capillary is also possible and improves interaction between the sample material (solution, vapor, or aerosol) and the plasma to promote desorption and ionization. The h-FAPA operates with a helium gas flow of 0.60 L/min outer, 0.30 L/min inner, and applied current of 30 mA at 200 V for 6 W of power. In addition, separation of the discharge proper and sample material prevents perturbations to the plasma. Optical-emission characterization and gas rotational temperatures reveal that the temperature of the discharge is not significantly affected (<3% change at 450 K) by water vapor during solution-aerosol sample introduction. The primary mass-spectral background species are protonated water clusters, and the primary analyte ions are protonated molecular ions (M + H(+)). Flexibility of the new ambient sampling source is demonstrated by coupling it with a laser ablation unit, a concentric nebulizer, and a droplet-on-demand system for sample introduction. A novel arrangement is also presented in which the central channel of the h-FAPA is used as the inlet to a mass spectrometer. PMID- 23808830 TI - Do drinking games matter? An examination by game type and gender in a mandated student sample. AB - BACKGROUND: College students who violate alcohol policies engage in riskier alcohol use and demonstrate more problems related to their use than non-violating peers. Drinking games (DG) have been linked to increased alcohol use and negative consequences. OBJECTIVES: The present study sought to assess potential differences in DG participation among mandated males and females by examining rates of endorsement, types of DG played, and how types of games are related to alcohol use and related consequences. METHODS: Participant data were obtained from 154 undergraduate students mandated to receive an alcohol intervention, RESULTS: DG players were found to have higher typical and peak blood alcohol concentrations, consume more drinks per week on average, consume more standard drinks per highest drinking occasion, and to experience a considerably greater number of alcohol-related consequences than non-players. Males endorsed greater participation in DG and cited "team" and "motor" games more often than females. "Gambling" games were endorsed equally by both sexes, but resulted in increased consequences for females only. CONCLUSION: Engaging in DG results in higher levels of alcohol consumption. The likelihood of consequences experienced may vary by type of DG in which individuals choose to participate, as well as by gender. Results from this study provide information that can be utilized in targeted alcohol programming efforts, not only for a high-risk population such as mandated students, but tailored to the specific needs of males and females. PMID- 23808831 TI - Investigation of the homogeneity of methacrylate allergens in commercially available patch test preparations. AB - BACKGROUND: The homogeneity of methacrylates in commercial patch test preparations has not yet been investigated. Inhomogeneous patch test preparations may give rise to false-negative or false-positive patch test results in patients suspected of having methacrylate allergy. OBJECTIVES: To investigate the homogeneity of methacrylates in commercial patch test preparations. METHODS: Fresh commercial patch test preparations of methyl methacrylate (MMA) and 2 hydroxyethyl methacrylate (2-HEMA) from three test material suppliers in Europe were analysed quantitatively by means of normal-phase high-performance liquid chromatography. RESULTS: The initial concentration of MMA in all six patch test preparations was lower than stated on the label, whereas four of six patch test preparations of 2-HEMA were in accordance with the stated concentrations. The concentration of MMA increased markedly from the top segment close to the tip of the syringe to the bottom segment adjacent to the piston in four syringes (3-6). In contrast, syringes with 2-HEMA maintained a constant concentration throughout the test preparation, apart from two syringes (11 and 12). CONCLUSION: Variations in concentration and heterogeneous distribution of MMA and 2-HEMA in patch test preparations may be an additional cause of variation in patch test results, besides other technical details and reading. PMID- 23808832 TI - Protein composition of different sized casein micelles in milk after the binding of lactoferrin or lysozyme. AB - Casein micelles with bound lactoferrin or lysozyme were fractionated into sizes ranging in radius from ~50 to 100 nm. The kappa-casein content decreased markedly and the alphaS-casein/beta-casein content increased slightly as micelle size increased. For lactoferrin, higher levels were bound to smaller micelles. The lactoferrin/kappa-casein ratio was constant for all micelle sizes, whereas the lactoferrin/alphaS-casein and lactoferrin/beta-casein ratio decreased with increasing micelle size. This indicates that the lactoferrin was binding to the surface of the casein micelles. For lysozyme, higher levels bound to larger casein micelles. The lysozyme/alphaS-casein and lysozyme/beta-casein ratios were nearly constant, whereas the lysozyme/kappa-casein ratio increased with increasing micelle size, indicating that lysozyme bound to alphaS-casein and beta casein in the micelle core. Lactoferrin is a large protein that cannot enter the casein protein mesh; therefore, it binds to the micelle surface. The smaller lysozyme can enter the protein mesh and therefore binds to the more charged alphaS-casein and beta-casein. PMID- 23808833 TI - Role of flow cytometry in myelodysplastic syndromes: diagnosis, classification, prognosis and response assessment. AB - Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid neoplasms. With the emergence of therapeutic options, attempts to standardize diagnostic, prognostic and response criteria to guide treatment decisions are increasingly important. This has been achieved in part by the revised 2008 World Health Organization classification and consensus guidelines outlining refined definitions and standards. Conventional criteria have limitations in terms of sensitivity and specificity. Multiparameter flow cytometry (FC) can be used real time, and is a highly reproducible and objective way of assessing the pattern of expression of multiple antigens on a single hematopoietic cell and defined subpopulations. By comparing antigen expression within maturing myelomonocytic populations with that identified on the equivalent normal cells, abnormalities identified may provide a diagnostic indication of stem cell dysmaturation. There are now increasingly robust data demonstrating the capacity of FC to discriminate MDS from non-clonal cytopenias and dysplasia, as well as further refine disease classification and prognostication, which will be reviewed here. PMID- 23808834 TI - Minimally invasive surgery in veterinary practice: a 2010 survey of diplomates and residents of the American College of Veterinary Surgeons. AB - OBJECTIVE: To report the current state of minimally invasive surgery (MIS) in veterinary surgical practice in 2010. STUDY DESIGN: Electronic questionnaire. SAMPLE POPULATION: Diplomates and residents of the American College of Veterinary Surgeons (ACVS). METHODS: A survey (38 questions for Diplomates, 23 questions for residents) was sent electronically to 1216 Diplomates and 300 residents. Questions were organized into 5 categories to investigate: (1) caseload and distribution of MIS cases; (2) MIS training; (3) MIS benefits, morbidity, limitations and motivating factors; (4) ACVS role; and (5) demographics of the study population. RESULTS: Eighty-six percent of small animal (SA) Diplomates, 99% of large animal (LA) Diplomates, and 98% of residents had performed MIS. Median LA caseload (30 cases/year; range, 1-600) was significantly higher than SA caseload (20 cases/year; range, 1-350). Descending order of case distribution was: arthroscopy > laparoscopy > endoscopic upper airway > thoracoscopy. Sixty percent of Diplomates and 98% of residents received MIS training during their residency. Residents' perspective of MIS training proficiency was positively correlated to caseload. Ninety-five percent of all respondents felt postoperative morbidity was less with MIS, and were motivated by patient benefits, maintaining a high standard of care, and personal interests. Fifty-eight percent of Diplomates and 89% of residents felt ACVS should be involved in developing MIS training. CONCLUSIONS: MIS is widely used by ACVS Diplomates and residents in clinical practice; however, important differences exist between SA and LA surgeons and practice types. MIS training in partnership with the ACVS is needed for continued development in veterinary surgery. PMID- 23808835 TI - Atypical location of lymphocytoma cutis in a child. AB - Lyme borreliosis is a common infectious disease that can affect myocardial muscle or the central nervous system if not treated at an early stage. Here we report a unique case of an atypical location of lymphocytoma cutis in a 3-year-old boy. Histologic and immunohistochemical analysis revealed the correct diagnosis. PMID- 23808836 TI - Eruptive and functional changes in periodontal ligament fibroblast orientation in CD44 wild-type vs. knockout mice. AB - BACKGROUND AND OBJECTIVE: Periodontal ligament (PDL) fibroblasts establish principal fibers of the ligament during tooth eruption, and maintain these fibers during occlusion. PDL development and occlusal adaptation includes changes in the orientation of PDL fibroblasts; however, the mechanism for these changes in orientation is unclear. The objective of this study was to compare PDL fibroblast orientation in different stages corresponding with first molar eruption and occlusion in CD44 wild-type (WT) and knockout (KO) mice. MATERIAL AND METHODS: CD44 WT and KO mice were raised to six postnatal stages corresponding with first molar (M1 ) eruption (postnatal day 8, 11, 14 and 18) and occlusion (postnatal day 26 and 41). Coronal sections of the first mandibular molar (M1 ) were prepared and the orientation of fibroblasts in the cervical root region was measured. Angle measurements were compared across developmental stages and between strains using Watson-Williams F-test (oriana software) and ANCOVA. RESULTS: PDL fibroblast orientation increased significantly in CD44 WT (9-87 degrees ) and KO mice (14-93 degrees ; p <= 0.05) between intraosseous eruption (day 11), mucosal penetration (day 14) and preocclusal eruption (day 18); however, the PDL fibroblast orientation did not change significantly with the onset of occlusion (day 26) or continued function (day 41). Within each strain, the variance in fibroblast orientation during preocclusal eruption (day 18) was significantly higher than the variance of all other time points (p < 0.0005). CD44 WT and KO mice showed a similar pattern of PDL development and eruption with a significant difference in CD44 WT vs. KO fibroblast orientations only during early function (day 26, 92 degrees vs 116 degrees ; p = 0.05). CONCLUSIONS: The development of PDL fibroblast orientation is highly similar between CD44 WT and KO mice. Between early (day 11) and late (day 18) eruptive stages PDL fibroblast orientation increases, corresponding with the upward movement of M1 . The PDL fibroblast orientation established in preocclusal eruption (day 18) is maintained during early (day 26) and late (day 41) stages of occlusal function, suggesting that PDL cells adapt to mechanical loads in the oral cavity before M1 occlusion. PMID- 23808837 TI - Assessing communication skills in dietetic consultations: the development of the reliable and valid DIET-COMMS tool. AB - BACKGROUND: There is an increasing emphasis on the development of communication skills for dietitians but few evidence-based assessment tools available. The present study aimed to develop a dietetic-specific, short, reliable and valid assessment tool for measuring communication skills in patient consultations: DIET COMMS. METHODS: A literature review and feedback from 15 qualified dietitians were used to establish face and content validity during the development of DIET COMMS. In total, 113 dietetic students and qualified dietitians were video recorded undertaking mock consultations, assessed using DIET-COMMS by the lead author, and used to establish intra-rater reliability, as well as construct and predictive validity. Twenty recorded consultations were reassessed by nine qualified dietitians to assess inter-rater reliability: eight of these assessors were interviewed to determine user evaluation. RESULTS: Significant improvements in DIET-COMMS scores were achieved as students and qualified staff progressed through their training and gained experience, demonstrating construct validity, and also by qualified staff attending a training course, indicating predictive validity (P < 0.05). An acceptable level of intra-rater reliability (rs = 0.90) and a moderate level of inter-rater reliability (r = 0.49) were demonstrated. Interviews identified many positive features and possible uses for DIET-COMMS in both pre- and post-registration settings. The need for assessor training was emphasised and how readily qualified dietitians would accept assessment of skills in practice was questioned. DISCUSSION: DIET-COMMS is a short, user-friendly, reliable and valid tool for measuring communication skills in patient consultations with both pre- and post-registration dietitians. Additional work is required to develop a training package for assessors and to identify how DIET COMMS assessment can acceptably be incorporated into practice. PMID- 23808838 TI - Unusual and highly tunable missing-linker defects in zirconium metal-organic framework UiO-66 and their important effects on gas adsorption. AB - UiO-66 is a highly important prototypical zirconium metal-organic framework (MOF) compound because of its excellent stabilities not typically found in common porous MOFs. In its perfect crystal structure, each Zr metal center is fully coordinated by 12 organic linkers to form a highly connected framework. Using high-resolution neutron power diffraction technique, we found the first direct structural evidence showing that real UiO-66 material contains significant amount of missing-linker defects, an unusual phenomenon for MOFs. The concentration of the missing-linker defects is surprisingly high, ~10% in our sample, effectively reducing the framework connection from 12 to ~11. We show that by varying the concentration of the acetic acid modulator and the synthesis time, the linker vacancies can be tuned systematically, leading to dramatically enhanced porosity. We obtained samples with pore volumes ranging from 0.44 to 1.0 cm(3)/g and Brunauer-Emmett-Teller surface areas ranging from 1000 to 1600 m(2)/g, the largest values of which are ~150% and ~60% higher than the theoretical values of defect-free UiO-66 crystal, respectively. The linker vacancies also have profound effects on the gas adsorption behaviors of UiO-66, in particular CO2. Finally, comparing the gas adsorption of hydroxylated and dehydroxylated UiO-66, we found that the former performs systematically better than the latter (particularly for CO2) suggesting the beneficial effect of the -OH groups. This finding is of great importance because hydroxylated UiO-66 is the practically more relevant, non-air sensitive form of this MOF. The preferred gas adsorption on the metal center was confirmed by neutron diffraction measurements, and the gas binding strength enhancement by the -OH group was further supported by our first-principles calculations. PMID- 23808839 TI - Cluster-tic syndrome: a cross-sectional study of cluster headache patients. AB - OBJECTIVE: To determine the prevalence and nature of trigeminal neuralgia in a large group of cluster headache patients. BACKGROUND: Cluster-tic syndrome is a rare headache syndrome in which trigeminal neuralgia and cluster headache co occur. The existence of cluster-tic syndrome as a separate entity is questioned, and figures on prevalence of simultaneous existence of cluster headache and trigeminal neuralgia are not available. METHODS: As part of a nationwide study on headache mechanisms in cluster headache (Leiden University Medical Centre Cluster headache Neuro Analysis programme), we collected clinical data of 244 cluster headache patients using a semistructured telephone interview in a cross-sectional design. RESULTS: In 11 (4.5%) cluster headache patients, attacks fulfilling International Headache Society criteria for trigeminal neuralgia were also present. In all cases, trigeminal neuralgia occurred ipsilateral to cluster headache and in the majority (82%) in the ophthalmic branch. In 8 of these 11 patients (73%), the frequency and time pattern of trigeminal neuralgia seemed to parallel cluster headache and was likely a part of the cluster headache spectrum. In the 3 remaining patients, cluster headache and trigeminal neuralgia were unrelated in time and appeared to occur independently. CONCLUSION: Trigeminal neuralgia co-occurred in 11/244 (4.5%) of cluster headache patients. In only 3 (1.2%) patients, trigeminal neuralgia seemed to occur independently from cluster headache episodes. Trigeminal neuralgia (-like) attacks in cluster headache patients are most of the time part of the cluster headache spectrum and should then probably not be treated separately. A shared underlying pathophysiological mechanism of cluster headache and trigeminal neuralgia is not supported by this study. PMID- 23808841 TI - Reflection as a component of formative assessment appears to be instrumental in promoting the use of feedback; an observational study. AB - BACKGROUND: Although the literature suggests that reflection has a positive impact on learning, there is a paucity of evidence to support this notion. AIM: We investigated feedback and reflection in relation to the likelihood that feedback will be used to inform action plans. We hypothesised that feedback and reflection present a cumulative sequence (i.e. trainers only pay attention to trainees' reflections when they provided specific feedback) and we hypothesised a supplementary effect of reflection. METHOD: We analysed copies of assessment forms containing trainees' reflections and trainers' feedback on observed clinical performance. We determined whether the response patterns revealed cumulative sequences in line with the Guttman scale. We further examined the relationship between reflection, feedback and the mean number of specific comments related to an action plan (ANOVA) and we calculated two effect sizes. RESULTS: Both hypotheses were confirmed by the results. The response pattern found showed an almost perfect fit with the Guttman scale (0.99) and reflection seems to have supplementary effect on the variable action plan. CONCLUSIONS: Reflection only occurs when a trainer has provided specific feedback; trainees who reflect on their performance are more likely to make use of feedback. These results confirm findings and suggestions reported in the literature. PMID- 23808840 TI - Ethnicity is a strong predictor for Helicobacter pylori infection in young women in a multi-ethnic European city. AB - BACKGROUND AND AIM: At the same time that Helicobacter pylori prevalence is declining in Western countries, immigrants from developing countries with high H. pylori prevalence have settled in Western urban areas. Actual epidemiological data on H. pylori in a migrant community may help in realizing a more selective approach to assess H. pylori-related diseases. We aimed to define H. pylori prevalence as well as risk groups for H. pylori in a cohort of young women living in a multi-ethnic European city. METHODS: We measured Immunoglobulin G (IgG) anti H. pylori and CagA-antibodies in serum of pregnant women included in a population based prospective cohort study, the Generation R study. Information on demographics and socioeconomic status was collected by questionnaires. Chi-square and logistic regression were used. RESULTS: In total, 3146 (46%) of the 6837 tested women (mean age 29.7 +/- 5.3) were H. pylori-positive and 1110 (35%) of them were CagA-positive. The H. pylori prevalence in Dutch women was 24%, which was significantly lower than in non-Dutch women (64%; P < 0.001). In particular, H. pylori positivity was found in 92% of Moroccan (odds ratio 19.2; 95% confidence interval 11.8-32.0), 80% of Cape Verdean (7.6; 5.0-11.5), 81% of Turkish (9.0; 6.7-12.1), 60% of Dutch Antillean (3.3; 2.3-4.7), and 58% of Surinamese women (3.0; 2.3-3.8). Among H. pylori-positive Dutch subjects, 19% were CagA-positive compared with 40% of the non-Dutch subjects (P < 0.001). CONCLUSIONS: Despite a general trend of declining prevalence in Western countries, H. pylori remains highly prevalent in migrant communities, which may constitute target groups for screening and eradication to prevent H. pylori related diseases. PMID- 23808843 TI - Are patients in remission from Cushing's syndrome mentally healthy? PMID- 23808844 TI - Formation and segmentation of the vertebrate body axis. AB - Body axis elongation and segmentation are major morphogenetic events that take place concomitantly during vertebrate embryonic development. Establishment of the final body plan requires tight coordination between these two key processes. In this review, we detail the cellular and molecular as well as the physical processes underlying body axis formation and patterning. We discuss how formation of the anterior region of the body axis differs from that of the posterior region. We describe the developmental mechanism of segmentation and the regulation of body length and segment numbers. We focus mainly on the chicken embryo as a model system. Its accessibility and relatively flat structure allow high-quality time-lapse imaging experiments, which makes it one of the reference models used to study morphogenesis. Additionally, we illustrate conservation and divergence of specific developmental mechanisms by discussing findings in other major embryonic model systems, such as mice, frogs, and zebrafish. PMID- 23808842 TI - A safe and efficient method to retrieve mesenchymal stem cells from three dimensional fibrin gels. AB - Mesenchymal stem cells (MSCs) display multipotent characteristics that make them ideal for potential therapeutic applications. MSCs are typically cultured as monolayers on tissue culture plastic, but there is increasing evidence suggesting that they may lose their multipotency over time in vitro and eventually cease to retain any resemblance to in vivo resident MSCs. Three-dimensional (3D) culture systems that more closely recapitulate the physiological environment of MSCs and other cell types are increasingly explored for their capacity to support and maintain the cell phenotypes. In much of our own work, we have utilized fibrin, a natural protein-based material that serves as the provisional extracellular matrix during wound healing. Fibrin has proven to be useful in numerous tissue engineering applications and has been used clinically as a hemostatic material. Its rapid self-assembly driven by thrombin-mediated alteration of fibrinogen makes fibrin an attractive 3D substrate, in which cells can adhere, spread, proliferate, and undergo complex morphogenetic programs. However, there is a significant need for simple cost-effective methods to safely retrieve cells encapsulated within fibrin hydrogels to perform additional analyses or use the cells for therapy. Here, we present a safe and efficient protocol for the isolation of MSCs from 3D fibrin gels. The key ingredient of our successful extraction method is nattokinase, a serine protease of the subtilisin family that has a strong fibrinolytic activity. Our data show that MSCs recovered from 3D fibrin gels using nattokinase are not only viable but also retain their proliferative and multilineage potentials. Demonstrated for MSCs, this method can be readily adapted to retrieve any other cell type from 3D fibrin gel constructs for various applications, including expansion, bioassays, and in vivo implantation. PMID- 23808845 TI - How microbiomes influence metazoan development: insights from history and Drosophila modeling of gut-microbe interactions. AB - Since Metchnikoff developed his views on the intestinal microflora, much effort has been devoted to understanding the role of gut microbiomes in metazoan physiology. Despite impressive data sets that have been generated by associating a phenotype-causing commensal community with its corresponding host phenotype, the field continues to suffer from descriptive and often contradictory reports. Hence, we cannot yet draw clear conclusions as to how the modifications of microbiomes cause physiological changes in metazoans. Unbiased, large-scale genetic screens to identify key genes, on both microbial and host sides, will be essential to gain mechanistic insights into gut-microbe interactions. The Drosophila genome-commensal microbiome genetic model has proven to be well suited to dissect the complex reciprocal cross talk between the host and its microbiota. In this review, we present a historical account, current views, and novel perspectives for future research directions based on the insights gleaned from the Drosophila gut-microbe interaction model. PMID- 23808846 TI - A multisection passive sampler for measuring sediment porewater profile of dichlorodiphenyltrichloroethane and its metabolites. AB - In situ measurements of hydrophobic organic chemicals in sediment porewater, a central component in assessing the bioavailability and mobility of chemicals in sediment, have been scarce. Here, we introduce a multisection passive sampler with low-density polyethylene (LDPE) as the sorbent phase, which is appropriate for measuring vertical concentration profiles of chemicals in sediment porewater. This sampler is composed of a series of identical sampling cells insulated with seclusion rings. In each section, sorption of chemicals into LDPE is diffusion controlled through the water layer separated from the sediment by a glass fiber filtration membrane and a porous stainless steel shield. Pilot laboratory testing indicated that the sampler can roughly determine the porewater concentrations of 1,1-dichloro-2,2-bis-(chlorophenyl)ethane (p,p'-DDD) and 1,1-dichloro-2,2-bis (chlorophenyl)ethylene (p,p'-DDE), comparable to those yielded through centrifugation/liquid-liquid extraction, a conventional technique for sampling sediment porewater. Field deployment of the sampler was performed in an urbanized coastal region to measure the depth profiles of dichlorodiphenyltrichloroethane and its metabolites in sediment porewater. Sampling rate-calibrated and performance reference compound-calibrated concentrations were calculated, which were consistent with those obtained by the centrifugation/liquid-liquid extraction method. These results verified the utility of the sampler for measuring depth profiles of sediment porewater chemicals. PMID- 23808847 TI - Use of natural orifice translumenal endoscopic surgery in the diagnosis of suspected tuberculous peritonitis: a retrospective case series of 7 patients. AB - BACKGROUND AND OBJECTIVE: In cases of ascites of unknown etiology, tuberculosis peritonitis (TBP) is a possible cause but a diagnostic challenge. This retrospective case series assessed the effectiveness and safety of diagnostic natural orifice translumenal endoscopic surgery (NOTES((r)); American Society for Gastrointestinal Endoscopy [Oak Brook, IL] and the Society of American Gastrointestinal and Endoscopic Surgeons [Los Angeles, CA]) in 7 consecutive patients with suspected TBP. SUBJECTS AND METHODS: Between September 2011 and August 2012, peritoneal biopsy was performed using transgastric NOTES for subsequent histology in 7 consecutive hospitalized patients who presented with ascites and were diagnosed with suspected TBP. The outcome measures included diagnostic accuracy and procedure-related morbidities. RESULTS: Diagnostic NOTES was successfully completed in all 7 patients. Peritoneoscopy with NOTES went uneventfully and lasted 5-10 minutes. Typical peritoneal nodules characteristic of TBP were identified in all patients and confirmed pathologically as TBP. No clinically significant adverse events occurred in any patients following NOTES, except for 1 patient who experienced mild and transient pyrexia. Postoperative blood culture detected no microbial growth. Follow-up upper gastrointestinal endoscopy showed that the gastric wall wound healed well with minimal scarring. All patients were prescribed a standard four-drug antituberculosis chemotherapy regimen. The treatment outcomes were determined to be effective or curative, and no relapse was detected within the follow-up period. CONCLUSIONS: NOTES is an effective and safe diagnostic technique in patients with suspected TBP presenting as ascites of unknown etiology. PMID- 23808848 TI - A new technique of mesh-reinforced pancreaticogastrostomy: report of 13 initial cases. AB - BACKGROUND: Pancreatic anastomotic leakage is a common problem after pancreaticoduodenectomy and is a leading cause of postoperative morbidity and mortality. It is important to establish a safe and simple technique of pancreatic enteric anastomosis to minimize pancreatic leakage. PATIENTS AND METHODS: From July 2009 to February 2012, a new method of mesh-reinforced pancreaticogastrostomy was performed in 13 patients after completion of the pancreaticoduodenal resection. Patient demographic data, pathology of lesions, operative parameters, and postoperative outcomes were analyzed. RESULTS: The mean operative time was 6.9 hours (range, 5-11 hours), and the mean time for pancreaticogastrostomy was 25 minutes (range, 22-35 minutes). Intraoperative tests showed all pancreatic anastomoses were watertight. There was no postoperative death. No patient developed clinically significant pancreatic leakage (grade B or C) after operation; 1 patient (7.7%) was recognized to have a grade A pancreatic leakage. No significant complication (hemorrhage, intra abdominal abscess, or cholangitis) was observed. The mean postoperative hospital stay was 20 days (range, 11-30 days). After discharge, all patients recovered well in the 4-week follow-up period without emergency room visit or re-admission. CONCLUSIONS: The mesh-reinforced pancreaticogastrostomy provides a new way to perform pancreatic-enteric drainage after pancreaticoduodenectomy and has the advantages of simplicity, ease of handling, and applicability to all types of pancreatic remnants. PMID- 23808849 TI - Recipient's unemployment restricts access to renal transplantation. AB - Equitable distribution of a scarce resource such as kidneys for transplantation can be a challenging task for transplant centers. In this study, we evaluated the association between recipient's employment status and access to renal transplantation in patients with end-stage renal disease (ESRD). We used data from the United States Renal Data System (USRDS). The primary variable of interest was employment status at ESRD onset. Two outcomes were analyzed in Cox model: (i) being placed on the waiting list for renal transplantation or being transplanted (whichever occurred first); and (ii) first transplant in patients who were placed on the waiting list. We analyzed 429 409 patients (age of ESRD onset 64.2 +/- 15.2 yr, 55.0% males, 65.1% White). Compared with patients who were unemployed, patients working full time were more likely to be placed on the waiting list/transplanted (HR 2.24, p < 0.001) and to receive a transplant once on the waiting list (HR 1.65, p < 0.001). Results indicate that recipient's employment status is strongly associated with access to renal transplantation, with unemployed and partially employed patients at a disadvantage. Adding insurance status to the model reduces the effect size, but the association still remains significant, indicating additional contribution from other factors. PMID- 23808850 TI - Controlled experiments measuring personal exposure to PM2.5 in close proximity to cigarette smoking. AB - Few measurements of exposure to secondhand smoke (SHS) in close proximity to a smoker are available. Recent health studies have demonstrated an association between acute (<2 h) exposures to high concentrations of SHS and increased risk of cardiovascular and respiratory disease. We performed 15 experiments inside naturally ventilated homes and 16 in outdoor locations, each with 2-4 non-smokers sitting near a cigarette smoker. The smoker's and non-smokers' real-time exposures to PM2.5 from SHS were measured by using TSI SidePak monitors to sample their breathing zones. In 87% of the residential indoor experiments, the smoker received the highest average exposure to SHS, with PM2.5 concentrations ranging from 50-630 MUg/m(3) . During the active smoking period, individual non-smokers sitting within approximately 1 m of a smoker had average SHS exposures ranging from negligible up to >160 MUg/m(3) of PM2.5 . The average incremental exposure of the non-smokers was higher indoors (42 MUg/m(3) , n = 35) than outdoors (29 MUg/m(3) , n = 47), but the overall indoor and outdoor frequency distributions were similar. The 10-s PM2.5 averages during the smoking periods showed great variability, with multiple high concentrations of short duration (microplumes) both indoors and outdoors. PMID- 23808851 TI - Effects of subinhibitory concentrations of antimicrobial agents on Escherichia coli O157:H7 Shiga toxin release and role of the SOS response. AB - Treatment of Escherichia coli O157:H7 by certain antimicrobial agents often exacerbates the patient's condition by increasing either the release of preformed Shiga toxins (Stx) upon cell lysis or their production through the SOS response triggered induction of Stx-producing prophages. Recommended subinhibitory concentrations (sub-MICs) of azithromycin (AZI), gentamicin (GEN), imipenem (IMI), and rifampicin (RIF) were evaluated in comparison to norfloxacin (NOR), an SOS-inducer, to assess the role of the SOS response in Stx release. Relative expression of recA (SOS-inducer), Q (late antitermination gene of Stx-producing prophage), stx1, and stx2 genes was assessed at two sub-MICs of the antimicrobials for two different strains of E. coli O157:H7 using reverse transcription-real-time polymerase chain reaction. Both strains at the two sub MICs were also subjected to Western blotting for LexA protein expression and to reverse passive latex agglutination for Stx detection. For both strains at both sub-MICs, NOR and AZI caused SOS-induced Stx production (high recA, Q, and stx2 gene expression and high Stx2 production), so they should be avoided in E. coli O157:H7 treatment; however, sub-MICs of RIF and IMI induced Stx2 production in an SOS-independent manner except for one strain at the first twofold dilution below MIC of RIF where Stx2 production decreased. Moreover, GEN caused somewhat increased Stx2 production due to its mode of action rather than any effect on gene expression. The choice of antimicrobial therapy should rely on the antimicrobial mode of action, its concentration, and on the nature of the strain. PMID- 23808853 TI - Looking at health through a "One Health" lens. PMID- 23808852 TI - Standardized dirts for testing the efficacy of workplace cleaning products: validation of their workplace relevance. AB - BACKGROUND: In order to assess the cleaning efficacy of occupational skin cleansers, standardized test dirts mimicking the spectrum of skin soiling at dirty workplaces are necessary. OBJECTIVES: To validate newly developed standardized test dirts (compliant with the EU Cosmetics Directive) for their occupational relevance. METHODS: In this single-blinded, monocentric questionnaire-based clinical trial, 87 apprentices of three trades (household management; house painting and varnishing; and metal processing) evaluated the cleanability of six standardized test dirts in relation to their workplace dirts. In addition, they judged the similarity of the test dirts to actual dirts encountered in their working environments. RESULTS: Most of the household management participants assessed the hydrophilic model dirt ('mascara'), the lipophilic model dirt ('W/O cream') and a film-forming model dirt ('disperse paint') as best resembling the dirts found at their workplaces. Most of the painters and varnishers judged the filmogenic model dirts ('disperse paint' and 'acrylic paint') as best resembling the dirts found at their workplaces. For the metal workers, the lipophilic and paste-like model dirts were most similar to their workplace dirts. CONCLUSIONS: The spectrum of standardized test dirts developed represents well the dirts encountered at various workplaces. The test dirts may be useful in the development and in vivo efficacy testing of occupational skin cleansers. PMID- 23808854 TI - Parenting strategies African American mothers employ to decrease sexual risk behaviors in their early adolescent daughters. AB - OBJECTIVE: The impact of parenting strategies on adolescent's behavior has been the focus of research in the past three decades; the findings have never been more critical, particularly among African American mothers. According to the World Health Organization, approximately 70% of all new HIV cases are among female African Americans (AA) aged 15-24 years. The purpose of this study is to explore the process by which AA mothers intervene with their early adolescent daughters to decrease risky sexual situations, with the long-term goal of HIV prevention. DESIGN AND SAMPLE: A total of 64 AA mother-daughter dyads were recruited and separate focus groups were conducted for mothers and daughters with 6-8 per group. METHOD: Focus group methodology with principles of participatory action research was employed to formulate focus group questions, recruit dyads, and to analyze the data. RESULTS: Five codes emerged: scaring, limit setting, monitoring, nurturing/instilling values and identifying with one's ethnicity. The findings also showed an interaction between neighborhood risks, mother-daughter relationships and parenting strategies. CONCLUSIONS: Parenting strategies could be targeted for public health prevention interventions with the long-term goal of HIV prevention. PMID- 23808855 TI - An integrative review of literature on the determinants of physical activity among rural women. AB - OBJECTIVES: The purpose of this integrative review is to analyze current, non experimental literature to identify factors that influence physical activity levels in rural women with a goal of informing nurses and improving the effectiveness of future physical activity interventions in this population. DESIGN AND SAMPLE: Whittemore and Knafl's (2005) integrative review methodology was used. The sample included 11 quantitative articles, seven qualitative studies, two studies that incorporated both methodologies, and one explanatory case study. MEASURES: Each article was evaluated for quality using the American Association of Critical-Care Nurses revised evidence leveling system. Data were analyzed and then synthesized using the Matrix Method. RESULTS: The terms "rural" and "physical activity" were diversely defined in the reviewed articles. The results revealed three categories of determinants: personal factors, socio economic factors, and physical environment factors. CONCLUSIONS: Effective nursing interventions to promote physical activity should address barriers and motivating factors in all three categories of determinants for maximum efficacy. Additional research that clearly defines and consistently applies the terms "rural" and "physical activity" is needed to strengthen knowledge in this area. PMID- 23808857 TI - Promoting community practitioners' use of evidence-based approaches to increase breast cancer screening. AB - Many women do not get mammography screenings at the intervals recommended for early detection and treatment of breast cancer. The Guide to Community Preventive Services (Community Guide) recommends a range of evidence-based strategies to improve mammography rates. However, nurses and others working in community-based settings make only limited use of these strategies. We report on a dissemination intervention that partnered the University of North Carolina with the Susan G. Komen Triangle Affiliate to disseminate Community Guide breast cancer screening strategies to community organizations. The intervention was guided by social marketing and diffusion of innovation theory and was designed to provide evidence and support via Komen's existing relationships with grantee organizations. The present study reports the findings from a formative evaluation of the intervention, which included a content analysis of 46 grant applications pre- and post intervention and focus groups with 20 grant recipients. PMID- 23808856 TI - Validation of self-reported colorectal cancer screening behaviors among Appalachian residents. AB - OBJECTIVES: We determined the validity of self-reported colorectal cancer (CRC) screening data provided by Appalachian Ohio residents and identified correlates of providing accurate data. DESIGN AND SAMPLE: We conducted cross-sectional telephone interviews between September 2009 and April 2010. Our study included Appalachian Ohio residents (n = 721) ages 51-75 years. MEASURES: We compared self reported CRC screening data to medical records to determine validity. Multivariable logistic regression was used to identify correlates of providing accurate self-reported screening data. RESULTS: About 68% of participants self reported having any CRC screening test within recommended guidelines, whereas medical records indicated that only 49% were within guidelines (concordance = 0.76). Concordance was higher for flexible sigmoidoscopy and fecal occult blood test compared with colonoscopy, although sensitivity and positive predictive value were much higher for colonoscopy. Participants overreported CRC screening behaviors for all tests. Participants who had a regular checkup in the last 2 years (OR = 2.78, 95% CI: 1.15-6.73), or who self-rated their health as good or better (OR = 1.88, 95% CI: 1.12-3.16) were more likely to provide accurate screening data. CONCLUSIONS: Many participants failed to provide accurate CRC screening data, and validity varied greatly across individual CRC screening tests. Future CRC screening studies among Appalachian residents should use medical records, if possible, to determine screening histories. PMID- 23808858 TI - Training and experience of nurses in responding to alcohol misuse in rural communities. AB - OBJECTIVE: Alcohol misuse by farmers continues to challenge rural nurses. This article reports on the experiences of Australian nurses participating in the Alcohol Intervention Training Program (AITP). DESIGN AND SAMPLE: Qualitative interviews of 15 rural and remote nurses. MEASURES: Semi-structured phone interviews were utilized to assess the response to and implementation of the AITP an intervention designed to build nurses' knowledge, confidence and skills when responding to alcohol misuse. It comprises practical and theoretical components and was designed for rural and remote settings where nurses encounter alcohol misuse. RESULTS: Nurses found the training provided new-or built on existing knowledge of alcohol misuse and offered practical hands-on "real life" skills. A range of workplace and personal situations where the content of the training was now being utilized were identified, and future use anticipated. Barriers to using the new knowledge and skills included both rural and generic issues. Constructive feedback to increasingly target the training to rural settings was recommended. CONCLUSIONS: The AITP is an effective training program. It can be further tailored to meet common needs of rural and remote nurses working with farmers who misuse alcohol, while recognizing diversity in rural practice. PMID- 23808859 TI - Accuracy of adults' perception of childhood obesity in a military environment. AB - OBJECTIVES: The aim of this study was to determine how accurately adults in a military environment identified images of children within four different categories: underweight, normal weight, overweight, and obese. DESIGN AND SAMPLE: For this descriptive correlational research study, the sample was composed of 1,016 adults. MEASURES: Chi-square analysis of participant's demographic characteristics and accuracy of identification of six different images of children was conducted. RESULTS: Statistical significance was demonstrated with participant's self-image and accuracy of identification in four of the six images. CONCLUSIONS: This research supports the conclusion that individuals who classify themselves as overweight or obese are very accurate in correctly classifying images of children in these categories. While this is true our findings demonstrate that a large number of participants do not correctly self identify themselves. This suggests that educational campaigns need to include educational components to increase awareness of what children are considered overweight or obese. Without this, the potential exists for the message to be missed as the parent could potentially perceive the overweight or obese child as normal. PMID- 23808860 TI - Health care providers' perspectives on low HPV vaccine uptake and adherence in Appalachian Kentucky. AB - OBJECTIVE: Previous intervention research conducted in Appalachian Kentucky resulted in extremely low uptake and adherence to the human papillomavirus (HPV) vaccine among women ages 18-26, despite provision of free vaccine. Because of these findings, the purpose of this qualitative, follow-up study was to elicit health care providers' perspectives on barriers and facilitators to HPV vaccination and suggested strategies for improving vaccination rates. DESIGN AND SAMPLE: Researchers conducted semi-structured qualitative interviews with a purposive sample of eight health care providers (seven nursing professionals, one physician) at the health clinic where the original HPV vaccination intervention took place. Interviews were audio-recorded and transcribed and authors used a constant-comparative method to analyze the data. RESULTS: Significant themes emerged from the interviews, centering around two primary issues: vaccine uptake and vaccine adherence. Related to uptake, health care providers identified perceived patient barriers and inadequate HPV vaccine education. They also identified the vaccine schedule and clinic-centered communication deficiencies as adherence-related barriers. CONCLUSION: These Appalachian Kentucky health care providers provided important insights into barriers and facilitators to HPV vaccine uptake and adherence that need to be readily addressed in this community. As informed by these providers, several suggestions for improving HPV vaccination, such as more targeted education efforts and patient-centered reminder systems, may be applicable to other nursing professionals working in rural and medically underserved communities. PMID- 23808861 TI - Perceived barriers to physical activity among pregnant women living in a rural community. AB - OBJECTIVE: The purpose of this research was to describe perceived barriers to physical activity among pregnant women living in a rural community. DESIGN AND SAMPLE: The project followed a simple descriptive design. The sample included 88 healthy pregnant women from a rural community in the southeast United States. MEASURES: The women completed the International Physical Activity Questionnaire (IPAQ) and an open-ended item seeking a description of personal barriers to engagement in regular physical activity. RESULTS: Scores on the IPAQ were generally equally distributed across categories of low, moderate, and high activity. A total of 42 barriers was described from 34% of the women. Seven themes emerged among the reported barriers: (1) symptoms of pregnancy, (2) family and childrearing activities, (3) lack of personal motivation, (4) time and employment demands, (5) perceptions of sufficient activity from daily life, (6) fear of injury, and (7) lack of a habit of activity. CONCLUSIONS: Barriers reported by the rural women were similar to those identified in other settings. Some perceptions confirmed myths about the health value of exercise during pregnancy, but did not confirm barriers commonly cited or assumed for reduced physical activity among rural residents. PMID- 23808862 TI - The strategies of Japanese public health nurses in medication support for high risk tuberculosis patients. AB - OBJECTIVE: The purpose of this study was to describe the support provided by Japanese public health nurses (PHNs) to high-risk tuberculosis (TB) patients, focusing specifically on the support aimed at preventing interruptions in treatment. DESIGN AND SAMPLE: A qualitative descriptive approach was used with a convenience sample of 11 PHNs in Japan who cared for TB patients at highest risk for medication adherence problems. MEASURES: Semi-structured interviews were conducted to learn the scope and practice of PHNs with high-risk TB patients. Data were analyzed using a qualitative descriptive analysis process. RESULTS: One main theme was identified: "Supporting the patients in overcoming tuberculosis, regaining health, and living a healthier life." Three categories with five subcategories described the nurses' activities: (1) empathetic and reliable support, (2) motivational strategies for medication adherence, and (3) developing a foundation for healthier life. CONCLUSIONS: The nurses interviewed described creative and extraordinary strategies used to promote medication adherence and facilitate development of a healthy posttreatment lifestyle. Their approach was patient-centered and culturally congruent. Findings may be transferrable to PHN practice in other regions as care for this economically disadvantaged and marginalized population is a critical need. PMID- 23808863 TI - Email for the provision of information on disease prevention and health promotion: a Cochrane review summary. PMID- 23808864 TI - Voluntary counseling and testing (VCT) for changing HIV-related risk behavior in developing countries: a Cochrane review summary. PMID- 23808865 TI - The complex microbiota of raw milk. AB - Here, we review what is known about the microorganisms present in raw milk, including milk from cows, sheep, goats and humans. Milk, due to its high nutritional content, can support a rich microbiota. These microorganisms enter milk from a variety of sources and, once in milk, can play a number of roles, such as facilitating dairy fermentations (e.g. Lactococcus, Lactobacillus, Streptococcus, Propionibacterium and fungal populations), causing spoilage (e.g. Pseudomonas, Clostridium, Bacillus and other spore-forming or thermoduric microorganisms), promoting health (e.g. lactobacilli and bifidobacteria) or causing disease (e.g. Listeria, Salmonella, Escherichia coli, Campylobacter and mycotoxin-producing fungi). There is also concern that the presence of antibiotic residues in milk leads to the development of resistance, particularly among pathogenic bacteria. Here, we comprehensively review these topics, while comparing the approaches, both culture-dependent and culture-independent, which can be taken to investigate the microbial composition of milk. PMID- 23808866 TI - The functions of autobiographical memory: an integrative approach. AB - Recent research in cognitive psychology has emphasised the uses, or functions, of autobiographical memory. Theoretical and empirical approaches have focused on a three-function model: autobiographical memory serves self, directive, and social functions. In the reminiscence literature other taxonomies and additional functions have been postulated. We examined the relationships between functions proposed by these literatures, in order to broaden conceptualisations and make links between research traditions. In Study 1 we combined two measures of individual differences in the uses of autobiographical memory. Our results suggested four classes of memory functions, which we labelled Reflective, Generative, Ruminative, and Social. In Study 2 we tested relationships between our four functions and broader individual differences, and found conceptually consistent relationships. In Study 3 we found that memories cued by Generative and Social functions were more emotionally positive than were memories cued by Reflective and Ruminative functions. In Study 4 we found that reported use of Generative functions increased across the lifespan, while reported use of the other three functions decreased. Overall our findings suggest a broader view of autobiographical memory functions that links them to ways in which people make meaning of their selves, their environment, and their social world more generally. PMID- 23808867 TI - Psychological and physiological predictors of health in romantic relationships: an attachment perspective. AB - This article reviews the burgeoning literature linking greater individual differences in attachment anxiety and attachment avoidance to poorer health. Extant research indicates that more anxiously and avoidantly attached individuals experience heightened psychological (e.g., distress) and physiological (e.g., HPA axis activation) responses to stressful situations, as well as have poorer mental (e.g., depression) and physical (e.g., immune system functioning) health. Research also suggests that perceived social support processes are sometimes beneficial for more anxiously and avoidantly attached persons' mental health, but are not helpful in alleviating physiological responses to stress. Future studies could fruitfully delve into the possible dyadic influences on health and interventions to improve the health experiences of more anxiously and avoidantly attached individuals. Lastly, future research could benefit from longitudinal explorations of health. PMID- 23808869 TI - Effects of splenectomy on hepatic gene expression profiles after massive hepatectomy in rats. AB - BACKGROUND AND AIM: Possible spleno-hepatic relationships affected by hepatectomy still remained unclear. We have previously reported that splenectomy may ameliorate liver injuries and promote appropriate liver regeneration after massive hepatectomy. Therefore, we investigated the effects of splenectomy on the DNA expression profile in the liver after massive hepatectomy in rats. METHODS: Rats were divided into the following two groups: 90% hepatectomy (Hx group) and 90% hepatectomy with splenectomy (Hx + Sp group). Rats were sacrificed 3 and 6 h after surgery, and mRNA from liver tissue was isolated and hybridized to Affymetrix GeneChip Rat Genome 230 2.0 Array (Affymetrix, Santa Clara, CA, USA) and a pathway analysis was done with Ingenuity Pathway Analysis (Ingenuity Systems, Mountain View, CA, USA). RESULTS: We determined the Hx + Sp/Hx ratio to assess the influence of splenectomy, and cut-off values were set at more than 2.0 fold or less than 1/2 (0.5)-fold. Immediate early response gene including early growth response-1 and FBJ murine osteosarcoma-related pathways were markedly downregulated by splenectomy. In contrast, heme oxygenase-1 gene-related pathway was upregulated by splenectomy. CONCLUSIONS: Splenectomy provided the protective effects for liver failure and promoted liver regeneration, possibly owing to the downregulation of immediate early response genes and upregulation of the heat shock protein, heme oxygenase-1. PMID- 23808868 TI - Preliminary evaluation of a model of stimulant use, oxidative damage and executive dysfunction. AB - BACKGROUND: Illicit stimulant use increases oxidative stress and oxidative stress has been found to be associated with deficits in memory, attention and problem solving. OBJECTIVE: To test a model of the association among oxidative DNA damage, a severe form of oxidative stress, and stimulant use, executive function and stimulant-use outcomes. METHODS: Six sites evaluating 12-step facilitation for stimulant abusers obtained peripheral blood samples from methamphetamine dependent (n = 45) and cocaine-dependent (n = 120) participants. The blood samples were submitted to a comet assay to assess oxidative DNA damage. Executive Dysfunction was assessed with the Frontal Systems Behavior Scale (FrSBe), which is a reliable and valid self-report assessment of executive dysfunction, disinhibition and apathy. Stimulant-use measures included self-reported stimulant use and stimulant urine drug screens (UDS). RESULTS: While more recent cocaine use (<30 days abstinence) was associated with greater oxidative DNA damage (W = 2.4, p < 0.05, d = 0.36), the results did not support the hypothesized relationship between oxidative DNA damage, executive dysfunction and stimulant use outcomes for cocaine-dependent patients. Support for the model was found for methamphetamine-dependent patients, with oxidative DNA damage significantly greater in methamphetamine-dependent patients with executive dysfunction (W = 2.2, p < 0.05, d = 0.64) and with executive dysfunction being a significant mediator of oxidative DNA damage and stimulant use during active treatment (ab = 0.089, p < 0.05). As predicted, neither disinhibition nor apathy were significant mediators of oxidative damage and future stimulant use. CONCLUSION: These findings provide preliminary support for a model in which oxidative damage resulting from methamphetamine use results in executive dysfunction, which in turn increases vulnerability to future stimulant use. PMID- 23808870 TI - Relationship between childhood obesity cut-offs and metabolic and vascular comorbidities: comparative analysis of three growth standards. AB - BACKGROUND: To compare the association between metabolic and vascular comorbidities and the body mass (BMI)-for-age cut-off criteria from three growth standards [Centers for Disease Control and Prevention (CDC), 2000; World Health Organization (WHO), 2007; Spanish Reference Criteria (Carrascosa Lezcano et al., 2008)] that are used to define being overweight and obese in childhood. METHODS: A prospective study was conducted in 137 children (aged 8-16 years). Based on BMI for-age Z-scores according to WHO cut-offs, 59 participants were obese, 35 were overweight and 43 were normal-weight. All participating children were subsequently reclassified applying the CDC and Spanish Reference Criteria. Blood pressure (BP), biochemical variables and vascular parameters (stiffness and intima-media thickness) were analysed. RESULTS: According to WHO and CDC references, 48% and 43% of the children, respectively, were categorised as obese, whereas 16% were considered as obese using the Spanish Reference Criteria. Applying WHO criteria, obese children showed significantly higher levels of insulin, homeostasis model assessment index and most vascular parameters, as well as lower high-density lipoprotein (HDL)-cholesterol than overweight children. Moreover, overweight children showed higher BP, insulin and uric acid, and lower HDL-cholesterol than normal weight children. The CDC criteria yielded similar results, although with fewer differences between obese and overweight children. Applying Spanish criteria, the differences between obese and overweight children disappeared. CONCLUSIONS: WHO and CDC BMI-for-age references and cut-offs are useful for defining obesity and being overweight in children because they clearly identify metabolic and vascular comorbidities. The Spanish Reference Criteria underdiagnose obesity because overweight children show comorbidities typical of the obese. PMID- 23808871 TI - Lipo-chitooligosaccharidic symbiotic signals are recognized by LysM receptor-like kinase LYR3 in the legume Medicago truncatula. AB - While chitooligosaccharides (COs) derived from fungal chitin are potent elicitors of defense reactions, structurally related signals produced by certain bacteria and fungi, called lipo-chitooligosaccharides (LCOs), play important roles in the establishment of symbioses with plants. Understanding how plants distinguish between friend and foe through the perception of these signals is a major challenge. We report the synthesis of a range of COs and LCOs, including photoactivatable probes, to characterize a membrane protein from the legume Medicago truncatula. By coupling photoaffinity labeling experiments with proteomics and transcriptomics, we identified the likely LCO-binding protein as LYR3, a lysin motif receptor-like kinase (LysM-RLK). LYR3, expressed heterologously, exhibits high-affinity binding to LCOs but not COs. Homology modeling, based on the Arabidopsis CO-binding LysM-RLK AtCERK1, suggests that LYR3 could accommodate the LCO in a conserved binding site. The identification of LYR3 opens up ways for the molecular characterization of LCO/CO discrimination. PMID- 23808872 TI - Predicting relapse risk in childhood acute lymphoblastic leukaemia. AB - Intensive multi-agent chemotherapy regimens and the introduction of risk stratified therapy have substantially improved cure rates for children with acute lymphoblastic leukaemia (ALL). Current risk allocation schemas are imperfect, as some children are classified as lower-risk and treated with less intensive therapy relapse, while others deemed higher-risk are probably over-treated. Most cooperative groups previously used morphological clearance of blasts in blood and marrow during the initial phases of chemotherapy as a primary factor for risk group allocation; however, this has largely been replaced by the detection of minimal residual disease (MRD). Other than age and white blood cell count (WBC) at presentation, many clinical variables previously used for risk group allocation are no longer prognostic, as MRD and the presence of sentinel genetic lesions are more reliable at predicting outcome. Currently, a number of sentinel genetic lesions are used by most cooperative groups for risk stratification; however, in the near future patients will probably be risk-stratified using genomic signatures and clustering algorithms, rather than individual genetic alterations. This review will describe the clinical, biological, and response based features known to predict relapse risk in childhood ALL, including those currently used and those likely to be used in the near future to risk-stratify therapy. PMID- 23808873 TI - Mass spectrometry characterization of trypanothione and novel peptides of medical importance isolated from Acanthamoeba polyphaga. AB - This paper presents unequivocal results about the presence of trypanothione and its precursor glutathionespermidine from the opportunistic human pathogen Acanthamoeba polyphaga. They were isolated by RP-HPLC as thiolbimane derivatives and characterized using matrix-assisted laser desorption ionization-time-of flight (MALDI-TOF/TOF). Additionally RP-HPLC demonstrated that thiol-bimane compounds corresponding to cysteine and glutathione were also present in A. polyphaga. Besides trypanothione, we want to report four new peptides in trophozoites, a tetrapeptide, a hexapeptide, a heptapeptide and a nonapeptide. Trypanothione and two of the thiol peptides, the hexapeptide and heptapeptide, are oxidized since the reduced forms increase in amount when the normal extract is treated by DTT or by electrolytic reduction that convert the oxidized forms to reduced ones. On the other hand, they disappear when the amoeba extract is treated with NEM or when the amoeba culture is treated with various inhibitors of NADPH-dependent disulfidereducing enzymes. Comparison of the thiol peptides, including trypanothione from A. polyphaga with extracts from human lymphocytes showed that they are not present in the latter. Therefore, some of the peptides here reported could be used as antigens for rapid detection of these parasites. In regard to the presence of the enzymes that synthesize and reduce trypanothione in A. polyphaga we suggest that they can be used as drug targets. PMID- 23808875 TI - Why supervisors should promote feedback-seeking behaviour in medical residency. AB - BACKGROUND: Individual disposition of goal orientation and situational factors of the working context, both generate and modulate motives to seek feedback. AIM: We looked for correlations between feedback-seeking and individual goal orientation, motives or concerns of feedback-seeking, working context of medical residents. We focussed on how promotion of feedback-seeking by supervisors and educational environment influenced motives and behaviours of feedback-seeking in residents. METHODS: Web-based administration of a Likert-type composite questionnaire to residents of a tertiary care teaching hospital in Switzerland and mini interviews. RESULTS: Fifty-six (45%) of 125 residents completed the questionnaire. After multiple regression analysis promotion of feedback-seeking through supervisors remained the sole predictor correlating with feedback-seeking through inquiry (R(2) = 16) and the motive of self-improvement (R(2) = 0.30). This predictor was also associated with reduced concerns of ego-protection (R(2) = 0.14) and impression-defence (R(2) = 0.18). Performance-avoid goal orientation was associated with concerns of impression-defence (R(2) = 0.36) and ego protection (R(2) = 0.48). Women had significantly more concerns of ego protection, residents with more than three years of experience more concerns of impression-defence. Disillusion that PG-training would ever improve, seemed the main reason to refuse participation CONCLUSIONS: Promotion of feedback-seeking through supervisors combined with delivery of high quality feedback may guide residents towards seeking feedback for professional self-improvement. PMID- 23808877 TI - An improved protocol for isolation and culturing of mouse spermatogonial stem cells. AB - Spermatogonial stem cells (SSCs) represent a unique testicular cell type that has the capacity for proliferating, differentiating, and transmitting genetic information. This particular cell type is a strong focus of stem cell research, with isolation and maintenance of SSCs as an important issue. Therefore, we attempted to optimize SSCs handling and to analyze different media and feeder layers, such as adult and embryonic Sertoli cells. The expression patterns of SSC specific proteins (alpha6 and beta1 integrins, Stra8, and DAZL) and restoration of spermatogenesis were chosen as parameters to demonstrate the efficacy of the protocol. SSCs were isolated from testes of 3- to 6-day-old mice using a magnetic activated cell-sorting system and Thy-1 antibody. After enrichment, SSCs were cultured for 7 days with different media and feeder layers. Then, SSCs were transplanted to recipient mice. Culturing on adult and embryonic Sertoli cells and in the presence of different growth factors [glial cell line-derived neurotrophic factor (GDNF), GDNF family receptor alpha1 (GFR-alpha1), and basic fibroblast growth factor (bFGF) resulted in an undifferentiated SSC phenotype with typical stem cell characteristics observed in vivo. The established co culture model could help to improve the recovery and quality of stem cell preparation of mammalian testis. PMID- 23808876 TI - Ultrasensitive impedimetric lectin biosensors with efficient antifouling properties applied in glycoprofiling of human serum samples. AB - Ultrasensitive impedimetric lectin biosensors recognizing different glycan entities on serum glycoproteins were constructed. Lectins were immobilized on a novel mixed self-assembled monolayer containing 11-mercaptoundecanoic acid for covalent immobilization of lectins and betaine terminated thiol to resist nonspecific interactions. Construction of biosensors based on Concanavalin A (Con A), Sambucus nigra agglutinin type I (SNA), and Ricinus communis agglutinin (RCA) on polycrystalline gold electrodes was optimized and characterized with a battery of tools including electrochemical impedance spectroscopy, various electrochemical techniques, quartz crystal microbalance (QCM), Fourier transform infrared (FT-IR) spectroscopy, atomic force microscopy (AFM), and X-ray photoelectron spectroscopy (XPS) and compared with a protein/lectin microarray. The lectin biosensors were able to detect glycoproteins from 1 fM (Con A), 10 fM (Ricinus communis agglutinin (RCA), or 100 fM (SNA) with a linear range spanning 6 (SNA), 7 (RCA), or 8 (Con A) orders of magnitude. Furthermore, a detection limit for the Con A biosensor down to 1 aM was achieved in a sandwich configuration. A nonspecific binding of proteins for the Con A biosensor was only 6.1% (probed with an oxidized invertase) of the signal toward its analyte invertase and a negligible nonspecific interaction of the Con A biosensor was observed in diluted human sera (1000*), as well. The performance of the lectin biosensors was finally tested by glycoprofiling of human serum samples from healthy individuals and those having rheumatoid arthritis, which resulted in a distinct glycan pattern between these two groups. PMID- 23808878 TI - Gene expression of Dnmt1 isoforms in porcine oocytes, embryos, and somatic cells. AB - In the mouse, the dynamics of genomic methylation and the initial events of gametic imprinting are controlled by the activity of an oocyte isoform of the DNA methyltransferase-1 (Dnmt1o) enzyme. The objectives of this study were to identify the alternative splicing variants of Dnmt1 in porcine oocytes and determine the gene expression pattern of the different Dnmt1 isoforms during embryo development. A rapid amplification of cDNA ends (RACE ) system was used to amplify the 5' cDNA end of Dnmt1 isoforms in porcine oocytes. RNA levels of the Dnmt1 isoforms were analyzed in porcine oocytes and embryos. DNMT1 protein expression of oocytes and somatic cells were analyzed by western blot and immunostaining. Two new Dnmt1o RNA isoforms were identified--Dnmt1o1 and Dnmt1o2. The previously reported somatic Dnmt1 isoform (Dnmt1s) was expressed at low but constant levels in oocytes and embryos from the two-cell to the blastocyst stage. Abundant RNA levels of Dnmt1o1 and Dnmt1o2 were detected in oocytes and embryos from the two- to the eight- to 16-cell stage. Levels of these Dnmt1o transcripts were low at the morula and blastocyst stages. Although Dnmt1s was present in all the somatic cell types analyzed, Dnmt1o1 and Dnmt1o2 were not detected in any somatic tissues. As predicted by the RNA sequence and verified by western blot analysis, Dnmt1o1 and Dnmt1o2 RNAs translate one DNMT1o enzyme. Western blot analysis confirmed that both the oocyte and the somatic forms of DNMT1 protein are present in porcine oocytes and early embryos, whereas somatic cells produce only DNMT1s protein. DNMT1o is localized mainly in the nuclei of oocytes and early embryos, whereas DNMT1s is expressed in the ooplasm cortex of oocytes and cytoplasm of early embryos. PMID- 23808879 TI - Transgenic chicken, mice, cattle, and pig embryos by somatic cell nuclear transfer into pig oocytes. AB - This study explored the possibility of producing transgenic cloned embryos by interspecies somatic cell nuclear transfer (iSCNT) of cattle, mice, and chicken donor cells into enucleated pig oocytes. Enhanced green florescent protein (EGFP) expressing donor cells were used for the nuclear transfer. Results showed that the occurrence of first cleavage did not differ significantly when pig, cattle, mice, or chicken cells were used as donor nuclei (p>0.05). However, the rate of blastocyst formation was significantly higher in pig (14.9+/-2.1%; p<0.05) SCNT embryos than in cattle (6.3+/-2.5%), mice (4.2+/-1.4%), or chicken (5.1+/-2.4%) iSCNT embryos. The iSCNT embryos also contained a significantly less number of cells per blastocyst than those of SCNT pig embryos (p<0.05). All (100%) iSCNT embryos expressed the EGFP gene, as evidenced by the green florescence under ultraviolet (UV) illumination. Microinjection of purified mitochondria from cattle somatic cells into pig oocytes did not have any adverse effect on their postfertilization in vitro development and embryo quality (p>0.05). Moreover, NCSU23 medium, which was designed for in vitro culture of pig embryos, was able to support the in vitro development of cattle, mice, and chicken iSCNT embryos up to the blastocyst stage. Taken together, these data suggest that enucleated pig oocytes may be used as a universal cytoplast for production of transgenic cattle, mice, and chicken embryos by iSCNT. Furthermore, xenogenic transfer of mitochondria to the recipient cytoplast may not be the cause for poor embryonic development of cattle-pig iSCNT embryos. PMID- 23808880 TI - Real-time observation of multiple-protein complex formation with single-molecule FRET. AB - Current single-molecule techniques do not permit the real-time observation of multiple proteins interacting closely with each other. We here report an approach enabling us to determine the single-molecule fluorescence resonance energy transfer (FRET) kinetics of multiple protein-protein interactions occurring far below the diffraction limit. We observe a strongly cooperative formation of multimeric soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes, which suggests that formation of the first SNARE complex triggers a cascade of SNARE complex formation. PMID- 23808874 TI - New targets and inhibitors of mycobacterial sulfur metabolism. AB - The identification of new antibacterial targets is urgently needed to address multidrug resistant and latent tuberculosis infection. Sulfur metabolic pathways are essential for survival and the expression of virulence in many pathogenic bacteria, including Mycobacterium tuberculosis. In addition, microbial sulfur metabolic pathways are largely absent in humans and therefore, represent unique targets for therapeutic intervention. In this review, we summarize our current understanding of the enzymes associated with the production of sulfated and reduced sulfur-containing metabolites in Mycobacteria. Small molecule inhibitors of these catalysts represent valuable chemical tools that can be used to investigate the role of sulfur metabolism throughout the Mycobacterial lifecycle and may also represent new leads for drug development. In this light, we also summarize recent progress made in the development of inhibitors of sulfur metabolism enzymes. PMID- 23808881 TI - Smoking reduces the risk of hypothyroidism and increases the risk of hyperthyroidism: evidence from 450,842 mothers giving birth in Denmark. AB - OBJECTIVE: Smoking may influence on the occurrence of thyroid disease, but studies have led to inconsistent results. In Denmark, information on maternal smoking during pregnancy is registered by midwives, and we investigated the association between maternal smoking as reported during pregnancy and the subsequent maternal risk of having hyper- or hypothyroidism diagnosed. DESIGN: Population-based cohort study. PARTICIPANTS: Using Danish nationwide registers, we identified mothers giving birth in Denmark, 1996-2008, and studied their first pregnancy in the study period. MEASUREMENTS: Information on maternal smoking during the pregnancy and maternal diagnosis of hyper- or hypothyroidism was obtained from the Danish National Hospital Register (DNHR) and prescription of thyroid medication from the Danish National Prescription Register (DNPR). Cox proportional hazards model was used to estimate hazard ratio (HR) with 95% confidence interval (95% CI) for onset of maternal hyper- or hypothyroidism after birth of the child in multivariate analyses adjusting for potential confounders. RESULTS: Among mothers included (n = 450 842), altogether 89,022 (19.7%) reported that they were smokers during the first pregnancy in the study period, and 8905 (2.0%) developed hyper (n = 3389)- or hypothyroidism (n = 5516) after birth of the child. Maternal smoking was associated with a subsequent decreased risk of developing hypothyroidism (adjusted HR 0.75 (95% CI 0.70-0.81)) and an increased risk of hyperthyroidism (1.38 (1.27-1.49)). CONCLUSIONS: Danish nationwide registration of maternal smoking during pregnancy adds further evidence to an association between smoking and thyroid dysfunction; smoking reduced the risk of hypothyroidism and increased the risk of hyperthyroidism. PMID- 23808882 TI - A population study of fractures: what we can learn and what we cannot learn. PMID- 23808883 TI - The carbohydrate switch between pathogenic and immunosuppressive antigen-specific antibodies. AB - IgG antibodies have one conserved N-glycosylation site at Asn 297 in each of their constant heavy chain regions. These Fc glycans influence the overall structure and pro- or anti-inflammatory effector functions of IgG antibodies. The biantennary core glycan structure, consisting of four N-acetyl-glucosamine (GlcNAc) and three mannose residues, can be further decorated with fucose, a bisecting GlcNAc and terminal galactose or galactose plus sialic acid. Non galactosylated (agalactosylated; G0) IgG antibodies have long been associated with pro-inflammatory effector functions in autoimmune patients with rheumatoid arthritis (RA). In contrast, it has been shown that sialylated IgGs are responsible for anti-inflammatory effects of intravenous immunoglobulin (IVIG; purified IgG from pooled human plasma), which is administered at high doses (2 g/kg) for the systemic treatment of autoimmune patients. It has become increasingly evident that pro-inflammatory immune responses, such as autoimmune reactions, primarily induce antigen-specific G0 IgGs, whereas tolerance induces immunosuppressive galactosylated and sialylated IgGs. Under physiological conditions, differentially glycosylated IgGs mediate their pro- or anti inflammatory effector functions obviously as immune complexes (IC) in an antigen specific manner. Therefore, antigen-specific galactosylated and sialylated IgGs may be a promising therapeutic tool for re-establishing tolerance against defined (self-) antigens in autoimmune or allergic patients. Here, we summarize these findings and outline our viewpoint on the development and function of differentially glycosylated antigen-specific IgG antibodies. PMID- 23808884 TI - Effects of acetaminophen and ibuprofen in children with migraine receiving preventive treatment with magnesium. AB - AIM: The purpose of this study was to evaluate both the effects of ibuprofen and/or acetaminophen for the acute treatment of primary migraine in children in or out prophylactic treatment with magnesium. METHODS: Children ranging from the ages of 5 to 16 years with at least 4 attack/month of primary migraine were eligible for participation the study. A visual analog scale was used to evaluate pain intensity at the moment of admission to the study (start of the study) and every month up to 18 months later (end of the study). RESULTS: One hundred sixty children of both sexes aged 5-16 years were enrolled and assigned in 4 groups to receive a treatment with acetaminophen or ibuprofen without or with magnesium. Migraine pain endurance and monthly frequency were similar in the 4 groups. Both acetaminophen and ibuprofen induced a significant decrease in pain intensity (P < .01), without a time-dependent correlation, but did not modify its frequency. Magnesium pretreatment induced a significant decrease in pain intensity (P < .01) without a time-dependent correlation in both acetaminophen- and ibuprofen-treated children and also significantly reduced (P < .01) the pain relief timing during acetaminophen but not during ibuprofen treatment (P < .01). In both acetaminophen and ibuprofen groups, magnesium pretreatment significantly reduced the pain frequency (P < .01). CONCLUSIONS: Magnesium increased the efficacy of ibuprofen and acetaminophen with not age-related effects. PMID- 23808885 TI - Telehealth remote monitoring for community-dwelling older adults with chronic obstructive pulmonary disease. AB - OBJECTIVE: To determine if self-monitoring via home-based telehealth equipment could, when combined with ongoing remote monitoring by a nurse, reduce the incidence of hospitalizations and emergency department (ED) presentations for people with chronic obstructive pulmonary disease (COPD). SUBJECTS AND METHODS: A randomized controlled trial was used to compare the outcomes for participants receiving the telehealth equipment and monitoring with those for participants in an information-only control group, over a period of 6 months. Participants receiving the telehealth intervention were taught to measure and record their vital signs (blood pressure, weight, temperature, pulse, and oxygen saturation levels) on a daily basis. These were then transmitted automatically via telephone to a secure Web site where they were monitored each day by the telehealth nurse. RESULTS: The telehealth group had fewer ED presentations and hospital admissions and a reduced length of stay in comparison with the control group. These results were not statistically significant. However, the reduction in health service use was large enough to result in significant cost savings, with the annual cost savings of the telehealth group compared with the control group being $2,931 per person. CONCLUSIONS: Telehealth monitoring of patient vital signs reduced health service utilization for individuals with COPD and resulted in significant cost savings. In terms of individual health benefits, improvements in participants' self-management behaviors and control over their condition was evident. PMID- 23808886 TI - Evaluation criteria for mobile teledermatology applications and comparison of major mobile teledermatology applications. AB - BACKGROUND: Mobile teledermatology applications have enabled increased patient access to dermatologic care. For groups interested in starting a mobile teledermatology program, selection of the appropriate application can be challenging. Having pretested evaluation criteria allows for efficient, systematic assessment of mobile teledermatology applications and identification of features important for comparison. The primary aim of this study is to determine a framework for evaluation of mobile teledermatology applications and to compare two major mobile teledermatology applications available in the United States using the proposed criteria. MATERIALS AND METHODS: We incorporated previous teledermatology application evaluation criteria and developed new evaluation criteria to reflect matters specific to the mobile platform. Through a systematic search, we identified two publicly available mobile teledermatology applications in the United States and applied the evaluation criteria. RESULTS: The 13-point evaluation criteria encompass three major domains: (1) technical specifications, (2) user experience and workflow, and (3) integration and scalability. The evaluation criteria provided an effective way of assessing the two mobile teledermatology applications. Both AccessDerm version 1.0 (Vignet Corp., McLean, VA) and ClickMedix version 1.3 (ClickMedix LLC, Rockville, MD) were capable of managing consultations. These applications adopted different approaches to balancing image quality versus data transmission, managing follow up patients, and enabling dialogue between providers. CONCLUSIONS: Mobile teledermatology provides convenient and scalable means of providing specialty care. The creation of mobile application evaluation criteria offers a useful guide for assessing future mobile applications. PMID- 23808887 TI - Evaluating opportunities for text message communication: a survey of parents and teens. AB - BACKGROUND: Text messaging is a widespread, cost-effective method for communicating. It is widely used by both parents and teens. The study objective was to survey teens and their parents to assess the capability and willingness of teens to receive healthcare-related text messages from their physician. SUBJECTS AND METHODS: Parents and teens (12-17 years old) at an adolescent clinic were asked to complete surveys. Surveys were available in hard copy or electronically (via Survey Monkey) using computer kiosks in the waiting room. Approval was received from two local Institutional Review Boards. RESULTS: Of the 93 pairs who began the survey, 47 pairs (51%) qualified and completed both the teen and parent surveys. Over 85% of teens were willing to receive texts from their doctor. Teens were most interested in appointment reminders (81%), immunization reminders (53%), and general test results (for example, strep [53%]). Parents' willingness to allow teens to receive text messages directly varied by content. Many parents preferred to also receive a copy of any text message sent to their teen. CONCLUSIONS: Both parents and teens endorse using text messages for appointment reminders. Parents appear willing for their teens to receive some health information directly. Future research should evaluate the efficacy of using text messages for communication with teens to improve care and utilization of services for adolescents. PMID- 23808888 TI - A retrospective study on patient characteristics and telehealth alerts indicative of key medical events for heart failure patients at a home health agency. AB - OBJECTIVE: To explore association of patient characteristics and telehealth alert data with all-cause key medical events (KMEs) of emergency department (ED) visits and hospitalizations as well as cardiac-related KMEs of ED visits, hospitalizations, and medication changes. MATERIALS AND METHODS: A 6-month retrospective study was conducted of electronic patient records of heart failure (HF) patients using telehealth services at a Massachusetts home health agency. Data collected included patient demographic, psychosocial, disease severity factors and telehealth vital signs alerts. Association between patient characteristics and KMEs was analyzed by Generalized Estimating Equations. RESULTS: The sample comprised 168 patients with a mean age of 83 years, 56% females, and 96% white. Ninety-nine cardiac-related KMEs and 87 all-cause KMEs were recorded for the subjects. Odds of a cardiac-related KME increased by 161% with the presence of valvular co-morbidity (p=0.001) and 106% with increased number of telehealth alerts (adjusted p<0.0001). Odds of an all-cause KME increased by 124% (p=0.02), 127% (p=0.01), and 70% (adjusted p<0.0001) with the presence of cancer co-morbidity, anxiety, and increased number of telehealth alerts, respectively. Overall, only 3% of all telehealth alerts were associated with KMEs. CONCLUSIONS: The very low proportion of telehealth vital sign alerts associated with KMEs indicates that telehealth alerts alone cannot inform the need for intervention within the larger context of HF care delivery in the homecare setting. Patient-relevant data such as psychosocial and symptom status, involvement with HF self-management, and presence of co-morbidities could further inform the need for interventions for HF patients in the homecare setting. PMID- 23808889 TI - Nanometric protein-patch arrays on glass and polydimethylsiloxane for cell adhesion studies. AB - We present a simple cost-effective benchtop protocol to functionalize glass and polydimethylsiloxane (PDMS) with nanometric protein patches for cell adhesion studies. Evaporation masks, covering macroscopic areas on glass, were made using improved strategies for self-assembly of colloidal microbeads which then served as templates for creating the protein patch arrays via the intermediate steps of organo-aminosilane deposition and polyethylene-glycol grafting. The diameter of the patches could be varied down to about 80 nm. The glass substrates were used for advanced optical imaging of T-lymphocytes to explore adhesion by reflection interference contrast microscopy and the possible colocalization of T-cell receptor microclusters and the activating protein patches by total internal reflection fluorescence microscopy. The selectively functionalized glass could also serve as template for transferring the protein nanopatches to the surface of a soft elastomer. We demonstrated successful reverse contact printing onto the surface of thin layers of PDMS with stiffness ranging from 30 KPa to 3 MPa. PMID- 23808890 TI - Stabilization of physical RAF/14-3-3 interaction by cotylenin A as treatment strategy for RAS mutant cancers. AB - One-third of all human cancers harbor somatic RAS mutations. This leads to aberrant activation of downstream signaling pathways involving the RAF kinases. Current ATP-competitive RAF inhibitors are active in cancers with somatic RAF mutations, such as BRAF(V600) mutant melanomas. However, they paradoxically promote the growth of RAS mutant tumors, partly due to the complex interplay between different homo- and heterodimers of A-RAF, B-RAF, and C-RAF. Based on pathway analysis and structure-guided compound identification, we describe the natural product cotylenin-A (CN-A) as stabilizer of the physical interaction of C RAF with 14-3-3 proteins. CN-A binds to inhibitory 14-3-3 interaction sites of C RAF, pSer233, and pSer259, but not to the activating interaction site, pSer621. While CN-A alone is inactive in RAS mutant cancer models, combined treatment with CN-A and an anti-EGFR antibody synergistically suppresses tumor growth in vitro and in vivo. This defines a novel pharmacologic strategy for treatment of RAS mutant cancers. PMID- 23808891 TI - The survival outcomes following liver transplantation (SOFT) score: validation with contemporaneous data and stratification of high-risk cohorts. AB - Models to project survival after liver transplantation are important to optimize outcomes. We introduced the survival outcomes following liver transplantation (SOFT) score in 2008 (1) and designed to predict survival in liver recipients at three months post-transplant with a C statistic of 0.70. Our objective was to validate the SOFT score, with more contemporaneous data from the OPTN database. We also applied the SOFT score to cohorts of the sickest transplant candidates and the poorest-quality allografts. Analysis included 21 949 patients transplanted from August 1, 2006, to October 1, 2010. Kaplan-Meier survival functions were used for time-to-event analysis. Model discrimination was assessed using the area under the receiver operating characteristic (ROC) curve. We validated the SOFT score in this cohort of 21 949 liver recipients. The C statistic was 0.70 (CI 0.68-0.71), identical to the original analysis. When applied to cohorts of high-risk recipients and poor-quality donor allografts, the SOFT score projected survival with a C statistic between 0.65 and 0.74. In this study, a validated SOFT score was informative among cohorts of the sickest transplant candidates and the poorest-quality allografts. PMID- 23808892 TI - Caffeine attenuates liver fibrosis via defective adhesion of hepatic stellate cells in cirrhotic model. AB - BACKGROUND AND AIM: Several epidemiological studies have shown that coffee intake attenuates the progression of liver fibrosis; however, the mechanism is unclear. AIMS: We investigated the direct effects of caffeine on hepatic stellate cells (HSCs) and assessed whether caffeine attenuated intrahepatic fibrosis in rat model of liver cirrhosis. METHODS: Human hepatic stellate cell line, an immortalized human HSCs line, was used in in vitro assay system. Cell migration and proliferation were assessed in presence of various caffeine concentrations (0, 1, 5, and 10 mmol), and levels of procollagen type Ic and alpha-smooth muscle actin (alpha-SMA) were measured by Western blot. Severity of liver inflammation and fibrosis were compared between thioacetamide-treated rats with and without caffeine supplementation. RESULTS: Caffeine increased HSCs apoptosis and intracellular F-actin and cyclic adenosine monophosphate expression. Caffeine also inhibited procollagen type Ic and alpha-SMA expression in a dose- and time dependent manner. In rat model, caffeine decreased periportal inflammation, levels of inflammatory cells (1.4 +/- 0.52 vs 2.6 +/- 0.46, P < 0.05), and fibrosis (2.1 +/- 0.35 vs 2.9 +/- 0.84, P < 0.05). Transforming growth factor beta and alpha-SMA expressions were also reduced by caffeine. CONCLUSION: Caffeine attenuates the progression of liver fibrosis by inhibiting HSCs adhesion and activation. PMID- 23808893 TI - Assessment of mitral annular and velocity vector imaging in acute myopericarditis. AB - A 25-year-old student presenting with pleuritic chest pain, elevated troponin levels and subtle electrocardiogram abnormalities was treated for presumptive myopericarditis. On echocardiography, a lower than expected mitral annular displacement and systolic velocity were identified along with abnormalities in left ventricular strain generation that matched areas of edema and necrosis by cardiac magnetic resonance imaging. The patient was treated with nonsteroidal antiinflammatory drugs and colchicine, and both the symptoms and echocardiographic abnormalities rapidly resolved. These novel findings suggest that changes in mitral annular displacement and systolic velocity occur in acute myopericarditis and may be useful in following the course of the disease. PMID- 23808894 TI - Climate change influences on marine infectious diseases: implications for management and society. AB - Infectious diseases are common in marine environments, but the effects of a changing climate on marine pathogens are not well understood. Here we review current knowledge about how the climate drives host-pathogen interactions and infectious disease outbreaks. Climate-related impacts on marine diseases are being documented in corals, shellfish, finfish, and humans; these impacts are less clearly linked for other organisms. Oceans and people are inextricably linked, and marine diseases can both directly and indirectly affect human health, livelihoods, and well-being. We recommend an adaptive management approach to better increase the resilience of ocean systems vulnerable to marine diseases in a changing climate. Land-based management methods of quarantining, culling, and vaccinating are not successful in the ocean; therefore, forecasting conditions that lead to outbreaks and designing tools/approaches to influence these conditions may be the best way to manage marine disease. PMID- 23808895 TI - Rehabilitation of pure alexia: a review. AB - Acquired reading problems caused by brain injury (alexia) are common, either as a part of an aphasic syndrome, or as an isolated symptom. In pure alexia, reading is impaired while other language functions, including writing, are spared. Being in many ways a simple syndrome, one would think that pure alexia was an easy target for rehabilitation efforts. We review the literature on rehabilitation of pure alexia from 1990 to the present, and find that patients differ widely on several dimensions, such as alexia severity and associated deficits. Many patients reported to have pure alexia in the reviewed studies, have associated deficits such as agraphia or aphasia and thus do not strictly conform to the diagnosis. Few studies report clear and generalisable effects of training, none report control data, and in many cases the reported findings are not supported by statistics. We can, however, tentatively conclude that Multiple Oral Re-reading techniques may have some effect in mild pure alexia where diminished reading speed is the main problem, while Tacile-Kinesthetic training may improve letter identification in more severe cases of alexia. There is, however, still a great need for well-designed and controlled studies of rehabilitation of pure alexia. PMID- 23808896 TI - Economic evaluation of an integrated care programme for patients with hand dermatitis. AB - BACKGROUND: Hand dermatitis has a large impact on society as a whole. OBJECTIVES: To evaluate the cost-effectiveness of integrated, multidisciplinary care as compared with usual care (UC) for patients with moderate to severe chronic hand dermatitis after 52 weeks. METHODS: Patients (n = 196) visiting the dermatology department at one of the participating hospitals for hand dermatitis were randomized to integrated care (IC) or UC. IC was provided by a multidisciplinary team, and integrated clinical and occupational care to optimize treatment of hand dermatitis. Effect outcomes were clinical assessment of hand dermatitis with the Hand Eczema Severity Index (HECSI), and disease-specific quality of life, work performance and quality-adjusted life-years with the EQ-5D. Incremental cost effectiveness ratios (ICERs) were calculated. The ICER indicates the additional investment needed to gain one unit of effect. RESULTS: The HECSI difference between both groups after 52 weeks was 8.7 (standard error 5.3, 95% confidence interval -1.8-18.9). No differences were found on secondary outcome measures. Mean total costs with IC (? 3613; SD 798) were significantly higher than with UC (? 1576, SD 430). The ICER for improvement in HECSI score was -247. IC was not considered to be cost-effective as compared with UC. The probability that IC was cost-effective was 90% at a ceiling ratio of ? 1500 per additional point improvement in HECSI score. CONCLUSION: Integrated care was neither cost effective, nor effective after 12 months follow-up, in contrast to our findings after 6 months. Decision makers should decide whether the clinical benefits of integrated care on the short term outweigh the higher costs compared to usual care. PMID- 23808897 TI - Timing of energy intake during the day is associated with the risk of obesity in adults. AB - BACKGROUND: The timing of energy intake is a modifiable behaviour that may influence energy regulation and the risk of obesity. We examined the associations of energy intake in the morning, midday and evening with body mass index (BMI) (n = 239). METHODS: Cross-sectional analyses were performed using data from the University of California, Los Angeles Energetics Study. Energy intake was assessed using three 24-h dietary recalls and stratified by time-of-day: morning (00.00 h to 11.00 h), midday (11.00 h to 17.00 h) and evening (17.00 h to 00.00 h). Sensitivity analysis was conducted among 'true-reporters', whose self reported energy intake was +/-25% of total energy expenditure measured by doubly labelled water (n = 99). Logistic regression models were performed adjusting for age, sex, race, education, total daily energy intake and physical activity. RESULTS: Energy intake in the morning was not associated with BMI. Participants who consumed >=33% (versus <33%) of their daily energy intake at 12.00 h were (nonsignificantly) less likely to be overweight/obese [odds ratio (OR) = 0.68; 95% confidence interval (CI) = 0.37-1.24] and this association was stronger and statistically significant among true-reporters (OR = 0.34; 95% CI = 0.12-0.95). Those who consumed >=33% of daily energy intake in the evening were two-fold more likely overweight/obese (OR = 2.00; 95% CI = 1.03-3.89), although this association was not significant among true-reporters (OR = 2.10; 95% CI = 0.60 7.29). CONCLUSIONS: These data indicate that eating more of the day's total energy intake at midday is associated with a lower risk of being overweight/obese, whereas consuming more in the evening is associated with a higher risk. Randomised trials are needed to test whether shifting energy intake earlier in the day could have a regulatory effect with respect to reducing intake in the evening, thereby promoting weight loss and maintenance. PMID- 23808898 TI - Epitope scanning indicates structural differences in brain-derived monomeric and aggregated mutant prion proteins related to genetic prion diseases. AB - Genetic Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia and prion protein cerebral amyloid angiopathy are clinically and neuropathologically distinct neurodegenerative diseases linked to mutations in the PRNP gene encoding the cellular prion protein (PrPC). How sequence variants of PRNP encode the information to specify these disease phenotypes is not known. It is suggested that each mutation produces a misfolded variant of PrPC with specific neurotoxic properties. However, structural studies of recombinant PrP did not detect major differences between wild-type and mutant molecules, pointing to the importance of investigating mutant PrPs from mammalian brains. We used surface plasmon resonance and a slot-blot immunoassay to analyse the antibody-binding profiles of soluble and insoluble PrP molecules extracted from the brains of transgenic mice modelling different prion diseases. By measuring the reactivity of monoclonal antibodies against different PrP epitopes, we obtained evidence of conformational differences between wild-type and mutant PrPs, and among different mutants. We detected structural heterogeneity in both monomeric and aggregated PrP, supporting the hypothesis that the phenotype of genetic prion diseases is encoded by mutant PrP conformation and assembly state. PMID- 23808899 TI - APOE e4 genotype and cigarette smoking in adults with normal cognition and mild cognitive impairment: a retrospective baseline analysis of a national dataset. AB - BACKGROUND: APOE e4 genotype is known to be a risk factor for Alzheimer's disease and atherosclerosis. Recently, published evidence has shown that APOE e4 genotype may also be associated with the cessation of cigarette smoking. OBJECTIVES: The aim of this retrospective analysis was to explore whether any past smoking outcomes differed based on APOE e4 genotype in a large national dataset. METHODS: Data were extracted from the National Alzheimer's Coordinating Center's longitudinal Uniform Data Set study. We limited this retrospective baseline analysis to the normal cognition (n = 2995) and mild cognitive impairment (n = 1627) groups that had APOE genotype and smoking data. Because this was an exploratory retrospective analysis, we conducted descriptive analyses on all variables based on APOE e4 genotype. We controlled for demographic, clinical, medication and neurocognitive data in the analyses. RESULTS: In both the normal cognition group and the mild cognitive impairment group, e4 carriers and e4 non carriers did not significantly differ on total years smoked, age when last smoked and the average # of packs/day smoked during the years they smoked. In both groups, e4 carriers and e4 non-carriers differed on various neurocognitive measures. CONCLUSION: These data do not support the recently published evidence of the association between APOE e4 genotype and smoking outcomes. SCIENTIFIC SIGNIFICANCE: Larger prospective clinical trials are needed to further explore the relationship between APOE genotype and smoking outcomes. PMID- 23808900 TI - Economic and clinical comparison of atypical depot antipsychotic drugs for treatment of chronic schizophrenia in the Czech Republic. AB - PURPOSE: The Czech Republic is faced with making choices between pharmaceutical products, including depot injectable antipsychotics. A pharmacoeconomic analysis was conducted to determine the cost-effectiveness of atypical depots. METHODS: An existing 1-year decision-analytic framework was adapted to model drug use in this healthcare system. The average direct costs to the General Insurance Company of the Czech Republic of using paliperidone palmitate (Xeplion(r)), risperidone (Risperdal Consta(r)), and olanzapine pamoate (Zypadhera(r)) were determined. Literature-derived clinical rates populated the model, with costs adjusted to 2012 Euros using the consumer price index. Outcomes included quality-adjusted life-years (QALYs), days in remission, and proportions hospitalized or visiting emergency rooms. One-way sensitivity analyses were calculated for all important inputs. A multivariate probability analysis was used to examine the stability of results using 10,000 iterations of simulated input over reasonable ranges of all included variables. RESULTS: Expected average costs/per patient treated were ?5377 for PP-LAI, ?6118 for RIS-LAI, and ?6537 for OLZ-LAI. Respective QALYs were 0.817, 0.809, and 0.811; ER visits were 0.127, 0.134, and 0.141; hospitalizations were 0.252, 0.298, and 0.289. Results were generally robust in sensitivity analyses. PP-LAI dominated RIS-LAI and OLZ-LAI in 90.2% and 92.1% of simulations, respectively. Results were insensitive to drug prices but sensitive to adherence and hospitalization rates. CONCLUSIONS: PP-LAI dominated the other two drugs, as it had a lower overall cost and superior clinical outcomes, making it the preferred choice. Using PP-LAI in place of RIS-LAI for chronic relapsing schizophrenia would reduce the overall costs of care for the healthcare system. PMID- 23808901 TI - Annual acquisition and administration cost of biologic response modifiers per patient with rheumatoid arthritis, psoriasis, psoriatic arthritis, or ankylosing spondylitis. AB - OBJECTIVE: To estimate annual biologic response modifier (BRM) cost per treated patient with rheumatoid arthritis, psoriasis, psoriatic arthritis, and/or ankylosing spondylitis receiving etanercept, abatacept, adalimumab, certolizumab, golimumab, infliximab, rituximab, or ustekinumab. METHODS: This was a cohort study of 69,349 commercially insured individuals in a nationwide claims database with one of these conditions that had a claim for one of these BRMs between January 2008 and December 2010 (the index BRM/index date). Cost per treated patient was calculated as the total BRM acquisition and administration cost to the payer in the first year after the index date (including costs of other BRMs after switching) divided by the number of patients who received the index BRM. Etanercept was selected as the reference for comparisons. RESULTS: Etanercept was the most commonly used index BRM (n = 32,298; 47%), followed by adalimumab (n = 20,582; 30%), infliximab (n = 11,157; 16%), abatacept (n = 2633; 4%), rituximab (n = 1359; 2%), golimumab (n = 687; <1%), ustekinumab (n = 388; <1%), and certolizumab (n = 245; <1%). Using etanercept as the reference, the cost per treated patient in the first year across all four conditions was 102% for adalimumab and 108% for infliximab. Newer BRMs had costs relative to etanercept that were 90% to 102% for rheumatoid arthritis, 132% for psoriasis, 100% for psoriatic arthritis, and 94% for ankylosing spondylitis. LIMITATIONS: Potential study limitations were the lack of clinical information (e.g., disease severity, treatment outcomes) or indirect costs, the inability to compare costs of newer BRMs across all four conditions, and much smaller sample sizes for newer BRMs. CONCLUSIONS: Of the BRMs that are approved for indications within all four conditions studied, etanercept had the lowest cost per treated patient when assessed across all four conditions. PMID- 23808902 TI - Cost-effectiveness of 3-year vs 1-year adjuvant therapy with imatinib in patients with high risk of gastrointestinal stromal tumour recurrence in the Netherlands; a modelling study alongside the SSGXVIII/AIO trial. AB - BACKGROUND: Surgical resection of gastrointestinal stromal tumour (GIST) is rarely curative in patients at high risk of tumour recurrence and therefore 1 year of post-surgery adjuvant imatinib therapy has been recommended in this sub group. Recently, adjuvant imatinib therapy administered for 3 years has been demonstrated to further increase recurrence-free survival and overall survival. The goal of this study was to assess the economic value of extending the duration of adjuvant imatinib therapy in high-risk patients in the Netherlands. METHODS: A multistate Markov model was developed to simulate how patients' clinical status after GIST excision evolves over time until death. The model structure encompassed four primary health states: free of recurrence, first GIST recurrence, second GIST recurrence, and death. Transition probabilities between the health states, data on medical care costs, and quality-of-life were obtained from published sources and from expert opinion. RESULTS: The expected number of life years (or quality-adjusted life years, QALYs) was higher in the 3-year group than in the 1-year group, 8.91 (6.55) and 7.04 (5.18) years, respectively. In the 3-year and 1-year group, the expected total costs amounted to ?120,195 and ?79,361, of which, ?74,631 (62%) and ?27,619 (35%) were adjuvant therapy drug costs, respectively. The difference in health benefits, that is 1.87 life years or 1.37 QALYs, and costs, ?40,835, resulted in incremental cost-effectiveness ratios (ICER) of ?21,865 per life year gained, and ?29,872 per QALY gained. LIMITATIONS: A limitation of the study was inherently related to the uncertainty around the predictions of RFS. Scenario analyses were conducted to test the sensitivity of different RFS predictions on the results. CONCLUSIONS: Delayed recurrence due to treatment with longer-term adjuvant imatinib therapy represents a cost-effective treatment option with an ICER below the generally accepted threshold in the Netherlands. PMID- 23808903 TI - Effective estimation of correct platelet counts in pseudothrombocytopenia using an alternative anticoagulant based on magnesium salt. AB - Pseudothrombocytopenia remains a challenge in the haematological laboratory. The pre-analytical problem that platelets tend to easily aggregate in vitro, giving rise to lower platelet counts, has been known since ethylenediamine-tetra acetic acid EDTA and automated platelet counting procedures were introduced in the haematological laboratory. Different approaches to avoid the time and temperature dependent in vitro aggregation of platelets in the presence of EDTA were tested, but none of them proved optimal for routine purposes. Patients with unexpectedly low platelet counts or flagged for suspected aggregates, were selected and smears were examined for platelet aggregates. In these cases patients were asked to consent to the drawing of an additional sample of blood anti-coagulated with a magnesium additive. Magnesium was used in the beginning of the last century as anticoagulant for microscopic platelet counts. Using this approach, we documented 44 patients with pseudothrombocytopenia. In all cases, platelet counts were markedly higher in samples anti-coagulated with the magnesium containing anticoagulant when compared to EDTA-anticoagulated blood samples. We conclude that in patients with known or suspected pseudothrombocytopenia the magnesium anticoagulant blood samples may be recommended for platelet counting. PMID- 23808904 TI - Letrozole stimulation in endometrial preparation for cryopreserved-thawed embryo transfer in women with polycystic ovarian syndrome: a pilot study. AB - OBJECTIVE: To study the efficiency of letrozole, an aromatase inhibitor, in endometrial preparation for cryopreserved-thawed embryo transfer (FET) in women with polycystic ovarian syndrome (PCOS). DESIGN: Retrospective observational study. PATIENTS: One hundred and twenty patients with PCOS who met the inclusion criteria for the study. MEASUREMENTS: We assessed in vitro fertilization outcomes in one hundred and twenty patients with PCOS (148 cycles) who were prepared for and underwent FET between June 2011 and December 2012. Patients were prepared for FET using artificial hormone cycles induced with oestrogen and progesterone supplementation (n = 76), letrozole stimulation (n = 40) or hMG stimulation (n = 32). RESULTS: There were no differences in demographic characteristics between the groups, except that the letrozole group had a higher incidence of embryo transfer failure in the past. The letrozole stimulation group had a significantly higher maximal endometrial thickness and significantly higher rates of clinical pregnancy per transfer, ongoing pregnancy per transfer and implantation, compared with the artificial and hMG stimulation groups. Differences in these parameters between the artificial and hMG stimulation groups were not significant. CONCLUSION: Using letrozole stimulation in endometrial preparation for cryopreserved-thawed embryo transfer in patients with PCOS may be associated with better outcomes than using hormonal manipulation or hMG stimulation. PMID- 23808905 TI - Uncompressed high-definition videoconferencing tools for telemedicine and distance learning. AB - Uncompressed high-definition (HD) video image quality is superior to compressed HD video provided in most commercially available videoconferencing products. Uncompressed HD videoconferencing tools provide a more immersive experience because there is no reduction of image information and, in most cases, lower latency. Four open source uncompressed video applications are reviewed that have been tested at the National Library of Medicine: three transmitting uncompressed HD video and one transmitting loosely compressed standard-definition video. The technical requirements for implementing each are described, and test results in terms of image quality, latency, and application reliability are presented. Because the hardware and bandwidth requirements for uncompressed HD video are relatively high and most applications are still under development, they are generally not ready for mass deployment. Some are, however, ready for pilot testing and experimentation in clinical settings by either those who have or anticipate having bandwidth sufficient to support them or those interested in researching the effects higher-quality video may have on diagnostic and other clinical outcomes. PMID- 23808906 TI - Design of a dynamic polymer interface for chiral discrimination. AB - Enantioselective wetting of a chiral polymer film was demonstrated. The contact angle of chiral liquids on the film was strongly dependent on their chirality although their physical properties including surface tension were identical. Such wetting behavior resulted from the enantioselective surface reorganization involving local conformational change of the polymer chains at the liquid interface. The concept of "dynamic interface for chiral discrimination" has possible potential for the development of materials capable of chiral sensing, optical resolution, and asymmetric synthesis. PMID- 23808907 TI - Morphological changes in skin of different phototypes under the action of topical corticosteroid therapy and tacrolimus. AB - BACKGROUND/PURPOSE: The present study aimed to investigate the influence of topical corticosteroid therapy and tacrolimus on morphological indices of different skin phototypes and to optimize topical therapy using the OCT technique. METHODS: Twenty healthy volunteers aging from 20 to 30 (14 men and 6 women) took part in the study: 10 persons with skin phototype I, II and 10 persons with skin phototype V, VI. Morphological state of the skin was assessed before and during application of topical steroids of different strength and calciumneurin inhibitors for 49 days. Morphological state was studied in vivo using the optical coherence tomograph. RESULTS: Morphological manifestations of skin atrophy with the use of clobetasol propionate appear earlier than with the use of hydrocortisone 17-butyrate; this process was faster in representatives of groups V, VI. Epidermal thinning in the zone of tacrolimus application was not recorded in any phototype. CONCLUSION: Recording of early preclinical signs of epidermis thinning in the course of OCT follow-up may be an indication for changing the corticosteroid therapy by calciumneurin inhibitors, which will permit to individualize the therapy, to increase its efficacy, and to minimize the possibility of complications in each particular case. PMID- 23808908 TI - Mathematical modelling of implant in an operated hernia for estimation of the repair persistence. AB - This paper presents mathematical modelling of an implanted surgical mesh used in the repair process of the abdominal hernia. The synthetic implant is simulated by a membrane structure. The author provides a material modelling of the implant based on the dense net model appropriate for technical fabrics. The accuracy of the proposed solution is evaluated by comparing the simulations of the dynamic behaviour of the system with the experiments carried out on physical models of implanted mesh. The model can be used to estimate the repair persistence for different mesh materials, fixing systems and different numbers of tacks to be provided during the surgery in order to resist the cough pressure and required action to avoid hernia recurrence. The persistence of the repaired hernia is assessed on the basis of the values of the forces in the tissue-implant joints because the usual form of the repair failure is due to as the joint disconnection or tissue failure. PMID- 23808909 TI - Contact sensitization to calocephalin, a sesquiterpene lactone of the guaianolide type from cushion bush (Leucophyta brownii, Compositae). AB - BACKGROUND: Cushion bush [Leucophyta brownii Cass. = Calocephalus brownii (Cass.) F. Muell.] is an Australian Compositae shrub that has been introduced into Scandinavia as a pot plant. The first case of sensitization occurred in a gardener, and the main allergen was identified as the guaianolide calocephalin. OBJECTIVE: To present the identification of the main allergen, and to assess the prevalence of sensitization to calocephalin in Compositae-allergic patients. MATERIALS AND METHODS: Calocephalin was isolated from a dichloromethane extract of aerial parts of cushion bush. Calocephalin 0.1% ethanol was included in the plant series in Malmo, Sweden, and Odense, Denmark. RESULTS: Nuclear magnetic resonance (NMR) analysis of calocephalin resulted in a revision of its chemical structure to 4alpha-acetoxy-1alpha,2alpha-epoxy-5alpha,10alphaH-guai-11(13)-en 12,8beta-olide. The prevalence of patch test positivity was up to 28% in aimed patch testing. Despite strongly positive patch test reactions, the relevance was unknown in the majority of cases, and only 1 person was occupationally sensitized. CONCLUSION: Calocephalin is a potent contact allergen, but, as cushion bush is a low-maintenance pot plant, primary sensitization is most likely to occur through occupational exposure. Positive reactions in Compositae sensitive persons probably occur because of cross-reactivity, and patients should be warned about contact with cushion bush plants. PMID- 23808910 TI - Fibroscan can avoid liver biopsy in Indian patients with chronic hepatitis B. AB - BACKGROUND AND AIM: Liver fibrosis is an established determinant of prognosis and therapy in chronic hepatitis B (CHB). The role of fibroscan in assessing fibrosis in CHB remains unclear. Present study was designed to correlate fibroscan with liver biopsy and determine whether fibroscan can avoid liver biopsy in patients with CHB. METHODS: Fibroscan and liver biopsy were performed in 382 consecutive patients with CHB. Biopsies were reviewed by pathologist blinded to the fibroscan value. Discriminant values of liver stiffness measurement (LSM) to reasonably exclude and predict significant fibrosis were calculated from receiver operating characteristic (ROC) curves. The factors affecting LSM independent of fibrosis were assessed. RESULTS: Three hundred fifty-seven patients were included (mean age 30.1 +/- 9.7 years, male : female 17 : 3). There was significant correlation between LSM and histological fibrosis (r = 0.58, P < 0.001). The area under ROC curve of LSM for significant fibrosis (F0-1 vs. F2-4), bridging fibrosis (F0-2 vs. F3-4), and cirrhosis (F0-3 vs. F4) was 0.84 (95% CI: 0.78-0.89), 0.94 (95% CI: 0.89-0.99), and 0.93 (95% CI: 0.85-1.00), respectively. LSM < 6.0 KPa could exclude significant (F >= 2) and bridging fibrosis (F >= 3) with a negative predictive value (NPV) of 92.4% and 99.5%, respectively. Cut-off of 9 KPa could detect significant (F >= 2) and bridging fibrosis (F >= 3) with specificity of 95% and 97%, respectively, and had a positive predictive value (PPV) of 84.3% in predicting significant fibrosis. LSM < 6 KPa and > 9 KPa matched with histological fibrosis in 227/250 (91%) patients. Therefore, fibroscan could avoid liver biopsy in 70% (250/357) patients with an accuracy > 90%. Histological fibrosis, ALT > 5 times, and age > 40 years were independent determinants of increased liver stiffness. CONCLUSIONS: Fibroscan accurately assessed fibrosis and could avoid liver biopsy in more than two-thirds of patients with CHB. PMID- 23808911 TI - Similarity searching for potent compounds using feature selection. AB - In similarity searching, compound potency is usually not taken into account. Given a set of active reference compounds, similarity to database molecules is calculated using different metrics without considering compound potency as a search parameter. Herein, we introduce a feature selection method for fingerprint similarity searching to maximize compound recall and preferentially detect potent compounds. On the basis of training examples, fingerprint features are selected that identify potent compounds and produce high recall. Using the reduced fingerprint representations, potent hits are preferentially detected, even if reference compounds have only moderate or low potency. Small sets of simple chemical features are found to yield high search performance. PMID- 23808912 TI - QTc interval prolongation for patients in methadone maintenance treatment: a five years follow-up study. AB - BACKGROUND: QTc prolongation for patients in methadone maintenance treatment (MMT) has been reported. In this study we wanted to identify the predictor factors for QTc prolongation >500 ms and other medical risk factors for mortality in this population. METHODS: A retrospective chart review study with 55 patients who had previously been included in our performance improvement project and who were eligible to be reviewed. A linear regression model with one-sided p value was used for data analysis. RESULTS: Over 5 years, 41% to 56% of patients had QTc > 450 and <500 ms and 4% to 10% of patients had at least one reading of QTc > 500 ms. This QTc prolongation from baseline showed statistical significance (p < 0.0001). Being diagnosed with congestive heart failure (CHF), elevated HgA1c level and recent cocaine use were significantly associated with QTc prolongation >500 ms. The model as a whole showed statistical significance (F = 3.50, p = 0.02). Being diagnosed with CHF and elevated HgA1c level was significantly associated with mortality. The model as a whole also showed statistical significance (F = 4.63, p = 0.01). CONCLUSIONS: This study confirms that methadone may be associated with QTc prolongation. It identified three risk factors for significant QTc prolongation for patients on MMT which are recent cocaine use, uncontrolled blood glucose and CHF. Two of these three risk facts (uncontrolled blood glucose and CHF) were associated with mortality in this cohort. Patients with these medical co-morbidities may benefit from EKG screening and aggressive treatment of the medical risk factors while taking MMT. PMID- 23808913 TI - On the limitations of fixed-step-size adaptive methods with response confidence. AB - The family of (non-parametric, fixed-step-size) adaptive methods, also known as 'up-down' or 'staircase' methods, has been used extensively in psychophysical studies for threshold estimation. Extensions of adaptive methods to non-binary responses have also been proposed. An example is the three-category weighted up down (WUD) method (Kaernbach, 2001) and its four-category extension (Klein, 2001). Such an extension, however, is somewhat restricted, and in this paper we discuss its limitations. To facilitate the discussion, we characterize the extension of WUD by an algorithm that incorporates response confidence into a family of adaptive methods. This algorithm can also be applied to two other adaptive methods, namely Derman's up-down method and the biased-coin design, which are suitable for estimating any threshold quantiles. We then discuss via simulations of the above three methods the limitations of the algorithm. To illustrate, we conduct a small scale of experiment using the extended WUD under different response confidence formats to evaluate the consistency of threshold estimation. PMID- 23808915 TI - Dehumanization and infrahumanization. AB - We review early and recent psychological theories of dehumanization and survey the burgeoning empirical literature, focusing on six fundamental questions. First, we examine how people are dehumanized, exploring the range of ways in which perceptions of lesser humanness have been conceptualized and demonstrated. Second, we review who is dehumanized, examining the social targets that have been shown to be denied humanness and commonalities among them. Third, we investigate who dehumanizes, notably the personality, ideological, and other individual differences that increase the propensity to see others as less than human. Fourth, we explore when people dehumanize, focusing on transient situational and motivational factors that promote dehumanizing perceptions. Fifth, we examine the consequences of dehumanization, emphasizing its implications for prosocial and antisocial behavior and for moral judgment. Finally, we ask what can be done to reduce dehumanization. We conclude with a discussion of limitations of current scholarship and directions for future research. PMID- 23808914 TI - Antimicrobial peptides targeting Gram-negative pathogens, produced and delivered by lactic acid bacteria. AB - We present results of tests with recombinant Lactococcus lactis that produce and secrete heterologous antimicrobial peptides with activity against Gram-negative pathogenic Escherichia coli and Salmonella . In an initial screening, the activities of numerous candidate antimicrobial peptides, made by solid state synthesis, were assessed against several indicator pathogenic E. coli and Salmonella strains. Peptides A3APO and Alyteserin were selected as top performers based on high antimicrobial activity against the pathogens tested and on significantly lower antimicrobial activity against L. lactis . Expression cassettes containing the signal peptide of the protein Usp45 fused to the codon optimized sequence of mature A3APO and Alyteserin were cloned under the control of a nisin-inducible promoter PnisA and transformed into L. lactis IL1403. The resulting recombinant strains were induced to express and secrete both peptides. A3APO- and Alyteserin-containing supernatants from these recombinant L. lactis inhibited the growth of pathogenic E. coli and Salmonella by up to 20-fold, while maintaining the host's viability. This system may serve as a model for the production and delivery of antimicrobial peptides by lactic acid bacteria to target Gram-negative pathogenic bacteria populations. PMID- 23808916 TI - Color psychology: effects of perceiving color on psychological functioning in humans. AB - Color is a ubiquitous perceptual stimulus that is often considered in terms of aesthetics. Here we review theoretical and empirical work that looks beyond color aesthetics to the link between color and psychological functioning in humans. We begin by setting a historical context for research in this area, particularly highlighting methodological issues that hampered earlier empirical work. We proceed to overview theoretical and methodological advances during the past decade and conduct a review of emerging empirical findings. Our empirical review focuses especially on color in achievement and affiliation/attraction contexts, but it also covers work on consumer behavior as well as food and beverage evaluation and consumption. The review clearly shows that color can carry important meaning and can have an important impact on people's affect, cognition, and behavior. The literature remains at a nascent stage of development, however, and we note that considerable work on boundary conditions, moderators, and real world generalizability is needed before strong conceptual statements and recommendations for application are warranted. We provide suggestions for future research and conclude by emphasizing the broad promise of research in this area. PMID- 23808917 TI - Gender similarities and differences. AB - Whether men and women are fundamentally different or similar has been debated for more than a century. This review summarizes major theories designed to explain gender differences: evolutionary theories, cognitive social learning theory, sociocultural theory, and expectancy-value theory. The gender similarities hypothesis raises the possibility of theorizing gender similarities. Statistical methods for the analysis of gender differences and similarities are reviewed, including effect sizes, meta-analysis, taxometric analysis, and equivalence testing. Then, relying mainly on evidence from meta-analyses, gender differences are reviewed in cognitive performance (e.g., math performance), personality and social behaviors (e.g., temperament, emotions, aggression, and leadership), and psychological well-being. The evidence on gender differences in variance is summarized. The final sections explore applications of intersectionality and directions for future research. PMID- 23808918 TI - A logistic challenge - use of electromyographic endotracheal tube in an extremely narrowed airway. PMID- 23808919 TI - Platinum-based oxygen reduction electrocatalysts. AB - An efficient oxygen reduction reaction (ORR) offers the potential for clean energy generation in low-temperature, proton-exchange membrane fuel cells running on hydrogen fuel and air. In the past several years, researchers have developed high-performance electrocatalysts for the ORR to address the obstacles of high cost of the Pt catalyst per kilowatt of output power and of declining catalyst activity over time. Current efforts are focused on new catalyst structures that add a secondary metal to change the d-band center and the surface atomic arrangement of the catalyst, altering the chemisorption of those oxygencontaining species that have the largest impact on the ORR kinetics and improving the catalyst activity and cost effectiveness. This Account reviews recent progress in the design of Pt-based ORR electrocatalysts, including improved understanding of the reaction mechanisms and the development of synthetic methods for producing catalysts with high activity and stability. Researchers have made several types of highly active catalysts, including an extended single crystal surface of Pt and its alloy, bimetallic nanoparticles, and self-supported, low-dimensional nanostructures. We focus on the design and synthetic strategies for ORR catalysts including controlling the shape (or facet) and size of Pt and its bimetallic alloys, and controlling the surface composition and structure of core-shell, monolayer, and hollow porous structures. The strong dependence of ORR performance on facet and size suggests that synthesizing nanocrystals with large, highly reactive {111} facets could be as important, if not more important, to increasing their activity as simply making smaller nanoparticles. A newly developed carbon monoxide (CO)-assisted reduction method produces Pt bimetallic nanoparticles with controlled facets. This CO-based approach works well to control shapes because of the selective CO binding on different, low-indexed metal surfaces. Post-treatment under different gas environments is also important in controlling the elemental distribution, especially the surface composition and the core-shell and bimetallic alloy nanostructures. Besides surface composition and facet, surface strain plays an important role in determining the ORR activity. The surface strain depends on the crystal size, the presence of an interface-lattice mismatch or twinned boundary, and between nanocrystals and extended single crystal surfaces, all of which may be factors in metal alloys. Since the common, effective reaction pathway for the ORR is a four-electron process and the surface binding of oxygen-containing species is typically the limiting step, density functional theory (DFT) calculation is useful for predicting the ORR performance over bimetallic catalysts. Finally, we have noticed there are variations among the published values for activity and durability of ORR catalysts in recent papers. The differences are often due to the data quality and protocols used for carrying out the analysis using a rotating disk electrode (RDE). Thus, we briefly discuss some practices used in such half-cell measurements, such as sample preparation and measurement, data reliability (in both kinetic current density and durability measurement) and iR correction that could lead to more consistency in measured values and in evaluating catalyst performances. PMID- 23808920 TI - Paediatric health-care professionals: relationships between psychological distress, resilience and coping skills. AB - AIM: To investigate the impact of regular exposure to paediatric medical trauma on multidisciplinary teams in a paediatric hospital and the relationships between psychological distress, resilience and coping skills. METHOD: Symptoms of post traumatic stress disorder, secondary traumatic stress, depression, anxiety, stress, burnout, compassion satisfaction, resilience and coping skills were measured in 54 health professionals and compared with published norms. RESULTS: Participants experienced more symptoms of secondary traumatic stress (P < 0.01), showed less resilience (P = 0.05) and compassion satisfaction (>= 0.01), more use of optimism and sharing as coping strategies, and less use of dealing with the problem and non-productive coping strategies than comparative groups. Non productive coping was associated with more secondary traumatic stress (r = 0.50, P = 0.05), burnout (r = 0.45, P = 0.01), post-traumatic stress disorder (r = 0.41, P = 0.05), anxiety (r = 0.42, P = 0.05), depression (r = 0.54, P = 0.01), and stress (r = 0.52, P = 0.01) and resilience was positively associated with optimism (r = 0.48, P = 0.01). Health professionals <25 years old used more non productive coping strategies (P = 0.05), less 'sharing as a coping strategy' (P = 0.05) and tended to have more symptoms of depression (P = 0.06). CONCLUSION: Paediatric medical trauma can adversely affect a health professional's well being, particularly those <25 years of age who make less use of positive coping strategies and more use of non-productive coping. These findings will assist the development of effective and meaningful interventions for health professionals working in paediatric hospitals. PMID- 23808921 TI - MtDNA depletions are also one of major cause of mitochondrial disease. PMID- 23808922 TI - Mitochondrial genome of Protobothrops mangshanensis (Squamata: Viperidae: Crotalinae). AB - Protobothrops mangshanensis is a venomous pit viper species endemic to Hunan province in China. In this study, the complete mitochondrial genome of P. mangshanensis had been determined. The circle genome with the 17,230 bp total length contained 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes and 2 control regions. Overall base composition of the complete mtDNA was 32.27% A, 24.16% T, 30.34% C and 13.23% G. All the genes in P. mangshanensis were distributed on the H-strand, except for the ND6 subunit gene and eight tRNA genes which were encoded on the L-strand. PMID- 23808923 TI - Mitochondrial and pedigree analysis in Przewalski's horse populations: implications for genetic management and reintroductions. AB - BACKGROUND AND AIMS: Przewalski's horses have been imported from the western zoos to China since 1985. Yet the genetic diversity in China's populations has not been studied, thus lacking of such knowledge inevitably affects this population's management. The aim of this study was to assess genetic diversity in Chinese population of Przewalski's horses via mitochondrial DNA (mtDNA) control region and pedigree analysis. MATERIALS AND METHODS: Two captive and one reintroduced populations were examined based on mitochondrial DNA control region variation via fecal sampling from 2010 to 2012, together with pedigree analysis. RESULTS: Amplification success rates of fecal mtDNA were as high as 96.2% (93.8%-100%), and were higher for sample in winter than in summer and autumn. Two haplotypes were identified and shared among three populations, but the proportion of individuals with each haplotype varied among the three populations (F(ST) = 0.10874, p = 0.00978). Haplotype diversity in the released population (0.153) was much lower than that in the two captive populations (0.4011 and 0.4966), in accordance with the direction of increase in probability of identity at the dam lines. CONCLUSION: Future concerns in Przewalski's horse population management should emphasize on strict reproduction control to minimize inbreeding in captivity, followed by long-term genetic diversity guidelines and non-invasive monitoring in the reintroduction programmes. PMID- 23808924 TI - The mitogenome of Leptobotia microphthalma (Teleostei, Cypriniformes: Cobitidae). AB - The Leptobotia microphthalma belongs to family Cobitidae, which is endemic to the upper reaches of the Yangtze River in China. In this studying, the complete mitochondrial genome sequence of L. microphthalma has been obtained with PCR, which contains 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes and a non coding control region with the total length of 16,512 bp. The gene arrangement and composition are similar to that of other vertebrates. Most of the genes are encoded on heavy strand, except for eight tRNA and ND6 genes. The complete mitochondrial genome sequence of L. microphthalma would contribute to better understand population genetics and protect its genetic diversity. PMID- 23808925 TI - The complete mitochondrial genome sequence of Heteromycteris japonicus (Pleuronectiformes: Soleidae). AB - The bamboo sole Heteromycteris japonicus (Pleuronectiformes: Soleidae) is characterized by both eyes on the right side of the body and a rostral hook. In this article, the complete mitochondrial genome sequence of this sole was first determined. The total length is 17,111 bp, including 13 protein-coding genes, 22 tRNA genes and 2 rRNA genes (12 S and 16 S), as well as a putative control region and a putative L-strand replication origin (OL). Gene contents, locations and arrangements are identical to those of typical bony fishes. Overall base composition of the mitogenome is 29.2%, 27.5%, 16.3% and 27.1% for A, C, G and T, with a high A + T content (56.3%). The determination of H. japonicus mitogenome sequence could contribute to understanding the systematic evolution of the genus Heteromycteris and further phylogenetic study on Soleidae and Pleuronectiformes. PMID- 23808926 TI - Reanalysis and revision of the complete mitochondrial genome of Rachycentron canadum (Teleostei, Perciformes, Rachycentridae). AB - The complete mitochondrial genome of cobia, Rachycentron canadum, was reanalyzed and revised. The genome is 18,008 bp in length, containing 13 protein-coding genes, 2 ribosomal RNA (rRNA) genes, 22 transfer RNA (tRNA) genes, and a control region or displacement loop (D-loop). The gene arrangement is identical to that observed in most vertebrates. Base composition on the heavy strand is 30.14% A, 25.22% C, 15.80% G and 28.84% T. The D-loop region exhibits an A + T rich pattern, containing short tandem repeats of TATATACATGG, TATATGCACAA and TATATGCACGG. The mitochondrial genome studied differs from the previously published genome in two segments; the control region to 12S and ND5 to tRNA(Glu). The 12S sequence also differs from those published in the databases. Phylogeny analyses revealed that the differences could be due to errors in sequence assembly and/or sample misidentification of the previous studies. PMID- 23808927 TI - Migraine management in community pharmacies: practice patterns and knowledge of pharmacy personnel in Thailand. AB - OBJECTIVES: To describe practice behavior and understanding among pharmacy personnel, both pharmacists and non-pharmacist staff, in the management of mild and moderate migraines. BACKGROUND: Migraine is recognized as a prevalent and chronic neurological disorder. In developing countries, such as Thailand, community pharmacies are a widely used source of health care for various illnesses including migraine. However, the quality of migraine management and knowledge among pharmacy personnel is unclear. METHODS: Cross-sectional study. The sample comprised 142 randomly selected community pharmacies in a city in the south of Thailand. Simulated clients visited the pharmacies twice, at least 1 month apart, to ask for the treatment of mild and moderate migraines. After the encounters, question asking, drug dispensing, and advice giving by pharmacy staff were recorded. Subsequently, the providers in 135 pharmacies participated in the interview to evaluate their knowledge in migraine management. RESULTS: The majority of pharmacy personnel were less likely to ask questions in cases of mild migraine when compared with moderate attack (mean score [full score = 12] 1.8 +/- 1.6 vs 2.6 +/- 1.5, respectively, P < 0.001). Mean difference of question asking between mild and moderate migraines was -0.8 (95% confidence interval -1.1 to 0.5, P < 0.001). Approximately 33% and 54% of the providers appropriately dispensed non-steroidal anti-inflammatory drugs for mild attack and ergotamine for moderate migraine, respectively, P < 0.001. Prophylactic medications (eg, atenolol, propranolol, flunarizine) were inappropriately recommended, particularly in moderate attack (28.2% vs 17.6% in mild migraine, P = 0.018). Less than 30% of providers advised the patients on the maximum limit of dose or discontinuity of medications when recovered. Compared with non-pharmacists, pharmacists tended to ask more questions, give more advice, and dispense less appropriately; however, there were no significant differences. The results from the interview showed that most pharmacy personnel had inadequate knowledge on migraine management. Pharmacists had better knowledge on question asking (mild migraine 5.1 +/- 2.1 vs 3.1 +/- 1.3, respectively, P < .001; moderate disorder 6.5 +/- 3.1 vs 3.9 +/- 2.1, respectively, P < .001) and tended to have more knowledge on advice giving but poorer drug dispensing in moderate migraine according to the guidelines, relative to non-pharmacists (20.5% vs 40.3%, P = .014). CONCLUSIONS: A large number of community pharmacists and non-pharmacist staff had inappropriate practice behavior and understanding. Continuing education and interventions are important to improve the practice and knowledge of pharmacy personnel, particularly the pharmacists. PMID- 23808928 TI - Emission rate, vibronic entanglement, and coherence in aggregates of conjugated polymers. AB - Here we have studied a dimer model of conjugated polymer aggregates based on the traditional J and H structures, with the extension in treating the electronic and vibrational degrees of freedom at par. We have considered various exchange symmetries corresponding to the parameters of the excited state Hamiltonian in assigning the symmetry of the vibronic states of the aggregate, going beyond the homodimer case. The emission rates are determined as a function of system parameters at low temperature for both types of aggregates. We have also determined the vibronic entanglement as a measure of the coupled electronic and vibrational motion as well as the exciton coherence number in the emitting state. As a function of interchain interaction strength, emission rate and entanglement grossly follow similar trends for the J-aggregate and opposite trends for the H aggregate in totally symmetric as well as asymmetric cases. Variation of other system parameters, like electronic excitation energy and electron-vibration coupling parameter are also thoroughly investigated in governing these quantities. The role of symmetry of the wave function in governing the spectra and the exciton coherence are also analyzed thoroughly, which offers a way to realize the connection between such macroscopic and microscopic quantum features. PMID- 23808930 TI - The windsock syndrome: subpulmonic obstruction by membranous ventricular septal aneurysm in congenitally corrected transposition of great arteries. AB - Anomalies of the membranous portion of the interventricular septum include perimembranous ventricular septal defect and/or membranous septal aneurysm (MSA). In congenitally corrected transposition of the great arteries (L-TGA in sinus solitus), the combination of ventricular inversion and arterial transposition creates a unique anatomic substrate that fosters subpulmonic left ventricular outflow tract obstruction by an MSA. The combination of an L-TGA with subpulmonic obstruction by an MSA is referred to as the windsock syndrome. We report a case of windsock syndrome in a 25-year-old man which is to our knowledge the first three-dimensional echocardiographic description of this congenital entity. PMID- 23808931 TI - Visual cortex processing in autism spectrum disorders (Commentary on Frey et al.). PMID- 23808929 TI - Genetic basis of neuronal individuality in the mammalian brain. AB - The mammalian brain is a complex multicellular system involving enormous numbers of neurons. The neuron is the basic functional unit of the brain, and neurons are organized by specialized intercellular connections into circuits with many other neurons. Physiological studies have revealed that individual neurons have remarkably selective response properties, and this individuality is a fundamental requirement for building complex and functionally diverse neural networks. Recent molecular biological studies have revealed genetic bases for neuronal individuality in the mammalian brain. For example, in the rodent olfactory epithelium, individual olfactory neurons express only one type of odorant receptor (OR) out of the over 1000 ORs encoded in the genome. The expressed OR determines the neuron's selective chemosensory response and specifies its axonal targeting to a particular olfactory glomerulus in the olfactory bulb. Neuronal diversity can also be generated in individual cells by the independent and stochastic expression of autosomal alleles, which leads to functional heterozygosity among neurons. Among the many genes that show autosomal stochastic monoallelic expression, approximately 50 members of the clustered protocadherins (Pcdhs) are stochastically expressed in individual neurons in distinct combinations. The clustered Pcdhs belong to a large subfamily of the cadherin superfamily of homophilic cell-adhesion proteins. Loss-of-function analyses show that the clustered Pcdhs have critical functions in the accuracy of axonal projections, synaptic formation, dendritic arborization, and neuronal survival. In addition, cis-tetramers, composed of heteromultimeric clustered Pcdh members, represent selective binding units for cell-cell interactions, and provide exponential numbers of possible cell-surface relationships between individual neurons. The extensive molecular diversity of neuronal cell-surface proteins affects neurons' individual properties and connectivities. The molecular features of the diverse clustered Pcdh molecules suggest that they provide a genetic basis for neuronal individuality and appropriate neuronal wiring in the brain. PMID- 23808932 TI - The fractal aggregation of asphaltenes. AB - This paper discusses time-resolved small-angle neutron scattering results that were used to investigate asphaltene structure and stability with and without a precipitant added in both crude oil and model oil. A novel approach was used to isolate the scattering from asphaltenes that are insoluble and in the process of aggregating from those that are soluble. It was found that both soluble and insoluble asphaltenes form fractal clusters in crude oil and the fractal dimension of the insoluble asphaltene clusters is higher than that of the soluble clusters. Adding heptane also increases the size of soluble asphaltene clusters without modifying the fractal dimension. Understanding the process of insoluble asphaltenes forming fractals with higher fractal dimensions will potentially reveal the microscopic asphaltene destabilization mechanism (i.e., how a precipitant modifies asphaltene-asphaltene interactions). It was concluded that because of the polydisperse nature of asphaltenes, no well-defined asphaltene phase stability envelope exists and small amounts of asphaltenes precipitated even at dilute precipitant concentrations. Asphaltenes that are stable in a crude oil-precipitant mixture are dispersed on the nanometer length scale. An asphaltene precipitation mechanism is proposed that is consistent with the experimental findings. Additionally, it was found that the heptane-insoluble asphaltene fraction is the dominant source of small-angle scattering in crude oil and the previously unobtainable asphaltene solubility at low heptane concentrations was measured. PMID- 23808933 TI - DockoMatic 2.0: high throughput inverse virtual screening and homology modeling. AB - DockoMatic is a free and open source application that unifies a suite of software programs within a user-friendly graphical user interface (GUI) to facilitate molecular docking experiments. Here we describe the release of DockoMatic 2.0; significant software advances include the ability to (1) conduct high throughput inverse virtual screening (IVS); (2) construct 3D homology models; and (3) customize the user interface. Users can now efficiently setup, start, and manage IVS experiments through the DockoMatic GUI by specifying receptor(s), ligand(s), grid parameter file(s), and docking engine (either AutoDock or AutoDock Vina). DockoMatic automatically generates the needed experiment input files and output directories and allows the user to manage and monitor job progress. Upon job completion, a summary of results is generated by Dockomatic to facilitate interpretation by the user. DockoMatic functionality has also been expanded to facilitate the construction of 3D protein homology models using the Timely Integrated Modeler (TIM) wizard. The wizard TIM provides an interface that accesses the basic local alignment search tool (BLAST) and MODELER programs and guides the user through the necessary steps to easily and efficiently create 3D homology models for biomacromolecular structures. The DockoMatic GUI can be customized by the user, and the software design makes it relatively easy to integrate additional docking engines, scoring functions, or third party programs. DockoMatic is a free comprehensive molecular docking software program for all levels of scientists in both research and education. PMID- 23808934 TI - Carriers of filaggrin gene (FLG) mutations avoid professional exposure to irritants in adulthood. AB - BACKGROUND: Loss-of-function mutations in the filaggrin gene (FLG) are associated with xerosis, atopic dermatitis, and early onset of hand eczema. Irritant exposure is a risk factor for occupational hand eczema, and FLG mutations increase the risk of occupational irritant contact dermatitis on the hands in hospital cohorts. It is unknown whether FLG mutations affect the level of irritant exposure. OBJECTIVES: To evaluate whether exposure to occupational irritants was dependent on FLG mutations, atopic dermatitis, and age at hand eczema onset. METHODS: Randomly chosen Danish adults completed a questionnaire on general health and occupational exposures. Genotyping for FLG mutations (R501X, 2282del4, and R2447X) and patch testing were performed. RESULTS: Overall, 38.7% of subjects reported present or previous occupational exposure to irritants. Among individuals who reported hand eczema onset before entering their work life, 50.6% (45/89) of FLG non-mutation carriers became exposed to irritants, as compared with 28.6% (4/14) of heterozygous and 0% (0/6) of homozygous mutation carriers (p = 0.006). Avoidance was conspicuous among mutation carriers reporting childhood hand eczema and atopic dermatitis (odds ratio 0.08, 95% confidence interval 0.01-0.65). CONCLUSIONS: Carriers of FLG mutations who have had hand eczema onset in childhood avoid occupational exposure to irritants; the association is most marked with homozygous mutation status combined with atopic dermatitis. PMID- 23808935 TI - Solar hydrogen generation by nanoscale p-n junction of p-type molybdenum disulfide/n-type nitrogen-doped reduced graphene oxide. AB - Molybdenum disulfide (MoS2) is a promising candidate for solar hydrogen generation but it alone has negligible photocatalytic activity. In this work, 5 20 nm sized p-type MoS2 nanoplatelets are deposited on the n-type nitrogen-doped reduced graphene oxide (n-rGO) nanosheets to form multiple nanoscale p-n junctions in each rGO nanosheet. The p-MoS2/n-rGO heterostructure shows significant photocatalytic activity toward the hydrogen evolution reaction (HER) in the wavelength range from the ultraviolet light through the near-infrared light. The photoelectrochemical measurement shows that the p-MoS2/n-rGO junction greatly enhances the charge generation and suppresses the charge recombination, which is responsible for enhancement of solar hydrogen generation. The p-MoS2/n rGO is an earth-abundant and environmentally benign photocatalyst for solar hydrogen generation. PMID- 23808936 TI - Quantification of changes in septal strain after alcohol septal ablation in hypertrophic obstructive cardiomyopathy-cases from the three-dimensional speckle tracking echocardiographic MAGYAR-path study. AB - Patients with hypertrophic obstructive cardiomyopathy undergoing alcohol septal ablation are presented. Three-dimensional speckle tracking echocardiography (3DSTE) is a new, noninvasive tool for quantification of myocardial deformation. In both cases, 3DSTE was performed 1 day before and 3 days after alcohol septal ablation to quantify changes in septal strain of ablated area. Results could suggest the possible role of 3DSTE in the quantitative evaluation of the success of alcohol septal ablation. PMID- 23808937 TI - Effects of switching acute treatment on disability in migraine patients using triptans. AB - OBJECTIVE: To assess the influence of switching acute treatment on headache related disability in a population sample of individuals with migraine using acute triptan therapy. BACKGROUND: Acute treatments for migraine are often modified in clinical practice. The effect of changes in treatment from one triptan to another or from a triptan to another medication class has rarely been studied. METHODS: Patterns of acute treatment for migraine were monitored from 1 year to the next in the American Migraine Prevalence and Prevention (AMPP) Study for the following couplets (2005-2006, 2006-2007, 2007-2008, and 2008-2009). Changes in medication regimens were classified as follows: (1) switch within the triptan class; (2) switch to combination analgesics containing opioids or barbiturates; (3) switch to non-steroidal anti-inflammatory drug (NSAID) agents; (4) maintaining current therapy (consistent use, "control"). We assessed change in migraine disability assessment scale score from the first to the second year of a couplet contrasting those with consistent use with those who changed acute treatment. Each individual contributed only 1 couplet to the analysis. Persons who added an acute treatment are considered in a separate manuscript. We modeled change in migraine disability assessment scale score as a function of change in medication regimen with consistent users as the control group. RESULTS: We identified 81 individuals who switched to another triptan, with a referent of 619 who remained consistent, 31 cases who switched to an opioid or barbiturate with a referent of 666 who remained consistent, and 20 cases who switched to an NSAID with a referent of 667 cases who remained consistent. In cell-mean coded analyses of covariance (ANCOVA), switching from one triptan to another or switching from a triptan to an opioid/barbiturate was never associated with significant improvements in headache-related disability compared with consistent treatment. Switching from a triptan to an NSAID was associated with significant increases in headache-related disability among those with high-frequency episodic/chronic migraine (HFEM/CM) compared with those with low-frequency episodic migraine (LFEM) (interaction = 34.81, 95% confidence interval 10.61 to 59.00). The same was true comparing high-frequency episodic/chronic migraine with those with moderate-frequency episodic migraine (interaction = 48.73, 95% confidence interval 2.63 to 94.83). CONCLUSIONS: In this observational study, switching triptan regimens does not appear to be associated with improvements in headache related disability and in some cases is associated with increased headache related disability. PMID- 23808938 TI - Aberrant cytokeratin expression as a possible prognostic predictor in poorly differentiated colorectal carcinoma. AB - BACKGROUND AND AIM: The cytokeratin (CK)7(-) /CK20(+) immunoprofile is characteristic of colorectal carcinoma (CRC), although CK7(+) or CK20(-) phenotypes are occasionally encountered, particularly in histologically variant CRCs. We analyzed CK7/CK20 profiles in variant CRCs in association with clinicopathologic parameters and prognosis. METHODS: CK expression in well- and moderately differentiated adenocarcinoma (WMDA) (n = 63), poorly differentiated adenocarcinoma (PDA) (n = 91), mucinous adenocarcinoma (MUA) (n = 81), signet ring cell carcinoma (SRCC) (n = 15), undifferentiated carcinoma (UDC) (n = 12), and adenosquamous carcinoma (n = 2) was analyzed using immunohistochemistry. Cut off scores were set at 1% for CK7 and 25% for CK20 using the receiver operating characteristic curve analysis of PDA. Association between CK20(-) and better prognosis in PDA was validated in the second cohort (n = 66). RESULTS: CK7/CK20 immunoprofiling revealed a predominant CK7(-) /CK20(+) profile in WMDA, MUA, and SRCC, while the majority of UDC was characterized by a CK7(-) /CK20(-) profile. The CK7/CK20 profile in PDA was variable. Contingency table analysis revealed that CK expression was not significantly associated with any clinicopathologic parameters in WMDA, PDA, and MUA. However, survival analysis demonstrated that CK20(-) was significantly associated with better prognosis in PDA. Although CK20( ) was significantly associated with mismatch repair deficiency in PDA, it was an independent prognostic factor in multivariate analysis. Finally, we confirmed that CK20 status, determined using a 25% cut-off score, was a significant prognostic parameter in the second PDA cohort. CONCLUSIONS: CK20 status may be used as a prognostic predictor of PDA. PMID- 23808939 TI - Epitope specificity of cross-clade neutralizing sera from Chinese HIV-1-positive individuals. AB - Induction of broadly neutralizing antibody is considered important for an effective HIV-1 vaccine. Identification and characterization of broadly neutralizing antibodies in HIV-1-infected patients will facilitate our understanding of the immune correlates to protection and the design of an effective prophylactic vaccine. A number of studies to probe the specificity of antibodies in broadly neutralizing sera in the United States and Europe have been reported. However, little is known about and would be interesting to investigate the immunological characteristics of HIV-1-positive sera in China where non-clade B viruses are prevalent and the circulating viral subtypes are distinct and more complex than both the United States and Europe. Here, we screened 80 Chinese HIV 1-positive sera against a minipanel of pseudoviruses representing various circulating HIV-1 subtypes in China and identified 8 cross-clade neutralizing sera (CNsera). Immunological characterization of the sera showed that gp120 targeting antibodies with multiple epitope specificities contributed to the cross clade neutralizing activity of these CNsera. V3-directed antibodies were prevalent in these CNsera, but did not mainly contribute to their neutralization breath and potency while CD4bs-specific, 2F5- and 4E10-like antibodies were rarely detected. 2G12-like neutralizing antibodies were more frequently detected in HIV-1 patients from China where recombinant subtype viruses are prevalent than in United States and Europe. One broadly neutralizing serum (Serum 45) was identified to contain antibodies with unknown epitope specificities that were sensitive to terminal glycan modifications on virus Env and insensitive to N160K mutagenesis, and correlated with the cross-clade neutralization activity of Serum 45. PMID- 23808940 TI - Quasiclassical trajectory studies of the O(3P) + CX4(vk = 0, 1) -> OXv + CX3(n1n2n3n4) [X = H and D] reactions on an ab initio potential energy surface. AB - We report quasiclassical trajectory calculations of the integral and differential cross sections and the mode-specific product state distributions for the "central barrier" O((3)P) + CH4/CD4(vk = 0, 1) [k = 1, 2, 3, 4] reactions using a full dimensional ab initio potential energy surface. The mode-specific vibrational distributions for the polyatomic methyl products are obtained by doing a normal mode analysis in the Eckart frame, followed by standard histogram binning (HB) and energy-based Gaussian binning (1GB). The reactant bending excitations slightly enhance the reactivity, whereas stretching excitations activate the reaction more efficiently. None of the reactant vibrational excitations is as efficient as an equivalent amount of translational energy to promote the reactions. The excitation functions without product zero-point energy (ZPE) constraint are in good agreement with previous 8-dimensional quantum mechanical (QM) results for the ground-state and stretching-excited O + CH4 reactions, whereas for the bending-excited reactions the soft ZPE constraint, which is applied to the sum of the product vibrational energies, provides better agreement with the QM cross sections. All angular distributions show the dominance of backward scattering indicating a direct rebound mechanism, in agreement with experiment. The title reactions produce mainly OH/OD(v = 0) products for all the initial states. HB significantly overestimates the populations of OH/OD(v = 1), especially in the energetic threshold regions, whereas 1GB provides physically correct results. The CH3/CD3 vibrational distributions show dominant populations for ground (v = 0), umbrella-excited (v2 = 1, 2), in-plane-bending-excited (v4 = 1), and v2 + v4 methyl product states. Neither translational energy nor reactant vibrational excitation transfers significantly into product vibrations. PMID- 23808941 TI - The degree to which physiotherapy literature includes physical activity as a component of health promotion in practice and entry level education: a scoping systematic review. AB - INTRODUCTION: Physiotherapists are well positioned to use physical activity as a health promotion (HP) strategy. This review examines the degree to which physiotherapy literature includes physical activity as a component of HP in practice and education. METHODS: Databases PubMed, Science Direct, CINAHL, Amed and Pedro were searched using a combination of keywords. If title, abstract or keywords were relevant, we proceeded to do a complete review. Only peer reviewed English work covering original research was included. Discussion and opinion papers, reviews, epidemiological studies, case studies or work not specifically addressing integration of HP were excluded. RESULTS: The information from 29 source articles was synthesized under the headings of acceptability of the HP role to physiotherapists and physiotherapy students; integration of HP into physiotherapy practice; HP interventions in physiotherapy practice; and HP in physiotherapy education and training. The findings were heterogenous, thereby limiting this review study to a scoping review. CONCLUSION: More interventional research is needed to develop efficacious strategies integrating physical activity as a HP strategy in physiotherapy practice. Contemporary physiotherapy entry-level education curricula need benchmark standards for HP training such as physical activity. PMID- 23808944 TI - Efficacy and safety of a WallFlex enteral stent for malignant gastric obstruction. AB - AIM: The aim of the present study was to investigate the efficacy and safety of a newly available enteral WallFlex stent for malignant gastric outlet obstruction (GOO). METHODS: Twenty-one consecutive patients with symptomatic (unable to take solids) malignant GOO treated by a WallFlex stent from April 2010 to February 2012 were included and analyzed retrospectively. Main outcome measurements were technical success, early complications, clinical response (elimination of the need for nasogastric tube drainage), clinical success (improvement of oral intake to a GOO score of 2 or 3), and duration of sustaining a GOO score of 2 or 3 after clinical success (median duration until reworsening of GOO score to <2 by the Kaplan-Meier method). A four-point GOO scoring system (0-3) was used for estimation of oral intake. RESULTS: Technical success rate was 100%. Bleeding and perforation after stent placement and stent dislocation/migration in the follow up period did not occur in any patients, whereas one patient (5%) developed moderate post-procedural pancreatitis. Clinical response and clinical success was achieved in all patients and in 81% (17/21), respectively. In 17 patients whose GOO score had improved to 2 or 3 after stent placement, eight (47%) developed reworsening of the GOO score to <2 with a median time of 148 days (95% confidence interval [CI], 0-328; Kaplan-Meier method). Median survival time after the initial intervention was 61 days (95% CI, 40-82). CONCLUSION: Placement of an enteral WallFlex stent in patients with malignant GOO is safe and effective. PMID- 23808943 TI - HMGB1 mediates splenomegaly and expansion of splenic CD11b+ Ly-6C(high) inflammatory monocytes in murine sepsis survivors. AB - BACKGROUND: More than 500,000 hospitalized patients survive severe sepsis annually in the USA. Recent epidemiological evidence, however, demonstrated that these survivors have significant morbidity and mortality, with 3-year fatality rates higher than 70%. To investigate the mechanisms underlying persistent functional impairment in sepsis survivors, here we developed a model to study severe sepsis survivors following cecal ligation and puncture (CLP). METHODS: Sepsis was induced in mice by CLP and survivors were followed for twelve weeks. Spleen and blood were collected and analyzed at different time points post sepsis. RESULTS: We observed that sepsis survivors developed significant splenomegaly. Analysis of the splenic cellular compartments revealed a major expansion of the inflammatory CD11b+ Ly-6CHigh pool. Serum high-mobility group box 1 (HMGB1) levels in the sepsis surviving mice were significantly elevated for 4-6 weeks after post-sepsis, and administration of an anti-HMGB1 monoclonal antibody significantly attenuated splenomegaly as well as splenocyte priming. Administration of recombinant HMGB1 to naive mice induced similar splenomegaly, leukocytosis and splenocyte priming as observed in sepsis survivors. Interestingly analysis of circulating HMGB1 from sepsis survivors by mass spectroscopy demonstrated a stepwise increase of reduced form of HMGB1 (with known chemo-attractant properties) during the first 3 weeks, followed by disulphide form (with known inflammatory properties) 4-8 weeks after CLP. DISCUSSION: Our results indicate that prolonged elevation of HMGB1 is a necessary and sufficient mediator of splenomegaly and splenocyte expansion, as well as splenocyte inflammatory priming in murine severe sepsis survivors. PMID- 23808942 TI - SERCA2 activity is involved in the CNP-mediated functional responses in failing rat myocardium. AB - BACKGROUND AND PURPOSES: Myocardial C-type natriuretic peptide (CNP) levels are increased in heart failure. CNP can induce negative inotropic (NIR) and positive lusitropic responses (LR) in normal hearts, but its effects in failing hearts are not known. We studied the mechanism of CNP-induced NIR and LR in failing hearts and determined whether sarcoplasmatic reticulum Ca(2+) ATPase2 (SERCA2) activity is essential for these responses. EXPERIMENTAL APPROACH: Contractility, cGMP levels, Ca(2+) transient amplitudes and protein phosphorylation were measured in left ventricular muscle strips or ventricular cardiomyocytes from failing hearts of Wistar rats 6 weeks after myocardial infarction. KEY RESULTS: CNP increased cGMP levels, evoked a NIR and LR in muscle strips, and caused phospholamban (PLB) Ser(16) and troponin I (TnI) Ser(23/24) phosphorylation in cardiomyocytes. Both the NIR and LR induced by CNP were reduced in the presence of a PKG blocker/cGMP analogue (Rp-8-Br-Pet-cGMPS) and the SERCA inhibitor thapsigargin. CNP increased the amplitude of the Ca(2+) transient and increased SERCA2 activity in cardiomyocytes. The CNP-elicited NIR and LR were not affected by the L-type Ca(2+) channel activator BAY-K8644, but were abolished in the presence of isoprenaline (induces maximal activation of cAMP pathway). This suggests that phosphorylation of PLB and TnI by CNP causes both a NIR and LR. The NIR to CNP in mouse heart was abolished 8 weeks after cardiomyocyte-specific inactivation of the SERCA2 gene. CONCLUSIONS AND IMPLICATIONS: We conclude that CNP-induced PLB and TnI phosphorylation by PKG in concert mediate both a predictable LR as well as the less expected NIR in failing hearts. PMID- 23808945 TI - Band ligation of gastric antral vascular ectasia is a safe and effective endoscopic treatment. AB - BACKGROUND AND AIM: Gastric antral vascular ectasia (GAVE) or 'watermelon stomach' is a rare and often misdiagnosed cause of occult upper gastrointestinal bleeding. Treatment includes conservative measures such as transfusion and endoscopic therapy. A recent report suggests that endoscopic band ligation (EBL) offers an effective alternative treatment. The aim of the present study is to demonstrate our experiences with this novel technique, and to compare argon plasma coagulation (APC) with EBL in terms of safety and efficacy. METHODS: A retrospective analysis of all endoscopies with a diagnosis of GAVE was carried out between 2004 and 2010. Case records were examined for information pertaining to the number of procedures carried out, mean blood transfusions, mean hemoglobin, and complications. RESULTS: A total of 23 cases of GAVE were treated. The mean age was 73.9 (55-89) years. Female to male ratio was 17:6 and mean follow up was 26 months. Eight patients were treated with EBL with a mean number of treatments of 2.5 (1-5). This resulted in a statistically significant improvement in the endoscopic appearance and a trend towards fewer transfusions. Of the eight patients treated with EBL, six (75%) patients had previously failed APC treatment despite having a mean of 4.7 sessions. Band ligation was not associated with any short- or medium-term complications. The 15 patients who had APC alone had a mean of four (1-11) treatments. Only seven (46.7%) of these patients had any endoscopic improvement with a mean of four sessions. CONCLUSIONS: EBL represents a safe and effective treatment for GAVE. PMID- 23808946 TI - Feasibility of spiral enteroscopy in Japanese patients: study in two tertiary hospitals. AB - BACKGROUND AND AIM: Despite recent advances in enteroscopy, such as balloon enteroscopy, accessing the small intestine remains challenging. Spiral enteroscopy is a novel technique in which an endoscope is fitted with a rotating overtube that has a soft spiral fin at the tip. Whereas spiral enteroscopy is beginning to be carried out in Western countries, it is not common in many Asian countries. The aim of the present study was to evaluate the efficacy and safety of spiral enteroscopy in Japanese patients. METHODS: We prospectively conducted spiral enteroscopy in patients with suspected or known small bowel disease. All procedures were carried out using a spiral overtube. The main outcome measurements of the study were diagnosis rate, endoscopic intervention rate, and complication rate. RESULTS: Thirty-two patients underwent spiral enteroscopy. Spiral enteroscopy diagnosed 16 patients (50%) with small intestinal lesions, including six malignant lymphomas (19%), three erosions or ulcers (9%), three polyps (9%), two angioectasias (6%), one carcinoma (3%), and one submucosal tumor (3%). Additionally, four patients underwent endoscopic interventions (13%). Mallory-Weiss syndrome occurred in one patient (3%). No perforation occurred in any patient (0%). CONCLUSIONS: Our initial experience of spiral enteroscopy suggests that it can be introduced safely, but it is relatively invasive and technically demanding. More experience is needed to conduct spiral enteroscopy easily and safely. PMID- 23808947 TI - What is the accuracy of autofluorescence imaging in identifying non-polypoid colorectal neoplastic lesions when reviewed by trainees? A pilot study. AB - BACKGROUND AND AIM: Non-polypoid colorectal neoplasms are difficult to identify using conventional white light (WL) colonoscopy. The aim of the present pilot study was to compare an autofluorescence imaging (AFI) system with conventional WL colonoscopy for the identification of non-polypoid neoplasms by trainees in a colonoscopic observational situation. METHODS: We selected clear images with both AFI and WL in the same field taken by experts at the National Cancer Center Hospital, Tokyo, from December 2009 to November 2010. One hundred and eighty sets of images (137 non-polypoid neoplasms and 43 without neoplasm) were selected. The images were reviewed by two trainees without AFI experience. After attending a short educational lecture on the AFI system, the reviewers determined the presence of lesions in the randomly arranged images. The accuracy of AFI and WL for identifying non-polypoid neoplasms by trainees was assessed. RESULTS: The sensitivity and specificity for identifying non-polypoid neoplasms by trainees was not significantly different between AFI and WL. However, the specificity tended to be lower in AFI images than in WL images. CONCLUSIONS: False-positive results tended to be more frequent for the AFI images than for the WL images. Further improvements in the technology and resolution are necessary for the AFI system to be useful for the detection of colorectal neoplasms. At present, clinical application of the AFI system may require more extensive structured training to improve its accuracy in the identification of non-polypoid colorectal neoplasms. PMID- 23808948 TI - Cap-assisted water immersion for minimal sedation colonoscopy: prospective, randomized, single-center trial. AB - BACKGROUND AND AIM: Water immersion insertion is able to reduce discomfort and need for sedation during colonoscopy. A cap attached to the colonoscope tip may improve insertion during air insufflation colonoscopy. According to several reports, both techniques alone may result in higher detection of neoplastic lesions. Our study was designed to evaluate the efficacy of cap-assisted water immersion compared to water immersion colonoscopy in minimally sedated patients. METHODS: A total of 208 consecutive outpatients were randomized to either cap assisted water immersion (Cap Water) or water immersion colonoscopy (Water). The primary endpoint was cecal intubation time. RESULTS: Cecal intubation time was 6.9 +/- 2.9 min in Cap Water and 7.4 +/- 4.2 min in the Water arm (P = 0.73). Success rate of minimal sedation colonoscopy was equal in both groups (92.9%, P = 1.00). From the endoscopist's point of view, there were non-significant trends towards lower discomfort (P = 0.06), less need for abdominal compression (P = 0.06) and lower difficulty score (P = 0.05) during Cap Water colonoscopy. Adenoma detection rate was similar in both arms (44% in Cap Water vs 45% in the Water group, P = 0.88). There were no complications recorded in the present study. CONCLUSIONS: In comparison with water immersion without cap, cap-assisted water immersion colonoscopy was not able to shorten the cecal intubation time. However, it has the possibility of reducing patient discomfort and difficulty of colonoscope insertion. Potential impact on improved detection of neoplastic lesions has to be evaluated by further studies. PMID- 23808949 TI - Role of long-term biliary stenting in choledocholithiasis. AB - BACKGROUND AND AIM: Endoscopic retrograde cholangiopancreatography (ERCP) is the treatment of choice for the management of choledocholithiasis. Biliary stenting facilitates repeated attempts at stone extraction. The aim of the present paper was to assess long-term outcomes of patients where biliary stenting was used as the primary treatment for the management of choledocholithiasis. METHODS: We undertook a review of a prospectively maintained database of all ERCP carried out at a single institution. All patients had stones not amenable to endoscopic retrieval. RESULTS: Between January 1998 and December 2008, 3655 ERCP were carried out in our unit. Of these, 201 (120 female) patients met our inclusion criteria. All patients underwent ERCP and sphincterotomy, followed by insertion of a double pigtail 7-Fr plastic stent. Repeat ERCP was not scheduled routinely. Stent change was only carried out in patients when clinical suspicion of stent blockage occurred. Median stent patency was 59.6 months (interquartile range 47.7 71.2). At 6 months, stent patency was 93.5%, and at 24 months, it was 81.9%. Serious adverse outcomes with blocked stents were uncommon, and tended to occur early. Cholangitis was seen in only 7.4% (6) of patients (median stent patency 11.8 months) and jaundice was seen in 18.5% (15 patients, median stent patency 7.2 months). CONCLUSION: Our data demonstrate median stent patency of almost 5 years. The low incidence of significant complications with blocked stents and excellent stent patency rates suggest that long-term biliary stenting is an acceptable alternative in elderly, frail patients with stones that are not endoscopically retrievable. PMID- 23808950 TI - Prospective randomized controlled study comparing cell block method and conventional smear method for bile cytology. AB - BACKGROUND AND AIM: There is a paucity of data on the cell block (CB) method for bile cytology. We compared the diagnostic efficacy of the CB method with that of conventional smear cytology for bile obtained by endoscopic retrograde cholangiopancreatography (ERCP) in a randomized controlled trial manner. METHODS: A total of 137 patients with biliary tract lesions suspicious of malignancy who had undergone bile collection under ERCP were recruited to this study. After sampling, the bile was randomized to the CB method (n = 69) or to smear cytology (n = 68). CB sections were prepared using the sodium alginate method and subjected to hematoxylin-eosin, Alcian blue-periodic acid-Schiff stain, and immunohistochemical stains. Both Papanicolaou and Giemsa stains were used for smear cytology. RESULTS: The final diagnosis was malignancy in 94 patients: bile duct cancer, 42; pancreatic head cancer, 34; gallbladder cancer, 16; and ampullary cancer, two. The diagnostic accuracy of the CB method and that of smear cytology were 64% and 53%, respectively (P = 0.20). The sensitivity of the CB method (53%) was significantly better than that of smear cytology (28%; P = 0.014). Their respective sensitivities were 80% and 31% (P = 0.002) for bile duct cancer, 20% and 15% (P = 1.0) for pancreatic head cancer, and 30% and 67% (P = 0.30) for gallbladder cancer. CONCLUSION: The CB method for bile cytology showed a higher diagnostic yield than smear cytology. Its diagnostic sensitivity was satisfactory in cases of bile duct cancer. PMID- 23808951 TI - A fast bilateral filter with application to artefact reduction. AB - Elastography in medical ultrasound is an imaging technique that displays information about tissue stiffness. However, elastography suffers from artefact noise that may come from two dominant sources: decorrelation error and amplitude modulation error. In order to reduce artefact and improve the quality of ultrasonic elastography, a fast bilateral filter is proposed in this study based on local histogram. The presented filter is derived from a conventional bilateral filter, and a local histogram is introduced to speed up the filter. The proposed algorithm can reduce artefact noise and, at the same time, maintain the tissue structure. Both simulation and phantom testing show that the proposed method can improve the quality of ultrasonic elastography in terms of tissue elastographic signal-to-noise ratio and elastographic contrast-to-noise ratio values. PMID- 23808952 TI - Psychometric properties of outcome measures for children and adolescents with brachial plexus birth palsy: a systematic review. AB - AIM: The aim of this review was to evaluate the psychometric properties of outcome measures used to quantify upper limb function in children and adolescents with brachial plexus birth palsy (BPBP). METHOD: Eleven electronic databases were searched to identify studies on the effects of conservative management to improve upper limb function in young people with BPBP. Outcome measures used in these studies were extracted and used in a subsequent search to identify studies that evaluated the psychometric properties of these measures. The methodological quality of these studies was rated using a standardized critical appraisal tool. RESULTS: Thirty-three outcome measures and 12 psychometric studies were identified. Nine outcome measures had some psychometric evidence, which was variable in quality. The outcome measures which seem to have the most robust psychometric properties include the Active Movement Scale, Assisting Hand Assessment, Pediatric Evaluation of Disability Index, and the Pediatric Outcomes Data Collection Instrument. INTERPRETATION: Further research is required to determine the psychometric properties of outcome measures used for children and adolescents with BPBP. Caution is required when interpreting the results of commonly used outcome measures in this population owing to their relatively unknown psychometric properties. PMID- 23808953 TI - High-performance bioassisted nanophotocatalyst for hydrogen production. AB - Nanophotocatalysis is one of the potentially efficient ways of capturing and storing solar energy. Biological energy systems that are intrinsically nanoscaled can be employed as building blocks for engineering nanobio-photocatalysts with tunable properties. Here, we report upon the application of light harvesting proton pump bacteriorhodopsin (bR) assembled on Pt/TiO2 nanocatalyst for visible light-driven hydrogen generation. The hybrid system produces 5275 MUmole of H2 (MUmole protein)(-1) h(-1) at pH 7 in the presence of methanol as a sacrificial electron donor under white light. Photoelectrochemical and transient absorption studies indicate efficient charge transfer between bR protein molecules and TiO2 nanoparticles. PMID- 23808954 TI - Novel concepts in nontypeable Haemophilus influenzae biofilm formation. AB - Nontypeable Haemophilus influenzae (NTHi) is a Gram-negative microbe that frequently colonizes the human host without obvious signs of inflammation, but is also a frequent cause of otitis media in children and exacerbations in chronic obstructive pulmonary disease patients. Accumulating data suggest that NTHi can reside in biofilms during both colonization and infection. Recent literature proposes roles for phosphorylcholine, sialic acid, bacterial DNA, but also eukaryotic DNA in the development of NTHi biofilms. However, many questions remain. Until now, there are insufficient data to explain how NTHi forms biofilms. Here, we review the recent advances in NTHi biofilm formation with particular focus on the role that neutrophils may play in this process. We propose that recruitment of neutrophils facilitates NTHi biofilm formation on mucosal sites by the initiation of neutrophil extracellular traps. PMID- 23808955 TI - Morphogenesis and molecular phylogeny of a new freshwater ciliate, Notohymena apoaustralis n. sp. (Ciliophora, Oxytrichidae). AB - The live morphology, infraciliature, and morphogenesis of a new oxytrichid ciliate, Notohymena apoaustralis n. sp. collected from a freshwater pond in Qingdao (Tsingtao), China, were studied in vivo and after protargol impregnation. Notohymena apoaustralis n. sp. is characterized as follows: undulating membranes in Notohymena-pattern; cortical granules yellow-green, grouped around the marginal cirri and dorsal bristles, and in short irregular rows elsewhere in the cell; single contractile vacuole positioned at anterior 1/3 of the body length; two macronuclear nodules and one micronucleus; about 39 adoral membranelles; 18 frontoventral transverse cirri in typical Oxytricha-pattern; one right and one left marginal row, almost confluent posteriorly; dorsal ciliature in typical Oxytricha-pattern; 8-10 caudal cirri arranged in three rows, one each at the posterior end of dorsal kineties 1, 2, and 4, indistinguishable from marginal cirri in life. The morphogenetic process in N. apoaustralis n. sp. is consistent with that of the type species, Notohymena rubescens Blatterer and Foissner, 1988. Phylogenetic analyses based on small subunit rDNA sequence data suggest a sister relationship between N. apoaustralis n. sp. and Paraurostyla weissei, which cluster in a clade with Rubrioxytricha ferruginea. PMID- 23808956 TI - Placental gene expression patterns of endoglin (CD105) in intrauterine growth restriction. AB - OBJECTIVE: In this study, we describe placental gene expression patterns of endoglin in pregnancies with intrauterine growth restriction (IUGR) compared to normal pregnancies. METHODS: Placental samples were obtained from 101 pregnancies with IUGR using 140 normal pregnancy cases as control. Gene expression patterns and protein levels of the endoglin were compared between the two groups. For the gene expression analysis real-time PCR was applied, while for the estimation of placental protein level we performed Western analysis. RESULTS: The placental endoglin gene was significantly overexpressed in the IUGR group versus the control group (Ln2(alpha): 1.69). The placental endoglin protein level proved to be significantly higher in case of IUGR (endoglin/beta-actin ratio: 13.8 +/- 2.3) versus the control cases (5.3 +/- 1.1). The placental gene expression as well as the protein levels of endoglin showed no significant difference between female and male newborns. Concerning the placental gene expression and protein level, no significant difference was justified between the more (0-5 percentile) and less (5-10 percentile) severe cases of IUGR. CONCLUSION: Increased placental gene expression of endoglin may result in vascular dysfunction leading to chronic fetal hypoxia, which may induce VEGF-A to stimulate angiogenesis. This can be explained as feed back response to restore fetal placental circulation. PMID- 23808957 TI - Comparative genome analysis of ciprofloxacin-resistant Pseudomonas aeruginosa reveals genes within newly identified high variability regions associated with drug resistance development. AB - The alarming rise of ciprofloxacin-resistant Pseudomonas aeruginosa has been reported in several clinical studies. Though the mutation of resistance genes and their role in drug resistance has been researched, the process by which the bacterium acquires high-level resistance is still not well understood. How does the genomic evolution of P. aeruginosa affect resistance development? Could the exposure of antibiotics to the bacteria enrich genomic variants that lead to the development of resistance, and if so, how are these variants distributed through the genome? To answer these questions, we performed 454 pyrosequencing and a whole genome analysis both before and after exposure to ciprofloxacin. The comparative sequence data revealed 93 unique resistance strain variation sites, which included a mutation in the DNA gyrase subunit A gene. We generated variation-distribution maps comparing the wild and resistant types, and isolated 19 candidates from three discrete resistance-associated high variability regions that had available transposon mutants, to perform a ciprofloxacin exposure assay. Of these region candidates with transposon disruptions, 79% (15/19) showed a reduction in the ability to gain high-level resistance, suggesting that genes within these high variability regions might enrich for certain functions associated with resistance development. PMID- 23808958 TI - Salmonella enterica serovar Typhimurium virulence-resistance plasmids derived from the pSLT carrying nonconventional class 1 integrons with dfrA12 gene in their variable region and sul3 in the 3' conserved segment. AB - Drug-resistant derivatives of serovar-specific virulence plasmids, such as pSLT, in clinically-relevant Salmonella enterica serovar Typhimurium strains, represent a threat for human health. We have analysed 14 S. Typhimurium isolates recovered in Italy and the United Kingdom from swine and from cases of human infection for the presence of virulence-resistance (VR) plasmids. They were negative for the multidrug resistance (MDR) region of the Salmonella genomic island 1 (SGI1), but expressed resistance to ampicillin, chloramphenicol, streptomycin/spectinomycin, sulfamethoxazole, and tetracyclines. The isolates were characterised by XbaI pulsed-field gel electrophoresis, multilocus sequence typing, and detection of resistance and virulence determinants (PCR/sequencing). Identification of VR plasmids was accomplished by PCR detection of bla genes (encoding ampicillin resistance), class 1 integrons and the pSLT virulence gene spvC. Plasmid analyses were performed by alkaline lysis, S1-nuclease digestion, replicon typing, conjugation, restriction analyses, and Southern blot/hybridization. Two blaOXA-1 positive isolates contained pSLT-derived plasmids related to pUO-StVR2. In nine isolates, eight from swine and one from a patient, MDR-conferring-IncFII-VR plasmids were detected. They contained the blaTEM-1 gene as well as a nonconventional class 1 integron with dfrA12-aadA2 gene cassettes in its variable region, and a sul3 gene in the 3' conserved segment. Restriction analysis suggested a novel pSLT variant. The results obtained underline the role of swine as a potential reservoir for the blaTEM-1-IncFII-plasmids. The occurrence and spread of virulence- and MDR-conferring plasmids should be considered as a potential public health problem. PMID- 23808959 TI - OXA-48 carbapenemase-producing Klebsiella pneumoniae isolated from Libyan patients. AB - Six multidrug-resistant Klebsiella pneumoniae isolates were recovered from injured Libyan combatants. Production of carbapenemase was screened by using commercial combination tablets from Rosco combined with a temocillin disk. Polymerase chain reaction (PCR) and sequencing were used to detect several carbapenemase genes and to characterize their genetic environment. Genetic support was studied by mating-out assays. Plasmid size was identified by the KADO method. PCR and sequencing allowed characterization of plasmid scaffold. Genotyping was performed by pulse-field gel electrophoresis (PFGE) and multilocus sequence typing. PCR was used to check for the presence of nine genes linked to virulence in K. pneumoniae. No carbapenemase was identified by Rosco disks, but all isolates showed high-level temocillin resistance. All of them harbored blaOXA 48 in the transposon Tn1999.2, on a self-conjugative plasmid of about 60 kb, similar to pOXA-48. PFGE revealed three clusters in which isolates were genetically related: The first comprised FM9 and FM10, and the second comprised FM1, FM4, and FM5. FM2 formed a third distinct clone. Sequence types ST101, ST11, and ST147 were identified in keeping with PFGE results. The entB, ycfM, ybtS, and mrkD genes were detected in all isolates, and kfu gene was present in the three ST101 strains. This work confirms the current and successful spread of blaOXA-48 by horizontal dissemination of a single IncL/M plasmid through different genetic backbones with strong epidemic potential. It also highlights the need for rapid and reliable phenotypic detection methods. Attempts to link virulence factors and the production of this carbapenemase deserve further studies. PMID- 23808960 TI - Long-term treatment of anxiety disorders with pregabalin: a 1 year open-label study of safety and tolerability. AB - OBJECTIVE: Short-term clinical trials have demonstrated the efficacy and safety of pregabalin in the treatment of generalized anxiety disorder (GAD). This study examined long-term safety and tolerability of pregabalin in patients with GAD, social anxiety disorder (SAD), or panic disorder (PD). RESEARCH DESIGN AND METHODS: Patients (n = 528) completing one of four randomized, double-blind, placebo-controlled trials of pregabalin for GAD, SAD, or PD were treated, open label, with flexible-dose pregabalin (150-600 mg/day) for 1 year. CLINICAL TRIAL REGISTRATION: NCT00150449. MAIN OUTCOME MEASURES: The primary outcomes were safety and tolerability. Illness severity was assessed at baseline and Weeks 27/52 using the Clinical Global Impression of Severity (CGI-S) scale. Patients were characterized as 'responders' or 'non-responders' based on CGI-S scores <=2 and >2, respectively. Analyses were performed on the total anxiety (GAD, SAD and PD) and GAD groups. RESULTS: During 1 year of treatment with pregabalin, dizziness (12.5%) was the only treatment-related adverse event (AE) occurring >=10%. Somnolence, weight gain, headache and insomnia occurred at 7.6%, 5.5%, 5.3% and 4.7%, respectively. Few treatment-related AEs were rated as severe in the total anxiety (5.1%) or GAD (3.6%) groups. Discontinuation rates due to AEs were similar (9.7% and 10.6%, respectively). No clinically significant laboratory, electrocardiogram, or other treatment-related safety findings were noted, except for treatment-related weight gain, which occurred in both the total (24.4%) and GAD (19.4%) groups. Mean CGI-S scores were similar at baseline in the total (n = 528; score, 3.4) and GAD groups (n = 330; score, 3.6), and CGI-S responder rates were similar at last-observation-carried-forward endpoint (51.3% and 48.1%, respectively). CONCLUSIONS: Pregabalin was generally well tolerated in the long-term treatment of anxiety disorders. Improvement in illness severity was maintained over time. The key limitations of this study were that it was not randomized and neither placebo- nor active-comparator-controlled. PMID- 23808961 TI - Treatment patterns and outcomes in patients with advanced melanoma in France. AB - BACKGROUND: Melanoma is associated with high mortality and poor response to standard chemotherapy. In order to benchmark benefits of recently introduced treatments, outcome with standard chemotherapy in everyday practice should be documented. OBJECTIVES: To document treatment pathways in patients with advanced melanoma, to compare clinical outcomes between treatment lines, and to measure associated healthcare resource utilisation in terms of hospital visits and adverse event management. METHODS: An observational, longitudinal survey of patients with unresectable stage III/IV melanoma in France evaluated 278 patients with >= 2 months follow-up. Data were collected retrospectively for 2-3 years following the index consultation. Treatment history was documented and outcomes determined for each treatment line. Complete and partial response rates were compared between treatment lines. Overall and progression-free survival were determined by Kaplan-Meier analysis. Health resource utilisation was documented hospitalisations, hospice stays, emergency room visits, outpatient visits and adverse event management. RESULTS: In total, 271 patients (97.5%) received first line therapy, 161 (57.9%) second-line therapy and 85 (30.6%) third-line therapy. The most frequent first-line therapy strategies were systemic treatment alone (46.5%) or in combination with surgery (22.9%). The most frequently used chemotherapy was dacarbazine monotherapy (62.3% of chemotherapy). Median duration of first-line systemic therapy was 11.9 (IQR: 6.6-24.0) weeks. First-line therapy was discontinued in 190 patients (68.3%), principally due to disease progression (150 patients). Median overall survival was 17.1 (95% CI: 14.6-20.1) months since diagnosis, 9.5 (95% CI: 6.7-12.8) months since initiation of first-line therapy and 5.3 (95% CI: 3.7-7.2) months since initiation of second-line therapy. Median progression-free survival time was 2.8 (95% CI: 2.5-3.3) months. Ninety-six patients (40.2%) received medication to manage adverse events and 131 patients (47.1%) required hospitalisation (mean: 3.1 hospitalisations; mean duration: 27 days). STUDY LIMITATIONS: The retrospective data collection precludes ascertainment of medical information and completion of missing data. CONCLUSIONS: Existing therapies provide limited survival benefit to patients with unresectable stage III/IV melanoma. New more effective treatment options are needed. PMID- 23808962 TI - Importance of acid-base equilibrium in electrocatalytic oxidation of formic acid on platinum. AB - Electro-oxidation of formic acid on Pt in acid is one of the most fundamental model reactions in electrocatalysis. However, its reaction mechanism is still a matter of strong debate. Two different mechanisms, bridge-bonded adsorbed formate mechanism and direct HCOOH oxidation mechanism, have been proposed by assuming a priori that formic acid is the major reactant. Through systematic examination of the reaction over a wide pH range (0-12) by cyclic voltammetry and surface enhanced infrared spectroscopy, we show that the formate ion is the major reactant over the whole pH range examined, even in strong acid. The performance of the reaction is maximal at a pH close to the pKa of formic acid. The experimental results are reasonably explained by a new mechanism in which formate ion is directly oxidized via a weakly adsorbed formate precursor. The reaction serves as a generic example illustrating the importance of pH variation in catalytic proton-coupled electron-transfer reactions. PMID- 23808963 TI - Hand eczema among healthcare professionals in the Netherlands: prevalence, absenteeism, and presenteeism. AB - BACKGROUND: Healthcare professionals have a high risk of developing hand eczema. Hand eczema can interfere with their work. OBJECTIVES: To investigate the prevalence of self-reported hand eczema among healthcare professionals in the Netherlands, and to investigate absenteeism and presenteeism resulting from hand eczema. METHODS: A questionnaire-based observational study was performed. Participants were recruited from hospitals and nursing homes in the Netherlands. The study population consisted of 1232 healthcare professionals. We used the NOSQ 2002 to measure hand eczema and the PRODISQ for absenteeism and presenteeism. RESULTS: The 1-year prevalence of hand eczema among healthcare professionals was 12%. Among all participants, 47% reported symptoms related to hand eczema. Sick leave resulting from hand eczema was reported by 0.3% of healthcare professionals in general, and by 1.7% of healthcare professionals with hand eczema. In the group with hand eczema, 3.1% reported a large effect on presenteeism. CONCLUSIONS: The 1-year prevalence of hand eczema among healthcare professionals in the Netherlands is low, but the prevalence of symptoms related to hand eczema is quite high. Hand eczema seems to have little impact on work in terms of absenteeism and presenteeism. PMID- 23808964 TI - Intermittent hoarseness with continuous interscalene brachial plexus catheter infusion due to deficient carotid sheath. PMID- 23808965 TI - The risk of headache attributed to surgical treatment of intracranial aneurysms: a cohort study. AB - OBJECTIVES: The aim of this study was to assess the risk of headache in patients undergoing surgical treatment of intracranial aneurysms. BACKGROUND: The risk of the post-craniotomy headache has never been studied. METHODS: Patients with intracranial aneurysm, who were consecutively admitted to the Hospital da Restauracao, Brazil, from May 2009 to October 2010, were interviewed before they underwent surgical or non-surgical treatment of the aneurysms. The patients were followed for 4 months after intervention. The International Headache Society criteria for post-craniotomy headache were used after surgery and adapted for headache after embolization (maximum intensity of pain on the same side of the aneurysm). We also used the Headache Impact Test, the Hospital Anxiety and Depression Scale, and the Epworth Sleepiness Scale. RESULTS: Of 101 patients enrolled, 53 patients underwent craniotomy and 48 patients embolization. The surgery group was younger and had fewer women. The incidence of headache was 28/51 cases (54.9%) after surgery and 12/47 cases (25.5%) after embolization (relative risk = 2.15; 95% confidence interval [CI] 1.24-3.72). The incidence of persistent headache was not different between the 2 groups. The only risk factor for headache after the intervention was craniotomy (odds ratio = 2.6; 95% CI 1.1 6.7) and for persistent headache was anxiety prior to treatment (odds ratio = 8.5; 95% CI 1.7-42.3). The headache after treatment was not associated with the risk of anxiety or depression after the intervention. CONCLUSIONS: Patients who underwent craniotomy had an increased risk of headache after treatment of intracranial aneurysms. The incidence of persistent headache after 3 months was higher among patients who had anxiety before the intervention. PMID- 23808966 TI - Molecular modeling of p38alpha mitogen-activated protein kinase inhibitors through 3D-QSAR and molecular dynamics simulations. AB - The p38 mitogen-activated protein kinase (MAPK) signaling pathway plays an essential role in inflammation and other physiological processes. Because specific inhibitors of p38alpha and p38beta MAPK block the production of the major inflammatory cytokines and other proteins, p38alpha and p38beta MAPK represent promising targets for the treatment of inflammation. In this work, a series of p38alpha inhibitors based on the structural scaffold of 4-benzoyl-5 aminopyrazole were analyzed using a combination of molecular modeling techniques. We generated three-dimensional quantitative structure-activity relationship (3D QSAR) models for both comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) to highlight the structural requirements for p38 MAPK inhibition. Furthermore, we employed molecular dynamics (MD) simulations and the MM/GBSA method to compare the binding modes and binding free energies of a potent and selective compound interacting with p38alpha, p38beta, p38gamma, and p38delta MAPK in detail. Contour maps generated via 3D-QSAR analysis identified several key interactions that were also indicated through MD simulations. The binding free energies calculated via the MM/GBSA method were strongly correlated with experimentally observed biological activities and explained the selective inhibition of p38alpha and p38beta, but not p38gamma and p38delta detected here. On the basis of the obtained results, we provide insights regarding the development of novel potent p38alpha MAPK inhibitors. PMID- 23808967 TI - Hypoglycaemia, fear of hypoglycaemia and quality of life in children with Type 1 diabetes and their parents. AB - AIM: To evaluate the association between fear of hypoglycaemia, episodes of hypoglycaemia and quality of life in children with Type 1 diabetes and their parents. METHODS: This was a cross-sectional, population-based study of 325 children with Type 1 diabetes and their parents. The children were aged 2-18 years. A total of 325 parents of the patients aged 2-18 years and 196 of the patients themselves (aged 8-18 years) completed questionnaires including the PedsQL Diabetes Module, the Hypoglycaemia Fear Survey and Clarke's hypoglycaemia awareness questionnaire. Data were compared with HbA1c results and the history of severe hypoglycaemia episodes. RESULTS: Parents with the highest levels of fear of hypoglycaemia reported that their children had a reduced quality of life (P < 0.001). Similarly children with the greatest fear also reported a reduced quality of life (P < 0.001); however a history of severe hypoglycaemia was not associated with the child's quality of life as perceived by the child or parent. Episodes of severe hypoglycaemia were associated with an increased fear of hypoglycaemia for the parents (P = 0.004) but not the children. Children in the highest fear quartile also had a higher HbA(1c) concentration compared with those in the lowest fear quartile [increase in HbA(1c) 7 mmol/mol (0.6%), P < 0.01]. CONCLUSIONS: Fear of hypoglycaemia and not episodes of hypoglycaemia per se is associated with increased psychological burden for children with Type 1 diabetes. Interventions to reduce fear of hypoglycaemia in these families may improve their quality of life. PMID- 23808968 TI - Quantitative time-resolved vibrational sum frequency generation spectroscopy as a tool for thin film kinetic studies: new insights into oleic acid monolayer oxidation. AB - Environmental air-water interfaces are often covered by thin films of surface active organic substances that play an important role for air-sea gas exchange and aerosol aging. Surface-sensitive vibrational sum frequency generation (VSFG) spectroscopy has been widely used to study the static structure of organic monolayers serving as simple model systems of such films. Probably due to the difficulties to correlate the SFG signal intensity with the surface concentration, corresponding time-resolved studies of surface reactions are scarce. In this study, quantitative time-resolved measurements have been performed on the oleic acid monolayer ozonolysis, which is considered a benchmark system for investigating the reactivity and fate of unsaturated natural organics. Surface concentration calibration data have been obtained by combining the pressure-area isotherm and VSFG spectra acquisition such that the 2D phase behavior of the oleic acid film could be properly taken into account. In contrast to literature reports, surface-active oxidation products were found to be negligible and do not interfere with the VSFG measurements. A pseudo-first-order kinetic analysis of the time-resolved data yielded a bimolecular rate constant of k2(oleic acid + O3 -> products) = (1.65 +/- 0.64) * 10(-16) cm(3) molecules(-1) s(-1), corresponding to an uptake coefficient of gamma = (4.7 +/- 1.8) * 10(-6). This result is in very good agreement with most recent monolayer measurements based on alternative methods and underlines the reliability of the time-resolved VSFG approach. PMID- 23808969 TI - Changes in CB(1) and CB(2) receptors in the post-mortem cerebellum of humans affected by spinocerebellar ataxias. AB - BACKGROUND AND PURPOSE: Spinocerebellar ataxias (SCAs) are a family of chronic progressive neurodegenerative diseases, clinically and genetically heterogeneous, characterized by loss of balance and motor coordination due to degeneration of the cerebellum and its afferent and efferent connections. Unlike other motor disorders, the possible role of changes in the endocannabinoid system in the pathogenesis of SCAs has not been investigated. EXPERIMENTAL APPROACH: The status of cannabinoid receptor type 1 (CB1 ) and cannabinoid receptor type 2 (CB2 ) receptors in the post-mortem cerebellum of SCA patients and controls was investigated using immunohistochemical procedures. KEY RESULTS: Immunoreactivity for the CB1 receptor, and also for the CB2 receptor, was found in the granular layer, Purkinje cells, neurons of the dentate nucleus and areas of white matter in the cerebellum of SCA patients at levels notably higher than controls. Double labelling procedures demonstrated co-localization of CB1 and, in particular, CB2 receptors with calbindin, supporting the presence of these receptors in Purkinje neurons. Both receptors also co-localized with Iba-1 and glial fibrillary acidic protein in the granular layer and white matter areas, indicating that they are present in microglia and astrocytes respectively. CONCLUSIONS AND IMPLICATIONS: Our results demonstrate that CB1 and CB2 receptor levels are significantly altered in the cerebellum of SCA patients. Their identification in Purkinje neurons, which are the main cells affected in SCAs, as well as the changes they experienced, suggest that alterations in endocannabinoid receptors may be related to the pathogenesis of SCAs. Therefore, the endocannabinoid system could provide potential therapeutic targets for the treatment of SCAs and its progression. LINKED ARTICLES: This article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-6. PMID- 23808970 TI - Improving data and knowledge management to better integrate health care and research. PMID- 23808971 TI - Fluorescence lifetime imaging microscopy for the detection of intracellular pH with quantum dot nanosensors. AB - While the use of quantum dot (QD) nanoparticles for bioimaging and sensing has been improved and exploited during the last several years, most studies have used emission intensity-based techniques. Fluorescence lifetime imaging microscopy (FLIM) can also be employed for sensing purposes, overcoming many of the limitations of the aforementioned systems. Herein, we show that the photoluminescence (PL) lifetime of mercaptopropionic acid-capped QDs (MPA-QDs) collected from FLIM images can be used to determine intracellular pH. The PL average lifetime of MPA-QDs varied from 8.7 ns (pH < 5) to 15.4 ns (pH > 8) in media mimicking the intracellular environment. These long decay times of QD nanoparticles make them easily distinguishable from intrinsic cell autofluorescence, improving selectivity in sensing applications. We demonstrate, for the first time, the successful detection of changes in the intracellular pH of different cell types by examining the PL decay time of QDs. In particular, the combination of FLIM methodologies with QD nanoparticles exhibits greatly improved sensitivity compared with other fluorescent dyes for pH imaging. A detailed description of the advantages of the FLIM technique is presented. PMID- 23808972 TI - Isolation of Toscana virus from the cerebrospinal fluid of a man with meningitis in Marseille, France, 2010. AB - Toscana virus (TOSV; Bunyaviridae, Phlebovirus) is an emerging arthropod-borne virus transmitted by phlebotomine sandflies. TOSV is a frequent cause of central nervous system infection during the warm season in several countries bordering the Mediterranean Sea. Here, we report a case of TOSV aseptic meningitis diagnosed in 2012 in Marseille, France. The virus strain was recovered in cell culture from the cerebrospinal fluid. New-generation sequencing based on Ion Torrent technology was used to determine its complete genome sequence. Phylogenetic analysis based on the partial L segment revealed that this isolate belongs to the lineage B together with other French, Spanish, and Moroccan strains. Although several cases of TOSV meningitis are reported in the literature, few of them are diagnosed by RT-PCR combined with virus isolation and further sequence characterization. This case report supports that virus isolation should be attempted whenever possible because this remains the gold standard technique for diagnosis of arthropod-borne viral infections. PMID- 23808974 TI - West nile virus infection in the Mesopotamia region, Syria border of Turkey. AB - We described the serological prevalence of West Nile Virus (WNV) antibodies among the human population in a historical and strategic region of Turkey. A serologic survey was conducted based on suspected cases in April, 2009, in the Mesopotamia region of Turkey, in the villages that were located alongside the Zergan River. All the sera were tested by enzyme-linked immunosorbent assay ELISA (EuroimmuneTM), and the positive samples were tested by immunofluorescent assay (IFA; EuroimmuneTM). As confirmation, neutralizing antibodies against WNV were tested by microneutralization assay (MNTA). In total, 307 individuals were included. The MNTA test was found to be positive among 52 individuals out of 307 (17%). In multivariate analysis, age >50 [odds ratio (OR)=5.2, confidence interval (CI) 2.76-9.97, p<0.001) and being in an occupational risk group (OR=2.02, CI 1.02-4.04, p=0.044) were found to be the risk factors for WNV seropositivity with the MNTA test. The physicians in the region should be aware of the risk of WNV infection and should be alerted to detect the clinical cases. PMID- 23808973 TI - Lymphatic filariasis transmission risk map of India, based on a geo-environmental risk model. AB - The strategy adopted by a global program to interrupt transmission of lymphatic filariasis (LF) is mass drug administration (MDA) using chemotherapy. India also followed this strategy by introducing MDA in the historically known endemic areas. All other areas, which remained unsurveyed, were presumed to be nonendemic and left without any intervention. Therefore, identification of LF transmission risk areas in the entire country has become essential so that they can be targeted for intervention. A geo-environmental risk model (GERM) developed earlier was used to create a filariasis transmission risk map for India. In this model, a Standardized Filariasis Transmission Risk Index (SFTRI, based on geo environmental risk variables) was used as a predictor of transmission risk. The relationship between SFTRI and endemicity (historically known) of an area was quantified by logistic regression analysis. The quantified relationship was validated by assessing the filarial antigenemia status of children living in the unsurveyed areas through a ground truth study. A significant positive relationship was observed between SFTRI and the endemicity of an area. Overall, the model prediction of filarial endemic status of districts was found to be correct in 92.8% of the total observations. Thus, among the 190 districts hitherto unsurveyed, as many as 113 districts were predicted to be at risk, and the remaining at no risk. The GERM developed on geographic information system (GIS) platform is useful for LF spatial delimitation on a macrogeographic/regional scale. Furthermore, the risk map developed will be useful for the national LF elimination program by identifying areas at risk for intervention and for undertaking surveillance in no-risk areas. PMID- 23808975 TI - Early detection of Trichinella spiralis in muscle of infected mice by real-time fluorescence resonance energy transfer PCR. AB - Real-time fluorescence resonance energy transfer (FRET) PCR and melting curve analysis using newly developed fluorophore-labeled hybridization probes were applied for the detection of Trichinella spiralis DNA in muscle of mice following oral inoculation with 300 T. spiralis larvae. The developed assay could detect and differentiate T. spiralis, Trichinella papuae, and Trichinella pseudospiralis DNAs by the different melting temperatures (Tm). The assay had a detection limit of 5 * 10(2) positive control plasmid copies, which was equivalent to 1 ng of T. spiralis DNA spiked into 250 mg of muscle sample. No fluorescence signal was detected when the technique was applied to the DNA of 27 parasites other than Trichinella spp. The assay could detect T. spiralis DNA in muscle at 7, 14, and 21 days postinoculation. The range, mean +/- standard deviation, and median of the Tm values of all positive muscle tissue samples were 60.4-60.8, 60.6 +/- 0.2, and 60.5, respectively. This assay provides an effective tool for the specific, sensitive, and high-throughput detection of T. spiralis DNA in muscle during the early stage of infection. In addition, the technique can be useful for epidemiologic surveillance in naturally infected wildlife. PMID- 23808976 TI - First record of Stegomyia albopicta in Turkey determined by active ovitrap surveillance and DNA barcoding. AB - Despite its confirmed establishment in neighboring Greece and Bulgaria, the presence of the Oriental invasive species Stegomyia albopicta (Skuse) (=Aedes albopictus) has never been confirmed in Turkey. Active surveillance for this container-breeding species was carried out using oviposition traps at 15 discrete sites in the towns of Ipsala (n=8 sites), Kesan (n=5) (Edirne District), and Malkara (n=2) (Tekirdag District) in the Thrace region of northwestern Turkey, from May 23 through November 10, 2011. Eggs collected were reared to the fourth larval instar and adult stages where possible to facilitate integrated morphological and molecular species identification. DNA barcodes (658 bp of the mitochondrial cytochrome c oxidase I [COI] gene) were compared with all four potentially invasive Stegomyia species: St. aegypti, St. albopicta, St. cretina, and St. japonica. Sequences generated for samples collected in Thrace Region were herein confirmed as St. albopicta, the first record of this vector species in Turkey. Eggs of St. albopicta were detected in two discrete localities: (1) In the grounds of a restaurant in Kesan (in week 36), and (2) in the customs area of the Turkish-Greek border at Ipsala (in weeks 32 and 38). Multiple detection of St. albopicta eggs indicates the possible establishment of the species in northwestern Turkey. Finding this important disease vector has implications for public health and requires the implementation of active vector monitoring programs and targeted vector suppression strategies to limit the spread of this invasive vector species in Turkey. PMID- 23808977 TI - Demonstration of Usutu virus antibodies in horses, Croatia. AB - We report the first serological evidence of Usutu virus (USUV) infection in horses in Croatia. During 2011, 1380 horse serum samples from healthy animals were collected from six northern Croatian counties. All samples were first screened for West Nile virus (WNV) immunoglobulin G (IgG) antibodies using an enzyme-linked immunosorbent assay (ELISA). Sixty-nine WNV ELISA-reactive samples were further tested for WNV antibodies by a virus neutralization assay (VN assay) and plaque reduction neutralization test (PRNT), and USUV by a VN assay and tick borne encephalitis virus (TBEV) antibodies by PRNT. During the same period, 306 human serum samples from patients coming for routine testing with no symptoms of acute febrile disease were tested for USUV IgG using ELISA. Reactive samples were tested for both USUV and WNV using a VN assay. USUV-specific neutralizing antibodies were detected in two of 69 WNV ELISA-reactive horse serum samples. Seropositive animals were found in two different regions of Croatia. One additional sample showed specific WNV-neutralizing antibodies that cross neutralized USUV. Only one human sample (0.3%) was reactive to USUV antibodies in an ELISA test. In a confirmatory test, WNV-neutralizing antibodies were detected, indicating cross-reactive antibodies with USUV in ELISA. The exposure to USUV was documented in two WNV ELISA-reactive horses at distant locations. These results indicate the presence of USUV in northern Croatia. PMID- 23808978 TI - Suspect vector transmission of human cutaneous anthrax during an animal outbreak in Southern Italy. AB - During an outbreak of sheep anthrax in Basilicata, southern Italy, the owner of a flock located about 3 km away from the affected farm developed skin lesions attributable to cutaneous anthrax. The DNA extracted from the human scabs confirmed the diagnosis, and a 15-loci multiple locus variable number tandem repeat (VNTR) analysis (MLVA) following single-nucleotide repeat (SNR) analysis yielded the same genotype as that found in the dead sheep. The breeder, who had not had contact with infected or dead animals, reported having been stung by gadflies. PMID- 23808979 TI - Portuguese hosts for Ornithodoros erraticus ticks. AB - The hematophagous soft tick Ornithodoros erraticus feeds nocturnally on multiple warm-blooded vertebrate hosts. This tick is often found living buried in the soil of traditional pigpens. O. erraticus is an important infectious disease vector both for humans and animals. In the Iberian Peninsula, this tick serves as the vector of human tick-borne relapsing fever caused by the spirochete Borrelia hispanica. The natural ecosystems maintaining this spirochete are not well understood, with details of competent vertebrate reservoirs and tick-host interactions poorly understood. Investigation of arthropod blood meal composition provides evidence linking the vector to specific hosts, providing insights into possible disease reservoirs. Ticks collected from two pigpens located in southern Portugal were subjected to blood meal analysis. PCR amplification of vertebrate cytochrome b was used to disclose the original host from which 349 ticks had derived their previous blood meal. Host origins for blood meal analysis from 79 of 349 ticks revealed that 46.8% had previously fed from pigs, 35.4% human, 13.9% bovine, 5.1% sheep, 1.3% rodent, and 1.3% from birds. Three samples revealed mixed blood meals, namely, human-pig (1.3%), sheep-pig (1.3%), and bovine-pig (1.3%). The major role of pigs as hosts is consistent with fieldwork observations and underlines the importance of pigs for maintaining O. erraticus tick populations. Humans serve as accidental hosts, frequently confirmed by reports from both producers and veterinarians. Other livestock species and wildlife prevalent in the region appear only to have a minor role in maintaining this tick. The results demonstrate the importance of blood meal analysis to determine tick hosts providing a tool for investigation of sylvatic cycle for Borrelia hispanica. PMID- 23808980 TI - Estimated incidence of erythema migrans in five regions of France and ecological correlations with environmental characteristics. AB - BACKGROUND: While several studies conducted on Lyme borreliosis (LB) risk in the United States showed an association with environmental characteristics, most of European studies considered solely the effect of climate characteristics. OBJECTIVES: The aims of this study were to estimate incidence of erythema migrans (EM) in five regions of France and to analyze associations with several environmental characteristics of the place of residence. METHODS: LB surveillance networks of general practitioners (GPs) were set up for a period of 2 years in five regions of France. Participating GPs reported all patients with EM during the study period. Data were pooled according to a standardized EM case definition. For each area with a participating GP, age-standardized incidence rates and ratios were estimated. Associations with altitude, indicators of landscape composition, and indicators of landscape configuration were tested with multivariate Poisson regression. RESULTS: Standardized estimated incidence rates of EM per 10(5) person-years were 8.8 [95% confidence interval (CI)=7.9-9.7] in Aquitaine, 40.0 (95% CI 36.4-43.6) in Limousin, 76.0 (95% CI 72.9-79.1) in the three participating departements of Rhone-Alpes, 46.1 (95% CI 43.0-49.2) in Franche-Comte, and 87.7 (95% CI 84.6-90.8) in Alsace. In multivariate analysis, age-adjusted incidence rates increased with the altitude (p<0.0001) and decreased with forest patch density (p<0.0001). CONCLUSION: The marked variations in EM risk among the five regions were partly related to differences in landscape and environmental characteristics. The latter may point out potential risk areas and provide information for targeting preventive actions. PMID- 23808981 TI - Tick-borne encephalitis virus and louping-ill virus may co-circulate in Southern Norway. AB - The European subtype of tick-borne encephalitis virus (TBEV-Eu) and louping-ill virus (LIV) are two closely related tick-borne flaviviruses. However, whereas the first is the cause of one of Europe's most important zoonoses, the latter most often only causes disease in sheep and grouse. TBEV-Eu is typically found in the forests of central and northeastern Europe, and LIV typically is found in sheep pastures in the British Isles. In the 1980s, however, LIV was isolated from sheep with encephalomyelitis in Norway. In the 1990s, the first cases of human TBEV were also detected in this country, but while Louping-ill in sheep is very rare, the number of human TBEV cases is increasing. No larger investigations of TBEV and/or LIV seroprevalence and distribution in Norway have been published. However, before such studies are initiated, it is pertinent to know if LIV and TBEV are potentially co-circulating. In the current study, we examined if antibodies against LIV and TBEV were found in wild cervids in one location (Farsund) in southern and one location (Molde) in northwestern Norway using a commercially available enzyme-linked immunosorbent assay for detection of anti TBEV immunoglobulin G (IgG) and a hemagglutination inhibition test for anti-LIV IgG. Positive results were confirmed by serum neutralization tests. In Farsund, 22 of 54 cervids had antibodies against TBEV and 8 antibodies against LIV. In Molde, 1 of 64 cervids was confirmed positive for TBEV, whereas none were positive for LIV. This shows that TBEV and LIV may co-circulate in southern Norway and that virus(es) antigenetically very similar to TBEV may be found in northwestern Norway. The latter is intriguing, because the climatic conditions typical of TBEV locations should not be expected this far north. PMID- 23808983 TI - Treating acute venous thromboembolism--shift with care. PMID- 23808984 TI - A predictive model for HIV type 1 coreceptor selectivity. AB - Despite its sequence variability and structural flexibility, the V3 loop of the HIV-1 envelope glycoprotein gp120 is capable of recognizing cell-bound coreceptors CCR5 and CXCR4 and infecting cells. Viral selection of CCR5 is associated with the early stages of infection, and transition to selection of CXCR4 indicates disease progression. We have developed a predictive statistical model for coreceptor selectivity that uses the discrete property of net charge and the binary coreceptor preference markers of the N(6)X(7)[T/S](8)X(9) glycosylation motif and 11/24/25 positive amino acid rule. The model is based on analysis of 2,054 V3 loop sequences from patient data and allows us to infer the most likely state of the disease from physicochemical characteristics of the sequences. The performance of the model is comparable to established sequence based predictive methods, and may be used in combination with other methods as a supportive diagnostic for coreceptor selection. This model may be used for personalized medical decisions in administering coreceptor-specific therapies. PMID- 23808985 TI - A potent anti-CD70 antibody-drug conjugate combining a dimeric pyrrolobenzodiazepine drug with site-specific conjugation technology. AB - A highly cytotoxic DNA cross-linking pyrrolobenzodiazepine (PBD) dimer with a valine-alanine dipeptide linker was conjugated to the anti-CD70 h1F6 mAb either through endogenous interchain cysteines or, site-specifically, through engineered cysteines at position 239 of the heavy chains. The h1F6239C-PBD conjugation strategy proved to be superior to interchain cysteine conjugation, affording an antibody-drug conjugate (ADC) with high uniformity in drug-loading and low levels of aggregation. In vitro cytotoxicity experiments demonstrated that the h1F6239C PBD was potent and immunologically specific on CD70-positive renal cell carcinoma (RCC) and non-Hodgkin lymphoma (NHL) cell lines. The conjugate was resistant to drug loss in plasma and in circulation, and had a pharmacokinetic profile closely matching that of the parental h1F6239C antibody capped with N-ethylmaleimide (NEM). Evaluation in CD70-positive RCC and NHL mouse xenograft models showed pronounced antitumor activities at single or weekly doses as low as 0.1 mg/kg of ADC. The ADC was tolerated at 2.5 mg/kg. These results demonstrate that PBDs can be effectively used for antibody-targeted therapy. PMID- 23808987 TI - Asymptomatic bacteriuria: prevalence rates of causal microorganisms, etiology of infection in different patient populations, and recent advances in molecular detection. AB - Bacteriuria, or the presence of bacteria in urine, is associated with both asymptomatic and symptomatic urinary tract infection and underpins much of the dynamic of microbial colonization of the urinary tract. The prevalence of bacteriuria in dissimilar patient groups such as healthy adults, institutionalized elderly, pregnant women, and immune-compromised patients varies widely. In addition, assessing the importance of 'significant bacteriuria' in infected individuals represents a diagnostic challenge, partly due to various causal microorganisms, and requires careful consideration of the distinct etiologies of bacteriuria in different populations and circumstances. Recent molecular discoveries have revealed how some bacterial traits can enable organisms to grow in human urine, which, as a fitness adaptation, is likely to influence the progression of bacteriuria in some individuals. In this review, we comprehensively analyze currently available data on the prevalence of causal organisms with a focus on asymptomatic bacteriuria in dissimilar populations. We evaluate recent advances in the molecular detection of bacteriuria from a diagnostic viewpoint and briefly discuss the potential benefits and some of the challenges of these approaches. Overall, this review provides an update on the comparative prevalence and etiology of bacteriuria from both microbiological and clinical perspectives. PMID- 23808986 TI - Phagotrophic protist diversity in the groundwater of a karstified aquifer - morphological and molecular analysis. AB - To clarify the structure of microbial food webs in groundwater, knowledge about the protist diversity and feeding strategies is essential. We applied cultivation dependent approaches and molecular methods for further understanding of protist diversity in groundwater. Groundwater was sampled from a karstified aquifer located in the Thuringian Basin (Thuringia, Germany). Cultivable protist abundance estimated up to 8,000 cells/L. Eleven flagellates, 10 naked amoebae, and one ciliate morpho-species were detected in groundwater enrichment cultures. Most of the flagellates morpho-species, typically < 10 MUm, were sessile or free swimming suspension feeders, e.g., Spumella spp., Monosiga spp., and mobile, surface-associated forms that grasp biofilms, e.g., Bodo spp. Naked amoebae, typically < 35 MUm, that grasp biofilms were represented by, e.g., Vahlkampfia spp., Vannella spp., and Hartmanella spp. The largest fraction of the 18S rRNA gene sequences was affiliated with Spumella-like Stramenopiles. Besides, also sequences affiliated with fungi and metazoan grazers were detected in clone libraries of the groundwater. We hypothesize that small sized protist species take refuge in the structured surface of the fractures and fissures of the karstified aquifer and mainly feed on biofilm-associated or suspended bacteria. PMID- 23808988 TI - Accuracy of prenatal culture in predicting intrapartum group B streptococcus colonization status. AB - OBJECTIVE: To evaluate the positive predictive value (PPV) of group B Streptococcus (GBS) cultures at 35-37 weeks of gestation relative to GBS colonization status at delivery. METHODS: Rectovaginal swabs from 221 women at labor in four Lisbon hospitals were collected for GBS screening according to the CDC guidelines. RESULTS: The PPV was 24.4%. IAP was administered to 100% of prenatally GBS positive women. There was no case of early onset GBS disease (EOD). CONCLUSIONS: Poor accuracy of prenatal cultures in identifying true candidates for IAP highlights the need for Portuguese clinical and laboratory guidelines to prevent EOD and antibiotic overtreatment of pregnant women. PMID- 23808989 TI - Abdominal fat interacts with PNPLA3 I148M, but not with the APOC3 variant in the pathogenesis of liver steatosis in chronic hepatitis C. AB - The patatin-like phospholipase domain-containing 3 gene (PNPLA3) and the apolipoprotein C3 gene (APOC3) have been studied in relation to liver steatosis and liver disease outcome. The aim of this study was to evaluate the influence of PNPLA3 p.I148M and APOC3 rs2854116 and rs2854117 polymorphisms on the clinical and histological presentation of chronic hepatitis C in an Italian population and their relationship with viral and anthropometric parameters. Patients with hepatitis C (n = 166) entered the study receiving a clinical, histological, virological and biochemical evaluation. APOC3 (rs2854116 and rs2854117) and PNPLA3 (p.I148M) variants were genotyped. PNPLA3 polymorphisms were associated with liver steatosis, which was significantly higher in patients with p.148I/M (P = 0.034) and p.148M/M (P = 0.004) variants than those homozygous for the PNPLA3 wild type. Excluding patients with HCV genotype 3, the association with liver steatosis and PNPLA3 variants was more marked (p.148I/I genotype vs p.148I/M, P = 0.02, and vs p.148M/M, P = 0.005). The APOC3 polymorphism was not associated with any of the evaluated parameters. Among the interacting factors, BMI and waist circumference correlated with liver steatosis (P = 0.008 and 0.004, respectively). Relationship between waist circumference and liver steatosis was analysed for the different PNPLA3 genotypes. Homozygous 148M patients showed a stronger correlation between waist circumference and steatosis than those carrying the other genotypes (P = 0.0047). In our hepatitis C-infected population, the PNPLA3 polymorphism influenced the development of liver steatosis, but not fibrosis progression. APOC3 polymorphisms had no effect on the development of steatosis and no influence on the PNPLA3 polymorphism. The amount of abdominal fat can increase the association of PNPLA3 p.I148M with liver steatosis. PMID- 23808990 TI - Long-term clearance of hepatitis C virus following interferon alpha-2b or peginterferon alpha-2b, alone or in combination with ribavirin. AB - Sustained virologic response (SVR) is the standard measure for evaluating response to therapy in patients with chronic hepatitis C (CHC). The aim of this study was to prospectively assess the durability of SVR in the pivotal studies of peginterferon (PEG-IFN) alpha-2b or IFN alpha-2b. We conducted two phase 3b long term follow-up studies of patients previously treated for CHC in eight prospective randomized studies of IFN alpha-2b and/or PEG-IFN alpha-2b. Patients who achieved SVR [undetectable hepatitis C virus (HCV) RNA 24 weeks after completion of treatment] were eligible for inclusion in these follow-up studies. In total, 636 patients with SVR following treatment with IFN alpha-2b and 366 with SVR following treatment with PEG-IFN alpha-2b were enrolled. Definite relapse (quantifiable serum HCV RNA with no subsequent undetectable HCV RNA) was reported in six patients treated with IFN alpha-2b and three patients treated with PEG-IFN alpha-2b. Based on these relapses, the point estimate for the likelihood of maintaining response after 5 years was 99.2% [95% confidence interval (CI), 98.1-99.7%] for IFN alpha-2b and 99.4% (95% CI, 97.7-99.9%) for PEG-IFN alpha-2b. Successful treatment of hepatitis C with PEG-IFN alpha-2b or IFN alpha-2b leads to clinical cure of hepatitis C in the vast majority of cases. PMID- 23808991 TI - Serum microRNA-122 kinetics in patients with chronic hepatitis C virus infection during antiviral therapy. AB - The levels of the liver-specific microRNA-122 (miR-122) circulating extracellularly in the blood have been shown to be increased upon liver damage. However, it is unknown if the levels of serum miR-122 are altered during antiviral therapy and reflect the therapeutic success. Here, we investigated miR 122 serum levels in patients with chronic hepatitis C virus (HCV) genotype 1 infection during antiviral therapy with pegylated interferon and ribavirin. Therefore, sera from 60 patients with chronic HCV infection genotype 1 showing sustained virological response (SVR), non-response or relapse to therapy obtained at baseline, 4, 12, 24 weeks, end of treatment and follow-up were analysed retrospectively for miR-122 content by quantitative real-time reverse transcription PCR. The time courses of miR-122 were correlated with HCV RNA as well as standard liver parameters. We found that while there was no relation between serum miR-122 and HCV RNA levels at baseline, the decline in HCV RNA upon beginning of the therapy closely correlated with the reduction of serum miR-122 in the three different patient groups. Moreover, the serum miR-122 level correlated well with alanine aminotransaminase, a marker of ongoing liver damage. At follow-up serum miR-122 levels remained low in SVR, but increased to baseline levels in patients not responding or showing relapse to therapy. In contrast, the serum concentration of the ubiquitously expressed miR-16 did not change during therapy. We conclude that the serum level of miR-122 well reflects the success of interferon/ribavirin therapy in patients with chronic HCV infection. PMID- 23808982 TI - Oral apixaban for the treatment of acute venous thromboembolism. AB - BACKGROUND: Apixaban, an oral factor Xa inhibitor administered in fixed doses, may simplify the treatment of venous thromboembolism. METHODS: In this randomized, double-blind study, we compared apixaban (at a dose of 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months) with conventional therapy (subcutaneous enoxaparin, followed by warfarin) in 5395 patients with acute venous thromboembolism. The primary efficacy outcome was recurrent symptomatic venous thromboembolism or death related to venous thromboembolism. The principal safety outcomes were major bleeding alone and major bleeding plus clinically relevant nonmajor bleeding. RESULTS: The primary efficacy outcome occurred in 59 of 2609 patients (2.3%) in the apixaban group, as compared with 71 of 2635 (2.7%) in the conventional-therapy group (relative risk, 0.84; 95% confidence interval [CI], 0.60 to 1.18; difference in risk [apixaban minus conventional therapy], -0.4 percentage points; 95% CI, -1.3 to 0.4). Apixaban was noninferior to conventional therapy (P<0.001) for predefined upper limits of the 95% confidence intervals for both relative risk (<1.80) and difference in risk (<3.5 percentage points). Major bleeding occurred in 0.6% of patients who received apixaban and in 1.8% of those who received conventional therapy (relative risk, 0.31; 95% CI, 0.17 to 0.55; P<0.001 for superiority). The composite outcome of major bleeding and clinically relevant nonmajor bleeding occurred in 4.3% of the patients in the apixaban group, as compared with 9.7% of those in the conventional-therapy group (relative risk, 0.44; 95% CI, 0.36 to 0.55; P<0.001). Rates of other adverse events were similar in the two groups. CONCLUSIONS: A fixed-dose regimen of apixaban alone was noninferior to conventional therapy for the treatment of acute venous thromboembolism and was associated with significantly less bleeding (Funded by Pfizer and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00643201). PMID- 23808992 TI - Adherence to PEG/ribavirin treatment for chronic hepatitis C: prevalence, patterns, and predictors of missed doses and nonpersistence. AB - Adherence to treatment for hepatitis C virus (HCV) maximizes treatment efficacy. Missed doses and failing to persist on treatment are two patient-level processes that are rarely defined or analysed separately from other factors affecting treatment adherence. We evaluated the prevalence and patterns of missed doses and nonpersistence, and identified patient characteristics associated with these outcomes. Missed doses of ribavirin (RBV) and peginterferon (PEG), measured prospectively in Virahep-C using electronic monitoring technology, were analysed using generalized estimating equations. Cox proportional hazards models analysed time to nonpersistence from baseline to week 24 (N = 401) and from week 24 to 48 in Responders (N = 242). Average proportion of PEG- and RBV-missed doses increased over time from 5% to 15% and 7% to 27%, respectively. Patients who were younger, African-American, unemployed, or unmarried were at greater risk of missing PEG from week 0 to 24; higher baseline depression predicted missing PEG from weeks 24 to 48. Patients who were younger or African-American were more likely to miss daily RBV from weeks 0 to 24; and those without private insurance or employment were more likely to miss RBV from weeks 24 to 48. Fifty-two patients failed to persist on treatment for patient-driven deviations. Predictors of nonpersistence from weeks 0 to 24 included younger age, lower education, public or no insurance, or worse baseline headaches. In conclusion, electronic monitoring and the prospective Virahep-C design afforded a unique opportunity to evaluate missing doses and nonpersistence separately, and identify patients at risk of nonadherence. These processes will be important to investigate as the dosing schedules of antiviral regimens become increasingly complex. PMID- 23808993 TI - Knowledge about infection is the only predictor of treatment in patients with chronic hepatitis C. AB - HCV is the leading cause of cirrhosis and liver cancer in the U.S. The Center for Disease Control (CDC) has recently recommended 'Birth Cohort Screening' of the U.S. Adult population to reduce the future burden of undiagnosed HCV infections in the U.S. Our aim was to assess independent predictors of receiving treatment in a cohort of HCV-infected patients. The Hepatitis C follow-up questionnaires of the National Health and Nutrition Examination Surveys (NHANES) conducted from 2001 to 2010 were used. The NHANES participants who tested positive for HCV RNA were followed by CDC 6 months after initial testing with questions related to their awareness of their infection and history or intention to receive treatment. A total of 500 NHANES participants tested positive for HCV RNA and were targeted for follow-up. Of these, only 203 had completed the follow-up questionnaire (response rate of 40.6%). Of these, only 101 (50%) knew about their HCV positivity before NHANES, and from them, only 34 (17%) had received treatment. In multivariate analysis, prior knowledge about their HCV infection in HCV-positive individuals was independently associated with receiving routine care from a doctor or HMO, with higher income, female gender, being in poor or fair health and not consuming excessive amounts of alcohol. On the other hand, the knowledge about HCV infection was the only independent predictor of receiving anti-HCV treatment (odds ratio 6.14). Knowledge about having HCV infection is the only independent predictor of receiving treatment. Therefore, birth cohort screening of the U.S. General population could lead to wider identification of HCV and potentially better management of the future burden of HCV and its complications. PMID- 23808995 TI - Complementary laboratory indices for predicting the disease status of patients with hepatitis B virus infection. AB - To identify complementary laboratory indices for determining the disease status of patients with hepatitis B virus. Subjects were divided into six groups: hepatitis B virus carrier, mild chronic hepatitis B, moderate chronic hepatitis B, severe chronic hepatitis B, fulminant hepatitis B and healthy controls. Serum alanine aminotransferase, total bilirubin and direct bilirubin were measured by an automatic analyser. The levels of T-cell immunoglobulin domain and mucin domain-containing molecule-3, macrophage inflammatory protein 2, neutrophil gelatinase-associated lipocalin and inducible nitric oxide synthase were measured by ELISA. T-cell immunoglobulin domain, mucin-domain-containing molecule-3, macrophage inflammatory protein 2 and inducible nitric oxide synthase levels were significantly higher in patients with severe chronic hepatitis B compared with those in patients with mild and moderate chronic hepatitis B or fulminant hepatitis B (P < 0.05). When normal or abnormal alanine aminotransferase was present, significant differences between macrophage inflammatory protein 2 and T cell immunoglobulin domain and mucin-domain-containing molecule-3 levels between patients with mild, moderate, severe chronic hepatitis B or fulminant hepatitis B were observed (P < 0.05). Our results suggest that T-cell immunoglobulin domain and mucin-domain-containing molecule-3 and macrophage inflammatory protein 2 could serve as alanine aminotransferase, direct bilirubin or total bilirubin complementary indices for determining the status of patients with hepatitis B. PMID- 23808994 TI - Ex vivo analysis of resident hepatic pro-inflammatory CD1d-reactive T cells and hepatocyte surface CD1d expression in hepatitis C. AB - Hepatic CD1d-restricted and natural killer T-cell populations are heterogeneous. Classical 'type 1' alpha-galactosylceramide-reactive CD1d-restricted T cells express 'invariant' TCRalpha ('iNKT'). iNKT dominating rodent liver are implicated in inflammation, including in hepatitis models. Low levels of iNKT are detected in human liver, decreased in subjects with chronic hepatitis C (CHC). However, high levels of human hepatic CD161(+/-) CD56(+/-) noninvariant pro inflammatory CD1d-restricted 'type 2' T cells have been identified in vitro. Unlike rodents, healthy human hepatocytes only express trace and intracellular CD1d. Total hepatic CD1d appears to be increased in CHC and primary biliary cirrhosis. Direct ex vivo analysis of human intrahepatic lymphocytes (IHL), including matched ex vivo versus in vitro expanded IHL, demonstrated detectable noninvariant CD1d reactivity in substantial proportions of HCV-positive livers and significant fractions of HCV-negative livers. However, alpha galactosylceramide-reactive iNKT were detected only relatively rarely. Liver CD1d restricted IHL produced IFNgamma, variable levels of IL-10 and modest levels of Th2 cytokines IL-4 and IL-13 ex vivo. In a novel FACS assay, a major fraction (10 20%) of hepatic T cells rapidly produced IFNgamma and up-regulated activation marker CD69 in response to CD1d. As previously only shown with murine iNKT, noninvariant human CD1d-specific responses were also augmented by IL-12. Interestingly, CD1d was found selectively expressed on the surface of hepatocytes in CHC, but not those CHC subjects with history of alcohol usage or resolved CHC. In contrast to hepatic iNKT, noninvariant IFNgamma-producing type 2 CD1d-reactive NKT cells are commonly detected in CHC, together with cognate ligand CD1d, implicating them in CHC liver damage. PMID- 23808996 TI - Demographic and serological characteristics of Asian Americans with hepatitis B infection diagnosed at community screenings. AB - There is limited information regarding follow-up and hepatitis B serological status of Asian Americans diagnosed with chronic hepatitis B (CHB) through community screening. The aims of this study were to evaluate the prevalence and characterize CHB among Asians living in Los Angeles, assess follow-up of individuals with CHB diagnosed at screening and compare with patients with CHB followed by community gastroenterologists. Between October 2007 and May 2010, 7387 Asians were tested for HBV. HBsAg positive individuals (CHB) underwent additional testing for ALT, HBeAg/anti-HBe and HBV DNA. Patients with CHB were contacted 6 months later to determine whether they received follow-up care. We compared serological patterns of these individuals with CHB to patients with CHB who were seen for the first time (treatment naive) by community gastroenterologists during the study period. Prevalence of CHB was 5.2%. About 99% patients with CHB were foreign-born, and only 27% could read/write English. 297 (77%) patients with CHB could be reached 6 months after diagnosis; 43% did not receive follow-up care, mostly because of lack of medical insurance. Patients with CHB followed by gastroenterologists were more likely to have insurance (69% vs 26%, P < 0.0001). 90% patients with CHB at screening were HBeAg negative/anti HBe positive with 62% having inactive disease compared to only 30% of patients seen by gastroenterologists (P < 0.0001). Among CHB participants, 13% met criteria for treatment compared to 51% of patients with CHB (P < 0.0001). Only a small number of CHB screening participants require antiviral therapy. Lack of medical insurance is the main reason for most patients with CHB not seeking follow-up care after screening. PMID- 23808997 TI - Increased regulatory T cells and impaired functions of circulating CD8 T lymphocytes is associated with viral persistence in Hepatitis B virus-positive newborns. AB - Hepatitis B Virus (HBV) infection in infancy or early childhood leads to high rate of persistent infection (25-90%). The immunological basis of high rate of viral persistence in vertically acquired HBV infections is not completely understood. CD8 T cells play a pivotal role in clearing the Hepatitis B virus infection in adults. Herein, we sought to delineate the role of T cells in viral persistence in HBsAg+ve newborns. At birth peripheral and cord blood of HBsAg+ve (N = 12), HBsAg-ve (N = 10) and healthy newborns (HC: N = 15) were evaluated for T-cell frequency and functionality by flow cytometry. No significant differences were observed in the frequency of CD8 and CD4 T cells in all the three groups. However, significantly higher frequency of FoxP3 expressing regulatory T cells were observed in HBsAg+ve (63.79%) compared with HBsAg-ve (28.12%) and HC (11.06%) (P < 0.05). Moreover, HBsAg+ve newborns showed functional defect in CD8 T cells by decreased IFN-gamma production and lower CD107A expression (cytotoxic capacity) compared with HBsAg-ve and HC, which positively correlated with decreased TCRzeta-chain expression CD8 T cells (r(2) > 0.93, P < 0.05). Despite equal frequency of CD8 T cells in all the three groups, CD8 T cells in HBsAg+ve newborns are dysfunctional. An expansion of regulatory T cells and impaired TCR signalling may represent the immune tolerant state of the adaptive immune system in response to chronic HBV infection. PMID- 23808998 TI - Evidence that pulmonary vascular pathology explains the decline in lung function associated with interferon alpha based therapies for chronic hepatitis C virus. PMID- 23808999 TI - Effect of berberine administration on metabolic syndrome, insulin sensitivity, and insulin secretion. AB - BACKGROUND: The aim of this study was to evaluate the effect of berberine administration on metabolic syndrome, insulin sensitivity, and insulin secretion. METHODS: A randomized, double-blind, placebo-controlled clinical trial was carried out in 24 patients with a diagnosis of metabolic syndrome. Glucose and insulin levels after a dextrose load were measured. Triglycerides and high density lipoprotein cholesterol concentrations at baseline were also measured. Twelve patients received berberine hydrochloride (500 mg) three times daily before meals for 3 months. The remaining 12 patients received placebo. Area under the curve (AUC) of glucose and insulin, total insulin secretion, first-phase of insulin secretion, and insulin sensitivity were assessed. RESULTS: After berberine administration, patients had a remission of 36% (P=0.037) in the presence of metabolic syndrome and a significant decrease in waist circumference in females (106+/-4 vs. 103+/-3 cm, P<0.05), systolic blood pressure (SBP) (123+/ 7 vs. 115+/-9 mmHg, P<0.01), triglycerides (2.4+/-0.7 vs. 1.4+/-0.5 mmol/L, P<0.01), area under the curve (AUC) of glucose (1182.1+/-253.6 vs. 1069.5+/-172.4 mmol/l, P<0.05), AUC of insulin (92,056+/-72,148 vs. 67,407+/-46,441 pmol/L, P<0.01), and insulinogenic index (0.78+/-0.69 vs. 0.62+/-0.46, P<0.05), as well as an increase in the Matsuda index (2.1+/-1.0 vs. 3.1+/-1.6, P<0.01). CONCLUSIONS: Administration of berberine leads to remission of metabolic syndrome and decreases in waist circumference, SBP, triglycerides, and total insulin secretion, with an increase in insulin sensitivity. PMID- 23809000 TI - Cardiovascular fitness, activity, and metabolic syndrome among college men and women. AB - BACKGROUND: The purpose of this cross-sectional study was to examine the impact of below-average cardiovascular fitness and inactivity on the metabolic syndrome among an understudied population-undergraduate men and women, ages 18-24 years. METHODS: Between January, 2010, and May, 2012, we assessed anthropometric, biochemical, and clinical measures in a convenience sample of students (n=1610) enrolled in an introductory nutrition course at a public university. We quantified the prevalence of metabolic syndrome criteria, estimated cardiovascular fitness via a 1-mile Rockport Walk Test, and evaluated daily activity via pedometer. Subjects were classified as below-average, average, and above-average fitness based upon the Rockport Walk Test; activity levels were classified as low active, somewhat active, active, or highly active according to average steps per day. RESULTS: Those with below-average fitness (10%) were at increased risk for being overfat, having abdominal obesity, and having the metabolic syndrome as compared to those with average or above-average fitness (odds ratio: 12.4, 10.0, and 4.7, respectively; all P<0.01). Twenty percent of subjects were low active (<7500 steps/day) and had a greater number of metabolic syndrome criteria as compared to very active subjects (>12,500 steps/day) (0.94+/ 0.05 vs. 0.73+/-0.05, P=0.01). CONCLUSIONS: Young, college-age adults with below average cardiovascular fitness and/or low activity levels are at increased risk for obesity and the metabolic syndrome. Future studies should examine how promoting lifestyle habits that increase physical activity and reduce sedentary behaviors during the young adult years can improve metabolic health. PMID- 23809001 TI - Reduced blood nrf-2 mRNA in local overweight boys at risk of metabolic complications: a study in San Luis City, San Luis, Argentina. AB - BACKGROUND: Childhood overweight (OW) is a matter of public health concern because of its long-term impact on adulthood health. NF-E2-related factor 2 (Nrf 2) regulates the antioxidant/lipogenic response to a sustained positive energy balance that prevails during weight gain. Here we aimed at studying a possible link between OW and Nrf-2-dependent antioxidant/lipogenic response in a local population of boys at risk of metabolic complications. METHODS: We measured clinical and biochemical parameters related to lipid metabolism, oxidative stress, and metabolic syndrome in a population of OW boys [body mass index (BMI) percentile >=85(th) and <95(th), n=22] and normal weight boys (NW; BMI percentile<85(th), n=27) from San Luis City, San Luis, Argentina. RESULTS: Compared to NW, OW boys had lower insulin sensitivity, an altered plasma lipid profile, and increased markers of oxidative stress and inflammatory fatty acids. OW boys also had a higher atherogenic index and peripheral insulin resistance than NW boys. We also found that glutathione peroxidase activity and the reduced glutathione to oxidized glutathione ratio were lower in OW boys than NW boys, suggesting that OW boys may have an altered antioxidant response to oxidative stress. Finally, Nrf-2 expression negatively correlated with metabolic syndrome parameters in OW boys. CONCLUSIONS: Our data suggest that OW boys have a reduced antioxidant and lipogenic response to a positive energy balance, resulting in oxidative stress, insulin resistance, and risk of developing metabolic complications. Our data also provide a rationale for nutritional interventions aimed at restoring Nrf-2 expression to reduce the risk of metabolic complications in OW boys. PMID- 23809002 TI - A generalized electrochemical aggregative growth mechanism. AB - The early stages of nanocrystal nucleation and growth are still an active field of research and remain unrevealed. In this work, by the combination of aberration corrected transmission electron microscopy (TEM) and electrochemical characterization of the electrodeposition of different metals, we provide a complete reformulation of the Volmer-Weber 3D island growth mechanism, which has always been accepted to explain the early stages of metal electrodeposition and thin-film growth on low-energy substrates. We have developed a Generalized Electrochemical Aggregative Growth Mechanism which mimics the atomistic processes during the early stages of thin-film growth, by incorporating nanoclusters as building blocks. We discuss the influence of new processes such as nanocluster self-limiting growth, surface diffusion, aggregation, and coalescence on the growth mechanism and morphology of the resulting nanostructures. Self-limiting growth mechanisms hinder nanocluster growth and favor coalescence driven growth. The size of the primary nanoclusters is independent of the applied potential and deposition time. The balance between nucleation, nanocluster surface diffusion, and coalescence depends on the material and the overpotential, and influences strongly the morphology of the deposits. A small extent of coalescence leads to ultraporous dendritic structures, large surface coverage, and small particle size. Contrarily, full recrystallization leads to larger hemispherical monocrystalline islands and smaller particle density. The mechanism we propose represents a scientific breakthrough from the fundamental point of view and indicates that achieving the right balance between nucleation, self-limiting growth, cluster surface diffusion, and coalescence is essential and opens new, exciting possibilities to build up enhanced supported nanostructures using nanoclusters as building blocks. PMID- 23809003 TI - Executive function in children and adolescents with unilateral cerebral palsy. AB - AIM: The aim of this study was to compare executive function in children with left- and right-sided unilateral cerebral palsy (CP) and typically developing children. METHOD: There was a cross-sectional cohort of 46 children with unilateral CP (24 right-side, 22 left-side; 25 males, 21 females; mean age 11y 1mo, SD 2y 5mo) and 20 typically developing children (nine males, 11 females; mean age 10y 10mo, SD 2y 4mo). Four cognitive domains of executive function were assessed: attentional control, cognitive flexibility, goal setting, and information processing. Subtests from the Delis-Kaplan Executive Function System, the Test of Everyday Attention for Children, the Rey-Osterrieth Complex figure, and the Wechsler Intelligence Scale for Children - Fourth Edition were utilized. Between-group differences (right unilateral CP, left unilateral CP, and typically developing children) were examined using analyses of covariance. RESULTS: Children with CP performed significantly more poorly than typically developing children on all executive function measures (aggregate executive function: F(1,63)=31.16; p<0.001; eta(2) =0.33). There were no significant differences between children with left and right unilateral CP, except in the case of inhibition/switching total errors, with children with left unilateral CP making fewer errors than children with right unilateral CP (F(1,39)=4.14; p=0.049; eta(2) =0.1). INTERPRETATION: Children and adolescents with unilateral CP experience difficulties across multiple executive function domains compared with typically developing children, irrespective of the side of hemiplegia. This finding supports an early vulnerability model of early brain injury and has implications for intervention for children with CP. PMID- 23809004 TI - Evaluation of a post-processing approach for multiscale analysis of biphasic mechanics of chondrocytes. AB - Understanding the mechanical behaviour of chondrocytes as a result of cartilage tissue mechanics has significant implications for both evaluation of mechanobiological function and to elaborate on damage mechanisms. A common procedure for prediction of chondrocyte mechanics (and of cell mechanics in general) relies on a computational post-processing approach where tissue-level deformations drive cell-level models. Potential loss of information in this numerical coupling approach may cause erroneous cellular-scale results, particularly during multiphysics analysis of cartilage. The goal of this study was to evaluate the capacity of first- and second-order data passing to predict chondrocyte mechanics by analysing cartilage deformations obtained for varying complexity of loading scenarios. A tissue-scale model with a sub-region incorporating representation of chondron size and distribution served as control. The post-processing approach first required solution of a homogeneous tissue level model, results of which were used to drive a separate cell-level model (same characteristics as the sub-region of control model). The first-order data passing appeared to be adequate for simplified loading of the cartilage and for a subset of cell deformation metrics, for example, change in aspect ratio. The second-order data passing scheme was more accurate, particularly when asymmetric permeability of the tissue boundaries was considered. Yet, the method exhibited limitations for predictions of instantaneous metrics related to the fluid phase, for example, mass exchange rate. Nonetheless, employing higher order data exchange schemes may be necessary to understand the biphasic mechanics of cells under lifelike tissue loading states for the whole time history of the simulation. PMID- 23809005 TI - Skin closure after laparotomy with staples or sutures: a study of the mature scar. AB - BACKGROUND: Surgeons are divided in their method of choice for skin closure following laparotomy. We suggest that the most important determinant should be the resulting scar. This study aims to compare both patients' and independent observers' assessment of mature laparotomy scars that had been closed with either subcuticular sutures or external staples. METHODS: Consecutive patients were enrolled at least 1 year following colorectal surgery. Scars were assessed with the validated Patient and Observer Scar Assessment Scoring (POSAS) tool. Photographs were assessed by a blinded independent panel. RESULTS: Overall, 232 patients were enrolled (90 suture, 143 staples). The two groups were well matched by factors affecting wound healing. Patients' overall opinion of their scar was significantly better for the Suture group than the Staples group (P = 0.028) despite there being no difference in their self-assessment of the components of their scar score (pain, itch, colour, stiffness, thickness, irregularity). The panel recorded similar overall scores for the Suture and Staples groups (P = 0.059). There was a significant lower (better) score recorded for the scar area component for the Suture group than the Staples group (P = 0.008) but no differences for the other components (vascularity, pigmentation or thickness). DISCUSSION: This study has shown that independent of skin closure method, patients who have undergone major abdominal surgery have a positive opinion of their mature scars. The patients' overall impression of the wound favours a sutured closure due to a smaller scar area (no staple marks). In all other respects, skin closure with staples would appear acceptable. PMID- 23809006 TI - Clinical implications for breath-powered powder sumatriptan intranasal treatment. AB - The acute treatment of migraine requires matching patient need to drug and formulation. In particular, nausea and vomiting, quick time to peak intensity, and the common gastroparesis of migraineurs, all call for a variety of non-oral formulations for treatment of attacks. A novel breath-powered powder sumatriptan intranasal treatment offers an improvement, at least in pharmacokinetics, over conventional liquid nasal sumatriptan spray. The device for delivery in this breath-powered nasal sumatriptan uses natural nose anatomy to close the soft palate and propel the sumatriptan high up in the nasal cavity on one side with bidirectional airflow coming out the other side. This approach has the potential to reduce adverse events and improve efficacy. Phase 3 data on this system are in press at the time of this writing and results appear promising. The clinical role for a fast acting non-oral nasal formulation will be in those for whom tablets are bound to fail, that is, in the setting of nausea and vomiting or when the time to central sensitization, allodynia, and disabling migraine is too short for the patient to respond to a tablet. This review provides a clinical perspective on the breath-powered powder sumatriptan intranasal treatment. PMID- 23809007 TI - Astragaloside IV protects heart from ischemia and reperfusion injury via energy regulation mechanisms. AB - OBJECTIVE: This study was designed to investigate the protective potential of AS IV against ischemia and I/R-induced myocardial damage, with focusing on possible involvement of energy metabolism modulation in its action and the time phase in which it takes effect. METHODS: SD rats were subjected to 30 minutes LADCA occlusion, followed by reperfusion. MBF, myocardial infarct size, and cardiac function were evaluated. Myocardial structure and myocardial apoptosis were assessed by double immunofluorescence staining of F-actin and TUNEL. Content of ATP, ADP, and AMP in myocardium, cTnI level, expression of ATP5D, P-MLC2, and apoptosis-related molecules were determined. RESULTS: Pretreatment with AS-IV suppressed MBF decrease, myocardial cell apoptosis, and myocardial infarction induced by I/R. Moreover, ischemia and I/R both caused cardiac malfunction, decrease in the ratio of ATP/ADP and ATP/AMP, accompanying with reduction of ATP 5D protein and mRNA, and increase in P-MLC2 and serum cTnI, all of which were significantly alleviated by pretreatment with AS-IV, even early in ischemia phase for the insults that were implicated in energy metabolism. CONCLUSIONS: AS-IV prevents I/R-induced cardiac malfunction, maintains the integrity of myocardial structure through regulating energy metabolism. The beneficial effect of AS-IV on energy metabolism initiates during the phase of ischemia. PMID- 23809008 TI - Neonatal electrophysiological predictors of cognitive and language development. PMID- 23809009 TI - Indirect activation of the SV23 and SV24 splice variants of human constitutive androstane receptor: analysis with 3-hydroxyflavone and its analogues. AB - BACKGROUND AND PURPOSE: Naturally occurring splice variants of human CAR (hCAR), including hCAR-SV23 (insertion of amino acids SPTV) and hCAR-SV24 (APYLT), have been shown to be expressed in liver. However, little is known regarding how hCAR SV23 and hCAR-SV24 are activated. Therefore, we investigated the mode of activation of these hCAR splice variants. EXPERIMENTAL APPROACH: Cell-based reporter gene assays, including ligand-binding domain transactivation assays and coactivator recruitment assays, were conducted on cultured HepG2 cells transfected with various constructs and treated with 3-hydroxyflavone or a hydroxylated (galangin, datiscetin, kaempferol, morin, quercetin or myricetin) or methylated (isorhamnetin, tamarixetin, or syringetin) analogue. KEY RESULTS: Among the flavonols investigated, only 3-hydroxyflavone increased hCAR-SV23 and hCAR-SV24 activities. 3-Hydroxyflavone did not transactivate the ligand-binding domain of these isoforms or recruit steroid receptor coactivators (SRC-1, SRC-2, or SRC-3). By comparison, 3-hydroxyflavone, galangin, datiscetin, kaempferol, quercetin, isorhamnetin and tamarixetin activated hCAR-WT, whereas none of the flavonols activated hCAR-SV25 (both SPTV and APYLT insertions). The flavonols 3 Hydroxyflavone, galangin, quercetin and tamarixetin transactivated the ligand binding domain of hCAR-WT, but only 3-hydroxyflavone recruited SRC-1, SRC-2 and SRC-3 to the receptor. CONCLUSION AND IMPLICATIONS: hCAR-SV23 and hCAR-SV24 can be activated by a mechanism that does not involve the ligand-binding domain of the receptor or recruitment of SRC-1, SRC-2, or SRC-3. 3-Hydroxyflavone and its structural analogues activated hCAR in an isoform-selective and chemical-specific manner. Overall, our study provides insight into a novel mode of ligand activation of hCAR-SV23 and hCAR-SV24. PMID- 23809010 TI - Near full-length genome sequence of a novel HIV type 1 second-generation recombinant form (CRF01_AE/CRF07_BC) identified among men who have sex with men in Jilin, China. AB - We report here a novel HIV-1 second-generation recombinant form (CRF01_AE/CRF07_BC) composed of CRF01_AE and CRF07_BC, identified among men who have sex with men (MSM) in Jilin, with four breakpoints observed in the pol, vif, and vpr genes. The CRF01_AE regions of the recombinant were clustered with the CRF01_AE lineage, which is mainly circulating among MSM in northern China, with the support of 100% bootstrap value, indicating that the parental origin of the CRF01_AE regions was from MSM, in which recombination events may be more likely to occur. To the best of our knowledge, this is the first detection of a novel HIV-1 second-generation recombinant form (CRF01AE/CRF07_BC) in Jilin, which indicates active transmission networks of HIV-1 infection among MSM in the region. Therefore, it is necessary to continue monitoring the molecular epidemiology of HIV-1 among MSM in Jilin to obtain a better understanding of the transmission and potential public health impact of HIV-1 among MSM in the region. PMID- 23809011 TI - SNP-based Bayesian networks can predict oral mucositis risk in autologous stem cell transplant recipients. AB - OBJECTIVE: Approximately 40% of patients receiving conditioning chemotherapy prior to autologous hematopoietic stem cell transplants (aHSCT) develop severe oral mucositis (SOM). Aside from disabling pain, ulcerative lesions associated with SOM predispose to poor health and economic outcomes. Our objective was to develop a probabilistic graphical model in which a cluster of single-nucleotide polymorphisms (SNPs) derived from salivary DNA could be used as a tool to predict SOM risk. METHODS: Salivary DNA was extracted from 153 HSCT patients and applied to Illumina BeadChips. Using sequential data analysis, we filtered extraneous SNPs, selected loci, and identified a predictive SNP network for OM risk. We then tested the predictive validity of the network using SNP array outputs from an independent HSCT cohort. RESULTS: We identified an 82-SNP Bayesian network (BN) that was related to SOM risk with a 10-fold cross-validation accuracy of 99.3% and an area under the ROC curve of 99.7%. Using samples from a small independent patient cohort (n = 16), we demonstrated the network's predictive validity with an accuracy of 81.2% in the absence of any false positives. CONCLUSIONS: Our results suggest that SNP-based BN developed from saliva-sourced DNA can predict SOM risk in patients prior to aHSCT. PMID- 23809013 TI - Professor Clemens von Sonntag (1936 - 2013). PMID- 23809012 TI - Comparative genomic analysis of six bacteria belonging to the genus Novosphingobium: insights into marine adaptation, cell-cell signaling and bioremediation. AB - BACKGROUND: Bacteria belonging to the genus Novosphingobium are known to be metabolically versatile and occupy different ecological niches. In the absence of genomic data and/or analysis, knowledge of the bacteria that belong to this genus is currently limited to biochemical characteristics. In this study, we analyzed the whole genome sequencing data of six bacteria in the Novosphingobium genus and provide evidence to show the presence of genes that are associated with salt tolerance, cell-cell signaling and aromatic compound biodegradation phenotypes. Additionally, we show the taxonomic relationship between the sequenced bacteria based on phylogenomic analysis, average amino acid identity (AAI) and genomic signatures. RESULTS: The taxonomic clustering of Novosphingobium strains is generally influenced by their isolation source. AAI and genomic signature provide strong support the classification of Novosphingobium sp. PP1Y as Novosphingobium pentaromaticivorans PP1Y. The identification and subsequent functional annotation of the unique core genome in the marine Novosphingobium bacteria show that ectoine synthesis may be the main contributing factor in salt water adaptation. Genes coding for the synthesis and receptor of the cell-cell signaling molecules, of the N-acyl-homoserine lactones (AHL) class are identified. Notably, a solo luxR homolog was found in strain PP1Y that may have been recently acquired via horizontal gene transfer as evident by the presence of multiple mobile elements upstream of the gene. Additionally, phylogenetic tree analysis and sequence comparison with functionally validated aromatic ring hydroxylating dioxygenases (ARDO) revealed the presence of several ARDOs (oxygenase) in Novosphingobium bacteria with the majority of them belonging to the Groups II and III of the enzyme. CONCLUSIONS: The combination of prior knowledge on the distinctive phenotypes of Novosphingobium strains and meta-analysis of their whole genomes enables the identification of several genes that are relevant in industrial applications and bioremediation. The results from such targeted but comprehensive comparative genomics analysis have the potential to contribute to the understanding of adaptation, cell-cell communication and bioremediation properties of bacteria belonging to the genus Novosphingobium. PMID- 23809014 TI - Integrating multi-platform genomic data using hierarchical Bayesian relevance vector machines. AB - BACKGROUND: Recent advances in genome technologies and the subsequent collection of genomic information at various molecular resolutions hold promise to accelerate the discovery of new therapeutic targets. A critical step in achieving these goals is to develop efficient clinical prediction models that integrate these diverse sources of high-throughput data. This step is challenging due to the presence of high-dimensionality and complex interactions in the data. For predicting relevant clinical outcomes, we propose a flexible statistical machine learning approach that acknowledges and models the interaction between platform specific measurements through nonlinear kernel machines and borrows information within and between platforms through a hierarchical Bayesian framework. Our model has parameters with direct interpretations in terms of the effects of platforms and data interactions within and across platforms. The parameter estimation algorithm in our model uses a computationally efficient variational Bayes approach that scales well to large high-throughput datasets. RESULTS: We apply our methods of integrating gene/mRNA expression and microRNA profiles for predicting patient survival times to The Cancer Genome Atlas (TCGA) based glioblastoma multiforme (GBM) dataset. In terms of prediction accuracy, we show that our non-linear and interaction-based integrative methods perform better than linear alternatives and non-integrative methods that do not account for interactions between the platforms. We also find several prognostic mRNAs and microRNAs that are related to tumor invasion and are known to drive tumor metastasis and severe inflammatory response in GBM. In addition, our analysis reveals several interesting mRNA and microRNA interactions that have known implications in the etiology of GBM. CONCLUSIONS: Our approach gains its flexibility and power by modeling the non-linear interaction structures between and within the platforms. Our framework is a useful tool for biomedical researchers, since clinical prediction using multi-platform genomic information is an important step towards personalized treatment of many cancers. We have a freely available software at: http://odin.mdacc.tmc.edu/~vbaladan. PMID- 23809015 TI - Predicting binding affinity of CSAR ligands using both structure-based and ligand based approaches. AB - We report on the prediction accuracy of ligand-based (2D QSAR) and structure based (MedusaDock) methods used both independently and in consensus for ranking the congeneric series of ligands binding to three protein targets (UK, ERK2, and CHK1) from the CSAR 2011 benchmark exercise. An ensemble of predictive QSAR models was developed using known binders of these three targets extracted from the publicly available ChEMBL database. Selected models were used to predict the binding affinity of CSAR compounds toward the corresponding targets and rank them accordingly; the overall ranking accuracy evaluated by Spearman correlation was as high as 0.78 for UK, 0.60 for ERK2, and 0.56 for CHK1, placing our predictions in the top 10% among all the participants. In parallel, MedusaDock, designed to predict reliable docking poses, was also used for ranking the CSAR ligands according to their docking scores; the resulting accuracy (Spearman correlation) for UK, ERK2, and CHK1 were 0.76, 0.31, and 0.26, respectively. In addition, performance of several consensus approaches combining MedusaDock- and QSAR predicted ranks altogether has been explored; the best approach yielded Spearman correlation coefficients for UK, ERK2, and CHK1 of 0.82, 0.50, and 0.45, respectively. This study shows that (i) externally validated 2D QSAR models were capable of ranking CSAR ligands at least as accurately as more computationally intensive structure-based approaches used both by us and by other groups and (ii) ligand-based QSAR models can complement structure-based approaches by boosting the prediction performances when used in consensus. PMID- 23809016 TI - Spinal anaesthesia for caesarean section in the presence of respiratory failure and spinal metastases from a soft tissue clear cell sarcoma. AB - Spinal metastases occur in up to 70% of all patients with cancer. However, only 10% are symptomatic. Before considering central neuraxial blockade in patients with malignancy, a history of back pain should be excluded. Anaesthetists should be aware that intrathecal and epidural injections could cause paraplegia if metastases are impinging on the spinal cord. Failure to achieve adequate sensory anaesthesia after central neuraxial blockade or presentation with postoperative paraplegia may indicate the presence of asymptomatic vertebral canal metastases. In this report, the anaesthetic management of a patient with respiratory failure and spinal metastases from a soft tissue sarcoma, requiring caesarean section is described. Sensory anaesthesia extending above a level of imminent cord compression was achieved despite loss of cerebrospinal fluid signal on magnetic resonance imaging. PMID- 23809017 TI - Biodegradation of thiocyanate by a novel strain of Burkholderia phytofirmans from soil contaminated by gold mine tailings. AB - A novel B. phytofirmans strain with the capacity to degrade thiocyanate was isolated from pH approximately 6.5 soil contaminated by effluent from gold mine tailings. This Burkholderia strain uses thiocyanate as its sole nitrogen source and can grow on acetate as a sole carbon source in a minimal medium. While biodegradation of thiocyanate has been reported to occur within alkaline environments (e.g. soda lakes and wastewater from coking plants), this work presents the first observation of thiocyanate degradation by Burkholderia at pH <9.0. Our findings therefore inform remediation strategies for thiocyanate contamination in nonalkaline soils and waters impacted by gold-mining activities. SIGNIFICANCE AND IMPACT OF THE STUDY: This work describes thiocyanate biodegradation by a novel Burkholderia phytofirmans strain isolated from circumneutral pH gold mining-contaminated soils. Previous reports of bacterial thiocyanate degradation have mainly focused on alkaline environments or culturing conditions (pH >= 9). Because cyanidation is used globally in gold mining, with thiocyanate as the major contaminant, our results will interest those working on biotechnological approaches to gold mine waste remediation. PMID- 23809018 TI - Transport of the botulinum neurotoxin-associating protein, nontoxic nonhemagglutinin, across the rat small intestinal epithelial cell monolayer. AB - Botulinum neurotoxin (BoNT) associates with nontoxic nonhemagglutinin (NTNHA) yielding a complex in culture. BoNT and NTNHA have similar domain organizations, implying that they share common functions, although this remains unclear. Here, we examined cell monolayer transport of serotype D NTNHA in the rat intestinal epithelial cell line IEC-6. NTNHA and BoNT both bound to the cell and were transported across the cell layer. NTNHA contains a QXW motif and a beta-trefoil fold, both common in sugar chain-recognizing proteins, whereas the QXW motif is absent in all BoNT serotypes. This could explain the distinct sugar chain recognizing properties of NTNHA and BoNT. PMID- 23809019 TI - Survival outcome of re-resection for recurrent liver metastases of colorectal cancer: a retrospective study. AB - BACKGROUND: This study aimed to investigate whether re-resection can achieve a good survival outcome in the treatment of recurrent liver metastases of colorectal cancer. METHODS: Prospectively collected data of patients who underwent hepatectomy for liver tumours were reviewed. Patients whose liver tumours were metastases of colorectal cancer were included in the study provided that they had no extrahepatic metastases and received no loco-ablative treatment simultaneous with hepatectomy. Patients who did not have recurrent liver metastasis after their first liver resection (group R) and patients who underwent re-resection for recurrent liver metastasis (group RR) were compared. RESULTS: In total, 321 patients were included in the study, with 307 in group R and 14 in group RR. The two groups had comparable demographics. Insignificantly more patients in group R received major resection (55.6% versus 30.8%, P = 0.079). The median blood loss volume was 0.6 (0-12.7) L in group R and 0.35 (0-15) L in group RR (P = 0.202). Group RR had a significantly smaller median tumour size (2.5 cm versus 3.5 cm, P = 0.020) and resection margin width (0.3 cm versus 0.7 cm, P = 0.037). On univariate analysis, re-resection was not a risk factor in overall survival. On multivariate analysis, post-operative complication (hazard ratio (HR) 1.66, 95% confidence interval (CI) 1.15-2.39, P = 0.007), microscopic margin involvement (HR 1.95, 95% CI 1.26-3.04, P = 0.003) and multiple tumours (HR 1.58, 95% CI 1.17-2.14, P = 0.003) were risk factors in overall survival. The two groups had no significant differences in disease-free survival and overall survival. CONCLUSION: Re-resection for recurrent colorectal liver metastases can achieve a favourable survival outcome at centres with expertise. PMID- 23809020 TI - Prevalence of diagnosed opioid abuse and its economic burden in the veterans health administration. AB - OBJECTIVE: Evaluate prevalence and risk-adjusted healthcare costs of diagnosed opioid abuse in the national Veterans Health Administration (VHA). Costs were compared between patients with and without diagnosed opioid abuse. DESIGN: Medical and pharmacy claims analysis of VHA data (10/01/2006 to 09/30/2010) were retrospectively analyzed. Prevalence was calculated as the percent of patients with diagnosed opioid abuse for the entire VHA membership and those with noncancer pain diagnoses, compared between patients prescribed opioids prior to abuse diagnosis and those not prescribed opioids through the VHA system. Healthcare utilization and costs were estimated using matching techniques and generalized linear models to control for clinical and demographic differences between patients with and without diagnosed opioid abuse. Separate comparisons were made (with diagnosed abuse vs. without) for each cohort: patients with/without opioid prescriptions. RESULTS: Five-year diagnosed opioid abuse was 1.11%. Among patients prescribed opioids, 5-year abuse prevalence was 3.04%. Pain patients prescribed opioids had the highest abuse rate at 3.26%. Adjusted annual healthcare costs for diagnosed opioid abuse patients were higher than for those without diagnosed abuse, (prescribed opioids overall healthcare costs: $28,882, with diagnosed abuse vs. $13,605 for those without; not prescribed opioids: $25,197 vs. $6350, P-value< 0.0001; opioid-specific healthcare costs for patients prescribed opioids: $8956 vs. $218; patients not prescribed opioids: $8733 vs. $20). CONCLUSIONS: Diagnosed opioid abuse prevalence is almost 7-fold higher in the veteran's administration population than in commercial health plans and translates to a significant economic burden. Appropriate interventions should be considered to prevent and reduce opioid abuse. PMID- 23809021 TI - Comparison of ProSeal LMA with Supreme LMA in paediatric patients. AB - BACKGROUND AND OBJECTIVE: Supreme laryngeal mask airway (S-LMA) has been improved in recent years, but comparative studies with a sizeable number of paediatric patients are limited in number. In this study, oropharyngeal leak pressures (OLPs) were compared between S-LMA and ProSeal laryngeal mask airway (P-LMA) in paediatric patients. METHODS: After obtaining approval from the ethics committee and written informed consent from the relatives of the patients, 60 patients, from 9 months to 5 years of age and 10-20 kg in weight, who were recommended for elective surgery were included in this prospective and randomised study. The patients were assigned to the S-LMA and P-LMA groups. OLP, insertion times, success rates, ease of airway device placement, fibre optical assessment, success rates and insertion times of an orogastric tube (OGT) were compared. RESULTS: P LMA was placed successfully in all the patients. One patient was intubated in the S-LMA group. The outcomes of a total of 59 patients were analysed. The insertion times of the airway devices were shorter in the S-LMA group than in the P-LMA group (S-LMA; 12.2 +/- 2.9, P-LMA; 15.4 +/- 3.7 s) (P = 0.001). The first insertion attempts of airway device placement were similar. The OLPs were similar (P-LMA; 17.2 +/- 2.3, S-LMA; 16.4 +/- 1.7 cm H2 O). The fibre-optically determined anatomic position was better in the P-LMA group (P = 0.02). The insertion time of the OGT was shorter with S-LMA than with P-LMA (P = 0.01). CONCLUSION: Our findings suggest that S-LMA has OLPs similar to those of P-LMA in paediatric patients and that S-LMA provides successful positive pressure ventilation. PMID- 23809022 TI - Floaters in Mohs micrographic surgery. AB - BACKGROUND: Floaters are dislodged pieces of tumor tissue than can obscure Mohs micrographic surgery (MMS) frozen sections and confound their interpretation. OBJECTIVE: To understand the common causes of floaters and identify management strategies. METHODS: An initial virtual consensus conference of Mohs surgeons based on a 60-item questionnaire. Data were validated in interviews with randomly selected Mohs surgeons. RESULTS: Based on retrospective reporting of 230 surgeon years and 170,404 cases of MMS by 26 surgeons, the mean rate of floaters per tumor treated was 1.8%, and the rate of floaters per tissue block was 0.70%. Not wiping blades between cuts when a stage is separated into subunits can predispose to floaters. There was also strong consensus that basal cell carcinomas, ulcerated tumors, and tissue from the first stage were more likely to yield floaters. There is little consensus on how to manage floaters, with possibilities including taking additional sections, taking an additional stage, or simply noting the floater. CONCLUSION: Floaters are not rare and can complicate MMS margin assessment. There is significant expert consensus regarding the causes of floaters and the tissue features that may predispose to them. Floaters may be prevented by minimizing their likely causes. There is less consensus on what to do with a floater. PMID- 23809023 TI - A threat to the understanding of oneself: intensive care patients' experiences of dependency. AB - This study examines the meaning of dependency on care as experienced by intensive care patients. Literature on the subject is sparse, but research from nonintensive settings shows that dependency is often experienced negatively. The study is based on in-depth qualitative semistructured interviews with three former patients characterized as narratives. The analysis is inspired by a phenomenological hermeneutical method. The study has found that dependency is experienced as difficult and that the experience seems to be attached to the relationship to oneself. Patients feel powerless and experience shame, their understanding of self is threatened, and they fight for independence in the course after intensive care. The findings might be influenced by the study being conducted in a Western country setting, where independence is valued. They can be used as means of reflection on nursing practice and matters such as communication and patient participation. PMID- 23809024 TI - Challenging the Tritope Model of T cell receptor structure-function relationships with classical data on 'super' and 'allo-MHC' antigens. AB - The response of the immune system to allo-MHC-encoded antigens and Mls 'superantigens' has been experimentally analysed in detail, but the data have not been coupled to a theoretical framework. It should therefore be instructive to see how well the newly proposed Tritope Model of TCR structure-function relationships deals with the signalling interactions between the TCR and the above antigens. We will pay heed to William Bateson's admonition, 'treasure the exceptions', by showing how a meaningful theory interrogates the data with the same validity that the data interrogate the theory. The concordances, as well as the contradictions, with the Tritope Model are a test of its heuristic value. PMID- 23809025 TI - Decisional capacity: toward an inclusionary approach. PMID- 23809027 TI - Moderate and severe traumatic brain injury: pathophysiology and management. AB - Traumatic brain injury (TBI) is a serious disorder that is all too common. TBI ranges in severity from mild concussion to a severe life-threatening state. Across this spectrum, rational therapeutic approaches exist. Early identification that TBI has occurred in a patient is paramount to optimal outcome. Proper clinical management should be instituted as soon as possible by appropriately trained medical providers. More seriously injured patients must be triaged to advanced care centers. It is only through this rational approach to TBI that patients may expect to achieve optimal clinical and functional outcome. PMID- 23809026 TI - Rice oxalate oxidase gene driven by green tissue-specific promoter increases tolerance to sheath blight pathogen (Rhizoctonia solani) in transgenic rice. AB - Rice sheath blight, caused by the necrotrophic fungus Rhizoctonia solani, is one of the most devastating and intractable diseases of rice, leading to a significant reduction in rice productivity worldwide. In this article, in order to examine sheath blight resistance, we report the generation of transgenic rice lines overexpressing the rice oxalate oxidase 4 (Osoxo4) gene in a green tissue specific manner which breaks down oxalic acid (OA), the pathogenesis factor secreted by R. solani. Transgenic plants showed higher enzyme activity of oxalate oxidase (OxO) than nontransgenic control plants, which was visualized by histochemical assays and sodium dodecylsulphate-polyacrylamide gel electrophoresis (SDS-PAGE). Transgenic rice leaves were more tolerant than control rice leaves to exogenous OA. Transgenic plants showed a higher level of expression of other defence-related genes in response to pathogen infection. More importantly, transgenic plants exhibited significantly enhanced durable resistance to R. solani. The overexpression of Osoxo4 in rice did not show any detrimental phenotypic or agronomic effect. Our findings indicate that rice OxO can be utilized effectively in plant genetic manipulation for sheath blight resistance, and possibly for resistance to other diseases caused by necrotrophic fungi, especially those that secrete OA. This is the first report of the expression of defence genes in rice in a green tissue-specific manner for sheath blight resistance. PMID- 23809028 TI - Managing subarachnoid hemorrhage in the neurocritical care unit. AB - Patients with aneurysmal subarachnoid hemorrhage who survive the initial hemorrhage require complex interventions to occlude the aneurysm, typically followed by a prolonged intensive care unit and hospital course to manage the complications that follow. Much of the morbidity and mortality from this disease happens in delayed fashion in the neurocritical care unit. Despite progress made in the last decades, much remains to be understood about this disease and how to best manage these patients. This article provides a review of current evidence and the authors' experience, aimed at providing practical aid to those caring for patients with this disease. PMID- 23809029 TI - Management of acute spinal cord injury in the neurocritical care unit. AB - Acute spinal cord injury (SCI) is associated with widespread disturbances not only affecting neurologic function but also leading to hemodynamic instability and respiratory failure. Traumatic SCI rarely occurs in isolation, and frequently is accompanied by trauma to other organ systems. Management of individuals with SCI is complex, requiring aggressive monitoring and prompt treatment when complications arise. Typically this level of care is provided in the neurocritical care unit. This article reviews the pathophysiology of the neurologic, cardiovascular, and pulmonary derangements following traumatic SCI and their management in the critical care setting. PMID- 23809030 TI - Intracerebral hemorrhage: new challenges and steps forward. AB - Intracerebral hemorrhage (ICH) is a significant cause of morbidity and mortality. With the aging population, increased use of anticoagulants, and changing racial and ethnic landscape of the United States, the incidence of ICH will increase over the next decade. Improvements in preventative strategies to treat hypertension and atrial fibrillation are necessary to change the trajectory of this increase. Advances in the understanding of ICH at the vascular and molecular level may pave the way to new treatment options. This article discusses the epidemiology, pathophysiology, and current treatment options for patients with ICH. Differences in outcome and treatment between patients taking and not taking anticoagulant therapies are considered. PMID- 23809031 TI - Management of intracerebral pressure in the neurosciences critical care unit. AB - Management of intracranial pressure in neurocritical care remains a potentially valuable target for improvements in therapy and patient outcomes. Surrogate markers of increased intracranial pressure, invasive monitors, and standard therapy, as well as promising new approaches to improve cerebral compliance are discussed, and a current review of the literature addressing this metric in neuroscience critical care is provided. PMID- 23809032 TI - Surgical treatment of elevated intracranial pressure: decompressive craniectomy and intracranial pressure monitoring. AB - Surgical techniques that address elevated intracranial pressure include (1) intraventricular catheter insertion and cerebrospinal fluid drainage, (2) removal of an intracranial space-occupying lesion, and (3) decompressive craniectomy. This review discusses the role of surgery in the management of elevated intracranial pressure, with special focus on intraventricular catheter placement and decompressive craniectomy. The techniques and potential complications of each procedure are described, and the existing evidence regarding the impact of these procedures on patient outcome is reviewed. Surgical management of mass lesions and ischemic or hemorrhagic stroke occurring in the posterior fossa is not discussed herein. PMID- 23809033 TI - Seizures and the neurosurgical intensive care unit. AB - The cause of seizures in the neurosurgical intensive care unit (NICU) can be categorized as emanating from either a primary brain pathology or from physiologic derangements of critical care illness. Patients are typically treated with parenteral antiepileptic drugs. For early onset ICU seizures that are easily controlled, data support limited treatment. Late seizures have a more ominous risk for subsequent epilepsy and should be treated for extended periods of time or indefinitely. This review ends by examining the treatment algorithms for simple seizures and status epilepticus and the role newer antiepileptic use can play in the NICU. PMID- 23809034 TI - Strategies for the use of mechanical ventilation in the neurologic intensive care unit. AB - Mechanical ventilation in neurologically injured patients presents unique challenges. Patients with acute neurologic injuries may require mechanical ventilation for reasons beyond respiratory failure. There is also a subset of pulmonary pathologic abnormality directly associated with neurologic injuries. Balancing the need to maintain brain oxygenation, cerebral perfusion, and control of intracranial pressure can be in conflict with concurrent ventilator strategies aimed at lung protection. Weaning and liberation from mechanical ventilation also require special considerations. These issues are examined in the ventilator management of the neurologically injured patient. PMID- 23809035 TI - Microdialysis in the neurocritical care unit. AB - Effective monitoring is critical for neurologically compromised patients, and several techniques are available. One of these tools, cerebral microdialysis (MD), was designed to detect derangements in cerebral metabolism. Although this monitoring device began as a research instrument, favorable results and utility have broadened its clinical applications. Combined with other brain monitoring techniques, MD can be used to estimate cerebral vulnerability, to assess tissue outcome, and possibly to prevent secondary ischemic injury by guiding therapy. This article reviews the literature regarding the past, present, and future uses of MD along with its advantages and disadvantages in the intensive care unit setting. PMID- 23809036 TI - Parenchymal brain oxygen monitoring in the neurocritical care unit. AB - Patients admitted to the neurocritical care unit (NCCU) often have serious conditions that can be associated with high morbidity and mortality. Pharmacologic agents or neuroprotectants have disappointed in the clinical environment. Current NCCU management therefore is directed toward identification, prevention, and treatment of secondary cerebral insults that evolve over time and are known to aggravate outcome. This strategy is based on a variety of monitoring techniques including use of intraparenchymal monitors. This article reviews parenchymal brain oxygen monitors, including the available technologies, practical aspects of use, the physiologic rationale behind their use, and patient management based on brain oxygen. PMID- 23809037 TI - Use of Transcranial Doppler (TCD) ultrasound in the Neurocritical Care Unit. AB - Transcranial Doppler (TCD) is a portable device that uses a handheld 2-MHz transducer. It is most commonly used in subarachnoid hemorrhage where cerebral blood flow velocities in major intracranial blood vessels are measured to detect vasospasm in the first 2 to 3 weeks. TCD is used to detect vasospasm in traumatic brain injury and post-tumor resection, measurement of cerebral autoregulation and cerebrovascular reactivity, diagnosis of acute arterial occlusions in stroke, screening for patent foramen ovale and monitoring of emboli. It can be used to detect abnormally high intracranial pressure and for confirmation of total cerebral circulatory arrest in brain death. PMID- 23809038 TI - Hypothermia in neurocritical care. AB - Hypothermia has long been recognized as an effective therapy for acute neurologic injury. Recent advances in bedside technology and greater understanding of thermoregulatory mechanisms have made this therapy readily available at the bedside. Critical care management of the hypothermic patient can be divided into 3 phases: induction, maintenance, and rewarming. Each phase has known complications that require careful monitoring. At present, hypothermia has only been shown to be an effective neuroprotective therapy in cardiac arrest survivors. The primary use of hypothermia in the neurocritical care unit is to treat increased intracranial pressure. PMID- 23809039 TI - Assessment of brain death in the neurocritical care unit. AB - This article reviews current guidelines for death by neurologic criteria and addresses topics relevant to the determination of brain death in the intensive care unit. The history of brain death as a concept leads into a discussion of the evolution of practice parameters, focusing on the most recent 2010 update from the American Academy of Neurology and the practice variability that exists worldwide. Proper transition from brain death determination to possible organ donation is reviewed. This review concludes with a discussion regarding ethical and religious concerns and suggestions on how families of patients who may be brain dead might be optimally approached. PMID- 23809040 TI - Neurocritical care in neurosurgery. PMID- 23809041 TI - Hospital charitable lotteries: taking a gamble on systems thinking. AB - RATIONALE, AIMS AND OBJECTIVES: The presence of lotteries can be witnessed worldwide. Charitable lotteries are often portrayed as 'good works', and recently, hospitals have utilized them as a popular fundraising vehicle to raise necessary funds to help achieve organizational goals and objectives. Research indicates that lotteries contribute to gambling-related harms; however, research into charitable lotteries has been underdeveloped. Both the gambling and the health care industries are complex and evolving, consisting of many interacting stakeholders with often different and competing interests. This article seeks to present systems thinking as a conceptual framework to help fill the gap in understanding the use of gambling within hospitals and its possible benefits and unforeseen negative consequences. Addressing the gap in knowledge is important to help inform decision making aimed at reducing gambling-related harms. METHOD: This article proposes how the school of systems thinking, specifically framing hospitals as complex adaptive systems and system dynamics modelling, can be utilized to understand the policy implications of the adoption of lotteries as a revenue source for hospitals. CONCLUSION: Hospitals have a duty to care, inform and protect. Hospital charitable lotteries have become big business; however, its incorporation into critical funding strategies needs to be carefully understood. Systems thinking theory and methodologies provide an integrated approach to examine this dynamic and evolving fundraising initiative. Findings from this article can inform the development of action strategies, including policy development at multiple levels. PMID- 23809043 TI - A single histrelin implant is effective for 2 years for treatment of central precocious puberty. AB - We investigated whether a "yearly" histrelin implant would provide pubertal suppression when left in place for 2 years. Equivalent suppression was observed when comparing 12 and 24 months in 33 children with central precocious puberty. A single implant for 2 years reduces cost and number of implant procedures. PMID- 23809042 TI - Risk factors for febrile status epilepticus: a case-control study. AB - OBJECTIVE: To identify risk factors for developing a first febrile status epilepticus (FSE) among children with a first febrile seizure (FS). STUDY DESIGN: Cases were children with a first FS that was FSE drawn from the Consequences of Prolonged Febrile Seizures in Childhood and Columbia cohorts. Controls were children with a first simple FS and separately, children with a first complex FS that was not FSE. Identical questionnaires were administered to family members of the 3 cohorts. Magnetic resonance imaging protocol and readings were consistent across cohorts, and seizure phenomenology was assessed by the same physicians. Risk factors were analyzed using logistic regression. RESULTS: Compared with children with simple FS, FSE was associated with younger age, lower temperature, longer duration (1-24 hours) of recognized temperature before FS, female sex, structural temporal lobe abnormalities, and first-degree family history of FS. Compared with children with other complex FS, FSE was associated with low temperature and longer duration (1-24 hours) of temperature recognition before FS. Risk factors for complex FS that was not FSE were similar in magnitude to those for FSE but only younger age was significant. CONCLUSIONS: Among children with a first FS, FSE appears to be due to a combination of lower seizure threshold (younger age and lower temperatures) and impaired regulation of seizure duration. Clinicians evaluating FS should be aware of these factors as many episodes of FSE go unnoticed. Further work is needed to develop strategies to prevent FSE. PMID- 23809044 TI - Effects of passive smoking on snoring in preschool children. AB - OBJECTIVE: To examine the association between passive smoking and snoring in preschool children using parent-reported questionnaires and urine cotinine levels. STUDY DESIGN: This was a population-based cross-sectional survey of 2954 children aged 2-6 years in Hong Kong. Parent-reported questionnaires provided information on snoring and household smoking. One-third of children randomly chosen from the cohort provided urine samples for cotinine analysis. Increased urine cotinine was defined as urinary cotinine concentration >= 30 ng/mg creatinine. Using multivariate logistic regression analysis, we analyzed the association between snoring and passive smoking, controlling for potential confounders including age, sex, body mass index z-score, atopic diseases, recent upper respiratory tract infection, parental allergy, parental education, family income, and bedroom-sharing. RESULTS: A total of 2187 completed questionnaires were included in the final analysis, and 724 children provided urine samples for cotinine measurement. After adjustment for confounding factors, questionnaire based household smoking (>10 cigarettes/d: OR = 2.22, 95% CI = 1.02-4.81) and increased urine cotinine (OR = 4.37, 95% CI = 1.13-16.95) were significant risk factors for habitual snoring (snoring >= 3 nights per week). For occasional snoring (snoring 1-2 nights per week), reported household smoking (1-10 cigarettes/d: OR = 1.41, 95% CI = 1.14-1.76; >10 cigarettes/d: OR = 1.56, 95% CI = 1.05-2.31), and increased urine cotinine (OR = 1.82, 95% CI = 1.03-3.20) were also identified as significant risk factors. A dose-effect relationship was found for snoring frequency and adjusted natural logarithms of urinary cotinine concentrations (P < .001). CONCLUSIONS: Environmental tobacco smoke exposure is an independent risk factor for snoring in preschool children. Parents' smoking cessation should be encouraged in management of childhood snoring. PMID- 23809045 TI - Protecting young children from life-threatening drug toxicity. PMID- 23809046 TI - Tongue fasciculations in the newborn. PMID- 23809047 TI - A newborn with an anorectal malformation. PMID- 23809048 TI - Congenital imprinting disorders: a novel mechanism linking seemingly unrelated disorders. PMID- 23809049 TI - Cow's milk allergy: a new approach needed? PMID- 23809050 TI - Aerosolized intranasal midazolam for safe and effective sedation for quality computed tomography imaging in infants and children. AB - This pilot study introduces the aerosolized route for midazolam as an option for infant and pediatric sedation for computed tomography imaging. This technique produced predictable and effective sedation for quality computed tomography imaging studies with minimal artifact and no significant adverse events. PMID- 23809051 TI - Erythematous scaly plaques and papules in a 9-month-old infant. PMID- 23809053 TI - Newsflash: pediatric residency and medical school can't teach everything. PMID- 23809052 TI - Validation of diagnostic codes for intussusception and quantification of childhood intussusception incidence in Ontario, Canada: a population-based study. AB - OBJECTIVES: To validate an algorithm to identify cases of intussusception using the health administrative data of Ontario, Canada, and to apply the algorithm to estimate provincial incidence of intussusception, preceding the introduction of the universal rotavirus vaccination program. STUDY DESIGN: We determined the accuracy of various combinations of diagnostic, procedural, and billing codes using the chart-abstracted diagnoses of patients of the Children's Hospital of Eastern Ontario as the reference standard. We selected an algorithm that maximized positive predictive value while maintaining a high sensitivity and used it to ascertain annual incidence of intussusception for fiscal years 1995-2010. We explored temporal trends in incidence using Poisson regression. RESULTS: The selected algorithm included only the International Classification of Diseases (ICD)-9 or ICD-10 code for intussusception in the hospitalization database and was sensitive (89.3%) and highly specific (>99.9%). The positive predictive value of the ICD code was 72.4%, and the negative predictive value was >99.9%. We observed the highest mean incidence (34 per 100000) in male children <1 year of age. Temporal trends in incidence varied by age group. There was a significant mean decrease in incidence of 4% per year in infants (<1 year) until 2004 and rates stabilized thereafter. CONCLUSIONS: We have demonstrated that intussusception can be accurately identified within health administrative data using validated algorithms. We have described changes in temporal trends in intussusception incidence in Ontario and established a baseline to allow ongoing monitoring as part of vaccine safety surveillance. PMID- 23809054 TI - Sequence of novel agents in multiple myeloma: an instrumental variable analysis. AB - Lenalidomide and bortezomib have not been compared prospectively and are currently used in sequence for patients with multiple myeloma; however, it is unknown whether a sequence of administration could result in improved outcomes. We retrospectively reviewed electronic records of patients with multiple myeloma who had used both agents in sequence at our institution: 97 patients had lenalidomide first and 111 had bortezomib first. On multivariable analysis, the sequence of therapy was not associated with outcome. These findings were confirmed with instrumental variable analyses. Finally, use of bortezomib first was associated with improved survival for patients with baseline renal insufficiency. PMID- 23809055 TI - Hepatitis B infection increases the risk of non-Hodgkin lymphoma: a meta-analysis of observational studies. AB - Hepatitis B virus (HBV) infection is a major public health problem and the association between HBV infection and non-Hodgkin lymphoma (NHL) is unclear. The primary aim of our study was to evaluate the association between HBV infection assessed by a positive hepatitis B surface antigen (HBsAg) and the incidence of NHL and subtypes using a meta-analysis of epidemiological studies. The random effects model was used to calculate the outcome. Our search yielded 17 case control and 5 cohort studies, including over 40,000 NHL cases. HBV infected individuals had an OR of 2.24 (95% CI 1.80-2.78; p <= 0.001) of developing NHL. In high HBV prevalent countries, there were increased odds of diffuse large B cell lymphoma and a trend toward increased odds of developing follicular and T cell lymphoma. Future research is needed to better understand the biological mechanisms responsible for lymphomagenesis in patients with HBV infection. PMID- 23809056 TI - A fraction rich in phenyl propanoids from L. divaricata aqueous extract is capable of inducing apoptosis, in relation to H2O2 modulation, on a murine lymphoma cell line. AB - Leukemia and lymphoma are a group of heterogeneous neoplastic disorder of white blood cells characterized by the uncontrolled proliferation and block in differentiation of hematopoietic cells. Nowadays, there is an interest in therapy with drugs of plant origin because conventional medicine can be inefficient or also results in side effects. Larrea divaricata Cav., is a plant widely distributed in Argentina that possess antiproliferative and antioxidant activities reported. Nordihydroguaiaretic acid (NDGA) was previously found in the plant and related to both antiproliferative and pro-proliferative actions on a lymphoma cell line. In order to demonstrate whether the presence of NDGA may be beneficial or not in the antiproliferative action of the aqueous extract, the extract of L. divaricata was submitted to a fractionation and fractions with and without NDGA were studied in a murine lymphocitic leukemia cell line (EL-4) proliferation. The effect of the most active fraction was studied in relation to H2O2 modulation and the synergistic action between compounds, found in fractions, was analyzed. The presence of NDGA was not a detonator for pro-proliferative action and its presence could be beneficial in low concentrations allowing a synergist antiproliferative action with other compounds. PMID- 23809057 TI - Sunburn risk among children and outdoor workers in South Africa and Reunion Island coastal sites. AB - To estimate potential sunburn risk for schoolchildren and outdoor workers, ground based ambient solar ultraviolet radiation (UVR) measurements were converted into possible child (5% of ambient solar UVR) and outdoor worker (20% of ambient solar UVR) solar UVR exposures by skin type and season for three coastal sites: Durban, Cape Point (South Africa) and Saint Denis (Reunion Island, France). Cumulative daily ambient solar UVR levels were relatively high at all sites, especially during summer, with maximum values of about 67, 57 and 74 Standard Erythemal Dose (SED) (1 SED = 100 J m(-2)) at Durban, Cape Point and Saint Denis respectively. Sunburn risk was evident for both children and outdoor workers, especially those with skin types I and II (extremely to moderately sensitive) during summer, early autumn and/or late spring at all three sites. Although results need to be verified with real-time, instantaneous and nonintegrated personal solar UVR measurements, this understanding of sunburn risk is useful for initiating the development skin cancer prevention and sun protection awareness campaigns in both countries. PMID- 23809058 TI - 3D matched pairs: integrating ligand- and structure-based knowledge for ligand design and receptor annotation. AB - We describe an extension to the matched molecular pairs approach that merges pairwise activity differences with three-dimensional contextual information derived from X-ray crystal structures and binding pose predictions. The incorporation of 3D binding poses allows the direct comparison of structural changes to diverse chemotypes in particular binding pockets, facilitating the transfer of SAR from one series to another. Integrating matched pair data with the receptor structure can also highlight activity patterns within the binding site--for example, "hot spot" regions can be visualized where changes in the ligand structure are more likely to impact activity. The method is illustrated using P38alpha structural and activity data to generate novel hybrid ligands, identify SAR transfer networks, and annotate the receptor binding site. PMID- 23809059 TI - Impact of physical size on gefitinib efficacy in patients with non-small cell lung cancer harboring EGFR mutations. AB - Gefitinib is an essential drug for the treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) gene mutations. The approved dosage is 250 mg/body/day without adjustment for physical size such as body surface area (BSA), and the impact of physical size on the efficacy of gefitinib has not been evaluated. Here, we sought to clarify this issue using a retrospective cohort. We reviewed the medical records of patients with consecutive advanced NSCLC harboring EGFR mutations who underwent gefitinib monotherapy at Okayama University Hospital. In total, 101 patients were included in this study, and the median BSA in this cohort was 1.5 m(2). The median progression-free survival (PFS) of the patients with higher BSA (>=1.5 m(2)) was significantly worse than that of those with lower BSA (< 1.5 m(2)) (10.4 vs. 18.0 months; p = 0.019, log-rank test). Multivariate analysis also showed a significant impact of BSA on PFS (hazards ratio, 2.34; 95% confidence interval, 1.78-2.89; p = 0.002). By contrast, no significant association between BSA and PFS was observed in those undergoing cytotoxic chemotherapy (4.0 vs. 5.1 months; p = 0.989, log-rank test), suggesting that BSA is a predictive, rather than a prognostic, marker for gefitinib therapy in EGFR-mutated NSCLC. In conclusion, BSA affected PFS in patients with EGFR-mutated NSCLC who underwent gefitinib monotherapy, suggesting the need for appraisal of BSA-based dose adjustment, even for this molecular target-based therapy. PMID- 23809060 TI - Mechanisms of resistance to EGFR tyrosine kinase inhibitors gefitinib/erlotinib and to ALK inhibitor crizotinib. AB - The discovery of several molecular alterations that underlie non-small cell lung cancer (NSCLC) pathogenesis has led to the development of targeted therapies. In particular, gefitinib and erlotinib have become the standard of care in patients harboring epidermal growth factor receptor mutations, while crizotinib showed an impressive efficacy in patients with ALK-positive NSCLC. Nevertheless, the occurrence of clinical resistance limits the long term results of these novel agents. The identification of the molecular mechanisms responsible for acquired resistance to targeted therapy is crucial in order to pursue the creation of rational strategies to overcome resistance. In the current review, we will focus on the acquired resistance mechanisms to EGFR-TKIs and crizotinib and the therapeutic strategies currently under study to overcome resistance. PMID- 23809061 TI - Detection of Escherichia coli O157:H7 using immunomagnetic separation and mPCR in Turkish foods of animal origin. AB - The present study was conducted to investigate the presence of Escherichia coli O157:H7 in food samples of animal origin and to detect its virulence genes by immunomagnetic separation technique and multiplex PCR (mPCR). A total of 500 samples (consisting of diced meat, minced meat, burger, raw cow's milk and raw cow's milk cheese) were analysed. Escherichia coli O157:H7 was detected in 5 (1%) of 500 analysed samples including two diced meat, one minced meat and two raw milk cheese. None of the burger samples tested contained E. coli O157:H7. Three isolates obtained from minced and diced meat were found to carry stx1 , stx2 , hlyA and eaeA genes whereas two isolates from raw-milk cheese were found to harbour the stx1 , eaeA and hlyA genes. The results of this study suggest that raw meat and raw-milk cheese tested could pose public health problems in consumers with regard to their virulence factors. SIGNIFICANCE AND IMPACT OF THE STUDY: Escherichia coli (E. coli) O157:H7 is an important human pathogen. Escherichia coli 0157:H7 infections have been associated with consumption of uncooked meat and meat products, as well as unpasteurized dairy products. This study demonstrated that without specific tests for E. coli virulence factors raw meat and raw-milk cheese could pose public health problems to Turkish consumers. PMID- 23809062 TI - Nautilus: a bioinformatics package for the analysis of HIV type 1 targeted deep sequencing data. AB - The advent of next generation sequencing technologies is providing new insight into HIV-1 diversity and evolution, which has created the need for bioinformatics tools that could be applied to the characterization of viral quasispecies. Here we present Nautilus, a bioinformatics package for the analysis of HIV-1 targeted deep sequencing data. The DeepHaplo module determines the nucleotide base frequency and read depth at each position and computes the haplotype frequencies based on the linkage among polymorphisms in the same next generation sequence read. The Motifs module computes the frequency of the variants in the setting of their sequence context and mapping orientation, which allows for the validation of polymorphisms and haplotypes when strand bias is suspected. Both modules are accessed through a user-friendly GUI, which runs on Mac OS X (version 10.7.4 or later), and are based on Python, JAVA, and R scripts. Nautilus is available from www.hivresearch.org/research.php?ServiceID=5&SubServiceID=6 . PMID- 23809063 TI - Cure for peritoneal metastases? An evidence-based review. AB - There is now a considerable body of published evidence supporting the use of a multimodal approach consisting of cytoreductive surgery (CS) and heated intraperitoneal chemotherapy (HIPEC) in the treatment of peritoneal metastases (PM) arising from selected gastrointestinal tract malignancies. In the absence of systemic metastases, it is thought that disease confined to the peritoneum may be eradicated through optimum cytoreduction. This review critically evaluates the current body of published evidence for the use of CS/HIPEC in the treatment of advanced colorectal, appendiceal and gastric cancer. Although its role remains less defined in patients with gastric PM, current evidence provides a compelling argument for its use in PM of colorectal and appendiceal origin. With a low mortality and acceptable morbidity rate, CS/HIPEC may offer hope of long-term survival and cure in a defined group of patients with this disease. PMID- 23809064 TI - Differences in healthcare utilization and associated costs between patients prescribed vs. nonprescribed opioids during an inpatient or emergency department visit. AB - OBJECTIVES: Compare healthcare resource utilization (HCRU) and costs between patients prescribed opioids (RxOP) and those who were not (NoRxOP) during an emergency department (ED) or inpatient visit. METHODS: Retrospective cohort analysis was performed (January 2006 to September 2010). Continuously eligible RxOP patients in ED/inpatient settings (January 2007 to September 2009) were included if age was >= 12 years by initial prescription date (or random date between first ED/inpatient admission and September 30, 2009 [NoRxOP patients]). Healthcare resource utilization and costs for 12 months after initial prescription were compared. Univariate descriptive analyses were performed for baseline and outcome variables and compared using appropriate tests. Risk adjustment compared HCRU between RxOP and NoRxOP cohorts for the postindex period. RESULTS: Of 27,599 eligible patients, RxOP patients (n = 18,819) were younger, less likely to be male, more likely to reside in southern United States and to have Preferred Provider Organization health plans, and had lower comorbidity index scores, compared with NoRxOP patients (n = 8,780). RxOP patients were less likely to have nonpain-related comorbidities and more frequently diagnosed with pain-related comorbidities. Unmatched and propensity matched RxOP patients experienced higher HCRU and costs in all subcategories (total, inpatient, outpatient ED, physician, pharmacy, other outpatient settings). Opioid abuse frequency was low in patients with common diagnoses/procedures within 3 months before initial prescription (0.48%). Average time to abuse was < 1 year (201 days). CONCLUSION: Most patients were prescribed opioids initially during ED/inpatient visits and incurred higher HCRU than those not prescribed opioids. Among those with diagnosed opioid abuse after initiating opioids, time to diagnosis was rapid (range: 14 to 260 days) for patients with common diseases and procedures. PMID- 23809065 TI - Rare inheritance of Leri-Weill Syndrome due to crossover of short stature Homeobox Gene (SHOX) Deletions between X and Y Chromosomes: a case report. AB - BACKGROUND: Leri-Weill syndrome (LWS) is a genetic disorder caused by deletions or mutations in the SHOX gene or by deletions downstream of the gene and is classically characterized by short stature, mesomelic shortening of forearms and legs, and Madelung deformity. Correct identification of short stature homeobox containing gene (SHOX) deficiency in children with growth problems is vital for appropriate initiation of growth hormone therapy. METHOD: We report a phenotypically normal 23 day old male infant born to a father diagnosed with Leri Weill syndrome at age 12 years with a documented SHOX deletion on his X chromosome. The patient's fetal long bones had been found to be about three weeks delayed in growth on prenatal ultrasound during the second trimester. RESULTS: The infant underwent genetic evaluation at 23 days of life and was found to have a SHOX deletion on Yp11.32 identified using single nucleotide polymorphism microarray (SNP) analysis and confirmed by FISH using a SHOX gene probe. CONCLUSION: We report the case of a male infant diagnosed with Leri-Weill syndrome with an unusual documented inheritance between father and son due to crossover between X and Y chromosomes during paternal meiosis. Our case is the youngest patient in literature documented by FISH analysis to have an X to Y chromosome transfer and the first of these patients diagnosed prior to onset of short stature or Madelung deformity. Our patient was identified prior to growth failure and can now be monitored for growth abnormalities with the ability to implement growth augmentation therapy without delay. Our case highlights the importance of advising affected SHOX patients of risks to future offspring and supports screening off-spring of parents carrying SHOX abnormalities regardless of sex. PMID- 23809066 TI - Perception of quality of care among residents of public nursing-homes in Spain: a grounded theory study. AB - BACKGROUND: The quality of care in nursing homes is weakly defined, and has traditionally focused on quantify nursing homes outputs and on comparison of nursing homes' resources. Rarely the point of view of clients has been taken into account. The aim of this study was to ascertain what means "quality of care" for residents of nursing homes. METHODS: Grounded theory was used to design and analyze a qualitative study based on in-depth interviews with a theoretical sampling including 20 persons aged over 65 years with no cognitive impairment and eight proxy informants of residents with cognitive impairment, institutionalized at a public nursing home in Spain. RESULTS: Our analysis revealed that participants perceived the quality of care in two ways, as aspects related to the persons providing care and as institutional aspects of the care's process. All participants agreed that aspects related to the persons providing care was a pillar of quality, something that, in turn, embodied a series of emotional and technical professional competences. Regarding the institutional aspects of the care's process, participants laid emphasis on round-the-clock access to health care services and on professional's job stability. CONCLUSIONS: This paper includes perspectives of the nursing homes residents, which are largely absent. Incorporating residents' standpoints as a complement to traditional institutional criteria would furnish health providers and funding agencies with key information when it came to designing action plans and interventions aimed at achieving excellence in health care. PMID- 23809067 TI - Small molecule inhibitors to manipulate adenovirus gene transfer. PMID- 23809068 TI - Schistosoma haematobium in China, ex-Africa: new populations at risk? PMID- 23809069 TI - Infectious disease surveillance among deployed military personnel: needs and opportunities for real-time febrile illness surveillance. PMID- 23809071 TI - Pre-travel consultation: evaluation of primary care physician practice in the Franche-Comte region. AB - BACKGROUND: Primary care physicians (PCP) are first in line to provide adequate pre-travel medical advice. Little data are available on the content of pre-travel PCP consultations in France. We undertook an observational survey to assess the level of specific knowledge among PCPs on health advice, vaccinations, and malaria prophylaxis. METHODS: Standardized questionnaires were sent to a random sample of 400 PCPs practicing in the Franche-Comte regions (eastern France) who were asked to complete and return it on a voluntary and anonymous basis. The questionnaire requested sociodemographic details, practice-related characteristics, and proposed three clinical situations with multiple choice questions (MCQ). To identify factors associated with a higher level of specific knowledge in travel medicine, results were studied by uni- and multivariate analyses. An overall score was calculated based on the MCQ answers and a motivation score was calculated based on parameters such as frequency and developments in pre-travel consulting at the practice, PCPs' personal experience as travelers, and the formal agreement of PCPs to administer yellow fever vaccination. RESULTS: The response rate was 37.5%, with 150 questionnaires returned completed and suitable for analysis. After multivariate logistic regression, the three variables associated with a higher score were: proximity of a vaccination center (p = 0.001), motivation score (p = 0.004), and absence of request for expert advice on malaria prophylaxis (p = 0.007). CONCLUSIONS: PCPs play an important role in travel medicine. This study showed that their high level of knowledge in travel medicine was mostly linked to their motivation to practice in this specialized discipline. PMID- 23809070 TI - Pre-travel consultation without injury prevention is incomplete. PMID- 23809072 TI - Travel-related leptospirosis: a series of 15 imported cases. AB - BACKGROUND: Leptospirosis belongs to the spectrum of travel-related infections. METHODS: We retrospectively studied all the consecutive cases of travel-related leptospirosis seen in our department between January 2008 and September 2011. Patients were included with a clinical picture compatible with the disease within 21 days after return, the presence of a thermoresistant antigen or IgM antibodies, Elisa >= 1 /400, and a positive microagglutination test (MAT) >= 1/100. RESULTS: Fifteen leptospirosis cases were evaluated. Exposure occurred in Asia (47%), Africa (20%), the Caribbean (20%), and Indian Ocean (13%). Fourteen patients were infected during water-related activities. On admission the most frequent symptoms were fever (100%), headache (80%), and digestive disorders (67%). Relevant laboratory findings included impaired liver function tests (100%), lymphocytopenia (80%), thrombocytopenia (67%), and elevated C-reactive protein (CRP) (67%). Our cases were confirmed by MAT that found antibodies against nine different serovars. Seven patients were cured with amoxicillin, four with doxycycline, two with ceftriaxone, one with ceftriaxone, doxycycline, and spiramycin, whereas one recovered spontaneously (retrospective diagnosis). Eight patients were hospitalized. All patients recovered. CONCLUSION: Our cases involved nine different serovars. They were related to travel in Asia, Africa, and the Caribbean. Bathing or other fresh-water leisure activities (canoeing, kayaking, rafting) are the most likely at-risk exposure. Any traveler with fever and at-risk exposure should be investigated for leptospirosis. PMID- 23809073 TI - Acute hepatitis in israeli travelers. AB - BACKGROUND: Acute hepatitis is a well-described cause of morbidity and sporadic mortality in travelers. Data regarding the epidemiology of hepatitis in travelers are lacking. The aim of this study is to describe the epidemiology of acute viral hepatitis among travelers returning from tropical countries, with particular attention to enterically transmitted hepatitis. METHODS: This study is a prospective observational study of ill-returned travelers who presented at two travel medicine clinics in Israel between the years 1997 and 2012. Data of patients with acute hepatitis were summarized. Only travelers were included, immigrants and foreign workers were excluded. RESULTS: Among 4,970 Israeli travelers who were seen during this period, 49 (1%) were diagnosed with acute hepatitis. Among them, hepatitis E virus (HEV) was the etiology in 19 (39%) cases and hepatitis A virus (HAV) was the etiology in 13 (27%) cases, demonstrating that 65% of all cases were due to enterically transmitted hepatitis. Acquiring acute hepatitis B (two cases) or acute hepatitis C (one case) was uncommon (6.1%). In 27% of the cases, no diagnosis was determined. Fifty-five percent of cases were imported from the Indian subcontinent, with a predominance of HEV infection (84%). A significant male predominance was seen in all groups regardless of etiology. Pre-travel consultation was documented in only 7% of those with vaccine preventable hepatitis (hepatitis A & B) compared to 89% in those with hepatitis E. CONCLUSIONS: Enterically transmitted hepatitis is the main causes of viral hepatitis among travelers. HEV is an emerging disease and has become the most common hepatitis among Israeli travelers. Although an efficacious vaccine has been developed, no licensed HEV vaccine is yet available. Although hepatitis A vaccine is highly efficacious, safe, and easily available, there is a stable number of HAV cases. PMID- 23809074 TI - A quality improvement initiative using a novel travel survey to promote patient centered counseling. AB - BACKGROUND: We sought to evaluate and provide better itinerary-specific care to precounseled travelers and to assess diseases occurring while traveling abroad by surveying a community population. An additional quality improvement initiative was to expand our post-travel survey to be a more valuable tool in gathering high quality quantitative data. METHODS: From de-identified data collected via post travel surveys, we identified a cohort of 525 patients for a retrospective observational analysis. We analyzed illness encountered while abroad, medication use, and whether a physician was consulted. We also examined itinerary variables, including continents and countries visited. RESULTS: The 525 post-travel surveys collected showed that the majority of respondents traveled to Asia (31%) or Africa (30%). The mean number of travel days was 21.3 (median, 14). Univariate analysis demonstrated a statistically significant increase of risk for general illness when comparing travel duration of less than 14 days to greater than 14 days (11.3% vs 27.7%, p < 0.001). Duration of travel was also significant with regard to development of traveler's diarrhea (TD) (p = 0.0015). Destination of travel and development of traveler's diarrhea trended toward significance. Serious illness requiring a physician visit was infrequent, as were vaccine related complications. CONCLUSIONS: Despite pre-travel counseling, traveler's diarrhea was the most common illness in our cohort; expanded prevention strategies will be necessary to lower the impact that diarrheal illness has on generally healthy travelers. Overall rates of illness did not vary by destination; however, there was a strong association between duration of travel and likelihood of illness. To further identify specific variables contributing to travel-related disease, including patient co-morbidities, reason for travel, and accommodations, the post-travel survey has been modified and expanded. A limitation of this study was the low survey response rate (18%); to improve the return rate, we plan to implement supplemental modalities including email and a web-based database. PMID- 23809075 TI - On the trail of preventing meningococcal disease: a survey of students planning to travel to the United States. AB - BACKGROUND: College freshmen living in dormitories are at increased risk for meningococcal disease. Many students become a high-risk population when they travel to the United States. This study surveyed the knowledge, attitudes toward, and behavior surrounding the disease among Taiwanese college students planning to study in the United States, and to identify factors that may affect willingness to accept meningococcal vaccination. METHODS: A cross-sectional survey of college students going to study in the United States was conducted in a medical center based travel medicine clinic. Background information, attitudes, general knowledge, preventive or postexposure management, and individual preventive practices were collected through a structured questionnaire. RESULTS: A total of 358 students were included in the final analysis. More than 90% of participants believed that preventing meningococcal disease was important. However, fewer than 50% of students accurately answered six of nine questions exploring knowledge of the disease, and only 17.3% of students knew the correct management strategy after close contact with patients. Logistic regression analysis showed that students who understood the mode of transmission (odds ratio: 3.21, 95% CI = 1.117-9.229), medication management (1.88, 1.045-3.38), and epidemiology (2.735, 1.478-5.061) tended to be vaccinated. CONCLUSIONS: Despite an overall positive attitude toward meningococcal vaccination, there was poor knowledge about meningococcal disease. Promoting education on the mode of transmission, epidemiology, and pharmacological management of the disease could increase vaccination rates. Both the governments and travel medicine specialists should work together on developing an education program for this high-risk group other than just requiring vaccination. PMID- 23809076 TI - Hypoxia-related altitude illnesses. AB - BACKGROUND: Millions of tourists and climbers visit high altitudes annually. Many unsuspecting and otherwise healthy individuals may get sick when sojourning to these high regions. Acute mountain sickness represents the most common illness, which is usually benign but can rapidly progress to the more severe and potentially fatal forms of high-altitude cerebral edema and high-altitude pulmonary edema. METHODS: Data were identified by searches of Medline (1965 to May 2012) and references from relevant articles and books. Studies, reviews, and books specifically pertaining to the epidemiology, prevention, and treatment of high-altitude illnesses in travelers were selected. RESULTS: This review provides information on geographical aspects, physiology/pathophysiology, clinical features, risk factors, and the prevalence of high-altitude illnesses and also state-of-the art recommendations for prevention and treatment of such illnesses. CONCLUSION: Given an increasing number of recreational activities at high and extreme altitudes, the general practitioner and specialist are in higher demand for medical recommendations regarding the prevention and treatment of altitude illness. Despite an ongoing scientific discussion and controversies about the pathophysiological causes of altitude illness, treatment and prevention recommendations are clearer with increased experience over the last two decades. PMID- 23809077 TI - Schistosoma haematobium infection in workers returning from Africa to China. AB - Schistosoma haematobium infection is mainly associated with urinary schistosomiasis. Here, we describe two cases of S haematobium infection in workers returning to China from Tanzania and Angola. They had hematuria and were misdiagnosed as having tuberculosis or tumor of the bladder. The diagnosis was established by discovery of eggs in the urine. PMID- 23809078 TI - Dengue surveillance in the French armed forces: a dengue sentinel surveillance system in countries without efficient local epidemiological surveillance. AB - Surveillance of travel-acquired dengue could improve dengue risk estimation in countries without ability. Surveillance in the French army in 2010 to 2011 highlighted 330 dengue cases, mainly in French West Indies and Guiana: DENV-1 circulated in Guadeloupe, Martinique, French Guiana, New Caledonia, Djibouti; DENV-3 in Mayotte and Djibouti; and DENV-4 in French Guiana. PMID- 23809079 TI - Travel-related chronic hemorrhagic leg ulcer infection by Shewanella algae. AB - Shewanella algae is an emerging seawater-associated bacterium. In immunocompromised patients, infections may result in bacteremia, osteomyelitis, and necrotizing fasciitis. Our patient, suffering from autoimmune vasculitis and myasthenia gravis, developed typical hemorrhagic bullae and leg ulcers because of S algae. She was treated efficiently with a combination of ciprofloxacin and piperacillin. PMID- 23809080 TI - Hookworm with hypereosinophilia: atypical presentation of a typical disease. AB - We describe a 55-year-old man returning from the Philippines infected with a hookworm, the novel bacterium Laribacter hongkongensis, and a Blastocystis hominis and presenting with both gastrointestinal and neurological symptoms. The high eosinophilia caused by the hookworm infection resulted in both gastrointestinal and neurological symptoms, resembling a hypereosinophilic syndrome. PMID- 23809081 TI - Dengue sentinel surveillance system in countries without efficient local epidemiological surveillance. PMID- 23809082 TI - What is the PRISM visual tool measuring? Risk affiliation? PMID- 23809083 TI - Response to letter. PMID- 23809084 TI - Distinct functional regions of the human polymeric immunoglobulin receptor. AB - The polymeric immunoglobulin receptor (pIgR) is a type I transmembrane protein that is expressed on the surfaces of glandular and intestinal epithelial cells. The extracellular portion of the pIgR is composed of six different domains. Domain 6 is involved in the enzymatic cleavage and release of the pIgR into the intestinal lumen as a free secretory component (fSC). A highly conserved 9-amino acid sequence is present in this region in various species. Although mutations in domain 6 are associated with particular diseases, such as IgA nephropathy and Epstein-Barr virus-related nasopharyngeal cancer, and the glutamic acid residues in the conserved 9-amino acid sequence are expected to be indispensable for the secretion of fSC, the importance of these residues has not been examined. In the present study, we attempted to examine the role of these residues in the enzymatic cleavage of the pIgR. The enzymatic cleavage of the pIgR was not affected by the presence of an alanine to valine substitution at position 580 or glutamine to alanine substitutions at positions 606 and/or 607, or the deletion of the whole 9-amino acid conserved sequence. Intriguingly, the 10 amino acid sequences flanking the N- and C-terminal ends of the conserved 9-amino acid sequence had opposite effects on pIgR cleavage. Namely, the N-terminal and C terminal sequences enhanced and reduced pIgR cleavage efficiency, respectively. These results indicated that the pIgR can be divided into several functionally distinct regions. PMID- 23809085 TI - Entropy and compression: two measures of complexity. AB - RATIONALE, AIMS AND OBJECTIVES: Traditional complexity measures are used to capture the amount of structured information present in a certain phenomenon. Several approaches developed to facilitate the characterization of complexity have been described in the related literature. Fetal heart rate (FHR) monitoring has been used and improved during the last decades. The importance of these studies lies on an attempt to predict the fetus outcome, but complexity measures are not yet established in clinical practice. In this study, we have focused on two conceptually different measures: Shannon entropy, a probabilistic approach, and Kolmogorov complexity, an algorithmic approach. The main aim of the current investigation was to show that approximation to Kolmogorov complexity through different compressors, although applied to a lesser extent, may be as useful as Shannon entropy calculated by approximation through different entropies, which has been successfully applied to different scientific areas. METHODS: To illustrate the applicability of both approaches, two entropy measures, approximate and sample entropy, and two compressors, paq8l and bzip2, were considered. These indices were applied to FHR tracings pertaining to a dataset composed of 48 delivered fetuses with umbilical artery blood (UAB) pH in the normal range (pH >= 7.20), 10 delivered mildly acidemic fetuses and 10 moderate to-severe acidemic fetuses. The complexity indices were computed on the initial and final segments of the last hour of labour, considering 5- and 10-minute segments. RESULTS: In our sample set, both entropies and compressors were successfully utilized to distinguish fetuses at risk of hypoxia from healthy ones. Fetuses with lower UAB pH presented significantly lower entropy and compression indices, more markedly in the final segments. CONCLUSIONS: The combination of these conceptually different measures appeared to present an improved approach in the characterization of different pathophysiological states, reinforcing the theory that entropies and compressors measure different complexity features. In view of these findings, we recommend a combination of the two approaches. PMID- 23809086 TI - Top 10 plant-parasitic nematodes in molecular plant pathology. AB - The aim of this review was to undertake a survey of researchers working with plant-parasitic nematodes in order to determine a 'top 10' list of these pathogens based on scientific and economic importance. Any such list will not be definitive as economic importance will vary depending on the region of the world in which a researcher is based. However, care was taken to include researchers from as many parts of the world as possible when carrying out the survey. The top 10 list emerging from the survey is composed of: (1) root-knot nematodes (Meloidogyne spp.); (2) cyst nematodes (Heterodera and Globodera spp.); (3) root lesion nematodes (Pratylenchus spp.); (4) the burrowing nematode Radopholus similis; (5) Ditylenchus dipsaci; (6) the pine wilt nematode Bursaphelenchus xylophilus; (7) the reniform nematode Rotylenchulus reniformis; (8) Xiphinema index (the only virus vector nematode to make the list); (9) Nacobbus aberrans; and (10) Aphelenchoides besseyi. The biology of each nematode (or nematode group) is reviewed briefly. PMID- 23809087 TI - The pelvic digit anomaly in a patient with multiple fractures: does it mimic the fracture? AB - Pelvic digit is a rare congenital anomaly where bone develops in the soft tissue adjacent to normal skeletal bone. Pelvic digits are most often associated with the ilium but may also pseudoarticulate with other pelvic bones or the abdominal wall. Its importance lies in its differentiation from acquired abnormalities due to trauma such as myositis ossificans and avulsion injuries of pelvis. In this article, we present a case of pelvic digit with multiple fractures. To avoid unnecessary investigation methods and treatment, this entity should be kept inmindwhen an atypical bone structure is noted around the pelvis. PMID- 23809088 TI - The efficiency of intraosseous human growth hormone administration: a feasibility pilot study in a rabbit model. AB - BACKGROUND: The use of protein- and peptide-based drugs in the treatment of disease has significantly increased in recent years. However, their chemical and physical properties make them unsuitable for simple oral delivery. OBJECTIVE: The objective of this proof-of-concept study was to examine the feasibility of protein administered via intraosseous (IO) injection. Human growth hormone (GH), a 22-kd protein, served as the model protein. RESULTS: An indwelling IO needle and intravenous (IV) line were placed in four New Zealand white male rabbits, and 50, 100, 200, or 400 MUg/kg of GH were injected. Blood samples were taken at different time points and analyzed for GH concentration. There were no significant pharmacokinetic differences between the IO and IV routes. For the 400 MUg/kg dose, the area under the serum GH concentration time curve was 100.55 +/- 46.7 MUg/min*mL with IV administration and 84.6 +/- 34 MUg/min*mL for IO (P = .73 compared to the IV route), Cmax measured 11.2 +/- 5 MUg/L and Tmax 0.9 +/- 0.7 minutes. For the 200 MUg/kg dose, the area under the curve was 68.5 +/- 16.7 MUg/min*mL with IV administration, and 85.1 +/- 1.5 MUg/min*mL (P = .39) for IO, Cmax measured 8.13 +/- 2.44 MUg/L and Tmax 1.92 +/- 1.06 minutes. CONCLUSIONS: The findings confirm that a large protein (22 kd) can be administered via IO injection, reaching blood levels comparable to IV injection. Further studies with a larger number of animals are required to evaluate the pharmacokinetics and pharmacodynamics of high-molecular-weight proteins injected by the IO route. PMID- 23809089 TI - A novel in-plane technique for ultrasound-guided pericardiocentesis. AB - Ultrasound-guided procedures are becoming very common in emergency medicine and critical care. Ultrasound guidance for pericardiocentesis has been shown to reduce errors as compared with the landmark-based technique. A simplified in plane ultrasound-guided pericardiocentesis allows the clinician an opportunity to visualize the needle and the guide wire during the procedure. In addition, post procedure ultrasound of the pericardial effusion, right ventricle and inferior vena cava allow the clinician confirmation of improvement of physiologic parameters that can lead to cardiovascular collapse from impending pericardial tamponade. PMID- 23809090 TI - Laboratory assessment of out-of-hospital interventions to control junctional bleeding from the groin in a manikin model. PMID- 23809091 TI - Pseudolithiasis after recent use of ceftriaxone: an unexpected diagnosis in a child with abdominal pain. PMID- 23809092 TI - Myasthenia gravis and Guillain-Barre cooccurrence syndrome. AB - OBJECTIVE: The objective of this study was to review all cases in literature in which the clinical manifestations of myasthenia gravis (MG) and Guillain-Barre syndrome (GBS) were presented in the same patient including a new case of our own and identify the clinical characteristics and possible mechanisms of this syndrome. METHODS: We reviewed 12 reports in which 13 cases were diagnosed as MG and GBS. The clinical manifestations of the 13 cases and our new case were analyzed in detail to show the characteristics of this kind of syndrome. RESULTS: Of all the cases, 5 females and 9 males, 6 of them were Chinese; 3 were Americans; 3 were Israelis; 1 was white and one was a Frenchman. The age of seven patients was no more than 45 years old. They all had the symptoms of extrocular muscle weakness. Nerve conduction and RNS abnormal were seen in all tested cases. Acetylcholine receptor antibody was positive in all tested patients. Prognosis was good in 8 of the 11 recorded patients. CONCLUSIONS: Although extremely rare, MG and GBS may present in the same patient with variant characteristics. The typical clinical characteristics of GBS and MG may be helpful for the diagnosis of future possible cases. PMID- 23809093 TI - A pig model for blunt chest trauma: no pulmonary edema in the early phase. AB - OBJECTIVE: Chest trauma remains a leading cause of trauma-death. Since lung contusion is one of the most important lesions implicated, the aim of this experimental study was to evaluate the cardiorespiratory consequences of an isolated lung contusion model. METHODS: Twenty-eight anesthetized pigs were studied during four hours. We induced a right lung contusion with five bolt shots (70 joules each) using a 22-caliber charge in twenty of them. Eight others pigs constituted the control group. The trauma consequences were assessed by histology, measurements of arterial oxygenation, plasma cytokines, pressure volume mechanics, hemodynamic monitoring using the PiCCO system and a pulmonary artery catheter. The extra-vascular lung water was measured using the gravimetric method. RESULTS: Histology confirmed an isolated right lung contusion without cardiac injury. Compared to baseline values, the trauma group was characterized by a decrease in cardiac index (3.3 +/- 0.8 vs 3.9 +/- 1.2 l/min/m(2); P < .05) and mean arterial pressure (80 +/- 21 vs 95 +/- 16 mmHg; P < .05) without preload or afterload modification. Oxygenation (PaO2/FiO2: 349 +/- 87 vs 440 +/- 75; P < .05) and static compliance (26.3 +/- 7.4 vs 30.3 +/- 7.8 ml/cmH2O; P < .05) were also impaired during two hours compared to baseline. No edema was noticed in either group whatever the lung considered. All measured cytokines were below the detection threshold. CONCLUSIONS: An isolated right lung contusion is associated with rapid but transient cardiorespiratory impairments. Despite the large extent of the lung contusion, no pulmonary edema appeared during the period studied. PMID- 23809094 TI - Technique of axillary use of a Combat Ready Clamp to stop junctional bleeding. PMID- 23809095 TI - Prehospital neurologic deterioration is independent predictor of outcome in traumatic brain injury: analysis from National Trauma Data Bank. AB - BACKGROUND: The prevalence and impact of prehospital neurologic deterioration (PhND) in patients with traumatic brain injury (TBI) have not been investigated. We aimed to determine the prevalence of PhND during emergency medical service (EMS) transportation among patients with TBI and its impact on patient's outcome. METHODS: We used the National Trauma Data Bank, using data files from 2009 to 2010 to identify patients with TBI through International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. The initial Glasgow Coma Scale (GCS) score ascertained at the scene by EMS was compared with the subsequent GCS score evaluation in the emergency department (ED) to identify neurologic deterioration (defined as a decrease in GCS of >=2 points). Patients' demographics, initial injury severity score (ISS), admission GCS score, and hospital outcome were compared between patients with PhND and patients without neurologic deterioration. RESULTS: A total of 257 127 patients with TBI were identified. Among patients with TBI, 22 254 patients had PhND, which comprised 9% of all patients with TBI. The mean of GCS score decrease during EMS transport was 5 points (+/-3). Patients without PhND tended to have higher GCS recorded by EMS (median, 15 vs 12; P < .0001). Patients with TBI who had PhND had significantly higher hospital length of stay and intensive care unit days after adjusting for baseline characteristics and EMS GCS score, EMS transport time, type of injury, presence of intracranial hemorrhages, and ED ISS (P < .0001). These patients had higher rate of in-hospital mortality after adjusting for the same variables (odds ratio, 2.30; 95% confidence interval, 2.18-2.41). CONCLUSION: Prehospital neurologic deterioration occurs in 9% of patients with TBI. It is more prevalent in men and associated with lower EMS GCS level and higher ED ISS. Prehospital neurologic deterioration is an independent predictor of worse hospital outcome and higher resource use in patients with TBI. PMID- 23809096 TI - Heart-type fatty acid-binding protein as a potential biomarker of acute carbon monoxide poisoning. AB - BACKGROUND: The aim of this study was to investigate the role of serum heart-type fatty acid-binding protein (H-FABP) in the evaluation of patients with carbon monoxide (CO) poisoning. METHODS: Forty patients with acute CO poisoning admitted to the emergency department and 15 healthy adults as the control group were included in the study. Serum H-FABP levels of patients were studied on admission and at the 6th, 12th, and 18th hours. Patients were divided into 3 groups according to clinical severity as mild, moderate, and severe. Patients were also divided into 2 groups according to treatment with hyperbaric oxygen (HBO) or normobaric oxygen. RESULTS: Serum H-FABP levels of the patients were higher than those of the control group. There was a negative correlation between H-FABP levels and Glasgow Coma Scale score on admission. Heart-type fatty acid-binding protein levels were significantly higher in patients in the severe compared with mild group. Heart-type fatty acid-binding protein levels in patients treated with HBO were significantly higher than in those treated with normobaric oxygen. The cutoff value of serum H-FABP as an indicator for HBO treatment was determined as 1.5 ng/mL or higher, with a sensitivity of 85.7% and specificity of 69.7%. Serial measurement revealed that H-FABP level peaked at the sixth hour and reduced over time but remained higher than in the control group at the 18th hour. CONCLUSION: Heart-type fatty acid-binding protein may be a promising novel biomarker in the evaluation of clinical severity and in the selection of patients for HBO therapy in acute CO poisoning. PMID- 23809098 TI - Work-related fatigue among medical personnel in Taiwan. AB - BACKGROUND/PURPOSE: Work-related fatigue among medical personnel is a major concern for patient safety, however heavy on-call duty is common in many hospitals. The purpose of this study was to investigate the prevalence of self reported work-related fatigue and its associated factors. METHODS: A cross sectional survey of 1833 participants was conducted in two hospitals in Taipei City, Taiwan, using a self-administered questionnaire. Participants reported their demographic characteristics, health-related behavior, health status and symptoms, and work-related fatigue during the past 3 months. RESULTS: The prevalence of work-related fatigue among the 1833 participants was 30.9%. Younger participants (20-29 years old) were more likely to report work-related fatigue than older participants (40-65 years old) [adjusted odds ratio (aOR) = 1.55, 95% confidence interval (CI) = 1.18-2.01]. Physicians, nurses, and medical technicians were more likely to report work-related fatigue symptoms than administrative personnel (aOR = 2.30, 95% CI = 1.57-2.79; aOR = 2.83, 95% CI = 1.87-3.99; and aOR = 2.01, 95% CI = 1.12-3.06, respectively). Those who drank coffee more than five times a week were more likely to report work-related fatigue than those who did not drink coffee at all (aOR = 2.53, 95% CI = 1.25 1.93). Participants with poor and very poor self-reported health were more likely to report work-related fatigue (aOR = 1.80, 95% CI = 1.26-2.38) than those who reported that their health was fair, good, or very good. CONCLUSION: We identified factors associated with work-related fatigue among hospital workers in Taipei City. These findings can be applied toward on-the-job training and the development of preventive measures for occupational safety in general hospitals. PMID- 23809097 TI - Decreased white matter integrity in neuropsychologically defined mild cognitive impairment is independent of cortical thinning. AB - Improved understanding of the pattern of white matter changes in early and prodromal Alzheimer's disease (AD) states such as mild cognitive impairment (MCI) is necessary to support earlier preclinical detection of AD, and debate remains whether white matter changes in MCI are secondary to gray matter changes. We applied neuropsychologically based MCI criteria to a sample of normally aging older adults; 32 participants met criteria for MCI and 81 participants were classified as normal control (NC) subjects. Whole-head high resolution T1 and diffusion tensor imaging scans were completed. Tract-Based Spatial Statistics was applied and a priori selected regions of interest were extracted. Hippocampal volume and cortical thickness averaged across regions with known vulnerability to AD were derived. Controlling for corticalthic kness, the MCI group showed decreased average fractional anisotropy (FA) and decreased FA in parietal white matter and in white matter underlying the entorhinal and posterior cingulate cortices relative to the NC group. Statistically controlling for cortical thickness, medial temporal FA was related to memory and parietal FA was related to executive functioning. These results provide further support for the potential role of white matter integrity as an early biomarker for individuals at risk for AD and highlight that changes in white matter may be independent of gray matter changes. PMID- 23809099 TI - A comparative analysis of neurosurgical online education materials to assess patient comprehension. AB - Americans have increasingly utilized the internet as a first-line resource for a variety of information, including healthcare-oriented materials. Therefore, these online resources should be written at a level the average American can understand. Patient education resources specifically written for and available to the public were downloaded from the American Association of Neurological Surgeons website and assessed for their level of readability using the Flesch Reading Ease, Flesch-Kincaid Grade Level, Simple Measure of Gobbledygook Grading, Coleman Liau Index, and Gunning-Fog Index. A total of 71 subsections from different neurosurgical specialties were reviewed, including Cerebrovascular, Spine and Peripheral Nerves, Neurotrauma and Critical Care, Pain, Pediatric, Stereotactic and Functional, and Tumor material. All neurosurgical subspecialty education material provided on the American Association of Neurological Surgeons website was uniformly written at a level that was too high, as assessed by all modalities. In order to reach a larger patient population, patient education materials on the American Association of Neurological Surgeons website should be revised with the goal of simplifying readability. PMID- 23809100 TI - Diagnosis and management of optic nerve sheath meningiomas. AB - Optic nerve sheath meningiomas account for a third of all intrinsic tumours of the optic nerve. Despite their classification as histologically benign tumours they cause progressive visual loss that often leads to blindness if left untreated. Recent therapeutic advances have increased the treatment options available to clinicians but patient management remains controversial. We systematically review the progress made in the diagnosis and management of optic nerve sheath meningiomas, clarify current best practice, and suggest future avenues for research. PMID- 23809101 TI - Genome Sequences of a Novel HIV-1 Circulating Recombinant Form (CRF59_01B) Identified among MSM in China. AB - We report here a novel HIV-1 circulating recombinant form (CRF59_01B), isolated from three epidemiologically unlinked men who have sex with men (MSM) in China. CRF59_01B was composed of subtype CRF01_AE and B, with four identical recombinant breakpoints observed in the pol, env genes and between the 3' tat (or rev) and vpu genes. The emergence of CRF59_01B suggests the increasing significance of homosexual transmission in China's HIV epidemic and may indicate an active transmission network of HIV infections among MSM population in China. Further studies of the molecular epidemiology of HIV-1 epidemic among MSM population in China are necessary to gain a fuller understanding of the transmission network and potential public health impact of HIV -1 among MSM population in this region. PMID- 23809102 TI - Evolution of dispersal and life history interact to drive accelerating spread of an invasive species. AB - Populations on the edge of an expanding range are subject to unique evolutionary pressures acting on their life-history and dispersal traits. Empirical evidence and theory suggest that traits there can evolve rapidly enough to interact with ecological dynamics, potentially giving rise to accelerating spread. Nevertheless, which of several evolutionary mechanisms drive this interaction between evolution and spread remains an open question. We propose an integrated theoretical framework for partitioning the contributions of different evolutionary mechanisms to accelerating spread, and we apply this model to invasive cane toads in northern Australia. In doing so, we identify a previously unrecognised evolutionary process that involves an interaction between life history and dispersal evolution during range shift. In roughly equal parts, life history evolution, dispersal evolution and their interaction led to a doubling of distance spread by cane toads in our model, highlighting the potential importance of multiple evolutionary processes in the dynamics of range expansion. PMID- 23809103 TI - Who's on first in exome and whole genome sequencing? Is it the patient or the incidental findings? PMID- 23809105 TI - Special Issue: State of the Art 2013. Preface. PMID- 23809104 TI - Spontaneous resorption of sequestrated lumbar disc fragment. PMID- 23809106 TI - Animal models for thrombotic thrombocytopenic purpura. AB - Thrombotic thrombocytopenic purpura (TTP) is a puzzling disorder in many ways. The disease is difficult to diagnose as analogous symptoms are also found in other microangiopathic disorders. Although ADAMTS13 deficiency is generally required to develop TTP, only some patients with severe ADAMTS13 deficiency do spontaneously develop this disease. It is therefore assumed that environmental and/or genetic factors are needed to cause acute TTP. Nevertheless, acute TTP like symptoms have also been observed in patients with moderate or normal levels of ADAMTS13. The development of animal models for TTP has allowed a closer look at the specific need for ADAMTS13 deficiency and the necessity for additional triggers in the pathophysiology of TTP. Mouse models for congenital TTP and a baboon model for acquired TTP have been generated. These animal models have also proven to be extremely valuable in developing new treatment strategies for TTP. In the current review, we discuss current animal models for TTP, what we have learned from them and how they were used to test new treatment strategies. PMID- 23809108 TI - Revisited role of microparticles in arterial and venous thrombosis. AB - Microparticles (MPs) represent a heterogeneous population of submicronic vesicles that are released in response to cell activation or apoptosis. MPs harbor a large repertoire of cell surface receptors and mRNA and biological activities representative of their parent cells and related to their involvement in many biological functions. Although MP generation is a physiological response, a dramatic increase in circulating MPs is detectable in a variety of thrombosis associated disorders compared with healthy individuals. In this review, we will discuss a new vision of MPs as complex and ambivalent structures that express both activators and inhibitors of coagulation but also convey fibrinolytic properties. After summarizing our current knowledge about the role of MPs in venous and arterial thrombosis, this review will explore how this new vision of MPs influences their definition as emergent biomarkers in thrombotic diseases. Among the studies that have aimed to establish a link between thrombosis and MPs, a few studies have demonstrated a predictive value of MPs. So far, it is unclear whether this limited causative association is the result of current technical concerns and limited standardization or has to be integrated into a more complex vision of the role of MPs as key systems for regulating the balance between coagulation and fibrinolysis. PMID- 23809109 TI - Innovation in detection of microparticles and exosomes. AB - Cell-derived or extracellular vesicles, including microparticles and exosomes, are abundantly present in body fluids such as blood. Although such vesicles have gained strong clinical and scientific interest, their detection is difficult because many vesicles are extremely small with a diameter of less than 100 nm, and, moreover, these vesicles have a low refractive index and are heterogeneous in both size and composition. In this review, we focus on the relatively high throughput detection of vesicles in suspension by flow cytometry, resistive pulse sensing, and nanoparticle tracking analysis, and we will discuss their applicability and limitations. Finally, we discuss four methods that are not commercially available: Raman microspectroscopy, micro nuclear magnetic resonance, small-angle X-ray scattering (SAXS), and anomalous SAXS. These methods are currently being explored to study vesicles and are likely to offer novel information for future developments. PMID- 23809107 TI - Structure-function and regulation of ADAMTS-13 protease. AB - ADAMTS-13, a plasma reprolysin-like metalloprotease, cleaves von Willebrand factor (VWF). Severe deficiency of plasma ADAMTS-13 activity results in thrombotic thrombocytopenic purpura (TTP), while mild to moderate deficiencies of plasma ADAMTS-13 activity are emerging risk factors for developing myocardial and cerebral infarction, pre-eclampsia, and malignant malaria. Moreover, Adamts13(-/ ) mice develop more severe inflammatory responses, leading to increased ischemia/perfusion injury and formation of atherosclerosis. Structure-function studies demonstrate that the N-terminal portion of ADAMTS-13 (MDTCS) is necessary and sufficient for proteolytic cleavage of VWF under various conditions and attenuation of arterial/venous thrombosis after oxidative injury. The more distal portion of ADAMTS-13 (TSP1 2-8 repeats and CUB domains) may function as a disulfide bond reductase to prevent an elongation of ultra-large VWF strings on activated endothelial cells and inhibit platelet adhesion/aggregation on collagen surface under flow. Remarkably, the proteolytic cleavage of VWF by ADAMTS-13 is accelerated by FVIII and platelets under fluid shear stress. A disruption of the interactions between FVIII (or platelet glycoprotein 1balpha) and VWF dramatically impairs ADAMTS-13-dependent proteolysis of VWF in vitro and in vivo. These results suggest that FVIII and platelets may be physiological cofactors regulating VWF proteolysis. Finally, the structure-function and autoantibody mapping studies allow us to identify an ADAMTS-13 variant with increased specific activity but reduced inhibition by autoantibodies in patients with acquired TTP. Together, these findings provide novel insight into the mechanism of VWF proteolysis and tools for the therapy of acquired TTP and perhaps other arterial thrombotic disorders. PMID- 23809110 TI - Evolutionary origins of the blood vascular system and endothelium. AB - Every biological trait requires both a proximate and evolutionary explanation. The field of vascular biology is focused primarily on proximate mechanisms in health and disease. Comparatively little attention has been given to the evolutionary basis of the cardiovascular system. Here, we employ a comparative approach to review the phylogenetic history of the blood vascular system and endothelium. In addition to drawing on the published literature, we provide primary ultrastructural data related to the lobster, earthworm, amphioxus, and hagfish. Existing evidence suggests that the blood vascular system first appeared in an ancestor of the triploblasts over 600 million years ago, as a means to overcome the time-distance constraints of diffusion. The endothelium evolved in an ancestral vertebrate some 540-510 million years ago to optimize flow dynamics and barrier function, and/or to localize immune and coagulation functions. Finally, we emphasize that endothelial heterogeneity evolved as a core feature of the endothelium from the outset, reflecting its role in meeting the diverse needs of body tissues. PMID- 23809111 TI - Synthetic microvessels. AB - The microvasculature is an immense organ that defines the environmental conditions within tissues in both health and disease, and is vital for the proper functions of all tissues. Here, we describe existing tools to study vascular cell function and our work using one platform of in vitro microvessels, which we employed to study vessel structure and remodeling, endothelial barrier function, angiogenesis, interactions between endothelial cells and perivascular cells, interactions between blood cells and the endothelium, and microvascular thrombosis. We also briefly discuss the potential future applications of these platforms in biology and medicine. PMID- 23809113 TI - Future of coagulation factor replacement therapy. AB - Over a million patients worldwide currently suffer from hemophilia and other congenital clotting factor deficiencies. Patients affected with hemophilia A and B are treated by intravenous replacement therapy of factor VIII and factor IX, respectively. Current hemophilia treatments have favorably supported their efficacy, tolerability, and safety profiles. The onset of alloantibodies inactivating the infused coagulation factor is the main problem in hemophilia patients rendering replacement therapies ineffective; another disadvantage is the short half-life of the infused clotting factors with the need for multiple and frequent infusions to manage a bleeding episode. Now, the challenge in the management of hemophilia treatment is the prolongation of the half-life and reduction in the immunogenicity of recombinant clotting factors. The bioengineering strategies, previously applied successfully to other therapeutic proteins, encourage the current efforts to produce novel coagulation factors with more prolonged bioavailability, with increased potency and resistance to inactivation and potentially reduced immunogenicity. PMID- 23809112 TI - Translational medicine advances in von Willebrand disease. AB - Following the recognition of von Willebrand disease (VWD) in 1926 and the cloning of the gene for von Willebrand factor (VWF) in 1985, significant advances have been made in our fundamental knowledge of both the disease and the protein. Some of this new knowledge has also begun to impact the clinical management of VWD. First, the progressive increase in our understanding of the molecular genetic basis of VWD has resulted in rational applications of molecular testing to complement the current range of phenotypic tests for VWD. These molecular genetic strategies are most effectively directed at the prenatal diagnosis of type 3 VWD and confirmatory testing for types 2B and 2N disease. In contrast, the use of molecular testing to clarify the diagnosis of type 1 VWD is of marginal benefit, at best. In terms of VWD therapies, a new recombinant VWF concentrate has recently completed successful clinical trials and is now awaiting more widespread application. There have even been some preclinical successes with VWF gene transfer although the clinical rationale for this therapeutic strategy needs careful consideration. Much more remains to be learnt about the biology of VWF and further translational advances for the enhancement of VWD care will inevitably be realized. PMID- 23809114 TI - Gene therapy for hemophilia. AB - Hemophilia A and B are X-linked monogenic disorders resulting from deficiencies of factor VIII and FIX, respectively. Purified clotting factor concentrates are currently intravenously administered to treat hemophilia, but this treatment is non-curative. Therefore, gene-based therapies for hemophilia have been developed to achieve sustained high levels of clotting factor expression to correct the clinical phenotype. Over the past two decades, different types of viral and non viral gene delivery systems have been explored for hemophilia gene therapy research with a variety of target cells, particularly hepatocytes, hematopoietic stem cells, skeletal muscle cells, and endothelial cells. Lentiviral and adeno associated virus (AAV)-based vectors are among the most promising vectors for hemophilia gene therapy. In preclinical hemophilia A and B animal models, the bleeding phenotype was corrected with these vectors. Some of these promising preclinical results prompted clinical translation to patients suffering from a severe hemophilic phenotype. These patients receiving gene therapy with AAV vectors showed long-term expression of therapeutic FIX levels, which is a major step forwards in this field. Nevertheless, the levels were insufficient to prevent trauma or injury-induced bleeding episodes. Another challenge that remains is the possible immune destruction of gene-modified cells by effector T cells, which are directed against the AAV vector antigens. It is therefore important to continuously improve the current gene therapy approaches to ultimately establish a real cure for hemophilia. PMID- 23809115 TI - Current knowledge on the genetics of incident venous thrombosis. AB - The genetic burden underlying venous thrombosis (VT) is characterized by a sibling relative risk of 2.5 and a strong heritability whose estimates varied from 35% to 60% according to different studies. However, the genetic factors identified so far only explain about 5% of VT heritability and just 16 genes have been robustly associated with the susceptibility to VT, most of them affecting the coagulation cascade. Eight of these have been identified during the last 5 years, thanks to the development of high-throughput micro-array genotyping technologies, which have radically changed the research landscape in human genetics. The present work is aimed at providing a historical review of the known genetic factors contributing to VT risk, as well as discussing future research strategies to follow to disentangle the whole spectrum of genetic variants associated with VT. PMID- 23809116 TI - The role of the laboratory in treatment with new oral anticoagulants. AB - Orally active small molecules that selectively and specifically inhibit coagulation serine proteases have been developed for clinical use. Dabigatran etexilate, rivaroxaban and apixaban are given at fixed doses and do not require monitoring. In most circumstances, these drugs have predictable bioavailability, pharmacokinetic effects, and pharmacodynamic effects. However, there will be clinical circumstances when assessment of the anticoagulant effect of these drugs will be required. The effect of these drugs on laboratory tests has been determined in vitro by spiking normal samples with a known concentration of active compound, or ex vivo by using plasma samples from volunteers and patients. Data on the sensitivity of different reagents are now available, and so guidance as to the effect and interpretation of a test result is now possible. Laboratories should be aware of the sensitivity of their own assays to each drug. This may be achieved by using appropriate calibrated plasma samples. PMID- 23809117 TI - Diagnostic and prognostic prediction models. AB - Risk prediction models can be used to estimate the probability of either having (diagnostic model) or developing a particular disease or outcome (prognostic model). In clinical practice, these models are used to inform patients and guide therapeutic management. Examples from the field of venous thrombo-embolism (VTE) include the Wells rule for patients suspected of deep venous thrombosis and pulmonary embolism, and more recently prediction rules to estimate the risk of recurrence after a first episode of unprovoked VTE. In this paper, the three phases that are recommended before a prediction model may be used in daily practice are described: development, validation, and impact assessment. In the development phase, the focus is on model development commonly using a multivariable logistic (diagnostic) or survival (prognostic) regression analysis. The performance of the developed model is expressed by discrimination, calibration and (re-) classification. In the validation phase, the developed model is tested in a new set of patients using these same performance measures. This is important, as model performance is commonly poorer in a new set of patients, e.g. due to case-mix or domain differences. Finally, in the impact phase the ability of a prediction model to actually guide patient management is evaluated. Whereas in the development and validation phase single cohort designs are preferred, this last phase asks for comparative designs, ideally randomized designs; therapeutic management and outcomes after using the prediction model is compared to a control group not using the model (e.g. usual care). PMID- 23809118 TI - Bleeders, bleeding rates, and bleeding score. AB - Bleeding symptoms are frequently reported even in otherwise healthy subjects, and differentiating a normal subject from a patient with a mild bleeding disorder (MBD) can be extremely challenging. The concept of bleeding rate, that is, the number of bleeding episodes occurring within a definite time, could be used as the unifying framework reconciling the bleeding risk observed in congenital and acquired coagulopathies into a single picture. For instance, primary prevention trials have shown that the incidence of non-major bleeding symptoms in normal subjects is around five per 100 person-years, and this figure is in accordance with the number of hemorrhagic symptoms reported by normal controls in observational studies on hemorrhagic disorders. The incidence of non-major bleeding in patients with MBDs (e.g. in patients with type 1 VWD carrying the C1130F mutation) is also strikingly similar with that of patients taking antiplatelet drugs, and the incidence in moderately severe bleeding disorders (e.g. type 2 VWD) parallels that of patients taking vitamin K antagonists. The severity of a bleeding disorder may therefore be explained by a bleeding rate model, which also explains several common clinical observations. Appreciation of the bleeding rate of congenital and acquired conditions and of its environmental/genetic modifiers into a single framework will possibly allow the development of better prediction tools in the coming years and represents a major scientific effort to be pursued. PMID- 23809119 TI - Optimal treatment duration of venous thrombosis. AB - Randomized controlled trials have shown that patients with venous thromboembolism benefit from a minimum of three months of anticoagulant therapy. After this period, it was suggested that patients with an expected annual recurrence rate of < 5% could safely discontinue treatment. Using a population-based approach for stratification, these patients are those with major transient risk factors, and represent the minority. For all other patients, including those with previous episodes of venous thromboembolism, cancer, or unprovoked events, this treatment duration may not be sufficiently protective. Because extending anticoagulation for additional three to nine months does not result in further, long-term reduction of recurrences, indefinite treatment duration should be considered. However, case-fatality rate for major bleeding in patients taking warfarin for more than three months is higher than case-fatality rate of recurrent venous thromboembolism. Thus, an individual patient approach to improve and increase the identification of those who can safely discontinue treatment at three months becomes necessary. Clinical prediction rules or management strategies based on D dimer levels or residual vein thrombosis have been proposed and need further refinement and validation. Specific bleeding scores are lacking. Meanwhile, the oral direct inhibitors have been proposed as potential alternatives to the vitamin K antagonists, and aspirin may provide some benefit in selected patients who discontinue anticoagulation. Deep vein thrombosis in unusual sites is associated with less, but potentially more severe recurrences, in particular in patients with splanchnic vein thrombosis who also face an increased risk of bleeding complications while on treatment. PMID- 23809120 TI - Venous thrombosis: understanding the paradoxes of recurrence. AB - The decision to continue anticoagulant treatment in patients with a first venous thrombosis after the initial treatment period has strong, life-long implications. Both the risk of recurrence when treatment is stopped and the risk of bleeding when it is continued are high and will persist over a patient's lifetime. For clinicians, rational strategies to stratify their patients into levels of risk of recurrence are limited. To support in the decision to continue or not, it is of the utmost importance to understand why some people develop a second event and others do not and how these people can be identified. This is not easy as, contrary to intuition, the risk profile of a recurrent event is entirely different from that of a first: Some genetic factors that have a major effect on first thrombosis only marginally predict recurrence, while, for instance, the opposite is true for male sex. These paradoxes can be explained when we understand etiology of a first event, how rates for first and second event cannot be directly compared, and how fixed risk factors cannot be predictors, while factors that are not causes can yet be predictors. Integrating all knowledge and combining the best predicting variables will ultimately lead to ways to estimate an individual's recurrence risk and hence to decide on optimal further treatment. PMID- 23809121 TI - Hemostatic disorders in women. AB - The past few decades have seen major advances in multidisciplinary obstetric care and management of gynecological conditions in women with bleeding disorders. Awareness of the impact of bleeding disorders has improved among the obstetric and gynecological community. Undiagnosed bleeding disorders can be the underlying cause for a significant proportion of women with heavy menstrual bleeding. They may also be the cause or a contributory factor for other gynecological problems, such as dysmenorrhea, intermenstrual bleeding, and endometriosis. Hemostatic assessment should be considered in women referred for menstrual abnormalities if they have a positive bleeding history as quantified by bleeding assessment tools. The reproductive choices and options for prenatal diagnosis are also expanding for families with hemophilia with a drive toward achieving a non-invasive approach. Current non-invasive prenatal diagnostic techniques are limited to identification of fetal gender. Research is ongoing to overcome the specific diagnostic challenges of identifying hemophilia mutations, utilizing free fetal DNA circulating in maternal plasma. The management of obstetric hemorrhage has recently evolved to include a greater focus on the identification of and early treatment for coagulation disorders. Deficiencies in certain hemostatic variables are associated with progression to more severe bleeding; therefore, specific interventions have been proposed to target this. Evidence is still lacking to support such strategy, and future research is required to assess the efficacy and the safety of these hemostatic interventions in women with persistent PPH. PMID- 23809122 TI - Thrombosis in women: what are the knowledge gaps in 2013? AB - Several aspects of the diagnostic and therapeutic management of women with venous thrombosis are uncertain. In this overview, I will discuss three major areas. First, the contribution of hormone use to venous thromboembolism (VTE) will be discussed as prudent prescribing of safe preparations can further reduce the risk of hormone-related VTE. Uncertainties remain regarding certain low-dose progestagens and transdermal routing of hormones and their associated risk of VTE. Second, I will review the diagnosis, treatment, and prevention of pregnancy related VTE. As direct evidence is largely absent for these individuals, these areas are subject to extrapolation from the non-pregnant population. There is therefore an urgent need for the evaluation of diagnostic strategies that safely exclude the diagnosis of acute pulmonary embolism in pregnant women without the need for diagnostic imaging, which is currently the gold standard, as no studies have confidently demonstrated the safety of ruling out VTE by clinical probability assessment combined with the use of D-dimer levels. Although identification of women at increased risk of pregnancy-related VTE is relatively well established, controversy remains for asymptomatic women from thrombophilic families. The optimal duration and intensity of anticoagulant treatment for, and prophylaxis of, pregnancy-related VTE with low molecular weight heparin is unknown. Third, anticoagulant therapy to prevent recurrence in women with unexplained recurrent miscarriage has shown to have no benefit and should not be prescribed. However, whether antithrombotic therapy prevents recurrent miscarriage in thrombophilic women, or in women with severe pregnancy complications, remains unknown and urgently requires future research. PMID- 23809124 TI - Clearance of von Willebrand factor. AB - Quantitative deficiencies in von Willebrand factor (VWF) are associated with abnormal hemostasis that can manifest in bleeding or thrombotic complications. Consequently, many studies have endeavored to elucidate the mechanisms underlying the regulation of VWF plasma levels. This review focuses on the role of VWF clearance pathways. A summary of recent developments are provided, including results from genetic studies, the relationship between glycosylation and VWF clearance, the contribution of increased VWF clearance to the pathogenesis of von Willebrand disease and the identification of VWF clearance receptors. These different studies converge in their conclusion that VWF clearance is a complex phenomenon that involves multiple mechanisms. Deciphering how such different mechanisms coordinate their role in this process is but one of the remaining challenges. Nevertheless, a better insight into the complex clearance pathways of VWF may help us to better understand the clinical implications of aberrant clearance in the pathogenesis of von Willebrand disease and perhaps other disorders as well as aid in developing alternative therapeutic approaches. PMID- 23809123 TI - The secretion of von Willebrand factor from endothelial cells; an increasingly complicated story. AB - von Willebrand factor (VWF) plays key roles in both primary and secondary hemostasis by capturing platelets and chaperoning clotting factor VIII, respectively. It is stored within the Weibel-Palade bodies (WPBs) of endothelial cells as a highly prothrombotic protein, and its release is thus necessarily under tight control. Regulating the secretion of VWF involves multiple layers of cellular machinery that act together at different stages, leading to the exocytic fusion of WPBs with the plasma membrane and the consequent release of VWF. This review aims to provide a snapshot of the current understanding of those components, in particular the members of the Rab family, acting in the increasingly complex story of VWF secretion. PMID- 23809125 TI - Models for thrombin generation and risk of disease. AB - Computational models can offer an integrated view of blood clotting dynamics and may ultimately be instructive regarding an individual's risk of bleeding or clotting. Appropriately, developed and validated models could allow clinicians to simulate the outcomes of therapeutics and estimate risk of disease. Computational models that describe the dynamics of thrombin generation have been developed and have been used in combination with empirical studies to understand thrombin dynamics on a mechanistic basis. The translation of an individual's specific coagulation factor composition data using these models into an integrated assessment of hemostatic status may provide a route for advancing the long-term goal of individualized medicine. This review details the integrated approaches to understanding: (i) What is normal thrombin generation in individuals? (ii) What is the effect of normal range plasma composition variation on thrombin generation in pathologic states? (iii) Can disease progression or anticoagulation be followed by understanding the boundaries of normal thrombin generation defined by plasma composition? (iv) What are the controversies and limitations of current computational approaches? Progress in these areas can bring us closer to developing models that can be used to aid in identifying hemostatic risk. PMID- 23809126 TI - Systems biology of coagulation. AB - Accurate computer simulation of blood function can inform drug target selection, patient-specific dosing, clinical trial design, biomedical device design, as well as the scoring of patient-specific disease risk and severity. These large-scale simulations rely on hundreds of independently measured physical parameters and kinetic rate constants. However, the models can be validated against large-scale, patient-specific laboratory measurements. By validation with high-dimensional data, modeling becomes a powerful tool to predict clinically complex scenarios. Currently, it is possible to accurately predict the clotting rate of plasma or blood in a tube as it is activated with a dose of tissue factor, even as numerous coagulation factors are altered by exogenous attenuation or potentiation. Similarly, the dynamics of platelet activation, as indicated by calcium mobilization or inside-out signaling, can now be numerically simulated with accuracy in cases where platelets are exposed to combinations of agonists. Multiscale models have emerged to combine platelet function and coagulation kinetics into complete physics-based descriptions of thrombosis under flow. Blood flow controls platelet fluxes, delivery and removal of coagulation factors, adhesive bonding, and von Willebrand factor conformation. The field of blood systems biology has now reached a stage that anticipates the inclusion of contact, complement, and fibrinolytic pathways along with models of neutrophil and endothelial activation. Along with '-omics' data sets, such advanced models seek to predict the multifactorial range of healthy responses and diverse bleeding and clotting scenarios, ultimately to understand and improve patient outcomes. PMID- 23809127 TI - Crossroads of coagulation and innate immunity: the case of deep vein thrombosis. AB - Deep vein thrombosis (DVT) is a common condition characterized by the formation of an occlusive blood clot in the venous vascular system, potentially complicated by detachment and embolization of thrombi into the lung. Recent evidence from mouse models has shed light on the sequence of events and on the cellular (innate immune cells, platelets) and molecular (hematopoietic tissue factor, nucleic acids) components involved. In response to decreased blood flow, circulating neutrophils and monocytes adhere to the activated endothelium within hours. They initiate and propagate DVT by interacting with platelets and by the exposure and activation of circulating tissue factor and FXII. Intravascular blood coagulation is also induced by extracellular nucleosomes released mainly from activated neutrophils. Interestingly, these mechanisms are closely linked to an evolutionary conserved immune defense mechanism activated in response to infections. In this review, we will give an overview of DVT and the role of innate immune pathways supporting this process. While the latter are aimed at preserving tissue integrity and function, uncontrolled blood coagulation and activation of immune cells may result in pathological thrombus formation and vascular occlusion. Understanding the molecular and cellular players triggering occlusion of large veins, and their distinction from physiological hemostasis, is important for the development of strategies to prevent and treat DVT. PMID- 23809128 TI - Mechanisms of anticoagulant and cytoprotective actions of the protein C pathway. AB - The protein C pathway provides multiple important functions to maintain a regulated balance between hemostasis and host defense systems in response to vascular and inflammatory injury. The anticoagulant protein C pathway is designed to regulate coagulation, maintain the fluidity of blood within the vasculature, and prevent thrombosis, whereas the cytoprotective protein C pathway prevents vascular damage and stress. The cytoprotective activities of activated protein C (APC) include anti-apoptotic activity, anti-inflammatory activity, beneficial alterations of gene expression profiles, and endothelial barrier stabilization. These cytoprotective activities of APC, which require the endothelial protein C receptor (EPCR) and protease-activated receptor-1 (PAR1), have been a major research focus. Recent insights, such as non-canonical activation of PAR1 at Arg46 by APC and biased PAR1 signaling, provided better understanding of the molecular mechanisms by which APC elicits cytoprotective signaling through cleavage of PAR1. The discovery and development of anticoagulant-selective and cytoprotective-selective APC mutants provided unique opportunities for preclinical research that has been and may continue to be translated to clinical research. New mechanisms for the regulation of EPCR functionality, such as modulation of EPCR-bound lipids that affect APC's cytoprotective activities, may provide new research directions to improve the efficacy of APC to convey its cytoprotective activities to cells. Moreover, emerging novel functions for EPCR expand the roles of EPCR beyond mediating protein C activation and APC-induced PAR1 cleavage. These discoveries increasingly develop our understanding of the protein C pathway, which will conceivably expand its physiological implications to many areas in the future. PMID- 23809129 TI - Thrombin inhibition by the serpins. AB - Thrombin is the central protease in the blood coagulation network. It has multiple substrates and cofactors, and it appears that four serpins are responsible for inhibiting the thrombin produced in haemostasis and thrombosis. Structural studies conducted over the last 10 years have resolved how thrombin recognises these serpins with the aid of cofactors. Although antithrombin (AT), protein C inhibitor (PCI), heparin cofactor II (HCII) and protease nexin-1 (PN1) all share a common fold and mechanism of protease inhibition, they have evolved radically different mechanisms for cofactor-assisted thrombin recognition. This is likely to be due to the varied environments in which thrombin is found. In this review, I discuss the unusual structural features of thrombin that are involved in substrate and cofactor recognition, the serpin mechanism of protease inhibition and the fate of thrombin in the complex, and how the four thrombin specific serpins exploit the special features of thrombin to accelerate complex formation. PMID- 23809131 TI - Encryption and decryption of tissue factor. AB - Tissue factor (TF) is a transmembrane cofactor that binds and promotes the catalytic activity of factor (F) VIIa. The TF/VIIa complex activates FX by limited proteolysis to initiate blood coagulation and helps provide the thrombin burst that is important for a stable thrombus. TF is present both in the extravascular compartment, where it functions as a hemostatic envelope, and the intravascular compartment, where it contributes to thrombus formation, particularly when endothelial disruption is minimal. The regulation of its cofactor function appears to differ in the two compartments. Intravascular TF derives predominately from leucocytes, with either monocytes or neutrophils implicated in different models of thrombosis. This TF exists mostly in a non coagulant or cryptic form and acute events lead to local decryption of TF and FX activation. A variety of experimental observations imply that decryption of leucocyte surface TF involves both a dithiol/disulfide switch and exposure of phosphatidylserine. The dithiol/disulfide switch appears to involve the Cys186 Cys209 disulfide bond in the membrane-proximal domain of TF, although this has not been demonstrated in vivo. Activation of a purinergic receptor or complement has recently been observed to decrypt TF on myeloid cells and a dithiol/disulfide switch and the oxidoreductase, protein disulfide isomerase, have been implicated in both systems. The molecular mechanism of action of protein disulfide isomerase in TF encryption/decryption, though, remains to be determined. PMID- 23809130 TI - The transition of prothrombin to thrombin. AB - The proteolytic conversion of prothrombin to thrombin catalyzed by prothrombinase is one of the more extensively studied reactions of blood coagulation. Sophisticated biophysical and biochemical insights into the players of this reaction were developed in the early days of the field. Yet, many basic enzymological questions remained unanswered. I summarize new developments that uncover mechanisms by which high substrate specificity is achieved, and the impact of these strategies on enzymic function. Two principles emerge that deviate from conventional wisdom that has otherwise dominated thinking in the field. (i) Enzymic specificity is dominated by the contribution of exosite binding interactions between substrate and enzyme rather than by specific recognition of sequences flanking the scissile bond. Coupled with the regulation of substrate conformation as a result of the zymogen to proteinase transition, novel mechanistic insights result for numerous aspects of enzyme function. (ii) The transition of zymogen to proteinase following cleavage is not absolute and instead, thrombin can reversibly interconvert between zymogen-like and proteinase like forms depending on the complement of ligands bound to it. This establishes new paradigms for considering proteinase allostery and how enzyme function may be modulated by ligand binding. These insights into the action of prothrombinase on prothrombin have wide-ranging implications for the understanding of function in blood coagulation. PMID- 23809132 TI - Tissue factor-integrin interactions in cancer and thrombosis: every Jack has his Jill. AB - Tissue factor (TF) is a 47 kDa membrane protein that initiates coagulation by binding to FVII(a) and FX(a) and is a risk factor for thrombosis in many disease states. In addition to its coagulant activity, TF also influences cancer progression by triggering signaling effects via a group of G-protein coupled receptors named protease-activated receptors (PARs). TF localizes to cytoskeletal structures in migrating cells, influences cytoskeleton reorganization and promotes migration. Recently, integrins, important mediators of cell motility, have emerged as important binding partners for TF and influence both TF coagulant and PAR-2-dependent signaling functions. Direct binding of TF to integrins also impacts processes such as cell migration and signaling independent of PAR-2. A recently discovered alternatively spliced, soluble TF isoform also ligates integrins to augment angiogenesis, thus fuelling cancer progression. To date, the literature describes a complex interplay between different integrin subunits and distinct TF isoforms, but our understanding of TF-integrin bidirectional regulation remains clouded. In this review, we aim to summarize the existing knowledge on integrin-TF interaction and speculate on its relevance to physiology and pathology. PMID- 23809133 TI - Fibrin(ogen) and thrombotic disease. AB - Fibrinogen is an abundant plasma protein that, when converted to fibrin by thrombin, provides the main building blocks for the clot. Dys-, a-, and hypo fibrinogenemias have been variably linked to a normal phenotype, bleeding or even thrombosis. Meanwhile, increased fibrinogen concentrations in the blood have been associated with risk for thrombosis. More recently, studies have focussed on abnormal fibrin structure as a cause for thrombosis. Fibrin clots that have high fiber density and increased resistance to fibrinolysis have been consistently associated with risk for thrombosis. Fibrin structure measurements can (i) provide an overall assessment of hemostatic capacity of a sample, (ii) include effects of thrombin generation and fibrinogen concentrations, (iii) include effects of fibrinogen mutations, polymorphisms, and modifications, and (iv) give an indication of clot mechanical strength and resistance to fibrinolysis. A fibrinogen splice variation of the gamma-chain (gamma') is discussed as a model for changes in fibrin structure in relation to thrombosis. Results from prospective studies on fibrin structure are awaited. Studies of fibrin formation under flow, interactions of fibrin with blood cells, the mechanical properties of the fibrin clot, and nanoscale/molecular characterization of fibrin formation are likely to expose new causal mechanisms for the role of fibrin in thrombotic disease. Future studies into the causality and mechanisms may lead to new opportunities using fibrin structure in the diagnosis or treatment of thrombosis. PMID- 23809134 TI - Insights into thrombin activatable fibrinolysis inhibitor function and regulation. AB - Fibrinolysis is initiated when the zymogen plasminogen is converted to plasmin via the action of plasminogen activators. Proteolytic cleavage of fibrin by plasmin generates C-terminal lysine residues capable of binding both plasminogen and the plasminogen activator, thereby stimulating plasminogen activator-mediated plasminogen activation and propagating fibrinolysis. This positive feedback mechanism is regulated by activated thrombin activatable fibrinolysis inhibitor (TAFIa), which cleaves C-terminal lysine residues from the fibrin surface, thereby decreasing its cofactor activity. TAFI can be activated by thrombin alone, but the rate of activation is accelerated when in complex with thrombomodulin. Plasmin is also known to activate TAFI. TAFIa has no known physiologic inhibitors and consequently, its primary regulatory mechanism involves its intrinsic thermal instability. The rate of TAFI activation and stability of the active form, TAFIa, function in maintaining its concentration above the threshold value required to down-regulate fibrinolysis. Although all methods to quantify TAFI or TAFIa have their limitations, epidemiologic studies have indicated that elevated TAFI levels are correlated with an increased risk of venous thrombosis. Major efforts have been made to develop TAFI inhibitors that can either directly interfere with TAFIa activity or impair its activation. However, the anti-inflammatory properties of TAFIa might complicate the development and application of a TAFIa inhibitor that aims to increase the efficiency of thrombolytic therapy. PMID- 23809135 TI - Antiplatelet therapy: new pharmacological agents and changing paradigms. AB - Recurrent atherothrombotic events in patients with acute coronary syndromes (ACS) and/or those undergoing percutaneous coronary intervention (PCI) are essentially platelet-driven processes, underscoring the need for effective pharmacological platelet inhibition. Dual antiplatelet therapy with aspirin and clopidogrel has been, for over a decade, the mainstay of antiplatelet management in ACS/PCI. However, atherothrombotic events continue to occur in a relevant proportion of subjects despite the benefit of this combination, which has led to the clinical development of newer and more potent antiplatelet drugs. Two of these, prasugrel and ticagrelor, have been recently approved for clinical use. The scope of this manuscript is to provide an up-to-date overview on new antiplatelet drugs in the setting of ACS and PCI, including the most recent advances on newly approved agents as well as on emerging compounds in clinical development. PMID- 23809136 TI - Platelet receptors activated via mulitmerization: glycoprotein VI, GPIb-IX-V, and CLEC-2. AB - While very different in structure, GPVI - the major collagen receptor on platelet membranes, the GPIb-IX-V complex - the receptor for von Willebrand factor, and CLEC-2, a novel platelet activation receptor for podoplanin, share several common features in terms of function and platelet activation signal transduction pathways. All employ Src family kinases (SFK), Syk, and other signaling molecules involving tyrosine phosphorylation, similar to those of immunoreceptors for T and B cells. There appear to be overlapping functional roles for these glycoproteins, and in some cases, they can compensate for each other, suggesting a degree of redundancy. New ligands for these receptors are being identified, which broadens their functional relevancy. This is particularly true for CLEC-2, whose functions beyond hemostasis are being explored. The common mode of signaling, clustering, and localization to glycosphingolipid-enriched microdomains (GEMs) suggest that GEMs are central to signaling function by ligand-dependent association of these receptors, SFK, Syk, phosphotyrosine phosphatases, and other signaling molecules. PMID- 23809137 TI - MicroRNAs in platelet production and activation. AB - Recent work by the Encyclopedia of DNA Elements project showed that non-protein coding RNAs account for an unexpectedly large proportion of the human genome. Among these non-coding RNAs are microRNAs (miRNAs), which are small RNA molecules that modulate protein expression by degrading mRNA or repressing mRNA translation. MiRNAs have been shown to play important roles in hematopoiesis including embryonic stem cell differentiation, erythropoiesis, granulocytopoiesis/monocytopoiesis, lymphopoiesis, and megakaryocytopoiesis. Additionally, disordered miRNA biogenesis and quantitative or qualitative alterations in miRNAs and their targets are associated with hematological pathologies. Platelets contain machinery to process pre-miRNAs into mature miRNAs, and specific platelet miRNA levels have been found to correlate with platelet reactivity. This review summarizes the current state of knowledge of miRNAs in megakaryocytes and platelets, and the exciting possibilities for future megakaryocyte-platelet transcriptome research. PMID- 23809138 TI - Improved neurocognitive functions correlate with reduced inflammatory burden in atrial fibrillation patients treated with intensive cholesterol lowering therapy. AB - BACKGROUND: Atrial fibrillation (AF) is associated with increased mortality and morbidity, including risk for cerebral macro- and microinfarctions and cognitive decline, even in the presence of adequate oral anticoagulation. AF is strongly related to increased inflammatory activity whereby anti-inflammatory agents can reduce the risk of new or recurrent AF. However, it is not known whether anti inflammatory therapy can also modify the deterioration of neurocognitive function in older patients with AF. In the present study, older patients with AF were treated with intensive lipid-lowering therapy with atorvastatin 40 mg and ezetimibe 10 mg, or placebo. We examined the relationship between neurocognitive functions and inflammatory burden. FINDINGS: Analysis of inflammatory markers revealed significant reductions in high sensitivity C-reactive protein (hs-CRP), fibroblast growth factor (FGF), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 receptor antagonist (IL-1RA), interleukin (IL)-9, IL-13 and IL-17, and interferon-gamma (IFNgamma) in the treatment group compared to placebo. Reduction in plasma concentration of IL-1RA, IL-2, IL-9 and IL-12, and macrophage inflammatory protein-1beta (MIP-1beta) correlated significantly with improvement in the neurocognitive functions memory and speed. Loss of volume in amygdala and hippocampus, as determined by magnetic resonance imaging (MRI), was reduced in the treatment arm, statistically significant for left amygdala. CONCLUSIONS: Anti inflammatory therapy through intensive lipid-lowering treatment with atorvastatin 40 mg and ezetimibe 10 mg can modify the deterioration of neurocognitive function, and the loss of volume in certain cerebral areas in older patients with AF. TRIAL REGISTRATION ClinicalTrials.gov: NCT00449410. PMID- 23809139 TI - Polymorphic variants of CYP17 and CYP19A and risk of infertility in endometriosis. AB - OBJECTIVE: Endometriosis is recognized as an estrogen-dependent disease. There are conflicting data demonstrating single nuclear polymorphisms (SNPs) of CYP17 and CYP19 steroidogenic genes as related to endometriosis risk. We assessed the CYP17 5'-untranslated region -34 A/G (rs743572) and CYP19 Ex10 + C1558T (rs10046) SNPs in stage I-II endometriosis. DESIGN: Case-control study. SETTING: Division of reproduction at a university department in Poland. POPULATION: A total of 115 women with diagnosed stage I-II endometriosis according to the revised American Society for Reproductive Medicine (rASRM) classification and 197 fertile women as controls. METHODS: The SNPs CYP17 -34 A/G and CYP19 Ex10 + C1558T were identified by high-resolution melting curve analysis. MAIN OUTCOME MEASURES: Genotype prevalence and odds ratio for recessive and dominant genetic model for CYP17 and CYP19 SNPs. RESULTS: We observed a significantly increased CYP17 GG and GA genotype frequency in women diagnosed with rASRM stage I-II endometriosis compared with fertile women (OR = 2.4; 95% CI 1.4-4.2, p = 0.002). We also found a significantly increased CYP17 G allele frequency in cases compared with controls (OR = 1.6; 95% CI 1.2-2.2, p = 0.004). There were no significant differences in the distribution of the CYP17 GG genotype and CYP19 Ex10 + C1558T polymorphism between women diagnosed with rASRM stage I-II endometriosis and controls. CONCLUSION: The CYP17 -34 G variant, previously associated with increased 17beta-estradiol production, displayed a contribution to stage I-II endometriosis in women from a Polish population. Increased 17beta-estradiol concentration in carriers of the CYP17 -34 G variant might contribute to endometriosis and associated pathological processes. PMID- 23809140 TI - Early loss of bone mineral density is correlated with a gain of fat mass in patients starting a protease inhibitor containing regimen: the prospective Lipotrip study. AB - BACKGROUND: HIV-infected patients starting antiretroviral treatment (ART) experience deep and early disorders in fat and bone metabolism, leading to concomitant changes in fat mass and bone mineral density. METHODS: We conducted a prospective study in treatment-naive HIV-infected patients randomized to receive two nucleoside reverse transcriptase inhibitors in combination with either a protease inhibitor (PI) or a non-nucleosidic reverse transcriptase inhibitor (NNRTI), to evaluate early changes in body composition, bone mineral density and metabolic markers as differentially induced by antiretroviral therapies. We measured changes in markers of carbohydrate, of fat and bone metabolism, and, using dual-emission X-ray absorptiometry (DXA), body composition and bone mineral density (BMD). Complete data on changes between baseline and after 21 months treatment were available for 35 patients (16 in the PI group and 19 in the NNRTI group). RESULTS: A significant gain in BMI and in total and lower limb fat mass was recorded only in patients receiving PI. A loss of lumbar BMD was observed in both groups, being higher with PI. Plasma markers of bone metabolism (alkaline phosphatase, osteocalcin, collagen crosslaps) and levels of parathormone and of 1,25diOH-vitamin D3 significantly increased in both groups, concomitant with a decline in 25OH-vitamin D3. Lipids and glucose levels increased in both groups but rise in triglyceride was more pronounced with PI. A correlation between loss of BMD and gain of fat mass is observed in patients starting PI. CONCLUSIONS: We evidenced an early effect of ART on lipid and bone metabolisms. PI lead to a significant gain in fat mass correlated with a sharp drop in BMD but active bone remodelling is evident with all antiretroviral treatments, associated with low vitamin D levels and hyperparathyroidism. In parallel, signs of metabolic restoration are evident. However, early increases in lean and fat mass, triglycerides, waist circumference and leptin are much more pronounced with PI. PMID- 23809141 TI - Emergence of VIM-4 metallo-beta-lactamase-producing Klebsiella pneumoniae ST15 clone in the Clinical Centre University of Pecs, Hungary. AB - Since November 2009 carbapenemase-producing Klebsiella pneumoniae isolates have been detected in increasing numbers at the Clinical Centre University of Pecs. Molecular typing was performed for 102 clinical isolates originating from different time periods and various departments of the Clinical Centre. Pulsed field gel electrophoresis revealed the predominance of a single clone (101/102), identified as sequence type ST15. PCR and sequencing showed the presence of blaCTX-M-15 and blaVIM-4 genes. The blaVIM-4 was located on a class 1 integron designated In238b. To our knowledge, this is the first description of a blaVIM-4 gene in the predominant CTX-M-15 extended spectrum beta-lactamase-producing Hungarian Epidemic Clone/ST15. PMID- 23809142 TI - A systematic review of variables associated with the relationship between obesity and depression. AB - Obesity is one of the leading causes of preventable diseases and disability worldwide, and depression is among the leading causes of burden of disease. Both disorders are increasingly prevalent and comorbid. This comorbidity compounds associated health. While there is consistent evidence of a bidirectional obesity depression relationship, little is known about the biopsychosocial variables associated with this relationship. A systematic review was undertaken to identify variables associated with the relationship between obesity (Body mass index > 30 kg m(-2) ) and depression. Forty-six studies were identified. Obesity, educational attainment, body image, binge eating, physical health, psychological characteristics and interpersonal effectiveness were consistently associated with the relationship between obesity and depression. The current review identified potential biopsychosocial variables associated with the relationship between obesity and depression. This knowledge can inform future research examining moderators, mediators and mechanisms of the relationship between obesity and depression. Improved understanding of this relationship will inform identification, prevention and intervention efforts. PMID- 23809143 TI - Cord blood monocytes, neutrophils and lymphocytes from preterm and full-term neonates show multiple aberrations in signalling profiles measured using phospho specific whole-blood flow cytometry. AB - Immaturity of the immune system renders newborns susceptible to infections. We searched for aberrations in leucocyte signalling profiles, using phospho-specific whole-blood flow cytometry, in cord blood of nine preterm (two born before 32nd gestational week) and nine full-term infants, born by caesarean section. Thirteen adults served as reference subjects. Monocyte NF-kappaB phosphorylation following tumour necrosis factor (TNF) or bacterial stimulation was higher in preterm neonates than in full-term neonates or adults, p38 phosphorylation following bacterial stimulation was higher in both preterm and full-term neonates than in adults, while STAT1 phosphorylation by IFN-gamma or IL-6, STAT3 phosphorylation by IL-6 and STAT5 phosphorylation by GM-CSF were lower in both full-term and preterm neonates than in adults. Neutrophil STAT1 and STAT3 phosphorylation following IFN-gamma stimulation and STAT5 phosphorylation following GM-CSF stimulation were lower in newborn neonates than in adults. In both CD3(+) CD4(+) and CD3(+) CD8(+) lymphocytes, NF-kappaB phosphorylation by TNF was higher and STAT5 phosphorylation by IL-2 was lower in preterm and full-term newborns than in adults. STAT6 phosphorylation by IL-4 was comparable in monocytes and lymphocytes of newborns and adults. The results suggest that innate immune signalling pathways responding to inflammatory stimuli are strongly functional in leucocytes of preterm neonates, which may render these neonates susceptible to inappropriate tissue injury. In leucocytes of both preterm and full-term newborns, responses needed against intracellular pathogens, and regulatory functions show immaturities, possibly contributing to worse control of infections. PMID- 23809144 TI - Intersectoral action for health equity as it relates to climate change in Canada: contributions from critical systems heuristics. AB - RATIONALE: Intersectoral action (ISA) has been at the forefront of public health policy discussions since the 1970s. ISA incorporates a broader perspective of public health issues and coordinates efforts to address the social, political, economic and environmental contexts from which health determinants operate and are created. Despite being forwarded as a useful way to address and treat complex or 'wicked' problems, such policy issues are still often addressed within, rather than across, disciplinary silos and ISA has been documented to fail more often than it succeeds. AIMS AND OBJECTIVES: This paper contributes to an understanding of ISA by outlining and applying critical systems heuristics (CSH) theory and methods. METHODS: CSH theory and methods are described and discussed before applying them to the example of addressing climate change and health equity through public health practice. RESULTS: CSH thinking provides useful tools to engage stakeholders, question relations of power that may exist between collaborating partners, and move beyond power inequalities that guide ISA initiatives. CONCLUSIONS: CSH is a compelling framing that can improve an understanding of the collaborative relationships that are a prerequisite for engaging in ISA to address complex or 'wicked' policy problems such as climate change. PMID- 23809145 TI - Changes in the neural correlates of implicit emotional face processing during antidepressant treatment in major depressive disorder. AB - An emerging hypothesis regarding the mechanisms underlying antidepressant pharmacotherapy suggests that these agents benefit depressed patients by reversing negative emotional processing biases (Harmer, 2008). Neuropsychological indices and functional neuroimaging measures of the amygdala response show that antidepressant drugs shift implicit and explicit processing biases away from the negative valence and toward the positive valence. However, few studies have explored such biases in regions extensively connected with the amygdala, such as the pregenual anterior cingulate cortex (pgACC) area, where pre-treatment activity consistently has predicted clinical outcome during antidepressant treatment. We used functional magnetic resonance imaging (fMRI) to investigate changes in haemodynamic response patterns to positive vs. negative stimuli in patients with major depressive disorder (MDD) under antidepressant treatment. Participants with MDD (n = 10) underwent fMRI before and after 8 wk sertraline treatment; healthy controls (n = 10) were imaged across an equivalent interval. A backward masking task was used to elicit non-conscious neural responses to sad, happy and neutral face expressions. Haemodynamic responses to emotional face stimuli were compared between conditions and groups in the pgACC. The response to masked-sad vs. masked-happy faces (SN-HN) in pgACC in the depressed subjects was higher in the pre-treatment condition than in the post-treatment condition and this difference was significantly greater than the corresponding change across time in the controls. The treatment-associated difference was attributable to an attenuated response to sad faces and an enhanced response to happy faces. Pre treatment pgACC responses to SN-HN correlated positively with clinical improvement during treatment. The pgACC participates with the amygdala in processing the salience of emotional stimuli. Treatment-associated functional changes in this limbic network may influence the non-conscious processing of such stimuli by reversing the negative processing bias extant in MDD. PMID- 23809146 TI - Mechanism of dual specificity kinase activity of DYRK1A. AB - The function of many protein kinases is controlled by the phosphorylation of a critical tyrosine residue in the activation loop. Dual specificity tyrosine phosphorylation-regulated kinases (DYRKs) autophosphorylate on this tyrosine residue but phosphorylate substrates on aliphatic amino acids. This study addresses the mechanism of dual specificity kinase activity in DYRK1A and related kinases. Tyrosine autophosphorylation of DYRK1A occurred rapidly during in vitro translation and did not depend on the non-catalytic domains or other proteins. Expression in bacteria as well as in mammalian cells revealed that tyrosine kinase activity of DYRK1A is not restricted to the co-translational autophosphorylation in the activation loop. Moreover, mature DYRK1A was still capable of tyrosine autophosphorylation. Point mutants of DYRK1A and DYRK2 lacking the activation loop tyrosine showed enhanced tyrosine kinase activity. A series of structurally diverse DYRK1A inhibitors was used to pharmacologically distinguish different conformational states of the catalytic domain that are hypothesized to account for the dual specificity kinase activity. All tested compounds inhibited substrate phosphorylation with higher potency than autophosphorylation but none of the tested inhibitors differentially inhibited threonine and tyrosine kinase activity. Finally, the related cyclin-dependent kinase-like kinases (CLKs), which lack the activation loop tyrosine, autophosphorylated on tyrosine both in vitro and in living cells. We propose a model of DYRK autoactivation in which tyrosine autophosphorylation in the activation loop stabilizes a conformation of the catalytic domain with enhanced serine/threonine kinase activity without disabling tyrosine phosphorylation. The mechanism of dual specificity kinase activity probably applies to related serine/threonine kinases that depend on tyrosine autophosphorylation for maturation. PMID- 23809147 TI - Beta diversity as the variance of community data: dissimilarity coefficients and partitioning. AB - Beta diversity can be measured in different ways. Among these, the total variance of the community data table Y can be used as an estimate of beta diversity. We show how the total variance of Y can be calculated either directly or through a dissimilarity matrix obtained using any dissimilarity index deemed appropriate for pairwise comparisons of community composition data. We addressed the question of which index to use by coding 16 indices using 14 properties that are necessary for beta assessment, comparability among data sets, sampling issues and ordination. Our comparison analysis classified the coefficients under study into five types, three of which are appropriate for beta diversity assessment. Our approach links the concept of beta diversity with the analysis of community data by commonly used methods like ordination and anova. Total beta can be partitioned into Species Contributions (SCBD: degree of variation of individual species across the study area) and Local Contributions (LCBD: comparative indicators of the ecological uniqueness of the sites) to Beta Diversity. Moreover, total beta can be broken up into within- and among-group components by manova, into orthogonal axes by ordination, into spatial scales by eigenfunction analysis or among explanatory data sets by variation partitioning. PMID- 23809148 TI - Immune-mediated limbic encephalitis-tip of the iceberg in childhood autoimmune epilepsy. PMID- 23809149 TI - The relationship between visceral adiposity and left ventricular diastolic function: results from the Baltimore Longitudinal Study of Aging. AB - BACKGROUND AND AIMS: It is unclear whether subcutaneous and visceral fat are differentially correlated to the decline in left ventricular (LV) diastolic function with aging. This study sought to examine the hypothesis that age-related changes in the regional fat distribution account for changes in LV diastolic function and to explore potential mediators of this association. METHODS AND RESULTS: In this cross-sectional study, we evaluated 843 participants of the Baltimore Longitudinal Study of Aging with echocardiogram, dual-energy X-ray absorptiometry (DEXA), abdominal computed tomography (CT) and blood tests performed at the same visit. LV diastolic function was assessed by parameters of LV relaxation (E/A ratio, Em and Em/Am ratio) and LV filling pressures (E/Em ratio). Total body fat was computed by DEXA, while visceral and subcutaneous fat were determined from abdominal CT. In multivariate models adjusted for demographics, cardiovascular risk factors, antihypertensive medications, physical activity and LV mass, both visceral and subcutaneous fat were associated with LV diastolic dysfunction. When both measures of adiposity were simultaneously included in the same model, only visceral fat was significantly associated with LV diastolic dysfunction. Triglycerides and sex-hormone binding globulin, but not adiponectin and leptin, were found to be significant mediators of the relationship between visceral fat and LV diastolic function, explaining 28-47% of the association. Bootstrapping analyses confirmed the significance of these findings. CONCLUSIONS: Increased visceral adiposity is associated with LV diastolic dysfunction, possibly through a metabolic pathway involving blood lipids and ectopic fat accumulation rather than adipokines. PMID- 23809150 TI - Influence of the Mediterranean diet on carotid intima-media thickness in hypercholesterolaemic children: a 12-month intervention study. AB - BACKGROUND AND AIMS: The Mediterranean diet has been recognised as having a protective role on the cardiovascular system due to its low lipid and high antioxidant content. Lipid profile and oxidant status represent two important risk factors related to endothelial dysfunction, even at early stages of cardiovascular diseases. The aim of the study was to evaluate the influence of a 12-month Mediterranean diet on the variation of lipid profile and carotid intima media thickness (cIMT) in pre-pubertal hypercholesterolaemic children. METHODS AND RESULTS: We performed a cross-sectional study comparing lipid profile and cIMT in a group of 68 pre-pubertal children (36 with hypercholesterolaemia and 32 controls). In addition, in the hypercholesterolaemic children a 12-month intervention programme with a Mediterranean diet was started to evaluate the variation of lipid profile and cIMT. At baseline, hypercholesterolaemic children showed a significantly higher cIMT (both right and left carotid artery) compared to controls (both p < 0.05). After 12 months of diet intervention, a significant reduction of total cholesterol, LDL-cholesterol and cIMT was documented (all p < 0.05). Furthermore, at the end of follow-up, delta body mass index-Standard Deviation score and delta LDL-cholesterol were significantly and independently related to the changes of cIMT (both p < 0.05). CONCLUSION: The Mediterranean diet represents a valid approach in the treatment of hypercholesterolaemia even during childhood. PMID- 23809151 TI - Loss of the R2R3 MYB, AtMyb73, causes hyper-induction of the SOS1 and SOS3 genes in response to high salinity in Arabidopsis. AB - Environmental stressors, including high salt, drought, and low or high temperatures, are often associated with significant losses in agricultural productivity. Plants have evolved a diverse array of signaling pathways to modulate their development in response to various environmental challenges. Here, we report the characterization of a member of the R2R3-MYB transcription factor family, AtMyb73. The expression of AtMyb73 was up-regulated by salt stress but not by other stresses. The maximum level of AtMyb73 expression occurred at 6h of 300mM NaCl treatment. Under salt stress, atmyb73 ko mutant plants exhibited higher survival rates compare to wild type (Col-0) plants. Using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis, we determined that the accumulation of salt overly sensitive (SOS) transcripts, SOS1 and SOS3, was higher in atmyb73 ko and atmyb73 eko plants than in wild type plants in response to 300mM NaCl treatment. These results indicate that AtMyb73 is a negative regulator of SOS induction in response to salt stress in Arabidopsis thaliana. PMID- 23809152 TI - Ozone therapy as an adjunct to vancomycin enhances bacterial elimination in methicillin resistant Staphylococcus aureus mediastinitis. AB - BACKGROUND: We aimed to investigate the influence of intraperitoneal ozone therapy on bacterial elimination and mediastinal inflammation in experimental Staphylococcus aureus mediastinitis. MATERIALS AND METHODS: Forty Wistar-Albino rats were randomized into five groups (eight per group) as follows: uncontaminated group, untreated contaminated group, ozone group, vancomycin group, and vancomycin + ozone group. Uncontaminated group underwent upper median sternotomy. The remaining four groups were inoculated with 0.5 mL 10(8) colony forming units/mL methicillin-resistant Staphylococcus aureus in the mediastinal and sternal layers. Untreated contaminated group had no treatment. Rats in the vancomycin group received intramuscular vancomycin (40 mg/kg/d), and ozone was administered intraperitoneally (70 MUg/mL, 1 mg/kg/d) in the ozone group for the treatment of mediastinitis. Vancomycin + ozone group rats were treated by the combination of both methods. At the end of 10 d, quantitative bacterial cultures and sternal tissue samples were obtained for determination of bacterial counts and histologic degree of inflammation. RESULTS: Both the vancomycin and the ozone treatments caused significant reduction of bacterial counts in quantitative bacterial cultures. Combination of vancomycin and ozone treatments resulted in further reduction of bacterial counts in mediastinum and sternum. Histologic examination of tissue samples revealed significant reduction in severity of mediastinitis related inflammation in vancomycin and vancomycin + ozone groups compared with untreated contaminated group. CONCLUSIONS: Ozone therapy as an adjunct to vancomycin leads to enhanced bacterial elimination in infected sternal and mediastinal tissues in experimental methicillin-resistant Staphylococcus aureus mediastinitis. The benefit of adjuvant ozone therapy is suggested to be related to its bactericidal effect. PMID- 23809153 TI - Ischemia reperfusion injury and the immune system. PMID- 23809154 TI - Autologous bone marrow-derived mesenchymal stem cell transplantation promotes liver regeneration after portal vein embolization in cirrhotic rats. AB - BACKGROUND: Preexisting cirrhosis usually leads to an inadequate and delayed regeneration of the future liver remnant (FLR) after portal vein embolization (PVE). Bone marrow-derived mesenchymal stem cells (BMSC) are promising candidates for therapeutic applications in liver diseases. In this study, the efficacy of autologous BMSCs transplantation to promote FLR regeneration was investigated in a rat cirrhotic model. METHODS: Autologous BMSCs were expanded and labeled with PKH26, and then were injected immediately into nonembolized lobes after PVE through portal vein in cirrhotic rat. At 7, 14, and 28 d after this, liver weight and Ki-67 labeling index were measured, and blood analysis was performed. Cirrhotic degree of FLR was assessed by hydroxyproline content assay and histopathology. Gene expressions of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), interleukin-10 (IL-10), and matrix metalloproteinase-9 (MMP-9) were detected with real-time reverse transcriptase polymerase chain reaction. Distribution and hepatocyte differentiation of BMSCs in FLR were determined by confocal microscopy. RESULTS: Autologous BMSCs significantly increased the FLR weight ratio to the total liver and the Ki-67 labeling index, and serum albumin levels were significantly higher and total bilirubin levels were significantly lower in the BMSCs group compared with the controls without BMSCs transplantation 14 and 28 d post-PVE. BMSCs significantly decreased the hydroxyproline content and collagen accumulation, up-regulated the expressions of HGF, IL-10, VEGF, and MMP-9 28 d post-PVE, and expressed hepatocyte-specific markers, such as alpha-fetoprotein, cytokeratin 18, and albumin in a time-dependent manner in FLR. CONCLUSIONS: Autologous BMSCs can differentiate into hepatocyte and promote FLR regeneration after PVE in cirrhotic liver, which may be through improving local microenvironment by decreasing cirrhosis, up-regulating the gene expressions of VEGF, HGF, IL-10, and MMP-9. PMID- 23809155 TI - Boosting lymphocyte production. AB - How lymphoid cell fate is orchestrated in early hematopoietic progenitors remains poorly understood. In this issue of Immunity, Satoh et al. (2013) show that the chromatin remodeler Satb1 promotes lymphocyte differentiation in both young and aged stem cells. PMID- 23809156 TI - Costimulatory genes: hotspots of conflict between host defense and autoimmunity. AB - To understand the adaptations of costimulatory molecules through mammalian evolution, Forni et al. (Forni et al., 2013) studied evolutionary selection in key costimulatory genes. Their results, presented in this issue of Immunity, suggest that the risk of autoimmmunity is balanced against efficacy of the anti pathogen immune response. PMID- 23809157 TI - K+ drops tilt the NLRP3 inflammasome. AB - Unwarranted NLRP3 activation causes inflammatory disease. Its activation must therefore be specifically licensed. In this issue of Immunity, Munoz-Planillo et al. (2013) reveal K+ efflux as the sole common denominator of an array of unrelated stimuli engaging this inflammasome. PMID- 23809158 TI - (De-) oiling inflammasomes. AB - Activation of inflammasome signaling can produce harmful inflammation. In this issue of Immunity, Yan et al. (2013) suggest that omega-3 fatty acids commonly found in marine oils can suppress activation of NLRP3 and NLRP1b inflammasomes. PMID- 23809159 TI - Instant recall: a key role for effector-phenotype CD8+ memory T cells in immune protection. AB - In this issue of Immunity, Olson et al. (2013) demonstrate that circulating CD8+ memory T cells with an effector-like phenotype, previously thought to be mostly senescent, provide robust protection from a secondary pathogen challenge despite their poor secondary proliferative response. PMID- 23809161 TI - K+ efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. AB - The NLRP3 inflammasome is an important component of the innate immune system. However, its mechanism of activation remains largely unknown. We show that NLRP3 activators including bacterial pore-forming toxins, nigericin, ATP, and particulate matter caused mitochondrial perturbation or the opening of a large membrane pore, but this was not required for NLRP3 activation. Furthermore, reactive oxygen species generation or a change in cell volume was not necessary for NLRP3 activation. Instead, the only common activity induced by all NLRP3 agonists was the permeation of the cell membrane to K+ and Na+. Notably, reduction of the intracellular K+ concentration was sufficient to activate NLRP3, whereas an increase in intracellular Na+ modulated but was not strictly required for inflammasome activation. These results provide a unifying model for the activation of the NLRP3 inflammasome in which a drop in cytosolic K+ is the common step that is necessary and sufficient for caspase-1 activation. PMID- 23809160 TI - Immune effector mechanisms implicated in atherosclerosis: from mice to humans. AB - According to the traditional view, atherosclerosis results from a passive buildup of cholesterol in the artery wall. Yet, burgeoning evidence implicates inflammation and immune effector mechanisms in the pathogenesis of this disease. Both innate and adaptive immunity operate during atherogenesis and link many traditional risk factors to altered arterial functions. Inflammatory pathways have become targets in the quest for novel preventive and therapeutic strategies against cardiovascular disease, a growing contributor to morbidity and mortality worldwide. Here we review current experimental and clinical knowledge of the pathogenesis of atherosclerosis through an immunological lens and how host defense mechanisms essential for survival of the species actually contribute to this chronic disease but also present new opportunities for its mitigation. PMID- 23809162 TI - Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation. AB - Omega-3 fatty acids (omega-3 FAs) have potential anti-inflammatory activity in a variety of inflammatory human diseases, but the mechanisms remain poorly understood. Here we show that stimulation of macrophages with omega-3 FAs, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and other family members, abolished NLRP3 inflammasome activation and inhibited subsequent caspase-1 activation and IL-1beta secretion. In addition, G protein-coupled receptor 120 (GPR120) and GPR40 and their downstream scaffold protein beta arrestin-2 were shown to be involved in inflammasome inhibition induced by omega 3 FAs. Importantly, omega-3 FAs also prevented NLRP3 inflammasome-dependent inflammation and metabolic disorder in a high-fat-diet-induced type 2 diabetes model. Our results reveal a mechanism through which omega-3 FAs repress inflammation and prevent inflammation-driven diseases and suggest the potential clinical use of omega-3 FAs in gout, autoinflammatory syndromes, or other NLRP3 inflammasome-driven inflammatory diseases. PMID- 23809163 TI - Specific gut commensal flora locally alters T cell tuning to endogenous ligands. AB - Differences in gut commensal flora can dramatically influence autoimmune responses, but the mechanisms behind this are still unclear. We report, in a Th1 cell-driven murine model of autoimmune arthritis, that specific gut commensals, such as segmented filamentous bacteria, have the ability to modulate the activation threshold of self-reactive T cells. In the local microenvironment of gut-associated lymphoid tissues, inflammatory cytokines elicited by the commensal flora dynamically enhanced the antigen responsiveness of T cells that were otherwise tuned down to a systemic self-antigen. Together with subtle differences in early lineage differentiation, this ultimately led to an enhanced recruitment of pathogenic Th1 cells and the development of a more severe form of autoimmune arthritis. These findings define a key role for the gut commensal flora in sustaining ongoing autoimmune responses through the local fine tuning of T-cell receptor-proximal activation events in autoreactive T cells. PMID- 23809165 TI - At the limits of a successful body plan - 3D microanatomy, histology and evolution of Helminthope (Mollusca: Heterobranchia: Rhodopemorpha), the most worm like gastropod. AB - BACKGROUND: Gastropods are among the most diverse animal clades, and have successfully colonized special habitats such as the marine sand interstitial. Specialized meiofaunal snails and slugs are tiny and worm-shaped. They combine regressive features - argued to be due to progenetic tendencies - with convergent adaptations. Microscopic size and concerted convergences make morphological examination non-trivial and hamper phylogenetic reconstructions. The enigmatic turbellarian-like Rhodopemorpha are a small group that has puzzled systematists for over a century. A preliminary molecular framework places the group far closer to the root of Heterobranchia - one of the major gastropod groups - than previously suggested. The poorly known meiofaunal Helminthope psammobionta Salvini-Plawen, 1991 from Bermuda is the most worm-shaped free-living gastropod and shows apparently aberrant aspects of anatomy. Its study may give important clues to understand the evolution of rhodopemorphs among basal heterobranchs versus their previously thought origin among 'higher' euthyneuran taxa. RESULTS: We describe the 3D-microanatomy of H. psammobionta using three-dimensional digital reconstruction based on serial semithin histological sections. The new dataset expands upon the original description and corrects several aspects. Helminthope shows a set of typical adaptations and regressive characters present in other mesopsammic slugs (called 'meiofaunal syndrome' herein). The taxonomically important presence of five separate visceral loop ganglia is confirmed, but considerable further detail of the complex nervous system are corrected and revealed. The digestive and reproductive systems are simple and modified to the thread-like morphology of the animal; the anus is far posterior. There is no heart; the kidney resembles a protonephridium. Data on all organ systems are compiled and compared to Rhodope. CONCLUSIONS: Helminthope is related to Rhodope sharing unique apomorphies. We argue that the peculiar kidney, configuration of the visceral loop and simplicity or lack of other organs in Rhodopemorpha are results of progenesis. The posterior shift of the anus in Helminthope is interpreted as a peramorphy, i.e. hypertrophy of body length early in ontogeny. Our review of morphological and molecular evidence is consistent with an origin of Rhodopemorpha slugs among shelled 'lower Heterobranchia'. Previously thought shared 'diagnostic' features such as five visceral ganglia are either plesiomorphic or convergent, while euthyneury and a double-rooted cerebral nerve likely evolved independently in Rhodopemorpha and Euthyneura. PMID- 23809164 TI - miR-142-3p prevents macrophage differentiation during cancer-induced myelopoiesis. AB - Tumor progression is accompanied by an altered myelopoiesis causing the accumulation of immunosuppressive cells. Here, we showed that miR-142-3p downregulation promoted macrophage differentiation and determined the acquisition of their immunosuppressive function in tumor. Tumor-released cytokines signaling through gp130, the common subunit of the interleukin-6 cytokine receptor family, induced the LAP* isoform of C/EBPbeta transcription factor, promoting macrophage generation. miR-142-3p downregulated gp130 by canonical binding to its messenger RNA (mRNA) 3' UTR and repressed C/EBPbeta LAP* by noncanonical binding to its 5' mRNA coding sequence. Enforced miR expression impaired macrophage differentiation both in vitro and in vivo. Mice constitutively expressing miR-142-3p in the bone marrow showed a marked increase in survival following immunotherapy with tumor specific T lymphocytes. By modulating a specific miR in bone marrow precursors, we thus demonstrated the feasibility of altering tumor-induced macrophage differentiation as a potent tool to improve the efficacy of cancer immunotherapy. PMID- 23809166 TI - [Intracavitary electrocardiogram during the insertion of peripherally inserted central catheters]. AB - OBJECTIVE: To evaluate the applicability, feasibility and accuracy of the IC-ECG with column of saline technique for verifying the final tip position of peripherally inserted central catheters (PICC) by specialist nurses. METHOD: A total of 99 consecutive PICC were inserted. Patients with no superficial ECG P wave, atrial fibrillation, or a pacemaker were excluded. The IC-ECG technique was performed on 84 patients. A chest x-ray was performed after insertion in all cases, in order to compare images with IC-ECG. RESULTS: The technique showed an applicability of 84.4%, an feasibility of 88%, and an accuracy of 87.8%. CONCLUSIONS: The IC-ECG technique for verification of catheter PICC tip locations with column of saline is easy to apply, is cost-effective, is achievable by nurses, and does not involve any risk for patients. The technique involves a learning curve, and it must be performed by qualified health care professionals. The technique is performed during the insertion of the catheter, so verification of the tip is made in situ. It reduces future re-insertions due to wrong positioning of the tip. PMID- 23809167 TI - Virtual training and coaching of health behavior: example from mindfulness meditation training. AB - OBJECTIVE: Computer-based virtual coaches are increasingly being explored for patient education, counseling, and health behavior training and coaching. The objective of this research was to develop and evaluate a Virtual Mindfulness Coach for training and coaching in mindfulness meditation. METHODS: The coach was implemented as an embodied conversational character, providing mindfulness training and coaching via mixed initiative, text-based, natural language dialog with the student, and emphasizing affect-adaptive interaction. (The term 'mixed initiative dialog' refers to a human-machine dialog where either can initiate a conversation or a change in the conversation topic.) RESULTS: Findings from a pilot evaluation study indicate that the coach-based training is more effective in helping students establish a regular practice than self-administered training using written and audio materials. The coached group also appeared to be in more advanced stages of change in terms of the transtheoretical model, and have a higher sense of self-efficacy regarding establishment of a regular mindfulness practice. CONCLUSION: These results suggest that virtual coach-based training of mindfulness is both feasible, and potentially more effective, than a self administered program. Of particular interest is the identification of the specific coach features that contribute to its effectiveness. PRACTICE IMPLICATIONS: Virtual coaches could provide easily accessible and cost-effective customized training for a range of health behaviors. The affect-adaptive aspect of these coaches is particularly relevant for helping patients establish long term behavior changes. PMID- 23809168 TI - Challenges in the communication between 'communication vulnerable' people and their social environment: an exploratory qualitative study. AB - OBJECTIVE: Communication vulnerable people are often unable to communicate effectively within their social environment, hindering client-centered care and participation in daily life. This study aims to explore the experiences of communication and the factors that influence this in long term care settings. METHODS: A qualitative study using the critical incident method. Communication vulnerable clients and people within their immediate environment were interviewed about their communication experiences. RESULTS: Thirty-nine individuals in three settings participated in the interviews, of which 14 were clients. Specific challenges in communication were presented in different relationships. The main influencing factors in the communication between clients and professionals were: effort put into improving the communication, knowledge of the professional, augmentative and alternative communication, time for communication and the influence and power of the client. CONCLUSION: Communication vulnerable people and people within their immediate environment face daily challenges in communicating with each other. In particular, communication among clients, can be very difficult. Augmentative and alternative communication tools are only rarely used. PRACTICE IMPLICATIONS: Professionals need to develop adequate knowledge and skills to improve their communication. Also, more attention should be focussed on use of AAC, communication between professionals and family members, and support in the communication among clients. PMID- 23809169 TI - Resilience to bullying victimization: the role of individual, family and peer characteristics. AB - Little research attention has been paid to bullied students who function better than expected and are therefore defined as "resilient". The present longitudinal study aimed to identify individual, family and peer factors that predict fewer than expected levels of depression and delinquency following experiences of bullying victimization. The sample consisted 3,136 adolescents. Self-report data were used to measure bullying victimization at age 13 and 14 and depression and delinquency at age 14. We examined the effects of gender, self-esteem, social alienation, parental conflict, sibling victimization and number of close friends on levels of emotional and behavioral resilience following bullying victimization. The resilience measures were derived by regressing depression and delinquency scores at age 14 on levels of bullying victimization at age 13 and 14, respectively. The adolescents who reported low depression despite frequently experiencing bullying tended to be male, had higher self-esteem, were feeling less socially alienated, were experiencing low levels of conflict with parents and were not victimized by siblings. On the other hand, the adolescents who reported low delinquency despite frequently experiencing bullying tended to be female, had higher self-esteem, were experiencing low levels of conflict with parents, were not victimized by siblings and had less close friends. Relationships with parents and siblings continue to play some role in promoting emotional and behavioral adjustment among victims of bullying and, therefore, interventions are more likely to be successful if they target both the psychosocial skills of adolescents and their relationships with their family. PMID- 23809170 TI - Advantage Medicare. PMID- 23809171 TI - Resident iPad use: has it really changed the game? AB - PURPOSE: The purpose of this study was to assess residents' usage patterns and opinions of the iPad as a tool for radiology education and clinical practice at an academic medical center. METHODS: All 38 radiology residents in our radiology program (postgraduate years 2 to 5) were provided with iPad 2 tablets and subscriptions to e-Anatomy and STATdx. After 6 months of device use, residents were surveyed to assess their opinions regarding the technology as a tool for education and clinical practice. RESULTS: A total of 36 residents (95%) completed the survey. Eighty-six percent reported daily iPad use. Radiology-specific applications, particularly e-Anatomy, were used weekly or daily by 88% of respondents. Most preferred to read journal articles on the iPad (70%), but the number of respondents preferring to read textbooks on the iPad (48.5%) compared with the traditional bound form (48.5%) was evenly divided. Residents were also divided on the clinical utility of the iPad. Most had not used the iPad to view radiologic examinations (75%). Fewer than half (47%) used their iPads during readout. Finally, only 12% had used the iPad to edit dictated reports. CONCLUSIONS: The iPad has generated excitement within the radiology community, particularly among resident educators, who are increasingly recognizing the unique needs of "millennial learners." This study showed that the majority of residents at the authors' institution have incorporated the iPad as an educational tool and use it as a learning aid. Incorporation of the iPad into clinical workflow has been less pronounced. PMID- 23809172 TI - C-Glucosides with heteroaryl thiophene as novel sodium-dependent glucose cotransporter 2 inhibitors. AB - Canagliflozin (1), a novel inhibitor for sodium-dependent glucose cotransporter 2 (SGLT2), has been developed for the treatment of type 2 diabetes. To investigate the effect of replacement of the phenyl ring in 1 with heteroaromatics, C glucosides 2 were designed, synthesized, and evaluated for their inhibitory activities against SGLT2. Of these, 3-pyridyl, 2-pyrimidyl or 5-membered heteroaryl substituted derivatives showed highly potent inhibitory activity against SGLT2, while 5-pyrimidyl substitution was associated with slightly reduced activity. In particular, 2g (TA-3404) had remarkable anti-hyperglycemic effects in high-fat diet fed KK (HF-KK) mice. PMID- 23809173 TI - [Clozapine-induced parotitis: a case study]. AB - INTRODUCTION: Clozapine is the drug of choice for patients with an unsatisfactory response to routine antipsychotic treatment. Side effects such as sedation, weight gain, hypotension and hypersialorrhea are frequently reported whereas clozapine-induced parotitis is a less known complication. CASE REPORT: We report the case of a 32-year-old woman with a refractory schizoaffective disorder, bipolar type. The failure to respond to at least two well-conducted antipsychotic trials with flupentixol and risperidone, led clinicians to prescribe clozapine, which was started three years earlier. Since its introduction, clozapine induced sialorrhea, which has been managed until now with anticholinergic medication. Recently, Mrs B. was hospitalized for a new relapse. Once treatment compliance checked (good level of plasmatic dosage), we decided to increase the dose of clozapine from 350 mg/d to 500 mg/d. Twenty days later, Mrs B. exhibited improvement of symptoms but complained of acute bilateral auricular pain and odynophagia. The bilateral and comparative clinical exam displayed a bilateral filling of the retromandibular depression, the painful swelling of the parotid gland, along with ptyalism and a slight inflammatory oedema of the Stenon duct orifice. Mrs B. was apyretic, with physiological constants within the limits of normal values. The biological analyses displayed a discrete inflammatory syndrome (mild hyperleucocytosis and anemia), a negative mumps IgM test and positive mumps IgG test, and a 1050 ng/mL clozapine blood level. Once viral parotitis was ruled out, the involvement of clozapine was evoked. Symptomatic medication was prescribed with per os analgesic (paracetamol) and antiseptic mouthwash (Eludril). Clozapine dosage was lowered to 400 mg/d. A week later, clinical examination confirmed improvement of the medical and psychiatric conditions. DISCUSSION: We report the case of a patient who developed a parotitis following clozapine dose adjustment. Clozapine induced parotitis was retained once the infectious and other organic etiologies had been ruled out. Previous cases of clozapine-induced parotitis have already been reported and we have some arguments to suspect this etiology in our case. First, Mrs B. experienced more hypersialorrhea with the increase in clozapine dosage. Second, the anticholinergic medication was interrupted 3 days before the episode of parotitis. Two main pathophysiological hypotheses, immune and inflammatory, have already been proposed to explain clozapine-induced parotitis. In the former, the immunomodulating properties of clozapine may sensitize the mononuclear blood cells, leading to the sialadenitis. The latter hypothesis is the more documented and proposes that clozapine-induced hypersialorrhea may be responsible for a chronic inflammatory state that can lead to the formation of a parotid lithiasis and consequently parotitis. This case report illustrates clozapine induced parotitis, a poorly known complication of this compound. Clinicians should be aware of its hypersialorrhea and inflammatory consequences in order to better prevent the occurrence of this complication. PMID- 23809174 TI - [Safeguarding the prescription of antipsychotics in the paediatric population: A French multicentric study in a treatment naive population]. PMID- 23809175 TI - [What nosographic framework for excessive tanning?]. AB - BACKGROUND: Socially valorised tanning, like other forms of behaviour, can take on an addictive aspect. Excessive tanning, defined by the presence of impulsivity and repetition of tanning that leads to personal distress, is a psychiatric disorder that has only recently been recognized. This finding is based on the observations of many dermatologists who report an addictive relationship in their patients with tanning cabins despite announcement of the diagnosis of malignant melanoma. OBJECTIVE: This article attempts to synthesize the existing literature on excessive tanning and addiction to investigate possible associations. This review focuses on the prevalence, clinical features, aetiology, and treatment of this disorder. METHODS: The literature review was conducted from 1983 to 2012, using PubMed, Google Scholar, EMBASE, and PsycInfo, using the following keywords alone or combined: Tanning, Addiction, Sunbeds, Skin cancer prevention, and Treatment. We investigated different models to determine how excessive tanning met these criteria. RESULTS: Excessive Tanning was described in the 2000s by an American dermatologist, Carolyn Heckman. Wartham et al. were the first to have proposed a theoretical framework for addiction to sunbathing, as well as two scales (m CAGE and m DSM IV) for the diagnosis and to assess the degree of addiction. These diagnostic criteria describe the craving like-symptoms, the feeling of losing control, or the continuation of the behavior despite knowledge of negative consequences. Excessive Tanning is not present in the classifications of the DSM or ICD, but may be related to Addiction, Obsessive-Compulsive Disorder, Impulse control disorders, Anorexia, or Body Dysmorphic Disorder. CONCLUSION: Excessive tanning can be included in the spectrum of behavioural addictions due its clinical characteristics in common with classics addictive disorders. They are a variety of other models, which may offer an explanation for or insight into tanning behaviour. Further studies must be controlled, notably on clinical psychopathology, neurobiology and management to improve our understanding of excessive tanning. PMID- 23809176 TI - Dementia in the oldest old: a multi-factorial and growing public health issue. AB - The population of oldest old, or people aged 85 and older, is growing rapidly. A better understanding of dementia in this population is thus of increasing national and global importance. In this review, we describe the major epidemiological studies, prevalence, clinical presentation, neuropathological and imaging features, risk factors, and treatment of dementia in the oldest old. Prevalence estimates for dementia among those aged 85+ ranges from 18 to 38%. The most common clinical syndromes are Alzheimer's dementia, vascular dementia, and mixed dementia from multiple etiologies. The rate of progression appears to be slower than in the younger old. Single neuropathological entities such as Alzheimer's dementia and Lewy body pathology appear to have declining relevance to cognitive decline, while mixed pathology with Alzheimer's disease, vascular disease (especially cortical microinfarcts), and hippocampal sclerosis appear to have increasing relevance. Neuroimaging data are sparse. Risk factors for dementia in the oldest old include a low level of education, poor mid-life general health, low level of physical activity, depression, and delirium, whereas apolipoprotein E genotype, late-life hypertension, hyperlipidemia, and elevated peripheral inflammatory markers appear to have less relevance. Treatment approaches require further study, but the oldest old may be more prone to negative side effects compared with younger patients and targeted therapies may be less efficacious since single pathologies are less frequent. We also highlight the limitations and challenges of research in this area, including the difficulty of defining functional decline, a necessary component for a dementia diagnosis, the lack of normative neuropsychological data, and other shortcomings inherent in existing diagnostic criteria. In summary, our understanding of dementia in the oldest old has advanced dramatically in recent years, but more research is needed, particularly among varied racial, ethnic, and socioeconomic groups, and with respect to biomarkers such as neuroimaging, modifiable risk factors, and therapy. PMID- 23809177 TI - Association between Internet overuse and aggression in Korean adolescents. AB - BACKGROUND: The purpose of this study was to examine the association between Internet overuse and aggression. METHODS: A total of 2336 high school students (boys, 57.5%; girls, 42.5%) in South Korea completed the structured questionnaire. The severity of Internet overuse was evaluated using Young's Internet Addiction Test. Aggression was measured using the Aggression Questionnaire, a modified hostility inventory by Buss and Perry. RESULTS: The proportions of boys who were classified as severe addicts and moderate addicts were 2.5% and 53.7%, respectively. For girls, the corresponding proportions were 1.9% and 38.9%, respectively. manova results for univariate analysis showed that sex, duration of Internet use, most-frequently used Internet activities, level of Internet addiction, smoking, alcohol, and caffeine were significantly associated with aggression scores. From multivariate analysis, it was found that smoking, alcohol, and level of Internet addiction were independently associated with all aggressive characteristics. Internet addiction scores were also significantly associated with all aggression scores from simple and multiple linear regression analyses (parameter estimate = 0.54-0.58 for total aggression). Pearson correlation results showed that Internet addiction scores revealed the highest correlation coefficients with aggression among Internet-related factors, age, and sex. Severe Internet-addicted boys showed higher scores in all aggression characteristics than severe Internet-addicted girls, even though it was not statistically significant in every characteristic. However, there was no sex effect on the association between Internet overuse and aggression. CONCLUSION: This study shows that Internet overuse is strongly associated with aggression in adolescents. PMID- 23809178 TI - Pharmacogenomics in cardiovascular disease: focus on aspirin and ADP receptor antagonists. AB - Antiplatelet agents like aspirin and adenosine diphosphate receptor antagonists are effective in reducing recurrent ischemic events. Considerable inter individual variability in the platelet inhibition obtained with these drugs has initiated a search for explanatory mechanisms and ways to improve treatment. In recent years, numerous genetic polymorphisms have been linked with reduced platelet inhibition and lack of clinical efficacy of antiplatelet drugs, particularly clopidogrel and aspirin. Consequently, attempts to adjust antiplatelet treatment according to genotype have been made, but the clinical benefit has been modest in studies performed so far. The progress in genome science over the last decade and the declining cost of sequencing technologies hold the promise of enabling genetically tailored antiplatelet therapy. However, more evidence is needed to clarify which polymorphisms may serve as targets to improve treatment. The present review outlines the panel of polymorphisms affecting the benefit of aspirin and adenosine diphosphate receptor antagonists, including novel and ongoing studies evaluating whether genotyping may be beneficial in tailoring antiplatelet therapy. PMID- 23809179 TI - The effects, safety and acceptability of compact, pre-filled, autodisable injection devices when delivered by lay health workers. AB - OBJECTIVES: To systematically assess (i) the effects and safety and (ii) the acceptability of using lay health workers (LHWs) to deliver vaccines and medicines to mothers and children through compact pre-filled autodisable devices (CPADs). METHODS: We searched electronic databases and grey literature. For the systematic review of effects and safety, we sought randomised and non-randomised controlled trials, controlled before-after studies and interrupted time series studies. For the systematic review of acceptability, we sought qualitative studies. Two researchers independently carried out data extraction, study quality assessment and thematic analysis of the qualitative data. RESULTS: No studies met our criteria for the review exploring the effects and safety of using LHWs to deliver CPADs. For the acceptability review, six qualitative studies assessed the acceptability of using LHWs to deliver hepatitis B vaccine, tetanus toxoid vaccine, gentamicin or oxytocin using UnijectTM devices. All studies took place in low- or middle-income countries and explored the perceptions of community members, LHWs, supervisors, health professionals or programme managers. Most of the studies were of low quality. Recipients generally accepted the intervention. Most health professionals were confident that LHWs could deliver the intervention with sufficient training and supervision, but some had problems delivering supervision. The LHWs perceived UnijectTM as effective and important and were motivated by positive responses from the community. However, some LHWs feared the consequences if harm should come to recipients. CONCLUSIONS: Evidence of the effects and safety of using CPADs delivered by LHWs is lacking. Evidence regarding acceptability suggests that this intervention may be acceptable although LHWs may feel vulnerable to blame. PMID- 23809180 TI - RNA interference of GGTA1 physiological and immune functions in immortalized porcine aortic endothelial cells. AB - BACKGROUND: Pig organs are commonly used in xenotransplantation, and alpha-1,3 galactose has been shown to be the main cause of hyperacute rejection. The development of transgenic pigs that lack alpha-1,3-galactosyltransferase (GGTA1) has overcome this problem to a certain extent, but transgenic pigs are difficult to maintain, making their usefulness in basic research limited. For this reason, we propose to establish a cell model to study hyperacute rejection. METHODS: Immortalized primary porcine aortic endothelial cells were transfected with a short hairpin RNA targeted to GGTA1. Cell proliferation, apoptosis, complement C3 activation, and the binding of human immunoglobulins and components of the complement system, including IgM, IgG, C3, and C5b-9, were examined. RESULTS: After RNA interference, GGTA1 was found to be reduced at both the transcript and protein level as assessed by quantitative polymerase chain reaction and flow cytometry, respectively. When cultured in the presence of human serum, the proliferation rate of the transfected cells was higher than that of untransfected cells, and the apoptosis rate was lower. Additionally, activation of C3 and the binding of human immunoglobulins IgM and IgG and complement component C3 and C5b 9 to the transfected cells were lower than in the immortalized group but higher than in untransfected cells. CONCLUSIONS: RNA interference of GGTA1 in cultured porcine endothelial cells reduces the reaction of immunoglobulin and complement system with the cells. Therefore, this in vitro cell model could be useful for further study of xenotransplantation. PMID- 23809181 TI - Evoked electromyography to rocuronium in orbicularis oris and gastrocnemius in facial nerve injury in rabbits. AB - BACKGROUND: Muscles innervated by the facial nerve show different sensitivities to muscle relaxants than muscles innervated by somatic nerves, especially in the presence of facial nerve injury. We compared the evoked electromyography (EEMG) response of orbicularis oris and gastrocnemius in with and without a non depolarizing muscle relaxant in a rabbit model of graded facial nerve injury. METHODS: Differences in EEMG response and inhibition by rocuronium were measured in the orbicularis oris and gastrocnemius muscles 7 to 42 d after different levels of facial nerve crush injuries in adult rabbits. RESULTS: Baseline EEMG of orbicularis oris was significantly smaller than those of the gastrocnemius. Gastrocnemius was more sensitive to rocuronium than the facial muscles (P < 0.05). Baseline EEMG and EEMG amplitude of orbicularis oris in the presence of rocuronium was negatively correlated with the magnitude of facial nerve injury but the sensitivity to rocuronium was not. No significant difference was found in the onset time and the recovery time of rocuronium among gastrocnemius and normal or damaged facial muscles. CONCLUSIONS: Muscles innervated by somatic nerves are more sensitive to rocuronium than those innervated by the facial nerve, but while facial nerve injury reduced EEMG responses, the sensitivity to rocuronium is not altered. Partial neuromuscular blockade may be a suitable technique for conducting anesthesia and surgery safely when EEMG monitoring is needed to preserve and protect the facial nerve. Additional caution should be used if there is a risk of preexisting facial nerve injury. PMID- 23809182 TI - Age-related disparities in use of completion lymphadenectomy for melanoma sentinel lymph node metastasis. AB - BACKGROUND: Guidelines recommend that patients with melanoma metastatic to the sentinel lymph node (SLN) undergo a completion lymphadenectomy (CLND) of the affected lymph node basin. We have previously reported on decreased use of SLN biopsy among elderly patients. We hypothesized that elderly patients with SLN metastases would have lower rates of CLND relative to their younger counterparts. METHODS: The Surveillance, Epidemiology, and End Results database was queried for patients who underwent SLN biopsy for intermediate thickness cutaneous melanoma (Breslow thickness 1.01 mm-4.00 mm) from 2004 to 2008 and were found to have SLN metastasis. Patients were categorized according to age by decade. We then used multivariate logistic regression models to predict receipt of CLND. Additional covariates included sex, race/ethnicity, T stage, tumor histology, tumor location, and ulceration. The likelihood of receiving a CLND was reported as OR with 95% CI; significance was set at P <= 0.05. RESULTS: Entry criteria were met by 765 patients. Of these, 548 (71.6%) patients underwent CLND. On multivariate analysis, patients in the age groups 70-79 y old (OR 0.39, CI 0.20-0.78; P = 0.007) and >= 80 y old (OR 0.27, CI 0.12-0.61; P = 0.001) were less likely to undergo CLND than the youngest age group (1-39 y old). CONCLUSIONS: Elderly patients with SLN metastasis are less likely to receive CLND than their younger counterparts. A multi-center randomized clinical trial evaluating the potential survival benefit of CLND is ongoing. Further research to assess reasons why the elderly are less likely to receive CLND are needed. PMID- 23809183 TI - Are flexion extension films necessary for cervical spine clearance in patients with neck pain after negative cervical CT scan? AB - BACKGROUND: There are variations in cervical spine (CS) clearance protocols in neurologically intact blunt trauma patients with negative radiological imaging but persistent neck pain. Current guidelines from the current Eastern Association for the Surgery of Trauma include options of maintaining the cervical collar or obtaining either magnetic resonance imaging (MRI) or flexion-extension films (FEF). We evaluated the utility of FEF in the current era of routine computerized tomography (CT) for imaging the CS in trauma. MATERIALS AND METHODS: All neurologically intact, awake, nonintoxicated patients who underwent FEF for persistent neck pain after negative CT scan of the CS at our level I trauma center over a 13-mo period were identified. Their charts were reviewed and demographic data obtained. RESULTS: There were 354 patients (58.5% male) with negative cervical CS CT scans who had FEF for residual neck pain. Incidental degenerative changes were seen in 37%--which did not affect their acute management. FEF were positive for possible ligamentous injury in 5 patients (1.4%). Two of these patients had negative magnetic resonance images and the other three had collars removed within 3 wk as the findings were ultimately determined to be degenerative. CONCLUSIONS: In the current era, where cervical CT has universally supplanted initial plain films, FEF appear to be of little value in the evaluation of persistent neck pain. Their use should be excluded from cervical spine clearance protocols in neurologically intact, awake patients. PMID- 23809184 TI - Subchondral cyst development and MMP-1 expression during progression of osteoarthritis: an immunohistochemical study. AB - BACKGROUND: Subchondral bone cyst (SBC) formation is often identified in patients with osteoarthritis. Furthermore, several studies have shown that expression of matrix metalloproteinases (MMPs) is elevated in patients with OA. OBJECTIVES: The aim of our study is to correlate the presence of SBCs and MMP-1 expression with the osteochondral alterations during OA progression. METHODS: We studied the cartilage and subchondral bone of 15 patients who had undergone total knee or hip replacement due to primary OA. As controls, we used the femoral heads of three patients without macroscopic OA changes. We evaluated three specimens per patient. RESULTS: Specimens were divided in four groups based on the Mankin histological severity score. Using immunohistochemistry, we noted SBCs at the site of greatest disease severity. Specifically, these were present more frequently in group III (Mankin score: 6-7) and IV (Mankin: >= 8), compared with group I (Mankin: 1-3) and II (Mankin: 4-5). Mild OA stages (Mankin: 1-6) were characterized by degeneration and thinning of the cartilage, followed by increased osteoblast and osteoclast activity of the subjacent bone and the subsequent appearance of SBCs. Simultaneously, we observed expression of MMP-1 in groups I and II in the cartilage and III and IV in both the cartilage and the subchondral bone. Moreover, osteoblast-like cells in the lining of the SBCs showed an increased expression of MMP-1 in stages III and IV. CONCLUSION: Our study provides immunohistological evidence that SBCs accumulate in advanced OA and contain activated cells, which express MMP-1, suggesting that they may thus participate in the osteochondral changes of OA. LEVEL OF EVIDENCE: Level III; prospective comparative study. PMID- 23809185 TI - Diversification under sexual selection: the relative roles of mate preference strength and the degree of divergence in mate preferences. AB - The contribution of sexual selection to diversification remains poorly understood after decades of research. This may be in part because studies have focused predominantly on the strength of sexual selection, which offers an incomplete view of selection regimes. By contrast, students of natural selection focus on environmental differences that help compare selection regimes across populations. To ask how this disparity in focus may affect the conclusions of evolutionary research, we relate the amount of diversification in mating displays to quantitative descriptions of the strength and the amount of divergence in mate preferences across a diverse set of case studies of mate choice. We find that display diversification is better explained by preference divergence rather than preference strength; the effect of the latter is more subtle, and is best revealed as an interaction with the former. Our findings cast the action of sexual selection (and selection in general) in a novel light: the strength of selection influences the rate of evolution, and how divergent selection is determines how much diversification can occur. Adopting this view will enhance tests of the relative role of natural and sexual selection in processes such as speciation. PMID- 23809186 TI - In vitro investigation of individual and combined cytotoxic effects of aflatoxin B1 and other selected mycotoxins on the cell line porcine kidney 15. AB - In the present study, we evaluated the nephrotoxicity of individual mycotoxins and combinations of aflatoxin B1 (AFB1), zearalenone (ZEA), deoxynivalenol (DON), and fumonisin B1 (FB1) to livestock using porcine kidney 15 cells (PK-15) as a disease model via biochemical approaches. The toxicity of individual mycotoxins on cell viability and cell membrane damage was determined using the MTT and lactate dehydrogenase (LDH) assays, respectively. Individual cytotoxicity of mycotoxins in increasing order were FB10.05). The risk of complications (retinal detachment, rubeosis, neovascular glaucoma) was greater between the second and third year. Mean 5-year survival was 87.5%. The rate of secondary enucleation was 8.5%. CONCLUSION: Protontherapy most often allows for preservation of the globe. Visual loss, often significant and permanent, is frequent. PMID- 23809201 TI - [Squamous cell carcinoma arising in a giant condyloma acuminatum - Buschke Lowenstein tumour]. PMID- 23809202 TI - Early pseudoaneurysm degeneration in biologic extracellular matrix patch for carotid repair. AB - A newly-approved carotid patch, derived from porcine small intestinal submucosa (SIS), is thought to allow functional tissue regeneration by acting as a biologic scaffold of extracellular matrix. We report three cases of asymptomatic pseudoaneurysm after SIS patch closure. At exploration there were intact suture lines, no growth from cultures, and central patch herniation. Histopathologic examination showed postendarterectomy neointima in the artery and disorganized collagen in the pseudoaneurysm. SIS patch remnants adjacent to macrophage infiltration and neovascularization indicated ongoing processes of degradation and synthesis. Imbalances between degradation and host tissue synthesis are problems that may unpredictably affect SIS patch integrity. PMID- 23809203 TI - Family history of aortic disease predicts disease patterns and progression and is a significant influence on management strategies for patients and their relatives. AB - BACKGROUND: While a positive family history (FH) is a known risk factor for developing an aneurysm, its association with the extent of disease has not been established. We evaluated the influence of a FH of aortic disease with respect to the pattern and distribution of aortic aneurysms in a given patient. METHODS AND RESULTS: From November 1999 to November 2011, 1263 patients were enrolled in physician-sponsored endovascular device trials to treat aortic aneurysms. Of the 555 patients who were alive and returning for follow-up, we obtained 426 (77%) family histories. Three-dimensional imaging studies were used to identify the presence of aneurysms; 36% (155/426) of patients had a FH of aortic aneurysms and 5% (21/155) had isolated intracranial aneurysms. A logistic regression model was used to compare aortic morphology between patients with a positive or negative FH for aneurysms. Patients with a positive FH of aortic aneurysms were younger at their initial aneurysm (63 vs 70 years; P < .0001), more frequently had proximal aortic involvement (root: odds ratio [OR], 5.4; P < .0001; ascending: OR, 2.9; P < .001; thoracic: OR, 2.2; P = .01) with over 50% of FH patients ultimately developing suprarenal aortic involvement (P = .0001) and had a greater incidence of bilateral iliac artery aneurysm (OR, 1.8; P = .03). CONCLUSIONS: FH is an important tool that provides insight into the expected behavior of the untreated aorta and has significant implications for the development of treatment strategies. These findings should be used to guide patient's management with regard to treatment, follow-up paradigms, genetic testing, and screening of other family members. PMID- 23809204 TI - Characterization of soils from an industrial complex contaminated with elemental mercury. AB - Historical use of liquid elemental mercury (Hg(0)l) at the Y-12 National Security Complex in Oak Ridge, TN, USA, resulted in large deposits of Hg(0)l in the soils. The fate and distribution of the spilled Hg(0) are not well characterized. In this study we evaluated analytical tools for characterizing the speciation of Hg in the contaminated soils and then used the analytical techniques to examine the speciation of Hg in two soil cores collected at the site. These include x-ray fluorescence (XRF), soil Hg(0) headspace analysis, and total Hg determination by acid digestion coupled with cold vapor atomic absorption (HgT). XRF was not found to be suitable for evaluating Hg concentrations in heterogeneous soils containing low concentration of Hg or Hg(0) because Hg concentrations determined using this method were lower than those determined by HgT analysis and the XRF detection limit is 20 mg/kg. Hg(0)g headspace analysis coupled with HgT measurements yielded good results for examining the presence of Hg(0)l in soils and the speciation of Hg. The two soil cores are highly heterogeneous in both the depth and extent of Hg contamination, with Hg concentrations ranging from 0.05 to 8400mg/kg. In the first core, Hg(0)l was distributed throughout the 3.2m depth, whereas the second core, from a location 12m away, contained Hg(0)l in a 0.3m zone only. Sequential extractions showed organically associated Hg dominant at depths with low Hg concentration. Soil from the zone of groundwater saturation showed reducing conditions and the Hg is likely present as Hg-sulfide species. At this depth, lateral Hg transport in the groundwater may be a source of Hg detected in the soil at the deeper soil depths. Overall, characterization of soils containing Hg(0)l is difficult because of the heterogeneous distribution of Hg within the soils. This is exacerbated in industrial facilities where fill materials make up much of the soils and historical and continued reworking of the subsurface has remobilized the Hg. PMID- 23809205 TI - Impact of annual body mass index gain on obesity development in Japanese 6-year old non-obese children. AB - BACKGROUND: Effective timing of preventive intervention for adolescent obesity in non-obese school-aged children remains unclear. The aim of this study was to examine the impact of annual body mass index (BMI) gain on the development of adolescent obesity in 6-year-old non-obese Japanese children. METHODS: Longitudinal weight and height data were collected annually from 9723 children aged 6-14 years, and individual per-year BMI gains were calculated. The BMI >= the 95th percentile for each age and sex defined obesity. In 6-year-old non-obese children, logistic regression analyses were applied to correlate the annual BMI gain at each age with obesity at a final survey. RESULTS: The 6-year-old non obese children who became obese at a final survey showed larger annual BMI gains at any age compared with their peers with respect to baseline BMI. Increases in annual BMI gain, even in early school age, raised the risk of adolescent obesity. Categorical analysis also showed that children aged 6-7 years with higher annual BMI gains than 1-SD above the mean had a significant risk for adolescent obesity (OR: 4.39 [95%CI: 2.98-6.46] in boys and 3.83 [95%CI: 2.60-5.63] in girls, respectively). CONCLUSIONS: A larger annual BMI gain at any school age is a risk for adolescent obesity in 6-year-old non-obese children with no critical period. This suggests the need for earlier and continuous school-based surveillance using annual BMI gain for preventive intervention of adolescent obesity development. PMID- 23809206 TI - Utility of the ISTH bleeding assessment tool in predicting platelet defects in participants with suspected inherited platelet function disorders. AB - BACKGROUND: The ISTH bleeding assessment tool (ISTH-BAT) was developed to record bleeding symptoms and to aid diagnosis in patients with a possible bleeding disorder. OBJECTIVES: To investigate the utility of the ISTH-BAT in predicting functional defects in platelet activation in participants with suspected inherited platelet function disorders. PATIENTS/METHODS: Participants with clinical evidence of excessive bleeding and suspected inherited platelet function disorders and healthy volunteers were recruited to the Genotyping and Phenotyping of Platelets study (GAPP; ISRCTN 77951167). The ISTH-BAT questionnaire was applied by a trained investigator prior to lumiaggregometry. RESULTS: One hundred participants were included (79 with suspected inherited platelet function disorders, and 21 healthy volunteers). The ISTH-BAT score in participants with suspected inherited platelet function disorders (median 12; interquartile range [IQR] 8-16) was significantly higher than in healthy volunteers (median 0; IQR 0 0). There was no difference between participants with suspected inherited platelet function disorders with a platelet defect detected by lumiaggregometry (median 11; IQR 8-16) and those with normal platelet function (median 12; IQR 8 14) (P > 0.05). The ISTH-BAT score was not associated with a demonstrable platelet defect on platelet function testing (area under the receiver operating characteristic curve = 0.501 [95% confidence interval 0.372-0.630, P = 0.98] and odds ratio 1.01 [95% confidence interval 0.93-1.09, P = 0.91]). CONCLUSIONS: The ISTH-BAT is a powerful tool for documenting lifelong bleeding history. However, the score obtained is not predictive of the presence of a platelet defect on lumiaggregometry in patients with suspected inherited platelet function disorders. PMID- 23809207 TI - Relationship between repolarization abnormalities and myocardial edema in atypical Tako-Tsubo syndrome. AB - In typical "apical" Tako-Tsubo syndrome (TTS), an association between dynamic T wave inversion/QTc interval prolongation and myocardial edema as evidenced by cardiac magnetic resonance has been reported. We describe a patient with atypical "mid-ventricular" TTS who showed T-waves inversion/QTc prolongation confined to the lateral leads. Cardiac magnetic resonance revealed transmural myocardial edema with the highest signal intensity in the mid-lateral wall, in accordance with the ECG location of repolarization abnormalities. This finding indicates that the association of dynamic T-wave inversion/QTc interval prolongation with myocardial edema is demonstrable also in atypical variant of TTS and contributes to support the emerging concept of a cause-effect relationship between transient myocardial edema and dynamic repolarization changes. PMID- 23809209 TI - Uterine leiomyoma extension into right atrium: a case report. PMID- 23809208 TI - A novel dengue virus detection method that couples DNAzyme and gold nanoparticle approaches. AB - BACKGROUND: Recent epidemics of dengue viruses (DENV) coupled with new outbreaks on the horizon have renewed the demand for novel detection methods that have the ability to identify this viral pathogen prior to the manifestation of symptoms. The ability to detect DENV in a timely manner is essential for rapid recovery from disease symptoms. A modified lab-derived 10-23 DNAzyme tethered to gold nanoparticles provides a powerful tool for the detection of viruses, such as DENV. RESULTS: We examined the effectiveness of coupling DNAzyme (DDZ) activation to the salt-induced aggregation of gold nanoparticles (AuNP) to detect dengue virus (DENV) progeny in mosquito cells. A DNAzyme was designed to recognize the 5' cyclization sequence (5' CS) that is conserved among all DENV, and conjugated to AuNPs. DDZ-AuNP has demonstrated the ability to detect the genomic RNA of our model dengue strain, DENV-2 NGC, isolated from infected Aedes albopictus C6/36 cells. These targeting events lead to the rapid aggregation of AuNPs, resulting in a red to clear color transition of the reaction mixes, and thus positive detection of the DENV RNA genome. The inclusion of SDS in the reaction mixture permitted the detection of DENV directly from cell culture supernatants without additional sample processing. Specificity assays demonstrated detection is DENV specific, while sensitivity assays confirm detection at levels of 1 * 10(1) TCID50 units. These results demonstrate DDZ-AuNP effectively detects DENV genomes in a sequence specific manner and at concentrations that are practical for field use. CONCLUSIONS: We have developed an effective detection assay using DNAzyme catalysis coupled with AuNP aggregation for the detection of DENV genomes in a sequence specific manner. Full development of our novel DDZ-AuNP detection method will provide a practical, rapid, and low cost alternative for the detection of DENV in mosquito cells and tissues, and possibly infected patient serum, in a matter of minutes with little to no specialized training required. PMID- 23809210 TI - August Hirt and "extraordinary opportunities for cadaver delivery" to anatomical institutes in National Socialism: a murderous change in paradigm. AB - German anatomical institutes always had problems obtaining sufficient cadavers for research and training. In the National Socialist (NS) period this changed. Universities could count on "extraordinary opportunities for cadaver delivery." Most frequently tacitly, many bodies were those of victims of NS crimes. Scientists increasingly exploited the exceptional political situation to systematically supplement their institutional collections. Their endeavors to fill the, in their terms, "lamentable gaps" in their collections took on truly bizarre forms. In Austria, Jewish cemeteries were plundered for racial-political expansion of anatomical collections. A change in paradigm was merely the next step: intentional murder for the benefit of NS-oriented science. In December of 1942, anatomists meeting in Tubingen discussed plans for "material acquisition." August Hirt, director of the anatomical institute at the Reichsuniversitat in Strasbourg, was to develop guidelines. There was express reference to "Auftrag Beger," which had already been conceived although not yet realized: at the behest of Hirt and the SS-scientific organization, "Ahnenerbe," the anthropologists Bruno Beger and Hans Fleischhacker selected 86 Jewish prisoners in Auschwitz in June of 1943 and deported them to the concentration camp at Struthof near Natzweiler, where they were murdered. The bodies were delivered to the anatomy department in Strasbourg for preparation and used as anatomical specimens. The Reichsuniversitat Strasbourg was considered a center of excellence for Nazi ideology. For modern scientists, the elucidation of these criminal acts is not exhausted in the search for an answer to the questions of perpetrator, place, modus operandi or motive. A suitable memorial to the victims must go beyond mere quantification. PMID- 23809211 TI - Translation of H. contortus and T. colubriformis from egg to establishment in grazing sheep is unaffected by rainfall timing, rainfall amount and herbage height under conditions of high soil moisture in the Northern Tablelands of NSW. AB - A field experiment was conducted at Armidale in the Northern Tablelands of NSW, Australia to determine the effects of simulated rainfall amount (0, 12 and 24 mm), rainfall timing (days -1, 0 and 3 relative to plot contamination) and herbage height (4 and 12 cm), on translation of Haemonchus contortus and Trichostrongylus colubriformis from egg to established stages in grazing sheep under conditions of high soil moisture (22-23%). The experiment was conducted in summer when temperature was not anticipated to be a limiting factor for development success. Development success was assessed using tracer sheep and expressed as percentage recovery of parasitic stages relative to egg output on pasture (translation%). For both species, translation (0.11% H. contortus; 0.55% T. colubriformis) was observed in the absence of simulated rainfall and was unaffected by treatment effects of rainfall amount and timing, and herbage height. We suggest that soil moisture (>20%) alone was sufficient to support development and translation (from eggs to parasitic stages in the gut of tracer animals) of these species which contrasts with expectations for development success on dry soils. These findings identify the importance of taking soil moisture into account when predicting the likely effects of rainfall and herbage height on development to L3 and ultimately in predictive epidemiological models of ovine gastrointestinal nematodiasis. PMID- 23809213 TI - IgA deficiency in primary antiphospholipid syndrome. PMID- 23809212 TI - Effects of hyperoxia on the permeability of 16HBE14o- cell monolayers--the protective role of antioxidant vitamins E and C. AB - The use of hyperoxia for critically ill patients is associated with adverse impacts resulting in lung injury accompanied by inflammation. The aim of this study was to evaluate aspects of mechanisms that contribute to hyperoxia-induced disruption of the epithelial permeability barrier, and also the protective effects of the antioxidants alpha-tocopherol and ascorbate. 16HBE14o- cells were cultured as monolayers at an air-liquid interface for 6 days, after which transepithelial electrical resistance reached 251.2 +/- 4.1 Omega.cm(2) (mean +/- standard error of the mean). They were then exposed for 24 h to normoxia (21% O2, 5% CO2), hyperoxia (95% O2, 5% CO2), hyperoxia with 10(-7) M alpha-tocopherol, hyperoxia with 10(-7) M ascorbate, hyperoxia with 10(-6) M ascorbate, and hyperoxia with a combination of alpha-tocopherol and ascorbate (10(-7) M and 10( 6) M, respectively). Significant reductions (P < 0.05) in transepithelial electrical resistance seen after hyperoxia (with or without antioxidants) were associated with reductions in the levels of zona occludens-1 (ZO-1) observed by immunohistochemistry, and downregulation of ZO-1 expression (P < 0.01) as compared with normoxia. In contrast, the expression levels of interleukin (IL)-8, IL-6 and tumour necrosis factor-alpha (TNF-alpha) were increased after hyperoxia (P < 0.01), and marked increases in the levels of these cytokines (ELISA) were seen in the medium (P < 0.001) as compared with normoxia. The antioxidant vitamins E and C had a partial protective effect against the hyperoxia-induced reduction in ZO-1 levels and the increase in levels of the proinflammatory cytokines IL-8, IL-6, and TNF-alpha. In conclusion, hyperoxia-induced epithelial disruption is associated with tight junction weakening, and induction of a proinflammatory environment. PMID- 23809214 TI - ACTH as first line treatment for acute calcium pyrophosphate crystal arthritis in 14 hospitalized patients. PMID- 23809215 TI - Suicides among cancer patients in Lithuania: a population-based census-linked study. AB - BACKGROUND: This study aims to estimate suicide risk and its socio-demographic determinants among cancer patients in the country showing the highest suicide rates among developed countries. METHODS: The study is based on a unique census linked dataset based on the linkages between the records from death and cancer registers and the 2001 population census records. Standardized mortality ratios for suicide (SMRs) were calculated for patients diagnosed with cancer in Lithuania between April 6, 2001 and December 31, 2009, relative to suicide rates in the general population. RESULTS: We found that the relative suicide risk was elevated for both males and females, with SMRs of 1.43 (95% CI 1.23-1.66) and 1.32 (95% CI 0.95-1.80), respectively. This relationship for females became statistically significant and stronger after excluding skin cancers. The highest suicide risks were observed at older ages and during the period shortly after the diagnosis. The groups showing an increased suicide risk include lower educated, non-married, and rural male patients. CONCLUSION: The results of our study point to inadequacies of the health care system in dealing with mental health problems of cancer patients. Interventions allowing early detection of depression or suicidal ideation may help to prevent suicide among cancer patients in Lithuania. PMID- 23809216 TI - Co-infection: new battlegrounds in HIV/AIDS. PMID- 23809217 TI - Panton-Valentine leucocidin and pneumonia. PMID- 23809218 TI - Panton-Valentine leucocidin and pneumonia--authors' reply. PMID- 23809219 TI - Behavioural research in epidemics. PMID- 23809220 TI - Behavioural research in epidemics. PMID- 23809221 TI - Rifampicin and moxifloxacin for tuberculous meningitis. PMID- 23809222 TI - Behavioural research in epidemics--authors' reply. PMID- 23809223 TI - Rifampicin and moxifloxacin for tuberculous meningitis. PMID- 23809225 TI - It sounds like a relapsing polychondritis. PMID- 23809224 TI - Rifampicin and moxifloxacin for tuberculous meningitis--authors' reply. PMID- 23809226 TI - Norepinephrine transporter occupancy in the human brain after oral administration of quetiapine XR. AB - Quetiapine, originally developed as an antipsychotic, demonstrates efficacy in clinical studies of schizophrenia, bipolar mania and depression, major depressive disorder and generalized anxiety disorder. This broad spectrum of efficacy was not predicted from the preclinical pharmacology of quetiapine. Binding studies in vitro show that quetiapine and its major active human metabolite, norquetiapine, have moderate to high affinity for dopamine D2 and serotonin 5-HT2A receptors, while norquetiapine alone has high affinity for the norepinephrine transporter (NET). This positron emission tomography (PET) study measured NET occupancy in human subjects treated with extended-release quetiapine (quetiapine XR) at doses relevant in the treatment of depression. PET measurements using the specific NET radioligand (S,S)-[(18)F]FMeNER-D2 were performed before and after quetiapine XR treatment at 150 and 300 mg/d for 6-8 d in nine healthy males (aged 21-33 yr). Regions of interest were defined for the thalamus, using the caudate as reference region. NET occupancy was calculated using a target:reference region ratio method. Plasma concentrations of quetiapine and norquetiapine were monitored during PET measurements. Following quetiapine XR treatment, the mean NET occupancy in the thalamus was 19 and 35%, respectively, at quetiapine XR doses of 150 and 300 mg/d. The estimated plasma concentration of norquetiapine corresponding to 50% NET occupancy was 161 ng/ml. This is the first demonstration of NET occupancy by an antipsychotic in the human brain. NET inhibition is accepted as a mechanism of antidepressant activity. NET occupancy may therefore contribute to the broad spectrum of efficacy of quetiapine. PMID- 23809227 TI - Cantharidin-based small molecules as potential therapeutic agents. AB - Chemical and pharmacological information on cantharidin-based small molecules was analyzed. The review summarizes new facts about blister beetles' metabolites for the period 2006-2012. General synthetic approaches to cantharidin-based small molecules as well as their chemical transformations and biological activities related to cantharidin, norcantharidin, cantharidimide, and norcantharimide analogs, especially their inhibitory activity of phosphoprotein phosphatases in cancer treatment, were discussed in this mini review, which could help to design new small molecule modulators for other biological models. PMID- 23809228 TI - Functional characterisation of human cells harbouring a novel t(2p;7p) translocation involving TNS3 and EXOC6B genes. AB - BACKGROUND: Tensin3 is an intracellular cytoskeleton-regulating protein, the loss of which is associated with increased cell motility, as has been observed in some human cancers. A novel chromosomal translocation, t(2;7)(p13;p12), present in a patient with a complex syndromic phenotype, directly involves Tensin3 (TNS3) and EXOC6B genes. This translocation could impair the expression of Tensin3 and ExoC6B proteins, and potentially produce two novel fusion transcripts. In the present study, we have investigated the expression and phenotypic features of these potential products in cultured cells from the proband. METHODS: Skin fibroblasts isolated from the proband as well as an age-matched control were grown in cell culture. Cells were used for quantitative RT-PCR, western blot and immunofluorescent confocal microscopy, which determined Tensin3 gene and protein expression. Phase-contrast and confocal microscopy additionally revealed cellular phenotype differences. A scratch wound assay monitored by live cell imaging measured cellular migration rates. RESULTS: The levels of Tensin3 at both mRNA and protein levels were lower in proband cells versus control fibroblasts. Proband cells displayed broader and shorter morphologies versus control fibroblasts, and immunofluorescent staining revealed additional Tensin3 expression along cytoskeletal filaments and the cell periphery only in control fibroblasts. In addition, proband fibroblasts showed a significantly higher migration rate than control cells over 24 h. CONCLUSIONS: The phenotypic changes observed in proband cells may arise from TNS3 haploinsufficiency, causing partial loss of full-length Tensin3 protein. These results further expose a role for Tensin3 in cytoskeletal organisation and cell motility and may also help to explain the syndromic features observed in the patient. PMID- 23809229 TI - Profiles of older patients in the emergency department: findings from the interRAI Multinational Emergency Department Study. AB - STUDY OBJECTIVE: We examine functional profiles and presence of geriatric syndromes among older patients attending 13 emergency departments (EDs) in 7 nations. METHODS: This was a prospective observational study of a convenience sample of patients, aged 75 years and older, recruited sequentially and mainly during normal working hours. Clinical observations were drawn from the interRAI Emergency Department Screener, with assessments performed by trained nurses. RESULTS: A sample of 2,282 patients (range 98 to 549 patients across nations) was recruited. Before becoming unwell, 46% were dependent on others in one or more aspects of personal activities of daily living. This proportion increased to 67% at presentation to the ED. In the ED, 26% exhibited evidence of cognitive impairment, and 49% could not walk without supervision. Recent falls were common (37%). Overall, at least 48% had a geriatric syndrome before becoming unwell, increasing to 78% at presentation to the ED. This pattern was consistent across nations. CONCLUSION: Functional problems and geriatric syndromes affect the majority of older patients attending the ED, which may have important implications for clinical protocols and design of EDs. PMID- 23809230 TI - Metabolic flexibility of enigmatic SAR324 revealed through metagenomics and metatranscriptomics. AB - Chemolithotrophy is a pervasive metabolic lifestyle for microorganisms in the dark ocean. The SAR324 group of Deltaproteobacteria is ubiquitous in the ocean and has been implicated in sulfur oxidation and carbon fixation, but also contains genomic signatures of C1 utilization and heterotrophy. Here, we reconstructed the metagenome and metatranscriptome of a population of SAR324 from a hydrothermal plume and surrounding waters in the deep Gulf of California to gain insight into the genetic capability and transcriptional dynamics of this enigmatic group. SAR324's metabolism is signified by genes that encode a novel particulate hydrocarbon monooxygenase (pHMO), degradation pathways for corresponding alcohols and short-chain fatty acids, dissimilatory sulfur oxidation, formate dehydrogenase (FDH) and a nitrite reductase (NirK). Transcripts of the pHMO, NirK, FDH and transporters for exogenous carbon and amino acid uptake were highly abundant in plume waters. Sulfur oxidation genes were also abundant in the plume metatranscriptome, indicating SAR324 may also utilize reduced sulfur species in hydrothermal fluids. These results suggest that aspects of SAR324's versatile metabolism (lithotrophy, heterotrophy and alkane oxidation) operate simultaneously, and may explain SAR324's ubiquity in the deep Gulf of California and in the global marine biosphere. PMID- 23809232 TI - Complement and innate immune evasion strategies of the human pathogenic fungus Candida albicans. AB - Candida albicans is a medically important fungus that can cause a wide range of diseases ranging from superficial infections to disseminated disease, which manifests primarily in immuno-compromised individuals. Despite the currently applied anti-fungal therapies, both mortality and morbidity caused by this human pathogenic fungus are still unacceptably high. Therefore new prophylactic and therapeutic strategies are urgently needed to prevent fungal infection. In order to define new targets for combating fungal disease, there is a need to understand the immune evasion strategies of C. albicans in detail. In this review, we summarize different sophisticated immune evasion strategies that are utilized by C. albicans. The description of the molecular mechanisms used for immune evasion does on one hand help to understand the infection process, and on the other hand provides valuable information to define new strategies and diagnostic approaches to fight and interfere with Candida infections. PMID- 23809231 TI - COMPLEXO: identifying the missing heritability of breast cancer via next generation collaboration. AB - Linkage analysis, positional cloning, candidate gene mutation scanning and genome wide association study approaches have all contributed significantly to our understanding of the underlying genetic architecture of breast cancer. Taken together, these approaches have identified genetic variation that explains approximately 30% of the overall familial risk of breast cancer, implying that more, and likely rarer, genetic susceptibility alleles remain to be discovered. PMID- 23809233 TI - MicroRNA networks regulate development of brown adipocytes. AB - Brown adipose tissue (BAT) is specialized for heat generation and energy expenditure as a defense against cold and obesity; in both humans and mice increased amounts of BAT are associated with a lean phenotype and resistance to development of the metabolic syndrome and its complications. Here we summarize recent research showing that several BAT-expressed microRNAs (miRNAs) play important roles in regulating differentiation and metabolism of brown and beige adipocytes; we discuss the key mRNA targets downregulated by these miRNAs and show how these miRNAs affect directly or indirectly transcription factors important for BAT development. We suggest that these miRNAs could be part of novel therapeutics to increase BAT in humans. PMID- 23809234 TI - Assessing patient preferences for the delivery of different community-based models of care using a discrete choice experiment. AB - OBJECTIVES: To assess patient preferences for different models of care defined by location of care, frequency of care and principal carer within community-based health-care services for older people. DESIGN: Discrete choice experiment administered within a face-to-face interview. SETTING: An intermediate care service in a large city within the United Kingdom. PARTICIPANTS: The projected sample size was calculated to be 200; however, 77 patients were recruited to the study. The subjects had recently been discharged from hospital and were living at home and were receiving short-term care by a publicly funded intermediate care service. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: The degree of preference, measured using single utility score, for individual service characteristics presented within a series of potential care packages. RESULTS: Location of care was the dominant service characteristics with care at home being the strongly stated preference when compared with outpatient care (0.003), hospital care (<0.001) and nursing home care (<0.001) relative to home care, although this was less pronounced among less sick patients. Additionally, the respondents indicated a dislike for very frequent care contacts. No particular type of professional carer background was universally preferred but, unsurprisingly, there was evidence that sick patients showed a preference for nurse-led care. CONCLUSIONS: Patients have clear preferences for the location for their care and were able to state preferences between different care packages when their ideal service was not available. Service providers can use this information to assess which models of care are most preferred within resource constraints. PMID- 23809235 TI - Statin therapy and levels of hemostatic factors in a healthy population: the Multi-Ethnic Study of Atherosclerosis: a reply to a rebuttal. PMID- 23809236 TI - Splenosis: an uncommon differential diagnosis in gynecology. AB - Splenosis consists of ectopic functioning splenic tissue that can be located anywhere within the abdomen or pelvis. It is a benign condition usually found incidentally and is usually asymptomatic. The need for therapy is controversial, and treatment is suggested only in symptomatic cases, primarily those related to pelvic or abdominal implants. PMID- 23809237 TI - Secondary cancer prevention: the clinico-pathological priority for the next decade. PMID- 23809238 TI - Advanced precancerous lesions within the GI tract: the molecular background. AB - The mainstream carcinogenic processes involved within the gastrointestinal tract are characterized by phenotypic multistep progression cascades that eventually result in full-blown cancers. In this scenario, the understanding of the molecular dysregulations underlying the precancerous lesions is increasing but still remains incomplete. However, in recent years, the enthusiastic rise of innovative technologies (i.e., next-generation sequencing, high-throughput microarray analysis, mass spectrometry based proteomics) and the unexpected discovery of new classes of biomarkers (i.e., miRNA, long-noncoding RNAs) prompted new strength in the exploration of the accurate and comprehensive molecular characterization of premalignant and malignant neoplastic lesions. The challenge ahead lies in the reliable identification of disease progression specific targets to enable molecular testing in the clinical management of the secondary prevention of gastrointestinal cancers. PMID- 23809239 TI - Esophageal squamous cell carcinoma with special reference to its early stage. AB - The term 'early squamous cell carcinoma of the oesophagus', which was previously restricted to superficial carcinoma with no lymph node metastasis, now encompasses intramucosal carcinoma regardless of the nodal status. Such lesions are rare in Western countries, where the experience is limited. In recent years, the development and greater use of chromoendoscopy and narrow band imaging (NBI), both of which facilitate the evaluation of mucosal morphology, have played an important role in the detection of early esophageal squamous cell carcinoma. In addition, the techniques and indications of endoscopic resection (mucosal resection [EMR] and mucosal dissection [ESD]) are still being refined. In the present article, we will discuss the clinical and pathologic features of esophageal early squamous cell carcinoma, as well as the epidemiology and aetiology of esophageal cancer in general. In addition, we will provide a therapeutic decision tree taking into account endoscopic and surgical modalities as they apply to early esophageal squamous cell carcinoma. PMID- 23809240 TI - Advanced precancerous lesions in the lower oesophageal mucosa: high-grade dysplasia and intramucosal carcinoma in Barrett's oesophagus. AB - Adenocarcinoma developed in Barrett's oesophagus is a tumour with an increasing incidence and still a poor prognosis. The only marker that can be used for surveillance remains dysplasia (intraepithelial neoplasia), especially when it is high-grade, that precedes intramucosal carcinoma. New forms of dysplasia have been described in complement to the classical intestinal type (foveolar dysplasia, basal crypt dysplasia). High-grade dysplasia and intramucosal carcinoma are diagnosed on biopsies taken during endoscopy. Standard endoscopy is now challenged by various techniques that represent recent major technical improvements (chromoendoscopy, virtual chromoendoscopy, optical frequency domain imaging, confocal laser endomicroscopy). In numerous cases, high-grade dysplasia and intramucosal carcinoma can be treated by endoscopic procedures, allowing a precise histopathological diagnosis on the resected specimen (endoscopic mucosal resection, submucosal endoscopic dissection) or destroying the neoplastic tissue. Radiofrequency ablation is currently considered as the best available technique for treatment of flat high grade dysplasia and for eradication of residual Barrett's mucosa after focal endoscopic mucosal resection. PMID- 23809241 TI - Precancerous lesions in the stomach: from biology to clinical patient management. AB - Gastric cancer is the final step in a multi-stage cascade triggered by long standing inflammatory conditions (particularly Helicobacter pylori infection) resulting in atrophic gastritis and intestinal metaplasia: these lesions represent the cancerization field in which (intestinal-type) gastric cancer develops. Intraepithelial neoplasia is consistently recognized as the phenotypic bridge between atrophic/metaplastic lesions and invasive cancer. This paper addresses the epidemiology, pathology, molecular profiling, and clinical management of advanced precancerous gastric lesions. PMID- 23809242 TI - Advanced precancerous lesions in the small bowel mucosa. AB - The small intestine has comparatively low rates of epithelial cancers and is, for the most part, inaccessible to ordinary endoscopic visualization. As a result, few solid data are available on the pathological, clinical, and therapeutic aspects of epithelial dysplasia in the small intestine. In this review, we discuss the duodenal adenoma, the most readily visualized dysplastic lesion of the small intestine and the only one that can be detected in an early phase and resected endoscopically before it progresses to high-grade or invasive carcinoma. Particular emphasis is placed on the relationship between duodenal adenoma and colon neoplasia. Because of their different behaviour, detection and management of ampullary adenomas is discussed separately. Even if the absolute risk remains small, the incidence of adenocarcinoma in the small bowel is increased 32-fold in patients with ileal Crohn's disease. Therefore, the follow up and management of these patients is discussed with particular emphasis on the occurrence of dysplasia in the small bowel mucosa of the post-restorative proctocolectomy patients. PMID- 23809243 TI - Advanced precancerous lesions (APL) in the colonic mucosa. AB - Colorectal cancer is a leading cause of cancer death worldwide. Most colorectal cancers are preventable. Surveillance colonoscopy is used to detect and remove precancerous lesions. Although the majority of precancerous lesions develop sporadically, some have an inherited component. In this review, we summarize the clinical, pathologic, and molecular features of advanced precancerous lesions of the colon. The most common and clinically important intestinal polyposis syndromes, and their genetics, are also discussed. Finally, current recommendations regarding the treatment and surveillance of precancerous lesions, both in the sporadic and in inherited setting, are reviewed. PMID- 23809244 TI - Precancerous lesions in inflammatory bowel disease. AB - Reduction of mortality from colorectal cancer is a prime goal in the clinical management of patients with extensive, longstanding ulcerative colitis and colonic Crohn's disease. The cornerstone of current cancer prevention efforts is endoscopic surveillance for colorectal dysplasia, or intraepithelial neoplasia, the direct histological precursor of cancer. A diagnosis of dysplasia provides a reliable indicator of heightened cancer risk and an end-point for colonoscopic surveillance allowing most patients to undergo prophylactic colectomy before the development of incurable cancer. This article reviews the classification, pathological criteria and clinical implications of colorectal dysplasia, current recommendations for the performance of surveillance colonoscopy, recent technical advances in colonoscopic imaging to enhance the detection of dysplasia, and a summary of the molecular genetic events implicated in its development. PMID- 23809245 TI - Advanced precancerous lesions in the liver. AB - We will focus on precursors of the most common liver cancer, i.e. hepatocellular carcinoma (HCC), which takes place in 90% of cases in a hepatitis/cirrhotic setting. High grade dysplastic nodules (HG-DN) are small sizable nodules and the most advanced precancerous lesions of the liver, with a risk of malignant transformation of about 30-40% at 24 months. We will survey the diagnostic distinction between them and early HCC from a clinical, radiological and pathological point of view. The use of a diagnostic algorithm supported by international guidelines is the best practice to manage HG-DN and early HCC. There is no typical imaging for HG-DN, needing all of them to be biopsied for characterization. The natural history of HG-DN is not predictable in individual cases and additional markers should be validated to increase the diagnostic accuracy and predict the behaviour. The treatment of HG-DN is under investigation. PMID- 23809246 TI - Precancerous lesions of the biliary tree. AB - The neoplasms of the biliary tree include the carcinomas of the intra- and extrahepatic bile ducts, the gallbladder and the ampulla. Two types of precancerous lesions precede these adenocarcinomas: the flat and non-tumour forming type that is called biliary intraepithelial neoplasia, and the papillary and tumour-forming type that has been named intraductal papillary neoplasm of the bile duct. Rarely also biliary mucinous cystic neoplasm can give rise to invasive biliary adenocarcinomas. This review discusses the pathological, molecular, epidemiological, clinical and prognostic features of the precancerous biliary lesions, separated according to their origin in the bile ducts, the ampulla and the gall bladder. PMID- 23809247 TI - Precancerous lesions of the pancreas. AB - Pancreatic cancer has a very poor prognosis, with a five year survival of only 5%. New studies have shown that it takes over 11 years for cells to develop invasive capability. This provides an opportunity to intervene if precursor lesions can be detected. This paper reviews the molecular, pathological, clinical findings and management of pancreatic intraepithelial neoplasia (PanIN), intraductal pancreatic mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN), three precursor lesions which can give rise to invasive carcinoma of the pancreas. PMID- 23809248 TI - Necrotizing myositis causes restrictive hypoventilation in a mouse model for human enterovirus 71 infection. AB - BACKGROUND: Enterovirus 71 (EV71) infections are associated with a high prevalence of hand, foot and mouth disease (HFMD) in children and occasionally cause lethal complications. Most infections are self-limiting. However, resulting complications, including aseptic meningitis, encephalitis, poliomyelitis-like acute flaccid paralysis, and neurological pulmonary edema or hemorrhage, are responsible for the lethal symptoms of EV71 infection, the pathogenesis of which remain to be clarified. RESULTS: In the present study, 2-week-old Institute of Cancer Research (ICR) mice were infected with a mouse-adapted EV71 strain. These infected mice demonstrated progressive paralysis and died within 12 days post infection (d.p.i.). EV71, which mainly replicates in skeletal muscle tissues, caused severe necrotizing myositis. Lesions in the central nervous system (CNS) and other tissues were not observed. CONCLUSIONS: Necrotizing myositis of respiratory-related muscles caused severe restrictive hypoventilation and subsequent hypoxia, which could explain the fatality of EV71-infected mice. This finding suggests that, in addition to CNS injury, necrotic myositis may also be responsible for the paralysis and death observed in EV71-infected mice. PMID- 23809249 TI - Factors influencing the response to specific immunotherapy for asthma in children aged 5-16 years. AB - BACKGROUND: The aim of this study was to evaluate the factors predicting the response to allergen-specific immunotherapy (ASIT) in children with asthma. METHODS: The case notes of children with asthma who received ASIT for 2 years were retrospectively reviewed. The cases were then divided into an effective clinical response group, defined as absence of asthma symptoms without requirement for medication for at least 6 months during follow up; and an ineffective clinical response group. At the time of initiating treatment, blood was collected for analysis of serum total IgE. Family history of atopy, history of passive smoking, onset age of wheezing and so on was obtained from each patient. Ten factors that may influence children's response were analyzed on logistic regression analysis and compared between groups. RESULTS: A total of 99 children with asthma received ASIT s.c. for 2 years during September 2007 February 2010. The average age was 8.66 +/- 0.30 years. Good response to ASIT was found in 72 cases, while an inadequate response was found in 27 cases. Of the 10 factors tested for correlation with clinical response to ASIT, a significant correlation was found with onset age of wheezing and airway hyperresponsiveness (AHR). The odds ratio for the onset age of wheezing was 2.81 (95% confidence interval [CI]: 1.40-5.65, P = 0.004) and that for AHR was 1.33 (95%CI: 1.04-1.70, P = 0.021). CONCLUSION: Potential predictors for the response to ASIT in children with asthma were identified. Onset age of wheezing and AHR may influence response to ASIT. PMID- 23809251 TI - Sauchinone blocks methamphetamine-induced hyperlocomotion and place preference in mice. AB - Sauchinone is a phytochemical known as a nitric oxide (NO) inhibitor. NO is a kind of neurotransmitter and involved in psychotic effect of abuse drug. In present, we carried out a study on the effect of sauchinone on methamphetamine induced alteration of behavior in mice. Locomotory activity and conditioned place preference (CPP) were used to evaluate behavioral changes. As a result, sauchinone inhibited the methamphetamine-induced hyperlocomotion in dose dependent manner, whereas sauchinone had no effect on normal locomotory activity. The inhibitory effect of sauchinone on methamphetamine-induced hyperlocomotion was reversed by treatment of molsidomine, a NO donor. Sauchinone also significantly blocked the acquisition and expression of CPP induced by methamphetamine in mouse. However, it did not produce place preference or place aversion, when it was treated alone in animals. Taken together, sauchinone blocked drug reward-related behavior as well as acute hyperlocomotion induced by methamphetamine treatment. PMID- 23809250 TI - Oleuropein and oleacein may restore biological functions of endothelial progenitor cells impaired by angiotensin II via activation of Nrf2/heme oxygenase 1 pathway. AB - Endothelial progenitor cells (EPCs) are responsible for neovascularization of ischaemic tissue and may participate in re-endothelization of an injured arterial wall. There is evidence that angiotensin II, by an increase of gp91phox expression and induction of ROS generation, accelerates cell senescence and impairs functions of EPCs. Oleacein is a main phenolic compound from olive oil, whereas oleuropein is present in olive leaves. Both compounds possess antioxidative, hypotensive and anti-inflammatory properties and show beneficial activity on the cardiovascular system. In this study, we examined whether oleoeuropein and oleacein could protect EPCs against impairment of their functions due to angiotensin-induced cell senescence. CD31(+)/VEGFR-2(+) cells were isolated from young healthy volunteers blood samples and cultured on fibronectin-coated plates with angiotensin (1.0MUM) in presence or absence of increasing concentrations (from 1.0 to 10.0 MUM) of oleoeuropein or oleacein. As compared to angiotensin II-treated cells, EPCs exposed to oleacein or oleuropein prior to angiotensin II showed a significant increase of proliferation and telomerase activity, and a decrease in the percentage of senescent cells and intracellular ROS formation. Oleacein and oleuropein restored migration, adhesion and tube formation of EPCs diminished by angiotensin II in a concentration dependent manner. This effect was related to NF-E2-related factor 2 (Nrf2) transcription factor activation and the increase of heme oxygenase-1 (HO-1) expression. PMID- 23809252 TI - Optimization of the ultrasound-assisted synthesis of lutein disuccinate using uniform design. AB - The ultrasound-assisted synthesis of lutein disuccinate from all-trans lutein (AL) and succinic anhydride (SA) was investigated in this study. Triethylamine was used as the catalyst. Based on the single-factor experiments, a 7-level-3 factor uniform design and response surface analysis were further employed to evaluate the effects of the selected variables including molar ratio of SA/AL, reaction time and ultrasonic power on the yield of lutein disuccinate. The results indicated that the data were adequately fitted into a second-order polynomial model; the molar ratio of SA/AL significantly affected the synthesis of lutein disuccinate, whereas reaction time and ultrasonic power did not. Based on ridge max analysis, the optimum condition for lutein disuccinate synthesis was predicted to be the molar ratio of SA/AL 265.3:1, ultrasonic power 300 W and reaction time 131.6 min with the lutein disuccinate yield of 80.53+/-0.18%, which give a 43.8% increase compared with the traditional method, and also significantly shorten the reaction time. PMID- 23809254 TI - Primary bone marrow mesenchymal stromal cells rescue the axonal phenotype of Twitcher mice. AB - Krabbe's disease (KD) is a demyelinating disorder caused by the deficiency of lysosomal galactocerebrosidase (GALC), affecting both the central (CNS) and the peripheral nervous system (PNS). A current therapy, hematopoietic stem cell transplantation (HSCT), is ineffective at correcting the PNS pathology. We have previously shown that systemic delivery of immortalized bone marrow-derived murine mesenchymal stromal cells (BM-MSCs) diminishes the neuropathology of transplanted Twitcher mice, a murine model of KD. In this study, to move one step closer to clinical application, the effectiveness of a systematic delivery of primary BM-MSCs to promote recovery of the Twitcher PNS was assessed. Primary BM MSCs grafted to the Twitcher sciatic nerve led to increased GALC activity that was not correlated to decreased psychosine (the toxic GALC substrate) accumulation. Nevertheless, BM-MSC transplantation rescued the axonal phenotype of Twitcher mice in the sciatic nerve, with an increased density of both myelinated and unmyelinated axons in transplanted animals. Whereas no increase in myelination was observed, upon transplantation an increased proliferation of Schwann cell precursors occurred. Supporting these findings, in vitro, BM-MSCs promoted neurite outgrowth of Twitcher sensory neurons and proliferation of Twitcher Schwann cells. Moreover, BM-MSCs expressed nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) and promoted increased BDNF synthesis by neighboring Schwann cells. Besides their action in neurons and glia, BM-MSCs led to macrophage activation in Twitcher sciatic nerves. In summary, primary BM-MSCs diminish the neuropathology of Twitcher sciatic nerves by coordinately affecting neurons, glia, and macrophages. PMID- 23809253 TI - Cystic fibrosis transmembrane conductance regulator degradation: cross-talk between the ubiquitylation and SUMOylation pathways. AB - Defining the significant checkpoints in cystic fibrosis transmembrane conductance regulator (CFTR) biogenesis should identify targets for therapeutic intervention with CFTR folding mutants such as F508del. Although the role of ubiquitylation and the ubiquitin proteasome system is well established in the degradation of this common CFTR mutant, the part played by SUMOylation is a novel aspect of CFTR biogenesis/quality control. We identified this post-translational modification of CFTR as resulting from its interaction with small heat shock proteins (Hsps), which were found to selectively facilitate the degradation of F508del through a physical interaction with the SUMO (small ubiquitin-like modifier) E2 enzyme, Ubc9. Hsp27 promoted the SUMOylation of mutant CFTR by the SUMO-2 paralogue, which can form poly-chains. Poly-SUMO chains are then recognized by the SUMO targeted ubiquitin ligase, RNF4, which elicited F508del degradation in a Hsp27 dependent manner. This work identifies a sequential connection between the SUMO and ubiquitin modifications of the CFTR mutant: Hsp27-mediated SUMO-2 modification, followed by ubiquitylation via RNF4 and degradation of the mutant via the proteasome. Other examples of the intricate cross-talk between the SUMO and ubiquitin pathways are discussed with reference to other substrates; many of these are competitive and lead to different outcomes. It is reasonable to anticipate that further research on SUMO-ubiquitin pathway interactions will identify additional layers of complexity in the process of CFTR biogenesis and quality control. PMID- 23809255 TI - Response to Letter to the Editor: 'Autologous skin cell spray transplantation: Still a mystery?'. PMID- 23809256 TI - Superior vena cava stenting guided by alternative imaging modalities in a patient with severe contrast allergy: a case report and brief literature review. AB - Major adverse reactions to iodinated radiocontrast media are an uncommon but serious complication of cardiac catheterizations. We present a case of a 52-year old woman with a sinus venosus atrial septal defect and partial anomalous pulmonary venous connection status post repair who presented with superior vena cava graft obstruction. Two overlapping stents were placed within the superior vena cava using gadolinium, CO2 angiography and transesophageal echocardiography for visualization of the graft stenoses. No iodinated media were used. PMID- 23809257 TI - COMBIT: protocol of a randomised comparison trial of COMbined modified constraint induced movement therapy and bimanual intensive training with distributed model of standard upper limb rehabilitation in children with congenital hemiplegia. AB - INTRODUCTION: Children with congenital hemiplegia often present with limitations in using their impaired upper limb which impacts on independence in activities of daily living, societal participation and quality of life. Traditional therapy has adopted a bimanual training approach (BIM) and more recently, modified constraint induced movement therapy (mCIMT) has emerged as a promising unimanual approach. Evidence of enhanced neuroplasticity following mCIMT suggests that the sequential application of mCIMT followed by bimanual training may optimise outcomes (Hybrid CIMT). It remains unclear whether more intensely delivered group based interventions (hCIMT) are superior to distributed models of individualised therapy. This study aims to determine the optimal density of upper limb training for children with congenital hemiplegia. METHODS AND ANALYSES: A total of 50 children (25 in each group) with congenital hemiplegia will be recruited to participate in this randomized comparison trial. Children will be matched in pairs at baseline and randomly allocated to receive an intensive block group hybrid model of combined mCIMT followed by intensive bimanual training delivered in a day camp model (COMBiT; total dose 45 hours direct, 10 hours of indirect therapy), or a distributed model of standard occupational therapy and physiotherapy care (SC) over 12 weeks (total 45 hours direct and indirect therapy). Outcomes will be assessed at 13 weeks after commencement, and retention of effects tested at 26 weeks. The primary outcomes will be bimanual coordination and unimanual upper-limb capacity. Secondary outcomes will be participation and quality of life. Advanced brain imaging will assess neurovascular changes in response to treatment. Analysis will follow standard principles for RCTs, using two-group comparisons on all participants on an intention-to-treat basis. Comparisons will be between treatment groups using generalized linear models. TRIAL REGISTRATION: ACTRN12613000181707. PMID- 23809259 TI - Individual differences in cognitive flexibility. PMID- 23809258 TI - Liver * receptor ligands disrupt breast cancer cell proliferation through an E2F mediated mechanism. AB - INTRODUCTION: Liver * receptors (LXRs) are members of the nuclear receptor family of ligand-dependent transcription factors and have established functions as regulators of cholesterol, glucose, and fatty acid metabolism and inflammatory responses. Published reports of anti-proliferative effects of synthetic LXR ligands on breast, prostate, ovarian, lung, skin, and colorectal cancer cells suggest that LXRs are potential targets in cancer prevention and treatment. METHODS: To further determine the effects of LXR ligands and identify their potential mechanisms of action in breast cancer cells, we carried out microarray analysis of gene expression in four breast cancer cell lines following treatments with the synthetic LXR ligand GW3965. Differentially expressed genes were further subjected to gene ontology and pathway analyses, and their expression profiles and associations with disease parameters and outcomes were examined in clinical samples. Response of E2F target genes were validated by real-time PCR, and the posited role of E2F2 in breast cancer cell proliferation was tested by RNA interference experiments. RESULTS: We observed cell line-specific transcriptional responses as well as a set of common responsive genes. In the common responsive gene set, upregulated genes tend to function in the known metabolic effects of LXR ligands and LXRs whereas the downregulated genes mostly include those which function in cell cycle regulation, DNA replication, and other cell proliferation related processes. Transcription factor binding site analysis of the downregulated genes revealed an enrichment of E2F binding site sequence motifs. Correspondingly, E2F2 transcript levels are downregulated following LXR ligand treatment. Knockdown of E2F2 expression, similar to LXR ligand treatment, resulted in a significant disruption of estrogen receptor positive breast cancer cell proliferation. Ligand treatment also decreased E2F2 binding to cis regulatory regions of target genes. Hierarchical clustering of breast cancer patients based on the expression profiles of the commonly downregulated LXR ligand-responsive genes showed a strong association of these genes with patient survival. CONCLUSIONS: Taken together, these results indicate that LXR ligands target gene networks, including those regulated by E2F family members, are critical for tumor biology and disease progression and merit further consideration as potential agents in the prevention and treatment of breast cancers. PMID- 23809260 TI - The second revision of the dopamine theory of schizophrenia: implications for treatment and drug development. PMID- 23809261 TI - Substantia nigra hyperactivity in schizophrenia. PMID- 23809262 TI - Viral vaccines: past successes and future challenges. PMID- 23809263 TI - The tetraspanin gene MaPls1 contributes to virulence by affecting germination, appressorial function and enzymes for cuticle degradation in the entomopathogenic fungus, Metarhizium acridum. AB - In most eukaryotes, tetraspanins regulate cellular activities by associating with other membrane components. In phytopathogenic fungi, the tetraspanin Pls1 controls appressorium-mediated penetration. However, regulation of Pls1 and its associated signalling pathways are not clear. In this study, the MaPls1 gene from the entomopathogenic fungus Metarhizium acridum was functionally characterized. MaPls1 was highly expressed in mycelium and appressorium, and accumulated on the plasma membrane or in the cytoplasm. Compared with a wild-type strain, the deletion mutant DeltaMaPls1 had delayed germination and appressorium formation and impaired turgor pressure on locust wings, but normal germination on medium and non-host insect matrices. Bioassays showed that DeltaMaPls1 had decreased virulence and hyphal body formation in haemolymph when topically inoculated, but was not different from wild type when the insect cuticle was bypassed. Moreover, the ability to grow out of the cuticle was impaired in DeltaMaPls1. Digital gene expression profiling revealed that genes involved in hydrolysing host cuticle and cell wall synthesis and remodelling were downregulated in DeltaMaPls1. MaPls1 participated in crosstalk with signalling pathways such as the cyclic adenosine monophosphate-dependent protein kinase A and calmodulin-dependent pathways. Taken together, these results demonstrated the important roles of MaPls1 at the early stage of infection-associated development in M. acridum. PMID- 23809264 TI - Adiposis dolorosa (Dercum's disease): MRI and ultrasound appearances. AB - AIM: To describe ultrasound and magnetic resonance imaging (MRI) features of adiposis dolorosa, Dercum's disease, and to evaluate the MRI features prospectively against a large number of MRI examinations. MATERIALS AND METHODS: Institutional review board approval for this study was obtained. The imaging features at MRI and ultrasound of 13 cases of adiposis dolorosa (nine female, four male; age range 32-72 years) were reviewed. MRI findings typical for adiposis dolorosa were proposed and prospectively evaluated on 6247 MRI examinations performed over a period of 8 months. RESULTS: Adiposis dolorosa demonstrates multiple, oblong, fatty lesions in the superficial subcutaneous fatty tissue. They are mostly <2 cm in long axis diameter. They demonstrate nodular ("blush-like") increased fluid signal at unenhanced MRI and are markedly hyperechoic at ultrasound. There is no contrast medium enhancement at MRI and no increased Doppler signal at ultrasound. Most lesions were clinically asymptomatic, some were painful/tender. There was no imaging evidence of oedema or inflammation. During prospective validation of these MRI features on 6247 MRI examinations, two cases with typical imaging features were encountered; both were diagnosed as adiposis dolorosa on clinical review. All cases of adiposis dolorosa showed these imaging findings. This results in a very low likelihood that a nodular, blush-like appearance of subcutaneous fat on MRI is not due to adiposis dolorosa. DISCUSSION: Adiposis dolorosa, Dercum's disease, should be suggested in the presence of multiple (many) small, oblong, fatty lesions in the subcutaneous fatty tissue in adult patients if they are hyperechoic on ultrasound imaging or blush-like at unenhanced MRI; typically a small number of these lesions are tender/painful. Imaging does not demonstrate inflammation or oedema in relation to these lesions. These MRI features should suggest the diagnosis and are likely to be pathognomonic. The radiologist is often the first to suggest the diagnosis based on the imaging features. PMID- 23809265 TI - Re: Comprehensive MRA of the lower limbs including high-resolution extended-phase infra-inguinal imaging with gadobenate dimeglumine: initial experience with inter individual comparison to the blood-pool contrast agent gadofosveset trisodium. PMID- 23809266 TI - Rectosigmoid endometriosis: comparison between CT water enema and video laparoscopy. AB - AIM: To evaluate the accuracy of water enema computed tomography (CT) for predicting the location of endometriosis in patients with contraindications to magnetic resonance imaging (MRI), focusing on rectosigmoid lesions and having laparoscopic and histological data as the reference standard. MATERIALS AND METHODS: Thirty-three women (mean age 33.4 +/- 3.1 years) suspected of having deep pelvic endometriosis underwent 64-row CT and video laparoscopy within 4 weeks. Two radiologists blinded to the clinical data evaluated the CT images obtained after colonic retrograde distension using water as the contrast medium, and a comparison with laparoscopic and histological findings was performed. CT sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy were calculated. The radiation dose to patients was estimated. Cohen's weighted kappa (kappa) test was used to evaluate the interobserver agreement. RESULTS: In 23 out of 33 patients (69%) intestinal implants were found at surgery and pathological examinations. CT confirmed the diagnosis of rectosigmoid endometriosis in 20 out of 23 implants. Three nodules located on the proximal sigmoid colon (two serosal lesions and one infiltrating the muscularis layer) with a diameter of less than 1 cm were not diagnosed. CT sensitivity, specificity, PPV, NPV, and accuracy values were 87, 100, 100, 77, and 91%, respectively. The mean effective dose estimate was 6.30 +/- 1.7 mSv. Almost perfect agreement between the two readers was found (k = 0.84). CONCLUSION: Water enema CT can play a role in the diagnosis of bowel endometriosis and represents another accurate potential tool for video laparoscopic approaches, especially in patients for whom MRI is contraindicated. PMID- 23809267 TI - Delayed gadolinium-enhanced MRI of cartilage of the ankle joint: results after autologous matrix-induced chondrogenesis (AMIC)-aided reconstruction of osteochondral lesions of the talus. AB - AIM: To assess cartilage quality using delayed gadolinium-enhanced magnetic resonance imaging after repair of osteochondral lesions of the talus using autologous matrix-induced chondrogenesis (AMIC). MATERIALS AND METHODS: A three dimensional (3D) spoiled gradient-echo (SGE) sequence at 3 T was used to obtain quantitative T1 relaxation times before and after Gd-DTPA2 (Magnevist, 0.2 mM/kg bod weight) administration to assess 23 cases of AMIC-aided repair of osteochondral lesions of the talus. Delta relaxation rates (DeltaR1) for reference cartilage (RC) and repair tissue (RT), and the relative delta relaxation rate (rDeltaR1) were calculated. The morphological appearance of the cartilage RT was graded on sagittal dual-echo steady-state (DESS) views according to the "magnetic resonance observation of cartilage repair tissue" (MOCART) protocol. The study was approved by the institutional review board and written consent from each patient was obtained. RESULTS: The AMIC cases had a mean T1 relaxation time of 1.194 s (SD 0.207 s) in RC and 1.470 s (SD 0.384 s) in RT before contrast medium administration. The contrast-enhanced T1 relaxation time decreased to 0.480 s (SD 0.114 s) in RC and 0.411 s (SD 0.096 s) in RT. There was a significant difference (p > 0.05) between the DeltaR1 in RC (1.372 * 10(-3)/s, range 0.526-3.201 * 10(-3)/s, SD 0.666 * 10(-3)/s) and RT (1.856 * 10(-3)/s, range 0.93-3.336 * 10(-3)/s, SD 0.609 * 10(-3)/s). The mean rDeltaR1 was 1.49, SD 0.45). The mean MOCART score at follow-up was 62.6 points (range 30-95, SD 15.3). CONCLUSION: The results of the present study suggest that repair cartilage resulting from AMIC-aided repair of osteochondral lesions of the talus has a significantly lower glycosaminoglycan (GAG) content than normal hyaline cartilage, but can be regarded as having hyaline-like properties. PMID- 23809269 TI - Multidetector CT assessment of caseous mitral valve calcification with evidence of fistulous communication to the left ventricle. PMID- 23809268 TI - Chest radiography for predicting the cause of febrile illness among inpatients in Moshi, Tanzania. AB - AIM: To describe chest radiographic abnormalities and assess their usefulness for predicting causes of fever in a resource-limited setting. MATERIALS AND METHODS: Febrile patients were enrolled in Moshi, Tanzania, and chest radiographs were evaluated by radiologists in Tanzania and the United States. Radiologists were blinded to the results of extensive laboratory evaluations to determine the cause of fever. RESULTS: Of 870 febrile patients, 515 (59.2%) had a chest radiograph available; including 268 (66.5%) of the adolescents and adults, the remainder were infants and children. One hundred and nineteen (44.4%) adults and 51 (20.6%) children were human immunodeficiency virus (HIV)-infected. Among adults, radiographic abnormalities were present in 139 (51.9%), including 77 (28.7%) with homogeneous and heterogeneous lung opacities, 26 (9.7%) with lung nodules, 25 (9.3%) with pleural effusion, 23 (8.6%) with cardiomegaly, and 13 (4.9%) with lymphadenopathy. Among children, radiographic abnormalities were present in 87 (35.2%), including 76 (30.8%) with homogeneous and heterogeneous lung opacities and six (2.4%) with lymphadenopathy. Among adolescents and adults, the presence of opacities was predictive of Streptococcus pneumoniae and Coxiella burnetii, whereas the presence of pulmonary nodules was predictive of Histoplasma capsulatum and Cryptococcus neoformans. CONCLUSIONS: Chest radiograph abnormalities among febrile inpatients are common in northern Tanzania. Chest radiography is a useful adjunct for establishing an aetiologic diagnosis of febrile illness and may provide useful information for patient management, in particular for pneumococcal disease, Q fever, and fungal infections. PMID- 23809270 TI - Pre-treatment with a sinus node blockade, ivabradine, before coronary CT angiography: a retrospective audit. AB - AIM: To evaluate whether a simple pre-treatment regimen of sinus node inhibition by ivabradine taken at home for only 1 day resulted in a lower pre-scanning heart rate (HR) and reduced the need for intravenous beta-blockers (BB) prior to coronary computed tomography angiography (CTA). MATERIALS AND METHODS: The pre treatment regimen for coronary CTA changed from using no medication at home (group 1 patients) to the use of 5 mg ivabradine twice a day (group 2 patients), to using 7.5 mg ivabradine twice a day (group 3 patients). The target HR was the same for groups 1 and 2, but lower for group 3. HRs and the use of intravenous BB before coronary CTA was performed were compared between the study groups. RESULTS: The mean HR immediately before the planned CTA procedure was significantly lower throughout groups 1-3 with values of 70 +/- 12.9, 64.9 +/- 9.8, and 63.2 +/- 10.6 beats/min in groups 1, 2, and 3, respectively (p < 0.001). This resulted in a significantly diminished use of intravenous BB in group 2 (mean 5.1 +/- 5.8 mg) compared to group 1 (mean 9 +/- 7.6 mg; p = 0.002). The target HR of 65 beats/min was achieved in 37%, 47%, and 61% of groups 1, 2, and 3, respectively (p < 0.0001). CONCLUSION: In conclusion, the administration of ivabradine tablets at home for only 1 day to patients scheduled for coronary CTA resulted in a significantly lower in-clinic HR and a significantly lower mean use of intravenous BB. PMID- 23809271 TI - ECG-gated imaging of the left atrium and pulmonary veins: Intra-individual comparison of CTA and MRA. AB - AIM: To compare electrocardiography (ECG)-gated computed tomography angiography (CTA) with ECG-gated magnetic resonance angiography (MRA) for assessment of the left atrium (LA) and pulmonary veins (PVs). MATERIAL AND METHODS: Twenty-nine consecutive patients who underwent both cardiac CTA and MRA were evaluated. Contrast-enhanced CTA was performed with prospective ECG-gating using a 320 detector row CT system. Contrast-enhanced MRA was performed with prospective ECG gating using a 1.5 T MRI system equipped with a 32 channel cardiac coil. MRA was acquired during free-breathing with a navigator-gated inversion-recovery prepared steady-state free precession sequence. Two readers independently assessed the CTA and MRA images for vascular definition of the PVs (from 0, not visualized, to 4, excellent definition) and ostial PV diameters. Variants of LA anatomy were assessed in consensus. RESULTS: CTA was successfully performed in all patients with a mean radiation exposure of 5.1 +/- 2.2 mSv. MRA was successfully performed in 27 of 29 patients (93 %). Visual definition of PVs was rated significantly higher on CTA compared to MRA (p < 0.0001; reader 1: excellent/good ratings of CTA versus MRA: 100% versus 86%; reader 2: excellent/good ratings of CTA versus MRA: 99% versus 89%). Assessment of ostial PV diameters showed good correlation between CTA and MRA (reader 1: Pearson r = 0.91; reader 2: Pearson r = 0.82). Moreover, agreement between both imaging methods for evaluation of variants of LA anatomy was high (agreement rate of 95% (95% CI: 92-99%). CONCLUSION: ECG-gated CTA provides higher image quality compared to ECG-gated MRA. Nevertheless, both CTA and MRA provided similar information of LA anatomy and ostial PV diameters. PMID- 23809272 TI - Statin therapy and levels of hemostatic factors in a healthy population: the Multi-Ethnic Study of Atherosclerosis: a rebuttal. PMID- 23809273 TI - Accuracy of matching optic discs with visual fields: the European Structure and Function Assessment Trial (ESAFAT). AB - PURPOSE: To determine the ability of ophthalmologists across Europe to match stereoscopic optic disc photographs to visual fields of varying severity. DESIGN: Evaluation and comparison of 2 diagnostic tests. PARTICIPANTS: A total of 109 of 260 invited ophthalmologists in 11 European countries. These had participated in the previous European Optic Disc Assessment Trial (EODAT), a trial on glaucoma diagnostic accuracy based on optic discs only. METHODS: Each participant matched stereo optic disc photographs of 40 healthy and 48 glaucomatous eyes to a visual field chosen from 4 options per disc. The 4 presented visual fields included the corresponding one and 3 other visual fields, varying in severity. The matching accuracy and any inaccuracy per disease severity were calculated. Classification accuracy (as glaucomatous or healthy) was compared with EODAT data. Duplicate slides allowed for the assessment of intraobserver agreement. MAIN OUTCOME MEASURES: Accuracy of matching optic discs with their corresponding visual field and of classifying them as healthy or glaucomatous; intraobserver agreement (kappa). RESULTS: The overall accuracy of ophthalmologists for correctly matching stereoscopic optic disc photographs to their visual fields was 58.7%. When incorrectly matched, the observers generally overestimated the visual field severity (P<0.001), notably in eyes with early glaucoma. The intraobserver agreement was, on average, moderate (0.52). CONCLUSIONS: European ophthalmologists correctly matched stereoscopic optic disc photographs to their corresponding visual field in only approximately 59% of cases. In most mismatches, the clinicians overestimated the visual field damage. PMID- 23809274 TI - Accuracy of pupil assessment for the detection of glaucoma: a systematic review and meta-analysis. AB - OBJECTIVE: To assess the accuracy of using pupillary light reflex (PLR) in detecting glaucoma. CLINICAL RELEVANCE: Glaucoma is a specific disease of the optic nerve and is often more severe in 1 eye. When large enough, this asymmetry in disease severity can cause a relative afferent pupillary defect (RAPD). Better detection of RAPDs may be one way to identify persons with glaucoma. METHODS: We searched Medline and Embase through June 2012 and searched bibliographies for relevant studies for additional references. Two authors independently reviewed all articles and selected studies that assessed PLRs in patients with glaucoma. We analyzed data using mixed-effect bivariate summary receiver operating characteristic meta-analysis models. RESULTS: A total of 30 studies were included in this review. An RAPD was observed in 9% to 82% of patients with glaucoma. Eleven studies with a total of 7271 participants were included in the analysis, and the pooled estimate corresponded to a sensitivity of 0.63 (95% confidence interval [CI], 0.43-0.80) and a specificity of 0.93 (95% CI, 0.85-0.97). After excluding 2 studies that used the swinging flashlight test, the sensitivity increased to 0.74 (95% CI, 0.59-0.85) with a specificity of 0.85 (95% CI, 0.77 0.90). Study designs and different pupil measurement techniques explained part of the heterogeneity between studies. CONCLUSIONS: Patients with glaucoma frequently have an abnormal PLR and comparing the responses between the 2 eyes can in part distinguish between those with glaucoma and those without the disease. Newer instruments and analytic approaches to assess pupil function may improve the performance of pupil screening. PMID- 23809275 TI - Predicting the need of tracheostomy amongst patients admitted to an intensive care unit: a multivariate model. AB - BACKGROUND: Patients requiring prolonged invasive mechanical ventilation are prone to complications, such as infections, tracheal stenosis and death. It has been proposed that early tracheostomy could have a role in preventing these outcomes, but the proper identification of patients at risk can be difficult. PURPOSE: The aim of this study was to develop a multivariate model that allows the early detection of patients that will require prolonged ventilatory support. PATIENTS AND METHODS: A retrospective cohort study was undertaken in the intensive care unit of the Hospital Naval Almirante Nef, Chile, between June 2011 and June 2012. The charts of all intubated patients were reviewed in search for early predictors of prolonged intubation (>7 days). Multivariate logistic regression analysis was used to detect statistically significant associations and to assess potential confounders. RESULTS: A total of 349 patients were admitted to the intensive care unit during the study period and 142 (40.7%) required invasive mechanical ventilation. Most of them were male (60.5%), with a mean age of 65.8 +/- 16.7 years. Thirty-five patients (24%) required to be ventilated for 7 days or more, and 16 (46%) were tracheostomized for this reason. The regression model showed that older age (p=0.026), a Pa/Fi ratio of less than 200 (p=0.046), and the presence of chronic pulmonary disease (p=0.035) or hypernatremia (p=0.012) on intubation day were significantly associated with the requirement of prolonged intubation. DISCUSSION: Invasive mechanical ventilation is a common reason for admittance to the ICU. The abovementioned predictors can be of assistance when selecting patients that could benefit from early tracheostomies, and are in agreement with earlier reports. Although the model's discriminating capacity was good, it is necessary to formally validate it before recommending its widespread use. PMID- 23809276 TI - The interprofessional sexual and reproductive health care team. PMID- 23809277 TI - Same-day LARC insertion attitudes and practices. AB - BACKGROUND: Little is known regarding clinicians' attitudes about or the extent to which the recommendation to offer same-day insertions for long-acting reversible contraception (LARC) is applied in practice. STUDY DESIGN: Since 2006, 47 family planning agencies in Colorado and Iowa participated in two initiatives to reduce unintended pregnancy by increasing LARC provision. Clinic directors (n = 45) and clinicians (n = 114) participating in these initiatives were interviewed and surveyed regarding their LARC provision practices and attitudes. RESULTS: Agencies required fewer visits for the contraceptive implant than for the intrauterine device (IUD). Only 18% of agencies typically offered an IUD, and 36% typically offered an implant in one visit. Years of experience and professional title significantly predicted attitudes about the number of visits required to get LARC. DISCUSSION: Barriers must be overcome for full implementation of professional LARC guidelines and for more women to receive chosen methods without the extra burden of multiple visits. PMID- 23809278 TI - Ulipristal acetate prevents ovulation more effectively than levonorgestrel: analysis of pooled data from three randomized trials of emergency contraception regimens. AB - BACKGROUND: The days just prior to ovulation are the most crucial for emergency contraception (EC) efficacy. Ulipristal acetate (UPA) and levonorgestrel's (LNG) capacity to inhibit follicular rupture have never been compared directly at this time of the cycle. STUDY DESIGN: Raw data from three pharmacodynamics studies with similar methodology were pooled to allow direct comparison of UPA, LNG and LNG + meloxicam's ability to prevent ovulation when administered orally in the advanced follicular phase, with a leading follicle of >= 18 mm. RESULTS: Forty eight LNG-treated (1.5 mg) cycles, 31 LNG (1.5 mg) + meloxicam (15 mg), 34 UPA (30 mg) cycles and 50 placebo cycles were compared. Follicle rupture was delayed for at least 5 days in 14.6%, 38.7%, 58.8% and 4% of the LNG-, LNG + meloxicam-, UPA- and placebo-treated cycles, respectively. UPA was more effective than LNG and placebo in inhibiting follicular rupture (p = .0001), while LNG, when administered at this time of the cycle, was not different than placebo. The addition of meloxicam improved the efficacy of LNG in preventing follicular rupture (p = .0292 vs. LNG; p = .0001 vs. placebo; non-significant vs. UPA). UPA was effective in preventing rupture in the 5 days following treatment, even when administered at the time of the luteinizing hormone (LH) surge (UPA 79%, LNG 14% and placebo 10%). None of the treatments were effective when administered on the day of the LH peak. The median time from treatment to rupture was 6 days during the ulipristal cycles and 2 days in the placebo and LNG/LNG + meloxicam cycles (p = .0015). CONCLUSION: Although no EC treatment is 100% effective in inhibiting follicular rupture when administered in the late follicular phase, UPA is the most effective treatment, delaying ovulation for at least 5 days in 59% of the cycles. LNG is not different from placebo in inhibiting follicular rupture at this advanced phase of the cycle. No treatment was effective in postponing rupture when administered on the day of LH peak. PMID- 23809279 TI - Use of wound dressings to enhance prevention of pressure ulcers caused by medical devices. AB - Medical device related pressure ulcers (MDR PUs) are defined as pressure injuries associated with the use of devices applied for diagnostic or therapeutic purposes wherein the PU that develops has the same configuration as the device. Many institutions have reduced the incidence of traditional PUs (sacral, buttock and heel) and therefore the significance of MDR PU has become more apparent. The highest risk of MDR PU has been reported to be patients with impaired sensory perception, such as neuropathy, and an impaired ability for the patient to communicate discomfort, for example, oral intubation, language barriers, unconsciousness or non-verbal state. Patients in critical care units typify the high-risk patient and they often require more devices for monitoring and therapeutic purposes. An expert panel met to review the evidence on the prevention of MDR PUs and arrived at these conclusions: (i) consider applying dressings that demonstrate pressure redistribution and absorb moisture from body areas in contact with medical devices, tubing and fixators, (ii) in addition to dressings applied beneath medical devices, continue to lift and/or move the medical device to examine the skin beneath it and reposition for pressure relief and (iii) when simple repositioning does not relieve pressure, it is important not to create more pressure by placing dressings beneath tight devices. PMID- 23809280 TI - The guitar-maker: model education. PMID- 23809281 TI - Education in CKD--learning in the 21st century. PMID- 23809282 TI - Education for patients with progressive CKD and acute-start dialysis. AB - For individuals living with CKD and those who have been discovered to have ESRD, the decisions facing them can be daunting. Such decisions include having renal replacement therapy (RRT) or conservative care, having a kidney transplant, or selecting a modality of dialysis that would fit their lifestyle and values. Education at this critical time is essential, but it must be tailored to the individual and his or her readiness to learn, and it must be provided with empathy and understanding of the chronicity of the disease and the magnitude of the effect of kidney failure on their life. We present strategies derived from education and psychology that can assist health-care practitioners to provide such education and support to individuals with advanced CKD. We also present an approach to educate and support those who have urgently started dialysis and require chronic RRT. This educational model has its basis in theories of education and decision-making and has been used with success in this population. PMID- 23809284 TI - Implementing patient education in the CKD clinic. AB - The passage of the Medicare Improvements for Patients and Providers Act (MIPPA) encouraged education for Stage 4 CKD patients by reimbursing qualified providers for formal instruction. This marked the first time Medicare reimbursed for kidney disease education. Although the law lays out specific requirements, it leaves much of the structure and content of the instruction up to the providers. The CKD clinic staffed by advanced practitioners (physician assistants, nurse practitioners, and/or clinical nurse specialists) provides a natural fit for patient education. Educated patients choose home modalities more frequently; more often start dialysis with a permanent vascular access; and generally score higher on tests measuring mood, mobility, and anxiety. However, sufficient research into the effects of CKD patient education is lacking. PMID- 23809283 TI - Health literacy: emerging evidence and applications in kidney disease care. AB - Health literacy represents the communication among patients, their social networks, providers, and health systems to promote patients' understanding and engagement in their care. This is particularly relevant in kidney disease, in which the complexity of the medical condition and the extent of the health-care team require strategies to overcome health-literacy-related barriers. Limited literacy is common in patients with all stages of kidney disease and is associated with important outcomes, including reduced knowledge, less adherence, hospitalization, and death. A growing understanding and characterization of the health system, or organizational health literacy, may further our understanding of this dynamic relationship. Although various valid methods exist, assessment of health literacy within individuals or systematically within care settings has not been routinely performed. This may be in part due to the limited research in kidney-specific strategies to address limited health literacy. Future research to understand the mechanisms of health literacy will permit targeted, efficient interventions to bridge gaps and improve outcomes even in patients with complex kidney disease. PMID- 23809285 TI - Recruiting the next generation of nephrologists. AB - The nephrology physician workforce substantially expanded during the past decade, as did the number of fellowship training positions. However, the number of U.S. medical graduates choosing nephrology careers has declined precipitously. Although workforce diversity has improved, the gains are modest. Leadership in kidney disease research and innovation is threatened by significant disincentives to the pursuit of research track careers. Meanwhile, various factors challenge reliable predictions of physician workforce demand: marked growth of the CKD and ESRD populations, shifting health care economics and access, restricted opportunities for international medical graduates, expansion of advanced practitioner utilization, and aging of the contemporary practicing physician cohort. Changing demographics and cultural shifts, including perceptions of work life balance and quality of life, increasingly influence medical student and resident career choices. Negative student and resident attitudes toward core nephrology educational experiences and perceptions of nephrology careers are disquieting. The American Society of Nephrology has initiated a series of programs aimed at renewing interest among students and residents in nephrology careers and research training and continuing to improve the diversity of the nephrology workforce, both critical to ensuring there will be enough nephrologists to care for a growing kidney disease population. PMID- 23809286 TI - Novel educational approaches to enhance learning and interest in nephrology. AB - The number of U.S. medical graduates pursuing careers in nephrology has declined over the last several years. Some of the proposed reasons for this declining interest include difficult-to-understand or unstimulating kidney pathophysiology courses in medical school; disheartening inpatient elective experiences; and few opportunities to experience the other aspects of nephrology careers such as outpatient nephrology clinics, outpatient dialysis, and kidney transplantation. Novel and alternative educational approaches should be considered by the nephrology training community to enhance the understanding of nephrology from medical school to fellowship training. Newer teaching methods and styles should also be incorporated to adapt to today's learner. These innovative educational approaches may not only increase interest in nephrology careers, but they may also enhance and maintain interest during nephrology fellowship. In this article, we will review several educational approaches that may enhance teaching and learning in nephrology. PMID- 23809287 TI - Online CKD education for medical students, residents, and fellows: training in a new era. AB - CKD and its complications are associated with substantial morbidity and mortality. Studies have highlighted significant deficiencies in resident knowledge and awareness of CKD and its complications. There is a need to improve CKD education through medical school and residency. There is also a need to provide alternatives to traditional teaching methods to meet the challenges of learning in the context of work-hour restrictions and increasing workload among residents and fellows. Internet-based learning resources offer various educational tools, including websites, kidney blogs, online modules, and smartphone applications, which could potentially and efficiently advance CKD knowledge among medical trainees. In this review, we describe several online resources for CKD education that could be useful for medical students, residents, and fellows. Increased awareness of these tools and their utilization may significantly influence and hopefully improve the recognition and management of patients with CKD. Future studies may help evaluate the effectiveness of these online learning methods and their effect on CKD patient outcomes. In addition, in light of increased concern about nephrology workforce issues, the potential for these online tools to augment interest in nephrology careers should be investigated. PMID- 23809288 TI - Using social media to create a professional network between physician-trainees and the American Society of Nephrology. AB - Twitter is the fastest growing social media network. It offers participants the ability to network with other individuals. Medical societies are interested in helping individuals network to boost recruitment, encourage collaboration, and assist in job placement. We hypothesized that the American Society of Nephrology (ASN) successfully used Twitter to create a network between participants and itself to stay connected with its members. Tweets from 3 Twitter networking sessions during Kidney Week 2011 were analyzed for content. These messages were used to create a network between all participants of the networking sessions. The network was analyzed for strength and influence by calculating clustering coefficients (CC) and eigenvector centrality (EC) scores, respectively. Eight moderators and 9 trainees authored 376 Twitter messages. Most tweets by trainees (64%) and moderators (61%) discussed 1 of 3 themes: networking, education, or navigating Kidney Week 2011. A total of 25 online network connections were established during the 3 sessions; 20% were bidirectional. The CC for the network was 0.300. All moderators formed at least 1 connection, but 7 of the 9 trainees failed to make any connections. ASN made 5 unidirectional and 0 bidirectional connections with a low EC of 0.108. ASN was unable to form powerful connections with trainees through Twitter, but medical societies should not be discouraged by the results reported in this investigation. As societies become more familiar with Twitter and understand the mechanisms to develop connections, these societies will have a greater influence within increasingly stronger networks. PMID- 23809289 TI - Using digital media to promote kidney disease education. AB - Health-care providers and patients increasingly turn to the Internet-websites as well as social media platforms-for health-related information and support. Informed by research on audience behaviors and preferences related to digital health information, the National Kidney Disease Education Program (NKDEP) developed a comprehensive and user-friendly digital ecosystem featuring content and platforms relevant for each audience. NKDEP's analysis of website metrics and social media conversation mapping related to CKD revealed gaps and opportunities, informing the development of a digital strategy to position NKDEP as a trustworthy digital source for evidence-based kidney disease information. NKDEP launched a redesigned website (www.nkdep.nih.gov) with enhanced content for multiple audiences as well as a complementary social media presence on Twitter and Facebook serving to drive traffic to the website as well as actively engage target audiences in conversations about kidney disease. The results included improved website metrics and increasing social media engagement among consumers and health-care providers. NKDEP will continue to monitor trends, explore new directions, and work to improve communication across digital platforms. PMID- 23809290 TI - Education of patients with chronic kidney disease at the interface of primary care providers and nephrologists. AB - Patient education is promoted as an integral part of effective kidney disease management. Programs and tools are available for providers and patients to support patient CKD education in primary care and nephrology. Challenges to providing patient education across practice settings include patients' lack of awareness of CKD as a medical entity, physician perceptions of their own lack of skill and ability to educate patients, differences in how primary care and nephrology physicians perceive collaborative care, and shortage of staff and time to support educational efforts. In addition, there is little research available to guide evidence-based practices for implementing early patient CKD education interventions across medical disciplines. Development and testing of patient education programs using early CKD multidisciplinary care, educational websites, and phone-based applications are all areas of growing research. More work is needed to provide evidence and support that physicians and other health professionals need to ensure a seamless patient education experience across the continuum of care. PMID- 23809291 TI - Tropical forests and global change: filling knowledge gaps. AB - Tropical forests will experience major changes in environmental conditions this century. Understanding their responses to such changes is crucial to predicting global carbon cycling. Important knowledge gaps exist: the causes of recent changes in tropical forest dynamics remain unclear and the responses of entire tropical trees to environmental changes are poorly understood. In this Opinion article, we argue that filling these knowledge gaps requires a new research strategy, one that focuses on trees instead of leaves or communities, on long term instead of short-term changes, and on understanding mechanisms instead of documenting changes. We propose the use of tree-ring analyses, stable-isotope analyses, manipulative field experiments, and well-validated simulation models to improve predictions of forest responses to global change. PMID- 23809292 TI - Lab tests on the biodegradation of chemically dispersed oil should consider the rapid dilution that occurs at sea. AB - Most crude oils spread on open water to an average thickness as low as 0.1 mm. The application of dispersants enhances the transport of oil as small droplets into the water column, and when combined with the turbulence of 1 m waves will quickly entrain oil into the top 1 m of the water column, where it rapidly dilutes to concentrations less than 100 ppm. In less than 24 h, the dispersed oil is expected to mix into the top 10 m of the water column and be diluted to concentrations well below 10 ppm, with dilution continuing as time proceeds. Over the multiple weeks that biodegradation takes place, dispersed oil concentrations are expected to be below 1 ppm. Measurements from spills and wave basin studies support these calculations. Published laboratory studies focused on the quantification of contaminant biodegradation rates have used concentrations orders of magnitude greater than this, as it was necessary to ensure the concentrations of hydrocarbons and other chemicals were higher than the detection limits of chemical analysis. However, current analytical methods can quantify individual alkanes and PAHs (and their alkyl homologues) at ppb and ppm levels. To simulate marine biodegradation of dispersed oil at dilute concentrations commonly encountered in the field, laboratory studies should be conducted at similarly low hydrocarbon concentrations. PMID- 23809293 TI - Baseline metals pollution profile of tropical estuaries and coastal waters of the Straits of Malacca. AB - The status report on metal pollution in tropical estuaries and coastal waters is important to understand potential environmental health hazards. Detailed baseline measurements were made on physicochemical parameters (pH, temperature, redox potential, electrical conductivity, salinity, dissolved oxygen, total dissolved solid), major ions (Na, Ca, Mg, K, HCO3, Cl, SO4 and NO3) and metals concentrations ((27)Al, (75)As, (138)Ba, (9)Be, (111)Cd, (59)Co, (63)Cu, (52)Cr, (57)Fe, (55)Mn, (60)Ni, (208)Pb, (80)Se, (66)Zn) at estuaries and coastal waters along the Straits of Malacca. Principal component analysis (PCA) was employed to reveal potential pollution sources. Seven principal components were extracted with relation to pollution contribution from minerals-related parameters, natural and anthropogenic sources. The output from this study will generate a profound understanding on the metal pollution status and pollution risk of the estuaries and coastal system. PMID- 23809294 TI - Successful management of neonatal myocardial infarction with ECMO and intracoronary r-tPA lysis. AB - Acute myocardial infarction (MI) is a life-threatening condition rarely encountered in neonates. The patients usually present with sudden cardiogenic shock. Clinical management in neonates is extremely challenging. If treatment is delayed, the prognosis is dismal. We report on a 4-day-old full-term male newborn presenting with acute MI and cardiogenic shock secondary to proximal thromboembolic occlusion of the left descending coronary artery. Hemodynamic stabilization could only be achieved after extracorporeal membrane oxygenation (ECMO) support. Coronary artery patency restoration was performed by selective intracoronary lysis with recombinant tissue plasminogen activator (r-tPA). ECMO support could be discontinued and myocardial function recovered within 6 weeks. We discuss the potential etiologies of acute perinatal MI and the role of ECMO support in the immediate post-MI period. Prompt recognition, timely referral to a cardiac center with availability of specialized advanced treatment options, and management in an orchestrated interdisciplinary approach are crucial for achieving a good outcome. PMID- 23809295 TI - Impact of Hepatitis C Virus (HCV) infection on biomolecular markers influencing the pathogenesis of bladder cancer. AB - OBJECTIVE: The present study was designed to determine the possible impact of hepatitis C virus (HCV) infection on the expression of telomerase (TERT), retinoblastoma (RB1), E2F3, TP53, CDKN1A (p21) and fibroblast growth factor receptor- 3 (FGFR3) genes in patients with bladder cancer (BC). MATERIALS AND METHODS: 100 patients with bladder cancer (15 female and 85 male) were divided into 2 groups; Group I: 50 HCV negative subjects (age range 36-79), and Group II: 50 HCV positive subjects (age range 42-80). Expressions of the telomerase, retinoblastoma (Rb), E2F3, TP53 and FGFR3 genes were tested by immunohistochemistry and real time PCR in tumour tissues and healthy bladder tissues. Also, telomerase activity was assessed by telomeric repeats amplification protocol (TRAP). RESULTS: Bladder tumors associated with HCV infection were of high grade and invasive squamous cell carcinomas (SCCs). Expressions of hTERT, Rb, E2F3, TP53 and FGFR3 as well as telomerase activity were significantly higher in bladder tissues of HCV-infected patients compared with bladder tissues of non infected patients (p<0.05). On the contrary, CDKN1A (p21) expression was significantly lower in bladder tissues of HCV-infected patients compared to bladder tissues of non infected patients (p<0.05). CONCLUSION: The expressions of hTERT, Rb, E2F3, TP53 and FGFR3 as well as the activity of telomerase were significantly high in malignant bladder tissues associated with HCV infection. On the other hand, CDKN1A (p21) expression was low in bladder tissues of HCV-infected subjects. Moreover, there was a positive correlation between HCV infection and expression of telomerase, E2F3, TP53 and FGFR3. There was a negative correlation between HCV infection and expression of Rb and p21. PMID- 23809296 TI - Effect of varying bulb height on articulation and nasalance in maxillectomy patients with hollow bulb obturator. AB - PURPOSE: To evaluate the effect of bulb height of hollow bulb obturator prosthesis on articulation and nasalance. METHOD: A total of 10 patients, who were to undergo maxillectomy falling under Aramany class-I and II, with normal speech and hearing pattern were selected for the study. They were provided 2 maxillary obturators, one extending full height of the defect and other with bulb height approximately up to inferior nasal concha. The patients were asked to wear each obturator for 6 weeks and the speech analysis was done to measure changes in articulation and nasalance at 6 different stages of treatment i.e. preoperative, postoperative (after complete healing), 24h and 6 weeks after providing full bulb height obturator and reduced bulb height obturator. Articulation was measured objectively for distortion, addition, substitution and omission by speech pathologist and nasalance was measured by Dr. SPEECH software. RESULT: Comparison between full and reduced bulb height for nasalance and articulation, showed that there was no statistical significant difference (P>0.05) between the two for both the parametres. CONCLUSION: Articulation and nasality improves after providing obturator. Articulation and nasalance both are independent of bulb height. PMID- 23809297 TI - Fatigue resistance and retentive force of cast clasps treated by shot peening. AB - PURPOSE: The fatigue failure of denture clasps has often been observed in removable partial denture rehabilitation. To increase their fatigue strength, shot peening was evaluated as a surface treatment. In this study, we evaluated the fatigue resistance and retention of cast clasps by using a shot peening treatment. METHODS: A cobalt-chromium (Co-Cr) alloy, commercial pure titanium (CP Ti), silver-palladium-gold (Ag-Pd-Au), and a gold-platinum (Au-Pt) alloy were cast and then treated with shot peening. The retentive forces of the clasps were measured up to a repetition of 10,000insertion/removal cycles in distilled water at 37 degrees C. A fatigue test was also performed using a 15-mm cantilever. Specimens were loaded with a constant deflection of 2.0mm with 20Hz. A shot peening treatment indicated a better stability of retentive forces than that without shot peening. The retentive force of Co-Cr clasps without shot peening was remarkably decreased at 500 cycles of insertion/removal repetition. RESULTS: The clasps with a shot peening treatment provided approximately 1.4-3.6 times higher fatigue strengths than those without a shot peening treatment. CONCLUSION: To prevent the fatigue failure of the denture clasps and use the dentures for long term, a shot peening treatment would be recommended. PMID- 23809298 TI - Orofacial pain: a primer. AB - Orofacial pain refers to pain associated with the soft and hard tissues of the head, face, and neck. It is a common experience in the population that has profound sociologic effects and impact on quality of life. New scientific evidence is constantly providing insight into the cause and pathophysiology of orofacial pain including temporomandibular disorders, cranial neuralgias, persistent idiopathic facial pains, headache, and dental pain. An evidence-based approach to the management of orofacial pain is imperative for the general clinician. This article reviews the basics of pain epidemiology and neurophysiology and sets the stage for in-depth discussions of various painful conditions of the head and neck. PMID- 23809299 TI - Clinical assessment of patients with orofacial pain and temporomandibular disorders. AB - Accurate diagnosis of chronic pain disorders of the mouth, jaws, and face is frequently complex. It is common for patients with chronic orofacial pain to consult multiple clinicians and receive ineffective treatment before a correct diagnosis is reached. This problem is a significant public health concern. Clinicians can minimize error by starting the diagnostic procedure with a careful, accurate history and thorough head and neck examination followed by a thoughtfully constructed differential diagnosis. The possibility that the patient has symptoms of a life-threatening underlying disease rather than a more common dental, sinus, or temporomandibular disorder must always be considered. PMID- 23809300 TI - Diagnostic imaging for temporomandibular disorders and orofacial pain. AB - The focus of this article is diagnostic imaging used for the evaluation of temporomandibular disorders and orofacial pain patients. Imaging modalities discussed include conventional panoramic radiography, panoramic temporomandibular joint imaging mode, cone beam computed tomography, and magnetic resonance imaging. The imaging findings associated with common diseases of the temporomandibular joint are presented and indications for brain imaging are discussed. Advantages and disadvantages of each imaging modality are presented as well as illustrations of the various imaging techniques. PMID- 23809301 TI - Differential diagnosis of orofacial pain and temporomandibular disorder. AB - When a patient complains of orofacial pain, health care providers must make a correct diagnosis. Doing this can be difficult, since various signs and symptoms may not be specific for 1 particular problem or disorder. One initially should formulate a broad differential diagnosis that can be narrowed after analysis of the history and examination. In this article, orofacial pain is categorized as being caused by: intracranial pain, headaches, neuropathic pain, intraoral pain, temporomandibular disorder, cervical pain, pain related to anatomically associated structures, referred pain, or mental illness. PMID- 23809302 TI - Intraoral pain disorders. AB - Dental and oral diseases are common findings in the general population. Pain associated with dental or periodontal disease is the primary reason why most patients seek treatment from providers. Thus, it is essential that all complaints of pain in the mouth and face include ruling out pain of dental origin. However, intraoral pain is not exclusively a result of dental disorders. This review outlines common somatic intraoral pain disorders, which can originate from disease involving one or more broad anatomic areas: the teeth, the surrounding soft tissues (mucogingival, tongue, and salivary glands), and bone. PMID- 23809303 TI - Disorders of the masticatory muscles. AB - Muscle disorders involving the masticatory muscles have been considered analogous to skeletal muscle disorders throughout the body. However, emerging research has shed new light on the varied etiology, clinical presentation, diagnosis, and treatment of myofascial pain and masticatory muscle disorders. This article reviews the etiology and classification of regional masticatory muscle disorders, the clinical examination of the patient, and evidence-based treatment recommendations. PMID- 23809304 TI - Epidemiology, diagnosis, and treatment of temporomandibular disorders. AB - Temporomandibular disorder (TMD) is a multifactorial disease process caused by muscle hyperfunction or parafunction, traumatic injuries, hormonal influences, and articular changes. Symptoms of TMD include decreased mandibular range of motion, muscle and joint pain, joint crepitus, and functional limitation or deviation of jaw opening. Only after failure of noninvasive options should more invasive and nonreversible treatments be initiated. Treatment can be divided into noninvasive, minimally invasive, and invasive options. Temporomandibular joint replacement is reserved for severely damaged joints with end-stage disease that has failed all other more conservative treatment modalities. PMID- 23809305 TI - Cranial neuralgias. AB - This article describes the clinical findings of cranial neuralgias, such as trigeminal neuralgia, glossopharyngeal neuralgia, nervus intermedius neuralgia, and others, and postherpetic neuralgia. Pathophysiology of these neuralgias, diagnostic methods, and treatment are also discussed. This information will enable the dentist to diagnose patients who have these rare conditions. PMID- 23809306 TI - Burning mouth syndrome. AB - Burning mouth syndrome (BMS) is a chronic condition that is characterized by burning symptoms of the oral mucosa without obvious clinical examination findings. This syndrome has complex characteristics, but its cause remains largely enigmatic, making treatment and management of patients with BMS difficult. Despite not being accompanied by evident organic changes, BMS can significantly reduce the quality of life for such patients. Therefore, it is incumbent on dental professionals to diagnose and manage patients with BMS as a part of comprehensive care. PMID- 23809307 TI - Primary headache disorders. AB - Primary headache disorders include migraine, tension-type headaches, and the trigeminal autonomic cephalgias (TACs). "Primary" refers to a lack of clear underlying causative pathology, trauma, or systemic disease. The TACs include cluster headache, paroxysmal hemicrania, and short-lasting neuralgiform headache attacks with conjunctival injection and tearing; hemicrania continua, although classified separately by the International Headache Society, shares many features of both migraine and the TACs. This article describes the features and treatment of these disorders. PMID- 23809308 TI - Topical medications as treatment of neuropathic orofacial pain. AB - Understanding mechanisms of neuropathic orofacial pain, targets of treatment, and basic pharmacology and working with informed compounding pharmacists may result in significant benefit for patients. The clinical significance of topical medications is improvement of quality of life for patients by providing a unique medication delivery system for neuropathic orofacial pain and other dental and extraoral conditions. The use of this route of administration has decreased or minimized side effects compared with other methods and is especially useful in medically compromised and elderly patients. These innovations, supported and improved by ongoing research, will augment the armamentarium of the clinician treating orofacial pain disorders. PMID- 23809309 TI - Orofacial pain. PMID- 23809310 TI - [The paradox of fatty diet on protease inhibitors against C hepatitis]. PMID- 23809311 TI - Cognitive stimulation in ICU patients: should we pay more attention? PMID- 23809313 TI - Technological and treatment imperatives, life-sustaining technologies, and associated ethical and social challenges. PMID- 23809312 TI - The role of exercise in modifying outcomes for people with multiple sclerosis: a randomized trial. AB - BACKGROUND: Despite the commonly known benefits of exercise and physical activity evidence shows that persons Multiple Sclerosis (MS) are relatively inactive yet physical activity may be even more important in a population facing functional deterioration. No exercise is effective if it is not done and people with MS face unique barriers to exercise engagement which need to be overcome. We have developed and pilot tested a Multiple Sclerosis Tailored Exercise Program (MSTEP) and it is ready to be tested against general guidelines for superiority and ultimately for its impact on MS relevant outcomes. The primary research question is to what extent does an MS Tailored Exercise Program (MSTEP) result in greater improvements in exercise capacity and related outcomes over a one year period in comparison to a program based on general guidelines for exercise among people with MS who are sedentary and wish to engage in exercise as part of MS self management. METHODS/DESIGN: The proposed study is an assessor-blind, parallel group, randomized controlled trial (RCT). The duration of the intervention will be one year with follow-up to year two. The targeted outcomes are exercise capacity, functional ambulation, strength, and components of quality of life including frequency and intensity of fatigue symptoms, mood, global physical function, health perception, and objective measures of activity level. Logistic regression will be used to test the main hypothesis related to the superiority of the MSTEP program based on a greater proportion of people making a clinically relevant gain in exercise capacity at 1 year and at 2 years, using an intention to-treat approach. Sample size will be 240 (120 per group). DISCUSSION: The MS community is clearly looking for interventions to help alleviate the disabling sequelae of MS and promote health. Exercise is a well-known intervention which has known benefits to all, yet few exercise regularly. For people with MS, the role of exercise in MS management needs to be rigorously assessed to inform people as to how best to use exercise to reduce disability and promote health. TRIAL REGISTRATION: Clinical Trials.gov: NCT01611987. PMID- 23809314 TI - Introduction to the Symposium on Regenerative Medicine. PMID- 23809315 TI - Professionalism: etiquette or habitus? PMID- 23809316 TI - Preferences for resuscitation and intubation among patients with do-not resuscitate/do-not-intubate orders. AB - OBJECTIVE: To determine the accuracy of do-not-resuscitate/do-not-intubate (DNR/DNI) orders in representing patient preferences regarding cardiopulmonary resuscitation (CPR) and intubation. PATIENTS AND METHODS: We conducted a prospective survey study of patients with documented DNR/DNI code status at an urban academic tertiary care center that serves approximately 250,000 patients per year. From October 1, 2010, to October 1, 2011, research staff enrolled a convenience sample of patients from the inpatient medical service, providing them with a series of emergency scenarios for which they related their treatment preference. We used the Kendall tau rank correlation coefficient to examine correlation between degree of illness reversibility and willingness to be resuscitated. Using bivariate statistical analysis and multivariate logistic regression analysis, we examined predictors of discrepancies between code status and patient preferences. Our main outcome measure was the percentage of patients with DNR/DNI orders wanting CPR and/or intubation in each scenario. We hypothesized that patients with DNR/DNI orders would frequently want CPR and/or intubation. RESULTS: We enrolled 100 patients (mean +/- SD age, 78 +/- 13.7 years). A total of 58% (95% CI, 48%-67%) wanted intubation for angioedema, 28% (95% CI, 20%-3.07%) wanted intubation for severe pneumonia, and 20% (95% CI, 13% 29%) wanted a trial resuscitation for cardiac arrest. The desire for intubation decreased as potential reversibility of the acute disease process decreased (Kendall tau correlation coefficient, 0.45; P<.0002). CONCLUSION: Most patients with DNR/DNI orders want CPR and/or intubation in hypothetical clinical scenarios, directly conflicting with their documented DNR/DNI status. Further research is needed to better understand the discrepancy and limitations of DNR/DNI orders. PMID- 23809317 TI - Substituted judgment in principle and practice: a national physician survey. AB - OBJECTIVE: To describe the extent to which US physicians endorse substituted judgments in principle or accommodate them in practice. PATIENTS AND METHODS: We surveyed a stratified, random sample of 2016 physicians by mail from June 25, 2010, to September 3, 2010. Primary outcome measures were agreement with 2 in principle statements about substituted judgment and, after an experimental vignette that varied the basis used by a patient's surrogate to refuse life saving treatment, responses indicating how appropriate it would be to overrule the surrogate's decision. RESULTS: Our response rate was 62% (1156 of 1875 respondents). When there is a conflict between what a surrogate believes a patient would have wanted (substituted judgment) and what the surrogate believes is in the patient's best interest, 4 of 5 physicians (78%) agreed that the surrogate should base their decision on substituted judgment. Yet we also found that 2 of 5 physicians (40%) agree that surrogates should make decisions they believe are in the patient's best interest, even if those seem to contradict the patient's prior wishes. In the experimental vignette, physicians were much more likely to oppose overruling a surrogate's refusal of life-sustaining medical treatment when that refusal was made on the basis of substituted judgment compared with when the refusal was made on the basis of the patient's best interest (50% vs 20%; odds ratio, 4.2; 95% CI, 2.7-6.3). Responses to the in principle items about substituted judgment were not consistently associated with responses to the experimental vignette. CONCLUSION: US physicians largely agree, in principle, that surrogates should prioritize what the patient would have wanted over what they believe is in the patient's best interest, although many physicians are ambivalent in cases in which the 2 norms conflict. Even physicians who reject the principle of substituted judgment tend to treat substituted judgment as the preferred norm for surrogate decision making when responding to a clinical vignette. PMID- 23809318 TI - The perioperative management of patients with left ventricular assist devices undergoing noncardiac surgery. AB - OBJECTIVE: To describe the perioperative management of patients with left ventricular assist devices (LVADs) who require general anesthesia while undergoing noncardiac surgery (NCS) at a single, large tertiary referral center. PATIENTS AND METHODS: Electronic medical records from September 2, 2005, through May 31, 2012, were retrospectively reviewed to evaluate the perioperative management and outcomes in LVAD patients undergoing NCS. Patients were included only if they required a general anesthetic and had previously been discharged from the hospital after initial LVAD implantation. RESULTS: Thirty-three patients with LVADs underwent general anesthesia for 67 noncardiac operations. The mean +/ SD time from LVAD implantation to NCS was 317 +/- 349 days. All but 1 patient had axial flow LVADs. Anticoagulation or antiplatelet agents were present within 7 days before NCS in 49 procedures (73%) and reversed in 32 of 49 (65%). No perioperative thrombotic complications related to anticoagulation or antiplatelet reversal were noted. Red blood cell, fresh frozen plasma, and platelet transfusions were administered during 10, 6, and 4 operations, respectively. The only intraoperative complication was surgical bleeding. Postoperative complications were present in 12 patients after NCS and were mainly composed of bleeding. Three patients died within 30 days of NCS, with the causes of death not attributed to NCS. CONCLUSION: Patients with LVAD safely underwent NCS in a multidisciplinary setting that included preoperative optimization by cardiologists familiar with LVADs when feasible. Anticoagulation or antiplatelet agents were present preoperatively in most patients with LVADs and were safely reversed when necessary for NCS. The relatively high occurrence of postoperative bleeding is consistent with previous series. PMID- 23809319 TI - Temporary is not always benign: similarities and differences between transient ischemic attack and angina. AB - The introduction of the tissue-based definition of transient ischemic attack (TIA), according to which TIA may be diagnosed only in the absence of an infarction on brain neuroimaging, prompts reflections about similarities and differences between TIA and angina. Both share transitory symptoms in the absence of tissue damage, whereas stroke and myocardial infarction are associated with tissue necrosis. Apart from this, TIA and angina are widely different with respect to pathophysiology, natural history, prognosis, and response to specific medical treatments. In general terms, it could be argued that TIA differs from angina as the brain differs from the heart in structure, physiology, metabolism, and performance. Most importantly, in TIA and angina, the reversible nature of symptoms cannot be assumed as a favorable prognostic indicator. In fact, reversibility of stable angina denotes a low-risk condition, whereas in TIA and unstable angina reversibility may suggest plaque instability and relevant risk of ischemic recurrences. PMID- 23809320 TI - 34-year-old man with exertional syncope, dyspnea, and chest pain. PMID- 23809321 TI - Emergency cardiac support with extracorporeal membrane oxygenation for cardiac arrest. AB - A 46-year-old woman with no major medical history presented to the emergency department with chest pain and evidence of anterior, anterolateral, and inferior ST-elevation myocardial infarction. Her condition quickly deteriorated into cardiogenic shock with ventricular arrhythmia. Despite revascularization of the left anterior descending artery and intravenous inotrope and antiarrhythmic therapy, her unstable hemodynamics and arrhythmias persisted. Early emergency initiation of venoarterial extracorporeal membrane oxygenation (ECMO) led to prompt hemodynamic and rhythm stability; however, adequate endogenous cardiac output did not ensue, and she was not able to be weaned from ECMO until hospital day 8. She subsequently recovered and continues to do well in the outpatient setting. This case demonstrates the remarkable hemodynamic and rhythm stability that early initiation of ECMO can provide in the setting of unstable myocardial infarction. PMID- 23809322 TI - Regenerative medicine primer. AB - The pandemic of chronic diseases, compounded by the scarcity of usable donor organs, mandates radical innovation to address the growing unmet needs of individuals and populations. Beyond life-extending measures that are often the last available option, regenerative strategies offer transformative solutions in treating degenerative conditions. By leveraging newfound knowledge of the intimate processes fundamental to organogenesis and healing, the emerging regenerative armamentarium aims to boost the aptitude of human tissues for self renewal. Regenerative technologies strive to promote, augment, and reestablish native repair processes, restituting organ structure and function. Multimodal regenerative approaches incorporate transplant of healthy tissues into damaged environments, prompt the body to enact a regenerative response in damaged tissues, and use tissue engineering to manufacture new tissue. Stem cells and their products have a unique aptitude to form specialized tissues and promote repair signaling, providing active ingredients of regenerative regimens. Concomitantly, advances in materials science and biotechnology have unlocked additional prospects for growing tissue grafts and engineering organs. Translation of regenerative principles into practice is feasible and safe in the clinical setting. Regenerative medicine and surgery are, thus, poised to transit from proof-of-principle studies toward clinical validation and, ultimately, standardization, paving the way for next-generation individualized management algorithms. PMID- 23809323 TI - 30-year-old woman with dyspnea, cough, hemoptysis, and a cavitary lung lesion. PMID- 23809324 TI - John Robert Vane--British pharmacologist and Nobel laureate. PMID- 23809326 TI - Tumorous PASH presenting as rapid unilateral breast enlargement. PMID- 23809327 TI - Dietary and ontogenic regulation of fatty acid desaturase and elongase expression in broiler chickens. AB - Effects of diet and ontogeny on the expression of fatty acid desaturases and elongases were examined in broiler chickens. In Study 1, 120 day-old male chicks received one of six diets with LA:ALA ranging from 46:4 to 16:34, for 33 days. Total n-6 PUFA decreased, and n-3 PUFA increased in response to a decrease in the dietary LA:ALA. FADS1, FADS2, ELOVL2 and ELOVL5 mRNAs were highest (P<0.05) in birds fed lower LA:ALA diets. In Study 2, 60 day-old male chicks were fed a basal diet, and liver samples were collected on day of hatch, and on days 2, 7, 14, 21 and 35 post-hatch. Total n-6 and n-3 PUFA increased (P<0.01) from days 7 to days 21. FADS1, FADS2 and ELOVL2 mRNAs generally increased (P<0.01) with age. These findings provide evidence for the dietary and developmental regulation of PUFA metabolism in broiler chickens. PMID- 23809328 TI - Metabolism of c9,t11-conjugated linoleic acid (CLA) in humans. AB - The c9,t11 isomer of conjugated linoleic acid (CLA) is the most abundant CLA form present in the human diet, and is particularly prevalent in milk and dairy products, and is known to exert several health benefits in experimental animal models. A possible mechanism of action of c9,t11CLA relies on its metabolism via desaturases and elongases and partial beta oxidation in peroxisomes. In this study, we aimed to establish plasma incorporation of c9,t11CLA and its downstream metabolites in healthy volunteers after daily dietary intakes of 0.8g, 1.6g or 3.2g of c9,t11CLA in capsule form for two months. Following supplementation, the plasma concentrations of c9,t11CLA and its metabolites conjugated dienes (CD) 18:3 and the beta oxidation product CD 16:2 were incorporated in a linear fashion, while on the other hand CD 20:3 reached a plateau following intakes of 1.6g/d of dietary intake, and was not further increased following higher CLA intakes. We may conclude that supplementation of c9,t11 CLA levels result in linear responses of CLA and its main metabolites in plasma. In addition, only the highest concentration of CLA intake tested (3.2g/d) yielded plasma concentrations of CLA and metabolites close to the range found sufficient to exert nutritional effects in experimental animal models. PMID- 23809329 TI - Metals contamination along the watershed and estuarine areas of southern Bohai Sea, China. AB - Distributions and magnitude of metals in water, sediment and soil collected from the watershed and estuarine areas of southern Bohai Sea, were investigated. The largest dissolved concentrations of As, Cu and Zn in water were 347.70, 2755.00, 2076.00 MUg/L, respectively, much higher than corresponding drinking water guidelines. The greatest concentrations of Cu, Zn, Cr, Ni, Pb, As and Cd in sediments were 1462.2, 1602.17, 196.43, 67.15, 63.54, 73.86 and 1.41 mg/kg, dw, respectively. The mean concentrations of Cu, Ni, Cd, Zn, Cr, Pb and As in soils were 24.67, 24.73, 0.14, 64.75, 56.52, 25.12 and 9.34 mg/kg, dw, respectively. Land use was confirmed to be an important factor of influence on soil metal concentrations. Metal contents along the watershed of Jie River were significantly greater than in other locations. The detection of metals in relatively high concentrations from different environmental matrices in this region indicates the necessity of further studies. PMID- 23809330 TI - Long term trends of Hg uptake in resident fish from a polluted estuary. AB - Mercury contamination of fish is dependent upon a system's ability to transform inorganic Hg into biologically available forms; however, fish biometrics also play an important role. To assess long term trends in Hg concentrations in sand flathead (Platycephalus bassensis) a polynomial model, corrected for fish length, was used to evaluate temporal trends and spatial variability, while growth rates were estimated using the Von Bertalanffy length-at-age model. Hg concentrations showed no decrease over time, and generally remained near recommended consumption levels (0.5 mg kg(-1)). Previously reported spatial differences in Hg concentrations were not supported by the data once the models were corrected for fish length. Growth rate variation accounted for a large part of the previously published spatial differences. These results suggest that inclusion of fish biometrics is necessary to facilitate an accurate interpretation of spatial and temporal trends of contaminant concentrations in long term estuarine and marine monitoring programs. PMID- 23809331 TI - Factors contributing to heavy metal accumulation in sediments and in the intertidal mussel Perna perna in the Gulf of Annaba (Algeria). AB - This paper presents the results of a seasonal survey of heavy metals accumulated in sediments and in the soft parts of the body of the mussel Perna perna at four stations in the Gulf of Annaba (Algeria). Pooled soft tissues from 10 mussels representing the entire range of sizes were digested in nitric acid. Statistical analysis reveals a significant seasonal effect on all the measured metals, the highest values being recorded in winter. With the exception of Cr, the levels for all metals were significantly higher in the east, at the outlet of the Seybouse River, than at all other monitoring stations. The study also shows that north western waters are subject to a significantly lower degree of heavy metal pollution than elsewhere in the gulf. Levels were nevertheless within the limits of public health standards. The results confirm the usefulness of P. perna as a bioindicator for heavy metal pollution. PMID- 23809332 TI - Assessing the environmental consequences of CO2 leakage from geological CCS: generating evidence to support environmental risk assessment. PMID- 23809333 TI - First record of sea snake (Hydrophis elegans, Hydrophiinae) entrapped in marine debris. AB - Entanglement in derelict fishing gear and other marine debris is a major threat to the survival of large marine wildlife like cetaceans, seabirds and sea turtles. However, no previous reports of entanglement or entrapment have been recorded in sea snakes (Hydrophiinae). We report here on a sea snake (Hydrophis elegans) found with a ceramic washer encircling its body captured from the north east coast of Queensland, Australia. The ring had constricted the body and over time caused extensive damage to the underlying tissues. A post-mortem examination showed the snake was severely emaciated as the ring restricted the passage of food to the stomach and intestine. This is the first record of mortality due to marine debris entrapment in sea snakes. PMID- 23809334 TI - Management of challenging cases of patients with cancer-associated thrombosis including recurrent thrombosis and bleeding: guidance from the SSC of the ISTH. PMID- 23809335 TI - Honey bee larval peritrophic matrix degradation during infection with Paenibacillus larvae, the aetiological agent of American foulbrood of honey bees, is a key step in pathogenesis. AB - Paenibacillus larvae, the aetiological agent of American foulbrood (AFB) of honey bees, causes a fatal intestinal infection in larvae and invades the haemocoel by breaching the midgut. The peritrophic matrix lining the midgut epithelium in insects constitutes an effective barrier against abrasive food particles, xenobiotics, toxins and pathogens. Pathogens like P. larvae entering the host through the gut first need to overcome this barrier. To better understand AFB pathogenesis, we analysed the fate of the peritrophic matrix in honey bee larvae during P. larvae infection. Using histochemical techniques, we first established that chitin is a major component of the honey bee larval peritrophic matrix. Rearing larvae on a diet containing a fluorochrome blocking formation of the peritrophic matrix or a bacterial endochitinase revealed that a fully formed peritrophic matrix is essential for larval survival. Larvae infected by P. larvae showed total degradation of the peritrophic matrix enabling the bacteria to directly attack the epithelial cells. Carbon source utilization tests confirmed that P. larvae is able to metabolize colloidal chitin. We propose that P. larvae degrades the peritrophic matrix to allow direct access of the bacteria or of bacterial toxins to the epithelium to prepare the breakthrough of the epithelial layer. PMID- 23809336 TI - Vasomotor dysfunction in the mesenteric artery after organ culture with cyclosporin A. AB - Cyclosporin A (CsA) is a widely used immunosuppressive agent that also causes hypertension. However, the molecular basis for CsA-induced hypertension remains elusive. In this study, we established an in vitro model for CsA-induced pathological changes in vasculature. Rat mesenteric arteries were incubated with CsA for 24 hr in an organ culture system. Both vasocontraction and vasorelaxation in mesenteric artery were studied using myograph technology, and mRNA expressions of the contractile receptors were determined by real-time PCR. The results showed that CsA increased the mRNA expression and contractile function of several G protein-coupled receptors (GPCRs), such as endothelin receptor type B (ETB ), 5 hydroxytryptamine type 1B (5-HT1B ) and 1D (5-HT1D ), in vascular smooth muscle cells. In addition, both nitric oxide (NO)-mediated vasorelaxation and endothelium-independent relaxation were impaired by CsA. In summary, this study showed the enhanced GPCRs-mediated contraction and reduced vasorelaxation in mesenteric artery after organ culture with CsA, which mimicked the CsA-induced pathological changes in the vascular system in vivo. Furthermore, this organ culture system would be an ideal in vitro tool to study the molecular mechanisms of CsA-induced hypertension. PMID- 23809337 TI - Wnt1 from cochlear schwann cells enhances neuronal differentiation of transplanted neural stem cells in a rat spiral ganglion neuron degeneration model. AB - Although neural stem cell (NSC) transplantation is widely expected to become a therapy for nervous system degenerative diseases and injuries, the low neuronal differentiation rate of NSCs transplanted into the inner ear is a major obstacle for the successful treatment of spiral ganglion neuron (SGN) degeneration. In this study, we validated whether the local microenvironment influences the neuronal differentiation of transplanted NSCs in the inner ear. Using a rat SGN degeneration model, we demonstrated that transplanted NSCs were more likely to differentiate into microtubule-associated protein 2 (MAP2)-positive neurons in SGN-degenerated cochleae than in control cochleae. Using real-time quantitative PCR and an immunofluorescence assay, we also proved that the expression of Wnt1 (a ligand of Wnt signaling) increases significantly in Schwann cells in the SGN degenerated cochlea. We further verified that NSC cultures express receptors and signaling components for Wnts. Based on these expression patterns, we hypothesized that Schwann cell-derived Wnt1 and Wnt signaling might be involved in the regulation of the neuronal differentiation of transplanted NSCs. We verified our hypothesis in vitro using a coculture system. We transduced a lentiviral vector expressing Wnt1 into cochlear Schwann cell cultures and cocultured them with NSC cultures. The coculture with Wnt1-expressing Schwann cells resulted in a significant increase in the percentage of NSCs that differentiated into MAP2-positive neurons, whereas this differentiation-enhancing effect was prevented by Dkk1 (an inhibitor of the Wnt signaling pathway). These results suggested that Wnt1 derived from cochlear Schwann cells enhanced the neuronal differentiation of transplanted NSCs through Wnt signaling pathway activation. Alterations of the microenvironment deserve detailed investigation because they may help us to conceive effective strategies to overcome the barrier of the low differentiation rate of transplanted NSCs. PMID- 23809338 TI - Nutrition and neurocognitive development. PMID- 23809339 TI - Oxygen in the delivery room. AB - Immediately after birth the newly born infant aerates the lungs, diminishes pulmonary vascular resistance, and initiates gas exchange. However, under certain circumstances this process will not be adequately accomplished. Asphyxia is characterized by periods of hypoxia and ischemia leading frequently to hypoxic ischemic encephalopathy. The mainstay of newborn resuscitation resides in the establishment of a functional residual capacity and an adequate oxygenation. Recent guidelines have established guidelines which provide counsel on the use of oxygen in term infants. However, preterm oxygenation in the delivery room (DR) has only been defined very vaguely. Herewith, we will address available information regarding the use of oxygen supplementation in the DR both in term and preterm babies for a satisfactory postnatal adaptation. PMID- 23809340 TI - Neonatal apnea and gastroesophageal reflux (GER): is there a problem? AB - Apnea of prematurity and gastroesophageal reflux (GER) are both common occurrences in preterm infants and widely perceived to be causally related. We seek in this review to provide a potential guideline for neonatal GER non pharmacologic and pharmacologic therapy. Available physiologic data suggest that when there is a temporal relationship apnea may be more likely to predispose to GER via esophageal sphincter relaxation than vice versa. Measurement of multiple intraluminal impedance via esophageal catheter in addition to esophageal pH has enhanced our understanding of GER, although it also did not demonstrate a causal relationship between apnea and GER. The incidence of GER may be modified by thickening feeds and position change without adverse effects. In contrast, pharmacotherapy including acid suppression therapy may have adverse effects and should only be used in infants with clear evidence of clinical benefit. PMID- 23809341 TI - Lung ultrasound: its role in neonatology and pediatrics. AB - BACKGROUND: Lung ultrasound (LUS) has become more and more popular in the first decade of the 21(st) century, both in neonatal and in pediatric age groups. Several papers addressed the usefulness of this procedure mainly because of its possibility to be utilised at the bedside, without risk of irradiation along with simple and immediate interpretations of the images. AIMS: The purpose of this paper is to update the knowledge on LUS related to the most common neonatal respiratory diseases and some pediatric acute lung diseases. STUDY DESIGN: We describe the technique of LUS execution, the normal LUS appearance and the LUS findings in the most common neonatal and pediatric acute diseases. SUBJECTS: LUS findings related to neonates of different gestational age as well as of pediatric patients from infancy to childhood are shown. OUTCOME MEASURES: Issues on the evolution and effect of treatment related to LUS findings of neonatal and pediatric respiratory diseases are discussed. RESULTS: LUS depicted peculiar and reproducible patterns in all the lung diseases described. CONCLUSIONS: The use of LUS in the clinical field seems to be a reasonable and easy-to-use practice that can be considered an extension of the clinical exam. As a consequence of this feature, LUS, to fully express its potential, must be performed by the clinician in charge of the patient. PMID- 23809342 TI - Epigenetics of allergy. AB - Epigenetics has recently been considered as a potential mechanism involved in the development of many disorders, including allergic diseases. Animal models have shown that environmental factors such as maternal tobacco smoke or mechanical ventilation can alter gene transcription and consequently the structure and function of lungs. Moreover, asthma and other allergic diseases (atopic dermatitis and food allergy) are influenced by epigenetics. In fact, the exposure to environmental factors during early childhood may induce a long-lasting altered genetic state adapting to a persistent "Th2 state" thus influencing the development of asthma or atopic dermatitis and food allergy if alterations involve the filaggrin gene. In conclusion, progresses have been made linking environmental pollution, environmental tobacco smoke (ETS) and diet exposure with atopy through epigenetic mechanisms. Furthermore, considerable advances have been made implicating epigenetic mechanisms in T cell differentiation. However, much more research is still needed, in particular to define the clinical consequences of such epigenetic alterations. PMID- 23809343 TI - Surfactant therapy: past, present and future. AB - Surfactant replacement in preterm infants with respiratory distress syndrome (RDS) has been a major therapeutic breakthrough and the most intensively studied intervention in neonatal medicine. Surfactant whether given prophylactically in the delivery room or in babies with established RDS reduces the severity of RDS, the incidence of air leaks and pneumothorax and, most importantly, neonatal death. Many randomized controlled trials have explored different strategies to optimize the effect of surfactant administration and have further improved neonatal outcome. Whenever indicated, surfactant should be administered as early as possible in the course of the RDS. PMID- 23809345 TI - Automation of respiratory support in premature infants. AB - Premature infants show a characteristic respiratory instability that is reflected in fluctuations in ventilation and gas exchange. Adapting the respiratory support on a continuous basis to the infant's needs is challenging and not always effective. Automatic modes of respiratory support have been developed to address these limitations. This article describes some of these automatic modes of respiratory support and provides a discussion on the state of the evidence. PMID- 23809344 TI - Old and new: appropriate dosing for neonatal antifungal drugs in the nursery. AB - Candida infections are a source of significant mortality and morbidity in the neonatal intensive care unit. Treatment strategies continue to change as additional antifungals become available and studies in neonates are performed. Amphotericin B deoxycholate has been favored for many years, but fluconazole has the most data supporting its use in neonatal Candida infections and is often employed for prophylaxis as well as treatment. Voriconazole and posaconazole have limited utility in the nursery and are rarely used. The echinocandins are increasingly administered for invasive Candida infections, although higher doses are required in neonates than in older children and adults. PMID- 23809346 TI - Treatment of bronchiolitis: state of the art. AB - Bronchiolitis is a leading cause of acute illness and hospitalization for infants and young children worldwide. It is usually a mild disease, but the few children developing severe symptoms need to be hospitalized and some will need ventilatory support. To date, the mainstay of therapy has been supportive care, i.e. assisted feeding and hydration, minimal handling, nasal suctioning and oxygen therapy. In recent years the delivery of oxygen has been improved by using a high-flow nasal cannula. At the same time, the discovery of nebulized hypertonic saline enables better airway cleaning with a benefit for respiratory function. The possible role of any pharmacological approach is still debated: many pharmacological therapies tried in the past, ranging from bronchodilators to corticosteroids, were found to offer no benefit in this disease. More recently, nebulized adrenaline demonstrated a short-term benefit. Prophylaxis and prevention, especially in children at high risk of severe infection, such as prematurely born infants and children with bronchopulmonary dysplasia, have a fundamental role in dealing with this disease. In this review, we focus on current recommendations for the management and prevention of bronchiolitis, paying particular attention to the latest literature in search of answers to the questions that remain open. PMID- 23809347 TI - Viral respiratory burden in moderate-to-late preterm infants. AB - More than 1 in 10 babies are born prematurely and most of them are born after gestational age 32 weeks. Mortality and morbidity are more common in these moderate-to-late preterm infants than in full-term children. In this review, mechanisms and epidemiology of long-term airway morbidity in moderate-to-late preterm infants will be discussed. We discuss the potential of viral respiratory infections to further aggravate abnormal lung function associated with preterm birth. PMID- 23809348 TI - Strategies to accelerate weaning from respiratory support. AB - Because mechanical ventilation is associated with severe complications in premature infants, it is important to limit its duration as much as possible. This can be accomplished by using strategies that preserve spontaneous respiration such as patient triggered and volume target ventilation. The use of respiratory stimulants and nasal CPAP or nasal IPPV after extubation are also effective and improve extubation success. A short course of systemic steroids can also expedite weaning and extubation. PMID- 23809349 TI - Fetal alcohol spectrum disorders and fetal alcohol syndrome: the state of the art and new diagnostic tools. AB - Ethanol consumption during pregnancy is a widespread problem which is increasing in the generation of young women. Gestational alcohol consumption causes fetal exposure to this teratogen and is associated with the onset of fetal alcohol spectrum disorders (FASD) including fetal alcohol syndrome (FAS). FASD and FAS can lead to several physical, cognitive and behavioral disabilities, whose early diagnosis is of primary importance to perform primary prevention with total abstinence from alcohol during pregnancy and secondary prevention in newborns and children for a proper follow up to reduce risk of secondary consequences. In recent years significant efforts have been made to understand the underlying mechanisms of this disease and to identify objective biological and instrumental diagnostic tools, such as exposure biomarkers in neonatal meconium and advanced magnetic resonance imaging. Nonetheless, further studies are still needed to implement our knowledge on fetal effects of ethanol, and multidisciplinary actions are necessary to raise awareness among women of childbearing age about the danger of consuming even small amounts of ethanol during pregnancy. PMID- 23809350 TI - Global perfusion assessment and tissue oxygen saturation in preterm infants: where are we? AB - Near infrared spectroscopy (NIRS) monitoring is a new challenge for clinicians who deal with early detection of dangerous hypoperfusion in the brain, as well as in splanchnic and renal districts in critically ill preterm infants. Previous studies performed on infants and children with congenital heart disease, demonstrated the efficacy of this non-invasive method in managing hypoperfusive states pre, post and during cardiac surgery. Its use has improved post surgery outcome. NIRS monitoring has been used also to assess therapeutic intervention utility. Early identification of silent hypoperfusion has made NIRS use in preterm infants very interesting for neonatologists, especially where other techniques have failed. In this work, literature on this topic has been carefully examined, particularly the "two site NIRS" use in preterm infants, to evaluate how regional splanchnic oxygen saturation changes, both in physiological events, such as enteral feeding and in hemodynamic disorders, that occur in patients with significant patent ductus and in hypoperfusive states that lead to necrotizing enterocolitis. PMID- 23809351 TI - Pharmacological resolution of a multiloculated Candida spp. liver abscess in a preterm neonate. AB - We report the case of a 31-week gestational age neonate with Candida albicans sepsis and a hepatic abscess. Diagnosis relied on clinical and radiological signs of sepsis, liver function impairment and culture isolation of Candida spp. from sterile sites. Liver ultrasound documented the presence of a multiloculated abscess. Treatment with micafungin (3 mg/kg/day) resulted in normalization of liver function and inflammatory laboratory values and improvement of clinical condition. After 30 days of treatment, the liver abscess resolved and at the 8 month follow up the infant is doing well. Prompt diagnosis and antifungal treatment avoided surgical drainage and liver surgery in this high-risk neonate. PMID- 23809352 TI - Maternal milk protects infants against bronchiolitis during the first year of life. Results from an Italian cohort of newborns. AB - OBJECTIVE: Bronchiolitis is one of the primary causes of hospitalization in infancy. We evaluated the effect of breastfeeding on the occurrence of hospitalization for bronchiolitis in the first year of life. METHODS: In a prospective cohort study, 1,814 newborns of =33 weeks of gestational age (wGA) were enrolled in 30 Italian Neonatology Units and followed-up for 1 year to assess hospitalizations for bronchiolitis. Children were grouped as 'never breastfed' and 'ever breastfed'; these latter were further divided into those 'exclusively breastfed' and 'breastfed associated with milk formula'. The risk of hospitalization for bronchiolitis was evaluated with survival analysis, and hazard ratios (HR) with 95% confidence interval [95% CI] were calculated. RESULTS: Among enrolled newborns 22.9% were 'never breastfed'; in the breastfed group, 65% were 'exclusively breastfed' and 35% were 'breastfed with associated milk formula'. At 12 months of age, the risk of hospitalization for bronchiolitis was significantly higher in the 'never breastfed' group (HR: 1.57; 95% CI: 1.00 2.48). 'Breastfed associated with formula milk' and 'exclusively breastfed' groups were at similar risk of hospitalization for bronchiolitis. This observed protective effect of maternal milk was not explained by the higher prevalence of conditions able to increase the risk of bronchiolitis among 'never breastfed newborns'. CONCLUSIONS: Breastfeeding, even in association with formula milk, reduces the risk of hospitalization for bronchiolitis during the first year of life. Encouraging breastfeeding might be an effective/inexpensive measure of prevention of lower respiratory tract infections in infancy. PMID- 23809353 TI - Urinary metabolomics in newborns infected by human cytomegalovirus: a preliminary investigation. AB - Human cytomegalovirus (HCMV) represents one of the most significant viral risks of birth defects and long-term sequelae. The severity of the infection depends on the form of the disease, which can be symptomatic or asymptomatic with or without sequelae. The aim of this study was to investigate in a population of newborns the impact of HCMV infection on the urine metabolome by using (1)H-nuclear magnetic resonance (NMR) spectroscopy combined with multivariate statistical analysis. Twenty-three children born from women with a primary HCMV infection during pregnancy were recruited. Twelve were HCMV infected at birth whereas eleven were not infected (control). The (1)H-NMR spectra were analyzed using a PLS-DA mathematical model in order to identify the discriminant metabolites between the asymptomatic and the control group. The most important metabolites characterizing the clustering of the samples were: myoinositol, glycine, 3 hydroxybutyrate, 3-aminoisobutyrate, creatine, taurine and betaine. These findings suggest the use of metabolomics as a useful new tool in the investigation of HCMV congenital infection. PMID- 23809354 TI - Candida pneumonia in a term infant after prolonged use of inhaled corticosteroids for bronchopulmonary dysplasia (BPD). AB - Candida spp. frequently cause invasive fungal disease in neonates, and many organs or apparatus can be involved through bloodstream dissemination. Though Candida spp. can heavily colonize the upper and lower respiratory tract, an end organ localization to the lung is not frequent and acquisition via descending/respiratory route is a questioned entity. Here we report the case of a young infant affected by bronchopulmonary dysplasia (BPD) and treated with inhaled steroids who developed Candida pneumonia likely acquired through descending route. PMID- 23809356 TI - Survival rate and prevalence of bronchopulmonary dysplasia in extremely low birth weight infants. AB - BACKGROUND: Bronchopulmonary dysplasia (BPD) continues to represent a significant cause of morbidity among survivors of severe prematurity in the NICU. The increasing prevalence of BPD over the decades has been suggested to be related to the increased survival of extremely low birthweight infants. AIMS: To evaluate differences in prevalence of BPD (BPD28d and BPD36wk) and as a function of survival rate in extremely low birth weight (ELBW) infants over time, and to explore its relationship with known associated risk factors. METHODS: Survival rate and prevalence of oxygen-dependency =28 days (BPD28d) and oxygen-dependency =36 weeks postmenstrual age (BPD36wk) were evaluated in ELBW newborns (mean gestational age: 27.12.2 weeks; mean birth weight: 817142 g) consecutively admitted to the Brindisi NICU over the last 26 years. Two arbitrarily chosen time periods were compared: Period 1: July 1st, 1986 to June 30, 2002 vs. Period 2: July 1st, 2002 to December 31, 2012. Analyzed variables included gestational age, birth weight, intubation time, hours of O2 administration, NCPAP, and use of surfactant. Differences between the time periods were assessed by chi-square statistics, Fisher's tests or Mann-Whitney test, as appropriate. A two-tailed p value <0.05 was considered to indicate statistical significance. RESULTS: Survival rate of ELBW infants over the examined time periods dramatically improved from 42.3% to 72.6% (p < 0.0001), whereas changes in the prevalence of BPD28d and BPD36wk were not statistically significant (30.5% vs. 39.3%, p = 0.2137 and 5.5% vs. 13.1%, p = 0.1452, respectively). Likewise, BPD severity was not significantly different between the two time periods (p = 0.1635). Gestational age and birth weight of surviving neonates did not significantly change between the two time periods (p = 0.8050 and p = 0.6986, respectively), whereas significantly increased intubation time (median values: 144 hours vs. 33 hours, p <0.0001) and use of exogenous surfactant (89.3% vs. 48.6%, p < 0.0001) was evidenced for the second time period, as well as NCPAP (median values: 600 hours vs. 377 hours, p = 0.0005). A statistically non-significant trend for a prolonged O2 administration in period 2 (p = 0.0850) was also observed. CONCLUSION: Our findings indicate that a significantly increased survival is not necessarily associated with a significant difference in the prevalence of BPD among ELBW infants. PMID- 23809355 TI - Human milk feeding prevents retinopathy of prematurity (ROP) in preterm VLBW neonates. AB - BACKGROUND: Retinopathy of prematurity (ROP) is a multifactorial disease, but little is known about its relationships with neonatal nutritional policies. Human, maternal milk is the best possible nutritional option for all premature infants, including those at high risk for severe complications of prematurity, such as ROP. OBJECTIVE: This is a secondary analysis of data collected during two multicenter RCTs performed consecutively (years 2004 through 2008) by a network of eleven tertiary NICUs in Italy. The two trials aimed at assessing effectiveness of fluconazole prophylaxis (Manzoni et al., N Engl J Med 2007 Jun 14;356(24):2483-95), and of bovine lactoferrin supplementation (Manzoni et al., JAMA 2009 Oct 7;302(13):1421-8), in prevention of invasive fungal infection, and of late-onset sepsis in VLBW infants, respectively. We tested the hypothesis that exclusive feeding with fresh maternal milk may prevent ROP of any stage - as defined by the ETROP study - in VLBW neonates, compared to formula feeding. METHODS: We analyzed the database from both trials. Systematic screening for detection of ROP was part of the protocol of both studies. The definition of threshold ROP was as defined by the ETROP study. Univariate analysis was performed to look for significant associations between ROP and several possible associated factors, and among them, the type of milk feeding (maternal milk or formula for preterms). When an association was indicated by p < 0.05, multiple logistic regression was used to determine the factors significantly associated with ROP. RESULTS: In both trials combined, 314 infants received exclusively human maternal milk (group A), and 184 a preterm formula because their mothers were not expected to breastfeed. The clinical, demographical and management characteristics of the neonates did not differ between the two groups, particularly related to the presence of the known risk factors for ROP. Overall, ROP incidence (any stage) was significantly lower in infants fed maternal milk (11 of 314; 3.5%) as compared to formula-fed neonates (29 of 184; 15.8%) (RR 0.14; 95% CI 0.12-0.62; p = 0.004). The same occurred for threshold ROP (1.3% vs. 12.3%, respectively; RR 0.19; 95% CI 0.05-0.69; p = 0.009). At multivariate logistic regression controlling for potentially confounding factors that were significantly associated to ROP (any stage) at univariate analysis (birth weight, gestational age, days on supplemental oxygen, systemic fungal infection, outborn, hyperglycaemia), type of milk feeding retained significance, human maternal milk being protective with p = 0.01. CONCLUSIONS: Exclusive human, maternal milk feeding since birth may prevent ROP of any stage in VLBW infants in the NICU. PMID- 23809357 TI - Metabolomics in neonatal life. AB - Metabolomics (or metabonomics) is based on the systematic study of the complete set of metabolites in a biological sample and is considered the most innovative of the 'omics' sciences. The metabolome is currently regarded as the 'new clinical biochemistry' it is the most predictive phenotype, through consideration of epigenetic differences. Among more than 5000 papers listed in PubMed on this topic in the last three years, less than 60 refer to neonatal life. Aim of this review is to present the clinical applications of metabolomics in neonatology, including results of recent studies performed in experimental models and newborns. PMID- 23809358 TI - Impact of renal dysfunction in cirrhotic patients with bacterial infections other than spontaneous bacterial peritonitis. AB - AIM: The impact of renal dysfunction has not been well evaluated among cirrhotic patients having bacterial infections other than spontaneous bacterial peritonitis (SBP). We aimed to examine the impact of renal function impairment (RFI) among cirrhotic patients with non-SBP bacterial infections. METHODS: Data of 7134 cirrhotic patients with non-SBP bacterial infections extracted from the Taiwan National Health Insurance Database, derived from the Taiwan National Health Insurance Program, in 2004 were analyzed. RESULTS: A total of 579 (8.1%) patients had renal dysfunction. Of these, 223 patients had acute renal failure (ARF), and 141 had end-stage renal disease (ESRD) requiring hemodialysis before admission. The overall 30-day, 1-year and 3-year mortalities were 15.8%, 39.3% and 54.5%, respectively. Compared with the non-RFI group, the adjusted hazard ratios (HR) of 30-day mortality for RFI, ARF and ESRD were 3.20 (P < 0.001), 4.81 (P < 0.001) and 1.59 (P = 0.015); the adjusted HR of 1-year mortality for RFI, ARF and ESRD were 2.68 (P < 0.001), 3.50 (P < 0.001) and 1.84 (P < 0.001), and adjusted HR of 3-year mortality for RFI, ARF and ESRD were 2.34 (P < 0.001), 2.97 (P < 0.001) and 1.76 (P < 0.001). The adjusted HR of 30-day, 1-year and 3-year mortalities for the ARF group were 2.98 (P < 0.001), 1.74 (P < 0.001) and 1.58 (P = 0.001) compared with the ESRD group, respectively. CONCLUSION: This population-based cohort study shows that RFI, especially ARF, is an independent poor prognostic factor in cirrhotic patients with non-SBP bacterial infections. PMID- 23809359 TI - Immunosenescence: a product of the environment? AB - The major function of the immune system is to provide protection against pathogens, in order to prevent infections and potential death. However, with increasing age the immune system undergoes alterations culminating in a progressive deterioration in the ability to respond to infection and vaccination. The precise mechanisms associated with immunosenescence have not been fully elucidated although extensive analyses have suggested that intrinsic defects within immune cells are potentially involved. Despite the stromal niche playing a critical role in the development and activation of immune cells, the role of extrinsic factors within the microenvironment in immunosenescence is less well understood. Moreover, emerging evidence suggests that the aged microenvironment contributes significantly to the age-associated decline of immune function and additionally may offer a potential target for rejuvenating the immune system. Indeed, rejuvenation strategies which have targeted the thymic stromal microenvironment have proved to be successful in recovering thymic function in the aged. PMID- 23809360 TI - Gender differences in blood pressure-related hypoalgesia in a general population: the Tromso Study. AB - An inverse association between resting blood pressure (BP) and acute pain sensitivity is well documented. Whether BP-related hypoalgesia differs by gender is unclear from prior work. Whether it increases proportionally with BP throughout the full BP range is also unknown. We examined BP-related hypoalgesia in a general population sample (n = 10,371, aged 30-87) of equal gender distribution reflecting the extremely low through hypertensive BP range. Resting BP was assessed and individuals participated in a standardized cold pressor test, providing pain ratings every 9 seconds. For systolic BP (SBP), a significant SBP * Gender interaction was observed on mean pain ratings (P < .001). Females displayed significant BP-related hypoalgesia (P < .001), with males showing a 38% smaller effect (P < .001). A similar DBP * Gender interaction was also observed (P < .05). Spline regression indicated a significant (P < .001) change in slope of the SBP-pain association at 140 mmHg. Among individuals with lower resting SBP (<140/90), increasing hypoalgesia with increasing SBP levels was observed (P < .001), with no further increases in those with higher BP (>=140/90; P > .10). This is the first large-scale study to confirm past results suggesting that BP related hypoalgesia differs by gender; that is, females exhibited greater hypoalgesia. BP-related hypoalgesia appears subject to ceiling effects in the hypertensive BP range. PERSPECTIVE: Females show greater BP-related hypoalgesia than males, highlighting gender differences in endogenous antinociceptive systems. Extent of BP-related hypoalgesia does not increase further once resting pressures reach the hypertensive range, suggesting persistent maximal demands on these antinociceptive systems among hypertensive individuals. PMID- 23809361 TI - Cyclotide biosynthesis. AB - Cyclotides are bioactive macrocyclic peptides from plants that are characterized by their exceptional stability and potential applications as protein engineering or drug design frameworks. Their stability arises from their unique cyclic cystine knot structure, which combines a head-to-tail cyclic peptide backbone with three conserved disulfide bonds having a knotted topology. Cyclotides are ribosomally synthesized by plants and expressed in a wide range of tissues, including leaves, flowers, stems and roots. Here we describe recent studies that have examined the biosynthesis of cyclotides and in particular the mechanism associated with post-translational backbone cyclization. PMID- 23809362 TI - Leveraging global resources to end the Alzheimer's pandemic. PMID- 23809363 TI - New and different approaches needed for the design and execution of Alzheimer's clinical trials. PMID- 23809364 TI - Designing drug trials for Alzheimer's disease: what we have learned from the release of the phase III antibody trials: a report from the EU/US/CTAD Task Force. AB - An international task force of investigators from academia, industry, nonprofit foundations, and regulatory agencies met in Monte Carlo, Monaco, on October 31, 2012, to review lessons learned from the recent bapineuzumab and solanezumab trials, and to incorporate insights gained from these trials into future clinical studies. Although there is broad consensus that Alzheimer's disease (AD) should be treated during its earliest stages, the concept of secondary prevention has evolved to be described more accurately as treatment of preclinical, presymptomatic, or early AD. There continues to be a strong emphasis on biomarkers and a need for new biomarkers; however, there has also been a realization, based on completed trials, that the most reliable indicator of clinical efficacy across the entire spectrum of disease from asymptomatic to AD dementia is likely a measure of cognition. The task force made many recommendations that should improve the likelihood of success in future trials, including larger phase 2 or combined phase 2/phase 3 studies, clear evidence of target engagement in the central nervous system, evidence of downstream effects on biomarkers before initiating phase 3 studies, consideration of adaptive and targeted trial designs, and use of sensitive measures of cognition as the most robust indicator of treatment benefit. PMID- 23809365 TI - Military risk factors for Alzheimer's disease. AB - Traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) are signature injuries of the wars in Iraq and Afghanistan and have been linked to an increased risk of Alzheimer's disease (AD) and other dementias. A meeting hosted by the Alzheimer's Association and the Veterans' Health Research Institute (NCIRE) in May 2012 brought together experts from the U.S. military and academic medical centers around the world to discuss current evidence and hypotheses regarding the pathophysiological mechanisms linking TBI, PTSD, and AD. Studies underway in civilian and military populations were highlighted, along with new research initiatives such as a study to extend the Alzheimer's Disease Neuroimaging Initiative (ADNI) to a population of veterans exposed to TBI and PTSD. Greater collaboration and data sharing among diverse research groups is needed to advance an understanding and appropriate interventions in this continuum of military injuries and neurodegenerative disease in the aging veteran. PMID- 23809367 TI - Alzheimer's disease public-private partnerships: A landscape of the global nonprofit community. PMID- 23809366 TI - Beyond amyloid: getting real about nonamyloid targets in Alzheimer's disease. AB - For decades, researchers have focused primarily on a pathway initiated by amyloid beta aggregation, amyloid deposition, and accumulation in the brain as the key mechanism underlying the disease and the most important treatment target. However, evidence increasingly suggests that amyloid is deposited early during the course of disease, even prior to the onset of clinical symptoms. Thus, targeting amyloid in patients with mild to moderate Alzheimer's disease (AD), as past failed clinical trials have done, may be insufficient to halt further disease progression. Scientists are investigating other molecular and cellular pathways and processes that contribute to AD pathogenesis. Thus, the Alzheimer's Association's Research Roundtable convened a meeting in April 2012 to move beyond amyloid and explore AD as a complex multifactorial disease, with the goal of using a more inclusive perspective to identify novel treatment strategies. PMID- 23809368 TI - Medicare Public Use Files and Alzheimer's disease factors in 2008 and 2010. PMID- 23809369 TI - Update on appropriate use criteria for amyloid PET imaging: dementia experts, mild cognitive impairment, and education. Amyloid Imaging Task Force of the Alzheimer's Association and Society for Nuclear Medicine and Molecular Imaging. AB - Amyloid PET imaging is a novel diagnostic test that can detect in living humans one of the two defining pathologic lesions of Alzheimer disease, amyloid-beta deposition in the brain. The Amyloid Imaging Task Force of the Alzheimer's Association and Society for Nuclear Medicine and Molecular Imaging previously published appropriate use criteria for amyloid PET as an important tool for increasing the certainty of a diagnosis of Alzheimer disease in specific patient populations. Here, the task force further clarifies and expands 3 topics discussed in the original paper: first, defining dementia experts and their use of proper documentation to demonstrate the medical necessity of an amyloid PET scan; second, identifying a specific subset of individuals with mild cognitive impairment for whom an amyloid PET scan is appropriate; and finally, developing educational programs to increase awareness of the amyloid PET appropriate use criteria and providing instructions on how this test should be used in the clinical decision-making process. PMID- 23809370 TI - NSAID, aspirin delays gastric ulcer healing with reduced accumulation of CXCR4(+)VEGFR1(+) cells to the ulcer granulation tissues. AB - BACKGROUND: Ulcer healing is a complex process, which involves cell migration, proliferation, angiogenesis and re-epithelialization. Several growth factors have been implicated in this process but the precise mechanism is not well understood. This study examined the involvement of VEGFR1 signaling in the gastric ulcer healing. METHODS: Gastric ulcers were induced by the serosal application of 100% acetic acid, and the areas of the ulcers were measured thereafter. RESULTS: The healing of acetic acid induced ulcers and the progenitor cells expressing CXCR4(+)VEGFR1(+) cell were significantly delayed in NSAID treated mice. The areas of the ulcer was significantly suppressed in tyrosine kinase-deficient VEGFR1 mice (VEGFR1TKKO) compared with wild type (WT) mice. The plasma level of SDF-1 and stem cell factor (SCF) and bone marrow level of pro-matrix metallopeptidase 9 (pro-MMP-9) were significantly reduced in VEGFR1TKKO mice. In VEGFR1 TKKOmice, the progenitor cells expressing CXCR4(+)VEGFR1(+) cell from bone marrow and the recruitment of these cells in healing ulcer were suppressed. Furthermore, VEGFR1 TKKO mice treated with NSAID did not suppress gastric ulcer healing compared to vehicle mice. These results suggested that NSAID suppressed VEGFR1 TK signaling plays a critical role in ulcer healing through mobilization of CXCR4(+)VEGFR1(+) cells. CONCLUSION: VEGFR1 signaling is required for healing of NSAID induced gastric ulcer and angiogenesis with increased recruitment of CXCR4(+)VEGFR1(+) cells to the ulcerative lesion. PMID- 23809371 TI - Ech1 is a potent suppressor of lymphatic metastasis in hepatocarcinoma. AB - We have previously demonstrated that Ech1 is involved in the lymphatic metastasis of tumors in vitro. Here, we gain an insight into the role that Ech1 is playing in Hca-F cell. The expression of Annexin A7, Gelsolin and Clic1 genes, which were also relevant to tumor lymphatic metastasis, had been inhibited due to downregulation Ech1 gene by Western blot analysis. And downregulated of Ech1 inhibits the metastasic capability of Hca-F cells to peripheral lymph nodes in vivo. Our work indicates although the involvement of Ech1 in tumor metastasis development and progression, but the subcellular location of Ech1 has not much contribution to that. PMID- 23809372 TI - LAT-1 functions as a promotor in gastric cancer associated with clinicopathologic features. AB - L-type amino-acid transporter 1 (LAT-1) is a member of system L-type transporters, essential for cells maintenance and proliferation. However, the role of LAT-1 remains illegible in gastric cancer (GC). In this study, we found that LAT-1 was aberrantly up-regulated in both GC cell lines (MKN-45, MGC-803 and CRL-5974) and human GC specimens. The expression characteristic of LAT-1 in GC was significantly associated with clinicopathologic features such as tumor size, lymph node metastasis, local invasion and TNM stage. By suppressing the expression of LAT-1 in MKN-45 cells, the cell cycle was arrested in G0/G1 phase, and the ability of cell proliferation was significantly decreased in vitro. Moreover, the cell migration and invasion of MKN-45 cells was significantly impaired by knocking down LAT-1. Thus, our results suggest that LAT-1 may function as an oncogene in GC, which provides us a new biomarker in GC and perhaps a potential target for GC prevention, diagnose and therapeutic treatment. PMID- 23809373 TI - Effects of parenting practices on sexual risk-taking among young people in Cameroon. AB - BACKGROUND: There is scanty evidence regarding the impact of parenting practices on young people's sexual risk-taking in sub-Saharan Africa. Moreover, the extent to which such practices have enduring consequences on adolescents and young adults is little documented. This study uses repeated measures of parent-child relationships, parental monitoring, and parent-child communication about sexual matters to shed some light in these two areas. METHODS: The analysis is based on time-dependent retrospective data on parenting practices which were retrieved from the Cameroon Family and Health Survey (CFHS). The study sample includes 447 sexually active and unmarried individuals aged 15-24 years old. Correlation analysis and multivariate logistic regressions are used. RESULTS: Young males and females reported high levels of parental monitoring, moderate quality of parent child relationships and low levels of parent-child communication on sexual matters. This study substantiates that the higher the quality of parent-child relationships, the lower the odds of young males having multiple sexual partners (0.63, p < 0.05), and the lower the odds of young females being sexually active (0.52, p < 0.10) or of having multiple sexual partners (0.64, p < 0.10) or of having occasional sexual partners (0.51, p < 0.05). Living with the biological father only was associated with higher odds of having multiple sexual partners (3.21, p < 0.10) and higher odds of occasional concurrent sexual partners (3.26, p < 0.10) among young males. Compared with their out-of-school counterparts, young males still enrolled in school were less likely to be sexually active in the last 12 months (0.33, p < 0.05) and less likely to have occasional concurrent sexual partners (0.57, p < 0.10), whereas young females still enrolled in school were more likely to be sexually active (2.25, p < 0.10) and less likely to use contraceptive consistently (0.36, p < 0.001). CONCLUSIONS: Reproductive health programs and interventions for preventing young people's risky sexual behaviors in sub-Saharan African settings must take into account the protective effects of parent-child relationships and the significance of parental monitoring over time. PMID- 23809374 TI - Renal sympathetic denervation for treatment of resistant hypertension - indigenous technique. AB - BACKGROUND: The endovascular approach of ablation of renal sympathetic nerves is found to be effective in the treatment of uncontrolled hypertension. We report here our experience with the procedure in eight patients with drug resistant hypertension. METHODS: We included patients in whom the blood pressure remained above 150/90 mmHg despite being on minimum three antihypertensive drugs. Radiofrequency ablation of the sympathetic nerves of both the renal arteries was done using conventional ablation catheters. The patients were followed at 1 month, 3 months and 6 months post procedure and blood pressure recorded. RESULTS: All patients underwent successful renal sympathetic denervation. The mean blood pressure of the patients was 181/102.5 mmHg before the procedure and the average requirement of antihypertensive drugs per day was 4. A significant reduction in both systolic and diastolic blood pressure was observed post procedure which sustained over the follow up period of six months. The mean blood pressure observed at 1-month, 3 and 6 months were 137.5/80 mmHg, 136/81 mmHg and 137.5/81 mmHg, respectively. The average requirement of the number of antihypertensives also was reduced to 2.5 at the end of 6 months. There were no procedural complications. CONCLUSION: Catheter based renal denervation causes substantial and sustained blood pressure reduction without serious adverse events in patients with resistant hypertension. PMID- 23809375 TI - Prevalence of coronary artery disease and coronary risk factors in Kerala, South India: a population survey - design and methods. AB - BACKGROUND: There is paucity of reliable contemporary data on prevalence of coronary artery disease (CAD) and risk factors in Indians. Only a few studies on prevalence of CAD have been conducted in Kerala, a Southern Indian state. The main objective of the Cardiological Society of India Kerala Chapter Coronary Artery Disease and Its Risk Factors Prevalence Study (CSI Kerala CRP Study) was to determine the prevalence of CAD and risk factors of CAD in men and women aged 20-79 years in urban and rural settings of three geographical areas of Kerala. METHODS: The design of the study was cross-sectional population survey. We estimated the sample size based on an anticipated prevalence of 7.4% of CAD for rural and 11% for urban Kerala. The derived sample sizes for rural and urban areas were 3000 and 2400, respectively. The urban areas for sampling constituted one ward each from three municipal corporations at different parts of the state. The rural sample was drawn from two panchayats each in the same districts as the urban sample. One adult from each household in the age group of 20-59 years was selected using Kish method. All subjects between 60 and 79 years were included from each household. A detailed questionnaire was administered to assess the risk factors, history of CAD, family history, educational status, socioeconomic status, dietary habits, physical activity and treatment for CAD; anthropometric measurements, blood pressure, electrocardiogram and fasting blood levels of glucose and lipids were recorded. PMID- 23809376 TI - Epidemiology of cardioprotective pharmacological agent use in stable coronary heart disease. AB - OBJECTIVE: To determine use of class and type of cardioprotective pharmacological agents in patients with stable coronary heart disease (CHD) we performed a prescription audit. METHODS: A cross sectional survey was conducted in major districts of Rajasthan in years 2008-09. We evaluated prescription for classes (anti-platelets, beta-blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), calcium channel blockers (CCB) and statins) and specific pharmacological agents at clinics of physicians in tertiary (n = 18), secondary (n = 69) and primary care (n = 43). Descriptive statistics are reported. RESULTS: Prescriptions of 2290 stable CHD patients were audited. Anti platelet use was in 2031 (88.7%), beta-blockers 1494 (65.2%), ACE inhibitors 1196 (52.2%), ARBs 712 (31.1%), ACE inhibitors - ARB combinations 19 (0.8%), either ACE inhibitors or ARBs 1908 (83.3%), CCBs 1023 (44.7%), statins 1457 (63.6%) and other lipid lowering agents in 170 (7.4%). Among anti-platelets aspirin clopidogrel combination was used in 88.5%. Top three molecules in beta-blockers were atenolol (37.8%), metoprolol (26.4%) and carvedilol (11.9%); ACE inhibitors ramipril (42.1%), lisinopril (20.3%) and perindopril (10.9%); ARB's losartan (47.7%), valsartan (22.3%) and telmisartan (14.9%); CCBs amlodipine (46.7%), diltiazem (29.1%) and verapamil (9.5%) and statins were atorvastatin (49.8%), simvastatin (28.9%) and rosuvastatin (18.3%). Use of metoprolol, ramipril, valsartan, diltiazem and atorvastatin was more at tertiary care, and atenolol, lisinopril, losartan, amlodipine and simvasatin in primary care (p < 0.01). CONCLUSIONS: There is low use of beta-blockers, ACE inhibitors, ARBs and statins in stable CHD patients among physicians in Rajasthan. Significant differences in use of specific molecules at primary, secondary and tertiary healthcare are observed. PMID- 23809377 TI - Intracoronary abciximab in STEMI using local drug delivery catheter - single center experience. AB - BACKGROUND: Despite restoration of epicardial flow during primary PCI in STEMI, microvascular obstruction may persist as a result of both atheromatous and thrombotic embolization and vasospasm. Compared with the systemic administration of IV pharmaco-therapies, highly localized administration of intracoronary pharmacotherapy may be associated with a several-hundred-fold increase in the local concentration of an agent in the epicardial artery and microcirculation. Despite restoration of epicardial flow during primary PCI in STEMI, microvascular obstruction may persist as a result of both atheromatous and thrombotic embolization and vasospasm. We are presenting our experience with use of intracoronary abciximab using local drug delivery catheter in STEMI patients. METHODS: We retrospectively evaluated 15 patients presented to us with STEMI undergoing primary PCI between March 2011 and September 2012 who had super selective intracoronary abciximab using local drug delivery catheter. With standard antiplatelet therapy, both Pre and Post TIMI flow, TMP grading were assessed. RESULTS: Mean age was 55 years. The TIMI flow increased by 3 grades in thirteen patients, TMP grading increased by 2 grades in five patients and by 3 grades in nine patients. Thus TIMI flow and TMP grading improved after super selective intracoronary abciximab. CONCLUSION: Super selective intracoronary abciximab using local drug delivery catheter during primary PCI in STEMI patients significantly improves TMP grading without increased risk of bleeding. This benefit is achieved even in patients without thrombus aspiration. We need to assess the long-term outcomes in the form of reduction in infarct size using this strategy in large group of patients. PMID- 23809378 TI - Glycoprotein IIb-IIIa inhibitors - do we still need them? PMID- 23809379 TI - Causes of failure with Szabo technique - an analysis of nine cases. AB - OBJECTIVE: The objective of this case series is to identify and define causes of failure of Szabo technique in rapid-exchange monorail system for ostial lesions. METHODS AND RESULTS: From March 2009 to March 2011, 42 patients with an ostial lesion were treated percutaneously at our institution using Szabo technique in a monorail stent system. All patients received unfractionated heparin during intervention. Loading dose of clopidogrel, followed by clopidogrel and aspirin was administered. In 57% of patients, drug-eluting stents were used and in 42.8% patients bare metal stents. The stent was advanced over both wires, the target wire and the anchor wire. The anchor wire, which was passed through the proximal trailing strut of the stent helps to achieve precise stenting. The procedure was considered to be successful if stent was placed precisely covering the lesion and without stent loss or anchor wire prolapsing. Of the total 42 patients, the procedure was successful in 33, while failed in 9. Majority of failures were due to wire entanglement, which was fixed successfully in 3 cases by removing and reinserting the anchor wire. Out of other three failures, in one stent dislodgment occurred, stent could not cross the lesion in one and in another anchor wire got looped and prolapsed into target vessel. CONCLUSION: This case series shows that the Szabo technique, in spite of some difficulties like wire entanglement, stent dislodgement and resistance during stent advancement, is a simple and feasible method for treating variety of ostial lesions precisely compared to conventional angioplasty. PMID- 23809380 TI - Assessment of mitral valve commissural morphology by transoesophageal echocardiography predicts outcome after balloon mitral valvotomy. AB - BACKGROUND: Balloon mitral valvotomy (BMV) is a safe and an effective treatment in patients with symptomatic rheumatic mitral stenosis. This study was conducted to validate the importance of assessing the morphology of mitral valve commissures by transoesophageal echocardiography and thereby predicting the outcome after balloon mitral valvotomy [BMV]. MATERIALS AND METHODS: Study consisted of 100 patients with symptomatic mitral stenosis undergoing BMV. The Commissural Morphology and Wilkins score were assessed by transoesophageal echocardiography. Both the commissures (anterolateral and posteromedial) were scored individually according to whether non-calcified fusion was absent (0), partial (1), or extensive (2) and calcification (score 0) and combined giving an overall commissural score of 0-4. Outcome of BMV was correlated with commissural score and Wilkins score. RESULTS: The commissural score and outcome after BMV correlated significantly. 66 of 70 patients (94%) with a commissural score of 3-4 obtained a good outcome compared with only six (20%) patients of 30 with a commissural score of 0-2 (positive and negative predictive accuracy 94% and 80%, respectively, p < 0.001). Increase in 2DMVA post BMV was more in patients with higher commissural score (score of 3-4). Wilkins score <8 usually predicts a good outcome but even in patients with Wilkins score >8 a commissural score >2 predicts a 50% chance of a good result. CONCLUSIONS: A higher commissural score predicts a good outcome after BMV hence it can be concluded that along with Wilkins score, commissural morphology and score should be assessed with TOE in patients undergoing BMV. PMID- 23809381 TI - Left ventricular myocardial performance in patients with dengue hemorrhagic fever and thrombocytopenia as assessed by two-dimensional speckle tracking echocardiography. AB - OBJECTIVES: We obtained longitudinal, radial and circumferential strains in patients with dengue hemorrhagic fever (DhF) and thrombocytopenia using two dimensional (2D) speckle tracking echocardiography to analyze left ventricular (LV) myocardial performance. METHODS: In this prospective study, 2D echocardiographic images of the left ventricle in the four-, three- and two chamber views and parasternal short-axis views at the basal, mid and apical levels were obtained in 40 subjects: 20 patients (23 +/- 8 years, 12 male) with DhF and thrombocytopenia and 20 healthy controls (23 +/- 5 years, 11 male). Of the 20 patients, imaging was performed again in 19 at discharge after a hospital stay of 8 +/- 1 days. Longitudinal, circumferential and radial strains were quantified and compared in an 18-segment model using a novel speckle tracking system. RESULTS: Left ventricular global ejection fraction was reduced in patients with DhF at presentation as compared with controls (51.25 +/- 0.96% vs. 59.32 +/- 1.26%; p = 0.032). Peak longitudinal strain in patients with DhF was significantly attenuated in the subendocardial region compared with normal controls (p < 0.001). A significant increase in circumferential strain for patients with DhF was evident only in the subepicardial region (p = 0.009). Patients with DhF showed significantly higher radial strain than controls (p < 0.001). On multivariate analysis, subendocardial longitudinal strain independently predicted the duration of hospital stay in patients with DhF. CONCLUSION: Assessment of speckle tracking echocardiography-derived LV mechanics helps in understanding myocardial mechanics in patients with DhF and thrombocytopenia. Identification of reduced LV longitudinal strain helps in understanding the mechanism of reduced LV myocardial performance seen in patients with DhF. PMID- 23809382 TI - Percutaneous closure of a large aortic paravalvular leak using two duct occluder devices. AB - A 21-year-old male presented with severe aortic paravalvular leak. He had undergone three cardiac surgeries and also had chronic kidney disease. It was decided for a trans-catheter closure owing to the risks of a fourth surgery and co-morbidity. The device was sized based on angiogram, balloon sizing and two dimensional transesophageal echo. There was significant residual leak after deployment of first device. Hence the defect was re-crossed and two duct occluder devices were positioned across the leak from two arterial access. After confirming position and satisfactory reduction in paravalvular leak, the devices were released in tandem. There was near abolition of leak. The patient is asymptomatic at three months follow up. Larger paravalvular leaks are better addressed with two devices of smaller size rather than a single large device. Technical considerations while deploying multiple devices are discussed. PMID- 23809383 TI - Three dimensional transesophageal echocardiography guided transcatheter closure of mitral paraprosthesis regurgitation - a case report. AB - The last two decades have witnessed vast advances in the field of cardiac intervention, particularly with regard to nonsurgical closure of structural heart diseases including para prosthetic valvular leaks. The use of imaging techniques to guide even well-established procedures enhances the efficiency and safety of these procedures. The present case report aims to highlight the role of three dimensional transesophageal echocardiography in pre, intra and post operative management of patients with mitral para prosthetic valvular regurgitation. PMID- 23809384 TI - Transcatheter closure of paravalvular leaks - how do I do it? PMID- 23809385 TI - Elevated levels of leukotriene B4 and thromboxane B2 distinguish chest pain of cardiac and non cardiac origin. AB - OBJECTIVE: Myocardial infarction (MI) is often preceded by severe chest pain. The use of inflammatory markers to distinguish between chest pain of cardiac and non cardiac origin are not well reported. The aim of the study was to distinguish the chest pain of non cardiac and cardiac origin by using reliable inflammatory markers. METHODS: The present study enrolled 80 subjects including chest pain which lead to myocardial infarction (n=40), non-cardiac chest pain (CP) patients (n=20) and healthy volunteers (N) (n=20). Leukotriene B4 (LTB4) and thromboxane B2 (TXB2) levels were analyzed along with hs-CRP. RESULTS: Receiver operating characteristic (ROC) curve analysis showed LTB4 and TXB2 to be a good discriminator between patients with chest pain of cardiac and non cardiac in origin. The area under the curve was found to be 0.988 and 0.925 for LTB4 and TXB2, respectively when compared with hs-CRP. The sensitivity and specificity of LTB4 and TXB2 were found to be 90, 85% and 95, 90%, respectively. CONCLUSION: The measurement of LTB4 and TXB2 levels may therefore be useful to distinguish the chest pain leading to MI from that of non cardiac in origin and for the management of the disease. PMID- 23809387 TI - Acute myocardial infarction following blunt chest trauma with intracranial bleed: a rare case report. AB - A young male following road traffic accident (RTA) with head injury and parietal bleed was diagnosed with STEMI based on ECG findings which is rare occurrence. Coronary angiography showed thrombotic ostial occlusion of LAD. Successful primary angioplasty using thrombo-aspiration was done, in difficult clinical scenario. The case was challenging in terms of use of anticoagulation and antiplatelet strategy in a rare etiology of acute myocardial infarction following road traffic accident. PMID- 23809388 TI - Double jeopardy. AB - Torsades de pointes ("twisting of points") (TdP) is a broad complex tachyarrhythmia which was first described in 1966 by Francois Dessertenne and usually results from prolongation of the QT interval.(1) A wide variety of drugs have been shown to prolong the QT interval in susceptible individuals.(2) We present the case of a former intravenous heroin user presenting with several episodes of TdP which were caused by QT prolongation due to methadone treatment and exacerbated by hepatitis B/C infection. Despite aggressive medical treatment and withdrawal of methadone, he had recurrent episodes of TdP which required continuous temporary cardiac pacing for six days. He was found to have moderate LV dysfunction on his echocardiogram and unobstructed coronary arteries on coronary angiography. He underwent implantation of a defibrillator due to concerns about further episodes of ventricular arrhythmias which could recur even in the absence of further methadone use. PMID- 23809386 TI - Prognostic utility of coronary computed tomographic angiography. AB - Coronary computed tomographic angiography (CCTA) employing CT scanners of 64 detector rows or greater represents a noninvasive method that enables accurate detection and exclusion of anatomically obstructive coronary artery disease (CAD), providing excellent diagnostic information when compared to invasive angiography. There are numerous potential advantages of CCTA beyond simply luminal stenosis assessment including quantification of atherosclerotic plaque volume as well as assessment of plaque composition, extent, location and distribution. In recent years, an array of studies has evaluated the prognostic utility of CCTA findings of CAD for the prediction of major adverse cardiac events, all-cause death and plaque instability. This prognostic information enhances risk stratification and, if properly acted upon, may improve medical therapy and/or behavioral changes that may enhance event-free survival. The goal of the present article is to summarize the current status of the prognostic utility of CCTA findings of CAD. PMID- 23809389 TI - Retrograde embolism from the descending thoracic aorta causing stroke: an underappreciated clinical condition. AB - The mechanism of retrograde aortic blood flow is a complex and underreported clinical phenomenon. Complex plaques of the aortic arch are considered high-risk sources of cerebral emboli.(1) Aortic plaques situated in the descending thoracic aorta are however often overlooked and in fact can be more frequent potential sources of cerebral embolism through the mechanism of retrograde aortic blood flow. We present the case of an elderly Caucasian female who experienced recurrent posterior circulation embolic strokes where the only possible underlying etiology was found to be an atheroma in the descending thoracic aorta, possibly showering retrograde emboli. PMID- 23809390 TI - Retrieving a deformed stent during transradial intervention: an alternative femoral approach using guide catheter shortening. AB - Stent dislodgment during percutaneous coronary intervention is a rare complication. We report a case of successful retrieval of a deformed coronary stent through alternative transfemoral approach while performing transradial procedure when the stent could not be retrieved safely from transradial route. PMID- 23809391 TI - Acute MI in a stented patient following snake bite-possibility of stent thrombosis - a case report. AB - Acute myocardial infarction following snake bite is rare with few reported cases in literature. A 60-year-old male underwent uneventful stenting to a critical stenosis in left anterior descending coronary artery in June 2012. A month later, he presented to the local hospital with history of snake bite. During admission he developed chest pain with ST-segment elevation in anterior leads consistent with stent thrombosis. He was successfully thrombolysed and his coronary angiogram 5 days later revealed patent stent with TIMI III flow and no evidence of thrombus. PMID- 23809392 TI - Pacemaker lead perforation causing hemopericardium eight years after implantation. AB - The number of patients with intracardiac devices, including permanent pacemakers and implantable cardioverter-defibrillators is increasing. Lead perforation is a recognized complication which most often occurs during or shortly following pacemaker implantation. Late lead perforation occurring over 30 days after device insertion is a rare, potentially life-threatening complication. We present a case of late lead perforation unmasked greater than eight years after pacemaker implantation by initiation of anticoagulation. PMID- 23809393 TI - Isolated non-obstructive accessory mitral valve tissue in an adult mimicking ruptured chordae. AB - Accessory mitral valve tissue is commonly associated with other congenital heart diseases and is usually detected in children causing left ventricular outflow tract obstruction. We present an adult patient with isolated non-obstructive accessory mitral valve tissue that was mimicking ruptured chordae of the mitral valve. Accessory mitral valve tissue in adults is very rare and can mimick various causes of left ventricular outflow tract obstruction. This patient represents the first case in literature wherein an unobstructive accessory mitral valve tissue simulated a ruptured chordae. This case illustrates that in patients with suspected mitral valve chordae rupture without any mitral regurgitation, this diagnosis should be considered, which can have therapeutic implications. PMID- 23809395 TI - Ventricular premature beat terminating SVT. PMID- 23809394 TI - Clinical application and laboratory protocols for performing contrast echocardiography. AB - Technically difficult echocardiographic studies with suboptimal images remain a significant challenge in clinical practice despite advances in imaging technologies over the past decades. Use of microbubble ultrasound contrast for left ventricular opacification and enhancement of endocardial border detection during rest or stress echocardiography has become an essential component of the operation of the modern echocardiography laboratory. Contrast echocardiography has been demonstrated to improve diagnostic accuracy and confidence across a range of indications including quantitative assessment of left ventricular systolic function, wall motion analysis, and left ventricular structural abnormalities. Enhancement of Doppler signals and myocardial contrast echocardiography for perfusion remain off-label uses. Implementation of a contrast protocol is feasible for most laboratories and both physicians and sonographers will require training in contrast specific imaging techniques for optimal use. Previous concerns regarding the safety of contrast agents have since been addressed by more recent data supporting its excellent safety profile and overall cost-effectiveness. PMID- 23809396 TI - Multiperforated atrial septal aneurysm associated with atrial fibrillation. PMID- 23809397 TI - Post myocardial infarction left ventricular dysfunction - assessment and follow up of patients undergoing surgical ventricular restoration by the endoventricular patchplasty. PMID- 23809398 TI - An unusual etiology of Kounis syndrome; warble fly. PMID- 23809400 TI - Recent spurt of coronary disease among relatively young cardiologists in India. PMID- 23809399 TI - Relationship of high-sensitive C-reactive protein with cardiovascular risk factors, clinical presentation and angiographic profile in patients with acute coronary syndrome: an Indian perspective. PMID- 23809401 TI - [The family medicine continues being a not much attractive speciality for the students of medicine]. PMID- 23809402 TI - Severe sleepiness and excess sleep duration induced by paroxetine treatment is a beneficial pharmacological effect, not an adverse reaction. AB - BACKGROUND: Severe sleepiness and excess sleep duration, "Hypersomnia", induced by paroxetine treatment are generally considered adverse drug reactions, however, our experience indicates that patients with depressive disorder who experience "Hypersomnia" during paroxetine treatment have good clinical response. The aim of this study was to determine if "Hypersomnia" during paroxetine treatment is a beneficial pharmacological effect or an adverse drug reaction, and to investigate the impact of genetic polymorphisms on individual differences in the occurrence of "Hypersomnia" induced by paroxetine. METHODS: A consecutive series of 46 Japanese patients with depressive disorder were treated with paroxetine. Patients who complained of great drowsiness or who slept for more than 12-h per day over seven days were identified as having experienced "Hypersomnia". For the clinical improvement rates and genotype distribution of the circadian locomotor output cycles kaput (CLOCK), serotonin transporter and cytochrome P450 2D6 (CYP2D6), the group that showed "Hypersomnia" induced by paroxetine treatment and the group that did not show "Hypersomnia" were compared statistically. RESULTS: Patients who experienced "Hypersomnia" (17.4%) showed a significantly higher response rate at two weeks than did patients who did not experience "Hypersomnia" (p=0.0127). No significant association between the occurrence of "Hypersomnia" and genetic polymorphisms was found. LIMITATIONS: We cannot exclude the risk of false positive errors due to the relatively small sample sizes. CONCLUSIONS: "Hypersomnia" during paroxetine treatment for depression is a beneficial pharmacological effect, not an adverse drug reaction. PMID- 23809404 TI - A little less saturation? PMID- 23809403 TI - Disability and comorbidity among major depressive disorder and double depression in African-American adults. AB - BACKGROUND: Few studies have examined differences in disability and comorbity among major depressive disorder (MDD), dysthymia, and double depression in African-Americans (AA). METHODS: A secondary analysis was performed on AA in the National Survey of American Life. Interviews occurred 2001-2003. A four stage national area probability sampling was performed. DSM-IV-TR diagnoses were obtained with a modified version of the World Health Organization's expanded version of the Composite International Diagnostic Interview. Disability was measured by interview with the World Health Organization's Disability Assessment Schedule II. RESULTS: Compared to non-depressed AA, AA endorsing MDD (t=19.0, p=0.0001) and double depression (t=18.7, p=0.0001) reported more global disability; AA endorsing MDD (t=8.5, p=0.0063) reported more disability in the getting around domain; AA endorsing MDD (t=19.1, p=0.0001) and double depression (t=12.1, p=0.0014) reported more disability in the life activities domain. AA who endorsed double depression reported similar disability and comorbidities with AA who endorsed MDD. Few AA endorsed dysthymia. LIMITATIONS: This was a cross sectional study subject to recall bias. The NSAL did not measure minor depression. CONCLUSIONS: The current study supports the idea of deleting distinct chronic subtypes of depression and consolidating them into a single category termed chronic depression. PMID- 23809406 TI - Infection among adult small bowel and multivisceral transplant recipients in the 30-day postoperative period. AB - BACKGROUND: Intestinal transplantation is a potential option for patients with short gut syndrome (SGS), and infection is common in the postoperative period. The aim of our study was to identify the incidence and characteristics of bacterial and fungal infections of adult small bowel or multivisceral (SB/MV) transplantation recipients in the 30-day postoperative period. METHODS: This retrospective chart review assessed the incidence and characteristics of bacterial and fungal infections in patients who underwent SB/MV transplant at our center between April 2004 and November 2008. Patient data were retrieved from computerized databases, flow-charts, and medical records. RESULTS: A total of 40 adult patients with a mean age of 38.7 +/- 13.4 years received transplants during this period: 27 patients received isolated SB, 12 received MV, and 1 received SB and kidney. Our immunosuppressive regimen included basiliximab for induction, and tacrolimus, sirolimus, and methylprednisolone for maintenance therapy. The most common indications for transplant were SGS, intestinal ischemia, Crohn's disease, trauma, motility disorders, and Gardner's syndrome. We report a 30-day postoperative infection rate of 57.5% and mean time to first infection of 10.78 +/- 8.99 days. A total of 36 infections were documented in 23 patients. Of patients who developed infections, 56.5% developed 1 infection, 30.4% developed 2 infections, and 13% developed 3 infections. The most common site of infection was the abdomen, followed by blood, urine, lung, and wound infection. The isolates were gram-negative bacteria in 49.3%, gram-positive bacteria in 39.4%, and 11.3% were fungi. The most common organisms were Pseudomonas (19%), Enterococcus (15%), and Escherichia coli (13%). Overall, 47% of infections were due to drug-resistant pathogens; 31% of E. coli and Klebsiella species were extended-spectrum beta lactamase-producing organisms, 36% of Pseudomonas was multidrug resistant (MDR), 75% of Enterococcus was vancomycin resistant, and 100% of Staphylococcus aureus was methicillin resistant. CONCLUSION: These findings demonstrate that bacterial and fungal infections remain an important complication in SB/MV transplant recipients within the early postoperative period. Infections due to MDR organisms have emerged as an important clinical problem in this patient population. PMID- 23809405 TI - Calcineurin-dependent ion channel regulation in heart. AB - Calcineurin, a serine-threonine-specific, Ca(2+)-calmodulin-activated protein phosphatase, conserved from yeast to humans, plays a key role in regulating cardiac development, hypertrophy, and pathological remodeling. Recent studies demonstrate that calcineurin regulates cardiomyocyte ion channels and receptors in a manner which often entails direct interaction with these target proteins. Here, we review the current state of knowledge of calcineurin-mediated regulation of ion channels in the myocardium with emphasis on the transient outward potassium current (Ito) and L-type calcium current (ICa,L). We go on to discuss unanswered questions that surround these observations and provide perspective on future directions in this exciting field. PMID- 23809407 TI - [The use of targeted therapies in oncology and their impact in the design of clinical trials: epidermal growth factor receptors 1 and 2 as a paradigm]. PMID- 23809408 TI - [Intraabdominal desmoid tumors]. PMID- 23809409 TI - [Current treatment of primary immune thrombocytopenia]. AB - Primary immune thrombocytopenia, also termed immune thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by premature platelet destruction and impaired platelet production. Traditional treatment of ITP has predominantly consisted of immune suppression and/or modulation. However, the understanding of the immune mediated impairment of platelet production has led to the development of new treatments that target the thrombopoietin receptor, promoting formation of megakaryocytes and increasing platelet counts. Best practice for the management of ITP has not yet been established because data from comparative studies are lacking. While some disagreement might still remain among experts concerning therapy (when, who, and how should be treated), in recent years different evidence-based practice guidelines have been published to assist healthcare professionals in the diagnosis and treatment of ITP. This review describes the current treatment landscape of ITP. PMID- 23809411 TI - Deep intronic 'mutations' cause hemophilia A: application of next generation sequencing in patients without detectable mutation in F8 cDNA. AB - BACKGROUND: In a small group of typical hemophilia A (HA) patients no mutations in the F8 coding sequence (cDNA) could be found. In the current study, we performed a systematic screening of genetic and non-genetic parameters associated with reduced FVIII:C levels in a group of mostly mild HA (only one moderate) patients with no detectable mutations in F8 cDNA. METHODS: We determined FVIII and VWF activity and antigen levels and performed VWF-FVIII binding (VWF:FVIIIB) and VWF-collagen binding assays (VWF:CB) as well as VWF multimer analysis. VWF was completely sequenced to exclude mutations. The F8 locus, including the introns, was sequenced using overlapping long-range PCRs (LR-PCRs) combined with a next generation sequencing (NGS) approach. Moreover, the F8 mRNA was analyzed quantitatively and qualitatively by real-time PCR (qRT) and overlapping reverse transcription (RT) PCRs, respectively. RESULTS: All VWF tests were normal. The LR PCRs demonstrated the integrity of the F8 locus. Eight unique polymorphisms were found in the patients, with two being recurrent. Furthermore, RT-PCRs analysis confirmed that two of the unique variants create detectable new cryptic splice sites in the patients that result in the introduction of intronic DNA sequences into the mRNA and create premature stop codons. CONCLUSION: By systematically excluding all possible causes of HA, we could with great certainty conclude that deep intronic mutations in F8, although rare, cause abnormal mRNA splicing, leading to mild HA. PMID- 23809410 TI - HIV risk in group sexual encounters: an event-level analysis from a national online survey of MSM in the U.S. AB - INTRODUCTION: Researchers have investigated group sexual encounters (GSEs) as potential sources for HIV/STI transmission among men who have sex with men (MSM); however, much of this work has focused on organized sex parties. AIM: To compare behavioral and social characteristics of groups of men who engaged in three types of GSEs: threesomes, spontaneous group sex, and organized sex parties. METHODS: In 2012, 1,815 U.S.-based MSM completed an online survey. MAIN OUTCOME MEASURE: We compared men based on their most recent type of GSE: threesome (68.2%), spontaneous group sex (19.7%), or organized sex party (12.1%). RESULTS: Using multinomial logistic regression, with type of GSE as the dependent variable, MSM who were HIV-positive, used stimulants (cocaine, methamphetamine, crack), consumed five or more alcoholic drinks, and reported receptive unprotected anal intercourse (UAI) during the most recent GSE had significantly higher odds of having had spontaneous group sex as compared to a threesome. MSM who were HIV positive, not in a relationship, and did not report receptive UAI during the most recent GSE had significantly higher odds of having attended an organized sex party as compared to a threesome. MSM who were in a relationship, had consumed five or more alcoholic drinks, had used stimulants, and reported receptive UAI during the most recent GSE had significantly higher odds of having had spontaneous group sex as compared to an organized sex party. Compared to others, those having engaged in a GSE were more likely to report recent UAI (65% vs. 45%). CONCLUSIONS: Men having engaged in a GSE were at greater risk for behaviors that transmit HIV and STIs. Unique social and behavioral characteristics inherent to threesomes, spontaneous group sex, and sex parties highlight the need to identify prevention strategies to help those who participate in GSEs reduce their risk for HIV and STI transmission. PMID- 23809412 TI - Optimization and model reduction in the high dimensional parameter space of a budding yeast cell cycle model. AB - BACKGROUND: Parameter estimation from experimental data is critical for mathematical modeling of protein regulatory networks. For realistic networks with dozens of species and reactions, parameter estimation is an especially challenging task. In this study, we present an approach for parameter estimation that is effective in fitting a model of the budding yeast cell cycle (comprising 26 nonlinear ordinary differential equations containing 126 rate constants) to the experimentally observed phenotypes (viable or inviable) of 119 genetic strains carrying mutations of cell cycle genes. RESULTS: Starting from an initial guess of the parameter values, which correctly captures the phenotypes of only 72 genetic strains, our parameter estimation algorithm quickly improves the success rate of the model to 105-111 of the 119 strains. This success rate is comparable to the best values achieved by a skilled modeler manually choosing parameters over many weeks. The algorithm combines two search and optimization strategies. First, we use Latin hypercube sampling to explore a region surrounding the initial guess. From these samples, we choose ~20 different sets of parameter values that correctly capture wild type viability. These sets form the starting generation of differential evolution that selects new parameter values that perform better in terms of their success rate in capturing phenotypes. In addition to producing highly successful combinations of parameter values, we analyze the results to determine the parameters that are most critical for matching experimental outcomes and the most competitive strains whose correct outcome with a given parameter vector forces numerous other strains to have incorrect outcomes. These "most critical parameters" and "most competitive strains" provide biological insights into the model. Conversely, the "least critical parameters" and "least competitive strains" suggest ways to reduce the computational complexity of the optimization. CONCLUSIONS: Our approach proves to be a useful tool to help systems biologists fit complex dynamical models to large experimental datasets. In the process of fitting the model to the data, the tool identifies suggestive correlations among aspects of the model and the data. PMID- 23809413 TI - Epidemiology of hospitalized heart failure: differences and similarities between patients with reduced versus preserved ejection fraction. AB - Annually, more than 1 million patients are hospitalized for heart failure (HF), translating to high healthcare utilization and cost burden. Among patients with hospitalized HF (HHF), approximately 50% have HF with preserved ejection fraction (HFpEF) and 50% have HF with reduced ejection fraction (HFrEF), with the proportion of patients with HFpEF increasing with time. This article defines the epidemiologic landscape of patients with HHF, comparing and contrasting those with HFpEF and HFrEF, and identifies key areas that require further investigation. More complete characterization of these populations may be the first step to developing effective therapies. PMID- 23809414 TI - Classification of patients hospitalized for heart failure. AB - Despite low inpatient mortality and effective symptomatic management, patients hospitalized for heart failure (HHF) experience high postdischarge mortality and rehospitalization rates. HHF represents a widely heterogeneous population with distinct clinical subsets that may require tailored management approaches. Despite this, however, HHF patients are almost uniformly managed with intravenous diuretics, with low uptake of new therapies during hospitalization. This article proposes a practical approach to classifying HHF patients that is focused on guiding individualized inpatient and postdischarge management. HHF is not a single disease but a manifestation of several cardiac and noncardiac processes and thus should be approached as such. PMID- 23809415 TI - Recognizing hospitalized heart failure as an entity and developing new therapies to improve outcomes: academics', clinicians', industry's, regulators', and payers' perspectives. AB - Hospitalized heart failure (HHF) is associated with unacceptably high postdischarge mortality and rehospitalization rates. This heterogeneous group of patients, however, is still treated with standard, homogenous therapies that are not preventing their rapid deterioration. The costs associated with HHF have added demands from society, government, and payers to improve outcomes. With coordinated and committed efforts in the development of new therapies, improvements may be seen in outcomes for patients with HHF. This article summarizes concepts in developing therapies for HHF discussed during a multidisciplinary panel at the Heart Failure Society of America's Annual Scientific Meeting, September 2012. PMID- 23809417 TI - Strategies to prevent postdischarge adverse events among hospitalized patients with heart failure. AB - Hospitalizations for heart failure (HF) are increasing, and HF is the primary cause of readmission for all Medicare patients. Inpatient HF mortality is poor, but most morbidity and mortality occurs after hospital discharge. Readmissions attributable to HF persist or increase over time after discharge, and past HF admissions predict both readmission and mortality. The heightened risk of readmission dissipates slowly after discharge, suggesting that any intervention should be part of a lasting care package in the outpatient setting. Interventions that apply to multiple common medical comorbidities may be more likely to reduce overall adverse events. PMID- 23809416 TI - Initial management of patients with acute heart failure. AB - Pressure exists to manage patients with acute decompensated heart failure (ADHF) efficiently in the acute-care environment. Although most patients present with worsening of chronic heart failure, some may present with undifferentiated dyspnea and new-onset heart failure. Others have significant comorbidities that complicate both the diagnosis and treatment. The treatment of patients with ADHF is prioritized based on vital signs and presenting phenotype. The risk stratification of patients is the subject of ongoing evaluation. The disposition of patients to areas other than a monitored inpatient bed, such as an emergency department-based observation unit, may prove effective. PMID- 23809418 TI - Optimal utilization and management of implanted cardiac rhythm devices in patients hospitalized for heart failure. AB - Improved utilization and optimization of device therapy in the management of patients with decompensated heart failure (HF) is an important clinical priority. Diagnostic cardiac rhythm device data have been shown to predict hospitalization for HF. Cardiac resynchronization therapy is a highly effective therapy for the prevention of HF hospitalization. Evaluation and optimization of cardiac resynchronization therapy should be considered in all patients admitted with HF despite cardiac resynchronization therapy. PMID- 23809419 TI - The potential role of nonpharmacologic electrophysiology-based interventions in improving outcomes in patients hospitalized for heart failure. AB - Hospitalization for heart failure (HHF) is commonly associated with symptomatic improvement in response to standard medical therapy, yet there remains a substantial risk of rehospitalization and death. Clinically stable outpatients and decompensated inpatients represent two types of patients with chronic heart failure. In the former, treatment of common heart rhythm disorders with nonpharmacologic electrophysiology-based interventions is of substantial benefit in select patients. The potential benefits of these interventions in the hospitalized setting are not well studied. In this review, current knowledge is discussed and future research directions are suggested with nonpharmacologic electrophysiology-based interventions to reduce the morbidity and mortality associated with patients with HHF. PMID- 23809420 TI - The role of micronutrients and macronutrients in patients hospitalized for heart failure. AB - The detrimental pathophysiology of heart failure (HF) leaves room for physiologic and metabolomic concepts that include supplementation of micronutrients and macronutrients in these patients. Hence myocardial energetics and nutrient metabolism may represent relevant treatment targets in HF. This review focuses on the role of nutritive compounds such as lipids, amino acids, antioxidants, and other trace elements in the setting of HF. Supplementation of ferric carboxymaltose improves iron status, functional capacity, and quality of life in HF patients. To close the current gap in evidence further interventional studies investigating the role of micro- and macronutrients are needed in this setting. PMID- 23809422 TI - A world view of heart failure requiring hospitalization. Foreword. PMID- 23809421 TI - Noncardiac comorbidities and acute heart failure patients. AB - The acute heart failure (AHF) population is a heterogeneous group with multiple interrelated noncardiovascular comorbidities. Chronic obstructive pulmonary disease, renal disease, diabetes, sleep apnea, and anemia affect the clinical characteristics and outcomes of patients with AHF and complicate inpatient management. This article summarizes the impact of these noncardiovascular comorbidities in patients with AHF. In some circumstances, careful attention to the diagnosis and management of these conditions in patients with AHF may help to improve patient outcomes. PMID- 23809423 TI - Hospitalizations for heart failure. Preface. PMID- 23809424 TI - [Quality of life of women GPs in Auvergne]. AB - BACKGROUND: The medical profession is feminising. In parallel, the importance of quality of life (QOL) must be addressed. Family practice needs personal investment and availability. This profession can have repercussions on womens' QOL. The objective of the study was to compare female GPs QOL to other women with the comparable socioprofessional status. The secondary objective was to study the influence of factors, such as workplace and work methods. METHOD: Comparative cross-sectional study. A self-assessed questionnaire, sent by post to 394 female general practitioners in Auvergne, each was asked to recruit one woman (non-GP), with similar age and socioprofessional status. RESULTS: A total of 148 female GPs (37.6%) and 122 non-GPs responded. The global score of QOL was lower in the GP group, noticeably showing a poorer QOL in the relational and material areas. The professional QOL was similar between the 2 groups. The study did not find a significant difference concerning the QOL in its physical and psychological dimensions. The main negative factors influencing the QOL were: age; isolation of the occupation; living alone; and liberal occupation. Working in a rural area did not influence the QOL. CONCLUSION: The profession of GPs remains demanding, and the female GP feels a poorer QOL. Nevertheless, they seem to like their job and they feel fulfilled. The uneasiness comes essentially from the lack of free time, and from low financial income. Working in association seems to be a first step to improve the QOL of female GPs. PMID- 23809425 TI - [Hospital consultations for deaf people]. PMID- 23809427 TI - Association of estrogen receptor alpha gene polymorphisms with metabolic syndrome in Egyptian women. AB - OBJECTIVE: Metabolic syndrome is a risk factor for coronary heart diseases as well as diabetes, fatty liver and several cancers. The prevalence of metabolic syndrome in women appears to be increasing, particularly in women of childbearing age. In the present study, we assessed the association of estrogen receptor-alpha gene polymorphisms (XbaI and PvuII) with metabolic syndrome and its related phenotypes. MATERIALS/METHODS: One hundred and fifty Egyptian female patients with metabolic syndrome (mean age 35.52+/-6.86) were compared with one hundred and fifty age matched healthy Egyptian women (controls). The component traits of metabolic syndrome were determined, and the XbaI and PvuII genotypes were assessed with the PCR-RFLP method. RESULTS: Our data indicated a significant difference in the allele frequencies of XbaI, but not PvuII, between the metabolic syndrome and control groups (P=0.0003 and P=0.164). Carriers of the minor alleles of XbaI and PvuII gene polymorphisms, in either the homozygous or heterozygous form, were associated with high diastolic blood pressure, high total cholesterol and LDL-c levels, increased HOMA-IR values and decreased QUICKI values compared to carriers of the major allele. However, only the minor G allele of XbaI was associated with measures of adiposity, specifically, BMI and waist circumference. CONCLUSIONS: The XbaI polymorphism of the estrogen receptor alpha gene is associated with metabolic syndrome. On the other hand, PvuII gene polymorphism is not associated with the occurrence of the disease in this sample of Egyptian women. PMID- 23809426 TI - Putative role of glycogen as a peripheral biomarker of GSK3beta activity. AB - Glycogen synthase kinase 3-beta (GSK3beta) has a pivotal role in several intracellular signaling cascades that are involved in gene transcription, cytoskeletal reorganization, energy metabolism, cell cycle regulation, and apoptosis. This kinase has pleiotropic functions, and the importance of its activity has recently been shown in neurons and platelets. In addition to its regulatory function in several physiological events, changes in GSK3beta activity have been associated with many psychiatric and neurodegenerative illnesses, such as Alzheimer's disease, schizophrenia and autism-spectrum disorders. Beside the reports of its involvement in several pathologies, it has become increasingly apparent that GSK3beta might be a common therapeutic target for different classes of psychiatric drugs, and also that the GSK3beta ratio may be a useful parameter to determine the biochemical changes that might occur during antidepressant treatment. Although GSK3beta is commonly described as a key enzyme in a plethora of signaling cascades, originally it was identified as playing an important role in the regulation of glycogen synthesis, given its ability to inactivate glycogen synthase (GS) by phosphorylation. Acting as a constitutively active kinase, GSK3beta phosphorylates GS, which results in a decrease of glycogen production. GSK3beta phosphorylation increases glycogen synthesis and storage, while its dephosphorylation decreases glycogen synthesis. Inactivation of GSK3beta leads to dephosphorylation of GS and increase in glycogen synthesis in the adipose tissue, muscle and liver. Glycogen levels are reduced by antidepressant treatment, and this effect seems to be related to an effect of drugs on GSK3beta activity. Peripherally, glycogen is also abundantly found in platelets, where it is considered a major energy source, required for a variety of its functions, including the release reaction. Recently, analysis of platelets from patients with late-life major depression showed that active forms of GSK3beta expression were upregulated by continuous treatment with sertraline. Here, we hypothesized that the quantification of glycogen in platelets might be used as a peripheral biomarker of GSK3beta activity. Since it has been recently demonstrated that the modulation of GSK3beta activity causes changes in glycogen stores, the glycogen levels in platelets could be used to assay the effects of drugs that have this kinase as a target, or diseases where its activity is affected. In conclusion, we hypothesized that the determination of glycogen peripherally may be useful to indicate a change in the activity of this enzyme, providing a faster and non invasive approach to guide the therapeutic procedures for the patient. PMID- 23809428 TI - Establishing a successful coronary CT angiography program in the emergency department: official writing of the Fellow and Resident Leaders of the Society of Cardiovascular Computed Tomography (FiRST). AB - Coronary CT angiography is an effective, evidence-based strategy for evaluating acute chest pain in the emergency department for patients at low-to-intermediate risk of acute coronary syndrome. Recent multicenter trials have reported that coronary CT angiography is safe, reduces time to diagnosis, facilitates discharge, and may lower overall cost compared with routine care. Herein, we provide a 10-step approach for establishing a successful coronary CT angiography program in the emergency department. The importance of strategic planning and multidisciplinary collaboration is emphasized. Patient selection and preparation guidelines for coronary CT angiography are reviewed with straightforward protocols that can be adapted and modified to clinical sites, depending on available cardiac imaging capabilities. Technical parameters and patient-specific modifications are also highlighted to maximize the likelihood of diagnostic quality examinations. Practical suggestions for quality control, process monitoring, and standardized reporting are reviewed. Finally, the role of a "triple rule-out" protocol is featured in the context of acute chest pain evaluation in the emergency department. PMID- 23809430 TI - Kinematic and electromyographic analysis of the Nordic Hamstring Exercise. AB - The Nordic Hamstring Exercise (NHE) has been introduced as a training tool to improve the efficiency of eccentric hamstring muscle contraction. The aim of this study was to perform a biomechanical analysis of the NHE. Eighteen participants (20.4+/-1.9years) performed two sets of five repetitions each of the NHE and maximal eccentric voluntary contraction (MEVC) of the knee flexors on an isokinetic dynamometer whilst knee angular displacement and electrical activity (EMG) of biceps femoris were measured. EMG was on average higher during the NHE (134.3% of the MEVC). During the forward fall of the NHE, the angle at which a sharp increase in downward velocity occurred varied between 47.9 and 80.5deg, while the peak knee angular velocity (pVelocity) varied between 47.7 and 132.8degs(-1). A significant negative correlation was found between pVelocity and peak EMG (r=-0.62, p<0.01) and EMG at 45deg (r=-0.75, p<0.01) expressed as a percentage of peak MEVC EMG. Some of the variables analyzed exhibited good to excellent levels of intra- and inter-session reliability. This type of analysis could be used to indirectly monitor the level of eccentric strength of the hamstring muscles while performing the NHE and potentially any training- or injury-related changes. PMID- 23809429 TI - Effect of steroid sparing agents on the clinical course of ulcerative colitis. PMID- 23809431 TI - Adherence to antiretroviral therapy (ART) among people living with HIV (PLHIV): a cross-sectional survey to measure in Lao PDR. AB - RATIONALE: Since 2001, antiretroviral therapy (ART) for people living with HIV (PLHIV) has been available in the Lao People's Democratic Republic (PDR). A key factor in the effectiveness of ART is good adherence to the prescribed regimen for both individual well-being and public health. Poor adherence can contribute to the emergence of drug resistant strains of the virus and transmission during risky behaviors. Increased access to ART in low-income country settings has contributed to an interest in treatment adherence in resource-poor contexts. This study aims to investigate the proportion of adherence to ART and identify possible factors related to non-adherence to ART among people living with HIV (PLHIV) in Lao PDR. METHODS: A cross-sectional study was conducted with adults living with HIV receiving free ART at Setthathirath hospital in the capital Vientiane and Savannakhet provincial hospitals from June to November 2011. Three hundred and forty six PLHIV were interviewed using an anonymous questionnaire. The estimation of the adherence rate was based on the information provided by the PLHIV about the intake of medicine during the previous three days. The statistical software Epidata 3.1 and Stata 10.1 were used for data analysis. Frequencies and distribution of each variable were calculated by conventional statistical methods. The chi square test, Mann-Whitney test and logistic regression were used for bivariate analyses. Multiple logistic regression analysis was conducted to determine the predictors of non-adherence to ART. A p value < 0.05 was considered to indicate statistical significance. RESULTS: Of a total of 346 patients, 60% reported more than 95% adherence to ART. Reasons for not taking medicine as required were being busy (97.0%), and being forgetful (62.2%). In the multivariate analysis, educational level at secondary school (OR=3.7, 95% CI:1.3-10.1, p=0.012); illicit drug use (OR=16.1, 95% CI:1.9-128.3, p=0.011); dislike exercise (OR=0.6, 95% CI:0.4-0.9, p=0.028), and forgetting to take ARV medicine during the last month (OR=2.3, 95% CI:1.4-3.7, p=0.001) were independently associated with non-adherence. CONCLUSIONS: Non-adherence to ART was associated with individual factors and exposure to ART. Priority measures to increase adherence to ART should aim to intensify counseling and comprehensive interventions, such as guidance for PLHIV on medication self-management skills, tailoring the regimen to the PLHIV life style, and improving adherence monitoring and health care services. PMID- 23809432 TI - Methodological and reporting quality of systematic reviews on tuberculosis. AB - BACKGROUND: Systematic reviews are used to inform tuberculosis (TB) guidelines. However, there are no data on whether TB systematic reviews are conducted well and reported transparently. METHODS: We searched four databases for reviews published between 2005 and 2010. Methodological quality was evaluated using AMSTAR and quality of reporting was assessed using PRISMA. RESULTS: Of 152 articles, 137 (90%) met the inclusion criteria. Only 3 of 11 AMSTAR quality items were met in most reviews: appropriate methods to combine findings (67%), comprehensive literature search (72%) and presentation of characteristics of included studies (90%). The other eight items were met in 4-53% of the reviews. Only 4% of the reviews disclosed conflicts of interest. The majority of the PRISMA items were reported in more than 60-76% of the reviews. Only nine items were reported in less than 55% of the reviews, the lowest being the full-search strategy (30%), risk of bias across studies in the Methods (27%) and Results (21%) sections, and indication of a review protocol (15%). CONCLUSIONS: Systematic reviews in our survey were well reported but generally of moderate to low quality. Better training, use of reporting guidelines and registration of systematic reviews could improve the quality of TB reviews. PMID- 23809434 TI - Unisexual cucumber flowers, sex and sex differentiation. AB - Sex is a universal phenomenon in the world of eukaryotes. Attempts have been made to understand regulatory mechanisms for plant sex determination by investigating unisexual flowers. The cucumber plant is one of the model systems for studying how sex determination is regulated by phytohormones. A systematic investigation of the development of unisexual cucumber flowers is summarized here, and it is suggested that the mechanism of the unisexual flower can help us to understand how the process leading to one type of gametogenesis is prevented. Based on these findings, we concluded that the unisexual cucumber flowers is not an issue of sex differentiation, but instead a mechanism for avoiding self-pollination. Sex differentiation is essentially the divergent point(s) leading to heterogametogenesis. On the basis of analyses of sex differentiation in unicellular organisms and animals as well as the core process of plant life cycle, a concept of "sexual reproduction cycle" is proposed for understanding the essential role of sex and a "progressive model" for future investigations of sex differentiation in plants. PMID- 23809433 TI - CA-S27: a novel Lewis a associated carbohydrate epitope is diagnostic and prognostic for cholangiocarcinoma. AB - Early and specific diagnosis is critical for treatment of cholangiocarcinoma (CCA). In this study, a carbohydrate antigen-S27 (CA-S27) monoclonal antibody (mAb) was established using pooled CCA tissue-extract as immunogen. The epitope recognized by CA-S27-mAb was a new Lewis-a (Le(a)) associated modification of MUC5AC mucin. A Soybean agglutinin/CA-S27-mAb sandwich ELISA to determine CA-S27 in serum was successfully developed. High level of CA-S27 was detected in serum of CCA patients and could differentiate CCA patients from those of gastro intestinal cancers, hepatomas, benign hepatobiliary diseases and healthy subjects with high sensitivity (87.5%) and high negative predictive value (90.4%). The level of serum CA-S27 was dramatically reduced after tumor removal, indicating tumor origin of CA-S27. Patients with high serum CA-S27 had significantly shorter survivals than those with low serum CA-S27 regardless of serum MUC5AC levels. Fucosyltransferase-III (FUT3) was shown to be a regulator of CA-S27 expression. Suppression of CA-S27 expression with siRNA-FUT3 or neutralization with CA-S27 mAb significantly reduced growth, adhesion, invasion and migration potentials of CCA cells in vitro. In summary, we demonstrate that serum CA-S27, a novel carbohydrate antigen, has potential as diagnostic and prognostic markers for CCA patients. CA-S27 involves in promoting cell growth, adhesion, migration and invasion of CCA cells. PMID- 23809435 TI - Energization of vacuolar transport in plant cells and its significance under stress. AB - The plant vacuole is of prime importance in buffering environmental perturbations and in coping with abiotic stress caused by, for example, drought, salinity, cold, or UV. The large volume, the efficient integration in anterograde and retrograde vesicular trafficking, and the dynamic equipment with tonoplast transporters enable the vacuole to fulfill indispensible functions in cell biology, for example, transient and permanent storage, detoxification, recycling, pH and redox homeostasis, cell expansion, biotic defence, and cell death. This review first focuses on endomembrane dynamics and then summarizes the functions, assembly, and regulation of secretory and vacuolar proton pumps: (i) the vacuolar H(+)-ATPase (V-ATPase) which represents a multimeric complex of approximately 800 kDa, (ii) the vacuolar H(+)-pyrophosphatase, and (iii) the plasma membrane H(+) ATPase. These primary proton pumps regulate the cytosolic pH and provide the driving force for secondary active transport. Carriers and ion channels modulate the proton motif force and catalyze uptake and vacuolar compartmentation of solutes and deposition of xenobiotics or secondary compounds such as flavonoids. ABC-type transporters directly energized by MgATP complement the transport portfolio that realizes the multiple functions in stress tolerance of plants. PMID- 23809436 TI - Roles of substance P and ATP in the subepithelial fibroblasts of rat intestinal villi. AB - The ingestion of food and water induces chemical and mechanical signals that trigger peristaltic reflexes and also villous movement in the gut. In the intestinal villi, subepithelial fibroblasts under the epithelium form contractile cellular networks and closely contact to the varicosities of substance P and nonsubstance P afferent neurons. Subepithelial fibroblasts of the duodenal villi possess purinergic receptor P2Y1 and tachykinin receptor NK1. ATP and substance P induce increase in intracellular Ca(2+) and cell contraction in subepithelial fibroblasts. They are highly mechanosensitive and release ATP by mechanical stimuli. Released ATP spreads to form an ATP "cloud" with nearly 1MUM concentration and activates the surroundings via P2Y1 and afferent neurons via P2X receptors. These findings suggest that villous subepithelial fibroblasts and afferent neurons interact via ATP and substance P. This mutual interaction may play important roles in the signal transduction of mechano reflex pathways including a coordinate villous movement and also in the maturation of the structure and function of the intestinal villi. PMID- 23809437 TI - Roles of arginine vasotocin receptors in the brain and pituitary of submammalian vertebrates. AB - This chapter reviews the functions of arginine vasotocin (AVT) and its receptors in the central nervous system (CNS) of primarily submammalian vertebrates. The V1a-type receptor, which is widely distributed in the CNS of birds, amphibians, and fish, is one of the most important receptors involved in the expression of social and reproductive behaviors. In mammals, the V1b receptor of arginine vasopressin, an AVT ortholog, is assumed to be involved in aggression, social memory, and stress responses. The distribution of the V1b-type receptor in the brain of submammalian vertebrates has only been reported in an amphibian species, and its putative functions are discussed in this review. The functions of V2-type receptor in the CNS are still unclear. Recent phylogenetical and pharmacological analyses have revealed that the avian VT1 receptor can be categorized as a V2b type receptor. The distribution of this newly categorized VT1 receptor in the brain of avian species should contribute to our knowledge of the possible roles of the V2b-type receptor in the CNS of other nonmammalian vertebrates. The functions of AVT in the amphibian and avian pituitaries are also discussed, focusing on the V1b- and V1a-type receptors. PMID- 23809438 TI - Roles of poly(ADP-ribose) glycohydrolase in DNA damage and apoptosis. AB - Poly(ADP-ribose) glycohydrolase (PARG) is the primary enzyme that catalyzes the hydrolysis of poly(ADP-ribose) (PAR), an essential biopolymer that is synthesized by poly(ADP-ribose) polymerases (PARPs) in the cell. By regulating the hydrolytic arm of poly(ADP-ribosyl)ation, PARG participates in a number of biological processes, including the repair of DNA damage, chromatin dynamics, transcriptional regulation, and cell death. Collectively, the research investigating the roles of PARG in the cell has identified the importance of PARG and its value as a therapeutic target. However, the biological role of PARG remains less understood than the role of PAR synthesis by the PARPs. Further complicating the study of PARG is the existence of multiple PARG isoforms in the cell, the lack of optimal PARG inhibitors, and the lack of viable PARG-null animals. This review will present our current knowledge of PARG, with a focus on its roles in DNA-damage repair and cell death. PMID- 23809439 TI - Prospective potency of TGF-beta1 on maintenance and regeneration of periodontal tissue. AB - Periodontal ligament (PDL) tissue, central in the periodontium, plays crucial roles in sustaining tooth in the bone socket. Irreparable damages of this tissue provoke tooth loss, causing a decreased quality of life. The question arises as to how PDL tissue is maintained or how the lost PDL tissue can be regenerated. Stem cells included in PDL tissue (PDLSCs) are widely accepted to have the potential to maintain or regenerate the periodontium, but PDLSCs are very few in number. In recent studies, undifferentiated clonal human PDL cell lines were developed to elucidate the applicable potentials of PDLSCs for the periodontal regenerative medicine based on cell-based tissue engineering. In addition, it has been suggested that transforming growth factor-beta 1 is an eligible factor for the maintenance and regeneration of PDL tissue. PMID- 23809440 TI - Calcium signaling in extraembryonic domains during early teleost development. AB - It is becoming recognized that the extraembryonic domains of developing vertebrates, that is, those that make no cellular contribution to the embryo proper, act as important signaling centers that induce and pattern the germ layers and help establish the key embryonic axes. In the embryos of teleost fish, in particular, significant progress has been made in understanding how signaling activity in extraembryonic domains, such as the enveloping layer, the yolk syncytial layer, and the yolk cell, might help regulate development via a combination of inductive interactions, cellular dynamics, and localized gene expression. Ca(2+) signaling in a variety of forms that include propagating waves and standing gradients is a feature found in all three teleostean extraembryonic domains. This leads us to propose that in addition to their other well characterized signaling activities, extraembryonic domains are well suited (due to their relative stability and continuity) to act as Ca(2+) signaling centers and conduits. PMID- 23809441 TI - New insights into the mechanism of force generation by kinesin-5 molecular motors. AB - Kinesin-5 motors are members of a superfamily of microtubule-dependent ATPases and are widely conserved among eukaryotes. Kinesin-5s typically form homotetramers with pairs of motor domains located at either end of a dumbbell shaped molecule. This quaternary structure enables cross-linking and ATP-driven sliding of pairs of microtubules, although the exact molecular mechanism of this activity is still unclear. Kinesin-5 function has been characterized in greatest detail in cell division, although a number of interphase roles have also been defined. The kinesin-5 ATPase is tuned for slow microtubule sliding rather than cellular transport and-in vertebrates-can be inhibited specifically by allosteric small molecules currently in cancer clinical trials. The biophysical and structural basis of kinesin-5 mechanochemistry is being elucidated and has provided further insight into kinesin-5 activities. However, it is likely that the precise mechanism of these important motors has evolved according to functional context and regulation in individual organisms. PMID- 23809442 TI - New insights into the functions of histidine-rich glycoprotein. AB - Histidine-rich glycoprotein (HRG) is one of the major plasma proteins; it has been isolated from the plasma of various mammals and chicken. HRG has a multidomain structure consisting of cystatin-like domains 1 and 2, Pro-rich domain 1, His-rich domain, Pro-rich domain 2, and C-terminal domain from its N terminus. The ability to bind a wide range of ligands suggests the multivalent function of HRG in blood coagulation, fibrinolysis, and innate immune systems. The local structure supports its binding capacities. Herein, the structural characteristics of HRG and its gene structure are described first. The functions of HRG in coagulation and fibrinolysis systems, the recently reported functions of HRG in angiogenesis, and HRG's antibacterial effect are described next. The activities of HRG in immune response are also reviewed. PMID- 23809443 TI - Appropriate use criteria get orthopaedic sports medicine and arthroscopy back on track. PMID- 23809444 TI - Expert panels: can they be trusted? PMID- 23809445 TI - Author's reply: To PMID 23402944. PMID- 23809447 TI - Glenohumeral chondrolysis: part I--clinical presentation and predictors of disease progression. AB - PURPOSE: The objective of this 2-part study is to report on the etiology, clinical findings, and predictors of disease progression (part I) and the results of treatment (part II) in a group of patients with glenohumeral chondrolysis. METHODS: Forty patients presented with glenohumeral chondrolysis after treatment elsewhere. Twenty patients have been followed up since their initial presentation before arthroplasty (group 1), and 20 patients were referred either for management of complications arising after prosthetic arthroplasty or for evaluation only (group 2). RESULTS: Thirty-seven patients received an intra articular pain pump (IAPP) delivering bupivacaine, and 3 patients had prominent suture anchors or tacks. Symptoms related to chondrolysis developed in patients at a mean of 9.8 months (range, 1 to 34 months) after the index procedure. Radiographs showed joint space obliteration in 30 of 40 patients at most recent follow-up or before arthroplasty. Of the patients receiving an IAPP delivering bupivacaine, the majority received 0.5% with epinephrine. Higher bupivacaine dose (P < .05) and female gender (P < .05) were associated with a longer interval to onset of symptoms. In addition, a shorter interval to onset of symptoms predicted the need for subsequent surgery (P < .05) and a shorter interval to second-look arthroscopy (P < .001). CONCLUSIONS: Post-arthroscopic glenohumeral chondrolysis is a devastating and rapidly evolving condition that most often strikes young patients. The use of IAPPs delivering local anesthetics should be abandoned because nearly all cases of glenohumeral chondrolysis in this series were associated with their use. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 23809446 TI - Postoperative fentanyl patch versus subacromial bupivacaine infusion in arthroscopic shoulder surgery. AB - PURPOSE: The purpose of our study was to compare the effectiveness of subacromial bupivacaine infusion and a transdermal fentanyl patch in the treatment of postoperative pain after arthroscopic shoulder surgery. METHODS: Sixty patients with rotator cuff disease scheduled for elective arthroscopic shoulder surgery were enrolled in the study. For the treatment of postoperative pain, 30 patients constituted group F and received a 12.0-MUg/h fentanyl patch for 72 hours and saline solution infusion in a subacromial manner at the rate of 4 mL/h. The remaining 30 patients constituted group B and received a placebo patch and an infusion of 2.5-mg/mL bupivacaine in a subacromial manner for 72 hours. The primary outcome measure was the postoperative numerical rating scale pain score. The consumption of opioids, ibuprofen, and acetaminophen was also recorded. The Constant scores and general recovery were followed up until the 90th postoperative day. RESULTS: There was no statistically significant difference in the numerical rating scale scores (P = .60) between the groups. No differences in the use of rescue analgesic were observed except that the patients receiving bupivacaine used more ibuprofen (median, 1,200 mg v 600 mg) during the day of surgery (P = .042). No difference was found in general recovery between the groups. CONCLUSIONS: A fentanyl patch delivering 12-MUg/h fentanyl offers an easy and safe treatment option as a part of multimodal analgesia with few adverse effects in the treatment of postoperative pain in a carefully selected patient group after arthroscopic shoulder surgery. LEVEL OF EVIDENCE: Level I, randomized controlled trial. PMID- 23809448 TI - Glenohumeral chondrolysis: part II--results of treatment. AB - PURPOSE: The objective of this 2-part study is to report on the etiology and disease progression (part I) and results of treatment (part II) of glenohumeral chondrolysis. METHODS: Forty patients presented with glenohumeral chondrolysis after treatment elsewhere. Twenty patients have been followed since their initial presentation and before prosthetic shoulder arthroplasty (group 1), and 20 patients were referred either for management of complications arising after shoulder arthroplasty or for evaluation only (group 2). All patients underwent standardized clinical and radiographic examination and completed shoulder specific self-assessment questionnaires at initial presentation and after prosthetic shoulder arthroplasty for patients in group 1. RESULTS: Thirty of 40 patients underwent subsequent arthroscopy for debridement, chondroplasty, capsular release, or a combination of these procedures. Of these, 23 patients (77%) required additional surgery, comprising 18 prosthetic shoulder arthroplasties performed at a mean 13 months of follow-up (range, 3 to 33 months), as well as 5 repeated arthroscopies. At most recent follow-up, 15 of 20 patients in group 1 had undergone shoulder arthroplasty, with improvements in active forward elevation from 92.6 degrees to 140.0 degrees (P < .0001), active abduction from 81.6 degrees to 131.3 degrees (P < .0001), active external rotation from 22.1 degrees to 49.3 degrees (P < .0001), and active internal rotation from the gluteal region to the T12 spinous process (P < .001). Pain scores improved from 6.4 to 3.4 (P < .01), and self-assessed outcome also improved significantly. Twelve patients in group 2 underwent shoulder arthroplasty, so overall 27 of 40 patients (68%) underwent prosthetic shoulder arthroplasty for chondrolysis at a mean of 32 months (range, 9 to 66 months) after the index procedure. CONCLUSIONS: Postarthroscopic glenohumeral chondrolysis is a devastating condition that strikes young patients, responds poorly to arthroscopic interventions, and often requires shoulder arthroplasty within a few years. Patients can expect improved range of motion and outcome after shoulder arthroplasty, but pain relief is often incomplete. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 23809449 TI - Rotator cuff tendon repair morphology comparing 2 single-anchor repair techniques. AB - PURPOSE: To compare the effect of 2 common rotator cuff repair techniques, for smaller tears limited to the use of a single anchor, on tendon morphology in relation to the footprint. METHODS: Six matched pairs of human shoulders were dissected, and a standardized 10-mm supraspinatus tendon tear was created. Two single-anchor repairs were performed: simple repair with the anchor on the footprint or inverted-mattress repair with the anchor 1 cm distal-lateral to the footprint. The repaired specimens were frozen in situ with liquid nitrogen. Coronal cross sections through the intact and repaired tendon were made. A digitizer was used to measure variables including tendon area and radius of tendon curvature. RESULTS: Comparing between repairs, we found significantly more gap formation for the simple repair at the repair cross section (3.67 +/- 0.32 mm v 0.68 +/- 0.10 mm, P = .00050). The simple repair had less tendon area (38.28 +/ 2.50 mm(2)v 58.65 +/- 4.06 mm(2), P = .0036) and a smaller radius of curvature (8.47 +/- 1.39 mm v 32.51 +/- 3.94 mm, P = .0046). For the simple repair, there was significantly more gap formation, less tendon area, and a smaller radius of tendon curvature for all repair cross sections compared with the intact cross sections (P < .05). For the inverted-mattress repair, there was more gap formation compared with the intact condition (P < .05), although it was less than 1 mm on average; for tendon area, radius of curvature, and tendon height, the cross section centered on the repair showed no differences compared with the intact control. CONCLUSIONS: For rotator cuff tears that are 10 mm or smaller and limited to the use of a single anchor, using a distal-lateral anchor position with tape-type suture can provide better maintenance of native tendon morphology and footprint dimensions when compared with repair that uses standard sutures and places the anchor on the footprint. CLINICAL RELEVANCE: For smaller tears, the inverted-mattress repair described in this article may provide a relatively improved healing environment compared with a simple repair on the footprint, potentially optimizing the prevention of early tear progression. PMID- 23809450 TI - The effect of ketorolac tromethamine, methylprednisolone, and platelet-rich plasma on human chondrocyte and tenocyte viability. AB - PURPOSE: The purpose of this study was to evaluate the effect on cell viability of the isolated and combined use of allogeneic platelet-rich plasma (PRP) and ketorolac tromethamine on human chondrocytes and tenocytes in a highly controlled in vitro environment. METHODS: PRP was produced from 8 subjects. Human chondrocytes (Lonza, Hopkinton, MA) and tenocytes isolated from samples of the long head of the biceps tendons were treated in culture with PRP, ketorolac tromethamine, and methylprednisolone, both alone and in combination. Control samples were treated in media containing 2% or 10% fetal bovine serum (FBS). Cells were exposed for 1 hour. Luminescence assays were obtained to examine cell viability after 24 hours and long-term effects on cell viability after 120 hours. Radioactive thymidine assay was used to measure proliferation after 120 hours. RESULTS: For chondrocytes, cell viability (120 hours) increased significantly with the treatment of PRP alone (43,949 +/- 28,104 cells; P < .001) and with the combination of ketorolac tromethamine and PRP (43,276 +/- 31,208; P < .001), compared with the 2% FBS group (7,397 +/- 470). Cell viability decreased significantly after exposure to methylprednisolone (1,323 +/- 776; P < .001) and its combination with PRP (4,381 +/- 5,116; p < .001). For tenocytes, cell viability (120 hours) was significantly higher with the treatment of PRP (61,287 +/- 23,273; P < .001) and the combined treatment of ketorolac tromethamine and PRP (52,025 +/- 17,307; P < .001), compared with the 2% FBS group (23,042 +/- 2,973). Cell viability decreased significantly after exposure to methylprednisolone (3,934 +/- 1,791; P = .001) and its combination with PRP (5,201 +/- 2,834; P = .003), compared with 2% FBS. CONCLUSIONS: Tendon and cartilage cells showed increased cell viability after an exposure to allogeneic PRP and ketorolac tromethamine. Exposure to methylprednisolone alone decreased cell viability, and addition of PRP could partially reverse this negative effect. CLINICAL RELEVANCE: Intra-articular injections of pain-modifying or anti inflammatory drugs are routinely given in orthopaedic practice. Among the many agents available for intra-articular injection, corticosteroids and local anesthetics are the most common in clinical practice. Potential detrimental side effects of intra-articular injections of corticosteroids and local anesthetics have prompted investigation into alternative treatment options such as combinations of PRP and ketorolac tromethamine. In vitro evaluation of their effect on cell viability might build a basis for further translational research and clinical application. PMID- 23809451 TI - Biomechanical performance of traditional arthroscopic knots versus slippage-proof knots. AB - PURPOSE: To compare the biomechanical, time, and profile characteristics of a new sliding locking knot termed the slippage-proof knot (SPK) and a modified slippage proof knot (MSPK) with those of traditional arthroscopic knots. METHODS: We evaluated the Samsung Medical Center (SMC) knot, Revo knot, SPK, and MSPK (an SPK with a single added half-hitch) tied with high-strength suture, with 11 trials of each cycled 1,000 times between 10 and 45 N and then loaded to failure. Total displacement during cyclical testing, maximal load to failure, and mode of failure were recorded for each knot. We also measured the dimensions of the knots and the time required to tie each knot. RESULTS: On load-to-failure testing, no difference in strength was found between the SMC and Revo knots (P = .082). The Revo knot and MSPK were also of equivalent strength (P = .183), and the SMC knot was 11% stronger than the MSPK (P = .017). All 3 of these knots were stronger than the SPK. On cyclical testing, the SMC knot, Revo knot, and MSPK allowed equivalent total displacement and allowed statistically less total displacement than the SPK. All SMC knots, Revo knots, and MSPKs failed by suture breakage, whereas the SPKs all slipped at failure. We found that the SPKs and MSPKs are tied more quickly than traditional knots. The SPK and MSPK dimensions are wider yet shorter than those of the other knots in the study. CONCLUSIONS: Our results indicate that the MSPK has biomechanical properties comparable to the SMC and Revo knots despite only requiring 1 added half-hitch, whereas the SPK was found to be significantly inferior to the other knots tested. We found that the slippage-proof knots (SPK and MSPK) were tied more quickly and have shorter, wider profiles than traditional knots. CLINICAL RELEVANCE: The MSPK has knot security comparable to the SMC and Revo knots while requiring only 1 added half hitch, and it may be most beneficial in cases in which a large number of knots will be tied because the fewer required half-hitches reduces the surgical time without reducing its biomechanical properties. PMID- 23809452 TI - Age-related differences in radiographic parameters for femoroacetabular impingement in hip arthroplasty patients. AB - PURPOSE: To compare the prevalence of femoroacetabular impingement (FAI) radiographic findings between patients aged younger than 50 years and those aged 50 years or older who underwent total hip arthroplasty. METHODS: Total hip arthroplasty patients aged younger than 50 years and those aged 50 years or older were identified retrospectively from a facility medical record database. Fifty patients from each group were randomly selected, and preoperative radiographs were collected. Dysplastic, inflammatory, post-traumatic, and osteonecrosis patients were excluded. Radiographs were evaluated for FAI-specific findings. Intraobserver and interobserver reliability was evaluated with kappa statistics for categorical variables and intraclass correlation coefficients for continuous variables. An independent t test was used to compare continuous variables, chi(2) analysis was used for discrete variables, and a z ratio was used to analyze proportions. RESULTS: The mean age between the subgroups of patients aged younger than 50 years and those aged 50 years or older (43 years and 68 years, respectively) was significantly different (P < .05). Findings in the subgroup aged younger than 50 years included significantly more men (P < .001), decreased lateral joint space with maintained medial joint space (P < .05), significantly greater alpha angle on both the anteroposterior view and the frog-leg lateral view (P < .05), significantly higher Tonnis and Sharp angles (P < .01), and significantly lower center-edge angle (P < .001). CONCLUSIONS: This retrospective case series shows an increased prevalence of FAI findings (specifically cam pathology) in a patient population aged younger than 50 years undergoing total hip arthroplasty when compared with a cohort aged 50 years or older. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 23809453 TI - Return to sport in Australian football league footballers after hip arthroscopy and midterm outcome. AB - PURPOSE: To study the return to sport in a series of professional athletes in a single sport (Australian Rules Football), operated on arthroscopically for hip joint pathology. METHODS: We performed a retrospective review of the senior author's surgical database starting in 2003. All of the patients who were Australian Football League (AFL) professional players with a minimum of 2 years' follow-up were included. Intra-articular pathologies were identified and treated. All patients were prospectively assessed with the modified Harris Hip Score (MHHS) and the Non-Arthritic Hip Score (NAHS). In addition, information about the active participation of the patients in their teams and return to professional sport was obtained from AFL registers and team physicians. RESULTS: Since 2003, the senior author has operated on 36 male professional AFL players; 26 of 27 with at least 2 years' follow-up were available for review. The mean age at the time of surgery was 22.1 years (range, 16 to 30 years), and 8 patients had bilateral pathology; therefore 34 hips were operated on. This report refers to those 26 players and 34 hips. All but 1 of the patients returned to play professionally. By the last survey (October 2011), 16 patients (62%) were still playing professional AFL football, and they have been playing for a mean of 52.5 months after surgery. Ten patients had retired from professional football, but they had all returned to play professionally after surgery. Only one of them retired for causes related to hip disability. There was a significant improvement in preoperative outcome scores. The MHHS and NAHS improved from 83.6 to 98 and from 85.3 to 97.1, respectively, in the players who were still playing (P < .05). Rim lesions were present in 33 hips (97%). Femoral osteochondroplasty was performed in 26 hips (76%). CONCLUSIONS: Arthroscopic treatment of intra-articular pathologies in professional athletes resulted in a 96% rate of return to elite level sport and a durable increase in the MHHS and NAHS. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 23809454 TI - Randomized controlled trial comparing all-inside anterior cruciate ligament reconstruction technique with anterior cruciate ligament reconstruction with a full tibial tunnel. AB - PURPOSE: The purpose of this investigation was to compare the clinical effectiveness of full-tunnel anterior cruciate ligament (ACL) reconstructive surgery with all-inside ACL reconstruction. METHODS: After statistical power analysis was performed and institutional review board approval and patient informed consent were obtained, 150 patients having ACL reconstruction were prospectively randomized to an all-inside or full-tibial tunnel technique. Outcome (International Knee Documentation Committee [IKDC] Knee Examination Form, IKDC Subjective Knee Evaluation Form, Knee Society Score [KSS], Short Form 12 [SF 12] score, femoral or tibial tunnel or socket widening, narcotic consumption, and visual analog scale [VAS] pain score compared with baseline) was measured and recorded preoperatively and at various postoperative time points with a minimum follow-up of 2 years. RESULTS: There were no differences between groups with regard to IKDC Knee Examination Form, IKDC Subjective Knee Evaluation Form, KSS score, SF-12 score, or femoral socket or tibial tunnel or socket widening, or narcotic consumption. The VAS pain score compared with baseline was significantly lower for the all-inside technique on day 1, on day 7, at 1.5 weeks, and at 24 months. CONCLUSIONS: The null hypothesis (no difference between all-inside ACL reconstruction and ACL reconstruction with a full tibial tunnel) is supported for IKDC scores, KSS score, SF-12 score, narcotic consumption, and tibial and femoral widening, whereas all-inside ACL reconstruction results in a lower VAS pain score compared with baseline. LEVEL OF EVIDENCE: Level I, randomized controlled clinical trial with greater than 80% patient follow-up 2 years postoperatively. PMID- 23809455 TI - Single-bundle versus double-bundle anterior cruciate ligament reconstruction: assessment with vertical jump test. AB - PURPOSE: The study was designed to compare the clinical results of traditional single-bundle (SB) anterior cruciate ligament (ACL) reconstruction with those of double-bundle (DB) ACL reconstruction. METHODS: This study comprised 80 patients aged 18 to 45 years with an isolated ACL lesion: 40 patients underwent SB reconstruction, and 40 patients underwent DB reconstruction. Patients were assessed preoperatively with functional assessment including the International Knee Documentation Committee 2000 knee subjective form and visual analog scale, as well as physical examination (including the pivot-shift test and instrumented knee laxity measurement). Vertical jump assessment with the Optojump system (Microgate, Bolzano, Italy) has been introduced as a method to compare functional ability between the 2 surgical techniques. The same protocol was repeated 6 months, 12 months, and 2 years after surgery. RESULTS: No statistically significant differences were noted between the groups concerning subjective evaluation, thigh girth difference, mean visual analog scale score, range of motion, and Lachman and anterior drawer tests (P = not significant). A statistically higher number of patients in the SB group showed a positive pivot shift test and a higher side-to-side difference when measured with the KT-1000 arthrometer (MEDmetric, San Diego, CA) than in the DB group (P < .001). Better mean jumping performance results were reported in the DB group compared with the SB group (P < .001). The average performance results for the injured limb were not significantly reduced compared with those of the uninjured limb in the DB group 12 months after surgery. At 2 years, a restoration of jumping ability in the ACL-reconstructed limb was achieved in both groups regardless of the technique used. CONCLUSIONS: DB ACL reconstruction has been proven to be superior to the SB technique with regard to knee stability and vertical jump performance. LEVEL OF EVIDENCE: Level II, prospective comparative study. PMID- 23809456 TI - Deep vein thrombosis after arthroscopic anterior cruciate ligament reconstruction: a prospective cohort study of 100 patients. AB - PURPOSE: To establish the incidence of venous thromboembolic complications as detected by bilateral complete compression ultrasonography (CCUS) after arthroscopic anterior cruciate ligament (ACL) reconstruction without thromboprophylaxis. METHODS: We performed a prospective cohort study to establish the incidence of venous thromboembolic complications after arthroscopic ACL reconstruction, as detected by bilateral CCUS at 14 days (range, 11 to 17 days) postoperatively. One hundred consecutive patients underwent bilateral extended ultrasonography. RESULTS: One hundred predominantly European patients with a mean age of 30 +/- 10 years and mean body mass index of 25 +/- 4 underwent ACL reconstruction with a mean operative duration of 68 +/- 23 minutes and a tourniquet time of 76 +/- 23 minutes. In 84% of patients an autologous hamstring graft was used, in 14% a bone-patellar tendon-bone graft was used, and 2 patients received an allograft. Of 100 patients, 9 (incidence, 9%; 95% confidence interval, 4.2 to 16.4) showed asymptomatic proximal or distal deep vein thrombosis on CCUS, of whom 4 (incidence, 4%; 95% confidence interval, 1.1 to 9.9) were symptomatic. A nonfatal pulmonary embolus developed in 1 patient during the 8-week follow-up period. CONCLUSIONS: This study shows that the incidence of venous thromboembolism after arthroscopic ACL reconstruction is relatively high; a 9% incidence of asymptomatic proximal or distal deep vein thrombosis was found, whereas 4% of patients were symptomatic. Further research is recommended to assess the need for thromboprophylaxis in patients undergoing ACL reconstruction, especially when risk factors are present. LEVEL OF EVIDENCE: Level IV, case series. PMID- 23809457 TI - Safety and efficiency of a 2-portal lateral approach to arthroscopic subtalar arthrodesis: a cadaveric study. AB - PURPOSE: To investigate the safety and efficiency of a 2-portal lateral (anterior and middle) approach to arthroscopic subtalar arthrodesis. METHODS: A cadaveric study was performed on 30 feet of 15 fresh cadaveric bodies (15 right and 15 left; 21 female specimens and 9 male specimens). The mean age at death was 78 +/- 6.7 years. The procedure was performed with the specimen in the supine position through 2 lateral (anterior and middle) sinus tarsi portals by use of a 4.0-mm arthroscope. A 3.5-mm synovial shaver was used for debridement, and a 4.5-mm shielded bur was used to resect posterior subtalar facets. The feet were then dissected. The primary outcomes were the percentage of resected joint surface and the distances between portals and both sural and superficial peroneal nerves. The secondary outcomes were injury of sinus tarsi ligaments and lateral arterial network, calcaneofibular ligament, peroneal tendons, flexor hallucis longus tendon, and posterior tibial neurovascular bundle. RESULTS: The mean percentages of resected talar and calcaneal posterior subtalar facets were 94% +/- 7.2% and 91% +/- 6.8%, respectively. The minimum distance of either subtalar portal to the nerves was 4 mm. No nerve injury was observed. In 28 of 30 cases, the lateral sinus tarsi arterial network was found intact. In all cases the inferior retinaculum extensor was transfixed by the portals. In all cases both cervical and interosseous talocalcaneal ligaments were found intact. In 3 cases a shaving lesion was observed on the peroneus brevis tendon. CONCLUSIONS: According to this cadaveric study, more than 90% freshening of the posterior subtalar articular facets can be achieved through a 2-portal lateral (anterior and middle) approach. This technique is reproducible and safe with regard to the surrounding nerves. CLINICAL RELEVANCE: The 2 lateral portals may offer a safe and effective alternative approach for arthroscopic arthrodesis of the posterior subtalar joint. PMID- 23809458 TI - MRI artifacts in the ferric chloride thrombus animal model: an alternative solution: preventing MRI artifacts after thrombus induction with a non ferromagnetic Lewis acid. PMID- 23809459 TI - Effect of lifetime alcohol consumption on the histological severity of non alcoholic fatty liver disease. AB - BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is defined based on recent alcohol consumption; however, remote or lifetime alcohol consumption is not taken into account. It is not known whether lifetime alcohol consumption contributes to the severity of disease in patients with NAFLD. To determine the effect of lifetime alcohol consumption on the histological severity in patients with NAFLD. PATIENTS & METHODS: Adults >18 years of age with presumed NAFLD and alcohol consumption <40 g/week were enrolled. Lifetime alcohol consumption was determined using a questionnaire. Patients with a history of long-term alcohol abuse or dependence were excluded. A liver biopsy was reviewed by a single pathologist in a blinded fashion. Demographic, clinical and histological findings were compared in those who had regular alcohol consumption and those who did not. RESULTS: A total of 77 patients had fatty liver on biopsy. Fifty-two patients had a history of regular alcohol consumption. The median lifetime cumulative alcohol intake was 24 gram-years. On multivariable analysis, increasing age (OR 1.07, 95% CI 1.01-1.14) was associated with severe liver disease, whereas alcohol consumption of >=24 gram-years was associated with less severe disease (OR 0.26, 95% CI 0.07-0.97, P = 0.04). Patients who continued to consume alcohol or had been abstinent for <=1 year had less severe disease. CONCLUSION: Some degree of regular alcohol consumption over the course of a lifetime compared to minimal intake appears to have a protective effect on the histological severity of liver disease among patients with strictly defined NAFLD. PMID- 23809460 TI - Innervation and histology of the clitoral-urethal complex: a cross-sectional cadaver study. AB - INTRODUCTION: Despite its central role in sexual function, we lack a description of the nerve distribution and histology for the central components of the clitoris. AIM: This study aims to characterize microscopic anatomy of the clitoral-urethral complex (CUC) and aid our understanding of sexual sensation METHODS: The CUC was excised from three female fresh-frozen cadavers en bloc and prepared in 5-MUm longitudinal sections with hematoxylin and eosin and S100 immunohistochemistry for neural elements. Approximately 20 sections were obtained from each specimen. On low power microscopy, the 30 most innervated fields on each section were identified. On high power, the total number of nerves per field was quantified, then was averaged. The histologic characteristics of each clitoral component were described. Two investigators evaluated all specimens. MAIN OUTCOME MEASURES: Descriptives of large (>=3 fibers) and small nerves based on location in the CUC. RESULTS: Nerve quantification revealed the glans to be the most populated by small nerves (52.1, standard deviation [SD] 26.2). As slices through each specimen moved caudad toward the urethra, the number of small nerves dramatically decreased from 40.4 (SD 10.8) in the body and 29.8 (SD 8.8) (superior CUC) near the bulb to 23.7 (SD 9.8) in the middle CUC and 20.5 (SD 10.4) (inferior CUC) near the urethra. Although the variation in small nerves was striking, large nerves were somewhat uniform and comprised a minority of the overall quantity. Neuroanatomy was consistent for all cadaver specimens. CONCLUSIONS: Our study provided a description of the nerve distribution throughout the central CUC. Increased density of small nerves in the glans suggests this is the location of heightened sensation. Decreasing quantity of nerves in segments closer to the urethra may indicate these zones are less important for sexual sensation. Knowledge of human clitoral innervation is important for understanding the complexities of the female sexual response cycle. PMID- 23809461 TI - Improvised peritoneal dialysis in an 18-month-old child with severe acute malnutrition (kwashiorkor) and acute kidney injury: a case report. AB - INTRODUCTION: Severe acute malnutrition is common in developing countries. Children with severe acute malnutrition are prone to complications, including electrolyte imbalance and infections. Our patient was an 18-month-old boy who had severe acute malnutrition (kwashiorkor) and developed acute kidney injury, which was managed with peritoneal dialysis using improvised equipment. This case report illustrates the importance of improvisation in resource-limited settings in providing lifesaving treatment. To the best of our knowledge, this is the first case report on peritoneal dialysis in a child with severe acute malnutrition (kwashiorkor). CASE PRESENTATION: We report a case of an 18-month-old Bantu African Tanzanian boy who had severe malnutrition and developed anuric acute kidney injury. He had severe renal dysfunction and was managed with peritoneal dialysis using an improvised catheter and bedside constituted fluids (from intravenous fluids) and was diuretic after 7 days of peritoneal dialysis, with complete recovery of renal functions after 2 weeks. CONCLUSION: Children with severe acute malnutrition who develop acute kidney injury should be offered peritoneal dialysis, which may be provided using improvised equipment in resource limited settings, as illustrated in this case report. PMID- 23809462 TI - Is there evidence for an emotion-related bias in verbal learning or memory in individuals putatively high at risk for mania? AB - There is broad evidence that individuals with bipolar disorder show deficits in verbal memory and learning. Such deficits seem to be independent of acute mood episodes and to manifest after the onset of the disorder. Less research has been conducted in relation to more specific memory functions, particularly to verbal memory and learning for emotional information. Therefore, the objective of the present study is to investigate if there is evidence for an affective memory bias in at-risk individuals before the onset of affective disorder. We applied the Emotional Auditive Verbal Learning Test to individuals at risk for mania and at risk for depression, as well as to a control group. We hypothesized a mania related memory bias for individuals at risk of mania. We found no evidence for an overall learning or memory deficit in the high-risk groups. All groups performed better learning and remembering neutral words compared to emotionally valenced words, however, contrary to our hypothesis there was no specific emotion-related learning or memory bias in the two high-risk groups. There was no evidence of impairments in verbal learning and memory overall and for emotional contents before the onset of affective disorders. PMID- 23809463 TI - Using a hybrid model to investigate the comorbidity and symptom overlap between social phobia and the other anxiety disorders and unipolar mood disorders. AB - New hybrid models of psychopathology have been proposed that combine the current categorical approach with symptom dimensions that are common across various disorders. The present study investigated the new hybrid model of social anxiety in a large sample of participants with anxiety disorders and unipolar mood disorders to improve understanding of the comorbidity and symptom overlap between social phobia (SOC) and the other anxiety disorders and unipolar mood disorders. Six hundred and eighty two participants from a specialized outpatient clinic for anxiety treatment completed a semi-structured diagnostic interview and the Multidimensional Assessment of Social Anxiety (MASA). A hybrid model symptom profile was identified for SOC and compared with each of the other principal diagnoses. Significant group differences were identified on each of the MASA scales. Differences also were identified when common sets of comorbidities were compared within participants diagnosed with SOC. The findings demonstrated the influence of both the principal diagnosis of SOC and other anxiety disorders and unipolar mood disorders as well as the influence of comorbid diagnoses with SOC on the six symptom dimensions. These findings highlight the need to shift to transdiagnostic assessment and treatment practices that go beyond the disorder specific focus of the current categorical diagnostic systems. PMID- 23809465 TI - Preserving a renal allograft following invasive Candida infection. PMID- 23809466 TI - Treatment of upper limb extensor hypertonia: case report. AB - We describe a case of wrist and finger extensor hypertonia treated successfully by division of the hypertonic musculotendinous units and functional replacement using conventional tendon transfer techniques for radial nerve palsy. This report emphasizes the important role of regional nerve blocks in assessment and in operative decision making in a case of extensor hypertonia of the upper limb. PMID- 23809464 TI - The post illumination pupil response is reduced in seasonal affective disorder. AB - Individuals with seasonal affective disorder (SAD) may have a decreased retinal sensitivity in the non-image forming light-input pathway. We examined the post illumination pupil response (PIPR) among individuals with SAD and healthy controls to identify possible differences in the melanopsin signaling pathway. We also investigated whether melanopsin gene (OPN4) variations would predict variability in the PIPR. Fifteen SAD and 15 control participants (80% women, mean age 36.7 years, S.D.=14.5) were assessed in the fall/winter. Participants were diagnosed based on DSM-IV-TR criteria. Infrared pupillometry was used to measure pupil diameter prior to, during, and after red and blue stimuli. In response to blue light, the SAD group had a reduced PIPR and a lower PIPR percent change relative to controls. The PIPR after the blue stimulus also varied on the basis of OPN4 I394T genotype, but not OPN4 P10L genotype. These findings may indicate that individuals with SAD have a less sensitive light input pathway as measured by the PIPR, leading to differences in neurobiological and behavioral responses such as alertness, circadian photoentrainment, and melatonin release. In addition, this sensitivity may vary based on sequence variations in OPN4, although a larger sample and replication is needed. PMID- 23809467 TI - Proximal row carpectomy: minimum 20-year follow-up. AB - PURPOSE: Proximal row carpectomy (PRC) is a motion-sparing procedure for degenerative disorders of the proximal carpal row. Reported results at a minimum 10-year follow-up consistently show maintenance of strength, motion, and satisfaction with an average conversion rate to radiocarpal arthrodesis of 12%. We hypothesized that PRC would continue to provide a high level of satisfaction and function at a minimum of 20 years. METHODS: Seventeen wrists in 16 patients, including 7 laborers, underwent PRC for symptomatic degenerative disorders of the proximal carpal row at an average age of 36 years. Patients returned for radiographic and clinical evaluation, and the Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) questionnaire and Patient-Related Wrist Evaluation were used for subjective assessment. Follow-up was a minimum of 20 years (average, 24 y). RESULTS: Eleven wrists (65%) underwent no further surgery at a minimum 20-year follow-up. The average time to failure of PRC, defined as the time from PRC to radiocarpal arthrodesis, was 11 years (range, 8 mo to 20 y). Ten of 11 patients who did not undergo radiocarpal arthrodesis continued to be satisfied, with minimal decrease in motion and grip strength compared with the uninvolved side. Average score for QuickDASH was 16 and for Patient-Related Wrist Evaluation was 26. The flexion-extension arc was 68 degrees , and grip strength was 72% of the contralateral side. All patients returned to their original employment. There was no correlation between degenerative radiographic changes and satisfaction level. The predicted probability of failure revealed a higher risk in patients who underwent PRC at a younger age, which leveled off at age 40 years. CONCLUSIONS: PRC provides satisfaction at a minimum of 20 years with a survival rate of 65%. Whereas we recommend a minimum age for PRC between 35 and 40 years, young patients should not be excluded as PRC candidates; these patients should undergo appropriate preoperative counseling of their increased failure risk secondary to their young age. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 23809469 TI - Negative-pressure wound therapy. PMID- 23809468 TI - Insertion profiles of 4 headless compression screws. AB - PURPOSE: In practice, the surgeon must rely on screw position (insertion depth) and tactile feedback from the screwdriver (insertion torque) to gauge compression. In this study, we identified the relationship between interfragmentary compression and these 2 factors. METHODS: The Acutrak Standard, Acutrak Mini, Synthes 3.0, and Herbert-Whipple implants were tested using a polyurethane foam scaphoid model. A specialized testing jig simultaneously measured compression force, insertion torque, and insertion depth at half-screw turn intervals until failure occurred. RESULTS: The peak compression occurs at an insertion depth of -3.1 mm, -2.8 mm, 0.9 mm, and 1.5 mm for the Acutrak Mini, Acutrak Standard, Herbert-Whipple, and Synthes screws respectively (insertion depth is positive when the screw is proud above the bone and negative when buried). The compression and insertion torque at a depth of -2 mm were found to be 113 +/- 18 N and 0.348 +/- 0.052 Nm for the Acutrak Standard, 104 +/- 15 N and 0.175 +/- 0.008 Nm for the Acutrak Mini, 78 +/- 9 N and 0.245 +/- 0.006 Nm for the Herbert-Whipple, and 67 +/- 2N, 0.233 +/- 0.010 Nm for the Synthes headless compression screws. CONCLUSIONS: All 4 screws generated a sizable amount of compression (> 60 N) over a wide range of insertion depths. The compression at the commonly recommended insertion depth of -2 mm was not significantly different between screws; thus, implant selection should not be based on compression profile alone. Conically shaped screws (Acutrak) generated their peak compression when they were fully buried in the foam whereas the shanked screws (Synthes and Herbert-Whipple) reached peak compression before they were fully inserted. Because insertion torque correlated poorly with compression, surgeons should avoid using tactile judgment of torque as a proxy for compression. CLINICAL RELEVANCE: Knowledge of the insertion profile may improve our understanding of the implants, provide a better basis for comparing screws, and enable the surgeon to optimize compression. PMID- 23809470 TI - Revision carpal tunnel surgery: a 10-year review of intraoperative findings and outcomes. AB - PURPOSE: To evaluate intraoperative findings and outcomes of revision carpal tunnel release (CTR) and to identify predictors of pain outcomes. METHODS: We performed a retrospective cohort study of all adult patients undergoing revision CTR between 2001 and 2012. Patients were classified according to whether they presented with persistent, recurrent, or new symptoms. We compared study groups by baseline characteristics, intraoperative findings, and outcomes (strength and pain). Within each group, we analyzed changes in postoperative pinch strength, grip strength, and pain from baseline. Predictors of postoperative average pain were examined using both multivariable linear regression analyses and univariable logistic regression to calculate odds ratios of worsened or no change in pain. RESULTS: We performed revision CTR in 97 extremities (87 patients). Symptoms were classified as persistent in 42 hands, recurrent in 19, and new in 36. The recurrent group demonstrated more diabetes and a longer interval from primary CTR, and was less likely to present with pain. Incomplete release of the flexor retinaculum and scarring of the median nerve were common intraoperative findings over all. Nerve injury was more common in the new group. Postoperative pinch strength, grip strength, and pain significantly improved from baseline in all groups, apart from strength measures in the recurrent group. Persistent symptoms and more than 1 prior CTR had higher odds of not changing or worsening postoperative pain. Higher preoperative pain, use of pain medication, and workers' compensation were significant predictors of higher postoperative average pain. CONCLUSIONS: Carpal tunnel release may not always be entirely successful. Most patients improve after revision CTR, but a methodical approach to diagnosis and adherence to safe surgical principles are likely to improve outcomes. Symptom classification, number of prior CTRs, baseline pain, pain medications, and workers' compensation status are important predictors of pain outcomes in this population. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III. PMID- 23809471 TI - Ewing sarcoma of the first metacarpal with a 9-year follow-up: case report. AB - Ewing sarcoma is a primary bone tumor that rarely occurs in the hand. We present a case involving the thumb metacarpal with long-term follow-up. Carpometacarpal and metacarpophalangeal arthrodeses with autograft are relatively simple procedures that stabilized the thumb and preserved satisfactory function. PMID- 23809472 TI - Limited arthrodesis of the wrist for treatment of giant cell tumor of the distal radius. AB - PURPOSE: To present the functional results of a technique of radiocarpal arthrodesis and reconstruction with a structural nonvascularized autologous bone graft after en bloc resection of giant cell tumors of the distal radius. METHODS: A total of 13 patients with a mean age of 37 years with aggressive giant cell tumor (Campanacci grade III) of distal radius were managed with en bloc resection and reconstruction with a structural nonvascularized bone graft. The primary outcome measure was the disability evaluated by the Musculoskeletal Tumor Society rating score of limb salvage. Secondary outcomes included survival of the reconstruction measured from the date of the operation to revision procedure for any reason (mechanical, infectious, or oncologic). Other outcomes included active wrist motion and ability to resume work. RESULTS: Mean follow-up period was 6 years (range, 2-14 y). The median arc of motion at the midcarpal joint was 40 degrees , median wrist flexion was 20 degrees , and median extension was 10 degrees . The median Musculoskeletal Tumor Society score based on the analysis of factors pertinent to the patient as a whole (pain, functional activities, and emotional acceptance) and specific to the upper limb (positioning of the hand, manual dexterity, and lifting ability) was 86%. Five patients underwent a second surgical procedure. The cumulative probability of reoperation for mechanical reason was 31% at similar follow-up times at 2, 5, and 10 years. CONCLUSIONS: This technique provided a stable wrist and partially restored wrist motion with limited pain. However, further surgical procedures may be necessary to reach this goal. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 23809473 TI - Analysis of primary resistance mutations to HIV-1 entry inhibitors in therapy naive subtype C HIV-1 infected mother-infant pairs from Zambia. AB - BACKGROUND: Small molecular CCR5 inhibitors represent a new class of drugs for treating HIV-1 infection. The evaluation of the primary resistance mutations associated with entry inhibitors during HIV-1 perinatal transmission is required because they may have a profound impact on the clinical management in MTCT. OBJECTIVES: To evaluate the primary resistance mutations to maraviroc and vicriviroc during perinatal transmission and analyze the sensitivity of Env derived from mother-infant pairs to maraviroc. STUDY DESIGN: Nine MIPs infected by subtype C HIV-1 were recruited to analyze the prevalence and transmission of primary resistance mutations to maraviroc and vicriviroc. Moreover, Env derived from six MIPs were employed to construct provirus clones and to analyze the sensitivity to maraviroc. RESULTS: Mutations A316T, conferring partial resistance to maraviroc, T307I and R315Q, both conferring partial resistance to vicriviroc are prevalent in mother and infant cohorts, indicating the transmission of primary resistance mutations during HIV-1 perinatal transmission. However, the mutations of acutely infected mothers seem to directly transmit to their corresponding infants, while some mutations at low frequency of chronically infected mothers would be lost during transmission. Moreover, provirus clones derived from acutely infected MIPs are less susceptible to maraviroc than those from chronically infected MIPs. CONCLUSIONS: Our study suggests that the transmission mode of primary resistance mutations and the sensitivity to maraviroc are dependent on infection status of MIPs either acutely or chronically infected. These results may indicate that higher dose of maraviroc could be needed for treatment of acutely infected MIPs compared to chronically infected MIPs. PMID- 23809474 TI - Influenza virus A(H3N2) strain isolated from cerebrospinal fluid from a patient presenting myelopathy post infectious. AB - BACKGROUND: Neurological involvement during influenza infection has been described during epidemics and is often consistent with serious sequelae or death. OBJECTIVE: To investigate the etiologic agent involved in myelopathy post influenza-like syndrome. STUDY DESIGN: This investigation focuses on virus isolation from the cerebrospinal fluid (CSF) collected from a 19-year-old male student presenting with clinical diagnosis of myelopathy post influenza-like syndrome. To achieve this goal, different cell cultures and molecular methodologies were carried out. RESULTS: Influenza virus A(H3N2) strain was isolated in MDCK cell culture; virus particles were observed under electron microscopy. Phylogenetics analyses showed that the Brazilian influenza A(H3N2) strains were closely related to the A/Perth/16/2009-like. CONCLUSION: This study demonstrates that influenza virus A(H3N2) strain was the cause of illness of the students. According to the Brazilian influenza virus sentinel surveillance data A/Perth/16/2009-LIKE (H3N2) strain has predominated during the 2010 influenza virus season in Brasilia-DF. PMID- 23809475 TI - Plasma cytokine levels and cytokine gene polymorphisms in Mexican patients during the influenza pandemic A(H1N1)pdm09. AB - BACKGROUND: In Mexico, the initial severe cases of the 2009 influenza pandemic virus A (H1N1) [A(H1N1)pdm09] were detected in early March. The immune mechanisms associated with the severe pneumonia caused by infection with this new virus have not been completely elucidated. Polymorphisms in interleukin genes have previously been associated with susceptibility to infectious diseases due to their influence on cytokine production. OBJECTIVES: The present case-control study was performed to compare several immunologic and genetic parameters of patients and controls during the initial phase of the pandemic. STUDY DESIGN: Sixty-five patients who were hospitalized due to infection with the influenza A(H1N1)pdm09 virus and 46 healthy controls were studied. A hemagglutination inhibition assay (HIA) was performed to measure anti-influenza antibody titers in these subjects. Protein levels of the cytokines interleukin (IL)-4, IL-6, IL-8, IL-10, tumor necrosis factor-alpha (TNFalpha), interferon gamma (IFNgamma), transforming growth factor beta (TGFbeta)1 and TGFbeta2 were quantified in plasma. Single nucleotide polymorphisms in IL6, IL10 and TNFalpha were also assessed. RESULTS: Influenza patients had lower antibody titers and produced significantly higher levels of IL-6, IL-10 and TNFalpha than healthy controls. The frequencies of the TNFalpha -308G, IL-10 -592C and IL-10 -1082A alleles and the IL10 -1082(A/A) genotype were associated with susceptibility to severe disease, while the haplotypes TNFalpha AG and IL-10 GTA and GCA were associated with protection from severe disease [P=0.016, OR (CI)=0.11 (0.01-0.96); P=0.0187, OR (CI)=0.34 (0.13-0.85); P=0.013, OR (CI)=0.39 (0.18-0.83)]. CONCLUSIONS: This study demonstrates that the influenza A(H1N1)pdm09 patients and healthy controls have different profiles of immune parameters and that there is an association between IL-10 and TNFalpha polymorphisms and the outcome of this disease. PMID- 23809477 TI - Beyond fasting plasma glucose: the association between coronary heart disease risk and postprandial glucose, postprandial insulin and insulin resistance in healthy, nondiabetic adults. AB - OBJECTIVE: Prediabetes is defined by elevations of plasma glucose concentration, and is aimed at identifying individuals at increased risk of type 2 diabetes and coronary heart disease (CHD). However, since these individuals are also insulin resistant and hyperinsulinemic, we evaluated the association between several facets of carbohydrate metabolism and CHD risk profile in apparently healthy, nondiabetic individuals. METHODS: Plasma glucose and insulin concentrations were measured before and at hourly intervals for eight hours after two test meals in 281 nondiabetic individuals. Insulin action was quantified by determining the steady-state plasma glucose (SSPG) concentration during the insulin suppression test. CHD risk was assessed by measurements of blood pressure and fasting lipoprotein profile. RESULTS: For purposes of analysis, the population was divided into tertiles, and the results demonstrated that the greater the 1) fasting plasma glucose (FPG) concentration, 2) incremental plasma insulin response to meals, and 3) SSPG concentration, the more adverse the CHD risk profile (p<0.05). In contrast, the CHD risk profile did not significantly worsen with increases in the incremental plasma glucose response to meals. CONCLUSIONS: In nondiabetic individuals, higher FPG concentrations, accentuated daylong incremental insulin responses to meals, and greater degrees of insulin resistance are each associated with worse CHD risk profile (higher blood pressures, higher triglycerides, and lower high density lipoprotein cholesterol concentrations). Interventional efforts aimed at decreasing CHD in such individuals should take these abnormalities into consideration. PMID- 23809476 TI - Validation of the Elecsys(r) HIV combi PT assay for screening and reliable early detection of HIV-1 infection in Asia. AB - BACKGROUND: The Elecsys(r) HIV combi PT assay was developed to allow earlier detection of HIV infection with increased sensitivity and specificity. OBJECTIVES: To validate the assay for screening and reliable early detection of HIV-1 infection in Asia. STUDY DESIGN: Samples tested reflected those routinely screened in Asia and comprised: HIV-1 antigen lysate (25 samples) and antibody (20 samples) dilutions; seven HIV-1 seroconversion panels (46 samples); 39 patient samples from early infection; 183 known-positive sera; HIV-1 p24 antigen sensitivity panel (seven samples); >500 routine clinical samples per center. The Elecsys(r) HIV combi PT assay was compared with fourth- (ADVIA Centaur(r) HIV combo, ARCHITECT(r) HIV combo, Elecsys(r) HIV combi) and third-generation (VIRONOSTIKA(r) HIV Uni-Form II Plus O, Zhuhai Livzon Anti-HIV EIA, Serodia(r) Particle Agglutination) assays commonly used in the region. RESULTS: Overall, the Elecsys(r) HIV combi PT showed superior or similar sensitivity to the comparators for detecting all subtypes. The assay correctly identified all positive samples, including those taken soon after infection, and detected seroconversion at a similar or shorter time interval than the comparators. The analytical sensitivity of Elecsys(r) HIV combi PT for HIV-1 p24 antigen was 0.90 IU/mL, which was lower than reported previously. The assay showed good specificity (99.86%) that was superior or equivalent to the other fourth-generation assays tested. CONCLUSIONS: These robust data demonstrate the good subtype inclusivity of the Elecsys(r) HIV combi PT assay and its suitability for screening and reliable early detection of HIV infection in Asia. PMID- 23809478 TI - Best practices in interprofessional education and training in surgery: experiences from American College of Surgeons-Accredited Education Institutes. AB - BACKGROUND: Interprofessional education (IPE) in health care describes a process for training that places health care learners from different professional disciplines into an environment or situation in which shared or linked educational goals are pursued. IPE represents a new way of thinking about education as a value proposition directed at high-quality interprofessional patient care and as such is an innovative strategy endorsed in statements by the Institute of Medicine and the World Health Organization. The requirements of the American College of Surgeons-accredited Education Institutes (ACS-AEIs) for Comprehensive (Level I) accreditation state that education and training activities at the accredited institutes (simulation centers) must be multidisciplinary in nature. Until recently, concepts of shared interprofessional educational goals and facilitation of interdisciplinary colearning have not been addressed explicitly by the Consortium of ACS-AEIs. METHODS: In March 2012, the ACS Education Division convened a forum on IPE at the Annual Meeting of the Consortium of ACS-accredited Education Institutes in Chicago, IL. Five different ACS-AEI perspectives on IPE and training were presented, covering (1) simulation based crisis resource management training for operating room teams, (2) the use of multidisciplinary simulation at an academic medical center-based simulation facility, (3) the development of a collaborative IPE curriculum between nursing and medical schools at a major university, (4) the development of a simulation based interprofessional obstetrics educational program at a university medical center, and (5) the development of an interprofessional macrosystem simulation program in conjunction with opening a new hospital facility. We describe these experiences and present them as best practices in simulation-based IPE in surgery. CONCLUSION: These IPE experiences in the ACS-AEIs reflect varied and robust approaches to integrated interdisciplinary teaching and learning. Demands and directives to increase these types of educational activities in the near future will have to be met with a wider range of offerings and greater specific knowledge and expertise within the ACS-AEI Consortium. PMID- 23809479 TI - The American College of Surgeons/Association of Program Directors in Surgery National Skills Curriculum: adoption rate, challenges and strategies for effective implementation into surgical residency programs. AB - BACKGROUND: The American College of Surgeons/Association of Program Directors in Surgery (ACS/APDS) National Skills Curriculum is a 3-phase program targeting technical and nontechnical skills development. Few data exist regarding the adoption of this curriculum by surgical residencies. This study attempted to determine the rate of uptake and identify implementation enablers/barriers. METHODS: A web-based survey was developed by an international expert panel of surgical educators (5 surgeons and 1 psychologist). After piloting, the survey was sent to all general surgery program directors via email link. Descriptive statistics were used to determine the residency program characteristics and perceptions of the curriculum. Implementation rates for each phase and module were calculated. Adoption barriers were identified quantitatively and qualitatively using free text responses. Standardized qualitative methodology of emergent theme analysis was used to identify strategies for success and details of support required for implementation. RESULTS: Of the 238 program directors approached, 117 (49%) responded to the survey. Twenty-one percent (25/117) were unaware of the ACS/APDS curriculum. Implementation rates for were 36% for phase I, 19% for phase II, and 16% for phase III. The most common modules adopted were the suturing, knot-tying, and chest tube modules of phase I. Over 50% of respondents identified lack of faculty protected time, limited personnel, significant costs, and resident work-hour restrictions as major obstacles to implementation. Strategies for effective uptake included faculty incentives, adequate funding, administrative support, and dedicated time and resources. CONCLUSION: Despite the availability of a comprehensive curriculum, its diffusion into general surgery residency programs remains low. Obstacles related to successful implementation include personnel, learner, and administrative issues. Addressing these issues may improve the adoption rate of the curriculum. PMID- 23809480 TI - Commentary on: the American College of Surgeons/Association of Program Directors in Surgery National Skills Curriculum: adoption rate, challenges and strategies for effective implementation into surgical residency programs. PMID- 23809481 TI - Barriers to adoption of the surgical resident skills curriculum of the American College of Surgeons/Association of Program Directors in Surgery. AB - BACKGROUND: The American College of Surgeons (ACS) and the Association of Program Directors in Surgery (APDS) jointly developed a standardized skills curriculum for surgical residents. This program was intended to be affordable, reproducible, reliable, and proficiency-based. Some experts have proposed mandating that all residency programs implement the curriculum. Although general surgery program directors have supported uniformly the use of simulation in training, one third of general surgery residencies have no simulation curricula. Our goal was to identify barriers to the implementation of the ACS/APDS curriculum. METHODS: The ACS/APDS skills curriculum was analyzed on the basis of the ACS website. All materials listed in each module in all 3 phases were tabulated. Supply costs per resident were calculated along with the time requirements for each. RESULTS: The approximate cost per resident for supplies to complete the entire ACS/APDS skills curriculum exceeds $30,000. The initial cost for the development of our surgery learning center was $4.5 million. Capital equipment and instruments were an additional cost. Time to complete the program was 90 h for each resident, with additional time commitments by surgery faculty, simulation center staff, educational development staff, and veterinary staff. Simulation staffing costs were $22,107. CONCLUSION: The ACS/APDS skills curriculum has a substantial resource commitment associated with its implementation. These capital, instrument, and personnel costs present a major challenge to residency programs that want to adopt this program. Faculty participation in the program poses an additional logistic challenge. Last, resident involvement must be scheduled within the 80-h work-week limit, impacting resident availability for their obligations of patient care. Re-examination of the scope and complexity appears warranted, along with development of low-fidelity substitutions for the proposed modules as well as opportunities for resource-sharing. PMID- 23809482 TI - Toronto orthopaedic boot camp III: examining the efficacy of student-regulated learning during an intensive, laboratory-based surgical skills course. AB - BACKGROUND: Previous studies have presented compelling data that a 1-month "boot camp"-style course can be a highly effective mechanism for teaching and developing targeted technical skills. In the current study, we examine whether performance of these targeted skills is improved when residents are trained using directed, student-led (SL) learning methods compared with traditional instructor led (IL) learning methods. METHODS: Twelve first-year orthopedic residents began their training with a 1-month, intensive skills course. Six residents were taught basic surgical skills using a format that focused on deliberate, SL exploration and practice of the skills under instructor supervision (SL group). The remaining residents were taught the same surgical skills using more traditional IL methods that included complete demonstration of the surgical task by an orthopedic surgeon, followed by an extended period of instruction (IL group). Performance on 4 targeted technical skills (sawing, bone drilling, suturing, and plaster splint application) was tested using an objective, structured assessment of technical skills examination for the 2 groups at the beginning and the end of the skills course. RESULTS: Before the start of the skills course, there were no differences in performance scores between the 2 groups. On completion of the skills course, mean global rating scores for the 4 surgical skills tasks were greater for the SL group compared with the IL group: SL, 3.95 +/- 0.1; IL, 3.42 +/- 0.1; F(1,10) = 7.66 P < .02. A similar pattern of results was revealed by the checklists scores, with the SL group outperforming the IL group: SL, 94.9 +/- 2.1; IL, 86.4 +/- 2.1; F(1,10) = 8.512; P < .02. CONCLUSION: Previous work has demonstrated the effectiveness of teaching basic surgical skills through an intensive course at the onset of residency. The present study shows that allowing surgical trainees to take a directed, student-regulated approach to learning basic surgical skills can further improve performance of these skills. PMID- 23809483 TI - Cadavers versus pigs: which are better for procedural training of surgery residents outside the OR? AB - BACKGROUND: Our objective was to compare the value of porcine versus cadaveric models for procedural training of general surgery residents outside the operating room (OR). METHODS: Two procedural workshops for general surgery residents based on the American College of Surgeons/Association of Program Directors in Surgery national skills curriculum were administered. During each workshop, 7 surgery faculty taught 16 residents level-appropriate operative procedures on 4 training models (2 cadaver torsos; 2 pigs). Participants compared the 2 models at the end of the workshops using a 10-point Likert scale and indicated their training model preference. Ratings were compared using a paired t test. RESULTS: Among the 39 participants (9 faculty and 30 residents) who provided ratings, the porcine models were rated lower for anatomic relevance (6.8 +/- 2.1 vs 9.1 +/- 1.5; P < .01) but higher for tissue handling (8.4 +/- 1.3 vs 7.2 +/- 2.0; P < .01) and ability to dissect/identify planes (8.6 +/- 1.2 vs 6.7 +/- 2.4; P < .01) compared with the cadavers. There were no differences in perceived similarity to live patient surgery and overall value of the 2 models for training (7.2 +/- 2.2 vs 6.9 +/- 2.5 and 8.5 +/- 1.6 vs 8.5 +/- 1.5, respectively). There were no differences between resident and faculty ratings. Eight (20%) participants preferred the porcine model for training, 5 (13%) the cadaveric model, 16 (41%) both, and 10 (26%) indicated differences in preference based on operative procedure. Participants rated highly the overall quality and value of these procedural workshops for their learning (8.4 +/- 1.1). CONCLUSION: Based on resident and faculty evaluations, both porcine and cadaveric models are deemed necessary and valuable for procedural training outside the OR. Such skills workshops should be incorporated into the surgical curriculum. PMID- 23809484 TI - Characteristics in response rates for surveys administered to surgery residents. AB - BACKGROUND: Surveys are important research tools that permit the accumulation of information from large samples that would otherwise be impractical to collect. Resident surveys have been used frequently to monitor the quality of postgraduate training. Low response rates threaten the utility of this research tool. The purpose of this study was to determine the standard response rate of surveys administered to surgery residents and identify characteristics associated with achieving greater response rates. METHODS: A search of peer-reviewed literature published between September 2003 and June 2011 was performed with the use of PubMed with Medical Subject Headings: "internship and residency," "surgery," "data collection," and "questionnaires." For inclusion, articles must have described a survey given to active surgery residents within the United States. Surveys were evaluated based on the following criteria: population size, response rate, incentive use, follow-up use, survey format (online vs paper), and institution versus national. RESULTS: Of 433 initial results, 47 met inclusion criteria with a mean response rate of 65.3%. Surveys administered in paper format had a greater response rate compared with those given electronically (mean 78.6% vs 36.4%, respectively, P < .001). Greatest mean response rates were seen for institutional surveys compared with those given nationally (83.1% vs 42% respectively, P < .001). CONCLUSION: Our review demonstrated that paper surveys administered at the institutional level and during assemblies integrated into residents' schedules demonstrated enhanced response rates. The validity and generalizability of data collected through such surveys will improve as the aspects which dictate response rate are better understood and implemented. PMID- 23809485 TI - Voice issues and laryngoscopy in thyroid surgery patients. PMID- 23809486 TI - Lipopolysaccharide-induced toll-like receptor 4 signaling enhances the migratory ability of human esophageal cancer cells in a selectin-dependent manner. AB - BACKGROUND: Esophageal cancer is an aggressive malignancy, and emerging data suggest that postoperative infections may promote cancer progression. Systemic exposure to lipopolysaccharide (LPS), a Gram-negative bacterial antigen involved in such infections, has been shown to increase cancer cell adhesion to the hepatic sinusoids in vivo. We investigated the direct impact of LPS on the migratory ability of esophageal cancer cells via the LPS receptor toll-like receptor 4 (TLR4). METHODS: Human esophageal squamous carcinoma cell lines and immortalized normal esophageal mucosa cells were tested for TLR4 surface expression by reverse transcription polymerase chain reaction (RT-PCR) and flow cytometry. TLR4 signaling in response to LPS stimulation was tested in these cells by measuring p38 MAP kinase phosphorylation on Western blot. The impact of TLR4 signaling was measured by static adhesion assays in vitro and on early in vivo migration by intravital microscopy of the liver. RESULTS: Upon LPS stimulation, phosphorylation of p38 was detected in the human esophageal cancer cells HKESC-2. Also, LPS-stimulated HKESC-2 cells showed a twofold increased adhesion to fibronectin and to hepatic sinusoidal endothelium. These effects were abolished by TLR4 inhibition using the small-molecule inhibitor eritoran. Adhesion to fibronectin and hepatic sinusoidal endothelium was also diminished by blockade of p38 phosphorylation and inhibitors of selectin-selectin ligand binding. CONCLUSION: LPS can increase the migratory ability of human esophageal cancer cells by increasing their adhesive properties through TLR4 signaling and selectin ligands. TLR4, p38, and selectin blockade may therefore prove to be a new therapeutic strategy for this aggressive malignancy. PMID- 23809487 TI - Is there an evidence-based argument for embracing an antimicrobial (triclosan) coated suture technology to reduce the risk for surgical-site infections?: A meta analysis. AB - BACKGROUND: It has been estimated that 750,000 to 1 million surgical-site infections (SSIs) occur in the United States each year, causing substantial morbidity and mortality. Triclosan-coated sutures were developed as an adjunctive strategy for SSI risk reduction, but a recently published systematic literature review and meta-analysis suggested that no clinical benefit is associated with this technology. However, that study was hampered by poor selection of available randomized controlled trials (RCTs) and low patient numbers. The current systematic review involves 13 randomized, international RCTs, totaling 3,568 surgical patients. METHODS: A systematic literature search was performed on PubMed, Embase/Medline, Cochrane database group (Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Health Economic Evaluations Database/Database of Health Technology Assessments), and www.clinicaltrials.gov to identify RCTs of triclosan-coated sutures compared with conventional sutures and assessing the clinical effectiveness of antimicrobial sutures to decrease the risk for SSIs. A fixed- and random-effects model was developed, and pooled estimates reported as risk ratio (RR) with a corresponding 95% confidence interval (CI). Publication bias was assessed by analyzing a funnel plot of individual studies and testing the Egger regression intercept. RESULTS: The meta analysis (13 RCTs, 3,568 patients) found that use of triclosan antimicrobial coated sutures was associated with a decrease in SSIs in selected patient populations (fixed effect: RR = 0.734; 95% CI: 0.590-0.913; P = .005; random effect: RR = 0.693; 95% CI: 0.533-0.920; P = .011). No publication bias was detected (Egger intercept test: P = .145). CONCLUSION: Decreasing the risk for SSIs requires a multifaceted "care bundle" approach, and this meta-analysis of current, pooled, peer-reviewed, randomized controlled trials suggests a clinical effectiveness of antimicrobial-coated sutures (triclosan) in the prevention of SSIs, representing Center for Evidence-Based Medicine level 1a evidence. PMID- 23809488 TI - Minimally invasive parathyroidectomy provides a conservative surgical option for multiple endocrine neoplasia type 1-primary hyperparathyroidism. AB - BACKGROUND: Many authors advocate routine subtotal parathyroidectomy or total parathyroidectomy and autotransplantation for patients with multiple endocrine neoplasia type 1 (MEN1). Many of these patients are young and recurrence may take decades. Four-gland parathyroid exploration carries a higher risk of complication than minimally invasive parathyroidectomy (MIP). The aim of this study was to assess the role of selective removal of only abnormal glands for MEN1 in the era of MIP. METHODS: For this retrospective, cohort study we collected data on patients undergoing parathyroidectomy for MEN1 from an endocrine surgery database. We reviewed preoperative localization studies, operative findings, histopathology, and clinical outcomes. RESULTS: Twenty-six patients underwent parathyroidectomy for MEN1-associated hyperparathyroidism over the 23-year study period. Six of 10 (60%) patients in the total parathyroidectomy group and 4 of 10 (40%) patients in the subtotal parathyroidectomy group developed hypocalcemia. The subtotal and total parathyroidectomy groups both had a recurrence rate of 30% with a mean follow-up rate of 106 and 133 months, respectively. The MIP group had no hypocalcemia or recurrence with a mean follow-up of 19 months. CONCLUSION: MIP with excision of only documented abnormal parathyroid glands provides an acceptable outcome for patients with MEN1, avoiding the potential for permanent hypoparathyroidism in young patients. It is accepted that recurrent disease is inevitable in these patients; however, such recurrence may take decades to occur and may be able to be dealt with by a further focused procedure. PMID- 23809489 TI - Clinical significance of microscopic anaplastic focus in papillary thyroid carcinoma. AB - BACKGROUND: On occasion, a microscopic anaplastic focus (MAF) is discovered in papillary thyroid carcinoma (PTC). The relevance of MAF has not been well studied with regard to its clinical implications. MAF is defined as the microscopic presence of focally dedifferentiated follicular cells within the PTC. METHODS: A total of 3,606 patients who underwent primary thyroid surgery between 1995 and 2007 were selected from the database of Seoul National University Hospital. Patients were divided into 3 groups based on histology: PTC without MAF (3,574 patients), PTC with MAF (13 patients), and anaplastic thyroid carcinoma (19 patients). RESULTS: Mean +/- standard deviation age was 48 +/- 12 years (range, 17-83) in the PTC without MAF group, 57 +/- 14 years (range, 29-76) in the PTC with MAF group, and 64 +/- 14 years (range, 24-86) in the ATC group (P < .001). Mean tumor sizes were 1.2 +/- 0.9 cm (range, 0.5-13), 2.1 +/- 1.2 cm (range, 0.7 5), and 3.7 +/- 1.4 cm (range, 0.4-6), respectively (P < .001). The median follow up was 32 months. The cause-specific survival at 5 years was 98% in the PTC without MAF group, 64% in the PTC with MAF group, and 11% in the ATC group (P < .001). Multivariate analysis showed that MAF was a prognostic factor for the outcome of PTC patients (hazard ratio, 12.9; 95% confidence interval, 3.1-54.1; P < .001). CONCLUSION: MAF negatively influenced the prognosis of patients with PTC. Further research and the design of more aggressive treatment strategies for MAF might be helpful for patients with PTC. PMID- 23809490 TI - Commentary on: guidelines for the review of pathology in the research context. PMID- 23809491 TI - Reply to Clark regarding "surgeon beware: many patients referred for parathyroidectomy are misdiagnosed with primary hyperparathyroidism". PMID- 23809492 TI - The DNA60IFX contest. PMID- 23809493 TI - Mechanical regulation of chondrogenesis. AB - Mechanical factors play a crucial role in the development of articular cartilage in vivo. In this regard, tissue engineers have sought to leverage native mechanotransduction pathways to enhance in vitro stem cell-based cartilage repair strategies. However, a thorough understanding of how individual mechanical factors influence stem cell fate is needed to predictably and effectively utilize this strategy of mechanically-induced chondrogenesis. This article summarizes some of the latest findings on mechanically stimulated chondrogenesis, highlighting several new areas of interest, such as the effects of mechanical stimulation on matrix maintenance and terminal differentiation, as well as the use of multifactorial bioreactors. Additionally, the roles of individual biophysical factors, such as hydrostatic or osmotic pressure, are examined in light of their potential to induce mesenchymal stem cell chondrogenesis. An improved understanding of biomechanically-driven tissue development and maturation of stem cell-based cartilage replacements will hopefully lead to the development of cell-based therapies for cartilage degeneration and disease. PMID- 23809494 TI - Human baroreflex rhythms persist during handgrip and muscle ischaemia. AB - AIM: To determine whether physiological, rhythmic fluctuations of vagal baroreflex gain persist during exercise, post-exercise ischaemia and recovery. METHODS: We studied responses of six supine healthy men and one woman to a stereotyped protocol comprising rest, handgrip exercise at 40% maximum capacity to exhaustion, post-exercise forearm ischaemia and recovery. We measured electrocardiographic R-R intervals, photoplethysmographic finger arterial pressures and peroneal nerve muscle sympathetic activity. We derived vagal baroreflex gains from a sliding (25-s window moved by 2-s steps) systolic pressure-R-R interval transfer function at 0.04-0.15 Hz. RESULTS: Vagal baroreflex gain oscillated at low, nearly constant frequencies throughout the protocol (at approx. 0.06 Hz - a period of about 18 s); however, during exercise, most oscillations were at low-gain levels, and during ischaemia and recovery, most oscillations were at high-gain levels. CONCLUSIONS: Vagal baroreflex rhythms are not abolished by exercise, and they are not overwhelmed after exercise during ischaemia and recovery. PMID- 23809495 TI - Twenty years of endocrinologic treatment in transsexualism: analyzing the role of chromosomal analysis and hormonal profiling in the diagnostic work-up. AB - OBJECTIVE: To demonstrate that adequate pubertal history, physical examination, and a basal hormone profile is sufficient to exclude disorders of sexual development (DSD) in adult transsexuals and that chromosomal analysis could be omitted in cases of unremarkable hormonal profile and pubertal history. DESIGN: Retrospective chart analysis. SETTING: Endocrine outpatient clinic of a psychiatric research institute. PATIENT(S): A total of 475 subjects (302 male-to female transsexuals [MtF], 173 female-to-male transsexuals [FtM]). Data from 323 (192 MtF/131 FtM) were collected for hormonal and pubertal abnormalities. Information regarding chromosomal analysis was available for 270 patients (165 MtF/105 FtM). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Pubertal abnormalities, menstrual cycle, and hormonal irregularities in relation to chromosomal analysis conducted by karyotype or hair root analysis. RESULT(S): In the MtF group, 5.2% of the patients reported pubertal irregularities and 5.7% hormonal abnormalities, and in the FtM group 3.8% and 19.1%, respectively. Overall chromosomal abnormality in both groups was 1.5% (2.9% in the FtM and 0.6% in the MtF group). The aneuploidies found included one gonosomal aneuploidy (45,X[10]/47,XXX[6]/46,XX[98]), two Robertsonian translocations (45,XXder(14;22)(q10;q10)), and one Klinefelter syndrome (47,XXY) that had already been diagnosed in puberty. CONCLUSION(S): Our data show a low incidence of chromosomal abnormalities and thus question routine chromosomal analysis at the baseline evaluation of transsexualism, and suggest that it be considered only in cases of abnormal history or hormonal examination. PMID- 23809496 TI - Reply of the authors. PMID- 23809497 TI - Age at menarche: a predictor of diminished ovarian function? AB - OBJECTIVE: To investigate whether age at menarche is associated with functional ovarian reserve (FOR) later in life. DESIGN: Retrospective cohort study. SETTING: Fertility center. PATIENT(S): Five hundred and two infertile women. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Levels of menarcheal age, antimullerian hormone (AMH), follicle-stimulating hormone (FSH), and functional ovarian reserve. RESULT(S): The mean age of the patients was 38.9 +/- 4.9 years, and their mean level of AMH was 1.4 +/- 2.0 ng/mL and of FSH was 10.7 +/- 6.1 mIU/mL. Their current age-specific diminished functional ovarian reserve (DFOR) was statistically significantly associated with early menarche, defined as age <13 years. Logistic regression analysis, adjusting for race, affirmed the higher likelihood of early age at menarche in infertile patients with DFOR. When women with DFOR were grouped into quartiles, early menarche (<25th percentile) was associated with statistically significantly higher DFOR risk than late menarche (>75th percentile). CONCLUSION(S): This study demonstrates a statistically significant impact of age at menarche on DFOR risk later in life among infertile women. The occurrence of menarche may relate to follicular pool size and/or speed of follicle recruitment, which in turn is predictive of occurrence of DFOR later in life. PMID- 23809498 TI - Have antimullerian hormone and antral follicle count been given the same opportunities? PMID- 23809499 TI - Isolation of spermatozoa with low levels of fragmented DNA with the use of flow cytometry and sorting. AB - OBJECTIVE: To develop a method to select spermatozoa with low DNA fragmentation rates for assisted reproduction technologies (ART). DESIGN: Multistep prospective cohort study. SETTING: University hospital. PATIENT(S): Semen samples of 34 infertile men were prepared in parallel with swim-up and fluorescence-activated cell sorting (FACS), and 11 semen samples were used for testing the staining strategy. INTERVENTION(S): Flow cytometric sorting of YO-PRO-stained spermatozoa. MAIN OUTCOME MEASURE(S): Assessment of recovery of spermatozoa and purity after sorting, quantification of sperm DNA fragmentation and viability after sorting and after swim up preparation. RESULT(S): Staining with YO-PRO could be performed successfully in regular culture medium, both dead and apoptotic spermatozoa were labeled without the dye entering the viable spermatozoa. Compared with the conventional swim-up method, the sorted viable population showed a significantly reduced number of spermatozoa with fragmented DNA. CONCLUSION(S): A novel method has been developed, which not only might improve the outcome of ART, but can also help to clarify the ongoing controversy of the role of DNA fragmentation in male infertility. PMID- 23809500 TI - Mindfulness-Based Program for Infertility: efficacy study. AB - OBJECTIVE: To present and determine the impact of the Mindfulness-Based Program for Infertility (MBPI). DESIGN: Controlled clinical trial. SETTING: University research unit. PATIENT(S): Fifty-five infertile women completed the MBPI, and 37 infertile women were assigned to a control group. INTERVENTION(S): The MBPI includes 10 weekly sessions, in a group format, with a duration of about 2 hours each (men attend three sessions). MAIN OUTCOME MEASURE(S): Standardized measures of depression, state anxiety, entrapment, defeat, internal and external shame, experiential avoidance, mindfulness, self-compassion, and infertility self efficacy were endorsed pre- and post-MBPI. RESULT(S): The MBPI group and the control group were shown to be equivalent at baseline. By the end of the MBPI, women who attended the program revealed a significant decrease in depressive symptoms, internal and external shame, entrapment, and defeat. Inversely, they presented statistically significant improvement in mindfulness skills and self efficacy to deal with infertility. Women in the control group did not present significant changes in any of the psychological measures, except for a decrease in self-judgment. CONCLUSION(S): Increasing mindfulness and acceptance skills, as well as cognitive decentering from thoughts and feelings, seem to help women to experience negative inner states in new ways, decreasing their entanglement with them and thus their psychological distress. Data suggest that the MBPI is an effective psychological intervention for women experiencing infertility. PMID- 23809501 TI - Early initiation of gonadotropin-releasing hormone antagonist treatment results in a more stable endocrine milieu during the mid- and late-follicular phases: a randomized controlled trial comparing gonadotropin-releasing hormone antagonist initiation on cycle day 2 or 6. AB - OBJECTIVE: To compare the effect of initiating GnRH antagonist (GnRH-a) on cycle day (CD) 2 vs. CD 6 on LH, E2, and P levels in the mid and late follicular phases. DESIGN: Nested study within a multicenter randomized controlled trial. SETTING: Reproductive medicine center in an university hospital. PATIENT(S): One hundred sixty patients undergoing IVF/intracytoplasmic sperm injection (ICSI). INTERVENTION(S): Recombinant FSH (150-225 IU) was administered daily from CD 2 onward. The study group (CD 2) started GnRH-a cotreatment on CD 2, whereas the control group (CD 6) started on CD 6. MAIN OUTCOME MEASURE(S): The follicular phase endocrine profile. RESULT(S): The LH levels on CD 6 were lower in the CD 2 group (0.6 +/- 0.4 vs. 1.9 +/- 1.4 IU/L). The CD 2 group demonstrated both lower E2 levels on CD 6 (520.1 +/- 429.6 pmol/L vs. 1,071.7 +/- 654.2 pmol/L) and on the day of hCG administration (3,341.4 +/- 1,535.3 pmol/L vs. 4,573.2 +/- 2,445.4 pmol/L). The P levels did not differ on CD 6 or on the day of hCG administration. CONCLUSION(S): Early initiation of GnRH-a cotreatment results in a more stable endocrine profile, with more physiological levels of E2 and LH during the follicular phase. The effect on clinical outcomes must be established in larger trials. CLINICAL TRIAL REGISTRATION NUMBER: NCT00866034. PMID- 23809502 TI - Age thresholds for changes in semen parameters in men. AB - OBJECTIVE: To determine whether age thresholds for elements of semen quality exist. DESIGN: Retrospective analysis (covariance and point-change analysis) of results of 4,822 semen analyses and 259 fluorescence in situ hybridization (FISH) analyses. SETTING: Reference laboratory within an infertility clinic. PATIENT(S): A total of 5,081 men aged 16.5-72.3 years. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Ejaculate volume, sperm concentration, sperm motility, sperm motion parameters, strict morphology, and results of FISH analysis. RESULT(S): Measured parameters of ejaculates did not change before 34 years of age. Immediately thereafter, total sperm numbers (and total motile) declined. Sperm concentration and the proportion of sperm of normal morphology declined after 40 years. Sperm motility and progressive parameters of motile sperm fell after 43 years and ejaculate volume after 45 years. The ratio of Y:X-bearing sperm in ejaculates decreased only after 55 years. CONCLUSION(S): Our findings project a declining likelihood of pregnancy following intercourse with men >34 years old, independent from the woman's age and increasing with advancing age. Age-related mechanisms associated with this oligoasthenoteratozoospermic progression are discussed. PMID- 23809504 TI - Sperm sorting for selection of healthy sperm: is it safe and useful? PMID- 23809503 TI - Paternal aging and associated intraindividual alterations of global sperm 5 methylcytosine and 5-hydroxymethylcytosine levels. AB - OBJECTIVE: To evaluate the relative intraindividual changes in sperm 5 methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) levels associated with age and to compare the levels of 5-hmC in mature human sperm to blood DNA. DESIGN: Prospective research study. SETTING: University-based andrology and in vitro fertilization (IVF) laboratory. PATIENT(S): Fifteen known fertile sperm donors, 22 other known fertile controls, and 41 male blood donors from a general population tissue bank. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Measurements of global 5-mC and 5-hmC levels via an enzyme-linked immunosorbent assay (ELISA)-based assay. RESULT(S): Global sperm 5-mC levels exhibit a statistically significant increase with age, and a similar trend was seen in 5 hmC levels. On average, in the age ranges we analyzed, 5-mC increased by 1.76% per year, and 5-hmC, though more variable, increased by approximately 5% per year. Additionally, we found that 5-hmC levels in sperm are 32.59% of that found in blood DNA. CONCLUSION(S): Global sperm DNA methylation patterns are stable over short periods of time but increase with age, which raises important questions regarding the risks of advanced paternal age. Additionally, as we would predict for a transcriptionally quiescent cell type, 5-hmC levels are statistically significantly lower in human sperm than in blood DNA. PMID- 23809505 TI - Use of clomiphene citrate in infertile women: a committee opinion. AB - This committee opinion describes the use of clomiphene citrate, including indications, use, monitoring, and side effects. There is also a discussion of adjuvants and alternatives to clomiphene citrate therapy. PMID- 23809506 TI - Differential expression of genes related to purinergic signaling in smooth muscle cells, PDGFRalpha-positive cells, and interstitial cells of Cajal in the murine colon. AB - BACKGROUND: Purinergic signaling provides regulation of colonic motility. Smooth muscle cells (SMC), interstitial cells of Cajal (ICC), and platelet-derived growth factor receptor alpha-positive (PDGFRalpha(+) ) cells are electrically coupled and form a functional (SIP) syncytium that constitutes the receptive field for motor neurotransmitters in the tunica muscularis. Each cell type in the SIP syncytium has specialized functions in mediating motor neurotransmission. We compared gene transcripts for purinergic receptors and membrane-bound enzymes for purine degradation expressed by each cell type of the SIP syncytium. METHODS: Fluorescence-activated cell sorting (FACS) was used to purify SMC, ICC, and PDGFRalpha(+) cells from mixed cell populations of colonic muscles dispersed from reporter strains of mice with constitutive expression of green fluorescent proteins. Differential expression of functional groups of genes related to purinergic signaling was determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). KEY RESULTS: We detected marked phenotypic differences among SMC, ICC, and PDGFRalpha(+) cells. Substantial numbers of genes of importance in purinergic neurotransmission were enriched in PDGFRalpha(+) cells in relation to SMC and ICC. Notably, genes related to mediating effects and extracellular biotransformation of enteric purinergic inhibitory neurotransmitters were strongly expressed by PDGFRalpha(+) cells. CONCLUSIONS & INFERENCES: Our results demonstrate differential expression of genes for proteins involved in purinergic signaling in the SIP syncytium. These results may further clarify the specific functions of each cell type, identify novel biomarkers for postjunctional cells, and provide hypotheses for further studies to understand the physiological roles of cells of the SIP syncytium. PMID- 23809507 TI - Predictors for future cystic fibrosis-related diabetes by oral glucose tolerance test. AB - BACKGROUND: An annual oral glucose tolerance test (OGTT) has become part of standard care in cystic fibrosis (CF) to screen for CF-related diabetes (CFRD). The objective of this study was to determine predictors for future CFRD derived from an OGTT. METHODS: Data were collected from 2001 to 2009 during a longitudinal prospective study on "Early Diagnosis of Diabetes Mellitus in CF Patients, trial number NCT00662714". The 1093 patients included in the analysis had at least two valid OGTTs each and no CFRD at the first glucose challenge. Normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and CFRD were defined using WHO criteria. In a subsample of 521 patients, the NGT group was further divided into patients with a 1-hour glucose level >11.1 mmol/l (indeterminate glucose tolerance -- INDET) and those with a lower level (no-INDET). Logistic regression analysis was used to identify predictors from the first OGTT for future diabetes. RESULTS: Compared with NGT (n = 838), IFG (n = 70; odds ratio [OR], 95% confidence interval: 2.92, 1.60-5.33) and IGT without IFG (n = 155, OR 2.37, 1.48-3.79) were both significant and independent risk factors for future CFRD. Patients with IGT and IFG (n = 30) had the highest risk (OR 5.30, 2.32-12.10). In the subsample analysis, INDET (n = 116) was associated with a significantly increased risk for future CFRD compared with no-INDET (n = 269; OR 2.81, 1.43-5.51). CONCLUSIONS: In this large study, IFT, IGT, and INDET were all predictors of future CFRD. The OGTT in patients with CF should include a 1-hour post-challenge value. PMID- 23809508 TI - Maximal daily dose of pancreatic enzyme replacement therapy in infants with cystic fibrosis: a reconsideration. AB - The current recommendations for dosing of pancreatic enzyme replacement therapy (PERT) in infants with cystic fibrosis (CF) were made using a limited evidence base. The per meal recommended dose was extrapolated from dosing guidelines for older patients into a maximal daily dose for infants. We discuss why this maximal daily dose recommendation may be insufficient for young infants with CF, although the optimal dose of PERT for infants with CF remains unknown. PMID- 23809509 TI - Reduced fat oxidation rates during submaximal exercise in boys with cystic fibrosis. AB - BACKGROUND: Exercise is a viable form of therapy for children with cystic fibrosis (CF). Understanding the energy sources used during exercise would aid CF patients in obtaining proper nutrition in order to sustain an active lifestyle. METHODS: Six boys with CF (mean age +/- SD: 14.8 +/- 2.3 yrs, FEV1: 99 +/- 18% predicted) and six matched controls (14.0 +/- 2.2 yrs) completed a session of two 30 min bouts of cycling at an intensity set at 50% peak mechanical power. Rates of total fat and carbohydrate (CHO) oxidation were calculated from expired gases. Plasma insulin, glucose and free fatty acid (FFA) were determined before, during and at the end of the exercise. RESULTS: Rates of fat oxidation (expressed in mean mg * kg body weight(-1) * min(-1) +/- SD) were significantly lower in children with CF (5.7 +/- 1.6) compared to controls (8.6 +/- 1.8, p < 0.05). Children with CF also had lower values than controls in amount of fat oxidized (CF: 17.3 +/- 5.0 g, controls: 26.1 +/- 5.9 g, p < 0.05) and percent of total energy expenditure from fat (CF: 32 +/- 6%, controls: 43 +/- 7%, p < .0.05), but a higher contribution from CHO (CF: 68 +/- 6%, controls: 57 +/- 7% p < .0.05). Plasma FFA was significantly lower in children with CF compared to controls during (CF: 252.5 +/- 117.9 MUM, controls: 602.2 +/- 295.6) and at the end of exercise (CF: 430.9 +/- 180.6, controls: 1147.5 +/- 473.5). There were no differences in the rates of CHO oxidation, insulin or glucose between groups. CONCLUSION: Fat metabolism during exercise is impaired in boys with CF and may be attributed to an inability to mobilize FFA. PMID- 23809511 TI - Para-articular osteochondroma of the temporomandibular joint. AB - A para-articular osteochondroma is a rare osteocartilaginous tumour that arises in the soft tissue adjacent to a joint but with no attachment to the bone. To our knowledge, this is the first case of one reported in the region of the temporomandibular joint (TMJ). The patient presented with severe preauricular pain caused by a para-auricular osteochondroma, which arose in the preauricular region just external to the TMJ. PMID- 23809510 TI - Cancer concepts and principles: primer for the interventional oncologist-part I. AB - A sophisticated understanding of the rapidly changing field of oncology, including a broad knowledge of oncologic disease and the therapies available to treat them, is fundamental to the interventional radiologist providing oncologic therapies, and is necessary to affirm interventional oncology as one of the four pillars of cancer care alongside medical, surgical, and radiation oncology. The first part of this review intends to provide a concise overview of the fundamentals of oncologic clinical trials, including trial design, methods to assess therapeutic response, common statistical analyses, and the levels of evidence provided by clinical trials. PMID- 23809512 TI - Renal effects of NO-inhibition in patients with cirrhosis vs. healthy controls: a randomized placebo-controlled crossover study. AB - BACKGROUND: Nitric oxide (NO) is an important regulator of renal hemodynamics and sodium excretion. Systemic and splanchnic NO-synthesis is increased in liver cirrhosis contributing to the characteristic hyperdynamic circulation. The significance of renal NO in human cirrhosis is not clear. AIMS: In order to clarify the role of NO in the regulation of renal hemodynamics and sodium excretion in human cirrhosis, we studied the effects of N(G)-monomethyl-L arginine (L-NMMA) - a nonselective NO-inhibitor - on blood pressure (MAP), heart rate (HR), GFR, RPF, UNa * V, FENa, FELi and plasma levels of renin, angII, aldo, ANP, BNP and cGMP in 13 patients with cirrhosis (Child gr.A: 8; Child gr.B+C: 5) and 13 healthy controls. METHODS: The study was randomized and placebo controlled. Renal hemodynamics were assessed by measuring renal clearance of (51) Cr-EDTA and (125) I-Hippuran for GFR and RPF, respectively. RESULTS: L-NMMA induced a similar, significant increase in MAP in both groups and a more pronounced relative decrease in HR in the CIR group (P = 0.0209, anova). L-NMMA did not change GFR in any group, but RPF decreased significantly in both groups, but most pronouncedly in CIR (P = 0.0478, anova). FENa decreased significantly in both groups after l-NMMA, but the response was again most pronounced in the CIR group (P = 0.0270, anova). All parameters remained stable after placebo. No significant differences were observed between the effects of L-NMMA in Child gr.A vs. Child gr. B+C patients. CONCLUSION: The data supports the hypothesis that renal NO is enhanced in human cirrhosis. PMID- 23809513 TI - Predictive value of PET-CT for pathological response in stages II and III breast cancer patients following neoadjuvant chemotherapy with docetaxel. AB - PURPOSE: To prospectively study the value of PET-CT with fluorine-18 fluorodeoxyglucose (FDG) to predict neoadjuvant chemotherapy (NAC) response of locoregional disease of stages II and III breast cancer patients. MATERIAL AND METHODS: A written informed consent and approval were obtained from the Ethics Committee. PET-CT accuracy in the prediction of pathologic complete response (pCR) after NAC was studied in primary tumors and lymph node metastasis in 43 women (mean age: 50 years: range: 27-71 years) with histologically proven breast cancer between December 2009 and January 2011. PET-CT was performed at baseline and after NAC. SUV(max) percentage changes (DeltaSUV(max)) were compared with pathology findings at surgery. Receiver-operator characteristic (ROC) analysis was used to discriminate between locoregional pCR and non-pCR. In patients not achieving pCR, it was investigated if DeltaSUV(max) could accurately identify the residual cancer burden (RCB) classes: RCB-I (minimal residual disease (MRD)), RCB II (moderate RD), and RCB-III (extensive RD). RESULTS: pCR was obtained in 11 patients (25.6%). Residual disease was found in 32 patients (74.4%): 16 (37.2%) RCB-I, 15 (35.6%) RCB-II and 2 (4.7%) RCB-III. Sensitivity, specificity, and accuracy to predict pCR were 90.9%, 90.6%, and 90.7%, respectively. Specificity was 94.1% in the identification of a subset of patients who had either pCR or MRD. CONCLUSION: Accuracy of DeltaSUV(max) in the locoregional disease of stages II and III breast cancer patients after NAC is high for the identification of pCR cases. Its specificity is potentially sufficient to identify a subgroup of patients who could be managed with conservative surgery. PMID- 23809515 TI - Multiple distant muscular metastases from non-small cell lung carcinoma evidenced by 18F-FDG PET/CT. PMID- 23809514 TI - An unusual case of metastatic extramammary Paget's disease of the vulva identified by 18F-FDG PET/CT. PMID- 23809516 TI - Cochlear implantation and cardiac associations. AB - INTRODUCTION: Cochlear implantation is a safe surgery for restoration of hearing in profoundly deaf candidates. Profound deafness may at times, manifest as a part of a syndrome associated with cardiac anomalies. Cardiac co-morbidities may influence cochlear implantation in a spectrum of ways from minor intra operative issues to major life threatening complications. Issues related to pre operative, intra operative and post operative care needs to be addressed by an efficient in house cardiologist. OBJECTIVES: Our retrospective study was aimed at analyzing the various cardiac co-morbidities encountered in 30 out of 500 cochlear implantees over a period of 14 years (July 1999-June 2012). This study was focused on developing a profile of cardiac complications influencing cochlear implantation and suggests a protocol for management of various cardiac issues related to cochlear implantation. Our article also reflects the cardiologist's perspective of peri-operative care to be given during cochlear implantation. Relevant literature has been reviewed. METHODS: Case series of 30 profoundly deaf children (below 12 years) who had associated cardiac problems and underwent cochlear implantation in our institution were included in our study. Overall cardiac disease was identified in 30 out of 500 implantees (16.6%) in our experience. The cardiac disease can be categorized into 3 groups: candidates with isolated Patent Ductus Arteriosus (PDA) as Group A (8/30), candidates with syndrome and other anomalies with PDA association as Group B (18/30), and candidates with syndromes without PDA association as Group C (4/30). RESULTS: The overall incidence of cardiac problems in profoundly deaf candidates is identified. Descriptive profile of the same has been created and appropriate management for the same described. CONCLUSIONS: A protocol for management of cardiac co-morbidities influencing cochlear implantation has been designed and detailed insight for the optimal management of these issues has been discussed with cardiologist's perspective. PMID- 23809517 TI - Comparison of reading skills between children with cochlear implants and children with typical hearing in Iran. AB - OBJECTIVE: Cochlear implantation has significant effects on language abilities and reading skills. The current study compared the reading performance of children with cochlear implants with that of typically developing children in second and third grades. SUBJECTS AND METHODS: This descriptive-analytic study was performed including 24 children with cochlear implants and 24 typically developing peers. The grade range of the participants was second and third grades. All of students were selected from Tehran city elementary schools. The reading performance of children was assessed by the "Nama" reading test. RESULTS: The results showed that the means of reading scores of typically developed children were significantly greater than the children with cochlear implants (P < 0.01) and there was a significant relationship between reading skills and age of surgery (P < 0.05). Also, there was a significant relationship between reading skills and the period of cochlear implantation (P < 0.05). CONCLUSIONS: Children with cochlear implants showed a weak performance in reading skills in comparison to typically developing children due to lower accessibility to phonological information. However, this limitation can be compensated for partly by early surgery. Parents should refer their deaf children for cochlear implantation before the age of language learning. PMID- 23809518 TI - Plasma exchange in severe leptospirosis with multi-organ failure: a case report. AB - INTRODUCTION: Leptospirosis presents with disease of variable severity; multi organ failure can occur. In this situation, plasma exchange has been used with positive results, although the mechanism of action has not been fully explained. CASE PRESENTATION: A 67-year-old Caucasian man developed severe leptospirosis with marked icterus, acute kidney injury and cardiorespiratory failure, after exposure to livestock. On the basis of previous reported cases, he was treated with plasma exchange. This led to a rapid improvement in his bilirubin level, cardiac and respiratory function, followed by renal function. CONCLUSION: We discuss the pathophysiology of the disease, and suggest that plasma exchange has a role in the treatment of severe sepsis caused by leptospirosis as well as immune complex-mediated organ injury. PMID- 23809519 TI - Bettering lives through teamwork. PMID- 23809521 TI - Patient and provider perspectives on methicillin-resistant Staphylococcus aureus: a qualitative assessment of knowledge, beliefs, and behavior. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of healthcare-associated infection. Individuals with spinal cord injuries and disorders (SCI/D) are at high risk of MRSA colonization and infection. The Department of Veterans Affairs (VA) released guidelines to prevent the spread of MRSA in Veterans with SCI/D; however, available patient educational materials did not address the unique issues for this population. OBJECTIVE: To assess perceptions of SCI/D providers and Veterans with SCI/D regarding MRSA and their educational needs about MRSA prevention, with an ultimate goal of developing patient educational materials that address the issues unique to SCI/D. METHODS: Purposive samples of SCI/D providers (six groups) and Veterans with SCI/D (one group) at two VA facilities participated in 60-90-minute focus group sessions. Qualitative data were analyzed using latent content and constant comparative techniques to identify focal themes. PARTICIPANTS: Thirty-three providers (physicians and nurses working in inpatient, outpatient, and homecare settings) and eight Veterans participated. RESULTS: Three overarching themes emerged from the analysis: knowledge about MRSA, hand hygiene, and barriers to educating Veterans with SCI/D. CONCLUSIONS: SCI/D providers and Veterans with SCI/D identified gaps in general MRSA knowledge, gaps in knowledge of good hand hygiene practices and of required frequency of hand hygiene, and barriers to educating Veterans with SCI/D during inpatient stays. Future educational materials and strategies should address these gaps. PMID- 23809520 TI - Decentralized cardiovascular autonomic control and cognitive deficits in persons with spinal cord injury. AB - Spinal cord injury (SCI) results in motor and sensory impairments that can be identified with the American Spinal Injury Association (ASIA) Impairment Scale (AIS). Although, SCI may disrupt autonomic neural transmission, less is understood regarding the clinical impact of decentralized autonomic control. Cardiovascular regulation may be altered following SCI and the degree of impairment may or may not relate to the level of AIS injury classification. In general, persons with lesions above T1 present with bradycardia, hypotension, and orthostatic hypotension; functional changes which may interfere with rehabilitation efforts. Although many individuals with SCI above T1 remain overtly asymptomatic to hypotension, we have documented deficits in memory and attention processing speed in hypotensive individuals with SCI compared to a normotensive SCI cohort. Reduced resting cerebral blood flow (CBF) and diminished CBF responses to cognitive testing relate to test performance in hypotensive non SCI, and preliminary evidence suggests a similar association in individuals with SCI. Persons with paraplegia below T7 generally present with a normal cardiovascular profile; however, our group and others have documented persistently elevated heart rate and increased arterial stiffness. In the non-SCI literature there is evidence supporting a link between increased arterial stiffness and cognitive deficits. Preliminary evidence suggests increased incidence of cognitive impairment in individuals with paraplegia, which we believe may relate to adverse cardiovascular changes. This report reviews relevant literature and discusses findings related to the possible association between decentralized cardiovascular autonomic control and cognitive dysfunction in persons with SCI. PMID- 23809522 TI - The association of opioid use with incident lower extremity fractures in spinal cord injury. AB - OBJECTIVE: To determine the association between opioid use and lower extremity fracture risk in men with spinal cord injury (SCI). DESIGN: Retrospective cohort study. SETTING: Veterans Affairs Healthcare System. PARTICIPANTS: In total, 7447 male Veterans with a history of a traumatic SCI identified from the Veterans Affairs (VA) Spinal Cord Dysfunction Registry (SCD) from September 2002 through October 2007 and followed through October 2010. OUTCOME MEASURES: Incident lower extremity fractures by use of opioids. RESULTS: In individuals identified from the VA SCD Registry 2002-2007, opioid use was quite common, with approximately 70% of the cohort having received a prescription for an opioid. Overall, there were 892 incident lower extremity fractures over the time period of this study (597 fractures in the opioid users and 295 fractures in the non-opioid users). After adjusting for covariates, there was a statistically significant relationship between opioid use and increased risk for lower extremity fractures (hazard ratio 1.82 (95% confidence interval 1.59-2.09)). Shorter duration of use (<6 months) and higher doses were positively related to fracture risk (P < 0.0001). CONCLUSIONS: Opioid use is quite common in SCI and is associated with an increased risk for lower extremity fractures. Careful attention to fracture prevention is warranted in patients with SCI, particularly upon initiation of an opioid prescription and when higher doses are used. PMID- 23809523 TI - Changes in pulmonary function measures following a passive abdominal functional electrical stimulation training program. AB - OBJECTIVE: To demonstrate the effect of a passive abdominal functional electrical stimulation (AFES) training program on unassisted respiratory measures in tetraplegia. DESIGN: Longitudinal feasibility study. SETTING: National spinal injuries unit in a university teaching hospital. PARTICIPANTS: Twelve patients with tetraplegic spinal cord injury, who could breathe independently, with reduced vital capacity and no visible abdominal movement. INTERVENTION: Three weeks of abdominal muscle conditioning using transcutaneous AFES. MAIN OUTCOME MEASURES: Forced vital capacity (FVC), forced exhaled volume in 1 second (FEV1), peak expiratory flow rate (PEF), and maximum exhaled pressure (MEP). RESULTS: Mean (SD) FVC increased by 0.36 l (0.23) during training (P = 0.0027). Mean (SD) FEV1 and PEF tended to increase by 0.18 l (0.16) and 0.39 l/seconds (0.35), respectively, but this was not significant. No significant change was found in the outcome measures during a 1-week pre-training control phase and during a 3 week post-training phase. CONCLUSIONS: The increase in FVC over the training period and the absence of change before or after training suggest that passive abdominal FES training can be used for respiratory rehabilitation in tetraplegia. PMID- 23809524 TI - Altered resting hemodynamics in lower-extremity arteries of individuals with spinal cord injury. AB - OBJECTIVE: To investigate lower-extremity arterial hemodynamics in individuals with spinal cord injury (SCI). We hypothesized that oscillatory shear index would be altered and resting mean shear would be higher in the lower-extremity arteries of SCI. RESEARCH: Cross-sectional study of men and women with SCIs compared to able-bodied controls. SUBJECTS: Subjects included 105 ages 18-72 years with American Spinal Injury Association (ASIA) Impairment Scale grades A, B, or C and injury duration at least 5 years. Subjects were matched for age and cardiovascular disease risk factors with 156 able-bodied controls. METHODS: Diameter and blood velocity were determined with subject at rest via ultrasound in superficial femoral, popliteal, brachial, and carotid arteries. Mean shear, antegrade shear, retrograde shear, and oscillatory shear index were calculated. RESULTS: Oscillatory shear index was lower in SCI compared to controls for superficial femoral (0.16 +/- 0.10 vs. 0.26 +/- 0.06, P < 0.01) and popliteal arteries (0.20 +/- 0.11 vs. 0.26 +/- 0.05, P < 0.01). Mean shear rate was higher in SCI compared to controls for superficial femoral (43.54 +/- 28.0 vs. 20.48 +/- 13.1/second, P < 0.01) and popliteal arteries (30.43 +/- 28.1 vs. 11.68 +/- 9.5/second, P < 0.01). CONCLUSIONS: The altered resting hemodynamics in SCI are consistent with an atheroprotective hemodynamic environment. PMID- 23809525 TI - Inpatient radiation exposure in patients with spinal trauma. AB - CONTEXT/OBJECTIVE: Radiation exposure from medical imaging is an important patient safety consideration; however, patient exposure guidelines and information on cumulative inpatient exposure are lacking. DESIGN/SETTING: Trauma patients undergo numerous imaging studies, and spinal imaging confers a high effective dose; therefore, we examined cumulative effective radiation dose in patients hospitalized with spinal trauma. We hypothesized that people with spinal cord injury (SCI) would have higher exposures than those with spine fractures due to injury severity. PARTICIPANTS/INTERVENTIONS: Retrospective data were compiled for all patients with spine injuries admitted to a level I trauma center over a 2 year period. OUTCOME MEASURES: Injury severity score (ISS) and cumulative radiation exposure were then determined for these patients, including 406 patients with spinal fractures and 59 patients with SCI. RESULTS: Cumulative effective dose was 45 millisieverts (mSv) in SCI patients, compared to 38 mSv in spinal fracture patients (P = 0.01). Exposure was higher in patients with an ISS over 16 (P = 0.001). Mean exposure in both groups far exceeded the European annual occupational exposure maximum of 20 mSv. More than one-third of patients with SCI exceeded the US occupational maximum of 50 mSv. CONCLUSION: Patients with SCI had significantly higher radiation exposure and ISS than those with spine fracture, but the effective dose was globally high. Dose did not correlate with injury severity for patients with SCI. While the benefits of imaging are clear, radiation exposure does involve risk and we urge practitioners to consider cumulative exposure when ordering diagnostic tests. PMID- 23809526 TI - Life satisfaction and life values in people with spinal cord injury living in three Asian countries: a multicultural study. AB - OBJECTIVE: To compare the differences in life satisfaction and life values among people with spinal cord injury (SCI) living in three economically similar Asian countries: India, Vietnam, and Sri Lanka. DESIGN: Cross-sectional and comparative investigation using the unified questionnaire. SETTING: Indian Spinal Injuries Centre in New Delhi (India), Spinal Cord Rehabilitation Department of the Bach Mai Hospital in Hanoi (Vietnam), and Foundation for the Rehabilitation of the Disabled in Colombo (Sri Lanka). PARTICIPANTS: Two hundred and thirty-seven people with SCI using a wheelchair; 79 from India, 92 from Vietnam, and 66 from Sri Lanka. OUTCOME MEASURES: Life Satisfaction Questionnaire, Chinese Value Survey. RESULTS: People with SCI in Vietnam had significantly higher general life satisfaction than participants in India and Sri Lanka. Significant differences were identified in several demographic and life situation variables among the three Asian countries. With regard to "Traditional", "Universal", and "Personal" life values significant differences among three participating countries were identified in all domains. No significant relationships were identified between life satisfaction and life values for people with SCI in India, Vietnam, or Sri Lanka. CONCLUSION: It could be presumed that particular demographic and life situation variables are more powerful factors of life satisfaction following SCI than the dominant culture of a country expressed by life values. PMID- 23809527 TI - Adaptation of computerized posturography to assess seated balance in persons with spinal cord injury. AB - BACKGROUND: The ability to retain or improve seated balance function after spinal cord injury (SCI) may mean the difference between independence and requiring assistance for basic activities of daily living. Compared with assessments of standing and walking balance, seated balance assessments remain relatively underemphasized and under-utilized. OBJECTIVE: To optimize tools for assessing seated balance deficits and recovery in SCI. DESIGN: Cross-sectional observational study of different methods for assessing seated balance function. SETTING: Veterans Affairs Center of Excellence for the Medical Consequences of Spinal Cord Injury. PARTICIPANTS: Seven able-bodied volunteers, seven participants with chronic motor-complete thoracic SCI. INTERVENTIONS: A computerized pressure-plate apparatus designed for testing standing balance was adapted into a seated balance assessment system. OUTCOME MEASURES: Seated section of Berg Balance Scale; modified functional reach test; and two posturography tests: limits of stability and clinical test of sensory integration on balance. RESULTS: Seated posturography demonstrated improved correlation with neurological level of lesion compared to that of routinely applied subjective clinical tests. CONCLUSION: Seated posturography represents an appealing outcome measure that may be applied toward the measurement of functional changes in response to various rehabilitation interventions in individuals with paralysis. PMID- 23809528 TI - Treatment with basic fibroblast growth factor-incorporated gelatin hydrogel does not exacerbate mechanical allodynia after spinal cord contusion injury in rats. AB - Besides stimulating angiogenesis or cell survival, basic fibroblast growth factor (bFGF) has the potential for protecting neurons in the injured spinal cord. OBJECTIVE: To investigate the effects of a sustained-release system of bFGF from gelatin hydrogel (GH) in a rat spinal cord contusion model. METHODS: Adult female Sprague-Dawley rats were subjected to a spinal cord contusion injury at the T10 vertebral level using an IH impactor (200 kdyn). One week after contusion, GH containing bFGF (20 ug) was injected into the lesion epicenter (bFGF - GH group). The GH-only group was designated as the control. Locomotor recovery was assessed over 9 weeks by Basso, Beattie, Bresnahan rating scale, along with inclined plane and Rota-rod testing. Sensory abnormalities in the hind paws of all the rats were evaluated at 5, 7, and 9 weeks. RESULTS: There were no significant differences in any of the motor assessments at any time point between the bFGF - GH group and the control GH group. The control GH group showed significantly more mechanical allodynia than did the group prior to injury. In contrast, the bFGF - GH group showed no statistically significant changes of mechanical withdrawal thresholds compared with pre-injury. CONCLUSION: Our findings suggest that bFGF-incorporated GH could have therapeutic potential for alleviating mechanical allodynia following spinal cord injury. PMID- 23809529 TI - Sperm chromatin condensation, DNA integrity, and apoptosis in men with spinal cord injury. AB - OBJECTIVES: To evaluate the effect of cord injury on (1) sperm parameters and (2) DNA chromatin status. DESIGN: Case-control study. SETTING: Data were collected from men referred to Research and Clinical Center for Infertility, Yazd, Iran. PARTICIPANTS: Thirty infertile men with the presence of any level of spinal cord injury (SCI) were compared with 30 healthy donors with definite fertility and normal sperm parameters. INTERVENTIONS: Not applicable. OUTCOME MEASURES: Sperm chromatin integrity was assessed using aniline blue (AB), chromomycin A3 (CMA3), toluidine blue (TB), and acridine orange (AO) assays. The rate of apoptotic spermatozoa was evaluated with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) staining. RESULTS: Sperm concentration, motility, and morphology in men with SCI were significantly decreased compared with control group (P < 0.05). In addition, with regard to cytochemical staining and TUNEL test, the rate of reacted spermatozoa was increased significantly in SCI group when compared with the controls (P < 0.05). The majority of AB, TB, AO, and CMA3 reacted spermatozoa were higher than the "cut-off" value in men with SCI, as were the number of apoptotic spermatozoa stained with TUNEL. CONCLUSION: Results showed that SCI disturbs sperm parameters, nuclear maturity, and DNA integrity of spermatozoa. Therefore, the production of spermatozoa with less condensed chromatin and more apoptotic rate increases after cord injury and this may be one possible cause of infertility following SCI. PMID- 23809530 TI - Neuroprotective effect of curcumin on spinal cord in rabbit model with ischemia/reperfusion. AB - BACKGROUND: Ischemic/reperfusion (I/R) injury of the spinal cord is a serious complication that can result from thoracoabdominal aortic surgery. OBJECTIVE: To investigate the neuroprotective effect of curcumin against I/R injury in a rabbit model. METHODS: A total of 36 rabbits were randomly divided into three groups: sham, I/R, and curcumin-treated group. Rabbits were subject to 30-min aortic occlusion to induce transient spinal cord ischemia. Neurological function was observed after reperfusion and spinal cord segment (L3-L5) was collected for histopathological evaluation. Malondialdehyde (MDA) and total superoxide dismutase (SOD) activity were also assayed. RESULTS: Rabbits in I/R group were induced to paraplegia. While after 48-hour treatment, compared with I/R group, curcumin significantly improved neurological function, reduced cell apoptosis and MDA levels as well as increased SOD activity (P < 0.05). CONCLUSIONS: The results suggest that curcumin, at least in an animal model, can attenuate transient spinal cord ischemic injury potentially via reducing oxidative damage, which may provide a novel approach in the treatment of spinal cord ischemic injury. PMID- 23809531 TI - Atypical autonomic dysreflexia during robotic-assisted body weight supported treadmill training in an individual with motor incomplete spinal cord injury. AB - CONTEXT/OBJECTIVE: A 41-year-old man with a history of C6 American Spinal Injury Association (ASIA) Impairment Scale (AIS) C spinal cord injury (SCI), enrolled in an Institutional Review Board (IRB)-approved, robotic-assisted body weight supported treadmill training (BWSTT), and aquatic exercise research protocol developed asymptomatic autonomic dysreflexia (AD) during training. Little information is available regarding the relationship of robotic-assisted BWSTT and AD. FINDINGS: After successfully completing 36 sessions of aquatic exercise, he reported exertional fatigue during his 10th Lokomat intervention and exhibited asymptomatic or silent AD during this and the three subsequent BWSTT sessions. Standard facilitators of AD were assessed and no obvious irritant identified other than the actual physical exertion and positioning required during robotic assisted BWSTT. CONCLUSIONS/CLINICAL RELEVANCE: Increased awareness of potential silent AD presenting during robotic assisted BWSTT training for individuals with motor incomplete SCI is required as in this case AD clinical signs were not concurrent with occurrence. Frequent vital sign assessment before, during, and at conclusion of each BWSTT session is strongly recommended. PMID- 23809532 TI - Spinal giant cell tumor in tuberous sclerosis: case report and review of the literature. AB - BACKGROUND: Patients affected by tuberous sclerosis (TS) have a greater incidence of tumors than the healthy population. Spinal tumours in TS are reported very rarely and consist mainly of sacrococcygeal and cervical chordomas. METHOD: Case report. FINDINGS: A 21-year-old man, affected by TS, presented a spinal dorsal T2 tumor that caused medullary compression. He underwent decompressive laminectomy and microsurgical excision of a giant cell tumor and an associated aneurysmal bone cyst. Postoperative hypofractionated radiotherapy was performed on the surgical field. At 2.4 years of follow-up the patient reported total recovery of neurological deficits and was free from tumor recurrence. CONCLUSION: Considering this association, which is the first reported in the literature, spinal magnetic resonance imaging with gadolinium should be performed at the onset of spinal pain in patients affected by TS. PMID- 23809533 TI - Arnold-Chiari 1 malformation type 1 with syringohydromyelia presenting as acute tetraparesis: a case report. AB - CONTEXT: A 19-year-old woman who presented to a community hospital after awakening with tetraparesis, generalized paresthesia, and severe neck pain, and was transferred to an acute care hospital. FINDINGS: Magnetic resonance imaging of the head and spine was performed and revealed a cystic lesion extending from the C1 level to the C6 level as well as an Arnold-Chiari type 1 malformation. Emergent surgical posterior fossa decompression with duraplasty and C1 laminectomy was undertaken. Most symptoms improved immediately postoperatively. On post-operative day 15, the patient was transferred to our acute rehabilitation hospital for an additional 16 days. With continued aggressive therapy, she demonstrated complete resolution of tetraparesis as well as significant improvement in muscle strength and function in addition to resolution of paresthesia and neck pain. Functional independence measure scores were 69/126 on admission to 110/126 on discharge from the rehabilitation hospital. Her tetraparesis eventually resolved; manual muscle testing scores on follow-up 2 months later were 5/5 in all four extremities. CLINICAL RELEVANCE: This is the first reported case of Chiari I malformation with syringohydromyelia presenting as acute tetraparesis, generalized paresthesia, and neck pain. Surgical decompression leading to resolution of symptoms made other etiologies extremely unlikely and there was no history of trauma. The different theories on the pathogenesis of syringomyelia are discussed. PMID- 23809534 TI - A peculiar complication of suprapubic catheterization: recurrent ureteral obstruction and hydronephrosis. AB - CONTEXT: Suprapubic cystostomy (SPC) catheterization is a common and important technique for the management of vesicular drainage, especially in patients with neurogenic bladder. Some serious complications include bowel perforation and obstruction. FINDINGS: A 55-year-old man with C6 American Spinal Injury Association B tetraplegia and a urethral stricture requiring a chronic SPC was admitted for recurrent urosepsis. Computed tomography (CT) of the abdomen revealed severe right hydronephrosis and hydroureter due to obstruction of the right distal ureter by the SPC tip. The SPC (30 French/10-mm silicone catheter with a 10-ml balloon) was removed and replaced with a similar suprapubic catheter (30 French/10-mm silicone catheter with an 8-ml balloon). Symptoms recurred 2 months later and he was readmitted for urosepsis. CT of the abdomen again revealed severe right hydronephrosis and hydroureter due to obstruction of the right distal ureter by the SPC tip. The SPC was removed, and the patient was given a 14 French/4.67-mm urethral silicone catheter with a 5-ml balloon. Follow up CT of the abdomen 2 months later showed complete resolution of the hydronephrosis and hydroureter. Of note, urodynamic studies 2 years earlier revealed an extremely small bladder with a capacity less than 20 ml. CONCLUSION: This case illustrates that obstruction of the ureter by the tip of an SPC can be a cause of recurrent hydronephrosis and urosepsis. PMID- 23809535 TI - Spinal cord injury facts and figures at a glance. PMID- 23809536 TI - Vitamin D, vitamin D binding protein, lung function and structure in COPD. AB - RATIONALE: Vitamin D and vitamin D binding protein (DBP) have been associated with COPD and FEV1. There are limited data regarding emphysema and vitamin D and DBP. OBJECTIVE: This is a pilot study of a portion of the subjects in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study designed to examine the relationship between vitamin D status, DBP, FEV1 and emphysema in COPD patients. METHODS: We measured serum 25(OH)D and DBP in 498 ECLIPSE subjects. Subjects were distributed amongst smoker controls, non-smoker controls, and GOLD stages 2, 3 and 4. Within each GOLD stage, the subjects were equally divided amongst high and low emphysema burden. The associations between 25(OH)D, DBP, and free vitamin D with FEV1, CT-defined emphysema, biomarkers and clinical data including CT-measured bone attenuation were assessed. MEASUREMENTS: 25(OH)D and DBP were measured using tandem mass spectroscopy and competitive enzyme-linked immunosorbent assay, respectively, MAIN RESULT: 25(OH)D was correlated with FEV1 (p = 0.01) and with severity of emphysema (p < 0.01). 25(OH)D was also associated with six-minute walk (p = 0.02), bronchodilator response (p = 0.04), and Clara cell secretory protein (CC 16) (p = 0.01). 25(OH)D levels were not associated with CT-measured bone attenuation, however DBP was associated with bone attenuation in subjects with emphysema. DBP was not associated with FEV1 or emphysema. 25(OH)D and DBP were inversely associated (p = 0.01). CONCLUSION: This is the first study to demonstrate a relationship between emphysema and vitamin D. We also provide further evidence for a relationship between vitamin D and FEV1. PMID- 23809537 TI - Definition of a core set of quality indicators for the assessment of HIV/AIDS clinical care: a systematic review. AB - BACKGROUND: Several organizations and individual authors have been proposing quality indicators for the assessment of clinical care in HIV/AIDS patients. Nevertheless, the definition of a consensual core set of indicators remains controversial and its practical use is largely limited. This study aims not only to identify and characterize these indicators through a systematic literature review but also to propose a parsimonious model based on those most used. METHODS: MEDLINE, SCOPUS, Cochrane databases and ISI Web of Knowledge, as well as official websites of organizations dealing with HIV/AIDS care, were searched for articles and information proposing HIV/AIDS clinical care quality indicators. The ones that are on patient's perspective and based on services set were excluded. Data extraction, using a predefined data sheet based on Cochrane recommendations, was done by one of the authors while a second author rechecked the extracted data for any inconsistency. RESULTS: A total of 360 articles were identified in our search query but only 12 of them met the inclusion criteria. We also identified one relevant site. Overall, we identified 65 quality indicators for HIV/AIDS clinical care distributed as following: outcome (n=15) and process-related (n=50) indicators; generic (n=36) and HIV/AIDS disease-specific (n=29) indicators; baseline examinations (n=19), screening (n=9), immunization (n=4), prophylaxis (n=5), HIV monitoring (n=16), and therapy (=12) indicators. CONCLUSIONS: There are several studies that set up HIV clinical care indicators, with only a part of them useful to assess the HIV clinical care. More importantly, HIV/AIDS clinical care indicators need to be valid, reliable and most of all feasible. PMID- 23809538 TI - PCSK9 inhibition--a new thrust in the prevention of heart disease: genetics does it again. PMID- 23809539 TI - Intracardiac echocardiogram-guided use of a Dormia basket to prevent major vegetation embolism during transvenous lead extraction. AB - We discuss a case of transvenous lead extraction (TLE) in a patient with a large vegetation. To prevent embolization, a Dormia basket was placed in the pulmonary artery trunk. After uncomplicated TLE, the basket was withdrawn, and vegetation material was retrieved from it. Our experience confirms that TLE is feasible even with large vegetations, and the pulmonary circulation may be protected with a simple intravascular device. PMID- 23809540 TI - Detection and treatment efficacy of hypoglycemic events in the everyday life of children younger than 7 yr. AB - BACKGROUND: Mild hypoglycemia is commonly observed in children treated for type 1 diabetes mellitus (T1DM). Hypoglycemia disturbs cognition and learning. OBJECTIVE: To describe how and to what extent hypoglycemia in young children with T1DM is detected in everyday life. To learn how parents and caregivers treat hypoglycemia and to evaluate how efficient this treatment is. METHODS: Twenty three children [12 girls, mean age: 4.5 yr, mean HbA1c: 59 mmol/mol (7.5%)], 17 of whom were treated with an insulin pump, underwent blinded continuous glucose monitoring (CGM). Data on symptoms and treatment of hypoglycemia were collected in a logbook. Plasma glucose values were collected through self-monitoring of blood glucose and entered in the logbook, and glucometer memories were uploaded. Data were collected during 1 wk in autumn and 1 wk in spring. RESULTS: Only 32% of all hypoglycemic events were detected despite plasma glucose being checked 10 times per day. Most hypoglycemic events were asymptomatic (90% overall and 98% of those occurring at night). Untreated hypoglycemic events were associated with a relapse into hypoglycemia within 3 h in the majority of events. Compared to treatment of hypoglycemia events with a defined dose of simple carbohydrates, treatment with a mixed meal resulted in a significantly higher glucose value 1 and 2 h after the hypoglycemia. CONCLUSION: For optimum treatment, children younger than 7 yr with T1DM need better strategies and support for detecting hypoglycemia with real-time CGM. Hypoglycemia should be treated with a defined dose of carbohydrates rather than a mixed meal. PMID- 23809541 TI - Restoration of virginity: women's demand and health care providers' response in Switzerland. AB - INTRODUCTION: As a result of transnational migration, health institutions are faced with growing demand for "restoration" of virginity. The practice of hymen reconstruction constitutes a challenge for health care providers in medical, ethical, judicial, social, and cultural dimensions, for which they are not well prepared. AIM: The aim of the presented nationwide survey was to investigate the experience of Swiss gynecologists with women requesting hymen reconstruction. METHODS: A questionnaire specifically designed for this purpose was sent to 100 public hospitals. MAIN OUTCOME MEASURES: Main outcome measures included demands for (number of requests, origin of women) and attitudes toward hymen reconstruction (requests granted, decision-making for or against intervention, surgical technique applied, problems associated with the requests for hymen repair, cost coverage, need for further information) in Switzerland. RESULTS: The response rate was 68%. Of the 43 clinics (63.2%) confronted with requests for hymen reconstruction, 38 (90.5%) claimed to see up to five patients per year. The predominantly mentioned countries of origin were Turkey in the German-speaking part and Arab countries in the French-speaking part. More than half of the clinics (27/64.3%) reported that they always (12/28.6%) or mostly (15/35.7%) granted the request. Decision for surgery was made after intensive counseling in 44.2% and on demand of the patient after brief counseling in 32.7%. The so-called approximation method was the most frequently applied surgical technique. A third of the participants (19/35.2%) reported problems with confidentiality. More than half of the clinics expressed their need for further information on this topic. CONCLUSIONS: Hymen reconstruction is rarely performed in Switzerland, even though two-thirds of the responding hospitals are confronted with this issue several times per year. No guidelines exist on how health professionals should deal with these requests. Interdisciplinary research on how to meet the needs of women and health care providers in such cross-cultural encounters is needed. PMID- 23809543 TI - Decreased event-based prospective memory functioning in individuals with Parkinson's disease. AB - The study was aimed at investigating the contribution of retrospective memory to prospective memory (PM) functioning in people with Parkinson's disease (PD). Twenty patients with PD without dementia and 20 normal controls were recruited. In the PM procedure, sequences of words were presented; in the inter-sequence delay, participants had to repeat sequence in the same or reverse order (ongoing task). At the occurrence of a target word, participants had to press a button on the keyboard (PM response). To evaluate the contribution of retrospective memory to PM performance, we manipulated the retrospective memory load of the target words (i.e., one vs. four words). The results show that patients with PD were poorer than controls in all PM conditions (p < .01). The memory load did not modulate differentially the PM performance of individuals in the two groups. Moreover, in PD patients, the ability to retrieve the target words in the episodic memory task was associated, at a lesser extent than in healthy controls, with the ability to activate the prospective intention at the occurrence of a target word. Our findings confirm PM decline in patients with PD without dementia. This flaw cannot be entirely explained by decreased retrospective memory. Altered self-retrieval processes might explain reduced PM performance of these individuals. This is a very relevant finding in the perspective of cognitive therapeutic intervention on PM that, in patients with PD, could be focused on mechanisms other than retrospective memory ones. PMID- 23809542 TI - The CYP2C19*17 variant is not independently associated with clopidogrel response. AB - BACKGROUND: Cytochrome P450 2C19 (CYP2C19) is the principal enzyme responsible for converting clopidogrel into its active metabolite, and common genetic variants have been identified, most notably CYP2C19*2 and CYP2C19*17, that are believed to alter its activity and expression, respectively. OBJECTIVE: We evaluated whether the consequences of the CYP2C19*2 and CYP2C19*17 variants on clopidogrel response were independent of each other or genetically linked through linkage disequilibrium (LD). PATIENTS/METHODS: We genotyped the CYP2C19*2 and CYP2C19*17 variants in 621 members of the Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and evaluated the effects of these polymorphisms singly and then jointly, taking into account LD, on clopidogrel prodrug level, clopidogrel active metabolite level, and adenosine 5'-diphosphate (ADP) stimulated platelet aggregation before and after clopidogrel exposure. RESULTS: The CYP2C19*2 and CYP2C19*17 variants were in LD (|D'| = 1.0; r(2) = 0.07). In association analyses that did and did not account for the effects of CYP2C19*17, CYP2C19*2 was strongly associated with levels of clopidogrel active metabolite (beta = -5.24, P = 3.0 * 10(-9) and beta = -5.36, P = 3.3 * 10(-14) , respectively) and posttreatment ADP-stimulated platelet aggregation (beta = 7.55, P = 2.9 * 10(-16) and beta = 7.51, P = 7.0 * 10(-15) , respectively). In contrast, CYP2C19*17 was marginally associated with clopidogrel active metabolite levels and ADP-stimulated platelet aggregation before (beta = 1.57, P = 0.04 and beta = -1.98, P = 0.01, respectively) but not after (beta = 0.40, P = 0.59 and beta = -0.13, P = 0.69, respectively) adjustment for the CYP2C19*2 variant. Stratified analyses of CYP2C19*2/CYP2C19*17 genotype combinations revealed that CYP2C19*2, and not CYP2C19*17, was the primary determinant in altering clopidogrel response. CONCLUSIONS: Our results suggest that CYP2C19*17 has a small (if any) effect on clopidogrel-related traits and that the observed effect of this variant is due to LD with the CYP2C19*2 loss-of-function variant. PMID- 23809544 TI - Electronic waste--time to take stock. PMID- 23809545 TI - Section 136 and police custody--an unacceptable situation. PMID- 23809546 TI - A new health department and a new future for China's health. PMID- 23809547 TI - NICE times: a valedictory dispatch. PMID- 23809548 TI - Middle East respiratory syndrome: new disease, old lessons. PMID- 23809549 TI - Oseltamivir resistance during treatment of H7N9 infection. PMID- 23809552 TI - Sepsis definitions. PMID- 23809553 TI - Sepsis definitions. PMID- 23809554 TI - Sepsis definitions. PMID- 23809555 TI - Standardised case definitions for adverse events following immunisation. PMID- 23809556 TI - Sepsis definitions - Authors' reply. PMID- 23809557 TI - Violent offending by UK veterans. PMID- 23809558 TI - Standardised case definitions for adverse events following immunisation - Authors' reply. PMID- 23809559 TI - Violent offending by UK veterans - Authors' reply. PMID- 23809560 TI - Tuberculosis vaccine trials. PMID- 23809561 TI - Tuberculosis vaccine trials. PMID- 23809562 TI - Tuberculosis vaccine trials - Authors' reply. PMID- 23809563 TI - Metal fume fever. PMID- 23809565 TI - Toward validation of the cepstral spectral index of dysphonia (CSID) as an objective treatment outcomes measure. AB - OBJECTIVES: To examine the validity of the Cepstral Spectral Index of Dysphonia (CSID) as an objective treatment outcomes measure of dysphonia severity. METHOD: Pre- and posttreatment samples of sustained vowel and connected speech productions were elicited from 112 patients across six diagnostic categories: unilateral vocal fold paralysis, adductor spasmodic dysphonia, primary muscle tension dysphonia, benign vocal fold lesions, presbylaryngis, and mutational falsetto. Listener ratings of severity in connected speech were compared with a three-factor CSID model consisting of the cepstral peak prominence (CPP), the low to-high spectral energy ratio, and its standard deviation. Two additional variables, the CPP standard deviation and gender, were included in the five factor CSID model to estimate severity of vowels. RESULTS: CSID-estimated severity for sustained vowels and connected speech was strongly associated with listener ratings pretreatment, posttreatment, and change observed pre- to posttreatment. Spectrum effects were examined, and severity of dysphonia did not influence the relationship between listener perceived severity and CSID-estimated severity. CONCLUSIONS: The results confirm a robust relationship between listener perceived and CSID-derived dysphonia severity estimates in sustained vowels and connected speech across diverse diagnoses and severity levels and support the clinical utility of the CSID as an objective treatment outcomes measure. PMID- 23809564 TI - From pathogen genomes to host plant processes: the power of plant parasitic oomycetes. AB - Recent pathogenomic research on plant parasitic oomycete effector function and plant host responses has resulted in major conceptual advances in plant pathology, which has been possible thanks to the availability of genome sequences. PMID- 23809566 TI - Subglottal pressure oscillations accompanying phonation. AB - Acoustic and aerodynamic properties of the voice source and vocal tract have been extensively analyzed during the last half century. Corresponding investigations of the subglottal system are rare but can be assumed to be relevant to voice production. In the present exploratory study, subglottal pressure was recorded in a male adult subject by means of tracheal puncture. Also recorded were the oral airflow and audio signals. Effects of vowel, phonation type, and vocal register shifts on the subglottal pressure waveform were examined. The moment of maximum flow declination rate was synchronous with the main positive peak of the subglottal pressure waveform. The three lowest subglottal resonance frequencies, determined by inverse filtering and long-term average spectra of the subglottal pressure during speech, were found to be about 500, 1220, and 2000Hz, irrespective of supraglottal variations and phonation type. However, the subglottal pressure waveform was affected by the supraglottal formants, whereas the radiated vowel spectra did not show clear influence by the subglottal resonances. The fundamental frequency immediately preceding and immediately following a register break in pitch glides did not show systematic relationships with formants or with the lowest subglottal resonance. PMID- 23809567 TI - The effect of gender on measures of electroglottographic contact quotient. AB - OBJECTIVES/HYPOTHESIS: The purpose of this study was to reevaluate the possible effect of gender on measures of electroglottographic contact quotient (CQ). In addition to criterion threshold methods frequently used for the computation of CQ's via electroglottography (EGG), derivative based methods of computing the EGG CQ that have not been previously evaluated in regard to their effectiveness in discriminating between male versus female EGG waveforms were also examined. STUDY DESIGN: Causal, mixed design. METHODS: EGG waveforms were recorded during sustained vowel production from normal voice men and women (total N = 50). Measures of EGG CQ were calculated using eight criterion thresholds (25-60% in 5% increments). In addition, CQs were computed using the EGG derivative (DEGG) as well as via two hybrid methods that combine thresholds with measures from the DEGG. RESULTS: Only CQs calculated via the DEGG showed a statistically significant difference in the direction anticipated via previous research (ie, men > women). In addition, the DEGG was the only method to show statistically significant differences in CQ useful in discriminating between "knee"-shaped opening phases observed in 76% of the men versus no "knee" opening phases observed in 64% of the women. CONCLUSIONS: The DEGG may provide advantages over other methods of EGG CQ analysis that are useful in revealing possible gender differences in vocal physiology. Further studies that examine the relationship between EGG, DEGG, and visualization of vocal fold dynamics via high-speed video may provide further insight into the possible differences between adult male versus female contacting and decontacting points during comfortable pitch and loudness phonation. PMID- 23809568 TI - Phonatory characteristics of the excised human larynx in comparison to other species. AB - OBJECTIVE: The purpose of this study was to determine the conditions needed to elicit phonation from excised human larynges and the resultant range of phonations produced; compare that with similar information previously obtained from canine, pig, sheep, and cow; and relate those findings to previously reported information about viscoelastic properties of the vocal fold tissue (ie, stress-strain curves and Young's modulus). METHODS: Six human larynges of the geriatric group (age range, 70-89) were mounted on the bench without supraglottic structures, and phonation was achieved with the flow of heated and humidified air through the tracheal tube. Using various sutures to mimic the function of the laryngeal muscles, the larynges were put through a series of sustained oscillations with adduction as a control parameter. RESULTS: The human larynges oscillated with an average frequency that was close to the canine larynges, but the oscillation behavior and wide frequency range were similar to those of pig larynges. The similarity of the wide vibration frequency ranges of human and pig larynges may be because of the nonlinear behavior of their elasticity, which is related to the high collagen content of the vocal folds. On the contrary, other species with limited frequency ranges showed almost linear stress-strain curves because of the higher elastin and lower collagen contents. CONCLUSIONS: The physiological differences in the linearity and ranges of oscillation of excised larynges reported in this study and previous studies are reflective of the tissue composition and mechanics. PMID- 23809570 TI - Top-down mechanisms in dysphonia perception: the need for blind tests. AB - The purpose of this study was to determine the extent to which the information a therapist or a physician has about a dysphonic speaker, particularly whether he or she is in the pretreatment or posttreatment period, can influence judgments of the patient's voice. The voices of 53 dysphonic speakers were used in the study. For each speaker, we selected a pair of voice samples recorded under different circumstances. Seven listeners who were speech therapists, ear, nose, and throat surgeons, or voice pathologists took blind-listening tests in which they were asked to compare the two voices in each pair (phase 1: blind listening). A few weeks later, the listeners took the very same test again, except that this time, they were given bogus information about whether the speaker had/had not been treated by laryngeal surgery or speech therapy (phase 2: influenced listening). The information given for each voice sample either reinforced the judgment made in phase 1 (eg, the voice judged to be better on the blind test was said to be posttreatment) or countered that judgment (eg, the voice rated as better on the blind test was said to be pretreatment). The influenced-listening results showed that in the reinforced condition, the original ratings were significantly amplified. By contrast, in the countering-influence condition, decision changes were frequent: we found that judgment reversals and the countering-information scores were almost independent of the blind-listening scores. These findings point out the dire need to use a blind protocol in perceptual assessments of dysphonia. PMID- 23809569 TI - In Vivo measurement of pediatric vocal fold motion using structured light laser projection. AB - OBJECTIVE: The aim of the study was to present the development of a miniature structured light laser projection endoscope and to quantify vocal fold length and vibratory features related to impact stress of the pediatric glottis using high speed imaging. STUDY DESIGN: The custom-developed laser projection system consists of a green laser with a 4-mm diameter optics module at the tip of the endoscope, projecting 20 vertical laser lines on the glottis. Measurements of absolute phonatory vocal fold length, membranous vocal fold length, peak amplitude, amplitude-to-length ratio, average closing velocity, and impact velocity were obtained in five children (6-9 years), two adult male and three adult female participants without voice disorders, and one child (10 years) with bilateral vocal fold nodules during modal phonation. RESULTS: Independent measurements made on the glottal length of a vocal fold phantom demonstrated a 0.13mm bias error with a standard deviation of 0.23mm, indicating adequate precision and accuracy for measuring vocal fold structures and displacement. First, in vivo measurements of amplitude-to-length ratio, peak closing velocity, and impact velocity during phonation in pediatric population and a child with vocal fold nodules are reported. CONCLUSION: The proposed laser projection system can be used to obtain in vivo measurements of absolute length and vibratory features in children and adults. Children have large amplitude-to-length ratio compared with typically developing adults, whereas nodules result in larger peak amplitude, amplitude-to-length ratio, average closing velocity, and impact velocity compared with typically developing children. PMID- 23809571 TI - Wendler glottoplasty: an effective pitch raising surgery in male-to-female transsexuals. AB - OBJECTIVES: Evaluation of the voice results after Wendler glottoplasty in male-to female transsexuals (MFTs). STUDY DESIGN: Retrospective case series. METHODS: We retrospectively reviewed 31 MFT patients treated with a Wendler glottoplasty technique. The procedure consists of the CO2-laser de-epithelialization of the anterior commissure along with the anterior third of the two vocal folds, the suturing of the two vocal folds with two 3.0 resorbable threads, and next, the application of fibrin sealant to strengthen the stitches. Voice assessment was based mainly on fundamental frequency, frequency range, maximum phonation time, phonation quotient, estimated subglottic pressure (ESGP), grade of dysphonia (G), and voice handicap index. The measurements were performed preoperatively and on the last follow-up visit and compared using IBM SPSS 20 statistical package (IBM Corp, Armonk, NY). The patients have been divided in two groups (group A younger than 40 years and group B of or older than 40 years) for assessing the influence of the age of treatment on the results. RESULTS: Group A included 19 individuals with mean age of 28.6 years (range: 16-39 years) and group B included 12 individuals with mean age of 51.9 years (range: 45-59 years). The mean follow-up period was 9.2 months. Three cases had previously undergone a cricothyroid approximation elsewhere. We found a significant improvement of mean F0 from 135.8 to 206.3Hz in total (P = 0.001) and also in both groups, especially in group A (mean F0-postop = 213.8Hz). The mean frequency range had a tendency to decrease postoperatively, whereas the ESGP was significantly higher in both total sample and group A (P = 0.001, respectively). G was increased postoperatively and presented a statistical significance in group B (P = 0.035). A revision Wendler procedure was necessary for three individuals (9.7%); two of them presented a suture's line breakdown because they did not follow the postoperative recommendations for voice rest and the third one had an insufficient web due to an insufficient estimation of the necessary correction. CONCLUSION: Wendler glottoplasty seems to be an effective technique to feminize the voice in MFTs with better results when performed in younger individuals. PMID- 23809572 TI - Acoustic, aerodynamic, and perceptual analyses of the voice of cochlear-implanted children. AB - OBJECTIVES: The purposes of this study were to compare, from an acoustic approach, the voice of cochlear-implanted children and the one of deaf children using conventional hearing aids (HA) to a control group; to characterize, from an aerodynamic approach, the voice of congenital/prelingual profound deaf children wearing cochlear implants for at least 3 years and implanted before 3 years old; and to classify, from a perceptual approach, the voice of implanted children, of fitted children with conventional HA, and of normal hearing (NH) children as "normal or dysphonic voices." METHODS: We analyzed 78 voices of children aged 5 13 years using EVA 2 workstation: 38 children with NH, 40 deaf children wearing HA and cochlear implants for at least 3 years and being implanted before 3 years old. Acoustic parameters were measured from a sustained vowel /a/ and speech production and aerodynamic parameters from a set of 10 syllables /pa/. Perceptive assessment was performed by a jury of experienced listeners using G component of Hirano's GRBAS (Grade, Rough, Breathy, Asthenic, Strained) scale. RESULTS: Some acoustic parameters differ significantly between NH children and deaf children's groups with HA and cochlear implants, whereas other parameters are similar between control and cochlear-implanted groups. Analysis of aerodynamic parameters indicates that the phonatory physiological behavior of the implanted group is following an evolution within the norm. Finally, results of perceptual analysis reveal that the implanted group's voice samples can be classified in the first two grades (G0=9, G1=11, n=20) according to the G component (overall dysphonia) of the GRBAS scale. CONCLUSION: Cochlear implants may improve the majority of acoustic parameters of the voice better than HA for deaf children. Glottal and laryngeal efficiencies were significantly increased with the chronological age and the time of wearing an implant. Results suggest that voices of implanted children in our study do not reveal vocal characteristics traditionally used to determine the dysphonic voice. PMID- 23809573 TI - [Obstetric outcomes following LOOP-excision]. AB - The obstetrical consequences of conisation for cervical intraepithelial neoplasia (CIN) should be considered since patients affected by these lesions are actually younger and most often desire further pregnancies. The loop electrosurgical excision procedure (LEEP), which is currently mostly used, achieves cure rate varying according to the authors between 80 and 95%. However, the most recent data show an increase of obstetrical morbidity, especially prematurity, after LEEP excision. As the frequency and severity of prematurity is correlated to the size and depth of the LEEP, we should minimize as much as possible the resection for these young patients. PMID- 23809574 TI - Tube thoracostomy in trauma: is it time for a checklist for chest tubes? PMID- 23809575 TI - Myopericytoma of the external auditory canal and tragus. AB - BACKGROUND: Myopericytoma is a relatively recently described skin and soft tissue tumour that demonstrates perivascular myoid cell or pericytic differentiation. Whilst the range of anatomical locations has expanded to include visceral locations, head and neck myopericytomas are rarely documented. There have been no previous reports of aural myopericytoma. CASE REPORT: This paper reports the clinicopathological features of a biopsy-proven, slow-growing, 20 * 20 mm, polypoid myopericytoma that involved the external auditory canal and tragus in an 18-year-old woman. Excision was curative. CONCLUSION: Heightened clinicopathological awareness of the expanding anatomical distribution of myopericytoma is critical to its diagnosis when it presents in unusual and novel locations. Myopericytoma should be added to the range of external auditory canal neoplasms, especially those characterised by an admixture PMID- 23809576 TI - iBIG: an integrative network tool for supporting human disease mechanism studies. AB - Understanding the mechanism of complex human diseases is a major scientific challenge. Towards this end, we developed a web-based network tool named iBIG (stands for integrative BIoloGy), which incorporates a variety of information on gene interaction and regulation. The generated network can be annotated with various types of information and visualized directly online. In addition to the gene networks based on physical and pathway interactions, networks at a functional level can also be constructed. Furthermore, a supplementary R package is provided to process microarray data and generate a list of important genes to be used as input for iBIG. To demonstrate its usefulness, we collected 54 microarrays on common human diseases including cancer, neurological disorders, infectious diseases and other common diseases. We processed the microarray data with our R package and constructed a network of functional modules perturbed in common human diseases. Networks at the functional level in combination with gene networks may provide new insight into the mechanism of human diseases. iBIG is freely available at http://lei.big.ac.cn/ibig. PMID- 23809577 TI - Understanding the pathological mechanisms underpinning functional impairments in schizophrenia: gamma oscillations versus mismatch negativity (MMN) as mediating factors. PMID- 23809578 TI - Alpha-synuclein expression patterns in the colonic submucosal plexus of the aging Fischer 344 rat: implications for biopsies in aging and neurodegenerative disorders? AB - BACKGROUND: This experiment assessed normative expression patterns of alpha synuclein (SYNC), including ganglionic remodeling and development of SYNC pathologies, in the submucosal plexus (SMP) of the colon during healthy aging. The observations address age-associated changes in bowel function and are relevant to evaluations of SMP-containing colonic biopsies for SYNC or synucleinopathies associated with aging and peripheral neurodegenerative diseases. METHODS: Colonic submucosal whole mounts from groups of virgin male Fischer 344 rats (n >= 8 per group) at 4, 8, 16, and 24 months of age were processed immunohistochemically for SYNC and the pan-neuronal marker HuC/D. In addition, macrophages immunoreactive for MHCII were examined. Stereological protocols were used to generate unbiased estimates of neuron density, neurons per ganglion, neurons per ganglionic area, and neuron size. KEY RESULTS: The protein SYNC was expressed in a subpopulation of SMP neurons, in both nucleus and cytoplasm. The general age-associated pattern across different cell counts was an increase in the number of SYNC+ neurons between 4 and 8 months of age, with progressively decreasing numbers of both SYNC+ and SYNC- neurons over the remaining lifespan. The soma size of SYNC+ neurons increased progressively with age. Aggregated SYNC occurred in the aging SMP, and macrophages with alternatively activated profiles were located adjacent to pathological SYNC deposits, consistent with ongoing phagocytosis. CONCLUSIONS & INFERENCES: Changes in SYNC expression with age, including a baseline of accumulating synucleinopathies in the healthy aging SMP, need to be considered when interpreting either functional disturbances or biopsies of the aging colon. PMID- 23809579 TI - Collaborative approaches towards building midwifery capacity in low income countries: a review of experiences. AB - OBJECTIVE: to explore collaborative approaches undertaken to build midwifery education, regulation and professional association in low income countries and identify evidence of strategies that may be useful to scale-up midwifery to achieve MDG 5. DESIGN: an integrative review involving a mapping exercise and a narrative synthesis of the literature was undertaken. The search included peer reviewed research and discursive literature published between 2002 and 2012. FINDINGS: fifteen papers were found that related to this topic: 10 discursive papers and five research studies. Collaborative approaches to build midwifery capacity come mainly from Africa and involve partnerships between low income countries and between low and high income countries. Most collaborations focus on building capacity across more than one area and arose through opportunistic and strategic means. A number of factors were found to be integral to maintaining collaborations including the establishment of clear processes for communication, leadership and appropriate membership, effective management, mutual respect, learning and an understanding of the context. Collaborative action can result in effective clinical and research skill building, the development of tailored education programmes and the establishment of structures and systems to enhance the midwifery workforce and ultimately, improve maternal and child health. KEY CONCLUSIONS: between country collaborations are one component to building midwifery workforce capacity in order to improve maternal health outcomes. IMPLICATIONS FOR PRACTICE: the findings provide insights into how collaboration can be established and maintained and how the contribution collaboration makes to capacity building can be evaluated. PMID- 23809580 TI - Factors affecting the quality of antenatal care provided to remote dwelling Aboriginal women in northern Australia. AB - OBJECTIVE: there is a significant gap in pregnancy and birth outcomes for Australian Aboriginal and Torres Strait Islander women compared with other Australian women. The provision of appropriate and high quality antenatal care is one way of reducing these disparities. The aim of this study was to assess adherence to antenatal guidelines by clinicians and identify factors affecting the quality of antenatal care delivery to remote dwelling Aboriginal women. SETTING AND DESIGN: a mixed method study drew data from 27 semi-structured interviews with clinicians and a retrospective cohort study of Aboriginal women from two remote communities in Northern Australia, who gave birth from 2004-2006 (n=412). Medical records from remote health centres and the regional hospital were audited. MEASUREMENTS AND FINDINGS: the majority of women attended antenatal care and adherence to some routine antenatal screening guidelines was high. There was poor adherence to local guidelines for follow-up of highly prevalent problems including anaemia, smoking, urinary tract infections and sexually transmitted infections. Multiple factors influenced the quality of antenatal care. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: the resourcing and organisation of health services and the beliefs, attitudes and practices of clinicians were the major factors affecting the quality of care. There is an urgent need to address the identified issues in order to achieve equity in women's access to high quality antenatal care with the aim of closing the gap in maternal and neonatal health outcomes. PMID- 23809581 TI - Independent factors associated with altered plasma active ghrelin levels in HCV infected patients. AB - BACKGROUND & AIMS: Metabolic disorders are frequently seen in hepatitis C virus (HCV)-infected patients. Ghrelin, a gut hormone, regulates hepatic metabolisms, and must be activated to exert its biological effects. The aims of this study were to investigate changes in plasma active ghrelin levels and identify independent factors associated with plasma active ghrelin levels in HCV-infected patients. METHODS: We enrolled patients with HCV infection (n = 96), hepatitis B virus (HBV) infection (n = 49), non-alcoholic fatty liver disease (NAFLD; n = 20) and healthy subjects (CON; n = 16). Plasma active ghrelin levels were measured using ELISA. Factors associated with plasma active ghrelin levels were assessed by multivariate and Spearman's correlation analyses. RESULTS: Plasma active ghrelin levels were significantly lower in relation to the severity of liver disease in both the HBV and HCV groups. Furthermore, HCV infection was identified as an independent factor associated with decreased plasma active ghrelin levels in the multivariate analysis (OR -3.05; 95% CI -0.93 to -19.51; P = 0.0192). Plasma active ghrelin levels were significantly correlated with serum albumin levels in the HCV group (rho = 0.497, P < 0.0001). CONCLUSIONS: We demonstrated that liver cirrhosis and HCV infection were independent factors associated plasma active ghrelin levels. Moreover, plasma active ghrelin levels were positively correlated with serum albumin levels among HCV-infected patients. Therefore, active ghrelin levels may be regulated by both progression of liver disease and HCV infection and could be involved in the regulation of serum albumin levels in HCV-infected patients. PMID- 23809582 TI - Molecular analysis of appendiceal mucinous cystadenoma and rectal adenocarcinoma in a patient with urothelial carcinoma: a case report. AB - INTRODUCTION: In this report, we present the case of a patient affected by appendiceal cystadenoma, a colorectal adenocarcinoma, and a concomitant bladder carcinoma, as well as the results of the molecular study of the most relevant mutational pathways involved in these tumors. CASE PRESENTATION: A 68-year-old Italian man was admitted to our unit complaining of macrohematuria, rectorrhagia, and rectal tenesmus for about 2 months. A colonoscopy showed the presence of a rectal lesion at 11cm from the anal margin; multiple biopsies were performed and a diagnosis of moderately differentiated adenocarcinoma was made. Abdominal ultrasonography and total body computed tomography performed subsequently to stage the rectal cancer showed the presence of two round nodules, interpreted as swollen lymph nodes of neoplastic origin, at the anterior aspect of the iliopsoas muscle and a budding lesion affecting the bladder. The patient underwent transurethral biopsy of the lesion in the right retrotrigonal region; the diagnosis was grade II urothelial carcinoma. The patient underwent an open anterior rectal resection with loco-regional lymphadenectomy. An enlarged appendix and a voluminous whitish soft-tissue lesion requiring an appendicectomy were detected perioperatively. Transurethral resection of the bladder lesion was also performed. The histological examination revealed that the nodular lesions in the appendix were due to a cystadenoma. For mutation analysis, genomic deoxyribonucleic acid was isolated from tumor tissue samples; for PIK3CA mutations, screening revealed that all three samples analyzed carried mutations in exon 9. CONCLUSIONS: Appendiceal mucoceles are rare but require adequate surgical treatment, given their malignant potential and the possibility of causing peritoneal pseudomyxoma. It is essential to make a correct preoperative evaluation based on a colonoscopy rather than ultrasound and computed tomography to exclude synchronous neoplasias often associated with mucoceles and to plan the optimum surgical strategy. The association between appendiceal mucoceles and other neoplasias is relatively frequent, especially with colorectal cancer. Oncogenic activation in the PIK3CA-depending pathway may contribute substantially to the pathogenesis of the different solid tumors in the same patient. PMID- 23809584 TI - Successful treatment of leiomyoma of the nipple with carbon dioxide laser. PMID- 23809583 TI - Prevalence of dystrophic epidermolysis bullosa in Spain: a population-based study using the 3-source capture-recapture method. Evidence of a need for improvement in care. AB - BACKGROUND: Dystrophic epidermolysis bullosa (DEB) is a rare disease that represents a heavy burden for both the patient and the health care system. There are currently no data on the prevalence of DEB in Spain. OBJECTIVE: To determine the prevalence of DEB in Spain. METHODS: We used data from 3 incomplete population-based sources (hospital dermatology departments, diagnostic laboratories performing antigenic mapping, genetic testing or both, and the Spanish Association of Epidermolysis Bullosa Patients [DEBRA]) and combined them using the 3-source capture-recapture methodology. RESULTS: We identified 152 living DEB patients. The estimated prevalence of DEB was 6.0 cases per million (95% CI, 4.2-11.8) in adults and 15.3 (95% CI, 10.4-40.8) in children under 18 years of age. The data indicated that 77% of the patients were not being followed up in specialized centers of reference; 65% had not had a genetic diagnosis, and 76% were not members of DEBRA. CONCLUSIONS: The prevalence of DEB in Spain is 6.0 patients per million (95% CI, 4.2-11.8), a figure higher than previous estimates in many areas, but similar to those found in other southern Europe countries. The north-south difference may represent real geographic differences in prevalence, but it might be due to the fact that most of the data come from registries with a lower than expected catchment. Many patients are not being followed up in centers of reference, do not have genetic diagnosis, and are not members of patients' associations, suggesting that there is room for considerable improvement in their care. PMID- 23809585 TI - Restoration of response to ustekinumab with narrowband UV-B phototherapy. PMID- 23809586 TI - Lichenoid graft-vs-host disease with exclusively cutaneous involvement after liver transplant. PMID- 23809587 TI - Biomaterial-based interventions for neuronal regeneration and functional recovery in rodent model of spinal cord injury: a systematic review. AB - CONTEXT: There is considerable interest in translating laboratory advances in neuronal regeneration following spinal cord injury (SCI). A multimodality approach has been advocated for successful functional neuronal regeneration. With this goal in mind several biomaterials have been employed as neuronal bridges either to support cellular transplants, to release neurotrophic factors, or to do both. A systematic review of this literature is lacking. Such a review may provide insight to strategies with a high potential for further investigation and potential clinical application. OBJECTIVE: To systematically review the design strategies and outcomes after biomaterial-based multimodal interventions for neuronal regeneration in rodent SCI model. To analyse functional outcomes after implantation of biomaterial-based multimodal interventions and to identify predictors of functional outcomes. METHODS: A broad PubMed, CINHAL, and a manual search of relevant literature databases yielded data from 24 publications; 14 of these articles included functional outcome information. Studies reporting behavioral data in rat model of SCI and employing biodegradable polymer-based multimodal intervention were included. For behavioral recovery, studies using severe injury models (transection or severe clip compression (>16.9 g) or contusion (50 g/cm)) were categorized separately from those investigating partial injury models (hemisection or moderate-to-severe clip compression or contusion). RESULTS: The cumulative mean improvements in Basso, Beattie, and Bresnahan scores after biomaterial-based interventions are 5.93 (95% CI = 2.41 - 9.45) and 4.44 (95% CI = 2.65 - 6.24) for transection and hemisection models, respectively. Factors associated with improved outcomes include the type of polymer used and a follow-up period greater than 6 weeks. CONCLUSION: The functional improvement after implantation of biopolymer-based multimodal implants is modest. The relationship with neuronal regeneration and functional outcome, the effects of inflammation at the site of injury, the prolonged survival of supporting cells, the differentiation of stem cells, the effective delivery of neurotrophic factors, and longer follow-up periods are all topics for future elucidation. Future investigations should strive to further define specific factors associated with improved functional outcomes in clinically relevant models. PMID- 23809588 TI - Active-resisted stance modulates regional bone mineral density in humans with spinal cord injury. AB - OBJECTIVE: In people with spinal cord injury (SCI), active-resisted stance using electrical stimulation of the quadriceps delivered a therapeutic stress to the femur (~150% of body weight) and attenuated bone mineral density (BMD) decline. In standard densitometry protocols, BMD is averaged over the entire bone cross section. An asymmetric adaptation to mechanical load may be masked by non responding regions. The purpose of this study was to test a novel method to assess regional BMD of the femur in individuals with SCI. We hypothesize that there will be regional bone-sparing changes as a result of active-resisted stance. DESIGN: Mixed cross-sectional and longitudinal. SETTING: Research laboratory. PARTICIPANTS: Twelve individuals with SCI and twelve non-SCI controls. INTERVENTION: Individuals with SCI experienced active-resisted stance or passive stance for up to 3 years. OUTCOME MEASURES: Peripheral quantitative computed tomography images from were partitioned so that femur anatomic quadrants could be separately analyzed. RESULTS: Over 1.5 years, the slope of BMD decline over time was slower at all quadrants for the active-resisted stance limbs. At >2 years of training, BMD was significantly higher for the active-resisted stance group than for the passive stance group (P = 0.007). BMD was preferentially spared in the posterior quadrants of the femur with active-resisted stance. CONCLUSIONS: A regional measurement technique revealed asymmetric femur BMD changes between passive stance and active-resisted stance. Future studies are now underway to better understand other regional changes in BMD after SCI. PMID- 23809589 TI - Correlation between time to diagnosis and rehabilitation outcomes in patients with spinal dural arteriovenous fistula. AB - BACKGROUND: Spinal dural arteriovenous fistulas (SDAVFs) are the most common spinal vascular malformations and can be a significant cause of myelopathy although they are under diagnosed. Surgical or embolization treatment of SDAVFs improved significantly in the last decade. However, a high percentage of patients are still left with severe disability. OBJECTIVE: To describe the correlation between time to diagnosis and the rehabilitation outcomes of eight patients with SDAVFs. DESIGN: Retrospective chart study of all SDAVF patients in 20 years. SETTING: A tertiary university rehabilitation center. MAIN OUTCOME MEASURES: The lower extremities motor score (LEMS), Functional Independence Measure (FIM), Spinal Cord Independence Measure (SCIM) and Walking Scale for Spinal Cord Injury (WISC II). Overall prognosis was evaluated using the Aminoff-Logue scale (ALS). RESULTS: There were seven men and one woman with mean age of 61.3 +/- 15 (30-72) and mean time until the diagnosis of SDAVF of 265.5 +/- 245 days (4-730). At the end of rehabilitation period, five of the eight patients remained wheelchair dependent. Strong correlation was found between LEMS, FIM, SCIM, and WISC II scores and the functional level according to the ALS scale. A significant correlation was found between time to diagnosis and the height of the SDAVF, the clinical and rehabilitation outcomes. Patients with high SDAVF which were diagnosed late had the poorest prognosis. CONCLUSIONS: The potential for functional ambulation in patients with SDAVF is related to the time of intervention. This finding emphasizes the important of early diagnosis and early intervention in SDAVF. PMID- 23809590 TI - Surgery for constipation in patients with prior spinal cord injury: the Department of Veterans Affairs experience. AB - OBJECTIVE: Patients with spinal cord injury (SCI) typically have difficulty with constipation. Some undergo surgery for bowel management. We predicted that SCI patients would have higher mortality and/or morbidity rates following such surgery than neurally intact patients receiving the same procedures. We sought to evaluate this using a large population-based data set. METHODS: Patients receiving care at Department of Veterans Affairs Medical Centers (DVAMCs) with computer codes for SCI and constipation who later underwent colectomy, colostomy, or ileostomy during fiscal years 1993-2002 were identified. Charts were requested from the VAMCs where the surgery had been performed and a retrospective chart review of these charts was done. We collected data on patient demographics, six specific pre-operative co-morbidities, surgical complications, and post-operative mortality. Comparisons were made to current literature evaluating a population receiving total abdominal colectomy and ileorectal anastomosis for constipation but not selected for SCI. RESULTS: Of 299 patients identified by computer search, 43 (14%) had codes for SCI and 10 of 43 (24%) met our inclusion criteria. All were symptomatic and had received appropriate medical management. Co-morbid conditions were present in 9 of 10 patients (90%). There were no deaths within 30 days. The complication rate was zero. The mean post-operative length of stay was 17 days. CONCLUSIONS: Patients with SCI comprise about 14% of the population who receive surgery for severe constipation in the Department of Veterans Affairs system. The mortality and morbidity rates in these patients are similar to those reported in other constipated patients who have surgery for intractable constipation. Our data suggest that stoma formation +/- bowel resection in patients with SCI is a safe and effective treatment for chronic constipation. PMID- 23809591 TI - Post-operative spinal epidural hematoma causing American Spinal Injury Association B spinal cord injury in patients with suction wound drains. AB - BACKGROUND: Subfascial wound suction drains are commonly used after spinal surgery to decrease the incidence of post-operative hematoma. However, there is a paucity of literature regarding their effectiveness. OBJECTIVE: To report four cases of post-operative spinal epidural hematoma causing massive neurological deficit in patients who had subfascial suction wound drains. METHODS: During an 8 year period, a retrospective review of 1750 consecutive adult spinal surgery cases was performed to determine the incidence, commonalities, and outcomes of catastrophic neurological deficit caused by post-operative spinal epidural hematoma. FINDINGS: Epidural hematoma causing major neurological deficit (American Spinal Injury Association B) was identified in 4 out of 1750 patients (0.23%). All four patients in this series had subfascial wound suction drains placed prophylactically at the conclusion of their initial procedure. RESULTS: Three patients developed massive neurological deficits with the drain in place; one patient had the drain removed at 24 hours and subsequently developed neurological symptoms during the following post-operative day. Significant risk factors for the development of hematoma were identified in two of the four patients. Average time to return to the operating room for hematoma evacuation was 6 hours (range 3-12 hours). Neurological status significantly improved in all four patients after hematoma evacuation. CONCLUSIONS: Post-operative epidural hematoma causing catastrophic neurological deficit is a rare complication after spinal surgery. The presence of suction wound drains does not appear to prevent the occurrence of this devastating complication. PMID- 23809592 TI - Isolated osteoblasts from spinal cord-injured rats respond less to mechanical loading as compared with those from hindlimb-immobilized rats. AB - BACKGROUND: The pathogenesis of osteoporosis after spinal cord injury (SCI) may be different from disuse osteoporosis. OBJECTIVE: To investigate whether there is the differential anabolic response to mechanical loading between osteoblasts from SCI rats and those from hindlimb-immobilized rats. METHODS: Femoral bone-marrow was harvested for osteoblast culture from SCI rats, hindlimb-immobilized rats, and control rats 3 weeks after animal model creation. At the stage of differentiation, rat osteoblasts were plated in six-well plates for stretching. Cyclic strains were applied for 48 hours, and then alkaline phosphatase (ALPase) activity, procollagen, and osteocalcin production, and gene expression of osteocalcin, runt-related transcription factor 2 (Runx2), and osterix were measured in osteoblasts from SCI rats, hindlimb-immobilized rats, and control rats. RESULTS: ALPase activity, procollagen, and osteocalcin production, and gene expression of osteocalcin, Runx2, and osterix were significantly lower in osteoblasts after stretching from SCI rats compared with those from hindlimb immobilized rats. However, there was no significant difference of these parameters between isolated osteoblasts from hindlimb-immobilized rats and those from control rats. CONCLUSION: The activity of isolated osteoblasts from SCI rats was lower than control rats, and this suggested that osteoblasts from SCI rats responded less to mechanical loading as compared with those from control rats. PMID- 23809593 TI - Skin thickness on bony prominences measured by ultrasonography in patients with spinal cord injury. AB - OBJECTIVE: The detailed assessment of soft tissues over bony prominences and identification of methods of predicting pressure sores would improve the quality of care for patients with spinal cord injury (SCI). Comparing skin thicknesses on bony prominences in patients with SCI to those in healthy individuals will represent, to our knowledge, the first study aimed at determining whether differences in skin thicknesses between these groups can be detected by ultrasound. DESIGN: In both patients and controls, skin thicknesses on the sites at risk for pressure ulcers - sacrum, greater trochanter, and ischium - were evaluated using high-frequency ultrasound. The waist was also evaluated by the same method for control as it was considered to be a pressure-free region. PARTICIPANTS: Thirty-two patients with complete thoracic SCI and 34 able-bodied individuals. RESULTS: The skin was significantly thinner over the sacrum and ischial tuberosity in individuals with SCI compared with healthy individuals. No significant differences were observed in skin thicknesses over the greater trochanter or the waist between the two groups. CONCLUSIONS: Protecting skin integrity in patients with paraplegia is challenging due to many contributing factors, such as prolonged pressure, frictional/shearing forces, and poor nutrition. Thinning of the skin can increase the risk of soft tissue damage, leading to pressure ulcers. The significant differences in skin thickness at the sacrum and ischium provide the basis for establishing the early signs of pressure damage. Measuring skin thickness by ultrasound is a reliable non-invasive method that could be a promising tool for predicting pressure ulcers. PMID- 23809594 TI - Messenger RNA expression patterns of p75 neurotrophin receptor and tropomyosin receptor-kinase A following spinal cord injury. AB - BACKGROUND: Induction of p75 neurotrophin receptor (p75NTR) could be one of the first steps that initiate apoptotic cascade after injury, or it may indicate regeneration responses undertaken by the injured system, possibly in collaboration with resident tropomyosin-receptor-kinase (Trk). OBJECTIVE: To measure quantitative changes in messenger RNA (mRNA) expression levels of p75NTR, Trk A, and caspase-9 in rat's injured spinal cord (SCI). The reciprocal interaction between Trk and p75NTR signaling pathways can dictate cellular responses to neurotrophins. p75NTR can regulate Trk-dependent responses, but the role of Trk in regulating p75NTR-dependent signaling is not well documented. DESIGN: Using real-time polymerase chain reaction, this study analyzed changes in the mRNA abundance of the mentioned genes at 6, 24, and 72 hours and 7 and 10 days after SCI in adult male rats. SCI was induced at T9 level by transsection. RESULTS: Results show a complicated temporal and spatial pattern of alteration with different degrees and direction (up- or down-regulation) in p75NTR, Trk A, and caspase-9 mRNA expression levels after SCI. The greatest variation was seen in center regions following SCI. This study shows that alteration in p75NTR, Trk A, and caspase-9 expression starts as early as 6 hours after SCI. Alterations in p75NTR, Trk A, and caspase-9 expression within the spinal cord may play a key role in the apoptotic cell death. CONCLUSION: Results suggest that the role of p75NTR is to eliminate damaged cells by activating the apoptotic machinery, especially at the center of damage and during first week after injury. PMID- 23809595 TI - Factors affecting the length of stay of patients with traumatic spinal cord injury in Tianjin, China. AB - PURPOSE: To describe the acute care length of stay (ACLOS) of adult patients with traumatic spinal cord injury (TSCI) in Tianjin, China, and identify the associated demographic and clinical factors. METHODS: TSCI patients admitted to a general hospital in Tianjin, China from 2004 to 2007 were identified. The predictor variables were demographic and clinical factors, including age, gender, etiology, level of injury, severity, associated injuries, surgery, and complications. The outcome variable was ACLOS. Multivariable linear regression analysis models were used to examine the association between predictor and outcome variables. RESULTS: This study included 631 TSCI patients. The mean ACLOS was 32.4 +/- 37.7 days, with a range of 1-294 days. The median number of hospitalization days was 21 days. Admission to a suburban hospital surgery, urinary infection, poorer functional status, pressure ulcers, and associated injuries were significantly associated with ACLOS. CONCLUSION: This study examined the effect of epidemiological and clinical factors on ACLOS in Tianjin, China. The factors that influenced the ACLOS were different from factors reported in other studies. More studies are needed in China to determine the effect of these factors on ACLOS in TSCI patients and to propose a predictive model. PMID- 23809596 TI - Bilateral upper-extremity deep vein thrombosis following central cord syndrome. AB - Deep vein thrombosis (DVT) is a common complication following spinal cord injury (SCI). Although DVT of the upper extremity is much less common than DVT of the lower extremities, the risk of pulmonary embolism following upper-extremity DVT should not be disregarded. METHOD: Case report. FINDINGS: A bilateral upper extremity DVT developed in a 51-year-old woman with SCI (central cord syndrome) being followed in our rehabilitation clinic. Medical treatment resulted in improvement in the clinical status of the patient as well as the regression in the thrombus. CONCLUSION: In patients with SCI, DVT should be kept in mind in the presence of pain and edema in the upper extremities, and prophylactic DVT treatment should be considered. PMID- 23809597 TI - Post-myelography paraplegia in a woman with thoracic stenosis. AB - CONTEXT: Myelography is a commonly performed diagnostic test used to assess spine pathology. Complications are unusual and usually self-limited. We report a rare case of transient paraplegia following myelography in a woman with thoracic stenosis. FINDINGS: A 51-year-old woman, 20 months status post-thoracic laminectomy, presented with progressive lower extremity weakness. The patient underwent myelography and post-myelography CT, and became paraplegic after the lumbar injection. Intravenous steroids were administered and a lumbar puncture was performed. The patient's neurologic function returned to baseline over the next 96 hours. CONCLUSION AND CLINICAL RELEVANCE: Myelography is generally a safe procedure, but on rare occasions serious complications can arise. Therapeutic maneuvers may be helpful in reversing neurologic deficit. PMID- 23809598 TI - Autonomic dysreflexia-induced reversible posterior leukoencephalopathy syndrome in patients with spinal cord injury: two case reports. AB - BACKGROUND/OBJECTIVES: To report two cases of reversible posterior leukoencephalopathy syndrome (RPLS) in patients with traumatic cervical spinal cord injury. DESIGN: Case report. SETTING: Rehabilitation Inpatient Unit, Pusan National University Hospital, Yangsan-si, Korea. RESULTS: Two men with spastic tetraplegia developed autonomic dysreflexia. Use of antihypertensive medication and Foley catheter insertion prevented further episodes of acute arterial hypertension and development of new symptoms. CONCLUSION: RPLS can occur in the setting of autonomic dysreflexia in patients with traumatic cervical cord injury. The prompt recognition of this syndrome is of importance to prevent further morbidity and mortality in patients with spinal cord injury. PMID- 23809599 TI - Editor's note. PMID- 23809600 TI - Nursing's contribution to research about parenting children with complex chronic conditions: an integrative review, 2002 to 2012. AB - Children with complex chronic conditions (CCC) need extensive, costly care, usually provided at home by parents. These children often rely on technology to survive or avoid complications. Children with CCC receive nursing care in hospital, community, and home settings. An integrative review of 22 nursing studies, from 2002 to 2012, of parenting for children with CCC was conducted to synthesize nursing research addressing parenting a child with a CCC and identify promising areas for future inquiry and development of supportive interventions and policies. Criteria for sampling in these studies were reviewed, and an updated definition for children with CCC is offered to replace an outdated definition of "medically fragile" children. Findings include the extensive impacts of providing complex care at home, including the tension between the difficulties and recognition of the rewards of providing that care. Disruptions occurred in emotional, role development, social, and moral realms. PMID- 23809601 TI - Internationally educated nurses in the United States: Their origins and roles. AB - Despite the importance of the internationally educated nurse (IEN) workforce, there has been little research on the employment settings of IENs and other aspects of their employment. We analyzed data from the 2008 National Sample Survey of Registered Nurses to characterize IENs in the United States using descriptive statistics and multivariate ordinary least squares regression. We find notable differences in the decade of immigration, current age, and highest nursing education across the countries in which IENs were educated. IENs are more likely to be employed in nursing and to work full-time. They receive higher total annual earnings and earn higher average hourly wages. However, when demographic, human capital, and employment characteristics are held constant, IENs from every country except Canada earn no more than U.S.-educated nurses. Future research should seek to identify the causes of these employment and earnings differences to understand the role and impact of the IEN workforce. PMID- 23809602 TI - Childhood sexual abuse moderates the relationship between sexual functioning and eating disorder psychopathology in anorexia nervosa and bulimia nervosa: a 1-year follow-up study. AB - INTRODUCTION: Sexual dysfunctions that affect all aspects of sexuality are common in patients with eating disorders. However, only few studies have provided longitudinal information on sexual functioning in patients with eating disorders. AIM: To evaluate the longitudinal course of sexual functioning, and how changes in psychopathology and history of childhood abuse interact with sexual functioning in patients with anorexia nervosa (AN) and bulimia nervosa (BN). METHODS: A total of 27 patients with AN and 31 with BN were assessed at baseline and at 1-year follow-up after a standard individual cognitive behavioral therapy (CBT). MAIN OUTCOME MEASURES: Subjects were studied by means of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders IV, Female Sexual Function Index (FSFI), Eating Disorder Examination Questionnaire, Beck Depression Inventory, Spielberg's State-Trait Anxiety Inventory, Symptom Checklist-90, and Childhood Experience of Care and Abuse Questionnaire. RESULTS: After treatment, both patients with AN and BN showed a significant improvement in the FSFI total score (P < 0.01 for both AN and BN) and all FSFI subscales, without significant between groups differences. Patients reporting childhood sexual abuse did not show a significant improvement in sexual functioning (beta = 0.05; P = 0.58). Reduction in eating disorder severity was directly associated with FSFI improvement, but only in those subjects with no history of sexual abuse (beta = 0.28; P = 0.01). CONCLUSIONS: Eating disorder-specific psychopathology could be considered as a specific maintaining factor for sexual dysfunction in eating disorders subjects. Subjects reporting a history of childhood sexual abuse represent a subpopulation of patients with a profound uneasiness, involving body perception, as well as sexual functioning, which appeared not to be adequately challenged during standard CBT intervention. The results, though original, should be considered as preliminary, given the relatively small sample size. PMID- 23809603 TI - Buddhist religious practices and blood pressure among elderly in rural Uttaradit Province, northern Thailand. AB - The purpose of this study was to test the relationship between Buddhist religious practices and blood pressure. A cross-sectional survey of Buddhist religious practices and blood pressure was conducted with 160 Buddhist elderly in rural Uttaradit, northern Thailand. After controlling for the variables of gender, status, education, salary, underlying hypertension, exercise, salt intake, and taking antihypertensive medications, it was found that lower systolic and diastolic blood pressure is associated with the Buddhist religious practice of temple attendance. The Buddhist older people who regularly attended a temple every Buddhist Holy day (which occurs once a week) were found to have systolic and diastolic blood pressure readings lower than people who did not attend as regularly. It is recommended that nurses advocate for temple attendance in the care protocols for older Buddhist hypertensive patients both in Thailand and internationally. PMID- 23809604 TI - The corpus callosum: imaging the middle of the road. PMID- 23809605 TI - Off-targets effects underlie the inhibitory effect of FAK inhibitors on platelet activation: studies using Fak-deficient mice. PMID- 23809606 TI - HIV or human papillomavirus co-infection among Brazilian individuals infected with hepatitis B and/or hepatitis C. AB - OBJECTIVE: To investigate the incidence of co-infection with HIV and human papillomavirus (HPV) among Brazilian individuals with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. METHODS: A prospective study was conducted that enrolled 103 individuals from the Ceara region of Brazil between January 4, 2010, and August 9, 2012. Eligible participants were men (n=45) or women (n=58) infected with HBV and/or HCV. Pap smears were collected from female patients. Material from male (urethra) and female (cervix) patients was then collected via DNA-HPV test and visual inspection with acetic acid. RESULTS: In all, 48 participants tested positive for HBV and 55 tested positive for HCV; 2 had dual infection with HBV and HCV. Co-infection with HIV was detected among 15 participants, whereas 20 participants were found to be co-infected with HPV. CONCLUSION: A high prevalence of co-infection with HIV and HPV was detected among Brazilian individuals with HBV and/or HCV. PMID- 23809607 TI - Perioperative risks associated with the operative treatment of clavicle fractures. AB - BACKGROUND: Clavicle fractures are a common injury among young adults who were historically treated non-operatively with satisfactory outcomes. However, more recent studies have shown a higher nonunion rate for displaced clavicle fractures treated conservatively. The purpose of this study is to investigate the midterm complications, clinical outcomes and overall patient satisfaction after osteosynthesis of midshaft clavicular fractures. PATIENTS AND METHODS: A total of 37 patients treated for a clavicle fracture from January 2007 to December 2008 with at least 12 months' follow-up were identified from a billing code search. At the latest follow-up appointment, the patients completed the Constant Shoulder, the Disabilities of the Arm, Shoulder and Hand scale (DASH) and the Medical Outcomes Study 36-Item Short-Form Health Survey version 2.0 (SF36v2) functional outcome surveys as well as a custom questionnaire to assess hand dominance, employment status, the amount of time taken before returning to work, the presence of numbness around the incision site (a surrogate marker of a supraclavicular nerve palsy), whether the patient desired the plate removed and/or if it was worth another surgery. RESULTS: With regard to the functional outcome surveys, the average DASH score was 11.8 +/- 16.4, the Constant score was 93.3 +/- 7.2, the SF36v2 physical component summary (PCS) was 50.7 +/- 10.1 and the SF36v2 mental component summary (MCS) 50.6 +/- 11.2. From the custom questionnaire, 27 patients (73%) found their cosmetic appearance acceptable while the remaining 10 patients (27%) were bothered by the appearance of the plate. The average time to return to work was 82.1 +/- 77.4 days. There were no infections, refractures or nonunions of the clavicle. CONCLUSION: As the relative indications for open reduction and internal fixation of clavicle fractures become more popular, such as cosmetic concerns or faster recovery, we wish to demonstrate that the procedure is not without risks, including implant discomfort requiring a subsequent operation for removal, numbness around the incision site and infection. Despite these risks, patients tend to be satisfied with the procedure and are able to function at levels equal to that of the general population. The purpose of this study is not to recommend for or against operative treatment of clavicle fractures but merely to demonstrate risks associated with the procedure. PMID- 23809608 TI - Is prophylactic Gentamicin associated with acute kidney injury in patients undergoing surgery for fractured neck of femur? PMID- 23809609 TI - Report of the first Asia-Pacific influenza summit, Asia-Pacific Alliance for the Control of Influenza (APACI), Bangkok, 12-13 June 2012. AB - On June 12-13, 2012, the Asia-Pacific Alliance for the Control of Influenza (APACI) convened jointly with the Influenza Foundation of Thailand and the Thailand Department of Disease Control, the First Asia-Pacific Influenza Summit. The objectives of the meeting were to review the current state of official influenza control policies in Asia-Pacific countries; identify, summarize and communicate influenza control strategies that have successfully increased vaccine uptake in the region; develop policy and advocacy approaches to improve influenza vaccine uptake in high-risk groups and healthcare workers in the region; and establish collaborative relationships to promote best practices for the control of influenza. In moving forward, the challenge for the region will be establishing collaborations able to effectively communicate risk and key messages about influenza vaccination. PMID- 23809610 TI - Varix of the retromandibular vein within the parotid gland: case study. AB - OBJECTIVE: To report a case of varix of the retromandibular vein within the parotid gland. METHODS: Case report, and discussion of the appropriate selection and use of radiological investigation techniques. RESULTS: A 64-year-old lady who presented with unilateral tinnitus underwent a magnetic resonance imaging scan to exclude a vestibular schwannoma. The magnetic resonance scout images revealed an incidental finding of a hyperechoic mass within the parotid gland. The mass was most consistent with a pleomorphic adenoma. Ultrasound-guided fine needle aspiration cytology was arranged; the ultrasound identified the mass as a varix of the retromandibular vein and fine needle aspiration cytology was not performed. CONCLUSION: A varix of the retromandibular vein is a very rare cause of a parotid mass. Appropriate radiological investigations can prevent unnecessary invasive investigations or procedures. PMID- 23809611 TI - [Anomalous mineralization: how and why cardiovascular tissue can mineralize it?]. PMID- 23809612 TI - Biomechanical analysis for primary stability of shoulder arthrodesis in different resection situations. AB - BACKGROUND: Only very few publications dealing with shoulder arthrodesis after bone resection procedures and no biomechanical studies are available. The presented biomechanical analysis should ascertain the type of arthrodesis with the highest primary stability in different bone loss situations. METHODS: On 24 fresh cadaveric shoulder specimens three different bone loss situations were investigated under the stress of abduction, adduction, anteversion and retroversion without destruction by the use of a material testing machine. In each of the testings a 16-hole reconstruction plate was used and compared to arthrodesis with an additional dorsal 6-hole plate. FINDINGS: The primary stability of shoulder arthrodesis with a 16-hole reconstruction plate after humeral head resection could be increased significantly if an additional dorsal plate was used. However, no significant improvement with the additional plate was detected after resection of the acromion. Of all investigated forms, arthrodesis after humeral head resection with additional plate showed the highest and arthrodesis after humeral head resection without additional plate showed the lowest force values. The mean values for forces achieved in abduction and adduction were considerably higher than those in anteversion and retroversion. INTERPRETATION: There are no consistent specifications of arthrodesis techniques after resection situation available, thus the presented biomechanical testings give important information about the most stable form of arthrodesis in different types of bone loss. These findings provide an opportunity to minimize complications such as pseudarthrosis for a satisfying clinical outcome. PMID- 23809613 TI - Missed opportunities for adolescent vaccination, 2006-2011. AB - OBJECTIVE: To describe missed opportunities for meningococcal (MCV); tetanus, diphtheria, acellular pertussis (Tdap); and human papillomavirus (HPV) vaccination among adolescents. METHODS: Retrospective electronic health record data review of adolescents aged 11-18 years at the time of their visit to a university-based pediatric practice in Seattle from 2006 to 2011. The primary outcome was missed vaccination opportunities, defined as the proportion of visits where a patient eligible for MCV, Tdap, and/or HPV remained unvaccinated. HPV vaccine analysis was limited to females. Bivariate and multivariate logistic regression assessed variables associated with missed vaccination opportunities. RESULTS: During the study period, 1,628 adolescents made 9,180 visits. The percentage of visits that were missed opportunities was 82% for MCV, 85% for Tdap, and 82% for the first HPV dose (HPV1), 63% for the second, and 71% for the third. Adolescents with at least one preventive care visit were significantly less likely to have missed opportunities for MCV, Tdap, or HPV1. Nonpreventive visits were associated with more missed opportunities for MCV (OR = 19.2, 95% CI 15.3-24.0), Tdap (OR = 25.8, 95% CI 19.3-34.6), and HPV1 (OR = 12.1, 95% CI 9.0 16.1) than preventive visits. Adolescent females were more likely to have a missed opportunity for HPV1 than Tdap (p < .001) or MCV (p = .03). CONCLUSIONS: Missed opportunities for adolescent vaccination against MCV, Tdap and HPV are common. Adolescents who utilize preventive care are less likely to have missed vaccination opportunities. Further research is needed to explore why missed vaccination opportunities occur and to develop evidence-based strategies to reduce missed opportunities and improve adolescent vaccination coverage. PMID- 23809614 TI - Alteration of human blood cell transcriptome in uremia. AB - BACKGROUND: End-stage renal failure is associated with profound changes in physiology and health, but the molecular causation of these pleomorphic effects termed "uremia" is poorly understood. The genomic changes of uremia were explored in a whole genome microarray case-control comparison of 95 subjects with end stage renal failure (n = 75) or healthy controls (n = 20). METHODS: RNA was separated from blood drawn in PAXgene tubes and gene expression analyzed using Affymetrix Human Genome U133 Plus 2.0 arrays. Quality control and normalization was performed, and statistical significance determined with multiple test corrections (qFDR). Biological interpretation was aided by knowledge mining using NIH DAVID, MetaCore and PubGene RESULTS: Over 9,000 genes were differentially expressed in uremic subjects compared to normal controls (fold change: -5.3 to +6.8), and more than 65% were lower in uremia. Changes appeared to be regulated through key gene networks involving cMYC, SP1, P53, AP1, NFkB, HNF4 alpha, HIF1A, c-Jun, STAT1, STAT3 and CREB1. Gene set enrichment analysis showed that mRNA processing and transport, protein transport, chaperone functions, the unfolded protein response and genes involved in tumor genesis were prominently lower in uremia, while insulin-like growth factor activity, neuroactive receptor interaction, the complement system, lipoprotein metabolism and lipid transport were higher in uremia. Pathways involving cytoskeletal remodeling, the clathrin coated endosomal pathway, T-cell receptor signaling and CD28 pathways, and many immune and biological mechanisms were significantly down-regulated, while the ubiquitin pathway and certain others were up-regulated. CONCLUSIONS: End-stage renal failure is associated with profound changes in human gene expression which appears to be mediated through key transcription factors. Dialysis and primary kidney disease had minor effects on gene regulation, but uremia was the dominant influence in the changes observed. This data provides important insight into the changes in cellular biology and function, opportunities for biomarkers of disease progression and therapy, and potential targets for intervention in uremia. PMID- 23809615 TI - Rationale and development of an on-line quality assurance programme for colposcopy in a population-based cervical screening setting in Italy. AB - BACKGROUND: Colposcopy, the key step in the management of women with abnormal Pap smear results, is a visual technique prone to observer variation, which implies the need for prolonged apprenticeship, continuous training, and quality assurance (QA) measures. Colposcopy QA programmes vary in level of responsibility of organizing subjects, geographic coverage, scope, model, and type of actions. The programmes addressing the clinical standards of colposcopy (quality of examination and appropriateness of clinical decisions) are more limited in space and less sustainable over time than those focused on the provision of the service (resources, accessibility, etc.). This article reports on the protocol of a QA programme targeting the clinical quality of colposcopy in a population-based cervical screening service in an administrative region of northern Italy. METHODS/DESIGN: After a situation analysis of local colposcopy audit practices and previous QA initiatives, a permanent web-based QA programme was developed. The design places more emphasis on providing education and feedback to participants than on testing them. The technical core is a log-in web application accessible on the website of the regional Administration. The primary objectives are to provide (1) a practical opportunity for retraining of screening colposcopists, and (2) a platform for them to interact with colposcopists from other settings and regions through exchange and discussion of digital colposcopic images. The retraining function is based on repeated QA sessions in which the registered colposcopists log-in, classify a posted set of colpophotographs, and receive on line a set of personal feedback data. Each session ends with a plenary seminar featuring the presentation of overall results and an interactive review of the test set of colpophotographs. This is meant to be a forum for an open exchange of views that may lead to more knowledge and more diagnostic homogeneity. The protocol includes the criteria for selection of colpophotographs and the rationale for colposcopic gold standards. DISCUSSION: This programme is an ongoing initiative open to further developments, in particular in the area of basic training. It uses the infrastructure of the internet to give a novel solution to technical problems affecting colposcopy QA in population-based screening services. PMID- 23809616 TI - Human leucocyte antigen alleles and haplotypes and their associations with antinuclear antibodies features in Chinese patients with primary biliary cirrhosis. AB - BACKGROUND & AIMS: Primary biliary cirrhosis (PBC) is an autoimmune liver disease. Genetic factors are critical in determining susceptibility to PBC. Among human leuocyte antigen (HLA) genes, an association between the DRB1*08 allele and PBC has been reported in many populations, but not in Chinese patients. METHODS: We investigated HLA-A, B, DRB1, and DQB1 alleles and haplotypes in 145 PBC patients and 500 healthy subjects. Patients were also stratified according to autoantibody features, and associations between these and HLA alleles were analyzed. RESULTS: Significant associations existed between HLA-DRB1*08:03 (22.1% vs. 9.0%, Pc < 0.0001, OR = 2.86), DQ2 (41.4% vs. 25.4%, Pc < 0.0001, OR = 2.07) and DQB1*06:01 (31.0% vs. 17.8%, Pc = 0.014, OR = 2.08) alleles and PBC. DRB1*08:03-DQB1*06:01 (22.1% vs. 8.2%, P < 0.0001, OR = 3.17) and DRB1*07:01 DQB1*02:02 haplotypes (28.3% vs. 17.6%, P = 0.005, OR = 1.85) were also associated with PBC susceptibility. In contrast, the DQB1*03:01 allele (21.4% vs. 39.2%, Pc < 0.0001, OR = 0.42) and DRB1*12:02-DQB1*03:01 haplotype (6.9% vs. 14.6%, P = 0.015, OR = 0.43) were significantly decreased in PBC patients compared with controls. DRB1*14:54 and DQ5(1) protected against antinuclear antibody (ANA) (OR = 0.25) and anti-gp210 antibody (OR = 0.39) production, respectively, while HLA-B*44:03 predisposed patients to anti-gp210 antibody (OR = 5.70) production. CONCLUSION: These results suggest that Chinese patients with PBC have a distinct genetic background in eastern Asia, and we confirmed the role of HLA genes in determining PBC susceptibility and autoantibody features in the Chinese population. PMID- 23809617 TI - Variation in the relationship between BMI and survival by socioeconomic status in Great Britain. AB - We investigate the relationship between obesity and survival, and the extent to which this relationship varies by socioeconomic status (SES). The underlying model is based on the "Pathways to health" framework in which SES affects health by modifying the relationship between lifestyles and health. We use data from the British Health and Lifestyle Survey (1984-1985) and the longitudinal follow-up in June 2009, and run parametric Gompertz survival models to investigate the association between obesity and survival, also accounting for interactions between obesity and both age and SES. Generally we find that obesity is negatively associated with survival, and that SES is positively associated with survival, in both men and women. The interactions between obesity and SES predict survival among women but not among men. Obesity compared with normal weight is associated with a reduction in survival of 3.3, 3.2 and 2.8 years in men aged 40, 50 and 60 years, respectively. Corresponding numbers among women in the lowest SES group are 13.1, 9.7 and 6.1 years, respectively; in the highest SES group they are 6.2, 3.1 and 0.1 years, respectively, a difference of approximately 6 years between the highest and lowest SES groups. PMID- 23809618 TI - Nickel recovery from electronic waste II electrodeposition of Ni and Ni-Fe alloys from diluted sulfate solutions. AB - This study focuses on the electrodeposition of Ni and Ni-Fe alloys from synthetic solutions similar to those obtained by the dissolution of electron gun (an electrical component of cathode ray tubes) waste. The influence of various parameters (pH, electrolyte composition, Ni(2+)/Fe(2+) ratio, current density) on the electrodeposition process was investigated. Scanning electron microscopy (SEM) and X-ray fluorescence analysis (XRFA) were used to provide information about the obtained deposits' thickness, morphology, and elemental composition. By controlling the experimental parameters, the composition of the Ni-Fe alloys can be tailored towards specific applications. Complementarily, the differences in the nucleation mechanisms for Ni, Fe and Ni-Fe deposition from sulfate solutions have been evaluated and discussed using cyclic voltammetry and potential step chronoamperometry. The obtained results suggest a progressive nucleation mechanism for Ni, while for Fe and Ni-Fe, the obtained data points are best fitted to an instantaneous nucleation model. PMID- 23809619 TI - Thermal and hydrometallurgical recovery methods of heavy metals from municipal solid waste fly ash. AB - Heavy metals in fly ash from municipal solid waste incinerators are present in high concentrations. Therefore fly ash must be treated as a hazardous material. On the other hand, it may be a potential source of heavy metals. Zinc, lead, cadmium, and copper can be relatively easily removed during the thermal treatment of fly ash, e.g. in the form of chlorides. In return, wet extraction methods could provide promising results for these elements including chromium and nickel. The aim of this study was to investigate and compare thermal and hydrometallurgical treatment of municipal solid waste fly ash. Thermal treatment of fly ash was performed in a rotary reactor at temperatures between 950 and 1050 degrees C and in a muffle oven at temperatures from 500 to 1200 degrees C. The removal more than 90% was reached by easy volatile heavy metals such as cadmium and lead and also by copper, however at higher temperature in the muffle oven. The alkaline (sodium hydroxide) and acid (sulphuric acid) leaching of the fly ash was carried out while the influence of temperature, time, concentration, and liquid/solid ratio were investigated. The combination of alkaline-acidic leaching enhanced the removal of, namely, zinc, chromium and nickel. PMID- 23809620 TI - An appraisal of service users' structured activity requirements in an Irish forensic setting. AB - Participating in purposeful and structured daily activities is an important factor contributing to the health and well-being of forensic service users. A survey was carried out in an Irish forensic mental health setting to identify whether service users meet the standard of 25-h weekly activities, a standard set by the Quality Network for Forensic Mental Health Services, London. The findings indicate that 57 (61%) out of 93 service users fully meet the criteria. Furthermore, service users within the medium- and low-security environments appear to be engaging to an increased number of structured activities in comparison to those in acute units. PMID- 23809621 TI - Hemoglobin, exercise training, and health status in patients with chronic heart failure (from the HF-ACTION randomized controlled trial). AB - Anemia is common in patients with chronic heart failure (HF), with a prevalence ranging from 10% to 56%, and may be a risk factor for poor outcomes. Anemia in HF remains poorly understood, with significant gaps in its impact on health-related quality of life (HRQoL), with most studies in HF being retrospective or from registries. The purpose of this study was to explore the relation of hemoglobin (Hgb) with HRQoL and training-induced changes in HRQoL in a cohort of patients in Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF ACTION). Using data from HF-ACTION, a randomized controlled trial of exercise training in patients with HF and low left ventricular ejection fractions, HRQoL was measured using the Kansas City Cardiomyopathy Questionnaire (KCCQ) at baseline, 3 and 12 months, and annually up to 4 years. Treatment group effects on HRQoL were estimated using linear mixed models according to the intention-to treat principle. It was hypothesized that baseline Hgb would be correlated with baseline KCCQ scales and that Hgb would moderate the beneficial effect of exercise training on HRQoL. Hgb level was not significantly correlated with baseline HRQoL. Baseline Hgb did not moderate the beneficial effect of exercise training on KCCQ overall or subscales relative to usual care. In conclusion, in the HF-ACTION cohort, there was no correlation with baseline Hgb and baseline HRQoL as measured by the KCCQ. In addition, the beneficial effects of HRQoL from exercise training were not modulated by baseline Hgb. PMID- 23809622 TI - Impact of location of epicardial adipose tissue, measured by coronary artery calcium-scoring computed tomography on obstructive coronary artery disease. AB - Epicardial adipose tissue (EAT) is considered to play a role in the pathogenesis of coronary atherosclerosis. However, whether total EAT volume or location specific EAT thickness may be a better predictor of obstructive coronary artery disease (CAD) is inconclusive. We investigated whether the total volume or location-specific thickness of EAT measured on computed tomography (CT) could be a useful marker of CAD on top of clinical risk factors and Agatston score. Two hundred eight consecutive subjects with clinical suspicion of CAD receiving coronary arterial calcium (CAC)-scoring CT and CT coronary angiography were retrospectively divided into 2 groups: an obstructive CAD group (n = 97) and a nonobstructive CAD group (n = 111). Total EAT volume and EAT thicknesses at different locations were measured on CAC-scoring CT. Left atrioventricular groove (AVG) EAT thickness was the sole EAT measurement that showed association with increasing number of vessels exhibiting >=50% stenosis (p for trend <0.001). Logistic regression showed that left AVG EAT thickness was the most important EAT predictor of obstructive CAD (odds ratio 1.16, 95% confidence interval 1.04 to 1.29, p = 0.006; optimal threshold >=15 mm, odds ratio 4.62, 95% confidence interval 2.24 to 9.56, p <0.001). Adding left AVG EAT thickness on top of clinical risk factors plus Agatston score improved prediction of obstructive CAD (area under the curve from 0.848 to 0.912, p = 0.002). In conclusion, excessive left AVG EAT adiposity is an important risk factor for obstructive CAD, independent of clinical risk factors and Agatston score. However, further trials are needed in investigation of combined assessment of location-specific EAT thickness and Agatston score on CAC scan as to whether this biomarker could improve CAD risk stratification in the general population. PMID- 23809623 TI - Introduction: back to the future: origins of polycystic ovary syndrome. AB - In this Views and Reviews section we explore the ontogeny of polycystic ovary syndrome (PCOS) from in utero through puberty linking together, where possible, basic and clinical scientists to explore the implications of basic research for our clinical understanding of the syndrome. PMID- 23809625 TI - The Kiss1 system and polycystic ovary syndrome: lessons from physiology and putative pathophysiologic implications. AB - Polycystic ovary syndrome (PCOS) is a highly prevalent heterogeneous disease characterized by ovulatory dysfunction, hyperandrogenism, and metabolic alterations. Women with PCOS commonly display dysregulated gonadotropin secretion with higher LH pulsatility and perturbed LH-FSH ratios, which likely contributes to the ovarian phenotype and might be indicative of disrupted GnRH secretory activity. Although the involvement of altered androgen and insulin levels in the pathogenesis of the neuroendocrine alterations of PCOS has been explored in various experimental and clinical settings, the ultimate mechanisms whereby such neurohormonal perturbations take place remain partially unknown. In recent years, kisspeptins, the products of the Kiss1 gene that operate via the surface receptor Gpr54, have emerged as essential elements of the reproductive brain that play an indispensable role in the control of gonadotropin secretion and ovulation. In addition, Kiss1 neurons in the brain are targets and transmitters of the regulatory actions of sex steroids and metabolic cues on the reproductive axis during early organizing periods and adulthood. Furthermore, Kiss1/kisspeptin expression has been documented in the ovary in various species, including humans; yet clear evidence for the involvement of kisspeptin signaling in the control of ovulation, or its alterations, is still pending. Based on these physiologic features, we discuss the putative pathophysiologic implications of alterations of the Kiss1 system in the generation of PCOS and summarize the scarce experimental and clinical evidence that might support such a role. PMID- 23809626 TI - Think before ordering that test. PMID- 23809627 TI - Plant genomics: sowing the seeds of success. PMID- 23809628 TI - Spontaneous left main dissection treated by percutaneous coronary intervention. AB - Spontaneous coronary artery dissection is a rare cause of acute coronary events or sudden cardiac death. The clinical presentation is highly variable and prognosis varies widely, depending mainly on how rapidly it is diagnosed. Prompt treatment is also essential, and includes medical management, percutaneous coronary intervention and surgical revascularization. We describe the case of a young woman presenting with spontaneous coronary artery dissection of the left main coronary artery, first diagnosed as coronary thrombus, who underwent successful percutaneous coronary stenting. This report highlights the need to include spontaneous coronary artery dissection in differential diagnosis of chest pain in young women and that distinguishing between coronary thrombus and coronary artery dissection is not always straightforward. To our knowledge this is the fourth case of left main stenting in a patient with spontaneous coronary artery dissection described in the literature. PMID- 23809624 TI - Ontogeny of polycystic ovary syndrome and insulin resistance in utero and early childhood. AB - Polycystic ovary syndrome (PCOS) is a prevalent hyperandrogenic infertility and cardiometabolic disorder that increases a woman's lifetime risk of type 2 diabetes mellitus. It is heritable and intensely familial. Progress toward a cure has been delayed by absence of an etiology. Evidence is mounting, however, for in utero T excess, together with gestational hyperglycemia, contributing to either early differentiation of PCOS or phenotypic amplification of its genotypes. Abnormal endocrine, ovarian, and hyperinsulinemic traits are detectable as early as 2 months of age in daughters of women with PCOS, with adiposity enhancement of hyperinsulinemia during childhood potentially contributing to hyperandrogenism and LH excess by adolescence. These findings encourage increasing clinical focus on early childhood markers for adiposity and hyperinsulinemia accompanying ovarian and adrenal endocrine abnormalities that precede a diagnosable PCOS phenotype. They raise the possibility for lifestyle or therapeutic intervention before and during pregnancy or during childhood and adolescence alleviating the manifestations of a familial genetic predisposition to PCOS. PMID- 23809629 TI - Ischemia induced by coronary steal through a patent mammary artery side branch: a role for embolization. AB - Non-occlusion of the internal mammary artery side branches may cause ischemia due to flow diversion after coronary artery bypass grafting. The authors present the case of a 67-year-old man with recurrent angina after undergoing myocardial revascularization with a left internal mammary artery to left anterior descending bypass. He presented with impaired anterior wall myocardial perfusion in the setting of a patent left internal mammary artery side branch. Effective percutaneous treatment was carried out through coil embolization, with improved flow and clinical symptoms, confirmed through ischemia testing. Coronary steal through a patent mammary artery side branch is a controversial phenomenon and this type of intervention should be considered only in carefully selected patients. PMID- 23809630 TI - Efficient butanol production without carbon catabolite repression from mixed sugars with Clostridium saccharoperbutylacetonicum N1-4. AB - Acetone-butanol-ethanol (ABE) fermentation using Clostridium saccharoperbutylacetonicum N1-4 and mixed sugars containing cellobiose and xylose was studied to establish efficient butanol production process without carbon catabolite repression (CCR). Although batch culture with glucose and xylose exhibited apparent CCR, we achieved simultaneous consumption of cellobiose and xylose. Moreover, preculture of the N1-4 strain with xylose yielded maximum butanol and solvent concentrations (16 and 23 g/L, respectively). Thus, we succeeded in ABE fermentation with mixed sugars of hexose and pentose, without CCR, by using wild-type ABE-producing clostridia. We also investigated the effect of various ratios of cellobiose and xylose on the fermentation process and yield. Increasing initial xylose concentration improved butanol and solvent concentrations and maximum xylose consumption rate. Fed-batch culture with cellobiose and xylose showed rapid and simultaneous sugar consumption and improved maximum consumption rate of both sugars. PMID- 23809631 TI - Galactofuranose-rich polysaccharides from Trebouxia sp. induce inflammation and exacerbate lethality by sepsis in mice. AB - Trebouxia sp. is a genus of green algae that is a symbiotic partner of lichenized fungi. Previous studies conduced demonstrated that Trebouxia sp. is able to produce galactofuranose-rich polysaccharides (beta-d-galactofuranan, mannogalactofuranan), which were able to activate macrophages in vitro. The present study was proposed to investigate the effects of SK10 polysaccharides fraction from Trebouxia sp. on the model of polymicrobial sepsis induced by cecal ligation and puncture in mice in vivo. The subcutaneous administration of SK10 increased the late mortality rate by 20%, stimulated neutrophil accumulation in lungs (indirectly measured through myeloperoxidase activity) and also Interleukin 1beta, creatinine and glucose serum levels. Moreover this study demonstrates the in vivo proinflammatory effects of polymers of galactofuranose and that they can act as pathogen-associated molecular patterns being highly recognized by the immune system of mammals, even if they come from a non-pathogenic microorganism. PMID- 23809632 TI - Sequence analysis and structure prediction of enoyl-CoA hydratase from Avicennia marina: implication of various amino acid residues on substrate-enzyme interactions. AB - Enoyl-CoA hydratase catalyzes the hydration of 2-trans-enoyl-CoA into 3 hydroxyacyl-CoA. The present study focuses on the correlation between the functional and structural aspects of enoyl-CoA hydratase from Avicennia marina. We have used bioinformatics tools to construct and analyze 3D homology models of A. marina enoyl-CoA hydratase (AMECH) bound to different substrates and inhibitors and studied the residues involved in the ligand-enzyme interaction. Structural information obtained from the models was compared with those of the reported crystal structures. We observed that the overall folds were similar; however, AMECH showed few distinct structural changes which include structural variation in the mobile loop, formation and loss of certain interactions between the active site residues and substrates. Some changes were also observed within specific regions of the enzyme. Glu106 is almost completely conserved in sequences of the isomerases/hydratases including AMECH while Glu86 which is the other catalytic residue in most of the isomerases/hydratases is replaced by Gly and shows no interaction with the substrate. Asp114 is located within 4A distance of the catalytic water which makes it a probable candidate for the second catalytic residue in AMECH. Another prominent feature of AMECH is the presence of structurally distinct mobile loop having a completely different coordination with the hydrophobic binding pocket of acyl portion of the substrate. PMID- 23809633 TI - Abolishing activity against ascorbate in a cytosolic ascorbate peroxidase from switchgrass. AB - Switchgrass (Panicum virgatum L.) is being developed as a bioenergy species. Recently an early version of its genome has been released permitting a route to the cloning and analysis of key proteins. Ascorbate peroxidases (APx) are an important part of the antioxidant defense system of plant cells and present a well studied model to understand structure-function relationships. Analysis of the genome indicates that switchgrass encodes several cytosolic ascorbate peroxidases with apparent varying levels of tissue expression. A major cytosolic ascorbate peroxidase was thus selected for further studies. This gene was cloned and expressed in Escherichia coli cells to obtain purified active protein. Full heme incorporation of the enzyme was achieved utilizing slow growth and supplementing the media with 5-aminolevulinic acid. The enzyme was observed to be monomeric in solution via size exclusion chromatography. Activity toward ascorbate was observed that was non-Michaelis-Menten in nature. A site-directed mutant, R172S, was made in an attempt to differentiate activity against ascorbate versus other substrates. The R172S protein exhibited negligible ascorbate peroxidase activity, but showed near wild type activity toward other aromatic substrates. PMID- 23809635 TI - On being your own boss. PMID- 23809634 TI - Thielavins A, J and K: alpha-Glucosidase inhibitors from MEXU 27095, an endophytic fungus from Hintonia latiflora. AB - Bioassay-guided fractionation of the bio-active organic extract obtained from solid-media culture of MEXU 27095, an endophytic fungus isolated from the Mexican medicinal plant Hintonia latiflora (Rubiaceae), led to separation of three tridepsides which were identified as thielavins A, J and K. All three compounds inhibited Saccharomyces cerevisieae alpha-glucosidase (alphaGHY) in a concentration-dependent manner with IC50 values of 23.8, 15.8, and 22.1MUM, respectively. Their inhibitory action was higher than that of acarbose (IC50=545MUM), used as a positive control. Kinetic analysis established that the three compounds acted as non-competitive inhibitors with ki values of 27.8, 66.2 and 55.4MUM, respectively (alpha=1.0, 1.2, 0.7, respectively); acarbose behaved as competitive inhibitor with a ki value of 156.1MUM. Thielavin J inhibited the activity of alpha-glucosidase from Bacillus stearothermophilus (alphaGHBs) with an IC50 of 30.5MUM, being less active than acarbose (IC50=0. 015MUM); in this case, compound (2) (ki=20.0MUM and alpha=2.9) and acarbose (ki=0.008MUM and alpha=1.9) behaved as non-competitive inhibitors. Docking analysis predicted that all three thielavins and acarbose bind to homologated alphaGHBs and to alphaGHY (PDB: 3A4A) in a pocket close to the catalytic site for maltose and isomaltose, respectively. The alpha-glucosidase inhibitory properties of thielavin K (3) were corroborated in vivo since it induced a noted antihyperglycemic action during an oral sucrose tolerance test (3.1, 10.0 and 31.6mg/kg) in normal and nicotinamide streptozotocin diabetic mice. In addition, at a dose of 10mg/kg, it provoked a moderate hypoglycemic activity in diabetic mice. PMID- 23809637 TI - Top 10 words of leadership advice ... or, things your mother never told you! PMID- 23809638 TI - Better health, better care, better value: National Expert Commission, part 2. PMID- 23809639 TI - Leaders hold an invitational Think Tank on undergraduate nursing education. PMID- 23809640 TI - Nursing entrepreneurship: motivators, strategies and possibilities for professional advancement and health system change. AB - In Canada, as well as internationally, efficiency-focused organizational restructuring in healthcare has resulted in stressful job change for nurses, although nurses continue to work in a system that values technology-based, physician-provided services. Employed nurses have had to participate in organizational activities that undermine their professional values and goals. Nursing entrepreneurship presents an opportunity to explore nursing's professional potential in nursing practice that is uniquely independent. In this study, a focused ethnographic approach was used to explore the experiences of self-employed nurses, who see themselves as leaders in advancing the profession of nursing and its contribution to healthcare. Key themes in the findings include the responses of self-employed nurses to health system change, expanded roles for nurses, the consequences of this non-traditional approach to nursing work and the possibilities for change that arise from nursing entrepreneurship. This research has implications for healthcare policy, professional advocacy and nursing education. PMID- 23809641 TI - Nursing entrepreneurship: a view from the field. PMID- 23809642 TI - Professional comportment: nurses, patients and family survey. AB - AIM: The aim of the study was to survey nurses, patients and families regarding their perceptions of nursing attire, identification and professional image. BACKGROUND: Recent changes in uniform policies have made it difficult for patients to identify the nurse. METHOD: A convenience sample of nurses (RNs, RPNs) and patients and families from an acute care facility in Canada were surveyed. Surveys included a combination of forced-choice questions and open text boxes. Quantitative data were analyzed, and a thematic content analysis was conducted. RESULTS: The nurse survey resulted in a 64% (n=642) response rate; the patient/family survey response rate was 70% (n=30). Fifty-three per cent of the patient/family advisory team members reported that the nurses did not look professional in comparison to 95% of the nurses who indicated they did. Three key themes emerged: professional image, nurse identification and adoption of a standardized uniform. CONCLUSION: Professional comportment of nurses includes attire suitable for the clinical area that reflects a professional image and allows patients and families to identify the nurses. IMPLICATIONS FOR NURSING LEADERSHIP: This study identified the need to engage nurses, patients and families to ensure professional comportment when uniform polices are developed. PMID- 23809643 TI - Curriculum review of an environmental health program: an international nursing experience. AB - Two nursing professors from a small Canadian university provided a leadership role in a curriculum review of an environmental health technology program in Zambia. The combined health and education experience of these two professionals was the optimal fit to help guide and facilitate the curriculum review. This review was part of a larger project that had the ultimate goal of improving environmental management in rural and peri-urban communities in order to reduce infant and under-five mortality rates, thereby addressing three of the UN Millennium Development Goals. Participants from two post-secondary educational institutions in Zambia and a non-governmental organization spent five days together reviewing the theoretical and practical components of the program. Theoretical content, practice opportunities and demonstrable student competencies were updated within existing resources. The collegiality and respect among the participants from many disciplines provided the basis for a positive experience in intersectoral collaboration and global health. PMID- 23809644 TI - Nurse retention: a review of strategies to create and enhance positive practice environments in clinical settings. AB - OBJECTIVES: This paper summarises and critically reviews strategies identified in the literature which support retention of nurses by the creation and enhancement of positive practice environments in the clinical setting. DESIGN: Literature review. DATA SOURCES: A literature search was undertaken in February 2012 of major healthcare-related databases, Cinahlplus, Medline, and Proquest. REVIEW METHODS: The keywords "nurs* AND practice AND environment" were used in the first instance. Additional keywords "retention strategies" were also searched. Abstracts were reviewed and articles which potentially outlined strategies were identified. Reference lists were scanned for other potential articles. Articles in languages other than English were excluded. Lake's Practice Environment Scale of the Nursing Work Index provided a framework from which to assess the strategies. RESULTS: Thirty-nine papers reported strategies for creating a positive practice environment. Only two articles reported on a pre-test post-test evaluation of the proposed strategy. Strategies included: empowering work environment, shared governance structure, autonomy, professional development, leadership support, adequate numbers and skill mix and collegial relationships within the healthcare team. CONCLUSIONS: Creating positive practice environments enhances nurse retention and facilitates quality patient care. Managers and administrators should assess and manage their practice environments using a validated tool to guide and evaluate interventions. PMID- 23809645 TI - Caregiving actions: Outgrowths of the family caregiver's conceptions of care. AB - Caregiving actions emanate from the family caregiver's care meanings. Therefore, this article presents caregiving actions as outgrowths of the family caregiver's cultural conceptions of care and as situated within constraining sociocultural factors. Qualitative data were collected through interviews and participant observations from 18 purposively selected family caregivers of people living with HIV/AIDS (PLWAs) in Addis Ababa, Ethiopia. Three lines of caregiving actions performed by the participating family caregivers are presented: nutritional and medication care actions, physical care actions, and psychological and spiritual care actions. We have also explicated the problematic situations and sociocultural factors constraining the family caregivers in performing the caregiving actions. This study underlines the significance of addressing such problematic situations as are raised, as well as the sociocultural issues that constrain the family caregivers' agentic scope for planning and executing caregiving actions. PMID- 23809646 TI - Somatodendritic 5-hydroxytryptamine1A (5-HT1A) autoreceptor function in major depression as assessed using the shift in electroencephalographic frequency spectrum with buspirone. AB - BACKGROUND: Positron emission tomography and post-mortem studies of the number of somatodendritic 5-hydroxytryptamine(1A) (5-HT(1A)) autoreceptors in raphe nuclei have found both increases and decreases in depression. However, recent genetic studies suggest they may be increased in number and/or function. The current study examined the effect of buspirone on the electroencephalographic (EEG) centroid frequency, a putative index of somatodendritic 5-HT(1A) receptor functional status, in a cohort of medication-free depressed patients and controls. METHOD: A total of 15 depressed patients (nine male) and intelligence quotient (IQ)-, gender- and age-matched healthy controls had resting EEG recorded from 29 scalp electrodes prior to and 30, 60 and 90 min after oral buspirone (30 mg) administration. The effect of buspirone on somatodendritic 5-HT(1A) receptors was assessed by calculating the EEG centroid frequency between 6 and 10.5 Hz. The effect of buspirone on postsynaptic 5-HT(1A) receptors was assessed by measuring plasma growth hormone, prolactin and cortisol concentrations. RESULTS: Analysis of variance revealed a significantly greater effect of buspirone on the EEG centroid frequency in patients compared with controls (F1,28 = 6.55, p = 0.016). There was no significant difference in the neuroendocrine responses between the two groups. CONCLUSIONS: These findings are consistent with an increase in the functional status of somatodendritic, but not postsynaptic, 5-HT1A autoreceptors, in medication-free depressed patients in line with hypotheses based on genetic data. This increase in functional status would be hypothesized to lead to an increase in serotonergic negative feedback, and hence decreased release of 5-HT at raphe projection sites, in depressed patients. PMID- 23809647 TI - Assessment of the suitability of mannitol salt agar for growing bovine-associated coagulase-negative staphylococci and its use under field conditions. AB - This study aimed at testing the applicability of mannitol salt agar (MSA), a medium generally used in human medicine for differentiating Staphylococcus aureus from coagulase-negative staphylococci (CNS), for culturing bovine-associated CNS species. All test isolates from a comprehensive collection of well-identified CNS species, including both reference strains and field isolates, were able to grow. Subsequently, bulk milk samples and teat apex swabs were used to examine the capability of MSA for yielding CNS under field conditions. Sixty-nine and 47 phenotypically different colonies were retrieved from bulk milk and teat apices, respectively. The majority of isolates from teat apices were staphylococci, whereas in bulk milk, staphylococci formed a minority. After 24h of growth, recovery of separate colonies of CNS was much more convenient on MSA compared to a non-selective blood agar. The results of this study indicate that MSA is a suitable medium for both growth and recovery of bovine-associated CNS. PMID- 23809648 TI - Influenza research in the Eastern Mediterranean Region: the current state and the way forward. AB - We searched published literature, surveillance data sources, and sequence databases to analyze the state of influenza virus research and to identify research gaps in the World Health Organization (WHO) Eastern Mediterranean Region. PubMed, Scopus, and other databases were searched for influenza publications and nucleotide sequences. WHO's FluNet was searched to determine virologic reporting from each country. We found that influenza research has increased in recent years with the emergence of H5N1 and pandemic H1N1. In some countries, influenza research is growing and is diversified, covering epidemiologic, veterinary, and basic science aspects. However, the volume and diversity of influenza research is low, especially in light of the burden of influenza in the region. To have contemporary and advanced research in the region, systematic surveillance in humans and animals, as well as at the human animal interface, needs to be boosted. Surveillance data should then be used to answer more important epidemiologic, virologic, immunologic, and basic science questions. PMID- 23809649 TI - Optimization of a real-time PCR assay for the detection of the quarantine pathogen Melampsora medusae f. sp. deltoidae. AB - Melampsora medusae (Mm), one of the causal agents of poplar rust, is classified as an A2 quarantine pest for European Plant Protection Organization (EPPO) and its presence in Europe is strictly controlled. Two formae speciales have been described within Mm, Melampsora medusae f. sp. deltoidae (Mmd), and Melampsora medusae f. sp. tremuloidae (Mmt) on the basis of their pathogenicity on Populus species from the section Aigeiros (e.g. Populus deltoides) or Populus (e.g. Populus tremuloides), respectively. In this study, a real-time polymerase chain reaction (PCR) assay was developed allowing the detection of Mmd, the forma specialis that is economically harmful. A set of primers and hydrolysis probe were designed based on sequence polymorphisms in the large ribosomal RNA subunit (28S). The real-time PCR assay was optimized and performance criteria of the detection method, i.e. sensitivity, specificity, repeatability, reproducibility, and robustness, were assessed. The real-time PCR method was highly specific and sensitive and allowed the detection of one single urediniospore of Mmd in a mixture of 2 mg of urediniospores of other Melampsora species. This test offers improved specificity over currently existing conventional PCR tests and can be used for specific surveys in European nurseries and phytosanitary controls, in order to avoid introduction and spread of this pathogen in Europe. PMID- 23809650 TI - A proteomic view of the response of Paracoccidioides yeast cells to zinc deprivation. AB - Zinc plays a critical role in a diverse array of biochemical processes. However, an excess of zinc is deleterious to cells; therefore, cells require finely tuned homeostatic mechanisms to balance the uptake and the storage of zinc. There is also increasing evidence supporting the importance of zinc during infection. To understand better how Paracoccidioides adapts to zinc deprivation, we compared the two-dimensional (2D) gel protein profile of yeast cells during zinc starvation to yeast cells grown in a zinc rich condition. Protein spots were selected for comparative analysis based on the protein staining intensity, as determined by image analysis. In response to zinc deprivation, a total of 423 out of 845 protein spots showed a significant change in abundance. Quantitative RT qPCR analysis of RNA from Paracoccidioides grown under zinc restricted conditions validated the correlation between the differentially regulated proteins and transcripts. According to the proteomic data, zinc deficiency may be a stressor to Paracoccidioides, as suggested by the upregulation of a number of proteins related to stress response, cell rescue, and virulence. Other process induced by zinc deprivation included gluconeogenesis. Conversely, the methylcitrate cycle was downregulated. Overall, the results indicate a remodelling of the Paracoccidioides response to the probable oxidative stress induced during zinc deprivation. PMID- 23809651 TI - Characterization of the mating-type genes in Leptographium procerum and Leptographium profanum. AB - Leptographium procerum and the closely related species Leptographium profanum, are ascomycetes associated with root-infesting beetles on pines and hardwood trees, respectively. Both species occur in North America where they are apparently native. L. procerum has also been found in Europe, China New Zealand, and South Africa where it has most probably been introduced. As is true for many other Leptographium species, sexual states have never been observed in L. procerum or L. profanum. The objectives of this study were to clone and characterize the mating type loci of these fungi, and to develop markers to determine the mating types of individual isolates. To achieve this, a partial sequence of MAT1-2-1 was amplified using degenerate primers targeting the high mobility group (HMG) sequence. A complete MAT1-2 idiomorph of L. profanum was subsequently obtained by screening a genomic library using the HMG sequence as a probe. Long range PCR was used to amplify the complete MAT1-1 idiomorph of L. profanum and both the MAT1-1 and MAT1-2 idiomorphs of L. procerum. Characterization of the MAT idiomorphs suggests that the MAT genes are fully functional and that individuals of both these species are self-sterile in nature with a heterothallic mating system. Mating type markers were developed and tested on a population of L. procerum isolates from the USA, the assumed center of origin for this species. The results suggest that cryptic sexual reproduction is occurring or has recently taken place within this population. PMID- 23809652 TI - Transcriptomic profiling-based mutant screen reveals three new transcription factors mediating menadione resistance in Neurospora crassa. AB - To gain insight into the regulatory mechanisms of oxidative stress responses in filamentous fungi, the genome-wide transcriptional response of Neurospora crassa to menadione was analysed by digital gene expression (DGE) profiling, which identified 779 upregulated genes and 576 downregulated genes. Knockout mutants affecting 130 highly-upregulated genes were tested for menadione sensitivity, which revealed that loss of the transcription factor siderophore regulation (SRE) (a transcriptional repressor for siderophore biosynthesis), catatase-3, cytochrome c peroxidase or superoxide dismutase 1 copper chaperone causes hypersensitivity to menadione. Deletion of sre dramatically increased transcription of the siderophore biosynthesis gene ono and the siderophore iron transporter gene sit during menadione stress, suggesting that SRE is required for repression of iron uptake under oxidative stress conditions. Contrary to its phenotype, the sre deletion mutant showed higher transcriptional levels of genes encoding reactive oxygen species (ROS) scavengers than wild type during menadione stress, which implies that the mutant suffers a higher level of oxidative stress than wild type. Uncontrolled iron uptake in the sre mutant might exacerbate cellular oxidative stress. This is the first report of a negative regulator of iron assimilation participating in the fungal oxidative stress response. In addition to SRE, eight other transcription factor genes were also menadione responsive but their single gene knockout mutants showed wild-type menadione sensitivity. Two of them, named as mit-2 (menadione induced transcription factor 2) and mit-4 (menadione induced transcription factor-4), were selected for double mutant analysis. The double mutant was hypersensitive to menadione. Similarly, the double mutation of mit-2 and sre also had additive effects on menadione sensitivity, suggesting multiple transcription factors mediate oxidative stress resistance in an additive manner. PMID- 23809653 TI - Oxidoreductases and cellulases in lichens: possible roles in lichen biology and soil organic matter turnover. AB - Lichens are symbiotic associations of a fungus (usually an Ascomycete) with green algae and/or a cyanobacterium. They dominate on 8 % of the world's land surface, mainly in Arctic and Antarctic regions, tundra, high mountain elevations and as components of dryland crusts. In many ecosystems, lichens are the pioneers on the bare rock or soil following disturbance, presumably because of their tolerance to desiccation and high temperature. Lichens have long been recognized as agents of mineral weathering and fine-earth stabilization. Being dominant biomass producers in extreme environments they contribute to primary accumulation of soil organic matter. However, biochemical role of lichens in soil processes is unknown. Our recent research has demonstrated that Peltigeralean lichens contain redox enzymes which in free-living fungi participate in lignocellulose degradation and humification. Thus lichen enzymes may catalyse formation and degradation of soil organic matter, particularly in high-stress communities dominated by lower plants. In the present review we synthesize recently published data on lichen phenol oxidases, peroxidases, and cellulases and discuss their possible roles in lichen physiology and soil organic matter transformations. PMID- 23809654 TI - Mutualism and asexual reproduction influence recognition genes in a fungal symbiont. AB - Mutualism between microbes and insects is common and alignment of the reproductive interests of microbial symbionts with this lifestyle typically involves clonal reproduction and vertical transmission by insect partners. Here the Amylostereum fungus-Sirex woodwasp mutualism was used to consider whether their prolonged association and predominance of asexuality have affected the mating system of the fungal partner. Nucleotide information for the pheromone receptor gene rab1, as well as the translation elongation factor 1alpha gene and ribosomal RNA internal transcribed spacer region were utilized. The identification of rab1 alleles in Amylostereum chailletii and Amylostereum areolatum populations revealed that this gene is more polymorphic than the other two regions, although the diversity of all three regions was lower than what has been observed in free-living Agaricomycetes. Our data suggest that suppressed recombination might be implicated in the diversification of rab1, while no evidence of balancing selection was detected. We also detected positive selection at only two codons, suggesting that purifying selection is important for the evolution of rab1. The symbiotic relationship with their insect partners has therefore influenced the diversity of this gene and influenced the manner in which selection drives and maintains this diversity in A. areolatum and A. chailletii. PMID- 23809655 TI - A novel subtilisin-like serine protease of Batrachochytrium dendrobatidis is induced by thyroid hormone and degrades antimicrobial peptides. AB - Batrachochytrium dendrobatidis (B. dendrobatidis), a chytrid fungus, is one of the major contributors to the global amphibian decline. The fungus infects both tadpoles and adult amphibians. Tadpoles are infected in their keratinized mouthparts, and infected adults exhibit hyperkeratosis and loss of righting reflex. Infections of adults may result in death from cardiac arrest in susceptible species. Thyroid hormone plays a key role in amphibian metamorphosis. The occurrence of B. dendrobatidis in tadpoles during metamorphosis may result in exposure of the fungus to host morphogens including TH. This exposure may induce gene expression in the fungus contributing to invasion and colonization of the host. Here, we demonstrate movement of fungal zoospores toward TH. Additionally, expression of a subtilisin-like serine protease is up-regulated in B. dendrobatidis cells exposed to TH. A gene encoding this protease was cloned from B. dendrobatidis and expressed in Escherichia coli. The protein was partially purified and characterized. The similarity between subtilases of human dermatophytes and the B. dendrobatidis subtilisin-like serine protease suggests the importance of this enzyme in B. dendrobatidis pathogenicity. Cleavage of frog skin antimicrobial peptides (AMPs) by this B. dendrobatidis subtilisin-like serine protease suggests a role for this enzyme in fungal survival and colonization. PMID- 23809656 TI - Systematic review and meta-analysis of nonpharmacological interventions for fatigue in children and adolescents with cancer. AB - BACKGROUND: Fatigue is one of the most distressing and prevalent symptoms reported by pediatric oncology patients. With the increase in cancer survival rates, medical teams have focused on methods that control cancer-related fatigue in children during the disease and its treatment in order to increase the quality of life for these patients. AIM: The objective of this systematic review was to synthesize the best available evidence concerning the effectiveness of nonpharmacological interventions for fatigue in children and adolescents with cancer. METHODS: The search strategy was designed to retrieve studies published between 1960 and 2010 in either English or Chinese. This review included randomized controlled trials and quasi-experimental studies. The studies that were selected for retrieval were assessed by two independent reviewers for methodological validity prior to inclusion in the review using standardized critical-appraisal instruments. RESULTS: The review included six studies, and the meta-analysis revealed a statistically significant effect of exercise interventions in reducing general fatigue (effect size = -0.76; 95% CI [-1.35, 0.17]) in children and adolescents with cancer. CONCLUSIONS AND IMPLICATIONS: The review provides an evidence-based guide to future priorities for clinical practice. Exercise interventions could reduce the levels of general fatigue in children aged 6-18 years. In particular, exercise interventions for fatigue are feasible and safe. PMID- 23809657 TI - The relationship between facility-based delivery and maternal and neonatal mortality in Sub-Saharan Africa. PMID- 23809658 TI - Using technology to effectively engage adolescents and young adults into care: STAR TRACK Adherence Program. PMID- 23809659 TI - The patient-provider relationship as experienced by a diverse sample of highly adherent HIV-infected people. AB - Qualitative interviews with 23 HIV-infected people who self-reported high-level adherence to antiretroviral therapy were used to examine the process by which they came to accept their HIV infection and engage in high-level adherence behaviors. A major theme that emerged during data analysis was the importance of the patient-provider relationship. The quality of the relationship between patient and provider emerged as an important component of working through early struggles with diagnosis and the on-going struggles of living with a chronic illness. A variety of factors impacting the patient-provider relationship emerged as subthemes. What can be taken from this study is the importance of the patient provider relationship in the effective self-management of HIV infection. Additionally, several specific behaviors can enhance the patient-provider relationship and help assure movement toward patient acceptance of the illness and engagement in high-level adherence behaviors. PMID- 23809660 TI - Attitudes toward transitioning in youth with perinatally acquired HIV and their family caregivers. AB - This study investigated the preparedness and views of patients with perinatally acquired HIV and their family caregivers about transitioning to adult medical care. Fifteen participants (ages 15-24 years) with perinatally acquired HIV and eight family caregivers participated in structured interviews. All interviews were recorded and analyzed for themes using qualitative research methodology. Three major themes emerged: (a) perceived lack of readiness for transition, (b) fear of change and anxiety about entering the adult health care system, and (c) burgeoning personal responsibility that comes with age. Participants also offered suggestions to improve the transition experience, including starting the process early with specific guidelines. All patients and family caregivers wanted early knowledge about transition; these individuals could be an important resource to find potential solutions to guide the transition process. Clinical outcomes must be assessed in patients undergoing transition to determine the effect on management of medical disease, and protocols must be developed. PMID- 23809661 TI - Erectile dysfunction, penile atherosclerosis, and coronary artery vasculopathy in heart transplant recipients. AB - INTRODUCTION: Vascular erectile dysfunction (ED) is the expression of a systemic vascular disease and in particular of endothelial dysfunction. Dysfunctional endothelium plays also a significant role in the onset and progression of coronary artery vasculopathy (CAV). AIM: This pilot study was designed to evaluate the prevalence and pathogenesis of ED and its correlation with CAV in heart transplanted male. METHODS: A total of 77 male heart transplanted patients (HTx) evaluated in our center (mean age 61.6 + 10.6 years) were enrolled in the study. MAIN OUTCOME MEASURES: All subjects underwent accurate medical history collection, including lifestyle (cigarette smoking, dietary and sedentary habits, drug intake, and erectile function before cardiac transplantation), physical examination (body mass index and arterial pressure), biochemical blood tests (fasting glucose, total cholesterol, high-density lipoprotein cholesterol, and triglycerides), and hormones (prolactin, luteinizing hormone and total testosterone). Furthermore, they were studied with penile, carotid, femoral echo color Doppler ultrasonography and coronary angiogram. RESULTS: Incidence of ED was 24% before HTx and increased up to 65% after. Postischemic cardiomiopathy was an indication to HTx in ED group more frequently than in patients without ED (No ED group) (45.1% vs. 20%). ED patients showed a lower peak systolic velocity, a higher cavernosal intima-media thickness (IMT), a higher prevalence of cavernosal plaques (26.7% vs. 5.2%, P < 0.05), peripheral vascular disease (60.87% vs. 26.1%, P < 0.05) and CAV (45.8% vs. 25.8%, P < 0.05) with respect to No-ED patients. Coronary flow reserve was significantly reduced in ED vs. No-ED patients (2.43 + 0.7 vs. 2.9 + 0.8, P < 0.04). Finally, cavernous plaque and testosterone plasma levels were statistically associated with CAV. CONCLUSIONS: We showed that ED is a frequent disease in HTx patients, more common when the original pathology is postischemic cardiomiopathy and associated with higher prevalence of cavernous plaques and CAV. Its evaluation should be integral to an HTx rehab program. PMID- 23809662 TI - MMP-2 is a disease-modifying gene in primary sclerosing cholangitis. AB - BACKGROUND: Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the bile ducts, frequently necessitating orthotopic liver transplantation (OLT), often accompanied by inflammatory bowel disease (IBD). Matrix metalloproteinases (MMPs) are associated with fibrotic diseases caused by the involvement in tissue remodelling. AIM: To evaluate the contribution of MMP-2 and -9 promoter polymorphisms to disease severity in PSC, as assessed by death or need for OLT. METHODS: Matrix metalloproteinase-2 (-1306 C/T) and -9 (-1562 C/T) gene promoter polymorphisms were analyzed in 132 PSC patients. Follow-up was from onset PSC until death, OLT or end of follow-up. RESULTS: Twenty-year cumulative incidence (CI) of death or OLT for PSC patients with MMP-2 CT genotype was 86.5% compared to 52.8% for CC genotype (P = 0.030) and reached 100% at 11.3 years for TT genotype. In patients with IBD, CIs were similar: 20-years CI of death or OLT for MMP-2 CT genotype was 86.0% compared to 49.0% for CC genotype and 100% at 11.3 years for TT genotype. Patients without IBD showed a similar trend in 20 years CI for MMP-2 CT (77.8%) compared to CC (57.8%) and CI for TT genotype reached 100% at 9.3 years. Multivariate analysis showed, along with age at diagnosis, a stepwise increase in hazard ratio for MMP-2 T-allele polymorphism for death or OLT. MMP-9 genotype was not associated with disease severity in PSC. CONCLUSION: Matrix metalloproteinase-2 C to T-1306 gene promoter polymorphism in PSC is an independent risk factor for disease severity as reflected by the need for OLT or disease progression leading to mortality. PMID- 23809663 TI - Cd isotopes as a potential source tracer of metal pollution in river sediments. AB - Tracing the sources of heavy metals in water environment is key important for our understanding of their pollution behavior. In this present study, Cd concentrations and Cd isotopic compositions in sediments were determined to effectively identify possible Cd sources. Results showed that elevated concentrations and high enrichment factor for Cd were found in all sediments, suggesting anthropogenic Cd origin. Cd isotopic compositions in sediments yielded relative variations ranged from -0.350/00 to 0.070/00 in term of delta(114/110)Cd (the mean: -0.080/00). Large fractionated Cd was found in sediments collected from a smelter and an E-waste town. Cd isotopic compositions and Cd concentrations measured in sediments allowed the identification of three main origins (dust from metal refining (delta(114/110)Cd < 0), slag of metal refining (delta(114/110)Cd > 0), and those delta(114/110)Cd = 0, such as background and mining activity). According to the actual precision obtained, Cd isotopes could be a potential tool for tracing metal pollution sources in water environment. PMID- 23809664 TI - Treatment reality in elderly patients with advanced ovarian cancer: a prospective analysis of the OVCAD consortium. AB - BACKGROUND: Approximately one third of women diagnosed with ovarian cancer is 70 years or older. Information on the treatment reality of these elderly patients is limited. METHODS: 275 patients with primary epithelial ovarian cancer FIGO stage II-IV undergoing cytoreductive surgery and platinum-based chemotherapy were prospectively included in this European multicenter study. Patients <70 and >=70 years were compared regarding clinicopathological variables and prognosis. RESULTS: Median age was 58 years (18-85); 47 patients (17.1%) were 70 years or older. The postoperative 60-day-mortality rate was 2.1% for elderly and 0.4% for younger patients (p < 0.001). Elderly patients were less likely to receive optimal therapy (no residual disease after surgery and platinum combination chemotherapy) compared to patients <70 years (40.4% vs. 70.1%, p < 0.001) and their outcome was less favorable regarding median PFS (12 vs. 20 months, p = 0.022) and OS (30 vs. 64 months, p < 0.001). However, in multivariate analysis age itself was not a prognostic factor for PFS while the ECOG performance status had prognostic significance in elderly patients. CONCLUSIONS: Elderly patients with ovarian cancer are often treated less radically. Their outcome is impaired despite no consistent prognostic effect of age itself. Biological age and functional status should be considered before individualized treatment plans are defined. PMID- 23809665 TI - Current status of biotechnology in Slovakia. AB - The United Nations Convention on Biological Diversity defines biotechnology as: 'Any technological application that uses biological systems, living organisms, or derivatives thereof, to make or modify products or processes for specific use.' In other words biotechnology is 'application of scientific and technical advances in life science to develop commercial products' or briefly 'the use of molecular biology for useful purposes'. This short overview is about different branches of biotechnology carried out in Slovakia and it shows that Slovakia has a good potential for further development of modern biotechnologies. PMID- 23809666 TI - A pilot study on quality of artesunate and amodiaquine tablets used in the fishing community of Tema, Ghana. AB - BACKGROUND: The ineffectiveness of artesunate and amodiaquine tablets in malaria treatment remains a health burden to WHO and governments of malaria-endemic countries, including Ghana. The proliferation of illegitimate anti-malarial drugs and its use by patients is of primary concern to international and local drug regulatory agencies because such drugs are known to contribute to the development of the malaria-resistant parasites in humans. No data exist on quality of these drugs in the fishing village communities in Ghana although the villagers are likely users of such drugs. A pilot study on the quality of anti-malarial tablets in circulation during the major fishing season at a malarious fishing village located along the coast of Tema in southern Ghana was determined. METHODS: Blisterpacks of anti-malarial tablets were randomly sampled. The International Pharmacopoeia and Global Pharma Health Fund Minilab protocols were used to assess the quality of anti-malarial tablets per blisterpacks allegedly manufactured by Guilin Pharmaceutical Co Ltd, China (GPCL) and Letap Pharmaceuticals Ltd, Ghana (LPL) and sold in chemical sales outlets at Kpone-on-Sea. Ferric chloride and cobaltous thiocyanate tests confirmed the presence of active ingredients in the tablets. A confirmatory test for the active ingredient was achieved with artesunate (ICRS1409) and amodiaquine (ICRS0209) reference standards. A high performance liquid chromatography analysis confirmed the amount of artesunate found in tablets. RESULTS: Based on the International Pharmacopoeia acceptable range of 96/98 to 102% for genuine artesunate per tablet, 10% [relative standard deviation (RSD): 3.2%] of field-selected artesunate blisterpack per tablets manufactured by GPCL, and 50% (RSD: 5.1%) of a similar package per tablet by LPL, passed the titrimetric test. However, 100% (RSD: 2.2%) of amodiaquine blisterpack per tablet by GPCL were found to be within the International Pharmacopeia acceptable range of 90 to 110% for genuine amodiaquine in tablet, whilst 17% of a similar package per tablet by LPL failed spectrophotometric testing. CONCLUSION: Inadequate amounts of artesunate and amodiaquine detected in the tablets suggest that both pharmaceutical companies may not be following recommended drug formulation procedures, or the active pharmaceutical ingredients might have been degraded by improper storage conditions. Thus, drugs being sold at Kpone-on-Sea, Ghana may likely be classified as substandard drugs and not suitable for malaria treatment. PMID- 23809669 TI - Microbial communities along biogeochemical gradients in a hydrocarbon contaminated aquifer. AB - Micro-organisms are known to degrade a wide range of toxic substances. How the environment shapes microbial communities in polluted ecosystems and thus influences degradation capabilities is not yet fully understood. In this study, we investigated microbial communities in a highly complex environment: the capillary fringe and subjacent sediments in a hydrocarbon-contaminated aquifer. Sixty sediment sections were analysed using terminal restriction fragment length polymorphism (T-RFLP) fingerprinting, cloning and sequencing of bacterial and archaeal 16S rRNA genes, complemented by chemical analyses of petroleum hydrocarbons, methane, oxygen and alternative terminal electron acceptors. Multivariate statistics revealed concentrations of contaminants and the position of the water table as significant factors shaping the microbial community composition. Micro-organisms with highest T-RFLP abundances were related to sulphate reducers belonging to the genus Desulfosporosinus, fermenting bacteria of the genera Sedimentibacter and Smithella, and aerobic hydrocarbon degraders of the genus Acidovorax. Furthermore, the acetoclastic methanogens Methanosaeta, and hydrogenotrophic methanogens Methanocella and Methanoregula were detected. Whereas sulphate and sulphate reducers prevail at the contamination source, the detection of methane, fermenting bacteria and methanogenic archaea further downstream points towards syntrophic hydrocarbon degradation. PMID- 23809667 TI - Myosteatosis and myofibrosis: relationship with aging, inflammation and insulin resistance. AB - The mechanisms impairing muscle quality and leading to myofibrosis (MF) and myosteatosis (MS) are incompletely known. In biopsies of paraspinous muscle (PM) of 16 elderly men undergoing elective vertebral surgery, we histologically determined the area of MF and MS expressed as muscle quality index (MQI), in order to investigate the relation between them, as well as the main predictors of muscle quality. Total PM area and intermuscular adipose tissue (IMAT) were evaluated by MRI and body composition by DXA. Circulating fasting glucose, insulin, hs-CRP, leptin, adiponectin and IL-6 were measured and HOMA index calculated. Quantification of gene expression in PM and in subcutaneous adipose tissue (SAT) overlying the muscle was performed by rt-PCR. The degree of MS and MF was significantly and positively related to each other and positively associated with BMI, waist, FM and FM% as well as with IMAT. The area of PM was negatively related with MF even after adjustment for weight. Leptin was positively associated with MF and MS, whereas hs-CRP to MF. In backward regression analyses, larger waist and smaller PM area explained 90% of MF variance, whereas leptin about 80% of MS variance. IL-6 expression in SAT was significantly higher in participants with higher MQI values. In PM biopsies we found significantly higher expression of SOCS-3 and a trend toward higher expression of myostatin with greater degrees of MQI. MS and MF are related phenomena that concur to alter muscle quality and both should be considered in further studies on the evolution of sarcopenia. PMID- 23809668 TI - Novel approaches for the identification of biomarkers of aggressive prostate cancer. AB - The ability to distinguish indolent from aggressive prostate tumors remains one of the greatest challenges in the management of this disease. Ongoing efforts to establish a panel of molecular signatures, comprising gene expression profiles, proteins, epigenetic patterns, or a combination of these alterations, are being propelled by rapid advancements in 'omics' technologies. The identification of such biomarkers in biological fluids is an especially attractive goal for clinical applications. Here, we summarize recent progress in the identification of candidate prognostic biomarkers of prostate cancer using biological fluid samples. PMID- 23809670 TI - Impact of subcarinal dissection on short-term outcome and survival following esophagectomy. AB - BACKGROUND: The purpose of this study was to investigate the impact of subcarinal dissection on short-term outcomes and survival after esophagectomy in patients with thoracic esophageal squamous cell carcinoma. METHODS: Patients without subcarinal dissection were matched randomly to patients with subcarinal dissection in a 1:1 ratio according to 5 baseline variables (gender, pathologic stage, tumor location, histologic grade, and surgical approach) that may have major impacts on short-term outcomes and survival after esophagectomy in patients with thoracic esophageal squamous cell carcinoma. Preoperative clinical characteristics, short-term outcomes, and survival after esophagectomy of the 2 groups were compared. RESULTS: There were 128 patients included in each group. Blood loss, postoperative pleural drainage volume, and the incidences of postoperative complications and pulmonary complications in the nondissection group were significantly less than in the dissection group. The comparison of overall survival curves and disease-free survival curves between the 2 groups showed no significant difference (P > .05). CONCLUSIONS: Subcarinal dissection might be futile for patients with thoracic esophageal squamous cell carcinoma. PMID- 23809671 TI - The clinical impact of early complete pancreatic head devascularisation during pancreatoduodenectomy. AB - BACKGROUND: Early inferior pancreaticoduodenal artery (IPDA) ligation reduces intraoperative blood loss during pancreatoduodenectomy, but the impact on oncologic and long-term outcomes remains unknown. The aim of this study was to review the impact of complete pancreatic head devascularization during pancreatoduodenectomy on blood loss, transfusion rates, and clinicopathologic outcomes. METHODS: Clinicopathologic and outcome data were retrieved from a prospective database for all pancreatoduodenectomies performed from April 2004 to November 2010 and compared between early (IPDA+; n = 62) and late (IPDA-; n = 65) IPDA ligation groups. RESULTS: Early IPDA ligation was associated with reduced blood loss (394 +/- 21 vs 679 +/- 24 ml, P < .001) and perioperative transfusion (P = .031). A trend toward improved R0 resection was seen in patients with pancreatic adenocarcinoma (IPDA+ vs IPDA-, 100% vs 82%; P = .059), but this did not translate to improved 2-year (IPDA+ vs IPDA-, 76% vs 65%; P = .426) or overall (P = .82) survival. CONCLUSIONS: Early IPDA ligation reduces blood loss and transfusion requirements. Despite overall survival being unchanged, a trend toward improved R0 resection is encouraging and justifies further studies to ascertain the true oncologic significance of this technique. PMID- 23809672 TI - Laparoscopic versus robotic rectal resection for rectal cancer in a veteran population. AB - BACKGROUND: Robotic rectal cancer resection remains controversial. We compared the safety and efficacy of laparoscopic vs robotic rectal cancer resection in a high-risk Veterans Health Administration population. METHODS: Patients who underwent minimally invasive rectal cancer resection were identified from an institutional colorectal cancer database. Baseline characteristics and outcomes were compared between robotic and laparoscopic groups. RESULTS: The robotic group (n = 13) did not differ significantly from the laparoscopic group (n = 59) with respect to baseline characteristics except for a higher rate of previous abdominal surgery. Robotic patients had significantly lower tumors, more advanced disease, a higher rate of preoperative chemoradiation, and were more likely to undergo abdominoperineal resection. Robotic rectal resection was associated with longer operative time. There were no differences in blood loss, conversion rates, postoperative morbidity, lymph nodes harvested, margin positivity, or specimen quality between groups. CONCLUSIONS: The robotic approach for rectal cancer resection is safe with similar postoperative and oncologic outcomes compared with laparoscopy. PMID- 23809673 TI - Comparison of breast magnetic resonance imaging clinical tumor size with pathologic tumor size in patients status post-neoadjuvant chemotherapy. AB - BACKGROUND: Neoadjuvant chemotherapy (NACT) is used in breast cancer to evaluate the response to treatment. We examined the usefulness of breast magnetic resonance imaging (MRI) in the evaluation of tumor response after NACT. METHODS: Breast MRIs of 87 women with MRI after NACT were reviewed. The Spearman coefficient was used for estimating the correlation between MRI and pathologic tumor sizes (ypTs). RESULTS: The median age was 50 years (range 25 to 83 years). The median MRI size was 1.25 cm (range 0 to 10 cm). The median ypT was 1.20 cm (range 0 to 10.4 cm). The Spearman coefficient between MRI and ypT was .78 (95% confidence interval, .67 to .85; P < .0001). MRI was found to have a positive predictive value of 92% and a negative predictive value of 64% for residual in breast disease. The sensitivity and specificity of MRI were 86% and 77%, respectively. CONCLUSIONS: MRI correlates well with the final pathology and can be a useful modality to predict residual disease after NACT and aid in surgical planning. PMID- 23809674 TI - Nonthyroidal illness syndrome in enterocutaneous fistulas. AB - BACKGROUND: The aim of this study was to investigate the incidence, etiology, clinical outcomes, and prognosis of nonthyroidal illness syndrome (NTIS) in patients with enterocutaneous fistulas. METHODS: We prospectively collected 226 patients with enterocutaneous fistulas. Demographics, Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment scores, C-reactive protein, body mass index, albumin, and thyroidal hormones were evaluated for each patient. RESULTS: The incidence of NTIS was 57.5% in patients with enterocutaneous fistulas. Age and the APACHE II and Sequential Organ Failure Assessment scores were significantly higher, whereas albumin was lower in the NTIS group compared with those in the euthyroid group. A decreased sum activity of deiodinases and a reduced ratio of total thyroxin/free thyroxin and total triiodothyronine/free triiodothyronine were observed in the NTIS group. Patients with NTIS suffered longer durations in the intensive care unit and higher possibilities of mechanical ventilation. The cumulative survival rate was significantly lower in the NTIS group. CONCLUSIONS: NTIS was common, and patients with NTIS displayed worse clinical outcome and prognosis. A hypodeiodination condition and a potential thyroid hormone-binding dysfunction may play a role in the etiology of NTIS. A low serum albumin concentration and a high APACHE II score were risk factors of NTIS in enterocutaneous fistulas. PMID- 23809675 TI - Planning of anatomical liver segmentectomy and subsegmentectomy with 3 dimensional simulation software. AB - BACKGROUND: The aim of this study was to evaluate whether 3-dimensional (3D) simulation software is applicable to and useful for anatomic liver segmentectomy and subsegmentectomy. METHODS: A prospective study of 83 consecutive patients who underwent anatomic segmentectomy or subsegmentectomy using the puncture method was performed. All patients underwent 3D simulation analysis (SA) preoperatively for planning operative procedures. The clinical information acquired by 3D SA and the consistency of virtual and real hepatectomy were evaluated. RESULTS: The time needed for completing 3D SA was 18.3 +/- .7 minutes. Three-dimensional SA proposed resection of multiple segments or subsegments in 29 patients (35%). It also helped complement the resection line in 26 patients (31%) who lacked a bold staining area on the liver surface. The volume of segment or subsegment calculated by 3D SA was correlated with the actual resected specimen (R(2) = .9942, P < .01). The bordering hepatic veins were clearly exposed in 71 patients (86%), in accordance with completed drawings by 3D SA. CONCLUSIONS: Three dimensional SA showed accurate completed drawings and assisted liver surgeons in planning and executing anatomic segmentectomy and subsegmentectomy. PMID- 23809676 TI - Beyond surgical care improvement program compliance: antibiotic prophylaxis implementation gaps. AB - BACKGROUND: Despite increased compliance with Surgical Care Improvement Project infection measures, surgical-site infections are not decreasing. The aim of this study was to test the hypothesis that documented compliance with antibiotic prophylaxis guidelines on a pediatric surgery service does not reflect implementation fidelity or adherence to guidelines as intended. METHODS: A 7-week observational study of elective pediatric surgical cases was conducted. Adherence was evaluated for appropriate administration, type, timing, weight-based dosing, and redosing of antibiotics. RESULTS: Prophylactic antibiotics were administered appropriately in 141 of 143 cases (99%). Of 100 cases (70%) in which antibiotic prophylaxis was indicated, compliance was documented in 100% cases in the electronic medical record, but only 48% of cases adhered to all 5 guidelines. Lack of adherence was due primarily to dosing or timing errors. CONCLUSIONS: Lack of implementation fidelity in antibiotic prophylaxis guidelines may partly explain the lack of expected reduction in surgical-site infections. Future studies of Surgical Care Improvement Project effectiveness should measure adherence and implementation fidelity rather than just documented compliance. PMID- 23809677 TI - [Comments on "Importance of ultrasound in a department of endocrinology"]. PMID- 23809678 TI - [Pneumopericardium and pneumomediastinum in a diabetic and cocaine user patient]. PMID- 23809679 TI - Relationship in Japan between maternal grandmothers' perinatal support and their self-esteem. AB - This study investigated the influence on their mental well-being of the perinatal support given by Japanese grandmothers. The Rosenberg self-esteem and the Center for Epidemiologic Studies Depression (CES-D) scales were used to assess grandmothers' mental well-being before and after their daughters' childbirth. Of 198 grandmothers, 176 (88.9%) supported their daughters and three patterns of perinatal support were observed: grandmothers' support at the grandparents' house before childbirth (n = 95) (Satogaeri bunben; Japanese traditional perinatal support), grandmothers' support at the grandparents' house after childbirth (n = 53); and grandmothers' support at the daughters' house (n = 28). Those who supported their daughters at the grandparents' house before childbirth - especially the middle-aged (less than 60 years old) - showed significantly lower scores of self-esteem. Scores of CES-D did not significantly change before and after childbirth in either subgroup of grandmothers. It was concluded that grandmothers play an important role in supporting their daughters, and Satogaeri bunben is a typical event in modern Japan. However, Satogaeri bunben is a burden for middle-aged grandmothers, and we need to support them. PMID- 23809680 TI - Addressing perceptual insensitivity to facial affect in violent offenders: first evidence for the efficacy of a novel implicit training approach. AB - BACKGROUND: Although impaired recognition of affective facial expressions has been conclusively linked to antisocial behavior, little is known about the modifiability of this deficit. This study investigated whether and under which circumstances the proposed perceptual insensitivity can be addressed with a brief implicit training approach. METHOD: Facial affect recognition was assessed with an animated morph task, in which the participants (44 male incarcerated violent offenders and 43 matched controls) identified the onset of emotional expressions in animated morph clips that gradually changed from neutral to one of the six basic emotions. Half of the offenders were then implicitly trained to direct attention to salient face regions (attention training, AT) using a modified dot probe task. The other half underwent the same protocol but the intensity level of the presented expressions was additionally manipulated over the course of training sessions (sensitivity to emotional expressions training, SEE training). Subsequently, participants were reassessed with the animated morph task. RESULTS: Facial affect recognition was significantly impaired in violent offenders as compared with controls. Further, our results indicate that only the SEE training group exhibited a pronounced improvement in emotion recognition. CONCLUSIONS: We demonstrated for the first time that perceptual insensitivity to facial affect can be addressed by an implicit training that directs attention to salient regions of a face and gradually decreases the intensity of the emotional expression. Future studies should focus on the potential of this intervention to effectively increase empathy and inhibit violent behavior in antisocial individuals. PMID- 23809681 TI - [Kernohan-Woltman notch phenomenon secondary to a cranial epidural hematoma]. AB - Kernohan-Woltman notch phenomenon is a paradoxical neurological manifestation which involves a motor deficit on the same side as the primary brain injury. It is produced mainly by acute or chronic subdural hematomas, and less frequently by post-traumatic epidural ones. It should be taken into consideration in cases of ipsilateral motor deficit, as it may lead to surgical procedures being performed on the incorrect side. We report the case of a 40 year old man who sustained a major head injury which was followed by a decreased level of consciousness and anisocoria. Computed tomography of the brain revealed a frontal and parietal epidural hematoma with right midline shift and uncal herniation. Craniotomy and drainage of the hematoma was performed, and on the sixth day after surgery it was observed that the patient had a brachio-crural right hemiparesis. Magnetic resonance imaging showed an ischemic area on the left capsule and cerebral peduncle consistent with the diagnosis of Kernohan-Woltman notch phenomenon. PMID- 23809682 TI - The English National Chlamydia Screening Programme: where next? PMID- 23809683 TI - In vitro activity of non-bactericidal concentrations of polymyxin B in combination with other antimicrobials against OXA-23-producing carbapenem resistant Acinetobacter baumannii. PMID- 23809684 TI - Antimicrobial susceptibility associated with bloodstream infections in children: a referral hospital-based study. PMID- 23809685 TI - Accuracy of noninvasive hemoglobin and invasive point-of-care hemoglobin testing compared with a laboratory analyzer. AB - INTRODUCTION: Hemoglobin concentration is assessed to detect anemia and its associated morbidities. Hemoglobin is usually determined from venous or capillary blood samples run on a laboratory analyzer. However, this method requires a needle stick and results can be delayed. It also exposes caregivers to risks associated with needle sticks and blood exposure. Noninvasive hemoglobin determination would be of benefit to patients and caregivers because it would allow for quick and painless point-of-care assessment. METHODS: Hemoglobin determination from a noninvasive spot check hemoglobin device (Pronto-7 with SpHb, Masimo) and an invasive point-of-care device (HemoCue) was compared with venous blood samples run on a laboratory hematology analyzer. RESULTS: A total of 440 outpatients and healthy volunteers were included (mean age 36 years, 62% female). Compared with the hematology analyzer, the bias +/- standard deviation of was -0.1 +/- 1.1 g/dL for SpHb and -0.1 +/- 1.6 g/dL for HemoCue. CONCLUSION: Noninvasive hemoglobin testing with SpHb provided similar accuracy as invasive point-of-care hemoglobin testing and may enable more efficient and effective patient care. PMID- 23809686 TI - Oral breathing and speech disorders in children. AB - OBJECTIVE: To assess speech alterations in mouth-breathing children, and to correlate them with the respiratory type, etiology, gender, and age. METHOD: A total of 439 mouth-breathers were evaluated, aged between 4 and 12 years. The presence of speech alterations in children older than 5 years was considered delayed speech development. The observed alterations were tongue interposition (TI), frontal lisp (FL), articulatory disorders (AD), sound omissions (SO), and lateral lisp (LL). The etiology of mouth breathing, gender, age, respiratory type, and speech disorders were correlated. RESULTS: Speech alterations were diagnosed in 31.2% of patients, unrelated to the respiratory type: oral or mixed. Increased frequency of articulatory disorders and more than one speech disorder were observed in males. TI was observed in 53.3% patients, followed by AD in 26.3%, and by FL in 21.9%. The co-occurrence of two or more speech alterations was observed in 24.8% of the children. CONCLUSION: Mouth breathing can affect speech development, socialization, and school performance. Early detection of mouth breathing is essential to prevent and minimize its negative effects on the overall development of individuals. PMID- 23809687 TI - An exploration of context and the use of evidence-based nonpharmacological practices in emergency departments. AB - BACKGROUND: The uptake of evidence in practice remains a challenge for healthcare professionals including nurses and providers. Increased use of evidence-based practices (EBPs) in healthcare settings may improve patient conditions such as pain and decrease the cost of health care. The relationship between context in the practice environment and uptake of EBP remains an understudied area. AIMS: This study explored the relationships of context including the elements of individual, unit, and hospital and the use of evidence-based nonpharmacological pediatric pain management practices (EBNPPs) using an existing data set of RNs and providers, defined as doctors of medicine and osteopathy, nurse practitioners, and physician assistants caring for children in the emergency department. METHODS: A secondary data analysis was conducted using correlation and regression. RESULTS: Initial analysis identified several significant positive correlations with individual, unit, and hospital context elements and EBNPP. A significant correlation was not found between evaluation and EBNPP and magnet status and EBNPP for RNs or providers. RN regression analyses found that knowledge and continuing education were significant predictors of EBNPP. Overall context was a significant predictor of EBNPP for both the RN and provider models. A pooled regression analysis with RNs and providers found that RNs had a significant increased use of EBNPP when compared to providers. CONCLUSIONS: Regression analyses found that overall context significantly predicted the use of EBPPM for RNs and providers although no one element-individual, unit, or hospital was identified as more important. The effect of context on EBNPP did not differ by profession in this sample. Future research should focus on the overall influence of context on EBP and consider other factors that may play a role in the uptake of EBP. PMID- 23809688 TI - Use APIC's mentoring program to take your profession to the next level. PMID- 23809689 TI - Diabetes and early postpartum methicillin-resistant Staphylococcus aureus infection in US hospitals. AB - BACKGROUND: The epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) infection in postpartum women is not well characterized. Because diabetes is a risk factor for some infections, we sought to characterize the relationship between diabetes and invasive MRSA infections in women admitted to US hospitals for delivery of an infant. METHODS: We used data from the Nationwide Inpatient Sample, a representative sample of US community hospitals. Multivariate hierarchical logistic regression was used to estimate odds ratios (OR), adjusting for age, race, selected comorbidities, and expected payer, and hospital teaching status, urbanicity, bed size, geographic region, and ownership. RESULTS: The odds ratio for prepregnancy diabetes was 3.4 (95% confidence interval: 1.9-6.0). The relationship remained strong after external adjustment for obesity (OR, 2.5; 95% CI: 1.3-4.8). The OR comparing women with complicated versus uncomplicated diabetes was 1.5 (95% CI: 0.3-6.0). We did not find an association with gestational diabetes (OR, 1.1; 95% CI: 0.7-1.7). CONCLUSION: Prepregnancy diabetes, but not gestational diabetes, appears to be a risk factor for invasive MRSA infection in the early postpartum period. Women with diabetic complications may be at additional risk, but estimates were imprecise. PMID- 23809690 TI - Does health care role and experience influence perception of safety culture related to preventing infections? AB - Growing evidence reveals the importance of improving safety culture in efforts to eliminate health care-associated infections. This multisite, cross-sectional survey examined the association between professional role and health care experience on infection prevention safety culture at 5 hospitals. The findings suggest that frontline health care technicians are less directly engaged in improvement efforts and safety education than other staff and that infection prevention safety culture varies more by hospital than by staff position and experience. PMID- 23809691 TI - The CLOSER (CLarifying Vaginal Atrophy's Impact On SEx and Relationships) survey: implications of vaginal discomfort in postmenopausal women and in male partners. AB - INTRODUCTION: Postmenopausal vaginal atrophy (VA) is a chronic condition with symptoms that include vaginal dryness, soreness, itching, burning, and dyspareunia. AIM: The CLarifying Vaginal Atrophy's Impact On SEx and Relationships survey evaluated the impact of VA on the physical and emotional aspects of sexual relationships between postmenopausal women and their male partners. METHODS: Four thousand one hundred females and 4,100 males representing the United Kingdom, Finland, Norway, Sweden, Denmark, Italy, France, Canada, and the United States were surveyed. Assessments included: (i) talking about VA and its symptoms; (ii) the impact of VA on intimacy, relationships, and women's self esteem; (iii) talking about VA and erectile dysfunction (ED); and (iv) the impact of local estrogen therapy (LET) on intimacy and relationships. MAIN OUTCOME MEASURES: Descriptive data on the impact of VA. RESULTS: Twenty-eight percent of women did not tell their partners when they first encountered vaginal discomfort, mainly because they felt "it was just a natural part of growing older" (52%) or because of "embarrassment" (21%). Eighty-two percent of males wanted their partner to share their experiences with VA; males were also more comfortable discussing VA than females (68% vs. 58%, respectively). Having sex less often (women: 58%, men: 61%), less satisfying sex (women: 49%, men: 28%), and putting off having sex (women: 35%, men: 14%) were the main effects of VA. Intimacy avoidance was attributed to painful sex (women: 55%, men: 61%) and women's reduced sexual desire (women: 46%, men: 43%). Discussions about vaginal discomfort and ED were generally limited to partners and healthcare providers (HCPs). LET use resulted in less painful sex (women: 62%, men: 59%) and more satisfying sex (women: 47%, men: 49%). CONCLUSIONS: VA has an adverse emotional and physical impact on postmenopausal women and their partners. These findings may encourage more open communication about VA between couples and their HCPs. PMID- 23809692 TI - A detailed evaluation of TomoDirect 3DCRT planning for whole-breast radiation therapy. AB - The goal of this work was to develop planning strategies for whole-breast radiotherapy (WBRT) using TomoDirect three-dimensional conformal radiation therapy (TD-3DCRT) and to compare TD-3DCRT with conventional 3DCRT and TD intensity-modulated radiation therapy (TD-IMRT) to evaluate differences in WBRT plan quality. Computed tomography (CT) images of 10 women were used to generate 150 WBRT plans, varying in target structures, field width (FW), pitch, and number of beams. Effects on target and external maximum doses (EMD), organ-at-risk (OAR) doses, and treatment time were assessed for each parameter to establish an optimal planning technique. Using this technique, TD-3DCRT plans were generated and compared with TD-IMRT and standard 3DCRT plans. FW 5.0cm with pitch = 0.250cm significantly decreased EMD without increasing lung V20Gy. Increasing number of beams from 2 to 6 and using an additional breast planning structure decreased EMD though increased lung V20Gy. Changes in pitch had minimal effect on plan metrics. TD-3DCRT plans were subsequently generated using FW 5.0cm, pitch = 0.250cm, and 2 beams, with additional beams or planning structures added to decrease EMD when necessary. TD-3DCRT and TD-IMRT significantly decreased target maximum dose compared to standard 3DCRT. FW 5.0cm with 2 to 6 beams or novel planning structures or both allow for TD-3DCRT WBRT plans with excellent target coverage and OAR doses. TD-3DCRT plans are comparable to plans generated using TD-IMRT and provide an alternative to conventional 3DCRT for WBRT. PMID- 23809693 TI - Analysis of high-dose rate brachytherapy dose distribution resemblance in CyberKnife hypofractionated treatment plans of localized prostate cancer. AB - The present study is to analyze the CyberKnife hypofractionated dose distribution of localized prostate cancer in terms of high-dose rate (HDR) brachytherapy equivalent doses to assess the degree of HDR brachytherapy resemblance of CyberKnife dose distribution. Thirteen randomly selected localized prostate cancer cases treated using CyberKnife with a dose regimen of 36.25Gy in 5 fractions were considered. HDR equivalent doses were calculated for 30Gy in 3 fractions of HDR brachytherapy regimen. The D5% of the target in the CyberKnife hypofractionation was 41.57 +/- 2.41Gy. The corresponding HDR fractionation (3 fractions) equivalent dose was 32.81 +/- 1.86Gy. The mean HDR fractionation equivalent dose, D98%, was 27.93 +/- 0.84Gy. The V100% of the prostate target was 95.57% +/- 3.47%. The V100% of the bladder and the rectum were 717.16 and 79.6mm(3), respectively. Analysis of the HDR equivalent dose of CyberKnife dose distribution indicates a comparable resemblance to HDR dose distribution in the peripheral target doses (D98% to D80%) reported in the literature. However, there is a substantial difference observed in the core high-dose regions especially in D10% and D5%. The dose fall-off within the OAR is also superior in reported HDR dose distribution than the HDR equivalent doses of CyberKnife. PMID- 23809694 TI - Health inequalities as a foundation for embodying knowledge within public health teaching: a qualitative study. AB - INTRODUCTION: Recent U.K. health policies identified nurses as key contributors to the social justice agenda of reducing health inequalities, on the assumption that all nurses understand and wish to contribute to public health. Following this policy shift, public health content within pre-registration nursing curricula increased. However, public health nurse educators (PHNEs) had various backgrounds, and some had limited formal public health training, or involvement in or understanding of policy required to contribute effectively to it. Their knowledge of this subject, their understanding and interpretation of how it could be taught, was not fully understood. METHODOLOGY: This research aimed to understand how public health nurse educators' professional knowledge could be conceptualised and to develop a substantive theory of their knowledge of teaching public health, using a qualitative data analysis approach. Qualitative in-depth semi-structured interviews (n=26) were conducted with eleven university-based PHNEs. RESULTS: Integrating public health into all aspects of life was seen as central to the knowing and teaching of public health; this was conceptualised as 'embodying knowledge'. Participants identified the meaning of embodying knowledge for teaching public health as: (a) possessing a wider vision of health; (b) reflecting and learning from experience; and (c) engaging in appropriate pedagogical practices. CONCLUSION: The concept of public health can mean different things to different people. The variations of meaning ascribed to public health reflect the various backgrounds from which the public health workforce is drawn. The analysis indicates that PHNEs are embodying knowledge for teaching through critical pedagogy, which involves them engaging in transformative, interpretive and integrative processes to refashion public health concepts; this requires PHNEs who possess a vision of what to teach, know how to teach, and are able to learn from experience. Their vision of public health is influenced by social justice principles in that health inequalities, socioeconomic determinants of health, epidemiology, and policy and politics are seen as essential areas of the public health curriculum. They believe in forms of teaching that achieve social transformation at individual, behavioural and societal levels, while also enabling learners to recognise their capacity to effect change. PMID- 23809695 TI - Specific inhibition of one DNMT1-including complex influences tumor initiation and progression. AB - BACKGROUND: Reactivation of silenced tumor suppressor genes by DNMT inhibitors has provided an alternative approach to cancer therapy. However, DNMT inhibitors have also been shown to induce or enhance tumorigenesis via DNA hypomethylation induced oncogene activation and chromosomal instability. To develop more specific DNMT inhibitors for efficient cancer therapy, we compared the effects of peptides designed to specifically disrupt the interaction of DNMT1 with different proteins. FINDINGS: Our data indicated that the use of an unspecific DNMT inhibitor (5aza-2deoxycytidine), a DNMT1 inhibitor (procainamide) or peptides disrupting the DNMT1/PCNA, DNMT1/EZH2, DNMT1/HDAC1, DNMT1/DNMT3b and DNMT1/HP1 interactions promoted or enhanced in vivo tumorigenesis in a mouse glioma model. In contrast, a peptide disrupting the DNMT1/DMAP1 interaction, which per se did not affect tumor growth, sensitized cancer cells to chemotherapy/irradiation induced cell death. Finally, our data indicated that the peptide disrupting the DNMT1/DMAP1 interaction increased the efficiency of temozolomide treatment. CONCLUSION: Our data suggest that the DNMT1/DMAP1 interaction could be an effective anti-cancer target and opens a new avenue for the development of new strategies to design DNMT inhibitors. PMID- 23809697 TI - Critical questions about early character acquisition-comment on Retallack 2012 : "some Ediacaran fossils lived on land". PMID- 23809696 TI - Peripheral blood derived gene panels predict response to infliximab in rheumatoid arthritis and Crohn's disease. AB - BACKGROUND: Biological therapies have been introduced for the treatment of chronic inflammatory diseases including rheumatoid arthritis (RA) and Crohn's disease (CD). The efficacy of biologics differs from patient to patient. Moreover these therapies are rather expensive, therefore treatment of primary non responders should be avoided. METHOD: We addressed this issue by combining gene expression profiling and biostatistical approaches. We performed peripheral blood global gene expression profiling in order to filter the genome for target genes in cohorts of 20 CD and 19 RA patients. Then RT-quantitative PCR validation was performed, followed by multivariate analyses of genes in independent cohorts of 20 CD and 15 RA patients, in order to identify sets ofinterrelated genes that can separate responders from non-responders to the humanized chimeric anti-TNFalpha antibody infliximab at baseline. RESULTS: Gene panels separating responders from non-responders were identified using leave-one-out cross-validation test, and a pool of genes that should be tested on larger cohorts was created in both conditions. CONCLUSIONS: Our data show that peripheral blood gene expression profiles are suitable for determining gene panels with high discriminatory power to differentiate responders from non-responders in infliximab therapy at baseline in CD and RA, which could be cross-validated successfully. Biostatistical analysis of peripheral blood gene expression data leads to the identification of gene panels that can help predict responsiveness of therapy and support the clinical decision-making process. PMID- 23809698 TI - Distal-less and dachshund pattern both plesiomorphic and apomorphic structures in chelicerates: RNA interference in the harvestman Phalangium opilio (Opiliones). AB - The discovery of genetic mechanisms that can transform a morphological structure from a plesiomorphic (=primitive) state to an apomorphic (=derived) one is a cardinal objective of evolutionary developmental biology. However, this objective is often impeded for many lineages of interest by limitations in taxonomic sampling, genomic resources, or functional genetic methods. In order to investigate the evolution of appendage morphology within Chelicerata, the putative sister group of the remaining arthropods, we developed an RNA interference (RNAi) protocol for the harvestman Phalangium opilio. We silenced the leg gap genes Distal-less (Dll) and dachshund (dac) in the harvestman via zygotic injections of double-stranded RNA (dsRNA), and used in situ hybridization to confirm RNAi efficacy. Consistent with the conserved roles of these genes in patterning the proximo-distal axis of arthropod appendages, we observed that embryos injected with Dll dsRNA lacked distal parts of appendages and appendage like structures, such as the labrum, the chelicerae, the pedipalps, and the walking legs, whereas embryos injected with dac dsRNA lacked the medial podomeres femur and patella in the pedipalps and walking legs. In addition, we detected a role for these genes in patterning structures that do not occur in well established chelicerate models (spiders and mites). Dll RNAi additionally results in loss of the preoral chamber, which is formed from pedipalpal and leg coxapophyses, and the ocularium, a dorsal outgrowth bearing the eyes. In one case, we observed that an embryo injected with dac dsRNA lacked the proximal segment of the chelicera, a plesiomorphic podomere that expresses dac in wild type embryos. This may support the hypothesis that loss of the cheliceral dac domain underlies the transition to the two-segmented chelicera of derived arachnids. PMID- 23809699 TI - Contingent interactions among biofilm-forming bacteria determine preservation or decay in the first steps toward fossilization of marine embryos. AB - Fossils of soft tissues provide important records of early animals and embryos, and there is substantial evidence for a role for microbes in soft tissue fossilization. We are investigating the initial events in interactions of bacteria with freshly dead tissue, using marine embryos as a model system. We previously found that microbial invasion can stabilize embryo tissue that would otherwise disintegrate in hours or days by generating a bacterial pseudomorph, a three dimensional biofilm that both replaces the tissue and replicates its morphology. In this study, we sampled seawater at different times and places near Sydney, Australia, and determined the range and frequency of different taphonomic outcomes. Although destruction was most common, bacteria in 35% of seawater samples yielded morphology-preserving biofilms. We could replicate the taphonomic pathways seen with seawater bacterial communities using single cultured strains of marine gammaproteobacteria. Each given species reproducibly generated a consistent taphonomic outcome and we identified species that yielded each of the distinct pathways produced by seawater bacterial communities. Once formed,bacterial pseudomorphs are stable for over a year and resist attack by other bacteria and destruction by proteases and other lytic enzymes. Competition studies showed that the initial action of a pseudomorphing strain can be blocked by a strain that destroys tissues. Thus embryo preservation in nature may depend on contingent interactions among bacterial species that determine if pseudomorphing occurs.We used Artemia nauplius larvae to show that bacterial biofilm replacement of tissue is not restricted to embryos, but is relevant for preservation of small multicellular organisms. We present a model for bacterial self-assembly of large-scale three-dimensional tissue pseudomorphs, based on smallscaleinteractions among individual bacterial cells to form local biofilms at structural boundaries within the tissue. Localbiofilms then conjoin to generate the pseudomorph. PMID- 23809701 TI - Jaw growth in the absence of teeth: the developmental morphology of edentulous mandibles using the p63 mouse mutant. AB - Mammalian tooth and jaw development must be coordinated well enough that these systems continue to function together properly throughout growth, thus optimizing an animal's survival and fitness, as well as a species' success. The persistent question is how teeth and jaws remain developmentally and functionally viable despite sometimes monumental evolutionary changes to tooth and jaw shape and size. Here we used the p63 mouse mutant to test the effect of tooth development - or the lack thereof - on normal mandible developmental morphology. Using 3D geometric morphometrics, we compared for the first time mandible shape among mice with normal tooth and jaw development against p63 double knock-out mice, with failed tooth development but apparently normal jaw development. Mandible shape differed statistically between toothless (p63(-/-) ) and toothed (p63(+/-) , p63(+/+) ) mice as early as embryonic day (E) 18. As expected, most of the shape difference in the p63(-/-) mandibles was due to underdeveloped alveolar bone related to arrested odontogenesis in these E18-aged mice. Mandible shape did not differ statistically between p63(+/-) and p63(+/+) adult mice, which showed normal tooth development. Our results support the idea of a gene regulatory network that is exclusive to the mandible and independent of the dentition. This study also underscores the biomechanical impact of the teeth on the developing alveolar bone. Importantly, this work shows quantitatively that the p63 mutant is an apt model with which to study mandible morphogenesis in isolation of odontogenesis to clarify developmental relationships between the teeth and jaws. PMID- 23809700 TI - Genetic and developmental analysis of differences in eye and face morphology between Drosophila simulans and Drosophila mauritiana. AB - Eye and head morphology vary considerably among insects and even between closely related species of Drosophila. Species of the D. melanogaster subgroup, and other Drosophila species, exhibit a negative correlation between eye size and face width (FW); for example, D. mauritiana generally has bigger eyes composed of larger ommatidia and conversely a narrower face than its sibling species. To better understand the evolution of eye and head morphology, we investigated the genetic and developmental basis of differences in eye size and FW between male D. mauritiana and D. simulans. QTL mapping of eye size and FW showed that the major loci responsible for the interspecific variation in these traits are localized to different genomic regions. Introgression of the largest effect QTL underlying the difference in eye size resulted in flies with larger eyes but no significant difference in FW. Moreover,introgression of a QTL region on the third chromosome that contributes to the FW difference between these species affected FW, but not eye size. We also observed that this difference in FW is detectable earlier in the development of the eye-antennal disc than the difference in the size of the retinal field. Our results suggest that different loci that act at different developmental stages underlie changes in eye size and FW. Therefore, while there is a negative correlation between these traits in Drosophila, we show genetically that they also have the potential to evolve independently and this may help to explain the evolution of these traits in other insects. PMID- 23809702 TI - The expression of limb gap genes in the mite Archegozetes longisetosus reveals differential patterning mechanisms in chelicerates. AB - The modular organization of arthropod limbs has lead to the evolution of a diversity of appendages within this phylum. A conserved trait within the arthropods is the utilization of a conserved set of regulatory genes that specify the appendage podomeres along the proximo-distal axis, termed the limb gap genes. These include extradenticle, homothorax, dachshund, and Distal-less. The deployment of these genes in the most basally branching arthropod group, the chelicerates, has only been studied in detail in two chelicerate groups, the harvestmen and spiders. Given the broad range of appendage diversity within the chelicerates, comparative studies of gap gene deployment in other chelicerates groups is needed. We therefore followed limb gap gene expression in a member of the largest chelicerate group, Acari, the oribatid mite Archegozetes longisetosus. We show that in contrast to many arthropod species, A. longisetosus expresses homothorax and extradenticle exclusively in the proximal portion of the appendages, which refutes the hypothesis of a sister-group relationship between chelicerates and myriapods. We also provide evidence that mites posses the ancestral chelicerate condition of possessing three-segmented chelicerae, which also express the gene dachshund. This adds support to the hypothesis that a cheliceral dachshund domain is ancestral to arachnids. Lastly, we provide evidence that the suppression of the fourth pair of walking legs, a putative synapomorphy for Acari, is accomplished by repressing the development of the medial and distal regions of the limb. PMID- 23809703 TI - Developmental expression and evolution of muscle-specific microRNAs conserved in vertebrates. AB - microRNAs (miRs) are small non-coding RNA molecules expressed in a tissue specific manner in numerous organisms. Among them, miR-1, miR-206, and miR-133, which are encoded as bicistronic gene clusters in the genome, play major roles in the control of vertebrate myogenesis. To address how the gene organization and function of these miRs evolved, we identified their homologues in the cyclostomes, the chondrichthyans and the teleosts, and examined their patterns of expression during development. It was suggested that the chondrichthyans and the cyclostome lampreys possess fewer miR-1/miR-133 genes than the medaka. The medaka additionally possessed the miR-206 gene which was not found in the genomes of chondrichthyans and lampreys. In contrast, the number and genomic organization of medaka miR-1(206)/miR-133 were similar to those found in mammals. In the lamprey, shark and medaka, miR-1 and miR-133 were expressed in both skeletal and cardiac muscle cells in adults, a developmental feature traced back to chordate invertebrates such as ascidians. We further examined the expression of these miRs in different muscle tissues in medaka embryos. miR-206 was expressed in both the tail and pectoral fin muscles, whereas miR-1, which shares the similar nucleotide sequence with miR-206, was not detectable in the embryonic pectoral fins. Comparison of the relative positions with the neighboring protein-coding genes showed high conservation of synteny between the miR-1(206)/miR-133 clusters in a single species, as well as across the vertebrate taxa. Our results suggest that, after the gene duplications, these muscle-specific miRs acquired differential regulatory functions and have contributed to the establishment of diverse and complex musculature of vertebrates. PMID- 23809704 TI - Parallel evolution of novelties: extremely long intromittent organs in the leaf beetle subfamily Criocerinae. AB - Extreme elongation of a part of the intromittent organ, the flagellum, has occurred several times in Criocerinae (Chrysomelidae). These leaf beetles have acquired a specialized pocket to store the flagellum in the abdominal cavity, at the same time allowing a quick control of movements of this structure during copulation. We investigated the morphogenesis of the intromittent organs of species with and without a flagellum to discuss the evolutionary background of parallel evolution of novel structures. We found that the specialized pocket is formed by the invagination of an epidermal layer and a resultant rotation of the primary gonopore. Invagination itself is a well-known phenomenon in morphogenetic processes, which leads us to hypothesize that the novelty is formed by co-opting a previously acquired genetic system. A large open-space is present within the intromittent organ during the entire morphogenesis in species without a flagellum, and the invagination in the species with a flagellum grows in the corresponding area. This means that there are no physical impediments for the growth of a large pocket. In addition the sites of muscular attachments in the species with a flagellum are also different from those without it. The differentiation of muscles is completed immediately before adult emergence, which means the muscles are adjustable during the entire morphogenesis in this group. Simple modifications probably based on a co-option of previously acquired genetic systems, the potential space for adding a new element, and an adjustable factor in morphogenesis of the intromittent organ facilitate the parallel evolution of the extreme elongation. PMID- 23809705 TI - Maternal education level and low birth weight: a meta-analysis. AB - OBJECTIVE: To assess the association between maternal education level and birth weight, considering the circumstances in which the excess use of technology in healthcare, as well as the scarcity of these resources, may result in similar outcomes. METHODS: A meta-analysis of cohort and cross-sectional studies was performed; the studies were selected by systematic review in the MEDLINE database using the following Key**words socioeconomic factors, infant, low birth weight, cohort studies, cross-sectional studies. The summary measures of effect were obtained by random effect model, and its results were obtained through forest plot graphs. The publication bias was assessed by Egger's test, and the Newcastle Ottawa scale was used to assess study quality. RESULTS: The initial search found 729 articles. Of these, 594 were excluded after reading the title and abstract; 21, after consensus meetings among the three reviewers; 102, after reading the full text; and three for not having the proper outcome. Of the nine final articles, 88.8% had quality >= six stars (Newcastle-Ottawa Scale), showing good quality studies. The heterogeneity of the articles was considered moderate. High maternal education showed a 33% protective effect against low birth weight, whereas medium degree of education showed no significant protection when compared to low maternal education. CONCLUSIONS: The hypothesis of similarity between the extreme degrees of social distribution, translated by maternal education level in relation to the proportion of low birth weight, was not confirmed. PMID- 23809706 TI - The relationship between knee arthroscopy and arthroplasty in patients under 65 years of age. AB - A private payer database was used to examine the incidence and rates of knee arthroscopy in patients less than 65 years of age and the subsequent risk of knee arthroplasty. Time to event analysis was performed using the Kaplan-Meier method; also, Cox regression analysis was used to evaluate the relative risk of subsequent knee arthroplasty for arthroscopic patients. Overall, 247,034 knee arthroscopies, done for injury or arthropathy, were identified between 2004 and 2009. Within 1-year of arthroscopy, 2.2% of arthropathy patients and 0.9% of injury patients underwent a knee arthroplasty. These increased to 5.2% and 2.4% at 5-years, respectively. The risk of arthroplasty following arthroscopy increased significantly with age. Further study is warranted to examine the benefit of arthroscopy in younger patients with OA. PMID- 23809708 TI - Letter to the editor Lustig et al entitled 'unsatifactory accuracy as determined by computer navigation of visionaire patient-specific instrumentation for total knee arthroplasty'. PMID- 23809707 TI - Retrieval analysis of posterior stabilized polyethylene tibial inserts and its clinical relevance. AB - This was a retrieval analysis of 83 PS inserts to assess the effect of limb alignment, implant position and joint line position on the pattern of wear in posterior stabilized (PS) tibial inserts. The total damage score was significantly higher in knees with postoperative varus alignment more than 3 degrees (P = 0.03). The total damage score to the post was significantly more in knees with joint line elevation more than 5 mm (9.7 +/- 3.9, compared to 6.5 +/- 3.7 in knees with less joint line elevation) (P = 0.05). Limb malalignment and joint line elevation resulted in more damage in PS inserts. An external rotation subluxation damage pattern was found in joint line elevation. PMID- 23809709 TI - Effectiveness of a multidimensional home nurse led heart failure disease management program--a French nationwide time-series comparison. AB - BACKGROUND: The purpose of this study was to assess the effectiveness of a disease management program (DMP) in heart failure (HF) on the incidence of HF hospitalizations and related costs in a real-world population-based setting. METHODS: Insuffisance CArdiaque en LORraine (ICALOR), a DMP for HF was established in 2006 in the French region of Lorraine. Patients were enrolled after an index HF hospitalization. They received educational and home-visit monitoring programs by HF-trained nurses. General physicians received automatic alerts about patients' significant clinical or biological changes. We used the ICALOR and the national diagnostic related group databases to conduct a comparison of time-series trends in HF hospitalizations in France. The economic impact was obtained using the national scale of costs in France. RESULTS: The median age of the 1222 patients recruited before 2010 was 76 years, and 65% were male. Upon enrollment, patients essentially presented with NYHA class II (n=537, 48%) or class III (n=359, 32%) symptoms. One-year mortality rate was 20.3%. The implementation of the ICALOR program was associated with a reduction in HF hospitalizations in Lorraine estimated by an absolute difference between the number of hospitalizations observed in the Lorraine region and that expected had it been similar to that observed in the whole country of -7.19% in 2010. The estimated annual hospital cost saved by ICALOR was ?1,927,648 in 2010. CONCLUSION: Coordinated DMP of HF might improve outcome cost-effectively when implemented in a real-world population setting, and was associated in Lorraine with a substantial modification of the trend of HF hospitalizations. PMID- 23809710 TI - A carbon responsive G-protein coupled receptor modulates broad developmental and genetic networks in the entomopathogenic fungus, Beauveria bassiana. AB - In fungi, G-protein coupled receptors (GPCRs) link ligand/nutrient sensing to growth, mating, developmental/life-stage activation and pathogenesis. A GPCR was characterized from the entomopathogenic fungus, Beauveria bassiana (BbGPCR3), which links nutrient sensing to stress response and development. DeltaBbGPCR3 mutants grew slower on various carbohydrates and displayed increased sensitivity to osmotic, oxidative and cell wall stresses. Gene expression profiling revealed a set of heat-shock and antioxidant factors that failed to be induced under oxidative stress and aberrant regulation of compatible solute-forming enzymes and cell wall biosynthesis/remodelling proteins in DeltaBbGPCR3 after osmotic stress. Glucose-specific developmental defects included reduced (> 90%) conidiation and reduced dimorphic transition to the production of yeast-like blastospores, effects suppressed in media containing trehalose or glycerol, but not by addition of cyclic AMP. Insect bioassays revealed reduced virulence in topical assays but no effect in intrahaemoceol injection assays, indicating that BbGPCR3 was important in sensing signals during the initial interaction with the host but dispensable for post-penetration events. Comparative gene expression profiling of DeltaBbGPCR3 mutants grown in glucose media compared with wild-type/glucose and DeltaBbGPCR3/trehalose grown cells revealed sets of genes misregulated and recovered, respectively. These data link BbGPCR3 to broad developmental and genetic networks that include the major MAP kinase pathways. PMID- 23809711 TI - Herpes zoster. AB - Herpes zoster is a common condition that significantly affects health-related quality of life. Most cases occur in immunocompetent individuals older than 60 years; however, immunosuppressed patients are at particularly high risk. Post herpetic neuralgia is the most common serious complication of herpes zoster, and is much more common in the very elderly. Vaccination with the zoster vaccine is recommended for most people older than 60, and reduces the incidence of herpes zoster and the occurrence of post-herpetic neuralgia. PMID- 23809713 TI - Pertussis. AB - Pertussis, or whopping cough, is an upper respiratory tract infection caused by Bordetella pertussis. It has long been a concern in pediatric populations, leading to aggressive vaccination strategies to help decrease pediatric disease. In recent years, recognition of pertussis infection in adult populations has increased, leading to more frequent diagnosis and recommendations for booster immunizations in the adult population. Early recognition and treatment as well as vaccination will help reduce the current increase in this disease. PMID- 23809712 TI - Clostridium difficile Infection. AB - Clostridium difficile is emerging as a common cause of infectious diarrhea. Incidence has increased dramatically since 2000, associated with a new strain that features both increased toxin production and increased resistance to antibiotics. For patients with mild to moderate disease, oral metronidazole is usually the first choice of treatment, and those with severe disease should be treated with vancomycin, with additional intravenous metronidazole in some cases. Fecal microbiota transplantation is a potentially promising therapy for patients with multiple recurrences of C difficile infection. Prevention of nosocomial transmission is crucial to reducing disease outbreaks in health care settings. PMID- 23809714 TI - Multidrug-resistant Tuberculosis. AB - Multidrug-resistant tuberculosis (MDR-TB) threatens to become the dominant form of tuberculosis in many parts of the world because of decades of inappropriate treatment on a global scale. Infection with MDR-TB is associated with poor outcomes because of delays in treatment and the need for complex, toxic, and long medication regimens. Most cases are undetected because of technological and economic barriers to diagnosing tuberculosis and the availability of assays to test for drug resistance. Experience in treating MDR-TB is scarce. Tuberculosis was once curable, but could become a potentially untreatable infectious disease unless efforts are made to control it. PMID- 23809715 TI - Infections in transplant patients. AB - Recipients of solid organ transplants (SOT) need primary care providers (PCPs) who are familiar with their unique needs and understand the lifelong infectious risks faced by SOT patients because of their need for lifelong immunosuppressive medications. SOT recipients can present with atypical and muted manifestations of infections, for which the knowledgable PCP will initiate a comprehensive evaluation. The goal of this article is to familiarize PCPs with the infectious challenges facing SOT patients. General concepts are reviewed, and a series of patient cases described that illustrate the specific learning points based on common presenting clinical symptoms. PMID- 23809716 TI - Methicillin-resistant Staphylococcus aureus infections. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is an important pathogen that has exploded into clinical prominence in a short period. New medications are available for the treatment of MRSA infections, each with its own pitfalls and caveats. However, the resistance profile of the bacteria is becoming more complex. Recent guidelines from the Infectious Diseases Society of America provide an evidence-based framework for the management of MRSA infections. This article provides additional practical advice on approaches to MRSA, including the detection, prevention, and management of a variety of its common presentations. PMID- 23809717 TI - Influenza. AB - Influenza is a common virus whose ability to change its genetic makeup allows for disease of pandemic proportion. This article summarizes the different strains of influenza circulating in the United States for the past century, the diagnosis and treatment of influenza, as well as the different ways to prevent disease. This information will be of value to clinicians caring for patients both in the hospital and in the community. PMID- 23809718 TI - Pneumococcus. AB - Pneumococcus is one of the most common bacterial pathogens encountered in medicine. This article summarizes the risk factors, pathogenesis, treatment, and prevention of the spectrum of disease caused by pneumococcus with particular emphasis on antibiotic resistance as well as immunization. This information is useful for physicians caring for patients both as inpatients and outpatients as well as for those concerned with public health and disease prevention. PMID- 23809719 TI - Complications of antibiotic therapy. AB - Antibiotics have greatly changed the practice of medicine for the better. Many infections commonly treated in the outpatient setting with antibiotics (eg, urinary tract infections, streptococcal pharyngitis), which previously caused significant morbidity and mortality, are now typically benign. However, with antibiotic therapy come side effects, ranging in severity from mild nausea to life-threatening cytopenias. This article highlights important complications of antibiotic therapy that may be encountered by outpatient providers. Side effects by system are discussed, and a few important drug-specific complications and important drug-drug interactions highlighted. PMID- 23809720 TI - Enterohemorrhagic Escherichia coli Infections and the Hemolytic-Uremic Syndrome. AB - Enterohemorrhagic Escherichia coli (EHEC; Shiga toxin/verotoxin-producing E. coli) can cause bloody diarrhea and the hemolytic-uremic syndrome (HUS), typically following consumption of contaminated food (including ground beef, leafy greens, and sprouts) and water. Often associated with foodborne outbreaks, EHEC possess unique virulence factors that facilitate effective colonization of the human gastrointestinal tract and subsequent release of Shiga toxin. This article reviews the epidemiology, pathogenesis, clinical presentation, treatment, and prevention of EHEC infections, focusing on E. coli O157:H7, the serotype most common in North America, and E. coli O104:H4, the serotype responsible for the EHEC outbreak in Germany in 2011. PMID- 23809721 TI - Infections in travelers. AB - Travel medicine continues to grow as international tourism and patient medical complexity increases. This article reflects the state of the current field, but new recommendations on immunizations, resistance patterns, and treatment modalities constantly change. The US Centers for Disease Control and the World Health Organization maintain helpful Web sites for both patient and physician. With thoughtful preparation and prevention, risks can be minimized and travel can continue as safely as possible. PMID- 23809722 TI - Serious group a streptococcal infections. AB - The spectrum of illnesses caused by group A streptococcus (GAS) includes invasive infections, noninvasive infections, and noninfectious complications. Increasingly virulent infections associated with high morbidity and mortality have been observed since the late 1980s and continue to be prevalent in North America and worldwide. Penicillin remains the therapy of choice, with the addition of clindamycin recommended in high risk cases. Early recognition of GAS as the cause of these serious clinical syndromes is critical for timely administration of appropriate therapy. In this review, the pathophysiology, clinical manifestations, and treatment of invasive GAS infections are discussed. PMID- 23809723 TI - Management of urinary tract infections in the era of increasing antimicrobial resistance. AB - Antimicrobial resistance of urinary pathogens is increasing. Most urinary tract infections (UTIs) should still be treated empirically. However, patients with recurrence or other risk factors for resistance may benefit from urine culture. Patients with recurrent UTI often resort to antibiotic prevention, a risky proposition in terms of resistance. Non-antimicrobial preventative methods should be considered first. If preventative antibiotics must be used, postcoital patient initiated protocols are effective and reduce overall antibiotic exposure compared with continuous prophylaxis. Consider referring patients for urologic evaluation when at risk for complicated UTIs or when recurrence continues despite conservative interventions. PMID- 23809724 TI - Infectious disease threats: what are we to do? Preface. PMID- 23809725 TI - Feasibility of early discharge strategies for neutropenic fever: outcomes of a Victorian organisational readiness assessment and pilot. AB - BACKGROUND: Although Australian consensus guidelines support the use of ambulatory care strategies for management of adult patients with low-risk neutropenic fever (NF), few centres have successfully implemented viable programmes. AIMS: To study the feasibility of an early discharge programme for adult patients with low-risk NF and assess organisational factors likely to influence successful implementation across participating Victorian hospitals. METHODS: Four hospitals participated in an organisational readiness assessment preceding selection of a pilot site for programme implementation. Prospective baseline auditing of current practice (i.e. inpatient care until resolution of NF) across three hospitals preceded programme implementation and evaluation. RESULTS: Barriers and facilitators to successful implementation were identified. One hundred and seventeen NF episodes were evaluated during audit phases. The frequency of low-risk NF presentations eligible for early discharge was low (less than two episodes per week). The programme reduced median (interquartile range) duration of parenteral antibiotics and length of stay for eligible patients (n = 11) from 4 (4, 5) days at baseline to 1 (1, 2) day during pilot (P = 0.02) and 4.5 (4, 5) days (baseline) to 2 (1, 3) days (pilot) (P = 0.02) respectively. The proportion of ineligible patients stepped down to oral antibiotics was improved from 38% (baseline) to 67% (pilot). No patients failed ambulatory care requiring readmission into hospital. CONCLUSION: The ambulatory care strategy for management of NF proposed by Australian consensus guidelines has been successfully piloted at a single Victorian centre. Organisational readiness tools can be used to identify potential barriers to the implementation of evidence based practices in patients with NF. PMID- 23809726 TI - Tattooing, piercing and inherited coagulation disorders. PMID- 23809727 TI - [Exposure to drugs of abuse in paediatrics]. PMID- 23809728 TI - Utilization of cardiothoracic surgeons for operative penetrating thoracic trauma and its impact on clinical outcomes. AB - BACKGROUND: Large series reporting outcomes for penetrating thoracic trauma have identified injury pattern and injury severity scoring as predictors of poor outcome. However, the impact of surgical expertise on patient outcomes has not been previously investigated. We sought to determine how often board-certified cardiothoracic surgeons are utilized for operative thoracic trauma and whether this has an effect on patient outcomes. METHODS: A level I trauma center registry was queried between 2003 and 2011. Records of patients undergoing surgery as a result of penetrating thoracic trauma were retrospectively reviewed. Patient demographics, injuries, injury severity, utilization of a cardiothoracic surgical operative consult and outcomes were recorded. Patients operated on by cardiothoracic surgeons were compared with patients operated on by trauma surgeons using stepwise multivariate analyses to determine the factors associated with utilization of cardiothoracic surgeons for operative thoracic trauma and survival. RESULTS: Cardiothoracic surgeons were used in 73.0% of cases (162 of 222) over the study period. The use of cardiothoracic surgeons increased incrementally both overall (38.5% to 73.9%), and for emergent/urgent cases (31.8% to 73.3%). When comparing patients undergoing operation on an emergent/urgent basis by cardiothoracic versus trauma surgeons, there was no significant difference with regard to demographics, mechanism of injury, injury severity scoring, or surgical morbidity. Stepwise logistic regression showed the presence of a cardiothoracic surgeon to be independently associated with survival (odds ratio 4.70; p = 0.019). CONCLUSIONS: Use of cardiothoracic surgeons for operative thoracic trauma increased over the study period. Outcomes for severely injured patients with elevated chest injury scores or decreased revised trauma scores may be improved with appropriate operative consultation with a board-certified cardiothoracic surgeon. PMID- 23809729 TI - Lung size mismatch and survival after single and bilateral lung transplantation. AB - BACKGROUND: A higher predicted total lung capacity (pTLC)-ratio (=pTLC donor/pTLC recipient), suggestive of oversized allografts, is associated with improved survival after lung transplantation. It is unknown whether the pTLC-ratio has a different association with survival in bilateral (BLT) versus single lung transplantation (SLT). METHODS: The pTLC-ratio was calculated for all adult patients in the United Network of Organ Sharing lung transplant (LTx) registry who underwent first-time LTx in the post lung allocation score era, between May 2005 and April 2010. The LTx recipients were stratified according to procedure (BLT vs SLT). Risk of death at 1 year after LTx was analyzed using Kaplan-Meier survival and Cox proportional hazards models. RESULTS: In the 4,520 BLT patients, each 0.1 increase in pTLC-ratio conferred a 7% decrease in the hazard for death at 1 year (p < 0.001) in univariate analysis. This association remained significant after controlling for diagnosis, comorbidities, acuity, donor, and transplant factors (hazard ratio [HR] 0.93, 95% confidence interval [CI] 0.88 to 0.98, p = 0.01). Additional adjustment by a propensity score to account for biases to oversizing showed similar results (HR 0.94, 95% CI 0.90 to 0.99, p = 0.018). In the 2,477 SLT patients, each 0.1 increase in pTLC-ratio conveyed a 6% decrease in the hazard for death at 1 year (p = 0.002) in univariate analysis, which did not persist in the multivariate model (HR 1.00, p = 0.8). CONCLUSIONS: A higher pTLC-ratio, suggestive of an oversized allograft, is associated with improved survival after lung transplantation. This association is primarily evident in BLT patients. PMID- 23809730 TI - Transapical approach to myectomy for midventricular obstruction in hypertrophic cardiomyopathy. AB - BACKGROUND: Midventricular obstruction in hypertrophic cardiomyopathy (HCM) is less common than subaortic obstruction, and there are few data on outcomes after surgical treatment. METHODS: We reviewed 56 consecutive patients (28 men) with HCM and midventricular obstruction who underwent myectomy between February 1997 and June 2012. Five patients had prior myectomy for subaortic obstruction. Mean age was 42 +/- 17 years. Preoperatively, 51% of patients had dyspnea, and the remaining had palpitations (25%), angina (5%), or syncope (9%). RESULTS: Midventricular obstruction was relieved by means of a transaortic myectomy in 5 patients, a transapical approach in 32 patients, and combined transaortic and transapical incisions in 19 patients. In 13 patients, an apical aneurysm or pouch was repaired at the time of midventricular myectomy. There were no early deaths. Intraoperative intraventricular gradients were reduced from 64 +/- 32 mm Hg before myectomy to 6 +/- 12 mm Hg postoperatively (p <= 0.0001). Early complications included atrial arrhythmias in 5 patients and reoperation for bleeding in 4 patients. Fifty patients had follow-up beyond 30 days (median, 1.6 years; range, 33 days to 13 years). Survival at 1 and 5 years was 100% and 95%, and average New York Heart Association class improved from 2.9 +/- 0.7 preoperatively to 1.3 +/- 0.6 postoperatively (p = 0.0001). There were no aneurysms related to the apical incision; 2 patients had late reoperation, 1 for resection of right atrial mass to prevent embolus. CONCLUSIONS: A transapical approach allows excellent exposure for midventricular myectomy and relief of intraventricular gradients and related symptoms. There were no complications unique to the apical incision, and 5-year survival was similar to expected survival (95% versus 97%). PMID- 23809731 TI - Hypercoagulability markers predict thrombosis in single ventricle neonates undergoing cardiac surgery. AB - BACKGROUND: Incidence of thrombosis in neonates undergoing cardiac surgery is as high as 20%, and single ventricle physiology (SVP) may present an even higher risk. We hypothesize that SVP is a risk factor for thrombosis in neonates undergoing cardiac surgery, and hypercoagulability biomarkers are predictive of postoperative thrombosis. METHODS: Records of 512 neonates undergoing cardiac surgery were retrospectively reviewed. Thrombosis was defined by clinical events (shunt thrombosis, limb ischemia, and stroke) or intravascular or cardiac thrombus by echocardiography. Clinical variables, including SVP and cardiopulmonary bypass (CPB), were analyzed using multivariable logistic regression. A hypercoagulability biomarker panel was obtained in a subset of patients with SVP and compared between neonates with and without thrombosis. RESULTS: Thrombosis was detected in 51 of 512 neonates undergoing cardiac surgery. Intensive care and hospital lengths of stay were longer in patients who experienced thrombosis compared with those who did not (14 +/- 13 vs 6 +/- 1 days, 23 +/- 4 vs 13 +/- 1 days, p < 0.001). The SVP and use of CPB were significant risk factors for thrombosis, and the rate of thrombosis in SVP patients was 16.2% (16 of 99) compared with 8.5% (35 of 413) in non-SVP patients (p = 0.038). Thrombin generation, plasminogen activator inhibitor, and thrombin activatable fibrinolysis inhibitor were significantly elevated in SVP patients with thrombosis compared to without thrombosis (p < 0.05). CONCLUSIONS: Single ventricle physiology patients are at higher risk for thrombosis compared with other neonates after cardiac surgery. Hypercoagulable panel testing may help risk stratify patients and guide patient specific anticoagulation management in the postoperative period. PMID- 23809732 TI - Immunopathological study of parasitic cholangitis in cetaceans. AB - This paper describes the immunophenotype of cellular inflammatory infiltrates in chronic cholangitis in six common dolphins (Delphinus delphis), four striped dolphins (Stenella coeruleoalba), three Atlantic spotted dolphins (Stenella frontalis) and one pygmy sperm whale (Kogia Breviceps) found stranded along the coasts of the Canary Islands (Spain). A panel of 5 antibodies previously tested in dolphins (anti-CD3, -IgG, -MHC class II, -S100 protein and -lysozyme) were used. The present work also reports cross reactivity with dolphin antigens of two antibodies not used to date in dolphins (anti-mouse iNOS and anti-mouse Foxp3). The most common type of cholangitis found was chronic granulomatous cholangitis, associated with the presence of the parasite Campula spp., or its eggs in bile ducts. The cellular composition of the hepatic inflammatory infiltrate associated to chronic parasitic cholangitis was closely similar to that found in the cortex of control lymph nodes, including the presence of S100(+) and MHC class II(+) dendritic-like cells in lymphoid follicles and interfollicular areas. Only occasional macrophages expressed iNOS, whereas Foxp3(+) lymphocytes were not found in any of the lesions described in the different types of cholangitis. PMID- 23809733 TI - Genomewide interaction and enrichment analysis on antidepressant response. AB - BACKGROUND: Genomewide association studies (GWASs) on antidepressant efficacy have yielded modest results. A possible reason is that response is influenced by other factors, which possibly interact with genetic variation. We used a GWAS model to predict antidepressant response, by including predictors previously known to affect response, such as quality of life (QoL). We also evaluated the association between genes, previously implicated in gene-environment (G * E) interactions, and response using an enrichment analysis. METHOD: We examined a sample of 1426 depressed patients from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial: 774 responders, 652 non-responders and 418,865 single nucleotide polymorphisms (SNPs) were analysed. First, in a GWAS model, we investigated whether genetic variations interact with patients' levels of QoL to predict response, after controlling for demographic characteristics, severity and population stratification. Second, we conducted an enrichment analysis exploring whether candidate genes that have emerged from prior G * E interaction studies on depression are associated with treatment response. RESULTS: The GWAS model, with QoL as a moderator, yielded one SNP (rs520210) associated with response in the NEDD4L gene (p = 3.64 * 10-8). In the Caucasian sample only, we observed a drop in significance for this SNP. The enrichment analysis showed that SNPs within serotonergic genes contained more significant markers that predicted response, compared with a random set of genes in the genome. CONCLUSIONS: Our findings point to possible target genes, which are proposed for further independent replication. Our enrichment analysis provides further support, in a genomewide context, of the role of serotonergic genes in influencing antidepressant response. PMID- 23809734 TI - [Biomarkers of cervical carcinogenesis associated with genital HPV infection]. PMID- 23809735 TI - The Cochrane hepato-biliary group as a resource example of evidence-based medicine for all. PMID- 23809736 TI - [Cancer and deep venous thrombosis: the purpose of the CATCH clinical trial]. AB - Cancer has the potential to induce hypercoagulable states. On the other hand, venous thromboembolism may be the harbinger of an occult cancer, may represent a complication of known malignant disease or complicate hospitalization, surgery or various systemic treatments. The importance of venous thromboembolism in patients with cancer is often underestimated resulting in under-diagnosis, which may lead to significant morbidity and mortality. However, many cancer patients do not receive prophylaxis and suitable treatment for venous thromboembolism. The author make some considerations on this disease by addressing the interest and the objectives of the clinical trial CATCH and use of sodium tinzaparin. PMID- 23809737 TI - [Atrial fibrillation in cerebrovascular disease: national neurological perspective]. AB - BACKGROUND: Cardioembolism due to atrial fibrillation assumes a dominant etiologic role in cerebrovascular diseases due to its growing incidence, high embolic risk and particular aspects of clinical events caused. Our objectives are to analyze the frequency of atrial fibrillation in patients with ischemic stroke, study the vital and functional impact of stroke due to different etiologies and evaluate antithrombotic options before and after stroke. METHODS: We conducted a retrospective study including patients admitted in a central hospital due to ischemic stroke in 2010 (at least one year of follow-up). Etiology of stroke was defined using the Trial of ORG 10172 in Acute Stroke (TOAST) classification, and functional outcome by modified Rankin scale. We performed a descriptive analysis of different stroke etiologies and antithrombotic medication in patients with atrial fibrillation. We then conducted a cohort study to evaluate the clinical impact of antithrombotic options in secondary prevention after cardioembolic stroke. RESULTS: In our population (n = 631) we found superior frequency of cardioembolism (34.5%) to that reported in the literature. Mortality, morbidity and antithrombotic options are similar to other previous series, confirming the severity of cardioembolic strokes and the underuse of vitamin K antagonists. Oral anticoagulation was effective in secondary prevention independently from post stroke functional condition. CONCLUSIONS: Despite unequivocal recommendations, oral anticoagulation is still underused in stroke prevention. This study confirms the clinical efficacy of vitamin K antagonists in secondary prevention independently from residual functional impairment. PMID- 23809738 TI - Predicting outcome after cardiopulmonary arrest in therapeutic hypothermia patients: clinical, electrophysiological and imaging prognosticators. AB - INTRODUCTION: Predicting outcome in comatose survivors of cardiac arrest is based on data validated by guidelines that were established before the era of therapeutic hypothermia. We sought to evaluate the predictive value of clinical, electrophysiological and imaging data on patients submitted to therapeutic hypothermia. MATERIALS AND METHODS: A retrospective analysis of consecutive patients receiving therapeutic hypothermia during years 2010 and 2011 was made. Neurological examination, somatosensory evoked potentials, auditory evoked potentials, electroencephalography and brain magnetic resonance imaging were obtained during the first 72 hours. Glasgow Outcome Scale at 6 months, dichotomized into bad outcome (grades 1 and 2) and good outcome (grades 3, 4 and 5), was defined as the primary outcome. RESULTS: A total of 26 patients were studied. Absent pupillary light reflex, absent corneal and oculocephalic reflexes, absent N20 responses on evoked potentials and myoclonic status epilepticus showed no false-positives in predicting bad outcome. A malignant electroencephalographic pattern was also associated with a bad outcome (p = 0.05), with no false-positives. Two patients with a good outcome showed motor responses no better than extension (false-positive rate of 25%, p = 0.008) within 72 hours, both of them requiring prolonged sedation. Imaging findings of brain ischemia did not correlate with outcome. DISCUSSION: Absent pupillary, corneal and oculocephalic reflexes, absent N20 responses and a malignant electroencephalographic pattern all remain accurate predictors of poor outcome in cardiac arrest patients submitted to therapeutic hypothermia. CONCLUSION: Prolonged sedation beyond the hypothermia period may confound prediction strength of motor responses. PMID- 23809739 TI - [Hypofractionation in locally advanced breast cancer: "flash" scheme]. AB - INTRODUCTION: Breast cancer is a major cause of death in our country. The Department of Radiation Oncology of Portuguese Institute of Oncology in Coimbra are using a scheme of hypofraccionation called "Flash" as a treatment option for elderly patients or low performance status, with locally advanced breast cancer, or with stage IIb or IV, as a neoadjuvante or palliative aim. OBJECTIVES: Evaluation of the therapeutic response, for the group of patients selected, who did the hypofractionated schemed, in a retrospective study. METHODS: Between January 2006 and December 2008, a total of 83 patients diagnosed with locally advanced breast cancer or with stage IIb or IV, were subjected to breast "Flash". The radiation dose prescribed was 13Gy in 2 fractions in 3 days (in 23 patients - 27.7%) and 26 Gy in 4 fractions in 5 weeks (60 patients - 72.3%), with 4MV photons, in the sick breast. Global survival was evaluated using the Kaplan-Meier method. Statistical analysis was performed by applying the version 17.0 of SPSS and statistical tests were evaluated at a significance level of 5%. RESULTS: 80 patients (96.4%) who have made breast "Flash" were female, aged between 59 and 93 years and performance status (Karnosfky scale) between 90 and 50%. In 72 patients (86.7%) the histology was invasive ductal carcinoma. Surgery was held in 53% of patients (44) after breast "Flash", the radical modified mastectomy was the most common surgical technique. The diagnosis of bone metastasis was made in 10 patients (12%), while the global survival rate was 68.7% (57 patients). 10 patients (12%) died because disease progression or persistence. In 50.6% (42 patients) there was no evidence of disease progression and 3.6% (3 patients) showed clinical improvement. CONCLUSIONS: The "Breast Flash" is a safe treatment modality, in terms of secondary effects, and a valid therapeutic option for elderly patients or low performance status, with the diagnosis of locally advanced cancer or stage IIb or IV, as neoadjuvante, adjuvant or palliative aim. There is a little risk of relapse or progression in patients with good conditions, so the global survival rate is greater in these cases. There is a little iatrogenesis associated with this type of treatment; just one patient had grade III radiodermatitis. PMID- 23809740 TI - [Esophageal perforation in children: a review of one pediatric surgery institution's experience (16 years)]. AB - INTRODUCTION: The objective of the study was to evaluate the experience of our service in the treatment of esophageal perforations. MATERIALS AND METHODS: Retrospective chart review of the nine cases occurred between January 1, 1996 and December 31, 2011. Seven occurred after accidental ingestion of foreign bodies and in two patients were iatrogenic lesions after esophagoscopy with dilation: a peptic stricture in one case and in the other stenosis of the esophageal anastomosis in a child operated for esophageal atresia. RESULTS: In 78% of cases the initial approach was medical, with healing of the perforation confirmed on average after 20 days, 22% of patients (2 cases) underwent surgery without success, one of them healed without sequelae having nothing by mouth and medical therapy, in the other case there was a need for further colon esophagoplasty. There was no mortality. DISCUSSION: Esophageal perforation is one of the most serious injuries of the alimentary tract, continues to be devastating, and difficult to diagnosis and treatment. The recognition of this complication is critical for a successful treatment. CONCLUSIONS: The delay of the diagnosis is associated with a mortality which can oscillate between 20 and 40%. PMID- 23809741 TI - Adverse events with the influenza A(H1N1) vaccine Pandemrix(r) at healthcare professionals in Portugal. AB - INTRODUCTION: Healthcare professionals were a priority group for Pandemrix(r) vaccination. Surveying this particularly committed group for vaccination related side effects could help to get valuable information about vaccine safety profile. Our aim was to identify the adverse events following immunization with Pandemrix(r) among healthcare professionals. MATERIAL AND METHODS: A questionnaire for active post-authorization monitoring of adverse events following immunization with the influenza vaccine A (H1N1) was designed and distributed to the vaccinated healthcare professionals working at 3 elected hospital centres in the Northern region, in the period from 26 October 2009 to 31 January 2010. RESULTS: From the 2358 vaccinated healthcare professionals that accepted to participate in this study, 864 (37%) returned back the fulfill questionnaire on time. Among these, 634 (73%) of healthcare professionals experienced at least one adverse event following immunization, but only 8% experienced an unexpected one. The adverse events most frequently reported were expected and very common: local reactions at the injection site (57%), myalgia (31%), fatigue (including asthenia) (24%) and headache (19%). No cases of major episodes, such as death or life-threatening events were reported. Female gender and existence of underlying conditions were independent risk factors to develop at least one adverse event following immunization to the pandemic vaccine. CONCLUSIONS: Our work suggests an acceptable safety profile of this pandemic flu vaccine among healthcare professionals. Both frequency and severity of the observed adverse event following immunization do not seem to be higher than expected. PMID- 23809742 TI - [A community-based study of stroke code users in northern Portugal]. AB - INTRODUCTION: By 2002 Portugal had one of the highest mortality rates due to cerebrovascular diseases among the European Countries. Meanwhile, several strategies have been adopted to improve prevention and treatment in the acute phase, amongst which the Stroke Code. The purpose of this study is to describe how this measure has been used and its outcome as part of a prospective community based study of stroke/TIA incidence in Northern Portugal. MATERIALS AND METHODS: Between 1st October 2009 and 30th September 2010 all strokes occurred in patients registered at Western Porto, Mirandela and Vila Pouca de Aguiar health centres have been recorded. For cases ascertainment multiple sources of information were used, including the WEB, letter, e-mail and Alert P1, as well as systematic searches on databases provided by the entities involved in this study: hospital emergency, discharge records, diagnosis procedures, death certificates, Stroke Code admissions and health centre emergency records. RESULTS: Six hundred strokes were recorded in a population of 241 000 (incidence rate of 250 / 100 000 person years) and 434 were first-ever-in-the-lifetime (180 / 100 000). There were 72 Stroke Code calls and in 66.7% of them a stroke was confirmed. Considering the criteria for Stroke Code call (age = 80 years, functional independency, the stroke signs/symptoms, and time after episode = 3 hours), only 15.9% patients "could" have access to it. Of those who used the Stroke Code, only 56.3% fulfilled the criteria. Considering all patients fulfilling Stroke Code criteria, 96.3% that used prehospital Stroke Code were inpatients, as well as 83.3% that used intra/interhospital Stroke Code and 64.0% of the remainder; this trend is also present in patients with ischaemic stroke submitted to fibrinolysis, 77.3%, 36.4% and 17.4%, respectively. A high post-stroke Rankin was more frequent among Stroke Code users (70.3% vs. 35.3%), but they exhibit more often the three stroke signs/symptoms (44.0% vs. 16.2%). After adjusting for age, sex and number of signs, the risk of a more severe post-stroke Rankin is not significantly different among patients using the prehospital Stroke Code (OR = 2.9, 95% CI: 0.8 - 10.2). CONCLUSIONS: The criteria for accessing the Stroke Code are currently restrictive. Though the Stroke Code is accessed in case of more severe patient's conditions, the proportion of patients treated with fibrinolysis is relatively high in comparison with other studies. PMID- 23809743 TI - [Skin cancer in kidney transplant recipients: incidence and association with clinical and demographic factors]. AB - INTRODUCTION AND OBJECTIVES: Organ transplanted recipients have a higher risk of non melanoma skin cancer. Our objectives were to determine incidence of skin cancer and search for associations with clinical or demographic factors in a series of kidney transplant recipients. MATERIALS AND METHODS: A prospective study with face-to-face interview of 127 kidney transplant recipients who were observed for the first time during the second half of 2010 and in 2011. All diagnosed skin cancers were confirmed by histopathology. A 5% significance level was used and statistical analysis performed with chi-square, Fisher's exact test or Mann Whitney test. RESULTS: The mean age was 53 (s = 12.98) and 67% were males. The mean number of years since the transplant was 8 (s = 4.61) and skin cancer was observed in 16% (20 / 127), with equal number of basaliomas and squamous cell carcinoma. In sun exposed areas, actinic keratoses and viral warts were present in 24% and 8%, respectively. Skin cancer was significantly associated with older age (p = 0.016), longer duration of immunosuppression (p = 0.003) as well as with previous outdoor work (p = 0.049) or actinic keratoses in sun exposed areas (p < 0.001). Present intake of azathioprine (n = 8) was the only medication associated with skin cancer (p = 0.035 in Fisher's exact test). CONCLUSIONS: Skin cancer incidence is high in our series and education about photoprotection should be given to these patients, as well as regular dermatologic surveillance. This regular follow up improves compliance with photoprotection measures and helps to decrease the incidence of non melanoma skin cancer. PMID- 23809744 TI - [Restraints to anticoagulation prescription in atrial fibrillation and attitude towards the new oral anticoagulants]. AB - INTRODUCTION AND OBJECTIVES: To evaluate the prescription rate of oral anticoagulants in atrial fibrillation, the factors associated with non prescription, the reasons referred by the physicians for not prescribing anticoagulants including the new generation anticoagulants, and to perform a medium term follow-up assessment. MATERIALS AND METHODS: Prospective study on consecutive patients with atrial fibrillation with hospital discharge. The CHA2DS2VASc and HASBLED scores, associated comorbidities and medication prescribed before and at discharge were assessed. At discharge, the reason for not prescribing oral anticoagulants and the new oral anticoagulants was indicated by the physician in a questionnaire. Exclusion: absolute contraindication for anticoagulation, CHA2DS2VASc = 1 and valvular disease. Follow-up data were obtained one year after the recruitment of the first patient. RESULTS: 103 candidates for oral anticoagulants were identified (79.6 +/- 8.0 years; CHA2DS2VASc 5.8 +/- 1.4; HASBLED 2.6 +/- 1.0; HASBLED = 3 in 55.3%); the anticoagulants were prescribed in 34.0% of the candidates. The factors associated with non-prescription were, in decreasing order of relevance: previous use of antiplatelet agents, bedridden and/or demented patient, absence of heart failure and number of bleeding risk factors. The reasons referred by physicians for non prescription were, in decreasing order of frequency: high bleeding risk, small benefit, inability to comply with the treatment regimen and difficulty in monitoring the international normalized ratio (INR). The new anticoagulants were not prescribed and the referred reasons were, in decreasing order of frequency: insufficient information on the drugs, high bleeding risk, high cost and small benefit. At 8.2 +/- 2.5 months of follow-up 33.3% of the patients were on anticoagulation and the new anticoagulants had not been prescribed. CONCLUSIONS: In this sample, the anticoagulants prescription rate was low and the factor most associated with non-prescription was the previous use of antiplatelet agents. Bleeding risk was the most referred barrier for prescription, followed by a small recognized benefit. The main referred barriers for new anticoagulants prescription were insufficient information and high bleeding risk. At medium-term follow-up the proportion of patients under anticoagulation was still low and the new anticoagulants had not been prescribed. PMID- 23809745 TI - [Alcohol consumption in the schooled youth: an old question revisited]. AB - INTRODUCTION: Adolescents crave for new experiences. Alcohol consumption arises in this context as an attitude trivialized and sometimes even urged socially, since access to alcohol is facilitated. It is associated to risky behaviors, with serious consequences for public health. MATERIAL AND METHODS: A descriptive cross sectional through an anonymous questionnaire applied to pupils in the district of Leiria. RESULTS: The final sample consisted of 405 individuals, 56% female, mean age of 16.5 +/- 1 years (15 - 18 years). The majority (48%) attended the 10th grade, 15.4% had reproved at least once. Ninety percent of the individuals had already consumed alcohol, at least once. The first contact with the alcohol was preferentially with friends (63%) in most cases due to curiosity (47%). The results showed higher rates of beer consumption and higher educational failure in males compared to females, which had a higher consumption of distilled beverages. In both sexes, there was a tendency for "binge drinking". The majority of the individuals (60%) consumed an average of 2-3 glasses per occasion but about 30% of boys reported consuming more than 4 drinks per occasion (7% until they are drunk), a trend that was not observed in girls. Most consumption took place in bars and nightclubs (60%). It was found that 41% of respondents went out at night at least once a week, 66% started out at night between 13 and 15 years of age, when they went 70% used to drink alcohol and 9% had experienced drugs at least once. When asked about false myths about alcohol, about 20% of young people felt that alcoholic beverages may quench your thirst, 34% believed that alcohol whet your appetite, 15.4% believed that there was no problem driving if they had not drunk a lot. CONCLUSION: The pattern of alcohol consumption in these adolescents is worrisome and with characteristics similar to those reported in other European studies. A strategy is needed urgently to change this old paradigm. PMID- 23809746 TI - [Biomarkers of cervical carcinogenesis associated with genital human papillomavirus infection]. AB - INTRODUCTION/OBJECTIVE: Persistent infection with high-risk human papillomavirus (HPV) types is a necessary cause for cervical cancer development. The aim of this study was to evaluate the significance of different molecular markers for cervical carcinogenesis, and to assess their association with cervical intraepithelial neoplasia. MATERIALS AND METHODS: 378 cervical samples from women attending to primary Health Clinics of the National Health Service and Gynaecological Outpatient Clinics and referred for HPV testing were analyzed between between January 2007 and December 2010. According to cytological diagnosis, five groups were defined: normal, ASCUS, LSIL, HSIL, and ICC. For the determination of viral DNA physical status was performed by using a real-time PCR methodology, over expression of E6/E7 mRNA NASBA amplification was performed with the NucliSENS EasyQ HPV assay and viral load was determined by a real-time PCR. HPV status was studied in relation to lesion severity. Statistical analysis was performed with SPSS software 16.0 and Chi-Square test. RESULTS: No significant statistical differences were found between the physical status of HPV 16 or 18 and lesion severity. Overexpression of E6/E7 mRNA increased with lesion severity. Viral load was significantly associated with the development of cervical intraepithelial lesion. CONCLUSIONS: Data suggests that viral integration for HPV 16 seems to be an early event on cervical carcinogenesis, not being suitable as a molecular marker. E6/E7 mRNA and viral load can be more valuable approaches to use as biomarkers in the prevention of cervical cancer development. PMID- 23809747 TI - Measuring emotional awareness from a cognitive-developmental perspective: Portuguese adaptation studies of the levels of emotional awareness scale. AB - INTRODUCTION: The Levels of Emotional Awareness Scale (LEAS) was developed to assess the emotional awareness construct, based on a cognitive-developmental perspective and influenced by the Piaget and Werner theories. It is composed of 20 emotion-evoking scenes and has been used in multiple researches related to emotion regulation, alexithymia and psychiatric disorders. It is a well documented, valid and reliable measure. Due to the extent of LEAS, some investigators have been using one of the parallel forms (LEAS-A), which is a part of the complete version, nevertheless there is a gap of studies concerning LEAS-A psychometric qualities. In the absence of measures for assessing the organization of the emotional experience in Portuguese samples, we developed the Portuguese version of LEAS, characterizing reliability and validity indicators and the same for LEAS-A. MATERIALS AND METHODS: Three different studies were carried out with these versions, two with university students and another with a sample from the general population. RESULTS: The Portuguese version showed high levels of reliability, superior to those found in other adaptation procedures. LEAS-A showed good reliability and indicators of discriminant and concurrent validities. The LEAS-A scores were independent from negative affect and related to the externally-oriented thinking involved in alexithymia. CONCLUSIONS: The Portuguese LEAS and LEAS-A show very adequate qualities, which allow for their scientific use. Implications for clinical and research contexts are discussed. PMID- 23809748 TI - Cytomegalovirus infection and cervical cancer: from past doubts to present questions. AB - BACKGROUND: Since early 60's that Cytomegalovirus was studied for its possible role in cervical cancer development. Despite several decades of studies and the description of CMV DNA in cervical samples, it is still doubtful what is the prevalence of Cytomegalovirus in cervix and if CMV can act as a co-factor in cervical carcinogenesis. METHODS: In this Systematic Review we intend to summarize the frequency of Cytomegalovirus in cervical samples by revising all published studies between 1980 and 2011 regarding the detection of Cytomegalovirus in cervical samples and the development of lesions/ invasive cervical cancer. Crude and adjusted frequencies of Cytomegalovirus infection were calculated according to country and world region. RESULTS: This study revealed that the worldwide crude frequency of Cytomegalovirus infection in the cervix was 18.9% in all cervical samples and 36.5% in HPV positive women. Cytomegalovirus infection was present in all different types of lesions: 17.4% in normal/ cervicitis, 28.0% in LSIL, 19.7% in HSIL and 44.4% in CIS/ICC. The overall rate of Cytomegalovirus infection varied from 1.58% to 61.0% with an increased incidence in less developed countries. CONCLUSION: In this study we described a high frequency of positive Cytomegalovirus cases in all types of cervical samples, with increased incidence in both HPV-infected women and CIS/ICC cases. Hence, despite results showed that Cytomegalovirus shedding in cervical samples is frequent more studies should be performed to clarify if Cytomegalovirus infection is an opportunistic infection in HPV-infected cases, or if it contributes for cervical immunosuppression that will favor HPV-associated carcinogenesis. PMID- 23809749 TI - [Observational studies in the era of evidence based medicine: short review on their relevance, taxonomy and designs]. AB - In this review of the literature, we distinguish between experimental and observational studies, highlighting the importance that the later have gained in the era of evidence-based medicine. We further analyze the value of observational studies in light of experimental studies. We present a taxonomy for observational studies based on units of observation and measurement (cross-sectional or longitudinal). We distinguish between descriptive studies and analytical studies. Then, and given its specificity, we define and present a classification for ecological studies. We define and consider the advantages and disadvantages of cross-sectional, case control and cohort studies. We analyze the strength of the evidence given by each study design. We finished by examining what should guide the choice of a study design. PMID- 23809750 TI - How fundamental knowledge aids implementation: ankle sprains as an example. AB - Over the years a number of high quality studies has established the effectiveness of external measures (tape, brace) and neuromuscular training for the prevention of ankle sprains. The general conclusion derived from these studies is that recurrent ankle sprains can be effectively prevented using any of these measures, and that measures are cost-beneficial. Nevertheless, despite the commonness of this type of injury and the availability of effective measures, implementation of prevention in clinical practice is lagging behind. In addition, although proven effective, a link between biomechanical and neurophysiological adaptations as a function of preventive measures, leading to clinical and functional improvements and ultimately ankle sprain recurrence prevention, has never been fully made. The current evidence on ankle sprains and their prevention provides ample opportunities to pursue a translational approach through which fundamental knowledge will provide guidance to specify the effective preventive program to its bare essentials and decrease user-burden while retaining full effectiveness. PMID- 23809751 TI - [Correct and timely referral of patients to centers of reference]. AB - The correct and timely referral of patients, from peripheral hospitals, without specialized surgical care, namely in hand surgery, like Plastic Surgery or Orthopedics is of crucial importance. The authors report the case of a patient that presents in the Plastic Surgery Department with a chronic infection of the hypothenar eminence of the right hand. The clinical history suggests the persistence of a foreign body, despite two previous surgical procedures for removal, performed in the residence hospital. Surgical exploration was performed and the foreign body was removed without complications. The intent of this presentation is to alert for the importance of the timely referral of patients that can benefit of specialized care, namely of plastic surgery, when this is no possible in the residence hospital, in view of better health care and better patient treatment. PMID- 23809752 TI - Anterior biopercular syndrome caused by unilateral infarction. AB - The anterior biopercular syndrome is characterized by facio-pharyngo-glosso masticatory diplegia, with automatic dissociation of movements. It generally translates bilateral opercular lesion, often of vascular etiology. There are very few cases described with unilateral lesions. We present the case of a patient with a bilateral anterior opercular syndrome caused by unilateral infarction. PMID- 23809754 TI - [Pneumo-encephalocele]. PMID- 23809753 TI - [Fahr syndrome]. PMID- 23809755 TI - [Portrait of King Carlos I of Portugal]. PMID- 23809757 TI - Numerical analysis for transverse microbead trapping using 30 MHz focused ultrasound in ray acoustics regime. AB - We have recently devised a remote acoustic manipulation method with high frequency focused ultrasonic beam of 30-200 MHz, and experimentally realized it by the intensity gradient near the beam's focus. A two-dimensional (or transverse) acoustic trapping was demonstrated by directly applying the acoustic radiation force on lipid spheres and leukemia cells that were individually moved towards the focus. Only longitudinal waves were then considered because both target and propagation media involved were fluid e.g., water or phosphate buffer saline. In order for our current technique to be applicable to bead-based assay approaches using micron-sized polystyrene spheres as in optical tweezers, the possibility of microbead trapping must first be investigated from theoretical perspective. In this paper, a simulation study in the ray acoustics regime (bead diameter D>ultrasonic wavelength lambda of trapping beam) is thus undertaken by calculating the acoustic radiation force on a polystyrene bead generated from 30 MHz focused beam of Gaussian intensity profile. Analytical trapping models for a bead located in the near-/far fields and on the focal plane are derived by incorporating both longitudinal- and shear force terms into our existing ray acoustics model for liquid targets. The net radiation force is computed by adding the two terms, and the resultant trapping force is defined as a negative net radiation force in the positive transverse direction (y>0). The magnitude of the trapping force and its spatial range are evaluated in the same direction by varying bead size (D=2 lambda=100 MUm or 3 lambda=150 MUm), location, and transducer's f-number (= 1 or 2). When the bead size is increased, all force components exerted on the bead is increased in the near field of ultrasound for both f-numbers. With f-number=1 being used, the peak longitudinal-, shear- , and net forces are -3.1 nN, -9.8 nN, and -12.7 nN for D=2 lambda, whereas the forces are increased to -5.3 nN, -21.0 nN, and -25.7 nN for D=3 lambda. In case of f number=2, the peak magnitudes of the forces are 1.2 nN, -7.8 nN, and -6.6 nN for D=2 lambda, whereas they are increased to 5.9 nN, -17.1 nN, and -12.0 nN for D=3 lambda. With f-number=1, the net trapping forces at (0, y, -2 lambda) can be reached to -39.8 nN for D=2 lambda and -65.2 nN for D=3 lambda, and -7.8 nN for D=2 lambda and -15.2 nN for D=3 lambda at (0, y, -14 lambda). When f-number=2 is used, the peak trapping forces at (0, y, -2 lambda) can be -3.4 nN for D=2 lambda and -5.9 n N for D=3 lambda, while they are -6.3 nN for D=2 lambda and -12.0 nN for D=3 lambda at (0, y, -14 lambda). In the near filed, the bead can be trapped in the range from 0 to 340 MUm for D=2 lambda, and from 0 to 380 MUm for D=3 lambda. The trapping range Rtrap with f-number=2 lies from 0 to 295 MUm for D=2 lambda, and from 0 to 340 MUm for D=3 lambda. As either a larger bead or a lower f-numbered trapping beam is used, a stronger trapping force can be produced in the region. When a bead is more closely positioned to the focus, the trapping occurs in multiple locations and the net force variation becomes more complicated. In the far field, with f-number=1 being used, the peak longitudinal , shear- , and net forces are 4.6 nN, 6.8 nN, and 11.4 nN for D=2 lambda, whereas the forces are increased to 11.4 nN, 12.1 nN, and 23.6 nN for D=3 lambda. In case of f-number=2, the maximum value of each force is 4.4 nN, 1.8 nN, and 5.0 nN for D=2 lambda, respectively, whereas it becomes 12.3 nN, -0.7 nN, and 10.6 nN for D=3 lambda. The bead is forced to move away from the beam axis by a positive net force for y>0 and a negative net force for y<0. With f-number=1, the peak repulsive forces at (0, y, 5 lambda) can be 25.8 nN for D=2 lambda and 49.9 nN for D=3 lambda, and 3.4 nN for D=2 lambda and 7.5 nN for D=3 lambda at (0, y, 20 lambda). When f-number=2 is used, the forces at (0, y, 5 lambda) can be 3.9 nN for D=2 lambda and 9.5 nN for D=3 lambda, while they are 3.7 nN for D=2 lambda and 7.8 nN for D=3 lambda at (0, y, 20 lambda). As the bead is placed farther away from the focus, the net repulsive force is reduced and yet the bead trapping is difficult throughout the far-field region. On the focal plane, with f number=1, the peak longitudinal-, shear- , and net trapping forces are 31.8 nN, 36.2 nN, and -16.5 nN for D=2 lambda, whereas the forces are changed to 73.9 nN, 58.2 nN, and -42.7 nN for D=3 lambda. In case of f-number=2, the peak magnitudes of the forces are 6.4 nN, -7.0 nN, and -1.6 nN for D=2 lambda, whereas they are increased to 18.1 nN, -15.8 nN, and -3.9 nN for D=3 lambda. The Rtrap ranges from 33 to 131 MUm for D=2 lambda, and from 52 to 170 MUm for D=3 lambda when f number=1. The Rtrap with f-number=2 is then located from 0 to 238 MUm for D=2 lambda, and from 73 to 288 MUm for D=3 lambda. Hence, the results suggest that microbeads such as polystyrene spheres may acoustically be controlled as remote handles with focused sound beam for bead-bioassay applications, where trapped beads can be used to induce cellular response change by exerting mechanical stress on single cells. PMID- 23809758 TI - Assessment of the Brettanomyces bruxellensis metabolome during sulphur dioxide exposure. AB - Brettanomyces bruxellensis displays a high degree of genotypic and phenotypic polymorphism and is the main yeast species involved in wine spoilage. The innate resistance of 108 B. bruxellensis strains to the antimicrobial agent SO2 used in winemaking was investigated. Nineteen strains (17.6%) were sensitive to SO2 , failing to grow at the lowest concentration tested (0.1 mg L(-1) molecular SO2). Twenty-nine strains (26.8%) grew at 0.1 mg L(-1), 42 strains (38.9%) grew at 0.2 mg L(-1) , and 16 strains (14.8%) were able to grow as high as 0.4 mg L(-1) mol. SO2. Two strains able to grow in the presence of 0.6 mg L(-1) mol. SO2 were further studied by GCMS-TOF analysis to define the metabolic response to SO2 treatment. Two hundred and fifty-three intracellular metabolites were detected. The main effect observed was a decrease in cytoplasmic levels of polyols and an increase in levels of some amino acids, alanine, glutamic acid, glycine, proline, 5-oxoproline, serine and valine, which were significantly accumulated in the presence of SO2. No alteration in the pentose phosphate pathway was observed, suggesting NADPH usage could be diverted to other pathways. Finally, a change in metabolites involved in the glycerophospholipid pathway (glycerol-3-phosphate and myo-inositol) was also found. PMID- 23809759 TI - Do romantic partners' responses to entry dyspareunia affect women's experience of pain? The roles of catastrophizing and self-efficacy. AB - INTRODUCTION: Entry dyspareunia is a sexual health concern which affects about 21% of women in the general population. Characterized by pain provoked during vaginal penetration, introital dyspareunia has been shown by controlled studies to have a negative impact on the psychological well-being, sexual function, sexual satisfaction, and quality of life of afflicted women. Many cognitive and affective variables may influence the experience of pain and associated psychosexual problems. However, the role of the partner's cognitive responses has been studied very little. AIM: The aim of the present study was to examine the associations between partners' catastrophizing and their perceptions of women's self-efficacy at managing pain on one side and women's pain intensity, sexual function, and sexual satisfaction on the other. METHODS: One hundred seventy-nine heterosexual couples (mean age for women = 31, SD = 10.0; mean age for men = 33, SD = 10.6) in which the woman suffered from entry dyspareunia participated in the study. Both partners completed quantitative measures. Women completed the Pain Catastrophizing Scale and the Painful Intercourse Self-Efficacy Scale. Men completed the significant-other versions of these measures. MAIN OUTCOME MEASURES: Dependent measures were women's responses to (i) the Pain Numeric Visual Analog Scale; (ii) the Female Sexual Function Index; and (iii) the Global Measure of Sexual Satisfaction scale. RESULTS: Controlled for women's pain catastrophizing and self-efficacy, results indicate that higher levels of partner perceived self-efficacy and lower levels of partner catastrophizing are associated with decreased pain intensity in women with entry dyspareunia, although only partner catastrophizing contributed unique variance. Partner perceived self-efficacy and catastrophizing were not significantly associated with sexual function or satisfaction in women. CONCLUSIONS: The findings suggest that partners' cognitive responses may influence the experience of entry dyspareunia for women, pointing toward the importance of considering the partner when treating this sexual health problem. PMID- 23809760 TI - A method for defining carpometacarpal joint kinematics from three-dimensional rotations of the metacarpal bones captured in vivo using computed tomography. AB - The carpometacarpal (CMC) joints of the hand facilitate motion of the metacarpals and are critical for functional tasks, especially tasks involving precision grasping. Despite their importance, only limited data describing metacarpal kinematics exist. In this short communication, we quantified in vivo metacarpal kinematics from a single subject and used these data to develop the kinematic functions necessary to add rotational degrees of freedom at the CMC joints to a biomechanical model of the hand. Computed tomography (CT) was used to capture three-dimensional rotations of the metacarpal bones of the ring and little fingers of the subject in seven different static postures, chosen to position the fourth and fifth metacarpals throughout a functional range of motion. The CT images were manually segmented, yielding digital surface representations of the metacarpals in each posture. From the surfaces, principal axes of rotation were defined by calculating orthonormal bases of the surface vertices. The three dimensional rotations of the fourth and fifth metacarpals were quantified in each posture about their principal axes, relative to a designated reference posture. For both metacarpals, ranges of rotations were computed about the principal axes across all seven postures. From the processed data, single axes and angles were calculated that were equivalent to the three dimensional ranges of motion. Finally, kinematic functions were defined that enabled modeling of the formation of a metacarpal arch by movement of the fourth and fifth CMC joints as one degree of freedom, coupled to a single generalized coordinate. PMID- 23809761 TI - Cyclo-oxygenase-2 expression is associated with vascular endothelial growth factor C expression and lymph node metastasis in oral squamous cell carcinoma. AB - PURPOSE: Cervical lymph node metastasis in oral squamous cell carcinoma (OSCC) is recognized as a poor prognostic factor, although its mechanism remains unclear. Recently, cyclo-oxygenase-2 (COX-2) level has been found to correlate highly with vascular endothelial growth factor C (VEGF-C) and lymph node metastasis, as in other solid tumors. However, there has been no report of this correlation in OSCC. Therefore, the aim of this study was to investigate whether COX-2 immunohistochemical expression in OSCC was associated with VEGF-C expression, histopathologic parameters, and lymph node metastasis. MATERIALS AND METHODS: Lymphatic vessel density, VEGF-C, and COX-2 immunohistochemical expression were examined pathologically in 60 specimens of invasive OSCC. Relations of histopathologic parameters to lymph node metastasis were analyzed. RESULTS: Expression levels of VEGF-C and COX-2 and lymphatic vessel density in the lymph node metastatic group were significantly higher than in the nonmetastatic group (P < .01). A significant correlation was found between the expression levels of VEGF-C and COX-2 (r = 0.512; P < .001). COX-2 expression was significantly related to lymph node metastasis (P = .004) and VEGF-C expression (P = .005). Univariate analysis showed that survival time was impaired by higher COX-2 and VEGF-C expression levels. Multivariate survival analysis showed that COX-2 expression was an independent prognostic factor. CONCLUSION: This study showed that VEGF-C expression was upregulated by COX-2 in OSCC. High VEGF-C expression appears to promote peritumoral lymphangiogenesis. These data indicated that lymph node metastasis is promoted by COX-2 and VEGF-C in OSCC. PMID- 23809762 TI - RAP1: protector of telomeres, defender against obesity. AB - Telomere dysfunction has previously been linked to metabolic disorders. In this issue of Cell Reports, Martinez et al. (2013) and Yeung et al. (2013) now extend this link, demonstrating that deletion of the telomere binding protein RAP1 leads to obesity and insulin resistance. PMID- 23809763 TI - Structure of stem cell growth factor R-spondin 1 in complex with the ectodomain of its receptor LGR5. AB - Leucine-rich repeat-containing G protein-coupled receptors 4-6 (LGR4-LGR6) are receptors for R-spondins, potent Wnt agonists that exert profound trophic effects on Wnt-driven stem cells compartments. We present crystal structures of a signaling-competent fragment of R-spondin 1 (Rspo1) at a resolution of 2.0 A and its complex with the LGR5 ectodomain at a resolution of 3.2 A. Ecto-LGR5 binds Rspo1 at its concave leucine-rich-repeat (LRR) surface, forming a dimeric 2:2 complex. Fully conserved residues on LGR4-LGR6 explain promiscuous binding of R spondins. A phenylalanine clamp formed by Rspo1 Phe106 and Phe110 pinches Ala190 of LGR5 and is critical for binding. Mutations related to congenital anonychia reduce signaling, but not binding of Rspo1 to LGR5. Furthermore, antibody binding to the extended loop of the C-terminal LRR cap of LGR5 activates signaling in a ligand-independent manner. Thus, our data reveal binding of R-spondins to conserved sites on LGR4-LGR6 and, in analogy to FSHR and related receptors, suggest a direct signaling role for LGR4-LGR6 in addition to its formation of Wnt receptor and coreceptor complexes. PMID- 23809764 TI - Eukaryote-specific insertion elements control human ARGONAUTE slicer activity. AB - We have solved the crystal structure of human ARGONAUTE1 (hAGO1) bound to endogenous 5'-phosphorylated guide RNAs. To identify changes that evolutionarily rendered hAGO1 inactive, we compared our structure with guide-RNA-containing and cleavage-active hAGO2. Aside from mutation of a catalytic tetrad residue, proline residues at positions 670 and 675 in hAGO1 introduce a kink in the cS7 loop, forming a convex surface within the hAGO1 nucleic-acid-binding channel near the inactive catalytic site. We predicted that even upon restoration of the catalytic tetrad, hAGO1-cS7 sterically hinders the placement of a fully paired guide-target RNA duplex into the endonuclease active site. Consistent with this hypothesis, reconstitution of the catalytic tetrad with R805H led to low-level hAGO1 cleavage activity, whereas combining R805H with cS7 substitutions P670S and P675Q substantially augmented hAGO1 activity. Evolutionary amino acid changes to hAGO1 were readily reversible, suggesting that loading of guide RNA and pairing of seed based miRNA and target RNA constrain its sequence drift. PMID- 23809765 TI - Does drug therapy reverse endothelial progenitor cell dysfunction in diabetes? AB - Endothelial progenitor cells (EPCs) are vital for the maintenance and repair of the endothelium. Decreased EPC number and function have been associated with increased cardiovascular (CVD) risk. Patients with diabetes have decreased number of circulating EPCs and decreased EPC function. This may account for some of the increased CVD risk seen in patients with diabetes that is not explained by traditional risk factors such as glycemic control, dyslipidemia and hypertension. Recent studies seem to indicate that drugs commonly used in diabetes patients such as metformin, thiazolidinediones, GLP-1 agonists, DPP-4 inhibitors, insulin, statins and ACE inhibitors may increase EPC number and improve EPC function. The mechanisms by which these drugs modulate EPC function may involve reduction in inflammation, oxidative stress and insulin resistance as well as an increase in nitric oxide (NO) bioavailability. This review will discuss the evidence in the literature regarding the above mentioned topics. PMID- 23809766 TI - Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma: multicentre, open-label, phase II safety study. AB - PURPOSE: We assessed the safety of the multikinase inhibitor regorafenib in patients with hepatocellular carcinoma (HCC) that had progressed following first line sorafenib. PATIENTS AND METHODS: Thirty-six patients with Barcelona Clinic Liver Cancer stage B or C HCC and preserved to mildly impaired liver function (Child-Pugh class A) received regorafenib 160 mg once daily in cycles of 3 weeks on/1 week off treatment until disease progression, unacceptable toxicity, death or patient/physician decision to discontinue. The primary end-point was safety; secondary end-points included efficacy (including time to progression and overall survival). RESULTS: The median treatment duration was 19.5 weeks (range 2-103). At data cutoff, three patients remained on treatment. Reasons for discontinuation were adverse events (n=20), disease progression (n=10), consent withdrawal (n=2) and death (n=1). Seventeen patients required dose reductions (mostly for adverse events [n=15]); 35 patients had treatment interruption (mostly for adverse events [n=32] or patient error [n=11]). The most frequent treatment-related adverse events were hand-foot skin reaction (any grade n=19; grade >=3 n=5), diarrhoea (n=19; n=2), fatigue (n=19; n=6), hypothyroidism (n=15; n=0), anorexia (n=13; n=0), hypertension (n=13; n=1), nausea (n=12; n=0) and voice changes (n=10; n=0). Disease control was achieved in 26 patients (partial response n=1; stable disease n=25). Median time to progression was 4.3 months. Median overall survival was 13.8 months. CONCLUSION: Regorafenib had acceptable tolerability and evidence of antitumour activity in patients with intermediate or advanced HCC that progressed following first-line sorafenib. PMID- 23809767 TI - Nuclear orphan receptor NR4A2 confers chemoresistance and predicts unfavorable prognosis of colorectal carcinoma patients who received postoperative chemotherapy. AB - BACKGROUND: NR4A2, an orphan nuclear receptor essential in neuron generation, has been recently linked to inflammatory and metabolic pathways of colorectal carcinoma (CRC). However, the effects of NR4A2 on chemo-resistance and postoperative prognosis of CRC remain unknown. METHODS: NR4A2 was transfected into CRC cells to investigate its effects on chemo-resistance to 5-fluorouracil and oxaliplatin and chemotherapeutics-induced apoptosis. We also investigated prostaglandin E2 (PGE2)-induced NR4A2 expression and its effect on chemo resistance. Tissue microarrays including 51 adenoma, 14 familial adenomatous polyposis with CRC, 17 stage IV CRC with adjacent mucosa and 682 stage I-III CRC specimens were examined immunohistochemically for NR4A2 expression. Median follow up time for stage I-III CRC patients was 53 months. RESULTS: Ectopic expression of NR4A2 increased the chemo-resistance, and attenuated the chemotherapeutics induced apoptosis. Transient treatment of PGE2 significantly up-regulated NR4A2 expression via protein kinase A pathway and increased the chemo-resistance. NR4A2 expression in epithelials consecutively increased from adenoma, adjacent mucosa to CRC (P(trend)<0.001). In multivariate Cox regression analyses, high NR4A2 expression in cancer nuclei (immunoreactive score >= 4) significantly predicted a shorter disease-specific survival (DSS) of CRC patients (hazard ratio [HR]=1.88, P=0.024). High NR4A2 expression specifically predicted a shorter DSS of colon cancer patients (dichotomisation, HR=2.55, log-rank test P=0.011), especially for those who received postoperative 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX) chemotherapy (3-score range, HR=1.86, log-rank test P=0.020). CONCLUSION: High expression of NR4A2 in CRC cells confers chemo-resistance, attenuates chemotherapeutics-induced apoptosis, and predicts unfavorable prognosis of colon cancer patients, especially for those who received postoperative chemotherapy. NR4A2 may be prognostic and predictive for colon cancer. PMID- 23809768 TI - Correction: The importance of microglia in the development of the vasculature in the central nervous system. AB - CORRECTION: After the publication of this work 1 it was brought to our attention that citations in the article were not correspondingly numbered in the reference list. To avoid confusion, the article is republished here in its entirety, with the citations referenced correctly.The Publisher and authors apologize to the readers for the inconvenience caused. ABSTRACT: The body's vascular system is thought to have developed in order to supply oxygen and nutrients to cells beyond the reach of simple diffusion. Hence, relative hypoxia in the growing central nervous system (CNS) is a major driving force for the ingression and refinement of the complex vascular bed that serves it. However, even before the establishment of this CNS vascular system, CNS-specific macrophages (microglia) migrate into the brain. Recent studies in mice point to the fundamental importance of microglia in shaping CNS vasculature during development, and re shaping these vessels during pathological insults. In this review, we discuss the origin of CNS microglia and their localization within the brain based on data obtained in mice. We then review evidence supporting a functional role of these microglia in developmental angiogenesis. Although pathologic processes such as CNS ischemia may subvert the developmental functions of microglia/macrophages with significant effects on brain neo-angiogenesis, we have left this topic to other recent reviews 23. PMID- 23809769 TI - Quality indicators for palliative care: update of a systematic review. AB - CONTEXT: In 2007, a systematic review revealed a number of quality indicators referring mostly to palliative care outcomes and processes. Psychosocial and spiritual aspects were scarcely represented. Most publications lacked a detailed description of the development process. With many initiatives and further developments expected, an update is needed. OBJECTIVES: This update gives an overview of the published quality indicators for palliative care and identifies any new developments since 2007 regarding the number and type of indicators developed and the methodology applied. METHODS: The same literature search as in the 2007 review was used to identify relevant publications up to October 2011. Publications describing development processes or characteristics of quality indicators for palliative care were selected by two reviewers independently. RESULTS: The literature search resulted in 435 hits in addition to the 650 hits found in the previous review. Thirteen new publications were selected in addition to the 16 publications selected earlier, describing 17 sets of quality indicators containing 326 indicators. These cover all domains of palliative care as defined by the U.S. National Consensus Project. Most indicators refer to care processes or outcomes. The extent to which methodological characteristics are described varies widely. CONCLUSION: Recent developments in measuring quality of palliative care using quality indicators are mainly quantitative in nature, with a substantial number of new indicators being found. However, the quality of the development process varies considerably between sets. More consistent and detailed methodological descriptions are needed for the further development of these indicators and improved quality measurement of palliative care. PMID- 23809770 TI - Large scale simulation of red blood cell aggregation in shear flows. AB - Aggregation of highly deformable red blood cells (RBCs) significantly affects the blood flow in the human circulatory system. To investigate the effect of deformation and aggregation of RBCs in blood flow, a mathematical model has been established by coupling the interaction between the fluid and the deformable solids. The model includes a three-dimensional finite volume method solver for incompressible viscous flows, the combined finite-discrete element method for computing the deformation of the RBCs, a JKR model-Johnson, Kendall and Roberts (1964-1971) (Johnson et al., 1971) to take account of the adhesion forces between different RBCs and an iterative direct-forcing immersed boundary method to couple the fluid-solid interactions. The flow of 49,512 RBCs at 45% concentration under the influence of aggregating forces was examined, improving the existing knowledge on simulating flow and structural characteristics of blood at a large scale: previous studies on the particular issue were restricted to simulating the flow of 13,000 aggregative ellipsoidal particles at a 10% concentration. The results are in excellent agreement with experimental studies. More specifically, both the experimental and the simulation results show uniform RBC distributions under high shear rates (60-100/s) whereas large aggregation structures were observed under a lower shear rate of 10/s. The statistical analysis of the simulation data also shows that the shear rate has significant influence on both the flow velocity profiles and the frequency distribution of the RBC orientation angles. PMID- 23809771 TI - Robotic application of a dynamic resultant force vector using real-time load control: simulation of an ideal follower load on Cadaveric L4-L5 segments. AB - Standard in-vitro spine testing methods have focused on application of isolated and/or constant load components while the in-vivo spine is subject to multiple components that can be resolved into resultant dynamic load vectors. To advance towards more in-vivo like simulations the objective of the current study was to develop a methodology to apply robotically-controlled, non-zero, real-time dynamic resultant forces during flexion-extension on human lumbar motion segment units (MSU) with initial application towards simulation of an ideal follower load (FL) force vector. A proportional-integral-derivative (PID) controller with custom algorithms coordinated the motion of a Cartesian serial manipulator comprised of six axes each capable of position- or load-control. Six lumbar MSUs (L4-L5) were tested with continuously increasing sagittal plane bending to 8 Nm while force components were dynamically programmed to deliver a resultant 400 N FL that remained normal to the moving midline of the intervertebral disc. Mean absolute load-control tracking errors between commanded and experimental loads were computed. Global spinal ranges of motion and sagittal plane inter-body translations were compared to previously published values for non-robotic applications. Mean TEs for zero-commanded force and moment axes were 0.7 +/- 0.4N and 0.03 +/- 0.02 Nm, respectively. For non-zero force axes mean TEs were 0.8 +/- 0.8 N, 1.3 +/- 1.6 Nm, and 1.3 +/- 1.6N for Fx, Fz, and the resolved ideal follower load vector FL(R), respectively. Mean extension and flexion ranges of motion were 2.6 degrees +/- 1.2 degrees and 5.0 degrees +/- 1.7 degrees , respectively. Relative vertebral body translations and rotations were very comparable to data collected with non-robotic systems in the literature. The robotically coordinated Cartesian load controlled testing system demonstrated robust real-time load-control that permitted application of a real-time dynamic non-zero load vector during flexion-extension. For single MSU investigations the methodology has potential to overcome conventional follower load limitations, most notably via application outside the sagittal plane. This methodology holds promise for future work aimed at reducing the gap between current in-vitro testing and in-vivo circumstances. PMID- 23809772 TI - Do spectral bands of fetal heart rate variability associate with concomitant fetal scalp pH? AB - BACKGROUND: Objective information on specific fetal heart rate (FHR) parameters would be advantageous when assessing fetal responses to hypoxia. Small, visually undetectable changes in FHR variability can be quantified by power spectral analysis of FHR variability. AIMS: To investigate the effect of intrapartum hypoxia and acidemia on spectral powers of FHR variability. STUDY DESIGN: This is a retrospective observational clinical study with data from an EU multicenter project. SUBJECTS: We had 462 fetuses with a normal pH-value (pH>7.20; controls) in fetal scalp blood sample (FBS) and 81 fetuses with a low scalp pH-value (<= 7.20; low-FBS pH-fetuses). The low-FBS pH-fetuses were further divided into two subgroups according to the degree of acidemia: fetuses with FBS pH7.11-7.20 (n = 58) and fetuses with FBS pH <=7.10 (n = 23). OUTCOME MEASURES: Spectral powers of FHR variability in relation to the concomitant FBS pH-value. RESULTS: Fetuses with FBS pH <=7.20 had increased spectral powers of FHR variability compared with controls (2.49 AU vs. 2.23 AU; p = 0.038). However, the subgroup of most affected fetuses (those with FBS pH <=7.10) had significantly lower FHR variability spectral powers when compared to fetuses with FBS pH7.11-7.20. CONCLUSIONS: This study shows that spectral powers of FHR variability change as a fetus becomes hypoxic, and that spectral powers decrease with deepening fetal acidemia. PMID- 23809773 TI - Analysis of the variation in meat inspection of pigs using variance partitioning. AB - According to legal regulations, all slaughtered pigs in the European Union are subject to routine meat inspection at the slaughterhouses. The resulting post mortem findings are valuable indicators that help improve slaughterhouse and farm management and can be used to establish a feedback system regarding animal health. A sufficiently high quality of meat inspection is therefore imperative, which implies that the results of the inspection must not depend on the person carrying out the examination. The objective of the study at hand is the estimation of the amount of variation in these post-mortem findings that can be attributed to the official meat inspectors. In order to reduce the influence of the heterogeneity in the health state of the pigs, the variation due to the farms of origin was considered in the statistical model as well. The analyzed meat inspection data were recorded by 12 official meat inspectors under real working conditions at an Austrian slaughterhouse. Logistic Multilevel Models with cross classified random effects were applied to 20 post-mortem findings. On the basis of these models, variance partitioning coefficients (VPCs) were used to estimate the amount of variation in the probabilities of these findings due to meat inspector and farm levels. The estimated VPCs suggest that especially meat inspection of blood aspiration, scalding water lungs, skin lesions and hepatitis can be deemed as not sufficiently standardized. Hardly any variation in meat inspection could be identified for other post-mortem findings, such as pericarditis, peritonitis, arthritis and milkspots. PMID- 23809774 TI - Evaluation of the performance of cellular and serological diagnostic tests for the diagnosis of tuberculosis in an alpaca (Vicugna pacos) herd naturally infected with Mycobacterium bovis. AB - Tuberculosis (TB) in llamas and alpacas has gained importance in recent years since they are imported into the European Union mainly for serving as pets and for production of natural fibre. The intradermal tuberculin test has been widely used for diagnosis of TB in these species showing lack of sensitivity (Se) although little information has been previously reported evaluating the effect on its performance of different PPD inoculation sites and time of readings. Moreover, different cost-effective serological assays have been developed in the recent years for TB diagnosis in camelids obtaining a variety of results and, for this reason, new assays still being developed. The main objectives of this study were: (1) to evaluate the performance of the intradermal tuberculin test using different inoculation sites (axillary, prescapular and cervical) and times of reading (72 and 120 h) and (2) to test a novel serological assay based on MPB83 antigen in a Mycobacterium bovis naturally infected alpaca herd in Spain. In regards to skin test, single intradermal tuberculin (SIT) test at the prescapular site and reading at 72 h showed the highest proportion of test-positive-culture positive animals among all culture positive animals (T+/C+), ranging from 53.8% (95% CI, 37.2-69.9) to 80% (95% CI, 44.4-97.5) using a more stringent interpretation than typically prescribed although, in general, low T+/C+ was achieved using both SIT and single comparative intradermal tuberculin (SCIT) tests alone. T+/C+ of the serological assay increased using samples collected 15 30 days after PPD injection [76.9% (95% CI, 60.7-88.9) - 100% (95% CI, 69.2 100)]. The best results of T+/C+ were obtained applying in parallel the most sensitive SIT test and serology using samples collected 15-30 days after PPD inoculation [90% (95% CI, 55.5-99.7)-100% (95% CI, 69.2-100)]. Therefore implementation of serology in parallel with the most sensitive skin test could maximize the detection of infected animals. PMID- 23809775 TI - Six-year longitudinal changes in body composition of middle-aged and elderly Japanese: age and sex differences in appendicular skeletal muscle mass. AB - AIM: Little is known about longitudinal changes of body composition measured by dual-energy X-ray absorptiometry (DXA) in middle-aged and elderly individuals. We evaluated longitudinal changes of body composition, and age and sex differences in appendicular skeletal muscle mass. METHODS: Participants were 1454 community dwelling Japanese men and women aged 40-79 years. Body composition at baseline and 6-year follow up was measured by DXA. RESULTS: Fat increased significantly in men of all ages, and in women aged in their 40s and 50s. Among men, arm lean tissue mass (LTM) changed by 0.9%, -0.5%, -1.4% and -3.7%, respectively, for the 40s to the 70s, and decreased significantly in the 60s and 70s. Leg LTM in men changed by -0.4%, -1.3%, -1.7% and -3.9%, respectively, and decreased significantly from the 50s to the 70s. Compared with the preceding age groups, significant differences were observed between the 60s and 70s in arm and leg LTM change in men. Among women, arm LTM changed by 0.7%, 0.2%, 1.6% and -1.5%, respectively, which was significant in the 60s and 70s. Leg LTM decreased significantly in all age groups of women by -2.0%, -2.8%, -2.4% and -3.9%, respectively. With respect to sex differences, leg LTM loss rates were significantly higher in women than men at the 40s and 50s. CONCLUSIONS: Longitudinal data suggest that arm and leg LTM decreased markedly in men in their 70s, and leg LTM had already decreased in women in their 40s. PMID- 23809776 TI - Prenatal diagnosis of haemophilia B: the Italian experience. AB - This article describes prenatal diagnosis (PND) of haemophilia B (HB) within the framework of Italian haemophilia centres and genetics laboratories. The study details the experience from six haemophilia genetic centres (three in the North, one in the Centre and two in the South of Italy) and summarizes the different techniques used to perform PND of HB during the last 15 years. To date, the Italian HB database includes 373 characterized unrelated patients and their genetic information has permitted the identification of 274 carriers of childbearing age. This database represents the main instrument for timely and precise PND. Sixty-six prenatal diagnoses were performed on 52 HB carriers whose average age at the time was 34 (ranging from 24 to 44 years). In 44 cases, genetic counselling for carrier status determination was performed before pregnancy, while eight were not studied prior to pregnancy. Foetal samples were obtained by chorionic villus sampling in 52 cases, by amniocentesis in 12 while two were diagnosed by analysis of free foetal DNA obtained from maternal peripheral blood. In 35 (53%) pregnancies the foetus was female. For 31 men (47%), haemophilia status was determined by analysis of previously determined informative markers or familial mutations (12 affected and 19 unaffected). There may be more than one laboratory involved in the PND diagnostic pathway (providing DNA extraction, karyotype analysis, gender determination, maternal contamination detection, molecular diagnosis and sequencing). Good communication between all the parties, coordinated by the haemophilia centre, is essential for a successful and rapid process. PMID- 23809777 TI - The effect of ultrasound-related stimuli on cell viability in microfluidic channels. AB - BACKGROUND: In ultrasonic micro-devices, contrast agent micro-bubbles are known to initiate cavitation and streaming local to cells, potentially compromising cell viability. Here we investigate the effects of US alone by omitting contrast agent and monitoring cell viability under moderate-to-extreme ultrasound-related stimuli. RESULTS: Suspended H9c2 cardiac myoblasts were exposed to ultrasonic fields within a glass micro-capillary and their viability monitored under different US-related stimuli. An optimal injection flow rate of 2.6 mL/h was identified in which, high viability was maintained (~95%) and no mechanical stress towards cells was evident. This flow rate also allowed sufficient exposure of cells to US in order to induce bioeffects (~5 sec), whilst providing economical sample collection and processing times. Although the transducer temperature increased from ambient 23 degrees C to 54 degrees C at the maximum experimental voltage (29 Vpp), computational fluid dynamic simulations and controls (absence of US) revealed that the cell medium temperature did not exceed 34 degrees C in the pressure nodal plane. Cells exposed to US amplitudes ranging from 0-29 Vpp, at a fixed frequency sweep period (tsw = 0.05 sec), revealed that viability was minimally affected up to ~15 Vpp. There was a ~17% reduction in viability at 21 Vpp, corresponding to the onset of Rayleigh-like streaming and a ~60% reduction at 29 Vpp, corresponding to increased streaming velocity or the potential onset of cavitation. At a fixed amplitude (29 Vpp) but with varying frequency sweep period (tsw = 0.02-0.50 sec), cell viability remained relatively constant at tsw >= 0.08 sec, whilst viability reduced at tsw < 0.08 sec and minimum viability recorded at tsw = 0.05 sec. CONCLUSION: The absence of CA has enabled us to investigate the effect of US alone on cell viability. Moderate-to extreme US-related stimuli of cells have allowed us to discriminate between stimuli that maintain high viability and stimuli that significantly reduce cell viability. Results from this study may be of potential interest to researchers in the field of US-induced intracellular drug delivery and ultrasonic manipulation of biological cells. PMID- 23809779 TI - Bridging the gap: pain medicine and palliative care. PMID- 23809780 TI - [Informed consent in anaesthesiology: period of notice as a requisite of validity]. AB - The analysis of one of the requisites of the validity of the informed consent, the notice period, during which the patient should be provided with information, so that he/she can reflect and fully exercise his/her Kantian right of self determination. National legislation appears to be insufficient when dealing with this issue, which is compensated for in some regional legislations. We conclude by pointing the need to provide the patient with information with sufficient notice prior to operations, so that he/she can ponder over his/her decision. PMID- 23809781 TI - [Analysis of difficult intubation factors in bariatric surgery. Influence of the choice of neuromuscular blocker on the availability of sugammadex]. AB - OBJECTIVE: To determine the incidence of difficult tracheal intubation (DTI), as well as predictive factors for DTI and what influences the choice of the neuromuscular blocking agent (succinylcholine or rocuronium). METHODS: This is an observational, prospective study on consecutive bariatric surgery patients. Tracheal intubation was performed by direct laryngoscopy with a preformed tracheal tube. DTI was considered when there was a Cormack-Lehane classification of iii-iv or when it was necessary to apply the DTI algorithm, which consisted in the use of Frova guide, and Airtraq video-laryngoscope as second choice, and finally awaking the patient and sugammadex reversal if rocuronium was the selected neuromuscular blocking agent. Thereafter, tracheal intubation was performed using an awake fibroscopic technique RESULTS: One hundred and sixty six patients were included. In one case, conscious fiberscope tracheal intubation was performed. Succinylcholine was selected for 14 patients, and rocuronium for 151 patients. Fifteen patients had a DTI (9%): in 4 Airtraq was deemed necessary. One patient received sugammadex to reverse neuromuscular blockade. Conscious tracheal intubation represented 1.2% (95% CI; 0.3-4%). DTI was associated with Mallampati score of 3-4 (odds ratio, 3 [95% CI; 1.37-6.8], sensitivity of 33%, specificity of 91%) and with thyromental distance<6cm (odds ratio, 4.8 [95% CI; 1.45-16]; sensitivity of 53%; specificity of 79%). CONCLUSION: Rescue airway protocol with Frova and Airtraq avoided the use of sugammadex, except in one patient. PMID- 23809782 TI - Quantitative analysis of normal fetal brain volume and flow by three-dimensional power Doppler ultrasound. AB - BACKGROUND: Assessment of the fetal brain volume and blood flow is important in the evaluation of fetal growth. We used three-dimensional (3D) ultrasound and power Doppler to assess the fetal brain volume and the blood flow index during normal gestation. The relationships of these parameters were further analyzed. METHODS: We assessed the total volume and the blood flow index of the fetal brain in normal pregnancies using 3D ultrasound (Voluson 730). The bilateral parietal diameter (BPD) plane was measured by a 3D transabdominal probe to scan the fetal brain under the power Doppler mode. Then, we quantitatively assessed the total volume of the fetal brain, mean grey area (MG), vascularization index (VI), flow index (FI), and vascularization-flow index (VFI) by applying Kretz VOCAL software. RESULTS: The study included 126 fetuses, ranging from 15 to 38 weeks of gestation. The total volume of the fetal brain was highly positively correlated with the gestational age (GA) (correlation coefficient [r] = 0.976, p < 0.0001). The MG, VI, and VFI were negatively correlated with the GA (correlation coefficient [r] = -0.520, p < 0.0001; [r] = -0.421, p < 0.001; [r] = -0.319, p < 0.0001). The FI was positively correlated with the GA (correlation coefficient [r] = 0.483, p < 0.0001). CONCLUSION: 3D ultrasound can be used to assess the fetal brain volume and blood flow development quantitatively. Our study indicates that the fetal brain vascularization and blood flow correlates significantly with the advancement of GA. This information may serve as a reference point for further studies of the fetal brain volume and blood flow in abnormal conditions. PMID- 23809784 TI - Delays in access to affordable medicines: putting policy into perspective. PMID- 23809783 TI - Follow-up of Helicobacter pylori infection in children over two decades (1988 2007): persistence, relapse and acquisition rates. AB - Helicobacter pylori culture on gastric biopsy was performed on 4964 subjects aged <18 years from 1988 to 2007 at a central laboratory in Brussels. The total number of biopsies increased markedly from 941 in 1988-1993 to 1608 in 2004-2007. Biopsies were repeated at least once for 922 subjects (603 initially negative and 319 initially positive for H. pylori). Persistence rate of H. pylori at 1 year after initial positive biopsy was greater in the 1998-2007 cohort than in the 1988-1997 cohort (72.7% vs. 45.8%, P = 0.002), suggesting a tailored selection of candidates for biopsy with non-invasive tests (13C urea breath test). Of 68 subjects initially positive and re-examined subsequently after a documented cure, re-infection/relapse rate was 48.6% within 5 years post-elimination of H. pylori. Acquisition rate over 10 years follow-up in the initially negative cohort (603 patients) was 38.7% (re-infection/relapse vs. acquisition: P < 0.001). Multivariate analysis showed a fourfold greater risk of H. pylori acquisition in children of non-European origin vs. European origin (P < 0.001). Clarithromycin and metronidazole susceptibility were determined in 226 and 223 paired positive cultures in cases of re-infection/relapse or persistence. An initial non susceptibility profile was highly predictive of a subsequent non-susceptibility profile, and the non-susceptible proportion increased markedly from 13.3% to 21.2% for clarithromycin (P < 0.001) and from 27.3% to 35.0% for metronidazole (P = 0.014), with no difference regarding European or non-European origin. PMID- 23809802 TI - Blood, biomarkers and beyond. Abstracts of the Medical Oncology Group of Australia Incorporated Annual Scientific Meeting. July 31-August 2, 2013. Melbourne, Victoria, Australia. PMID- 23809803 TI - Measurement of activity coefficients of mixtures by head-space gas chromatography: general procedure. AB - Head-space gas chromatography (HS-GC) is an applicable method to perform vapor liquid equilibrium measurements and determine activity coefficients. However, the reproducibility of the data may be conditioned by the experimental procedure concerning to the automated pressure-balanced system. The study developed in this work shows that a minimum volume of liquid in the vial is necessary to ensure the reliability of the activity coefficients since it may become a parameter that influences the magnitude of the peak areas: the helium introduced during the pressurization step may produce significant variations of the results when too small volume of liquid is selected. The minimum volume required should thus be evaluated prior to obtain experimentally the concentration in the vapor phase and the activity coefficients. In this work, the mixture acetonitrile-toluene is taken as example, requiring a sample volume of more than 5mL (about more than 25% of the vial volume). The vapor-liquid equilibrium and activity coefficients of mixtures at different concentrations (0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 molar fraction) and four temperatures (35, 45, 55 and 70 degrees C) have been determined. Relative standard deviations (RSD) lower than 5% have been obtained, indicating the good reproducibility of the method when a sample volume larger than 5mL is used. Finally, a general procedure to measure activity coefficients by means of pressure-balanced head-space gas chromatography is proposed. PMID- 23809786 TI - Feasibility and safety of laparoscopic total proctocolectomy with ileal pouch anal anastomosis for severe ulcerative colitis. AB - INTRODUCTION: The laparoscopic approach is accepted as a treatment option for patients with ulcerative colitis (UC) who are otherwise in good health. However, its application for patients with severe UC remains controversial. The purpose of this study was to evaluate the feasibility of the laparoscopic approach for severe UC cases. Short- and long-term clinical outcomes after laparoscopic total proctocolectomy with ileal pouch-anal anastomosis were compared between severe and mild-to-intermediate UC patients. METHODS: Cases treated between March 2002 and September 2010 were retrieved retrospectively from the database of Kyoto Medical Center and Kyoto University Hospital. Intraoperative complications and short- and long-term clinical outcomes were compared. RESULTS: A total of 31 patients underwent laparoscopic total proctocolectomy with ileal pouch-anal anastomosis. A comparison of short- and long-term clinical outcomes after one- or two-stage laparoscopic ileal pouch-anal anastomosis between severe (n = 7) and mild-to-intermediate (n = 21) UC patients revealed no significant differences. The proportion of patients with restoration of intestinal continuity did not differ between the groups (severe: 86%, mild to intermediate: 95%; P = 0.69). CONCLUSION: The present findings suggest that laparoscopic total proctocolectomy with ileal pouch-anal anastomosis for severe UC patients could be a good alternative approach when performed by an experienced hand. PMID- 23809804 TI - Solvent-impregnated agarose gel liquid phase microextraction of polycyclic aromatic hydrocarbons in water. AB - A new microextraction procedure termed agarose gel liquid phase microextraction (AG-LPME) combined with gas chromatography-mass spectrometry (GC-MS) was developed for the determination of selected polycyclic aromatic hydrocarbons (PAHs) in water. The technique utilized an agarose gel disc impregnated with the acceptor phase (1-octanol). The extraction procedure was performed by allowing the solvent-impregnated agarose gel disc to tumble freely in the stirred sample solution. After extraction, the agarose gel disc was removed and subjected to centrifugation to disrupt its framework and to release the impregnated solvent, which was subsequently withdrawn and injected into the GC-MS for analysis. Under optimized extraction conditions, the new method offered high enrichment factors (89-177), trace level LODs (9-14ngL(-1)) and efficient extraction with good relative recoveries in the range of 93.3-108.2% for spiked drinking water samples. AG-LPME did not exhibit any problems related to solvent dissolution, and it provided high extraction efficiencies that were comparable to those of hollow fiber liquid phase microextraction (HF-LPME) and significantly higher than those of agarose film liquid phase microextraction (AF-LPME). This technique employed a microextraction format and utilized an environmentally compatible solvent holder that supported the green chemistry concept. PMID- 23809805 TI - Matrix solid-phase dispersion combined with gas chromatography-mass spectrometry for the determination of fifteen halogenated flame retardants in mollusks. AB - This study presents the development and validation of a new analytical method for the simultaneous determination of fifteen analytes classified as halogenated flame retardants (HFRs) - nine brominated diphenyl ethers (BDEs) and six novel HFRs - in different kinds of mollusks using matrix solid-phase dispersion (MSPD) followed by gas chromatography coupled to negative chemical ionization-mass spectrometry (GC-NCI-MS). The proposed method is the first one developed for such a broad range of HFRs in aquatic biota, featuring several advantages, including low solvent and sample intake, simplicity of operation, reduced cost and integration of extraction and clean-up into a single step. Under optimal conditions, 0.5g of freeze-dried sample, 0.5g of a primary-secondary amine (PSA) as solid support, a sorbent combination of 1.75g of florisil (deactivated with 5% Milli-Q water), 1.75g of acidified silica (10% (w/w) H2SO4) and 0.5g of silica, and 10mL dichloromethane as elution solvent were used. Standard addition over the extract was required however for the correct quantification due to matrix effects in the GC system, particularly for novel HFRs, that could not be compensated with the internal standards. The method afforded LODs in the range of 0.003-0.07ngg( 1) dry weight (0.0006-0.014ngg(-1) on a wet weight basis, assuming an 80% sample water content), except for decabromodiphenyl ethane (DBDPE) (0.6ngg(-1) dry weight, 0.12ngg(-1) wet weight). The accuracy of the method was evaluated with three different types of spiked mollusk species using surrogate standards and standard addition over the extract for quantification and the recoveries were in the 70-120% range, except for bis(2-ethylhexyl)-3,4,5,6-tetrabromo-phthalate (DEHTBP) in clam (Ruditapes philippinarum) samples (46% recovery). Moreover, the method was successfully validated with standard reference materials (SRMs) of salmon and mussel tissues for BDEs. Finally, the method was applied to the determination of HFRs in different kind of freeze-dried mollusks: mussel (Mytilus galloprovincialis), cockle (Cerastoderma edule) and clam (R. philippinarum). Raft cultured mussels showed the highest concentrations of HFRs (up to 0.8ngg(-1) wet weight of BDE-209). PMID- 23809806 TI - On the use of ionic liquid capillary columns for analysis of aromatic hydrocarbons in low-boiling petrochemical products by one-dimensional and comprehensive two-dimensional gas chromatography. AB - One-dimensional and comprehensive two-dimensional flow modulated gas chromatography with simultaneous flame ionization and mass spectrometric detection were applied for the identification and quantification of benzene, toluene, ethyl benzene and xylenes (BTEX) as well as of all C9-C11 aromatic hydrocarbons in the low-boiling petroleum products gasoline, reformate and fluid catalytic cracking (FCC) samples. GC*GC experiments were performed on two reversed phase polarity column sets namely SLB-IL100 (25m*250MUm i.d.*0.2MUm df)+HP-5MS (5m*250MUm i.d.*0.25MUm df) and SLB-IL111 (30m*250MUm i.d.*0.2MUm df)+HP-5MS (5m*250MUm i.d.*0.25MUm df). The one-dimensional GC experiments were carried out on the same ionic liquid columns. The most powerful method is GC*GC on the SLB-111+HP-5MS column combination. Quantitative analysis of individual aromatic hydrocarbons (C6-C11) present in gasoline, reformate and fluid catalytic cracking (FCC) samples was performed by GC*GC-FID using the internal normalization method. Mass spectra obtained by GC*GC-qMSD were used for identification of the aromatic hydrocarbons in these samples. PMID- 23809808 TI - Bone density in apheresis donors compared with blood donors. PMID- 23809809 TI - Large volume apheresis: electrolyte imbalance and loss of platelets; watch for clinically relevant disturbances. PMID- 23809810 TI - Plasmapheresis in antibody incompatible renal transplantation--moving to a quantifiable approach? PMID- 23809811 TI - Effects of G-CSF in healthy stem cell donors. PMID- 23809812 TI - Panorama of adverse events during cytapheresis. PMID- 23809813 TI - Plasmapheresis and clotting activation. PMID- 23809814 TI - Certification of donor apheresis nurses: keys to develop an effective training program. PMID- 23809815 TI - Extracorporeal photochemotherapy (ECP) in children. PMID- 23809816 TI - Plasmapheresis in healthy donors in the Netherlands: cohort study of risk factors for donor complications. PMID- 23809817 TI - Challenges in transfusion of patients with sickle cell disease. PMID- 23809818 TI - Extracorporeal photopheresis, the Dutch experience. PMID- 23809819 TI - Comparison of apheresis and 24h RT held red cell concentrates by measurement of storage lesion parameters and neutrophil activating factors during 42-day storage. PMID- 23809820 TI - Donor lymphocyte collections using the spectra Optia MNC version 5. PMID- 23809821 TI - High efficiency stem cell collection collecting from children and adolescents. PMID- 23809822 TI - Optimization of MNC collection efficiency depending on patient WBC precount with Amicus. PMID- 23809823 TI - Erythrocyte-exchange in sickle-cell disease patients. A comparison between Caridian COBE Spectra and Optia cell separators. PMID- 23809824 TI - Therapeutic plasma exchange (TPE) as a new therapy option on the Amicus. PMID- 23809825 TI - Initial experience using the Amicus separator for passive column treatment. PMID- 23809826 TI - The lipoproteins selections aphereses with LDL Lipopak 400. PMID- 23809827 TI - Immune adsorption of anti-A/B antibodies prior to ABO-mismatched kidney transplantation: the Leiden experience. PMID- 23809828 TI - The efficiency of therapeutic erythrocytapheresis compared to phlebotomy in relation to blood volume and delta-hematocrit: an evaluation in hereditary hemochromatosis polycythemia vera and secondary erythrocytosis. PMID- 23809829 TI - Plasmapheresis as a tool for large volume collection of diagnostic biomarkers. PMID- 23809830 TI - Use of Plerixafor in patients that show failure of peripheral blood stem cell mobilization with G-CSF. Experience of three Dutch centers. PMID- 23809831 TI - Treatment of chronic GVHD with extracorporeal photochemotherapy. PMID- 23809832 TI - Best practice recommendations in: (1) Peripheral blood stem cell mobilization and collection and (2) acute and chronic GvHD treatment using extracorporeal photopheresis. A joint effort from SIdEM (Societa Italiana di Emaferesi e Manipolazione Cellulare) and GITMO (Gruppo Italiano Trapianto di Midollo Osseo). PMID- 23809833 TI - One week education in apheresis at Dharmais National Cancer Hospital. PMID- 23809834 TI - Does standard intravenous calcium gluconate administration during peripheral blood stem cell collection reduce the chance of a citrate reaction? PMID- 23809835 TI - The ins and outs of hemapheresis units in the Netherlands: practice and organization. PMID- 23809837 TI - Isolation of infraspinatus in clinical test positions. AB - OBJECTIVES: Existing clinical tests for infraspinatus lack accuracy and differentiation from supraspinatus is difficult. We aimed to find a position that isolated infraspinatus contraction from supraspinatus and to analyse the contraction characteristics of lower (oblique) and upper (transverse) parts of infraspinatus. DESIGN: Within-participant, repeated measures experimental study. METHODS: Intramuscular electromyography was used to measure the level of activation (electromyographic amplitude as a percentage of maximal voluntary contraction) of infraspinatus and supraspinatus on 15 healthy participants. Participants produced an isometric external rotation force at the shoulder, against manual resistance in shoulder positions of neutral, flexion, abduction and extension. Longitudinal force along the humeral axis was also applied. RESULTS: The two parts of infraspinatus demonstrated different patterns of electromyographic activation. The oblique part of infraspinatus was "markedly active" in all positions while the transverse part was mostly "moderately active". Comparing supraspinatus with infraspinatus, it was found that infraspinatus was significantly more active than supraspinatus from the positions of shoulder flexion and neutral with the highest ratios observed in the position of shoulder flexion. Longitudinal humeral force was not an important factor. CONCLUSIONS: If isometric external rotation of the shoulder is performed against resistance, the oblique part of infraspinatus will be working harder than the transverse part, irrespective of shoulder position. If differentiation of infraspinatus contraction from supraspinatus is desired, external rotation should be performed from a position of shoulder flexion or neutral. Resisted external rotation in shoulder flexion may form the basis of the development of a more accurate clinical test for infraspinatus. PMID- 23809839 TI - Acute physiological and performance responses to repeated sprints in varying degrees of hypoxia. AB - OBJECTIVES: Our aim was to determine the effects of different inspired oxygen fractions on repeated sprint performance and cardiorespiratory and neuromuscular responses, to construct a hypoxic dose response. DESIGN: Nine male well-trained multi-sport athletes completed 10*6s all-out running sprints with 30s recovery in 5 conditions with different inspired oxygen fraction (FIO2: 12%, 13%, 14%, 15%, 21%). METHODS: Peak running speed was measured in each sprint and electromyography data were recorded from m. vastus lateralis in parallel with heart rate and blood oxygen saturation. Cardiorespiratory response was assessed via breath by breath expired air analysis and muscle oxygenation status was evaluated via near infrared spectroscopy. RESULTS: In parallel with the higher heart rate, minute ventilation, blood lactate concentration, and muscle deoxygenation; lower blood oxygen saturation, pulmonary oxygen uptake and integrated EMG (all p<0.05) were registered in all hypoxic conditions, with the greatest changes from baseline observed during the 13% trial. However, fatigue index and speed decrement were significantly greater only during the 12% vs 21% trial (p<0.05). CONCLUSIONS: Physiological responses associated with performing 10*6s sprints interspersed with 30s passive recovery was incrementally greater as FIO2 decreased to 13%, yet fatigue development was significantly exacerbated relative to normoxia (FIO2: 21%) only at the 12% FIO2. PMID- 23809838 TI - Flow-mediated dilation and exercise blood pressure in healthy adolescents. AB - OBJECTIVES: Exercise blood pressure is a robust predictor of cardiovascular disease risk. Endothelial dysfunction occurs early in development of cardiovascular disease and is associated with greater exercise blood pressure in adults. However, it is not yet clear whether endothelial function is associated with exercise blood pressure in youth. The purpose of this study was to examine the relationship between endothelial function, indexed by brachial artery flow mediated dilation, and submaximal exercise blood pressure in healthy adolescents. DESIGN: Cross-sectional study. METHODS: Adolescents (N=45) completed a graded submaximal treadmill test. Blood pressure was measured during rest and each exercise stage. Ultrasound measurement of brachial artery flow-mediated dilation was completed on a separate visit. Pearson correlations and multiple regression were used to assess the unadjusted and multivariate adjusted associations between flow-mediated dilation and exercise blood pressure, respectively. RESULTS: Lower flow-mediated dilation was associated with lower diastolic blood pressure (r=0.37, p=0.01) and greater pulse pressure (r=-0.38, p=0.01) during exercise. The significance did not change when adjusting for age, gender, fitness, or resting blood pressure. Exploratory analyses suggest that flow-mediated dilation was associated with exercise diastolic blood pressure primarily among adolescents with low resting diastolic blood pressure. CONCLUSIONS: Studies in youth are important to understand the early pathogenesis of cardiovascular disease. Findings from this study suggest that endothelial function may play a role in regulating blood pressure responses during submaximal exercise in healthy adolescents. PMID- 23809840 TI - XYLH encodes a xylose/H+ symporter from the highly related yeast species Debaryomyces fabryi and Debaryomyces hansenii. AB - The closely related yeasts Debaryomyces fabryi and Debaryomyces hansenii are excellent xylose consumers. We previously described the activity of a high affinity xylose/H(+) symport from an industrial strain of D. hansenii subsequently reclassified as D. fabryi. We now report the identification of the gene encoding this permease, AY347871.2. This was retrieved from D. fabryi gDNA using a degenerate primer PCR strategy, based on conserved regions from the amino acid sequences of three well-characterized bacterial xylose/H(+) symporters. This sequence is 86% identical to another, DEHA2C11374p from D. hansenii type strain. DEHA2C11374p was conceptually ascribed to the major facilitator superfamily. The putative amino acid sequence of AY347871.2 and DEHA2C11374p presented a hydrophobicity pattern compatible with plasma membrane proteins. The last was functionally expressed in Saccharomyces cerevisiae. The sensitivity of transport activity to a protonophore confirmed its dependence on proton motive force, as expected from a symporter. We named D. fabryi AY347871.2 and D. hansenii DEHA2C11374p as XYLH from Xylose/H(+) symport. Based on the very high similarity, we suggested that Scheffersomyces stipitis Xut3 and Aspergillus nidulans AN8400.2 may also encode xylose high-affinity permeases. PMID- 23809841 TI - Endovenous valve transfer for chronic deep venous insufficiency. AB - OBJECTIVES: The aims of the study were to test the safety and efficacy of a custom-made endovenous valve transfer stent, and delivery system in animals and humans. METHODS: The internal jugular veins of 16 sheep, weighing 45-55 kg, were used. A segment of vein with venous valve was enclosed circumferentially with a barbed stent. This segment from the internal jugular vein was introduced and deployed remotely into the contralateral internal jugular vein. Harvesting occurred acutely (one sheep) and at 1, 3, and 6 months postoperatively (five sheep per group). Operative competence testing, histological and scanning electron microscopic (SEM) examinations were performed. Four males with recalcitrant ulcers (mean age of 22 years) had axillary veins transferred from the popliteal vein and were followed for a mean of 3.8 years. RESULTS: At harvest, all the transferred valves were competent, with no evidence of thrombosis, tilting, endoleak, or migration with normal macroscopic and SEM findings. Although only 50% of the ulcers completely healed in humans, the remainder were improved, with all valves being competent and patent. CONCLUSIONS: Endovenous valve transfer with a custom-made circumferential stent produces near perfect results in sheep and encouraging results in a small pilot study. PMID- 23809842 TI - Varicose vein recurrence and patient satisfaction 10-14 years following combined superficial and perforator vein surgery: a prospective case study. AB - OBJECTIVE: To assess real long-term varicose vein recurrence and patient satisfaction following surgical intervention with combined subfascial endoscopic perforator surgery (SEPS) and superficial venous surgery. METHOD: Prospective consecutive case study (C3-C4). Patients were included March 1993 to September 1998 and 83/104 legs of 80/100 patients were re-assessed 2008; 71 legs underwent duplex ultrasound scanning (DUS). RESULTS: The median follow up was 12 years (range 10-14). Twelve patients/legs had undergone additional vein surgery during follow-up. Incompetent lower leg perforators were noted in 18/71 limbs (25%). Following groin surgery 23/51 (45%) showed a duplex detected groin recurrence, neovascularization dominated 18/23. In legs where primary great saphenous vein (GSV) surgery had been performed, groin recurrence was found in 14/37 (38%). Previously unknown deep vein incompetence was detected in 14/71 legs (20%), six had axial reflux. The correlation between DUS-detected recurrence and remaining symptoms and cosmetic result was low. The overall satisfaction was high, 70/82 (85%). Patient satisfaction did not deteriorate over time (p < .557). CONCLUSION: Despite a fair number of DUS-detected recurrences, the overall long-term result, from the patients' point of view was surprisingly favorable. Technically well performed open venous surgery seems to result in a durable long-term outcome. PMID- 23809843 TI - Breast cancer and venous disease: a retrospective cohort study. AB - BACKGROUND: Breast cancer (BC) and chronic venous disease (CVD) are in some way related to hormonal effects, and often the clinical manifestations of CVD intersect with the clinical course of BC. This article describes the correlations between these clinical conditions. METHODS: A total of 1138 female patients with BC were retrospectively reviewed in a 5-year period to obtain clinical information about the frequency and characteristics of contemporary CVD and the relative correlations with estrogen and progesterone receptor status. RESULTS: The presence of BC was associated with concomitant CVD clinical manifestations in patients with positive estrogen receptor status, whereas no association was found in patients with negative estrogen receptor status. The presence of negative estrogen receptor status associated with positive progesterone receptor status seemed to be even protective against CVD. Patients with more severe manifestations of CVD had positive estrogen receptor status. CONCLUSIONS: BC and CVD seem to be strongly associated. Positive estrogen receptor status may predispose to a more severe clinical course of venous disease when it occurs in patients with BC. PMID- 23809844 TI - Supercritical fluid chromatography/Orbitrap mass spectrometry based lipidomics platform coupled with automated lipid identification software for accurate lipid profiling. AB - We developed a practical analytical system for high-throughput and comprehensive lipid profiling using a supercritical fluid chromatography (SFC) system coupled to an Orbitrap Fourier transform mass spectrometer (Orbitrap FT-MS). Using our SFC method, polar lipid molecular species were separated based on not only their fatty acyl moieties but also their polar head groups, using a single octadecylsilyl (ODS) column. In addition, because automatic data processing software was used for the identification of lipid molecular species, the analysis time including data processing was about a half an hour per sample. A variety of lipid molecular species were detected in mouse plasma, and isomers which often co elute in reverse phase separation were identified accurately and quantified individually. To the best of our knowledge, this is the first report describing the chromatographic separation of lipids based on both fatty acyl moieties and polar head groups, using a single ODS column. Our results demonstrate that SFC/MS is a powerful tool for the simultaneous analysis of diverse lipid molecular species. PMID- 23809845 TI - Determination of organophosphorus pesticides and metabolites in cereal-based baby foods and wheat flour by means of ultrasound-assisted extraction and hollow-fiber liquid-phase microextraction prior to gas chromatography with nitrogen phosphorus detection. AB - A new method based on hollow-fiber liquid-phase microextraction (HF-LPME) has been developed for the determination of a group of organophosphorus pesticides, including some of their metabolites, in two commercial cereal-based baby foods and one wheat flour prior to gas chromatography-nitrogen phosphorus detection. Samples were first extracted by ultrasound-assisted extraction with acetonitrile (ACN) containing 1.25% (v/v) of formic acid. After evaporation and reconstitution in Milli-Q water, the HF-LPME procedure, using 1-octanol as extraction solvent, was applied followed by a desorption step in ACN, which clearly improved the performance of the technique. The effects of sample pH, ionic strength, stirring rate, extraction temperature and time as well as the desorption procedure were investigated. Under the optimum conditions that involved the extraction of the analytes from 10 mL of the water reconstituted extract at pH 7.0 containing 5% (w/v) of NaCl for 45 min at 960 rpm, the method was validated in terms of linearity, precision and accuracy. The limits of detection (LODs) were between 0.29 and 3.20 MUg/kg. The extraction of Milli-Q water, as an example of the applicability of the procedure to aqueous samples, allowed achieving LODs in the range 0.01-0.04 MUg/L. Such values, together with the ones achieved for the rest of the samples, are below or equal to the maximum residue limits specified by the European Union. PMID- 23809846 TI - Study of physicochemical interaction of aryloxyaminopropanol derivatives with teicoplanin and vancomycin phases in view of quantitative structure-property relationship studies. AB - The aim of this work was to study the physicochemical interactions between chiral stationary phases and chiral molecules and to elucidate which of the specific interactions are more or less important. The HPLC separation of 58 aryloxyaminopropanols was performed on two chiral stationary phases containing the macrocyclic antibiotics teicoplanin or vancomycin and using a methanol/acetonitrile/acetic acid/triethylamine mobile phase (volume ratios 45/55/0.3/0.2). The resolution of enantiomers (Rij) as the target variable was predicted for the mentioned kind of compounds by means of thoroughly selected descriptors provided by the applied Dragon software. The created QSPR models can be considered as a way to explore and discover new relationships or interactions between the quantitative structure and resolution of enantiomers. For calculation and validation of the QSPR models, different modelling methodologies were applied based on MLR (multiple linear regression) and ANN (artificial neural network) techniques. Both methods exhibit an ability for successful prediction of the enantioresolution characteristics of the studied molecules. The results seem to demonstrate that it is possible to predict resolution values of enantiomeric separations of related compounds on given chromatographic systems. PMID- 23809847 TI - Extraction and sample preparation. PMID- 23809849 TI - N- versus O-alkylation: utilizing NMR methods to establish reliable primary structure determinations for drug discovery. AB - A classic synthetic issue that remains unresolved is the reaction that involves the control of N- versus O-alkylation of ambident anions. This common chemical transformation is important for medicinal chemists, who require predictable and reliable protocols for the rapid synthesis of inhibitors. The uncertainty of whether the product(s) are N- and/or O-alkylated is common and can be costly if undetermined. Herein, we report an NMR-based strategy that focuses on distinguishing inhibitors and intermediates that are N- or O-alkylated. The NMR strategy involves three independent and complementary methods. However, any combination of two of the methods can be reliable if the third were compromised due to resonance overlap or other issues. The timely nature of these methods (HSQC/HMQC, HMBC. ROESY, and (13)C shift predictions) allows for contemporaneous determination of regioselective alkylation as needed during the optimization of synthetic routes. PMID- 23809848 TI - Inverting hydrolases and their use in enantioconvergent biotransformations. AB - Owing to the more abundant occurrence of racemic compounds compared to prochiral or meso forms, most enantiomerically pure products are obtained via racemate resolution. This review summarizes (chemo)enzymatic enantioconvergent processes based on the use of hydrolytic enzymes, which are able to invert a stereocenter during catalysis that can overcome the 50%-yield limitation of kinetic resolution. Recent developments are presented in the fields of inverting or retaining sulfatases, epoxide hydrolases and dehalogenases, which allow the production of secondary alcohols or vicinal diols at a 100% theoretical yield from a racemate via enantioconvergent processes. PMID- 23809850 TI - Synthesis and characterization of a pH-sensitive conjugate of isoniazid with Fe3O4@SiO2 magnetic nanoparticles. AB - The Letter describes the preparation and characterization of a conjugate of isoniazid (INH) with magnetic nanoparticles Fe3O4@SiO2 115+/-60 nm in size. The INH molecules were attached to the surface of nanoparticles by a covalent pH sensitive amidine bond. The conjugate was characterized by X-ray diffraction, SEM, dynamic light scattering, IR spectroscopy and microanalysis. The conjugate released isoniazid under in vitro conditions (pH=4; 37 degrees C; t1/2~115 s). In addition, the cytotoxicity of the Fe3O4@SiO2-INH conjugate was evaluated in SK BR-3 cells using the xCELLigence system. PMID- 23809851 TI - Correlation of hydrogen-bonding propensity and anticancer profile of tetrazole tethered combretastatin analogues. AB - A series of 1,5-disubstituted tetrazole-tethered combretastatin analogues with extended hydrogen-bond donors at the ortho-positions of the aryl A and B rings were developed and evaluated for their antitubulin and antiproliferative activity. We wanted to test whether intramolecular hydrogen-bonding used as a conformational locking element in these analogues would improve their activity. The correlation of crystal structures with the antitubulin and antiproliferative profiles of the modified analogues suggested that hydrogen-bond-mediated conformational control of the A ring is deleterious to the bioactivity. In contrast, although there was no clear evidence that intramolecular hydrogen bonding to the B ring enhanced activity, we found that increased substitution on the B ring had a positive effect on antitubulin and antiproliferative activity. Among the various analogues synthesized, compounds 5d and 5e, having hydrogen bonding donor groups at the ortho and meta-positions on the 4-methoxy phenyl B ring, are strong inhibitors of tubulin polymerization and antiproliferative agents having IC50 value in micromolar concentrations. PMID- 23809852 TI - Elastomeric microparticles for acoustic mediated bioseparations. AB - BACKGROUND: Acoustophoresis has been utilized successfully in applications including cell trapping, focusing, and purification. One current limitation of acoustophoresis for cell sorting is the reliance on the inherent physical properties of cells (e.g., compressibility, density) instead of selecting cells based upon biologically relevant surface-presenting antigens. Introducing an acoustophoretic cell sorting approach that allows biochemical specificity may overcome this limitation, thus advancing the value of acoustophoresis approaches for both the basic research and clinical fields. RESULTS: The results presented herein demonstrate the ability for negative acoustic contrast particles (NACPs) to specifically capture and transport positive acoustic contrast particles (PACPs) to the antinode of an ultrasound standing wave. Emulsification and post curing of pre-polymers, either polydimethylsiloxane (PDMS) or polyvinylmethylsiloxane (PVMS), within aqueous surfactant solution results in the formation of stable NACPs that focus onto pressure antinodes. We used either photochemical reactions with biotin-tetrafluorophenyl azide (biotin-TFPA) or end functionalization of Pluronic F108 surfactant to biofunctionalize NACPs. These biotinylated NACPs bind specifically to streptavidin polystyrene microparticles (as cell surrogates) and transport them to the pressure antinode within an acoustofluidic chip. CONCLUSION: To the best of our knowledge, this is the first demonstration of using NACPs as carriers for transport of PACPs in an ultrasound standing wave. By using different silicones (i.e., PDMS, PVMS) and curing chemistries, we demonstrate versatility of silicone materials for NACPs and advance the understanding of useful approaches for preparing NACPs. This bioseparation scheme holds potential for applications requiring rapid, continuous separations such as sorting and analysis of cells and biomolecules. PMID- 23809853 TI - Impact of personality and depression on quality of life in patients with severe haemophilia in Korea. AB - Among reports on the psychological variables that influence quality of life (QoL), none has addressed the impact of personality on QoL in patients with haemophilia. We investigated the impact of psychosocial variables including depression and personality on QoL in patients with severe haemophilia. A cross sectional survey examining psychosocial and clinical characteristics was administered to Korean patients with severe haemophilia. Personality traits were ascertained using the 10-item short version of the Big Five Inventory, which quantifies five personality dimensions including extraversion, agreeableness, conscientiousness, neuroticism and openness. Patient QoL and depression were measured by the World Health Organization Quality of Life-abbreviated version and the Beck Depression Inventory (BDI) respectively. Multivariate linear regression analyses were used for each domain to determine the impact of psychological variables on QoL. Of the 53 subjects who consented to participate, 46 cases were finally analysed. Multivariate linear regression analyses demonstrated that agreeableness was significantly and positively associated with the physical health domain of QoL. Openness was independently and positively associated with the psychological and social relationship domains of QoL. BDI scores were significantly and negatively associated with all four domains of the QoL. Persistent pain and joint impairment showed strong associations with all domains in a univariate analysis, but the impact was attenuated after adjusting for psychosocial variables. Personality and depression had strong impacts on QoL independent of physical status in patients with severe haemophilia. Providing psychological screening and intervention are recommended for enhancing QoL in patients with severe haemophilia. PMID- 23809854 TI - Profile of elderly with multiple physician visits: advocacy for tailored comprehensive geriatric assessment use in clinics. AB - AIM: The rapid growth of the elderly population has given rise to the need for better geriatric care. The present study explored the common conditions of elderly outpatients with multiple physician visits in order to develop feasible clinical indicators that can be rapidly administered for the evaluation of geriatric syndromes in outpatient settings. METHODS: The National Health Insurance Research Database (2008) was analyzed. Claims for elderly outpatients with more than two physician visits in the same day were retrieved. The primary diagnoses, types of prescriptions and comorbidities were cross-examined. RESULTS: The overall prevalence rate for elderly patients with multiple physician visits ranged from 28.41% to 39.40%, and which increased steadily with age. A maximum of seven physician visits in a single day was observed. The most common multiple physician visit was two visits per day, with a prevalence rate of 30.97%. The two most common accompanying conditions were hypertension (3.79%) and type 2 diabetes mellitus (3.68%). There was a greater relative increase in the prevalence of senile dementia and chronic obstructive pulmonary disease in older age groups. The three overall leading specialties were cardiology, internal medicine, and ophthalmology; however, rehabilitation medicine was the most common female specific specialty. The most commonly prescribed medications were antihypertension drugs. The most prevalent comorbidity was type 2 diabetes mellitus and hypertension. CONCLUSION: We conclude that our data represent crucial information for the design of concise assessment metrics for application to the most chronic conditions in an effort to implement better geriatric healthcare. PMID- 23809855 TI - Changes to sexual and intimate relationships in the postnatal period: women's experiences with health professionals. AB - Women navigate many social changes when they become a mother, often including considerable changes to intimate and sexual relationships. This paper draws on data collected in an Australian multicentre prospective nulliparous pregnancy cohort study and a nested qualitative substudy exploring women's experiences of sex and intimacy after the birth of their first child. In all, 1507 women were recruited in early pregnancy (mean gestation 15 weeks) and completed self administered questionnaires at 3, 6 and 12 months and 4.5 years postpartum. Eighteen participants were interviewed 2.5-3.5 years after the birth of their first child regarding sex and intimacy after having a baby. Interviews were transcribed verbatim and analysed using interpretive phenomenological analysis. Cohort data reveal a considerable drop in both emotional satisfaction and physical pleasure in intimate relationships after birth, with emotional satisfaction continuing to fall up until 4.5 years postpartum. Less than one quarter of participants reported that their general practitioner had asked directly about sexual health or relationship problems in the first 3 months postpartum (23% and 18%, respectively). In contrast, 13% of women reported that a maternal and child health nurse had asked directly about sexual problems since the birth, and 31% had asked directly about relationship problems. In-depth interviews revealed that relationships with intimate partners were important issues for women following childbirth, and women were seeking reassurance from health professionals that their changing experiences of sex and intimacy after childbirth were 'normal'. Some women felt they had 'fallen through the gaps' and there was not an opportunity provided by health professionals for them to discuss changes affecting their sexual and intimate relationships. The findings suggest that intimate relationships are significantly strained in the years following childbirth and women want more information from primary health care professionals regarding changes to intimate and sexual relationships after childbirth. PMID- 23809856 TI - Abrupt transition to heightened poliomyelitis epidemicity in England and Wales, 1947-1957, associated with a pronounced increase in the geographical rate of disease propagation. AB - The abrupt transition to heightened poliomyelitis epidemicity in England and Wales, 1947-1957, was associated with a profound change in the spatial dynamics of the disease. Drawing on the complete record of poliomyelitis notifications in England and Wales, we use a robust method of spatial epidemiological analysis (swash-backwash model) to evaluate the geographical rate of disease propagation in successive poliomyelitis seasons, 1940-1964. Comparisons with earlier and later time periods show that the period of heightened poliomyelitis epidemicity corresponded with a sudden and pronounced increase in the spatial rate of disease propagation. This change was observed for both urban and rural areas and points to an abrupt enhancement in the propensity for the geographical spread of polioviruses. Competing theories of the epidemic emergence of poliomyelitis in England and Wales should be assessed in the light of this evidence. PMID- 23809857 TI - Florid lobular carcinoma in situ: molecular profiling and comparison to classic lobular carcinoma in situ and pleomorphic lobular carcinoma in situ. AB - We evaluated genomic alterations and biomarker expression in 20 florid lobular carcinomas in situ using array-based comparative genomic hybridization and immunohistochemical analysis. The genetic characteristics of florid lobular carcinoma in situ were compared with 20 classic lobular carcinomas in situ and 21 pleomorphic lobular carcinomas in situ (which included 8 apocrine variants), from our previously published data performed on a similar array-based comparative genomic hybridization platform. All 20 florid lobular carcinoma in situ cases were E-cadherin negative, and 92% were positive for estrogen receptor. Cyclin D1 expression correlated significantly negatively with estrogen receptor expression and was higher in cases with cyclin D1 (CCND1) gene amplification. Compared with classic lobular carcinoma in situ, florid lobular carcinoma in situ displayed significantly more fraction genome alteration (mean, 0.109 versus 0.072; P=.007), fraction genome loss (mean, 0.06 versus 0.03; P=.007), numbers of breakpoints (mean, 11.55 versus 6.95; P=.002), numbers of chromosome with breakpoints (mean, 5.85 versus 3.8; P=.004), and higher numbers of amplifications (mean, 2.10 versus 0.25; P=.03). Interestingly, florid lobular carcinoma in situ had the same genetic complexity as apocrine pleomorphic lobular carcinoma in situ. Our study demonstrated that florid lobular carcinoma in situ shares the cytologic features, E-cadherin loss, and the lobular genetic signature of 1q gain and 16q loss found in classic lobular carcinoma in situ. However, this variant demonstrates more genomic alterations than classic lobular carcinoma in situ and shares the same genetic complexity as apocrine pleomorphic lobular carcinoma in situ. Our data support the conclusion that florid lobular carcinoma in situ is genetically more advanced compared with the indolent phenotype of classic lobular carcinoma in situ. This may explain the greater frequency of concurrent invasive carcinoma in florid lobular carcinoma in situ compared with classic lobular carcinoma in situ. PMID- 23809858 TI - Self-concept clarity, thin-ideal internalization, and appearance-related social comparison as predictors of body dissatisfaction. AB - This study examined the associations among self-concept clarity, thin-ideal internalization, appearance-related social comparison tendencies, and body dissatisfaction. Female university students (N=278) completed self-report measures of these constructs. Structural equation modeling revealed several key findings: (a) thin-ideal internalization mediated the link between appearance related social comparison tendencies and body dissatisfaction; (b) self-concept clarity was negatively associated with both thin-ideal internalization and appearance-related social comparison tendencies; and (c) thin-ideal internalization mediated the link between self-concept clarity and body dissatisfaction. These findings suggest that low self-concept clarity might contribute to body image problems because it increases women's vulnerability to thin-ideal internalization and appearance-related social comparison tendencies. PMID- 23809859 TI - Internalization of U.S. female beauty standards as a mediator of the relationship between Mexican American women's acculturation and body dissatisfaction. AB - The relationships among acculturation, internalization of U.S. sociocultural standards of female beauty, and body dissatisfaction were examined in a sample of 211 Mexican American college women. Structural equation modeling was used to identify the paths among these three factors. Results demonstrated that there are two distinct types of body dissatisfaction: global evaluations and composite site specific evaluations. The relationships between acculturation toward dominant U.S. culture and both types of body dissatisfaction were found to be fully mediated by internalization of U.S. standards of female beauty. There were no relationships between Mexican orientation and any of the study variables. The results from this study imply that it is important for therapists working with Mexican American female clients to assess the client's level of acculturation, examine the cultural (U.S. and Mexican) messages the client receives, and explore how these messages impact her body image. PMID- 23809860 TI - Enhanced orbitofrontal cortex function and lack of attentional bias to cocaine cues in recreational stimulant users. AB - BACKGROUND: Although cocaine is known to be a highly addictive drug, there appears to be a select subset of individuals who are able to use the substance recreationally without developing dependence. These individuals do not report experiencing feelings of craving for cocaine, an important distinction from dependent users. However, no prior studies have compared attentional bias with cocaine cues between these groups to confirm this difference. Additionally, previous investigations into cognitive abilities in these individuals have been conflicting, and no research has been conducted on the neurobiological processes underlying cognitive functioning in this group. METHODS: This study administered the emotional cocaine-word Stroop to 27 recreational cocaine users, 50 stimulant dependent individuals, and 52 healthy control participants during functional magnetic resonance imaging scanning. Behavioral and functional imaging results were compared between groups to assess attentional bias and cognitive effort to resist salient cocaine stimuli. RESULTS: Recreational users did not exhibit attentional bias to the cocaine words and did not differ from control subjects on task performance. Conversely, stimulant-dependent individuals were significantly more impaired on the task. Recreational participants also displayed a unique pattern of activation during performance, with significant underactivation in the orbitofrontal and anterior cingulate cortices compared with both dependent users and control subjects. CONCLUSIONS: The absence of bias to cocaine-related stimuli in recreational users indicates they do not share attentional preference for these words with dependent users. Their distinct pattern of activation suggests a decreased need for cognitive control due to diminished desire for the drug, potentially serving as a resilience factor against dependence. PMID- 23809861 TI - Magnetic field induced formation of visually structural colored fiber in micro space. AB - A new type of photonic crystal structural colored fiber was prepared by assembling superparamagnetic chains on the surface of a flexible fiber in a magnetic field under photopolymerization. In this system, fixed structural colors (blue, green, and red) were generated instantaneously. The fiber with multi stopband can also be prepared by carefully controlling the size of the magnetic spheres in each photopolymerization procedure. This method would be fast and facile for the further study of structural color on the surface of the fiber, and the process may be used to simulate the conventional fiber coloration process. PMID- 23809862 TI - Synthesis of poly (methyl methacrylate)-b-polystyrene with high molecular weight by DPE seeded emulsion polymerization and its application in proton exchange membrane. AB - In this article, we present poly (methyl methacrylate)-b-polystyrene (PMMA-b-PS) with different block ratios and high molecular weight, which was synthesized by environmentally friendly seeded emulsion polymerization with 1,1-diphenylethylene (DPE) as a chain transfer agent. Polymerization kinetics in the first and second stage was investigated. Stable latex and homogeneous latex particles were obtained with the characterization of laser light scattering (LLS) and transmission electron microscopy (TEM). SEC and (1)H NMR revealed the successful preparation of block copolymers with high molecular weight and two different block ratios. The morphology of microphase separation of block copolymer thin films was investigated by AFM, and long-range order lamellar morphology was observed after vapor-annealing. The block copolymer with block ratio of almost 1:1 and higher molecular weight than that of previous PMMA-b-PS was sulfonated with acetyl sulfate, and the sulfonation was confirmed by FTIR, (1)H NMR, and TGA. Then, the sulfonated PMMA-b-PS was casted as membranes. The electrochemical impedance spectroscopy displayed that membranes possessed favorable proton conductivity and fine dimensional stability, and they could be candidates as proton exchange membranes. PMID- 23809863 TI - Current resources for evidence-based practice, July/August 2013. PMID- 23809865 TI - Artemisinin resistance needs to be defined rigorously to be understood: response to Dondorp and Ringwald. PMID- 23809864 TI - Comparative effectiveness of monotherapies and combination therapies for patients with hypertension: protocol for a systematic review with network meta-analyses. AB - BACKGROUND: Hypertension has been cited as the most common attributable risk factor for death worldwide, and in Canada more than one of every five adults had this diagnosis in 2007. In addition to different lifestyle modifications, such as diet and exercise, there exist many pharmaco-therapies from different drug classes which can be used to lower blood pressure, thereby reducing the risk of serious clinical outcomes. In moderate and severe cases, more than one agent may be used. The optimal mono- and combination therapies for mild hypertension and moderate/severe hypertension are unclear, and clinical guidelines provide different recommendations for first line therapy. The objective of this review is to explore the relative benefits and safety of different pharmacotherapies for management of non-diabetic patients with hypertension, whether of a mild or moderate to severe nature. METHODS/DESIGN: Searches involving MEDLINE and the Cochrane Database of Systematic Reviews will be used to identify related systematic reviews and relevant randomized trials. The outcomes of interest include myocardial infarction, stroke, incident diabetes, heart failure, overall and cardiovascular related death, and important side effects (cancers, depression, syncopal episodes/falls and sexual dysfunction). Randomized controlled trials will be sought. Two reviewers will independently screen relevant reviews, titles and abstracts resulting from the literature search, and also potentially relevant full-text articles in duplicate. Data will be abstracted and quality will be appraised by two team members independently. Conflicts at all levels of screening and abstraction will be resolved through team discussion. Random effect pairwise meta-analyses and network meta-analyses will be conducted where deemed appropriate. Analyses will be geared toward studying treatment of mild hypertension and moderate/severe hypertension separately. DISCUSSION: Our systematic review results will assess the extent of currently available evidence for single agent and multi-agent pharmacotherapies in patients with mild, moderate and severe hypertension, and will provide a rigorous and updated synthesis of a range of important clinical outcomes for clinicians, decision makers and patients. TRIAL REGISTRATION: PROSPERO Registration Number: CRD42013004459. PMID- 23809866 TI - Metal tooth-like surgical templates for tooth autotransplantation in adolescents. AB - OBJECTIVES: The aim of this study was to suggest a way to fabricate surgical templates to assist the surgeon in preparing the recipient socket when performing premolar autotransplantation. METHODS: Premolars used previously for extractions of periodontal ligament (PDL) fibroblasts were used in this study as archetype of models for tooth transplantation. Eighty-four mandibular and maxillary first and second extracted premolars were reviewed. All teeth were extracted for orthodontic reasons. From these teeth, eight teeth were selected to serve as archetype of models in which all the other teeth were at equal size or smaller in maximum 2 mm in M-D or B-L dimension. These teeth were sent to dental technician to perform identical archetype stainless steel templates. During autotransplantation immediately following donor tooth extraction, the appropriate template is chosen out of the toothlike stainless steel surgical templates and the donor tooth is then immediately replaced in its socket. This enables the surgeon to prepare the recipient site without manipulating the donor tooth and thus preventing damage to the PDL cells of the donor tooth. Only after the recipient site had been prepared to the appropriate size and shape according to the template, the donor tooth is removed from its socket, immediately placed at the recipient site and splinted as recommended. CONCLUSIONS: The advantage of the presented metal tooth-like surgical templates described in this study is that a set of stents has been produced by replicating different common shape adolescent premolars that reflect the biological variation in size and shape of these teeth. PMID- 23809867 TI - The impact of high-risk drivers and benefits of limiting their driving degree of freedom. AB - The perception of drivers regarding risk-taking behaviour is widely varied. High risk drivers are the segment of drivers who are disproportionately represented in the majority of crashes. This study examines the typologies of drivers in risk taking behaviour, the common high-risk driving errors (speeding, close following, abrupt lane-changing and impaired driving), their safety consequences and the technological (ITS) devices for their detection and correction. Limiting the driving degree of freedom of high-risk drivers is proposed and its benefits on safety as well as traffic operations are quantified using VISSIM microscopic traffic simulation at various proportions of high-risk drivers; namely, 4%, 8% and 12%. Assessment of the safety benefits was carried out by using the technique of simulated vehicle conflicts which was validated against historic crashes, and reduction in travel time was used to quantify the operational benefits. The findings imply that limiting the freedom of high-risk drivers resulted in a reduction of crashes by 12%, 21% and 27% in congested traffic conditions; 9%, 13% and 18% in lightly congested traffic conditions as well as 9%, 10% and 17% in non congested traffic conditions for high-risk drivers in proportions of 4%, 8% and 12% respectively. Moreover, the surrogate safety measures indicated that there was a reduction in crash severity levels. The operational benefits amounted to savings of nearly 1% in travel time for all the proportions of high-risk drivers considered. The study concluded that limiting the freedom of high-risk drivers has safety and operational benefits; though there could be social, legal and institutional concerns for its practical implementation. PMID- 23809869 TI - Short-term preoperative diet modification reduces steatosis and blood loss in patients undergoing liver resection. AB - BACKGROUND: Steatosis and steatohepatitis have been associated with increased morbidity and mortality after liver resection. Our objective was to determine the effect of a preoperative calorie-restricted diet on steatosis and steatohepatitis in patients undergoing liver resection. METHODS: We studied 111 consecutive patients who had major elective hepatic resections. More than 90% of the patients had cancer resections. The mean body mass index was 27.2; 32% had a body mass index >=30. A week-long calorie- and fat-restricted diet was instituted in the most recent patient group (n = 51). We retrospectively evaluated steatosis and steatohepatitis in the diet and no-diet control groups. Clinical outcomes of the 2 groups, including complications and blood loss, were compared. RESULTS: The preoperative diet patients had less steatosis (15.7% vs 25.5% of hepatocytes containing fat, P = .05) than the nondiet controls. A lower percentage of patients in the diet group had steatohepatitis than in the nondiet group (15% vs 27%, P =.02). Preoperative diet patients had less mean intraoperative blood loss than nondiet patients (600 mL vs 906 mL, P = .002). There was no difference in overall or infectious complications between the groups. CONCLUSION: We have shown for the first time that short-term calorie restriction before liver resection significantly reduces both hepatic steatosis and steatohepatitis. Dietary modification also was associated with decreased intraoperative blood loss. This intervention is easily instituted; therefore, it is clinically feasible. PMID- 23809870 TI - Experience with laparoscopic treatment for paraesophageal hiatal hernia. AB - INTRODUCTION: Paraesophageal hiatal hernia is often associated with a number of complications such as intestinal obstruction, gastric volvulus and acute pancreatitis, each of which can result in critical conditions requiring surgery. Herein, we report our surgical procedure for paraesophageal hiatal hernia. METHODS: Since 2003, we have surgically treated hiatal hernia in 18 patients, including 2 men and 16 women, with a mean age of 73 years. Thirteen patients (72.2%) had a type-I hiatal hernia, two (11.1%) had type III and three (16.7%) had type IV. The operative procedure consisted of a crural repair and anti-reflux maneuver. RESULTS: Laparoscopic procedures were completed in all patients. The mean operation time was 160.2 min for type I and 230.8 min for types III and IV. The mean postoperative hospital stay was 7.8 days, and there was no mortality. Three patients relapsed during the mean follow-up period of 74.9 months. Two of them were asymptomatic and one required laparoscopic reoperation. CONCLUSION: Laparoscopic surgery for paraesophageal hiatal hernia is safe and effective with minimal morbidity and early recovery. However, it is important to determine the appropriate timing of surgery based on the severity of the hernia and the patient's general status and comorbidities. PMID- 23809871 TI - Rivaroxaban and other novel oral anticoagulants: pharmacokinetics in healthy subjects, specific patient populations and relevance of coagulation monitoring. AB - Unlike traditional anticoagulants, the more recently developed agents rivaroxaban, dabigatran and apixaban target specific factors in the coagulation cascade to attenuate thrombosis. Rivaroxaban and apixaban directly inhibit Factor Xa, whereas dabigatran directly inhibits thrombin. All three drugs exhibit predictable pharmacokinetic and pharmacodynamic characteristics that allow for fixed oral doses in a variety of settings. The population pharmacokinetics of rivaroxaban, and also dabigatran, have been evaluated in a series of models using patient data from phase II and III clinical studies. These models point towards a consistent pharmacokinetic and pharmacodynamic profile, even when extreme demographic factors are taken into account, meaning that doses rarely need to be adjusted. The exception is in certain patients with renal impairment, for whom pharmacokinetic modelling provided the rationale for reduced doses as part of some regimens. Although not routinely required, the ability to measure plasma concentrations of these agents could be advantageous in emergency situations, such as overdose. Specific pharmacokinetic and pharmacodynamic characteristics must be taken into account when selecting an appropriate assay for monitoring. The anti-Factor Xa chromogenic assays now available are likely to provide the most appropriate means of determining plasma concentrations of rivaroxaban and apixaban, and specific assays for dabigatran are in development. PMID- 23809872 TI - Ethanol drinking in withdrawal seizure-prone and -resistant selected mouse lines. AB - Withdrawal Seizure-Prone (WSP) and Withdrawal Seizure-Resistant (WSR) mouse lines were bidirectionally selectively bred, respectively, to have severe or mild ethanol withdrawal handling-induced convulsions (HICs) after cessation of 3 days of ethanol vapor inhalation. Murine genotypes with severe withdrawal have been found to show low ethanol consumption, and high consumers show low withdrawal. An early drinking study with WSP and WSR mice showed modest evidence consistent with this genetic correlation, but there were several limitations to that experiment. We therefore conducted a thorough assessment of two bottle ethanol preference drinking in both replicate pairs of WSP/WSR selected lines in mice of both sexes. Greater preference drinking of WSR-2 than WSP-2 female mice confirmed the earlier report. However, in the parallel set of selected lines, the WSP-1 mice drank more than the WSR-1s. Naive mice tested for preference for sucrose, saccharin and quinine did not differ markedly for any tastant. Finally, in a test of binge-like drinking, Drinking in the Dark (DID), WSP mice drank more than WSR mice and attained significantly higher (but still modest) blood ethanol concentrations. Tests of acute withdrawal after DID showed a mild, but significant elevation in handling-induced convulsions in the WSP line. These results provide further evidence that 2-bottle ethanol preference and DID are genetically distinguishable traits. PMID- 23809873 TI - Effect of prenatal alcohol exposure on bony craniofacial development: a mouse MicroCT study. AB - Craniofacial bone dysmorphology is an important but under-explored potential diagnostic feature of fetal alcohol spectrum disorders. This study used longitudinal MicroCT 3D imaging to examine the effect of prenatal alcohol exposure on craniofacial bone growth in a mouse model. C57BL/6J dams were divided into 3 groups: alcohol 4.2% v/v in PMI(r) liquid diet (ALC), 2 weeks prior to and during pregnancy from embryonic (E) days 7-E16; pair-fed controls (PF), isocalorically matched to the ALC group; chow controls (CHOW), given ad libitum chow and water. The MicroCT scans were performed on pups on postnatal days 7 (P7) and P21. The volumes of the neurocranium (volume encased by the frontal, parietal, and occipital bones) and the viscerocranium (volume encased by the mandible and nasal bone), along with total skull bone volume, head size, and head circumference were evaluated using general linear models and discriminant analyses. The pups in the alcohol-treated group, when compared to the chow-fed controls (ALC vs CHOW) and the isocaloric-fed controls (ALC vs PF), showed differences in head size and circumference at P7 and P21, the total skull volume and parietal bone volume at P7, and volume of all the tested bones except nasal at P21. There was a growth trend of ALC < CHOW and ALC < PF. While covarying for gender and head size or circumference, the treatment affected the total skull and mandible at P7 (ALC > CHOW), and the total skull, parietal bone, and occipital bone at P21 (ALC < CHOW, ALC < PF). While covarying for the P7 measures, the treatment affected only the 3 neurocranial bones at P21 (ALC < CHOW, ALC < PF). Discriminant analysis sensitively selected between ALC and CHOW (AUC = 0.967), between ALC and PF (AUC = 0.995), and between PF and CHOW (AUC = 0.805). These results supported our hypothesis that craniofacial bones might be a reliable and sensitive indicator for the diagnosis of prenatal alcohol exposure. Significantly, we found that the neurocranium (upper skull) was more sensitive to alcohol than the viscerocranium (face). PMID- 23809874 TI - Six minute walk test in type III spinal muscular atrophy: a 12month longitudinal study. AB - The aim of our longitudinal multicentric study was to establish the changes on the 6min walk test (6MWT) in ambulant SMA type III children and adults over a 12month period. Thirty-eight ambulant type III patients performed the 6MWT at baseline and 12months after baseline. The distance covered in 6min ranged between 75 and 510m (mean 294.91, SD 127) at baseline and between 50 and 611m (mean 293.41m, SD 141) at 12months. The mean change in distance between baseline and 12months was -1.46 (SD 50.1; range: -183 to 131.8m). The changes were not correlated with age or baseline values (p>.05) even though younger patients reaching puberty, had a relatively higher risk of showing deterioration of more than 30m compared to older patients. Our findings provide the first longitudinal data using the 6MWT in ambulant SMA patients. PMID- 23809876 TI - Identifying information needs among children and teens living with haemophilia. AB - Transitioning from one life stage to the next can be difficult, but for those living with a chronic condition, it can be even more challenging. Children and adolescents with haemophilia need help to manage transitions while dealing with the complications of their disorder. The National Haemophilia Foundation (NHF), headquartered in New York City, has an extensive information centre on bleeding disorders, but it was not clear how much material existed on the topic of transition. The objectives of this project were to (i) assess the availability of literature about transition for children and adolescents living with haemophilia, (ii) determine which transition issues were the most relevant and (iii) develop and test information products that would address those transition issues. An inventory of NHF's resources and an environmental scan over the Internet was performed. Focus groups were conducted to determine messaging. Video prototypes containing messages were created, tested by focus groups and revised. The literature search yielded limited information available on transition for children and adolescents with haemophilia. Results of the formative research indicated that adolescents wanted more information on sports participation and disclosure of their condition (e.g. to peers, teachers, coaches, health care providers). Video was found to be the preferred delivery format. Children and adolescents living with haemophilia need information to help them transition through life. As a result of this study, two educational products were produced, but several more are recommended to guide these individuals in making healthy transitions into adulthood. PMID- 23809875 TI - Active drug encapsulation and release kinetics from hydrogel-in-liposome nanoparticles. AB - Herein, we demonstrate for the first time the use of hydrogel-in-liposome nanoparticles (lipogels) as a promising drug delivery vehicle for the active encapsulation of the anticancer drug 17-DMAPG, a geldanamycin (GA) derivative. This model drug was chosen due to its improved aqueous solubility (4.6 mg/ml) compared to the parent GA (<0.01 mg/ml), and presence of a tertiary amine which readily protonates at low pH. For the design of lipogels, a PAA hydrogel core was formed inside liposomes through UV-initiated DEAP activation and polymerization of AA and BA. We have demonstrated here that electrostatic interactions between drug and gel are critical for active encapsulation and sustained release of 17 DMAPG. We found that optimal loading conditions could be obtained (88% loading efficiency) through control of pH, temperature and incubation time. Dramatic sustained drug release from lipogels was achieved independent of the external solution pH (ca. 54 h to 50% drug release) and confirmed that the lipid bilayer was intact in the presence of the gel core. In vitro cell culture studies revealed that at the highest concentration tested, which corresponded to approximately 0.4 mg/ml of material, lipogels did not exert cytotoxicity to cells. PMID- 23809877 TI - Severe hand, foot and mouth disease in Shenzhen, South China: what matters most? AB - Case report data and a matched case-control study were used to investigate the epidemiological characteristics of hand, foot and mouth disease (HFMD) in children in Shenzhen, China between 2008 and 2011. Multivariate analyses were used to evaluate factors associated with severity of infection. Laboratory tests were performed to determine aetiological identification for samples from 163 severe and fatal cases as well as an outpatient-based HFMD sentinel surveillance system (n = 446). All identified EV71 belonged to sub-genotype C4a. No major changes in the CA16 and EV71 viruses were found until the end of 2011. Annual attack rates and the case-severity ratios (CSRs) rose from 0.82/1000 and 0.56/1000, respectively, in 2008 to 2.12/1000 and 6.13/1000 in 2011. The CSR was higher in migrants than in local residents. The adjusted odds ratio (OR) of having a severe attack for being a migrant was 2.45, having a fever >39 degrees C (OR 5.77), visiting a private clinic (OR 2.65), longer time from symptom onset to diagnosis (OR 1.49), visiting a doctor (OR 1.51), early use of intramuscular pyrazolone (OR 3.36), early use of intravenous glucocorticoids (OR 2.28), or the combination of both (OR 3.75). The mortality and increasing case severity appears to be associated with socioeconomic factors including migration and is of worldwide concern. PMID- 23809878 TI - Mechanism of autoimmune hepatic fibrogenesis induced by an adenovirus encoding the human liver autoantigen cytochrome P450 2D6. AB - Autoimmune hepatitis type 2 (AIH-2) is a severe autoimmune liver disease with unknown etiology. We recently developed the CYP2D6 mouse model for AIH-2, in which mice are challenged with an adenovirus (Ad-2D6) expressing human cytochrome P450 2D6 (hCYP2D6), the major autoantigen in AIH-2. Such mice develop chronic hepatitis with cellular infiltrations and generation of hCYP2D6-specific antibodies and T cells. Importantly, the CYP2D6 model represents the only model displaying chronic fibrosis allowing for a detailed investigation of the mechanisms of chronic autoimmune-mediated liver fibrogenesis. We found that hCYP2D6-dependent chronic activation of hepatic stellate cells (HSC) resulted in an increased extracellular matrix deposition and elevated expression of alpha smooth muscle actin predominantly in and underneath the liver capsule. The route of Ad-2D6 infection dramatically influenced the activation and trafficking of inflammatory monocytes, NK cells and hCYP2D6-specific T cells. Intraperitoneal Ad 2D6 infection caused subcapsular fibrosis and persistent clustering of inflammatory monocytes. In contrast, intravenous infection caused an accumulation of hCYP2D6-specific CD4 T cells throughout the liver parenchyma and induced a strong NK cell response preventing chronic HSC activation and fibrosis. In summary, we found that the location of the initial site of inflammation and autoantigen expression caused a differential cellular trafficking and activation and thereby determined the outcome of AIH-2-like hepatic damage and fibrosis. PMID- 23809880 TI - Mercury cycling in agricultural and managed wetlands of California, USA: seasonal influences of vegetation on mercury methylation, storage, and transport. AB - Plants are a dominant biologic and physical component of many wetland capable of influencing the internal pools and fluxes of methylmercury (MeHg). To investigate their role with respect to the latter, we examined the changing seasonal roles of vegetation biomass and Hg, C and N composition from May 2007-February 2008 in 3 types of agricultural wetlands (domesticated or white rice, wild rice, and fallow fields), and in adjacent managed natural wetlands dominated by cattail and bulrush (tule). We also determined the impact of vegetation on seasonal microbial Hg methylation rates, and Hg and MeHg export via seasonal storage in vegetation, and biotic consumption of rice seed. Despite a compressed growing season of ~3months, annual net primary productivity (NPP) was greatest in white rice fields and carbon more labile (leaf median C:N ratio=27). Decay of senescent litter (residue) was correlated with microbial MeHg production in winter among all wetlands. As agricultural biomass accumulated from July to August, THg concentrations declined in leaves but MeHg concentrations remained consistent, such that MeHg pools generally increased with growth. Vegetation provided a small, temporary, but significant storage term for MeHg in agricultural fields when compared with hydrologic export. White rice and wild rice seeds reached mean MeHg concentrations of 4.1 and 6.2ng gdw(-1), respectively. In white rice and wild rice fields, seed MeHg concentrations were correlated with root MeHg concentrations (r=0.90, p<0.001), suggesting transport of MeHg to seeds from belowground tissues. Given the proportionally elevated concentrations of MeHg in rice seeds, white and wild rice crops may act as a conduit of MeHg into biota, especially waterfowl which forage heavily on rice seeds within the Central Valley of California, USA. Thus, while plant tissues and rhizosphere soils provide temporary storage for MeHg during the growing season, export of MeHg is enhanced post-harvest through increased hydrologic and biotic export. PMID- 23809879 TI - Rethinking mechanisms of autoimmune pathogenesis. AB - Why exactly some individuals develop autoimmune disorders remains unclear. The broadly accepted paradigm is that genetic susceptibility results in some break in immunological tolerance, may enhance the availability of autoantigens, and may enhance inflammatory responses. Some environmental insults that occur on this background of susceptibility may then contribute to autoimmunity. In this review we discuss some aspects related to inhibitory signaling and rare genetic variants, as well as additional factors that might contribute to autoimmunity including the possible role of clonal somatic mutations, the role of epigenetic events and the contribution of the intestinal microbiome. Genetic susceptibility alleles generally contribute to the loss of immunological tolerance, the increased availability of autoantigens, or an increase in inflammation. Apart from common genetic variants, rare loss-of-function genetic variants may also contribute to the pathogenesis of autoimmunity. Studies of an inhibitory signaling pathway in B cells helped identify a negative regulatory enzyme called sialic acid acetyl esterase. The study of rare genetic variants of this enzyme provides an illustrative example showing the importance of detailed functional analyses of variant alleles and the need to exclude functionally normal common or rare genetic variants from analysis. It has also become clear that pathways that are functionally impacted by either common or rare defective variants can also be more significantly compromised by gene expression changes that may result from epigenetic alterations. Another important and evolving area that has been discussed relates to the role of the intestinal microbiome in influencing helper T cell polarization and the development of autoimmunity. PMID- 23809881 TI - Mercury cycling in agricultural and managed wetlands of California, USA: experimental evidence of vegetation-driven changes in sediment biogeochemistry and methylmercury production. AB - The role of live vegetation in sediment methylmercury (MeHg) production and associated biogeochemistry was examined in three types of agricultural wetlands (domesticated or white rice, wild rice, and fallow fields) and adjacent managed natural wetlands (cattail- and bulrush or tule-dominated) in the Yolo Bypass region of California's Central Valley, USA. During the active growing season for each wetland, a vegetated:de-vegetated paired plot experiment demonstrated that the presence of live plants enhanced microbial rates of mercury methylation by 20 to 669% (median=280%) compared to de-vegetated plots. Labile carbon exudation by roots appeared to be the primary mechanism by which microbial methylation was enhanced in the presence of vegetation. Pore-water acetate (pw[Ac]) decreased significantly with de-vegetation (63 to 99%) among all wetland types, and within cropped fields, pw[Ac] was correlated with both root density (r=0.92) and microbial Hg(II) methylation (kmeth. r=0.65). Sediment biogeochemical responses to de-vegetation were inconsistent between treatments for "reactive Hg" (Hg(II)R), as were reduced sulfur and sulfate reduction rates. Sediment MeHg concentrations in vegetated plots were double those of de-vegetated plots (median=205%), due in part to enhanced microbial MeHg production in the rhizosphere, and in part to rhizoconcentration via transpiration-driven pore water transport. Pore-water concentrations of chloride, a conservative tracer, were elevated (median=22%) in vegetated plots, suggesting that the higher concentrations of other constituents around roots may also be a function of rhizoconcentration rather than microbial activity alone. Elevated pools of amorphous iron (Fe) in vegetated plots indicate that downward redistribution of oxic surface waters through transpiration acts as a stimulant to Fe(III) reduction through oxidation of Fe(II)pools. These data suggest that vegetation significantly affected rhizosphere biogeochemistry through organic exudation and transpiration-driven concentration of pore-water constituents and oxidation of reduced compounds. While the relative role of vegetation varied among wetland types, macrophyte activity enhanced MeHg production. PMID- 23809882 TI - A comprehensive description of functioning and disability in children with velopharyngeal insufficiency. AB - Children with velopharyngeal insufficiency (VPI) experience functional impairments in a variety of areas that extend beyond the primary physical impairment associated with this disorder. At present, the physical deficits associated with VPI have been studied extensively; however, a comprehensive description of social and communicative participation in this population is needed. Therefore, a biopsychosocial framework such as the International Classification of Functioning, Disability and Health for Children and Youth (ICF CY), may offer an enhanced understanding of the daily experiences of children with VPI. Specifically, the ICF-CY framework is intended to model complex nonlinear systems, and as such, to describe functioning as the interaction of multiple components from which a limitation in communicative participation may emerge. This paper describes how the ICF-CY framework can be utilized to comprehensively describe functioning and disability in children with VPI by describing the interaction of components of this framework. LEARNING OUTCOMES: As a result of this activity, the reader will be able to: (1) discuss the utility of the ICF-CY in describing the multi-dimensional nature of velopharyngeal insufficiency (VPI); (2) describe interrelationships between functioning and disability in children with VPI; and (3) identify how limitations in communicative participation may emerge from the interaction of components of the ICF-CY in children with VPI. PMID- 23809883 TI - Leveraging changing gender norms to address concurrency: focus group findings from South African university students. AB - Background This study aims to complement recent research on sexual concurrency in South Africa by providing a deeper understanding of women's roles and motivations for engaging in and accepting their partners' concurrency. Our goal is to inform the implementation of more effective interventions that embrace the powerful role that women can play in healthy sexual decision-making in consensual relationships. METHODS: We conducted 12 focus groups with male and female students at the University of KwaZulu-Natal. Drawing on a subset of those focus groups, we examined the gender norms underpinning the apparently widespread acceptance of concurrent sexual partnerships. Our analysis focusses on women's attitudes and behaviours towards concurrency - from both men's and women's perspectives - with a goal of identifying opportunities to engage women as agents of change in sexual partnership patterns in their communities. RESULTS: Our findings indicate that: (1) concurrent sexual partnerships were the norm among male students and increasingly common among female students; (2) material gain and changes in women's perceptions of their roles and power in relationships were the primary female motives for concurrency; (3) peer pressure, a perceived innate need and a fear of being alone were the primary male motives for concurrency; (4) women often know that their partners are cheating and stay with them because they believe they are the most important partner, for financial reasons, or because they worry they will not find another partner. CONCLUSIONS: HIV prevention interventions in populations where concurrency is common would benefit from emphasising women's role and power in taking greater control of their own sexual decision-making in consensual and nonviolent relationships. PMID- 23809885 TI - Adenocarcinoma of the anal canal - a systematic review. AB - AIM: The prognosis of anal adenocarcinoma is poor and the management remains controversial. We carried out a literature review to identify current practice in the management of anal adenocarcinoma. METHOD: A systematic review of the literature was performed for studies in the English language published between 1950 and 2011. All those that focused on the management of anal adenocarcinoma were considered for inclusion. RESULTS: Sixteen retrospective observational studies were identified; no randomized trials were found. Most of the studies contained small numbers of patients due to the rarity of anal adenocarcinoma. Treatment included local excision), radiotherapy, chemotherapy, chemoradiotherapy and abdominoperineal excision. Most studies concluded that a multimodality approach, combining radical surgical resection with neoadjuvant/adjuvant chemoradiotherapy was the optimal management strategy. CONCLUSION: The prognosis of anal adenocarcinoma is poor, and there is little information on the optimal management. The relevant studies indicate that a combination of radical surgical resection and pre- or postoperative chemoradiotherapy offers the best chance of survival. PMID- 23809884 TI - Interventions to decrease the risk of adverse cardiac events for post-surgery or chemotherapy patients taking serotonin (5-HT3) receptor antagonists: protocol for a systematic review and network meta-analysis. AB - BACKGROUND: Patients undergoing surgery or chemotherapy often experience nausea and vomiting. To increase their quality of life and treatment satisfaction, antiemetic medication, such as serotonin receptor antagonists, is often prescribed for patients experiencing these symptoms. However, early warning signs suggest that serotonin receptor antagonists can cause harm, including arrhythmia. Our objective is to identify the most effective interventions that mitigate the risk of adverse cardiac events associated with serotonin receptor antagonists in patients undergoing surgery and chemotherapy through a systematic review and network meta-analysis. METHODS/DESIGN: We will search electronic databases (for example, MEDLINE, Embase) from inception onwards, as well as dissertations and governmental reports, to identify interventions (for example, telemetry, electrocardiography, electrolyte monitoring) that decrease the cardiac risk associated with serotonin receptor antagonists among surgery and chemotherapy patients. Eligible comparators include placebo or supportive care; eligible study designs are experimental studies (randomized controlled trials (RCTs), quasi RCTs, non-RCTs), non-experimental studies (interrupted time series, controlled before-and-after studies), and cohort studies. Outcomes of interest include arrhythmia, sudden cardiac death, QT prolongation, PR prolongation, and all-cause mortality. We will include unpublished studies and studies published in languages other than English.Draft inclusion and exclusion criteria will be established and pilot tested amongst the team. Subsequently, two team members will screen the results in duplicate and resolve conflicts through discussion. The same process will be followed to screen full-text articles, data abstraction, and appraise quality or risk of bias. To determine validity of results, experimental and quasi experimental studies will be assessed using the Cochrane Effective Practice and Organisation of Care (EPOC) Risk of Bias tool, while cohort studies will be appraised using the Newcastle-Ottawa Scale. We anticipate sufficient data and homogeneity to conduct random effects meta-analysis and network or mixed treatment comparisons meta-analysis, if appropriate. DISCUSSION: Our results will provide information regarding the utility of different strategies that can be used to mitigate cardiac risk amongst patients taking serotonin antagonist receptors. Such results are likely to be of use to clinicians prescribing these agents, as well as policy makers responsible for making decisions about antiemetic medications. TRIAL REGISTRATION: PROSPERO registry number: CRD42013003565. PMID- 23809886 TI - Flexural strengths of conventional and nanofilled fiber-reinforced composites: a three-point bending test. AB - OBJECTIVES: The purpose of this study was to evaluate the effect of the introduction of nanofillers on the mechanical properties of fiber-reinforced composites (FRCs) for stabilization and conservative treatment of multiple traumatized anterior teeth. In particular, the aim of the research was to point out the force levels of two sizes (diameters 0.6 and 0.9 mm) of both conventional and nanofilled FRCs. METHODS: Eighty FRCs samples were divided into eight groups, each consisting of 10 specimens. Conventional (groups 1, 2, 3, and 4) and nanofilled (groups 5, 6, 7, and 8) FRC samples were evaluated. Each FRC was tested in two diameters (0.6 and 0.9 mm) and under two deflections (1 and 2 mm). Each sample was polymerized with the same halogen curing unit and then evaluated with a 3-point bending test on a universal testing machine after 48 h of dry storage. RESULTS: Nanofilled FRCs showed significantly higher load values than conventional FRCs. Moreover, 0.9-mm-diameter FRCs showed significantly higher load value than 0.6-mm-diameter FRCs. Specimens tested at 2-mm deflection showed significantly higher load values than those tested at 1-mm deflection. CONCLUSIONS: Nanofilled FRCs showed significantly higher load values than conventional FRCs. Higher flexural strength values were recorded with 1-mm deflection for both FRC tested. PMID- 23809887 TI - Frailty among community-dwelling elderly Mexican people: prevalence and association with sociodemographic characteristics, health state and the use of health services. AB - AIM: To estimate the prevalence of frailty phenotypes and their association with the sociodemographic characteristics, health state and the use of health services in the last 6 months among community-dwelling elderly in Mexico City. METHODS: The present study included 1933 elderly individuals from Mexico City. We estimated the prevalence of the frailty phenotype based on Fried and Walston. Household interviews were carried out to collect information on sociodemographics (sex, age, education, marital status, live alone, paid job), health state (activities of daily living, cognitive function, depression, comorbidity, nutritional status) and the use of health services in the last 6 months. RESULTS: The estimated prevalence of frailty was 15.7%, pre-frailty at 33.3% and non frailty at 51.0%. The statistically relevant associations in the pre-frail elderly were female (OR 0.83), older age (OR 2.48), single (OR 1.03), living alone (OR 1.23), no paid work (OR 0.82), limitations in the basic activities of daily living (OR 2.11) and instrumental activities of daily living (OR 2.10), cognitive impairment (OR 1.49), depression symptoms (OR 3.82), underweight/malnourished (OR 1.89), overweight/obesity (OR 0.80), moderate comorbidity (OR 2.05), and use of health services (OR 1.04) using the non-frail phenotype as the comparison category. Frailly is associated with female (OR 1.05), older age (OR 10.32), less educated (OR 2.51), single OR 1.39), living alone (OR 0.86), no paid work (OR 1.16), limitations in the basic activities of daily living (OR 7.66) and instrumental activities of daily living (OR 8.42), cognitive impairment (OR 3.02), depression symptoms (OR 11.23), underweight/malnourished (OR 1.49), overweight/obesity (OR 0.49), moderate comorbidity (OR 3.55), and use of health services (OR 1.99) using the non-frail phenotype as the comparison category. CONCLUSIONS: The results suggest that older age, disability, comorbidity, cognitive impairment and depression could have an influence role in frailty. PMID- 23809888 TI - New oral anticoagulants: discussion on monitoring and adherence should start now! AB - New oral anticoagulants (NOACs) have been introduced to improve anticoagulant therapy worldwide, but safe implementation may require additional measures. First, optimization of dose adjustment based on therapeutic levels of the drug may be more appropriate than fixed dose therapy. The development and implementation in quantitative laboratory assays will enable further dose optimization. Second, non-adherence to medication is a potential threat to the safe use of NOACs. Since cardiovascular medication may not be optimally used in about 50% of patients, procedures to improve adherence are imperative, also for NOAC therapy and in particular in elderly patients. PMID- 23809889 TI - The activation of vivax malaria hypnozoites by infectious diseases. AB - The periodicity of vivax malaria relapses may be explained by the activation of latent hypnozoites acquired from a previous malarial infection. The activation stimulus could be the febrile illness associated with acute malaria or a different febrile infection. We review historical records to examine the association between relapses of Plasmodium vivax and febrile infectious diseases. In data from British soldiers in Palestine, epidemic falciparum malaria triggered a smaller epidemic of P vivax relapses only in those who had been extensively exposed to malaria previously. Relapses did not follow pandemic influenza infection. Evidence from three simultaneous typhoid and malaria epidemics suggest that typhoid fever might activate P vivax hypnozoites. Some data lend support to the notion that vivax malaria relapse followed febrile illness caused by relapsing fever, trench fever, epidemic typhus, and Malta fever (brucellosis). These observations suggest that systemic parasitic and bacterial infections, but not viral infections, can activate P vivax hypnozoites. Specific components of the host's acute febrile inflammatory response, and not fever alone, are probably important factors in the provocation of a relapse of vivax malaria. PMID- 23809890 TI - Review: Evaluation of Foot-and-Mouth Disease Control Using Fault Tree Analysis. AB - An outbreak of foot-and-mouth disease (FMD) causes huge economic losses and animal welfare problems. Although much can be learnt from past FMD outbreaks, several countries are not satisfied with their degree of contingency planning and aiming at more assurance that their control measures will be effective. The purpose of the present article was to develop a generic fault tree framework for the control of an FMD outbreak as a basis for systematic improvement and refinement of control activities and general preparedness. Fault trees are typically used in engineering to document pathways that can lead to an undesired event, that is, ineffective FMD control. The fault tree method allows risk managers to identify immature parts of the control system and to analyse the events or steps that will most probably delay rapid and effective disease control during a real outbreak. The present developed fault tree is generic and can be tailored to fit the specific needs of countries. For instance, the specific fault tree for the 2001 FMD outbreak in the UK was refined based on control weaknesses discussed in peer-reviewed articles. Furthermore, the specific fault tree based on the 2001 outbreak was applied to the subsequent FMD outbreak in 2007 to assess the refinement of control measures following the earlier, major outbreak. The FMD fault tree can assist risk managers to develop more refined and adequate control activities against FMD outbreaks and to find optimum strategies for rapid control. Further application using the current tree will be one of the basic measures for FMD control worldwide. PMID- 23809891 TI - Significance of metabolic stress, lipid mobilization, and inflammation on transition cow disorders. AB - The incidence and severity of disease in cows is greatest during the transition period, when immune functions are impaired. Intense lipid mobilization is associated with both metabolic and infectious diseases in the transition cow. Significant increases in plasma nonesterified fatty acids contribute to oxidative stress and uncontrolled inflammatory responses. A dysfunctional inflammatory response is the common link between metabolic and infectious diseases around the time of calving. Intervention strategies that can reduce lipid mobilization may improve inflammatory responses and reduce the economic losses associated with health disorders during the transition period. PMID- 23809892 TI - Metabolic control of feed intake: implications for metabolic disease of fresh cows. AB - The objective of this article is to discuss metabolic control of feed intake in the peripartum period and its implications for metabolic disease of fresh cows. Understanding how feed intake is controlled during the transition from gestation to lactation is critical to both reduce risk and successfully treat many metabolic diseases. PMID- 23809893 TI - Insulin resistance in dairy cows. AB - Glucose is the molecule that drives milk production, and insulin plays a pivotal role in the glucose metabolism of dairy cows. The effect of insulin on the glucose metabolism is regulated by the secretion of insulin by the pancreas and the insulin sensitivity of the skeletal muscles, the adipose tissue, and the liver. Insulin resistance may develop as part of physiologic (pregnancy and lactation) and pathologic processes, which may manifest as decreased insulin sensitivity or decreased insulin responsiveness. A good knowledge of the normal physiology of insulin is needed to measure the in vivo insulin resistance of dairy cows. PMID- 23809894 TI - Assessing and managing body condition score for the prevention of metabolic disease in dairy cows. AB - Body condition score (BCS) is an assessment of a cow's body fat (and muscle) reserves, with low values reflecting emaciation and high values equating to obesity. The intercalving profile of BCS is a mirror image of the milk lactation profile. The BCS at which a cow calves, her nadir BCS, and the amount of BCS lost after calving are associated with milk production, reproduction, and health. Genetics, peripartum nutrition, and management are factors that likely interact with BCS to determine the risk of health disorders. PMID- 23809895 TI - Energy and protein nutrition management of transition dairy cows. AB - The aims of this article are to briefly review some of the underlying physiology of changes that occur around calving, examine the potential to control the risk of disease in this period, increase milk production, and improve reproductive performance through better nutritional management. Practical guidelines for veterinarians and advisors are provided. PMID- 23809896 TI - Mineral and antioxidant management of transition dairy cows. AB - Transition management needs to be fully integrated to be effective. We discuss and demonstrate this concept in the context of a study that used these principles. The roles of calcium, magnesium, phosphorus and dietary anion cation difference in influencing the pathophysiology and incidence of hypocalcemia are highlighted. Recent understandings of the pivotal role of skeleton in metabolism are reviewed. Micronutrient mineral and vitamin needs are addressed in the context of exposure of periparturient cattle to oxidative stress and inflammatory disorders. This article provides a series of practical approaches to improving transition diets. PMID- 23809897 TI - Using nonesterified fatty acids and beta-hydroxybutyrate concentrations during the transition period for herd-level monitoring of increased risk of disease and decreased reproductive and milking performance. AB - Dairy cows visit a state of negative energy balance (NEB) as they transition from late gestation to early lactation. At the individual level, there are several metabolic adaptations to manage NEB, including mobilization of nonesterified fatty acids (NEFA) from body fat reserves and glucose sparing for lactogenesis. Based on current pen-level feeding and management practices, strategies to minimize excessive NEB in both the individual and herd should focus on herd-level testing and management. This article reviews strategies for testing and monitoring of excessive NEB at the herd level through individual testing of 2 energy markers: NEFA and beta-hydroxybutyrate. PMID- 23809898 TI - Use of the liver activity index and other metabolic variables in the assessment of metabolic health in dairy herds. AB - The usefulness of the metabolic profile in dairy cows has been questioned because of poor standardization of procedures, high cost of analysis, and perceived inefficiency of the approach. Composite indices based on multiple variables, namely the Liver Activity Index and the Liver Functionality Index, which consider the pattern of changes of some negative acute-phase proteins in the first month of lactation, appear promising in the assessment of metabolic health status and the prediction of lactational and reproductive performance. The application of such indices depends on their reliability and on making them practical and economical regarding test cost and number of sampling points required. PMID- 23809899 TI - Ketosis treatment in lactating dairy cattle. AB - This article provides an update on ketosis treatment regimens. The ketosis treatment literature is reviewed and the findings are summarized. Current treatment recommendations and areas for future research are provided. PMID- 23809900 TI - Oral calcium supplementation in peripartum dairy cows. AB - Hypocalcemia in dairy cattle around parturition can be manifest as clinical milk fever or subclinical hypocalcemia. Subclinical hypocalcemia has the greatest economic effect because it affects a much higher proportion of cows. Oral calcium supplements are used to mitigate the effects of both forms of hypocalcemia. Oral calcium supplements are appropriate for cows displaying early clinical signs of hypocalcemia and prophylactically to lessen the negative impacts of hypocalcemia. PMID- 23809901 TI - Metabolic diseases of dairy cattle. PMID- 23809902 TI - Realization of a multipath ultrasonic gas flowmeter based on transit-time technique. AB - A microcomputer-based ultrasonic gas flowmeter with transit-time method is presented. Modules of the flowmeter are designed systematically, including the acoustic path arrangement, ultrasound emission and reception module, transit-time measurement module, the software and so on. Four 200 kHz transducers forming two acoustic paths are used to send and receive ultrasound simultaneously. The synchronization of the transducers can eliminate the influence caused by the inherent switch time in simple chord flowmeter. The distribution of the acoustic paths on the mechanical apparatus follows the Tailored integration, which could reduce the inherent error by 2-3% compared with the Gaussian integration commonly used in the ultrasonic flowmeter now. This work also develops timing modules to determine the flight time of the acoustic signal. The timing mechanism is different from the traditional method. The timing circuit here adopts high capability chip TDC-GP2, with the typical resolution of 50 ps. The software of Labview is used to receive data from the circuit and calculate the gas flow value. Finally, the two paths flowmeter has been calibrated and validated on the test facilities for air flow in Shaanxi Institute of Measurement & Testing. PMID- 23809903 TI - Reduction in community-onset methicillin-resistant Staphylococcus aureus rates in an urban Canadian hospital setting. AB - Community-onset methicillin resistant Staphylococcus aureus (CO-MRSA) became a prominent cause of infection in North America in 2003, with a peak in the epidemic noted by multiple groups in the USA between 2005 and 2007. We reviewed rates of MRSA in two hospitals in Vancouver, Canada, to observe changes in epidemiology from 2003 to 2011. Episodes of emergency department (ED) MRSA bacteraemia and wounds were extracted from the laboratory database, with rates calculated per 10,000 ED visits. All cases were assumed to be community onset, as they were diagnosed in the ED. A peak in ED MRSA bacteraemias occurred in 2005, at 7.8/10,000 ED visits. By 2011, rates of ED bacteraemia declined significantly to 3.3/10,000 ED visits (P13,000 persons exposed to the potentially contaminated drug, 741 confirmed drug-related infections, and 55 deaths. Fatal meningitis and localized epidural, paraspinal, and peripheral joint infections occurred. Tissues from 40 laboratory-confirmed cases representing these various clinical entities were evaluated by histopathological analysis, special stains, and IHC to characterize the pathological features and investigate the pathogenesis of infection, and to evaluate methods for detection of Exserohilum in formalin-fixed, paraffin-embedded (FFPE) tissues. Fatal cases had necrosuppurative to granulomatous meningitis and vasculitis, with thrombi and abundant angioinvasive fungi, with extensive involvement of the basilar arterial circulation of the brain. IHC was a highly sensitive method for detection of fungus in FFPE tissues, demonstrating both hyphal forms and granular fungal antigens, and PCR identified Exserohilum in FFPE and fresh tissues. Our findings suggest a pathogenesis for meningitis involving fungal penetration into the cerebrospinal fluid at the injection site, with transport through cerebrospinal fluid to the basal cisterns and subsequent invasion of the basilar arteries. Further studies are needed to characterize Exserohilum and investigate the potential effects of underlying host factors and steroid administration on the pathogenesis of infection. PMID- 23809918 TI - Ultrasound of the sural nerve: normal anatomy on cadaveric dissection and case series. AB - The sural nerve is a small sensory nerve innervating the lateral aspect of the ankle and foot. Clinical symptoms of pathology may present as atypical sensory changes in this region. We present the normal anatomy and ultrasound technique for examination of the sural nerve based on an anatomical dissection, as well as imaging in a normal volunteer. We also present a case series (n=10) of different conditions of the sural nerve that we encountered based on a review of interesting cases from 4 institutions. The pathological conditions included neuropathy related to stripping or venous laser surgery, compression by abscess, Lyme disease, nerve tumors, traumatic transsection, and encasement by fibrous plaque and edema. Ultrasound with its exquisite resolution is the preferred imaging method for examining the sural nerve in patients with unexplained sensory changes at the lateral aspect of the ankle and foot. PMID- 23809917 TI - 18F-FDG PET/CT in detection of gynecomastia in patients with hepatocellular carcinoma. AB - OBJECTIVE: We retrospectively investigate the prevalence of gynecomastia as false positive 2-[18F]fluoro-2-deoxy-d-glucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) imaging in patients with hepatocellular carcinoma (HCC). METHODS: Among the 127 male HCC patients who underwent 18F-FDG PET/CT scan, the 18FDG uptakes at the bilateral breasts in 9 patients with gynecomastia were recorded as standard uptake value (SUVmax) and the visual interpretation in both early and delayed images. RESULTS: The mean early SUVmax was 1.58/1.57 (right/left breast) in nine gynecomastia patients. The three patients with early visual score of 3 had higher early SUVmaxs. CONCLUSION: Gynecomastia is a possible cause of false-positive uptake on 18F-FDG PET/CT images. PMID- 23809920 TI - Molecular biology and epidemiology of dianthoviruses. AB - The genus Dianthovirus is one of eight genera in the family Tombusviridae. All the genera have monopartite positive-stranded RNA genomes, except the dianthoviruses which have bipartite genomes. The dianthoviruses are distributed worldwide. Although they share common structural features with the other Tombusviridae viruses in their virions and the terminal structure of the genomic RNAs, the bipartite nature of the dianthovirus genome offers an ideal experimental system with which to study basic issues of virology. The two genomic RNAs seem to use distinct strategies to regulate their translation, transcription, genome replication, genome packaging, and cell-to-cell movement during infection. This review summarizes the current state of our knowledge of the dianthoviruses, with its main emphasis on the molecular biology of the virus, including the viral and host factors required for its infection of host plants. The epidemiology of the virus and the possible viral impacts on agriculture and the environment are also discussed. PMID- 23809921 TI - Viral and nonviral elements in potexvirus replication and movement and in antiviral responses. AB - In Potato virus X, a member of the genus Potexvirus, special sequences and structures at the 5' and 3' ends of the nontranslated region function as cis acting elements for viral replication. These elements greatly affect interactions between viral RNAs and those between viral RNAs and host factors. The potexvirus genome encodes five open-reading frames. Viral replicase, which is required for the synthesis of viral RNA, binds viral RNA elements and host factors to form a viral replication complex at the host cellular membrane. The coat protein (CP) and three viral movement proteins (TGB1, TGB2, and TGB3) have critical roles in mediating cell-to-cell viral movement through plasmodesmata by virion formation or by nonvirion ribonucleoprotein (RNP) complex formation with viral movement proteins (TGBs). The RNP complex, like TGB1-CP-viral RNA, is associated with viral replicase and used for immediate reinitiation of viral replication in newly invaded cells. Higher plants have defense mechanisms against potexviruses such as Rx-mediated resistance and RNA silencing. The CP acts as an avirulence effector for plant defense mechanisms, while TGB1 functions as a viral suppressor of RNA silencing, which is the mechanism of innate immune resistance. Here, we describe recent findings concerning the involvement of viral and host factors in potexvirus replication and in antiviral responses to potexvirus infection. PMID- 23809922 TI - Influenza virus transcription and replication. AB - The influenza A viruses cause yearly epidemics and occasional pandemics of respiratory disease, which constitute a serious health and economic burden. Their genome consists of eight single-stranded, negative-polarity RNAs that associate to the RNA polymerase and many nucleoprotein monomers to form ribonucleoprotein complexes (RNPs). Here, we focus on the organization of these RNPs, as well as on the structure and interactions of its constitutive elements and we discuss the mechanisms by which the RNPs transcribe and replicate the viral genome. PMID- 23809919 TI - Mechanisms of reovirus bloodstream dissemination. AB - Many viruses cause disease within an infected host after spread from an initial portal of entry to sites of secondary replication. Viruses can disseminate via the bloodstream or through nerves. Mammalian orthoreoviruses (reoviruses) are neurotropic viruses that use both bloodborne and neural pathways to spread systemically within their hosts to cause disease. Using a robust mouse model and a dynamic reverse genetics system, we have identified a viral receptor and a viral nonstructural protein that are essential for hematogenous reovirus dissemination. Junctional adhesion molecule-A (JAM-A) is a member of the immunoglobulin superfamily expressed in tight junctions and on hematopoietic cells that serves as a receptor for all reovirus serotypes. Expression of JAM-A is required for infection of endothelial cells and development of viremia in mice, suggesting that release of virus into the bloodstream from infected endothelial cells requires JAM-A. Nonstructural protein sigma1s is implicated in cell cycle arrest and apoptosis in reovirus-infected cells but is completely dispensable for reovirus replication in cultured cells. Surprisingly, a recombinant sigma1s-null reovirus strain fails to spread hematogenously in infected mice, suggesting that sigma1s facilitates apoptosis of reovirus-infected intestinal epithelial cells. It is possible that apoptotic bodies formed as a consequence of sigma1s expression lead to reovirus uptake by dendritic cells for subsequent delivery to the mesenteric lymph node and the blood. Thus, both host and viral factors are required for efficient hematogenous dissemination of reovirus. Understanding mechanisms of reovirus bloodborne spread may shed light on how microbial pathogens invade the bloodstream to disseminate and cause disease in infected hosts. PMID- 23809923 TI - The molecular biology of ilarviruses. AB - Ilarviruses were among the first 16 groups of plant viruses approved by ICTV. Like Alfalfa mosaic virus (AMV), bromoviruses, and cucumoviruses they are isometric viruses and possess a single-stranded, tripartite RNA genome. However, unlike these other three groups, ilarviruses were recognized as being recalcitrant subjects for research (their ready lability is reflected in the sigla used to create the group name) and were renowned as unpromising subjects for the production of antisera. However, it was recognized that they shared properties with AMV when the phenomenon of genome activation, in which the coat protein (CP) of the virus is required to be present to initiate infection, was demonstrated to cross group boundaries. The CP of AMV could activate the genome of an ilarvirus and vice versa. Development of the molecular information for ilarviruses lagged behind the knowledge available for the more extensively studied AMV, bromoviruses, and cucumoviruses. In the past 20 years, genomic data for most known ilarviruses have been developed facilitating their detection and allowing the factors involved in the molecular biology of the genus to be investigated. Much information has been obtained using Prunus necrotic ringspot virus and the more extensively studied AMV. A relationship between some ilarviruses and the cucumoviruses has been defined with the recognition that members of both genera encode a 2b protein involved in RNA silencing and long distance viral movement. Here, we present a review of the current knowledge of both the taxonomy and the molecular biology of this genus of agronomically and horticulturally important viruses. PMID- 23809925 TI - Quality of life in paediatric haemophilia A patients. PMID- 23809926 TI - Antithrombin deficiency in three Japanese families: one novel and two reported point mutations in the antithrombin gene. AB - INTRODUCTION: Inherited antithrombin (AT) deficiency is associated with a predisposition to familial venous thromboembolic disease. We analyzed the AT gene in three unrelated patients with an AT deficiency who developed thrombosis. MATERIALS AND METHODS: We analyzed the SERPINC1 gene in three patients. Additionally, we expressed the three mutants in the COS-1 cells and compared their secretion rates and levels of AT activity with those of the wild-type (WT). RESULTS: We identified three distinct heterozygous mutations of c.2534C>T: p.56Arginine -> Cysteine (R56C), c.13398C>A: p.459Alanine -> Aspartic acid (A459D) and c.2703C>G: p.112 Proline -> Arginine (P112R). In the in vitro expression experiments, the AT antigen levels in the conditioned media (CM) of the R56C mutant were nearly equal to those of WT. In contrast, the AT antigen levels in the CM of the A459D and P112R mutants were significantly decreased. The AT activity of R56C was decreased in association with a shorter incubation time in a FXa inhibition assay and a thrombin inhibition-based activity test. However, the AT activity of R56C was comparable to that of WT when the incubation time was increased. CONCLUSIONS: We concluded that the R56C mutant is responsible for type II HBS deficiency. We considered that the A459D and P112R mutants can be classified as belonging to the type I AT deficiency. PMID- 23809927 TI - Results expression for tests used to measure the anticoagulant effect of new oral anticoagulants. AB - Results of clotting tests used to measure the effect of old and new antithrombotic drugs can be expressed in different ways and this is considered as one of the sources of variability to explain the differences of results obtained for the same patient plasma when tested in different laboratories. This is particularly important for patient on vitamin K antagonists and led to the development of the international normalized ratio system of results reporting in this setting. Although standardization of results expression for the tests meant to measure the anticoagulant effect of new oral anticoagulants (NOA) is presently not perceived as an issue, it may become crucially important at the time when test-specific cut off values will be available to help assessing the risk of bleeding in individual patients who are on over-dosage. Effort should therefore be made to harmonize as much as possible results obtained in different laboratories using the same method, but different reagents. This article is aimed at discussing different options of results reporting of tests for NOA and their merits/pitfalls. PMID- 23809928 TI - Endovascular approach for peripheral arterial injuries. AB - BACKGROUND: In appropriate situations, treatment of arterial injuries with stent grafts decreases operative time, estimated blood loss, and iatrogenic complications when compared with open treatment. The purpose of this study was to describe the recent experience and outcomes of this technique in a large tertiary hospital. METHODS: The medical records of 16 patients with peripheral arterial injuries were analyzed in a retrospective single-institution review. RESULTS: Injuries were caused by trauma in 6 patients (38%), iatrogeny during vascular access in 6 (38%), and complications of open surgical procedures in 4 (25%). The subclavian-axillary segment was involved in 5 cases (31%), femoropopliteal artery in 5 (31%), carotid artery in 3 (19%), and iliac arteries in another 3 (19%). Clinical presentation of the injury was pseudoaneurysm in 8 cases (50%), arteriovenous fistula (AVF) in 3 (19%), bleeding in 3 (19%), and pseudoaneurysm associated with AVF in 2 (13%). All patients were hemodynamically stable at evaluation, and were treated with balloon-expanding or self-expanding stent grafts. All patients were followed up with a duplex scan, with a mean follow-up time of 17.3 months. No deaths or amputations occurred. Four patients (25%) returned with occluded stent grafts. Among them, 3 presented with mild or no symptoms. One patient was treated with open vascular bypass to treat limiting-arm symptoms. CONCLUSIONS: Treating penetrating arterial injuries with stent grafts was shown to be safe and effective. PMID- 23809929 TI - Long-term outcome of morphology and function after soft tissue injury of the forearm with vascular involvement. AB - BACKGROUND: We sought to assess long-term changes in bone, muscle area, and muscle strength at different levels of the forearm and hand mobility according to arterial patency and nerve damage after surgically treated trauma related to involuntary local cutting/piercing injuries. METHODS: Forty subjects were evaluated 11 years after surgery for traumatic lesions involving the major vascular axis of the distal forearm. Peripheral quantitative computed tomography was used to measure cortical bone mineral density (BMD) and muscle area at the proximal radius, trabecular BMD at the distal radius, and cortical BMD at the third finger. Hand grip strength was assessed using dynamometry. Muscle area and hand grip strength were corrected for the limb dominance effect. RESULTS: All subjects had reduced trabecular BMD at the distal radius on the affected side (Delta, -5.8%; P < 0.001) and reduced cortical BMD in the third finger (Delta, 2.8%; P < 0.05). Hand grip strength was significantly lower on the affected side. According to vascular patency, only subjects with nonpreserved blood flow had significantly reduced distal radius BMD (Delta, -6.7%; P = 0.004), and those with nerve damage had a significant reduction in BMD at the third finger (Delta, 3.5%; P = 0.05). Moreover, nerve injury was associated with the presence of clinical symptoms and hand functional impairment. CONCLUSIONS: The absence of blood flow and nerve damage after forearm trauma caused by involuntary cutting/piercing injuries causes remarkable permanent impairment in musculoskeletal structures, hand grip strength, and hand functionality. PMID- 23809930 TI - Femoro-femoral crossover graft and simultaneous reconstruction of the proximal deep femoral artery. AB - BACKGROUND: The goal of this study was to describe and review the results of a technique in which reconstruction of the common and profunda femoral arteries is combined with a femoro-femoral crossover graft using the same synthetic graft. A synthetic bifurcated graft (such as the ones used for aortobifemoral reconstruction), in which one limb is cut off, is used, leaving an enlarging patch at the end where the proximal anastomosis will be fashioned. METHODS: From January 1972 to January 2000, 6 patients underwent this reconstruction for severe limb ischemia. Patients were followed up in the outpatient clinic every 6 months. RESULTS: No postoperative mortality and no major complications were seen. One patient had a superficial wound infection, which resolved with conservative treatment. Five patients had a patent graft at an average follow-up of 39 months. CONCLUSIONS: Using the same synthetic graft allows angioplasty of the common and profunda femoral arteries of the donor side and revascularization of the opposite lower limb, with good short- and long-term results. PMID- 23809931 TI - Intact giant abdominal aortic aneurysm due to Takayasu arteritis. AB - A 35-year-old male fisherman was admitted with complaints of increasing back pain and abdominal discomfort of 1-year duration. Physical examination revealed a prominently visible, expansile, pulsatile, well-defined, nontender abdominal mass in the epigastric, umbilical and both lumbar areas. Computed tomographic (CT) angiography revealed a large juxtarenal aortic aneurysm with a maximum transverse diameter of 14.7 cm with bi-iliac extensions. Anatomy of the aneurysm did not permit endovascular aneurysm repair (EVAR). The patient underwent open surgical inclusion repair using an aorto-bi-iliac, 16 mm * 8 mm, collagen-impregnated, bifurcated Dacron graft. Postoperative recovery was uncomplicated and he left the hospital on postoperative day 5 in good health and has remained so up to the most recent 8-month follow-up. Histopathologic study showed signature features of Takayasu arteritis. PMID- 23809924 TI - Genetic variation and HIV-associated neurologic disease. AB - HIV-associated neurologic disease continues to be a significant complication in the era of highly active antiretroviral therapy. A substantial subset of the HIV infected population shows impaired neuropsychological performance as a result of HIV-mediated neuroinflammation and eventual central nervous system (CNS) injury. CNS compartmentalization of HIV, coupled with the evolution of genetically isolated populations in the CNS, is responsible for poor prognosis in patients with AIDS, warranting further investigation and possible additions to the current therapeutic strategy. This chapter reviews key advances in the field of neuropathogenesis and studies that have highlighted how molecular diversity within the HIV genome may impact HIV-associated neurologic disease. We also discuss the possible functional implications of genetic variation within the viral promoter and possibly other regions of the viral genome, especially in the cells of monocyte-macrophage lineage, which are arguably key cellular players in HIV-associated CNS disease. PMID- 23809932 TI - From the "bell-bottom" to a migrated "running stent" and then a successful conversion to hypogastric branched endograft. AB - Preservation of one or both internal iliac arteries (IIA) during endovascular repair of an abdominal aortic aneurysm (AAA) reduces the risk of buttock claudication, sexual dysfunction, and pelvic ischemia. Various techniques have been reported for this purpose. We report a case involving the proximal migration of a bell-bottom limb of a previous endovascular aneurysm repair (EVAR), leading to a type I distal endoleak. On reconstruction, the stent graft resembled a person running and was subsequently named a "running stent"; this had no particular clinical relevance. The patient was successfully treated endovascularly using a branched iliac device. To our knowledge, this is the first reported case of the use of an iliac branched device to treat a type 1b endoleak. PMID- 23809933 TI - Bailout chimney technique for graft detachment in a mycotic infrarenal aneurysm. AB - Mycotic aortic aneurysm is a not-so-rare condition and its modalities of treatment are still debated. Graft detachment represents a catastrophic complication after open repair of an abdominal aortic aneurysm. The dehiscence of a graft may have several causes, such as infection, fatigue of materials, and progression of the disease. In recent years, the use of the chimney technique has increased the applicability of endovascular aortic repair for challenging neck anatomies in the abdominal aorta. We report a case involving the use of the bailout chimney technique for graft detachment in a previously treated mycotic infrarenal aortic aneurysm. PMID- 23809934 TI - Single-center experience on endovascular repair of noninfected extracranial internal carotid artery pseudoaneurysms. AB - In the period ranging from 2006 to 2010, 5 endovascular interventions for carotid pseudoaneurysm (4 post-carotid endarterectomy [post-CEA] and 1 posttraumatic), without signs of infection, were carried out. All patients were neurologically asymptomatic. A covered stent was used in 4 cases. The fifth patient, undergoing a third endovascular procedure after a re-do open surgical repair of a post-CEA pseudoaneurysm, was treated with a bare stent. The technical success rate was 100%. A type 1 endoleak at the end of the procedure was observed in 1 patient, but it disappeared before discharging. No perioperative neurologic events occurred. At the most recent mean follow-up of 24 months, all patients are alive, without neurologic symptoms, and all have maintained patency of the internal carotid artery and are pseudoaneurysm-free. PMID- 23809935 TI - Usefulness of aneurysm sac angiography in therapeutic management of an endoleak after endovascular aneurysm repair. AB - Endoleak treatment after endovascular aneurysm repair (EVAR) can be difficult and complex. The key to success lies mostly in the accurate interpretation of imaging tests. We describe the case of a patient who was urgently operated on due to an episode of acute arterial ischemia in the left lower limb for stent-graft iliac limb thrombosis and a proximal type I endoleak. We highlight the importance of performing aneurysm sac angiography as part of an effective therapeutic strategy. PMID- 23809936 TI - Endovascular treatment of a left subclavian pseudoaneurysm induced by ingestion of a foreign body. AB - Subclavian artery-esophageal fistula is a life-threatening entity. It usually occurs in cases of an aberrant right subclavian artery. A fistula between a non aberrant subclavian artery and esophagus is extremely rare and difficult to diagnose. It is generally due to ingestion of a foreign body and it is often lethal. We present a case of subclavian artery-esophageal fistula complicated by mediastinitis in a 45-year-old man. The fistula, induced by ingestion of a fish bone, was successfully treated by endovascular stent grafting and left thoracotomy. PMID- 23809938 TI - Upper extremity thromboembolism in a patient with subclavian steal syndrome. AB - Subclavian steal is the physiologic process whereby blood flow through a vertebral artery is reversed at the level of the basilar artery as a means of supplying arterial inflow to the ipsilateral subclavian artery. This occurs in the setting of ipsilateral subclavian artery origin occlusion. We describe a case in which a patient with subclavian steal syndrome developed acute upper extremity ischemia secondary to thromboemboli from a chronically occluded ipsilateral subclavian stent (at the origin of the left subclavian artery). He subsequently underwent staged left upper extremity arterial thromboembolectomy followed by definitive revascularization via carotid-subclavian bypass. In addition, subclavian artery ligation proximal to the ipsilateral vertebral artery was performed. The patient's sensory and motor neurologic hand function returned to baseline with restoration of symmetric upper extremity arterial occlusion pressures and pulse volume recordings. A search of the literature revealed that this was the first case report of acute thromboembolic hand ischemia in the setting of subclavian steal. PMID- 23809937 TI - Spiral vein graft for internal jugular bypass in a patient with multiple sclerosis and suspected chronic cerebrospinal venous insufficiency. AB - Chronic cerebrospinal venous insufficiency (CCSVI) has been implicated as a contributing factor to multiple sclerosis (MS). This theory is strongly debated within the neurology and radiology communities. This report presents the case of a 45-year-old man with known MS and suspected CCSVI who had undergone previous internal jugular angioplasty and stenting. The patient reported dramatic improvement of symptoms after intervention. The stent thrombosed despite antithrombotic medication, and several endovascular interventions failed to restore long-term patency. Open venous reconstruction of the internal jugular vein was performed with a spiral graft from the saphenous vein. The patient's symptoms improved for several weeks until the venous reconstruction occluded. This case is the first reported open venous reconstruction for suspected CCSVI. PMID- 23809939 TI - Orthopoxvirus variola infection of Cynomys ludovicianus (North American black tailed prairie dog). AB - Since the eradication of Smallpox, researchers have attempted to study Orthopoxvirus pathogenesis and immunity in animal models in order to correlate results human smallpox. A solely human pathogen, Orthopoxvirus variola fails to produce authentic smallpox illness in any other animal species tested to date. In 2003, an outbreak in the USA of Orthopoxvirus monkeypox, revealed the susceptibility of the North American black-tailed prairie dog (Cynomys ludovicianus) to infection and fulminate disease. Prairie dogs infected with Orthopoxvirus monkeypox present with a clinical scenario similar to ordinary smallpox, including prodrome, rash, and high mortality. This study examines if Black-tailed prairie dogs can become infected with O. variola and serve as a surrogate model for the study of human smallpox disease. Substantive evidence of infection is found in immunological seroconversion of animals to either intranasal or intradermal challenges with O. variola, but in the absence of overt illness. PMID- 23809941 TI - The effects of nicotine on cone and rod b-wave responses in larval zebrafish. AB - Acetylcholine is present in and released from starburst amacrine cells in the inner plexiform layer (IPL), but its role in retinal function except, perhaps, in early development, is unclear. Nicotinic acetylcholine receptors are thought to be present on ganglion, amacrine, and bipolar cell processes in the IPL, and it is known that acetylcholine increases the spontaneous and light-evoked responses of retinal ganglion cells. The effects of acetylcholine on bipolar cells are not known, and here we report the effects of nicotine on the b-wave of the electroretinogram in larval zebrafish. The b-wave originates mainly from ON bipolar cells, and the larval zebrafish retina is cone-dominated. Only small rod responses can be elicited with dim lights in wild-type larval zebrafish retinas, but rod responses can be recorded over a range of intensities in a mutant ( n o optokinetic response f ) fi sh that has no cone function. We fi nd that nicotine strongly enhances cone-driven b-wave response amplitudes but depresses rod driven b-wave response amplitudes without, however, affecting rod- or cone-driven b-wave light sensitivity. PMID- 23809942 TI - Intraocular lens dislocation. PMID- 23809940 TI - Ski protein levels increase during in vitro progression of HPV16-immortalized human keratinocytes and in cervical cancer. AB - We compared the levels of the Ski oncoprotein, an inhibitor of transforming growth factor-beta (TGF-beta) signaling, in normal human keratinocytes (HKc), HPV16 immortalized HKc (HKc/HPV16), and differentiation resistant HKc/HPV16 (HKc/DR) in the absence and presence of TGF-beta. Steady-state Ski protein levels increased in HKc/HPV16 and even further in HKc/DR, compared to HKc. TGF-beta treatment of HKc, HKc/HPV16, and HKc/DR dramatically decreased Ski. TGF-beta induced Ski degradation was delayed in HKc/DR. Ski and phospho-Ski protein levels are cell cycle dependent with maximal Ski expression and localization to centrosomes and mitotic spindles during G2/M. ShRNA knock down of Ski in HKc/DR inhibited cell proliferation. More intense nuclear and cytoplasmic Ski staining and altered Ski localization were found in cervical cancer samples compared to adjacent normal tissue in a cervical cancer tissue array. Overall, these studies demonstrate altered Ski protein levels, degradation and localization in HPV16 transformed human keratinocytes and in cervical cancer. PMID- 23809943 TI - Sectioning a luxated intraocular lens inside the vitreous cavity. AB - We describe a new technique for sectioning an intraocular lens (IOL) inside the vitreous cavity. The IOL had a broken haptic and was accidentally luxated after a complicated cataract surgery with posterior capsule rupture. The primary indication to cut the IOL in half inside the vitreous cavity is to preserve the anterior capsule integrity, especially in a small-sized capsulotomy, allowing subsequent implantation of a new IOL in the sulcus with the optical zone captured in the capsulorhexis. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 23809944 TI - Management and outcomes of intraocular lens dislocation in patients with pseudoexfoliation. AB - PURPOSE: To analyze the outcomes of surgery for dislocated intraocular lenses (IOLs) in patients with pseudoexfoliation (PXF). SETTING: Private practice, Boston, Massachusetts, USA. DESIGN: Retrospective case study. METHODS: Eyes with PXF and IOL dislocations that had IOL exchange or repositioning were reviewed. An outcomes analysis compared the surgical techniques with regard to corrected distance visual acuity (CDVA), intraocular pressure (IOP), and glaucoma medication requirements. RESULTS: The IOL exchange was performed in 64 eyes (79%) and IOL repositioning in 17 eyes (21%). The CDVA improved in all eyes, from a preoperative mean of 0.78 logMAR +/- 0.50 (SD) to a mean of 0.35 +/- 0.31 logMAR at the final follow-up (mean 2.5 +/- 2.6 years) (P<.0001). The mean IOP was reduced by 4.2 mm Hg at the final follow-up (P<.0001). The mean glaucoma medication requirement remained stable at the final follow-up compared with the preoperative levels (P>.05). There were no significant differences in the mean CDVA, IOP, or glaucoma medication requirement between eyes that had IOL exchange and eyes that had IOL repositioning. There were no significant intraoperative complications. The most common postoperative complication was a transient decrease in IOP to 5 mm Hg or lower or an increase in IOP to 30 mm Hg or higher. CONCLUSIONS: Patients with PXF having surgical treatment of IOL dislocation have the potential for excellent visual outcomes with minimal intraoperative and postoperative complications. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 23809945 TI - Combined wavefront-guided laser in situ keratomileusis and aspheric ablation profile with iris registration to correct myopia. AB - PURPOSE: To compare the effects of a combined wavefront-guided and aspheric ablation profile with an aspheric ablation profile alone to correct myopia in patients with a preoperative total higher-order aberration root mean square (HOA RMS) lower than 0.30 MUm in both eyes. SETTING: Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China. DESIGN: Comparative case series. METHODS: Laser in situ keratomileusis was performed, with 1 eye randomized to wavefront guided with aspheric ablation and the fellow eye to aspheric ablation only. The uncorrected (UDVA) and corrected (CDVA) distance visual acuities, manifest subjective refraction, corneal topography, RMS value of total and grouped HOAs, and contrast sensitivity were measured preoperatively and 1 and 6 months postoperatively. RESULTS: The study enrolled 62 eyes (31 patients). The increasing factors of total HOA RMS, 3rd-order RMS and 4th-order RMS were 2.09, 2.09, and 1.99, respectively, in the wavefront-guided with aspheric ablation group and 2.52, 2.68, and 2.51, respectively, in the aspheric ablation only group at 6 months; the aspheric ablation group had statistically significantly larger increasing factors (P=.016, P=.038, and P=.027, respectively). The reduction in contrast sensitivity log values was statistically significantly less in the wavefront-guided with aspheric ablation group than in the aspheric ablation only group except at 1.5 cycles per degree. CONCLUSION: The wavefront-guided with aspheric ablation profile was associated with better limitation of HOAs and faster recovery of mesopic contrast sensitivity for patients with a preoperative total HOA RMS lower than 0.30 MUm. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 23809946 TI - Resolution of negative dysphotopsia after laser anterior capsulotomy. AB - It has been suggested that a clear anterior nasal capsule contributes to negative dysphotopsia and that symptoms may resolve with opacification of the capsule. We describe a case in which negative dysphotopsia occurred despite a translucent anterior peripheral capsule and resolved following laser removal of the anterior nasal capsule. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 23809947 TI - Neodymium:YAG laser anterior capsulectomy: surgical option in the management of negative dysphotopsia. AB - This report describes 6 cases in which neodymium:YAG (Nd:YAG) laser anterior capsulectomy achieved limited success in treating negative dysphotopsia. In 5 eyes with the Akreos AO MI60L posterior chamber intraocular lens (PC IOL), the dysphotopsia symptoms resolved completely (3 eyes) and partially (2 eyes) depending on the extent of the Nd:YAG laser anterior capsulectomy. In 1 eye with the Acrysof IQ toric PC IOL, the symptoms did not improve. Success with this procedure in patients with the Akreos AO MI60L PC IOL supports the role of the anterior capsule in the etiology and mechanism of negative dysphotopsia. Because the anterior capsulectomy did not resolve the symptoms in the patient with the Acrysof IQ toric PC IOL, the anterior capsule should be considered an optical risk factor for negative dysphotopsia and important in the manifestation of symptoms in only some patients. Other primary optical factors that have been described can presumably manifest negative dysphotopsia symptoms independent of light scatter from the anterior capsule. FINANCIAL DISCLOSURE: The author has no financial or proprietary interest in any material or method mentioned. PMID- 23809948 TI - Postoperative analysis of glued intrascleral fixation of intraocular lens and comparison of intraoperative parameters and visual outcome with 2 methods of haptic externalization. PMID- 23809949 TI - Prevalence, surgical management, and complication rate in patients unable to lie flat for cataract surgery. PMID- 23809950 TI - July consultation #2. PMID- 23809951 TI - Cataract Surgical Problem: July consultation #1. PMID- 23809952 TI - July consultation #3. PMID- 23809953 TI - July consultation #4. PMID- 23809954 TI - July consultation #5. PMID- 23809955 TI - July consultation #7. PMID- 23809956 TI - July consultation #6. PMID- 23809957 TI - July consultation #8. PMID- 23809958 TI - July consultation #9. PMID- 23809959 TI - Reply: Rasch modified NEI VF-11R or actually the VF-11R? PMID- 23809960 TI - Rasch modified NEI VF-11R or actually the VF-11R? PMID- 23809961 TI - Etienne Hirsch: unlocking Parkinson's mysteries. PMID- 23809962 TI - The Harvard Biomarker Study's big plan. PMID- 23809963 TI - A helicopter emergency medical service may allow faster access to highly specialised care. AB - INTRODUCTION: Centralization of the hospital system entails longer transport for some patients. A physician-staffed helicopter may provide effective triage, advanced management and fast transport to highly specialized treatment for time critical patients. The aim of this study was to describe activity and possible beneficial effect of a physician-staffed helicopter in a one-year trial period in eastern Denmark. MATERIAL AND METHODS: This was a prospective observational study of all missions related to a daylight operating, physician-staffed helicopter. We recorded information about the activity during 12 months, focusing on dispatchment, diagnoses, medical interventions, admission patterns and 30-day mortality. RESULTS: There were a total of 574 missions resulting in 609 patient contacts. Activity ranged from 22 to 76 missions per month. The helicopter was grounded 6% of its operating time, mainly due to weather conditions. The primary patient categories were trauma (43.5%) and cardiac disease (26.1%). The physician acted as Medical Incident Officer at three major incidents. A total of 53 endotracheal intubations, 13 intraosseous cannula insertions and four tube thoracostomies were performed. The median hospital length-of-stay was four days, 30-day mortality was 6.1% and 86 patients were transferred to intensive care units. CONCLUSION: The physician-staffed helicopter had approximately two missions per day the first year, mainly in relation to trauma and cardiac patients needing specialized treatment. Advanced medical interventions were commonly performed. FUNDING: Funded by Trygfonden. TRIAL REGISTRATION: not relevant. PMID- 23809964 TI - Use of professional profiles in applications for specialist training positions. AB - INTRODUCTION: The seven roles of the CanMEDS system have been implemented in Danish postgraduate medical training. For each medical specialty, a professional profile describes which elements of the seven roles the specialty deems important for applicants for a specialist training position. We investigated use of professional profiles among the 38 Danish specialty societies in order to ascertain the use of the seven roles. MATERIAL AND METHODS: We used information from the websites of the Postgraduate Medical Training Secretariats in March 2012. For each profile, we extracted information on how the seven roles were described, how the roles were ranked by importance, whether a score sheet was used by the appointment committee and whether the profile had been updated. RESULTS: Twenty-four (63%) of the 38 profiles described the contents for all of the seven roles and four (11%) described the contents only for some of the roles. Nine specialties (24%) described a clear ranking of the seven roles with the medical expert and scholar roles generally ranked as most important. Seven specialties (18%) used standardised score sheets as part of the application process. Four (11%) specialties had updated their professional profiles. CONCLUSION: The majority of specialties described the seven roles in their professional profiles, but the level of detail varied substantially. Few specialties described whether the roles were ranked by importance or provided specific guidelines for appointment committees on how the contents of the profiles should be interpreted. We suggest that specialties seek inspiration for updating their profiles, and that they use the contents from all specialties provided at a website. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 23809965 TI - Caregiver burden and psychosocial services in patients with early and late onset Alzheimer's disease. AB - INTRODUCTION: The purpose of the study was to analyse caregiver burden and consumption of psychosocial services in a consecutive group of patients with early onset Alzheimer's disease (EOAD) compared with a matching group with late onset Alzheimer's disease (LOAD). MATERIAL AND METHODS: This was a case-control study with 42 patients who were matched according to disease severity at the time of diagnosis. Caregivers in both groups were interviewed using the Neuro Psychiatric Inventory (NPI), the Activities of Daily Living (ADL) scale and the Resource Utilization in Dementia scale. The quantitative outcomes were compared statistically. RESULTS: The EOAD group had a significantly higher ADL score than the LOAD group. There was a trend towards caregivers in the LOAD group spending more time helping the patients, and they needed more social services than the EOAD group. NPI scores were not significantly different, but a tendency towards a higher caregiver burden in the EOAD group was observed. CONCLUSION: The higher caregiver burden in patients with EOAD--despite a better ADL function than LOAD patients--suggests that the existing psychosocial services might be particularly insufficient for caregivers in EOAD. FUNDING: The study was funded by a three month scholarship grant from the research fund at Roskilde Hospital. TRIAL REGISTRATION: not relevant. PMID- 23809966 TI - Patient perspectives on quality of life after penile cancer. AB - INTRODUCTION: Penile cancer (PC) is a rare, but ominous disease. In 50-60% of squamous cell carcinomas of the penis, human papilloma virus infection, particularly with types 16 and 18, is part of the pathogenesis. Depending on cancer invasiveness, PC is treated with local resection of the glans and partial or total penectomy. This quality of life (QoL) study aimed at obtaining in-depth knowledge about patients' experiences with PC. MATERIAL AND METHODS: A literature study was carried out to identify relevant topics for a semi-structured interview. Qualitative interviews with four former PC patients were transcribed verbatim and analysed using a medical anthropological approach. The analysis focused on the ways patients frame their disease experiences and relate the physical, sexual and emotional disease impact. RESULTS: Varying degrees of amputation affected the participants' sexual capabilities. Still, three participants (aged 66-72 years) said that their partner relationships were not negatively affected by the disease. In contrast, the impact on sexual function and self-esteem had been devastating to the fourth participant (aged 44 years) who was single and worried about the disease impeding his chance of finding love in life. For all participants, having had a potentially fatal disease put the physical disease impact into perspective. CONCLUSION: PC may greatly impact the psycho-sexual QoL of PC patients, particularly at a younger age and depending on their partnership status. Disease impact appears to be related to age, overall life situation and the cancer experience. FUNDING: The study was funded by an unrestricted research grant from Sanofi Pasteur MSD. TRIAL REGISTRATION: not relevant. PMID- 23809967 TI - Endoscopic brush cytology from the biliary duct system is still valuable. AB - INTRODUCTION: The aim of this study was to define sensitivity, specificity and positive and negative predictive values of endoscopic retrograde cholangiopancreatography (ERCP) brush cytology from biliary strictures obtained over a period of 12 years in a county hospital in Denmark. MATERIAL AND METHODS: Patients with cytology specimens identified by brushings of the bile duct, pancreatic duct and ampulla of Vater were included. The specimens were reported as unsatisfactory, normal, atypical, suspicious for malignancy or malignant. Our evaluation comprised 75 specimens. For the statistical analysis, an atypical cytology result was considered benign, and a suspicious result was considered malignant. The cytological diagnoses were compared with the final diagnoses which were established either by histopathology (surgery, biopsy or autopsy) or by at least one year of clinical follow-up. RESULTS: Of the 75 specimens included, 40 were diagnosed as cytologically benign (35 normal and five atypical) and 35 as cytologically malignant (22 suspicious for malignancy and 13 malignant). Comparing the cytological diagnosis with the final diagnosis, we found 35 to be true positives, 22 to be true negatives, zero to be false positives and 18 to be false negatives. Of the five atypical specimens, four were false negatives. The operating characteristics were: 66% sensitivity, 100% specificity, 100% positive predictive value and 55% negative predictive value. The diagnostic accuracy was 76%. CONCLUSION: Suspicion and malignant cytology are reliable with a specificity of 100%. In these cases, we recommend that the patients are considered for surgical or oncological treatment without further histological investigations. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 23809968 TI - Iodine deficiency in Danish pregnant women. AB - INTRODUCTION: Maternal iodine requirements increase during pregnancy. Studies performed before the introduction of mandatory iodine fortification of salt in Denmark in 2000 showed that pregnant women with no intake of iodine-containing supplements were moderately iodine-deficient and showed signs of thyroidal stress. We investigated the intake of iodine-containing supplements and urinary iodine excretion in Danish pregnant women after the introduction of iodine fortification of salt. MATERIAL AND METHODS: We conducted a cross-sectional study between June and August 2012 in an area of Denmark where iodine deficiency had previously been moderate. Pregnant women coming to Aalborg University Hospital for obstetric ultrasound were recruited consecutively. Participants filled in a questionnaire and handed in a spot urine sample for measurement of iodine and creatinine. RESULTS: Among the pregnant women included (n = 245) 84.1% reported an intake of iodine-containing supplements, and compared with those not taking iodine supplements the median urinary iodine concentration was significantly higher in this group: 109 g/l (25th-75th percentile: 66-191 ug/l). On the other hand, the median urinary iodine concentration was considerably below the recommended level, even for the non-pregnant state in pregnant women with no iodine supplement intake: 68 ug/l (35-93 ug/l), p < 0.001. CONCLUSION: The majority of pregnant women took iodine-containing supplements, but the subgroup of non-users was still iodine-deficient after the introduction of iodine fortification of salt. Iodine supplement intake during pregnancy in Denmark should be officially recommended. FUNDING: The study was supported by a grant from Musikforlaeggerne Agnes og Knut Morks Fond and from Speciallaege Heinrich Kopps Legat. TRIAL REGISTRATION: not relevant. PMID- 23809969 TI - A minority of patients discharged within 24 hours after laparoscopic colon resection. AB - INTRODUCTION: Fast-track laparoscopic colon surgery has gained wide acceptance worldwide. Post-operative hospital stays of 2-5 days have typically been reported. However, in our department some of the patients have been discharged within 24 h after surgery. The aim of this study was to describe differences in demographic and perioperative data between those patients discharged within 24 h and those discharged on days 2-4 post-operatively. MATERIAL AND METHODS: Data were collected retrospectively from August 2008 to May 2012. A total of 24 patients undergoing elective right-sided hemicolectomy or sigmoidectomy for colon cancer were discharged within 24 h. These 24 patients were compared with 209 patients undergoing the same procedures, but discharged on the second to the fourth post-operative day. All patients were operated laparoscopically according to our fast-track regimen. Demographic data and short-term outcomes were compared between the two groups. RESULTS: We found that the median age (64 years versus 70 years) (p = 0.018) as well as the median operating time (120 min. versus 155 min.) (p = 0.002) were significantly lower for the 24-h stay group. No other significant differences were found between the two groups. CONCLUSION: This study showed that discharge within the first 24 h after elective laparoscopic fast track colon surgery was significantly associated with lower age and shorter duration of surgery. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 23809970 TI - Elective surgery after successful endoscopic decompression of sigmoid volvulus may be considered. AB - INTRODUCTION: Volvulus is an axial twist of any part of the gastrointestinal tract along its mesentery. If it goes unattended, it will cause bowel obstruction and bowel ischaemia with gangrene and perforation. The primary treatment is endoscopic desufflation, but the place for elective surgery is controversial. Volvulus is a rare condition in Western Europe and North America that most often affects elderly of either gender. MATERIAL AND METHODS: We reviewed all records on patients admitted to our hospital during an 11-year period. Age at first admission, co-morbidity and number of readmissions were registered. The results of primary endoscopic treatment and any surgery were registered together with complications, 30-day and one-year moratality rates. RESULTS: A total of 41 patients were treated. The mean age at first admission was 70 years. Significant co-morbidity was found in 33 patients (81%). Thirty patients (73%) were treated for recurrence. Fourteen patients were treated with decompression alone, and 27 patients were operated (14 acute and 13 elective cases). The 30-day mortality was 43% after acute operation and 8% after elective operation (p < 0.05). In the group of patients with decompression alone, the one-year mortality was 50%. CONCLUSION: Elective surgery should be considered because of a high recurrence rate and one-year mortality after initially successful decompression. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 23809971 TI - Primary percutaneous coronary intervention delay for patients living in a peripheral area in Denmark. AB - INTRODUCTION: In patients with ST-elevation myocardial infarction (STEMI), timely primary percutaneous coronary intervention (PPCI) is superior to thrombolysis and it is the preferred treatment in Denmark. The prognosis depends on the time delay until coronary blood flow is re-established. The purpose of this registry study was to evaluate the PPCI treatment delay of the triage algorithm in a peripheral area in the Region of Central Jutland in the context of European guidelines. MATERIAL AND METHODS: From 1 September 2009 through 31 August 2010, we included all PPCI-treated patients from the catchment area of Regional Hospital Herning (RHH) who were diagnosed with probable STEMI based on the first electrocardiography wirelessly transmitted to the physician on call at RHH after symptom onset. RESULTS: A total of 101 patients were included, 77% were males and their median age was 63.4 years. The median distance to the PCI centre was 120.3 (range 63.5-174.2) km. The 2008 European guidelines on transportation delay were fulfilled for 35 (35%) patients and the 2012 European guidelines for seven (7%) patients. Overall, 46% of the patients had a delay from first medical contact to PCI < 120 min., 9% a delay < 90 min. and none a delay < 60 min. CONCLUSION: Our registry study showed that 35% and 7% of PPCI patients from a peripherally located area in Denmark met the 2008 and 2012 European guidelines for an acceptable transport delay to a PCI centre, respectively. Our current PPCI triage strategy therefore needs reconsideration. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 23809972 TI - More than half of the medical students who apply for a dispensation drop out and need focused counselling. AB - INTRODUCTION: The Student Counselling Service at the Faculty of Health Sciences, Aarhus University, Denmark, has experienced an increase in medical students with poor mental well-being. MATERIAL AND METHODS: This was a descriptive, retrospective survey of 1,056 medical students commencing their studies in the period from September 2003 to February 2006. The study had a four-year follow-up period. Demographics, delay, discontinuation and dispensations were determined. Each application was reviewed and the reasons why each student applied were recorded. RESULTS: Applicants were significantly older than non-applicants. 90.9% of the dispensations were related to first-year examinations (50 students). A significantly higher number of dispensation applicants (58.2%) discontinued their studies (32 students) compared with dispensation non-applicants. 54.6% of the applicants (30 students) did not pass their first-year examinations. The study time was delayed by more than two years among 67.3% of the applicants (37 students). 27.3% of the applicants were students with a foreign qualifying exam (15 students). Females listed mainly emotional reasons in their applications. Such reasons included, among others, depression, stress and anxiety. In contrast, males listed study- and family-related issues. CONCLUSION: Focused student counselling is recommended for all students of medicine, especially in the first year of their studies. Furthermore, lessons aiming to build study skills and teach students how to cope with study-related stress and exam-related anxiety are recommended. Particular attention should be given to foreign students. Each applicant should be advised individually. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 23809973 TI - The majority of surgical departments adhere to national Danish guidelines for surveillance after colorectal cancer surgery. AB - INTRODUCTION: In 2003 the use of post-operative surveillance (POS) after surgery for colorectal cancer (CRC) in Denmark was studied. Diversity in the choice and frequency of surveillance modalities was found. Subsequently, the Danish Colorectal Cancer Group (DCCG) has published guidelines for POS. In the same period, the number of departments performing CRC surgery has been reduced by 50% nationally. The aim of the present study was to describe the POS after CRC in Denmark following a reduction in the number of departments performing operations for CRC and the DCCG's publication of national recommendations for POS programmes. MATERIAL AND METHODS: Questionnaires were sent to all 19 departments that performed operations for CRC. Questions concerned the diagnostic modalities used for detecting recurrences and metachrone cancers. RESULTS: All departments returned their questionnaires. All departments had a formal POS programme. The recommendations given by the DCCG were met by 17 departments (89%) with regard to liver metastases, by 16 departments (84%) with regard to lung metastases and by 16 departments (84%) with regard to metachrone cancers. CONCLUSION: As opposed to what was observed in 2003, all departments offered a POS programme after CRC surgery in 2012. Almost all departments met the DCCG recommendations, probably owing to the centralization of CRC surgery and the DCCG's introduction of national guidelines. Hopefully, this will contribute to a better survival for CRC patients in the future, although more research is needed to establish optimal post-operative surveillance. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 23809974 TI - Promising results using sentinel node biopsy as a substitute for radical lymphadenectomy in endometrial cancer staging. AB - INTRODUCTION: The objective of this study was to evaluate the efficacy of the sentinel node (SN) procedure in endometrial cancer patients. MATERIAL AND METHODS: This was a prospective follow-up study including patients referred to Herlev Hospital, Denmark, to be treated for endometrial cancer in the period from October 2005 to December 2008. Hysteroscopy was performed with a 4.5 mm hysteroscope. Injections of 100-150 MBq (99m)Tc-traced colloid were administered subendometrially, and a dynamic scintigram was made. SN(s) identified with a gammaprobe were resected at the operation, and frozen sections were performed, followed by radical pelvic and para-aortic lymphadenectomy. RESULTS: A total of 32 patients were included. Among patients without clinical macro-metastases (n = 27), the SNs were detected by gamma probe in 23 (85.2%), and in most patients (n = 17, 74.0%) one (n = 12) or two (n = 5) SNs were found. The consistency between the scintigram and peroperative findings increased from 50.0% to 78.9% when the dose of (99m)Tc was increased to 150 MBq, mostly because the detection failure rate was lower at the higher dose: 4.8% versus 18.2%. By frozen section all macro metastases were confirmed, but only one micro-metastasis was diagnosed. All subsequent lymph node metastases found in the final histology were found in SNs, i.e. no false negative SNs were found. CONCLUSION: The SN procedure can be used for endometrial cancer and it has a high detection rate and no false negative SNs were detected. The sensitivity of the SN procedure may be increased by the use of single-photon emission computed tomography (SPECT)/computed tomography (CT) and peroperative cytokeratin (CK) staining of the SN(s). FUNDING: External funding was received from the following University Foundation, Copenhagen County Research, Manufacturer Einar Willumsen's Memorial Foundation, Toyota Foundation Denmark, Lilly Benthine Lund Foundation. TRIAL REGISTRATION: The study was registered with the Danish Data Protection Agency. PMID- 23809975 TI - Physician-staffed emergency helicopter reduces transportation time from alarm call to highly specialized centre. AB - INTRODUCTION: Since 2007, the number of Danish emergency departments has decreased from 44 to 21. Longer distances to specialized treatment have increased the demand for advanced prehospital treatment. A Danish 24/7 Helicopter Emergency Medical System (HEMS) project in western Denmark was initiated on 6 January 2011. The HEMS provides prehospital care delivered by a specialized anaesthesiologist. This study evaluated the effect of HEMS on the time to treatment by a physician (time-to-doctor) and the time from a 112 emergency call to arrival at the highly specialized centre (time-to-centre) for patients with ST-elevation myocardial infarction (STEMI) or severe injury (Injury Severity Score > 15). MATERIAL AND METHODS: In this prospective study with a matched historical control group, the time-to-doctor and the time-to-centre for patients with STEMI or severe injury transported by HEMS were compared with geographically matched patients with the same diagnoses and who were transported by ambulance. RESULTS: Time-to-centre was reduced from 102 to 84 min. for STEMI and from 322 to 97 min. for severely injured patients after HEMS implementation. HEMS did not substantially reduce time-to-doctor, mainly because of increased availability of physician-staffed cars. In 56% of cases, HEMS was dispatched secondarily more than 30 min. after the ambulance had been dispatched. CONCLUSION: Using HEMS reduced time to arrival at a highly specialized centre for patients with STEMI or severe injury. Simultaneous dispatch of an ambulance and HEMS shows potential for further reduction in the time-to-centre and the time-to-doctor. FUNDING: not relevant. TRIAL REGISTRATION: The trial is registered at the Danish Data Protection Agency. PMID- 23809976 TI - On 5-fluorouracil therapy of colorectal cancer. PMID- 23809978 TI - The double burden. AB - One third of the world's population is latently infected with Mycobacterium tuberculosis, and with the lifestyle changes succeeding the on-going urbanization, populations already burdened by tuberculosis are experiencing a dramatic increase in chronic diseases, with diabetes being a serious challenge. Tuberculosis and diabetes are not only becoming co-existing diseases. In fact, the diseases interact, and there is evidence to suggest that especially diabetes disease increases the susceptibility for developing active tuberculosis disease. Furthermore, it is plausible that tuberculosis leads to, either transient or permanent, impairment of the glucose metabolism, which ultimately will turn into diabetes. A number of studies from the Americas, Europe, Asia, and, most lately, from sub-Saharan Africa have reported strong association between tuberculosis and diabetes; on average, the estimated risk of active tuberculosis is thrice as high among people with diabetes. The study from sub-Saharan Africa was conducted in Tanzania and is the basis of this thesis. Based on available evidence on the association between tuberculosis and diabetes, the primary aim of the study was to assess the role of diabetes for tuberculosis risk, manifestations, treatment outcomes and survival in a Tanzanian population of tuberculosis patients and non tuberculosis neighbourhood controls. The study was conducted in Mwanza City in northern Tanzania, with a population exceeding half a million inhabitants, with tuberculosis and HIV being common infections in the region, but with little knowledge about the prevalence of diabetes. We recruited newly diagnosed pulmonary tuberculosis patients from spring 2006 and continuously till the fall 2009, with all participating in a nutritional intervention running in parallel with the medical tuberculosis treatment. All participants underwent diabetes and HIV testing as well as a series of measurements such as anthropometric, clinical and paraclinical parameters. The population was followed up during treatment (2 and 5 months) to assess treatment outcome as well as after one year to assess their survival status. Based on data from 1,250 tuberculosis patients and 350 neighbourhood controls, we found that 38 and 21%, respectively, had impaired glycaemia, and that the prevalence of diabetes was 17 and 9% among tuberculosis patients and controls, respectively. This difference in prevalence between patients and controls was equivalent to an adjusted odds ratio of more than four, indicating a strong association between tuberculosis and diabetes. Furthermore, we found that diabetes was associated with tuberculosis among both participants with or without HIV co-infection. Despite the strong association, diabetes had only moderate clinical implications when the tuberculosis patients initiated the tuberculosis treatment; the patients with diabetes co-morbidity had a minor elevation in the immune response and more frequently reported to have fever. Furthermore, diabetes did not seem to delay time to sputum conversion during treatment. Nevertheless, diabetes co-morbidity led to impaired treatment outcome with slower recovery of weight and haemoglobin and a more than four times higher mortality rate within the initial phase of tuberculosis treatment. In conclusion, in the African region, the double burden of tuberculosis and diabetes is becoming a major health problem. Although the tuberculosis incidence has stabilized during the last decade, the increasing incidence of diabetes will possibly interfere with tuberculosis control and may, consequently, make the tuberculosis incidence increase again. Future research strategies should focus on enhanced diagnostic tools to identify tuberculosis patients with diabetes co-morbidity, and on the role of disease-disease, drug-disease and drug-drug interactions between tuberculosis and diabetes diseases and treatments. PMID- 23809977 TI - Early clinical outcomes following laparoscopic inguinal hernia repair. AB - Laparoscopic inguinal hernia repair (TAPP) has gained increasing popularity because of less post-operative pain and a shorter duration of convalescence compared with open hernia repair technique (Lichtenstein). However, investigation of duration of convalescence with non-restrictive recommendations, and a procedure-specific characterization of the early clinical outcomes after TAPP was lacking. Furthermore, optimization of the post-operative period with fibrin sealant versus tacks for fixation of mesh, and the glucocorticoid dexamethasone versus placebo needed to be investigated in randomized clinical trials. The objective of this PhD thesis was to characterize the early clinical outcomes after TAPP and optimize the post-operative period. The four studies included in this thesis have investigated duration of convalescence and procedure-specific post-operative pain and other early clinical outcomes after TAPP. Furthermore, it has been shown that fibrin sealant can improve the early post-operative period compared with tacks, while dexamethasone showed no advantages apart from reduced use of antiemetics compared with placebo. Based on these findings, and the existing knowledge, 3-5 days of convalescence should be expected when 1 day of convalescence is recommended and future studies should focus on reducing intraabdominal pain after TAPP. Fibrin sealant can optimize the early clinical outcomes but the risk of hernia recurrence and chronic pain needs to be evaluated. Dexamethasone should be investigated in higher doses. PMID- 23809979 TI - Bone graft materials in fixation of orthopaedic implants in sheep. AB - Bone graft is widely used within orthopaedic surgery especially in revision joint arthroplasty and spine fusion. The early implant fixation in the revision situation of loose joint prostheses is important for the long-term survival. Bone autograft has been considered as gold standard in many orthopaedic procedures, whereas allograft is the gold standard by replacement of extensive bone loss. However, the use of autograft is associated with donor site morbidity, especially chronic pain. In addition, the limited supply is a significant clinical challenge. Limitations in the use of allograft include the risk of bacterial contamination and disease transmission as well as non-union and poor bone quality. Other bone graft and substitutes have been considered as alternative in order to improve implant fixation. Hydroxyapatite and collagen type I composite (HA/Collagen) have the potential in mimicking skeletal bones. The osteoconductive properties of the composite might be improved by adding bone marrow aspirate (BMA), which can be harvested during surgery. Other alternatives to bone graft are demineralised bone matrix (DBM) and human cancellous bone (CB). DBM is prepared by acid extraction of human bone and includes bone collagen, morphogenetic proteins and growth factors. The combination of DBM with CB and with allograft might improve the healing potential of these grafts around non cemented orthopaedic implants and thereby the implant fixation. Study I investigates the effect of HA/Collagen composite alone and in combination with BMA on the early fixation of porous coated titanium implants. In addition, the study compares also the effect of autograft with the gold standard allograft. By using a sheep model, the implants were inserted in the trabecular bone of femoral condyles. The test biomaterials were placed in a well defined peri-implant gap. After the observation period, the bone-implant specimens were harvested and evaluated mechanically by a destructive push-out test and analyzed histologically qualitatively and quantitatively. Study II investigates the effect of DBM alone and in combination with CB or allograft. The control group in study I and II was allograft. Study III is a methodological study and investigates the potential systematic bias by applying the traditional sampling method, which includes evaluating the mechanical fixation by using the superficial part and the histological analysis by using the profound part of the implant. The implants in this study were inserted in the proximal humerus and only allograft was used in the peri-implant gap. In study I, the mechanical testing showed failure by the preloading in the composite group with and without BMA. There were no bone ongrowth and sparely bone formation in the gap by the composite group. Adding BMA to the composite has no beneficial effect on implant fixation. No significant difference between autograft and allograft on mechanical fixation, bone ongrowth and bone formation. In study II the combination of DBM with CB or allograft showed no significant differences on the mechanical testing and histological analysis to the control group, whereas DBM alone showed significant low mechanical fixation, low bone ongrowth and low bone formation. Study III showed no significant difference between the sampling methods. In conclusion, HA/Collagen composite alone or in combination with BMA has no effect on the early fixation of porous coated titanium implants. Autograft has comparable effect on allograft with regard to early implant fixation. The combination of DBM with CB may represent an alternative to allograft. In study III, mechanical testing and histological analysis can be applied either from the superficial or the profound part of the implant. By applying the histological analysis from the superficial part and the mechanical testing from the profound part, an extra section is required. PMID- 23809980 TI - Oxidatively generated DNA/RNA damage in psychological stress states. AB - Both non-pathological psychological stress states and mental disorders are associated with molecular, cellular and epidemiological signs of accelerated aging. Oxidative stress on nucleic acids is a critical component of cellular and organismal aging, and a suggested pathogenic mechanism in several age-related somatic disorders. The overall aim of the PhD project was to investigate the relation between psychopathology, psychological stress, stress hormone secretion and oxidatively generated DNA and RNA damage, as measured by the urinary excretion of markers of whole-body DNA/RNA oxidation (8-oxodG and 8-oxoGuo, respectively). The main hypothesis was that psychological stress states are associated with increased DNA/RNA damage from oxidation. In a study of 40 schizophrenia patients and 40 healthy controls matched for age and gender, we found that 8-oxodG/8-oxoGuo excretion was increased in schizophrenia patients, providing a possible molecular link between schizophrenia and its associated signs of accelerated aging. We found no association between psychopathology, perceived stress or cortisol secretion and 8-oxodG/8-oxoGuo excretion in the patients. In the controls, there were positive correlations between 8-oxodG/8 ocoGuo excretion and 9AM plasma cortisol, but no associations to perceived stress. In an animal study of experimentally induced chronic stress performed in metabolism cages, we found no increase in urinary 8-oxodG/8-oxoGuo or cerebral (hippocampal and frontal cortex) levels of oxidatively generated nucleic acid damage. However, there was a trend towards an increased expression of genes involved in DNA repair, possibly reflecting a compensatory mechanism. In a study of 220 elderly, mostly healthy individuals from the Italian InChianti cohort, we found a significant association between the 24 h urinary cortisol excretion and the excretion of 8-oxodG/8-oxoGuo, determined in the same samples. Collectively, the studies could not confirm an association between psychological stress and oxidative stress on nucleic acids. Systemic oxidatively generated DNA/RNA damage was increased in schizophrenia, and linked to cortisol levels in healthy humans. Finally, the cerebral repair of DNA may be an aspect of the adaptation that, to our knowledge, has not previously been addressed. PMID- 23809981 TI - Risk factors for developing atopic dermatitis. AB - The aim of this thesis was to investigate possible risk factors affecting the development of AD. AD is a frequent disease among children and has a substantial impact on the lives of both the child and its family. A better understanding of the disease would enable better treatment, prevention and information to the families involved. Previous risk factor studies have been hampered by an unsuitable study design and/or difficulties in standardization when diagnosing AD, which limit their conclusions. In paper I, we conducted a traditional cross sectional analysis testing 40 possible risk factors for developing AD at 3 years of age. Our data suggested a strong heredity of AD and confirmed the risk associated with the non-functional FLG allele mutations after adjustments for confounders. Besides this mother's dermatitis and father's allergic rhinitis were found to increase the risk of AD. Perinatal exposure to dog was the only environmental exposure that significantly reduced the disease manifestation, suggesting other, yet unknown environmental factors affecting the increasing prevalence of AD in children. Length at birth was shown to be inversely associated with the risk of later developing AD. This traditional risk factor analysis led to two borderline significant results: duration of exclusive breastfeeding and mother's alcohol intake during the 3rd trimester. Since these possible two risk factors could neither be rejected nor accepted, we decided to do two in-depth studies, further investigating these, using longitudinal data information and data analysis instead of the traditional cross-sectional approach (paper II & III). In paper II, we investigated the risk of developing AD and wheezy symptoms until age 2 years depending on duration of breastfeeding. We found an increased risk of AD, but a protective effect on wheezy disorders in infancy from exclusive breastfeeding. The effect of exclusive breastfeeding on the risk of development of AD was significant after adjustment for demographics, FLG variants R501X and 2282del4 status, parent's AD and pets at home (RR 2.09, 95% CI 1.15-3.80, p=0.016). In addition, there was a significant effect of duration of exclusive breastfeeding (p=0.043), as the relative risk of AD was increased in proportion to increased duration of breastfeeding. The risk associated with exclusive breastfeeding was not explained by the fatty acid composition of mother's milk, though a trend showed higher risk of AD if mother's milk had low concentrations of n-3 fatty acids. In paper III, we found that alcohol intake during pregnancy was associated with a significantly higher risk of developing AD in the offspring, with the effect persisting throughout the whole 7 years follow-up period (HR 1.44, 95% CI 1.05-1.99, p=0.024). The increased risk was still significant after confounder adjustment for mother's education, AD and smoking habits during the 3rd trimester. There was no association between alcohol intake during pregnancy and other atopic endpoints (wheeze episodes, asthma, allergic rhinitis, blood eosinophil count, total IgE, sensitization, cord blood IgE and nasal eosinophilia). However, the underlying explanation was not clear. The thesis is based on data collected as part of the ongoing COPSAC cohort. The cohort is a longitudinal, prospective birth cohort following 411 children born to mothers with asthma. This selection of high-risk children restricts the interpretation of the results and they cannot necessarily be expanded to apply to the general population. PMID- 23809983 TI - Pain, pain catastrophizing, and history of intentional overdoses and attempted suicide. AB - BACKGROUND: The management of pain patients with analgesics is challenging, with one of the risks being overdose with prescribed medications and death. In this study, we examined relationships between pain and pain catastrophizing, and past history of intentional overdoses and suicide attempts. METHOD: Using a cross sectional approach and a self-report survey methodology, we examined 239 consecutive internal medicine outpatients in the United States. We inquired about pain "today, over the past month," and "over the past year;" and assessed pain catastrophizing with the Pain Catastrophizing Scale (PCS), past histories of intentional overdoses, and suicide attempts. RESULTS: There were statistically significant relationships between all of the pain variables, as well as PCS scores, and history of intentional overdoses. There were also statistically significant relationships between all of the pain variables, as well as PCS scores, and history of suicide attempts. CONCLUSIONS: Although we cannot discern causal relationships, findings indicate that patients with pain complaints and pain catastrophizing have a greater likelihood of having past histories of intentional overdoses and suicide attempts. We discuss the potential implications of these findings. PMID- 23809984 TI - Genetic and antigenic analyses of Porphyromonas gingivalis FimA fimbriae. AB - The periodontal pathogen Porphyromonas gingivalis generally expresses two distinct fimbriae, FimA and Mfa1, which play a role in biofilm formation. The fimA gene that encodes FimA fimbrilin is polymorphic, and polymerase chain reaction analysis has identified six genotypes called types I-V and Ib. We found recently that fimbriae exhibit antigenic heterogeneity among the genotypes. In the present study, we analysed the fimA DNA sequences of 84 strains of P. gingivalis and characterized the antigenicity of FimA fimbriae. Strains analysed here comprised 10, 16, 29, 13, 10 and 6 strains of types I, Ib, II, III, IV and V, respectively. DNA sequencing revealed that type Ib does not represent a single cluster and that type II sequences are remarkably diverse. In contrast, the fimA sequences of the other types were relatively homogeneous. Antigenicity was investigated using antisera elicited by pure FimA fimbriae of types I-V. Antigenicity correlated generally with the respective genotype. Type Ib strains were recognized by type I antisera. However, some strains showed cross reactivity, especially, many type II strains reacted with type III antisera. The levels of fimbrial expression were highly variable, and expression was positively correlated with ability of biofilm formation on a saliva-coated plate. Further, two strains without FimA and Mfa1 fimbriae expressed fimbrial structures, suggesting that the strains produce other types of fimbriae. PMID- 23809985 TI - Tail-end troubles: imaging of soft-tissue buttock tumours. AB - Primary soft-tissue buttock tumours are relatively common entities, although they are infrequently reported in the literature. The buttock can be a difficult anatomical site to treat soft-tissue tumours due to the proximity of the sciatic nerve and the propensity of tumours at this site to extend into the pelvis and perineum. Therefore, the radiologist plays an important role in the multidisciplinary assessment of these lesions. Cross-sectional imaging, principally magnetic resonance imaging, is used to determine the exact location and extension of the tumour. Furthermore, certain tumours have characteristic imaging appearances that can help to establish a suitably ordered differential diagnosis. From our prospectively maintained database at The Royal Marsden Hospital, including 225 cases that were treated at the Sarcoma Unit over a 30 year period, we present examples of benign and malignant primary soft-tissue buttock tumours and describe the pertinent imaging characteristics, with emphasis on computed tomography and magnetic resonance imaging findings. PMID- 23809982 TI - Recombinant streptokinase suppositories in the treatment of acute haemorrhoidal disease. Multicentre randomized double-blind placebo-controlled trial (THERESA 2). AB - AIM: A four-arm multicentre randomized double-blind placebo-controlled trial was undertaken to assess the effect and safety of suppositories containing recombinant streptokinase (rSK) at two dose levels (100,000 IU and 200,000 IU) with sodium salicylate (SS) compared with placebo and SS for the treatment of acute haemorrhoidal disease. METHOD: Patients with acute symptoms of haemorrhoids were randomized to four treatment groups: (I) placebo, (II) SS, (III) SS + rSK 100,000 IU and (IV) SS + rSK 200,000 IU per suppository. Inpatient treatment was by four suppositories given every 6 h to discharge at 24 h. Evaluations were made at the time of discharge (24 h) and at 3, 5 and 20 days later. The main end-point was the degree of relief of pain, oedema and reduction in the size of the lesion by 90% on day 5. Adverse events and the occurrence of anti-SK antibodies were also determined. RESULTS: Eighty patients were included. Respective response rates in the four groups were 16%, 30%, 25% and 52%. In the last group there was a significant difference (36.8%) compared with control (95% CI 7.0-58.4%). The time to response was significantly shorter (median 5 days) in the 200,000 IU rSK group with respect to the others. There were no adverse events attributable to the treatment. No increase in anti-SK antibodies was detected 20 days after treatment. CONCLUSION: Suppositories with 200,000 IU rSK showed a significant improvement in symptoms of acute haemorrhoids, with an adequate safety profile. PMID- 23809986 TI - Do antibiotics decrease implant failure and postoperative infections? A systematic review and meta-analysis. AB - The purpose of this study was to systematically review and perform a comprehensive meta-analysis of the current literature to answer the following question: among patients receiving dental implants, does the use of antibiotics, when compared with a control group, reduce the frequency of implant failure and postoperative infection? A manual and electronic PubMed search of the literature was made to identify randomized controlled trials (RCTs) on the efficacy of antibiotics compared with a control group (not receiving antibiotics or receiving placebo). Four RCTs were included in the final review. These four RCTs grouped a total of 2063 implants and a total of 1002 patients. Antibiotic use significantly lowered the implant failure rate (P = 0.003), with an odds ratio of 0.331, implying that antibiotic treatment reduced the odds of failure by 66.9%. The number needed to treat (NNT) to prevent one patient from having an implant failure was 48 (95% confidence interval 31-109). In contrast, antibiotic use did not significantly reduce the incidence of postoperative infection (P = 0.754). Based on the results of this meta-analysis, and pending further research in the field, it can be concluded that there is evidence in favour of systematic antibiotic use in patients receiving dental implants, since such treatment significantly reduces implant failure. In contrast, antibiotic use does not exert a significant preventive effect against postoperative infection. Our recommendations for future research focus on the performance of large-scale RCTs to identify the best choice of antibiotic, timing of administration, and dose. Increased effort is also required to reach consensus and define the most effective antibiotic treatment protocol for patients who are allergic to beta lactams and for those who are not. PMID- 23809987 TI - Ocular complications after posterior superior alveolar nerve block: a case of trochlear nerve palsy. AB - Many intraoperative complications occurring during third molar surgery are described in the literature. Unilateral trochlear nerve palsy secondary to dental anaesthesia is a rare complication. We report the case of a 36-year-old healthy man, ASA I classification, requiring upper third molar extraction. Articaine 1:200,000 epinephrine for right posterior superior alveolar (PSA) nerve block was administered locally in the mucobuccal fold above the upper third molar. A few minutes after PSA nerve block the patient experienced double-vision. The patient was subsequently visited by an ophthalmologist and the condition was diagnosed as transient unilateral vertical diplopia due to temporary paralysis of the superior oblique muscle as a result of the anaesthetic solution involving the IV cranial nerve. The authors report this unusual case and discuss the possible anatomical pathways that might explain this rare phenomenon. PMID- 23809988 TI - Maxillary sinus recovery and nasal ventilation after Le Fort I osteotomy: a prospective clinical, endoscopic, functional and radiographic evaluation. AB - The condition of the maxillary sinus is not routinely assessed before a Le Fort I osteotomy. Performing this procedure in an infected sinus might account for a considerable proportion of the complications, such as excessive bleeding and sinusitis. The aim of this study was to evaluate the maxillary sinus and nasal ventilation after Le Fort I osteotomy. Twenty patients were evaluated before and 2 months after surgery using validated questionnaires for sinonasal complaints (RSOM-31 and VAS score), nasal endoscopy, peak nasal inspiratory flow (PNIF), and a computed tomography (CT) scan. There were no differences in complaints before and 2 months after surgery (P>0.24). Also, the PNIF did not change significantly (P=0.10). On CT evaluation before surgery, a previously unnoted sinusitis was diagnosed in two patients. Postoperatively, a thickened sinus mucosa was present in all patients near the osteotomy line, the osteosyntheses, and around sequesters. This report describes maxillary sinus evaluation after Le Fort I osteotomy in a more comprehensive way by using CT. The Le Fort I procedure did not influence already existing physical or mental complaints, and nasal ventilation was not negatively affected. However, evaluation of sinonasal pathology should be emphasized in the preoperative work-up. PMID- 23809989 TI - The genetics of equine osteochondrosis. AB - Osteochondrosis (OC) develops in growing horses due to disturbed differentiation and maturation of cartilage, particularly at the predilection sites of the fetlock, hock and stifle joints. Horses with osteochondrotic lesions are at a high risk of developing orthopaedic problems later in life. This article briefly reviews the published heritability estimates for OC and offers perspectives for selection in the horse industry. Heritabilities for OC in Warmblood and Standardbred horses have been estimated at 0.1-0.4 in animal threshold models. Whole genome scans using microsatellites have identified 14 quantitative trait loci (QTL) and the eight most important QTL have been refined using dense marker maps. Genome-wide association studies with single nucleotide polymorphisms revealed further QTL in Thoroughbred, Standardbred and Hanoverian horses. Only a few QTL have corresponding locations among the different breeds. Comparative genomics using positional candidate genes and next-generation-sequencing may lead to new insights into the genetic determination of equine OC and might help in understanding the molecular mechanisms of its pathogenesis. Implementation of selection schemes based on breeding values, or even genomic selection against OC, should be considered as an option for improving equine musculoskeletal health. PMID- 23809990 TI - Replication timing regulation of eukaryotic replicons: Rif1 as a global regulator of replication timing. AB - Origins of DNA replication on eukaryotic genomes have been observed to fire during S phase in a coordinated manner. Studies in yeast indicate that origin firing is affected by several factors, including checkpoint regulators and chromatin modifiers. However, it is unclear what the mechanisms orchestrating this coordinated process are. Recent studies have identified factors that regulate the timing of origin activation, including Rif1 which plays crucial roles in the regulation of the replication timing program in yeast as well as in higher eukaryotes. In mammalian cells, Rif1 appears to regulate the structures of replication timing domains through its ability to organize chromatin loop structures. Regulation of chromatin architecture by Rif1 may be linked to other chromosome transactions including recombination, repair, or transcription. This review summarizes recent progress in the effort to elucidate the regulatory mechanisms of replication timing of eukaryotic replicons. PMID- 23809991 TI - Percutaneous flexor tenotomy for preventing and treating toe ulcers in people with diabetes mellitus. AB - INTRODUCTION: The purpose was to examine the effectiveness of flexor tenotomy in a modified technique to prevent and heal neuropathic and neuroischaemic pressure ulcers on the tip of the toe in claw- or hammer-toe deformities in people with diabetes. PATIENTS AND METHODS: A consequetive 4 years series of 38 patients was retrospectively studied. Percutaneous tenotomy on the superficial and deep flexor tendons was performed in 65 toes through a small transverse plantar stab incision just proximal to the web level. There were 16 (42%) patients with 27 ulcerated toes and 22 (58%) patients with 38 toes with impending ulceration. Ten patients had neuropathic ulcers and six patients had neuro-ischaemic ulcers. Sixteen patients (42%) had macrovascular disease. Ten (26%) had proliferative rethinopathy, 7 (18%) macroalbuminuria and 18 (47%) microalbuminuria. RESULTS: All surgical incisions healed uneventfully. Twenty-five (93%) of the toe ulcers healed in median 21 days (range 7-224 days). Three patients had recurrence of the ulcer. There were no infections in the incisions or toe amputations. No patients treated with preventive tenotomy experienced toe ulceration. No complications were recorded in neuro-ischaemic ulcers. During the follow up period of median 31 months (range 2-48 months) 33 other ulcers were recorded in 18 patients (47%). One of these developed a transfer ulceration under the adjacent metatarso phalangeal joint and another had a late pressure ulcer on a neighbouring toe. The other 31 ulcers were not related to ulcers treated with tenotomy. CONCLUSION: Tenotomy is a simple, safe and effective procedure for preventing and treating distal plantar neuropathic toe ulcers in claw toe or hammer toe deformities in people with diabetes with or without serious co-morbidity. The results suggest that tenotomy should be considered also in neuroischaemic ulcers. PMID- 23809993 TI - Surgeons and imaging-are self-reads a mistake? PMID- 23809992 TI - Normal standards for computer-ECG programs for prognostically and diagnostically important ECG variables derived from a large ethnically diverse female cohort: the Women's Health Initiative (WHI). AB - BACKGROUND: Substantial new information has emerged recently about the prognostic value for a variety of new ECG variables. The objective of the present study was to establish reference standards for these novel risk predictors in a large, ethnically diverse cohort of healthy women from the Women's Health Initiative (WHI) study. METHODS AND RESULTS: The study population consisted of 36,299 healthy women. Racial differences in rate-adjusted QT end (QT(ea)) and QT peak (QT(pa)) intervals as linear functions of RR were small, leading to the conclusion that 450 and 390 ms are applicable as thresholds for prolonged and shortened QT(ea) and similarly, 365 and 295 ms for prolonged and shortened QT(pa), respectively. As a threshold for increased dispersion of global repolarization (T(peak)T(end) interval), 110 ms was established for white and Hispanic women and 120 ms for African-American and Asian women. ST elevation and depression values for the monitoring leads of each person with limb electrodes at Mason-Likar positions and chest leads at level of V1 and V2 were first computed from standard leads using lead transformation coefficients derived from 892 body surface maps, and subsequently normal standards were determined for the monitoring leads, including vessel-specific bipolar left anterior descending, left circumflex artery and right coronary artery leads. The results support the choice 150 MUV as a tentative threshold for abnormal ST-onset elevation for all monitoring leads. Body mass index (BMI) had a profound effect on Cornell voltage and Sokolow-Lyon voltage in all racial groups and their utility for left ventricular hypertrophy classification remains open. CONCLUSIONS: Common thresholds for all racial groups are applicable for QT(ea), and QT(pa) intervals and ST elevation. Race-specific normal standards are required for many other ECG parameters. PMID- 23809994 TI - Ileal or ileocecal resection for chronic radiation enteritis with small bowel obstruction: outcome and risk factors. AB - BACKGROUND: The choice of the optimum surgical procedure for chronic radiation enteritis (CRE) has not reached a consensus over the years. This study aimed to evaluate the outcomes in patients undergoing ileal or ileocecal resection for CRE and to identify predictive risk factors for postoperative complications. METHODS: Univariate and multivariate analyses of a retrospectively gathered database (2001 to 2011) were performed on a cohort of patients (N = 158) undergoing ileal or ileocecal resection for CRE obstruction at a single institution. RESULTS: Overall and major morbidity rates were 57.0% (90 patients) and 28.5% (45 patients), respectively. Surgical complications occurred in 20 patients (12.7%) and postoperative permanent parenteral nutrition dependence was 12.1% (12 of 99 patients). Multivariate analysis determined that an American Association of Anesthesiologists' score of III or higher, anemia, low platelet level, intraoperative transfusion, presence of radiation uropathy, and experience of surgeons were independent risk factors for Clavien-Dindo grades III to V morbidity. CONCLUSIONS: Ileal or ileocecal resection for CRE has an acceptable risk of permanent intestinal failure and surgical complications. This study also provides the 1st evidence of predictive risk factors for postoperative morbidity of ileal or ileocecal resection for CRE. PMID- 23809995 TI - Effects of montelukast on the healing of ischemic colon anastomoses. AB - BACKGROUND: The aim of this study was to examine whether treatment with montelukast, a selective leukotriene antagonist, would affect anastomotic healing in a reperfused colon rat model with remote ischemia/reperfusion injury. METHODS: Rats (n = 12 per group) were intraperitoneally administered normal saline or 10 mg/kg montelukast sodium 60 minutes before and for 5 days after surgery. Ischemia was induced for 45 minutes through superior mesenteric artery occlusion. A left colon anastomosis was made. Blood and perianastomotic tissue samples were obtained on postoperative day 5. RESULTS: Mean anastomotic bursting pressures of the control and montelukast groups were 159.17 +/- 29.99 and 216.67 +/- 26.40, respectively (P < .001). Compared with saline, montelukast treatment increased the mean tissue hydroxyproline level (2.46 +/- .30 vs 3.61 +/- .33 MUmol/L) and decreased tissue caspase-3 activity (36.06 +/- 5.72 vs 21.78 +/- 3.87) and malondialdehyde levels (3.43 +/- .34 vs 2.29 +/- .34 nmol/g) (P < .001 for all). Other plasma markers of injury also showed differences. CONCLUSIONS: Montelukast prevented ischemia/reperfusion-induced damage in a rat model of colonic anastomotic wound healing. PMID- 23809996 TI - The role of diabetes and other co-morbidities on survival after esophageal cancer surgery in a population-based study. AB - BACKGROUND: There is limited knowledge on how diabetes and other comorbidities influence the survival of patients undergoing curative esophageal cancer surgery. METHODS: A population-based and prospective cohort study included patients who underwent surgical resection for esophageal or cardia cancer in Sweden from 2001 to 2005, with follow-up until 2011. Associations between diabetes and other comorbidities in relation to postoperative mortality were analyzed using Cox proportional-hazards regression with adjustment for potential confounding factors. RESULTS: Among 609 patients, 67 (11%) with diabetes had no increased risk for mortality compared with those without diabetes (hazard ratio, .81; 95% confidence interval, .60 to 1.09). Compared with patients without any predefined comorbidities, those with 1 (hazard ratio, 1.15; 95% confidence interval, .93 to 1.43) or >=2 comorbidities (hazard ratio, 1.05; 95% confidence interval, .83 to 1.33) had no statistically significantly increased risk for mortality. CONCLUSIONS: This study revealed no strongly increased risk for mortality in patients with diabetes or other comorbidities selected for esophageal cancer surgery. PMID- 23809997 TI - Mapping glycoconjugate-mediated interactions of marine Bacteroidetes with diatoms. AB - The degradation of diatoms is mainly catalyzed by Bacteroidetes and this process is of global relevance for the carbon cycle. In this study, a combination of catalyzed reporter deposition-fluorescence in situ hybridization (CARD-FISH) and fluorescent lectin binding analysis (FLBA) was used to identify and map glycoconjugates involved in the specific interactions of Bacteroidetes and diatoms, as well as detritus, at the coastal marine site Helgoland Roads (German Bight, North Sea). The study probed both the presence of lectin-specific extracellular polymeric substances (EPS) of Bacteroidetes for cell attachment and that of glycoconjugates on diatoms with respect to binding sites for Bacteroidetes. Members of the clades Polaribacter and Ulvibacter were shown to form microcolonies within aggregates for which FLBA indicated the presence of galactose containing slime. Polaribacter spp. was shown to bind specifically to the setae of the abundant diatom Chaetoceros spp., and the setae were stained with fucose-specific lectins. In contrast, Ulvibacter spp. attached to diatoms of the genus Asterionella which bound, among others, the mannose-specific lectin PSA. The newly developed CARD-FISH/FLBA protocol was limited to the glycoconjugates that persisted after the initial CARD-FISH procedure. The differential attachment of bacteroidetal clades to diatoms and their discrete staining by FLBA provided evidence for the essential role that formation and recognition of glycoconjugates play in the interaction of bacteria with phytoplankton. PMID- 23809998 TI - Should European perinatal indicators be revisited? AB - OBJECTIVES: Our study presents the results of a survey of physicians and/or researchers working in 21 European countries, on their opinion about the relevance of perinatal indicators, in order to compare it with the EURO-PERISTAT recommendations. STUDY DESIGN: In this cross-sectional study, we selected 21 out of the initial set of 34 indicators of the national data supply on the European Perinatal Health Report, and added four other indicators based on expert opinion. The relative relevance of these 25 perinatal indicators was then rated by 134 respondents--expert physicians and/or researchers who have published in perinatal medicine--through a web-based survey. We summarized our data using descriptive statistics. RESULTS: The top five perinatal indicators, according to the respondents' rating were: neonatal mortality rate by gestational age, birth weight and plurality; percentage of highly preterm babies delivered in units without a NICU; prevalence of severe maternal morbidity; severe neonatal morbidity among babies at high risk and prevalence of hypoxic-ischemic encephalopathy. Of these top five indicators, however, only neonatal mortality rate by gestational age, birth weight and plurality was considered a core indicator, in 2003. Moreover, severe neonatal morbidity among babies at high risk and prevalence of hypoxic-ischemic encephalopathy, that were considered in 2003 as requiring further development, were now considered by the respondents as highly relevant. CONCLUSIONS: Current views of European physicians and/or researchers working in the perinatal field may not be in agreement with the EURO PERISTAT recommendations. A revision of the set of perinatal indicators is, therefore, mandatory if a more comprehensive view of health care systems performance across Europe is to be achieved. PMID- 23809999 TI - Offspring birth weight and maternal fasting lipids in women screened for gestational diabetes mellitus (GDM). AB - OBJECTIVES: Maternal lipid metabolism is altered during pregnancy but little is known about the influence of these alterations on either intrauterine fetal development or maternal wellbeing. The purpose of this study was to examine the relationship between both fasting cholesterol and triglycerides and offspring birth weight in women screened selectively for gestational diabetes mellitus (GDM). STUDY DESIGN: In a prospective observational study in a University Maternity Hospital, women were recruited at their convenience when they were screened for GDM with a diagnostic 75 g oral glucose tolerance test (OGTT). An additional sample was taken for a lipid profile at the time the fasting glucose was obtained. Clinical and socio-demographic details were recorded. RESULTS: Of the 189 women recruited, the mean age was 32 years, 35.4% (n=67) were primigravidas, 44.1% (n=82) were obese and 11.6% (n=22) had an abnormal OGTT. On univariate analysis, increasing birth weight was correlated positively with multiparity, first trimester body mass index (BMI), GDM and hypertriglyceridaemia but not with cholesterol levels. On multivariate analysis, increased birth weight correlated positively only with hypertriglyceridaemia. CONCLUSIONS: This study provides further evidence that maternal hypertriglyceridaemia is important in programming intrauterine fetal growth and raises questions about whether women should be screened selectively for dyslipidaemia before, during and after pregnancy. PMID- 23810000 TI - The benefit of adjuvant chemotherapy combined with postoperative radiotherapy for endometrial cancer: a meta-analysis. AB - The objective of our study was to determine whether adjuvant chemotherapy combined with postoperative radiotherapy would have benefits for the disease-free survival and overall survival in patients with high-risk endometrial cancer. Electronic searches for studies of adjuvant chemotherapy combined with postoperative radiotherapy in endometrial cancer patients between March 1971 and March 2012 were made on MEDLINE, SCOPUS, and the Cochrane library. Articles with more than 4 stars on the Newcastle-Ottawa scale or a score of more than 4 on the modified Jadad scale were included. A meta-analysis was performed, and pooled hazard ratios (HR) of progression-free survival (PFS) and overall survival (OS) between patients whose adjuvant chemotherapy was combined with radiotherapy (the CTx+RTx group) and patients with adjuvant radiotherapy only (the RTx group) were derived from the fixed effect model or random effect model. Three observational studies and 3 randomized clinical trials (RCTs) were included in the final analysis. Subgroup analysis for FIGO stage showed that the CTx+RTx group had a more significant survival benefit compared to that of the RTx group in advanced stage endometrial cancer (OS HR 0.53, 95% CI 0.36-0.80; PFS HR 0.54, 95% CI 0.37 0.77), but no significant benefit in early stage endometrial cancer (OS HR 0.96, 95% CI 0.70-1.32; PFS HR 1.00, 95% CI 0.39-2.58). This meta-analysis suggests that adjuvant chemotherapy combined with postoperative radiotherapy could probably reduce disease progression and overall death in patients with advanced stage disease. In order to examine whether the multimodal treatment has benefit in high-risk endometrial cancer, we need further large-scale RCTs. PMID- 23810001 TI - Pharmacovigilance monitoring of a cohort of pregnant women vaccinated against influenza A(H1N1) variant virus in the Nord-Pas de Calais region of northern France. AB - OBJECTIVE: During the 2009-2010 influenza A variant virus (A(H1N1)v) pandemic in France, a national pharmacovigilance program was set up to monitor vaccinated, pregnant women, especially the reactogenicity of the vaccine and its impact on the outcome of pregnancy and on the newborn. Here, we present the results for the cohort of pregnant women constituted in the Nord-Pas de Calais region of northern France. STUDY DESIGN: Vaccinated pregnant women were included in the study by the region's vaccination centers between November 2009 and April 2010. RESULTS: Eight hundred and six pregnant women were included and 781 were followed up until delivery. The risk of adverse events after vaccination and the maternal, fetal and neonatal medical conditions in our cohort did not appear different from the risk observed in the general population. CONCLUSIONS: Our results suggest that A(H1N1)v vaccination of pregnant women did not have an adverse impact on the pregnancies' course and outcome. PMID- 23810003 TI - The epidemiology and molecular mechanisms linking obesity, diabetes, and cancer. AB - The worldwide epidemic of obesity is associated with increasing rates of the metabolic syndrome and type 2 diabetes. Epidemiological studies have reported that these conditions are linked to increased rates of cancer incidence and mortality. Obesity, particularly abdominal obesity, is associated with insulin resistance and the development of dyslipidemia, hyperglycemia, and ultimately type 2 diabetes. Although many metabolic abnormalities occur with obesity and type 2 diabetes, insulin resistance and hyperinsulinemia appear to be central to these conditions and may contribute to dyslipidemia and altered levels of circulating estrogens and androgens. In this review, we will discuss the epidemiological and molecular links between obesity, type 2 diabetes, and cancer, and how hyperinsulinemia and dyslipidemia may contribute to cancer development. We will discuss how these metabolic abnormalities may interact with estrogen signaling in breast cancer growth. Finally, we will discuss the effects of type 2 diabetes medications on cancer risk. PMID- 23810002 TI - Estrogen-mediated mechanisms to control the growth and apoptosis of breast cancer cells: a translational research success story. AB - The treatment and prevention of solid tumors have proved to be a major challenge for medical science. The paradigms for success in the treatment of childhood leukemia, Hodgkin's disease, Burkett's lymphoma, and testicular carcinoma with cytotoxic chemotherapy did not translate to success in solid tumors--the majority of cancers that kill. In contrast, significant success has accrued for patients with breast cancer with antihormone treatments (tamoxifen or aromatase inhibitors) that are proved to enhance survivorship, and remarkably, there are now two approved prevention strategies using either tamoxifen or raloxifene. This was considered impossible 40 years ago. We describe the major clinical advances with nonsteroidal antiestrogens that evolved into selective estrogen receptor modulators (SERMs) which successfully exploited the ER target selectively inside a woman's body. The standard paradigm that estrogen stimulates breast cancer growth has been successfully exploited for over 4 decades with therapeutic strategies that block (tamoxifen, raloxifene) or reduce (aromatase inhibitors) circulating estrogens in patients to stop breast tumor growth. But this did not explain why high-dose estrogen treatment that was the standard of care to treat postmenopausal breast cancer for 3 decades before tamoxifen caused tumor regression. This paradox was resolved with the discovery that breast cancer resistance to long-term estrogen deprivation causes tumor regression with physiologic estrogen through apoptosis. The new biology of estrogen action has been utilized to explain the findings in the Women's Health Initiative that conjugated equine estrogen alone given to postmenopausal women, average age 68, will produce a reduction of breast cancer incidence and mortality compared to no treatment. Estrogen is killing nascent breast cancer cells in the ducts of healthy postmenopausal women. The modulation of the ER using multifunctional medicines called SERMs has provided not only significant improvements in women's health and survivorship not anticipated 40 years ago but also has been the catalyst to enhance our knowledge of estrogen's apoptotic action that can be further exploited in the future. PMID- 23810004 TI - Sex hormone receptors in breast cancer. AB - The dependency of certain breast cancers on estrogen is undeniably one of the most important observations in oncology. Since this early observation, there has been a tremendous effort to define the precise roles of the estrogen receptor (ER) in the pathogenesis of breast cancer. Estrogen signaling pathways can also be exploited as effective targets for cancer treatment. Both ligand-dependent and ligand-independent receptor activation pathways have been successfully blocked by hormonal therapies including selective ER modulators such as tamoxifen, by blocking and accelerating the degradation of ER (fulvestrant), and by depleting tissue levels of estrogen (aromatase inhibitors). Because of the immense prognostic and predictive value of the ER and PR receptor, accurately defining hormone dependency is also of paramount importance. Despite this avalanche of discovery and development resulting in improved outcome for the patient, resistance to these therapies, both intrinsic and acquired, is well known. Uncovering the various mechanisms of resistance has deepened scientific understanding of posttranslational modifications of these receptors, as well as their cross talk with other receptor families such as the HER-2/neu receptor. The recent discovery that orphan estrogen-related receptors may also play an important role in breast cancer is just starting to be appreciated. A clear understanding of the historical perspective and the intricacies of ER structure and function is required to improve current therapeutic strategies for breast cancer. PMID- 23810005 TI - Modulation of estrogen receptor alpha activity and expression during breast cancer progression. AB - Seventy percent of breast tumors express the estrogen receptor (ER), which is generally considered to predict a better outcome relative to ER-negative tumors, as they often respond to antiestrogen therapies. During cancer progression, mammary tumors can escape from estrogen control, resulting in the acquisition of invasive properties and resistance to treatment. ER expression is a dynamic phenomenon and is finely regulated at numerous levels, including the gene, mRNA, and protein levels. As a consequence, many molecular mechanisms have been implicated in modulating ER activity and estrogen signaling in mammary cancer. In fact, one-third of ER-positive breast cancer cells do not respond to first-line endocrine therapies, and a large subset of relapsing tumors retain ER expression. Increased knowledge of these mechanisms has led to the development of better prognostic methods and targeted therapies for patients; however, additional research is still needed to improve patient survival. In this chapter, we focus on the signaling pathways leading to changes in or loss of ER activity in breast cancer progression. PMID- 23810006 TI - Targeting progesterone receptors in breast cancer. AB - Hormone receptors represent the earliest biomarkers used in breast cancer not only as prognosis markers but, in addition, to decide treatment. However, mostly estrogen receptors have been used as therapeutic targets. There is compelling evidence indicating that progesterone receptors (PRs) play a hierarchical role in breast cancer growth and that they might be potentially used to improve the success of endocrine treatments. The two PR isoforms, PR-A and PR-B, play differential roles in regulating gene expression. Tumors overexpressing one or other PR isoform may respond different to endocrine treatment. In this chapter, we highlight the evidence regarding progestins as promoters or inhibitors of cell proliferation in order to understand the dual role of PR in regulating tumor growth, underscoring thus the need of biomarkers to identify which patients may benefit with an antiprogestin/progestin treatment. PMID- 23810008 TI - FOXP1 and estrogen signaling in breast cancer. AB - Breast cancers are considered to be primarily regulated by estrogen signaling pathways because estrogen-dependent proliferation is observed in the majority of breast cancer cases. Thus, hormone therapy using antiestrogen drugs such as tamoxifen is effective for breast cancers expressing estrogen receptor alpha (ERalpha). However, acquired resistance during the endocrine therapy is a critical unresolved problem in breast cancer. Recently, a forkhead transcription factor FOXA1 has been reported to play an important role in the regulation of ERalpha-mediated transcription and proliferation of breast cancer. Interestingly, immunohistochemical analysis of breast cancer specimens has revealed that nuclear immunoreactivities of FOXP1 as well as those of FOXA1 are positively correlated with hormone receptor status, including ERalpha and progesterone receptor. In particular, the double-positive immunoreactivities of FOXP1 and FOXA1 are significantly associated with a favorable prognosis for survival of breast cancer patients receiving adjuvant tamoxifen therapy. The functions of FOXP1 and FOXA1 have been characterized in cultured cells; further, similar to FOXA1, FOXP1 is assumed to be a critical transcription factor for ERalpha signaling, and both forkhead transcription factors can serve as predictive factors for acquired endocrine resistance in breast cancer. PMID- 23810007 TI - The hyperplastic phenotype in PR-A and PR-B transgenic mice: lessons on the role of estrogen and progesterone receptors in the mouse mammary gland and breast cancer. AB - Progesterone receptor (PR) belongs to the superfamily of steroid receptors and mediates the action of progesterone in its target tissues. In the mammary gland, in particular, PR expression is restricted to the luminal epithelial cell compartment. The generation of estrogen receptor-alpha (ER) and PR knockout mice allowed the specific characterization of the roles of each of these in mammary gland development: ER is critical for ductal morphogenesis, whereas PR has a key role in lobuloalveolar differentiation. To further study the role PR isoforms have in mammary gland biology, transgenic mice overexpressing either the "A" (PR A) or the "B" (PR-B) isoforms of PR were generated. Overexpression of the A isoform of PR led to increased side branching, multilayered ducts, loss of basement membrane integrity, and alterations in matrix metalloproteinase activation in the mammary gland. Moreover, levels of TGFbeta1 and p21 were diminished and those of cyclin D1 increased. Interestingly, the phenotype was counteracted by antiestrogens, suggesting that ER is essential for the manifestation of the hyperplasias. Mice overexpressing the B isoform of PR had limited ductal growth but retained the ability to differentiate during pregnancy. Levels of latent and active TGFbeta1 were increased compared to PR-A transgenics. The phenotypes of these transgenic mice are further discussed in the context of the impact of progesterone on mammary stem cells and breast cancer. We conclude that an adequate balance between the A and B isoforms of PR is critical for tissue homeostasis. Future work to further understand the biology of PR in breast biology will hopefully lead to new and effective preventive and therapeutic alternatives for patients. PMID- 23810009 TI - Role of KLF5 in hormonal signaling and breast cancer development. AB - Steroid hormones, including ovarian steroid hormones progesterone and estrogen and androgen, play vital roles in the development of normal mammary gland and breast cancer via their receptors. How these hormones regulate these physiological and pathological processes remains to be elucidated. Kruppel-like factor 5 (KLF5) is a transcription factor playing significant roles in breast carcinogenesis, whose expression has been shown to be regulated by hormones. In this review, the relationships among hormonal signaling, KLF5, and breast cancer are summarized and discussed. PMID- 23810010 TI - Dynamic regulation of steroid hormone receptor transcriptional activity by reversible SUMOylation. AB - Transcription complexes containing steroid hormone receptors (SRs) have been well characterized at selected canonical target genes. More recently, the advent of whole genome technologies has allowed for complete SR transcriptome analyses in diverse cell types and in response to a variety of cellular stimuli. These types of studies have revealed little overlap between the tissue or cell type-specific transcriptomes of a given SR, suggesting that all SRs are highly context dependent transcription factors. However, the mechanisms controlling SR promoter selectivity have not been fully elucidated. Many factors may influence SR promoter selectivity, including chromatin structure, cofactor availability, and posttranslational modifications to SRs and/or their numerous coregulators; this review focuses on the impact that covalent attachment of small ubiquitin-like modifier (SUMO) moieties to SRs (i.e., SUMOylation) have on the transcriptional regulation of SR target genes. PMID- 23810012 TI - The functional role of Notch signaling in triple-negative breast cancer. AB - The term "triple-negative breast cancer" (TNBC) is a heterogeneous subtype of breast cancer. Unfortunately, due to the lack of expression of hormone receptors and human epidermal growth factor receptor-2, therefore the lack of US Food and Drug Administration-approved targeted therapies, TNBC has the worst prognosis of all subtypes of breast cancer. Notch signaling has emerged as a pro-oncogene in several human malignancies and has particularly been associated with the triple negative subtype of breast cancer. This chapter explores the role of Notch signaling in triple negative and other subtypes of breast cancer, the relationship of Notch with other breast cancer biomarkers, prognostic indicators associated with Notch, and potential therapeutic strategies targeting Notch inhibition. Hopefully, better understanding of this signaling pathway in the future will lead to optimal molecular therapeutic treatments for TNBC patients, improving their quality of life and outcome. PMID- 23810011 TI - Beta-endorphin neuron regulates stress response and innate immunity to prevent breast cancer growth and progression. AB - Body and mind interact extensively with each other to control health. Emerging evidence suggests that chronic neurobehavioral stress can promote various tumor growth and progression. The biological reaction to stress involves a chemical cascade initiated within the central nervous system and extends to the periphery, encompassing the immune, endocrine, and autonomic systems. Activation of sympathetic nervous system, such as what happens in the "fight or flight" response, downregulates tumor-suppressive genes, inhibits immune function, and promotes tumor growth. On the other hand, an optimistic attitude or psychological intervention helps cancer patients to survive longer via increase in beta endorphin neuronal suppression of stress hormone levels and sympathetic outflows and activation of parasympathetic control of tumor suppressor gene and innate immune cells to destroy and clear tumor cells. PMID- 23810013 TI - ADAM22 as a prognostic and therapeutic drug target in the treatment of endocrine resistant breast cancer. AB - The development of breast cancer resistance to endocrine therapies may result from an increase in cellular plasticity, permitting the emergence of a hormone independent tumor. ADAM proteins are multidomain transmembrane proteins that have a diverse array of functions in both natural physiology and disease. A number of ADAM proteins have been implicated in the occurrence of breast cancer, including ADAM 9, ADAM12, ADAM15, ADAM17, ADAM22, and ADAM28. ADAM22 expression is driven by the coactivator protein SRC-1 in response to tamoxifen treatment in the resistant setting. ADAM22 is an ER-independent predictor of disease-free survival. LGI1 is a neuropeptide that binds ADAM22 in the nervous system. In addition to being a ligand for ADAM11, ADAM22, and ADAM23, LGI1 may play a role as a tumor suppressor. Furthermore, LGI1 may act to reduce cell migration and may impair proliferation. Therapies based on LGI1 may provide a building block for future therapies in ADAM22-positive breast cancer. PMID- 23810015 TI - Adherence rates and correlates in long-term hormonal therapy. AB - Breast cancer outcomes have improved markedly in the past few decades, due in part to the use of adjuvant hormonal therapy. To receive the optimal benefits of adjuvant therapies such as tamoxifen and aromatase inhibitors (AIs), patients need to take these agents orally each day for 5 years. Current evidence indicates that nonadherence is considerable and increases over time and the side effect profiles for tamoxifen and AIs present considerable barriers to optimal adherence. Interventions, both pharmacologic and nonpharmacologic, hold potential to treat adjuvant hormonal treatment side effects and improve adherence. More research and approaches to intervention to enhance the adherence need to be developed and tested. PMID- 23810017 TI - Turkey's democratic transition to universal health coverage. PMID- 23810014 TI - Alpha-actinin 4 and tumorigenesis of breast cancer. AB - Alpha-actinins (ACTNs) were originally identified as cytoskeletal proteins which cross-link filamentous actin to establish cytoskeletal architect that protects cells from mechanical stress and controls cell movement. Notably, unlike other ACTNs, alpha-actinin 4 (ACTN4) displays unique characteristics in signaling transduction, nuclear translocation, and gene expression regulation. Initial reports indicated that ACTN4 is part of the breast cancer cell motile apparatus and is highly expressed in the nucleus. These results imply that ACTN4 plays a role in breast cancer tumorigenesis. While several observations in breast cancer and other cancers support this hypothesis, little direct evidence links the tumorigenic phenotype with ACTN4-mediated pathological mechanisms. Recently, several studies have demonstrated that in addition to its role in coordinating cytoskeleton, ACTN4 interacts with signaling mediators, chromatin remodeling factors, and transcription factors including nuclear receptors. Thus, ACTN4 functions as a versatile promoter for breast cancer tumorigenesis and appears to be an ideal drug target for future therapeutic development. PMID- 23810018 TI - Antipsychotics for acute schizophrenia: making choices. PMID- 23810019 TI - Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. AB - BACKGROUND: The question of which antipsychotic drug should be preferred for the treatment of schizophrenia is controversial, and conventional pairwise meta analyses cannot provide a hierarchy based on the randomised evidence. We aimed to integrate the available evidence to create hierarchies of the comparative efficacy, risk of all-cause discontinuation, and major side-effects of antipsychotic drugs. METHODS: We did a Bayesian-framework, multiple-treatments meta-analysis (which uses both direct and indirect comparisons) of randomised controlled trials to compare 15 antipsychotic drugs and placebo in the acute treatment of schizophrenia. We searched the Cochrane Schizophrenia Group's specialised register, Medline, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for reports published up to Sept 1, 2012. Search results were supplemented by reports from the US Food and Drug Administration website and by data requested from pharmaceutical companies. Blinded, randomised controlled trials of patients with schizophrenia or related disorders were eligible. We excluded trials done in patients with predominant negative symptoms, concomitant medical illness, or treatment resistance, and those done in stable patients. Data for seven outcomes were independently extracted by two reviewers. The primary outcome was efficacy, as measured by mean overall change in symptoms. We also examined all-cause discontinuation, weight gain, extrapyramidal side-effects, prolactin increase, QTc prolongation, and sedation. FINDINGS: We identified 212 suitable trials, with data for 43 049 participants. All drugs were significantly more effective than placebo. The standardised mean differences with 95% credible intervals were: clozapine 0.88, 0.73-1.03; amisulpride 0.66, 0.53-0.78; olanzapine 0.59, 0.53-0.65; risperidone 0.56, 0.50-0.63; paliperidone 0.50, 0.39-0.60; zotepine 0.49, 0.31-0.66; haloperidol 0.45, 0.39-0.51; quetiapine 0.44, 0.35-0.52; aripiprazole 0.43, 0.34 0.52; sertindole 0.39, 0.26-0.52; ziprasidone 0.39, 0.30-0.49; chlorpromazine 0.38, 0.23-0.54; asenapine 0.38, 0.25-0.51; lurasidone 0.33, 0.21-0.45; and iloperidone 0.33, 0.22-0.43. Odds ratios compared with placebo for all-cause discontinuation ranged from 0.43 for the best drug (amisulpride) to 0.80 for the worst drug (haloperidol); for extrapyramidal side-effects 0.30 (clozapine) to 4.76 (haloperidol); and for sedation 1.42 (amisulpride) to 8.82 (clozapine). Standardised mean differences compared with placebo for weight gain varied from 0.09 for the best drug (haloperidol) to -0.74 for the worst drug (olanzapine), for prolactin increase 0.22 (aripiprazole) to -1.30 (paliperidone), and for QTc prolongation 0.10 (lurasidone) to -0.90 (sertindole). Efficacy outcomes did not change substantially after removal of placebo or haloperidol groups, or when dose, percentage of withdrawals, extent of blinding, pharmaceutical industry sponsorship, study duration, chronicity, and year of publication were accounted for in meta-regressions and sensitivity analyses. INTERPRETATION: Antipsychotics differed substantially in side-effects, and small but robust differences were seen in efficacy. Our findings challenge the straightforward classification of antipsychotics into first-generation and second-generation groupings. Rather, hierarchies in the different domains should help clinicians to adapt the choice of antipsychotic drug to the needs of individual patients. These findings should be considered by mental health policy makers and in the revision of clinical practice guidelines. FUNDING: None. PMID- 23810021 TI - Heterogeneity and clinical reality. PMID- 23810020 TI - Universal health coverage in Turkey: enhancement of equity. AB - Turkey has successfully introduced health system changes and provided its citizens with the right to health to achieve universal health coverage, which helped to address inequities in financing, health service access, and health outcomes. We trace the trajectory of health system reforms in Turkey, with a particular emphasis on 2003-13, which coincides with the Health Transformation Program (HTP). The HTP rapidly expanded health insurance coverage and access to health-care services for all citizens, especially the poorest population groups, to achieve universal health coverage. We analyse the contextual drivers that shaped the transformations in the health system, explore the design and implementation of the HTP, identify the factors that enabled its success, and investigate its effects. Our findings suggest that the HTP was instrumental in achieving universal health coverage to enhance equity substantially, and led to quantifiable and beneficial effects on all health system goals, with an improved level and distribution of health, greater fairness in financing with better financial protection, and notably increased user satisfaction. After the HTP, five health insurance schemes were consolidated to create a unified General Health Insurance scheme with harmonised and expanded benefits. Insurance coverage for the poorest population groups in Turkey increased from 2.4 million people in 2003, to 10.2 million in 2011. Health service access increased across the country in particular, access and use of key maternal and child health services improved to help to greatly reduce the maternal mortality ratio, and under-5, infant, and neonatal mortality, especially in socioeconomically disadvantaged groups. Several factors helped to achieve universal health coverage and improve outcomes. These factors include economic growth, political stability, a comprehensive transformation strategy led by a transformation team, rapid policy translation, flexible implementation with continuous learning, and simultaneous improvements in the health system, on both the demand side (increased health insurance coverage, expanded benefits, and reduced cost-sharing) and the supply side (expansion of infrastructure, health human resources, and health services). PMID- 23810022 TI - Assessing comparative effectiveness of new drugs before approval using prospective network meta-analyses. PMID- 23810023 TI - Systematic review showed measures of individual burden of osteoarthritis poorly capture the patient experience. AB - OBJECTIVE: The objective of this study was to describe the content of questionnaires used in the assessment of the individual burden of osteoarthritis. STUDY DESIGN AND SETTING: A systematic search of computerized databases was conducted to identify self-report measures of osteoarthritis burden. The content of identified measures was assessed against the eight-domain Personal Burden of Osteoarthritis (PBO) model, which covers physical distress, fatigue, physical limitations, psychosocial distress, physical deconditioning, financial hardship, sleep disturbances, and lost productivity. The PBO was derived from extensive consultations with osteoarthritis patients and clinicians. RESULTS: A review of 5,703 publications identified 158 multi-item self-report measures of the individual burden of osteoarthritis. Content analysis showed that the dimensions of physical limitations, physical distress, and psychosocial distress were well represented by the identified questionnaires. The physical deconditioning and financial hardship dimensions were the least represented in the identified measures. The World Health Organization Quality of Life Scale gave the best coverage of PBO elements, with items matching seven of the eight PBO domains. CONCLUSION: Despite the large number of questionnaires identified, many aspects of the individual burden of osteoarthritis are not well represented by currently available measures. This may result in systematic gaps in how experiences of people with osteoarthritis are represented in research studies. PMID- 23810024 TI - Better reporting and greater homogeneity in outcome measures are seen in randomized trial protocols when guidelines exist. AB - OBJECTIVE: Outcome Measures in Rheumatology promotes standardized outcome measures. No such organization exists for nephrology. We compared the reporting and homogeneity of outcome measures in registered protocols of randomized trials in rheumatology and nephrology. STUDY DESIGN AND SETTING: Data were extracted from protocols for rheumatoid arthritis or nephroprotection registered in ClinicalTrials.gov. We rated five outcome items (domain, specific measurement, specific metric, method of aggregating data, and time frame) to obtain a 5-point score. We split outcomes into clusters that could be pooled for meta-analysis, and assessed the proportion of trials and patients by cluster. RESULTS: We selected 75 protocols for rheumatology and 66 for nephrology. A high adjusted score for outcomes was associated with rheumatology protocols (odds ratio, 4.2; 95% confidence interval, 2.39, 7.39). We retained 13 clusters of outcomes for rheumatology, and one of one outcome (American College Rheumatology Criteria) could pool 87.1% of trials and 92.8% of patients. We retained eight clusters for nephrology, and one of four outcomes (assessing proteinuria) could pool 83.1% of trials and 44.7% of patients. CONCLUSIONS: The reporting and homogeneity of outcomes is better in registered protocols of rheumatology than nephrology. The presence of international guidelines on outcome measurement may explain the differences. PMID- 23810025 TI - Mechanisms can help to use patients' experiences of chronic disease in research and practice: an interpretive synthesis. AB - OBJECTIVE: To identify and examine mechanisms through which patients' experiences of chronic disease can be accessed, understood, and used to improve outcomes, health care costs, and quality of life for individual patients. STUDY DESIGN AND SETTING: Interpretive synthesis of the research literature on chronic disease and associated areas of clinical practice and service development. Searches of electronic databases (MEDLINE, EMBASE, and British Nursing Index), Internet searches, and snowballing techniques identified 66 relevant publications. The analysis focused on identifying mechanisms; their strengths, weaknesses, and impact. RESULTS: Ten mechanisms were identified, each with differing potential to access and reach patients; involve patients in decisions about what information is important; enable patients to share experiences/expertise and validate their knowledge; allow professionals and patients to deliberate and build understanding; support shared decision-making, continuity/partnership development, and potential to use patients' experiences. The extent to which patients' experiences led to improved outcomes, health care costs, or quality of life related to the aims of individual studies. CONCLUSION: Patients can contribute to improving the design and delivery of chronic disease health care and research if appropriate mechanisms are in place. There is a need for future research about optimal configurations of mechanisms and links between mechanisms across health care and research. PMID- 23810027 TI - Interrupted time-series analysis yielded an effect estimate concordant with the cluster-randomized controlled trial result. AB - OBJECTIVE: We reanalyzed the data from a cluster-randomized controlled trial (C RCT) of a quality improvement intervention for prescribing antihypertensive medication. Our objective was to estimate the effectiveness of the intervention using both interrupted time-series (ITS) and RCT methods, and to compare the findings. STUDY DESIGN AND SETTING: We first conducted an ITS analysis using data only from the intervention arm of the trial because our main objective was to compare the findings from an ITS analysis with the findings from the C-RCT. We used segmented regression methods to estimate changes in level or slope coincident with the intervention, controlling for baseline trend. We analyzed the C-RCT data using generalized estimating equations. Last, we estimated the intervention effect by including data from both study groups and by conducting a controlled ITS analysis of the difference between the slope and level changes in the intervention and control groups. RESULTS: The estimates of absolute change resulting from the intervention were ITS analysis, 11.5% (95% confidence interval [CI]: 9.5, 13.5); C-RCT, 9.0% (95% CI: 4.9, 13.1); and the controlled ITS analysis, 14.0% (95% CI: 8.6, 19.4). CONCLUSION: ITS analysis can provide an effect estimate that is concordant with the results of a cluster-randomized trial. A broader range of comparisons from other RCTs would help to determine whether these are generalizable results. PMID- 23810026 TI - The Oxford Implementation Index: a new tool for incorporating implementation data into systematic reviews and meta-analyses. AB - OBJECTIVES: This article presents a new tool that helps systematic reviewers to extract and compare implementation data across primary trials. Currently, systematic review guidance does not provide guidelines for the identification and extraction of data related to the implementation of the underlying interventions. STUDY DESIGN AND SETTING: A team of systematic reviewers used a multistaged consensus development approach to develop this tool. First, a systematic literature search on the implementation and synthesis of clinical trial evidence was performed. The team then met in a series of subcommittees to develop an initial draft index. Drafts were presented at several research conferences and circulated to methodological experts in various health-related disciplines for feedback. The team systematically recorded, discussed, and incorporated all feedback into further revisions. A penultimate draft was discussed at the 2010 Cochrane-Campbell Collaboration Colloquium to finalize its content. RESULTS: The Oxford Implementation Index provides a checklist of implementation data to extract from primary trials. Checklist items are organized into four domains: intervention design, actual delivery by trial practitioners, uptake of the intervention by participants, and contextual factors. Systematic reviewers piloting the index at the Cochrane-Campbell Colloquium reported that the index was helpful for the identification of implementation data. CONCLUSION: The Oxford Implementation Index provides a framework to help reviewers assess implementation data across trials. Reviewers can use this tool to identify implementation data, extract relevant information, and compare features of implementation across primary trials in a systematic review. The index is a work-in-progress, and future efforts will focus on refining the index, improving usability, and integrating the index with other guidance on systematic reviewing. PMID- 23810028 TI - Risk of attrition in a longitudinal study of skin cancer: logistic and survival models can give different results. AB - OBJECTIVES: Longitudinal studies are a major tool for public health research, but their value can be undermined by attrition. Identification of factors associated with attrition through modeling depends on the efficient use of data and is conditional on modeling assumptions being met. The primary aim of this study was to compare the performance of four models in analyzing attrition risk. STUDY DESIGN AND SETTING: Data from participants who were lost to follow-up from The Nambour Skin Cancer Study between 1992 and 2000 were analyzed using logistic and survival models, for all-cause and nondeath attritions. RESULTS: During follow up, 321 (19.8%) of 1,621 participants were lost to follow-up; 70 (4.3%) because of death and 251 (15.5%) for other reasons. Using survival models showed skin cancer diagnosis to be associated with increased all-cause attrition (hazard ratio: 2.3; 95% confidence interval [95% CI]: 1.5, 3.4) and nondeath attrition (subhazard ratio: 1.9; 95% CI: 1.0, 3.3). Using logistic regression resulted in inverse associations being observed for both all-cause attrition (odds ratio [OR]: 0.7; 95% CI: 0.5, 1.1) and nondeath attrition (OR: 0.5; 95% CI: 0.3, 1.0). CONCLUSION: These results demonstrate the relative inadequacy of a logistic as opposed to a survival approach when analyzing attrition risk in the presence of time-varying covariates and multiple timepoints. PMID- 23810029 TI - Telephone follow-up was more expensive but more efficient than postal in a national stroke registry. AB - OBJECTIVE: To compare the efficiency and differential costs of telephone- vs. mail-based assessments of outcome in patients registered in a national clinical quality of care registry, the Australian Stroke Clinical Registry (AuSCR). STUDY DESIGN AND SETTING: The participants admitted to hospital with stroke or transient ischemic attack were randomly assigned to complete a health questionnaire by mail or telephone interview at 3-6 months postevent. Response rate, researcher burden, and costs of each method were compared. RESULTS: Compared with the participants in the mail questionnaire arm (n=277; 50% female; mean age: 70 years), those in the telephone arm (n=282; 45% female; mean age: 68 years) required a shorter time to complete the follow-up (mean difference: 24.2 days; 95% confidence interval [CI]: 15.0, 33.5 days). However, the average cost of completing a telephone follow-up was greater (US$20.87 vs. US$13.86) and had a similar overall response to the mail method (absolute difference: 0.57%; 95% CI: 4.8%, 6%). CONCLUSION: Posthospital stroke outcome data were slower to collect by mail, but the method achieved a similar completion rate and was significantly cheaper to conduct than follow-up telephone interview. Findings are informative for planning outcome data collection in large numbers of patients with acute stroke. PMID- 23810030 TI - Time from (clinical or certainty) diagnosis to treatment onset in cancer patients: the choice of diagnostic date strongly influences differences in therapeutic delay by tumor site and stage. AB - OBJECTIVES: To analyze whether differences between the interval from suspicion or clinical diagnosis to treatment onset (IClinDT) and the interval from certainty diagnosis to treatment onset (ICertDT) varied by tumor site, stage, and mode of hospital admission. STUDY DESIGN AND SETTING: From our hospital cancer registry, we selected all 8,814 patients with breast, colorectal, lung, prostate, or cervical cancer diagnosed between 1992 and 2006. We compared IClinDT and ICertDT with density plots and logistic regression. RESULTS: IClinDT was up to three times higher than ICertDT. There were very large differences among stages and within each stage in IClinDT and ICertDT. Tumor stage significantly influenced the difference between the two intervals in three of the five locations (breast, lung, and prostate cancer); as stage worsened, the difference between IClinDT and ICertDT became smaller. In all tumor sites, the difference was larger in scheduled than in emergency admissions. Overall, therapeutic delays--even when measured by ICertDT--were disturbingly common for important subgroups of patients. CONCLUSION: The difference between IClinDT and ICertDT varied highly by tumor site, stage, and mode of hospital admission. More standardized definitions and procedures to calculate time intervals between cancer diagnosis and treatment onset are needed. PMID- 23810031 TI - A population-based description of atrial fibrillation in the emergency department, 2002 to 2010. AB - STUDY OBJECTIVE: We aimed to describe the demographics, care, and outcomes of patients with atrial fibrillation in the emergency department (ED), as well as temporal changes over time. METHODS: In this retrospective cohort study, we used a province-wide database to identify all adult patients who were treated in a nonpediatric ED in the province of Ontario with a primary diagnosis of atrial fibrillation, April 2002 to March 2010. We determined the frequency and rate of ED visits and assessed patient demographics, ED care, and outcomes, both overall and by year. RESULTS: During the 8-year study period, 113,786 patients made 143,003 ED visits for atrial fibrillation, accounting for 0.5% of all ED visits. The annual number of ED visits increased from 15,931 to 20,168 (29.4%; 95% confidence interval [CI] 28.7% to 30.1%) between 2002 and 2010, whereas the crude rate increased from 172 per 100,000 to 195 per 100,000 persons. Median age was 72.0 years (Interquartile range 61.0 to 80.0 years) and 50.8% were women, which did not change significantly during the study period. The percentage of index ED visits with a physician billing for cardioversion increased from 6.3% (95% CI 5.9% to 6.7%) to 11.8% (95% CI 11.3% to 12.3%). Although the percentage of patients with a CHADS2 score greater than or equal to 2 increased from 49.3% (95% CI 48.4% to 50.2%) to 53.6% (95% CI 52.9% to 54.4%) and high-acuity ED triage scores increased from 41.1% (95% CI 40.2% to 42.0%) to 62.5% (95% CI 61.7% to 63.2%), hospital admissions decreased from 48.1% (95% CI 47.3% to 49.0%) to 38.4% (95% CI 37.6% to 39.2%). Thirty-day mortality was 3.3% (95% CI 3.2% to 3.4%) and showed a slight downward trend during the study period (P=.05), whereas subsequent hospitalizations within 30 days for atrial fibrillation or stroke (2.8%; 95% CI 2.7% to 2.9%) and repeated ED visits (7.3%; 95% CI 7.1% to 7.4%) remained unchanged. CONCLUSION: The number of ED visits for atrial fibrillation increased markedly during an 8-year period. Although it appears that slightly higher-risk patients are being treated in the province's EDs, fewer patients are being admitted to the hospital, and mortality rates have not increased. PMID- 23810032 TI - Fabrication of tin-filled carbon nanofibres by microwave plasma vapour deposition and their in situ heating observation by environmental transmission electron microscopy. AB - Sn-filled carbon nanofibres (CNFs) are fabricated by microwave plasma chemical deposition. Scanning electron microscopy observations revealed the existence of a Sn island under the CNFs. The structure of the CNFs is investigated, and the behaviour of Sn in the internal space of CNFs is revealed by performing in situ heating observations by environmental transmission electron microscopy (ETEM). ETEM observations reveal that they have low-crystallized carbon wall and Sn occupies not only the CNF's internal space but also its carbon wall. The Sn inside the CNF is completely covered by the carbon wall. Further, the in situ heating observations reveal that Sn within the internal space and the carbon wall of the CNFs diffused to the outside during heating. Moreover, it is found that higher membered carbon rings and defects in the graphite layer act as diffusion routes between disordered carbon layers. PMID- 23810033 TI - Expression and characterization of anionic components in the tubulointerstitial compartment of rat kidney during polymicrobial sepsis. AB - The aim of the study was to evaluate sialic acids and hyaluronan expression, anionic components important for the structure and function of the renal tubulointerstitial compartment, in the early stages of sepsis. Two groups of rats were used: (1) sham-operated controls; (2) cecal ligation and puncture (CLP) (polymicrobial sepsis model). A search for microbial growth was made in the peritoneal fluid to document infection. Tubular function was evaluated by means of urinary protein loss, urinary Na(+) and urea excretion. Kidney samples were processed to analyze histology, sialic acids (lectin histochemistry) and hyaluronan (immunohistochemistry) expression. Results showed increased urinary protein loss and fractional excretion of Na(+) and urea reduction in the CLP group. Histological changes, particularly in the cortex and in proximal tubules of the CLP group, were observed. In septic rats, compared to controls, sialic acids decreased in amount and their acetylation increased in the tubules, although to a lesser extent in the proximal portion. Hyaluronan was expressed in the medullary interstitium and in a few areas of cortex in controls. In septic rats it increased in the cortical interstitium and appeared in proximal tubules. These results suggest correlation between expression changes of anionic components and tubulointerstitium morphofunctional alterations during sepsis. A role of these molecules in protection/defense and repair processes may be suggested. PMID- 23810034 TI - Effects of dietary extra-virgin olive oil on oxidative stress resulting from exhaustive exercise in rat skeletal muscle: a morphological study. AB - Physical exercise induces oxidative stress through production of reactive oxygen species and can cause damage to muscle tissue. Oxidative stress, resulting from exhaustive exercise is high and improvement of antioxidant defenses of the body may ameliorate damage caused by free radicals. Extra-virgin olive oil is widely considered to possess anti-oxidative properties. The aim of this study was to determine if extra-virgin olive oil improved the adaptive responses in conditions of oxidative stress. Twenty-four 12-week-old male Sprague-Dawley rats were divided in three groups: (1) rats fed with standard chow and not subjected to physical exercise; (2) rats fed with standard chow and subjected to exhaustive exercise; (3) rats fed with a diet rich in oleic acid, the major component of extra-virgin olive oil, and subjected to exhaustive exercise. Exhaustive exercise consisted of forced running in a five-lane 10 degrees inclined treadmill at a speed of 30 m/min for 70-75 min. We studied some biomarkers of oxidative stress and of antioxidant defenses, histology and ultrastructure of the Quadriceps femoris muscle (Rectus femoris). We observed that, in rats of group 3, parameters indicating oxidative stress such as hydroperoxides and thiobarbituric acid reactive substances decreased, parameters indicating antioxidant defenses of the body such as non-enzymatic antioxidant capacity and Hsp70 expression increased, and R. femoris muscle did not show histological and ultrastructural alterations. Results of this study support the view that extra-virgin olive oil can improve the adaptive response of the body in conditions of oxidative stress. PMID- 23810035 TI - Development of a traffic noise prediction model on inland waterway of China using the FHWA. AB - Based on the local environmental standards, vessels types and traffic conditions, an inland waterway traffic noise prediction model was developed for use in China. This model was modified from the US FHWA model by adding the ground absorption and water surface attenuation correction terms to the governing equations. The parameters that were input into the equations, including traffic flow, vessel speed, distance from the center of the inland waterway to the receiver, position and height of the barriers and buildings, location of the receiver, type of ground, percentage of soft ground cover within the segment, and water surface conditions were re-defined. The model was validated by comparing the measured noise levels obtained at 33 sampling sites from Shugang Channel, Yanhe Channel and Danjinlicaohe Channel in China with the predicted values. The deviation between the predicted and measured noise levels within the range of +/-1.5dB(A) was 81.8%. The mean difference between the predicted and measured noise levels was 0.15+/-1.75dB(A). However, the noise levels predicted developed model are generally higher than the measured levels. Overall, the comparison has proved that the developed method is of a high precision, and that it can be applied to estimate the traffic noise exposure level on inland waterway in China. PMID- 23810036 TI - Happy 20th anniversary! PMID- 23810037 TI - The need to know. PMID- 23810038 TI - Accelerating tooth movement: the case for corticotomy-induced orthodontics. PMID- 23810039 TI - Accelerating tooth movement: the case against corticotomy-induced orthodontics. PMID- 23810041 TI - Evaluation of 3 retention protocols using the American Board of Orthodontics cast and radiograph evaluation. AB - INTRODUCTION: The purpose of this study was to quantify tooth movement among different retention protocols after the orthodontic appliances were removed. METHODS: A total of 90 patients were evaluated using the American Board of Orthodontics discrepancy index and the cast and radiograph evaluation at debond and the 1-year recall. These patients were equally divided into 3 retention protocols: upper Hawley/lower Hawley, upper Hawley/lower bonded, and upper Essix/lower bonded. The patients were then equally grouped by extraction or nonextraction treatment and case complexity. Paired t tests were used to compare the paired sample means. Analysis of variance tests were used to compare the means for more than 2 groups. A 2-sided 0.05 alpha level was used to define statistical significance. RESULTS: The upper Hawley/lower bonded showed the greatest amount of settling, and the upper Essix/lower bonded had the least settling, but these differences were statistically insignificant. The differences between the extraction and nonextraction treatments were not significant. The group with low discrepancy index scores showed significantly more settling than did the group with high discrepancy index scores. CONCLUSIONS: The cast and radiograph evaluation variables that improved overall were marginal ridges, overjet, occlusal contacts, interproximal contacts, root angulation, and total cast and radiograph score. The cast and radiograph evaluation variables that worsened were alignment/rotation, buccolingual inclination, and occlusal relationship. Extraction or nonextraction treatment led to no real difference in settling. The discrepancy index, or initial case complexity, was the greatest factor in determining the improvement of occlusion or settling during the retention phase. PMID- 23810042 TI - Effect of piezopuncture on tooth movement and bone remodeling in dogs. AB - INTRODUCTION: The aim of the study was to elucidate whether a newly developed, minimally invasive procedure, piezopuncture, would be a logical modification for accelerating tooth movement in the maxilla and the mandible. METHODS: Ten beagle dogs were divided into 2 groups. Traditional orthodontic tooth movement was performed in the control group. In the experimental group, a piezotome was used to make cortical punctures penetrating the gingiva around the moving tooth. Measurements were made in weeks 1 through 6. Tooth movement and bone apposition rates from the histomorphometric analyses were evaluated by independent t tests. RESULTS: The cumulative tooth movement distance was greater in the piezopuncture group than in the control group: 3.26-fold in the maxilla and 2.45-fold in the mandible. Piezopuncture significantly accelerated the tooth movements at all observation times, and the acceleration was greatest during the first 2 weeks for the maxilla and the second week for the mandible. Anabolic activity was also increased by piezopuncture: 2.55-fold in the maxilla and 2.35-fold in the mandible. CONCLUSIONS: Based on the different effects of piezopuncture on the maxilla and the mandible, the results of a clinical trial of piezopuncture with optimized protocols might give orthodontists a therapeutic benefit for reducing treatment duration. PMID- 23810043 TI - Phenotypic diversity in white adults with moderate to severe Class III malocclusion. AB - INTRODUCTION: Class III malocclusion is characterized by a composite of dentoskeletal patterns that lead to the forward positioning of the mandibular teeth in relation to the maxillary teeth and a concave profile. Environmental and genetic factors are associated with this condition, which affects 1% of the population in the United States and imposes significant esthetic and functional burdens on affected persons. The purpose of this study was to capture the phenotypic variation in a large sample of white adults with Class III malocclusion using multivariate reduction methods. METHODS: Sixty-three lateral cephalometric variables were measured from the pretreatment records of 292 white subjects with Class II malocclusion (126 male, 166 female; ages, 16-57 years). Principal component analysis and cluster analysis were used to capture the phenotypic variation and identify the most homogeneous groups of subjects to reduce genetic heterogeneity. RESULTS: Principal component analysis resulted in 6 principal components that accounted for 81.2% of the variation. The first 3 components represented variation in mandibular horizontal and vertical positions, maxillary horizontal position, and mandibular incisor angulation. The cluster model identified 5 distinct subphenotypes of Class III malocclusion. CONCLUSIONS: A spectrum of phenotypic definitions was obtained replicating results of previous studies and supporting the validity of these phenotypic measures in future research of the genetic and environmental etiologies of Class III malocclusion. PMID- 23810044 TI - Effect of fixed orthodontic appliances bonded with different etching techniques on tooth color: a prospective clinical study. AB - INTRODUCTION: For most orthodontic patients, esthetic concerns are as important as functional demands. The purpose of this study was to assess the effect of self etching primer and conventional acid etching on tooth color after orthodontic treatment. METHODS: A total of 34 patients were enrolled in a clinical trial and divided into 2 groups based on age: adolescents (<=17 years) and adults (>17 years). Tooth color of all maxillary and mandibular anterior teeth was measured before bonding and after debonding using a spectrophotometer (Vita Easyshade Compact; Vita Zahnfabrik, Bad Sackingen, Germany). Two types of etching techniques were used for orthodontic bonding, self-etching primer and conventional acid etching, in a randomized split-mouth design. Tooth color measurements were done according to the system of the Commission Internationale de l'Eclairage (lightness, red/green, and yellow/blue). The corresponding tooth color differences between pretreatment and posttreatment, etching groups, sexes, and age groups were calculated. RESULTS: Tooth color was significantly changed in all (L, a, b) color parameters (P <0.05). The lightness value decreased by 2.16 units, and the red/green and yellow/blue values increased by 0.32 and 1.78, respectively. The average tooth color difference after orthodontic treatment was 2.85 units. No significant difference was found between self-etching primer and conventional acid etching in their effects on tooth color (P >0.05). Men and adolescents had more color change than did girls and adults (P <0.05). CONCLUSIONS: Fixed orthodontic appliances caused tooth color changes; self etching primer and conventional acid etching had similar effects on tooth color; men and adolescents had greater color changes than did girls and adults. PMID- 23810045 TI - Root proximity and inclination of orthodontic mini-implants after placement: cone beam computed tomography evaluation. AB - INTRODUCTION: Root contact by mini-implants should be avoided. Prolonged contact can damage the root and might cause external root resorption. To reduce the proximity of a mini-implant to the root, information about positioning of the implants and the variability of inclination is useful. The purpose of this study was to investigate root proximity and variability of the placement inclination of a mini-implant according to placement position. METHODS: Fifty patients with 147 implants (diameter, 1.6 mm; length, 8 mm) were included. Cone-beam computed tomography images were taken of the area around the implant-placement site. The distances between the root and the mini-implant, and the vertical and horizontal inclinations of the placed implants, were measured. RESULTS: Of 147 implants, approximately 20% were in contact with a root. The vertical inclinations of the mini-implants were 48.3 degrees to 50.4 degrees in the maxilla and 57.5 degrees to 63.3 degrees in the mandible. In the right maxilla, the incidence of root contact with the distal adjacent tooth was significantly greater than that with the mesial tooth. CONCLUSIONS: One fifth of the mini-implants in this study contacted adjacent roots. During placement of mini-implants in the buccal maxillary right alveolar bone, contact with the root of the distal adjacent tooth should be avoided. PMID- 23810046 TI - Evaluation of skeletal and dental asymmetries in Angle Class II subdivision malocclusions with cone-beam computed tomography. AB - INTRODUCTION: The purpose of this study was to determine whether Angle Class II subdivision malocclusions have skeletal or dental asymmetries between the Class II and Class I sides. METHODS: A sample of 54 untreated Angle Class II subdivision patients with pretreatment photos and cone-beam computed tomography (CBCT) scans was used. The photos were used to identify the Class II subdivision malocclusion and to record the amount of crowding per quadrant. Landmarks were plotted on each CBCT volume so that direct 3-dimensional measurements could be made to compare the positions and dimensions of the skeletal and dental structures on the Class II side vs the Class I side. RESULTS: Significant differences were found for 2 skeletal measurements: the position of the maxilla relative to the cranial base, and the mandibular dimension from the mandibular foramen to the mental foramen. Statistically significant dental differences were found for the position of the mandibular first molars and canines in relation to the maxilla and the mandible. Statistically significant differences were found for the maxillary first molars and canines in relation to the mandible. CONCLUSIONS: There were significant skeletal and dental differences between the Class I and Class II sides. The dental asymmetries accounted for about two thirds of the total asymmetry. PMID- 23810047 TI - Systemic consumption of probiotic curd and use of probiotic toothpaste to reduce Streptococcus mutans in plaque around orthodontic brackets. AB - INTRODUCTION: The objectives of the study were to evaluate and compare the effects of the systemic consumption of probiotic curd and the topical application of probiotic toothpaste on the Streptococcus mutans levels in the plaque of orthodontic patients. METHODS: The study consisted of 60 orthodontic patients divided into 3 groups of 20 each. Group 1 was the control group. The patients in group 2 were given probiotic curd, and those in group 3 were asked to brush twice daily with probiotic toothpaste (GD toothpaste; Dental Asia Manufacturing, Shah Alam, Selangor, Malaysia). Samples were collected at 2 times: before the study began and after 30 days. Plaque specimens were collected from the labial surfaces immediately surrounding the orthodontic brackets of the maxillary lateral incisors using a 4-pass technique. The presence of S mutans was evaluated using real-time polymerase chain reaction. Statistical analysis was performed, and comparisons were made using a 2-tailed chi-square test for categorical data (P <0.05). RESULTS: At the end of the study, there were reductions in S mutans concentration in groups 2 and 3 that were statistically significant compared with group 1, but there was no statistically significant difference between groups 2 and 3. CONCLUSIONS: The consumption of probiotic curd and the use of probiotic toothpaste cause a significant decrease in the S mutans levels in the plaque around brackets in orthodontic patients. Although the probiotic toothpaste was more effective than systemic consumption, this was not statistically significant. PMID- 23810048 TI - Relationship between odontogenic bacteremia and orthodontic stripping. AB - INTRODUCTION: The aim of this study was to evaluate the prevalence of bacteremia associated with an orthodontic stripping procedure. METHODS: The study included 29 orthodontic patients (mean age, 18.2 +/- 3.4 years). We used a standardized stripping procedure: a perforated stripping disk with a contra-angle hand piece was used at a low speed (<15,000 rpm; 10 seconds) on the mandibular anterior teeth. Blood samples were collected by inserting a cannula into the left antecubital fossa. A baseline sample was taken before treatment, and a second sample was taken after the stripping procedure. These samples were inoculated into aerobic and anaerobic blood culture bottles and incubated, and the bacterial cultures were identified; the samples collected before and after the stripping procedure were statistically analyzed. RESULTS: Transient bacteremia was not detected in any pretreatment blood sample, but it was found in 1 postoperative blood sample; this sample tested positive for Streptococcussanguis. CONCLUSIONS: The bacterial species in the positive postoperative blood sample was S sanguis, which might be associated with infective endocarditis. Clinicians should explain the level of risk to the patient and consult a concerned medical specialist. PMID- 23810049 TI - Craniofacial morphology in pediatric patients with persistent obstructive sleep apnea with or without positive airway pressure therapy: a cross-sectional cephalometric comparison with controls. AB - INTRODUCTION: Compression on the midface with nasal mask-delivered positive airway pressure (PAP) therapy in growing patients might contribute to midface retrusion. The objective of this study was to investigate the association between long-term PAP use and craniofacial morphologic pattern in children with persistent obstructive sleep apnea. METHODS: Images generated with cone-beam volumetric imaging were used to complete lateral cephalometric analyses of anteroposterior projection of the midface region. The study group included 12 subjects (10 boys, 2 girls; mean age, 9.0 years) who used PAP therapy for at least 6 months and at least 6 hours per night. Measurements from this group were compared with those of a control group of 11 subjects (5 boys, 6 girls; mean age, 9.6 years) with obstructive sleep apnea who did not have PAP. Measurements were taken at 1 time point. RESULTS: No significant differences were identified between the groups for any cephalometric variable. Multivariate linear regression analysis also did not identify a significant association between the number of months of PAP therapy and the cephalometric variables. Cephalometric data for both groups were pooled for comparison with appropriate published normative values for age and sex. Anterior cranial base length, overall anteroposterior length of the maxillary base, and mandibular body length were significantly shorter than normal in the subjects compared with published normative values. CONCLUSIONS: No association was demonstrated between midface projection and PAP use in growing patients. When compared with normative data for anterior cranial base, children with obstructive sleep apnea had shorter maxillary and mandibular lengths. PMID- 23810050 TI - Durability of esthetic improvement following Icon resin infiltration of multibracket-induced white spot lesions compared with no therapy over 6 months: a single-center, split-mouth, randomized clinical trial. AB - INTRODUCTION: White spot lesions that form during orthodontic treatment are a problem for patients and clinicians. Lesion infiltration with low-viscosity light cured resin has been proposed as a treatment to inhibit further demineralization. The purpose of this study was to assess the durability of assimilation of white spot lesions and sound adjacent enamel achieved over 6 months with resin infiltration. METHODS: Twenty-one consecutive subjects with 231 noncavitated, unrestored white spot lesions after multibracket treatment were recruited at the Department of Orthodontics, University of Gottingen (Germany), for lesion infiltration. A simple randomized, split-mouth, controlled design was used to allocate subjects to the treatment and control groups. In the treatment group, white spot lesion infiltration of the anterior teeth was performed with low viscosity light-cured resin after enamel conditioning with a 15% HCl gel. Color and lightness of the white spot lesions and the sound adjacent enamel were assessed with a spectrophotometer before infiltration and after 1 day, 1 week, 4 weeks, 3 months, and 6 months, using the system of the Commission Internationale de l'Eclairage. Multifactorial analysis of variance with repeated measures and pair-wise comparisons were used to analyze the effects of infiltration and time elapsed on the color differences at an alpha level of 5% and a power of 80%. RESULTS: Analysis of 20 subjects and 39 quadrants in each group (108 teeth in the control group; 111 teeth in the treatment group) showed that both parameters of treatment and time duration had globally a highly significant influence on the color difference values. Assimilation of white spot lesion color to the surrounding enamel after infiltration was stable with no significant changes over 6 months; the mean color difference of white spot lesions vs sound adjacent enamel (DeltaE baseline vs 6 months) was 2.55 (95% confidence interval [CI], 1.431-3.678). The untreated control teeth showed no significant changes over 6 months compared with the baseline: mean (DeltaE), 0.29 (95% CI, -0.335-0.928). No important adverse events or side effects were observed. CONCLUSIONS: Resin infiltration improves the esthetic appearance of demineralized teeth. The results showed sufficient durability over 6 months. PMID- 23810051 TI - Prevalence of peg-shaped maxillary permanent lateral incisors: A meta-analysis. AB - INTRODUCTION: The aim of this meta-analysis was to gain more insight into the prevalence of peg-shaped maxillary permanent lateral incisors and their associations with race, population type, sex, and sidedness. METHODS: Electronic searches and supplementary hand searches initially yielded 3337 records. After applying inclusion and exclusion criteria, 30 articles about 36 studies were included. The overall pooled prevalence estimate was calculated with a random effects model. An estimated risk ratio was used for sex comparison. RESULTS: The overall prevalence of peg-shaped maxillary permanent lateral incisors was 1.8%. No publication bias was found. The occurrence rates were higher in Mongoloid (3.1%) than in black (1.5%) and white (1.3%) patients, and in orthodontic patients (2.7%) than in the general population (1.6%) and dental patients (1.9%). Women were 1.35 times more likely than men to have peg-shaped maxillary permanent lateral incisors. The prevalence rates of unilateral (0.8%) and bilateral peg shaped maxillary permanent lateral incisors were approximately the same. However, among the unilateral lateral incisors, the left side (0.4%) was twice as common as the right side (0.2%). In addition, contralateral lateral incisor hypodontia was seen in 55.5% of the subjects with unilateral lateral incisors. CONCLUSIONS: The prevalence of peg-shaped maxillary permanent lateral incisors varies by race, population type, and sex. The prevalence rates were higher among Mongoloid people, orthodontic patients, and women. Although the prevalence of unilateral and bilateral lateral incisors was the same, the left side was twice as common as the right side. Subjects with unilateral peg-shaped maxillary permanent lateral incisors might have a 55% chance of having lateral incisor hypodontia on the contralateral side. PMID- 23810052 TI - Implant rehabilitation of canines in case of bilaterally missing maxillary lateral incisors. AB - This article reports the successful treatment of a patient with a malocclusion and missing maxillary lateral incisors with an unusual implant-prosthetic rehabilitation in place of the canines. A man, 25 years 5 months of age, was referred by his general dentist with the chief complaint of retained maxillary deciduous canines. He had a skeletal Class I and an Angle Class I malocclusion with an open-bite tendency and prolonged retention of both deciduous canines. The malocclusion was treated with extraction of the maxillary deciduous canines, a fixed edgewise appliance, and implant-prosthesis rehabilitation in place of the canines. A functional and an esthetic occlusion was achieved. PMID- 23810053 TI - Orthodontically induced eruption of a horizontally impacted maxillary central incisor. AB - This case report presents the clinical features and periodontal findings in a patient with a horizontally impacted maxillary central incisor that had been exposed and aligned after a closed-eruption surgical technique. By combining 3 treatment stages-maxillary expansion, crown exposure surgery, and induced eruption-the horizontally impacted incisor was successfully moved into proper position. The patient finished treatment with a normal and stable occlusion between the maxillary and mandibular arches, and an adequate width of attached gingiva, even in the area surrounding the crown. The 5-year follow-up of stability and periodontal health demonstrated esthetic and functional outcomes after orthodontically induced tooth eruption. Clinical evaluation showed that the treated central incisor had periodontal clinical variables related to visible plaque, bleeding on probing, width of attached gingiva, and crown length that resembled the contralateral incisor. PMID- 23810054 TI - Glossectomy as an adjunct to correct an open-bite malocclusion with shortened maxillary central incisor roots. AB - A young man, 19 years of age, with the chief complaint of an anterior open bite, came for orthodontic treatment with a skeletal Class I relationship, anterior open bite, shortened maxillary incisor roots, and relative macroglossia. The malocclusion was treated by extracting the maxillary first premolars and using a fixed edgewise appliance. A partial glossectomy was performed before the orthognathic surgery with a 3-piece segmental LeFort I mandibular setback, and advancement was achieved with a reduction genioplasty. A functional and esthetic occlusion with an improved facial profile was established, and the apex of the maxillary left central incisor became slightly rounded after prolonged and significant tooth movement. Four years after treatment, there was occlusal stability of the results, and no further root shortening was observed. PMID- 23810055 TI - Palatally impacted maxillary canine with congenitally missing lateral incisors and midline diastema. AB - Multiple treatment options are available for patients who have impacted canines in addition to congenitally missing lateral incisors. This article describes the treatment of a 13-year-old postpubertal girl with bilaterally impacted permanent maxillary canines, missing lateral incisors, retained deciduous canines, and a midline diastema. The orthodontic treatment plan included extraction of the deciduous canines. A lingual and labial approach (1-couple force system) was used to move the permanent canines into the arch. Through a collaborative team effort, including an orthodontist and a periodontist, the outcome was excellent esthetically and functionally. PMID- 23810056 TI - Computed gray levels in multislice and cone-beam computed tomography. AB - INTRODUCTION: Gray level is the range of shades of gray in the pixels, representing the x-ray attenuation coefficient that allows for tissue density assessments in computed tomography (CT). An in-vitro study was performed to investigate the relationship between computed gray levels in 3 cone-beam CT (CBCT) scanners and 1 multislice spiral CT device using 5 software programs. METHODS: Six materials (air, water, wax, acrylic, plaster, and gutta-percha) were scanned with the CBCT and CT scanners, and the computed gray levels for each material at predetermined points were measured with OsiriX Medical Imaging software (Geneva, Switzerland), OnDemand3D (CyberMed International, Seoul, Korea), E-Film (Merge Healthcare, Milwaukee, Wis), Dolphin Imaging (Dolphin Imaging & Management Solutions, Chatsworth, Calif), and InVivo Dental Software (Anatomage, San Jose, Calif). The repeatability of these measurements was calculated with intraclass correlation coefficients, and the gray levels were averaged to represent each material. Repeated analysis of variance tests were used to assess the differences in gray levels among scanners and materials. RESULTS: There were no differences in mean gray levels with the different software programs. There were significant differences in gray levels between scanners for each material evaluated (P <0.001). CONCLUSIONS: The software programs were reliable and had no influence on the CT and CBCT gray level measurements. However, the gray levels might have discrepancies when different CT and CBCT scanners are used. Therefore, caution is essential when interpreting or evaluating CBCT images because of the significant differences in gray levels between different CBCT scanners, and between CBCT and CT values. PMID- 23810057 TI - How to report reliability in orthodontic research: Part 1. AB - In reporting reliability, duplicate measurements are often needed to determine if measurements are sufficiently in agreement among the observers (interobserver agreement) and/or within the same observer (intraobserver agreement). Some reports are often analyzed inappropriately using paired t tests and/or correlation coefficients. The aim of this article is to highlight the statistical problems of reliability testing using paired t tests and correlation coefficients and to encourage good reliability reporting within orthodontic research. With regard to the complex issue of reliability, a simple and singular statistical approach is not available. However, some methods are better than others. A graphic technique based on the Bland-Altman plot that can be simultaneously applied for both intra- and interobserver reliability will also be discussed. PMID- 23810059 TI - Myo-inositol metabolism in appropriately grown and growth-restricted fetuses: a proton magnetic resonance spectroscopy study. AB - OBJECTIVE: Myo-inositol (Myo-ins) is a marker of neuroglial cells, being present in the astrocytes of brain tissue, but also functions as an osmolyte. Numbers of astrocytes are known to increase following injury to the brain. Growth-restricted fetuses are at increased risk of later neurodevelopmental impairments even in the absence of overt lesions and despite preserved/increased cerebral blood flow. This study aims to investigate brain Myo-ins metabolism in fetuses with intrauterine growth restriction (IUGR) and evidence of cerebral redistribution using magnetic resonance spectroscopy (MRS) at a short echo time. STUDY DESIGN: Biometry and Doppler assessment of blood flow was assessed using ultrasound in 28 fetuses with IUGR and 47 appropriately grown control subjects. MRI was used to exclude overt brain injury. Proton magnetic resonance spectroscopy of the fetal brain was then performed at an echo time of 42 ms to examine the Myo-ins:Choline (Cho), Myo-ins:Creatine (Cr) and Cho:Cr ratios. RESULTS: No alterations in brain Myo-ins:Cho, Myo-ins:Cr or Cho:Cr ratios were detected between appropriately grown and growth restricted fetuses. CONCLUSIONS: IUGR is not associated with a measureable difference in brain myo-inositol ratios. This may be due to the protective effects of preserved cerebral blood flow in growth restriction and comparable astrocyte numbers when compared to controls. PMID- 23810058 TI - Safety of serotonin (5-HT3) receptor antagonists in patients undergoing surgery and chemotherapy: protocol for a systematic review and network meta-analysis. AB - BACKGROUND: Serotonin (5-HT3) receptor antagonists are a class of antiemetic medications often used to prevent nausea and vomiting among patients undergoing chemotherapy, radiotherapy or surgery. However, recent studies suggest that these agents might be associated with increased cardiac harm. To examine this further, we are proposing to conduct a systematic review and network meta-analysis on the comparative safety of 5-HT3 receptor antagonists among patients undergoing chemotherapy or surgery. METHODS/DESIGN: Studies reporting one or more safety outcomes of interest for 5-HT3 receptor antagonists compared with each other, placebo, and/or other anti-emetic agents (for example, benzamides, phenothiazines, butyrophenones, antihistamines, and anticholinergics) among children and adult patients undergoing surgery or chemotherapy will be included. Our primary outcome of interest is arrhythmia. Our secondary outcomes include cardiac death, QT prolongation, PR prolongation, all-cause mortality, nausea, and vomiting. We will include experimental studies, quasi-experimental studies (namely controlled before-after and interrupted time series), and observational studies (namely cohort studies). We will not limit inclusion by publication status, time period, duration of follow-up or language of dissemination.Electronic databases (for example, MEDLINE, EMBASE) will be searched from inception onwards. These main searches will be supplemented by searching for difficult to locate and unpublished studies, such as dissertations, and governmental reports. The eligibility criteria will be pilot-tested and subsequently used to screen the literature search results by two reviewers in duplicate. A similar process will be followed for full-text screening, data abstraction, and risk of bias/methodological quality appraisal. The Cochrane Risk of Bias tool will be used to appraise experimental and quasi-experimental studies, and cohort studies will be assessed using the Newcastle Ottawa Scale. If the data allows, random effects meta-analysis and a network (that is, mixed treatment comparisons) meta-analysis will be conducted. All analyses will be conducted separately for different study designs, patient populations (for example, children and adults), and reason for administering 5-HT3 receptor antagonists (for example, post-surgery and chemotherapy). DISCUSSION: Our results will help inform patients, clinicians, and health policy-makers about the potential safety concerns, as well as the comparative safety, of using these antiemetic agents. TRIAL REGISTRATION: PROSPERO registry number:CRD42013003564. PMID- 23810060 TI - Placental gene expression patterns of epidermal growth factor in intrauterine growth restriction. AB - OBJECTIVE: In this study, we compared human placental gene expression patterns of epidermal growth factor (EGF) in pregnancies with intrauterine growth restriction (IUGR) vs. normal pregnancies as control. STUDY DESIGN: Gene expression of EGF was determined from human placental samples collected from all pregnancies presenting with IUGR at our institution during the study period January 1, 2010 January 1, 2011. Multiple clinical variables were also assessed including maternal age, gestational weight gain, increase of BMI during pregnancy and fetal gender. RESULTS: A total of 241 samples were obtained (101 in the IUGR pregnancy group, 140 in the normal pregnancy group). EGF was found to be underexpressed in the IUGR group compared to normal pregnancy (Ln2(alpha): -1.54; p<0.04). Within the IUGR group no fetal gender-dependent difference was seen in EGF gene expression (Ln2(alpha): 0.44; p<0.06). Similarly, no significant difference in EGF expression was noted in cases with more vs. less severe forms of IUGR (Ln2(alpha): -0.08; p=0.05). IUGR pregnancies were significantly more common in the maternal age group 35-44 years compared to other age groups. Gestational weight gain and gestational BMI increase were significantly lower in IUGR pregnancies compared to controls. CONCLUSIONS: Placental expression of EGF was found to be reduced in IUGR pregnancies vs. normal pregnancies. This may partly explain the smaller placental size and placental dysfunction commonly seen with IUGR. An increased incidence of IUGR was observed with maternal age exceeding 35 years. The probability of IUGR correlated with lower gestational weight gain and lower BMI increase during pregnancy. PMID- 23810061 TI - Bilirubin influences the clinical presentation of pre-eclampsia. AB - OBJECTIVES: Pre-eclampsia is a placental, inflammatory disease modified by maternal anti-oxidant status to give a syndrome. In its most severe forms pre eclampsia is followed by maternal and neonatal mortality and morbidity. Bilirubin is a known antioxidant and as such is associated with a reduced risk of cardiovascular and respiratory disease. Hence we aimed to find an association between maternal bilirubin levels and the clinical severity of the disease. STUDY DESIGN: A retrospective observational study of 50,712 pregnancies, 925 of which had pre-eclampsia (1999-2010), to examine the association between bilirubin level and perinatal outcome. RESULTS: In women with pre-eclampsia, those with bilirubin levels in the lowest quintile were more likely to require caesarean section (p=0.001, aOR 2.59 (1.52-5.72)). The lowest quintile of bilirubin levels is associated with an increased risk of poor maternal (p=0.002, aOR 3.52 (95%CI 1.6 7.7)) and infant/fetal (p=0.001, OR=3.05 (95%CI=1.63-5.72)) outcome. CONCLUSIONS: Low levels of bilirubin were associated with poor maternal and infant outcomes in women diagnosed with pre-eclampsia. Bilirubin may act as an anti-oxidant in this condition and thus modify the disease. PMID- 23810062 TI - Long-term incidence of febrile UTI after DxHA treatment of VUR. AB - PURPOSE: To assess the long-term incidence of febrile urinary tract infection (fUTI) in children treated by endoscopic injection of dextranomer/hyaluronic acid (DxHA) for vesicoureteral reflux (VUR). MATERIALS AND METHODS: Prospective study from January 2002 to December 2009 in children treated at our institution for VUR by endoscopic injection of DxHA. All children underwent clinical and renal/bladder ultrasound follow up at 3 months after procedure, then annually. Post-operative voiding cystourethrogram (VCUG) control was performed only for patients with recurrent fUTI. RESULTS: 227 children (177 female) were included. Mean patient age at inclusion was 4.7 years. The mean duration of follow-up was 51.6 months. During follow-up, 18.9% had one or several fUTIs, of whom 48.8% had VUR at VCUG. No recurrence of fUTI was observed after 4 years of follow-up. We identified three risk factors for fUTI recurrence: cystitis cystica at the time of injection (p = 0.007), preoperative renal scarring (p = 0.018), and the disappearance of the implant at 3-month follow-up ultrasound (p = 0.037). CONCLUSIONS: The long-term incidence of recurrent fUTI after endoscopic treatment of VUR is low. Our data show that the clinical results of endoscopic treatment should be interpreted with a follow up of at least 4 years. PMID- 23810064 TI - Prolonged preoperative hospital stay is a risk factor for complications after emergency colectomy for severe colitis. AB - AIM: Risk factors for postoperative complications in patients undergoing emergency colectomy for severe colitis in inflammatory bowel disease have hardly been studied. Therefore, this study aimed to define predictors of a complicated postoperative course in these patients. METHOD: A retrospective review was performed of 71 consecutive patients who underwent emergency colectomy for severe colitis between 1999 and 2012 at a tertiary referral centre. Complications were graded according to the Clavien-Dindo classification. Patients with a complication Grade II or higher were compared with those with no complications or a Grade I complication. RESULTS: Nineteen patients (26.7%) had at least one postoperative complication classified as Clavien-Dindo Grade II or higher. In the group with postoperative complications, patients had a higher age (mean 45 vs 35 years, P = 0.020) and a higher body mass index (BMI) (mean 25.9 vs 21.0 kg/m(2), P = 0.006). Length of preoperative hospital stay (median 15 vs 6 days, P = 0.032) was longer in the group with postoperative complications. During the study period, the preoperative hospital stay decreased by 0.8 days per study year (95% CI 0.2-1.5 days, P < 0.001). This did not influence the complication rate over time, however. CONCLUSION: Factors increasing the risk of complications after emergency colectomy for severe colitis were a higher age, a higher BMI and a longer preoperative hospital stay. PMID- 23810063 TI - Genetic variation and relationships of seven sturgeon species and ten interspecific hybrids. AB - BACKGROUND: Sturgeon cultivation is important for both industry and aquaculture in China. To date, more than 17 species or strains have been farmed for fillets and caviar production. Crossbreeding among different sturgeon species is frequent and the F2 hybrids are fertile. However, large-scale farming can have negative impacts on wild populations i.e. escape of exotic sturgeons and must be taken into consideration. Escape of exotic sturgeons can cause severe ecological problems, including threatening native sturgeon species once the exotic varieties become established or hybridize with native individuals. However, little is known about their genetic resources and variation. METHODS: Genetic diversity and introgression of seven sturgeon species were analyzed using mitochondrial DNA cytochrome oxidase subunit I (COI) and nine microsatellite markers. This study included 189 individuals from seven sturgeon species and 277 individuals from ten lineages of F2 hybrid strains. RESULTS: MtDNA COI sequences (632 bp long) were generated from 91 individuals across the 17 sturgeon strains and produced 23 different haplotypes. Haplotype diversity was high (h = 0.915 +/- 0.015) and nucleotide diversity was low (pi = 0.03680 +/- 0.00153) in the seven sturgeon species and ten interspecific hybrids. Phylogenetic analyses resulted in almost identical tree topologies, and different haplotype structures were mainly related with sturgeons of different female parents. Analysis of molecular variance revealed that 81.73% of the genetic variance was due to matrilineal differences, while 9.40% resulted from strain variation. Pairwise Fst values obtained with POLYSAT software, were high among strains and ranged from 0.031 to 0.164. Admixture analysis assigned seven distinct groups and ten genotypes of admixed clusters composed of hybrid strains using STRUCTURE when assuming K = 7. CONCLUSIONS: The interspecific mtDNA gene tree corresponded to the expected taxonomic divisions. These relationships were also supported by the results from the microsatellite analysis and contributed to unambiguously identify seven sturgeon species and ten F2 hybrid strains from sturgeon farms in China. Moreover, we found that introgressive hybridization is pervasive, exists in both purebred and hybrid sturgeons, and may reflect widespread mismanagement in sturgeon breeding in China. PMID- 23810065 TI - Distribution of amoxicillin-resistant oral streptococci in dental plaque specimens obtained from Japanese children and adolescents at risk for infective endocarditis. AB - BACKGROUND: Infective endocarditis (IE) is known to be a life-threatening disease and prevention of its onset is important. Oral amoxicillin (AMPC) is generally prescribed to patients at risk for IE prior to undergoing risky procedures, such as invasive dental treatments. We previously found that approximately 5% of systemically healthy Japanese subjects harbor strains highly resistant to AMPC. In the present study, the prevalence of strains in patients at risk for IE was investigated. METHODS AND RESULTS: Thirty-four Japanese children and adolescents designated at risk for IE by their cardiovascular surgeons participated. Dental plaque specimens were obtained at recall examinations for dental checkups and placed in sterile phosphate-buffered saline, then diluted and streaked onto selective media for oral streptococci and also media containing AMPC. Nine strains with a minimum inhibitory concentration of AMPC of 16MUg/mL or more were isolated from 7 of the subjects (20.6%), each of which was also resistant to other antibiotics analyzed except for new quinolone drugs. The 16S rRNA sequence of each strain demonstrated that all were oral streptococcal species. In addition, dental plaque specimens collected from 5 subjects after an additional interval of 3-4 months showed that 2 harbored the same clones at different time points. CONCLUSIONS: These findings suggest a higher prevalence of AMPC-resistant strains in children and adolescents at risk for IE as compared to systemically healthy subjects. Thus, alternative antibiotics should be considered for such subjects when performing prophylaxis procedures. PMID- 23810066 TI - Significant suppression of myocardial (18)F-fluorodeoxyglucose uptake using 24-h carbohydrate restriction and a low-carbohydrate, high-fat diet. AB - OBJECTIVES: (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) is a useful tool for evaluating inflammation. Because, myocardial-FDG uptake occurs with diverse physiology, it should be suppressed during evaluation of myocardial inflammation by FDG-PET/CT. Diets inducing fat-based metabolism, such as a low-carbohydrate, high-fat diet (LCHF), are used in uptake-suppression protocols. However, a complete suppression of myocardial-FDG uptake has not been established. Hence, we assessed the efficacy of 24-h carbohydrate restriction along with an LCHF diet compared to that of the conventional protocol in suppressing myocardial-FDG uptake and also compared fat and glucose metabolism between these protocols. METHODS: Fourteen healthy volunteers agreed to undergo >24-h carbohydrate restriction (glucose, <10g) and drank an LCHF beverage an hour before FDG administration. A scan performed under conventional fasting protocol served as the control. The maximal standardized uptake values (SUVmax) of the left ventricular (LV) myocardium, and left atrium lumen (blood pool), liver, and lung fields as background, were measured. Blood sugar, free fatty acids (FFAs), insulin, and triglyceride concentrations were measured just before FDG injection and compared between the 2 protocols. RESULTS: Global LV myocardial uptake was significantly lower with the diet-preparation protocol (SUVmax 1.31 [1.15-1.49] vs. 2.98 [1.76-6.43], p=0.001). Target-to background ratios [myocardium-to-blood ratio (MBR), myocardium-to-lung ratio (MLR), and myocardium-to-liver ratio (MLvR)] were also significantly lower with the diet-preparation protocol [MBR: 0.75 (0.68-0.84) vs. 1.63 (0.98-4.09), p<0.001; MLR: 1.87 (1.53-2.47) vs. 4.54 (2.53-12.78), p=0.004; MLvR: 0.48 (0.44 0.56) vs. 1.11 (0.63-2.32), p=0.002]. Only insulin levels were significantly different between the subjects in each protocol group (11.3 [6.2-15.1] vs. 3.9 [2.9-6.2]). CONCLUSION: Carbohydrate restriction together with an LCHF supplement administered 1h before FDG significantly suppressed myocardial-FDG uptake. FFAs and insulin might not directly affect myocardial-FDG uptake. PMID- 23810067 TI - With reference to article: "Impact of the first-generation drug-eluting stent implantation on periprocedural myocardial injury in patients with stable angina pectoris". Dewetting problem. PMID- 23810068 TI - Relation of epicardial fat thickness and brachial flow-mediated vasodilation with coronary artery disease. AB - OBJECTIVE: The purpose of this study is to investigate the presence of a statistical association between epicardial fat thickness (EFT) and coronary artery disease (CAD) and between flow-mediated vasodilation (FMD) and CAD. METHODS: We measured the EFT and FMD in 64 subjects with suspected stable angina pectoris. The patients were separated into two groups according to their coronary angiography results: 34 patients with CAD and 30 patients with normal coronary arteries (NCA). RESULTS: EFT was significantly higher in the patients with CAD than the NCA group (6.43 +/- 0.90 mm vs. 5.35 +/- 0.75 mm, p<0.001) while FMD was significantly lower in the patients with CAD than those in the NCA group (6.41 +/ 2.51% vs. 8.33 +/- 3.45%, p=0.015). No significant correlation was found between EFT and FMD. After adjustment for EFT, FMD, age, sex, ejection fraction, glucose, and low-density lipoprotein cholesterol through multivariate logistic regression analysis, EFT (odds ratio: 6.325, 95% confidence interval 2.289-17.476, p<0.001) and age (odds ratio: 1.093, 95% confidence interval 1.008-1.185, p=0.032) remained significant predictors of CAD. A cut-off value of EFT>=5.8mm predicted the presence of CAD with 77% sensitivity and 70% specificity. CONCLUSION: An echocardiographic EFT assessment is independently associated with the presence of CAD. Thus, EFT may be helpful in cardiometabolic risk stratification and therapeutic interventions. PMID- 23810070 TI - Algorithm for probable acute coronary syndrome using high-sensitivity troponin T assay vs fourth-generation troponin T assay. AB - BACKGROUND: Chest pain represents between 5% and 10% of annual visits to emergency departments (EDs) and near 25% of hospitalizations. Characterization of chest pain is sometimes difficult, and strategies should focus on preventing inappropriate discharge of patients with acute coronary syndrome. The goal of our study is to compare negative predictive value of the algorithm in the chest pain unit using the fourth-generation troponin T assay (4GTT) vs high-sensitivity troponin T assay (HSTT). METHODS: We included 600 patients with probable acute coronary syndrome, who were discharged from the chest pain unit without an acute coronary syndrome: 300 patients in the 4GTT group and 300 patients in the HSTT group. Clinical and laboratory variables were analyzed. All the patients were followed up at 30 days, and the cardiovascular events were recorded. RESULTS: Major cardiac events occurred in only 3 (1.2%) in the HSTT group vs 5 (1.7%) in the 4GTT group (P, nonsignificant). The negative predictive value was 99% in both groups. Emergency department length of stay was 4.3 +/- 2.6 hours in HSTT group vs 10 +/- 3.4 hours in the 4GTT group (P = .01). CONCLUSION: The algorithm in the chest pain unit using HSTT showed to have the same negative predictive value as the algorithm with the 4GTT but with a shorter stay in the ED. PMID- 23810071 TI - Rhabdomyolysis caused by peripheral T-cell lymphoma in skeletal muscle. AB - We report a rare case of rhabdomyolysis caused by peripheral T-cell lymphoma (PTCL) in skeletal muscle. A 62-year-old man was admitted with complaints of sudden muscle weakness. Laboratory abnormalities were identified including markedly elevated creatinine-phosphokinase, peaking at 62,640 IU/L and serum creatinine (Cr) at 5.0 mg/dL. Computed tomography scans revealed tumorous swelling of the right psoas major muscle and the obturator internus muscles. Consequently, he was diagnosed with acute renal failure caused by rhabdomyolysis and was treated with hydration and continuous hemodiafiltration, which resulted in significant improvement in renal function (Cr 1.79 mg/dL). However, the cause of the rhabdomyolysis remained unclear, and he suddenly developed a remittent fever and suffered from hemophagocytic syndrome. Serum ferritin level dramatically increased to 104,707.0 ng/mL and creatinine level to 4.09 mg/dL. We performed a biopsy of inguinal lymph nodes, leading to a diagnosis of PTCL. Finally, he was diagnosed with rhabdomyolysis caused by PTCL. Methylprednisolone pulse therapy markedly improved his general condition and renal function (Cr 1.48 mg/dL), and computed tomography scans revealed that tumorous swelling was greatly diminished. Except when the cause of rhabdomyolysis is readily apparent, such as in cases of trauma, drug and thrombophlebitis, one should consider that rhabdomyolysis may be a sequel of lymphoma. PMID- 23810069 TI - Insulin resistance negatively affects long-term outcome in non-diabetic patients with coronary artery disease after therapies to reduce atherosclerotic risk factors. AB - BACKGROUND: Insulin resistance (IR) is a predictor of cardiovascular (CV) events even before the onset of diabetes. However, it is unclear whether changes in IR after a reduction of atherosclerotic burden may affect long-term outcome in patients with coronary artery disease (CAD). This study examined whether changes in IR after therapy to reduce atherosclerotic risk factors provides prognostic information on future CV events in non-diabetic patients with CAD. METHODS AND RESULTS: This study enrolled 175 non-diabetic patients with newly diagnosed CAD and IR. IR was defined as the homeostasis model assessment of IR (HOMA-IR)>/=2.5. Evaluation of HOMA-IR was repeated at entry (1st test) and 6 months after individualized, optimized therapy including medications and lifestyle changes (2nd test). After the 2nd test, all patients were prospectively followed-up for 3 years or until the occurrence of one of the following events: CV death, nonfatal myocardial infarction, unstable angina requiring coronary revascularization, or ischemic stroke. IR was improved (HOMA-IR<2.5) after 6 months in 71 (41%) patients, whereas IR persisted in 104 (59%) patients. During the follow-up period, events occurred in 21 (20%) of the 104 patients with persistent IR and 3 (4%) of the 71 patients with improved IR (p<0.01). In multivariate stepwise Cox proportional hazards analysis, persistent IR was an independent predictor of future CV events (HR 4.8, 95% CI 1.4-11.2, p<0.01). CONCLUSIONS: The presence of IR despite optimized therapies to reduce atherosclerotic risk factors represents an adverse outcome predictor in non-diabetic patients with CAD. PMID- 23810072 TI - Upstream antiactivation antiplatelet therapy: first, do no harm. Then consider doing some good. PMID- 23810073 TI - Old wine in new bottle: utility of contrast-enhanced point-of-care echocardiogram in the ED. PMID- 23810074 TI - Irreversible third-degree heart block and pacemaker implant in a case of flecainide toxicity. AB - An 82-year-old white woman was seen in the emergency department (ED) after ingesting 400 mg of flecainide in an attempt to treat an episode of dizziness and palpitations that occurred while she was gardening. Consequently, she developed bradycardia, hypotension, and complete heart block. In addition to supportive care, she also received sodium bicarbonate, atropine, calcium gluconate, and dopamine in an effort to reverse the heart block. The patient continued to remain in heart block and was sent to the cardiac catheterization laboratory for placement of an external pacing wire, which stabilized the patient. After further evaluation, a permanent pacemaker was implanted during her admission. External pacing wires may be useful in the treatment of complete heart block in cases of flecainide poisoning when a patient is unresponsive to drug therapy provided in the ED. PMID- 23810075 TI - Reversible cardiogenic shock due to catecholamine-induced cardiomyopathy: a variant of takotsubo? AB - Catecholamine-induced cardiomyopathy, including takotsubo, neurogenic stunned myocardium, and pheochromocytoma-related cardiomyopathy, is a reversible and generally benign condition. We are reporting a case series of young women who had cardiogenic shock and pulmonary edema due to severe left ventricular systolic dysfunction, which completely recovered in the course of 2 to 3 weeks. Both patients had high catecholamine levels, due to pheochromocytoma in the first case and due to intravenous high-dose catecholamines in the second case. We suggest that screening for pheochromocytoma should be considered in patients who present with takotsubo cardiomyopathy without obvious cause. Most importantly, widely used intravenous catecholamines may cause severe transient left ventricular dysfunction, and consideration should be given to noncatecholamine vasopressors. PMID- 23810076 TI - Derivation of the 12-lead electrocardiogram and 3-lead vectorcardiogram. AB - OBJECTIVE: The cardiac dipolar field is represented by the measured 12-lead electrocardiogram (ECG) and 3-lead vectorcardiogram (VCG). The objective is to derive the 12-lead ECG and 3-lead VCG from 3 measured leads acquired from only 5 electrodes. METHODS: This is a retrospective blinded study comparing measured and derived ECG and VCG tracings. A nonlinear optimization model was used to synthesize the derived 12-lead ECG and 3-lead derived VCG from leads I, II, and V2. A total of 367 measured 12-lead electrocardiograms and 3-lead vectorcardiograms of varying morphologies were acquired from archived digital ECG databases. All tracings were interpreted by 2 blinded physician reference standards. The derived vs measured tracings were compared quantitatively using Pearson correlation and root mean square error. Qualitative comparisons were determined by physician percent agreement analysis and adjudication. RESULTS: The correlations between the measured and derived ECGs and VCGs were high (r=0.867). No clinically significant differences were noted in 98.1% of cases. Electrocardiographic rate, rhythm, segment, axis, and acute myocardial infarction interpretations showed 100% correlation. Root mean square error compared favorably against other synthesis techniques. Overall percent agreements for the various ECG morphologies were noted to be 98.4% to 100%. CONCLUSIONS: The 12-lead ECG and 3-lead VCG can be derived accurately from 3 measured leads with high quantitative and qualitative correlations. These derived tracings can be acquired instantaneously and displayed in real time from a cardiac rhythm monitor. This will allow for immediate, on-demand, convenient, and cost-effective acquisition and analysis of the 12-lead ECG and 3-lead VCG in areas of acute patient care. PMID- 23810077 TI - Prevalence of remission and recovery in schizophrenia in the Czech Republic. AB - OBJECTIVE: The aim of the study was to map the point prevalence of remission and recovery in patients with schizophrenia in the Czech Republic. METHOD: The point symptomatic remission criteria were based on the definition of remission in schizophrenia according to Andreasen, without the time criterion. The definition of complete remission contained, in addition to the point-symptomatic remission criteria, a time aspect which was determined by the absence of psychiatric hospitalisation or a change in antipsychotic medications due to inefficiency in the preceding six months. Functional remission was defined by a total score on the PSP scale in the range between 71 and 100 points. Recovery was defined by the simultaneous fulfilment of the criteria for complete and functional remission. RESULTS: A total of 481 patients with schizophrenia were included in the study. The point-symptomatic remission criteria were fulfilled in a total of 258 patients (54%); complete remission occurred in a total of 214 patients (44%). Functional remission was reached by 124 patients (26%) in total. Recovery was proven in a total of 91 patients (19%). CONCLUSION: The ascertained data are in accordance with the results of methodologically similar studies and confirm the known trajectories of the course of schizophrenia. PMID- 23810078 TI - Sociodemographic and psychiatric predictors of attrition in a prospective psychiatric epidemiological study among the general population. Result of the Netherlands Mental Health Survey and Incidence Study-2. AB - BACKGROUND: In prospective psychiatric epidemiological studies, attrition at follow-up can be selective, and can bias the research findings. Therefore, knowledge of predictors of attrition and of its different types (noncontact, refusal, inability to participate) is of importance. METHODS: By means of (multinomial) logistic regression analyses, predictors of attrition were studied in the first 3-year follow-up of the second Netherlands Mental Health Survey and Incidence Study (NEMESIS-2), a prospective psychiatric epidemiological study among 6646 subjects of the general population aged 18-64 years. Baseline sociodemographic characteristics, physical health, mental disorders and their clinical characteristics, and experience with the previous interview were studied as predictors of attrition and of its different types. RESULTS: The attrition rate at follow-up was 20.2%. Refusal (14.2%) was more common than noncontact (4.6%) and inability to participate (1.4%). Compared to respondents, nonrespondents were more often younger, lower educated, unemployed and born outside the Netherlands. A less positive experience with the baseline interview and shorter interview duration also predicted attrition. Any 12-month mental disorder, the categories and separate mental disorders, and their clinical characteristics, were not significantly associated with attrition, after controlling for sociodemographics. Sociodemographic predictors and experience with the baseline interview differed between the three types of attrition, but these types were also hardly or not associated with previous mental disorders. CONCLUSIONS: The authors conclude that bias due to selective attrition was limited to sociodemographics and experience with the baseline interview. Mental health status at baseline was not of influence, possibly due to the large time investment to persuade respondents to re-participate and to find them in case of noncontact or removal to an unknown address. During follow-up waves of future prospective studies it is important to implement an intensive recruitment period with special efforts among young adults and the lower educated. PMID- 23810079 TI - Coping profiles in bipolar disorder. AB - OBJECTIVE: As coping responses have the capacity to distinctly influence the illness course in affective disorders, they form targets for psychological intervention. Beneficial effects have been reported for interventions incorporating adaptive coping in bipolar disorder. Identification of differential coping preferences in bipolar disorder sub-types has etiological and clinical implications. As most studies to date have focused exclusively on bipolar I disorder, the current study examines coping profiles in those with a bipolar I or II disorder, contrasted with unipolar depressive and healthy controls. METHODS: Groups were derived on the basis of agreement between clinician and DSM-IV diagnoses. Participants (94 bipolar I, 114 bipolar II, 109 unipolar recurrent depression, 100 healthy controls) completed coping style measures including the Brief Cope, Responses to Positive Affect questionnaire, Response Styles Questionnaire, the Coping Inventory for Prodromes of Mania, and the Cognitive Emotion Regulation Questionnaire. RESULTS: Bipolar (I and II) participants were more likely than unipolar participants to ruminate about positive affect, and engage in risk taking when faced with negative affect. Medication status and current mood symptoms influenced risk-taking scores in the bipolar sub-sets, however rumination about positive affect appeared to represent a trait-like response in those with a bipolar II disorder. Behavioral coping strategies differentiated bipolar sub-types, with bipolar II participants being less likely to seek support when faced with stress, and less likely to engage in strategies to down-regulate hypomania. CONCLUSION: Coping style differences were observed between bipolar sub-types. Further consideration of such differentiating characteristics should serve to direct the focus towards specific targets for clinical intervention, reflecting nuances integral to the differing conditions. PMID- 23810081 TI - Phospholipid-functionalized mesoporous silica nanocarriers for selective photodynamic therapy of cancer. AB - This paper describes the fabrication of a highly efficient, non-cytotoxic drug delivery platform designed for photodynamic therapy (PDT): phospholipid-capped, protoporphyrin IX-loaded and FITC-sensitized mesoporous silica nanocarriers (Lipo FMSNs/PpIX). After derivatization with folate on the phospholipid-capped FMSNs (denoted fa-Lipo-FMSNs/PpIX, the so-called nanoPDT system), we confirmed the nanoPDT systems' selective targeting of and entry into the folic acid receptor overexpressed HeLa cells by means of cell viability assessment and confocal microscopic analysis. The decrease in the unfavorable dark toxicity of fa-Lipo FMSNs/PpIX enabled the delivery of high concentrations of PpIX into cells. Moreover, the cellular uptake of the nanoPDT systems was greater than that of free PpIX. Upon irradiation with visible light, the nanoPDT system generated singlet oxygen efficaciously in aqueous environments-a decisive factor affecting its therapeutic applicability in PDT, demonstrating enhanced in vitro photocytotoxicity. Furthermore, an in vivo study of subcutaneous melanoma in nude mice inoculated with B16F10 cells revealed the capability for the nanoPDT system to mitigate nearly 65% of tumor growth. PMID- 23810082 TI - Statistical shape analysis of clavicular cortical bone with applications to the development of mean and boundary shape models. AB - During car collisions, the shoulder belt exposes the occupant's clavicle to large loading conditions which often leads to a bone fracture. To better understand the geometric variability of clavicular cortical bone which may influence its injury tolerance, twenty human clavicles were evaluated using statistical shape analysis. The interior and exterior clavicular cortical bone surfaces were reconstructed from CT-scan images. Registration between one selected template and the remaining 19 clavicle models was conducted to remove translation and rotation differences. The correspondences of landmarks between the models were then established using coordinates and surface normals. Three registration methods were compared: the LM-ICP method; the global method; and the SHREC method. The LM ICP registration method showed better performance than the global and SHREC registration methods, in terms of compactness, generalization, and specificity. The first four principal components obtained by using the LM-ICP registration method account for 61% and 67% of the overall anatomical variation for the exterior and interior cortical bone shapes, respectively. The length was found to be the most significant variation mode of the human clavicle. The mean and two boundary shape models were created using the four most significant principal components to investigate the size and shape variation of clavicular cortical bone. In the future, boundary shape models could be used to develop probabilistic finite element models which may help to better understand the variability in biomechanical responses and injuries to the clavicle. PMID- 23810080 TI - Differential and synergistic effects of mechanical stimulation and growth factor presentation on vascular wall function. AB - We investigated the hypothesis that immobilizing TGF-beta1 within fibrin hydrogels may act in synergy with cyclic mechanical stimulation to enhance the properties of vascular grafts. To this end, we engineered a fusion TGF-beta1 protein that can covalently anchor to fibrin during polymerization upon the action of factor XIII. We also developed a 24-well based bioreactor in which vascular constructs can be mechanically stimulated by distending the silastic mandrel in the middle of each well. TGF-beta1 was either conjugated to fibrin or supplied in the culture medium and the fibrin-based constructs were cultured statically for a week followed by cyclic distention for another week. The tissues were examined for myogenic differentiation, vascular reactivity, mechanical properties and ECM content. Our results showed that some aspects of vascular function were differentially affected by growth factor presentation vs. pulsatile force application, while others were synergistically enhanced by both. Overall, this two-prong biomimetic approach improved ECM secretion, vascular reactivity and mechanical properties of vascular constructs. These findings may be applied in other tissue engineering applications such as cartilage, tendon or cardiac regeneration where growth factors TGF-beta1 and mechano-stimulation play critical roles. PMID- 23810083 TI - Prevalence and determinants of tobacco use among Iraqi adolescents: Iraq GYTS 2012. AB - BACKGROUND: The use of any form of tobacco by 13-15 year old individuals is 10% globally as identified through the Global Youth Tobacco Survey (GYTS). This study aimed at assessing the prevalence and determinants of tobacco use among Iraqi adolescents. METHODS: A cross sectional study was carried out on 1750 participants selected randomly from preparatory and secondary schools in Baghdad, Iraq in 2012. Through a multistage stratified random sample scheme. The GYTS questionnaire was applied. RESULTS: The study results indicated that 21.8% of Iraqi adolescents are tobacco users (male 27.1%, female 12.7%). Cigarette smoking was noted as the main type of tobacco use (13.9%) followed by shisha (4.8%) and pipe (1.4%). The stepwise logistic regression indicated a number of predictors of tobacco use. Male adolescents were twice more likely to be tobacco users than female students (OR 2.31; 95%C.I: 1.57-3.42). Furthermore, students whose parents or sibling were smokers had doubled the risk of tobacco use relative to those with no parents or siblings current smokers (OR1.97; 95%C.I: 1.04-2.77 and OR1.86; 95%C.I: 1.21-2.87 respectively). Having close friends who smoked was also identified as an important risk factor towards adolescent tobacco use. Those who reported that some of their friends smoked were 2.67 times more likely to be smokers (95%C.I: 1.83-3.89), while those who reported that most/all of their friends were smokers were 8.18 times more likely to be smokers themselves (95%C.I: 4.65-14.39). CONCLUSION: Smoking rates among Iraqi adolescents were found to be among the higher rates of adolescent smoking prevalence in the Middle East. Multiple family and peer related characteristics were related to tobacco use. Preventive activities should take place to curb the tobacco epidemic in Iraq. PMID- 23810084 TI - Foreign body impaction of the vertebral canal. AB - Foreign body impactions in the aerodigestive tract are common, but have the potential for serious complications. A foreign body may disrupt the mucosal lining and migrate regionally thereby risking impingement or injury to critical neurovascular structures in the cervical region. It is important to recognize potential complications that may arise from luminal compromise. In such cases, expeditious surgical treatment is warranted. PMID- 23810085 TI - A new rapid test for fecal calprotectin predicts endoscopic remission and postoperative recurrence in Crohn's disease. AB - INTRODUCTION: Fecal calprotectin (FC), as determined by the enzyme-linked immunoassay (ELISA) test, has been proposed as a promising biomarker of endoscopic activity in Crohn's disease (CD). However data on its accuracy in predicting endoscopic remission according to location and postoperative recurrence (POR) is scarce. Our objective was to evaluate the ability of FC determined by a new quantitative point-of-care test (FC-QPOCT) to predict endoscopic remission and POR in CD patients. METHODS: FC was determined simultaneously by an enzyme-linked immunoassay test (FC-ELISA) and a FC-QPOCT in CD patients undergoing colonoscopy. Clinical disease activity was assessed according to the Crohn's Disease Activity Index (CDAI). Endoscopic results were assessed according to the Crohn's Disease Endoscopic Activity Index of Severity (CDEIS) and postoperative recurrence according to the Rutgeerts' score. RESULTS: A total of 115 ileocolonoscopies were performed (29 on patients with ileocolonic resection). FC levels correlated more closely with the CDEIS than leucocytes, platelets or CRP. The prediction of "endoscopic remission" (CDEIS<3), using FC QPOCT (cut-off 272 MUg/g) and FC-ELISA (cut-off 274 MUg/g) presented an AUC of 0.933 and 0.935 respectively. FC-QPOCT results correlated better with endoscopic activity in the ileocolonic location (Pearson's correlation, r=0.879; P<0.001), than the colonic (r=0.725; P<0.001) or the ileal location (r=0.437; P=0.016). Median FC-QPOCT levels discriminated Rutgeerts' score i0-i1 from i2-i4 (98 (range 30-306) MUg/g vs. 234.5 (range 100-612) MUg/g respectively, P=0.012). CONCLUSIONS: FC determined by rapid quantitative test predicts "endoscopic remission" and endoscopic postoperative recurrence in CD patients. PMID- 23810086 TI - Estimate of body motion during voluntary body sway movements. AB - Balance control can be interpreted as a combination of state feedback control with optimal state estimation. In this framework, state estimation uses an internal model of body and sensor dynamics to process sensory information and determine body orientation. The aim of this study was to assess the ability of the brain to create accurate state estimation when the congruence between sensory information was altered. Participants stood upright on a force platform with a monitor directly in front of them at eye level displaying their center of pressure (CP) position in real-time. When a target appeared on the monitor, participants had to move their CP as fast and as accurately as possible within the target. Voluntary balance pointing movements were made with the head either straight or rotated about the trunk, and mapping directions of the CP were changed on the basis of experimental conditions. Manipulating the sensory information congruency caused less accurate state estimation of the body motion leading to larger signed and absolute angular errors and a greater area of the final CP position were measured. These results suggest that performing head centered to trunk-centered sensorimotor transformation reduces the accuracy in the state estimation of body motion during a balance pointing task. PMID- 23810087 TI - Clinical assessment of reactive postural control among physiotherapists in Ontario, Canada. AB - Reactive postural control, the ability to recover from an external perturbation to stability, ultimately determines whether an individual will fall following a loss of balance and should be routinely incorporated in balance assessment. The purpose of this study was to identify (1) methods used to assess reactive postural control in clinical practice and (2) factors associated with regular assessment of reactive postural control. A cross-sectional survey was conducted. Three hundred and fifty-seven physiotherapists in Ontario, Canada who treated adults with balance impairments answered questions about the components of balance they assess and how they assess reactive control in their practice. Of the 273 respondents who assessed reactive postural control at least some of the time, 15.4% used a standardized measure, 79.1% used a non-standardized approach, and 5.5% used both. Forty-five methods of assessing reactive control were reported. The most common methods used were non-standardized perturbations (43.5%; 104/239 respondents) and movement observation (18.8%; 45/239). The remaining 43 methods were each used by less than 8% of respondents. Practice area had the strongest association with regular assessment of reactive postural control (>60% of the time), and respondents working with neurological disorders were more likely to regularly evaluate reactive control than those working with people with orthopedic conditions. Despite the availability of valid standardized measures to evaluate reactive postural control, respondents relied primarily on non-standardized approaches and observational assessment. Future work should examine the factors influencing choice of reactive control assessment tools and awareness of standardized measures for reactive postural control. PMID- 23810088 TI - Recovery of static stability following a concussion. AB - The purpose of this study was to use centre of pressure (COP) measurements to determine if static balance deficits had recovered when concussed athletes were cleared to return to play. Nine concussed varsity football players were matched with nine teammates who served as controls. Static balance in the anterior posterior (A/P) and medial-lateral (M/L) directions was assessed during quiet stance with eyes open and eyes closed. Results showed that concussed football players displayed greater A/P COP displacements in the acute phase, which recovered by RTP; however, COP velocity remained elevated compared to controls even at RTP, particularly in the A/P direction. This balance control deficit in the A/P direction may suggest vestibular impairment, likely due to poor sensorimotor integration of the lateral vestibulospinal tract. The observed persistence of balance control deficits in concussed football players at RTP are usually undetected by traditional assessments because the current study used higher-order COP analysis. Future RTP balance measures may want to incorporate higher-order measures of balance. PMID- 23810089 TI - The correlation between movement of the center of mass and the kinematics of the spine, pelvis, and hip joints during body rotation. AB - Body rotation is associated with many activities. The concomitant movement of the center of mass (COM) is essential for effective body rotation. This movement is considered to be influenced by kinematic changes in the spine, pelvis, and hip joints. However, there is no research on the association between COM movement and kinematic changes during body rotation. We aimed to investigate the association between COM movement and the kinematics of the spine, pelvis, and hip joints during body rotation in standing. Twenty-four healthy men were included in the study. COM movement during active body rotation in a standing position was measured. We evaluated pelvic shift and changes in the angles of the spine, pelvis, and hip joints. We calculated the Pearson correlation coefficients to analyze the relationship between COM movement and kinematic changes in the spine, pelvis, and hip joints. There were significant correlations between lateral COM movement to the rotational side and pelvic shift to the rotational side, and between posterior COM movement and pelvic shift to the posterior side. In addition, lateral COM movement to the rotational side showed significant and negative correlation with spinal flexion and was significantly and positively correlated with the change in anterior pelvic tilt. Clinicians need to take particular note of both spinal and pelvic motion in the sagittal plane, as well as the pelvic shift, to speculate COM movement during body rotation in standing. PMID- 23810090 TI - Associations of self-report measures with gait, range of motion and proprioception in patients with lumbar spinal stenosis. AB - INTRODUCTION: Spinal stenosis is defined as neurogenic claudication due to narrowing of the spinal canal lumen diameter. As the disease progresses, ambulation and gait may be impaired. Self-report measures are routinely used in the clinical setting to capture data related to lumbar pain symptoms, function and perceived disability. The associations between self-report measures and objective measures of physical function in patients with lumbar spinal stenosis are not well characterized. The purpose of this study was to determine the correlation between self-reported assessments of function with objective biomechanical measures of function. METHODS: 25 subjects were enrolled in this study. Subjects completed self-report questionnaires and biomechanical assessments of gait analysis, lumbar 3D ROM and lumbar proprioception. Correlations were determined between self-report measures and biomechanical data. RESULTS: The Oswestry Disability Index (ODI) was strongly correlated with stride length and gait velocity and weakly correlated with base of support. ODI was also weakly correlated with left lateral bending proprioception but not right lateral bending. The SF12 was not significantly correlated with any of the biomechanical measurements. Pain scores were weakly correlated with velocity, and base of support, and had no correlation any of the other biomechanical measures. DISCUSSION: There is a strong correlation between gait parameters and functional disability as measured with the ODI. Quantified gait analysis can be a useful tool to evaluate patients with lumbar spinal stenosis and to assess the outcomes of treatments on this group of patients. PMID- 23810091 TI - Effects of dual-tasking on control of trunk movement during gait: respective effect of manual- and cognitive-task. AB - Trunk control during gait provides a stable platform for vision and head control. However, in dual-task gait, cognitive tasks result in increased trunk movements, reduced gait speed, and increased gait variability. Manual tasks have been associated with reduced gait speed, but their effects on trunk movement have not been fully investigated. Furthermore, the fear of falling (FoF) during dual-task gait remains relatively unstudied. We aimed to assess trunk movements during cognitive-task gait (CG) and manual-task gait (MG), and examine the effects of CG and MG on individuals with and without FoF. The participants were 117 healthy older adults. We used two triaxial accelerometers: one to record trunk movements at the L3 spinous process and one at the heel to measure initial contact. Participants counted backward by one (CG) or carried a ball on a tray (MG), and we calculated stride time variability and standardized root-mean-square trunk accelerations in the mediolateral (ML) and anteroposterior (AP) directions. CG significantly increased lower trunk oscillations in the ML (t=4.9, p<0.001) and AP directions (t=6.1, p<0.001). Conversely, MG significantly decreased trunk oscillations in the ML (t=-5.9, p<0.001) and AP directions (t=-8.3, p<0.001). The difference in trunk oscillations during CG in the ML direction was significantly larger in subjects with FoF than without FoF (t=2.6, p<0.01). We conclude that for the tasks we studied, CG and MG have different effects on trunk movement. Finally, FoF was associated with changes in trunk movement in the ML direction during CG but not MG. PMID- 23810092 TI - Evaluating runners with and without anterior knee pain using the time to contact the ankle joint complexes' range of motion boundary. AB - BACKGROUND: Little biomechanical evidence exists to support the association between excessive foot pronation and anterior knee pain (AKP). One issue could be the way excessive pronation has been defined. Recent evidence has suggested that evaluating pronation in the context of the joint's available range of motion (ROM, anatomical threshold) provides greater insight on when pronation contributes to injury. Theoretically, quantifying the amount of time the joint has to respond before reaching end range (neuromuscular threshold) could provide additional insight. Therefore the purpose of this study was to use a neuromuscular threshold, the time to contact (TtC) the ankle joint complex's ROM boundary, to evaluate runners with and without AKP. METHODS: Nineteen healthy and seventeen runners with AKP had their ROM and running biomechanics evaluated. The TtC was calculated using each individual's angular distance from end range (eversion buffer) and eversion velocity. Data were recorded over ten stance phases and evaluated using a one way analysis of variance and 95% confidence intervals. RESULTS: Runners with AKP had significantly shorter TtC the joint's ROM boundary when compared to healthy runners (64.0 ms vs. 35.6 ms, p=0.01). While not statistically significant, this shorter TtC was in large part due to having a smaller eversion buffer, however velocity was found to have a substantial influence on the TtC of select individuals. These results provide evidence that a link between pronation and AKP exists when using anatomical and neuromuscular based thresholds. PMID- 23810093 TI - Double-leg stance and dynamic balance in individuals with functional ankle instability. AB - To investigate whether double-leg stance could reveal balance deficits in subjects with functional ankle instability (FAI) and whether such an assessment of static balance would be correlated with measures of dynamic instability, 16 individuals with FAI and 16 healthy controls participated in this study. Static postural control was tested using double-leg stance (either with the eyes open (EO) or closed (EC)) on a dual-plate force platform. Dynamic balance was evaluated using the Multiple Hop Test (MHT) and a weight-shifting task. FAI subjects were significantly less stable in the anteroposterior direction during double-leg stance (as assessed by velocity of centre of pressure, VCP), both for the EO and EC condition. In the mediolateral direction the VCP values were also higher in FAI, but significance was only found for the EC condition (p=.02). FAI subjects made significantly more balance errors compared to healthy controls (p<.001) on both the affected and less affected leg during MHT. There were no significant differences between FAI and healthy subjects during the weight shifting task. No relationship was found between double-leg stance and MHT measures (all correlations (rs) less than .30). This study suggests that static postural control during double-leg stance is impaired in FAI subjects. Although dynamic balance during MHT is also affected, no significant relationship was found between static and dynamic measurements, which indicate that they are most probably related to different aspects of postural control. PMID- 23810094 TI - Increased prevalence of non-compaction. PMID- 23810095 TI - Reply to Jerome Verine's letter to the editor Re: Rodolfo Montironi, Marina Scarpelli, Liang Cheng, et al. Immunoglobulin G4-related disease in genitourinary organs: an emerging fibroinflammatory entity often misdiagnosed preoperatively as cancer. PMID- 23810097 TI - Omalizumab in patients with symptomatic chronic idiopathic/spontaneous urticaria despite standard combination therapy. AB - BACKGROUND: Patients with chronic idiopathic urticaria/chronic spontaneous urticaria (CIU/CSU) often continue to experience symptoms despite receiving standard-of-care therapy with H1-antihistamines along with 1 or more add-on therapies. OBJECTIVES: We sought to evaluate the safety and efficacy of 24 weeks of treatment with omalizumab in patients with persistent CIU/CSU despite treatment with H1-antihistamines at up to 4 times the approved dose plus H2 antihistamines, leukotriene receptor antagonists, or both. METHODS: In this phase III study patients were randomized to receive 6 subcutaneous injections at 4-week intervals of either 300 mg of omalizumab or placebo, followed by a 16-week observation period. The primary objective of the study was to evaluate the overall safety of omalizumab compared with placebo. Efficacy (itch severity, hive, and urticaria activity scores) was evaluated at weeks 12 and 24. RESULTS: The overall incidence and severity of adverse events and serious adverse events were similar between omalizumab and placebo recipients; the safety profile was consistent with omalizumab in patients with allergic asthma. At week 12, the mean change from baseline in weekly itch severity score was -8.6 (95% CI, -9.3 to 7.8) in the omalizumab group compared with -4.0 (95% CI, -5.3 to -2.7) in the placebo group (P < .001). Significant improvements were seen for additional efficacy end points at week 12; these benefits were sustained to week 24. CONCLUSION: Omalizumab was well tolerated and reduced the signs and symptoms of CIU/CSU in patients who remained symptomatic despite the use of H1-antihistamines (up to 4 times the approved dose) plus H2-antihistamines, leukotriene receptor antagonists, or both. PMID- 23810098 TI - Newborn screening for severe combined immunodeficiency and T-cell lymphopenia in California: results of the first 2 years. AB - BACKGROUND: Assay of T-cell receptor excision circles (TRECs) in dried blood spots obtained at birth permits population-based newborn screening (NBS) for severe combined immunodeficiency (SCID). OBJECTIVE: We sought to report the first 2 years of TREC NBS in California. METHODS: Since August 2010, California has conducted SCID NBS. A high-throughput TREC quantitative PCR assay with DNA isolated from routine dried blood spots was developed. Samples with initial low TREC numbers had repeat DNA isolation with quantitative PCR for TRECs and a genomic control, and immunophenotyping was performed within the screening program for infants with incomplete or abnormal results. Outcomes were tracked. RESULTS: Of 993,724 infants screened, 50 (1/19,900 [0.005%]) had significant T-cell lymphopenia. Fifteen (1/66,250) required hematopoietic cell or thymus transplantation or gene therapy; these infants had typical SCID (n = 11), leaky SCID or Omenn syndrome (n = 3), or complete DiGeorge syndrome (n = 1). Survival to date in this group is 93%. Other T-cell lymphopenic infants had variant SCID or combined immunodeficiency (n = 6), genetic syndromes associated with T-cell impairment (n = 12), secondary T-cell lymphopenia (n = 9), or preterm birth (n = 8). All T-cell lymphopenic infants avoided live vaccines and received appropriate interventions to prevent infections. TREC test specificity was excellent: only 0.08% of infants required a second test, and 0.016% required lymphocyte phenotyping by using flow cytometry. CONCLUSIONS: TREC NBS in California has achieved early diagnosis of SCID and other conditions with T-cell lymphopenia, facilitating management and optimizing outcomes. Furthermore, NBS has revealed the incidence, causes, and follow-up of T-cell lymphopenia in a large diverse population. PMID- 23810099 TI - Activation of group 2 innate lymphoid cells: a new role for cysteinyl leukotrienes. PMID- 23810100 TI - Role of diet and gut microbiota in management of inflammatory bowel disease in an Asian migrant. PMID- 23810101 TI - Letter to the editor. PMID- 23810102 TI - Monitoring of extra-axial brain tumor response to radiotherapy using pseudo continuous arterial spin labeling images: preliminary results. AB - INTRODUCTION: Technological developments have increased the ease of performing perfusion MRI by arterial spin labeling (ASL) in clinical settings. The objective of this study was to evaluate the effects of radiotherapy on extra-axial brain tumors by using MR perfusion images obtained using the pseudo-continuous arterial spin labeling (pcASL) method. MATERIALS AND METHODS: Six consecutive patients (nine lesions) with extra-axial brain tumors treated only with radiotherapy were enrolled in this study. MR examinations, including pcASL imaging, were performed before and after radiotherapy. Cerebral blood flow, maximum tumor blood flow (mTBF), tumor volume and the ratio of signal enhancement by contrast material (enhancement ratio) were evaluated in serial examinations during the course of radiotherapy. Both the percentage change in mTBF (mTBF ratio) and the percentage change in volume (volume ratio) were calculated using values obtained before and after radiotherapy. The correlation between the volume ratio and the mTBF ratio was assessed using linear regression analysis and Spearman's rank correlation coefficient (rs). RESULTS: A strong correlation was demonstrated between the tumor volume ratio and the mTBF ratio before and after radiotherapy (rs=0.93, P<.01). However, no significant correlation was identified between changes in enhancement and volume ratio (rs=0.20) or between changes in enhancement and mTBF ratio (rs=0.30) before and after radiotherapy. CONCLUSION: The mTBF measured using pcASL may serve as an additive index for tumor volume when determining tumor response to radiotherapy even in the absence of contrast material. PMID- 23810103 TI - Safety, effectiveness, and cost of dipeptidyl peptidase-4 inhibitors versus intermediate acting insulin for type 2 diabetes: protocol for a systematic review and network meta-analysis. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) results from insulin resistance and relative insulin deficiency. T2DM treatment is a step-wise approach beginning with lifestyle modifications (for example, diet, exercise), followed by the addition of oral hypoglycemic agents (for example, metformin). Patients who do not respond to first-line therapy are offered second-line therapy (for example, sulfonylureas). Third-line therapy may include insulin and/or dipeptidyl peptidase-4 (DPP-4) inhibitors.It is unclear whether DPP-4 inhibitors are safer and more effective than intermediate acting insulin for third-line management of T2DM. As such, our objective is to evaluate the comparative effectiveness, safety and cost-effectiveness of DPP-4 inhibitors versus intermediate acting insulin for T2DM patients who have failed both first- and second-line diabetes treatments. DESIGN/METHODS: Electronic searches of MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, and grey literature (for example, trial registries, public health websites) will be conducted to identify studies examining DPP-4 inhibitors compared with each other, intermediate acting insulin, no treatment, or placebo for adults with T2DM. The outcomes of interest include glycosylated hemoglobin (A1C) (primary outcome), as well as emergency department visits, physician visits, hospital admissions, weight gain, quality of life, microvascular complications, macrovascular complications, all-cause mortality, and cost (secondary outcomes). Randomized clinical trials (RCTs), quasi-RCTs, non RCTs, controlled before-after, interrupted time series, cohort studies, and cost studies reporting data on these outcomes will be included. Eligibility will not be restricted by publication status, language of dissemination, duration of study follow-up, or time period of study conduct.Two reviewers will screen the titles and abstracts resulting from the literature search, as well as potentially relevant full-text articles, in duplicate. Data will be abstracted and quality will be appraised by two team members independently. Conflicts at all levels of screening and abstraction will be resolved through team discussion.Our results will be described narratively. Random effects meta-analysis and network meta analysis will be conducted, if feasible and appropriate. DISCUSSION: Our systematic review results can be used to determine the most effective, safe and cost-effective third-line strategies for managing T2DM. This information will be of great use to health policy-makers and clinicians, as well as patients living with T2DM and their families. TRIAL REGISTRATION: PROSPERO registry number: CRD42013003624. PMID- 23810105 TI - Meta-analysis of confocal laser endomicroscopy for the detection of colorectal neoplasia. AB - AIM: Confocal laser endomicroscopy (CLE) is a recently developed technique used to image colorectal neoplasia. Trials have shown varied results when it is compared with conventional colonoscopy. A meta-analysis was performed to determine the diagnostic accuracy of CLE in the detection of colorectal neoplasia. METHOD: A search was performed for studies assessing the accuracy of CLE in colorectal neoplasia. Studies comparing CLE diagnostic accuracy with conventional endoscopy in the detection of colorectal neoplasia were included. Exclusion criteria included case reports or case series, reviews, duplicate reports or insufficient data in the paper. Seventy-eight titles came up in the initial search and six studies were selected. These were subjected to a meta analysis. In all, 284 patients with 1030 lesions were included. Each patient underwent conventional colonoscopy and CLE. Per-lesion sensitivity and specificity with 95% CI were calculated. RESULTS: In the individual studies, the sensitivity ranged from 33.3% to 100% and specificity from 71.6% to 99.4%. The weighted and total pooled result (random effects model) for sensitivity was 81% (95% CI 77-85) and for specificity was 88% (95% CI 85-90). The area under the weighted symmetric summary receiver operating curve was 0.9186. In the endoscope based CLE subgroup, the sensitivity was 82% (95% CI 69-91) and specificity was 94% (95% CI 91-96). In the probe-based CLE subgroup, the sensitivity was 81% (95% CI 76-85) and the specificity was 75% (95% CI 69-81). CONCLUSION: CLE, using either the endoscope-based CLE or probe-based CLE technique, has high sensitivity and specificity. It could therefore be considered as an alternative endoscopic method to distinguish neoplastic from non-neoplastic lesions. PMID- 23810104 TI - Effect of smoking on outcomes of urothelial carcinoma: a systematic review of the literature. AB - CONTEXT: Cigarette smoking is the best-established risk factor for urothelial carcinoma (UC). However, the effect of smoking on outcomes of UC patients remains debated. OBJECTIVE: To integrate the available evidence regarding the impact of smoking status and smoking exposure on recurrence, progression, cancer-specific mortality, and any-cause mortality in patients with UC of the bladder (UCB) and upper tract UC (UTUC) treated with transurethral resection of the bladder (TURB), radical cystectomy (RC), or radical nephroureterectomy (RNU). EVIDENCE ACQUISITION: A systematic search of the literature was conducted using the Medline, Embase, and Scopus databases, which was limited to articles published in English between January 1974 and March 2013. Articles were also extracted from the reference lists of identified studies and reviews. We selected 29 articles (15 TURB, 7 RC, and 7 RNU) according to predefined inclusion criteria and the Preferred Reporting Items for Systematic Reviews and Meta-analyses. EVIDENCE SYNTHESIS: The majority of studies demonstrated an association with disease recurrence in patients treated with TURB, while evidence for associations with disease progression, cancer-specific mortality, and any-cause mortality was less abundant. While two studies showed no association of smoking with outcomes of T1 UCB, there was mixed evidence for an association of smoking with response to intravesical therapy. For patients treated with RC, there was minimal support for an association of smoking with all outcomes. In a majority of studies of patients receiving RNU for UTUC, smoking was associated with intravesical recurrence, disease recurrence, cancer-specific mortality, and any-cause mortality. There was also evidence for a beneficial effect of smoking cessation on UC prognosis. Finally, findings regarding gender-specific effects of smoking on prognosis were contradictory. We note that there was marked heterogeneity in patient populations and smoking categorizations across studies, precluding a meta-analysis. CONCLUSIONS: Smoking may lead to less favorable outcomes for UCB and UTUC patients, and smoking cessation may mitigate this effect. The current evidence base lacks studies on the effects of smoking on prognosis in numerous clinical demographic subgroups of UC patients, as well as prospective investigation of smoking cessation. PMID- 23810106 TI - Was Akhenaten really sick? AB - The depictions of Akhenaten have long interested medicine and above all endocrinology because of the eunuch gynoid morphology of this pharaoh. These depictions call to mind various diagnostic hypotheses that have been successively considered as endocrinology progresses, with emphasis on the three diseases recently identified (gynecomastia family, Kennedy's disease, and fertile eunuch syndrome), which are compatible with the now proven fertility of Akhenaten. PMID- 23810109 TI - Effects of a low-volume, nutrient- and energy-dense oral nutritional supplement on nutritional and functional status: a randomized, controlled trial in nursing home residents. AB - OBJECTIVES: Although oral nutritional supplements (ONS) are known to be effective to treat malnutrition in the elderly, evidence from nursing home populations, including individuals with dementia, is rare, especially with regard to functionality and well-being. A known barrier for ONS use among elderly is the volume that needs to be consumed, resulting in low compliance and thus reduced effectiveness. This study aimed to investigate the effects of a low-volume, energy- and nutrient-dense ONS on nutritional status, functionality, and quality of life (QoL) of nursing home residents. DESIGN: Randomized controlled intervention trial. SETTING: Six nursing homes in Nurnberg and Fuerth, Germany. PARTICIPANTS: Nursing home residents affected by malnutrition or at risk of malnutrition. INTERVENTION: Random assignment to intervention (IG) and control group (CG), receiving 2 * 125 mL ONS (600 kcal, 24 g protein) per day and routine care, respectively, for 12 weeks. MEASUREMENTS: Nutritional (weight, body mass index [BMI], upper arm and calf circumferences, MNA-SF) and functional parameters (handgrip strength, gait speed, depressive mood [GDS], cognition [MMSE], activities of daily living [Barthel ADL]) as well as QoL (QUALIDEM) were assessed at baseline (T1) and after 12 weeks (T2). ONS intake was registered daily and compliance calculated. RESULTS: A total of 77 residents (87 +/- 6 y, 91% female) completed the study; 78% had dementia (MMSE <17) and 55% were fully dependent (ADL <=30). Median compliance was 73% (IQR 23.5%-86.5%) with median intake of 438 (141-519) kcal per day. Body weight, BMI, and arm and calf circumferences increased in the IG (n = 42) and did not change in the CG (n = 35). Changes of all nutritional parameters except MNA-SF significantly differed between groups in favor of the IG (P < .05). GDS, handgrip strength, and gait speed could not be assessed in 46%, 38%, and 49% of participants at T1 and/or T2, because of immobility and cognitive impairment. In residents able to perform the test at both times, functionality remained stable in IG and CG, except for ADLs, deteriorating in both groups. From 10 QoL categories, "positive self-perception" increased in IG (78 [33-100] to 83 [56-100]; P < .05) and tended to decrease in CG (100 [78-100] to 89 [56-100]; P = .06), "being busy" significantly dropped in CG (33 [0-50] to 0 [0-50]; P < .05). CONCLUSION: Low-volume, nutrient- and energy dense ONS were well accepted among elderly nursing home residents with high functional impairment and resulted in significant improvements of nutritional status and, thus, were effective to support treatment of malnutrition. Assessment of function was hampered by dementia and immobility, limiting the assessment of functionality, and highlighting the need for better tools for elderly with functional impairments. ONS may positively affect QoL but this requires further research. PMID- 23810110 TI - SARC-F: a simple questionnaire to rapidly diagnose sarcopenia. PMID- 23810108 TI - Social inequalities in mental health and mortality among refugees and other immigrants to Sweden--epidemiological studies of register data. AB - The aim of this PhD project was to increase knowledge, using population-based registers, of how pre- and post-migration factors and social determinants of health are associated with inequalities in poor mental health and mortality among refugees and other immigrants to Sweden. Study I and II had cross-sectional designs and used logistic regression analysis to study differences in poor mental health (measured with prescribed psychotropic drugs purchased) between refugee and non-refugee immigrants. In Study I, there was a significant difference in poor mental health between female refugees and non-refugees (OR=1.27; CI=1.15 1.40) when adjusted for socio-economic factors. In Study II, refugees of most origins had a higher likelihood of poor mental health than non-refugees of the same origin. Study III and IV had cohort designs and used Cox regression analysis. Study III analysed mortality rates among non-labour immigrants. Male refugees had higher relative risks of mortality from cardiovascular disease (HR=1.53; CI=1.04-2.24) and external causes (HR=1.59; CI=1.01-2.50) than male non refugees did, adjusted for socio-economic factors. Study IV included the population with a strong connection to the labour market in 1999 to analyse the relative risk of hospitalisation due to depressive disorder following unemployment. The lowest relative risk was found among employed Swedish-born men and the highest among foreign-born females who lost employment during follow-up (HR=3.47; CI=3.02-3.98). Immigrants, and particularly refugees, have poorer mental health than native Swedes. Refugee men have a higher relative mortality risk for cardiovascular disease and external causes of death than do non refugees. The relative risk of hospitalisation due to depressive disorder following unemployment was highest among immigrant women. To promote mental health and reduce mortality among immigrants, it is important to consider pre- and post-migration factors and the general social determinants of health. PMID- 23810111 TI - Reduced expression of Na+/H+ exchanger isoform 3 (NHE-3) in preeclamptic placentas. AB - Although the etiology of preeclampsia is unknown, accumulated evidence suggests that the expression of a variety of syncytiotrophoblast transporters is reduced or abnormal. Here, we have examined the expression of NHE-3 in preeclamptic placentas. We found that NHE-3 expression significantly decreased and its labeling was almost undetectable in the cytosol of syncytiotrophoblast cells. Even though the inductor mechanisms of NHE-3 decrease are not clear yet, we speculated that alterations in TNF-alpha and aldosterone levels observed in preeclampsia might be downregulating NHE-3 expression. Further studies are needed to define whether these alterations play a direct role either in the pathogenesis or in the adaptative response of preeclampsia. PMID- 23810112 TI - Tricuspid annuloplasty concomitant with mitral valve surgery: effects on right ventricular remodeling. AB - OBJECTIVES: Tricuspid valve annuloplasty (TVP) has been advocated concomitantly with left-sided cardiac surgery in case of more than moderate tricuspid regurgitation (TR) or tricuspid annular dilation (TAD) (diameter >40 mm or 21 mm/m2) even in the absence of significant TR. Data on postoperative right ventricular (RV) remodeling are lacking in such patients. METHODS: Preoperative and postoperative echocardiography data from 45 consecutive TVP procedures, performed in mitral valve surgery in a single tertiary center, were retrospectively analyzed and compared with a propensity-matched control group of 33 procedures without concomitant TVP. RV function and geometry was analyzed by measuring RV size, fractional area change, and end-diastolic sphericity index (RVSI = long-axis length/short-axis width) and compared at baseline versus follow up. RESULTS: At a mean follow-up of 5 months, a favorable change in RV geometry was observed in TVP patients (RVSI increased from 1.99 +/- 0.33 to 2.21 +/- 0.42; P = .001), whereas the opposite was observed in the control group (RVSI decreased from 2.34 +/- 0.52 to 2.17 +/- 0.13; P = .05). Only in control patients, indexed RV end-diastolic area increased significantly (P = .003). In TVP patients, when comparing patients with baseline more than moderate TR (n = 13) to patients with isolated TAD (n = 32), there was a significant decrease in RV end-diastolic area only in the group with more than moderate TR (from 12.9 +/- 3.5 cm(2)/m(2) to 10.3 +/- 1.9 cm(2)/m(2); P = .009). CONCLUSIONS: Adding TVP to mitral valve surgery in patients with more than moderate TR or TAD leads to favorable changes in RV geometry and prevents postoperative RV dilation. This is most pronounced in patients with more than moderate TR at baseline. PMID- 23810113 TI - Prognostic factors after complete resection of pN2 non-small cell lung cancer. AB - OBJECTIVES: This retrospective, multicenter study aimed to determine prognostic factors of completely resected pathologic N2 stage IIIA non-small cell cancer (NSCLC). METHODS: From 25 participating hospitals, 496 patients (325 men and 171 women; median age, 65 years) who underwent complete resection without preoperative treatment for pT1-3 N2 M0, stage IIIA NSCLC between 2000 and 2004 were enrolled. Lobectomy/bilobectomy was performed in 462 patients and pneumonectomy in 34. Some kind of adjuvant chemotherapy was administered to 296 patients. Survivals were calculated using the Kaplan-Meier method, and prognostic factors were determined using the Cox proportional hazards model. RESULTS: Five year overall survival (OS) and disease-free survival (DFS) were 44.8% and 24.2%, respectively. pT classification (hazard ratio (HR), pT1/pT2/pT3 = 1/1.32/2.03), single or multiple N2 metastases (HR, single/multiple = 1/1.36), and skip or nonskip N2 metastasis (HR, skip/nonskip = 1/1.30) were found to be independent prognostic factors for DFS. Sex (HR, female/male = 1/1.36), performance status (HR, PS-0/PS-1 = 1/1.37), tumor diameter (HR, 1.12 per 1-cm increase), pT-factor (HR, pT1/pT2/pT3 = 1/1.37/2.22), and extent of N2 metastasis (HR, localized/extended = 1/1.39) were shown to be independent prognostic factors for OS. CONCLUSIONS: We found that pT classification was a significant prognostic indicator for OS and DFS whereas tumor diameter, performance status, and sex were ones for OS. Single N2 metastasis and skip N2 metastasis were demonstrated as favorable prognostic factors for DFS, limited N2 metastasis was one for OS, and these should be considered as stratification factors for trial on adjuvant therapy. PMID- 23810114 TI - Conservative management of postoperative bronchopleural fistulas. AB - OBJECTIVE: A bronchopleural fistula (BPF) is a serious complication after pulmonary resection and carries a high mortality rate. It remains a therapeutic challenge. The lack of a consensus suggests that no optimal therapy is available; however, endoscopic closure of a fistula may avoid extensive and potentially risky surgery. METHODS: Seventeen patients (15 men and 2 women) with a BPF after a pneumonectomy (n = 2) or a lobectomy (n = 15), seen between 1995 and 2010, were reviewed. Their median age was 50 years (range, 14-75 years). Underlying diseases were malignant (n = 4) and nonmalignant (n = 13). RESULTS: The mean interval between surgery and fistula development was 20 days (range, 5-270 days). Clinical symptoms leading to a diagnosis of BPF were a persistent air leak (n = 2), a persistent air leak associated with pleural empyema (n = 3), pleural empyema alone (n = 11), and dyspnea (n = 1). Mean fistula size was 3.3 mm (range, 2-9 mm). Treatment consisted of oriented pleural drainage, adequate antibiotic therapy, and endoscopic closure of the fistula with local application of silver nitrate through a flexible bronchoscope (3-15 sessions, 3 times per week). Fistula closure was successful in 16 patients, but failed in 1 patient, who died from acute respiratory distress. CONCLUSIONS: BPF is a severe complication in thoracic surgery. The combination of pleural drainage, adequate antibiotic treatment, and mucosal application of silver nitrate, through a flexible bronchoscope, is an efficient alternative and avoids extensive surgical intervention. PMID- 23810115 TI - Acute splenic syndrome in an African-American male with sickle cell trait on a commercial airplane flight. AB - BACKGROUND: Patients with sickle cell trait (SCT) generally suffer few effects of sickle cell disease. Acute splenic syndrome is a rare but well-documented complication of SCT that can present in the setting of low oxygen tension that occurs with major changes in altitude, either by unpressurized air flight or ground travel such as mountain climbing. OBJECTIVE: Our objective was to increase emergency physician awareness of the rare diagnosis of altitude-induced splenic infarction in patients with SCT by presenting and reviewing recorded literature. CASE REPORT: This is an unusual case of a man with SCT who suffered acute splenic syndrome while on a pressurized airplane flight subsequently requiring splenectomy. CONCLUSIONS: Although it is a rare phenomenon, patients with SCT who are exposed to high altitudes can be subject to splenic syndrome. There are many patients who are unaware that they have SCT, which makes the diagnosis challenging for emergency physicians. In addition, because patients with SCT generally do not have complications related to their disease, diagnosing splenic syndrome might be delayed, potentially resulting in inadequate hydration, pain management, and other supportive treatment, which ultimately leads to worsening splenic syndrome and splenectomy. PMID- 23810116 TI - Case report: ovarian torsion in pregnancy - diagnosis and management. AB - BACKGROUND: Ovarian torsion (OT) is one of the most common gynecologic surgical emergencies. All age groups can be affected, but ovarian stimulation, as found during early pregnancy or infertility treatment, is a major risk factor. OBJECTIVE: Diagnosing OT in early pregnancy can be challenging. Patients frequently present with abdominal pain and non-specific symptoms. Missed diagnosis of OT could lead not only to ovarian necrosis and sepsis, but also threaten the pregnancy. The objective of this article is to present a case of OT in early pregnancy and to review its epidemiology, diagnosis, and treatment. CASE REPORT: A 30-year-old woman at 10 weeks gestational age presented to the Emergency Department (ED) with 2 h duration of abdominal pain, nausea, and vomiting. The patient was not on ovarian stimulation treatments. A bedside ED ultrasound showed an enlarged edematous right ovary with a large cyst, but without flow on color Doppler. Immediate obstetric consultation was initiated. Eventual radiology ultrasound showed decreased but present flow in the right ovary. The patient underwent emergent laparoscopic surgery, during which the necrotic right ovary was removed. She was placed on progesterone therapy upon hospital discharge and eventually delivered a healthy term infant. CONCLUSIONS: Ovarian torsion in pregnancy is increasing in frequency due to the growing prevalence of ovarian stimulation treatment. Although diagnostic ultrasound is a frequently used imaging tool in patients with suspected OT, the mere presence of blood flow on Doppler ultrasonography of the adnexa has a poor negative predictive value. A high clinical suspicion and early laparoscopic management correlate with favorable maternal and fetal outcomes. PMID- 23810117 TI - Unrecognized carbon monoxide poisoning leads to a multiple-casualty incident. AB - BACKGROUND: Carbon monoxide (CO) is regarded as a leading cause of morbidity and mortality. It endangers not only patients, but also health care professionals, especially emergency medical services (EMS) personnel because CO exposure is often unknown at the time EMS is called. OBJECTIVE: Our objective was to report a case of unrecognized CO exposure during the treatment of a patient that finally led to the hospitalization of 11 EMS personnel. CASE REPORT: A 71-year-old man was found unconscious in the basement of his house. EMS was called and, due to ST segment elevations on electrocardiogram, the patient was treated for acute coronary syndrome. Unknown to EMS personnel, ongoing CO exposure was the cause of the patient's symptoms. EMS staff finally had to be evacuated by firefighters, and a total of 12 persons, including the initial patient, had to be hospitalized. CONCLUSIONS: In the prehospital setting, hazardous environments always have to be considered as potential causes of a patient's altered status. Together with the correct use of modern equipment, such as permanently switched-on CO detectors, this can help avoid harm to both patients and staff. PMID- 23810118 TI - Herlyn Werner Wunderlich syndrome: an unusual presentation of acute vaginal pain. AB - BACKGROUND: Herlyn Werner Wunderlich Syndrome (HWWS) is a congenital abnormality of the Mullerian duct system resulting in uterovaginal duplication, obstructive hemivagina, and ipsilateral renal agenesis. It typically presents shortly after menarche with gradual onset of progressive pelvic pain. CASE REPORT: We report a case of a 19-year-old female who presented to the Emergency Department with sudden onset of severe vaginal pain that was determined to be due to hematocolpos; imaging confirmed the diagnosis of HWWS. CONCLUSIONS: To the best of our knowledge abrupt onset of vaginal pain due to HWWS has not been reported previously. We present this case to increase awareness among emergency physicians of this rare and interesting entity. PMID- 23810119 TI - Resting-state fMRI mapping of cerebellar functional dysconnections involving multiple large-scale networks in patients with schizophrenia. AB - BACKGROUND: Recent findings have indicated that patients with schizophrenia have altered cortico-cerebellar connectivity, but the nature of these network dysconnections remains unclear. AIMS: We applied a network-based approach to investigate the functional connectivity (FC) of the cerebellum in patients with schizophrenia. METHODS: Thirty-six patients with schizophrenia and 36 healthy controls underwent resting functional magnetic resonance imaging. We derived the following 6 major networks by applying group independent component analysis: (1) the cingulo-opercular network (CON); (2) the dorsal default-mode networks (dDMN); (3) the ventral default-mode network (vDMN); (4) the left frontoparietal networks (lFPN); (5) the right frontoparietal network (rFPN); and (6) the motor network (MOT). We defined 12 regions of interest (ROIs) by selecting the first 2 peaks of each network in the cerebellum. The FC map of all ROIs was calculated for each participant and compared between groups. RESULTS: The schizophrenic patients showed a decrease in FC between the cerebellar ROIs and the thalamus in all networks except the MOT. The FC decreased between cerebellar ROIs and the frontal cortex in the CON, rFPN, and MOT. However, the FC increased with the precentral gyrus and postcentral gyrus for the CON, lFPN, and dDMN. An increased FC with the occipital fusiform gyrus and the temporal occipital fusiform gyrus was also noted in the dDMN, vDMN, and MOT. CONCLUSIONS: The dysconnection of the cerebellum in the examined patients with schizophrenia was network-specific. The cerebellar thalamic dysconnections were the most prominent findings and were common to all cognitive-related networks, whereas the cortico-cerebellar connectivity involved both an increase and decrease in FC, and depended more on the nature of the specific network. PMID- 23810120 TI - General intellectual functioning as a buffer against theory-of-mind deficits in individuals at ultra-high risk for psychosis. AB - The influence of neurocognition, including general intelligence, on theory of mind (ToM) among patients with schizophrenia spectrum disorder is controversial. The purpose of the present study was to identify the influences of the non-ToM cognition and general intelligence on ToM performance in individuals at ultra high risk (UHR) for psychosis. Fifty-five UHR subjects and 58 healthy controls (HCs) completed neurocognitive, verbal, and nonverbal ToM tasks. UHR individuals showed poorer performance in the two verbal ToM tasks, the false-belief task and the strange-story tasks. Moreover, the UHR subjects displayed poorer recall on the interference list of the verbal learning test. Linear regression analysis revealed that neurocognitive functioning, including executive functioning, working memory, and general intelligence, accounted for significant amounts of the variance in the results for UHR individuals: 20.4% in the false-belief task, 44.0% in the strange-story task, and 49.0% in the nonverbal cartoon task. Neurocognition, including general intelligence, was not a significant contributor to performance on ToM tasks in HCs. ToM deficits were not noted in UHR individuals with above-average IQ scores (>= 110) compared with UHR subjects with IQ scores less than 110, who displayed significant differences on all ToM tasks compared with HCs. The present results suggest that ToM deficits in UHR individuals are complex and may be influenced by non-ToM cognition. Our findings are discussed in relation to the role of neurocognitive abilities in ToM-related impairments in UHR individuals. PMID- 23810122 TI - A detailed analysis of the effect of repetitive transcranial magnetic stimulation on negative symptoms of schizophrenia: a double-blind trial. AB - OBJECTIVE: The aim of the study was to assess the effect of rTMS not only on the general severity of negative schizophrenia symptoms, but also particularly on their individual domains, such as affective flattening or blunting, alogia, avolition or apathy, anhedonia, and impaired attention. METHODS: Forty schizophrenic male patients on stable antipsychotic medication with prominent negative symptoms were included in the study. They were divided into two groups: 23 were treated with active and 17 with placebo rTMS. Both treatments were similar, but placebo rTMS was administered using a purpose-built sham coil. Stimulation was applied to the left dorsolateral prefrontal cortex (DLPFC). The stimulation frequency was 10 Hz; stimulation intensity was 110% of the individual motor threshold intensity. Each patient received 15 rTMS sessions on 15 consecutive working days (five working days "on" and two weekend days "off" design). Each daily session consisted of 20 applications of 10-second duration with 30-second intervals between sequences. The patients and raters were blind to condition of stimulation treatment. RESULTS: The active rTMS led to a statistically significantly higher reduction of the Scale for the Assessment of Negative Symptoms (SANS) total score and of all domains of negative symptoms of schizophrenia. After Bonferroni adjustments for multiple testing, the statistical significance disappeared in alogia only. CONCLUSION: High-frequency rTMS stimulation over the left DLPFC at a high stimulation intensity with a sufficient number of applied stimulating pulses may represent an efficient augmentation of antipsychotics in alleviating the negative symptoms of schizophrenia. PMID- 23810121 TI - Neurocognitive development in first episode psychosis 5 years follow-up: associations between illness severity and cognitive course. AB - Cognitive deficits are documented in first-episode psychosis (FEP), but the continuing course is not fully understood. The present study examines the longitudinal development of neurocognitive function in a five year follow-up of FEP-patients, focusing on the relation to illness severity, as measured by relapses and diagnostic subgroups. The study is an extension of previous findings from the TIPS-project, reporting stability over the first two years. Sixty-two FEP patients (53% male, age 28 +/- 9 years) were neuropsychologically examined at baseline and at 1, 2, and 5 year follow-ups. The test battery was divided into five indices; Verbal Learning, Executive Function, Impulsivity, Motor Speed, and Working Memory. To investigate the effect of illness severity, the sample was divided in groups based on number of relapses, and diagnostic subgroups, respectively. Impulsivity and Working Memory improved significantly in the first two years, followed by no change over the next three years. Motor Speed decreased significantly from 2 to 5 years. Number of relapses was significantly related to Verbal Learning and Working Memory, showing a small decrease and less improvement, respectively, in patients with two or more episodes. No significant association was found with diagnostic group. Neurocognitive stability as well as change was found in a sample of FEP-patients examined repeatedly over 5 years. Of potential greater importance for understanding how psychotic illnesses progress, is the finding of significant associations between neurocognition and number of relapses but not diagnostic group, indicating that neurocognition is more related to recurring psychotic episodes than to the descriptive diagnosis per se. PMID- 23810123 TI - Beta EEG band: a measure of functional brain damage and language reorganization in aphasic patients after recovery. AB - Functional reorganization of language was investigated in a group of eleven non fluent aphasic patients after linguistic recovery and in a group of matched healthy adults. The ElectroEncephaloGram (EEG) was recorded from 38 scalp electrodes and high-beta band (21-28 Hz), an index of cognitive cortical arousal, was computed as normalized percentage across 0-100 Hz spectral range in six electrode clusters during three linguistic tasks: Phonological, Semantic and Orthographic/visuo-perceptual. During the Phonological task, controls showed greater beta activation on left versus right central cluster, whereas aphasic patients exhibited an inverted pattern of lateralization. In addition, patients' left central cluster, located over the core lesion, showed reduced beta activity with respect to controls. A similar inhibited activation was found in aphasics' left posterior cluster located over undamaged areas. At left anterior locations, aphasics, unlike controls, exhibited larger left versus right beta activity during both Phonological and Orthographic/visuo-perceptual tasks. Results point to substantial reorganization of language in recovered non-fluent aphasics at left prefrontal sites located anterior to the damaged Broca's area and inhibited language-related activation in left posterior undamaged, but disconnected, regions. PMID- 23810124 TI - Two phenotypes of arthropathy in long-term controlled acromegaly? A comparison between patients with and without joint space narrowing (JSN). AB - BACKGROUND: Arthropathy is an invalidating complication of acromegaly, also in long-term controlled patients, and is radiographically characterized by osteophytes and preserved joint spaces. However, joint space narrowing (JSN) is observed in the minority of patients. It is unknown whether JSN is the end-stage of acromegalic arthropathy or whether this feature develops independently of acromegaly. OBJECTIVE: To gain insight into the pathophysiology of acromegalic arthropathy, and, more specifically, in the process of JSN, risk factors for radiographic JSN were studied in a cross-sectional study. METHODS: We studied hips and knees of 89 well-controlled acromegaly patients (mean age 58.3 yr, 51% female). Joints were divided into two groups based on the presence of JSN, defined as an Osteoarthritis Research Society (OARSI) score >= 1. Potential risk factors for JSN were assessed, and its relationship to joint complaints. Individual knees and hips were analyzed in a Generalized Estimating Equations model, adjusted for age, sex, BMI and intra-patient effect. RESULTS: In controlled acromegaly, JSN was found in, respectively, 10.3% and 15.4% of the hips and knees. Increasing age and female sex were associated with more JSN; acromegaly-specific risk factors for JSN were joint-site specific. In the hip, JSN was related to more active disease: higher pre-treatment GH/IGF-1, longer and more severe GH exposure and immediate postoperative cure was less frequently achieved. In the knee, especially previous knee surgery, not acromegaly-specific characteristics, was associated with JSN. The presence of JSN was associated with more joint complaints. CONCLUSIONS: JSN is an infrequent finding in patients with acromegalic arthropathy, but it is associated with more symptoms. This study indicates that, at least in the hip, early and ongoing GH/IGF-1 activity play a role in JSN development. PMID- 23810125 TI - Right of admission reserved, no matter the path. AB - Native CRISPR-Cas adaptive immunity systems prevent plasmid conjugation and virus mediated gene transfer. Zhang et al. have recently reported in Molecular Cell that natural transformation is also limited by a simple endogenous CRISPR system, which would make an optimal candidate tool for functional applications such as genome editing. PMID- 23810127 TI - Quality improvement in childhood obesity management through the maintenance of certification process. AB - OBJECTIVE: To assess the Health and Obesity: Prevention and Education (HOPE) Curriculum Project, a web-based clinician education program that promotes appropriate screening, prevention, and management of weight among youth by pediatric practitioners, based on the 2007 Expert Committee recommendations. The project currently provides Maintenance of Certification (MOC) Part 4 credit through the American Board of Pediatrics. STUDY DESIGN: Participants identified themselves to the HOPE MOC Part 4 program. Enrollees were required to complete all continuing medical education modules (10.5 hours). Knowledge acquisition and self-reported confidence levels related to screening, prevention, and management practices of pediatric obesity were measured using preknowledge and postknowledge questionnaires. Participants were also required to perform a quality improvement project and submit practice performance data from repeated medical chart reviews over time. Knowledge acquisition, self-efficacy, and practice performance data were analyzed using repeated-measures analyses. RESULTS: The 51 participants demonstrated significant improvements in knowledge acquisition and self-efficacy scores after viewing individual modules. In addition, participants demonstrated significant improvements in measured clinical compliance with recommended practices over time. CONCLUSIONS: Participation in the HOPE MOC Part 4 program appeared to improve knowledge acquisition, self-efficacy, and physician compliance with recommended practice recommendations for the screening, prevention, and management of pediatric obesity. Further data are required to determine whether such practice-based improvements translate into actual reduction in patient weight and/or reduction in health-related costs related to overweight and obesity in youth. PMID- 23810126 TI - An encapsulation of iron homeostasis and virulence in Cryptococcus neoformans. AB - Vertebrate hosts actively sequester iron, and fungal and other pathogens must therefore adapt to a severe limitation in iron availability to cause disease. Recent studies reveal that the pathogenic fungus Cryptococcus neoformans overcomes iron limitation by multiple mechanisms that target transferrin and heme. The regulation of iron uptake is mediated by an interconnected set of transcription factors that include the master iron regulator Cir1 and the pH responsive factor Rim101. These factors integrate iron homeostasis with a myriad of other functions including pH sensing, nutrient and stress signaling pathways, virulence factor elaboration, and cell wall biogenesis. PMID- 23810129 TI - 47,XYY syndrome: clinical phenotype and timing of ascertainment. AB - OBJECTIVE: To describe auxologic, physical, and behavioral features in a large cohort of males with 47,XYY (XYY), ages newborn to young adult. STUDY DESIGN: This is a cross-sectional descriptive study of male subjects with XYY who were evaluated at 1 of 2 specialized academic sites. Subjects underwent a history, physical examination, laboratory testing, and cognitive/behavioral evaluation. RESULTS: In 90 males with XYY (mean age 9.6 +/- 5.3 years [range 0.5-36.5]), mean height SD was above average (1.0 +/- 1.2 SD). Macrocephaly (head circumference >2 SD) was noted in 28/84 (33%), hypotonia in 57/90 (63%), clinodactyly in 47/90 (52%), and hypertelorism in 53/90 (59%). There was testicular enlargement for age (>2 SD) in 41/82 (50%), but no increase in genital anomalies. No physical phenotypic differences were seen in boys diagnosed prenatally vs postnatally. Testosterone, luteinizing hormone, and follicle stimulating hormone levels were in the normal range in most boys. There was an increased incidence of asthma, seizures, tremor, and autistic spectrum disorder (ASD) compared with the general population rates. Prenatally diagnosed boys scored significantly better on cognitive testing and were less likely to be diagnosed with ASD (P < .01). CONCLUSIONS: The XYY phenotype commonly includes tall stature, macrocephaly, macroorchidism, hypotonia, hypertelorism, and tremor. Physical phenotypic features were similar in boys diagnosed prenatally vs postnatally. Prenatal diagnosis was associated with higher cognitive function and less likelihood of an ASD diagnosis. PMID- 23810131 TI - Practical management of heart failure with preserved ejection fraction. A modest proposal. PMID- 23810130 TI - Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors: proposals of the working group on perioperative haemostasis (GIHP) - March 2013. AB - Direct new oral anticoagulants (NOACs) - inhibitors of thrombin or factor Xa - are intended to be used largely in the treatment of venous thromboembolic disease or the prevention of systematic embolism in atrial fibrillation, instead of vitamin K antagonists. Like any anticoagulant treatment, they are associated with spontaneous or provoked haemorrhagic risk. Furthermore, a significant proportion of treated patients are likely to be exposed to emergency surgery or invasive procedures. Given the absence of a specific antidote, the action to be taken in these situations must be defined. The lack of data means that it is only possible to issue proposals rather than recommendations, which will evolve according to accumulated experience. The proposals presented here apply to dabigatran (Pradaxa((r))) and rivaroxaban (Xarelto((r))); data for apixaban and edoxaban are still scarce. For urgent surgery with haemorrhagic risk, the drug plasma concentration should be less or equal to 30ng/mL for dabigatran and rivaroxaban should enable surgery associated with a high bleeding risk. Beyond that, if possible, the intervention should be postponed by monitoring the drug concentration. The course to follow is then defined according to the NOAC and its concentration. If the anticoagulant dosage is not immediately available, worse propositions, based on the usual tests (prothrombin time and activated partial thromboplastin time), are presented. However, these tests do not really assess drug concentration or the risk of bleeding that depends on it. In case of serious bleeding in a critical organ, the effect of anticoagulant therapy should be reduced using a non-specific procoagulant drug as a first-line approach: activated prothrombin complex concentrate (aPCC) (FEIBA((r)) 30-50U/kg) or non activated PCC (50U/kg). In addition, for any other type of severe haemorrhage, the administration of a procoagulant drug, which is potentially thrombogenic in these patients, is discussed according to the NOAC concentration and the possibilities of mechanical haemostasis. PMID- 23810132 TI - Mood disorders in DSM-5: best diagnoses today and a bridge to tomorrow. PMID- 23810133 TI - Cannabis and psychosis: have we found the missing links? AB - BACKGROUND: The association between cannabis and psychosis has long been a matter of debate, with cannabis widely perceived as a harmless recreational drug. METHODS: Electronic bibliographic databases like PubMed and Google Scholar were searched using the format "(psychosis or schizophrenia or synonyms) and (cannabis or synonyms)". Cross-linked searches were made taking the lead from key articles. Recent articles and those exploring the genetic factors or gene-environment interaction between cannabis use and psychosis were focussed upon. RESULTS: Heavy cannabis use at a n young age, in association with genetic liability to psychosis and exposure to environmental stressors like childhood trauma and urban upbringing increases the risk of psychotic outcome in later life. CONCLUSION: Cannabis acts as a component cause of psychosis, that is, it increases the risk of psychosis in people with certain genetic or environmental vulnerabilities, though by itself, it is neither a sufficient nor a necessary cause of psychosis. Although significant progress has been made over the last few years, we are yet to find all the missing links. Further work is necessary to identify all the factors that underlie individual vulnerability to cannabis-related psychosis and to elucidate the biological mechanisms underlying this risk. PMID- 23810134 TI - Prevalence and predictors of pain in patients with major depressive disorder. AB - INTRODUCTION: Pain is common in patients with major depressive disorder (MDD). This paper aimed to determine the prevalence of and examine the predictors of pain in patients with MDD. METHOD: This study was conducted at a university hospital. The prevalence of pain in adult outpatients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition MDD was compared with that in a matched age and sex control group of general patients in the waiting area within the hospital. Depression and pain were measured using the 17-item Hamilton Rating Scale for Depression (HAM-D) and a 10-point rating scale for pain (RSP) (from no pain at all to the most severe pain), respectively. RESULTS: Forty MDD and 40 general patients with matched age and sex (controls) participated in this study. Compared with the control group (47.5%), 95% of MDD patients had pain (p<0.001). The RSP scores of MDD patients were significantly higher than those of the controls (p<0.001). The mean number of pain locations was also significantly larger than in the MDD patients (p<0.001). Among the 11 male and 29 female patients with MDD, the multiple linear regression analysis revealed that the HAM D score and history of sexual assault were significant predictors of pain. SUMMARY: The present findings suggest that, compared with general patients, individuals with MDD have more pain in terms of the prevalence, severity, and number of locations. Severe depression and history of sexual assault are predictors of pain in MDD patients. Pain and depression are highly correlated and should be taken into account in individuals with these symptoms. PMID- 23810135 TI - A scientometrics approach to schizophrenia research in India: an analysis of publications output during 2002-11. AB - OBJECTIVES: This study analyses the research output of India in schizophrenia research during 2002-11 on several parameters including the growth, rank and global publications share, citation impact, share of international collaborative papers, contribution of major collaborative partner countries, contribution of various subject-fields, contribution and impact of most productive institutions and authors, media of communication and characteristics of high cited papers. METHODS: The Scopus Citation Database has been used to retrieve the data for 10 years (2002-11) by searching the keywords schizophrenia research in the combined Title, Abstract and Keywords fields. RESULTS: Among the top 20 most productive countries in schizophrenia research, India ranks at 15th position (with 882 papers) with a global publication share of 1.58% and an annual average publication growth rate of 21.80% during 2002-11. Its citation impact per paper was 3.60 international collaborative publications share was 26.98% during 2002 11. CONCLUSIONS: Concludes that India needs to increase both the quantity and quality of research and also increase the international collaborative research, besides strengthening and modernizing its research infrastructure. There is need to treat schizophrenia as a priority area in the current and future national S & T plans of India. PMID- 23810136 TI - Oppositional Defiant Disorder: prevalence based on parent and teacher ratings of Malaysian primary school children. AB - BACKGROUND: This study examined the prevalence rate of Oppositional Defiant Disorder (ODD) in Malaysian primary school children. METHODS: In all 934 Malaysian parents and teachers completed ratings of their children using a scale comprising DSM-IV-TR ODD symptoms. RESULTS: Results showed rates of 3.10%, 3.85%, 7.49% and 0.64% for parent, teacher, parent or teacher ("or-rule"), and parent and teacher ("and-rule") ratings, respectively. When the functional impairment criterion was not considered, the rate reported by parents was higher at 13.28%. DISCUSSION: The theoretical, diagnostic and cultural implications of the findings are discussed. PMID- 23810137 TI - PRISM: Promoting Resilience, Independence and Self Management--a strategy to manage chronic mental illnesses. AB - Many transformations in how mental health care is delivered have required the development of new ways of providing care, treatment and support to mental health consumers. In the recent past, to support consumers and their carers adequately and appropriately, there has been emphasis on case management and care coordination. There is a need to consider whether over-emphasis on case management should be limited to the minority of mental health consumers who are unable to make competent decisions, whereas majority of consumers should take complete charge of their own treatment. PRISM (Promoting Resilience, Independence and Self Management) is a conceptual framework that potentially offers an opportunity to empower consumers to take charge of their own treatment by using specific tools, including a PRISM Pack, Take Charge Sheet, Protocol for Appropriate Care and use of methods that ensure that the mental health consumer does become a key decision maker with regard to their own care and treatment. PMID- 23810138 TI - A study examining depression in restless legs syndrome. AB - BACKGROUND: Distress is known to occur in RLS subjects consequent to symptoms. However, studies regarding prevalence of depression in RLS are scarce. This study was conducted to find out prevalence of depression in RLS patients and to explore possible underlying factors. METHOD: 112 consecutive RLS subjects presenting to sleep-clinic were included in this study. History regarding RLS, depression and sleep-disturbances was sought. Depression and insomnia were diagnosed using DSM IV-TR criteria. Subjects were specifically asked whether they had depressive episodes in past one year. Severity of RLS and insomnia was measured using Hindi versions of IRLS and ISI, respectively. Family history of depression and RLS was also asked. RESULTS: One year prevalence of depression was 41.8%. MDD was reported by 33% and dysthymia by 8.8%. Both the groups were comparable with respects to demographic and clinical features, viz., age, gender, duration, severity and family history of RLS. Duration, number of episodes and severity of insomnia were comparable between groups, so was the family history of depression. In 37.8% of the subjects with MDD, depressive symptoms preceded RLS while in 51.4% of them, they followed onset of RLS. Total duration of RLS symptoms did not correlate with total duration of depression (r(2)=0.07; P=0.64). CONCLUSION: Clinical depression is seen in more than a third of RLS patients. Depression is not affected by clinical picture of RLS and it is not consequent to sleep disturbance. Perhaps, it is a co-morbid condition. PMID- 23810139 TI - Predictors of depression among patients with diabetes mellitus in Southern India. AB - OBJECTIVE: Diabetes mellitus and depression are major public health problems and are significantly linked with each other. This research study intends to assess for undiagnosed depression and its predictors among adult diabetic patients. METHODS: A cross-sectional study was done among 100 patients with type 2 diabetes mellitus attending the diabetic clinic of a tertiary care hospital. Depression was assessed using Patient Health Questionnaire-9 (PHQ-9). Chi-square test was performed and odds ratios (OR) with 95% confidence interval (95% CI) were obtained. Mann Whitney U and Pearson correlation tests were done. Logistic regression was carried out to determine the predictors of depression and adjusted odds ratios with 95% confidence intervals were obtained. RESULTS: The prevalence of depression was 49% (95% CI 39.1-58.9%). The predictors of depression were female gender, elevated fasting blood sugar (FBS) level, physical disability and lack of physician's advice about lifestyle modifications. FBS values were significantly higher in depressed individuals as compared to the non-depressed (p value 0.002). A positive correlation (r=0.38, p value 0.01) was obtained between PHQ-9 scores and the FBS values of the diabetic subjects. CONCLUSIONS: Subjects with diabetes are highly prone for comorbid depression. Physicians should be sensitive towards the need for assessing for possible depression and its risk factors in diabetic patients. PMID- 23810128 TI - Probability of treatment following acute decline in lung function in children with cystic fibrosis is related to baseline pulmonary function. AB - OBJECTIVE: To determine whether the association between high forced expiratory volume in 1 second (FEV1) and increased rate of decline in FEV1 in children with cystic fibrosis could be due to less frequent intervention after acute declines (sudden decline events) in FEV1. STUDY DESIGN: Patients with cystic fibrosis aged 6-17 years enrolled in the Epidemiologic Study of Cystic Fibrosis were assessed for a sudden decline event, defined as a 10% relative decline in FEV1% predicted from an average of 3 consecutive stable baseline spirometries. The likelihood of therapeutic intervention within 14 days before and 56 days after this event was then related to their baseline FEV1% predicted age-specific decile using a logistic regression adjusting for age group (6-12 years, 13-17 years) and presence of Pseudomonas aeruginosa on respiratory culture. RESULTS: A total of 10 888 patients had at least 1 sudden decline event in FEV1. Patients in the highest FEV1 decile were significantly less likely than those in the lowest decile to receive intravenous antibiotics (OR, 0.14; 95% CI, 0.11-0.18; P < .001) or be hospitalized (OR, 0.18; 95% CI, 0.14-0.23; P < .001) following decline. CONCLUSIONS: Children and adolescents with high baseline lung function are less likely to receive a therapeutic intervention following an acute decline in FEV1, which may explain their greater rate of FEV1 decline. PMID- 23810140 TI - Correlates of depression, anxiety and stress among Malaysian university students. AB - INTRODUCTION: University students face not only challenges related with independent living, but also academic challenges. This predisposes them to depression, anxiety and stress, which are fairly common. OBJECTIVE: The aim was to assess the prevalence of depression, anxiety and stress, and identify their correlates among university students. METHODS: A cross-sectional study was conducted on 506 students between the ages of 18 and 24 years from four public universities in the Klang Valley, Malaysia. Through an anonymous, self administered questionnaire, they were assessed by the Depression Anxiety Stress Scale-21 (DASS-21). Data on socio-demographic, family characteristics and living arrangement were also obtained. Student's t-test and one-way ANOVA were used to explore association between these aspects. RESULTS: Analysis showed among all students, 27.5% had moderate, and 9.7% had severe or extremely severe depression; 34% had moderate, and 29% had severe or extremely severe anxiety; and 18.6% had moderate and 5.1% had severe or extremely severe stress scores based on the DASS 21 inventory. Both depression and anxiety scores were significantly higher among older students (20 and above) and those born in rural areas. Whereas, higher stress scores were significantly higher among older students (20 and above), females, Malays and those whose family had either low or high incomes compared to those with middle incomes. CONCLUSIONS: The prevalence of anxiety is much higher than either depression or stress, with some differences in their correlates except for age. These differences need to be further explored for development of better intervention programs and appropriate support services targeting this group. PMID- 23810141 TI - Schizophrenia patients experience substantial social cognition deficits across multiple domains in remission. AB - Knowledge about SC (social cognition) during remission would inform us whether such deficits are trait- or state-markers of the disorder, as well as highlight its relevance for rehabilitation. We aimed to compare SC deficits and their relative independence from NC (neuro-cognition) deficits in remitted schizophrenia patients and matched health controls using comprehensive, culturally sensitive standardized tools. 60 schizophrenia patients meeting modified standardized criteria for remission and 60 age, gender and education matched healthy controls were compared on culturally validated tests of SC-Social Cognition Rating Tool in Indian Setting (SOCRATIS) & Tool for Recognition of Emotions in Neuropsychiatric Disorders (TRENDS) to assess theory of mind, attributional bias, social perception and emotion recognition and NC (attention/vigilance, speed of processing, visual and verbal learning, working memory and executive functions). Patients had deficits in both SC and NC compared to healthy controls. Deficits in SC were largely independent of NC performance, and SC deficits persisted after adjusting for deficits in NC function. The effect sizes (Cohen's d) for SC deficits ranged from 0.37 to 2.23. All patients scored below a defined cut-off in at least one SC domain. SC deficits are likely to be state-independent in schizophrenia, as they are present in remission phase of the illness. This supports their status as a possible composite-endophenotype in schizophrenia. PMID- 23810142 TI - Does change in definition of psychotic symptoms in diagnosis of schizophrenia in DSM-5 affect caseness? AB - Psychotic symptoms are a central element in the diagnosis of schizophrenia, although their precise definition has varied through the multiple iterations of DSM and the ICD. Schneiderian first-rank symptoms (FRS) have received a particularly prominent position in the diagnostic criteria of schizophrenia since ICD-9 and DSM-III. In the current iteration of DSM (DSM-IV-TR), whereas two characteristic symptoms are ordinarily required to meet criterion A, only a single symptom is necessary if the psychotic symptom happens to be a FRS, notably a bizarre delusion or auditory hallucination of a running commentary or 'conversing voices'. Because of limited data in support of the special treatment of FRS, DSM-5 has made changes to criterion A, requiring that at least two psychotic symptoms be present in all cases with at least one of these symptoms being a delusion, hallucination, or disorganized speech. To assess the impact of these changes on the prevalence of schizophrenia, we examined a research dataset of 221 individuals with DSM-IV schizophrenia to study the prevalence and co occurrence of various criterion A symptoms. Although bizarre delusions and/or Schneiderian hallucinations were present in 124 patients (56.1%), they were singly determinative of diagnosis in only one patient (0.46%). Additionally, only three of the 221 patients (1.4%) with DSM-IV schizophrenia did not have a delusion, hallucination, or disorganized speech. DSM-5 changes in criteria A should have a negligible effect on the prevalence of schizophrenia, with over 98% of individuals with DSM-IV schizophrenia continuing to receive a DSM-5 diagnosis of schizophrenia in this dataset. PMID- 23810143 TI - Psychotic versus non-psychotic major depressive disorder: a comparative naturalistic study. AB - OBJECTIVE: Psychotic depressed patients were found to have more severe cognitive deficits, poorer treatment response and higher suicidal risk respect to non psychotic depressives. Aim of the present research was to compare clinical variables and outcome between psychotic and non-psychotic major depressive patients. METHOD: A sample of 36 major depressed patients was divided into two groups according to the presence of psychotic symptoms. Structured Clinical Interview for DSM (SCID-I) and Hamilton Depression Rating Scale (HAM-D) were administered to the patients at baseline by trained raters. One-way analysis of variance (ANOVAs) and chi-square tests were performed to compare the two groups. Binary logistic regression was performed to assess the risk of lack of response/remission in patients with psychotic symptoms and the risk of developing psychotic symptoms in major depressives with a family history of schizophrenia or bipolar disorder. RESULTS: Psychotic major depressives presented more severe illness as showed by HAM-D baseline scores (F=17.20, p<0.001), a longer duration of hospitalization (F=7.64, p=0.009) and they were more frequently treated with clomipramine (chi(2)=16.22, p=0.027). Psychotic symptoms were predictive of lack of remission (OR=4.09, p=0.05) and family history of schizophrenia/psychotic bipolar disorder was associated with psychotic major depression (OR=10.81, p=0.04). CONCLUSIONS: Patients with psychotic symptoms present a more severe course of illness as showed by long hospitalizations and lower rates of remission. Psychotic depressives show more frequently a family history of "major psychoses" suggesting a continuum in psychotic disorders and a genetic association of major psychotic depression with bipolar disorder and schizophrenia. PMID- 23810144 TI - Untreated major depressive disorder with and without atypical features: a clinical comparative study. AB - AIMS AND METHOD: A comparative study of major depression with and without atypical features (as per DSM IV TR criteria) was planned to assess illness characteristics, resulting dysfunction and co-morbidities, which can have important implications in its management. Serially, 107 newly registered patients with depression not taking any treatment for at least a month were included. Patients with psychotic features in present or past, known bipolar disorder and likely organic aetiology were excluded. They were interviewed using SCID I (Structured clinical interview for DSM IV axis I disorders). Impulsiveness, suicidal ideation and functioning in various spheres was also assessed and compared between those with and without atypical features. RESULTS: Atypical features were seen in a significant number (55.14%) of patients especially from urban and semi-urban areas. Interpersonal sensitivity and leaden paralysis were the commonest atypical features apart from mood reactivity. Presence of hypersomnia and/or hyperphagia documented in 36 (33.65%) of 107 patients. Comparison of patients with and without atypical features revealed no significant difference in illness characteristics including suicidal ideation. However, they differed in level of impulsiveness and associated psychiatric co-morbidities. Also, deterioration of functioning with rising HDRS was more significant in patients without atypical features. CLINICAL IMPLICATIONS: Presence of atypical features is common in patients with major depressive disorder. These patients should be vigilantly assessed and managed in view of equal morbidity but different co-morbidities like anxiety and soft bipolar disorders than those without atypical features. PMID- 23810145 TI - Neuropsychiatric manifestations and treatment of disseminated neurocysticercosis: a compilation of three cases. AB - BACKGROUND: Neurocysticercosis (NCC) is the most serious form of cysticercal infection and is a major public health problem in the developing world. NCC presents with a range of psychiatric symptoms besides neurological symptoms. There have been few reports from the Asian continent describing the neuropsychiatric manifestations. Our aim was to report manifestations and treatment issues in three cases with disseminated NCC. METHODS AND RESULTS: Informed consent was obtained from all the three patients for the purpose of reporting. All three had multiple cysticerci in the brain and presented with several neuropsychiatric manifestations. All the patients had epilepsy and in addition they had varying psychiatric symptoms of delusions, hallucinations and catatonia, and cognitive symptoms. Also, interestingly in one patient, worsening of psychiatric and neurological symptoms correlated with anti-helminthic treatment. The psychotic symptoms responded to anti-psychotic treatment in one case. Anti-epileptics and steroid courses when given improved the clinical status. CONCLUSION: NCC presents with a myriad of manifestations. Epilepsy, psychotic and cognitive symptoms respond to symptomatic treatment. Use of anti parasitic agents might worsen the symptoms as has been reported in a few cases earlier. PMID- 23810146 TI - No association between DRD4 gene and SRI treatment response in obsessive compulsive disorder: need for a novel approach. PMID- 23810147 TI - Becoming child and adolescent psychiatrists: unmet needs also in Japan? PMID- 23810148 TI - Knowledge of dementia among Chinese American immigrants. PMID- 23810149 TI - Do you D.A.RE. take the USMLEs?: the stages an IMG (International Medical Graduate) goes through while taking the "Steps": my experience. PMID- 23810150 TI - Referral to palliative care in COPD and other chronic diseases: a population based study. AB - AIM: To describe how patients with COPD, heart failure, dementia and cancer differ in frequency and timing of referral to palliative care services. METHODS: We performed a population-based study with the Sentinel Network of General Practitioners in Belgium. Of 2405 registered deaths respectively 5%, 4% and 28% were identified as from COPD, heart failure or cancer and 14% were diagnosed with severe dementia. GPs reported use and timing of palliative care services and treatment goals in the final three months of life. RESULTS: Patients with COPD (20%) were less likely than those with heart failure (34%), severe dementia (37%) or cancer (60%) to be referred to palliative care services (p < 0.001). The median days between referral and death was respectively 10, 12, 14 and 20. Patients with COPD who were not referred more often received treatment with a curative or life-prolonging goal and less often with a palliative or comfort goal than did the other patients who were not referred. CONCLUSION: Patients with COPD are underserved in terms of palliative care compared to those with other chronic life-limiting diseases. Awareness of palliative care as an option for patients with COPD needs to increase in palliative care services, physicians and the general public. PMID- 23810152 TI - Early regular egg exposure in infants with eczema: A randomized controlled trial. AB - BACKGROUND: Observational studies suggest that early regular ingestion of allergenic foods might reduce the risk of food allergy. OBJECTIVE: We sought to determine whether early regular oral egg exposure will reduce subsequent IgE mediated egg allergy in infants with moderate-to-severe eczema. METHODS: In a double-blind, randomized controlled trial infants were allocated to 1 teaspoon of pasteurized raw whole egg powder (n = 49) or rice powder (n = 37) daily from 4 to 8 months of age. Cooked egg was introduced to both groups after an observed feed at 8 months. The primary outcome was IgE-mediated egg allergy at 12 months, as defined based on the results of an observed pasteurized raw egg challenge and skin prick tests. RESULTS: A high proportion (31% [15/49]) of infants randomized to receive egg had an allergic reaction to the egg powder and did not continue powder ingestion. At 4 months of age, before any known egg ingestion, 36% (24/67) of infants already had egg-specific IgE levels of greater than 0.35 kilounits of antibody (kUA)/L. At 12 months, a lower (but not significant) proportion of infants in the egg group (33%) were given a diagnosis of IgE-mediated egg allergy compared with the control group (51%; relative risk, 0.65; 95% CI, 0.38-1.11; P = .11). Egg-specific IgG4 levels were significantly (P < .001) greater in the egg group at both 8 and 12 months. CONCLUSION: Induction of immune tolerance pathways and reduction in egg allergy incidence can be achieved by early regular oral egg exposure in infants with eczema. Caution needs to be taken when these high-risk infants are first exposed to egg because many have sensitization already by 4 months of age. PMID- 23810151 TI - Current smoking as a predictor of chronic musculoskeletal pain in young adult twins. AB - Chronic pain is common during adolescence and young adulthood and is associated with poor quality of life, depression, and functional disability. Recognizing that chronic pain has significant consequences, it is important to identify modifiable health behaviors that may place young adults at risk for chronic pain. This study examines associations between chronic musculoskeletal pain and smoking in young adult twins (n = 1,588, ages 18-30) participating in a statewide twin registry. Twins completed questionnaires assessing smoking, mood (anxiety, depressive symptoms, and stress), and chronic musculoskeletal pain. Analyses examined associations between chronic pain and smoking, particularly the role of genetics/shared familial factors and psychological symptoms. As predicted, results revealed a near-2-fold increased risk for chronic musculoskeletal pain in twins who currently smoked compared to nonsmokers, even when accounting for psychological factors. Results of within-pair analyses were only minimally attenuated, suggesting that associations between smoking and chronic musculoskeletal pain are better accounted for by nonshared factors than by shared familial factors/genetic effects. Future twin research is needed to identify what nonshared factors (eg, attitudes, direct effects of smoking on pain) contribute to these associations to further understand comorbidity. Longitudinal studies and recruitment of participants prior to smoking initiation and chronic pain onset will better identify causal associations. PERSPECTIVE: This article describes associations between musculoskeletal pain and smoking in young adult twins, taking into account psychological symptoms. Findings highlight the importance of nonshared factors in associations between pain and smoking and the need to explore the roles of lifestyle, individual attitudes, and direct effects of smoking on pain. PMID- 23810153 TI - Thymic stromal lymphopoietin receptor blockade reduces allergic inflammation in a cynomolgus monkey model of asthma. AB - BACKGROUND: Thymic stromal lymphopoietin (TSLP) pathway blockade is a potential strategy for asthma treatment because the main activities of TSLP are activation of myeloid dendritic cells (mDCs) and modulation of cytokine production by mast cells. TSLP-activated mDCs prime the differentiation of naive T cells into inflammatory TH2 cells. OBJECTIVE: We sought to investigate mechanisms underlying the development of allergic lung inflammation in cynomolgus monkeys using gene expression profiling and to assess the effect of thymic stromal lymphopoietin receptor (TSLPR) blockade in this model. METHODS: An mAb against human TSLPR was generated and confirmed to be cross-reactive to cynomolgus monkey. Animals were dosed weekly with either vehicle or anti-TSLPR mAb for 6 weeks, and their responses to allergen challenge at baseline, week 2, and week 6 were assessed. RESULTS: After 6 weeks of treatment, anti-TSLPR mAb-treated animals showed reduced bronchoalveolar lavage (BAL) fluid eosinophil counts, reduced airway resistance in response to allergen challenge, and reduced IL-13 cytokine levels in BAL fluid compared with values seen in vehicle-treated animals. Expression profiling of BAL fluid cells collected before and after challenge showed a group of genes upregulated by allergen challenge that strongly overlapped with 11 genes upregulated in dendritic cells (DCs) when in vitro stimulated by TSLP (TSLP-DC gene signature). The number of genes differentially expressed in response to challenge was reduced in antibody-treated animals after 6 weeks relative to vehicle-treated animals. Expression of the TSLP-DC gene signature was also significantly reduced in antibody-treated animals. CONCLUSION: These results demonstrate promising efficacy for TSLPR blockade in an allergic lung inflammation model in which TSLP activation of mDCs might play a key role. PMID- 23810155 TI - Management of complicated duodenal diverticula. AB - The duodenum is the second most common location of intestinal diverticula after the colon. Duodenal diverticulum (DD) is usually located in the second portion of the duodenum (D2), close to the papilla. Most duodenal diverticula are extraluminal and acquired rather than congenital; more rare is the congenital, intraluminal diverticulum. DD is usually asymptomatic and discovered incidentally, but can become symptomatic in 1% to 5% of cases when complicated by gastroduodenal, biliary and/or pancreatic obstruction, by perforation or by hemorrhage. Endoscopic treatment is the most common first-line treatment for biliopancreatic complications caused by juxtapapillary diverticula and also for bleeding. Conservative treatment of perforated DD based on fasting and broad spectrum antibiotics may be offered in some selected cases when diagnosis is made early in stable patients, or in elderly patients with comorbidities who are poor operative candidates. Surgical treatment is currently reserved for failure of endoscopic or conservative treatment. The main postoperative complication of diverticulectomy is duodenal leak or fistula, which carries up to a 30% mortality rate. PMID- 23810154 TI - Mouse allergen is the major allergen of public health relevance in Baltimore City. AB - BACKGROUND: Cockroach and mouse allergens have both been implicated as causes in inner-city asthma morbidity in multicenter studies, but whether both allergens are clinically relevant within specific inner-city communities is unclear. OBJECTIVE: Our study aimed to identify relevant allergens in Baltimore City. METHODS: One hundred forty-four children (5-17 years old) with asthma underwent skin prick tests at baseline and had clinical data collected at baseline and 3, 6, 9, and 12 months. Home settled dust samples were collected at the same time points for quantification of indoor allergens. Participants were grouped based on their sensitization and exposure status to each allergen. All analyses were adjusted for age, sex, and serum total IgE level. RESULTS: Forty-one percent were mouse sensitized/exposed, and 41% were cockroach sensitized/exposed based on bedroom floor exposure data. Mouse sensitization/exposure was associated with acute care visits, decreased FEV1/forced vital capacity percentage values, fraction of exhaled nitric oxide levels, and bronchodilator reversibility. Cockroach sensitization/exposure was only associated with acute care visits and bronchodilator reversibility when exposure was defined by using bedroom floor allergen levels. Mouse-specific IgE levels were associated with poor asthma health across a range of outcomes, whereas cockroach-specific IgE levels were not. The relationships between asthma outcomes and mouse allergen were independent of cockroach allergen. Although sensitization/exposure to both mouse and cockroach was generally associated with worse asthma, mouse sensitization/exposure was the primary contributor to these relationships. CONCLUSIONS: In a community with high levels of both mouse and cockroach allergens, mouse allergen appears to be more strongly and consistently associated with poor asthma outcomes than cockroach allergen. Community-level asthma interventions in Baltimore should prioritize reducing mouse allergen exposure. PMID- 23810156 TI - Tualang honey supplement improves memory performance and hippocampal morphology in stressed ovariectomized rats. AB - Recently, our research team has reported that Tualang honey was able to improve immediate memory in postmenopausal women comparable with that of estrogen progestin therapy. Therefore the aim of the present study was to examine the effects of Tualang honey supplement on hippocampal morphology and memory performance in ovariectomized (OVX) rats exposed to social instability stress. Female Sprague-Dawley rats were divided into six groups: (i) sham-operated controls, (ii) stressed sham-operated controls, (iii) OVX rats, (iv) stressed OVX rats, (v) stressed OVX rats treated with 17beta-estradiol (E2), and (vi) stressed OVX rats treated with Tualang honey. These rats were subjected to social instability stress procedure followed by novel object recognition (NOR) test. Right brain hemispheres were subjected to Nissl staining. The number and arrangement of pyramidal neurons in regions of CA1, CA2, CA3 and the dentate gyrus (DG) were recorded. Two-way ANOVA analyses showed significant interactions between stress and OVX in both STM and LTM test as well as number of Nissl positive cells in all hippocampal regions. Both E2 and Tualang honey treatments improved both short-term and long-term memory and enhanced the neuronal proliferation of hippocampal CA2, CA3 and DG regions compared to that of untreated stressed OVX rats. PMID- 23810157 TI - Spatio-temporal gait characteristics during transitions from trot to canter in horses. AB - Gaits can be defined based upon specific interlimb coordination patterns characteristic of a limited range of speeds, with one or more defining variables changing discontinuously at a transition. With changing speed, horses perform a repertoire of gaits (walk, trot, canter and gallop), with transitions between them. Knowledge of the series of kinematic events necessary to realize a gait is essential for understanding the proximate mechanisms as well as the control underlying gait transitions. We studied the kinematics of the actual transition from trot to canter in miniature horses. The kinematics were characterized at three different levels: the whole-body level, the spatio-temporal level of the foot falls and the level of basic limb kinematics. This concept represents a hierarchy: the horse's center of mass (COM) moves forward by means of the coordinated action of the limbs and changes in the latter are the result of alterations in the basic limb kinematics. Early and short placement of the fore limb was observed before the dissociation of the footfalls of one of the diagonal limb pairs when entering the canter. Dissociation coincided with increased amplitude and wavelength of the oscillations of the trunk in the sagittal plane. The increased amplitude cannot be explained solely by the passive effects of acceleration or by neck and head movements which are inconsistent with the timing of the transition. We propose that the transition is initiated by the fore limb followed by subsequent changes in the hind limbs in a series of kinematic events that take about 2.5 strides to complete. PMID- 23810158 TI - The admission systemic inflammatory response syndrome predicts outcome in patients undergoing emergency surgery. AB - OBJECTIVE: To investigate the incidence of systemic inflammatory response syndrome (SIRS) on emergency department admission and the prognostic significance of SIRS in patients undergoing emergency surgery. METHODS: This is a retrospective study of 889 adults who were admitted as emergency cases and were operated on within 24 hours of admission. Data on patient demography, clinical information including comorbidities, categories of surgery, American Society of Anesthesiologists physical status, SIRS score, postoperative outcomes including duration of mechanical ventilation, intensive care unit (ICU) and hospital lengths of stay, and mortality were collected. RESULTS: SIRS occurred in 43% of the patients and was associated with a significantly worse outcome in terms of duration of ventilator use (10.5 +/- 15.4 vs. 3.5 +/- 4.4 days, p < 0.001), ICU stay (11.2 +/- 13.6 vs. 5.0 +/- 5.4 days, p < 0.001), hospital length of stay (19.4 +/- 22.4 vs. 7.1 +/- 7.6 days, p < 0.001) and mortality (12.7% vs. 0.4%, p < 0.001). After adjusting for covariates (including age, gender, American Society of Anesthesiologists physical status, comorbid conditions, and surgery categories), SIRS was independently associated with higher mortality (adjusted odd ratio, 21.5; 95% confidence interval (CI), 4.9-93.2), longer ventilator duration (adjusted coefficient, 7.8; 95% CI, 3.2-12.5), longer ICU stay (adjusted coefficient, 6.2; 95% CI, 2.6-9.8) and longer hospital stay (adjusted coefficient, 9.7; 95% CI, 7.5-11.9). CONCLUSION: The presence of SIRS at admission in patients receiving emergency surgery predicted worse outcomes and higher mortality rates. PMID- 23810159 TI - Proximal direct endarterectomy combined with simultaneous distal endovascular therapy for chronic full-length occlusion of the superficial femoral artery in elderly patients. AB - BACKGROUND AND PURPOSE: The most proximal ostial site of the chronic occlusive superficial femoral artery is not suitable for ballooning or stenting because the deep femoral artery may be occluded by these procedures. Thus, the feasibility of performing an open endarterectomy for the occluded ostium of the superficial femoral arteries combined with an endovascular therapy for the remaining distal site was evaluated. METHODS: Eleven critically ischemic limbs in 10 elderly patients with poor general health were enrolled. They had full-length occlusion of the superficial femoral artery involving its ostium. The ostial site was managed with an open endarterectomy followed by endovascular therapy for the remaining distal site. RESULTS: All procedures were successfully performed. All patients experienced pain relief, and the wounds healed. During the follow-up observation period (average: 23.9 +/- 14.7 months), nine patients died. None of the patients, including those who had lost patency of the superficial femoral artery, received major amputation. CONCLUSION: Elderly patients, including those who were in terminal stage, were able to withstand the operation, and their postoperative quality of life was not compromised. Although the patency following the surgery was limited, sparing the deep femoral artery could either prevent or delay the recurrence of critical limb ischemia. PMID- 23810160 TI - Infrahepatic inferior vena cava clamping in hepatectomy for tumors involving hepatocaval confluence. AB - BACKGROUND: Massive hemorrhage and the need for blood transfusion carry a high rate of morbidity and mortality after hepatectomy. The aim of this study was to evaluate the safety and potential benefit of infrahepatic inferior vena cava (IVC) clamping in hepatectomy for tumors involving hepatocaval confluence. METHODS: We conducted a retrospective analysis of 113 consecutive patients who underwent hepatectomy with infrahepatic IVC clamping (n = 60, Group A) and without infrahepatic IVC clamping (n = 53, Group B) as the initial treatment for tumors involving hepatocaval confluence. RESULTS: In Group A, central venous pressure reduced from 7.6 +/- 3.2 to 4.4 +/- 2.7 cm H2O (p < 0.001). Patients in Group A experienced less blood loss (477.3 +/- 340.3 vs. 794.5 +/- 602.7 mL, p = 0.001), fewer blood transfusion requirements (8.3% vs. 22.6%, p = 0.034), lower postoperative complications (40% vs. 60.4%, p = 0.031), and shorter hospital stay (10.7 +/- 2.2 vs. 12.9 +/- 4.8 days, p = 0.008) than those in Group B. CONCLUSION: Infrahepatic IVC clamping is generally effective and safe in controlling bleeding during hepatectomy for tumors involving hepatocaval confluence. PMID- 23810161 TI - Carcinoid tumors of the lung: a report of 11 cases. AB - OBJECTIVE: Carcinoid tumors of the lung are rare, and account for 1% of all primary tumors of the lung. This study was undertaken to investigate the histological characteristics and clinical behavior of carcinoid tumors of the lung. METHODS: We have retrospectively reviewed the hospital records of 11 consecutive patients undergoing surgical treatment for carcinoid tumors of the lung between 1992 and 2007. RESULTS: Patients with carcinoid tumors accounted for 0.8% (11 of 1319) of the patients undergoing surgical treatment for nonsmall cell lung cancer. The group comprised six males and five females with a mean age at presentation of 58.6 years (range 27-78 years). All of the operations were lobectomies, including two sleeve lobectomies. Six patients had typical and five had atypical carcinoid tumors. Seven patients had stage IA disease, two had stage IB, one had stage IIA, and one had stage IIIA. Recurrent tumors developed in two of the five patients affected by atypical carcinoid tumors, but none of the six patients with typical carcinoid tumors. Overall, the 5-year survival rate of patients with both typical and atypical carcinoid tumors was 90.9%. CONCLUSION: Survival of carcinoid tumors was favorable. In this analysis, two patients with atypical carcinoid had postoperative recurrences. Recurrence was more common among patients with atypical carcinoid tumors. PMID- 23810162 TI - Emphysematous pyelonephritis: an 8-year retrospective review across four acute hospitals. AB - OBJECTIVE: To retrospectively review our experience of managing patients with emphysematous pyelonephritis (EPN). METHODS: Case notes of patients with EPN were reviewed. The patients' demographic data, clinical presentation, investigation findings, treatment, and outcome were studied. RESULTS: Twelve patients were diagnosed with EPN. Majority (66.7%) of them had diabetes mellitus. All patients had been evaluated by computed tomography (CT). Using the classification proposed by Wan et al, five patients had type 1 EPN, whereas six, two, and four patients had Huang and Tseng CT class 2, 3a, and 3b EPN, respectively. Immediate nephrectomy was performed in six patients, whereas conservative treatment was adopted in the other six. In the nephrectomy group, one patient died of disseminated sepsis after a protracted course. Conservative treatment failed in three patients, who succumbed despite salvage nephrectomy in two of them. Analysis revealed that severe hyperglycemia and radiological CT class (both Wan and Huang systems) were significant predictors of mortality from EPN. CONCLUSION: Severe hyperglycemia and CT class of EPN are significant risk factors for death. CT is the investigation of choice for correct diagnosis of EPN. Additional intervention should be offered to EPN patients with Wan type 1 and Huang and Tseng class 3 CT features. PMID- 23810163 TI - Mullerian inhibiting substance expression in papillary thyroid cancer. AB - OBJECTIVE: To examine the expression of Mullerian inhibiting substance (MIS) in papillary thyroid cancer. MATERIALS AND METHODS: The MIS expression was examined by studying the immunohistochemistry in deparafinized sections prepared from tissue blocks of patients who were diagnosed with papillary thyroid cancer, as given in the pathology archive records (n = 23). RESULTS: In all the cases studied, 50% (n = 10) showed strong staining and 50% showed moderate staining. The percentage of staining was found to be 94.2 +/- 3.1% in strongly stained cases and 92.2 +/- 2.1% in moderately stained cases. Normal thyroid tissues neighboring the tumor did not display any staining. CONCLUSION: The MIS expression can be used as a significant tool in differential diagnosis of papillary thyroid cancer and also to shed light on its etiopathogenesis. PMID- 23810164 TI - Wide composite resection of follicular thyroid carcinoma with metastases to sternum: report of two cases. AB - Follicular thyroid carcinoma (FTC) with sternum metastasis is rarely reported. Conservative treatments always result in a poor prognosis. We report two cases of FTC presenting with a large symptomatic solitary metastatic lesion in the sternum. Surgical intervention included total thyroidectomy, combined with wide composite resection of the sternal manubrium, as well as the adjacent clavicular head and ribs. A large defect with exposed pericardium and great vessels was found post resection in both cases. Because the ipsilateral vessels were sacrificed, a contralateral extended pedicled pectoralis major adipofascial flap was designed and transposed to cover the underlying vital organs. The patients received both adjuvant I-131 and radiotherapy postoperatively. The treatment was uneventful, and the patients are well and asymptomatic 5 years after the treatment. Wide composite resection and appropriate adjuvant therapies may offer a survival benefit in patients with advanced FTC with sternum metastasis. PMID- 23810165 TI - Neoadjuvant chemotherapy and salvage surgery for an aldosterone-producing adrenal carcinoma with inferior vena cava thrombus: case report and literature review. AB - Inferior vena cava (IVC) thrombus is a rare presentation of adrenal carcinoma. Hyperladosteronism is rarely associated with it. We report a case of an aldosterone-producing left adrenal carcinoma with IVC thrombus and invasion of multiple organs, treated with neoadjuvant chemotherapy and salvage surgery. The patient is alive and asymptomatic after 46 months. Surgical aspects and therapeutic options are discussed and compared with the current medical literature. This is believed to be the first report of multiple organ resection combined with IVC thrombus removal for a functioning adrenal carcinoma. PMID- 23810166 TI - Comparison between ImmunoCard STAT!((r)) and real-time PCR as screening tools for both O157:H7 and non-O157 Shiga toxin-producing Escherichia coli in Southern Alberta, Canada. AB - An increasing number of non-O157 Shiga toxin-producing Escherichia coli (STEC) infections and outbreaks have been reported. In this study, we evaluated the performance of ImmunoCard STAT!((r)) (Meridian Bioscience, Inc., Cincinnati, OH, USA) as a method to screen stool specimens for STEC (O157 and non-O157). An in house real-time PCR method was used as the "gold standard". We also evaluated the prevalence and clinical characteristics of STEC infections in the Alberta South West Zone. From July to November 2011, 819 stool specimens submitted for routine stool culture were tested. With our in-house real-time PCR, 7 O157:H7 and 10 non O157 STEC isolates were identified for a total of 17 STECs. In comparison, ImmunoCard STAT!((r)) identified a total of 6, resulting in a sensitivity and specificity of 35% and 99%, respectively (P < 0.05). Because of the low sensitivity, ImmunoCard STAT!((r)) cannot be recommended as a routine screening test for STEC from enriched stool specimens. The rate of STEC positivity as detected by PCR was 2.08%, of which 0.86% was O157:H7 and 1.22% non-O157 STEC. Five of the 7 cases of STEC O157 infection experienced bloody diarrhea, and 1 developed hemolytic uremic syndrome. PMID- 23810167 TI - Estimating the demand for drop-off recycling sites: a random utility travel cost approach. AB - Drop-off recycling is one of the most widely adopted recycling programs in the United States. Despite its wide implementation, relatively little literature addresses the demand for drop-off recycling. This study examines the demand for drop-off recycling sites as a function of travel costs and various site characteristics using the random utility model (RUM). The findings of this study indicate that increased travel costs significantly reduce the frequency of visits to drop-off sites implying that the usage pattern of a site is influenced by its location relative to where people live. This study also demonstrates that site specific characteristics such as hours of operation, the number of recyclables accepted, acceptance of commingled recyclables, and acceptance of yard-waste affect the frequency of visits to drop-off sites. PMID- 23810168 TI - What are the lessons of recent obstetric legal cases? AB - In this chapter, I review the ways in which the courts have handled a number of obstetric cases that have been brought to trial in the last 5 years, and compare the ways in which cases were approached previously. The aim is to draw lessons for the benefit of lawyers, patients, doctors, midwives, expert witnesses, and hospital managers. The increasing complexity of modern obstetric patients, the rising expectations of society, the shortage of experienced staff on labour wards, and unrealistic expectations of some experts all make it difficult for the courts to handle these cases. PMID- 23810169 TI - Complications after laparoscopic and open subtotal colectomy for inflammatory colitis: a case-matched comparison. AB - AIM: The aim of this study was to compare the early postoperative outcome of patients undergoing laparoscopic subtotal colectomy with those undergoing open subtotal colectomy for colitis refractory to medical treatment. METHOD: A retrospective observational study was carried out of patients who underwent subtotal colectomy for refractory colitis, at a single centre, between 2006 and 2012. Patients were matched for age, gender, American Society of Anesthesiology (ASA) grade, urgency of operation and immunosuppressant/modulator treatment. The primary outcome measure was the number of postoperative complications, classified using the Clavien-Dindo scale. Secondary end-points included procedure duration, laparoscopic conversion rates, blood loss, 30-day readmission rates and length of hospital stay. RESULTS: Ninety-six patients were included, 39 of whom had laparoscopic surgery. Thirty-two of these were matched to similar patients who underwent an open procedure. The overall duration of the procedure was longer for laparoscopic surgery than for open surgery (median: 240 vs 150 min, P < 0.005) but estimated blood loss was less (median: 75 vs 400 ml, P < 0.005). In the laparoscopic group, 23 patients experienced 27 complications, and in the open surgery group, 23 patients experienced 30 complications. Most complications were minor (Grade I/II), and the distribution of complications, by grade, was similar between the two groups. There was no statistically significant difference in 30 day readmission rates between the laparoscopic and open groups (five readmissions vs eight readmissions, P = 0.536). Length of hospital stay was 4 days shorter for laparoscopic surgery, but this difference was not statistically significant (median: 7 vs 11 days, P = 0.159). CONCLUSION: In patients requiring colectomy for acute severe colitis, laparoscopic surgery reduced blood loss but increased operating time and was not associated with a reduction in early postoperative complications, length of hospital stay or readmission rates. PMID- 23810170 TI - 'Uncrunching' time: medical schools' use of social media for faculty development. AB - PURPOSE: The difficulty of attracting attendance for in-person events is a problem common to all faculty development efforts. Social media holds the potential to disseminate information asynchronously while building a community through quick, easy-to-use formats. The authors sought to document creative uses of social media for faculty development in academic medical centers. METHOD: In December 2011, the first author (P.S.C.) examined the websites of all 154 accredited medical schools in the United States and Canada for pages relevant to faculty development. The most popular social media sites and searched for accounts maintained by faculty developers in academic medicine were also visited. Several months later, in February 2012, a second investigator (C.W.S.) validated these data via an independent review. RESULTS: Twenty-two (22) medical schools (14.3%) employed at least one social media technology in support of faculty development. In total, 40 instances of social media tools were identified--the most popular platforms being Facebook (nine institutions), Twitter (eight institutions), and blogs (eight institutions). Four medical schools, in particular, have developed integrated strategies to engage faculty in online communities. CONCLUSIONS: Although relatively few medical schools have embraced social media to promote faculty development, the present range of such uses demonstrates the flexibility and affordability of the tools. The most popular tools incorporate well into faculty members' existing use of technology and require minimal additional effort. Additional research into the benefits of engaging faculty through social media may help overcome hesitation to invest in new technologies. PMID- 23810171 TI - To what extent does employer-paid health insurance reduce the use of public hospitals? AB - OBJECTIVE: This study examines the extent to which employer-paid health insurance has led to substitution of public with private hospital use in Denmark. METHODS: Individual-person-level data for the entire Danish privately employed, full-time working population is used in an observational design. The effect of having employer-paid health insurance on the utilisation of public hospitals is estimated using propensity score matching in order to control for risk selection, based on a number of individual- and company-level characteristics. The outcome is defined as the total consumption of health care services provided by public hospitals. RESULTS: The effect of employer-paid health insurance is estimated to correspond to a significant 10% reduction in the total use of public hospitals. The effect appears to be robust to alternative methodological specifications and is supported from the analysis of alternative outcome measures. CONCLUSION: The rise in the number of individuals with employer-paid health insurance seems to have alleviated the pressure on public hospitals in Denmark. Future studies should confirm the magnitude of this effect, preferably based on empirical data with repeated measurements of insurance status. PMID- 23810172 TI - What (or who) causes health inequalities: theories, evidence and implications? AB - Health inequalities are the unjust differences in health between groups of people occupying different positions in society. Since the Black Report of 1980 there has been considerable effort to understand what causes them, so as to be able to identify actions to reduce them. This paper revisits and updates the proposed theories, evaluates the evidence in light of subsequent epidemiological research, and underlines the political and policy ramifications. The Black Report suggested four theories (artefact, selection, behavioural/cultural and structural) as to the root causes of health inequalities and suggested that structural theory provided the best explanation. These theories have since been elaborated to include intelligence and meritocracy as part of selection theory. However, the epidemiological evidence relating to the proposed causal pathways does not support these newer elaborations. They may provide partial explanations or insights into the mechanisms between cause and effect, but structural theory remains the best explanation as to the fundamental causes of health inequalities. The paper draws out the vitally important political and policy implications of this assessment. Health inequalities cannot be expected to reduce substantially as a result of policy aimed at changing health behaviours, particularly in the face of wider public policy that militates against reducing underlying social inequalities. Furthermore, political rhetoric about the need for 'cultural change', without the required changes in the distribution of power, income, wealth, or in the regulatory frameworks in society, is likely to divert from necessary action. PMID- 23810173 TI - Gender differences in cigarette consumption in Turkey: evidence from the Global Adult Tobacco Survey. AB - OBJECTIVE: The aim of this study is to examine the potential factors associated with both smoking participation and the level of cigarette consumption in Turkey from a gender perspective, the understanding of which are crucial to the formulation and implementation of anti-smoking policies. METHODS: The Global Adult Tobacco Survey for 2008 is used in the analysis. Since the dependent variable, the number of cigarettes smoked per day, consists of nonnegative integer values, Negative Binomial and Zero-inflated Negative Binomial models are used as an estimation methodology. The zero-inflated model allows the interpretation of smoking propensity and smoking intensity behaviours separately. RESULTS: The main findings of this study are twofold. First, the factors affecting the smoking behaviour of males and females are different. Second, there are also differences between the factors affecting the decisions of whether to smoke and how much to smoke for both genders. Cigarette prices, for example, affect the level of cigarette consumption of females but not of males whereas pro cigarette marketing affects the decision of how much to smoke for males with no effect on female smoking. CONCLUSIONS: The findings highlight the importance of gender differences in cigarette consumption. Overall, education programs, cigarette taxation and tobacco advertising bans have different effects on each gender whereas social interaction is important for cigarette smoking behaviour of both genders. The anti-smoking policies can be more effective if policy makers take into account gender differences in both smoking propensity and intensity. PMID- 23810174 TI - Diaphragmatic hernia after esophagectomy in 440 patients with long-term follow up. AB - BACKGROUND: Postesophagectomy diaphragmatic hernia (PDH) is a recognized but severely under-reported and potentially hazardous event. Information regarding the natural course of this condition and guidelines regarding indications for reoperative intervention are lacking. In this study we aim to describe the frequency, predictors of incidence, and indications for repair. METHODS: Cross sectional imaging (computed tomography scan) from patients who underwent esophagectomy between January 2001 and December 2007 at a single center were reviewed by two radiologists blinded to previous reports and clinical outcomes. Patients with PDH were compared with a similar cohort who did not have hernia. Patient characteristics, outcomes, and hernia descriptors including longitudinal progression were recorded. Multivariable logistic regression analyses identified predictors of PDH and need for repair. RESULTS: Of a total of 440 patients who underwent esophagectomy, 67 (15%) were radiologically diagnosed with PDH. Of these, only 7 of 67 cases (10%) were prospectively reported by the radiologist. Median time interval from esophagectomy to hernia was 2 years. Type of esophagectomy was an independent predictor for hernia developing (p = 0.027). Patients with high body mass index were less prone to have PDH (p = 0.043). Thus far, 9 patients (2%) have required surgical intervention, all for hernia-related symptoms or progression. Despite mesh repair, 4 of 9 have recurred and 2 were re repaired. There was 1 PDH-associated death, 8 years after transhiatal resection. CONCLUSIONS: Variables contributing to PDH are both technical and patient dependent. Whereas the majority of patients with PDH have not required repair, a small portion who became symptomatic or had large, progressive hernia required remedial surgery. Postesophagectomy patients require long-term surveillance for PDH. PMID- 23810175 TI - Diagnosis and surgical outcomes for primary malignant melanoma of the esophagus: a single-center experience. AB - BACKGROUND: We summarize the experience of diagnosis and surgical therapy for primary malignant melanoma of the esophagus (PMME). METHODS: Clinical data of 13 patients diagnosed as having PMME treated by surgery as their primary therapy from 2000 to 2012 were retrospectively analyzed, and survival information was collected through follow-up. RESULTS: The average age (+/-standard deviation) of participants in this study was 66.4+/-7.6 years, and 84.6% were male. Overall, 61.5% of tumors were located in the lower thoracic esophagus. The accuracies of clinical T stage, N stage, and TNM stage were 53.9%, 46.2%, and 38.5%, respectively, compared with pathological staging (kappa=0.252, p=0.023). Surgical mortality and morbidity were 7.7% and 53.9%, respectively. The incidence of lymph node metastasis for patients with tumor invading within the mucosa was 0, but increased to 42.9% (3 of 7) with tumor invading to the submucosal layer. Primary malignant melanoma of the esophagus in the mid third of the thoracic esophagus had a greater chance to metastasize to perigastric lymph nodes (2 of 5) than to middle mediastinal lymph nodes (1 of 5). For PMME located at the lower third of the thoracic esophagus, upper mediastinal lymph node metastasis was more likely to occur (2 of 4) with tumor invasion penetrating the proper muscle layer. Recurrence occurred within 1 year in all patients with tumor later than Stage Ib. The most common recurrent organ was the liver. The overall 1-year and 5-year postoperative survival rates were 54.0% and 35.9%, respectively, and lymph node metastasis was the independent predictive factor for postoperative survival (p=0.013; odds ratio, 15.05). CONCLUSIONS: Despite the similarity in lymph node metastatic patterns to squamous cell carcinoma, PMME is more inclined to distant metastasis. Clinical staging was inconsistent with pathological staging for PMME based on endoscopy and computed tomography. Surgical therapy was the optimal treatment for PMME at an earlier stage. Early diagnosis and aggressive lymph node dissection were beneficial for accurate staging, potentially reducing recurrence and thus improving survival. PMID- 23810176 TI - Modifications, classification, and outcomes of elephant-trunk procedures. AB - BACKGROUND: There are a variety of modified elephant-trunk methods, including use of endovascular stents. Our objectives were to classify these modifications, compare outcomes between the classic anastomotic site and these alternatives, and investigate time to second-stage elephant-trunk completion. METHODS: From May 1992 to January 2011, 526 patients underwent a first-stage elephant-trunk procedure and were the subject of analysis. RESULTS: Distal aortic anastomosis was located before the brachiocephalic artery in 6 patients (1.1%), between brachiocephalic and left common carotid artery (LCCA) in 1 (0.19%), between LCCA and left subclavian artery (LSCA) in 154 (29%), and beyond the LSCA (classic) in 365 (69%). Stroke occurred in 8% (n = 42) overall, 10% (n = 16) in the LCCA-LSCA group, and 6.8% (n = 25) in the classic group. Risk factors were older age and acute dissection. Thirty-day mortality was 7.6% (n = 40) and was similar for LCCA LSCA (9.7%) and classic sites (6.3%; p = 0.7); risk factors included older age, smaller body surface area, and end-organ dysfunction. Likelihood of death before second-stage elephant trunk at 1, 4, and 8 years after operation was 16%, 22%, and 27%, respectively. The larger the distal aorta, the more likely was second stage completion (p < 0.0001); when greater than 6 cm, 80% had second-stage completion. CONCLUSIONS: The elephant-trunk operation is safe for a broad population, including when anastomotic sites are other than beyond the LSCA. Without second-stage completion, patient mortality increases markedly after 4 years. PMID- 23810177 TI - Aortic valve prosthesis-patient mismatch and long-term outcomes: 19-year single center experience. AB - BACKGROUND: The clinical effects of prosthesis-patient mismatch (PPM) after aortic valve replacement, with respect to morbidity and survival, remain controversial, particularly in high-risk patient subgroups. METHODS: Patients undergoing aortic valve replacement from January 1992 to December 2010 were classified according to effective orifice area index into severe PPM (effective orifice area index<0.65 cm2/m2), moderate PPM (effective orifice area index 0.65 to 0.85 cm2/m2), and absent PPM (effective orifice area index>0.85 cm2/m2). Analyses examined major morbidity and total all-cause death. RESULTS: Prosthesis patient mismatch was classified as severe (92 of 1,060; 8.7%), moderate (440 of 1,060; 41.5%), or absent (528 of 1,060; 49.8%). Moderate and severe PPM were unrelated to in-hospital morbidity or mortality. There were 440 deaths (41.5%) at 5.6 years median follow-up (interquartile range, 2.9 to 9.1). Trend toward poorer survival according to PPM group (chi2=5.46; p=0.07) was attenuated further with covariate adjustment. Sensitivity analyses demonstrated discrete mortality effects for moderate PPM in association with concomitant coronary artery bypass grafting, impaired left ventricular function, and older age (significant hazard ratios range, 1.05 to 1.57). Severe PPM also increased mortality risk in association with older age, concomitant coronary artery bypass grafting, and New York Heart Association Class III or IV (significant hazard ratios range, 1.06 to 2.65). CONCLUSIONS: Prosthesis-patient mismatch was not associated with mortality in covariate-adjusted models. However, a discrete mortality risk was attributable to moderate and severe PPM in patients of older age, or those with left ventricular dysfunction, New York Heart Association class III or IV, and concomitant coronary artery bypass grafting. PMID- 23810178 TI - Directed epicardial assistance in ischemic cardiomyopathy: flow and function using cardiac magnetic resonance imaging. AB - BACKGROUND: Heart failure after myocardial infarction (MI) is a result of increased myocardial workload, adverse left ventricular (LV) geometric remodeling, and less efficient LV fluid movement. In this study we utilize cardiac magnetic resonance imaging to evaluate ventricular function and flow after placement of a novel directed epicardial assist device. METHODS: Five swine underwent posterolateral MI and were allowed to remodel for 12 weeks. An inflatable bladder was positioned centrally within the infarct and secured with mesh. The device was connected to an external gas exchange pump, which inflated and deflated in synchrony with the cardiac cycle. Animals then underwent cardiac magnetic resonance imaging during active epicardial assistance and with no assistance. RESULTS: Active epicardial assistance of the infarct showed immediate improvement in LV function and intraventricular flow. Ejection fraction significantly improved from 26.0% +/- 4.9% to 37.3% +/- 4.5% (p < 0.01). End systolic volume (85.5 +/- 12.7 mL versus 70.1 +/- 11.9 mL, p < 0.01) and stroke volume (28.5 +/- 4.4 mL versus 39.9 +/- 3.1 mL, p = 0.03) were also improved with assistance. End-diastolic volume and regurgitant fraction did not change with treatment. Regional LV flow improved both qualitatively and quantitatively during assistance. Unassisted infarct regional flow showed highly discoordinate blood movement with very slow egress from the posterolateral wall. Large areas of stagnant flow were also identified. With assistance, posterolateral wall blood velocities improved significantly during both systole (26.4% +/- 3.2% versus 12.6% +/- 1.2% maximum velocity; p < 0.001) and diastole (54.3% +/- 9.3% versus 24.2% +/- 2.5% maximum velocity; p < 0.01). CONCLUSIONS: Directed epicardial assistance can improve LV function and flow in ischemic cardiomyopathy. This novel device may provide a valuable alternative to currently available heart failure therapies. PMID- 23810180 TI - New antibiotics for paediatric use: a review of a decade of regulatory trials submitted to the European Medicines Agency from 2000--why aren't we doing better? AB - New initiatives have been introduced in Europe and the USA to encourage more rapid development of antibiotics. The need to ensure these new antibiotics can be safely used in children, and especially neonates, is important owing to high antimicrobial resistance in these patient groups. This review aims to determine what lessons can be learnt from the recent regulatory processes to speed up access to new medicines for children, focusing on antibiotics licensed for adults by the EMA since 2000. For the 11 newly approved antibiotics, 31 clinical trials enrolling children in Europe were identified. However, many of these trials included both adults and children but did not provide a subset analysis for paediatrics, limiting the relevance of their findings. Some studies have been prematurely terminated and others are apparently active but are still not yet recruiting patients. Among paediatric-specific studies, 18 evaluate safety and efficacy of new compounds, 4 are pharmacokinetic studies, but only 2 focus on neonates. Nearly all studies with an agreed Paediatric Investigation Plan have just started or are not yet recruiting. For most antibiotics, despite adult phase 3 studies being completed, with specific concerns for particular drugs already noted, it will take another 3-5 years before adequate prescribing information becomes available for paediatricians. Evidence from this review suggests that we could do better. Lessons should be learnt from paediatric antiretroviral development, with neonatal and paediatric pharmacokinetic, clinical trial and pharmacovigilance drug development programmes being run directly in parallel with adult studies-not a decade behind. PMID- 23810179 TI - Thoracoscopic Nuss procedure for young adults with pectus excavatum: excellent midterm results and patient satisfaction. AB - BACKGROUND: Chest wall remodeling by substernal placement of a Nuss bar is the treatment of choice for children with pectus excavatum; however, it has not yet gained widespread acceptance in adults. We demonstrate that thoracoscopic Nuss bar insertion in young adults is safe and leads to excellent results. METHODS: Adult patients who underwent thoracoscopic Nuss bar insertion at one institution between 2006 and 2012 were identified. Data on demographics, postoperative outcomes, quality of life, and cosmetic satisfaction was collected. A validated single-step quality of life survey was administered to patients. Student's t test and the Wilcoxon rank sum test were used for statistical analysis. RESULTS: Seventy-three patients (65 male, 8 female) with a median age of 20 years (range, 16 to 51) were included. The median follow-up was 44.6 months (range, 36.9 to 73.26). Most patients (59 of 73, 81%) had one bar placed. The median length of hospital stay was 5 days (range, 3 to 9) and the median duration of epidural anesthesia was 3 days (range, 0 to 7). There were 4 reoperations (5.5%) in the immediate postoperative period: 2 for bar displacement and 2 for poor cosmesis. All reoperations were performed thoracoscopically. Other postoperative complications included pneumothorax (3 of 73, 4.1%) and ileus (1 of 73, 1.3%). Fifty-one patients participated in a quality-of-life survey (73% response rate). The mean self-esteem score improved from 4.6 of 10 preoperatively to 6.5 of 10 postoperatively (p=0.002). The social impact of the pectus deformity became less significant (mean preoperative score 3.6, mean postoperative score 2.8, p=0.02). The severity of initial postoperative pain was much improved on follow-up. The vast majority of patients (41 of 51, 80%) were satisfied with the cosmetic result, and 96% (49 of 51) would opt to have the surgery again. CONCLUSIONS: For young adults who wish to correct their pectus deformity, a thoracoscopic Nuss procedure is safe and results in a high rate of patient satisfaction, significant improvement in self-image, and excellent midterm cosmetic results. PMID- 23810181 TI - Communication skills in context: trends and perspectives. AB - OBJECTIVE: Doctor-patient communication has been well researched. Less is known about the educational background of communication skills training. Do we aim for optimal performance of skills, or rather attempt to help students become skilled communicators? METHODS: An overview is given of the current view on optimal doctor-patient communication. Next we focus on recent literature on how people acquire skills. These two topics are integrated in the next chapter, in which we discuss the optimal training conditions. RESULTS: A longitudinal training design has more lasting results than incidental training. Assessment must be in line with the intended learning outcomes. For transfer, doctor-patient communication must be addressed in all stages of health professions training. CONCLUSION: Elementary insights from medical education are far from realised in many medical schools. Doctor-patient communication would benefit strongly from more continuity in training and imbedding in the daily working contexts of doctors. PRACTICE IMPLICATIONS: When an educational continuum is realised and attention for doctor patient communication is embedded in the working context of doctors in training the benefits will be strong. Training is only a part of the solution. In view of the current dissatisfaction with doctor-patient communication a change in attitude of course directors is strongly called for. PMID- 23810182 TI - Neurorehabilitation of congenital mirror movements enhanced by stroke: a case report with fMRI study. PMID- 23810183 TI - Cerebrospinal fluid lactate in post-neurosurgical bacterial meningitis diagnosis. AB - BACKGROUND: Differential diagnosis between post-neurosurgical bacterial meningitis (PNBM) and aseptic meningitis is difficult. Inflammatory and biochemical cerebrospinal fluid (CSF) changes mimic those classically observed after CNS surgery. CSF lactate assay has therefore been proposed as a useful PNBM marker. OBJECTIVE: To evaluate the diagnostic accuracy of CSF lactate as a PNBM marker in patients hospitalized after a neurosurgical procedure. METHODS: Between July 2005 and June 2009, a prospective clinical study, in which all patients with clinical suspicion of PNBM were enrolled, was conducted at our neurosurgical Intensive Care Unit. PNBM diagnosis was categorized as proven, probable or negative before the analysis. RESULTS: Seventy-nine patients, 51 males with a mean age of 50 years (range 32-68 years) were included. Surgery was elective in 76% patients, mostly for brain tumors (57%); thirty PNBM episodes were identified. CSF parameters were significantly different in glucose concentration (27 mg% vs. 73 mg%, p<0.001), lactate (8 mmol/L vs. 2.8 mmol/L, p<0.001), CSF neutrophil pleocytosis (850 mm(-3) vs. 10mm(-3), p<0.001), and protein levels (449 mg% vs. 98 mg%) between the PNBM and non-PNBM groups. The ROC curve that best fits PNBM diagnosis is lactate. CONCLUSION: Increased CSF lactate is a useful PNBM marker, with better predictive value than CSF hypoglycorrhachia or pleocytosis. Lactate levels >= 4 mmol/L showed 97% sensitivity and 78% specificity, with a 97% negative predictive value. PMID- 23810184 TI - The future of imaging in veterinary oncology: learning from human medicine. AB - Imaging technology is critical for adequate diagnosis and staging in human and veterinary oncology. Sensitive detection of lesions is necessary to determine appropriate local or systemic therapy and to monitor therapeutic results. New technology in digital radiography, ultrasound, and computed tomography (CT) scanning are now widely available in veterinary medicine. Advanced imaging with high-detail CT scans, magnetic resonance imaging (MRI), and positron-emission tomography (PET) are now available in academic centers and some private specialty practices. This review describes the current and future applications of these new imaging systems and modalities in veterinary oncology and how advanced imaging contributes to diagnosis, staging, and monitoring of cancers. The potential of molecular imaging for accurate, minimally invasive diagnosis and monitoring is discussed. PMID- 23810185 TI - Expression of reference genes and T helper 17 associated cytokine genes in the equine intestinal tract. AB - There is accumulating evidence for the involvement of pro-inflammatory cytokines associated with a T helper 17 response in intestinal disorders such as inflammatory bowel disease (IBD) in humans. The involvement of interleukin (IL) 17 or IL-23 in equine IBD has not been studied and most gene expression studies in the equine intestine have been limited to the use of a single non-validated reference gene. In this study, expression of the reference gene candidates beta2 microglobulin (beta2M), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), histone H2A type 1, hypoxanthine-guanine phosphoribosyltransferase (HPRT), 60S ribosomal protein L32 (RPL32), succinate dehydrogenase complex subunit A (SDHA) and transferrin receptor 1 protein coding (TFRC)in the equine intestine was evaluated by quantitative PCR. Three to four reference genes were adequate for normalisation of gene expression in the healthy duodenum, mid-jejunum, colon and rectum, although each segment required a unique combination of reference genes. No combination of the evaluated genes was optimal for the caecum and ileum. Another combination of reference genes (GAPDH, HPRT, RPL32 and SDHA) was optimal for normalisation of rectal samples from healthy and IBD-affected horses, indicating that reference genes should be re-evaluated if material from diseased specimens is analysed. Basal expression of IL-12p40, IL-17A and IL-23p19 was detected in each segment, which will enable gene expression studies of these cytokines by relative quantification. PMID- 23810186 TI - Early embryonic development, assisted reproductive technologies, and pluripotent stem cell biology in domestic mammals. AB - Over many decades assisted reproductive technologies, including artificial insemination, embryo transfer, in vitro production (IVP) of embryos, cloning by somatic cell nuclear transfer (SCNT), and stem cell culture, have been developed with the aim of refining breeding strategies for improved production and health in animal husbandry. More recently, biomedical applications of these technologies, in particular, SCNT and stem cell culture, have been pursued in domestic mammals in order to create models for human disease and therapy. The following review focuses on presenting important aspects of pre-implantation development in cattle, pigs, horses, and dogs. Biological aspects and impact of assisted reproductive technologies including IVP, SCNT, and culture of pluripotent stem cells are also addressed. PMID- 23810187 TI - Cell organelles. PMID- 23810188 TI - Comparison between the deconvolution and maximum slope 64-MDCT perfusion analysis of the esophageal cancer: is conversion possible? AB - PURPOSE: To estimate if CT perfusion parameter values of the esophageal cancer, which were obtained with the deconvolution-based software and maximum slope algorithm are in agreement, or at least interchangeable. METHODS: 278 esophageal tumor ROIs, derived from 35 CT perfusion studies that were performed with a 64 MDCT, were analyzed. "Slice-by-slice" and average "whole-covered-tumor-volume" analysis was performed. Tumor blood flow and blood volume were manually calculated from the arterial tumor-time-density graphs, according to the maximum slope methodology (BF(ms) and BV(ms)), and compared with the corresponding perfusion values, which were automatically computed by commercial deconvolution based software (BF(deconvolution) and BV(deconvolution)), for the same tumor ROIs. Statistical analysis was performed using Wilcoxon matched-pairs test, paired-samples t-test, Spearman and Pearson correlation coefficients, and Bland Altman agreement plots. RESULTS: BF(deconvolution) (median: 74.75 ml/min/100g, range, 18.00-230.5) significantly exceeded the BF(ms) (25.39 ml/min/100g, range, 7.13-96.41) (Z=-14.390, p<0.001), while BV(deconvolution) (median: 5.70 ml/100g, range: 2.10-15.90) descended the BV(ms) (9.37 ml/100g, range: 3.44-19.40) (Z= 13.868, p<0.001). Both pairs of perfusion measurements significantly correlated with each other: BF(deconvolution), versus BF(ms) (rS=0.585, p<0.001), and BV(deconvolution), versus BV(ms) (rS=0.602, p<0.001). Geometric mean BF(deconvolution)/BF(ms) ratio was 2.8 (range, 1.1-6.8), while geometric mean BV(deconvolution)/BV(ms) ratio was 0.6 (range, 0.3-1.1), within 95% limits of agreement. CONCLUSIONS: Significantly different CT perfusion values of the esophageal cancer blood flow and blood volume were obtained by deconvolution based and maximum slope-based algorithms, although they correlated significantly with each other. Two perfusion-measuring algorithms are not interchangeable because too wide ranges of the conversion factors were found. PMID- 23810189 TI - Diffusion-weighted MRI of the prostate at 3.0 T: comparison of endorectal coil (ERC) MRI and phased-array coil (PAC) MRI-The impact of SNR on ADC measurement. AB - PURPOSE: To compare ADC values measured from diffusion-weighted MR (DW-MR) images of the prostate obtained with both endorectal and phased-array coils (ERC+PAC) to those from DW-MRI images obtained with an eight-channel torso phased-array coil (PAC) at 3.0 T. METHODS: The institutional review board issued a waiver of informed consent for this HIPAA-compliant study. Twenty-five patients with biopsy proven prostate cancer underwent standard 3-T MRI using 2 different coil arrangements (ERC+PAC and PAC only) in the same session. DW-MRI at five b-values (0, 600, 1000, 1200, and 1500 s/mm(2)) were acquired using both coil arrangements. On b=0 images, signal-to-noise ratios (SNRs) were measured as the ratio of the mean signal from PZ and TZ ROIs to the standard deviation from the mean signal in an artifact-free ROI in the rectum. Matching regions-of-interest (ROIs) were identified in the peripheral zone and transition zone on ERC-MRI and PAC-MRI. For each ROI, mean ADC values for all zero and non-zero b-value combinations were computed. RESULTS: Mean SNR with ERC-MRI at PZ (66.33 +/- 27.07) and TZ (32.69 +/- 12.52) was 9.27 and 5.52 times higher than with PAC-MRI ((7.32 +/- 2.30) and (6.13 +/- 1.56), respectively) (P<0.0001 for both). ADCs from DW-MR images obtained with all b-values in the PZ and TZ were significantly lower with PAC-MRI than with ERC-MRI (P<0.001 for all). CONCLUSION: Lower SNR of DW-MR images of the prostate obtained with a PAC can significantly decrease ADC values at higher b-values compared to similar measurements obtained using the ERC. To address these requirements, clinical MR systems should have image processing capabilities which incorporate the noise distribution. PMID- 23810190 TI - Putting the brakes on anticancer therapies: suppression of innate immune pathways by tumor-associated myeloid cells. AB - Accumulating evidence has revealed that immunogenic cell death triggered by particular chemotherapeutic agents plays a critical role in harnessing antitumor immunity to clinical responses. However, negative regulatory pathways exist which suppress the induction of effective immune responses by a broad spectrum of anticancer therapies including 'non-immunogenic' regimens. Tumor-associated myeloid cells are unique in that they are capable of manipulating responses to anticancer drugs by utilizing negative regulatory factors of innate immune pathways, including damage-associated molecule-mediated pattern recognition and tolerogenic phagocytosis. Further elucidation of the molecular mechanisms regulating innate immune responses of tumor-associated myeloid cells under cellular stress should enhance the development of new molecular targeting therapies for patients with treatment-refractory cancers. PMID- 23810191 TI - Which method better evaluates the molecular response in newly diagnosed chronic phase chronic myeloid leukemia patients with imatinib treatment, BCR-ABL(IS) or log reduction from the baseline level? AB - The molecular response of chronic myeloid leukemia (CML) patients to tyrosine kinase inhibitor treatment can be evaluated either by BCR-ABL mRNA levels on international scale (IS) or by log reduction from the baseline level of the laboratory. Both methods were compared in 248 newly diagnosed chronic phase CML patients treated with imatinib. The major molecular responses (MMR) obtained by both methods predict progression-free survival (PFS, all P<0.0001). Thirty-six patients, who were identified as MMR patients by the IS method but as non-MMR patients by the log reduction method, had the same PFS as MMR patients identified by both methods. The molecular responses of patients at 3 and 6 months, as evaluated by the two methods, have similar predictive values on their cytogenetic responses at 12 months and on their molecular responses at 18 months. Both <= 10%(IS) and >= 1 log reduction at 3 months and <= 1%(IS) at 6 months were significantly associated with PFS (P=0.0011, 0.0090, and 0.0064). The percentages of patients with BCR-ABL(IS) of <= 1%, >1-10%, and of >10% at 3 months and 6 months in the German CML Study IV were similar with those with corresponding BCR ABL(IS) in our center, but was significantly different with those evaluated by the log reduction method. Therefore, the molecular response evaluated by BCR ABL(IS) has similar trends in PFS and in response prediction, but can better differentiate patients than that by the log reduction method. Furthermore, the IS method allows comparison among molecular response results from different laboratories. PMID- 23810192 TI - Genetic and neural mechanisms that inhibit Drosophila from mating with other species. AB - Genetically hard-wired neural mechanisms must enforce behavioral reproductive isolation because interspecies courtship is rare even in sexually naive animals of most species. We find that the chemoreceptor Gr32a inhibits male D. melanogaster from courting diverse fruit fly species. Gr32a recognizes nonvolatile aversive cues present on these reproductively dead-end targets, and activity of Gr32a neurons is necessary and sufficient to inhibit interspecies courtship. Male-specific Fruitless (Fru(M)), a master regulator of courtship, also inhibits interspecies courtship. Gr32a and Fru(M) are not coexpressed, but Fru(M) neurons contact Gr32a neurons, suggesting that these genes influence a shared neural circuit that inhibits interspecies courtship. Gr32a and Fru(M) also suppress within-species intermale courtship, but we show that distinct mechanisms preclude sexual displays toward conspecific males and other species. Although this chemosensory pathway does not inhibit interspecies mating in D. melanogaster females, similar mechanisms appear to inhibit this behavior in many other male drosophilids. PMID- 23810194 TI - Magnetic resonance imaging-targeted prostate biopsies: now is the time to START. PMID- 23810193 TI - Ribosome profiling provides evidence that large noncoding RNAs do not encode proteins. AB - Large noncoding RNAs are emerging as an important component in cellular regulation. Considerable evidence indicates that these transcripts act directly as functional RNAs rather than through an encoded protein product. However, a recent study of ribosome occupancy reported that many large intergenic ncRNAs (lincRNAs) are bound by ribosomes, raising the possibility that they are translated into proteins. Here, we show that classical noncoding RNAs and 5' UTRs show the same ribosome occupancy as lincRNAs, demonstrating that ribosome occupancy alone is not sufficient to classify transcripts as coding or noncoding. Instead, we define a metric based on the known property of translation whereby translating ribosomes are released upon encountering a bona fide stop codon. We show that this metric accurately discriminates between protein-coding transcripts and all classes of known noncoding transcripts, including lincRNAs. Taken together, these results argue that the large majority of lincRNAs do not function through encoded proteins. PMID- 23810195 TI - In pre-school children, cortisol secretion remains stable over 12 months and is related to psychological functioning and gender. AB - OBJECTIVES: Cross-sectional studies provide evidence that cortisol secretion as a marker of hypothalamus-pituitary-adrenocortical axis activity (HPA AA) is related to psychological functioning and behavior. However, there are no studies of the stability of the HPA AA in pre-schoolers over the longer term. The aim of the present study was therefore to investigate cortisol secretion in pre-schoolers longitudinally, and to predict psychological functioning 12 months later. METHOD: 92 pre-schoolers (mean age: 5.4 years; 44% females) took part in a follow-up assessment 12 months after initial assessment. Cortisol secretion was assessed both at baseline (morning cortisol secretion) and under challenge conditions, and a thorough psychological assessment was included. RESULTS: Increased cortisol secretion at 5.4 years predicted increased cortisol secretion and psychological difficulties at 6.4 years. Compared to boys, girls had higher cortisol secretion at both 5.4 and 6.4 years. Cross-sectionally, at the age of 6.4 years, levels of cortisol secretion impacted differentially on girls' and boys' behavior. CONCLUSION: In pre-schoolers, HPA axis activity at 5.4 years is stable over the following 12 months and is associated with psychological functioning. Pre schoolers with higher cortisol levels are at increased risk of developing further psychological difficulties. Gender affects the manner in which HPA axis activity impacts on psychological functioning. Moreover, gender differences in cortisol secretion occur already in prepubertal children and appear to be independent from sex steroids. PMID- 23810197 TI - Genetic modulation of borderline personality disorder: systematic review and meta analysis. AB - Borderline personality disorder (BPD) is a highly prevalent psychiatric disorder with high morbidity and mortality. Early theories ascribed an environmental etiology of BPD, but growing evidence supports a genetic vulnerability as well. The primary aim of this study was to systematically review genetic association studies focused on BPD. PubMed, ISI Web of Knowledge and PsycINFO databases were searched for studies published until December 2012. Meta-analyses were also performed when three or more studies reported genetic data on the same polymorphism. Data were analyzed with Cochrane Collaboration Review Manager Software (RevMan, version 5.0). Quality and publication bias were assessed. The systematic review of association studies examining genetic polymorphisms and BPD produced conflicting results. Meta-analyses were performed for three serotonergic polymorphisms: two common polymorphisms of the serotonin transporter gene (SLC6A4), the promoter insertion/deletion (5-HTTLPR) and the intron 2 VNTR (STin2 VNTR), and the rs1800532 (A218C) polymorphism of the tryptophan hydroxylase 1 gene (TPH1), all showing no association. No direct role of genetic polymorphisms was found in BPD. However, a few studies only are present in literature to draw definite conclusions. Further studies focusing on gene * gene and gene * environment interactions are needed to more deeply dissect the genetic role in the modulation of BPD. PMID- 23810196 TI - Visual processing in anorexia nervosa and body dysmorphic disorder: similarities, differences, and future research directions. AB - Anorexia nervosa (AN) and body dysmorphic disorder (BDD) are psychiatric disorders that involve distortion of the experience of one's physical appearance. In AN, individuals believe that they are overweight, perceive their body as "fat," and are preoccupied with maintaining a low body weight. In BDD, individuals are preoccupied with misperceived defects in physical appearance, most often of the face. Distorted visual perception may contribute to these cardinal symptoms, and may be a common underlying phenotype. This review surveys the current literature on visual processing in AN and BDD, addressing lower- to higher-order stages of visual information processing and perception. We focus on peer-reviewed studies of AN and BDD that address ophthalmologic abnormalities, basic neural processing of visual input, integration of visual input with other systems, neuropsychological tests of visual processing, and representations of whole percepts (such as images of faces, bodies, and other objects). The literature suggests a pattern in both groups of over-attention to detail, reduced processing of global features, and a tendency to focus on symptom-specific details in their own images (body parts in AN, facial features in BDD), with cognitive strategy at least partially mediating the abnormalities. Visuospatial abnormalities were also evident when viewing images of others and for non appearance related stimuli. Unfortunately no study has directly compared AN and BDD, and most studies were not designed to disentangle disease-related emotional responses from lower-order visual processing. We make recommendations for future studies to improve the understanding of visual processing abnormalities in AN and BDD. PMID- 23810198 TI - Everyday memory strategies for medication adherence. AB - The need to manage chronic diseases and multiple medications increases for many older adults. Older adults are aware of memory declines and incorporate compensatory techniques. Everyday memory strategies used to support medication adherence were investigated. A survey distributed to 2000 households in the Atlanta metropolitan area yielded a 19.9% response rate including 354 older adults, aged 60-80 years. Older adults reported forgetting to take their medications, more so as their activity deviated from normal routines, such as unexpected activities. The majority of older adults endorsed at least two compensatory strategies, which they perceived to be more helpful in normal routines. Compensatory strategies were associated with higher education, more medications, having concern, and self-efficacy to take medications. As memory changes, older adults rely on multiple cues, and perceive reliance on multiple cues to be helpful. These data have implications for the design and successful implementation of medication reminder systems and interventions. PMID- 23810199 TI - [Descriptive study of alcohol consumption in adolescents of Gandia]. AB - INTRODUCTION: The morbidity and mortality in developed countries is related to habits acquired in adolescence. Alcohol is the drug most consumed by Spanish adolescents, making its abuse a concern for public health. OBJECTIVE: To evaluate the pattern of alcohol consumption of 4th year secondary school pupils in the city of Gandia, the defining characteristics of this population and the environment in which this takes place. METHODOLOGY: This is a descriptive study of alcohol use in adolescents aged 15 to 18 years of Gandia, which was carried out through a survey of different issues related to health habits, nine of which relate to consumption alcohol. RESULTS: Of the 346 adolescents surveyed, 98% were minors, 93.3% had tried an alcoholic drink. Just under half (48.5%) took part in street binge-drinking, and 45.5% had got drunk at least once. Consumption was mainly during the weekend. More than three-quarters (76.6%) had their first contact with alcohol in the family. CONCLUSION: Alcohol use among adolescents is high, with consumption is mostly at weekends and with a high prevalence of alcohol intoxication, drinking in public places, and with friends. PMID- 23810200 TI - Successful management of a thoracic cerebrospinal fluid cutaneous fistula in a two year old child using a thoracic epidural blood patch. AB - A case of persistent thoracic cerebrospinal fluid cutaneous fistula in a toddler following radiographically confirmed epidural catheter placement is reported. Treatment of the fistula with a thoracic epidural blood patch was successful. PMID- 23810202 TI - Interstitial cells of Cajal: crucial for the development of megacolon in human Chagas' disease? AB - AIM: Megacolon, chronic dilation of a colonic segment,is accompanied by extensive myenteric neuron loss. However, this fails to explain unequivocally the formation of megacolon. We aimed to study further enteric structures that are directly or indirectly involved in colonic motility. METHOD: From surgically removed megacolon segments of seven Chagasic patients, three sets of cryosections from oral, megacolonic and anal zones were immunohistochemically quadruple-stained for smooth-muscle actin (SMA), synaptophysin (SYN, for nerve fibres), S100 (glia) and c-Kit (interstitial cells of Cajal, ICCs). Values of area measurements were related to the appropriate muscle layer areas and these proportions were compared with those of seven non-Chagasic control patients. RESULTS: Whereas nerve and glia profile proportions did not mirror unequivocally the changes of Chagasic colon calibre (nondilation/dilation/nondilation), the proportions of SMA (i.e. muscle tissue density) and c-Kit (i.e. ICC density) did so: they decreased from the oral to the megacolonic segment but increased to the anal zones (muscle tissue density: control 68.3%, oral 54.3%, mega 42.1%, anal 47.6%; ICC-density: control 1.8%, oral 1.1%, mega 0.4, anal 0.8%). CONCLUSION: Of the parameters evaluated, muscle tissue and ICC densities may be involved in the formation of Chagasic megacolon, although the mechanism of destruction cannot be deduced. PMID- 23810201 TI - The role of resistance and aerobic exercise training on insulin sensitivity measures in STZ-induced Type 1 diabetic rodents. AB - Individuals with Type 1 Diabetes Mellitus (T1DM) can develop insulin resistance. Regular exercise may improve insulin resistance partially through increased expression of skeletal muscle GLUT4 content. OBJECTIVE: To examine if different exercise training modalities can alter glucose tolerance through changes in skeletal muscle GLUT4 content in T1DM rats. METHODS: Fifty rats were divided into 5 groups; control, diabetic control, diabetic resistance exercised, and diabetic high and low intensity treadmill exercised. Diabetes was induced using multiple low dose Streptozotocin (20 mg/kg/day) injections and blood glucose concentrations were maintained moderately hyperglycemic through subcutaneous insulin pellets. Resistance trained rats climbed a ladder with incremental loads, while treadmill trained rats ran on a treadmill at 27 or 15 m/min, respectively, all for 6 weeks. RESULTS: At weeks 3 and 6, area under the curve measurements following an intravenous glucose tolerance test (AUC-IVGTT) in all diabetic groups were higher than control rats (p<0.05). At 6 weeks, all exercise groups had significantly lower AUC-IVGTT values than diabetic control animals (p<0.05). Treadmill trained rats had the lowest insulin dose requirement of the T1DM rats and the greatest reduction in insulin dosage was evident in high intensity treadmill exercise. Concomitant with improvements in glucose handling improvements, tissue-specific elevations in GLUT4 content were demonstrated in both red and white portions of vastus lateralis and gastrocnemius muscles, suggesting that glucose handling capacity was altered in the skeletal muscle of exercised T1DM rats. CONCLUSIONS: These results suggest that, while all exercise modalities can improve glucose tolerance, each mode leads to differential improvements in insulin requirements and protein content alterations. PMID- 23810203 TI - Human housekeeping genes, revisited. AB - Housekeeping genes are involved in basic cell maintenance and, therefore, are expected to maintain constant expression levels in all cells and conditions. Identification of these genes facilitates exposure of the underlying cellular infrastructure and increases understanding of various structural genomic features. In addition, housekeeping genes are instrumental for calibration in many biotechnological applications and genomic studies. Advances in our ability to measure RNA expression have resulted in a gradual increase in the number of identified housekeeping genes. Here, we describe housekeeping gene detection in the era of massive parallel sequencing and RNA-seq. We emphasize the importance of expression at a constant level and provide a list of 3804 human genes that are expressed uniformly across a panel of tissues. Several exceptionally uniform genes are singled out for future experimental use, such as RT-PCR control genes. Finally, we discuss both ways in which current technology can meet some of past obstacles encountered, and several as yet unmet challenges. PMID- 23810206 TI - Potential errors in staging primary pulmonary adenocarcinomas by sublobar resection. AB - INTRODUCTION: There is increasing interest in treating patients with stage I pulmonary adenocarcinoma with sublobar resection and staging lymphadenectomy (StLN), but there is no information on the potential impact of this approach on staging. METHODS: A total of 241 consecutive wedge resections followed by immediate completion lobectomy (n = 225), bilobectomy (n = 3), or trisegmentectomy (n = 13) ("second specimens") and StLN were retrieved from our database. Tumor location, size, pT, and distance to closest margin (D) in the wedge specimens were compared with the presence of residual and/or additional tumor nodules in the lung and metastatic tumor in N1 lymph nodes of the "second specimens." RESULTS: Residual tumor (n = 14), additional tumor nodules (n = 9), and both (n = 1) were present in the lung parenchyma of 24 "second specimens." Problems orienting residual tumor to tumor in the wedge made it difficult to accurately determine overall tumor size and final pT in some cases. In 10 of the 241 cases, metastatic tumor was present only in N1 lymph nodes in the "second specimen." CONCLUSIONS: Sublobar resections with StLN would have potentially understaged 19 (7.9%) of 241 patients (9 as pT1 or pT2 instead of pT3, 9 as pN0 instead of pN1, and 1 as pT1N0 instead of pT3N1). Preoperative positron emission tomography/computed tomography suggested the presence of more than 1 parenchymal tumor nodule and/or metastatic tumor in N1 lymph nodes of the "second specimen" in only 5 of these cases. Sublobar resections may miss additional tumor nodules and positive lymph nodes and understage a small proportion of pulmonary adenocarcinoma patients. PMID- 23810205 TI - Acute and chronic MRI changes in the spine and spinal cord after surgical stem cell grafting in patients with definite amyotrophic lateral sclerosis: post infusion injuries are unrelated with clinical impairment. AB - OBJECTIVE: To report MRI spinal changes after surgical infusion of bone marrow stem cells (BMSc) in ALS patients and assess their correlation with clinical events and functional performance. METHODS: BMSc were surgically injected in the thoracic spinal cord of 11 ALS patients (6/5 male/female; median age 46years). We performed first-week and third, sixth, ninth and twelfth post-surgical months spinal MRIs. The spinal changes in the postsurgical week and follow-up MRIs, as well as clinical events, functional scales and respiratory and electromyography data, were longitudinally monitored. Correlations between the imaging and clinical data were evaluated with the Spearman's test. RESULTS: Transient extradural fluid collections (100%), transient spinal cord T2 hyperintensity (81.8%), and chronic spinal cord deformities (63.6%) were the dominating MRI changes. Spinal cord hemorrhages (27.3%) and cystic myelomalacia (1/11 patients) were important although unusual findings. During the follow-up, minor adverse events of mild to moderate intensity eventually improved. Initial and follow-up imaging scores showed a strongly positive correlation (r 0.879, P<0.001). The initial and delayed clinical scores did not correlate. There was no significant correlation between any of the imaging scores and clinical data. CONCLUSIONS: Infusion of BMSc produces a variety of spinal changes apparently unrelated with clinical events and disease worsening. PMID- 23810208 TI - No effects of slow oscillatory transcranial direct current stimulation (tDCS) on sleep-dependent memory consolidation in healthy elderly subjects. AB - BACKGROUND: Studies in young healthy volunteers provided evidence of a beneficial impact of an anodal time-varied transcranial direct current stimulation (tDCS) during early slow wave rich sleep on declarative memory but not on procedural memory. OBJECTIVE/HYPOTHESIS: The present study investigated whether sleep dependent memory consolidation can also be affected by slow oscillating tDCS in a population of elderly subjects. METHODS: 26 subjects (69.1 years +/- 7.7 years) received bi-frontal anodal stimulation (max. current density: 0.331 mA/cm(2)) during early NREM sleep in a double-blind placebo-controlled randomized crossover study. Stimulation effects on offline consolidation were tested by using a declarative and a procedural memory task. Furthermore, sleep stages were scored, EEG power was analyzed and spindle densities were assessed. RESULTS: Independently from stimulation condition, performance in both memory tasks significantly decreased overnight. Stimulation revealed no significant effect on sleep-dependent memory consolidation. Verum tDCS was accompanied by significantly more time awake and significantly less NREM stage 3 sleep during five 1-min stimulation free intervals. CONCLUSIONS: The results of the present study are in line with other studies showing that offline consolidation during sleep varies with age and is less pronounced in the elderly than in young or middle-aged subjects. Contrary to an almost identical positive study in young adults, slow oscillatory tDCS applied to the elderly failed to show a beneficial effect on memory consolidation in the present study. PMID- 23810207 TI - Cholinergic receptor activation supports persistent firing in layer III neurons in the medial entorhinal cortex. AB - Medial temporal lobe (MTL) areas are crucial for memory tasks such as spatial working memory and temporal association memory, which require an active maintenance of memory for a short period of time (a few hundred milliseconds to tens of seconds). Recent work has shown that the projection from layer III neurons in the medial entorhinal cortex (MEC) to hippocampal region CA1, the temporoammonic (TA) pathway, might be specially important for these memory tasks. In addition, lesions to the entorhinal cortex disrupt persistent firing in CA1 which is believed to support active maintenance of memory. Injection of cholinergic antagonists and group I mGlu receptor antagonists to the MEC impairs spatial working memory and temporal association memory. Consistent with this, we have shown that group I mGlu receptor activation supports persistent firing in principal cells of the MEC layer III in vitro (Yoshida et al. [39]). However, it still remains unknown whether cholinergic receptor activation also supports persistent firing in MEC layer III neurons. In this paper, we tested this in MEC layer III cells using both ruptured and perforated whole-cell recordings in vitro. We report that the majority of cells we recorded from in MEC layer III show persistent firing during perfusion of the cholinergic agonist carbachol (2 10MUM). In addition, repeated stimulation gradually suppressed persistent firing. We further discuss the possible role of persistent firing in memory function in general. PMID- 23810209 TI - Concentrations of C-reactive protein, serum amyloid A, and haptoglobin in uterine arterial and peripheral blood in bitches with pyometra. AB - Pyometra is a life-threatening reproductive disorder that affects the uterus of female dogs. This study was designed to identify the possible indicators of uterine inflammation by comparing C-reactive protein (CRP), serum amyloid A (SAA), and haptoglobin (Hp) concentrations in uterine arterial and peripheral venous blood in bitches with open- and closed-cervix pyometra. CRP, SAA, and Hp concentrations were higher in bitches with closed-cervix pyometra irrespective of the site of blood collection. Higher acute-phase protein concentrations were observed in peripheral compared with uterine arterial blood in bitches with closed-cervix pyometra, whereas the levels were comparable in dogs with open cervix pyometra. Our results indicate that mean acute-phase protein concentrations differ according to pyometra type/severity and blood source and suggest the possible use of peripheral blood levels of CRP, SAA, and Hp to monitor inflammation during the course of pyometra. PMID- 23810210 TI - ERCC1, MLH1, MSH2, MSH6, and betaIII-tubulin: resistance proteins associated with response and outcome to platinum-based chemotherapy in malignant pleural mesothelioma. AB - INTRODUCTION: Platinum-based chemotherapy is besides the standard antifolate therapy with pemetrexed, the cornerstone for treatment of patients with malignant pleural mesothelioma (MPM), and its efficacy depends on several DNA repair enzymes. Therefore, these enzymes could be biomarkers for "tailoring" chemotherapy. This study evaluated enzymes involved in repair of platinum-caused DNA damage, potentially resulting in a biomarker panel associated with patient response and outcome to platinum-based chemotherapy. MATERIAL AND METHODS: Pre- or posttreatment specimens from a total of 103 patients with MPM who were undergoing first-line chemotherapy were tested separately. Immunohistochemistry for ERCC1 (endonuclease excision repair cross-complementing 1), MLH1 (MutL homologue 1), MutS homologue (MSH) 2, MSH6, and betaIII-tubulin protein expression, and pyrosequencing for ERCC1 codon 118 and C8092A polymorphisms were performed, and their results were correlated to clinicopathologic data. RESULTS: ERCC1, MLH1, MSH2, MSH6, and betaIII-tubulin were expressed in human MPM specimens at different intensities. When considering only pretreatment specimens, MSH6 protein levels were correlated to progression during chemotherapy (P = .0281). MLH1 protein levels (P = .0205), and ERCC1 codon 118 polymorphisms (P <= .0001) were significantly associated with progression-free survival. A significant association between ERCC1 protein levels and overall survival was noted (P = .032). Analyses of posttreatment specimens revealed significant associations between betaIII-tubulin protein levels and progression-free survival (P = .0066). ERCC1 C8092A polymorphisms were significantly associated with progression-free survival and overall survival (P = .0463 and P = .0080, respectively) in this group. CONCLUSIONS: Enzymes involved in DNA repair mechanisms are associated with patient response and outcome to platinum-based chemotherapy. Their assessment may be a helpful tool to tailor platinum-based chemotherapy of MPM patients who might expect the largest clinical benefit. Prospective validation of this biomarker panel is warranted. PMID- 23810211 TI - Contamination profile of DDT and HCH in surface sediments and their spatial distribution from North-East India. AB - Contamination status and spatial distribution of DDTs and HCHs were investigated in sediments collected from ponds and riverine system from districts Nagaon and Dibrugarh, North East India. A total of 113 surface sediment samples were collected from both the districts including 43 from ponds/wetlands and 70 from rivers/streams. Based on dry weight (dw), the mean concentration of ?HCH and ?DDT in sediments were found to be 287 ng/g (71.2-834 ng/g) and 321 ng/g (30.1-918 ng/g) for district Dibrugarh while 330 ng/g (39.2-743 ng/g) and 378 ng/g (72.5 932 ng/g) for district Nagaon, respectively. DDTs and HCHs in sediments were well influenced by total organic carbon, clay and silt content of sediments. Source identification revealed that sediment residue levels have originated from long and recent mixed source of technical HCH and Lindane for HCHs and mainly technical DDT for DDTs. Majority of samples exceeded the sediment quality guidelines (SQG) for gamma-HCH, p,p'-DDT and ?DDT indicating potential environmental risk. This baseline data can be used as reference for regular ecological and future POPs monitoring program. PMID- 23810212 TI - Evaluation of biochemical markers in the golden mussel Limnoperna fortunei exposed to glyphosate acid in outdoor microcosms. AB - In this study, the impact of technical grade glyphosate acid on Limnoperna fortunei was assessed employing outdoor microcosms treated with nominal glyphosate concentrations of 1, 3 and 6 mg L(-1). At the end of the experiment (26 days), catalase (CAT), superoxide dismutase (SOD), glutathione-S-transferase (GST), acetylcholinesterase (AChE), carboxylesterases (CES) and alkaline phosphatase (ALP) activities, and lipid peroxidation levels were analyzed. GST and ALP activities and lipid peroxidation levels showed a significant increase with respect to controls in the mussels exposed to glyphosate (up to 90, 500 and 69 percent, respectively). CES and SOD activities showed a significant decrease in glyphosate exposed bivalves with respect to controls (up to 48 and 37 percent, respectively). CAT and AChE did not show differences between exposed and no exposed bivalves. The increase in lipid peroxidation levels and the decrease in SOD and CES activities observed in L. fortunei indicate that glyphosate had adverse effects on the metabolism of this bivalve. The results of the present study also indicate that a "multibiomarker approach" provides a more precise knowledge of the impact of glyphosate on L. fortunei. PMID- 23810213 TI - Free fibula with physis need additional vascularisation other than the peroneal vessels alone: Re: "The use of a free vascularised fibula to reconstruct the radius following the resection of an osteosarcoma in a paediatric patient". PMID- 23810214 TI - A study of the combination of triamcinolone and 5-fluorouracil in modulating keloid fibroblasts in vitro. AB - BACKGROUND: Preliminary clinical trials suggest a superior effect when steroids and 5-fluorouracil are injected together for the intralesional therapy of keloids. In addition, it has been proposed that low-dose 5-fluorouracil may have advantages over conventional high dosages. We explored the molecular basis for the potential synergy involved in the combined treatment with triamcinolone and 5 fluorouracil. METHODS: The effects of triamcinolone alone or in combination with low-dose 5-fluorouracil on cell proliferation, cell-cycle progression, apoptosis and regulation of p53, p21, type I collagen (Col-1), vascular endothelial growth factor (VEGF), transforming growth factor-beta1 (TGF-beta1) and matrix metalloproteinase-2 (MMP-2) production in primary cultured keloid fibroblasts were examined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), flow cytometric and Western blotting assays. RESULTS: Triamcinolone suppressed cell proliferation and induced G1 cell-cycle arrest but not apoptosis. By contrast, 5-fluorouracil induced G2 cell-cycle arrest and apoptosis that may be associated with p53 activation and p21 up-regulation. The modulation of Col-1, VEGF, TGF-beta1 and MMP-2 expression by triamcinolone and 5-fluorouracil alone or their combination varied between individual cell lines; the trend is to promote a reduction in Col-1 and TGF-beta1 but up-regulation of MMP-2 expression. 5 Fluorouracil played a predominant role in the combined treatment leading to more significant cell proliferation inhibition, apoptosis, Col-1 suppression and MMP-2 induction (p < 0.05). CONCLUSIONS: Our data provide the molecular-based evidence for the observed clinical benefits of adding 5-fluorouracil to a steroid injection for improved scar regression and reduced recurrence of keloids. We expect fewer undesirable side effects in the combined treatment when the lower therapeutic dose of the individual drugs is to be used. PMID- 23810215 TI - Technical tip: a case demonstrating the synchronous placement of implantable cardioverter defibrillator and bilateral breast augmentation. PMID- 23810216 TI - Multiple schwannomas of the upper limb related exclusively to the ulnar nerve in a patient with segmental schwannomatosis. AB - Schwannomas are benign encapsulated tumours arising from the sheaths of peripheral nerves. They present as slowly enlarging solitary lumps, which may cause neurological defects. Multiple lesions are rare, but occur in patients with neurofibromatosis type 2 or schwannomatosis. Positive outcomes have been reported for surgical excision in solitary schwannomas. However, the role of surgery in patients with multiple lesions is less clear. The risk of complications such as iatrogenic nerve injury and the high likelihood of disease recurrence mean that surgical intervention should be limited to the prevention of progressive neurological deficit. We report a case of a 45 year old male who presented with multiple enlarging masses in the upper limb and sensory deficit in the distribution of the ulnar nerve. The tumours were found to be related exclusively to the ulnar nerve during surgical exploration and excision, a rare phenomenon. The masses were diagnosed as schwannomas following histopathological analysis, allowing our patient to be diagnosed with the rare entity segmental schwannomatosis. One year post-operatively motor function was normal, but intermittent numbness still occurred. Two further asymptomatic schwannomas developed subsequently and were managed conservatively. PMID- 23810217 TI - Heterotopic implantation of amputated digits following constriction ring syndrome: a case series. PMID- 23810218 TI - Study of serum ferritin in donors of two red blood cells units collected by apheresis. AB - OBJECTIVE: To analyze the recovery of iron stores without supplementation, when keeping an interval of six months between donations. MATERIAL AND METHODS: From April 2007 to May 2011, 308 regular and voluntary donors were selected. The apheresis collections were performed using ALYX(r) Component Collection System FenwalTM. The hematological parameters were analyzed using the Cell DIN Sapphire Abbot Diagnostics, and the serum ferritin by sandwich immunoassay method with fluorescence detection in final phase (ELFA) - Vidas(r) Ferritin-Biomerieux SA. A descriptive statistical analysis was performed for each hematological parameters and serum ferritin. RESULTS: The median hemoglobin concentration was 15.6g/dL (14, 18.4) in the first procedure and remains constant at subsequent donations. The ferritin median concentration was 64.6 MUg/L (7.2, 886). A decrease of 15.6% was observed when compared the first to the second procedure with a median 54.6 MUg/L (8.3, 213.7). Paradoxically, this decrease is not evident in the subsequent procedures, where an increase of 14.6% and 3.4% for the third and fourth procedure respectively was observed. Changes in ferritin values show statistically significant differences between the first and second collection, but this difference disappeared in subsequent donations. The analysis of MCH in each collection indicates that the significant difference between first and second donation (p1-2<0.05) and between first and third (p1-3=0.015), agree with the greatest decline of the ferritin found between procedures and the beginning of the stabilization of ferritin levels. COMMENTARY: The determination of ferritin appears not to be the most important parameter to consider at the time of donor selection and suggests that other factors unrelated to the donation may play a significant role. A decrease in serum ferritin was observed at the beginning, but it seems to attend a recovery and stabilization in the successive procedures. PMID- 23810219 TI - Comparison of the efficacy of peripheral blood stem cell mobilization using G-CSF alone from healthy donors and patients with hematologic malignancies. AB - Peripheral blood stem cell (PBSC) collection using granulocyte colony-stimulating factor (G-CSF) alone is superior to the combination of chemotherapy and G-CSF in terms of low morbidity, short duration of mobilization and low cost. We retrospectively compared the results of PBSC collection using G-CSF alone in 11 patients with malignant lymphoma (ML), 23 patients with plasma cell neoplasms (PCN) and 48 healthy donors. The geometric mean number of CD34(+) cells/kg obtained on the first day of collection was 0.99 * 10(6)/kg in ML patients, 2.26 * 10(6)/kg in PCN patients, and 3.36 * 10(6)/kg in healthy donors. The probability of collecting at least 1 * 10(6)/kg CD34(+) cells/kg during a single course of apheresis was 90.9% in ML patients, 95.7% in PCN patients, and 100% in healthy donors. In a multiple regression analysis of the CD34(+) cell yields on the first day of apheresis, we identified disease, the baseline white blood cell count (WBC), platelet count, and lactate dehydrogenase as independent significant variables. Particularly, disease was strongly associated with the CD34(+) cell yield, probably due to the difference in the number of previous chemotherapy cycles. In conclusion, the minimal dose of CD34(+) cells for autologous transplantation was collected in almost all patients with hematological malignancies. However, patients who have received repeated cycles of chemotherapy, such as patients with ML, and those who have low WBC counts and/or platelet counts may be at higher risk for poor mobilization. PMID- 23810220 TI - Interleukin-17 in veterinary animal species and its role in various diseases: a review. AB - Interleukin 17 (IL-17) as one of the pro-inflammatory cytokines is a very important player in the immune response to many pathogens and seems to play a role also in certain chronic and autoimmune diseases. Many studies showing the importance of this cytokine were conducted on murine models and human patients. In recent years, some experiments with other animals in which interleukin-17 was measured were carried out. This review is focused on the findings that have been observed and described in important veterinary species of animals. PMID- 23810221 TI - Pharmacotherapy for alcohol dependence: status of current treatments. AB - The efficacy of medications for alcohol dependence remains modest, and there are no strong clinical predictors of treatment response. Approved medications include acamprosate (an N-methyl-d-aspartate receptor (NMDA) modulator), disulfiram (an acetaldehyde dehydrogenase inhibitor) and naltrexone (an opioid antagonist) while nalmefene (an opioid antagonist) is currently under review for approval in Europe. Clinical trials suggest that baclofen (a GABA-B agonist) and topiramate (an anticonvulsant) may be promising candidates, while several other drug candidates are currently evaluated at early clinical stages. PMID- 23810222 TI - The facts about health services provided during recent events in Istanbul. PMID- 23810223 TI - Primary sclerosing cholangitis. AB - Primary sclerosing cholangitis is the classic hepatobiliary manifestation of inflammatory bowel disease and is generally chronic and progressive. Patients frequently present with asymptomatic, anicteric cholestasis, but many develop progressive biliary strictures with time, leading to recurrent cholangitis, biliary cirrhosis, and end-stage liver disease. Medical treatment does not slow the progression of disease, and many patients need liver transplantation, after which recurrent disease is a risk. The increased incidence of hepatobiliary cancer, which is not related to the underlying severity of biliary fibrosis, is of particular concern. Risk of colorectal cancer is also increased in patients with coexistent inflammatory bowel disease. Mechanistic insights have arisen from studies of secondary sclerosing cholangitis, in which a similar clinical profile is associated with a specific cause, and genomic studies have elucidated potential disease-initiating pathways in the primary form. The close association between inflammatory bowel disease and primary sclerosing cholangitis underscores the need to further understand the role of environmental factors in generation of lymphocytes that are postulated to be retargeted, deleteriously, to the biliary tree. Treatment of primary sclerosing cholangitis is confined to supportive measures, but advances in pathobiology suggest that new stratified approaches will soon be available. PMID- 23810224 TI - Next steps for research on hormonal contraception and HIV. PMID- 23810225 TI - Immune response to hepatitis B vaccine in a group of health care workers in Sri Lanka. AB - Health care workers (HCWs) are considered at high risk of acquiring the hepatitis B virus (HBV). Seroconversion rates after vaccination against HBV among HCWs have not previously been available in Sri Lanka. In the current study, the response to HBV surface antigen (HBsAg) vaccine was assessed in a selected group of HCWs by testing for antibodies against HBsAg (anti-HBs). This was a retrospective descriptive study to measure the anti-HBs levels, using an ELISA, in an immunized group of HCW referred to Department of Microbiology, Faculty of Medicine, University of Peradeniya, Sri Lanka. Among the 342 participants, 9.9% (n=34) were non-responders. Female participants had a significantly higher immune response (94.7%) than males (p<0.05). The results of the study found no significant decline in the immune response with time (p > 0.05). Post HBsAg vaccination immunity in HCW in Sri Lanka is similar to that of global rates with similar gender variation. Anti-HBs levels should be tested in all HCW following HBsAg vaccination so that necessary precautions can be taken. PMID- 23810226 TI - A synonymous polymorphic variation in ACADM exon 11 affects splicing efficiency and may affect fatty acid oxidation. AB - In recent studies combining genome-wide association and tandem-MS based metabolic profiling, a single-nucleotide polymorphism (SNP), rs211718C>T, located far upstream of the MCAD gene (ACADM) was found to be associated with serum concentrations of medium-chain acylcarnitines indicating improved beta-oxidation of medium-chain fatty acids. We examined the functional basis for this association and identified linkage between rs211718 and the intragenic synonymous polymorphic variant c.1161A>G in ACADM exon 11 (rs1061337). Employing minigene studies we show that the c.1161A allele is associated with exon 11 missplicing, and that the c.1161G allele corrects this missplicing. This may result in production of more full length MCAD protein from the c.1161G allele. Our analysis suggests that the improved splicing of the c.1161G allele is due to changes in the relative binding of splicing regulatory proteins SRSF1 and hnRNP A1. Using publicly available pre-aligned RNA-seq data, we find that the ACADM c.1161G allele is expressed at significantly higher levels than the c.1161A allele across different tissues. This supports that c.1161A>G is a functional SNP, which leads to higher MCAD expression, perhaps due to improved splicing. This study is a proof of principle that synonymous SNPs are not neutral. By changing the binding sites for splicing regulatory proteins they can have significant effects on pre mRNA splicing and thus protein function. In addition, this study shows that for a sequence variation to have an effect, it might need to change the balance in the relative binding of positive and negative splicing factors. PMID- 23810227 TI - Tetrahydrobiopterin therapy vs phenylalanine-restricted diet: impact on growth in PKU. AB - BACKGROUND: Treatment of phenylketonuria based upon strict vegetarian diets, with very low phenylalanine intake and supplemented by phenylalanine-free formula, has proven to be effective in preventing the development of long-term neurological sequelae due to phenylalanine accumulation. On the other hand, such diets have occasionally been reported to hinder normal development, some individuals presenting with growth retardation. Tetrahydrobiopterin therapy has opened up new treatment options for a significant proportion of phenylketonuric patients, enabling them to eat normal diets and be freed from the need to take synthetic supplements. However, little is known about how this therapy affects their physical development. METHODS: We conducted a retrospective longitudinal study examining anthropometric characteristics (height, weight, body mass index and growth speed Z-scores) in a cohort of phenylketonuric patients on tetrahydrobiopterin therapy (38 subjects) comparing their characteristics with those of a group of phenylketonuric patients on phenylalanine-restricted diets (76 subjects). Nutritional issues were also considered, to further explore the possibility of higher natural protein intake being associated with better physical development. Data were collected every six months over two different periods of time (two or five years). RESULTS: No improvement was observed in the aforementioned anthropometric variables in the cohort on tetrahydrobiopterin therapy, from prior to starting treatment to when they had been taking the drug for two or five years. Rather, in almost all cases there was a fall in the mean Z score for the variables during these periods, although the changes were not significant in any case. Further, we found no statistically differences between the two groups at any considered time point. Growth impairment was also noted in the phenylketonuric patients on low-phenylalanine diets. Individuals on tetrahydrobiopterin therapy increased their natural protein intake and, in some instances, this treatment enabled individuals to eat normal diets, with protein intake meeting RDAs. No association was found, however, between higher protein intake and growth. CONCLUSION: Our study identified growth impairment in patients with phenylketonuria on tetrahydrobiopterin, despite higher intakes of natural proteins. In fact, individuals undergoing long-term tetrahydrobiopterin treatment seemed to achieve similar developmental outcomes to those attained by individuals on more restricted diets. PMID- 23810228 TI - Chest radiography after endotracheal tube placement: is it necessary or not? AB - PURPOSE: The aim of this study was to evaluate the necessity of chest x-ray (CXR) in detecting the endotracheal tube (ETT) misplacement after the intubation. BASIC PROCEDURES: In this cross-sectional study, we took a CXR after confirming the ETT placement by physical examination. The distance between the tip of the ETT and carina was then evaluated and graded as satisfactory if it was more than 2 cm. MAIN FINDINGS: During the study period, 381 patients were intubated in the emergency department (ED). According to the CXR findings, the distance between the ETT and carina was more than 2 cm in 336 patients (88.2%), whereas it was less than 2 cm in 45 patients (11.8%). Fourteen ETTs (3.6%) were judged to be too low with 6 (1.5%) of these being right bronchus intubations. One patient had a CXR confirming left bronchial intubation. PRINCIPAL CONCLUSIONS: Although ED intubations have high success rate, the complications of inappropriate intubations are highly remarkable that postintubation CXR remains a necessary step to minimize the misplacement of the tube. PMID- 23810229 TI - Measuring fidelity to a culturally adapted HIV prevention intervention for men in substance abuse treatment. AB - A fidelity measure was developed for use with Real Men Are Safe-Culturally Adapted (REMAS-CA), an HIV prevention intervention for ethnically diverse men in substance abuse treatment. The aims of this analysis were to: 1) assess the reliability of the Fidelity Rating and Skill Evaluation (FRASE); 2) measure improvement in therapist competence and adherence over time while delivering REMAS-CA; and 3) identify which modules of REMAS-CA were most difficult to deliver. Results showed that, 1) the FRASE was a reliable instrument; 2) therapists achieved adequate adherence and competence after training and demonstrated significant improvement over time in Global Empathy; and 3) Sessions 4 and 5 of REMAS-CA contained the most challenging modules for therapists to deliver. Recommendations for future REMAS-CA therapist trainings and fidelity monitoring are made. PMID- 23810230 TI - The RoadMAP Relapse Prevention Group Counseling ToolkitTM: counselor adherence and competence outcomes. AB - Training counselors in empirically supported treatments (ESTs) far exceeds the ever decreasing resources of community-based treatment agencies. The purpose of this study was to examine outpatient substance abuse group counselors' (n=19) adherence and competence in communicating and utilizing concepts associated with empirically-supported relapse prevention treatment following a brief multimedia toolkit (RoadMAP ToolkitTM) training. Moderate or large baseline to post-training effect sizes for counselor adherence to toolkit content were identified for 13 of 21 targeted behaviors (overall d range=.06-2.85) with the largest gains on items measuring active skill practice. Post-training adherence gains were largely maintained at the 6-month follow-up, although no statistically significant improvements were identified over time for counselor competence. This study provides important preliminary support for using a multi-media curriculum approach to increase empirically-supported relapse prevention skills among group counselors. Future research should focus on finding ways to improve counselor skill level and to determine the impact of the Toolkit on client outcomes. PMID- 23810231 TI - A Windows application for computing standardized mortality ratios and standardized incidence ratios in cohort studies based on calculation of exact person-years at risk. AB - Standardized mortality ratios and standardized incidence ratios are widely used in cohort studies to compare mortality or incidence in a study population to that in the general population on a age-time-specific basis, but their computation is not included in standard statistical software packages. Here we present a user friendly Microsoft Windows program for computing standardized mortality ratios and standardized incidence ratios based on calculation of exact person-years at risk stratified by sex, age and calendar time. The program offers flexible import of different file formats for input data and easy handling of general population reference rate tables, such as mortality or incidence tables exported from cancer registry databases. The application of the program is illustrated with two examples using empirical data from the Bavarian Cancer Registry. PMID- 23810232 TI - Establishment of sequential software processing for a biomechanical model of mandibular reconstruction with custom-made plate. AB - The aim of this study is to describe the sequential software processing of computed tomography (CT) dataset for reconstructing the finite element analysis (FEA) mandibular model with custom-made plate, and to provide a theoretical basis for clinical usage of this reconstruction method. A CT scan was done on one patient who had mandibular continuity defects. This CT dataset in DICOM format was imported into Mimics 10.0 software in which a three-dimensional (3-D) model of the facial skeleton was reconstructed and the mandible was segmented out. With Geomagic Studio 11.0, one custom-made plate and nine virtual screws were designed. All parts of the reconstructed mandible were converted into NURBS and saved as IGES format for importing into pro/E 4.0. After Boolean operation and assembly, the model was switched to ANSYS Workbench 12.0. Finally, after applying the boundary conditions and material properties, an analysis was performed. As results, a 3-D FEA model was successfully developed using the softwares above. The stress-strain distribution precisely indicated biomechanical performance of the reconstructed mandible on the normal occlusion load, without stress concentrated areas. The Von-Mises stress in all parts of the model, from the maximum value of 50.9MPa to the minimum value of 0.1MPa, was lower than the ultimate tensile strength. In conclusion, the described strategy could speedily and successfully produce a biomechanical model of a reconstructed mandible with custom-made plate. Using this FEA foundation, the custom-made plate may be improved for an optimal clinical outcome. PMID- 23810233 TI - Integrated Risk Index of Chemical Aquatic Pollution (IRICAP): case studies in Iberian rivers. AB - The hazard of chemical compounds can be prioritized according to their PBT (persistence, bioaccumulation, toxicity) properties by using Self-Organizing Maps (SOM). The objective of the present study was to develop an Integrated Risk Index of Chemical Aquatic Pollution (IRICAP), useful to evaluate the risk associated to the exposure of chemical mixtures contained in river waters. Four Spanish river basins were considered as case-studies: Llobregat, Ebro, Jucar and Guadalquivir. A SOM-based hazard index (HI) was estimated for 205 organic compounds. IRICAP was calculated as the product of the HI by the concentration of each pollutant, and the results of all substances were aggregated. Finally, Pareto distribution was applied to the ranked lists of compounds in each site to prioritize those chemicals with the most significant incidence on the IRICAP. According to the HI outcomes, perfluoroalkyl substances, as well as specific illicit drugs and UV filters, were among the most hazardous compounds. Xylazine was identified as one of the chemicals with the highest contribution to the total IRICAP value in the different river basins, together with other pharmaceutical products such as loratadine and azaperol. These organic compounds should be proposed as target chemicals in the implementation of monitoring programs by regulatory organizations. PMID- 23810234 TI - Trends in the burden of infectious disease hospitalizations among the elderly in the last decade. AB - BACKGROUND: Infectious disease is a leading cause of hospitalization. We investigated trends in infectious disease hospitalizations among the elderly in the last decade. METHODS: A total of 81,077 hospitalizations of elderly patients between 2001 and 2010 were available on the computerized database of the Ha'emek Medical Center, Israel. The proportion of hospitalizations attributable to infectious diseases was calculated. RESULTS: Overall, lower respiratory tract infection (LRTI) accounted for 41.0% of hospitalizations attributable to infectious diseases followed by kidney, urinary tract and bladder infections (UTI) (21.4%), upper respiratory tract infections (URTI) (10.2%), and hepatobiliary tract infections (9.8%). The proportion of hospitalizations attributable to infectious diseases increased by 14.2% during the study period, rising from 16.9% in 2001 (1023 infectious disease hospitalizations of a total of 6043 hospitalizations) to 19.3% in 2010 (1907 infectious disease hospitalizations of a total of 9876 hospitalizations) (P for trend<0.001). A significant increasing trend persisted after adjustment for age, ethnicity, and season, resulting in an increase from 16.9% in 2001 to 18.8% in 2010 (P for trend=0.001). A significant increasing trend was observed in males (P for trend<0.001) and a borderline significant trend was observed in females (P for trend=0.062). The proportion of hospitalizations attributable to infectious diseases was higher in males and increased with age. LRTI and URTI were the major contributors to the increasing trend (P for trend=0.018 and <0.001, respectively). CONCLUSIONS: This study shows an increasing trend in infectious disease hospitalizations among the elderly in the last decade. Public health measures are needed to reduce infectious disease hospitalizations. PMID- 23810235 TI - Improving health care transitions for older adults through the lens of quality improvement. PMID- 23810236 TI - Vitamin D and muscle function: is there a threshold in the relation? AB - OBJECTIVES: First, to determine the association between serum 25 hydroxyvitamin D (25OHD) concentration and muscle mass, strength, and performance. Second, to explore if there is a threshold in the association. DESIGN: Cross-sectional, single-center study. SETTING: The central part of the Netherlands (52 degrees Northern latitude). PARTICIPANTS: A total of 802 independently living men and postmenopausal women 40 to 80 years of age. MEASUREMENTS: Health-related and lifestyle factors, including physical activity, 25OHD concentration, lean mass, handgrip strength, knee extension strength, and physical performance were determined. RESULTS: Overall, higher 25OHD level was significantly associated with higher lean mass (22.6 g per nmol/L, 95% CI 7.3-37.9), handgrip strength (0.020 kg per nmol/L, 95% CI 0.001-0.038), and physical performance (0.006 points per nmol/L, 95% CI 0.001-0.012), after adjustment for various confounders. This association was most pronounced below a 25OHD level of 60 nmol/L, with lean mass increase 79.6 g per nmol/L (95% CI 40.8-118.4, P < .01), handgrip strength 0.09 kg per nmol/L (95% CI 0.045-0.141, P < .01), and physical performance 0.02 points per nmol/L (95% CI 0.005-0.032, P < .01), and these significant associations attenuated to null above this threshold. CONCLUSION: In middle-aged men and (postmenopausal) women, a higher 25OHD level was significantly associated with higher lean mass, muscle strength, and performance. These associations were most pronounced below 60 nmol/L and absent above 60 nmol/L, indicating a ceiling effect. PMID- 23810237 TI - Unusual cause of dizziness: occult temporal lobe encephalocele into transverse sinus. PMID- 23810238 TI - A general approach to power calculation for relationship testing. AB - This paper is motivated by power considerations in connection with relationship testing. Given the true relationship between a set of individuals, a claimed relationship between the same individuals, and a set of genetic markers, we compute the power of exclusion, i.e., the probability that the genotypes will be incompatible with the claimed relationship. If exclusion is impossible, as will be the case if it is required for instance to distinguish between sibs and half sibs, we rather obtain the distribution of the likelihood ratio. The problem we are addressing can also be seen as a standard way of measuring the ability of a battery of tests to resolve claimed family relationships. In particular, simple exclusion probabilities are regularly calculated worldwide as a part of designing forensic marker sets. Our approach to these problems is guided by a natural way of calculating exclusion probabilities on a computer. We present a user friendly implementation for this as part of the R package paramlink, originally designed by one of the authors (MDV) for pedigree manipulations and likelihood computations. By doing so we are able to handle problems more challenging than we have seen in the literature. Specifically, we deal with complex pedigrees with arbitrary inbreeding and conditioning. We present examples for autosomal as well as X-linked markers and some formulae to validate the results. The examples indicate a wide range of applications. Details are presented for an immigration case where previously reported calculations are extended to account for possible inbreeding and known genotypes. The supplementary material includes a tutorial on how to perform these calculations in paramlink. PMID- 23810239 TI - Diffuse ST-elevation following J-wave presentation as an uncommon electrocardiogram pattern of Tako-Tsubo cardiomyopathy. AB - BACKGROUND: Tako-Tsubo cardiomyopathy (TTC) is characterized by symptoms, ECG changes with elevated cardiac markers mimicking acute myocardial infarction, left ventricular (LV) wall motion abnormalities in the apical region with preserved function of base, and normal coronary arteries. Usual ECG anomalies heralding TTC are ST-elevation in anterior leads, QT prolongation and negative T-waves. METHODS: We report the unusual case of TTC with an uncommon ECG presentation: J wave in inferior leads followed by diffuse ST-elevation. RESULTS: An 82-year-old woman was admitted for dyspnea and chest pain following exacerbation of chronic obstructive pulmonary disease. ECG showed J-wave in inferior leads followed by diffuse ST-elevation. The patient was monitored in intensive care unit and treated with diuretics. Both ECG and echocardiography anomalies gradually recovered. CONCLUSIONS: Diffuse ST-elevation following J-waves may be considered as a possible ECG pattern of presentation in case of TTC. PMID- 23810241 TI - Accurate detection of copy number changes in DNA extracted from formalin-fixed, paraffin-embedded melanoma tissue using duplex ratio tests. AB - A minority of melanocytic lesions cannot confidently be classified as benign or malignant on histopathological examination, causing diagnostic uncertainty. DNA copy number changes can be used to distinguish nevi from melanoma, although the use of FFPE tissue can pose technical challenges. DNA copy number assays, called duplex ratio tests, have been developed with duplex real-time PCR, using a simple method with potential for high throughput. Five duplex ratio test assays targeting loci with common DNA copy number changes in melanoma were designed and tested using DNA extracted from FFPE samples microdissected from melanoma, common nevi, benign tonsil (10 each), and two melanoma cell lines. The assays proved accurate when DNA extracted from fresh and FFPE melanoma cell lines were compared (intraclass correlation coefficient, 0.99) and gave precise results when repeated on DNA from FFPE tissue (intraclass correlation coefficient range, 0.90 to 0.96). In combination, duplex ratio test values from three of the assays distinguished between the nevi and melanomas with 100% sensitivity (95% CI, 69.1% to 100%) and 100% specificity (95% CI, 69.1% to 100%). Duplex ratio test assays have been shown to be accurate and precise and can distinguish melanomas from common nevi using DNA from FFPE tissue. Appropriately designed assays could have value in assessment of other cancers. PMID- 23810240 TI - Rapid desensitization induces internalization of antigen-specific IgE on mouse mast cells. AB - BACKGROUND: Rapid desensitization transiently prevents severe allergic reactions, allowing administration of life-saving therapies in previously sensitized patients. However, the mechanisms underlying successful rapid desensitization are not fully understood. OBJECTIVES: We sought to investigate whether the mast cell (MC) is an important target of rapid desensitization in mice sensitized to exhibit IgE-dependent passive systemic anaphylaxis in vivo and to investigate the antigen specificity and underlying mechanisms of rapid desensitization in our mouse model. METHODS: C57BL/6 mice (in vivo) or primary isolated C57BL/6 mouse peritoneal mast cells (PMCs; in vitro) were passively sensitized with antigen specific anti-2,4-dinitrophenyl IgE, anti-ovalbumin IgE, or both. MCs were exposed over a short period of time to increasing amounts of antigen (2,4 dinitrophenyl-human serum albumin or ovalbumin) in the presence of extracellular calcium in vitro or by means of intravenous administration to sensitized mice in vivo before challenging the mice with or exposing the PMCs to optimal amounts of specific or irrelevant antigen. RESULTS: Rapidly exposing mice or PMCs to progressively increasing amounts of specific antigen inhibited the development of antigen-induced hypothermia in sensitized mice in vivo and inhibited antigen induced PMC degranulation and prostaglandin D2 synthesis in vitro. Such MC hyporesponsiveness was induced antigen-specifically and was associated with a significant reduction in antigen-specific IgE levels on MC surfaces. CONCLUSIONS: Rapidly exposing MCs to progressively increasing amounts of antigen can both enhance the internalization of antigen-specific IgE on the MC surface and also desensitize these cells in an antigen-specific manner in vivo and in vitro. PMID- 23810242 TI - BCR-ABL1 RT-qPCR for monitoring the molecular response to tyrosine kinase inhibitors in chronic myeloid leukemia. AB - The pathognomonic genetic alteration in chronic myeloid leukemia is the formation of the BCR-ABL1 fusion gene, which produces a constitutively active tyrosine kinase that drives leukemic transformation. Targeted tyrosine kinase inhibitor treatment with imatinib, nilotinib, dasatinib, bosutinib, and ponatinib is the cornerstone of modern therapy for this hematologic malignancy. Real-time quantitative RT-PCR (RT-qPCR, also RQ-PCR) of BCR-ABL1 RNA is a necessary laboratory technique for monitoring the efficacy of tyrosine kinase inhibitor therapy and quantitatively assessing minimal residual disease. The molecular response measured by BCR-ABL1 RT-qPCR assists in identifying suboptimal responses and can help inform the decision to switch to alternative therapies that may be more efficacious (or to pursue more stringent monitoring). Furthermore, the tyrosine kinase inhibitor-mediated molecular response provides valuable risk stratification and prognostic information on long-term outcomes. Despite these attributes, informed, universal, practical utilization of this well-established monitoring test will require heightened efforts by the molecular diagnostics laboratory community to adopt the standardized reporting units of the International Scale. Without widespread adoption of the International Scale, the consensus major molecular response and early molecular response treatment thresholds will not be definable, and optimal clinical outcomes for patients with chronic myeloid leukemia may not be achieved. PMID- 23810243 TI - CD47 and osteopontin expression in diffuse large B-cell lymphoma with nodal and intravascular involvement. PMID- 23810244 TI - Validation of the Freiburg Comorbidity Index in 466 multiple myeloma patients and combination with the international staging system are highly predictive for outcome. AB - BACKGROUND: The outcomes of MM patients vary considerably and depend on a variety of host- and disease-related risks. As yet, a comorbidity risk index in MM patients has neither been standardized nor validated. PATIENTS AND METHODS: We conducted an initial analysis in 127 MM patients and developed the FCI, validating it in an independent cohort of 466 MM patients. The FCI includes patients' Karnofsky Performance Status, renal and lung disease status. We compared the prognostic information of this validated FCI with established comorbidity indices (Hematopoietic Cell Transplantation-Specific Comorbidity Index and Kaplan Feinstein), the International Staging System (ISS), MM therapy, and age. RESULTS: Our validation confirmed that patients with 0, 1, or 2 to 3 FCI risk factors display significantly different overall survival (OS) of not reached, 86, and 39 months, respectively (P < .0001). Via multivariate analysis including the FCI, ISS, therapy, and age, the FCI retained its independent prognostic significance (P < .0015). The combination of the FCI and ISS allowed definition of 3 distinct subgroups with low-risk (FCI 0 and ISS I-II), intermediate-risk (all remaining), and high-risk (FCI 1-3 and ISS III) with OS probabilities at 5-years of 85%, 74%, and 42%, respectively (P < .0001). CONCLUSION: Our validation analysis demonstrated that the FCI remains a reliable comorbidity index, is simpler to generate than other available comorbidity scores, and contributes valuable information to the ISS. Their combination allows the definition of low-, intermediate-, and high-risk patients. These results advocate use of the FCI in future prospective studies and might guide personalized treatment strategies. PMID- 23810245 TI - Phase I-II clinical trial of oxaliplatin, fludarabine, cytarabine, and rituximab therapy in aggressive relapsed/refractory chronic lymphocytic leukemia or Richter syndrome. AB - BACKGROUND: To improve outcomes of patients with Richter syndrome (RS) and relapsed/refractory chronic lymphocytic leukemia (CLL), we modified the OFAR1 regimen (oxaliplatin and cytarabine doses of the oxaliplatin, fludarabine, cytarabine, and rituximab) for this phase I-II study (OFAR2). PATIENTS AND METHODS: OFAR2 consisted of oxaliplatin at 30 mg/m(2) on days 1 to 4, fludarabine at 30 mg/m(2), cytarabine at 0.5 g/m(2), rituximab at 375 mg/m(2) on day 3, and pegfilgrastim at 6 mg on day 6. Fludarabine and cytarabine were given on days 2 and 3 (cohort 1), days 2 to 4 (cohort 2), or days 2 to 5 (cohort 3) every 4 weeks. Phase II followed the "3 + 3" design of phase I. RESULTS: The 102 patients (CLL, 67; RS, 35) treated had heavily pretreated high-risk disease. Twelve patients were treated in phase I; cohort 2 was the phase II recommended dose. The most common toxicities were hematologic. Response rates (phase II) were 38.7% for RS (complete response [CR], 6.5%) and 50.8% for relapsed/refractory CLL (CR, 4.6%). The median survival durations were 6.6 (RS) and 20.6 (CLL) months. Among 9 patients who underwent allogeneic stem cell transplantation (SCT) as post remission therapy, none has died (median follow-up, 15.9 months). CONCLUSION: OFAR2 had significant antileukemic activity in RS and relapsed/refractory CLL. Patients undergoing SCT as post-remission therapy had favorable outcomes. PMID- 23810247 TI - Serum microRNA-1 and microRNA-122 are prognostic markers in patients with hepatocellular carcinoma. AB - BACKGROUND: The identification of new biomarkers to predict the aggressiveness of hepatocellular carcinoma (HCC) and supplement the current set of prognosis and treatment algorithms is an important clinical need. Extracellular microRNAs (miRNAs) circulating in the blood are a new class of highly promising disease markers. AIM: Here we investigated the prognostic potential of miR-1 and miR-122 in sera from patients with HCC. METHODS: RNA was extracted from 195 sera of HCC patients and 54 patients with liver cirrhosis, obtained at the time of study enrolment. miR-1 and miR-122 levels were correlated with overall survival (OS), Cancer of the Liver Italian Program (CLIP) score, Barcelona Clinic Liver Cancer stage, clinical chemistry parameters and tumor specific treatment. RESULTS: Patients with higher miR-1 and miR-122 serum levels showed longer OS than individuals with lower miR-1 and miR-122 serum concentrations (hazard ratio [HR] 0.440, 95% confidence interval [CI] 0.233-0.831, P=0.011 for miR-1 and HR 0.493, 95% CI 0.254-0.956, P=0.036 for miR-122, respectively). Serum miR-1 and miR-122 concentrations did not differ significantly between patients with HCC and liver cirrhosis. An age-, sex-, tumor stage and treatment-adjusted multivariate Cox regression analysis revealed that miR-1 serum levels (HR 0.451, 95% CI 0.228 0.856, P=0.015) were independently associated with OS, whereas serum miR-122 was not. miR-1 serum levels showed no relevant correlation with clinical chemistry liver parameters, whereas serum miR-122 correlated with clinical chemistry parameters of hepatic necroinflammation, liver function and synthetic capacity. CONCLUSION: Our data indicate that serum miR-1 is a new independent parameter of OS in HCC patients and may therefore improve the predictive value of classical HCC staging scores. PMID- 23810246 TI - Outcomes of patients with metastatic clear-cell renal cell carcinoma treated with pazopanib after disease progression with other targeted therapies. AB - AIM: The multi-tyrosine kinase inhibitor pazopanib prolongs progression-free survival (PFS) versus placebo in treatment-naive and cytokine-refractory metastatic clear-cell renal cell carcinoma (ccRCC). Outcomes and safety data with pazopanib after targeted therapy (TT) are limited. METHODS: We retrospectively evaluated records of consecutive patients with metastatic ccRCC who had progressive disease (PD) after TT and received pazopanib from November 2009 through November 2011. Tumour response was assessed by a blinded radiologist using Response Evaluation Criteria In Solid Tumours (RECIST). PFS and overall survival (OS) were estimated by Kaplan-Meier methods. RESULTS: Ninety-three patients were identified. Median number of prior TTs was 2 (range, 1-5). There were 68 events (PD or death). Among 85 evaluable patients, 13 (15%) had a partial response. Median PFS was 6.5 months (95% CI: 4.5-9.7); median OS was 18.1 months (95% CI: 10.26-NA). Common adverse events (AEs) included fatigue (44%), elevated transaminases (35%), diarrhoea (30%), hypothyroidism (18%), nausea/vomiting (17%), anorexia (14%) and hypertension exacerbation (14%); 91% of AEs were grade 1/2. Eleven patients (12%) discontinued therapy due to AEs. There were no treatment-related deaths. CONCLUDING STATEMENT: Pazopanib demonstrated efficacy in patients with metastatic ccRCC after PD with other TTs. Toxicity overall was mild/moderate and manageable. PMID- 23810248 TI - Glutathione S-transferase M1 and T1 polymorphisms: susceptibility and outcomes in muscle invasive bladder cancer patients. AB - BACKGROUND: We investigated whether genetic polymorphisms in the glutathione S transferase mu (GSTM1) and theta (GSTT1) genes modulated risk, disease progression and survival in primary muscle invasive bladder cancer (MIBC). METHODS: GSTM1 and GSTT1 polymorphisms were analysed by multiplex polymerase chain reaction (PCR) using blood genomic DNA in 110 MIBC patients and 220 gender- and age-matched healthy controls. The influence of the genetic polymorphisms on patient survival was evaluated by Kaplan-Meier survival curves and Cox Proportional Hazard models. We also evaluated whether cigarette smoking and treatment modality modified the association between genotype and prognosis. RESULTS: GSTM1-null individuals exhibited increased risk for MIBC and an association with cigarette smoking. GSTT1-null subjects showed significant disease progression and cancer-specific death. In the combined analysis, GSTT1 null genotype was an independent risk factor for disease progression and cancer specific death regardless of GSTM1 genotype. Significant differences in progression-free survival (PFS) and cancer-specific survival (CSS) were seen based on GSTT1 genotype. The survival impact of the GSTT1 genotype was only valid for smokers. The GSTT1-null genotype was an independent prognostic factor for shorter PFS in patients who received chemotherapy and those who did not undergo radical cystectomy. By multivariate Cox regression analysis, GSTT1-null genotype was a predictive factor for disease progression and cancer specific survival regardless of treatment modality. CONCLUSIONS: The GSTM1-null genotype plays an important role in genetic susceptibility to MIBC and the GSTT1-null genotype is associated with disease progression and shorter survival in MIBC. PMID- 23810249 TI - Crosstalk between colon cancer cells and macrophages via inflammatory mediators and CD47 promotes tumour cell migration. AB - Tumour-associated macrophages (TAMs) of the M2 phenotype are present in the stroma of many tumours and are frequently associated with the progression of several types of cancer. We investigated the role of M2 macrophages in colon cancer progression and found that human colon cancer tissue had elevated numbers of CD68(+) (macrophage marker) cells and CD206(+) (M2 macrophage marker) cells and increased CD47 expression. To explore potential interplay between colon cancer cells and M2 macrophages, we differentiated the monocyte cell line THP-1 into M1 and M2 macrophages (CD206(high) and Th2 cytokine-secreting cells), respectively. M2 macrophages migrated faster than M1 macrophages towards SW480 conditioned medium. Similarly, M2 macrophage-conditioned medium induced SW480 cell migration and CD47 expression. Factors released by macrophages were involved in this induction. In addition, SW480 cells migrated faster when co-cultured with M2 macrophages. Inhibition of CD47 with blocking antibodies or siRNA significantly reduced the migration of SW480 cells in the presence of M2 macrophages. This effect was further decreased via blocking antibodies against the CD47 ligand signal-regulatory protein alpha (SIRPalpha). Additionally, cancer cells also secreted significant levels of IL-10, thereby promoting M2 macrophage differentiation. These findings indicate that a TAM-enriched tumour microenvironment promotes colon cancer cell migration and metastasis. PMID- 23810250 TI - Involvement of FOS-mediated miR-181b/miR-21 signalling in the progression of malignant gliomas. AB - Recently, a group of microRNAs (miRNAs) were shown to be dysregulated in gliomas, and involved in glioma development. However, the effect of miRNA-miRNA functional networks on gliomas is poorly understood. In this study, we identified that FBJ murine osteosarcoma viral oncogene homolog (FOS)-mediated miR-181b/miR-21 signalling was critical for glioma progression. Using microarrays and quantitative RT-PCR (qRT-PCR), we found increased FOS in high grade gliomas. FOS depletion (via FOS-shRNA), inhibited invasion and promoted apoptosis in glioma cells. Using microarrays, combined with Pearson correlation analysis, we found FOS positively correlated with miR-21 expression. Reduction of FOS inhibited miR 21 expression by binding to the miR-21 promoter using luciferase reporter assays. Introduction of miR-21 abrogated FOS knockdown-induced cell invasion and apoptosis. Moreover, bioinformatics and luciferase reporter assays showed that miR-181b modulated FOS expression by directly targeting the binding site within the 3'UTR. Expression of FOS with a FOS cDNA lacking 3'UTR overrided miR-181b induced miR-21 expression and cell function. Finally, immunohistochemistry (IHC) and in situ hybridisation (ISH) analysis revealed a significant correlation in miR-181b, FOS and miR-21 expression in nude mouse tumour xenograft and human glioma tissues. To our knowledge, it is the first time to demonstrate that miR 181b/FOS/miR-21 signalling plays a critical role in the progression of gliomas, providing important clues for understanding the key roles of transcription factor mediated miRNA-miRNA functional network in the regulation of gliomas. PMID- 23810251 TI - Association between vaccination and Guillain-Barre syndrome. PMID- 23810252 TI - Risk of Guillain-Barre syndrome after seasonal influenza vaccination and influenza health-care encounters: a self-controlled study. AB - BACKGROUND: The possible risk of Guillain-Barre syndrome from influenza vaccines remains a potential obstacle to achieving high vaccination coverage. However, influenza infection might also be associated with Guillain-Barre syndrome. We aimed to assess the risk of Guillain-Barre syndrome after seasonal influenza vaccination and after influenza-coded health-care encounters. METHODS: We used the self-controlled risk interval design and linked universal health-care system databases from Ontario, Canada, with data obtained between 1993 and 2011. We used physician billing claims for influenza vaccination and influenza-coded health care encounters to ascertain exposures. Using fixed-effects conditional Poisson regression, we estimated the relative incidence of hospitalisation for primary coded Guillain-Barre syndrome during the risk interval compared with the control interval. FINDINGS: We identified 2831 incident admissions for Guillain-Barre syndrome; 330 received an influenza vaccine and 109 had an influenza-coded health care encounter within 42 weeks before hospitalisation. The risk of Guillain-Barre syndrome within 6 weeks of vaccination was 52% higher than in the control interval of 9-42 weeks (relative incidence 1.52; 95% CI 1.17-1.99), with the greatest risk during weeks 2-4 after vaccination. The risk of Guillain-Barre syndrome within 6 weeks of an influenza-coded health-care encounter was greater than for vaccination (15.81; 10.28-24.32). The attributable risks were 1.03 Guillain-Barre syndrome admissions per million vaccinations, compared with 17.2 Guillain-Barre syndrome admissions per million influenza-coded health-care encounters. INTERPRETATION: The relative and attributable risks of Guillain-Barre syndrome after seasonal influenza vaccination are lower than those after influenza illness. Patients considering immunisation should be fully informed of the risks of Guillain-Barre syndrome from both influenza vaccines and influenza illness. FUNDING: Canadian Institutes of Health Research. PMID- 23810253 TI - Derivation of human peripheral blood derived endothelial progenitor cells and the role of osteopontin surface modification and eNOS transfection. AB - Endothelial coverage of blood-contacting biomaterial surfaces has been difficult to achieve. A readily available autologous source of endothelium combined with an appropriate attachment substrate would improve the chances of developing functional surfaces. Here we describe methods to derive high quantities of human endothelial progenitor cells (EPCs) from peripheral blood monocytes (PBMCs) obtained by leukapheresis. These cells are morphologically and phenotypically similar to human umbilical vein endothelial cells (HUVECs); however, their expression of the key vascular factor - endothelial nitric oxide synthase (eNOS) is markedly lower than that observed in HUVECs. We demonstrate that eNOS levels can be restored with plasmid-based transfection. To promote EPC adherence we examined substrate enhancement with a matricellular protein associated with vascular repair, osteopontin (OPN). We observed dose- and time-dependent responses of OPN in EPC adhesion, spreading, and haptotactic migration of EPCs in Boyden chamber assays. In addition, the combination of the OPN coating and enhanced eNOS expression in EPCs maximally enhanced cell adhesion (39.6 +/- 1.7 and 49.4 +/- 2.4 cells/field for 0 and 1 nM OPN) and spreading (84.7 +/- 3.5% and 92.1 +/- 3.9% for 0 nM and 1 nM OPN). These data highlight the direct effects of OPN on peripheral blood derived EPCs, suggesting that OPN works by mediating progenitor cell adhesion during vascular injury. The combination of autologous EPCs and OPN coatings could be a promising method of developing functional endothelialized surfaces. PMID- 23810254 TI - Off-the-shelf human decellularized tissue-engineered heart valves in a non-human primate model. AB - Heart valve tissue engineering based on decellularized xenogenic or allogenic starter matrices has shown promising first clinical results. However, the availability of healthy homologous donor valves is limited and xenogenic materials are associated with infectious and immunologic risks. To address such limitations, biodegradable synthetic materials have been successfully used for the creation of living autologous tissue-engineered heart valves (TEHVs) in vitro. Since these classical tissue engineering technologies necessitate substantial infrastructure and logistics, we recently introduced decellularized TEHVs (dTEHVs), based on biodegradable synthetic materials and vascular-derived cells, and successfully created a potential off-the-shelf starter matrix for guided tissue regeneration. Here, we investigate the host repopulation capacity of such dTEHVs in a non-human primate model with up to 8 weeks follow-up. After minimally invasive delivery into the orthotopic pulmonary position, dTEHVs revealed mobile and thin leaflets after 8 weeks of follow-up. Furthermore, mild moderate valvular insufficiency and relative leaflet shortening were detected. However, in comparison to the decellularized human native heart valve control - representing currently used homografts - dTEHVs showed remarkable rapid cellular repopulation. Given this substantial in situ remodeling capacity, these results suggest that human cell-derived bioengineered decellularized materials represent a promising and clinically relevant starter matrix for heart valve tissue engineering. These biomaterials may ultimately overcome the limitations of currently used valve replacements by providing homologous, non-immunogenic, off the-shelf replacement constructs. PMID- 23810255 TI - pH/temperature sensitive magnetic nanogels conjugated with Cy5.5-labled lactoferrin for MR and fluorescence imaging of glioma in rats. AB - Glioma is the most common primary brain tumor and causes a disproportionate level of morbidity and mortality across a wide range of individuals. From previous clinical practices, definition of glioma margin is the key point for surgical resection. In order to outline the exact margin of glioma and provide a guide effect for the physicians both at pre-surgical planning stage and surgical resection stage, pH/temperature sensitive magnetic nanogels conjugated with Cy5.5 labled lactoferrin (Cy5.5-Lf-MPNA nanogels) were developed as a promising contrast agent. Due to its pH/te mperature sensitivity, Cy5.5-Lf-MPNA nanogels could change in its hydrophilic/hydrophobic properties and size at different pH and temperatures. Under physiological conditions (pH 7.4, 37 degrees C), Cy5.5 Lf-MPNA nanogels were hydrophilic and swollen, which could prolong the blood circulation time. In the acidic environment of tumor tissues (pH 6.8, 37 degrees C), Cy5.5-Lf-MPNA nanogels became hydrophobic and shrunken, which could be more easily accumulated in tumor tissue and internalized by tumor cells. In addition, lactoferrin, an effective targeting ligand for glioma, provides active tumor targeting ability. In vivo studies on rats bearing in situ glioma indicated that the MR/fluorescence imaging with high sensitivity and specificity could be acquired using Cy5.5-Lf-MPNA nanogels due to active targeting function of the Lf and enhancement of cellular uptake by tailoring the hydrophilic/hydrophobic properties of the nanogels. With good biocompatibility shown by cytotoxicity assay and histopathological analysis, Cy5.5-Lf-MPNA nanogels are hopeful to be developed as a specific and high-sensitive contrast agent for preoperative MRI and intraoperative fluorescence imaging of glioma. PMID- 23810256 TI - Relationships between childhood sexual abuse and substance use and sexual risk behaviors during adolescence: An integrative review. AB - BACKGROUND: Childhood sexual abuse (CSA) is thought to be a precursor to substance use and sexual risk behaviors during adolescence. To inform adolescent prevention efforts, information is needed to explicate the nature of the relationships between CSA and these health risks. The aim of this study was to summarize the current literature on the associations between a history of CSA and substance use and sexual risk behaviors during adolescence. METHODS: We conducted a systematic literature search and an integrative review. RESULTS: Current evidence implicates CSA as a robust precursor to the use of a wide variety of substances and multiple sexual risk behaviors during adolescence. CONCLUSION: Screening for CSA in adolescents at risk and incorporating strategies that enhance CSA recovery in adolescent prevention programs are warranted. Future research that includes longitudinal designs, uses multiple methods of assessment, and identifies pathways between CSA and adolescent health risks is recommended. PMID- 23810257 TI - Regional cytokine responses to pulmonary aspergillosis in immunocompetent rats. AB - Rat models of pulmonary aspergillosis are used widely in diagnostic studies and in exploring antifungal therapeutic modalities, but there is lack of data concerning antifungal immunity in rats. In this study, cytokine response to pulmonary infection to Aspergillus fumigatus in non-immunosuppressed rats is explored. Temporal display (from the start of infection up to its eradication) of proinflammatory cytokines (IFN-gamma and IL-17) as well as Th2/anti-inflammatory ones (IL-4 and IL-10) was explored by measuring their presence in the environment in which elimination of infection occur (lung homogenates), by production of these mediators by lung cells (recovered by enzyme digestion or by bronchoalveolar lavage) as well as by cells of draining lymph nodes (as sites of generation of cytokine-producing cells). Reduction of infection (1 * 107conidia) was associated with an increase of IFN-gamma and IL-17 content in lung homogenates, but with unchanged IL-4 and IL-10 content. Lung cells produced proinflammatory cytokines with differential dynamics (IFN-gamma earlier than IL 17). Differential pattern of Th2/anti-inflammatory cytokine production by lung cells was observed (unchanged IL-4 and increased IL-10), with the levels of the latter higher than proinflammatory cytokines. Upregulation of IFN-gamma, IL-17 and IL-10 production and gene expression, but downregulation of IL-4, by draining lymph node cells (dLN cells) accounted essentially for the observed ex vivo cytokine response in lungs. Similar pattern of cytokine production by dLN cells following restimulation with A. fumigatus conidia confirmed the specificity of cytokine response to the fungus. Draining lymph node CD4+ cells seems to be the main source of proinflammatory cytokines, significant contributors to IL-10 production and the target for down regulation of IL-4. The knowledge of immune based mechanisms of defense against A. fumigatus in rats might be helpful in the future use of rat models of pulmonary aspergillosis particularly those that develop immune-based therapeutic interventions as an adjunct treatment of fungal diseases. PMID- 23810258 TI - Anatomy- vs. fluence-based planning for prostate cancer treatments using VMAT. AB - The purpose of this study was to compare the planning approaches used in two treatment planning systems (TPS) provided by Elekta for VMAT treatments. Ten prostate patients were studied retrospectively. Plan comparison was performed in terms of delivery efficiency and accuracy, as well as in terms of target coverage and critical organ protection by utilizing physical and radiobiological indices. These include: DVH (dose volume histogram) values, CI (conformity index), HI(%) (homogeneity index) and TCP (tumor control probability) for target coverage; mean doses, DVH values, dose to the normal non-target tissue, NTCP (normal tissue complication probability) and GI (gradient index) for critical organ sparing; MU/fraction and treatment time for delivery efficiency. The comparisons were performed using the two-sided Wilcoxon matched-pair signed rank test. Plans generated using the anatomy-based approach in ERGO++ and fluence-based approach in Monaco were found similar in terms of target coverage and TCP values, as well as in terms of rectum protection and corresponding NTCP values. The former exhibited increased delivery efficiency (comparable to that of 3D conformal radiotherapy) due to the relatively larger segments used. On the other hand advantages of the fluence-based approach in Monaco include increased conformity, better target dose homogeneity and higher dose gradient (lower dose to normal non target-tissue) mainly due to the higher degree of modulation offered by the fluence-based approach, while the Monte Carlo algorithm used for dose calculation provides plans with increased accuracy despite the relatively small segments used. PMID- 23810259 TI - The prognosis of patients on hemodialysis with foot lesions. AB - OBJECTIVE: Many studies have shown the high prevalence and incidence of peripheral arterial disease and the marked morbidity and mortality associated with peripheral arterial disease in hemodialysis patients. The purpose of this retrospective study was to clarify the probability of survival and limb salvage in patients with foot lesions and how to manage these patients. METHODS: Data were collected in a retrospectively maintained database for 319 lower limbs with foot lesions in 234 hemodialysis patients treated in a university hospital between 1980 and 2011. Variances influencing survival and limb salvage were compared using log-rank tests and Cox regression analysis. These variables were examined using Kaplan-Meier analysis. Significant factors in bivariate analysis were included in a logistic regression model to determine independent predictors and the probability of failure. RESULTS: The 234 patients (72% men) were a mean age of 65.4 years on admission, and 84% had diabetes. The mean duration of hemodialysis was 6.8 years. During the follow-up period, 171 patients (73%) died. The 1-, 3-, 5-, and 7-year survival rates were 65.2%, 35.5%, 23.4%, and 12.8%, respectively. According to Cox multivariate models, age at admission and ischemic changes on an electrocardiogram independently increased the risk of death (hazard ratios, 1.02 and 1.48, respectively). Conversely, hyperlipidemia independently decreased the risk of death (hazard ratio, 0.56). Critical limb ischemia was present in 247 limbs (77%). Arterial reconstruction was done in 88 limbs (28%), and 119 limbs (37%) required major amputation. The overall 1-, 3-, 5- and 7-year limb salvage rates were 68.9%, 57.2%, 53.8%, and 51.7 %, respectively. According to Cox multivariate models, patent arterial reconstruction and albumin independently decreased the risk of major amputation (hazard ratios, 0.265 and 0.392, respectively). CONCLUSIONS: Hemodialysis patients with foot lesions have a poor prognosis, with high rates of mortality and amputation. Prompt assessments of the severity of systemic conditions, such as cardiac ischemia, and focal wound conditions, such as ischemia and infection, are necessary to treat hemodialysis patients with foot lesions. PMID- 23810260 TI - Clinical outcomes of single versus staged hybrid repair for thoracoabdominal aortic aneurysm. AB - OBJECTIVE: We investigated the outcomes of hybrid repair of thoracoabdominal aortic aneurysms and performed meta-analyses and meta-regressions to assess whether the number of stages during hybrid repair is associated with mortality. METHODS: Review methods were according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The primary outcome was 30-day mortality. Secondary outcomes of procedural and clinical success were reported descriptively. Meta-analyses, meta-regressions, and logistic regressions were performed to estimate the odds ratio (OR) describing the association between the staging of the operation and in-hospital death. RESULTS: We included 19 studies of 660 patients. Procedures were single-staged in 288 patients and staged in 372. Perioperative mortality ranged from 0% to 44.4%, and spinal cord ischemia ranged from 0% to 15.3%. After a mean follow-up of 26 months (range, 6-88.5 months), the overall mortality was 20.8%. The meta-regression of all studies' summary data (OR, 0.64; 95% confidence interval [CI], 0.19-2.16; P = .45; I(2) = 0.42) and a meta-regression where mortality rates in four studies were stratified by operative staging (OR, 0.57; 95% CI, 0.24-1.36; P = .19; I(2) = 0.38) supported a two-stage procedure but failed to reach statistical significance. Logistic regressions of individual patient data from a single center demonstrated evidence that a staged procedure was safer (adjusted OR, 0.04; 95% CI, 0.00-0.96; P < .05). CONCLUSIONS: Hybrid repair of thoracoabdominal aortic aneurysms may reduce early morbidity and mortality even in a group considered high risk for open surgery but still carries risks of perioperative complications. This study suggested advantages to a staged procedure, but statistically significant evidence is lacking. Prospective data are still needed to optimize hybrid repair and best define its role. PMID- 23810261 TI - Abdominal aortic rupture from an impaling osteophyte following blunt trauma. AB - Blunt injury of the abdominal aorta is highly fatal. We present an unusual case of an osteophyte impaling the abdominal aorta treated by endovascular repair. A 77-year-old man sustained a thoracolumbar fracture-dislocation with posterior aortic rupture between his celiac and superior mesenteric artery origins. His aortic injury was treated with a stent graft, excluding the celiac origin. He was dismissed on postoperative day 6. At 6 months, he had returned to most preinjury activities, and at 2-year follow-up, he continues to have good functional outcome. Endovascular repair may be successfully employed in select aortic injuries in hemodynamically stable patients. PMID- 23810262 TI - Open surgical management of complications from indwelling radial artery catheters. AB - BACKGROUND: Cannulation of the radial artery is frequently performed for invasive hemodynamic monitoring. Complications arising from indwelling catheters have been described in small case series; however, their surgical management is not well described. Understanding the presentation and management of such complications is imperative to offer optimal treatment, particularly because the radial artery is increasingly accessed for percutaneous coronary interventions. METHODS: We conducted a retrospective review to identify patients who underwent surgical intervention for complications arising from indwelling radial artery catheters from 1997 to 2011. RESULTS: We identified 30 patients who developed complications requiring surgical intervention. These complications were categorized into ischemic and nonischemic, with 15 patients identified in each cohort. All patients presenting with clinical hand or digital ischemia underwent thrombectomy and revascularization. Complications in the nonischemic group included three patients with deep abscesses with concomitant arterial thrombosis, two with deep abscesses alone, and 10 with pseudoaneurysms. Treatment strategy in this group varied with the presenting pathology. Among the entire case series, three patients required reintervention after the initial surgery, all in individuals initially presenting with ischemia who developed recurrent thrombosis of the radial artery. There were no digital or hand amputations in this series. However, the overall in-hospital mortality in these patients was 37%, reflecting the severity of illness in this patient cohort. Three patients who were positive for heparin-induced thrombocytopenia antibody had 100% mortality compared with those who were negative (P = .04, Fisher exact test). In-hospital mortality was higher in patients presenting with initial ischemia than in those with nonischemic complications (53% vs 20%; P = .06). Among 10 patients who presented with pseudoaneurysms, five (50%) were septic at presentation with positive blood cultures, and six (60%) had positive operating room cultures. Staphylococcus aureus was identified as the causative organism in all of these patients. CONCLUSIONS: Complications of radial artery cannulation requiring surgical intervention can represent infectious and ischemic sequelae and have the potential to result in major morbidity, including digital or hand amputation and sepsis, or death. Although surgical treatment is successful and often required in these patients to treat severe hand ischemia, hemorrhage, or vascular infection, these complications tend to occur in critically ill hospitalized patients with an extremely high mortality. This must be taken into consideration when planning surgical intervention in this patient cohort. Finally, radial arterial cannulation sites should not be overlooked when searching for occult septic sources in critically ill patients. PMID- 23810263 TI - Factors associated with rapid failure in a Treatment Alternatives for Safer Communities (TASC) program. AB - OBJECTIVE: Identify factors associated with early treatment failure in a Treatment Alternatives for Safer Communities (TASC) program, a case management criminal justice diversion program for individuals under community corrections supervision. METHODS: Demographics, medication history, substance dependence, and criminal history variables for 21,419 individuals were used as predictor variables for successful treatment outcome in a Cox Proportional Hazards Survival analysis which was used to assess the relationship between predictor variables and the length of time before treatment failure. RESULTS: Early treatment failure was associated with a number of factors linked to social stability, including: being divorced separated or widowed, being less educated, being without insurance or on government insurance, and being unemployed. Regarding addiction and criminal history, being dependent on cocaine or opioids and being under supervision for person, property, or court offenses were risk factors. Being male and being a member of a racial minority were also risk factors for early treatment failure. Meeting criteria for sedative/hypnotic dependence and being under legal supervision for a substance offense were associated with a longer duration of time to treatment failure. CONCLUSIONS: Social stability, addiction history, and current criminal charges all appear to influence performance in TASC. Individuals with multiple risk factors may benefit from referral to a higher level of care upon admittance to TASC. PMID- 23810264 TI - Depressive symptoms moderate treatment response to brief intervention for prevention of alcohol exposed pregnancy. AB - The previously published randomized controlled trial, EARLY, tested the efficacy of a motivational interviewing (MI) plus feedback condition against a video information (VI) condition and an informational brochure (IB) condition in reducing drinking and/or increasing contraception effectiveness, and found that drinking and rates of effective contraception improved in all conditions. In this reanalysis of the data from EARLY, potential moderating effects of depressive, global distress, and anxiety symptoms in response to the three brief interventions to reduce alcohol exposed pregnancy risk were examined. Women with higher levels of depression at baseline reported greater improvements in the MI plus feedback condition versus the VI and IB conditions with depression moderating both drinking and contraceptive effectiveness. Global distress moderated only drinking behavior in the MI plus feedback but not other groups and anxiety was not a moderator of outcome in any of the intervention groups. Depressed or distressed women at risk for AEP may benefit from an AEP risk reduction intervention that incorporates interaction with a treatment provider versus educational information provided via video or written materials. PMID- 23810265 TI - Ethnicity as a moderator of motivational interviewing for incarcerated adolescents after release. AB - Motivational interviewing (MI) has been found to be an effective treatment for substance using populations, including incarcerated adolescents. Although some studies suggest MI is more successful with individuals from minority backgrounds, the research remains mixed. The current study investigated the impact of ethnicity on treatment in reducing alcohol and marijuana use among incarcerated adolescents. Adolescents (14-19 years of age) were recruited from a state juvenile correctional facility and randomly assigned to receive MI or relaxation therapy (RT) (N=147; 48 White, 51 Hispanic, and 48 African American; 126 male; 21 female). Interviews were conducted at admission to the facility and 3 months after release. Results suggest that the effects of MI on treatment outcomes are moderated by ethnicity. Hispanic adolescents who received MI significantly decreased total number of drinks on heavy drinking days (NDHD) and percentage of heavy drinking days (PHDD) as compared to Hispanic adolescents who received RT. These findings suggest that MI is an efficacious treatment for an ethnic minority juvenile justice-involved population in need of evidence-based treatments. PMID- 23810266 TI - Using chi-Squared Automatic Interaction Detection (CHAID) modelling to identify groups of methadone treatment clients experiencing significantly poorer treatment outcomes. AB - In times of scarce resources it is important for services to make evidence based decisions when identifying clients with poor outcomes. chi-Squared Automatic Interaction Detection (CHAID) modelling was used to identify characteristics of clients experiencing statistically significant poor outcomes. A national, longitudinal study recruited and interviewed, using the Maudsley Addiction Profile (MAP), 215 clients starting methadone treatment and 78% were interviewed one year later. Four CHAID analyses were conducted to model the interactions between the primary outcome variable, used heroin in the last 90 days prior to one year interview and variables on drug use, treatment history, social functioning and demographics. Results revealed that regardless of these other variables, males over 22 years of age consistently demonstrated significantly poorer outcomes than all other clients. CHAID models can be easily applied by service providers to provide ongoing evidence on clients exhibiting poor outcomes and requiring priority within services. PMID- 23810267 TI - Effect of a pharmacist intervention on asthma control. A cluster randomised trial. AB - INTRODUCTION: Achievement and maintenance of good asthma control is a major objective in asthma management. However, asthma control in many patients is suboptimal, due to improper use of asthma medications and non-adherence. The aim of this study was to evaluate the effect of a pharmacist intervention on asthma control in adult patients. METHODS: A 6-month cluster randomized controlled trial was undertaken with allocation of community pharmacies to intervention or control group. Adult asthma patients in the intervention group received a protocol-based intervention addressing individual needs related to asthma control, inhaler technique and medication adherence. Patients in the control group received usual care. Main variables were measured at baseline, 3 and 6 months. RESULTS: 336 patients completed the study, 150 in the control group and 186 in the intervention group. The intervention resulted in enhanced asthma control: Patients receiving the intervention had an Odds ratio of 3.06 (95% CI:1.63-5.73; p < 0.001) of having controlled asthma six months later. In the intervention group mean ACQ scores significantly improved [0.66 points (SD: 0.78); p < 0.001] and the number of controlled asthma patients increased by 30.1% (p < 0.001) after 6 months. The intervention also resulted in improved medication adherence (by 40.3%, p < 0.001) and inhaler technique (by 56.2%, p < 0.001). No significant changes for any of these variables were observed in the control group. CONCLUSION: The AFasma study focused on the important outcomes of asthma management, and showed that through the designed intervention, community pharmacists can increase controlled asthma patients compared to usual care. Trial registration NCT01085474. PMID- 23810268 TI - Incidence and risk of treatment-related mortality in cancer patients treated with EGFR-TKIs: a meta-analysis of 22 phase III randomized controlled trials. AB - Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have become the cornerstone in the treatment of lung cancers that harbor EGFR mutations, but also play an important role in the treatment of other lung cancers and have been investigated among various types of solid tumors. However, these drugs have been associated with an increase in the risk of potentially life threatening adverse event, such as arterial and venous thrombotic events. We performed a meta-analysis to determine the incidence and risk of fatal adverse events (FAEs) in cancer patients treated with EGFR-TKIs. Incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated using a random effects model. A total of 13,825 patients from 22 trials were included. Among patients treated with EGFR-TKIs, the overall incidence of FAEs was 1.9% (95%CI: 1.2-2.9%), and the risk of FAEs was 0.99 (95%CI: 0.70-1.41, p = 0.97). No increase in FAEs was detected in any prespecified subgroup. Additionally, using EGFR-TKIs as salvage treatment significantly reduced the risk of FAEs when compared to the controls (RR 0.51, 95%CI: 0.29-0.87, p = 0.013). In conclusion, this analysis suggests that the use of EGFR-TKIs does not increase the risk of FAEs in patients with advanced solid tumors, and EGFR-TKIs are safety and tolerable for cancer patients, especially for those previously treated patients. PMID- 23810269 TI - Functional and psychological variables both affect daily physical activity in COPD: a structural equations model. AB - BACKGROUND: Daily physical activity (DPA) level is reduced in patients with COPD. The aim of this study was to investigate the association of DPA with functional and psychological variables in these patients. METHODS: 155 COPD patients (102 males, median (IQR) age 62 years (54-69 years), predicted FEV1 60% (40-75%) were included. We assessed DPA (DigiWalker SW-200), functional capacity and psychological factors. RESULTS: DPA level was significantly associated with all functional capacity variables and two psychological variables (Perceived Physical Ability Subscale, depression subscale of the Hospital Anxiety and Depression Scale). The six-minute walking distance and St. George Respiratory Questionnaire activity score explained 37% of the variance of DPA in a regression analysis. A structural equations model revealed that psychological variables indirectly explained DPA through functional capacity variables. DPA was stronger associated with functional capacity variables and weaker with psychological variables in patients with lower functional status than in patients with higher functional status. CONCLUSIONS: Higher levels of DPA are associated with better functional capacity, but interestingly, DPA is also affected by psychological factors, though only indirectly, via functional capacity. The effect of specific treatment addressing psychological factors on DPA level and exercise tolerance needs further investigation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00614796. PMID- 23810270 TI - The relationship between cortical excitability and pain catastrophizing in myofascial pain. AB - Pain catastrophizing regularly occurs in chronic pain patients. It has been suggested that pain catastrophizing is a stable, person-based construct. These findings highlight the importance of investigating catastrophizing in conceptualizing specific approaches for pain management. One important area of investigation is the mechanism underlying pain catastrophizing. Therefore, this study explored the relationship between a neurophysiological marker of cortical excitability, as assessed by transcranial magnetic stimulation, and catastrophizing, as assessed by the Brazilian Portuguese Pain Catastrophizing Scale, in patients with chronic myofascial pain syndrome. The Pain Catastrophizing Scale is a robust questionnaire used to examine rumination, magnification and helplessness that are associated with the experience of pain. We include 24 women with myofascial pain syndrome. The Brazilian Portuguese Pain Catastrophizing Scale and cortical excitability were assessed. Functional and behavioral aspects of pain were evaluated with a version of the Profile of Chronic Pain scale and by multiple pain measurements (eg, pain intensity, pressure pain threshold, and other quantitative sensory measurements). Intracortical facilitation was found to be significantly associated with pain catastrophizing (beta = .63, P = .001). Our results did not suggest that these findings were influenced by other factors, such as age or medication use. Furthermore, short intracortical inhibition showed a significant association with pressure pain threshold (beta = .44, P = .04). This study elaborates on previous findings indicating a relationship between cortical excitability and catastrophizing. The present findings suggest that glutamatergic activity may be associated with mechanisms underlying pain catastrophizing; thus, the results highlight the need to further investigate the neurophysiological mechanisms associated with pain and catastrophizing. PERSPECTIVE: This study highlights the relationship between cortical excitability and catastrophizing. Cortical measures may illuminate how catastrophizing responses may be related to neurophysiological mechanisms associated with chronic pain. PMID- 23810272 TI - Assisted reproduction and child neurodevelopmental outcomes: a systematic review. AB - OBJECTIVE: To systematically review the existing literature on neurodevelopmental outcomes in children born after medically assisted reproduction compared with those of children born after spontaneous conception. DESIGN: Systematic review. SETTING: Not applicable. PATIENT(S): Children born after medically assisted reproduction vs. reference groups of spontaneously conceived children. INTERVENTION(S): Data were reviewed from worldwide published articles, without restrictions as to publication year or language. A total of 80 studies included between 31 and 2,446,044 children. MAIN OUTCOME MEASURE(S): Child neurodevelopmental outcomes categorized as cognitive, behavioral, emotional or psychomotor development, or diagnoses of mental disorders. RESULT(S): For infants, studies on psychomotor development showed no deficits, but few investigated cognitive or behavioral development. Studies on toddlers generally reported normal cognitive, behavioral, socio-emotional, and psychomotor development. For children in middle childhood, development seems comparable in children born after assisted reproduction and controls, although fewer studies have been conducted with follow-up to this age. Very few studies have assessed neurodevelopmental outcomes among teens, and the results are inconclusive. Studies investigating the risk of diagnoses of mental disorders are generally large, with long follow-up, but the results are inconsistent. CONCLUSION(S): It may tentatively be concluded that the neurodevelopment of children born after fertility treatment is overall comparable to that in children born after spontaneous conception. PMID- 23810271 TI - Effectiveness of a topical local anaesthetic spray as analgesia for dressing changes: a double-blinded randomised pilot trial comparing an emulsion with an aqueous lidocaine formulation. AB - BACKGROUND: Partial thickness skin graft wounds are painful. Topically applied lidocaine has been used for analgesia in several clinical trials. This study compared the effectiveness of two different formulations of topical local anaesthetic for dressing changes of partial thickness skin graft donor sites. METHODS: A double-blind randomised controlled, pilot trial was conducted in 29 patients undergoing split thickness skin graft surgery. Subjects were randomised to either a 3% lidocaine emulsion formulation "Treatment E" (NOPAYNETM) or a 4% aqueous solution "Treatment A" (XylocaineTM). Subjects received one spray per 3 cm(2) of donor site area followed by up to two further spays as required. Endpoints included pain intensity measured by the numerical rating scale (NRS) up to 1h after dressing change commencement, sting sensation, overall satisfaction and lidocaine plasma concentration. RESULTS: The 60 min pain scores for E and A were 1.3 +/- 0.3 (mean +/- SEM) and 1.8 +/- 0.4 (p=0.98) respectively. Nearly 90% of patients were very satisfied with their treatment. The mean plasma concentrations of lidocaine for A and E were 0.132 mg/l and 0.040 mg/l respectively (p=0.069). CONCLUSION: The topical local anaesthetic formulations achieved low pain scores during dressing changes. The safety profile was potentially improved with the emulsion formulation of lidocaine. PMID- 23810273 TI - [A review of bioethics in the Intensive Care Unit: The autonomy and role of relatives and legal representatives]. AB - In recent decades we have witnessed a change in mentality in which patient autonomy has reached significant preponderance, with informed consent as the prime example. The approach in situations where the patient cannot make decisions varies from one country to another, affording greater or lesser importance to the wishes of the family when a surrogate has not been designated. Several studies show discrepancies between the decisions of patients and that the decisions which their surrogates have taken for them. We review concepts such as greatest benefit, evaluate the potential limitations of advance care directives, and consider different options when the action or treatment proposed by professionals comes into conflict with the ideas expressed by the patient's family or surrogates, and which has led to different legally sanctioned solutions in some regions. PMID- 23810275 TI - Rapid improvement of refractory pyoderma gangrenosum with infliximab gel in a patient with ulcerative colitis. PMID- 23810274 TI - Trends in venous thromboembolism among pregnancy-related hospitalizations, United States, 1994-2009. AB - OBJECTIVE: The purpose of this study was to evaluate national trends in the rate of pregnancy-related hospitalizations for venous thromboembolism (VTE) from 1994 2009 and to estimate the prevalence of comorbid conditions among these hospitalizations. STUDY DESIGN: An estimated 64,413,973 pregnancy-related hospitalizations among women 15-44 years old were identified in the 1994-2009 Nationwide Inpatient Sample. Trends in VTE-associated pregnancy hospitalizations were evaluated with the use of variance-weighted least squares regression. Chi square tests were used to assess changes in prevalence of demographics and comorbid conditions, and multivariable logistic regression was used to evaluate the likelihood of VTE during the study period after adjustment for comorbid conditions. Antepartum, delivery, and postpartum hospitalizations were evaluated separately and reported in 4-year increments. RESULTS: From 1994-2009, there was a 14% increase in the rate of overall VTE-associated pregnancy hospitalizations; antepartum and postpartum hospitalizations with VTE increased by 17% and 47%, respectively. Between 1994-1997 and 2006-2009, the prevalence of hypertension and obesity doubled among all VTE-associated pregnancy hospitalizations; significant increases in diabetes mellitus and heart disease were also noted. A temporal increase in the likelihood of a VTE diagnosis in pregnancy was observed for antepartum hospitalizations from 2006-2009 when compared with 1994-1997 (adjusted odds ratio, 1.62; 95% confidence interval, 1.48-1.78). CONCLUSION: There has been an upward trend in VTE-associated pregnancy hospitalizations from 1994-2009 with concomitant increases in comorbid conditions. Clinicians should have a heightened awareness of the risk of VTE among pregnant women, particularly among those with comorbid conditions, and should have a low threshold for evaluation in women with symptoms or signs of VTE. PMID- 23810277 TI - Letter to the editor. PMID- 23810276 TI - Pharmacokinetics of rosuvastatin/olmesartan fixed-dose combination: a single dose, randomized, open-label, 2-period crossover study in healthy Korean subjects. AB - BACKGROUND: Rosuvastatin, a lipid-lowering agent, has been widely used with olmesartan, a long-acting angiotensin II receptor blocker, indicated for the treatment of dyslipidemia accompanied by hypertension. A fixed-dose combination (FDC) tablet of these 2 drugs was recently developed to enhance the dosing convenience and to increase patient compliance while yielding pharmacokinetic profiles comparable to coadministration of each drug as individual tablets. OBJECTIVE: The goal of present study was to compare the pharmacokinetic profiles of single-dose administration of an FDC tablet containing rosuvastatin/olmesartan 20/40 mg (test formulation) with coadministration of a rosuvastatin 20-mg tablet and a olmesartan 40-mg tablet (reference formulation) in healthy Korean male volunteers, for the purpose of determining bioequivalence. METHODS: This single dose, randomized, open-label, 2-period crossover study enrolled subjects aged 20 to 50 years and within 20% of ideal body weight. Each subject received a single dose of the test and reference formulations orally in a fasted state, with a 7 day washout period between the administrations. Blood samples were collected up to 72 hours after dosing, and pharmacokinetic parameters were determined for rosuvastatin, its active metabolite (N-desmethyl rosuvastatin), and olmesartan. Bioequivalence was concluded if the 90% CIs of the geometric mean ratios for the primary pharmacokinetic parameters were within the predetermined range of 80% to 125%. Adverse events (AEs) were evaluated based on subject interviews and physical examinations. RESULTS: Among the 58 enrolled subjects, 54 completed the study. The 90% CIs of the geometric mean ratios of the primary pharmacokinetic parameters were as follows: rosuvastatin: AUC(last), 85.60% to 97.40% and C(max), 83.16% to 98.21%; N-desmethyl rosuvastatin: AUC(last), 82.08% to 93.45% and C(max), 79.23% to 93.41%; and olmesartan: AUC(last), 97.69% to 105.69% and C(max), 100.35% to 109.42%. The most frequently noted AE was headache, occurring in 3 and 6 patients with the test and reference formulations, respectively. All of the AEs were expected, and there was no significant difference in the prevalences of AEs between the 2 formulations. CONCLUSIONS: The pharmacokinetic properties of the newly developed FDC tablet of rosuvastatin/olmesartan 20/40 mg suggest that it is bioequivalent to co-administration of each drug as individual tablets in these healthy Korean male subjects. The two formulations were well tolerated, with no serious AEs observed. ClinicalTrials.gov identifier: NCT01823900. PMID- 23810278 TI - Paolo Calabresi: the supremo of synaptic plasticity. PMID- 23810279 TI - Deconstructing a fruit serving: comparing the antioxidant density of select whole fruit and 100% fruit juices. AB - Research suggests phytonutrients, specifically phenolic compounds, within fruit may be responsible for the putatively positive antioxidant benefits derived from fruit. Given the prominence of fruit juice in the American diet, the purpose of this research was to assess the antioxidant density of fresh fruit and 100% fruit juice for five commonly consumed fruits and juices and to compare the adequacy of 100% juice as a dietary equivalent to whole fruit in providing beneficial antioxidants. Antioxidant density was measured using an oxygen radical absorbance capacity method on six samples assayed in triplicate for each fruit (grape, apple, orange, grapefruit, pineapple), name-brand 100% juice, and store-brand 100% juice. One-way analysis of variance and Tukey's honestly significant difference or Student t test were used to assess significance (P<0.05). Antioxidant density (mmol TE/100 g) of apple, orange, and grapefruit was 23% to 54% higher than the mean antioxidant density of name-brand and store-brand juices for each fruit; however, only apple and grapefruit exhibited significantly greater (P<0.05) antioxidant density than either of their name-brand or store brand juices. In contrast, the mean antioxidant density of name-brand grape and pineapple juice was higher than fresh grape or pineapple fruit; however, both fresh grapes and commercial grape juice contained significantly more (P<0.05) antioxidants than store-brand grape juice. Regardless of the convenience of fruit juice, results support the recommendations of the 2010 Dietary Guidelines for Americans for increasing fruit servings in the whole fruit form due to their provision of beneficial antioxidants and fiber with approximately 35% less sugar. PMID- 23810280 TI - Peritoneal metastases from colorectal cancer: patient selection for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. AB - Cytoreductive surgery (CRS) in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) is an established treatment modality for patients with pseudomyxoma peritonei. The majority of patients with pseudomyxoma who have complete tumour removal and HIPEC are cured. Over the last decade CRS for peritoneal metastasis of colorectal origin has emerged as an effective treatment strategy in carefully selected patients. Although convincing evidence is limited, available data shows promising results. The key to a successful outcome is appropriate selection of patients. In patients with extensive peritoneal disease, where complete cytoreduction is not achieved, surgical treatment may not be beneficial and might impair quality of life. In this paper we discuss the challenges of selecting patients with colorectal peritoneal metastases who are likely to benefit from CRS with HIPEC. PMID- 23810281 TI - Epimeric methylsulfinyladenosine derivatives from the marine ascidian Herdmania momus. AB - Investigation of the secondary metabolites of the ascidian Herdmania momus led to the isolation and characterization of four new nucleoside derivatives (1-4). Structural studies showed that these derivatives represent a series of rare methylsulfinyladenosine derivatives of interconvertible transesterification isomers and/or sulfinyl epimers. The antiviral activities of these rare nucleosides were evaluated against a series of human pathogenic viruses. PMID- 23810282 TI - Synthesis and evaluation of diaryl sulfides and diaryl selenide compounds for antitubulin and cytotoxic activity. AB - We have devised a procedure for the synthesis of analogs of combretastatin A-4 (CA-4) containing sulfur and selenium atoms as spacer groups between the aromatic rings. CA-4 is well known for its potent activity as an inhibitor of tubulin polymerization, and its prodrugs combretastatin A-4 phosphate (CA-4P) and combretastatin A-1 phosphate (CA-1P) are being investigated as antitumor agents that cause tumor vascular collapse in addition to their activity as cytotoxic compounds. Here we report the preparation of two sulfur analogs and one selenium analog of CA-4. All synthesized compounds, as well as several synthetic intermediates, were evaluated for inhibition of tubulin polymerization and for cytotoxic activity in human cancer cells. Compounds 3 and 4 were active at nM concentration against MCF-7 breast cancer cells. As inhibitors of tubulin polymerization, both 3 and 4 were more active than CA-4 itself. In addition, 4 was the most active of these agents against 786, HT-29 and PC-3 cancer cells. Molecular modeling binding studies are also reported for compounds 1, 3, 4 and CA 4 to tubulin within the colchicine site. PMID- 23810283 TI - CD56 expression is an independent prognostic factor for relapse in acute myeloid leukemia with t(8;21). AB - We investigated the significance of surface antigen expression for prognosis by focusing on a specific subtype, AML with t(8;21). The investigation included 144 patients with AML with t(8;21) in the JALSG AML97 study. AML with t(8;21) expressed CD19 (36%), CD34 (96%), and CD56 (65%) more frequently than did other subtypes of AML. CD19 expression had a significant favorable effect on CR (95.7% vs. 83.8%; P=0.049). Univariate analysis showed that increased white blood cell (WBC) counts (WBC >= 20 * 10(9)/L), CD19 negativity, and CD56 positivity were critical adverse factors for relapse after CR; multivariate analysis revealed that WBC count and CD56 expression were independent adverse risk factors (HR 2.18; P=0.045, HR 2.30; P=0.011, respectively). We concluded that CD56 expression has a possible role in risk stratification for patients with AML with t(8;21). PMID- 23810284 TI - Effects of knee flexion on the femoropopliteal artery: a computational study. AB - During knee flexion, the muscles of the upper leg impose various loads on the underlying femoropopliteal artery resulting in radial compression, bending, torsion, axial extension and axial compression. Measuring the dynamic force environment of the femoropopliteal artery and quantifying its resulting deformation characteristics is an essential input to peripheral device design. The goal of this study was to create an anatomically accurate, three dimensional finite element model capable of capturing the loading conditions and deformation characteristics of the femoropopliteal artery during knee flexion. Three dimensional geometries of the muscle, bone, arterial and soft tissues of the leg were constructed from CT scan data and meshed for finite element analysis. Knee flexion was simulated and deformation characteristics of length change (axial compression), curvature, radial compression and axial twist were quantified and compared to previous experimental studies. The model predicts 8.23% shortening and an average curvature of 0.294+/-0.26 cm(-1) in the vessel after knee flexion, with maximum stresses of 61.17 kPa and maximum strains of 0.16%. The model created replicates known in vivo deformation characteristics seen previously in angiographic images and for the first time associates femoropopliteal artery deformation characteristics with stress and strain levels within the arterial tissue. PMID- 23810285 TI - Phytochemical constituents of Sarracenia purpurea L. (pitcher plant). AB - From the leaves of Sarracenia purpurea, collected in Mistissini, Quebec, Canada, four goodyerosides and three phenolics and nine known compounds, were isolated. The structures of the compounds were determined by mass spectrometry, including HRMS, and by 1D and 2D NMR spectroscopy. PMID- 23810286 TI - Cytotoxic constituents from Celastrus paniculatus induce apoptosis and autophagy in breast cancer cells. AB - Celastrus paniculatus is a traditional medicinal plant with diverse pharmacological activities. To identify its bioactive constituents, three new beta-dihydroagarofuranoid sesquiterpenes were isolated from the whole plant, of which the major constituent is (1alpha,2alpha,8beta,9beta)-1,8-bis(acetyloxy)-2,9 bis(benzoyloxy)-14-hydroxy-beta-dihydroagarofuran. It was assessed for its antiproliferative activity, and it suppressed the viability of MCF-7 breast cancer cells with an IC50 of 17+/-1MUM. This growth inhibition was, in part, attributable to apoptosis. Moreover, this drug treatment led to LC3B-II accumulation, indicative of autophagy. Western blot analysis established its ability to target a broad range of signaling effectors related to survival and cell cycle progression, including Akt, NF-kappaB, p53, and MAP kinases. In addition, flow cytometry analysis indicates increased reactive oxygen species production in response to this compound. Taken together, these findings suggest a pleiotropic mode of mechanism that underlies the antiproliferative activity of this compound in MCF-7 breast cancer cells. PMID- 23810287 TI - Adjuvant therapy for resectable pancreatic adenocarcinoma: review of the current treatment approaches and future directions. AB - Adenocarcinoma of the pancreas carries a uniformly poor prognosis with high rates of loco-regional as well as systemic recurrence. Outcomes remain poor, even for early stage and resectable disease. It is perceived as inherently resistant to most of the currently available treatment options. Evidence supports the need for adjuvant chemotherapy but controversy remains in relation to the use of combined therapy, novel agents and the most appropriate timing of therapy. Despite no clear consensus, mainstay of treatment following resection is based primarily on single agent gemcitabine. Promising new agents and molecules of prognostic as well as predictive value under evaluation offer intriguing data, despite issues surrounding adjuvant therapy strategies. In this article, we sought to review the different therapeutic adjuvant modalities and future directions. PMID- 23810288 TI - Stereotactic radiosurgery in the treatment of brain metastases: the current evidence. AB - Chemotherapy has made substantial progress in the therapy of systemic cancer, but the pharmacological efficacy is insufficient in the treatment of brain metastases. Fractionated whole brain radiotherapy (WBRT) has been a standard treatment of brain metastases, but provides limited local tumor control and often unsatisfactory clinical results. Stereotactic radiosurgery using Gamma Knife, Linac or Cyberknife has overcome several of these limitations, which has influenced recent treatment recommendations. This present review summarizes the current literature of single session radiosurgery concerning survival and quality of life, specific responses, tumor volumes and numbers, about potential treatment combinations and radioresistant metastases. Gamma Knife and Linac based radiosurgery provide consistent results with a reproducible local tumor control in both single and multiple brain metastases. Ideally minimum doses of >=18Gy are applied. Reported local control rates were 90-94% for breast cancer metastases and 81-98% for brain metastases of lung cancer. Local tumor control rates after radiosurgery of otherwise radioresistant brain metastases were 73-90% for melanoma and 83-96% for renal cell cancer. Currently, there is a tendency to treat a larger number of brain metastases in a single radiosurgical session, since numerous studies document high local tumor control after radiosurgical treatment of >3 brain metastases. New remote brain metastases are reported in 33 42% after WBRT and in 39-52% after radiosurgery, but while WBRT is generally applied only once, radiosurgery can be used repeatedly for remote recurrences or new metastases after WBRT. Larger metastases (>8-10cc) should be removed surgically, but for smaller metastases Gamma Knife radiosurgery appears to be equally effective as surgical tumor resection (level I evidence). Radiosurgery avoids the impairments in cognition and quality of life that can be a consequence of WBRT (level I evidence). High local efficacy, preservation of cerebral functions, short hospitalization and the option to continue a systemic chemotherapy are factors in favor of a minimally invasive approach with stereotactic radiosurgery. PMID- 23810289 TI - Revitalizing the HIV response in Pakistan: a systematic review and policy implications. AB - BACKGROUND: We sought to describe the epidemiology of HIV in Pakistan and prioritize interventions to improve the effectiveness and efficiency of the response to HIV. METHODS: We conducted a systematic review of the epidemiology of HIV in Pakistan. Data sources included PUBMED and EMBASE and unpublished reports from public, non-governmental organizations and provincial and national stakeholders. We focused on findings from the last 5 years and only evaluated data before 2005 on at risk groups where there were insufficient data published after 2005. A population attributable risk analysis was conducted to estimate the burden of HIV among most at risk populations (people who inject drugs, female sex workers, male sex workers, Hijra or transgender sex workers and men who have sex with men). RESULTS: Pakistan has a concentrated epidemic of HIV-1 among most at risk populations with very low prevalence rates in the general population (0.04%). The majority of current HIV infections are estimated to occur among four at risk populations, despite their accounting for under 2% of all adults. Injecting drug users accounted for 36.4% of HIV cases - the largest share of infections in any one group. Female, male and transgender sex workers accounted for 24%, 12% and 17.5% respectively, a cumulative population attributable risk of 53.5% of all infections occurring among sex workers. CONCLUSION: Pakistan must continue to invest in targeted, evidence-based interventions to prevent the spread of HIV and curb the epidemic trajectory in Pakistan. A comprehensive range of services should include needle and syringe exchange, opiate substitution therapy for people who inject drugs, outreach and engagement with injecting drug users, Hijra' community as well as male and female sex workers and their clients and improved linkage between services and voluntary counseling, testing and anti retroviral therapy. PMID- 23810290 TI - Harlequin syndrome, a rare neurological disease. PMID- 23810291 TI - Toward a structure-based comprehension of the lectin pathway of complement. AB - To initiate the lectin pathway of complement pattern recognition molecules bind to surface-linked carbohydrates or acetyl groups on pathogens or damaged self tissue. This leads to activation of the serine proteases MASP-1 and MASP-2 resulting in deposition of C4 on the activator and assembly of the C3 convertase. In addition MASP-3 and the non-catalytic MAp19 and MAp44 presumably play regulatory functions, but the exact function of the MASP-3 protease remains to be established. Recent functional studies have significantly advanced our understanding of the molecular events occurring as activation progresses from pattern recognition to convertase assembly. Furthermore, atomic structures derived by crystallography or solution scattering of most proteins acting in the lectin pathway and two key complexes have become available. Here we integrate the current functional and structural knowledge concerning the lectin pathway proteins and derive overall models for their glycan bound complexes. These models are used to discuss cis- versus trans-activation of MASP proteases and the geometry of C4 deposition occurring on glycans in the lectin pathway. PMID- 23810292 TI - Pertuzumab in breast cancer: a systematic review. AB - Pertuzumab is a monoclonal antibody that represents the first among a new class of agents known as human epidermal growth factor receptor (HER) dimerization inhibitors. This is the first systematic review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to synthesize all available data of pertuzumab in breast cancer. The search strategy retrieved 11 studies that evaluated pertuzumab. One study was conducted in the neoadjuvant setting (417 patients), whereas all the others dealt with patients with recurrent, metastatic, or refractory disease (1023 patients). Six studies were conducted in HER2(+) breast cancer population (1354 patients), whereas 5 studies (86 patients) were conducted in HER2(-) (or unknown HER2 status) disease. Pertuzumab is the most recent agent approved by the US Food and Drug Administration in combination with trastuzumab and docetaxel for the treatment of patients with HER2(+) metastatic breast cancer who have not received prior anti HER2 therapy or chemotherapy for metastatic disease. This approval has been based on data from a phase III Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) study. The antitumor activity with the significant reduction in the risk of progression or death, as reflected upon the increase of 6.1 months in median progression-free survival, indicates that pertuzumab may provide an avenue for achieving additional benefit for patients with HER2(+). Moreover, pertuzumab seems to have a putative role in the management of patients with HER2 who are resistant to trastuzumab. The promising role of pertuzumab in the neoadjuvant and adjuvant settings remains to be further investigated and established in the future. PMID- 23810293 TI - Breast cancer expression of DAP12 is associated with skeletal and liver metastases and poor survival. AB - BACKGROUND: The transmembrane adapter protein, DAP12, transduces activation signals for several arrays of receptors, including human signal-regulatory protein, DAP12-associating lectin-1, triggering receptor expressed on myeloid cells-1, -2, and -3, in natural killer cells, granulocytes, monocytes/macrophages, and dendritic cells. The macrophage-specific antigen, Cluster of Differentiation 163 (CD163), is expressed in breast and colorectal cancers and is associated with early cancer recurrence and poor prognosis. It was recently shown that fusion between intestinal tumor cells and macrophages results in nuclear reprogramming with hybrid transcripts from both cells of origin. The role of DAP12 in the fusion process is not known. This study investigates the expression of DAP12 in BRC cells, and its relation to other macrophage traits and to the clinical progression of disease. MATERIALS AND METHODS: Immunostaining of DAP12 and CD163 was performed and evaluated in paraffin-embedded specimens from 132 patients with BRC. The outcomes were analyzed in relation to clinicopathological data. RESULTS: DAP12 expression in cancer cells was positive in 66 percent of the cancers and was associated with high tumor grade (P = .015), and with liver (P = .047) and skeletal (P = .067), but not with lung metastases (P = 1.00). Patients with BRC expressing DAP12 had poor prognosis, with higher recurrence rates of skeletal (P = .018) and liver metastases (P = .047), and shorter survival time (P = .0060). CONCLUSION: We suggest that macrophage traits in BRC cells facilitate the metastatic process and that DAP12 expression might promote metastatic homing to bone and liver tissues. PMID- 23810294 TI - Inhibition of C2C12 myotube atrophy by a novel HSP70 inducer, celastrol, via activation of Akt1 and ERK1/2 pathways. AB - Celastrol (CEL) is known as a potent inducer of heat shock protein (HSP) in non muscle cells and exhibits cytoprotective function and inhibitory effects on proteasome and glucocorticoid receptor activities. To investigate an anti atrophic effect of CEL on skeletal muscle cells, C2C12 myotubes were treated with 150 MUM dexamethasone (DEX) for 24h and 1.5 MUM CEL was added for the last 6h during the 24h DEX treatment. Compared to the control, the myotube diameter was reduced by a factor of 0.30 by DEX, but CEL treatment almost abrogated the DEX induced atrophy. CEL treatment also increased expression of HSP72 and phosphorylation of heat shock transcription factor 1 (p-HSF1) 11-fold and 3.4 fold, respectively, as well as accumulation of p-HSF1 in the nucleus. Furthermore, CEL treatment elevated activities of Akt1, p70/S6K and ERK1/2 2.0- to 4.4-fold whereas DEX had no effect on these signaling activities. Inhibition of Akt1 and ERK1/2 pathways by specific inhibitors confirmed CEL-induced anti atrophic effect. Moreover, DEX-mediated downregulation of FoxO3 phosphorylation and upregulation of MuRF1 expression and proteasome activity were abrogated by CEL treatment. These results demonstrate a novel anti-atrophic function of CEL in muscle cells via both activation of protein anabolic signals and suppression of catabolic signaling activities. PMID- 23810295 TI - Transarterial treatment of congenital renal arteriovenous fistulas. AB - OBJECTIVE: Congenital renal arteriovenous fistulas (CRAVF) represent a distinct clinical entity with characteristic hemodynamic and angiographic features. Treatment is warranted given potential for growth with renal and hemodynamic compromise. We report our experience in a rare series of treated symptomatic CRAVFs. METHODS: Over a 10-year period, patients treated for symptomatic CRAVFs (no history of predisposing renal pathology, instrumentation, neoplasm, or trauma) were retrospectively investigated for clinical presentation, imaging features, treatment outcomes, and complications. Technical success included delivery of embolic agent with complete obliteration of fistula. Clinical success included resolution of symptoms and freedom from recurrence and/or reintervention. Renal parenchymal loss was estimated by postembolization angiography and categorized as 0%, <25%, 25%-50%, or >50%. RESULTS: Twenty-five patients were referred with a presumptive diagnosis of intraparenchymal renal artery aneurysms. Of these, 10 had true intrarenal aneurysms, three had angiomyolipomas, and 12 had CRAVFs (mean age, 54; range, 29-71 years; eight women). Presenting symptoms included hematuria (eight gross, eight microscopic), refractory hypertension (diastolic blood pressure >= 90 mm Hg despite three or more medications; n = 6), flank pain (n = 8), high-output state (HOS; featuring tachycardia and jugular venous distention; n = 3), and flank bruit (n = 1). Defining angiographic features included a high-flow AVF fed by a single, enlarged intrarenal branch shunting into an aneurismal draining vein, occasionally featuring a calcified rim (four patients). All patients underwent transarterial embolization with coils (n = 5), coils and n-butylcyanoacrylate (n = 3), detachable balloons (n = 2), or Amplatzer plugs (n = 2). Technical success was 100%. Hematuria, tachycardia, jugular venous distension, pain, and bruit resolved in all. Hypertension improved in four of six patients (required less than three medications postembolization). Complications included postembolization syndrome in nine patients. Parenchymal loss was limited to <25% and observed in five patients without development of acute kidney injury or worsening hypertension. There were no recurrences or reinterventions at a mean follow-up of 55 months (range, 5-96 months). There was one death at 8 years follow-up from intercurrent coronary disease in a patient without high-output state. CONCLUSIONS: With greater awareness and accurate diagnosis, effective and durable transarterial treatment of CRAVFs can be safely performed. PMID- 23810296 TI - Outcomes of a novel technique of endovascular repair of aneurysmal internal iliac arteries using iliac branch devices. AB - OBJECTIVE: To present midterm outcomes of a novel technique of endovascular repair of aneurysmal internal iliac arteries (AIIAs) using iliac branch devices (IBDs). METHODS: Between January 2005 and August 2012, 129 patients with aneurysms involving the iliac bifurcation underwent placement of IBDs. In particular, between April 2010 and August 2012, 16 consecutive patients with aortoiliac or solitary iliac aneurysms and coexisting AIIAs were treated with the novel suggested strategy. The follow-up included physical examination and computed tomography (CT) angiography postoperatively, duplex scan at 3 months, CT scan at 6 months, and then CT scan annually. RESULTS: The technical success rate was 100%. The primary patency rate for the overall 21 internal iliac branches (five patients with bilateral aneurysms) was 95.3%. The overall assisted patency was 100%. No patient had evidence of type I/III endoleak during the follow-up of 2 years. Two patients showed type II endoleaks originating from the abdominal aneurysm sac and are under radiological surveillance. CONCLUSIONS: Our 2-year experience with the described novel approach showed its safety and feasibility, expanding the applicability of IBDs also in case of coexisting AIIAs. Long-term results and an increased number of treated patients with this technique are needed. PMID- 23810297 TI - The rise and fall of renal artery angioplasty and stenting in the United States, 1988-2009. AB - OBJECTIVE: Optimal management of renal artery stenosis (RAS) remains unclear. Recent randomized controlled trials have shown no clear benefit with percutaneous transluminal angioplasty with or without stenting (PTRA/S) over medical management. We hypothesize that interventions for RAS are decreasing nationally. METHODS: The Nationwide Inpatient Sample, 1988-2009, was used to identify patients with a diagnosis of renal artery atherosclerosis undergoing open surgical repair (bypass or endarterectomy) or PTRA/S. The rate of interventions, in-hospital death, and perioperative outcomes were analyzed over time. Additionally, we used individual state inpatient and ambulatory databases to better understand the influence of outpatient procedures on current volume and trends. RESULTS: We identified 308,549 PTRA/S and 33,147 open surgical repairs. PTRA/S increased from 1.9/100K adults in 1988 to 13.7 in 2006 followed by a decrease to 6.7 in 2009. Open surgical repair steadily decreased from 1.3/100K adults in 1988 to 0.3 in 2009. In 2009, PTRA/S procedures (6.4/100K adults) greatly outnumbered procedures done by open repair alone (0.1/100K), combined open renal and aortic repair (0.2/100K), and combined PTRA/S and endovascular aneurysm repair (0.3/100K). From 2005 to 2009 33,953 patients underwent PTRA/S in the states of New Jersey Maryland, Florida, and California combined. The total number of PTRA/S performed in the outpatient setting remained stable from 2005 (3.8/100K) to 2009 (3.7/100K), whereas the total number of inpatient procedures mirrored the national trend, declining from 2006 (7.9/100K) to 2009 (4.2/100K). PTRA/S had lower in-hospital mortality (0.9% vs 4.1%; P < .001) compared with open repair. PTRA/S patients were more likely to be discharged home (86.2% vs 76.3%; P < .001) and had a shorter length of stay (4.4 vs 12.3 days; P < .001). Mortality was higher after combined open renal and open aortic surgery compared to open repair alone (6.5% vs 4.1%; P < .001). Mortality was similar for combined PTRA/S and endovascular aneurysm repair compared with PTRA/S alone (1.2% vs 0.9%; P = .04). CONCLUSIONS: The performance of PTRA/S procedures for the management of RAS has decreased significantly after 2006. An increasing proportion of these procedures are performed in the outpatient setting. PTRA/S remains the dominant revascularization procedure for RAS with lower in-hospital mortality and morbidity than surgery. PMID- 23810298 TI - Prevention of vascular access hand ischemia using the axillary artery as inflow. AB - BACKGROUND: Avoiding dialysis access-associated ischemic steal syndrome (DASS) in patients with upper extremity peripheral vascular occlusive disease while creating a functional hemodialysis vascular access may be challenging. We constructed an autogenous access with primary proximalization of the arterial inflow to prevent hand ischemia in patients at high risk for this complication. METHODS: Patients requiring hemodialysis access with physical findings suggesting a high risk of access-related hand ischemia (absent radial, ulnar, and brachial palpable pulses associated with small calcified vessels by ultrasound examination) underwent a primary arteriovenous fistula transposition procedure utilizing the axillary artery for inflow. The arteriovenous fistula was either a reversed flow basilic vein transposition supplemented by valvulotomy (n = 22); a translocated reversed basilic vein (n = 4); a cephalic vein harvested into the forearm and placed in a loop configuration for axillary artery inflow (n = 3); or a translocated reversed saphenous vein (n = 1). RESULTS: Thirty patients with a mean age of 60 years (range, 31-83 years) underwent successful primary axillary artery inflow procedures during a 3-year period. Of these, 23 (77%) were female and 25 (83%) were diabetic. Twenty-one (70%) had previous vascular access procedures and 10 (33%) were obese. No patient developed postoperative ischemia. Three individuals died 2, 14, and 19 months following surgery, none related to vascular access. Three accesses failed after 1, 5, and 7 months and could not be salvaged. Life-table primary, primary assisted, and cumulative patency rates were 57%, 78%, and 87% respectively at 1 year with a mean follow-up of 7 months (range, 1-25 months). Cephalic vein outflow was associated with fewer access failures, fewer interventions postoperatively, and lower rates of arm swelling (P < .01). CONCLUSIONS: Creating a basilic vein transposition for vascular access utilizing axillary artery inflow is a good option for patients with severe peripheral vascular disease. It offers a high patency rate and the prevention of DASS. Retrograde basilic vein outflow through the median cubital and cephalic vein is associated with the best outcome and is the recommended configuration. PMID- 23810299 TI - Predictors of percutaneous access failure requiring open femoral surgical conversion during endovascular aortic aneurysm repair. AB - OBJECTIVE: To determine predictors of percutaneous (PEVAR) access failure requiring conversion to an open approach (OEVAR) during endovascular aortic aneurysm repair (EVAR). METHODS: A single-center retrospective review of all EVAR patients from January 2009 through June 2011 with multivariate analysis of clinical and anatomic variables that could impact access outcome was conducted. Target vessel calcification was categorized as mild, moderate, or severe based on circumferential calcium arc (<1/3, 1/3 to 1/2, and >1/2 respectively), dyslipidemia (defined as low-density lipoprotein >130 mg/dL or receiving lipid lowering medication), and obesity (defined as body mass index [BMI] >30). RESULTS: We investigated 400 access sites for 200 patients who underwent EVAR. The study cohort's characteristics included an average age of 72.8 +/- 9.0 years, vessel size of 9.6 +/- 1.8 mm, sheath size of 17.1 +/- 3.0 Fr, BMI of 27.6 +/- 5.3, and estimated glomular filtration rate of 68.5 +/- 24.2 mL/min. Comorbidities included dyslipidemia in 129 patients (64.5%) and diabetes in 54 patients (27%). There were 132 OEVAR (66 patients), two mixed OEVAR with contralateral PEVAR (one patient), and 266 (133 patients) PEVAR approaches. Use of PEVAR increased over time (45.5% [2009], 77.8% [2010], and up to 88.5% [2011]; P = .001) while conversions decreased (24.3% [2009], 8.7% [2010], and 4.3% [2011]; P = .001]. More OEVAR patients (35.8%) stayed longer than 3 days compared with 21.1% for PEVAR (P = .028). For the 266 PEVAR approaches, 32 access sites (12.0%) had to be converted. Severely calcified arteries were most predictive of conversion (odds ratio [OR], 36.4; P < .001). Year of procedure (2010; OR, 0.17; P = .001; 2011, OR, 0.20; P = .049), female gender (OR, 3.1; P = .017), moderately calcified arteries (OR, 2.5; P = .085), and age (OR, 2.3 [per decade]; P = .002) were all also significant. Vessel size, sheath size, and BMI were found to be nonsignificant predictors of conversion. CONCLUSIONS: PEVAR was found to be safe, reliable, and feasible. Several factors, including learning curve, vessel calcification, age, and female gender predicted conversion of PEVAR to OEVAR. PMID- 23810300 TI - Radiation exposure to operating room personnel and patients during endovascular procedures. AB - OBJECTIVE: To characterize radiation exposure to patients and operating room personnel during fluoroscopic procedures. METHODS: Patient dose information was collected from the imaging equipment. Real-time dosimetry was used to measure doses to the operators, scrub nurse, radiologic technologist (RT), and anesthesiologist in 39 cases of endovascular thoracoabdominal aortic aneurysm repair using fenestrated endografts. Overall equivalent doses and dose rates at time points of interest were noted and compared with the corresponding patient doses. RESULTS: The dosimeter on the anesthesia equipment received 143 MUSv (38 247) more radiation per case than the average operator, and the scrub nurse and RT received 106 MUSv (66-146) and 100 MUSv (55-145) less, respectively. Adjusting for protective lead aprons by the Webster methodology, the average operator received an effective dose of 38 MUSv. Except for the RT, personnel doses were well correlated with patient dose as measured by kerma area product (KAP) (r = .82 for average operator, r = .85 for scrub nurse, and r = .86 for anesthesia; all P < .001) but less well correlated with fluoroscopy time or cumulative air kerma (CAK). When preoperative cone beam computed tomography was performed, the equivalent dose to the RT was 1.1 MUSv (0.6-1.5) when using shielding and 37 MUSv (22-53) when unshielded. Digital subtraction acquisitions accounted for a large fraction of all individuals' doses. Decreasing field size (and thus, increasing magnification) was associated with decreased KAP (r = .47; P < .001) and increased CAK (r = -.56; P < .001). The square of the field size correlated strongly with the KAP/CAK ratio (r = .99; P < .001). Increased lateral angulation of the C-arm increased both CAK and KAP (at field size, 22 cm; r = .54 and r = .44; both P < .001) and the average dose rate to an operator was 1.78 (1.37-2.31) times as high in a lateral projection as in a posterior-anterior projection. CONCLUSIONS: Personnel doses were best correlated with KAP and less well correlated with fluoroscopy time or CAK. The dosimeter on the anesthesia equipment recorded the highest doses attributable to ineffective shielding. Operators can reduce the effective dose to themselves, the patient, and other personnel by minimizing the use of digital subtraction acquisitions, avoiding lateral angulation, using higher magnification levels when possible, and being diligent about the use of shielding during fluoroscopy cases. PMID- 23810301 TI - A comparison of the outcomes of one-stage and two-stage brachiobasilic arteriovenous fistulas. AB - OBJECTIVE: The brachiobasilic arteriovenous fistula (BBAVF) can be formed in one or two stages. This study examined the failure rates and functional patencies of one-stage vs two-stage brachiobasilic transposition fistulas to compare the two surgical techniques. METHODS: We retrospectively identified all the patients who underwent BBAVF access surgery at King's College Hospital between January 1, 2009, and December 31, 2011 (3 years). Patients were divided into two groups according to one-stage or two-stage procedure. All patients were seen in the access clinic 4 to 6 weeks postoperatively, and their fistulas were scanned (duplex). The surveillance of fistulas consists of duplex scans every 6 months to assess volume flow. RESULTS: During the study interval, 149 brachiobasilic transpositions (65 one-stage and 84 two-stage) were performed in 141 patients. Patients undergoing the two-stage procedure had a smaller mean preoperative vein diameter (4.0 +/- 1.1 vs 3.6 +/- 1.3 mm; P = .041) and tended to be older (58 +/- 15 vs 63 +/- 15 years; P = .062). Mean overall follow-up was 559 +/- 333 days. There was no difference in primary failure between the two groups (45% vs 42%; P = .718). At 1 year, the two-stage BBAVFs had significantly better primary (71% vs 87%; P = .034), assisted primary (77% vs 95%; P = .017), and secondary functional (79% vs 95%; P = .026) patencies. The same applied to 2-year primary (53% vs 75%; P = .034), assisted primary (57% vs 77%; P = .017), and secondary functional (57% vs 77%; P = .026) patencies. Multivariate Cox regression showed that the one stage procedure was 3.2 times more likely to fail (P = .028). Men were 2.7 times more likely to lose their access (P = .054). CONCLUSIONS: This study describes a large series of BBAVFs and makes an extensive comparison between the one-stage and two-stage operations. Significantly improved overall functional patency is demonstrated for the two-stage operation. PMID- 23810302 TI - Up-regulation of heme oxygenase-1 contributes to the amelioration of aluminum induced oxidative stress in Medicago sativa. AB - In this report, pharmacological, histochemical and molecular approaches were used to investigate the effect of heme oxygenase-1 (HO-1) up-regulation on the alleviation of aluminum (Al)-induced oxidative stress in Medicago sativa. Exposure of alfalfa to AlCl3 (0-100 MUM) resulted in a dose-dependent inhibition of root elongation as well as the enhancement of thiobarbituric acid reactive substances (TBARS) content. 1 and 10 MUM (in particular) Al(3+) increased alfalfa HO-1 transcript or its protein level, and HO activity in comparison with the decreased changes in 100 MUM Al-treated samples. After recuperation, however, TBARS levels in 1 and 10 MUM Al-treated alfalfa roots returned to control values, which were accompanied with the higher levels of HO activity. Subsequently, exogenous CO, a byproduct of HO-1, could substitute for the cytoprotective effects of the up-regulation of HO-1 in alfalfa plants upon Al stress, which was confirmed by the alleviation of TBARS and Al accumulation, as well as the histochemical analysis of lipid peroxidation and loss of plasma membrane integrity. Theses results indicated that endogenous CO generated via heme degradation by HO-1 could contribute in a critical manner to its protective effects. Additionally, the pretreatments of butylated hydroxytoluene (BHT) and hemin, an inducer of HO-1, exhibited the similar cytoprotective roles in the alleviation of oxidative stress, both of which were impaired by the potent inhibitor of HO-1, zinc protoporphyrin IX (ZnPP). However, the Al-induced inhibition of root elongation was not influenced by CO, BHT and hemin, respectively. Together, the present results showed up-regulation of HO-1 expression could act as a mechanism of cell protection against oxidative stress induced by Al treatment. PMID- 23810303 TI - [Radiotherapy after testicular-sparing surgery for bilateral or monorchide testicular tumours: an innovative approach]. AB - Testicular-sparing surgery may avoid definitive testosterone supplementation and preserve fertility in selected cases of men presenting with bilateral testicular tumours or in case of monorchidia. Testicular-sparing surgery may enable the conservation of both endocrine function and spermatogenesis in selected young men in order to preserve natural fatherhood, avoid definitive androgen replacement therapy and probably improve quality of life by reducing psychosexual consequences of anorchia. The tumorectomy must be followed by an external irradiation of the remaining testicle to eradicate testicular intratubular neoplasia revealed in 82% of cases after per-surgery biopsy. This approach concerns some rare indications. Dose level and technical consideration are still debated. PMID- 23810304 TI - [Radiosensitization induced by vemurafenib]. AB - The recent use of vemurafenib, a specific inhibitor of BRAF, has led to a significant improvement in disease-free survival and overall survival of patients treated for a BRAF-mutated metastatic melanoma. This new class of drugs is not devoid of side effects, including skin effects. In particular, its association with concomitant radiotherapy should be taken into consideration, vemurafenib appearing to be radiosensitizer. The radiation oncologist must be aware of this potential toxicity, which is not uncommon in clinical practice. PMID- 23810305 TI - [Last resort surgical management of postradiation urinary cystitis after external beam radiation for prostate cancer: a monocentric analysis]. AB - PURPOSE: To assess functional outcomes obtained after surgical management of post radiation urinary incontinence after prostate cancer. PATIENTS AND METHOD: A retrospective review of the data from patients treated in our centre between September 2004 and February 2012 by surgery for vesicosphincteric injuries after prostatic external beam radiation therapy was performed. RESULTS: A total of seven men with a median age of 70 years +/- 4.1 were included. Mean follow-up was 32.3 months +/- 29 (3-86). All patients underwent a partial cystectomy and augmentation enterocystoplasty. The vesicocutaneous fistula rate was 33% occurring within a mean time of 18.5 days +/- 2.1 (17-20). The mean length of urinary catheter and hospital stay were respectively 16 days +/- 8.4 (12-35) and 18 days +/- 7.8 (13-37). Five patients underwent asynchronous insertion of artificial urinary sphincter. The success rate of partial cystectomy and augmentation enterocystoplasty with asynchronous implantation of artificial urinary sphincter to treat post-radiation urinary incontinence was 71.5%. The median time between partial cystectomy and augmentation enterocystoplasty and artificial urinary sphincter implantation was 27.6months +/- 26.4 (7-72). CONCLUSION: Surgical management of post-radiation urinary cystitis offers good functional outcomes albeit its morbidity is not negligible. It should be proposed only in expert surgical centres. PMID- 23810306 TI - Colonisation with multi-resistant Enterobacteriaceae in hospitalised Danish patients with a history of recent travel: a cross-sectional study. AB - BACKGROUND: The global spread of multi-resistant Enterobacteriaceae is a new challenge in health care. Travelling in high endemic areas has been associated with colonisation. This study was performed among patients hospitalised for any reason, with recent travel abroad to identify the rate for colonisation with multi-resistant bacteria. METHODS: In a 3-month period (2011) all patients admitted to a the Department of Infectious Diseases, Aarhus University Hospital, Denmark with a travel history within the last three months were screened for multi-drug resistant bacteria by a rectal swab. RESULTS: A total of 88 adult patients were included. None were carriers of carbapenemase-producing bacilli. 12.5% were colonised with extended spectrum beta-lactamase producing Escherichia coli (ESBL-EC). Diarrhoea during travel was significantly associated with colonisation. More than 80% of the ESBL-EC colonised patients had been abroad longer than two weeks (P < 0.05). Less than 40% of patients with ESBL-EC had self limiting diarrhoea at the time of admission. CONCLUSIONS: A significant proportion of patients with a recent travel history was colonised with ESBL-EC at hospitalisation (12.5%). Less than half of the travellers with ESBL-EC had gastrointestinal symptoms. Diarrhoea during travel and travelling time > two weeks were associated with colonisation with ESBL-EC. PMID- 23810307 TI - The potential for pneumococcal vaccination in Hajj pilgrims: expert opinion. AB - Hajj is the annual pilgrimage to Mecca in the Kingdom of Saudi Arabia, and is one of the largest mass gathering events in the world. Acute respiratory tract infections are very common during Hajj, primarily as a result of close contact among pilgrims, intense congestion, shared accommodation and air pollution. A number of vaccines are (or have been) recommended for Hajj pilgrims in recent years. Several additional vaccines could significantly reduce the morbidity and mortality at Hajj and should be considered in health recommendations for pilgrims. Pneumococcal vaccines (particularly for those aged >65 years) are widely available, and have been shown to reduce the burden of disease associated with Streptococcus pneumoniae infection. Importantly, a considerable percentage of Hajj pilgrims have pre-existing illnesses or are elderly, both important risk factors for pneumococcal infection. While there are substantial gaps that need to be addressed regarding our knowledge of the exact burden of disease in Hajj pilgrims and the effectiveness of pneumococcal vaccination in this population, S. pneumoniae may be an important cause of illness among this group of travelers. It can be assumed that the majority of pneumococcal serotypes circulating during Hajj are included in the existing pneumococcal vaccines. PMID- 23810308 TI - Epidemiology and impact of varicella vaccination: a longitudinal study 1994-2011. AB - OBJECTIVE: This study examines the epidemiology of varicella infection and the impact of vaccination in a population in Eastern Saudi Arabia. METHODS: All reported cases of varicella infection from 1994 to 2011 were analyzed. RESULTS: A total of 19,577 patients with varicella were reported during the study period, and 8869 were female and 10,248 were male, with a male to female ratio of 1.15:1. Most of the cases were reported in patients between one to four year of age (n = 5625; 29.4%) and five to nine years of age (n = 6614; 34.6%) years of age. The highest numbers of cases were reported in March-May corresponding to the spring time (39.3%) compared with 21.2% in the winter and 25.4% in the summer time. The childhood varicella vaccine was introduced in 1998 and was made mandatory in 2008. The total number of cases decreased from 10,070 in the pre-vaccination period to 1577 cases in the mandatory vaccination period. The incidence rate decreased from 739.8 in 1994 to 355.3 in 1998, to 88.1 in 2011 per 100,000 population (P < 0.0001). Patients less than one year of age constituted 8.3% of cases in 1994-1997 prior to vaccination, 5.4% in 1998-2008 during the initial vaccination phase and 3.4% during the mandatory vaccination period (P < 0.0001). CONCLUSION: The introduction of varicella vaccine resulted in a significant reduction in the incidence rates between 1994 and 2011. PMID- 23810309 TI - Clinical outcomes of percutaneous drainage of breast fluid collections after mastectomy with expander-based breast reconstruction. AB - PURPOSE: To determine clinical outcomes of patients who underwent imaging-guided percutaneous drainage of breast fluid collections after mastectomy and breast reconstruction. MATERIALS AND METHODS: A retrospective review was performed including all consecutive patients who underwent percutaneous drainage of fluid collections after mastectomy with tissue expander-based reconstruction between January 2007 and September 2012. During this period, 879 mastectomies (563 patients) with expander-based breast reconstruction were performed. Fluid collections developed in 28 patients (5%), which led to 30 imaging-guided percutaneous drainage procedures. The median follow-up time was 533 days. Patient characteristics, surgical technique, microbiology analysis, and clinical outcomes were reviewed. RESULTS: The mean age of patients was 51.5 years (range, 30.9-69.4 y), and the median time between breast reconstruction and drainage was 35 days (range, 4-235 d). Erythema and swelling were the most common presenting symptoms. The median volume of fluid evacuated at the time of drain placement was 70 mL. Drains were left in place for a median 14 days (range, 6-34 d). Microorganisms were detected in the fluid in 12 of 30 drainage procedures, with Staphylococcus aureus being the most common microorganism. No further intervention was needed in 21 of 30 drainage procedures (70%). However, surgical intervention (removal of expanders) was needed after 6 (20%) drainage procedures, and additional percutaneous drainage procedures were performed after 3 (10%) drainage procedures. CONCLUSIONS: Percutaneous drainage is an effective means of treating postoperative fluid collections after expander-based breast reconstruction and can obviate the need for repeat surgery in most cases. PMID- 23810310 TI - Use of the Endurant stent graft system for ruptured infrarenal aortic aneurysms: short-term experience in nine patients. AB - PURPOSE: To report the early results of use of the Endurant stent graft in the treatment of ruptured abdominal aortic aneurysms (AAAs). MATERIALS AND METHODS: Nine consecutive patients (seven men and two women; mean age, 76 y; range, 65-87 y) underwent endovascular aneurysm repair (EVAR) for a ruptured AAA with the Endurant stent graft between April and December 2012. EVAR was emergent in all cases. Early technical success, clinical success, major complication, and mortality rates were analyzed. RESULTS: Intraoperative immediate technical success was achieved in all nine patients. The 30-day clinical success rate was 67% (six of nine patients). The 30-day mortality rate was 33% (three of nine patients). During a mean follow-up of 6 months (range, 3-10 mo), none of the cases required reintervention; there was one late death attributed to probable endograft infection. CONCLUSIONS: The short-term results of EVAR with the Endurant stent graft in patients with ruptured AAAs are encouraging. PMID- 23810311 TI - Retrospective review of angiography before cannulation of newly created vascular accesses in hemodialysis patients. AB - PURPOSE: To investigate vascular access status before first cannulation and the clinical implications of angiography performed before cannulation. MATERIALS AND METHODS: A retrospective review of 300 consecutive patients who underwent angiography after vascular access surgery and before cannulation between August 2004 and April 2010 was performed. Angiography was performed 4-6 weeks after the surgery but before the first cannulation. RESULTS: Angiography revealed 94 (31.3%) cases of severe stenosis (>= 50% luminal narrowing) that required percutaneous transluminal angioplasty (PTA) or a second operation. No stenosis was observed in 122 (40.7%) cases, and mild stenosis (< 50% luminal narrowing) was observed in 84 (28%) cases. For the 94 cases with severe stenosis, PTA was performed in 66, and a second operation was performed in 16. In the other cases (n = 12), HD was maintained by a permanent catheter, or the patients were transferred to another institution. PTA was an immediate success in all patients who underwent the procedure except two. Of 84 patients with mild stenosis, 70 were followed for 1 year; vascular access dysfunction occurred in 15, and 11 of these underwent successful PTA. Of the 122 patients with normal angiographic findings, 102 were followed for 1 year, and vascular access dysfunction did not occur in any of these patients. CONCLUSIONS: Early postoperative angiography before the first hemodialysis is helpful for the early detection and treatment of vascular access dysfunction. PMID- 23810313 TI - Muscle MRI reveals distinct abnormalities in genetically proven non-dystrophic myotonias. AB - We assessed the presence, frequency and pattern of MRI abnormalities in non dystrophic myotonia patients. We reviewed T1-weighted and STIR (short-tau inversion-recovery) 3T MRI sequences of lower limb muscles at thigh and calf level in 21 patients with genetically confirmed non-dystrophic myotonia: 11 with CLCN1 mutations and 10 with SCN4A mutations, and 19 healthy volunteers. The MRI examinations of all patients showed hyperintensity within muscles on either T1 weighted or STIR images. Mild extensive or marked T1-weighted changes were noted in 10/21 patients and no volunteers. Muscles in the thigh were equally likely to be affected but in the calf there was sparing of tibialis posterior. Oedema was common in calf musculature especially in the medial gastrocnemius with STIR hyperintensity observed in 18/21 patients. In 10/11 CLCN1 patients this included a previously unreported "central stripe", also present in 3/10 SCN4A patients but no volunteers. Degree of fatty infiltration correlated with age (rho=0.46, p<0.05). Muscle MRI is frequently abnormal in non-dystrophic myotonia providing evidence of fatty infiltration and/or oedema. The pattern is distinct from other myotonic disorders; in particular the "central stripe" has not been reported in other conditions. Correlations with clinical parameters suggest a potential role for MRI as a biomarker. PMID- 23810314 TI - [Practitioner blindness? Lifestyle medicine is a reality! Screening without prevention, rational?]. PMID- 23810315 TI - Transmitting biological effects of stress in utero: implications for mother and offspring. AB - The developing foetus makes adaptations to an adverse in utero environment which may lead to permanent changes in structure and physiology, thus 'programming' the foetus to risk of ill health in later life. Epidemiological studies have shown associations between low birth weight, a surrogate marker of an adverse intrauterine environment, and a range of diseases in adult life including cardiometabolic and psychiatric disease. These associations do not apply exclusively to low birth weight babies but also to newborns within the normal birth weight range. Early life stress, including stressors in the prenatal and early postnatal period, is a key factor that can have long-term effects on offspring health. Animal studies show this is mediated through changes in the maternal and foetal hypothalamic-pituitary-adrenal axes resulting in foetal exposure to excess glucocorticoids. Data in humans are more limited but support that the biological effects of stress in utero may be transmitted through changes in glucocorticoid action or metabolism. Common contemporary physical and social stressors of maternal obesity and socio-economic deprivation impact on the maternal response to pregnancy and the prevailing hormonal milieu that the developing foetus will be exposed to. Prenatal stress may also be compounded by early postnatal stresses such as childhood maltreatment with resultant adverse effects for the offspring. Understanding of the mechanisms whereby these stressors are transmitted from mother to foetus will not only improve our knowledge of normal foetal development but will also help identify novel pathways for early intervention either in the periconceptional, pregnancy or the early postpartum period. PMID- 23810312 TI - Cancer concepts and principles: primer for the interventional oncologist-part II. AB - This is the second of a two-part overview of the fundamentals of oncology for interventional radiologists. The first part focused on clinical trials, basic statistics, assessment of response, and overall concepts in oncology. This second part aims to review the methods of tumor characterization; principles of the oncology specialties, including medical, surgical, radiation, and interventional oncology; and current treatment paradigms for the most common cancers encountered in interventional oncology, along with the levels of evidence that guide these treatments. PMID- 23810317 TI - Apropos 'a review of dengue as an emerging disease in Pakistan'. PMID- 23810316 TI - Indolamine 2,3-dioxygenase regulation and neuropsychiatric symptoms. PMID- 23810318 TI - Making every contact count: an evaluation. AB - OBJECTIVES: To conduct an initial evaluation of a behaviour change programme called 'Making Every Contact Count' (MECC). STUDY DESIGN: Retrospective interview study. METHODS: In depth qualitative interviews with key stakeholders engaged in the delivery of MECC which were digitally recorded, transcribed and analysed thematically using framework analysis. RESULTS: The responses of those involved were generally favourable and although the 'intuitive' nature of the idea of Making Every Contact Count clearly resonated with interviewees, the take up was variable across different organisations. CONCLUSIONS: The approach to MECC described here was based on some of the principles outlined in the NICE Guidance on behaviour change published in 2007. The report shows that MECC has considerable potential for changing staff behaviour in relation promoting health enhancing behaviour among members of the general public coming into contact with services. PMID- 23810319 TI - Challenges and lessons learned from implementing a risk-based approach to school advice and closure during the containment phase of the 2009 influenza pandemic in the West Midlands, England. AB - OBJECTIVE: School closure as a social distancing measure was used in some countries during the initial phases of the influenza A(H1N1)pdm09 pandemic. The objective of this paper is to describe the use of a risk-based approach to public health interventions for schools during the 'containment phase' of the pandemic and to describe lessons learnt. METHODS: The development of a framework for risk assessment and decision-making to determine school closures in the West Midlands, England, during the 'containment phase' of influenza A(H1N1)pdm09 pandemic is described. RESULTS: Using the framework developed during the 'containment phase', assessments were conducted for 344 educational institutions who reported confirmed cases or 'particularly high absenteeism'. Of these, 209 (60%) had confirmed cases and 65 were closed, mainly for public health or operational reasons. Schools were closed on an individual basis, during the most intense period of the pandemic and for an average period of six days (maximum 11 days). The risk-based approach evolved as experience and knowledge of influenza A(H1N1)pdm09 pandemic virus increased, however some decisions were difficult to communicate to parents, schools and stakeholders particularly when the number of schools affected escalated and the pandemic response phases changed. CONCLUSION: The management of school closures is an 'uncertain art'. Numerous challenges and lessons were identified in attempting, during the containment phase of the influenza A(H1N1)pdm09 pandemic, to ensure consistency and transparency in an increasingly complex process. The overall approach described could be further developed to improve decision-making for infectious diseases in schools. PMID- 23810320 TI - Anticoagulation for emergency department patients with atrial fibrillation: is our duty to inform or prescribe? PMID- 23810321 TI - Dynamics of copper and zinc sedimentation in a lagooning system receiving landfill leachate. AB - This study characterises the sediment dredged from a lagooning system composed of a settling pond and three lagoons that receive leachates from a municipal solid waste (MSW) landfill in France. Organic carbon, carbonate, iron oxyhydroxides, copper (Cu) and zinc (Zn) concentrations were measured in the sediment collected from upstream to downstream in the lagooning system. In order to complete our investigation of sedimentation mechanisms, leachates were sampled in both dry (spring) and wet (winter) seasonal conditions. Precipitation of calcite and amorphous Fe-oxyhydroxides and sedimentation of organic matter occurred in the settling pond. Since different distributions of Zn and Cu concentrations are measured in sediment samples collected downstream in the lagooning system, it is suggested that these elements were not distributed in a similar way in the leachate fractions during the first stage of treatment in the settling pond, so that their sedimentation dynamics in the lagooning system differ. In the lagoons, it was found that organic carbon plays a major role in Cu and Zn mobility and trapping. The presence of macrophytes along the edges provided an input of organic matter that enhanced Cu and Zn scavenging. This edge effect resulted in a two-fold increase in Cu and Zn concentrations in the sediment deposited near the banks of the lagoons, thus confirming the importance of vegetation for the retention of Cu and Zn in lagooning systems. PMID- 23810322 TI - Optimising energy recovery and use of chemicals, resources and materials in modern waste-to-energy plants. AB - Due to ongoing developments in the EU waste policy, Waste-to-Energy (WtE) plants are to be optimized beyond current acceptance levels. In this paper, a non exhaustive overview of advanced technical improvements is presented and illustrated with facts and figures from state-of-the-art combustion plants for municipal solid waste (MSW). Some of the data included originate from regular WtE plant operation - before and after optimisation - as well as from defined plant scale research. Aspects of energy efficiency and (re-)use of chemicals, resources and materials are discussed and support, in light of best available techniques (BAT), the idea that WtE plant performance still can be improved significantly, without direct need for expensive techniques, tools or re-design. In first instance, diagnostic skills and a thorough understanding of processes and operations allow for reclaiming the silent optimisation potential. PMID- 23810323 TI - Prevalence, clinical characteristics, and outcomes associated with eccentric versus concentric left ventricular hypertrophy in heart failure with preserved ejection fraction. AB - Although concentric remodeling (CR) and concentric hypertrophy (CH) are common forms of left ventricular (LV) remodeling in heart failure with preserved ejection fraction (HFpEF), eccentric hypertrophy (EH) can also occur in these patients. However, clinical characteristics and outcomes of EH have not been well described in HFpEF. We prospectively studied 402 patients with HFpEF, divided into 4 groups based on LV structure: normal geometry (no LV hypertrophy [LVH] and relative wall thickness [RWT] <=0.42); CR (no LVH and RWT >0.42); CH (LVH and RWT >0.42); and EH (LVH and RWT <=0.42). We compared clinical, laboratory, echocardiographic, invasive hemodynamic, and outcome data among groups. Of 402 patients, 48 (12%) had EH. Compared with CH, patients with EH had lower systolic blood pressure and less renal impairment despite similar rates of hypertension. After adjustment for covariates, EH was associated with reduced LV contractility compared with CH: lower LVEF (beta coefficient = -3.2; 95% confidence interval [CI] -5.4 to -1.1%) and ratio of systolic blood pressure to end-systolic volume (beta coefficient = -1.0; 95% CI -1.5 to -0.5 mm Hg/ml). EH was also associated with increased LV compliance compared with CH (LV end-diastolic volume at an idealized LV end-diastolic pressure of 20 mm Hg beta coefficient = 14.2; 95% CI 9.4 to 19.1 ml). Despite these differences, EH and CH had similarly elevated cardiac filling pressures and equivalent adverse outcomes. In conclusion, the presence of EH denotes a distinct subset of HFpEF that is pathophysiologically similar to HF with reduced EF (HFrEF) and may benefit from HFrEF therapy. PMID- 23810325 TI - A novel method of gastrojejunal tube placement using endoclips in pediatric patients: a case series. PMID- 23810324 TI - Effect of positive well-being on incidence of symptomatic coronary artery disease. AB - Although negative emotions and psychiatric morbidity have often been found to increase incident coronary artery disease (CAD) risk, fewer studies have shown positive emotions to be protective against CAD; none have been performed in high risk healthy populations, taking risk factors into account. Thus, we examined the effect of positive well-being on incident CAD in both a high-risk initially healthy population and a national probability sample. We screened healthy siblings of probands with documented early-onset CAD from 1985 to 2007 in the GeneSTAR (Genetic Study of Atherosclerosis Risk) population and examined sociodemographic data, risk factors, and positive well-being using the General Well-Being Schedule. We further classified siblings into high-, intermediate-, and low-risk strata according to the Framingham risk score and followed them for 5 to 25 years. Siblings (n = 1,483) with greater baseline General Well-Being Schedule total scores were significantly less likely to develop CAD (hazard ratio 0.67, 95% confidence interval 0.58 to 0.79), independent of age, gender, race, and traditional risk factors. Protection was strongest in the high Framingham risk score stratum (hazard ratio 0.52, 95% confidence interval 0.30 to 0.90). The findings were replicated in the first National Health and Nutrition Examination Survey and Epidemiologic Follow-up Study (n = 5,992; hazard ratio 0.87, 95% confidence interval 0.83 to 0.93). In conclusion, positive well-being was associated with nearly a 1/3 reduction in CAD in a high-risk population with a positive family history, a nearly 50% reduction in incident CAD in the highest risk stratum in those with a positive family history, and a 13% reduction in incident CAD in a national probability sample, independent of the traditional CAD risk factors. PMID- 23810326 TI - Endoscopic needle-knife therapy for ileal pouch sinus: a novel approach for the surgical adverse event (with video). AB - BACKGROUND: Pouch sinus is an adverse event in patients undergoing ileal pouch surgery. OBJECTIVE: To evaluate the efficacy of needle-knife therapy in managing pouch sinus and to assess factors associated with the healing of pouch sinus. DESIGN: An historical cohort study from a prospectively collected database. SETTING: A high-volume specialized pouch center. PATIENTS: From tertiary-care pouch center. INTERVENTIONS: Endoscopic needle-knife therapy. RESULTS: This cohort consisted of 65 patients. Men accounted for 76.9% (n = 50). The median interval from colectomy to the diagnosis of pouch sinus was 4.0 years (interquartile range [IQR]: 2.0-7.5). Pouch sinus was located at the anastomosis in 59 patients (90.8%), at the mid pouch suture line in 4 patients (6.2%), and at the tip of "J" in 2 patients (3.1%). The mean depth of the pouch sinus was 4.4 +/ 1.8 cm. Twenty patients (30.8%) had complex pouch sinuses. After a median of 2.0 needle-knife therapies (IQR: 1.5-3.5) during a follow-up period of 1.1 years (IQR: 0.4-2.8), 28 patients (43.1%) with pouch sinus experienced a complete response, 27 (41.5%) had a partial response, and 10 (15.4%) had persistent sinus. Fifty-three patients (81.5%) maintained a functional pouch at the last follow-up. Multivariate analysis showed that a longer duration from colectomy to diagnosis of pouch sinus (odds ratio: 0.85; 95% confidence interval: 0.73-0.99; P = .033) and complex sinuses (odds ratio: 0.17; 95% confidence interval: 0.04-0.70; P = .014) were inversely associated with the healing of pouch sinuses, whereas the increased sessions of needle-knife therapy (odds ratio: 1.36; 95% confidence interval: 1.01-1.81; P = .041) improved the healing of the pouch sinuses. LIMITATIONS: Single-center study with a relatively small number of patients. CONCLUSION: In experienced hands, endoscopic needle-knife therapy is an efficacious and safe procedure for pouch sinuses. A longer duration from colectomy to diagnosis of pouch sinus and complex pouch sinuses appeared to be associated with a higher risk for nonhealing of the sinus, suggesting that early diagnosis and intervention have an impact on outcomes. PMID- 23810327 TI - Standardized endoscopic submucosal tunnel dissection for management of early esophageal tumors (with video). PMID- 23810328 TI - Patient-controlled analgesia with inhaled methoxyflurane versus conventional endoscopist-provided sedation for colonoscopy: a randomized multicenter trial. AB - OBJECTIVE: Inhaled methoxyflurane (Penthrox, Medical Device International, Melbourne, Australia) has been used extensively in Australasia (Australia and New Zealand) to manage trauma-related pain. The aim is to evaluate the efficacy, safety, and outcome of Penthrox for colonoscopy. DESIGN: Prospective randomized study. SETTING: Three tertiary endoscopic centers. PATIENTS: Two hundred fifty one patients were randomized to receive either Penthrox (n = 125, 70 men, 51.4 +/ 1.1 years old) or intravenous midazolam and fentanyl (M&F; n = 126, 72 men, 54.9 +/- 1.1 years old) during colonoscopy. MAIN OUTCOME MEASUREMENT: Discomfort (visual analogue scale [VAS] pain score), anxiety (State-Trait Anxiety Inventory Form Y [STAI-Y] anxiety score), colonoscopy performance, adverse events, and recovery time. RESULTS: Precolonoscopy VAS pain and STAI-Y scores were comparable between the 2 groups. There were no differences between groups in (1) pain VAS or STAI Y-1 anxiety scores during or immediately after colonoscopy, (2) procedural success rate (Penthrox: 121/125 vs M&F: 124/126), (3) hypotension during colonoscopy (7/125 vs 8/126), (4) tachycardia (5/125 vs 3/126), (5) cecal arrival time (8 +/- 1 vs 8 +/- 1 minutes), or (6) polyp detection rate (30/125 vs 43/126). Additional intravenous sedation was required in 10 patients (8%) who received Penthrox. Patients receiving Penthrox alone had no desaturation (oxygen saturation [SaO(2)] < 90%) events (0/115 vs 5/126; P = .03), awoke quicker (3 +/- 0 vs 19 +/- 1 minutes; P < .001) and were ready for discharge earlier (37 +/- 1 vs 66 +/- 2 minutes; P < .001) than those receiving intravenous M&F. LIMITATIONS: Inhaled Penthrox is not yet available in the United States and Europe. CONCLUSIONS: Patient-controlled analgesia with inhaled Penthrox is feasible and as effective as conventional sedation for colonoscopy with shorter recovery time, is not associated with respiratory depression, and does not influence the procedural success and polyp detection. PMID- 23810329 TI - Endoscopic resection of hilar papillomatosis after Whipple procedure for ampullary adenoma. PMID- 23810331 TI - Preoperative plasma D-dimer levels predict survival in patients with operable non small cell lung cancer independently of venous thromboembolism. AB - BACKGROUND AND AIMS: D-dimer is a stable end product of fibrin degradation that is associated with advanced tumor stage and poor prognosis in lung cancer patients. Venous thromboembolism (VTE) is a frequent complication of cancer and is associated with a poor prognosis in cancer patients. The purpose of the study is to elucidate whether the increased mortality in non-small cell lung (NSCLC) patients with elevated D-dimer levels is independent of VTE. PATIENTS AND METHODS: A retrospective review was conducted of 232 patients with operable NSCLC from January 2007 to June 2008. All the patients underwent a pneumonectomy, lobectomy or wedge resection. We assessed the ability of preoperative plasma D dimer levels to predict 1-year mortality and overall survival among them, and a multivariable Cox proportional-hazard regression analysis was performed after controlling for the following potential confounding factors: age, gender, TNM stage, histology, tumor size, VTE and surgical interventions. RESULTS: The overall 1-year survival rate was 91.4% (95% confidence interval (CI), 82.7 94.8%), with a 76.5% survival (95% CI, 71.4-81.6%) in the high D-dimer group and a 93.9% survival (95% CI, 86.4-97.9%) in the normal D-dimer group. Comparing the high D-dimer group with the normal D-dimer group, the adjusted hazard ratio for 1 year mortality and overall survival was 3.19 (95% CI, 1.18-7.12) and 1.54 (95% CI, 1.11-2.78) respectively. CONCLUSION: Our study concluded that the preoperative plasma D-dimer level is an important prognostic biomarker in patients with operable NSCLC that is independent of VTE. PMID- 23810330 TI - Is intraoperative neuromonitoring associated with better functional outcome in patients undergoing open TME? Results of a case-control study. AB - AIMS: Intraoperative neuromonitoring (IONM) aims to control nerve-sparing total mesorectal excision (TME) for rectal cancer in order to improve patients' functional outcome. This study was designed to compare the urogenital and anorectal functional outcome of TME with and without IONM of innervation to the bladder and the internal anal sphincter. METHODS: A consecutive series of 150 patients with primary rectal cancer were analysed. Fifteen match pairs with open TME and combined urogenital and anorectal functional assessment at follow up were established identical regarding gender, tumour site, tumour stage, neoadjuvant radiotherapy and type of surgery. Urogenital and anorectal function was evaluated prospectively on the basis of self-administered standardized questionnaires, measurement of residual urine volume and longterm-catheterization rate. RESULTS: Newly developed urinary dysfunction after surgery was reported by 1 of 15 patients in the IONM group and by 6 of 15 in the control group (p = 0.031). Postoperative residual urine volume was significantly higher in the control group. At follow up impaired anorectal function was present in 1 of 15 patients undergoing TME with IONM and in 6 of 15 without IONM (p = 0.031). The IONM group showed a trend towards a lower rate of sexual dysfunction after surgery. CONCLUSIONS: In this study TME with IONM was associated with significant lower rates of urinary and anorectal dysfunction. Prospective randomized trials are mandatory to evaluate the definite role of IONM in rectal cancer surgery. PMID- 23810333 TI - Re: Taylor et al. Breast cancer surgery without suction drainage: The impact of adopting a 'no drains' policy on symptomatic seroma formation rates. Eur J surg oncol 2013;39(4):334-338. PMID- 23810332 TI - Quality assurance in head and neck surgical oncology: EORTC 24954 trial on larynx preservation. AB - BACKGROUND: The Head and Neck Cancer Group (HNCG) of the EORTC conducted a quality assurance program in the EORTC 24954 trial on larynx preservation. In this multicentre study, patients with resectable advanced squamous cell carcinoma of the larynx or hypopharynx were randomly assigned for treatment with sequential or alternating chemoradiation. The need for a quality assurance program is the evaluation and prevention of differences in treatments between centres in this multidisciplinary study. METHOD: The surgical subcommittee of the HNCG prepared a questionnaire, and clinical records of all patients were verified during audits of independent teams. Data relating institutional practices were collected during a face to face interview with members of the local team. RESULTS: 271 clinical records from the nine main contributing centres were reviewed. The main difference between centres was the time interval between first consultation and treatment initiation, with a mean of 45 days. On the pathology report the nodal involvement was described by level in 36% of the cases according to the American Academy of Otolaryngology-Head and Neck Surgery classification. Extranodal spread was not always described in neck dissection specimens. CONCLUSION: The EORTC 24954 trial on larynx preservation was the first prospective trial with a quality assurance program in head and neck surgical oncology. The analysis shows similarities in practices, but also points out some important differences between centres. Operation reports were fairly complete, but uniformity in pathology reports should be improved. PMID- 23810334 TI - Hyperthermic intraperitoneal chemotherapy during primary tumour resection limits extent of bowel resection compared to two-stage treatment. AB - AIM: To compare the clinical outcome of a one-stage, primary tumour resection and hyperthermic intraperitoneal chemotherapy (HIPEC) procedure, versus a two-stage procedure of tumour resection and secondary HIPEC in colorectal cancer (CRC) patients with synchronous peritoneal carcinomatosis. METHODS: A prospective database of all patients treated with HIPEC in the St. Antonius Hospital in the Netherlands between 2005 and 2012 was analysed. RESULTS: A total of 72 patients with synchronous peritoneal carcinomatosis (PC) from CRC were included. In 20 patients (27.8%) the primary tumour was resected simultaneously with HIPEC (early referral). In the other 52 patients (72.2%) the primary tumour was resected prior to the HIPEC procedure (late referral). During CRS + HIPEC following late referral, 22 (59.5%) of the 37 anastomoses of the earlier operation were resected, revealing malignancy in 12 (54.5%) on histopathological examination. In twenty (27.8%) patients a permanent colostomy was constructed after HIPEC. Ten of these patients had complete bowel continuity after earlier primary resection. The relaparotomy rate was higher in patients after a resection of a previous anastomosis (36.4%) compared to 12% in the rest of the patients (P = 0.02). CONCLUSIONS: Resection of the primary tumour simultaneously with HIPEC in patients with synchronous PC from CRC may prevent extended bowel resections and permanent colostomy. Our data support early referral of patients with PC from colorectal cancer. PMID- 23810335 TI - Measurement of foot placement and its variability with inertial sensors. AB - Gait parameters such as stride length, width, and period, as well as their respective variabilities, are widely used as indicators of mobility and walking function. Foot placement and its variability have thus been applied in areas such as aging, fall risk, spinal cord injury, diabetic neuropathy, and neurological conditions. But a drawback is that these measures are presently best obtained with specialized laboratory equipment such as motion capture systems and instrumented walkways, which may not be available in many clinics and certainly not during daily activities. One alternative is to fix inertial measurement units (IMUs) to the feet or body to gather motion data. However, few existing methods measure foot placement directly, due to drift associated with inertial data. We developed a method to measure stride-to-stride foot placement in unconstrained environments, and tested whether it can accurately quantify gait parameters over long walking distances. The method uses ground contact conditions to correct for drift, and state estimation algorithms to improve estimation of angular orientation. We tested the method with healthy adults walking over-ground, averaging 93 steps per trial, using a mobile motion capture system to provide reference data. We found IMU estimates of mean stride length and duration within 1% of motion capture, and standard deviations of length and width within 4% of motion capture. Step width cannot be directly estimated by IMUs, although lateral stride variability can. Inertial sensors measure walks over arbitrary distances, yielding estimates with good statistical confidence. Gait can thus be measured in a variety of environments, and even applied to long-term monitoring of everyday walking. PMID- 23810336 TI - Muscle fatigue during repetitive voluntary contractions: a comparison between children with cerebral palsy, typically developing children and young healthy adults. AB - AIM: To combine peak torque and EMG analyses to investigate the hypothesis that 1) children with cerebral palsy (CP) have lower muscle fatigability than typically developing children (TD) and whether 2) muscle fatigue correlates with muscle strength. METHODS: Seven CP children, eight TD children and ten young healthy adults (YHA) performed an all-out fatigue test of 35 maximal concentric knee extension and flexion contractions on an isokinetic dynamometer. Angular velocity was set at 60 degrees /s. Peak torque (PT) was determined per repetition and either normalized to bodyweight or maximum voluntary torque. Surface-EMG of quadriceps and hamstring muscles was measured to obtain changes in median frequency (EMG-mf) and smooth rectified EMG amplitude per contraction. RESULTS: Decline in PT differed between all groups for extensors and flexors, where YHA showed the largest decline and CP children the smallest decline over the course of the test. YHA showed a larger decline in EMG-mf of all quadriceps and hamstrings than TD and CP children, while TD children showed a larger decline in EMG-mf of m.rectus femoris and m.vastus lateralis than CP children. INTERPRETATION: Results confirm that children with CP show lower fatigability than TD children and that the lower fatigability coincides with lower maximal muscle strength. PMID- 23810337 TI - Effect of anticipation on knee kinematics during a stop-jump task. AB - Knee stability during a functional assessment of the stop-jump task is a key factor to determine if an athlete is adequately rehabilitated after knee ligamentous injury. This study aimed to investigate knee stability due to the effect of anticipation on landing maneuvers during planned and unplanned stop jump tasks. Knee kinematics of ten healthy male participants were collected using an optical motion analysis system during stop-jump tasks. Stop jumps were performed in four different landing positions either in planned movement or in an unplanned movement on a signal triggered as participants passed through a photocell gate. Kinematic data at the time of foot strike at landing in the stop jump considered for investigating the anticipation effect during the stop-jump tasks. Two-way multivariate analysis of variance (MANOVA) with repeated measures and stratified paired t-tests were conducted to compare the knee kinematics data between planned and unplanned tasks. Statistical significance was set at the p<0.05 level. External rotational angle showed a significant decrease in unplanned stop-jump tasks during forward (p<0.05) and right (p<0.05) jumps when compared to that of planned tasks. Flexion angle and abduction angle during forward, vertical and right jumps were significantly decreased in the unplanned tasks. Anticipation significantly influenced the landing maneuvers of stop-jump task. The results indicated that both planned and unplanned stop-jump tasks should be considered when monitoring the rehabilitation progress after a ligamentous injury. PMID- 23810338 TI - Ultrasound stimulated production of a fibrinolytic enzyme. AB - The present study is aimed at enhanced production of a fibrinolytic enzyme from Bacillus sphaericus MTCC 3672 under ultrasonic stimulation. Various process parameters viz; irradiation at different growth phases, ultrasonication power, irradiation duration, duty cycle and multiple irradiation were studied for enhancement of fibrinolytic enzyme productivity. The optimum conditions were found as follows, irradiation of ultrasonic waves to fermentation broth at 12 h of growth phase with 25 kHz frequency, 160 W ultrasound power, 20% duty cycle for 5 min. The productivity of fibrinolytic enzyme was increased 1.82-fold from 110 to 201 U/mL compared with the non sonicated control fermentation. Drop in glucose concentration from 0.41% to 0.12% w/v in ultrasonicated batch implies that, ultrasonication increases the cell permeability, improves substrate intake and progresses metabolism of microbial cell. Microscopic images before and after ultrasonic stimulation clearly signifies the impact of duty cycle on decreasing biomass concentration. However, environmental scanning electron micrograph does not show any cell lysis at optimum ultrasonic irradiation. Offshoots of our results will contribute to fulfill the demand of enhancement of microbial therapeutic enzyme productivity, through ultrasonication stimulation. PMID- 23810339 TI - Effectiveness of a Clinical Skills Workshop for drug-dosage calculation in a nursing program. AB - BACKGROUND: Mathematical and calculation skills are widely acknowledged as being key nursing competences if patients are to receive care that is both effective and safe. Indeed, weaknesses in mathematical competence may lead to the administration of miscalculated drug doses, which in turn may harm or endanger patients' lives. However, little attention has been given to identifying appropriate teaching and learning strategies that will effectively facilitate the development of these skills in nurses. One such approach may be simulation. OBJECTIVES: To evaluate the effectiveness of a Clinical Skills Workshop on drug administration that focused on improving the drug-dosage calculation skills of second-year nursing students, with a view to promoting safety in drugs administration. DESIGN: A descriptive pre-post test design. SETTINGS: Educational. Simulation center. PARTICIPANTS: The sample population included 77 nursing students from a Northern Italian University who attended a 30-hour Clinical Skills Workshop over a period of two weeks. METHODS: The workshop covered integrated teaching strategies and innovative drug-calculation methodologies which have been described to improve psychomotor skills and build cognitive abilities through a greater understanding of mathematics linked to clinical practice. RESULTS: Study results showed a significant improvement between the pre- and the post-test phases, after the intervention. Pre-test scores ranged between 0 and 25 out of a maximum of 30 points, with a mean score of 15.96 (SD 4.85), and a median score of 17. Post-test scores ranged between 15 and 30 out of 30, with a mean score of 25.2 (SD 3.63) and a median score of 26 (p<0.001). CONCLUSIONS: Our study shows that Clinical Skills Workshops may be tailored to include teaching techniques that encourage the development of drug dosage calculation skills, and that training strategies implemented during a Clinical skills Workshop can enhance students' comprehension of mathematical calculations. PMID- 23810340 TI - A core competency model for Chinese baccalaureate nursing graduates: a descriptive correlational study in Beijing. AB - BACKGROUND: A review of the literature showed that the core competencies needed by newly graduated Chinese nurses were not as of yet undocumented. OBJECTIVE: To develop a psychometrically sound instrument for identifying and measuring the core competencies needed by Chinese nursing baccalaureate graduates. DESIGN: Descriptive correlational and multicentre study. SETTING: Seven major tertiary teaching hospitals and three major medical universities in Beijing. PARTICIPANTS: 790 subjects, including patients, nursing faculty members, doctors and nurses. METHOD: A reliable and valid self-report instrument, consisting of 58 items, was developed using multiple methods. It was then distributed to 790 subjects to measure nursing competency in a broader Chinese context. The psychometric characteristics of reliability and validity were supported by descriptive and inferential analyses. RESULTS: The final instrument consists of six dimensions with 47 items. The content validity index was 0.90. The overall scale reliability was 0.97 with dimensions range from 0.87 to 0.94. Six domains of core competencies were identified: professionalism; direct care; support and communication; application of professional knowledge; personal traits; and critical thinking and innovation. CONCLUSION: The findings of this study provide valuable evidence for a psychometrically sound measurement tool, as well as for competency-based nursing curriculum reform. PMID- 23810341 TI - Reply: To PMID 23415805. PMID- 23810342 TI - Chronic diarrhea after autologous stem cell transplantation for peripheral T-cell lymphoma. PMID- 23810343 TI - Clarification of linaclotide clinical trial information in a recent review on constipation. PMID- 23810344 TI - A diagnosis that eats at you. PMID- 23810345 TI - Unusual colon biopsy. PMID- 23810346 TI - An unusual cause of abdominal pain. PMID- 23810347 TI - A ball inside the abdomen? PMID- 23810348 TI - Magnetic resonance colonography for the detection of colorectal neoplasia. PMID- 23810349 TI - Reply: To PMID 23261065. PMID- 23810351 TI - Signal intensity changes for the middle cerebral artery on 3-dimensional time-of flight magnetic resonance angiography indicate acute hemodynamic changes after carotid endarterectomy. AB - BACKGROUND: For 3-dimensional time-of-flight magnetic resonance angiography (3D TOF-MRA), the signal intensity (SI) loss depends on the flow velocity. In this study, we aimed to evaluate whether 3D-TOF-MRA could be used as an alternative to single-photon emission computed tomography (SPECT) for assessing the increase in the regional cerebral blood flow (rCBF) after carotid endarterectomy (CEA). To do this, we compared the SI of the middle cerebral artery (MCA) on magnetic resonance angiography (MRA) and the rCBF on SPECT. METHODS: We enrolled 30 patients with internal carotid artery stenosis. SPECT and MRA were performed before and 3-4 days after CEA. rCBF was assessed using SPECT, and the SI of the MCA was assessed using single-slab 3D-TOF-MRA. Regions of interest were placed in the bilateral middle M1 portions of the MCA on MRA, and their mean SI was measured. The increase ratio of the rCBF on SPECT and the increase ratio of the SI of the MCA on MRA were calculated using the formula: (post-CEA ipsilateral/post-CEA contralateral)/(pre-CEA ipsilateral/pre-CEA contralateral). RESULTS: A significant correlation was observed between the increase ratio of the rCBF on SPECT and the increase ratio of the SI of the MCA on MRA (r=.894, y=.4863+.5184x, P<.001). All values obtained by MRA were greater than or equal to the SPECT values, indicating that MRA tends to overestimate the post-CEA rCBF increase. CONCLUSION: Because MRA identified increased rCBF after CEA, we recommend that patients first be screened using MRA. PMID- 23810350 TI - The emergence of endovascular treatment-only centers for treatment of intracranial aneurysms in the United States. AB - BACKGROUND: Because of the availability of new technology, the spectrum of endovascular treatment for intracranial aneurysms has expanded widely. Some centers have started offering only endovascular treatment to patients with intracranial aneurysms (endovascular treatment-only centers [ETOCs]). Our objective was to identify the proportion and outcome of patients treated at ETOCs in the United States. METHODS: We determined the proportion of ETOCs in the United States using Nationwide Inpatient Survey data files from 2010. We compared short-term outcomes between ETOCs and endovascular and surgical treatment centers (ESTCs). The outcomes studied were none to minimal disability, moderate to severe disability, in-hospital mortality, postprocedure complications, length of stay, and hospital charges. RESULTS: Out of 85 hospitals performing endovascular treatment of unruptured aneurysms, 13 (15%) were categorized as ETOCs. Out of the 10,447 patients with unruptured aneurysms, 1245 (12%) were treated at ETOCs. ETOCs were more likely to be nonteaching hospitals (55% versus 45%, P=.02). The rates of in-hospital mortality (1.2% versus 1.8%) and none to minimal disability (88% versus 84%) were similar in patients treated at ETOCs and ESTC hospitals. The mean hospitalization charges were similar, but length of stay (4+/-7 days versus 6+/-10 days, P<.0001) was significantly shorter among patients treated at ETOCs. Only 2.7% patients required secondary neurosurgical procedures at the ETOCs compared with 5.8% in ESTCs (P=.09). CONCLUSION: The recent emergence of ETOCs and provision of treatment with comparable outcomes and shorter length of stay at these hospitals may change the pattern of intracranial aneurysm treatment in the United States. PMID- 23810352 TI - Integration of intensive care treatment and neurorehabilitation in patients with disorders of consciousness: a program description and case report. AB - Severe brain injuries frequently result in disorders of consciousness, requiring intensive care unit treatment. We present a rehabilitative system that integrates neurorehabilitation into intensive care treatment. The system will be described using the case report of a young man who was in a vegetative state after a severe traumatic brain injury that resulted in major medical problems and complications. Despite these challenges, interdisciplinary therapies can be applied throughout the rehabilitative process. The patient in our case report showed significant improvements and functional gains during the course of treatment. Additional data from other patients support the feasibility of this system and show that integrating neurorehabilitation into intensive care treatment is possible and can lead to improved outcomes in this patient population. We will discuss the advantages, special features, and limitations of the system. Additional studies are needed to further demonstrate the efficacy of this approach compared with standard treatment. PMID- 23810353 TI - Descriptive characteristics and rehabilitation outcomes in active duty military personnel and veterans with disorders of consciousness with combat- and noncombat related brain injury. AB - OBJECTIVE: To report the injury and demographic characteristics, medical course, and rehabilitation outcome for a consecutive series of veterans and active duty military personnel with combat- and noncombat-related brain injury and disorder of consciousness (DOC) at the time of rehabilitation admission. DESIGN: Retrospective study. SETTING: Rehabilitation center. PARTICIPANTS: From January 2004 to October 2009, persons (N=1654) were admitted to the Polytrauma Rehabilitation System of Care. This study focused on the N=122 persons admitted with a DOC. Participants with a DOC were primarily men (96%), on active duty (82%), >=12 years of education, and a median age of 25. Brain injury etiologies included mixed blast trauma (24%), penetrating (8%), other trauma (56%), and nontrauma (13%). Median initial Glasgow Coma Scale score was 3, and rehabilitation admission Glasgow Coma Scale score was 8. Individuals were admitted for acute neurorehabilitation approximately 51 days postinjury with a median rehabilitation length of stay of 132 days. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Recovery of consciousness and the FIM instrument. RESULTS: Most participants emerged to regain consciousness during neurorehabilitation (64%). Average gains +/- SD on the FIM cognitive and motor subscales were 19 +/- 25 and 7 +/- 8, respectively. Common medical complications included spasticity (70%), dysautonomia (34%), seizure occurrence (30%), and intracranial infection (22%). Differential outcomes were observed across etiologies, particularly for those with blast-related brain injury etiology. CONCLUSIONS: Despite complex comorbidities, optimistic outcomes were observed. Individuals with severe head injury because of blast-related etiologies have different outcomes and comorbidities observed. Health-services research with a focus on prevention of comorbidities is needed to inform optimal models of care, particularly for combat injured soldiers with blast-related injuries. PMID- 23810354 TI - Randomized trial investigating the efficacy of manual lymphatic drainage to improve early outcome after total knee arthroplasty. AB - OBJECTIVE: To investigate the efficacy of manual lymphatic drainage (MLD) in the early postoperative period after total knee arthroplasty (TKA) to reduce edema and pain and improve knee range of motion. DESIGN: Prospective randomized controlled trial. SETTING: Private hospital and functional rehabilitation clinic. PARTICIPANTS: Consecutive sample of patients (N=43; 53 knees) scheduled for TKA. INTERVENTION: MLD (vs no MLD) on days 2, 3, and 4 postoperatively. Both groups underwent conventional, concomitant physical therapy. MAIN OUTCOME MEASURES: Clinical assessment was undertaken pre- and postoperatively prior to and after the designated postoperative MLD sessions (days 2, 3, and 4) and at 6 weeks postsurgery. This included active knee flexion and extension range of motion, lower limb girths (ankle, midpatella, thigh, and calf), and knee pain using a numeric rating scale and the Knee Injury and Osteoarthritis Outcome Score. RESULTS: A significant group effect was observed for active knee flexion, with post hoc tests demonstrating a significantly greater active knee flexion in the MLD group when compared with the control (no MLD) group at the final measure prior to hospital discharge (day 4 postsurgery) and at 6 weeks postsurgery. There were no further group effects observed for the remaining patient-reported and functional outcomes. CONCLUSIONS: MLD in the early postoperative stages after TKA appears to improve active knee flexion up to 6 weeks postsurgery, in addition to conventional care. PMID- 23810356 TI - Differential effects of cardiovascular and resistance exercise on functional mobility in individuals with advanced cancer: a randomized trial. AB - OBJECTIVE: To compare the effects of resistance and cardiovascular exercise on functional mobility in individuals with advanced cancer. DESIGN: Prospective, 2 group pretest-posttest pilot study with randomization to either resistance or cardiovascular exercise mode. SETTING: Comprehensive community cancer center and a hospital-based fitness facility. PARTICIPANTS: Volunteer sample of individuals (N=66; 30 men; 36 women; mean age, 62y) with advanced cancer recruited through the cancer center, palliative care service, rehabilitation department, and a local hospice. INTERVENTIONS: Ten weeks of individualized resistance or cardiovascular exercise, prescribed and monitored by oncology-trained exercise personnel. MAIN OUTCOME MEASURES: Functional mobility was assessed using the Short Physical Performance Battery (SPPB); self-reported pain and fatigue were assessed secondarily using visual analog scales. Data were analyzed using a split plot 2*2 analysis of variance (alpha=.05). RESULTS: Fifty-two patients (78.8%) completed the study: 23 (67.7%) of 34 patients in the resistance arm and 29 (90.6%) of 32 patients in the cardiovascular arm. No participant withdrew because of study adverse events. Ten-week outcomes (n=52) included a significant increase in SPPB total score (P<.001), increase in gait speed (P=.001), and reduction in fatigue (P=.05). Although cardiovascular exercise participants had a modestly greater improvement in SPPB total score than resistance training participants (F1,49=4.21, P=.045), the difference was not confirmed in a subsequent intention to-treat analysis (N=66). CONCLUSIONS: Individuals with advanced cancer appear to benefit from exercise for improving functional mobility. Neither resistance nor cardiovascular exercise appeared to have a strong differential effect on outcome. PMID- 23810355 TI - Functional status impairment is associated with unplanned readmissions. AB - OBJECTIVE: To determine whether functional status on admission to a Comprehensive Integrated Inpatient Rehabilitation Program (CIIRP) is associated with unplanned readmission to acute care. DESIGN: Retrospective cohort study. SETTING: Academic hospital-based CIIRP. PARTICIPANTS: Consecutive patients (N=1515) admitted to a CIIRP between January 2009 and June 2012. INTERVENTIONS: Patients' functional status, the primary exposure variable, was assessed using tertiles of the total FIM score at CIIRP admission, with secondary analyses using the FIM motor and cognitive domains. A propensity score, consisting of 25 relevant clinical and demographic variables, was used to adjust for confounding in the analysis. MAIN OUTCOME MEASURES: Readmission to acute care was categorized as (1) readmission before planned discharge from the CIIRP, (2) readmission within 30 days of discharge from the CIIRP, and (3) total readmissions from both groups, with total readmissions being the a priori primary outcome. RESULTS: Among the 1515 patients, there were 347 total readmissions. Total readmissions were significantly associated with FIM scores, with adjusted odds ratios (AORs) and 95% confidence intervals (CIs) for the lowest and middle FIM tertiles versus the highest tertile (AOR=2.6; 95% CI, 1.9-3.7; P<.001 and AOR=1.7; 95% CI, 1.2-2.4; P=.002, respectively). There were similar findings for secondary analyses of readmission before planned discharge from the CIIRP (AOR=3.5; 95% CI, 2.2-5.8; P<.001 and AOR=2.1; 95% CI, 1.3-3.5l P=.002, respectively), and a weaker association for readmissions after discharge from the CIIRP (AOR=1.6; 95% CI, 1.0 2.4; P=.047 and AOR=1.3; 95% CI, 0.8-1.9; P=.28, respectively). The FIM motor domain score was more strongly associated with readmissions than the FIM cognitive score. CONCLUSIONS: Functional status on admission to the CIIRP is strongly associated with readmission to acute care, particularly for motor aspects of functional status and readmission before planned discharge from the CIIRP. Efforts to reduce hospital readmissions should consider patient functional status as an important and potentially modifiable risk factor. PMID- 23810357 TI - Extended-release quetiapine fumarate (quetiapine XR) monotherapy and quetiapine XR or lithium as add-on to antidepressants in patients with treatment-resistant major depressive disorder. AB - BACKGROUND: Patients with treatment-resistant major depressive disorder (MDD) remain a common clinical challenge. METHODS: This 6-week, randomised, open-label, rater-blinded trial evaluated once-daily extended-release quetiapine fumarate (quetiapine XR; 300 mg/day) as add-on to ongoing antidepressant and quetiapine XR monotherapy (300 mg/day) compared with add-on lithium (0.6-1.2 mmol/L) in patients with treatment-resistant MDD. Primary efficacy measure: change in Montgomery Asberg Depression Rating Scale (MADRS) total score from randomisation to week 6 with a pre-specified non-inferiority limit of 3 points on the MADRS. RESULTS: At week 6, both add-on quetiapine XR (n=231) and quetiapine XR monotherapy (n=228) were non-inferior to add-on lithium (n=229); least squares means (LSM) differences (97.5% CI) in MADRS total score changes were -2.32 (-4.6, -0.05) and -0.97 (-3.24, 1.31), respectively. LSM MADRS total score change was numerically greater at day 4 for both quetiapine XR groups (add-on and monotherapy; p<0.01) compared with add-on lithium. At week 6, the differences between groups for the secondary endpoints of MADRS response (>= 50% reduction in total score), MADRS remission (total score <= 10, add-on quetiapine XR only) and Clinical Global Impressions ('much'/'very much' improved) were numerically similar. Overall tolerability was consistent with the known profiles of both treatments. LIMITATIONS: Limitations included the open-label study design (although MADRS and laboratory measurements were performed by treatment-blinded raters) and relatively short study duration with no assessments in the continuation phase. CONCLUSIONS: Add-on quetiapine XR (300 mg/day) and quetiapine XR monotherapy (300 mg/day) are non-inferior to add-on lithium in the management of patients with treatment-resistant MDD. PMID- 23810358 TI - Depression and anxiety among migrants in Austria: a population based study of prevalence and utilization of health care services. AB - BACKGROUND: Although migrants form a large part of the Austrian population, information about mental health of migrants in Austria is scarce. Therefore, we compared the prevalence of dysphoric disorders (depression and anxiety) and the corresponding utilization of health care services of Eastern European, western and other migrants with the non-migrant population in Austria. METHODS: We performed a telephone survey on a random sample of the general population of Austria aged 15 years and older (n=3509) between October 2010 and September 2011. Depression and anxiety were measured with the Patient Health Questionnaire-4 and utilization of health care services in the last 4 weeks was inquired. RESULTS: 15.0% of our sample had a migration background. Female migrants from Eastern Europe, first and second generation, had a higher prevalence of dysphoric disorders (29.7% and 33.4% respectively) than Austrian women (15.2%) (p<0.001). The prevalence in the other migrant groups did not differ significantly from the Austrian population. There was no gender difference in dysphoric disorders in the Austrian population. After adjustment for age and chronic diseases, having a dysphoric disorder was associated with a higher utilization of health care services among migrant and Austrian women, but not among men. LIMITATIONS: Because of the explorative nature of the study multiple testing correction was not performed. The reason for health care utilization was not assessed. CONCLUSIONS: Mental health of female migrants from Eastern Europe should be studied in more detail; men could be an underserved group, both in migrants and Austrians. PMID- 23810361 TI - Treating anxious depression using repetitive transcranial magnetic stimulation. AB - BACKGROUND: A subset of patients given a clinical diagnosis of major depressive disorder (MDD) are described as having "anxious depression," a presentation that, in some studies, has been an indicator of poor response to pharmacotherapy. The aim of this study was to determine if anxious depression is associated with attenuated response to repetitive transcranial magnetic stimulation (rTMS), an FDA-approved treatment for MDD. METHODS: Participants were 32 adult outpatients with treatment resistant MDD who were referred for rTMS. The Hamilton Rating Scale for Depression (HAMD) was administered to assess treatment response, and anxious depression was defined as a score of seven or above on the anxiety/somatization factor of the HAMD. A quarter of the sample met the anxious depression criterion at pretreatment. RESULTS: Both depression (total score) and anxiety symptoms improved from pre- to post-treatment with moderate to large treatment effects. Patients with and without anxious depression demonstrated similar rates of improvement in depression. Patients with versus without anxious depression demonstrated larger improvements in anxiety. LIMITATIONS: The sample size was small, and assessments did not include structured diagnostic interview or independent measures of anxiety symptoms. CONCLUSIONS: For the sample as a whole, there were significant improvements in both depression and anxiety. Anxious depression was not associated with attenuated treatment response to rTMS. PMID- 23810360 TI - Psychostimulants for managing unipolar and bipolar treatment-resistant melancholic depression: a medium-term evaluation of cost benefits. AB - BACKGROUND: We earlier reported an open study of 50 unipolar and bipolar treatment resistant depressed patients indicating that psychostimulants may have differential superiority for the melancholic depressive sub-type. We designed an extension study to examine cost benefits of psychostimulants more closely for those only with melancholic depression. METHOD: The sample comprised patients clinically diagnosed with melancholic depression who had failed to respond to and/or experienced significant side-effects with at least two antidepressants. Data were collected for 61 unipolar and 51 bipolar II patients receiving a psyschostimulant for a mean interval of 69 weeks. Benefits and side-effects were assessed. RESULTS: Effectiveness ratings were similar across unipolar and bipolar sub-sets. Psychostimulants were judged as 'very' effective for 20% of patients and 'somewhat' effective for 50%. Forty percent judged the psychostimulant as being 'as effective' or as 'superior' to previously prescribed antidepressants, and worthy of being maintained. Significant side-effects were experienced by 40% of patients, requiring medication to be ceased in 12%. Twenty percent of the bipolar patients experienced a worsening of highs. LIMITATIONS: The study was uncontrolled and retrospective, no formal rater-completed or patient-completed interval measures of severity were completed, while diagnostic judgments about melancholic depression and bipolar disorder were clinically judged. CONCLUSIONS: This open study suggests that psychostimulants may be efficacious antidepressant options for managing unipolar and bipolar melancholia, often seemingly having very rapid onset and generally requiring only low doses, and arguing the need for controlled studies in melancholic patients. PMID- 23810362 TI - Meigs-like syndrome presenting as cardiac tamponade. PMID- 23810359 TI - Altered overnight modulation of spontaneous waking EEG reflects altered sleep homeostasis in major depressive disorder: a high-density EEG investigation. AB - BACKGROUND: Prior investigations have suggested sleep homeostasis is altered in major depressive disorder (MDD). Low frequency activity (LFA) in the electroencephalogram during waking has been correlated with sleep slow wave activity (SWA), suggesting that waking LFA reflects sleep homeostasis in healthy individuals. This study investigated whether the overnight change in waking LFA and its relationship with sleep SWA are altered in MDD. METHODS: 256-channel high density electroencephalography (hdEEG) recordings during waking (pre- and post sleep) and during sleep were collected in 14 unmedicated, unipolar MDD subjects (9 women) and age- and sex-matched healthy controls (HC). RESULTS: Waking LFA (3.25-6.25 Hz) declined significantly overnight in the HC group, but not in the group of MDD subjects. Overnight decline of waking LFA correlated with sleep SWA in frontal brain regions in HC, but a comparable relationship was not found in MDD. LIMITATIONS: This study is not able to definitely segregate overnight changes in the waking EEG that may occur due to homeostatic and/or circadian factors. CONCLUSIONS: MDD involves altered overnight modulation of waking low frequency EEG activity that may reflect altered sleep homeostasis in the disorder. Future research is required to determine the functional significance and clinical implications of these findings. PMID- 23810363 TI - Multiplex PCR-based detection of circulating tumor cells in lung cancer patients using CK19, PTHrP, and LUNX specific primers. AB - INTRODUCTION: The aim of this study was to develop a multiplex polymerase chain reaction (PCR)-based method for detection of circulating tumor cells in peripheral blood of lung cancer (LC) patients. PATIENTS AND METHODS: Peripheral blood was collected from 71 healthy donors and 125 LC patients at different pathological stages. Samples were analyzed using multiplex PCR, and specific primers for CK19, PTHrP, and LUNX mRNA. The sensitivity of our method was set at 10 LC cells (A549 cells) in 3 mL of peripheral blood of healthy donors using spiking experiments. RESULTS: The detection rates in LC patients for CK19, PTHrP, and LUNX were 45.6%, 64.8%, and 28%, and in healthy individuals were 7%, 7%, and 5.6%, respectively. Overall, our method produced 77.8% positive detections for at least 1 molecular marker. Twenty-eight (22.2%) were negative for expression of all markers, 39 (31.2%) were positive for expression of 1 marker, 42 (33.6%) were positive for expression of 2 markers, and 17 (13.6%) were positive for expression of all 3 markers. Detection of CK19 mRNA expression positively correlated with LC stage and distant metastases. PTHrP mRNA detection correlated positively with LC stage, presence of bone metastasis, and squamous cell carcinoma, and LUNX mRNA detection correlated with lymph node involvement. Combined detection of 2 or 3 markers was significantly correlated with metastatic disease, and negative detection of all 3 molecular markers was correlated with early stage nonmetastatic disease. CONCLUSION: Multiple PCR-based detection of CK19, PTHrP, and LUNX mRNA expression provides useful information for disease stage and dissemination in LC patients. PMID- 23810365 TI - What's the fuss over human frontal lobe evolution? AB - Evolutionary neuroscientists seek to understand what makes the human neocortex special aside from its extraordinary expansion. New analyses find that the frontal lobes of humans are not relatively enlarged given our species' brain size. But are statistical cut-offs masking biologically meaningful changes in the size of the human prefrontal cortex? PMID- 23810364 TI - A case series of lengthy progression-free survival with pemetrexed-containing therapy in metastatic non--small-cell lung cancer patients harboring ROS1 gene rearrangements. PMID- 23810366 TI - Evaluation of biochemical and redox parameters in rats fed with corn grown in soil amended with urban sewage sludge. AB - The increased production of urban sewage sludge requires alternative methods for final disposal. A very promising choice is the use of sewage sludge as a fertilizer in agriculture, since it is rich in organic matter, macro and micronutrients. However, urban sewage sludge may contain toxic substances that may cause deleterious effects on the biota, water and soil, and consequently on humans. There is a lack of studies evaluating how safe the consumption of food cultivated in soils containing urban sewage sludge is. Thus, the aim of this paper was to evaluate biochemical and redox parameters in rats fed with corn produced in a soil treated with urban sewage sludge for a long term. For these experiments, maize plants were grown in soil amended with sewage sludge (rates of 5, 10 and 20 t/ha) or not (control). Four different diets were prepared with the corn grains produced in the field experiment, and rats were fed with these diets for 1, 2, 4, 8 and 12 weeks. Biochemical parameters (glucose, total cholesterol and fractions, triglycerides, aspartate aminotransferase and alanine aminotransferase) as well the redox state biomarkers such as reduced glutathione (GSH), malondialdehyde (MDA), catalase, glutathione peroxidase and butyrylcholinesterase (BuChE) were assessed. Our results show no differences in the biomarkers over 1 or 2 weeks. However, at 4 weeks BuChE activity was inhibited in rats fed with corn grown in soil amended with sewage sludge (5, 10 and 20 t/ha), while MDA levels increased. Furthermore, prolonged exposure to corn cultivated in the highest amount per hectare of sewage sludge (8 and 12 weeks) was associated with an increase in MDA levels and a decrease in GSH levels, respectively. Our findings add new evidence of the risks of consuming food grown with urban sewage sludge. However, considering that the amount and type of toxic substances present in urban sewage sludge varies considerably among different sampling areas, further studies are needed to evaluate sludge samples collected from different sources and/or undergoing different types of treatment. PMID- 23810367 TI - Amendment in phosphorus levels moderate the chromium toxicity in Raphanus sativus L. as assayed by antioxidant enzymes activities. AB - Chromium (Z=24), a d-block element, is a potent carcinogen, whereas phosphorus is an essential and limiting nutrient for the plant growth and development. This study undertakes the role of phosphorus in moderating the chromium toxicity in Raphanus sativus L., as both of them compete with each other during the uptake process. Two-factor complete randomized experiment (5 chromium * 5 phosphorus concentrations) was conducted for twenty eight days in green house. The individuals of R. sativus were grown in pots supplied with all essential nutrients. The toxic effects of chromium and the moderation of toxicity due to phosphorus amendment were determined as accumulation of chromium, nitrogen, phosphorus in root tissues and their effects were also examined in the changes in biomass, chlorophyll and antioxidant enzyme levels. Cr and N accumulation were almost doubled at the highest concentration of Cr supply, without any P amendment, whereas at the highest P concentration (125 mM), the accumulation was reduced to almost half. A significant reduction in toxic effects of Cr was determined as there was three-fold increase in total chlorophyll and biomass at the highest P amendment. Antioxidant enzymes like superoxide dismutase, catalase, peroxidase and lipid peroxidation were analyzed at various levels of Cr each amended with five levels of P. It was observed that at highest level of P amendment, the reduction percentage in toxicity was 33, 44, 39 and 44, correspondingly. Conclusively, the phosphorus amendment moderates the toxicity caused by the supplied chromium in R. sativus. This finding can be utilized to develop a novel technology for the amelioration of chromium stressed fields. PMID- 23810368 TI - Ecological risk assessment of impacted estuarine areas: integrating histological and biochemical endpoints in wild Senegalese sole. AB - The analysis of multiple biomarker responses is nowadays recognized as a valuable tool to circumvent potential confounding factors affecting biomonitoring studies and allows a better understanding of the mechanisms underlying exposure to natural mixtures of toxicants. For the purpose of an environmental risk assessment (ERA) in an impacted estuary in SW Europe (the Sado, Portugal), juvenile Solea senegalensis from commercial fishing areas were surveyed for histopathological liver alterations and biochemical biomarkers. Although the findings revealed moderate differences in the patterns of histopathological traits between urban/industrial- and agricultural-influenced areas within the same estuary, no significant distinction was found between the cumulative alterations in animals from the two sites. The overall level of histopathological injury was low and severe traits like neoplasms or pre-neoplastic foci were absent. While metallothionein induction and lipid peroxidation could relate to histopathological condition indices, the activity of anti-oxidant enzymes appeared to be impaired in animals collected off the estuary's heavy-industry belt (the most contaminated site), which may partially explain some degree of hepatic integrity loss. Overall, the results are consistent with low-moderate contamination of the estuary and indicate that oxidative stress is the most important factor accounting for differences between sites. The study highlights the need of integrating multiple biomarkers when multiple environmental stressors are involved and the advantages of surveying toxicity effects in field-collected, foraging, organisms. PMID- 23810369 TI - Dual phenotypic transmission in Brugada syndrome. AB - BACKGROUND: Brugada syndrome is a genetic heart disease with autosomal dominant inheritance. Family screening commonly detects one parent responsible for transmission of the disease. AIMS: To describe atypical transmission of Brugada syndrome. METHODS: Between 2001 and 2007, systematic screening, including an electrocardiogram, ajmaline challenge and DNA sequencing of the SCN5A gene, of the first-degree relatives of 62 probands with Brugada syndrome was performed (Programme Hospitalier de Recherche Clinique). RESULTS: In two families, both parents transmitted Brugada syndrome to their offspring. In the first family, the proband presented Brugada electrocardiogram features with ajmaline challenge and carried a new SCN5A mutation (p.V1281F). The mutation was also identified in the mother, who had a type 1 aspect on inferior leads with ajmaline. The proband's father presented a typical Brugada electrocardiogram pattern on lead V2 with ajmaline and no SCN5A gene mutation. In the second family, the proband was a boy aged 2.5 years who had been resuscitated from sudden cardiac death. Ajmaline challenge revealed a typical Brugada electrocardiogram pattern in both parents but with no mutation in the genes studied. CONCLUSION: Family studies should always be exhaustive and discovery of one parent with Brugada syndrome does not eliminate the need for screening of the other parent. PMID- 23810370 TI - Intraoperative relationship of the spinal accessory nerve to the internal jugular vein: variation from cadaver studies. AB - PURPOSE: Conflicting locations of the spinal accessory nerve (SAN) with respect to the internal jugular vein (IJV) are reported in the literature and anatomy texts. The objective of this study is to analyze this anatomic relationship specifically at the level of the posterior belly of the digastric muscle where it is encountered most often during surgery. MATERIAL AND METHODS: This study is a case series with planned chart review of all operative reports for neck dissections/explorations performed between June 2002 to June 2008 at an academic tertiary care referral center. Inclusion criteria required intraoperative identification of the SAN at the level of the posterior belly of the digastric muscle. Patients undergoing revision neck dissection were excluded. Data is presented using descriptive statistics. RESULTS: One hundred ninety-seven patients were identified; 175 met inclusion criteria. Thirty-two patients received bilateral neck dissections/explorations, resulting in a total of 207 SANs for analysis. The most common location of the SAN was lateral to the IJV (198; 95%). In 6 (2.8%) cases the SAN was identified medial to the IJV and 2 nerves pierced the IJV. A new variant of the SAN splitting around the SAN was identified. CONCLUSION: The majority of SANs course lateral to the IJV at the level of the posterior belly of the digastrics muscle (95%). This intraoperative finding differs from cadaveric studies. Discrepancies may reflect variation in the level at which the nerve was identified, as well as tissue changes related to cadaver versus in vivo studies. PMID- 23810371 TI - Quantitative single cell and single molecule proteomics for clinical studies. AB - A central aspect of cellular systems biology is the study of cell-to-cell variability driven by network control of molecular noise. Proteins are produced in stochastic bursts and, although time averaging smoothes their accumulated levels, variation in their copy number is substantial in members of environmental sensing and signalling networks. We have developed a label-free, microfluidic antibody capture chip platform called the MAC chip, to quantify precisely the copy numbers of many proteins from a single cell in a multiplexed single assay format. We intend to investigate protein noise in circulating tumour cells (CTCs) isolated from biopsies of cancer patients through the identification of biomolecular signatures, such as p53 tumour suppressor protein, which correlate with biological properties and clinical outcomes during treatment. PMID- 23810372 TI - Systems and synthetic biology underpinning biotechnology. PMID- 23810373 TI - Combined exposure to tobacco smoke and ethanol during adolescence leads to short- and long-term modulation of anxiety-like behavior. AB - BACKGROUND: Tobacco smoking is associated with alcohol drinking and consumption of both drugs typically begins during adolescence. Since anxiety is considered a relevant factor for both smoking and drinking due to its motivating force for a continued consumption, anxiety alterations shared by these two drugs could explain their co-use and co-abuse. METHODS: Here, we investigated the short- and long-term effects of adolescent tobacco smoke and/or ethanol exposure on anxiety levels. From postnatal day 30-45, Swiss mice were exposed to tobacco smoke (SMK- whole body exposure, 8 h/day) and/or ethanol (ETOH--25% solution, 2g/kg i.p. injected every other day) as follows: (1) SMK+ETOH exposure; (2) SMK exposure; (3) ETOH exposure; (4) Control. Anxiety levels were assessed with the elevated plus maze and open field tests. RESULTS: By the end of exposure, SMK female mice presented an anxiolytic response in the elevated plus maze and this response was intensified by co-exposure to ethanol. A short-term deprivation from SMK elicited an anxiogenic state in females in this maze. Although neither smoke nor ethanol effects persisted one month post-exposure, SMK+ETOH male and female mice exhibited an anxiogenic response in the open field. CONCLUSION: Adolescent female mice are more susceptible to the anxiolytic effects of SMK. The stronger effect in SMK+ETOH group suggests that, in females, the combined exposure leads to lower anxiety levels. Anxiety levels do not seem to be relevant during a short-term SMK+ETOH deprivation, however, increased anxiety during long-term smoking and drinking deprivation demonstrate late-emergent effects both in males and females. PMID- 23810374 TI - Report on the first WHO integrated meeting on development and clinical trials of influenza vaccines that induce broadly protective and long-lasting immune responses: Hong Kong SAR, China, 24-26 January 2013. AB - On January 24-26, 2013, the World Health Organization convened the first integrated meeting on "The development and clinical trials of vaccines that induce broadly protective and long-lasting immune responses" to review the current status of development and clinical evaluation of novel influenza vaccines as well as strategies to produce and deliver vaccines in novel ways. Special attention was given to the development of possible universal influenza vaccines. Other topics that were addressed included an update on clinical trials of pandemic and seasonal influenza vaccines in high-risk groups and vaccine safety, as well as regulatory issues. PMID- 23810375 TI - Anti-HBs evaluation and booster dose in vaccinated healthcare students. PMID- 23810376 TI - Membrane proteins of Mycoplasma bovis and their role in pathogenesis. AB - Mycoplasma membrane proteins influence cell shape, cell division, motility and adhesion to host cells, and are thought to be integrally involved in the pathogenesis of mycoplasmoses. Many of the membrane proteins predicted from mycoplasma genome sequences remain hypothetical, as their presence in cellular protein preparations is yet to be established experimentally. Recent genome sequences of several strains of Mycoplasma bovis have provided further insight into the potential role of the membrane proteins of this pathogen in colonisation and infection. This review highlights recent advances in knowledge about the influence of M. bovis membrane proteins on the pathogenesis of infection with this species and identifies future research directions for enhancing our understanding of the role of these proteins. PMID- 23810377 TI - Treatment rationale and study design for a randomized, double-blind, placebo controlled phase II study evaluating onartuzumab (MetMAb) in combination with bevacizumab plus mFOLFOX-6 in patients with previously untreated metastatic colorectal cancer. AB - BACKGROUND: Dysregulation of the hepatocyte growth factor (HGF)/MET pathway is associated with poor prognosis, more aggressive biological characteristics of the tumor, and shortened survival in patients with metastatic colorectal cancer (mCRC). Onartuzumab (MetMAb) is a recombinant humanized monovalent monoclonal antibody directed against MET. We present the treatment rationale and protocol for an ongoing randomized multicenter placebo-controlled phase II study designed to evaluate the efficacy and safety of MetMAb combined with bevacizumab and mFOLFOX-6 (5-fluoruracil, leucovorin, and oxaliplatin). PATIENTS AND METHODS: Eligible patients with previously untreated mCRC are randomized 1:1 to either mFOLFOX-6 combined with bevacizumab and placebo followed by 5 fluorouracil/leucovorin plus bevacizumab and placebo or mFOLFOX6, bevacizumab plus MetMAb followed by 5 FU/LV, bevacizumab, and MetMAb. The primary end point of this study is progression-free survival (PFS) in the intent-to-treat (ITT) population. Secondary end points include overall survival (OS), objective response rate, and safety. Subanalyses will be performed to evaluate the effect of MET receptor expression on study primary and secondary end points. Correlative studies will be performed on tissue- and blood-derived biomarkers related to both HGF/MET signaling and other associated pathway markers. PMID- 23810378 TI - PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy. AB - Short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Rieger anomaly, and teething delay (SHORT) syndrome is a developmental disorder with an unknown genetic cause and hallmarks that include insulin resistance and lack of subcutaneous fat. We ascertained two unrelated individuals with SHORT syndrome, hypothesized that the observed phenotype was most likely due to de novo mutations in the same gene, and performed whole-exome sequencing in the two probands and their unaffected parents. We then confirmed our initial observations in four other subjects with SHORT syndrome from three families, as well as 14 unrelated subjects presenting with syndromic insulin resistance and/or generalized lipoatrophy associated with dysmorphic features and growth retardation. Overall, we identified in nine affected individuals from eight families de novo or inherited PIK3R1 mutations, including a mutational hotspot (c.1945C>T [p.Arg649Trp]) present in four families. PIK3R1 encodes the p85alpha, p55alpha, and p50alpha regulatory subunits of class IA phosphatidylinositol 3 kinases (PI3Ks), which are known to play a key role in insulin signaling. Functional data from fibroblasts derived from individuals with PIK3R1 mutations showed severe insulin resistance for both proximal and distal PI3K-dependent signaling. Our findings extend the genetic causes of severe insulin-resistance syndromes and provide important information with respect to the function of PIK3R1 in normal development and its role in human diseases, including growth delay, Rieger anomaly and other ocular affections, insulin resistance, diabetes, paucity of fat, and ovarian cysts. PMID- 23810379 TI - SHORT syndrome with partial lipodystrophy due to impaired phosphatidylinositol 3 kinase signaling. AB - The phosphatidylinositol 3 kinase (PI3K) pathway regulates fundamental cellular processes such as metabolism, proliferation, and survival. A central component in this pathway is the p85alpha regulatory subunit, encoded by PIK3R1. Using whole exome sequencing, we identified a heterozygous PIK3R1 mutation (c.1945C>T [p.Arg649Trp]) in two unrelated families affected by partial lipodystrophy, low body mass index, short stature, progeroid face, and Rieger anomaly (SHORT syndrome). This mutation led to impaired interaction between p85alpha and IRS-1 and reduced AKT-mediated insulin signaling in fibroblasts from affected subjects and in reconstituted Pik3r1-knockout preadipocytes. Normal PI3K activity is critical for adipose differentiation and insulin signaling; the mutated PIK3R1 therefore provides a unique link among lipodystrophy, growth, and insulin signaling. PMID- 23810380 TI - miR-196a ameliorates phenotypes of Huntington disease in cell, transgenic mouse, and induced pluripotent stem cell models. AB - Huntington disease (HD) is a dominantly inherited neurodegenerative disorder characterized by dysregulation of various genes. Recently, microRNAs (miRNAs) have been reported to be involved in this dysregulation, suggesting that manipulation of appropriate miRNA regulation may have a therapeutic benefit. Here, we report the beneficial effects of miR-196a (miR196a) on HD in cell, transgenic mouse models, and human induced pluripotent stem cells derived from one individual with HD (HD-iPSCs). In the in vitro results, a reduction of mutant HTT and pathological aggregates, accompanying the overexpression of miR-196a, was observed in HD models of human embryonic kidney cells and mouse neuroblastoma cells. In the in vivo model, HD transgenic mice overexpressing miR-196a revealed the suppression of mutant HTT in the brain and also showed improvements in neuropathological progression, such as decreases of nuclear, intranuclear, and neuropil aggregates and late-stage behavioral phenotypes. Most importantly, miR 196a also decreased HTT expression and pathological aggregates when HD-iPSCs were differentiated into the neuronal stage. Mechanisms of miR-196a in HD might be through the alteration of ubiquitin-proteasome systems, gliosis, cAMP response element-binding protein pathway, and several neuronal regulatory pathways in vivo. Taken together, these results show that manipulating miR-196a provides beneficial effects in HD, suggesting the potential therapeutical role of miR-196a in HD. PMID- 23810381 TI - TM4SF20 ancestral deletion and susceptibility to a pediatric disorder of early language delay and cerebral white matter hyperintensities. AB - White matter hyperintensities (WMHs) of the brain are important markers of aging and small-vessel disease. WMHs are rare in healthy children and, when observed, often occur with comorbid neuroinflammatory or vasculitic processes. Here, we describe a complex 4 kb deletion in 2q36.3 that segregates with early childhood communication disorders and WMH in 15 unrelated families predominantly from Southeast Asia. The premature brain aging phenotype with punctate and multifocal WMHs was observed in ~70% of young carrier parents who underwent brain MRI. The complex deletion removes the penultimate exon 3 of TM4SF20, a gene encoding a transmembrane protein of unknown function. Minigene analysis showed that the resultant net loss of an exon introduces a premature stop codon, which, in turn, leads to the generation of a stable protein that fails to target to the plasma membrane and accumulates in the cytoplasm. Finally, we report this deletion to be enriched in individuals of Vietnamese Kinh descent, with an allele frequency of about 1%, embedded in an ancestral haplotype. Our data point to a constellation of early language delay and WMH phenotypes, driven by a likely toxic mechanism of TM4SF20 truncation, and highlight the importance of understanding and managing population-specific low-frequency pathogenic alleles. PMID- 23810383 TI - Suicide attempts by deliberate self-poisoning in children and adolescents. AB - AIM: The objective of the study was to examine the toxicological characteristics of suicide attempts by deliberate self-poisoning in children and adolescents. METHOD: From the Toxicological Information Centre's database, the inquiries due to the suicide attempts in children (9-13 years old) and adolescents (14-18 years old) were evaluated. RESULTS AND CONCLUSIONS: From 10,492 calls concerning suicide attempts, 2393 concerned children and adolescents. Most suicide attempts were attempted in spring (31.3%). Among the toxic agents, drugs were used in 97.8% cases. The most frequent ingestions appeared using drugs affecting the nervous system and anti-inflammatory non-steroids. The dose was evaluated as toxic in 73.4%, severely toxic in 3.0% and unknown in 11.2% cases. Only one in 10 children used a non-toxic dose. Girls, more frequently than boys (13.2% vs. 8.9%), used non-toxic doses. The symptoms of moderate and severe intoxications were present in 10.5% of the cases. Poison centre consultation was accessed within the first hour after the ingestion in one-fifth of the patients. In both age groups, the severity of the intoxication was greater among elder males who reached the medical facilities later than 4 h after the poisoning. The combinations of three or more drugs affecting central nervous system were present in the most severe cases. PMID- 23810382 TI - Mutations in PIK3R1 cause SHORT syndrome. AB - SHORT syndrome is a rare, multisystem disease characterized by short stature, anterior-chamber eye anomalies, characteristic facial features, lipodystrophy, hernias, hyperextensibility, and delayed dentition. As part of the FORGE (Finding of Rare Disease Genes) Canada Consortium, we studied individuals with clinical features of SHORT syndrome to identify the genetic etiology of this rare disease. Whole-exome sequencing in a family trio of an affected child and unaffected parents identified a de novo frameshift insertion, c.1906_1907insC (p.Asn636Thrfs*18), in exon 14 of PIK3R1. Heterozygous mutations in exon 14 of PIK3R1 were subsequently identified by Sanger sequencing in three additional affected individuals and two affected family members. One of these mutations, c.1945C>T (p.Arg649Trp), was confirmed to be a de novo mutation in one affected individual and was also identified and shown to segregate with the phenotype in an unrelated family. The other mutation, a de novo truncating mutation (c.1971T>G [p.Tyr657*]), was identified in another affected individual. PIK3R1 is involved in the phosphatidylinositol 3 kinase (PI3K) signaling cascade and, as such, plays an important role in cell growth, proliferation, and survival. Functional studies on lymphoblastoid cells with the PIK3R1 c.1906_1907insC mutation showed decreased phosphorylation of the downstream S6 target of the PI3K-AKT-mTOR pathway. Our findings show that PIK3R1 mutations are the major cause of SHORT syndrome and suggest that the molecular mechanism of disease might involve downregulation of the PI3K-AKT-mTOR pathway. PMID- 23810384 TI - Identification of primary polydipsia in a severe and persistent mental illness outpatient population: a prospective observational study. AB - Studies to date have only investigated primary polydipsia in hospitalized psychiatric patient populations, where rates range from 3% to 25%. The objective of the present study was to determine the occurrence of primary polydipsia in a psychiatric outpatient population, and to determine the perceptions of outpatients with self-induced water intoxication regarding reasons for drinking excess fluids, health risks, and insight into their behavior. All 115 psychiatric outpatients from a Community Outreach Program in Kingston, Ontario, were invited to participate in this study. Of these, 89 (77.4%) were enrolled. Data collection included chart reviews, structured interviews, weight measurements, and urine collection. The incidence of primary polydipsia was found to be 15.7%. One-half of the polydipsic people presenting with medical complications suggestive for water intoxication had cigarette smoking as a strong correlate. There were interesting answers to the self-induced water intoxication questionnaire. These showed a lack of knowledge related to the normal quantity of fluids necessary daily and about healthy behaviors. Excessive drinking occurs in psychiatric patient populations outside of institutional/hospital settings. Patients have limited awareness of the severity and possible complications from their problem. Given the prevalence of polydipsia, more effort should be put into identifying and treating this problem. PMID- 23810385 TI - Design of an implantable seismic sensor placed on the ossicular chain. AB - This paper presents a design guideline for matching a fully implantable middle ear microphone with the physiology of human hearing. The guideline defines the first natural frequency of a seismic sensor placed at the tip of the manubrium mallei with respect to the frequency-dependence hearing of the human ear as well as the deflection of the ossicular chain. A transducer designed in compliance with the guideline presented reduces the range of the output signal while preserving all information obtained by the ossicular chain. On top of a output signal compression, static deflections, which can mask the tiny motions of the ossicles, are reduced. For guideline verification, a microelectromechanical system (MEMS) based on silicon on insulator technology was produced and tested. This prototype is capable of resolving 0.4 pm/Hz with a custom made read-out circuit. For a bandwidth of 0.1 kHz, this deflection is comparable with the lower threshold of speech (~ 40 phon). PMID- 23810386 TI - Update on the diagnosis, pathogenesis, and treatment strategies for central neurocytoma. AB - Central neurocytomas are rare benign tumors of the central nervous system that are typically located in the lateral ventricles. Since they were first reported in the early 1980s, many advancements have been made in terms of their diagnosis and treatment. Despite the progress made, the origin of these rare tumors and effective newer treatment strategies remain elusive. Central neurocytomas represent 0.1-0.5% of all primary brain tumors. Since they are typically intraventricular, these tumors tend to present clinically with hydrocephalus. CT scanning and MRI are useful in localizing these tumors; however, due to their numerous ambiguous features, the ultimate diagnosis relies on immunohistochemistry and electron microscopy studies of sampled tissue. Currently, surgical removal with a gross-total resection of these tumors is the treatment of choice. Various radiotherapy techniques, including both conventional radiotherapy and stereotactic radiosurgery, have been shown to be useful in cases of residual tumor after sub-total resection and tumor recurrence. The benign nature of these tumors tends to offer a favorable outcome for most patients; however, recurrence rates are relatively high and tumors with high-grade features or extraventricular location tend to have a less favorable prognosis. We present a comprehensive review of these rare tumors, including their epidemiology, clinical presentation, radiological presentation, histopathological findings, and options for intervention including surgery, radiation therapy, stereotactic radiosurgery, and chemotherapy. PMID- 23810387 TI - Rankin scale as a potential measure of global disability in early Parkinson's disease. AB - We conducted an exploratory analysis of the utility of the modified Rankin Scale (mRS) as a global measure of disability in early Parkinson's diesase (PD) using the baseline data from a large cohort of PD patients enrolled in a longitudinal study of creatine. The mRS is scored 0-6 with lower scores reflecting less disability. For the analysis the mRS score was dichotomized at <2 versus >=2. We explored the association of the mRS with multiple measures of PD-related impairments, including the Unified Parkinson Disease Rating Scale (UPDRS); cognitive function characterized by the Symbol Digit Modalities--verbal, and Scales for Outcomes in Parkinson's disease--cognition (SCOPA-COG); quality of life (Parkinson's disease questionnaire [PDQ-39]) and EuroQOL; Beck Depression Inventory II (BDI); and Total Functional Capacity (TFC). We also investigated the interaction between variables. One thousand seven hundred forty-one patients were included in the analysis of which 374 had a mRS score of 2 or above. In the univariate model, all interested measures except SCOPA-COG (p=0.23) had significant association with mRS (p<0.001) after controlling for confounders. In the multivariate model, UPDRS Part II and III (activities of daily living and motor), BDI, TFC and PDQ-39 were significant (p<0.05). The mRS has a significant association with the wide spectrum of measures of impairment and quality of life in early PD and shows good potential to be a global measure of disability in early PD. The sensitivity of the mRS to change and performance of the scale in more advanced PD will have to be established longitudinally. PMID- 23810388 TI - The risks of computed tomography go beyond radiation. PMID- 23810389 TI - Himalayan Osborn waves. PMID- 23810390 TI - Trends in postacute care and staffing in US nursing homes, 2001-2010. AB - OBJECTIVE: The objective of this study was to document the growth of postacute care and contemporaneous staffing trends in US nursing homes over the decade 2001 to 2010. DESIGN: We integrated data from all US nursing homes longitudinally to track annual changes in the levels of postacute care intensity, therapy staffing and direct-care staffing separately for freestanding and hospital-based facilities. SETTING: All Medicare/Medicaid-certified nursing homes from 2001 to 2010 based on the Online Survey Certification and Reporting System database merged with facility-level case mix measures aggregated from resident-level information from the Minimum Data Set and Medicare Part A claims. MEASUREMENTS: We created a number of aggregate case mix measures to approximate the intensity of postacute care per facility per year, including the proportion of SNF-covered person days, number of admissions per bed, and average RUG-based case mix index. We also created measures of average hours per resident day for physical and occupational therapists, PT/OT assistants, PT/OT aides, and direct-care nursing staff. RESULTS: In freestanding nursing homes, all postacute care intensity measures increased considerably each year throughout the study period. In contrast, in hospital-based facilities, all but one of these measures decreased. Similarly, therapy staffing has risen substantially in freestanding homes but declined in hospital-based facilities. Postacute care case mix acuity appeared to correlate reasonably well with therapy staffing levels in both types of facilities. CONCLUSION: There has been a marked and steady shift toward postacute care in the nursing home industry in the past decade, primarily in freestanding facilities, accompanied by increased therapy staffing. PMID- 23810391 TI - Efficient myogenic differentiation of human adipose-derived stem cells by the transduction of engineered MyoD protein. AB - Human adipose-derived stem cells (hASCs) have great potential as cell sources for the treatment of muscle disorders. To provide a safe method for the myogenic differentiation of hASCs, we engineered the MyoD protein, a key transcription factor for myogenesis. The engineered MyoD (MyoD-IT) was designed to contain the TAT protein transduction domain for cell penetration and the membrane-disrupting INF7 peptide, which is an improved version of the HA2 peptide derived from influenza. MyoD-IT showed greatly improved nuclear targeting ability through an efficient endosomal escape induced by the pH-sensitive membrane disruption of the INF7 peptide. By applying MyoD-IT to a culture, hASCs were efficiently differentiated into long spindle-shaped myogenic cells expressing myosin heavy chains. Moreover, these cells differentiated by an application of MyoD-IT fused to myotubes with high efficiency through co-culturing with mouse C2C12 myoblasts. Because internalized proteins can be degraded in cells without altering the genome, the myogenic differentiation of hASCs using MyoD-IT would be a safe and clinically applicable method. PMID- 23810392 TI - Negative regulation of RIG-I-mediated antiviral signaling by TRK-fused gene (TFG) protein. AB - RIG-I (retinoic acid inducible gene I)-mediated antiviral signaling serves as the first line of defense against viral infection. Upon detection of viral RNA, RIG-I undergoes TRIM25 (tripartite motif protein 25)-mediated K63-linked ubiquitination, leading to type I interferon (IFN) production. In this study, we demonstrate that TRK-fused gene (TFG) protein, previously identified as a TRIM25 interacting protein, binds TRIM25 upon virus infection and negatively regulates RIG-I-mediated type-I IFN signaling. RIG-I-mediated IFN production and nuclear factor (NF)-kappaB signaling pathways were upregulated by the suppression of TFG expression. Furthermore, vesicular stomatitis virus (VSV) replication was significantly inhibited by small inhibitory hairpin RNA (shRNA)-mediated knockdown of TFG, supporting the suppressive role of TFG in RIG-I-mediated antiviral signaling. Interestingly, suppression of TFG expression increased not only RIG-I-mediated signaling but also MAVS (mitochondrial antiviral signaling protein)-induced signaling, suggesting that TFG plays a pivotal role in negative regulation of RNA-sensing, RIG-I-like receptor (RLR) family signaling pathways. PMID- 23810393 TI - Impaired lipid accumulation in the liver of Tsc2-heterozygous mice during liver regeneration. AB - Tuberin is a negative regulator of mTOR pathway. To investigate the function of tuberin during liver regeneration, we performed 70% hepatectomy on wild-type and Tsc2+/- mice. We found the tuberin phosphorylation correlated with mTOR activation during early liver regeneration in wild-type mice. However, liver regeneration in the Tsc2+/- mice was not enhanced. Instead, the Tsc2+/- livers failed to accumulate lipid bodies, and this was accompanied by increased mortality. These findings suggest that tuberin plays a critical role in liver energy balance by regulating hepatocellular lipid accumulation during early liver regeneration. These effects may influence the role of mTORC1 on cell growth and proliferation. PMID- 23810394 TI - Downregulation of BTG3 in non-small cell lung cancer. AB - BTG3 is identified as a tumor suppressor gene in some malignancies. Btg3 deficient mice display a higher incidence of lung cancer. These results suggest that BTG3 plays an important role in lung tumorigenesis, although the underlying mechanisms are unknown. The BTG3 expression was detected using immunohistochemical staining and our results showed that the expression of BTG3 was reduced in lung cancer compared to benign lung tissues. We identified two BTG3 isoforms present in lung cancer: Full-length BTG3 and BTG3b lacking the 44 amino acids. BTG3 was predominantly expressed in benign lung tissues, whereas its expression was generally undetectable in lung cancer and cancer cell lines. Functional analysis revealed that BTG3 but not BTG3b inhibited lung cancer growth. Our results disclosed an important role of BTG3 in lung tumorigenesis. PMID- 23810395 TI - Do bone loss and reconstruction procedures differ at revision of cemented unicompartmental knee prostheses according to the use of metal-back or all polyethylene tibial component? AB - INTRODUCTION: Results of unicompartmental knee arthroplasty (UKA) revision are known but the severity of bone loss and the need for reconstruction are not detailed for different tibial implants. HYPOTHESIS: Metal-backing UKA revision exposes the patient to more severe tibial bone loss and requires more substantial reconstruction procedures than cemented polyethylene UKA revision. MATERIALS AND METHODS: This retrospective series of 23 revisions of UKA to total knee arthroplasty (TKA) compared 11 all-polyethylene UKAs with 12 metal-backing UKAs. Factors that contributed to failure were aseptic loosening (n=12) and osteoarthritis evolution (n=11). Both groups were similar regarding the demographic and clinical features. We reported bone loss and the reconstruction procedure to fill it according to the initially used tibial implant. The results were evaluated with the IKS score to a follow-up of 37 months (range, 24-67 months). RESULTS: There were more tibial segmental bone loss (10 versus 3) and more metal wedges (8/12 versus 2/11) in metal-backing UKA revision (P<0.05). Tibial stems were more often used in metal-backing UKA revision (12/12 versus 7/11) (P=0.04). The results of TKA at follow-up did not differ according to whether the revised tibial implant was all polyethylene (IKS=155 [range, 107 195]) or metal-back (IKS=155 [range, 127-172]). DISCUSSION: This study suggests that metal-backing UKA revision exposes the patient to more severe tibial bone loss requiring more substantial reconstruction. These results must be confirmed on a larger population, but surgeons should be alerted to this kind of revision surgery, which warrants having available a revision knee prothesis. LEVEL OF EVIDENCE: Level III, case-control study. PMID- 23810396 TI - Changes in weight after traumatic brain injury in adult patients: a longitudinal study. AB - BACKGROUND & AIMS: Although changes in weight have been reported after traumatic brain injury (TBI), their frequency and underlying factors are little known. Our aim was to determine the prevalence of weight changes and the associated factors during the recovery phase after TBI. METHODS: Longitudinal follow-up of adults with TBI. Multivariate analysis was carried out on weight change, demographic data, dysexecutive syndrome, eating behavior, physical activity, therapeutic classes and metabolic complications. RESULTS: 107 patients (81 males/26 females), age 36 +/- 13 yrs, baseline BMI 23.3 +/- 3.9, followed for 38 (8-66) months, were included. In intensive care, patients lost a mean 11 +/- 6 kg. End of follow-up, mean BMI was not different to pre-TBI BMI, but patients could be categorized in 3 groups: stable (30%), loss (28%, -8 +/- 7 kg) and gain (42%, +9 +/- 6 kg). Sex, age, severity of TBI, intensive care weight loss, physical activity, therapeutic classes and the occurrence of metabolic syndrome did not differ between the groups. Factors related to weight gain were hyperphagia, OR 4.5 (IC95%, 1.6-12.1) and presence of a dysexecutive syndrome, OR 2.5 (IC95%, 1.03-6.3). Factors related to weight loss were hypophagia, OR 4.1 (IC95%, 1.5-10.9) and higher pre TBI BMI, OR 4.9 (IC95%, 1.7-14.0). CONCLUSIONS: Over a median period of 38 months, 42% of TBI patients gained and 28% lost weight. Factors associated with these changes were the presence of a behavioral dysexecutive syndrome for weight gain, oral food intake and initial BMI, which were inversely associated with weight at end of follow-up. These findings highlight the importance of evaluating the time course of weight changes and providing specific nutritional care. PMID- 23810397 TI - A 3-month at-home tube feeding in 118 bulimia nervosa patients: a one-year prospective survey in adult patients. AB - BACKGROUND & AIMS: To study the 1-yr follow-up of 118 bulimia nervosa (BN) patients after a 3-month at-home tube feeding (TF) in a prospective study. METHODS: At-home TF lasted 3 months, including one month of exclusive TF (no food). All patients fulfilled 4 questionnaires (score of binge/purging episodes (BP), eating disorder inventory, anxiety, depression), before, at the 3-month TF point, and 6 and 12 months latter. RESULTS: The score of BP episodes dramatically decreased from 28.8 +/- 15 (before TF) to 7.3 +/- 5.4 at 3 months, as well as at 1 yr (15.1 +/- 6.2). We also obtained a 50% decrease in Beck score (depression) and Hamilton score (anxiety). Curiously, there was no difference between the BP scores of the patients following psychotherapy and those who did not, despite lower scores for anxiety and depression. CONCLUSION: In conclusion, in bulimia nervosa patients having normal BMI and purging behavior, home-TF allow to obtain total withdrawal from bingeing/purging in at least 75% of the cases at short term (3 months) and in 25% of the patients at one year, whatever the patients have or have not psychotherapy. PMID- 23810398 TI - Ascorbic acid reduces gentamicin-induced nephrotoxicity in rats through the control of reactive oxygen species. AB - BACKGROUND & AIM: Oxidative stress has been implicated in the pathophysiology of many forms of acute renal failure. The aim was examine the effect of vitamin C on oxidative stress and its relationship with nitric oxide on gentamicin-induced nephrotoxicity in rats. METHODS: We utilized 32 Wistar rats allocated in four groups of eight animals each: control (CTL), vitamin C (VIT C), gentamicin (GENTA), and GENTA + VIT C; all groups were treated during seven days. RESULTS: Serum urea and creatinine, serum and renal tissue malondialdehyde, blood superoxide anion and hydrogen peroxide in GENTA were increased vs CTL and vs VIT C, and decreased in GENTA + VIT C vs GENTA (all P < 0.05). Serum nitric oxide increased in GENTA vs CTL and vs VIT C, and reduced in GENTA + VIT C vs GENTA (P < 0.001). Urinary nitric oxide was reduced in GENTA vs CTL and vs VIT C and increased in GENTA + VIT C vs GENTA (P < 0.001). Severe degeneration of proximal tubules was present in GENTA, but only mild lesions were observed in GENTA + VIT C. CONCLUSION: This study suggests that VIT C is a valuable tool to protect against GENTA-induced nephrotoxicity, by reducing reactive oxygen species and increasing the nitric oxide. PMID- 23810399 TI - The influence of advancing age on quality of life and rate of recovery after treatment for burn. AB - BACKGROUND: With an ageing population the prevalence of burns in the elderly is increasing. The influence of increasing age on post-burn quality of life (QoL) is unquantified. AIM: To examine the effect of ageing on QoL recovery after burn. METHODS: The Burn Specific Health Scale-Brief (BSHS-B) and Short Form Health Outcomes (SF-36), collected up to 24 months post-injury, for patients treated by the Royal Perth Hospital Burn Service were analysed. Multivariable analysis was adjusted for demographic and injury factors. The impact of ageing on rate of recovery was examined using BSHS-B normative data. RESULTS: The cohort (n=1051) was 79.6% male with mean TBSA of 8% and age of 37.3 years. The SF-36 showed advancing age predicted poorer outcomes in physical function, role physical, vitality and role emotional domains but reduced bodily pain. The BSHS-B was affected by injury factors, not ageing. The standardised rate of recovery after burn improved with advancing age. The provision of surgery positively affected most outcomes assessed. CONCLUSION: This study quantified the impact of ageing on post-burn QoL recovery and confirmed that physical function suffered to the greatest degree. The results emphasise the importance of pro-active burn surgery and physical rehabilitation strategies with older patients. PMID- 23810401 TI - [Analysis of several containment measures of pharmaceutical expenditure in an Ambulatory Surgery Centre]. AB - OBJECTIVE: In the context of the current crisis, sustainability of National Health Service must be considered a priority issue. To compare several cost saving measures in drug expenditure due to outpatient drug treatment after surgery in an Ambulatory Surgical Centre. MATERIAL AND METHOD: Pharmaco-economic analysis of cost minimization of ambulatory pharmaceutical services during the year 2011. A total of 3,346 patients were operated on and discharged on the same day, were included. Treatments were collected from the discharge report of each patient. We compared changes in real outpatient drug spending after separately applying each of the following measures: 1) increasing the co-payment; 2) improving the quality of prescribing; 3) dispensing by units of drugs through pharmacies, and 4) dispensing through the hospital pharmacy service. RESULTS: The real outpatient pharmaceutical expenditure was 29,454.21?. Increasing the co payment mean a transfer of 2,091.82? from the funding institutions to users. Improving the quality of prescriptions, dispensing through units of drugs in the pharmacy, and dispensing through the hospital pharmacy service led to a pharmaceutical expenditure of 24,215.14?, 21,766.24? and 7,827.71?, respectively. CONCLUSIONS: Only considering co-payment to contain pharmaceutical expenditure arising from prescribing in an Ambulatory Surgical Centre is the least effective measure. The most effective measure, for this purpose, is the supply of drugs through the hospital pharmacy service. PMID- 23810402 TI - [Premedication with intranasal fentanyl and midazolam in uncooperative patients]. PMID- 23810400 TI - Salivary gland cancer stem cells. AB - Emerging evidence suggests the existence of a tumorigenic population of cancer cells that demonstrate stem cell-like properties such as self-renewal and multipotency. These cells, termed cancer stem cells (CSC), are able to both initiate and maintain tumor formation and progression. Studies have shown that CSC are resistant to traditional chemotherapy treatments preventing complete eradication of the tumor cell population. Following treatment, CSC are able to re initiate tumor growth leading to patient relapse. Salivary gland cancers are relatively rare but constitute a highly significant public health issue due to the lack of effective treatments. In particular, patients with mucoepidermoid carcinoma or adenoid cystic carcinoma, the two most common salivary malignancies, have low long-term survival rates due to the lack of response to current therapies. Considering the role of CSC in resistance to therapy in other tumor types, it is possible that this unique sub-population of cells is involved in resistance of salivary gland tumors to treatment. Characterization of CSC can lead to better understanding of the pathobiology of salivary gland malignancies as well as to the development of more effective therapies. Here, we make a brief overview of the state-of-the-science in salivary gland cancer, and discuss possible implications of the cancer stem cell hypothesis to the treatment of salivary gland malignancies. PMID- 23810403 TI - [Doses of anti-infectives for systemic use are scarcely notified in clinical cases reported to the Revista Espanola de Anestesiologia y Reanimacion]. AB - OBJECTIVE: To describe the frequency of dose notification of antiinfectives for systemic use in clinical cases published in Revista Espanola de Anestesiologia y Reanimacion. MATERIAL AND METHOD: Review of individualized clinical cases published in the sections "Clinical case" or "Letter to the Editor" of the above mentioned journal from year 2010 to 2012, and identification of the drugs and their therapeutic regimens cited in such publications, being dose notification the main variable. Drugs have been classified according to the Anatomical Therapeutic Chemical Classification System. RESULTS: One thousand one hundred and thirty-five drugs cited 1,317 times were identified in 167 articles describing the clinical pictures of 182 patients, 73 of the citations (5.6%) regarding to drugs belonging to group J (Antiinfectives for systemic use) which were divided into perioperative prophylaxis (n=15) and active treatment (n=58). Doses were scarcely notified for group J drugs as a whole (27.4%), but especially for active treatment (17.2%) compared to perioperative prophylaxis (66.7%), percentage which was similar to those more classical anesthetic drugs (fentanyl: 86.6%; remifentanil: 70.5%; sevoflurane: 78%; propofol: 79%; rocuronium:79.6%; cisatracurium: 68.4%) or even for antiemetics (ondansetron: 92.3%; dexamethasone: 84.6%). CONCLUSIONS: Quality of case reports could be improved by including dose notification for antiinfective agents. PMID- 23810404 TI - [Combined epidural-spinal analgesia during labor: a quantitative systematic review of the literature (meta-analysis)]. AB - OBJECTIVE: To perform a meta-analysis on the use of combined epidural-intrathecal analgesia during labor, including intrathecal fentanyl and/or morphine compared to usual epidural techniques. MATERIAL AND METHOD: A literature search was made looking for randomized clinical trials in MEDLINE, EMBASE and Cochrane Library. The size of the effect for quantitative variables was analyzed by weighted mean difference; for qualitative variables, by odds ratio. Variables analyzed were: labor duration, type of delivery (spontaneous, instrumental and caesarean section), motor blockade, pain, and satisfaction. The analysis used in most cases was a random effects model. RESULTS: A total of 21 trials, which included 3.646 patients, were selected out of the 38 initially found. The type of delivery variable with its 3 subgroups was the only one to show uniformity (p>Q 0.1; I(2)<50%). There were no differences in the variables analyzed except pain, which was advantageous for the group with intrathecal fentanyl or morphine by 0.55 points out of 10. CONCLUSION: Combined analgesia including intrathecal fentanyl morphine does not offer significant advantages compared to the standard epidural. PMID- 23810405 TI - [Hypobaric metameric subarachnoid anaesthesia for anaesthetic management in vertebral reinforcement techniques. Our experience in 6 cases]. AB - Vertebral reinforcement techniques, such as percutaneous vertebroplasty and kyphoplasty, are minimally invasive procedures used in the treatment of fractured or collapsed vertebras. The anaesthetic techniques employed during these procedures are diverse and with variable results. We report 6 cases, vertebroplasty and kyphoplasty using subarachnoid metameric anaesthesia with a hypobaric technique. Haemodynamic stability and analgesia were satisfactory in all of them. PMID- 23810407 TI - Syphilitic angina. PMID- 23810408 TI - Managing murine food allergy with Cissampelos sympodialis Eichl (Menispermaceae) and its alkaloids. AB - Food allergy is a severe human disease with imminent risk of life. Cissampelos sympodialis (Menispermaceae) is a native Brazilian plant used in Brazilian folk medicine for the treatment of respiratory allergies. In this study the experimental model of food allergy induced by ovalbumin (OVA) was used to determine whether the alcoholic extract of the plant (AFL) and its alkaloids match a therapeutic approach for this disease. Animal weight, diarrhea, OVA specific IgE levels, inflammatory cell and cytokine profiles, mucus production and proportion of T cells on the mesenteric lymph node (MLN) were evaluated. Warifteine (W) or methyl-warifteine (MW) alkaloids slightly improve diarrhea score independently of AFL and all treatments decreased the OVA-specific IgE levels. Stimulated mesenteric lymph node (MLN) cells in the presence of the alkaloids diminished the IL-12p70 levels independently of IFN-gamma or IL-13 secretion. The alkaloids increased the number of Treg cells on MLN and reduced the number of eosinophils and mast cells as well as mucus production in the gut. Therefore, the alkaloids modulate the immune response in food allergy by increasing regulatory T cells in MLN independently of Th1 or Th2 profiles. PMID- 23810409 TI - Protective effect of augmenter of liver regeneration on vincristine-induced cell death in Jurkat T leukemia cells. AB - Augmenter of liver regeneration (ALR) is a crucial factor in the process of proliferation of hepatocytes. Recently, it has been demonstrated that ALR plays an important role of anti-apoptosis in several cell lines, but the biological effects of ALR in acute T lymphoblastic leukemia have remained unclear. In this study, we investigated the effect of ALR on Jurkat T leukemia cell growth and survival. We found that ALR was up-regulated in Jurkat cells and could reduce the sensitivity of Jurkat cells to vincristine, but had a minimal effect on proliferation of Jurkat cells. Results from analysis of flow cytometry showed ALR attenuated apoptotic cells and inhibited G2/M-arrest in vincristine-treated Jurkat cells. Following incubation with ALR, an increase in pro-caspase8, pro caspase3, pro-PARP and Bcl-2 levels was observed in vincristine-treated Jurkat cells. In summary, the results of this study demonstrate that ALR protects Jurkat T leukemia cells from vincristine-induced cell death via regulation of apoptotic signaling pathways and cell cycle. PMID- 23810410 TI - Anti-inflammatory effect of thalidomide in paraquat-induced pulmonary injury in mice. AB - Thalidomide has been used in inflammatory and autoimmune disorders due to its anti-inflammatory activity. Paraquat (PQ) poisoning causes severe lung injury. PQ induced pulmonary inflammation and fibrosis are due to its ability to induce oxidative stress, inflammatory and fibrotic reactions. This study was designed to evaluate the anti-inflammatory and anti-fibrotic effect of thalidomide on PQ induced lung damage in a mouse model. Mice were injected with a single dose of PQ (20mg/kg, i.p.), and treated with thalidomide (25 and 50mg/kg/day, i.p.) for six days. Lung tissues were dissected six days after PQ injection. The results showed that thalidomide ameliorated the biochemical and histological lung alterations induced by PQ. Thalidomide decreased production of inflammatory and fibrogenic cytokine tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and transforming growth factor (TGF)-beta1. In addition thalidomide reduced myeloperoxidase (MPO), nitric oxide (NO), and hydroxyproline content in lung tissue. Taken together, the results of this study suggest that thalidomide might be a valuable therapeutic drug in preventing the progression of PQ-induced pulmonary injury. PMID- 23810411 TI - TREM-1 inhibition attenuates inflammation and tumor within the colon. AB - The role of myeloid cell receptor TREM-1 as an amplifier of inflammation has been widely accepted and more interestingly, TREM-1 has been implicated in tumorigenesis. However, it is not clear whether TREM-1 links colon inflammation and tumor in vivo. This study aimed to investigate whether inhibition of proinflammatory TREM-1 would prevent aberrant inflammation and tumor development within the colon. In the present study, the mouse model of DSS-induced colitis and colitis-associated tumorigenesis was used. In vivo, the treatment with the TREM-1 antagonist LP17 or control peptide was initiated at the beginning of or after induction of experimental colitis or colitis-associated tumorigenesis. As a result, TREM-1 inhibition by LP17 treatment ameliorated the development of inflammation and tumor within the colon through exerting anti-inflammatory effects. In addition, LP17 decreased intestinal epithelial proliferation in DSS induced colitis. Taken together, TREM-1 plays critical roles in colon inflammation and tumor and targeting TREM-1 may represent a novel therapeutic strategy for colon inflammation and associated cancer. PMID- 23810406 TI - Primacy of the 3B approach to control risk factors for cardiovascular disease in type 2 diabetes patients. AB - BACKGROUND: Individually, diabetes mellitus, hypertension, and dyslipidemia have been shown to increase the risk of cardiovascular disease. While traditional management of Type 2 diabetes has focused mainly on glycemic control, robust evidence supports the integration of hypertension and dyslipidemia management to reduce the risk of cardiovascular disease. The primary objective of this study was to assess the level of control of blood glucose, blood pressure, and blood lipids (3Bs) among patients with type 2 diabetes. An additional objective was to investigate the impact of hospital type, physician specialty, treatment pattern, and patient profile on clinical outcomes. METHODS: This was a cross-sectional, multicenter observational study. A nationally representative sample of outpatients with established type 2 diabetes were enrolled at hospitals representative of geographic regions, tiers, and physician specialties in China. Main clinical measurements were the levels of glycosylated hemoglobin (HbA1c), blood pressure, and total serum cholesterol in reference to target goals. RESULTS: A total of 25,817 adults with type 2 diabetes (mean age 62.6 years, 47% male) were enrolled at 104 hospitals. Seventy-two percent reported comorbid hypertension, dyslipidemia, or both. Patients with concurrent type 2 diabetes, hypertension, and dyslipidemia were 6 times more likely to report a prior history of cardiovascular disease compared with those with type 2 diabetes alone. The mean HbA1c level was 7.6%. While 47.7%, 28.4%, and 36.1% of patients achieved the individual target goals for control of blood glucose (HbA1c <7%), blood pressure (systolic blood pressure <130 mm Hg, diastolic blood pressure <80 mm Hg), and blood lipids (total cholesterol <4.5 mmol/L), respectively, only 5.6% achieved all 3 target goals. Lower body mass index (<24 kg/m(2)), no active smoking or drinking, higher education, and diabetes duration <5 years were independent predictors of better cardiovascular disease risk control. CONCLUSION: Achieving adequate control of risk factors for cardiovascular disease in patients with type 2 diabetes remains a clinical challenge. Interventions to achieve control of 3Bs coupled with modification of additional cardiovascular disease predictors are crucial for optimization of clinical outcomes in patients with type 2 diabetes. PMID- 23810413 TI - Human complement control and complement evasion by pathogenic microbes--tipping the balance. AB - Complement is a central homeotic system of mammals and represents the first defense line of innate immunity. The human complement system is aimed to maintain homeostasis by recognizing and removing damaged or modified self material, as well as infectious foreign microbes. However, pathogenic microbes also control and escape the host complement and immune attack. The increasing resistance of microbial pathogens to either antibiotics or antifungal drugs is a major health problem and is of global interest. Therefore the topic how pathogenic microbes escape human complement and immune control is of high and of central interest. Identifying and defining the action of proteins involved in this intense immune interaction and understanding how these proteins interact is of relevance to design new control strategies. In this review we summarize the complement system of the human host and how this cascade drives effector functions. In addition, we summarize how diverse pathogenic microbes control, modulate and block the complement response of their host. The characterization of pathogen derived virulence factors and complement escape proteins reveals patterns of multiplicity, diversity and redundancy among pathogen encoded proteins. Sequence variability of immune and also complement escape proteins is largely driven by antigenic diversity and adaptive immunity. However common complement escape principles are, emerging in terms of conserved binding repertoire for host regulators and evasion among the large variety of infectious microbes. These conserved and common escape features are relevant and they provide challenging options for new therapeutic approaches. PMID- 23810414 TI - Circumferential or sectored beam arrangements for stereotactic body radiation therapy (SBRT) of primary lung tumors: effect on target and normal-structure dose volume metrics. AB - To compare 2 beam arrangements, sectored (beam entry over ipsilateral hemithorax) vs circumferential (beam entry over both ipsilateral and contralateral lungs), for static-gantry intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) delivery techniques with respect to target and organs-at-risk (OAR) dose-volume metrics, as well as treatment delivery efficiency. Data from 60 consecutive patients treated using stereotactic body radiation therapy (SBRT) for primary non-small-cell lung cancer (NSCLC) formed the basis of this study. Four treatment plans were generated per data set: IMRT/VMAT plans using sectored (-s) and circumferential (-c) configurations. The prescribed dose (PD) was 60Gy in 5 fractions to 95% of the planning target volume (PTV) (maximum PTV dose ~ 150% PD) for a 6-MV photon beam. Plan conformality, R50 (ratio of volume circumscribed by the 50% isodose line and the PTV), and D2cm (Dmax at a distance >=2cm beyond the PTV) were evaluated. For lungs, mean doses (mean lung dose [MLD]) and percent V30/V20/V10/V5Gy were assessed. Spinal cord and esophagus Dmax and D5/D50 were computed. Chest wall (CW) Dmax and absolute V30/V20/V10/V5Gy were reported. Sectored SBRT planning resulted in significant decrease in contralateral MLD and V10/V5Gy, as well as contralateral CW Dmax and V10/V5Gy (all p < 0.001). Nominal reductions of Dmax and D5/D50 for the spinal cord with sectored planning did not reach statistical significance for static gantry IMRT, although VMAT metrics did show a statistically significant decrease (all p < 0.001). The respective measures for esophageal doses were significantly lower with sectored planning (p < 0.001). Despite comparable dose conformality, irrespective of planning configuration, R50 significantly improved with IMRT s/VMAT-c (p < 0.001/p = 0.008), whereas D2cm significantly improved with VMAT-c (p < 0.001). Plan delivery efficiency improved with sectored technique (p < 0.001); mean monitor unit (MU)/cGy of PD decreased from 5.8 +/- 1.9 vs 5.3 +/- 1.7 (IMRT) and 2.7 +/- 0.4 vs 2.4 +/- 0.3 (VMAT). The sectored configuration achieves unambiguous dosimetric advantages over circumferential arrangement in terms of esophageal, contralateral CW, and contralateral lung sparing, in addition to being more efficient at delivery. PMID- 23810412 TI - Complement therapy in atypical haemolytic uraemic syndrome (aHUS). AB - Central to the pathogenesis of atypical haemolytic uraemic syndrome (aHUS) is over-activation of the alternative pathway of complement. Inherited defects in complement genes and autoantibodies against complement regulatory proteins have been described. The use of plasma exchange to replace non-functioning complement regulators and hyper-functional complement components in addition to the removal of CFH-autoantibodies made this the 'gold-standard' for management of aHUS. In the last 4 years the introduction of the complement inhibitor Eculizumab has revolutionised the management of aHUS. In this review we shall discuss the available literature on treatment strategies to date. PMID- 23810415 TI - Age differences in fear retention and extinction in male Sprague-Dawley rats: effects of ethanol challenge during conditioning. AB - Pavlovian fear conditioning is an ideal model to investigate how learning and memory are influenced by alcohol use during adolescence because the neural mechanisms involved have been studied extensively. In Exp 1, adolescent and adult male Sprague-Dawley rats were non-injected or injected with saline, 1 or 1.5 g/kg ethanol intraperitoneally 10 min prior to tone or context conditioning. Twenty four hours later, animals were tested for tone or context retention and extinction, with examination of extinction retention conducted 24h thereafter. In Exp 2, a context extinction session was inserted between the tone conditioning and the tone fear retention/extinction days to reduce pre-CS baseline freezing levels at test. Basal levels of acquisition, fear retention, extinction, and extinction retention after tone conditioning were similar between adolescent and adult rats. In contrast adolescents showed faster context extinction than adults, while again not differing from adults during context acquisition, retention or extinction retention. In terms of ethanol effects, adolescents were less sensitive to ethanol-induced context retention deficits than adults. No age differences emerged in terms of tone fear retention, with ethanol disrupting tone fear retention at both ages in Exp 1, but at neither age in Exp 2, a difference seemingly due to group differences in pre-CS freezing during tone testing in Exp 1, but not Exp 2. These results suggest that age differences in the acute effects of ethanol on cognitive function are task-specific, and provide further evidence for age differences cognitive functioning in a task thought to be hippocampally related. PMID- 23810416 TI - Loss of rostral brainstem cholinergic activity results in decreased ultrasonic vocalization behavior and altered sensorimotor gating. AB - The parabigeminal (PBG), pedunculopontine (PPTg), and laterodorsal tegmental (LDTg) nuclei located in the rostral brainstem are the primary sources of the neurotransmitter acetylcholine (ACh) for the midbrain and thalamus, and as part of the ascending reticular activating system, these cholinergic signaling pathways regulate mouse behavioral responses to sensory stimuli. Here, I report that mice harboring a conditional deletion of ACh synthesis specifically within these nuclei (ChAT(En1 KO)) exhibit decreased ultrasonic vocalizations both as pups and adults, consistent with their previously reported hypoactivity when exploring the novel environment of the open field arena. Furthermore, in prepulse inhibition (PPI) tests, ChAT(En1 KO) animals exhibited increased sensorimotor gating in comparison to control littermates. These data suggest that ACh signaling arising from the rostral brainstem modulates animal behavior in part by tuning the levels of sensorimotor gating. Thus, the net effect of this cholinergic activity is to increase sensitivity to environmental stimuli, and loss of this pathway contributes to the hypoactivity in these mutants by raising the sensory threshold for eliciting exploratory behaviors. PMID- 23810417 TI - Modulation of weanling pig cellular immunity in response to diet supplementation with 25-hydroxyvitamin D(3). AB - There is still significant debate over the effects that vitamin D3 has on the immune system, as both pro-inflammatory and anti-inflammatory cellular responses have been described. The objective of this study was to use a weanling pig model of nutritional supplementation to provide a broad functional look at the immune cellular changes that occur as a result of vitamin D3 nutritional supplementation. We identified a significant impact on cellular immune parameters, particularly in pigs supplemented with a commercial hydroxylated version of vitamin D3, 25-hydroxyvitamin D3 [25(OH)D3; Hy.D]. We found that significant increases in leukocyte cell numbers reflected parallel increases in serum 25(OH)D3. Multi-site, multi-parametric analysis of functional traits also showed positive modulation of leukocyte survival and phagocytic capacity across blood and bronchoalveolar compartments, highlighting the potential impact on systemic and mucosal antimicrobial responses. In all, our work supports previous observations regarding the positive immunomodulatory role of vitamin D3 and points to 25(OH)D3 (Hy.D) as a superior dietary supplement for weanling pigs. PMID- 23810418 TI - Interferon-mediated host response in experimentally induced salmonid alphavirus 1 infection in Atlantic salmon (Salmo salar L.). AB - Salmonid alphavirus (SAV) infection in cultured salmonids causes severe economic losses across Europe. Immune protection and antiviral mechanisms of the host against SAV are poorly characterised in vivo. Analysis of immune gene expression in head kidney of Atlantic salmon (Salmo salar L.) experimentally infected with SAV 1, using a quantitative reverse transcription polymerase chain reaction (qRT PCR), revealed rapid induction of interferon I (INF-I), interferon II (INF-II) and INF-I associated Mx genes in SAV 1 infected fish compared to control fish injected with tissue culture supernatant. Mx protein was found to be highly expressed in the heart and mucosal membranes of infected fish by immunohistochemistry (IHC). Interestingly, the pathological changes that were observed in the target tissues of the virus became visible some time after peak expression of genes associated with the INF-I-pathway in head kidney tissue. These findings suggest that a non-specific antiviral immune response is rapidly induced during the early stages of SAV infection in salmon. PMID- 23810419 TI - Macrophage migration is controlled by Tribbles 1 through the interaction between C/EBPbeta and TNF-alpha. AB - In mammals, three Tribbles gene family members have been identified, Tribbles 1, 2 and 3 (Trib1, Trib2 and Trib3). All family members are considered to be pseudokinases in that they contain domains homologous to serine/threonine kinase catalytic cores, but they lack several conserved residues in the ATP-binding pocket. Trib1 is implicated in the inflammatory response pathway through its ability to regulate mitogen-activated protein kinase (MAPK), nuclear factor kappa B (NF-kappaB) and CCAAT Enhancer Binding Protein (C/EBP). However, its role in macrophages function is unknown. Here, we investigated the functional role of Trib1 in Toll-like receptor-mediated inflammatory responses to IFN-gamma in RAW264.7 cells. In gene knock-down experiments in macrophages using small interfering RNAs targeted to Trib1, it was observed that TNF-alpha production was increased following treatment with IFN-gamma and/or TLR2 ligands. Finally, Trib1 silenced macrophages failed to show MCP-1 induced chemokinesis and indicating involvement of Trib1 in controlling of macrophage migration. This work demonstrates that Trib1 contributes to the pro-inflammatory response caused by TLR2 ligands and controls macrophage migration as well as being a biomarker in macrophage-related diseases in both human and veterinary medicine. PMID- 23810420 TI - Analysis of soluble CD14 and its use as a biomarker in neonatal foals with septicemia and horses with recurrent airway obstruction. AB - Soluble CD14 (sCD14) binds bacterial lipopolysaccharide (LPS) and acts as an anti inflammatory LPS-inhibitor in vivo. In humans, sCD14 is one of the soluble biomarkers used for various inflammatory diseases and conditions, however, sCD14 assays have not yet been evaluated in horses. Here, we developed and optimized a bead-based assay for the quantification of sCD14 in horses. The assay was then used to determine native sCD14 concentrations in serum from healthy and septic foals, in the colostrum of healthy mares and in plasma from adult horses with recurrent airway obstruction (RAO) and control horses. Healthy foals and adult horses had sCD14 concentrations in serum or plasma in the high ng/ml range. The concentration of sCD14 in colostrum samples from healthy mares was in the MUg/ml range. Foals with septicemia and adult horses with RAO had significantly higher sCD14 concentrations in their circulation than the respective control groups. The findings suggest that sCD14 can become a valuable biomarker for neonatal septicemia, RAO and possibly also for other inflammatory diseases in horses. Further studies and larger samples numbers are required to determine normal sCD14 concentration ranges and those that are indicative of disease progression, severity or prognosis. PMID- 23810421 TI - Revision total hip arthroplasty for large medial defects with witch's hat-shaped structural allografts--minimum 10-year follow-up. AB - A witch's hat-shaped structural allograft can restore bone stock over acetabular medial wall during revision total hip arthroplasty, which may be of importance for future re-revisions. However, long-term results are unclear. A retrospective review of 104 consecutive hips in 96 patients was performed to determine survivorship and functions. The minimum follow-up was 10 years. Nine patients required re-revision for cup aseptic loosening with a mean time to revision of 4.5 years. Kaplan-Meier survivorship was 89.4% at the endpoint. Radiographic evaluation revealed sixteen instances of minor medial wall graft absorption without significant cup migration. The mean modified Harris Hip Scores were 36 preoperatively and 86 at last follow-up. Revision acetabular surgery using a witch's hat-shaped allograft to restore acetabular medial wall provides an excellent alternative. PMID- 23810422 TI - A woman with "artistic-pattern" colonic ulcers. PMID- 23810423 TI - Functionalized hydroxyethylamine based peptide nanostructures as potential inhibitors of falcipain-3, an essential proteases of Plasmodium falciparum. AB - Self-assembled peptide based nanostructures gained enough popularity due to their easy biocompatibility and numerous potential applications. An excellent model of self-assembly of hydroxyethylamine based peptide nanostructures was synthesized and characterized by DLS and TEM. Spherical nano structures of I and III were observed with particle size ~50 and ~80nm, respectively. Further, I and III were screened against anti-malarial target, falcipain-3 (FP3), a crucial cysteine protease involved as a major hemoglobinase of Plasmodium falciparum. Interestingly, compound III completely inhibited the activity of FP3. The effective concentration (1.5MUM) of III found to be more potent than I. This biochemical result was substantiated by molecular-docking studies indicating III to be best inhibitor of FP3. This is the first report showing that bis hydroxethylamine based peptide nanostructures could be very effective inhibitor of malarial cysteine proteases. PMID- 23810424 TI - Acyclic phosph(on)ate inhibitors of Plasmodium falciparum hypoxanthine-guanine xanthine phosphoribosyltransferase. AB - The pathogenic protozoa responsible for malaria lack enzymes for the de novo synthesis of purines and rely on purine salvage from the host. In Plasmodium falciparum (Pf), hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) converts hypoxanthine to inosine monophosphate and is essential for purine salvage making the enzyme an anti-malarial drug target. We have synthesized a number of simple acyclic aza-C-nucleosides and shown that some are potent inhibitors of Pf HGXPRT while showing excellent selectivity for the Pf versus the human enzyme. PMID- 23810425 TI - Design and synthesis of novel series of 5-HT6 receptor ligands having indole, a central aromatic core and 1-amino-4 methyl piperazine as a positive ionizable group. AB - The exclusive distribution of 5-HT6 receptor in the brain regions and high affinity for antipsychotic and antidepressant drugs makes 5-HT6 receptor a promising target in treatment of CNS diseases. Based on a pharmacophore model reported in the literature, we designed and synthesized a novel series of 5-HT6 receptor ligands having indole as a central aromatic core and 1-amino-4-methyl piperazine as positive ionizable group. Out of 32 compounds we have successfully identified 10 new compounds as 5-HT6 receptor antagonists. The structure-activity relationship (SAR) studies have been carried out by mapping the compounds with the 3D QSAR model. PMID- 23810426 TI - Effect of age on febrile response in patients with healthcare-associated bloodstream infection. AB - OBJECTIVE: This study aimed to determine the effect of age on febrile response in patients with healthcare-associated bloodstream infection (BSI). METHODS: This was a retrospective observational study using medical records as the primary source of data. Three indicators measured body temperature changes: basal body temperature (BBT), body temperature at infection onset (onset T), and maximum temperature (max T) during the infection period. RESULTS: In a sample of 230 patients there was no significant correlation between BBT or onset T and age. Max T was significantly correlated with age (r = -.191, p = .004). There was wide variation in onset T in all age groups. CONCLUSIONS: Age showed no effect on BBT and onset T, but blunted max T in patients with bacteremia. This variability in onset T in all age groups emphasizes the need for early recognition of subtle signs of infection and the need to use an individualized definition of fever. PMID- 23810427 TI - The effect of neck torsion on joint position error in subjects with chronic neck pain. AB - The conventional cervical joint position error (JPE) test has been used as a measure of cervical afferent dysfunction in people with neck pain. However, head movement during the test may also stimulate the vestibular system. This study's objective is to investigate the effect of the modified JPE test with a neck torsion manoeuvre in order to determine if the new test is a more definitive measure of cervical afferent dysfunction. Twenty five volunteers with chronic neck pain and 26 healthy controls aged 18 to 60 were assessed on three tests of JPE: 'JPE conventional', 'JPE torsion' and 'Enbloc' (Control) using Fastrak and laser apparatus. The neck pain group was found to have significantly greater JPE in one conventional JPE test and almost all the torsion tests (p < 0.05). No differences in Enbloc(Control) tests were seen. Moderate to strong significant correlations were also seen between measures of JPE using the Fastrak and laser methodology (p <= 0.01). The results of this preliminary study indicate that 'JPE torsion' may be a more suitable test than 'JPE conventional' for cervical afferent dysfunction in people with chronic neck pain although future comparisons with people suffering from vestibulopathy is warranted to support these findings. Additionally, the laser method is comparable to Fastrak and may be useful as a clinical measure of repositioning errors for both conventional and torsion tests. PMID- 23810429 TI - The relationship between self-determined motivation and physical activity in adolescent boys. AB - BACKGROUND: Physical education (PE) lessons and leisure-time represent two important opportunities for adolescents to accumulate moderate-to-vigorous physical activity (MVPA). PURPOSE: Framed by self-determination theory, this study investigated how much of the observed variation in adolescent boys' MVPA levels (during PE and leisure-time) was explained by individual- and class-level motivation. METHODS: Cross-sectional design. Adolescent boys (N = 61, M = 14.36 years, SD = .48 years) completed motivation questionnaires and wore an accelerometer during a PE lesson and across 7 consecutive days. RESULTS: Self determined motivation toward PE predicted MVPA during PE lessons (R(2) = .31). Self-determined motivation toward leisure-time physical activity was positively associated with MVPA during leisure-time (R(2) = .08). CONCLUSIONS: Findings support the tenets of self-determination theory and suggest that motivation may be an important correlate of adolescent boys' MVPA in PE lessons and during leisure-time. Also, results indicated that teachers' behavior may be an important determinant of MVPA in PE lessons, while individual motivation may be more important in leisure-time. PMID- 23810428 TI - A case-control study of risk and protective factors for incarceration among urban youth. AB - PURPOSE: Each day in the United States, approximately 100,000 youth are under correctional supervision. The purpose of this study is to examine the early risk and protective factors for incarceration using a high-risk sample of urban youth. METHODS: Data were obtained from 2,165 (54 who were incarcerated) youth who participated in Project Northland Chicago. Participants were matched exactly on gender, race/ethnicity, and aggressive behavior in sixth grade. Bivariate and multivariate conditional logistic regression analyses were used to examine the risk and protective factors present at sixth grade that increased the odds of incarceration at 12th grade. RESULTS: The early risk factors for incarceration were age (odds ratio [OR] = 2.51; 95% confidence interval [CI] 1.71-3.69), having been sent to detention (1-3 times: OR = 2.24; 95% CI 1.15-4.37; 4+ times: OR = 3.49; 95% CI 1.40-8.72), and the number of hours spent participating in a sport (OR = 1.11; 95% CI 1.03-1.20). Substance use was not significantly related to incarceration after adjusting for other behavioral and contextual risk factors. CONCLUSIONS: General problem behaviors (nonaggressive) strongly predict incarceration among at-risk youth. Implications for prevention programs are discussed. PMID- 23810430 TI - Sp-2-propylthio-ATP-alpha-B and Sp-2-propylthio-ATP-alpha-B,beta-gamma dichloromethylene are novel potent and specific agonists of the human P2Y11 receptor. AB - The human P2Y11 nucleotide receptor mRNA was found in virtually all human tissues, and the receptor serves many physiological roles, such as immune response regulation. The Ala-87-Thr-P2Y11 receptor single nucleotide polymorphism was linked to increased risk for acute myocardial infarction. To facilitate the development of new therapeutic applications involving cells expressing several P2 receptor subtypes, the availability of specific and potent agonists is mandatory. Here, we synthesized a series of novel adenine nucleotide derivatives, based upon the potent P2Y11 receptor agonists AR-C67085. Features of the novel nucleotide derivatives are a propylthio substitution at C2-adenine and a Palpha-borano or Palpha-thio substitution of non-bridging oxygen atom. The latter substitutions introduce a chiral center at the alpha-phosphate. Sp-isomers of Palpha-borano- and Rp-isomers of Palpha-thio-substituted nucleotides are preferred by the P2Y11 receptor. As recently reported by us, diastereoselectivity of the P2Y11 receptor is opposite to that of the P2Y1 receptor. Therefore, we exploit this characteristic to increase nucleotide selectivity. At the P2Y11 receptor, the Sp isomers of 2-propylthio-ATP-alpha-B (2B) and 2-propylthio-ATP-alpha-B,beta-gamma dichloromethylene (4B) were the most potent of the novel nucleotide series, with EC50 values of 0.03 MUM for both, being ca. 80-fold more potent than 2-propylthio ATP and ATP (EC50 = 2.6 MUM). We conclude that the borano-substitution at the alpha-phosphate of 2-propylthio-ATP enhances nucleotide potency at the P2Y11 receptor. The combination with a Pbeta-Pgamma-dichloromethylene group in 4B results in a nucleotide, which shows higher selectivity for the P2Y11 receptor over the P2Y11 receptor than 2B making it the most promising of the novel P2Y11 receptor agonists. PMID- 23810431 TI - Mesothelin expression and survival outcomes in triple receptor negative breast cancer. AB - BACKGROUND: Mesothelin is an ideal tumor-associated marker for the development of targeted therapy due to its limited expression in normal tissues. The aim of this study was to evaluate mesothelin expression in triple-negative breast cancer (TNBC) and its correlation with survival outcomes. METHODS: Mesothelin expression was completed by using immunohistochemistry and was quantified by the H score. An H score > 10 was considered positive. Patient characteristics were compared by mesothelin expression. The Kaplan-Meier product limit method was used to estimate survival outcomes. Cox proportional hazards models was used to adjust for patient and tumor characteristics. RESULTS: The median age was 52 years. Of the 109 patients with TNBC, 37 (34%) were positive for mesothelin expression. There were no differences on patient and/or tumor characteristics by mesothelin expression with the exception of high frequency of lymphovascular space invasion in mesothelin-negative tumors (2P = .03). At a median follow-up of 75.8 months, 20 (18.3%) patients had experienced a recurrence, and 22 (20.2%) had died. Five-year progression-free survival was 87% and 92% in patients with mesothelin-positive and those with mesothelin-negative tumors (2P = .43). Five-year overall survival was 85% and 91% in patients with mesothelin-positive and those with mesothelin negative tumors (2P = .57), respectively. Mesothelin expression was not an independent predictor of survival outcomes. CONCLUSION: Mesothelin expression was identified in 34% of patients with TNBC. Mesothelin expression did not correlate with survival outcomes in patients with TNBC. PMID- 23810432 TI - A normalized PID controller in networked control systems with varying time delays. AB - It requires not only simplicity and flexibility but also high specified stability and robustness of system to design a PI/PID controller in such complicated networked control systems (NCSs) with delays. By gain and phase margins approach, this paper proposes a novel normalized PI/PID controller for NCSs based on analyzing the stability and robustness of system under the effect of network induced delays. Specifically, We take into account the total measured network delays to formulate the gain and phase margins of the closed-loop system in the form of a set of equations. With pre-specified values of gain and phase margins, this set of equations is then solved for calculating the closed forms of control parameters which enable us to propose the normalized PI/PID controller simultaneously satisfying the following two requirements: (1) simplicity without re-solving the optimization problem for a new process, (2) high flexibility to cope with large scale of random delays and deal with many different processes in different conditions of network. Furthermore, in our method, the upper bound of random delay can be estimated to indicate the operating domain of proposed PI/PID controller. Finally, simulation results are shown to demonstrate the advantages of our proposed controller in many situations of network-induced delays. PMID- 23810433 TI - Oxytocin and psychotherapy: a pilot study of its physiological, behavioral and subjective effects in males with depression. AB - Individual psychotherapy is an important treatment for a number of psychiatric conditions and involves a unique form of human attachment. This raises the question of whether oxytocin (OT), the paradigmatic "attachment hormone", may have benefits in this context. In this randomized, double-blind, crossover trial, we gave male psychiatric outpatients with major depressive disorder 40 IU intranasal OT or placebo before a videotaped session with a therapist and measured a number of subjective, physiological, and behavioral parameters. We report three main findings. Surprisingly - in contrast to prior reports of OT's anxiolytic properties - we found OT caused an increase in anxiety over the course of the therapy session. Secondly, though it had no main effect on cortisol, eye contact, or overall behavior, we did find that OT caused a decrease in nonverbal behaviors that cut off social contact, after controlling for level of depressive symptoms. Lastly, we replicated prior findings that OT improves social cognition (performance on the reading the mind in the eyes test (RMET)), albeit in a depressed patient group. These results inform future studies of oxytocin and psychotherapy and suggest that in certain clinical populations and contexts, OT has heterogeneous subjective effects which may include acute anxiogenesis. Moreover, the similarity of some of these acute effects to those of single-dose serotonergic antidepressants raises interesting questions about the potential antidepressant benefits of chronic OT administration. PMID- 23810434 TI - A response to the commentary "Indolamine 2,3-dioxygenase regulation and neuropsychiatric symptoms" by Loftis, J.M. on "Serotonin and interleukin-6: the role of genetic polymorphisms in IFN-induced neuropsychiatric symptoms" by Udina, M., Moreno-Espana, J., Navines, R., Gimenez, D., Langohr, K., Gratacos, M., Capuron, L., de la Torre, R., Sola, R., Martin-Santos, R. http:??dx.doi.org/10.1016/j.psyneuen.2013.03.007. PMID- 23810435 TI - Motor skills at 23 years of age in young adults born preterm with very low birth weight. AB - BACKGROUND: Motor skills have previously not been reported in young adults born with very low birth weight (VLBW), although they are commonly reported in children and adolescents. AIM: To compare fine and gross motor skills in VLBW young adults with matched term-born controls, and to study longitudinal changes in the VLBW group. STUDY DESIGN: A geographically based follow-up study of a VLBW group and a control group. SUBJECTS: Thirty-six VLBW (birth weight <= 1500 g) young adults, including four participants with cerebral palsy (CP), and 37 matched controls (birth weight >= 10th centile) were examined at 14 and 23 years of age. OUTCOME MEASURES: Fine and gross motor skills were assessed using Grooved Pegboard test (GP), Trail Making Test-5 (TMT-5), Movement Assessment Battery for Children-2 (Movement ABC-2) and High-level Mobility Assessment Tool (HiMAT). RESULTS: VLBW young adults were slower than controls on GP (p = 0.026) and TMT-5 (p < 0.001). Mean total Movement ABC-2 score was 69.7 +/- 20.2 in the VLBW group compared with 74.1 +/- 14.4 in the control group (p = 0.017). Differences were also seen in manual dexterity and balance. Additionally, HiMAT showed reduced balance and speed in gross motor skills in the VLBW group. The proportion of participants with motor problems did not change between age 14 and 23. After exclusion of participants with CP, scores were essentially the same. CONCLUSION: VLBW young adults had overall poorer fine and gross motor skills compared with controls. Reduced speed seemed to be an underlying problem. Longitudinal findings indicate that VLBW children have not outgrown their motor problems when entering adulthood. PMID- 23810436 TI - Emerging insights into florigen transport. AB - The photoperiodic control of flowering in plants begins with the perception of seasonal changes in day length and consequential induction of a mobile floral stimulus in leaves. This stimulus called florigen is transported from leaves to the shoot apical meristem to provoke the initiation of floral meristems. Decades of efforts have identified that the proteins encoded by FLOWERING LOCUS T (FT) in Arabidopsis and its orthologs in other plant species are part of the long-sought florigen. Emerging evidence suggests that long-distance transport of FT towards the shoot apical meristem occurs through the phloem in a regulated manner. This review summarizes the recent advances in understanding florigen transport and discusses the proven and potential regulators required for this process. PMID- 23810437 TI - Morphologic characterization and distribution of endocrine cells in the large intestine of the opossum Didelphis aurita (Wied-Neuwied, 1826). AB - This study was designed to investigate the morphology and distribution of argyrophil, argentaffins, and insulin-immunoreactive endocrine cells in the large intestine of the opossum Didelphis aurita. Fragments of the large intestine of 10 male specimens of the opossum D. aurita were collected, processed, and submitted for histochemistry, immunohistochemistry, and scanning electron microscopy. The tunics of the large intestine of D. aurita presented morphological characteristics that have already been described for eutherian mammals. The morphometric data showed that the inner circular layer of all portions and regions analyzed is thicker relative to the longitudinal layer, and these layers in the rectum are thicker compared to the cecum and ascending colon. The majority of mucus-secreting cells have acid and neutral mucins, suggesting that the production of mucus is mixed. The number of these cells increases in the region of the cecum toward the rectum. Important findings include the occurrence of argyrophil, argentaffins, and insulin-immunoreactive endocrine cells in all segments of the large intestine of the opossum (D. aurita). To the best of our knowledge, this is the first report about the presence of insulin-immunoreactive endocrine cells in the large intestine of the opossum (D. aurita). PMID- 23810438 TI - Smooth muscle tumor of uncertain malignant potential of the urinary bladder: a case report and review of the literature. PMID- 23810439 TI - Metabolic and prostate-specific antigen response after abiraterone acetate withdrawal: a new clinical scenario for castration-resistant prostate cancer? PMID- 23810440 TI - Influence of body mass index and smoking on the long-term survival of patients with renal cell cancer. AB - BACKGROUND: Smoking and obesity are known risk factors for renal cell carcinoma (RCC). We determined the influence of smoking, body mass index (BMI), and symptoms on the survival of patients with RCC. PATIENTS AND METHODS: In this retrospective study, the relative overall survival (OS) up to 25 years was calculated among 948 Finnish patients with RCC diagnosed between 1964 and 1997 using a Bayesian univariate analysis and the life-table method. RESULTS: Obese patients had better OS than did normal or underweight patients (median, 5.9 years, 3.4 years, and 12 months, respectively), with lower stage and more asymptomatic tumors at diagnosis and fewer relapses during surveillance. Clinical presentation of the tumor was a stronger prognostic factor than BMI; however, asymptomatic patients with a low BMI had poorer survival compared with normal or overweight patients. There was no difference in tumor stage or presentation at diagnosis between the nonsmokers and smokers; however, the smokers had more relapses with shorter disease-free intervals (DFIs) than did the nonsmokers. The OS was poorer in the smokers (4.2 years compared with 6.6 years in nonsmokers), but no difference was observed in cancer-specific survival (CSS). CONCLUSION: Overweight patients have better survival, with more asymptomatic or local tumors. The clinical presentation was a stronger prognostic factor than BMI. Additionally, survival is poorer in smokers, even if there is no difference in tumor stage or symptoms. PMID- 23810441 TI - Intermediate-term outcomes of robot-assisted laparoscopic nephroureterectomy in upper urinary tract urothelial carcinoma. AB - BACKGROUND: The purpose of this study was to evaluate the intermediate-term oncological outcomes after (RAL-NU) for UUT-UC. PATIENTS AND METHODS: Between May 2007 and December 2010, 32 patients with UUT-UC underwent RAL-NU. Data were obtained from a prospectively maintained database. RESULTS: Median patient age was 66.5 years. Final pathological stage was pathologic stage Ta (pTa) in 12.5% (n = 4) of patients, pT1 in 28.1% (n = 9), pT2 in 18.8% (n = 6), pT3 in 40.6% (n = 13), and pT4 in 0%. High-grade lesions were present in 81.2% (n = 26) of patients and multifocal disease was present in 25.0% (n = 8). Positive surgical margins occurred in 1 patient. Median follow-up was 45.5 months (range, 24-65). At 2 and 5 years, overall survival was 81.3% and 60.9%; cancer-specific survival was 87.3% and 75.8%, and nonurothelial recurrence-free survival was 71.5% and 68.1%, respectively. On univariate analysis, female sex, positive surgical margins, and pathological tumor stage pT2 and higher are associated with reduced recurrence-free survival (P = .035 and .011, respectively). On multivariate analysis, only female sex and pathological stage pT2 or higher were significant factors (P = .020 and .049, respectively). No factors were found to affect cancer specific survival. CONCLUSION: To our knowledge, this represents the largest and longest follow-up after RAL-NU to date. Intermediate-term oncological outcomes seem comparable with those of open and laparoscopic nephroureterectomy. We recommend further larger studies with longer follow-up periods to further define the role of RAL-NU in the treatment of UUT-UC. PMID- 23810442 TI - Yonsei criteria: a new protocol for active surveillance in the era of robotic and local ablative surgeries. AB - BACKGROUND: The objective of this study was to develop a new AS protocol and compare it with the existing selected published AS protocols by examining the pathological characteristics of post-RARP specimens in patients eligible for AS. MATERIALS AND METHODS: From a database of 1046 patients, 344 post-RARP patients with biopsy Gleason scores <= 6 prostate cancer (PCa) without neoadjuvant therapy were included. Six AS protocols were identified and evaluated for pathological and oncological end points. Four new AS criteria were proposed and evaluated. The probabilities of each end point were estimated using logistic regression modeling. Areas under the receiver operating curve were calculated for each protocol and end point. RESULTS: Across all the selected protocols, biochemical recurrence occurred in 0 to 1.9% of patients; extracapsular extension (ECE) in 0 to 5.9%; lymph node involvement (LNI) in 0 to 1.3%; and upgrading to Gleason score >= 7 in 12.9% to 36.4%. We found that our new AS criteria: cT1-cT2 PCa; biopsy Gleason score <= 6; prostate-specific antigen <= 10 ng/mL; <= 1 positive biopsy core; and <= 50% core involvement compared favorably with other protocols. Area under the receiver operating curve analyses showed good predictive power of our AS criteria for the pathological and oncological end points of our study. CONCLUSION: Existing AS protocols do not satisfactorily predict insignificant PCas in our cohort, hence necessitating the need for new AS criteria in the era of robotic and local ablative surgeries. No patients in our cohort had biochemical recurrence, LNI, or ECE of their PCas when our protocol was applied. PMID- 23810443 TI - Neutrophil and platelet complexes and their relevance to neutrophil recruitment and activation. AB - The manifestation of platelet 'satallitism' around neutrophils in whole blood is a long acknowledged phenomenon [1]. Circulating platelet-neutrophil complexes (PNC) occur in a diverse range of inflammatory disorders and infections that affect numerous organs of the body. Animal models have revealed that the formation of PNC is required for the recruitment of neutrophils to inflamed tissue, since platelets 'prime' neutrophils for efficient adhesion to vascular endothelium via the up-regulation of integrins and enhanced responsiveness to chemokines (Fig. 1). Perhaps surprisingly, the surface contact between platelets and neutrophils additionally enhances other neutrophil functions, such as chemotaxis that is required for migration into tissues, trans-cellular production of eicosanoids, phagocytosis and trapping of pathogens, increased respiratory burst leading to the production of reactive oxygen species (ROS), and modulation of neutrophil apoptosis (Fig. 1). Platelet P-selectin appears to have a particular role in enhancing the majority of these activities, and the influence of platelet P-selectin is not therefore confined to the initial rolling events in the process of neutrophil extravasation. PMID- 23810444 TI - 7b, a novel naphthalimide derivative, exhibited anti-inflammatory effects via targeted-inhibiting TAK1 following down-regulation of ERK1/2- and p38 MAPK mediated activation of NF-kappaB in LPS-stimulated RAW264.7 macrophages. AB - Inflammatory response plays an important role not only in the normal physiology but also in the pathology such as cancers. 7b, a novel naphthalimide-based DNA intercalator, has exhibited anti-inflammatory effects in phorbol12-myristate 13 acetate/phytohemagglutinin (PMA/PHA)-induced inflammatory responses of Jurkat T cells in our previous study. Here, we tried to further investigate its anti inflammatory potential and the possible underlying mechanisms in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and primary mouse macrophages. In our current study, ELISA and Real-time PCR revealed that non-toxic doses of 7b reduced the production and expression of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6) in LPS-induced RAW264.7 cells and primary mouse macrophages. Moreover, 7b dose-dependently suppressed the production of prostaglandin E2 (PGE2), nitric oxide (NO). Except for COX-1, non-toxic doses of 7b exhibited parallel inhibition of LPS-induced expression of COX-2 and iNOS at both mRNA and protein levels. The molecular mechanism was associated with inhibition of the phosphorylation/degradation of IkappaB-alpha and nuclear translocation of the NF kappaB p65. Further analysis of upstream mechanisms showed that blocking of NF kappaB activation by 7b was mediated by inhibiting TAK1-downstream extracellular signal-regulated kinase (ERK1/2) and p38 kinase signal pathway. Taken together, these results indicated that 7b exhibited anti-inflammatory effects by targeting inhibiting TAK1, leading to ERK1/2- and p38 MAPK-mediated inactivation of NF kappaB in LPS-stimulated RAW264.7 cells, and this would make 7b a strong candidate for further study as anti-inflammatory agent. PMID- 23810445 TI - Suppression of inducible nitric oxide synthase expression induced by Toll-like receptor agonists by (E)-1-(2-(2-nitrovinyl)phenyl)pyrrolidine. AB - Toll-like receptors (TLRs) recognize many pathogen-associated molecular patterns and induce innate immunity. TLR signaling pathways induce the activation of various transcription factors, such as nuclear factor-kappaB (NF-kappaB), leading to the induction of pro-inflammatory gene products, such as inducible nitric oxide synthase (iNOS). Here, we investigated the effect of an (E)-1-(2-(2 nitrovinyl)phenyl)pyrrolidine (NVPP), previously synthesized in our laboratory, on inflammation by modulating NF-kappaB activation and iNOS expression induced by TLR agonists in murine macrophages. NVPP suppressed NF-kappaB activation and iNOS expression induced by lipopolysaccharide (TLR4 agonist), polyriboinosinic polyribocytidylic acid (TLR3 agonist), and macrophage-activating lipopeptide 2kDa (TLR2 and TLR6 agonist). All the results suggest that NVPP is suitable for development as a new anti-inflammatory drug. PMID- 23810446 TI - Clinical outcomes of intraocular lens scaffold surgery: a one-year study. AB - PURPOSE: To evaluate the safety and 1-year outcome of the intraocular lens (IOL) scaffold technique in eyes with soft to moderate nuclear remnants after intraoperative posterior capsule rupture (PCR). DESIGN: Single-center, retrospective, interventional, noncomparative, consecutive case series. PARTICIPANTS: A total of 20 eyes of 20 patients who had intraoperative PCR underwent IOL scaffold surgery in a tertiary clinic. METHODS: A retrospective analysis of medical records of a consecutive series of patients who underwent IOL scaffold surgery from August 2011 to February 2013 was reviewed. All surgeries were performed by a single surgeon, and a 3-piece, 6.0-mm optic, acrylic, foldable IOL with a modified C-loop haptic configuration was implanted in all eyes. MAIN OUTCOME MEASURES: The preoperative and postoperative parameters evaluated were uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), specular microscopy, gonioscopy, ultrasound biomicroscopy, central macular thickness, intraocular pressure (IOP), and anterior and posterior segment inflammation. The final visual outcome at 1 year was evaluated. RESULTS: At 1-year follow-up, the mean postoperative UDVA and CDVA in Snellen's decimal equivalent was 0.58 +/- 0.15 and 0.90 +/- 0.17, respectively. The IOL was placed in the sulcus for 14 eyes and in the capsular bag for 3 eyes, and glued intrascleral fixation of IOL was performed in 3 eyes. The mean postoperative refractive error at the final examination was -0.4 +/- 0.05 diopter (standard error of mean). Postoperative CDVA of 20/20 and 20/30 was achieved in 75% (15 eyes) and 25% (5 eyes), respectively. There was no correlation between preoperative specular count and percentage loss of cells (P = 0.602; r(2)=0.015). The mean central macular thickness at 1 year was 182.5 +/- 11.79 MUm. Clinical macular edema was observed in 1 of 20 eyes (5%). CONCLUSIONS: The IOL scaffold provided an effective, relatively noninvasive means of emulsifying moderate to soft nuclear remnants in eyes with intraoperative PCR, with a good visual outcome and a favorable complication rate. PMID- 23810447 TI - A rudimentary tragus in the nasopharynx: case report, literature review, and discussion of embryologic development. AB - We describe the rare case of a nine year-old girl with a several month history of mouth breathing and nasal obstruction due to a rudimentary tragus in the nasopharynx. We focus on the accessory tragus and its origins by describing the embryologic development of the external ear. Based on our review of the medical literature, this is the first report of a nasopharyngeal mass with a pathologic diagnosis of a rudimentary tragus. PMID- 23810448 TI - Brain circuitry mediating arousal from obstructive sleep apnea. AB - Obstructive sleep apnea (OSA) is a disorder of repetitive sleep disruption caused by reduced or blocked respiratory airflow. Although an anatomically compromised airway accounts for the major predisposition to OSA, a patient's arousal threshold and factors related to the central control of breathing (ventilatory control stability) are also important. Arousal from sleep (defined by EEG desynchronization) may be the only mechanism that allows airway re-opening following an obstructive event. However, in many cases arousal is unnecessary and even worsens the severity of OSA. Mechanisms for arousal are poorly understood. However, accumulating data are elucidating the relevant neural pathways and neurotransmitters. For example, serotonin is critically required, but its site of action is unknown. Important neural substrates for arousal have been recently identified in the parabrachial complex (PB), a visceral sensory nucleus in the rostral pons. Moreover, glutamatergic signaling from the PB contributes to arousal caused by hypercapnia, one of the arousal-promoting stimuli in OSA. A major current focus of OSA research is to find means to maintain airway patency during sleep, without sleep interruption. PMID- 23810449 TI - Midgut morphophysiology in Sitophilus zeamais Motschulsky, 1855 (Coleoptera: Curculionidae). AB - Sitophilus zeamais is one of the most aggressive pests of stored grains, causing a significant decrease in the nutritional quality of the grains and major losses in economic trade. The foraging capacity of this pest is assigned to its highly efficient digestive system. Investigations on the morphofunctional features of the midgut, which is the most active region of the alimentary canal, are fundamental to understand the feeding habits of this species. In this study, the midgut of adult insects was isolated, processed, and analyzed on light microscopy, scanning and transmission electron microscopy, protein and enzymatic activities determination, including analyses of the starch hydrolysis products. In S. zeamais, the midgut was differentiated into anterior midgut and posterior midgut, and consisted of digestive, regenerative and endocrine cells. The anterior midgut showed high density of regenerative crypts. Cells containing organelles associated with protein synthesis and presence of amylases and lipases indicated that majority of the digestion process occurred in the anterior midgut. The posterior midgut exhibited numerous gastric caeca and peritrophic membrane. Cells with poorly differentiated cytoplasmic into organelles, elongated microvilli, and low enzymatic activities indicated that the posterior midgut was mainly involved in absorption. PMID- 23810451 TI - Repair of multiple finger defects using the dorsal homodigital island flaps. AB - BACKGROUND: Providing soft-tissue coverage for multiple finger defects remains a challenge for the hand surgeons. This article reports reconstruction of multiple digital defects using the dorsal homodigital island flaps based on the dorsal branch of the digital artery. METHODS: Over 3 years, a retrospective study was conducted with 12 patients who had multiple finger defects treated with the dorsal homodigital island flaps. Our series included nine male and three female patients. There were 30 soft-tissue defects in 30 fingers. The injured fingers included seven index, nine long, nine ring and five little fingers. The average size of soft-tissue defects and flaps was 2.4 +/- 0.4 cm * 1.7 +/- 0.2 cm and 2.6 +/- 0.4 cm * 1.9 +/- 0.2 cm, and the mean pedicle length was 1.1 +/- 0.2 cm. RESULTS: Full flap survival was achieved in 26 fingers. Partial distal flap necrosis was noted in four fingers, which healed without surgical intervention. At a median of 20 (range, 19-23) months' follow-up, the static two-point discrimination on the flap averaged 9.1 +/- 1.6 mm, and the median (range) Semmes Weinstein monofilament score was 3.84 (3.84-4.17). The donor-site morbidity was accepted. According to the Michigan Hand Outcomes Questionnaire, seven patients were strongly satisfied and five were satisfied with functional recovery of the reconstructed fingers. CONCLUSIONS: The dorsal homodigital island flap, based on the dorsal branch of the digital artery, is less invasive, versatile and technically easy for simultaneous coverage of small-to-moderate defects in multiple fingers. PMID- 23810452 TI - Comparison of circumferential pelvic sheeting versus the T-POD on unstable pelvic injuries: A cadaveric study of stability. AB - OBJECTIVES: Commercially available binder devices are commonly used in the acute treatment of pelvic fractures, while many advocate simply placing a circumferential sheet for initial stabilization of such injuries. We sought to determine whether or not the T-POD would provide more stability to an unstable pelvic injury as compared to circumferential pelvic sheeting. METHODS: Unstable pelvic injuries (OTA type 61-C-1) were surgically created in five fresh, lightly embalmed whole human cadavers. Electromagnetic sensors were placed on each hemi pelvis. The amount of angular motion during testing was measured using a Fastrak, three-dimensional, electromagnetic motion analysis device (Polhemus Inc., Colchester, VT). Either a T-POD or circumferential sheet was applied in random order for testing. The measurements recorded in this investigation included maximum displacements for sagittal, coronal, and axial rotation during application of the device, bed transfer, log-rolling, and head of bed elevation. RESULTS: There were no differences in motion of the injured hemi-pelvis during application of either the T-POD or circumferential sheet. During the bed transfer, log-rolling, and head of bed elevation, there were no significant differences in displacements observed when the pelvis was immobilized with either a sheet or pelvic binder (T-POD). CONCLUSIONS: A circumferential pelvic sheet is more readily available, costs less, is more versatile, and is equally as efficacious at immobilizing the unstable pelvis as compared to the T-POD. We advocate the use of circumferential sheeting for temporary stabilization of unstable pelvic injuries. PMID- 23810450 TI - Clearance of the mutant androgen receptor in motoneuronal models of spinal and bulbar muscular atrophy. AB - Spinal and bulbar muscular atrophy (SBMA) is an X-linked motoneuron disease caused by an abnormal expansion of a tandem CAG repeat in exon 1 of the androgen receptor (AR) gene that results in an abnormally long polyglutamine tract (polyQ) in the AR protein. As a result, the mutant AR (ARpolyQ) misfolds, forming cytoplasmic and nuclear aggregates in the affected neurons. Neurotoxicity only appears to be associated with the formation of nuclear aggregates. Thus, improved ARpolyQ cytoplasmic clearance, which indirectly decreases ARpolyQ nuclear accumulation, has beneficial effects on affected motoneurons. In addition, increased ARpolyQ clearance contributes to maintenance of motoneuron proteostasis and viability, preventing the blockage of the proteasome and autophagy pathways that might play a role in the neuropathy in SBMA. The expression of heat shock protein B8 (HspB8), a member of the small heat shock protein family, is highly induced in surviving motoneurons of patients affected by motoneuron diseases, where it seems to participate in the stress response aimed at cell protection. We report here that HspB8 facilitates the autophagic removal of misfolded aggregating species of ARpolyQ. In addition, though HspB8 does not influence p62 and LC3 (two key autophagic molecules) expression, it does prevent p62 bodies formation, and restores the normal autophagic flux in these cells. Interestingly, trehalose, a well-known autophagy stimulator, induces HspB8 expression, suggesting that HspB8 might act as one of the molecular mediators of the proautophagic activity of trehalose. Collectively, these data support the hypothesis that treatments aimed at restoring a normal autophagic flux that result in the more efficient clearance of mutant ARpolyQ might produce beneficial effects in SBMA patients. PMID- 23810453 TI - Ethos, mythos, and thanatos: spirituality and ethics at the end of life. AB - Every ethos implies a mythos in the sense that every systematic approach to ethics is inevitably based on some fundamental religious or religion-like story that gives answers to questions such as: Where did I come from? Where am I going? How am I to live? These narratives generally lay hidden beneath the plane of the interpersonal interactions that characterize all clinical encounters, but caring for patients who are approaching death brings them closer to the surface. For many patients and practitioners, these narratives will be expressed in explicitly religious language; others may invoke a sense of "immanent transcendence" that affords a spiritual perspective without requiring theism or notions of eternity. In caring for patients at the end of life, practitioners should strive to be more conscious of the narratives that undergird their own spiritual and ethical positions as well as seek to understand those of the patients they serve. PMID- 23810454 TI - Central auditory processing during chronic tinnitus as indexed by topographical maps of the mismatch negativity obtained with the multi-feature paradigm. AB - This study aimed to compare the neural correlates of acoustic stimulus representation in the auditory sensory memory on an automatic basis between tinnitus subjects and normal hearing (NH) controls, using topographical maps of the MMNs obtained with the multi-feature paradigm. A new and faster paradigm was adopted to look for differences between 2 groups of subjects. Twenty-eight subjects with chronic subjective idiopathic tinnitus and 33 matched healthy controls were included in the study. Brain electrical activity mapping of multi feature MMN paradigm was recorded from 32 surface scalp electrodes. Three MMN parameters for five deviants consisting frequency, intensity, duration, location and silent gap were compared between the two groups. The MMN amplitude, latency and area under the curve over a region of interest comprising: F3, F4, Fz, FC3, FC4, FCz, and Cz were computed to provide better signal to noise ratio. These three measures could differentiate the cognitive processing disturbances in tinnitus sufferers. The MMN topographic maps revealed significant differences in amplitude and area under the curve for frequency, duration and silent gap deviants in tinnitus subjects compared to NH controls. The current study provides electrophysiological evidence supporting the theory that the pre-attentive and automatic central auditory processing is impaired in individuals with chronic tinnitus. Considering the advantages offered by the MMN paradigm used here, these data might be a useful reference point for the assessment of sensory memory in tinnitus patients and it can be applied with reliability and success in treatment monitoring. PMID- 23810455 TI - Forelimb amputation-induced reorganization in the cuneate nucleus (CN) is not reflected in large-scale reorganization in rat forepaw barrel subfield cortex (FBS). AB - We examined reorganization in cuneate nucleus (CN) in juvenile rat following forelimb amputation (n=34) and in intact controls (n=5) to determine whether CN forms a substrate for large-scale reorganization in forepaw barrel subfield (FBS) cortex. New input from the shoulder first appears in the FBS 4 weeks after amputation, and by 6 weeks, the new shoulder input comes to occupy most of the FBS. Electrophysiological recording was used to map CN in controls and in forelimb amputees during the first 12 weeks following deafferentation and at 26 and 30 weeks post-amputation. Mapping was confined to a location 300 MUm anterior to the obex where a medial-to-lateral row of electrode penetrations traversed through a complete complement of cytochrome-oxidase stained clusters (called barrelettes) that are associated with the representation of the glabrous forepaw digits and pads and adjacent non-cluster zones that are associated with the representation of the wrist, arm, and shoulder. Following amputation, non-cluster zones became occupied with new input from the body/chest and head/neck, while the cluster zone remained largely devoid of new input except at the border. A regression analysis comparing controls and amputees over the first 12 weeks post amputation found significant differences for the total area of new input from the body/chest and head/neck in the non-cluster zones, while no significant differences were found for any new input into the cluster zone. When the averaged areas of a body-part representation were re-examined as a percentage of the averaged zonal area, a non-significant increase in new input from the body was observed within the cluster zone during post-amputation weeks 2-3 that returned to baseline in the subsequent weeks. In contrast, significant differences in averaged area of body-part representations for body/chest and head/neck were found in non-cluster zones over the first 12 weeks post-amputation. The present findings suggest that reorganization occurs only within the non-cluster zones whereby new input from the body/chest and head/neck moves in and occupies the deafferented territory immediately after amputation. Additionally, the lack of significant differences in new shoulder input in either cluster or non-cluster zones over the first 12 weeks after amputation suggests that CN provides an unlikely substrate for large-scale reorganization in the FBS. PMID- 23810456 TI - Management of tumour spillage during parotid surgery for pleomorphic adenoma. AB - Over the decades parotid surgery for benign tumours has developed into a reproducible, conservative operation with low morbidity. Despite the advances tumour spillage can still occur, and its management remains controversial. Since no universal consensus exists the aim of this article is to review the approach to tumour spillage and derive a protocol for its management based on existing evidence. PMID- 23810457 TI - Relation between preoperative computed tomographic criteria of injury to the nasofrontal outflow tract and operative findings in fractures of the frontal sinus. AB - Injury to the nasofrontal outflow tract is important in the treatment of fractures of the frontal sinus. In 2008 preoperative computed tomographic (CT) criteria or signs of such injuries were proposed and stated to be reliable. The aim of this study was to evaluate the validity of these criteria by comparing the radiological evidence with the operative findings. Thirty-nine patients for whom the data from preoperative CT could be compared with operative findings were eligible for the study, all but 4 of whom had at least one indicator of injury to the outflow tract. Patients whose tracts were found to be obstructed at operation had at least 2 preoperative CT signs of obstruction of the tract. If the outflow tract was obstructed all 3 criteria were significantly more likely to be present than if it was intact (p=0.02). Two criteria or fewer did not correlate significantly with obstruction. Fractures were managed by reconstruction (n=18), obliteration (n=11), or cranialisation (n=10). This study is the first to our knowledge to examine the correlation between preoperative CT criteria and operative findings, and there was a significant difference in the number of criteria present depending on whether the outflow tract was intact or injured. Our findings allow for more accurate planning of management of fractures of the frontal sinus. PMID- 23810458 TI - A rat model of metastatic spinal cord compression using human prostate adenocarcinoma: histopathological and functional analysis. AB - BACKGROUND CONTEXT: Cancer is a major global public health problem responsible for one in every four deaths in the United States. Prostate cancer alone accounts for 29% of all cancers in men and is the sixth leading cause of death in men. It is estimated that up to 30% of patients with cancer will develop metastatic disease, the spine being one of the most frequently affected sites in patients with prostate cancer. PURPOSE: To study this condition in a preclinical setting, we have created a novel animal model of human metastatic prostate cancer to the spine and have characterized it histologically, functionally, and via bioluminescence imaging. STUDY DESIGN: Translational science investigation of animal model of human prostate cancer in the spine. METHODS: Luciferase-positive human prostate tumor cells PC3 (PC3-Luc) were injected in the flank of athymic male rats. PC3-Luc tumor samples were then implanted into the L5 vertebral body of male athymic rats (5 weeks old). Thirty-two rats were randomized into three surgical groups: experimental, control, and sham. Tumor growth was assessed qualitatively and noninvasively via bioluminescence emission, upon luciferin injection. To determine the functional impact of tumor growth in the spine, rats were evaluated for gait abnormalities during gait locomotion using video-assisted gait analysis. Rats were euthanized 22 days after tumor implantation, and spines were subjected to histopathological analyses. RESULTS: Twenty days after tumor implantation, the tumor-implanted rats showed distinct signs of gait disturbances: dragging tail, right- or left-hind limb uncoordination, and absence of toe clearance during forward limb movement. At 20 days, all rats experienced tumor growth, evidenced by bioluminescent signal. Locomotion parameters negatively affected in tumor-implanted rats included stride length, velocity, and duration. At necropsy, all spines showed evidence of tumor growth, and the histological analysis found spinal cord compression and peritumoral osteoblastic reaction characteristic of bony prostate tumors. None of the rats in the sham or control groups demonstrated any evidence of bioluminescence signal or signs of gait disturbances. CONCLUSIONS: In this project, we have developed a novel animal model of metastatic spine cancer using human prostate cancer cells. Tumor growth, evaluated via bioluminescence and corroborated by histopathological analyses, affected hind limb locomotion in ways that mimic motor deficits present in humans afflicted with metastatic spine disease. Our model represents a reliable method to evaluate the experimental therapeutic approaches of human tumors of the spine in animals. Gait locomotion and bioluminescence analyses can be used as surrogate noninvasive methods to evaluate tumor growth in this model. PMID- 23810459 TI - Cell surface-associated compounds of probiotic lactobacilli sustain the strain specificity dogma. AB - Probiotic lactobacilli can positively impact on the health status of targeted (diseased) populations but efficacy depends strongly on the strain employed and the molecular basis for this phenomenon is poorly understood. This review discusses the current state-of-the-art in the field of molecular probiotic-host interactions, focusing on subtle strain-specific differences in the biochemical characteristics of cell surface-associated probiotic ligands and the consequences thereof for the immune responses elicited. This research is bound to enhance our understanding of strain-specificity in relation to probiotic functionality and will allow molecular science-based design of screening and characterization assays targeted to improved selection of probiotic candidate strains. Moreover, identified bioactive effector molecules could be isolated or produced for administration in a more pharmacological regime. PMID- 23810460 TI - Electroacupuncture at acupoints could predict the outcome of anterior nucleus thalamus high-frequency electrical stimulation in medically refractory epilepsy. AB - Preliminary reports have demonstrated that anterior nucleus thalamus high frequency electrical stimulation (ANT-HFS) is an effective treatment for patients who suffer from medically refractory epilepsy. However, its extensive application has been hampered by the high cost and the unpredictable outcome before the operation. Just like ANT-HFS in the brain, electroacupuncture (EA) at acupoints with electrical stimulation is also efficient in treating medically refractory epilepsy. Although the therapeutic mechanisms involve different activated positions, the neurotransmitters generated by the electrical stimulation are similar. It has been demonstrated that both ANT-HFS and EA at acupoints are related to an imbalance between the excitatory [glutamate (Glu), aspartate (Asp)] and inhibitory [GABA, glycine (Gly) and taurine (Tau)] neuronal transmitters. We, therefore, hypothesize that outcome of EA at acupoints can predict the therapeutic effect of ANT-HFS. PMID- 23810461 TI - Study on the regulation of cell adhesion molecule expression and function in placenta from women with intrahepatic cholestasis of pregnancy. AB - Intrahepatic cholestasis of pregnancy (ICP) is a common complication of pregnancy manifested as skin pruritus of cholestasis. ICP occurs mainly in the second or third trimester of pregnancy and may cause fetal distress, unexpected intrauterine fetal death and does serious harm to maternal and fetal health. The pathogenesis of ICP is still unclear. In ICP placentas, placental syncytiotrophoblasts are the most direct contact between maternal high bile acid environment and fetus. Our previous study found that in ICP placental syncytiotrophoblasts, both mRNA expression level and protein expression level of vascular cell adhesion molecule-1 (VCAM-1), were significantly elevated. Since VCAM-1 is important in inflammatory injury of lymphocytes, we speculate that ICP pathogenesis may be associated with VCAM-1 up-regulation which may lead to inflammatory injury and cause intrauterine fetal distress, intrauterine fetal death and other adverse outcomes. Elucidation of this mechanism should help reveal the ICP pathogenesis and facilitate the clinical treatment of intrauterine fetal death. PMID- 23810462 TI - Therapeutics for HIV-1 reactivation from latency. AB - Intensive combined antiretroviral therapy successfully suppresses HIV-1 replication and AIDS disease progression making infection manageable, but it is unable to eradicate the virus that persists in long-lived, drug-insensitive and immune system-insensitive reservoirs thus asking for life-long treatments with problems of compliance, resistance, toxicity and cost. These limitations and recent insights into latency mechanisms have fueled a renewed effort in finding a cure for HIV-1 infection. Proposed eradication strategies involve reactivation of the latent reservoir upon induction of viral transcription followed by the elimination of reactivated virus-producing cells by viral cytopathic effect or host immune response. Several molecules identified by mechanism-directed approaches or in large-scale screenings have been proposed as latency reversing agents. Some of them have already entered clinical testing in humans but with mixed or unsatisfactory results. PMID- 23810463 TI - Mechanistic modeling of destratification in cryogenic storage tanks using ultrasonics. AB - Stratification is one of the main causes for vaporization of cryogens and increase of tank pressure during cryogenic storage. This leads subsequent problems such as cavitation in cryo-pumps, reduced length of storage time. Hence, it is vital to prevent stratification to improve the cost efficiency of storage systems. If stratified layers exist inside the tank, they have to be removed by suitable methods without venting the vapor. Sonication is one such method capable of keeping fluid layers mixed. In the present work, a mechanistic model for ultrasonic destratification is proposed and validated with destratification experiments done in water. Then, the same model is used to predict the destratification characteristics of cryogenic liquids such as liquid nitrogen (LN2), liquid hydrogen (LH2) and liquid ammonia (LNH3). The destratification parameters are analysed for different frequencies of ultrasound and storage pressures by considering continuous and pulsed modes of ultrasonic operation. From the results, it is determined that use of high frequency ultrasound (low power/continuous; high-power/pulsing) or low frequency ultrasound (continuous operation with moderate power) can both be effective in removing stratification. PMID- 23810464 TI - Do psychiatric disorders continue during pregnancy in women with hyperemesis gravidarum: a prospective study. AB - OBJECTIVE: We aimed to determine Axis I psychiatric disorders in women with hyperemesis gravidarum (HG) and to follow up the course of psychiatric disorder and its association with nausea and vomiting (NV) during pregnancy. METHODS: The study sample was composed of 47 patients with HG. Psychiatric interviews were conducted using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (SCID-I). Other psychiatric interviews were performed in the second and third trimesters. On each visit, the subjects completed the Beck Depression Inventory and the Beck Anxiety Inventory. RESULTS: The prevalence of any anxiety disorder was 25.5%, and the prevalence of any mood disorder was 14.9% in women with HG in the first trimester. Psychiatric disorders continued throughout the pregnancy in two thirds of the women who had HG and a psychiatric diagnosis. Any SCID diagnosis in the first trimester was higher in women whose NV had partially resolved than in women whose NV had fully resolved (P<.05). CONCLUSION: The present studies suggest that psychiatric disorders may play a significant role in the etiology of HG. Our findings presented a potential connection between HG and anxiety disorders and major depressive disorder. Additionally, the NV symptoms in women with HG and a psychiatric disorder may persist during pregnancy. PMID- 23810466 TI - A multicentre randomised trial comparing weekly paclitaxel + S-1 with weekly paclitaxel + 5-fluorouracil for patients with advanced gastric cancer. AB - PURPOSE: This study aimed to compare the efficacy and toxicity of weekly paclitaxel plus S-1 with weekly paclitaxel plus 5-fluorouracil in treating advanced gastric cancer as first line regimen. The primary end-point was disease control rate (DCR). METHODS: Patients with advanced or recurrent gastric cancer were randomly assigned to an experimental arm or a control arm. The experimental arm's dosage schedule was paclitaxel 60 mg/m2 (intravenous infusion) on days 1, 8 and 15 and S-1 80-120 mg/d (oral administration) on days 1-14. Control arm patients were given the same paclitaxel, combined with 5-fluorouracil 500 mg/m2 (continuous intravenous infusion) on days 1-5; and leucovorin 20 mg/m2 (intravenous infusion) on days 1-5. All schedules were repeated every 28 d. RESULTS: A total of 240 patients were enrolled and equally randomised into two arms. The overall response rate and DCR of the experimental arm was non-inferior to that of the control arm both in the per-protocol set and the full analysis set. The secondary end-point median progression-free survival (PFS) of the experimental and control arms was 153 and 129 d, with the hazard ratio of 0.641 (95% CI: 0.473-0.868, P = 0.004). The hazard ratio of the time to treatment failure of the two arms was 1.449 (95% CI: 0.705-2.980, P = 0.229). The six-month PFS rates of both arms were similar (31.3% versus 31.8%, P = 0.94). Cox regression analysis indicated that only treatment regimen and age were independent predictive factors for PFS. The most common adverse events were haematological and gastrointestinal. The rates of grade 3-4 adverse events were not significantly different between the two study arms and were mostly lower than 5%. CONCLUSION: Weekly paclitaxel combined with S-1 is an active and well tolerated regimen, supporting the view that S-1 can be an alternative for infusional 5-fluorouracil for advanced gastric cancer. PMID- 23810468 TI - Organism, machine, artifact: The conceptual and normative challenges of synthetic biology. AB - Synthetic biology is an emerging discipline that aims to apply rational engineering principles in the design and creation of organisms that are exquisitely tailored to human ends. The creation of artificial life raises conceptual, methodological and normative challenges that are ripe for philosophical investigation. This special issue examines the defining concepts and methods of synthetic biology, details the contours of the organism-artifact distinction, situates the products of synthetic biology vis-a-vis this conceptual typology and against historical human manipulation of the living world, and explores the normative implications of these conclusions. In addressing the challenges posed by emerging biotechnologies, new light can be thrown on old problems in the philosophy of biology, such as the nature of the organism, the structure of biological teleology, the utility of engineering metaphors and methods in biological science, and humankind's relationship to nature. PMID- 23810465 TI - Correlates of depressive symptoms among at-risk youth presenting to the emergency department. AB - OBJECTIVE: The study's objective was to identify correlates of depressive symptoms among at-risk youth in an urban emergency department (ED). METHOD: A systematic sample of adolescents (ages 14-18) in the ED were recruited as part of a larger study. Participants reporting past-year alcohol use and peer aggression self-administered a survey assessing: demographics, depressive symptoms and risk/protective factors. Logistic regression identified factors associated with depressive symptoms. RESULTS: Among 624 adolescents (88% response rate) meeting eligibility criteria, 22.8% (n=142) screened positive for depressive symptoms. In logistic regression, depressive symptoms were positively associated with female gender [odds ratio (OR): 2.84, 95% confidence interval (CI): 1.78-4.51], poor academic performance (OR: 1.57, 95% CI: 1.01-2.44), binge drinking (OR: 1.88, 95% CI: 1.21-2.91), community violence exposure (OR: 2.25, 95% CI: 1.59-3.18) and dating violence (OR: 2.14, 95% CI: 1.36-3.38) and were negatively associated with same-sex mentorship (OR: 0.52, 95% CI: 0.29-0.91) and older age (OR: 0.55, 95% CI 0.34-0.89). Including gender interaction terms did not significantly change findings. CONCLUSIONS: Screening and intervention approaches for youth in the urban ED should address the co-occurrence of depressive symptoms with peer and dating violence, alcohol and nonmarijuana illicit drug use. PMID- 23810467 TI - A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer. AB - BACKGROUND: Poly(ADP-ribose) polymerase (PARP)-inhibitors and anti-angiogenics have activity in recurrent ovarian and breast cancer; however, the effect of combined therapy against PARP and angiogenesis in this population has not been reported. We investigated the toxicities and recommended phase 2 dosing (RP2D) of the combination of cediranib, a multitargeted inhibitor of vascular endothelial growth factor receptor (VEGFR)-1/2/3 and olaparib, a PARP-inhibitor (NCT01116648). METHODS: Cediranib tablets once daily and olaparib capsules twice daily were administered orally in a standard 3+3 dose escalation design. Patients with recurrent ovarian or metastatic triple-negative breast cancer were eligible. Patients had measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or met Gynecologic Cancer InterGroup (GCIG) CA125 criteria. No prior PARP-inhibitors or anti-angiogenics in the recurrent setting were allowed. RESULTS: 28 patients (20 ovarian, 8 breast) enrolled to 4 dose levels. 2 dose limiting toxicities (DLTs) (1 grade 4 neutropenia >= 4 days; 1 grade 4 thrombocytopenia) occurred at the highest dose level (cediranib 30 mg daily; olaparib 400 mg twice daily [BID]). The RP2D was cediranib 30 mg daily and olaparib 200 mg BID. Grade 3 or higher toxicities occurred in 75% of patients, and included grade 3 hypertension (25%) and grade 3 fatigue (18%). One grade 3 bowel obstruction occurred. The overall response rate (ORR) in the 18 RECIST evaluable ovarian cancer patients was 44%, with a clinical benefit rate (ORR plus stable disease (SD) > 24 weeks) of 61%. None of the seven evaluable breast cancer patients achieved clinical response; two patients had stable disease for > 24 weeks. INTERPRETATION: The combination of cediranib and olaparib has haematologic DLTs and anticipated class toxicities, with promising evidence of activity in ovarian cancer patients. PMID- 23810469 TI - A dark business, full of shadows: analogy and theology in William Harvey. AB - In a short work called De conceptione appended to the end of his Exercitationes de generatione animalium (1651), William Harvey developed a rather strange analogy. To explain how such marvelous productions as living beings were generated from the rather inauspicious ingredients of animal reproduction, Harvey argued that conception in the womb was like conception in the brain. It was mostly rejected at the time; it now seems a ludicrous theory based upon homonymy. However, this analogy offers insight into the structure and function of analogies in early modern natural philosophy. In this essay I hope to not only describe the complex nature of Harvey's analogy, but also offer a novel interpretation of his use of analogical reasoning, substantially revising the account offered by Guido Giglioni (1993). I discuss two points of conceptual change and negotiation in connection with Harvey's analogy, understanding it as both a confrontation between the border of the natural and the supernatural, as well as a moment in the history of psychology. My interpretation touches upon a number of important aspects, including why the analogy was rejected, how Harvey systematically deployed analogies according to his notions of natural philosophical method, how the analogy fits into contemporary discussions of analogies in science, and finally, how the analogy must be seen in the context of changing Renaissance notions of the science of the soul, ultimately confronting the problem of how to understand final causality in Aristotelian science. In connection with the last, I conclude the essay by turning to how Harvey embeds the analogy within a natural theological cosmology. PMID- 23810470 TI - Organisms ? Machines. AB - The machine conception of the organism (MCO) is one of the most pervasive notions in modern biology. However, it has not yet received much attention by philosophers of biology. The MCO has its origins in Cartesian natural philosophy, and it is based on the metaphorical redescription of the organism as a machine. In this paper I argue that although organisms and machines resemble each other in some basic respects, they are actually very different kinds of systems. I submit that the most significant difference between organisms and machines is that the former are intrinsically purposive whereas the latter are extrinsically purposive. Using this distinction as a starting point, I discuss a wide range of dissimilarities between organisms and machines that collectively lay bare the inadequacy of the MCO as a general theory of living systems. To account for the MCO's prevalence in biology, I distinguish between its theoretical, heuristic, and rhetorical functions. I explain why the MCO is valuable when it is employed heuristically but not theoretically, and finally I illustrate the serious problems that arise from the rhetorical appeal to the MCO. PMID- 23810471 TI - Estimating maternal mortality and causes in South Africa: national and provincial levels. AB - OBJECTIVES: maternal mortality estimates for South Africa have methodological weaknesses. This study uses the Growth Balance Method to adjust reported household female deaths and pregnancy-related deaths and the relational Gompertz model to adjust reported number of live births and estimate maternal mortality in South Africa at national and provincial level; examines the potential impact of HIV/AIDS prevalence; and investigates the recorded direct causes of maternal mortality. DESIGN: data from the 2001 Census, 2007 Community Survey and death registrations were utilised. Information on household deaths, including pregnancy related deaths was collected from the aforementioned census and survey. SETTING: enumerated households in the 2001 Census and a nationally representative sample of 250,348 households in the 2007 Community Survey. PARTICIPANTS: information about members of households who died in the preceding 12 months was collected, and of these deaths whether there were women aged 15-49 who died while pregnant or within 42 days after childbirth. FINDINGS: maternal mortality ratio of 764 per 100,000 live births in 2007, ranging from 102 per 100,000 live births in the Western Cape province to 1639 in the Eastern Cape. Maternal infections and parasitic diseases as well as other maternal diseases complicating pregnancy, childbirth and the puerperium are the major causes. The study found a weak correlation between provincial HIVprevalence and maternal mortality ratio. CONCLUSION: despite strategies to improve maternal and child health, maternal mortality remains high in South Africa and it is unlikely that the Millennnium Developmemnt Goal of reducing maternal will be achieved. PMID- 23810472 TI - Endoscopic transethmoidal approach with or without medial rectus detachment for orbital apical cavernous hemangiomas. AB - PURPOSE: To determine the indications for the addition of a transcaruncular approach along with detachment of the medial rectus muscle during the removal of small apical cavernous hemangiomas using an endoscopic transethmoidal approach. DESIGN: Retrospective, noncomparative case series. METHODS: Multicenter study of 12 patients with apical orbital tumors removed using an endoscopic transethmoidal approach. The decision to detach the medial rectus muscle with the addition of a transcaruncular approach was made during surgery for tumors largely lateral to the medial rectus muscle. Tumors adjacent to the medial orbital wall were removed via an endoscopic transethmoidal approach alone. RESULTS: Seven tumors were removed via an endoscopic transethmoidal approach combined with medial rectus muscle detachment, whereas 5 patients underwent removal without detachment of the medial rectus. All patients had visual impairment. Complete excision of the hemangiomas was achieved in all patients and tumor size ranged from 6 * 5 mm to 20 * 12 mm. The mean postoperative follow-up time was 11.8 +/- 4.3 months. At final follow-up, the best-corrected visual acuity improved in 11 patients. Three patients had transient horizontal diplopia resulting from partial paralysis of the medial rectus muscle after detachment during surgery. CONCLUSIONS: The endoscopic transethmoidal approach with or without medial rectus detachment is a promising approach for selected small cavernous hemangiomas located at the deep medial orbital apex. Detachment of the medial rectus muscle can be a useful technique for tumors located largely lateral to the medial rectus muscle. Further studies will be required to demonstrate the safety and efficacy of this technique. PMID- 23810473 TI - Retained lens fragments after cataract surgery: outcomes of same-day versus later pars plana vitrectomy. AB - PURPOSE: To compare visual acuity outcomes and adverse events in patients with retained lens fragments who underwent same-day versus later pars plana vitrectomy (PPV). DESIGN: Retrospective, interventional case series. METHODS: Single-center study evaluating all patients with retained lens fragments that underwent PPV over a 22-year period (1990 through 2011). RESULTS: The study included 569 eyes of 568 patients with a mean age of 74.6 years and a median follow-up of 8 months (range, 1 week to 100 months). One hundred seventeen patients (22%) underwent same-day vitrectomy, 131 patients (23%) underwent PPV within 1 week, and 321 patients (57%) underwent PPV more than 1 week later. Median time to vitrectomy in the same week group was 5 days, compared with 22 days in the delayed group. At the last examination, 61%, 63%, and 56% of patients undergoing PPV on the same day, within 1 week, and more than 1 week later, respectively, achieved best corrected visual acuity (BCVA) of 20/40 or better (P = .35), and 16%, 15%, and 21%, respectively, had BCVA of 20/200 or worse (P = .29). There were no differences between groups when assessing cystoid macular edema (P = .96), retinal detachment (P = .096), elevated intraocular pressure (P = .88), or suprachoroidal hemorrhage (P = .26). CONCLUSIONS: Patients undergoing same-day versus a later PPV (within 1 week or more than 1 week later) for retained lens fragments had similar visual acuity outcomes and complication rates. Although same-day surgery may be attractive logistically in many cases, our retrospective data suggest equivalent outcomes for surgical timing. PMID- 23810474 TI - Choroidal thickness changes after intravitreal ranibizumab and photodynamic therapy in recurrent polypoidal choroidal vasculopathy. AB - PURPOSE: To evaluate subfoveal choroidal thickness changes in cases with recurrent polypoidal choroidal vasculopathy (PCV) after combination therapy with intravitreal ranibizumab and photodynamic therapy (PDT). DESIGN: Retrospective observational case series study. METHODS: We measured subfoveal choroidal thickness in PCV using optical coherence tomography (OCT) before and after PDT. In recurrent cases, the choroidal thickness was measured at the time of the recurrence. In nonrecurrent cases, choroidal thickness was measured 1 year after PDT. RESULTS: Combination therapy was performed in 27 eyes (27 patients). Polypoidal lesions regressed within 3 months after initial treatment in all eyes. Retreatment was needed in 10 of 27 eyes (37.0%) after more than 3 months of follow-up. In recurrent cases, subfoveal choroid decreased from 188 MUm at baseline to 157 MUm 3 months after PDT (P < .01); however, choroidal thickness increased to 179 MUm with recurrence (P = .54 compared to baseline; average, 8.0 months). In nonrecurrent cases, subfoveal choroid decreased from 257 MUm at baseline to 210 MUm 3 months after PDT and 212 MUm 1 year after PDT (P < .01, respectively). CONCLUSION: Subfoveal choroidal thickness in PCV at the time of recurrence returned to the baseline level after choroidal thinning as a result of PDT treatment. Choroidal thickness changes after PDT examined using OCT may reflect disease activity in PCV. PMID- 23810475 TI - Diagnostic precision of retinal nerve fiber layer and macular thickness asymmetry parameters for identifying early primary open-angle glaucoma. AB - PURPOSE: To evaluate the diagnostic capabilities of intereye and intraeye differences in retinal nerve fiber layer (RNFL) thickness and macular thickness for identifying early primary open-angle glaucoma (POAG). DESIGN: Prospective, cross-sectional cohort study. METHODS: All subjects were enrolled from an ongoing institutional glaucoma study. We used spectral-domain optical coherence tomography (Spectralis; Heidelberg Engineering) to obtain macular thickness (posterior pole asymmetry scan) and RNFL thickness (circumpapillary scan) in both eyes of 50 early POAG and 50 control subjects. Early POAG subjects had glaucomatous optic neuropathy with mild, reproducible visual field loss in at least 1 eye, and control subjects had normal intraocular pressures, visual fields, and optic nerves. We recorded total, superior, and inferior RNFL and macular thicknesses and then calculated intereye and intraeye differences (asymmetry parameters). Statistical evaluation included receiver operating characteristic and multivariate logistic regression analyses. RESULTS: Intereye macular thickness asymmetry had the highest diagnostic sensitivity (88% at 80% specificity; 83% at 95% specificity), followed by total RNFL thickness (88% at 80% specificity; 75% at 95% specificity). Parameters with the largest areas under the receiver operating characteristic curves were: total RNFL thickness (0.937), intereye RNFL asymmetry (0.921), intereye macular thickness asymmetry (0.913), inferior RNFL thickness (0.905), superior RNFL thickness (0.887), intereye inferior macular thickness asymmetry (0.872), and intraeye macular thickness asymmetry (0.860). These 7 values were not significantly different. In multivariate logistic regression analyses, intraeye macular thickness asymmetry, intereye macular thickness asymmetry, intereye RNFL thickness asymmetry, and total RNFL thickness were related independently to early POAG. CONCLUSIONS: Structural asymmetry parameters performed well, identifying early POAG as well as RNFL thickness. Further study is indicated to validate these results. PMID- 23810476 TI - Choroideremia: towards a therapy. AB - PURPOSE: To review what progress has been made towards the application of ocular gene therapy to prevent progressive vision loss in patients affected by choroideremia. DESIGN: A Perspective based on the collective opinions of researchers and clinicians actively engaged in vision research on choroideremia and a review of current literature. METHODS: Researchers from Europe, Canada, Australia, and the United States were convened to the first International Choroideremia Research Symposium held in Sommieres, France in September 2011. Attendees shared their collective understanding of the pathophysiology of choroideremia and current trends in the development of treatments, with an emphasis on the potential of gene therapy as an achievable approach. Supplemental perspectives are provided along with an update of progress made since the meeting. RESULTS: The complexity of treating a retinal disease such as choroideremia that affects multiple tissue layers has been brought to light. The genetic basis of choroideremia must be thoroughly deciphered and appropriate clinical tests selected to follow disease progression and evaluate the efficiency of treatments. CONCLUSIONS: Whereas the time frame for the development of therapies for some retinal dystrophies may be in the years hence, gene therapy trials for choroideremia have started in the United Kingdom and results are pending. These first trials may help resolve the remaining issues associated with the treatment of this disease. PMID- 23810477 TI - Scheimpflug corneal power measurements for intraocular lens power calculation in cataract surgery. AB - PURPOSE: To compare the keratometric (K) readings from the Pentacam-HR (High Resolution) unit with the automated K values from the IOLMaster keratometer (KIOLM), and to evaluate them in the commonly used intraocular lens (IOL) power calculation formulas for routine cataract surgery. DESIGN: Prospective, comparative observational study. METHODS: setting: Private practice, Lynwood, California. study population: Fifty cataractous eyes scheduled for surgery between July and August 2012. observation procedure: The K readings from the Pentacam-HR unit taken at the 2-, 3-, 4-, and 5-mm zones and the 2-, 3-, 4-, and 5-mm rings, respectively, from 3 different maps: sagittal corneal front (KF), true net power (KTNP), and total refractive power (KRP) are compared with KIOLM. IOL power calculations were performed with each of the 25 sets of K readings. main outcome measures: The IOL prediction median absolute error (MedAE) obtained with each measurement. RESULTS: KF averaged 0.03-0.13 diopter (D) higher than KIOLM (P > .05), KTNP averaged 1.16-1.21 D lower than KIOLM (P > .001), and KRP averaged 0.23-0.72 D lower than KIOLM (P > .001), with large variations in the measurements. The MedAE obtained with the different Pentacam K readings ranged from 0.44-0.64 D vs 0.52 D obtained with KIOLM (P > .05). MedAE was lower in all categories when the pupil was 3 mm or smaller. CONCLUSION: The Pentacam KF values were the closest to KIOLM and the KF readings from the 2-mm ring yielded the best results for IOL power calculation. PMID- 23810478 TI - Behavioral Activation System (BAS) differences in bipolar I and II disorder. AB - BACKGROUND: A growing body of evidence supports the Behavioral Activation System (BAS) dyresgulation model of bipolar disorder, however its application to bipolar II disorder is limited. The current study examines its potential relevance to bipolar I and II disorders. We specifically sought to determine whether bipolar sub-types would differ in terms of BAS sensitivity, and examined for differential prospective relationships between BAS sensitivity and bipolar I and II symptom expression. METHOD: Participants were recruited from the Sydney-based Black Dog Institute. Diagnostic groups were derived on the basis of agreement between clinician and DSM-IV diagnoses from structured interviews. Baseline measures of BAS sensitivity, mood symptoms and anxiety were completed. Self-rated mood was assessed over a 6-month period. Clinician-rated mood status was re-assessed at follow-up to determine the predictive utility of BAS scores. RESULTS: The sample comprised 151 bipolar participants (69 bipolar I, 82 bipolar II). BAS-Drive and Reward Responsiveness scores were significantly higher in bipolar I disorder participants. BAS sub-scale scores were uniquely positively associated with mood variability in bipolar I and II disorder. BAS-Drive and Reward Responsiveness scores were positively associated with bipolar I hypo(mania), and with the former also positively associated with bipolar II depression. BAS scores did not predict bipolar I or II mood episode status at 6-month follow-up. LIMITATIONS: BAS sensitivity was self-reported; inability to establish independence of BAS scores from residual symptoms; lack of controlling for medication effects; inability to determine the influence of life events; length of follow-up period may have not been sufficient to evaluate the predictive utility of BAS sensitivity for mood episodes or detect course of illness differences across bipolar sub-types. CONCLUSIONS: Differences in BAS sensitivity and associations with mood variability were quantified in bipolar I and II disorder, suggesting the need for tailored treatments for these separate conditions. Further investigation of the role of the BAS in bipolar sub-types is warranted. PMID- 23810479 TI - Systematic review and voxel-based meta-analysis of diffusion tensor imaging studies in bipolar disorder. AB - BACKGROUND: Diffusion tensor imaging (DTI) studies have shown changes in the microstructure of white matter in bipolar disorder. Studies suggest both localised, predominantly fronto-limbic, as well as more widespread changes in white matter, but with some apparent inconsistency. A meta-analysis of white matter alterations in adults with bipolar disorder was undertaken. METHOD: Whole brain DTI studies comparing adults with bipolar disorder to healthy controls on fractional anisotropy (FA) were retrieved using searches of MEDLINE and EMBASE from between 2003 and December 2012. White-matter tract involvement was collated and quantified. Clusters of significantly altered FA were meta-analysed using effect-size signed differential mapping (ES-SDM). RESULTS: Ten VBA studies (252 patients and 256 controls) and five TBSS studies (138 patients and 98 controls) met inclusion criteria. Sixty-one clusters of significantly different FA between bipolar disorder and healthy controls were identified. Analysis of white-matter tracts indicated that all major classes of tracts are implicated. ES-SDM meta analysis of VBA studies revealed three significant clusters of decreased FA in bipolar disorder (a right posterior temporoparietal cluster and two left cingulate clusters). Findings limited to the Bipolar Type I papers were more robust. LIMITATIONS: Voxel-based studies do not accurately identify tracts, and our ES-SDM analysis used only published peak voxels rather than raw DTI data. CONCLUSIONS: There is consistent data indicating widespread white matter involvement with decreased white matter FA demonstrated in three disparate areas in bipolar disorder. White matter alterations are not limited to anterior fronto limbic pathways in bipolar disorder. PMID- 23810480 TI - Reference values for anxiety questionnaires: the Leiden Routine Outcome Monitoring Study. AB - BACKGROUND: The monitoring of patients with an anxiety disorder can benefit from Routine Outcome Monitoring (ROM). As anxiety disorders differ in phenomenology, several anxiety questionnaires are included in ROM: Brief Scale for Anxiety (BSA), PADUA Inventory Revised (PI-R), Panic Appraisal Inventory (PAI), Penn State Worry Questionnaire (PSWQ), Worry Domains Questionnaire (WDQ), Social Interaction, Anxiety Scale (SIAS), Social Phobia Scale (SPS), and the Impact of Event Scale-Revised (IES-R). We aimed to generate reference values for both 'healthy' and 'clinically anxious' populations for these anxiety questionnaires. METHODS: We included 1295 subjects from the general population (ROM reference group) and 5066 psychiatric outpatients diagnosed with a specific anxiety disorder (ROM patient-group). The MINI was used as diagnostic device in both the ROM reference group and the ROM patient group. To define limits for one-sided reference intervals (95th percentile; P95) the outermost 5% of observations were used. Receiver Operating Characteristics (ROC) analyses were used to yield alternative cut-off values for the anxiety questionnaires. RESULTS: For the ROM reference-group the mean age was 40.3 years (SD=12.6), and for the ROM patient group it was 36.5 years (SD=11.9). Females constituted 62.8% of the reference group and 64.4% of the patient-group. P95 ROM reference group cut-off values for reference versus clinically anxious populations were 11 for the BSA, 43 for the PI-R, 37 for the PAI Anticipated Panic, 47 for the PAI Perceived Consequences, 65 for the PAI Perceived Self-efficacy, 66 for the PSWQ, 74 for the WDQ, 32 for the SIAS, 19 for the SPS, and 36 for IES-R. ROC analyses yielded slightly lower reference values. The discriminative power of all eight anxiety questionnaires was very high. LIMITATIONS: Substantial non-response and limited generalizability. CONCLUSIONS: For eight anxiety questionnaires a comprehensive set of reference values was provided. Reference values were generally higher in women than in men, implying the use of gender-specific cut-off values. Each instrument can be offered to every patient with MAS disorders to make responsible decisions about continuing, changing or terminating therapy. PMID- 23810481 TI - Highlights in basic autonomic neurosciences: cross-organ sensitization between the bladder and bowel. PMID- 23810482 TI - The predictive and prognostic value of sex in early-stage colon cancer: a pooled analysis of 33,345 patients from the ACCENT database. AB - PURPOSE: To compare long-term outcomes between men and women in a large cohort of clinical trial participants with early-stage colon cancer, specifically by examining whether the prognostic effect of sex varies based on age, stage of disease, and type of adjuvant therapy received. METHODS: A pooled analysis of individual patient data from 33,345 patients with colon cancer enrolled in 24 phase III studies of various adjuvant systemic therapies was conducted. Chemotherapy consisted of (1) fluorouracil (5-FU), (2) 5-FU variations, (3) 5-FU plus oxaliplatin, (4) 5-FU plus irinotecan, or (5) oral fluoropyrimidine-based regimens. The primary endpoint was disease-free survival; secondary endpoints included overall survival and time to recurrence. Stratified Cox models were used to assess the effect of sex on outcomes. Multivariate models were used to assess adjusted effects and to explore the interaction among sex and other factors. RESULTS: A total of 18,244 (55%) men and 15,101 (45%) women were included. In the entire cohort, the median age was 61 years; 91% (24,868) were white; 31% (10,347) and 69% (22,964) had stage I/II and III disease, respectively. Overall, men had inferior prognoses when compared with women for time to recurrence (hazard ratio [HR] 1.05 [95% CI, 1.01-1.09]) and other endpoints after adjusting for age, stage, and treatment. Sex was not a predictive factor of treatment efficacy (P for interaction between sex and treatment when adjusting for age and stage were .40, .67, and .77 for disease-free survival, overall survival, and time to recurrence, respectively). In exploratory analyses, worse outcomes in men were more prominent in the older patients when adjusting for stage and treatment (HR 1.08 in age <= 65 years vs. HR 1.18 in age > 65 years; interaction P = .016 for disease-free survival). The stage of disease and type of adjuvant regimen did not modify the prognostic value of sex. CONCLUSIONS: Sex is a modest independent prognostic marker for patients with early-stage colon cancer, particularly in older patients. PMID- 23810483 TI - Sequence and phylogenetic analysis of virulent Newcastle disease virus isolates from Pakistan during 2009-2013 reveals circulation of new sub genotype. AB - Despite observing the standard bio-security measures at commercial poultry farms and extensive use of Newcastle disease vaccines, a new genotype VII-f of Newcastle disease virus (NDV) got introduced in Pakistan during 2011. In this regard 300 ND outbreaks recorded so far have resulted into huge losses of approximately USD 200 million during 2011-2013. A total of 33 NDV isolates recovered during 2009-2013 throughout Pakistan were characterized biologically and phylogenetically. The phylogenetic analysis revealed a new velogenic sub genotype VII-f circulating in commercial and domestic poultry along with the earlier reported sub genotype VII-b. Partial sequencing of Fusion gene revealed two types of cleavage site motifs; lentogenic (112)GRQGRL(117) and velogenic (112)RRQKRF(117) along with some point mutations indicative of genetic diversity. We report here a new sub genotype of virulent NDV circulating in commercial and backyard poultry in Pakistan and provide evidence for the possible genetic diversity which may be causing new NDV out breaks. PMID- 23810484 TI - Structural synaptic plasticity in the hippocampus induced by spatial experience and its implications in information processing. AB - INTRODUCTION: Long-lasting memory formation requires that groups of neurons processing new information develop the ability to reproduce the patterns of neural activity acquired by experience. DEVELOPMENT: Changes in synaptic efficiency let neurons organise to form ensembles that repeat certain activity patterns again and again. Among other changes in synaptic plasticity, structural modifications tend to be long-lasting which suggests that they underlie long-term memory. There is a large body of evidence supporting that experience promotes changes in the synaptic structure, particularly in the hippocampus. CONCLUSION: Structural changes to the hippocampus may be functionally implicated in stabilising acquired memories and encoding new information. PMID- 23810485 TI - Non-breathing-related sleep disorders following stroke. AB - INTRODUCTION: It has been shown that sleep-related breathing disorders, especially sleep apnea, are very common in patients who have had a stroke, and that they also reduce the potential for neurological recovery. Nevertheless, other sleep disorders caused by stroke (excessive daytime sleepiness, insomnia, sleep related movement disorders) can also cause or increase stroke-related disability, and this fact is less commonly known. DEVELOPMENT: Studies with polysomnography have shown many abnormalities in sleep architecture during the acute phase of stroke; these abnormalities have a negative impact on the patient's quality of life although they tend to improve with time. This also happens with other sleep disorders occurring as the result of a stroke (insomnia, narcolepsy, restless legs syndrome, periodic limb movement disorder and REM sleep behavior disorder), which are nevertheless potentially treatable. In this article, we briefly review the physiopathology and epidemiology of the disorders listed above in order to raise awareness about the importance of these disorders and the effects they elicit in stroke patients. CONCLUSIONS: Sleep disorders that are not breathing-related have scarcely been studied in stroke patients despite the fact that almost all such disorders may present as a result of a cerebrovascular event. PMID- 23810486 TI - Pregnancy outcomes among women with Marfan syndrome. AB - OBJECTIVE: To determine cardiac and obstetric outcomes among women with Marfan syndrome (MS) whose pregnancies were managed in accordance with the French national guidelines. METHODS: A descriptive analysis was conducted for a prospective cohort of 18 women with MS who gave birth in the maternity unit of Bichat-Claude Bernard Hospital, Paris, France, between January 1, 1998, and May 31, 2011. The study hospital was the national referral center for MS and related diseases. RESULTS: A total of 22 pregnancies were recorded among the study cohort. Of these, 21 were managed according to the national guidelines. One woman who was referred to the study hospital during late pregnancy was not managed according to the national guidelines; this patient experienced aortic dissection at 37 weeks. In the cohort, aortic diameter did not increase significantly during pregnancy. Vascular fetal growth restriction was observed in 7 (31.8 %) of the pregnancies. Cesarean delivery was planned for 17 (77.3%) of the pregnancies. CONCLUSION: Risk of aortic dissection was low among a cohort of pregnant women with MS who were managed according to the French national guidelines. PMID- 23810487 TI - Kit-like 18F-labeling of RGD-19F-arytrifluroborate in high yield and at extraordinarily high specific activity with preliminary in vivo tumor imaging. AB - INTRODUCTION: Positron Emission Tomography (PET) is a rapidly expanding, cutting edge technology for preclinical evaluation, cancer diagnosis and staging, and patient management. A one-step aqueous (18)F-labeling method, which can be applied to peptides to provide functional in vivo images, has been a long standing challenge in PET imaging. Over the past few years, we have sought a rapid and mild radiolabeling method based on the aqueous radiosynthesis of in vivo stable aryltrifluoroborate (ArBF(3)(-)) conjugates. Recent access to production levels of (18)F-Fluoride led to a fluorescent-(18)F-ArBF(3)(-) at unprecedentedly high specific activities of 15Ci/MUmol. However, extending this method to labeling peptides as imaging agents has not been explored. METHODS: In order to extend these results to a peptide of clinical interest in the context of production-level radiosynthesis, we applied this new technology for labeling RGD, measured its specific activity by standard curve analysis, and carried out a preliminary evaluation of its imaging properties. RESULTS: RGD was labeled in excellent radiochemical yields at exceptionally high specific activity (~14Ci/MUmol) (n = 3). Preliminary tumor-specific images corroborated by ex vivo biodistribution data with blocking controls show statistically significant albeit relatively low tumor uptake along with reasonably high tumor:blood ratios (n = 3). CONCLUSIONS: Isotope exchange on a clinically useful (18)F-ArBF(3)(-) radiotracer leads to excellent radiochemical yields and exceptionally high specific activities while the anionic nature of the aryltrifluoroborate prosthetic results in very rapid clearance. Since rapid clearance of the radioactive tracer is generally desirable for tracer development, these results suggest new directions for varying linker arm composition to slightly retard clearance rather than enhancing it. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: This work is the first to use production levels of (18)F-activity to directly label RGD at specific activities that are an order of magnitude higher than most reports and thereby increases the distribution window for radiotracer production and delivery. PMID- 23810488 TI - Radiosynthesis and evaluation of new alpha1-adrenoceptor antagonists as PET radioligands for brain imaging. AB - INTRODUCTION: Evaluation of the alpha1-adrenoceptors in relation to brain pathophysiology and drug treatment has been hindered by lack of alpha1 adrenoceptor specific radioligands with sufficient brain exposure. Our aim was to develop an alpha1-adrenoceptor specific PET radioligand for brain imaging. METHODS: Two sertindole analogues 1-(4-fluorophenyl)-5-(1-methyl-1H-1,2,4-triazol 3-yl)-3-(1-[(11)C]methylpiperidin-4-yl)-1H-indole [(11)C]3 and 1-(4-fluorophenyl) 3-(1-[(11)C]methylpiperidin-4-yl)-5-(pyrimidin-5-yl)-1H-indole ([(11)C]Lu AA27122) [(11)C]4 were synthesized and evaluated as alpha1-adrenoceptor PET radioligands in cynomolgus monkey. Compounds 3 and 4 were selected due to their promising in vitro preclinical profile; high affinity and selectivity for the alpha1-adrenoceptor, favourable blood brain barrier permeability rates in Caco-2 monolayers and promising brain tissue/plasma ratio, assessed by equilibrium dialysis of free fraction in plasma and brain homogenate. RESULTS: Compounds [(11)C]3 and [(11)C]4 were synthesized from their desmethyl piperidine precursors with high specific radioactivity (>370 GBq/MUmol) using [(11)C]methyl iodide. The 1,2,4-triazole analogue [(11)C]3 exhibited poor brain uptake, but the corresponding pyrimidyl analogue [(11)C]4 exhibited high brain exposure and binding in alpha1-adrenoceptor rich brain regions. However, the binding could not be inhibited by pretreatment with prazosin (0.1 mg/kg and 0.3 mg/kg). The results were extended by autoradiography of [(11)C]4 binding in human brain sections and competition with antagonists from different structural families, revealing that only a minor portion of the observed binding of [(11)C]4 in brain was alpha1 adrenoceptor specific. CONCLUSION: Though [(11)C]3 and [(11)C]4 proved not suitable as PET radioligands, the study provided further understanding of structural features influencing brain exposure of the chemical class of compounds related to the antipsychotic drug sertindole. It provided valuable insight in the delicacy of blood brain barrier penetration for structurally related compounds and underlines the importance for improved protocols for evaluation of brain penetration of future PET ligands. PMID- 23810489 TI - Factors associated with menopausal symptom severity in middle-aged Brazilian women from the Brazilian Western Amazon. AB - OBJECTIVE: To determine the frequency and severity of menopausal symptoms and associated factors in middle-aged Brazilian women. METHODS: A cross-sectional study was carried out involving 1415 women aged 35-65 years attended at the Outpatient unit of the Clinicas Hospital of Rio Branco, Acre state, Brazil. The Menopause Rating Scale (MRS) was used to assess the severity of menopause symptoms. The Stata 10 statistical package was used for all data analysis whereas Pearson's x(2) nonparametric association test was used for bivariate analysis, adopting a level of statistical significance of 5%. On the multivariate analysis, independent variables positively associated with the dependent model were retained in the final model (p<0.005). RESULTS: Overall, 54.1% of participants were premenopausal, 10.1% perimenopausal, and 35.8% postmenopausal. Irritability was the most frequent symptom (78.3%), followed by joint and muscular discomfort (74.8%), and anxiety (72.7%). Mean total MRS score was 15.6+8.8 (median 15). After adjusting for confounding factors, the logistic regression analysis found low educational level (OR:1.53; [95% CI:1.21-1.95]; p<0.001); self-perceived poor/very poor health (OR:4.48; [95% CI: 3.53-5.69]; p<0.001), and menopausal transition phase (OR:1.73; [95% CI:1.18-2.53]; p=0.005) to be statistically significantly associated with more severe menopausal symptoms. CONCLUSION: Among Brazilian women, atypical symptoms of the menopause were the most frequently reported. Severe menopausal symptoms were more likely in women with low educational level, self-perceived poor health and at the menopausal transition phase. PMID- 23810490 TI - Diagnosis and management of osteoporosis in postmenopausal women and older men in the UK: National Osteoporosis Guideline Group (NOGG) update 2013. AB - Since the launch in 2008 by the National Osteoporosis Guideline Group (NOGG), of guidance for the diagnosis and management of osteoporosis in postmenopausal women and older men in the UK there have been significant advances in risk assessment and treatment. These have been incorporated into an updated version of the guideline, with an additional focus on the management of glucocorticoid-induced osteoporosis, the role of calcium and vitamin D therapy and the benefits and risks of long-term bisphosphonate therapy. The updated guideline is summarised below. The recommendations in the guideline are intended to aid management decisions but do not replace the need for clinical judgement in the care of individuals in clinical practice. PMID- 23810491 TI - Effect of basal metabolic rate on the bone mineral density in middle to old age women in Taiwan. AB - BACKGROUND: Basal metabolic rate (BMR) reflects a combination of cardiopulmonary function and lean body mass resulting from regular physical activity. Though many studies have examined the relationships between bone mineral density (BMD) and body composition, little is known regarding the relationship between BMD and BMR. OBJECTIVE: The purpose of this study was to investigate the relationship between BMR, anthropometric parameters, body composition and BMD in postmenopausal women in Taiwan. METHODS: Two hundred and eighty-nine women between the ages of 40 and 80 years were included in this cross-sectional study. The following parameters were assessed: height, body weight, total body fat (TBF), BMR, waist-to-hip ratio, grip strength, and back strength. Differences in all variables between osteoporotic and non-osteoporotic women (categorized according to decades in age) were calculated using a one-way analysis of variance (ANOVA) and a Bonferroni post-hoc test. Multiple linear regression with a backward stepwise approach was performed to evaluate the relationship between these measurements and BMD. RESULTS: Among women over 50 years of age, those who were non-osteoporotic had higher BMR, BMI, and body fat by comparison to their osteoporotic counterparts (p<0.05 for all). Multiple linear regression revealed that BMR and body fat significantly predicted BMD of the femoral neck (adjusted beta coefficients of 0.304 and 0.190, respectively; p<0.05 for both). BMR and body fat also predicted an increased vertebral BMD (adjusted beta coefficients of 0.310 and 0.141, respectively; p<0.05 for both). CONCLUSION: BMR is closely associated with BMD in elderly persons, and may be a novel target for interventions aimed at preventing the age-related decline in BMD. PMID- 23810492 TI - Regarding "Percutaneous balloon humeroplasty for Hill-Sachs lesions: a novel technique". PMID- 23810493 TI - The two-component system CBO2306/CBO2307 is important for cold adaptation of Clostridium botulinum ATCC 3502. AB - Clostridium botulinum is a notorious foodborne pathogen. Its ability to adapt to and grow at low temperatures is of interest for food safety. Two-component systems (TCSs) have been reported to be involved in cold-shock and growth at low temperatures. Here we show the importance of TCS CBO2306/CBO2307 in the cold shock response of C. botulinum ATCC 3502. The relative expression levels of the cbo2306 and cbo2307 were up to 4.4-fold induced in the cold-shocked cultures but negatively regulated in the late-log and stationary growth phase in relation to early logarithmic growth phase in non-shocked cultures. Importance of the CBO2306/CBO2307 in the cold stress was further demonstrated by impaired growth of insertional cbo2306 or cbo2307 knockout mutants in relation to the wild-type strain ATCC 3502. The results suggest that the TCS CBO2306/CBO2307 is important for cold-shock response and adaptation of C. botulinum ATCC 3502 to low temperature. PMID- 23810494 TI - The lived experience of parents of children admitted to the pediatric intensive care unit in Lebanon. AB - BACKGROUND: Family caregivers have a significant responsibility in the care of their child in the Pediatric Intensive Care Unit (PICU). Parents staying with their child in the PICU have particular needs that should be acknowledged and responded to by clinicians. Several studies have been conducted in the USA and Europe to try to understand the experience of family caregivers of children admitted to the Pediatric Intensive Care Unit. There are no such studies in Lebanon or the Middle East where the culture and support systems differ from other countries. OBJECTIVE: To understand the lived experience of Lebanese parents of children admitted to the PICU in a tertiary hospital in Beirut. DESIGN: Phenomenological study. METHODS: The study followed purposeful sampling in which 10 parents (mother or father) of children admitted to PICU were interviewed. Data were analyzed following the hermeneutical process as described by Diekelmann and Ironside (1998). RESULTS: A constitutive pattern "Journey into the unknown" which constitutes an overarching theme and four major themes with subthemes emerged from the data. These were: We are human beings with dignity "; "looking for a healthier environment"; Dependence on God and "The need to be in the loop" reveal the parents' journey into the unknown. CONCLUSION: This qualitative study adds to the knowledge that would help health care workers understand the experience of Lebanese parents with a child in PICU and to highlight the significance of this experience to them. The findings could be used to inform the development of a PICU parental satisfaction instrument for the sample group. PMID- 23810495 TI - Nurses' response to frequency and types of electrocardiography alarms in a non critical care setting: a descriptive study. AB - BACKGROUND: An important role of the registered nurse is to identify patient deterioration by monitoring the patient condition and vital signs. Increasingly, this is supplemented with continuous electrocardiographic (ECG) monitoring. Continuous monitoring is inefficient in identifying deterioration because of the high number of false and nuisance alarms. Lack of strong evidence or formal guidelines for the care of patients receiving ECG monitoring has led clinicians to rely too heavily on this technology without consideration of its limitations. The nursing workload associated with alarm management remains unexamined. OBJECTIVE: To describe nurses' routine practices related to continuous ECG monitoring, frequency and types of alarms, their associated nursing interventions, and the impact on the patient's plan of care. METHODS: Design. Prospective, descriptive, observational study. Setting and participants. Between January 2011 and March 2011 we observed nine Registered Nurses providing care for patients receiving continuous ECG monitoring in non-critical care areas. The PI and two research assistants observed each nurse for two 3-h observation periods and recorded data on a researcher designed observation tool. At the end of each observation period, the observers printed the alarm events as recorded by the central monitoring computer. RESULTS: Nurses responded to 46.8% of all alarms. During the observation period, there were no dysrhythmia adverse events. One patient had a change in condition requiring transfer to a higher level of care. A range of nursing interventions occurred in response to alarms. CONCLUSION: Nurses routine practices related to monitoring continue to reveal gaps in practice related to alarm management. Observations of practice also revealed the difficulties and complexities of managing alarm systems and the range of nursing interventions associated with managing alarms. PMID- 23810496 TI - Synthesis and biological evaluation of aminobenzimidazole derivatives with a phenylcyclohexyl acetic acid group as anti-obesity and anti-diabetic agents. AB - A series of benzimidazole derivatives with a phenylcyclohexyl acetic acid group as DGAT-1 inhibitors was developed. Among the benzimidazole series, compound 5k showed submicromolar in vitro activity toward human and mouse DGAT-1, good selectivity toward DGAT-2, human liver metabolic stability, and pharmacokinetic (PK) and safety profiles such as hERG, CYP and acute toxicity. Additionally, 5k showed good in vivo efficacy in 4weeks study with DIO mouse model. PMID- 23810497 TI - Hydantoin based inhibitors of MMP13--discovery of AZD6605. AB - Piperidine ether and aryl piperazine hydantoins are reported as potent inhibitors of MMP13. A medicinal chemistry campaign focused on replacing the reverse hydroxamate zinc binding group associated with historical inhibitors with a hydantoin zinc binding group then optimising MMP13 potency, solubility and DMPK properties whilst maintaining good selectivity over MMP14. A number of high quality candidates were progressed and following rat and dog safety evaluation, AZD6605 (3m) was identified as a candidate drug. PMID- 23810498 TI - Controlling persister cells of Pseudomonas aeruginosa PDO300 by (Z)-4-bromo-5 (bromomethylene)-3-methylfuran-2(5H)-one. AB - Pseudomonas aeruginosa is a major pathogen causing chronic pulmonary infections; for example, 80% of cystic fibrosis patients get infected by this bacterium as the disease progresses. Such chronic infections are challenging because P. aeruginosa exhibits high-level tolerance to antibiotics by forming biofilms (multicellular structures attached to surfaces), by entering dormancy and forming antibiotic tolerant persister cells, and by conversion to the mucoid phenotype. Recently, we reported that a synthetic quorum sensing inhibitor, (Z)-4-bromo-5 (bromomethylene)-3-methylfuran-2(5H)-one (BF8), can sensitize both planktonic and biofilm-associated persister cells of P. aeruginosa PAO1 to antibiotics at the concentrations non-inhibitory to its growth. In this study, we further characterized the effects of this compound on the mucoid strain P. aeruginosa PDO300. BF8 was found to reduce persistence during the growth of PDO300 and effectively kill the persister cells isolated from PDO300 cultures. In addition to planktonic cells, BF8 was also found to inhibit biofilm formation of PDO300 and reduce associated persistence. These findings broaden the activities of this class of compounds and indicate that BF8 also has other targets in P. aeruginosa in addition to quorum sensing. PMID- 23810499 TI - Investigation of the protein alkylation sites of the STAT3:STAT3 inhibitor Stattic by mass spectrometry. AB - STAT3 (Signal Transducer and Activator of Transcription factor 3) is constitutively active in a wide range of human tumours. Stattic is one of the first non-peptidic small molecules reported to inhibit formation of the STAT3:STAT3 protein dimer complex. A mass spectrometry method has been developed to investigate the binding of Stattic to the un-phosphorylated STAT3betatc (U STAT3) protein. Alkylation of four cysteine residues has been observed with possible reaction at a fifth which could account for the mechanism of action. PMID- 23810500 TI - Reply to Letter to the editor - is no difference always a good thing? Panayiotis A. Kyzas. PMID- 23810501 TI - A multiplex qPCR gene dosage assay for rapid genotyping and large-scale population screening for deletional alpha-thalassemia. AB - The predominant determinants of alpha-thalassemia are deletions in the human alpha-globin gene cluster. A rapid DNA-based assay is needed for mass screening in thalassemia-prevention programs. Herein, we established a novel quadruplex TaqMan qPCR gene dosage assay with two separate combination reactions. The assay directly determined the copy number of human alpha-globin genes based on relative quantitation of three target genes (HBA2, HBA1, and HBZ or HBPA1) versus a control gene (CREBBP). The assay showed good accuracy, with mean intra-assay and interassay variations of 3.31% +/- 1.02% and 5.49% +/- 0.32%, respectively. The assay was evaluated using 678 pretyped clinical DNA samples containing six alpha thalassemia deletions in 13 genotypes and 186 normal samples previously screened by multiplex ligation-dependent probe amplification or gap PCR. As determined by the 2(-DeltaDeltaCq) method, deleted gene dosage ratios were 0.46 to 0.60 in heterozygotes, 0.0 in homozygotes, and 0.97 to 1.07 in nondeleted samples. We found 99.3% concordance between the quantitative PCR and multiplex ligation dependent probe amplification or gap-PCR results. Furthermore, routine screening for alpha-thalassemia deletions was performed on 3000 random samples in a blind analysis. Results for all 279 positives, which had different deletions, were fully coincident with results from standard methods. We also identified two novel deletions confirmed by multiplex ligation-dependent probe amplification. Assays using the novel method are simple and suitable for rapid genotyping and mass screening. PMID- 23810502 TI - Similarities of molecular genetic changes in synchronous and metachronous colorectal cancers are limited and related to the cancers' proximities to each other. AB - Synchronous and metachronous colorectal cancers are distinct primary neoplasms diagnosed either simultaneously or sequentially in the same patient. Because they arise in a common genetic and environmental background, they offer a unique opportunity to study molecular genetic changes occurring during carcinogenesis. We evaluated tumors from 50 patients with synchronous and five additional patients with metachronous cancers for loss of heterozygosity of the genes APC and DCC, KRAS and BRAF gene mutations, and microsatellite instability and methylation. Standard PCR methods were used. Approximately two thirds of the synchronous tumors that were informative for each of the five primary molecular genetic changes showed the same results when located in the same colon segment. However, there was less consistency of molecular findings for the synchronous pairs separated by one or more colonic segments, with half or more of these pairs showing different molecular results. Metachronous tumors also showed variation of molecular genetic findings, but this was less when the subsequent tumor was close to the segment of the first tumor. Molecular genetic findings between synchronous and metachronous tumors can be different, even for tumors sharing the same microenvironment of the same colon segment. These findings support the concept that a mutagen might produce different genetic pathways in two proximate tumors. PMID- 23810503 TI - Comparison of high-resolution melting analysis, TaqMan Allelic discrimination assay, and sanger sequencing for Clopidogrel efficacy genotyping in routine molecular diagnostics. AB - Clopidogrel, as a routine antiplatelet drug, is widely used in patients to reduce cardiovascular events following percutaneous coronary intervention. Because of genetic variation, patients undergoing percutaneous coronary intervention show differing responses to clopidogrel therapy. Recently, five single nucleotide polymorphisms (SNPs) within CYP2C19 (rs4244285, rs4986893, rs12248560), ABCB1 (rs1045642), and ITGB3 (rs5918) were identified that contribute prominently to variability in response to clopidogrel. Given that Sanger sequencing is labor intensive and time consuming, rapid genotyping methods for SNP detection are urgently required before clopidogrel therapy. Accordingly, we developed a high resolution melting analysis (HRMA) and TaqMan allelic discrimination assay (TaqMan) to genotype those five SNPs, and compared these two assays with Sanger sequencing on accuracy of genotyping as well as operational characteristics. These two assays showed high accuracy (0.995, 95% CI 0.991 to 0.998 for HRMA; 0.997, 95% CI 0.994 to 0.999 for TaqMan, respectively), sensitivity (0.996, 95% CI 0.989 to 1.002 for HRMA; 0.998, 95% CI 0.993 to 1.002 for TaqMan, respectively), and specificity (0.995, 95% CI 0.991 to 0.999 for HRMA; 0.996, 95% CI 0.993 to 1.000 for TaqMan, respectively). Our study indicates that HRMA and TaqMan are easier to operate and obviously faster than Sanger sequencing. In conclusion, HRMA and TaqMan are rapid, convenient, and reliable assays for clopidogrel efficacy genotyping. PMID- 23810504 TI - A multiplexed fragment analysis-based assay for detection of JAK2 exon 12 mutations. AB - Mutations within exon 12 of the JAK2 gene occur in most cases of JAK2 V617F mutation negative polycythemia vera. Several methods have been developed to identify exon 12 mutations, with both Sanger sequencing and high resolution melting (HRM) being widely used. However, mutations can occur at allelic levels lower than 15%, which may hamper detection by these methods. We developed a novel fragment analysis-based assay capable of detecting nearly all JAK2 exon 12 mutations associated with polycythemia vera down to a sensitivity of 2% mutant allele. Test results were reviewed from a set of 20 reference cases and 1731 consecutive specimens that were referred to our laboratory for testing. Assay performance was compared to sequencing and HRM across a series of 27 specimens with JAK2 exon 12 mutations. Positive cases consisted of 22 with deletion mutations, four with duplications, and one with K539L. Nine cases had mutation levels between 6% and 15% that may not be reliably detected by sequencing or HRM. All cases were easily interpreted in the fragment analysis assay. Sequencing, HRM, and fragment analysis each represent viable platforms for detection of JAK2 exon 12 mutations. Our method performed favorably by providing a simple, robust, and highly sensitive solution for JAK2 exon 12 mutation testing. PMID- 23810505 TI - Novel CFTR variants identified during the first 3 years of cystic fibrosis newborn screening in California. AB - California uses a unique method to screen newborns for cystic fibrosis (CF) that includes gene scanning and DNA sequencing after only one California-40 cystic fibrosis transmembrane conductance regulator (CFTR) panel mutation has been identified in hypertrypsinogenemic specimens. Newborns found by sequencing to have one or more additional mutations or variants (including novel variants) in the CFTR gene are systematically followed, allowing for prospective assessment of the pathogenic potential of these variants. During the first 3 years of screening, 55 novel variants were identified. Six of these novel variants were discovered in five screen-negative participants and three were identified in multiple unrelated participants. Ten novel variants (c.2554_2555insT, p.F1107L, c.-152G>C, p.L323P, p.L32M, c.2883_2886dupGTCA, c.2349_2350insT, p.K114del, c. 602A>T, and c.2822delT) were associated with a CF phenotype (42% of participants were diagnosed at 4 to 25 months of age), whereas 26 were associated with CFTR related metabolic syndrome to date. Associations with the remaining novel variants were confounded by the presence of other diseases or other mutations in cis or by inadequate follow-up. These findings have implications for how CF newborn screening and follow-up is conducted and will help guide which genotypes should, and which should not, be considered screen positive for CF in California and elsewhere. PMID- 23810506 TI - Interhemispheric balance in Parkinson's disease: a transcranial magnetic stimulation study. AB - BACKGROUND: Parkinson's disease (PD) is characterized by various changes in motor excitability. OBJECTIVE: To examine through Transcranial Magnetic Stimulation (TMS) cortical excitability, specifically addressing interhemispheric connections in PD. METHODS: Nineteen PD patients with a predominant involvement of the left hemibody (7 females, age 61.7 years,) and 13 controls (6 females, age 61.5 years) entered the study. Patients were subdivided into two groups (early and advanced) according to the time from PD diagnosis. Participants underwent evaluation of Resting Motor Threshold (RMT) and ipsilateral Silent Period (iSP), induced by suprathreshold TMS on the ipsilateral-M1, measured as suppression of voluntary EMG activity. Mirror Movements (MM) were EMG-recorded and scored, in three upper limb muscles, during unilateral voluntary hand movement. Patients were studied at baseline (OFF drug) and after acute levodopa challenge (ON). RESULTS: PD patients showed a general reduction in RMT vs controls (P < 0.01 for right and left hemisphere) in both drug conditions. Early PD had a significantly lower RMT over the right vs the left hemisphere (P = 0.027); this difference was no longer significant after levodopa. In early PD patients, MM were mainly observed in the right arm during voluntary activation of the left, more affected side both in OFF (P = 0.033) and in ON (P = 0.046). In PD, RMT of the left, less affected M1 was significantly correlated with the right lateralized motor score (P = 0.011; Spearman's coefficient = -0.585), as well as with disease duration. In PD patients, a shorter (P = 0.039) and smaller (P = 0.037) iSP was detected when the stimulus was applied to the worse M1 (right) compared with the contralateral side. This asymmetry was significant only OFF drug. In the PD group iSP-duration from the right, less affected APB was negatively correlated with the MM recorded from the same side during the voluntary movement of the worse side (Spearman's coefficient = -0.498; P = 0.035). CONCLUSIONS: Increased cortical motor excitability in PD, consistent with previous findings, is more evident in the worse hemisphere, particularly in early PD. Asymmetric motor involvement is also associated with excessive involuntary mirroring and defective interhemispheric inhibition, both unfavoring the more affected side. Altogether, these findings suggest that asymmetric motor involvement in PD, particularly in the earlier phases of the disease, affects the interhemispheric balance of cortical excitability, movement lateralization and transcallosal inhibition. PMID- 23810507 TI - The role of cholinergic anti-inflammatory pathway in acetic acid-induced colonic inflammation in the rat. AB - The "cholinergic anti-inflammatory pathway" provides neurological modulation of cytokine synthesis to limit the magnitude of the immune response. This study aimed to evaluate the impact of the cholinergic anti-inflammatory pathway on the extent of tissue integrity, oxidant-antioxidant status and neutrophil infiltration to the inflamed organ in a rat model of acetic acid-induced colitis. Colitis was induced by intrarectal administration of 5% acetic acid (1ml) to Sprague-Dawley rats (200-250g; n=7-8 per group). Control group received an equal volume of saline intrarectally. The rats were treated with either nicotine (1mg/kg/day) or huperzine A (0.1mg/kg/day) intraperitoneally for 3 days. After decapitation, the distal colon was scored macroscopically and microscopically. Tissue samples were used for the measurement of malondialdehyde (MDA) and glutathione (GSH) levels, and myeloperoxidase (MPO) activity. Formation of reactive oxygen species was monitored by using chemiluminescence (CL). Nuclear factor (NF)-kappaB expression was evaluated in colonic samples via immunohistochemical analysis. Trunk blood was collected for the assessment of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-10, resistin and visfatin levels. Both nicotine and huperzine A reduced the extent of colonic lesions, increased colonic MDA level, high MPO activity and NF-kappaB expression in the colitis group. Elevation of serum IL-1beta level due to colitis was also attenuated by both treatments. Additionally, huperzine A was effective to reverse colitis-induced high lucigenin-enhanced CL values and serum TNF-alpha levels. Colitis group revealed decreased serum visfatin levels compared to control group which was completely reversed by nicotine. In conclusion, modulation of the cholinergic system either by nicotine or ACh esterase inhibition improved acetic acid-induced colonic inflammation as confirmed by macroscopic and microscopic examination and biochemical assays. PMID- 23810508 TI - Silibinin as a potential therapeutic for sulfur mustard injuries. AB - Sulfur mustard (SM) is a vesicating chemical warfare agent causing skin blistering, ulceration, impaired wound healing, prolonged hospitalization and permanent lesions. Silibinin, the lead compound from Silybum marianum, has also been discussed as a potential antidote to SM poisoning. However, its efficacy has been demonstrated only with regard to nitrogen mustards. Moreover, there are no data on the efficacy of the water-soluble prodrug silibinin-bis-succinat (silibinin-BS). We investigated the effect of SIL-BS treatment against SM toxicity in HaCaT cells with regard to potential reduction of necrosis, apoptosis and inflammation including dose-dependency of any protective effects. We also demonstrated the biotransformation of the prodrug into free silibinin. HaCaT cells were exposed to SM (30, 100, and 300MUM) for 30min and treated thereafter with SIL-BS (10, 50, and 100MUM) for 24h. Necrosis and apoptosis were quantified using the ToxiLight BioAssay and the nucleosome ELISA (CDDE). Pro-inflammatory interleukins-6 and -8 were determined by ELISA. HaCaT cells, incubated with silibinin-BS were lysed and investigated by LC-ESI MS/MS. LC-ESI MS/MS results suggest that SIL-BS is absorbed by HaCaT cells and biotransformed into free silibinin. SIL-BS dose-dependently reduced SM cytotoxicity, even after 300MUM exposure. Doses of 50-100MUM silibinin-BS were required for significant protection. Apoptosis and interleukin production remained largely unchanged by 10 50MUM silibinin-BS but increased after 100MUM treatment. Observed reductions of SM cytotoxicity by post-exposure treatment with SIL-BS suggest this as a promising approach for treatment of SM injuries. While 100MUM SIL-BS is most effective to reduce necrosis, 50MUM may be safer to avoid pro-inflammatory effects. Pro-apoptotic effects after high doses of SIL-BS are in agreement with findings in literature and might even be useful to eliminate cells irreversibly damaged by SM. Further investigations will focus on the protective mechanism of silibinin and its prodrug and should establish an optimum concentration for treatment. PMID- 23810509 TI - The influence of acetabular bone cracks in the press-fit hip replacement: Numerical and experimental analysis. AB - BACKGROUND: The press-fit hip acetabular prosthesis implantation can cause crack formation in the thin regions surrounding the acetabular. As a consequence the presence of cracks in this region can lead to poor fixation and fibrous tissue formation. METHODS: Numerical and experimental models of commercial press-fit hip replacements were developed to compare the behavior between the intact and implanted joints. Numerical models with an artificial crack and without crack were considered. The iliac and the femur were created through 3D geometry acquisition based on composite human replicas and 3D-Finite Element models were generated. FINDINGS: The mechanical behavior was assessed numerically and experimentally considering the principal strains. The comparison between Finite Element model predictions and experimental measurements revealed a maximum difference of 9%. Similar distribution of the principal strains around the acetabular cavity was obtained for the intact and implanted models. When comparing the Von Mises stresses, it is possible to observe that the intact model is the one that presents the highest stress values in the entire acetabular cavity surface. INTERPRETATION: The crack in the posterior side changes significantly the principal strain distribution, suggesting bone loss after hip replacement. Relatively to micromotions, these were higher on the superior side of the acetabular cavity and can change the implant stability and bone ingrowth. PMID- 23810510 TI - The effect of obsessive-compulsive symptomatology on executive functions in schizophrenia: a systematic review and meta-analysis. AB - The presence of obsessive-compulsive symptoms (OCS) and obsessive-compulsive disorder (OCD) is frequent in patients with schizophrenia and has been associated with greater functional impairment. The impact of these features on cognitive function is unclear. In this article, we performed a systematic review and meta analysis to assess the effect of OCS/OCD on executive functions in schizophrenia patients. Results indicate that schizophrenia patients with OCS/OCD were more impaired in abstract thinking than schizophrenia patients without OCS/OCD. This finding provides support to the double jeopardy hypothesis and may partially explain the greater functional impairment shown in schizo-obsessive patients compared to those with schizophrenia. Inconsistent results were found for set shifting, cognitive flexibility, cognitive inhibition and verbal fluency, as indicated by the high statistical heterogeneity found. Potential sources of heterogeneity such as definition of OCS/OCD, age of onset, severity of negative symptoms and premorbid intelligence were planned to be explored but there was an insufficient number of studies to perform these analyses. Our findings highlight the complexity of the relationship between OCS/OCD and schizophrenia and warrant further investigation of the cognitive function of schizo-obsessive patients. PMID- 23810511 TI - Empathic accuracy and cognition in schizotypal personality disorder. AB - Interpersonal dysfunction contributes to significant disability in the schizophrenia spectrum. Schizotypal Personality Disorder (SPD) is a schizophrenia related personality demonstrating social cognitive impairment in the absence of frank psychosis. Past research indicates that cognitive dysfunction or schizotypy may account for social cognitive dysfunction in this population. We tested SPD subjects and healthy controls on the Empathic Accuracy (EA) paradigm and the Reading of the Mind in the Eyes Test (RMET), assessing the impact of EA on social support. We also explored whether EA differences could be explained by intelligence, working memory, trait empathy, or attachment avoidance. SPD subjects did not differ from controls in RMET, but demonstrated lower EA during negative valence videos, associated with lower social support. Dynamic, multimodal EA paradigms may be more effective at capturing interpersonal dysfunction than static image tasks such as RMET. Schizotypal severity, trait empathy, and cognitive dysfunction did not account for empathic dysfunction in SPD, although attachment avoidance is related to empathic differences. Empathic dysfunction for negative affect contributes to decreased social support in the schizophrenia spectrum. Future research may shed further light on potential links between attachment avoidance, empathic dysfunction, and social support. PMID- 23810512 TI - The scaffold protein Atg11 recruits fission machinery to drive selective mitochondria degradation by autophagy. AB - As the cellular power plant, mitochondria play a significant role in homeostasis. To maintain the proper quality and quantity of mitochondria requires both mitochondrial degradation and division. A selective type of autophagy, mitophagy, drives the degradation of excess or damaged mitochondria, whereas division is controlled by a specific fission complex; however, the relationship between these two processes, especially the role of mitochondrial fission during mitophagy, remains unclear. In this study, we report that mitochondrial fission is important for the progression of mitophagy. When mitophagy is induced, the fission complex is recruited to the degrading mitochondria through an interaction between Atg11 and Dnm1; interfering with this interaction severely blocks mitophagy. These data establish a paradigm for selective organelle degradation. PMID- 23810513 TI - Adult duct-lining cells can reprogram into beta-like cells able to counter repeated cycles of toxin-induced diabetes. AB - It was recently demonstrated that embryonic glucagon-producing cells in the pancreas can regenerate and convert into insulin-producing beta-like cells through the constitutive/ectopic expression of the Pax4 gene. However, whether alpha cells in adult mice display the same plasticity is unknown. Similarly, the mechanisms underlying such reprogramming remain unclear. We now demonstrate that the misexpression of Pax4 in glucagon(+) cells age-independently induces their conversion into beta-like cells and their glucagon shortage-mediated replacement, resulting in islet hypertrophy and in an unexpected islet neogenesis. Combining several lineage-tracing approaches, we show that, upon Pax4-mediated alpha-to beta-like cell conversion, pancreatic duct-lining precursor cells are continuously mobilized, re-express the developmental gene Ngn3, and successively adopt a glucagon(+) and a beta-like cell identity through a mechanism involving the reawakening of the epithelial-to-mesenchymal transition. Importantly, these processes can repeatedly regenerate the whole beta cell mass and thereby reverse several rounds of toxin-induced diabetes, providing perspectives to design therapeutic regenerative strategies. PMID- 23810514 TI - Solving delay differential equations in S-ADAPT by method of steps. AB - S-ADAPT is a version of the ADAPT program that contains additional simulation and optimization abilities such as parametric population analysis. S-ADAPT utilizes LSODA to solve ordinary differential equations (ODEs), an algorithm designed for large dimension non-stiff and stiff problems. However, S-ADAPT does not have a solver for delay differential equations (DDEs). Our objective was to implement in S-ADAPT a DDE solver using the methods of steps. The method of steps allows one to solve virtually any DDE system by transforming it to an ODE system. The solver was validated for scalar linear DDEs with one delay and bolus and infusion inputs for which explicit analytic solutions were derived. Solutions of nonlinear DDE problems coded in S-ADAPT were validated by comparing them with ones obtained by the MATLAB DDE solver dde23. The estimation of parameters was tested on the MATLB simulated population pharmacodynamics data. The comparison of S-ADAPT generated solutions for DDE problems with the explicit solutions as well as MATLAB produced solutions which agreed to at least 7 significant digits. The population parameter estimates from using importance sampling expectation-maximization in S-ADAPT agreed with ones used to generate the data. PMID- 23810515 TI - Evaluation of bone regenerative capacity following distraction osteogenesis of goat mandibles using two different bone cutting techniques. AB - PURPOSE: To compare the regenerative capacity of goat mandibles following sagittal split osteotomy and distraction osteogenesis with a vertical body osteotomy. ANIMALS AND METHODS: Bilateral vertical and sagittal body osteotomy was performed on the left and right sides of the mandibles in 18 goats. The distraction period lasted for 10 days at 1 mm/day. Animals were sacrificed at 0, 10, and 35 days post-distraction. Bone mineral density (BMD) and bone volume (BV) were analysed by microcomputed tomography (MCT). Types of bone and cells present in the regenerated defect sites were analysed histologically. RESULTS: At 0, 10, and 35 days, BMD was 0.358 +/- 0.012, 0.410 +/- 0.012, and 1.070 +/- 0.019, respectively, for vertical osteotomy and 0.420 +/- 0.013, 0.421 +/- 0.009 and 1.182 +/- 0.030, respectively, for sagittal osteotomy. BV was 973.310 +/- 5.048, 1234.589 +/- 4.159, and 2121.867 +/- 6.519, respectively, for vertical osteotomy and 995.967 +/- 2.781, 1755.938 +/- 4.379, and 2618.441 +/- 21.429, respectively, for sagittal osteotomy at these three time points. BMD and BV differed significantly at all three times. Histological analysis shows that sagittal splitting was characterized by more robust lamellar bone formation bridging the distraction gap than vertical body osteotomy. CONCLUSION: Both MCT and histological analyses showed that distraction using the sagittal osteotomy technique resulted in significantly higher BV and BMD than using vertical body osteotomy. PMID- 23810516 TI - Prolonged peripheral nerve blockade in patients using lithium carbonate. AB - Peripheral nerve blocks with local anaesthesia are routinely utilized in oral surgical procedures to achieve anaesthesia at the operative site. A number of local tissue factors as well as systemic conditions and medications may alter the onset, depth and duration of peripheral nerve blocks. This article describes two cases of extremely prolonged anaesthesia in patients treated with chronic oral lithium carbonate who had been administered inferior alveolar, lingual, long buccal, greater palatine and posterior superior alveolar nerve blocks with lidocaine with adrenaline for surgical removal of an upper and a lower third molar tooth. A possible relation with systemic lithium therapy and its probable mode of action are explored. PMID- 23810517 TI - Time-response relationships for the accumulation of Cu, Ni and Zn by seven spotted ladybirds (Coccinella septempunctata L.) under conditions of single and combined metal exposure. AB - Accumulation, and therefore toxicity, of trace metals in invertebrates may be affected by potential interactive effects that can occur amongst different metallic elements. However, there is little data on the nature and effects of such interactions in terrestrial systems. This work reports the interactions among Cu, Ni and Zn during accumulation by the beetle Coccinella septempunctata. Test animals were treated with 500mgkg(-1) of each metal singularly and in combination for 15d. The effects of treatment with a single metal had no effect on the baseline concentrations of the other two. Time-response relationships for Cu and Ni after treatment with one metal were curvilinear, demonstrating that the metals were initially accumulated, but after ~8d regulatory mechanisms became effective. This resulted in decreasing concentrations in test animals despite continued treatment. In contrast, the time-response relationship for Zn was linear. Treatment with metals in combination markedly altered the time-response relationships with all three metals showing a linear trend and the slope of the Zn relationship increasing significantly. After 15d of exposure this had the effect of increasing the metal concentration in animals exposed in combination compared to those exposed singularly by 144% to 38.3mgkg(-1) for Cu, 141% to 27.5mgkg(-1) for Ni and 55% to 311mgkg(-1) for Zn. For all metals, differences amongst treatments were significant, indicating that inter-element interactions can enhance the concentration of trace metals in C. septempunctata. PMID- 23810518 TI - Bioadsorption and bioaccumulation of chromium trivalent in Cr(III)-tolerant microalgae: a mechanisms for chromium resistance. AB - Anthropogenic activity constantly releases heavy metals into the environment. The heavy metal chromium has a wide industrial use and exists in two stable oxidation states: trivalent and hexavalent. While hexavalent chromium uptake in plant cells has been reported that an active process by carrying essential anions, the cation Cr(III) appears to be taken up inactively. Dictyosphaerium chlorelloides (Dc1M), an unicellular green alga is a well-studied cell biological model organism. The present study was carried out to investigate the toxic effect of chromium exposures on wild-type Cr(III)-sensitive (Dc1M(wt)) and Cr(III)-tolerant (Dc1M(Cr(III)R30)) strains of these green algae, and to determine the potential mechanism of chromium resistance. Using cell growth as endpoint to determine Cr(III)-sensitivity, the IC50(72) values obtained show significant differences of sensitivity between wild type and Cr(III)-tolerant cells. Scanning electron microscopy (SEM) showed significant morphological differences between both strains, such as decrease in cell size or reducing the coefficient of form; and transmission electron microscopy (TEM) revealed ultrastructural changes such as increased vacuolization and cell wall thickening in the Cr(III)-tolerant strain with respect to the wild-type strain. Energy dispersive X-ray analysis (SEM/XEDS) revealed that Cr(III)-tolerant D. chlorelloides cells are able to accumulate considerable amounts of chromium distributed in cell wall (bioadsorption) as well as in cytoplasm, vacuoles, and chloroplast (bio-accumulation). Morphological changes of Cr(III)-tolerant D. chlorelloides cells and the presence of these electron-dense bodies in their cell structures can be understood as a Cr(III) detoxification mechanism. PMID- 23810519 TI - Ranking of ecotoxisity tests for underground water assessment using the Hasse diagram technique. AB - The present study deals with the novel application of the Hasse diagram technique (HDT) for the specific ranking of ecotoxicity tests capable of assessment of underground water quality. The area studied is a multi-municipal landfill in the northern Poland. The monitoring network of the landfill constitutes of 27 piezometers for underground water monitoring and two observation points at surface water courses. After sampling, chemical analysis of various water parameters was performed (pH, conductivity, temperature, turbidity (TURB), color, taste, smell and atmospheric conditions: temperature, precipitation and cloud cover, heavy metals content (Cu, Zn, Pb, Cd, Cr(6+), Hg), total organic carbon (TOC), sum of Polycyclic Aromatic Hydrocarbons (PAHs), Na, Mg, K, Ca, Mn, Fe, Ni, alkalinity (Alkal), general hardness, total suspended matter (SUSP), Biological Oxygen Demand (BOD), Chemical Oxygen Demand (COD), chlorides, fluorides, sulphides, sulphates, ammonium nitrogen, total nitrogen, nitrate and nitrite nitrogen, volatile phenols, ether extracts (ETHER), dry residues (DRY_RES), dissolved compounds). Parallel to the chemical parameters assessment six different ecotoxicity tests were applied (% root length(PG)/germination(PR) inhibition of Sorghum saccharatum (respectively PGSS/PRSS), Sinapis alba (respectively PGSA/PRSA), Lepidium sativum (respectively PGLS/PRLS), % bioluminescence inhibition of Vibrio fischeri (MT), % mortality of Daphnia magna (DM), % mortality of Thamnocephalus platyrus (TN)). In order to determine the applicability of the various ecotoxicity tests, a ranking of samples from different monitoring levels according to the test used (attributes) is done by using HDT. Further, the sensitivity of the biotests was determined and compared. From the sensitivity analysis of the both monitoring levels was evident that the choice of ecotoxicity tests could be optimized by the use of HDT strategy. Most reliable results could be expected by the application of root growth inhibition of Sorghum saccharatum (PGSS test). In order to clarify the relationship between the chemical parameters measured and each of the ecotoxicity tests a optimized similarity analysis between Hasse diagrams for the ecotoxicity tests for different levels of monitoring and Hasse diagrams obtained by the use of the chemical parameters was performed. Finally, it could be concluded that for reliable monitoring of underground waters passing a dump collector following chemical parameters are of significance: water hardness, dissolved matter, total nitrogen (ammonia and nitrate nitrogen), nickel, chlorides, alkalinity, total organic carbon and ether extract and the proper battery test could include PGSA, PGSS and PRSS. PMID- 23810520 TI - Algicidal activity of Salvia miltiorrhiza Bung on Microcystis aeruginosa--towards identification of algicidal substance and determination of inhibition mechanism. AB - The present study was to isolate and identify a potent algicidal compound from extract of Salvia miltiorrhiza and study the potential inhibition mechanism on Microcystis aeruginosa. Column chromatography and bioassay-guided fractionation methods were carried out to yield neo-przewaquinone A, which was identified by spectral analysis. The EC50 of neo-przewaquinone A on M. aeruginosa were 4.68 mg L(-1). In addition, neo-przewaquinone A showed relatively higher security on Chlorella pyrenoidosa and Scenedesmus obliquus, with the EC50 values of 14.78 and 10.37 mg L(-1), respectively. For the potential inhibition mechanisms, neo przewaquinone A caused M. aeruginosa cells morphologic damage or lysis, increased malondialdehyde content and decreased the soluble protein content, total antioxidant and superoxide dismutase activity, and significantly inhibited three photosynthesis-related genes (psaB, psbD, and rbcL). The results demonstrated the algicidal effect of neo-przewaquinone A on M. aeruginosa and provided the possible inhibition mechanisms. PMID- 23810521 TI - Subsequent malignancies after photon versus proton radiation therapy. PMID- 23810522 TI - [The Ineq-Cities research project on urban health inequalities: knowledge dissemination and transfer in Spain]. AB - The Ineq-Cities project analyzed inequalities in mortality in small areas and described interventions to reduce inequalities in health in 16 European cities. This field note describes the dissemination of the project in Spain. In accordance with the recommendations of the project, the objective was to translate relevant results to key stakeholders - mainly technical staff, municipal officers and local social agents - and to provide an introduction to urban inequalities in health and strategies to address them. Twenty-four workshops were given, attended by more than 350 professionals from 92 municipalities. Knowledge dissemination consisted of the publication of a short book on inequalities in health and the approach to this problem in cities and three articles in nonspecialized media, a proposal for a municipal motion, and knowledge dissemination activities in social networks. Users rated these activities highly and stressed the need to systematize these products. This process may have contributed to the inclusion of health inequalities in the political agenda and to the training of officers to correct them. PMID- 23810523 TI - [Nosocomial flu infection]. PMID- 23810524 TI - [Impact of the provision of fortified cornmeal on anemia in preschoolers in the indigenous areas of Mexico]. AB - OBJECTIVE: To estimate changes in anemia status in preschool age children at 9 months after the provision of soy- and iron-fortified cornflour. METHODS: A non experimental pre-post evaluation study was performed in a sample of 98 boys and 96 boys aged between 6 and 24 months. We analyzed demographic, anthropometric, and biochemical variables. RESULTS: During the 9-month period, the hemoglobin level increased from 11.0 to 11.9 mg/dL (p<0,001). The prevalence of anemia (hemoglobin <11.0mg/dL) decreased from 52.6% to 25.3% (p<0,001). The indicators of height for age and body mass index changed from -2.1 (-5.5 to 2.8) to -2.3 ( 6.5 to 1.3) (p<0,001) and from 0,4 (-3.1 to 2.9) to 0,7 (-2.2 to 3.9) (p<0,001), respectively. CONCLUSIONS: The decreased prevalence of anemia suggests that the provision of soy- (3%) and iron-fortified flour is a viable alternative for combating childhood anemia. PMID- 23810526 TI - [Promoting good practice in scientific publication: Gaceta Sanitaria and the Committee on Publication Ethics]. PMID- 23810525 TI - [An experience of the use of cell culture-derived influenza vaccines in an influenza vaccination campaign]. PMID- 23810527 TI - Bone protection and anti-epileptic drugs: the effect of audit and computer messaging on supplementation prescribing practices. AB - OBJECTIVE: This audit assessed the impact of individualised written recommendations and a computer message, on repeat prescriptions for calcium and vitamin D supplements, for patients on long term AEDs. METHODS: 1041 adult patients with epilepsy were retrospectively followed from 2004, from the time of the introduction of the Quality and Outcomes Framework (QOF) and the publication of the National Institute of Clinical Evidence (NICE) guidelines for epilepsy, up until 2011. In 2009 a clinical notes review of 414 of the above patients, in Ellesmere Port and Neston (13 practices) was performed, suggesting supplementation, where appropriate, in a written report. A computer message was added to relevant prescriptions also recommending supplements, in the above practices plus all 26 practices in Chester and the surrounding area. The number of patients receiving repeat prescription for supplements in each area between 2004 and 2011 was analysed. RESULTS: There was a significant increase in the repeat prescriptions of supplements in 2010/11 after the interventions, the increase being most marked in Ellesmere Port and Neston where both written recommendations and computer message had occurred compared with the two areas with the computer message only. CONCLUSION: Quality audit with written recommendations, and a message added to the General Practice (GP) computer systems significantly increased the number of repeat prescriptions of calcium and vitamin D supplements in this group of patients. PRACTICE IMPLICATIONS: Where clear guidelines are established, this study demonstrates that continuing education and counselling of GPs and use of computer messaging would result in improved compliance with such guidelines. PMID- 23810528 TI - In patients with schizophrenia, non-fatal suicidal self-directed violence is positively associated with present but not past smoking. PMID- 23810529 TI - Diffusion dynamics of socially learned foraging techniques in squirrel monkeys. AB - Social network analyses and experimental studies of social learning have each become important domains of animal behavior research in recent years yet have remained largely separate. Here we bring them together, providing the first demonstration of how social networks may shape the diffusion of socially learned foraging techniques. One technique for opening an artificial fruit was seeded in the dominant male of a group of squirrel monkeys and an alternative technique in the dominant male of a second group. We show that the two techniques spread preferentially in the groups in which they were initially seeded and that this process was influenced by monkeys' association patterns. Eigenvector centrality predicted both the speed with which an individual would first succeed in opening the artificial fruit and the probability that they would acquire the cultural variant seeded in their group. These findings demonstrate a positive role of social networks in determining how a new foraging technique diffuses through a population. PMID- 23810530 TI - New transitional fleas from China highlighting diversity of Early Cretaceous ectoparasitic insects. AB - Fleas are a group of highly specialized blood-feeding ectoparasites whose early evolutionary history is poorly known. Although several recent discoveries have shed new light on the origin of the group, a considerable gap exists between stem fleas and crown fleas. Here we report a new transitional flea, Saurophthirus exquisitus sp. nov., assigned to a new family Saurophthiridae fam. nov., from the Lower Cretaceous Yixian Formation of northeastern China. Saurophthirids are more similar to crown fleas than other stem fleas in having a relatively small body size, relatively short and slender piercing-sucking stylet mouthparts, comparably short and compact antennae, rows of short and stiff bristles on the thorax, and highly elongated legs. The new finding greatly improves our understanding of the morphological transition to the highly specialized body plan of extant fleas. However, saurophthirids also display several features unknown in other fleas, and some of these features are suggestive of a possible ectoparasitic relationship to contemporaneous pterosaurs, though other possibilities exist. The new fossils, in conjunction with previous discoveries, highlight a broad diversity of ectoparasitic insects in the mid-Mesozoic. PMID- 23810531 TI - VAL- and AtBMI1-mediated H2Aub initiate the switch from embryonic to postgerminative growth in Arabidopsis. AB - Plant B3-domain transcription factors have an important role in regulating seed development, in particular seed maturation and germination. Among the B3 factors, the AFL (ABSCISIC ACID INSENSITIVE3 [ABI3], FUSCA3 [FUS3], and LEAFY COTYLEDON2 [LEC2]) proteins activate the seed maturation program in a complex network, while the VAL (VP1/ABI3-LIKE) 1/2/3 proteins suppress AFL action in order to initiate germination and vegetative development through an as yet unknown mechanism. In addition, the AFL genes and LEAFY COTYLEDON1 (LEC1), referred as seed maturation genes, are epigenetically repressed after germination by the Polycomb group (PcG) machinery via its histone-modifying activities: the histone H3 lysine 27 trimethyltransferase activity of the PcG repressive complex 2 (PRC2) and the E3 H2A monoubiquitin ligase activity of the PRC1. Both histone modifications are required for the repression; however, the underlying mechanism is far from clear, because the localization and the role of H2Aub marks are still unknown. In this work, we demonstrate that VAL proteins and AtBMI1-mediated H2Aub initiate repression of seed maturation genes. After the initial off switch, the repression is maintained by PRC2-mediated H3K27me3. Our results indicate that the regulation of seed maturation genes does not follow the classic hierarchical model proposed for animal PcG-mediated repression, since the PRC1 activity is required for the H3K27me3 modification of these genes. Furthermore, we show different mechanisms to achieve PcG repression in plants, as the repression of genes involved in other processes has different requirements for H2Aub and H3K27me3 marking. PMID- 23810532 TI - Context-specific reweighting of auditory spatial cues following altered experience during development. AB - BACKGROUND: Neural systems must weight and integrate different sensory cues in order to make decisions. However, environmental conditions often change over time, altering the reliability of different cues and therefore the optimal way for combining them. To explore how cue integration develops in dynamic environments, we examined the effects on auditory spatial processing of rearing ferrets with localization cues that were modified via a unilateral earplug, interspersed with brief periods of normal hearing. RESULTS: In contrast with control animals, which rely primarily on timing and intensity differences between their two ears to localize sound sources, the juvenile-plugged ferrets developed the ability to localize sounds accurately by relying more on the unchanged spectral localization cues provided by the single normal ear. This adaptive process was paralleled by changes in neuronal responses in the primary auditory cortex, which became relatively more sensitive to these monaural spatial cues. Our behavioral and physiological data demonstrated, however, that the reweighting of different spatial cues disappeared as soon as normal hearing was experienced, showing for the first time that this type of plasticity can be context specific. CONCLUSIONS: These results show that developmental changes can be selectively expressed in response to specific acoustic conditions. In this way, the auditory system can develop and simultaneously maintain two distinct models of auditory space and switch between these models depending on the prevailing sensory context. This ability is likely to be critical for maintaining accurate perception in dynamic environments and may point toward novel therapeutic strategies for individuals who experience sensory deficits during development. PMID- 23810533 TI - Phage-mediated selection on microbiota of a long-lived host. AB - It is increasingly apparent that the dynamic microbial communities of long-lived hosts affect their phenotype, including resistance to disease. The host microbiota will change over time due to immigration of new species, interaction with the host immune system, and selection by bacteriophage viruses (phages), but the relative roles of each process are unclear. Previous metagenomic approaches confirm the presence of phages infecting host microbiota, and experimental coevolution of bacteria and phage populations in the laboratory has demonstrated rapid reciprocal change over time. The key challenge is to determine whether phages influence host-associated bacterial communities in nature, in the face of other selection pressures. I use a tree-bacteria-phage system to measure reciprocal changes in phage infectivity and bacterial resistance within microbial communities of tree hosts over one season. An experimental time shift shows that bacterial isolates are most resistant to lytic phages from the prior month and least resistant to those from the future month, providing clear evidence for both phage-mediated selection on bacterial communities and bacterial-mediated selection on phage communities in nature. These reciprocal changes suggest that phages indeed play a key role in shaping the microbiota of their eukaryotic hosts. PMID- 23810534 TI - Changes in cell morphology are coordinated with cell growth through the TORC1 pathway. AB - BACKGROUND: Growth rate is determined not only by extracellular cues such as nutrient availability but also by intracellular processes. Changes in cell morphology in budding yeast, mediated by polarization of the actin cytoskeleton, have been shown to reduce cell growth. RESULTS: Here we demonstrate that polarization of the actin cytoskeleton inhibits the highly conserved Target of Rapamycin Complex 1 (TORC1) pathway. This downregulation is suppressed by inactivation of the TORC1 pathway regulatory Iml1 complex, which also regulates TORC1 during nitrogen starvation. We further demonstrate that attenuation of growth is important for cell recovery after conditions of prolonged polarized growth. CONCLUSIONS: Our results indicate that extended periods of polarized growth inhibit protein synthesis, mass accumulation, and the increase in cell size at least in part through inhibiting the TORC1 pathway. We speculate that this mechanism serves to coordinate the ability of cells to increase in size with their biosynthetic capacity. PMID- 23810535 TI - Cell-fibronectin interactions propel vertebrate trunk elongation via tissue mechanics. AB - During embryonic development and tissue homeostasis, cells produce and remodel the extracellular matrix (ECM). The ECM maintains tissue integrity and can serve as a substrate for cell migration. Integrin alpha5 (Itgalpha5) and alphaV (ItgalphaV) are the alpha subunits of the integrins most responsible for both cell adhesion to the ECM protein fibronectin (FN) and FN matrix fibrillogenesis. We perform a systems-level analysis of cell motion in the zebrafish tail bud during trunk elongation in the presence and absence of normal cell-FN interactions. Itgalpha5 and ItgalphaV have well-described roles in cell migration in vitro. However, we find that concomitant loss of itgalpha5 and itgalphaV leads to a trunk elongation defect without substantive alteration of cell migration. Tissue-specific transgenic rescue experiments suggest that the FN matrix on the surface of the paraxial mesoderm is required for body elongation via its role in defining tissue mechanics and intertissue adhesion. PMID- 23810536 TI - CEP120 and SPICE1 cooperate with CPAP in centriole elongation. AB - Centrosomes organize microtubule (MT) arrays and are comprised of centrioles surrounded by ordered pericentriolar proteins. Centrioles are barrel-shaped structures composed of MTs, and as basal bodies they template the formation of cilia/flagella. Defects in centriole assembly can lead to ciliopathies and genome instability. The assembly of procentrioles requires a set of conserved proteins. It is initiated at the G1-to-S transition by PLK4 and CEP152, which help recruit SASS6 and STIL to the vicinity of the mother centriole to organize the cartwheel. Subsequently, CPAP promotes centriolar MT assembly and elongation in G2. While centriole integrity is maintained by CEP135 and POC1 through MT stabilization, centriole elongation requires POC5 and is restricted by CP110 and CEP97. How strict control of centriole length is achieved remains unclear. Here, we show that CEP120 and SPICE1 are required to localize CEP135 (but not SASS6, STIL, or CPAP) to procentrioles. CEP120 associates with SPICE1 and CPAP, and depletion of any of these proteins results in short procentrioles. Furthermore, CEP120 or CPAP overexpression results in excessive centriole elongation, a process dependent on CEP120, SPICE1, and CPAP. Our findings identify a shared function for these proteins in centriole length control. PMID- 23810537 TI - Spindle pole body history intrinsically links pole identity with asymmetric fate in budding yeast. AB - BACKGROUND: Budding yeast is a unique model for exploring differential fate in a cell dividing asymmetrically. In yeast, spindle orientation begins with the old spindle pole body (SPB) (from the preceding cell cycle) contacting the bud by its existing astral microtubules (aMTs) while the new pole delays astral microtubule organization. This appears to prime the inheritance of the old pole by the bud. The basis for this asymmetry and the discrimination of the poles by virtue of their history remain a mystery. RESULTS: Here, we report that asymmetric aMT organization stems from an outstanding structural asymmetry linked to the SPB cycle. We show that the gamma-tubulin nucleation complex (gammaTC) favors the old spindle pole, an asymmetry inherent to the outer plaque (the cytoplasmic face of the SPB). Indeed, Spc72 (the receptor for the gammaTC) is acquired by the new SPB outer plaque partway through spindle assembly. The significance of this asymmetry was explored in cells expressing an Spc72(1-276)-Cnm67 fusion that forced symmetric nucleation at the SPB outer plaques. This manipulation triggered simultaneous aMT organization by both spindle poles from the outset and led to symmetric contacts between poles and the bud, effectively disrupting the program for spindle polarity. Temporally symmetric aMT organization perturbed Kar9 polarization by randomizing the choice of the pole to be guided toward the bud. Accordingly, the pattern of SPB inheritance was also randomized. CONCLUSIONS: Spc72 differential recruitment imparting asymmetric aMT organization represents the most upstream determinant linking SPB historical identity and fate. PMID- 23810538 TI - "Fitness fingerprints" mediate physiological culling of unwanted neurons in Drosophila. AB - BACKGROUND: The flower gene has been previously linked to the elimination of slow dividing epithelial cells during development in a process known as "cell competition." During cell competition, different isoforms of the Flower protein are displayed at the cell membrane and reveal the reduced fitness of slow proliferating cells, which are therefore recognized, eliminated, and replaced by their normally dividing neighbors. This mechanism acts as a "cell quality" control in proliferating tissues. RESULTS: Here, we use the Drosophila eye as a model to study how unwanted neurons are culled during retina development and find that flower is required and sufficient for the recognition and elimination of supernumerary postmitotic neurons, contained within incomplete ommatidia units. This constitutes the first description of the "Flower Code" functioning as a cell selection mechanism in postmitotic cells and is also the first report of a physiological role for this cell quality control machinery. CONCLUSIONS: Our results show that the "Flower Code" is a general system to reveal cell fitness and that it may play similar roles in creating optimal neural networks in higher organisms. The Flower Code seems to be a more general mechanism for cell monitoring and selection than previously recognized. PMID- 23810539 TI - Mental imagery changes multisensory perception. AB - Multisensory interactions are the norm in perception, and an abundance of research on the interaction and integration of the senses has demonstrated the importance of combining sensory information from different modalities on our perception of the external world. However, although research on mental imagery has revealed a great deal of functional and neuroanatomical overlap between imagery and perception, this line of research has primarily focused on similarities within a particular modality and has yet to address whether imagery is capable of leading to multisensory integration. Here, we devised novel versions of classic multisensory paradigms to systematically examine whether imagery is capable of integrating with perceptual stimuli to induce multisensory illusions. We found that imagining an auditory stimulus at the moment two moving objects met promoted an illusory bounce percept, as in the classic cross-bounce illusion; an imagined visual stimulus led to the translocation of sound toward the imagined stimulus, as in the classic ventriloquist illusion; and auditory imagery of speech stimuli led to a promotion of an illusory speech percept in a modified version of the McGurk illusion. Our findings provide support for perceptually based theories of imagery and suggest that neuronal signals produced by imagined stimuli can integrate with signals generated by real stimuli of a different sensory modality to create robust multisensory percepts. These findings advance our understanding of the relationship between imagery and perception and provide new opportunities for investigating how the brain distinguishes between endogenous and exogenous sensory events. PMID- 23810540 TI - A dual operator view of habitual behavior reflecting cortical and striatal dynamics. AB - Habits are notoriously difficult to break and, if broken, are usually replaced by new routines. To examine the neural basis of these characteristics, we recorded spike activity in cortical and striatal habit sites as rats learned maze tasks. Overtraining induced a shift from purposeful to habitual behavior. This shift coincided with the activation of neuronal ensembles in the infralimbic neocortex and the sensorimotor striatum, which became engaged simultaneously but developed changes in spike activity with distinct time courses and stability. The striatum rapidly acquired an action-bracketing activity pattern insensitive to reward devaluation but sensitive to running automaticity. A similar pattern developed in the upper layers of the infralimbic cortex, but it formed only late during overtraining and closely tracked habit states. Selective optogenetic disruption of infralimbic activity during overtraining prevented habit formation. We suggest that learning-related spiking dynamics of both striatum and neocortex are necessary, as dual operators, for habit crystallization. PMID- 23810542 TI - Acquired hypocalciuric hypercalcemia in a patient with CKD. AB - We present a case of an 82-year-old woman with elevated parathyroid hormone (PTH) levels, hypocalciuria, hypercalcemia, and stage 3 chronic kidney disease. Hypocalciuria initially was attributed to chronic kidney disease, and hypercalcemia was attributed to primary hyperparathyroidism. Subsequent laboratory studies showed autoantibodies in the patient's serum directed against the calcium-sensing receptor (CaSR). Functional testing in a CaSR-transfected human embryonic kidney-293 cell line showed that the patient's antibodies inhibited CaSR-mediated intracellular signaling that ordinarily would have been stimulated by extracellular calcium ions. Her serum calcium and PTH levels were normalized by treatment with the calcimimetic cinacalcet. We advise consideration of the presence of inhibitory autoantibodies directed at the CaSR in patients with hypercalcemic hyperparathyroidism and unexplained hypocalciuria or with confounding conditions affecting interpretation of urinary calcium measurement. A calcimimetic is an effective treatment for the hypercalcemia and elevated PTH levels in acquired hypocalciuric hypercalcemia caused by inhibitory anti-CaSR autoantibodies. PMID- 23810543 TI - A facile one-pot hydrothermal method to produce SnS2/reduced graphene oxide with flake-on-sheet structures and their application in the removal of dyes from aqueous solution. AB - In this article, we report a novel one-pot synthesis of SnS2/reduced graphene oxide (rGO) flake-on-sheet nanocomposites via in situ reduction of graphene oxide (GO) by Sn(2+) under hydrothermal conditions. The morphology and structure of the obtained product were characterized by transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction instrument (XRD), X-ray photoelectron spectroscopy (XPS), and Raman spectroscopy. The adsorption characteristics of the SnS2/rGO nanocomposites were examined using an organic dye Rhodamine B (RhB) as adsorbate. SnS2/rGO exhibited superior adsorption behavior for RhB. The adsorption kinetics and adsorption isotherm were investigated. The adsorption of RhB by SnS2/rGO was well fitted to the Langmuir isotherm model, and the resultant kinetic data were well described by pseudo second-order model. PMID- 23810541 TI - Differential innervation of direct- and indirect-pathway striatal projection neurons. AB - The striatum integrates information from multiple brain regions to shape motor learning. The two major projection cell types in striatum target different downstream basal ganglia targets and have opposing effects on motivated behavior, yet differential innervation of these neuronal subtypes is not well understood. To examine whether input specificity provides a substrate for information segregation in these circuits, we used a monosynaptic rabies virus system to generate brain-wide maps of neurons that form synapses with direct- or indirect pathway striatal projection neurons. We discovered that sensory cortical and limbic structures preferentially innervated the direct pathway, whereas motor cortex preferentially targeted the indirect pathway. Thalamostriatal input, dopaminergic input, as well as input from specific cortical layers, was similar onto both pathways. We also confirm synaptic innervation of striatal projection neurons by the raphe and pedunculopontine nuclei. Together, these findings provide a framework for guiding future studies of basal ganglia circuit function. PMID- 23810544 TI - Fabrication of nanogel core-silica shell and hollow silica nanoparticles via an interfacial sol-gel process triggered by transition-metal salt in inverse systems. AB - Nanogel (hydrophilic polymer nanoparticles) core-silica shell nanoparticles were successfully fabricated via hydrolysis and condensation reaction of tetraethoxysilane (TEOS). Transition-metal tetrafluoroborate-containing nanogels were used as templates for fabrication in inverse systems (cyclohexane as continuous phase). Magnetic, hollow silica particles were subsequently formed by removing the polymer core and converting iron salts to iron oxides via heat treatment. We propose that the formation of the core-shell morphology is induced by the promoted precipitation of silica species at the surface of nanogels due to the interaction between silica species and transition-metal tetrafluoroborate. The influence of the synthesis parameters (type and amount of salts, pH of the nanogels, and amount of TEOS) on the particle morphology was systematically investigated. The pore properties and specific surface area of the hollow silica particles could be modified by the varying the amount of salt. PMID- 23810545 TI - Modelling CEC variations versus structural iron reduction levels in dioctahedral smectites. Existing approaches, new data and model refinements. AB - A model was developed to describe how the 2:1 layer excess negative charge induced by the reduction of Fe(III) to Fe(II) by sodium dithionite buffered with citrate-bicarbonate is balanced and applied to nontronites. This model is based on new experimental data and extends structural interpretation introduced by a former model [36-38]. The 2:1 layer negative charge increase due to Fe(III) to Fe(II) reduction is balanced by an excess adsorption of cations in the clay interlayers and a specific sorption of H(+) from solution. Prevalence of one compensating mechanism over the other is related to the growing lattice distortion induced by structural Fe(III) reduction. At low reduction levels, cation adsorption dominates and some of the incorporated protons react with structural OH groups, leading to a dehydroxylation of the structure. Starting from a moderate reduction level, other structural changes occur, leading to a reorganisation of the octahedral and tetrahedral lattice: migration or release of cations, intense dehydroxylation and bonding of protons to undersaturated oxygen atoms. Experimental data highlight some particular properties of ferruginous smectites regarding chemical reduction. Contrary to previous assumptions, the negative layer charge of nontronites does not only increase towards a plateau value upon reduction. A peak is observed in the reduction domain. After this peak, the negative layer charge decreases upon extended reduction (>30%). The decrease is so dramatic that the layer charge of highly reduced nontronites can fall below that of its fully oxidised counterpart. Furthermore, the presence of a large amount of tetrahedral Fe seems to promote intense clay structural changes and Fe reducibility. Our newly acquired data clearly show that models currently available in the literature cannot be applied to the whole reduction range of clay structural Fe. Moreover, changes in the model normalising procedure clearly demonstrate that the investigated low tetrahedral bearing nontronites (SWa-1, GAN and NAu-1) all exhibit the same behaviour at low reduction levels. Consequently, we restricted our model to the case of moderate reduction (<30%) in low tetrahedral Fe-bearing nontronites. Our adapted model provides the relative amounts of Na(+) (p) and H(+) (ni) cations incorporated in the structure as a function of the amount of Fe reduction. Two equations enable the investigated systems to be described: p=m/(1+Kr.omega.mrel) and ni=Kr.omega.m.mrel/(1+Kr.omega.mrel); where m is the Fe(II) content, mrel, the reduction level (m/mtot), omega, the cation exchange capacity (CEC, and Kr, an empirical constant specific to the system. PMID- 23810546 TI - Controlled assembly of graphene oxide nanosheets within one-dimensional polymer nanostructure. AB - We have demonstrated that the location and distribution of graphene oxide nanosheets (GONs) confined in 1D polymer composites were readily controlled depending on the processing conditions of electrospinning such as the types of polymers and the solvents used for the fabrication. The uniform bead-free poly(vinyl alcohol) (PVA)/GON composite nanofibers (NFs) even at high GON loading were obtained from the homogeneous polymer solutions attributable to the favorable interactions, as elucidated by spectroscopic data, thereby showing significant enhancement of their physical properties. The GONs were localized in the surface regions of the PVA-NFs due to the rapid convective evaporation of the water molecules, with concomitant aggregation into several sheets (<10 layers). In contrast, the co-continuous internal morphology of PVA/GON-NFs was constructed using less-volatile, polar dimethylformamide (DMF) solvents. Furthermore, the GONs were uniformly distributed in the more compatible polymer matrices such as polyacrylonitrile (PAN) and polystyrene (PS). Therefore, the distribution of GONs in 1D nanofibers was governed by the kinetics of solvent evaporation and the interaction with the polymer matrices. PMID- 23810547 TI - Assessment of stability of surface anchors for antibacterial coatings and immobilized growth factors on titanium. AB - Titanium (Ti) has been functionalized with biomolecules for biomedical purposes. However, there is very limited information on the stability of such functionalities. Ti surface functionalized with carboxymethyl chitosan (CMCS) and bone morphogenetic protein 2 (BMP-2) has been reported to inhibit bacterial colonization while at the same time enhances osteoblast functions. In this work, three types of anchoring molecules, (3-aminopropyl) triethoxysilane (Silane), dopamine (DA), and polydopamine (PDA), were used for immobilizing the CMCS on Ti. The CMCS-modified surfaces were subjected to 70% ethanol treatment, autoclaving, and prolonged immersion in phosphate buffered saline (PBS). After the treatment procedures, the ability of the CMCS-modified substrates to inhibit colonization by Staphylococcus epidermidis (S. epidermidis) was assessed to evaluate the stability of the immobilized CMCS. The bacterial adhesion assays showed that the CMCS-DA- and CMCS-PDA-modified Ti remained stable after 70% ethanol treatment, autoclaving, and prolonged immersion in PBS, whereas the CMCS-Silane-modified Ti was less stable after autoclaving and prolonged immersion in PBS. The CMCS-DA- and CMCS-PDA-modified Ti substrates were functionalized with BMP-2 and used to support osteoblast growth. Evaluation of alkaline phosphatase (ALP) activity and calcium deposition from osteoblasts cultured on these substrates, which have been treated with 70% ethanol, or subjected to autoclaving, and prolonged immersion in PBS indicated that the immobilized BMP-2 on these surfaces retained its bioactivity. PMID- 23810548 TI - Pediatric peritonsillar abscess: Quinsy ie versus interval tonsillectomy. AB - PERITONSILLAR ABSCESS: Quinsy versus interval tonsillectomy. OBJECTIVES STUDY DESIGN: Case series with chart review. METHODS: We reviewed the records of children treated for peritonsillar abscess between 2007 and 2011 at an academic tertiary pediatric hospital. We identified patients by searching the hospital database for all children treated for the ICD-9 code 475 (peritonsillar abscess). Data points extracted included length of stay, intraoperative blood loss, operative time, and incidence of complications. Statistical analysis was performed to identify significant differences between treatment categories. Children who never received a tonsillectomy (CPT codes 42820/42821/42825/42826) were excluded. RESULTS: 34 children received tonsillectomy for peritonsillar abscess from 2007 to 2011. Of these: 23 received a Quinsy tonsillectomy, and 11 received antibiotics with or without incision and drainage, followed by tonsillectomy a minimum of 2 weeks later. Total hospital days in treatment course was 2.2 days for Quinsy tonsillectomy group and 2.3 days for the interval tonsillectomy group. Estimated blood loss was less than 20 ml for both groups. Operative time was 38 min for Quinsy tonsillectomy and 39 min for interval tonsillectomy. There were no post-tonsillectomy hemorrhages. One patient in the interval tonsillectomy group required readmission for dehydration. CONCLUSION: There were no significant differences in total hospital days, blood loss, operative time, or post-operative complications between Quinsy tonsillectomy and interval tonsillectomy in the treatment of pediatric peritonsillar abscess. PMID- 23810549 TI - Bifid nose - a mild degree of frontonasal dysplasia. A case report. AB - Frontonasal dysplasia is an unusual congenital condition with a wide phenotypic range. Because of this, only a small number of cases and their management have been reported in the literature. The ideal surgical procedures to correct mild cases of frontonasal dysplasia, and the time to perform them, are still controversial. The case of a 9-month-old girl with a mild form of this condition (a congenital bifid nose and a duplicated frenulum), and its surgical management, is presented. The surgery achieved an early improvement of the patient's appearance and she had no complications. In the future, it is probable that she will need secondary rhinoplasty to aid in the projection of the tip and refine the shape of the nose. PMID- 23810550 TI - Young cochlear implant users' auditory development as measured and monitored by the LittlEARS(r) Auditory Questionnaire: a Turkish experience. AB - OBJECTIVE: This study aims to assess the usefulness of the LittlEARS((r)) Auditory Questionnaire (LEAQ) in determining the audiological development of Turkish children who have received a cochlear implant. METHODS: 20 children received a cochlear implant before their 3rd birthday. Each child's progress was evaluated with the LittlEARS((r)) Auditory Questionnaire at first device fitting and then at 3-month intervals for 2 years. Scores were compared with the age related norms established by hearing children. RESULTS: All children showed a significant increase in LittlEARS((r)) Auditory Questionnaire scores over time. Nearly all children showed a growth in auditory skills similar to that of hearing children. Children without additional needs showed more development than did children with additional needs. CONCLUSIONS: The LittlEARS((r)) Auditory Questionnaire is useful for monitoring the audiological development of young children with a cochlear implant. Confirmation that a cochlear implant user is achieving typical auditory milestones serves to boost parental morale during a child's pre-verbal stage when parents may be anxious about their child's ability to talk. The questionnaire could also be useful as an early warning system. Poor scores likely indicate that something is impeding the child's development. This should prompt professionals to try to identify the impediment, whether technical, medical, social or educational and, possibly, eliminate/mitigate its effects while the child is still in his/her critical development stages. PMID- 23810551 TI - Granulocytic sarcoma of pediatric head and neck: an institutional experience. AB - OBJECTIVE: To demonstrate a case series of granulocytic sarcoma of the head and neck found in the pediatric population and review long-term outcomes. METHODS: A pathology database at a tertiary hospital was searched for patients with biopsy specimens from the head and neck diagnosed as granulocytic sarcoma. RESULTS: There were 6 cases between 1992 and 2004 that met inclusion criteria. Subjects' age ranged from 22 months to 14 years old. In three cases, the patients were diagnosed with acute myeloid leukemia (AML) based on biopsy results; 2 patients were already diagnosed with AML when diagnosed with granulocytic sarcoma, and in 1 case, a relapse of AML was diagnosed. In all cases, patients began induction chemotherapy. Two patients died during induction chemotherapy from infection. The remaining 4 patients underwent bone marrow transplants. One patient had a relapse post-transplant and died. Only one patient was healthy two years post-transplant. CONCLUSION: The results of this series suggest granulocytic sarcoma must be on the differential when tumors present in the head and neck region in pediatric patients. In our series, 100% of the patients with granulocytic sarcoma had underlying AML. The long-term prognosis of patients with AML who developed granulocytic sarcoma is quite poor. PMID- 23810552 TI - Chromatin modifications as determinants of muscle stem cell quiescence and chronological aging. AB - The ability to maintain quiescence is critical for the long-term maintenance of a functional stem cell pool. To date, the epigenetic and transcriptional characteristics of quiescent stem cells and how they change with age remain largely unknown. In this study, we explore the chromatin features of adult skeletal muscle stem cells, or satellite cells (SCs), which reside predominantly in a quiescent state in fully developed limb muscles of both young and aged mice. Using a ChIP-seq approach to obtain global epigenetic profiles of quiescent SCs (QSCs), we show that QSCs possess a permissive chromatin state in which few genes are epigenetically repressed by Polycomb group (PcG)-mediated histone 3 lysine 27 trimethylation (H3K27me3), and a large number of genes encoding regulators that specify nonmyogenic lineages are demarcated by bivalent domains at their transcription start sites (TSSs). By comparing epigenetic profiles of QSCs from young and old mice, we also provide direct evidence that, with age, epigenetic changes accumulate and may lead to a functional decline in quiescent stem cells. These findings highlight the importance of chromatin mapping in understanding unique features of stem cell identity and stem cell aging. PMID- 23810553 TI - Regulation of Tcf7l1 DNA binding and protein stability as principal mechanisms of Wnt/beta-catenin signaling. AB - Wnt/beta-catenin signal transduction requires direct binding of beta-catenin to Tcf/Lef proteins, an event that is classically associated with stimulating transcription by recruiting coactivators. This molecular cascade plays critical roles throughout embryonic development and normal postnatal life by affecting stem cell characteristics and tumor formation. Here, we show that this pathway utilizes a fundamentally different mechanism to regulate Tcf7l1 (formerly named Tcf3) activity. beta-catenin inactivates Tcf7l1 without a switch to a coactivator complex by removing it from DNA, which leads to Tcf7l1 protein degradation. Mouse genetic experiments demonstrate that Tcf7l1 inactivation is the only required effect of the Tcf7l1-beta-catenin interaction. Given the expression of Tcf7l1 in pluripotent embryonic and adult stem cells, as well as in poorly differentiated breast cancer, these findings provide mechanistic insights into the regulation of pluripotency and the role of Wnt/beta-catenin in breast cancer. PMID- 23810554 TI - Aurora A kinase regulates mammary epithelial cell fate by determining mitotic spindle orientation in a Notch-dependent manner. AB - Cell fate determination in the progeny of mammary epithelial stem/progenitor cells remains poorly understood. Here, we have examined the role of the mitotic kinase Aurora A (AURKA) in regulating the balance between basal and luminal mammary lineages. We find that AURKA is highly expressed in basal stem cells and, to a lesser extent, in luminal progenitors. Wild-type AURKA expression promoted luminal cell fate, but expression of an S155R mutant reduced proliferation, promoted basal fate, and inhibited serial transplantation. The mechanism involved regulation of mitotic spindle orientation by AURKA and the positioning of daughter cells after division. Remarkably, this was NOTCH dependent, as NOTCH inhibitor blocked the effect of wild-type AURKA expression on spindle orientation and instead mimicked the effect of the S155R mutant. These findings directly link AURKA, NOTCH signaling, and mitotic spindle orientation and suggest a mechanism for regulating the balance between luminal and basal lineages in the mammary gland. PMID- 23810555 TI - Cell-cycle kinases coordinate the resolution of recombination intermediates with chromosome segregation. AB - Homologous recombination leads to the formation of DNA joint molecules (JMs) that must be resolved to allow chromosome segregation, but how resolution is temporally coupled with chromosome segregation is unknown. Here, we have analyzed the role of the cell-cycle kinases Cdk and Cdc5 in coordinating these events through their involvement in the phosphoregulation of the Mus81-Mms4 nuclease. By identifying CDC5 and MMS4 mutants that uncouple Mus81-Mms4 activation from cell cycle progression, we show that JM disengagement, prior to anaphase initiation, safeguards chromosome segregation. By simultaneously stimulating the cleavage of cohesin and activating Mus81-Mms4 at the G2/M transition, Cdk and Cdc5 coordinate the sequential elimination of all chromosomal interactions in preparation for chromosome segregation. Conversely, untimely Cdc5 expression increases crossover frequency due to premature activation of Mus81-Mms4. Therefore, temporal restriction of JM resolution, imposed by Cdk/Cdc5, minimizes the potential for loss of heterozygosity while preventing chromosome missegregation and aneuploidy. PMID- 23810557 TI - Subunits of the histone chaperone CAF1 also mediate assembly of protamine-based chromatin. AB - One of the most dramatic forms of chromatin reorganization occurs during spermatogenesis, when the paternal genome is repackaged from a nucleosomal to a protamine-based structure. We assessed the role of the canonical histone chaperone CAF1 in Drosophila spermatogenesis. In this process, CAF1 does not behave as a complex, but its subunits display distinct chromatin dynamics. During histone-to-protamine replacement, CAF1-p180 dissociates from the DNA while CAF1 p75 binds and stays on as a component of sperm chromatin. Association of CAF1-p75 with the paternal genome depends on CAF1-p180 and protamines. Conversely, CAF1 p75 binds protamines and is required for their incorporation into sperm chromatin. Histone removal, however, occurs independently of CAF1 or protamines. Thus, CAF1-p180 and CAF1-p75 function in a temporal hierarchy during sperm chromatin assembly, with CAF1-p75 acting as a protamine-loading factor. These results show that CAF1 subunits mediate the assembly of two fundamentally different forms of chromatin. PMID- 23810556 TI - Checkpoint kinases regulate a global network of transcription factors in response to DNA damage. AB - DNA damage activates checkpoint kinases that induce several downstream events, including widespread changes in transcription. However, the specific connections between the checkpoint kinases and downstream transcription factors (TFs) are not well understood. Here, we integrate kinase mutant expression profiles, transcriptional regulatory interactions, and phosphoproteomics to map kinases and downstream TFs to transcriptional regulatory networks. Specifically, we investigate the role of the Saccharomyces cerevisiae checkpoint kinases (Mec1, Tel1, Chk1, Rad53, and Dun1) in the transcriptional response to DNA damage caused by methyl methanesulfonate. The result is a global kinase-TF regulatory network in which Mec1 and Tel1 signal through Rad53 to synergistically regulate the expression of more than 600 genes. This network involves at least nine TFs, many of which have Rad53-dependent phosphorylation sites, as regulators of checkpoint kinase-dependent genes. We also identify a major DNA damage-induced transcriptional network that regulates stress response genes independently of the checkpoint kinases. PMID- 23810558 TI - Reactivation of the same synapses during spontaneous up states and sensory stimuli. AB - In the mammalian brain, calcium signals in dendritic spines are involved in many neuronal functions, particularly in the induction of synaptic plasticity. Recent studies have identified sensory stimulation-evoked spine calcium signals in cortical neurons in vivo. However, spine signaling during ongoing cortical activity in the absence of sensory input, which is essential for important functions like memory consolidation, is not well understood. Here, by using in vivo two-photon imaging of auditory cortical neurons, we demonstrate that subthreshold, NMDA-receptor-dependent spine calcium signals are abundant during up states, but almost absent during down states. In each neuron, about 500 nonclustered spines, which are widely dispersed throughout the dendritic field, are on average active during an up state. The same subset of spines is reliably active during both sensory stimulation and up states. Thus, spontaneously recurring up states evoke in these spines "patterned" calcium activity that may control consolidation of synaptic strength following epochs of sensory stimulation. PMID- 23810559 TI - De novo DNA methylation in the male germ line occurs by default but is excluded at sites of H3K4 methylation. AB - To understand what dictates the emerging patterns of de novo DNA methylation in the male germline, we mapped DNA methylation, chromatin, and transcription changes in purified fetal mouse germ cells by using methylated CpG island recovery assay (MIRA)-chip, chromatin immunoprecipitation (ChIP)-chip, and strand specific RNA deep sequencing, respectively. Global de novo methylation occurred by default in prospermatogonia without any apparent trigger from preexisting repressive chromatin marks but was preceded by broad, low-level transcription along the chromosomes, including the four known paternally imprinted differentially methylated regions (DMRs). Default methylation was excluded only at precisely aligned constitutive or emerging peaks of H3K4me2, including most CpG islands and some intracisternal A particles (IAPs). Similarly, each maternally imprinted DMR was protected from default DNA methylation among highly methylated DNA by an H3K4me2 peak and transcription initiation at least in one strand. Our results suggest that the pattern of de novo DNA methylation in prospermatogonia is dictated by opposing actions of broad, low-level transcription and dynamic patterns of active chromatin. PMID- 23810560 TI - Proviral silencing in embryonic cells is regulated by Yin Yang 1. AB - Embryonic cells transcriptionally repress the expression of endogenous and exogenous retroelements. Trim28, a key player in this silencing, is known to act in a large DNA-bound complex, but the other components of the complex are not fully characterized. Here, we show that the zinc finger protein Yin Yang 1 (YY1) is one such component. YY1 binds to the long terminal repeat (LTR) region of both exogenous and endogenous retroviruses (ERVs). Deletion of the YY1-binding site from the retroviral genome leads to a major loss of silencing in embryonic cells and a coordinated loss of repressive histone marks from the proviral chromatin. Depletion of YY1 protein results in marked upregulation of expression of exogenous viruses and of selected ERVs. Finally, we report an embryonic cell specific interaction between YY1 and Trim28. Our results suggest a major role for YY1 in the silencing of both exogenous retroviruses and ERVs in embryonic cells. PMID- 23810561 TI - Dpp signaling determines regional stem cell identity in the regenerating adult Drosophila gastrointestinal tract. AB - The gastrointestinal tract is lined by a series of epithelia that share functional requirements but also have distinct, highly specialized roles. Distinct populations of somatic stem cells (SCs) regenerate these epithelia, yet the mechanisms that maintain regional identities of these SCs are not well understood. Here, we identify a role for the BMP-like Dpp signaling pathway in diversifying regenerative processes in the adult gastrointestinal tract of Drosophila. Dpp secreted from enterocytes at the boundary between the posterior midgut and the middle midgut (MM) sets up a morphogen gradient that selectively directs copper cell (CC) regeneration from gastric SCs in the MM and thus determines the size of the CC region. In vertebrates, deregulation of BMP signaling has been associated with Barrett's metaplasia, wherein the squamous esophageal epithelium is replaced by a columnar epithelium, suggesting that the maintenance of regional SC identities by BMP is conserved. PMID- 23810562 TI - Is the creation of artificial life morally significant? AB - In 2010, the Venter lab announced that it had created the first bacterium with an entirely synthetic genome. This was reported to be the first instance of 'artificial life,' and in the ethical and policy discussions that followed it was widely assumed that the creation of artificial life is in itself morally significant. We cast doubt on this assumption. First we offer an account of the creation of artificial life that distinguishes this from the derivation of organisms from existing life and clarify what we mean in asking whether the creation of artificial life has moral significance. We then articulate and evaluate three attempts to establish that the creation of artificial life is morally significant. These appeal to (1) the claim that the creation of artificial life involves playing God, as expressed in three distinct formulations; (2) the claim that the creation of artificial life will encourage reductionist attitudes toward the living world that undermine the special moral value accorded to life; and (3) the worry that artificial organisms will have an uncertain functional status and consequently an uncertain moral status. We argue that all three attempts to ground the moral significance of the creation of artificial life fail, because none of them establishes that the creation of artificial life is morally problematic in a way that the derivation of organisms from existing life forms is not. We conclude that the decisive moral consideration is not how life is created but what non-genealogical properties it possesses. PMID- 23810563 TI - Serum preadipocyte factor-1 is increased in fetuses of pregnancy complicated with severe preeclampsia. AB - BACKGROUND: Preadipocyte factor-1 (Pref-1), an inhibitor of adipocyte differentiation, is increased in fetal blood of small for gestational age (SGA) and is considered a factor involved in determining adiposity and associated with high risk of metabolic diseases in adulthood. Preeclampsia is a condition closely associated with SGA, however, the alteration of Pref-1 of in fetuses of preeclampsia remains unknown. The aims of the current investigation were to clarify the alteration of serum Pref-1 in fetuses of preeclamptic pregnancy and to explore possible role of Pref-1 in metabolic diseases in late life. METHODS: Cord blood samples were taken at birth from 45 fetuses of normal pregnancy, 16 of gestational hypertension, 29 of mild preeclampsia and 29 of severe preeclampsia. Serum Pref-1 concentrations were measured with ELISA. RESULTS: There were significant differences in cord blood Pref-1 and neonatal birth weight among normal pregnancy, gestational hypertension, mild and severe preeclampsia (F=8.557, P<0.001 for Pref-1; F=38.405, P<0.001 for birth weight). Serum Pref-1 was significantly higher while birth weight were lower in severe preeclampsia than normal pregnancy, gestational hypertension and mild preeclampsia respectively (P<=0.001 for all). However, either serum Pref-1 or birth weight did not significantly differ among normal pregnancy, gestational hypertension and mild preeclampsia (P>0.05 for all). Fetal Pref-1 concentration was significantly negatively correlated with birth weight (R(2)=0.175, P=0.027 for severe preeclampsia; R(2)=0.209, P<0.001 for preeclampsia; R(2)=0.25, P<0.001 for all subjects). CONCLUSIONS: Increased serum Pref-1 was demonstrated in fetuses of preeclampsia-complicated pregnancy, and it may be proposed that Pref-1 is among the possible mediators leading to high risk of metabolic diseases in adulthood. PMID- 23810564 TI - Predictive value of phosphorylated axonal neurofilament subunit H for clinical outcome in patients with acute intracerebral hemorrhage. AB - BACKGROUND: Phosphorylated axonal neurofilament subunit H (pNF-H) is a biomarker of axonal injury. We investigated whether plasma pNF-H concentrations were associated with 6-month clinical outcomes and early neurological deterioration (END) of patients with acute intracerebral hemorrhage. METHODS: Plasma pNF-H concentrations of 112 patients and 112 healthy individuals were quantified by ELISA. Unfavorable outcome was defined as modified Rankin Scale score >2. Associations of plasma pNF-H concentrations with END, 6-month mortality and unfavorable outcome were evaluated. RESULTS: Plasma pNF-H concentrations were increased in patients than in healthy individuals [700.2 (430.8) pg/ml vs. 25.5 (32.4) pg/ml, P<0.001]. A logistic regression analysis selected plasma pNF-H concentration as an independent predictor for 6-month mortality [OR: 1.287, 95% CI: 1.140-1.524, P<0.001], 6-month unfavorable outcome (OR 1.265, 95% CI 1.121 1.517, P<0.001) and END (OR 1.246, 95% CI 1.109-1.498, P<0.001). A receiver operating characteristic curve analysis showed that plasma pNF-H concentration predicted 6-month clinical outcomes and END with high area under curves (all P<0.001). The predictive value of pNF-H was similar to that of the National Institutes of Health Stroke Scale score (all P>0.05). In a combined logistic regression model, pNF-H did not improve the predictive value of National Institutes of Health Stroke Scale score (all P>0.05). CONCLUSIONS: Increased plasma pNF-H concentration was highly associated with 6-month clinical outcomes and END of patients with intracerebral hemorrhage. PMID- 23810565 TI - Platelet-derived nucleotides promote tumor-cell transendothelial migration and metastasis via P2Y2 receptor. AB - Tumor cells can activate platelets, which in turn facilitate tumor cell survival and dissemination. The exact mechanisms by which platelets promote metastasis have remained unclear. Here, we show that adenine nucleotides released from tumor cell-activated platelets induce opening of the endothelial barrier to allow transendothelial migration of tumor cells and thereby promote cancer cell extravasation. We identified the endothelial P2Y2 receptor, which is activated by ATP, as the primary mediator of this effect. Mice deficient in P2Y2 or lacking ATP secretion from platelets show strongly reduced tumor cell metastasis. These findings demonstrate a mechanism by which platelets promote cancer cell metastasis and suggest the P2Y2 receptor and its endothelial downstream signaling mechanisms as a target for antimetastatic therapies. PMID- 23810566 TI - Improved air trapping evaluation in chest computed tomography in children with cystic fibrosis using real-time spirometric monitoring and biofeedback. AB - BACKGROUND: The quality of chest Computed Tomography (CT) images in children is dependent upon a sufficient breath hold during CT scanning. This study evaluates the influence of spirometric breath hold monitoring with biofeedback software on inspiratory and expiratory chest CT lung density measures, and on trapped air (TA) scoring in children with cystic fibrosis (CF). This is important because TA is an important component of early and progressive CF lung disease. METHODS: A cross sectional comparison study was completed for chest CT imaging in two cohorts of CF children with comparable disease severity, using spirometric breath hold monitoring and biofeedback software (Copenhagen (COP)) or unmonitored breath hold manoeuvres (Gothenburg (GOT)). Inspiratory-expiratory lung density differences were calculated, and TA was scored to assess the difference between the two cohorts. RESULTS: Eighty-four chest CTs were evaluated. Mean (95%CI) change in inspiratory-expiratory lung density differences was 436 Hounsfield Units (HU) (408 to 464) in the COP cohort with spirometric breath hold monitoring versus 229 HU (188 to 269) in the GOT cohort with unmonitored breath hold manoeuvres (p<0.0001). The Mean TA (95%CI) score was 6.93 (6.05 to 7.82) in COP patients and 3.81 (2.89 to 4.73) in GOT (p<0.0001) patients. CONCLUSIONS: In children with comparable CF lung disease, spirometric breath hold monitoring during examination yielded a large difference in lung volume between inhalation and exhalation, and allowed for a significantly greater measured change in lung density and TA score, compared to unmonitored breath hold maneuvers. This has implications to the clinical use of chest CT, especially in children with early CF lung disease. PMID- 23810567 TI - O-H anharmonic vibrational motions in Cl(-)...(CH3OH)(1-2) ionic clusters. Combined IRPD experiments and AIMD simulations. AB - The structures of Cl(-)-(Methanol)1,2 clusters have been unraveled combining Infrared Predissociation (IR-PD) experiments and DFT-based molecular dynamics simulations (DFT-MD) at 100 K. The dynamical IR spectra extracted from DFT-MD provide the initial 600 cm(-1) large anharmonic red-shift of the O-H stretch from uncomplexed methanol (3682 cm(-1)) to Cl(-)-(Methanol)1 complex (3085 cm(-1)) as observed in the IR-PD experiment, as well as the subtle supplementary blue- and red-shifts of the O-H stretch in Cl(-)-(Methanol)2 depending on the structure. The anharmonic vibrational calculations remarkably provide the 100 cm(-1) O-H blue-shift when the two methanol molecules are simultaneously organized in the anion first hydration shell (conformer 2A), while they provide the 240 cm(-1) O-H red-shift when the second methanol is in the second hydration shell of Cl(-) (conformer 2B). RRKM calculations have also shown that 2A/2B conformers interconvert on a nanosecond time-scale at the estimated 100 K temperature of the clusters formed by evaporative cooling of argon prior to the IR-PD process. PMID- 23810568 TI - The influence of muscle strength on the gait profile score (GPS) across different patients. AB - BACKGROUND: Muscle strength greatly influences gait kinematics. The question was whether this association is similar in different diseases. METHODS: Data from instrumented gait analysis of 716 patients were retrospectively assessed. The effect of muscle strength on gait deviations, namely the gait profile score (GPS) was evaluated by means of generalised least square models. This was executed for seven different patient groups. The groups were formed according to the type of disease: orthopaedic/neurologic, uni-/bilateral affection, and flaccid/spastic muscles. RESULTS: Muscle strength had a negative effect on GPS values, which did not significantly differ amongst the different patient groups. However, an offset of the GPS regression line was found, which was mostly dependent on the basic disease. Surprisingly, spastic patients, who have reduced strength and additionally spasticity in clinical examination, and flaccid neurologic patients showed the same offset. Patients with additional lack of trunk control (Tetraplegia) showed the largest offset. CONCLUSION: Gait kinematics grossly depend on muscle strength. This was seen in patients with very different pathologies. Nevertheless, optimal correction of biomechanics and muscle strength may still not lead to a normal gait, especially in that of neurologic patients. The basic disease itself has an additional effect on gait deviations expressed as a GPS-offset of the linear regression line. PMID- 23810569 TI - The relationship between clinical measurements and gait analysis data in children with cerebral palsy. AB - Spasticity is a common impairment that interferes with motor function (particularly gait pattern) in children with cerebral palsy (CP). Gait analysis and clinical measurements are equally important in evaluating and treating gait disorders in children with CP. This study aimed to explore the relationship between the spasticity of lower extremity muscles and deviations from the normal gait pattern in children with CP. Thirty-six children with spastic CP (18 with spastic hemiplegia [HS] and 18 with spastic diplegia [DS]), ranging in age from 7 to 12 years, participated in the study. The children were classified as level I (n=24) or level II (n=12) according to the Gross Motor Function Classification System. Spasticity levels were evaluated with the Dynamic Evaluation of Range of Motion (DAROM) using the accelerometer-based system, and gait patterns were evaluated with a three dimensional gait analysis using the Zebris system (Isny, Germany). The Gillette Gait Index (GGI) was calculated from the gait data. The results show that gait pathology in children with CP does not depend on the static and dynamic contractures of hip and knee flexors. Although significant correlations were observed for a few clinical measures with the gait data (GGI), the correlation coefficients were low. Only the spasticity of rectus femoris showed a fair to moderate correlation with GGI. In conclusion, the results indicate the independence of the clinical evaluation and gait pattern and support the view that both factors provide important information about the functional problems of children with CP. PMID- 23810570 TI - The forensic analysis of office paper using carbon isotope ratio mass spectrometry--part 2: method development, validation and sample handling. AB - This paper describes the development and validation of a method for the analysis of office papers by measuring carbon isotopes using isotope ratio mass spectrometry (IRMS). The method development phase included testing protocols for storage, sample materials, set-up of the analytical run; and examining the effects of other paper examination procedures on IRMS results. A method validation was performed so that the Delta(plus) XP IRMS instrument (Thermo Finnigan, Bremen, Germany) with Flash EATM 1112 could be used to measure document paper samples for forensic casework. A validation protocol that would meet international standards for laboratory accreditation (international standard ISO 17025) was structured so that the instruments performance characteristics could be observed. All performance characteristics measured were found to be within an acceptable range and an expanded measurement uncertainty for the measurement of carbon isotopes in paper was calculated at 0.260/00, with a coverage factor of 2. This method was utilized in a large-scale study, published as part one of this series, that showed that IRMS of document papers is useful as a chemical comparison technique for 80 gsm white office papers. PMID- 23810571 TI - Isolated lower brachial plexus (Klumpke) palsy with compound arm presentation: case report. AB - Klumpke palsy has yet to be clearly documented in the newborn, because previous reports lack any description of the obstetrical history, clinical progression, or outcome. Based on a high incidence of breach presentation in the few clinical series that report Klumpke palsy, hyperabduction with arm overhead during delivery has been the presumed mechanism. We report a child with isolated lower brachial plexus palsy and Horner syndrome who presented at birth with a vertex compound arm presentation. Recognition of this condition and details of the clinical progression and outcome are important, because guidelines for management are currently not available. PMID- 23810572 TI - Articular cartilage thickness at the distal radius: a cadaveric study. AB - PURPOSE: Articular stepoffs that occur after fracture and are greater in size than the thickness of the articular surface seem to result in arthritis. The thickness of a joint's cartilage may, therefore, set the limit for acceptable stepoff when treating fractures. The goal of our study was to determine the thickness of the articular cartilage at the distal radius. METHODS: We conducted a cadaveric study of 19 wrists to measure the thickness of cartilage at the distal radius. After harvest, we made multiple slices of each radius and used a standardized technique to directly measure the articular cartilage in the scaphoid and lunate fossae and along the interfossal ridge. RESULTS: The average cartilage thickness in our cohort was 0.6 mm. The average articular surface thickness was < 1 mm in all measured areas (scaphoid fossa, 0.7 mm; interfossal ridge, 0.8 mm; lunate fossa, 0.6 mm). Among the samples, 98% had an average thickness of < 1 mm. The maximum recorded thickness was 1.1 mm. CONCLUSIONS: Our study quantifies the thickness of the articular cartilage at the distal radius. Our finding of cartilage thicknesses of < 1 mm is consistent with multiple clinical studies, suggesting that stepoffs of > 1 mm result in radiographic signs of arthritis. This provides further evidence linking the thickness of articular cartilage to radiographic outcomes and, possibly, clinical outcomes. CLINICAL RELEVANCE: Our findings provide anatomic support for using 1 mm or less as an acceptable articular stepoff size in the treatment of fractures of the distal radius. PMID- 23810573 TI - EGFR tyrosine kinase inhibitors beyond focal progression obtain a prolonged disease control in patients with advanced adenocarcinoma of the lung. AB - INTRODUCTION: Recent data show that EGFR pathway and its inhibition maintain their role after progression of disease during EGFR TKI therapy in NSCLCs. We conducted a retrospective study with the aim of evaluating efficacy and feasibility of prosecution of EGFR TKI therapy beyond focal progression associated to locoregional radiotherapy. METHODS: We retrospectively analyzed the data of all NSCLC patients treated with EGFR TKIs in our institution from 2004 to 2012. We included in the analysis patients that after a focal disease progression, meant as a single lesion RECIST progression, have been treated with definitive locoregional radiotherapy, associated to continuation of EGFR TKI therapy until further progression. RESULTS: 15 out of 147 patients (10%) satisfied inclusion criteria. The median progression free survival, measured from the date of focal progression until further progression of disease or death by any cause, was 10,9 months (range 3-32 months). The corresponding 6 and 12 months PFS rates were 73% and 33%, respectively. CONCLUSION: The longer disease control observed in our patients suggests that continuation of EGFR TKI beyond focal progression associated to a locoregional treatment is an efficacious therapeutic strategy. PMID- 23810574 TI - Tumor recurrence is independent of pancreatic fistula in patients after pancreaticoduodenectomy for pancreatic ductal adenocarcinoma. AB - BACKGROUND: Recurrence of pancreatic adenocarcinoma after pancreaticoduodenectomy (PD) can be increased in patients with pancreatic fistula (PF). The purpose of our study was to determine if a relationship exists between PF and tumor recurrence (both peritoneal and local) in patients after PD for pancreatic ductal adenocarcinoma. STUDY DESIGN: A single-institution, retrospective analysis of 221 patients who underwent PD from January 2001 to December 2009 was conducted. Electronic charts and medical records were queried for tumor characteristics, recurrence, and complications. Presence and grading of PF was determined using the criteria of the International Study Group on Pancreatic Fistula. Data were analyzed using chi-square and Kaplan-Meier survival statistics. RESULTS: There were 114 male and 107 female patients. Mean age was 66 years (range 35 to 91 years). The vast majority (84%) of patients had stage II disease; 143 (65%) had positive lymph nodes (median 2 positive nodes; range 1 to 17 positive nodes). Pancreatic fistula developed in 23 patients (grade A, n = 9; grade B, n = 13; grade C, n = 1; 10.2%). Peritoneal recurrence was noted in 20 patients (9%). Of the 23 patients with PF, peritoneal recurrence developed in 3 (13%). Of the 198 patients without PF, peritoneal recurrence developed in 17 (10%). Local recurrence occurred in 47 patients (21%), 5 (2%) in patients with PF and 42 (21%) in those without PF (p = NS). In Kaplan-Meier survival analysis, there was no significant difference in recurrence-free survival (p = 0.4) and overall survival (p = 0.3) for those with PF vs those without PF. CONCLUSIONS: Patients with PF after PD were not found to have a significant increase in local or peritoneal recurrence. Therefore, in this analysis, postoperative PF does not appear to serve as an adverse prognostic marker. PMID- 23810575 TI - Outcomes of discharge after elective laparoscopic colorectal surgery with transversus abdominis plane blocks and enhanced recovery pathway. AB - BACKGROUND: Enhanced recovery pathways (ERP) have been well shown to permit early recovery and discharge. The addition of a transversus abdominis plane (TAP) block to a standard pathway may improve these outcomes. We evaluated the addition of a TAP block to an established ERP. STUDY DESIGN: One hundred consecutive patients underwent elective laparoscopic colectomy by a single surgeon. A laparoscopic guided TAP block was administered at the end of the procedure. Patients followed an established ERP that included overnight intravenous patient-controlled analgesia pump, diet and oral analgesia on postoperative day 1, and standardized discharge criteria. RESULTS: The mean age was 60.5 years (range 15 to 92 years), 62 patients were female, and mean body mass index was 28.4 kg/m(2) (range 18 to 46 kg/m(2)). Median hospital stay was 2 days and mean length of stay was 2.9 days. Patients were grouped and analyzed by the day of discharge. Sixty-two percent of patients were discharged within 48 hours (27 on day 1; 35 on day 2). There was no mortality. Only 1 patient discharged within 48 hours of surgery developed a complication. Two patients were readmitted, both of whom were discharged more than 48 hours after surgery. CONCLUSIONS: Transversus abdominis plane blocks with an ERP contribute to a short length of stay after laparoscopic colectomy, without increasing complication or readmission rates. PMID- 23810576 TI - Cost effectiveness of intraoperative pathology examination during diagnostic hemithyroidectomy for unilateral follicular thyroid neoplasms. AB - BACKGROUND: The use of intraoperative pathology examination (IPE) during diagnostic hemithyroidectomy for a follicular neoplasm is controversial. Although this service rarely alters intraoperative decision making, it does provide patients with the possibility of avoiding reoperation for completion thyroidectomy if malignancy is detected. We hypothesized diagnostic hemithyroidectomy with IPE for a unilateral follicular thyroid neoplasm diagnosed on fine-needle aspiration is not cost effective compared with diagnostic hemithyroidectomy alone. STUDY DESIGN: Cost-effectiveness analysis with a Markov decision model was performed comparing diagnostic hemithyroidectomy without IPE, diagnostic hemithyroidectomy with IPE, and total thyroidectomy. Treatment outcomes and their probabilities were identified based on literature review. Costs were estimated using data from Medicare, the US Bureau of Labor Statistics, and the Nationwide Inpatient Sample. Sensitivity analysis and a 1,000-iteration Monte Carlo simulation were used to examine the uncertainty of cost, probability, and utility estimates in the model. RESULTS: Diagnostic hemithyroidectomy without IPE had an expected cost of US$7,665 and an effectiveness of 23.95 quality adjusted life years and dominated both the IPE and total thyroidectomy strategies. Intraoperative pathology examination became cost effective during one way sensitivity analysis if the sensitivity of IPE increased from 14.3% to 34.4%, the specificity increased from 98.6% to 99.8%, or the pretest probability of malignancy increased from 25% to 43%. Monte Carlo simulation demonstrated that the intraoperative pathology strategy was not cost effective in 92.7% of iterations. CONCLUSIONS: Intraoperative pathology examination is not cost effective in the diagnosis of follicular thyroid neoplasms during diagnostic hemithyroidectomy. Improvements in both the sensitivity and specificity of this service would be needed to justify its use. PMID- 23810577 TI - Psychometric properties of the Scale for Quality Evaluation of the Bachelor Degree in Nursing Version 2 (QBN 2). AB - To evaluate all the variables that affect nursing education is important for nursing educators to have valid and reliable instruments that can measure the perceived quality of the Bachelor Degree in Nursing. This study testing the Scale for Quality Evaluation of the Bachelor Degree in Nursing instrument and its psychometric properties with a descriptive design. Participant were first, second and third year students of the Bachelor Degree in Nursing Science from three Italian universities. The Scale for Quality Evaluation of Bachelor Degree in Nursing consists of 65 items that use a 4 point Likert scale ranging from "strongly disagree" to "strongly agree". The instrument comes from a prior version with 41 items that were modified and integrated with 24 items to improve reliability. Six hundred and fifty questionnaires were completed and considered for the present study. The mean age of the students was 24.63 years, 65.5% were females. Reliability of the scale resulted in a very high Cronbach's alpha (0.96). The construct validity was tested with factor analysis that showed 7 factors. The Scale for Quality Evaluation of the Bachelor Degree in Nursing, although requiring further studies, represents a useful instrument to measure the quality of the Bachelor Nursing Degree. PMID- 23810579 TI - The heart of the matter: protection of the myocardium from T cells. AB - Myocardial inflammation and damage can lead to lethal acute or chronic cardiac failure. A variety of regulatory mechanisms limit the magnitude and duration of T cell responses in the heart. Insights into these regulatory mechanisms have come from studies of specific deficiencies in central or peripheral T cell tolerance which cause or enhance the severity of myocarditis. Under non-inflammatory conditions, constitutive DC presentation of cardiac peptides to naive T cells in cardiac draining lymph nodes tolerizes recirculating naive T cells specific for these antigens. Cardiac antigen-specific naive T cells, especially those specific of alpha-myosin heavy chain peptides, become activated and differentiate into expanded clones of effector T cells under various conditions, such as cardiac infection and/or genetic variations in peripheral tolerance. The pathology that these effector cells cause in the myocardium is limited by PD-L1 expressed on myocardial cells in response to inflammatory cytokines, and by CTLA-4 dependent mechanisms. The PD-1:PD-L1 pathway works together with other control mechanisms to keep the heart safe from T cells, and combined impairment of this pathway along with other regulatory mechanisms synergize to cause myocarditis. T cell derived IFNgamma contributes to the inflammatory damage to the heart in autoimmune myocarditis, but it also engages regulatory mechanisms that limit disease, including upregulation of PD-L1, and differentiation of TNF and iNOS expressing DCs from monocytes. iNOS derived from these DCs and other IFNgamma stimulated cells inhibits expansion of T cells that cause myocarditis. Regulatory T cells also appear to be critical for suppression of effector T cells specific for myocardial antigens. PMID- 23810578 TI - Breakdown of immune privilege and spontaneous autoimmunity in mice expressing a transgenic T cell receptor specific for a retinal autoantigen. AB - Despite presence of circulating retina-specific T cells in healthy individuals, ocular immune privilege usually averts development of autoimmune uveitis. To study the breakdown of immune privilege and development of disease, we generated transgenic (Tg) mice that express a T cell receptor (TCR) specific for interphotoreceptor retinoid-binding protein (IRBP), which serves as an autoimmune target in uveitis induced by immunization. Three lines of TCR Tg mice, with different levels of expression of the transgenic R161 TCR and different proportions of IRBP-specific CD4+ T cells in their peripheral repertoire, were successfully established. Importantly, two of the lines rapidly developed spontaneous uveitis, reaching 100% incidence by 2 and 3 months of age, respectively, whereas the third appeared "poised" and only developed appreciable disease upon immune perturbation. Susceptibility roughly paralleled expression of the R161 TCR. In all three lines, peripheral CD4+ T cells displayed a naive phenotype, but proliferated in vitro in response to IRBP and elicited uveitis upon adoptive transfer. In contrast, CD4+ T cells infiltrating uveitic eyes mostly showed an effector/memory phenotype, and included Th1, Th17 as well as T regulatory cells that appeared to have been peripherally converted from conventional CD4+ T cells rather than thymically derived. Thus, R161 mice provide a new and valuable model of spontaneous autoimmune disease that circumvents the limitations of active immunization and adjuvants, and allows to study basic mechanisms involved in maintenance and breakdown of immune homeostasis affecting immunologically privileged sites such as the eye. PMID- 23810580 TI - Chronic intermittent toluene inhalation in adolescent rats alters behavioural responses to amphetamine and MK801. AB - Abuse of toluene-containing inhalants is common during adolescence, with ongoing chronic misuse associated with adverse outcomes and increased risk for addictive behaviours in adulthood. However, the mechanisms mediating the adaptive processes related to these outcomes are not well defined. To model human abuse patterns we exposed male adolescent Wistar rats (postnatal day 27) to chronic intermittent inhaled toluene (CIT, 10,000 ppm) or air (control) for 1h/day, three times/week for 3 weeks. The effects of CIT on behaviour and recovery were monitored. Locomotor activity was recorded following two consecutive injections of amphetamine (1mg/kg, i.p.) 72 and 96 h after the last exposure. This was followed with injection of the NMDA receptor antagonist MK801 (0.5mg/kg, i.p.) 20 days after the last exposure. CIT resulted in a significant and persistent retardation in weight gain during the exposure period and abstinence (p<0.05). Repeated exposure resulted in tolerance to the onset of toluene-induced behaviours and recovery latency. There was a reduction in the acute stimulant effects of amphetamine in CIT-exposed animals and an increase in the magnitude of locomotor activity (p<0.0125) following a subsequent exposure when compared to the responses observed in controls; this was associated with altered locomotor responses to MK801. Repeated exposure to CIT during adolescence alters parameters of growth, as measured by body weight, and leads to tolerance, indicating that increasing concentrations of the compound may be needed to reach the same behavioural state. Toluene during this period also alters responses to a psychostimulant which may be related to long-term glutamatergic dysfunction. PMID- 23810581 TI - LKB1 downregulation may be independent of promoter methylation or FOXO3 expression in head and neck cancer. AB - The serine/threonine kinase liver kinase B 1 (LKB1) is a multifunctional protein and has been associated with various cancer types. Although the tumor suppressor function of LKB1 is attributed mainly to its ability to phosphorylate directly different adenosine monophosphate-activated protein kinases, its regulation is still poorly understood. More recently, it has been shown that LKB1 expression can be regulated by forkhead box O transcription factors via cis-acting elements, which are found in the promoter region of the LKB1 gene. In this study, we investigated LKB1 messenger RNA expression levels in association with the promoter methylation of the gene and forkhead box O member 3 (FOXO3) messenger RNA expression in head and neck squamous cell carcinoma (HNSCC) tumor samples. Our results show that LKB1 expression is downregulated, especially in advanced stage tumor samples, and this downregulation was not the result of promoter methylation or modulation by FOXO3 (P = 0.656). Despite observing a positive association between the LKB1 and FOXO3 expression levels in the tumors, this association was not statistically significant (P = 0.24). Our results indicate that downregulation of LKB1 is independent of FOXO3 and may be implicated in the progression of HNSCC. PMID- 23810582 TI - Noninvasive assessment of insulin resistance in the liver using the fasting (13)C glucose breath test. AB - Evaluating hepatic insulin resistance (IR) is the key to making a sensitive an accurate diagnosis of glucose intolerance. However, there is currently no suitable method to perform this procedure. This study was conducted to investigate whether the fasting (13)C-glucose breath test (FGBT) is useful as a convenient and highly sensitive clinical test for evaluating hepatic IR. Healthy nonobese subjects and a disease group consisting of patients with mild glucose intolerance were administered 100 mg (13)C-glucose after an overnight fast. A series of breath samples was collected until 360 minutes after ingestion, and the (13)CO2-to-(12)CO2 ratio was measured using an infrared spectrometer and was plotted as a kinetic curve of (13)C excretion. The area under the curve until 360 minutes (AUC360) of the (13)C excretion kinetic curve of the FGBT reflects the efficiency of energy production in the liver. First, we assessed the correlations between the AUC360 (or the (13)C excretion rate at 120 minutes) and the HOMA-IR and HbA1c levels as standard measurements of IR and diabetes mellitus (DM). There were relatively strong correlation coefficients (r = -0.49 to -0.81, r(2) = 0.24 0.66, P < 0.01; n = 35 males, n = 33 females). Second, we compared the AUC360 of healthy subjects and that of the patients with mild glucose intolerance. The AUC360 of the healthy subjects was consistently higher than that of the patients with mild glucose intolerance. The presence of IR or DM in males and females was diagnosed using cutoff values. The FGBT is a novel glucose metabolism test that can be used conveniently and safely to evaluate the balance of glucose metabolism in the liver. This test has excellent sensitivity for diagnosing alterations in hepatic glucose metabolism, particularly hepatic IR. PMID- 23810584 TI - Letter to the Editor regarding proteomic strategies and biomarker identification in melanoma. PMID- 23810583 TI - Can routine automated urinalysis reduce culture requests? AB - OBJECTIVES: There are a substantial number of unnecessary urine culture requests. We aimed to investigate whether urine dipstick and microscopy results could accurately rule out urinary tract infection (UTI) without urine culture. DESIGN AND METHODS: The study included a total of 32,998 patients (11,928 men and 21,070 women, mean age: 39 +/- 32 years) with a preliminary diagnosis of UTI and both urinalysis and urinary culture were requested. All urine cultures were retrospectively reviewed; association of culture positivity with a positive urinalysis result for leukocyte esterase (LE) and nitrite in chemical analysis and pyuria (WBC) and bacteriuria in microscopy was determined. Diagnostic performance of urinalysis parameters for detection of UTI was evaluated. RESULTS: In total, 758 (2.3%) patients were positive by urine culture. Out of these culture positive samples, ratios of positive dipstick results for LE and nitrite were 71.0% (n=538) and 17.7% (n=134), respectively. The positive microscopy results for WBC and bacteria were 68.2% (n=517) and 78.8% (n=597), respectively. Negative predictive values for LE, nitrite, bacteriuria and WBC were very close to 100%. CONCLUSIONS: Most of the samples have no or insignificant bacterial growth. Urine dipstick and microscopy can accurately rule out UTI. Automated urinalysis is a practicable and faster screening test which may prevent unnecessary culture requests for majority of patients. PMID- 23810585 TI - TYMS serves as a prognostic indicator to predict the lymph node metastasis in Chinese patients with colorectal cancer. AB - OBJECTIVE: The current study is to evaluate the effect of thymidylate synthase (TYMS) on lymph node metastasis (LNM) in Chinese colorectal cancer (CRC) patients, and develop potential LNM-associated biomarkers for CRC. DESIGN AND METHODS: Differences in TYMS gene expression between primary CRC with LNM (LNM CRC) and without LNM (non-LNM CRC) were assessed using quantitative real-time PCR analysis in 100 Chinese colorectal cancer patients. The relationship between clinicopathological parameters and prognosis of candidate biomarkers was also examined in the experiment. RESULTS: TYMS was significantly upregulated in LNM CRC compared with non-LNM CRC, which was confirmed by real-time quantitative polymerase chain reaction. Overexpression of TYMS was significantly associated with LNM (P<0.001), advanced TNM stage (P<0.001), increased 5-year recurrence rate (P<0.001) and decreased 5-year overall survival rate (P<0.001). Univariate and multivariate analyses indicated that TYMS expression was an independent prognostic factor for recurrence and survival of CRC patients (P<0.05). CONCLUSIONS: TYMS effect on lymph node metastasis in CRC might serve as a potential biomarker for LNM and a prognostic factor in CRC. Over-expression of TYMS is a predicting factor to the poor outcome in clinical colorectal cancer patients. PMID- 23810586 TI - Intake of specific fatty acids and fat alters growth, health, and titers following vaccination in dairy calves. AB - Typical fatty acid profiles of milk and milk replacer (MR) differ. Calf MR in the United States are made from animal fat, which are low in short- and medium-chain fatty acids and linolenic acid. Two 56-d trials compared a control MR containing 27% crude protein and formulated with 3 fat and fatty acid compositions. The 3 MR treatments were (1) only animal fat totaling 17% fat (CON), (2) animal fat supplemented with butyrate, medium-chain fatty acids, and linolenic acid using a commercial product (1.25% NeoTec4 MR; Provimi North America, Brookville, OH) totaling 17% fat (fatty acid-supplemented; FA-S), and (3) milk fat totaling 33% fat (MF). The MR were fed at 660 g of dry matter from d 0 to 42 and weaned. Starter (20% crude protein) and water were fed ad libitum for 56 d. Trial 1 utilized Holstein calves (24 female, 24 male) during summer months and trial 2 utilized Holstein calves (48 male) during fall months. Calves (41+/-1 kg of initial body weight; 2 to 3d of age) were sourced from a single farm and housed in a naturally ventilated nursery without added heat. Calves were in individual pens with straw bedding. Calf was the experimental unit. Data for each trial were analyzed as a completely randomized design with a 3 (MR treatment) * 2 (sex) factorial arrangement of treatments in trial 1 with repeated measures and as a completely randomized design with 3 MR treatments in trial 2 with repeated measures. Preplanned contrast statements of treatments CON versus FA-S and CON versus MF were used to separate means. We found no interactions of MR treatment by sex. Calf average daily gain, hip width change, and feed efficiency differed (CONFA-S). Titers to bovine respiratory parainfluenza-3 and bovine virus diarrhea type 1 (vaccinations to these pathogens were on d 7 and 28) in serum samples taken on d 49 and 56 differed (CONFA-S; CONFA-S; CON>MF). Calves fed FA-S and MF had improved growth and feed efficiency compared with calves fed CON, whereas calves fed FA-S also had improved measurements related to health and immunity. PMID- 23810587 TI - Technical note: Evaluation of odor from vaginal discharge of cows in the first 10 days after calving by olfactory cognition and an electronic device. AB - The objective of this study was to determine test characteristics (i.e., intra- and interobserver variability, intraassay variability, sensitivity, and specificity) of an evaluation of odor from vaginal discharge (VD) of cows in the first 10 d postpartum conducted by olfactory cognition and an electronic device, respectively. In experiment 1, 16 investigators (9 veterinary students and 7 licensed veterinarians) evaluated 5 VD samples each on 10 different days. The kappa test revealed an agreement between investigators (interobserver) of kappa=0.43 with a Fleiss adjusted standard error of 0.0061. The overall agreement was the same for students (kappa=0.28) and veterinarians (kappa=0.28). Mean agreement within observers (intraobserver) was kappa=0.52 for all observers, and 0.49 and 0.62 for students and veterinarians, respectively. In experiment 2, the repeatability of an electronic device (DiagNose; C-it, Zutphen, the Netherlands) was tested. Therefore, 5 samples of VD from 5 cows were evaluated 10 times each. The repeatability was 0.97, determined by Cronbach's alpha. In experiment 3, 20 samples collected from healthy cows and 20 of cows with acute puerperal metritis were evaluated by the 16 investigators and the DiagNose using a dichotomous scale (1=cow with acute puerperal metritis; 0=healthy cow). Sensitivity and specificity of olfactory evaluation was 75.0 and 60.1% compared with 92.0 and 100%, respectively, for the electronic nose device. The study revealed a considerable subjectivity of the human nose concerning the classification into healthy and sick animals based on the assessment of vaginal discharge. The repeatability of the electronic nose was higher. In conclusion, the DiagNose system, although imperfect, is a reasonable tool to improve odor assessment of VD. The current system, however, is not suitable as a screening tool in the field. Further research is warranted to adapt such electronic devices to practical on-farm screening tools. PMID- 23810588 TI - Identification of quantitative trait loci underlying milk traits in Spanish dairy sheep using linkage plus combined linkage disequilibrium and linkage analysis approaches. AB - In this study, 2 procedures were used to analyze a data set from a whole-genome scan, one based on linkage analysis information and the other combing linkage disequilibrium and linkage analysis (LDLA), to determine the quantitative trait loci (QTL) influencing milk production traits in sheep. A total of 1,696 animals from 16 half-sib families were genotyped using the OvineSNP50 BeadChip (Illumina Inc., San Diego, CA) and analysis was performed using a daughter design. Moreover, the same data set has been previously investigated through a genome wide association (GWA) analysis and a comparison of results from the 3 methods has been possible. The linkage analysis and LDLA methodologies yielded different results, although some significantly associated regions were common to both procedures. The linkage analysis detected 3 overlapping genome-wise significant QTL on sheep chromosome (OAR) 2 influencing milk yield, protein yield, and fat yield, whereas 34 genome-wise significant QTL regions were detected using the LDLA approach. The most significant QTL for protein and fat percentages was detected on OAR3, which was reported in a previous GWA analysis. Both the linkage analysis and LDLA identified many other chromosome-wise significant associations across different sheep autosomes. Additional analyses were performed on OAR2 and OAR3 to determine the possible causality of the most significant polymorphisms identified for these genetic effects by the previously reported GWA analysis. For OAR3, the analyses demonstrated additional genetic proof of the causality previously suggested by our group for a single nucleotide polymorphism located in the alpha-lactalbumin gene (LALBA). In summary, although the results shown here suggest that in commercial dairy populations, the LDLA method exhibits a higher efficiency to map QTL than the simple linkage analysis or linkage disequilibrium methods, we believe that comparing the 3 analysis methods is the best approach to obtain a global picture of all identifiable QTL segregating in the population at both family-based and population-based levels. PMID- 23810589 TI - Short communication: Glucose infusion into early postpartum cows defines an upper physiological set point for blood glucose and causes rapid and reversible changes in blood hormones and metabolites. AB - Low blood glucose concentrations after calving are associated with infertility in postpartum dairy cows perhaps because glucose is a master regulator of hormones and metabolites that control reproductive processes. The hypothesis was that low blood glucose postpartum is caused by inadequate glucose entry rate relative to whole-body demand as opposed to the alternative possibility that postpartum cows have a lower regulatory set point for blood glucose. Eight early postpartum (10 to 25 d) dairy cows (5 Holstein and 3 Guernsey) were jugular catheterized. During the first 24 h, cows were infused with physiological saline at 83.3 mL/h. After 24 h, the infusion solution was switched to 50% dextrose that was infused at a rate of 41.7 mL/h (total daily glucose dose=500 g). On d 3 and d 4, the rate of glucose infusion was increased to 83.3 mL/h (daily dose=1,000 g) and 125 mL/h (daily dose=1,500 g), respectively. On d 5, physiological saline was infused at 83.3 mL/h. Blood was sampled hourly through a second jugular catheter (contralateral side) and analyzed for glucose, nonesterified fatty acids, beta hydroxybutyrate, insulin-like growth factor 1, and insulin. Blood glucose concentrations on d 1 (saline infusion) averaged 53.4+/-1.7 mg/dL. Blood glucose concentrations increased on d 2 when cows were infused with 500 g/d and increased further on d 3 when cows were infused with 1,000g of glucose/d. Increasing the infusion rate to 1,500 g/d on d 4 did not cause a further increase in blood glucose concentrations. Based on a segmented regression analysis, the upper physiological set point for blood glucose was 72.1 mg/dL. Both insulin and insulin-like growth factor 1 concentrations increased in response to glucose infusion and decreased when cows were infused with saline on d 5. Serum nonesterified fatty acids and beta-hydroxybutyrate concentrations decreased in response to glucose infusion and rebounded upward on d 5 (saline infusion). In conclusion, early postpartum cows had circulating blood glucose concentrations that were well below the upper set point defined in this study (72.1 mg/dL). Infusing approximately 1,000 g of glucose daily increased blood glucose to the physiological set point and rapidly changed the hormonal and metabolic profile that typifies postpartum cows. The inability of the early postpartum cow to achieve an adequate entry rate for glucose relative to whole-body demand is a possible mechanism that links postpartum physiology and nutrition to reproduction in dairy cows. PMID- 23810590 TI - A low membrane lipid phase transition temperature is associated with a high cryotolerance of Lactobacillus delbrueckii subspecies bulgaricus CFL1. AB - The mechanisms of cellular damage that lactic acid bacteria incur during freeze thaw processes have not been elucidated to date. Fourier transform infrared spectroscopy was used to investigate in situ the lipid phase transition behavior of the membrane of Lactobacillus delbrueckii ssp. bulgaricus CFL1 cells during the freeze-thaw process. Our objective was to relate the lipid membrane behavior to membrane integrity losses during freezing and to cell-freezing resistance. Cells were produced by using 2 different culture media: de Man, Rogosa, and Sharpe (MRS) broth (complex medium) or mild whey-based medium (minimal medium commonly used in the dairy industry), to obtain different membrane lipid compositions corresponding to different recovery rates of cell viability and functionality after freezing. The lipid membrane behavior studied by Fourier transform infrared spectroscopy was found to be different according to the cell lipid composition and cryotolerance. Freeze-resistant cells, exhibiting a higher content of unsaturated and cyclic fatty acids, presented a lower lipid phase transition temperature (Ts) during freezing (Ts=-8 degrees C), occurring within the same temperature range as the ice nucleation, than freeze-sensitive cells (Ts=+22 degrees C). A subzero value of lipid phase transition allowed the maintenance of the cell membrane in a relatively fluid state during freezing, thus facilitating water flux from the cell and the concomitant volume reduction following ice formation in the extracellular medium. In addition, the lipid phase transition of freeze-resistant cells occurred within a short temperature range, which could be ascribed to a reduced number of fatty acids, representing more than 80% of the total. This short lipid phase transition could be associated with a limited phenomenon of lateral phase separation and membrane permeabilization. This work highlights that membrane phase transitions occurring during freeze thawing play a fundamental role in the cryotolerance of Lb. delbrueckii ssp. bulgaricus CFL1 cells. PMID- 23810591 TI - Assets of imputation to ultra-high density for productive and functional traits. AB - The aim of this study was to evaluate different-density genotyping panels for genotype imputation and genomic prediction. Genotypes from customized Golden Gate Bovine3K BeadChip [LD3K; low-density (LD) 3,000-marker (3K); Illumina Inc., San Diego, CA] and BovineLD BeadChip [LD6K; 6,000-marker (6K); Illumina Inc.] panels were imputed to the BovineSNP50v2 BeadChip [50K; 50,000-marker; Illumina Inc.]. In addition, LD3K, LD6K, and 50K genotypes were imputed to a BovineHD BeadChip [HD; high-density 800,000-marker (800K) panel], and with predictive ability evaluated and compared subsequently. Comparisons of prediction accuracy were carried out using Random boosting and genomic BLUP. Four traits under selection in the Spanish Holstein population were used: milk yield, fat percentage (FP), somatic cell count, and days open (DO). Training sets at 50K density for imputation and prediction included 1,632 genotypes. Testing sets for imputation from LD to 50K contained 834 genotypes and testing sets for genomic evaluation included 383 bulls. The reference population genotyped at HD included 192 bulls. Imputation using BEAGLE software (http://faculty.washington.edu/browning/beagle/beagle.html) was effective for reconstruction of dense 50K and HD genotypes, even when a small reference population was used, with 98.3% of SNP correctly imputed. Random boosting outperformed genomic BLUP in terms of prediction reliability, mean squared error, and selection effectiveness of top animals in the case of FP. For other traits, however, no clear differences existed between methods. No differences were found between imputed LD and 50K genotypes, whereas evaluation of genotypes imputed to HD was on average across data set, method, and trait, 4% more accurate than 50K prediction, and showed smaller (2%) mean squared error of predictions. Similar bias in regression coefficients was found across data sets but regressions were 0.32 units closer to unity for DO when genotypes were imputed to HD density. Imputation to HD genotypes might produce higher stability in the genomic proofs of young candidates. Regarding selection effectiveness of top animals, more (2%) top bulls were classified correctly with imputed LD6K genotypes than with LD3K. When the original 50K genotypes were used, correct classification of top bulls increased by 1%, and when those genotypes were imputed to HD, 3% more top bulls were detected. Selection effectiveness could be slightly enhanced for certain traits such as FP, somatic cell count, or DO when genotypes are imputed to HD. Genetic evaluation units may consider a trait-dependent strategy in terms of method and genotype density for use in the genome-enhanced evaluations. PMID- 23810592 TI - Short communication: Comparison of the newly developed DVE/OEB (2010) system and the National Research Council (2001) model in modeling metabolic characteristics of proteins in dairy cattle. AB - The truly absorbed protein in the small intestine/degraded protein balance (DVE/OEB)2010 system is a recently developed protein evaluation system for ruminants. The objective of this study was to compare the DVE/OEB2010 system with the National Research Council (2001) model in determining the metabolic characteristics of proteins in dairy cattle. The metabolic characteristics of proteins in bioethanol feedstock and their co-products were compared in terms of (1) truly absorbed rumen synthesized microbial protein in the small intestine; (2) truly absorbed rumen undegraded feed protein in the small intestine; (3) endogenous protein in the digestive tract; (4) total truly absorbed protein in the small intestine; and (5) protein degraded balance. The DVE/OEB2010 system predicted 30% more truly absorbed rumen synthesized microbial protein in the small intestine, 4% more truly absorbed rumen undegraded feed protein in the small intestine, 64% more endogenous protein, 9% more total truly absorbed protein in the small intestine, but 27% less degraded protein balance. PMID- 23810593 TI - Genetic analysis of the Fourier-transform infrared spectra of bovine milk with emphasis on individual wavelengths related to specific chemical bonds. AB - Fourier-transform infrared (FTIR) spectra are used to predict the fat, protein, casein, and lactose contents of milk. These estimates are currently used to predict the individual estimated breeding values of animals. The objective of the present study was to estimate the genetic variation and heritabilities of the milk transmittance spectrum at each individual FTIR wave. Milk was sampled once per cow from a total of 1,064 Italian Brown Swiss cows from 30 herds, sired by 50 artificial insemination sires. The FTIR spectra of all samples were collected within 3 h of sampling from 25 mL of milk. The obtained spectral range comprised wavenumbers 5,000 to 930*cm(-1), corresponding to wavelengths 2.00 to 10.76 MUm and frequencies from 149.9 to 27.9 THz, for a total of 1,056 waves. These were acquired using a MilkoScan FT120 FTIR interferometer (Foss Electric A/S, Hillerod, Denmark). Each spectral data point was treated as a single trait and analyzed using an animal model REML method. The results indicated that the transmittance of the bovine milk FTIR spectrum was heritable for most individual waves in the wavenumber interval from 5,000 to 930*cm(-1). Moreover, the transmittance of contiguous FTIR waves was much more highly correlated in terms of the average value and phenotypic variation, compared with genetic variation. In the present study, we characterized 5 regions of the FTIR spectrum that were relevant to the analysis of milk; 2 regions, one in the transition area between the short-wavelength infrared (SWIR) and mid-wavelength infrared (MWIR) divisions of the electromagnetic spectrum (SWIR-MWIR region) and another very short region in the MWIR division (MWIR-2 region), were characterized by very high phenotypic variability in the transmittance of individual milk samples within each wave. This was caused by the absorption peaks of water, which can mask the effects of other important milk components. These regions also showed high genetic variability in transmittance, and the heritability estimates of individual waves were generally very low (with some exceptions). The 3 other identified regions contained many transmittance peaks that represented important chemical bonds; these showed much lower phenotypic and genetic variability in terms of individual waves, but relatively higher and less variable heritability estimates. Among them, the SWIR region (near-infrared) showed a peculiar cyclic pattern of the heritability coefficients of transmittance, the MWIR-1 region was particularly important for the estimation of fat, and the MWIR-LWIR region (also known also as the "fingerprint region") had 3 areas of relatively high heritability. In summary, we found that the transmittance data from the FTIR spectra of milk have genetic variability that may prove useful for the direct genetic improvement of dairy species, rather than only through indirect phenotypic predictions of individual milk quality and technological traits. PMID- 23810594 TI - Prepartum nutritional strategy affects reproductive performance in dairy cows. AB - Negative energy balance during early postpartum is associated with reduced reproductive performance in dairy cows. A pooled statistical analysis of 7 studies completed in our group from 1993 to 2010 was conducted to investigate the association between prepartum energy feeding regimen and reproductive performance. The interval from calving to pregnancy (days to pregnancy, DTP) was the dependent variable to assess reproductive performance. Individual data for 408 cows (354 multiparous and 54 primiparous) were included in the analysis. The net energy for lactation (NEL) intake was determined from each cow's average dry matter intake and calculated dietary NEL density. Treatments applied prepartum were classified as either controlled-energy (CE; limited NEL intake to <=100% of requirement) or high-energy (HE; cows were allowed to consume >100%) diets fed during the far-off (FO) or close-up (CU) dry periods. Cow was the experimental unit. The Cox proportional hazard model revealed that days to pregnancy was shorter for CE (median=157 d) than HE (median=167 d) diets during the CU period [hazard ratio (HR)=0.70]. Cows fed HE diets during the last 4 wk prepartum lost more body condition score in the first 6 wk postpartum than those fed CE diets ( 0.43 and -0.30, respectively). Cows fed CE diets during the FO period had lower nonesterified fatty acids concentrations in wk 1, 2, and 3 of lactation than cows fed HE diets. Higher nonesterified fatty acids concentration in wk 1 postpartum was associated with a greater probability of disease (n=251; odds ratio=1.18). Cows on the CE regimen during the FO period had greater plasma glucose concentrations during wk 1 and 3 after calving than cows fed the HE regimen. Higher plasma glucose (HG) concentration compared with lower glucose (LG) in wk 3 (HG: n=154; LG: n=206) and wk 4 (HG: n=71; LG: n=254) after calving was associated with shorter days to pregnancy (wk 3: median=151 and 171 d for HG and LG, respectively, and HR=1.3; wk 4: median=148 and 167 d, respectively, and HR=1.4). In the first 2 wk after calving, cows that received HE diets in the FO period had higher concentrations of total lipids and triglyceride and greater ratio of triglyceride to glycogen in liver than cows fed CE diets. In conclusion, cows fed CE diets during the CU period had a shorter interval between parturition and conception, which may be explained by increased NEL intake during the first 4 wk postpartum and lower incidence of peripartal diseases. Lower body condition score loss during the first 6 wk postpartum and slightly higher glucose concentration at wk 3 likely contributed to improved reproductive performance. PMID- 23810595 TI - Short communication: Fractional milking distribution of immunoglobulin G and other constituents in colostrum. AB - The provision of quality colostrum with a high concentration of immunoglobulins is critical for newborn calf health. Because first colostrum may be low in overall concentration to effectively reduce the risk of newborn infections, we tested equivalent milking fractions of colostrum for possible IgG differences. The objective of this study was to determine if the fractional composition of colostrum changes during the course of milking with a focus on immunoglobulins. Twenty-four Holstein and Simmental cows were milked (first colostrum) within 4h after calving. The colostrum of 1 gland per animal was assembled into 4 percentage fractions over the course of milking: 0 to 25%, 25 to 50%, 50 to 75%, and 75 to 100%. The IgG concentration among the various fractions did not change in any significant pattern. Concentration of protein, casein, lactose and somatic cell count remained the same or exhibited only minor changes during the course of fractional milking colostrum. We determined that no benefit exists in feeding any particular fraction of colostrum to the newborn. PMID- 23810596 TI - Short communication: Survey of animal-borne pathogens in the farm environment of 13 dairy operations. AB - A survey was conducted on 13 dairies to determine the occurrence of 5 animal borne pathogens (Salmonella enterica, Escherichia coli O157:H7, Campylobacter jejuni, Mycobacterium avium ssp. paratuberculosis, and Cryptosporidium parvum) and their distributions across farm elements (feces, bedding, milk filters, stored manure, field soil, and stream water). Presence of C. parvum was measured only in feces and stored manure. All but one farm were positive for at least one pathogen species, and 5 farms were positive for 3 species. Escherichia coli O157:H7 was detected on 6 farms and in all farm elements, including milk filters. Mycobacterium avium ssp. paratuberculosis was detected on 10 of 13 farms and in all farm elements except for milk filters. Salmonella enterica and C. jejuni were detected at lower frequencies and were not identified in soil, stream water, or milk filters on any of the 13 farms. Cryptosporidium parvum was detected in feces but not in stored manure. Stored manure had the highest occurrence of pathogens (73%), followed by feces (50%), milk filters, bedding, soil, and water (range from 23 to 31%). Association of pathogen presence with farm management factors was examined by t-test; however, the small number of study farms and samples may limit the scope of inference of the associations. Pathogens had a higher prevalence in maternity pen bedding than in calf bedding, but total pathogen occurrence did not differ in calf compared with lactating cow feces or in soils with or without manure incorporation. Herd size and animal density did not appear to have a consistent effect on pathogen occurrence. The extent of pathogen prevalence and distribution on the farms indicates considerable public health risks associated with not only milk and meat consumption and direct animal contact, but also potential dissemination of the pathogens into the agroecosystem. PMID- 23810597 TI - Effects of 8 chemical and bacterial additives on the quality of corn silage. AB - This project aimed to evaluate the effects 8 additives on the fermentation, dry matter (DM) losses, nutritive value, and aerobic stability of corn silage. Corn forage harvested at 31% DM was chopped (10mm) and treated with (1) deionized water (control); (2) Buchneri 500 (BUC; 1*10(5) cfu/g of Pediococcus pentosaceus 12455 and 4*10(5) cfu/g of Lactobacillus buchneri 40788; Lallemand Animal Nutrition, Milwaukee, WI); (3) sodium benzoate (BEN; 0.1% of fresh forage); (4) Silage Savor acid mixture (SAV: 0.1% of fresh forage; Kemin Industries Inc., Des Moines, IA); (5) 1*10(6) cfu/g of Acetobacter pasteurianus-ATCC 9323; (6) 1*10(6) cfu/g of Gluconobacter oxydans-ATCC 621; (7) Ecosyl 200T (1*10(5) cfu/g of Lactobacillus plantarum MTD/1; Ecosyl Products Inc., Byron, IL); (8) Silo-King WS (1.5*10(5) cfu/g of L. plantarum, P. pentosaceus and Enterococcus faecium; Agri King, Fulton, IL); and (9) Biomax 5 (BIO; 1*10(5) cfu/g of L. plantarum PA-28 and K-270; Chr. Hansen Animal Health and Nutrition, Milwaukee, WI). Treated forage was ensiled in quadruplicate in mini silos at a density of 172 kg of DM/m(3) for 3 and 120 d. After 3 d of ensiling, the pH of all silages was below 4 but ethanol concentrations were least in BEN silage (2.03 vs. 3.24% DM) and lactic acid was greatest in SAV silage (2.97 vs. 2.51% DM). Among 120-d silages, additives did not affect DM recovery (mean=89.8% +/- 2.27) or in vitro DM digestibility (mean=71.5% +/- 0.63). The SAV silage had greater ammonia-N (0.85 g/kg of DM) and butyric acid (0.22 vs. 0.0% DM) than other treatments. In contrast, BEN and Silo King silages had the least ammonia-N concentration and had no butyric acid. The BEN and A. pasteurianus silages had the lowest pH (3.69) and BEN silage had the least ethanol (1.04% DM) and ammonia nitrogen (0.64 g/kg DM) concentrations, suggesting that fermentation was more extensive and protein degradation was less in BEN silages. The BUC and BIO silages had greater acetic acid concentrations than control silages (3.19 and 3.19 vs. 2.78% DM), but yeast counts did not differ. Aerobic stability was increased by 64% by BUC (44.30 h) and by 35% by BEN (36.49 h), but other silages had similar values (27.0+/-1.13 h). PMID- 23810598 TI - Growth, survival, and peptidolytic activity of Lactobacillus plantarum I91 in a hard-cheese model. AB - In this work, we studied the growth, survival, and peptidolytic activity of Lactobacillus plantarum I91 in a hard-cheese model consisting of a sterile extract of Reggianito cheese. To assess the influence of the primary starter and initial proteolysis level on these parameters, we prepared the extracts with cheeses that were produced using 2 different starter strains of Lactobacillus helveticus 138 or 209 (Lh138 or Lh209) at 3 ripening times: 3, 90, and 180 d. The experimental extracts were inoculated with Lb. plantarum I91; the control extracts were not inoculated and the blank extracts were heat-treated to inactivate enzymes and were not inoculated. All extracts were incubated at 34 degrees C for 21 d, and then the pH, microbiological counts, and proteolysis profiles were determined. The basal proteolysis profiles in the extracts of young cheeses made with either strain tested were similar, but many differences between the proteolysis profiles of the extracts of the Lh138 and Lh209 cheeses were found when riper cheeses were used. The pH values in the blank and control extracts did not change, and no microbial growth was detected. In contrast, the pH value in experimental extracts decreased, and this decrease was more pronounced in extracts obtained from either of the young cheeses and from the Lh209 cheese at any stage of ripening. Lactobacillus plantarum I91 grew up to 8 log during the first days of incubation in all of the extracts, but then the number of viable cells decreased, the extent of which depended on the starter strain and the age of the cheese used for the extract. The decrease in the counts of Lb. plantarum I91 was observed mainly in the extracts in which the pH had diminished the most. In addition, the extracts that best supported the viability of Lb. plantarum I91 during incubation had the highest free amino acids content. The effect of Lb. plantarum I91 on the proteolysis profile of the extracts was marginal. Significant changes in the content of free amino acids suggested that the catabolism of free amino acids by Lb. plantarum I91 prevailed in a weakly proteolyzed medium, whereas the release of amino acids due to peptidolysis overcame their catabolism in a medium with high levels of free amino acids. Lactobacillus plantarum I91 was able to use energy sources other than lactose to support its growth because equivalent numbers of cells were observed in extracts containing residual amounts of lactose and in lactose-depleted extracts. The contribution of Lb. plantarum I91 to hard-cooked cheese peptidolysis was negligible compared with that of the starter strain; however, its ability to transform amino acids is a promising feature of this strain. PMID- 23810599 TI - The influence of sweeteners in probiotic Petit Suisse cheese in concentrations equivalent to that of sucrose. AB - As in the case of probiotic functional foods in recent years, demand has increased notably for light or diet foods with added sweeteners. However, little is known about the effect of different sweeteners on the microorganisms present. Thus, the objective of the current study was to establish the ideal sucrose concentration and equivalent concentrations of different sweeteners and to determine, by microbiological analyses, the influence of these compounds on the viability of the starter and probiotic cultures used in the production of strawberry-flavored Petit Suisse cheese during its shelf life. The ideal sucrose concentration was determined using the just-about-right (JAR) scale, and the equivalent concentrations of the sweeteners were subsequently determined by the magnitude estimation method. Microbiological analyses were also carried out to check the viability of the cultures during the product's shelf life. The results showed that the compounds Neotame (NutraSweet, Chicago, IL) and stevia presented, respectively, the greatest and least sweetening power of the sweeteners tested. None of the sweeteners used in this study exerted a negative effect on the viability of the starter or probiotic cultures, and thus we were able to obtain a probiotic, functional food with reduced calorie content. PMID- 23810600 TI - Short communication: Interrelationship between butyrate and glucose supply on butyrate and glucose oxidation by ruminal epithelial preparations. AB - The aim of this study was to determine whether dietary Na-butyrate supplementation affects butyrate and glucose oxidation by ruminal epithelial preparations and whether this effect can be acutely modulated by substrate (glucose and butyrate) supply. Eighteen Suffolk wether lambs (6 lambs/treatment) were blocked by body weight and, within block, randomly assigned to the control treatment (CON) or to diets containing differing Na-butyrate inclusion rates (1.58 or 3.16%) equating to 1.25 (B1.25), and 2.50% (B2.50) butyrate on a dry matter basis, respectively. All lambs received their diet for a period of 14 d. After dietary adaptation, lambs were killed and the ruminal epithelium was harvested from the ventral sac, minced finely, and used for in vitro incubations. Incubation medium contained either a constant concentration of glucose (4 mM) with increasing butyrate concentrations (0, 5, 15, 25, or 40 mM) or a constant butyrate concentration (15 mM) with increasing glucose concentrations (0, 1, 2, 4, or 8 mM) to allow for the evaluation of whether acute changes in the concentration of metabolic substrates affect the oxidation of glucose and butyrate. We observed no interactions between the in vivo and in vitro treatments. Increasing dietary butyrate supplementation linearly decreased glucose oxidation by ruminal epithelial preparations, but had no effect on butyrate oxidation. Increasing butyrate concentration in vitro decreased (cubic effect) glucose oxidation when butyrate concentration ranged between 5 and 15 mM; however, glucose oxidation was increased with a butyrate concentration of 40 mM. Butyrate oxidation decreased (cubic effect) as glucose concentration increased from 1 to 4 mM; however, butyrate oxidation increased when glucose was included at 8mM. The results of this study demonstrate that dietary butyrate supplementation can decrease glucose oxidation by the ruminal epithelium, but the relative supply of glucose and butyrate has a pronounced effect on substrate oxidation. PMID- 23810601 TI - Factors associated with milking characteristics in dairy cows. AB - Milking characteristics, and in particular milking duration, are a known contributor to costs in dairy production systems. Results from previous studies suggest that higher-yielding animals, on average, milk for a longer duration. Culling or selection for reduced milking duration alone may, therefore, reduce milk yield. Here, we propose 2 new traits, residual milking duration (RMD) and residual milking duration including somatic cell score (RMDS). Residual milking duration is represented by the residuals from a least squares regression of milking duration on milk yield; RMDS is represented by the residuals from a least squares regression of milking duration on both milk yield and somatic cell score [i.e., logarithm (base 10) of somatic cell count]. The mathematical properties of least squares regression ensure than the residual traits are independent from the regressor variables, or, in other words, RMDS is not correlated with either milk yield or somatic cell score. Both RMD and RMDS were defined using electronically measured individual cow milking duration from 235,036 part-day milking events from 74,607 cows from 1,075 Irish dairy herds. Twenty-four percent of the variation in milking duration was explained by the multiple regression model containing both milk yield and somatic cell score. The phenotypic standard deviation of RMD and RMDS was 102.2 and 98.2s, respectively, suggesting large variation in milking duration independent of milk yield (and somatic cell score). The correlation of RMD and RMDS with average milk flow rate, which may also be considered a measure of milking efficiency, was -0.74 and -0.75, respectively. Neither RMD nor RMDS was correlated with somatic cell score. However, average milk flow rate was correlated with milk yield (0.57) and milking duration ( 0.38). Both RMD and RMDS are useful traits, which exhibit considerable variation and, therefore, can be used by farmers to identify phenotypically slower milking animals irrespective of milk yield (and somatic cell score). However, because of the lack of a correlation between RMD and somatic cell score in the sample population used in the present study, RMD and RMDS values per milking were almost identical. PMID- 23810602 TI - Shedding light on nuclear actin dynamics and function. AB - The functions of nuclear actin have been a mystery for many years. Recent papers demonstrate that the nuclear and cytoplasmic actin pools are in dynamic communication, but that not all nuclear actin freely exchanges. Extracellular signals can induce changes in nuclear actin dynamics, affecting activity of the myocardin-related transcription factor (MRTF) transcriptional coactivators, which reversibly bind G-actin. By contrast, actin is stably associated with the Ino80 chromatin remodelling complex, where it plays a role in the recognition of nucleosome linker DNA. PMID- 23810603 TI - Intraoperative anatomical variations during greater occipital nerve decompression. AB - OBJECT: A study was conducted to elucidate anatomical variations of the GON and surrounding occipital tissues. METHODS: Anatomical and surgical variations were prospectively recorded for 272 patients who underwent greater occipital nerve (GON) decompression by a single surgeon between 2003 and 2012. Data collection was performed intraoperatively and specifically for the purposes of this study. Documented anatomical variations of the GON and surrounding occipital region included the extension of trapezius musculature to the midline, abnormal lymph nodes, and GON branching. Necessary variations in the surgical procedure were also noted, including resection of a lateral portion of semispinalis capitis muscle and occipital arterectomy. RESULTS: The GON pierced the semispinalis muscle in all patients bilaterally. The extension of trapezius musculature to the midline was discovered in 67.3 percent of patients and lymph node enlargement was discovered in 1.5 percent of patients. Branching of the GON was noted in 7.4 percent of patients and muscles or vessels between GON branches were noted in 3.7 percent of patients. Occipital arterectomy was required in 64.0 percent of patients and resection of a lateral segment of semispinalis muscle was required in 10.7 percent of patients. CONCLUSIONS: The new anatomical variations described in this study improve understanding of the intraoperative anatomy of the occipital region and prevent difficulty in finding the GON due to dissection in the wrong plane, ensuring that MH patients receive maximal benefit from surgical treatment. PMID- 23810604 TI - The trap door flap: a reliable, reproducible method of anterior pinna reconstruction. AB - INTRODUCTION: Resection of skin cancers of the conchal fossa and anti-helical rim presents a challenging reconstructive problem. A full thickness skin graft is often used following excision of the cartilage underlying the lesion. Colour mismatch, a contour defect and a donor site scar are potential drawbacks to this method of reconstruction. The postauricular trap door flap offers a superior option for these defects. AIMS: This study aims to assess the reliability and outcomes of the trap door flap for defects of the anterior surface of the pinna. METHODS: A retrospective review of all trap door flaps carried out in Galway University Hospital was carried out. Charts were reviewed in order to examine operative notes and assess for any complications and length of follow up. RESULTS: 45 Patients were operated on by a single surgeon. The age range was 61 93 years. The majority of lesions excised were from the conchal area with 6 defects predominantly involving the scapha. No partial or complete flap loss occurred. 2 patients required further excision due to an incomplete margin and a local recurrence respectively. Follow up ranged from 3 months to 4 years with excellent cosmetic results were achieved in all cases with no scar issues at the flap or donor sites. CONCLUSION: The trap door flap is an excellent method of conchal reconstruction. It is reliable and reproducible with no flap loss demonstrated in our series of 45 patients. Large defects can be reconstructed with this flap and the cosmetic result in terms of colour and contour, as well as a hidden donor site scar, make this a superior option to a full thickness skin graft. PMID- 23810605 TI - Tendon 'turnover lengthening' technique. AB - Tendon defect reconstruction is amongst the most technically challenging areas in hand surgery. Tendon substance deficiency reconstruction techniques include lengthening, grafting, two-stage reconstruction and tendon transfers, however each is associated with unique challenges over and above direct repair. We describe a novel 'turnover lengthening' technique for hand tendons that has successfully been applied to the repair of several cases, including a case of attritional flexor and traumatic extensor tendon rupture in two presented patients where primary tenorrhaphy was not possible. In both cases a good post operative outcome was achieved, as the patients were happy having returned back to normal activities of daily living such that they were discharged 12 weeks post operatively. Our technique avoids the additional morbidity and complications associated with grafting, transfers and two stage reconstructions. It is quick, simple and reproducible for defects not exceeding 3-4 cm, provides a means of immediate one stage reconstruction, no secondary donor site morbidity and does not compromise salvage by tendon transfer and/or two-stage reconstruction in cases of failure. To our knowledge no such technique has been previously been described to reconstruct such hand tendon defects. PMID- 23810606 TI - Pie crusting of acellular dermal matrix may help decrease incidence of seromas in breast reconstruction. PMID- 23810607 TI - Laparoscopic gastric plication: technical report. AB - BACKGROUND: Laparoscopic gastric plication is an emerging restrictive bariatric procedure but still lacks standardization of the technique. The aim of this study was to apply a standardized, modified 3-port approach to laparoscopic gastric plication to improve outcomes. METHODS: The modified laparoscopic gastric plication technique was applied for 63 morbidly obese patients between March 2010 and January 2013. There were 9 men and 54 women, with a mean age of 34.2 years (range 20-48 years) and a mean body mass index of 38.9 kg/m(2) (range 32-65 kg/m(2)). RESULTS: There were no deaths, no conversion to laparotomy, no reoperation, and no readmission. Percent excess weight loss was 41%, 52%, and 60% at 3, 6, and 12 months, respectively. There were no major complications reported in our study, but prolonged early postoperative nausea and vomiting occurred in 3 of 63 (4.8%) patients who had been successfully treated with proton pump inhibitors and antiemetics. CONCLUSIONS: Our initial experience showed that the 4 bite technique starting 2 cm below the angle of His with tight calibration of the gastric tube for obese patients is feasible, effective, and well tolerated, with a low frequency of major problems. PMID- 23810609 TI - Airway management in obese patients. AB - The well-known difficulties in airway management in obese patients are caused by obesity-related airways and respiratory changes. Anesthesiologists confront a number of troubles, including rapid oxygen desaturation, difficulty with laryngoscopy/intubation and mask ventilation, and increased susceptibility to the respiratory depressant effects of anesthetic drugs. Preoperative assessment of the airways in the obese should include examination of specific predictors of difficult mask ventilation other than those for difficult intubation. Difficulties in airway management are decreased after providing optimal preoxygenation and positioning ("ramped"). Other strategies may include availability of alternative airway management devices, including new video laryngoscopes that significantly improve the visualization of the larynx and thereby facilitate intubation. If awake intubation is mandatory, it may be performed with fibrobronchoscope after providing an adequate topical anesthesia and sedation with short-acting drugs, such as remifentanil. Succinylcholine for rapid sequence induction might be replaced by rocuronium where sugammadex is available for reversal. A complete reversal of neuromuscular block, measured by train-of-four monitoring, should be obtained before extubation, which requires a fully awake patient in the same position with airway equipment used for intubation. PMID- 23810608 TI - Predictors and outcomes of adolescent bariatric support group attendance. AB - BACKGROUND: Attending support groups connects adults undergoing bariatric surgery to peers and may improve weight loss efficacy. Predictors and outcomes of support group attendance of adolescents undergoing bariatric surgery are unknown. The objective of this cohort study was to determine the rate, predictors, and outcomes of support group attendance in a free-standing adolescent bariatric program. METHODS: Charts of 68 consecutive adolescents who underwent laparoscopic Roux-en-Y gastric bypass or vertical sleeve gastrectomy were retrospectively reviewed, and demographic and anthropometric variables and support group and clinic visit attendance were recorded. Prospectively collected vitamin adherence data were also analyzed. Univariate analyses evaluated characteristics and multivariate analyses evaluated predictors of support group attendance, clinic visit attendance, and vitamin adherence. RESULTS: Of the 68 patients, one third attended 1-3 support sessions, one third attended >= 4, and one third were nonattenders. Greater distance from clinical center (P = .01) and caregiver bariatric history (P = .05) were associated with decreased attendance. Only high preoperative body mass index (P<.01) and caregiver bariatric history (P<.01) were independently associated with decreased attendance. Increased attendance was associated with higher 6-month (P = .03) and 12-month (P<.01) clinic visit attendance but not with multivitamin adherence (P = .33). CONCLUSIONS: Caregiver bariatric history and higher preoperative body mass index were associated with decreasing attendance at an adolescent bariatric support group program. This highlights a need to encourage attendance in these patients, because adolescent attendance at support group sessions was positively associated with greater adherence to scheduled clinic visits postoperatively, which may positively influence long-term outcomes. PMID- 23810610 TI - Two-stage surgery in a morbidly obese patient: laparoscopic pylorus-preserving pancreaticoduodenectomy after laparoscopic sleeve gastrectomy. PMID- 23810611 TI - Prevalence of hiatal hernia in the morbidly obese. AB - BACKGROUND: Morbidly obese patients commonly have gastroesophageal reflux (GERD) and associated hiatal hernias. As such, some surgeons routinely perform a concomitant hiatal hernia repair during bariatric surgery. However, the intraoperative inspection for a hiatal hernia based on laparoscopic visualization can be misleading. The aim of this study was to assess the prevalence of hiatal hernias in morbidly obese patients based on preoperative upper gastrointestinal (GI) contrast study. METHODS: Data on 181 patients who underwent routine upper GI contrast study as part of a preoperative workup for bariatric surgery were reviewed. The upper GI studies were examined for the presence of hiatal hernias and GERD. Hiatal hernias were categorized by size as small (<=2 cm), moderate (2 5 cm), or large (>5 cm). GERD was based on radiologic evidence and categorized as mild, moderate, or severe. RESULTS: The mean age of the cohort was 44 years, with a mean body mass index of 43 kg/m(2). Of the 181 patients overall, based on the upper GI contrast study, the prevalence of hiatal hernia was 37.0% and of GERD was 39.8%; the prevalence of moderate or large hiatal hernia was 4.4%, and the prevalence of moderate or severe GERD was 13.3%. CONCLUSIONS: Based on upper GI contrast study, we identified the presence of a hiatal hernia in nearly 40% of morbidly obese patients. The results from this study suggest that surgeons should evaluate the morbidly obese patient for the presence of hiatal hernias and perform concomitant repair at the time of the bariatric procedure, particularly in patients undergoing gastric banding and sleeve gastrectomy, while less so in the gastric bypass patient. PMID- 23810612 TI - Role of polyamines in regulating silymarin production in Silybum marianum (L.) Gaertn (Asteraceae) cell cultures under conditions of calcium deficiency. AB - As part of our efforts to identify the possible role of polyamines (PAs) in silymarin (Sm) production, the effects of calcium deprivation on cell growth and on endogenous PAs levels and Sm production by milk thistle (Silybum marianum (L.) Gaertn) grown in cell cultures were examined. Young cultured cells of the H2 line of S. marianum were transferred to a medium without calcium and with ethylene glycol-bis-(beta-aminoethyl) ether-N,N,N',N'-tetraacetic acid present to chelate any free calcium in order to analyze the effects of this medium on the levels of PAs and Sm produced by the cells. During the 17 days of exposure to this calcium free medium most of the cell populations were in the G0/G1 phase (from day 7 to day 14 of culture) while PA levels underwent a progressive decline up to day 17, after which they were no longer detectable. We observed that putrescine (Put) accumulation was always lower than that observed under normal conditions. The lack of calcium in the MS medium advances the onset of the stationary phase, whose beginning is marked by an increase in the Put/spermidine (Spd) index, raising the production of Sm; the suspensions were productive for a longer time and hence produced more of the substance. Our results indicate that under stress conditions the production of Sm in young-cell suspensions of S. marianum is not associated with high levels of PAs in the medium--contrary to what one would expect--allowing us to conclude that growth inhibition appears to be the factor responsible for the maximum Sm accumulation while PAs are not directly involved in the Sm synthesis pathway by milk thistle grown in culture. PMID- 23810613 TI - Human parechovirus type 3 central nervous system infections in Israeli infants. AB - INTRODUCTION: Human parechoviruses (HPeV) have been recognized as the causative agents of central nervous system (CNS) infection of infants and young children in different parts of the world. The role of HPeV in CNS infection of Israeli infants and children is unknown. OBJECTIVES: To assess the detection rate of HPeV in enterovirus RT-PCR-negative cerebrospinal fluid (CSF) samples obtained during the years 2007-2009 from children 0-5 years old with suspected CNS infection or from very young infants with unexplained fever in four medical centers in Israel. STUDY DESIGN: A total of 367 CSF samples were retrospectively tested for the presence of HPeV RNA using nested RT-PCR assay. Positive samples were further typed on the basis of molecular sequencing. Retrospective analysis of the medical charts was performed. RESULTS: HPeV3 RNA was detected in CSF obtained between May and September 2008 in 13 patients, all of whom were <3 months old (3.5% of all CSFs; 11.3% of all infants<3 months in 2008). The HPeV-positive CSF samples were without pleocytosis. All HPeV3-positive patients recovered without obvious short term sequelae. CONCLUSION: HPeV infection could play an important role in summertime febrile/CNS illness in young infants during specific years with high HPeV activity. PCR detection of parechoviral RNA in CSF should be included in the diagnostic evaluation of fever or CNS infection of neonates and very young infants. The rapid identification of HPeV in CSF could curtail unnecessary empirical antibiotic treatment and shorten hospital stay in selected patients. PMID- 23810614 TI - Relapse of hepatitis C virus after 14 months of sustained virological response following pegylated-interferon alpha plus ribavirin therapy in a human immunodeficiency virus type 1 infected patient. AB - It has been demonstrated that sustained virological response (SVR) in patients with chronic hepatitis C indicates resolution of infection. We describe a late hepatitis C virus (HCV) relapse with nearly identical HCV genotype 1a RNA, 14 months after a SVR achievement following a 12-month pegylated-interferon plus ribavirin treatment in a human immunodeficiency virus (HIV) infected patient. This virological relapse occurred concomitantly with interruption of highly active antiretroviral therapy and subsequent increased immunosuppression. HCV retreatment was successful and HCV RNA was undetectable at 50 months of follow up. This case suggests that late relapse of HCV infection in HIV-positive patients with SVR is possible in case of increased immunodeficiency related to highly active antiretroviral therapy interruption. In such circumstances, a close monitoring of HCV viremia and aminotransferases should be performed. PMID- 23810615 TI - The effects of TNF-alpha inhibitor therapy on arterial stiffness and endothelial dysfunction in rheumatoid arthritis: a meta-analysis. PMID- 23810616 TI - Donor-site morbidity of free fibula and DCIA flaps. AB - PURPOSE: This study evaluated and compared the long-term donor-site morbidity of the free fibula flap with the deep circumflex iliac artery (DCIA) flap in maxillofacial reconstruction. MATERIALS AND METHODS: Thirty-four patients (19 in the fibula group and 15 in the DCIA group) were evaluated for long-term morbidity. All clinical data were analyzed, including primary disease, type of defect, type of flap, length of bone harvested, total blood loss, operating time, length of hospitalization, and postoperative unaided gait. Subjective evaluation included cosmesis, function, and pain. Objective evaluation included physical examination, neurosensory assessment, Stony Brook Scar Evaluation, gait assessment, and goniometric measurement of range of movement. RESULTS: In the subjective evaluation, no significant differences in cosmetic outcome, functional loss, wound healing, or pain between the 2 groups were noted (P > .05). However, neurosensory deficit was worse in the DCIA group (P <= .05). In the objective evaluation, 4 patients (27%) in the DCIA group had neurosensory deficit in the lateral thigh region. The DCIA group had a better Stony Brook Scar score (median, 5) than the fibula group (median, 4; P <= .05). However, there was no difference in walking ability between the 2 groups (P > .05). Goniometric measurement showed a significant difference between the operated and unoperated sites in the 2 groups; however, it was not severe enough in either group to affect patients' function. In the fibula group, 7 patients (38.9%) had claw toe deformity and 2 patients (12.1%) had weakness of the great toe, and the mean American Orthopedic Foot and Ankle Society score was 96.89. In the DCIA group, 1 patient (8.3%) had a hernia and the mean Harris Hip score was 98.33. CONCLUSION: Given that these 2 options present donor-site concerns, the authors consider the fibula free flap the first choice for maxillofacial reconstruction in most cases and the DCIA free flap a reliable complementary flap in selected patients. PMID- 23810617 TI - Metastatic squamous cell carcinoma of an unknown primary site with cardiac involvement: case report. AB - Head and neck squamous cell carcinomas frequently metastasize to cervical lymph nodes. Distant metastasis by hematogenous dissemination pathways is less common. Cardiac involvement is a particularly rare occurrence. The first case of cardiac metastasis was reported in the early 18th century as a postmortem discovery. Since then, there have been sporadic reports of oropharyngeal cancer with cardiac metastasis. This report describes a case of metastatic squamous cell carcinoma of an unknown primary site involving the lungs, heart, and soft tissue of the bilateral paraspinal regions and lower extremity. PMID- 23810618 TI - Image-guided surgical navigation for removal of foreign bodies in the deep maxillofacial region. AB - PURPOSE: Most trauma surgeons encounter numerous penetrating injuries. Some foreign bodies can cause pain, infection, and discomfort to the patient. Serious functional disorders also are likely to occur. Foreign bodies in critical areas must be removed. This report describes the use of image-guided technology for the removal of foreign bodies deep in the maxillofacial region. PATIENTS AND METHODS: From 2008 through 2011, 5 patients with foreign bodies in the maxillofacial area underwent image-guided removal at the authors' department. The STN navigation system (Stryker-Leibinger, Freiburg, Germany) was used for surgical planning and intraoperative navigation. Preoperatively, computerized tomography and digital subtraction angiography were used to create 3-dimensional views of the region to aid surgeons in more accurately defining the spatial location of the foreign object. During surgery, the foreign objects and surgical instruments were visualized on the screen. RESULTS: In all 5 cases, the foreign bodies were removed by minimally invasive access without any complications. Surgical time was approximately 40% shorter compared with the conventional technique of not using image-guided navigation. A 1-year postoperative evaluation showed that the patients' complaints and symptoms had resolved, function was restored, and esthetics were remarkably improved. CONCLUSION: Navigation-guided removal of foreign bodies in the complex, deep maxillofacial region in proximity to vital areas can be regarded an ideal and valuable option for these potentially complicated procedures. PMID- 23810619 TI - Mandibular reconstruction assisted by preoperative simulation and accurate transferring templates: preliminary report of clinical application. AB - PURPOSE: This study investigated the application of a computer-aided design and manufacturing technique of defining tumor resection, fibula cutting, and positioning by surgical templates in mandibular reconstructive surgery. MATERIALS AND METHODS: Four patients who required mandibulectomy and simultaneous reconstruction were enrolled in this study. Preoperative surgical simulation was performed. The surgical templates that defined tumor resection, fibula cutting, and positioning were designed and fabricated. RESULTS: The surgeries were performed to the preoperative plan. All flaps survived. Superimposition of the postoperative image and the preoperative plan showed a satisfactory surgical accuracy. CONCLUSIONS: This method of defining tumor resection, fibula cutting, and positioning by surgical templates was accurate enough for mandibular reconstructive surgery. PMID- 23810620 TI - Changes in the upper airway after counterclockwise maxillomandibular advancement in young Korean women with class II malocclusion deformity. AB - PURPOSE: To evaluate the change in the upper airway in a Class II malocclusion deformity after counterclockwise maxillomandibular advancement. MATERIALS AND METHODS: Seventeen young Korean women with a Class II malocclusion deformity who had undergone Le Fort I and bilateral mandibular ramus sagittal split osteotomy in a counterclockwise rotation were enrolled in the present study. The upper airway was measured at 3 different levels (uvula tip, low C2, and mid C3) using lateral cephalograms at 3 points: preoperatively (T0) and 2 (T2) and 12 (T12) months postoperatively. The changes in the upper airway were then compared. RESULTS: The mandible advanced an average of 7.0 +/- 3.8 mm. The upper airway had widened considerably at all 3 levels at T2 and had decreased slightly at T12, especially at the low C2 level compared with T0. However, the upper airway at T12 remained wider than at T0 at all 3 levels. The mandibular advancement and upper airway width correlated only at T12 at the mid C3 level. CONCLUSIONS: The upper airway became wider in patients with a Class II malocclusion deformity who had undergone mandibular advancement. However, this might become narrower with time. PMID- 23810621 TI - The ultimate intra-/extra-dimensional attentional set-shifting task for mice. AB - BACKGROUND: Alterations in executive control and cognitive flexibility, such as attentional set-shifting abilities, are core features of several neuropsychiatric diseases. The most widely used neuropsychological tests for the evaluation of attentional set shifting in humans are the Wisconsin Card Sorting Test and the Cambridge Neuropsychological Test Automated Battery Intra-/Extra-Dimensional set shift task (ID/ED). These tasks have proven clinical relevance and have been successfully adapted for monkeys. However, similar tasks currently available for rodents are limited, mainly because of their manual-based testing procedures. The current limitations of rodent attentional set-shifting tasks are hampering translational advances in psychiatric medicine. METHODS: To closely mimic the Cambridge Neuropsychological Test Automated Battery ID/ED task in primates, we present the development of a novel operant-based two-chamber ID/ED "Operon" task for mice. RESULTS: We show the ability of this novel task to measure attentional set shifting in mice and the effects of genetic and pharmacologic manipulations of dopamine and glutamate. In genetically modified mice with reduced catechol-O methyltransferase activity there was selective improvement on extradimensional shift abilities and impairment of serial reversal learning. Chronic administration of phencyclidine produced a selective impairment of extradimensional shift while producing a generalized decrease in latency to respond. CONCLUSIONS: We demonstrate that this novel ID/ED Operon task may be an effective preclinical tool for drug testing and large genetic screening relevant to the study of executive dysfunctions and cognitive symptoms of psychiatric disorders. These findings may help elucidate the biological validity of similar findings in humans. PMID- 23810623 TI - Estimation of the reproduction number of salmon pancreas disease virus subtype 3 in homogeneously mixed populations of Norwegian farmed Atlantic salmon. AB - The reproduction number (R) of salmon pancreas disease (PD) was estimated within homogeneously mixing populations (within-cage) of Norwegian farmed Atlantic salmon (Salmo salar L.) based on data collected during PD epidemics from 10 cages at 2 farming sites. Two approaches were used: (a) estimation of an overall reproduction number (R(cmd)) and a time-dependent reproduction number (R(t)) using mortality records during PD epidemics, and (b) estimating the reproduction number during the early stage of infection (R(sd)) based on data from a surveillance program for SPDV subtype 3. The R(cmd) estimates based on the mortality data ranged from 1.02 to 1.45, and the R(sd) estimates ranged from 1.0 to 2.9. Plots of the R(t) estimates covering the whole epidemic period yielded an increasing slope prior to SPDV3 detection. This study presents a framework for the quantitative measurement of a PD epidemic that could be useful for the evaluation of prevention methods. The time-dependent R(t) estimate can provide an early warning of PD outbreaks. PMID- 23810624 TI - Misleading guidance for decision making on tsetse eradication: response to Shaw et al. (2013). PMID- 23810622 TI - Indiscriminate amygdala response to mothers and strangers after early maternal deprivation. AB - BACKGROUND: In altricial species, maternal stimuli have powerful effects on amygdala development and attachment-related behaviors. In humans, maternal deprivation has been associated with both "indiscriminate friendliness" toward non-caregiving adults and altered amygdala development. We hypothesized that maternal deprivation would be associated with reduced amygdala discrimination between mothers and strangers and increased parent report of indiscriminate friendliness behaviors. METHODS: Sixty-seven youths (33 previously institutionalized; 34 comparison; age-at-scan 4-17 years) participated in a functional magnetic resonance imaging experiment designed to examine amygdala response to mother versus stranger faces. In-scanner behavior was measured. Indiscriminate friendliness was assessed with parental report. RESULTS: Comparison youth showed an amygdala response that clearly discriminated mother versus stranger stimuli. Previously institutionalized youths, by contrast, exhibited reduced amygdala discrimination between mothers and strangers. Reduced amygdala differentiation correlated with greater reports of indiscriminate friendliness. These effects correlated with age-at-adoption, with later adoptions being associated with reduced amygdala discrimination and more indiscriminate friendliness. CONCLUSIONS: Our results suggest that early maternal deprivation is associated with reduced amygdala discrimination between mothers and strangers, and reduced amygdala discrimination was associated with greater reports of indiscriminate friendliness. Moreover, these effects increased with age-at adoption. These data suggest that the amygdala, in part, is associated with indiscriminate friendliness and that there might be a dose-response relationship between institutional rearing and indiscriminate friendliness. PMID- 23810625 TI - Nutritional status predicts preterm death in older people: a prospective cohort study. AB - BACKGROUND & AIMS: There is an association between malnutrition and mortality. However, it is uncertain whether this association is independent of confounders. The aim of the present study was to examine whether nutritional status, defined according to the three categories in the full Mini Nutritional Assessment (MNA) instrument, is an independent predictor of preterm death in people 65 years and older. METHODS: This prospective cohort study included individuals aged >=65 years who were admitted to hospital between March 2008 and May 2009 and followed up after 50 months (n = 1767). Nutritional status was assessed with the MNA, and possible risk factors associated with malnutrition were recorded during participants hospital stay. Main outcome measure was overall survival. RESULTS: Based on the MNA definitions, 628 (35.5%) were well-nourished, 973 (55.1%) were at risk of malnutrition, and 166 (9.4%) of the participants were malnourished at baseline. During the follow-up period 655 (37.1%) participants died. At follow up, the survival rates were 75.2% for well-nourished participants, 60.0% for those at risk of malnutrition, and 33.7% for malnourished participants (p < 0.001). After adjusting for confounders the hazard ratios (95% CI) for all-cause mortality were 1.56 (1.18-2.07) in the group at risk of malnutrition and 3.71 (2.28-6.04) in the malnourished group. CONCLUSIONS: Nutritional status defined according to the three categories in the full MNA independently predicts preterm death in people aged 65 years and older. These findings are clinically important and emphasise the usefulness of the MNA for screening of nutritional status. PMID- 23810626 TI - Long-term effect of the Go4it group treatment for obese adolescents: a randomised controlled trial. AB - BACKGROUND & AIMS: Few studies evaluating treatment of adolescent obesity have been published. Therefore, long-term effects of the Go4it group treatment for obese adolescents were examined. METHODS: Obese adolescents (11-18 years) visiting an outpatient paediatric obesity clinic were randomly assigned to 1) intervention group (Go4it) or 2) current regular care i.e. referral to a dietician in the home care setting (controls). Linear mixed models analysis was performed to evaluate intervention effects. Effect modification by sex, age and ethnicity was checked. Outcome measures included body mass index standard deviation score (BMIsds), body composition and metabolic components at 6 and 18 months follow-up. RESULTS: 122 adolescents, 71 Go4it and 51 controls, with a mean BMIsds of 2.9 +/- 0.5 were randomised. At 18 months a modest significant reduction in BMIsds (between group difference: -0.16; 95%CI: -0.30, -0.02; p = .028) was observed. None of the other body composition or metabolic components showed significant treatment effects. Ethnicity was a significant effect modifier. Posthoc analysis showed a large significant reduction on BMIsds (between group difference: -0.35; 95%CI: -0.64, -0.07) at 18 months for obese adolescents from western descent, while no effect was observed for adolescents from non-western descent. Significant treatment effects were also observed for systolic and diastolic blood pressure, as well as HDL cholesterol level, but only for obese adolescents from western descent. CONCLUSIONS: Go4it showed promising long-term effects on BMIsds compared with regular care in obese adolescents. Larger benefits were achieved for adolescents of western ethnicity. This trial was registered at www.trialregister.nl with the Netherlands Trial Register as ISRCTN27626398. PMID- 23810627 TI - [Enhanced prenatal HIV couple oriented counselling session and couple communication about HIV (ANRS 12127 Prenahtest Trial)]. AB - BACKGROUND: The Prenahtest study investigated the efficacy of a couple-oriented HIV counselling session (COC) in encouraging couple HIV counselling and testing, and improving intra-couple communication about sexual and reproductive health. We report here on the effect of COC on intra-couple communication about HIV. METHODS: Within this 4-country trial (India, Georgia, Dominican Republic and Cameroon), 484 to 491 pregnant women per site were recruited and individually randomized to receive either the COC intervention, enhanced counselling with role playing, or standard post-test HIV counselling. Women were interviewed at recruitment, before HIV testing (T0), and 2 to 8 weeks after post-test HIV counselling (T1). Four dichotomous variables documented intra-couple communication about HIV at T1: 1) discussion about HIV, 2) discussion about condom use, 3) suggesting HIV testing and 4) suggesting couple HIV counselling to the partner. An intra-couple HIV communication index was created: low degree of communication ("yes" response to zero or one of the four variables), intermediate degree of communication ("yes" to two or three variables) or high degree of communication ("yes" to the four variables). To estimate the impact of COC on the intra-couple HIV communication index, multivariable logistic regressions were conducted. RESULTS: One thousand six hundred and seven women were included in the analysis of whom 54 (3.4%) were HIV-infected (49 in Cameroon). In the four countries, the counselling group was associated with intra-couple HIV communication (P<=0.03): women allocated to the COC group were significantly more likely to report high or intermediate degrees of intra-couple communication about HIV (versus low degree of communication) than women allocated to standard counselling. CONCLUSION: COC improved short-term communication about HIV within couples in different sociocultural contexts, a positive finding for a couple approach to HIV prevention. PMID- 23810628 TI - [Discovery and follow-up of a lead-poisoning outbreak in a shantytown of Le Port, Reunion Island]. AB - BACKGROUND: A national survey conducted in 2008-2009 by the French Institute for Public Health Surveillance for detection of lead impact in childhood identified a high blood lead level in a young boy living in the town of "Le Port", Reunion Island. Previously, cases of lead-poisoning on the island had been exceptional; only a dozen cases were reported in the 1980s in adults, related to the use of lead-containing instruments for food preparations. METHODS: The family of the index case was invited to participate in screening tests and an environmental investigation was conducted using a standardized questionnaire. Screening was then broadened to the neighborhood of the index case and samples of soil outside the home and in the immediate vicinity were taken. The environmental survey was then extended with soil samples taken from the entire geographical area. Information was then provided to local inhabitants (87 families and 287 people) in order to encourage lead blood testing for all children under six years and all pregnant women living in the area. RESULTS: The index case lived in the neighborhood of "The Oasis", a shantytown of Le Port. The results of soil analysis revealed heterogeneous pollution of superficial soils by lead throughout the area of the shantytown, the highest level recorded (5200mg/kg) reached more than 300 times the background level of the natural soils of the island. The screening identified 76 cases of childhood lead-poisoning (blood lead level greater or equal to 100MUg/L) among 148 samples (51%). All cases of blood poisoning involved children under the age of 15 years. The median age of children with a positive test was 5.6 years; the median blood lead level was 196MUg/L [102 392MUg/L]. CONCLUSION: The main hypothesis to explain the contamination of the soil in the area of the shantytown is the presence of waste deposits (car batteries) and diffuse activities of metal recovery. The authorities managed to remove all the families from the environmental exposure to lead by rapidly ensuring rehousing outside the contaminated area. PMID- 23810629 TI - [Birth preparedness in antenatal care: effects of health center characteristics]. AB - AIM: Counseling relating to birth preparedness is an essential component of the WHO Focused Antenatal Care model. During the antenatal visits, women should receive the information and education they need to make choices to reduce maternal and neonatal risks. The objective of this study conducted among women attending antenatal visits in rural Burkina Faso was to search for a link between the characteristics of the center delivering the health care and the probability of being exposed to information and advice relating to birth preparedness. METHODS: A multilevel study was performed using survey data from women (n=464) attending health centres (n=30) in two rural districts in Burkina Faso (Dori and Koupela). The women were interviewed using the modified questionnaire of the Johns Hopkins Program for International Education in Gynecology and Obstetrics (JHPIEGO). RESULTS: Women reported receiving advice about institutional delivery (72%), signs of danger (55%), cost of institutional delivery (38%) and advice on transportation in the event of emergency (12%). One independent factor was found to be associated with reception of birth preparedness advice: number of antenatal visits attended. Compared with women from Dori, women from Koupela were more likely to have received information on signs of danger (OR=3.72; 95%CI: 1.26 7.89), institutional delivery (OR=4.37; 95%CI: 1.70-10.14), and cost of care (OR=3.01; 95%CI: 1.21-7.46). The reduced volume of consultations per day and the availability of printed materials significantly remain associated with information on the danger signs and with the institutional delivery advices. Comparison by center activity level showed that women attending health centers delivering less than 10 antenatal visits per day were more likely to receive information on signs of danger (OR=2.63; 95%CI: 1.12-6.24) and to be advised about institution delivery (OR=6.30; 95%CI: 2.47-13.90) compared to health centers delivering more than 20 antenatal visits per day. Women attending health centres equipped with printed materials (posters, illustrated documents) were more likely to receive information on signs of danger (OR=4.25; 95%CI: 1.81 12.54) and be advised about institutional delivery (OR=6.85; 95%CI: 3.17-14.77). CONCLUSION: Efforts should be made to reach women with birth preparedness messages. Rural health centres in Burkina Faso need help to upgrade their organizational services and provide patients with printed materials so they can improve antenatal care delivery. PMID- 23810631 TI - Children with autism spectrum disorder are more trusting than typically developing children. AB - The current study examined whether children with autism spectrum disorder (ASD) had an indiscriminate trust bias whereby they would believe any information provided by an unfamiliar adult with whom they had no interactive history. Young school-aged children with ASD and their age- and ability-matched typically developing (TD) peers participated in a simple hide-and-seek game. In the game, an experimenter with whom the children had no previous interactive history pointed to or left a marker on a box to indicate the whereabouts of a hidden reward. Results showed that although young school-aged ASD children did not blindly trust any information provided by the unfamiliar adult, they appeared to be more trusting in the adult informant than did their age- and ability-matched TD children. PMID- 23810630 TI - Registered dietitians making a difference: early medical record documentation of estimated energy requirement in critically ill children is associated with higher daily energy intake and with use of the enteral route. AB - BACKGROUND: Establishing a caloric requirement or energy target is a recommended part of any nutrition care plan. OBJECTIVE: Our objective was to describe early documentation of a caloric requirement in critically ill children, and to determine if this would have any effect on daily energy intake and route of nutrition. DESIGN: We used a descriptive chart review of a subgroup of patients included as part of a larger, retrospective multicenter study. Variables of interest included nutritional intake information, as well as presence/absence and amount of a documented caloric requirement within 48 hours of admission. PARTICIPANTS: Five of the original 12 study centers collected the required supplementary data. Enrolled patients were those who were admitted to our pediatric intensive care unit (PICU) from January 1, 2007, through December 31, 2008; were between ages 30 days and 18 years; and had a length of stay in the PICU >= 96 hours. STATISTICAL ANALYSIS: Energy intake among patients with and without a documented caloric requirement was analyzed using Mann-Whitney U tests. The difference of receiving enteral nutrition among patients with and without a caloric requirement was analyzed using a chi(2) test. RESULTS: We studied 1,349 patients, of whom 644 (47.7%) had a caloric requirement documented (95.6% of caloric requirements were entered by a registered dietitian) in the medical record; these patients had higher total daily energy intake and were more likely to be fed enterally during the first 4 days of PICU admission than those without a documented caloric requirement (P<0.001 for all comparisons). CONCLUSIONS: Less than half of critically ill children studied had a caloric requirement documented in the medical record; when a caloric requirement was documented in the medical record of a critically ill child, a registered dietitian had likely made the note. Having a caloric requirement documented in the medical record is associated with a higher energy intake and the use of the enteral route. PMID- 23810632 TI - EP News: Clinical. PMID- 23810633 TI - Cryopreservation induces macrophage colony stimulating factor from human periodontal ligament cells in vitro. AB - Cryopreservation is used to protect vital periodontal ligaments during the transplantation of teeth. We investigated which gene products implicated in root resorption are upregulated in human periodontal ligament cells by cryopreservation, and whether cryopreservation affects the expression of macrophage-colony stimulating factor (M-CSF) in human periodontal ligament cells. We used customized microarrays to compare gene expression in human periodontal ligament cells cultured from teeth immediately after extraction and from cryopreserved teeth. Based on the result of these assays, we examined M-CSF expression in periodontal ligament cells from the immediately extracted tooth and cryopreserved teeth by real-time PCR, enzyme-linked immunosorbent assay (ELISA), Western blot analysis, and immunofluorescence. We also investigated whether human bone marrow cells differentiate into tartrate-resistant acid phosphatase (TRAP) positive osteoclasts when stimulated with RANKL (Receptor Activator for Nuclear Factor kappa B Ligand) together with any secreted M-CSF present in the supernatants of the periodontal ligament cells cultured from the various groups of teeth. M-CSF was twofold higher in the periodontal ligament cells from the rapid freezing teeth than in those from the immediately extracted group (p < 0.05). Cryopreservation increased M-CSF expression in the periodontal ligament cells when analyzed by real time PCR, ELISA, Western blotting, and immunofluorescence (p < 0.05). TRAP positive osteoclasts were formed in response to RANKL and the secreted M-CSF present in the supernatants of all the experimental groups except negative control. These results demonstrate that cryopreservation promotes the production of M-CSF, which plays an important role in root resorption by periodontal ligament cells. PMID- 23810634 TI - Corticospinal excitability during walking in humans with absent and partial body weight support. AB - OBJECTIVE: To establish changes in corticospinal excitability with absent and partial body weight support (BWS), and determine test-retest reliability of motor evoked potentials (MEPs) recordings during stepping in healthy humans. METHODS: The tibialis anterior (TA) and soleus MEPs during stepping at 0 and at 25 BWS were recorded in two experimental sessions in the same subjects. Transcranial magnetic stimulation was delivered randomly across the step cycle at 1.2*TA MEP resting threshold. The non-stimulated associated electromyogram (EMG) was subtracted from the TA and soleus MEPs at identical time windows and bins of the step cycle, and the resultant values were normalized to the maximal homologous EMG activity during stepping. The relationship between MEPs and background EMG activity was determined for each BWS level and session tested. RESULTS: The TA MEPs were facilitated at heel contact, progressively decreased during the stance phase, and facilitated throughout the swing phase of the step cycle. In contrast, the soleus MEPs were progressively increased at early-stance, depressed at the stance-to-swing transition, and remained depressed throughout the swing phase. The TA and soleus MEPs were modulated in a similar pattern across sessions at 0 and at 25 BWS, and were linearly related to the associated background EMG activity. CONCLUSIONS: These results provide evidence that reduced body weight loading does not alter the strength of corticospinal excitability, and that MEPs can be reliably recorded at different sessions during stepping in healthy humans. SIGNIFICANCE: A rehabilitation strategy to restore gait in neurological disorders utilizes BWS during stepping on a motorized treadmill. Based on our findings, the strength of corticospinal drive will not be affected negatively during stepping under conditions of partial body loading. PMID- 23810635 TI - Interictal network properties in mesial temporal lobe epilepsy: a graph theoretical study from intracerebral recordings. AB - OBJECTIVE: Graph theoretical analysis of functional connectivity data has demonstrated a small-world topology of brain networks. There is increasing evidence that the topology of brain networks is changed in epilepsy. Here we investigated the basal properties of epileptogenic networks by applying graph analysis to intracerebral EEG recordings of patients presenting with drug resistant partial epilepsies during the interictal period. METHODS: Interictal EEG activity was recorded in mesial temporal lobe of 11 patients with mesial temporal lobe epilepsy (MTLE group) and compared with a "control" group of 8 patients having neocortical epilepsies (non MTLE group) in whom depth-EEG recordings eventually showed an ictal onset outside the MTL structures. Synchronization likelihood (SL) was calculated between selected intracerebral electrodes contacts to obtain SL-weighted graphs. Mean normalized clustering index, average path length and small world index S were calculated to characterize network organization. RESULTS: Broadband SL values were higher in the MTLE group. Although a small-world pattern was found in the two groups, normalized clustering index and to a lesser extend average path length were higher in the MTLE group. CONCLUSIONS: We demonstrated a trend toward a more regular (less random) configuration of interictal epileptogenic networks. In addition S index was found to correlate with epilepsy duration. SIGNIFICANCE: These topological alterations might be a surrogate marker of human focal epilepsy and disclose some changes over time. PMID- 23810636 TI - Conflict control processing in adults with developmental dyslexia: an event related potentials study. AB - OBJECTIVE: The present study investigated the time course for processing conflict in dyslexic adults using a flanker task. METHODS: Sixteen dyslexic and 15 control adults performed a flanker task comprising congruent and incongruent trials in which participants had to indicate the direction of targets surrounded by flankers. Early negative potentials associated with orienting of attention (i.e., N1) and conflict monitoring (i.e., N2) and two positive potentials associated with conflict resolution (i.e., P3b and Nogo P3) were recorded. RESULTS: The behavioral data showed differences between incongruent and congruent trials for reaction times in both groups but for error rate only in dyslexics. As in previous studies, controls displayed greater N1, N2 and NoGo P3 as well as a smaller P3b in incongruent trials. Dyslexics lacked N1, N2 and P3b modulation whereas NoGo P3 effect was preserved. CONCLUSION: Dyslexics showed impairments in conflict monitoring and in some aspects of conflict resolution (i.e., the allocation of attentional resources) whereas other aspects of conflict resolution (i.e., the inhibition) were preserved. SIGNIFICANCE: This is the first study to investigate conflict control processing in dyslexic adults using ERPs. Results provide evidence for deficits in orienting of attention, conflict monitoring and allocation of attentional resources in dyslexics. PMID- 23810637 TI - Response to 'changes in renal resistive index after urologic interventions: were untreated kidneys really affected?'. PMID- 23810638 TI - Nanotechnology-based restorative materials for dental caries management. AB - Nanotechnology has been applied to dental materials as an innovative concept for the development of materials with better properties and anticaries potential. In this review we discuss the current progress and future applications of functional nanoparticles incorporated in dental restorative materials as useful strategies to dental caries management. We also overview proposed antimicrobial and remineralizing mechanisms. Nanomaterials have great potential to decrease biofilm accumulation, inhibit the demineralization process, to be used for remineralizing tooth structure, and to combat caries-related bacteria. These results are encouraging and open the doors to future clinical studies that will allow the therapeutic value of nanotechnology-based restorative materials to be established. PMID- 23810639 TI - Neurochemical abnormalities in unmedicated bipolar depression and mania: a 2D 1H MRS investigation. AB - The neurobiology and neurochemistry of bipolar disorder and its different phases are poorly understood. This study investigated metabolite abnormalities in both unmedicated bipolar depression as well as mania using 2D 1H magnetic resonance spectroscopy imaging (MRSI). MRSI data were obtained from 24 unmedicated bipolar disorder (BP) subjects (12 (hypo)manic (BPM)) and 12 depressed (BPD), and 20 closely matched healthy controls. 2D 1H MRSI data were collected from a 15-mm axial slice placed along the anterior commissure-posterior commissure (AC-PC) line to measure brain metabolites bilaterally in the thalamus and also the anterior and posterior cingulate cortex (ACC and PCC). Brain Lac/Cr levels were significantly increased in the BP group as a whole compared to healthy controls. Glutamate abnormalities varied across bipolar state as well as brain region: significantly increased Glx/Cr values were found in the left thalamus in BPD, but BPM had decreased Glu/Cr and Glx/Cr levels in the PCC when compared to healthy controls and decreased Glu/Cr levels even when compared to the BPD subjects group. The findings of the study point to state-related abnormalities of oxidative and glutamate metabolism in bipolar disorder. PMID- 23810640 TI - Magnetic resonance spectroscopy imaging of lactate in patients with bipolar disorder. AB - Although brain lactate levels are typically low and difficult to measure, a few previous investigators have reported that brain lactate levels are elevated in patients with bipolar disorder. The present study investigated the distribution of lactate in bipolar and healthy brains using 2D proton magnetic resonance spectroscopic imaging on a 4-Tesla magnetic resonance imaging system. Ratios of the concentration of lactate to N-acetylaspartate, and of lactate to total creatine, were significantly higher in bipolar than in healthy subjects. Lactate signals were primarily localized to the bipolar subjects' caudate and anterior cingulate cortices, components of the frontal-subcortical circuit, suggesting that affective dysregulation may be related to metabolic abnormalities in this network. PMID- 23810641 TI - Padded self-adhesive strap immobilization following newborn bladder exstrophy closure: the Utah straps. AB - PURPOSE: Several methods have been described for immobilization of the pelvis following bladder exstrophy closure, which can be challenging to manage. We hypothesized that immobilization can be significantly simplified using a modified mermaid wrap with padded Velcro(r) straps around the thigh and lower leg. MATERIALS AND METHODS: We retrospectively reviewed all patients who underwent bladder exstrophy closure in the newborn period at our institution from 1990 through 2010. Patients with cloacal exstrophy and those who underwent delayed closure due to other medical conditions were excluded. We collected data on closure technique, length of stay and complications of the primary closure as outcomes. RESULTS: A total of 20 boys and 7 girls underwent closure of classic bladder exstrophy. Followup ranged from 2 to 22 years. Seven boys underwent complete primary repair and 13 underwent staged repair. All patients had the legs stabilized with a modified wrap technique using 2 lengths of Velcro straps lined with self-adhering open cell foam pads for 3 weeks. Complications of exstrophy closure included bladder dehiscence in 1 patient (4%) and incisional hernia in 2 (7%). Following complete primary repair urethrocutaneous fistula developed in 2 patients and urethral stricture in 2. Average length of stay for patients without significant prematurity was 15 days. CONCLUSIONS: Padded Velcro strap immobilization simplifies postoperative care, provides secure fixation, decreases length of stay, and enables parents to hold and bond with the child shortly after repair. We advocate this simplified technique, which can be applied with a rate of complications that is comparable to other procedures. PMID- 23810642 TI - Air cystoscopy is superior to water cystoscopy for the diagnosis of active hematuria. AB - PURPOSE: We evaluated the clinical use of air cystoscopy, including its possible advantages and disadvantages over water cystoscopy. MATERIALS AND METHODS: Two independent observers prospectively studied consecutive patients who underwent water cystoscopy first and then air cystoscopy at our center from May to September 2012. The indication for rigid cystoscopy in the operating room was noted independently by either observer. Findings after rigid cystoscopy were correlated with the results of flexible water and air cystoscopy using the Pearson correlation and Student t-test. RESULTS: Included in the study were 57 patients with active hematuria, of whom 36 had bladder cancer, and 257 with a history of bladder tumor. The cause of bleeding was clearly identified on water cystoscopy in 22 patients (38%), including tumors in 17 and prostate bleeding in 5, and by air cystoscopy in 49 (86%), including tumors in 32 and prostate bleeding in 17. For diagnosing bladder tumors air cystoscopy had higher sensitivity than water cystoscopy (88% vs 47%, p=0.003) and similar specificity (97% vs 100%, p=0.93). In the 295 patients without hematuria there was no difference in the indication compared to that identified on rigid cystoscopy (43 vs 43, p=1.0). Water cystoscopy revealed more small papillary tumors than air cystoscopy but the number was not significantly different (76 vs 67, p=0.26). All such implants identified on water cystoscopy alone were less than 2 mm. No complication specifically related to air cystoscopy was noted. CONCLUSIONS: We found no statistical difference between water and air cystoscopy in patients without hematuria. Air cystoscopy had higher sensitivity and specificity for diagnosing active hematuria while adding almost no specific complications to the procedure. PMID- 23810643 TI - Acute effects of beer on endothelial function and hemodynamics: a single-blind, crossover study in healthy volunteers. AB - OBJECTIVE: Moderate consumption of beer is associated with lower cardiovascular (CV) risk. The goal of this study was to determine the effect of beer consumption on CV risk. To explore the underlying mechanisms, we studied the acute effects of the constituents of beer (alcohol and antioxidants), on established predictors of CV risk: endothelial function, aortic stiffness, pressure wave reflections and aortic pressure. METHODS: In a randomized, single-blind, crossover study, 17 healthy, non-smoking, men (ages 28.5 +/- 5.2 y with body mass index 24.4 +/- 2.5 kg/m(2)) consumed on three separate occasions, at least 1 wk apart: 1. 400 mL of beer and 400 mL water, 2. 800 mL of dealcoholized beer (same amount of polyphenols as in the 400 mL of beer), and 3. 67 mL of vodka and 733 mL water (same amount of alcohol as in the 400 mL of beer). Each time aortic stiffness (pulse wave velocity), pressure wave reflections (AIotax), aortic and brachial pressure (Sphygmocor device), and endothelial function (brachial flow mediated dilatation) were assessed at fast and 1 and 2 h postprandial. RESULTS: Aortic stiffness was significantly and similarly reduced by all three interventions. However, endothelial function was significantly improved only after beer consumption (average 1.33%, 95% confidence interval [CI] 0.15-2.53). Although wave reflections were significantly reduced by all three interventions (average of beer: 9.1%, dealcoholized beer: 2.8%, vodka 8.5%, all CI within limits of significance), the reduction was higher after beer consumption compared with dealcoholized beer (P = 0.018). Pulse pressure amplification (i.e., brachial/aortic) was increased by all three test drinks. CONCLUSIONS: Beer acutely improves parameters of arterial function and structure, in healthy non smokers. This benefit seems to be mediated by the additive or synergistic effects of alcohol and antioxidants and merits further investigation. PMID- 23810645 TI - Comparison of sampling methods for the detection of human rhinovirus RNA. AB - BACKGROUND: Obtaining a nasal swab (NS) from a child for human rhinovirus (HRV) RNA detection is simple and well tolerated even for repeated sampling, but only few studies have compared them qualitatively and quantitatively with other sampling methods. OBJECTIVES: Real-time PCR was used to study the stability of HRV genomes in swabs, and to compare different swabs and induced sputum specimens with nasopharyngeal aspirates (NPAs). STUDY DESIGN: Replicate swabs in a dry test tube were stored at room temperature or mailed to the laboratory before freezing, and compared to freshly frozen specimens. To compare sampling methods, paediatric patients had NPA, NS and throat swab collected. In paired sputum and NPA specimens, viral load was correlated to the amount of beta-actin mRNA. RESULTS: Specimens were stable at room temperature for at least 4 days and survived mailing without loss of HRV detectability. As compared to NPA, NS had an equal diagnostic sensitivity, with no significant quantitative difference using flocked nylon swabs and a 2.2-fold drop in the average copy number using cotton swabs. The diagnostic sensitivity of cotton swab-collected throat specimens was 97%, with a 26-fold lower mean copy number. Sputum specimens had higher HRV RNA (2.3 fold) and beta-actin mRNA (1.6-fold) copy numbers than NPAs, but there was a poor correlation between HRV RNA and beta-actin mRNA. CONCLUSION: HRV remains well detectable by PCR in specimens mailed to the laboratory. The diagnostic efficacy of NPA can be obtained with NS, quantitative comparison and patient comfort favouring flocked nylon-tipped over cotton-tipped swabs. PMID- 23810644 TI - A double-blind, placebo-controlled trial of topiramate for the treatment of comorbid cocaine and alcohol dependence. AB - BACKGROUND: Topiramate increases GABAergic activity and antagonizes the AMPA/kainate subtype of glutamate receptors. Through these mechanisms of action, topiramate may reduce alcohol and cocaine reward and may reduce alcohol and cocaine craving. Topiramate has been shown to reduce drinking in persons with alcohol dependence, and reduce relapse in stimulant-dependent patients. The current trial was intended to test the ability of topiramate to promote cocaine and alcohol abstinence among patients addicted to both drugs. METHODS: The study was a double-blind, placebo-controlled, 13-week trial involving 170 cocaine and alcohol dependent subjects. After achieving a period of cocaine and alcohol abstinence, subjects were randomized to topiramate, 300 mg daily, or identical placebo capsules. In addition, subjects received weekly individual psychotherapy. Primary outcome measures included self-reported alcohol and cocaine use, and thrice weekly urine drug screens. Secondary outcome measures included cocaine and alcohol craving, Addiction Severity Index results, cocaine withdrawal symptoms, and clinical global improvement ratings. RESULTS: Topiramate was not better than placebo in reducing cocaine use on the a priori primary outcome measure, or in reducing alcohol use. Topiramate was not better than placebo in reducing cocaine craving. Topiramate-treated subjects, compared to placebo-treated subjects, were more likely to be retained in treatment and more likely to be abstinent from cocaine during the last three weeks of the trial. Subjects who entered treatment with more severe cocaine withdrawal symptoms responded better to topiramate. DISCUSSION: Topiramate plus cognitive behavioral therapy may reduce cocaine use for some patients with comorbid cocaine and alcohol dependence. PMID- 23810646 TI - Different drug-resistant influenza A(H3N2) variants in two immunocompromised patients treated with oseltamivir during the 2011-2012 influenza season in Italy. AB - BACKGROUND: Monitoring the emergence of drug-resistant influenza variants is crucial in influenza surveillance programs. OBJECTIVES: Influenza A kinetics and the emergence of drug-resistant strains in hospitalized patients treated with oseltamivir were investigated. STUDY DESIGN: Sequential samples from oseltamivir treated and -untreated hospitalized patients in the period November 2011 through April 2012 were analyzed. NA gene was sequenced in samples from oseltamivir treated patients. Clonal analysis of the viral population was performed in patients unresponsive to treatment. Viral kinetics was determined in 24 (14 immunocompromised and 10 immunocompetent) A(H3N2)-positive patients treated and 24 (10 immunocompromised and 14 immunocompetent) untreated patients. RESULTS: Viral shedding was significantly reduced in treated vs untreated immunocompromised patients (7 vs 22 days, p<0.05, respectively). Viral load decreased significantly in immunocompromised and immunocompetent treated patients as compared with immunocompromised and immunocompetent untreated patients (0.73 and 0.93 vs 0.47 and 0.45 log10/day, p<0.05). In two (8.3%) treated patients with prolonged virus shedding, the oseltamivir resistance R292K mutation was revealed. In these patients, clonal analysis of the virus population showed the presence of additional oseltamivir-resistant mutants (E119V, N294S and deletion Del247-250). CONCLUSIONS: Oseltamivir resistance is reported for the first time in A(H3N2) virus strains during the 2011-2012 influenza season. Different drug-resistant viruses emerged in hospitalized immunocompromised patients showing prolonged virus shedding. PMID- 23810647 TI - Osteochondral scaffold reconstruction for complex knee lesions: a comparative evaluation. AB - BACKGROUND: The primary aim of the present study is to evaluate the results obtained in challenging knee lesions with the implant of an osteochondral scaffold and concomitant treatment of all comorbidities. The secondary aim is to compare the results obtained with those found when a chondral scaffold was applied. MATERIALS AND METHODS: Patients affected by complex lesions of the knee articular surface were included. "Complex cases" were defined according to the following criteria: previous clinical history of intra-articular fracture, lesion located at the tibial plateau, concurrent knee axial realignment procedure, concurrent meniscal scaffold or allograft implantation, and multiple articular surface lesions treated. Thirty-three patients were treated with the implantation of an osteochondral scaffold. The results of a homogeneous group of 23 patients previously treated and prospectively evaluated after implantation of a chondral scaffold were analyzed and compared. RESULTS: IKDC subjective score improved significantly from pre-operative (40.4+/-14.1) to 12months' follow-up (69.6+/ 17.0; p<0.0005) with a further improvement at the final evaluation at 24months (75.5+/-15.0; p=0.038). The same positive trend was confirmed by the VAS and Tegner scores. At final follow-up the group treated with the osteochondral scaffold presented a better subjective IKDC score with respect to the group treated with the chondral scaffold (p=0.034). CONCLUSIONS: A regenerative procedure to address the entire osteochondral unit, together with the treatment of all comorbidities, might offer good results also in complex cases otherwise doomed to non-biological resurfacing. LEVEL OF EVIDENCE III: Comparative study. PMID- 23810649 TI - Students teaching students: evaluation of a "near-peer" teaching experience. AB - RATIONALE AND OBJECTIVES: Teaching is an important skill. Academic physicians teach on a daily basis, and nearly all physicians occasionally teach colleagues and patients. There are generally few opportunities for medical students to learn teaching skills. We developed a novel "near-peer" teaching program in which fourth-year students cotaught first-year students. MATERIALS AND METHODS: Eighteen fourth-year students enrolled in our institution's primary senior radiology elective learned the basics of ultrasound through a series of lectures and hands-on scanning sessions. Each fourth-year student, paired with a radiology resident or attending, then cotaught a first-year anatomy small group session. After instruction, voluntary surveys were administered to assess the perceived value of the "near-peer" teaching experience. RESULTS: Seventeen of 18 (94%) and 104 of 120 (87%) administered surveys were returned by fourth- and first-year students, respectively. Sixteen (94%) and 99 (95%) of the fourth- and first-year students reported they "enjoyed" or "really enjoyed" the near-peer teaching experience. Fourteen (82%) of the fourth years perceived improvement in their teaching skills and an increase in their knowledge. Only 8 (47%) of the fourth years thought they were "helpful" or "very helpful," though 92 (88%) of the first years identified their fourth-year co-instructors as "helpful" or "very helpful." CONCLUSIONS: We piloted a novel "near-peer" program. Both senior and freshman students enjoyed the experience, and fourth years thought the session was educational for them as well. Although most fourth years did not judge themselves as helpful, first-year students overwhelmingly considered them a useful addition to the session. PMID- 23810648 TI - Patellar tendon autograft reconstruction of the anterior cruciate ligament with and without lateral plasty in advanced-stage chronic laxity. A clinical, prospective, randomized, single-blind study using passive dynamic X-rays. AB - PURPOSE: A prospective randomized study was performed to assess the influence of extra-articular ilio-tibial band tenodesis on the results of arthroscopic anterior cruciate ligament (ACL) reconstruction in patients with advanced-stage chronic anterior laxity of the knee. METHODS: Preoperatively, the two constituent groups of our series of 120 patients: group 1 (Kenneth Jones) and group 2 (Kenneth Jones+extra-articular ilio-tibial band tenodesis) were strictly comparable with regard to demographic data, activity level, interval between the injury and the operation, and even objective laxity. Through radiological measurements made by passive dynamic X-rays, we studied the evolution of the objective laxity on the two compartments (medial and lateral) of the knee before the surgery and in review. RESULTS: At 2 years follow-up, there was no significant difference between the two groups in terms of the subjective result, sports, and the overall international knee documentation committee score, however, In terms of objective laxity; Gain laxity obtained after surgery on the lateral compartment, was statistically higher in cases of extra-articular associated plasty (+29%), by cons in cases of intra-articular reconstruction alone, the laxity of the lateral compartment was poorly controlled and has continued to evolve despite the plasty of the ACL. CONCLUSION: The indication of an associated extra-articular plasty remains very discussed but we plead for an objective criterion with knowing the importance of preoperative objective laxity especially that of the lateral compartment to decide if it necessary, or not, being associated. LEVEL OF EVIDENCE: Level I, therapeutic prospective randomized trial. PMID- 23810650 TI - The 13-point Likert scale: a breakthrough in educational assessment. PMID- 23810651 TI - Multiple recurrent mutations at four human Y-chromosomal single nucleotide polymorphism sites in a 37 bp sequence tract on the ARSDP1 pseudogene. AB - The male-specific region of the human Y chromosome (MSY) is passed down clonally from father to son and mutation is the single driving force for Y-chromosomal diversification. The geographical distribution of MSY variation is non-random. Therefore, Y-chromosomal single nucleotide polymorphisms (Y-SNPs) are of forensic interest, as they can be utilized, e.g. for deducing the bio-geographical origin of biological evidence. This extra information can complement short tandem repeat data in criminal investigations. For forensic applications, however, any targeted marker has to be unequivocally interpretable. Here, we report findings for 17 samples from a population study comprising specimens from ~3700 men living in Tyrol (Austria), indicating apparent homoplasic mutations at four Y-SNP loci on haplogroup R-M412/L51/S167, R-U152/S28, and L-M20 Y chromosomes. The affected Y SNPs P41, P37, L202, and L203 mapped to a 37bp region on Yq11.21. Observing in multiple phylogenetic contexts up to four homoplasic mutations within such a short sequence tract is unlikely to result from a series of independent parallel mutations. Hence, we rather propose X-to-Y gene conversion as a more likely scenario. Practical implications arising from markers exhibiting paralogues on the Y chromosome or sites with a high propensity to recurrent mutation for database searches are addressed. PMID- 23810652 TI - Long-term outcomes of coil packing for visceral aneurysms: correlation between packing density and incidence of coil compaction or recanalization. AB - PURPOSE: To evaluate the correlation between packing density and the incidence of coil compaction or recanalization of visceral artery aneurysms (VAAs) after coil packing. MATERIALS AND METHODS: Between July 2004 and April 2012, coil packing was performed for 46 true visceral aneurysms (16 splenic, 11 pancreaticoduodenal, eight renal, six hepatic, three superior mesenteric, one right gastric, and one gastroepiploic) in 42 patients. The size and volume of the aneurysm, packing density, and the incidences of compaction and recanalization were evaluated retrospectively. RESULTS: The mean follow-up period was 37 months +/- 8 (range, 11-80 mo). The mean packing density was 19% +/- 8 (range, 5%-42%), mean aneurysm size was 19 mm +/- 8 (range, 5-40 mm), and mean volume was 4,108 mm(3) +/- 5,435 (range, 72-26,235 mm(3)). Compaction and recanalization occurred in two (4%) and 12 aneurysms (26%), respectively. The mean packing density was significantly lower in aneurysms with compaction or recanalization than in unaffected aneurysms (12% vs 22%; P = .00014). There was a significant difference in mean packing density between small (< 20 mm; 22%) and large (>= 20 mm) aneurysms (15%; P = .0045). The mean size and volume were significantly larger for coil-compacted or recanalized aneurysms than for unaffected aneurysms (P < .05). In aneurysms with a packing density of at least 24%, no compaction or recanalization occurred. CONCLUSIONS: Coil compaction or recanalization after coil packing for VAAs more often occurs after insufficient embolization with low packing density and in patients with large aneurysms. PMID- 23810653 TI - Pharmacy 2.0: a scoping review of social media use in pharmacy. AB - New "social" information and communication technologies such as social media and smartphones are allowing non-experts to access, interpret and generate medical information for their own care and the care of others. Pharmacists may also benefit from increased connectivity, but first there needs to be an understanding of how pharmacists engage with social media. A scoping review methodology was used to describe pharmacist and pharmacy student participation in social media networks and to describe the gaps in research. Three themes that emerged from reviewing social media use in pharmacy education were student engagement, boundaries and e-professionalism. For pharmacists, the themes of liability and professional use were prominent. Few pharmacy leadership organizations are providing guidance on social media but that appears to be changing. As the control of medical knowledge shifts from health professionals to the larger social community, pharmacists need to be present. Social media use and training in undergraduate programs is promising but experienced pharmacists also need to join the conversation. PMID- 23810655 TI - Whole blood rotation thromboelastometry (ROTEM(r)) profiles in subjects with non neoplastic portal vein thrombosis. AB - The coagulation pattern and the determinants of portal vein thrombosis (PVT), both in patients with and without cirrhosis, are still largely unknown. The aim of this study was to evaluate whole blood thromboelastometry profile, performed by ROTEM(r), of both cirrhotic and non-cirrhotic subjects with PVT. Two different groups were considered: i) 14 non-cirrhotic PVT patients, ii) 35 cirrhotic patients with PVT. Controls were sex- and age-matched healthy volunteers and cirrhotic subjects without PVT, respectively. ROTEM(r) assays (i.e. INTEM, EXTEM, NATEM, and FIBTEM) and traditional coagulative parameters (i.e. platelet count, PT/INR, aPTT, and fibrinogen) were performed on blood samples from each subject. There were no significant differences in ROTEM(r) profile, as for INTEM, EXTEM, and NATEM assays, and in traditional coagulative parameters, between PVT patients, both with and without cirrhosis, and control groups. Interestingly, Maximum Clot Firmness (MCF) in FIBTEM was significantly higher in non-cirrhotic PVT patients (19 mm) than in healthy volunteers (11 mm, p<0.05). The amplitude of MCF in FIBTEM revealed to be a useful tool to discriminate non-cirrhotic subjects with PVT from those without thrombotic events. Larger prospective studies are needed to evaluate the relevance of the association between the alterations of ROTEM(r) profiles and PVT in cirrhotic patients. PMID- 23810656 TI - The zinc finger transcription factor Jing is required for dendrite/axonal targeting in Drosophila antennal lobe development. AB - An important role in olfactory system development is played by transcription factors which act in sensory neurons or in their interneuron targets as cell autonomous regulators of downstream effectors such as cell surface molecules and signalling systems that control neuronal identity and process guidance. Some of these transcriptional regulators have been characterized in detail in the development of the neural elements that innervate the antennal lobe in the olfactory system of Drosophila. Here we identify the zinc finger transcription factor Jing as a cell autonomously acting transcriptional regulator that is required both for dendrite targeting of projection neurons and local interneurons as well as for axonal targeting of olfactory sensory neurons in Drosophila olfactory system development. Immunocytochemical analysis shows that Jing is widely expressed in the neural cells during postembryonic development. MARCM based clonal analysis of projection neuron and local interneuron lineages reveals a requirement for Jing in dendrite targeting; Jing loss-of-function results in loss of innervation in specific glomeruli, ectopic innervation of inappropriate glomeruli, aberrant profuse dendrite arborisation throughout the antennal lobe, as well as mistargeting to other parts of the CNS. ey-FLP-based MARCM analysis of olfactory sensory neurons reveals an additional requirement for Jing in axonal targeting; mutational inactivation of Jing causes specific mistargeting of some olfactory sensory neuron axons to the DA1 glomerulus, reduction of targeting to other glomeruli, as well as aberrant stalling of axons in the antennal lobe. Taken together, these findings indicate that Jing acts as a key transcriptional control element in wiring of the circuitry in the developing olfactory sensory system in Drosophila. PMID- 23810658 TI - Effectiveness of heat treatment to protect introduced denitrifying bacteria from eukaryotic predatory microorganisms in a pilot-scale bioreactor. AB - Bioaugmentation of bioreactor systems with pre-cultured bacteria has proven difficult because inoculated bacteria are easily eliminated by predatory eukaryotic-microorganisms. Here, we demonstrated an intermediate thermal treatment was effective for protecting introduced denitrifying bacteria from eukaryotic predators and consequently allowed the inoculated bacteria to survive longer in a denitrification reactor. PMID- 23810657 TI - Diversity of sulfur-cycle prokaryotes in freshwater lake sediments investigated using aprA as the functional marker gene. AB - The diversity of sulfate-reducing prokaryotes (SRPs) and sulfur-oxidizing prokaryotes (SOPs) in freshwater lake ecosystems was investigated by cloning and sequencing of the aprA gene, which encodes for a key enzyme in dissimilatory sulfate reduction and sulfur oxidation. To understand their diversity better, the spatial distribution of aprA genes was investigated in sediments collected from six geographically distant lakes in Antarctica and Japan, including a hypersaline lake for comparison. The microbial community compositions of freshwater sediments and a hypersaline sediment showed notable differences. The clones affiliated with Desulfobacteraceae and Desulfobulbaceae were frequently detected in all freshwater lake sediments. The SOP community was mainly composed of four major phylogenetic groups. One of them formed a monophyletic cluster with a sulfur oxidizing betaproteobacterium, Sulfuricella denitrificans, but the others were not assigned to specific genera. In addition, the AprA sequences, which were not clearly affiliated to either SRP or SOP lineages, dominated the libraries from four freshwater lake sediments. The results showed the wide distribution of some sulfur-cycle prokaryotes across geographical distances and supported the idea that metabolic flexibility is an important feature for SRP survival in low sulfate environments. PMID- 23810659 TI - Fermentation of non-sterilized fish biomass with a mixed culture of film-forming yeasts and lactobacilli and its effect on innate and adaptive immunity in mice. AB - Non-sterilized fish waste containing fish bones was fermented using combined starter cultures of film-forming yeast (Candida ethanolica) and lactic acid bacteria (LAB; Lactobacillus casei and Lactobacillus rhamnosus) in order to obtain a liquefied fermented broth without spoiling. During the entire fermentation, the number of LAB cells was maintained at a high level (6 * 10(8)-5 * 10(7) cells/ml). Although the number of general bacteria was 10(6)cell/ml after adding non-sterilized fish biomass, its growth was suppressed to be 1-3 * 10(4) cells/ml. The entire biomass had completely liquefied and the fermented broth contained all 20 alpha-amino acids composed of protein and also various kinds of minerals in abundance. The weight of mice group fed the fermented broth content feed (sample feed) for 31 days significantly increased compared with that fed no broth feed (control feed) (21.37 g vs 20.76 g (p < 0.05). No abnormal behavior and appearance were observed. All internal organs (the heart, the liver, the lung, the intestines, and the spleen) of both groups were confirmed to be normal by visual observation. In peripheral blood, the percentages of NK cells and CD8+ T cells of the mice in the sample feed group increased significantly relative to those in the control feed group (NK cells: 19% vs 11%, CD8+ T cells: 9% vs 5%, p < 0.05). In the spleen, the percentage of NK cells in the sample feed group also increased significantly compared to that in the control feed group (p < 0.05). The fermented fish biomass is expected to be effective for innate and adaptive immunity and thus fit for animal feed. PMID- 23810660 TI - [Findings of the (18)F-FDG PET-CT in a cardiac angiosarcoma complicated by a cardiac rupture]. AB - Primary malignant tumors of the heart are a rare condition. The most common type is the cardiac angiosarcoma. The symptoms of this disease are very nonspecific and can be very difficult to diagnose by conventional imaging techniques. We report the case of a male patient with cardiac angiosarcoma who also had a rare complication, this being cardiac rupture, which required the use of (18)F-FDG PET CT to demonstrate the mass malignancy and to reach a definitive diagnosis. PMID- 23810661 TI - Interaction of the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) and opioid receptors in spinal cord nociceptive reflexes. AB - AIMS: We previously observed that the adenosine A1 receptor agonist N6 cyclopentyladenosine (CPA) is a very effective antinociceptive agent on intact but not on spinalized adult rats with inflammation. Since a close connection between opioid and adenosine A1 receptors has been described, we studied a possible relationship between these systems in the spinal cord. MAIN METHODS: CPA mediated antinociception was challenged by the selective adenosine A1 receptor antagonist 8-cyclopentyl-1, 3-dimethylxanthine (CPT) and by the opioid receptor antagonist naloxone on male adult Wistar rats with carrageenan-induced inflammation. Withdrawal reflexes activated by noxious mechanical and electrical stimulation were recorded using the single motor technique in intact and sham spinalized animals. KEY FINDINGS: CPA was very effective in intact and sham spinalized rats but not in spinalized animals. Full reversal of CPA antinociception was observed with i.v. 1mg/kg of naloxone but not with 20mg/kg of CPT i.v. in responses to noxious mechanical and electrical stimulation. CPT fully prevented CPA from any antinociceptive action whereas naloxone did not modify CPA activity. These results suggest a centrally-mediated action, since CPA depressed the wind-up phenomenon which is derived of the activity of spinal cord neurons. SIGNIFICANCE: The present study provides strong in vivo evidence of an antinociceptive activity mediated by the adenosine A1 receptor system in the spinal cord, linked to an activation of opioid receptors in adult animals with inflammation. PMID- 23810662 TI - Anticipatory effects on anterior cruciate ligament loading during sidestep cutting. AB - BACKGROUND: A key to understanding potential anterior cruciate ligament injury mechanisms is to determine joint loading characteristics associated with an injury-causing event. However, direct measurement of anterior cruciate ligament loading during athletic tasks is invasive. Thus, previous research has been unable to study the association between neuromuscular variables and anterior cruciate ligament loading. Therefore, the purpose of this study was to determine the influence of movement anticipation on anterior cruciate ligament loading using a musculoskeletal modeling approach. METHODS: Twenty healthy recreationally active females were recruited to perform anticipated and unanticipated sidestep cutting. Three-dimensional kinematics and kinetics of the right leg were calculated. Muscle, joint and anterior cruciate ligament forces were then estimated using a musculoskeletal model. Dependent t-tests were conducted to investigate differences between the two cutting conditions. FINDINGS: ACL loading significantly increased during unanticipated sidestep cutting (p<0.05). This increase was primarily due to a significant increase in the sagittal plane ACL loading, which contributed 62% of the total loading. Frontal plane ACL loading contributed 26% and transverse plane ACL loading contributed 12%. INTERPRETATION: These results suggest that anterior cruciate ligament loading resulted from a multifaceted interaction of the sagittal plane shear forces (i.e., quadriceps, hamstrings, and tibiofemoral), as well as the frontal and transverse plane knee moments. Additionally, the results of this study confirm the hypothesis in the current literature that unanticipated movements such as sidestep cutting increase anterior cruciate ligament loading. PMID- 23810663 TI - Biomechanics of the heel-raise test performed on an incline in two knee flexion positions. AB - BACKGROUND: Although single-legged heel-raise cycles are often performed on an incline in different knee flexion positions to discriminate the relative contribution of the triceps surae muscles, detailed kinematic and kinetic analyses of this procedure are not available. Our study characterizes and compares the biomechanics and clinical outcomes of single-legged heel-raise cycles performed to volitional exhaustion on an incline with the knee straight (0 degrees ) and bent (45 degrees ), considering the effect of sex and age. METHODS: Fifty-six male and female volunteers, with equal numbers of younger (20 to 40 years of age) and older (40 to 60 years of age) individuals, completed a maximal number of heel-raise cycles on an incline at both nominal knee angles. Kinematic and kinetic data were acquired during testing using a 3D motion capturing system and multi-axial force plate. The impact of fatigue on performance was quantified using changes in maximal voluntary isometric contraction force and biomechanical performance of cycles. FINDINGS: Overall, participants completed three more cycles and maintained better biomechanical performance with 45 degrees than 0 degrees of knee flexion. More precisely, the decreases in maximal heel-raise heights, plantar-flexion angles at maximal height and ranges of ankle motion per cycle were all smaller with the knee bent. However, several outcomes indicated similar plantar-flexion fatigue at both knee angles. Males demonstrated a more rapid decline in peak ground reaction forces during testing; but otherwise, neither sex nor age significantly impacted outcomes. INTERPRETATION: It is concluded that the differences discerned here in the biomechanics of single legged heel-raise cycles performed at 0 degrees and 45 degrees of knee flexion to volitional exhaustion on an incline may be too small to identify in clinical settings or reflect substantial alterations in the relative contribution of the triceps surae muscles. PMID- 23810665 TI - Generation of high-producing cell lines by overexpression of cell division cycle 25 homolog A in Chinese hamster ovary cells. AB - To improve the efficiency of conventional gene amplification systems, the effect of cell cycle modification during the gene amplification process on IgG production was investigated in Chinese hamster ovary (CHO) cells. The full-length cDNA of CHO cell division cycle 25 homolog A (Cdc25A) was introduced into CHO DG44 cells and the effects of CDC25A overexpression on the cell cycle, transgene copy number and IgG productivity were examined. Both wild-type and mutated CDC25A overexpressing CHO cells showed a rapid increase in transgene copy number compared with mock cells during the gene amplification process, in both cell pools and individual clones. High-producing clones were obtained with high frequency in CDC25A-overexpressing cell pools. The specific production rate of the isolated clone CHO SD-S23 was up to 2.9-fold higher than that of mock cells in the presence of 250 nM methotrexate (MTX). Cell cycle analysis revealed that the G2 to M phase transition rate was increased ~1.5-fold in CDC25A overexpressing CHO cells under MTX treatment. Our results show the improvement of conventional gene amplification systems via cell cycle engineering at an early stage of cell line development. PMID- 23810664 TI - Effect of metformin on prostate cancer outcomes after radical prostatectomy. AB - OBJECTIVE: Recent studies have shown a relative risk reduction in the incidence of prostate cancer in patients taking metformin. However, there are conflicting findings on the effect of metformin on established cases of prostate cancer. In this study we evaluated the effect of metformin on survival and pathologic outcomes in established prostate cancer. MATERIALS AND METHODS: We retrospectively identified 12,052 patients who underwent radical prostatectomy between 1997 and 2010 at Mayo Clinic. Among these, 885 (7.3%) were diabetics, including 323 taking and 562 not taking metformin. Kaplan-Meier method was utilized to calculate rates of biochemical recurrence (BCR), systemic progression (SP), and all-cause mortality (ACM). Cox models were used to estimate the metformin hazard ratio (HR) adjusted for clinical and pathologic variables. RESULTS AND CONCLUSIONS: Median follow-up was 5.1 years. In univariate analysis, metformin HR (95% confidence intervals) was not significant for BCR (1.13 [0.84, 1.52]; P = 0.40), SP (1.37 [0.69, 2.72]; P = 0.37), and ACM (1.32 [0.84, 2.05]; P = 0.23). After adjusting for covariates of interest, the HRs for metformin among diabetics remained nonsignificant for BCR (0.91 [0.67, 1.24]; P = 0.55), SP (0.83 [0.39, 1.74]; P = 0.62); and ACM (1.16 [0.73, 1.86]; P = 0.53). No significant difference was seen between metformin users and nonusers in the final pathologic Gleason score (P = 0.33), stage (P = 0.1), rate of positive surgical margins (P = 0.29), or tumor volume (P = 0.76). Metformin use was not associated with a risk reduction in BCR, SP, or ACM. Besides presenting survival data, our results describing metformin's effect on final pathology are unique. PMID- 23810666 TI - Isolation and characterization of a mutant recombinant Saccharomyces cerevisiae strain with high efficiency xylose utilization. AB - A recombinant xylose-utilizing Saccharomyces cerevisiae strain carrying one copy of heterologous XYL1 and XYL2 from Pichia stipitis and endogenous XKS1 under the control of the TDH3 promoter in the chromosomal DNA was constructed from the industrial haploid yeast strain NAM34-4C, which showed thermotolerance and acid tolerance. The recombinant S. cerevisiae strain SCB7 grew in minimal medium containing xylose as the sole carbon source, and its shortest generation time (G(short)) was 5 h. From this strain, four mutants showing rapid growth (G(short) = 2.5 h) in the minimal medium were isolated. The mutants carried four mutations that were classified into three linkage groups. Three mutations were dominant and one mutation was recessive to the wild type allele. The recessive mutation was in the PHO13 gene encoding para-nitrophenyl phosphatase. The other mutant genes were not linked to TAL1 gene encoding transaldolase. When the mutants and their parental strain were used for the batch fermentation in a complex medium at pH 4.0 containing 30 g/L xylose at 35 degrees C with shaking (60 rpm) and an initial cell density (Absorbance at 660 nm) of 1.0, all mutants showed efficient ethanol production and xylose consumption from the early stage of the fermentation culture. In two mutants, within 24 h, 4.8 g/L ethanol was produced, and the ethanol yield was 47%, which was 1.4 times higher than that achieved with the parental strain. The xylose concentration in the medium containing the mutant decreased linearly at a rate of 1 g/L/h until 24 h. PMID- 23810667 TI - Solubilized matrix derived from decellularized liver as a growth factor immobilizable scaffold for hepatocyte culture. AB - Tissue engineering requires growth factors, cells and a scaffold to permit effective tissue regeneration. This study focused on the development of a scaffold for liver tissue engineering, because the liver is a central organ for metabolism. We aimed to develop a scaffold to promote expression of liver specific functions of hepatocytes, with a focus on immobilizing growth factors onto an organ-specific matrix for liver tissue regeneration. Solubilized extracellular matrix from decellularized liver (L-ECM) was obtained following Triton X-100 treatment and consisted of protein and polysaccharide. L-ECM was found to immobilize hepatocyte growth factor (HGF), even in the presence of albumin, with an efficiency of 75%. Additionally, the immobilized HGF on L-ECM film was stably remained in culture condition for 5 days. Immobilized HGF promoted hepatocyte migration, thus indicating that L-ECM-immobilized HGF maintained its native biological activity. Furthermore, L-ECM stimulated the expression of liver-specific functions, including albumin secretion, urea synthesis and ethoxyresorufin-O-deethylase activity, in primary rat hepatocytes cultured in growth factor-free medium. In summary, L-ECM has the potential to become an effective material in the field of regenerative medicine. PMID- 23810668 TI - Characteristics of biochar and its application in remediation of contaminated soil. AB - Biochar is produced by thermal decomposition of biomass under oxygen-limited conditions (pyrolysis), and it has received attention in soil remediation and waste disposal in recent years. The characteristics of biochar are influenced mainly by the preparation temperature and biomass. Higher pyrolysis temperature often results in the increased surface area and carbonized fraction of biochar leading to high sorption capability for pollutants. Biochars derived from various source materials show different properties of surface area, porosity and the amount of functional groups which are important concerning on the effect of biochar. Biochar has been proved to be effective in improving soil properties and increasing crop biomass. It has also been suggested that it can even enhance crop resistance to disease. Biochar has recently been used to remediate soil with both heavy metal and organic pollutants. The mechanism is electrostatic interaction and precipitation in the case of heavy metal, and the surface adsorption, partition and sequestration in the case of organic contaminants. However, application of biochar in soil has been shown to result in decreased efficacy of pesticides, which indicates a trade-off between the potentially promising effect of biochar on pesticide remediation and its negative effect on pesticide efficacy. While arguments on the effectiveness of biochar appear sound, further research is needed prior to widespread application of biochar in soil remediation. PMID- 23810669 TI - Separation and characterization of the immunostimulatory components in unpolished rice black vinegar (kurozu). AB - Unpolished rice black vinegar (kurozu), a traditional Japanese vinegar, is considered to have beneficial health effects. Kurozu is produced via a static fermentation process involving the saccharification of rice by Aspergillus oryzae, alcohol fermentation by Saccharomyces cerevisiae, and the oxidation of ethanol to acetic acid by acetic acid bacteria such as Acetobacter pasteurianus. Since this process requires about 6 months' fermentation and then over a year of aging, most of these organisms die during the production process and so microbial components, which might stimulate the innate immune system, are expected to be present in the vinegar. In this study, we investigated whether microbial components are present in kurozu, and after confirming this we characterized their immunostimulatory activities. Lyophilized kurozu stimulated murine spleen cells to produce tumor necrosis factor (TNF)-alpha, at least in part, via Toll like receptor (TLR) 2 and the Nod-like receptors NOD1 and 2. The active components associated with TLR2 activation were concentrated by Triton X-114 water phase partitioning and hydrophobic interaction chromatography on Octyl Sepharose. TLR4-activating components were also enriched by these methods. The concentrated preparation stimulated murine spleen cells to produce TNF-alpha and interferon (IFN)-gamma. These results indicate that long-term fermented kurozu contains immunostimulatory components and that the TLR2 and TLR4-activating immunostimulatory components of kurozu are hydrophobic. These components might be responsible for the beneficial health effects of kurozu. PMID- 23810670 TI - Effect of single pyrrole replacement with beta-alanine on DNA binding affinity and sequence specificity of hairpin pyrrole/imidazole polyamides targeting 5' GCGC-3'. AB - N-Methylpyrrole (Py)-N-methylimidazole (Im) polyamides are small organic molecules that can recognize predetermined DNA sequences with high sequence specificity. As many eukaryotic promoter regions contain highly GC-rich sequences, it is valuable to synthesize and characterize Py-Im polyamides that recognize GC-rich motifs. In this study, we synthesized four hairpin Py-Im polyamides 1-4, which recognize 5'-GCGC-3' and investigated their binding behavior with surface plasmon resonance assay. Py-Im polyamides 2-4 contain two, one, and one beta-alanine units, replacing the Py units of 1, respectively. The binding affinities of 2-4 to the target DNA increased 430, 390, and 610-fold, respectively, over that of 1. The association and dissociation rates of 2 to the target DNA were improved by 11 and 37-fold, respectively, compared with those of 1. Interestingly, the association and dissociation rates of 3 and 4 were higher than those of 2, even though the binding affinities of 2, 3, and 4 to the target DNA were comparable to each other. The binding affinity of 2 to DNA with a 2bp mismatch was reduced by 29-fold, compared with that to the matched DNA. Moreover, the binding affinities of 3 and 4 to the same mismatched DNA were reduced by 270 and 110-fold, respectively, indicating that 3 and 4 have greater specificities than 2 and are suitable as DNA-binding modules for engineered epigenetic regulation. PMID- 23810672 TI - A 2,6,9-hetero-trisubstituted purine inhibitor exhibits potent biological effects against multiple myeloma cells. AB - A focused library of hetero-trisubstituted purines was developed for improving the cell penetrating and biological efficacy of a series of anti-Stat3 protein inhibitors. From this SAR study, lead agent 22e was identified as being a promising inhibitor of MM tumour cells (IC50's <5MUM). Surprisingly, biophysical and biochemical characterization proved that 22e was not a Stat3 inhibitor. Initial screening against the kinome, prompted by the purine scaffold's history for targeting ATP binding pockets, suggests possible targeting of the JAK family kinases, as well for ABL1 (nonphosphorylated F317L) and AAK1. PMID- 23810671 TI - Anti-inflammatory and anti-apoptotic effects of (RS)-glucoraphanin bioactivated with myrosinase in murine sub-acute and acute MPTP-induced Parkinson's disease. AB - This study was focused on the possible neuroprotective role of (RS) glucoraphanin, bioactivated with myrosinase enzyme (bioactive RS-GRA), in an experimental mouse model of Parkinson's disease (PD). RS-GRA is one of the most important glucosinolates, a thiosaccharidic compound found in Brassicaceae, notably in Tuscan black kale seeds. RS-GRA was extracted by one-step anion exchange chromatography, further purified by gel-filtration and analyzed by HPLC. Following, pure RS-GRA was characterized by (1)H and (13)C NMR spectrometry and the purity was assayed by HPLC analysis of the desulfo-derivative according to the ISO 9167-1 method. The obtained purity has been of 99%. To evaluate the possible pharmacological efficacy of bioactive RS-GRA (administrated at the dose of 10mg/kg, ip +5MUl/mouse myrosinase enzyme), C57BL/6 mice were used in two different sets of experiment (in order to evaluate the neuroprotective effects in different phases of the disease), according to an acute (2 injections.40mg/kg MPTP) and a sub-acute (5 injections.20mg/kg MPTP) model of PD. Behavioural test, body weight changes measures and immunohistochemical localization of the main PD markers were performed and post-hoc analysis has shown as bioactive RS-GRA is able to reduce dopamine transporter degradation, tyrosine hydroxylase expression, IL-1beta release, as well as the triggering of neuronal apoptotic death pathway (data about Bax/Bcl-2 balance and dendrite spines loss) and the generation of radicalic species by oxidative stress (results focused on nitrotyrosine, Nrf2 and GFAP immunolocalization). These effects have been correlated with the release of neurotrophic factors, such as GAP-43, NGF and BDNF, that, probably, play a supporting role in the neuroprotective action of bioactive RS-GRA. Moreover, after PD-induction mice treated with bioactive RS-GRA are appeared more in health than animals that did not received the treatment both for phenotypic behaviour and for general condition (movement coordination, presence of tremors, nutrition). Overall, our results suggest that bioactive RS-GRA can protect neurons against the neurotoxicity involved in PD via an anti-apoptotic/anti inflammatory action. PMID- 23810673 TI - Synthesis and alpha-glucosidase inhibitory activity evaluation of N-substituted aminomethyl-beta-d-glucopyranosides. AB - A series of N-substituted 1-aminomethyl-beta-d-glucopyranoside derivatives was prepared. These novel synthetic compounds were assessed in vitro for inhibitory activity against yeast alpha-glucosidase and both rat intestinal alpha glucosidases maltase and sucrase. Most of the compounds displayed alpha glucosidase inhibitory activity, with IC50 values covering the wide range from 2.3MUM to 2.0mM. Compounds 19a (IC50=2.3MUM) and 19b (IC50=5.6MUM) were identified as the most potent inhibitors for yeast alpha-glucosidase, while compounds 16 (IC50=7.7 and 15.6MUM) and 19e (IC50=5.1 and 10.4MUM) were the strongest inhibitors of rat intestinal maltase and sucrase. Analysis of the kinetics of enzyme inhibition indicated that 19e inhibited maltase and sucrase in a competitive manner. The results suggest that the aminomethyl-beta-d glucopyranoside moiety can mimic the substrates of alpha-glucosidase in the enzyme catalytic site, leading to competitive enzyme inhibition. Moreover, the nature of the N-substituent has considerable influence on inhibitory potency. PMID- 23810674 TI - Investigations on synthesis and structure elucidation of novel [1,2,4]triazolo[1,2-a]pyridazine-1-thiones and their inhibitory activity against inducible nitric oxide synthase. AB - The inducible nitric oxide synthase (iNOS) is a target of great research interest due to its importance in a number of diseases, for example, septic shock and inflammatory lung diseases. A variety of 3-substituted [1,2,4]triazolo[1,2 a]pyridazine derivatives was synthesized by ring closure with hexahydropyridazine 1-carbothioamide by using aliphatic and aromatic aldehydes. The activity of the new substances was tested on the insulin-secreting rat insulinoma cell line RINm5F. iNOS was expressed through exposure to interleukin-1beta (IL-1beta) and interferon-gamma (IFN-gamma). A number of the investigated compounds were more active than the reference inhibitor aminoguanidine (AG). Structure-activity relationships showed that a phenyl substituent in position 3 is apparently essential for inhibition. PMID- 23810675 TI - Synthesis, evaluation and molecular dynamics study of some new 4-aminopyridine semicarbazones as an antiamnesic and cognition enhancing agents. AB - Some new semicarbazones of 4-aminopyridine were synthesized and evaluated for antiamnesic, cognition enhancing and anticholinesterase activities. The results illustrated a significant cognition enhancing effect on elevated plus maze model with a significant reversal of scopolamine-induced amnesia. A significant inhibition in acetycholinesterase (AChE) activity by all the synthesized compounds in specific brain regions that is, prefrontal cortex, hippocampus and hypothalamus was observed. Compound 4APi exhibited significant antiamnesic and cognition enhancing activity which was comparable with standard drug donepezil. Its enzyme kinetic study revealed a non-competitive inhibition of AChE and a competitive inhibition of butyrylcholinesterase (BChE). Docking studies predicted the binding modes of these compounds in AChE active site, which were further processed for molecular dynamics simulation for calculating binding free energies using Molecular Mechanics-Generalized Born Surface Area (MM/GBSA). All the computational study confirmed their consensual interaction with AChE justifying the experimental outcome. PMID- 23810676 TI - Oxazolopyridines and thiazolopyridines as monoamine oxidase B inhibitors for the treatment of Parkinson's disease. AB - In Parkinson's disease, the motor impairments are mainly caused by the death of dopaminergic neurons. Among the enzymes which are involved in the biosynthesis and catabolism of dopamine, monoamine oxidase B (MAO-B) has been a therapeutic target of Parkinson's disease. However, due to the undesirable adverse effects, development of alternative MAO-B inhibitors with greater optimal therapeutic potential towards Parkinson's disease is urgently required. In this study, we designed and synthesized the oxazolopyridine and thiazolopyridine derivatives, and biologically evaluated their inhibitory activities against MAO-B. Structure activity relationship study revealed that the piperidino group was the best choice for the R(1) amino substituent to the oxazolopyridine core structure and the activities of the oxazolopyridines with various phenyl rings were between 267.1 and 889.5nM in IC50 values. Interestingly, by replacement of the core structure from oxazolopyrine to thiazolopyridine, the activities were significantly improved and the compound 1n with the thiazolopyridine core structure showed the most potent activity with the IC50 value of 26.5nM. Molecular docking study showed that van der Waals interaction in the human MAO-B active site could explain the enhanced inhibitory activities of thiazolopyridine derivatives. PMID- 23810677 TI - Solid-phase synthesis of 5'-triphosphate 2'-5'-oligoadenylates analogs with 3'-O biolabile groups and their evaluation as RNase L activators and antiviral drugs. AB - 5'-Triphosphate 2'-5'-oligoadenylate (2-5A) is the central player in the 2-5A system that is an innate immunity pathway in response to the presence of infectious agents. Intracellular endoribonuclease RNase L activated by 2-5A cleaves viral and cellular RNA resulting in apoptosis. The major limitations of 2 5A for therapeutic applications is the short biological half-life and poor cellular uptake. Modification of 2-5A with biolabile and lipophilic groups that facilitate its uptake, increase its in vivo stability and release the parent 2-5A drug in an intact form offer an alternative approach to therapeutic use of 2-5A. Here we have synthesized the trimeric and tetrameric 2-5A species bearing hydrophobic and enzymolabile pivaloyloxymethyl groups at 3'-positions and a triphosphate at the 5'-end. Both analogs were able to activate RNase L and the production of the trimer 2-5A (the most active) was scaled up to the milligram scale for antiviral evaluation in cells infected by influenza virus or respiratory syncytial virus. The trimer analog demonstrated some significant antiviral activity. PMID- 23810678 TI - Prevention of postoperative recurrence with azathioprine or infliximab in patients with Crohn's disease: an open-label pilot study. AB - BACKGROUND AND AIMS: Patients with Crohn's disease (CD) often require surgery over their clinical course. However, endoscopic and clinical recurrence of disease appear respectively in up to 80% and 30% of patients after one year. Thus, a prophylactic treatment is needed to reduce the possibility of recurrence. Both azathioprine and infliximab have been demonstrated to be effective, but head to head studies have not been performed so far. Aim of this open-label prospective study was to analyse endoscopic, histological and clinical recurrence after one year of treatment with azathioprine or infliximab as postoperative therapies in CD patients with "high risk" of recurrence. METHODS: Consecutive CD patients who underwent curative ileocolonic resection were randomized (1:1) to receive infliximab (standard induction and maintenance schedule) or azathioprine (2.5 mg/kg/day) for 1 year. Co-primary endpoints were endoscopic, histological and clinical recurrence after 12 months of therapy. RESULTS: Twenty-two consecutive CD patients (15 male; median age 32 years, IQR 22-38) were enrolled after curative ileocolonic resection. Eleven patients were treated with infliximab and 11 received azathioprine. Among patients treated with azathioprine, 4/10 (40%) had endoscopic recurrence compared to 1/11 (9%) in the infliximab group (p=0.14). Eight out of 10 (80%) among those who received azathioprine had severe histological activity, whereas 2/11 (18%) in the infliximab group presented histological recurrence (p=0.008). No significant clinical differences were found between the two groups. CONCLUSIONS: Infliximab was more effective than azathioprine in reducing histological, but not endoscopic and clinical recurrence after curative ileocolonic resection in "high risk" CD patients. PMID- 23810679 TI - Non-displaced pediatric orbital fracture with displacement of the inferior rectus muscle into the maxillary sinus: a case report and review of the literature. AB - Orbital fractures occur less frequently in the pediatric population than in the adult population. Due to the elasticity of the bones that comprise the orbital floor it is not uncommon for the orbital floor to fracture and immediately self reduce. This puts the muscles and soft tissues of the orbital floor at an increased risk of entrapment. There is no exact agreement in the literature as to the ideal timing of surgical intervention for these types of injuries. However, there are many surgeons who advise early intervention in the first few days of the injury. This article describes a case of a non-displaced orbital fracture with displacement of the inferior rectus into the maxillary sinus that was treated in the first 24 h and resulted in an excellent outcome. PMID- 23810680 TI - High-density polytetrafluoroethylene membranes in guided bone and tissue regeneration procedures: a literature review. AB - Expanded polytetrafluoroethylene (e-PTFE) has been used successfully as a membrane barrier for regeneration procedures. However, when exposed to the oral cavity, its high porosity increases the risk of early infection, which can affect surgical outcomes. An alternative to e-PTFE is non-expanded and dense polytetrafluoroethylene (n-PFTE), which results in lower levels of early infection following surgical procedures. The aim of this literature review was to analyze and describe the available literature on n-PFTE, report the indications for use, advantages, disadvantages, surgical protocols, and complications. The medical databases Medline-PubMed and Cochrane Library were searched and supplemented with a hand search for reports published between 1980 and May 2012 on n-PTFE membranes. The search strategy was limited to animal, human, and in vitro studies in dental journals published in English. Twenty-four articles that analyzed the use of n-PTFE as a barrier membrane for guided tissue regeneration and guided bone regeneration around teeth and implants were identified: two in vitro studies, seven experimental studies, and 15 clinical studies. There is limited clinical and histological evidence for the use of n-PTFE membranes at present, with some indications in guided tissue regeneration and guided bone regeneration in immediate implants and fresh extraction sockets. PMID- 23810681 TI - Pre-emptive effect of dexamethasone and methylprednisolone on pain, swelling, and trismus after third molar surgery: a split-mouth randomized triple-blind clinical trial. AB - The aim of this study was to compare the effect of dexamethasone 8 mg and methylprednisolone 40 mg for the control of pain, swelling, and trismus following the extraction of impacted third molars. Sixteen healthy patients with a mean age of 20.3 (standard deviation 1.25) years received a single oral dose of either drug 1 h prior to each surgical procedure (left and right teeth). At 24, 48, and 72 h and 7 days following surgery, swelling was determined using linear measurements on the face and trismus was determined by maximal mouth opening. Postoperative pain was self-recorded by the patients using a visual analogue scale at 8-h intervals for a period of 72 h. Data analysis involved descriptive statistics and the Wilcoxon, and paired t tests (P < 0.05). Dexamethasone controlled swelling better than methylprednisolone at all postoperative evaluations (P < 0.02) and led to greater mouth opening 48 h after surgery (P = 0.029). No statistically significant difference was found between drugs with regard to pain. In conclusion, pre-emptive dexamethasone 8 mg demonstrated better control of swelling and limited mouth opening in comparison to methylprednisolone 40 mg, with no differences between drugs regarding pain control. PMID- 23810682 TI - Effects of a novel cell stabilizing reagent on DNA amplification by PCR as compared to traditional stabilizing reagents. AB - Stabilization of nucleated blood cells by cell stabilizing reagent (BCT reagent) present in the Cell-Free DNA BCT blood collection device and consequent prevention of cell-free DNA contamination by cellular DNA during sample storage and shipping have previously been reported. This study was conducted to investigate the effect of this novel cell stabilizing reagent on DNA amplification by PCR as compared to traditional cell stabilizing reagents, formaldehyde and glutaraldehyde. A 787 bp long DNA fragment from human glyceraldehydes-3-phosphate dehydrogenase (GAPDH) gene was amplified by PCR and used as model system. DNA samples and blood samples were treated with BCT reagent, 0.1% formaldehyde or 0.1% glutaraldehyde at room temperature. DNA amplification was studied using conventional and real-time quantitative PCR. Results indicate that exposure of DNA to the BCT reagent for up to 14 days had no effect on DNA amplification by PCR as compared to the untreated control DNA. However, there was statistically significant decrease in DNA amplification in the DNA samples treated with formaldehyde and glutaraldehyde. We conclude that the BCT reagent used in Cell-Free DNA BCT blood collection device to prevent cell free DNA contamination by cellular DNA had no effect on DNA amplification by PCR. PMID- 23810683 TI - H89 (N-[2-p-bromocinnamylamino-ethyl]-5-isoquinolinesulphonamide) induces autophagy independently of protein kinase A inhibition. AB - Autophagy is a degradation pathway for cytoplasmic proteins and organelles in eukaryotes. Although the mechanisms of autophagy regulation are not completely understood, the target of rapamycin (TOR) signaling pathway plays a major role in controlling the induction of autophagy. Cyclic adenosine monophosphate (cAMP)/cAMP-dependent protein kinase A (PKA) has also been shown to regulate autophagy in yeast and mammalian cells. In an effort to elucidate the role of the cAMP/PKA pathway in autophagy, we used the PKA inhibitor N-[2-p bromocinnamylamino-ethyl]-5-isoquinolinesulphonamide (H89) to treat mammalian cells. Our data demonstrated that H89 induced autophagy at 10 MUM, which is a commonly used concentration for PKA inhibition, but PKA inhibition was not involved in the induction of autophagy. The effects of cAMP on autophagy seemed to be dependent on the cell type and the culture conditions. In addition, we investigated which protein kinase was involved in H89-induced autophagy because several kinases other than PKA have been shown to be inhibited by 10 MUM of H89. There was no protein kinase largely responsible for autophagy induction, although the inhibition of Akt, which is a downstream effector protein kinase of phosphatidylinositol-3-kinase, appeared to be partially associated. Furthermore, H89-induced autophagy was independent of TOR. H89 is a widely used PKA inhibitor, but PKA-independent effects have been reported. Therefore, it is suggested that autophagy induction is a nonspecific effect of H89, and H89-induced autophagy is independent of the cAMP-PKA and the TOR pathways. PMID- 23810684 TI - Regression of endometrial implants treated with vitamin D3 in a rat model of endometriosis. AB - Endometriosis is one of the most frequent gynecological diseases. In addition to their side effects, available medical therapies may decrease fertility. Current understanding of endometriosis focuses on the role of the immune system in its pathophysiology. Recent research shed light on the immunomodulatory effect of vitamin D3. Thus, this study was designed to study the effect of vitamin D3 on regression of endometriotic implants in a rat surgical model. Vitamin D3 reduced cyst cross sectional area by 48.8%. Histologically, vitamin D treatment produced fibrosis as well as apoptosis in the stroma. The results of the present study suggest that vitamin D3 administration may have a beneficial effect in treating endometriosis. PMID- 23810685 TI - Anti-inflammatory effect of tetrahydrocoptisine from Corydalis impatiens is a function of possible inhibition of TNF-alpha, IL-6 and NO production in lipopolysaccharide-stimulated peritoneal macrophages through inhibiting NF-kappaB activation and MAPK pathway. AB - The extracts or constituents from Corydalis impatiens are known to have many pharmacological activities. Tetrahydrocoptisine (THC), a protoberberine compound from Corydalis impatiens, was found to possess a potent anti-inflammatory effect in different acute or chronic inflammation model animals. Pretreatment with THC (i.p.) inhibited the paw and ear edema in the carrageenan-induced paw edema assay and xylene-induced ear edema assay, respectively. In the lipopolysaccharide (LPS) induced systemic inflammation model, THC significantly inhibited serum tumor necrosis factor-alpha (TNF-alpha) release in mice. To clarify its possible molecular mechanisms underlying this anti-inflammatory effect, we investigated the effect of THC on LPS-induced responses in peritoneal macrophages. Our data demonstrated that THC significantly inhibited LPS-induced TNF-alpha, interleukin 6(IL-6) and nitric oxide (NO) production. THC inhibited the production of TNF alpha and IL-6 by down-regulating LPS-induced IL-6 and TNF-alpha mRNA expression. Furthermore, it attenuated the phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) and phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2) as well as the expression of nuclear factor kappa B(NF-kappaB), in a concentration-dependent manner. Taken together, our data suggest that THC is an active anti-inflammatory constituent by inhibition of TNF-alpha, IL-6 and NO production possibly via down-regulation of NF-kappaB activation, phospho-ERK1/2 and phospho-p38MAPK signal pathways. PMID- 23810686 TI - Treatment with exendin-4 improves the antidiabetic efficacy and reverses hepatic steatosis in glucokinase activator treated db/db mice. AB - The glucokinase activators improve the fasting as well as postprandial glucose control and are important investigational drugs for the treatment of diabetes. However, recent studies have implicated that continuous activation of glucokinase with a small molecule activator can increase hepatic triglycerides and the long term glucose control is not achieved. In this study, we investigated the effect of combination of glucokinase activator (GKA, Piragliatin) with GLP-1 receptor agonist exendin-4 (Ex-4) in male db/db mice. Twelve weeks combination treatment in the db/db mice resulted in a significant decrease in body weight gain, food consumption, random glucose and %HbA1c. The decrease in serum glucose and %HbA1c in combination group was more profound and significantly different than that of individual treatment (GKA or Ex-4) group. GKA treatment increased hepatic triglycerides, whereas combination of Ex-4 with GKA attenuated hepatic steatosis. The combination of GKA with Ex-4 reduced the hepatic lipid accumulation, improved the insulin sensitivity, and reduced hepatic glucose production in db/db mice. Overall, our data indicate that combination of GKA and GLP-1 receptor agonist Ex 4 improves glucose homeostasis, shows antiobesity activity, without causing harmful side effects like fatty liver. PMID- 23810687 TI - Resveratrol and grape juice differentially ameliorate cardiovascular autonomic modulation in L-NAME-treated rats. AB - Polyphenols consumption detected in red wine and grape juice may prevent or help in the treatment of hypertension. However, cardiovascular autonomic effects of polyphenols were poorly studied. Therefore, we evaluated the effects of resveratrol and grape juice treatments in hemodynamics, baroreflex sensitivity, heart rate (HR) and blood pressure (BP) variability and cardiac redox parameters. Male Wistar rats were divided in 3 groups (n=7/each) and treated for 30 days: only L-NAME-treated (60 mg/kg/day by oral gavage), L-NAME+resveratrol (L-NAME+R) and L-NAME+grape juice (L-NAME+G). BP signal was directly recorded and pulse interval (PI) and systolic arterial pressure (SAP) variability were analyzed in time and frequency domains. Baroreflex sensitivity (BRS) was determined by the alpha index. Oxidized and reduced glutathione concentrations were determined in cardiac tissue. L-NAME increased BP with no differences among groups (mean BP: L NAME=124+/-4, L-NAME+R=126+/-3 and L-NAME+G=125+/-4 mmHg). PI and SAP variability expressed by total variance were also similar among groups. However, normalized low frequency (LF) and high frequency (HF) components of PI variability were lower and higher, respectively, in both R and G-treated groups when compared to only L-NAME group. Interestingly, sympathetic modulation to the vessels (LF from SAP variability) and BRS were decreased and increased, respectively, only in L NAME+R rats. Additionally, GSH/GSSG ratios were higher in L-NAME+R and L-NAME+G than in L-NAME group. Our results indicate that resveratrol and grape juice treatments can modulate autonomic function and promote cardiac redox benefits even when nitric oxide is decreased. Moreover, resveratrol influences not only cardiac but also vascular autonomic modulation. PMID- 23810688 TI - Efficacy and safety of traditional chinese medicine (Shenqi particle) for patients with idiopathic membranous nephropathy: a multicenter randomized controlled clinical trial. AB - BACKGROUND: To compare the safety and efficacy of the traditional Chinese medicine Shenqi particle and standard therapy with prednisone and cyclophosphamide (control) in adult patients with idiopathic membranous nephropathy (IMN). STUDY DESIGN: Open-label, multicenter, parallel, randomized, controlled clinical trial. SETTING & PARTICIPANTS: From April 2008 to February 2011, a total of 190 patients with biopsy-proven IMN from 7 hospitals in China participated in the study. All patients had nephrotic syndrome with estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m(2). INTERVENTION: Shenqi particle (9.6 g 3 times per day) or prednisone (1 mg/kg/d tapering to 0.17 mg/kg/d) and cyclophosphamide (total dose of 9-12 g per square meter of body surface area) for 48 weeks. OUTCOMES: Primary outcomes included complete remission, defined as proteinuria (24-hour urine protein excretion) <=0.3 g/d, or partial remission, defined as proteinuria with protein excretion >0.3-<3.5 g/d and a 50% reduction from its peak value at 48 weeks. Secondary outcomes included serum albumin level, eGFR, doubling of serum creatinine level, end-stage renal disease, and death. RESULTS: Baseline values for proteinuria and eGFR were 5.34 +/- 2.74 g/d and 84.0 +/- 27.4 mL/min/1.73 m(2) for the Shenqi particle group and 5.33 +/- 2.47 g/d and 83.8 +/- 24.9 mL/min/1.73 m(2) for the control group, respectively. 132 patients (63 Shenqi particle group, 69 control group) completed the study. Change in urinary protein excretion in the Shenqi particle group was 3.01 (95% CI, -3.68 to -2.34) g/d, and in the control group, -3.28 (95% CI, -3.98 to -2.58) g/d; the mean difference between groups was 0.27 (95% CI, -0.70 to 1.23) g/d (P = 0.6). Changes in eGFR were 12.3 (95% CI, 4.99 to 19.6) mL/min/1.73 m(2) in the Shenqi particle group and -2.8 (95% CI, -10.32 to 4.77) mL/min/1.73 m(2) in the control group; the mean difference between groups was 15.1 (95% CI, 4.56 to 25.55) mL/min/1.73 m(2) (P = 0.005). Severe adverse events occurred in only the control group (14.5%) and included lung infection, liver injury, and pneumonia. LIMITATIONS: High rate of loss to follow-up and lack of observation period prior to the study. CONCLUSIONS: Shenqi particle may be a promising alternative therapy for adults with IMN and nephrotic syndrome. PMID- 23810689 TI - Patient care staffing levels and facility characteristics in U.S. hemodialysis facilities. AB - BACKGROUND: Higher numbers of registered nurses (RNs) per patient have been associated with improved patient outcomes in acute-care facilities. Variation in and associations of patient care staffing levels and hemodialysis facility characteristics have not been examined previously. STUDY DESIGN: Cross-sectional study using Poisson regression to examine associations between patient care staffing levels and hemodialysis facility characteristics. SETTING & PARTICIPANTS: 4,800 US hemodialysis facilities in the 2009 Centers for Medicare & Medicaid (CMS) End-Stage Renal Disease Annual Facility Survey (CMS-2744 form). PREDICTORS: Facility characteristics, including profit status, freestanding status, chain affiliation, and geographic region, adjusted for facility size, capacity, functional type, and urbanicity. OUTCOMES: Patient care staffing levels, including ratios of RNs, licensed practical nurses (LPNs), patient care technicians (PCTs), composite staff (RN + LPN + PCT), social workers, and dietitians to in-center hemodialysis patients. RESULTS: After adjusting for background facility characteristics, ratios of RNs and LPNs to patients were 35% (P < 0.001) and 42% (P < 0.001) lower, respectively, but the PCT to patient ratio was 16% (P < 0.001) higher in for-profit than nonprofit facilities (rate ratios of 0.65 [95% CI, 0.63-0.68], 0.58 [95% CI, 0.51-0.65], and 1.16 [95% CI, 1.12 1.19], respectively). Regionally, compared to the Northeast, the adjusted RN to patient ratio was 14% (P < 0.001) lower in the Midwest, 25% (P < 0.001) lower in the South, and 18% (P < 0.001) lower in the West. Even after additional adjustments, the large for-profit chains had significantly lower RN and LPN to patient ratios than the largest nonprofit chain, but a significantly higher PCT to patient ratio. Overall composite staffing levels also were lower in for-profit and chain-affiliated facilities. The patterns hold when hospital-based units were excluded. LIMITATIONS: Nursing hours were not available. Two part-time staff were counted as one full-time equivalent, which may not always be accurate. CONCLUSIONS: The significant variation in patient care staffing levels and its associations with facility characteristics warrants inclusion in future large scale hemodialysis outcomes studies. End-stage renal disease networks and hemodialysis facilities should attend to quality assurance and performance improvement initiatives that maximize licensed nurse staffing levels in hemodialysis facilities. PMID- 23810690 TI - Pathogenesis of ANCA-associated vasculitis: new possibilities for intervention. AB - The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) comprise granulomatosis with polyangiitis (GPA), primarily associated with antibodies to proteinase 3 (PR3-ANCA); microscopic polyangiitis (MPA); and eosinophilic granulomatosis with polyangiitis (EGPA), both principally associated with antibodies to myeloperoxidase (MPO-ANCA). Genetic and environmental factors are involved in their etiopathogenesis, with a possible role for silica exposure in AAVs and Staphylococcus aureus infection in GPA. The distinct associations of PR3-ANCA and MPO-ANCA with different HLA class II antigens, which are stronger than those with the associated diseases, suggest a pathogenic role for those ANCAs and indicate that GPA and MPA are different diseases. Both in vitro and in vivo experimental data have shown that MPO-ANCA can induce necrotizing small vessel vasculitis and glomerulonephritis. The additional role of the alternative pathway of complement activation has been demonstrated in human and experimental pathology. Also, T cells seem to be involved in lesion development, particularly in the kidney. Granuloma formation, as seen in PR3-ANCA-associated GPA, is not well explained by the presence of autoantibodies in experimental models. Here, T cells seem crucial. Recently obtained insights into the pathogenesis of AAVs have led to more targeted treatment of these life-threatening diseases. PMID- 23810692 TI - On peginesatide and anemia treatment in CKD. PMID- 23810693 TI - Common and uncommon CT findings in rupture and impending rupture of abdominal aortic aneurysms. AB - The rapid imaging evaluation and diagnosis of rupture and impending rupture of an abdominal aortic aneurysm (AAA) is imperative. This article describes the imaging findings of rupture, impending rupture, and other abdominal aortic abnormalities. It is important not to overlook AAA as the consequences can be life threatening. All patients who had open or endovascular repair of AAA rupture over 6 years (2008-2012) were identified from our departmental database. The computed tomography (CT) images of 99 patients were reviewed for relevant findings. The mean age of the patients was 65 years and 85% were male. PMID- 23810694 TI - Mortality reporting in interventional radiology: experience of a pilot audit with the Scottish Audit of Surgical Mortality. AB - AIM: To describe the initial pilot phase of the 2009 Scottish Audit of Surgical Mortality (SASM), which includes outcomes and difficulties that arose during any interventional radiology (IR) procedure performed on patients in this audit over an 18 month period. MATERIALS AND METHODS: Approximately 40 consultant interventional radiologists from all units in Scotland elected to participate in the audit. Each response was then peer reviewed after anonymisation of the patient and institution. If a relevant ACON (area for consideration or area of concern) was generated, this was checked by one of the other reviewers before communication with the original reporting radiologist and colleagues. There was then a right of reply by the reporting unit before formal documentation was sent out. RESULTS: Initial results were analysed after 18 months period, during which time 95 forms relating to deaths of surgical inpatients were sent to interventional radiologists identified as having been involved in an IR procedure at some time during the patient's admission. Seventy-one forms had been returned by July 2010, of which 46 had gone through the entire SASM process. From these, 10 ACONs were attributed. Anonymised case vignettes and reports from these were used as educational tools. CONCLUSION: Involvement with SASM is a useful process. Significant safety issues and learning points were identified in the pilot. The majority of ACONs identified by the audit were in patients who had undergone percutaneous biliary interventions. PMID- 23810691 TI - Association of a reduction in central obesity and phosphorus intake with changes in urinary albumin excretion: the PREMIER study. AB - BACKGROUND: Excess adiposity and dietary factors may be important determinants of urinary albumin excretion (UAE). STUDY DESIGN: Observational analysis of PREMIER, a randomized trial designed to lower blood pressure using behavioral interventions (counseling on weight loss, healthy diet, and exercise). SETTING & PARTICIPANTS: 481 participants with normal kidney function who provided adequate 24-hour urine collections at baseline and 6 months. PREDICTORS: Change in waist circumference; 24-hour urine sodium, potassium, and phosphorus excretion; and protein intake estimated from urea nitrogen. OUTCOMES & MEASUREMENTS: The primary outcome was change in log-transformed 24-hour UAE over 6 months. RESULTS: After 6 months, the proportion of individuals with UAE >=10 mg/d decreased from 18.7% to 12.7% (P < 0.001). Changes in mean waist circumference (-4.2 +/- 6.6 [SD] cm), 24 hour excretion of sodium (-28.2 +/- 71.7 mmol/d), potassium (+8.4 +/- 27.8 mmol/d), phosphorus (-27.7 +/- 314.1 mg/d), and protein intake (-1.7 +/- 19.4 g/d) were observed. After adjustment for relevant covariates, the following variables were associated significantly with reduction in ln(UAE) in separate models: decrease in waist circumference (P = 0.001), decrease in 24-hour urine phosphorus excretion (P < 0.001), and decrease in protein intake (P = 0.01). In a multivariable model including these 3 predictors, decreases in waist circumference (P = 0.002) and 24-hour urine phosphorus excretion (P = 0.03), but not change in protein intake (P = 0.5), remained associated significantly with reduction in ln(UAE). These associations remained significant even after adjustment for changes in blood pressure and insulin resistance. Baseline UAE and metabolic syndrome modified the relationship of waist circumference with ln(UAE); specifically, individuals with higher UAE and baseline metabolic syndrome experienced greater reductions in ln(UAE) from decreases in waist circumference. LIMITATIONS: Observational study with potential for confounding. CONCLUSIONS: In adults with normal kidney function, decreases in waist circumference and 24-hour urine phosphorus excretion are associated with reductions in UAE. These findings support the rationale for clinical trials to determine whether reducing dietary phosphorus intake or waist circumference could prevent chronic kidney disease or slow its progression. PMID- 23810695 TI - Macromolecular symmetric assembly prediction using swarm intelligence dynamic modeling. AB - Proteins often assemble in multimeric complexes to perform a specific biologic function. However, trapping these high-order conformations is difficult experimentally. Therefore, predicting how proteins assemble using in silico techniques can be of great help. The size of the associated conformational space and the fact that proteins are intrinsically flexible structures make this optimization problem extremely challenging. Nonetheless, known experimental spatial restraints can guide the search process, contributing to model biologically relevant states. We present here a swarm intelligence optimization protocol able to predict the arrangement of protein symmetric assemblies by exploiting a limited amount of experimental restraints and steric interactions. Importantly, within this scheme the native flexibility of each protein subunit is taken into account as extracted from molecular dynamics (MD) simulations. We show that this is a key ingredient for the prediction of biologically functional assemblies when, upon oligomerization, subunits explore activated states undergoing significant conformational changes. PMID- 23810696 TI - Energetic pathway sampling in a protein interaction domain. AB - The affinity and specificity of protein-ligand interactions are influenced by energetic crosstalk within the protein domain. However, the molecular details of such intradomain allostery are still unclear. Here, we have experimentally detected and computationally predicted interaction pathways in the postsynaptic density 95/discs large/zonula occludens 1 (PDZ)-peptide ligand model system using wild-type and circularly permuted PDZ proteins. The circular permutant introduced small perturbations in the tertiary structure and a concomitant rewiring of allosteric pathways, allowing us to describe how subtle changes may reshape energetic signaling. The results were analyzed in the context of other members of the PDZ family, which were found to contain distinct interaction pathways for different peptide ligands. The data reveal a fascinating scenario whereby several energetic pathways are sampled within one single domain and distinct pathways are activated by specific protein ligands. PMID- 23810698 TI - Structure and substrate-induced conformational changes of the secondary citrate/sodium symporter CitS revealed by electron crystallography. AB - The secondary Na+/citrate symporter CitS of Klebsiella pneumoniae is the best characterized member of the 2-hydroxycarboxylate transporter family. The recent projection structure gave insight into its overall structural organization. Here, we present the three-dimensional map of dimeric CitS obtained with electron crystallography. Each monomer has 13 a-helical transmembrane segments; six are organized in a distal helix cluster and seven in the central dimer interface domain. Based on structural analyses and comparison to VcINDY, we propose a molecular model for CitS, assign the helices, and demonstrate the internal structural symmetry. We also present projections of CitS in several conformational states induced by the presence and absence of sodium and citrate as substrates. Citrate binding induces a defined movement of a helices within the distal helical cluster. Based on this, we propose a substrate translocation site and conformational changes that are in agreement with the transport model of ''alternating access''. PMID- 23810697 TI - The asymmetric structure of an icosahedral virus bound to its receptor suggests a mechanism for genome release. AB - Simple, spherical RNA viruses have well-understood, symmetric protein capsids, but little structural information is available for their asymmetric components, such as minor proteins and their genomes, which are vital for infection. Here, we report an asymmetric structure of bacteriophage MS2, attached to its receptor, the F-pilus. Cryo-electron tomography and subtomographic averaging of such complexes result in a structure containing clear density for the packaged genome, implying that the conformation of the genome is the same in each virus particle. The data also suggest that the single-copy viral maturation protein breaks the symmetry of the capsid, occupying a position that would be filled by a coat protein dimer in an icosahedral shell. This capsomere can thus fulfill its known biological roles in receptor and genome binding and suggests an exit route for the genome during infection. PMID- 23810699 TI - Dietary soybean protein concentrate-induced intestinal disorder in marine farmed Atlantic salmon, Salmo salar is associated with alterations in gut microbiota. AB - The aquaculture industry has made substantial progress in reducing the fishmeal content of feeds for carnivorous species, driven by demand for improved sustainability and reduced cost. Soybean protein concentrate (SPC) is an attractive replacement for fishmeal, but intestinal disorders have been reported in Atlantic salmon (Salmo salar) fed these diets at high seawater temperatures, with preliminary evidence suggesting SPC induces these disorders by altering the intestinal microbiota. We compared the intestinal microbiota of marine-farmed S. salar fed experimental diets with varying levels of SPC in mid- and late-summer. Terminal restriction fragment length polymorphism (T-RFLP) and 16S rRNA clone library analysis revealed the microbiota adherent to the intestinal tract of salmon is complex at the population level, but simple and highly variable at the individual level. Temporal changes were observed with the bacterial diversity increasing in the intestinal tract in late summer. A Verrucomicrobia was the most frequently observed ribotype in early summer, whilst an Aliivibrio was the most frequently observed ribotype in late summer. Feeding SPC to salmon increased the bacterial diversity of the intestinal tract and resulted in the presence of bacteria not normally associated with marine fish (Escherichia and Propionibacterium). These diet-induced changes to the intestinal-microbiome could be ameliorated by inclusion of a prebiotic (mannan-oligosaccharide or MOS) to the diet. None of the experimental diets induced inflammation of the intestine as assessed by histopathology and expression of inflammatory cytokines. Our results support the "dysbiosis" hypothesis that SPC adversely affects the intestinal microbiota of Atlantic salmon. PMID- 23810700 TI - Prevalence and antimicrobial resistance of non-typhoidal Salmonella serotypes isolated from laying hens and broiler chicken farms in N'Djamena, Chad. AB - This study aimed at updating knowledge on the prevalence and antimicrobial resistance characteristics of Salmonella isolated from poultry in the province of N'Djamena, Chad. The results collected during this study provide the first baseline data on the prevalence of contamination by Salmonella in laying hens and broiler chicken farms in N'Djamena. All samples were collected from sixteen poultry farms over two periods of six months each: from August 2010 to January 2011 and from September 2011 to February 2012. Diagnostic methods used during this study allowed to isolate eighty four Salmonella strains, belonging to twenty seven different serotypes. The most frequent serotypes were Salmonella Colindale (19%) followed by S. Minnesota (18%) S. Havana and S. Riggil (each 6%), S. Kottbus and S. Amager (4.7%), S. Idikan, Mississipi, and Muenchen (3.6%). Other serotypes were poorly represented. The majority of these serotypes were susceptible to all antibiotics tested (CLSI Standards), except some S. Colindale isolates that exhibited a decreased susceptibility to fluoroquinolones, S. Limete resistant to three antibiotics and S. Minnesota isolates resistant to five different antimicrobial classes. The different serotypes and antibiotic resistance profiles that were observed highlight the substantial diversity of Salmonella in Chad, the contribution of avian isolates to human salmonellosis and Salmonella's capacity to colonize all types of environment worldwide. PMID- 23810701 TI - Positive immunostaining of thyroid transcription factor-1 in primary nasopharyngeal papillary adenocarcinoma. PMID- 23810702 TI - Application and development of ultrasonics in dentistry. AB - Since the 1950s, dentistry's ultrasonic instruments have developed rapidly. Because of better visualization, operative convenience, and precise cutting ability, ultrasonic instruments are widely and efficiently applied in the dental field. This article describes the development and improvement of ultrasonic instruments in several dental fields. Although some issues still need clarification, the results of previous studies indicate that ultrasonic instruments have a high potential to become convenient and efficient dental tools and deserve further development. PMID- 23810703 TI - Serum proteome predicts virological response in chronic hepatitis C genotype 1b patients treated with pegylated interferon plus ribavirin. AB - BACKGROUND/PURPOSE: Whether serum proteome changes can predict treatment response in chronic hepatitis C remains unclear. We investigated the association between serum proteome changes and virological responses in chronic hepatitis C virus genotype 1b (HCV-1b) patients treated with pegylated interferon (PegIFN) plus ribavirin (RBV). METHODS: One hundred and thirty-six HCV-1b patients who had completed a course of PegIFN plus RBV for 24 weeks, had a 24-week follow-up, and had pretreatment serum available were enrolled. These patients were divided into training and validation groups. We used matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS) for peptide profiling and ClinPro Tools version 2.0 bioinformatics software for data analysis. RESULTS: Seventy-four patients (54%) had a sustained virological response (SVR), whereas 62 did not. We identified three protein peaks in pretreatment sera where the expression levels significantly differed between SVR and non-SVR (p < 0.05). Using the class prediction tool composed of the three protein peaks, we were able to correctly predict SVR in 95% of validation group patients with sensitivity = 95%, specificity = 56.3%, positive predictive value = 73.1%, and negative predictive value = 90%. We also identified a set of 20 protein peaks where the expression levels significantly differed in pretreatment sera between patients with nonresponse (NR) and virological response (SVR plus relapse; p < 0.05). Using the class prediction tool composed of these 20 protein peaks, we were able to correctly predict virological NR in 82% of validation group patients with sensitivity = 100%, specificity = 82%, positive predictive value = 92.6%, and negative predictive value = 100%. CONCLUSION: Pretreatment serum proteome allows prediction of SVR and NR to PegIFN plus RBV treatment in HCV-1b patients. PMID- 23810704 TI - Limberg skin flap for treatment of necrosis and bleeding at haemodialysis arteriovenous angioaccess puncture sites. AB - OBJECTIVE: To assess the efficacy of a Limberg skin flap to treat non-infected necrosis and bleeding at angioaccess puncture sites. METHODS: Retrospective analysis of 40 selected (no infection, necrosis <20 mm diameter) patients (25 arteriovenous fistulae [AVF], 15 grafts) treated between 1998 and 2012 by rhomboid excision, vessel repair, and a locally rotated full-thickness Limberg skin flap together with early postoperative percutaneous transluminal angioplasty (PTA; n = 23/40). Success was defined as wound healing and angioaccess patency without complications. RESULTS: Success rates at 1 and 6 months were 96% (24/25) and 76% (19/25), respectively, for AVF, and 80% (12/15) and 40% (6/15) for arteriovenous grafts. Complications included flap necrosis (n = 2), graft thrombosis (n = 4), minor sepsis (n = 1), death (n = 2), and new puncture site necrosis (n = 3). Four patients were lost to follow-up. CONCLUSIONS: Vessel or graft repair, PTA for distal stenoses and local debridement followed by a Limberg skin flap for tissue defects prevented further bleeding and maintained vascular access patency in 25/40 (62%) patients. PMID- 23810705 TI - Commentary on "Incidence and clinical impact of stent fractures after primary stenting for TASC C and D femoropopliteal lesions at 1 year". PMID- 23810706 TI - Commentary on "A 14-year experience with aortic endograft infection: management and results". PMID- 23810708 TI - Estimating risk factors for acinetobacter bacteremia in pediatric settings. PMID- 23810707 TI - Midbrain-hindbrain malformations in patients with malformations of cortical development and epilepsy: a series of 220 patients. AB - Midbrain-hindbrain malformations (MHM) may coexist with malformations of cortical development (MCD). This study represents a first attempt to investigate the spectrum of MHM in a large series of patients with MCD and epilepsy. We aimed to explore specific associations between MCD and MHM and to compare two groups of patients: MCD with MHM (wMHM) and MCD without MHM (w/oMHM) with regard to clinical and imaging features. Two hundred and twenty patients (116 women/104 men, median age 28 years, interquartile range 20-44 years at the time of assessment) with MCD and epilepsy were identified at the Departments of Neurology and Pediatrics, Innsbruck Medical University, Austria. All underwent high resolution MRIs (1.5-T) between 01.01.2002 and 31.12.2011. Midbrain-hindbrain structures were visually assessed by three independent raters. MHM were seen in 17% (38/220) of patients. The rate of patients wMHM and w/oMHM differed significantly (p=0.004) in three categories of MCD (category I - to abnormal neuronal proliferation; category II - to abnormal neuronal migration; and category III - due to abnormal neuronal late migration/organization): MCD due to abnormal neuronal migration (31%) and organization (23%) were more commonly associated with MHM compared to those with MCD due to abnormal neuronal proliferation (9%). Extensive bilateral MCD were seen more often in patients wMHM compared to those w/oMHM (63% vs. 36%; p=0.004). In wMHM group compared to w/oMHM group there were higher rates of callosal dysgenesis (26% vs. 4%; p<0.001) and hippocampal abnormalities (52% vs. 27%; p<0.001). Patients wMHM were younger (median 25 years vs. 30 years; p=0.010) at the time of assessment and had seizure onset at an earlier age (median 5 years vs. 12 years; p=0.043) compared to those w/oMHM. Patients wMHM had higher rates of learning disability (71% vs. 38%; p<0.001), delayed developmental milestones (68% vs. 35%; p<0.001) and neurological deficits (66% vs. 47%; p=0.049) compared to those w/oMHM. The groups (wMHM and w/oMHM) did not differ in their response to antiepileptic treatment, seizure outcome, seizure types, EEG abnormalities and rate of status epilepticus. Presence of MHM in patients with MCD and epilepsy is associated with severe morphological and clinical phenotypes. PMID- 23810709 TI - Therapeutic effects of blood purification in treatment of fulminant hepatic failure. AB - OBJECTIVES: To evaluate the clinical effects of blood purification for treating fulminant hepatic failure (FHF). METHODS: Thirty-three severe FHF patients with hepatic encephalopathy (HE) above grade III were subjected to a combined blood purification treatment in addition to the comprehensive liver protection therapy. Patients underwent continuous hemofiltration on a daily basis during the daytime followed by sequential treatment with plasma exchange or hemodialysis every 2-3 days. The therapeutic effects of this treatment were evaluated. RESULTS: After treatment with blood purification, restoration of consciousness (those who abandoned the treatment without restoration of consciousness were excluded) was achieved in 6 of 8 cases (75%) in acute liver failure (ALF) group, 3 of 3 cases (100%) in subacute liver failure (SALF) group, and 9 of 14 cases (64.29%) in acute/subacute on chronic liver failure (A/SCLF) group. Of all cases, 11 patients restored consciousness after 7 days in a coma. The rate of long-term survival (those who abandoned the treatment were excluded) was 3/7 (42.86%) for ALF group, 2/2 (100%) for SALF group, and 1/11 (9.09%) for A/SCLF group. The levels of hemoglobin and platelet in peripheral blood were significantly reduced after blood purification. CONCLUSIONS: Treatment of FHF patients with daily continuous hemofiltration during the daytime is effective in treating HE and in improving health status in the early stages of the disease. Long-term prognosis also benefits from this treatment. The rate of consciousness recovery and long-term survival is highest in SALF group followed by ALF group. This treatment is less effective in A/SCLF patients. It should be noted that blood purification procedure may cause damage to blood cells. PMID- 23810710 TI - Subchronic exposure to ethyl tertiary butyl ether resulting in genetic damage in Aldh2 knockout mice. AB - Ethyl tertiary butyl ether (ETBE) is biofuel additive recently used in Japan and some other countries. Limited evidence shows that ETBE has low toxicity. Acetaldehyde (AA), however, as one primary metabolite of ETBE, is clearly genotoxic and has been considered to be a potential carcinogen. The aim of this study was to evaluate the effects of ALDH2 gene on ETBE-induced genotoxicity and metabolism of its metabolites after inhalation exposure to ETBE. A group of wild type (WT) and Aldh2 knockout (KO) C57BL/6 mice were exposed to 500ppm ETBE for 1 6h, and the blood concentrations of ETBE metabolites, including AA, tert-butyl alcohol and 2-methyl-1,2-propanediol, were measured. Another group of mice of WT and KO were exposed to 0, 500, 1750, or 5000ppm ETBE for 6h/day with 5 days per weeks for 13 weeks. Genotoxic effects of ETBE in these mice were measured by the alkaline comet assay, 8-hydroxyguanine DNA-glycosylase modified comet assay and micronucleus test. With short-term exposure to ETBE, the blood concentrations of all the three metabolites in KO mice were significantly higher than the corresponding concentrations of those in WT mice of both sexes. After subchronic exposure to ETBE, there was significant increase in DNA damage in a dose dependent manner in KO male mice, while only 5000ppm exposure significantly increased DNA damage in male WT mice. Overall, there was a significant sex difference in genetic damage in both genetic types of mice. These results showed that ALDH2 is involved in the detoxification of ETBE and lack of enzyme activity may greatly increase the sensitivity to the genotoxic effects of ETBE, and male mice were more sensitive than females. PMID- 23810711 TI - Understanding referral patterns to an epilepsy clinic: professional perceptions of factors influencing the referral of older adults. AB - PURPOSE: The number of older patients with epilepsy has been increasing steadily, however older adults have been shown to be referred less commonly to specialist epilepsy services than younger individuals. The aim of this study was to explore staff perceptions of why older adults may be under-represented in epilepsy clinics. METHOD: We conducted 19 interviews with potential referrers and staff providing services including GPs, geriatricians, neurologists, service and clinical managers and epilepsy nurses. Data were analysed using principles of thematic analysis to identify and examine recurring views and perceptions. RESULTS: Seven key factors were suggested as leading to under-referral of older adults: patient difficulties accessing hospital; patient reluctance to attend clinics; unclear referral pathway; complex differential diagnosis; gaps in referrer knowledge; the length of time since onset; and particular characteristics of older patients. CONCLUSION: While recognising the limitations of the study we believe that it provides valuable further understanding of referral patterns to specialist epilepsy services. Future studies will need to determine whether the assumptions made by the interviewees about the thoughts and wishes of older people with epilepsy were correct or not. To understand this issue more clearly, we plan to sample the views of patients directly. Of particular concern are assumptions regarding older patient's willingness to attend appointments and about the impact of seizures on the life of an older adult. PMID- 23810712 TI - No evidence for a role of the coding variant of the Toll-like receptor 4 gene in temporal lobe epilepsy. AB - PURPOSE: There is evidence that inflammatory mechanisms play a role in the pathogenesis of temporal lobe epilepsy (TLE). Coding variants in Toll-like receptor 4 (TLR4) gene have been reported to be associated with inflammatory diseases. The aim of this study was to determine whether a functional polymorphism rs4986790 in the TLR4 gene is associated with susceptibility and clinical features of TLE. METHODS: A total of 345 patients with TLE and 370 age matched controls were genotyped using TaqMan Allelic Discrimination assays, on an Applied Biosystems PCR platform. RESULTS: There was no significant difference in allele frequency or genotype of TLR4 between TLE patients and controls. Moreover, the clinical characteristics of these patients were unrelated to the presence of this polymorphism. CONCLUSION: Our data suggest that rs4986790 in the TLR4 gene is unlikely to influence significantly the risk of developing TLE or its severity. PMID- 23810713 TI - Interaction of mouse TTC30/DYF-1 with multiple intraflagellar transport complex B proteins and KIF17. AB - Intraflagellar transport (IFT) is a microtubule based system that supports the assembly and maintenance of cilia. Genetic and biochemical studies have identified two distinct complexes containing multiple proteins that are part of the IFT machinery. In this study we prepared mouse pituitary cells that expressed an epitope-tagged IFT protein and immuno-purified the IFT B complex from these cells. Mass spectrometry analysis of the isolated complex led to identification of a number of well known components of the IFT B complex. In addition, peptides corresponding to mouse tetratricopeptide repeat proteins, TTC30A1, TTC30A2 and TTC30B were identified. The mouse Ttc30A1, Ttc30A2, Ttc30B genes are orthologs of Caenorhabditis elegans dyf-1, which is required for assembly of the distal segment of the cilia. We used co-immunoprecipitation studies to provide evidence that, TTC30A1, TTC30A2 or TTC30B can be incorporated into a complex with a known IFT B protein, IFT52. We also found that TTC30B can interact with mouse KIF17, a kinesin which participates in IFT. In vitro expression in a cell-free system followed by co-immunoprecipitation also provided evidence that TTC30B can directly interact with several different IFT B complex proteins. The findings support the view that mouse TTC30A1, TTC30A2 and TTC30B can contribute to the IFT B complex, likely through interactions with multiple IFT proteins and also suggest a possible link to the molecular motor, KIF17 to support transport of cargo during IFT. PMID- 23810715 TI - Manual disfluency in drawing while producing and listening to disfluent speech. AB - This study investigated the extent to which manual fluency was associated with speech fluency in fluent speakers engaged in dual motor tasks. Thirteen right handed adult females repeatedly drew circles with a pen on a digitizer tablet under five conditions: (1) a baseline (without reading or listening to speech), (2) reading fluently, (3) reading disfluently, (4) listening to fluent speech, and (5) listening to disfluent speech. The primary measure of disfluency was normalized mean squared jerk (NJ) in the pen strokes. Pen stroke time (ST) and pressure (PP) were also measured. NJ of the circle movements was significantly increased in both the disfluent reading and the disfluent listening conditions (p<0.05), compared to the baseline condition. In the fluent listening and reading conditions, NJ in circle drawing was unaltered compared to the baseline condition. Relative to baseline, ST increased significantly (p<0.05), but to a similar extent in all experimental conditions. Significantly (p<.05) greater pen pressure were also found in the disfluent versus fluent conditions. Positive correlations (r=0.33-0.63) were found between NJ and ST across conditions. These findings demonstrate that in dual-tasks, speech fluency can influence manual fluency. This is consistent with the corpus of data showing neural connectivity between manual and speech tasks, as well between perception and production. The mirror neuron system is implicated as a mechanism involved in forging these links. PMID- 23810716 TI - Characterization of lower-limbs inter-segment coordination during the take-off extension in ski jumping. AB - Take-off, the most important phase in ski jumping, has been primarily studied in terms of spatio-temporal parameters; little is known about its motor control aspects. This study aims to assess the inter-segment coordination of the shank thigh and thigh-sacrum pairs using the continuous relative phase (CRP). In total 87 jumps were recorded from 33 athletes with an inertial sensor-based system. The CRP curves indicated that the thighs lead the shanks during the first part of take-off extension and that the shanks rotated faster at the take-off extension end. The thighs and sacrum first rotated synchronously, with the sacrum then taking lead, with finally the thighs rotating faster. Five characteristic features were extracted from the CRP and their relationship with jump length was tested. Three features of the shank-thigh pair and one of the thigh-sacrum pair reported a significant association with jump length. It was observed that athletes who achieved longer jumps had their thighs leading their shanks during a longer time, with these athletes also having a more symmetric movement between thighs and sacrum. This study shows that inter-segment coordination during the take-off extension is related to performance and further studies are necessary to contrast its importance with other ski jumping aspects. PMID- 23810714 TI - Tool manipulation knowledge is retrieved by way of the ventral visual object processing pathway. AB - Using functional Magnetic Resonance Imaging (fMRI), we find that object manipulation knowledge is accessed by way of the ventral object processing pathway. We exploit the fact that parvocellular channels project to the ventral but not the dorsal stream, and show that increased neural responses for tool stimuli are observed in the inferior parietal lobule when those stimuli are visible only to the ventral object processing stream. In a control condition, tool-preferences were observed in a superior and posterior parietal region for stimuli titrated so as to be visible by the dorsal visual pathway. Functional connectivity analyses confirm the dissociation between sub-regions of parietal cortex according to whether their principal afferent input is via the ventral or dorsal visual pathway. These results challenge the 'Embodied Hypothesis of Tool Recognition', according to which tool identification critically depends on simulation of object manipulation knowledge. Instead, these data indicate that retrieval of object-associated manipulation knowledge is contingent on accessing the identity of the object, a process that is subserved by the ventral visual pathway. PMID- 23810718 TI - Mid-upper-arm circumference and arm-to-height ratio in evaluation of overweight and obesity in Han children. AB - BACKGROUND: The purposes of this study were: (1) to analyze whether mid-upper-arm circumference (MUAC) could be used to determine overweight and obese children and to propose the optimal cutoffs of MUAC in Han children aged 7-12 years; and (2) to evaluate the feasibility and accuracy of the arm-to-height ratio (AHtR) and propose the optimal cutoffs of AHtR for identifying overweight and obesity. MATERIALS AND METHODS: In 2011, anthropometric measurements were assessed in a cross-sectional, population-based study of 2847 Han children aged 7-12 years. Overweight and obesity were defined according to the 2004 Group of China Obesity Task Force definition. The AHtR was calculated as arm circumference/height. Receiver operating characteristic curve analyses were performed to assess the accuracy of MUAC and AHtR as diagnostic tests for elevated body mass index (BMI; defined as BMI >= 85(th) percentiles). RESULTS: The accuracy levels of MUAC for identifying elevated BMI [as assessed by area under the curve (AUC)] were over 0.85 (AUC: approximately 0.934-0.975) in both genders and across all age groups. The MUAC cutoff values for elevated BMI were calculated to be approximately 18.9 23.4 cm in boys and girls. The accuracy levels of AHtR for identifying elevated BMI (as assessed by AUC) were also over 0.85 (AUC: 0.956 in boys and 0.935 in girls). The AHtR cutoff values for elevated BMI were calculated to be 0.15 in boys and girls. CONCLUSION: This study demonstrates that MUAC and AHtR are simple, inexpensive, and accurate measurements that may be used to identify overweight and obese Han children. Compared with MUAC, AHtR is a nonage-dependent index with higher applicability to screen for overweight and obese children. PMID- 23810717 TI - The HsRAD51B-HsRAD51C stabilizes the HsRAD51 nucleoprotein filament. AB - There are six human RAD51 related proteins (HsRAD51 paralogs), HsRAD51B, HsRAD51C, HsRAD51D, HsXRCC2, HsXRCC3 and HsDMC1, that appear to enhance HsRAD51 mediated homologous recombinational (HR) repair of DNA double strand breaks (DSBs). Here we model the structures of HsRAD51, HsRAD51B and HsRAD51C and show similar domain orientations within a hypothetical nucleoprotein filament (NPF). We then demonstrate that HsRAD51B-HsRAD51C heterodimer forms stable complex on ssDNA and partially stabilizes the HsRAD51 NPF against the anti-recombinogenic activity of BLM. Moreover, HsRAD51B-HsRAD51C stimulates HsRAD51 mediated D-loop formation in the presence of RPA. However, HsRAD51B-HsRAD51C does not facilitate HsRAD51 nucleation on a RPA coated ssDNA. These results suggest that the HsRAD51B HsRAD51C complex plays a role in stabilizing the HsRAD51 NPF during the presynaptic phase of HR, which appears downstream of BRCA2-mediated HsRAD51 NPF formation. PMID- 23810719 TI - "Oxygen with love" and diode laser treatment decreases comorbidity and avoidable blindness due to retinopathy of prematurity: results achieved in the past 12 years. AB - AIM: To determine whether the "Oxygen with Love" (OWL) and diode laser treatment provided in a neonatal intensive care unit has reduced the risk of avoidable blindness caused by retinopathy of prematurity (ROP) over the past decade. MATERIALS AND METHODS: A prospective observational cohort study was performed, in which 351 infants were examined for ROP. The inclusion conditions were as follows: preterm infants, birthweight <1500 g or <32 weeks' gestational age, and birth between 1 Jan 2000 to 31 August 2012. From mid-2009, the OWL program was implemented and the ventilation protocols for such infants were amended. We tested whether the incidence of unfavorable structural outcomes of ROP had decreased following these changes. RESULTS: From 2004 to 2012, the survival rates of younger children increased (p < 0.003). From 2005 to 2012, laser treatment rather than cryotherapy was applied, and the incidence of unfavorable structural outcomes of ROP fell from 13% to 5.6% (not significant). From 2009 to 2012, the incidence of ROP decreased from 55% to 29% (p < 0.002). From 1 August 2009 to 31 August 2012, there was less need for ablative treatment for premature infants, with the rate falling from 11.81% to 3.9% (p < 0.03). This improvement was significantly associated with a reduction in the number of days of intubation (p < 0.0017), lower rates of sepsis (p < 0.003), and improvements in postnatal weight gain (p < 0.0002). CONCLUSION: The introduction of the OWL program, together with lower rates of sepsis, improvements in postnatal weight gain, and the use of diode laser treatment, has reduced the incidence of unfavorable structural outcomes of ROP. PMID- 23810720 TI - Pediatric providers' attitudes toward retail clinics. AB - OBJECTIVE: To describe pediatric primary care providers' attitudes toward retail clinics and their experiences of retail clinics use by their patients. STUDY DESIGN: A 51-item, self-administered survey from 4 pediatric practice-based research networks from the midwestern US, which gauged providers' attitudes toward and perceptions of their patients' interactions with retail clinics, and changes to office practice to better compete. RESULTS: A total of 226 providers participated (50% response). Providers believed that retail clinics were a business threat (80%) and disrupted continuity of chronic disease management (54%). Few (20%) agreed that retail clinics provided care within recommended clinical guidelines. Most (91%) reported that they provided additional care after a retail clinic visit (median 1-2 times per week), and 37% felt this resulted from suboptimal care at retail clinics "most or all of the time." Few (15%) reported being notified by the retail clinic within 24 hours of a patient visit. Those reporting prompt communication were less likely to report suboptimal retail clinic care (OR 0.20, 95% CI 0.10-0.42) or disruption in continuity of care (OR 0.32, 95% CI 0.15-0.71). Thirty-six percent reported changes to office practice to compete with retail clinics (most commonly adjusting or extending office hours), and change was more likely if retail clinics were perceived as a threat (OR 3.70, 95% CI 1.56-8.76); 30% planned to make changes in the near future. CONCLUSIONS: Based on the perceived business threat, pediatric providers are making changes to their practice to compete with retail clinics. Improved communication between the clinic and providers may improve collaboration. PMID- 23810721 TI - Circulating adropin concentrations in pediatric obstructive sleep apnea: potential relevance to endothelial function. AB - OBJECTIVE: To test the hypothesis that concentrations of adropin, a recently discovered peptide that displays important metabolic and cardiovascular functions, are lower in obstructive sleep apnea (OSA), especially when associated with endothelial dysfunction. STUDY DESIGN: Age-, sex-, and ethnicity-matched children (mean age, 7.2 +/- 1.4 years) were included into 1 of 3 groups based on the presence of OSA in an overnight sleep study, and on the time to postocclusive maximal reperfusion (Tmax >45 seconds) with a modified hyperemic test. Plasma adropin concentrations were assayed using a commercial enzyme-linked immunosorbent assay kit. RESULTS: Among controls, the mean morning adropin concentration was 7.4 ng/mL (95% CI, 5.2-16.3 ng/mL). Children with OSA and abnormal endothelial function (EF) (OSA(+)/EF(+) group) had significantly lower adropin concentrations (2.7 +/- 1.1 ng/mL; n = 35) compared with matched controls (7.6 +/- 1.4 ng/mL; n = 35; P < .001) and children with OSA and normal EF (OSA(+)/EF(-) group; 5.8 +/- 1.5 ng/mL; n = 47; P < .001). A plasma adropin concentration <4.2 ng/mL reliably predicted EF status, but individual adropin concentrations were not significantly correlated with age, body mass index z score, obstructive apnea-hypopnea index, or nadir oxygen saturation. Mean adropin concentration measured after adenotonsillectomy in a subset of children with OSA (n = 22) showed an increase in the OSA(+)/EF(+) group (from 2.5 +/- 1.4 to 6.4 +/ 1.9 ng/mL; n = 14; P < .01), but essentially no change in the OSA(+)EF(-) group (from 5.7 +/- 1.3 to 6.4 +/- 1.1 ng/mL; n = 8; P > .05). CONCLUSION: Plasma adropin concentrations are reduced in pediatric OSA when endothelial dysfunction is present, and return to within normal values after adenotonsillectomy. Assessment of circulating adropin concentrations may provide a reliable indicator of vascular injury in the context of OSA in children. PMID- 23810722 TI - Maternal lipids and small for gestational age birth at term. AB - OBJECTIVE: To compare maternal lipid and lipoprotein concentrations between small for gestational age (SGA) infants and infants with normal growth born at term. STUDY DESIGN: This was a case-control study nested within a large (n = 5337) prospective multicenter cohort of pregnant women followed to delivery. SGA cases (n = 323) were all term infants with birth weight below the 10th percentile for their gestational age and sex. Controls (n = 671) were selected at random from term infants with birth weight between the 25th and 75th percentiles. Plasma samples obtained at 24-26 weeks were analyzed for lipoproteins using a recently developed nuclear magnetic resonance-based procedure that distinguishes high density lipoprotein (HDL) and low-density lipoprotein particles of different sizes. Apolipoprotein A-1 and C-II levels were analyzed using turbidimetric methods. RESULTS: Compared with controls, mothers of SGA cases had significantly higher mean concentrations of total HDL particles, medium and small HDL particles, and apolipoprotein A-1, with evidence of a dose-response relationship across quartiles of the control distribution. aORs for the highest quartiles were 2.8 (95% CI, 1.7-4.5) for total HDL particles and 3.1 (95% CI, 1.9-5.0) for apolipoprotein A-1. CONCLUSION: Our results suggest that the higher HDL particle and apolipoprotein A-1 concentrations in mothers of SGA cases may reflect defective placental transport of HDL, which could compromise cholesterol uptake by the developing fetus. PMID- 23810723 TI - Budesonide versus prednisone with azathioprine for the treatment of autoimmune hepatitis in children and adolescents. AB - OBJECTIVE: To compare the effect of budesonide vs prednisone therapy both in combination with azathioprine in pediatric patients with autoimmune hepatitis (AIH). STUDY DESIGN: Forty-six patients with AIH (11 males and 35 females) aged 9 17 years were enrolled in a 6-month, prospective, double-blind, randomized, active-controlled, multicenter phase IIb study evaluating budesonide (n = 19; 3 mg twice or 3 times daily) vs prednisone (n = 27; 40 mg/day tapered to 10 mg/day), both with azathioprine (1-2 mg/kg/day), followed by a further 6 months of open-label budesonide therapy. The primary efficacy endpoint was complete biochemical remission (normal serum alanine aminotransferase and aspartate aminotransferase levels) without predefined steroid-specific side effects. RESULTS: We observed no statistically significant difference in the percentage of patients who met the primary endpoint between the budesonide (3 of 19; 16%) and prednisone groups (4 of 27; 15%) after 6 months, nor in the percentage of patients who experienced biochemical remission (budesonide, 6 of 19 [32%]; prednisone, 9 of 27 [33%]), lack of steroid-specific side effects (budesonide, 10 of 19 [53%]; prednisone, 10 of 27 [37%]). The mean weight gain was 1.2 +/- 3.5 kg in the budesonide group and 5.1 +/- 4.9 kg in the prednisone group (P = .006). A total of 42 patients received open-label budesonide treatment for another 6 months. After 12 months, 46% of these patients achieved complete remission. CONCLUSION: Oral budesonide with azathioprine can induce and maintain remission in pediatric patients with AIH and may be considered an alternative therapy to prednisone. The treatment causes fewer side effects and does not lead to weight gain; however, it may be less effective than prednisone in inducing remission. PMID- 23810724 TI - A child with epilepsy and skin lesions. PMID- 23810726 TI - The promise and potential of continuous improvement in the pediatric intensive care unit: the evolving story from the United kingdom paediatric intensive care audit network. PMID- 23810727 TI - Online in vivo dosimetry in high dose rate prostate brchytherapy with MOSkin detectors: in phantom feasibility study. AB - MOSkin detectors were studied to perform real-time in vivo dose measurements in high dose rate prostate brachytherapy. Measurements were performed inside an urethral catheter in a gel phantom simulating a real prostate implant. Measured and expected doses were compared and the discrepancy was found to be within 8.9% and 3.8% for single MOSkin and dual-MOSkin configurations, respectively. Results show that dual-MOSkin detectors can be profitably adopted in prostate brachytherapy treatments to perform real-time in vivo dosimetry inside the urethra. PMID- 23810725 TI - Mitochondrial hepatopathies: advances in genetics, therapeutic approaches, and outcomes. PMID- 23810728 TI - Yersinia enterocolitica inactivates NK cells. AB - Natural Killer (NK) cells serve as an important source of proinflammatory cytokines early during infection. Hypothesizing that Yersinia enterocolitica might interact with and inactivate NK cells, we examined NK cell-Y. enterocolitica interactions in vitro and in vivo. Y. enterocolitica adheres to NK cells in an Invasin dependent manner and inhibits NK cell cytotoxicity and IFN gamma production induced by IL-12+IL-18 or IL-12 alone. YopP, an acetyltransferase known to inhibit MAPK and NFkappaB signaling, suppresses IL-12 and IL-12+IL-18 mediated IFN-gamma production in NK cells by inhibiting phosphorylation of Tyk2 and STAT4 in addition to MAPK. YopP inhibits induction of all genes whose expression is induced by IL-12+IL-18 in NK cells. Y. enterocolitica-mediated adherence to and inactivation of NK cells also occurs after infection in vivo. Thus, we present the first report of a bacterial pathogen inactivating NK cells, and report interaction with Tyk2-STAT4 signaling as a novel function of YopP. PMID- 23810729 TI - Laparoendoscopic single-site pyeloplasty: outcomes of an international multi institutional study of 140 patients. AB - OBJECTIVE: To report an international, multi-institutional series of laparoendoscopic single-site pyeloplasty (LESS-P) with analysis of functional outcomes. MATERIALS AND METHODS: LESS-P cases performed between October 2007 and June 2012 at 7 institutions worldwide per individual institutional protocols, entry criteria, and techniques were included. Patient characteristics, operative indications, perioperative outcomes, and postoperative follow-up were retrospectively collected and analyzed. RESULTS: The study included 140 adult patients (age 39.9 +/- 15.7 years; body mass index 24.8 +/- 4.2 kg/m(2); 15% with previous abdominal surgery) who underwent unilateral LESS-P, most of whom (94.3%) had dismembered reconstructions. Mean operative time was 202.1 +/- 47 minutes with an estimated blood loss of 61.2 +/- 44.6 mL. Robotic laparoendoscopic single site surgery was applied in 31 patients (22.1%). A single 2-3 mm accessory port was used in 44 patients (31.4%) and a single 5-12 mm accessory port was added in 9 patients (6.4%), whereas 10 patients (7.1%) were converted to conventional multiport laparoscopy. No patients required conversion to open surgery, nor were any intraoperative complications reported. Length of hospitalization was 2.4 +/- 1.6 days. The overall 90-day postoperative complication rate was 18.6%, mostly low-grade complications (Clavien I-II). With a mean follow-up of 14.0 +/- 10.8 months, 93.4% had resolution of symptoms and 94.4% had radiographic evidence demonstrating resolution of ureteropelvic junction obstruction. Assessment of drainage with diuretic nuclear renal scan provided evidence of improvement in 86.5% of patients on their first postoperative renal scan. CONCLUSION: This study highlights the most comprehensive experience with LESS-P reported to date. Outcome measures parallel those of large published series of conventional laparoscopic pyeloplasty. Despite these encouraging findings, longer follow-up is needed to determine the efficacy and durability of this approach for the treatment of ureteropelvic junction obstruction. PMID- 23810731 TI - Clinical decision support systems: need for evidence, need for evaluation. PMID- 23810732 TI - Protective function of nitric oxide on marine phytoplankton under abiotic stresses. AB - As an important signaling molecule, nitric oxide (NO) plays diverse physiological functions in plants, which has gained particular attention in recent years. We investigated the roles of NO in the growth of marine phytoplankton Platymonas subcordiforms and Skeletonema costatum under abiotic stresses. The growth of these two microalgae was obviously inhibited under non-metal stress (sodium selenium, Na2SeO3), heavy metal stress (lead nitrate, Pb(NO3)2), pesticide stress (methomyl) and UV radiation stress. After the addition of different low concentrations of exogenous NO (10(-10)-10(-8) mol L(-1)) twice each day during cultivation, the growth of these two microalgae was obviously promoted. Results showed that NO could relieve the oxidative stresses to protect the growth of the two microalgae. For different environmental stress, there is a different optimum NO concentration for marine phytoplankton. It is speculated that the protective effect of NO is related to its antioxidant ability. PMID- 23810733 TI - Biomimetic mineralisation of phosphorylated dentine by CPP-ACP. AB - OBJECTIVES: Casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) has the potential to induce the biomimetic mineralisation of dentine collagen fibrils. This study aimed to demonstrate in vitro the ability of CPP-ACP to form apatite crystals on phosphorylated dentine collagen fibrils. METHODS: Dentine slices with a 2-mm thickness were prepared from sound human third molars. The slices were etched with phosphoric acid to expose the collagen fibres. Sodium trimetaphosphate was then used to phosphorylate the exposed collagen fibres. CPP ACP paste was topically applied to the surface of the phosphorylated slices, which were then immersed in a metastable calcium phosphate remineralising solution and incubated at 37 degrees C for 10 days. The CPP-ACP paste and the remineralising solution were replaced every two days. Phosphorylated dentine slices without a CPP-ACP application and non-phosphorylated dentine slices with a CPP-ACP application were prepared and used for comparison. The slices were examined using scanning electron microscope (SEM), diffuse reflectance-Fourier transform infrared spectroscopy (DR-FTIR) and X-ray diffraction (XRD). RESULTS: The SEM results revealed the presence of intrafibrillar and interfibrillar crystal nucleation and growth along the phosphorylated dentine collagen fibres. The DR-FTIR and XRD confirmed that the crystals were hydroxyapatite. No apatite crystal nucleation and growth were observed in either the slices that had no non phosphorylation or those without CPP-ACP application. CONCLUSIONS: CPP-ACP can induce the biomimetic mineralisation of dentine through apatite formation along and between the phosphorylated dentine collagen fibres. CLINICAL SIGNIFICANCE: The in vitro study imitated the application of CPP-ACP to exposed dentine tooth surfaces in the mouth. This could lead to the development of a new therapeutic technique for the treatment of tooth hypersensitivity. PMID- 23810734 TI - Effect of electric arc, gas oxygen torch and induction melting techniques on the marginal accuracy of cast base-metal and noble metal-ceramic crowns. AB - OBJECTIVES: The aim of this study was to identify the most appropriate alloy composition and melting technique by evaluating the marginal accuracy of cast metal-ceramic crowns. METHODS: Seventy standardised stainless-steel abutments were prepared to receive metal-ceramic crowns and were randomly divided into four alloy groups: Group 1: palladium-gold (Pd-Au), Group 2: nickel-chromium-titanium (Ni-Cr-Ti), Group 3: nickel-chromium (Ni-Cr) and Group 4: titanium (Ti). Groups 1, 2 and 3 were in turn subdivided to be melted and cast using: (a) gas oxygen torch and centrifugal casting machine (TC) or (b) induction and centrifugal casting machine (IC). Group 4 was melted and cast using electric arc and vacuum/pressure machine (EV). All of the metal-ceramic crowns were luted with glass-ionomer cement. The marginal fit was measured under an optical microscope before and after cementation using image analysis software. All data was subjected to two-way analysis of variance (ANOVA). Duncan's multiple range test was run for post-hoc comparisons. The Student's t-test was used to investigate the influence of cementation (alpha=0.05). RESULTS: Uncemented Pd-Au/TC samples achieved the best marginal adaptation, while the worst fit corresponded to the luted Ti/EV crowns. Pd-Au/TC, Ni-Cr and Ti restorations demonstrated significantly increased misfit after cementation. CONCLUSIONS: The Ni-Cr-Ti alloy was the most predictable in terms of differences in misfit when either torch or induction was applied before or after cementation. Cemented titanium crowns exceeded the clinically acceptable limit of 120MUm. CLINICAL SIGNIFICANCE: The combination of alloy composition, melting technique, casting method and luting process influences the vertical seal of cast metal-ceramic crowns. An accurate use of the gas oxygen torch may overcome the results attained with the induction system concerning the marginal adaptation of fixed dental prostheses. PMID- 23810735 TI - CD4(+)FoxP3(+) T regulatory cells in drug-susceptible and multidrug-resistant tuberculosis. AB - Regulatory T cells (Treg) increase in active tuberculosis (TB). However, whether Treg-mediated immune suppression affect the susceptibility to active TB or development of multidrug-resistant (MDR) TB is not yet clear. We compared circulatory Treg frequencies in drug susceptible (DS) and MDR TB before and after anti-TB treatment. Circulatory Treg frequencies were measured in blood samples from 33 DS TB, 7 mycobacterial culture-positive active MDR TB, 16 stable MDR TB who had been culture negative for at least 6 months, and 14 healthy controls before and after treatment. Treg frequency was measured by flow cytometry using cell-surface marker CD4 and intracellular marker FoxP3. Treg frequency was higher in DS TB and active MDR TB patients than in healthy controls (p < 0.05), with no significant difference between the former. Treg frequency was higher in patients with sputum acid-fast bacilli smear-positive TB than in patients with smear negative TB, but the increase did not correlate with the radiologic extent of TB or presence of a cavity. After successful treatment, Treg decreased to control levels in DS TB and MDR TB patents. The pattern of change, in which Treg frequency increased during active infection and normalized to control levels after successful treatment, was similar in DS and MDR TB patients. PMID- 23810736 TI - What are the neurocognitive correlates of basic self-disturbance in schizophrenia?: Integrating phenomenology and neurocognition. Part 1 (Source monitoring deficits). AB - Phenomenological research indicates that disturbance of the basic sense of self may be a core phenotypic marker of schizophrenia spectrum disorders. Basic self disturbance refers to disruption of the sense of ownership of experience and agency of action and is associated with a variety of anomalous subjective experiences. Little is known about the neurocognitive underpinnings of basic self disturbance. In these two theoretical papers (of which this is Part 1), we review some recent phenomenological and neurocognitive research and point to a convergence of these approaches around the concept of self-disturbance. Specifically, we propose that subjective anomalies associated with basic self disturbance may be associated with: 1. source monitoring deficits, which may contribute particularly to disturbances of "ownership" and "mineness" (the phenomenological notion of presence or self-affection) and 2. aberrant salience, and associated disturbances of memory, prediction and attention processes, which may contribute to hyper-reflexivity, disturbed "grip" or "hold" on the perceptual and conceptual field, and disturbances of intuitive social understanding ("common sense"). In this paper (Part 1) we focus on source monitoring deficits. Part 2 (this issue) addresses aberrant salience. Empirical studies are required in a variety of populations in order to test these proposed associations between phenomenological and neurocognitive aspects of self-disturbance in schizophrenia. An integration of findings across the phenomenological and neurocognitive "levels" would represent a significant advance in the understanding of schizophrenia and possibly enhance early identification and intervention strategies. PMID- 23810737 TI - Lack of secondary pathology in the thalamus after focal cerebral ischemia in nonhuman primates. AB - Remote regions such as the thalamus undergo secondary degeneration after cerebral ischemia. In rodents, the pathology in the thalamus is characterized by a robust inflammatory reaction, beta-amyloid (Abeta) accumulation and calcification. Here we studied whether nonhuman primates subjected to middle cerebral artery occlusion (MCAO) display a similar pathology. Common marmosets (n=4) were subjected to transient MCAO for 3 h. Two sham-operated animals served as controls. All animals underwent MRI examination (T2) on postoperative day 7 to assess the location of the infarct. After a 45-day follow-up period, the animals were perfused for histology to evaluate beta-amyloid and calcium load in the peri infarct regions and the thalamus. There was no Abeta or calcium staining in the sham-operated marmosets. The contralateral hemisphere was devoid of Abeta and calcium staining in MCAO animals, except calcium staining in one animal. In the ipsilateral cortex, patchy groups of Abeta-positive cells were observed. Occasional calcium staining was observed in the peri-infarct regions, lesion core, and remote regions such as the substantia nigra. The most important, the thalamus was devoid of any sign of Abeta and calcium aggregation in MCAO animals. Staining for glial fibrillary acidic protein (GFAP) showed marked astrogliosis in the ipsilateral cortex and thalamus. In conclusion, our preliminary study in marmosets did not identify Abeta and calcium pathology in the thalamus following cerebral ischemia as shown in rodents. PMID- 23810738 TI - Increased excitability in serotonin neurons in the dorsal raphe nucleus in the 6 OHDA mouse model of Parkinson's disease. AB - The serotonin system has recently been demonstrated to have an important role in Parkinson's disease, in particular in response to L-DOPA treatment. It has been shown that central serotonin neurons convert peripherally administered L-DOPA to dopamine. Striatal dopamine release by these serotonin neurons is believed to be a main player in the induction of the troublesome L-DOPA-induced dyskinesias, which develops in patients within 5-10 years after the use of the drug. Electrophysiological characterization of midbrain dopamine neurons and dorsal raphe nucleus serotonin neurons has further revealed close interaction between these two cells groups. These data indicate that the loss of dopamine neurons and fibers alone and following L-DOPA treatment might change the electrophysiological properties of the serotonin neurons in the dorsal raphe nucleus. Although in vivo data have indicated changes in firing properties following dopamine depletion by 6-OHDA, the data have been conflicting. We therefore investigated the electrophysiological properties of serotonin neurons following dopamine degeneration and L-DOPA treatment in the 6-OHDA-lesion mouse model of Parkinson's disease using in vitro patch clamp technique in acute slices. We found that 6 OHDA lesions alone significantly increased spontaneous and maximal firing discharges of serotonin neurons, which were accompanied by respective changes in the action potential waveforms. L-DOPA treatment did not reverse this increase in spontaneous frequency, but partially normalized AP properties. Our data demonstrate that the intrinsic excitability of serotonin neurons is altered in response to both dopamine degeneration as well as subsequent L-DOPA treatment. This lesion- and treatment-induced plasticity of the serotonin might contribute to its role in L-DOPA induced dyskinesia. PMID- 23810739 TI - New hope for prevention of preterm delivery. AB - This Commentary highlights the article by Sundaram et al that described a novel use of a common organic solvent, N,N-dimethylacetamide (DMA) in preventing inflammation-mediated preterm birth. PMID- 23810741 TI - Salmonella spp. fecal shedding detected by real-time PCR in competing endurance horses. AB - Fecal shedding of Salmonella spp. was recently documented in 8% of endurance horses presented to equine referral centers for colic. Previous studies have documented fecal shedding of Salmonella spp. in as few as 0.8% of the general horse population, although horses with colic appear to be at higher risk. Fecal Salmonella spp. shedding before and after endurance horse competitions has not been evaluated. Fecal samples were collected from 204 horses during three separate 100 mile endurance competitions. Following incubation in selenite broth, 289 fecal samples were tested by real-time PCR analysis for Salmonella spp. Only one post-race sample (0.5% tested positive for Salmonella spp. in this study and no pre-race sample was available from this horse. Results suggest that fecal shedding of Salmonella spp. is uncommon in endurance horses during competitions. Further research is needed to confirm and identify the source of Salmonella spp. infection in endurance horses with colic requiring treatment at referral centers. PMID- 23810742 TI - Comparison of intrarectal ozone, ozone administered in acupoints and meloxicam for postoperative analgesia in bitches undergoing ovariohysterectomy. AB - Since all analgesics currently available for use in dogs have been associated with some adverse effects, the search for an effective analgesic that does not cause harm is important. This study investigated the postoperative analgesic effects of ozone administered either intrarectally or into acupoints in bitches undergoing ovariohysterectomy (OH). Twenty-four healthy adult bitches were randomly assigned to one of the three treatments 10 min after sedation, as follows: 0.2mg/kg of intramuscular (IM) meloxicam (M); rectal insufflation of 10 mL of 30 MUg/mL ozone (OI), or acupoint injection of 0.5 mL ozone (30 MUg/mL; OA). Following sedation with acetylpromazine, anaesthesia was induced with propofol and fentanyl and maintained with isoflurane/O2. Pain was assessed using the modified Glasgow pain scale (MGPS) and the visual analogue scale (VAS) on the day before surgery, before anaesthesia, and at 1, 2, 4, 6, 8, 12 and 24h after surgery. Rescue analgesia was performed using 0.5mg/kg of morphine IM if MGPS was >3.33 points. No statistically significant differences in pain scales were found among the three analgesic protocols or the time points in each group (P>0.05). Two dogs treated with OA required rescue analgesia. Meloxicam, rectal insufflation of ozone and ozone injected into acupoints provided satisfactory analgesia for 24h in bitches undergoing elective OH. Ozone had no measurable adverse effects and is an alternative option to promote pain relief. PMID- 23810743 TI - In vitro pharmacodynamics of gamithromycin against Mycoplasma mycoides subspecies mycoides Small Colony. AB - Mycoplasma mycoides mycoides Small Colony (MmmSC) is the causative agent of contagious bovine pleuropneumonia (CBPP), which is responsible for major economic losses in sub-Saharan Africa. Current control relies on live attenuated vaccines, which are of limited efficacy, and antimicrobials are now being assessed as an alternative or adjunct to vaccination. The objective of this study was to determine the in vitro effector kinetics of the macrolide antimicrobial, gamithromycin, against MmmSC in artificial medium and adult bovine serum. Furthermore, it was determined if any differences in gamithromycin activity between these two matrices were mirrored by the older macrolides, tylosin and tilmicosin. Minimum inhibitory concentrations (MICs) for gamithromycin, tylosin and tilmicosin against MmmSC strains B237 and Tan8 were determined in artificial medium and serum. Time-kill curves were constructed at concentrations corresponding to multiples of the MIC for all three macrolides in artificial medium and for gamithromycin in serum. Data were fitted to sigmoid Emax models. Post-antibiotic effects (PAE) were established by exposing strain B237 to antimicrobials at 10* MIC for 1h and monitoring mycoplasma growth thereafter. MICs for gamithromycin, tylosin and tilmicosin were 64-, 8- and 64-fold lower, respectively, in serum than in artificial medium at an inoculum size of 10(6)cfu/mL B237. A similar pattern emerged for Tan8. All three antimicrobials were mycoplasmastatic with maximum effects of -0.44, -0.32 and -0.49log10(cfu/mL) units for gamithromycin, tylosin and tilmicosin, respectively, against B237 in artificial medium. Tylosin and tilmicosin elicited longer PAEs than gamithromycin. In conclusion, gamithromycin, tylosin and tilmicosin all demonstrated in vitro efficacy against MmmSC and represent potential candidates for clinical studies to assess their therapeutic effect against CBPP. PMID- 23810744 TI - Arthroscopic optical coherence tomography provides detailed information on articular cartilage lesions in horses. AB - Arthroscopy enables direct inspection of the articular surface, but provides no information on deeper cartilage layers. Optical coherence tomography (OCT), based on measurement of reflection and backscattering of light, is a diagnostic technique used in cardiovascular surgery and ophthalmology. It provides cross sectional images at resolutions comparable to that of low-power microscopy. The aim of this study was to determine if OCT is feasible for advanced clinical assessment of lesions in equine articular cartilage during diagnostic arthroscopy. Diagnostic arthroscopy of 36 metacarpophalangeal joints was carried out ex vivo. Of these, 18 joints with varying degrees of cartilage damage were selected, wherein OCT arthroscopy was conducted using an OCT catheter (diameter 0.9 mm) inserted through standard instrument portals. Five sites of interest, occasionally supplemented with other locations where defects were encountered, were arthroscopically graded according to the International Cartilage Repair Society (ICRS) classification system. The same sites were evaluated qualitatively (ICRS classification and morphological description of the lesions) and quantitatively (measurement of cartilage thickness) on OCT images. OCT provided high resolution images of cartilage enabling determination of cartilage thickness. Comparing ICRS grades determined by both arthroscopy and OCT revealed poor agreement. Furthermore, OCT visualised a spectrum of lesions, including cavitation, fibrillation, superficial and deep clefts, erosion, ulceration and fragmentation. In addition, with OCT the arthroscopically inaccessible area between the dorsal MC3 and P1 was reachable in some cases. Arthroscopically guided OCT provided more detailed and quantitative information on the morphology of articular cartilage lesions than conventional arthroscopy. OCT could therefore improve the diagnostic value of arthroscopy in equine orthopaedic surgery. PMID- 23810745 TI - Severity of emphysema predicts location of lung cancer and 5-y survival of patients with stage I non-small cell lung cancer. AB - BACKGROUND: Non-small cell lung cancer (NSCLC) has a predilection to occur in emphysematous lungs. The relation between the regional severity of emphysema and the location of NSCLC as well as long-term survival has been poorly studied. METHODS: Computed tomography (CT) scans of 153 patients with biopsy-proven stage I NSCLC diagnosed between 2001 and 2006 were assigned an emphysema severity score in four regions of the lung. The location of the cancer was compared with the severity of emphysema in that region. Survival was also analyzed. RESULTS: Thirty nine patients had no emphysema documented on CT scan and 114 did. The most common location of cancer was the right upper quadrant with 37% of cancers, followed by the left upper quadrant with 23% of cancers. Twenty-two percent of the cancers occurred in the right lower quadrant, and only 12% were in the left lower quadrant. There is a strong association for cancer being located in the area with the highest degree of emphysema (P < 0.001). Emphysema severity score was also associated with long-term survival (log-rank P = 0.03). CONCLUSIONS: The regional severity of emphysema assessed via a visual scale using CT appears to be associated with the location of lung cancer and is an independent predictor of long-term survival. PMID- 23810746 TI - Microarray analysis of liver gene expression before and after induced hemorrhagic shock in a rat model. AB - BACKGROUND: Cell proliferation, renewal, and apoptosis factors are related to hemorrhagic shock (HS) survival. OBJECTIVE: Hepatic gene expression before and 24 h after induced HS were compared. METHODS: Male Sprague-Dawley rats aged 8-9 wk (n = 11) were subjected to blood loss, and HS was induced in 9 rats (blood loss <0.1 mL) by left lobular hepatectomy with fixed-volume blood loss (2.5 mL/100 g) for this self-controlled study. In 3 randomly selected rats surviving >24 h post HS, hepatic tissue samples collected pre-HS (n = 3; group A) and 24 h post-HS (n = 3; group B) were used for microarray analysis (21,793 genes) of differentially expressed genes using pathway, gene ontology, and network analyses. Real-time reverse transcriptase polymerase chain reaction confirmed Aldh1a1, Aldh1a7, amine oxidase, copper containing 3, cytochrome P450 26A1, histidine decarboxylase 1, and epoxide hydrolase 2 expression using a beta-actin reference. RESULTS: Four rats survived 24 h after HS. Microarray revealed 562 upregulated and 634 downregulated genes in group A compared with group B. Gene ontology analysis revealed differentially expressed genes involved in cholesterol metabolic processes, extracellular stimuli response, sterol metabolic processes, hormonal stimuli response, steroid metabolic processes, endogenous stimulus response, oxidation and reduction reactions, organic substance response, and fatty acid metabolic processes. CONCLUSIONS: HS pathogenesis involves numerous interrelated signaling pathways. Redox reaction and fatty acid metabolism pathway involvement in traumatic HS recovery, as well as other pathways, may provide novel targets for better understanding the pathology of HS and developing treatments to limit post-HS organ failure. PMID- 23810747 TI - Agreement of self-reported hormone receptor status with cancer registry data in young breast cancer patients. AB - BACKGROUND: Though breast cancer subtype is a key determinant of treatment choice and prognosis, few studies have assessed breast cancer patients' knowledge of estrogen and progesterone receptor (ER/PR) status. METHODS: Women diagnosed with invasive breast cancer at age 18-64 years in 2007 were recruited from the Pennsylvania Cancer Registry, and mailed a questionnaire that asked respondents to identify their ER/PR status. There were 2191 respondents included in the analysis. Agreement between self-report and cancer registry ER/PR status was assessed using kappa statistic. Logistic regression was used to assess the association of demographic, socioeconomic, and tumor factors with inaccurate self report of ER/PR status. RESULTS: Fifty-nine percent of respondents reported ER/PR positive status, 15% reported ER/PR negative status, 17% responded 'don't know', and 9% did not respond. Overall, there was 69% agreement between self-report and cancer registry data, and fair agreement as measured by kappa (0.36). After excluding women who did not know or did not report their ER/PR status, there was 93% agreement, and substantial agreement as measured by kappa (0.76). Women who were older, non-white, less educated, lower income, and had ER/PR negative disease were significantly more likely to inaccurately report their ER/PR status. CONCLUSIONS: Though a significant proportion of women do not know their hormone receptor status, women who reported their ER/PR status were accurate. Our results suggest room for improvement in patient knowledge of tumor subtypes, but also that self-reported ER/PR status may be a useful surrogate when medical record or cancer registry data is unavailable. PMID- 23810748 TI - A simple classification of facial asymmetry by TML system. AB - This study proposes a system for classifying facial asymmetry with accompanying mandibular prognathism to facilitate choice of surgical method. We examined hard and soft tissue measurements obtained from posterior-anterior cephalometric radiographs and clinical facial photographs of 153 patients (86 male, 67 female), classifying them according to menton deviation with transverse asymmetry (T), maxillary cant (M), and lip cant (L). The T-group is subclassified according to direction of transverse asymmetry (H). Statistical analysis of menton deviation, cant and transverse asymmetry was performed for each group. The various relationships observed among the groups indicate that most cases (85%) were not effectively correctable using conventional surgical methods. As such, the authors believe that analysing facial asymmetry in terms of the classification system presented in this study and employing surgical methods appropriate to each case will help achieve more harmonious aesthetic outcomes. PMID- 23810749 TI - Biological dose escalation and hypofractionation: what is there to be gained and how will it best be done? AB - The evidence supporting dose escalation for localised prostate cancer is widely accepted, but in tandem with improvements in biochemical control, dose escalation increases side-effects. In a scenario where most patients achieve control of their cancer, quality of life concerns predominate. Here we examine the biological ways in which an effective dose can be escalated without an unacceptable increase in toxicity. Possible avenues include exploiting the unusual radiobiology of prostate cancer by hypofractionation, the use of image guidance, adaptive planning and prostate motion management. We await with anticipation the results of large randomised trials of hypofractionation, moderate and profound, to establish whether we can further improve the balance between cure and quality of life. PMID- 23810750 TI - Development of a strategic process using checklists to facilitate team preparation and improve communication during neonatal resuscitation. AB - BACKGROUND: To improve our neonatal resuscitations we review video recordings of actual high-risk deliveries as an ongoing quality review process. In order to help identify and review errors that occurred during resuscitation we educated our resuscitation teams using crew resource management and in March 2009 developed a checklist to be used for potentially high-risk resuscitations. OBJECTIVE: To describe our experience using checklists as an essential component of the actual resuscitation of potentially high-risk infants. DESIGN/METHODS: The checklist includes pre- and debrief components, along with duty-specific sub lists (MD, RT, RN). The debrief is conducted upon completion of the resuscitation and addresses what was done well, what was not done well, and how it could have been improved. We reviewed all available checklists from March 2009 to November 2011 (n=260). We then performed a second review to determine if experience has changed the leaders perception of how resuscitation was being performed from November 2011 to May 2012 (n=185). RESULTS: We reviewed 445 completed checklists with quality assurance video review. During the initial cohort the most commonly described problems were: communication (n=58), equipment preparation and use (n=56), inappropriate decisions (n=87), leadership (n=56), and procedures (n=25). The number of debriefs where communication was identified as a problem decreased from 23% in the first time period to 4% (p<0.001) in the latter. CONCLUSIONS: The use of checklists during neonatal resuscitation was helpful in improving overall communication, and allowed for rapid identification of issues that need to be addressed by institutional leaders. There needs to be further evaluation of the utility and benefit of checklists for neonatal resuscitation. Based on our past and present experience we encourage the use of checklists for neonatal resuscitation teams. PMID- 23810751 TI - [Effect of SSRIs on bone metabolism]. AB - INTRODUCTION: SSRIs have been shown to affect bone health in adults, but this has been poorly studied in children. Given the frequency of SSRI prescription in children and adolescents, it is crucial to evaluate the impact of SSRIs on bone growth because the bone mass attained early in life is the most important predictor of a normal bone constitution. Experimental studies have demonstrated a direct functional role of serotonin in bone metabolism, independently of hyperprolactinemia or growth hormone levels. We have reviewed the literature on serotonin and bone metabolism, including experimental studies, clinical studies in adults as well as in the pediatric population. EXPERIMENTAL STUDIES: Experimental studies have shown that 5-HT transporter (5-HTT) is expressed in all kind of bone cells and is highly specific of the 5-HT recapture. 5-HTT inhibition by the SSRIs in these cells affects their function in vitro. Even though a few studies have suggested exposure to SSRIs could be beneficial by an anabolic effect on the trabecular bone, more concluding studies have demonstrated that SSRIs negatively affect bone growth, resulting in a specific bone phenotype including a reduction in bone mass, an altered bone architecture, and decreased mechanical properties. This phenotype is most probably the consequence of a decrease in bone formation, rather than an increase in bone resorption and is a direct and dose-dependent effect. However, many aspects of this bone effect of 5 HTT inhibition need to be further clarified, including the signal ways for 5-HTT and 5-HT receptors, origins of 5-HT in bone, and methods to isolate the inhibitory effect of 5-HTT specifically on bone. CLINICAL STUDIES: Metabolic and neuroendocrine side effects have been documented in children and adolescents taking SSRIs but the specific and direct effect of these molecules on bone metabolism has been poorly studied in this population. In adults, clinical studies have shown an association between the use of SSRIs and bone demineralization as well as reduction in bone mass, especially in the elderly and post-menopausal women. However, depression itself has been associated with a lower bone mass and increased risk of osteoporosis. In children, case reports show a decrease in growth due to a decreased secretion of growth hormone, but not by a direct effect. One cross-sectional study suggests a decrease in bone mass following SSRI treatment that is independent of variation in prolactin levels, but without elevation of fracture risk. These results, however, need to be replicated in further studies. CONCLUSION: Our review shows that experimental studies have demonstrated the implication of the serotonin system in bone metabolism. Mice with genetic disruption of 5-HTT have a bone phenotype of decreased bone mass, altered architecture, and decreased mechanical properties. Clinical studies exploring the effect of SSRIs on bone metabolism are scarce in children. However, results in adults tend to show a deleterious effect in the elderly. Regarding the frequency of SSRI prescription in the pediatric population, it is becoming urgent to better explore the effect of SSRIs on bone growth of children, as it can have major implications on the ulterior follow-up and on the precautions to take. PMID- 23810752 TI - [Interactive rTMS protocols in psychiatry]. AB - BACKGROUND: The efficiency of repetitive transcranial magnetic stimulation (rTMS) in the treatment of psychiatric disorders is robust for major depressive episode (MDE) while results are encouraging for schizophrenia. However, rTMS protocols need to be optimized. Basic researches in TMS led to the concept of "state dependency TMS". This concept suggests that the neural circuits' activation states, before and during the stimulation, influence the pulse effect. Indeed, TMS effect must be seen, not simply as a stimulus, but also as the result of an interaction between a stimulus and a level of brain activity. Those data suggest that rTMS efficiency could be increased in psychiatric disorders by triggering patients' neurocognitive activities during stimulation. Thus "interactive rTMS protocols" have been submitted. OBJECTIVES: This article provides a review and a classification of different interactive protocols implemented in the treatment of MDE and schizophrenia. Protocols' interactions with cognitive activities and brain electrical activities will be discussed. LITERATURE FINDINGS: Interactive rTMS protocols that manipulate cognitive activities have been developed for MDE treatments. They aim at regulating emotional states of depressed patients during the stimulation. The patients perform emotional tasks in order to activate cortical networks involving the left dorsolateral prefrontal cortex (DLPFC) into a state that may be more sensitive to the rTMS pulse effect. Simultaneous cognitive behavioral therapy ("CBT rTMS") and cognitive-emotional reactivation ("affective rTMS") have thus been tested during left DLPFC rTMS in MDE. Interactive rTMS protocols that manipulate brain electrical activities have been developed for MDE and schizophrenia treatments. Two categories of protocols should be identified. In the first set, personalized brain activity has been analyzed to determine the parameters of stimulation (i.e. frequency of stimulation) matching the patient ("personalized rTMS"). Personalized rTMS protocols can be made "online" or "offline" depending on whether the EEG activity is measured during or prior to rTMS. Online protocol is called "contingent rTMS": it consists in stimulating the brain only when a specific EEG pattern involving the intensity of alpha rhythm is recorded and recognized. Offline protocol is called "alpha rTMS", and relies on ascertaining frequency of stimulation in accordance with personalized alpha peak frequency prior to rTMS. In the second set, electrical brain activity is modulated before or during rTMS in order to stimulate the DLPFC in optimal conditions. Brain activity modulation may be obtained by transcranial direct current stimulation ("tDCS rTMS") or EEG biofeedack ("EEG-biofeedback rTMS"). CONCLUSION: Interactive rTMS studies have various limitations, notably their exploratory character on a small sample of patients. Furthermore, their theoretical neurocognitive framework justification remains unclear. Nonetheless, interactive rTMS protocols allow us to consider a new field of rTMS, where cognitive and cerebral activities would no longer be considered as simple neural noise, leading to a kind of "first person rTMS", and certainly to innovative therapy in psychiatry. PMID- 23810753 TI - [Benzodiazepine dependence and the risk of depression and anxiety disorders: seniors' health study]. AB - AIM OF THE STUDY: The objective of this study is to examine the relationship between benzodiazepine dependence and anxiety disorders and depression in people aged 65 years and over. We referred to the data from the study on the health of seniors, a survey of a representative sample of 707 benzodiazepine users living in the community in Quebec, Canada. Benzodiazepine dependence, anxiety disorders and depression were measured using self-reported questionnaires based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth revised edition. RESULTS: Seniors have consumed an average daily dose of 6.1+/ 7.6mg diazepam equivalent to an average of 205+/-130 days. The prevalence of benzodiazepine dependence has been estimated at 9.5%. This dependence increases the risk of minor depression for females (relative risk [RR]=4.36, confidence interval 95% [95% CI]=1.19 to 15.99). CONCLUSION: The results of this study suggest that the use of benzodiazepines is far from being optimal among seniors in Quebec. The proportion of seniors who develop an addiction is important. The results illustrate the need to develop and implement programs to improve the quality of benzodiazepine use among this population. PMID- 23810755 TI - Coping with dementia in care homes. PMID- 23810754 TI - [Manipulation in the exercise of psychiatric interviews]. AB - INTRODUCTION: The term "manipulation" is defined as "getting someone to behave otherwise than he spontaneously would". Unlike cognitive therapies, it does not involve cognitive functioning and may increase psychotherapies' efficiency. METHOD: In the absence of data in the scientific literature (Medline and Web of Science), we propose a synthesis of theoretical data from social psychology with a reflection on its applications in the daily practice of psychiatry. RESULTS: Firstly we present auto-manipulation: the "chilling effect" is the fact that people tend to keep to a decision and to duplicate it, even if it does not work. The commitment of the patient, i.e., the degree to which he/she identifies with his/her act, will be even stronger if the patient's sense of freedom is high. The rationalization process is the ability for individuals to revisit their beliefs after being forced to issue a behavior (that he/she did not adhere to) to justify it a posteriori. In the second part, we present techniques for hetero manipulation. Priming is to ask about a low effort to "initiate" the behavior. The lure technique is to hide convenience or invent fictitious benefits of a product, but is not ethical. The labeling technique is to assign an individual to a positive value regardless of his or her behavior, which increases the probability of emission of positive behaviors. The touch technique, whatever the cultural context, encourages a patient to have more confidence in his/her therapist and to make them friendly towards the person involved by creating a positive mood, reduces stress in patients before surgery, and improve the academic performance of students. DISCUSSION AND CONCLUSION: We propose reflections on the application of these concepts in daily practice in the psychiatric interview. These techniques seem fundamental in improving therapeutic alliance and the likelihood of good compliance in our patients, and should be known to all practitioners. PMID- 23810756 TI - MicroRNA-133b stimulates ovarian estradiol synthesis by targeting Foxl2. AB - Forkhead L2 (Foxl2) is expressed in ovarian granulosa cells and participates in steroidogenesis by transcriptionally regulating target genes such as steroidogenic acute regulatory protein (StAR) and CYP19A1. In this study, a direct link between microRNA-133b (miR-133b) and Foxl2-mediated estradiol release in granulosa cells was established. miR-133b was involved in follicle-stimulating hormone (FSH)-induced estrogen production. Luciferase assays confirmed that miR 133b was bound to the 3' untranslated region (3'UTR) of Foxl2 mRNA. Consistent with this finding, miR-133b overexpression reduced the Foxl2 levels. Furthermore, miR-133b inhibited Foxl2 binding to the StAR and CYP19A1 promoter sequences. These results demonstrate that miR-133b down-regulates Foxl2 expression in granulosa cells by directly targeting the 3'UTR, thus inhibiting the Foxl2 mediated transcriptional repression of StAR and CYP19A1to promote estradiol production. PMID- 23810757 TI - Clinical validation of a next-generation sequencing screen for mutational hotspots in 46 cancer-related genes. AB - Transfer of next-generation sequencing technology to a Clinical Laboratory Improvement Amendments-certified laboratory requires vigorous validation. Herein, we validated a next-generation sequencing screen interrogating 740 mutational hotspots in 46 cancer-related genes using the Ion Torrent AmpliSeq cancer panel and Ion Torrent Personal Genome Machine (IT-PGM). Ten nanograms of FFPE DNA was used as template to amplify mutation hotspot regions of 46 genes in 70 solid tumor samples, including 22 archival specimens with known mutations and 48 specimens sequenced in parallel with alternate sequencing platforms. In the archival specimens, the IT-PGM detected expected nucleotide substitutions (n = 29) and four of six insertions/deletions; in parallel, 66 variants were detected. These variants, except a single nucleotide substitution, were confirmed by alternate platforms. Repeated sequencing of progressively diluted DNA from two cancer cell lines with known mutations demonstrated reliable sensitivity at 10% variant frequency for single nucleotide variants with high intrarun and inter-run reproducibility. Manual library preparation yielded relatively superior sequencing performance compared with the automated Ion Torrent OneTouch system. Overall, the IT-PGM platform with the ability to multiplex and simultaneously sequence multiple patient samples using low amounts of FFPE DNA was specific and sensitive for single nucleotide variant mutation analysis and can be incorporated easily into the clinical laboratory for routine testing. PMID- 23810758 TI - Comparison of clinical targeted next-generation sequence data from formalin-fixed and fresh-frozen tissue specimens. AB - Next-generation sequencing (NGS) has emerged as a powerful technique for the detection of genetic variants in the clinical laboratory. NGS can be performed using DNA from FFPE tissue, but it is unknown whether such specimens are truly equivalent to unfixed tissue for NGS applications. To address this question, we performed hybridization-capture enrichment and multiplexed Illumina NGS for 27 cancer-related genes using DNA from 16 paired fresh-frozen and routine FFPE lung adenocarcinoma specimens and conducted extensive comparisons between the sequence data from each sample type. This analysis revealed small but detectable differences between FFPE and frozen samples. Compared with frozen samples, NGS data from FFPE samples had smaller library insert sizes, greater coverage variability, and an increase in C to T transitions that was most pronounced at CpG dinucleotides, suggesting interplay between DNA methylation and formalin induced changes; however, the error rate, library complexity, enrichment performance, and coverage statistics were not significantly different. Comparison of base calls between paired samples demonstrated concordances of >99.99%, with 96.8% agreement in the single-nucleotide variants detected and >98% accuracy of NGS data when compared with genotypes from an orthogonal single-nucleotide polymorphism array platform. This study demonstrates that routine processing of FFPE samples has a detectable but negligible effect on NGS data and that these samples can be a reliable substrate for clinical NGS testing. PMID- 23810759 TI - MECP2 gene study in a large cohort: testing of 240 female patients and 861 healthy controls (519 females and 342 males). AB - The MECP2 gene located on Xq28 is one of the most important genes contributing to the spectrum of neurodevelopmental disorders. Therefore, we present our experience in the molecular study of this gene. MECP2 was thoroughly tested for the presence of mutations (sequencing of four exons and rearrangements) in 120 female patients: 28 with classic Rett syndrome, five with atypical Rett syndrome, and 87 with heterogeneous phenotypes with some Rett-like features. Another 120 female patients with intellectual disability of unknown origin were also studied, but in these cases we only tested exons 3 and 4. Finally, 861 healthy controls (519 females and 342 males) were also studied for exon 3 and 4. Eighteen different pathological mutations were found, five of them previously undescribed, and four large deletions detected by multiplex ligation-dependent probe amplification. All were de novo mutations not present in the parents. In conclusion, i) MECP2 is one of the most important genes in the diagnosis of genetic intellectual disability in females; ii) MECP2 must be studied not only in patients with classical/atypical Rett syndrome but also in patients with other phenotypes related to Rett syndrome; and iii) for the new variants, it is important to perform complementary studies, including the analysis of large populations of healthy individuals and the use of in silico programs. PMID- 23810760 TI - A holistic view on dermatitis: patch testing should be considered in patients with atopic dermatitis. PMID- 23810761 TI - A holistic view on dermatitis: patch testing should be considered in patients with atopic dermatitis. Reply. PMID- 23810762 TI - alpha-Purothionin, a new wheat allergen associated with severe allergy. PMID- 23810763 TI - The German Infant Nutritional Intervention (GINI) study and formulation issues. PMID- 23810764 TI - Cord serum 25-hydroxyvitamin D and risk of early childhood transient wheezing and atopic dermatitis. AB - BACKGROUND: There is increasing evidence of the effect of maternal vitamin D intake during pregnancy on the risk of asthma and allergic outcomes in offspring. However, studies on the relationship between cord levels of 25-hydroxyvitamin D (25[OH]D) and asthma and allergic diseases are very few. OBJECTIVE: Our aim was to investigate the associations between cord serum 25(OH)D levels and asthma, wheezing, allergic rhinitis, and atopic dermatitis in the offspring from birth to 5 years. METHODS: Cord blood samples were collected at birth and analyzed for 25(OH)D levels in 239 newborns from the Etude des Determinants pre et post natals du developpement et de la sante de l'Enfant (EDEN) birth cohort. The children were followed up until age 5 years by using International Study of Asthma and Allergies in Childhood-based symptom questionnaires. RESULTS: The median cord serum level of 25(OH)D was 17.8 ng/mL (interquartile range, 15.1 ng/mL). By using multivariable-adjusted logistic regression models, a significant inverse association was observed between cord serum 25(OH)D levels and risk of transient early wheezing and early- and late-onset atopic dermatitis, as well as atopic dermatitis, by the ages of 1, 2, 3, and 5 years. We found no association between cord serum 25(OH)D levels and asthma and allergic rhinitis at age 5 years. CONCLUSIONS: Cord serum 25(OH)D levels were inversely associated with the risk of transient early wheezing and atopic dermatitis by the age of 5 years, but no association was found with asthma and allergic rhinitis. PMID- 23810765 TI - The German Infant Nutritional Intervention (GINI) study and formulation issues. Reply. PMID- 23810766 TI - IL-33 is more potent than IL-25 in provoking IL-13-producing nuocytes (type 2 innate lymphoid cells) and airway contraction. AB - BACKGROUND: IL-25 and IL-33 belong to distinct cytokine families, but experimental mouse studies suggest their immunologic functions in type 2 immunity are almost entirely overlapping. However, only polymorphisms in the IL-33 pathway (IL1RL1 and IL33) have been significantly associated with asthma in large-cohort genome-wide association studies. OBJECTIVE: We sought to identify distinct pathways for IL-25 and IL-33 in the lung that might provide insight into their roles in asthma pathogenesis and potential for therapeutic intervention. METHODS: IL-25 receptor-deficient (Il17rb(-/-)), IL-33 receptor-deficient (ST2, Il1rl1(-/ )), and double-deficient (Il17rb(-/-)Il1rl1(-/-)) mice were analyzed in models of allergic asthma. Microarrays, an ex vivo lung slice airway contraction model, and Il13(+/eGFP) mice were then used to identify specific effects of IL-25 and IL-33 administration. RESULTS: Comparison of IL-25 and IL-33 pathway-deficient mice demonstrates that IL-33 signaling plays a more important in vivo role in airways hyperreactivity than IL-25. Furthermore, methacholine-induced airway contraction ex vivo increases after treatment with IL-33 but not IL-25. This is dependent on expression of the IL-33 receptor and type 2 cytokines. Confocal studies with Il13(+/eGFP) mice show that IL-33 more potently induces expansion of IL-13 producing type 2 innate lymphoid cells, correlating with airway contraction. This predominance of IL-33 activity is enforced in vivo because IL-33 is more rapidly expressed and released in comparison with IL-25. CONCLUSION: Our data demonstrate that IL-33 plays a critical role in the rapid induction of airway contraction by stimulating the prompt expansion of IL-13-producing type 2 innate lymphoid cells, whereas IL-25-induced responses are slower and less potent. PMID- 23810767 TI - Recombinant Mal d 1 is a reliable diagnostic tool for birch pollen allergen associated apple allergy. PMID- 23810768 TI - Lack of evidence for intrathecal tryptase synthesis in patients with systemic mastocytosis. PMID- 23810769 TI - Modeling the coupled extracellular and intracellular environments in mammalian cell culture. AB - The regulation of metabolism in mammalian cell culture is closely linked to the process of apoptosis-programmed cell death. Apoptosis negatively impacts culture viability, product yield, and quality. An improved understanding of the interaction between apoptosis and metabolism will give rise to better control over the culture process, and thus improvements in product yield. This study presents a mathematical model that describes both the metabolic fluxes involving the extracellular metabolites and the progression of apoptosis in terms of intracellular caspases, and thus highlights the interactions between these two processes. The model is trained and validated against experimental observations of Chinese Hamster Ovary cell culture producing monoclonal antibody. Importantly, the model describes the continued production of monoclonal antibody in post exponential phase by incorporating different rates of antibody production for separate sub-populations within the culture. A parameter estimability test was applied on the combined model to assess the confidence in parameter estimates. PMID- 23810770 TI - Early-onset or rapidly progressive scoliosis in children: check the eyes! AB - Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare autosomal recessive disorder characterized by the absence of conjugate horizontal eye movements, and progressive scoliosis developing in childhood and adolescence, caused by mutations in the ROBO3 gene which has an important role in axonal guidance and neuronal migration. We describe two female children aged 12 years and 18 months, with progressive scoliosis, in whom the neurological examination showed absent conjugate horizontal eye movements, but preserved vertical gaze and convergence. Cerebral Magnetic resonance imaging findings included pontine hypoplasia, absent facial colliculi, butterfly configuration of the medulla and a deep midline pontine cleft, while Diffusion tensor imaging (DTI) maps showed the absence of decussating ponto-cerebellar fibers and superior cerebellar peduncles. Somatosensory and motor evoked potential studies demonstrated ipsilateral sensory and motor responses. The diagnosis was confirmed by the identification of bi allelic mutations in the ROBO3 gene. PMID- 23810771 TI - Valproic acid promotes human hair growth in in vitro culture model. AB - BACKGROUND: beta-Catenin, the transducer of Wnt signaling, is critical for the development and growth of hair follicles. In the absence of Wnt signals, cytoplasmic beta-catenin is phosphorylated by glycogen synthase kinase (GSK)-3 and then degraded. Therefore, inhibition of GSK-3 may enhance hair growth via beta-catenin stabilization. Valproic acid is an anticonvulsant and a mood stabilizing drug that has been used for decades. Recently, valproic acid was reported to inhibit GSK-3beta in neuronal cells, but its effect on human hair follicles remains unknown. OBJECTIVES: To determine the effect of VPA on human hair growth. METHODS: We investigated the effect of VPA on cultured human dermal papilla cells and outer root sheath cells and on an in vitro culture of human hair follicles, which were obtained from scalp skin samples of healthy volunteers. Anagen induction by valproic acid was evaluated using C57BL/6 mice model. RESULTS: Valproic acid not only enhanced the viability of human dermal papilla cells and outer root sheath cells but also promoted elongation of the hair shaft and reduced catagen transition of human hair follicles in organ culture model. Valproic acid treatment of human dermal papilla cells led to increased beta-catenin levels and nuclear accumulation and inhibition of GSK 3beta by phosphorylation. In addition, valproic acid treatment accelerated the induction of anagen hair in 7-week-old female C57BL/6 mice. CONCLUSIONS: Valproic acid enhanced human hair growth by increasing beta-catenin and therefore may serve as an alternative therapeutic option for alopecia. PMID- 23810772 TI - Aberrant distribution patterns of corneodesmosomal components of tape-stripped corneocytes in atopic dermatitis and related skin conditions (ichthyosis vulgaris, Netherton syndrome and peeling skin syndrome type B). AB - BACKGROUND: Atopic dermatitis (AD), Netherton syndrome (NS) and peeling skin syndrome type B (PSS) may show some clinical phenotypic overlap. Corneodesmosomes are crucial for maintaining stratum corneum integrity and the components' localization can be visualized by immunostaining tape-stripped corneocytes. In normal skin, they are detected at the cell periphery. OBJECTIVE: To determine whether AD, NS, PSS and ichthyosis vulgaris (IV) have differences in the corneodesmosomal components' distribution and corneocytes surface areas. METHODS: Corneocytes were tape-stripped from a control group (n=12) and a disease group (37 AD cases, 3 IV cases, 4 NS cases, and 3 PSS cases), and analyzed with immunofluorescent microscopy. The distribution patterns of corneodesmosomal components: desmoglein 1, corneodesmosin, and desmocollin 1 were classified into four types: peripheral, sparse diffuse, dense diffuse and partial diffuse. Corneocyte surface areas were also measured. RESULTS: The corneodesmosome staining patterns were abnormal in the disease group. Other than in the 3 PSS cases, all three components showed similar patterns in each category. In lesional AD skin, the dense diffuse pattern was prominent. A high rate of the partial diffuse pattern, loss of linear cell-cell contacts, and irregular stripping manners were unique to NS. Only in PSS was corneodesmosin staining virtually absent. The corneocyte surface areas correlated significantly with the rate of combined sparse and dense diffuse patterns of desmoglein 1. CONCLUSION: This method may be used to assess abnormally differentiated corneocytes in AD and other diseases tested. In PSS samples, tape stripping analysis may serve as a non invasive diagnostic test. PMID- 23810773 TI - Reduction of CC-chemokine ligand 5 by aryl hydrocarbon receptor ligands. AB - BACKGROUND: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that recognizes a large number of xenobiotics, such as polycyclic aromatic hydrocarbons (PAHs), dioxins, and some endogenous ligands. Despite numerous investigations targeting AhR ligands, the precise physiological role of AhR remains unknown. OBJECTIVE: We explored novel AhR target genes, especially focused on inflammatory chemokine. METHODS: We treated (1) HaCaT, a human keratinocyte cell line, (2) normal human epidermal keratinocytes (NHEKs), and (3) mouse primary keratinocytes with AhR ligands, such as 6-formylindolo[3,2 b]carbazole (FICZ; endogenous ligand) and benzo[a]pyrene (BaP; exogenous ligand). Then, we detected mRNA and protein of chemokine using quantitative RT-PCR and ELISA. We next clarified the relationship between AhR and chemokine expression using AhR siRNA. In addition, we measured serum chemokine levels in patients with Yusho disease (oil disease), who were accidentally exposed to dioxins in the past. RESULTS: We identified CC-chemokine ligand 5 (CCL5), a key mediator in the development of inflammatory responses, as the AhR target gene. AhR ligands (FICZ and BaP) significantly reduced CCL5 mRNA and protein expression in HaCaT cells. These effects were observed in NHEKs and mouse primary keratinocytes. AhR knockdown with siRNA restored CCL5 inhibition by AhR ligands. In addition, AhR ligands exhibited a dose-dependent suppression of CCL5 production induced by Th1 derived cytokines. Finally, serum levels of CCL5 in patients with Yusho disease, were significantly lower than in controls. CONCLUSION: Our findings indicate that CCL5 is a target gene for AhR, and might be associated with the pathology of dioxin exposure. PMID- 23810774 TI - 850nm light-emitting-diode phototherapy plus low-dose tacrolimus (FK-506) as combination therapy in the treatment of Dermatophagoides farinae-induced atopic dermatitis-like skin lesions in NC/Nga mice. AB - BACKGROUND: Light emitting diode (LED) phototherapy is an effective alternative for the treatment of inflammatory skin disorders. Tacrolimus (FK-506) is a potent immunomodulating agent, which has been used to treat AD. Combination therapy is often used in the treatment of AD to improve therapeutic efficacy or to reduce the dose of each drug. OBJECTIVE: To investigate the therapeutic efficacy of monotherapy with either 850nm LED phototherapy or low-dose FK-506, and combination therapy in Dermatophagoides farina (Df)-induced AD-like skin lesions in NC/Nga mice. METHODS: The Df-induced NC/Nga mice with a clinical score of 7 were used for treatment with LED (10 and 25J/cm(2)) alone, low-dose FK-506 (1mg/kg) or in combination. The synergistic effects of combined therapy were evaluated by dermatitis scores, skin histology, skin barrier function, and immunological parameters, such as IgE, NO, Th2-mediated cytokines and chemokines. RESULTS: Combination therapy with 850nm (25J/cm(2)) LED and low-dose FK-506 showed a significant reduction in the severity of skin lesions. Combined therapy decreased in the serum level of IgE, NO, and in the splenic level of Th2-mediated cytokines and chemokines. Combination therapy significantly also reduced the inflammatory cellular infiltrate into the skin lesions. Moreover, combination therapy led to recovery of skin barrier function in the skin lesions. CONCLUSIONS: The use of combination of LED phototherapy and low-dose immunosuppressant improved Df-induced AD-like skin lesions in an NC/Nga mouse model by dominantly reducing IgE, NO, suppressing Th2-mediated immune responses, and inhibiting inflammatory cells, as well as improving skin barrier function. PMID- 23810775 TI - WITHDRAWN: When all else fails: 21st Century Amateur Radio as an emergency communications medium. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.transci.2013.08.002. The duplicate article has therefore been withdrawn. The Publisher expresses their sincere apologies to the authors and the editors for this error. PMID- 23810776 TI - Effect of soft and semirigid ankle orthoses on Star Excursion Balance Test performance in patients with functional ankle instability. AB - OBJECTIVES: To evaluate the effect of soft and semirigid ankle orthoses on dynamic balance assessed using Star Excursion Balance Test in patients with functional ankle instability compared with healthy individuals. DESIGN: Non experimental, observational study with multiple-factor design, including group (functional ankle instability and healthy) as the between-subjects factor and orthotics condition (no orthosis, soft orthosis and semirigid orthosis) as the within-subjects factor. METHODS: Sixteen unilateral functional ankle instability patients and a group of 16 healthy control individuals, matched for age, height and weight, participated in the study. Dynamic balance was tested with and without wearing ankle orthosis. Reach distance of participants in 3 bracing conditions were measured in anteromedial, medial and posteromedial directions of Star Excursion Balance Test. Average of 3 trials in 3 measured directions, normalized to leg length of each participant, was used for statistical analysis. RESULTS: There were no differences among orthotics conditions in healthy people. However, normalized reach distance increased from no-orthosis to semirigid to soft orthoses in FAI patients. Differences were significant between soft and no orthosis (13% in anteromedial, 14% in medial and 15% in posteromedial direction p=0.01) and between semirigid and no-orthosis (10% in anteromedial, 8.5% in medial and 8.5% in posteromedial direction, p=0.01) conditions in all 3 measured directions. The difference between soft and semirigid orthoses was significant (6% difference, p<0.05) only in PM direction. CONCLUSIONS: Ankle orthoses improve reach distance in functional ankle instability patients in various reach directions. Soft orthosis has a more pronounced effect on dynamic balance, especially in posteromedial direction, compared with semirigid orthosis. PMID- 23810777 TI - Thermal phase transition behavior of lipid layers on a single human corneocyte cell. AB - We have improved the selected area electron diffraction method to analyze the dynamic structural change in a single corneocyte cell non-invasively stripped off from human skin surface. The improved method made it possible to obtain reliable diffraction images to trace the structural change in the intercellular lipid layers on a single corneocyte cell during heating from 24 degrees C to 100 degrees C. Comparison of the results with those of synchrotron X-ray diffraction experiments on human stratum corneum sheets revealed that the intercellular lipid layers on a corneocyte cell exhibit essentially the same thermal phase transitions as those in a stratum corneum sheet. These results suggest that the structural features of the lipid layers are well preserved after the mechanical stripping of the corneocyte cell. Moreover, electron diffraction analyses of the thermal phase transition behaviors of the corneocyte cells that had the lipid layers with different distributions of orthorhombic and hexagonal domains at 24 degrees C suggested that small orthorhombic domains interconnected with surrounding hexagonal domains transforms in a continuous manner into new hexagonal domains. PMID- 23810778 TI - Endometrial marginal zone B-cell MALT-type lymphoma: case report and literature review. AB - Primary NHL of the female genital tract are relatively uncommon, accounting for only 2% of all extranodal primary lymphomas, and for less than 0.5% of gynaecologic cancers. Primary endometrial lymphomas can be considered a rarity, with less than 50 instances reported in the literature. We describe a case of primary marginal zone B-cell MALT-type lymphoma of the endometrium, of which there were only other 5 case reports in the literature. We also present a review of the literature. PMID- 23810779 TI - Impact of diabetes and prediabetes on the short-term prognosis in patients with acute ischemic stroke. AB - OBJECTIVE: We aimed to explore the association between abnormal glucose metabolism such as diabetes, prediabetes, and short-term prognosis in patients with acute ischemic stroke. METHODS: Of 242 consecutive acute ischemic stroke patients, a 75-g oral glucose tolerance test was administered to 116 patients without previously diagnosed diabetes. One hundred forty patients were classified into diabetes, 52 patients were prediabetes (impaired glucose tolerance or impaired fasting glucose or both), and 50 patients were normal glucose tolerance (NGT). The association between each glycemic status and early neurological deterioration (END; increase in the NIH Stroke Scale (NIHSS) of >=2 points during the first 14days after admission) or poor short-term outcome (30-day modified Ranking Scale [mRS] score 2-6) was evaluated. RESULTS: In multivariable analysis, the risk of END was significantly higher in the diabetes group than in the NGT group (ORs=11.354; 95% CI, 1.492-86.415; p=0.019), even after adjustment for possible confounding factors (ORs=12.769; 95% CI, 1.361-119.763; p=0.026). Similar but insignificant associations were observed between prediabetes and NGT groups (ORs=6.369; 95% CI, 0.735-55.177; p=0.093). The risk of poor outcome (30 day mRS 2-6) was significantly higher in the diabetes group (ORs=3.667; 95% CI, 1.834-7.334; p<0.001) than in the NGT group, even after adjusting for confounding factors (ORs=3.340; 95% CI, 1.361-8.195; p=0.008). Similar but insignificant associations were observed between prediabetes and NGT groups (ORs=2.058; 95% CI, 0.916-4.623; p=0.08). CONCLUSION: In our patient population, both diabetes and prediabetes were associated with a poor early prognosis after acute ischemic stroke. PMID- 23810780 TI - Induction of vascular remodeling: a novel therapeutic approach in EAE. AB - While the pathologic events associated with multiple sclerosis (MS), diffuse axonal injury, cognitive damage, and white matter plaques, have been known for some time, their etiology is unknown and therapeutic efforts are still somewhat disappointing. This may be due to a lack of fundamental knowledge on how to maintain tissue homeostasis and buffer the brain from secondary injury. Maintenance of homeostasis in the brain is the result of regulatory adjustments by cellular constituents of the neurovascular unit (pericytes, endothelial cells, astrocytes, and neurons) that include induction of adaptive vascular remodeling. Results from our laboratory and others suggest that aspects of stress induced adaptation are seen in MS and in the murine model of experimental autoimmune encephalomyelitis (EAE), vascular remodeling is ineffective and biometabolic balance is disrupted. In murine white matter, capillary density is 1/2 that observed in gray matter thus disruption of vascular homeostasis will have a profound impact on tissue integrity. We therefore hypothesized that restoration of microvascular angiodynamics would augment tissue plasticity mitigating the extent of secondary injury and sparing cognitive decline in patients with MS. To test this hypothesis, we have performed preclinical studies and characterized changes in angiodynamics in myelin oligodendrocyte glycoprotein (MOG) peptide (35 55)-induced EAE in C57BL/6 mice with or without concomitant exposure to chronic mild low oxygen. We have reported that exposure to chronic mild low oxygen ameliorated clinical disease in EAE. While the mechanisms of protection are unclear, results suggest that normobaric hypoxia stabilizes the stress response, promotes physiological angiogenesis, and is neuroprotective. PMID- 23810781 TI - Immunity to Ichthyophthirius infections in fish: a synopsis. AB - Ichthyophthirius multifiliis is a ciliated protozoan parasite that infects freshwater fish. It has been the subject of both applied and basic research for over 100years, which can be attributed to its world-wide distribution and its significant economic impact on both food and aquarium fish production. I. multifiliis serves as a model for studies in fish on innate and acquired immunity, as well as on mucosal immunity. Although an obligate parasite, I. multifiliis is relatively easily passaged from infected to naive fish in laboratory aquaria, and is easily observed and manipulated under laboratory conditions. It parasitizes the epithelia of the skin and gills, which facilitates in vivo experimentation and quantification of challenge. This review provides a description of both mucosal and systemic innate and adaptive immune responses to parasite infection, a synopsis of host-parasite immunobiology, vaccine research, and suggested areas for future research to address critical remaining questions. Studies in carp and rainbow trout have shown that extensive tissue damage occurs when the parasite invades the epithelia of the skin and gills and substantial focal and systemic inflammatory responses are elicited by the innate immune response. The adaptive immune response is initiated when phagocytic cells are activated by antigens released by the parasite. It is not known whether activated T and B cells proliferate locally in the skin and gills following infection or migrate to these sites from the spleen or anterior kidney. I. multifiliis infection elicits both mucosal and systemic antibody production. Fish that survive I. multifiliis infection acquire protective immunity. Memory B cells provide long-term humoral memory. This suggests that protective vaccines are theoretically possible, and substantial efforts have been made toward developing vaccines in various fish species. Exposure of fish to controlled surface infections or by intracoelomic injection of live theronts provides protection. Vaccination with purified immobilization antigens, which are GPI-anchored membrane proteins, also provides protection under laboratory conditions and immobilization antigens are currently the most promising candidates for subunit vaccines against I. multifiliis. PMID- 23810782 TI - Modular organization of cancer signaling networks is associated with patient survivability. AB - Molecular signaling networks are believed to determine cancer robustness. Although cancer patient survivability was reported to correlate with the heterogeneous connectivity of the signaling networks inspired by theoretical studies on the increase of network robustness due to the heterogeneous connectivity, other theoretical and data analytic studies suggest an alternative explanation: the impact of modular organization of networks on biological robustness or adaptation to changing environments. In this study, thus, we evaluate whether the modularity-robustness hypothesis is applicable to cancer using network analysis. We focus on 14 specific cancer types whose molecular signaling networks are available in databases, and show that modular organization of cancer signaling networks is associated with the patient survival rate. In particular, the cancers with less modular signaling networks are more curable. This result is consistent with a prediction from the modularity-robustness hypothesis. Furthermore, we show that the network modularity is a better descriptor of the patient survival rate than the heterogeneous connectivity. However, these results do not contradict the importance of the heterogeneous connectivity. Rather, they provide new and different insights into the relationship between cellular networks and cancer behaviors. Despite several limitations of data analysis, these findings enhance our understanding of adaptive and evolutionary mechanisms of cancer cells. PMID- 23810784 TI - Rats with metabolic syndrome resist the protective effects of N-acetyl l-cystein against impaired spermatogenesis induced by high-phosphorus/zinc-free diet. AB - Consumption of relatively high amounts of processed food can result in abnormal nutritional status, such as zinc deficiency or phosphorus excess. Moreover, hyperphosphatemia and hypozincemia are found in some patients with diabetic nephropathy and metabolic syndrome. The present study investigated the effects of high-phosphorus/zinc-free diet on the reproductive function of spontaneously hypertensive rats/NDmcr-cp (SHR/cp), a model of the metabolic syndrome. We also investigated the effects of antioxidant, N-acetyl-l-cysteine (NAC), on testicular dysfunction under such conditions. Male SHR/cp and control rats (Wistar Kyoto rats, WKY) were divided into three groups; rats fed control diet (P 0.3%, w/w; Zn 0.2%, w/w), high-phosphorus and zinc-deficient diet (P 1.2%, w/w; Zn 0.0%, w/w) with vehicle, or high-phosphorus and zinc-deficient diet with NAC (1.5mg/g/day) for 12 weeks (n=6 or 8 rats/group). The weights of testis and epididymis were significantly reduced by high-phosphate/zinc-free diet in both SHR/cp and WKY. The same diet significantly reduced caudal epididymal sperm count and motility and induced histopathological changes in the testis in both strains. Treatment with NAC provided significant protection against the toxic effects of the diet on testicular function in WKY, but not in SHR/cp. The lack of the protective effects of NAC on impaired spermatogenesis in SHR/cp could be due to the more pronounced state of oxidative stress observed in these rats compared with WKY. PMID- 23810783 TI - All-trans-retinoid acid (ATRA) may have inhibited chondrogenesis of primary hind limb bud mesenchymal cells by downregulating Pitx1 expression. AB - Despite frequently well-established role of all-trans-retinoid acid (ATRA) in congenital limb deformities, its mechanism of action, thus far, is still ambiguous. Pitx1, which is expressed in the hindlimb bud mesenchyme, or its pathways may be etiologically responsible for the increased incidence of clubfoot. Here, we sought to investigate the mechanisms whereby Pitx1 regulated chondrogenesis of hindlimb bud mesenchymal cells in vitro. E12.5 embryonic rat hind limb bud mesenchymal cells were treated with ATRA at appropriate concentrations. Cell Counting Kit-8 (CCK-8) assay was performed to evaluate cell proliferation. Hematoxylin-safranin-O-fast-green staining assays were used to observe cartilage nodules, and Pitx1 expression was examined by immunofluorescent microscopy. Real-time quantitative PCR and immunoblotting assays were applied to determine the mRNA expressions of Pitx1, Sox9 and type II collagen (Col2al), respectively. The results showed that ATRA inhibited the proliferation of hind limb bud cells dose-dependently. ATRA also induced a dose-dependent reduction in the number of cartilage nodules and the area of cartilage nodules compared with controls. Our real-time quantitative RT-PCR assays revealed that the mRNA expression of Pitx1, Sox9 and Col2al were significantly downregulated by ATRA. Furthermore, our immunofluorescent microscopy and Western blotting assays indicated that Pitx1 was mainly expressed in the cartilage nodules and the levels of Pitx1, Sox9 and Col2al were also downregulated by ATRA dose-dependently. The results indicated that ATRA may decrease chondrogenesis of hind limb bud mesenchymal cells by inhibiting cartilage-specific molecules, such as Sox9 and Col2al, via downregulating Pitx1 expression. PMID- 23810785 TI - Yeasts isolated from nosocomial urinary infections: antifungal susceptibility and biofilm production. AB - BACKGROUND: Urinary Candida infections in the hospital environment are frequent and need to be better understood. AIMS: To compare the results of antifungal susceptibility profiles of yeasts isolated from patients with urinary infections obtained by broth microdilution method (BM) and by disk diffusion (DD), and also evaluate the capacity of these yeasts to form biofilms. METHODS: Only yeasts obtained from pure urine cultures with counts higher than 10(5) colony-forming units per milliliter, without bacteria development, of symptomatic patients were included. The isolates were identified by classical methods and the antifungal susceptibility tests were performed with the following drugs: amphotericin B, ketoconazole, fluconazole, itraconazole, voriconazole and caspofungin. The biofilm studies were carried out in polystyrene microtitration plates. RESULTS: Ninety-five yeasts isolates were analyzed, including 40 Candida albicans, 31 Candida glabrata, 24 Candida tropicalis. In general, the majority of the isolates were susceptible to the tested drugs but some resistance was observed, especially against fluconazole. Great variability in the antifungal susceptibility results was observed with the different tested drugs and a few discrepancies were observed between both methods. We suggest that in case of DD resistance this result should be confirmed by BM, the standard method. C. tropicalis isolates showed high biofilm production (91.7%) compared to C. albicans (82.5%) and C. glabrata (61.3%), with statistical significance (p=0.0129). CONCLUSIONS: Candiduria in critical patients requires major attention and a better control. The different susceptibility results obtained in this study showed the need to identify yeasts up to the species level, especially in patients with urinary tract infection. The development of techniques of antifungal susceptibility tests can help the clinicians in the empiric treatment of candiduria. PMID- 23810786 TI - Native trees of the Northeast Argentine: natural hosts of the Cryptococcus neoformans-Cryptococcus gattii species complex. AB - BACKGROUND: In Argentina, information about epidemiology and environmental distribution of Cryptococcus is scarce. The city of Resistencia borders with Brazil and Paraguay where this fungus is endemic. All these supported the need to investigate the ecology of the genus and the epidemiology of cryptococcosis in this area. AIMS: The aim was to investigate the presence of species of Cryptococcus neoformans-Cryptococcus gattii complex and their genotypes in trees of the city of Resistencia. METHODS: One hundred and five trees were sampled by swabbing technique. The isolates were identified using conventional and commercial methods and genotyped by PCR-RFLP (Restriction Fragment Length Polymorphism). RESULTS: Cryptococcus was found in 7 out of the total trees. 6 out of 7 Cryptococcus isolates were identified as C. neoformans and one as C. gattii. C. gattii was isolated from Grevillea robusta. C. neoformans strains were isolated from Tabebuia avellanedae and Peltophorum dubium. Genotyping showed that all C. neoformans belonged to the VNI type and C. gattii belonged to the VGI type. CONCLUSIONS: This represents the first study on the ecology of Cryptococcus spp. associated to trees from northeastern Argentina, and the first report describing Grevillea robusta as a host of members of this fungal genus. Another finding is the isolation of C. neoformans from Tabebuia avellanedae and Peltophorum dubium, both tree species native to northeastern Argentina. PMID- 23810787 TI - Selected wild strains of Agaricus bisporus produce high yields of mushrooms at 25 degrees C. AB - BACKGROUND: To cultivate the button mushroom Agaricus bisporus in warm countries or during summer in temperate countries, while saving energy, is a challenge that could be addressed by using the biological diversity of the species. AIMS: The objective was to evaluate the yield potential of eight wild strains previously selected in small scale experiments for their ability to produce mature fruiting bodies at 25 degrees C and above. METHODS: Culture units of 8 kg of compost were used. The yield expressed as weight or number per surface unit and earliness of fruiting were recorded during cultivation in climatic rooms at 17, 25 or 30 degrees C. RESULTS: Only strains of A. bisporus var. burnettii were able to fruit at 30 degrees C. At 25 degrees C they produced the highest yields (27 kg m(-2)) and had best earliness. The yields at 25 degrees C for the strains of A. bisporus var. bisporus ranged from 12 to 16 kg m(-2). The yield ratios 25 degrees C/17 degrees C ranged from 0.8 to 1.2. CONCLUSIONS: The variety burnettii originated in the Sonoran Desert in California showed adaptation for quickly producing fruiting bodies at high temperature when humidity conditions were favorable. Strains of the variety bisporus showed interesting potentials for their ability to produce mature fruiting bodies at higher temperature than present cultivars and might be used in breeding programs. PMID- 23810788 TI - The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial. AB - BACKGROUND: Poly(ADP-ribose) polymerase (PARP) is implicated in DNA repair and transcription regulation. Niraparib (MK4827) is an oral potent, selective PARP-1 and PARP-2 inhibitor that induces synthetic lethality in preclinical tumour models with loss of BRCA and PTEN function. We investigated the safety, tolerability, maximum tolerated dose, pharmacokinetic and pharmacodynamic profiles, and preliminary antitumour activity of niraparib. METHODS: In a phase 1 dose-escalation study, we enrolled patients with advanced solid tumours at one site in the UK and two sites in the USA. Eligible patients were aged at least 18 years; had a life expectancy of at least 12 weeks; had an Eastern Cooperative Oncology Group performance status of 2 or less; had assessable disease; were not suitable to receive any established treatments; had adequate organ function; and had discontinued any previous anticancer treatments at least 4 weeks previously. In part A, cohorts of three to six patients, enriched for BRCA1 and BRCA2 mutation carriers, received niraparib daily at ten escalating doses from 30 mg to 400 mg in a 21-day cycle to establish the maximum tolerated dose. Dose expansion at the maximum tolerated dose was pursued in 15 patients to confirm tolerability. In part B, we further investigated the maximum tolerated dose in patients with sporadic platinum-resistant high-grade serous ovarian cancer and sporadic prostate cancer. We obtained blood, circulating tumour cells, and optional paired tumour biopsies for pharmacokinetic and pharmacodynamic assessments. Toxic effects were assessed by common toxicity criteria and tumour responses ascribed by Response Evaluation Criteria in Solid Tumors (RECIST). Circulating tumour cells and archival tumour tissue in prostate patients were analysed for exploratory putative predictive biomarkers, such as loss of PTEN expression and ETS rearrangements. This trial is registered with ClinicalTrials.gov, NCT00749502. FINDINGS: Between Sept 15, 2008, and Jan 14, 2011, we enrolled 100 patients: 60 in part A and 40 in part B. 300 mg/day was established as the maximum tolerated dose. Dose-limiting toxic effects reported in the first cycle were grade 3 fatigue (one patient given 30 mg/day), grade 3 pneumonitis (one given 60 mg/day), and grade 4 thrombocytopenia (two given 400 mg/day). Common treatment-related toxic effects were anaemia (48 patients [48%]), nausea (42 [42%]), fatigue (42 [42%]), thrombocytopenia (35 [35%]), anorexia (26 [26%]), neutropenia (24 [24%]), constipation (23 [23%]), and vomiting (20 [20%]), and were predominantly grade 1 or 2. Pharmacokinetics were dose proportional and the mean terminal elimination half-life was 36.4 h (range 32.8-46.0). Pharmacodynamic analyses confirmed PARP inhibition exceeded 50% at doses greater than 80 mg/day and antitumour activity was documented beyond doses of 60 mg/day. Eight (40% [95% CI 19-64]) of 20 BRCA1 or BRCA2 mutation carriers with ovarian cancer had RECIST partial responses, as did two (50% [7-93]) of four mutation carriers with breast cancer. Antitumour activity was also reported in sporadic high-grade serous ovarian cancer, non-small-cell lung cancer, and prostate cancer. We recorded no correlation between loss of PTEN expression or ETS rearrangements and measures of antitumour activity in patients with prostate cancer. INTERPRETATION: A recommended phase 2 dose of 300 mg/day niraparib is well tolerated. Niraparib should be further assessed in inherited and sporadic cancers with homologous recombination DNA repair defects and to target PARP-mediated transcription in cancer. FUNDING: Merck Sharp and Dohme. PMID- 23810789 TI - PARP inhibitors: pitfalls and promises. PMID- 23810790 TI - Establishment and evaluation of a swine model of acute myocardial infarction and reperfusion-ventricular fibrillation-cardiac arrest using the interventional technique. AB - BACKGROUND: Ventricular fibrillation is the main cause of sudden cardiac death among patients with acute myocardial infarction (AMI). Substantial benefits could be obtained by both researchers and practitioners if an AMI reperfusion ventricular fibrillation-cardiac arrest model were established. METHODS: Twenty swine were anesthetized and underwent occlusion of the left anterior descending branch for 90 minutes prior to blood reperfusion. Throughout this process, continuous 12-lead electrocardiography (ECG) was used to monitor heart rate, rhythm, and electrocardiogram alteration. Thereafter, AMI was confirmed by ECG and left ventricular angiography. Heart tissue was collected for pathological analysis, and for evaluation of the establishment of a model of AMI reperfusion. RESULTS: Seven swine died during the model establishment, and the 13 surviving swine were proven to have myocardial infarction; nine of those survivors had ventricular fibrillation-cardiac arrest after reperfusion based on the electrocardiograph and pathological examination. CONCLUSION: Blocking the left anterior descending branch by inflation of an over-the-wire coronary balloon catheter in swine can result in successful establishment of a swine model of AMI and reperfusion-ventricular fibrillation-cardiac arrest, with good reproducibility and a high survival rate. PMID- 23810791 TI - Chocolate and the brain: neurobiological impact of cocoa flavanols on cognition and behavior. AB - Cocoa products and chocolate have recently been recognized as a rich source of flavonoids, mainly flavanols, potent antioxidant and anti-inflammatory agents with established benefits for cardiovascular health but largely unproven effects on neurocognition and behavior. In this review, we focus on neuromodulatory and neuroprotective actions of cocoa flavanols in humans. The absorbed flavonoids penetrate and accumulate in the brain regions involved in learning and memory, especially the hippocampus. The neurobiological actions of flavanols are believed to occur in two major ways: (i) via direct interactions with cellular cascades yielding expression of neuroprotective and neuromodulatory proteins that promote neurogenesis, neuronal function and brain connectivity, and (ii) via blood-flow improvement and angiogenesis in the brain and sensory systems. Protective effects of long-term flavanol consumption on neurocognition and behavior, including age- and disease-related cognitive decline, were shown in animal models of normal aging, dementia, and stroke. A few human observational and intervention studies appear to corroborate these findings. Evidence on more immediate action of cocoa flavanols remains limited and inconclusive, but warrants further research. As an outline for future research on cocoa flavanol impact on human cognition, mood, and behavior, we underscore combination of functional neuroimaging with cognitive and behavioral measures of performance. PMID- 23810792 TI - How to critically read the GI epidemiology literature. PMID- 23810793 TI - Octaphlorethol A isolated from Ishige foliacea inhibits alpha-MSH-stimulated induced melanogenesis via ERK pathway in B16F10 melanoma cells. AB - In this study, the potent skin-whitening effects of Octaphlorethol A (OPA) isolated from Ishige foliacea was investigated through inhibitory effect of melanin synthesis and tyrosinase activity in alpha-melanocyte stimulating hormone (alpha-MSH) induced B16F10 melanoma cells. OPA markedly inhibited melanin synthesis and tyrosinase activity in a concentration-dependent manner. We also found that OPA decreased microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein-1 and -2 (TRP-1 and TRP-2) protein expressions. Moreover, OPA reduces p38 MAPK protein levels and activates extracellular signal-regulated kinase (ERK) and c-jun N-terminal kinases (JNKs) protein expressions in B16F10 cells. A specific ERK inhibitor PD98059 significantly blocks OPA-inhibited melanin synthesis and tyrosinase activity, whereas a p38MAP and JNK inhibitor had no effect. These findings provide evidence demonstrating that the anti-melanogenic effect of OPA is mediated through the activation of ERK signal pathway in B16F10 cells. These results indicate that OPA has the potential to be used as a melanogenesis inhibitor in the food and cosmetics industry. PMID- 23810794 TI - Resveratrol regulates the cell viability promoted by 17beta-estradiol or bisphenol A via down-regulation of the cross-talk between estrogen receptor alpha and insulin growth factor-1 receptor in BG-1 ovarian cancer cells. AB - Endocrine disrupting chemicals (EDCs) and estrogens appear to promote development of estrogen-dependent cancers, including breast and ovarian carcinomas. In this study, we evaluated the cell viability effect of BPA on BG-1 human ovarian cancer cells, along with the growth inhibitory effect of resveratrol (trans-3,4,5 trihydroxystilbene; RES), a naturally occurring phytoestrogen. In addition, we investigated the underlying mechanism(s) of BPA and RES in regulating the interaction between estrogen receptor alpha (ERalpha) and insulin-like growth factor-1 receptor (IGF-1R) signals, a non- genomic pathway induced by 17beta estradiol (E2). BPA induced a significant increase in BG-1 cell growth and up regulated mRNA levels of ERalpha and IGF-1R. In parallel with its mRNA level, the protein expression of ERalpha was induced, and phosphorylated insulin receptor substrate-1 (p-IRS-1), phosphorylated Akt1/2/3, and cyclin D1 were increased by BPA or E2. However, RES effectively reversed the BG-1 cell proliferation induced by E2 or BPA by inversely down-regulating the expressions of ERalpha, IGF-1R, p IRS-1, and p-Akt1/2/3, and cyclin D1 at both transcriptional and translational levels. Taken together, these results suggest that RES is a novel candidate for prevention of tumor progression caused by EDCs, including BPA via effective inhibition of the cross-talk of ERalpha and IGF-1R signaling pathways. PMID- 23810796 TI - Genotoxicity and induction of DNA damage responsive genes by food-borne heterocyclic aromatic amines in human hepatoma HepG2 cells. AB - Heterocyclic aromatic amines (HAAs) are potential human carcinogens formed in well-done meats and fish. The most abundant are 2-Amino-1-methyl-6 phenylimidazo[4,5-b]pyridine (PhIP), 2-Amino-3,8-dimethylimidazo[4,5 f]quinoxaline (MeIQx), 2-Amino-3,4,8-trimethyl-3H-imidazo[4,5-f]quinoxaline (4,8 DiMeIQx) and 2-Amino-3-methyl-3H-imidazo[4,5-f]quinoline (IQ). HAAs exert genotoxic activity after metabolic transformation by CYP1A enzymes, that is well characterized, however the genomic and intervening responses are not well explored. We have examined cellular and genomic responses of human hepatoma HepG2 cells after 24h exposure to HAAs. Comet assay revealed increase in formation of DNA strand breaks by PhIP, MeIQx and IQ but not 4,8-DiMeIQx, whereas increased formation of micronuclei was not observed. The four HAAs up-regulated expression of genes encoding metabolic enzymes CYP1A1, CYP1A2 and UGT1A1 and expression of TP53 and its downstream regulated genes CDKN1A, GADD45alpha and BAX. Consistent with the up-regulation of CDKN1A and GADD45alpha the cell-cycle analysis showed arrest in S-phase by PhIP and IQ, and in G1-phase by 4,8-DiMeIQx and MeIQx. The results indicate that upon exposure to HAAs the cells respond with the cell-cycle arrest, which enables cells to repair the damage or eliminate them by apoptosis. However, elevated expression of BCL2 and down-regulation of BAX may indicate that HAAs could suppress apoptosis meaning higher probability of damaged cells to survive and mutate. PMID- 23810795 TI - Sasa quelpaertensis Nakai extract and its constituent p-coumaric acid inhibit adipogenesis in 3T3-L1 cells through activation of the AMPK pathway. AB - In this study, we investigated the effects of Sasa quelpaertensis Nakai extract (SQE) and its main constituent, p-coumaric acid, on adipogenesis in 3T3-L1 cells. SQE markedly inhibited adipogenesis by downregulating the expression of CCAAT/enhancer-binding protein alpha (C/EBPalpha), peroxisome proliferator activated receptor gamma (PPARgamma), sterol regulatory element-binding protein 1c (SREBP-1c), and aP2. It also decreased the expression of fatty acid synthase (FAS) and adiponectin mRNAs in differentiating adipocytes. SQE increased AMP activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) phosphorylation during the early phase of MDI-induced differentiation, suggesting that SQE exerted its anti-adipogenic effect via AMPK activation at an early stage of the differentiation process. p-Coumaric acid suppressed adipogenesis by attenuating the expression of C/EBPalpha, PPARgamma, and SREBP-1c during the late phase of MDI-induced differentiation. In addition, p-coumaric acid increased the phosphorylation of AMPK and ACC, and the expression of carnitine palmitoyl transferase-1 (CPT-1) mRNA, in fully differentiated adipocytes, indicating that it promotes fatty acid beta-oxidation via AMPK signaling. Taken together, our data suggest that SQE and p-coumaric acid might have the anti-obesitic effects via AMPK pathway in 3T3-L1 cells. PMID- 23810797 TI - Protective role of sodium selenite on histopathological lesions, decreased T-cell subsets and increased apoptosis of thymus in broilers intoxicated with aflatoxin B1. AB - For evaluating the ability of selenium (Se) in counteracting the adverse effects of aflatoxin B1 (AFB1), two hundred 1-day-old male Avian broilers, divided into five groups, were fed with basal diet (control group), 0.3 mg/kg AFB1 (AFB1 group), 0.3 mg/kg AFB1+0.2 mg/kg Se (+Se group I), 0.3mg/kg AFB1+0.4 mg/kg Se (+Se group II) and 0.3mg/kg AFB1+0.6 mg/kg Se (+Se group III), respectively. Compared with control group, the decreased relative weight of thymus and percentages of mature thymocytes, congestion in medulla and much debris in cortex of thymus, and the increased apoptotic thymocytes were observed in AFB1 group. However, supplied dietary sodium selenite could increase the relative weight of thymus and percentages of mature thymocytes, and alleviate histopathological lesions. Compared with AFB1 group, the percentages of apoptotic thymocytes detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling method and flow cytometry method in three +Se groups were decreased, the expression of Caspase-3 and Bax, through quantitative real-time PCR and immunohistochemical method, in three +Se groups were decreased, while the expression of Bcl-2 was increased. The results indicate that sodium selenite supplied in the diet, through a mechanism of apoptosis regulation, may ameliorated AFB1-induced lesions of thymus and accordingly improve the impaired cellular immune function. PMID- 23810799 TI - Post-ischemic administration of progesterone reduces caspase-3 activation and DNA fragmentation in the hippocampus following global cerebral ischemia. AB - Delayed death of hippocampal CA1 pyramidal neurons following global cerebral ischemia/reperfusion may be mediated, in part, by caspase-3 activation resulting in DNA fragmentation. Progesterone (P4) is known to exert neuroprotective effects in several models of brain injury. This study was designed to assess the effect of P4 on caspase-3 levels and activation, and DNA fragmentation in the hippocampus following global cerebral ischemia/reperfusion. Adult male Sprague Dawley rats were subjected to global ischemia by the four-vessel occlusion model. P4 (8 mg/kg), or its vehicle were administered i.v. at 15 min, 2, 6, 24, 48 and 70 h of reperfusion. Remaining pyramidal neurons were assesed by the Nissl staining technique, caspase-3 levels and activation by immunohistochemistry and an in situ activity assay, and DNA fragmentation by the TUNEL method. Post ischemic progesterone treatment significantly reduced the ischemia/reperfusion induced increase in caspase-3 levels and activation at 72 h, and DNA fragmentation and CA1 neuronal loss at 7 days. Present results suggest the reduction of caspase-3 levels/activation, and DNA fragmentation, as a part of the neuroprotective effects of progesterone against global cerebral ischemia/reperfusion injury. PMID- 23810800 TI - Visual emotional information processing in male schizophrenia patients: combining ERP, clinical and behavioral evidence. AB - We used event-related potentials (ERPs) to examine the time course of visual emotion processing in schizophrenia. ERPs were recorded in 19 chronic male schizophrenia patients and 16 healthy controls (HC) while they viewed IAPS pictures used to induce positive, negative, or neutral mood, presented in a blocked design across three separate occasions. Electrophysiologically, groups differences were found in early potentials (the first 200 ms of picture viewing): C1, P1, and N1; also, less positive, broadly distributed P2 was found in the patient group. P2 amplitude to negative valenced pictures only was correlated with self-reported negative mood in the patients. The groups did not differ in late-occurring potentials, specifically the late positive potential (500-1000 ms latency window). Patients reported more negative affect before and after the three types of mood induction; however, mood induction influenced both groups in the same direction. Both groups showed similar subjective valence and arousal ratings of evocative stimuli. The ERP results suggest that visual evocative stimuli are differentially processed within the first 200 ms, and that the early stages of visual evocative stimuli processing are abnormal in schizophrenia, irrespective of stimulus valence. The correlation found between sensory abnormalities in negative pictures processing and negative mood suggests a relationship between abnormal sensory processes and increased negative mood experience in patients. PMID- 23810802 TI - The histidine triad nucleotide binding 1 protein is involved in nicotine reward and physical nicotine withdrawal in mice. AB - Smoking rates among individuals with schizophrenia are significantly higher than the general population. One possible explanation for this comorbidity is that there are shared genes and biological pathways between smoking and schizophrenia. The histidine triad nucleotide binding protein 1 (HINT1) is a potential candidate, as genetic association and expression studies implicate the gene in both schizophrenia and nicotine dependence; however, the behavioral role of HINT1 in nicotine dependence is unknown. Thus, the goal of the current study was to determine the behavioral role of HINT1 in nicotine dependence. We tested male HINT1 wild-type (+/+) and knockout (-/-) mice in the nicotine conditioned place preference (CPP) test of reward, a nicotine withdrawal model assessing both physical and affective signs, and the nicotine withdrawal conditioned place aversion (CPA) test. HINT1 -/- mice failed to develop a significant nicotine CPP and physical withdrawal signs (hyperalgesia and somatic signs) were attenuated in HINT1 -/- mice. Conversely, HINT1 -/- mice developed a significant nicotine withdrawal CPA similar to their ++ counterparts. Overall, our data support a role for the HINT1 gene in mediating behaviors associated with nicotine reward and physical nicotine withdrawal, and provide insight into the role of HINT1 in nicotine dependence-like behaviors. PMID- 23810801 TI - FDG-PET imaging reveals local brain glucose utilization is altered by class I histone deacetylase inhibitors. AB - The purpose of this work--the first of its kind--was to evaluate the impact of chronic selective histone deacetylase (HDAC) inhibitor treatment on brain activity using uptake of the radioligand (18)F-fluorodeoxyglucose and positron emission tomography ((18)FDG-PET). HDAC dysfunction and other epigenetic mechanisms are implicated in diverse CNS disorders and animal research suggests HDAC inhibition may provide a lead toward developing improved treatment. To begin to better understand the role of the class I HDAC subtypes HDAC 1, 2 and 3 in modulating brain activity, we utilized two benzamide inhibitors from the literature, compound 60 (Cpd-60) and CI-994 which selectively inhibit HDAC 1 and 2 or HDACs 1, 2 and 3, respectively. One day after the seventh treatment with Cpd 60 (22.5 mg/kg) or CI-994 (5 mg/kg), (18)FDG-PET experiments (n=11-12 rats per treatment group) revealed significant, local changes in brain glucose utilization. These 2-17% changes were represented by increases and decreases in glucose uptake. The pattern of changes was similar but distinct between Cpd-60 and CI-994, supporting that (18)FDG-PET is a useful tool to examine the relationship between HDAC subtype activity and brain activity. Further work using additional selective HDAC inhibitors will be needed to clarify these effects as well as to understand how brain activity changes influence behavioral response. PMID- 23810798 TI - MicroRNAs as pharmacological targets in diabetes. AB - Diabetes is characterized by high levels of blood glucose due to either the loss of insulin-producing beta-cells in the pancreas, leading to a deficiency of insulin in type 1 diabetes, or due to increased insulin resistance, leading to reduced insulin sensitivity and productivity in type 2 diabetes. There is an increasing need for new options to treat diabetes, especially type 2 diabetes at its early stages due to an ineffective control of its development in patients. Recently, a novel class of small noncoding RNAs, termed microRNAs (miRNAs), is found to play a key role as important transcriptional and posttranscriptional inhibitors of gene expression in fine-tuning the target messenger RNAs (mRNAs). miRNAs are implicated in the pathogenesis of diabetes and have become an intriguing target for therapeutic intervention. This review focuses on the dysregulated miRNAs discovered in various diabetic models and addresses the potential for miRNAs to be therapeutic targets in the treatment of diabetes. PMID- 23810803 TI - Median nerve stimulation modulates extracellular signals in the primary motor area of a macaque monkey. AB - Aiming to better define the functional influence of somatosensory stimuli on the primary motor cortex (M1) of primates, we investigated changes in extracellular neural activity induced by repetitive median nerve stimulation (MNS). We described neural adaptation and signal integration in both the multiunit activity (MUA) and the local field potential (LFP). To identify integration of initial M1 activity in the MNS response, we tested the correlation between peak amplitude responses and band energy preceding the peaks. Most of the sites studied in the M1 resulted responsive to MNS. MUA response peak amplitude decreased significantly in time in all sites during repetitive MNS, LFP response peak amplitude instead resulted more variable. Similarly, correlation analysis with the initial activity revealed a significant influence when tested using MUA peak amplitude modulation and a less significant correlation when tested using LFP peak amplitude. Our findings improve current knowledge on mechanisms underlying early M1 changes consequent to afferent somatosensory stimuli. PMID- 23810804 TI - Hyperphosphorylation of tau protein by calpain regulation in retina of Alzheimer's disease transgenic mouse. AB - Aim to investigate phosphorylated tau expression and its pathogenic mechanism in eye of Alzheimer's disease (AD) transgenic mice. Levels of tau, phosphorylated tau and other related factors (p35/p25, Cyclin-dependent kinase 5 (Cdk5), calpain) were observed by western blot. beta-Amyloid (Abeta) plaques and neuron fibrillary tangles (NFTs) in APP/PS1 double transgenic mice were detected by immuno-histochemistry. We found that hyper-expression of phosphorylated tau was detected in retina, and only a few or no expressed in optic nerve, cornea and lens of transgenic mice. Increased senile plaques (Abeta) and NFTs were observed in transgenic mice accompanying with increased tau phosphorylation. The increased tau phosphorylation was associated with a significant increase in production of p35 and p25, and up-regulation of calpain. In conclusion, phosphorylated tau level was highly expressed in retina of AD transgenic mice. The pathogenic mechanism of AD was triggered by accelerating tau pathology via calpain-mediated tau hyper-phosphorylation in retina of an AD mice model. PMID- 23810805 TI - First isolation of Clostridium perfringens type E from a goat with diarrhea. AB - A 2-day-old goat died suddenly after the onset of severe diarrhea. No specific gross lesions were observed except for a remarkably thin intestinal wall and watery intestinal contents. Histopathological analysis revealed large numbers of Gram-positive bacilli layered upon the intestinal epithelia of the small intestine. Heavy growth of only Clostridium perfringens type E, and no detection of the other enteric pathogens in the small intestine, suggests that C. perfringens type E contributed to the death of this kid. To our knowledge, this is the first isolation of C. perfringens type E from a goat with diarrhea. PMID- 23810806 TI - Mode of binding of RNA polymerase alpha subunit to the phased A-tracts upstream of the phospholipase C gene promoter of Clostridium perfringens. AB - Three phased A5-6-tracts lie upstream of the promoter of plc encoding the alpha toxin (phospholipase C) of Clostridium perfringens. The alpha subunits of C. perfringens RNA polymerase bind directly to the phased A-tracts via the C terminal domain of the alpha subunit (alphaCTD). To identify the amino acid residues involved in the binding of C. perfringens alpha subunits to the phased A tracts, 27 amino acid residues in C. perfringens alphaCTD were substituted with alanine. The affinities of the mutated alpha subunits for the phased A-tracts were examined by gel shift assays and surface plasmon resonance (SPR). The SPR analyses revealed that the phased A-tracts themselves facilitated a complex formation between the phased A-tracts and C. perfringens alpha subunits [Kd was 6.1 (+/-0.3) * 10(-8) M], and that Arg261, Asn264, Gly292 and Lys294 in C. perfringens alphaCTD were critical for the binding to the phased A-tracts. The topology of these amino acid residues on the predicted structure of C. perfringens alphaCTD indicated a contact path with the phased A-tracts that was similar to that of Escherichia coli alphaCTD with the upstream (UP) element. On the other hand, SPR analyses at different temperatures (15, 25 and 37 degrees C) indicated that the affinity of the C. perfringens alpha subunits for the phased A tracts increased in a low-temperature-dependent manner, whereas that of the E. coli alpha subunit for the UP element did not. This suggests that the phased A tracts may not simply be a subset of the UP element, and that they show specific binding activity with the RNA polymerase alpha subunit. PMID- 23810807 TI - Functional and structural evaluation of lamotrigine treatment in rat models of acute and chronic ocular hypertension. AB - Voltage gated sodium channels (Nav), are proposed mediators of neuronal damage in ischemic and excitotoxicity disease models. We evaluated the neuroprotective effects of lamotrigine, a Nav blocker, in the acute and chronic rat ocular hypertension models. Additionally, expression of the main Nav subtypes in the optic nerve (ON) was assessed to test whether their upregulation plays a role in the pathogenesis of ocular hypertension induced optic neuropathy. Unilateral intraocular pressure (IOP) elevation was induced for 60 min (80 mmHg) and 14-21 days (670-859 mmHg*day) in the acute and chronic models, respectively. Lamotrigine was administered at dosages of 10 mg/kg twice daily and 12.5 mg/kg once daily in the acute (n = 9) and chronic (n = 11) trials, respectively. Treatment began 2 days prior to IOP elevation until sacrifice. Outer and inner retinal function was evaluated with dark- and light-adapted flash electroretinography and pattern electroretinography, respectively, 6 and 14 days post acute IOP elevation and 13, 28 and 48 days post chronic IOP elevation. Retinal ganglion cell and axon densities and inflammatory reaction were evaluated through Fluorogold, Bielschowsky's silver impregnation and ED1 labeling respectively. Immunohistochemistry for Nav1.1, 1.2 and 1.6 was performed in ONs of untreated rats 7 and 15 days post IOP elevation in the acute model and after 7, 28 and 50 days in the chronic model. In the acute model, no differences were found in the a-wave amplitudes between lamotrigine-treated and vehicle-treated rats. B-wave amplitudes decreased by 40-66% in both treatment groups 6 days post IOP elevation, with no significant difference between groups (p = 0.38). However, a partial recovery of b-wave amplitudes was found in lamotrigine-treated rats between day 6 and day 14 post procedure (p < 0.05). No differences were found in any other parameter tested in this model. Similarly, lamotrigine treatment did not result in any beneficial effect in structural parameters of the chronic model. Functional evaluation of this model was inconclusive due to super-normal values in the hypertensive eyes. Up-regulation of Nav1.1 and 1.2 expression was found in both models, beginning by day 7; an increase of the former continued in a time-dependent manner in the chronic model. Nav1.6 labeling was inconclusive. In conclusion we found lamotrigine treatment to be mostly ineffective in both acute and chronic ocular hypertension models. PMID- 23810808 TI - Regulation of Na,K-ATPase beta1-subunit in TGF-beta2-mediated epithelial-to mesenchymal transition in human retinal pigmented epithelial cells. AB - Proliferative vitreo retinopathy (PVR) is associated with extracellular matrix membrane (ECM) formation on the neural retina and disruption of the multilayered retinal architecture leading to distorted vision and blindness. During disease progression in PVR, retinal pigmented epithelial cells (RPE) lose cell-cell adhesion, undergo epithelial-to-mesenchymal transition (EMT), and deposit ECM leading to tissue fibrosis. The EMT process is mediated via exposure to vitreous cytokines and growth factors such as TGF-beta2. Previous studies have shown that Na,K-ATPase is required for maintaining a normal polarized epithelial phenotype and that decreased Na,K-ATPase function and subunit levels are associated with TGF-beta1-mediated EMT in kidney cells. In contrast to the basolateral localization of Na,K-ATPase in most epithelia, including kidney, Na,K-ATPase is found on the apical membrane in RPE cells. We now show that EMT is also associated with altered Na,K-ATPase expression in RPE cells. TGF-beta2 treatment of ARPE-19 cells resulted in a time-dependent decrease in Na,K-ATPase beta1 mRNA and protein levels while Na,K-ATPase alpha1 levels, Na,K-ATPase activity, and intracellular sodium levels remained largely unchanged. In TGF-beta2-treated cells reduced Na,K-ATPase beta1 mRNA inversely correlated with HIF-1alpha levels and analysis of the Na,K-ATPase beta1 promoter revealed a putative hypoxia response element (HRE). HIF-1alpha bound to the Na,K-ATPase beta1 promoter and inhibiting the activity of HIF-1alpha blocked the TGF-beta2 mediated Na,K-ATPase beta1 decrease suggesting that HIF-1alpha plays a potential role in Na,K-ATPase beta1 regulation during EMT in RPE cells. Furthermore, knockdown of Na,K-ATPase beta1 in ARPE-19 cells was associated with a change in cell morphology from epithelial to mesenchymal and induction of EMT markers such as alpha-smooth muscle actin and fibronectin, suggesting that loss of Na,K-ATPase beta1 is a potential contributor to TGF-beta2-mediated EMT in RPE cells. PMID- 23810810 TI - TGF-beta2 promotes RPE cell invasion into a collagen gel by mediating urokinase type plasminogen activator (uPA) expression. AB - Transforming growth factor-beta (TGF-beta) is one of the main epithelial mesenchymal transition (EMT)-inducing factors. In general, TGF-beta-induced EMT promotes cell migration and invasion. TGF-beta also acts as a potent regulator of pericellular proteolysis by regulating the expression and secretion of plasminogen activators. Urokinase-type plasminogen activator (uPA) is a serine protease that binds to its cell surface receptor (uPAR) with high affinity. uPA binding to uPAR stimulates uPAR's interaction with transmembrane proteins, such as integrins, to regulate cytoskeletal reorganization and cell migration, differentiation and proliferation. However, the influence of TGF-beta and the uPA/uPAR system on EMT in retinal pigment epithelial (RPE) cells is still unclear. The purpose of this study was to determine the effect of TGF-beta2, which is the predominant isoform in the retina, and the uPA/uPAR system on RPE cells. In this study, we first examined the effect of TGF-beta2 and/or the inhibitor of uPA (u-PA-STOP((r))) on the proliferation of a human retinal pigment epithelial cell line (ARPE-19 cells). Treatment with TGF-beta2 or u-PA-STOP((r)) suppressed cell proliferation. Combination treatment of TGF-beta2 and u-PA STOP((r)) enhanced cell growth suppression. Furthermore, western blot analysis, fibrin zymography and real-time reverse transcription PCR showed that that TGF beta2 induced EMT in ARPE-19 cells and that the expression of uPA and uPAR expression was up-regulated during EMT. The TGF-beta inhibitor SB431542 suppressed TGF-beta2-stimulated uPA expression and secretion but did not suppress uPAR expression. Furthermore, we seeded ARPE-19 cells onto Transwell chambers and allowed them to invade the collagen matrix in the presence of TGF-beta2 alone or with TGF-beta2 and u-PA-STOP((r)). TGF-beta2 treatment induced ARPE-19 cell invasion into the collagen gel. Treatment with a combination of TGF-beta2 and the uPA inhibitor strongly inhibited ARPE-19 cell invasion compared with treatment with TGF-beta2 alone. Furthermore, the interaction between uPA and ARPE-19 cells was analyzed using a surface plasmon biosensor system. The binding of uPA to ARPE 19 cells was observed. In addition, TGF-beta2 significantly promoted the binding activity of uPA to ARPE-19 cells in a time-dependent or cell-number-dependent fashion. These results indicate that TGF-beta-induced EMT-associated phenotype changes in ARPE-19 cells and the invasiveness of ARPE-19 cells into a collagen gel matrix are mediated, at least in part, by uPA. PMID- 23810809 TI - Attenuation of streptozotocin-induced diabetic retinopathy with low molecular weight fucoidan via inhibition of vascular endothelial growth factor. AB - Diabetic retinopathy (DR) is a hyperglycemia-induced ischemic disorder characterized by microvascular dysfunction and neovascularization. It is a leading cause of blindness in many countries, yet efficient drugs are limited now for prevention and treatment of DR. Low molecular weight fucoidan (LMWF), extract from brown algae, has been shown to possess multiple biological activities like anti-inflammation, anti-oxidation and anti-aggregation, which all could be beneficial for attenuating ischemia-induced tissue damages. Here, by comparing with calcium dobesilate, the potent antioxidant compound currently used for the treatment of DR, we investigated the protective effect of LMWF against DR in streptozotocin-induced diabetic mice and high glucose-promoted vascular endothelial growth factor (VEGF) production and cell proliferation in microvascular endothelial cells. One week after diabetes induction, the mice were administered with LMWF (50, 100 or 200 mg/kg/day) or calcium dobesilate (200 mg/kg/day) for four months, then the retinal pathological changes and neovascularization were detected by hematoxylin-eosin staining and fluorescein dextran angiography, respectively. Immunofluorescence staining, ELISA and RT-PCR were used to examine the expression levels of hypoxia-inducible factor-1alpha (HIF-1alpha) and VEGF in retina and endothelial cells. Here, we found that LMWF resembled calcium dobesilate, in alleviating retinal pathological change and hindering neovascularization due to diabetes in vivo. The relative levels of VEGF expression and HIF-1alpha induction were also less in retinas of LMWF- or calcium dobesilate-treated diabetic mice than those in retinas of control mice. Furthermore, high glucose-induced VEGF overexpression and cell proliferation in primary cultured vascular endothelial cells were also inhibited by LMWF in a dose dependent manner. Therefore, this study demonstrated that LMWF alleviates diabetic retinal neovascularization and damage likely through lowering HIF-1alpha and VEGF expressions, providing a potential candidate drug for prevention and treatment of diabetic retinopathy. PMID- 23810811 TI - A systematic comparison between subjects with no pain and pain associated with active myofascial trigger points. AB - OBJECTIVE: To determine whether standard evaluations of pain distinguish subjects with no pain from those with myofascial pain syndromes (MPS) and active myofascial trigger points (MTrPs) and to assess whether self-reports of mood, function, and health-related quality of life differ between these groups. DESIGN: A prospective, descriptive study. SETTING: University. PATIENTS: Adults with and without neck pain. METHODS: We evaluated adults with MPS and active (painful) MTrPs and those without pain. Subjects in the "active" (A) group had at least one active MTrP with spontaneous pain that was persistent, lasted longer than 3 months, and had characteristic pain on palpation. Subjects in the "no pain" (NP) group had no spontaneous pain. However, some of these subjects had discomfort upon MTrP palpation (latent MTrP), whereas others in the NP group had no discomfort upon palpation of nodules or had no nodules. OUTCOME MEASURES: Each participant underwent range of motion measurement, a 10-point manual muscle test, and manual and algometric palpation. The latter determined the pain/pressure threshold using an algometer of 4 predetermined anatomic sites along the upper trapezius. Participants rated pain using a verbal analog scale (0-10) and completed the Brief Pain Inventory and Oswestry Disability Scale (which included a sleep subscale), the Short -Form 36 Health Survey, and the Profile of Mood States. RESULTS: The A group included 24 subjects (mean age 36 years; 16 women), and the NP group included 26 subjects (mean age 26 years; 12 women). Group A subjects differed from NP subjects in the number of latent MTrPs (P = .0062), asymmetrical cervical range of motion (P = .01 for side bending and P = .002 for rotation), and in all pain reports (P < .0001), algometry (P < .03), Profile of Mood States (P < .038), Short Form 36 Health Survey (P < .01), and Oswestry Disability Scale (P < .0001). CONCLUSION: A systematic musculoskeletal evaluation of people with MPS reliably distinguishes them from subjects with no pain. The 2 groups are significantly different in their physical findings and self-reports of pain, sleep disturbance, disability, health status, and mood. These findings support the view that a "local" pain syndrome has significant associations with mood, health-related quality of life, and function. PMID- 23810812 TI - A preliminary assessment of a novel pneumatic unloading knee brace on the gait mechanics of patients with knee osteoarthritis. AB - OBJECTIVES: To determine whether a knee brace incorporating inflatable air bladders can alter the net peak external knee adduction moment in persons with medial compartment knee osteoarthritis. DESIGN: Prospective cohort study. SETTING: Motion analysis laboratory. PARTICIPANTS: Subjects (n = 18) diagnosed with knee osteoarthritis as defined by the Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. METHODS: Instrumented gait analysis was performed while subjects walked with and without the knee brace. When subjects wore the knee brace, the air bladders were either uninflated or inflated to 7 psi. The net external knee adduction moment was obtained by subtracting the abduction moment produced by the knee brace (estimated using a finite element analysis model) from the external knee adduction moment (estimated using a camera-based motion analysis system). MAIN OUTCOME MEASUREMENTS: The net external knee adduction moment was compared across all testing conditions. RESULTS: A 7.6% decrease in net peak external knee adduction moment was observed when subjects wore the knee brace uninflated compared with when they did not wear the brace. Inflation of the bladders to 7 psi led to a 26.0% decrease in net peak external knee adduction moment. CONCLUSIONS: The results of the study suggest that the effects of an unloading knee brace may be enhanced by incorporating inflatable air bladders into the design of the brace, thus leading to an improved correction of the excessive peak external knee adduction moment observed in patients with medial compartment knee osteoarthritis. PMID- 23810813 TI - Medical device-related hospital-acquired pressure ulcers in children: an integrative review. AB - The management, cost, physical and emotional suffering associated with pressure ulcers have a significant impact on the health status of patients-especially infants and children. The purpose of this integrative review was to identify factors associated with medical device-related (MDR) hospital acquired pressure ulcers (HAPUs) in the pediatric population. Pediatric MDR HAPUs are becoming more prevalent and require further exploration in terms of describing devices which cause injury and preventive interventions to improve patient outcomes. Opportunities to uncover new methods for addressing this important problem and to inform and advance the state of the science in this evolving area exist. PMID- 23810814 TI - WITHDRAWN: A Descriptive Review Article for Pump Initiation in a Pediatric Diabetes Centre. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, DOI of original article:10.1016/j.pedn.2013.01.005. The duplicate article has therefore been withdrawn. PMID- 23810815 TI - Optimal time interval between a single course of antenatal corticosteroids and delivery for reduction of respiratory distress syndrome in preterm twins. AB - OBJECTIVE: The objective of the study was to investigate the effect of a single course of antenatal corticosteroid (ACS) therapy on the incidence of respiratory distress syndrome (RDS) in preterm twins according to the time interval between ACS administration and delivery. STUDY DESIGN: We performed a retrospective cohort study of twins born between 24 and 34 weeks of gestation from November 1995 to May 2011. Subjects were grouped on the basis of the time interval between the first ACS dose and delivery: the ACS-to-delivery interval of less than 2 days (n = 166), 2-7 days (n = 114), and more than 7 days (n = 66). Pregnancy and neonatal outcomes of each group were compared with a control group of twins who were not exposed to ACS (n = 122). Multiple logistic regression analysis was used to examine the association between the ACS-to-delivery interval and the incidence of RDS after adjusting for potential confounding variables. RESULTS: Compared with the ACS nonexposure group, the incidence of RDS in the group with an ACS-to delivery interval of less than 2 days was not significantly different (adjusted odds ratio [aOR], 1.089; 95% confidence interval [CI], 0.524-2.262; P = .819). RDS occurred significantly less frequently when the ACS-to-delivery interval was between 2 and 7 days (aOR, 0.419; 95% CI, 0.181-0.968; P = .042). However, there was no significant reduction in the incidence of RDS when the ACS-to-delivery interval exceeded 7 days (aOR, 2.205; 95% CI, 0.773-6.292; P = .139). CONCLUSION: In twin pregnancies, a single course of ACS treatment was associated with a decreased rate of RDS only when the ACS-to-delivery interval was between 2 and 7 days. PMID- 23810816 TI - A new enzyme-linked immunosorbent assay system for human hepatic triglyceride lipase. AB - BACKGROUND: The objective of this study was to establish a new sandwich based enzyme linked immunosorbent assay (ELISA) for measuring the protein mass of human hepatic triacylglyceride lipase (HTGL). METHOD: Two mouse monoclonal antibodies raised against human HTGL were used for the sandwich ELISA. The post-heparin plasma (PHP) samples obtained at a heparin dose of 50 unit/kg from 124 normolipidemic subjects were used for this ELISA. RESULTS: The dynamic assay range of the developed ELISA for the HTGL was from 0.47 to 30 ng/ml. The CV was <7% in both intra- and inter-assays, and it did not cross-react with lipoprotein lipase or endothelial lipase (EL). The HTGL concentration in PHP showed a strong correlation with HTGL activity [n=121, r=0.778, p<0.001]. There was a weak relation of HTGL concentration against high-density lipoprotein cholesterol (HDL C) [n=123, r=-0.229, p=0.011] but no relations against total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), small dense LDL, remnant like particles cholesterol (RLP-C) and RLP-TG were confirmed. Interestingly, a weak but positive correlation between HTGL concentration and EL concentration was shown [n=122, p=0.013, r=0.224]. CONCLUSION: These results indicate that this new sandwich ELISA for measuring HTGL concentration in PHP can be applied in a daily clinical practice. PMID- 23810817 TI - A comparison between two powder compaction parameters of plasticity: the effective medium A parameter and the Heckel 1/K parameter. AB - The purpose of the research was to introduce a procedure to derive a powder compression parameter (EM A) representing particle yield stress using an effective medium equation and to compare the EM A parameter with the Heckel compression parameter (1/K). 16 pharmaceutical powders, including drugs and excipients, were compressed in a materials testing instrument and powder compression profiles were derived using the EM and Heckel equations. The compression profiles thus obtained could be sub-divided into regions among which one region was approximately linear and from this region, the compression parameters EM A and 1/K were calculated. A linear relationship between the EM A parameter and the 1/K parameter was obtained with a strong correlation. The slope of the plot was close to 1 (0.84) and the intercept of the plot was small in comparison to the range of parameter values obtained. The relationship between the theoretical EM A parameter and the 1/K parameter supports the interpretation of the empirical Heckel parameter as being a measure of yield stress. It is concluded that the combination of Heckel and EM equations represents a suitable procedure to derive a value of particle plasticity from powder compression data. PMID- 23810819 TI - Total arsenic, inorganic arsenic, and other elements concentrations in Italian rice grain varies with origin and type. AB - Rice is comparatively efficient at assimilating inorganic arsenic (Asi), a class one, non-threshold carcinogen, into its grain, being the dominant source of this element to mankind. Here it was investigated how the total arsenic (Ast) and Asi content of Italian rice grain sourced from market outlets varied by geographical origin and type. Total Cr, Cd Se, Mg, K, Zn, Ni were also quantified. Ast concentration on a variety basis ranged from means of 0.18 mg kg(-1) to 0.28 mg kg(-1), and from 0.11 mg kg(-1) to 0.28 mg kg(-1) by production region. For Asi concentration, means ranged from 0.08 mg kg(-1) to 0.11 mg kg(-1) by variety and 0.10 mg kg(-1) to 0.06 mg kg(-1) by region. There was significant geographical variation for both Ast and Asi; total Se and Ni concentration; while the total concentration of Zn, Cr, Ni and K were strongly influenced by the type of rice. PMID- 23810818 TI - Occurrence of estrogenic activities in second-grade surface water and ground water in the Yangtze River Delta, China. AB - Second-grade surface water and ground water are considered as the commonly used cleanest water in the Yangtze River Delta, which supplies centralized drinking water and contains rare species. However, some synthetic chemicals with estrogenic disrupting activities are detectable. Estrogenic activities in the second-grade surface water and ground water were surveyed by a green monkey kidney fibroblast (CV-1) cell line based ER reporter gene assay. Qualitative and quantitative analysis were further conducted to identify the responsible compounds. Estrogen receptor (ER) agonist activities were present in 7 out of 16 surface water and all the ground water samples. Huaihe River and Yangtze River posed the highest toxicity potential. The highest equivalent (2.2 ng E2/L) is higher than the predicted no-effect-concentration (PNEC). Bisphenol A (BPA) contributes to greater than 50% of the total derived equivalents in surface water, and the risk potential in this region deserves more attention and further research. PMID- 23810820 TI - Influence of biochar on isoproturon partitioning and bioaccessibility in soil. AB - The influence of biochar (5%) on the loss, partitioning and bioaccessibility of (14)C-isoproturon ((14)C-IPU) was evaluated. Results indicated that biochar had a dramatic effect upon (14)C-IPU partitioning: (14)C-IPU extractability (0.01 M CaCl2) in biochar-amended treatments was reduced to <2% while, (14)C-IPU extractability in biochar free treatments decreased with ageing from 90% to 40%. A partitioning model was constructed to derive an effective partition coefficient for biochar:water (KBW of 7.82 * 10(4) L kg(-1)). This was two orders of magnitude greater than the apparent Kfoc value of the soil organic carbon:water (631 L kg(-1)). (14)C-radiorespirometry assays indicated high competence of microorganisms to mineralise (14)C-IPU in the absence of biochar (40.3 +/- 0.9%). Where biochar was present (14)C-IPU mineralisation never exceeded 2%. These results indicate reduced herbicide bioaccessibility. Increasing IPU application to *10 its recommended dose was ineffective at redressing IPU sequestration and its low bioaccessibility. PMID- 23810821 TI - A new genotype of Cryptosporidium from giant panda (Ailuropoda melanoleuca) in China. AB - Fifty-seven fecal samples were collected from giant pandas (Ailuropoda melanoleuca) in the China Conservation and Research Centre for the Giant Panda (CCRCGP) in Sichuan and examined for Cryptosporidium oocysts by Sheather's sugar flotation technique. An 18-year-old male giant panda was Cryptosporidium positive, with oocysts of an average size of 4.60*3.99 MUm (n=50). The isolate was genetically analyzed using the partial 18S rRNA, 70 kDa heat shock protein (HSP70), Cryptosporidium oocyst wall protein (COWP) and actin genes. Multi-locus genetic characterization indicated that the present isolate was different from known Cryptosporidium species and genotypes. The closest relative was the Cryptosporidium bear genotype, with 11, 10, and 6 nucleotide differences in the 18S rRNA, HSP70, and actin genes, respectively. Significant differences were also observed in the COWP gene compared to Cryptosporidium mongoose genotype. The homology to the bear genotype at the 18S rRNA locus was 98.6%, which is comparable to that between Cryptosporidium parvum and Cryptosporidium hominis (99.2%), or between Cryptosporidium muris and Cryptosporidium andersoni (99.4%). Therefore, the Cryptosporidium in giant pandas in this study is considered as a new genotype: the Cryptosporidium giant panda genotype. PMID- 23810822 TI - Imaging mass spectrometry: challenges in visualization of drug distribution in solid tumors. AB - Mass spectrometry imaging (MSI) is an emerging technique that allows molecular visualization of the distribution of drugs and metabolites in a two-dimensional space directly in biological tissues. Imaging drug distribution inside a tumor is an important tool to support strategies to improve penetration of anticancer drugs and consequently the outcome of chemotherapy. MSI has some advantages in comparison to other imaging techniques, that is, whole body autoradiography, positron emission tomography or microscopy imaging. It is a label-free technique with better specificity and provides the possibility to combine histological data with MS ones and to visualize simultaneously the distribution of biomarkers in relation to tumor heterogeneity. We overview here publications on MSI applied to studies of the distribution of anticancer agents in tumor tissue. In addition, we focused our attention on technical limitations and future perspectives pertaining to this technique. PMID- 23810823 TI - Genome-based cancer therapeutics: targets, kinase drug resistance and future strategies for precision oncology. AB - Extraordinary progress has been made in our detailed understanding of the genetic and epigenetic mechanisms responsible for oncogenesis and cancer progression. Empowered by next-generation sequencing, many new targets and pathways have been identified to exploit oncogene and non-oncogene addiction and synthetic lethality. Kinase inhibitors feature strongly in the druggable cancer genome and 19 have been approved in oncology. While survival gains are valuable, drug resistance has emerged as the major challenge. The clonal heterogeneity and evolution of cancers is an intrinsic problem, together with feedback loops, kinase switching and activation of alternative targets and pathways. The solution to drug resistance will require the use of rationally targeted combinational regimens. The application of adaptive treatment cycles based on ongoing multi technology profiling will be the key to long-term therapeutic success. PMID- 23810824 TI - Graphene-based materials biocompatibility: a review. AB - Graphene-based materials (GBMs) have broad potential applications in biomedical engineering and biotechnology. However, existing studies regarding biological effects of GBMs often present contradictory or inconclusive results. This work presents a review of published data in order to provide a critical overview of the state of the art. Firstly, the distinct physical-chemical nature of the GBMs available is clarified, as well as the production methods involved. The review then discusses the available in vitro (with bacterial and mammalian cells) and in vivo studies concerning evaluation of GBMs biocompatibility, as well as existing hemocompatibility studies. The biocompatibility issues concerning composite materials that incorporate GBMs are addressed in a separate section, since encapsulation in a polymer matrix modifies biological interactions. The most pertinent questions that should be addressed in future works are also emphasized. PMID- 23810825 TI - Automated multi-day tracking of marked mice for the analysis of social behaviour. AB - A quantitative description of animal social behaviour is informative for behavioural biologists and clinicians developing drugs to treat social disorders. Social interaction in a group of animals has been difficult to measure because behaviour develops over long periods of time and requires tedious manual scoring, which is subjective and often non-reproducible. Computer-vision systems with the ability to measure complex social behaviour automatically would have a transformative impact on biology. Here, we present a method for tracking group housed mice individually as they freely interact over multiple days. Each mouse is bleach-marked with a unique fur pattern. The patterns are automatically learned by the tracking software and used to infer identities. Trajectories are analysed to measure behaviour as it develops over days, beyond the range of acute experiments. We demonstrate how our system may be used to study the development of place preferences, associations and social relationships by tracking four mice continuously for five days. Our system enables accurate and reproducible characterisation of wild-type mouse social behaviour and paves the way for high throughput long-term observation of the effects of genetic, pharmacological and environmental manipulations. PMID- 23810826 TI - Role of glutamate receptors and nitric oxide on the effects of glufosinate ammonium, an organophosphate pesticide, on in vivo dopamine release in rat striatum. AB - The purpose of the present work was to assess the possible role of glutamatergic receptors and nitric oxide (NO) production on effects of glufosinate ammonium (GLA), an organophosphate pesticide structurally related to glutamate, on in vivo striatal dopamine release in awake and freely moving rats. For this, we used antagonists of NMDA (MK-801 and AP5) or AMPA/kainate (CNQX) receptors, or nitric oxide synthase (NOS) inhibitors (l-NAME and 7-NI), to study the effects of GLA on release of dopamine from rat striatum. So, intrastriatal infusion of 10mM GLA significantly increased dopamine levels (1035+/-140%, compared with basal levels) and administration of GLA to MK-801 (250MUM) or AP5 (650MUM) pretreated animals, produced increases in dopamine overflow that were ~40% and ~90% smaller than those observed in animals not pretreated with MK-801 or AP5. Administration of GLA to CNQX (500MUM) pretreated animals produced an effect that was not significantly different from the one produced in animals not pretreated with CNQX. On the other hand, administration of GLA to l-NAME (100MUM) or 7-NI (100MUM) pretreated animals, produced increases in dopamine overflow that were ~80% and ~75% smaller than those observed in animals not pretreated with these inhibitors. In summary, GLA appears to act, at least in part, through an overstimulation of NMDA (and not AMPA/kainate) receptors with possible NO production to induce in vivo dopamine release. Administration of NMDA receptor antagonists and NOS inhibitors partially blocks the release of dopamine from rat striatum. PMID- 23810827 TI - How children with facial differences are perceived by non-affected children and adolescents: perceiver effects on stereotypical attitudes. AB - Children with a facial difference are presumed to be at risk of social stigmatization. The purposes of this study were twofold: (1) to assess the effect of facial differences on social perceptions by unaffected children and adolescents; and (2) to identify perceiver characteristics that predict stereotypical attitudes toward facial differences. Participants were 344 non affected children and adolescents, ages 8-17 years. Participants rated digitally altered images of 12 children depicted either with or without a facial difference. Results show that participants attributed less favorable characteristics to children with a facial difference than to those without. Moreover, participants reported less willingness to interact with or befriend a child with a facial difference. Significant predictors of low discriminative attitudes were older participant age and previous contact with someone with a facial difference. Our data call attention to the need for public education programs targeted at reducing negative attitudes toward facial differences. PMID- 23810828 TI - The impact of exposure to addictive drugs on future generations: Physiological and behavioral effects. AB - It is clear that both genetic and environmental factors contribute to drug addiction. Recent evidence indicating trans-generational influences of drug abuse highlight potential epigenetic factors as well. Specifically, mounting evidence suggests that parental ingestion of abused drugs influence the physiology and behavior of future generations even in the absence of prenatal exposure. The goal of this review is to describe the trans-generational consequences of preconception exposure to drugs of abuse for five major classes of drugs: alcohol, nicotine, marijuana, opioids, and cocaine. The potential epigenetic mechanisms underlying the transmission of these phenotypes across generations also are detailed. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. PMID- 23810831 TI - Importance of recognition loops B and D in the activation of human 5-HT3 receptors by 5-HT and meta-chlorophenylbiguanide. AB - The 5-HT3 receptor is a cation selective member of the pentameric Cys-loop ligand gated ion channels. While five subunits are known to exist, only two receptor subtypes have been significantly characterized: the homomeric receptor consisting of five A subunits and the heteromeric receptor containing both A and B subunits. The agonist recognition and activation of these receptors is orchestrated by six recognition loops three, A-C, on the principal subunit, and three, D-F, on the complementary subunit. In this study we have focused on the B loop of the principal subunit and loop D of the complementary subunit where aligned amino acids differ between the two subunits. A mutational analysis has been carried out using both 5-HT and m-chlorophenylbiguanide (mCPBG) to characterize receptor activation in the mutant receptors using two-electrode voltage clamp in Xenopus oocytes. The results show that the B loop W178I mutation of the 5-HT3A subunit markedly reduces the efficacy of mCPBG in both the homomeric and heteromeric receptors, while activation by 5-HT remains intact. Replacement of the D loop amino acid triplet RQY of the 5-HT3A subunit, with the aligned residues from the 5-HT3B subunit, QEV, converts 5-HT to a weak partial agonist in both the homomer and heteromer, but does not compromise activation by mCPBG. Exchange of the RQY triplet for the 5-HT3B subunit homologue, QEV, increases the Hill coefficient and decreases the EC50 of this mutant when expressed with the wild type 5-HT3A subunit. PMID- 23810829 TI - Intrathecal P/Q- and R-type calcium channel blockade of spinal substance P release and c-Fos expression. AB - Intrathecal (IT) studies have shown that several voltage sensitive calcium channels (VSCCs), such as the L-, N- and T-type may play roles in nociception and that of these only the N-type regulates primary afferent substance P (SP) release. However, the actions of other VSCCs at the spinal level are not well known. We investigated the roles of spinal P/Q- and R-type VSCCs, by IT administration of R-type (SNX-482) and P/Q-type (omega-agatoxin IVA) VSCC blockers on intraplantar formalin-evoked flinching, SP release from primary afferents and c-Fos expression in spinal dorsal horn. Intraplantar injection of formalin (2.5%, 50 MUL) produced an intense, characteristic biphasic paw flinching response. In rats with IT catheters, IT SNX-482 (0.5 MUg) reduced formalin-evoked paw flinching in both phase 1 and 2 compared with vehicle. Intraplantar formalin caused robust neurokinin 1 receptor (NK1r) internalization (indicating SP release) and c-Fos expression in the ipsilateral dorsal horn, which were blocked by IT SNX-482. IT omega-agatoxin IVA (0.03, 0.125 and 0.5 MUg) did not reduce formalin-evoked paw flinching or c-Fos expression at any doses, with higher doses resulting in motor dysfunction. Thus, we demonstrated that blockade of spinal R-type, but not P/Q type VSCCs attenuated formalin-induced pain behavior, NK1r internalization and c-Fos expression in the superficial dorsal horn. This study supports a role for Cav2.3 in presynaptic neurotransmitter release from peptidergic nociceptive afferents and pain behaviors. PMID- 23810832 TI - Morphological features of iPS cells generated from Fabry disease skin fibroblasts using Sendai virus vector (SeVdp). AB - We generated iPS cells from human dermal fibroblasts (HDFs) of Fabry disease using a Sendai virus (SeVdp) vector; this method has been established by Nakanishi et al. for pathogenic evaluation. We received SeVdp vector from Nakanishi and loaded it simultaneously with four reprogramming factors (Klf4, Oct4, Sox2, and c-Myc) to HDFs of Fabry disease; subsequently, we observed the presence of human iPS-like cells. The Sendai virus nucleocapsid protein was not detected in the fibroblasts by RT-PCR analysis. Additionally, we confirmed an undifferentiated state, alkaline phosphatase staining, and the presence of SSEA 4, TRA-1-60, and TRA-1-81. Moreover, ultrastructural features of these iPS cells included massive membranous cytoplasmic bodies typical of HDFs of Fabry disease. Thus, we successfully generated human iPS cells from HDFs of Fabry disease that retained the genetic conditions of Fabry disease; also, these abnormal iPS cells could not be easily differentiated into mature cell types such as neuronal cells, cardiomyocytes, etc. because of a massive accumulation of membranous cytoplasmic bodies in lysosomes, possibly the persistent damages of intracellular architecture. PMID- 23810830 TI - Coupling of gene expression in medial prefrontal cortex and nucleus accumbens after neonatal ventral hippocampal lesions accompanies deficits in sensorimotor gating and auditory processing in rats. AB - BACKGROUND: After neonatal ventral hippocampal lesions (NVHLs), adult rats exhibit evidence of neural processing deficits relevant to schizophrenia, including reduced prepulse inhibition (PPI) of acoustic startle and impaired sensory processing. In intact rats, the regulation of PPI by the ventral hippocampus (VH) is mediated via interactions with medial prefrontal cortex (mPFC) and nucleus accumbens (NAC). We assessed PPI, auditory-evoked responses and expression of 7 schizophrenia-related genes in mPFC and NAC, in adult rats after sham- or real NVHLs. METHODS: Male inbred Buffalo (BUF) rat pups (d7; n=36) received either vehicle or ibotenic acid infusion into the VH. PPI and auditory evoked dentate gyrus local field potentials (LFPs) were measured on d56 and d66, respectively. Brains were processed for RT-PCR measures of mPFC and NAC Comt, Erbb4, Grid2, Ncam1, Slc1a2, Nrg1 and Reln. RESULTS: NVHL rats exhibited significant deficits in PPI (p=0.005) and LFPs (p<0.015) proportional to lesion size. Sham vs. NVHL rats did not differ in gene expression levels in mPFC or NAC. As we previously reported, multiple gene expression levels were highly correlated within- (mean r's~0.5), but not across-brain regions (mean r's~0). However, for three genes--Comt, Slc1a2 and Ncam1--after NVHLs, expression levels became significantly correlated, or "coupled," across the mPFC and NAC (p's<0.03, 0.002 and 0.05, respectively), and the degree of "coupling" increased with VH lesion size. CONCLUSIONS: After NVHLs that disrupt PPI and auditory processing, specific gene expression levels suggest an abnormal functional coupling of the mPFC and NAC. This model of VH-mPFC-NAC network dysfunction after NVHLs may have implications for understanding the neural basis for PPI- and related sensory processing deficits in schizophrenia patients. PMID- 23810833 TI - Trends in head injuries associated with mandatory bicycle helmet legislation targeting children and adolescents. AB - BACKGROUND: Bicycling related head injuries (HIs) can be severe. Helmet use reduces head injury risk; however, there are few controlled studies of the effect of helmet legislation. We conducted this study to investigate changes in HIs after bicycle helmet legislation targeting those <18 in Alberta, Canada in 2002. METHODS: Bicyclist and pedestrian (control) HI rates and HIs as a proportion of all injuries were compared for the three years (1999-2001) before and four years (2003-2006) after bicycle helmet legislation in three age groups (children: <13, adolescents: 13-17, and adults: 18+). RESULTS: There were 41,270 ED visits and 2782 hospitalizations for bicyclists and 9836 ED visits and 2029 hospitalizations for pedestrians (excluding the legislation year 2002). The rate of ED HIs declined for child bicyclists and child pedestrians, while the rate of non-HIs declined in adult bicyclists and child pedestrians. The rate of hospitalized HIs declined in child bicyclists and all ages of pedestrians while non-HI rates declined for child and adult pedestrians. Non-HI rates for adolescent and adult bicyclists increased. After adjusting for sex and location, the proportion of ED bicycle HIs declined by 9% (APR=0.91; 95% CI: 0.86, 0.95) in children, was unchanged among adolescents and increased in adults (APR=1.08; 95% CI: 1.01, 1.15). The proportion of bicycle HI related hospitalizations decreased by 30% (APR=0.70; 95% CI: 0.55, 0.90) in children, 36% (APR=0.64; 95% CI: 0.49, 0.84) in adolescents and 24% (APR=0.76; 95% CI: 0.63, 0.91) in adults. There were no observed changes in the proportion of pedestrian HIs resulting in ED visits or hospitalizations. INTERPRETATION: Our data indicate significant declines in the proportion of child bicyclist ED HIs and child, adolescent and adult bicyclist HI hospitalizations. This is in contrast to no significant trends in the proportion of ED or hospitalized HIs among pedestrians and the unexpected increases in the proportion of ED HIs for adult bicyclists. Comparing bicyclist and pedestrian trends in the proportion of child and adolescent HIs suggests a bicycle helmet legislation effect. PMID- 23810834 TI - Ergonomic analyses within the French transport and logistics sector: first steps towards a new "act elsewhere" prevention approach. AB - Statistics from the French Employee National Health Insurance Fund indicate high accident levels in the transport sector. This study represents initial thinking on a new approach to transport sector prevention based on the assumption that a work situation could be improved by acting on another interconnected work situation. Ergonomic analysis of two connected work situations, involving the road haulage drivers and cross-docking platform employees, was performed to test this assumption. Our results show that drivers are exposed to a number of identified risks, but their multiple tasks raise the question of activity intensification. The conditions, under which the drivers will perform their work and take to the road, are partly determined by the quality and organisation of the platform with which they interact. We make a number of recommendations (e.g. changing handling equipment, re-appraising certain jobs) to improve platform organisation and employee working conditions with the aim of also improving driver conditions. These initial steps in this prevention approach appear promising, but more detailed investigation is required. PMID- 23810835 TI - A novel chemiluminescent ELISA for detecting furaltadone metabolite, 3-amino-5 morpholinomethyl-2-oxazolidone (AMOZ) in fish, egg, honey and shrimp samples. AB - In this study, an indirect competitive enzyme-linked immunosorbent assay with chemiluminescent (CLELISA) detection for 3-amino-5-morpholinomethyl-2-oxazolidone (AMOZ) was developed. A monoclonal antibody (MAb) against AMOZ was prepared through immunizing BALB/c mice with 4-carboxybenzaldehyle derivatized AMOZ (CPAMOZ), conjugated with bovine serum albumin (BSA) as antigen. The effects of the substrates luminol, p-iodophenol and urea peroxide on the performance of the assay were studied and optimized. In addition, the specificity of the MAb, estimated as the cross-reactivity values with 4-nitrobenzaldehyde derivatized AMOZ (NPAMOZ), CPAMOZ and AMOZ, was 100%, 27.45% and 0.18%, respectively. The sensitivity of the developed CLELISA was estimated as 50% inhibitory concentration (IC50) value (0.14MUg/l) with a linear working range between 0.03 and 64MUg/l, and a limit of detection of 0.01MUg/l. The CLELISA described in this study was 5-fold more sensitive than the indirect competitive ELISA previously developed in our laboratory. Finally, this new CLELISA was compared with a commercial kit to detect NPAMOZ in spiked fish, shrimp, honey and egg samples. The recovery values from four spiked fish, shrimp, honey and egg samples with different concentrations of NPAMOZ in CLELISA were 92.1-107.7%. Thus, the immunoassay method described here has a broad detection range and high sensitivity and is a valid and cost-effective means for high throughput monitoring of residual AMOZ levels in fish, shrimps, honey and eggs with potential applications in other animal tissues. PMID- 23810836 TI - Slc10A4 - what do we know about the function of this "secret ligand carrier" protein? AB - This commentary discusses the possible functions of a relatively newly described solute carrier protein, Slc10a4, in regards to a recent article by Zelano et al. (2013) published in the January issue of Experimental Neurology, 239, 73-81. Slc10a4 belongs to the sodium-bile acid cotransporter family (Slc10), but does not show plasma membrane transport activity of bile acids and related molecules. It is co-localized with synaptic vesicle transporters for acetylcholine and dopamine. In Slc10a4 lacking mice, Zelano et al. found increased excitability in hippocampal slices and in vivo responses to pilocarpine, but not kainate. These findings are critically examined here. This author speculates on the possible function of Slc10a4, but remains partial about "specific effects of Slc10a4 in cholinergic systems". It is hoped that approaches targeting human SLC10A4 can be discovered for potential clinical use in neurological disorders, such as Alzheimer's and Parkinson's disease, schizophrenia and addiction. Conversely, some side effects are expected due to peripheral Slc10a4 localization in sympathetic and parasympathetic nerves, as well as mast cells. PMID- 23810837 TI - Complex regulation of autophagy in cancer - integrated approaches to discover the networks that hold a double-edged sword. AB - Autophagy, a highly regulated self-degradation process of eukaryotic cells, is a context-dependent tumor-suppressing mechanism that can also promote tumor cell survival upon stress and treatment resistance. Because of this ambiguity, autophagy is considered as a double-edged sword in oncology, making anti-cancer therapeutic approaches highly challenging. In this review, we present how systems level knowledge on autophagy regulation can help to develop new strategies and efficiently select novel anti-cancer drug targets. We focus on the protein interactors and transcriptional/post-transcriptional regulators of autophagy as the protein and regulatory networks significantly influence the activity of core autophagy proteins during tumor progression. We list several network resources to identify interactors and regulators of autophagy proteins. As in silico analysis of such networks often necessitates experimental validation, we briefly summarize tractable model organisms to examine the role of autophagy in cancer. We also discuss fluorescence techniques for high-throughput monitoring of autophagy in humans. Finally, the challenges of pharmacological modulation of autophagy are reviewed. We suggest network-based concepts to overcome these difficulties. We point out that a context-dependent modulation of autophagy would be favored in anti-cancer therapy, where autophagy is stimulated in normal cells, while inhibited only in stressed cancer cells. To achieve this goal, we introduce the concept of regulo-network drugs targeting specific transcription factors or miRNA families identified with network analysis. The effect of regulo-network drugs propagates indirectly through transcriptional or post-transcriptional regulation of autophagy proteins, and, as a multi-directional intervention tool, they can both activate and inhibit specific proteins in the same time. The future identification and validation of such regulo-network drug targets may serve as novel intervention points, where autophagy can be effectively modulated in cancer therapy. PMID- 23810838 TI - Captured streams and springs in combined sewers: a review of the evidence, consequences and opportunities. AB - Captured streams and springs may be flowing in combined sewers, increasing clean baseflow in pipes and wastewater treatment works (WwTWs), reducing pipe capacity and increasing treatment costs. The UK water industry is aware of this in principle, but there has been no explicit discussion of this in the published literature, nor have there been any known attempts to manage it. Instead, the current focus is on the similar intrusion of groundwater infiltration through pipe cracks and joints. We have conducted a thorough review of literature and international case studies to investigate stream and spring capture, finding several examples with convincing evidence that this occurs. We identify three modes of entry: capture by conversion, capture by interception, and direct spring capture. Methods to identify and quantify capture are limited, but the experience in Zurich suggests that it contributed 7-16% of the baseflow reaching WwTWs. There are negative impacts for the water industry in capital and operational expenditure, as well as environmental and social impacts of loss of urban streams. For a typical WwTW (Esholt, Bradford) with 16% of baseflow from captured streams and springs, we conservatively estimate annual costs of L 2 million to L 7 million. A detailed case study from Zurich is considered that has successfully separated captured baseflow into daylighted streams through the urban area, with multiple economic, environmental and social benefits. We conclude that there is a strong case for the UK water industry to consider captured streams and springs, quantify them, and assess the merits of managing them. PMID- 23810839 TI - Regional variations in trabecular architecture of the lumbar vertebra: associations with age, disc degeneration and disc space narrowing. AB - Previous studies suggest that age and disc degeneration are associated with variations in vertebral trabecular architecture. In particular, disc space narrowing, a severe form of disc degeneration, may predispose the anterior portion of a vertebra to fracture. We studied 150 lumbar vertebrae and 209 intervertebral discs from 48 cadaveric lumbar spines of middle-aged men to investigate regional trabecular differences in relation to age, disc degeneration and disc narrowing. The degrees of disc degeneration and narrowing were evaluated using radiography and discography. The vertebrae were dried and scanned on a MUCT system. The MUCT images of each vertebral body were processed to include only vertebral trabeculae, which were first divided into superior and inferior regions, and further into central and peripheral regions, and then anterior and posterior regions. Structural analyses were performed to obtain trabecular microarchitecture measurements for each vertebral region. On average, the peripheral region had 12-15% greater trabecular bone volume fraction and trabecular thickness than the central region (p<0.01). Greater age was associated with better trabecular structure in the peripheral region relative to the central region. Moderate and severe disc degeneration were associated with higher trabecular thickness in the peripheral region of the vertebral trabeculae (p<0.05). The anterior region was of lower bone quality than the posterior region, which was not associated with age. Slight to moderate narrowing was associated with greater trabecular bone volume fraction in the anterior region of the inferior vertebra (p<0.05). Similarly, greater disc narrowing was associated with higher trabecular thickness in the anterior region (p<0.05). Better architecture of peripheral trabeculae relative to central trabeculae was associated with both age and disc degeneration. In contrast to the previous view that disc narrowing stress-shields the anterior vertebra, disc narrowing tended to associate with better trabecular architecture in the anterior region, as opposed to the posterior region. PMID- 23810841 TI - Effect of vitamin D replacement on hip structural geometry in adolescents: a randomized controlled trial. AB - BACKGROUND: We have shown in a randomized controlled trial that vitamin D increases bone mass, lean mass and bone area in adolescent girls, but not boys. These increments may translate into improvements in bone geometry and therefore bone strength. This study investigated the impact of vitamin D on hip geometric dimensions from DXA-derived hip structural analyses in adolescents who participated in the trial. METHODS: 167 girls (mean age 13.1 years) and 171 boys (mean age 12.7 years) were randomly assigned to receive weekly placebo oil or vitamin D3, at doses of 1400 IU or 14,000 IU, in a double blind placebo controlled 1-year trial. DXA images were obtained at baseline and one year, and hip images were analyzed using the hip structural analysis (HSA) software to derive parameters of bone geometry. These include outer diameter (OD), cross sectional area (CSA), section modulus (Z), and buckling ratio (BR) at the narrow neck (NN), intertrochanteric (IT), and shaft (S) regions. Analysis of Covariance (ANCOVA) was used to examine group differences for changes of bone structural parameters. RESULTS: In the overall group of girls, vitamin D supplementation increased aBMD (7.9% and 6.8% in low and high doses, versus 4.2% in placebo) and reduced the BR of NN (6.1% and 2.4% in low and high doses, versus 1.9% in placebo). It also improved aBMD (7.9% and 5.2% versus 3.6%) and CSA (7.5% and 5.1% versus 4.1%) of the IT and OD of the S (2.4% and 2.5% versus 0.8% respectively). Significant changes in the OD and BR of the NN, in the overall group of girls remained, after adjusting for lean mass, and were unaffected with further adjustments for lifestyle, pubertal status, and height measures. Conversely, boys did not exhibit any significant changes in any parameters of interest. A dose effect was not detected and subgroup analyses revealed no beneficial effect of vitamin D by pubertal stage. CONCLUSIONS: Vitamin D supplementation improved bone mass and several DXA-derived structural bone parameters, in adolescent girls, but not boys. This occurred at a critical site, the femoral neck, and if maintained through adulthood could improve bone strength and lower the risk of hip fractures. PMID- 23810840 TI - Childhood socioeconomic status and adult femoral neck bone strength: findings from the Midlife in the United States Study. AB - PURPOSE: Bone acquisition in childhood impacts adult bone mass, and can be influenced by childhood socioeconomic conditions. Socioeconomic status is also associated with body weight which affects the load that bone is exposed to in a fall. We hypothesized that socioeconomic advantage in childhood is associated with greater bone strength relative to load in adulthood. METHODS: Hip dual x-ray absorptiometry scans from 722 participants in the Midlife in the United States Study were used to measure femoral neck size and bone mineral density, and combined with body weight and height to create composite indices of femoral neck strength relative to load in different failure modes: compression, bending, and impact. A childhood socioeconomic advantage score was created for the same participants from parental education, self-rated financial status relative to others, and not being on welfare. Multiple linear regression was used to determine the association of childhood socioeconomic advantage with femoral neck composite strength indices, stratified by gender and race (white/non-white), and adjusted for study site, age, menopause status in women, education, and current financial advantage. RESULTS: Childhood socioeconomic advantage was independently associated with higher indices of all three composite strength indices in white men (adjusted standardized effect sizes, 0.19 to 0.27, all p values<0.01), but not in the other three race/gender groups. Additional adjustment for adult obesity, physical activity in different life stages, smoking, and heavy drinking over the life-course significantly attenuated the associations in white men. CONCLUSIONS: Socioeconomic disadvantage in childhood is associated with lower hip strength relative to load in white men, and these influences are dampened by healthy lifestyle choices. PMID- 23810842 TI - Eurycomanone, the major quassinoid in Eurycoma longifolia root extract increases spermatogenesis by inhibiting the activity of phosphodiesterase and aromatase in steroidogenesis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Eurycoma longifolia Jack (Simaroubaceae family), known locally as 'Tongkat Ali' by the ethnic population, is popularly taken as a traditional remedy to improve the male libido, sexual prowess and fertility. Presently, many tea, coffee and carbonated beverages, pre-mixed with the root extract are available commercially for the improvement of general health and labido. Eurycomanone, the highest concentrated quassinoid in the root extract of E. longifolia improved fertility by increasing testosterone and spermatogenesis of rats through the hypothalamus-pituitary-gonadal axis, but the mechanisms underlying the effects are not totally clear. AIM OF THE STUDY: To provide evidences on the plant ethnopharmacological use and the involvement of eurycomanone, the major indigenous plant quassinoid in testosterone steroidogenesis and spermatogenesis increase. MATERIAL AND METHODS: The rat testicular Leydig cell-rich interstitial cells were isolated and incubated in the culture medium M199. The viability of the cells was determined with trypan blue staining and the concentration of the viable cells was counted with a haemocytometer. The 3beta-hydroxysteroid dehydrogenase (HSD) staining method was used to measure the abundance of Leydig cells in the preparation. Eurycomanone and the standard steroidogenesis inhibitors were incubated with 1.0 * 10(5) cells, and after 2h, the testosterone and the oestrogen concentrations were determined by the ELISA method. Computational molecular docking was performed to determine the binding affinity of the compound at the respective steroidogenesis enzymes. RESULTS: Eurycomanone (EN) significantly increased testosterone production dose-dependently at 0.1, 1.0 and 10.0 MUM (P<0.05), but the two lower doses when combined with 3-isobutyl-1-methylxanthine (IBMX), the phosphodiesterase inhibitor were not significantly higher than EN or IBMX alone, except at a higher concentration. The molecular docking studies indicated EN and IBMX were binding at different sites of the enzyme. EN has no reversal of inhibition by aminoglutethimide, ketoconazole or nifedipine at the respective steroidogenesis enzyme. The quassinoid was also non-responsive to the inhibition of oestrogen receptor by tamoxifen, but displayed improved formestane inhibition of aromatase in reducing oestrogen production. The molecular docking studies further supported that EN and formestane bound to aromatase with similar orientations and free energy binding values. CONCLUSION: Eurycomanone enhanced testosterone steroidogenesis at the Leydig cells by inhibiting aromatase conversion of testosterone to oestrogen, and at a high concentration may also involve phosphodiesterase inhibition. The quassinoid may be worthy for further development as a phytomedicine to treat testosterone-deficient idiopathic male infertility and sterility. PMID- 23810843 TI - In vitro and in vivo immunostimulatory effects of hot water extracts from the leaves of Artemisia princeps Pampanini cv. Sajabal. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia princeps Pampanini (Asteraceae) is used as a traditional medicine to immune function-related diseases, such as dysmenorrhea, inflammation, cancer, and ulcers. AIM OF THE STUDY: The purpose of this study is to evaluate the immunostimulatory effects of the hot water extract from the leaves of Artemisia princeps Pampanini (WAPP) in recombinant interferon gamma (rIFN-gamma)-primed RAW 264.7 macrophages and in cyclophosphamide (20mg/kg, i.p.)-induced immunosuppressed Sprague-Dawley rats. MATERIALS AND METHODS: RAW 264.7 macrophages were treated with WAPP and production and expressions of nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) via nuclear factor-kappaB (NF-kappaB) were detected by immunoassay, western blot, qRT-PCR and reporter gene assay. In addition, in vivo immunomodulatory activity was studied by cyclophosphamide-induced myelosuppression in rats. RESULTS: In rIFN-gamma-primed RAW 264.7 macrophages, pretreatment with WAPP increased the productions of nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha),and increased the expressions of inducible nitric oxide synthase (iNOS) at the protein level and of iNOS and TNF-alpha at the mRNA level. Molecular data revealed that WAPP upregulated the transcriptional activity and translocation of nuclear factor kappaB (NF-kappaB) by activating inhibitory kappa B-alpha (IkappaB-alpha) degradation and phosphorylation. Furthermore, WAPP upregulated the phosphorylations of p38 MAP kinase, c-Jun NH2-terminal kinase (JNK), and extracellular signal-regulated kinase 1/2 (ERK1/2). In cycloheximide-induced immunosuppressed rats, pretreatment with WAPP (100, 200, or 400mg/kg, p.o.) increased the serum levels of albumin and globulin, and reduced immobility times. CONCLUSION: Our results suggest that upregulations of the expressions of iNOS and TNF-alpha via the activations of NF-kappaB and MAPK are responsible for the immunostimulatory effects of WAPP. PMID- 23810844 TI - Enrichment of IL-12-producing plasmacytoid dendritic cells in donor bone marrow grafts enhances graft-versus-leukemia activity in allogeneic hematopoietic stem cell transplantation. AB - A critical question in the field of allogeneic hematopoietic stem cell transplantation (HSCT) is how to enhance graft-versus-leukemia (GVL) activity while limiting graft-versus-host-disease (GVHD). We have previously reported that donor bone marrow (BM) precursors of plasmacytoid dendritic cells (pre-pDCs) can polarize donor T cells toward Th1 immunity and augment the GVL activity of donor T cells while attenuating their GVHD activity in a murine model of allogeneic HSCT. Clinical data on the role of donor pre-pDCs and conventional DCs (cDCs) on transplantation outcomes has been conflicting. To test the effect of increasing the proportion of pre-pDCs versus cDCs in a BM graft, we enriched CD11b(-) pDCs by selectively depleting the CD11b(+) myeloid DC (mDC) population from BM using FACS sorting in a murine model of allogeneic BM transplantation. Donor T cell expansion and GVL activity were greater in mice that received BM depleted of mDCs compared with mice that received undepleted BM. GVHD was not increased by depleting mDCs. To examine the mechanism through which mDC depletion enhances the GVL activity of donor T cells, we used BM and pDCs from IL-12p40KO mice, and found that the increased GVL activity of mDC-depleted BM was IL-12-dependent. This study indicates that a clinically translatable strategy of engineering the DC content of grafts can improve clinical outcomes in allogeneic HSCT through the regulation of donor T cell activation and GVL activity. PMID- 23810845 TI - Interventions for caregivers of children who disclose sexual abuse: a review. AB - The importance of interventions for non-offending caregivers following the disclosure of child sexual abuse (CSA) is increasingly recognised in the literature. These interventions are particularly important given what is currently known about the impact of CSA disclosure on non-offending caregivers and the value of caregiver support in assisting their children's recovery. This review provides summary background information on the prevalence and short-term impact of CSA on children, with a particular focus on variables that mediate outcomes including caregiver support. The impact of a child's disclosure on the non-offending caregiver is discussed considering both the emotional effects and changes in their support networks. Furthermore, we examine the associated needs of non-offending caregivers including information, emotional support, support around their own victimisation if relevant, and parenting assistance. Finally, we provide a detailed review of the specific interventions available for caregivers after such a disclosure is made. These interventions include those that just provide information, support groups, psycho-educational groups, support incorporated into the child's intervention, and individual caregiver support. We conclude that interventions for non-offending caregivers are vital in the recovery of the child and their caregiver following CSA and discuss future research considerations. PMID- 23810846 TI - Delivery for women with a previous cesarean: guidelines for clinical practice from the French College of Gynecologists and Obstetricians (CNGOF). AB - The primary cause of uterine scars is a previous cesarean. In women with a previous cesarean, the risks of maternal complications are rare and similar after a trial of labor after cesarean (TOLAC) and after an elective repeat cesarean delivery (ERCD), but the risk of uterine rupture is higher with TOLAC (level of evidence [LE]2). Maternal morbidity in women with previous cesareans is higher when TOLAC fails than when it leads to successful vaginal delivery (LE2). Although maternal morbidity increases progressively with the number of ERCD, maternal morbidity of TOLAC decreases with the number of successful previous TOLAC (LE2). The risk-benefit ratio considering the risks of short- and long-term maternal complications is favorable to TOLAC in most cases (LE3). Globally, neonatal complications are rare regardless of the mode of delivery for women with previous cesareans. The risks of fetal, perinatal, and neonatal mortality during TOLAC are low. Nonetheless, these risks are significantly higher than those associated with ERCD (LE2). The risks of mask ventilation, intubation for meconium-stained amniotic fluid, and neonatal sepsis all increase in TOLAC (LE2). The risk of transient respiratory distress increases in ERCD (LE2). To reduce this risk, and except in particular situations, ERCD must not be performed before 39 weeks (grade B). TOLAC is possible for women with a previous cesarean before 37 weeks, with 2 previous cesareans, with a uterine malformation, a low vertical incision or an unknown incision, with a myomectomy, postpartum fever, an interval of less than 6 months between the last cesarean delivery and the conception of the following pregnancy, if the obstetric conditions are favorable (professional consensus). ERCD is recommended in women with a scar in the uterine body (grade B) and a history of 3 or more cesareans (professional consensus). Ultrasound assessment of the risk of uterine rupture in women with uterine scars has not been shown to have any clinical utility and is therefore not recommended during pregnancy to help decide the mode of delivery (professional consensus). Use of X ray pelvimetry to decide about TOLAC is associated with an increase in the repeat cesarean rate without any reduction in the rate of uterine rupture (LE2). It is unnecessary for deciding mode of delivery and for managing labor during TOLAC (grade C). TOLAC should be encouraged for women with a previous vaginal delivery either before or after the cesarean, a favorable Bishop score or spontaneous labor, and for preterm births (grade C). For women with a fetus with an estimated weight of more than 4500 g, especially in the absence of a previous vaginal delivery and those with supermorbid obesity (BMI>50), ERCD must be planned from the outset (grade C). For all of the other clinical situations envisioned (maternal age>35 years, diabetes, morbid obesity, prolonged pregnancy, breech presentation and twin pregnancy), TOLAC is possible but the available data do not allow specific guidelines about the choice of mode of delivery, in view of the low levels of proof (grade C). The decision about planned mode of delivery must be shared by the patient and her physician and made by the 8th month, taking into account the individual risk factors for TOLAC failure and uterine rupture (professional consensus). TOLAC is the preferred choice for women who do not have several risk factors (professional consensus). The availability onsite of an obstetrician and anesthetist must be pointed out to the patient. If the woman continues to prefer a repeat cesarean after adequate information and time to think about it, her preference should be honored (professional consensus). Labor should be induced in woman with a previous cesarean only for medical indications (professional consensus). Induction of labor increases the risk of uterine rupture, which can be estimated at 1% if oxytocin is used and 2% with vaginal prostaglandins (LE2). Mechanical methods of induction have not been studied sufficiently. Misoprostol appears to increase the risk of uterine rupture strongly (LE4). Based on the information now available, its use is not recommended (professional consensus). Routine use of internal tocodynamometry does not prevent uterine rupture (professional consensus). The increased risk of uterine rupture associated with oxytocin use is dose-dependent (LE3). In the active phase, it is recommended that the total duration of failure to progress should not exceed 3h; at that point, a cesarean should be performed (professional consensus). Epidural analgesia must be encouraged. The simple existence of a uterine scar is not an indication for a routine manual uterine examination after VBAC (grade C). PMID- 23810847 TI - Classification of tea category using a portable electronic nose based on an odor imaging sensor array. AB - A developed portable electronic nose (E-nose) based on an odor imaging sensor array was successfully used for classification of three different fermentation degrees of tea (i.e., green tea, black tea, and Oolong tea). The odor imaging sensor array was fabricated by printing nine dyes, including porphyrin and metalloporphyrins, on the hydrophobic porous membrane. A color change profile for each sample was obtained by differentiating the image of sensor array before and after exposure to tea's volatile organic compounds (VOCs). Multivariate analysis was used for the classification of tea categories, and linear discriminant analysis (LDA) achieved 100% classification rate by leave-one-out cross validation (LOOCV). This study demonstrates that the E-nose based on odor imaging sensor array has a high potential in the classification of tea category according to different fermentation degrees. PMID- 23810848 TI - Simultaneous monitoring of superoxides and intracellular calcium ions in neutrophils by chemiluminescence and fluorescence: evaluation of action mechanisms of bioactive compounds in foods. AB - We have developed a measuring system for simultaneous monitoring of chemiluminescence and fluorescence, which indicate respectively, (i) generation of superoxide anion radicals (O2(-*)) and (ii) change in the intracellular calcium ion concentration ([Ca(2+)]i) of neutrophils triggered by the mechanism of innate immune response. We applied this measuring system for establishing a method to distinguish between anti-inflammatory actions and antioxidant actions caused by bioactive compounds. We evaluated anti-inflammatory agents (zinc ion [Zn(2+)] and ibuprofen) and antioxidants (superoxide dismutase [SOD] and ascorbic acid). It was shown that ibuprofen and Zn(2+) were anti-inflammatory while SOD and ascorbic acid were anti-oxidative. We conclude that it is possible to determine the mechanism of action of bioactive compounds using this method. PMID- 23810849 TI - Simultaneous quantification of verbenalin and verbascoside in Verbena officinalis by ATR-IR and NIR spectroscopy. AB - Attenuated-total-reflectance infrared spectroscopy (ATR-IR) and near-infrared diffuse reflectance spectroscopy (NIR) in hyphenation with multivariate analysis was utilized to quantify verbenalin and verbascoside in Verbena officinalis. A new high performance liquid chromatography (HPLC) method as a reference was established and validated. For both vibrational spectroscopic methods test-set and cross validation were performed. Different data-pre-treatments like SNV, 1st and 2nd derivative were applied to remove systematic errors and were evaluated. Quality parameters obtained for the test-set validation revealed that ATR-IR (verbenalin: R(2)=0.94, RPD=4.23; verbascoside: R(2)=0.93, RPD=3.63) has advantages over NIR (verbenalin: R(2)=0.91, RPD=3.75; verbascoside: R(2)=0.80, RPD=2.35) in the given application. PMID- 23810850 TI - Investigation of transport of genistein, daidzein and their inclusion complexes prepared with different cyclodextrins on Caco-2 cell line. AB - Isoflavonoids are widespread constituents in medical plants especially in legumes (Fabaceae), but occur in other different plant families as well (Rosaceae, Iridaceae, Amaranthaceae). Their antioxidant, estrogen-like, anti-inflammatory and analgesic effects make them promising compounds in therapy of important disorders especially in estrogen related diseases. Poor solubility in aqueous system of genistein and daidzein needs a solubility enhancement for pharmaceutical use. These compounds are suitable guest molecules for inclusion complex formation with cyclodextrins (CDs) considering matching their size and polarity. The molecular encapsulation with beta-cyclodextrin (beta-CD), gamma cyclodextrin (gamma-CD), hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and random methyl-beta cyclodextrin (RAMEB-CD) results in a solid, molecularly dispersed form and in a significantly improved aqueous solubility of genistein and daidzein. Determining enhancement in solubility and bioavailability we investigated the transport of these inclusion complexes across Caco-2 cell line comparing that of the pure compounds and found significant improving effect of the different CD derivatives on membrane permeation of the two isoflavone aglycons. PMID- 23810851 TI - Inhibitory effect of silver diamine fluoride on dentine demineralisation and collagen degradation. AB - OBJECTIVE: To investigate the inhibitory effects of 38% silver diamine fluoride (SDF) on demineralised dentine. METHODS: Human dentine blocks were demineralised and allocated to four groups: SF, F, S and W. The blocks in group SF received a topical application of 38% SDF solution (253,900ppm Ag, 44,800ppm F), group F received a 10% sodium fluoride solution (44,800ppm F), group S received a 42% silver nitrate solution (253,900ppm Ag) and group W received deionised water (control). They were subjected to pH cycling using demineralisation solution (pH 5) and remineralisation solution (pH 7) for 8 days. The surface morphology, crystal characteristics, lesion depth and collagen matrix degradation of the specimens were investigated by scanning electron microscopy (SEM), X-ray diffraction (XRD), micro-CT testing and spectrophotometry with a hydroxyproline assay. RESULTS: The surface morphology under SEM showed evident demineralisation with exposed collagen in groups S and W, but not in group SF. Clusters of granular spherical grains were observed in the cross-sections of specimens in groups SF and F. XRD revealed precipitates of silver chloride in groups SF and S. The mean lesion depths (+/-SD) of groups SF, F, S and W were 182 +/- 32MUm, 204 +/- 26MUm, 259 +/- 42MUm and 265 +/- 40MUm, respectively (SDF, F eRF1?eRF3) and nature of tRNA and was enhanced by eEF2. The mobility of posttermination ribosomes suggests that some reinitiation events could involve 80S ribosomes rather than 40S subunits. PMID- 23810860 TI - Impact of anthropogenic and natural processes on the evolution of groundwater chemistry in a rapidly urbanized coastal area, South China. AB - The moving of manufacturing industry from developed countries to Dongguan, China, promoted the semi-urbanization and rural industrialization in this area. It is urgent to acquire the impact of the enhanced anthropogenic pressure on the evolution of groundwater chemistry in this area. The objectives, in this study, were to understand the evolution of groundwater chemistry in Dongguan area based on the comparison of hydrochemical data variations and land use changes during the urbanization, to distinguish the impact of natural processes and anthropogenic activities on the groundwater chemistry by using principal components analysis (PCA) and hierarchical cluster analysis (HCA), and to discuss the origins of trace elements in groundwater. Eighteen physico-chemical parameters were investigated at 73 groundwater sites during July 2006. By analyzing the hydrochemical data, it shows that lateral flow from rivers and agricultural irrigation are the mechanisms controlling the groundwater chemistry in the river network area where the cation exchange of Na(+) in sediments taken up by the exchanger Ca(2+) occurs. Seawater intrusion is the mechanism controlling the groundwater chemistry in the coast area where the cation exchange of Ca(2+) in sediments taken up by the exchanger Na(+) occurs. The ion exchange reaction for fissured aquifer is weak in the study area. In addition, the comparison of hydrochemical data between in 2006 and in 1980 shows that anthropogenic activities such as excessive application of agricultural fertilizers, inappropriate emissions of domestic sewage and excessive emissions of SO2 are responsible for the occurrences of groundwater with NO3(-), SO4(2-) and Mg(2+) types. Four principal components (PCs) were extracted from PCA, which explain 80.86% of the total parameters in water chemistry: PC1, the seawater intrusion and As contamination; PC2, the water-rock interaction, surface water recharge and acidic precipitation; PC3, heavy metal pollution from industry; and PC4, agricultural pollution and sewage intrusion. Four clusters were generated from HCA: cluster 1 is mainly influenced by the industrialization; cluster 2 is mainly affected by the water-rock interaction and the irrigation and lateral flow of river water; cluster 3 is mainly influenced by the seawater intrusion; and cluster 4 is mainly influenced by the sewage intrusion and agricultural pollution. The results show that both natural processes such as seawater intrusion, water-rock interaction and lateral flow of river water and anthropogenic activities such as industrialization, sewage intrusion and agricultural pollution are the two major factors for the evolution of groundwater chemistry in Dongguan area. PMID- 23810861 TI - Antimony migration trends from a small arms firing range compared to lead, copper, and zinc. AB - Small arms firing ranges (SAFRs) contain a mixed amount of bullets and bullet fragments accumulated throughout their designed lifetime. Lead-antimony (Pb-Sb) alloy copper (Cu) jacketed bullets are a common modern ammunition used at SAFRs. The impact of bullets with berm material (i.e., soil) generates a heterogeneous distribution of bullets and bullet fragments in the surrounding soil. As bullets and bullet fragments corrode in the berm soil, the migration potential for antimony compared to other metals is quite high. The goal of this study was to evaluate the spatial Sb migration potential from an SAFR as compared to lead, copper, and zinc (Zn) migration from the same SAFR. Berm soil samples were collected along with surface and ground water samples for a preliminary investigation of the Sb migration from an active SAFR. In addition, different aqueous sample preservation techniques were used and evaluated. Soil sample analysis results show the presence of the metals (i.e., Pb, Sb, Cu, and Zn) in the range floor soil samples, indicating the migration of these metals from the berm to the range floor. The groundwater samples indicate that Sb was migrating from the SAFR more readily than the other metals based on the concentration of Sb in the monitoring well farthest from the SAFR berm. PMID- 23810862 TI - Phototransformation of the sunlight filter benzophenone-3 (2-hydroxy-4 methoxybenzophenone) under conditions relevant to surface waters. AB - The UV filter benzophenone-3 (BP3) has UV photolysis quantum yield PhiBP3=(3.1+/ 0.3).10(-5) and the following second-order reaction rate constants: with (*)OH, k(BP3,(*)OH)=(2.0+/-0.4).10(10) M(-1) s(-1); with the triplet states of chromophoric dissolved organic matter ((3)CDOM*), K(BP3,(3)CDOM*)=(1.1+/ 0.1).10(9) M(-1) s(-1); with (1)O2, k(BP3,(1)O2)=(2.0+/-0.1).10(5) M(-1) s(-1), and with CO3(-*), k(BP3,CO3(-*))<5.10(7) M(-1) s(-1). These data allow the modelling of BP3 photochemical transformation, which helps filling the knowledge gap about the environmental persistence of this compound. Under typical surface water conditions, direct photolysis and reactions with (*)OH and (3)CDOM* would be the main processes of BP3 phototransformation. Reaction with (*)OH would prevail at low DOC, direct photolysis at intermediate DOC (around 5 mg C L(-1)), and reaction with (3)CDOM* at high DOC. If the reaction rate constant with CO3( *) is near the upper limit of experimental measures (5.10(7) M(-1) s(-1)), the CO3(-*) degradation process could be somewhat important for DOC<1 mg C L(-1). The predicted half-life time of BP3 in surface waters under summertime conditions would be of some weeks, and it would increase with increasing depth and DOC. BP3 transformation intermediates were detected upon reaction with (*)OH. Two methylated derivatives were tentatively identified, and they were probably produced by reaction between BP3 and fragments arising from photodegradation. The other intermediates were benzoic acid (maximum concentration ~10% of initial BP3) and benzaldehyde (1%). PMID- 23810863 TI - Facilitation of face recognition through the retino-tectal pathway. AB - Humans can shift their gazes faster to human faces than to non-face targets during a task in which they are required to choose between face and non-face targets. However, it remains unclear whether a direct projection from the retina to the superior colliculus is specifically involved in this facilitated recognition of faces. To address this question, we presented a pair of face and non-face pictures to participants modulated in greyscale (luminance-defined stimuli) in one condition and modulated in a blue-yellow scale (S-cone-isolating stimuli) in another. The information of the S-cone-isolating stimuli is conveyed through the retino-geniculate pathway rather than the retino-tectal pathway. For the luminance stimuli, the reaction time was shorter towards a face than towards a non-face target. The facilitatory effect while choosing a face disappeared with the S-cone stimuli. Moreover, fearful faces elicited a significantly larger facilitatory effect relative to neutral faces, when the face (with or without emotion) and non-face stimuli were presented in greyscale. The effect of emotional expressions disappeared with the S-cone stimuli. In contrast to the S cone stimuli, the face facilitatory effect was still observed with negated stimuli that were prepared by reversing the polarity of the original colour pictures and looked as unusual as the S-cone stimuli but still contained luminance information. These results demonstrate that the face facilitatory effect requires the facial and emotional information defined by luminance, suggesting that the luminance information conveyed through the retino-tectal pathway is responsible for the faster recognition of human faces. PMID- 23810864 TI - Implicit measurement of positive and negative future thinking as a predictor of depressive symptoms and hopelessness. AB - Research using explicit measures has linked decreased positive future thinking, but not increased negative future thinking, with clinical depression. However, individuals may be unable or unwilling to express thoughts about the future, and can be unaware of implicit beliefs that can influence their behavior. Implicit measures of cognition may shed light on the role of future thinking in depression. To our knowledge, the current study presents the first implicit measure of positive and negative future thinking. A sample of 71 volunteers (38 healthy; 33 with sub-clinical depression) completed both implicit and explicit measures of positive and negative future thinking. The findings indicate differences in the evaluation of both positive and negative future events between the two groups. However, group differences were more pronounced on the implicit measure. These findings point to the potential utility of an implicit measure of future thinking in mental health research and clinical practice. PMID- 23810865 TI - Temperature and the catalytic activity of enzymes: a fresh understanding. AB - The discovery of an additional step in the progression of an enzyme from the active to inactive state under the influence of temperature has led to a better match with experimental data for all enzymes that follow Michaelis-Menten kinetics, and to an increased understanding of the process. The new model of the process, the Equilibrium Model, describes an additional mechanism by which temperature affects the activity of enzymes, with implications for ecological, metabolic, structural, and applied studies of enzymes. PMID- 23810866 TI - Dose-dependent diastolic dysfunction and early death in a mouse model with cardiac troponin mutations. AB - Our aim was to explore the dose-dependent diastolic dysfunction and the mechanisms of heart failure and early death in transgenic (TG) mice modeling human restrictive cardiomyopathy (RCM). The first RCM mouse model (cTnI(193His) mice) carrying cardiac troponin I (cTnI) R193H mutation (mouse cTnI R193H equals to human cTnI R192H) was generated several years ago in our laboratory. The RCM mice manifested a phenotype similar to that observed in RCM patients carrying the same cTnI mutation, i.e. enlarged atria and restricted ventricles. However, the causes of heart failure and early death observed in RCM mice remain unclear. In this study, we have produced RCM TG mice (cTnI(193His)-L, cTnI(193His)-M and cTnI(193His)-H) that express various levels of mutant cTnI in the heart. Histological examination and echocardiography were performed on these mice to monitor the time course of the disease development and heart failure. Our data demonstrate that cTnI mutation-caused diastolic dysfunction is dose-dependent. The key mechanism is myofibril hypersensitivity to Ca(2+) resulting in an impaired relaxation in the mutant cardiac myocytes. Prolonged relaxation time and delay of Ca(2+) decay observed in the mutant cardiac myocytes are correlated with the level of the mutant protein in the heart. Markedly enlarged atria due to the elevated end-diastolic pressure and myocardial ischemia are observed in the heart of the transgenic mice. In the mice with the highest level of the mutant protein, restricted ventricles and systolic dysfunction occur followed immediately by heart failure and early death. Diastolic dysfunction caused by R193H troponin I mutation is specific, showing a dose-dependent pattern. These mouse models are useful tools for the study of diastolic dysfunction. Impaired diastole can cause myocardial ischemia and fibrosis formation, resulting in the development of systolic dysfunction and heart failure with early death in the RCM mice with a high level of the mutant protein in the heart. PMID- 23810867 TI - What was the intracardiac echocardiographic instrument and methodology used to detect and quantify the vegetation on implantable electronic device? PMID- 23810868 TI - Intracoronary optical coherence tomography: are we getting too close to the light? PMID- 23810869 TI - Patients with heart failure have an increased risk of incident cancer. AB - OBJECTIVES: This study sought to evaluate the risk of cancer in patients with heart failure (HF) compared with community controls and to determine the impact of cancer post-HF on outcomes. BACKGROUND: HF is associated with excess morbidity and mortality. Noncardiac causes of adverse outcomes in HF are increasingly recognized, but not fully characterized. METHODS: In a case-control study, we compared the history of cancer among community subjects newly diagnosed with HF from 1979 to 2002 to age-, sex-, and date-matched community controls without HF (961 pairs). Individuals without cancer at the index date (596 pairs) were followed for cancer in a cohort design, and the survival of HF patients who developed cancer was assessed. RESULTS: Before the index date, 22% of HF cases and 23% of controls had a history of cancer (odds ratio [OR]: 0.94; 95% confidence interval [CI]: 0.75 to 1.17). During 9,203 person-years of follow-up (7.7 +/- 6.4 years), 244 new cancer cases were identified; HF patients had a 68% higher risk of developing cancer (hazard ratio [HR]: 1.68; 95% CI: 1.13 to 2.50) adjusted for body mass index, smoking, and comorbidities. The HRs were similar for men and women, with a trend toward a stronger association among subjects <=75 years of age (p = 0.22) and during the most recent time period (p = 0.075). Among HF cases, incident cancer increased the risk of death (HR: 1.56; 95% CI: 1.22 to 1.99) adjusted for age, sex, index year, and comorbidities. CONCLUSIONS: HF patients are at increased risk of cancer, which appears to have increased over time. Cancer increases mortality in HF, underscoring the importance of noncardiac morbidity and of cancer surveillance in the management of HF patients. PMID- 23810870 TI - Mental stress and cardiac troponin: keep calm and carry on? PMID- 23810871 TI - Natriuretic peptides and primary prevention: the new world? PMID- 23810872 TI - Incident cancer in patients with heart failure: causation or mere association? PMID- 23810873 TI - Post-traumatic stress disorder and coronary heart disease. PMID- 23810874 TI - PONTIAC (NT-proBNP selected prevention of cardiac events in a population of diabetic patients without a history of cardiac disease): a prospective randomized controlled trial. AB - OBJECTIVES: The study sought to assess the primary preventive effect of neurohumoral therapy in high-risk diabetic patients selected by N-terminal pro-B type natriuretic peptide (NT-proBNP). BACKGROUND: Few clinical trials have successfully demonstrated the prevention of cardiac events in patients with diabetes. One reason for this might be an inaccurate selection of patients. NT proBNP has not been assessed in this context. METHODS: A total of 300 patients with type 2 diabetes, elevated NT-proBNP (>125 pg/ml) but free of cardiac disease were randomized. The "control" group was cared for at 4 diabetes care units; the "intensified" group was additionally treated at a cardiac outpatient clinic for the up-titration of renin-angiotensin system (RAS) antagonists and beta-blockers. The primary endpoint was hospitalization/death due to cardiac disease after 2 years. RESULTS: At baseline, the mean age of the patients was 67.5 +/- 9 years, duration of diabetes was 15 +/- 12 years, 37% were male, HbA1c was 7 +/- 1.1%, blood pressure was 151 +/- 22 mm Hg, heart rate was 72 +/- 11 beats/min, median NT-proBNP was 265.5 pg/ml (interquartile range: 180.8 to 401.8 pg/ml). After 12 months there was a significant difference between the number of patients treated with a RAS antagonist/beta-blocker and the dosage reached between groups (p < 0.0001). Blood pressure was significantly reduced in both (p < 0.05); heart rate was only reduced in the intensified group (p = 0.004). A significant reduction of the primary endpoint (hazard ratio: 0.351; 95% confidence interval: 0.127 to 0.975, p = 0.044) was visible in the intensified group. The same was true for other endpoints: all-cause hospitalization, unplanned cardiovascular hospitalizations/death (p < 0.05 for all). CONCLUSIONS: Accelerated up-titration of RAS antagonists and beta-blockers to maximum tolerated dosages is an effective and safe intervention for the primary prevention of cardiac events for diabetic patients pre-selected using NT-proBNP. (Nt-proBNP Guided Primary Prevention of CV Events in Diabetic Patients [PONTIAC]; NCT00562952). PMID- 23810875 TI - Paradoxical response to exercise in asymptomatic hypertrophic cardiomyopathy: a new description of outflow tract obstruction dynamics. AB - OBJECTIVES: The purpose of this study was to analyze left ventricular obstruction in patients with hypertrophic cardiomyopathy (HCM) during exercise echocardiography. BACKGROUND: Despite the association of symptoms with left ventricular outflow tract obstruction in HCM, there exist paradoxical situations in which significant intraventricular gradients (>50 mm Hg) at rest occur in conjunction with excellent exercise tolerance. METHODS: To examine this phenomenon, we performed exercise echocardiography and analyzed the clinical status of 107 HCM patients with and without resting obstruction. RESULTS: At rest, 69 patients had no obstruction and 38 exhibited an intraventricular gradient, 9 of whom exhibited a decrease in gradient of at least 30 mm Hg (99.4 +/- 35.5 mm Hg to 30.2 +/- 14.3 mm Hg, p < 0.001) during exercise (paradoxical response to exercise [PRE]). The PRE patients presented with a significantly lower New York Heart Association clinical class and higher left ventricular volumes and arterial pressure both at rest and during exercise than HCM patients in whom the gradient increased or did not change during stress echocardiography. Finally, PRE patients exhibited a trend toward a reduced rate of cardiac events. CONCLUSIONS: Our study reports a subgroup of HCM patients, designated PRE based on a decreased intraventricular gradient during exercise. The reduced exertional obstruction may account for the better functional class and trend toward fewer clinical events in PRE patients. PMID- 23810876 TI - Lessons from the heart: troponin elevations in patients with established peripheral artery disease. PMID- 23810878 TI - Challenges of diagnosis and risk stratification in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia. PMID- 23810877 TI - Prevalence and trends of metabolic syndrome in the adult U.S. population, 1999 2010. AB - OBJECTIVES: This study sought to characterize the prevalence of metabolic syndrome (MetS), its 5 components, and their pharmacological treatment in U.S. adults by sex and race/ethnicity over time. BACKGROUND: MetS is a constellation of clinical risk factors for cardiovascular disease, stroke, kidney disease, and type 2 diabetes mellitus. METHODS: Prevalence estimates were estimated in adults (>= 20 years of age) from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2010 (in 2-year survey waves). The biological thresholds, defined by the 2009 Joint Scientific Statement, were: 1) waist circumference >= 102 cm (males adults) and >= 88 cm (female adults); 2) fasting plasma glucose >= 100 mg/dl; 3) blood pressure of >= 130/85 mm Hg; 4) triglycerides >= 150 mg/dl; and 5) high-density lipoprotein-cholesterol (HDL-C) <40 mg/dl (male adults) and <50 mg/dl (female adults). Prescription drug use was estimated for lipid modifying agents, anti-hypertensives, and anti-hyperglycemic medications. RESULTS: From 1999 and 2000 to 2009 and 2010, the age-adjusted prevalence of MetS (based on biologic thresholds) decreased from 25.5% (95% confidence interval [CI]: 22.5% to 28.6%) to 22.9% (95% CI: 20.3% to 25.5%). During this period, hypertriglyceridemia prevalence decreased (33.5% to 24.3%), as did elevated blood pressure (32.3% to 24.0%). The prevalence of hyperglycemia increased (12.9% to 19.9%), as did elevated waist circumference (45.4% to 56.1%). These trends varied considerably by sex and race/ethnicity. Decreases in elevated blood pressure, suboptimal triglycerides, and high-density lipoprotein-cholesterol prevalence have corresponded with increases in anti-hypertensive and lipid-modifying drugs, respectively. CONCLUSIONS: The increasing prevalence of abdominal obesity, particularly among female adults, highlights the urgency of addressing abdominal obesity as a healthcare priority. The use of therapies for MetS components aligns with favorable trends in their prevalence. PMID- 23810879 TI - Eplerenone: another drug to add to the mix? PMID- 23810880 TI - A randomized comparison of pulmonary vein isolation with versus without concomitant renal artery denervation in patients with refractory symptomatic atrial fibrillation and resistant hypertension. PMID- 23810881 TI - Safety and efficacy of eplerenone in patients at high risk for hyperkalemia and/or worsening renal function: analyses of the EMPHASIS-HF study subgroups (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure). AB - OBJECTIVES: The study sought to investigate the safety and efficacy of eplerenone in patients at high risk for hyperkalemia or worsening renal function (WRF) in EMPHASIS-HF, a trial that enrolled patients at least 55 years old with heart failure and reduced ejection fraction (HF-REF), in New York Heart Association (NYHA) functional class II and with an estimated glomerular filtration rate (eGFR) >30 ml/min/1.73 m(2) and serum potassium <5.0 mmol/l. Patients were receiving optimal therapy and most had been hospitalized for a cardiovascular reason within 180 days of inclusion. BACKGROUND: Underuse of eplerenone in patients with HF-REF may be due to fear of inducing hyperkalemia or WRF in high risk patients. METHODS: This was a pre-specified analysis of subgroups of patients at high risk of hyperkalemia or WRF (patients >= 75 years of age, with diabetes, with eGFR <60 ml/min/1.73 m(2), and with systolic blood pressure < median of 123 mm Hg), examining the major safety measures (potassium >5.5, >6.0, and <3.5 mmol/l; hyperkalemia leading to study-drug discontinuation or hospitalization; and hospitalization for WRF) as well as the primary outcome (hospitalization for HF or cardiovascular mortality). RESULTS: In all high-risk subgroups, patients treated with eplerenone had an increased risk of potassium >5.5 mmol/l but not of potassium >6.0 mmol/l, and of hospitalization for hyperkalemia or discontinuation of study medication due to adverse events. Eplerenone was effective in reducing the primary composite endpoint in all subgroups. CONCLUSIONS: In patients with chronic HF-REF, in NYHA functional class II, and meeting specific inclusion and exclusion criteria, including an eGFR >30 ml/min/1.73 m(2) and potassium <5.0 mmol/l, eplerenone was both efficacious and safe when carefully monitored, even in subgroups at high risk of developing hyperkalemia or WRF. (A Comparison Of Outcomes In Patients In New York Heart Association [NYHA] Class II Heart Failure When Treated With Eplerenone Or Placebo In Addition To Standard Heart Failure Medicines [EMPHASIS-HF Study]; NCT00232180). PMID- 23810882 TI - Survival after shock therapy in implantable cardioverter-defibrillator and cardiac resynchronization therapy-defibrillator recipients according to rhythm shocked. The ALTITUDE survival by rhythm study. AB - OBJECTIVES: This study sought to determine if the risk of mortality associated with inappropriate implantable cardioverter-defibrillator (ICD) shocks is due to the underlying arrhythmia or the shock itself. BACKGROUND: Shocks delivered from ICDs are associated with an increased risk of mortality. It is unknown if all patients who experience inappropriate ICD shocks have an increased risk of death. METHODS: We evaluated survival outcomes in patients with an ICD and a cardiac resynchronization therapy defibrillator enrolled in the LATITUDE remote monitoring system (Boston Scientific Corp., Natick, Massachusetts) through January 1, 2010. First shock episode rhythms from 3,809 patients who acutely survived the initial shock were adjudicated by 7 electrophysiologists. Patients with a shock were matched to patients without a shock (n = 3,630) by age at implant, implant year, sex, and device type. RESULTS: The mean age of the study group was 64 +/- 13 years, and 78% were male. Compared with no shock, there was an increased rate of mortality in those who received their first shock for monomorphic ventricular tachycardia (hazard ratio [HR]: 1.65, p < 0.0001), ventricular fibrillation/polymorphic ventricular tachycardia (HR: 2.10, p < 0.0001), and atrial fibrillation/flutter (HR: 1.61, p = 0.003). In contrast, mortality after first shocks due to sinus tachycardia and supraventricular tachycardia (HR: 0.97, p = 0.86) and noise/artifact/oversensing (HR: 0.91, p = 0.76) was comparable to that in patients without a shock. CONCLUSIONS: Compared with no shock, those who received their first shock for ventricular rhythms and atrial fibrillation had an increased risk of death. There was no significant difference in survival after inappropriate shocks for sinus tachycardia or noise/artifact/oversensing. In this study, the adverse prognosis after first shock appears to be more related to the underlying arrhythmia than to an adverse effect from the shock itself. PMID- 23810883 TI - Exercise testing in asymptomatic gene carriers exposes a latent electrical substrate of arrhythmogenic right ventricular cardiomyopathy. AB - OBJECTIVES: The aim of this study was to determine if exercise testing could expose a latent electrical substrate of arrhythmogenic right ventricular cardiomyopathy (ARVC) in asymptomatic gene carriers. BACKGROUND: Management of asymptomatic ARVC gene carriers is challenging because of variable penetrance of disease and the recognition that sudden cardiac death may be the first clinical manifestation. METHODS: Exercise-induced abnormalities during exercise treadmill testing (ETT) were initially compared in 60 subjects: 30 asymptomatic ARVC gene carriers and 30 healthy controls. In phase 2 of the study, ETT results of 25 patients with ARVC with histories of sustained ventricular arrhythmia or cardiac arrest were evaluated to determine if ETT abnormalities in asymptomatic gene carriers were common to patients with a malignant electrical form of the disease. RESULTS: Depolarization abnormalities during ETT were found to develop more frequently in asymptomatic gene carriers compared with healthy controls: epsilon waves appeared in 4 of 28 (14%) compared with 0 of 30 (0%) (p = 0.048), premature ventricular contractions in 17 of 30 (57%) compared with 3 of 30 (10%) (p = 0.0003), and new QRS terminal activation duration >= 55 ms in 7 of 22 (32%) compared with 2 of 29 (7%) (p = 0.03). Superior axis premature ventricular contractions occurred only in gene carriers. In the second phase of the study, the frequency of these abnormalities was found to be high in patients with symptomatic ARVC: new epsilon waves appeared in 3 of 18 (17%), superior axis premature ventricular contractions in 21 of 25 (84%), and new terminal activation duration >= 55 ms in 8 of 12 (67%). CONCLUSIONS: Exercise testing exposes a latent electrical substrate in asymptomatic ARVC gene carriers that is shared by patients with ARVC with histories of ventricular arrhythmia. ETT may be useful in guiding treatment decisions, exercise prescription, and prioritizing medical surveillance in asymptomatic ARVC gene carriers. PMID- 23810884 TI - In vivo diagnosis of plaque erosion and calcified nodule in patients with acute coronary syndrome by intravascular optical coherence tomography. AB - OBJECTIVES: The aim of this study was to characterize the morphological features of plaque erosion and calcified nodule in patients with acute coronary syndrome (ACS) by optical coherence tomography (OCT). BACKGROUND: Plaque erosion and calcified nodule have not been systematically investigated in vivo. METHODS: A total of 126 patients with ACS who had undergone pre-intervention OCT imaging were included. The culprit lesions were classified as plaque rupture (PR), erosion (OCT-erosion), calcified nodule (OCT-CN), or with a new set of diagnostic criteria for OCT. RESULTS: The incidences of PR, OCT-erosion, and OCT-CN were 43.7%, 31.0%, and 7.9%, respectively. Patients with OCT-erosion were the youngest, compared with those with PR and OCT-CN (53.8 +/- 13.1 years vs. 60.6 +/ 11.5 years, 65.1 +/- 5.0 years, p = 0.005). Compared with patients with PR, presentation with non-ST-segment elevation ACS was more common in patients with OCT-erosion (61.5% vs. 29.1%, p = 0.008) and OCT-CN (100% vs. 29.1%, p < 0.001). The OCT-erosion had a lower frequency of lipid plaque (43.6% vs. 100%, p < 0.001), thicker fibrous cap (169.3 +/- 99.1 MUm vs. 60.4 +/- 16.6 MUm, p < 0.001), and smaller lipid arc (202.8 +/- 73.6 degrees vs. 275.8 +/- 60.4 degrees , p < 0.001) than PR. The diameter stenosis was least severe in OCT-erosion, followed by OCT-CN and PR (55.4 +/- 14.7% vs. 66.1 +/- 13.5% vs. 68.8 +/- 12.9%, p < 0.001). CONCLUSIONS: Optical coherence tomography is a promising modality for identifying OCT-erosion and OCT-CN in vivo. The OCT-erosion is a frequent finding in patients with ACS, especially in those with non-ST-segment elevation ACS and younger patients. The OCT-CN is the least common etiology for ACS and is more common in older patients. (The Massachusetts General Hospital Optical Coherence Tomography Registry; NCT01110538). PMID- 23810886 TI - Rare variant of pulmonary arteriovenous fistula: direct communication between right pulmonary artery and left atrium associated with aortopulmonary collaterals. PMID- 23810885 TI - Post-traumatic stress disorder and incidence of coronary heart disease: a twin study. AB - OBJECTIVES: The aim of this study was to determine whether post-traumatic stress disorder (PTSD) is associated with coronary heart disease (CHD) using a prospective twin study design and objective measures of CHD. BACKGROUND: It has long been hypothesized that PTSD increases the risk of CHD, but empirical evidence using objective measures is limited. METHODS: We conducted a prospective study of middle-aged male twins from the Vietnam Era Twin Registry. Among twin pairs without self-reported CHD at baseline, we selected pairs discordant for a lifetime history of PTSD, pairs discordant for a lifetime history of major depression, and pairs without either condition. All underwent a clinic visit after a median follow-up of 13 years. Outcomes included clinical events (myocardial infarction, other hospitalizations for CHD and coronary revascularization) and quantitative measures of myocardial perfusion by [(13)N] ammonia positron emission tomography, including a stress total severity score and coronary flow reserve. RESULTS: A total of 562 twins (281 pairs) with a mean age of 42.6 years at baseline were included in this study. The incidence of CHD was more than double in twins with PTSD (22.6%) than in those without PTSD (8.9%; p < 0.001). The association remained robust after adjusting for lifestyle factors, other risk factors for CHD, and major depression (odds ratio: 2.2; 95% confidence interval: 1.2 to 4.1). Stress total severity score was significantly higher (+95%, p = 0.001) and coronary flow reserve was lower (-0.21, p = 0.02) in twins with PTSD than in those without PTSD, denoting worse myocardial perfusion. Associations were only mildly attenuated in 117 twin pairs discordant for PTSD. CONCLUSIONS: Among Vietnam-era veterans, PTSD is a risk factor for CHD. PMID- 23810887 TI - Reply: Dabigatran's 'real-world' data about risk of myocardial infarction and gastrointestinal bleeding contradicts with randomized trials. PMID- 23810888 TI - Understanding implantable cardioverter-defibrillator shocks and mortality: on trial. PMID- 23810889 TI - Reply: What was the intracardiac echocardiographic instrument and methodology used to detect and quantify the vegetation on implantable electronic device? PMID- 23810890 TI - Dabigatran's 'real-world' data about risk of myocardial infarction and gastrointestinal bleeding contradicts with randomized trials. PMID- 23810891 TI - Cardiac hypertrophy, accessory pathway, and conduction system disease in an adolescent: the PRKAG2 cardiac syndrome. PMID- 23810892 TI - Et Tu PDE2? PMID- 23810893 TI - Phosphodiesterase-2 is up-regulated in human failing hearts and blunts beta adrenergic responses in cardiomyocytes. AB - OBJECTIVES: This study investigated whether myocardial phosphodiesterase-2 (PDE2) is altered in heart failure (HF) and determined PDE2-mediated effects on beta adrenergic receptor (beta-AR) signaling in healthy and diseased cardiomyocytes. BACKGROUND: Diminished cyclic adenosine monophosphate (cAMP) and augmented cyclic guanosine monophosphate (cGMP) signaling is characteristic for failing hearts. Among the PDE superfamily, PDE2 has the unique property of being able to be stimulated by cGMP, thus leading to a remarkable increase in cAMP hydrolysis mediating a negative cross talk between cGMP and cAMP signaling. However, the role of PDE2 in HF is poorly understood. METHODS: Immunoblotting, radioenzymatic- and fluorescence resonance energy transfer-based assays, video edge detection, epifluorescence microscopy, and L-type Ca2(+) current measurements were performed in myocardial tissues and/or isolated cardiomyocytes from human and/or experimental HF, respectively. RESULTS: Myocardial PDE2 expression and activity were ~2-fold higher in advanced human HF. Chronic beta-AR stimulation via catecholamine infusions in rats enhanced PDE2 expression ~2-fold and cAMP hydrolytic activity ~4-fold, which correlated with blunted cardiac beta-AR responsiveness. In diseased cardiomyocytes, higher PDE2 activity could be further enhanced by stimulation of cGMP synthesis via nitric oxide donors, whereas specific PDE2 inhibition partially restored beta-AR responsiveness. Accordingly, PDE2 overexpression in healthy cardiomyocytes reduced the rise in cAMP levels and L-type Ca2(+) current amplitude, and abolished the inotropic effect following acute beta-AR stimulation, without affecting basal contractility. Importantly, PDE2-overexpressing cardiomyocytes showed marked protection from norepinephrine induced hypertrophic responses. CONCLUSIONS: PDE2 is markedly up-regulated in failing hearts and desensitizes against acute beta-AR stimulation. This may constitute an important defense mechanism during cardiac stress, for example, by antagonizing excessive beta-AR drive. Thus, activating myocardial PDE2 may represent a novel intracellular antiadrenergic therapeutic strategy in HF. PMID- 23810894 TI - Incremental value of cardiac magnetic resonance imaging in arrhythmic risk stratification of arrhythmogenic right ventricular dysplasia/cardiomyopathy associated desmosomal mutation carriers. AB - OBJECTIVES: The aim of this study was to identify the incremental value and optimal role of cardiac magnetic resonance (CMR) imaging in arrhythmic risk stratification of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)-associated desmosomal mutation carriers without histories of sustained ventricular arrhythmia. BACKGROUND: Risk stratification of ARVD/C mutation carriers is challenging. METHODS: Sixty-nine patients (mean age 27.0 +/- 15.3 years, 42% men) harboring ARVD/C-associated pathogenic mutations (83% plakophilin 2) without prior sustained ventricular arrhythmias were included. Electrocardiographic and 24-h Holter monitoring findings closest to presentation were analyzed for electrical abnormalities per revised task force criteria. CMR studies were done to identify abnormal cardiac structure and function according to the revised task force criteria. RESULTS: Overall, 42 patients (61%) presented with electrical abnormalities on the basis of electrocardiography and Holter monitoring, of whom 20 (48%) had abnormal results on CMR. Only 1 of 27 patients (4%) without electrical abnormalities at initial evaluation had abnormal CMR results. Over a mean follow-up period of 5.8 +/- 4.4 years, 11 patients (16%) experienced sustained ventricular arrhythmias, exclusively in patients with both electrical abnormalities (electrocardiography and/or Holter monitoring) and abnormal CMR results. CONCLUSIONS: These results suggest that electrical abnormalities on electrocardiography and Holter monitoring precede detectable structural abnormalities in ARVD/C mutation carriers. Therefore, evaluation of cardiac structure and function using CMR is probably not necessary in the absence of baseline electrical abnormalities. Among ARVD/C mutation carriers, the presence of both electrical and CMR abnormalities identifies patients at high risk for events and thus patients who might benefit from prophylactic implantable cardioverter-defibrillator placement. PMID- 23810895 TI - Syncope without prodromes in patients with normal heart and normal electrocardiogram: a distinct entity. AB - OBJECTIVES: This study sought to investigate the clinical and laboratory findings of patients affected by sudden-onset syncope without prodromes who had a normal heart and normal electrocardiogram. BACKGROUND: The pathophysiology of syncope in these patients is uncertain. METHODS: We compared the clinical and laboratory findings of 15 patients with sudden-onset syncope without prodromes who had a normal heart and normal electrocardiogram (the study group) with those of 31 patients with established vasovagal syncope (VVS). RESULTS: The patients in the study group were older than those with VVS (age 61 +/- 12 years vs. 46 +/- 17 years) and had a history of fewer episodes of syncope (median of 2 [interquartile range [IQR]: 1 to 2.5] vs. 9 [IQR: 4 to 15] years) that were of more recent onset (median of 1 [IQR: 0 to 1] vs. 10.5 [IQR: 3.3 to 27] years). The study group had lower median baseline adenosine plasmatic levels than the VVS group (0.25 MUmol/l [95% confidence interval: 0.10 to 1.51] vs. 0.85 MUmol/l [95% confidence interval: 0.32 to 2.80]). On receiver-operating characteristic curve analysis, the adenosine plasmatic level of <=0.36 best discriminated between groups, displaying 73% sensitivity and 93% specificity. Tilt table testing was more frequently positive in patients with VVS than in the study group (74% vs. 33%). A similarly high positivity rate of adenosine/adenosine triphosphate testing was found in both groups. CONCLUSIONS: Common clinical features and a low adenosine plasmatic level define a distinct form of syncope, distinguish it from VVS, and suggest a causal role of the adenosine pathway. PMID- 23810897 TI - Voltage-controlled cellular viability of preosteoblasts on polarized cpTi with varying surface oxide thickness. AB - Cathodic voltage shifts of metallic biomaterials were recently shown to induce cell apoptosis in-vitro. The details of the reduction-based physico-chemical phenomena have not yet been fully elucidated. This study shows how surface oxide thickness of commercially pure titanium affects the voltage viability range, and whether anodic oxidation can extend this range. Cell viability, cytoskeletal organization, and cellular adhesion on bare and anodized Ti, at -500, -400 mV(Ag/AgCl) and open circuit potential were assessed. Surfaces were characterized using contact angle measurement and atomic force microscopy, and the observed cellular response was related to the changes in electrochemical currents, and impedance of the samples. Results show that anodization at 9 V in phosphate buffer saline generates a compact surface oxide with comparable surface roughness and energy to the starting bare surface. The anodized surface extends the viability range at 24h from -400 mV(Ag/AgCl) by about -100 mV, which corresponds to an increase in impedance of the surface from 58 kOmega cm(2) to 29 MOmega cm(2) at -400 mV(Ag/AgCl) and results in low average current densities below 0.1 MUA cm(-2). The results demonstrate that the voltage range for cell viability under cathodic polarization is expanded due to anodization of the surface oxide and lowering of cathodic currents. PMID- 23810896 TI - The association between cortisol response to mental stress and high-sensitivity cardiac troponin T plasma concentration in healthy adults. AB - OBJECTIVES: The objective of this study was to examine the association between cortisol response to mental stress and high-sensitivity cardiac troponin T (hs cTnT) in healthy older individuals without history of cardiovascular disease (CVD). BACKGROUND: Mental stress is a recognized risk factor for CVD, although the mechanisms remain unclear. Cortisol, a key stress hormone, is associated with coronary atherosclerosis and may accentuate structural and functional cardiac disease. METHODS: This cross-sectional study involved 508 disease-free men and women aged 53 to 76 years drawn from the Whitehall II epidemiological cohort. We evaluated salivary cortisol response to standardized mental stress tests (exposure) and hs-cTnT plasma concentration using a high-sensitivity assay (outcome). We measured coronary calcification using electron-beam dual-source computed tomography and Agatston scores. RESULTS: After adjustment for demographic and clinical variables associated with CVD as well as for inflammatory factors, we found a robust association between cortisol response and detectable hs-cTnT (odds ratio [OR]: 3.98; 95% confidence interval [CI]: 1.60 to 9.92; p = 0.003). The association remained when we restricted the analysis to participants without coronary calcification (n = 222; OR: 4.77; 95% CI: 1.22 to 18.72; p = 0.025) or when we further adjusted for coronary calcification in participants with positive Agatston scores (n = 286; OR: 7.39; 95% CI: 2.22 to 26.24; p = 0.001). CONCLUSIONS: We found that heightened cortisol response to mental stress was associated with detectable plasma levels of cTnT using high sensitivity assays in healthy participants, independently of coronary atherosclerosis. Further research is needed to understand the role of psychosocial stress in the pathophysiology of cardiac cell damage. PMID- 23810898 TI - Xlr1 is involved in the transcriptional control of the pentose catabolic pathway, but not hemi-cellulolytic enzymes in Magnaporthe oryzae. AB - Magnaporthe oryzae is a fungal plant pathogen of many grasses including rice. Since arabinoxylan is one of the major components of the plant cell wall of grasses, M. oryzae is likely to degrade this polysaccharide for supporting its growth in infected leaves. D-Xylose is released from arabinoxylan by fungal depolymerising enzymes and catabolized through the pentose pathway. The expression of genes involved in these pathways is under control of the transcriptional activator XlnR/Xlr1, conserved among filamentous ascomycetes. In this study, we identified M. oryzae genes involved in the pentose catabolic pathway (PCP) and their function during infection, including the XlnR homolog, XLR1, through the phenotypic analysis of targeted null mutants. Growth of the Deltaxlr1 strain was reduced on D-xylose and xylan, but unaffected on L-arabinose and arabinan. A strong reduction of PCP gene expression was observed in the Deltaxlr1 strain on D-xylose and L-arabinose. However, there was no significant difference in xylanolytic and cellulolytic enzyme activities between the Deltaxlr1 mutant and the reference strain. These data demonstrate that XLR1 encodes the transcriptional activator of the PCP in M. oryzae, but does not appear to play a role in the regulation of the (hemi-) cellulolytic system in this fungus. This indicates only partial similarity in function between Xlr1 and A. niger XlnR. The deletion mutant of D-xylulose kinase encoding gene (XKI1) is clearly unable to grow on either D-xylose or L-arabinose and showed reduced growth on xylitol, L-arabitol and xylan. Deltaxki1 displayed an interesting molecular phenotype as it over-expressed other PCP genes as well as genes encoding (hemi-) cellulolytic enzymes. However, neither Deltaxlr1 nor Deltaxki1 showed significant differences in their pathogeny on rice and barley compared to the wild type, suggesting that D-xylose catabolism is not required for fungal growth in infected leaves. PMID- 23810899 TI - Rapid construction of parallel analysis of RNA end (PARE) libraries for Illumina sequencing. AB - MicroRNAs (miRNAs) are ~21nt small RNAs that pair to their target mRNAs and in many cases trigger cleavage, particularly in plants. Although many computational tools can predict miRNA:mRNA interactions, it remains critical to validate cleavage events, due to miRNA function in translational repression or due to high rates of false positives (over 90%) for unvalidated target predictions. A few years ago, three laboratories described similar methods to validate cleavage of miRNA targets by the cloning en masse of 5' ends of cleaved or uncapped mRNAs. To take advantage of the recent progress in high-throughput sequencing technology, we have devised an updated protocol to (1) enable much faster library preparation, and (2) reduce the cost by pooling indexed samples together for sequencing. Here we provide a step-by-step protocol for PARE library construction, starting from total RNA. This protocol has been successfully used in our laboratory to validate miRNA targets in a variety of plant species. We also provide advice for troubleshooting on some common issues. PMID- 23810900 TI - Direct ethanol fermentation from lignocellulosic biomass by Antarctic basidiomycetous yeast Mrakia blollopis under a low temperature condition. AB - Antarctic basidiomycetous yeast Mrakia blollopis SK-4 has unique fermentability for various sugars under a low temperature condition. Hence, this yeast was used for ethanol fermentation from glucose and also for direct ethanol fermentation (DEF) from cellulosic biomass without/with Tween 80 at 10 degrees C. Maximally, 48.2 g/l ethanol was formed from 12% (w/v) glucose. DEF converted filter paper, Japanese cedar and Eucalyptus to 12.2 g/l, 12.5 g/l and 7.2 g/l ethanol, respectively. In the presence of 1% (v/v) Tween 80, ethanol concentration increased by about 1.1-1.6-fold compared to that without Tween 80. This is the first report on DEF using cryophilic fungi under a low temperature condition. We consider that M. blollopis SK-4 has a good potential for ethanol fermentation in cold environments. PMID- 23810901 TI - Weather entrainment and multispectral diel activity rhythm of desert hamsters. AB - The circadian rhythm of animals is an adaptation to predictable variation in environmental conditions. Multiple internal oscillators may allow animals to cope with environmental oscillations in different frequencies. Heat stress and dramatic differences between night and day temperatures are the main selective pressures of the diel activity of desert mammals, particularly small-sized rodents. We tested the hypotheses that the diel activities of desert hamsters (Phodopus roborovskii) would be entrained by ambient humidity and temperature. We predicted that increases in night temperature and humidity would improve the propensity to perform activities of the hamster. We observed hourly activities of desert hamsters under semi natural conditions for 24 consecutive hours, with seven replicates in 7 different days. We fit generalized linear mixed models to observed proportions of active hamsters, temperatures, and relative humidity. Observed diel activities of desert hamsters consisted of three harmonic oscillations in the periodicities of 24 h, 12 h, and 6 h, respectively. Furthermore, probabilities to perform activities were positively related to night temperature and humidity. Therefore, the diel activities of desert hamsters are synchronized by atmospheric humidity, temperatures, and environmental cues of ultradian fluctuations. PMID- 23810902 TI - Trashing of single-stranded DNA generated during processing of arrested replication fork in E. coli. AB - We analyzed formation of single-stranded DNA (ssDNA) related to SOS induction in nalidixilate (Nal)-treated Escherichia coli, using immunofluorescence microscopy accompanied by computer analysis. We found enhancement of both ssDNA concentrations and cells having ssDNA foci that often localized around cellpoles. Analyzing several mutants deficient in DNA repair or replication, we found, after Nal treatment, that recN, recA, uvrD and dnaB failed to increase ssDNA concentration and that recG and particularly ruvA only partially enhanced it. In Nal-treated recB mutant, despite its failure in SOS induction, ssDNA foci positive cells increased with a slight enhancement of its concentration. These observations suggest the existence of a cellular process that sequesters genotoxic ssDNA as inert form, offering a new concept for SOS suppressor genes action. PMID- 23810903 TI - Topological plasticity of enzymes involved in disulfide bond formation allows catalysis in either the periplasm or the cytoplasm. AB - The transmembrane enzymes disulfide bond forming enzyme B (DsbB) and vitamin K epoxide reductase (VKOR) are central to oxidative protein folding in the periplasm of prokaryotes. Catalyzed formation of structural disulfide bonds in proteins also occurs in the cytoplasm of some hyperthermophilic prokaryotes through currently, poorly defined mechanisms. We aimed to determine whether DsbB and VKOR can be inverted in the membrane with retention of activity. By rational design of inversion of membrane topology, we engineered DsbB mutants that catalyze disulfide bond formation in the cytoplasm of Escherichia coli. This represents the first engineered inversion of a transmembrane protein with demonstrated conservation of activity and substrate specificity. This successful designed engineering led us to identify two naturally occurring and oppositely oriented VKOR homologues from the hyperthermophile Aeropyrum pernix that promote oxidative protein folding in the periplasm or cytoplasm, respectively, and hence defines the probable route for disulfide bond formation in the cytoplasm of hyperthermophiles. Our findings demonstrate how knowledge on the determinants of membrane protein topology can be used to de novo engineer a metabolic pathway and to unravel an intriguingly simple evolutionary scenario where a new "adaptive" cellular process is constructed by means of membrane protein topology inversion. PMID- 23810904 TI - The structure of the neisserial lipooligosaccharide phosphoethanolamine transferase A (LptA) required for resistance to polymyxin. AB - Gram-negative bacteria possess an outer membrane envelope consisting of an outer leaflet of lipopolysaccharides, also called endotoxins, which protect the pathogen from antimicrobial peptides and have multifaceted roles in virulence. Lipopolysaccharide consists of a glycan moiety attached to lipid A, embedded in the outer membrane. Modification of the lipid A headgroups by phosphoethanolamine (PEA) or 4-amino-arabinose residues increases resistance to the cationic cyclic polypeptide antibiotic, polymyxin. Lipid A PEA transferases are members of the YhjW/YjdB/YijP superfamily and usually consist of a transmembrane domain anchoring the enzyme to the periplasmic face of the cytoplasmic membrane attached to a soluble catalytic domain. The crystal structure of the soluble domain of the protein of the lipid A PEA transferase from Neisseria meningitidis has been determined crystallographically and refined to 1.4A resolution. The structure reveals a core hydrolase fold similar to that of alkaline phosphatase. Loop regions in the structure differ, presumably to enable interaction with the membrane-localized substrates and to provide substrate specificity. A phosphorylated form of the putative nucleophile, Thr280, is observed. Metal ions present in the active site are coordinated to Thr280 and to residues conserved among the family of transferases. The structure reveals the protein components needed for the transferase chemistry; however, substrate-binding regions are not evident and are likely to reside in the transmembrane domain of the protein. PMID- 23810906 TI - GroEL/ES buffering and compensatory mutations promote protein evolution by stabilizing folding intermediates. AB - Maintaining stability is a major constraint in protein evolution because most mutations are destabilizing. Buffering and/or compensatory mechanisms that counteract this progressive destabilization during functional adaptation are pivotal for protein evolution as well as protein engineering. However, the interplay of these two mechanisms during a full evolutionary trajectory has never been explored. Here, we unravel such dynamics during the laboratory evolution of a phosphotriesterase into an arylesterase. A controllable GroEL/ES chaperone co expression system enabled us to vary the selection environment between buffering and compensatory, which smoothened the trajectory along the fitness landscape to achieve a >10(4) increase in arylesterase activity. Biophysical characterization revealed that, in contrast to prevalent models of protein stability and evolution, the variants' soluble cellular expression did not correlate with in vitro stability, and compensatory mutations were linked to a stabilization of folding intermediates. Thus, folding kinetics in the cell are a key feature of protein evolvability. PMID- 23810905 TI - The Role of Aromatic-Aromatic Interactions in Strand-Strand Stabilization of beta Sheets. AB - Aromatic-aromatic interactions have long been believed to play key roles in protein structure, folding, and binding functions. However, we still lack full understanding of the contributions of aromatic-aromatic interactions to protein stability and the timing of their formation during folding. Here, using an aromatic ladder in the beta-barrel protein, cellular retinoic acid-binding protein 1 (CRABP1), as a case study, we find that aromatic pi stacking plays a greater role in the Phe65-Phe71 cross-strand pair, while in another pair, Phe50 Phe65, hydrophobic interactions are dominant. The Phe65-Phe71 pair spans beta strands 4 and 5 in the beta-barrel, which lack interstrand hydrogen bonding, and we speculate that it compensates energetically for the absence of strand-strand backbone interactions. Using perturbation analysis, we find that both aromatic aromatic pairs form after the transition state for folding of CRABP1, thus playing a role in the final stabilization of the beta-sheet rather than in its nucleation as had been earlier proposed. The aromatic interaction between strands 4 and 5 in CRABP1 is highly conserved in the intracellular lipid-binding protein (iLBP) family, and several lines of evidence combine to support a model wherein it acts to maintain barrel structure while allowing the dynamic opening that is necessary for ligand entry. Lastly, we carried out a bioinformatics analysis and found 51 examples of aromatic-aromatic interactions across non-hydrogen-bonded beta-strands outside the iLBPs, arguing for the generality of the role played by this structural motif. PMID- 23810907 TI - The influence of demographic stochasticity on evolutionary dynamics and stability. AB - We derive the frequency-dependent selection coefficient caused by "demographic" stochasticity resulting from the random sampling of opponents an individual faces during behavioral "contests" with other individuals. The mean, variance, and higher moments of fitness all influence the direction and strength of selection. A frequency-dependent trait can be stable when an individual's fitness depends upon an infinite number of contests with other individuals and unstable when it depends upon a finite number of contests. Conversely, unstable equilibria for an infinite number of contests can be stable when there is a finite number of contests. At stable equilibria for a finite number of contests, higher moments of fitness can outweigh the joint influence of the first two moments so that natural selection favors "within-generation" or developmental-trait variation (also known as phenotypic plasticity) contrary to the claim that natural selection always acts against such variation. We use second-moment estimates of the fitness functions in a diffusion approximation to compute fixation probabilities of competing strategies. These estimates are shown to be qualitatively consistent with those derived from simulations when population sizes are sufficiently large to ignore the contribution of higher-moment terms. We also show that explicit solutions to the diffusion approximation only exist for pair-wise interactions that lead to positive frequency-dependent selection. PMID- 23810908 TI - Sulforaphane inhibits PDGF-induced proliferation of rat aortic vascular smooth muscle cell by up-regulation of p53 leading to G1/S cell cycle arrest. AB - Vascular diseases such as atherosclerosis and restenosis artery angioplasty are associated with vascular smooth muscle cell (VSMC) proliferation and intimal thickening arterial walls. In the present study, we investigated the inhibitory effects of sulforaphane, an isothiocyanate produced in cruciferous vegetables, on VSMC proliferation and neointimal formation in a rat carotid artery injury model. Sulforaphane at the concentrations of 0.5, 1.0, and 2.0 MUM significantly inhibited platelet-derived growth factor (PDGF)-BB-induced VSMC proliferation in a concentration-dependent manner, determined by cell count. The IC50 value of sulforaphane-inhibited VSMC proliferation was 0.8 MUM. Sulforaphane increased the cyclin-dependent kinase inhibitor p21 and p53 levels, while it decreased CDK2 and cyclin E expression. The effects of sulforaphane on vascular thickening were determined 14 days after the injury to the rat carotid artery. The angiographic mean luminary diameters of the group treated with 2 and 4 MUM sulforaphane were 0.25+/-0.1 and 0.09+/-0.1 mm2, respectively, while the value of the control groups was 0.40+/-0.1 mm2, indicating that sulforaphane may inhibit neointimal formation. The expression of PCNA, maker for cell cycle arrest, was decreased, while that of p53 and p21 was increased, which showed the same pattern as one in in-vitro study. These results suggest that sulforaphane-inhibited VSMC proliferation may occur through the G1/S cell cycle arrest by up-regulation of p53 signaling pathway, and then lead to the decreased neointimal hyperplasia thickening. Thus, sulforaphane may be a promising candidate for the therapy of atherosclerosis and post-angiography restenosis. PMID- 23810909 TI - PTHrP in differentiating human mesenchymal stem cells: transcript isoform expression, promoter methylation, and protein accumulation. AB - Human PTHrP gene displays a complex organization with nine exons producing diverse mRNA variants due to alternative splicing at 5' and 3' ends and the existence of three different transcriptional promoters (P1, P2 and P3), two of which (P2 and P3) contain CpG islands. It is known that the expression of PTHrP isoforms may be differentially regulated in a developmental stage- and tissue specific manner. To search for novel molecular markers of stemness/differentiation, here we have examined isoform expression in fat-derived mesenchymal stem cells both maintained in stem conditions and induced toward adipo- and osteogenesis. In addition, the expression of the splicing isoforms derived from P2 and P3 promoters was correlated to the state of methylation of the latter. Moreover, we also performed a quantitative evaluation of intracellular and secreted PTHrP protein product in undifferentiated stem cells and in parallel cultures at various differentiation stages. The data obtained indicate that from the stemness condition to that of osteo- and adipo-genic differentiated cells, the expression of isoforms becomes increasingly selective, thereby being a potential gene signature for the monitoring of cell stem or committed/differentiating state and that the switching-off of PTHrP isoform expression is mostly promoter methylation-dependent. Moreover, PTHrP intracellular retention is down-regulated in osteo-differentiating cells whereas the secretion of the protein in the extracellular medium is up-regulated with respect to stem cells, thereby suggesting that these variations of the intracellular and extracellular levels of PTHrP could potentially be enclosed in the list of the available protein signature of osteogenic differentiation. PMID- 23810910 TI - Uncovering the secretes of mesenchymal stem cells. AB - Mesenchymal stem cells (MSC) show great promise in a wide array of therapeutic applications due mainly to their capacity to suppress immune and inflammatory reactions and instigate normal tissue repair processes. The secretion of bioactive factors is thought to play a predominant role in the mechanisms of action for these clinically relevant functions. As such, a large body of MSC research has focussed on characterization of the MSC secretome; including both soluble factors and factors released in extracellular vesicles (e.g., exosomes and microvesicles). This review provides an overview of our current knowledge of the MSC secretome in the context of determining the clinical relevance of these cells. In addition, the review summarizes various approaches that have been utilized to identify proteins secreted by MSC and discusses the advantages and limitations of different proteomic methods. Finally, we discuss issues that must be addressed before the clinical relevance of research into the MSC secretome can be realized. PMID- 23810911 TI - Lipid signaling cascades of orexin/hypocretin receptors. AB - Orexins - orexin-A and orexin-B - are neuropeptides with significant role in regulation of fundamental physiological processes such as sleep-wakefulness cycle. Orexins act via G-protein-coupled OX1 and OX2 receptors, which are found, in addition to the central nervous system, also in a number of peripheral organs. Orexin receptors show high degree of signaling promiscuity. One particularly prominent way of signaling for these receptors is via phospholipase cascades, including the phospholipase C, phospholipase D and phospholipase A2 cascades, and also diacylglycerol lipase and phosphoinositide-3-kinase pathways. Most analyses have been performed in recombinant cells; there are indications of some of these cascades in native cells while the significance of other cascades remains to be shown. In this review, I present these pathways, their activation mechanisms and their physiological significance. PMID- 23810912 TI - Highly selective detection of bacterial alarmone ppGpp with an off-on fluorescent probe of copper-mediated silver nanoclusters. AB - In this study, a facile strategy for highly selective and sensitive detection of bacterial alarmone, ppGpp, which is generated when bacteria face stress circumstances such as nutritional deprivation, has been established by developing an off-on fluorescent probe of Cu(2+)-mediated silver nanoclusters (Ag NCs). This work not only achieves highly selective detection of ppGpp in a broad range concentration of 2-200 MUM, but also improves our understanding of the specific recognitions among DNA-Ag NCs, Cu(2+), and ppGpp. The present strategy, together with other reports on the Ag NCs-related analytical methods, has also identified that Ag NCs functionalized with different molecules on their surfaces can be engineered fluorescent probes for a wide range of applications such as biosensing and bioimaging. PMID- 23810913 TI - Highly selective ratiometric fluorescent probe for Au3+ and its application to bioimaging. AB - The 4-propargylamino-1,8-naphthalimide based fluorescent probe 1 has been explored as a sensor for selective detection of Au(3+). 4-Amino-1,8 naphthalimides, that possess typical intramolecular charge transfer (ICT) electronic characteristics, have been widely used as versatile platforms for fluorescent probes. The newly designed probe 1 contains a propargylamine moiety at C-4 of the naphthalimide chromophore that reacts with Au(3+) to generate a product that has distinctly different electronic properties from 1. Specifically, the probe undergoes a remarkable change in its absorption spectrum upon addition of Au(3+) that is associated with a distinct color change from yellow to light pink. In addition, a blue shift of ca. 56 nm also takes place in the emission spectra of the probe. Consequently, 1 serves as a reaction-based sensor or so called chemodosimeter for Au(3+). Importantly, surfactants enhance the rate of reaction of 1 with Au(3+), thus, enhancing its use as a real time sensor. Finally, the results of studies probing its application to bioimaging of Au(3+) in live cells show that the probe 1 has a unique ability to sense Au(3+) in cells and, in particular, in lipid droplets within cells. PMID- 23810915 TI - PTGS2 (Cyclooxygenase-2) expression and survival among colorectal cancer patients: a systematic review. AB - BACKGROUND: Studies have examined whether tumor expression of PTGS2 (also known as COX-2), an enzyme inhibited by nonsteroidal anti-inflammatory drugs such as aspirin, is associated with prognosis in patients with colorectal cancer. However, results to date have been mixed. METHODS: Using terms for PTGS2 and colorectal cancer, the Medline, Embase, and Web of Science databases were systematically searched for studies published, in any language, until December 2011. Random effects meta-analyses were used to calculate pooled HRs [95% confidence intervals (CI)] for the association between PTGS2 expression and tumor recurrence, colorectal cancer-specific survival, and overall survival. RESULTS: In total, 29 studies, which had prognostic data on 5,648 patients, met the inclusion criteria. PTGS2-positive patients were at an increased risk of tumor recurrence (n = 9 studies; HR, 2.79; 95% CI, 1.76-4.41; P < 0.001) and had poorer colorectal cancer-specific survival (n = 7; HR, 1.36; 95% CI, 1.02-1.82; P = 0.04). However, there was funnel plot asymmetry, possibly due to publication bias, for the association with cancer-specific survival but less so for recurrence. PTGS2 expression was not associated with overall survival [(n = 16; pooled unadjusted HR, 1.30; 95% CI, 0.94-1.79; P = 0.11) and (n = 9; pooled adjusted HR, 1.02; 95% CI, 0.72-1.45; P = 0.91)]. CONCLUSIONS: PTGS2 expression was associated with an increased risk of tumor recurrence and poorer colorectal cancer-specific survival but not overall survival among patients with colorectal cancer. However, confounding by tumor characteristics such as tumor stage seems likely. IMPACT: There is insufficient evidence to recommend PTGS2 expression as a prognostic marker in patients with colorectal cancer. Furthermore, studies providing adjusted results are required. PMID- 23810914 TI - The auxin response factor transcription factor family in soybean: genome-wide identification and expression analyses during development and water stress. AB - In plants, the auxin response factor (ARF) transcription factors play important roles in regulating diverse biological processes, including development, growth, cell division and responses to environmental stimuli. An exhaustive search of soybean genome revealed 51 GmARFs, many of which were formed by genome duplications. The typical GmARFs (43 members) contain a DNA-binding domain, an ARF domain and an auxin/indole acetic acid (AUX/IAA) dimerization domain, whereas the remaining eight members lack the dimerization domain. Phylogenetic analysis of the ARFs from soybean and Arabidopsis revealed both similarity and divergence between the two ARF families, as well as enabled us to predict the functions of the GmARFs. Using quantitative real-time polymerase chain reaction (qRT-PCR) and available soybean Affymetrix array and Illumina transcriptome sequence data, a comprehensive expression atlas of GmARF genes was obtained in various organs and tissues, providing useful information about their involvement in defining the precise nature of individual tissues. Furthermore, expression profiling using qRT PCR and microarray data revealed many water stress-responsive GmARFs in soybean, albeit with different patterns depending on types of tissues and/or developmental stages. Our systematic analysis has identified excellent tissue-specific and/or stress-responsive candidate GmARF genes for in-depth in planta functional analyses, which would lead to potential applications in the development of genetically modified soybean cultivars with enhanced drought tolerance. PMID- 23810917 TI - Uterine lymphatic drainage is unaffected from injection technique and operators: Identical sentinel node detection in two cases of endometrial cancer. AB - INTRODUCTION: Sentinel node (SN) mapping with cervical injection of 99m technetium (99mTc) albumin nanocolloid in early endometrial cancer has been shown to be feasible and data emerging from recent large series support the incorporation of SN mapping algorithm in endometrial cancer staging. PRESENTATION OF CASE: We report two cases of SN mapping which demonstrated identical migration of both radioactive technetium and blue dye in the same patients that were re injected because surgical intervention was postponed due to transitory cardiac contraindications. DISCUSSION: As clearly demonstrated in cervical cancer, SN mapping through intracervical injection of both radioactive technetium and blue dye seems to be effective and easy to perform, providing good results in patients with endometrial cancer. Our report highlights the reproducibility of SN mapping that has been strongly confirmed in both patients, even if re-injections were performed by different operators. Preoperative SPECT/CT imaging seems to enhance accuracy in SN localization and also improves its intraoperative detection in early endometrial cancer. CONCLUSION: The anatomically defined bilateral uterus drainage strongly confirms the reproducibility of SN mapping, that seems to be unaffected by after injection technique or operators. PMID- 23810918 TI - Primary malignant melanoma of the esophagogastric junction: Report of a case. AB - INTRODUCTION: Primary malignant melanoma of the gastrointestinal tract is very rare, especially in the stomach. We report an extremely rare case of primary malignant melanoma of the esophagogastric junction mainly situated in the stomach. PRESENTATION OF CASE: The patient was a 72-year-old woman who complained of shortness of breath due to severe anemia. Upper endoscopy revealed a soft easy bleeding polypoid tumor just adjacent to the esophagogastric junction in the stomach. Biopsy of the tumor did not indicate a definite result, except malignant tumor. We performed total gastrectomy with splenectomy, and histological and immunohistological examination revealed malignant melanoma of the esophagogastric junction. She had no remote metastasis or lymphnodal metastasis at the point of surgery; however, she died of multiple metastases 11 months after the operation. DISCUSSION: A definite preoperative diagnosis of primary malignant melanoma was very difficult to make from the preoperative biopsy specimen. This present case was first misinterpreted as undifferentiated carcinoma, or malignant lymphoma. Following the diagnosis of malignant melanoma, the question arose as to whether this was primary or metastatic (as malignant melanoma from other sites is known to metastasize to the stomach). Finally this tumor was diagnosed as a primary one due to the pathologic characteristics such as the existence of junctional activities. CONCLUSION: We report an extremely rare case of primary malignant melanoma of the esophagogastric junction present in the stomach. PMID- 23810916 TI - Pleiotropy between genetic markers of obesity and risk of prostate cancer. AB - BACKGROUND: To address inconsistent findings of obesity and prostate cancer risk, we analyzed the association between prostate cancer and genetic markers of obesity and metabolism. METHODS: Analyses included 176,520 single-nucleotide polymorphisms (SNP) associated with 23 metabolic traits. We examined the association between SNPs and prostate cancer in 871 cases and 906 controls, including 427 high-grade cases with Gleason >= 7. Genetic risk scores (GRS) for body mass index (BMI) and waist-to-hip ratio (WHR) were also created by summing alleles associated with increasing BMI or WHR. RESULTS: Prostate cancer was associated with five loci, including cyclin M2, with P values less than 1 * 10( 4). In addition, the WHR GRS was associated with high-grade prostate cancer versus controls [OR, 1.05; 95% confidence interval (CI), 1.00-1.11; P = 0.048] and high-grade prostate cancer versus low-grade prostate cancer (OR, 1.07; 95% CI, 1.01-1.13; P = 0.03). None of these findings exceeds the threshold for significance after correction for multiple testing. CONCLUSIONS: Variants in genes known to be associated with metabolism and obesity may be associated with prostate cancer. We show evidence for pleiotropy between WHR GRS and prostate cancer grade. This finding is consistent with the function of several WHR genes and previously described relationships with cancer traits. IMPACT: Limitations in standard obesity measures suggest alternative characterizations of obesity may be needed to understand the role of metabolic dysregulation in prostate cancer. The underlying genetics of WHR or other Metabochip SNPs, while not statistically significant beyond multiple testing thresholds within our sample size, support the metabolic hypothesis of prostate carcinogenesis and warrant further investigation in independent samples. PMID- 23810919 TI - Clinical challenges in drug induced pancreatitis: Presentation of two cases and review of the literature. AB - INTRODUCTION: A wide variety of drugs have been reported to cause pancreatitis. Although the incidence of drug induced acute pancreatitis is low, the disease is associated with substantial morbidity and mortality, which makes timely identification of the causative agent important. PRESENTATION OF CASE: Herein, we report two patients with clinical, biochemical, and radiological evidence of acute pancreatitis. There were no etiologic factors except their prescribed drugs. DISCUSSION: The majority of patients with acute pancreatitis recover uneventfully, but there remains an uncontrollable risk of mortality. It is prudent to withdraw a medication with a known association with acute pancreatitis. Necessity of multi-drug regimens especially in oncological patients however, presents a challenge. CONCLUSION: Corticosteroid pulse therapy was easily detectable as the causative agent in our first case, but combined anti neoplastic drug therapy and additional multi-drug regimen presented great difficulties in identifying single causative agent in our second patient. PMID- 23810920 TI - Laparoscopic cholecystectomy in situs inversus totalis: Feasibility and review of literature. AB - INTRODUCTION: Situs inversus totalis is a rare anomaly characterized by transposition of organs to the opposite site of the body. Laparoscopic cholecystectomy in those patients is technically more demanding and needs reorientation of visual-motor skills to left upper quadrant. PRESENTATION OF CASE: Herein, we report a 10 year old boy presented with left hypochondrium and epigastric pain 2 months duration. The patient had not been diagnosed as situs inversus totalis before. The patient exhibit a left sided "Murphy's sign". Diagnosis of situs inversus totalis was confirmed with ultrasound, computerized tomography (CT) and magnetic resonant image (MRI) with presence of multiple gall bladder stones with no intra or extrabiliary duct dilatation. The patient underwent laparoscopic cholecystectomy for cholelithiasis. DISCUSSION: Feasibility and technical difficulty in diagnosis and treatment of such case pose challenge problem due to the contra lateral disposition of the viscera. Difficulty is encountered in skelatonizing the structures in Calot's triangle, which consume extra time than normally located gall bladder. A summary of additional 50 similar cases reported up to date in the medical literature is also presented. CONCLUSION: Laparoscopic cholecystectomy is feasible and should be done in situs inversus totalis by experienced laparoscopic surgeon, as changes in anatomical disposition of organ not only influence the localization of symptoms and signs arising from a diseased organ but also imposes special demands on the diagnosis and surgical skills of the surgeon. PMID- 23810921 TI - Continuous reinfusion of succus entericus associated with fistuloclysis in the management of a complex jejunal fistula on the abdominal wall. AB - INTRODUCTION: Fistuloclysis is an alternative method for enteral nutrition infusion, and has been successfully employed for the management of patients with high output small bowel fistula. However it has some deficiencies also. PRESENTATION OF CASE: A 42-year-old woman with multiple high output enterocutaneous fistula was submitted to fistuloclysis with reinfusion of chyme, after a period of several complications due to parenteral nutrition. DISCUSSION: Enteral nutrition provide better nutrition and fewer complications than parenteral nutrition. The enterocutaneous fistula usually does not allow enteral nutrition, however the use of fystuloclysis can fix this issue. The reinfusion of chyme provide the possibility of oral intake and better control of hydroeletrolitics disorders. CONCLUSION: More studies on the physiological effects of the chyme recirculation could add more data contributing to the clarification of this complex issue, but we believe that patients with high output and very proximal enterocutaneous fistula can be sucessfully treated with fistuloclysis and recirculation of chyme. PMID- 23810922 TI - Oligomerization of DDR1 ECD affects receptor-ligand binding. AB - Discoidin domain receptor 1 (DDR1) is a widely expressed receptor tyrosine kinase (RTK) which regulates cell differentiation, proliferation and migration and remodeling of the extracellular matrix. Collagen(s) are the only known ligand for DDR1. We have previously reported that collagen stimulation leads to oligomerization of the full length receptor. In this study we investigated the effect of oligomerization of the DDR1 extracellular domain (ECD) pre and post ligand binding. Solid phase binding assays showed that oligomers of recombinant DDR1-Fc bound more strongly to collagen compared to dimeric DDR1-Fc alone. In addition, DDR1-Fc itself could oligomerize upon in-vitro binding to collagen when examined using atomic force microscopy. Inhibition of dynamin mediated receptor endocytosis could prevent ligand induced endocytosis of DDR1b-YFP in live cells. However inhibition of receptor endocytosis did not affect DDR1 oligomerization. In summary our results demonstrate that DDR1 ECD plays a crucial role in receptor oligomerization which mediates high-affinity interactions with its ligand. PMID- 23810924 TI - Socio-emotional regulation in children with intellectual disability and typically developing children, and teachers' perceptions of their social adjustment. AB - This study examined the extent to which socio-emotional regulation displayed in three dyadic interactive play contexts (neutral, competitive or cooperative) by 45 children with intellectual disability compared with 45 typically developing children (matched on developmental age, ranging from 3 to 6 years) is linked with the teachers' perceptions of their social adjustment. A Coding Grid of Socio Emotional Regulation by Sequences (Baurain & Nader-Grosbois, 2011b, 2011c) focusing on Emotional Expression, Social Behavior and Behavior toward Social Rules in children was applied. The Social Adjustment for Children Scale (EASE, Hugues, Soares-Boucaud, Hochman, & Frith, 1997) and the Assessment, Evaluation and Intervention Program System (AEPS, Bricker, 2002) were completed by teachers. Regression analyses emphasized, in children with intellectual disability only, a positive significant link between their Behavior toward Social Rules in interactive contexts and the teachers' perceptions of their social adjustment. Children with intellectual disabilities who listen to and follow instructions, who are patient in waiting for their turn, and who moderate their externalized behavior are perceived by their teachers as socially adapted in their daily social relationships. The between-groups dissimilarity in the relational patterns between abilities in socio-emotional regulation and social adjustment supports the "structural difference hypothesis" with regard to the group with intellectual disability, compared with the typically developing group. Hierarchical cluster cases analyses identified distinct subgroups showing variable structural patterns between the three specific categories of abilities in socio-emotional regulation and their levels of social adjustment perceived by teachers. In both groups, several abilities in socio-emotional regulation and teachers' perceptions of social adjustment vary depending on children's developmental age. Chronological age in children with intellectual disability had no impact on their socio emotional regulation and social adjustment. PMID- 23810925 TI - Mental additions and verbal-domain interference in children with developmental dyscalculia. AB - This study examined the involvement of verbal and visuo-spatial domains in solving addition problems with carrying in a sample of children diagnosed with developmental dyscalculia (DD) divided into two groups: (i) those with DD alone and (ii) those with DD and dyslexia. Age and stage matched typically developing (TD) children were also studied. The addition problems were presented horizontally or vertically and associated with verbal or visuo-spatial information. Study results showed that DD children's performance on mental calculation tasks was more impaired when they tackled horizontally presented addition problems compared to vertically presented ones that are associated to verbal domain involvement. The performance pattern in the two DD groups was found to be similar. The theoretical, clinical and educational implications of these findings are discussed. PMID- 23810926 TI - Neuromuscular differences between boys with and without intellectual disability during squat jump. AB - The purpose of this study was to identify the differences in vertical squat jump (SJ) between volunteers with and without intellectual disability (ID). Thirteen boys with ID (average intelligence quotient, estimated by Wisk III test: 55.6 +/- 11.2) and 13 peers without disabilities performed maximal SJ on a force platform. Kinematic data were captured using a six-camera 3D motion analysis system and electromyographic (EMG) activity was recorded using surface electrodes. Unpaired T-test determined the statistical difference between the two groups. The obtained results indicated that the group with ID, jumped lower, developed lower vertical ground reaction forces, knee power output, knee angular velocity, and take-off velocity, and showed longer propulsion duration, decreased mean to maximum agonist EMG activity and higher antagonist/agonist activity ratio. The deficit in the SJ observed in individuals with ID was attributed to a deficit in the examined mechanical and neuromuscular parameters, and especially to the agonist and antagonist co-contraction. PMID- 23810923 TI - Stress-vs-time signals allow the prediction of structurally catastrophic events during fracturing of immature cartilage and predetermine the biomechanical, biochemical, and structural impairment. AB - OBJECTIVE: Trauma-associated cartilage fractures occur in children and adolescents with clinically significant incidence. Several studies investigated biomechanical injury by compressive forces but the injury-related stress has not been investigated extensively. In this study, we hypothesized that the biomechanical stress occurring during compressive injury predetermines the biomechanical, biochemical, and structural consequences. We specifically investigated whether the stress-vs-time signal correlated with the injurious damage and may allow prediction of cartilage matrix fracturing. METHODS: Superficial and deeper zones disks (SZDs, DZDs; immature bovine cartilage) were biomechanically characterized, injured (50% compression, 100%/s strain-rate), and re-characterized. Correlations of the quantified functional, biochemical and histological damage with biomechanical parameters were zonally investigated. RESULTS: Injured SZDs exhibited decreased dynamic stiffness (by 93.04+/-1.72%), unresolvable equilibrium moduli, structural damage (2.0+/-0.5 on a 5-point-damage scale), and 1.78-fold increased sGAG loss. DZDs remained intact. Measured stress vs-time-curves during injury displayed 4 distinct shapes, which correlated with histological damage (p<0.001), loss of dynamic stiffness and sGAG (p<0.05). Damage prediction in a blinded experiment using stress-vs-time grades was 100% correct and sensitive to differentiate single/complex matrix disruptions. Correlations of the dissipated energy and maximum stress rise with the extent of biomechanical and biochemical damage reached significance when SZDs and DZDs were analyzed as zonal composites but not separately. CONCLUSIONS: The biomechanical stress that occurs during compressive injury predetermines the biomechanical, biochemical, and structural consequences and, thus, the structural and functional damage during cartilage fracturing. A novel biomechanical method based on the interpretation of compressive yielding allows the accurate prediction of the extent of structural damage. PMID- 23810927 TI - The influence of participation in leisure activities on quality of life in Spanish children and adolescents with Cerebral Palsy. AB - Participation is an important modifiable quality of life (QOL) determinant and a key outcome measure. The aim of this study was to confirm if participation in leisure activities affects the QOL domains in children and adolescents with Cerebral Palsy (CP) in Spain. A total of 206 children and adolescents with CP (and their parents), 115 boys and 91 girls, mean age of 11.96 years (SD=3.00; range 8-18 years) participated in the study. Distribution according to the Gross Motor Function Classification System (GMFCS) was 24.3% Level I, 18% Level II, 18% Level III, 12.6% Level IV, and 27.2% Level V. Participation in leisure activities was assessed using the Spanish version of Children's Assessment of Participation and Enjoyment (CAPE) and QOL using the KIDSCREEN parents' version. Diversity, intensity and enjoyment of participation explained the levels of QOL in the Physical well-being, Psychological well-being, Autonomy, Parent relation & home life and Social support & peers domains, independently of gender, age and level of impairment (motor and intellectual). We also found that intensity and enjoyment of participation in informal activities had more influence on the different QOL domains. The most influenced domain by the enjoyment of participation in all domains and types of CAPE activities was Psychological well being. The participation in leisure activities had a positive effect on the QOL of the Spanish children and adolescents with CP. PMID- 23810928 TI - Effects of self-controlled feedback on learning of a throwing task in children with spastic hemiplegic cerebral palsy. AB - The purpose of this study was to examine the effect of self-controlled feedback on learning a throwing task in children with spastic hemiplegic cerebral palsy (SHCP). In order to achieve the research objectives, using a semi-experimental method, 20 children with SHCP (7-12 years old) were selected from special schools in Tehran, Iran. After showing the participants how to do the throwing task, a pre-test with 10 trials was conducted to homogenize the participants. Then, they were randomly assigned to two groups (self-control group and yoked group) to be examined in acquisition, retention, and transfer phases. Children in self-control group requested feedback when necessary during the acquisition phase. In contrast, participants in yoked-group replicated the feedback schedules of their counterparts in self-control group without any choice. A multivariate analysis of variance (MANOVA) was performed to analyze the data. Based on the results, a significant difference was not found between the self-control and yoked-group in acquisition phase (F=.538, p<.473). However, there was a significant difference between the two groups in retention (F=11.72, p<.003) and transfer (F=6.74, p<.018) phases. Thus, based on the better results obtained in the self-control condition, this type of feedback can be used in physiotherapy programs related to children with CP to improve their motor skills and independence movements. PMID- 23810929 TI - An analysis of the topography, severity, potential sources of reinforcement, and treatments utilized for skin picking in Prader-Willi syndrome. AB - We examined the topography, severity, potential sources of reinforcement, and treatments utilized for skin-picking behavior shown by individuals with Prader Willi syndrome (PWS). The parents of 55 individuals with PWS, aged 6-25 years, were interviewed about their child's skin-picking behavior using the Self-Injury Trauma Scale (SIT; Iwata, Pace, Kissel, Nau, & Farber, 1990) and the Functional Analysis Screening Tool (FAST; Iwata, DeLeon, & Roscoe, 2013). Results showed that skin picking in PWS occurred on the extremities (i.e., arms, legs, hands, and feet) for 75% of cases and resulted in bodily injury for 83.7% cases. Skin picking posed a high risk to the individual concerned in 41.8% of cases. Automatic sensory stimulation was identified as a potential source of reinforcement in the majority of cases (52.7%) followed by access to social attention or preferred items (36.4%). Treatments utilized by parents were primarily behavioral strategies (56.3%) followed by basic first aid (54.5%). There were no differences in the topography, severity or potential source of reinforcement between those with the deletion (DEL) subtype and those with the uniparental disomy (UPD) subtype. Taken together, these data indicate that skin picking shown by individuals with PWS is a particularly severe and intractable behavioral issue that may be maintained by (as yet unknown) sensory consequences. Further studies to identify the determinants of skin picking in PWS are therefore needed. The implications for interventions are discussed. PMID- 23810930 TI - Examining the relationships between attention deficit/hyperactivity disorder and developmental coordination disorder symptoms, and writing performance in Japanese second grade students. AB - The purpose of this study was to explore the relationships between attention deficit/hyperactivity disorder and developmental coordination disorder symptoms and writing performance in Japanese second grade students from regular classrooms. The second grade students (N=873) in Japanese public elementary schools participated in this study. We examined a variety of writing tasks, such as tracing, copying, handwriting (Hiragana and Katakana), and spelling (Hiragana, Katakana, and Kanji). We employed the Japanese version of the home form ADHD rating scale (ADHD-RS) and the Japanese version of the Developmental Coordination Disorder Questionnaire (DCDQ-J) to assess the developmental characteristics of the participating children. Seven writing performance scores were submitted to a principal component analysis with a promax rotation, which yielded three composite scores (Spelling Accuracy, Tracing and Copying Accuracy, and Handwriting Fluency). A multiple regression analysis found that inattention predicted Spelling Accuracy and Handwriting Fluency and that hyperactive impulsive predicted Handwriting Fluency. In addition, fine motor ability predicted Tracing and Copying Accuracy. The current study offered empirical evidence suggesting that developmental characteristics such as inattention and fine motor skill are related to writing difficulties in Japanese typical developing children. PMID- 23810932 TI - Evolution and the variation of mammalian sex ratios at birth: reflections on Trivers and Willard (1973). AB - The Trivers-Willard (TW) argument may be interpreted to yield a large class of true predictions and a small class of false predictions. This would explain the relative numbers of empirical successes and failures of TW. It is argued here that in mammals (including man), one cause of these failures is a constraint imposed by a small minority of females in the breeding population. These are females that are stressed and consequently have high testosterone (T) levels which in turn cause (a) reproductive impairment and (b) (contrary to TW, but in conformity with my hypothesis) a tendency to produce sons. TW reasoning applies to both parents, not just the mother. Indeed, the TW prediction seems fulfilled more generally by fathers than by mothers. My hormonal hypothesis can apparently explain both the successes and the failures of TW. PMID- 23810931 TI - Evolution of the pair rule gene network: Insights from a centipede. AB - Comparative studies have examined the expression and function of homologues of the Drosophila melanogaster pair rule and segment polarity genes in a range of arthropods. The segment polarity gene homologues have a conserved role in the specification of the parasegment boundary, but the degree of conservation of the upstream patterning genes has proved more variable. Using genomic resources we identify a complete set of pair rule gene homologues from the centipede Strigamia maritima, and document a detailed time series of expression during trunk segmentation. We find supportive evidence for a conserved hierarchical organisation of the pair rule genes, with a division into early- and late activated genes which parallels the functional division into primary and secondary pair rule genes described in insects. We confirm that the relative expression of sloppy-paired and paired with respect to wingless and engrailed at the parasegment boundary is conserved between myriapods and insects; suggesting that functional interactions between these genes might be an ancient feature of arthropod segment patterning. However, we find that the relative expression of a number of the primary pair rule genes is divergent between myriapods and insects. This corroborates suggestions that the evolution of upper tiers in the segmentation gene network is more flexible. Finally, we find that the expression of the Strigamia pair rule genes in periodic patterns is restricted to the ectoderm. This suggests that any direct role of these genes in segmentation is restricted to this germ layer, and that mesoderm segmentation is either dependent on the ectoderm, or occurs through an independent mechanism. PMID- 23810933 TI - Mineralization-driven bone tissue evolution follows from fluid-to-solid phase transformations in closed thermodynamic systems. AB - The fundamental mechanisms that govern bone mineralization have been fairly well evidenced by means of experimental research. However, rules for the evolution of the volume and composition of the bone tissue compartments (such as the mineralized collagen fibrils and the extrafibrillar space in between) have not been provided yet. As an original contribution to this open question, we here test whether mineralizing bone tissue can be represented as a thermodynamically closed system, where crystals precipitate from an ionic solution, while the masses of the fibrillar and extrafibrillar bone tissue compartments are preserved. When translating, based on various experimental and theoretical findings, this mass conservation proposition into diffraction-mass density relations, the latter are remarkably well confirmed by independent experimental data from various sources. Resulting shrinkage and composition rules are deemed beneficial for further progress in bone materials science and biomedical engineering. PMID- 23810934 TI - Lateral cascade of indirect effects in food webs with different types of adaptive behavior. AB - It is widely recognized that indirect effects due to adaptive behaviors can have important effects on food webs. One consequence may be to change how readily perturbations propagate through the web, because species' behaviors as well as densities may respond to perturbations. It is not well understood which types of behavior are more likely to facilitate versus inhibit propagation of disturbances through a food web, or how this might be affected by the shape of a food web or the patterns of interaction strengths within it. We model two simple, laterally expanded food webs (one with three trophic levels and one with four), and compare how various adaptive behaviors affect the potential for a newly introduced predator to change the equilibrium densities of distant species. Patterns of changes in response to the introduction were qualitatively similar across most models, as were the ways in which patterns of direct interaction strengths affected those responses. Depending on both the web structure and the specific adaptive behavior, the potential for density changes to propagate through the web could be either increased or diminished relative to the no-behavior model. Two behaviors allowed density changes to propagate through a four-level web that precluded such propagation in the no-behavior model, and each of these two behaviors led to qualitatively different patterns of density changes. In the one model (diet choice) in which density changes were able to propagate in both web structures, patterns of density changes differed qualitatively between webs. Some of our results flowed from the fact that behaviors did not interact directly in the systems we considered, so that indirect effects on distant species had to be at least partly density-mediated. Our models highlight this as an inherent limitation of considering in isolation behaviors that are strictly foraging related or strictly defense-related, making a case for the value of simultaneously considering multiple interacting types of behavior in the same model. PMID- 23810935 TI - Developmentally programmed cell death in Drosophila. AB - During the development of metazoans, programmed cell death (PCD) is essential for tissue patterning, removal of unwanted cells and maintaining homeostasis. In the past 20 years Drosophila melanogaster has been one of the systems of choice for studies involving developmental cell death, providing an ideal genetically tractable model of intermediary complexity between Caenorhabditis elegans and mammals. The lessons learned from studies using Drosophila indicate both the conserved nature of the many cell death pathways as well as novel and unexpected mechanisms. In this article we review the understanding of PCD during Drosophila development, highlighting the key mechanisms that are evolutionarily conserved as well as apparently unusual pathways, which indicate divergence, but provide evidence of complexity acquired during organismic evolution. This article is part of a Special Section entitled: Cell Death Pathways. PMID- 23810937 TI - Optimal isolation control strategies and cost-effectiveness analysis of a two strain avian influenza model. AB - The most important and effective measures against disease outbreaks in the absence of valid medicines or vaccine are quarantine and isolation strategies. In this paper optimal control theory is applied to a system of ordinary differential equation describing a two-strain avian influenza transmission via the Pontryagin's Maximum Principle. To this end, a pair of control variables representing the isolation strategies for individuals with avian and mutant strains were incorporated into the transmission model. The infection averted ratio (IAR) and the incremental cost-effectiveness ratio (ICER) were calculated to investigate the cost-effectiveness of all possible combinations of the control strategies. The simulation results show that the implementation of the combination strategy during the epidemic is the most cost-effective strategy for avian influenza transmission. This is followed by the control strategy involving isolation of individuals with the mutant strain. Also observed was the fact that low mutating and more virulent virus results in an increased control effort of isolating individuals with the avian strain; and high mutating with more virulent virus results in increased efforts in isolating individuals with the mutant strain. PMID- 23810936 TI - The giardial VPS35 retromer subunit is necessary for multimeric complex assembly and interaction with the vacuolar protein sorting receptor. AB - The retromer is a pentameric protein complex that mediates the retrograde transport of acid hydrolase receptors between endosomes and the trans-Golgi network and is conserved across all eukaryotes. Unlike other eukaryotes, the endomembrane system of Giardia trophozoite is simple and is composed only of the endoplasmic reticulum and peripheral vesicles (PVs), which may represent an ancient organellar system converging compartments such as early and late endosomes and lysosomes. Sorting and trafficking of membrane proteins and soluble hydrolases from the endoplasmic reticulum to the PVs have been described as specific and conserved but whether the giardial retromer participates in receptor recycling remains elusive. Homologs of the retromer Vacuolar Protein Sorting (Vps35p, Vps26p, and Vps29p) have been identified in this parasite. Cloning the GlVPS35 subunit and antisera production enabled the localization of this protein in the PVs as well as in the cytosol. Tagged expression of the subunits was used to demonstrate their association with membranes, and immunofluorescence confocal laser scanning revealed high degrees of colabeling between the retromer subunits and also with the endoplasmic reticulum and PV compartment markers. Protein protein interaction data revealed interaction between the subunits of GlVPS35 and the cytosolic domain of the hydrolase receptor GlVps. Altogether our data provide original information on the molecular interactions that mediate assembly of the cargo-selective retromer subcomplex and its involvement in the recycling of the acid hydrolase receptor in this parasite. PMID- 23810938 TI - New paradigm for drug developments--from emerging market statistical perspective. AB - Paradigm for new drug development has changed dramatically over the last decade. Even though new technology increases efficiency in many aspects, partially due to much more stringent regulatory requirements, it actually now takes longer and costs more to develop a new drug. To deal with challenge, some initiatives are taken by the pharmaceutical industry. These initiatives include exploring emerging markets, conducting global trials and building research and development centers in emerging markets to curb spending. It is particularly the current trend that major pharmaceutical companies offshore a part of their biostatistical support to China. In this paper, we first discuss the skill set for trial statisticians in the new era. We then elaborate on some of the approaches for acquiring statistical talent and capacity in general, particularly in emerging markets. We also make some recommendations on the use of the PDUFA strategy and collaborations among industry, health authority and academia from emerging market statistical perspective. PMID- 23810940 TI - Absence of nasal bone and brachydactyly: a probable new familial syndrome. AB - Brachydactyly is a relatively common congenital abnormality and can be associated with many other malformations. However, brachydactyly in association with absence of nasal bone is rare. Two Chinese siblings with a combination of nasal bone absence and brachydactyly are presented, apparently without other abnormalities. This combination of features do not fit into any previously described syndrome and we suggest that this case represents a new familial syndrome. Molecular genetics screening didn't revealed any specific pathogenic variants in the two siblings. PMID- 23810939 TI - Weight management for individuals with intellectual and developmental disabilities: rationale and design for an 18 month randomized trial. AB - Weight management for individuals with intellectual and developmental disabilities (IDD) has received limited attention. Studies on weight management in this population have been conducted over short time frames, in small samples with inadequate statistical power, infrequently used a randomized design, and have not evaluated the use of emerging effective dietary strategies such as pre packaged meals (PMs). Low energy/fat PMs may be useful in individuals with IDD as they simplify meal planning, limit undesirable food choices, teach appropriate portion sizes, are convenient and easy to prepare, and when combined with fruits and vegetables provide a high volume, low energy dense meal. A randomized effectiveness trial will be conducted in 150 overweight/obese adults with mild to moderate IDD, and their study partners to compare weight loss (6 months) and weight maintenance (12 months) between 2 weight management approaches: 1. A Stop Light Diet enhanced with reduced energy/fat PMs (eSLD); and 2. A recommended care reduced energy/fat meal plan diet (RC). The primary aim is to compare weight loss (0-6 months) and weight maintenance (7-18 months) between the eSLD and RC diets. Secondarily, changes in chronic disease risk factors between the eSLD and RC diets including blood pressure, glucose, insulin, LDL-cholesterol, and HDL cholesterol will be compared during both weight loss and weight maintenance. Finally, potential mediators of weight loss including energy intake, physical activity, data recording, adherence to the diet, study partner self-efficacy and daily stress related to dietary change will be explored. PMID- 23810941 TI - Mutation spectrum of primary hyperoxaluria type 1 in Tunisia: implication for diagnosis in North Africa. AB - BACKGROUND: Primary hyperoxaluria type 1 (PH1) is an autosomal recessive inherited metabolic disease, characterized by progressive kidney failure due to renal deposition of calcium oxalate. Mutations in the AGXT gene, encoding the liver-specific enzyme alanine glyoxylate aminotransferase, are responsible for the disease. We aimed to determine the mutational spectrum causing PH1 and to provide an accurate tool for diagnosis as well as for prenatal diagnosis in the affected families. METHODS: Direct sequencing was used to detect mutations in the AGXT gene in DNA samples from 13 patients belonging to 12 Tunisian families. RESULTS: Molecular analysis revealed five mutations causing PH1 in Tunisia. The mutations were identified along exons 1, 2, 4, 5 and 7. The most predominant mutations were the Maghrebian "p.I244T" and the Arabic "p.G190R". Furthermore, three other mutations characteristic of different ethnic groups were found in our study population. These results confirm the mutational heterogeneity related to PH1 in Tunisian population. All the mutations are in a homozygous state, reflecting the high impact of endogamy in our population. CONCLUSION: Mutation analysis through DNA sequencing can provide a useful first line investigation for PH1. This identification could provide an accurate tool for prenatal diagnosis, genetic counseling and screen for potential presymptomatic individuals. PMID- 23810942 TI - SYCP3-like X-linked 2 is expressed in meiotic germ cells and interacts with synaptonemal complex central element protein 2 and histone acetyltransferase TIP60. AB - Meiosis is the process by which diploid germ cells produce haploid gametes. A key event is the formation of the synaptonemal complex. In the pachytene stage, the unpaired regions of X and Y chromosomes form a specialized structure, the XY body, within which gene expression is mostly silenced. In the present study, we showed that SYCP3-like X-linked 2 (SLX2, 1700013H16Rik), a novel member of XLR (X linked Lymphocyte-Regulated) family, was specifically expressed in meiotic germ cells. In the spermatocyte SLX2 was distributed in the nucleus of germ cells at the preleptotene, leptotene and zygotene stages and is then restricted to the XY body at the pachytene stage. This localization change is coincident with that of phosphorylated histone H2AX (gammaH2AX), a well-known component of the sex body. Through yeast two-hybrid screening and coimmunoprecipitation assays, we demonstrated that SLX2 interacts with synaptonemal complex central element protein 2 (SYCE2), an important component of synaptonemal complex, and histone acetyltransferase TIP60, which has been implicated in remodeling phospho-H2AX containing nucleosomes at sites of DNA damage. These results suggest that SLX2 might be involved in DNA recombination, synaptonemal complex formation as well as sex body maintenance during meiosis. PMID- 23810943 TI - The skeleton in the closet. AB - The origins of fibrodysplasia ossificans progressiva (FOP) in human history are unknown but the condition has been well described since Freke's account in 1740. Important contributions by physicians and scientists in the past two and a half centuries have converged on the remarkable skeleton of Harry Eastlack at The Mutter Museum of The College of Physicians in Philadelphia. PMID- 23810944 TI - Characterization of the complete mitochondrial genome of Diaphania pyloalis (Lepidoptera: Pyralididae). AB - The complete mitochondrial genome (mitogenome) of Diaphania pyloalis (Lepidoptera: Pyralididae) was determined to be 15,298 bp and has the typical gene organization of mitogenomes from lepidopteran insects. It consists of 13 protein-coding genes (PCGs), two rRNA genes, 22 tRNA genes and an A+T-rich region. The A+T content of this mitogenome is 80.83% and the AT skew is slightly positive. All PCGs are initiated by ATN codons, except for cytochrome c oxidase subunit 1 (cox1) gene which is initiated by CGA. Only the cox2 gene has an incomplete stop codon consisting of just a T. All the tRNA genes display a typical clover-leaf structure of mitochondrial tRNA. The A+T-rich region of the mitogenome is 332 bp in length, including several common features found in lepidopteran mitogenomes. Phylogenetic analysis showed that the D. pyloalis is close to Pyralididae. PMID- 23810946 TI - Structural and functional studies with mytoxin II from Bothrops moojeni reveal remarkable similarities and differences compared to other catalytically inactive phospholipases A2-like. AB - Lys49-phospholipases A2 (Lys49-PLA2s) are proteins found in bothropic snake venoms (Viperidae family) and belong to a class of proteins which presents a phospholipase A2 scaffold but are catalytically inactive. These proteins (also known as PLA2s-like toxins) exert a pronounced local myotoxic effect and are not neutralized by antivenom, being their study relevant in terms of medical and scientific interest. Despite of the several studies reported in the literature for this class of proteins only a partial consensus has been achieved concerning their functional-structural relationships. In this work, we present a comprehensive structural and functional study with the MjTX-II, a dimeric Lys49 PLA2 from Bothrops moojeni venom which includes: (i) high-resolution crystal structure; (ii) dynamic light scattering and bioinformatics studies in order to confirm its biological assembly; (iii) myographic and electrophysiological studies and, (iv) comparative studies with other Lys49-PLA2s. These comparative analyses let us to get important insights into the role of Lys122 amino acid, previously indicated as responsible for Lys49-PLA2s catalytic inactivity and added important elements to establish the correct biological assembly for this class of proteins. Furthermore, we show two unique sequential features of MjTX-II (an amino acid insertion and a mutation) in comparison to all bothropic Lys49 PLA2s that lead to a distinct way of ligand binding at the toxin's hydrophobic channel and also, allowed the presence of an additional ligand molecule in this region. These facts suggest a possible particular mode of binding for long-chain ligands that interacts with MjTX-II hydrophobic channel, a feature that may directly affect the design of structure-based ligands for Lys49-PLA2s. PMID- 23810945 TI - Effects of enzymatically inactive recombinant botulinum neurotoxin type A at the mouse neuromuscular junctions. AB - Botulinum neurotoxin A (BoNT/A) is used clinically to treat several neurological and metabolic diseases. However, the mechanisms that underlie the clinical use of the toxin remain still to be elusive. BoNT/A inhibits acetylcholine (ACh) release at the motor nerve terminals (MNT) and causes neuroparalysis. The toxic effects of BoNT/A at the MNT occur in sub-pico molar range, and it is invaluable to determine the half-life and the persistence of catalytic activity of the toxin to develop therapeutics against BoNT/A intoxication. However, the use of extremely low concentrations of BoNT/A in cellular, or animal models due to high toxicity makes it difficult to determine new cellular mechanisms and binding or interacting partners of BoNT/A. In order to address this, a catalytically deactivated, non-toxic version of BoNT/A, designated as DrBoNT/A, was characterized. DrBoNT/A lacks endoprotease activity (SNAP-25 cleavage) at concentrations as high as 46,875-fold, compared to wild-type BoNT/A. Unlike BoNT/A injection (3.2 pg), injection of the recombinant product (150 ng or 3.2 pg) into mouse hind limbs failed to cause neuroparalysis as exhibited by the lack of inhibition of toe spread reflex (ability of the mouse to spread its hindlimb toes), and inhibit ACh release at the MNT. The in vitro experiments also demonstrate that DrBoNT/A uptake (at concentrations equivalent to BoNT/A), internalization and localization at the MNT remained unaltered. In addition, modeling studies support that DrBoNT/A lacked the zinc binding ability, and the ability to directly participate in the hydrolysis of SNAP-25 substrate. Collectively, we demonstrate that DrBoNT/A is non-toxic to the MNT and can be used as a surrogate tool to understand the mechanism by which BoNT/A modulates signal transduction mechanisms. PMID- 23810947 TI - Cueing an unresolved personal goal causes persistent ruminative self-focus: an experimental evaluation of control theories of rumination. AB - BACKGROUND AND OBJECTIVES: Control theory predicts that the detection of goal discrepancies initiates ruminative self-focus (Martin & Tesser, 1996). Despite the breadth of applications and interest in control theory, there is a lack of experimental evidence evaluating this prediction. The present study provided the first experimental test of this prediction. METHODS: We examined uninstructed state rumination in response to the cueing of resolved and unresolved goals in a non-clinical population using a novel measure of online rumination. RESULTS: Consistent with control theory, cueing an unresolved goal resulted in significantly greater recurrent intrusive ruminative thoughts than cueing a resolved goal. Individual differences in trait rumination moderated the impact of the goal cueing task on the extent of state rumination: individuals who had a stronger tendency to habitually ruminate were more susceptible to the effects of cueing goal discrepancies. LIMITATIONS: The findings await replication in a clinically depressed sample where there is greater variability and higher levels of trait rumination. CONCLUSIONS: These results indicate that control theories of goal pursuit provide a valuable framework for understanding the circumstances that trigger state rumination. Additionally, our measure of uninstructed online state rumination was found to be a valid and sensitive index of the extent and temporal course of state rumination, indicating its value for further investigating the proximal causes of state rumination. PMID- 23810948 TI - Production of furfural from pentosan-rich biomass: analysis of process parameters during simultaneous furfural stripping. AB - Among the furan-based compounds, furfural (FUR) shows interesting properties as building-block or industrial solvent. It is produced from pentosan-rich biomass via xylose cyclodehydration. The current FUR production makes use of homogeneous catalysts and excessive amounts of steam. The development of greener furfural production and separation techniques implies the use of heterogeneous catalysts and innovative separation processes. This work deals with the conversion of corncobs as xylose source to be dehydrated to furfural. The results reveal differences between the use of direct corncob hydrolysis and dehydration to furfural and the prehydrolysis and dehydration procedures. Moreover, this work focuses on an economical analysis of the main process parameters during N2 stripping and its economical comparison to the current steam-stripping process. The results show a considerable reduction of the annual utility costs due to use of recyclable nitrogen and the reduction of the furfural purification stages. PMID- 23810949 TI - Enhanced membrane filtration of wood hydrolysates for hemicelluloses recovery by pretreatment with polymeric adsorbents. AB - In this study adsorption of foulants from birch and pine/eucalyptus wood hydrolysates on two polymeric adsorbents was studied aiming to reduce the membrane fouling. The effect of the pretreatment of hydrolysate on polyethersulphone membrane performance was studied in dead-end filtration experiments. Adsorption pretreatment improved significantly filtration capacity and decreased membrane fouling. Especially high-molecular weight lignin was efficiently removed. A multistep adsorption pretreatment was found to reduce the amount of adsorbent required. While large adsorbent amount was shown to increase flux in filtration, it was found also to cause significant hemicellulose losses. PMID- 23810950 TI - Treatment of swine wastewater using chemically modified zeolite and bioflocculant from activated sludge. AB - Sterilization, alkaline-thermal and acid-thermal treatments were applied to activated sludge and the pre-treated sludge was used as raw material for Rhodococcus R3 to produce polymeric substances. After 60 h of fermentation, bioflocculant of 2.7 and 4.2 g L(-1) were produced in sterilized and alkaline thermal treated sludge as compared to that of 0.9 g L(-1) in acid-thermal treated sludge. Response surface methodology (RSM) was employed to optimize the treatment process of swine wastewater using the composite of bioflocculant and zeolite modified by calcining with MgO. The optimal flocculating conditions were bioflocculant of 24 mg L(-1), modified zeolite of 12 g L(-1), CaCl2 of 16 mg L( 1), pH of 8.3 and contact time of 55 min, and the corresponding removal rates of COD, ammonium and turbidity were 87.9%, 86.9%, and 94.8%. The use of the composite by RSM provides a feasible way to improve the pollutant removal efficiencies and recycle high-level of ammonium from wastewater. PMID- 23810951 TI - Bioenergy co-products derived from microalgae biomass via thermochemical conversion--life cycle energy balances and CO2 emissions. AB - An investigation of the potential to efficiently convert lipid-depleted residual microalgae biomass using thermochemical (gasification at 850 degrees C, pyrolysis at 550 degrees C, and torrefaction at 300 degrees C) processes to produce bioenergy derivatives was made. Energy indicators are established to account for the amount of energy inputs that have to be supplied to the system in order to gain 1 MJ of bio-energy output. The paper seeks to address the difference between net energy input-output balances based on a life cycle approach, from "cradle-to-bioenergy co-products", vs. thermochemical processes alone. The experimental results showed the lowest results of Net Energy Balances (NEB) to be 0.57 MJ/MJ bio-oil via pyrolysis, and highest, 6.48 MJ/MJ for gas derived via torrefaction. With the complete life cycle process chain factored in, the energy balances of NEBLCA increased to 1.67 MJ/MJ (bio-oil) and 7.01 MJ/MJ (gas). Energy efficiencies and the life cycle CO2 emissions were also calculated. PMID- 23810952 TI - Riccardin D induces cell death by activation of apoptosis and autophagy in osteosarcoma cells. AB - Macrocyclic bisbibenzyls, characteristic components derived from liverworts, have various biological activities. Riccardin D (RD), a liverwort-derived naturally occurring macrocyclic bisbibenzyl, has been found to exert anticancer effects in multiple cancer cell types through apoptosis induction. However, the underlying mechanisms of such effects remain undefined. In addition, whether RD induces other forms of cell death such as autophagy is unknown. In this study, we found that the arrest of RD-caused U2OS (p53 wild) and Saos-2 (p53 null) cells in G1 phase was associated with the induction of p53 and p21(WAF1) in U2OS cells. RD mediated cell cycle arrest was accompanied with apoptosis promotion as indicated by changes in nuclear morphology and expression of apoptosis-related proteins. Further studies revealed that the antiproliferation of RD was unaffected in the presence of p53 inhibitor but was partially reversed by a pan-inhibitor of caspases, suggesting that p53 was not required in RD-mediated apoptosis and that caspase-independent mechanisms were involved in RD-mediated cell death. Except for apoptosis, RD-induced autophagy occurred as evidenced by the accumulation of microtubule-associated protein-1 light chain-3B-II, formation of AVOs, punctate dots, and increased autophagic flux. Pharmacological blockade of autophagy activation markedly attenuated RD-mediated cell death. RD-induced cell death was significantly restored by the combination of autophagy and caspase inhibitors in osteosarcoma cells. Overall, our study revealed RD-induced caspase-dependent apoptosis and autophagy in cancer cells, as well as highlighted the importance of continued investigation on the use of RD as a potential anticancer candidate. PMID- 23810953 TI - Association between mental health and fall injury in Canadian immigrants and non immigrants. AB - The study was to determine the association between mental health and the incidence of injury among Canadian immigrants and non-immigrants. We used data from 15,405 individuals aged 12 years or more, who were living in British Columbia, Canada, and participated in the 2007-2008 Canadian Community Health Survey (CCHS). We calculated a 12-month cumulative incidence of fall injury based on self-reporting. Logistic regression model was used to examine the association of the 12-month cumulative incidence of fall injury with immigration status and mental health before and after adjustment for covariates. The results show that self-reported mood and anxiety disorders were significantly associated with an increased incidence of fall injury. The adjusted odds ratios were 1.81 (95% CI: 1.37, 2.38) for mood disorder and 1.55 (95% CI: 1.12, 2.13) for anxiety disorder. Immigrant status was a significant effect modifier for the association between mental health and fall injury, with stronger associations in immigrants than in non-immigrants especially in elderly people. People with poor self perceived health were more likely to have a fall injury. Both mental health and general health were related to fall injury. There was a stronger association between mental health and fall injury in immigrants compared with non-immigrants in the elderly. More attention should be paid to mental health in immigrants associated with fall injury. PMID- 23810954 TI - Efficacy of Origanum vulgare L. and Rosmarinus officinalis L. essential oils in combination to control postharvest pathogenic Aspergilli and autochthonous mycoflora in Vitis labrusca L. (table grapes). AB - This study evaluated the efficacy of the application of the essential oils of Origanum vulgare L. (OVEO) and Rosmarinus officinalis L. (ROEO) alone and in combination to inhibit Aspergillus flavus URM 4540 and Aspergillus niger URM 5842 in fungal growth media and on Vitis labrusca L. (table grapes). The influence on the autochthonous mycoflora and the physical, physicochemical and sensory characteristics of the grapes during storage (25 degrees C, 12days and 12 degrees C, 24days) were also studied. The application of the essential oils in different concentrations (Minimum Inhibitory Concentration - MIC, 1/2 MIC+1/2 MIC and 1/4 MIC+1/4 MIC) inhibited the mycelial growth and spore germination of the test fungi and inhibited the growth of the assayed fungal strains in artificially contaminated grapes and the autochthonous mycoflora of grapes stored at both room and cold temperatures. In general, the application of OVEO and/or ROEO at sub lethal concentrations preserved the quality of grapes as measured by their physical, physicochemical and sensory attributes throughout the assessed storage time. These results demonstrate the potential of the combination of OVEO and ROEO at sub-lethal concentrations to control postharvest pathogenic fungi in fruits, particularly, A. flavus and A. niger in table grapes. PMID- 23810955 TI - Rapid detection and identification of Bacillus anthracis in food using pyrosequencing technology. AB - The development of advanced methodologies for the detection of Bacillus anthracis has been evolving rapidly since the release of the anthrax spores in the mail in 2001. Recent advances in detection and identification techniques could prove to be an essential component in the defense against biological attacks. Sequence based such as pyrosequencing, which has the capability to determine short DNA stretches in real-time using biotinylated PCR amplicons, has potential biodefense applications. Using markers from the virulence plasmids (pXO1 and pXO2) and chromosomal regions, we have demonstrated the power of this technology in the rapid, specific and sensitive detection of B. anthracis spores in food matrices including milk, juice, bottled water, and processed meat. The combined use of immunomagnetic separation and pyrosequencing showed positive detection when liquid foods (bottled water, milk, juice), and processed meat were experimentally inoculated with 6CFU/mL and 6CFU/g, respectively, without an enrichment step. Pyrosequencing is completed in about 60min (following PCR amplification) and yields accurate and reliable results with an added layer of confidence. The entire assay (from sample preparation to sequencing information) can be completed in about 7.5h. A typical run on food samples yielded 67-80bp reads with 94-100% identity to the expected sequence. This sequence based approach is a novel application for the detection of anthrax spores in food with potential application in foodborne bioterrorism response and biodefense involving the use of anthrax spores. PMID- 23810956 TI - Listeria monocytogenes responds to cell density as it transitions to the long term-survival phase. AB - Listeria monocytogenes was recently found to enter a long-term-survival (LTS) phase, which may help explain its persistence in natural environments and within food processing plants. The purpose of this study was to investigate the effects of initial cell density, initial pH and type of broth (fresh vs. spent) on the transition of L. monocytogenes to the LTS phase and model the change in viable population density with time. Initial cell density (~10(6)-~10(10)CFU/ml) and initial pH (5.36-6.85) both significantly affected the transition of L. monocytogenes to the LTS phase (P<0.001) with initial cell density being the main determining factor. In contrast, type of broth did not significantly affect cell density change during the transition of stationary-phase cells at high initial density to the LTS phase (P>0.05). After 30-d incubation no significant differences in cell densities were observed between either type of broth or between any of the initial cell density/pH treatment combinations (P>0.05), where the mean viable cell density was 4.3+/-1.1*10(8)CFU/ml. L. monocytogenes responded to viable cell density in accordance with the logistic equation during transition to the LTS phase. The Agr quorum-sensing system does not appear to play a role in the transition to the LTS phase. Further research is needed to better understand the control mechanisms utilized by L. monocytogenes as it transitions to a coccoid, resistant and stable density state in the LTS phase. PMID- 23810957 TI - Protective effect of high-dose montelukast on salbutamol-induced homologous desensitisation in airway smooth muscle. AB - Montelukast (MK) is a potent cysteinyl-leukotriene receptor antagonist that causes dose-related improvements in chronic asthma. We sought to determine whether MK was able to prevent salbutamol-induced tolerance in airway smooth muscle. Homologous beta2-adrenoceptor desensitisation models were established in guinea-pigs and in human bronchial smooth muscle cells (BSMC) by chronic salbutamol administration. Characterisation tools included measurement of the response of tracheal smooth muscle tissues to salbutamol, analysis of gene expression and receptor trafficking, evaluation of intracellular cAMP levels and phosphodiesterase (PDE) activity in human bronchial smooth muscle cells. Salbutamol-induced beta2-adrenoceptor desensitisation was characterised by beta2 agonist hyporesponsiveness (-30%, p < 0.001) in desensitised tracheal smooth muscle, as compared to controls. MK, given intraperitoneally at 5 mg/kg/day for 6 consecutive days, completely restored tissue responsiveness to salbutamol. Prolonged salbutamol treatment significantly decreased cAMP synthesis, induced a complete removal of the beta2-adrenoceptor from plasma membrane with a parallel increase in the cytosol and increased PDE4D5 gene transcription and PDE activity in human bronchial smooth muscle cells. In homologously desensitised BSMC, MK 30 MUM for 24 h was able to prevent salbutamol subsensitivity and such an effect was associated with inhibition of salbutamol-induced PDE4 activity and restoration of membrane beta2-adrenoceptor expression and function. These findings suggest the presence of a favourable interaction between MK and beta2-adrenoceptor agonists that might improve the therapeutic index of bronchodilators in patients with chronic respiratory diseases. PMID- 23810958 TI - Re: The influence of angioarchitecture on management of pediatric intracranial arteriovenous malformations. PMID- 23810959 TI - England's national programme for IT. PMID- 23810960 TI - Record number of fake drugs are seized in crackdown. PMID- 23810961 TI - GP who ran out of hours service provided inadequate care, tribunal hears. PMID- 23810963 TI - Failure to tackle health inequalities is a false economy, meeting hears. PMID- 23810964 TI - Doctors brand CQC as not fit for purpose. PMID- 23810965 TI - Thermal stratification patterns in urban ponds and their relationships with vertical nutrient gradients. AB - Ponds that collect and process stormwater have become a prominent feature of urban landscapes, especially in areas recently converted to residential land use in North America. Given their increasing number and their tight hydrological connection to residential catchments, these small aquatic ecosystems could play an important role in urban biogeochemistry. However, some physicochemical aspects of urban ponds remain poorly studied. Here we assessed the frequency and strength of water column stratification, using measurements of vertical water temperature profiles at high spatial and temporal frequency, in 10 shallow urban stormwater management ponds in southern Ontario, Canada. Many of the ponds were well stratified during much of the summer of 2010 as indicated by relatively high estimates of thermal resistance to mixing (RTRM) indices. Patterns of stratification reflected local weather conditions but also varied among ponds depending on their morphometric characteristics such as maximum water depth and surface area to perimeter ratio. We found greater vertical nutrient gradients and more phosphorus accumulation in bottom waters in ponds with strong and persistent stratification, which likely results from limited particle resuspension and more dissolved phosphorus (P) release from sediments. However, subsequent mixing events in the fall diminished vertical P gradients and possibly accelerated internal loading from the sediment-water interface. Our results demonstrate that stormwater ponds can experience unexpectedly long and strong thermal stratification despite their small size and shallow water depth. Strong thermal stratification and episodic mixing in ponds likely alter the quantity and timing of internal nutrient loading, and hence affect water quality and aquatic communities in downstream receiving waters. PMID- 23810966 TI - Biomass production in agroforestry and forestry systems on salt-affected soils in South Asia: exploration of the GHG balance and economic performance of three case studies. AB - This study explores the greenhouse gas balance and the economic performance (i.e. net present value (NPV) and production costs) of agroforestry and forestry systems on salt-affected soils (biosaline (agro)forestry) based on three case studies in South Asia. The economic impact of trading carbon credits generated by biosaline (agro)forestry is also assessed as a potential additional source of income. The greenhouse gas balance shows carbon sequestration over the plantation lifetime of 24 Mg CO2-eq. ha(-1) in a rice-Eucalyptus camaldulensis agroforestry system on moderately saline soils in coastal Bangladesh (case study 1), 6 Mg CO2 eq. ha(-1) in the rice-wheat- Eucalyptus tereticornis agroforestry system on sodic/saline-sodic soils in Haryana state, India (case study 2), and 96 Mg CO2 eq. ha(-1) in the compact tree (Acacia nilotica) plantation on saline-sodic soils in Punjab province of Pakistan. The NPV at a discount rate of 10% is 1.1 k? ha( 1) for case study 1, 4.8 k? ha(-1) for case study 2, and 2.8 k? ha(-1) for case study 3. Carbon sequestration translates into economic values that increase the NPV by 1-12% in case study 1, 0.1-1% in case study 2, and 2-24% in case study 3 depending on the carbon credit price (1-15 ? Mg(-1) CO2-eq.). The analysis of the three cases indicates that the economic performance strongly depends on the type and severity of salt-affectedness (which affect the type and setup of the agroforestry system, the tree species and the biomass yield), markets for wood products, possibility of trading carbon credits, and discount rate. PMID- 23810967 TI - Memantine, a promising drug for the prevention of neuropathic pain in rat. AB - N-methyl-D-aspartate (NMDA) receptor antagonists are used for post-surgery neuropathic pain but severe side-effects limit their clinical use. Memantine, when given after surgery, shows conflicting results as regard to neuropathic pain alleviation. Here memantine is administered in animals before or after spinal nerve ligation (SNL) in order to evaluate the induced antinociceptive/cognitive effects and associated molecular events, including the phosphorylation of several tyrosine (pTyr(1336), pTyr(1472)) and serine (pSer(1303)) residues in the NR2B subunit of the NMDA receptor. Spinal nerve ligated and sham animals received memantine (20mg/kg/day) or vehicle (1ml/kg/day) by intraperitoneal route. Pre emptive protocol started 4 days before surgery and continued for 2 days post surgery. In the post-operative protocol, the 7 day-treatment began on the day of surgery. Tests were done before and after surgery. Tactile allodynia, mechanical hyperalgesia and spatial memory were evaluated by von Frey, Randall & Selitto and Y-maze-tests respectively, and molecular events by western-blot analysis. Spinal nerve ligated animals displayed nociception, impaired memory and increased expression of the 3 phosphorylated residues. Post-operative memantine had no beneficial effect. Pre-emptive memantine prevented the development of post surgical nociception, impairment of spatial memory and did not increase the expression of pTyr(1472)NR2B at spinal, insular and hippocampal levels. Memantine administered a few days before surgery is a promising strategy to alleviate neuropathic pain development and impairment of cognitive function in animals. The pivotal role of pTyr(1472)NR2B must be studied further, and these findings will now be challenged in patients for the prevention of postsurgical neuropathic pain. PMID- 23810968 TI - mTOR inactivation by ROS-JNK-p53 pathway plays an essential role in psedolaric acid B induced autophagy-dependent senescence in murine fibrosarcoma L929 cells. AB - Pseudolaric acid B (PAB), the primary biologically active compound isolated from the root bark of P. kaempferi Gordon, has been reported to exhibit anti-tumor effect primarily via cell cycle arrest and apoptosis. Our previous study demonstrated that PAB triggered mitotic catastrophe in L929 cells. In addition, a small percentage of the cells undergoing mitotic catastrophe displayed an apoptotic phenotype. Therefore, we continued to investigate the fate of the other cells. The results indicated that PAB induced senescence through p19-p53-p21 and p16-Rb pathways in L929 cells. PAB also triggered autophagy via inhibiting Akt mammalian target of rapamycin (mTOR) activity in L929 cells. In addition, autophagy was demonstrated to reinforce senescence through regulating the senescence pathways. Thus, we focused on the detailed molecular mechanisms whereby autophagy promoted senescence. Reactive oxygen species (ROS) plays an important in autophagy and senescence. We found that PAB triggered a ROS-JNK-p53 positive feedback loop and this feedback loop played a crucial role in autophagy via repressing the activation of mTOR. Furthermore, ROS-JNK-p53 positive feedback loop was demonstrated to regulate senescence. Tuberous sclerosis proteins1 and 2, also known as TSC1 and TSC2, form a protein-complex. TSC1/TSC2 heterodimer is a downstream target of growth factor-phosphoinositide 3-kinase-Akt signaling which negatively regulates mTOR activity. Activation of mTOR by insulin or inhibition of endogenous TSC2 levels by siRNA obviously delayed PAB-induced senescence. In conclusion, mTOR inactivation by ROS-JNK-p53 pathway played an important role in autophagy-dependent senescence in PAB-treated L929 cells. PMID- 23810969 TI - An efficient and scalable extraction and quantification method for algal derived biofuel. AB - Microalgae are capable of synthesizing a multitude of compounds including biofuel precursors and other high value products such as omega-3-fatty acids. However, accurate analysis of the specific compounds produced by microalgae is important since slight variations in saturation and carbon chain length can affect the quality, and thus the value, of the end product. We present a method that allows for fast and reliable extraction of lipids and similar compounds from a range of algae, followed by their characterization using gas chromatographic analysis with a focus on biodiesel-relevant compounds. This method determines which range of biologically synthesized compounds is likely responsible for each fatty acid methyl ester (FAME) produced; information that is fundamental for identifying preferred microalgae candidates as a biodiesel source. Traditional methods of analyzing these precursor molecules are time intensive and prone to high degrees of variation between species and experimental conditions. Here we detail a new method which uses microwave energy as a reliable, single-step cell disruption technique to extract lipids from live cultures of microalgae. After extractable lipid characterization (including lipid type (free fatty acids, mono-, di- or tri acylglycerides) and carbon chain length determination) by GC-FID, the same lipid extracts are transesterified into FAMEs and directly compared to total biodiesel potential by GC-MS. This approach provides insight into the fraction of total FAMEs derived from extractable lipids compared to FAMEs derived from the residual fraction (i.e. membrane bound phospholipids, sterols, etc.). This approach can also indicate which extractable lipid compound, based on chain length and relative abundance, is responsible for each FAME. This method was tested on three species of microalgae; the marine diatom Phaeodactylum tricornutum, the model Chlorophyte Chlamydomonas reinhardtii, and the freshwater green alga Chlorella vulgaris. The method is shown to be robust, highly reproducible, and fast, allowing for multiple samples to be analyzed throughout the time course of culturing, thus providing time-resolved information regarding lipid quantity and quality. Total time from harvesting to obtaining analytical results is less than 2h. PMID- 23810970 TI - Evaluation of molecular assays for identification Campylobacter fetus species and subspecies and development of a C. fetus specific real-time PCR assay. AB - Phenotypic differentiation between Campylobacter fetus (C. fetus) subspecies fetus and C. fetus subspecies venerealis is hampered by poor reliability and reproducibility of biochemical assays. AFLP (amplified fragment length polymorphism) and MLST (multilocus sequence typing) are the molecular standards for C. fetus subspecies identification, but these methods are laborious and expensive. Several PCR assays for C. fetus subspecies identification have been described, but a reliable comparison of these assays is lacking. The aim of this study was to evaluate the most practical and routinely implementable published PCR assays designed for C. fetus species and subspecies identification. The sensitivity and specificity of the assays were calculated by using an extensively characterized and diverse collection of C. fetus strains. AFLP and MLST identification were used as reference. Two PCR assays were able to identify C. fetus strains correctly at species level. The C. fetus species identification target, gene nahE, of one PCR assay was used to develop a real-time PCR assay with 100% sensitivity and 100% specificity, but the development of a subspecies venerealis specific real-time PCR (ISCfe1) failed due to sequence variation of the target insertion sequence and prevalence in other Campylobacter species. None of the published PCR assays was able to identify C. fetus strains correctly at subspecies level. Molecular analysis by AFLP or MLST is still recommended to identify C. fetus isolates at subspecies level. PMID- 23810971 TI - Review of Campylobacter spp. in drinking and environmental waters. AB - Consumption of contaminated drinking water is a significant cause of Campylobacter infections. Drinking water contamination is known to result from septic seepage and wastewater intrusion into non-disinfected sources of groundwater and occasionally from cross-connection into drinking water distribution systems. Wastewater effluents, farm animals and wild birds are the primary sources contributing human-infectious Campylobacters in environmental waters, impacting on recreational activities and drinking water sources. Culturing of Campylobacter entails time-consuming steps that often provide qualitative or semi-quantitative results. Viable but non-culturable forms due to environmental stress are not detected, and thus may result in false-negative assessments of Campylobacter risks from drinking and environmental waters. Molecular methods, especially quantitative PCR applications, are therefore important to use in the detection of environmental Campylobacter spp. Processing large volumes of water may be required to reach the desired sensitivity for either culture or molecular detection methods. In the future, applications of novel molecular techniques such as isothermal amplification and high-throughput sequencing applications are awaited to develop and become more affordable and practical in environmental Campylobacter research. The new technologies may change the knowledge on the prevalence and pathogenicity of the different Campylobacter species in the water environment. PMID- 23810972 TI - White matter microstructure correlates of narrative production in typically developing children and children with high functioning autism. AB - This study investigated the relationship between white matter microstructure and the development of morphosyntax in a spoken narrative in typically developing children (TD) and in children with high functioning autism (HFA). Autism is characterized by language and communication impairments, yet the relationship between morphosyntactic development in spontaneous discourse contexts and neural development is not well understood in either this population or typical development. Diffusion tensor imaging (DTI) was used to assess multiple parameters of diffusivity as indicators of white matter tract integrity in language-related tracts in children between 6 and 13 years of age. Children were asked to spontaneously tell a story about at time when someone made them sad, mad, or angry. The story was evaluated for morphological accuracy and syntactic complexity. Analysis of the relationship between white matter microstructure and language performance in TD children showed that diffusivity correlated with morphosyntax production in the superior longitudinal fasciculus (SLF), a fiber tract traditionally associated with language. At the anatomical level, the HFA group showed abnormal diffusivity in the right inferior longitudinal fasciculus (ILF) relative to the TD group. Within the HFA group, children with greater white matter integrity in the right ILF displayed greater morphological accuracy during their spoken narrative. Overall, the current study shows an association between white matter structure in a traditional language pathway and narrative performance in TD children. In the autism group, associations were only found in the ILF, suggesting that during real world language use, children with HFA rely less on typical pathways and more on alternative ventral pathways that possibly mediate visual elements of language. PMID- 23810973 TI - A wearable multi-channel fNIRS system for brain imaging in freely moving subjects. AB - Functional near infrared spectroscopy (fNIRS) is a versatile neuroimaging tool with an increasing acceptance in the neuroimaging community. While often lauded for its portability, most of the fNIRS setups employed in neuroscientific research still impose usage in a laboratory environment. We present a wearable, multi-channel fNIRS imaging system for functional brain imaging in unrestrained settings. The system operates without optical fiber bundles, using eight dual wavelength light emitting diodes and eight electro-optical sensors, which can be placed freely on the subject's head for direct illumination and detection. Its performance is tested on N=8 subjects in a motor execution paradigm performed under three different exercising conditions: (i) during outdoor bicycle riding, (ii) while pedaling on a stationary training bicycle, and (iii) sitting still on the training bicycle. Following left hand gripping, we observe a significant decrease in the deoxyhemoglobin concentration over the contralateral motor cortex in all three conditions. A significant task-related DeltaHbO2 increase was seen for the non-pedaling condition. Although the gross movements involved in pedaling and steering a bike induced more motion artifacts than carrying out the same task while sitting still, we found no significant differences in the shape or amplitude of the HbR time courses for outdoor or indoor cycling and sitting still. We demonstrate the general feasibility of using wearable multi-channel NIRS during strenuous exercise in natural, unrestrained settings and discuss the origins and effects of data artifacts. We provide quantitative guidelines for taking condition-dependent signal quality into account to allow the comparison of data across various levels of physical exercise. To the best of our knowledge, this is the first demonstration of functional NIRS brain imaging during an outdoor activity in a real life situation in humans. PMID- 23810974 TI - Serotonin 2A receptors contribute to the regulation of risk-averse decisions. AB - Pharmacological studies point to a role of the neurotransmitter serotonin (5-HT) in regulating the preference for risky decisions, yet the functional contribution of specific 5-HT receptors remains to be clarified. We used pharmacological fMRI to investigate the role of the 5-HT2A receptors in processing negative outcomes and regulating risk-averse behavior. During fMRI, twenty healthy volunteers performed a gambling task under two conditions: with or without blocking the 5 HT2A receptors. The volunteers repeatedly chose between small, likely rewards and large, unlikely rewards. Choices were balanced in terms of expected utility and potential loss. Acute blockade of the 5-HT2A receptors with ketanserin made participants more risk-averse. Ketanserin selectively reduced the neural response of the frontopolar cortex to negative outcomes that were caused by low-risk choices and were associated with large missed rewards. In the context of normal 5 HT2A receptor function, ventral striatum displayed a stronger response to low risk negative outcomes in risk-taking as opposed to risk-averse individuals. This (negative) correlation between the striatal response to low-risk negative outcomes and risk-averse choice behavior was abolished by 5-HT2A receptor blockade. The results provide the first evidence for a critical role of 5-HT2A receptor function in regulating risk-averse behavior. We suggest that the 5-HT2A receptor system facilitates risk-taking behavior by modulating the outcome evaluation of "missed" reward. These results have implications for understanding the neural basis of abnormal risk-taking behavior, for instance in pathological gamblers. PMID- 23810975 TI - From Vivaldi to Beatles and back: predicting lateralized brain responses to music. AB - We aimed at predicting the temporal evolution of brain activity in naturalistic music listening conditions using a combination of neuroimaging and acoustic feature extraction. Participants were scanned using functional Magnetic Resonance Imaging (fMRI) while listening to two musical medleys, including pieces from various genres with and without lyrics. Regression models were built to predict voxel-wise brain activations which were then tested in a cross-validation setting in order to evaluate the robustness of the hence created models across stimuli. To further assess the generalizability of the models we extended the cross validation procedure by including another dataset, which comprised continuous fMRI responses of musically trained participants to an Argentinean tango. Individual models for the two musical medleys revealed that activations in several areas in the brain belonging to the auditory, limbic, and motor regions could be predicted. Notably, activations in the medial orbitofrontal region and the anterior cingulate cortex, relevant for self-referential appraisal and aesthetic judgments, could be predicted successfully. Cross-validation across musical stimuli and participant pools helped identify a region of the right superior temporal gyrus, encompassing the planum polare and the Heschl's gyrus, as the core structure that processed complex acoustic features of musical pieces from various genres, with or without lyrics. Models based on purely instrumental music were able to predict activation in the bilateral auditory cortices, parietal, somatosensory, and left hemispheric primary and supplementary motor areas. The presence of lyrics on the other hand weakened the prediction of activations in the left superior temporal gyrus. Our results suggest spontaneous emotion-related processing during naturalistic listening to music and provide supportive evidence for the hemispheric specialization for categorical sounds with realistic stimuli. We herewith introduce a powerful means to predict brain responses to music, speech, or soundscapes across a large variety of contexts. PMID- 23810976 TI - Prenatal exposure to antidepressants is associated with small but significant differences in pregnancy and delivery outcomes. PMID- 23810977 TI - 18F-fluorodeoxyglucose positron emission tomography/computer tomography as an objective tool for assessing disease activity in Sjogren's syndrome. AB - OBJECTIVE: This study aims to determine the value of FDG-PET/CT to assess disease activity in patients with Sjogren's syndrome (SS). METHODS: Thirty-two patients with SS who underwent PET/CT were retrospectively analyzed. PET/CT activity score was measured using a 6-point scale including the 6 following items (0/1: absence or presence of an item): lymphadenopathy on CT, high-resolution CT (HRCT) evidence of interstitial lung disease (ILD), parotid glands SUVmax >3, submandibular glands SUVmax >3, lymph node uptake, ILD uptake. Combined PET/CT score was correlated to ESSDAI (EULAR Sjogren's Syndrome Disease Activity Index) score and other parameters of SS activity. RESULTS: Pathological FDG uptake was observed in 75% of patients (24/32): lymph-nodes (n=19, 60%), salivary glands (n=17, 53%), lungs (n=9, 28%), and thyroid (n=2). Median ESSDAI and PET/CT activity scores were 9.5 [5-12] and 2 [0-3], respectively. PET/CT activity score correlated with ESSDAI (r=0.49, p=0.005), unlike SUVmax. Patients with a high ESSDAI score had a higher PET/CT activity score than patients with a low ESSDAI score (3 vs 1, p=0.004). PET was also correlated with gammaglobulin levels (r=0.43, p=0.02), but not with the presence of cryoglobulinemia, activated complement or beta-2 microglobulin levels. The FDG uptake in patients with lymphoma (n=4) was higher than in patients without lymphoma (SUVmax=5.4 vs. 3.2, p=0.05). CONCLUSION: We described a new PET/CT activity score, which correlates to ESSDAI and could help to assess disease activity in SS patients. PET can also help in the diagnosis of lymphoma, even if inflammatory lymph nodes can be frequently observed in SS patients. PMID- 23810978 TI - Hormone-regulated transcriptomes: lessons learned from estrogen signaling pathways in breast cancer cells. AB - Recent rapid advances in next generation sequencing technologies have expanded our understanding of steroid hormone signaling to a genome-wide level. In this review, we discuss the use of a novel genomic approach, global nuclear run-on coupled with massively parallel sequencing (GRO-seq), to explore new facets of the steroid hormone-regulated transcriptome, especially estrogen responses in breast cancer cells. GRO-seq is a high throughput sequencing method adapted from conventional nuclear run-on methodologies, which is used to obtain a map of the position and orientation of all transcriptionally engaged RNA polymerases across the genome with extremely high spatial resolution. GRO-seq, which is an excellent tool for examining transcriptional responses to extracellular stimuli, has been used to comprehensively assay the effects of estrogen signaling on the transcriptome of ERalpha-positive MCF-7 human breast cancer cells. These studies have revealed new details about estrogen-dependent transcriptional regulation, including effects on transcription by all three RNA polymerases, complex transcriptional dynamics in response to estrogen signaling, and identification novel, unannotated non-coding RNAs. Collectively, these studies have been useful in discerning the molecular logic of the estrogen-regulated mitogenic response. PMID- 23810980 TI - Preliminary investigation of a highly sulfated galactofucan fraction isolated from the brown alga Sargassum polycystum. AB - A fucoidan preparation was isolated from the brown alga Sargassum polycystum (Fucales, Sargassaceae). The preparation was fractionated by anion-exchange chromatography, and two highly sulfated fractions F3 and F4 were obtained. The fractions were quite similar in composition, but different in chemical structure. F4 was analyzed by chemical methods, including desulfation, methylation, Smith degradation, and partial acid hydrolysis with mass-spectrometric monitoring, as well as by NMR spectroscopy. Several 2D NMR procedures, including HMQC-TOCSY and HMQC-NOESY, were used to obtain reliable structural information from the complex spectra. Molecules of F4 were shown to contain a backbone built up mainly of 3 linked alpha-L-fucopyranose 4-sulfate residues, as in many other fucoidans, but rather short sequences of these residues are interspersed by single 2-linked alpha-D-galactopyranose residues also sulfated at position 4. This rather unusual structural feature should have a great influence on the conformation of the polymeric molecule and may be important for biological activity of the polysaccharide. Hence, F4 is an example of a new sulfated galactofucan isolated from the brown alga. According to the data obtained, the distribution of galactose residues along the polysaccharide backbone seems to be not strictly regular, but the definitive sequence of monomers in the polymeric molecules awaits additional investigation. PMID- 23810979 TI - Cortical PKC inhibition promotes axonal regeneration of the corticospinal tract and forelimb functional recovery after cervical dorsal spinal hemisection in adult rats. AB - Our previous study shows that conventional protein kinases C (cPKCs) are key signaling mediators that are activated by extracellular inhibitory molecules. Inhibition of cPKC by intrathecal infusion of a cPKC inhibitor, GO6976, into the site of dorsal hemisection (DH) induces regeneration of lesioned dorsal column sensory, but not corticospinal tract (CST), axons. Here, we investigated whether a direct cortical delivery of GO6976 into the soma of corticospinal neurons promotes regeneration of CST and the recovery of forelimb function in rats with cervical spinal cord injuries. We report that cortical delivery of GO6976 reduced injury-induced activation of conventional PKCalpha and PKCbeta1 in CST neurons, promoted regeneration of CST axons through and beyond a cervical DH at C4, formed new synapses on target neurons caudal to the injury, and enhanced forelimb functional recovery in adult rats. When combined with lenti-Chondroitinase ABC treatment, cortical administration of GO6976 promoted even greater CST axonal regeneration and recovery of forelimb function. Thus, this study has demonstrated a novel strategy that can promote anatomical regeneration of damaged CST axons and partial recovery of forelimb function. Importantly, such an effect is critically dependent on the efficient blockage of injury-induced PKC activation in the soma of layer V CST neurons. PMID- 23810981 TI - Chemical structures of the secondary cell wall polymers (SCWPs) isolated from bovine mastitis Streptococcus uberis. AB - The cell envelope of Gram-positive bacteria is decorated with a variety of polysaccharides. In this study wall teichoic acid (WTA) and neutral polysaccharides were isolated from the cell envelope of bovine mastitis Streptococcus uberis. The polysaccharides were released by lysozyme treatment, and purified by hydrophobic interaction chromatography. Further separation was achieved utilizing anion-exchange chromatography which yielded two products, that is, a neutral polysaccharide with a high content of Rha and less Glc (rhamnan) and an anionic phosphate-rich one containing glycerol and Glc (WTA). The structures of these molecules were elucidated applying 1D and 2D nuclear magnetic resonance experiments as well as chemical analyses. In the rhamnan sample two independent molecules were identified, that is, a glucorhamnan with the structure ->2)-alpha-L-Rhap-(1->3)-[alpha-D-Glcp-(1->2)-]alpha-L-Rhap-(1->, and a homopolymeric rhamnan ->2)-alpha-L-Rhap-(1->3)-alpha-L-Rhap-(1->. The WTA comprised a polyphosphoglycerol chain substituted nonstoichiometrically with beta Glcp. PMID- 23810982 TI - Effects of dopamine receptor blockade on the intensity-response function of ERG b and d-waves in dark adapted eyes. AB - The effects of dopamine receptor blockade by sulpiride (D2-class antagonist) and sulpiride plus SCH 23390 (D1-class antagonist) on the V - log I function of the ERG b- and d-waves were investigated in dark adapted frog eyes. We observed that sulpiride enhanced the amplitude of the suprathreshold b- and d-waves in the lower intensity range, where the responses were mediated by rods, but diminished it in the higher intensity range, where the responses were mediated by cones. A similar effect on the b-, but not d-wave amplitude was seen during the perfusion with sulpiride plus SCH 23390. The d-wave amplitude was enhanced over the whole intensity range with the exception of the highest intensities during the combined D1 and D2 receptor blockade. The results obtained indicate that the endogenous dopamine has an overall inhibitory action on the suprathreshold rod-mediated ON and OFF responses, while its action on the cone-mediated responses shows clear ON OFF asymmetry. It is excitatory upon the ON responses, but inhibitory upon the OFF responses except for those in the highest intensity range. Participation of different types of dopamine receptors (predominantly D2 for the ON versus D1 for the OFF response) is probably responsible for this difference. PMID- 23810983 TI - A duplex SYBR Green I-based real-time RT-PCR assay for the simultaneous detection and differentiation of Massachusetts and non-Massachusetts serotypes of infectious bronchitis virus. AB - Infectious bronchitis is a highly contagious viral disease of poultry caused by infectious bronchitis virus (IBV) and is considered one of the most economically important viral diseases of chickens. Control of IBV has been attempted using live attenuated and inactivated vaccines. Live attenuated vaccines of the Massachusetts (Mass.) serotype are the most commonly used for this purpose. Due to the continuous emergence of new variants of the infectious bronchitis virus, the identification of the type of IBV causing an outbreak in commercial poultry is important in the selection of the appropriate vaccine(s) capable of inducing a protective immune response. The present work was aimed at developing and evaluating a duplex SYBR Green I-based real-time RT-PCR (rRT-PCR) assay for the simultaneous detection and differentiation of Mass. and non-Mass. serotypes of IBV. The duplex rRT-PCR yielded curves of amplification with two specific melting curves (Tm1 = 83 degrees C +/- 0.5 degrees C and Tm2 = 87 degrees C +/- 0.5 degrees C) and only one specific melting peak (Tm = 87 degrees C +/- 0.5 degrees C) when the IBV Mass. serotype and IBV non-Mass. serotype strains were evaluated, respectively. The detection limit of the assay was 8.2 gene copies/MUL based on in vitro transcribed RNA and 0.1 EID50/mL. The assay was able to detect all the IBV strains assessed and discriminated well among the IBV Mass. and the IBV non-Mass. serotypes strains. In addition, amplification curves were not obtained with any of the other viruses tested. From the 300 field samples tested, the duplex rRT-PCR yielded a total of 80 samples that were positive for IBV (26.67%), 73 samples identified as the IBV Mass. serotype and seven samples as identified as the IBV non-Mass. serotype. A comparison of the performance of test as assessed with field samples revealed that the duplex rRT-PCR detected a higher number of IBV-positive samples than when conventional RT-PCR or virus isolation tests were used. The duplex rRT-PCR presented here is a useful tool for the rapid identification of outbreaks and for surveillance programmes during IB-suspected cases, particularly in countries with a vaccination control programme. PMID- 23810984 TI - Effortful control, positive emotional expression, and behavior problems in children born preterm. AB - The present study focused on the role of high effortful control in the expression of positive emotion and development of behavior problems in children born preterm (mean gestational age = 31.4 weeks). Using data from a prospective longitudinal study, the present study assessed effortful control and behavior problems at 24 and 36 months and positive emotional expression at 24 months in a sample of 173 children born preterm. Less positive emotional expression was associated with higher effortful control for boys but not girls. Higher effortful control was associated with fewer total behavior problems, but this relation was attenuated when socioeconomic assets were included in the model. More socioeconomic assets were associated with fewer behavior problems for both boys and girls and higher effortful control for girls. Socioeconomic assets appear to be an important factor in the development of effortful control and behavior problems in children born preterm regardless of gender, whereas positive emotional expression was important for boys. Future intervention research should examine fostering adaptive levels of effortful control in high-risk populations as a means to facilitate resilience processes. PMID- 23810985 TI - Predictors of early person reference development: maternal language input, attachment and neurodevelopmental markers. AB - In a longitudinal natural language development study in Germany, the acquisition of verbal symbols for present persons, absent persons, inanimate things and the mother-toddler dyad was investigated. Following the notion that verbal referent use is more developed in ostensive contexts, symbolic play situations were coded for verbal person reference by means of noun and pronoun use. Depending on attachment classifications at twelve months of age, effects of attachment classification and maternal language input were studied up to 36 months in four time points. Hierarchical regression analyses revealed that, except for mother absence, maternal verbal referent input rates at 17 and 36 months were stronger predictors for all referent types than any of the attachment organizations, or any other social or biological predictor variable. Attachment effects accounted for up to 9.8% of unique variance proportions in the person reference variables. Perinatal and familial measures predicted person references dependent on reference type. The results of this investigation indicate that mother-reference, self-reference and thing-reference develop in similar quantities measured from the 17-month time point, but are dependent of attachment quality. PMID- 23810986 TI - Hybrid density functional based study on the band structure of trioctahedral mica and its dependence on the variation of Fe(2+) content. AB - A hybrid density functional based study of a phyllosilicate (PS) is presented here for the first time. Using all-electron electronic structure calculations with the B3LYP hybrid functional, we have investigated the electronic and structural properties of a series of trioctahedral 1M-polytype K-bearing micas starting from phlogopite (the Mg-end member), ending with the annite (the Fe-end member), and passing through the biotite (a solid solution of the end members). Electronic band gap is calculated for all the compositions and nature of the electronic transition is discussed with the aid of band structure and density of states plots. An excellent agreement with the available experimental data has been observed. An insulator to semiconductor transition is explained on the basis of orbital hybridization. A further comparison is made using the pure GGA functional. For the completeness of the study, the dielectric properties of phlogopite are calculated using the coupled perturbed Kohn-Sham scheme, as implemented within the CRYSTAL09 code. PMID- 23810988 TI - Insulin-like growth factor binding protein-3 (IGFBP-3) plays a role in the anti tumorigenic effects of 5-Aza-2'-deoxycytidine (AZA) in breast cancer cells. AB - Breast cancer progression is associated with loss of estrogen receptor (ER alpha), often due to epigenetic silencing. IGFBP genes have consistently been identified among the most common to be aberrantly methylated in tumours. To understand the impact of losing IGFBP-3 tumour expression via DNA methylation, we treated four breast cancer cell lines (MCF-7, T47D, Hs578T and MDA-MB-231) with a DNA methyltransferase inhibitor, 5-Aza-2'-deoxycytidine (AZA) to determine IGFBP 3's role in the effects of AZA on total cell number and survival relative to changes in the ER. AZA induced cell growth inhibition, death and a reduction in the formation of colonies, despite increasing ER-alpha expression in ER-negative cells but reducing ER-alpha in ER-positive cells. Regardless of the differential effects on the ER-alpha, AZA consistently increased the abundance of IGFBP-3 and negating this increase in IGFBP-3 with siRNA reduced the AZA-induced growth inhibition and induction of cell death and virtually negated the AZA-induced inhibition of colony formation. With ER-alpha positive cells AZA increased the abundance of the tumour suppressor gene, p53 and induced demethylation of the IGFBP-3 promoter, whereas with ER negative cells, AZA epigenetically increased the transcription factor AP2-alpha, which when silenced prevented the increase in IGFBP-3. IGFBP-3 plays an important role in the anti-tumorigenic effects of AZA on breast cancer cells. PMID- 23810987 TI - Evidence for defective Rab GTPase-dependent cargo traffic in immune disorders. AB - A fully functional immune system is essential to protect the body against pathogens and other diseases, including cancer. Vesicular trafficking provides the correct localization of proteins within all cell types, but this process is most exquisitely controlled and coordinated in immune cells because of their specialized organelles and their requirement to respond to selected stimuli. More than 60 Rab GTPases play important roles in protein trafficking, but only five Rab-encoding genes have been associated with inherited human disorders, and only one of these (Rab27a) causes an immune defect. Mutations in RAB27A cause Griscelli Syndrome type 2 (GS2), an autosomal recessive disorder of pigmentation and severe immune deficiency. In lymphocytes, Munc13-4 is an effector of Rab27a, and mutations in the gene encoding this protein (UNC13D) cause Familial Hemophagocytic Lymphohistiocytosis Type 3 (FHL3). The immunological features of GS2 and FHL3 include neutropenia, thrombocytopenia, and immunodeficiency due to impaired function of cytotoxic lymphocytes. The small number of disorders caused by mutations in genes encoding Rabs could be due to their essential functions, where defects in these genes could be lethal. However, with the increasing use of next generation sequencing technologies, more mutations in genes encoding Rabs may be identified in the near future. PMID- 23810989 TI - Prostaglandin E(2) and insulin-like growth factor I interact to enhance proliferation of theca externa cells from chicken prehierarchical follicles. AB - The interactive effect of insulin-like growth factor I (IGF-I) and prostaglandin E2 (PGE2) on the proliferation of theca externa cells (TECs) was investigated in the prehierarchical small yellow follicles of laying hens. IGF-I manifested a proliferating effect like PGE2 on TECs, but this stimulating effect was restrained by AG1024 (IGF-IR inhibitor), KP372-1 (PKB/AKT inhibitor) or NS398 (COX-2 inhibitor). AG1024, KP372-1 or NS398 abolished IGF-I-stimulated COX-2 expression and PGE2 production. Meanwhile, KP372-1, NS398 or AG1024 depressed the PGE2-stimulated expression of COX-2 and IGF-IR mRNA. Therefore, the IGF-I receptor pathway up-regulates COX-2 expression and PGE2 synthesis via PKB signaling cascade, and then PGE2 stimulates IGF-IR mRNA expression to promote TEC proliferation in an autocrine pattern. Overall, the reciprocal stimulation of intracellular PGE2 and IGF-I may enhance TEC proliferation and facilitate the development of chicken prehierarchical follicles. PMID- 23810990 TI - Stripes disrupt odour attractiveness to biting horseflies: battle between ammonia, CO2, and colour pattern for dominance in the sensory systems of host seeking tabanids. AB - As with mosquitoes, female tabanid flies search for mammalian hosts by visual and olfactory cues, because they require a blood meal before being able to produce and lay eggs. Polarotactic tabanid flies find striped or spotted patterns with intensity and/or polarisation modulation visually less attractive than homogeneous white, brown or black targets. Thus, this reduced optical attractiveness to tabanids can be one of the functions of striped or spotty coat patterns in ungulates. Ungulates emit CO2 via their breath, while ammonia originates from their decaying urine. As host-seeking female tabanids are strongly attracted to CO2 and ammonia, the question arises whether the poor visual attractiveness of stripes and spots to tabanids is or is not overcome by olfactory attractiveness. To answer this question we performed two field experiments in which the attractiveness to tabanid flies of homogeneous white, black and black-and-white striped three-dimensional targets (spheres and cylinders) and horse models provided with CO2 and ammonia was studied. Since tabanids are positively polarotactic, i.e. attracted to strongly and linearly polarised light, we measured the reflection-polarisation patterns of the test surfaces and demonstrated that these patterns were practically the same as those of real horses and zebras. We show here that striped targets are significantly less attractive to host-seeking female tabanids than homogeneous white or black targets, even when they emit tabanid-luring CO2 and ammonia. Although CO2 and ammonia increased the number of attracted tabanids, these chemicals did not overcome the weak visual attractiveness of stripes to host-seeking female tabanids. This result demonstrates the visual protection of striped coat patterns against attacks from blood-sucking dipterans, such as horseflies, known to transmit lethal diseases to ungulates. PMID- 23810991 TI - Melatonin ameliorates chronic mild stress induced behavioral dysfunctions in mice. AB - Melatonin, a neurohormone, is known to regulate several physiological functions, especially the circadian homeostasis, mood and behavior. Chronic exposure to stress is involved in the etiology of human affective disorders, and depressed patients have been reported to show changes in the circadian rhythms and nocturnal melatonin concentration. The present study was conducted to evaluate a possible beneficial action of chronic night-time melatonin treatment against chronic mild stress (CMS) induced behavioral impairments. As expected in the present study, the stress exposed mice showed reduced weight gain, hedonic deficit, cognitive deficits and decreased mobility in behavioral despair test. Interestingly, CMS exposed mice showed less anxiety. Chronic night-time melatonin administration significantly ameliorated the stress-induced behavioral disturbances, especially the cognitive dysfunction and depressive phenotypes. In conclusion, the present findings suggest the mitigating role of melatonin against CMS-induced behavioral changes, including the cognitive dysfunctions and reaffirm its potential role as an antidepressant. PMID- 23810992 TI - Dietary variety is associated with larger meals in female rhesus monkeys. AB - The complex, interacting influences on eating behavior and energy expenditure prevent elucidation of the causal role of any single factor in the current obesity epidemic. However, greater variety in the food supply, particularly in the form of highly palatable, energy-dense foods, has likely made a contribution. This study was undertaken to test the hypothesis that greater dietary variety is associated with greater caloric intake within individual meals consumed by free feeding, socially-housed female rhesus monkeys. Meal patterns were assessed during two, two-week dietary phases. One phase consisted of a choice between a standard chow diet and a highly palatable diet (HPD). The other phase consisted of access to the chow only. Food intake for each subject was recorded continuously using previously validated, automated feeders, and a meal was defined based on a minimum kilocalorie requirement and a minimum inter-meal interval. During the choice condition, animals electively consumed mixed meals that incorporated both diets as well as other meals that consisted exclusively of a single diet - chow-only or HPD-only. Animals consumed the most calories per meal when the meal was comprised of both the chow and HPD, which differed in caloric density, flavor, and texture. Interestingly, however, there was no significant difference in the amount of calories consumed as HPD-only meals in the choice condition compared to meals in the chow-only, no choice condition, suggesting consumption of a single food during a meal, regardless of palatability, provides a constant sensory experience that may lead to more rapid habituation and subsequent meal cessation. Additionally, during the dietary choice condition, animals consumed fewer calories in the form of chow-only meals. Thus, the present results suggest that limiting dietary variety, regardless of palatability, may be a useful strategy for weight loss in overweight and obese individuals by reducing caloric intake within individual meals. PMID- 23810993 TI - Phylogeny and divergence times of Australian Sphenomorphus group skinks (Scincidae, Squamata). AB - The Australian Sphenomorphus group is a diverse clade (c. 250 species) of scincid lizards (skinks) incorporating more than half of the Australian scincid fauna. Previous phylogenetic analyses of mitochondrial and nuclear gene sequence data for selected Australian Sphenomorphus group scincids have provided support for several morphologically- and ecologically-distinct clades; however, the relationships among these clades are only incompletely resolved. This paper presents a new phylogenetic analysis of the Australian Sphenomorphus group, based on nucleotide sequences for three regions of the mitochondrial genome and four nuclear genes (5645 aligned sites in total). Phylogenies generated using standard concatenation and multi-species coalescent approaches are generally similar, and nearly all conflicting nodes are weakly supported. Monophyly of a number of genera and other (informal) supra-specific taxa, including Calyptotis, Ctenotus, Eremiascincus, Hemiergis, Lerista, Notoscincus, the 'Eulamprus' quoyii group, and the 'Glaphyromorphus' crassicaudis group is well supported in all analyses. There is significant support for a clade including the 'Eulamprus' tenuis group, Gnypetoscincus, and Nangura, and a clade comprising Coeranoscincus, Coggeria, Ophioscincus, and Saiphos receives at least marginal support (posterior probabilities above 0.93). All analyses indicate that Anomalopus is polyphyletic, although topology tests suggest that support for this result is equivocal. Divergence times inferred using relaxed molecular clock methods are consistent with an Oligocene origin of the Australian Sphenomorphus group following trans oceanic dispersal from Asia. Age estimates for clades distributed primarily in arid habitats (c. 9-17 million years) are generally younger than those for clades occurring in mesic environments (c. 15-22 million years); however, arid-zone clades are substantially more diverse, including nearly 80% of all Australian Sphenomorphus group scincids. This pattern conforms well with reconstructions of Australian palaeo-environments during the Cenozoic, which indicate a progressive shift from widespread mesic habitats in the Early Miocene (prior to 16 Mya) to predominantly arid environments 4-2 Mya. PMID- 23810994 TI - Volitional control of the heart rate. AB - The heart rate is largely under control of the autonomic nervous system. The aim of the present study is to investigate the interactions between the brain and heart underlying volitional control of the heart and to explore the effectiveness of volition as a strategy to control the heart rate without biofeedback. Twenty seven healthy male subjects voluntarily participated in the study and were instructed to decrease and increase their heart beats according to rhythmic, computer generated sound either 10% faster or slower than the subjects' measured heart rate. Sympathetic and parasympathetic activities were estimated with the heart rate variability (HRV) obtained by power spectral analysis of RR intervals. Functional coupling patterns of cerebral cortex with the heart were determined by Partial directed coherence (PDC). In HR(slow) task; HR and sympathetic activity significantly decreased. However parasympathetic activity and power spectral density of EEG in low Alpha (8-10.5 Hz) band significantly increased. Moreover information flow from parietal area (P3 and P4) to RR interval significantly increased. During HR(quick) task; HR, sympathetic activity and power spectral density of EEG in low Beta (14-24 Hz) band significantly increased. Parasympathetic activity significantly decreased. Information flow from FT8, CZ and T8 electrodes to RR interval significantly increased. Our findings suggested that the heart beat can be controlled by volition and is related to some special areas in the cortex. PMID- 23810995 TI - Pathophysiology of sleep-dependent memory consolidation processes in children. AB - Cognitive impairments are often associated with abnormal sleep activity in developmental disorders and pathologies of childhood. Besides, accumulated evidence indicates that post-training sleep benefits to the consolidation of recently learned information in healthy adults and children. Although sleep dependent consolidation effects in children are clearly established for declarative memories, they remain more debated in the procedural memory domain. Nowadays, recent experimental data suggest close interactions between the development of sleep-dependent plasticity markers, cortical maturation and cognition in children. In the present review, we propose that studying sleep and memory consolidation processes in developmental disorders and acquired childhood pathologies can provide novel, enlightening clues to understand the pathophysiological mechanisms subtending the disruption of long-term cerebral plasticity processes eventually leading to cognitive and learning deficits in children. PMID- 23810997 TI - Psychophysiology and cognitive neuroscience of sleep and sleep disorders. PMID- 23810996 TI - The catechol-o-methyltransferase Val158 Met polymorphism modulates organization of regional cerebral blood flow response to working memory in adults. AB - This study examined the effect of catechol-o-methyltransferase (COMT) Val(158)Met genotypes on the co-activation of brain areas involved in cognition during a working memory (WM) task. The pattern of concomitant region of interest (ROI) activation during WM performance varied by genotype: Val/Val showing the least and Met/Met the most covariance. There were no differences of performance on the WM task between the COMT genotypes. However, relatively better performance was associated with less concomitance of dorsolateral prefrontal cortex (DLPFC) and cingulate cortex for Val/Val, but more concomitance of DLPFC with AH for Met/Met. Within genotypes WM performance was significantly correlated with rCBF to the amygdala/hippocampus (AH) for Val/Val (r = 0.44, p = 0.009), to the parietal lobe for Val/Met (r = 0.29, p = 0.03), and to the thalamus for Met/Met (r = 0.32, p = 0.04). Different genotypes showed different regional specificity and concomitant activation patterns suggesting that varying dopamine availability induces different brain processing pathways to achieve similar WM performance. PMID- 23810998 TI - Degradation of a model azo dye in submerged anaerobic membrane bioreactor (SAMBR) operated with powdered activated carbon (PAC). AB - This work investigated the anaerobic degradation of the model azo dye Remazol Yellow Gold RNL in an upflow anaerobic sludge blanket reactor (UASB) and two submerged anaerobic membrane (SAMBR) bioreactors, one of which (SAMBR-1) was operated with powdered activated carbon (PAC) in its interior. The reactors were operated at 35 degrees C with a hydraulic retention time of 24 h in three operational phases, aimed to assess the effect of external sources of carbon (glucose) or redox mediator (yeast extract) on the removal or color and organic matter. The results showed that removal efficiencies of COD (73-94%) and color (90-94%) were higher for SAMBR-1 when compared to SAMBR-2 (operated without PAC) and UASB reactors. In addition, the presence of PAC in SAMBR-1 increased reactor stability, thereby leading to a lower accumulation of volatile fatty acids (VFA). The microfiltration membrane was responsible for an additional removal of ~50% of soluble residual COD in the form of VFA, thus improving permeate quality. On its turn, PAC exhibited the ability to adsorb byproducts (aromatic amines) of azo dye degradation as well as to act as source of immobilized redox mediator (quinone groups on its surface), thereby enhancing color removal. PMID- 23810999 TI - Comparative analysis of the enzyme activities and the bacterial community structure based on the aeration source supplied to an MBR to treat urban wastewater. AB - A comparative analysis was performed in a pilot-scale membrane bioreactor (MBR) treating urban wastewater supplied with either pure oxygen (O2) or air, to assess the influence of each aeration source on the diversity and activity of the bacterial communities in the sludge. The MBR was operated in three experimental stages with different concentrations of volatile suspended solids (VSS) and temperature, and under both aeration conditions. alpha-Glucosidases, proteases, esterases and phosphatases were tested as markers of organic matter removal in the sludge, and the diversity of the bacterial community was analysed by fingerprinting (temperature-gradient gel electrophoresis of partially-amplified 16S-rRNA genes). Redundancy analysis (RDA) revealed that temperature and VSS concentration were the only factors that significantly influenced the levels of enzyme activities and the values of both the Shannon-Wiener diversity index (H') and the functional organisation index (Fo), while the bacterial community structure experienced significant changes depending on the aeration source supplied in each experimental stage. PMID- 23811000 TI - Study of chemical and thermal treatment of kaolinite and its influence on the removal of contaminants from mining effluents. AB - The effects of chemical and thermal treatments on the structure of kaolinite were examined, as well as the influence of those changes upon the removal of etheramine, a cationic collector used in the processing of iron ore. The materials were characterized using XRD, XRF, specific surface area (SBET), FTIR, zeta potential and a test for determination of acid sites. The effects of the treatments on the structure of kaolinite were evaluated using chemometric tools developed from principal components analysis algorithms and hierarchical components analysis. The parameters evaluated in the kinetic study of adsorption were contact time, initial concentration of etheramine, quantity of adsorbent and pH. The adsorption of etheramine in the samples subjected to chemical treatments could be explained by a pseudo-second order model, whilst for the sample subjected to thermal treatment, better fit was with the pseudo-first order model. With regard to adsorption isotherms, it was shown that for the three adsorbents used, adsorption followed the Langmuir model. The maximum quantities adsorbed were 27 mg g(-1), 29 mg g(-1) and 59 mg g(-1), respectively, for the samples subjected to acid, thermal and peroxide treatments. The treatment with peroxide was found to be the most suitable for removal of etheramine. PMID- 23811002 TI - Identification of the binding site for fondaparinux on Beta2-glycoprotein I. AB - Antiphospholipid syndrome (APS) is an autoimmune disease with clinical manifestations of thrombosis and pregnancy complications. Beta2-glycoprotein I (beta2GPI) is the major antigen for the APS-related antibodies. Heparin, low molecular weight heparin and the synthetic pentasaccharide fondaparinux are commonly used for prophylaxis and treatment of thrombosis in patients with antiphospholipid syndrome. These antithrombotic drugs bind and activate antithrombin III to inactivate blood clotting proteases. Heparin and heparin derivatives might have a direct beneficial effect in APS via binding to beta2GPI and interfering with prothrombotic properties of beta2GPI/antibody complexes. We compared fondaparinux to heparin regarding its ability to bind beta2GPI and inhibit the binding of beta2GPI/antibody complexes to negatively charged phospholipids and endothelial cells. Although heparin and fondaparinux bind beta2GPI at therapeutically relevant doses, neither fondaparinux nor heparin was efficient in inhibition of the binding of beta2GPI/antibody complexes to negatively charged phospholipids and endothelial cells. Our studies suggest that these drugs do not act on pathological properties of beta2GPI/antibody complexes, emphasizing the need for a new treatment specific for beta2GPI-related thrombosis in APS. We observed that the binding interface of fondaparinux on beta2GPI does not include the lysine residues known to be critical for binding of heparin. The docking model of the beta2GPI complex with fondaparinux is in agreement with multiple experimental observations. PMID- 23811003 TI - Selection and validation of endogenous controls for microRNA expression studies in endometrioid endometrial cancer tissues. AB - OBJECTIVES: microRNAs comprise a family of small, non-coding RNAs, which regulate gene expression at the posttranscriptional level. Multiple studies implicated important roles of microRNAs in various malignancies including endometrioid endometrial carcinoma (EEC). qPCR is widely used in the studies investigating microRNA expression. Relative quantification of microRNA expression requires proper normalization methods and endogenous controls are widely used for this purpose. The aim of this study was experimental identification of stable endogenous controls for normalization of microRNA qPCR expression studies in EEC. METHODS: Expression of twelve candidate endogenous controls (miR-16, miR-26b, miR 92a, RNU44, RNU48, U75, U54, U6, U49, RNU6B, RNU38B, U18A) was investigated in tissue samples obtained from 45 patients (30 EEC, 15 normal endometrium) using qPCR. Stability of candidate endogenous controls was evaluated using NormFinder, geNorm, BestKeeper and equivalency test. The results were then validated using larger group of samples. RESULTS: RNU48, U75 and RNU44 were identified as stably and equivalently expressed between malignant and normal tissues. Both NormFinder and geNorm indicated that those three snRNAs were optimal for qPCR data normalization in EEC tissues. CONCLUSIONS: In conclusion, we suggest that average expression of those snoRNAs could be used as a reliable endogenous control in microRNA qPCR studies in endometrioid endometrial cancer. In addition to identifying suitable endogenous controls in EEC, our study presents an appropriate strategy for validation of candidate reference genes for any microRNA qPCR study. PMID- 23811004 TI - A novel upregulation of glutathione peroxidase 1 by knockout of liver regenerating protein Reg3beta aggravates acetaminophen-induced hepatic protein nitration. AB - Murine regenerating islet-derived 3beta (Reg3beta) represents a homologue of human hepatocarcinoma-intestine-pancreas/pancreatic-associated protein and enhances mouse susceptibility to acetaminophen (APAP)-induced hepatotoxicity. Our objective was to determine if and how knockout of Reg3beta (KO) affects APAP (300 mg/kg, ip)-mediated protein nitration in mouse liver. APAP injection produced greater levels of hepatic protein nitration in the KO than in the wild-type mice. Their elevated protein nitration was alleviated by a prior injection of recombinant mouse Reg3beta protein and was associated with an accelerated depletion of the peroxynitrite (ONOO(-)) scavenger glutathione by an upregulated hepatic glutathione peroxidase-1 (GPX1) activity. The enhanced GPX1 production in the KO mice was mediated by an 85% rise (p<0.05) in the activity of selenocysteine lyase (Scly), a key enzyme that mobilizes Se for selenoprotein biosynthesis. Knockout of Reg3beta enhanced AP-1 protein and its binding activity to the Scly gene promoter, upregulating its gene transcription. However, knockout of Reg3beta did not affect gene expression of other key factors for selenoprotein biosynthesis. In conclusion, our findings unveil a new metabolic role for Reg3beta in protein nitration and a new biosynthesis control of GPX1 by a completely "unrelated" regenerating protein, Reg3beta, via transcriptional activation of Scly in coping with hepatic protein nitration. Linking selenoproteins to tissue regeneration will have profound implications in understanding the mechanism of Se functions and physiological coordination of tissue regeneration with intracellular redox control. PMID- 23811005 TI - Therapeutic efficacy and molecular mechanisms of snake (Walterinnesia aegyptia) venom-loaded silica nanoparticles in the treatment of breast cancer- and prostate cancer-bearing experimental mouse models. AB - The treatment of drug-resistant cancer is a clinical challenge, and thus screening for novel anticancer drugs is critically important. We recently demonstrated a strong enhancement of the antitumor activity of snake (Walterinnesia aegyptia) venom (WEV) in vitro in breast carcinoma, prostate cancer, and multiple myeloma cell lines but not in normal cells when the venom was combined with silica nanoparticles (WEV+NP). In the present study, we investigated the in vivo therapeutic efficacy of WEV+NP in breast cancer- and prostate cancer-bearing experimental mouse models. Xenograft breast and prostate tumor mice models were randomized into 4 groups for each cancer model (10 mice per group) and were treated with vehicle (control), NP, WEV, or WEV+NP daily for 28 days post tumor inoculation. The tumor volumes were monitored throughout the experiment. On Day 28 post tumor inoculation, breast and prostate tumor cells were collected and either directly cultured for flow cytometry analysis or lysed for Western blot and ELISA analysis. Treatment with WEV+NP or WEV alone significantly reduced both breast and prostate tumor volumes compared to treatment with NP or vehicle alone. Compared to treatment with WEV alone, treatment of breast and prostate cancer cells with WEV+NP induced marked elevations in the levels of reactive oxygen species (ROS), hydroperoxides, and nitric oxide; robust reductions in the levels of the chemokines CXCL9, CXCL10, CXCL12, CXCL13, and CXCL16 and decreased surface expression of their cognate chemokine receptors CXCR3, CXCR4, CXCR5, and CXCR6; and subsequent reductions in the chemokine-dependent migration of both breast and prostate cancer cells. Furthermore, we found that WEV+NP strongly inhibited insulin-like growth factor 1 (IGF-1)- and epidermal growth factor (EGF)-mediated proliferation of breast and prostate cancer cells, respectively, and enhanced the induction of apoptosis by increasing the activity of caspase-3,-8, and -9 in both breast and prostate cancer cells. In addition, treatment of breast and prostate cancer cells with WEV+NP or WEV alone revealed that the combination of WEV with NP robustly decreased the phosphorylation of AKT, ERK, and IkappaBalpha; decreased the expression of cyclin D1, surviving, and the antiapoptotic Bcl-2 family members Bcl-2, Bcl-XL, and Mcl-1; markedly increased the expression of cyclin B1 and the proapoptotic Bcl-2 family members Bak, Bax, and Bim; altered the mitochondrial membrane potential; and subsequently sensitized tumor cells to growth arrest. Our data reveal the therapeutic potential of the nanoparticle-sustained delivery of snake venom against different cancer cell types. PMID- 23811006 TI - Determination of malondialdehyde in biological fluids by high-performance liquid chromatography using rhodamine B hydrazide as the derivatization reagent. AB - Malondialdehyde (MDA) is a biomarker for lipid peroxidation, and studies of sensitive and selective analytical methods for it are very important for pathological research. The aim of this work was to develop and validate a novel HPLC method for the quantification of MDA in biological fluids using rhodamine B hydrazide (RBH) as the derivatization reagent. After pretreatment and derivatization in acid medium at 50 degrees C for 40 min, the RBH-derivatized MDA was separated on a Kromasil C18 column at 25 degrees C and detected by a fluorescence detector at excitation wavelength of 560 nm and emission wavelength of 580 nm. The results showed linearity in the range of 0.8-1500.0 nM with a detection limit of 0.25 nM (S/N = 3). The recovery of MDA from plasma and urine was 91.50 to 99.20%, with a relative standard deviation range of 1.45 to 3.26%. In comparison to other methods reported for the determination of MDA, the proposed method showed superiority in simplicity, more sensitivity, shorter derivatization time, and less interference. The developed method was applied to quantification of MDA in human biological fluids collected from five volunteers with a concentration range of 24.62-245.00 nM. PMID- 23811007 TI - The inclusion complex of 4-hydroxynonenal with a polymeric derivative of beta cyclodextrin enhances the antitumoral efficacy of the aldehyde in several tumor cell lines and in a three-dimensional human melanoma model. AB - 4-Hydroxynonenal (HNE) is the most studied end product of the lipoperoxidation process, by virtue of its relevant biological activity. The antiproliferative and proapoptotic effects of HNE have been widely demonstrated in a great variety of tumor cell types in vitro. Thus, it might represent a promising new molecule in anticancer therapy strategies. However, the extreme reactivity of this aldehyde, as well as its insolubility in water, a limiting factor for drug bioavailability, and its rapid degradation by specific enzymes represent major obstacles to its possible in vivo application. Various strategies can used to overcome these problems. One of the most attractive strategies is the use of nanovehicles, because loading drugs into nanosized structures enhances their stability and solubility, thus improving their bioavailability and their antitumoral effectiveness. Several natural or synthetic polymers have been used to synthesize nanosized structures and, among them, beta-cyclodextrin (betaCD) polymers are playing a very important role in drug formulation by virtue of the ability of betaCD to form inclusion compounds with a wide range of solid and liquid molecules by molecular complexation. Moreover, several betaCD derivatives have been designed to improve their physicochemical properties and inclusion capacities. Here we report that the inclusion complex of HNE with a derivative of betaCD, the betaCD-poly(4-acryloylmorpholine) conjugate (PACM-betaCD), enhances the aldehyde stability. Moreover, the inclusion of HNE in PACM-betaCD potentiates its antitumor effects in several tumor cell lines and in a more complex system, such as a human reconstructed skin carrying melanoma tumor cells. PMID- 23811008 TI - Targeted paclitaxel nanoparticles modified with follicle-stimulating hormone beta 81-95 peptide show effective antitumor activity against ovarian carcinoma. AB - The majority of patients with advanced ovarian cancer will experience a relapse and ultimately die from refractory diseases. Targeted therapy shows promise for these patients. Novel therapeutic strategies should be developed on the basis of the molecular mechanisms involved in ovarian cancer and the steroid hormone environment of ovaries. The ovary is the main target organ of follicle stimulating hormone (FSH), which bind to its receptor with high affinity. In this study a FSH receptor-targeting ligand, FSH beta 81-95 peptide, was used as a targeting moiety to synthesize an FSH receptor-mediated drug delivery system. FSH beta 81-95 peptide-conjugated nanoparticles (FSH81-NPs) and paclitaxel-loaded FSH81-NPs (FSH81-NP-PTXs) were synthesized. In vitro studies showed that FSH beta 81-95 peptide enabled the specific uptake of cytotoxic drugs and increased the intracellular paclitaxel concentration in FSH receptor-expressing cancer cells, resulting in enhanced cytotoxic effects. In vivo studies showed that FSH81-NP PTXs possessed higher antitumor efficacy against FSH receptor-expressing tumors without any clinical signs of adverse side effects or body weight loss due to modification with FSH beta 81-95 peptide. Therefore, FSH binding peptide-targeted drug delivery system exhibited high potential in the treatment of ovarian cancer, and tumor targeting via reproductive hormone receptors might improve the outcome of diseases. PMID- 23811009 TI - Time to first cigarette predicts cessation outcomes in adolescent smokers. AB - INTRODUCTION: This study examined the relationship between the time to the first cigarette (TTFC) of the morning with quit status among adolescent smokers at the completion of a school-based smoking cessation program. Among those who did not quit, the relationship of TTFC with changes in cigarettes/day (CPD) was also examined. METHODS: A total of 1,167 adolescent smokers (1,024 nonquitters and 143 quitters) from 4 states participating in efficacy and effectiveness studies of the Not-On-Tobacco (N-O-T) cessation program were assessed prior to entry into the program and again 3 months later at the end of treatment. Linear and logistic regression analyses determined the influence of treatment condition, age, gender, motivation to quit, confidence in quitting ability, baseline CPD, and TTFC on quit status and end-of-treatment CPD. RESULTS: Adolescents with a TTFC of >30min of waking were twice as likely to quit at end of treatment. Additionally, among those who did not quit at end of treatment (n = 700 for TTFC <=30min and n = 324 for TTFC for >30min), those with a TTFC within 30min of waking smoked a greater number of CPD. The relationships of TTFC with both of these outcomes remained when controlling for all other predictor variables. CONCLUSIONS: Identifying adolescent smokers who smoke their first cigarette of the day within the first 30min of waking prior to a quit attempt may help to classify those individuals as having a greater risk for cessation failure. Thus, TTFC may be a behavioral indicator of nicotine dependence in adolescents. PMID- 23811010 TI - Role transitions in emerging adulthood are associated with smoking among Hispanics in Southern California. AB - INTRODUCTION: Smoking initiation seldom occurs after emerging adulthood, making prevention critical during this phase of the life course. Among emerging adults, Hispanics have an especially high risk for cigarette use. Emerging adulthood scholars suggest role transitions commonly experienced by this age group may lead to substance use including cigarette experimentation and/or progression, contributing to the high smoking rates exhibited by Hispanics. METHODS: Hispanic emerging adults (aged 18-24) completed surveys indicating which of a comprehensive list of role transitions they had experienced in the past year. Separate logistic regression models explored the association between each individual role transition and smoking in the past 30 days, controlling for age and gender and using a Bonferonni correction. RESULTS: Among the sample of emerging adults (n = 1,390), 41% were male, the average age was 21, and about 21% reported cigarette use in the past 30 days. Losing a job, becoming a family member's caregiver, starting to date someone new, experiencing a breakup, being arrested, and becoming addicted to illicit drugs and/or alcohol were all associated with smoking. CONCLUSIONS: The stress associated with navigating through changes in critical periods of the life course may lead some emerging adults to smoke. Future research should be directed toward determining what specific mechanisms make these transitional processes risk factors for smoking. These determinations could prove critical if effective prevention programs are to be designed that lead to a decrease in the smoking prevalence among Hispanic emerging adults. PMID- 23811011 TI - Evaluation of use of stage of tobacco epidemic to predict post-immigration smoking behaviors. AB - INTRODUCTION: This research uses the Lopez stage of tobacco epidemic model to evaluate post-immigration smoking behavior. Stage is a composite measure of tobacco norms of a country: smoking prevalence, cigarette consumption, and tobacco-related morbidity. The Lopez model characterizes the changing relationship between smoking prevalence and tobacco-related mortality and morbidity as a country progresses through the 4 successive stages of the tobacco epidemic. METHODS: Survey data from Southeast Asian and Latino immigrants (from stage 1 and stage 2 countries) (n = 2,076) were used to evaluate stage of tobacco epidemic of country of emigration. Stage was compared with standard acculturation measures and community identification measures to understand post-immigration smoking behavior in the United States. Comparative analysis by stage and gender includes bivariate associations and logistic regression models to predict post immigration smoking behavior. RESULTS: Males:Pre-immigration prevalence and consumption rates of our study sample conform to prevalence and consumption of stage 1 and stage 2 countries predicted by the Lopez model. Post-immigration smoking uptake is equivalent to pre-immigration uptake for stage 1 males. The uptake rate for stage 2 males post-immigration is significantly lower (22.1%) than pre-immigration uptake (41.4%). Stage is a statistically significant predictor of post-immigration smoking uptake (OR = 3.08, CI = 1.82-5.22, p < .01). Females:Stage of country of birth is not significantly predictive of post migration smoking uptake. CONCLUSIONS: The finding of stage to be a strong predictor of post-immigration smoking behavior among males provides a promising measurement tool. Prevalence and consumption of females in our study sample support the need for revisions to the stage model. PMID- 23811012 TI - Hepatitis B in Ghana's upper west region: a hidden epidemic in need of national policy attention. AB - Like many countries in Sub-Saharan Africa, Hepatitis B virus (HBV) is highly prevalent in Ghana. Using qualitative methods, this paper draws from the political ecology of health theoretical framework to examine perceptions and understandings of HBV in the Upper West Region of Ghana. The findings reveal that extremely low levels of knowledge and pervasive lay misconceptions about the disease within this geographic context are shaped by large scale structural influences. Furthermore, in this context there is essentially no access to HBV immunizations, testing or treatment services which reinforces potential routes for the spread of HBV. An explosive spread of HBV is brewing with the potential to diffuse across space and time while, within the institutional contexts, it is the HIV epidemic that is largely consuming both policy attention and intervention. PMID- 23811013 TI - Increased odor detection speed in highly anxious healthy adults. AB - Anxiety can either impair or enhance performance depending on the context. Increased sensitivity to threat seems to be an important feature of sensory processing in anxiety since anxious individuals tend to be more attentive to threatening visual stimuli. Evidence of anxiety effects in olfaction is rare; though alterations of olfactory performance in psychiatric patients and some effects of trait and state anxiety on olfactory performance have been reported. Our main objective was thus to investigate whether olfactory processing speed varies as a function of trait anxiety levels. We additionally investigated a possible preferential bias for unpleasant odors in highly anxious participants. Thirty-eight healthy adults participated in a simple odor detection task, where response times (RTs) and anxiety levels were measured. We compared RTs to a pleasant and an unpleasant food odor between high- and low-trait anxiety participants. We found that high-trait anxiety participants detected both odors faster than low-trait anxiety participants, independently of odor pleasantness. Moreover, trait anxiety levels significantly correlated with reaction times to both odors, indicating that trait anxiety but not odor pleasantness influences olfactory detection speed. These findings provide new insights into olfactory processing in healthy adults showing how various levels of trait anxiety affect the olfactory modality. PMID- 23811014 TI - Localization of odors can be learned. AB - Chemicals selectively stimulating the olfactory nerve typically cannot be localized in a lateralization task. Purpose of this study was to investigate whether the ability of subjects to localize an olfactory stimulus delivered passively to 1 of the 2 nostrils would improve under training. Fifty-two young, normosmic women divided in 2 groups participated. One group performed olfactory lateralization training, whereas the other group performed cognitive tasks. Results showed that only subjects performing lateralization training significantly improved in their ability to lateralize olfactory stimuli compared with subjects who did not undergo such training. PMID- 23811016 TI - Stromal derived growth factor-1 (CXCL12) modulates synaptic transmission to immature neurons during post-ischemic cerebral repair. AB - In response to ischemic injury, the brain mounts a repair process involving the development of new neurons, oligodendrocytes, and astrocytes. However, the manner in which new neurons integrate into existing brain circuitry is not well understood. Here we observed that during the four weeks after transient middle cerebral artery occlusion (MCAO), doublecortin (DCX)-expressing neural progenitors originating in the subventricular zone (SVZ) were present in the ischemic lesion borderzone, where they received gamma-aminobutyric acid (GABA) inputs, a feature that is common to newly developing neurons. The chemokine stromal derived factor-1 (SDF-1 or CXCL12) was enriched in lesional endothelial and microglial cells for up to four weeks after transient MCAO, and application of SDF-1 to acute brain slices enhanced GABAergic inputs to the new neurons. These observations suggest that SDF-1 is in a position to coordinate neovascularization and neurogenesis during the repair process after cerebral ischemia-reperfusion. PMID- 23811015 TI - HIV-1 Tat protein variants: critical role for the cysteine region in synaptodendritic injury. AB - HIV-1 enters the central nervous system early in infection; although HIV-1 does not directly infect neurons, HIV-1 may cause a variety of neurological disorders. Neuronal loss has been found in HIV-1, but synaptodendritic injury is more closely associated with the neurocognitive disorders of HIV-1. The HIV-1 transactivator of transcription (Tat) protein causes direct and indirect damage to neurons. The cysteine rich domain (residues 22-37) of Tat is important for producing neuronal death; however, little is known about the effects of the Tat protein functional domains on the dendritic network. The ability of HIV-1 Tat 1 101 Clades B and C, Tat 1-86 and Tat 1-72 proteins, as well as novel peptides (truncated 47-57, 1-72delta31-61, and 1-86 with a mutation at Cys22) to produce early synaptodendritic injury (24h), relative to later cell death (48h), was examined using cell culture. Treatment of primary hippocampal neurons with Tat proteins 1-72, 1-86 and 1-101B produced a significant early reduction in F-actin labeled puncta, implicating that these peptides play a role in synaptodendritic injury. Variants with a mutation, deletion, or lack of a cysteine rich region (1 86[Cys22], 1-101C, 1-72delta31-61, or 47-57) did not cause a significant reduction in F-actin rich puncta. Tat 1-72, 1-86, and 1-101B proteins did not significantly differ from one another, indicating that the second exon (73-86 or 73-101) does not play a significant role in the reduction of F-actin puncta. Conversely, peptides with a mutation, deletion, or lack of the cysteine rich domain (22-37) failed to produce a loss of F-actin puncta, indicating that the cysteine rich domain plays a key role in synaptodendritic injury. Collectively, these results suggest that for Tat proteins, 1) synaptodendritic injury occurs early, relative to cell death, and 2) the cysteine rich domain of the first exon is key for synaptic loss. Preventing such early synaptic loss may attenuate HIV-1 associated neurocognitive disorders. PMID- 23811017 TI - Changes in mammary secretory tissue during lactation in ovariectomized dairy cows. AB - In dairy animals, the milk yield (MY) changes during a lactation and is influenced by several physiological, livestock management and environmental factors. The MY produced by a mammary gland depends on synthetic activity of mammary epithelial cells (MECs) as well as MEC number and mammary secretory tissue organization. It has been suggested that ovarian steroids (estradiol and progesterone) have a negative effect on MY in lactating cows. In a previous study, we showed that the suppression of ovarian secretions by an ovariectomy improved lactation persistency in dairy cows. Here we were interested in the effects of ovariectomy on plasma estradiol and progesterone concentrations and on changes that occur in mammary secretory tissue during lactation. We demonstrated that the ovariectomy of lactating cows at the time of the lactation peak induced a rapid and dramatic drop in plasma progesterone and a smaller reduction in plasma estradiol. Interestingly, the study of the changes in mammary secretory tissue over time revealed that the improvement of MY measured in the ovariectomized cows was associated with a limited increase in estradiol receptivity in MECs, a reduced mammary tissue remodeling and reduced blood protein concentration in milk, in late lactation. These results suggest that ovarian secretions, particularly estradiol and progesterone, act to enhance processes for mammary gland involution in late-lactating dairy cows. PMID- 23811018 TI - Synthesis and crystallographic study of 1,25-dihydroxyergocalciferol analogs. AB - The hybrid analogs of 1,25-dihydroxyergocalciferol (PRI-5201 and PRI-5202) were synthesized as potential anticancer agents using a convergent strategy. The analogs were designed by combining a 19-nor modification of the A-ring with the homologated and rigidified ergocalciferol-like side-chain of the previously obtained analogs PRI-1906 and PRI-1907. The strategy also allowed the novel efficient synthesis of 19-nor-1,25-dihydroxyergocalciferol (paricalcitol, PRI 5100) and its (24R)-diastereomer (PRI-5101). The single crystal X-ray structures of the 19-nor analogs (PRI-5100 and PRI-5101) were solved and refined. The A-ring of both analogs adopts exclusively chair beta-conformation in the solid state. The side-chain of these analogs is coplanar with the CD-ring plane, while it is perpendicular in 1,25-dihydroxycholecalciferol. PMID- 23811019 TI - A synthetic steroid 5alpha-androst-3beta,5,6beta-triol blocks hypoxia/reoxygenation-induced neuronal injuries via protection of mitochondrial function. AB - Ischemic stroke is a leading cause of death worldwide, yet therapies are limited. During periods of ischemia following reperfusion in ischemic stroke, not only loss of energy supply, but a few other factors including mitochondrial dysfunction and oxidative stress also make vital contribution to neuronal injury. Here we synthesized a steroid compound 5alpha-androst-3beta,5,6beta-triol by 3 steps starting from dehydroepiandrosterone and examined its effect on mitochondrial function and oxidative stress in primary cultured cortical neurons exposed to hypoxia followed by reoxygenation. 5alpha-Androst-3beta,5,6beta-triol dose-dependently protected cortical neurons from hypoxia/reoxygenation exposure. Rates of reduction in neuronal viability, loss of mitochondrial membrane potential, disruption of ATP production and oxidative stress were ameliorated in 5alpha-androst-3beta,5,6beta-triol pretreated cultures. In summary, these results suggest that 5alpha-androst-3beta,5,6beta-triol is neuroprotective against hypoxia/reoxygenation induced neuronal injuries through mediation of mitochondrial function and oxidative stress. PMID- 23811020 TI - Host-lipidome as a potential target of protozoan parasites. AB - Host-lipidome caters parasite interaction by acting as first line of recognition, attachment on the cell surface, intracellular trafficking, and survival of the parasite inside the host cell. Here, we summarize how protozoan parasites exploit host-lipidome by suppressing, augmenting, engulfing, remodeling and metabolizing lipids to achieve successful parasitism inside the host. PMID- 23811021 TI - Temporal variation of Trypanosoma cruzi discrete typing units in asymptomatic Chagas disease patients. AB - Chagas disease caused by Trypanosoma cruzi is a public health problem in Latin America. This parasite displays a high genetic diversity evidenced in six Discrete Typing Units (DTUs) namely TcI-TcVI. The aim of this study was to observe the temporal variation of the DTUs in asymptomatic patients at three different times (10 days interval). The results showed that intermittence is the rule in the bloodstream of Chagas disease patients. The patients showed different detectable DTUs with short time intervals, which favors the clonal histiotropic model and the multiclonality structure of this parasite. PMID- 23811022 TI - Experimental in situ exposure of the seagrass Posidonia oceanica (L.) Delile to 15 trace elements. AB - The Mediterranean seagrass Posidonia oceanica (L.) Delile has been used for trace element (TE) biomonitoring since decades ago. However, present informations for this bioindicator are limited mainly to plant TE levels, while virtually nothing is known about their fluxes through P. oceanica meadows. We therefore contaminated seagrass bed portions in situ at two experimental TE levels with a mix of 15 TEs (Al, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Mo, Ag, Cd, Pb and Bi) to study their uptake and loss kinetics in P. oceanica. Shoots immediately accumulated pollutants from the beginning of exposures. Once contaminations ended, TE concentrations came back to their original levels within two weeks, or at least showed a clear decrease. P. oceanica leaves exhibited different uptake kinetics depending on elements and leaf age: the younger growing leaves forming new tissues incorporated TEs more rapidly than the older senescent leaves. Leaf epiphytes also exhibited a net uptake of most TEs, partly similar to that of P. oceanica shoots. The principal route of TE uptake was through the water column, as no contamination of superficial sediments was observed. However, rhizomes indirectly accumulated many TEs during the overall experiments through leaf to rhizome translocation processes. This study thus experimentally confirmed that P. oceanica shoots are undoubtedly an excellent short-term bioindicator and that long-term accumulations could be recorded in P. oceanica rhizomes. PMID- 23811023 TI - Immunomodulating effects of environmentally realistic copper concentrations in Mytilus edulis adapted to naturally low salinities. AB - The monitoring of organisms' health conditions by the assessment of their immunocompetence may serve as an important criterion for the achievement of the Good Environmental Status (GES) as defined in the Marine Strategy Framework Directive (EU). In this context, the complex role of natural environmental stressors, e.g. salinity, and interfering or superimposing effects of anthropogenic chemicals, should be carefully considered, especially in scenarios of low to moderate contamination. Organisms from the Baltic Sea have adapted to the ambient salinity regime, however energetically costly osmoregulating processes may have an impact on the capability to respond to additional stress such as contamination. The assessment of multiple stressors, encompassing natural and anthropogenic factors, influencing an organisms' health was the main aim of the present study. Immune responses of Mytilus edulis, collected and kept at natural salinities of 120/00 (LS) and 200/00 (MS), respectively, were compared after short-term exposure (1, 7 and 13 days) to low copper concentrations (5, 9 and 16 MUg/L Cu). A significant interaction of salinity and copper exposure was observed in copper accumulation. LS mussels accumulated markedly more copper than MS mussels. No combined effects were detected in cellular responses. Bacterial clearance was mostly achieved by phagocytosis, as revealed by a strong positive correlation between bacterial counts and phagocytic activity, which was particularly pronounced in LS mussels. MS mussels, on the other hand, seemingly accomplished bacterial clearance by employing additional humoral factors (16 MUg/L Cu). The greatest separating factor in the PCA biplot between LS and MS mussels was the proportion of granulocytes and hyalinocytes while functional parameters (phagocytic activity and bacterial clearance) were hardly affected by salinity, but rather by copper exposure. In conclusion, immune responses of the blue mussel may be suitable and sensitive biomarkers for the assessment of ecosystem health in brackish waters (10-200/00S). PMID- 23811024 TI - Organic solvents impair life-traits and biomarkers in the New Zealand mudsnail Potamopyrgus antipodarum (Gray) at concentrations below OECD recommendations. AB - Potamopyrgus antipodarum is a gastropod mollusk proposed for use in the development of reproduction tests within the Organization for Economic Cooperation and Development (OECD). Numerous chemicals, including endocrine disrupters, are relatively water-insoluble, and water-miscible solvents are currently used for testing them. OECD recommends a maximum concentration of 100 MUll(-1). As several studies highlighted effects of lower concentrations of solvents, this study assessed the effects of 20 MUll(-1) acetone, ethanol, methanol and dimethylsulfoxide (DMSO) on juvenile and adult snails during 42 days. Ethanol decreased juvenile growth, while acetone increased the rate of embryonic development. All solvents increased estradiol-like levels in adult snails. DMSO only increased mRNA expression of vitellogenin-like gene, while acetone, ethanol and methanol decreased mRNA expression of three nuclear receptor (estrogen receptor-like, ecdysone-induced protein and chicken ovalbumin upstream promoter transcription factor) genes as well as of genes encoding proteins involved in genomic (prohibitin-2) and non-genomic (striatin) pathways of estrogens activity in vertebrates. This study highlights the confounding effects of low concentrations of solvents and recommends avoiding their use. Where solvent use is inevitable, their concentrations and type should be investigated for suitability for the measured endpoints prior to use in chemical testing strategies. PMID- 23811025 TI - Mice selectively bred for High and Low fear behavior show differences in the number of pMAPK (p44/42 ERK) expressing neurons in lateral amygdala following Pavlovian fear conditioning. AB - Individual variability in the acquisition, consolidation and extinction of conditioned fear potentially contributes to the development of fear pathology including posttraumatic stress disorder (PTSD). Pavlovian fear conditioning is a key tool for the study of fundamental aspects of fear learning. Here, we used a selected mouse line of High and Low Pavlovian conditioned fear created from an advanced intercrossed line (AIL) in order to begin to identify the cellular basis of phenotypic divergence in Pavlovian fear conditioning. We investigated whether phosphorylated MAPK (p44/42 ERK/MAPK), a protein kinase required in the amygdala for the acquisition and consolidation of Pavlovian fear memory, is differentially expressed following Pavlovian fear learning in the High and Low fear lines. We found that following Pavlovian auditory fear conditioning, High and Low line mice differ in the number of pMAPK-expressing neurons in the dorsal sub nucleus of the lateral amygdala (LAd). In contrast, this difference was not detected in the ventral medial (LAvm) or ventral lateral (LAvl) amygdala sub nuclei or in control animals. We propose that this apparent increase in plasticity at a known locus of fear memory acquisition and consolidation relates to intrinsic differences between the two fear phenotypes. These data provide important insights into the micronetwork mechanisms encoding phenotypic differences in fear. Understanding the circuit level cellular and molecular mechanisms that underlie individual variability in fear learning is critical for the development of effective treatment of fear-related illnesses such as PTSD. PMID- 23811026 TI - Midkine overcomes neurite outgrowth inhibition of chondroitin sulfate proteoglycan without glial activation and promotes functional recovery after spinal cord injury. AB - Injuries in the mammalian central nervous system induce a variety of factors which promote or inhibit neuronal axon regeneration/sprouting. However, the inhibitory activities are much stronger, and indeed are the major obstacle to functional recovery. Chondroitin sulfate proteoglycans (CSPGs) are produced by activated glial cells, and are among the strongest inhibitors. Here, we investigated the role of the growth factor midkine (MK), which binds to CSPGs, in neuronal injury. MK expression was induced by spinal cord injury, and was mainly produced by activated astrocytes. A prolonged culture of neurons also produced MK. MK not only enhanced neurite outgrowth on the substratum coated with poly-l lysine, but also overcame the neurite growth inhibition by the CSPG substratum. Moreover, we found that MK activated neither astrocytes nor microglia as evaluated by morphological changes and cell proliferation or nitric oxide production. These properties would be advantageous for the treatment of neuronal injuries in vivo. Therefore, we next explored the therapeutic effect of MK in a rat spinal cord injury model. MK or vehicle was administered intrathecally for 2 weeks using an osmotic pump after spinal cord contusion injury. Rats treated with MK showed significantly better functional recovery after 5 weeks. These results suggest that MK may offer a potent alternative for the treatment of neuronal injuries without activating glial cells. PMID- 23811027 TI - Correlation of Abeta oligomer levels in matched cerebrospinal fluid and serum samples. AB - We recently reported a newly developed enzyme-linked immunosorbent assay (ELISA) for high molecular weight amyloid-beta (Abeta) oligomers in which the same Abeta monoclonal antibody, BAN50, was used for both capture and detection in a single antibody sandwich enzyme linked immunosorbent assay (ELISA) system. Although our previous data have suggested that this assay will be useful for the early diagnosis of Alzheimer disease (AD) in cerebrospinal fluid (CSF) samples, the invasive CSF sampling procedure, with associated potential complications, limits use of these samples in routine clinical practice. In this study, we have demonstrated that our ELISA can detect signals in 60% of serum samples and in 80% of CSF samples obtained from non-demented subjects. Heterophilic antibodies that are reported to be a primary confounding factor in this type of ELISA system did not affect the signals obtained. Although the levels of serum Abeta oligomers were unexpectedly high, suggesting the possible detection of non-pathological Abeta complexes associated with serum carrier proteins, they did show a significant positive correlation with the levels obtained from matched CSF samples. This correlation between CSF and serum Abeta oligomer levels implies that the levels of serum Abeta oligomers measured with our ELISA might be useful as a marker for AD that reflects an intact system of Abeta transport across the blood brain barrier. PMID- 23811028 TI - Association of MTHFR C677T polymorphism with susceptibility to migraine in the Chinese population. AB - A number of genes have been implicated in the pathogenesis of migraine, a common neurological disorder also in China. However, data on association of genetic variations with migraine susceptibility among Chinese, which might be different from people of other ethnic background, are still scarce. We have therefore investigated the association of polymorphisms in four genes, MTHFR C677T, ACE I/D, MAOA T941G and TNF-beta G252A, which are considered to be with risk of migraine. A case-control study including a cohort of 151 migraine cases and 137 ethnically matched controls was conducted. The genotypes of each polymorphism followed the Hardy-Weinberg equilibrium in the two groups. Genotypic distribution of MTHFR C677T was significantly different with higher frequency of allele T in the migraine cohort as compared with that in controls (OR=1.686, 95%CI: 1.175 2.420, P=0.004). No difference was found between migraine with aura (MA) patients and controls, but T allele frequency was significantly higher in migraine without aura (MO) than in controls (OR=1.744, 95% CI: 1.202-2.532, P=0.003). No difference in genotypic and allelic distributions was observed between migraine patients and controls for the other polymorphisms, including ACE I/D, MAOA T941G, and TNF-beta G252A. Our data suggested that MTHFR C677T polymorphism plays a role in Chinese migraine susceptibility, especially in MO. PMID- 23811029 TI - Pharmacological study of cholinergic system on cardiovascular regulation in the cuneiform nucleus of rat. AB - In the present study the effect of cholinergic system of Cuneiform nucleus (CnF) on central regulation of cardiovascular system was investigated. Two doses of acetylcholine (Ach; 90 and 150 nmol), atropine (3 and 9 nmol) and hexamethonium (Hexa; 100 and 300 nmol) were microinjected into the CnF. The maximum changes of MAP and HR were compared with control group (independent t-test). Both doses of Ach significantly decreased MAP but had no significant effect on HR. Administration of atropine and Hexa by themselves did not alter the MAP or HR. However, both doses of atropine and higher dose of Hexa significantly attenuated the hypotensive effect of Ach with no significant effect on HR. Our results suggest the involvement of CnF cholinergic system only on central blood pressure regulation that strongly mediated by muscarinic receptors. PMID- 23811031 TI - Valuing the chances of survival of two distinct Eurasian lynx populations in Poland - do people want to keep the doors open? AB - This study investigates individuals' preferences toward protection programs aimed at increasing the chances of survival of the two distinct Eurasian lynx populations in Poland. Those two groups, the Lowland and the Carpathian population, are exposed to different risks of extinction as they have different numbers, different-sized areas of occupation and different migration possibilities. Using a discrete choice experiment we examine the influence of the initial degree of endangerment on the allocation of respondents' funds. The results show that people prefer to invest in the conservation of the lynx population, which has initially lower chances of survival. The main driver of respondents' choices seems to be loss aversion rather than the urge to invest in an option with an expected higher outcome. This observation can be interpreted as people trying to keep all the options - doors - open by devoting more funds to the more vulnerable population than to the more stable one. Employing a scale extended latent class model allowed us to detect segments among individuals showing different types of response behavior, including a form of serial non participation. PMID- 23811030 TI - A multidisciplinary support programme increases the efficiency of pegylated interferon alfa-2a and ribavirin in hepatitis C. AB - BACKGROUND & AIMS: Adherence to antiviral treatment is important to achieve sustained virological response (SVR) in chronic hepatitis C (CHC). We evaluated the efficiency of a multidisciplinary support programme (MSP), based on published HIV treatment experience, to increase patient adherence and the efficacy of pegylated interferon alfa-2a and ribavirin in CHC. METHODS: 447 patients receiving antiviral treatment were distributed into 3 groups: control group (2003 2004, n=147), MSP group (2005-2006, n=131), and MSP-validation group (2007-2009, n=169). The MSP group included two hepatologists, two nurses, one pharmacist, one psychologist, one administrative assistant, and one psychiatrist. Cost effectiveness analysis was performed using a Markov model. RESULTS: Adherence and SVR rates were higher in the MSP (94.6% and 77.1%) and MSP-validation (91.7% and 74.6%) groups compared to controls (78.9% and 61.9%) (p<0.05 in all cases). SVR was higher in genotypes 1 or 4 followed by the MSP group vs. controls (67.7% vs. 48.9%, p=0.02) compared with genotypes 2 or 3 (87.7% vs. 81.4%, p=n.s.). The MSP was the main predictive factor of SVR in patients with genotype 1. The rate of adherence in patients with psychiatric disorders was higher in the MSP groups (n=95, 90.5%) compared to controls (n=28, 75.7%) (p=0.02). The cost per patient was ? 13,319 in the MSP group and ? 16,184 in the control group. The MSP group achieved more quality-adjusted life years (QALYs) (16.317 QALYs) than controls (15.814 QALYs) and was dominant in all genotypes. CONCLUSIONS: MSP improves patient compliance and increases the efficiency of antiviral treatment in CHC, being cost-effective. PMID- 23811032 TI - The Bartonella henselae SitABCD transporter is required for confronting oxidative stress during cell and flea invasion. AB - Bartonella henselae is a zoonotic pathogen that possesses a flea-cat-flea transmission cycle and causes cat scratch disease in humans via cat scratches and bites. In order to establish infection, B. henselae must overcome oxidative stress damage produced by the mammalian host and arthropod vector. B. henselae encodes for putative Fe2+ and Mn2+ transporter SitABCD. In B. henselae, SitAB knockdown increases sensitivity to hydrogen peroxide. We consistently show that SitAB knockdown decreases the ability of B. henselae to survive in both human endothelial cells and cat fleas, thus demonstrating that the SitABCD transporter plays an important role during the B. henselae infection cycle. PMID- 23811034 TI - A clinical molecular genetic service for United Kingdom families with choroideraemia. AB - A diagnosis of choroideraemia (CHM) can be made clinically, based on the fundus examination and a family history consistent with X-linked inheritance. Molecular genetic testing offers a means of confirming the clinical diagnosis, establishing carrier status and allows presymptomatic diagnosis for families who wish to pursue these options. The aim of this study was to examine the uptake and assess the results from a diagnostic molecular genetics service for CHM. We have carried out a comprehensive audit of all molecular genetic results of UK NHS patients and families referred to the North West Regional Molecular Genetics Laboratory in Manchester, UK over a 55 month period. 110 people were referred to this service for testing including diagnostic, carrier and predictive requests. Putative pathogenic mutations were identified in 65/83 (78%) of male index cases. The identification of a familial pathogenic change enabled carrier testing in 16 asymptomatic females and predictive testing in 3 males. Case examples illustrate the range of cases referred for testing and also reflect the need for genetic counselling that results from offering a molecular diagnostic service such as this. Clinical molecular testing for CHM is available clinically and can be used to support the clinical diagnosis and management of patients with choroideraemia as well as their families. Case studies demonstrate the need to provide genetic testing to families and the potential clinical utility of testing. PMID- 23811035 TI - Normal intelligence and premature ovarian failure in an adult female with a 7.6 Mb de novo terminal deletion of chromosome 9p. AB - Distal deletion 9p is associated with gonadal dysfunction in XY individuals. Little is known about the gonadal function and fertility of XX females with this condition. We report on an affected 31-year-old infertile woman presenting with premature ovarian failure, mild dysmorphic features, a history of mild developmental delay and an otherwise normal female phenotype. Cytogenetic analysis showed a deletion 9p with the karyotype 46,XX,del(9)(p23-24) in lymphocytes. The subsequent oligonucleotide array-based CGH analysis with genomic DNA from peripheral blood revealed a terminal deletion of approximately 7.6 Mb. SNP microarray analyses of the patient and her unaffected parents confirmed the deletion breakpoint and revealed a de novo mutation of paternal origin. This is apparently the first description of an adult woman with a cytogenetically visible terminal deletion of chromosome 9p. The fertility problems observed in this patient complement earlier findings in prepubertal and pubertal 46,XX-girls with 9p deletions, who displayed a phenotype ranging from primary ovarian dysfunction and mild gonadotropin hyperresponses to positive menses. DMRT1 is hemizygous in our patient. We discuss the role of DMRT1 in female gonadal development. PMID- 23811033 TI - Applications of snake venom components to modulate integrin activities in cell matrix interactions. AB - Snake venom proteins are broadly investigated in the different areas of life science. Direct interaction of these compounds with cells may involve a variety of mechanisms that result in diverse cellular responses leading to the activation or blocking of physiological functions of the cell. In this review, the snake venom components interacting with integrins will be characterized in context of their effect on cellular response. Currently, two major families of snake venom proteins are considered as integrin-binding molecules. The most attention has been devoted to the disintegrin family, which binds certain types of integrins through specific motifs recognized as a tri-peptide structurally localized on an integrin-binding loop. Other snake venom integrin-binding proteins belong to the C-type lectin family. Snake venom molecules bind to the cellular integrins resulting in a modulation of cell signaling and in consequence, the regulation of cell proliferation, migration and apoptosis. Therefore, snake venom research on the integrin-binding molecules may have significance in biomedicine and basic cell biology. PMID- 23811036 TI - Charcot-Marie-Tooth 1B caused by expansion of a familial myelin protein zero (MPZ) gene duplication. AB - Charcot-Marie-Tooth (CMT) disease is a group of hereditary disorders affecting the motor and sensory nerves of the peripheral nervous system. CMT patterns of inheritance include dominant, recessive, and X-linked disorders. Charcot-Marie Tooth disease, type 1B (CMT1B, OMIM 118200) is an autosomal dominant neuropathy caused by mutations in myelin protein zero (MPZ, OMIM 159440), a structural protein of peripheral myelin. Most causative MPZ mutations are missense sequence variants; however, recent clinical reports have described cases of CMT1B caused by increased dosage of the MPZ gene, with over-expression of the MPZ protein suspected to be causative of the disorder. We report an unusual case of early onset de novo CMT1B, caused by amplification of a familial, apparently benign, MPZ duplication. PMID- 23811037 TI - Ovarian cancer stem cells: Molecular concepts and relevance as therapeutic targets. AB - In spite of recent progress in cancer therapeutics and increased knowledge about the cellular and molecular biology of cancer, ovarian cancer still remains a clinical challenge. Chemoresistance followed by tumor recurrence are major causes of poor survival rates of ovarian cancer patients. In recent years, ovarian cancer has been described as a stem cell disease. In this scenario, a small percentage of ovarian tumor cells with cancer stem cell-like properties should survive therapeutic treatments by activating the self-renewal and differentiating pathways resulting in tumor progression and clinical recurrence. The mere concept that a small subset of cells in the tumor population drives tumor formation and recurrence after therapies has major implications for therapeutic development. This review focuses on the current understanding of normal and malignant ovarian stem cells in an attempt to contribute to our understanding the mechanisms responsible for tumor development as well as recurrence after chemotherapy. We also discuss recent findings on the cancer stem cell niche and how tumor and associated cells in the niche may respond to chemotherapeutic stress by activating autocrine and paracrine programs which may opt as survival mechanisms for residual cells in response to frontline chemotherapy. Using mouse ovarian cancer models we highlight the role of cancer stem cells in response to chemotherapy, and relate how cancer stem cells may impact on recurrence. Understanding the distinct mechanisms that facilitate cancer stem cell survival and propagation are likely to reveal opportunities for improving the treatment outcomes for ovarian cancer patients. PMID- 23811038 TI - Decarboxylase gene expression and cadaverine and putrescine production by Serratia proteamaculans in vitro and in beef. AB - Studies of the molecular basis of microbial metabolic activities that are important for the changes in food quality are valuable in order to help in understanding the behavior of spoiling bacteria in food. The growth of a psychrotrophic Serratia proteamaculans strain was monitored in vitro and in artificially inoculated raw beef. Two growth temperatures (25 degrees C and 4 degrees C) were tested in vitro, while growth at 15 degrees C and 4 degrees C was monitored in beef. During growth, the expression of inducible lysine and ornithine-decarboxylase genes was evaluated by quantitative reverse transcription PCR (qRT-PCR), while the presence of cadaverine and putrescine was quantified by LC-ESI-MS/MS. The expression of the decarboxylase genes, and the consequent production of cadaverine and putrescine were shown to be influenced by the temperature, as well as by the complexity of the growth medium. Generally, the maximum gene expression and amine production took place during the exponential and early stationary phase, respectively. In addition, lower temperatures caused slower growth and gene downregulation. Higher amounts of cadaverine compared to putrescine were found during growth in beef with the highest concentrations corresponding to microbial loads of ca. 9CFU/g. The differences found in gene expression evaluated in vitro and in beef suggested that such activities are more reliably investigated in situ in specific food matrices. PMID- 23811039 TI - Effect of aging on the cerebral processing of thermal pain in the human brain. AB - The perception of pain changes as people age. However, how aging affects the quality of pain and whether specific pain-processing brain regions mediate this effect is unclear. We hypothesized that specific structures in the cerebral nociceptive system mediate the effect of aging on the variation in different pain psychophysical measures. We examined the relationships between painful heat stimulation to the foot and both functional magnetic resonance imaging signals and gray matter volume in 23 healthy subjects (aged 25~71 years). Increased age was related to decreased subjective ratings of overall pain intensity and the "sharp" quality of pain. Group activation maps of multiple linear regression analyses revealed that age predicted responses in the middle insular cortex (IC) and primary somatosensory cortex (S1) to pain stimuli after controlling for their gray matter volumes. Blood oxygenation level-dependent signals in the contralateral middle IC and S1 were related to ratings of "sharpness," but not any affective descriptors of pain. Importantly, activity in the contralateral middle IC specifically mediated the effect of age on overall pain perception, whereas activity in the contralateral S1 mediated the relationship between age and sharp sensation to pain. The analyses of gray matter volume revealed that key nociceptive cerebral regions did not undergo significant age-related gray matter loss. However, the volume of the cingulate cortex covaried with pain perception after adjusting for corresponding neural activity to pain. These results suggest that age-related functional alterations in pain-processing regions are responsible for changes in pain perception during normal aging. PMID- 23811040 TI - Temporal stability of conditioned pain modulation in healthy women over four menstrual cycles at the follicular and luteal phases. AB - Conditioned pain modulation (CPM) is a phenomenon that may be tested with a dynamic quantitative sensory test that assesses the inhibitory aspect of this pain modulatory network. Although CPM has been adopted as a clinical assessment tool in recent years, the stability of the measure has not been determined over long time intervals. The question of stability over time is crucial to our understanding of pain processing, and critical for the use of this tool as a clinical test. The primary objective of this study was to evaluate the stability of a CPM paradigm over time in healthy women. The secondary objective was to determine the potential influence of menstrual cycle phase on CPM. CPM was assessed 8 times in 22 healthy women during the follicular and luteal phases of 4 different cycles. The CPM effect was evidenced by a reduction in the pain rating of a test stimulus (6.3 +/- 0.2) with the introduction of a conditioning stimulus (5.0 +/- 0.3; P < 0.001). The intraclass correlation coefficient for the CPM effect was modest (0.39; CI = 0.23-0.59), suggesting that there is significant variation in CPM over long time intervals. CPM did not vary across phases in the menstrual cycle. Prior to the adoption of CPM as a clinical tool to predict individual risk and aid diagnosis, additional research is needed to establish the measurement properties of CPM paradigms and evaluate factors that influence CPM effects. PMID- 23811041 TI - Local cytokine changes in complex regional pain syndrome type I (CRPS I) resolve after 6 months. AB - There is evidence that inflammatory processes are involved in at least the early phase of complex regional pain syndrome (CRPS). We compared a panel of pro- and antiinflammatory cytokines in skin blister fluids and serum from patients with CRPS and patients with upper-limb pain of other origin (non-CRPS) in the early stage (< 1 year) and after 6 months of pain treatment. Blister fluid was collected from the affected and contralateral nonaffected side. We used a multiplex-10 bead array cytokine assay and Luminex technology to measure protein concentrations of the cytokines interleukin-1 receptor antagonist (IL-1RA), IL-2, IL-6, IL-8, IL-10, IL-12p40, and tumor necrosis factor-alpha (TNF-alpha) and the chemokines eotaxin, monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein-1beta (MIP-1beta). We found bilaterally increased proinflammatory TNF-alpha and MIP-1beta and decreased antiinflammatory IL-1RA protein levels in CRPS patients compared to non-CRPS patients. Neither group showed side differences. After 6 months under analgesic treatment, protein levels of all measured cytokines in CRPS patients, except for IL-6, significantly changed bilaterally to the level of non-CRPS patients. These changes were not related to treatment outcome. In serum, only IL-8, TNF-alpha, eotaxin, MCP-1, and MIP-1beta were detectable without intergroup differences. Blister fluid of CRPS patients showed a bilateral proinflammatory cytokine profile. This profile seems to be relevant only at the early stage of CRPS. Almost all measured cytokine levels were comparable to those of non-CRPS patients after 6 months of analgesic treatment and were not related to treatment outcome. PMID- 23811042 TI - TRPV1 channels make major contributions to behavioral hypersensitivity and spontaneous activity in nociceptors after spinal cord injury. AB - Chronic neuropathic pain is often a severe and inadequately treated consequence of spinal cord injury (SCI). Recent findings suggest that SCI pain is promoted by spontaneous activity (SA) generated chronically in cell bodies of primary nociceptors in dorsal root ganglia (DRG). Many nociceptors express transient receptor potential V1 (TRPV1) channels, and in a preceding study most dissociated DRG neurons exhibiting SA were excited by the TRPV1 activator, capsaicin. The present study investigated roles of TRPV1 channels in behavioral hypersensitivity and nociceptor SA after SCI. Contusive SCI at thoracic segment T10 increased expression of TRPV1 protein in lumbar DRG 1 month after injury and enhanced capsaicin-evoked ion currents and Ca2+ responses in dissociated small DRG neurons. A major role for TRPV1 channels in pain-related behavior was indicated by the ability of a specific TRPV1 antagonist, AMG9810, to reverse SCI-induced hypersensitivity of hind limb withdrawal responses to mechanical and thermal stimuli at a dose that did not block detection of noxious heat. Similar reversal of behavioral hypersensitivity was induced by intrathecal oligodeoxynucleotides antisense to TRPV1, which knocked down TRPV1 protein and reduced capsaicin-evoked currents. TRPV1 knockdown also decreased the incidence of SA in dissociated nociceptors after SCI. Prolonged application of very low concentrations of capsaicin produced nondesensitizing firing similar to SA, and this effect was enhanced by prior SCI. These results show that TRPV1 makes important contributions to pain-related hypersensitivity long after SCI, and suggest a role for TRPV1-dependent enhancement of nociceptor SA that offers a promising target for treating chronic pain after SCI. PMID- 23811043 TI - Validation of reference genes for quantitative real-time PCR during Chinese wolfberry fruit development. AB - Lycium barbarum L., a woody bush that grows in Eurasia and North Africa, is an ornamental and medicinal plant. Its fruits have been used for centuries in China as a traditional herbal medicine and as a valuable nourishing tonic. There has been no report describing the selection of reference genes for stringent normalization for quantitative PCR (qPCR) in L. barbarum. The present study identified reliable reference genes for normalization of qPCR data in L. barbarum during fruit development from among eight candidate genes (GAPDH, TEF G, EF 1a, UBQ, TUB a, SAMS, EF2 and Hsp80) using the geNorm and NormFinder statistical algorithms. The results showed that the best-ranked references genes differed across the samples. A combination of GAPDH and EF1a would be appropriate as a reference panel for normalizing gene expression data across fruit developmental stages. A combination of EF 1a and SAMS would be appropriate as a reference panel for normalizing gene expression data at the stage A tested, whereas the combination of TUB a, and TEF G was the most suitable for stage B. EF2 and Hsp80 exhibited the most stable expression under stage C and stage D. NormFinder ranking of reference gene candidates was slightly different from that determined by geNorm. These results provide guidelines for the selection of reference genes under different development stages and also represent a foundation for more accurate and widespread use of qRT-PCR in L. barbarum gene analysis. PMID- 23811044 TI - Dietary probiotic supplementation modulated gut microbiota and improved growth of juvenile rainbow trout (Oncorhynchus mykiss). AB - In aquaculture, infectious diseases are the major cause of economic losses. Probiotic supplementation may change the microbiota of the digestive tract and modulate the immune defences and nutritional performance. This study was conducted to evaluate the dietary supplementation of multi-species (A: Bacillus sp., Pediococcus sp., Enterococcus sp., Lactobacillus sp.) and single-species probiotics (B: Pediococcus acidilactici) on growth performance and gut microbiota of rainbow trout (Oncorhynchus mykiss). A basal diet was supplemented with probiotic A or B, at two concentrations each (A1, A2, B1 and B2) or not supplemented (control treatment). Diets were distributed to 30 groups of 20 fish, 3 times a day. The gut microbiota was analysed at the end of the feeding trial (96 days) with 16S rDNA denaturing gradient gel electrophoresis (16S-DGGE). Changes in gut microbial community were assessed by Shannon index (H') and number of operational taxonomic units (OTUs). After 56 days of feeding, weight gain was significantly improved in fish fed diet A1 when compared to the control group. Dietary probiotic supplementation changed the gut microbial composition. Number of OTUs (R) was higher in fish fed A1 (multi-species at lower concentration) than in control group, while H' was higher in fish fed A1, B1 and B2. PMID- 23811045 TI - Energy expenditure during activity in the American lobster Homarus americanus: Correlations with body acceleration. AB - How animals manage time and expend energy has implications for survivorship. Being able to measure key metabolic costs of animals under natural conditions is therefore an important tool in behavioral ecology. One method for estimating activity-specific metabolic rate is via derived measures of acceleration, often 'overall dynamic body acceleration' (ODBA), recorded by an instrumented acceleration logger. ODBA has been shown to correlate well with rate of oxygen consumption (Vo2) in a range of species during activity in the laboratory. This study devised a method for attaching acceleration loggers to decapod crustaceans and then correlated ODBA against concurrent respirometry readings to assess accelerometry as a proxy for activity-specific energy expenditure in a model species, the American lobster Homarus americanus. Where the instrumented animals exhibited a sufficient range of activity levels, positive linear relationships were found between Vo2 and ODBA over 20min periods at a range of ambient temperatures (6, 13 and 20 degrees C). Mixed effect linear models based on these data and morphometrics provided reasonably strong predictive power for estimating activity-specific Vo2 from ODBA. These Vo2-ODBA calibrations demonstrate the potential of accelerometry as an effective predictor of behavior-specific metabolic rate of crustaceans in the wild during periods of activity. PMID- 23811046 TI - Inhibition of HIV-1 enzymes, antioxidant and anti-inflammatory activities of Plectranthus barbatus. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Plectranthus barbatus is widely used in African countries as an herbal remedy to manage HIV/AIDS and related conditions. AIM OF THE STUDY: To investigate the HIV-1 inhibitory, anti-inflammatory and antioxidant properties of P. barbatus and thereby provide empirical evidence for the apparent anecdotal success of the extracts. MATERIALS AND METHODS: Ethanolic extract of P. barbatus's leaves was screened against two HIV-1 enzymes: protease (PR) and reverse transcriptase (RT). Cytotoxicity of the extract was determined through measuring tetrazolium dye uptake of peripheral blood mononuclear cells (PBMCs) and the TZM-bl cell line. Confirmatory assays for cytotoxicity were performed using flow cytometry and real-time cell electronic sensing (RT-CES). The free radical scavenging activity of the extract was investigated with 2,2-diphenyl-1 picrylhydrazyl while the anti-inflammatory properties of the plant extract were investigated using a Th1/Th2/Th17 cytometric bead array technique. RESULTS: P. barbatus extract inhibited HIV-1PR and the 50% inhibitory concentration (IC50) was 62.0 ug/ml. The extract demonstrated poor inhibition of HIV-1 RT. Cytotoxicity testing presented CC50 values of 83.7 and 50.4 ug/ml in PBMCs and TZM-bl respectively. In addition, the extract stimulated proliferation in HIV negative and positive PBMCs treated. RT-CES also registered substantial TZM-bl proliferation after extract treatment. The extract exhibited strong antioxidant activity with an IC50 of 16 ug/ml and reduced the production of pro-inflammatory cytokines indicating anti-inflammatory potential. CONCLUSION: This is the first demonstration of the in vitro anti HIV-1 potential of P. barbatus including direct activity as well as through the stimulation of protective immune and inflammation responses. The low cytotoxicity of the extract is also in agreement with the vast anecdotal use of this plant in treating various ailments with no reported side-effects. PMID- 23811047 TI - Traditional uses, phytochemistry, pharmacology, pharmacokinetics and quality control of Polyporus umbellatus (Pers.) Fries: a review. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Polyporus umbellatus (Pers.) Fries (Polyporaceae, Zhuling ) has been commonly used in medicine for a wide range of ailments related to the edema, scanty urine, vaginal discharge, urinary dysfunction, as well as jaundice and diarrhea. AIM OF THE REVIEW: The present paper reviewed the traditional uses, propagation, phytochemistry, pharmacology, pharmacokinetics and quality control of Polyporus umbellatus. MATERIALS AND METHODS: All the available information on Polyporus umbellatus was collected via a library and electronic search (using Web of Science, Pubmed, ScienceDirect, Splinker, Google Scholar, etc.). RESULTS: Phytochemical studies showed the presence of many valuable secondary metabolites such as steroids, polysaccharides, anthraquinones and nucleosides. Crude extracts and isolated compounds showed a wide spectrum of pharmacological activities including diuretic, nephroprotective, anti-cancer, immuno-enhancing, hepatoprotective, anti-inflammatory and antioxidative activities. The pharmacokinetic studies demonstrated that the ergosterol and ergone had a high distribution and absorption in the plasma and the two main components of Polyporus umbellatus were mainly excreted by faeces. The determination of multiple chemical components was successfully applied to the quality control of Polyporus umbellatus. CONCLUSIONS: Modern phytochemical, pharmacological and metabonomic investigations showed that the crude extracts and isolated compounds from Polyporus umbellatus possess many kinds of biological functions, especially in the diuretic activities and the treatment of kidney diseases as well as anti-cancer, immuno-enhancing and hepatoprotective activities. The pathways of the distribution, absorption, metabolism and excretion of main steroidal compounds were clarified by pharmacokinetic studies. Most of the pharmacological studies were conducted using crude and poorly characterized extracts of Polyporus umbellatus in animals especially in case of diuretic activities and the treatment of kidney diseases. Thus, more bioactive components especially diuretic compounds should be identified using bioactivity guided isolation strategies and the possible mechanism of action as well as potential synergistic or antagonistic effects of multi-component mixtures derived from Polyporus umbellatus need to be evaluated integrating pharmacological, pharmacokinetic, bioavailability-centered and physiological approaches. In addition, more experiments including in vitro, in vivo and clinical studies should be encouraged to identify any side effects or toxicity. These achievements will further expand the existing therapeutic potential of Polyporus umbellatus and provide a beneficial support to its future further clinical use in modern medicine. PMID- 23811048 TI - HPLC-DAD determination of seven antioxidants and caffeine in different phytopharmaceuticals. AB - A high-performance liquid chromatography method employing diode array detection was developed to determine levels of the major catechins, proanthocyanidin (procyanidin B2), caffeine, thymoquinone and carvacrol and its isomer, thymol, which are present in different natural complex matrices found in commercial products of Camellia sinensis L. and/or Nigella sativa L. Reversed-phase separation was performed on a C18 column by using gradient elution by varying the proportions of solvent A (distilled water containing 0.05% orthophosphoric acid) and solvent B (acetonitrile), with a flow rate of 1.5 mL/min and duration of 31 min. Excellent linearity was observed for all standard calibration curves, and correlation coefficients were above 0.9996. The developed method is efficient, with high reproducibility and sensitivity, and is ideally suited for rapid and routine analysis of principal components in these promising medicinal plants. PMID- 23811049 TI - A Candida albicans PeptideAtlas. AB - Candida albicans public proteomic datasets, though growing steadily in the last few years, still have a very limited presence in online repositories. We report here the creation of a C. albicans PeptideAtlas comprising near 22,000 distinct peptides at a 0.24% False Discovery Rate (FDR) that account for over 2500 canonical proteins at a 1.2% FDR. Based on data from 16 experiments, we attained coverage of 41% of the C. albicans open reading frame sequences (ORFs) in the database used for the searches. This PeptideAtlas provides several useful features, including comprehensive protein and peptide-centered search capabilities and visualization tools that establish a solid basis for the study of basic biological mechanisms key to virulence and pathogenesis such as dimorphism, adherence, and apoptosis. Further, it is a valuable resource for the selection of candidate proteotypic peptides for targeted proteomic experiments via Selected Reaction Monitoring (SRM) or SWATH-MS. BIOLOGICAL SIGNIFICANCE: This C. albicans PeptideAtlas resolves the previous absence of fungal pathogens in the PeptideAtlas project. It represents the most extensive characterization of the proteome of this fungus that exists up to the current date, including evidence for uncharacterized ORFs. Through its web interface, PeptideAtlas supports the study of interesting proteins related to basic biological mechanisms key to virulence such as apoptosis, dimorphism and adherence. It also provides a valuable resource to select candidate proteotypic peptides for future (SRM) targeted proteomic experiments. This article is part of a Special Issue entitled: Trends in Microbial Proteomics. PMID- 23811050 TI - The role of heat stress on the age related protein carbonylation. AB - Since the proteins are involved in many physiological processes in the organisms, modifications of proteins have important outcomes. Protein modifications are classified in several ways and oxidative stress related ones take a wide place. Aging is characterized by the accumulation of oxidized proteins and decreased degradation of these proteins. On the other hand protein turnover is an important regulatory mechanism for the control of protein homeostasis. Heat shock proteins are a highly conserved family of proteins in the various cells and organisms whose expressions are highly inducible during stress conditions. These proteins participate in protein assembly, trafficking, degradation and therefore play important role in protein turnover. Although the entire functions of each heat shock protein are still not completely investigated, these proteins have been implicated in the processes of protection and repair of stress-induced protein damage. This study has focused on the heat stress related carbonylated proteins, as a marker of oxidative protein modification, in young and senescent fibroblasts. The results are discussed with reference to potential involvement of induced heat shock proteins. This article is part of a Special Issue entitled: Protein Modifications. BIOLOGICAL SIGNIFICANCE: Age-related protein modifications, especially protein carbonylation take a wide place in the literature. In this direction, to highlight the role of heat shock proteins in the oxidative modifications may bring a new aspect to the literature. On the other hand, identified carbonylated proteins in this study confirm the importance of folding process in the mitochondria which will be further analyzed in detail. PMID- 23811051 TI - Proteomic analysis of mycelium and secretome of different Botrytis cinerea wild type strains. AB - The necrotrophic fungus Botrytis cinerea is a very damaging phytopathogen of wide host range and environmental persistence. It is difficult to control because of its genetic versatility, expressed in the many phenotypical differences among isolates. The genomes of the B. cinerea B05.10 and T4 strains have been recently sequenced, becoming a model system for necrotrophic pathogens, and thus opening new alternatives for functional genomics analysis. In this work, the mycelium and secreted proteome of six wild-type strains with different host range, and grown in liquid minimal medium, have been analyzed by using complementary gel-based (1 DE and 2-DE) and gel-free/label-free (nUPLC-MS(E)) approaches. We found differences in the protein profiles among strains belonging to both the mycelium and the secretome. A total of 47 and 51 variable proteins were identified in the mycelium and the secretome, respectively. Some of them, such as malate dehydrogenase or peptidyl-prolyl cis-trans isomerase from the mycelium, and endopolygalacturonase, aspartic protease or cerato-platanin protein from the secretome have been reported as virulence factors, which are involved in host tissue invasion, pathogenicity or fungal development. BIOLOGICAL SIGNIFICANCE: The necrotrophic fungus Botrytis cinerea is an important phytopathogen of wide host range and environmental persistence, causing substantial economic losses worldwide. In this work, the mycelium and secreted proteome of six B. cinerea wild-type strains with different host range have been analyzed by using complementary gel-based and gel-free/label-free approaches. Fungal genetic versatility was confirmed at the proteome level for both mycelium proteome and secreted proteins. A high number of hypothetical proteins with conserved domains related to toxin compounds or to unknown functions were identified, having qualitative differences among strains. The identification of hypothetical proteins suggests that the B. cinerea strains differ mostly in processes involved in adaptation to a particular environment or a growth condition, rather than in essential metabolic reactions. Proteomics can help in the identification of variable proteins related to the infection and colonization of host plant tissues, as well as of virulence and aggressiveness factors among different B. cinerea wild-type strains. This article is part of a Special Issue entitled: Trends in Microbial Proteomics. PMID- 23811052 TI - Vaccine potential of recombinant cathepsin B against Fasciola gigantica. AB - In Fasciola gigantica, cathepsin Bs, especially cathepsin B2 and B3 are expressed in early juvenile stages, and are proposed to mediate the invasion of host tissues. Thus they are thought to be the target vaccine candidates that can block the invasion and migration of the juvenile parasite. To evaluate their vaccine potential, the recombinant cathepsin B2 (rFgCatB2) and cathepsin B3 (rFgCatB3) were expressed in yeast, Pichia pastoris, and used to immunize mice in combination with Freund's adjuvant to evaluate the protection against the infection by F. gigantica metacercariae, and the induction of immune responses. Mice immunized with both recombinant proteins exhibited high percent of parasite reduction at 60% for rFgCatB2 and 66% for rFgCatB3. Immunization by both antigens induced continuously increasing levels of IgG1 and IgG2a with a higher level of IgG1 isotype, indicating the mixed Th1/Th2 responses with Th2 predominating. When examined individually, the higher levels of IgG1 and IgG2a were correlated with the lower numbers of worm recoveries. Thus, both cathepsin B2 and cathepsin B3 are plausible vaccine candidates whose potential should be further tested in large economic animals. PMID- 23811053 TI - Apo states of calmodulin and CaBP1 control CaV1 voltage-gated calcium channel function through direct competition for the IQ domain. AB - In neurons, binding of calmodulin (CaM) or calcium-binding protein 1 (CaBP1) to the CaV1 (L-type) voltage-gated calcium channel IQ domain endows the channel with diametrically opposed properties. CaM causes calcium-dependent inactivation and limits calcium entry, whereas CaBP1 blocks calcium-dependent inactivation (CDI) and allows sustained calcium influx. Here, we combine isothermal titration calorimetry with cell-based functional measurements and mathematical modeling to show that these calcium sensors behave in a competitive manner that is explained quantitatively by their apo-state binding affinities for the IQ domain. This competition can be completely blocked by covalent tethering of CaM to the channel. Further, we show that Ca(2+)/CaM has a sub-picomolar affinity for the IQ domain that is achieved without drastic alteration of calcium-binding properties. The observation that the apo forms of CaM and CaBP1 compete with each other demonstrates a simple mechanism for direct modulation of CaV1 function and suggests a means by which excitable cells may dynamically tune CaV activity. PMID- 23811054 TI - A pseudo-atomic model for the capsid shell of bacteriophage lambda using chemical cross-linking/mass spectrometry and molecular modeling. AB - Bacteriophage lambda is one of the most exhaustively studied of the double stranded DNA viruses. Its assembly pathway is highly conserved among the herpesviruses and many of the bacteriophages, making it an excellent model system. Despite extensive genetic and biophysical characterization of many of the lambda proteins and the assembly pathways in which they are implicated, there is a relative dearth of structural information on many of the most critical proteins involved in lambda assembly and maturation, including that of the lambda major capsid protein. Toward this end, we have utilized a combination of chemical cross linking/mass spectrometry and computational modeling to construct a pseudo-atomic model of the lambda major capsid protein as a monomer, as well as in the context of the assembled procapsid shell. The approach described here is generalizable and can be used to provide structural models for any biological complex of interest. The procapsid structural model is in good agreement with published biochemical data indicating that procapsid expansion exposes hydrophobic surface area and that this serves to nucleate assembly of capsid decoration protein, gpD. The model further implicates additional molecular interactions that may be critical to the assembly of the capsid shell and for the stabilization of the structure by the gpD decoration protein. PMID- 23811055 TI - Dissection of conformational conversion events during prion amyloid fibril formation using hydrogen exchange and mass spectrometry. AB - A molecular understanding of prion diseases requires an understanding of the mechanism of amyloid fibril formation by the prion protein. In particular, it is necessary to define the sequence of the structural events describing the conformational conversion of monomeric PrP to aggregated PrP. In this study, the sequence of the structural events in the case of amyloid fibril formation by recombinant mouse prion protein at pH7 has been characterized by hydrogen deuterium exchange and mass spectrometry. The observation that fibrils are substantially more stable to hydrogen-deuterium exchange than is native monomer allows both forms to be quantified during the course of the aggregation reaction. Under the aggregation conditions utilized, native monomeric protein and amyloid fibrils are the only forms of the protein detectable during the course of the fibril formation reaction, suggesting that monomer directly adds on to the fibril template. Conformational conversion is shown to occur in two steps after the binding of monomer to fibril, with helix 1 unfolding only after helices 2 and 3 transform into beta-sheet. Local stability in the beta-sheet core region (residues ~159-225) of the fibrils is shown to be sequence dependent in that it varies along the length of the core, and local stability in protein molecules that are ordered in the structurally heterogeneous sequence segment 109-132 is shown to be similar to that in the core. This new understanding of the structural events during prion protein aggregation has important bearing on our comprehension of the molecular basis of prion pathogenesis. PMID- 23811056 TI - Dissecting partner recognition by an intrinsically disordered protein using descriptive random mutagenesis. AB - In view of getting insights into the molecular determinants of the binding efficiency of intrinsically disordered proteins (IDPs), we used random mutagenesis. As a proof of concept, we chose the interaction between the intrinsically disordered C-terminal domain of the measles virus nucleoprotein (NTAIL) and the X domain (XD) of the viral phosphoprotein and assessed how amino acid substitutions introduced at random within NTAIL affect partner recognition. In contrast with directed evolution approaches, we did not apply any selection and used the gene library approach not for production purposes but for achieving a better understanding of the NTAIL/XD interaction. For that reason, and to differentiate our approach from similar approaches that make use of systematic (i.e., targeted) mutagenesis, we propose to call it "descriptive random mutagenesis" (DRM). NTAIL variants generated by error-prone PCR were picked at random in the absence of selection pressure and were characterized in terms of sequence and binding abilities toward XD. DRM not only identified determinants of NTAIL/XD interaction that were in good agreement with previous work but also provided new insights. In particular, we discovered that the primary interaction site is poorly evolvable in terms of binding abilities toward XD. We also identified a critical NTAIL residue whose role in stabilizing the NTAIL/XD complex had previously escaped detection, and we identified NTAIL regulatory sites that dampen the interaction while being located outside the primary interaction site. Results show that DRM is a valuable approach to study binding abilities of IDPs. PMID- 23811058 TI - Buried and accessible surface area control intrinsic protein flexibility. AB - Proteins experience a wide variety of conformational dynamics that can be crucial for facilitating their diverse functions. How is the intrinsic flexibility required for these motions encoded in their three-dimensional structures? Here, the overall flexibility of a protein is demonstrated to be tightly coupled to the total amount of surface area buried within its fold. A simple proxy for this, the relative solvent-accessible surface area (Arel), therefore shows excellent agreement with independent measures of global protein flexibility derived from various experimental and computational methods. Application of Arel on a large scale demonstrates its utility by revealing unique sequence and structural properties associated with intrinsic flexibility. In particular, flexibility as measured by Arel shows little correspondence with intrinsic disorder, but instead tends to be associated with multiple domains and increased alpha-helical structure. Furthermore, the apparent flexibility of monomeric proteins is found to be useful for identifying quaternary-structure errors in published crystal structures. There is also a strong tendency for the crystal structures of more flexible proteins to be solved to lower resolutions. Finally, local solvent accessibility is shown to be a primary determinant of local residue flexibility. Overall, this work provides both fundamental mechanistic insight into the origin of protein flexibility and a simple, practical method for predicting flexibility from protein structures. PMID- 23811057 TI - Abeta monomers transiently sample oligomer and fibril-like configurations: ensemble characterization using a combined MD/NMR approach. AB - Amyloid beta (Abeta) peptides are a primary component of fibrils and oligomers implicated in the etiology of Alzheimer's disease (AD). However, the intrinsic flexibility of these peptides has frustrated efforts to investigate the secondary and tertiary structure of Abeta monomers, whose conformational landscapes directly contribute to the kinetics and thermodynamics of Abeta aggregation. In this work, de novo replica exchange molecular dynamics (REMD) simulations on the microseconds-per-replica timescale are used to characterize the structural ensembles of Abeta42, Abeta40, and M35-oxidized Abeta42, three physiologically relevant isoforms with substantially different aggregation properties. J-coupling data calculated from the REMD trajectories were compared to corresponding NMR derived values acquired through two different pulse sequences, revealing that all simulations converge on the order of hundreds of nanoseconds-per-replica toward ensembles that yield good agreement with experiment. Though all three Abeta species adopt highly heterogeneous ensembles, these are considerably more structured compared to simulations on shorter timescales. Prominent in the C terminus are antiparallel beta-hairpins between L17-A21, A30-L36, and V39-I41, similar to oligomer and fibril intrapeptide models that expose these hydrophobic side chains to solvent and may serve as hotspots for self-association. Compared to reduced Abeta42, the absence of a second beta-hairpin in Abeta40 and the sampling of alternate beta topologies by M35-oxidized Abeta42 may explain the reduced aggregation rates of these forms. A persistent V24-K28 bend motif, observed in all three species, is stabilized by buried backbone to side-chain hydrogen bonds with D23 and a cross-region salt bridge between E22 and K28, highlighting the role of the familial AD-linked E22 and D23 residues in Abeta monomer folding. These characterizations help illustrate the conformational landscapes of Abeta monomers at atomic resolution and provide insight into the early stages of Abeta aggregation pathways. PMID- 23811059 TI - Testing the effects of e-mailed personalized feedback on risky alcohol use among college students. AB - OBJECTIVE: Although research utilizing the Internet to intervene with college student drinkers is growing, this study is the first to investigate the use of a theoretically-based and empirically supported personalized feedback form delivered via a single e-mail to college students. METHOD: Students (n=191) completed measures of their alcohol use, related consequences, and peer perceptions at baseline and 6weeks after the intervention. Students were randomly assigned to receive either e-mailed personalized feedback or e-mailed generic feedback. RESULTS: Students who received e-mailed personalized feedback reported consuming significantly fewer drinks in a given week, as well as a fewer number of days being drunk in the previous 30days. They also exhibited a significant reduction in the number of days they perceived their peers to have drunk alcohol and in the amount of alcohol they perceived their peers to consume per drinking occasion. CONCLUSION: e-Mailed personalized feedback appears to help students become more aware of normative drinking behavior and reduce the quantity of alcohol they consume. Furthermore, e-mailed personalized feedback may be a cost effective manner in which to intervene with college student drinkers. PMID- 23811060 TI - Concordance between self-report and urine drug screen data in adolescent opioid dependent clinical trial participants. AB - Objective measures of drug use are very important in treatment outcome studies of persons with substance use disorders, but obtaining and interpreting them can be challenging and not always practical. Thus, it is important to determine if, and when, drug-use self-reports are valid. To this end we explored the relationships between urine drug screen results and self-reported substance use among adolescents and young adults with opioid dependence participating in a clinical trial of buprenorphine-naloxone. In this study, 152 individuals seeking treatment for opioid dependence were randomized to a 2-week detoxification with buprenorphine-naloxone (DETOX) or 12weeks of buprenorphine-naloxone (BUP), each with weekly individual and group drug counseling. Urine drug screens and self reported frequency of drug use were obtained weekly, and patients were paid $5 for completing weekly assessments. At weeks 4, 8, and 12, more extensive assessments were done, and participants were reimbursed $75. Self-report data were dichotomized (positive vs. negative), and for each major drug class we computed the kappa statistic and the sensitivity, specificity, positive predictive value, and negative predictive value of self-report using urine drug screens as the "gold standard". Generalized linear mixed models were used to explore the effect of treatment group assignment, compensation amounts, and participant characteristics on self-report. In general, findings supported the validity of self-reported drug use. However, those in the BUP group were more likely to under-report cocaine and opioid use. Therefore, if used alone, self report would have magnified the treatment effect of the BUP condition. PMID- 23811061 TI - Clusters of personality traits and psychological symptoms associated with later benzodiazepine prescriptions in the general population: The HUNT Cohort Study. AB - OBJECTIVE: The aim of this population-based study was to identify factors associated with later benzodiazepine prescriptions, including clusters of personality traits, self-esteem characteristics, sleep difficulties, depression and anxiety symptoms. METHODS: A 13year historical cohort study (n=58,967) was carried out and baseline measures of self-reported depression and anxiety symptoms, sleep difficulties, self-esteem and personality traits were obtained from the second wave of the Nord-Trondelag Health Study (HUNT 2, 1995-1997), Norway. Data on benzodiazepine prescriptions were collected from the Norwegian Prescription Database (NorPD, 2004-2008) for each case in the cohort. RESULTS AND CONCLUSIONS: We found that a combined high extraversion and high neuroticism personality score at baseline was associated with increased benzodiazepine prescription rates. Further, sleep difficulties, low self-esteem and high depression and anxiety scores were also linked to later prescriptions of benzodiazepines, in particular chronic and high dose benzodiazepine prescriptions patterns. The findings are discussed in relation to prescription practice and policy. PMID- 23811062 TI - Exploring relationships between facets of self-esteem and drinking behavior among diverse groups of young adults. AB - Theory and empirical evidence suggest that North American-based measures of self esteem, which measure individualistic positive self-regard, may be less applicable to Eastern cultures. In the present exploratory study, we examined how different conceptualizations of self-esteem, as measured by the Rosenberg Self esteem Scale and the Collective Self-esteem (CSE) Scale, predicted drinking behavior among three groups of American college students (N=326) with varying ethnicities: White, Korean, and Chinese/Taiwanese. Hierarchical negative binomial regression was employed to evaluate these relations. Ethnic identity was controlled for in all analyses. Findings indicated that while global self-esteem was positively associated with drinking for the whole sample, ethnicity moderated this relationship such that global self-esteem was related to drinking for White participants but not for their Chinese/Taiwanese counterparts. In addition, while CSE did not associate with drinking for the whole sample, effects emerged for specific ethnicities. Specifically, private CSE was associated with less drinking for Korean and Chinese/Taiwanese participants. Depending on specific Asian ethnicity, public CSE served as a risk (Korean participants) or a protective factor (Chinese/Taiwanese participants) for drinking. Findings suggest that above and beyond ethnic identity, differential relationships between facets of self esteem and drinking behavior may exist among White, Korean, and Chinese/Taiwanese young adults. Intervention and prevention programs should develop strategies to help Chinese/Taiwanese and Korean American young adults cultivate protective factors within domains of CSE. PMID- 23811063 TI - Characterization of a new zeaxanthin producing strain of Chlorella saccharophila isolated from New Zealand marine waters. AB - A fast growing strain of Chlorella saccharophila was isolated from the marine water of New Zealand and grown in heterotrophic conditions using glucose or glycerol as a carbon source. Biomass production was found to be higher in culture fed with glucose (2.14+/-0.08 g L(-1)) as compared to glycerol (0.378+/-0.04 g L( 1)). Lipid accumulation was similar for both carbon sources, at approximately 22% of dry cell weight. However, carotenoid yield was higher with glycerol (0.406+/ 0.0125 mg g(-1)) than with glucose (0.21+/-0.034 mg g(-1)). Further optimization of the growth of the isolate gave maximal carotenoid production of 16.39+/-1.19 mg g(-1) total carotenoid, containing 11.32+/-0.64 mg g(-1) zeaxanthin and 5.07+/ 0.55 mg g(-1) beta-carotene. Comparison of various chemical and physical carotenoid extraction methods showed that ultrasonication was required for maximum extraction yields. The new strain has potential for biofuel, with carotenoid co-production. PMID- 23811064 TI - Effects of Ca2+ on activity restoration of the damaged anammox consortium. AB - Intracellular free Ca(2+) are canonically well known as significant "second messenger" in cells and regarded as critical regulators of bacterial metabolism. We investigated the influence of Ca(2+) dosage on the restoration of anammox consortium, in which nearly 80% cells were dead or badly damaged. Chemical analysis and flow cytometry (FCM) demonstrated that Ca(2+) dosage was of primary importance and the restoration process was apparently faster with increasing Ca(2+) as its concentration was ranged 0.02-0.5mM in feeding. Using FCM and Fura red fluorescence labeling for analysis of intracellular free Ca(2+), we found a strong correlation between external Ca(2+) concentration in feeding and the levels of steady-state intracellular free Ca(2+), the abundance of which was considered as the intrinsic causes for favoring anammox consortium restoration. This study provides new insight into the ions effects on rapid restoration of damaged anammox consortium, targeting efficient nitrogen removal from wastewater with anammox process. PMID- 23811065 TI - Butyric acid from anaerobic fermentation of lignocellulosic biomass hydrolysates by Clostridium tyrobutyricum strain RPT-4213. AB - A novel Clostridium tyrobutyricum strain RPT-4213 was found producing butyrate under strict anaerobic conditions. This strain produced 9.47 g L(-1) butyric acid from MRS media (0.48 g/g glucose). RPT-4213 was also used to ferment dilute acid pretreated hydrolysates including wheat straw (WSH), corn fiber (CFH), corn stover (CSH), rice hull (RHH), and switchgrass (SGH). Results indicated that 50% WSH with a Clostridia medium (Ct) produced the most butyric acid (8.06 g L(-1), 0.46 g/g glucose), followed by 50% SGH with Ct (6.01 g L(-1), 0.44 g/g glucose), however, 50% CSH Ct showed growth inhibition. RPT-4213 was then used in pH controlled bioreactor fermentations using 60% WSH and SGH, with a dilute (0.5*) Ct medium, resulting 9.87 g L(-1) butyric acid in WSH (yield 0.44 g/g) and 7.05 g L(-1) butyric acid in SGH (yield 0.42 g/g). The titer and productivity could be improved through process engineering. PMID- 23811066 TI - Evaluation of thermal, ultrasonic and alkali pretreatments on mixed-microalgal biomass to enhance anaerobic methane production. AB - Anaerobic digestion was regarded as one of the ways to recover energy from mixed microalgae biomass in this study. After applying thermal-, ultrasonic-, and alkali-pretreatments to raw microalgae biomass to promote the digestion efficiency, a biochemical methane potential was investigated to evaluate the effectiveness of the pre-treatments for the purpose. As the pretreatment intensity increased, the solubilization of the mixed microalgae increased. However, the increased solubilization was not followed proportionally by the increased methane production. The highest methane productivity was achieved by the thermal-pretreatment at 120 degrees C (405 mL CH4/g-VS), which was 1.2 times higher than that of the non-pretreatment condition (336 mL CH4/g-VS). The net energy analysis revealed that only the pretreatment adjusted to pH 9 yielded a slightly higher energy gains (12.8 kJ/g-VS) than that of non-pretreatment condition (11.9 kJ/g-VS). These findings recommend direct supply of microalgae biomass for anaerobic digestion. PMID- 23811067 TI - Effects of dilution rate and water reuse on biomass and lipid production of Scenedesmus obliquus in a two-stage novel photobioreactor. AB - Continuous culture of fresh water microalgae Scenedesmus obliquus was developed in a two-stage photobioreactor, avoiding the intermediate harvesting step to achieve a half-way point between the progressive and the sudden N-starvation strategies, guaranteeing light limited conditions in the first stage and N-stress conditions in the second stage. This methodology resulted in biomass productivity values at the best dilution rate (0.118 days(-1)) of 15.25+/-1.06 g m(-2) d(-1), slightly higher than that expected according to batch experiment (12.90+/-0.75 g m(-2) d(-1)). The dilution rate that maximized the lipid content was coincident with that for the maximum biomass productivity, resulting in a intensification of the lipid productivity. Microalgae can be successfully cultured in reused medium clarified by high pH flocculation-sedimentation and neutralized by bubbling the photobioreactors outlet CO2 current through it. Microalgae flocculation with NaOH does not result in a variation of the obtained lipid profile. PMID- 23811068 TI - Incidence and significance of intraoperative cerebrospinal fluid leak in endoscopic pituitary surgery using intrathecal fluorescein. AB - OBJECTIVE: The true rate of intraoperative cerebrospinal fluid (iCSF) leak during pituitary surgery is not well known because small iCSF leaks are easily missed. Our objective is to determine the rate and significance of iCSF leak in endoscopic pituitary surgery with intrathecal (IT) fluorescein administration and determine factors predictive of iCSF leak. METHODS: IT fluorescein was administered in 203 consecutive endoscopic, endonasal pituitary surgeries. The rate of iCSF leak was noted prospectively and correlated with tumor diameter and volume, gross total resection, and the learning curve. Postoperative CSF leak rate, complications, and nasoseptal flap utility were also investigated. RESULTS: The rate of iCSF leak was 61% overall, 44% for tumors<2 cm compared to 72% for tumors>=2 cm and 35% for tumors<1.5 cm3 compared to 68% for those>=1.5 cm3 (P<0.001). Postoperative CSF leak was significantly lower after the first 50 cases (0.7% vs. 10%; P<0.005) with overall leak of 3%. For tumors>2 cm, the introduction of nasoseptal flap reduced the rate of postoperative CSF leak from 5.6% to 1.4%. We did not find any complications clearly related with the use of IT fluorescein. CONCLUSION: The rate of iCSF leak during endoscopic pituitary surgery using IT fluorescein is higher than previously reported. Tumor diameter and volume are best predictors of the risk of iCSF leak. Based on this knowledge and a closure algorithm that includes a lumbar drain and nasoseptal flap for larger tumors (>2.5 cm), we can conclude that the postoperative CSF leak rate remains exceptionally low, particularly once the learning curve is overcome. PMID- 23811069 TI - Concentric craniotomy: removal of tumor involving the skull and the intracranial space. AB - BACKGROUND: Removal of a tumor involving both the intracranial space and the skull presents technical challenges. This is especially so if there is a potential for significant hemorrhage due to a hemangioma or a significant attachment to the brain as with a meningioma. CASE DESCRIPTION: We describe a technique where the tumor attached to the skull is left undisturbed and a second wider concentric craniotomy exposes normal dura. The entire tumor, both intracranial and that involving the skull and dura, can then be removed as one specimen. CONCLUSION: The technique we describe, a concentric craniotomy, transforms a difficult operation with the potential for significant hemorrhage into a more standard removal of a convexity tumor. PMID- 23811070 TI - Normalizing dopamine D2 receptor-mediated responses in D2 null mutant mice by virus-mediated receptor restoration: comparing D2L and D2S. AB - D2 receptor null mutant (Drd2(-/-)) mice have altered responses to the rewarding and locomotor effects of psychostimulant drugs, which is evidence of a necessary role for D2 receptors in these behaviors. Furthermore, work with mice that constitutively express only the D2 receptor short form (D2S), as a result of genetic deletion of the long form (D2L), provides the basis for a current model in which D2L is thought to be the postsynaptic D2 receptor on medium spiny neurons in the basal forebrain, and D2S the autoreceptor that regulates the activity of dopamine neurons and dopamine synthesis and release. Because constitutive genetic deletion of the D2 or D2L receptor may cause compensatory changes that influence functional outcomes, our approach is to identify aspects of the abnormal phenotype of a Drd2(-/-) mouse that can be normalized by virus mediated D2 receptor expression. Drd2(-/-) mice are deficient in basal and methamphetamine-induced locomotor activation and lack D2 receptor agonist-induced activation of G protein-regulated inward rectifying potassium channels (GIRKs) in dopaminergic neurons. Here we show that virus-mediated expression of D2L in the nucleus accumbens significantly restored methamphetamine-induced locomotor activation, but not basal locomotor activity, compared to mice receiving the control virus. It also restored the effect of methamphetamine to decrease time spent in the center of the activity chamber in female but not male Drd2(-/-) mice. Furthermore, the effect of expression of D2S was indistinguishable from D2L. Similarly, virus-mediated expression of either D2S or D2L in substantia nigra neurons restored D2 agonist-induced activation of GIRKs. In this acute expression system, the alternatively spliced forms of the D2 receptor appear to be equally capable of acting as postsynaptic receptors and autoreceptors. PMID- 23811071 TI - Exercise facilitates the action of dietary DHA on functional recovery after brain trauma. AB - The abilities of docosahexaenoic acid (DHA) and exercise to counteract cognitive decay after traumatic brain injury (TBI) is getting increasing recognition; however, the possibility that these actions can be complementary remains just as an intriguing possibility. Here we have examined the likelihood that the combination of diet and exercise has the added potential to facilitate functional recovery following TBI. Rats received mild fluid percussion injury (mFPI) or sham injury and then were maintained on a diet high in DHA (1.2% DHA) with or without voluntary exercise for 12days. We found that FPI reduced DHA content in the brain, which was accompanied by increased levels of lipid peroxidation assessed using 4-hydroxy-2-hexenal (4-HHE). FPI reduced the enzymes acyl-CoA oxidase 1 (Acox1) and 17beta-hydroxysteroid dehydrogenase type 4 (17beta-HSD4), and the calcium-independent phospholipases A2 (iPLA2), which are involved in metabolism of membrane phospholipids. FPI reduced levels of syntaxin-3 (STX-3), involved in the action of membrane DHA on synaptic membrane expansion, and also reduced brain derived neurotrophic factor (BDNF) signaling through its tyrosine kinase B (TrkB) receptor. These effects of FPI were optimally counteracted by the combination of DHA and exercise. Our results support the possibility that the complementary action of exercise is exerted on restoring membrane homeostasis after TBI, which is necessary for supporting synaptic plasticity and cognition. It is our contention that strategies that take advantage of the combined applications of diet and exercise may have additional effects to the injured brain. PMID- 23811072 TI - A neuregulin 1 transmembrane domain mutation causes imbalanced glutamatergic and dopaminergic receptor expression in mice. AB - The neuregulin 1 gene has repeatedly been identified as a susceptibility gene for schizophrenia, thus mice with genetic mutations in this gene offer a valuable tool for studying the role of neuregulin 1 in schizophrenia-related neurotransmission. In this study, slide-based receptor autoradiography was used to quantify glutamatergic N-methyl-d-aspartate (NMDA), dopaminergic D2, cannabinoid CB1 and acetylcholine M1/4 receptor levels in the brains of male heterozygous transmembrane domain neuregulin 1 mutant (Nrg1(+/-)) mice at two ages. Mutant mice expressed small but significant increases in NMDA receptor levels in the cingulate cortex (7%, p=0.044), sensory cortex (8%, p=0.024), and motor cortex (8%, p=0.047), effects that were independent of age. In the nucleus accumbens and thalamus Nrg1(+/-) mice exhibited age-dependent alterations in NMDA receptors. Nrg1(+/-) mice showed a statistically significant increase in NMDA receptor levels in the nucleus accumbens of 14-week-old Nrg1(+/-) mice compared to control littermates of the same age (12%, p=0.026), an effect that was not seen in 20-week-old mice. In contrast, NMDA receptor levels in the thalamus, while initially unchanged in 14-week-old mice, were then decreased in the 20-week old Nrg1(+/-) mice compared to control littermates of the same age (14%, p=0.011). Nrg1(+/-) mutant mice expressed a significant reduction in D2 receptor levels (13-16%) in the striatum compared to controls, independent of age. While there was a borderline significant increase (6%, p=0.058) in cannabinoid CB1 receptor levels in the substantia nigra of Nrg1(+/-) mice compared to controls, CB1 as well as acetylcholine M1/4 receptors showed no change in Nrg1(+/-) mice in any other brain region examined. These data indicate that a Nrg1 transmembrane mutation produces selective imbalances in glutamatergic and dopaminergic neurotransmission, which are two key systems believed to contribute to schizophrenia pathogenesis. While the effects on these systems are subtle, they may underlie the susceptibility of these mutants to further impacts. PMID- 23811074 TI - Acetylcholine leads to signal transducer and activator of transcription 1 (STAT 1) mediated oxidative/nitrosative stress in human bronchial epithelial cell line. AB - The induction of nitric oxide synthase (iNOS) expression via the signal transducer and activator of transcription 1 (STAT-1) is involved in the mechanism of oxidative/nitrosative stress. We investigated whether acetylcholine (ACh) generates oxidative/nitrosative stress in bronchial epithelial cells during airway inflammation of COPD and evaluated the effects of Tiotropium, a once-daily antimuscarinic drug, and Olodaterol, a long-acting beta2-agonist on these mechanisms. Human bronchial epithelial cells (16-HBE) were stimulated (4h, 37 degrees C) with induced sputum supernatants (ISSs) from healthy controls (HC) (n=10), healthy smokers (HS) (n=10) or COPD patients (n=10), as well as with ACh (from 1MUM to 100MUM). The activation of STAT-1 pathway (STAT-1Ser727 and STAT 1Tyr701) and iNOS was evaluated in the cell lysates by Western blot analysis as well as nitrotyrosine levels by ELISA, while reactive oxygen species (ROS) were evaluated by flow cytometry. Finally, the effect of Tiotropium (Spiriva(r)) (100nM), alone or in combination with Olodaterol (1nM), was tested in this model. ISSs from COPD patients significantly increased the phosphorylation of STAT 1Ser727 and STAT-1Tyr701, iNOS and ROS/Nitrotyrosine when compared with ISSs from HC or HS subjects in 16-HBE cells. Furthermore, synthetic ACh increased all these parameters in stimulated 16HBE when compared with untreated cells. Tiotropium and Olodaterol reduced the oxidative/nitrosative stress generated by ACh and ISSs. We concluded that ACh mediated the oxidative/nitrosative stress involving the STAT-1 pathway activation in human bronchial epithelial cells during COPD. beta2-Long acting and antimuscarinic drugs, normally used in the treatment of COPD as bronchodilator, might be able to control these cellular events. PMID- 23811073 TI - Long-term effects of cocaine experience on neuroplasticity in the nucleus accumbens core of addiction-prone rats. AB - Repeated exposure to drugs of abuse is associated with structural plasticity in brain reward pathways. Rats selectively bred for locomotor response to novelty differ on a number of neurobehavioral dimensions relevant to addiction. This unique genetic animal model was used here to examine both pre-existing differences and long-term consequences of repeated cocaine treatment on structural plasticity. Selectively bred high-responder (bHR) and low-responder (bLR) rats received repeated saline or cocaine injections for 9 consecutive days. Escalating doses of cocaine (7.5, 15 and 30 mg/kg) were administered on the first (day 1) and last (day 9) days of treatment and a single injection of the intermediate dose (15 mg/kg) was given on days 2-8. Motor activity in response to escalating doses of cocaine was compared on the first and last days of treatment to assess the acute and sensitized response to the drug. Following prolonged cocaine abstinence (28 days), spine density was examined on terminal dendrites of medium spiny neurons in the nucleus accumbens core. Relative to bLRs, bHRs exhibited increased psychomotor activation in response to both the acute and repeated effects of cocaine. There were no differences in spine density between bHR and bLR rats under basal conditions or following repeated saline treatment. However, spine density differed markedly between these two lines following prolonged cocaine abstinence. All spine types were decreased in cocaine-treated bHRs, while only mushroom spines were decreased in bLRs that received cocaine. Changes in spine density occurred specifically near the branch point of terminal dendrites. These findings indicate that structural plasticity associated with prolonged cocaine abstinence varies markedly in two selected strains of rats that vary on numerous traits relevant to addiction. Thus, genetic factors that contribute to individual variation in the behavioral response to cocaine also influence cocaine-induced structural plasticity. PMID- 23811075 TI - Conserved residues in RF-NH2 receptor models identify predicted contact sites in ligand-receptor binding. AB - Peptides in the RF-NH2 family are grouped together based on an amidated dipeptide C terminus and signal through G-protein coupled receptors (GPCRs) to influence diverse physiological functions. By determining the mechanisms underlying RF-NH2 signaling targets can be identified to modulate physiological activity; yet, how RF-NH2 peptides interact with GPCRs is relatively unexplored. We predicted conserved residues played a role in Drosophila melanogaster RF-NH2 ligand receptor interactions. In this study D. melanogaster rhodopsin-like family A peptide GPCRs alignments identified eight conserved residues unique to RF-NH2 receptors. Three of these residues were in extra-cellular loops of modeled RF-NH2 receptors and four in transmembrane helices oriented into a ligand binding pocket to allow contact with a peptide. The eighth residue was unavailable for interaction; yet its conservation suggested it played another role. A novel hydrophobic region representative of RF-NH2 receptors was also discovered. The presence of rhodopsin-like family A GPCR structural motifs including a toggle switch indicated RF-NH2s signal classically; however, some features of the DMS receptors were distinct from other RF-NH2 GPCRs. Additionally, differences in RF NH2 receptor structures which bind the same peptide explained ligand specificity. Our novel results predicted conserved residues as RF-NH2 ligand-receptor contact sites and identified unique and classic structural features. These discoveries will aid antagonist design to modulate RF-NH2 signaling. PMID- 23811076 TI - A new anti-infective strategy to reduce the spreading of antibiotic resistance by the action on adhesion-mediated virulence factors in Staphylococcus aureus. AB - Staphylococcus aureus is a flexible microbial pathogen frequently isolated from community-acquired and nosocomial infections. S. aureus expresses a wide array of secreted and cell surface-associated virulence factors, including proteins that promote adhesion to damaged tissue and to the surface of host cells, and that bind proteins in blood to help evade immune responses. Furthermore, surface proteins have a fundamental role in virulence related properties of S. aureus, including biofilm formation. The present study evaluates the anti-infective capabilities of a secreted protein of Serratia marcescens (serratiopeptidase, SPEP), in impairing some staphylococcal virulence-related properties, such as attachment to inert surfaces and adhesion/invasion on eukaryotic cells. SPEP seems to exert its action by modulating specific proteins. It is not assessed if this action is due to the proteolytic activity of SPEP or to a specific mechanism which triggers an out/inside signal. Proteomic studies performed on surface proteins extracted from SPEP treated S. aureus cultures revealed that a number of proteins are affected by the treatment. Among these we found the adhesin/autolysin Atl, SdrD, Sbi, EF-Tu and EF-G. EF-Tu and EF-G are known to perform a variety of function, depending on their cytoplasmic or surface localization. All these factors can facilitate bacterial colonization, persistence and invasion of host tissues. Our results suggest that SPEP could be developed as a potential "anti-infective agent" capable to hinder the entry of S. aureus into human tissues, and also impairs the ability of this pathogen to adhere to prostheses, catheters and medical devices. PMID- 23811077 TI - Comparative immunochemical characteristics of botulinum neurotoxin type A and its associated proteins. AB - Clostridium botulinum strains secrete their neurotoxins (BoNT) along with a group of neurotoxin-associated proteins (NAPs) that enhance the oral toxicity and provide protection to the neurotoxin against acidity, temperature and proteases in the G.I. tract. A major component of NAPs is Hn-33, a 33 kDa protein, which is also protease resistant and strongly protects BoNT. The complex form of BoNT/A is used as a commercial therapeutic formulation against many neuromuscular disorders and for cosmetic purposes. Immune response against this formulation could hinder its long-term use; therefore, it is important to characterize the immunological properties of the associated proteins. This study aims to understand the immunological reactivity of BoNT/A complex, BoNT, NAPs, and Hn-33 through a series of competitive enzyme-linked immunosorbent assays (ELISA). The results indicated that BoNT/A complex competed 6 times more with complex antibodies compared to the neurotoxin confirming that the higher immunogenicity of BoNT/A complex was indeed a result of the associated proteins with the neurotoxin complex. While the nearly identical immuno-reactivity of BoNT/A complex and Hn-33 with Hn-33 antibodies indicated that the reactivity was due to the higher immunogenicity not the abundance of Hn-33 in the complex. Both the ELISA and immuno-blot results implied that Hn-33 is primarily responsible for eliciting the antibody response in BoNT/A complex. PMID- 23811079 TI - Dermatological conditions in military conscripts. AB - BACKGROUND: Published studies regarding skin conditions in the military are mainly cross-sectional studies from clinical encounters during war campaigns and military training. AIMS: To determine the incidence and spectrum of dermatological conditions in a cohort of military conscripts in Singapore. Soldiers diagnosed with contact dermatitis (CD) were further analysed for body area involvement, possible occupational and/or environmental causative agent and restrictions issued. METHODS: Retrospective cohort study. Subjects' diagnoses and demographic variables were extracted from electronic medical records. Medical records of CD cases were reviewed to characterize the nature of exposure and operational impact on training. RESULTS: The incidence of reporting of new dermatological complaints was 24.5 per 100 military conscripts per year. Dermatological conditions with the highest incidence over the period of full-time military service included fungal skin infection (6.7/100 conscripts/year), non specific dermatitis (4.9/100 conscripts/year) and insect bite reaction (1.8/100 conscripts/year). The annual incidence of contact dermatitis over the same period was 0.4/100 conscripts. CONCLUSIONS: In a military population based in the tropics fungal skin infections, non-specific dermatitis and insect bite reactions were the commonest reasons for dermatological consultation. CD incidence was 0.4 per 100 conscripts per year. PMID- 23811078 TI - Antioxidant and anti-aging activities of mycelial polysaccharides from Lepista sordida. AB - The intracellular polysaccharides (CLSP) were extracted from Lepista sordida mycelium in submerged culture followed by concentration and ethanol precipitation. The antioxidant activities of CLSP were evaluated both in vitro and in vivo. In vitro antioxidant assay, CLSP had noticeable scavenging activities on superoxide anion, hydroxyl radical and 2,2-diphenyl-1-picryl hydrazyl (DPPH) radical. For antioxidant testing in vivo, different doses of CLSP were orally administrated over a period of 6 weeks in a D-galactose induced aged mice model. As results, CLSP significantly inhibited the formation of malondialdehyde (MDA) and raised the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in mice brains and serums in a dose-dependent manner. The results provide a reference for large-scale production of CLSP by submerged fermentation and suggested that CLSP had potent antioxidant activity and could be explored as a potential dietary supplement to retard aging and attenuate age-related diseases in humans. PMID- 23811083 TI - Computational studies on Alzheimer's disease associated pathways and regulatory patterns using microarray gene expression and network data: revealed association with aging and other diseases. AB - Alzheimer's disease (AD), which is one of the most common age-associated neurodegenerative disorders, affects millions of people worldwide. Due to its polygenic nature, AD is believed to be caused not by defects in single genes, but by variations in a large number of genes and their complex interactions, which ultimately contribute to the broad spectrum of disease phenotypes. Extraction of insights and knowledge from microarray and network data will lead to a better understanding of complex diseases. The present study aimed to identify genes with differential topology and their further association with other biological processes that regulate causative factors for AD, ageing (AG) and other diseases. Our analysis revealed a common sharing of important biological processes and putative candidate genes among AD and AG. Some significant novel genes and other variants for various biological processes have been reported as being associated with AD, AG, and other diseases, and these could be implicated in biochemical events leading to AD from AG through pathways, interactions, and associations. Novel information for network motifs such as BiFan, MIM (multiple input module), and SIM (single input module) and their close variants has also been discovered and this implicit information will help to improve research into AD and AG. Ten major classes for TFs (transcription factors) have been identified in our data, where hundreds of TFBS patterns are being found associated with AD, and other disease. Structural and physico-chemical properties analysis for these TFBS classes revealed association of biological processes involved with other severe human disease. Nucleosomes and linkers positional information could provide insights into key cellular processes. Unique miRNA (micro RNA) targets were identified as another regulatory process for AD. The association of novel genes and variants of existing genes have also been explored for their interaction and association with other diseases that are either directly or indirectly implicated through AG and AD. PMID- 23811080 TI - Implantable cardioverter-defibrillators in lamin A/C mutation carriers with cardiac conduction disorders. AB - BACKGROUND: Sudden cardiac death is frequent in patients with lamin A/C gene (LMNA) mutations and may be related to ventricular arrhythmias (VA). OBJECTIVE: To evaluate a strategy of prophylactic implantable cardioverter-defibrillator (ICD) implantation in LMNA mutation carriers with significant cardiac conduction disorders. METHODS: Forty-seven consecutive patients (mean age 38 +/- 11 years; 26 men) were prospectively enrolled between March 1999 and April 2009. Prophylactic ICD implantation was performed in patients with significant cardiac conduction disorders: patients requiring permanent pacing for bradycardia or already implanted with a pacemaker at the initial presentation, or patients with a PR interval of >0.24 seconds and either complete left bundle branch block or nonsustained ventricular tachycardia. RESULTS: Twenty-one (45%) patients had significant conduction disorders and received a prophylactic ICD. Among ICD recipients, no patient died suddenly and 11 (52%) patients required appropriate ICD therapy during a median follow-up of 62 months. Left ventricular ejection fraction was >=45% in 9 patients at the time of the event. Among the 10 patients without malignant VA, device memory recorded nonsustained ventricular tachycardia in 8 (80%). The presence of significant conduction disorders was the only factor related to the occurrence of malignant VA (hazard ratio 5.20; 95% confidence interval 1.14-23.53; P = .03). CONCLUSIONS: Life-threatening VAs are common in patients with LMNA mutations and significant cardiac conduction disorders, even if left ventricular ejection fraction is preserved. ICD is an effective treatment and should be considered in this patient population. PMID- 23811082 TI - Effect of substrate competition in kinetic models of metabolic networks. AB - Substrate competition can be found in many types of biological processes, ranging from gene expression to signal transduction and metabolic pathways. Although several experimental and in silico studies have shown the impact of substrate competition on these processes, it is still often neglected, especially in modelling approaches. Using toy models that exemplify different metabolic pathway scenarios, we show that substrate competition can influence the dynamics and the steady state concentrations of a metabolic pathway. We have additionally derived rate laws for substrate competition in reversible reactions and summarise existing rate laws for substrate competition in irreversible reactions. PMID- 23811084 TI - Synthesis of oligosaccharide fragments of the rhamnogalacturonan of Nerium indicum. AB - Three trisaccharides, one pentasaccharide, and one heptasaccharide, namely alpha D-GalA-(1->2)-alpha-L-Rha-(1->4)-beta-D-GalA-OC3H7 (1), alpha-L-Rha-(1->4)-alpha D-GalA-(1->4)-beta-D-GalA-OC3H7 (2), alpha-D-GalA-(1->4)-alpha-D-GalA-(1->2) alpha-L-Rha-OC3H7 (3), alpha-D-GalA-(1->2)-alpha-L-Rha-(1->4)-alpha-D-GalA-(1->2) alpha-L-Rha-(1->4)-beta-D-GalA-OC3H7 (4), and alpha-D-GalA-(1->2)-alpha-L-Rha-(1 >4)-alpha-D-GalA-(1->2)-alpha-L-Rha-(1->4)-alpha-D-GalA-(1->2)-alpha-L-Rha-(1->4) beta-D-GalA-OC3H7 (5), which are relevant to the fragments of the rhamnogalacturonan of Nerium indicum, were concisely synthesized. The syntheses feature highly stereoselective formation of the alpha-D-GalA-linkage with GalA N phenyltrifluoroacetimidates as donors. PMID- 23811086 TI - Synthesis and biological evaluation of ursolic acid-triazolyl derivatives as potential anti-cancer agents. AB - A series of ursolic acid-1-phenyl-1H-[1,2,3]triazol-4-ylmethylester congeners have been designed and synthesized in an attempt to develop potent antitumor agents. A regioselective approach using Huisgen 1,3-dipolar cycloaddition reaction of ursolic acid-alkyne derivative with various aromatic azides was employed to target an array of triazolyl derivatives in an efficient manner. Their structures were confirmed by using (1)H NMR, (13)C NMR, IR and MS analysis. All the compounds were evaluated for anti-cancer activity against a panel of four human cancer cell lines including A-549 (lung), MCF-7 (breast), HCT-116 (colon), THP-1 (leukemia) and a normal human epithelial cell line (FR-2) using sulforhodamine-B assay. The pharmacological results showed that most of the compounds displayed high level of antitumor activities against the tested cancer cell lines compared with ursolic acid. Compounds 7b, 7g, 7p and 7r were found to be the most potent compounds in this study. PMID- 23811085 TI - Synthesis and biological activity evaluation of 5-pyrazoline substituted 4 thiazolidinones. AB - A series of novel 5-pyrazoline substituted 4-thiazolidinones have been synthesized. Target compounds were evaluated for their anticancer activity in vitro within DTP NCI protocol. Among the tested compounds, the derivatives 4d and 4f were found to be the most active, which demonstrated certain sensitivity profile toward the leukemia subpanel cell lines with GI50 value ranges of 2.12 4.58 MUM (4d) and 1.64-3.20 MUM (4f). The screening of antitrypanosomal and antiviral activities of 5-(3-naphthalen-2-yl-5-aryl-4,5-dihydropyrazol-1-yl) thiazolidine-2,4-diones was carried out with the promising influence of the mentioned compounds on Trypanosoma brucei, but minimal effect on SARS coronavirus and influenza types A and B viruses. PMID- 23811087 TI - Synthesis and antibacterial activities of N-substituted-glycinyl 1H-1,2,3 triazolyl oxazolidinones. AB - A series of 1H-1,2,3-triazolyl piperazino oxazolidinone analogs with optionally varied glycinyl substitutions were synthesized and their antibacterial activity assessed against a panel of susceptible and resistant Gram-positive and selected Gram-negative bacteria including clinical isolates. The N-aroyl- and N heteroaroyl-glycinyl (MIC: 0.06-4 MUg/ml) derivatives were more potent than the N acylglycinyl (2-8 MUg/ml) derivatives against all Gram-positive bacteria tested. Nitro substitution on aryl and heteroaryl rings significantly enhanced activity against Gram-positive bacteria, as noted with the 3,5-dinitrobenzoyl (6m and 6n) and 5-nitro-2-furoyl (6u and 6v) derivatives with MIC ranges of and 0.25-0.5 and 0.06-0.5 MUg/ml, respectively. These nitro analogs also showed more potent extended activity against Moraxella catarrhalis, with MICs ranges of 0.25-1 MUg/ml, compared to linezolid (MIC: 8 MUg/ml). Hence, the presence of the N-aroyl and/or N-heteroaroyl glycinyl structural motifs as spacer group could significantly enhance the antibacterial activities of 1H-1,2,3-triazolyl oxazolidinone class of compounds. PMID- 23811081 TI - Sinus rhythm restores ventricular function in patients with cardiomyopathy and no late gadolinium enhancement on cardiac magnetic resonance imaging who undergo catheter ablation for atrial fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) and systolic heart failure (HF) frequently coexist. Restoration of sinus rhythm by catheter ablation may result in a variable improvement in left ventricular (LV) function. Late-gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging identifies irreversible structural change and may predict incomplete recovery of LV function. OBJECTIVE: To prospectively select patients with AF and symptomatic HF but without LV LGE and report the impact of AF ablation on LV function. METHODS: Patients with AF and symptomatic HF (LV ejection fraction <50%) resistant to at least 1 antiarrhythmic drug and prior electrical cardioversion underwent contrast enhanced CMR. LGE-negative patients underwent pulmonary vein isolation and left atrial roof line with continued antiarrhythmic medications until follow-up CMR 6 months postablation. Sixteen patients (aged 52 +/- 11 years; mean AF duration 37 +/- 39 months; left atrial size 44 +/- 13 mL/m(2)) underwent AF ablation. RESULTS: At 6 months, 15 of the 16 patients maintained sinus rhythm and underwent CMR. LV ejection fraction increased from 40% +/- 10% at baseline to 60% +/- 6% (P < .001) and LV end-systolic volume index decreased from 52 +/- 12 to 36 +/- 9 mL/m(2) (P < .001). Left atrial size decreased from 44 +/- 13 to 36 +/- 11 mL/m(2) (P < .01). CONCLUSIONS: In patients with AF and LV dysfunction in the absence of LGE on CMR, ventricular function normalizes following the restoration of sinus rhythm. CMR may assist in the selection of patients with combined AF and systolic HF most likely to benefit from catheter ablation. PMID- 23811089 TI - First synthesis and biological evaluation of 4-amino-2-aryl-6,9 dichlorobenzo[g]pteridines as inhibitors of TNF-alpha and IL-6. AB - A direct new synthetic method on the chemistry of benzo[g]pteridines is reported. Reactions between 5,8-dichloro-2,3-dicyanoquinoxaline and benzamidines gave 4 amino-2-aryl-6,9-dichlorobenzo[g]pteridines in high to quantitative yields. The molecular structure of an N-acetyl derivative of a member of this family of compounds, 4-acetamido-6,9-dichloro-2-phenylbenzo[g]pteridine, was determined by X-ray crystallography. The synthesized compounds were evaluated for their potential anti-inflammatory activity as inhibitors of the pro-inflammatory cytokines TNF-alpha and IL-6. Compounds 5b, 5d and 5i showed the highest level of inhibition of both cytokines. The rest of the compounds into the series (5a, 5f, 5g and 5h), with the only exceptions of compounds 5c and 5e, which were unable to inhibit TNF-alpha and were the two compounds with the lower effect upon IL-6, were also able to reach good levels of inhibition of TNF-alpha and even higher levels of inhibition of IL-6. PMID- 23811088 TI - Modulation of alphavbeta3- and alpha5beta1-integrin-mediated adhesion by dehydro beta-amino acids containing peptidomimetics. AB - A novel class of low molecular weight ligands of alphavbeta3 and alpha5beta1 integrins, that possess a dehydro-beta-amino acid as conformationally constrained core, linked to the pharmacophoric moieties mimicking the RGD recognition sequence, have been synthesized through a very simple protocol. Cell adhesion assays and integrin-mediated signaling activation experiments suggested a good affinity of these compounds toward both integrin receptors. Moreover, further elongation with two glycine units allowed to obtain an excellent dual inhibitor. Structural models for alphavbeta3 integrin-ligand binding confirmed that the dehydro-beta-amino derivatives are able to act as an electrostatic clamp by establishing several stabilizing interactions with the receptor. PMID- 23811092 TI - Novel 2-(2,4-dioxo-1,3-thiazolidin-5-yl)acetamides as antioxidant and/or anti inflammatory compounds. AB - A series of novel N-(4-aryl-1,3-thiazol-2-yl)-2-(2,4-dioxo-1,3-thiazolidin-5 yl)acetamides (4a-k) and N-(1,3-benzothiazol-2-yl)-2-(2,4-dioxo-1,3-thiazolidin-5 yl)acetamide derivatives (4l-o) are synthesized and evaluated for their anti inflammatory and antioxidant activity (DPPH radical scavenging, superoxide anion scavenging, lipid peroxide inhibition, erythrocyte hemolytic inhibition). Compounds 4k and 4l have exhibited good antioxidant activity in four assays, while compounds 4c, 4d, 4m, 4n and 4o have shown good DPPH radical scavenging efficacy. Compounds 4a, 4h, 4i, 4k, 4m and 4n have possessed excellent anti inflammatory activity. N-[4-(o-methoxyphenyl)-1,3-thiazol-2-yl]-2-(2,4-dioxo-1,3 thiazolidin-5-yl)acetamide (4k) and N-(6-nitro-/methoxy-1,3-benzothiazol-2-yl)-2 (2,4-dioxo-1,3-thiazolidin-5-yl)acetamide (4m and 4n) have exhibited both antioxidant and anti-inflammatory activities. PMID- 23811094 TI - Failed attempts to help and harm: intention versus outcome in preverbal infants' social evaluations. AB - Mature moral judgments include an analysis of both the outcomes of others' actions as well as the mental states that drive them. While adults easily incorporate both intention and outcome into their moral evaluations, scores of developmental studies suggest that it may be uniquely difficult for young children to privilege intention in their judgments of right and wrong (e.g., Piaget, 1932/1965), leading to the conclusion that the 'moral mind' of the young child is fundamentally different from that of older children and adults. The current studies utilize a puppet-choice methodology shown to provoke reliable social preferences throughout the first year after birth (e.g., Hamlin, Wynn, & Bloom, 2007), and provide evidence that 8-month-old infants incorporate, and even privilege, intentions in their social evaluations. In contrast, 5-month-olds appear only able to distinguish characters who intend the outcomes they cause. Such results suggest that one requirement for mature moral judgments, the ability to distinguish between intentions and outcomes in morally relevant events, is present by 8months of age. PMID- 23811090 TI - Synthesis, biological evaluation and molecular docking studies of some pyrimidine derivatives. AB - Some novel pyrimidine-5-carbonitrile derivatives bearing various substituent have been synthesized. The structures of target compounds were confirmed by elemental analysis and spectral data. Some selected members of the newly synthesized compounds were investigated for their cytotoxic potency against certain human tumor cell lines. Five representative active anticancer compounds 6a, 6c, 6d, 17a and 18a were subjected to docking using MOE program on the 3D structure of two enzymes, namely; thymidylate synthase and dihydrofolate reductase. The antimicrobial activities of the synthesized compounds were tested against Staphylococcus aureus, Pseudomonas aeruginosa, Shigella flexneri and Candida albicans. Compounds 2c, 7a and 9c showed broad spectrum antimicrobial activity. PMID- 23811091 TI - Quercitylcinnamates, a new series of antidiabetic bioconjugates possessing alpha glucosidase inhibition and antioxidant. AB - Antidiabetic agents possessing dual functions, alpha-glucosidase inhibition and antioxidant, have been accepted to be more useful than currently used antidiabetic drugs because they not only suppress hyperglycemia but also prevent risk of complications. Herein, we design antidiabetic bioconjugates comprising of (+)-proto-quercitol as a glucomimic and cinnamic analogs as antioxidant moieties. Fifteen quercitylcinnamates were synthesized by direct coupling through ester bond in the presence of DCC and DMAP. Particular quercityl esters 6a, 7a and 8a selectively inhibited rat intestinal maltase and sucrose 4-6 times more potently than their parents 6, 7 and 8. Of synthesized bioconjugates, 6a was the most potent inhibitor against maltase and sucrose with IC50 values of 5.31 and 43.65 MUM, respectively. Of interest, its inhibitory potency toward maltase was 6 times greater than its parent, caffeic acid (6), while its radical scavenging (SC50 0.11 mM) was comparable to that of commercial antioxidant BHA. Subsequent investigation on mechanism underlying inhibitory effect of 6a indicated that it blocked maltase and sucrose functions by mixed inhibition through competitive and noncompetitive manners. PMID- 23811095 TI - LNETWORK: an efficient and effective method for constructing phylogenetic networks. AB - MOTIVATION: The evolutionary history of species is traditionally represented with a rooted phylogenetic tree. Each tree comprises a set of clusters, i.e. subsets of the species that are descended from a common ancestor. When rooted phylogenetic trees are built from several different datasets (e.g. from different genes), the clusters are often conflicting. These conflicting clusters cannot be expressed as a simple phylogenetic tree; however, they can be expressed in a phylogenetic network. Phylogenetic networks are a generalization of phylogenetic trees that can account for processes such as hybridization, horizontal gene transfer and recombination, which are difficult to represent in standard tree like models of evolutionary histories. There is currently a large body of research aimed at developing appropriate methods for constructing phylogenetic networks from cluster sets. The Cass algorithm can construct a much simpler network than other available methods, but is extremely slow for large datasets or for datasets that need lots of reticulate nodes. The networks constructed by Cass are also greatly dependent on the order of input data, i.e. it generally derives different phylogenetic networks for the same dataset when different input orders are used. RESULTS: In this study, we introduce an improved Cass algorithm, Lnetwork, which can construct a phylogenetic network for a given set of clusters. We show that Lnetwork is significantly faster than Cass and effectively weakens the influence of input data order. Moreover, we show that Lnetwork can construct a much simpler network than most of the other available methods. AVAILABILITY: Lnetwork has been built as a Java software package and is freely available at http://nclab.hit.edu.cn/~wangjuan/Lnetwork/. CONTACT: maozuguo@hit.edu.cn SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23811093 TI - Synthesis of 4-aminoquinoline-pyrimidine hybrids as potent antimalarials and their mode of action studies. AB - One of the most viable options to tackle the growing resistance to the antimalarial drugs such as artemisinin is to resort to synthetic drugs. The multi target strategy involving the use of hybrid drugs has shown promise. In line with this, new hybrids of quinoline with pyrimidine have been synthesized and evaluated for their antiplasmodial activity against both CQ(S) and CQ(R) strains of Plasmodium falciparum. These depicted activity in nanomolar range and were found to bind to heme as well as AT rich pUC18 DNA. PMID- 23811096 TI - Toll-like receptor 4 orchestrates neutrophil recruitment into airways during the first hours of Bordetella pertussis infection. AB - Most of the knowledge on the impact of Bordetella pertussis lipo-oligosaccharide (LOS) on the infectious process was obtained when the bacteria was established within the host. The aim of the present work was to determine the role of TLR4 at a very early step of the infectious process. To this end we used a transcriptomic approach on B. pertussis intranasal infection model in C3H/HeN, a TLR4-competent mouse strain, and C3H/HeJ, a TLR4-deficient mouse strain. The expression of approximately 140 genes was significantly changed 2 h post-infection in the C3H/HeN animals compared to the C3H/HeJ animals, which were essentially non responders at this early time point. Pathways specific for immunity and defense, chemokine- and cytokine-mediated functions and TLR signaling, were activated upon infection in the TLR4 competent mice either at 2 h or 24 h. Furthermore, we observed that TLR4 signaling is absolutely required to promote the rapid recruitment of neutrophils into the airways. Interestingly, the depletion of those neutrophils impacted on B. pertussis lung counts in the first three days, thereby exacerbating the lung infection. In summary, we determined that TLR4 is a central player in initial neutrophil recruitment and orchestration of the very early innate defense against B. pertussis. PMID- 23811098 TI - Changes in sensory properties and consumer acceptance of reduced fat pork Lyon style and liver sausages containing inulin and citrus fiber as fat replacers. AB - The effects of fat reduction in Lyon-style (25% fat) and liver sausages (30% fat) using inulin, citrus fiber and partially rice starch were studied in terms of sensory properties and consumer acceptance. Fat reduced Lyon-style sausages (3 to 17% fat) and liver sausages (3 to 20% fat) were respectively compared to the full fat controls. Reducing fat in Lyon-style sausages decreased meat flavor, aftertaste meat flavor, greasiness and juiciness, and enhanced color intensity, spiciness, spicy aftertaste, raspy throat, coarseness and firmness scores. But adding inulin and citrus fiber led to sensory characteristics similar to the full fat reference. Regarding liver sausages, attribute scores in greasiness, creaminess, lumpiness and foamy were decreased with fat reduction and simultaneous addition of fibers. Color intensity, spiciness, firmness and attribute furred tongue were increased. Consumer tests revealed acceptable fat reduced (32 to 90% less than control) and fiber enriched (1.0 to 5.6%) sausages. Drivers of liking were found to relate not only to high-fat but also to low-fat samples. PMID- 23811097 TI - NLRP6 in infection and inflammation. AB - NLRs play fundamental roles in host-defense and inflammatory disorders. NLRP6 is a newly characterized member of this family that inhibits NF-kappaB and MAP kinase dependent immune signaling to hamper anti-microbial defense. Further, NLRP6 regulates intestinal inflammation by maintaining gut microbiota composition. In this review, we examine the recent studies and emphasize the key functions regulated by NLRP6. PMID- 23811099 TI - Evaluation of genetic fidelity among micropropagated plants of Gloriosa superba L. using DNA-based markers--a potential medicinal plant. AB - Malabar glory lily (Gloriosa superba L.) is a medicinally potent plant species used for the production of alkaloid colchicine. With ever increasing demand, there is a pressing need to conserve it through biotechnological approaches. A large number of complete plantlets were obtained by direct regeneration from the non-dormant tuber explants on Murashige and Skoog (MS) medium supplemented with 2.0 mg/l 6-benzylaminopurine (BAP)+0.5 mg/l alpha-naphthalene acetic acid (NAA). Large number of plants can be produced in vitro under aseptic conditions, but there is always a danger of producing somaclonal variants by tissue culture technology. Thus, the genetic stability of micropropagated clones was evaluated using random amplified polymorphic DNA (RAPD) and inter simple sequence repeat (ISSR) analysis. During the study a total of 80 (50 RAPD and 30 ISSR) primers were screened, out of which 10 RAPD and 7 ISSR primers produced a total of 98 (49 RAPD and 49 ISSR) clear, distinct and reproducible amplicons. The amplification products of the regenerated plants showed similar banding patterns to that of the mother plant thus demonstrating the homogeneity of the micropropagated plants. This is the first report that evaluates the use of genetic markers to establish genetic fidelity of micropropagated G. superba using RAPD and ISSR, which can be successfully applied for the mass multiplication, germplasm conservation and further genetic transformation assays for colchicine production to meet the ever increasing demand of this medicinally potent plant for industrial and pharmaceutical uses. PMID- 23811100 TI - Inhibitory effects of alpha-mangostin on mammalian DNA polymerase, topoisomerase, and human cancer cell proliferation. AB - We found that the ethanol extract of mangosteen (Garcinia mangostana L.) fruit rind had a strong inhibitory effect on mammalian DNA polymerase (pol) activity and isolated alpha-mangostin as a potent pol inhibitor from the extract. In this study, the inhibitory activities against mammalian pols by alpha-mangostin and its related five compounds, 3-isomangostin, xanthone, 9,10-anthraquinone, 9 anthracenecarboxylic acid, and anthracene, were investigated. alpha-Mangostin was the most potent inhibitor of the mammalian pol species among the tested compounds, with IC50 values of 14.8-25.6 MUM. This compound also inhibited human DNA topoisomerases (topos) I and II activities with IC50 values of 15.0 and 7.5 MUM, respectively, but did not inhibit the activities of other DNA metabolic enzymes tested. alpha-Mangostin also did not directly bind to double-stranded DNA as determined by thermal transition analysis. alpha-Mangostin was found to suppress human colon HCT116 carcinoma cell proliferation with an LC50 of 18.5 MUM, inhibit the activity of cellular topos, halt cell cycle in the G2/M phase, and induce apoptosis. These results suggest that decreased proliferation by alpha mangostin may be a result of the inhibition of cellular topos rather than pols, and alpha-mangostin might be an anticancer chemotherapeutic agent. PMID- 23811101 TI - Selaginella tamariscina (Beauv.) possesses antimetastatic effects on human osteosarcoma cells by decreasing MMP-2 and MMP-9 secretions via p38 and Akt signaling pathways. AB - Selaginella tamariscina is a traditional medicinal plant for treatment of some advanced cancers in the Orient. However, the effect of S. tamariscina on metastasis of osteosarcoma and the underlying mechanism remain unclear. We tested the hypothesis that S. tamariscina suppresses cellular motility, invasion and migration and also investigated its signaling pathways. This study demonstrates that S. tamariscina, at a range of concentrations (from 0 to 50 MUg/mL), concentration-dependently inhibited the migration/invasion capacities of three osteosarcoma cell lines without cytotoxic effects. Zymographic and western blot analyses revealed that S. tamariscina inhibited the matrix metalloproteinase (MMP)-2 and MMP-9 enzyme activity, as well as protein expression. Western blot analysis also showed that S. tamariscina inhibits phosphorylation of p38 and Akt. Furthermore, SB203580 (p38 inhibitor) and LY294002 (PI3K inhibitor) showed the similar effects as S. tamariscina in U2OS cells. In conclusion, S. tamariscina possesses an antimetastatic activity in osteosarcoma cells by down-regulating MMP 2 and MMP-9 secretions and increasing TIMP-1 and TIMP-2 expressions through p38 and Akt-dependent pathways. S. tamariscina may be a powerful candidate to develop a preventive agent for osteosarcoma metastasis. PMID- 23811102 TI - Dietary exposure of the Belgian adult population to non-dioxin-like PCBs. AB - Non-dioxin-like polychlorinated biphenyls (ndl-PCBs), and some of their metabolites, might initiate neurological, neuroendocrinological, immunological and carcinogenic effects. Dietary exposure of the Belgian adult population to ndl PCBs was investigated in this study. Foods from five food groups, collected in Belgium in 2008, were analyzed by GC-MS/MS for the six indicator PCBs (PCB 28, 52, 101, 138, 153 and 180). Results were expressed as the sum of the six congeners. A dietary exposure assessment was performed, combining ndl-PCBs levels found in food with data from the national food consumption survey of 2004. Fish and fish products were the dominating food group in terms of contamination level, with the highest levels measured in the composite sample "other fishes" (18.58 ng/g FW). The dietary exposure of the Belgian population (n=3083) to ndl-PCBs ranged from 5.33 ng/kg b.w./day on average to 16.10 ng/kg b.w./day at the 99th percentile, using the lower bound concentration. The mean dietary exposure mainly originates from Fish and fish products (54.3%), followed by dairy products (28.5%). As neither EFSA nor JECFA have set a Tolerable Daily Intake for ndl PCBs, uncertainty remains about how to interpret the exposure data in terms of public health. PMID- 23811103 TI - A correlative study on data from pork carcass and processed meat (Bauernspeck) for automatic estimation of chemical parameters by means of near-infrared spectroscopy. AB - The use of near-infrared spectroscopy (NIRS) is proposed in this study for the characterization of the quality parameters of a smoked and dry-cured meat product known as Bauernspeck (originally from Northern Italy), as well as of some technological traits of the pork carcass used for its manufacturing. In particular, NIRS is shown to successfully estimate several key quality parameters (including water activity, moisture, dry matter, ash and protein content), suggesting its suitability for real time application in replacement of expensive and time consuming chemical analysis. Furthermore, a correlative approach based on canonical correlation analysis was used to investigate the spectral regions that are mostly correlated to the characteristics of interest. The identification of these regions, which can be linked to the absorbance of the main functional chemical groups, is intended to provide a better understanding of the chemical structure of the substrate under investigation. PMID- 23811104 TI - Antioxidant effects of soy sauce on color stability and lipid oxidation of raw beef patties during cold storage. AB - This study was conducted to evaluate the antioxidant effects of soy sauce on lipid oxidation and color stability of raw beef patties. Raw beef patties were formulated with four solutions such as NaCl (sodium chloride solution), NaCl/SS (1:1 ratio of sodium chloride and soy sauce solution), SS (soy sauce solution), or SS/A (soy sauce solution combined with 0.05% ascorbic acid) in the same salt concentration. Addition of soy sauce resulted in the decreased pH, lightness, and increased yellowness. Treatment SS/A had the lowest percent of metmyoglobin during storage (P<0.05). A reduction (P<0.05) in the 2-thiobarbituric acid, peroxide, and conjugated diene concentration as result of soy sauce addition were observed in treatments SS and SS/A at the end of the storage period. There were no differences (P>0.05) in free fatty acid concentration at the end of storage. The combined addition of soy sauce and ascorbic acid greatly improved (P<0.05) color stability and retarded lipid oxidation. PMID- 23811105 TI - Vitamin (B1, B2, B3 and B6) content and oxidative stability of Gastrocnemius muscle from dry-cured hams elaborated with different nitrifying salt contents and by two ageing times. AB - The effect of the amount of added nitrate and nitrate plus nitrite to dry-cured hams on the vitamin (B1, B2, B3, B6) content, the antioxidant enzyme superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSHPx) activities and the thiobarbituric acid reactive substances (TBARS) was assessed in Gastrocnemius muscle at the end of two ripening processes. Five different curing mixtures (Hi N: 600 KNO3; Lo-N: 150 KNO3; Hi-Mix: 600 KNO3+600 NaNO2; Lo-Mix: 150 KNO3+150 NaNO2; Hi-Mix/Asc: 600 KNO3+600 NaNO2+500 sodium ascorbate, expressed as mg of salts added on surface per kg of fresh ham) were evaluated in dry-cured hams aged for 11.5months (standard process, SP) and 22months (long process, LP). Minor differences in target parameters between the hams due to the process were found. The amount of nitrate when it was added alone or as a mixture of nitrate and nitrite, as well as the ascorbate addition to dry-cured hams did not affect vitamin B1, B2 and B3 contents. The level of vitamin B6 was affected by both the amount and the mixture of salts; the addition of nitrite reduced around 40% the content of vitamin B6, but it was not affected by nitrate or ascorbate. The activity of SOD and CAT decreased with the amount of nitrate and nitrite, while GSHPx and TBARS resulted unaffected. PMID- 23811106 TI - Effect of fat level on physicochemical, volatile compounds and sensory characteristics of dry-ripened "chorizo" from Celta pig breed. AB - A traditional Spanish dry-ripened sausage "chorizo" from Celta pig breed was formulated with 10, 20 and 30% of back fat (LF, MF and HF, respectively). An increase in fat content significantly affected the chemical composition of the sausages at the end of ripening (higher fat content and lower protein content and moisture) and physico-chemical parameters (lower pH, aw, hardness, springiness and chewiness and higher TBARS index, L*, a* and b* values). With the increase of fat in the sausage formulation a higher total content of free fatty acids (FFA) was also obtained, showing a greater lipolysis than in LF sausages. All these parameters were significantly affected by ripening time. A lower total content of volatile compounds were found in HF sausages, being detected 3 alcohols, 4 aldehydes, 12 esters, 3 ketones, 7 aliphatic and 4 aromatic hydrocarbons. Sensorial analysis showed differences for fat level and fat-lean cohesiveness within appearance attributes; odour intensity and spices odour within odour attributes and hardness within texture attributes. PMID- 23811107 TI - T-2 toxin exposure induces apoptosis in rat ovarian granulosa cells through oxidative stress. AB - OBJECTIVE: To investigate the reproductive toxicity and cytotoxicity of T-2 toxin, which is a mycotoxin, and to explore its potential apoptotic induction mechanism. METHODS: ovarian granulosa cells of rats were treated with T-2 toxin (1-100nM) for 24h. The cytotoxicity was assessed with MTT bioassay and apoptotic cells were detected by flow cytometry, and further identified by chromatin condensation and nuclear fragmentation with Hoechst 33258 under microscope; reactive oxygen species (ROS) with DCFH-DA was analyzed by fluorometry; total superoxide dismutase (SOD) was determined by NBT staining method. Glutathione peroxidase (GSHPx) activity was detected by UV colorimetric assay. The activity of catalase (CAT) in granulosa cells was measured by the Aebi method, and malondialdehyde (MDA) content was determined by thiobarbituric acid assay. RESULTS: T-2 toxin dose-dependently inhibited the growth of granulosa cells and resulted in apoptosis in rat granulosa cells. Treatment with T-2 toxin could induce ROS and MDA accumulation in granulosa cells, acompanying with losses of activities of SOD, GSH-Px and CAT, whereas T-2 toxin-induced apoptosis in granulosa cells could be significantly inhibited through the use of antioxidant Trolox. CONCLUSION: These data suggest that T-2 toxin may induce the apoptosis in rat granulosa cells through oxidative stress. PMID- 23811108 TI - Carbonic anhydrase activity from the gilthead sea bream (Sparus aurata) liver: the toxicological effects of heavy metals. AB - Many studies have shown that metal ions may lead to oxidative stress in biological systems. Accordingly, DNA damage, protein modification, enzyme inhibition and activation, lipid peroxidation and many other effects may occur in living organisms. Many different formations of metal ions may enter human cells along with water, air, and various foods, and humans are negatively affected by these conditions, either directly or indirectly. These effects may cause irreversible damage to human metabolism. In this study, the toxicological effects of heavy metals on carbonic anhydrase enzyme activity from the gilthead sea bream liver were investigated. The carbonic anhydrase enzyme was purified via affinity chromatography and had a specific activity of 6775.5EUmg(-1). The kinetics and characteristic properties, such as optimum pH, stable pH, optimum temperature, activation energy (Ea), activation enthalpy (DeltaH), Q10, Km, and Vmax, were determined for the purified enzyme SDS-polyacrylamide gel electrophoresis showed a single band and molecular weight of the subunit was approximately 25kDa. Cd(II), Cu(II), Ni(II) and Ag(I) inhibited the enzyme activity in vitro. The type of inhibition and Ki values for these metals were calculated from Lineweaver-Burk plots as 17.74mM, 36.20mM, 12.85mM and 0.025mM for Cd(II), Cu(II), Ni(II) and Ag(I), respectively. All the metals were noncompetitive inhibitors. PMID- 23811109 TI - Echocardiographic assessment of myocardial function in workers occupationally exposed to lead without clinically evident heart disease. AB - PURPOSE: The aim of the study was to evaluate echocardiographic changes in workers occupationally exposed to low doses of lead. METHODS: We enrolled 63 men occupationally exposed to lead into the study (group I). Unexposed group consisted of 49 healthy men (group II). Blood lead concentration (Pb-B) and blood zinc protoporphyrin concentration (ZnPP) were determined. Transthoracic echocardiographic examination was performed. RESULTS: In the studied groups, selected on the criterion of occupational exposure to lead, comparative analysis of echocardiographic parameters indicated statistically significant differences. A negative linear correlations between ZnPP and E' was observed in group I. It was proved that a higher concentration of ZnPP is independent risk factor of lowering the E' mean value in group I. CONCLUSIONS: Occupational exposure to low doses of lead is associated with the occurrence of discreet morphological and functional heart changes that in the future may predispose to disclosed pathology of heart. PMID- 23811110 TI - Effect of blueberry pretreatment on diethylnitrosamine-induced oxidative stress and liver injury in rats. AB - Diethylnitrosamine (DEN) treatment increases the generation of reactive oxygen species (ROS), apoptosis, necrosis and proliferation in the liver. Blueberries (BB; Vaccinium corymbosum L.) contain polyphenols and other active components and have high antioxidant capacities. We investigated the effect of BB pretreatment on DEN-induced liver injury and oxidative and nitrosative stress in male rats. Rats were fed with 5% and 10% BB containing diet for six weeks and DEN (200mg/kg; i.p.) was applied two days before the end of this period. Liver function tests were determined in serum and histopathological evaluation was performed in the liver tissue. Apoptosis-related proteins, Bax and B cell lymphoma-2 (Bcl-2) and proliferating cell nuclear antigen (PCNA) expressions were also examined. Oxidative and nitrosative stress were evaluated in the liver by measuring thiobarbituric acid reactive substances, diene conjugate, protein carbonyl and nitrotyrosine levels, and glutathione levels and glutathione peroxidase, superoxide dismutase and glutathione transferase (GST) activities. Pretreatment with high dose of BB reduced apoptotic, necrotic and proliferative changes in the liver induced by DEN. Dietary BB also decreased hepatic lipid peroxidation, protein oxidation and nitrotyrosine levels together with increased GST activity. In conclusion, BB may have an inhibiting effect on acute liver injury by reducing apoptosis, necrosis, proliferation, oxidative and nitrosative stress in DEN treated rats. PMID- 23811111 TI - Efficiencies of fragmentation of glycosaminoglycan chloramides of the extracellular matrix by oxidizing and reducing radicals: potential site-specific targets in inflammation? AB - Hypochlorous acid and its conjugate base, hypochlorite ions, produced under inflammatory conditions, may produce chloramides of glycosaminoglycans, these being significant components of the extracellular matrix (ECM). This may occur through the binding of myeloperoxidase directly to the glycosaminoglycans. The N Cl group in the chloramides is a potential selective target for both reducing and oxidizing radicals, leading possibly to more efficient and damaging fragmentation of these biopolymers relative to the parent glycosaminoglycans. To investigate the effect of the N-Cl group, we used ionizing radiation to produce quantifiable concentrations of the reducing radicals, hydrated electron and superoxide radical, and also of the oxidizing radicals, hydroxyl, carbonate, and nitrogen dioxide, all of which were reacted with hyaluronan and heparin and their chloramides in this study. PAGE gels calibrated for molecular weight allowed the consequent fragmentation efficiencies of these radicals to be calculated. Hydrated electrons were shown to produce fragmentation efficiencies of 100 and 25% for hyaluronan chloramide (HACl) and heparin chloramide (HepCl), respectively. The role of the sulfate group in heparin in the reduction of fragmentation can be rationalized using mechanisms proposed by M.D. Rees et al. (J. Am. Chem. Soc.125:13719-13733; 2003), in which the initial formation of an amidyl radical leads rapidly to a C-2 radical on the glucosamine moiety. This is 100% efficient at causing glycosidic bond breakage in HACl but only 25% efficient in HepCl, the role of the sulfate group being to favor the nonfragmentary routes for the C-2 radical. The weaker reducing agent, the superoxide radical, did not cause fragmentation of either HACl or HepCl although kinetic reactivity had been demonstrated in earlier studies. Experiments using the oxidizing radicals, hydroxyl and carbonate, both potential in vivo species, showed significant increases in fragmentation efficiencies for both HACl and HepCl, relative to the parent molecules. The carbonate radical was shown to be involved in site-specific reactions at the N-Cl groups, reacting via abstraction of Cl, to produce the same amidyl radical produced by one-electron reductants such as the hydrated electron. As for the hydrated electrons, the data support fragmentation efficiencies of 100 and 29% for reaction of carbonate radicals at N-Cl for HACl and HepCl, respectively. For the weaker oxidant, nitrogen dioxide, no fragmentation was observed, probably because of a low kinetic reactivity and low reduction potential. It seems likely therefore that the N-Cl group can direct damage to extracellular matrix glycosaminoglycan chloramides, which may be produced under inflammatory conditions. The in vivo species, the carbonate radical, is also much more likely to be site-specific in its reactions with such components of the ECM than the hydroxyl radical. PMID- 23811112 TI - Randomized controlled trial of danoprevir plus peginterferon alfa-2a and ribavirin in treatment-naive patients with hepatitis C virus genotype 1 infection. AB - BACKGROUND & AIMS: The combination of a hepatitis C virus (HCV) protease inhibitor, peginterferon, and ribavirin is the standard of care for patients with HCV genotype 1 infection. We report the efficacy and safety of response-guided therapy with danoprevir (a potent second-generation protease inhibitor), peginterferon alfa-2a (40 KD), and ribavirin in these patients. METHODS: Treatment-naive patients (N = 237) were randomly assigned to groups given 12 weeks of danoprevir (300 mg every 8 hours; 600 mg every 12 hours, and 900 mg every 12 hours) or placebo plus peginterferon alfa-2a and ribavirin, followed by peginterferon alfa-2a and ribavirin. Patients given danoprevir who had an extended rapid virologic response (eRVR4-20: HCV RNA <15 IU/mL during weeks 4-20) stopped therapy at week 24; those without an eRVR4-20 continued therapy to 48 weeks. Patients who were given placebo received 48 weeks of peginterferon alfa-2a and ribavirin. The primary efficacy end point was sustained virologic response (SVR: HCV RNA <15 IU/mL after 24 weeks without treatment). RESULTS: Rates of SVR were higher among patients given danoprevir 300 mg (68%), 600 mg (85%), and 900 mg (76%) than placebo (42%) (95% confidence interval: 26%-59%). Seventy-nine percent of patients given danoprevir 600 mg had an eRVR4-20; among these, 96% had an SVR. Serious adverse events were reported in 7% to 8% of patients given danoprevir and 19% given placebo. Four patients given danoprevir (1 patient in the 600-mg group and 3 in the 900-mg group) had reversible, grade 4 increases in alanine aminotransferase, which led to early discontinuation of the 900-mg arm of the study. CONCLUSIONS: The combination of danoprevir, peginterferon alfa-2a, and ribavirin leads to high rates of SVR in patients with HCV genotype 1 infection, but high doses of danoprevir can lead to grade 4 increases in alanine aminotransferase. Studies of lower doses of danoprevir with ritonavir, to reduce overall danoprevir exposure while maintaining potent antiviral activity, are underway; Clinicaltrials.gov number, NCT00963885. PMID- 23811113 TI - Liposomal-praziquantel: efficacy against Schistosoma mansoni in a preclinical assay. AB - Currently, schistosomiasis mansoni is treated clinically with praziquantel (PZQ). Nevertheless, cases of tolerance and resistance to this drug have been reported, creating the need to develop new drugs or to improve existing drugs. Considering the small number of new drugs against Schistosoma mansoni, the design of nanotechnology-based drug delivery systems is an important strategy in combating this disease. The aim of this study was to evaluate the activity of PZQ containing liposome (lip.PZQ) on S. mansoni, BH strain. Mice were treated orally with different concentrations of PZQ and lip.PZQ 30 and 45 days following infection. The number of worms, recovered by perfusion of the hepatic portal system, and the number of eggs found in the intestine and liver were analysed. Parasite egg counts were also performed. The most active formulation for all parameters was 300mg/kg of lip.PZQ, since as it decreased the total number of worms by 68.8%, the number of eggs in the intestine by 79%, and the number of hepatic granulomas by 98.4% compared to untreated controls. In addition, this concentration decreased egg counts by 55.5%. The improved efficacy of the treatment with lip.PZQ, especially when administered 45 days following infection, compared with the positive-control group (untreated) and the groups that received free PZQ, can be explained by greater bioavailability in the host organism; the preferred target of lip.PZQ is the liver, and lip.PZQ is better absorbed by the tegument of S. mansoni, which has an affinity for phospholipids. PMID- 23811115 TI - Detection of sentinel lymph node metastases in cervical cancer: assessment of KRT19 mRNA in the one-step nucleic acid amplification (OSNA) method. AB - OBJECTIVE: The purpose of this study was to examine the utility of the one-step nucleic acid amplification (OSNA) assay using cytokeratin (CK) 19 (KRT19) messenger RNA (mRNA) for the detection of sentinel lymph node (SLN) metastases in cervical cancer patients. METHODS: To determine a cutoff value, KRT19 mRNA was assessed by OSNA assay using 239 lymph nodes (LNs) (217 histopathologically negative LNs and 22 positive LNs). A cutoff value was determined by statistical analysis of the copy numbers obtained by OSNA assay. Subsequently, performance evaluation of the OSNA assay (applying the cutoff value above) on 130 SLNs (32 patients) was used to investigate (through concordance) whether the OSNA assay exhibited diagnostic performance equivalent to the two-mm interval histopathological examination. RESULTS: Two hundred fifty copies/MUL of KRT19 mRNA in the OSNA assay appeared to be an optimal cutoff value. In performance evaluation of the OSNA assay, we identified five positive SLNs and 125 negative SLNs by OSNA assay using KRT19 mRNA, exhibiting 96.2% agreement with two-mm interval histopathological examination. CONCLUSIONS: Our results indicated that the KRT19 mRNA OSNA assay can detect LN metastases as accurately as two-mm interval histopathological examination and thus may be an effective additional or alternative method for a rapid intra-operative examination of SLNs in cervical cancer. PMID- 23811114 TI - Multiple roles of the gene zinc finger homeodomain-2 in the development of the Drosophila wing. AB - The gene zfh2 and its human homolog Atbf1 encode huge molecules with several homeo- and zinc finger domains. It has been reported that they play important roles in neural differentiation and promotion of apoptosis in several tissues of both humans and flies. In the Drosophila wing imaginal disc, Zfh2 is expressed in a dynamic pattern and previous results suggest that it is involved is proximal distal patterning. In this report we go further in the analysis of the function of this gene in wing development, performing ectopic expression experiments and studying its effects in genes involved in wing development. Our results suggest that Zfh2 plays an important role controlling the expression of several wing genes and in the specification of those cellular properties that define the differences in cell proliferation between proximal and distal domains of the wing disc. PMID- 23811116 TI - Electrochemotherapy can be used as palliative treatment in patients with repeated loco-regional recurrence of squamous vulvar cancer: a preliminary study. AB - OBJECTIVE: Electrochemotherapy (ECT) is an attractive treatment for solid cutaneous tumours with a good response rate (55-92%). No studies have evaluated ECT performed in vulvar cancer. The aim of our study was to evaluate the safety, local tumour efficacy and relief of symptoms of ECT treatment in patients affected by recurrence of squamocellular vulvar cancer (V-SCC) unsuitable for standard treatments. METHODS: We enrolled nine patients with histological diagnosis of recurrence of V-SCC. Intravenous bleomycin was injected under general sedation after an accurate mapping of all lesions and ECT was performed. Patients were reviewed after one, three and six months. Response to therapy was evaluated using RECIST criteria and quality of life (QoL) was evaluated via questionnaires. RESULTS: The median age was 84 years (range 80-90 years). The main location of recurrences was the vulva (87.5%). Multiple lesions were present in 25% of cases. No peri-operative complications were observed. Response to therapy was complete in 62.5% of patients, partial in 12.5%, no change was observed in 12.5% and progression of disease in 12.5% of patients respectively. Evaluation of symptoms showed a significant reduction of pain, bleeding, odour (p < 0.04) and urinary discomfort (p < 0.04). We observed two relapses at four and seven months after treatment. After nine months fifty percent of patients were alive. CONCLUSIONS: Our preliminary study showed that ECT is a suitable procedure in elderly patients with loco-regional vulvar cancer relapses. ECT can be used as palliative therapy and the treatment relieves symptoms and improves QoL. PMID- 23811117 TI - Overfitting in prediction models - is it a problem only in high dimensions? AB - The growing recognition that human diseases are molecularly heterogeneous has stimulated interest in the development of prognostic and predictive classifiers for patient selection and stratification. In the process of classifier development, it has been repeatedly emphasized that in situations where the number of candidate predictor variables is much larger than the number of observations, the apparent (training set, resubstitution) accuracy of the classifiers can be highly optimistically biased and hence, classification accuracy should be reported based on evaluation of the classifier on a separate test set or using complete cross-validation. Such evaluation methods have however not been the norm in the case of low-dimensional, p12 months in 38 patients). The patterns of recurrence were presented as loco-regional recurrence in 36 (50%) and distant metastasis in 36 patients (50%). Types of the initial treatment included operations in 28 (39%), chemotherapy and/or radiotherapy in 38 (53%) and radiofrequency ablation in 2 patients (3%). Four patients (6%) rejected treatment. Forty-three patients (62%) presented a good response to the initial treatment. Thirty-seven patients (51%) died, and the cause of death in all of these patients was cancer-related. The median survival duration after recurrence was 43.6 (1-136) months. Univariate analysis identified no recurrence of symptoms, a good response to treatment and a longer RFI as good prognostic factors, while a good response to treatment and a longer RFI were independent prognostic factors in multivariate analysis. CONCLUSIONS: Most postoperative recurrences were detected in an asymptomatic condition during the routine follow-up period, and a good response to initial treatment and a longer RFI were significant predictors of better post-recurrence survival in patients with completely resected Stage I NSCLC. PMID- 23811123 TI - Aorta-right atrial tunnel in an adult. PMID- 23811124 TI - Low-expression of microRNA-107 inhibits cell apoptosis in glioma by upregulation of SALL4. AB - Glioma is the most common highly malignant primary brain tumor. The molecular pathways that result in the pathogenesis of glioma remain elusive. In this study, we found microRNA-107 (miR-107) was downregulated in glioma tissues and cell lines. Our results revealed miR-107 overexpression suppressed cell proliferation in glioma cells, whereas miR-107 knockdown promoted cell growth in MO59K. miR-107 expression induced apoptosis in glioma cells possibly through the increase in Fas (TNFRSF6)-associated via death domain (FADD) expression and activation of caspases-8 and -3/7. Moreover, the activity of caspase-8 in miR-107 overexpressing SHG44 cells was suppressed with FADD knockdown. The tumor growth in nude mice bearing miR-107-overexpressing SHG44 cells was blocked through apoptosis induction. Sal-like 4 (Drosophila) (SALL4) level was reduced upon miR 107 overexpression in glioma cells, and the inverse was observed upon miR-107 knockdown in MO59K. Using a luciferase reporter system, SALL4 3'-UTR-dependent luciferase activity was reduced by miR-107 mimics or increased by an inhibitor of miR-107. In SHG44, SALL4 downregulation triggered growth inhibition and activated FADD-mediated cell apoptosis pathway. The caspase-8 activity in miR-107 overexpressing SHG44 cells was suppressed with SALL4 upregulation. Furthermore, primary glioma tumors with low miR-107 expression show elevated SALL4 level. An obvious inverse correlation was observed between miR-107 expression and SALL4 level in clinical glioma samples. Therefore, our results demonstrate upregulation of miR-107 suppressed glioma cell growth through direct targeting of SALL4, leading to the activation of FADD/caspase-8/caspase-3/7 signaling pathway of cell apoptosis. These data suggest miR-107 is a potential therapeutic target against glioma. PMID- 23811125 TI - New perspectives in nanomedicine. AB - Recent advances in nanotechnology have revolutionised all aspects of life, from engineering to cosmetics. One of the most exciting areas of development is that of nanomedicine. Due to their size (less than 100nm in one aspect), nanoparticles exhibit properties that are unlike that of the same material in bulk size. These unique properties are being exploited to create new diagnostics and therapeutics for application in a broad spectrum of organ systems. Indeed, nanoparticles are already being developed as effective carriers of drugs to target regions of the body that were previously hard to access using traditional drug formulation methods. However, in addition to their role as a vehicle for drug delivery, nanoparticles themselves have the potential to have therapeutic benefit. Through manipulation of their elemental composition, size, shape, charge and surface modification or functionalisation it may be possible to target particles to specific organs where they may elicit their therapeutic effect. In this review we will focus on the recent advances in nanotechnology for therapeutic applications with a particular focus on the respiratory system, cancer and vaccinations. In addition we will also address developments in the field of nanotoxicology and the need for concomitant studies in to the toxicity of emerging nanotechnologies. It is possible that the very properties that make nanoparticles a desirable technology for therapeutic intervention may also lead to adverse health effects. It is thus important to determine, and appreciate, the fine balance between the efficacy and toxicity of nanomedicine. PMID- 23811126 TI - Mechanisms for surface contamination of soils and bottom sediments in the Shagan River zone within former Semipalatinsk Nuclear Test Site. AB - The Shagan River is the only surface watercourse within the former Semipalatinsk Test Site (STS). Research in the valley of the Shagan River was carried out to study the possible migration of artificial radionuclides with surface waters over considerable distances, with the possibility these radionuclides may have entered the Irtysh River. The investigations revealed that radioactive contamination of soil was primarily caused by the first underground nuclear test with soil outburst conducted at the "Balapan" site in Borehole 1004. The surface nuclear tests carried out at the "Experimental Field" site and global fallout made insignificant contributions to contamination. The most polluted is the area in the immediate vicinity of the "Atomic" Lake crater. Contamination at the site is spatial. The total area of contamination is limited to 10-12 km from the crater piles. The ratio of plutonium isotopes was useful to determine the source of soil contamination. There was virtual absence of artificial radionuclide migration with surface waters, and possible cross-border transfer of radionuclides with the waters of Shagan and Irtysh rivers was not confirmed. PMID- 23811127 TI - Translocation of (125)I, (75)Se and (36)Cl to edible parts of radish, potato and green bean following wet foliar contamination under field conditions. AB - Specific translocation factor values (ftr) for (129)I, (79)Se and (36)Cl following foliar transfer are still missing from the IAEA reference databases. The translocation of the short-lived isotopes, (125)I, (75)Se, and (36)Cl, to radish, potato and green bean edible parts was measured under field conditions following acute and chronic wet foliar contamination at various plant growth stages in the absence of leaching caused by rain. The translocation factors obtained for (125)I ranged from 0.8 to 2.6% for radish, from 0.1 to 2.3% for potato and from 0.1 to 2.6% for bean. The translocation factors obtained for (75)Se ranged from 6.3 to 21% for radish, from 1.6 to 32.6% for potato and from 7.7 to 22.8% for bean (values similar to Cs or even higher). The translocation factors obtained for (36)Cl were close to those for (75)Se and ranged from 4.3 to 28.8% for radish, from 0.5 to 31.5% for potato and from 4.3 to 16.3% for bean. Iodide showed the lowest apparent mobility because of its preferential fixation in or on the leaves and a significant amount was probably volatilized. Selenite internal transfer was significant and possibly followed the sulfur metabolic pathway. Chloride was very mobile and quickly diffused throughout the plant. The translocation factors varied with the growth stage and depended on the development state of the edible tissue and its associated sink strength for nutrients and assimilates. For radish, translocation was high during the early vegetative stages. For potato, wheat and bean, a major peak in translocation was seen during the flowering growth stage and the concomitant growth of potato tubers. An additive effect of successive contamination events on translocated elements was shown in radish but not in bean and potato. The highest translocation value obtained for an acute contamination event was shown to be an adequate, conservative indicator of chronic contamination in absence of specific values. Due to the absence of rain leaching during the experiment this study probably provides translocation values among the highest that could be recorded. PMID- 23811128 TI - Determination of mechanisms and parameters which affect radon entry into a room. AB - There are practically no direct techniques for measuring radon entry rate in the rooms. The suggested technique allows estimating such parameter under real conditions. The technique for radon diagnostic procedures including radon entry rate and air change rate assessment was proposed and tested in the field under various experimental conditions. The method consists of the continuous measurement of radon concentration, temperature and pressure difference between indoor and outdoor atmosphere. It was demonstrated that the study of dependence of radon entry rate on temperature difference DeltaT between indoor and outdoor atmosphere allows to estimate the dominant radon entry mechanism - diffusion mechanism (absence of the dependence on DeltaT) or convective (radon entry rate increase at DeltaT increase). It was shown that simultaneous measurements of time series of radon concentration and pressure difference between building envelope and outdoor atmosphere allow assessing such room parameter as Effective Leakage Area. The approach applied in this paper to estimate the air change rate practically is not differing from tracer gas techniques when the constant gas entry rate is used. It was shown that radon could be used as kind of tracer gas to estimate the air change rate. Obtained measurement results for all buildings confirmed the seasonal variations of radon concentrations. A correlation of radon concentration and air change rate with outside temperature occurred in general. PMID- 23811129 TI - TOCATTA: a dynamic transfer model of (3)H from the atmosphere to soil-plant systems. AB - This paper describes a dynamic compartment model (TOCATTA) that simulates tritium transfer in agricultural plants of several categories including vegetables, pasture and annual crops, exposed to time-varying HTO concentrations of water vapour in the air and possibly in irrigation and rainwater. Consideration is also given to the transfer pathways of HTO in soil. Though the transfer of tritium is quite complex, from its release into the environment to its absorption and its incorporation within the organic material of living organisms, the TOCATTA model is relatively simple, with a limited number of compartments and input parameters appropriate to its use in an operational mode. In this paper, we took the opportunity to have data obtained on an ornamental plant - an indoor palm tree - within an industrial building where tritium was released accidentally over several weeks (or months). More specifically, the model's ability to provide hindsight on the chronology of the release scenario is discussed by comparing model predictions of TFWT and OBT activity concentrations in the plant leaves with measurements performed on three different leaves characterized by different developmental stages. The data-model comparison shows some limitations, mainly because of a lack of knowledge about the initial conditions of the accident and when it actually started and about the processes involved in the transfer of tritium. Efforts are needed in both experimental and modelling areas for future evaluation of tritium behaviour in agricultural soil and plants exposed to gaseous HTO releases and/or to irrigation with contaminated water. PMID- 23811130 TI - Monitoring rainwater and seaweed reveals the presence of (131)I in southwest and central British Columbia, Canada following the Fukushima nuclear accident in Japan. AB - Detailed analysis of (131)I levels in rainwater and in three species of seaweed (Fucus distichus Linnaeus, Macrocystis pyrifera, and Pyropia fallax) collected in southwest British Columbia and Bella Bella, B.C., Canada was performed using gamma-ray spectroscopy following the Fukushima nuclear power plant accident on March 11, 2011. Maximum (131)I activity was found to be 5.8(7) Bq/L in rainwater collected at the campus of Simon Fraser University in Burnaby, B.C. nine days after the accident. Concomitantly, maximum observed activity in the brown seaweed F. distichus Linnaeus was observed to be 130(7) Bq/kg dry weight in samples collected in North Vancouver 11 days following the accident and 67(6) Bq/kg dry weight in samples collected from the Bamfield Marine Sciences Centre on Vancouver Island 17 days following the accident. The (131)I activity in seaweed samples collected in southwest B.C. following the Fukushima accident was an order of magnitude less than what was observed following Chernobyl. Iodine-131 activity in F. distichus Linnaeus remained detectable for 60 days following the accident and was detectable in each seaweed species collected. The Germanium Detector for Elemental Analysis and Radioactivity Studies (GEARS) was modeled using the Geant4 software package and developed as an analytical tool by the Nuclear Science group in the Simon Fraser University Department of Chemistry for the purpose of these measurements. PMID- 23811131 TI - Influence of storage temperature and moisture on the performance of microsphere/hydrogel composites. AB - The current study involved investigation of the effect of storage temperature and moisture on the performance of poly(lactide-co-glycolide) (PLGA) microsphere/poly(vinyl-alcohol) (PVA) hydrogel composites. Physical aging occurred in composites stored at 25 degrees C due to structural relaxation. The glass transition temperature (Tg) and enthalpy of relaxation of the composites increased leading to a slower cumulative % release. The Tg of composites incubated at 40 degrees C, 75% RH decreased significantly due to the plasticization effect of absorbed water, whereas no change was observed in the Tg of microspheres alone; indicating that the hydrogel component enhanced water absorption. PLGA degradation occurred leading to significantly faster dexamethasone release following incubation at 40 degrees C, 75% RH for 1 month. No significant change was observed in the in vitro release profiles of composites after 6 months storage at 25 degrees C, 60% RH, however, release was accelerated following 12 months storage. Accordingly, exposure of the composites to ambient temperature/moisture during storage, shipping or handling may cause physical aging, plasticization, and degradation and hence, their performance may be affected. The extent to which the performance of the composite is affected by storage temperature and moisture is a net effect of physical aging and moisture induced plasticization/hydrolytic degradation. PMID- 23811132 TI - Mixed protein-DNA gel particles for DNA delivery: role of protein composition and preparation method on biocompatibility. AB - Mixtures of two cationic proteins were used to prepare protein-DNA gel particles, employing associative phase separation and interfacial diffusion (Moran et al., 2009a). By mixing the two proteins, we have obtained particles that displayed higher loading efficiency and loading capacity values than those obtained in single-protein systems. However, nothing is known about the adverse effects on haemocompatibility and cytotoxicity of these protein-DNA gel particles. Here, we examined the interaction of protein-DNA gel particles obtained by two different preparation methods, and their components, with red blood cells and established cells. From a haemolytic point of view, these protein-DNA gel particles were demonstrated to be promising long-term blood-contacting medical devices. Safety evaluation with the established cell lines revealed that, in comparison with proteins in solution, the cytotoxicity was reduced when administered in the protein-DNA systems. In comparison with large-sized particles, the cytotoxic responses of small-sized protein-DNA gel particles showed to be strongly dependent of both the protein composition and the cell line being the tumour cell line HeLa more sensitive to the deleterious effects of the mixed protein-based particles. The observed trends in haemolysis and cell viabilities were in agreement with the degree of complexation values obtained for the protein-DNA gel particles prepared by both preparation methods. PMID- 23811133 TI - Spelaeicoccus albus gen. nov., sp. nov., an actinobacterium isolated from a natural cave. AB - A novel Gram-stain-positive, non-endospore-forming, coccoid actinobacterium, designated strain D3-40(T), was isolated from the soil of a natural cave and characterized by means of a polyphasic taxonomic analysis. 16S rRNA gene sequence analysis showed that strain D3-40(T) is a member of the suborder Micrococcineae and forms a distinct branch at the base of a Brevibacteriaceae cluster. Its closest relative is the type strain of Brevibacterium samyangense (95.7 % sequence similarity). The chemotaxonomic characteristics were as follows: the cell-wall peptidoglycan contained meso-diaminopimelic acid as the diagnostic diamino acid; the major menaquinone was MK-9(H2); the polar lipids consisted of phosphatidylglycerol, phosphatidylinositol, an unknown glycolipid and an unknown phospholipid; the major fatty acids were anteiso-C15 : 0, anteiso-C17 : 0, iso C15 : 0, C16 : 0 and cyclohexyl-C17 : 0; mycolic acids were absent. The G+C content of the DNA was 64.3 mol%. On the basis of morphological, chemotaxonomic and phylogenetic data, it is suggested that the organism represents a novel species of a new genus within the family Brevibacteriaceae, for which the name Spelaeicoccus albus gen. nov., sp. nov. is proposed. The type strain of the type species is D3-40(T) ( = KCTC 29141(T) = DSM 26341(T)). PMID- 23811134 TI - Halomonas zincidurans sp. nov., a heavy-metal-tolerant bacterium isolated from the deep-sea environment. AB - A Gram-stain-negative, aerobic, rod-like, motile by peritrichous flagella and moderately halophilic bacterium, designated strain B6(T), was isolated a deep-sea sediment collected from the South Atlantic Ocean. The isolate grew with 0.5-15 % (w/v) NaCl, at 4-37 degrees C and pH 5.0-8.5 and showed a high tolerance to zinc, manganese, cobalt and copper ions. The major fatty acids were C16 : 0, C19 : 0 cyclo omega8c, C12 : 0 3-OH and C12 : 0. The predominant ubiquinone was Q-9. The genomic DNA G+C content was 61.1 mol%. Phylogenetic analysis based on 16S rRNA gene comparisons indicated that strain B6(T) belonged to the genus Halomonas, and the closest relative was Halomonas xinjiangensis TRM 0175(T) (96.1 %). Based upon the phenotypic, chemotaxonomic and genetic data, strain B6(T) represents a novel species from the genus Halomonas, for which the name Halomonas zincidurans sp. nov. is proposed. The type strain is B6(T) ( = CGMCC 1.12450(T) = JCM 18472(T)). PMID- 23811135 TI - Isolation and characterization of Desulfocurvus thunnarius sp. nov., a sulfate reducing bacterium isolated from an anaerobic sequencing batch reactor treating cooking wastewater. AB - A novel anaerobic, chemo-organotrophic, sulfate-reducing bacterium, designated strain Olac 40(T), was isolated from a Tunisian wastewater digestor. Cells were curved, motile rods or vibrios (5.0-7.0*0.5 um). Strain Olac 40(T) grew at temperatures between 15 and 50 degrees C (optimum 40 degrees C), and between pH 5.0 and 9.0 (optimum pH 7.1). It did not require NaCl for growth but tolerated it up to 50 g l(-1) (optimum 2 g l(-1)). In the presence of sulfate or thiosulfate, strain Olac 40(T) used lactate, pyruvate and formate as energy sources. Growth was observed on H2 only in the presence of acetate as carbon source. In the presence of sulfate or thiosulfate, the end products of lactate oxidation were acetate, sulfide and CO2. Sulfate, thiosulfate and sulfite were used as terminal electron acceptors, but not elemental sulfur, nitrate or nitrite. The genomic DNA G+C content of strain Olac 40(T) was 70 mol%. The profile of polar lipids consisted of phosphatidylglycerol, phosphatidylethanolamine, aminophospholipid and four phospholipids. The main fatty acids were C16 : 0, anteiso-C15 : 0 and iso-C15 : 0. Phylogenetic analysis of the 16S rRNA gene sequence indicated that strain Olac 40(T) was affiliated with the family Desulfovibrionaceae within the class Deltaproteobacteria. On the basis of 16S rRNA gene sequence comparisons and physiological characteristics, strain Olac 40(T) is proposed to be assigned to a novel species of the genus Desulfocurvus, for which the name Desulfocurvus thunnarius is proposed. The type strain is Olac 40(T) ( = DSM 26129(T) = JCM 18546(T)). PMID- 23811136 TI - Paenalcaligenes hermetiae sp. nov., isolated from the larval gut of Hermetia illucens (Diptera: Stratiomyidae), and emended description of the genus Paenalcaligenes. AB - A novel Gram-stain-negative, facultatively anaerobic, non-motile and short rod shaped bacterium, strain KBL009(T), was isolated from the larval gut of Hermetia illucens. Strain KBL009(T) grew optimally at 37 degrees C, at pH 6.0 and with 1 2 % (w/v) NaCl. The 16S rRNA gene sequence of strain KBL009(T) showed 97.6 % similarity to that of Paenalcaligenes hominis CCUG 53761A(T) indicating its classification with the genus Paenalcaligenes. The major fatty acids were cyclo C17 : 0, C16 : 0 and summed feature 2 (comprising C14 : 0 3-OH/iso-C16 : 1). The respiratory quinones were ubiquinone-8 (Q-8), predominating, and a minor amount of Q-7. The polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, one unknown aminolipid and five unknown polar lipids. The polyamine pattern contained predominantly putrescine and relatively high amounts of spermidine. The betaproteobacterial-specific 2-hydroxyputrescine could only be detected in trace amounts. The G+C content of genomic DNA was 56.1 mol%. Results from DNA-DNA hybridization with P. hominis KCTC 23583(T) unambiguously demonstrated that strain KBL009(T) represents a novel species in the genus Paenalcaligenes. Based on phenotypic, genotypic and phylogenetic characterization, the novel species Paenalcaligenes hermetiae sp. nov. is proposed. The type strain is KBL009(T) ( = KACC 16840(T) = JCM 18423(T)). An emended description of the genus Paenalcaligenes is also provided. PMID- 23811137 TI - Georgenia sediminis sp. nov., a moderately thermophilic actinobacterium isolated from sediment. AB - A Gram-stain-positive actinobacterium, designated strain SCSIO 15020(T), was isolated from sediment of the South China Sea, and characterized by using a polyphasic approach. The temperature range for growth was 24-60 degrees C, with optimal growth occurring at 50 degrees C. The pH range for growth was 6-10 (optimum pH 8-9). The NaCl concentration range for growth was 0-5 % (w/v). The peptidoglycan type was A4alpha. Polar lipids contained diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol, phosphatidylinositol mannoside and an unknown polar lipid. The major menaquinone was MK-8(H4); MK-7(H4) was present as a minor component. The major fatty acids (>5 %) were anteiso-C15 : 0, iso-C15 : 0 and iso-C16 : 0. The DNA G+C content of strain SCSIO 15020(T) was 73.2 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain SCSIO 15020(T) belonged to the genus Georgenia, with the closest neighbours being Georgenia muralis 1A-C(T) (96.3 % similarity), Georgenia thermotolerans TT02 04(T) (95.7 %) and Georgenia ruanii YIM 004(T) (95.6 %). Based on evidence from the present polyphasic study, strain SCSIO 15020(T) is considered to represent a novel species of the genus Georgenia, for which the name Georgenia sediminis sp. nov. is proposed. The type strain is SCSIO 15020(T) ( = DSM 25884(T) = NBRC 108941(T)). PMID- 23811138 TI - Shimia haliotis sp. nov., a bacterium isolated from the gut of an abalone, Haliotis discus hannai. AB - A novel Gram-stain-negative, motile, rod-shaped bacterium, designated strain WM35(T), was isolated from the intestinal tract of an abalone, Haliotis discus hannai, which was collected from the northern coast of Jeju in Korea. The cells of the isolate grew optimally at 30 degrees C, pH 7, and with 3 % (w/v) NaCl. Based on 16S rRNA gene sequence similarity comparisons, strain WM35(T) was grouped in the genus Shimia and was closely related to the type strains of Shimia isoporae (98.7 % similarity) and Shimia marina (97.8 % similarity). The major cellular fatty acids were summed feature 8 and C16 : 0 2-OH. Ubiquinone Q-10 was the predominant respiratory quinone. The polar lipids of strain WM35(T) comprised phosphatidylcholine, phosphatidylglycerol, diphosphatidylglycerol, an unidentified aminolipid and an unidentified lipid. The DNA G+C content of the isolate was 53.8 mol%. DNA-DNA hybridization values indicated <16 % genomic relatedness with members of the genus Shimia. The physiological, chemical and genotypic analyses indicated that strain WM35(T) represents a novel species of the genus Shimia, for which the name Shimia haliotis sp. nov. is proposed. The type strain is WM35(T) ( = KACC 17212(T) = JCM 18870(T)). PMID- 23811139 TI - Allokutzneria multivorans sp. nov., an actinomycete isolated from soil. AB - An actinomycete with well-branched mycelia, designated strain YIM 120521(T), was isolated from soil collected from the banks of the Nujiang River, Yunnan Province, south-west China. Both aerial and substrate mycelia were white and non pigmented. Growth was observed at 4-40 degrees C (optimum 28 degrees C), pH 6.0 9.0 (optimum 7.0) and in 0-4 % (w/v) NaCl (optimum 0 %). Analysis of the 16S rRNA gene sequence revealed that strain YIM 120521(T) belongs to the genus Allokutzneria with the highest sequence similarity to Allokutzneria albata DSM 44149(T) (98.4 %). However, the mean DNA-DNA relatedness value between the two strains was below 70 %. Chemotaxonomic characteristics supported the inclusion of strain YIM 120521(T) in the genus Allokutzneria, with rhamnose, arabinose, glucose, galactose and mannose as the whole-cell sugars, meso-diaminopimelic acid as the cell-wall diamino acid and MK-9(H4) as the predominant menaquinone. On the basis of physiological, biochemical and chemotaxonomic characteristics, strain YIM 120521(T) is considered to represent a novel species of the genus Allokutzneria, for which the name Allokutzneria multivorans sp. nov. is proposed. The type strain is YIM 120521(T) ( = JCM 17342(T) = DSM 45532(T)). PMID- 23811140 TI - Cohaesibacter haloalkalitolerans sp. nov., isolated from a soda lake, and emended description of the genus Cohaesibacter. AB - Two novel Gram-stain-negative, motile, catalase-negative and oxidase-positive strains of bacteria (JC131(T) and JC112) were isolated from Lonar, a soda lake in India. Based on 16S rRNA gene sequence similarity studies, strains JC131(T) and JC112 belong to the family Cohaesibacteraceae of the class Alphaproteobacteria and were most closely related to Cohaesibacter marisflavi DQHS21(T) (98.0 %) and Cohaesibacter gelatinilyticus CL-GR15(T) (96.0 %). Polar lipids of strains JC131(T) and JC112 include phosphatidylglycerol, phosphatidylethnolamine, phosphatidylmonomethylethanolamine, diphosphatidylglycerol and two unidentified lipids (L1 and L2). Both strains have diplopterol, diploptene, an unidentified hopane (UH) and bacteriohopane derivatives (BHD1 and 2) as major hopanoids and an unidentified pigment (P1). The predominant isoprenoid quinone of both strains was ubiquinone-10 (Q10). Whole-cell fatty acid analysis of both strains revealed that C18 : 1omega7c was the predominant cellular fatty acid and significant proportions of C16 : 0, summed feature 3 (C16 : 1omega7c and/or iso-C15 : 0 2 OH), 11-methyl C18 : 1omega7c, C18 : 1omega9c, C18 : 0 and C20 : 1omega7c were also detected. The DNA G+C content of strains JC131(T) and JC112 was 54.6 and 53.8 mol%, respectively. The genome reassociation (based on DNA-DNA hybridization) of strains JC131(T) and JC112 with Cohaesibacter marisflavi NCCB 100300(T) ( = DQHS21(T)) was about 58 %, while between JC131(T) and JC112 it was about 87 %. On the basis of physiological, biochemical and chemotaxonomical properties, strains JC131(T) and JC112 are differentiated from the other two members of the genus Cohaesibacter. Strains JC131(T) and JC112 represent a novel species of the genus Cohaesibacter, for which the name Cohaesibacter haloalkalitolerans sp. nov. is proposed. The type strain is JC131(T) ( = KCTC 32038(T) = NBRC 109022(T)). An emended description of the genus Cohaesibacter is presented. PMID- 23811141 TI - Oceanirhabdus sediminicola gen. nov., sp. nov., an anaerobic bacterium isolated from sea sediment. AB - A novel anaerobic bacterium, designated NH-JN4(T) was isolated from a sediment sample collected in the South China Sea. Cells were Gram-stain-positive, spore forming, peritrichous and rod-shaped (0.5-1.2*2.2-7 um). The temperature and pH ranges for growth were 22-42 degrees C and pH 6.0-8.5. Optimal growth occurred at 34-38 degrees C and pH 6.5-7.0. The NaCl concentration range for growth was 0.5-6 % (w/v) with an optimum of 2.5 %. Catalase and oxidase were not produced. Substrates which could be utilized were peptone, tryptone, yeast extract, beef extract and glycine. Main fermentation products from PYG medium were formate, acetate, butyrate and ethanol. Strain NH-JN4(T) could utilize sodium sulfite as an electron acceptor. No respiratory quinone was detected. The predominant fatty acids were anteiso-C15 : 0, C16 : 0, iso-C15 : 0, anteiso-C17 : 0 and C16 : 0 DMA. The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol and glycolipids. The DNA G+C content was 35.8 mol%. Phylogenetic analysis based on the 16S rRNA gene sequence revealed that strain NH-JN4(T) was a member of family Clostridiaceae, and was most closely related to Clostridium limosum ATCC 25620(T), Clostridium proteolyticum DSM 3090(T), Clostridium histolyticum ATCC 19401(T) and Clostridium tepidiprofundi SG 508(T), showing 94.0, 93.0, 92.9 and 92.3 % sequence similarity, respectively. On the basis of phenotypic, genotypic and chemotaxonomic properties, strain NH-JN4(T) represents a novel species of a new genus in the family Clostridiaceae, for which the name Oceanirhabdus sediminicola gen. nov., sp. nov. is proposed. The type strain of the type species is NH-JN4(T) ( = JCM 18501(T) = CCTCC AB 2013103(T) = KCTC 15322(T)). PMID- 23811142 TI - Maternal and early life arsenite exposure impairs neurodevelopment and increases the expression of PSA-NCAM in hippocampus of rat offspring. AB - Although epidemiological investigations indicate that chronic arsenic exposure can induce developmental neurotoxicity in children, the molecular mechanisms are still poorly understood. Neural cell adhesion molecules (NCAMs) play critical roles during the development of nervous system. Polysialylation of NCAM (PSA NCAM) is a critical functional feature of NCAM-mediated cell interactions and functions. The present study aimed at investigating the effects of maternal and early life arsenite exposure on NCAM and PSA-NCAM in rat offspring. To this end, mother rats were divided into three groups and exposed to 0, 2.72 and 13.6mg/L sodium arsenite, respectively, during gestation and lactation. After weaning, rat offspring drank the same solution as their mothers. Neural reflex parameters, arsenic level of hippocampus, ultra-structural changes of hippocampus, the expression of NCAM, PSA-NCAM and two polysialyltransferases (STX and PST) in rat offspring were assessed. Arsenite exposure significantly prolonged the time of completing reflex response of surface righting, negative geotaxis and cliff avoidance of rat offspring in 13.6mg/L As-exposed group. Neurons and capillaries presented pathological changes and the expression of NCAM, PSA-NCAM, STX and PST were up-regulated in hippocampus of rat offspring exposed to arsenite. These results indicated that maternal arsenite exposure increases the expression of PSA NCAM, NCAM and polysialyltransferases in hippocampus of rat offspring on postnatal day (PND) 21 and PND120, which might contribute to the impaired neurodevelopment following arsenite exposure. PMID- 23811143 TI - Alteration of Th1/Th2/Th17 cytokine profile and humoral immune responses associated with chromate exposure. AB - BACKGROUND: The role of chromate exposure in the deregulation of total lymphocyte and other immune factors is largely unclear. OBJECTIVES: We aimed to examine alteration of the Th1/Th2/Th17 cytokine profile and humoral indicators caused by occupational chromate exposure. METHODS: A cross-sectional study was conducted in two similar workshops (groups 1 and 2) with 106 male occupational workers and 50 matched local controls. Environmental and biological exposures were assessed by measuring chromium concentrations in workplace air, and in whole blood and urine samples of the workers. Cytokines in serum (IL-2, IL-4, IL-6, IL-10, TNF-alpha, IFN-gamma, IL-17A) were determined by CBA assay, while immunoglobin (IgA, IgM, IgG, IgE) and complement (C3, C4) were evaluated by immunonephelometric and ELISA methods. Micronucleus analysis was also used to explore the relationship between genotoxicity and immunotoxicity. RESULTS: Compared with the control group, environmental chromate exposure in groups 1 and 2 was much higher, and the mean values of IL-6, IL-10, IFN-gamma, IL-17A and IFN-gamma/IL-4 were significantly decreased in group 1. In group 2, IgA and IgG levels were reduced, while C3 and C4 were increased. Levels of IFN-gamma, IgG and IgA were all inversely associated with whole blood chromium, while C3 and C4 were positively associated with whole blood chromium (p<0.05). Both IL-10 and IL-17A were inversely associated with urine chromium. Correlations were also found between IL-10, IL-17A and micronucleus (r=-0.329, r=-0.312, respectively). CONCLUSIONS: Occupational exposure to chromate could downregulate the cellular and humoral factors of the immune system. PMID- 23811144 TI - Competition between virus-derived and endogenous small RNAs regulates gene expression in Caenorhabditis elegans. AB - Positive-strand RNA viruses encompass more than one-third of known virus genera and include many medically and agriculturally relevant human, animal, and plant pathogens. The nematode Caenorhabditis elegans and its natural pathogen, the positive-strand RNA virus Orsay, have recently emerged as a new animal model to understand the mechanisms and evolution of innate immune responses. In particular, the RNA interference (RNAi) pathway is required for C. elegans resistance to viral infection. Here we report the first genome-wide analyses of gene expression upon viral infection in C. elegans. Using the laboratory strain N2, we identify a novel C. elegans innate immune response specific to viral infection. A subset of these changes is driven by the RNAi response to the virus, which redirects the Argonaute protein RDE-1 from its endogenous small RNA cofactors, leading to loss of repression of endogenous RDE-1 targets. Additionally, we show that a C. elegans wild isolate, JU1580, has a distinct gene expression signature in response to viral infection. This is associated with a reduction in microRNA (miRNA) levels and an up-regulation of their target genes. Intriguingly, alterations in miRNA levels upon JU1580 infection are associated with a transformation of the antiviral transcriptional response into an antibacterial-like response. Together our data support a model whereby antiviral RNAi competes with endogenous small RNA pathways, causing widespread transcriptional changes. This provides an elegant mechanism for C. elegans to orchestrate its antiviral response, which may have significance for the relationship between small RNA pathways and immune regulation in other organisms. PMID- 23811145 TI - De novo DNA demethylation and noncoding transcription define active intergenic regulatory elements. AB - Deep sequencing of mammalian DNA methylomes has uncovered a previously unpredicted number of discrete hypomethylated regions in intergenic space (iHMRs). Here, we combined whole-genome bisulfite sequencing data with extensive gene expression and chromatin-state data to define functional classes of iHMRs, and to reconstruct the dynamics of their establishment in a developmental setting. Comparing HMR profiles in embryonic stem and primary blood cells, we show that iHMRs mark an exclusive subset of active DNase hypersensitive sites (DHS), and that both developmentally constitutive and cell-type-specific iHMRs display chromatin states typical of distinct regulatory elements. We also observe that iHMR changes are more predictive of nearby gene activity than the promoter HMR itself, and that expression of noncoding RNAs within the iHMR accompanies full activation and complete demethylation of mature B cell enhancers. Conserved sequence features corresponding to iHMR transcript start sites, including a discernible TATA motif, suggest a conserved, functional role for transcription in these regions. Similarly, we explored both primate-specific and human population variation at iHMRs, finding that while enhancer iHMRs are more variable in sequence and methylation status than any other functional class, conservation of the TATA box is highly predictive of iHMR maintenance, reflecting the impact of sequence plasticity and transcriptional signals on iHMR establishment. Overall, our analysis allowed us to construct a three-step timeline in which (1) intergenic DHS are pre-established in the stem cell, (2) partial demethylation of blood-specific intergenic DHSs occurs in blood progenitors, and (3) complete iHMR formation and transcription coincide with enhancer activation in lymphoid specified cells. PMID- 23811147 TI - Mixed ligand complex formation of 2-aminobenzamide with Cu(II) in the presence of some amino acids: synthesis, structural, biological, pH-metric, spectrophotometric and thermodynamic studies. AB - Mixed ligand Cu(II) complexes of 2-aminobenzamide (2AB) and amino acids viz., glycine (gly), L-alanine (ala), L-valine (val) and L-phenylalanine (phe) have been synthesised and characterized by various physico-chemical and spectral techniques. The calculated g-tensor values for Cu(II) complexes at 77 K and 300 K, show the distorted octahedral geometry which has been confirmed from the absorption studies. Consequently, the thermal studies illustrate that the loss of water and acetate molecules in the initial stage which are followed by the decomposition of organic residues. The powder X-ray diffraction and SEM analysis reflect that all the complexes have well-defined crystallinity nature with homogeneous morphology. The binding activities of CT DNA with CuAB complexes have been examined by absorption studies. Further, the oxidative cleavage interactions of 2-aminobenzamide and CuAB complexes with DNA were studied by gel electrophoresis method in H2O2 medium. Also, the complex formation of Cu(II) involving 2-aminobenzamide and amino acids were carried out by a combined pH metric and spectrophotometric techniques in 50% (v/v) water-ethanol mixture at 300, 310, 320 and 330+/-0.1 K with I=0.15 mol dm(-3) (NaClO4). In solution, CuAB and CuAB2 species has been detected and the binding modes of 2-aminobenzamide and amino acids in both binary and mixed ligand complexes are same. The calculated stabilization value of DeltalogK, log X and log X' indicates higher stabilities for the mixed ligand complexes rather than their binary species. The thermodynamic parameters like DeltaG, DeltaH and DeltaS have been determined from temperature dependence of the stability constant. In vitro biological activities of 2-aminobenzamide, CuA and CuAB complexes show remarkable activities against some bacterial and fungal strains. The percentage distribution of various binary and mixed ligand species in solution at dissimilar pH intervals were also evaluated. PMID- 23811146 TI - Role of microRNAs in atrial fibrillation: new insights and perspectives. AB - MicroRNAs (miRNAs) are small non-coding RNA molecules that negatively regulate gene expression of their targets at the post-transcriptional levels. They typically affect the mRNA stability or translation finally leading to the repression of target gene expression. Notably, it is thought that miRNAs are crucial for regulating gene expression during heart diseases, such as atrial fibrillation (AF). Numerous studies identify specific miRNA expression profiles associated to different histological features of AF, both in animal models and in patients. Therefore, we review the latest experimental approaches from the perspective of understanding miRNA gene expression regulatory networks in AF. In addition, miRNAs have also emerged as possible therapeutic targets for the treatment of AF. In this review, we discuss the experimental evidence about miRNAs both as potential non-invasive early diagnostic markers and as novel therapeutic targets in AF. PMID- 23811148 TI - Optical properties of water soluble CdSe quantum dots modified by a novel biopolymer based on sodium alginate. AB - Water soluble CdSe quantum dots (QDs) were modified using a novel biopolymer based on the graft copolymerization of poly (acrylic acid) as a monomer onto sodium alginate as a backbone at room temperature. The obtained CdSe QDs were characterized by Fourier transform infrared spectrometer, thermo-gravimetry analysis, transmission electron microscopy, and dynamic light scattering. Optical properties of the prepared CdSe QDs were investigated by absorption and fluorescence spectra. It was found that the resultant QDs incredibly exhibited high fluorescence intensity and quantum yields. Lastly, the influence of the aging time on the fluorescence intensity of the modified CdSe QDs was studied by their fluorescence spectra. Due to the optical behavior of this modified QDs; it could be of potential interest in biological systems. PMID- 23811149 TI - Study on the interaction of the epilepsy drug, zonisamide with human serum albumin (HSA) by spectroscopic and molecular docking techniques. AB - In the present investigation, an attempt has been made to study the interaction of zonisamide (ZNS) with the transport protein, human serum albumin (HSA) employing UV-Vis, fluorometric, circular dichroism (CD) and molecular docking techniques. The results indicated that binding of ZNS to HSA caused strong fluorescence quenching of HSA through static quenching mechanism, hydrogen bonds and van der Waals contacts are the major forces in the stability of protein ZNS complex and the process of the binding of ZNS with HSA was driven by enthalpy (DeltaH=-193.442 kJ mol(-1)). The results of CD and UV-Vis spectroscopy showed that the binding of this drug to HSA induced conformational changes in HSA. Furthermore, the study of molecular docking also indicated that zonisamide could strongly bind to the site I (subdomain IIA) of HSA mainly by hydrophobic interaction and there were hydrogen bond interactions between this drug and HSA, also known as the warfarin binding site. PMID- 23811150 TI - FT-Raman, FT-IR and UV-visible spectral investigations and ab initio computations of anti-epileptic drug: vigabatrin. AB - Vibrational analysis of anti-epileptic drug vigabatrin, a structural GABA analog was carried out using NIR FT-Raman and FTIR spectroscopic techniques. The equilibrium geometry, various bonding features and harmonic vibrational wavenumbers were studied using density functional theory method. The detailed interpretation of the vibrational spectra has been carried out with the aid of VEDA.4 program. Vibrational spectra, natural bond orbital analysis and optimized molecular structure show clear evidence for the effect of electron charge transfer on the activity of the molecule. Predicted electronic absorption spectrum from TD-DFT calculation has been compared with the UV-vis spectrum. The Mulliken population analysis on atomic charges and the HOMO-LUMO energy were also calculated. Good consistency is found between the calculated results and experimental data for the electronic absorption as well as IR and Raman spectra. The blue-shifting of the C-C stretching wavenumber reveals that the vinyl group is actively involved in the conjugation path. The NBO analysis confirms the occurrence of intramolecular hyperconjugative interactions resulting in ICT causing stabilization of the system. PMID- 23811151 TI - DNA interaction of [Cu(dmp)(phen-dion)] (dmp=4,7 and 2,9 dimethyl phenanthroline, phen-dion=1,10-phenanthroline-5,6-dion) complexes and DNA-based electrochemical biosensor using chitosan-carbon nanotubes composite film. AB - The interaction of two new water-soluble [Cu(4,7-dmp)(phen-dione)Cl]Cl (1) and [Cu(2,9-dmp)(phen-dione)Cl]Cl (2) which dmp is dimethyl-1,10-phenanthroline and phen-dion represents 1,10-phenanthroline-5,6-dion, with DNA in solution and immobilized DNA on a chitosan-carbon nanotubes composite modified glassy carbon electrode were investigated by cyclic voltammetry and UV-Vis spectroscopy techniques. In solution interactions, spectroscopic and electrochemical evidences indicate outside binding of these complexes. To clarify the binding mode of complexes, it was done competition studies with Hoechst and Neutral red as groove binder and intercalative probes, respectively. All these results indicating that, these two complexes (1) and (2) interact with DNA via groove binding and partially intercalative modes, respectively. The electrochemical characterization experiments showed that the nanocomposite film of chitosan-carbon nanotubes could effectively immobilize DNA and greatly improve the electron-transfer reactions of the electroactive molecules that latter finding is the result of strong interactions between captured DNA and Cu complexes. This result indicates that these complexes could be noble candidates as hybridization indicators in further studies. At the end, these new complexes showed excellent antitumor activity against K562 (human chronic myeloid leukemia) cell lines. PMID- 23811152 TI - IgG4 specific to Toxoplasma gondii excretory/secretory antigens in serum and/or cerebrospinal fluid support the cerebral toxoplasmosis diagnosis in HIV-infected patients. AB - Cerebral toxoplasmosis is the most common neurological opportunistic disease manifested in HIV infected patients. Excretory/secretory antigens (ESA) are serological markers for the diagnosis of reactivation of the infection in HIV infected patients with cerebral toxoplasmosis. Immunosuppressed patients develop high antibody titers for ESA. However, little is known about the humoral response for these antigens. The present study analyzed the profile of antibody recognition against ESA in comparison with tachyzoite lysate antigen (TLA) in 265 sera and 270 cerebrospinal fluid (CSF) samples from infected patients with Toxoplasma gondii and or HIV and in sera of 50 healthy individuals. The samples of sera and CSF were organized in 8 groups. The sera sample groups were: Group I Se/CT/AIDS (patients with cerebral toxoplasmosis/AIDS) with 58 samples; Group II - Se/ONinf/AIDS/PosT (patients with AIDS/other neuroinfections/positive toxoplasmosis) with 49 samples; Group III - Se/ONinf/AIDS/NegT (patients with AIDS/other neuroinfections/negative toxoplasmosis) with 58 samples; Group IV - Se/PosT/NegHIV (individuals with asymptomatic toxoplasmosis/negative HIV) with 50 samples and Group V - Se/NegT/NegHIV (healthy individuals/negative toxoplasmosis and HIV) with 50 samples. The CSF sample groups were: Group VI - CSF/CT/AIDS (patients with cerebral toxoplasmosis/AIDS) with 99 samples; Group VII - CSF/ONinf/AIDS/PosT (patients with AIDS/other neuroinfections/positive toxoplasmosis) with 112 samples, and Group VIII - CSF/ONinf/AIDS/NegT (patients with AIDS/other neuroinfections/negative toxoplasmosis) with 59 samples. Levels of IgM, IgA, IgE, IgG and subclasses were determined by ELISA against TLA and ESA antigens. IgM, IgA or IgE antibodies against ESA or TLA were not detected in sera from patients with toxoplasmosis suggesting that all patients were in chronic phase of the infection. High levels of IgG1 against TLA were found in sera samples from groups I, II and IV and in CSF samples from groups VI and VII; whereas IgG2, IgG3 and IgG4 levels were not detected in the same sera or CSF sample groups. However, patients from groups I and VI, that had tachyzoites circulating in blood and CSF respectively, produced a mix of IgG1 and IgG4 antibodies against ESA. IgG2 against ESA were predominant in serum from patients with the latent (non-active) T. gondii infection/HIV negative and in CSF samples from patients with other neuroinfections and positive toxoplasmosis (groups IV and VII, respectively). IgG4 levels against ESA were found to be significantly (P<0.05 and P<0.005) higher in patients with cerebral toxoplasmosis (groups I and VI, respectively) in comparison with groups II, IV and VII. This data suggest that IgG4 can be valuable for supporting the diagnosis of focal brain lesions, caused by T. gondii infection, in HIV-infected patients. This approach might be useful, mainly when molecular investigation to detect parasites is not available. PMID- 23811153 TI - Phylogenetic analysis of small ruminant lentiviruses in mixed flocks: multiple evidence of dual infection and natural transmission of types A2 and B1 between sheep and goats. AB - Previous molecular analyses of small ruminant lentivirus (SRLV) populations in single species herds in Quebec, Canada, have revealed a relatively simple structure where goats and sheep appeared exclusively infected with B1 and A2 subtypes respectively. The present work aimed at extending these earlier findings with the analysis of SRLVs in mixed flocks. Molecular analyses revealed a more complex picture of SRLV population structure in mixed herds compared to single species herds. Notably, phylogenetic analyses of long gag sequences strongly support transmission of A2 subtype from sheep to goats as well as transmission of B1 subtype from goats to sheep. Hence, this work uncovered for the first time natural transmission between sheep and goats of North American subtype A2. In addition, multiple evidences of mixed infection of sheep and goats with A2 and B1 subtypes were found. The data reported in this study reinforces the concept of a genetic continuum of SRLVs where strains are exchanged between sheep and goats under favourable conditions and in the absence of specific species barriers. Most interestingly, this study suggests that dual infection, which is a hallmark of the lentivirus paradigm HIV, may not be such rare events in small ruminants but may simply be understudied and underreported. Overall, the present data shows that sheep and goats in Canada can be infected with both SRLV A and B types, sometimes simultaneously, and that mixed flocks may represent a breeding ground for their evolution. PMID- 23811154 TI - A mass-differentiated library strategy for identification of sugar nucleotidyltransferase activities from cell lysates. AB - Sugar nucleotidyltransferases, or nucleotide sugar pyrophosphorylases, are ubiquitous enzymes whose activities have been correlated to disease states and pathogen virulence. Here we report a rapid "one-pot" method to identify a range of sugar nucleotidyltransferase activities of purified proteins or in cell lysates using a mass-differentiated carbohydrate library designed for mass spectrometry-based analysis. PMID- 23811155 TI - Development of a new colorimetric assay for lipoxygenase activity. AB - Lipoxygenases (LOXs) are a family of non-heme iron-containing dioxygenases that catalyze the hydroperoxidation of lipids, containing a cis,cis-1,4-pentadiene structure. A rapid and reliable colorimetric assay for determination of the activity of three human functional lipoxygenase isoforms (5-lipoxygenase, platelet 12-lipoxygenase, and 15-lipoxygenase-1) is developed in this article. In the new assay, LOX-derived lipid hydroperoxides oxidize the ferrous ion (Fe2+) to the ferric ion (Fe3+), the latter of which binds with thiocyanate (SCN-) to generate a red ferrithiocyanate (FTC) complex. The absorbance of the FTC complex can be easily measured at 480 nm. Because 5-LOX can be stimulated by many cofactors, the effects of its cofactors (Ca2+, ATP, dithiothreitol, glutathione, L-alpha-phosphatidylcholine, and ethylenediaminetetraacetic acid) on the color development of the FTC complex are also determined. The assay is adaptive for purified LOXs and cell lysates containing active LOXs. We use the new colorimetric assay in a 96-well format to evaluate several well-known LOX inhibitors, the IC50 values of which are in good agreement with previously reported data. The reliability and reproducibility of the assay make it useful for in vitro screening for inhibitors of LOXs and, therefore, should accelerate drug discovery for clinical application. PMID- 23811156 TI - Quantification of metabolic activity of cultured plant cells by vital staining with fluorescein diacetate. AB - The metabolic activity of suspension cultures of Sonneratia alba cells was quantified by measurement of the hydrolysis of fluorescein diacetate (FDA). FDA is incorporated into live cells and is converted into fluorescein by cellular hydrolysis. Aliquots (0.1-0.75 g) of S. alba cells were incubated with FDA at a final concentration of 222 MUg/ml suspension for 60 min. Hydrolysis was stopped, and fluorescein was extracted by the addition of acetone and quantified by measurement of absorbance at 490 nm. Fluorescein was produced linearly with time and cell weight. Cells of S. alba are halophilic and proliferated well in medium containing 50 and 100 mM NaCl. Cells grown in medium containing 100 mM NaCl showed 2- to 3-fold higher FDA hydrolysis activity than those grown in NaCl-free medium. When S. alba cells grown in medium supplemented with 50 mM NaCl were transferred to fresh medium containing 100 mM mannitol, cellular FDA hydrolysis activity was down-regulated after 4 days of culture, indicating that the moderately halophilic S. alba cells were sensitive to osmotic stress. Quantification of cellular metabolic activity via the in vivo FDA hydrolysis assay provides a simple and rapid method for the determination of cellular activity under differing culture conditions. PMID- 23811157 TI - A comparison of Forster resonance energy transfer analysis approaches for Nanodrop fluorometry. AB - Ensemble Forster resonance energy transfer (FRET) results can be analyzed in a variety of ways. Due to experimental artifacts, the results obtained from different analysis approaches are not always the same. To determine the optimal analysis approach to use for Nanodrop fluorometry, we have performed both ensemble and single-molecule FRET studies on oligomers of double-stranded DNA. We compared the single-molecule FRET results with those obtained using various ensemble FRET analysis approaches. This comparison shows that for Nanodrop fluorometry, analyzing the increase of the acceptor fluorescence is less likely to introduce errors in estimates of FRET efficiencies compared with analyzing the fluorescence intensity of the donor in the absence and presence of the acceptor. PMID- 23811158 TI - Latency of chromatic information in area V4. AB - In the primate visual system, information about color is known to be carried in separate divisions of the retino-geniculo-cortical pathway. From the retina, responses of photoreceptors to short (S), medium (M), and long (L) wavelengths of light are processed in two different opponent pathways. Signals in the S-opponent pathway, or blue/yellow channel, have been found to lag behind signals in the L/M opponent pathway, or red/green channel in primary visual area V1, and psychophysical studies have suggested similar perceptual delays. However, more recent psychophysical studies have found that perceptual differences are negligible with the proper controls, suggesting that information between the two channels is integrated at some stage of processing beyond V1. To study the timing of color signals further downstream in visual cortex, we examined the responses of neurons in area V4 to colored stimuli varying along the two cardinal axes of the equiluminant opponent color space. We used information theory to measure the mutual information between the stimuli presented and the neural responses in short time windows in order to estimate the latency of color information in area V4. We found that on average, despite the latency difference in V1, information about S-opponent signals arrives in V4 at the same time as information about L/M opponent signals. This work indicates a convergence of signal timing among chromatic channels within extrastriate cortex. PMID- 23811159 TI - Spectral response of solvent-cast polyvinyl chloride (PVC) thin film used as a long-term UV dosimeter. AB - The spectral response of solvent-cast polyvinyl chloride (PVC) thin film suitable for use as a long-term UV dosimeter has been determined by measuring the UV induced change in the 1064 cm(-1) peak intensity of the PVC's infrared (IR) spectra as a function of the wavelength of the incident radiation. Measurements using cut-off filters, narrow band-pass filters and monochromatic radiation showed that the 16 MUm PVC film responds mainly to the UVB band. The maximum response was at 290 nm and decreasing exponentially with wavelength up to about 340 nm independent of temperature and exposure dose. The most suitable concentration (W/V%) of PVC/Tetrahydrofuran solution was found to be 10% and the best thickness for the dosimeter was determined as 16 MUm. PMID- 23811160 TI - A novel development of dithizone as a dual-analyte colorimetric chemosensor: detection and determination of cyanide and cobalt (II) ions in dimethyl sulfoxide/water media with biological applications. AB - The behavior of dithizone (DTZ), an easily available dye has been studied for the first time in chromogenic sensing of CN(-) as an anionic species and for Co(2+) as a cationic species in DMSO/H2O media. So employing DTZ an efficient colorimetric chemosensor was afforded with a chromogenic selectivity for Co(2+) over other cations with detection limit of 0.04 MUmol L(-1). The complex of Co(2+) with DTZ also displayed ability to detect up to 0.43 MUmol L(-1) CN(-) (K(+) salts) among other competing anions through a fast response time of less than 30s which is much lower than most recently reported chromogenic probes. The linear dynamic ranges for the determination of Co(2+) and CN(-) were 0.3-4.4 and 3.3-58.6 MUmol L(-1) respectively. This method could have potential application in a variety of cases requiring rapid and accurate analysis of Co(2+) and CN(-) for human serum and water samples. PMID- 23811161 TI - Purification and characterization of a novel thermostable luciferase from Benthosema pterotum. AB - A novel luciferase from Benthosema pterotum, collected from Port of Jask, close to Persian Gulf, was purified for the first time, using Q-Sepharose anion exchange chromatography. The molecular mass of the novel enzyme, measured by SDS PAGE technique, was about 27 kDa and its Km value is 0.4 MUM; both values are similar to those of other coelenterazine luciferases. B. pterotum (BP) luciferase showed maximum intensity of emitted light at 40 degrees C, in 20mM Tris buffer, pH 9 and 20 mM magnesium concentration. Experimental measurements indicated that BP luciferase is a relatively thermostable enzyme; furthermore it shows a high residual activity at extreme pH values. Its biological activity is strongly inhibited by 1 mM Cu(2+), Zn(2+) and Ni(2+), while calcium and mainly magnesium ions strongly increase BP luciferase activity. The B. pterotum luciferase generated blue light with a maximum emission wavelength at 475 nm and showed some similarity with other luciferases, while other parameters appeared quite different, in this way, confirming that a novel protein has been purified. PMID- 23811162 TI - Characterization and determination of lignin in different types of Iraqi phoenix date palm pruning woods. AB - This study aimed to find analytical data base for Iraqi phoenix date palm pruning woods, which produced by pruning process at the season of date palm production. Lignin has been extracted and purified for five types of Iraqi date palm using Klason lignin method. The weight of the extracted lignin ranged from 0.410 g to 0.720 g, and the lignin % ranged from 17.6 to 36. The other ingredients (waxes, oils, resin, and proteins of wood gums) % ranged from 20 to 29.5. FT-IR characterization showed that the (-OH) phenolic group appear in Ashrasi lignin structure only and disappear in other lignin samples, and the (4-O-5 inter monomeric lignin linkage) showed strong to moderate intensity peaks for all studied samples except the Austa omran sample has a weak intensity peaks. Also (DODO inter monomeric lignin linkage) showed strong intensity peaks for all studied samples except the Barban sample showed moderate intensity peaks. UV-vis characterization showed that the lowest absorption maximum (266 nm) corresponds to Barban lignin sample, while the highest absorption maximum (271 nm) corresponds to Sultani lignin sample. PMID- 23811163 TI - Preparation of multifunctional cationized cotton fabric based on TiO2 nanomaterials. AB - A novel approach for imparting multi-functional properties, i.e., UV-protecting, self-cleaning, water repellent as well as anti-bacterial properties onto cotton fabric is described. This research mainly deals with ecofriendly multifunctional cationized cotton fabrics using nanomaterialss based on TiO2 nanoparticles. In this study cotton fabric was cationized with two durable cationizing agent, 3 chloro-2-hydroxypropyl trimethyl ammonium chloride (Quat 188) and diallyl dimethyl ammonium chloride (DADMAC) using pad-batch method. The application of TiO2 nanomaterials on cotton 100% fabrics was achieved by using 1,2,3,4-butane tetracarboxilic acids [BTCA] as polycarboxilic cid cross linker with Sodium hypophosphite (SHP) as catalyst through conventional pad-dry-cure method. UV protection, antibacterial and self-cleaning performances are investigated. Water repellent property of treated cationized cotton fabric post treated with stearic acid was also investigated. PMID- 23811164 TI - WITHDRAWN: Varying levels and function of several biological macromolecules in myocardium. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 23811165 TI - Roboneuron: a simple and robust real-time analog spike simulator and calibrator. AB - BACKGROUND: Modern computerized spike recording systems are increasingly powerful and sophisticated. However, this increases the importance of performing validation by recording signals from a system with a known input-output relationship. NEW METHOD: We present here a simple and robust analog circuit that uses a minimum number of commonly available components to simulate two independently spiking neurons. The two neurons generate asynchronous overlapping spikes. These can be independently set to spike at either a constant rate, or at a rate set by an external control voltage. RESULTS: The circuit is simple enough to easily assemble by hand, however, standard files for ordering commercial printed circuit boards are also supplied. Several units were built by different people, using both hand-assembly and commercially manufactured printed circuit boards: all worked well. The circuit is robust with respect to supply voltages and component values. COMPARISON WITH EXISTING METHODS: Existing analog circuits tend to be complex, hard to assemble, and use hard-to-find components. Digital simulators typically require specific development systems that have steep learning curves and are likely to change radically or become unavailable very quickly. This system has been optimized to be robust, simple, and use only commonly available components. CONCLUSIONS: When validating a system there could be an advantage to using a calibrator that is robust, whose input-output relationship is simple, and whose design is stable over time. PMID- 23811166 TI - Track structure based modelling of chromosome aberrations after photon and alpha particle irradiation. AB - A computational model of radiation-induced chromosome aberrations in human cells within the PARTRAC Monte Carlo simulation framework is presented. The model starts from radiation-induced DNA damage assessed by overlapping radiation track structures with multi-scale DNA and chromatin models, ranging from DNA double helix in atomic resolution to chromatin fibre loops, heterochromatic and euchromatic regions, and chromosome territories. The repair of DNA double-strand breaks via non-homologous end-joining is followed. Initial spatial distribution and complexity, diffusive motion, enzymatic processing, synapsis and ligation of individual DNA ends from the breaks are simulated. To enable scoring of different chromosome aberration types resulting from improper joining of DNA fragments, the repair module has been complemented by tracking the chromosome origin of the ligated fragments and the positions of centromeres. The modelled motion of DNA ends has sub-diffusive characteristics and corresponds to measured chromatin mobility within time-scales of a few hours. The calculated formation of dicentrics after photon and alpha-particle irradiation in human fibroblasts is compared to experimental data (Cornforth et al., 2002, Radiat Res 158, 43). The predicted yields of dicentrics overestimate the measurements by factors of five for gamma-rays and two for alpha-particle irradiation. Nevertheless, the observed relative dependence on radiation dose is correctly reproduced. Calculated yields and size distributions of other aberration types are discussed. The present work represents a first mechanistic approach to chromosome aberrations and their kinetics, combining full track structure simulations with detailed models of chromatin and accounting for the kinetics of DNA repair. PMID- 23811167 TI - DNA double strand breaks induced by the indirect effect of radiation are more efficiently repaired by non-homologous end joining compared to homologous recombination repair. AB - The aim of this study was to investigate the relative involvement of three major DNA repair pathways, i.e., non-homologous end joining (NHEJ), homologous recombination (HRR) and base excision (BER) in repair of DNA lesions of different complexity induced by low- or high-LET radiation with emphasis on the contribution of the indirect effect of radiation for these radiation qualities. A panel of DNA repair-deficient CHO cell lines was irradiated by (137)Cs gamma-rays or radon progeny alpha-particles. Irradiation was also performed in the presence of 2M DMSO to reduce the indirect effect of radiation and the complexity of the DNA damage formed. Clonogenic survival and micronucleus assays were used to estimate efficiencies of the different repair pathways for DNA damages produced by direct and indirect effects. Removal of the indirect effect of low-LET radiation by DMSO increased clonogenic survival and decreased MN formation for all cell lines investigated. A direct contribution of the indirect effect of radiation to DNA base damage was suggested by the significant protection by DMSO seen for the BER deficient cell line. Lesions formed by the indirect effect are more readily repaired by the NHEJ pathway than by HRR after irradiation with gamma-rays or alpha-particles as evaluated by cell survival and the yields of MN. The results obtained with BER- and NHEJ-deficient cells suggest that the indirect effect of radiation contributes significantly to the formation of repair substrates for these pathways. PMID- 23811168 TI - DNA damage in hair root cells as a biomarker for gamma ray exposure. AB - The purpose of the present research is to examine whether human hair root cells can be used for dose assessment after in vitro exposure to ionizing radiation. Hair root samples plucked from random head regions were collected from 5 healthy human subjects. Some of these hair samples were used as control and some were irradiated with 0.5-5Gy of gamma ray using a Cs-137 gamma irradiator at a dose rate of 0.14Gy/s. DNA damage (single-strand breaks) was determined in hair root cells of these samples using the comet assay technique. The comet assay parameters, tail length (TL) and tail moment (TM), showed a significant increase (p<.05) in single-strand DNA breaks in hair roots cells of the exposed samples compared to control. A linear dose-effect relationship was observed when tail moment or tail length was plotted against the log of the radiation dose. This research suggests a possible use of human hair root cell DNA damage as a biomarker especially for low dose radiation. PMID- 23811169 TI - Access to improved water and its relationship with diarrhoea in Kathmandu Valley, Nepal: a cross-sectional study. AB - OBJECTIVE: To assess the associations between diarrhoea and types of water sources, total quantity of water consumed and the quantity of improved water consumed in rapidly growing, highly populated urban areas in developing countries. DESIGN: Cross-sectional analysis using population-representative secondary data obtained from an interview survey conducted by the Asian Development Bank for the 2009 Kathmandu Valley Water Distribution, Sewerage and Urban Development Project. SETTING: Kathmandu Valley, Nepal. PARTICIPANTS: 2282 households. METHODS: A structured questionnaire was used to collect information from households on the quantity and sources of water consumed; health, socioeconomic and demographic status of households; drinking water treatment practices and toilet facilities. RESULTS: Family members of 179 households (7.8%) reported having developed diarrhoea during the previous month. For households in which family members consumed less than 100 L of water per capita per day (L/c/d), which is the minimum quantity recommended by WHO, the risk of contracting diarrhoea doubled (1.56-fold to 2.92-fold). In households that used alternative water sources (such as wells, stone spouts and springs) in addition to improved water (provided by a water management authority), the likelihood of contracting diarrhoea was 1.81-fold higher (95% CI 1.00 to 3.29) than in those that used only improved water. However, access to an improved water source was not associated with a lower risk of developing diarrhoea if optimal quantities of water were not consumed (ie, <100 L/c/d). These results were independent of socioeconomic and demographic variables, daily drinking water treatment practices, toilet facilities and residential areas. CONCLUSIONS: Providing access to a sufficient quantity of water-regardless of the source-may be more important in preventing diarrhoea than supplying a limited quantity of improved water. PMID- 23811170 TI - Improving ethnic monitoring for telephone-based healthcare: a conversation analytic study. AB - OBJECTIVES: Medical and healthcare organisations-including the national cancer support and helpline organisation that is the subject of this study-are expected to collect and monitor information about the ethnicity of their client populations. Information about ethnicity is important for a variety of reasons, including monitoring need and targeting healthcare services appropriately. Previous survey and interview research has suggested that collecting ethnicity data from service users can be incomplete and of variable quality-pointing to a need for an improved understanding of the (interactional) difficulties involved when call-handlers ask callers about their ethnicity. DESIGN: This study analyses a corpus of real-life audio-recorded calls to a national cancer helpline in the UK, focusing on the way that call-handlers collect the ethnic monitoring data. SETTING: A major national cancer helpline in the UK. PARTICIPANTS: A sample of 273 recorded calls were recorded, of which 267 were frontline calls in which call handlers are expected to ask the ethnicity monitoring question. RESULTS: Findings suggest that caller uncertainty about how to answer the question, resistance to answering and call-handler presumption can compromise the effectiveness of ethnic monitoring. It is likely to be improved by changing how the ethnicity monitoring question is asked. Changes include avoiding open question formats to ease caller uncertainty; offering callers a rationale (account) for the question to minimise resistance and confirming the accuracy of the ethnic category recorded. CONCLUSIONS: We recommend that telephone-based healthcare personnel avoid asking the ethnicity monitoring question in an 'open' format; instead, a question containing a (short) standardised list can assist callers in responding. A training tool has been developed that applies this and other findings, with a view to improving ethnic monitoring. PMID- 23811171 TI - Accuracy of routinely recorded ethnic group information compared with self reported ethnicity: evidence from the English Cancer Patient Experience survey. AB - OBJECTIVE: To describe the accuracy of ethnicity coding in contemporary National Health Service (NHS) hospital records compared with the 'gold standard' of self reported ethnicity. DESIGN: Secondary analysis of data from a cross-sectional survey (2011). SETTING: All NHS hospitals in England providing cancer treatment. PARTICIPANTS: 58 721 patients with cancer for whom ethnicity information (Office for National Statistics 2001 16-group classification) was available from self reports (considered to represent the 'gold standard') and their hospital record. METHODS: We calculated the sensitivity and positive predictive value (PPV) of hospital record ethnicity. Further, we used a logistic regression model to explore independent predictors of discordance between recorded and self-reported ethnicity. RESULTS: Overall, 4.9% (4.7-5.1%) of people had their self-reported ethnic group incorrectly recorded in their hospital records. Recorded White British ethnicity had high sensitivity (97.8% (97.7-98.0%)) and PPV (98.1% (98.0 98.2%)) for self-reported White British ethnicity. Recorded ethnicity information for the 15 other ethnic groups was substantially less accurate with 41.2% (39.7 42.7%) incorrect. Recorded 'Mixed' ethnicity had low sensitivity (12-31%) and PPVs (12-42%). Recorded 'Indian', 'Chinese', 'Black-Caribbean' and 'Black African' ethnic groups had intermediate levels of sensitivity (65-80%) and PPV (80-89%, respectively). In multivariable analysis, belonging to an ethnic minority group was the only independent predictor of discordant ethnicity information. There was strong evidence that the degree of discordance of ethnicity information varied substantially between different hospitals (p<0.0001). DISCUSSION: Current levels of accuracy of ethnicity information in NHS hospital records support valid profiling of White/non-White ethnic differences. However, profiling of ethnic differences in process or outcome measures for specific minority groups may contain a substantial and variable degree of misclassification error. These considerations should be taken into account when interpreting ethnic variation audits based on routine data and inform initiatives aimed at improving the accuracy of ethnicity information in hospital records. PMID- 23811172 TI - The effect of a web-based depression intervention on suicide ideation: secondary outcome from a randomised controlled trial in a helpline. AB - OBJECTIVES: The effect of web-based interventions for depression on suicide ideation in callers to helplines is not known. The aim of this study was to determine if web-based Cognitive Behaviour Therapy (CBT) with and without telephone support is effective in reducing suicide ideation in callers to a helpline compared with treatment as usual (TAU). A secondary aim was to examine the factors that predict change in suicide ideation. Putative predictors included level of baseline depression, suicide behaviour, baseline anxiety and type of intervention. DESIGN: Randomised controlled trial. SETTING: Lifeline, Australia's 24 h telephone counselling service participants: 155 callers to a national helpline service with moderate-to-high psychological distress. INTERVENTIONS: Participants were recruited and randomised to receive either 6 weeks of internet CBT plus weekly telephone follow-up; internet CBT only; weekly telephone follow up only or a wait-list TAU control group. PRIMARY AND SECONDARY OUTCOME MEASURES: Suicidal ideation was measured using four items from the 28-item General Health Questionnaire. Predictors of change in ideation were tested using logistic regression analysis. RESULTS: Regardless of the intervention condition, participants showed significant reductions in suicidal ideation over 12 months (p<0.001). Higher baseline suicidal behaviour decreased the odds of remission of suicidal ideation at postintervention (OR 0.409, p<0.001). However, change in depression over the course of the interventions was associated with improvement in suicide ideation (OR 1.165, p<0.001). CONCLUSIONS: Suicide ideation declines with and without proactive intervention. Improvements in depression are associated with the resolution of suicide ideation. Specific interventions focusing on suicide ideation should be further investigated. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN93903959. PMID- 23811173 TI - Participants' perspectives on making and maintaining behavioural changes in a lifestyle intervention for type 2 diabetes prevention: a qualitative study using the theory domain framework. AB - OBJECTIVES: In a qualitative substudy, we sought to elicit participants' perspectives of their behavioural change and maintenance of new behaviours towards intervention optimisation. SETTING: The intervention was delivered in leisure and community settings in a local authority, which according to the UK government statistics ranks as 1 of the 10 most socioeconomically deprived areas in England. PARTICIPANTS: We recruited 218 adults aged 40-65 years at elevated risk of type 2 diabetes (Finnish Diabetes Risk Score>=11) to the intervention. Follow-up at 12 months was completed by 134 (62%). We recruited 15 participants, purposively sampled for physical activity increase, to the qualitative substudy. INTERVENTION: Lifestyle intervention can prevent type 2 diabetes, but translation to service provision remains challenging. The 'New life, New you' intervention aimed to promote physical activity, healthy eating and weight loss, and included supervised group physical activity sessions. Behavioural change and weight loss at 12-month follow-up were encouraging. DESIGN: We conducted 15 individual semistructured interviews. The Framework approach, with a comparison of emerging themes, was used in analysis of the transcribed data and complemented by the Theory Domains Framework. RESULTS: Themes emerging from the data were grouped as perceptions that promoted initiating, enacting and maintaining behavioural change. The data were then categorised in accordance with the Theory Domains Framework: intentions and goals; reinforcement; knowledge; social role and identity; social influences; skills and beliefs about capabilities; behavioural regulation, memory, emotion, attention and decision processes and environmental context and resources. Participant perceptions of intervention features that facilitated behavioural change processes were then similarly analysed. CONCLUSIONS: Social influences, reference to social role and identity (eg, peer support), and intentions and goals (eg, to lose weight) were dominant themes across the three phases of behavioural change. Reinforcement, regulation and decision processes were more evident in the maintenance phase. The socioeconomic status of participants was reflected in the environmental context and resource theme. Analysis of phases and theoretical domains of behavioural change added depth and utility to inform intervention optimisation. We will develop the intervention with improved peer support and explicit monitoring of the behavioural change techniques used, prior to a definitive trial. PMID- 23811174 TI - Poor self-rated health and its associations with somatisation in two Australian national surveys. AB - OBJECTIVES: It is hypothesised that across two national surveys poor self-rated health will be independently associated with somatisation and will result in high rates of service use after adjusting for established diagnoses. DESIGN: Two cross sectional population-based surveys were conducted in 1997 and 2007. The use of both surveys allowed replication of results. SETTING: Australia. PARTICIPANTS: The 1997 and 2007 National Surveys of Mental Health and Well-Being were based on stratified, multistage area probability samples of persons living in private dwellings in Australia. The 1997 survey included 10 641 respondents aged 18-75 years, a response rate of 78%. The 2007 survey included 8841 respondents aged 16 85 years, a response rate of 60%. MAIN OUTCOME MEASURES: Self-rated health. RESULTS: Approximately 15% of the Australian population rated their health as fair or poor in both surveys. The independent relationship between self-rated health and somatisation was replicated across both surveys in multivariate analyses. Individuals with negative self-rated health were 4.1 times as likely to screen positive for health anxiety (OR 4.1, 95% CI 2.8 to 5.9) and 3.4 times as likely to be diagnosed with neurasthenia (OR 3.4, 95% CI 2.2 to 5.2), when compared with individuals who rated their health positively. Individuals with negative self-rated health were also more likely to use health services after controlling for demographics and mental and physical illness. CONCLUSIONS: These results confirm both of the study hypotheses: (1) that negative self-rated health was powerfully and independently associated with somatisation and (2) that this relationship manifested itself in high rates of service use, even after adjusting for an extensive range of demographics and psychiatric and physical conditions. PMID- 23811175 TI - Out-of-hours primary percutaneous coronary intervention for ST-elevation myocardial infarction is not associated with excess mortality: a study of 3347 patients treated in an integrated cardiac network. AB - OBJECTIVES: Timely delivery of primary percutaneous coronary intervention (PPCI) is the treatment of choice for ST-segment elevation myocardial infarction (STEMI). Optimum delivery of PPCI requires an integrated network of hospitals, following a multidisciplinary, consultant-led, protocol-driven approach. We investigated whether such a strategy was effective in providing equally effective in-hospital and long-term outcomes for STEMI patients treated by PPCI within normal working hours compared with those treated out-of-hours (OOHs). DESIGN: Observational study. SETTING: Large PPCI centre in London. PARTICIPANTS: 3347 STEMI patients were treated with PPCI between 2004 and 2012. The follow-up median was 3.3 years (IQR: 1.2-4.6 years). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary endpoint was long-term major adverse cardiac events (MACE) with all-cause mortality a secondary endpoint. RESULTS: Of the 3347 STEMI patients, 1299 patients (38.8%) underwent PPCI during a weekday between 08:00 and 18:00 (routine hours group) and 2048 (61.2%) underwent PPCI on a weekday between 18:00 and 08:00 or a weekend (OOHs group). There were no differences in baseline characteristics between the two groups with comparable door-to-balloon times (in-hours (IHs) 67.8 min vs OOHs 69.6 min, p=0.709), call-to-balloon times (IHs 116.63 vs OOHs 127.15 min, p=0.60) and procedural success. In hospital mortality rates were comparable between the two groups (IHs 3.6% vs OOHs 3.2%) with timing of presentation not predictive of outcome (HR 1.25 (95% CI 0.74 to 2.11). Over the follow-up period there were no significant differences in rates of mortality (IHs 7.4% vs OFHs 7.2%, p=0.442) or MACE (IHs 15.4% vs OFHs 14.1%, p=0.192) between the two groups. After adjustment for confounding variables using multivariate analysis, timing of presentation was not an independent predictor of mortality (HR 1.04 95% CI 0.78 to 1.39). CONCLUSIONS: This large registry study demonstrates that the delivery of PPCI with a multidisciplinary, consultant-led, protocol-driven approach provides safe and effective treatment for patients regardless of the time of presentation. PMID- 23811176 TI - Two-group randomised, parallel trial of cognitive and exposure therapies for problem gambling: a research protocol. AB - BACKGROUND: Problem gambling is a serious public health concern at an international level where population prevalence rates average 2% or more and occurs more frequently in younger populations. The most empirically established treatments until now are combinations of cognitive and behavioural techniques labelled cognitive behaviour therapy (CBT). However, there is a paucity of high quality evidence for the comparative efficacy of core CBT interventions in treating problem gamblers. This study aims to isolate and compare cognitive and behavioural (exposure-based) techniques to determine their relative efficacy. METHODS: A sample of 130 treatment-seeking problem gamblers will be allocated to either cognitive or exposure therapy in a two-group randomised, parallel design. Repeated measures will be conducted at baseline, mid and end of treatment (12 sessions intervention period), and at 3, 6 and 12 months (maintenance effects). The primary outcome measure is improvement in problem gambling severity symptoms using the Victorian Gambling Screen (VGS) harm to self-subscale. VGS measures gambling severity on an extensive continuum, thereby enhancing sensitivity to change within and between individuals over time. DISCUSSION: This article describes the research methods, treatments and outcome measures used to evaluate gambling behaviours, problems caused by gambling and mechanisms of change. This study will be the first randomised, parallel trial to compare cognitive and exposure therapies in this population. ETHICS AND DISSEMINATION: The study was approved by the Southern Adelaide Health Service/Flinders University Human Research Ethics Committee. Study findings will be disseminated through peer reviewed publications and conference presentations. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN 12610000828022. PMID- 23811177 TI - Correction. PMID- 23811178 TI - Size before numbers: conceptual size primes numerical value. AB - The present work examined the influence of conceptual object size on numerical processing. In two experiments, pictures of conceptually large or small animals of equal retinal size served as prime stimuli appearing before numerically big or small integer targets. Participants were instructed to perform an unbiased parity judgment task on the target integers. When the prime's conceptual size was congruent with the target's numerical value, participants' reaction time was faster than when the two were incongruent with each other. This influence of conceptual object size on numerical value perception suggests that both types of magnitudes share similar mental representations. Our results are in accord with recent theories (e.g., Cantlon, Platt, & Brannon, 2009; Henik, Leibovich, Naparstek, Diesendruck, & Rubinsten, 2012) that emphasize the evolutionary importance of evaluation and perception of sizes to the development of the numerical system. PMID- 23811179 TI - Effects of dilution on the properties of nC60. AB - C60 forms colloidally stable nanoparticles (nC60) via extended mixing or solvent exchange. Many studies on the environmental impacts of nC60 use aliquots from a large batch of nC60 suspension and either dilute them or subject them to other modifications under the assumption that the properties of the parent suspension remain stable over time and are unaltered by these manipulations. In the present study, nC60 produced via stirring in the presence of sodium citrate (cit/nC60) was characterized with respect to particle size, surface charge, and morphology following dilution. Counter-intuitively, the results show that the colloidal properties of diluted cit/nC60 are not fixed despite constant solution chemistry and are dependent upon the ratios of [C60] to [Na(+)] and [citrate]. In some cases, diluted nC60 had significantly different morphology. This study suggests that any experiment involving modifications of stock nC60 suspensions must take the altered colloidal properties of the diluted nC60 into consideration. PMID- 23811180 TI - Sorption of antibiotic sulfamethoxazole varies with biochars produced at different temperatures. AB - Sorption of sulfonamides on biochars is poorly understood, thus sulfamethoxazole (SMX) sorption on biochars produced at 300-600 degrees C was determined as a function of pH and SMX concentration, as well as the inorganic fractions in the biochars. Neutral SMX molecules (SMX(0)) were dominant for sorption at pH 1.0 6.0. Above pH 7.0, although biochars surfaces were negatively-charged, anionic SMX species sorption increased with pH and is regulated via charge-assisted H bonds. SMX(0) sorption at pH 5.0 was nonlinear and adsorption-dominant for all the biochars via hydrophobic interaction, pi-pi electron donor-acceptor interaction and pore-filling. The removal of inorganic fraction reduced SMX sorption by low-temperature biochars (e.g., 300 degrees C), but enhanced the sorption by high-temperature biochars (e.g., 600 degrees C) due to the temperature-dependent inorganic fractions in the biochars. These observations are useful for producing designer biochars as engineered sorbents to reduce the bioavailability of antibiotics and/or predict the fate of sulfonamides in biochar amended soils. PMID- 23811181 TI - Simultaneous 3D imaging of sound-induced motions of the tympanic membrane and middle ear ossicles. AB - Efficient transfer of sound by the middle ear ossicles is essential for hearing. Various pathologies can impede the transmission of sound and thereby cause conductive hearing loss. Differential diagnosis of ossicular disorders can be challenging since the ossicles are normally hidden behind the tympanic membrane (TM). Here we describe the use of a technique termed optical coherence tomography (OCT) vibrography to view the sound-induced motion of the TM and ossicles simultaneously. With this method, we were able to capture three-dimensional motion of the intact TM and ossicles of the chinchilla ear with nanometer-scale sensitivity at sound frequencies from 0.5 to 5 kHz. The vibration patterns of the TM were complex and highly frequency dependent with mean amplitudes of 70-120 nm at 100 dB sound pressure level. The TM motion was only marginally sensitive to stapes fixation and incus-stapes joint interruption; however, when additional information derived from the simultaneous measurement of ossicular motion was added, it was possible to clearly distinguish these different simulated pathologies. The technique may be applicable to clinical diagnosis in Otology and to basic research in audition and acoustics. PMID- 23811182 TI - Predictors of poor neurological outcome in adult comatose survivors of cardiac arrest: a systematic review and meta-analysis. Part 1: patients not treated with therapeutic hypothermia. AB - AIMS AND METHODS: To systematically review the accuracy of early (<=7 days) predictors of poor outcome defined as death or vegetative state (Cerebral Performance Categories [CPC] 4-5) or death, vegetative state or severe disability (CPC 3-5) in comatose survivors from cardiac arrest not treated using therapeutic hypothermia (TH). PubMed, Scopus and the Cochrane Database of Systematic reviews were searched for eligible studies. Sensitivity, specificity, false positive rates (FPR) for each predictor were calculated and results of predictors with similar time points and outcome definitions were pooled. Quality of evidence (QOE) was evaluated according to the GRADE guidelines. RESULTS: 50 studies (2828 patients) were included in final analysis. Presence of myoclonus at 24-48h, bilateral absence of short-latency somatosensory evoked potential (SSEP) N20 wave at 24-72h, absence of electroencephalographic activity >20-21MUV <=72h and absence of pupillary reflex at 72h predicted CPC 4-5 with 0% FPR and narrow (<10%) 95% confidence intervals. Absence of SSEP N20 wave at 24h predicted CPC 3 5 with 0% [0-8] FPR. Serum thresholds for 0% FPR of biomarkers neuron specific enolase (NSE) and S-100B were highly inconsistent among studies. Most of the studies had a low or very low QOE and did not report blinding of the treating team from the results of the investigated predictor. CONCLUSIONS: In comatose resuscitated patients not treated with TH presence of myoclonus, absence of pupillary reflex, bilateral absence of N20 SSEP wave and low EEG voltage each predicted poor outcome early and accurately, but with a relevant risk of bias. PMID- 23811183 TI - Outer membrane protein OmpW of Escherichia coli is required for resistance to phagocytosis. AB - Eight-stranded beta-barrel outer membrane proteins can confer bacterial virulence via resistance to host innate defenses. This resistance function of OmpW, which was recently identified as an eight-stranded beta-barrel protein, was investigated in this study. Our results demonstrated that upregulation of OmpW correlated with increased bacterial survival during phagocytosis. Bacterial mutants harboring a deletion of ompW exhibited a significantly increased phagocytosis rate. Both observations suggest that the OmpW protein protects bacteria against host phagocytosis. In addition, expression of ompW is regulated by iron, which implies that the resistance provided by OmpW may be an important factor in iron-related infectious diseases. Furthermore, OmpW has been identified as a protective antigen that protects mice against bacterial infection and is therefore a promising target for vaccine development against infectious diseases. PMID- 23811184 TI - How do public health practitioners in China perceive injury prevention? A survey. AB - To report public health practitioners' perceptions of injury prevention in Changsha, China. We undertook a cross-sectional study at Changsha, Hunan, China. An anonymous self-reported survey was conducted to ascertain the proportion of respondents who answered negatively to questions about the value of injury prevention. Over 20% of respondents answered 'unpreventable' or 'don't know' to whether injuries from natural environmental disaster, homicide/assault, poisoning, animal bite, cut/pierce, suffocation and electric current were preventable. More than 40% of respondents answered 'no' or 'don't know' to whether the prevention of injuries from homicide/assault, cut/pierce, fall, suicide/self-harm, drowning, road traffic crash and fire/burn belonged to the job of public health. Only 48% of respondents supported building a division/office within the Centers for Disease Control and Preventions at all levels. Many public health practitioners in Changsha had misperception about injury prevention. Education and training are needed to correct their misperception. PMID- 23811186 TI - PAX8 is expressed in anaplastic thyroid carcinoma diagnosed by fine-needle aspiration: a study of three cases with histological correlates. AB - OBJECTIVE: It is difficult to diagnose anaplastic thyroid carcinoma (ATC) in a fine-needle aspiration (FNA) sample because, given the loss of morphological and immunophenotypical follicular thyroid features, its cytology resembles that of other undifferentiated neoplasms. Recent studies have shown that immunostaining for paired box gene 8 (PAX8), a transcription factor expressed in normal thyroid, is effective for diagnosing ATCs on histology. The aim of this study was to evaluate whether PAX8 could be used to identify ATCs on cytology also. DESIGN AND METHODS: We selected three PAX8-immunostained undifferentiated FNA samples previously diagnosed as suspected ATCs, whose cell block had been negative for the expression of TGB and thyroid transcription factor-1. Matched histological samples, available in two cases, were also processed for PAX8 immunohistochemistry. RESULTS: All three FNA samples were PAX8 positive. Two samples that had an epithelioid pattern showed a diffuse, intense nuclear signal. The third sample, which had a spindle-cell pattern, showed less intense and more patchy staining. Matched histology yielded overlapping results. CONCLUSIONS: PAX8 immunocytochemistry can help cytopathologists to diagnose ATCs. PMID- 23811185 TI - Do changes in circulating biomarkers track with each other and with functional changes in older adults? AB - BACKGROUND: It is unclear if changes in proposed circulating biomarkers of aging are strongly correlated to each other or functional change. We tested if biomarker changes track with each other and with functional measures over 9 years in older adults. METHODS: Dehydroepiandrosterone sulfate (DHEAS), adiponectin, insulin-like growth factor 1 (IGF-1), IGF binding proteins 1 (IGFBP-1) and 3 (IGFBP-3), interleukin-6 (IL-6), cholesterol, and function (gait speed, grip strength, Modified Mini Mental Status Exam [3MSE] and Digit Symbol Substitution Test [DSST] scores) were measured in 1996-1997 and 2005-2006 in the Cardiovascular Health Study All Stars study (N = 901, mean [standard deviation, SD] age 85.3 [3.6] years in 2005-2006). Adjusted Pearson correlations illustrated if biomarkers tracked together. Multivariable linear regression demonstrated if biomarker changes tracked with functional changes. RESULTS: Correlations among biomarker changes were mostly <0.2. In models with each biomarker entered separately, a 1-SD increase biomarker change was associated with change in function as follows: grip strength (DHEAS beta = 0.61kg, p = .001; IL-6 beta = 0.46kg, p = .012; cholesterol men beta = 0.79kg, p = .016); gait speed (DHEAS beta = 0.02 meters per second, p = .039; IL-6 beta = -0.018 meters per second, p = .049); and DSST score (DHEAS women beta = 1.46, p = .004; IL-6 beta = -0.83, p = .027). When biomarkers were entered in the same model, significant associations remaining were as follows: grip strength (DHEAS beta = 0.54kg, p = .005; IL-6 beta = -0.43kg, p = .022); 3MSE score (IGF-1 beta = 0.96, p = .04; IGFBP-3 beta = -1.07, p = .024); and DSST score (DHEAS women beta = 1.27, p = .012; IL-6 beta = 0.80, p = .04). CONCLUSION: Changes in biomarkers were poorly correlated, supporting a model of stochastic, independent change across systems. DHEAS and IL 6 tracked most closely with function, illustrating that changes in inflammation and sex steroids may play dominant roles in changes of these functional outcomes. PMID- 23811187 TI - Roux-en-Y gastric bypass and calorie restriction induce comparable time-dependent effects on thyroid hormone function tests in obese female subjects. AB - OBJECTIVE: Obesity and weight loss influence thyroid hormone physiology. The effects of weight loss by calorie restriction vs Roux-en-Y gastric bypass (RYGB) in obese subjects have not been studied in parallel. We hypothesized that differences in transient systemic inflammation and catabolic state between the intervention types could lead to differential effects on thyroid hormone physiology. DESIGN AND METHODS: We recruited 12 lean and 27 obese females with normal fasting glucose (normal glucose tolerant (NGT)) and 27 obese females with type 2 diabetes mellitus (T2DM) for this study. Weight loss was achieved by restrictive treatment (gastric banding or high-protein-low-calorie diet) or by RYGB. Fasting serum leptin, TSH, triiodothyronine (T3), reverse T3 (rT3), and free thyroxine (fT4) concentrations were measured at baseline and 3 weeks and 3 months after the start of the interventions. RESULTS: Obesity was associated with higher TSH, T3, and rT3 levels and normal fT4 levels in all the subjects when compared with the controls. After 3 weeks, calorie restriction and RYGB induced a decline in TSH levels and a rise in rT3 and fT4 levels. The increase in rT3 levels correlated with serum interleukin 8 (IL8) and IL6 levels. After 3 months, fT4 and rT3 levels returned to baseline levels, whereas TSH and T3 levels were persistently decreased when compared with baseline levels. No differences in the effects on thyroid hormone parameters between the interventions or between NGT and T2DM subjects were observed at any time point. CONCLUSIONS: In summary, weight loss directly influences thyroid hormone regulation, independently of the weight loss strategy used. The effects may be explained by a combination of decreased leptin levels and transient changes in peripheral thyroid hormone metabolism. PMID- 23811188 TI - Pregnancy outcomes in women with severe hypothyroidism. AB - OBJECTIVE: Hypothyroidism during pregnancy has been associated with adverse obstetrical outcomes. Most studies have focused on subjects with a mild or subclinical disorder. The aims of the present study were to determine the relative rate of severe thyroid dysfunction among pregnant women with hypothyroidism, identify related factors and analyse the impact on pregnancy outcomes. DESIGN: A retrospective case series design was employed. METHODS: The study group included 101 pregnant women (103 pregnancies) with an antenatal serum TSH level >20.0 mIU/l identified from the 2009-2010 computerised database of a health maintenance organisation. Data were collected from the medical records. Pregnancy outcomes were compared with those of a control group of 205 euthyroid pregnant women during the same period. RESULTS: The study group accounted for 1.04% of all insured pregnant women with recorded hypothyroidism during the study period. Most cases had an autoimmune aetiology. All women were treated with levothyroxine (L-T4) during pregnancy. Maximum serum TSH level measured was 20.11 150 mIU/l (median 32.95 mIU/l) and median serum TSH level 0.36-75.17 mIU/l (median 7.44 mIU/l). The mean duration of hypothyroidism during pregnancy was 21.2 +/- 13.2 weeks (median 18.5 weeks); in 36 cases (34.9%), all TSH levels during pregnancy were elevated. Adverse pregnancy outcomes included abortions in 7.8% of the cases, premature deliveries in 2.9% and other complications in 14.6%, with no statistically significant differences from the control group. Median serum TSH level during pregnancy was positively correlated with the rate of abortions+premature deliveries and rate of all pregnancy-related complications (P<0.05). CONCLUSIONS: Abortions and premature deliveries occur infrequently in women with severe hypothyroidism. Intense follow-up and L-T4 treatment may improve pregnancy outcomes even when target TSH levels are not reached. PMID- 23811189 TI - Pygidial gland chemistry and potential alarm-recruitment function in column foraging, but not solitary, Nearctic Messor harvesting ants (Hymenoptera: Formicidae: Myrmicinae). AB - We investigated the role of the pygidial gland on foraging behavior in two ecologically dominant column foraging Nearctic harvesting ants (Messor pergandei and Messor andrei). Using chemical analyses and behavioral tests, we show that n tridecane is the major biologically active compound of pygidial gland secretions in both species, and that this chemical functions as a powerful alarm-recruitment pheromone. Another major compound of pygidial gland contents is benzaldehyde; this substance does not release behavioral reactions in M. pergandei workers but might function as a defensive secretion. Six solitary foraging Nearctic Messor and two column foraging Palearctic Messor species, did not have large pygidial gland reservoirs. PMID- 23811190 TI - Endocrine regulation of non-circadian behavior of circadian genes in insect gut. AB - The linden bug Pyrrhocoris apterus exhibits a robust diapause response to photoperiod. Photoperiod strongly affected basal levels of circadian gene transcripts in the gut, via the neuroendocrine system. Cryptochrome 2 (cry2) mRNA level was much higher in diapause promoting short days (SD) than in reproduction promoting long days (LD), while Par Domain Protein 1 (Pdp1) mRNA level was higher in LD than in SD. The effect of photoperiod on gene expression was mediated by the neurosecretory cells of the pars intercerebralis (PI) and the juvenile hormone (JH) producing corpus allatum (CA). In LD-females, CA ablation resulted in SD-like levels of gene transcripts, while PI ablation had little effect. Conversely, in SD-females, CA ablation had only a little effect, while PI ablation resulted in LD-like levels of gene transcripts. Thus, the CA is responsible for LD-like characteristics of gene expression in reproducing females and the PI is responsible for SD-like characteristics of gene expression in diapausing females. A simultaneous ablation of both PI and CA revealed two roles of PI in SD-females: (1) inhibition of CA, and (2) weak CA-independent stimulation of cry2 mRNA. Overall, our results indicate that peripheral circadian gene expression in the gut reflects the physiological state of females (with respect to diapause or reproduction) rather than the external light-dark cycle. PMID- 23811191 TI - PPARalpha-mediated responses in human adult liver stem cells: In vivo/in vitro and cross-species comparisons. AB - The peroxisome proliferator-activated receptor alpha (PPARalpha) is a ligand activated transcription factor that regulates a variety of biological processes including lipid metabolism and energy homeostasis. Peroxisome proliferators (PPs) are carcinogens in rodents, while humans are resistant to peroxisome proliferation and carcinogenesis. In this study, we examined the differential gene expression elicited by clofibrate (CLO) and WY-14,643 (WY) in C57BL/6 mouse liver compared to responses in human HepG2 hepatoma and HL1-1 adult stem cells. Mice were gavaged with sesame oil, 300mg/kg CLO or WY for 2, 4, 8, 12, 18 or 24h, or daily for 4 or 14 days. Although no significant changes in body weight gain were observed, WY induced relative liver weight at 4 and 14 days. Genome-wide hepatic gene expression analysis identified 719 and 1443 differentially expressed unique genes elicited by CLO and WY, respectively (|fold change|>1.5, P1(t)>0.99). Functional analysis associated the gene expression changes with lipid metabolism, transport, cell cycle and immune response. Most differentially expressed genes were in common to both treatments and clustered together only at early time points (2-8h). Complementary QRT-PCR studies in human HL1-1 and HepG2 cells treated with 50MUM WY or DMSO for 1, 2, 4, 8, 12, 24 or 48h identified a minimal number of conserved orthologous responses (e.g., Pdk4, Adfp and Angptl4) while some genes (i.e., Bmf, a tumor suppressor) exhibited induction in human cells but repression in mice. These data suggest that PPs elicit species-specific PPARalpha-mediated gene expression. PMID- 23811192 TI - Respiratory failure in a mouse model of myotonic dystrophy does not correlate with the CTG repeat length. AB - Myotonic dystrophy (DM1) is a multisystemic disease caused by an expansion of CTG repeats in the region of DMPK, the gene encoding DM protein kinase. The severity of muscle disability in DM1 correlates with the size of CTG expansion. As respiratory failure is one of the main causes of death in DM1, we investigated the correlation between respiratory impairment and size of the (CTG)n repeat in DM1 animal models. Using pressure plethysmography the respiratory function was assessed in control and transgenic mice carrying either 600 (DM600) or >1300 CTG repeats (DMSXL). The statistical analysis of respiratory parameters revealed that both DM1 transgenic mice sub-lines show respiratory impairment compared to control mice. In addition, there is no significant difference in breathing functions between the DM600 and DMSXL mice. In conclusion, these results indicate that respiratory impairment is present in both transgenic mice sub-lines, but the severity of respiratory failure is not related to the size of the (CTG)n expansion. PMID- 23811193 TI - Chronic ethanol exposure during development: disturbances of breathing and adaptation. AB - The effects of prenatal exposure to some drugs of abuse, such as nicotine, on breathing function have been clearly established. However, the case of alcohol (ethanol), the most widely consume drug of abuse, remains unknown. Prenatal ethanol consumption in humans may lead to fetal alcohol syndrome and although the effect of chronic prenatal ethanol exposure (CPEE) on cognitive function is frequently studied, nothing is known about CPEE's effects on breathing as compared with other drugs of abuse. The role of nicotine for example, in human neonatal pathology, such as sudden infant death syndrome, is acknowledged today, whereas the full scope of CPEE's role is only recently emerging. Here, we review preclinical investigations on the effects of CPEE on breathing in different animal models, including possible mechanisms of adaptation to CPEE. These recent preclinical studies shed new light on a widely used drug of abuse and should facilitate the understanding of the danger posed by alcohol consumption during pregnancy. PMID- 23811195 TI - Enzymatic and structural characterization of hydrolysis of gibberellin A4 glucosyl ester by a rice beta-D-glucosidase. AB - In order to identify a rice gibberellin ester beta-D-glucosidase, gibberellin A4 beta-D-glucosyl ester (GA4-GE) was synthesized and used to screen rice beta glucosidases. Os3BGlu6 was found to have the highest hydrolysis activity to GA4 GE among five recombinantly expressed rice glycoside hydrolase family GH1 enzymes from different phylogenic clusters. The kinetic parameters of Os3BGlu6 and its mutants E178Q, E178A, E394D, E394Q and M251N for hydrolysis of p-nitrophenyl beta D-glucopyranoside (pNPGlc) and GA4-GE confirmed the roles of the catalytic acid/base and nucleophile for hydrolysis of both substrates and suggested M251 contributes to binding hydrophobic aglycones. The activities of the Os3BGlu6 E178Q and E178A acid/base mutants were rescued by azide, which they transglucosylate to produce beta-D-glucopyranosyl azide, in a pH-dependent manner, while acetate also rescued Os3BGlu6 E178A at low pH. High concentrations of sodium azide (200-400 mM) inhibited Os3BGlu6 E178Q but not Os3BGlu6 E178A. The structures of Os3BGlu6 E178Q crystallized with either GA4-GE or pNPGlc had a native alpha-D-glucosyl moiety covalently linked to the catalytic nucleophile, E394, which showed the hydrogen bonding to the 2-hydroxyl in the covalent intermediate. These data suggest that a GH1 beta-glucosidase uses the same retaining catalytic mechanism to hydrolyze 1-O-acyl glucose ester and glucoside. PMID- 23811194 TI - Respiration and heart rate complexity: effects of age and gender assessed by band limited transfer entropy. AB - Aging and disease are accompanied with a reduction of complex variability in the temporal patterns of heart rate. This reduction has been attributed to a break down of the underlying regulatory feedback mechanisms that maintain a homeodynamic state. Previous work has established the utility of entropy as an index of disorder, for quantification of changes in heart rate complexity. However, questions remain regarding the origin of heart rate complexity and the mechanisms involved in its reduction with aging and disease. In this work we use a newly developed technique based on the concept of band-limited transfer entropy to assess the aging-related changes in contribution of respiration and blood pressure to entropy of heart rate at different frequency bands. Noninvasive measurements of heart beat interval, respiration, and systolic blood pressure were recorded from 20 young (21-34 years) and 20 older (68-85 years) healthy adults. Band-limited transfer entropy analysis revealed a reduction in high frequency contribution of respiration to heart rate complexity (p<0.001) with normal aging, particularly in men. These results have the potential for dissecting the relative contributions of respiration and blood pressure-related reflexes to heart rate complexity and their degeneration with normal aging. PMID- 23811197 TI - Structure of a simplified beta-hairpin and its ATP complex. AB - The capacity of three designed duodecamer peptides with the low diversity sequence: H1phi2I3K4I5D6G7K8phi9I10K11H12 where phi is His, Phe or Trp, to adopt a beta-hairpin conformation was studied using NMR spectroscopy. Whereas KIAbetaH, the variant with His at positions two and nine, is disordered, KIAbetaF, the peptide with Phe at these positions, adopts a small population of beta-hairpin. A high population of beta-hairpin structure was detected for KIAbetaW, the variant with Trp. Utilizing NMR data, the structure of KIAbetaW was solved and it reveals a beta-hairpin stabilized by hydrophobic interactions between Ile residues on one face and Trp-Trp and cation-pi interactions on the opposite face. Upon adding ATP, these peptides show chemical shift changes indicative of ATP binding. The binding of ATP to KIAbetaW shows a KD ~ 20 MUM at pH 5, 5 degrees C and has a 1:1 stoichiometry. The KIAbetaW-ATP complex was determined using NMR spectroscopy and reveals the adenine ring sandwiched between the two Trp indole rings and that ATP binding induces important conformational changes in His1, Trp2, Lys4, Trp9 and Lys11 in the beta-hairpin. The implications of these results for the hypothetic presence of beta-hairpins and amyloids alongside RNAs on the prebiotic Earth are discussed. PMID- 23811196 TI - Structure of pyrazole derivatives impact their affinity, stoichiometry, and cooperative interactions for CYP2E1 complexes. AB - CYP2E1 plays a critical role in detoxification and carcinogenic activation of drugs, pollutants, and dietary compounds; however, these metabolic processes can involve poorly characterized cooperative interactions that compromise the ability to understand and predict CYP2E1 metabolism. Herein, we employed an array of ten azoles with an emphasis on pyrazoles to establish the selectivity of catalytic and cooperative CYP2E1 sites through binding and catalytic studies. Spectral binding studies for monocyclic azoles suggested two binding events, while bicyclic azoles suggested one. Pyrazole had moderate affinity toward the CYP2E1 catalytic site that improved when a methyl group was introduced at either position 3 or 4. The presence of methyl groups simultaneously at positions 3 and 5 blocked binding, and a phenyl group at position 3 did not improve binding affinity. In contrast, pyrazole fusion to a benzene or cyclohexane ring greatly increased affinity. The consequences of these binding events on CYP2E1 catalysis were studied through inhibition studies with 4-nitrophenol, a substrate known to bind both sites. Most pyrazoles shared a common mixed cooperative inhibition mechanism in which pyrazole binding rescued CYP2E1 from substrate inhibition. Overall, inhibitor affinities toward the CYP2E1 catalytic site were similar to those reported in binding studies, and the same trend was observed for binding at the cooperative site. Taken together, these studies identified key structural determinants in the affinity and stoichiometry of azole interactions with CYP2E1 and consequences on catalysis that further advance an understanding of the relationship between structure and function for this enzyme. PMID- 23811198 TI - Reactive thioglucoside substrates for beta-glucosidase. AB - A new, very efficient, class of thioglycoside substrates has been found for beta glucosidase. While thioglycosides are usually resistant to hydrolysis, even in the presence of acids or most glycohydrolases, the beta-D-glucopyranosides of 2 mercaptobenzimidazole (GlcSBiz) and 2-mercaptobenzoxazole (GlcSBox) have been found to be excellent substrates for beta-glucosidase from both sweet almond (a family 1 glycohydrolase) and Aspergillus niger (a family 3 glycohydrolase), reacting nearly as well as p-nitrophenyl beta-D-glucoside. The enzyme-catalyzed hydrolysis of GlcSBiz proceeds with retention of configuration. As with the (1000 fold slower) hydrolysis of phenyl thioglucosides catalyzed by the almond enzyme, the pL (pH/pD)-independent kcat/KM does not show a detectable solvent deuterium kinetic isotope effect (SKIE), but unlike the hydrolysis of phenyl thioglucosides, a modest SKIE is seen on kcat [(D2O)kcat=1.28 (+/-0.06)] at the pL optimum (5.5<=pL<=6.6). A solvent isotope effect is also seen on the KM for the N-methyl analog of GlcSBiz. These results suggest that the mechanism for the hydrolysis of the beta-thioglucoside of 2-mercaptobenzimidazole and of 2 mercaptobenzoxazole involves remote site protonation (at the ring nitrogen) followed by cleavage of the thioglucosidic bond resulting in the thione product. PMID- 23811199 TI - Differential responses of SOD1-deficient mouse embryonic fibroblasts to oxygen concentrations. AB - Superoxide dismutase (SOD) plays a role in antioxidation, and SOD1-knockout (KO) mice show moderate phenotypes. Primary cultured mouse embryonic fibroblasts (MEFs) lead to growth failure and eventual death under normoxic culture (20% oxygen). We attempted to elucidate the molecular mechanisms responsible for the oxygen toxicity in SOD1-KO MEFs. Increases in reactive oxygen species, lipid peroxidation products, and senescence-associated beta-galactosidase activity were observed in SOD1-KO MEFs. Hypoxic culture (2% oxygen) averted immediate cell death but could not recover the proliferative ability of the SOD1-KO cells. The cell cycles of SOD1-deficient MEFs were arrested at the G2 and M phases, leading to the accumulation of tetraploid cells under hypoxic culture. The suppressed expression of cyclin A2 and B1 and the concomitant induction of p21(Waf1) were evident in SOD1-KO cells. The phosphorylation of p53 and histone H2Ax and the induction of the two proapoptotic genes Bax and Noxa were evident in SOD1 deficient MEFs and more enhanced under normoxic culture than under hypoxic culture. We concluded that low levels of oxygen consumption moderately activates the p53 pathway, and leads to cellular senescence, but that high levels of oxygen consumption hyperactivates the p53 pathway, which results in cell death in SOD1 deficient MEFs. PMID- 23811200 TI - Mining the brain metabolome to understand behavioural disruptions induced in mouse fed Hypochoeris radicata (L.), a neurotoxic plant for horse. AB - Mining the brain metabolome to understand behavioural disruptions induced in mouse fed Hypochoeris radicata (L.), a neurotoxic plant for horse. C57BL/6J mice orally exposed to 9% H. radicata (HR) are metabolically competent laboratory animals which can be used as model of Australian stringhalt, a neurological horse disease induced by HR ingestion. So, the present study was conducted to assess the brain metabolome and the behavioural performances of mice fed with a 9%-HR based diet for 21 days. By the end of the period of exposure, mice were investigated for motor activity and coordination, anxiety level, learning and memory performances, social behaviour and rewarding properties of for the plant. Thus, the animals were sacrificed and the brain metabolome was studied using (1)H NMR spectroscopy. HR-exposed mice displayed a motor hyperactivity in several tasks, a less resignation in the forced swimming test, and paradigm place preference for the plant. A bootstrap-based regularized canonical analysis performed on merged behavioural and metabolic datasets showed a clear relationship in HR-treated mice between an increase in cerebral scyllo-inositol, an increased motor activity, and seemingly rewarding properties of HR. These results underlie the interest of such a dual approach to characterize functional end-points of a pathophysiological model of the Australian stringhalt in equine species. PMID- 23811201 TI - Isolation of Toxoplasma gondii strains similar to Africa 1 genotype in Turkey. AB - INTRODUCTION: Toxoplasma gondii is a protozoon parasite that has a worldwide dissemination. It can cause serious clinical problems such as congenital toxoplasmosis, retinochoroiditis, and encephalitis. Currently, T. gondii genotypes are being associated with these clinical presentations which may help clinicians design their treatment strategy. CASE REPORTS: Two T. gondii strains named Ankara and Ege-1 were isolated from newborns with congenital toxoplasmosis in Central and Western Anatolia, respectively. Ankara and Ege-1 strains were isolated from the cerebrospinal fluid of newborns. According to microsatellite analysis, Ankara and Ege-1 strains were sorted as Africa 1 genotype. CONCLUSION: T. gondii strains isolated in Turkey were first time genotyped in this study. Africa 1 genotype has previously been isolated in immunosuppressed patients originating from sub-Saharan Africa. The reason of detecting a strain mainly detected in Africa can be associated with Turkey's specific geographical location. Turkey is like a bridge between Asia, Europe and Africa. Historically, Anatolia was on the Silk Road and other trading routes that ended in Europe. Thus, detecting Africa 1 strain in Anatolia can be anticipated. Consequently, strains detected mainly in Europe and Asia may also be detected in Anatolia and vice versa. Therefore, further studies are required to isolate more strains from Turkey. PMID- 23811202 TI - Membrane active chelators as novel anti-African trypanosome and anti-malarial drugs. AB - Malaria (Plasmodium spp.) and human African trypanosomiasis (Trypanosoma brucei spp.) are vector borne, deadly parasitic diseases. While chemotherapeutic agents for both diseases are available, difficulty in disease eradication and development of drug resistance require that new therapies targeting unexplored pathways or exploiting novel modes of action be developed. Intracellular Plasmodium and extracellular Trypanosoma brucei may have unique and essential requirements for divalent metal ions, beyond that deemed physiological for the host. Membrane Active Chelators (MACs), biologically active only in a hydrophobic lipid environment, are able to bind metal ions at elevated non-physiological concentrations in the vicinity of cell membranes. A dose-response relationship study using validated viability assays revealed that two MAC drugs, DP-b99 and DP 460, were cytotoxic for these parasites in vitro. The 50% effective concentration (EC50) values for DP-b99 and DP-460 were 87 MUM and 39 MUM for Trypanosoma brucei brucei and 21 MUM and 28 MUM for erythrocytic Plasmodium falciparum, respectively. Furthermore, drug potency was maintained for at least 24h in serum containing medium at 37 degrees C. While the exact mechanism of action of MACs against intracellular malaria and extracellular African trypanosome parasites has yet to be determined, their potential as antiparasitic agents warrants further investigation. PMID- 23811203 TI - A rare case of a 39 year old male with a parasite called Dioctophyma renale mimicking renal cancer at the computed tomography of the right kidney. A case report. AB - We present a very rare case of a 39 year old patient with Dioctophyma renale depicted as a Bosniak cyst IV of the right kidney who was finally subjected to a robotic assisted radical nephrectomy. PMID- 23811204 TI - New linezolid-like 1,2,4-oxadiazoles active against Gram-positive multiresistant pathogens. AB - The synthesis and the in vitro antibacterial activity of novel linezolid-like oxadiazoles are reported. Replacement of the linezolid morpholine C-ring with 1,2,4-oxadiazole results in an antibacterial activity against Staphylococcus aureus both methicillin-susceptible and methicillin-resistant comparable or even superior to that of linezolid. While acetamidomethyl or thioacetoamidomethyl moieties in the C(5) side-chain are required, fluorination of the phenyl B ring exhibits a slight effect on an antibacterial activity but its presence seems to reduce the compounds cytotoxicity. Molecular modeling performed using two different approaches - FLAP and Amber software - shows that in the binding pose of the newly synthesized compounds as compared with the crystallographic pose of linezolid, the 1,2,4-oxadiazole moiety seems to perfectly mimic the function of the morpholinic ring, since the H-bond interaction with U2585 is retained. PMID- 23811205 TI - Propidium monoazide does not fully inhibit the detection of dead Campylobacter on broiler chicken carcasses by qPCR. AB - A real time quantitative PCR combined with propidium monoazide (PMA) treatment of samples was implemented to quantify live C. jejuni, C. coli and C. lari on broiler chicken carcasses at selected processing steps in the slaughterhouse. The samples were enumerated by culture for comparison. The Campylobacter counts determined with the PMA-qPCR and the culture method were not concordant. We conclude that the qPCR combined with PMA treatment of the samples did not fully reduce the signal from dead cells. PMID- 23811206 TI - In vitro selection of a DNA aptamer targeted against Shigella dysenteriae. AB - To identify DNA aptamers demonstrating binding specificity for Shigella dysenteriae, a whole-bacterium Systemic Evolution of Ligands by Exponential enrichment (SELEX) method was applied to a combinatorial library of single stranded DNA (ssDNA) molecules. After several rounds of selection using S. dysenteriae as the target, the highly enriched oligonucleotide pool was sequenced and then grouped into different families based on primary sequence homologies and similarities in the secondary structures. Aptamer S 1, which showed particularly high binding affinity in preliminary studies, was chosen for further characterisation. This aptamer displayed a dissociation constant (Kd value) of 23.47 +/- 2.48 nM. Binding assays to assess the specificity of aptamer S 1 showed high binding affinity for S. dysenteriae and low apparent binding affinity for other bacteria. The ssDNA aptamers generated may serve as a new type of molecular probe for microbial pathogens, as it has the potential to overcome the tedious isolation and purification requirements for complex targets. PMID- 23811207 TI - Development of a rapid phage-based method for the detection of viable Mycobacterium avium subsp. paratuberculosis in blood within 48 h. AB - The aim of this study was to develop a methodology to rapidly detect viable Mycobacterium avium subsp. paratuberculosis (MAP) in clinical blood samples. MAP cells spiked into commercially available blood were recovered using optimised peptide-mediated magnetic separation (PMMS) and detected using a phage-based method, and the identity of the cells detected confirmed using nested-PCR amplification of MAP signature sequences (IS900). The limit of detection was determined to be 10 MAP cells per ml of blood and was used to detect MAP present in clinical bovine blood samples. Using the PMMS-phage method there was no difference when detecting MAP from whole blood or from isolated buffy coat. MAP was detected in animals that were milk-ELISA positive (15 animals) by PMMS-phage and no MAP was detected in blood samples from an accredited Johne's disease free herd (5 animals). In a set of samples from one herd (10 animals) that came from animals with variable milk ELISA status, the PMMS-phage results agreed with the positive milk-ELISA results in all but one case. These results show that the PMMS phage method can detect MAP present in naturally infected blood. Total assay time is 48 h and, unlike PCR-based detection tests, only viable cells are detected. A rapid method for detecting MAP in blood could further the understanding of disseminated infection in animals with Johne's disease. PMID- 23811208 TI - Real Time PCR to detect and differentiate Campylobacter fetus subspecies fetus and Campylobacter fetus subspecies venerealis. AB - Bovine venereal campylobacter infection, caused by Campylobacter fetus venerealis, is of significant economic importance to the livestock industry. Unfortunately, the successful detection and discrimination of C. fetus venerealis from C. fetus fetus continue to be a limitation throughout the world. There are several publications warning of the problem with biotyping methods as well as with recent molecular based assays. In this study, assessed on 1071 isolates, we report on the successful development of two Real Time SYBR(r) Green PCR assays that will allow for the detection and discrimination of C. fetus fetus and C. fetus venerealis. The sensitivity reported here for the C. fetus (CampF4/R4) and the C. fetus venerealis (CampF7/R7) specific PCR assays are 100% and 98.7% respectively. The specificity for these same PCR assays are 99.6% and 99.8% respectively. PMID- 23811209 TI - DNase I and Proteinase K eliminate DNA from injured or dead bacteria but not from living bacteria in microbial reference systems and natural drinking water biofilms for subsequent molecular biology analyses. AB - Molecular techniques, such as polymerase chain reaction (PCR) and quantitative PCR (qPCR), are very sensitive, but may detect total DNA present in a sample, including extracellular DNA (eDNA) and DNA coming from live and dead cells. DNase I is an endonuclease that non-specifically cleaves single- and double-stranded DNA. This enzyme was tested in this study to analyze its capacity of digesting DNA coming from dead cells with damaged cell membranes, leaving DNA from living cells with intact cell membranes available for DNA-based methods. For this purpose, an optimized DNase I/Proteinase K (DNase/PK) protocol was developed. Intact Staphylococcus aureus cells, heat-killed Pseudomonas aeruginosa cells, free genomic DNA of Salmonella enterica, and a mixture of these targets were treated according to the developed DNase/PK protocol. In parallel, these samples were treated with propidium monoazide (PMA) as an already described assay for live-dead discrimination. Quantitative PCR and PCR-DGGE of the eubacterial 16S rDNA fragment were used to test the ability of the DNase/PK and PMA treatments to distinguish DNA coming from cells with intact cell membranes in the presence of DNA from dead cells and free genomic DNA. The methods were applied to three months old autochthonous drinking water biofilms from a pilot facility built at a German waterworks. Shifts in the DNA patterns observed after DGGE analysis demonstrated the applicability of DNase/PK as well as of the PMA treatment for natural biofilm investigation. However, the DNase/PK treatment demonstrated some practical advantages in comparison with the PMA treatment for live/dead discrimination of bacterial targets in drinking water systems. PMID- 23811210 TI - The use of a rapid assay to detect the neuraminidase production in oral Porphyromonas spp. isolated from dogs and humans. AB - Neuraminidase was produced by 32.1% and 28.5% of Porphyromonas from dogs with and without periodontitis, respectively; and by 31.8% of bacteria from humans. The presence of neuraminidase in Porphyromonas spp. suggests that this enzyme can be involved with the pathogenesis of the periodontal disease, and the use of this assay to detect the neuraminidase production in oral Porphyromonas species is suggested. PMID- 23811211 TI - Optimization of Campylobacter growth conditions for further identification by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). AB - Growth conditions - including growth medium and incubation temperature - may influence the identification of Campylobacter by MALDI-TOF MS. For each bacterial species, medical microbiologists should be aware of such potential influences on spectral data before analyzing and interpreting MALDI-TOF MS results. PMID- 23811212 TI - Fear of negative evaluation and attentional bias for facial expressions: an event related study. AB - Numerous studies have shown an exacerbation of attentional bias towards threat in anxiety states. However, the cognitive mechanisms responsible for these attentional biases remain largely unknown. Further, the authors outline the need to consider the nature of the attentional processes in operation (hypervigilance, avoidance, or disengagement). We adapted a dot-probe paradigm to record behavioral and electrophysiological responses in 26 participants reporting high or low fear of evaluation, a major component of social anxiety. Pairs of faces including a neutral and an emotional face (displaying anger, fear, disgust, or happiness) were presented during 200 ms and then replaced by a neutral target to discriminate. Results show that anxious participants were characterized by an increased P1 in response to pairs of faces, irrespective of the emotional expression included in the pair. They also showed an increased P2 in response to angry-neutral pairs selectively. Finally, in anxious participants, the P1 response to targets was enhanced when replacing emotional faces, whereas non anxious subjects showed no difference between the two conditions. These results indicate an early hypervigilance to face stimuli in social anxiety, coupled with difficulty in disengaging from threat and sustained attention to emotional stimuli. They are discussed within the framework of current models of anxiety and psychopathology. PMID- 23811213 TI - Huang-Lian-Jie-Du-Decotion induced protective autophagy against the injury of cerebral ischemia/reperfusion via MAPK-mTOR signaling pathway. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Huang-Lian-Jie-Du-Decotion (HLJDD, Hwangryun-Hae Dok-Decotion in Japan), an ancient antipyretic and detoxifying traditional Chinese medicine formula, was reported to have protective effect on ischemic stroke. AIM OF THE RESEARCH: To investigate the therapeutic effect of HLJDD on ischemic stroke and explore its mode of action. MATERIAL AND METHODS: A model of ischemic stroke in the rat was established after transient middle cerebral artery occlusion (MCAO) followed by reperfusion. Rats were assigned randomly to groups of control, sham, transient ischemia/reperfusion (I/R), and three treatment groups by HLJDD at 2.5, 5.0, 10.0mg/kg. The neurological deficit, the cerebral infarct size, morphology abnormality, biochemical parameters were examined, and the levels of relevant proteins were determined by immunoblotting analysis to evaluate the protective effects of HLJDD on ischemic stroke and explore the underlying mechanism. RESULTS: Compared with I/R group, HLJDD significantly ameliorated neurological deficit and histopathology changes, decreased infarct area, and restored the levels of biochemical indicators including nitric oxide (NO), malondialdehyde (MDA), glutathione (GSH), glutathione disulfide (GSSG), total superoxide dismutase (T-SOD), Cu/Zn-SOD, Mn-SOD and glutathione peroxidase (GSH-PX). HLJDD also notably elevated the levels of microtubule-associated protein 1 light chain 3 (LC3), Beclin-1, and other autophagy related genes (Atgs), promoted the activation of extracellular signal-regulated kinases (ERK), protein kinase B (Akt), 3-phosphoinositide-dependent kinase (PDK1), and inhibited the activation of mammalian target of rapamycin (mTOR), c-Jun N-terminal protein kinases (JNK), p38, phosphatase and tensin homolog (PTEN). CONCLUSION: HLJDD showed neuroprotective effects on ischemic stroke, at least in part to the induced protective autophagy via the regulation of mitogen-activated protein kinase (MAPK) signals. This Akt-independent protective autophagy is favorable in the treatment of stroke, avoiding unfavorable side-effects associated with the inactivation of Akt. The efficacy of HLJDD on ischemic stroke and its safety warranted by its long-term clinical use in traditional Chinese medicine favored further study to develop HLJDD as an effective therapeutic agent to treat ischemic stroke. PMID- 23811214 TI - Inhibition of pancreatic lipase, alpha-glucosidase, alpha-amylase, and hypolipidemic effects of the total flavonoids from Nelumbo nucifera leaves. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Nelumbo nucifera Gaertn. leaves have been used as medicinal herbs in the past 1300 years, specifically utilized to cure hyperlipidemia, hyperglycemia, and obesity. It has been recorded in the most famous medicinal book in China for more than 400 years. The present study aims to identify the potential therapeutic activities of the flavonoids isolated from Nelumbo nucifera leaves. MATERIALS AND METHODS: Nelumbo nucifera leaf flavonoids (NLF) were tested for the inhibition of lipase, alpha-glucosidase, and alpha amylase activities in vitro. A single dose of NLF was administered by oral gavage in mice for acute toxicity. Wistar rats with high-fat diet-induced hyperlipidemia and two other animal models were used to evaluate the hypolipidemic effects of NLF. RESULTS: Our in vitro biochemistry tests revealed that the NLF showed high inhibitory activity against porcine pancreatic lipase, alpha-amylase, and alpha glucosidase with IC50 values of 0.38 +/- 0.022, 2.20 +/- 0.18, and 1.86 +/- 0.018 mg/mL, respectively. Furthermore, the NLF significantly lowered the lipid components, such as the total cholesterol, triglycerides, low-density lipoprotein cholesterol, and malondialdehyde, in various established in vivo systems and raised the high-density lipoprotein cholesterol. Moreover, the NLF alleviated high-fat diet-induced lipid accumulation in the liver. CONCLUSIONS: The results demonstrate that NLFs can effectively ameliorate hyperlipidemia and inhibit the key enzymes related to type 2 diabetes mellitus. Our findings may provide new pharmacological basis for the treatment of hyperlipidemia, hyperglycemia, and obesity using NLFs. PMID- 23811215 TI - In vitro antioxidant and anti-inflammatory activities of extracts from Potentilla recta and its main ellagitannin, agrimoniin. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Potentilla recta is one of the numerous cinquefoil species growing in Poland. It is used in traditional medicine e.g. in the treatment of skin inflammation. AIM OF THE STUDY: The purpose of the present study is to evaluate antioxidant and anti-inflammatory activities of extracts and subfractions of the P. recta herb (obtained by using solvents of different polarity) in in vitro systems as well as to examine their chemical composition. MATERIALS AND METHODS: Antioxidant activities of the extracts, subfractions and agrimoniin were evaluated using DPPH and three other radicals (O2(-), H2O2, and HClO) generated in cell-free systems. Anti-hyaluronidase activity was measured by using the turbidimetric method. Inhibition of lipoxidase activity was measured spectrophotometrically, using linoleic acid as a substrate. The composition of the most active subfraction was determined using the HPLC-DAD-MS(n) method. RESULTS: All tested samples showed scavenging activity against all the examined reactive species in a concentration-dependent manner. The highest scavenging activity against DPPH, H2O2 and HClO was observed in the ethyl acetate subfraction (PRE3) (SC50 +/- SEM [MUg/mL]: 25.39 +/- 2.49, 1.79 +/- 0.25 and 8.52 +/- 1.16 respectively). It was only in the xanthine/xanthine oxidase system that the antioxidation potential of the diethyl ether subfraction (PRE2) (SC50 +/- SEM [MUg/mL]: 6.59 +/- 1.33) was higher than that of the subfraction PRE3 (SC50 +/- SEM [MUg/mL]: 8.57 +/- 1.37). Also, in the studies of lipoxidase and hyaluronidase inhibition activity the strongest effect was observed for PRE3, with IC50 [MUg/mL] = 86.31 +/- 5.46, and 12.99 +/- 1.31, respectively. The chromatographic method (HPTLC-DPPH) revealed that the principal substance responsible for the activity, is a tannin like compound. Isolated agrimoniin showed significant reactive oxygen species scavenging activity and significant enzyme inhibition activity (including xanthine oxidase inhibition activity). Agrimoniin exerted the strongest scavenging activity against H2O2 (SC50 +/- SEM [MUM]: 0.20 +/- 0.01). This compound also significantly inhibited the enzymatic activity of lipoxidase (IC50 [MUM] = 36.47 +/- 1.29), and, particularly, of hyaluronidase (IC50 [MUM] = 2.65 +/- 0.40). CONCLUSIONS: The strong scavenging activity against H2O2, and the inhibition of the enzymatic activity of lipoxidase, and particularly, hyaluronidase observed for the tested subfractions and agrimoniin, partly explain the beneficial effects of P. recta in treatment of skin inflammation. PMID- 23811216 TI - Delivery of dimethyloxallyl glycine in mesoporous bioactive glass scaffolds to improve angiogenesis and osteogenesis of human bone marrow stromal cells. AB - Development of hypoxia-mimicking bone tissue engineering scaffolds is of great importance in stimulating angiogenesis for bone regeneration. Dimethyloxallyl glycine (DMOG) is a cell-permeable, competitive inhibitor of hypoxia-inducible factor prolyl hydroxylase (HIF-PH), which can stabilize hypoxia-inducible factor 1alpha (HIF-1alpha) expression. The aim of this study was to develop hypoxia mimicking scaffolds by delivering DMOG in mesoporous bioactive glass (MBG) scaffolds and to investigate whether the delivery of DMOG could induce a hypoxic microenvironment for human bone marrow stromal cells (hBMSC). MBG scaffolds with varied mesoporous structures (e.g. surface area and mesopore volume) were prepared by controlling the contents of mesopore-template agent. The composition, large-pore microstructure and mesoporous properties of MBG scaffolds were characterized. The effect of mesoporous properties on the loading and release of DMOG in MBG scaffolds was investigated. The effects of DMOG delivery on the cell morphology, cell viability, HIF-1alpha stabilization, vascular endothelial growth factor (VEGF) secretion and bone-related gene expression (alkaline phosphatase, ALP; osteocalcin, OCN; and osteopontin, OPN) of hBMSC in MBG scaffolds were systematically investigated. The results showed that the loading and release of DMOG in MBG scaffolds can be efficiently controlled by regulating their mesoporous properties via the addition of different contents of mesopore-template agent. DMOG delivery in MBG scaffolds had no cytotoxic effect on the viability of hBMSC. DMOG delivery significantly induced HIF-1alpha stabilization, VEGF secretion and bone-related gene expression of hBMSC in MBG scaffolds in which DMOG counteracted the effect of HIF-PH and stabilized HIF-1alpha expression under normoxic condition. Furthermore, it was found that MBG scaffolds with slow DMOG release significantly enhanced the expression of bone-related genes more than those with instant DMOG release. The results suggest that the controllable delivery of DMOG in MBG scaffolds can mimic a hypoxic microenvironment, which not only improves the angiogenic capacity of hBMSC, but also enhances their osteogenic differentiation. PMID- 23811218 TI - In vitro and in vivo corrosion, cytocompatibility and mechanical properties of biodegradable Mg-Y-Ca-Zr alloys as implant materials. AB - This study introduces a class of biodegradable Mg-Y-Ca-Zr alloys novel to biological applications and presents evaluations for orthopedic and craniofacial implant applications. Mg-Y-Ca-Zr alloys were processed using conventional melting and casting techniques. The effects of increasing Y content from 1 to 4 wt.% as well as the effects of T4 solution treatment were assessed. Basic material phase characterization was conducted using X-ray diffraction, optical microscopy and scanning electron microscopy. Compressive and tensile tests allowed for the comparison of mechanical properties of the as-cast and T4-treated Mg-Y-Ca-Zr alloys to pure Mg and as-drawn AZ31. Potentiodynamic polarization tests and mass loss immersion tests were used to evaluate the corrosion behavior of the alloys. In vitro cytocompatibility tests on MC3T3-E1 pre-osteoblast cells were also conducted. Finally, alloy pellets were implanted into murine subcutaneous tissue to observe in vivo corrosion as well as local host response through H&E staining. SEM/EDS analysis showed that secondary phase intermetallics rich in yttrium were observed along the grain boundaries, with the T4 solution treatment diffusing the secondary phases into the matrix while increasing the grain size. The alloys demonstrated marked improvement in mechanical properties over pure Mg. Increasing the Y content contributed to improved corrosion resistance, while solution treated alloys resulted in lower strength and compressive strain compared to as cast alloys. The Mg-Y-Ca-Zr alloys demonstrated excellent in vitro cytocompatibility and normal in vivo host response. The mechanical, corrosion and biological evaluations performed in this study demonstrated that Mg-Y-Ca-Zr alloys, especially with the 4 wt.% Y content, would perform well as orthopedic and craniofacial implant biomaterials. PMID- 23811217 TI - Thiol-ene Michael-type formation of gelatin/poly(ethylene glycol) biomatrices for three-dimensional mesenchymal stromal/stem cell administration to cutaneous wounds. AB - Mesenchymal stromal/stem cells (MSCs) are considered promising cellular therapeutics in the fields of tissue engineering and regenerative medicine. MSCs secrete high concentrations of immunomodulatory cytokines and growth factors, which exert paracrine effects on infiltrating immune and resident cells in the wound microenvironment that could favorably promote healing after acute injury. However, better spatial delivery and improved retention at the site of injury are two factors that could improve the clinical application of MSCs. In this study, we utilized thiol-ene Michael-type addition for rapid encapsulation of MSCs within a gelatin/poly(ethylene glycol) biomatrix. This biomatrix was also applied as a provisional dressing to full thickness wounds in Sprague-Dawley rats. The three-way interaction of MSCs, gelatin/poly(ethylene glycol) biomatrices, and host immune cells and adjacent resident cells in the wound microenvironment favorably modulated wound progression and host response. In this model we observed attenuated immune cell infiltration, lack of foreign giant cell (FBGC) formation, accelerated wound closure and re-epithelialization, as well as enhanced neovascularization and granulation tissue formation by 7 days. The MSC entrapped in the gelatin/poly(ethylene glycol) biomatrix localized cell presentation adjacent to the wound microenvironment and thus mediated the early resolution of inflammatory events and facilitated the proliferative phases in wound healing. PMID- 23811219 TI - 20-Hydroxyecdysone-induced transcriptional activity of FoxO upregulates brummer and acid lipase-1 and promotes lipolysis in Bombyx fat body. AB - In a previous study, we have shown that the molting hormone, 20-hydroxyecdysone (20E), reduces insect food consumption resulting in fat body lipolysis during the non-feeding molting and pupation stages, and assumed that the transcription factor FoxO is involved in this process. To verify this hypothesis, we cloned foxO from the silkworm, Bombyx mori. During molting and pupation, FoxO is highly expressed and predominantly localizes in the nuclei of fat body cells. 20E induced foxO mRNA expression and FoxO nuclear localization resulting in an increase of FoxO transcriptional activity. RNAi of foxO prior to the 4th larval molting downregulated two lipase genes--the insect adipose triacylglycerol lipase homologue, brummer, and an acid lipase, acid lipase-1, in the fat body. Overexpression of the constitutively-active form of foxO (foxO(CA)) upregulated brummer and acid lipase-1 in both the fat body and Bombyx Bm-12 cells. Putative FoxO-response elements (FREs) are present in the promoter regions of brummer and acid lipase-1, and mutation of the FREs attenuated their FoxO-induced luciferase activities. ChIP assay revealed that FoxO binds directly to those FREs. Moreover, foxO(CA) overexpression in vivo doubled lipid concentration in the hemolymph, increased total lipase activity, and slightly but significantly reduced lipid content in the fat body. Taken together, we conclude that 20E increases the transcriptional activity of FoxO which, in turn, upregulates brummer and acid lipase-1 and induces lipolysis in the Bombyx fat body during molting and pupation. PMID- 23811220 TI - Enhancement of skin radical scavenging activity and stratum corneum lipids after the application of a hyperforin-rich cream. AB - Hyperforin is well-known for its anti-inflammatory, anti-tumor, anti-bacterial, and antioxidant properties. The application of a hyperforin-rich verum cream could strengthen the skin barrier function by reducing radical formation and stabilizing stratum corneum lipids. Here, it was investigated whether topical treatment with a hyperforin-rich cream increases the radical protection of the skin during VIS/NIR irradiation. Skin lipid profile was investigated applying HPTLC on skin lipid extracts. Furthermore, the absorption- and scattering coefficients, which influence radical formation, were determined. 11 volunteers were included in this study. After a single cream application, VIS/NIR-induced radical formation could be completely inhibited by both verum and placebo showing an immediate protection. After an application period of 4weeks, radical formation could be significantly reduced by 45% following placebo application and 78% after verum application showing a long-term protection. Furthermore, the skin lipids in both verum and placebo groups increased directly after a single cream application but only significantly for ceramide [AP], [NP1], and squalene. After long-term cream application, concentration of cholesterol and the ceramides increased, but no significance was observed. These results indicate that regular application of the hyperforin-rich cream can reduce radical formation and can stabilize skin lipids, which are responsible for the barrier function. PMID- 23811221 TI - Assessment of absorption potential of poorly water-soluble drugs by using the dissolution/permeation system. AB - This study aims to assess the absorption potential of oral absorption of poorly water-soluble drugs by using the dissolution/permeation system (D/P system). The D/P system can be used to perform analysis of drug permeation under dissolution process and can predict the fraction of absorbed dose in humans. When celecoxib at 1/100 of a clinical dose was applied to the D/P system, percentage of dose dissolved and permeated significantly decreased with an increase in the applied amount, resulting in the oral absorption being predicted to be 22-55%. Whereas similar dissolution and permeation profiles of montelukast sodium were observed, estimated absorption (69-85%) was slightly affected. Zafirlukast absorption (33 36%) was not significantly affected by the dose, although zafirlukast did not show complete dissolution. The relationship between clinical dose and predicted oral absorption of drugs corresponded well to clinical observations. The limiting step of the oral absorption of celecoxib and montelukast sodium was solubility, while that of zafirlukast was dissolution rate. However, due to high permeability of montelukast, oral absorption was not affected by dose. Therefore, the D/P system is a useful tool to assess the absorption potential of poorly water soluble drugs for oral use. PMID- 23811223 TI - Search for the exit: Voyager 1 at heliosphere's border with the galaxy. AB - We report measurements of energetic (>40 kiloelectron volts) charged particles on Voyager 1 from the interface region between the heliosheath, dominated by heated solar plasma, and the local interstellar medium, which is expected to contain cold nonsolar plasma and the galactic magnetic field. Particles of solar origin at Voyager 1, located at 18.5 billion kilometers (123 astronomical units) from the Sun, decreased by a factor of >10(3) on 25 August 2012, while those of galactic origin (cosmic rays) increased by 9.3% at the same time. Intensity changes appeared first for particles moving in the azimuthal direction and were followed by those moving in the radial and antiradial directions with respect to the solar radius vector. This unexpected heliospheric "depletion region" may form part of the interface between solar plasma and the galaxy. PMID- 23811224 TI - Genetics. Moving beyond "isolated" gene patents. PMID- 23811222 TI - Identification of wheat gene Sr35 that confers resistance to Ug99 stem rust race group. AB - Wheat stem rust, caused by Puccinia graminis f. sp. tritici (Pgt), is a devastating disease that can cause severe yield losses. A previously uncharacterized Pgt race, designated Ug99, has overcome most of the widely used resistance genes and is threatening major wheat production areas. Here, we demonstrate that the Sr35 gene from Triticum monococcum is a coiled-coil, nucleotide-binding, leucine-rich repeat gene that confers near immunity to Ug99 and related races. This gene is absent in the A-genome diploid donor and in polyploid wheat but is effective when transferred from T. monococcum to polyploid wheat. The cloning of Sr35 opens the door to the use of biotechnological approaches to control this devastating disease and to analyses of the molecular interactions that define the wheat-rust pathosystem. PMID- 23811226 TI - Magnetic field observations as Voyager 1 entered the heliosheath depletion region. AB - Magnetic fields measured by Voyager 1 (V1) show that the spacecraft crossed the boundary of an unexpected region five times between days 210 and ~238 in 2012. The magnetic field strength B increased across this boundary from ~0.2 to ~0.4 nanotesla, and B remained near 0.4 nanotesla until at least day 270, 2012. The strong magnetic fields were associated with unusually low counting rates of >0.5 mega-electron volt per nuclear particle. The direction of B did not change significantly across any of the five boundary crossings; it was very uniform and very close to the spiral magnetic field direction, which was observed throughout the heliosheath. The observations indicate that V1 entered a region of the heliosheath (the heliosheath depletion region), rather than the interstellar medium. PMID- 23811225 TI - Cytochrome P450 drives a HIF-regulated behavioral response to reoxygenation by C. elegans. AB - Oxygen deprivation followed by reoxygenation causes pathological responses in many disorders, including ischemic stroke, heart attacks, and reperfusion injury. Key aspects of ischemia-reperfusion can be modeled by a Caenorhabditis elegans behavior, the O2-ON response, which is suppressed by hypoxic preconditioning or inactivation of the O2-sensing HIF (hypoxia-inducible factor) hydroxylase EGL-9. From a genetic screen, we found that the cytochrome P450 oxygenase CYP-13A12 acts in response to the EGL-9-HIF-1 pathway to facilitate the O2-ON response. CYP 13A12 promotes oxidation of polyunsaturated fatty acids into eicosanoids, signaling molecules that can strongly affect inflammatory pain and ischemia reperfusion injury responses in mammals. We propose that roles of the EGL-9-HIF-1 pathway and cytochrome P450 in controlling responses to reoxygenation after anoxia are evolutionarily conserved. PMID- 23811227 TI - Voyager 1 observes low-energy galactic cosmic rays in a region depleted of heliospheric ions. AB - On 25 August 2012, Voyager 1 was at 122 astronomical units when the steady intensity of low-energy ions it had observed for the previous 6 years suddenly dropped for a third time and soon completely disappeared as the ions streamed away into interstellar space. Although the magnetic field observations indicate that Voyager 1 remained inside the heliosphere, the intensity of cosmic ray nuclei from outside the heliosphere abruptly increased. We report the spectra of galactic cosmic rays down to ~3 * 10(6) electron volts per nucleon, revealing H and He energy spectra with broad peaks from 10 * 10(6) to 40 * 10(6) electron volts per nucleon and an increasing galactic cosmic-ray electron intensity down to ~10 * 10(6) electron volts. PMID- 23811228 TI - The gene Sr33, an ortholog of barley Mla genes, encodes resistance to wheat stem rust race Ug99. AB - Wheat stem rust, caused by the fungus Puccinia graminis f. sp. tritici, afflicts bread wheat (Triticum aestivum). New virulent races collectively referred to as "Ug99" have emerged, which threaten global wheat production. The wheat gene Sr33, introgressed from the wild relative Aegilops tauschii into bread wheat, confers resistance to diverse stem rust races, including the Ug99 race group. We cloned Sr33, which encodes a coiled-coil, nucleotide-binding, leucine-rich repeat protein. Sr33 is orthologous to the barley (Hordeum vulgare) Mla mildew resistance genes that confer resistance to Blumeria graminis f. sp. hordei. The wheat Sr33 gene functions independently of RAR1, SGT1, and HSP90 chaperones. Haplotype analysis from diverse collections of Ae. tauschii placed the origin of Sr33 resistance near the southern coast of the Caspian Sea. PMID- 23811229 TI - Ligand- and drug-binding studies of membrane proteins revealed through circular dichroism spectroscopy. AB - A great number of membrane proteins have proven difficult to crystallise for use in X-ray crystallographic structural determination or too complex for NMR structural studies. Circular dichroism (CD) is a fast and relatively easy spectroscopic technique to study protein conformational behaviour. In this review examples of the applications of CD and synchrotron radiation CD (SRCD) to membrane protein ligand binding interaction studies are discussed. The availability of SRCD has been an important advancement in recent progress, most particularly because it can be used to extend the spectral region in the far-UV region (important for increasing the accuracy of secondary structure estimations) and for working with membrane proteins available in only small quantities for which SRCD has facilitated molecular recognition studies. Such studies have been accomplished by probing in the near-UV region the local tertiary structure of aromatic amino acid residues upon addition of chiral or non-chiral ligands using long pathlength cells of small volume capacity. In particular, this review describes the most recent use of the technique in the following areas: to obtain quantitative data on ligand binding (exemplified by the FsrC membrane sensor kinase receptor); to distinguish between functionally similar drugs that exhibit different mechanisms of action towards membrane proteins (exemplified by secretory phospholipase A2); and to identify suitable detergent conditions to observe membrane protein-ligand interactions using stabilised proteins (exemplified by the antiseptic transporter SugE). Finally, the importance of characterising in solution the conformational behaviour and ligand binding properties of proteins in both far- and near-UV regions is discussed. This article is part of a Special Issue entitled: Structural and biophysical characterisation of membrane protein-ligand binding. PMID- 23811230 TI - Three unique Sendai virus antigenic peptides screened from nucleocapsid protein by overlapping peptide array. AB - Sendai virus (SeV) is strictly monitored in laboratory rodents. Currently, complete virions have been used as antigens in SeV serological tests. However, the complexity of SeV virion antigen limits the accuracy of the diagnostic method. In the current study, complete SeV virion antigen was separated on SDS PAGE and analyzed, with nucleocapsid protein (NP) showing predominant antigenicity. A peptide array containing overlapping 14-mer peptides covering the entire NP was developed. The array used SeV positive serum and resulted in four antigenic linear peptides being identified, which were located in the carboxyl terminus of NP. The four peptides were coated on ELISA plates and tested with SeV positive and SeV negative sera, and the antigenicity of three peptides, NP413 428, NP473-490 and NP507-524, was confirmed. Mixture of the three peptides showed comparable sensitivity and better specificity in clinical rat sera ELISA tests compared with complete SeV virion antigen. In conclusion, the three peptides, NP413-428, NP473-490 and NP507-524, would be good candidates as linear antigens for SeV detection. PMID- 23811231 TI - A new approach for diagnosis of bovine coronavirus using a reverse transcription recombinase polymerase amplification assay. AB - Bovine coronavirus (BCoV) is an economically significant cause of calf scours and winter dysentery of adult cattle, and may induce respiratory tract infections in cattle of all ages. Early diagnosis of BCoV helps to diminish its burden on the dairy and beef industry. Real-time RT-PCR assay for the detection of BCoV has been described, but it is relatively expensive, requires well-equipped laboratories and is not suitable for on-site screening. A novel assay, using reverse transcription recombinase polymerase amplification (RT-RPA), for the detection of BCoV is developed. The BCoV RT-RPA was rapid (10-20 min) and has an analytical sensitivity of 19 molecules. No cross-reactivity with other viruses causing bovine gastrointestinal and/or respiratory infections was observed. The assay performance on clinical samples was validated by testing 16 fecal and 14 nasal swab specimens and compared to real-time RT-PCR. Both assays provided comparable results. The RT-RPA assay was significantly more rapid than the real time RT-PCR assay. The BCoV RT-RPA constitutes a suitable accurate, sensitive and rapid alternative to the common measures used for BCoV diagnosis. In addition, the use of a portable fluorescence reading device extends its application potential to use in the field and point-of-care diagnosis. PMID- 23811232 TI - Effects of study precision and risk of bias in networks of interventions: a network meta-epidemiological study. AB - BACKGROUND: Empirical research has illustrated an association between study size and relative treatment effects, but conclusions have been inconsistent about the association of study size with the risk of bias items. Small studies give generally imprecisely estimated treatment effects, and study variance can serve as a surrogate for study size. METHODS: We conducted a network meta epidemiological study analyzing 32 networks including 613 randomized controlled trials, and used Bayesian network meta-analysis and meta-regression models to evaluate the impact of trial characteristics and study variance on the results of network meta-analysis. We examined changes in relative effects and between studies variation in network meta-regression models as a function of the variance of the observed effect size and indicators for the adequacy of each risk of bias item. Adjustment was performed both within and across networks, allowing for between-networks variability. RESULTS: Imprecise studies with large variances tended to exaggerate the effects of the active or new intervention in the majority of networks, with a ratio of odds ratios of 1.83 (95% CI: 1.09,3.32). Inappropriate or unclear conduct of random sequence generation and allocation concealment, as well as lack of blinding of patients and outcome assessors, did not materially impact on the summary results. Imprecise studies also appeared to be more prone to inadequate conduct. CONCLUSIONS: Compared to more precise studies, studies with large variance may give substantially different answers that alter the results of network meta-analyses for dichotomous outcomes. PMID- 23811233 TI - Abortion before & after Roe. AB - We use unique data on abortions performed in New York State from 1971 to 1975 to demonstrate that women traveled hundreds of miles for a legal abortion before Roe. A 100-mile increase in distance for women who live approximately 183 miles from New York was associated with a decline in abortion rates of 12.2 percent whereas the same change for women who lived 830 miles from New York lowered abortion rates by 3.3 percent. The abortion rates of nonwhites were more sensitive to distance than those of whites. We found a positive and robust association between distance to the nearest abortion provider and teen birth rates but less consistent estimates for other ages. Our results suggest that even if some states lost all abortion providers due to legislative policies, the impact on population measures of birth and abortion rates would be small as most women would travel to states with abortion services. PMID- 23811234 TI - PPAR activation as a regulator of lipid metabolism, nitric oxide production and lipid peroxidation in the placenta from type 2 diabetic patients. AB - Peroxisome proliferator activated receptors (PPARs) are ligand activated transcription factors with crucial functions in lipid homeostasis, anti inflammatory processes and placental development. Maternal diabetes induces a pro inflammatory environment and alters placental development. We investigated whether PPARs regulate lipid metabolism and nitric oxide (NO) production in placental explants from healthy and type 2 diabetic (DM2) patients. We found decreased PPARalpha and PPARgamma concentrations, no changes in PPARdelta concentrations, and increased lipids, lipoperoxides and NO production in placentas from DM2 patients. PPARalpha agonists reduced placental concentrations of triglycerides and both PPARalpha and PPARdelta agonists reduced concentrations of phospholipids, cholesteryl esters and cholesterol. PPARgamma agonists increased lipid concentrations in placentas from DM2 patients and more markedly in placentas from healthy patients. Endogenous ligands for the three PPAR isotypes reduced NO production and lipoperoxidation in placentas from DM2 patients. We conclude that PPARs play a role in placental NO and lipid homeostasis and can regulate NO production, lipid concentrations and lipoperoxidation in placentas from DM2 patients. PMID- 23811235 TI - Ponatinib is a potent inhibitor of wild-type and drug-resistant gatekeeper mutant RET kinase. AB - RET kinase is aberrantly activated in thyroid cancers and in rare cases of lung and colon cancer, and has been validated as a molecular target in these tumors. Vandetanib was recently approved for the treatment of medullary thyroid cancer. However, vandetanib is ineffective in vitro against RET mutants carrying bulky aminoacids at position 804, the gatekeeper residue, similarly to drug-resistant BCR-ABL mutants in chronic myeloid leukemia. Ponatinib is a multi-target kinase inhibitor that was recently approved for treatment-refractory Philadelphia positive leukemia. We show here potent inhibition of oncogenic RET by ponatinib, including the drug-insensitive V804M/L mutants. Ponatinib inhibited the growth of RET+ and BCR-ABL+ cells with similar potency, while not affecting RET-negative cells. Both in biochemical and in cellular assays ponatinib compared favorably with known RET inhibitors, such as vandetanib, cabozantinib, sorafenib, sunitinib and motesanib, used as reference compounds. We suggest that ponatinib should be considered for the treatment of RET+ tumors, in particular those expressing vandetanib-resistant V804M/L mutations. PMID- 23811237 TI - Armstrong-McGehee mechanism revisited: competitive exclusion and coexistence of nonlinear consumers. AB - A number of mechanisms have been proposed to explain the coexistence of species engaging in exploitative competition. The Armstrong-McGehee mechanism relies on different levels of nonlinearity in functional response between competing consumers and their ability to avoid competitive exclusion through temporal resource partitioning during endogenously generated fluctuations. While previous studies have mainly focused on cases where one consumer has nonlinear functional response and the other consumer has linear functional response, our study assessed coexistence and competitive exclusion under a more realistic scenario with two nonlinear consumers. Using analytical and numerical methods we found that the potential of coexistence of the two consumers decreases with increasing nonlinearity in the more linear species; increasing nonlinearity in the more nonlinear species, however, resulted in non-monotonic changes in the parameter space allowing coexistence. When coexistence potential is quantified under the presupposition that each consumer must be able to persist with the resource by itself, coexistence becomes consistently less likely with increasing similarity of the functional responses of the two consumers. Our results suggest that the Armstrong-McGehee mechanism is unlikely to operate as the sole coexistence promoting mechanism in communities with generally nonlinear consumer-resource interactions. However, its role as a module in more complex systems and in synergy with other factors remains to be established. PMID- 23811236 TI - Gene dosage of Otx2 is important for fertility in male mice. AB - Together, the hypothalamus, pituitary and gonads direct the development and regulation of reproductive function in mammals. Gonadotropin-releasing hormone (GnRH) expression is limited to ~800 neurons that originate in the olfactory placode then migrate to the hypothalamus. Coordination of the hypothalamic pituitary-gonadal (HPG) axis is dependent upon correct neuronal migration of GnRH neurons into the hypothalamus followed by proper synthesis and pulsatile secretion of GnRH. Defects in any one of these processes causes infertility. Otx2, the vertebrate homologue of Drosophila orthodenticle, is a transcription factor that has been shown to be critical for normal brain and eye development and is expressed in both the developing GnRH neurons and the pituitary, suggesting that this gene may play a critical role in development of the HPG axis. As Otx2-null mice are embryonic lethal, we have analyzed the reproductive capacity of heterozygous Otx2 mice to determine the contribution of Otx2 gene dosage to normal HPG axis function. Our data reveal that correct dosage of Otx2 is critical for normal fertility as loss of one allele of Otx2 leads to a discernible reproductive phenotype in male mice due to disruption of the migration of GnRH neurons during development. PMID- 23811238 TI - Evaluation of the effects of P(II) deficiency and the toxicity of PipX on growth characteristics of the P(II)-Less mutant of the cyanobacterium Synechococcus elongatus. AB - Among the known functions of the P(II) protein (the glnB gene product) in the cyanobacterium Synechococcus elongatus, negative regulation of the activity of PipX, a transcriptional co-activator of the NtcA regulon, has been thought to be essential for cell viability, because all the P(II)-less mutants thus far constructed carry spontaneous mutations in pipX. PipX is thus deduced to be a toxic protein, but its toxicity has not been clearly defined because of the lack of P(II)-deficient mutants carrying wild-type pipX. In this study, we developed a method to construct a targeted P(II)-less mutant of S. elongatus without the pipX mutation and determined the contribution of PipX to the detrimental effects of P(II) deficiency. Growth defects of the mutant were severe under nitrogen-replete conditions, i.e. in the presence of ammonium, but were also apparent under nitrogen-limited conditions. Genetic analyses indicated that the growth impairment observed under the nitrogen-limited conditions is largely due to the toxicity of PipX. Some of the phenotypes observed under the nitrogen-replete conditions, including reduced pigmentation and death of most of the cells after transfer from nitrogen-limited conditions to nitrogen-replete conditions, were ascribed to the toxicity of PipX, but inactivation of pipX only partially rescued the growth defect observed in the presence of ammonium, indicating the presence of an as yet unknown P(II) function(s) required for normal growth. Effects of ammonium addition on the nitrite uptake activity of the glnB mutant revealed a new function for P(II) in regulation of the activity of the ABC-type cyanate/nitrite transporter. PMID- 23811239 TI - Stage of hilar cholangiocarcinoma predicts recurrence of biliary obstruction in patients with metal stents. AB - BACKGROUND & AIMS: Most patients with hilar cholangiocarcinomas present with unresectable tumors, so only palliative biliary drainage with self-expanding metal stents (SEMS) is possible. Stents eventually cease to function because of tumor overgrowth and/or other causes, so it is important to identify factors that affect stent patency and failure. We examined the patency of endoscopically placed SEMS in patients with hilar cholangiocarcinoma and factors associated with patency. METHODS: We performed a retrospective study of 120 consecutive patients (mean age, 67 +/- 14.6 years; 74 male) who presented with obstructive jaundice from hilar cholangiocarcinoma and underwent bilateral SEMS from September 2006 through April 2012 at 2 US tertiary medical centers. We collected data on patient demographics and survival, success of stent placement and function, and immediate adverse events. The primary outcome was duration of stent patency (time from insertion to failure). RESULTS: Thirty-eight patients had stage 1 hilar cholangiocarcinomas, 45 had stage 2, 12 had stage 3, and 25 had stage 4. The median length of the hilar stricture was 9 mm (range, 8-50 mm). The stent was successfully passaged across the stricture in all patients and was functional in 115; its median length was 8 mm (range, 8-10 mm), and diameter was 80 mm (range, 60-100 mm). Fourteen patients had immediate adverse events, including perforation (n = 2), bleeding (n = 2), pancreatitis (n = 9), and cholangitis (n = 1). Median survival was 17 weeks (range, 1-211 weeks), and 50 patients had stent occlusion. On Kaplan-Meier analysis, the median time from stent placement to occlusion was 17 weeks (range, 1-104 weeks). More patients with stage 3 or 4 tumors (64%) had SEMS occlusion than patients with stage 1 or 2 tumors (28%) in univariate analysis (P = .017). In multivariate analysis, only cancer stage was independently and significantly associated with patency (P = .006; hazard ratio, 2.77); age, sex, length of stricture, and SEMS diameter and length were not. CONCLUSIONS: The cumulative patency of bilateral SEMS for hilar cholangiocarcinoma significantly decreases as tumor stage increases. Age, sex, length of stricture, and SEMS diameter and length are not associated with SEMS patency. PMID- 23811240 TI - Fever of undetermined origin: cervical diskitis-osteomyelitis associated with esophageal self-expanding metal stent. PMID- 23811242 TI - Noninvasive methods of assessing nonalcoholic fatty liver disease: what the clinician needs to know. PMID- 23811241 TI - Hepatitis B and C in African Americans: current status and continued challenges. AB - Viral hepatitis remains a public health concern in the United States, resulting in excess morbidity and mortality for the individual and representing a burden to societies as evidenced by billions of dollars in health care expenditures. As with many chronic diseases, race and ethnicity influence various aspects of disease pathogenesis, including mechanisms of persistence, disease progression, disease sequelae, and response to therapy. For hepatitis B and C infections, African Americans disproportionately bear a large burden of disease in the United States. The role and importance of African American race, however, have been less well-characterized in the literature among the population of viral hepatitis infected individuals. The differences in epidemiology, manifestations of liver disease, response to therapy, and differential trends in liver transplantation in African Americans compared with other racial and ethnic groups deserve special attention. This review will address the current status of hepatitis B and C infection in African Americans in the United States and identify some of the remaining challenges in diagnosis, characterization of natural history, and treatment. For the purposes of this review, the terms African American and black will be used interchangeably throughout the text. PMID- 23811243 TI - Perianal papillomatous Crohn's disease in a male adolescent. PMID- 23811244 TI - Patients don't know their polyps, but do they know when to repeat colonoscopy? PMID- 23811245 TI - Advanced endoscopic imaging: a review of commercially available technologies. AB - The rapid strides made in innovative endoscopic technology to improve mucosal visualization have revolutionized endoscopy. Improved lesion detection has allowed the modern endoscopist to provide real-time optical diagnosis. Improvements in image resolution, software processing, and optical filter technology have resulted in the commercial availability of high-definition endoscopy as well as optical contrast techniques such as narrow-band imaging, flexible spectral imaging color enhancement, and i-scan. Along with autofluorescence imaging and confocal laser endomicroscopy, these techniques have complemented and enhanced traditional white light endoscopy. They have the potential to serve as red-flag techniques to improve detection of mucosal abnormalities as well as allow optical diagnosis and virtual histology of detected lesions. This review will focus on these emerging commercially available technologies and aims to provide an overview of the technologies, their clinical applicability, and current status. PMID- 23811246 TI - Association between body mass index and quality of split bowel preparation. AB - BACKGROUND & AIMS: Little is known about the association between obesity and bowel preparation. We investigated whether body mass index (BMI) is an independent risk factor for inadequate bowel preparation in patients who receive split preparation regimens. METHODS: We performed a retrospective study of data from 2163 consecutive patients (mean age, 60.6 +/- 10.5 y; 93.8% male) who received outpatient colonoscopies in 2009 at the Veterans Affairs Medical Center in Indianapolis, Indiana. All patients received a split preparation, categorized as adequate (excellent or good, based on the Aronchick scale) or inadequate. We performed a multivariable analysis to identify factors independently associated with inadequate preparation. RESULTS: Bowel preparation quality was inadequate for 44.2% of patients; these patients had significantly higher mean BMIs than patients with adequate preparation (31.2 +/- 6.5 vs 29.8 +/- 5.9, respectively; P < .0001) and Charlson comorbidity scores (1.5 +/- 1.6 vs 1.1 +/- 1.4; P < .0001). Independent risk factors for inadequate preparation were a BMI of 30 kg/m(2) or greater (odds ratio [OR], 1.46; 95% confidence interval [CI], 1.21-1.75; P < .0001), use of tobacco (OR, 1.28; 95% CI, 1.07-1.54; P = .0084) or narcotics (OR, 1.28; 95% CI, 1.04-1.57; P = .0179), hypertension (OR, 1.30; 95% CI, 1.07-1.57; P = .0085), diabetes (OR, 1.38; 95% CI, 1.12-1.69; P = .0021), and dementia (OR, 3.02; 95% CI, 1.22-7.49; P = .0169). CONCLUSIONS: BMI is an independent factor associated with inadequate split bowel preparation for colonoscopy. Additional factors associated with quality of bowel preparation include diabetes, hypertension, dementia, and use of tobacco and narcotics. Patients with BMIs of 30 kg/m(2) or greater should be considered for more intensive preparation regimens. PMID- 23811247 TI - Can daily coffee consumption reduce liver disease-related mortality? PMID- 23811248 TI - Do endoscopic antireflux procedures fit in the current treatment paradigm of gastroesophageal reflux disease? AB - Gastroesophageal reflux disease (GERD) is a common condition requiring considerable medical resources. The mainstay of therapy is proton pump inhibitors (PPIs), which are effective at reducing acid reflux. In patients who have refractory acid reflux and esophagitis despite high-dose PPI, or are intolerant of the side effects of PPI therapy, surgical fundoplication is the primary therapy. The risk and cost gap between medical therapy and surgery has resulted in substantial interest in less-invasive endoscopic therapies. In this review, we discuss the underlying physiology of GERD along with the anatomic hurdles that must be overcome to develop an effective antireflux procedure. We also review the current published literature and assess the clinical efficacy of the devices that have been studied or currently are being investigated. Despite promising early studies, many of the devices fall short in high-quality randomized controlled trials. Furthermore, the physiologic aberration resulting in GERD oftentimes is addressed inadequately. Although there is certainly a need for less-invasive, safe, and effective therapy for reflux, therapy will need to withstand the established clinical efficacy of both PPI and surgical fundoplication. At present, we have the luxury of time to wait for such a device to become available. PMID- 23811249 TI - Alcoholic hepatitis: current challenges and future directions. AB - Alcoholic hepatitis is a distinct clinical syndrome among people with chronic and active alcohol abuse, with a potential for 30%-40% mortality at 1 month among those with severe disease. Corticosteroids or pentoxifylline are the current pharmacologic treatment options, but they provide only about 50% survival benefit. These agents are recommended for patients with modified discriminant function (mDF) >= 32 or Model for End-Stage Liver Disease score >= 18. The Lille score is used to determine response to steroids. Currently, a minimum of 6 months of abstinence from alcohol use is required for patients to receive a liver transplant, a requirement that cannot be met by patients with severe alcoholic hepatitis nonresponsive to steroids (Lille score >= 0.45). Data are emerging on the benefit of liver transplantation in select patients with first episode of severe alcoholic hepatitis. This review also focuses on recent treatment trials in alcoholic hepatitis including liver transplantation and its associated controversies, as well as possible future targets and pharmacologic treatment options for patients with alcoholic hepatitis that are being pursued through upcoming consortium studies. PMID- 23811250 TI - Factors that affect life expectancy of patients with gastric adenocarcinoma. AB - BACKGROUND & AIMS: We used a new, semi-parametric method to estimate life expectancy and expected years of life lost (EYLL) after diagnosis of gastric cancer and assess whether patients' sex or tumor type or location had any effects. METHODS: We performed a nationwide retrospective cohort study of 35,576 patients with gastric cancer who were registered in the Taiwan Cancer Registry from 1998 through 2007; data were collected until the end of 2010. The Monte Carlo method and tables in Taiwan National Vital Statistics database were matched to the cohort reference populations on the basis of age and sex. The estimated regression line and the survival curve of reference populations were used to extrapolate the survival curve beyond 2010. We compared patients' age at diagnosis, life expectancy, and EYLL based on sex, tumor type, and location. RESULTS: In Taiwan, gastric cancer is more prevalent among men, and 88.6% of tumors are adenocarcinomas. Patients with adenocarcinoma of the gastric cardia have shorter life expectancies and greater EYLL than those with noncardia tumors (P < .05). Women with gastric adenocarcinoma are diagnosed at a younger age and have longer life expectancies but more EYLL than men with such tumors (P < .05). The estimated years of life saved if gastric adenocarcinoma is diagnosed at an early stage and cured are 22,827 years (2.62 years/case) for women and 33,700 years (1.97 years/case) for men. CONCLUSION: Among patients with gastric cancer, men and patients with adenocarcinomas of the cardia have shorter life expectancies and more EYLL. Early detection of gastric adenocarcinoma can increase life expectancy. PMID- 23811252 TI - True costs of infliximab testing and administration. PMID- 23811251 TI - Accuracy of international guidelines for identifying significant fibrosis in hepatitis B e antigen--negative patients with chronic hepatitis. AB - BACKGROUND & AIMS: Differing threshold levels of hepatitis B virus (HBV) DNA and alanine aminotransferase (ALT) are recommended by international guidelines for commencement of antiviral therapy. These guidelines advocate therapy for patients with significant fibrosis (METAVIR score >=F2); we assessed the accuracy of these guideline-defined thresholds in identifying patients with >=F2 fibrosis. METHODS: We applied the European (European Association for the Study of the Liver [EASL] 2012), Asian-Pacific (Asian-Pacific Association for the Study of the Liver [APASL] 2012), American (American Association for the Study of Liver Diseases [AASLD] 2009), and United States Panel Algorithm (USPA 2008) criteria to 366 consecutive hepatitis B e antigen-negative patients with liver biopsy samples: EASL, ALT >laboratory-defined upper limit of normal (ULN) and HBV DNA >=2000 IU/mL (n = 171); APASL, ALT >2-fold laboratory-defined ULN and HBV DNA >=2000 IU/mL (n = 87); AASLD, ALT >2-fold the updated ULN (0.5-fold ULN [corresponding to <=19 U/L] for women and 0.75-fold the ULN [corresponding to <=30 U/L] for men) and HBV DNA >=20,000 IU/mL (n = 53); and USPA, ALT >updated ULN (>0.5-fold ULN for women and >0.75-fold ULN for men) and HBV DNA >=2000 IU/mL (n = 173). RESULTS: Overall, 113 patients (30.9%) had >=F2 fibrosis, which was more frequent among patients who fulfilled any guideline criteria (45.7% vs 17.9% for those who did not fulfill any criteria, P < .0001). In applying the EASL, AASLD, APASL, and USPA criteria, sensitivity and specificity values for detection of >=F2 fibrosis were 45.6%, 58.5%, 56.3%, and 45.7% (P = .145) and 82.1%, 73.8%, 77.1%, and 82.4% (P = .366), respectively. The EASL criteria (area under the receiver operating characteristic [AUROC] curve, 0.66; 95% confidence interval [CI], 0.61-0.71) and USPA criteria (AUROC, 0.66; 95% CI, 0.58-0.73) performed better than APASL (AUROC, 0.64; 95% CI, 0.59-0.69; P = .421) and significantly better than the AASLD criteria (AUROC, 0.59; 95% CI, 0.54-0.64; P = .013). CONCLUSIONS: In hepatitis B e antigen-negative patients with chronic hepatitis, the EASL, AASLD, APASL, and USPA criteria identify patients with >=F2 fibrosis with low levels of accuracy. However, the EASL and USPA criteria are the most accurate for identification of these patients. PMID- 23811253 TI - Proximal megacolon in an adult. PMID- 23811254 TI - Comparative effectiveness of infliximab and adalimumab for Crohn's disease. AB - BACKGROUND & AIMS: Antibodies against tumor necrosis factor-alpha are widely used to treat patients with Crohn's disease (CD). This study compared the effectiveness of infliximab and adalimumab, the 2 most commonly used anti-tumor necrosis factor agents, in patients with CD. METHODS: We conducted a retrospective cohort study by using U.S. Medicare data from 2006 through 2010. Patients with CD who were new users of infliximab (n = 1459) or adalimumab (n = 871) after January 31, 2007, were included. Patients older than age 85 and those with rheumatoid arthritis, psoriasis, psoriatic arthritis, or ankylosing spondylitis were excluded. The primary outcome measures were disease persistence on therapy at week 26, surgery (including bowel resection, creation of an ostomy, or surgical treatment of a perforation or abscess), and hospitalization for CD. Propensity score-adjusted logistic and Cox regression were used to compute adjusted odds ratios or hazard ratios and 95% confidence intervals (CIs). RESULTS: After 26 weeks of treatment, 49% of patients receiving infliximab remained on drug, compared with 47% of those receiving adalimumab (odds ratio, 0.98; 95% CI, 0.81-1.19). Fewer patients treated with infliximab underwent surgery than those treated with adalimumab, but this difference was not statistically significant (5.5 vs 6.9 surgeries per 100 person-years; hazard ratio, 0.79; 95% CI, 0.60-1.05). Rates of hospitalization did not differ between groups (hazard ratio, 0.88; 95% CI, 0.72-1.07). CONCLUSIONS: We observed similar effectiveness of infliximab and adalimumab for CD on the basis of 3 clinically important outcome measures. PMID- 23811256 TI - Radiofrequency ablation for Barrett's esophagus, for whom and by whom? PMID- 23811255 TI - Capping the gastric acid pocket to reduce postprandial acid gastroesophageal reflux. PMID- 23811257 TI - Novel quinoxaline 1,4-di-N-oxide derivatives as new potential antichagasic agents. AB - As a continuation of our research and with the aim of obtaining new agents against Chagas disease, an extremely neglected disease which threatens 100 million people, eighteen new quinoxaline 1,4-di-N-oxide derivatives have been synthesized following the Beirut reaction. The synthesis of the new derivatives was optimized through the use of a new and more efficient microwave-assisted organic synthetic method. The new derivatives showed excellent in vitro biological activity against Trypanosoma cruzi. Compound 17, which was substituted with fluoro groups at the 6- and 7-positions of the quinoxaline ring, was the most active and selective in the cytotoxicity assay. The electrochemical study showed that the most active compounds, which were substituted by electron withdrawing groups, possessed a greater ease of reduction of the N-oxide groups. PMID- 23811258 TI - Synthesis and anticancer activities of 5,6,7-trimethoxy-N-phenyl(ethyl)-4 aminoquinazoline derivatives. AB - A series of 5,6,7-trimethoxy-N-phenyl(ethyl)-4-aminoquinazoline compounds was prepared by microwave irradiation and conventional heating methods. Compounds 6p, 6q, and 6x strongly inhibited extracellular regulated kinase1/2 (ERK1/2) phosphorylation induced by epidermal growth factor (EGF) at 1.28 MUM in PC3 cells. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that all compounds had certain anticancer activities, and the IC50 values of 6x were 6.2 +/- 0.9, 3.2 +/- 0.1, and 3.1 +/- 0.1 MUM against PC3, BGC823, and Bcap37 cells, respectively. Acridine orange/ethidium bromide staining, Hoechst 33258 staining, DNA ladder, and flow cytometry analyses revealed that 6x induced cell apoptosis in PC3 cells, with apoptosis ratios of 11.6% at 1 MUM and 31.8% at 10 MUM after 72 h. PMID- 23811259 TI - Antimicrobial activity of imidazo[1,5-a]quinoxaline derivatives with pyridinium moiety. AB - 3-Phenyl(methyl)-5-alkyl-1-(pyridin-3-yl)imidazo[1,5-a]quinoxalin-4-ones (2a-f) and their N-alkyl-pyridinium salts (3a-o), including 1,n-bis{3-(3 phenylimidazo[1,5-a]quinoxalin-4(5H)-on-1-yl)pyridinium}alkane dibromides (4a-d, 5, 6) have been synthesized. It has been established that the antimicrobial properties of imidazo[1,5-a]quinoxaline derivatives are connected with the presence of various alkyl substituents in the position 1 of the pyridine ring and in the position 5 of the imidazo[1,5-a]quinoxaline system. Chlorides and iodides are more active towards bacteria than fungi. Compounds 3d, 3e, 3m and 3n showed an effective bacteriostatic activity. Compound showed not only well defined bacteriostatic activities but also good fungistatic activities, with the MIC values comparable with the reference drugs. Toxicity of more effective (imidazo[1,5-a]quinoxalin-4-on-1-yl)-1-pyridinium halides was examined in mice. PMID- 23811260 TI - Genotoxicity evaluation of nanosized titanium dioxide, synthetic amorphous silica and multi-walled carbon nanotubes in human lymphocytes. AB - Toxicological characterization of manufactured nanomaterials (NMs) is essential for safety assessment, while keeping pace with innovation from their development and application in consumer products. The specific physicochemical properties of NMs, including size and morphology, might influence their toxicity and have impact on human health. The present work aimed to evaluate the genotoxicity of nanosized titanium dioxide (TiO2), synthetic amorphous silica (SAS) and multiwalled carbon nanotubes (MWCNTs), in human lymphocytes. The morphology and size of those NMs were characterized by transmission electron microscopy, while the hydrodynamic particle size-distributions were determined by dynamic light scattering. Using a standardized procedure to ensure the dispersion of the NMs and the cytokinesis-block micronucleus assay (without metabolic activation), we observed significant increases in the frequencies of micronucleated binucleated cells (MNBCs) for some TiO2 NMs and for two MWCNTs, although no clear dose response relationships could be disclosed. In contrast, all forms of SAS analyzed in this study were unable to induce micronuclei. The present findings increase the weight of evidence towards a genotoxic effect of some forms of TiO2 and some MWCNTs. Regarding safety assessment, the differential genotoxicity observed for closely related NMs highlights the importance of investigating the toxic potential of each NM individually, instead of assuming a common mechanism and equal genotoxic effects for a set of similar NMs. PMID- 23811261 TI - Effect of miltefosine on erythrocytes. AB - BACKGROUND: Miltefosine, an alkylphosphocholine drug with antiparasite, antibacterial, antifungal and antineoplastic potency, is the only oral drug that can be used to treat visceral and cutaneous leishmaniasis. The effect of miltefosine is at least partially due to triggering of apoptosis. Similar to apoptosis of nucleated cells, erythrocytes may enter suicidal death or eryptosis, which is characterized by cell shrinkage and by cell membrane scrambling with phosphatidylserine-exposure at the erythrocyte surface. Eryptosis may be triggered following increase of cytosolic Ca(2+)-level ([Ca(2+)]i). The present study explored, whether miltefosine elicits eryptosis. METHODS: Cell volume has been estimated from forward scatter, phosphatidylserine-exposure from annexin-V binding, hemolysis from hemoglobin release, [Ca(2+)]i from Fluo3-fluorescence. RESULTS: A 48 h exposure to miltefosine (>= 4.9 MUM) was followed by significant decrease of forward scatter and significant increase of annexin-V-binding. The effect was paralleled by significant increase of [Ca(2+)]i. The annexin-V-binding following miltefosine treatment was significantly blunted in the nominal absence of extracellular Ca(2+). CONCLUSION: Miltefosine stimulates eryptosis, an effect at least partially due to stimulation of Ca(2+) entry. PMID- 23811262 TI - NCTC 2544 and IL-18 production: a tool for the in vitro identification of photoallergens. AB - PURPOSE: Differentiation between photoallergenic and phototoxic reactions induced by low molecular weight compounds represents a current problem. The use of keratinocytes as a potential tool for the detection of photoallergens as opposed to photoirritants is considered an interesting strategy for developing in vitro methods. We have previously shown that IL-18 production in the human keratinocyte cell line NCTC 2455 is a good model for the in vitro identification of contact sensitizers. The purpose of this manuscript is to summarize data obtained in the NCTC 2544 assay as an in vitro model to identify photoallergens and discriminate them from phototoxic chemicals. METHODS: The effect of UVA radiation (3.5J/cm(2)) over NCTC 2544 cells irradiated and non irradiated, and treated with increasing concentrations of various compounds including negative compounds (irritants and allergens), ibuprofen and acridine (photoirritants); ketoprofen, promethazine and chlorpromazine (photoirritants/photoallergens); benzophenone, 4-tert-butyl-4 methoxy-dibenzoylmethane, 2-ethylexyl-p-methoxycinnamate and 6-methylcumarin (photoallergens) was investigated. Twenty-four hours after exposure, cytotoxicity was evaluated by the MTT assay, while a commercially available ELISA kit was used to assess the intracellular content of IL-18. RESULT: At no cytotoxic concentrations, allergens and photoallergens induce a dose-related increase in the production of IL-18, whereas irritants and photoirritants failed, indicating the possibility to use the NCTC 2544 assay to identify in vitro photoallergens. PMID- 23811263 TI - Cancer-related genes transcriptionally induced by the fungicide penconazole. AB - Penconazole is a systemic triazole fungicide mainly used on grapes. The UE Maximum Residue Level (MRL) for penconazole is set at 0.2ppm in wine and grapes. In the aim of identifying potential biomarkers of exposure to penconazole and possibly highlighting its endocrine disrupting mode of action, we used a transcriptomics-based approach to detect genes, that are transcriptionally modulated by penconazole, by using an appropriate in vitro model. T-47D cells were treated with commercial penconazole or penconazole contaminated grape extracts for 4h at doses close to the MRL. The whole-genome transcriptomic profile was assessed by using genome 44K oligo-microarray slides. The list of common genes generated by the two treatments could be representative of potential markers of exposure. In order to understand the role of these genes in key events related to adversity, a pathway analysis was performed on a list of genes with the same modulation trend (up or down). The analysis returned a set of genes involved in Thyroid Cancer Pathway, thus confirming a role of penconazole in endocrine disrupting mediated effects and strongly suggesting a possible mode of action in thyroid carcinogenesis. PMID- 23811264 TI - The Cosmetics Europe strategy for animal-free genotoxicity testing: project status up-date. AB - The Cosmetics Europe (formerly COLIPA) Genotoxicity Task Force has driven and funded three projects to help address the high rate of misleading positives in in vitro genotoxicity tests: The completed "False Positives" project optimized current mammalian cell assays and showed that the predictive capacity of the in vitro micronucleus assay was improved dramatically by selecting more relevant cells and more sensitive toxicity measures. The on-going "3D skin model" project has been developed and is now validating the use of human reconstructed skin (RS) models in combination with the micronucleus (MN) and Comet assays. These models better reflect the in use conditions of dermally applied products, such as cosmetics. Both assays have demonstrated good inter- and intra-laboratory reproducibility and are entering validation stages. The completed "Metabolism" project investigated enzyme capacities of human skin and RS models. The RS models were shown to have comparable metabolic capacity to native human skin, confirming their usefulness for testing of compounds with dermal exposure. The program has already helped to improve the initial test battery predictivity and the RS projects have provided sound support for their use as a follow-up test in the assessment of the genotoxic hazard of cosmetic ingredients in the absence of in vivo data. PMID- 23811265 TI - Genotoxicological assessment of two reactive dyes extracted from cotton fibres using artificial sweat. AB - Human eyes have a remarkable ability to recognize hundreds of colour shades, which has stimulated the use of colorants, especially for clothing, but toxicological studies have shown that some textile dyes can be hazardous to human health. Under conditions of intense perspiration, dyes can migrate from coloured clothes and penetrate into human skin. Garments made from cotton fabrics are the most common clothing in tropical countries, due to their high temperatures. Aiming to identify safe textile dyes for dyeing cotton fabrics, the genotoxicity [in vitro Comet assay with normal human dermal fibroblasts (NHDF), Tail Intensity] and mutagenicity [Salmonella/microsome preincubation assay (30min), tester strains TA98, TA100, YG1041 and YG1042] of Reactive Blue 2 (RB2, CAS No. 12236-82-7, C.I. 61211) and Reactive Green 19 (RG19, CAS No. 61931-49-5, C.I. 205075) were evaluated both in the formulated form and as extracted from cotton fibres using different artificial sweats. Both the dyes could migrate from cotton fibres to sweat solutions, the sweat composition and pH being important factors during this extraction. However, the dye sweat solutions showed no genotoxic/mutagenic effects, whereas a weak mutagenic potential was detected by the Ames test for both dyes in their formulated form. These findings emphasize the relevance of textile dyes assessment under conditions that more closely resemble human exposure, in order to recognize any hazard. PMID- 23811266 TI - Evaluation of the cyto/genotoxicity profile of oxime K048 using human peripheral blood lymphocytes: an introductory study. AB - This study investigates the effects of oxime K048 (730, 200, and 7.3nM) on the viability and chromosome stability of human peripheral blood lymphocytes (PBLs) after a 30min exposure in vitro. Cytotoxicity was tested by a viability assay with ethidium bromide and acridine orange. For the evaluation of the genotoxic potential, we used comet assays, cytokinesis-blocked micronucleus (CBMN) assay, and chromosome aberration (CA) analysis. We found acceptable cytotoxicity for K048 (9.7+/-2.1% non-viable PBL at highest concentration vs. 7.3+/-2.5% in control; apoptosis dominated over necrosis). Overall primary DNA damage was low and not significantly different from controls. The hOGG1-comet assay showed a slight increase in the level of oxidative DNA damage. In oxime treated PBLs, we found 13-19 MN compared to 15 MN in control cultures. The frequencies and types of CA in oxime-treated PBLs did not significantly differ from controls. K048 showed acceptable biocompatibility at the level of cell viability and chromatin/chromosome integrity. Since no increase in secondary genome damage was detected, the primary DNA lesions may have resulted from treatment-induced cell stress, subsequently becoming repaired and not fixed as chromosome aberrations. The toxicity profile of K048 should be further studied and compared with other clinically relevant oximes. PMID- 23811267 TI - Mood and cognitive function following repeated transcranial direct current stimulation in healthy volunteers: a preliminary report. AB - Although mood and cognitive function have been reported to change following transcranial direct current stimulation (tDCS) in patients with neurological and psychiatric diseases, little is known about the effects of repeated tDCS on mood and cognition in healthy humans. We recruited 11 healthy male participants for this single-blind, sham-controlled crossover trial. We used Profile of Mood States, brief-form (POMS), and CogHealth (Detection Task, Identification Task, One Back Task, One Card Learning Task and Continuous Monitoring Task) to evaluate the changes in mood and cognitive function, respectively, before and immediately after 4-daily, 20 min, 1 mA sham or anodal tDCS over the left dorsolateral prefrontal cortex (DLPFC). While there were no significant changes in six factors of POMS and performance (speed and accuracy) of CogHealth between sham and anodal stimulation, the accuracy of One Card Learning was increased at the end of the experiment. Signal detection analyses revealed that both hit rate and discriminability were improved in this task. These results suggest that 4-daily anodal tDCS over left DLPFC may not change mood and cognitive function in healthy subjects, and further support the safety of tDCS. A slight improvement in a visual recognition and learning task at the end of experiment may be susceptible to practice effects. PMID- 23811268 TI - Autophagy regulation and its role in cancer. AB - The modulation of macroautophagy is now recognized as one of the hallmarks of cancer cells. There is accumulating evidence that autophagy plays a role in the various stages of tumorigenesis. Depending on the type of cancer and the context, macroautophagy can be tumor suppressor or it can help cancer cells to overcome metabolic stress and the cytotoxicity of chemotherapy. Recent studies have shed light on the role of macroautophagy in tumor-initiating cells, in tumor immune response cross-talk with the microenvironment. This review is intended to provide an up-date on these aspects, and to discuss them with regard to the role of the major signaling sub-networks involved in tumor progression (Beclin 1, MTOR, p53 and RAS) and in regulating autophagy. PMID- 23811270 TI - Diallyl trisulfide suppresses dextran sodium sulfate-induced mouse colitis: NF kappaB and STAT3 as potential targets. AB - Diallyl trisulfide (DATS), one of the volatile constituents of garlic oil, has been reported to possess antioxidant, anti-inflammatory, and anti-carcinogenic properties. In this study, DATS (10MUmol) given orally for 7days before and for another 7days after starting administration of 2.5% dextran sulfate sodium (DSS) in drinking water protected against colitis induced by DSS in male ICR mice. DATS significantly inhibited the DSS-induced DNA binding of NF-kappaB, phosphorylation of IkappaBalpha and the expression of pro-inflammatory proteins, such as cyclooxygenase-2 and inducible nitric oxide synthase, which are major target proteins of NF-kappaB. The DSS-induced DNA binding and phosphorylation at the Tyr 705 residue of signal transducer and activator of transcription 3 (STAT3), and expression of its major target protein cyclin D1 in mouse colonic mucosa were also attenuated by DATS administration. Likewise, DSS-induced phosphorylation of extracellular signal-regulated kinase 1/2 was suppressed by DATS treatment. In conclusion, DATS ameliorates the DSS-induced mouse colitis presumably by blocking inflammatory signaling mediated by NF-kappaB and STAT3. PMID- 23811269 TI - Integrated network analyses for functional genomic studies in cancer. AB - RNA-interference (RNAi) studies hold great promise for functional investigation of the significance of genetic variations and mutations, as well as potential synthetic lethalities, for understanding and treatment of cancer, yet technical and conceptual issues currently diminish the potential power of this approach. While numerous research groups are usefully employing this kind of functional genomic methodology to identify molecular mediators of disease severity, response, and resistance to treatment, findings are generally confounded by "off target" effects. These effects arise from a variety of issues beyond non-specific reagent behavior, such as biological cross-talk and feedback processes so thus can occur even with specific perturbation. Interpreting RNAi results in a network framework instead of merely as individual "hits" or "targets" leverages contributions from all hit/target contributions to pathways via their relationships with other network nodes. This interpretation can ameliorate dependence upon individual reagent performance and increase confidence in biological validation. Here we provide background on RNAi studies in cancer applications, review key challenges with functional genomics, and motivate the use of network models grounded in pathway analyses. PMID- 23811271 TI - Hypoxia-induced regulation of the very low density lipoprotein receptor. AB - The very low density lipoprotein receptor (VLDLr) is highly upregulated during hypoxia in mouse cardiomyocytes and in human and mouse ischemic hearts causing a detrimental lipid accumulation. To know how the gene is regulated is important for future studies. In this study, we have thoroughly mapped the 5'-flanking region of the mouse VLDLr promoter and show that the hypoxia-mediated increase in VLDLr expression is dependent on Hif-1alpha binding to a hypoxia responsive element (HRE) located at -162 to -158bp 5'of translation start. We show that classical HRE sites and the previously described PPARgamma and Sp1 binding are not involved in the hypoxia-induced regulation of the VLDLr promoter. Using a chromatin immunoprecipitation (ChIP) assay, we show that Hif-1alpha specifically binds and activates the mouse VLDLr promoter at the previously described non classical HRE in HL-1 cells. We also show that the same HRE is present and active in response to hypoxia in human cardiomyocytes, however at a different location ( 812bp from translation start). These results conclude that in the hypoxic hearts of mice and men, the VLDLr gene is regulated by a direct binding of Hif-1alpha to the VLDLr promoter. PMID- 23811272 TI - Differential role of thiopurine methyltransferase in the cytotoxic effects of 6 mercaptopurine and 6-thioguanine on human leukemia cells. AB - The thiopurine antimetabolites, 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are inactive pro-drugs that require intracellular metabolism for activation to cytotoxic metabolites. Thiopurine methyltransferase (TPMT) is one of the most important enzymes in this process metabolizing both 6-MP and 6-TG to different methylated metabolites including methylthioinosine monophosphate (meTIMP) and methylthioguanosine monophosphate (meTGMP), respectively, with different suggested pharmacological and cytotoxic properties. While meTIMP is a potent inhibitor of de novo purine synthesis (DNPS) and significantly contributes to the cytotoxic effects of 6-MP, meTGMP, does not add much to the effects of 6-TG, and the cytotoxicity of 6-TG seems to be more dependent on incorporation of thioguanine nucleotides (TGNs) into DNA rather than inhibition of DNPS. In order to investigate the role of TPMT in metabolism and thus, cytotoxic effects of 6-MP and 6-TG, we knocked down the expression of the gene encoding the TPMT enzyme using specifically designed small interference RNA (siRNA) in human MOLT4 leukemia cells. The knock-down was confirmed at RNA, protein, and enzyme function levels. Apoptosis was determined using annexin V and propidium iodide staining and FACS analysis. The results showed a 34% increase in sensitivity of MOLT4 cells to 1MUM 6-TG after treatment with TPMT-targeting siRNA, as compared to cells transfected with non-targeting siRNA, while the sensitivity of the cells toward 6-MP was not affected significantly by down-regulation of the TPMT gene. This differential contribution of the enzyme TPMT to the cytotoxicity of the two thiopurines is probably due to its role in formation of the meTIMP, the cytotoxic methylated metabolite of 6-MP, while in case of 6-TG methylation by TPMT substantially deactivates the drug. PMID- 23811273 TI - The purinergic component of human bladder smooth muscle cells' proliferation and contraction under physiological stretch. AB - OBJECTIVE: To investigate whether cyclic stretch induces proliferation and contraction of human smooth muscle cells (HBSMCs), mediated by P2X purinoceptor 1 and 2 and the signal transduction mechanisms of this process. METHODS: HBSMCs were seeded on silicone membrane and stretched under varying parameters; (equibiaxial elongation: 2.5%, 5%, 10%, 15%, 20%, 25%), (Frequency: 0.05Hz, 0.1Hz, 0.2Hz, 0.5Hz, 1Hz). 5-Bromo-2-deoxyuridine assay was employed for proliferative studies. Contractility of the cells was determined using collagen gel contraction assay. After optimal physiological stretch was established; P2X1 and P2X2 were analyzed by real time polymerase chain reaction and Western Blot. Specificity of purinoceptors was maintained by employing specific inhibitors; (NF023 for P2X1, and A317491for P2X2), in some experiments. RESULTS: Optimum proliferation and contractility were observed at 5% and 10% equibiaxial stretching respectively, applied at a frequency of 0.1Hz; At 5% stretch, proliferation increased from 0.837+/-0.026 (control) to 1.462+/-0.023%, p<0.05. Mean contraction at 10% stretching increased from 31.7+/-2.3%, (control) to 78.28 +/-1.45%, p< 0.05. Expression of P2X1 and P2X2 was upregulated after application of stretch. Inhibition had effects on proliferation (1.232+/-0.051, p<0.05 NF023) and (1.302+/-0.021, p<0.05 A314791) while contractility was markedly reduced (68.24+/-2.31, p<0.05 NF023) and (73.2+/-2.87, p<0.05 A314791). These findings shows that mechanical stretch can promote magnitude-dependent proliferative and contractile modulation of HBSMCs in vitro, and P2X1 and 2 are at least partially responsible in this process. PMID- 23811274 TI - CITED2 modulates estrogen receptor transcriptional activity in breast cancer cells. AB - Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2) is a member of the CITED family of non-DNA binding transcriptional co activators of the p300/CBP-mediated transcription complex. Previously, we identified CITED2 as being overexpressed in human breast tumors relative to normal mammary epithelium. Upon further investigation within the estrogen receptor (ER)-positive subset of these breast tumor samples, we found that CITED2 mRNA expression was elevated in those associated with poor survival. In light of this observation, we investigated the effect of elevated CITED2 levels on ER function. While ectopic overexpression of CITED2 in three ER-positive breast cancer cell lines (MCF-7, T47D, and CAMA-1) did not alter cell proliferation in complete media, growth was markedly enhanced in the absence of exogenous estrogen. Correspondingly, cells overexpressing CITED2 demonstrated reduced sensitivity to the growth inhibitory effects of the selective estrogen receptor modulator, 4-hydroxytamoxifen. Subsequent studies revealed that basal ER transcriptional activity was elevated in CITED2-overexpressing cells and was further increased upon the addition of estrogen. Similarly, basal and estrogen induced expression of the ER-regulated genes trefoil factor 1 (TFF1) and progesterone receptor (PGR) was higher in cells overexpressing CITED2. Concordant with this observation, ChIP analysis revealed higher basal levels of CITED2 localized to the TFF-1 and PGR promoters in cells with ectopic overexpression of CITED2, and these levels were elevated further in response to estrogen stimulation. Taken together, these data indicate that CITED2 functions as a transcriptional co-activator of ER in breast cancer cells and that its increased expression in tumors may result in estrogen-independent ER activation, thereby reducing estrogen dependence and response to anti-estrogen therapy. PMID- 23811275 TI - IRF-1-binding site in the first intron mediates interferon-gamma-induced optineurin promoter activation. AB - Optineurin is an adaptor protein involved in signal transduction, membrane vesicle trafficking and autophagy. Optineurin expression is induced by cytokines. Previously we have shown that tumor necrosis factor-alpha activates optineurin promoter through NF-kappaB-binding site in the core promoter. However, this promoter was not activated by interferon-gamma. Here, we report identification of a functional IRF-1-binding site in the first intron of human optineurin gene that mediates interferon-gamma-induced activation of the promoter. Optineurin promoter, containing the contiguous intronic sequences with IRF-1 responsive sites, is strongly activated by IRF-1. Mutational inactivation of IRF-1 site resulted in loss of activation of the promoter by interferon-gamma and also by IRF-1. We also show that IRF-1 cooperates with NF-kappaB to activate optineurin promoter. The synergistic effect of these two transcription factors (IRF-1 and NF kappaB) may be involved in cooperative induction of optineurin promoter by interferon-gamma and tumor necrosis factor-alpha. PMID- 23811277 TI - Ab initio simulation on the crystal structure and elastic properties of carbonated apatite. AB - Ab initio quantum mechanical (QM) calculations were employed to study the crystal structure and elastic properties of carbonated apatite (CAp). Two locations for the carbonate ion in the apatite lattice were considered: carbonate substituting for OH(-) ion (type-A), and for PO4(3-) ion (type-B) with possible charge compensation mechanisms. A combined type-AB substitution (two carbonate ions replacing one phosphate group and one hydroxyl group, respectively) was also investigated. The results show that the most energetically stable substitution is type-AB, followed by type-A and then type-B. The most stable configuration of type-A has its carbonate triangular plane almost parallel to c-axis at z=0.46. The lowest energy configuration of type-B is that with a sodium ion substituting for a calcium ion for charge balance and the carbonate lying on the b/c-plane of apatite. Lattice parameter changes after carbonate substitution in hydroxyapatite (HA) agree with reported experimental results qualitatively: for type-A, lattice parameter a increases but c decreases; and for type-B, lattice parameter a decreases but c increases. Using the calculated CAp stable structures, we also calculated the elastic properties of CAp and compared them with those of HA and biological apatites. PMID- 23811276 TI - Bioerodible calcium sulfate/poly(beta-amino ester) hydrogel composites. AB - The capacity to quickly regenerate or augment bone lost as a result of resorption is crucial to ensure suitable application of prosthetics for restoring masticatory function. Calcium sulfate hemihydrate (CS)-based bone graft substitute composites containing poly(beta-amino ester) (PBAE) biodegradable hydrogel particles were developed to act as a 'tenting' barrier to soft tissue infiltration, potentially providing adequate space to enable vertical bone regeneration. CS has long been recognized as an osteoconductive biomaterial with an excellent reputation as a biocompatible substance. Composite samples were fabricated with varying amounts (1 or 10 wt%) and sizes (53-150 or 150-250 MUm) of gel particles embedded in CS. The swelling and degradation rates of PBAE gels alone were rapid, resulting in complete degradation in less than 24h, an important characteristic to aid in controlled release of drug. MicroCT images revealed a homogeneous distribution of gel particles within the CS matrix. All CS samples degraded via surface erosion, with the amount of gel particles (i.e., 10 wt% gel particles) having only a small, but significant, effect on the dissolution rate (4% vs. 5% per day). Compression testing determined that the amount, but not the size, of gel particles had a significant effect on the overall strength of the composites. As much as a 75% drop in strength was seen with a 10 wt% loading of particles. A pilot study using PBAE particles loaded with the multipotential drug curcumin demonstrated sustained release of drug from CS composites. By adjusting the amount and/or size of the biodegradable gel particles embedded in CS, mechanical strength and degradation rates of the composites, as well as the drug release kinetics, can be tuned to fabricate, multi-functional 'space-making' bone grafting substitutes. PMID- 23811278 TI - Stress-relaxation response of human menisci under confined compression conditions. AB - The objective of this study was to determine the viscoelastic properties of human meniscal tissue during stress-relaxation under confined compression conditions. Lateral and medial longitudinal meniscus plugs of 25 donor knees (ntotal=150) were exposed to stress-relaxation tests under confined compression conditions at three compression levels (epsilon=0.1; 0.15; 0.2). Mathematical modelling using an exponential 1D-diffusion equation was used to predict the viscoelastic properties. Subsequently, finite element (FE) models were created using identical geometry, properties and test conditions as used for the in-vitro tests. Two constitutively different underlying mathematical formulations were applied to the FE models to reveal possible differences in their predictions for the relaxation response. While the first FE model mimicked the analytical model (FE1), the second FE model used a different biphasic, non-linear approach (FE2). Regression analyses showed promising coefficients of determination (R(2)>0.73) between the experimental data and the predictions obtained from the diffusion equation and the two FE models. Mean aggregate modulus, predicted with the diffusion equation (HA=64.0 kPa) was lower than those obtained with the two FE analyses (HA,FE1=91.9 kPa; HA,FE2=81.5 kPa). Mean hydraulic permeability (kFE2=1.5*10(-15)m(4)/Ns) of the second FE2 approach was statistically lower (p<0.01) than the other permeability values (k=3.9*10(-15)m(4)/Ns; kFE1=3.4*10(-15)m(4)/Ns). These differences are mainly due to the different underlying mathematical models used. However, when compared with corresponding literature, the results of the present study indicated good agreement. The results of the present study contribute to a better understanding of the complex nature of meniscal tissue and might also have an impact on the design of future meniscal substitutes. PMID- 23811279 TI - Structural and mechanical multi-scale characterization of white New-Zealand rabbit Achilles tendon. AB - Multi-scale characterization of structures and mechanical behavior of biological tissues are of huge importance in order to evaluate the quality of a biological tissue and/or to provide bio-inspired scaffold for functional tissue engineering. Indeed, the more information on main biological tissue structures we get, the more relevant we will be to design new functional prostheses for regenerative medicine or to accurately evaluate tissues. From this perspective, we have investigated the structures and their mechanical properties from nanoscopic to macroscopic scale of fresh ex-vivo white New-Zealand rabbit Achilles tendon using second harmonic generation (SHG) microscopy, atomic force microscopy (AFM) and tensile tests to provide a "simple" model whose parameters are relevant of its micro or nano structure. Thus, collagen fiber's crimping was identified then measured from SHG images as a plane sine wave with 28.4 +/- 5.8 MUm of amplitude and 141 +/- 41 MUm of wavelength. Young's moduli of fibrils (3.0 GPa) and amorphous phases (223 MPa) were obtained using TH-AFM. From these investigations, a non-linear Zener model linking a statistical Weibull's distribution of taut fibers under traction to crimp fibers were developed. This model showed that for small strain (<0.1), the amorphous inter-fibrils phase in collagen fibers is more solicited than collagen fibrils themselves. The results open the way to modeled macroscopic mechanical behavior of aligned-crimped collagen soft tissues using multi-scale tendon observations under static or dynamic solicitations. PMID- 23811280 TI - Associations of symptoms and subtypes of attention-deficit hyperactivity disorder with visuospatial planning ability in youth. AB - Little is known about which ADHD core symptom or subtype is most associated with visuospatial planning deficit. This issue was investigated in a sample of 408 youths with current DSM-IV diagnosis of ADHD, and 332 youths without lifetime ADHD, aged 8-17 years (mean age 12.02+/-2.24). All the participants and their mothers were interviewed using the Chinese Kiddie Epidemiologic version of the Schedule for Affective Disorders and Schizophrenia to obtain information about ADHD symptoms and diagnosis and other psychiatric disorders. In addition to clinical assessments, the participants were assessed with the WISC-III and the Stocking of Cambridge task of the Cambridge Neuropsychological Test Automated Battery. Multi-level regression models were used for data analysis. The results showed that univariate analyses revealed that inattention, hyperactivity, and impulsivity were significantly associated with visuospatial planning, and the magnitude of such association was amplified with increased task difficulties. Only inattention independently predicted visuospatial planning in a model that included all three ADHD symptoms. After further controlling for comorbidity, age of assessment, treatment with methylphenidate, and Full-scale IQ, inattention was still independently associated with visuospatial planning indexed by mean moves needed to solve problems. In subtype comparison, participants with combined subtype and those with prominently inattentive subtype, rather than prominently hyperactivity/impulsivity subtype, had poorer visuospatial planning performance. Our findings indicate that inattention is independently associated with impaired visuospatial planning, and dimensional approach retains the important distinction among ADHD symptoms than subtype approach in understanding the neuropsychological functioning of ADHD. PMID- 23811281 TI - Chikungunya fever: epidemiology, clinical syndrome, pathogenesis and therapy. AB - Chikungunya virus (CHIKV) is the aetiological agent of the mosquito-borne disease chikungunya fever, a debilitating arthritic disease that, during the past 7years, has caused immeasurable morbidity and some mortality in humans, including newborn babies, following its emergence and dispersal out of Africa to the Indian Ocean islands and Asia. Since the first reports of its existence in Africa in the 1950s, more than 1500 scientific publications on the different aspects of the disease and its causative agent have been produced. Analysis of these publications shows that, following a number of studies in the 1960s and 1970s, and in the absence of autochthonous cases in developed countries, the interest of the scientific community remained low. However, in 2005 chikungunya fever unexpectedly re-emerged in the form of devastating epidemics in and around the Indian Ocean. These outbreaks were associated with mutations in the viral genome that facilitated the replication of the virus in Aedes albopictus mosquitoes. Since then, nearly 1000 publications on chikungunya fever have been referenced in the PubMed database. This article provides a comprehensive review of chikungunya fever and CHIKV, including clinical data, epidemiological reports, therapeutic aspects and data relating to animal models for in vivo laboratory studies. It includes Supplementary Tables of all WHO outbreak bulletins, ProMED Mail alerts, viral sequences available on GenBank, and PubMed reports of clinical cases and seroprevalence studies. PMID- 23811282 TI - The NF-kappaB inhibitor SC75741 protects mice against highly pathogenic avian influenza A virus. AB - The appearance of pandemic H1N1 and highly pathogenic avian H5N1 viruses in humans as well as the emergence of seasonal H1N1 variants resistant against neuraminidase inhibitors highlight the urgent need for new and amply available antiviral drugs. We and others have demonstrated that influenza virus misuses the cellular IKK/NF-kappaB signaling pathway for efficient replication suggesting that this module may be a suitable target for antiviral intervention. Here, we show that the novel NF-kappaB inhibitor SC75741 significantly protects mice against infection with highly pathogenic avian influenza A viruses of the H5N1 and H7N7 subtypes. Treatment was efficient when SC75741 was given intravenously in a concentration of 5mg/kg/day. In addition, application of SC75741 via the intraperitoneal route resulted in a high bioavailability and was also efficient against influenza when given 15 mg/kg/day or 7.5 mg/kg/twice a day. Protection was achieved when SC75741 was given for seven consecutive days either prior to infection or as late as four days after infection. SC75741 treatment showed no adverse effects in the concentrations required to protect mice against influenza virus infection. Although more pre-clinical studies are needed SC75741 might be a promising candidate for a novel antiviral drug against influenza viruses that targets the host cell rather than the virus itself. PMID- 23811283 TI - Multiple heterologous M2 extracellular domains presented on virus-like particles confer broader and stronger M2 immunity than live influenza A virus infection. AB - The influenza M2 ectodomain (M2e) is poorly immunogenic and has some amino acid changes among isolates from different host species. We expressed a tandem repeat construct of heterologous M2e sequences (M2e5x) derived from human, swine, and avian origin influenza A viruses on virus-like particles (M2e5x VLPs) in a membrane-anchored form. Immunization of mice with M2e5x VLPs induced protective antibodies cross-reactive to antigenically different influenza A viruses and conferred cross protection. Anti-M2e antibodies induced by heterologous M2e5x VLPs showed a wider range of cross reactivity to influenza A viruses at higher levels than those by live virus infection, homologous M2e VLPs, or M2e monoclonal antibody 14C2. Fc receptors were found to be important for mediating protection by immune sera from M2e5x VLP vaccination. The present study provides evidence that heterologous recombinant M2e5x VLPs can be more effective in inducing protective M2e immunity than natural virus infection and further supports an approach for developing an effective universal influenza vaccine. PMID- 23811284 TI - Comparative proteomics analysis by DIGE and iTRAQ provides insight into the regulation of phenylpropanoids in maize. AB - The maize pericarp color1 (p1) gene encodes a Myb transcription factor that regulates the accumulation of 3-deoxyflavonoid pigments called phlobaphenes. The Unstable factor for orange1 (Ufo1) is a dominant epigenetic modifier of the p1 that results in ectopic pigmentation in pericarp. Presence of Ufo1-1 correlates with pleiotropic growth and developmental defects. To investigate the Ufo1-1 induced changes in the proteome, we conducted comparative proteomics analysis of P1-wr; Ufo1-1 pericarps using the 2-D DIGE and iTRAQ techniques. Most of the identified proteins were found to be involved in glycolysis, protein synthesis and modification, flavonoid and lignin biosynthesis and defense responses. Further, immunoblot analysis of internode protein extracts demonstrated that caffeoyl CoA O-methyltransferase (COMT) is post-transcriptionally down regulated in P1-wr; Ufo1-1 plants. Consistent with the down regulation of COMT, the concentrations of p-coumaric acid, syringaldehydes, and lignin are reduced in P1 wr; Ufo1-1 internodes. The reductions in these phenylpropanoids correlate with the bent stalk and stunted growth of P1-wr; Ufo1-1 plants. Finally, over expression of the p1 in transgenic plants is also correlated with a lodging phenotype and reduced COMT expression. We conclude that ectopic expression of p1 can result in developmental defects that are correlated with altered regulation and synthesis of phenylpropanoid compounds including lignin. BIOLOGICAL SIGNIFICANCE: Transcription factors have specific expression patterns that ensure that the biochemical pathways under their control are active in relevant tissues. Plant breeders can select for alleles of transcription factors that produce desirable expression patterns to improve a plant's growth, development, and defense against insects and pathogens. The resulting de novo accumulation of metabolites in plant tissues in significant quantities could have beneficial and/or detrimental consequences. To understand this problem we investigated how the aberrant expression of a classically-studied transcription factor pericarp color1 (p1) which regulates phenylpropanoid metabolism, affects the maize proteome in pericarp tissue. We utilized a dominant mutant Unstable factor for orange 1-1 (Ufo1-1) which reduces the epigenetic suppression of p1 in various tissues throughout the maize plant. Our proteomic analysis shows how, in the presence of Ufo1-1, key enzymes of the glycolytic and shikimic acid pathways were modulated to produce substrates required for flavonoid synthesis. The finding that the presence of Ufo1-1 affected the expression levels of various enzymes in the lignin pathway was of particular interest. We show that lignin was reduced in Ufo1-1 plants expressing p1 and was associated with the post-transcriptional down regulation of CoA O-methyltransferase (COMT) enzyme. We further correlated the down-regulation of COMT with plant bending phenotype in Ufo1-1 plants expressing p1 and to a stalk lodging phenotype of transgenic p1 plants. This study demonstrates that although there can be adverse consequences to aberrantly overexpressing transcription factors, there might also be benefits such as being able to reduce lignin content for biofuel crops. However, more research will be required to understand the genetic and epigenetic regulation of transcription factors and how their expression can be optimized to obtain desired traits in preferred tissue types. This article is part of a Special Issue entitled: Translational Plant Proteomics. PMID- 23811285 TI - RON confers lapatinib resistance in HER2-positive breast cancer cells. AB - Lapatinib-resistance is a major problem for HER2-positive breast cancer treatment. SK-BR-3-LR, a lapatinib-resistant cell clone, was established from HER2-positive SK-BR-3 breast cancer cells following chronic exposure to lapatinib. The PI3K/AKT signaling pathway was demonstrated to be resistant to HER2 inhibition in SK-BR-3-LR cells. However, both small-molecular Recepteur d'Origine Nantais (RON) inhibitors and RON-targeted small interfering RNA (siRNA) effectively restored lapatinib sensitivity in these cells by inhibiting PI3K/AKT activation. Our results demonstrate for the first time the important role of RON in mediating lapatinib resistance and suggest that RON-targeted therapy may become a novel, promising therapeutic strategy after the failure of lapatinib treatment in patients with HER2-positive breast cancer. PMID- 23811286 TI - P21-activated kinase 1 promotes colorectal cancer survival by up-regulation of hypoxia-inducible factor-1alpha. AB - P21 activated kinase 1 (PAK1) enhances colorectal cancer (CRC) progression by stimulating Wnt/beta-catenin and Ras oncogene, which promote CRC survival via stimulation of hypoxia-inducible factor 1alpha (HIF-1alpha). The aim of this study was to assess the mechanism involved in the stimulation by PAK1 of CRC survival. PAK1 promoted CRC cell survival by up-regulation of HIF-1alpha. PAK1 was over-expressed and hyper-activated in tumors of ApcDelta(14/+) mice, which was correlated with over-expression of HIF-1alpha and beta-catenin. Inhibition of PAK1 decreased tumor growth and the expression of HIF-1alpha and beta-catenin in tumors of ApcDelta(14/+) mice, and suppressed xenograft tumor survival in SCID mice. These findings indicate that PAK1 stimulates CRC survival by up-regulation of HIF-1alpha. PMID- 23811287 TI - Calyxin Y induces hydrogen peroxide-dependent autophagy and apoptosis via JNK activation in human non-small cell lung cancer NCI-H460 cells. AB - Calyxin Y has been recently isolated from Alpinia katsumadai which has a folk use as an anti-tumor medicine. Calyxin Y induced caspase-dependent cell death in NCI H460 cells, and concomitantly, provoked cytoprotective autophagy with the upregulation of critical Atg proteins. The cleavage of Atg proteins by caspases acted as a switch between autophagy and apoptosis induced by calyxin Y. Intracellular hydrogen peroxide (H2O2) production was triggered upon exposure to calyxin Y via the induction of autophagy and apoptosis. We provided evidence that activated JNK was upstream effectors controlling both autophagy and apoptosis in response to elevated H2O2. Therefore, our findings demonstrate that calyxin Y serves multiple roles as a promising chemotherapeutic agent that induces H2O2 dependent autophagy and apoptosis via JNK activation. PMID- 23811288 TI - Polyphenol tri-vanillic ester 13c inhibits P-JAK2V617F and Bcr-Abl oncokinase expression in correlation with STAT3/STAT5 inactivation and apoptosis induction in human leukemia cells. AB - Constitutive activity of kinases has been reported in many types of cancers, so that inhibition of "onco-kinases" became a validated anti-cancer strategy. We found that the polyphenol 13c, a tri-vanillate derivative, inhibited kinase phosphorylation in leukemia cells. P-JAK2, P-Src and P-PI3Kp85 inhibition occurred independently of phosphatase involvement in JAK2V617F expressing HEL cells while 13c inhibited Bcr-Abl expression without inhibition of phosphorylation in chronic myelogenous leukemia cell lines (K562, MEG-01). In correlation with kinase inhibition, 13c abolished constitutive P-STAT3/P-STAT5 expression, down-regulated Mcl-1 and c-Myc gene expression and induced apoptosis. Altogether, polyphenol 13c displays potential antitumor activities by affecting onco-kinases and STAT activities. PMID- 23811289 TI - Autophagy in cellular transformation, survival and communication with the tumor microenvironment. AB - Autophagy describes several metabolic pathways, by which cytoplasmic constituents are imported into lysosomes for degradation. These pathways and in particular macroautophagy play an important role during oncogenesis by apparently inhibiting cellular transformation initially, but then ensuring tumor cell survival in established cancers. Furthermore, the conditioning of the tumor microenvironment, including the cross-talk with the immune system, is influenced by autophagy. These multiple facets of autophagy regulation in tumors will be discussed in the series of review articles of this issue of Seminars in Cancer Biology. A comprehensive understanding of this pathway in oncology is needed to efficiently apply autophagy regulating tumor therapies, which are already in use. PMID- 23811291 TI - New long circulating magnetoliposomes as contrast agents for detection of ischemia-reperfusion injuries by MRI. AB - New long circulating magnetoliposomes coated with polyethylene glycol (PEG), and loaded with PEG-coated 10nm superparamagnetic iron oxide nanoparticles (SPION), were developed. The magnetoliposomes relaxivities r1, r2 measured in a magnetic field of 7 T showed a minor effect on T1, but a major effect on T2. These nanosystems were used as a negative contrast agent for MRI in a nonclinical study to visualize, in a rat model of liver ischemia, ischemia-reperfusion injuries. Magnetic resonance micro-images (MRM) at 7 T were obtained for rat liver with and without magnetoliposomes administration and analyzed in comparison with liver biomarkers and histological results. These new long circulating magnetoliposomes enhanced the detection of lesions indicating their potential use as efficient MRI negative contrast agent for the detection of liver ischemia-reperfusion injuries. FROM THE CLINICAL EDITOR: This paper describes the generation of PEGylated magnetoliposomes and demonstrates their feasibility as negative contrast agents in a liver ischemia-reperfusion rat model. PMID- 23811290 TI - In vivo human time-exposure study of orally dosed commercial silver nanoparticles. AB - Human biodistribution, bioprocessing and possible toxicity of nanoscale silver receive increasing health assessment. We prospectively studied commercial 10- and 32-ppm nanoscale silver particle solutions in a single-blind, controlled, cross over, intent-to-treat, design. Healthy subjects (n=60) underwent metabolic, blood counts, urinalysis, sputum induction, and chest and abdomen magnetic resonance imaging. Silver serum and urine content were determined. No clinically important changes in metabolic, hematologic, or urinalysis measures were identified. No morphological changes were detected in the lungs, heart or abdominal organs. No significant changes were noted in pulmonary reactive oxygen species or pro inflammatory cytokine generation. In vivo oral exposure to these commercial nanoscale silver particle solutions does not prompt clinically important changes in human metabolic, hematologic, urine, physical findings or imaging morphology. Further study of increasing time exposure and dosing of silver nanoparticulate silver, and observation of additional organ systems are warranted to assert human toxicity thresholds. FROM THE CLINICAL EDITOR: In this study, the effects of commercially available nanoparticles were studied in healthy volunteers, concluding no detectable toxicity with the utilized comprehensive assays and tests. As the authors rightfully state, further studies are definitely warranted. Studies like this are much needed for the more widespread application of nanomedicine. PMID- 23811292 TI - Micelle-based activatable probe for in vivo near-infrared optical imaging of cancer biomolecules. AB - Near-infrared (NIR: 800-1000 nm) fluorescent probes, which activate their fluorescence following interaction with functional biomolecules, are desirable for noninvasive and sensitive tumor diagnosis due to minimal tissue interference. Focusing on bioavailability and applicability, we developed a probe with a self assembling polymer micelle, a lactosome, encapsulating various quantities of NIR dye (IC7-1). We also conjugated anti-HER2 single chain antibodies to the lactosome surface and examined the probe's capacity to detect HER2 in cells and in vivo. Micelles encapsulating 20mol% IC7-1 (hIC7L) showed 30-fold higher fluorescence (lambdaem: 858 nm) after micelle denaturation compared to aqueous buffer. Furthermore, antibody modification allowed specific activation of the probe (HER2-hIC7L) following internalization by HER2-positive cells, with the probe concentrating in lysosomes. HER2-hIC7L intravenously administered to mice clearly and specifically visualized HER2-positive tumors by in vivo optical imaging. These results indicate that HER2-hIC7L is a potential activatable NIR probe for sensitive tumor diagnosis. FROM THE CLINICAL EDITOR: Near-infrared probes that activate their fluorescence following interaction with specific biomolecules are desirable for noninvasive and sensitive tumor detection due to minimal tissue interference. This team of authors developed a probe termed hIC7L and demonstrate its potential in HER2 tumor diagnosis. PMID- 23811293 TI - Movement under uncertainty: the effects of the rubber-hand illusion vary along the nonclinical autism spectrum. AB - Recent research has begun to investigate sensory processing in relation to nonclinical variation in traits associated with the autism spectrum disorders (ASD). We propose that existing accounts of autistic perception can be augmented by considering a role for individual differences in top-down expectations for the precision of sensory input, related to the processing of state-dependent levels of uncertainty. We therefore examined ASD-like traits in relation to the rubber hand illusion: an experimental paradigm that typically elicits crossmodal integration of visual, tactile, and proprioceptive information in an unusual illusory context. Individuals with higher ASD-like traits showed reduced effects of the rubber-hand illusion on perceived arm position and reach-to-grasp movements, compared to individuals with lower ASD-like traits. These differences occurred despite both groups reporting the typical subjective experience of the illusion concerning visuotactile integration and ownership for the rubber hand. Together these results suggest that the integration of proprioceptive information with cues for arm position derived from the illusory context differs between individuals partly in relation to traits associated with ASD. We suggest that the observed differences in sensory integration can be best explained in terms of differing expectations regarding the precision of sensory estimates in contexts that suggest uncertainty. PMID- 23811294 TI - Widowhood and depression: new light on gender differences, selection, and psychological adjustment. AB - OBJECTIVES: To document short- and long-term trajectories of depressive symptoms following widowhood and to test whether these trajectories vary by gender and anticipatory spousal loss. METHOD: Eight waves of prospective panel data from the Health and Retirement Study, over a 14-year period, are used to evaluate gender differences in depressive symptoms following widowhood in late midlife. Short term trajectories are modeled using a linear regression of change in Center for Epidemiologic Studies Depression (CES-D) score on duration of widowhood. Long term trajectories are modeled using a mixed-effects hierarchical linear model of CES-D scores over time. RESULTS: We find no gender differences in bereavement effects on depressive symptoms in either short or long term, net of widowhood duration. When spousal death is anticipated, both men and women return to their prewidowhood levels of depressive symptoms within 24 months of becoming widowed. Across marital groups, the continuously married are better off compared with the widowed even prior to spousal loss, whereas early, long-term widowhood is associated with worse outcomes compared with late widowhood. DISCUSSION: Although men and women do not differ in trajectories of depressive symptoms following widowhood, given similar circumstances, women are distinctly disadvantaged in that they are more likely to become widowed and under less favorable conditions. PMID- 23811295 TI - Memory compensation in older adults: the role of health, emotion regulation, and trait mindfulness. AB - OBJECTIVES: The current study examined associations between everyday memory compensation and 3 person-level resource domains (i.e., health, emotion regulation, and trait mindfulness) in older adults. METHOD: In this cross sectional study, 89 healthy, community-dwelling older adults (ages 51-85 years) completed the multidimensional Memory Compensation Questionnaire, along with measures of self-reported health status, emotion regulation strategies, and trait mindfulness. RESULTS: Hierarchical regressions (covarying for age, gender, and education) showed that poorer mental health (especially for older adults) and physical health functioning were related to using compensatory strategies (e.g., reliance on others and investment of time and effort) more frequently. Cognitive reappraisers reported using more internal mnemonic strategies. Conversely, having a more mindful predisposition was associated with less frequent use of compensatory strategies, especially for middle-aged adults. DISCUSSION: The results suggest that health-related quality of life, adaptive strategies to regulate emotions, and trait mindfulness are additional contexts that determine the degree of engagement in everyday memory compensation and ultimately to successful aging. PMID- 23811296 TI - Detection and isolation of auto-reactive human antibodies from primary B cells. AB - The isolation of human monoclonal antibodies (hmAb) has emerged as a versatile platform in a wide variety of contexts ranging from vaccinology to therapeutics. In particular, the presence of high titers of circulating auto-antibodies is implicated in the pathology and outcome of autoimmune diseases. Therefore, the molecular characterization of these hmAb provides an avenue to understanding the pathogenesis of autoimmune diseases. Additionally, the phenotype of the auto reactive B cells may have direct relevance for therapeutic intervention. In this report, we describe a high-throughput single-cell assay, microengraving, for the screening, characterization and isolation of anti-citrullinated protein antibodies (ACPA) from peripheral blood mononuclear cells (PBMC) of rheumatoid arthritis (RA) patients. Stimulated B cells are profiled at the single-cell level in a large array of sub-nanoliter nanowells (~10(5)), assessing both the phenotype of the cells and their ability to secrete cyclic-citrullinated peptide (CCP)-specific antibodies. Single B cells secreting ACPA are retrieved by automated micromanipulation, and amplification of the immunoglobulin (Ig) heavy and light chains is performed prior to recombinant expression. The methodology offers a simple, rapid and low-cost platform for isolation of auto-reactive antibodies from low numbers of input cells and can be easily adapted for isolation and characterization of auto-reactive antibodies in other autoimmune diseases. PMID- 23811297 TI - S-sulfhydration/desulfhydration and S-nitrosylation/denitrosylation: a common paradigm for gasotransmitter signaling by H2S and NO. AB - Sulfhydryl groups on protein Cys residues undergo an array of oxidative reactions and modifications, giving rise to a virtual redox zip code with physiological and pathophysiological relevance for modulation of protein structure and functions. While over two decades of studies have established NO-dependent S-nitrosylation as ubiquitous and fundamental for the regulation of diverse protein activities, proteomic methods for studying H2S-dependent S-sulfhydration have only recently been described and now suggest that this is also an abundant modification with potential for global physiological importance. Notably, protein S-sulfhydration and S-nitrosylation bear striking similarities in terms of their chemical and biological determinants, as well as reversal of these modifications via group transfer to glutathione, followed by the removal from glutathione by enzymes that have apparently evolved to selectively catalyze denitrosylation and desulfhydration. Here we review determinants of protein and low-molecular-weight thiol S-sulfhydration/desulfhydration, similarities with S nitrosylation/denitrosylation, and methods that are being employed to investigate and quantify these gasotransmitter-mediated cell signaling systems. PMID- 23811298 TI - Time-resolved fluorescence anisotropy and fluctuation correlation analysis of major histocompatibility complex class I proteins in fibroblast cells. AB - Major histocompatibility complex class I proteins, MHC(I), are expressed in almost all nucleated cells and synthesized in the endoplasmic reticulum (ER). The orientation and mobility of these complexes are crucial in their biological function in the immune system, i.e., the cytosolic pathogen peptides loading and their presentation to T-cell receptors at the plasma membrane, where cell destruction is triggered. Here, we investigate the structural flexibility and associations of GFP-encoded MHC(I) alleles (H2L(d)), namely H2L(d)GFPin and H2L(d)GFPout, in cultured mouse fibroblast cells. Time-resolved fluorescence anisotropy of H2L(d)GFPin in the ER indicates a dominant overall tumbling motion of 56+/-7 ns (ER), with a fast conformational flexibility, as compared with a restricted rotation of H2L(d)GFPout. At the single-molecule level, the diffusion coefficient of H2L(d)GFPin and H2L(d)GFPout in the ER is (1.8+/-0.5)*10(-9) and (2.1+/-0.6)*10(-9) cm(2)/s, respectively, as revealed by fluorescence correlation spectroscopy. A complementary immunoblotting of H2L(d)GFP constructs, isolated from mouse fibroblast cells, reveals band at 75 kDa as compared with 29 kDa of the free EGFP. These real-time dynamics provide new insights into the structural flexibility and intracellular associations of GFP-labeled MHC(I) alleles (H2L(d)) in living cells. PMID- 23811299 TI - Myeloid cells as effector cells for monoclonal antibody therapy of cancer. AB - Monoclonal antibodies (mAbs) have become an important addition to chemo- and/or radiotherapy for the treatment of cancer. They have multiple effector functions that can lead to eradication of tumor, including induction of apoptosis, growth inhibition, and initiation of complement-dependent lysis. Furthermore, mAbs can recruit immune effector cells. Traditionally, natural killer cells have been considered as the main effector cell population in mAb-mediated tumor killing. Myeloid cells have potent cytotoxic ability, as well. Monocytes and macrophages have been shown to induce antibody-dependent cytotoxicity and phagocytosis of tumor cells in the presence of IgG anti-tumor mAb. Furthermore, neutrophils are the most abundant population of circulating white blood cells, and as such may constitute a formidable source of effector cells. However, when targeting neutrophils for tumor therapy, antibodies of the IgA subclass may be more effective. This article focuses on enlisting myeloid effector cells for mAb-based immunotherapy of cancer. Additionally, methods to study mAb-dependent phagocytosis of tumor cells by macrophages are compared. PMID- 23811300 TI - Nanoparticle-DNA-polymer composites for hepatocellular carcinoma cell labeling, sensing, and magnetic resonance imaging. AB - This paper describes comparative studies and protocols in (1) self-assembling of ultrasmall superparamagnetic iron oxide nanoparticle (NP), circular plasmid DNA, and branched polyethylenimine (PEI) composites; (2) magnetofection; (3) gene delivery, (4) magnetic resonance imaging (MRI), and (5) cytotoxicity of the composites toward hepatocellular carcinoma HepG2 cells. PMID- 23811301 TI - Hepatitis B virus splicing is enhanced prior to development of hepatocellular carcinoma. AB - BACKGROUND & AIMS: The hepatitis B virus (HBV) genome encodes specific sequence elements which promote splicing of viral DNA. It has been previously suggested that spliced HBV (spHBV) variants promote viral replication and protein production, leading to hepatocellular carcinoma (HCC). In this study, we have analysed changes in spHBV over time; providing the first longitudinal analysis of spHBV in relation to the development of HCC. METHODS: Serial serum samples were collected from 165 patients with chronic HBV monoinfection, including 58 patients who later developed HCC. Real-time PCR was used to amplify and quantify wt and sp DNA loads. RESULTS: spHBV was detected in over 80% of patients with chronic HBV infection. Median serum spHBV levels were significantly higher in HCC patients than HCC-free control patients (p<0.001). Univariate analysis revealed a strong correlation between time to HCC diagnosis and spHBV DNA levels (tau=0.203; p=0.016). Asian HBV genotype (p=0.025) and increased viral load (p<0.001) were also significantly associated with increased spHBV DNA levels. Multiple regression analysis revealed time to diagnosis of HCC, Asian HBV genotypes, and viral load to be associated with increased spHBV DNA (model p<0.001; R(2)=0.189). CONCLUSIONS: HBV splicing is a common event during chronic infection and increases prior to diagnosis of HCC. Measurement of HBV splicing may prove a valuable adjunct to be used in the identification of chronically infected patients who are at increased risk of developing HCC. PMID- 23811302 TI - Hepatic ischemia and reperfusion injury: effects on the liver sinusoidal milieu. AB - Ischemia-reperfusion injury is an important cause of liver damage occurring during surgical procedures including hepatic resection and liver transplantation, and represents the main underlying cause of graft dysfunction post transplantation. Cellular and biochemical processes occurring during hepatic ischemia-reperfusion are diverse and complex, and include the deregulation of the healthy phenotype of all liver cellular components. Nevertheless, a significant part of these processes are still unknown or unclear. The present review aims at summarizing the current knowledge in liver ischemia-reperfusion, but specifically focusing on liver cell phenotype and paracrine interaction deregulations. Moreover, the most updated therapeutic strategies including pharmacological, genetic and surgical interventions, as well as some of the scientific controversies in the field will be described. Finally, the importance of considering the subclinical situation of liver grafts when translating basic knowledge to the bedside is discussed. PMID- 23811303 TI - Radiation lobectomy: time-dependent analysis of future liver remnant volume in unresectable liver cancer as a bridge to resection. AB - BACKGROUND & AIMS: Portal vein embolization (PVE) is a standard technique for patients not amenable to liver resection due to small future liver remnant ratio (FLR). Radiation lobectomy (RL) with (90)Y-loaded microspheres (Y90) is hypothesized to induce comparable volumetric changes in liver lobes, while potentially controlling the liver tumor and limiting tumor progression in the untreated lobe. We aimed at testing this concept by performing a comprehensive time-dependent analysis of liver volumes following radioembolization. METHODS: 83 patients with right unilobar disease with hepatocellular carcinoma (HCC; N=67), cholangiocarcinoma (CC; N=8) or colorectal cancer (CRC; N=8) were treated by Y90 RL. The total liver volume, lobar (parenchymal) and tumor volumes, FLR and percentage of FLR hypertrophy from baseline (%FLR hypertrophy) were assessed on pre- and post-Y90 CT/MRI scans in a dynamic fashion. RESULTS: Right lobe atrophy (p=0.003), left lobe hypertrophy (p<0.001), and FLR hypertrophy (p<0.001) were observed 1 month after Y90 and this was consistent at all follow-up time points. Median %FLR hypertrophy reached 45% (5-186) after 9 months (p<0.001). The median maximal %FLR hypertrophy was 26% (-14 -> 86). Portal vein thrombosis was correlated to %FLR hypertrophy (p=0.02). Median Child-Pugh score worsening (6 -> 7) was seen at 1 to 3 months (p=0.03) and 3 to 6 months (p=0.05) after treatment. Five patients underwent successful right lobectomy (HCC N=3, CRC N=1, CC N=1) and 6 HCCs were transplanted. CONCLUSIONS: Radiation lobectomy by Y90 is a safe and effective technique to hypertrophy the FLR. Volumetric changes are comparable (albeit slightly slower) to PVE while the right lobe tumor is treated synchronously. This novel technique is of particular interest in the bridge-to resection setting. PMID- 23811304 TI - Possible involvement of CCL1-CCR8 interaction in lymphocytic recruitment in IgG4 related sclerosing cholangitis. AB - BACKGROUND & AIMS: IgG4-related sclerosing cholangitis and type 1 autoimmune pancreatitis (IgG4-SC/AIP) are characterized by massive lymphoplasmacytic infiltration including Th2 and regulatory T cells (Tregs). This study was conducted to address which chemotactic factors are involved in this condition. METHODS: Chemokine expression profiles in tissue were examined in IgG4-SC/AIP (n=17), classical primary sclerosing cholangitis (IgG4(low) PSC, n=17), PSC with elevated serum/tissue IgG4 levels (IgG4(high) PSC, n=5), and primary biliary cirrhosis (n=7). We focused on five chemotactic factors/receptors (CCL1-CCR8, CCL17/CCL22-CCR4), given that CCR4 and CCR8 are predominantly expressed in both Th2 and Tregs. RESULTS: In conjunction with higher expression levels of IL-4 and IL-10, expression values of CCL1 and CCR8 transcripts were significantly higher in IgG4-SC/AIP than in IgG4(low) PSC (p=0.002) and IgG4(high) PSC (p=0.023). CCL1 and CCR8 were also overexpressed in IgG4(high) PSC than in IgG4(low) PSC (p=0.023). No difference was seen for CCL17, CCL22, and CCR4. In situ hybridization revealed CCL1 to be predominantly expressed in the pancreatic duct epithelium, peribiliary glands, and vascular endothelial cells including the ones involved in obliterative phlebitis in IgG4-SC/AIP, in contrast to IgG4(high) PSC where this chemotactic factor was positive in several infiltrating lymphocytes. These CCL1-expressing sites were infiltrated by CCR8(+) lymphocytes. On immunohistochemistry, GATA3(+) Th2 lymphocytes and FOXP3(+) Tregs were significantly larger in number in IgG4-SC/AIP, with the GATA3(+)/T-bet(+) cell ratio to be shifted in favour of Th2 in periductal and perivascular areas. CONCLUSIONS: CCL1-CCR8 interaction may play a critical role in lymphocytic recruitment in IgG4-SC/AIP, leading to duct-centred inflammation and obliterative phlebitis. PMID- 23811305 TI - Steroids in biliary atresia: single surgeon, single centre, prospective study. AB - BACKGROUND & AIMS: The effect of adjuvant steroids in infants with biliary atresia (BA) is not clear and evidence of benefit is lacking. METHODS: During the period Jan. 2000-Dec. 2011, 153 infants with isolated (CMV IgM-ve) BA underwent Kasai portoenterostomy (KPE) at<70 days. They were divided into three groups: LOW dose steroid (from a previous randomized trial; starting prednisolone 2mg/kg/day, n=18), HIGH-dose steroid (starting prednisolone 5mg/kg/day, n=44), and NO steroid [n=72+19 placebo (from randomized trial)=91]. Outcome was assessed by early liver biochemistry, clearance of jaundice (<20 MUmol/L), and actuarial native liver survival. Data are quoted as median (IQ range) and compared with non-parametric ANOVA, Chi or Log-rank tests as appropriate. p <= 0.05 was regarded as significant. RESULTS: All three groups were comparable for age (ANOVA, p=0.31) and a surrogate marker of liver fibrosis [aspartate-aminotransferase index (APRi), ANOVA, p=0.67]. At 1 month post KPE, there was a significant reduction in bilirubin [58 (25-91) vs. 91 (52-145)MUmol/L, p=0.0015], AST [118 (91-159) vs. 155 (108-193)IU/L, p=0.0015], and APRi [0.49 (0.28-0.89) vs. 0.82 (0.45-1.2), p=0.005] for HIGH vs. NO steroid. There was a significant increase in % clearance of jaundice with the use of steroids [47/91 (52%) vs. 12/18 (67%) vs. 29/44 (66%); steroids vs. no steroids, p=0.037]. There was no statistical difference in 4-year patient survival (96% vs. 94% vs. 95%) or native liver survival (4 year=46% vs. 50 vs. 57%). CONCLUSIONS: The adjuvant use of prednisolone significantly improved early post-operative liver biochemistry (especially at the higher dose), and increased the proportion of infants who cleared their jaundice at 6 months post-KPE. PMID- 23811306 TI - Early prediction of response to sorafenib in patients with advanced hepatocellular carcinoma: the role of dynamic contrast enhanced ultrasound. AB - BACKGROUND & AIMS: Sorafenib has become the standard first-line treatment for patients with advanced HCC and acts by inducing alterations in tumor vascularity. We wanted to evaluate the feasibility of dynamic CEUS (D-CEUS) as a predictor of early tumor response to sorafenib and to correlate functional parameters with clinical efficacy end points. METHODS: Twenty-eight HCC patients treated with sorafenib 400mg bid were prospectively enrolled. CEUS was performed at baseline (T0) and after 15 (T1) and 30 (T2) days of treatment. Tumor vasculature was assessed in a specific harmonic mode associated with a perfusion and quantification software (Q-Lab, Philips). Variations between T1/T2 and T0 were calculated for five D-CEUS functional parameters (peak intensity, PI; time to PI, TP; area under the curve, AUC; slope of wash in, Pw; mean transit time, MTT) and were compared for responders and non-responders. The correlation between D-CEUS parameters, overall survival (OS), and progression-free survival (PFS) was also assessed. A p value <0.05 was considered statistically significant. RESULTS: The percentage variation at T1 significantly correlated with response in three D-CEUS parameters (AUC, PI and Pw; p=0.002, <0.001, and 0.003, respectively). A decrease of AUC (p=0.045) and an increased/unchanged value of TP (p=0.029) and MTT (p=0.010) were associated with longer survival. Three D-CEUS parameters (AUC, TP, Pw) were significantly associated with PFS. CONCLUSIONS: D-CEUS provides a reliable and early measure of efficacy for anti-angiogenic therapies and could be an excellent tool for selecting patients who will benefit from treatment. PMID- 23811307 TI - TIPS: 25 years later. AB - In the 25 years since the first TIPS intervention has been performed, technical standards, indications, and contraindications have been set up. The previous considerable problem of shunt failure by thrombosis or intimal proliferation in the stent or in the draining hepatic vein has been reduced considerably by the availability of polytetrafluoroethylene (PTFE)-covered stents resulting in reduced rebleeding and improved survival. Unfortunately, most clinical studies have been performed prior to the release of the covered stent and, therefore, do not represent the present state of the art. In spite of this, TIPS has gained increasing acceptance in the treatment of the various complications of portal hypertension and vascular diseases of the liver. PMID- 23811308 TI - Oxidative albumin damage in chronic liver failure: relation to albumin binding capacity, liver dysfunction and survival. AB - BACKGROUND & AIMS: Impaired binding function of albumin has been demonstrated in end-stage liver disease. This and other functional disturbances of albumin may be related to oxidative stress which is believed to play an important role in the pathogenesis of liver failure as well as sepsis. The aim of the present study was to relate oxidative modification of albumin to loss of albumin binding function in advanced chronic liver failure and in sepsis. METHODS: Patients with decompensated cirrhosis or sepsis and healthy controls were investigated. Three fractions of albumin were separated by chromatography according to the redox state of cysteine-34: non-oxidized human mercaptalbumin, reversibly oxidized human non-mercaptalbumin-1, and irreversibly oxidized human non-mercaptalbumin-2 (HNA2). Binding properties of albumin site II were measured using dansylsarcosine as a ligand. RESULTS: Both in cirrhotic and septic patients, fractions of oxidized albumin were increased and binding capacity for dansylsarcosine was decreased. Mass spectroscopy confirmed specific oxidation of cysteine-34. In cirrhotic patients, dansylsarcosine binding correlated strongly with liver function parameters and moderately with HNA2. Baseline levels of HNA2 accurately predicted 30-day and 90-day survival in cirrhotic patients and this was confirmed in an external validation cohort. CONCLUSIONS: Our results suggest that oxidative damage impairs binding properties of albumin. In advanced liver disease, reduced binding capacity of albumin site II is mainly related to impaired liver function. The plasma level of HNA2 is closely related to survival and may represent a novel biomarker for liver failure. PMID- 23811310 TI - Animal models of CNS disorders. AB - There is intense interest in the development and application of animal models of CNS disorders to explore pathology and molecular mechanisms, identify potential biomarkers, and to assess the therapeutic utility, estimate safety margins and establish pharmacodynamic and pharmacokinetic parameters of new chemical entities (NCEs). This is a daunting undertaking, due to the complex and heterogeneous nature of these disorders, the subjective and sometimes contradictory nature of the clinical endpoints and the paucity of information regarding underlying molecular mechanisms. Historically, these models have been invaluable in the discovery of therapeutics for a range of disorders including anxiety, depression, schizophrenia, and Parkinson's disease. Recently, however, they have been increasingly criticized in the wake of numerous clinical trial failures of NCEs with promising preclinical profiles. These failures have resulted from a number of factors including inherent limitations of the models, over-interpretation of preclinical results and the complex nature of clinical trials for CNS disorders. This review discusses the rationale, strengths, weaknesses and predictive validity of the most commonly used models for psychiatric, neurodegenerative and neurological disorders as well as critical factors that affect the variability and reproducibility of these models. It also addresses how progress in molecular genetics and the development of transgenic animals has fundamentally changed the approach to neurodegenerative disorder research. To date, transgenic animal models?have not been the panacea for drug discovery that many had hoped for. However continual refinement of these models is leading to steady progress with the promise of eventual therapeutic breakthroughs. PMID- 23811309 TI - Animal models of human disease: inflammation. AB - Animals have been used as models to study inflammation and autoimmunity for more than 80 years. During that time it has been understood that although the use of such models is an important and necessary part of understanding human disease, they inevitably display significant differences from the human disease state. Since our understanding of human inflammation and autoimmunity is necessarily incomplete, it may be concluded that the animal models will also be reflective of the state of knowledge regarding such diseases. Nevertheless, animal models of rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis have been successfully used to enhance the understanding of the human disease and have made significant contributions to the development of powerful new therapies. However, there are exceptions. One of the most persistent has been the study of sepsis where the animal models have been woefully inadequate in uncovering targets for drug discovery and have led to repeated clinical failures. As will be explained, only by using newly developed genomics tools has it been possible to uncover the differences between sepsis in mice and sepsis in man. It is concluded that approaches using the newer genomic and proteomic data derived from human tissues, will make possible the development of animal models with more predictive power as aids to drug discovery. PMID- 23811311 TI - Subunit composition and kinetics of the Renshaw cell heteromeric nicotinic receptors. AB - In Renshaw cells (RCs) of newborn mice, activation of motoneurons elicits a four component synaptic current (EPSC) mediated by two glutamate receptors and two nicotinic receptors (nAChRs). We have analyzed the nicotinic component of the EPSC which is blocked by dihydro-beta-erythroidine (DHbetaE) with the dual objective of identifying the nAChR subunits involved and of understanding the kinetics of the response. The sensitivity to DHbetaE of the peak of the EPSC was differentially affected by genetic deletion of three specific nAChR subunits: alpha2, beta2 and beta4. The comparison of these effects with published findings on recombinant receptors suggests that, in WT mice, two heteromeric assemblies, alpha4beta2 and alpha2beta4, coexist in variable proportions in a given RC. Some results seem to require, however, the involvement of an additional subunit. The effects of DHbetaE on the decay of the EPSCs were compared in WT mice and in PRiMA(-/-) mice, in which the decay is prolonged by the absence of central acetylcholinesterase. In PRiMA(-/-) mice DHbetaE shortened the decay of the EPSC. In WT mice it did not alter the decay but reduced the amplitude of both components of the EPSC. The results can be interpreted by assuming that the nAChRs exist in two stoichiometries, subsynaptic "low sensitivity" nAChRs and extrasynaptic "high sensitivity" nAChRs activated by spillover. PMID- 23811312 TI - Nicotinic acetylcholine receptors containing the alpha6 subunit contribute to ethanol activation of ventral tegmental area dopaminergic neurons. AB - Nicotine and alcohol are often co-abused suggesting a common mechanism of action may underlie their reinforcing properties. Both drugs acutely increase activity of ventral tegmental area (VTA) dopaminergic (DAergic) neurons, a phenomenon associated with reward behavior. Recent evidence indicates that nicotinic acetylcholine receptors (nAChRs), ligand-gated cation channels activated by ACh and nicotine, may contribute to ethanol-mediated activation of VTA DAergic neurons although the nAChR subtype(s) involved has not been fully elucidated. Here we show that expression and activation of nAChRs containing the alpha6 subunit contribute to ethanol-induced activation of VTA DAergic neurons. In wild type (WT) mouse midbrain sections that contain the VTA, ethanol (50 or 100 mM) significantly increased firing frequency of DAergic neurons. In contrast, ethanol did not significantly increase activity of VTA DAergic neurons in mice that do not express CHRNA6, the gene encoding the alpha6 nAChR subunit (alpha6 knock-out (KO) mice). Ethanol-induced activity in WT slices was also reduced by pre application of the alpha6 subtype-selective nAChR antagonist, alpha-conotoxin MII[E11A]. When co-applied, ethanol potentiated the response to ACh in WT DAergic neurons; whereas co-application of ACh and ethanol failed to significantly increase activity of DAergic neurons in alpha6 KO slices. Finally, pre application of alpha-conotoxin MII[E11A] in WT slices reduced ethanol potentiation of ACh responses. Together our data indicate that alpha6-subunit containing nAChRs may contribute to ethanol activation of VTA DAergic neurons. These receptors are predominantly expressed in DAergic neurons and known to be critical for nicotine reinforcement, providing a potential common therapeutic molecular target to reduce nicotine and alcohol co-abuse. PMID- 23811313 TI - Patient experiences with inpatient care in rural China. AB - OBJECTIVE: To describe patient experiences with hospital inpatient care among participants living in rural China and to examine their associations with sociodemographic characteristics, hospital type and province. DESIGN: Cross sectional study using data from questionnaires administered to members of randomly selected households in 2010. We used linear and logistic regression to determine associations between patient ratings of care and key components of their experience and between patient ratings of care and sociodemographic characteristics, hospital type and province. SETTING: Households located in seven provinces in rural China. PARTICIPANTS: Household members >15 years who reported being admitted to the hospital within the last 365 days with valid data on our outcome measures (n = 443). MAIN OUTCOME MEASURES: Patient evaluations of health care experiences. RESULTS: Approximately 31% of participants rated their experiences 5.0 out of 5.0 (best), but 22% rated their experiences <=3.0. Fifteen percent would not recommend the facility to family and friends. Five factors emerged, of which, 'communication with nurses' was most strongly and consistently associated with overall patient ratings. Multivariable models showed that ratings for township and county-level hospitals were significantly lower than above county-level hospitals. Variation also existed across the seven provinces. CONCLUSIONS: Findings suggest that patients on average have high ratings of hospital care, but a notable proportion of participants, particularly those receiving care in county-level hospitals, continue to be less than fully satisfied. As China further develops its health system, establishing routine monitoring of patients' experiences will be important to ensure the system is responsive to the population needs. PMID- 23811315 TI - Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia. PMID- 23811314 TI - Intrathecal injection of adenosine 2A receptor agonists reversed neuropathic allodynia through protein kinase (PK)A/PKC signaling. AB - A single intrathecal dose of adenosine 2A receptor (A2AR) agonist was previously reported to produce a multi-week reversal of allodynia in a chronic constriction injury (CCI) model of neuropathic pain. We aimed to determine if this long-term reversal was induced by A2AR agonism versus more generalized across adenosine receptor subtypes, and begin to explore the intracellular signaling cascades involved. In addition, we sought to identify whether the enduring effect could be extended to other models of neuropathic pain. We tested an A1R and A2BR agonist in CCI and found the same long duration effect with A2BR but not A1R agonism. An A2AR agonist (ATL313) produced a significant long-duration reversal of mechanical allodynia induced by long established CCI (administered 6 weeks after surgery), spinal nerve ligation and sciatic inflammatory neuropathy. To determine if ATL313 had a direct effect on glia, ATL313 was coadministered with lipopolysaccharide to neonatal microglia and astrocytes in vitro. ATL313 significantly attenuated TNFalpha production in both microglia and astrocytes but had no effect on LPS induced IL-10. Protein kinase C significantly reversed the ATL313 effects on TNFalpha in vitro in microglia and astrocytes, while a protein kinase A inhibitor only effected microglia. Both intrathecal PKA and PKC inhibitors significantly reversed the effect of the A2AR agonist on neuropathic allodynia. Therefore, A2AR agonists administered IT remain an exciting novel target for the treatment of neuropathic pain. PMID- 23811316 TI - Arm-cranking exercise reduced oxidative damage in adults with chronic spinal cord injury. AB - OBJECTIVE: To assess the effect of a 12-week arm-cranking exercise program on reducing oxidative damage in untrained adults with chronic spinal cord injury (SCI). DESIGN: Randomized controlled trial. SETTING: Community-based supervised intervention. PARTICIPANTS: Male adults with complete SCI at or below the fifth thoracic level (T5) (N=17) volunteered for this study. Participants were randomly allocated to the intervention (n=9) or control (n=8) group using a concealed method. INTERVENTION: A 12-week arm-cranking exercise program, 3 sessions/wk, consisting of warming-up (10-15min) followed by a main part in arm-crank (20 30min [increasing 2min and 30s every 3wk]) at a moderate work intensity of 50% to 65% of the heart rate reserve (starting at 50% and increasing 5% every 3 weeks) and by a cooling-down period (5-10min). MAIN OUTCOME MEASURES: Plasmatic levels of total antioxidant status as well as erythrocyte glutathione peroxidase activity were measured. Lipid and protein oxidation were determined as malondialdehyde and carbonyl group levels, respectively. Furthermore, physical fitness and body composition were assessed. RESULTS: When compared with baseline results, maximum oxygen consumption was significantly increased (P=.031), suggesting an improvement in physical fitness in the intervention group. Regarding the antioxidant defense system, it was found that both total antioxidant status (P=.014) and erythrocyte glutathione peroxidase activity (P=.027) were significantly increased at the end of the training program. As a consequence, plasmatic levels of malondialdehyde (P=.008) and carbonyl groups (P=.022) were significantly reduced. CONCLUSION: A 12-week arm-cranking exercise program improved the antioxidant defense system in adults with chronic SCI, which may finally attenuate both lipid and protein oxidation in this population. PMID- 23811317 TI - A primary care-based randomized controlled trial of 12-week whole-body vibration for balance improvement in type 2 diabetes mellitus. AB - OBJECTIVE: To determine whether a 12-week whole-body vibration (WBV) training program improved balance in participants with type 2 diabetes mellitus (T2DM). DESIGN: Randomized controlled trial. SETTING: Primary health care setting. PARTICIPANTS: Participants with T2DM (N=50). INTERVENTIONS: Participants were randomly allocated to either a WBV group (n=25), which performed a 12-week WBV based exercise program on an oscillating platform (12-16Hz-4mm; 3 sessions/wk), or a usual-care control group (n=25). MAIN OUTCOME MEASURES: Clinical and sociodemographic variables were recorded at baseline. Static balance and dynamic balance were also assessed at baseline by measuring postural sway (measurement of center of pressure [COP] excursions in the anteroposterior and mediolateral directions) using a Wii Balance Board and the Timed Up and Go test. RESULTS: Significant between-group differences in COP excursions with participants' eyes closed were found with their feet apart and feet together. In addition, participants in the WBV group exhibited significantly lower COP excursions with their eyes closed after the intervention, while participants in the control group experienced a nonsignificant deterioration in COP excursions (ie, greater excursion) with their eyes open (mediolateral axis). There was no significant difference in the Timed Up and Go test values postintervention. CONCLUSIONS: WBV provides a safe and well-tolerated approach to improve balance in participants with T2DM. These findings may have important implications for falls prevention in those with T2DM in the primary health care setting. PMID- 23811318 TI - Discrimination of animate and inanimate motion in 9-month-old infants: an ERP study. AB - Simple geometric shapes moving in a self-propelled manner, and violating Newtonian laws of motion by acting against gravitational forces tend to induce a judgement that an object is animate. Objects that change their motion only due to external causes are more likely judged as inanimate. How the developing brain is employed in the perception of animacy in early ontogeny is currently unknown. The aim of this study was to use ERP techniques to determine if the negative central component (Nc), a waveform related to attention allocation, was differentially affected when an infant observed animate or inanimate motion. Short animated movies comprising a marble moving along a marble run either in an animate or an inanimate manner were presented to 15 infants who were 9 months of age. The ERPs were time-locked to a still frame representing animate or inanimate motion that was displayed following each movie. We found that 9-month-olds are able to discriminate between animate and inanimate motion based on motion cues alone and most likely allocate more attentional resources to the inanimate motion. The present data contribute to our understanding of the animate-inanimate distinction and the Nc as a correlate of infant cognitive processing. PMID- 23811319 TI - Depletion of regulatory T cells by targeting folate receptor 4 enhances the potency of a GM-CSF-secreting tumor cell immunotherapy. AB - In this report, a Treg-depleting anti-FR4 antibody is combined with a GM-CSF secreting tumor cell immunotherapy (GVAX) for treatment of melanoma-bearing animals. Median survival time (MST) of animals treated with GVAX was 41 days, compared to a MST of 32 days in untreated animals. Anti-FR4 monotherapy had no effect on MST. Combination of anti-FR4 and GVAX significantly prolonged MST to 55 days, suggesting that these two agents can function cooperatively. Combination therapy increased expression of IFN-gamma and granzyme B by CD8 T cells. In contrast to anti-CD25-mediated Treg depletion, administration of anti-FR4 after GVAX did not reduce efficacy, suggesting that anti-FR4 does not deplete effector cells induced by GVAX. Triple combination of a blocking CTLA4 antibody with GVAX and anti-FR4 further enhanced overall survival and reduced growth of well established melanomas. Considered together, anti-FR4 antibody and GVAX may be a promising approach for the treatment of patients with cancer. PMID- 23811320 TI - Atypical presentation of a cryopyrin-associated periodic syndrome, revealing a novel NLRP3 mutation. PMID- 23811323 TI - The origin of scientific neurology and its consequences for modern and future neuroscience. AB - John Hughlings Jackson (1835-1911) created a science of brain function that, in scope and profundity, is among the great scientific discoveries of the 19th century. It is interesting that the magnitude of his achievement is not completely recognized even among his ardent admirers. Although thousands of practitioners around the world use the clinical applications of his science every day, the principles from which bedside neurology is derived have broader consequences-for modern and future science-that remain unrecognized and unexploited. This paper summarizes the scientific formalism that created modern neurology, demonstrates how its direct implications affect a current area of neuroscientific research, and indicates how Hughlings Jackson's ideas form a path toward a novel solution to an important open problem of the brain and mind. PMID- 23811322 TI - Beyond taxol: microtubule-based treatment of disease and injury of the nervous system. AB - Contemporary research has revealed a great deal of information on the behaviours of microtubules that underlie critical events in the lives of neurons. Microtubules in the neuron undergo dynamic assembly and disassembly, bundling and splaying, severing, and rapid transport as well as integration with other cytoskeletal elements such as actin filaments. These various behaviours are regulated by signalling pathways that affect microtubule-related proteins such as molecular motor proteins and microtubule severing enzymes, as well as a variety of proteins that promote the assembly, stabilization and bundling of microtubules. In recent years, translational neuroscientists have earmarked microtubules as a promising target for therapy of injury and disease of the nervous system. Proof-of-principle has come mainly from studies using taxol and related drugs to pharmacologically stabilize microtubules in animal models of nerve injury and disease. However, concerns persist that the negative consequences of abnormal microtubule stabilization may outweigh the positive effects. Other potential approaches include microtubule-active drugs with somewhat different properties, but also expanding the therapeutic toolkit to include intervention at the level of microtubule regulatory proteins. PMID- 23811324 TI - Mesencephalic complex I deficiency does not correlate with parkinsonism in mitochondrial DNA maintenance disorders. AB - Genetic evidence from recessively inherited Parkinson's disease has indicated a clear causative role for mitochondrial dysfunction in Parkinson's disease. This role has long been discussed based on findings that toxic inhibition of mitochondrial respiratory complex I caused parkinsonism and that tissues of patients with Parkinson's disease show complex I deficiency. Disorders of mitochondrial DNA maintenance are a common cause of inherited neurodegenerative disorders, and lead to mitochondrial DNA deletions or depletion and respiratory chain defect, including complex I deficiency. However, parkinsonism associates typically with defects of catalytic domain of mitochondrial DNA polymerase gamma. Surprisingly, however, not all mutations affecting DNA polymerase gamma manifest as parkinsonism, but, for example, spacer region mutations lead to spinocerebellar ataxia and/or severe epilepsy. Furthermore, defective Twinkle helicase, a close functional companion of DNA polymerase gamma in mitochondrial DNA replication, results in infantile-onset spinocerebellar ataxia, epilepsy or adult-onset mitochondrial myopathy, but not typically parkinsonism. Here we sought for clues for this specificity in the neurological manifestations of mitochondrial DNA maintenance disorders by studying mesencephalic neuropathology of patients with DNA polymerase gamma or Twinkle defects, with or without parkinsonism. We show here that all patients with mitochondrial DNA maintenance disorders had neuronopathy in substantia nigra, most severe in DNA polymerase gamma-associated parkinsonism. The oculomotor nucleus was also affected, but less severely. In substantia nigra, all patients had a considerable decrease of respiratory chain complex I, but other respiratory chain enzymes were not affected. Complex I deficiency did not correlate with parkinsonism, age, affected gene or inheritance. We conclude that the cell number in substantia nigra correlated well with parkinsonism in DNA polymerase gamma and Twinkle defects. However, complex I defect is a general consequence of mitochondrial DNA maintenance defects, and does not explain manifestation of parkinsonism or degree of mesencephalic cell death in patients with mitochondrial DNA maintenance disorders. PMID- 23811326 TI - Small heterodimer partner overexpression partially protects against liver tumor development in farnesoid X receptor knockout mice. AB - Farnesoid X receptor (FXR, Nr1h4) and small heterodimer partner (SHP, Nr0b2) are nuclear receptors that are critical to liver homeostasis. Induction of SHP serves as a major mechanism of FXR in suppressing gene expression. Both FXR(-/-) and SHP(-/-) mice develop spontaneous hepatocellular carcinoma (HCC). SHP is one of the most strongly induced genes by FXR in the liver and is a tumor suppressor, therefore, we hypothesized that deficiency of SHP contributes to HCC development in the livers of FXR(-/-) mice and therefore, increased SHP expression in FXR(-/ ) mice reduces liver tumorigenesis. To test this hypothesis, we generated FXR(-/ ) mice with overexpression of SHP in hepatocytes (FXR(-/-)/SHP(Tg)) and determined the contribution of SHP in HCC development in FXR(-/-) mice. Hepatocyte-specific SHP overexpression did not affect liver tumor incidence or size in FXR(-/-) mice. However, SHP overexpression led to a lower grade of dysplasia, reduced indicator cell proliferation and increased apoptosis. All tumor-bearing mice had increased serum bile acid levels and IL-6 levels, which was associated with activation of hepatic STAT3. In conclusion, SHP partially protects FXR(-/-) mice from HCC formation by reducing tumor malignancy. However, disrupted bile acid homeostasis by FXR deficiency leads to inflammation and injury, which ultimately results in uncontrolled cell proliferation and tumorigenesis in the liver. PMID- 23811325 TI - Chronic moderate sleep restriction in older long sleepers and older average duration sleepers: a randomized controlled trial. AB - Epidemiologic studies have consistently shown that sleeping <7 h and >=8 h is associated with increased mortality and morbidity. The risks of short sleep may be consistent with results from experimental sleep deprivation studies. However, there has been little study of chronic moderate sleep restriction and little evaluation of older adults who might be more vulnerable to negative effects of sleep restriction, given their age-related morbidities. Moreover, the risks of long sleep have scarcely been examined experimentally. Moderate sleep restriction might benefit older long sleepers who often spend excessive time in bed (TIB) in contrast to older adults with average sleep patterns. Our aims are: (1) to examine the ability of older long sleepers and older average sleepers to adhere to 60 min TIB restriction; and (2) to contrast effects of chronic TIB restriction in older long vs. average sleepers. Older adults (n = 100) (60-80 years) who sleep 8-9 h per night and 100 older adults who sleep 6-7.25 h per night will be examined at 4 sites over 5 years. Following a 2-week baseline, participants will be randomized to one of two 12-week treatments: (1) a sleep restriction involving a fixed sleep-wake schedule, in which TIB is reduced 60 min below each participant's baseline TIB; and (2) a control treatment involving no sleep restriction, but a fixed sleep schedule. Sleep will be assessed with actigraphy and a diary. Measures will include glucose tolerance, sleepiness, depressive symptoms, quality of life, cognitive performance, incidence of illness or accident, and inflammation. PMID- 23811328 TI - Involvement of HIF-2alpha-mediated inflammation in arsenite-induced transformation of human bronchial epithelial cells. AB - Arsenic is a well established human carcinogen that causes diseases of the lung. Some studies have suggested a link between inflammation and lung cancer; however, it is unknown if arsenite-induced inflammation causally contributes to arsenite caused malignant transformation of cells. In this study, we investigated the molecular mechanisms underlying inflammation during neoplastic transformation induced in human bronchial epithelial (HBE) cells by chronic exposure to arsenite. The results showed that, on acute or chronic exposure to arsenite, HBE cells over-expressed the pro-inflammatory cytokines, interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-1beta (IL-1beta). The data also indicated that HIF-2alpha was involved in arsenite-induced inflammation. Moreover, IL-6 and IL-8 were essential for the malignant progression of arsenite-transformed HBE cells. Thus, these experiments show that HIF-2alpha mediates arsenite-induced inflammation and that such inflammation is involved in arsenite-induced malignant transformation of HBE cells. The results provide a link between the inflammatory response and the acquisition of a malignant transformed phenotype by cells chronically exposed to arsenite and thus establish a previously unknown mechanism for arsenite-induced carcinogenesis. PMID- 23811327 TI - Chronic cadmium exposure in vitro induces cancer cell characteristics in human lung cells. AB - Cadmium is a known human lung carcinogen. Here, we attempt to develop an in vitro model of cadmium-induced human lung carcinogenesis by chronically exposing the peripheral lung epithelia cell line, HPL-1D, to a low level of cadmium. Cells were chronically exposed to 5 MUM cadmium, a noncytotoxic level, and monitored for acquired cancer characteristics. By 20 weeks of continuous cadmium exposure, these chronic cadmium treated lung (CCT-LC) cells showed marked increases in secreted MMP-2 activity (3.5-fold), invasion (3.4-fold), and colony formation in soft agar (2-fold). CCT-LC cells were hyperproliferative, grew well in serum-free media, and overexpressed cyclin D1. The CCT-LC cells also showed decreased expression of the tumor suppressor genes p16 and SLC38A3 at the protein levels. Also consistent with an acquired cancer cell phenotype, CCT-LC cells showed increased expression of the oncoproteins K-RAS and N-RAS as well as the epithelial-to-mesenchymal transition marker protein Vimentin. Metallothionein (MT) expression is increased by cadmium, and is typically overexpressed in human lung cancers. The major MT isoforms, MT-1A and MT-2A were elevated in CCT-LC cells. Oxidant adaptive response genes HO-1 and HIF-1A were also activated in CCT LC cells. Expression of the metal transport genes ZNT-1, ZNT-5, and ZIP-8 increased in CCT-LC cells culminating in reduced cadmium accumulation, suggesting adaptation to the metal. Overall, these data suggest that exposure of human lung epithelial cells to cadmium causes acquisition of cancer cell characteristics. Furthermore, transformation occurs despite the cell's ability to adapt to chronic cadmium exposure. PMID- 23811329 TI - Toxicity assessments of nonsteroidal anti-inflammatory drugs in isolated mitochondria, rat hepatocytes, and zebrafish show good concordance across chemical classes. AB - To reduce costly late-stage compound attrition, there has been an increased focus on assessing compounds in in vitro assays that predict attributes of human safety liabilities, before preclinical in vivo studies are done. Relevant questions when choosing a panel of assays for predicting toxicity are (a) whether there is general concordance in the data among the assays, and (b) whether, in a retrospective analysis, the rank order of toxicity of compounds in the assays correlates with the known safety profile of the drugs in humans. The aim of our study was to answer these questions using nonsteroidal anti-inflammatory drugs (NSAIDs) as a test set since NSAIDs are generally associated with gastrointestinal injury, hepatotoxicity, and/or cardiovascular risk, with mitochondrial impairment and endoplasmic reticulum stress being possible contributing factors. Eleven NSAIDs, flufenamic acid, tolfenamic acid, mefenamic acid, diclofenac, meloxicam, sudoxicam, piroxicam, diflunisal, acetylsalicylic acid, nimesulide, and sulindac (and its two metabolites, sulindac sulfide and sulindac sulfone), were tested for their effects on (a) the respiration of rat liver mitochondria, (b) a panel of mechanistic endpoints in rat hepatocytes, and (c) the viability and organ morphology of zebrafish. We show good concordance for distinguishing among/between NSAID chemical classes in the observations among the three approaches. Furthermore, the assays were complementary and able to correctly identify "toxic" and "non-toxic" drugs in accordance with their human safety profile, with emphasis on hepatic and gastrointestinal safety. We recommend implementing our multi-assay approach in the drug discovery process to reduce compound attrition. PMID- 23811330 TI - High-throughput respirometric assay identifies predictive toxicophore of mitochondrial injury. AB - Many environmental chemicals and drugs negatively affect human health through deleterious effects on mitochondrial function. Currently there is no chemical library of mitochondrial toxicants, and no reliable methods for predicting mitochondrial toxicity. We hypothesized that discrete toxicophores defined by distinct chemical entities can identify previously unidentified mitochondrial toxicants. We used a respirometric assay to screen 1760 compounds (5 MUM) from the LOPAC and ChemBridge DIVERSet libraries. Thirty-one of the assayed compounds decreased uncoupled respiration, a stress test for mitochondrial dysfunction, prior to a decrease in cell viability and reduced the oxygen consumption rate in isolated mitochondria. The mitochondrial toxicants were grouped by chemical similarity and two clusters containing four compounds each were identified. Cheminformatic analysis of one of the clusters identified previously uncharacterized mitochondrial toxicants from the ChemBridge DIVERSet. This approach will enable the identification of mitochondrial toxicants and advance the prediction of mitochondrial toxicity for both drug discovery and risk assessment. PMID- 23811331 TI - The underlying toxicological mechanism of chemical mixtures: a case study on mixture toxicity of cyanogenic toxicants and aldehydes to Photobacterium phosphoreum. AB - Intracellular chemical reaction of chemical mixtures is one of the main reasons that cause synergistic or antagonistic effects. However, it still remains unclear what the influencing factors on the intracellular chemical reaction are, and how they influence on the toxicological mechanism of chemical mixtures. To reveal this underlying toxicological mechanism of chemical mixtures, a case study on mixture toxicity of cyanogenic toxicants and aldehydes to Photobacterium phosphoreum was employed, and both their joint effects and mixture toxicity were observed. Then series of two-step linear regressions were performed to describe the relationships between joint effects, the expected additive toxicities and descriptors of individual chemicals (including concentrations, binding affinity to receptors, octanol/water partition coefficients). Based on the quantitative relationships, the underlying joint toxicological mechanisms were revealed. The result shows that, for mixtures with their joint effects resulting from intracellular chemical reaction, their underlying toxicological mechanism depends on not only their interaction with target proteins, but also their transmembrane actions and their concentrations. In addition, two generic points of toxicological mechanism were proposed including the influencing factors on intracellular chemical reaction and the difference of the toxicological mechanism between single reactive chemicals and their mixtures. This study provided an insight into the understanding of the underlying toxicological mechanism for chemical mixtures with intracellular chemical reaction. PMID- 23811332 TI - Association of brominated proteins and changes in protein expression in the rat kidney with subcarcinogenic to carcinogenic doses of bromate. AB - The water disinfection byproduct bromate (BrO3(-)) produces cytotoxic and carcinogenic effects in rat kidneys. Our previous studies demonstrated that BrO3( ) caused sex-dependent differences in renal gene and protein expression in rats and the elimination of brominated organic carbon in their urine. The present study examined changes in renal cell apoptosis and protein expression in male and female F344 rats treated with BrO3(-) and associated these changes with accumulation of 3-bromotyrosine (3-BT)-modified proteins. Rats were treated with 0, 11.5, 46 and 308 mg/L BrO3(-) in drinking water for 28 days and renal sections were prepared and examined for apoptosis (TUNEL-staining), 8-oxo-deoxyguanosine (8-oxoG), 3-BT, osteopontin, Kim-1, clusterin, and p-21 expression. TUNEL staining in renal proximal tubules increased in a dose-related manner beginning at 11.5mg BrO3(-)/L in female rats and 46 mg/L in males. Increased 8-oxoG staining was observed at doses as low as 46 mg/L. Osteopontin expression also increased in a dose-related manner after treatment with 46 mg/L, in males only. In contrast, Kim-1 expression increased in a dose-related manner in both sexes, although to a greater extent in females at the highest dose. Clusterin and p21 expression also increased in a dose-related manner in both sexes. The expression of 3-BT-modified proteins only increased in male rats, following a pattern previously reported for accumulation of alpha-2u-globulin. Increases in apoptosis in renal proximal tubules of male and female rats at the lowest doses suggest a common mode of action for renal carcinogenesis for the two sexes that is independent of alpha-2u-globulin nephropathy. PMID- 23811333 TI - Simplifying the synthesis of SIgA: combination of dIgA and rhSC using affinity chromatography. AB - The mucosal epithelia together with adaptive immune responses, such as local production and secretion of dimeric and polymeric immunoglobulin A (IgA), are a crucial part of the first line of defense against invading pathogens. IgA is primarily secreted as SIgA and plays multiple roles in mucosal defense. The study of SIgA-mediated protection is an important area of research in mucosal immunity but an easy, fast and reproducible method to generate pathogen-specific SIgA in vitro has not been available. We report here a new method to produce SIgA by co purification of dimeric IgA, containing J chain, and recombinant human SC expressed in CHO cells. We previously reported the generation, production and characterization of the human recombinant monoclonal antibody IgA2 b12. This antibody, derived from the variable regions of the neutralizing anti-HIV-1 mAb IgG1 b12, blocked viral attachment and uptake by epithelial cells in vitro. We used a cloned CHO cell line that expresses monomeric, dimeric and polymeric species of IgA2 b12 for large-scale production of dIgA2 b12. Subsequently, we generated a CHO cell line to express recombinant human secretory component (rhSC). Here, we combined dIgA2 b12 and CHO-expressed rhSC via column chromatography to produce SIgA2 b12 that remains fully intact upon elution with 0.1M citric acid, pH 3.0. We have performed biochemical analysis of the synthesized SIgA to confirm the species is of the expected size and retains the functional properties previously described for IgA2 b12. We show that SIgA2 b12 binds to the HIV-1 gp120 glycoprotein with similar apparent affinity to that of monomeric and dimeric forms of IgA2 b12 and neutralizes HIV-1 isolates with similar potency. An average yield of 6 mg of SIgA2 b12 was achieved from the combination of 20mg of purified dIgA2 b12 and 2L of rhSC-containing CHO cell supernatant. We conclude that synthesized production of stable SIgA can be generated by co-purification. This process introduces a simplified means of generating a variety of pathogen-specific SIgA antibodies for research and clinical applications. PMID- 23811334 TI - Estimating the distance separating fluorescent protein FRET pairs. AB - Forster resonance energy transfer (FRET) describes a physical phenomenon widely applied in biomedical research to estimate separations between biological molecules. Routinely, genetic engineering is used to incorporate spectral variants of the green fluorescent protein (GFPs), into cellular expressed proteins. The transfer efficiency or rate of energy transfer between donor and acceptor FPs is then assayed. As appreciable FRET occurs only when donors and acceptors are in close proximity (1-10nm), the presence of FRET may indicate that the engineered proteins associate as interacting species. For a homogeneous population of FRET pairs the separations between FRET donors and acceptors can be estimated from a measured FRET efficiency if it is assumed that donors and acceptors are randomly oriented and rotate extensively during their excited state (dynamic regime). Unlike typical organic fluorophores, the rotational correlation times of FPs are typically much longer than their fluorescence lifetime; accordingly FPs are virtually static during their excited state. Thus, estimating separations between FP FRET pairs is problematic. To overcome this obstacle, we present here a simple method for estimating separations between FPs using the experimentally measured average FRET efficiency. This approach assumes that donor and acceptor fluorophores are randomly oriented, but do not rotate during their excited state (static regime). This approach utilizes a Monte-Carlo simulation generated look-up table that allows one to estimate the separation, normalized to the Forster distance, from the average FRET efficiency. Assuming a dynamic regime overestimates the separation significantly (by 10% near 0.5 and 30% near 0.75 efficiencies) compared to assuming a static regime, which is more appropriate for estimates of separations between FPs. PMID- 23811335 TI - Composition of long chain polyunsaturated fatty acids (LC-PUFAs) in different encephalic regions and its association with behavior in spontaneous hypertensive rat (SHR). AB - Long chain polyunsaturated fatty acids (LC-PUFAs) are hypothesized to play an important role in attention deficit/hyperactivity disorder (ADHD). This study evaluated LC-PUFAs composition in different encephalic regions by gas chromatography and its association with behavior on the attentional set-shifting task, open field test and the Morris water maze of spontaneous hypertensive rat (SHR)-a genetic animal model of ADHD. In behavioral tests, the SHRs exhibited deficiencies in attentional set-shifting, autonomic activities and spatial learning and memory. In all the studied encephalic regions, we observed higher concentration of docosahexaenoic acid (DHA) and arachidonic acid (AA) and higher AA/DHA ratio in the SHRs compared with the Wistar-Kyoto (WKY) and Sprague-Dawley (SD) rats (p<0.01), which was associated with abnormal behavior in the SHRs. This study provided an appropriate animal model for study on the relationship between LC-PUFAs and ADHD. Our results prove abnormal neurobehaviour associated with imbalance of AA/DHA ratio and highlights the significance of normal AA/DHA ratio in behavior. PMID- 23811336 TI - G-Quadruplex conformational change driven by pH variation with potential application as a nanoswitch. AB - BACKGROUND: G-Quadruplex is a highly polymorphic structure, and its behavior in acidic condition has not been well studied. METHODS: Circular dichroism (CD) spectra were used to study the conformational change of G-quadruplex. The thermal stabilities of the G-quadruplex were measured with CD melting. Interconversion kinetics profiles were investigated by using CD kinetics. The fluorescence of the inserted 2-Aminopurine (Ap) was monitored during pH change and acrylamide quenching, indicating the status of the loop. Proton NMR was adopted to help illustrate the change of the conformation. RESULTS: G-Quadruplex of specific loop was found to be able to transform upon pH variation. The transformation was resulted from the loop rearrangement. After screening of a library of diverse G quadruplex, a sequence exhibiting the best transformation property was found. A pH-driven nanoswitch with three gears was obtained based on this transition cycle. CONCLUSIONS: Certain G-quadruplex was found to go through conformational change at low pH. Loop was the decisive factor controlling the interconversion upon pH variation. G-Quadruplex with TT central loop could be converted in a much milder condition than the one with TTA loop. It can be used to design pH-driven nanodevices such as a nanoswitch. GENERAL SIGNIFICANCE: These results provide more insights into G-quadruplex polymorphism, and also contribute to the design of DNA-based nanomachines and logic gates. PMID- 23811338 TI - Binding of transition metal ions to albumin: sites, affinities and rates. AB - BACKGROUND: Serum albumin is the most abundant protein in the blood and cerebrospinal fluid and plays a fundamental role in the distribution of essential transition metal ions in the human body. Human serum albumin (HSA) is an important physiological transporter of the essential metal ions Cu(2+), and Zn(2+) in the bloodstream. Its binding of metals like Ni(2+), Co(2+), or Cd(2+) can occur in vivo, but is only of toxicological relevance. Moreover, HSA is one of the main targets and hence most studied binding protein for metallodrugs based on complexes with Au, Pt and V. SCOPE OF REVIEW: We discuss i) the four metal binding sites so far described on HSA, their localization and metal preference, ii) the binding of the metal ions mentioned above, i.e. their stability constants and association/dissociation rates, their coordination chemistry and their selectivity versus the four binding sites iii) the methodology applied to study issues of items i and ii and iv) oligopeptide models of the N-terminal binding site. MAJOR CONCLUSIONS: Albumin has four partially selective metal binding sites with well-defined metal preferences. It is an important regulator of the blood transport of physiological Cu(II) and Zn(II) and toxic Ni(II) and Cd(II). It is also an important target for metal-based drugs containing Pt(II), V(IV)O, and Au(I). GENERAL SIGNIFICANCE: The thorough understanding of metal binding properties of serum albumin, including the competition of various metal ions for specific binding sites is important for biomedical issues, such as new disease markers and design of metal-based drugs. This article is part of a Special Issue entitled Serum Albumin. PMID- 23811337 TI - Honokiol: a non-adipogenic PPARgamma agonist from nature. AB - BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists are clinically used to counteract hyperglycemia. However, so far experienced unwanted side effects, such as weight gain, promote the search for new PPARgamma activators. METHODS: We used a combination of in silico, in vitro, cell-based and in vivo models to identify and validate natural products as promising leads for partial novel PPARgamma agonists. RESULTS: The natural product honokiol from the traditional Chinese herbal drug Magnolia bark was in silico predicted to bind into the PPARgamma ligand binding pocket as dimer. Honokiol indeed directly bound to purified PPARgamma ligand-binding domain (LBD) and acted as partial agonist in a PPARgamma-mediated luciferase reporter assay. Honokiol was then directly compared to the clinically used full agonist pioglitazone with regard to stimulation of glucose uptake in adipocytes as well as adipogenic differentiation in 3T3-L1 pre-adipocytes and mouse embryonic fibroblasts. While honokiol stimulated basal glucose uptake to a similar extent as pioglitazone, it did not induce adipogenesis in contrast to pioglitazone. In diabetic KKAy mice oral application of honokiol prevented hyperglycemia and suppressed weight gain. CONCLUSION: We identified honokiol as a partial non-adipogenic PPARgamma agonist in vitro which prevented hyperglycemia and weight gain in vivo. GENERAL SIGNIFICANCE: This observed activity profile suggests honokiol as promising new pharmaceutical lead or dietary supplement to combat metabolic disease, and provides a molecular explanation for the use of Magnolia in traditional medicine. PMID- 23811339 TI - H19 inhibits RNA polymerase II-mediated transcription by disrupting the hnRNP U actin complex. AB - BACKGROUND: H19 was one of the earliest identified, and is the most studied, long noncoding RNAs. It is presumed that H19 is essential for regulating development and disease conditions, and it is associated with carcinogenesis for many types. However the biological function and regulatory mechanism of this conserved RNA, particularly with respect to its effect on transcription, remain largely unknown. METHODS: We performed RNA pulldown, RNA immunoprecipitation and deletion mapping to identify the proteins that are associated with H19. In addition, we employed EU (5-ethynyl uridine) incorporation, immunoprecipitation and Western blotting to investigate the functional aspects of H19. RESULTS: Our research further verifies that H19 is bound to hnRNP U, and this interaction is located within the 5' 882 nt region of H19. Moreover, H19 disrupts the interaction between hnRNP U and actin, which inhibits phosphorylation at Ser5 of the RNA polymerase II (Pol II) C terminal domain (CTD), consequently preventing RNA Pol II-mediated transcription. We also showed that hnRNP U is essential for H19-mediated transcription repression. CONCLUSIONS: In this study, we demonstrate that H19 inhibits RNA Pol II-mediated transcription by disrupting the hnRNP U-actin complex. GENERAL SIGNIFICANCE: These data suggest that H19 regulates general transcription and exerts wide-ranging effects in organisms. PMID- 23811340 TI - Ovarian cancer ascites-derived vitronectin and fibronectin: combined purification, molecular features and effects on cell response. AB - BACKGROUND: Intra-abdominal ascites is a complication of ovarian cancers and constitutes a permissive microenvironment for metastasis. Since fibronectin and vitronectin are key actors in ovarian cancer progression, we investigated their occurrence and molecular characteristics in various ascites fluids and the influence of these ascites-derived proteins on cell behavior. METHODS: Fibronectin and vitronectin were investigated by immunoblotting within various ascites fluids. A combined affinity-based protocol was developed to purify both proteins from the same sample. Each purified protein was characterized with regard to its molecular features (molecular mass of isoforms, tryptophan intramolecular environment, hydrodynamic radii), and its influence on cell adhesion. RESULTS: Fibronectin and vitronectin were found in all tested ascites. Several milligrams of purified proteins were obtained from ascites of varying initial volumes. Molecular mass isoforms and conformational lability of proteins differed according to the ascites of origin. When incorporated into the cancer cell environment, ascites-derived fibronectin and vitronectin supported cell adhesion and migration with various degrees of efficiency, and induced the recruitment of integrins into focal contacts. CONCLUSIONS: To our knowledge, this is the first combined purification of two extracellular matrix proteins from a single pathological sample containing a great variety of bioactive molecules. This study highlights that ascites-derived fibronectin and vitronectin exhibit different properties depending on the ascites. GENERAL SIGNIFICANCE: Investigating the relationships between the molecular properties of ascites components and ovarian cancer cell phenotype according to the ascites may be critical for a better understanding of the recurrence of this lethal disease and for further biomarker identification. PMID- 23811342 TI - Cell response to PEGylated poly(dopamine) coated liposomes considering shear stress. AB - BACKGROUND: Liposomes have gained immerse attention in the field of drug delivery as carriers of therapeutic molecules. Their modification with a polymer either to make them stealth (e.g. using PEG) and/or more stable (e.g. using poly(dopamine) (PDA)) is a crucial aspect to improve their performance e.g. the blood circulation time. Despite their potential, there are only a few commercialized liposome-based formulations for intravenous drug delivery. Hence, there is still considerable need to address the challenges involved in the design and characterization of liposomal therapeutics. In the latter case, it is of paramount importance to consider the dynamic in vivo environment, e.g. the interstitial fluidic pressure in tumors, blood flow, or bile flow in the liver. METHODS: The PEGylation of PDA films was characterized by quartz crystal microbalance with dissipation monitoring, and the optimized protocol was used to assemble PEGylated PDA coated liposomes (LPDA_PEG). Dynamic light scattering, a plate reader, a flow cytometer and a cytotoxicity assay were used to characterize the liposomes and quantify cellular association/uptake and cell viability in the presence and absence of shear stress after 30min and 4h. The immortalized skeletal mouse myoblast (C2C12) cell line was chosen as model cancer cells, and a hepatic cell line (HepG2) was selected due to their importance in nanosized drug carrier clearance from the system in the liver. RESULTS: The presence of hydrophilic cargo did not affect the PDA assembly process. In the absence of shear stress, there was no difference in cellular uptake/association of both PDA coated liposomes (LPDA) and LPDA_PEG for hepatocytes while myoblasts preferentially internalized/associated with LPDA. In the presence of shear stress, hepatocytes preferentially internalized/associated with LPDA after 30min, while there was only a significant difference for myoblasts after 4h. The cell viability remained unaffected in all cases. CONCLUSIONS: LPDA_PEG are a promising platform towards drug delivery. The nature of cells and fluidic flow are important factors to be considered in their characterization using cell cultures. GENERAL SIGNIFICANCE: These findings will contribute in the better understanding of polymer coated liposomes with cells. The importance of microfluidics in cell culture based characterization is demonstrated, and this will eventually affect the way advanced drug delivery vehicles are designed and characterized prior to animal experiments. PMID- 23811341 TI - Serum albumins-unusual allergens. AB - BACKGROUND: Albumins are multifunctional proteins present in the blood serum of animals. They can bind and transport a wide variety of ligands which they accommodate due to their conformational flexibility. Serum albumins are highly conserved both in amino acid sequence and three-dimensional structure. Several mammalian and avian serum albumins (SAs) are also allergens. Sensitization to one of the SAs coupled with the high degree of conservation between SAs may result in cross-reactive antibodies in allergic individuals. Sensitivity to SA generally begins with exposure to an aeroallergen, which can then lead to cross sensitization to serum albumins present in food. SCOPE OF REVIEW: This review focuses on the allergenicity of SAs presented in a structural context. MAJOR CONCLUSIONS: SA allergenicity is unusual taking into account the high sequence identity and similarity between SA from different species and human serum albumin. Cross-reactivity of human antibodies towards different SAs is one of the most important characteristics of these allergens. GENERAL SIGNIFICANCE: Establishing a relationship between sequence and structure of different SAs and their interactions with antibodies is crucial for understanding the mechanisms of cross-sensitization of atopic individuals. Structural information can also lead to better design and production of recombinant SAs to replace natural proteins in allergy testing and desensitization. Therefore, structural analyses are important for diagnostic and treatment purposes. This article is part of a Special Issue entitled Serum Albumin. PMID- 23811343 TI - A chondroitin synthase-1 (ChSy-1) missense mutation in a patient with neuropathy impairs the elongation of chondroitin sulfate chains initiated by chondroitin N acetylgalactosaminyltransferase-1. AB - BACKGROUND: Previously, we identified two missense mutations in the chondroitin N acetylgalactosaminyltransferase-1 gene in patients with neuropathy. These mutations are associated with a profound decrease in chondroitin N acetylgalactosaminyltransferase-1 enzyme activity. Here, we describe a patient with neuropathy who is heterozygous for a chondroitin synthase-1 mutation. Chondroitin synthase-1 has two glycosyltransferase activities: it acts as a GlcUA and a GalNAc transferase and is responsible for adding repeated disaccharide units to growing chondroitin sulfate chains. METHODS: Recombinant wild-type chondroitin synthase-1 enzyme and the F362S mutant were expressed. These enzymes and cells expressing them were then characterized. RESULTS: The mutant chondroitin synthase-1 protein retained approximately 50% of each glycosyltransferase activity relative to the wild-type chondroitin synthase-1 protein. Furthermore, unlike chondroitin polymerase comprised of wild-type chondroitin synthase-1 protein, the non-reducing terminal 4-O-sulfation of GalNAc residues synthesized by chondroitin N-acetylgalactosaminyltransferase-1 did not facilitate the elongation of chondroitin sulfate chains when chondroitin polymerase that consists of the mutant chondroitin synthase-1 protein was used as the enzyme source. CONCLUSIONS: The chondroitin synthase-1 F362S mutation in a patient with neuropathy resulted in a decrease in chondroitin polymerization activity and the mutant protein was defective in regulating the number of chondroitin sulfate chains via chondroitin N-acetylgalactosaminyltransferase-1. Thus, the progression of peripheral neuropathies may result from defects in these regulatory systems. GENERAL SIGNIFICANCE: The elongation of chondroitin sulfate chains may be tightly regulated by the cooperative expression of chondroitin synthase-1 and chondroitin N-acetylgalactosaminyltransferase-1 in peripheral neurons and peripheral neuropathies may result from synthesis of abnormally truncated chondroitin sulfate chains. PMID- 23811344 TI - Effect of poly(phosphate) anions on glyceraldehyde-3-phosphate dehydrogenase structure and thermal aggregation: comparison with influence of poly(sulfoanions). AB - BACKGROUND: It is well documented that poly(sulfate) and poly(sulfonate) anions suppress protein thermal aggregation much more efficiently than poly(carboxylic) anions, but as a rule, they denature protein molecules. In this work, a polymer of different nature, i.e. poly(phosphate) anion (PP) was used to elucidate the influence of phosphate groups on stability and thermal aggregation of the model enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). METHODS: Isothermal titration calorimetry and differential scanning calorimetry were used for studying the protein-polyanion interactions and the influence of bound polyanions on the protein structure. The enzymatic activity of GAPDH and size of the complexes were measured. The aggregation level was determined from the turbidity. RESULTS: Highly polymerized PP chains were able to suppress the aggregation completely, but at significantly higher concentrations as compared with poly(styrenesulfonate) (PSS) or dextran sulfate chains of the same degree of polymerization. The effect of PP on the enzyme structure and activity was much gentler as opposed to the binding of dextran sulfate or, especially, PSS that denatured GAPDH molecules with the highest efficacy caused by short PSS chains. These findings agreed well with the enhanced affinity of polysulfoanions to GAPDH. CONCLUSIONS: The revealed trends might help to illuminate the mechanism of control of proteins functionalities by insertion of charged groups of different nature through posttranslational modifications. GENERAL SIGNIFICANCE: Practical implementation of the results could be the use of PP chains as promising tools to suppress the proteins aggregation without noticeable loss in the enzymatic activity. PMID- 23811345 TI - Extensive evaluations of the cytotoxic effects of gold nanoparticles. AB - BACKGROUND: Many in vitro studies have revealed that the interference of dye molecules in traditional nanoparticle cytotoxicity assays results in controversial conclusions. The aim of this study is to establish an extensive and systematic method for evaluating biological effects of gold nanoparticles in mammalian cell lines. METHODS: We establish the cell-impedance measurement system, a label-free, real-time cell monitoring platform that measures electrical impedance, displaying results as cell index values, in a variety of mammalian cell lines. Cytotoxic effects of gold nanoparticles are also evaluated with traditional in vitro assays. RESULTS: Among the six cell lines, gold nanoparticles induce a dose-dependent suppression of cell growth with different levels of severity and the suppressive effect of gold nanoparticles was indirectly associated with their sizes and cellular uptake. Mechanistic studies revealed that the action of gold nanoparticles is mediated by apoptosis induction or cell cycle delay, depending on cell type and cellular context. Although redox signaling is often linked to the toxicity of nanoparticles, in this study, we found that gold nanoparticle-mediated reactive oxygen species generation was not sustained to notably modulate proteins involved in antioxidative defense system. CONCLUSION: The cell-impedance measurement system, a dye-free, real-time screening platform, provides a reliable analysis for monitoring gold nanoparticle cytotoxicity in a variety of mammalian cell lines. Furthermore, gold nanoparticles induce cellular signaling and several sets of gene expression to modulate cellular physical processes. GENERAL SIGNIFICANCE: The systematic approach, such as cell-impedance measurement, analyzing the toxicology of nanomaterials offers convincing evidence of the cytotoxicity of gold nanomaterials. PMID- 23811346 TI - Akt signaling and freezing survival in the wood frog, Rana sylvatica. AB - BACKGROUND: The wood frog (Rana sylvatica) exhibits well-developed natural freeze tolerance supported by multiple mechanisms of biochemical adaptation. The present study investigated the role and regulation of the Akt signaling pathway in wood frog tissues (with a focus on liver) responding to freezing stress. METHODS: Immunoblotting was used to assess total and phospho-Akt levels, total and phospho PDK1, PTEN protein level, as well as total and phospho-FOXO1 levels. RT-PCR was used to investigate transcript levels of PTEN and microRNAs. RESULTS: Akt was inhibited in skeletal muscle, kidney and heart after 24h freezing exposure with a reversal after thawing. The responses of the main kinase (PDK-1) and phosphatase (PTEN) that regulate Akt were consistent with freeze activation of Akt in liver; freezing exposure activated PDK-1 via enhanced Ser-241 phosphorylation whereas PTEN protein levels were reduced. Levels of three microRNAs (miR-26a, miR-126 and miR-217) that regulate pten expression were elevated in liver during freezing. One well-known role of Akt is in anti-apoptosis, mediated in part by Akt phosphorylation of Ser-256 on FOXO1. Freezing triggered an increase in liver phospho-FOXO1 Ser-256 content, suggesting that an important action of Akt may be apoptosis inhibition. CONCLUSIONS: Akt activation in wood frog is stress and tissue specific, with multi-facet regulations (posttranslational and posttranscriptional) involved in supporting this specific signal transduction response. GENERAL SIGNIFICANCE: This study implicates the Akt pathway in the metabolic reorganization of cellular metabolism in support of freezing survival. PMID- 23811347 TI - Complexity and conundrums. Citizens' evaluations of potentially contentious novel food technologies using a deliberative discourse approach. AB - This research considers the processes involved in the formation of attitudes by citizens on potentially contentious novel food technologies (NFTs). Observations of one-to-one deliberative discourses between food scientists and citizens, during which they discussed these technologies, form the basis of this enquiry. This approach enables an exploration of how individuals construct meaning around as well as interpret information about the technologies. Thematic analysis identifies key features that provide the frameworks for citizens' evaluations. How individuals make sense of these technologies is shaped by their beliefs, values and personal characteristics; their perceptions of power and control over the development and sale of NFT related products; and, the extent to which these products are relevant to their personal lives. Internal negotiations between these influences are evident, and evaluations are based on the relative importance of each influence to the individual. Internal conflicts and tensions are associated with citizens' evolving evaluative processes, which may in turn present as attitude ambivalence and instability. Many challenges are linked with engaging with the general public about these technologies, as levels of knowledge, understanding and interest vary. PMID- 23811348 TI - Intuitive eating is associated with interoceptive sensitivity. Effects on body mass index. AB - Intuitive eating is relevant for adaptive eating, body weight and well-being and impairments are associated with dieting and eating disorders. It is assumed to depend on the ability to recognize one's signs of hunger and fullness and to eat accordingly. This suggests a link to the individual ability to perceive and processes bodily signals (interoceptive sensitivity, IS) which has been shown to be associated with emotion processing and behavior regulation. This study was designed to clarify the relationships between IS as measured by a heartbeat perception task, intuitive eating and body mass index (BMI) in N=111 healthy young women. Intuitive eating was assessed by the Intuitive Eating Scale (IES) with three facets, reliance on internal hunger and satiety cues (RIH), eating for physical rather than emotional reasons (EPR), and unconditional permission to eat when hungry (UPE). IS was not only positively related to total IES score and RIH and EPR, and negatively predicted BMI, but also proved to fully mediate the negative relationship between RIH, as well as EPR and BMI. Additionally, the subjective appraisal of one's interoceptive signals independently predicted EPR and BMI. IS represents a promising mechanism in research on eating behavior and body weight. PMID- 23811349 TI - A bitter sweet asynchrony. The relation between eating attitudes, dietary restraint on smell and taste function. AB - Research has demonstrated that individuals with eating disorders have an impaired sense of smell and taste, though the influence of eating attitudes, dietary restraint and gender in a non-clinical sample is unknown. In two studies (study 1: 32 females, 28 males; study 2: 29 females) participants completed questionnaires relating to Eating Attitudes (EAT) and dietary restraint (DEBQ) followed by an odour (study 1: isoamyl acetate, study 2: chocolate) threshold and taste test. In study 2 we also measured the number of fungiform papillae taste buds. Study one revealed that increases in pathological eating attitudes predicted poorer olfactory sensitivity (males/females) and lower bitterness ratings for the bitter tastant (females only), suggestive of poorer taste acuity. In study two we found that both eating attitudes and restraint predicted poorer sensitivity to an odour associated to a forbidden food (chocolate) and that increasing eating attitudes predicted higher sweetness ratings for the bitter tastant. Interestingly increases in restraint were associated with an increased number of fungiform papillae which was not related to bitter or sweet intensity. These findings demonstrate that in a young healthy sample that subtle differences in eating pathology and dietary restraint predict impaired olfactory function to food related odours. Further that perception of bitter tastants is poorer with changes in eating pathology but not dietary restraint. PMID- 23811350 TI - Innate and adaptive immune responses of Arctic charr (Salvelinus alpinus, L.) during infection with Aeromonas salmonicida subsp. achromogenes and the effect of the AsaP1 toxin. AB - Aeromonas salmonicida subsp. achromogenes, the causative agent of atypical furunculosis in many fish species, secretes the toxic metalloendopeptidase AsaP1. This study aimed to analyze innate and adaptive immune parameters induced in Arctic charr (Salvelinus alpinus, L.) infected with wild type (wt) A. salmonicida subsp. achromogenes and its isogenic asaP1 deletion mutant (AsaP1-deficient). Head-kidney, liver and spleen were obtained from i.p. infected charr (wt, AsaP1 deficient), during a time schedule of 7 d post infection. Reverse transcription quantitative real-time PCR (RT-qPCR) was applied to study the expression of immune parameters: pro-inflammatory cytokines IL-1beta and TNF-alpha; anti inflammatory cytokine IL-10; chemokines CXCL-8 (IL-8) and CC-chemokine; the cytokines IFN-gamma and IL-4/13A as tracers for Th1 and Th2 immune responses, respectively; and the cell markers CD8alpha and CD83. In addition, lymphoid organs were histopathologically examined at days 3 and 7 post infection, including B (IgM) and T (CD3epsilon) cell staining. The detected immune responses were initially driven by innate mechanisms represented by the up-regulation of pro-inflammatory cytokines and chemokines and later on by adaptive Th2 related responses cumulating in B-cell recruitment as shown by regulation of immune parameters in spleen and head-kidney, with significant differences between mutant and wt infected fish. Histological sections revealed IgM-positive cells around ellipsoid arterioles in spleen, while CD3epsilon positive cells were found in clusters scattered all over the section. However, histopathological differences were only detected between infected and non-infected fish, but not between AsaP1 deficient mutant and wt infected fish. This work represents the first study on innate and adaptive immune responses of Arctic charr induced by a bacterial infection. PMID- 23811351 TI - The major fimbrial subunit protein of Edwardsiella tarda: vaccine potential, adjuvant effect, and involvement in host infection. AB - Edwardsiella tarda is a Gram-negative bacterium that is reckoned one of the most severe fish pathogens. In this study, we analyzed the biological properties of the E. tarda major fimbrial subunit protein, FimA. We found that mutation of fimA resulted in defective biofilm growth, attenuated infectivity against host cells, and impaired ability to disseminate into and colonize host tissues following experimental infection. When used as a subunit vaccine, recombinant FimA (rFimA) elicited a high level of protection in turbot (Scophthalmus maximus) against lethal E. tarda challenge. Immunological analysis showed that rFimA vaccination induced production of specific serum antibodies that bound to live E. tarda via interaction with the FimA on bacterial cells, and that antibody-E. tarda interaction blocked bacterial infection. Furthermore, passive immunization of turbot with anti-rFimA serum before E. tarda infection reduced bacterial loads in fish tissues to significant extents. To examine the adjuvant potential of FimA, turbot were vaccinated with rVhhP2, a protective Vibrio harveyi antigen, in the presence or absence of rFimA. Subsequent analysis showed that the presence of rFimA significantly augmented the protectivity of rVhhP2. ELISA and quantitative real time RT-PCR showed that rFimA significantly increased rVhhP2-specific serum antibody production and enhanced the expression of immune relevant genes. Taken together, these results indicate that FimA is a virulence-associated protein that possesses vaccine as well as adjuvant potentials, and that the immunoprotectivity of FimA is most likely due to its ability to induce specific immune response that inhibits E. tarda infection. PMID- 23811352 TI - Dietary effect of Rubus coreanus ethanolic extract on immune gene expression in white leg shrimp, Penaeus vannamei. AB - The objective of this study was to evaluate the effect of dietary supplementation of a Rubus coreanus ethanolic extract on immunostimulatory response in white leg shrimp Penaeus vannamei. Shrimps with an average initial weight of 0.5 +/- 0.04 g were collected and acclimatized for 10 days. Four experimental diets including a control diet, a probiotic diet and 0.25 and 0.5% of R. coreanus ethanolic extract (RcEE) diets were used to feed the shrimps. After 8 weeks of culture, shrimp fed with probiotic and 0.25% RcEE diet had showed significant enhancement in the growth while shrimp fed with 0.5% RcEE diet showed significantly increased expression of immune genes and antioxidant enzymes activities. One week of challenge experiments for all the four diets fed shrimps showed decreased cumulative mortality in the 0.5% RcEE diets fed shrimps, when compared with the probiotic and 0.25% RcEE diet fed shrimp groups. The results indicates that R. coreanus ethanolic extract could be used as a herbal immunostimulant for shrimps to increase its immunity and disease resistance against the bacterial pathogen, Vibrio alginolyticus. PMID- 23811353 TI - Molecular and functional characterizations of a Kunitz-type serine protease inhibitor FcKuSPI of the shrimp Fenneropenaeus chinensis. AB - Serine proteinase inhibitors play important and diverse roles in biological processes such as coagulation, defense mechanisms, and immune responses. Here, we identified and characterized a Kunitz-type proteinase inhibitor, designated FcKuSPI, of the BPTI/Kunitz family of serine proteinase inhibitors from the hemocyte cDNA library of the shrimp Fenneropenaeus chinensis. The deduced amino acid sequence of FcKuSPI comprises 80 residues with a putative signal peptide of 15 amino acids. The predicted molecular weight of the mature peptide is 7.66 kDa and its predicted isoelectric point is 8.84. FcKuSPI includes a Kunitz domain containing six conserved cysteine residues that are predicted to form three disulfide bonds. FcKuSPI shares 44-53% homology with BPTI/Kunitz family members from other species. FcKuSPI mRNA was expressed highly in the hemocytes and moderately in muscle in healthy shrimp. Recombinant FcKuSPI protein demonstrated anti-protease activity against trypsin and anticoagulant activity against citrated human plasma in a dose-dependent manner in in vitro assays. PMID- 23811354 TI - Valproic acid-induced gene expression responses in rat whole embryo culture and comparison across in vitro developmental and non-developmental models. AB - Transcriptomic evaluations may improve toxicity prediction of in vitro-based developmental models. In this study, transcriptomics was used to identify VPA induced gene expression changes in rat whole embryo culture (WEC). Furthermore, VPA-induced responses were compared across in vitro-based developmental models, such as the cardiac and neural embryonic stem cells (ESTc and ESTn, respectively) and the zebrafish embryotoxicity model. VPA-induced gene regulation in WEC corresponded with observed morphological effects and previously suggested mechanisms of toxicity. Gene Ontology term-directed analysis showed conservation of VPA-induced gene expression changes across in vitro-based developmental models, with ESTc and ESTn exhibiting complementary responses. Furthermore, comparison of in vitro-based developmental and non-developmental models revealed that more generalized VPA-induced effects can be detected using non-developmental models whereas developmental models provide added value when assessing developmental-specific effects. These analyses can be used to optimize test batteries for the detection of developmental toxicants in vitro. PMID- 23811355 TI - Could genetic polymorphisms related to oxidative stress modulate effects of heavy metals for risk of human preterm birth? AB - Human preterm birth (PTB) is a complex medical outcome influenced by a combination of genetic and environmental factors. Research on the causative factors of PTB has mostly focused on demographic, socio-behavioral and environmental risk factors. Recent studies turn the spotlight on the effects of heavy metals exposure on adverse pregnancy outcomes. Here we present and evaluate the hypothesis that heavy metals may cause PTB through oxidative stress, and that this effect may be modified by polymorphisms in genes related to oxidative stress. Indeed, accumulating data suggest that the risk of PTB is correlated with polymorphisms in genes involved in detoxification, oxidative stress and lipid metabolism. These and other polymorphisms have independently been associated with susceptibility to the adverse effects of heavy metals. PMID- 23811356 TI - The sensitivity of single air parcel trajectory calculations to starting elevation. AB - Trajectory models are frequently used to characterize the atmospheric transport pathways for airborne gases and aerosols. Users of these models must specify a starting elevation for their calculations. The variation of wind with altitude causes trajectory models to be sensitive to the starting elevation, particularly when single trajectories rather than Lagrangian particle dispersion simulations are used to characterize atmospheric transport. In this work we systematically investigate and quantify the sensitivity of single trajectory calculations to the starting elevation. The analysis was based on an eight-year database of daily, 48 h back-trajectories calculated for ten sites. Trajectories were calculated at four different starting elevations, and the horizontal difference between endpoints was determined for five upwind travel times. Trajectory model calculations were found to be strongly sensitive to starting elevation. A 500 m difference in starting elevation leads to an average horizontal separation of 326 km after 48 h. Mean horizontal separations of 627 km and 886 km were found for starting elevation differences of 1000 m and 1500 m, respectively. A seasonal dependence of the sensitivity was found, with the smallest separations occurring during the summer, the largest during winter, and intermediate values during the fall and spring. A linear relationship was observed between trajectory model sensitivity and difference in starting elevation. Empirical equations were presented to approximate this relationship. PMID- 23811357 TI - Disposal of pesticide waste from agricultural production in the Al-Batinah region of Northern Oman. AB - During the last two decades Oman has experienced rapid economic development but this has been accompanied by environmental problems. Manufacturing and agricultural output have increased substantially but initially this was not balanced with sufficient environmental management. Although agriculture in Oman is not usually considered a major component of the economy, government policy has been directed towards diversification of national income and as a result there has been an increasing emphasis on revenue from agriculture and an enhancement of production via the use of irrigation, machinery and inputs such as pesticides. In recent years this has been tempered with a range of interventions to encourage more sustainable production. Certain pesticides have been prohibited; there has been a promotion of organic agriculture and an emphasis on education and awareness programs for farmers. The last point is of especial relevance given the nature of the farm labour market in Oman and a reliance on expatriate and often untrained labour. The research, through a detailed stratified survey, explores the state of knowledge at farm-level regarding the safe disposal of pesticide waste and what factors could enhance or indeed operate against the spread and implementation of that knowledge. Members of the recently constituted Farmers Association expressed greater environmental awareness than their non-member counterparts in that they identified a more diverse range of potential risks associated with pesticide use and disposed of pesticide waste more in accordance with government policy, albeit government policy with gaps. Workers on farms belonging to Association members were also more likely to adhere to government policy in terms of waste disposal. The Farmers Association appears to be an effective conduit for the diffusion of knowledge about pesticide legislation and general awareness, apparently usurping the state agricultural extension service. PMID- 23811358 TI - Distribution of polychlorinated biphenyls in an urban riparian zone affected by wastewater treatment plant effluent and the transfer to terrestrial compartment by invertebrates. AB - In this study, we investigated the distribution of polychlorinated biphenyls (PCBs) in a riparian zone affected by the effluent from a wastewater treatment plant (WWTP). River water, sediment, aquatic invertebrates and samples from the surrounding terrestrial compartment such as soil, reed plants and several land based invertebrates were collected. A relatively narrow range of delta(13)C values was found among most invertebrates (except butterflies, grasshoppers), indicating a similar energy source. The highest concentration of total PCBs was observed in zooplankton (151.1 ng/g lipid weight), and soil dwelling invertebrates showed higher concentrations than phytophagous insects at the riparian zone. The endobenthic oligochaete Tubifex tubifex (54.28 ng/g lw) might be a useful bioindicator of WWTP derived PCBs contamination. High bioaccumulation factors (BAFs) were observed in collected aquatic invertebrates, although the biota-sediment/soil accumulation factors (BSAF) remained relatively low. Emerging aquatic insects such as chironomids could carry waterborne PCBs to the terrestrial compartment via their lifecycles. The estimated annual flux of PCBs for chironomids ranged from 0.66 to 265 ng?m(-2)?y(-1). Although a high prevalence of PCB-11 and PCB-28 was found for most aquatic based samples in this riparian zone, the mid-chlorinated congeners (e.g. PCB-153 and PCB-138) became predominant among chironomids and dragonflies as well as soil dwelling invertebrates, which might suggest a selective biodriven transfer of different PCB congeners. PMID- 23811359 TI - Adrenergic regulation of cardiac ionic channels: role of membrane microdomains in the regulation of kv4 channels. AB - The heart must constantly adapt its activity to the needs of the body. In any potentially dangerous or physically demanding situation the activated sympathetic nervous system leads a very fast cardiac response. Under these circumstances, alpha1-adrenergic receptors activate intracellular signaling pathways that finally phosphorylate the caveolae-located subpopulation of Kv4 channels and reduce the transient outward K(+) current (Ito) amplitude. This reduction changes the shape of the cardiac action potential and makes the plateau phase to start at higher voltages. This means that there are more calcium ions entering the myocyte and the result is an increase in the strength of the contraction. However, an excessive reduction of Ito could dangerously prolong action potential duration and this could cause arrhythmias when the heart rate is high. This excessive current reduction does not occur because there is a second population of Ito channels located in non-caveolar membrane rafts that are not accessible for alpha1-AR mediated regulation. Thus, the location of the components of a given transduction signaling pathway in membrane domains determines the correct and safe behavior of the heart. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. Guest Editor: Jean Claude Herve. PMID- 23811360 TI - Identification and characterization of the channel-forming protein in the cell wall of Corynebacterium amycolatum. AB - The mycolic-acid layer of certain gram-positive bacteria, the mycolata, represents an additional permeability barrier for the permeation of small water soluble solutes. Consequently, it was shown in recent years that the mycolic acid layer of individual bacteria of the group mycolata contains pores, called porins, for the passage of hydrophilic solutes. Corynebacterium amycolatum, a pathogenic Corynebacterium species, belongs to the Corynebacteriaceae family but it lacks corynomycolic acids in its cell wall. Despite the absence of corynomycolic acids the cell wall of C. amycolatum contains a cation-selective cell wall channel, which may be responsible for the limited permeability of the cell wall of C. amycolatum. Based on partial sequencing of the protein responsible for channel formation derived from C. amycolatum ATCC 49368 we were able to identify the gene coram0001_1986 within the known genome sequence of C. amycolatum SK46 that codes for the cell wall channel. The corresponding gene of C. amycolatum ATCC 49368 was cloned into the plasmid pXHis for its expression in Corynebacterium glutamicum ?porA?porH. Biophysical characterization of the purified protein (PorAcoram) suggested that coram0001_1986 is indeed the gene coding for the pore-forming protein PorAcoram in C. amycolatum ATCC 49368. The protein belongs to the DUF (Domains of Unknown Function) 3068 superfamily of proteins, mainly found in bacteria from the family Corynebacteriaceae. The nearest relative to PorAcoram within this family is an ORF which codes for PorAcres, which was also recognized in reconstitution experiments as a channel-forming protein in Corynebacterium resistens. PMID- 23811362 TI - ESR spin trapping for characterization of radical formation in Lactobacillus acidophilus NCFM and Listeria innocua. AB - In this study, radicals in pure cultures of Lactobacillus acidophilus NCFM and Listeria innocua were detected in a quantitative way by electron spin resonance spectroscopy using spin trapping with 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) or N-tert-butyl-alpha-phenylnitrone (PBN). No adverse effect of spin trap addition on viability was observed for any of the bacterial strains. L. acidophilus NCFM had a higher production of radicals than L. innocua when incubated in a growth medium. Furthermore, by using DMPO in a buffer system, the radicals produced by L. acidophilus NCFM could be identified as hydroxyl radicals. The presence of polyethylene glycol, impermeable for bacterial cells, decreased the signal intensity of the ESR spectrum of the DMPO-OH adduct in cultures of L. acidophilus NCFM and indicated quenching of hydroxyl radicals outside the bacteria. This suggests that radical production is an extracellular event for L. acidophilus NCFM. PMID- 23811361 TI - Structural adaptations of proteins to different biological membranes. AB - To gain insight into adaptations of proteins to their membranes, intrinsic hydrophobic thicknesses, distributions of different chemical groups and profiles of hydrogen-bonding capacities (alpha and beta) and the dipolarity/polarizability parameter (pi*) were calculated for lipid-facing surfaces of 460 integral alpha helical, beta-barrel and peripheral proteins from eight types of biomembranes. For comparison, polarity profiles were also calculated for ten artificial lipid bilayers that have been previously studied by neutron and X-ray scattering. Estimated hydrophobic thicknesses are 30-31A for proteins from endoplasmic reticulum, thylakoid, and various bacterial plasma membranes, but differ for proteins from outer bacterial, inner mitochondrial and eukaryotic plasma membranes (23.9, 28.6 and 33.5A, respectively). Protein and lipid polarity parameters abruptly change in the lipid carbonyl zone that matches the calculated hydrophobic boundaries. Maxima of positively charged protein groups correspond to the location of lipid phosphates at 20-22A distances from the membrane center. Locations of Tyr atoms coincide with hydrophobic boundaries, while distributions maxima of Trp rings are shifted by 3-4A toward the membrane center. Distributions of Trp atoms indicate the presence of two 5-8A-wide midpolar regions with intermediate pi* values within the hydrocarbon core, whose size and symmetry depend on the lipid composition of membrane leaflets. Midpolar regions are especially asymmetric in outer bacterial membranes and cell membranes of mesophilic but not hyperthermophilic archaebacteria, indicating the larger width of the central nonpolar region in the later case. In artificial lipid bilayers, midpolar regions are observed up to the level of acyl chain double bonds. PMID- 23811363 TI - Sorption properties of a new thermosensitive copolymeric sorbent bearing phosphonic acid moieties in multi-component solution of cationic species. AB - In this paper, original thermosensitive copolymers bearing phosphonic acid groups, namely the poly(N-n-propylacrylamide-stat-2 (methacryloyloxy)methylphosphonic acid) (P(NnPAAm-stat-hMAPC1)) were synthesized, and their sorption properties for three divalent cations (Ni(2+), Ca(2+), Cd(2+)) and one trivalent cation (Al(3+)) have been investigated. The sorption experiments were performed with increasing relative amount of cationic pollution compared to the amount of sorption sites (C(n+)/P ratio) in mono and multi component solutions to investigate the sorption mechanisms. C(n+)/P proved to strongly affect the sorption capacity and high capacities were obtained for all cations at highest C(n+)/P ratios, reaching one mole of C(sorbed)(n+) per phosphonated moiety. For divalent cations, sorption mechanisms were likely to be described by electrostatic interactions only, whereas for aluminum trivalent cation the sorption not only resulted from electrostatic interactions but also from the formation of coordination binding. The selectivity of the phosphonic acid moieties for aluminum cations was demonstrated, highlighting the interest of P(NnPAAm-stat-(h)MAPC1) for their use for the treatment of metallic pollution from wastewater. PMID- 23811364 TI - Photocatalytic generation of multiple ROS types using low-temperature crystallized anodic TiO2 nanotube arrays. AB - This study investigates the photocatalytic efficiency, type of reactive oxygen species (ROS) produced, and potential for structural and morphological modification of anodic TiO2 nanotubes (NTs) synthesized using a novel, energy efficient, low temperature crystallization process. These TiO2 NTs show greater photocatalytic efficiency than traditional high-temperature sintered NTs or supported Degussa P25 TiO2, as measured by degradation of methyl orange, a model organic dye pollutant. EPR analysis shows that low-temperature crystallized TiO2 NTs generate both hydroxyl radicals and singlet oxygen, while high-temperature sintered TiO2 NTs generate primarily hydroxyl radicals but no singlet oxygen. This "cocktail" of reactive oxygen species, combined with an increased surface area, contributes to the increased efficiency of this photocatalytic material. Furthermore, variation of the NT crystallization parameters enables control of structural and morphological properties so that TiO2-NTs can be optimized for scale-up and for specific treatment scenarios. PMID- 23811365 TI - Biological anoxic treatment of O2-free VOC emissions from the petrochemical industry: a proof of concept study. AB - An innovative biofiltration technology based on anoxic biodegradation was proposed in this work for the treatment of inert VOC-laden emissions from the petrochemical industry. Anoxic biofiltration does not require conventional O2 supply to mineralize VOCs, which increases process safety and allows for the reuse of the residual gas for inertization purposes in plant. The potential of this technology was evaluated in a biotrickling filter using toluene as a model VOC at loads of 3, 5, 12 and 34 g m(-3)h(-1) (corresponding to empty bed residence times of 16, 8, 4 and 1.3 min) with a maximum elimination capacity of ~3 g m(-3)h(-1). However, significant differences in the nature and number of metabolites accumulated at each toluene load tested were observed, o- and p cresol being detected only at 34 g m(-3)h(-1), while benzyl alcohol, benzaldehyde and phenol were detected at lower loads. A complete toluene removal was maintained after increasing the inlet toluene concentration from 0.5 to 1 g m(-3) (which entailed a loading rate increase from 3 to 6 g m(-3)h(-1)), indicating that the system was limited by mass transfer rather than by biological activity. A high bacterial diversity was observed, the predominant phyla being Actinobacteria and Proteobacteria. PMID- 23811366 TI - Desorption of arsenic from exhaust activated carbons used for water purification. AB - This work aims to the analysis of arsenic desorption from an exhaust activated carbon used for the purification of a natural water. This last was used to mimic the properties of common groundwater or drinking water. Different low-cost and harmless eluting solutions were considered, including distilled water, natural water, saline (NaCl, CaCl2 and NaNO3) and basic (NaOH) solutions. Experimental results showed that, for 1g of activated carbon with arsenic loading close to the maximum value available for the model natural water (omega ~ 0.1 mg/g), it is possible to recover more than 80% of the arsenic using 20 ml of 0.1 M sodium chloride solution. A temperature variation within 20 and 40 degrees C has scarce effect on desorption efficiency. A comparison between desorption data and adsorption isotherms data suggests that arsenic adsorption is actually a reversible process. Therefore, it is virtually possible to increase arsenic recovery efficiency close to 100% by increasing the NaCl concentration or the volume of the desorption solution, but a preliminary cost benefit analysis lead to consider a NaCl 0.1M solution as an optimal solution for practical applications. PMID- 23811367 TI - Atrazine dissipation and its impact on the microbial communities and community level physiological profiles in a microcosm simulating the biomixture of on-farm biopurification system. AB - The effects of repeated atrazine application (40 mg a.i.kg(-1)) on its degradation, microbial communities and enzyme activities were studied in a peat based biomixture composed by straw, soil and peat in the volumetric proportions of 2:1:1 that can be used in on-farm biopurification system. Atrazine removal efficiency was high (96%, 78% and 96%) after each atrazine application and did not show a lag phase. Microbial enzyme activities were reduced significantly with atrazine application but rapidly recovered. Microbial diversity obtained by BiologEcoplate was similar after the first and second atrazine application. However, an inhibitory effect was observed after the third application. After each atrazine application, culturable fungi were reduced, but rapidly recovered without significant changes in culturable bacteria and actinomycetes compared to the control. Denaturing gradient gel electrophoresis (DGGE) patterns demonstrated that microbial community structure remained relatively stable in time when compared to the controls. In conclusion, our results demonstrated that after successive ATZ applications, the peat based biomixture had a good degradation capacity. Moreover, microbiological assays demonstrated the robustness of the peat based biomixture from a microbiological point of view to support pesticide degradation. PMID- 23811368 TI - Column and batch tests of sulfonamide leaching from different types of soil. AB - Sulfonamides (SAs) and their metabolites present severe hazards to human health and the environment, mainly because of antibiotic resistance. Knowledge of their bioavailability, including their sorption to soils and their impact on the soil groundwater pathway, is crucial to their risk assessment. Laboratory batch and column leaching tests are important tools for determining the release potential of contaminants from soil or waste materials. Batch and column tests were carried out with soils differing in particle size distribution, organic matter content and pH, each spiked with sulfonamides (sulfadimethoxine (SDM), sulfaguanidine (SGD), sulfisoxazole (SX)). In order to test the applicability of leaching tests to polar contaminants batch and column tests were also compared. In the column tests, release was found to depend on the properties of both soil and sulfonamides. The fastest release was observed for coarse-grained soil with the smallest organic matter content (MS soil; 100% decrease in concentration until liquid-to-solid ratio (L/S) of 0.9 L kg(-1) for all SAs). The slowest release was established for sulfadimethoxine (24.5% decrease in concentration until L/S 1.22 L kg(-1)). The results of the batch and column tests were comparable to a large extent, with slightly higher concentrations being obtained in the column test experiments of fine-grained soils with a high organic matter content. PMID- 23811369 TI - Preparation of graphitic carbon nitride (g-C3N4)/WO3 composites and enhanced visible-light-driven photodegradation of acetaldehyde gas. AB - Novel visible-light-driven graphitic carbon nitride (g-C3N4)/WO3 composite photocatalysts were prepared, and the acetaldehyde (CH3CHO) degradation activity of these composites was evaluated. The prepared g-C3N4/WO3 composites were characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), ultraviolet-visible diffuse reflection spectroscopy (UV-vis), and the N2 gas adsorption Brunauer-Emmett-Teller (BET) method (N3-BET). The WO3 particles, which were 100-300 nm in size, were in direct contact with the g-C3N4 sheet surface. The optical band gap and specific surface area of the g-C3N4/WO3 composites were in the range of 2.65-2.75 eV and 4-7 m(2)/g, respectively. The g C3N4/WO3 composites exhibited higher activity for the photodegradation of CH3CHO under visible light irradiation compared to g-C3N4. The optimal WO3 content for the CH3CHO photodegradation activity of the heterojunction structures was determined. The synergistic effect of g-C3N4 and WO3 was considered to lead to improved photogenerated carrier separation. A possible degradation mechanism of CH3CHO over the g-C3N4/WO3 composite photocatalyst under visible light irradiation was proposed. These results should usefully expand applications of g C3N4 as a visible-light-driven photocatalyst. PMID- 23811370 TI - Source apportionment of perfluorinated compounds (PFCs) in sediments: using three multivariate factor analysis receptor models. AB - Understanding the levels, distribution and sources of perfluorinated compounds (PFCs) in sediments is of great significance for the management of aquatic environments. In this work, 26 sediment samples were collected from Dianchi Lake in China and ten PFCs compounds were measured. The concentrations of the total PFCs (?PFCs) in the sediments ranged from 0.21 to 2.45 ng g(-1)dw (dry weight), with an average value of 0.95 ng g(-1)dw. PFOS was the most abundant compound among the ten PFCs with the average concentration of 0.33 ng g(-1)dw, followed by PFOA at 0.21 ng g(-1)dw. A two-dimensional HCA (hierarchical cluster analysis) heat map was depicted to analyze the spatial variation of individual PFCs compound and the possible origins in the sediments. Two groups were clustered by HCA, showing the possible source categories (PFOS-cluster and PFOA-cluster). Additionally, PCA-MLR, PMF and Unmix models were employed to quantitatively calculate the contribution of extracted sources. Three models concluded consistent results that PFOS-factor and PFOA-factor were the two main source categories for PFCs in the sediments. The contribution percentages were 43% (PCA MLR), 48% (PMF) and 46% (Unmix) from the former source, and were 54% (PCA-MLR), 43% (PMF) and 44% (Unmix) from the latter source, respectively. The findings and the approaches used in this work can provide useful information for further study of source apportionment for PFCs in sediments and other environmental compartments. PMID- 23811371 TI - Cu2+ sequestration by amine-functionalized silica nanotubes. AB - A novel method for Cu(2+) sequestration in Cu(2+) aqueous solution has been demonstrated using amine-functionalized double-walled silica nanotubes (DWSNTs). Herein, the precipitation method and the adsorption method are combined to remove Cu(2+) in the Cu(2+) aqueous solution. Primary (1 degrees ), secondary (2 degrees ), tertiary (3 degrees ), di-, tri-amines are immobilized on the surface of DWSNT as the adsorption site. The results show that the Cu(2+) adsorption amount on the amine-functionalized DWSNTs is in the following order: tri-amine>di-amine>1 degrees amine>2 degrees amine>3 degrees amine. The complexed Cu(2+)s with the amine-functionalized DWSNTs become Cu(OH)2 crystals due to the reaction with OH( )s dissociated from water. Thus, the amine-functionalized DWSNTs show the superior sequestration capacity of Cu(2+) in the Cu(2+) aqueous solution owing to the Cu(OH)2 crystals growth on them. FT-IR, FEG-SEM, HR-TEM, and XRD studies demonstrate the mechanism of the Cu(2+) adsorption and the Cu(OH)2 crystals growth. The crystallization-technique of the heavy metal ion on the amine functionalized DWSNTs is also expected to have potential applications such as the facile synthesis of nano- and microparticles, and the metal catalyst supporter. PMID- 23811372 TI - Enhanced arsenic removal from water by hierarchically porous CeO2-ZrO2 nanospheres: role of surface- and structure-dependent properties. AB - Arsenic contaminated natural water is commonly used as drinking water source in some districts of Asia. To meet the increasingly strict drinking water standards, exploration of efficient arsenic removal methods is highly desired. In this study, hierarchically porous CeO2-ZrO2 nanospheres were synthesized, and their suitability as arsenic sorbents was examined. The CeO2-ZrO2 hollow nanospheres showed an adsorption capacity of 27.1 and 9.2 mg g(-1) for As(V) and As(III), respectively, at an equilibrium arsenic concentration of 0.01 mg L(-1) (the standard for drinking water) under neutral conditions, indicating a high arsenic removal performance of the adsorbent at low arsenic concentrations. Such a great arsenic adsorption capacity was attributed to the high surface hydroxyl density and presence of hierarchically porous network in the hollow nanospheres. The analysis of Fourier transformed infrared spectra and X-ray photoelectron spectroscopy demonstrated that the adsorption of arsenic on the CeO2-ZrO2 nanospheres was completed through the formation of a surface complex by substituting hydroxyl with arsenic species. In addition, the CeO2-ZrO2 nanospheres were able to remove over 97% arsenic in real underground water with initial arsenic concentration of 0.376 mg L(-1) to meet the guideline limit of arsenic in drinking water regulated by the World Health Organization without any pre-treatment and/or pH adjustment. PMID- 23811373 TI - A novel electrochemical sensor for the analysis of beta-agonists: the poly(acid chrome blue K)/graphene oxide-nafion/glassy carbon electrode. AB - A novel modified electrode was constructed by the electro-polymerization of 4,5 dihydroxy-3-[(2-hydroxy-5-sulfophenyl)azo]-2,7-naphthalenedisulfonic acid trisodium salt (acid chrome blue K (ACBK)) at a graphene oxide (GO)-nafion modified glassy carbon electrode (GCE). The characterization of an electrochemically synthesized poly-ACBK/GO-nafion film was investigated by electrochemical impedance spectroscopy (EIS), cyclic voltammetry (CV), atomic force microscopy (AFM) and scanning electron microscopy (SEM) techniques, and the results were interpreted and compared at each stage of the electrode construction. Electrochemical oxidation of eight beta-agonists - clenbuterol, salbutamol, terbutaline, ractopamine, dopamine, dobutamine, adrenaline, and isoprenaline, was investigated by CV at the different electrodes. At the poly ACBK/GO-nafion/GCE, the linear sweep voltammetry peak currents of the eight beta agonists increased linearly with their concentrations in the range of 1.0-36.0 ng mL(-1), respectively, and their corresponding limits of detection (LODs) were within the 0.58-1.46 ng mL(-1) range. This electrode showed satisfactory reproducibility and stability, and was used successfully for the quantitative analysis of clenbuterol in pork samples. PMID- 23811374 TI - Efficient photocatalytic decolorization of some textile dyes using Fe ions doped polyaniline film on ITO coated glass substrate. AB - In this study, the photocatalytic decolorization of four commercial textile dyes with different structures has been investigated using electrochemically synthesized polyaniline and Fe ions doped polyaniline on ITO coated glass substrate as photocatalyst in aqueous solution under UV irradiation for the first time. Scanning electron microscopy, atomic force microscopy, FT-IR spectra, UV vis spectroscopy measurements were used to characterize the electrochemically synthesized polymer film photocatalyst. Film hydrophilicity was assessed from contact angle measurements. The results show that both of the polymer films exhibit good photocatalytic performance. Surprisingly, it was determined that by using Fe(II) ions during polymerization, it is possible to modify the surface roughness and wettability of the produced polyaniline films which favors their photocatalytic activity in water-based solutions. All four of the used dyes (methylene blue, malachite green, methyl orange and methyl red) were completely decolorizated in 90 min of irradiation under UV light by using Fe ions doped polyaniline at the dye concentration of 1.5 * 10(-5)M, while the decolorization of those dyes were between 43% and 83% by using polyaniline as photocatalyst. Hence, it may be a viable technique for the safe disposal of textile wastewater into waste streams. PMID- 23811375 TI - Determination of estrogenic potential in waste water without sample extraction. AB - This study describes the modification of the ER-Calux assay for testing water samples without sample extraction (NE-(ER-Calux) assay). The results are compared to those obtained with ER-Calux assay and a theoretical estrogenic potential obtained by GC-MSD. For spiked tap and waste water samples there was no statistical difference between estrogenic potentials obtained by the three methods. Application of NE-(ER-Calux) to "real" influent and effluents from municipal waste water treatment plants and receiving surface waters found that the NE-(ER-Calux) assay gave higher values compared to ER-Calux assay and GC-MSD. This is explained by the presence of water soluble endocrine agonists that are usually removed during extraction. Intraday dynamics of the estrogenic potential of a WWTP influent and effluent revealed an increase in the estrogenic potential of the influent from 12.9 ng(EEQ)/L in the morning to a peak value of 40.0 ng(EEQ)/L in the afternoon. The estrogenic potential of the effluent was 10%. RESULTS: In total 72 volume loading steps were analysed, of which 41 showed a positive volume response. Receiver operating characteristic (ROC) curve analysis revealed an area under the curve (AUC) of 0.70 for PPV, 0.72 for SVV and 0.77 for RSVT. Areas under the curves of all variables did not differ significantly from each other (P>0.05). Suggested cut-off values were 9.9% for SVV, 10.1% for PPV, and 19.7 degrees for RSVT as calculated by the Youden Index. CONCLUSION: In predicting fluid responsiveness the new automated RSVT appears to be as accurate as established dynamic indicators of preload PPV and SVV in patients after major surgery. The automated RSVT is clinically easy to use and may be useful in guiding fluid therapy in ventilated patients. PMID- 23811426 TI - Regional anaesthesia to prevent chronic pain after surgery: a Cochrane systematic review and meta-analysis. AB - BACKGROUND: Regional anaesthesia may reduce the risk of persistent (chronic) pain after surgery, a frequent and debilitating condition. We compared regional anaesthesia vs conventional analgesia for the prevention of persistent postoperative pain (PPP). METHODS: We searched the Cochrane Central Register of Controlled Trials, PubMed, EMBASE, and CINAHL from their inception to May 2012, limiting the results to randomized, controlled, clinical trials (RCTs), supplemented by a hand search in conference proceedings. We included RCTs comparing regional vs conventional analgesia with a pain outcome at 6 or 12 months. The two authors independently assessed methodological quality and extracted data. We report odds ratios (ORs) with 95% confidence intervals (CIs) as our summary statistic based on random-effects models. We grouped studies according to surgical interventions. RESULTS: We identified 23 RCTs. We pooled data from 250 participants in three trials after thoracotomy with outcomes at 6 months. Data favoured epidural anaesthesia for the prevention of PPP with an OR of 0.33 (95% CI 0.20-0.56). We pooled two studies investigating paravertebral block for breast cancer surgery; pooled data of 89 participants with outcomes ~ 6 months favoured paravertebral block with an OR of 0.37 (95% CI 0.14-0.94). Adverse effects were reported sparsely. CONCLUSIONS: Epidural anaesthesia and paravertebral block, respectively, may prevent PPP after thoracotomy and breast cancer surgery in about one out of every four to five patients treated. Small numbers, performance bias, attrition, and incomplete outcome data especially at 12 months weaken our conclusions. PMID- 23811427 TI - Translocation dynamics of tRNA-mRNA in the ribosome. AB - Translocation of tRNA-mRNA complex in the ribosome is an essential step in the elongation cycle of protein synthesis. However, some important issues concerning the molecular mechanism of the tRNA-mRNA translocation catalyzed by EF-G.GTP or by EF-G.GDPNP remain controversial. For example, can EF-G.GTP selectively bind to the hybrid pretranslocation state or bind to both the non-rotated pretranslocation and the hybrid pretranslocation states? Does the greater potency of EF-G in the presence of GTP rather than GDPNP in facilitating translocation derive from the effects on transition from the classical non-rotated to hybrid state (the first step of the translocation) or on transition from the hybrid to posttranslocation state (the second step)? Here, based on our proposed model, we study theoretically the dynamics of the tRNA-mRNA translocation through the ribosome catalyzed by EF-G.GTP and by EF-G.GDPNP. By comparing our theoretical results with the available experimental data, we show that EF-G.GTP can also bind to the classical non-rotated pretranslocation state and the greater potency of GTP hydrolysis in facilitating translocation of tRNA-mRNA complex derives from its effects on the second step of the translocation process. PMID- 23811428 TI - Functional role of alpha7 nicotinic receptor in chronic neuropathic and inflammatory pain: studies in transgenic mice. AB - A growing body of evidence indicates that alpha7 nicotinic receptor subtypes play an important role in chronic inflammatory and neuropathic pain signaling. In the present study, we investigated the role of the endogenous alpha7 nicotinic receptors (nAChRs) signaling in pain and inflammation using transgenic mice. For that we evaluated pain-related behaviors in the alpha7 mutant mice (KO) and its complementary alpha7 hypersensitive mice (KI) expressing the L250T alpha7 nAChRs and their respective WT mice in acute, chronic inflammatory and neuropathic mouse models. alpha7 KO and KI mice showed no significant changes in pain responses evoked by acute noxious thermal and mechanical stimuli as compared with WT littermates. While alpha7 KO mice showed no alterations in thermal and mechanical allodynia compared to WT mice after chronic nerve injury in the CCI test, alpha7 KI mice showed a significant reduction in these pain-related responses. However, marked increase in edema, hyperalgesia, and allodynia associated with intraplantar CFA injection was observed in the alpha7 KO mice compared with the WT littermates. In contrast, alpha7 KI mice displayed lesser degree of hyperalgesia and allodynia after CFA injection. Finally, the ability of systemic nicotine to reverse already-developed mechanical allodynia produced by intraplantar CFA seen in WT mice was lost in the alpha7 KO animals. Overall, our results demonstrate that endogenous alpha7 nAChRs mechanisms play an important role in chronic inflammatory and neuropathic pain models. This provides an additional rationale for the utility of alpha7 nAChR agonists in the treatment of inflammatory and chronic pain. PMID- 23811429 TI - Comparative pharmacokinetics of paclitaxel after oral administration of Taxus yunnanensis extract and pure paclitaxel to rats. AB - Taxus yunnanensis (T. yunnanensis) is endemic to China and has been used in traditional medicine for the treatment of cancer, diabetic ailments and others. Paclitaxel is a representative antitumor compound in the Taxus species. The pharmacokinetic behavior of paclitaxel after oral administration of the crude extract of T. yunnanensis has not been investigated. This study attempts to compare the pharmacokinetics of paclitaxel after an oral administration of the crude extract of the twigs and leaves of T. yunnanensis and pure paclitaxel. A UPLC and a UPLC/MS/MS analysis method were developed for the determination of paclitaxel in T. yunnanensis extract and in the comparative pharmacokinetic study. Caco-2 cells were used to investigate the transport profile of paclitaxel in vitro. In the pharmacokinetic study, rats were randomly grouped and administered with T. yunnanensis extract or pure paclitaxel. The results showed that the AUC and C(max) of paclitaxel in rats receiving the T. yunnanensis extract were significantly increased than those receiving the pure paclitaxel, and the in vitro Caco-2 cell monolayer transport study found that the coexisting constituents in the extract of T. yunnanensis could inhibit the efflux of paclitaxel. These findings suggested that the oral absorption and bioavailability of paclitaxel in T. yunnanensis extract were remarkably higher when compared with the pure paclitaxel, and the coexisting constituents in the T. yunnanensis extract might play an important role for the enhancement of the oral absorption and bioavailability of paclitaxel. PMID- 23811430 TI - A liquid chromatography-tandem mass spectrometry method for pharmacokinetics and tissue distribution of a camptothecin quaternary derivative in rats. AB - A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to identify and quantify the camptothecin quaternary derivative CPT8 for application in pharmacokinetics and tissue distribution studies. Rat plasma and tissue samples were extracted with methanol by using camptothecin as the internal standard (IS). Chromatographic separation of CPT8 and the IS was achieved using a Hypersil GOLD C18 column, with a flow rate of 1.0 mL/min followed by quantification with tandem mass spectrometry, operating with electrospray ionization in the positive ion mode and by applying multiple reaction monitoring. The MS/MS ion transitions were monitored at m/z 484.3-361.2 for CPT8 and m/z 349.0-305.2 for the IS (CPT). A calibration curve was constructed using CPT8 concentrations ranging from 2.5 ng/mL to 2500 ng/mL (r>0.993). The efficiency of CPT8 extraction from plasma and tissue samples ranged from 91.23% to 105.4%. Intra- and inter-day precision (relative standard deviation) values were 0.21% and 7.25%, respectively. No matrix effects were observed. The freeze-thaw stability, post-extraction stability, and stability following short- and long term storage at low temperatures ranged from 84.12% to 108.2%. The preclinical data obtained using this method is expected to facilitate future clinical investigations of CPT8. PMID- 23811431 TI - Triterpene saponins from Tabellae Clinopodii. AB - Three new triterpene saponins, named Clinoposaponin A, Clinoposaponin B, and Clinoposaponin C along with three known triterpene saponins were isolated from the Tabellae Clinopodii. The structures of these compounds were elucidated by means of various spectroscopic analyses. All of the isolated compounds were tested against Hela, HCT-8, AGS, and MCF-7 human cancer cell lines and showed moderate cytotoxic activities with IC50 values between 4.1 and 19.7 MUM. PMID- 23811432 TI - New eudesmenoic acid methyl esters from the seed oil of Jatropha curcas. AB - Three new eudesmenoic acid methyl esters (1-3), as well as five known compounds, including three germacranolides (4-6) and two eudesmanolides (7 and 8), were isolated from the seed oil of Jatropha curcas. The new compounds were elucidated by means of spectroscopic methods, including extensive NMR spectra. In addition, the structure of 8 was confirmed by a single-crystal X-ray diffraction analysis. Among the isolates, compounds 4-6 were the first reported from the genus Jatropha. Using MTS viability assay, the cytotoxicity of compounds 2-8 were evaluated against HL-60, SMMC-7721, A-549, MCF-7, and SW480 human tumor cell lines. Compounds 4 and 5 showed remarkable cytotoxicity against all the tested cell lines with IC50 values from 0.5 to 3.5 MUM, and the new compound 3 displayed selective cytotoxic activity against A-549 cell with an IC50 value of 7.24 MUM, but slight cytotoxicity against HL-60 and MCF-7 with IC50 values of 23.77 and 22.37 MUM, respectively. PMID- 23811433 TI - Generation of a large number of functional dendritic cells from human monocytes expanded by forced expression of cMYC plus BMI1. AB - Anticancer vaccination therapies with monocyte-derived dendritic cells (DC) are widely conducted. A large number of primary monocytes (approximately 10(8) cells) are needed to generate the number of DC required to achieve an effect upon vaccination, and monocytes are usually purified from peripheral blood mononuclear cells obtained by apheresis procedure, which is somehow invasive for cancer patients. As a means to facilitate the generation of DC for therapeutic use, we herein report a method to amplify human monocytes. We found that lentivirus mediated transduction of cMYC along with BMI1 induced proliferation of CD14(+) monocytes derived from 9 out of 12 blood donors, and we named the monocyte derived proliferating cells CD14-ML. Their proliferation continued for 3-5 weeks in the presence of M-CSF and GM-CSF, resulting in 20-1000-fold amplification. Importantly, the expanded CD14-ML differentiated into fully functional DC (CD14 ML-DC) upon the addition of IL-4 to the culture. We successfully stimulated autologous CD8(+) T cells with CD14-ML-DC pulsed with cytomegalovirus peptide or MART-1 peptide to generate antigen-specific CTL lines. This is the first report describing the method for in vitro expansion of human peripheral blood monocytes. PMID- 23811434 TI - The complete mitochondrial genomes of deep-sea squid (Bathyteuthis abyssicola), bob-tail squid (Semirossia patagonica) and four giant cuttlefish (Sepia apama, S. latimanus, S. lycidas and S. pharaonis), and their application to the phylogenetic analysis of Decapodiformes. AB - We determined the complete mitochondrial (mt) genomes of the deep-sea squid (Bathyteuthis abyssicola; supperfamily Bathyteuthoidea), the bob-tail squid (Semirossia patagonica; order Sepiolida) and four giant cuttlefish (Sepia apama, S. latimanus, S. lycidas and S. pharaonis; order Sepiida). The unique structures of the mt genomes of Bathyteuthis and Semirossia provide new information about the evolution of decapodiform mt genomes. We show that the mt genome of B. abyssicola, like those of other oegopsids studied so far, has two long duplicated regions that include seven genes (COX1-3, ATP6 and ATP8, tRNA(Asn), and either ND2 or ND3) and that one of the duplicated COX3 genes has lost its function. The mt genome of S. patagonica is unlike any other decapodiforms and, like Nautilus, its ATP6 and ATP8 genes are not adjacent to each other. The four giant cuttlefish have identical mt gene order to other cuttlefish determined to date. Molecular phylogenetic analyses using maximum likelihood and Bayesian methods suggest that traditional order Sepioidea (Sepiolida+Sepiida) is paraphyletic and Sepia (cuttlefish) has the sister-relationship with all other decapodiforms. Taking both the phylogenetic analyses and the mt gene order analyses into account, it is likely that the octopus-type mt genome is an ancestral state and that it had maintained from at least the Cephalopoda ancestor to the common ancestor of Oegopsida, Myopsida and Sepiolida. PMID- 23811435 TI - Molecular systematics of Dendrobium (Orchidaceae, Dendrobieae) from mainland Asia based on plastid and nuclear sequences. AB - Dendrobium is one of the three largest genera and presents some of the most intricate taxonomic problems in the family Orchidaceae. Based on five DNA markers and a broad sampling of Dendrobium and its relatives from mainland Asia (109 species), our results indicate that mainland Asia Dendrobium is divided into eight clades (with two unplaced species) that form polytomies along the spine of the cladogram. Both Dendrobium and Epigeneium are well supported as monophyletic, whereas sect. Dendrobium, sect. Densiflora, sect. Breviflores, sect. Holochrysa, are paraphyletic/polyphyletic. Many ignored phylogenetic relationships, such as the one of major clades formed by D. jenkinsii and D. lindleyi (two members of sect. Densiflora), the Aphyllum group, the Devonianum group, the Catenatum group, the Crepidatum group, and the Dendrobium moniliforme complex are well supported by both molecular and morphological evidence. Based on our data, we propose to broaden sect. Dendrobium to include sect. Stuposa, sect. Breviflores, and sect. Holochrysa and to establish a new section to accommodate D. jenkinsii and D. lindleyi. Our results indicated that it is preferable to use a broad generic concept of Dendrobium and to pursue an improved infrageneric classification at sectional level, taking into account both morphology and current molecular findings. PMID- 23811436 TI - A molecular phylogeny of nephilid spiders: evolutionary history of a model lineage. AB - The pantropical orb web spider family Nephilidae is known for the most extreme sexual size dimorphism among terrestrial animals. Numerous studies have made Nephilidae, particularly Nephila, a model lineage in evolutionary research. However, a poorly understood phylogeny of this lineage, relying only on morphology, has prevented thorough evolutionary syntheses of nephilid biology. We here use three nuclear and five mitochondrial genes for 28 out of 40 nephilid species to provide a more robust nephilid phylogeny and infer clade ages in a fossil-calibrated Bayesian framework. We complement the molecular analyses with total evidence analysis including morphology. All analyses find strong support for nephilid monophyly and exclusivity and the monophyly of the genera Herennia and Clitaetra. The inferred phylogenetic structure within Nephilidae is novel and conflicts with morphological phylogeny and traditional taxonomy. Nephilengys species fall into two clades, one with Australasian species (true Nephilengys) as sister to Herennia, and another with Afrotropical species (Nephilingis Kuntner new genus) as sister to a clade containing Clitaetra plus most currently described Nephila. Surprisingly, Nephila is also diphyletic, with true Nephila containing N. pilipes+N. constricta, and the second clade with all other species sister to Clitaetra; this "Nephila" clade is further split into an Australasian clade that also contains the South American N. sexpunctata and the Eurasian N. clavata, and an African clade that also contains the Panamerican N. clavipes. An approximately unbiased test constraining the monophyly of Nephilengys, Nephila, and Nephilinae (Nephila, Nephilengys, Herennia), respectively, rejected Nephilengys monophyly, but not that of Nephila and Nephilinae. Further data are therefore necessary to robustly test these two new, but inconclusive findings, and also to further test the precise placement of Nephilidae within the Araneoidea. For divergence date estimation we set the minimum bound for the stems of Nephilidae at 40 Ma and of Nephila at 16 Ma to accommodate Palaeonephila from Baltic amber and Dominican Nephila species, respectively. We also calibrated and dated the phylogeny under three different interpretations of the enigmatic 165 Ma fossil Nephila jurassica, which we suspected based on morphology to be misplaced. We found that by treating N. jurassica as stem Nephila or nephilid the inferred clade ages were vastly older, and the mitochondrial substitution rates much slower than expected from other empirical spider data. This suggests that N. jurassica is not a Nephila nor a nephilid, but possibly a stem orbicularian. The estimated nephilid ancestral age (40-60 Ma) rejects a Gondwanan origin of the family as most of the southern continents were already split at that time. The origin of the family is equally likely to be African, Asian, or Australasian, with a global biogeographic history dominated by dispersal events. A reinterpretation of web architecture evolution suggests that a partially arboricolous, asymmetric orb web with a retreat, as exemplified by both groups of "Nephilengys", is plesiomorphic in Nephilidae, that this architecture was modified into specialized arboricolous webs in Herennia and independently in Clitaetra, and that the web became aerial, gigantic, and golden independently in both "Nephila" groups. The new topology questions previously hypothesized gradual evolution of female size from small to large, and rather suggests a more mosaic evolutionary pattern with independent female size increases from medium to giant in both "Nephila" clades, and two reversals back to medium and small; combined with male size evolution, this pattern will help detect gross evolutionary events leading to extreme sexual size dimorphism, and its morphological and behavioral correlates. PMID- 23811437 TI - Targeted gene delivery by new folate-polycationic amphiphilic cyclodextrin-DNA nanocomplexes in vitro and in vivo. AB - AIM: Development and evaluation of a new targeted gene delivery system by first preforming self-assembled nanocomplexes from a polycationic amphiphilic cyclodextrin (paCD) and pDNA and then decorating the surface of the nanoparticles with folic acid (FA). EXPERIMENTAL SECTION: The cyclodextrin derivative (T2) is a tetradecacationic structure incorporating 14 primary amino groups and 7 thioureido groups at the primary face of a cyclomaltoheptaose (beta-CD) core and 14 hexanoyl chains at the secondary face. RESULTS AND CONCLUSIONS: T2 complexed and protected pDNA (luciferase-encoding plasmid DNA, pCMVLuc) and efficiently mediated transfection in vitro and in vivo with no associated toxicity. The combination of folic acid with CDplexes afforded ternary nanocomplexes (Fol CDplexes) that enhanced significantly the transfection activity of pCMVLuc in human cervix adenocarcinoma HeLa cells, especially when formulated with 1 MUg FA/MUg DNA. The observed transfection enhancement was associated to specific folate receptor (FR)-mediated internalization of Fol-CDplexes, as corroborated by employing a receptor-deficient cell line (HepG2) and an excess of free folic acid. The in vivo studies, including luciferase reporter gene expression and biodistribution, indicated that 24h after intravenous administration of the T2 pDNA nanocomplexes, transfection takes part mainly in the liver and partially in the lung. Interestingly, the corresponding Fol-CDplexes lead to an increase in the transfection activity in the lung and the liver compared to non-targeted CDplexes. Folate-CDplexes developed in this study have improved transfection efficiency and although various methods have been used for the preparation of ligand-DNA-complexes, covalent binding is usually needed and insoluble aggregates are formed unless the concentration of the components is minimized. However, the complexes developed by first time in this work were prepared by simple mixing. The synthetic nature of this formulation provides the potential of flexibility in terms of composition and the capability of inexpensive and large-scale production of the complexes. These nanovectors may be an adequate alternative to viral vectors for gene therapy in the future. PMID- 23811438 TI - Preparation of Bovine Serum Albumin (BSA) nanoparticles by desolvation using a membrane contactor: a new tool for large scale production. AB - Albumin nanoparticles are attractive drug delivery systems as they can be prepared under soft conditions and incorporate several kinds of molecules. The aim of this study was to upscale the desolvation process for preparing Bovine Serum Albumin (BSA) nanoparticles using a membrane contactor. At a first step, the BSA nanoparticles were prepared at small scale using a syringe pump. BSA nanoparticles of 139 nm in size, with a polydispersity index of 0.046, were obtained at the optimal conditions: pH 8.2, 100 mg mL(-1) BSA albumin solution (2 mL), and 1 mL min(-1) flow rate of ethanol addition (8 mL). The upscaling with a membrane contactor was achieved by permeating ethanol through the pores of a Shirasu Porous Glass (SPG Technology Co., Japan) membrane and circulating the aqueous phase tangentially to the membrane surface. By increasing the pressure of the ethanol from 1 to 2.7 bars, a progressive decrease in nanoparticle size was obtained with a high nanoparticles yield (around 94-96%). In addition, the flow rate of the circulating phase did not affect the BSA nanoparticle characteristics. At the optimal conditions (pH 8.2, 100 mg mL(-1) BSA albumin solution, pressure of ethanol 2.7 bars, flow rate of the circulating phase 30.7 mL s(-1)), the BSA nanoparticles showed similar characteristics to those obtained with the syringe pump. Large batches of BSA nanoparticles were prepared up to 10 g BSA. The BSA nanoparticles were stable at least during 2 months at 4 degrees C, and their characteristics were reproducible. It was then concluded that the membrane contactor technique could be a suitable method for the preparation of albumin nanoparticles at large scale with properties similar to that obtained at small scale. PMID- 23811439 TI - Formulation development and evaluation of Diltiazem HCl sustained release matrix tablets using HPMC K4M and K100M. AB - The aim of this study was to develop a sustained release hydrophilic matrix tablet of Diltiazem HCl and evaluates the effect of formulation variables (e.g. lubricant, binder, polymer content and viscosity grades of HPMC) on drug release. Twelve different formulations (F1-F12) were prepared by direct compression. The results of the physical parameters and assay were found to be within the acceptable range. Rate of drug release was found to be slow as the fraction of the polymer was increased from 20-50%. The drug release rate from tablets containing K4M was effectively controlled by increasing the talc concentration, whereas the burst effect was reduced by increasing binder content. The drug release was higher with K4M as compare to K100M. Model-dependent and independent methods were used for data analysis and the best results were observed for K4M in Higuchi (R(2)=0.9903-0.9962) and K100M in Baker and Lonsdale (R(2)=0.9779 0.9941). The release mechanism of all formulations was non-Fickian. F7 (50% K4M, 2% talc, 10% Avicel PH101) and F11 (40% K100M) were very close to targeted release profile. F12 (50% K100M) exhibited highest degree of swelling and lowest erosion. The f1 and f2 test were performed taking F11 as a reference formulation. PMID- 23811440 TI - Counter irritant activity of Carthamus oxycantha. AB - Many locally occurring species of Asteraceae are used as medicinal plants by various tribal and ethnic communities in Pakistan. Carthamus oxycantha is often occurs as weed in cultivated fields. Folk medicines indicated its use as an anti inflammatory and wound healing plant. It is used for wound healing by the local population in the form of powder paste. No scientific Report, about the behavior of this plant has so far been published. The counter irritant studies of locally occurring Carthamus oxycantha was carried out. The main objectives of the project were to evaluate its wound healing effects on animal skin and the identity and characterization of chromatographically isolated fractions. For this purpose, different solvents with a broad range of polarity were successively used to extract non-polar compounds (petroleum ether extract), constituents intermediate polarities (chloroform extract) and polar constituents (methanol extract) from the whole herb of Carthamus oxycantha. The counter irritant activity of the crude extracts and isolated fractions was evaluated on rabbit's skin. Five fractions Co 1 to Co-5 were isolated from the active chloroform extract by column and thin layer chromatography. Co-1, Co-3 and Co-5 appeared to be the most potent counter irritant than others. A possible structure-activity relationship of these active compounds was investigated by using spectroscopy (UV and FTIR analysis). PMID- 23811441 TI - Hypoglycaemic effects of alcoholic root extract of Borassus flabellifer (Linn.) in normal and diabetic rats. AB - The objective of the study was to investigate the alcoholic (ALEBF) extract of B. flabellifer for their hypoglycaemic effects in normal and diabetic rats. Diabetes was induced in rats by single dose administration of alloxan (120 mg/kg, i.p.) or by injecting dexamethasone (10 mg/kg, i.p.) for 10 days. In normal rats, ALEBF (100, 200 and 400 mg/kg) had significantly decreased the blood glucose level in a dose dependent manner after repeated administration for 7 days. In alloxan induced diabetic rats, extract (ALEBF) had decreased blood sugar level and improved glucose tolerance in alloxan induced diabetic rats at the end of 1st, 2nd , 3rd and 4th week after test extract treatment. However, the insulin levels of extract treated group did not significantly change after 28 days treatment with the extract. It did not alter the insulin levels. In alloxan model, repeated dose administration of ALEBF had showed significant increase in body weight, prevention of elimination of sugar in urine and reduced the mortality rate induced by alloxan. In dexamethasone induced insulin resistance diabetic rats, repeated administration of ALEBF inhibited the increase in blood glucose level, improved glucose tolerance and reduced the insulin levels as compared dexamethasone induced diabetic rats. PMID- 23811442 TI - Prolonged preconditioning with natural honey against myocardial infarction injuries. AB - Potential protective effects of prolonged preconditioning with natural honey against myocardial infarction were investigated. Male Wistar rats were pre treated with honey (1%, 2% and 4%) for 45 days then their hearts were isolated and mounted on a Langendorff apparatus and perfused with a modified Krebs Henseleit solution during 30 min regional ischemia fallowed by 120 min reperfusion. Two important indexes of ischemia-induced damage (infarction size and arrhythmias) were determined by computerized planimetry and ECG analysis, respectively. Honey (1% and 2%) reduced infarct size from 23+/-3.1% (control) to 9.7+/-2.4 and 9.5+/-2.3%, respectively (P<0.001). At the ischemia, honey (1%) significantly reduced (P<0.05) the number and duration of ventricular tachycardia (VT). Honey (1% and 2%) also significantly decreased number of ventricular ectopic beats (VEBs). In addition, incidence and duration of reversible ventricular fibrillation (Rev VF) were lowered by honey 2% (P<0.05). During reperfusion, honey produced significant reduction in the incidences of VT, total and Rev VF, duration and number of VT. The results showed cardioprotective effects of prolonged pre-treatment of rats with honey following myocardial infarction. Maybe, the existence of antioxidants and energy sources (glucose and fructose) in honey composition and improvement of hemodynamic functions may involve in those protective effects. PMID- 23811443 TI - Identification of Sulfamoylbenzamide derivatives as selective Cathepsin D inhibitors. AB - Aspartic proteases play very important role in post translational processing of proteins and several of them are essential for organism's viability. Here we present the enzyme inhibition activities of different Sulfamoylbenzamide derivatives against two aspartic proteases cathepsin D and plasmepsin II. Cathepsin D is an aspartic protease that degrades proteins at acidic pH in the lysosomes, or extracellular matrix. It is overexpressed by epithelial breast cancer cells and hence hyper-secreted. On the other hand plasmepsin II is an essential enzyme of Plasmodium falciperum. Cathepsin D and Plasmepsin II are pivotal drug targets for treatment of breast cancer and malaria respectively. Virtual screening of Sulfamoylbenzamide compounds followed by enzyme inhibition assays revealed these compounds as selective Cathepsin D inhibitors while inactive against Plasmepsin-II. IC50 values of five Sulfamoylbenzamide compounds tested are in range of 1.25-2.0 MUM. N-(3-chlorophenyl)-2-sulfamoylbenzamide is identified as the most potent of all tested Sulfamoylbenzamide compounds with IC50 1.25 MUM. It was also noted that the docking score of theses compounds was better in case of Cathepsin D as compared to Plasmepsin-II. Docking score ranges from -29.9+/-1.16 to -35.1+/-0.13 in case of Cathepsin D, while from -24.0+/-0.10 to -29.5+/-0.10 in case of Plasmepsin-II. PMID- 23811444 TI - Isolation and characterization of different strains of Bacillus licheniformis for the production of commercially significant enzymes. AB - Utilization of highly specific enzymes for various industrial processes and applications has gained huge momentum in the field of white biotechnology. Selection of a strain by efficient plate-screening method for a specific purpose has also favored and boosted the isolation of several industrially feasible microorganisms and screening of a large number of microorganisms is an important step in selecting a potent culture for multipurpose usage. Five new bacterial isolates of Bacillus licheniformis were discovered from indigenous sources and characterized on the basis of phylogeny using 16S rDNA gene analysis. Studies on morphological and physiological characteristics showed that these isolates can easily be cultivated at different temperatures ranging from 30 degrees C to 55 degrees C with a wide pH values from 3.0 to 11.0 All these 05 isolates are salt tolerant and can grow even in the presences of high salt concentration ranging from 7.0 to 12.0%. All these predominant isolates of B. licheniformis strains showed significant capability of producing some of the major industrially important extracellular hydrolytic enzymes including alpha-amylase, glucoamylase, protease, pectinase and cellulase in varying titers. All these isolates hold great potential as commercial strains when provided with optimum fermentation conditions. PMID- 23811445 TI - Cytotoxicity of alkaloids isolated from Peganum harmala seeds. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Peganum harmala is used in traditional medicine to treat a number of diseases including cancer. Our preliminary studies show that the alkaloidal extract of PH seed is cytotoxic to several tumor cell lines in vitro and has antitumor effect in a tumor model in vivo. The present investigation was aimed at extending our previous studies in identifying the components in P. harmala seed-extract responsible for the cytotoxic effects, and study the cytotoxic and antiproliferative activity of isolated alkaloids and total alkaloidal fraction (TAF) in several tumor cell lines. Four alkaloids: harmalicidine, harmine, peganine (vasicine) and vasicinone were isolated from the P. harmala seed-extract and their activity and that of TAF were tested a) for their cytotoxic activity against four tumor cell lines [three developed by us by chemical-induction in Wistar rats: 1) Med-mek carcinoma ; 2) UCP-med carcinoma ; 3) UCP-med sarcoma] ; and 4) SP2/O-Ag14, and b) for antiproliferative effect on cells of Jurkat, E6-1 clone (inhibition of incorporation of {(3)H-thymidine} in cellular DNA). The alkaloids and TAF inhibited the growth of tumor cell lines to varying degrees; Sp2/O-Ag14 was the most sensitive, with IC50 values (concentration of the active substance that inhibited the growth of the tumor cells by 50%) ranging between 2.43 MUg/mL and 19.20 MUg/mL, while UCP-med carcinoma was the least sensitive (range of IC50 = 13.83 MUg/mL to 59.97 MUg/mL). Of the substances evaluated, harmine was the most active compound (IC50 for the 4 tumor cell lines varying between 2.43 MUg/mL and 18.39 MUg/mL), followed by TAF (range of IC50 = 7.32 MUg/mL to 13.83 MUg/mL); peganine was the least active (IC50 = 50 MUg/mL to > 100 MUg/mL). In terms of antiproliferative effect, vasicinone and TAF were more potent than other substances: the concentration of vasicinone, and TAF needed to inhibit the incorporation of {(3)H-TDR} in the DNA cells of Jurkat, E6-1 clone by 50% (IC50) were 8.60 +/- 0.023 MUg/mL and 8.94 +/- 0.017 MUg/mL, respectively, while peganine was the least active (IC50 >100 MUg/mL). The IC50 values for harmalacidine (27.10 +/- 0.011 MUg/mL) and harmine (46.57 +/- 0.011 MUg/mL) were intermediate. The harmala alkaloids inhibited the growth of four tumor cell lines, and proliferation of Jurkat cells with varying potencies. Harmine was the most potent in inhibiting cell growth, and vasicinone was most active as antiproliferating substance. The TAF had significant cytotoxic as well as antiproliferating activity. PMID- 23811446 TI - Spray-dried gastroretentive floating microparticles: preparation and in vitro evaluation. AB - The full factorial design was employed to evaluate contribution of drug: polymer and Eudragit RS 100: Eudragit RL 100 on entrapment efficiency, time for maximum drug release, percentage of drug release. Floating microparticles were prepared using spray drying technique. Microparticles were evaluated for buoyancy and drug release study using paddle type dissolution apparatus using pH 1.2 buffer as dissolution medium. All the formulations showed good buoyancy with more than 90% microparticles floating for 12hrs. It was found that amount of polymer affected entrapment efficiency (P<0.05). Eudragit RS 100: Eudragit RL100 affected time for maximum drug release (P<0.05). The diffusion coefficient (n) value of the optimized formula was found to be 0.7042 which indicates mechanism of release is anomalous transport. Fourier Transform Infrared Spectroscopy and Differential Scanning Calorimetry studies showed that drug and excipients are compatible. Size of the microparticles ranged from 21-30 MUM. Scanning electron microscopy showed that microparticles are spherical and non-aggregated. In this study it was found that spray drying can be used to produce floating microparticles successfully without use of solvents like dichloromethane, which is a class II solvent or aromatic solvents like ethyl acetate. PMID- 23811447 TI - Antibacterial effect of mango (Mangifera indica Linn.) leaf extract against antibiotic sensitive and multi-drug resistant Salmonella typhi. AB - Alternative herbal medicine has been used to treat various infections from centuries. Natural plants contain phytoconstituents having similar chemical properties as of synthetic antibiotics. Typhoid fever is a serious infection and failure of its treatment emerged multi-drug resistant (MDR) bugs of Salmonella typhi. Due to multiple and repeated issues with antibiotics efficacy, it became essential to evaluate biological properties of plants from different geographical origins. Mango leaves have been Reported for various medicinal effects like antioxidant, antimicrobial, antihelminthic, antidiabetic and antiallergic etc. Objective of present study was to investigate anti-typhoid properties of acetone mango leaf extract (AMLE) against antibiotic sensitive and MDR S. typhi isolates. A total of 50 isolates of S. typhi including MDR (n=30) and antibiotic sensitive (n=20) were investigated. Staphylococcus aureus (ATCC 25923) and Salmonella typhimurium (ATCC14028) were used as quality control strains. AMLE was prepared and its antibacterial activity was evaluated by agar well diffusion screening method and minimum inhibitory concentration (MIC), by agar dilution technique. Zone of inhibition (mm) of AMLE against MDR and antibiotic sensitive isolates was 18+/-1.5mm (Mean+/-S.D). Zone of S. aureus (ATCC 25923) and S. typhimurium (ATCC14028) was 20+/-1.5mm (Mean+/-S.D). MIC of AMLE was Reported in range from 10-50 mg/ml. The present study described the inhibitory effects of mango leaves against S. typhi. PMID- 23811448 TI - Green tea catechins based functional drink (Green cool) improves the antioxidant status of SD rats fed on high cholesterol and sucrose diets. AB - In the recent epoch, functional and nutraceuticals foods are gaining wide range of acceptability from the consumers. In the present research investigation, efforts were directed to exploit the green tea phytochemicals. Functional beverage was prepared with catechins and epigallocatechins gallate (EGCG) added individually @550 mg/500mL in respective drink. Prepared drinks were evaluated for their physicochemical analysis. Efficacy trial was also conducted, in which diets consisting of high sucrose and cholesterol were provided to rats with concurrent intake of functional drinks. CIE-Lab Color analysis of functional drinks showed that indices of color tonality were non-significantly affected. However, decreasing trend in pH and increased tendency in acidity of drink was noted. While scores for sensory evaluation remained in acceptable range showing suitability for industrial applications. Results of efficacy trial revealed that functional drinks improved serum antioxidant potential of rats. Thus results paved the way for the development of functional beverages using green tea catechins for vulnerable segments. PMID- 23811449 TI - The effect of high-fructose intake on the vasopressor response to angiotensin II and adrenergic agonists in Sprague-Dawley rats. AB - Effect of losartan was assessed on systemic haemodynamic responses to angiotensin II (Ang II) and adrenergic agonists in the model of high-fructose-fed rat. Twenty four Sprague-Dawley (SD) rats were fed for 8 weeks either 20% fructose solution (FFR) or tap water (C) ad libitum. FFR or C group received losartan (10mg/kg/day p.o.) for 1 week at the end of feeding period (FFR-L and L) respectively, then the vasopressor responses to Ang II, noradrenaline (NA), phenylephrine (PE) and methoxamine (ME) were determined. The responses (%) to NA, PE, ME and Ang II in FFR were lower (P<0.05) than C (FFR vs. C; 22+/-2 vs. 32+/-2, 30+/-3 vs. 40+/-3, 9+/-1 vs. 13+/-1, 10+/-1 vs. 17+/-1) respectively. L group had blunted (P<0.05) responses to NA, PE, ME and Ang II compared to C (L vs. C; 26+/-2 vs. 32+/-2, 30+/-3 vs. 40+/-3, 7+/-0.7 vs. 13+/-1, 5+/-0.4 vs. 17+/-1) respectively. FFR-L group had aggravated (P<0.05) response to NA and ME, but blunted response to Ang II compared to FFR (FFR-L vs. FFR; 39+/-3 vs. 22+/-2, 11+/-1 vs. 9+/-1, 3+/-0.4 vs. 10+/-1) respectively. Fructose intake for 8 weeks results in smaller vasopressor response to adrenergic agonists and Ang II. Data also demonstrated an important role played by Ang II in the control of systemic haemodynamics in FFR and point to its interaction with adrenergic neurotransmission. PMID- 23811450 TI - Truncated Type II isopentenyl diphosphate isomerase from hyperthermophilic Achaeon Thermococcus kodakaraensis implicates the necessity of its N-terminal amino acid residues in protein thermostability. AB - The enzyme isopentenyl diphosphate isomerase (IDI, EC 5.3.3.2) interconverts isopentenyl diphosphate and dimethylallyl diphosphate. We had previously cloned Tk-idi gene encoding the thermostable Tk-IDI enzyme from Thermococcus kodakaraensis KOD1. Four putative start codons were found on Tk-idi gene at 123, 213, 297 and 321 positions downstream of the first start codon. In the present work four mutants were obtained by deleting 123, 213, 297 and 321 nucleotides from the 5'-end of Tk-idi gene to obtain Tk-idim, Tk-idim1, Tk-idim2, and Tk idim3, respectively. When we tried to express these truncated genes in Escherichia coli only Tk-idim was expressed in the active form. The product, Tk IDIM, was purified and characterized. The molecular mass of the enzyme, estimated by gel filtration chromatography, was 300 kDa which indicated that the truncated enzyme retained the octameric form. The removal of 41 N-terminal amino acids did not exhibit a significant effect on the enzyme activity however, the thermostability of the enzyme decreased. The decrease in thermostability of Tk IDIM correlated well with the results of circular dichroism (CD) analysis and structural modeling. PMID- 23811451 TI - Synthesis, conjugation and evaluation of some novel polymers and their micro particles for sustained release drug formulations. AB - To prepare and evaluate three novels functionalized polymers (PGA, PGA-co caprolactone & PGA-co-pentadecalactone) for the development of nanoparticles which were further used in the development of a novel polymeric prodrug using Ibuprofen as a model drug. The Ibuprofen-polymer prodrug was developed by coupling the drug to one of the three prepared polyester polymers via ester linkage. A hydrolytic enzyme was used to prepare two polymer monomers, glycerol and polyvinyl adipate, which are non toxic, ester linked biological monomers. The polymers and their prodrug were characterized using NMR, GPC, UV spectrophotometer and DSC. In vitro drug release study of Ibuprofen-polymer conjugate was performed in phosphate buffer PH 7.4 using a roller (Stuart STR 1) placed in an incubator (Stuart SI 60) and the temperature was kept constant at 37 +/- 1 degrees C. Among the three polymers, glycerol-adipate-co-pentadecalactone was observed to give a burst release following slow release in the medium. These characteristics suggest that these polymers can be successfully used in sustained release drug formulations. PMID- 23811452 TI - 3-[(2-chloroquinolin-3-yl)methyl]quinazolin-4(3H)-ones as potential larvicidal agents. AB - The larvicidal effect of series of 3-[(2-chloroquinolin-3-yl)methyl] uinazolin 4(3H)-ones, 5a-e, against Chironomus tentans Fabricius has been investigated. The results showed that tested compounds demonstrated strong larvicidal activity, and caused high percentage of mortality after 24 h at the doses of 40-100 ?g/ml, especially in the case of 3-[(2-chloro-8-methyquinolin-3-yl)methyl]quinazolin 4(3H)-one, 5b, that act as a promising larvicidal agent. PMID- 23811453 TI - Phytochemical, antimicrobial, insecticidal and brine shrimp lethality bioassay of the crude methanolic extract of Ajuga parviflora Benth. AB - Methanolic extract of medicinal herb Ajuga parviflora Benth. was evaluated for phytochemical screening (the plant extract showed the presence of aromatic compounds, carbohydrates, glycosides, tannins, alkaloids, polyphenols, quinines and dions, aminophenols, steroids/sterols, flavonoids and terpenoids), antimicrobial activities against various strains of bacteria and fungi by using disc diffusion method and insecticidal activities against red flour beetle (Tribolium castaneum), wheat weevil (Sitophilis granaries) and their larvae. The crude extract showed anti-bacterial activity against all strains with a maximum zone of inhibition of 12mm diameter against Citrobacter and Pseudomonas aurogenosa. Standard drugs Ampicillin, Gentamicin and Amoxicillin were used in parallel. The crude extract did not show antifungal activity against the tested strains of fungi even at high doses. The crude methanolic extract was also used for insecticidal activity against the two types of insects and their larva. The extract showed no significant mortality in the tested strains. For brine shrimp lethality bioassay different concentrations 10, 100 and 1000ug/ml of the medicinal herb A. parviflora methanolic extract were used. After 24 hrs the percent mortality and LD50 value was calculated through probit analysis. The LD50 value of extract was 321.42MUg/mL while that of standard drug cyclophosphamide was 16.09ug/ml. PMID- 23811454 TI - Comparison of chemical composition of Aerva javanica seed essential oils obtained by different extraction methods. AB - Aerva javanica (Burm.f.) Juss. ex Schult. seed essential oils were obtained by hydrodistillation (HD) and dry steam distillation (SD) extracting methods and analyzed by using gas chromatography-mass spectrometry(GC-MS). Twenty and eighteen components representing 90.5% and 95.6% of the seed essential oil were identified, using hydrodistillation and dry steam distillation, respectively. The major constituent identified from seed essential oil obtained by HD were heptacosane (25.4%), 3-allyl-6-methoxyphenol (14.1%), pentacosane (12.1%), 6,10,14-trimethyl-2-pentade-canone (7.9%), nonacosane (7.1%), tricosane (3.6%), alpha-farnesene (3.5%), dodecanal (2.7%) and octacosane (2.1%). Whereas the major constituent identified from seed essential oil obtained by SD were heptacosane (41.4%), pentacosane (21.2%), nonacosane (14.8%), tricosane (6.3%), octacosane (4.2%) and tetracosane (3.0%). PMID- 23811455 TI - The effects of taurochenodeoxycholic acid in preventing pulmonary fibrosis in mice. AB - The present study prepared the pulmonary fibrosis model in mice by using Bleomycin and carry out the investigations on the effects of taurochenodeoxycholic acid (TCDCA) in preventing pulmonary fibrosis in mice. Expression profiles of the bile acid receptors in the lung of mice FXRalpha and TGR5 were examined, and pulmonary coefficient, pathohistology as well as expression of TNF-alpha, MMP-2, MMP-9 and TIMP-2 in pulmonary fibrosis mice. The results showed that FXRalpha and TGR5 simultaneously expressed in the lung of the mice; TCDCA in dosages of 0.05 and 0.1g/kg can extremely significantly decrease the pulmonary coefficient in the model mice (P>0.01), TCDCA in a dosage of 0.2g/kg significantly decreased the pulmonary coefficient in the model mice (P<0.05); TCDCA in dosages of 0.05 and 0.1g/kg significantly reduce the pathological damages on their lungs; TCDCA can extremely significantly decrease the expression levels of TNF-alpha and TIMP-2 in pulmonary tissues in the pulmonary fibrosis mice (P>0.01), the expression level of MMP-9 extremely significantly increased (P>0.01), while it has no significant effects on MMP2. The results as mentioned above indicated that TCDCA had antagonistic actions on pulmonary fibrosis in mice. PMID- 23811456 TI - A model portraying experimental loss of hair cell: the use of distortion product otoacoustic emission in the assessment of rat's ear. AB - The use of rats in research academies to study deafness is widespread, meanwhile medicinal methods to eliminate hair cells is also increasing. Thus, aminoglycosides and loop diuretics have grasped more attention. This study aimed at establishing an animal model in which a rapid distortion of the hair cell of cochlea administering amikacin and furosemide and using distortion product otoacoustic emission (DPOAE) the functioning of rat's ear would be assessed. Forty-eight male Sprague-Dawley rats (mean weight 200-250g) were randomly divided into six equal groups. Except the control group the rest received 0.5mg/g, 0.75mg/g, 1mg/g, 1.25mg/g, and 1.5mg/g, of subcutaneous amikacin respectively. 30 minutes later every rat received 0.1mg/g of furosemide intrapritoneally. DPOAE of rats was measured before these injections and 72 hours later. Then tissue sections of the rat's cochlea were prepared. All the cases had a significant decrease in their DPOAE with the frequencies 2KHz-8KHz (p<0.05). The most change in DPOAE was in rats which had received 1mg/g - 1.5mg/g amikacin. Histological studies approved distortion of hair cell even the apical turn. To establish a deafness model due losing hair cells, it is possible to use a combination of 1mg/g amikacin and 0.1mg/g furosemide. Besides, to approve deafness DPOAE resulted can be used. PMID- 23811457 TI - Adrenaline improves endurance of rabbit gastrocnemius: a study with continuous high frequency stimulation. AB - Beta adrenoceptor agonists are well known for their potentiating effects on peak twitch and tetanic tension and defatiguing effects on skeletal muscles. Adrenaline (ADR) is one of these agonist which is known for inotropism but less described for fatigue. In addition, studies on high frequency stimulation (HFS) of skeletal muscles are scarce and not available for tetanization fatigue related with endurance and recovery under the influence of ADR. We hypothesized that ADR can maintain peak tetanic tension (PTT) produced by mammalian skeletal muscles for longer period as well as help in recovery from fatigue on continuous HFS. Gastrocnemius muscles (medial Belly) from both limbs were isolated from Rabbits (Oryctologus cunniculus) and continuously stimulated at High frequency of 80Hz for 20Sec. Tetanic tensions were recorded digitally with the measurement of PTT at different time points during this stimulation. Time (T50) was also noted at which muscle force was reduced to 50%. At 20Sec of continuous stimulation, mean PTT(% of initial) was declined significantly in both the ADR treated and control CTL muscles being greater in CTL ones. T50 was found 74.9% greater in ADR than CTL, being significant. When muscles, which were fatigued with same stimulation protocol, were allowed to recover with and without adrenaline, the PTT recovers by 3.4 folds in ADR and about 2 folds only in CTL. Significant differences between CTL and ADR treated-continuously stimulated high frequency fatigued muscles confirm the hypothesis that in mammalian muscles ADR increases the endurance by delaying the high frequency fatigue and helps in its recovery. PMID- 23811458 TI - Preparation and evaluation of lipid vesicles of camptothecin as targeted drug delivery system. AB - Site-specific delivery of anticancer based therapy of human cancers has led to several remarkable outcomes, particularly in the therapy of breast cancer and lymphoma. Camptothecin, a plant secondary metabolite is widely used in the treatment of metastatic breast cancer and lymphoma. However its side effect profile often results in cessation of therapy. In this study the principle of both active as well as passive targeting using camptothecin loaded stealth liposomes as per the magic gun approach was followed. Stealth liposomes of camtothecin were prepared by thin film hydration method using a PEGylated phospholipid like DSPE-MPEG 2000. Similarly conventional liposomes were prepared using phospholipids like DPPC, DSPC. Conventional liposomes were coated with a hydrophilic biocompatible polymer like chitosan. It was found that chitosan coating of the conventional liposomes increased the physical stability of the liposomal suspension. Further, chitosan coated conventional liposomes and the PEGylated liposomes released the drug for a prolonged period of time, compared to the uncoated conventional liposomes. In vivo screening of the formulations for their antitumor efficacy was carried out in rats. Breast cancer was induced in female Sprague-Dawley rats using an indirectly acting chemical carcinogen DMBA (7, 12 dimethyl benz(a)anthracene). It was found that there was significant decrease (P>0.01) in tumor volume in the rat group treated with test 2 formulation and test 1 formulation compared to standard free CPT. However the chitosan coated liposomal formulation showed a better antitumor efficacy than that of the PEGylated liposomal formulation. PMID- 23811459 TI - Screening of Bunium bulbocastanum for antibacterial, antifungal, phytotoxic and haemagglutination activities. AB - The current study was aimed at screening the Bunium bulbocastanum for its antibacterial, antifungal, phytotoxic and haemagglutination activities.The crude methanolic extract and n-hexane fraction showed significant (89%) and good activity (61%) against Staphylococcus aureus while the CHCl3fraction was moderately active against S.aureus (53%). Moderate activitywas shown by the EtOAc fraction against B. subtilis (44%). This fraction was inactive against P.aerogenosa and S.aureus. The aqueous fraction showed significant activity against B. subtilis (85%), moderate against S.aureus(34 %) and E. coli (33%)and low activity against P.aerogenosa(29%). Our results for antifungal assay indicated that all the test samples were inactive against all the test fungi. The phytotoxic activity of the plant at 1000 and 100 MUg/ml was: crude methanolic extract (53.33 and 46.66%), n-hexane (46.66 and 26.66%), CHCl3 (20 and 6.66%), EtOAc (46.66 and 26.66%) and aqueous (40 and 33.33%). All the test samples (crude methanolic extract and fractions) of B. bulbocastanum were unable to agglutinate RBCs of the human blood indicating that this species lack phytolectins. PMID- 23811460 TI - Optimization of growth conditions for the isolation of dextran producing Leuconostoc spp. from indigenous food sources. AB - Leuconostoc are known to produce dextran, which have great commercial importance in chemical, medical and food industry. The present study is an attempt to select the best medium for the isolation of indigenous dextran producing Leuconostoc, measuring their enzyme activities for dextransucrase, production of dextran and identification of dextran producing Leuconostoc CMG706, CMG707, CMG710 and CMG713. Since, dextran producing Leuconostoc produce slimy colonies, twenty-four slime producing bacterial strains were isolated from different food sources, fruits and vegetables. Three different isolation medium were evaluated for the isolation of Leuconostoc only and the best one was found to be one containing sucrose and sodium azide. Further, all slime producing bacterial strains were screened for enzyme activity of dextransucrase, which is responsible for dextran production. Four bacterial strains CMG706, CMG707, CMG710 and CMG713 giving high enzyme activities were selected for dextran production and identified. PMID- 23811461 TI - Anti-inflammatory and gastroprotective activities of the aqueous extract of Micromeria fruticosa (L.) Druce ssp Serpyllifolia in mice. AB - Micromeria fruticosa is used widely in many Mediterranean regions for various inflammatory conditions. The aim of this work was to assess the anti-inflammatory and gastroprotective activities of the aqueous extract of Micromeria fruticosa. The aqueous extract of Micromeria fruticosa was tested orally in mice at doses of 50, 100 and 200 mg/kg in carrageenan-induced paw edema, vascular permeability, myeloperoxidase activity (MPO) and indomethacin-induced gastric ulceration. In the paw edema model, the extract at dose of 200 mg/ kg, exhibited a significant anti-inflammatory effect, while the extract at 100 and 200 mg/kg reduced significantly the vascular permeability and MPO activity in a dose dependant manner. Oral pretreatment of the aqueous extract reduced significantly the development of gastric lesions induced by indomethacin at dose of 200 mg/kg only. Results suggest that the aqueous extract of Micromeria fruticosa has both anti inflammatory as well as, gastroprotective activities. Thus it could be used as an alternative or supplementary herbal remedy for the treatment of inflammatory diseases especially when combined with strong anti-inflammatory medications that have ulcerogenic side effects such as NSAIDs. PMID- 23811462 TI - Trace element geochemistry of Manilkara zapota (L.) P. Royen, fruit from winder, Balochistan, Pakistan in perspective of medical geology. AB - An integrated study of rocks, soils and fruits of Manilkara zapota (L.) (Sapotaceae) of Winder area have been carried out to elaborate trace elements relationship between them. The igneous rocks of the study area have elevated amount of certain trace elements, upon weathering these elements are concentrated in the soil of the area. The trace elements concentration in the soil were found in the range of 0.8-197 for Fe, 1.23-140 for Mn, 0.03-16.7 for Zn, 0.07-9.8 for Cr, 0.05-2.0 for Co, 0.52-13.3 for Ni, 0.03-8.8 for Cu, 0.08-10.55 for Pb and 0.13-1.8MUg/g for Cd. The distribution pattern of elements in the rocks and soils reflected genetic affiliation. Promising elements of edible part of the fruit were Fe (14.17), Mn (1.49), Cr (2.96), Ni (1.13), Co (0.92), Cu (1.70) and Zn (1.02MUg/g). The concentration of these elements in the fruits is above the optimum level of recommended dietary intake, probably due to this, disorder in the human health is suspected in the inhabitants of the area. PMID- 23811463 TI - Assessment of CYP2B6 activity in rats: a cocktail study with bupropion alone and in combined with tolbutamide. AB - A "cocktail"of numerous probe drugs to assess the metabolic activity of the corresponding cytochrome P450 enzymes requires that there is no problem of interaction among them. Some interactions among probe drugs can appear and may affect the rate of biotransformation of other ones. To develop a useful "cocktail" of probe drugs, our presented work was aimed on the influence of tolbutamide on cytochrome P450-mediated metabolism of bupropion. The biotransformation rates of bupropion administered either separately or in combined with tolbutamide were compared in this new study. The results revealed that tolbutamide had significantly decreased the rate of bupropion hydroxylation. Thus, due to shift in cytochrome P450 enzyme metabolic activity some extent differential results in the rate of P450-mediated metabolism can be observed when comparing assessment using combination of two model drugs with the common way (single marker use). PMID- 23811464 TI - Impact of herbal drug combination on lipid profile, renal and cardiac parameters. AB - For the past two decades, there has been an increasing interest in the investigation of medicinal plants as potential sources of new therapeutic agents; hence it is crucial to recognize the apparent toxicity that might occur while using herbal medicines. This study was undertaken in rabbits to assess the safety profile of an herbal drug combination. It was tested in 3 different doses for a period of 45 days, each group comprising of seven rabbits of either sex. Biochemical test and histopathological assessment were performed at the completion of dosing using standards reagent kits. The result shows that high dose of herbal drug (10ml/kg) revealed significant increase in serum lactate dehydrogenase, total protein and creatinine (P<0.05); more over there was highly significant decrease in triglycerides (P>0.05) at the completion of dosing. PMID- 23811465 TI - Significance of herbal medicine in removing excessive iron content in human. AB - Heavy metals in cigarette tobacco such as iron may cause a serious damage on human health. Surveys showed that the accumulation of certain toxic heavy metals like cadmium, mercury, iron is very often due to the effect of smoking. This work involved 15 volunteers in two randomly divided groups having the habit of cigarette smoking over 15 cigarettes / day. Concentration level of iron in blood and urine before and after treatment using the herbal medicine, widely used in Europe, is analyzed. Determination of Iron concentration in blood and urine was calculated by Inductively Coupled Plasma-Atomic Emission Spectrometry (ICP-AES) according to the procedure DIN EN ISO 11885 ("E22" from April 1998). The analysis shows that the concentration of iron in blood and urine samples in both groups increased in some volunteers instead of decrease. The independent T-test shows that the mean of iron concentration in the group A and group B had no significant difference (p>0.05). The results suggested that the herbal medicine under test does not have significant influence on reduction of iron concentration levels. PMID- 23811466 TI - Antibacterial activity of local herbs collected from Murree (Pakistan) against multi-drug resistant Klebsiella pneumonae, E. coli and methyciline resistant Staphylococcus aureus. AB - Exploring healing power in plants emerged in prehistory of human civilization. Sustaining good health has been achieved over the millions of years by use of plant products in various traditional sockets. A major contribution of medicinal plants to health care systems is their limitless possession of bioactive components that stimulate explicit physiological actions. Luckily Pakistan is blessed with huge reservoir of plants with medicinal potential and some of them; we focused in this study for their medicinal importance.In this study we checked the antibacterial activity inherent in Ricinus communis, Solanum nigrum, Dodonaea viscose and Berberis lyceum extracts for multidrug resistance bacterial strains Klebsiella pneumonae, E. coli and methyciline resistant Staphylococcus aureus. MRSA showed sensitivity for Ricinus communis. Multidrug resistant Klebsiella pneumonae was sensitive with Pine roxburgii and Ricinus communis but weakly susceptible for Solanum nigrum. Multidrug resistant E. coli was resistant to all plant extracts. Treatment of severe infections caused by the bacterial strains used in this study with Ricinus communis, Pine roxburgii and Solanum nigrum can lower the undesired side effects of synthetic medicine and also reduce the economic burden. PMID- 23811467 TI - Making personalized prostate cancer medicine a reality: challenges and opportunities in the re-establishment of gold standards. AB - Prostate cancer is a serious multidimensional disorder that arises because of misrepresentation of signaling cascades and acquired resistance against apoptosis. It is progressively becoming more insurmountable because of rheostat like switching of oncogenic signaling in androgen dependent and androgen depleted microenvironment. Additionally, oncogenic fusion proteins have been explored in prostate cancer tissues thus adding another layer of complexity to the targeting of protein network in cancer cell and generate hurdles in the standardization of therapy. In this Review we briefly describe identified oncogenic fusion transcripts in prostate cancer and suggest utilization of this biomarker for prostate cancer diagnosis alongwith standard PSA and immunohistochemistry analysis in Pakistan. We also provide overview of animal model studies to interpret the efficacy of vitamins. PMID- 23811468 TI - Review on the demographic and social impact of methadone-medication therapy on Malaysian patients. AB - This study is an observational cross-sectional study aimed to examine the possible demographic and social characteristics of patients enrolled at the Methadone Maintenance Therapy Adherence Clinic (MMTAC) in Malaysia. Medical records from year 2009 - 2011 were Reviewed. Demographic, social characteristics and laboratory examinations such as age, gender, race, clinic attendances and urine analysis were recorded. Subjects were selected by means of convenient sampling but based on the specified inclusion and exclusion criteria. Data were analyzed by either Chi-square test, Fisher's exact test Mann-Whitney U-test, with the limit of significance was set at p < 0.05. Demographically, this study found that the ratio of Malays, Chinese and Indian enrolled to the MMTAC program is similar to the distribution of races in Malaysia. Their starting age for drug use was between 14-35 years and the age to enrolment between 30-58 years. Socially, many are unemployed, lowly educated and married. Most are drug users with a high percentage of HCV accompanied with impaired liver function. Retention rate was 87% but illicit drug use was at 57.50%. However, percentage of employment increased significantly after therapy. The study managed to identify several demographical and social distributions of patients attending the MMTAC. Although attendance rate was high, many were on illicit drug use. Nevertheless, employment rate improved significantly. PMID- 23811469 TI - TRPC signaling mechanisms and therapeutic opportunities: trapdoors are monitored by gatekeepers. AB - This Review summarizes our current state of knowledge of the functional role of TRPC channels in health and disease, with particular emphasis on current advancements in the field. Additionally, this Review provides an up-to-date summary of SKF-96365 acting on TRPC channels, and discusses strategies to further investigate the potential of these channels for therapeutic intervention. PMID- 23811470 TI - Analysis of protein aggregation kinetics using short amino acid peptide tags. AB - Understanding protein solubility, and consequently aggregation, is an important issue both from an academic and a biotechnological application viewpoints. Here we report the effects of 10 representative amino acids on the aggregation kinetics of proteins. The effects were determined by measuring the solubility of a simplified bovine pancreatic trypsin inhibitor (BPTI) variant, to which short artificial tags containing the amino acid of interest were added at its C terminus. We determined the solubility of the tagged variants as a function of equilibration time (20 min to 48 h) and total protein concentration ranging from 0.10mg/ml to 25.0mg/ml. We observed, as anticipated, that proteins precipitated when the total protein concentration exceeded a critical value. However, when the total protein concentration was further increased, the apparent solubility reached a concentration above the critical value, and slowly decreased to a value under the critical concentration upon increasing the equilibration period. We rationalized these observations by identifying three different solubility values, the "transient solubility (TS)", the "aggregation initiation concentration (AIC)" and the "long-term solubility (LS)". AIC and LS are parameters determined essentially by the amino acid types composing the tags and could be considered as an amino acid's intrinsic property. On the other hand, TS is an apparent solubility that is measured after some (20 min in our case) equilibration time and is often considered as the "solubility" of the protein. Similar aggregation kinetic patterns were observed with natural proteins, indicating the generality of the observations made using our model protein. PMID- 23811471 TI - The protein-protein interaction network of the human Sirtuin family. AB - Protein-protein interaction networks are useful for studying human diseases and to look for possible health care through a holistic approach. Networks are playing an increasing and important role in the understanding of physiological processes such as homeostasis, signaling, spatial and temporal organizations, and pathological conditions. In this article we show the complex system of interactions determined by human Sirtuins (Sirt) largely involved in many metabolic processes as well as in different diseases. The Sirtuin family consists of seven homologous Sirt-s having structurally similar cores but different terminal segments, being rather variable in length and/or intrinsically disordered. Many studies have determined their cellular location as well as biological functions although molecular mechanisms through which they act are actually little known therefore, the aim of this work was to define, explore and understand the Sirtuin-related human interactome. As a first step, we have integrated the experimentally determined protein-protein interactions of the Sirtuin-family as well as their first and second neighbors to a Sirtuin-related sub-interactome. Our data showed that the second-neighbor network of Sirtuins encompasses 25% of the entire human interactome, and exhibits a scale-free degree distribution and interconnectedness among top degree nodes. Moreover, the Sirtuin sub interactome showed a modular structure around the core comprising mixed functions. Finally, we extracted from the Sirtuin sub-interactome subnets related to cancer, aging and post-translational modifications for information on key nodes and topological space of the subnets in the Sirt family network. PMID- 23811472 TI - A biomechanical modeling study of the effects of the orbicularis oris muscle and jaw posture on lip shape. AB - PURPOSE: The authors' general aim is to use biomechanical models of speech articulators to explore how possible variations in anatomical structure contribute to differences in articulatory strategies and phone systems across human populations. Specifically, they investigated 2 issues: (a) the link between lip muscle anatomy and variability in lip gestures and (b) the constraints of coupled lip/jaw biomechanics on jaw posture in labial sounds. METHOD: The authors used a model coupling the jaw, tongue, and face. First, the influence of the orbicularis oris (OO) anatomical implementation was analyzed by assessing how changes in depth (from epidermis to the skull) and peripheralness (proximity to the lip horn center) affected lip shaping. Second, the capability of the lip/jaw system to generate protrusion and rounding, or labial closure, was evaluated for different jaw heights. RESULTS: Results showed that a peripheral and moderately deep OO implementation is most appropriate for protrusion and rounding; a superficial implementation facilitates closure; protrusion and rounding require a high jaw position; and closure is achievable for various jaw heights. CONCLUSIONS: Models provide objective information regarding possible links between anatomical and speech production variability across humans. Comparisons with experimental data will illustrate how motor control and cultural factors cope with these constraints. PMID- 23811473 TI - Influence of analogy instruction for pitch variation on perceptual ratings of other speech parameters. AB - PURPOSE: Analogy is the similarity of different concepts on which a comparison can be based. Recently, an analogy of "waves at sea" was shown to be effective in modulating fundamental frequency (F0) variation. Perceptions of intonation were not examined, as the primary aim of the work was to determine whether analogy instruction had a negative impact on other parameters of the speech signal compared with explicit instruction. The purpose of this study was (a) to determine whether changes in the standard deviation of F0, acoustically, resulted in similar changes in the perception of pitch variability and (b) to determine the perceptual influence of analogy vs. explicit instructions on speech naturalness, loudness, and rate. METHOD: Ten speech-language pathologists were asked to listen to and rate pitch variation, speech naturalness, loudness, and rate for 74 Cantonese speech samples using a visual analogue scale, which allowed raters to indicate their subjective perceptions of each parameter. RESULTS: It is revealed that listeners perceived pitch variation to be greater and speech to be more natural in analogy-instructed, rather than explicitly instructed, speech. No differences were perceived for ratings of speech loudness or speech rate. CONCLUSION: It is concluded that analogy instruction has a less negative impact on the naturalness of speech than explicit instruction and may provide a better method by which to manipulate desired pitch variation. PMID- 23811474 TI - Writing treatment for aphasia: a texting approach. AB - PURPOSE: Treatment studies have documented the therapeutic and functional value of lexical writing treatment for individuals with severe aphasia. The purpose of this study was to determine whether such retraining could be accomplished using the typing feature of a cellular telephone, with the ultimate goal of using text messaging for communication. METHOD: A 31-year-old man with persistent Broca's aphasia, severe apraxia of speech, global dysgraphia, and right hemiparesis participated in this study. Using a multiple baseline design, relearning and maintenance of single-word spellings (and oral naming) of targeted items were examined in response to traditional Copy and Recall Treatment (CART) for handwriting and a new paradigm using 1-handed typing on a cell phone keyboard (i.e., a texting version of CART referred to as T-CART). RESULTS: Marked improvements were documented in spelling and spoken naming trained in either modality, with stronger maintenance for handwriting than cell phone typing. Training resulted in functional use of texting that continued for 2 years after treatment. CONCLUSIONS: These results suggest that orthographic retraining using a cell phone keyboard has the potential to improve spelling knowledge and provide a means to improve functional communication skills. Combined training with both handwriting and cell phone typing should be considered in order to maximize the durability of treatment effects. PMID- 23811475 TI - Emotional facial and vocal expressions during story retelling by children and adolescents with high-functioning autism. AB - PURPOSE: People with high-functioning autism (HFA) have qualitative differences in facial expression and prosody production, which are rarely systematically quantified. The authors' goals were to qualitatively and quantitatively analyze prosody and facial expression productions in children and adolescents with HFA. METHOD: Participants were 22 male children and adolescents with HFA and 18 typically developing (TD) controls (17 males, 1 female). The authors used a story retelling task to elicit emotionally laden narratives, which were analyzed through the use of acoustic measures and perceptual codes. Naive listeners coded all productions for emotion type, degree of expressiveness, and awkwardness. RESULTS: The group with HFA was not significantly different in accuracy or expressiveness of facial productions, but was significantly more awkward than the TD group. Participants with HFA were significantly more expressive in their vocal productions, with a trend for greater awkwardness. Severity of social communication impairment, as captured by the Autism Diagnostic Observation Schedule (ADOS; Lord, Rutter, DiLavore, & Risi, 1999), was correlated with greater vocal and facial awkwardness. CONCLUSIONS: Facial and vocal expressions of participants with HFA were as recognizable as those of their TD peers but were qualitatively different, particularly when listeners coded samples with intact dynamic properties. These preliminary data show qualitative differences in nonverbal communication that may have significant negative impact on the social communication success of children and adolescents with HFA. PMID- 23811476 TI - Isothermal detection of multiple point mutations by a surface plasmon resonance biosensor with Au nanoparticles enhanced surface-anchored rolling circle amplification. AB - In this study, we developed a surface plasmon resonance (SPR) DNA biosensor method using surface-anchored rolling circle amplification (RCA) and Au nanoparticles modified probes (AuNPs) to isothermally detect multiple point mutations associated with drug-resistance in multidrug-resistant Mycobacterium Tuberculosis (MDRTB). A set of probes contains an allele-specific padlock probe (PLP), a capture probe and an AuNPs. The linear PLPs, circularized by ligation upon the recognition of the point mutation on DNA targets, hybridize to the capture probes via the specific tag/anti-tag recognition. Upon recognition each point mutation is identified by locating into the corresponding channel on the chip. Then the immobilized primer (capture probe)-template (circular PLP) complex are amplified isothermally as RCA and further amplified by AuNPs. The RCA products immobilized on the chip surface cause great SPR angle changes consequently. The 5 pM synthetic oligonucleotides and 8.2 pg uL(-1) of genomic DNA from clinical samples can be detected by the method. The positive mutation detection is achieved with a wild-type to mutant ratio of 5000:1. The method was demonstrated by targeting five clinically meaningful mutations in MDRTB. Thirty clinical samples were identified and they were in good agreement with the results from sequencing. PMID- 23811477 TI - Glycated hemoglobin (HbA1c) affinity biosensors with ring-shaped interdigital electrodes on impedance measurement. AB - Glycated hemoglobin (HbA1c) is one of the most important diagnostic assays for the long-term mark of glycaemic control in diabetes. This study presents an affinity biosensor for HbA1c detection which is label-free based on the impedance measurement, and it features low cost, low sample volume, and requires no additional reagent in experiments. The ring-shaped interdigital electrodes (RSIDEs) are designed to promote the distribution uniformity and immobilization efficiency of HbA1c, and are further employed to characterize the impedance change and identify various concentrations of HbA1c. The self-assembled monolayer (SAM) of thiophene-3-boronic acid (T3BA) is provided to modify the gold electrode surface. Afterwards, the esterification reaction between HbA1c and T3BA produces a relative change of electrical property on the electrode surface. The RSIDEs with SAM of T3BA exhibit a wide range from 100 to 10 ng/uL producing an approximate logarithmic decrease of impedance, a low detection limit of 1 ng/uL, a good selectivity and short-term stability for HbA1c determination. The remarkable advantages (miniaturization and low-cost) fill the bill of point-care diagnostics for portable sensor development. PMID- 23811478 TI - One-step signal amplified lateral flow strip biosensor for ultrasensitive and on site detection of bisphenol A (BPA) in aqueous samples. AB - A one-step signal amplified lateral flow strip (LFS) biosensor has been developed for ultrasensitive and on-site visual detection of bisphenol A (BPA). This signal amplified LFS was based on the dual labeling using different-sized gold nanoparticles (Duo-LFS). This Duo-LFS could achieve BPA detection with 0.5 ng/mL as the visual sensitivity by naked eye observation and with 0.076 ng/mL as the limit of detection (LOD) for semi-quantitative detection by software analysis, which is at least 10-fold improvement of the sensitivity of traditional LFS based methods. This one-step signal amplified lateral flow strip biosensor and related signal enhancement method could be adopted as a potential generous technique for all LFS-based detection methods. PMID- 23811479 TI - Paper-based chemiresistor for detection of ultralow concentrations of protein. AB - A new paper-based chemiresistor composed of a network of single-wall carbon nanotubes (SWCNTs) and anti-human immunoglobulin G (anti-HIgG) is reported herein. SWCNTs act as outstanding transducers because they provide high sensitivity in terms of resistance changes due to immunoreaction. As a result, the resistance-based biosensor reaches concentration detection as low as picomolar. The resulting paper-based biosensor is sensitive, selective and employs low-cost substrate and simple manufacturing stages. Since chemiresistors require low-power equipment and are able to detect low concentrations with inexpensive materials, the present approach may pave the way for the development of resistive biosensors at very low-cost with high performances. PMID- 23811480 TI - Bioinspired polydopamine as the scaffold for the active AuNPs anchoring and the chemical simultaneously reduced graphene oxide: characterization and the enhanced biosensing application. AB - We report here an efficient approach to enhance the performance of biosensing platform based on graphene or graphene derivate. Initially, graphene oxides (GO) nanosheets were reduced and surface functionalized by one-step oxidative polymerization of dopamine in basic solution at environment friendly condition to obtain the polydopamine (Pdop) modified reduced graphene oxides (PDRGO). The bioinspired surface was further used as a support to anchor active gold nanoparticles (AuNPs). The morphology and structure of the as-prepared AuNPs/PDRGO nanocomposite were investigated by field-emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR). Electrochemical studies demonstrate that the as prepared AuNPs/PDRGO hybrid materials possess excellent electrochemical properties and electrocatalytic activity toward the oxidation of NADH at low potential (0.1 V vs. SCE) with the fast response (15s) and the broad linear range (5.0 * 10(-8)-4.2 * 10(-5)M). Thus, this AuNPs/PDRGO nanocomposite can be further used to fabricate a sensitive alcohol biosensor using alcohol dehydrogenase (ADH), by simply incorporating the specific enzyme within the composite matrix with the aid of chitosan (Chit). PMID- 23811481 TI - Enzyme-free and ultrasensitive electrochemical detection of nucleic acids by target catalyzed hairpin assembly followed with hybridization chain reaction. AB - An isothermal, enzyme-free and ultrasensitive protocol for electrochemical detection of DNA is proposed based on the ingenious combination of target catalyzed hairpin assembly and hybridization chain reaction (HCR) strategies for two-step signal amplification. The DNA hairpin assembly on the electrode is triggered by target DNA, accompanied by the release of target DNA for the successive hybridization and assembly process. The newly emerging DNA fragment on the electrode after hairpin assembly is further used to propagate the HCR between methylene blue-labeled signal probe and auxiliary probe, inducing a remarkably amplified electrochemical signal. The current dual signal amplification strategy is relatively simple and inexpensive owing to avoid the use of any kind of enzyme or sophisticated equipment. It can achieve a sensitivity of 0.1 fM with a wide linear dynamic range from 1 * 10(-15) to 1 * 10(-10)M and discriminate mismatched DNA from perfect matched target DNA with a high selectivity. The high sensitivity and selectivity make this method a great potential for early diagnosis in gene related diseases. PMID- 23811482 TI - Power-free chip enzyme immunoassay for detection of prostate specific antigen (PSA) in serum. AB - A power-free, portable "Chip EIA" was designed to render the popular Enzyme Linked Immunosorbent Assay (ELISA) more suitable for point-of-care testing. A number of microfluidic platforms have enabled miniaturization of the conventional microtitre plate ELISA, however, they require external pumping systems, valves, and electric power supply. The Chip EIA platform has eliminated the need for pumps and valves through utilizing a simple permanent magnet and magnetic nanoparticles. The magnetic nanoparticles act as solid support to capture the target and are then moved through chambers harboring different reagents necessary to perform a sandwich ELISA. The use of magnetic nanoparticles increases the volume-to-surface ratio reducing the assay time to 30 min. Changing the color of horseradish peroxidase (HRP) substrate to green indicates a positive result. In addition, a quantitative read-out was obtained through the use of cellphone camera imaging and analyzing the images using Matlab(r). Cell phones, including smart ones, are readily available almost everywhere. The Chip EIA device was used to assay total prostate specific antigen (tPSA) in 19 serum samples. The PSA Chip EIA was tested for accuracy, precision, repeatability, and the results were correlated to the commercial Beckman Colter, Hybritech immunoassay(r) for determination of tPSA in serum samples with a Pearson correlation coefficient (R(2)=0.96). The lower detection limit of the PSA Chip EIA was 3.2 ng/mL. The assay has 88.9% recovery and good reproducibility (% CV of 6.5). We conclude that the developed Chip EIA can be used for detection of protein biomarkers in biological specimens. PMID- 23811483 TI - An electrochemical immunosensor for sensitive detection of Escherichia coli O157:H7 using C60 based biocompatible platform and enzyme functionalized Pt nanochains tracing tag. AB - A sensitive and efficient electrochemical immunosensor was designed for amperometric detection of heat-killed Escherichia coli O157:H7 (E. coli O157:H7). The immunosensing platform was first composed of fullerene (C60), ferrocene (Fc) and thiolated chitosan (CHI-SH) composite nano-layer which could offer rich -SH functional groups and maintain good biocompatibility. Then the Au nanoparticles coated SiO2 nanocomposites (Au-SiO2) were assembled on the CHI-SH/Fc/C60 composite. Next, the large amount of avidin (SA) was coated on the Au-SiO2 surface, which was used to immobilize biotinylated capture antibodies of E. coli O157:H7 (bio-Ab1) through the covalent reaction between biotin and avidin. With surface area enhancement by C60 and Au-SiO2, and directional immobilization by avidin-biotin system, the amount of immobilized bio-Ab1 can be enhanced obviously. For signal amplification, the glucose oxidase (GOD) loaded Pt nanochains (PtNCs) were used as tracing tag to label signal antibodies (Ab2). With a sandwich-type immunoreaction, the concentration volume of heat-killed E. coli O157:H7 ranged from 3.2 * 10(1) to 3.2 * 10(6)CFU/mL with a limit of detection down to 15 CFU/mL (S/N=3), which could be well accepted for early clinical detection. The studied system provides new opportunities, and might speed up disease diagnosis, treatment and prevention with pathogen. PMID- 23811484 TI - Impedimetric immunosensor based on gold nanoparticles modified graphene paper for label-free detection of Escherichia coli O157:H7. AB - In this study, a low-cost and robust impedimetric immunosensor based on gold nanoparticles modified free-standing graphene paper electrode for rapid and sensitive detection of Escherichia coli O157:H7 (E. coli O157:H7) was developed. Graphene paper was prepared by chemical reduction of graphene oxide paper obtained from vacuum filtration method. Scanning electron microscope, Raman spectroscopy and X-ray diffraction techniques were employed to investigate the surface morphology and crystal structure of the prepared graphene paper. The gold nanoparticles were grown on the surface of graphene paper electrode by one-step electrodeposition technique. The immobilization of anti-E. coli O157:H7 antibodies on paper electrode were performed via biotin-streptavidin system. Electrochemical impedance spectroscopy was used to detect E. coli O157:H7 captured on the paper electrode. Results show that the developed paper immunosensor possesses greatly enhanced sensing performance, such as wide linear range (1.5 * 10(2)-1.5 * 10(7) cfu mL(-1)), low detection limit (1.5 * 10(2) cfu mL(-1)), and excellent specificity. Furthermore, flexible test demonstrate the graphene paper based sensing device has high tolerability to mechanical stress. The strategy of structurally integrating metal nanomaterials, graphene paper, and biorecognition molecules would provide new insight into design of flexible immunosensors for routine sensing applications. PMID- 23811485 TI - A FRET ratiometric fluorescence sensing system for mercury detection and intracellular colorimetric imaging in live Hela cells. AB - The detection of mercury in biological systems and its imaging is of highly importance. In this work, a ratiometric fluorescence sensor is developed based on fluorescence resonance energy transfer (FRET) with N-acetyl-L-cysteine functionalized quantum dots (NAC-QDs) as donor and Rhodamine 6G derivative mercury conjugate (R6G-D-Hg) as acceptor. Mercury annihilates the fluorescence of NAC-QDs at 508 nm and meanwhile interacts with R6G derivative to form a fluorescent conjugate giving rise to emission at 554 nm. Resonance energy transfer from NAC-QDs to R6G-D-Hg is triggered by mercury resulting in concentration-dependent variation of fluorescence ratio F508/F554. A linear calibration of F508/F554 versus mercury concentration is obtained within 5-250 MUg L(-1), along with a detection limit of 0.75 MUg L(-1) and a RSD of 3.2% (175 MUg L(-1)). The sensor generates colorimetric images for mercury within 0-250 MUg L(-1), facilitating visual detection of mercury with a distinguishing ability of 50 MUg L(-1). This feature is further demonstrated by colorimetric imaging of intracellular mercury. On the other hand, the NAC-QDs/R6G-D FRET sensing system is characterized by a combination of high sensitivity and selectivity. The present study provides an approach for further development of ratiometric sensors dedicated to selective in vitro or in vivo sensing some species of biologically interest. PMID- 23811487 TI - Characterization of beta-casein gene in Indian riverine buffalo. AB - The study aimed at characterization of buffalo beta-casein gene and its promoter by PCR-SSCP analysis. Complete beta-casein exon VII region analysis revealed two SSCP band patterns, with pattern-I representing predominant allele B (85%) present in homozygous (genotype BB) condition and pattern-II representing a rare allele A1 present in heterozygous condition (genotype A1B). Sequencing of two patterns revealed three nucleotide substitutions at codon 68, 151 and 193 of exon VII. The cDNA sequence of buffalo beta-casein gene indicated three further nucleotide substitutions between allele A1 and B at codon 10, 39, and 41. Analysis of beta-casein proximal promoter region (-350 upstream to +32) revealed four SSCP band patterns. These SSCP patterns corresponded to nucleotide substitutions at seven locations within 382 bp 5' UTR region of beta-casein gene. Haplotype analysis suggested pattern-I of exon VII (wild type) was associated with three types of promoters and pattern-II of exon VII (rare type) corresponded to one exclusive type of promoter. The study suggested two haplotypes of exon VII and four haplotypes of promoter for buffalo beta-casein. PMID- 23811488 TI - GSTP1 Ile105Val polymorphism and colorectal cancer risk: an updated analysis. AB - BACKGROUND: Many studies have investigated the association between the Glutathione S transferase-P1 (GSTP1) Ile105Val polymorphism and colorectal cancer (CRC) susceptibility, but the results were conflicting. The aim of this study is to quantitatively summarize the relationship between this polymorphism and CRC risk. METHODS: Two investigators independently searched the Medline, Embase, China National Knowledge Infrastructure (CNKI) and Chinese Biomedicine databases for studies published before December 2012. Summary odds ratios (ORs) and 95% confidence intervals (95% CIs) for GSTP1 polymorphism and CRC were calculated in a fixed-effects model (the Mantel-Haenszel method) and a random-effects model (the DerSimonian and Laird method) when appropriate. RESULTS: This meta-analysis included 29 case-control studies, which included 8160 CRC cases and 10,450 controls. Overall, the variant genotypes (ValVal and IleVal) of the Ile105Val were not associated with CRC risk when compared with the wild-type IleIle homozygote. Similarly, no associations were found in the dominant and recessive models. When stratifying for ethnicity, source of controls, study sample size and genotyping methods, no evidence of significant association was observed in any subgroup, except among those studies taking others as genotyping methods (recessive model, OR=0.71, 95%CI=0.52-0.96). Limiting the analysis to the studies within Hardy-Weinberg equilibrium, the results were persistent and robust. No publication bias was found in the present study. CONCLUSION: This updated meta analysis suggests that the GSTP1 Ile105Val polymorphism may not be associated with CRC risk, while the observed decrease in risk of CRC may be due to small study bias. PMID- 23811486 TI - White matter microstructure correlates of inhibition and task-switching in adolescents. AB - Although protracted prefrontal gray matter development is associated with concomitant executive function (EF) development in adolescents, few studies have explored the relationship between white matter and EF. This study examined the relationship between white matter microstructure and two aspects of EF, inhibition and task-switching, in a sample of 84 adolescents using diffusion tensor imaging (DTI). Tract-Based Spatial Statistics (TBSS) were used to examine fractional anisotropy (FA) and mean diffusivity (MD). Adolescents completed the Color-Word Interference task from the Delis-Kaplan Executive Function System, a clinical version of the Stroop task. Inhibition and task-switching performance were group normalized and measured using both reaction time and errors. Performance and the interaction of age and performance were regressed on FA and MD white matter skeletons, controlling for age and IQ, separately for inhibition and task-switching. Follow up analyses examined the relative contributions of axial and radial diffusivities. Greater FA in the anterior corona radiata (ACR) was associated with better inhibition, independent of age. Greater FA in the SCR and precentral gyrus white matter were associated with better task-switching, regardless of age, whereas an association between FA in the ACR and task switching was dependent on age. There were no significant associations between MD and performance. Results suggest better inhibition and task-switching are associated with greater integrity of white matter microstructure in regions supporting cross-cortical and cortical-subcortical connections stemming from the prefrontal cortex. These findings are consistent with functional studies of cognitive control and models of EF that propose separate, yet related, latent factors. PMID- 23811489 TI - Chronic risperidone exposure does not show any evidence of bone mass deterioration in animal model of schizophrenia. AB - BACKGROUND: It has been shown that bone mass is centrally regulated. Thus schizophrenia being a disease of the central nervous system is an interesting model for studying bone. Most second generation antipsychotic drugs including risperidone are used in the treatment of schizophrenia. Weight gain and metabolic disturbances are common side effects. OBJECTIVE: The aims of this study were to investigate bone mass, body composition and light microscopic pathology examinations of femur in an animal model of schizophrenia (pharmacologically induced by postnatally administered phencyclidine-PCP) and to further examine the effects of chronic treatment with risperidone on these parameters in rats. METHODS: Four groups of male rats were studied:1) control group-NaCl postnatally administered, n=9; 2) PCP group-postnatal PCP administration to rat pups (on day 2,6,9 and 12), n=6; 3) risperidone group-rats treated with risperidone alone for 9weeks from day 35 (NaCl-RSP group, n=7); 4) PCP rats treated with risperidone for 9weeks from day 35 (PCP-RSP group, n=7). Bone mass and body composition were measured in vivo by dual X ray absorptiometry (areal DXA and fat mass). Light microscopic analysis of the femoral metaphysis was performed in all groups after sacrificing the animals. RESULTS: Postnatal phencyclidine (PCP) administration to rat pups caused a long lasting reduction of total bone mass versus control animals (aDXA 128+/-2mg/cm(2) vs 139+/-5mg/cm(2), p<0.05). Examination of the femoral bone revealed a decrease in the number and thickness of the metaphyseal trabecule and cortical thinning. There was a decrease in total and retroperitoneal fat. Nine weeks of administration of risperidone alone to rats, resulted in significant weight gain and had no effect on bone mass versus control animals (aDXA was 136+/-7mg/cm(2) vs 139+/-5mg/cm(2), p>0.05). Furthermore, there were no changes in the light microscopic analysis of femoral metaphysis in comparison with controls. When PCP rats were treated with risperidone, they did not change their body weight nor bone mass versus PCP alone (aDXA 126+/-2mg/cm(2) vs 128+/-2mg/cm(2), p>0.05) but intriguingly on examination of the femoral bone an increase in the number and thickness of the metaphyseal trabecule was found (trabecular thickness 0.6+/-0.1MUm vs 0.35+/-0.1MUm, p<0.01). CONCLUSION: This study shows that in the PCP rat model of schizophrenia bone mass is reduced. When PCP rats were treated with risperidone bone mass remained unchanged but intriguingly and unexpectedly light microscopic examination of femoral metaphysis showed an increase in thickness of metaphyseal trabeculae. The mechanism of risperidone's action on bone remains to be clarified. PMID- 23811490 TI - The contribution of hip geometry to the prediction of hip osteoarthritis. AB - OBJECTIVE: To determine how well measures of hip geometry can predict radiological incident hip osteoarthritis (HOA) compared to well known clinical risk factors. DESIGN: The study population is part of the Rotterdam Study, a prospective population-based cohort. Baseline pelvic radiographs were used to measure hip geometry by two methods: Statistical Shape Models (SSM) and predefined geometry parameters (PGPs). Incident HOA (Kellgren and Lawrence (KL) >= 2) was assessed in 688 participants after 6.5 years without radiographic HOA at baseline. The ability to predict HOA was quantified using the area under the Receiver Operating Characteristics (ROC) curve (AUC). RESULTS: Comparison of the two methods showed that both contain information that is not captured by the other method. At 6.5 years follow-up 132 hips had incident HOA. Five PGPs (Wiberg angle, Neck Width (NW), Pelvic Width (PW), Hip Axis Length (HAL) and Triangular Index (TI)) and two SSM (modes 5 and 9) were significant predictors of HOA (P = 0.007). Hip geometry added 7% to the prediction obtained by clinical risk factors (AUC = 0.67 (geometry), 0.66 (gender, age, Body Mass Index (BMI)) and combining both: AUC = 0.73, respectively). Mode 12 (associated with position of the femoral head in acetabulum) and Wiberg angle were predictors of HOA in participants without radiological signs at baseline (KL = 0). Although the strength of the prediction decreased for all variables at a longer follow-up, the contribution of hip geometry was still significant (P = 0.01). CONCLUSIONS: Hip geometry has a moderate ability to predict HOA in participants with and without initial signs of osteoarthritis (OA), similar to and largely independent of the predictive value of clinical risk factors. PMID- 23811491 TI - Manual therapy, exercise therapy, or both, in addition to usual care, for osteoarthritis of the hip or knee. 2: economic evaluation alongside a randomized controlled trial. AB - OBJECTIVE: To evaluate the cost effectiveness of manual physiotherapy, exercise physiotherapy, and a combination of these therapies for patients with osteoarthritis of the hip or knee. METHODS: 206 Adults who met the American College of Rheumatology criteria for hip or knee osteoarthritis were included in an economic evaluation from the perspectives of the New Zealand health system and society alongside a randomized controlled trial. Resource use was collected using the Osteoarthritis Costs and Consequences Questionnaire. Quality-adjusted life years (QALYs) were calculated using the Short Form 6D. Willingness-to-pay threshold values were based on one to three times New Zealand's gross domestic product (GDP) per capita of NZ$ 29,149 (in 2009). RESULTS: All three treatment programmes resulted in incremental QALY gains relative to usual care. From the perspective of the New Zealand health system, exercise therapy was the only treatment to result in an incremental cost utility ratio under one time GDP per capita at NZ$ 26,400 (-$34,081 to $103,899). From the societal perspective manual therapy was cost saving relative to usual care for most scenarios studied. Exercise therapy resulted in incremental cost utility ratios regarded as cost effective but was not cost saving. For most scenarios combined therapy was not as cost effective as the two therapies alone. CONCLUSIONS: In this study, exercise therapy and manual therapy were more cost effective than usual care at policy relevant values of willingness-to-pay from both the perspective of the health system and society. Trial registration number Australian New Zealand Clinical Trials Registry ACTRN12608000130369. PMID- 23811492 TI - Marijuana smoking does not accelerate progression of liver disease in HIV hepatitis C coinfection: a longitudinal cohort analysis. AB - BACKGROUND: Marijuana smoking is common and believed to relieve many symptoms, but daily use has been associated with liver fibrosis in cross-sectional studies. We aimed to estimate the effect of marijuana smoking on liver disease progression in a Canadian prospective multicenter cohort of human immunodeficiency virus/hepatitis C virus (HIV/HCV) coinfected persons. METHODS: Data were analyzed for 690 HCV polymerase chain reaction positive (PCR-positive) individuals without significant fibrosis or end-stage liver disease (ESLD) at baseline. Time-updated Cox Proportional Hazards models were used to assess the association between the average number of joints smoked/week and progression to significant liver fibrosis (APRI >= 1.5), cirrhosis (APRI >= 2) or ESLD. RESULTS: At baseline, 53% had smoked marijuana in the past 6 months, consuming a median of 7 joints/week (IQR, 1-21); 40% smoked daily. There was no evidence that marijuana smoking accelerates progression to significant liver fibrosis (APRI >= 1.5) or cirrhosis (APRI >= 2; hazard ratio [HR]: 1.02 [0.93-1.12] and 0.99 [0.88-1.12], respectively). Each 10 additional joints/week smoked slightly increased the risk of progression to a clinical diagnosis of cirrhosis and ESLD combined (HR, 1.13 [1.01-1.28]). However, when exposure was lagged to 6-12 months before the diagnosis, marijuana was no longer associated with clinical disease progression (HR, 1.10 [0.95-1.26]). CONCLUSIONS: In this prospective analysis we found no evidence for an association between marijuana smoking and significant liver fibrosis progression in HIV/HCV coinfection. A slight increase in the hazard of cirrhosis and ESLD with higher intensity of marijuana smoking was attenuated after lagging marijuana exposure, suggesting that reverse causation due to self medication could explain previous results. PMID- 23811493 TI - Left ventricular hypertrophy and endothelial dysfunction in chronic kidney disease. AB - Aim Mortality, predominantly due to cardiovascular events, is high in patients with chronic kidney disease (CKD) and left ventricular hypertrophy (LVH) is a strong risk factor. Vascular endothelial dysfunction (ED) is common in CKD, but its potential contribution to LVH in non-dialysis CKD is unknown. This study investigated the association of ED with LVH in non-dialysis CKD patients. METHODS AND RESULTS: We studied 30 CKD patients (17 pre-dialysis and 13 renal transplant recipients) and 29 age-gender-matched controls. In both groups, high-sensitivity C-reactive protein (hsCRP) levels, systemic ED (brachial artery flow-mediated dilatation, FMD), and LVH using two-dimensional echocardiography were measured. LV mass index (LVMI) was calculated using Penn formula and indexed by height. CKD patients had higher CRP levels (3.9 +/- 2.8 vs. 1.0 +/- 0.7 mg/L; P < 0.001), reduced FMD (3.2 +/- 2.1 vs. 6.1 +/- 1.9%; P < 0.001), and increased LVMI (146.1 +/- 40.2 vs. 105.3 +/- 26.2 g/m; P < 0.001), compared with controls. In CKD patients, LVMI increased with decreasing FMD (r = -0.371; P = 0.043) and FMD decreased with increasing CRP (r = -0.741; P < 0.001). Patients with low FMD <2.3% had higher CRP and LVMI (161.9 +/- 48.9 vs. 130.4 +/- 20.7 g/m; P = 0.033), compared with CKD patients with FMD >=2.3%. There was no significant difference in age, blood pressure, cholesterol, FMD, and LVMI between pre-dialysis and post renal transplant CKD patients. In multivariate regression, the relationship between LVMI and FMD remained significant after adjusting for age, diabetes, and smoking (adjacent beta = -0.396; P = 0.004). CONCLUSION: This pilot study demonstrates for the first time a relationship of ED with LVH in non-dialysis CKD patients; suggesting but not proving a cause-effect relationship. PMID- 23811494 TI - Concordance and reproducibility between M-mode, tissue Doppler imaging, and two dimensional strain imaging in the assessment of mitral annular displacement and velocity in patients with various heart conditions. AB - AIMS: Mitral annular (MA) displacement reflects longitudinal left ventricular (LV) deformation and systolic velocity measurements reflect the rate of contraction; both are valuable in the diagnosis and prognosis of cardiac disease. The aim of this study was to test the agreement and reproducibility between motion mode (M-mode), colour tissue Doppler imaging (TDI), and two-dimensional strain imaging (2DSI) when measuring MA displacement and systolic velocity. METHODS AND RESULTS: Using GE Healthcare Vivid 7 and E9 and Echopac BT11 software, MA displacement and velocity measurements by 2DSI, TDI, and M-mode determined in the septal and lateral walls in the apical four-chamber view were assessed in 50 control subjects and in 168 patients with various cardiac anomalies known to affect longitudinal displacement such as heart failure, mitral regurgitation, LV hypertrophy, and LV dilation. Intra- and inter-observer variability were tested using the Bland-Altman method in 125 patients. A relatively low bias between M-mode and TDI with respect to MA displacement (mean difference +/- 1.96 standard deviation: 0.08 +/- 0.35 cm) and a low bias between TDI and 2DSI with respect to MA peak systolic velocity (-0.13 +/- 1.87 cm/s) were found. Reproducibility was acceptable for all methods with TDI having the lowest intra- and inter-observer variability. CONCLUSION: LV function could be assessed in terms of MA displacement and systolic velocity using M-mode, TDI, and 2DSI. None of the measurement techniques are, however, interchangeable. Overall, TDI seems to be the most robust method, having the lowest observer variability. PMID- 23811495 TI - Generation and evaluation of a human corneal model cell system for ophthalmologic issues using the HPV16 E6/E7 oncogenes as uniform immortalization platform. AB - The present study aimed at employing the human papillomavirus type 16 (HPV16) E6/E7 gene platform, to create a uniform authentic in vitro model cell system of the human cornea for ophthalmologic issues and here especially for prospective biomaterial evaluations for therapeutic regenerative approaches. Therefore, HPV16 E6/E7 genes were employed as uniform platform to immortalize primary human corneal keratinocytes (IHCK), fibroblasts (IHCF), and endothelial (IHCE) cells. qPCR revealed that E6/E7 mRNA transcription persisted at rising passages and FISH detection of the chromosome portfolio 1, 8, 10 and 18 showed fairly the disomic cytogenetic status. Hot spot passages proved oscillation of aneuploidies in the entire passage spectrum under study, while hot spot aneuploidies annotated prevalence for distinct chromosomes. Though IIF revealed general endurance, tissue-innate corneal biomarkers were modulated, i.e. expressed in a temporal confluence, temporal-spatial or passage-dependent manner. In summary, by the fairly normal chromosomal status, and expression of tissue-innate biomarkers, we created for the first time a uniform authentic in vitro model cell system of the human cornea, by application of the HPV16 E6/E7 immortalization platform only. This system renders a precious tool for prospective iterative in vitro studies on issues such as corneal tissue homeostasis, pharmaceutical generics, and/or evaluation of new biomaterials for clinical corneal applications. PMID- 23811496 TI - Histidine based adsorbents for selective removal of monoclonal immunoglobulin IgM antibodies from Waldenstrom's macroglobulinemia patient sera: a preliminary study. AB - Waldenstrom's macroglobulinemia (WM) is considered by the Revised European American Lymphoma (REAL) and World Health Organization (WHO) as a clinical lympho plasmacytic syndrome associated with high monoclonal (IgM) secretion. The hyper viscosity syndrome is associated with several clinical disorders of monoclonal IgM. Patients with clinical symptoms of hyper viscosity should be treated with plasma pheresis, which is limited by its non-selective removal of all plasma components. These limitations have steered efforts to find a more specific removal according to clinical needs and avoiding plasma components replacement. Removal by specific adsorption is the most powerful selective apheresis technique. The active adsorbed ligand is covalently bound to an insoluble matrix through which plasma is passed. Amino acids have been introduced as ligands in clinical apheresis for the removal of auto antibodies associated with autoimmune diseases. The present preliminary study describes the binding of monoclonal IgM antibodies from sera of patients with WM, on histidine immobilized to activated sepharose. The advantages of efficient binding and elution, suggest histidine adsorbents as prospective clinical means suitable for the removal of monoclonal IgM from sera of patients diagnosed with WM. The advantages of efficient adsorption and elution, non toxicity of histidine, good selectivity, good stability, as well as their low cost strongly suggest histidine adsorbents as prospective clinical means suitable for the removal of monoclonal IgM from sera of patients diagnosed with WM. PMID- 23811497 TI - Quantification of vitamin D and 25-hydroxyvitamin D in soft tissues by liquid chromatography-tandem mass spectrometry. AB - Inadequate data on tissue distribution of vitamin D and its metabolites remains a barrier to defining health outcomes of vitamin D intake and 25-hydroxyvitamin D (25(OH)D) status. The purpose of this study was to develop a method for the analysis of vitamin D2 (ergocalciferol), vitamin D3 (cholecalciferol), 25(OH)D2, and 25(OH)D3 in soft tissues, and determine distribution in select tissues from a dose-response study of vitamin D2 and vitamin D3 in rats. Liver, gastrocnemius muscle, and epididymal fat homogenates were analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS) with electrospray ionization following liquid liquid extraction, solid-phase extraction, and derivatization with 4-phenyl-1,2,4 triazoline-3,5-dione (PTAD). A dose-response was observed in most tissues for vitamin D and 25(OH)D from both vitamers. Vitamin D concentration was greater in epididymal fat than gastrocnemius muscle and liver, but 25(OH)D concentration was not significantly different between tissues. Soft tissues of rats fed crystalline vitamin D3 had higher concentrations of total vitamin D than those of rats fed yeast-derived vitamin D2, while total 25(OH)D concentrations were similar between vitamin D sources. This method is well suited to more complete studies of vitamin D bioavailability and metabolite tissue distribution. PMID- 23811498 TI - Lentiviral mediated expression of a NGF-soluble Nogo receptor 1 fusion protein promotes axonal regeneration. AB - Nogo receptor 1 (NgR1) mediates the inhibitory effects of several myelin associated inhibitors (MAIs) on axonal regeneration in the central nervous system. A truncated soluble NgR1 (sNgR) has been reported to act as a decoy receptor to block the actions of MAIs. In this study, we fused the sNgR to nerve growth factor (NGF) and used NGF as a carrier to deliver sNgR to the intercellular space to neutralize MAIs. NGF in NGF-sNgR remained biologically active and induced sprouting of calcitonin gene related peptide containing axons when expressed in the spinal cord using a lentiviral vector (LV). Secreted NGF sNgR promoted neurite outgrowth of dissociated dorsal root ganglion neurons on myelin protein substrate. In a rat dorsal column transection model, regenerating sensory axons were found to grow into the lesion cavity in animals injected with LV/NGF-sNgR, while in animals injected with LV/GFP or LV/NGF-GFP few sensory axons entered the lesion cavity. The results indicate that NGF-sNgR fusion protein can reduce the inhibition of MAIs and facilitate sensory axon regeneration. The fusion constructs may be modified to target other molecules to promote axonal regeneration and the concept may also be adapted to develop gene therapy strategies to treat other disorders. PMID- 23811499 TI - Rapid detection of Ceratocystis platani inoculum by quantitative real-time PCR assay. AB - Ceratocystis platani is the causal agent of canker stain of plane trees, a lethal disease able to kill mature trees in one or two successive growing seasons. The pathogen is a quarantine organism and has a negative impact on anthropogenic and natural populations of plane trees. Contaminated sawdust produced during pruning and sanitation fellings can contribute to disease spread. The goal of this study was to design a rapid, real-time quantitative PCR assay to detect a C. platani airborne inoculum. Airborne inoculum traps (AITs) were placed in an urban setting in the city of Florence, Italy, where the disease was present. Primers and TaqMan minor groove binder (MGB) probes were designed to target cerato-platanin (CP) and internal transcribed spacer 2 (ITS2) genes. The detection limits of the assay were 0.05 pg/MUl and 2 fg/MUl of fungal DNA for CP and ITS, respectively. Pathogen detection directly from AITs demonstrated specificity and high sensitivity for C. platani, detecting DNA concentrations as low as 1.2 * 10(-2) to 1.4 * 10(-2) pg/MUl, corresponding to ~10 conidia per ml. Airborne inoculum traps were able to detect the C. platani inoculum within 200 m of the closest symptomatic infected plane tree. The combination of airborne trapping and real time quantitative PCR assay provides a rapid and sensitive method for the specific detection of a C. platani inoculum. This technique may be used to identify the period of highest risk of pathogen spread in a site, thus helping disease management. PMID- 23811500 TI - Establishment of a simple Lactobacillus plantarum cell consortium for cellulase xylanase synergistic interactions. AB - Lactobacillus plantarum is an attractive candidate for bioprocessing of lignocellulosic biomass due to its high metabolic variability, including its ability to ferment both pentoses and hexoses, as well as its high acid tolerance, a quality often utilized in industrial processes. This bacterium grows naturally on biomass; however, it lacks the inherent ability to deconstruct lignocellulosic substrates. As a first step toward engineering lignocellulose-converting lactobacilli, we have introduced genes coding for a GH6 cellulase and a GH11 xylanase from a highly active cellulolytic bacterium into L. plantarum. For this purpose, we employed the recently developed pSIP vectors for efficient secretion of heterologous proteins. Both enzymes were secreted by L. plantarum at levels estimated at 0.33 nM and 3.3 nM, for the cellulase and xylanase, respectively, in culture at an optical density at 600 nm (OD600) of 1. Transformed cells demonstrated the ability to degrade individually either cellulose or xylan and wheat straw. When mixed together to form a two-strain cell-based consortium secreting both cellulase and xylanase, they exhibited synergistic activity in the overall release of soluble sugar from wheat straw. This result paves the way toward metabolic harnessing of L. plantarum for novel biorefining applications, such as production of ethanol and polylactic acid directly from plant biomass. PMID- 23811501 TI - Measurement of predation and biofilm formation under different ambient oxygen conditions using a simple gasbag-based system. AB - Bdellovibrio bacteriovorus and Micavibrio aeruginosavorus are Gram-negative bacteria characterized by predatory behavior. The aim of this study was to evaluate the ability of the predators to prey in different oxygen environments. When placed on an orbital shaker, a positive association between the rate of aeration and predation was observed. To further examine the effects of elevated ambient oxygen levels on predation, a simple gasbag system was developed. Using the system, we were able to conduct experiments at ambient oxygen levels of 3% to 86%. When placed in gasbags and inflated with air, 50% O2, and 100% O2, positive predation was seen on both planktonic and biofilm-grown prey cells. However, in low-oxygen environments, predatory bacteria were able to attack only prey cells grown as biofilms. To further evaluate the gasbag system, biofilm development of Gram-positive and Gram-negative microorganisms was also measured. Although the gasbag system was found to be suitable for culturing bacteria that require a low oxygen environment, it was not capable of supporting, with its current configuration, the growth of obligate anaerobes in liquid or agar medium. PMID- 23811502 TI - HylA, an alternative hydrolase for initiation of catabolism of the phenylurea herbicide linuron in Variovorax sp. strains. AB - Variovorax sp. strain WDL1, which mineralizes the phenylurea herbicide linuron, expresses a novel linuron-hydrolyzing enzyme, HylA, that converts linuron to 3,4 dichloroaniline (DCA). The enzyme is distinct from the linuron hydrolase LibA enzyme recently identified in other linuron-mineralizing Variovorax strains and from phenylurea-hydrolyzing enzymes (PuhA, PuhB) found in Gram-positive bacteria. The dimeric enzyme belongs to a separate family of hydrolases and differs in Km, temperature optimum, and phenylurea herbicide substrate range. Within the metal dependent amidohydrolase superfamily, HylA and PuhA/PuhB belong to two distinct protein families, while LibA is a member of the unrelated amidase signature family. The hylA gene was identified in a draft genome sequence of strain WDL1. The involvement of hylA in linuron degradation by strain WDL1 is inferred from its absence in spontaneous WDL1 mutants defective in linuron hydrolysis and its presence in linuron-degrading Variovorax strains that lack libA. In strain WDL1, the hylA gene is combined with catabolic gene modules encoding the downstream pathways for DCA degradation, which are very similar to those present in Variovorax sp. SRS16, which contains libA. Our results show that the expansion of a DCA catabolic pathway toward linuron degradation in Variovorax can involve different but isofunctional linuron hydrolysis genes encoding proteins that belong to evolutionary unrelated hydrolase families. This may be explained by divergent evolution and the independent acquisition of the corresponding genetic modules. PMID- 23811503 TI - Detection of the emerging Shiga toxin-producing Escherichia coli O26:H11/H- sequence type 29 (ST29) clone in human patients and healthy cattle in Switzerland. AB - Shiga toxin-producing Escherichia coli O26:H11/H(-) strains showing the characteristics of the emerging human-pathogenic ST29 clone (stx2a(+) only, eae(+), plasmid gene profile hlyA(+) etpD(+)) were detected from human patients and healthy cattle, indicating a possible reservoir. Sheep also appear to shed strains related to the new pathogenic clone O26:H11/H(-) (ST29, stx1a(+) only, eae(+), plasmid gene profile hlyA(+) etpD(+)). PMID- 23811504 TI - pA506, a conjugative plasmid of the plant epiphyte Pseudomonas fluorescens A506. AB - Conjugative plasmids are known to facilitate the acquisition and dispersal of genes contributing to the fitness of Pseudomonas spp. Here, we report the characterization of pA506, the 57-kb conjugative plasmid of Pseudomonas fluorescens A506, a plant epiphyte used in the United States for the biological control of fire blight disease of pear and apple. Twenty-nine of the 67 open reading frames (ORFs) of pA506 have putative functions in conjugation, including a type IV secretion system related to that of MOBP6 family plasmids and a gene cluster for type IV pili. We demonstrate that pA506 is self-transmissible via conjugation between A506 and strains of Pseudomonas spp. or the Enterobacteriaceae. The origin of vegetative replication (oriV) of pA506 is typical of those in pPT23A family plasmids, which are present in many pathovars of Pseudomonas syringae, but pA506 lacks repA, a defining locus for pPT23A plasmids, and has a novel partitioning region. We selected a plasmid-cured derivative of A506 and compared it to the wild type to identify plasmid-encoded phenotypes. pA506 conferred UV resistance, presumably due to the plasmid-borne rulAB genes, but did not influence epiphytic fitness of A506 on pear or apple blossoms in the field. pA506 does not appear to confer resistance to antibiotics or other toxic elements. Based on the conjugative nature of pA506 and the large number of its genes that are shared with plasmids from diverse groups of environmental bacteria, the plasmid is likely to serve as a vehicle for genetic exchange between A506 and its coinhabitants on plant surfaces. PMID- 23811506 TI - Assessment of anaerobic toluene biodegradation activity by bssA transcript/gene ratios. AB - Benzylsuccinate synthase (bssA) genes associated with toluene degradation were profiled across a groundwater contaminant plume under nitrate-reducing conditions and were detected in significant numbers throughout the plume. However, differences between groundwater and core sediment samples suggested that microbial transport, rather than local activity, was the underlying cause of the high copy numbers within the downgradient plume. Both gene transcript and reactant concentrations were consistent with this hypothesis. Expression of bssA genes from denitrifying toluene degraders was induced by toluene but only in the presence of nitrate, and transcript abundance dropped rapidly following the removal of either toluene or nitrate. The drop in bssA transcripts following the removal of toluene could be described by an exponential decay function with a half-life on the order of 1 h. Interestingly, bssA transcripts never disappeared completely but were always detected at some level if either inducer was present. Therefore, the detection of transcripts alone may not be sufficient evidence for contaminant degradation. To avoid mistakenly associating basal-level gene expression with actively degrading microbial populations, an integrated approach using the ratio of functional gene transcripts to gene copies is recommended. This approach minimizes the impact of microbial transport on activity assessment and allows reliable assessments of microbial activity to be obtained from water samples. PMID- 23811505 TI - Quantification of endospore-forming firmicutes by quantitative PCR with the functional gene spo0A. AB - Bacterial endospores are highly specialized cellular forms that allow endospore forming Firmicutes (EFF) to tolerate harsh environmental conditions. EFF are considered ubiquitous in natural environments, in particular, those subjected to stress conditions. In addition to natural habitats, EFF are often the cause of contamination problems in anthropogenic environments, such as industrial production plants or hospitals. It is therefore desirable to assess their prevalence in environmental and industrial fields. To this end, a high sensitivity detection method is still needed. The aim of this study was to develop and evaluate an approach based on quantitative PCR (qPCR). For this, the suitability of functional genes specific for and common to all EFF were evaluated. Seven genes were considered, but only spo0A was retained to identify conserved regions for qPCR primer design. An approach based on multivariate analysis was developed for primer design. Two primer sets were obtained and evaluated with 16 pure cultures, including representatives of the genera Bacillus, Paenibacillus, Brevibacillus, Geobacillus, Alicyclobacillus, Sulfobacillus, Clostridium, and Desulfotomaculum, as well as with environmental samples. The primer sets developed gave a reliable quantification when tested on laboratory strains, with the exception of Sulfobacillus and Desulfotomaculum. A test using sediment samples with a diverse EFF community also gave a reliable quantification compared to 16S rRNA gene pyrosequencing. A detection limit of about 10(4) cells (or spores) per gram of initial material was calculated, indicating this method has a promising potential for the detection of EFF over a wide range of applications. PMID- 23811507 TI - Pleiotropic effects of GacA on Pseudomonas fluorescens Pf0-1 in vitro and in soil. AB - Pseudomonas species can exhibit phenotypic variation resulting from gacS or gacA mutation. P. fluorescens Pf0-1 is a gacA mutant and exhibits pleiotropic changes following the introduction of a functional allele. GacA enhances biofilm development while reducing dissemination in soil, suggesting that alternative Gac phenotypes enable Pseudomonas sp. to exploit varied environments. PMID- 23811508 TI - Functional characterization of key enzymes involved in L-glutamate synthesis and degradation in the thermotolerant and methylotrophic bacterium Bacillus methanolicus. AB - Bacillus methanolicus wild-type strain MGA3 secretes 59 g/liter(-1) of l glutamate in fed-batch methanol cultivations at 50 degrees C. We recently sequenced the MGA3 genome, and we here characterize key enzymes involved in l glutamate synthesis and degradation. One glutamate dehydrogenase (GDH) that is encoded by yweB and two glutamate synthases (GOGATs) that are encoded by the gltAB operon and by gltA2 were found, in contrast to Bacillus subtilis, which has two different GDHs and only one GOGAT. B. methanolicus has a glutamine synthetase (GS) that is encoded by glnA and a 2-oxoglutarate dehydrogenase (OGDH) that is encoded by the odhAB operon. The yweB, gltA, gltB, and gltA2 gene products were purified and characterized biochemically in vitro. YweB has a low Km value for ammonium (10 mM) and a high Km value for l-glutamate (250 mM), and the Vmax value is 7-fold higher for l-glutamate synthesis than for the degradation reaction. GltA and GltA2 displayed similar Km values (1 to 1.4 mM) and Vmax values (4 U/mg) for both l-glutamate and 2-oxoglutarate as the substrates, and GltB had no effect on the catalytic activities of these enzymes in vitro. Complementation assays indicated that GltA and not GltA2 is dependent on GltB for GOGAT activity in vivo. To our knowledge, this is the first report describing the presence of two active GOGATs in a bacterium. In vivo experiments indicated that OGDH activity and, to some degree, GOGAT activity play important roles in regulating l glutamate production in this organism. PMID- 23811509 TI - Genetic determinants for n-butanol tolerance in evolved Escherichia coli mutants: cross adaptation and antagonistic pleiotropy between n-butanol and other stressors. AB - Cross-tolerance and antagonistic pleiotropy have been observed between different complex phenotypes in microbial systems. These relationships between adaptive landscapes are important for the design of industrially relevant strains, which are generally subjected to multiple stressors. In our previous work, we evolved Escherichia coli for enhanced tolerance to the biofuel n-butanol and discovered a molecular mechanism of n-butanol tolerance that also conferred tolerance to the cationic antimicrobial peptide polymyxin B in one specific lineage (green fluorescent protein [GFP] labeled) in the evolved population. In this work, we aim to identify additional mechanisms of n-butanol tolerance in an independent lineage (yellow fluorescent protein [YFP] labeled) from the same evolved population and to further explore potential cross-tolerance and antagonistic pleiotropy between n-butanol tolerance and other industrially relevant stressors. Analysis of the transcriptome data of the YFP-labeled mutants allowed us to discover additional membrane-related and osmotic stress-related genes that confer n-butanol tolerance in E. coli. Interestingly, the n-butanol resistance mechanisms conferred by the membrane-related genes appear to be specific to n butanol and are in many cases antagonistic with isobutanol and ethanol. Furthermore, the YFP-labeled mutants showed cross-tolerance between n-butanol and osmotic stress, while the GFP-labeled mutants showed antagonistic pleiotropy between n-butanol and osmotic stress tolerance. PMID- 23811510 TI - Disruption of cell-to-cell signaling does not abolish the antagonism of Phaeobacter gallaeciensis toward the fish pathogen Vibrio anguillarum in algal systems. AB - Quorum sensing (QS) regulates Phaeobacter gallaeciensis antagonism in broth systems; however, we demonstrate here that QS is not important for antagonism in algal cultures. QS mutants reduced Vibrio anguillarum to the same extent as the wild type. Consequently, a combination of probiotic Phaeobacter and QS inhibitors is a feasible strategy for aquaculture disease control. PMID- 23811511 TI - Combined genomics and experimental analyses of respiratory characteristics of Shewanella putrefaciens W3-18-1. AB - It has previously been shown that the Shewanella putrefaciens W3-18-1 strain produces remarkably high current in microbial fuel cells (MFCs) and can form magnetite at 0 degrees C. To explore the underlying mechanisms, we developed a genetic manipulation method by deleting the restriction-modification system genes of the SGI1 (Salmonella genome island 1)-like prophage and analyzed the key genes involved in bacterial respiration. W3-18-1 has less respiratory flexibility than the well-characterized S. oneidensis MR-1 strain, as it possesses fewer cytochrome c genes and lacks the ability to oxidize sulfite or reduce dimethyl sulfoxide (DMSO) and timethylamine oxide (TMAO). W3-18-1 lacks the hydrogen producing Fe-only hydrogenase, and the hydrogen-oxidizing Ni-Fe hydrogenase genes were split into two separate clusters. Two periplasmic nitrate reductases (NapDAGHB and NapDABC) were functionally redundant in anaerobic growth of W3-18-1 with nitrate as the electron acceptor, though napDABC was not regulated by Crp. Moreover, nitrate respiration started earlier in W3-18-1 than in MR-1 (with NapDAGHB only) under microoxic conditions. These results indicate that Shewanella putrefaciens W3-18-1 is well adapted to habitats with higher oxygen levels. Taken together, the results of this study provide valuable insights into bacterial genome evolution. PMID- 23811512 TI - Chitin amendment increases soil suppressiveness toward plant pathogens and modulates the actinobacterial and oxalobacteraceal communities in an experimental agricultural field. AB - A long-term experiment on the effect of chitin addition to soil on the suppression of soilborne pathogens was set up and monitored for 8 years in an experimental field, Vredepeel, The Netherlands. Chitinous matter obtained from shrimps was added to soil top layers on two different occasions, and the suppressiveness of soil toward Verticillium dahliae, as well as plant-pathogenic nematodes, was assessed, in addition to analyses of the abundances and community structures of members of the soil microbiota. The data revealed that chitin amendment had raised the suppressiveness of soil, in particular toward Verticillium dahliae, 9 months after the (second) treatment, extending to 2 years following treatment. Moreover, major effects of the added chitin on the soil microbial communities were detected. First, shifts in both the abundances and structures of the chitin-treated soil microbial communities, both of total soil bacteria and fungi, were found. In addition, the abundances and structures of soil actinobacteria and the Oxalobacteraceae were affected by chitin. At the functional gene level, the abundance of specific (family-18 glycoside hydrolase) chitinase genes carried by the soil bacteria also revealed upshifts as a result of the added chitin. The effects of chitin noted for the Oxalobacteraceae were specifically related to significant upshifts in the abundances of the species Duganella violaceinigra and Massilia plicata. These effects of chitin persisted over the time of the experiment. PMID- 23811514 TI - Indigenous microbiota and habitat influence Escherichia coli survival more than sunlight in simulated aquatic environments. AB - The reported fate of Escherichia coli in the environment ranges from extended persistence to rapid decline. Incomplete understanding of factors that influence survival hinders risk assessment and modeling of the fate of fecal indicator bacteria (FIB) and pathogens. FIB persistence in subtropical aquatic environments was explored in outdoor mesocosms inoculated with five E. coli strains. The manipulated environmental factors were (i) presence or absence of indigenous microbiota (attained by natural, disinfected, and cycloheximide treatments), (ii) freshwater versus seawater, and (iii) water column versus sediment matrices. When indigenous microbes were removed (disinfected), E. coli concentrations decreased little despite exposure to sunlight. Conversely, under conditions that included the indigenous microbiota (natural), significantly greater declines in E. coli occurred regardless of the habitat. The presence of indigenous microbiota and matrix significantly influenced E. coli decline, but their relative importance differed in freshwater versus seawater. Cycloheximide, which inhibits protein synthesis in eukaryotes, significantly diminished the magnitude of E. coli decline in water but not in sediments. The inactivation of protozoa and bacterial competitors (disinfected) caused a greater decline in E. coli than cycloheximide alone in water and sediments. These results indicate that the autochthonous microbiota are an important contributor to the decline of E. coli in fresh and seawater subtropical systems, but their relative contribution is habitat dependent. This work advances our understanding of how interactions with autochthonous microbiota influence the fate of E. coli in aquatic environments and provides the framework for studies of the ecology of enteric pathogens and other allochthonous bacteria in similar environments. PMID- 23811513 TI - Identification and characterization of a Mucilaginibacter sp. strain QM49 beta glucosidase and its use in the production of the pharmaceutically active minor ginsenosides (S)-Rh1 and (S)-Rg2. AB - Here, we isolated and characterized a new ginsenoside-transforming beta glucosidase (BglQM) from Mucilaginibacter sp. strain QM49 that shows biotransformation activity for various major ginsenosides. The gene responsible for this activity, bglQM, consists of 2,346 bp and is predicted to encode 781 amino acid residues. This enzyme has a molecular mass of 85.6 kDa. Sequence analysis of BglQM revealed that it could be classified into glycoside hydrolase family 3. The enzyme was overexpressed in Escherichia coli BL21(DE3) using a maltose binding protein (MBP)-fused pMAL-c2x vector system containing the tobacco etch virus (TEV) proteolytic cleavage site. Overexpressed recombinant BglQM could efficiently transform the protopanaxatriol-type ginsenosides Re and Rg1 into (S) Rg2 and (S)-Rh1, respectively, by hydrolyzing one glucose moiety attached to the C-20 position at pH 8.0 and 30 degrees C. The Km values for p-nitrophenyl-beta-d glucopyranoside, Re, and Rg1 were 37.0 +/- 0.4 MUM and 3.22 +/- 0.15 and 1.48 +/- 0.09 mM, respectively, and the Vmax values were 33.4 +/- 0.6 MUmol min(-1) mg(-1) of protein and 19.2 +/- 0.2 and 28.8 +/- 0.27 nmol min(-1) mg(-1) of protein, respectively. A crude protopanaxatriol-type ginsenoside mixture (PPTGM) was treated with BglQM, followed by silica column purification, to produce (S)-Rh1 and (S)-Rg2 at chromatographic purities of 98% +/- 0.5% and 97% +/- 1.2%, respectively. This is the first report of gram-scale production of (S)-Rh1 and (S)-Rg2 from PPTGM using a novel ginsenoside-transforming beta-glucosidase of glycoside hydrolase family 3. PMID- 23811515 TI - Host association of Cryptosporidium parvum populations infecting domestic ruminants in Spain. AB - A stock of 148 Cryptosporidium parvum DNA extracts from lambs and goat kids selected from a previous study examining the occurrence of Cryptosporidium species and GP60 subtypes in diarrheic lambs and goat kids in northeastern Spain was further characterized by a multilocus fragment typing approach with six mini- and microsatellite loci. Various degrees of polymorphism were seen at all but the MS5 locus, although all markers exhibited two major alleles accounting for more than 75% of isolates. A total of 56 multilocus subtypes (MLTs) from lambs (48 MLTs) and goat kids (11 MLTs) were identified. Individual isolates with mixed MLTs were detected on more than 25% of the farms, but most MLTs (33) were distinctive for individual farms, revealing the endemicity of cryptosporidial infections on sheep and goat farms. Comparison with a previous study in calves in northern Spain using the same six-locus subtyping scheme showed the presence of host-associated alleles, differences in the identity of major alleles, and very little overlap in MLTs between C. parvum isolates from lambs and those from calves (1 MLT) or isolates from lambs and those from goat kids (3 MLTs). The Hunter-Gaston index of the multilocus technique was 0.976 (95% confidence interval [CI], 0.970 to 0.982), which supports its high discriminatory power for strain typing and epidemiological tracking. Population analyses revealed the presence of two host-associated subpopulations showing epidemic clonality among the C. parvum isolates infecting calves and lambs/goat kids, respectively, although evidence of genetic flow between the two subpopulations was also detected. PMID- 23811517 TI - Rapid identification of Bacillus anthracis spores in suspicious powder samples by using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). AB - Rapid and reliable identification of Bacillus anthracis spores in suspicious powders is important to mitigate the safety risks and economic burdens associated with such incidents. The aim of this study was to develop and validate a rapid and reliable laboratory-based matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) analysis method for identifying B. anthracis spores in suspicious powder samples. A reference library containing 22 different Bacillus sp. strains or hoax materials was constructed and coupled with a novel classification algorithm and standardized processing protocol for various powder samples. The method's limit of B. anthracis detection was determined to be 2.5 * 10(6) spores, equivalent to a 55-MUg sample size of the crudest B. anthracis-containing powder discovered during the 2001 Amerithrax incidents. The end-to-end analysis method was able to successfully discriminate among samples containing B. anthracis spores, closely related Bacillus sp. spores, and commonly encountered hoax materials. No false-positive or -negative classifications of B. anthracis spores were observed, even when the analysis method was challenged with a wide range of other bacterial agents. The robustness of the method was demonstrated by analyzing samples (i) at an external facility using a different MALDI-TOF MS instrument, (ii) using an untrained operator, and (iii) using mixtures of Bacillus sp. spores and hoax materials. Taken together, the observed performance of the analysis method developed demonstrates its potential applicability as a rapid, specific, sensitive, robust, and cost-effective laboratory-based analysis tool for resolving incidents involving suspicious powders in less than 30 min. PMID- 23811516 TI - Frequent occurrence of mixed Enterocytozoon bieneusi infections in humans. AB - Enterocytozoon bieneusi (phylum Microsporidia) is a human pathogen with a broad host range. Following the sequencing of 3.8 Mb of the estimated 6-Mb E. bieneusi genome, simple sequence repeats (micro- and minisatellites) were identified. Sequencing of four such repeats from various human and animal E. bieneusi isolates identified extensive sequence polymorphism and enabled the development of a multilocus genotyping method to study the epidemiology of this pathogen. We genotyped E. bieneusi DNA extracted from 197 fecal samples originating from children with diarrhea who were residing in Kampala, Uganda. Three newly identified microsatellite markers and the internal transcribed spacer were PCR amplified, and multiple cloned amplicons for each marker were sequenced from each individual. Most microsatellite sequences were unique to the Ugandan population. Significantly, polymorphism not only was present among isolates but was also found within isolates. This observation suggests that infections with heterogeneous E. bieneusi populations are common in this region. However, the data do not exclude that some of the polymorphism originates from divergent paralogs within the genome. The frequent occurrence of multiple sequences within an isolate precluded the identification of multilocus genotypes. This observation raises the possibility that in a region in which the prevalence of E. bieneusi is high, sequencing of uncloned PCR products may not be adequate for multilocus genotyping. PMID- 23811519 TI - Fermentation temperature modulates phosphatidylethanolamine and phosphatidylinositol levels in the cell membrane of Saccharomyces cerevisiae. AB - During alcoholic fermentation, Saccharomyces cerevisiae is exposed to a host of environmental and physiological stresses. Extremes of fermentation temperature have previously been demonstrated to induce fermentation arrest under growth conditions that would otherwise result in complete sugar utilization at "normal" temperatures and nutrient levels. Fermentations were carried out at 15 degrees C, 25 degrees C, and 35 degrees C in a defined high-sugar medium using three Saccharomyces cerevisiae strains with diverse fermentation characteristics. The lipid composition of these strains was analyzed at two fermentation stages, when ethanol levels were low early in stationary phase and in late stationary phase at high ethanol concentrations. Several lipids exhibited dramatic differences in membrane concentration in a temperature-dependent manner. Principal component analysis (PCA) was used as a tool to elucidate correlations between specific lipid species and fermentation temperature for each yeast strain. Fermentations carried out at 35 degrees C exhibited very high concentrations of several phosphatidylinositol species, whereas at 15 degrees C these yeast strains exhibited higher levels of phosphatidylethanolamine and phosphatidylcholine species with medium-chain fatty acids. Furthermore, membrane concentrations of ergosterol were highest in the yeast strain that experienced stuck fermentations at all three temperatures. Fluorescence anisotropy measurements of yeast cell membrane fluidity during fermentation were carried out using the lipophilic fluorophore diphenylhexatriene. These measurements demonstrate that the changes in the lipid composition of these yeast strains across the range of fermentation temperatures used in this study did not significantly affect cell membrane fluidity. However, the results from this study indicate that fermenting S. cerevisiae modulates its membrane lipid composition in a temperature-dependent manner. PMID- 23811518 TI - Functional gene analysis of freshwater iron-rich flocs at circumneutral pH and isolation of a stalk-forming microaerophilic iron-oxidizing bacterium. AB - Iron-rich flocs often occur where anoxic water containing ferrous iron encounters oxygenated environments. Culture-independent molecular analyses have revealed the presence of 16S rRNA gene sequences related to diverse bacteria, including autotrophic iron oxidizers and methanotrophs in iron-rich flocs; however, the metabolic functions of the microbial communities remain poorly characterized, particularly regarding carbon cycling. In the present study, we cultivated iron oxidizing bacteria (FeOB) and performed clone library analyses of functional genes related to carbon fixation and methane oxidization (cbbM and pmoA, respectively), in addition to bacterial and archaeal 16S rRNA genes, in freshwater iron-rich flocs at groundwater discharge points. The analyses of 16S rRNA, cbbM, and pmoA genes strongly suggested the coexistence of autotrophic iron oxidizers and methanotrophs in the flocs. Furthermore, a novel stalk-forming microaerophilic FeOB, strain OYT1, was isolated and characterized phylogenetically and physiologically. The 16S rRNA and cbbM gene sequences of OYT1 are related to those of other microaerophilic FeOB in the family Gallionellaceae, of the Betaproteobacteria, isolated from freshwater environments at circumneutral pH. The physiological characteristics of OYT1 will help elucidate the ecophysiology of microaerophilic FeOB. Overall, this study demonstrates functional roles of microorganisms in iron flocs, suggesting several possible linkages between Fe and C cycling. PMID- 23811521 TI - Multiaxial mechanical properties and constitutive modeling of human adipose tissue: a basis for preoperative simulations in plastic and reconstructive surgery. AB - A preoperative simulation of soft tissue deformations during plastic and reconstructive surgery is desirable to support the surgeon's planning and to improve surgical outcomes. The current development of constitutive adipose tissue models, for the implementation in multilayer computational frameworks for the simulation of human soft tissue deformations, has proved difficult because knowledge of the required mechanical parameters of fat tissue is limited. Therefore, for the first time, human abdominal adipose tissues were mechanically investigated by biaxial tensile and triaxial shear tests. The results of this study suggest that human abdominal adipose tissues under quasi-static and dynamic multiaxial loadings can be characterized as a nonlinear, anisotropic and viscoelastic soft biological material. The nonlinear and anisotropic features are consequences of the material's collagenous microstructure. The aligned collagenous septa observed in histological investigations causes the anisotropy of the tissue. A hyperelastic model used in this study was appropriate to represent the quasi-static multiaxial mechanical behavior of fat tissue. The constitutive parameters are intended to serve as a basis for soft tissue simulations using the finite element method, which is an apparent method for obtaining promising results in the field of plastic and reconstructive surgery. PMID- 23811520 TI - Psychrophilic and psychrotolerant fungi on bats and the presence of Geomyces spp. on bat wings prior to the arrival of white nose syndrome. AB - Since 2006, Geomyces destructans, the causative agent of white nose syndrome (WNS), has killed over 5.7 million bats in North America. The current hypothesis suggests that this novel fungus is an invasive species from Europe, but little is known about the diversity within the genus Geomyces and its distribution on bats in the United States. We documented the psychrophilic and psychrotolerant fungal flora of hibernating bats prior to the arrival of WNS using culture-based techniques. A total of 149 cultures, which were obtained from 30 bats in five bat hibernacula located in four caves and one mine, were sequenced for the entire internal transcribed spacer (ITS) nuclear ribosomal DNA (nrDNA) region. Approximately 53 operational taxonomic units (OTUs) at 97% similarity were recovered from bat wings, with the community dominated by fungi within the genera Cladosporium, Fusarium, Geomyces, Mortierella, Penicillium, and Trichosporon. Eleven Geomyces isolates were obtained and placed in at least seven distinct Geomyces clades based on maximum-likelihood phylogenetic analyses. Temperature experiments revealed that all Geomyces strains isolated are psychrotolerant, unlike G. destructans, which is a true psychrophile. Our results confirm that a large diversity of fungi, including several Geomyces isolates, occurs on bats prior to the arrival of WNS. Most of these isolates were obtained from damaged wings. Additional studies need to be conducted to determine potential ecological roles of these abundant Geomyces strains isolated from bats. PMID- 23811522 TI - In situ laccase treatment enhances the fermentability of steam-exploded wheat straw in SSCF processes at high dry matter consistencies. AB - This work evaluates the in situ detoxification of inhibitory lignocellulosic broths by laccases to facilitate their fermentation by the xylose-consuming Saccharomyces cerevisiae F12. Treatment of wheat straw slurries with laccases prior to SSCF processes decreased the total phenolic content by 50-80%, reducing the lag phase and increasing the cell viability. After laccase treatment, a negative impact on enzymatic hydrolysis was observed. This effect, together with the low enzymatic hydrolysis yields when increasing consistency, resulted in a decrease in final ethanol yields. Furthermore, when using high substrate loading (20% DM (w/v)), high concentration of inhibitors prevailed in broths and the absence of an extra nitrogen source led to a total cell growth inhibition within the first 24h in non-treated samples. This inhibition of growth at 20% DM (w/v) was overcome by laccase treatment with no addition of nitrogen, allowing S. cerevisiae F12 to produce more than 22 g/L of ethanol. PMID- 23811523 TI - Effect of gaseous cement industry effluents on four species of microalgae. AB - Experiments were performed at lab scale in order to test the possibility to grow microalgae with CO2 from gaseous effluent of cement industry. Four microalgal species (Dunaliella tertiolecta, Chlorella vulgaris, Thalassiosira weissflogii, and Isochrysis galbana), representing four different phyla were grown with CO2 enriched air or with a mixture of gasses mimicking the composition of a typical cement flue gas (CFG). In a second stage, the culture submitted to the CFG received an increasing concentration of dust characteristic of cement industry. Results show that growth for the four species is not affected by the CFG. Dust added at realistic concentrations do not have any impact on growth. For dust concentrations in two ranges of magnitude higher, microalgae growth was inhibited. PMID- 23811524 TI - Enhanced CO2 sequestration by a novel microalga: Scenedesmus obliquus SA1 isolated from bio-diversity hotspot region of Assam, India. AB - The present study aimed to isolate a high CO2 and temperature tolerant microalga capable of sequestering CO2 from flue gas. Microalga strain SA1 was isolated from a freshwater body of Assam and identified as Scenedesmus obliquus (KC733762). At 13.8+/-1.5% CO2 and 25 degrees C, maximum biomass (4.975+/-0.003 g L(-1)) and maximum CO2 fixation rate (252.883+/-0.361 mg L(-1) d(-1)) were obtained which were higher than most of the relevant studies. At elevated temperature (40 degrees C) and 13.8+/-1.5% CO2 maximum biomass (0.883+/-0.001 g L(-1)) was obtained. The carbohydrate, protein, lipid, and chlorophyll content of the CO2 treated SA1 were 30.87+/-0.64%, 9.48+/-1.65%, 33.04+/-0.46% and 6.03+/-0.19% respectively, which were higher than previous reports. Thus, SA1 could prove to be a potential candidate for CO2 sequestration from flue gas as well as for the production of value added substances. PMID- 23811527 TI - Response: selection bias in cohorts of cases. PMID- 23811526 TI - Perceived risks to smoking cessation among treatment-seeking French light smokers. AB - OBJECTIVE: This study investigated perceived risks to cessation expressed by light smokers and the association with cessation outcomes at one month post-quit date. METHOD: Data from adult light smokers attending French smoking cessation services nationwide between October 2007 and December 2010 were analyzed, retrospectively. In order to identify perceived risks, we performed a thematic analysis of answers to an open-ended question. Bivariate analysis and multivariate logistic modelling were used to assess predictors of abstinence and relapse. RESULTS: Eleven themes were identified, among which weight concerns were the most important for women while men cited withdrawal most often. A protective effect of nicotine replacement therapy prescription on cessation was uncovered among men concerned about withdrawal as well as weight-concerned women. Fear of depression and need for moral support doubled the odds of relapse for women only. CONCLUSIONS: Considering the growing prevalence of light smokers in the general population, our findings suggest the importance of taking into account perceived risks to quitting. Without adapted treatment and counselling, they represent significant barriers to abstinence for treatment seeking light smokers. PMID- 23811525 TI - Insufficient and excessive amounts of sleep increase the risk of premature death from cardiovascular and other diseases: the Multiethnic Cohort Study. AB - OBJECTIVE: To explore an independent association between self-reported sleep duration and cause-specific mortality. METHODS: Data were obtained from the Multiethnic Cohort Study conducted in Los Angeles and Hawaii. RESULTS: Among 61,936 men and 73,749 women with no history of cancer, heart attack or stroke, 19,335 deaths occurred during an average 12.9year follow-up. Shorter (<=5h/day) and longer (>=9h/day) sleepers of both sexes (vs. 7h/day) had an increased risk of all-cause and cardiovascular disease (CVD) mortality, but not of cancer mortality. Multivariable hazard ratios for CVD mortality were 1.13 (95% CI 1.00 1.28) for <=5h/day and 1.22 (95% CI 1.09-1.35) for >=9h/day among men; and 1.20 (95% CI 1.05-1.36) for <=5h/day and 1.29 (95% CI 1.13-1.47) for >=9h/day among women. This risk pattern was not heterogeneous across specific causes of CVD death among men (Phetero 0.53) or among women (Phetero 0.72). The U-shape association for all-cause and CVD mortality was observed in all five ethnic groups included in the study and by subgroups of age, smoking status, and body mass index. CONCLUSION: Insufficient or excessive amounts of sleep were associated with increased risk of mortality from CVD and other diseases in a multiethnic population. PMID- 23811528 TI - Population-level interventions to reduce alcohol-related harm: an overview of systematic reviews. AB - OBJECTIVE: To analyse available review-level evidence on the effectiveness of population-level interventions in non-clinical settings to reduce alcohol consumption or related health or social harm. METHOD: Health, social policy and specialist review databases between 2002 and 2012 were searched for systematic reviews of the effectiveness of population-level alcohol interventions on consumption or alcohol-related health or social outcomes. Data were extracted on review research aim, inclusion criteria, outcome indicators, results, conclusions and limitations. Reviews were quality-assessed using AMSTAR criteria. A narrative synthesis was conducted overall and by policy area. RESULTS: Fifty-two reviews were included from ten policy areas. There is good evidence for policies and interventions to limit alcohol sale availability, to reduce drink-driving, to increase alcohol price or taxation. There is mixed evidence for family- and community-level interventions, school-based interventions, and interventions in the alcohol server setting and the mass media. There is weak evidence for workplace interventions and for interventions targeting illicit alcohol sales. There is evidence of the ineffectiveness of interventions in higher education settings. CONCLUSION: There is a pattern of support from the evidence base for regulatory or statutory enforcement interventions over local non-regulatory approaches targeting specific population groups. PMID- 23811529 TI - The role of a lack of social integration in never having undergone breast cancer screening: results from a population-based, representative survey in the Paris metropolitan area in 2010. AB - OBJECTIVES: This study aims to investigate the association between social contact and social support and women's breast cancer screening (BCS) practices, taking their socioeconomic status (SES) into account. METHODS: The SIRS survey was conducted in 2010 in the Paris metropolitan area among a representative sample of 3000 French-speaking adults. For the 784 women aged 50years or older with no history of breast cancer, multivariate logistic regressions and bootstrap methods were used to analyze the factors associated with never having undergone BCS. RESULTS: 6.5% of these women had never undergone BCS. In multivariate analysis, being older, having a low education level, having poor-quality health insurance, and having one or less than one social contact per 3-day period were significantly associated with never having undergone BCS during their lifetime, but the level of social support was not. The strength of the association with a low frequency of social contact tended to increase with age. CONCLUSION: This study analyzed the role of social contact in social inequalities in BCS practices in the Paris metropolitan area. Like SES, social integration and social isolation should be taken into consideration by public health professionals and practitioners when planning BCS programs and incentives. PMID- 23811530 TI - Laetiporus sulphureus, edible mushroom from Serbia: investigation on volatile compounds, in vitro antimicrobial activity and in situ control of Aspergillus flavus in tomato paste. AB - The volatile compounds of fruiting bodies of wild Laetiporus sulphureus (Bull.) Murrill, growing on willow trees from Serbia, were isolated and extracted using methanol, acetone and dichloromethane and investigated by GC/MS-SPME. A total of 56 components were identified in the extracts. Hydrocarbons predominated (76.90%, 77.20%, and 43.10%) in dichloromethane, acetone and methanol extracts, respectively. Fatty acids, esters and sesquiterpenes were present in amounts equal or lower than 2.00%. Ketones were represented with moderate amount with the exception of methanol extract where it reached as much as 28.90% of the total investigated compounds. Extracts were also tested for antimicrobial activity with and without the addition of food additive - potassium disulfite in vitro against eight bacterial and eight fungal species, and in situ in tomato paste against Aspergillus flavus. All the tested extracts showed good antimicrobial activity, but methanol extract with addition of E224 showed the best antimicrobial activity in vitro. In situ results indicate complete inhibition of A. flavus growth in tomato paste after 15 days of the treatment. This study is the first report on volatile composition of L. sulphureus growing wild in Serbia. We describe for the first time the application of its extract as antifungal food preservative. PMID- 23811531 TI - In vitro antioxidant and antiproliferative effects of ellagic acid and its colonic metabolite, urolithins, on human bladder cancer T24 cells. AB - Urolithins were the metabolites of ellagic acid by intestinal flora in gastrointestinal tract. In previous research, it was found that urolithins could mainly inhibit prostate cancer and colon cancer cell growth. However, there is no report about bladder cancer therapy of urolithins. In this paper, three urolithin type compounds (urolithin A, urolithin B, 8-OMe-urolithin A) and ellagic acid were evaluated for antiproliferative activity in vitro against human bladder cancer cell lines T24. The IC50 values for T24 cell inhibition were 43.9, 35.2, 46.3 and 33.7 MUM for urolithin A, urolithin B, 8-OMe-urolithin A and ellagic acid, respectively. After the administration of urolithins and ellagic acid, we found these compounds could increase mRNA and protein expression of Phospho-p38 MAPK, and decrease mRNA and protein expression of MEKK1 and Phospho-c-Jun in T24 cells. Caspase-3 was also activated and PPAR-gamma protein expression increased in drug-induced apoptosis. And what's more, the antioxidant assay afforded by three urolithins and EA treatments were associated with decreases in the intracellular ROS and MDA levels, and increased SOD activity in H2O2-treated T24 cells. The results suggested that these compounds could inhibit cell proliferation by p38-MAPK and/or c-Jun medicated caspase-3 activation and reduce the oxidative stress status in bladder cancer. PMID- 23811532 TI - The hypothalamic-pituitary-gonadal axis is target of cadmium toxicity. An update of recent studies and potential therapeutic approaches. AB - This review presents an overview of neuroendocrine disruption induced by cadmium on the hypothalamic-pituitary-gonadal (HHG) axis. This review focuses on a number of hypotheses: (1) the HHG axis is a physiological target on cadmium toxicity; (2) cadmium could induce chronotoxicity on this neuroendocrine axis by disrupting the daily pattern of the HHG axis activity; (3) cadmium exposure throughout life could contribute to the oxidative stress and the circadian rhythms disruption induced by aging on the HHG; and (4) cadmium induces oxidative stress in the HHG axis so antioxidants could prevent or reduce cadmium toxicity in this system. Cadmium disrupts the regulatory mechanisms of this physiological axis, by altering neurotransmitters involved in this regulation at the hypothalamic level, altering gonadotropin hormone secretion, and by affecting testicular or ovarian structure and activity. These effects are age-dependent and they could be related to the circadian rhythms of this physiological axis. Several antioxidant agents could have a protective action against the neuroendocrine toxicity of cadmium on the reproductive system. A comprehensive view of the physiological axis may provide a better understanding about the neuroendocrine toxicity of cadmium on the reproductive system, so this perspective is recommended for undertaking further studies. PMID- 23811534 TI - Relative weights of the backpacks of elementary-aged children. AB - The purpose of the study was to describe the range of relative backpack weights of one group of elementary-aged children and the extent to which they exceeded recommended levels. A second purpose was to explore whether gender and age help predict the relative weight of children's backpacks. Ninety-five 8- to 12-year old elementary school students (56% girls; 88% car or bus riders) participated. Their school backpacks were weighed, and their age, gender, and mode of transportation to school were recorded. Only 40% of the sample carried backpacks that were less than 10% of their body weights. Five percent of the students' backpacks exceeded 20% of their body weights. Neither age group nor gender significantly predicted relative backpack weight or relative weight levels. Recommendations are made for ways to reduce the weight these young children carry. PMID- 23811533 TI - kappa-Selenocarrageenan prevents microcystin-LR-induced hepatotoxicity in BALB/c mice. AB - Microcystins (MCs) are a family of cyclic heptapeptides that are produced by blooming algae Microcystis. MCs have been implicated in the development of liver cancer, necrosis and even intrahepatic bleeding. Effective prophylactic approaches and complete removal of MCs are urgently needed. Accumulating evidence suggests that microcystin-LR (MC-LR)-induced damage is accompanied by oxidative stress. Supplementation of Se can enhance resistance to oxidative stress. Therefore, in the present study, we investigated the protective effects of kappa Selenocarrageenan (Se-Car), a kind of organic Se compound, in Balb/c mice exposed to MC-LR. Our results proved that Se-Car could significantly ameliorate the hepatic damage induced by MC-LR, including serum markers of liver dysfunction, oxidative damages and histological alterations. Furthermore, Se-Car could significantly alleviate the up-regulation of the molecular targets indicating mitochondrial dysfunction and endoplasmic reticulum stress induced by MC-LR. In conclusion, Se-Car showed clear protection against toxicity induced by MC-LR. Thus, Se-Car could be useful as a new category of anti-MC-LR toxicity reagent. PMID- 23811535 TI - The role of insulin-thyroid hormone interaction on beta-adrenoceptor-mediated cardiac responses. AB - beta-adrenoceptor-mediated responses are known to be attenuated in diabetic rat hearts, related to decreased receptor sensitivity and density. These impaired responses were improved with insulin in diabetic rats, but not in thyroidectomized diabetic rats. We aimed to investigate the possible interaction between insulin and thyroid hormones to restore diabetes-induced alterations on beta-adrenoceptor-mediated responses. Male Sprague-Dawley rats were divided into seven groups: control (C), diabetic (D), insulin-treated diabetic (DI), thyroidectomized diabetic (TxD), insulin-treated thyroidectomized diabetic (TxDI), insulin+low dose 3,3',5-triiodo-L-thyronine (T3) treated (TxDIT2.5) or insulin+high dose T3 (TxDIT5) treated thyroidectomized diabetic rats. Diabetes was induced with 38 mg/kg streptozotocin. Cardiac function was assessed through pressure-volume analysis and papillary muscle experiments. QPCR and western blot experiments were performed to evaluate cardiac gene expressions. Hemodynamic parameters were impaired in diabetes, and were mostly corrected in DI and TxDIT5 groups. Isoprenaline- and BRL37344-induced contractile responses were also decreased in diabetes. Isoprenaline responses were improved significantly in DI and TxDIT5 groups, whereas BRL 37344-mediated responses were increased slightly. Reduced beta1-adrenoceptor and SERCA 2A mRNA levels in diabetes were corrected in DI and TxDIT5 groups. Decreased SERCA 2A and increased beta3-adrenoceptor protein levels in diabetes were improved in DI and TxDIT5 groups. No significant changes were found in phospholamban or endothelial nitricoxide synthase protein levels. These results show that the beneficial effects of insulin on beta-adrenoceptor mediated responses in diabetic rats are dependent upon adequate concentrations of thyroid hormones. PMID- 23811537 TI - Unrelated donor allogeneic hematopoietic cell transplantation is underused as a curative therapy in eligible patients from the United States. AB - Allogeneic hematopoietic cell transplantation (alloHCT) is a curative therapy for hematologic disorders including acute lymphoblastic and myeloid leukemia, chronic lymphocytic and myeloid leukemia, Hodgkin's and non-Hodgkin lymphoma, multiple myeloma, and myelodysplastic syndrome. To determine the utilization of alloHCT from unrelated donors (URDs) in the United States, we calculated the number of patients diagnosed with hematologic disorders age 20 to 74 years based on 2004 to 2008 Surveillance, Epidemiology and End Results and 2007 US Census data, estimated the percentage of patients who would be eligible for URD alloHCT after discounting the mortality rate during induction therapy and the rate of severe comorbidities, and compared these with the actual 2007 alloHCTs facilitated by the National Marrow Donor Program. We found that the number of URD alloHCT as a percentage of the estimated potential transplantations ranged from 11% for multiple myeloma to 54% for chronic myeloid leukemia, with an average percentage of 26% for all the disorders considered. In an analysis stratified by age groups (20 to 44, 45 to 64, and 65 to 74 years), the utilization of URD alloHCT was higher in younger patients than in older patients for all disorders. Of acute lymphoblastic and myeloid leukemia patients, approximately 66% underwent URD alloHCT later in the course of their disease (in second or greater complete remission). URD alloHCT is likely underused for potentially curable hematologic disorders, particularly in older patients. Understanding the reasons for low use of alloHCT may lead to strategies to expand the use of this curative therapy for more patients with hematologic disorders. PMID- 23811536 TI - Accuracy and impact of Xpert MTB/RIF for the diagnosis of smear-negative or sputum-scarce tuberculosis using bronchoalveolar lavage fluid. AB - RATIONALE: The accuracy and impact of new tuberculosis (TB) tests, such as Xpert MTB/RIF, when performed on bronchoalveolar lavage fluid (BALF) obtained from patients with sputum-scarce or smear-negative TB is unclear. METHODS: South African patients with suspected pulmonary TB (n=160) who were sputum-scarce or smear-negative underwent bronchoscopy. MTB/RIF was performed on uncentrifuged BALF (1 ml) and/or a resuspended pellet of centrifuged BALF (~10 ml). Time to TB detection and anti-TB treatment initiation were compared between phase one, when MTB/RIF was performed as a research tool, and phase two, when it was used for patient management. RESULTS: 27 of 154 patients with complete data had culture confirmed TB. Of these, a significantly lower proportion were detected by smear microscopy compared with MTB/RIF (58%, 95% CI 39% to 75% versus 93%, 77% to 98%; p<0.001). Of the 127 patients who were culture negative, 96% (91% to 98%) were MTB/RIF negative. When phase two was compared with phase one, MTB/RIF reduced the median days to TB detection (29 (18-41) to 0 (0-0); p<0.001). However, more patients initiated empirical therapy (absence of a positive test in those commencing treatment) in phase one versus phase two (79% (11/14) versus 28% (10/25); p=0.026). Consequently, there was no detectable difference in the overall proportion of patients initiating treatment (26% (17/67; 17% to 37%) versus 36% (26/73; 26% to 47%); p=0.196) or the days to treatment initiation (10 (1-49) versus 7 (0-21); p=0.330). BALF centrifugation, HIV coinfection and a second MTB/RIF did not result in detectable changes in accuracy. CONCLUSIONS: MTB/RIF detected TB cases more accurately and more rapidly than smear microscopy and significantly reduced the rate of empirical treatment. PMID- 23811538 TI - Remediation of metal polluted hotspot areas through enhanced soil washing- evaluation of leaching methods. AB - Soil washing offers a permanent remediation alternative for metal polluted sites. In addition, the washed out metals can be recovered from the leachate and re introduced into the social material cycle instead of landfilled. In this paper, soil, bark and bark-ash washing was tested on four different metal polluted soil and bark samples from hotspots at former industrial sites. Six different leaching agents; HCl, NH4Cl, lactic acid, EDDS and two acidic process waters from solid waste incineration, were tested, discussed and evaluated. For the soil washing processes, the final pH in the leachate strongly influences the metal leachability. The results show that a pH < 2 is needed to achieve a high leaching yield, while <50 w% of most metals were leached when the pH was higher than 2 or below 10. The acidic process waste waters were generally the most efficient at leaching metals from all the samples studied, and as much as 90-100 w% of the Cu was released from some samples. Initial experiments show that from one of these un-purified leachates, Cu metal (>99% purity) could be recovered. After a single leaching step, the metal contents of the soil residues still exceed the maximum limits according to the Swedish guidelines. An additional washing step is needed to reduce the contents of easy soluble metal compounds in the soil residues. The overall results from this study show that soil and bark-ash washing followed by metal recovery is a promising on-site permanent alternative to remediate metal polluted soils and to utilize non-used metal resources. PMID- 23811540 TI - Adipose mesenchymal stem cells protect chondrocytes from degeneration associated with osteoarthritis. AB - Our work aimed at evaluating the role of adipose stem cells (ASC) on chondrocytes from osteoarthritic (OA) patients and identifying the mediators involved. We used primary chondrocytes, ASCs from different sources and bone marrow mesenchymal stromal cells (MSC) from OA donors. ASCs or MSCs were co-cultured with chondrocytes in a minimal medium and using cell culture inserts. Under these conditions, ASCs did not affect the proliferation of chondrocytes but significantly decreased camptothecin-induced apoptosis. Both MSCs and ASCs from different sources allowed chondrocytes in the cocultures maintaining a stable expression of markers specific for a mature phenotype, while expression of hypertrophic and fibrotic markers was decreased. A number of factors known to regulate the chondrocyte phenotype (IL-1beta, IL-1RA, TNF-alpha) and matrix remodeling (TIMP-1 and -2, MMP-1 and -9, TSP-1) were not affected. However, a significant decrease of TGF-beta1 secretion by chondrocytes and induction of HGF secretion by ASCs was observed. Addition of a neutralizing anti-HGF antibody reversed the anti-fibrotic effect of ASCs whereas hypertrophic markers were not modulated. In summary, ASCs are an interesting source of stem cells for efficiently reducing hypertrophy and dedifferentiation of chondrocytes, at least partly via the secretion of HGF. This supports the interest of using these cells in therapies for osteo-articular diseases. PMID- 23811541 TI - Protein identification in two phases of 1,3-propanediol production by proteomic analysis. AB - Proteomic analysis by two-dimensional electrophoresis (2D)-mass spectrometry was used to identify differentially expressed proteins in the Clostridium sp. native strain (IBUN 158B) in two phases of the 1,3-propanediol (1,3-PD) production (lag phase and exponential growth phase). Intracellular protein fraction extraction conditions were standardised, as well as the 2D electrophoresis. Differences were found between both of the growth phases evaluated here. Thirty-two of the differentially expressed proteins were chosen to be identified by tandem mass spectrometry (MALDI TOF/TOF). The presence of four enzymes implicated in the 1,3 PD metabolic pathway was recorded: one from the reductive route (1,3-propanediol dehydrogenase) and three from the oxidative route (3-hydroxybutyryl-CoA dehydrogenase, NADPH-dependent butanol dehydrogenase and phosphate butyryl transferase). The following enzymes which have not been previously reported for Clostridium sp., were also identified: phosphoglycerate kinase, glucose 6 phosphate isomerase, deoxyribose phosphate aldolase, transketolase, cysteine synthetase, O-acetylhomoserine sulphhydrylase, glycyl-tRNA ligase, aspartate-beta semialdehyde dehydrogenase, inosine-5-monophosphate dehydrogenase, aconitate hydratase and the PrsA protein. The foregoing provides a novel contribution towards knowledge of the native strain for the purpose of designing genetic manipulation strategies to obtain strains with high production of 1,3-PD. BIOLOGICAL SIGNIFICANCE: The article "Protein identification in two phases of 1,3 propanediol production by proteomic analysis" provides a novel contribution towards knowledge regarding the Colombian Clostridium sp. native strain (IBUN 158B) because this is a new approximation in comparative proteomics in two phases of the bacterial growth and 1,3-propanediol (1,3-PD) production conditions. The proteomic studies are very important to identify the enzymes that are expressed at different stages of production and therefore genes of interest in the genetic manipulation strategies; the results can be taken into account in future studies in metabolic engineering when optimising 1,3-PD production, in a cost-effective process having direct industrial applications. PMID- 23811542 TI - Development of an obesity management ontology based on the nursing process for the mobile-device domain. AB - BACKGROUND: Lifestyle modification is the most important factor in the management of obesity. It is therefore essential to enhance client participation in voluntary and continuous weight control. OBJECTIVE: The aim of this study was to develop an obesity management ontology for application in the mobile-device domain. We considered the concepts of client participation in behavioral modification for obesity management and focused on minimizing the amount of information exchange between the application and the database when providing tailored interventions. METHODS: An obesity management ontology was developed in seven phases: (1) defining the scope of obesity management, (2) selecting a foundational ontology, (3) extracting the concepts, (4) assigning relationships between these concepts, (5) evaluating representative layers of ontology content, (6) representing the ontology formally with Protege, and (7) developing a prototype application for obesity management. RESULTS: Behavioral interventions, dietary advice, and physical activity were proposed as obesity management strategies. The nursing process was selected as a foundation of ontology, representing the obesity management process. We extracted 127 concepts, which included assessment data (eg, sex, body mass index, and waist circumference), inferred data to represent nursing diagnoses and evaluations (eg, degree of and reason for obesity, and success or failure of lifestyle modifications), and implementation (eg, education and advice). The relationship linking concepts were "part of", "instance of", "derives of", "derives into", "has plan", "followed by", and "has intention". The concepts and relationships were formally represented using Protege. The evaluation score of the obesity management ontology was 4.5 out of 5. An Android-based obesity management application comprising both agent and client parts was developed. CONCLUSIONS: We have developed an ontology for representing obesity management with the nursing process as a foundation of ontology. PMID- 23811539 TI - Fibronectin extra domain A (EDA) sustains CD133(+)/CD44(+) subpopulation of colorectal cancer cells. AB - Fibronectin is a major extracellular matrix glycoprotein with several alternatively spliced variants, including extra domain A (EDA), which was demonstrated to promote tumorigenesis via stimulating angiogenesis and lymphangiogenesis. Given that CD133(+)/CD44(+) cancer cells are critical in tumorigenesis of colorectal cancer (CRC), we hypothesize that fibronectin EDA may promote tumorigenesis by sustaining the properties of CD133(+)/CD44(+) colon cancer cells. We found that tumor tissue and serum EDA levels are substantially higher in advanced versus early stage human CRC. Additionally we showed that tumor tissue EDA levels are positively correlated with differentiation status and chemoresistance, and correlated with a poor prognosis of CRC patients. We also showed that in colon cancer cells SW480, CD133(+)/CD44(+) versus CD133(-)/CD44(-) cells express significantly elevated EDA receptor integrin alpha9beta1. Silencing EDA in SW480 cells reduces spheroid formation and cells positive for CD133 or CD44, which is associated with reduced expressions of embryonic stem cell markers and increased expressions of differentiation markers. Blocking integrin alpha9beta1 function strongly reversed the effect of EDA overexpression. We also provided evidence suggesting that EDA sustains Wnt/beta-catenin signaling activity via activating integrin/FAK/ERK pathway. In xenograft models, EDA silenced SW480 cells exhibit reduced tumorigenic and metastatic capacity. In conclusion, EDA is essential for the maintenance of the properties of CD133(+)/CD44(+) colon cancer cells. PMID- 23811543 TI - SNPs located at CpG sites modulate genome-epigenome interaction. AB - DNA methylation is an important molecular-level phenotype that links genotypes and complex disease traits. Previous studies have found local correlation between genetic variants and DNA methylation levels (cis-meQTLs). However, general mechanisms underlying cis-meQTLs are unclear. We conducted a cis-meQTL analysis of the Genetics of Lipid Lowering Drugs and Diet Network data (n = 593). We found that over 80% of genetic variants at CpG sites (meSNPs) are meQTL loci (P value<10(-9)), and meSNPs account for over two thirds of the strongest meQTL signals (P-value<10(-200)). Beyond direct effects on the methylation of the meSNP site, the CpG-disrupting allele of meSNPs were associated with lowered methylation of CpG sites located within 45 bp. The effect of meSNPs extends to as far as 10 kb and can contribute to the observed meQTL signals in the surrounding region, likely through correlated methylation patterns and linkage disequilibrium. Therefore, meSNPs are behind a large portion of observed meQTL signals and play a crucial role in the biological process linking genetic variation to epigenetic changes. PMID- 23811545 TI - Detection of IL-20R1 and IL-20R2 mRNA in C57BL/6 mice astroglial cells and brain cortex following LPS stimulation. AB - BACKGROUND: Astrocytes, which comprise ~90% of overall brain mass, are involved in brain immunity. These cells represent the non-professional class of CNS resident APCs and may promote or inhibit CNS inflammation depending on the cytokines they secrete. IL-10 family of cytokines and their receptors, IL-20R1 and IL-20R2, may have a role in shifting astrocytes to a neuroprotective or neurodegenerative function. OBJECTIVE: To address the expression of IL-20R1 and IL-20R2 cytokine receptors in astrocytes and brain cortex of C57BL/6 mice. METHODS: We investigated the expression of IL-20R1 and IL-20R2 in C57BL/6 mice astroglial cells and brain cortex in response to lipopolysaccharide (LPS), using reverse-transcription polymerase chain reaction (RT-PCR) method. RESULTS: Astrocytes were able to express IL-20R1 and IL-20R2 mRNA not only in response to LPS stimulation but also in the absence of LPS. Furthermore, we found the expression of IL-20R1 and IL-20R2 mRNA in the cortex of adult C57BL/6 mice. CONCLUSIONS: IL-20R1 and IL-20R2 are constitutively express in the brain. Since most neuropathological processes involve astrocytes and inflammatory cytokines, these findings have important implications for future therapeutic strategies. PMID- 23811546 TI - Long acting propranolol and HSP-70 rich tumor lysate reduce tumor growth and enhance immune response against fibrosarcoma in Balb/c mice. AB - BACKGROUND: Noradrenaline (NA), the principal neurotransmitter released from sympathetic nerve terminals, influences T-cell maturation, not only directly in developing T cells, but also indirectly, by acting on the thymic nonlymphoid cells. In vitro and in vivo studies have demonstrated the anti-proliferative, anti-migratory, anti-angiogenic and cytotoxic properties of propranolol, beta-AR blocker, against various cancers. OBJECTIVES: To evaluate the effect of propranolol on efficacy of HSP-70 rich lysate vaccine in immunotherapy of fibrosarcoma. METHODS: Mouse fibrosarcoma WEHI-164 cells were used to immunize tumor-bearing mice with or without propranolol and HSP-70. Splenocytes proliferation, cytotoxicity activity of the splenocytes, naturally occurring CD4+ CD25high T-reg cells and IFN-gamma and IL-4 secretion as well as tumor size, were assessed to describe the anti-tumor immune response. RESULTS: A significant increase in the level of IFN-gamma in the mice vaccinated with WEHI-164 cells enriched with HSP-70 and co-treated with propranolol was observed compared to controls. However, HSP enrichment or propranolol treatment alone did not enhance the immune response as measured by the level of IFN-gamma. Likewise, a decrease in tumor growth in the test group (p<0.01) and a significant increase in CTL activity (p<0.05) was observed. CONCLUSION: HSP enriched vaccine shows anti-tumor activity, probably due to the modulation of immune responses. PMID- 23811547 TI - Interleukin-17 serum levels and TLR4 polymorphisms in ulcerative colitis. AB - BACKGROUND: Inflammatory bowel disease, an autoimmune disease, has two clinical manifestations including Crohn's disease and ulcerative colitis (UC). IL-17 has been the target of intensive research in autoimmune diseases. The influence of Toll like receptor 4 (TLR-4) gene polymorphisms on IL-17 production has also been revealed in UC patients and tissue inflammation in mice. OBJECTIVES: To investigate the association between the TLR-4 gene polymorphisms, Asp299Gly and Thr399Ile and IL-17 serum levels with ulcerative colitis. Additionally, we aimed to study modulation effects of forenamed gene polymorphisms on IL-17 serum levels in UC patients and controls. METHODS: A total of 256 healthy controls and 85 UC patients enrolled in our study. DNA was extracted and PCR-RFLP technique was employed to determine Asp299Gly and Thr399Ile polymorphisms in TLR-4 gene and IL 17 serum levels were measured by ELISA method. RESULTS: There was no significant difference between the frequency of Asp299Gly A>G and Thr399Ile C>T in UC patients and controls. While IL-17 serum levels in UC patients were significantly higher than controls (p=0.003), no significant difference in IL-17 levels between different genotypes existed. Additionally, a significant inverse relationship was observed between hemoglobin level and IL-17 serum levels in UC patients (p=0.039). CONCLUSIONS: Increased IL-17 serum levels in our UC patients might be explained through the synergistic activity of IL-17/IL-23 axis and pro inflammatory cytokines, causing severe clinical outcome in patients with IBD. The prolonged excretion of blood in stool driven by inflammatory process which causes iron metabolism disorder and anemia may elucidate the inverse correlation between hemoglobin and IL-17 serum levels in UC patients. Lack of association between the TLR-4 gene polymorphisms and UC in our study was consistent with the results from other Caucasian populations. PMID- 23811548 TI - Hyperthermia increases natural killer cell cytotoxicity against SW-872 liposarcoma cell line. AB - BACKGROUND: Although there is convincing data in support of the effectiveness of hyperthermia in tumor therapy, the molecular mechanisms underlying the clinical effects of hyperthermia are still poorly understood. OBJECTIVE: To investigate natural killer (NK) cell cytotoxicity against heat-treated SW-872 and HeLa tumor cell lines. METHODS: NKG2D ligands and HLA class I transcription were examined using quantitative real-time PCR in treated tumor cell lines at 0, 2, 4, 6 and 12 h following thermal treatment at 39C and 42C for 1 h. The expression of MICA/B, ULBP1 and ULBP2 were also determined by flow cytometry. NK92-MI cytotoxic activity against heat-treated target cell lines was assessed by LDH release as well as annexin-V and 7-AAD assays. RESULTS: Our results showed that heat treatment at 39C improved the cytolytic activity of NK cells against SW-872 cells without increasing NKG2D ligand concentration or decreasing HLA class I levels. CONCLUSION: The observed increase in the cytotoxicity of NK cells against SW-872 cells after hyperthermia does not coincide with changes in MICA/B, ULBP1 and ULBP2 ligands of NKG2, however, the expression of other ligands in target cells may have made the cells susceptible to the cytotoxic effect of NK cells. PMID- 23811549 TI - MiR-143 induces expression of AIM2 and ASC in Jurkat cell line. AB - BACKGROUND: Absent in Melanoma 2 (AIM2) is an intracellular microbial dsDNA sensor which plays an important role in production of proinflammatory cytokines through Apoptosis associated Speck-like protein containing a Caspase activation and recruitment domain (ASC) and Caspase-1. Micro-RNAs (miRNAs) play important roles in regulation of immune related genes. However, there is little information regarding the effects of miRNAs on the AIM2 and ASC expression. OBJECTIVE: To determine the mRNA levels of AIM2 and ASC in Jurkat cell line following introducing miRNA-143 (miR-143). METHODS: MiR-143, a scrambled sequence and PBS were introduced separately, to the Jurkat cell lines and the mRNA levels of AIM2 and ASC were examined in parallel with beta-actin and GAPDH (as housekeeping genes) using Real-Time PCR technique. RESULTS: The mRNA levels of AIM2 and ASC were significantly increased in the miR-143 transfected Jurkat cells when compared to the scrambled sequence or PBS treated cells. CONCLUSIONS: miR-143 can lead to increased expression of AIM2 and ASC mRNAs. Considering the significance of AIM2 and ASC in DNA sensing and inflammosome formation, it can be considered as a therapeutic agent for the treatment of chronic infectious diseases, especially viral infections. PMID- 23811551 TI - Immune deviation in recurrent vulvovaginal candidiasis: correlation with iron deficiency anemia. AB - BACKGROUND: Iron Deficiency Anemia (IDA) has been controversially linked to IL-4 production in previous studies. A predominant Th1 response leads to resistance against recurrent vulvovaginal candidiasis (RVVC), whereas a Th2 response exacerbates the disease. OBJECTIVE: To investigate the possible effect of iron deficiency on the host's susceptibility to RVVC as a result of the Th1/Th2 cytokine polarization. METHODS: We conducted a case-control study of 92 women in 4 groups based on strict inclusion and exclusion criteria: RVVC+IDA+ group consisted of 23 women with RVVC and IDA; RVVC+ IDA- group consisted of 23 women with RVVC without IDA; RVVC-IDA+ group consisted of 23 women without RVVC and with IDA and RVVC- IDA- group consisted of 23 healthy women. The iron parameters and key cytokines (IFN-gamma, IL-10, IL-12, IL-4) were measured in blood samples. RESULTS: Comparison of IL-4 production between RVVC+ IDA+ (12.2 +/- 1.3 pg/ml) and RVVC+ IDA- (2.4 +/- 4.0 pg/ml) groups (p=0.044), between RVVC- IDA+ (14.6 +/- 1.7 pg/ml) and RVVC- IDA- (1.28 +/- 3.6 pg/ml) groups (p=0.006), between RVVC- IDA+ (14.6 +/- 1.7 pg/ml) and RVVC+ IDA-) 2.4 +/- 4.0 pg/ml) groups (p=0.009) and also between RVVC+ IDA+ and RVVC- IDA- (1.28 +/- 3.6 pg/ml) groups (p=0.03) showed significant differences. We found a significant positive correlation between IL-4 and total iron binding capacity (TIBC, p=0.046) and between serum IL 10 and Hb levels (p=0.041) in the RVVC+ IDA- group. There was also a significant negative correlation between serum IL-4 and levels of serum iron (SI, p=0.041) in the RVVC- IDA- group. CONCLUSION: It seems that IDA determines the balance between and the intensity of Th1 and Th2 arms of the immune response and leads to a deviation toward Th2 response which could contribute to recurrence of candidiasis. PMID- 23811550 TI - Immunogenicity of a new recombinant IpaC from Shigella dysenteriae type I in guinea pig as a vaccine candidate. AB - BACKGROUND: Recombinant vaccine technology is one of the most developed means in controlling infectious diseases. However, an effective vaccine against Shigella is still missing. OBJECTIVE: To evaluate recombinant IpaC protein of Shigella as a vaccine candidate. METHODS: In this study we cloned IpaC gene into an expression vector in prokaryotic system. The protein expression was evaluated by SDS-PAGE and Western-Blotting analysis. The recombinant protein was purified using Ni-NTA affinity chromatography. Guinea pigs were immunized with the recombinant protein and the level of immunogenicity was examined by ELISA and Western blotting of IpaC. Challenge test was done through the intraoculary injection of Shigella dysenteriae (6*108 CFU/eye) and after 48 hours was scored for keratoconjunctivitis. RESULTS: The results showed a remarkable level of immunogenicity in terms of antibody response and protection against keratoconjunctivitis in tested animals. The recombinant IpaC protein provided a protective system against Shigella dysenteriae type I during the challenge test. CONCLUSION: The results showed the potential of using recombinant IpaC in preparation of vaccine in perspective studies. PMID- 23811552 TI - Ten-year treatment outcomes including blood cell count disturbances in patients with simple renal cysts. AB - BACKGROUND: The simple renal cyst is the most common benign kidney disease. It may cause pain and hypertension, especially if significantly enlarged. As in polycystic kidney disease, blood cell count disturbances are frequently observed in simple renal cysts. The aim of our study was to assess such disturbances, changes in blood pressure, and complication rate in our patients undergoing surgery due to simple renal cyst in the last 10 years. MATERIAL AND METHODS: 210 patients with simple renal cysts were underwent surgery between 2002 and 2012. Two different kinds of operation were conducted: aspiration of cyst fluid with injection of sclerosing agent, and laparoscopic/retroperitoneoscopic decortications of the cyst wall. A control group comprised 134 patients with benign prostate hyperplasia. The following data were obtained: cyst burden, hematocrit, hemoglobin, red blood cells, thrombocytes, occurrence of pain, and blood pressure before and after the operation. Complications were collected and presented in Clavien score. RESULTS: Hematocrit, hemoglobin, and red blood cells were significantly increased in the experimental group. A positive correlation was observed between cyst burden and the parameters mentioned above. Of 91 patients with hypertension, 56 (61.7%) had blood pressure reduction after the operation. Treatment relieved the loin pain in 132 (88%) patients. Complications occurred in 15 (7.4%) patients. CONCLUSIONS: Patients with simple renal cysts have high values of red blood cells, hematocrit, and hemoglobin. Treatment decreases blood pressure in patients with hypertension. Complications after treatment are rare and mild. PMID- 23811553 TI - Study on development of polymeric micellar gene carrier and evaluation of its functionality. AB - Polymeric micelles, which are formed by the self-assembly of block copolymers, can load various substances and have received attention as drug carriers. Negatively charged nucleic acids such as DNA or RNA are some of the drugs delivered by polyion complex-based polymeric micelles (polyplex micelles). Polyplex micelles are expected to be nonviral gene carriers instead of viral vectors, which have several problems including safety, the limited size of the loading gene, and productivity. In this review, recent studies by our group on smart polyplex micelles delivering genes will be introduced. PMID- 23811554 TI - Anti-obesity effect of alkaline reduced water in high fat-fed obese mice. AB - Whether or not alkaline reduced water (ARW) has a positive effect on obesity is unclear. This study aims to prove the positive effect of ARW in high-fat (HF) diet-induced obesity (DIO) in C57BL/6 mice model. Toward this, obesity was induced by feeding the C57BL/6 male mice with high-fat diet (w/w 45% fat) for 12 weeks. Thereafter, the animals were administered with either ARW or tap water. Next, the degree of adiposity and DIO-associated parameters were assessed: clinico-pathological parameters, biochemical measurements, histopathological analysis of liver, the expression of cholesterol metabolism-related genes in the liver, and serum levels of adipokine and cytokine. We found that ARW-fed mice significantly ameliorated adiposity: controlled body weight gain, reduced the accumulation of epididymal fats and decreased liver fats as compared to control mice. Accordingly, ARW coordinated the level of adiponectin and leptin. Further, mRNA expression of cytochrome P450 (CYP)7A1 was upregulated. In summary, our data shows that ARW intake inhibits the progression of HF-DIO in mice. This is the first note on anti-obesity effect of ARW, clinically implying the safer fluid remedy for obesity control. PMID- 23811555 TI - alpha-Lipoic acid attenuates light insults to neurones. AB - The aim of this study was to determine whether alpha-lipoic acid (LA) is effective in blunting the detrimental effect of light to transformed retinal ganglion cells (RGC-5 cells) in culture. In this study, RGC-5 cells were exposed to light (400-760 nm; 1000 lx) for 48 h with or without LA. For cell assessment, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and 4-[3-( iodophenyl)-2-(4-nitrophenyl)-2H-5-tetzolio]-1,3-benzene disulfonate (WST-1) reduction assays were used to assess cell and mitochondrial viability respectively. Furthermore, cells were stained for reactive oxygen species (ROS), Apoptosis DNA breakdown and Apoptosis membrane alteration. Antioxidant-capacity, glutathione (GSH) and gluthathione-S-transferase (GST) were determined as well. Light reduced cell viability, affected mitochondrial function, increased the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)-positive cells and enhanced labelling for ROS. These effects were all attenuated by the presence of LA. LA also stimulated GSH and GST. These findings support the view that light can affect mitochondria which could lead to retinal ganglion cell apoptosis and LA can blunt by decreasing ROS generation and stimulating GSH and GST. PMID- 23811556 TI - Nitric oxide promotes survival of cerebral cortex neurons with simultaneous addition of [Fe(II)(beta-citryl-L-glutamate)] complex in primary culture. AB - It has been reported that the activity of mitochondrial aconitase (m-aconitase) is rapidly inhibited in a variety of cells when exposed to nitric oxide (NO). In present study, we found that NO significantly increased the number of surviving neurons via enhanced mitochondrial functions with simultaneous addition of the [Fe(II)(beta-citryl-L-glutamate; beta-CG)] complex. In vitro, a variety of aconitase-inhibitors, such as fluorocitrate, cyanide ion, ferricyanide ([Fe(CN)6]), and various oxidants including superoxide anion, inhibited the activity of m-aconitase even in the presence of Fe(II), whereas a NO-donor, nitroprusside (SNP) ([Fe(CN)5NO]), was the only agent that significantly increased activity of that enzyme. Therefore, it is reasonable to assume that NO released from SNP promotes Fe-dependent activation of aconitase. All other tested NO-donors, including 3-morpholino-sydnonimine (SIN), Deta NONOate (NOC18), and NaNO2, also promoted activation of m-aconitase in time- and dose-dependent manners in the presence of Fe(II). The promoting effects of the NO-donors on activation disappeared with the addition of NO-scavengers. In intact mitochondria, all tested NO-donors promoted reactivation of aconitase in a dose dependent manner in the presence of Fe(II), whereas that was not seen in its absence. These findings suggest that NO released from NO-donors promotes Fe dependent activation of aconitase. In mixed neuronal and glial cultures, NO donors except for SNP enhanced mitochondrial activity at low concentrations. Furthermore, simultaneous addition of the [Fe(II)(beta-CG)] complex significantly enhanced those activities and greatly increased the number of surviving neurons. Thus, NO can carry Fe ions into m-aconitase via the guide of the tag of beta-CG addressed to the enzyme. PMID- 23811557 TI - Different apoptotic effects of triterpenoid saponin-rich Gypsophila oldhamiana root extract on human hepatoma SMMC-7721 and normal human hepatic L02 cells. AB - The roots of Gypsophila oldhamiana are rich in triterpenoid saponins with antitumor properties. Although previous reports have revealed the anticancer potency of some Gypsophila species, the underlying molecular mechanisms of this activity have not been studied in detail. The purpose of the present study was to prepare a triterpenoid saponin-rich G. oldhamiana root extract (TGOE) determined by LC-electrospray ionization (ESI)-MS(n) for biological studies and to evaluate the different anti-proliferative activities and apoptotic effects of TGOE on human hepatoma SMMC-7721 and normal human hepatic L02 cells. 3-(4,5 Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that TGOE selectively inhibited the proliferation of SMMC-7721 cells in a dose dependent manner with IC50 value of 19.50+/-3.63 ug/mL, while the cytotoxic effects of TGOE on L02 cells were much lower with IC50 value of 40.48+/-3.74 ug/mL. Analysis of apoptotic morphological changes and flow cytometry indicated that TGOE might preferentially induce apoptosis in SMMC-7721 cells, while exhibited much lower effects on L02 cells. Western blot analysis showed that the different apoptotic effects of TGOE on SMMC-7721 and L02 cells were due to different protein regulation of caspase-3 and mitogen activated protein kinases (MAPKs). TGOE significantly activated caspase-3 and increased the phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), while decreased the phosphorylation of p38 in SMMC-7721 cells. However, the expression of these proteins was not statistically changed in L02 cells, except for the up-regulation of p38 phosphorylation. These results suggest that TGOE may have potential beneficial effects against hepatocellular carcinoma. PMID- 23811558 TI - Ginsenoside Rh1 eliminates the cytoprotective phenotype of human immunodeficiency virus type 1-transduced human macrophages by inhibiting the phosphorylation of pyruvate dehydrogenase lipoamide kinase isozyme 1. AB - Red ginseng (the steamed root of Panax ginseng C.A. MEYER, Araliaceae), which contains ginsenosides as its main constituents, is frequently used to treat tumor, inflammation, diabetes, stress and acquired immunodeficiency syndrome in Asian countries. Of these ginsenosides, only protopanaxadiol compound K has been reported to abolish the cytoprotective phenotype of human immunodeficiency virus type 1 (HIV-1)-transfected human macrophages. Here, we investigated the anti cytoprotective effect of protopanaxatriol ginsenoside Rh1 on Tat-expressing cytoprotective CHME5 cells and D3-infected human primary macrophages. Treatment with ginsenoside Rh1 in the presence of lipopolysaccharide/cycloheximide (LPS/CHX) potently abolished the cytoprotective phenotype of Tat-transduced CHME5 cells as well as D3-infected human primary macrophages. Ginsenoside Rh1 significantly inhibited LPS/CHX-induced Akt phosphorylation, as well as mammalian target of rapamycin and Bcl-2-associated death promoter activation in both cell types. Furthermore, ginsenoside Rh1 inhibited pyruvate dehydrogenase lipoamide kinase isozyme 1 (PDK-1) phosphorylation. However, ginsenoside Rh1 did not inhibit phosphoinositide 3-kinase phosphorylation. Ginsenosides Rh1 in the presence of miltefosine (5 uM) additively increased the anti-cytoprotective activity against HIV-1 Tat-expressing macrophages. On the basis of these findings, we propose that ginsenoside Rh1 could possibly eliminate HIV-1 infected macrophages by inhibiting the PDK1/Akt pathway. PMID- 23811559 TI - Sulphur antioxidants inhibit oxidative stress induced retinal ganglion cell death by scavenging reactive oxygen species but influence nuclear factor (erythroid derived 2)-like 2 signalling pathway differently. AB - This study aimed to show if two different sulphur containing drugs sulbutiamine and acetylcysteine (NAC) could attenuate the effects of two different insults being serum deprivation and glutamate/buthionine sulfoximine (GB)-induced death to transformed retinal ganglion cell line (RGC-5) in culture. Cells were exposed to either 5 mM of GB for 24 h or serum deprivation for 48 h with inclusion of either NAC or sulbutiamine. Cell viability, microscopic evidence for apoptosis, caspase 3 activity, reactive oxygen species (ROS), glutathione (GSH), catalase and gluthathione-S-transferase (GST) were determined. The effects of NAC and sulbutiamine on the oxidative stress related transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf-2) levels and its dependent phase II enzyme haemeoxygenase-1 (HO-1) were carried out using Western blot and quantitative polymerase chain reaction (PCR). NAC and sulbutiamine dose-dependently attenuated serum deprivation-induced cell death. However NAC but not sulbutiamine attenuated GB-induced cell death. NAC and sulbutiamine both independently stimulated the GSH and GST production but scavenged different types of ROS with different efficacy. Moreover only sulbutiamine stimulated catalase and significantly increased Nrf-2 and HO-1 levels. In addition, the pan caspase inhibitor, benzoylcarbonyl-Val-Ala Asp-fluoromethyl ketone (z-VAD-fmk) attenuated the negative effect of serum deprivation while the necroptosis inhibitor (necrostatin-1) counteracted solely an insult of GB. The neuroprotective actions of NAC and sulbutiamine in GB or serum-deprivation insult are therefore different. PMID- 23811560 TI - Glycolaldehyde induces cytotoxicity and increases glutathione and multidrug resistance-associated protein levels in Schwann cells. AB - Schwann cell injury is observed in diabetic neuropathy. It is speculated that glycolaldehyde (GA), a precursor of advanced glycation end products (AGEs), contributes to the pathogenesis and development of diabetic neuropathy. Here, we demonstrated for the first time that GA at near-physiological concentration decreased the viability of rat Schwann cells. In contrast, methylglyoxal, glyoxal, and 3-deoxyglucosone, all of which are AGE precursors, had no effects on cell viability. It is well known that methylglyoxal causes oxidative damage. In the present study, however, GA failed to induce reactive oxygen species production in Schwann cells. The addition of glutathione (GSH) or N-acetyl-L cysteine protected Schwann cells from the loss of viability induced by GA. Moreover, GA increased intracellular GSH level and gamma-glutamylcysteine synthetase mRNA level. Flow cytometric analysis revealed that GA increased multidrug-resistance-associated protein 1 (MRP1) level as well. Moreover, we demonstrated that the knockdown of MRP1 with small interfering RNA (siRNA) enhanced the loss of cell viability induced by GA. Taken together, these findings suggest that MRP1, together with GSH, plays an important role in the GA-induced toxicity in Schwann cells. PMID- 23811561 TI - Erythropoietin prevents hypoxia-induced GATA-4 ubiquitination via phosphorylation of serine 105 of GATA-4. AB - Erythropoietin (EPO), an essential hormone for erythropoiesis, can provide protection against myocardial ischemia/reperfusion (I/R) injury and hypoxic apoptosis. GATA-4 is a zinc finger transcription factor, and its activation and post-translational modification are essential components in the transcriptional response to hypoxia. GATA-4 has also been reported to play a role in the cellular mechanisms of EPO-induced myocardial protection against I/R injury. In this study, we aimed to investigate the influence of EPO on GATA-4 protein stability and post-translational modification under hypoxic conditions without reperfusion. EPO induced cell viability under long-term hypoxia. EPO significantly increased phosphorylation of GATA-4 via the extracellular signal-regulated kinase (ERK) signaling pathway and reduced hypoxia-induced GATA-4 ubiquitination, which enhanced GATA-4 stability under hypoxia. ERK activation by over-expression of constitutively active mitogen-activated protein kinase 1 (MEK1) strongly increased GATA-4 phosphorylation and its protein levels and decreased GATA-4 ubiquitination under hypoxia. Despite ERK activation, GATA-4 ubiquitination was not affected under hypoxia in a GATA-4-S105A mutant. Under hypoxic condition without reperfusion, EPO-induced ERK activation was associated with post translational modification of GATA-4, mediated by enhancement of phosphorylation of GATA-4 at Ser-105. Subsequent attenuation of GATA-4 ubiquitination led to increases in GATA-4 protein stability, which resulted in increased cell viability under hypoxia. PMID- 23811562 TI - Sauchinone, a lignan from Saururus chinensis, protects human skin keratinocytes against ultraviolet B-induced photoaging by regulating the oxidative defense system. AB - Ultraviolet (UV) radiation from sunlight induces matrix metalloproteinase (MMP) expression, which are responsible for collagenous extracellular matrix proteins breakdown in skin, causing photoaging. Sauchinone is reported to have various bioactivity such as antioxidative, hepatoprotective, and anti-inflammatory effects. In the present study, we investigated the protective effect of sauchinone against UVB (50 mJ/cm(2))-induced photoaging in HaCaT human epidermal keratinocytes. Sauchinone, at 5-40 uM, significantly protected keratinocytes against UVB-induced damage as assessed by cell viability and toxicity assay. Additionally, sauchinone, at 20-40 uM, prevented the upregulation of MMP-1 proteins and reduction of type 1 collagen induced by UVB. Other assays revealed that, in keratinocytes, sauchinone decreased reactive oxygen species (ROS) production and increased glutathione levels and heme oxygenase-1. Sauchinone also inhibited UVB-induced phosphorylation of mitogen-activated protein kinase (MAPK) signaling pathways. These results demonstrated that sauchinone protects skin keratinocytes through inhibition of extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 MAPK signaling via upregulation of oxidative defense enzymes. PMID- 23811563 TI - Study of umbelliferone hydroxylation to esculetin catalyzed by polyphenol oxidase. AB - We characterize umbelliferone, a derivative of 2,4-dihydroxycoumaric acid, as a substrate of polyphenol oxidase. This enzyme hydroxylates umbelliferone to esculetin, its o-diphenol, and then oxidizes it to o-quinone. The findings show that umbelliferone, an intermediate in one of the coumarin biosynthesis pathways, may be transformed into its o-diphenol, esculetin, which is also an intermediate in the same pathway. The activity of the enzyme on umbelliferone was followed by measuring the consumption of oxygen, spectrophotometrically and by HPLC. Kinetic constants characterizing the hydroxylation process were: kcat=0.09+/-0.02 s(-1) and Km=0.17+/-0.06 mM. The o-diphenol, esculetin, was a better substrate and when its oxidation was followed spectrophotometrically, the kinetic constants were: kcat=1.31+/-0.25 s(-1) and Km=0.035+/-0.002 mM. Both compounds therefore can be considered as alternative substrates to L-tyrosine and L-3,4 dihydroxyphenylalanine (L-DOPA), since both indirectly inhibit melanogenesis. PMID- 23811564 TI - In vivo pharmacokinetics and pharmacodynamics of positional isomers of mono PEGylated recombinant human granulocyte colony stimulating factor in rats. AB - In this study, the pharmacokinetic and pharmacodynamic properties of Lys(35), Met(N-terminal), and Lys(17)-mono-PEGylated recombinant human granulocyte colony stimulating factor (rhG-CSF) positional isomers were evaluated in rats. The in vitro biological activities of Lys(35), Met(N-terminal), and Lys(17)-mono PEGylated rhG-CSF were determined by examining NFS-60 cell proliferation. Plasma concentrations of rhG-CSF and white blood cell (WBC) counts and absolute neutrophil conunt (ANC) were measured and pharmacokinetic and pharmacodynamic properties were determined after a single subcutaneous administration of the Lys(35), Met(N-terminal), or Lys(17) isomers at 0.1 mg/kg in rats. The in vitro biological activities of Lys(35), Met(N-terminal), and Lys(17)-mono-PEGylated rhG CSF individual positional isomers were 20.1%, 37.4%, and 15.3%, respectively, that of rhG-CSF. However, all three mono-PEGylated rhG-CSF isomers had a greater blood half-life (T1/2) and in vivo efficacy as determined by WBC counts and ANC than rhG-CSF, but no significant difference was observed between the three isomers. In conclusion, Lys(35), Met(N-terminal), and Lys(17)-mono-PEGylated rhG CSF individual positional isomers exhibit an enhanced the in vivo pharmacokinetics and pharmacodynamics. Furthermore, three isomers have comparable in vivo pharmacokinetic and pharmacodynamic properties, but their in vitro biological activities are PEGylation site dependent. PMID- 23811565 TI - RecQ5 protein translocation into the nucleus by a nuclear localization signal. AB - RecQ5, a member of the RecQ helicase family, maintains genome stability via participation in many DNA metabolic processes including DNA repair, DNA resolution, and RNA transcription, processes occurring in the nucleus. Previously, we reported that RecQ5 and Rad51, also involved in DNA repair, become co-localized in nuclei when co-expressed in cultured cells. Nuclear localization of RecQ5 appears to be important for cellular function along with Rad51. However, little is known about the nuclear localization of RecQ5. Here, we generated enhanced green fluorescent protein (EGFP)-tagged RecQ5 transgenic flies and analyzed localization of this protein in early embryos by live imaging. In syncytial embryos, RecQ5 was localized synchronously in interphase nuclei, and spread repeatedly over the embryos in mitosis. Thus, RecQ5 was transported into nuclei at the early interphase. Furthermore, we examined the subcellular localization of a series of truncated forms of Drosophila RecQ5 in cultured cells to determine the nuclear localization signal (NLS). Entire coding or deleted RecQ5 sequences of various sizes were ligated into EGFP vectors, which were then used to transfect cultured Drosophila cells. The region responsible for nuclear localization of Drosophila RecQ5 contained a short stretch of positively charged basic amino acids, 2 of which were particularly important for the nuclear localization. This stretch was sufficient for nuclear localization when fused with EGFP. Although the NLS of Drosophila RecQ5 was distinct from that of human RECQL5 in terms of position and amino acid sequence, this fly RecQ5 protein was translocated into the nucleus by an NLS. PMID- 23811566 TI - Analysis of carboxy terminal domain of metalloprotease of elastolytic Aeromonas hydrophila. AB - We examined the ability of Aeromonas hydrophila to lyse elastin. Eight of 13 strains showed elastolytic activity on agar medium containing elastin and 5 strains did not. In order to examine the involvement of the metalloprotease of A. hydrophila (AMP) in elastolytic activity, we made the amp-deletion mutant strain from an elastolytic strain. The elastolytic activity of the strain decreased with this deletion. The analysis of AMP released into the culture supernatant showed that AMP appeared outside of the cell as the intermediate consisting of a mature domain and carboxy terminal (C-terminal) propeptide domain. Further analysis showed that the intermediate has the ability to lyse elastin and that loss of the C-terminal domain causes loss of the elastolytic activity of the intermediate. We then determined the nucleotide sequence of the amps of all strains used in this study. Phylogenetic analysis revealed that these AMPs were divided into three groups. The AMPs from elastolytic strains belong to group I or group II, and AMPs from non-elastolytic strains belong to group III. The distance between group I and group II is small, but group III is located separately from groups I and II. Comparison of the amino acid residues of the C-terminal domain revealed that there are 13 amino acid residues specific to the C-terminal domain of group III. This indicates that the conformation of the C-terminal propeptide domain formed by these specific amino acid residues is important for AMP to express elastolytic activity. PMID- 23811567 TI - Gene silencing in a mouse lung metastasis model by an inhalable dry small interfering RNA powder prepared using the supercritical carbon dioxide technique. AB - In this study, a novel dry small interfering RNA (siRNA) powder for inhalation, containing chitosan and mannitol, was prepared using the supercritical carbon dioxide (CO2) technique. Although the siRNA/chitosan powder was difficult to disperse because of a long needle-like structure, it could be reduced to fragments of 10-20 um by manual grinding, which allowed for administration into mice. Electrophoresis revealed that the supercritical CO2 technique and manual grinding didn't greatly affect the integrity of the siRNA. Furthermore, the siRNA was more stable in the lungs than in blood, suggesting the utility of pulmonary delivery. Biodistribution experiments using Cy5.5-labeled siRNA demonstrated that pulmonary administration of the powder achieved a prolonged exposure of the siRNA/chitosan complex on the lung epithelial surface at a higher concentration. For the evaluation of the in-vivo gene silencing effect of the siRNA/chitosan powder, mice bearing colon26/Luc cells were used. The powder significantly inhibited the increase in luminescence intensity in the lungs, but the siRNA/chitosan solution and a non-specific dry siRNA/chitosan powder didn't, indicating the effective and specific gene silencing against the tumor cells metastasized in the lungs of mice by the siRNA/chitosan powder. These results strongly indicate that inhalable dry siRNA powders have the possibility of effective pulmonary gene silencing and that the supercritical CO2 technique can be applied to the production. PMID- 23811568 TI - Increase in secretory sphingomyelinase activity and specific ceramides in the aorta of apolipoprotein E knockout mice during aging. AB - Atherosclerosis is caused by many factors, one of which is oxidative stress. We recently demonstrated that systemic oxidative stress increased secretory sphingomyelinase (sSMase) activity and generated ceramides in the plasma of diabetic rats. In addition, we also showed that the total ceramide level in human plasma correlated with the level of oxidized low-density lipoprotein. To investigate the relationship between ceramide species and atherogenesis during aging, we compared age-related changes in ceramide metabolism in apolipoprotein E knock out mice (apoE(-/-)) and wild type mice (WT). Although the total plasma ceramide level was higher in apoE(-/-) than that in WT at all ages, it decreased with increasing age. sSMase activity increased at 65 weeks (w) of age in both strains of mice. When apoE(-/-) developed atherosclerosis at 15 w of age, C18:0, C22:0, and C24:0 ceramide levels in the apoE(-/-) aorta significantly increased. Furthermore, at 65 w of age C16:0 and C24:1 ceramide levels were significantly higher than those in WT. These results suggested that elevation in levels of specific ceramide species due to sSMase activity contributed to atherogenesis during aging. PMID- 23811570 TI - The importance of interaction with membrane lipids through the pleckstrin homology domain of the guanine nucleotide exchange factor for rho family small guanosine triphosphatase, FLJ00018. AB - FLJ00018, a heterotrimeric guanosine 5'-triphosphate (GTP)-binding protein (G protein) Gbetagamma subunit-activated guanine nucleotide exchange factor for Rho family small GTPases, regulates cellular responses, including cell morphological changes and gene transcriptional regulation, and targets the cellular membranes. FLJ00018 contains a Dbl homology (DH) domain in addition to a pleckstrin homology (PH) domain. Here we show that the PH domain of FLJ00018 is required for FLJ00018 induced, serum response element-dependent gene transcription. Although the PH domain of KIAA1415/P-Rex1, another Gbetagamma subunit-activated guanine nucleotide exchange factor for Rho family small GTPases, binds to phosphatidylinositol 3,4,5-triphosphate and phosphatidylinositol 3,4 bisphosphate, the PH domain of FLJ00018 binds to polyphosphoinositides including phosphatidylinositol 4,5-bisphosphate, and phosphatidic acid. These results suggest that FLJ00018 is targeted via its PH domain to cellular membranes. PMID- 23811569 TI - Structural requirements for potent direct inhibition of human cytochrome P450 1A1 by cannabidiol: role of pentylresorcinol moiety. AB - Our recent work has shown that cannabidiol (CBD) exhibits the most potent direct inhibition of human cytochrome P450 1A1 (CYP1A1) among the CYP enzymes examined. However, the mechanism underlying this CBD inhibition remains to be clarified. Thus, to elucidate the structural requirements for the potent inhibition by CBD, the effects of CBD and its structurally related compounds on CYP1A1 activity were investigated with recombinant human CYP1A1. Olivetol, which corresponds to the pentylresorcinol moiety of CBD, inhibited the 7-ethoxyresorufin O-deethylase activity of CYP1A1; its inhibitory effect (IC50=13.8 uM) was less potent than that of CBD (IC50=0.355 uM). In contrast, d-limonene, which corresponds to the terpene moiety of CBD, only slightly inhibited CYP1A1 activity. CBD-2'-monomethyl ether (CBDM) and CBD-2',6'-dimethyl ether inhibited CYP1A1 activity with IC50 values of 4.07 and 23.0 uM, respectively, indicating that their inhibitory effects attenuated depending on the level of methylation on the free phenolic hydroxyl groups in the pentylresorcinol moiety of CBD. Cannabidivarin inhibited CYP1A1 activity, although its inhibitory potency (IC50=1.85 uM) was lower than that of CBD. The inhibitory effects of Delta(9)-tetrahydrocannabinol and cannabielsoin (IC50s ~10 uM), which contain a free phenolic hydroxyl group and are structurally constrained, were less potent than that of CBDM, which contains a free phenolic hydroxyl group and is rotatable between pentylresorcinol and terpene moieties. These results suggest that the pentylresorcinol structure in CBD may have structurally important roles in direct CYP1A1 inhibition, although the whole structure of CBD is required for overall inhibition. PMID- 23811571 TI - Pharmacological characterization of BR-A-657, a highly potent nonpeptide angiotensin II receptor antagonist. AB - The pharmacological profile of BR-A-657, 2-n-butyl-5-dimethylamino-thiocarbonyl methyl-6-methyl-3-{[2-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl}-pyrimidin-4(3H) one, a new nonpeptide AT1-selective angiotensin receptor antagonist, has been investigated in a variety of in vitro and in vivo experimental models. In the present study, BR-A-657 displaced [(125)I][Sar(1)-Ile(8)]angiotensin II (Ang II) from its specific binding sites to AT1 subtype receptors in membrane fractions of HEK-293 cells with an IC50 of 0.16 nM. In a functional assay using isolated rabbit thoracic aorta, BR-A-657 inhibited the contractile response to Ang II (pD'2: 9.15) with a significant reduction in the maximum. In conscious rats, BR-A 657 (0.01, 0.1, 1 mg/kg; intravenously (i.v.)) dose-dependently antagonized Ang II-induced pressor responses. In addition, BR-A-657 dose-dependently decreased mean arterial pressure in furosemide-treated rats and renal hypertensive rats. Moreover, BR-A-657 given orally at 1 and 3 mg/kg reduced blood pressure in conscious renal hypertensive rats. Taken together, these findings indicate that BR-A-657 is a potent and specific antagonist of Ang II at the AT1 receptor subtype, and reveal the molecular basis responsible for the marked lowering of blood pressure in conscious rats. PMID- 23811572 TI - Cytosolic low molecular weight protein-tyrosine phosphatase activity and clinical manifestations of diabetes. AB - BACKGROUND: Biochemical, epidemiological and experimental evidence suggests that cytosolic low molecular weight protein-tyrosine phosphatase (cLMWPTP) genetic variability may have a role in the clinical manifestations of diabetes mellitus. In this article, the authors review data from their laboratory supporting the hypothesis that high cLMWPTP activity favors severe manifestations of diabetes. METHODS: In 829 type 2 diabetic patients, the authors have studied the association between clinical parameters and cLMWPTP activity. The cLMWPTP genotype was determined in all subjects. RESULTS: In diabetic subjects, low activity cLMWPTP protects against extreme increase of glycemic level (patients studied 489). The correlation between glycemic level and glycated hemoglobin concentration is increasing with cLMWPTP activity (patients studied 270). In diabetic subjects with coronary artery disease, left ventricular ejection fraction is negatively correlated with cLMWPTP activity (patients studied 70). CONCLUSIONS: All these observations point to a negative effect of high cLMWPTP activity on clinical manifestation of diabetes in accordance with theoretical and experimental data and suggest that pharmacological decrease of cLMWPTP activity could have beneficial effects on the clinical evolution of this disease. Moreover, in diabetic subjects with high activity ACP1 genotype, an intensive treatment could help to prevent severe clinical manifestations. PMID- 23811573 TI - Providencia rettgeri: an unusual cause of central nervous system infections. AB - Providencia, unlike other enterobacteriaceae, is a lesser known causative agent of hospital-acquired and community-acquired neuroinfection. Two cases of meningitis and one patient with subdural empyema, where Providencia rettgeri was the causative agent, are reported. To the authors' knowledge, this is the first report of hospital-acquired and community-acquired meningitis or empyema caused by P rettgeri. PMID- 23811574 TI - Massive splenomegaly secondary to prolidase deficiency. PMID- 23811575 TI - Vasculitis mimics: cocaine-induced midline destructive lesions. AB - It has been recognized that nasal cocaine abuse can induce midline destructive lesions that can mimic different disorders, including small-vessel vasculitis. The authors reported 2 cases of patients referred to the rheumatology clinic with a previous diagnosis of granulomatosis with polyangiitis (Wegener's granulomatosis), presenting with chronic perforation in the palate, refractory to immunosuppressant therapy. In both patients, laboratory investigation revealed antineutrophil cytoplasmic antibody positivity. A differential diagnosis between cocaine-induced midline destructive lesions and granulomatosis with polyangiitis is also difficult to establish because of the presence of antineutrophil cytoplasmic antibody in both disorders. Given the high prevalence of cocaine use, awareness of this mimic is essential to avoid a misdiagnosis and the use of unnecessary and potential toxic therapies. PMID- 23811576 TI - Panoramic radiomorphometric indices as reliable parameters in predicting osteoporosis. AB - BACKGROUND: The purpose was to evaluate the significance of panoramic radiomorphometric indices (mandibular cortical index [MCI], mental index [MI] and panoramic mandibular index [PMI]) as useful tools for identifying osteoporosis. METHODS: One hundred healthy women aged >= 30 years were included. Digital panoramic images and bone mineral density (BMD) of the lumbar spines were recorded. Radiomorphometric indices (MCI, MI and PMI) were measured and categorized. RESULTS: Interobserver agreements were kappa = 0.922 for the MCI and alpha = 0.902 and 0.702 for the PMI and MI, respectively. The indices MI, PMI and BMD showed a statistically significant positive correlation with the t score (r = 0.47, 0.36 and 0.96, respectively). The MI showed a statistically significant positive correlation with the PMI (r = 0.72). Sensitivity, specificity and diagnostic accuracy of the MI at a cutoff point of 4.5 mm were 76.9%, 54.1% and 63%, respectively, whereas for the MCI were 66.7%, 75.4% and 72%, respectively. CONCLUSIONS: Panoramic indices (MI, PMI and MCI) were positively correlated with the t score and BMD of the lumbar spines. The MCI was found to be the most reproducible index. PMID- 23811577 TI - Unusual case of prosthetic shoulder joint infection due to Clostridium difficile. AB - Extraintestinal manifestatation such as prosthetic joint infection due to Clostridium difficile is a rare diagnosis. A 47-year-old female patient presented with chronic pain in left shoulder prosthetic joint. Plain roentgenogram of left shoulder prosthetic joint revealed anterior dislocation and loosening of prosthesis. The synovial fluid cultures and intraoperative deep joint cultures repeatedly grew Clostridium difficile. Patient was treated with antimicrobial therapy and surgical debridement with complete removal of hardware and revision arthroplasty. PMID- 23811578 TI - Study on the treatment of acute thallium poisoning. AB - BACKGROUND: Acute thallium poisoning rarely occurs but is a serious and even fatal medical condition. Currently, patients with acute thallium poisoning are usually treated with Prussian blue and blood purification therapy. However, there are few studies about these treatments for acute thallium poisoning. METHODS: Nine patients with acute thallium poisoning from 1 family were treated successfully with Prussian blue and different types of blood purification therapies and analyzed. RESULTS: Prussian blue combined with sequential hemodialysis, hemoperfusion and/or continuous veno-venous hemofiltration were effective for the treatment of patients with acute thallium poisoning, even after delayed diagnosis. CONCLUSIONS: Blood purification therapies help in the clearance of thallium in those with acute thallium poisoning. Prussian blue treatment may do the benefit during this process. PMID- 23811580 TI - Autophagy: a key pathway of TNF-induced inflammatory bone loss. AB - Autophagy describes the degradation of unnecessary or dysfunctional cellular components through the lysosomal machinery. Autophagy is essentially required to prevent accumulation of cellular damage and to ensure cellular homeostasis. Indeed, impaired autophagy has been implicated in a variety of different diseases. We examined the role of autophagy in inflammatory bone loss. We demonstrated that autophagy is activated by the pro-inflammatory cytokine tumor necrosis factor (TNF/TNFalpha) in osteoclasts of patients with rheumatoid arthritis (RA). Autophagy induces osteoclast differentiation and stimulates osteoclast-mediated bone resorption in vitro and in vivo, thereby highlighting autophagy as a novel mediator of TNF-induced bone resorption. PMID- 23811581 TI - [Bone structure and strength in the proximal femur - changes due to age and medical treatment]. AB - Understanding bone strength scientifically requires knowledge of the material strength of a bone fragment, and understanding the bone strength of a specific part of a bone requires a destruction test using a cadaver bone. Since these tests cannot be used clinically, bone strength evaluation with the advanced medical technology of "predictive estimation of bone strength based on a finite element method using quantitative CT" has been developed to estimate bone strength with consideration of anatomical bone structure of the proximal femur. Today this method has come to be clinically applicable with actual patients. Investigations in our hospital have also led to the finding that while the proximal femur is strong enough for a standing load in daily life, it does not readily withstand the load from falls in accidents, and has a structure such that fractures may be predicted to occur at about one-third that size. PMID- 23811582 TI - [Effect of age and anti-osteoporotic drugs on bone strength and structure of the distal radius]. AB - The distal radius constitutes a proximal part of the wrist joint, which bears axial load from the carpal bones. Based on the biomechanical experiments, the load transmitted from the carpal bones to the distal articular surface of the radius is greater to the lunate fossa than the scaphoid fossa. The findings are consistent with the results obtained from HR-pQCT analysis of the distal radius. As ageing, bone mineral densities of the distal radius decrease, and structures of the cortical and trabecular bones also deteriorate. Such deterioration can be prevented by osteoporotic medicines such as PTH or bisphosphonate. Denosumab has been shown to increase mechanical indices of the bone structure of the distal radius. The distal radius of the individual is fractured when the load over approximately 5 times (2.5SD) of the weight is applied. It is possible to predict load of fracture in the distal radius from the results of DXA derived BMD or HR pQCT derived bone parameters. We should not miss the opportunity of treatment for osteoporosis when the patients with fragility distal radius fracture are seen. PMID- 23811583 TI - [Effects of aging and therapy on the structural properties and strength of vertebral body]. AB - Bone strength depends on its structure and its material properties. Structural properties are determined by the size and shape of bone and also the microarchitecture. Material properties are determined by mineral crystallinity, collagen structure and microdamage in bone. The strength of bone is adapted to the needs of physical activities by biologic mechanisms, bone modeling and remodeling. The deterioration of bone strength in postmenopausal women is characterized by a trabecular bone deficit with poor trabecular connectivity and followed by a cortical bone deficit with trabeculation of endocortical bone and intracortical porosity due to accelerated bone remodeling. Trabecular bone is getting more fragile with age by poor adaptation to mechanical load by modeling. As a consequence, the endplate collapses and vertebral body fracture occurs. The deterioration of bone strength could be improved by osteoporosis treatment using antiresorber or teriparatide, and these drugs would decrease the risk of vertebral fracture consequently. PMID- 23811584 TI - [The changes of bone architecture in atypical femoral fracture]. AB - The feature of atypical femoral fracture is stress induced cortical bone reaction. It was considered to be the accumulation of microdamage which come from increasing of mechanical stress by femoral lateral bowing, and the decreased of ability of microdamage repair system. PMID- 23811579 TI - Comparison of intradermal and intramuscular delivery followed by in vivo electroporation of SIV Env DNA in macaques. AB - A panel of SIVmac251 transmitted Env sequences were tested for expression, function and immunogenicity in mice and macaques. The immunogenicity of a DNA vaccine cocktail expressing SIVmac239 and three transmitted SIVmac251 Env sequences was evaluated upon intradermal or intramuscular injection followed by in vivo electroporation in macaques using sequential vaccination of gp160, gp120 and gp140 expressing DNAs. Both intradermal and intramuscular vaccination regimens using the gp160 expression plasmids induced robust humoral immune responses, which further improved using the gp120 expressing DNAs. The responses showed durability of binding and neutralizing antibody titers and high avidity for>1 y. The intradermal DNA delivery regimen induced higher cross-reactive responses able to neutralize the heterologous tier 1B-like SIVsmE660_CG7V. Analysis of cellular immune responses showed induction of Env-specific memory responses and cytotoxic granzyme B(+) T cells in both vaccine groups, although the magnitude of the responses were ~10x higher in the intramuscular/electroporation group. The cellular responses induced by both regimens were long lasting and could be detected ~1 y after the last vaccination. These data show that both DNA delivery methods are able to induce robust and durable immune responses in macaques. PMID- 23811585 TI - [Osteoarthritis and bone structural changes]. AB - Bone morphological abnormalities, such as acetabular dysplasia, femoroacetabular impingement (FAI) , and knee varus deformity, are causes of osteoarthritis (OA) . These deformities have complex three-dimensional characteristics, and an accurate image assessment is not always easy. In recent years, statistical shape models (SSM) have been applied to analyzing variations of bone morphology in OA. Bone microstructural changes in OA include bone sclerosis, subchondral cysts, and osteophytes. Recent studies show that various pathological changes in subchondral bone affect the onset and development of OA, becoming targets for new drugs. Quantitative methods to analyze the subchondral trabecular bone of OA patients using MDCT and 3TMRI are currently under development. PMID- 23811586 TI - [Bone structure in rheumatoid arthritis]. AB - In rheumatoid arthritis (RA) , the osteoclast pathway is activated by abnormal immune conditions accompanied by chronic inflammation, resulting in periarticular osteoporosis and local bone destruction around joints. In addition, multiple factors, including reduced physical activity and pharmacotherapies such as steroids, lead to systemic osteoporosis. These conditions cause decreasing bone mineral density and deterioration of bone quality, and expose patients to increased risk of fracture. Understanding the bone structures of RA and evaluating fracture risk are central to the treatment of RA. PMID- 23811587 TI - [The effects of glucocorticoid on bone architecture and strength]. AB - Glucocorticoid-induced osteoporosis is the leading cause of osteoporosis in young adults and the most common cause of secondary osteoporosis. Glucocorticoid use results in rapid bone loss and elevated risk of fracture. However, glucocorticoid induced osteoporosis is characterized by relative dissociation between the bone mineral density values and the fracture risk, which is higher than expected based on the bone mineral density values. The excess bone fragility from glucocorticoid treatment is multifactorial. Recently, many published studies have focused on the cellular and molecular mechanisms of bone metabolism, the pathophysiology of glucocorticoid-induced osteoporosis, and the imaging assessment of bone fragility in glucocorticoid-induced osteoporosis. In this review, recent advances in glucocorticoid-induced osteoporosis are summarized, particularly recent progress in our understanding of the effects of glucocorticoid on bone architecture and strength resulting in improved insight that might result in the development of new treatment options in the near future. PMID- 23811588 TI - [Bone architecture and strength in diabetes mellitus]. AB - Increased fracture risks in diabetes mellitus (DM) have been attributed to deteriorated bone quality both in type 1 and 2 DM because increased risks are disproportionate to their bone mineral densities (BMD) . Although still very little is known about bone architecture in type 1 DM, recent advancement in the techniques, such as high-resolution peripheral quantitative CT (HR-pQCT) and trabecular bone score (TBS) , have revealed that, in type 2 DM, bone microstructure is compromised despite preserved BMD, which may account for high fracture risk in DM. PMID- 23811589 TI - [Bone structural properties and bone strength in CKD]. AB - Bone fracture risk in patients with chronic kidney disease (CKD) is much higher than that in healthy subjects. Frailty caused by neuromuscular impairment as well as bone fragility due to bone loss and impaired bone quality is thought to be involved in the elevated fracture risk in CKD. Altered material and structural properties might be attributed to the reduced bone strength. The structural properties in CKD patients are characterized in 1) cortical thinning and cortical porosity, and 2) irregular thickening and loss of connectivity in trabecular bone. Interestingly, recent findings suggest that skeletal changes in the structural properties may be initiated at earlier stage of CKD than we expected. PMID- 23811590 TI - [Bone architecture and strength on unloading]. AB - The bone loss due to space flight or prolonged bed rest observes early stage of unloading and causes both decreased bone formation and increased bone resorption. Mechanical unloading induced not only both tarbecular and cortical bone loss but also greater decline bone structure in weight-bearing bone. These findings and further examination concern about pathophysiolosy will allow for better understanding of unloading-associated bone loss and for development of effective countermeasures. PMID- 23811591 TI - [Effect on bone structure and strength by novel anti-osteoporotic agents]. AB - Recent progress in understanding molecular processes underlying osteoporosis has resulted in the development of several new anti-osteoporotic agents that are currently being explored in clinical trials. Denosumab, a monoclonal antibody directed against RANKL, has just approved in Japan and some additional new therapies are lining up for clinical approval in the coming years. Potential agents include cathepsin K inhibitor and sclerostin. Here, I will provide a short overview on these three agents focusing on their effect on structural properties and bone strength. PMID- 23811592 TI - [Bone micro-structural changes following osteoporotic drug treatment]. AB - Osteoporotic drugs improve bone mechanical integrity by increasing bone mass and also by improving bone structure and quality, where controlling bone metabolism. Changes in trabecular microstructure can be detected since early period after starting drug treatment. Effects on bone metabolism of anti-resorptive agent of bisphosphonates are totally opposite from those of anabolic agent of teriparatide, however these different drug treatments results in the improvement of trabecular microstructure as well. PMID- 23811593 TI - [Effect of anti-osteoporotic agents on cortical microstructure]. AB - The incidence of non-vertebral fracture increases in old age, and the deterioration of cortical micro-structure is considered to be one of important reason to cause non-vertebral fracture. In this chapter, the age-related change of cortical microstructure, relationship with bone strength are discussed as well as the effect of anti-osteoporotic drugs on cortical bone ; bisphosphonate, teriparatide, active vitamin D3, and denosumab. PMID- 23811594 TI - [The changes in bone geometric parameters by medication]. AB - The changes in bone geometric parameters (hip structure analysis, HSA) by medication are reviewed. HSA parameters are strongly correlated with CT parameters. Raloxifene, bisphosphonate (alendronate, risedronate, minodronate) , and denosumab improved section modulus (index for bending force) more than bone mineral density, and the improvements in section modulus are superior in intertrochanter than in femoral neck. The tendency to change in femoral shaft is approximately similar in femoral neck and intertrochanter. On the other hand, the tendency to change in these parameters in teriparatide (20MUg/day) is different from raloxifene, bisphosphonate, and denosumab. Teriparatide improved section modulus and bone mineral density in femoral neck and intertrochanter, but the improvement in section modulus was approximately similar in bone mineral density and the improvement in intertrochanter is not higher than femoral neck. The femoral shaft did not show significant change. PMID- 23811595 TI - Skin graft hypertrichosis associated with prostaglandin analog in the treatment of glaucoma. AB - Prostaglandin analogs are commonly used in the treatment of glaucoma. They are a safe and effective treatment associated with few side effects. Common local side effects include conjunctival hyperemia, iris pigmentation, and eyelash hypertrichosis. The authors present a case of a patient using travoprost treatment for primary open-angle glaucoma, who underwent excision of a lower eyelid basal cell carcinoma and reconstruction with an upper eyelid tarsoconjunctival flap and overlying skin graft. The patient developed hypertrichosis of the skin graft attributable to prostaglandin analog use. PMID- 23811596 TI - Rate of vascularization and exposure of silicone-capped porous polyethylene spherical implants: an animal model. AB - PURPOSE: This pilot study examines the rates of exposure and fibrovascular ingrowth of silicone-capped, porous, polyethylene orbital implants in the New Zealand white rabbit animal model. METHODS: Unwrapped, silicone-capped, porous, polyethylene orbital spheres were implanted in 16 enucleated rabbit orbits. Four implants were removed at 3, 6, 9, and 12-month intervals and submitted for histopathologic analysis. A board-certified pathologist reviewed and graded vascular ingrowth, inflammation type, and severity for all specimens. RESULTS: Fibrovascular ingrowth in the center of all implants occurred as early as 3 months. No fibrovascular ingrowth occurred at the interface between the silicone cap and the porous polyethylene implant. The overlying Tenon's and conjunctival tissues remained intact without significant host inflammatory response. No implant exposure occurred at any time point. CONCLUSIONS: Silicone-capped porous polyethylene orbital implants appear to offer an inexpensive, easy-to-manufacture implant that resists exposure without the need for a wrapping material and achieves successful biointegration soon after implantation. PMID- 23811597 TI - Orbitomalar suspension with combined single drill hole canthoplasty. AB - PURPOSE: Whether resulting from a surgical complication or involutional change, lower eyelid retraction and canthal dystopia can lead to lagophthalmos and frank ectropion. The authors present their experience with a single drill hole fixation for both the lateral canthus and suborbicularis oculi fat for severe canthal dystopia and lower eyelid retraction. METHODS: In this retrospective, consecutive study, the medical records of 13 patients who underwent single drill hole canthoplasty and suborbicularis oculi fat suspension were reviewed. A 4-0 nonabsorbable polypropylene suture was used to secure the canthal tendon, passed through a single lateral orbital rim drill hole from inside out. The suborbicularis oculi fat was then suspended in the same manner. Outcome measurements included linear marginal reflex distance 2, lagophthalmos, and subjective assessment of the results by the patient. RESULTS: Preoperatively, the average linear marginal reflex distance 2 was 7.3 +/- 1.0 mm, the average lagophthalmos was 3.5 +/- 0.8 mm, and the average horizontal palpebral fissure width was 25.7 +/- 1.3 mm. Postoperatively, average linear marginal reflex distance 2 was 5.3 +/- 0.7 mm (p < 0.05), average lagophthalmos was 0.3 +/- 0.4 mm (p < 0.05), and average horizontal palpebral fissure width was 30.2 +/- 0.7 mm (p < 0.05). All patients noted symptomatic relief and were satisfied with the appearance of their eyelids at 6 months of follow up. CONCLUSIONS: Single drill hole canthoplasty with suborbicularis oculi fat suspension is a viable alternative to previously described procedures. By using a single bony drill hole, rigid fixation is achieved with avoidance of multiple fixation points. PMID- 23811598 TI - Is liver biopsy a problem for patients on chronic hemodialysis? PMID- 23811599 TI - Pseudoaneurysm developed after percutaneous endoscopic gastrostomy: a report of two cases. AB - Percutaneous endoscopic gastrostomy (PEG) is widely performed. However, despite its widespread use, complications often follow and some of them are life threatening. We report on two patients who developed pseudoaneurysm after PEG and how the bleeding was stemmed by transcatheter arterial embolization. Case 1 is an 84-year-old man. PEG by the pull method using One Step Button 24 Fr was performed. Blood-laced vomiting, followed by hemorrhagic shock was observed on day 21. Pseudoaneurysm less than 10 mm in diameter was observed in the gastroepiploic artery by urgent percutaneous abdominal angiography. A microcatheter was advanced selectively and the affected area was embolized by metallic coils and n-butyl cyanoacrylate. Case 2 is an 89-year-old man. PEG by the pull method using One Step Button 24 Fr was performed. On day 28, bleeding from the gastrostomy portion occurred and the patient went into shock. On urgent percutaneous abdominal angiography, pseudoaneurysm ~5 mm in diameter was detected in the left gastric artery. A microcatheter was advanced selectively and the affected area was embolized by metallic coils and n-butyl cyanoacrylate. In the present two cases, gastrostomies were created in the anterior wall of the mid body portion as suitable for PEG position, but the bleedings occurred because of pseudoaneurysm formation accompanied by damage to the gastroepiploic or the left gastric artery. Those who perform PEG on a regular basis should be aware of the possibility of pseudoaneurysm as a serious adverse event. PMID- 23811601 TI - Choice of anti-hypertensive agents in diabetic subjects. AB - Hypertension is an extremely common co-morbid condition in diabetes leading to acceleration in micro-vascular and macro-vascular complications. The use of anti hypertensives in diabetic patients should be considered in the context of preventing the development of complications. Various factors contribute to the pathophysiology of diabetes in hypertension. With the advancements in technology, the understanding of the pathophysiological mechanisms has increased, and this can contribute in providing evidence for beneficial role of certain anti hypertensives. Many clinical trials have been carried out for use of diuretics, beta blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. The present review gives an overview of pathophysiological mechanisms of hypertension and diabetes in addition to the details of clinical trials of anti-hypertensives in diabetic patients. This is an attempt to provide some evidences for the clinicians, which may serve as a guide for use of anti-hypertensives in clinical practice. PMID- 23811600 TI - Chaperones as thermodynamic sensors of drug-target interactions reveal kinase inhibitor specificities in living cells. AB - The interaction between the HSP90 chaperone and its client kinases is sensitive to the conformational status of the kinase, and stabilization of the kinase fold by small molecules strongly decreases chaperone interaction. Here we exploit this observation and assay small-molecule binding to kinases in living cells, using chaperones as 'thermodynamic sensors'. The method allows determination of target specificities of both ATP-competitive and allosteric inhibitors in the kinases' native cellular context in high throughput. We profile target specificities of 30 diverse kinase inhibitors against >300 kinases. Demonstrating the value of the assay, we identify ETV6-NTRK3 as a target of the FDA-approved drug crizotinib (Xalkori). Crizotinib inhibits proliferation of ETV6-NTRK3-dependent tumor cells with nanomolar potency and induces the regression of established tumor xenografts in mice. Finally, we show that our approach is applicable to other chaperone and target classes by assaying HSP70/steroid hormone receptor and CDC37/kinase interactions, suggesting that chaperone interactions will have broad application in detecting drug-target interactions in vivo. PMID- 23811603 TI - Associations of serum fetuin-A levels with insulin resistance and vascular complications in patients with type 2 diabetes. AB - OBJECTIVE: We examined the relationship between serum fetuin-A, insulin resistance (IR), metabolic syndrome (MS) and vascular complications including cardiac autonomic neuropathy (CAN) in patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 172 T2DM patients were recruited and evaluated for diabetic microangiopathies (nephropathy, retinopathy and peripheral neuropathy) including CAN. Serum fetuin-A levels were measured by enzyme-linked immunosorbent assay (ELISA), and the IR was assessed by the index of homeostasis model [homeostasis model assessment-insulin resistance (HOMA-IR)]. Atherosclerotic burden was assessed by ankle-brachial index (ABI) and brachial-ankle pulse wave velocity (baPWV). RESULTS: Serum fetuin-A levels showed significant positive correlations with HOMA-IR (r = 0.196, p = 0.022), and the mean levels of HOMA-IR were significantly increased progressively across fetuin-A tertiles (p for trend = 0.044). Serum fetuin-A showed significant positive correlations with baPWV, systolic blood pressure (BP), total cholesterol, triglycerides, serum fasting c peptide and negative correlations with ABI. Serum fetuin-A levels were also negatively correlated with serum adiponectin and positively correlated with serum tumour necrosis factor-alpha (TNF-alpha). The mean levels of serum fetuin-A were not significantly different according to the presence of each microangiopathies including CAN. Also, the mean levels of serum fetuin-A were not different between patients with MS and without MS. CONCLUSIONS: This present study showed that levels of serum fetuin-A are significantly associated with IR and arterial stiffness assessed by baPWV, while there are no associations with each microangiopathies in patients with T2DM. PMID- 23811602 TI - Improvement of arterial wall characteristics by the low-dose fluvastatin and valsartan combination in type 1 diabetes mellitus patients. AB - We tested whether short-term, low-dose treatment with the fluvastatin and valsartan combination could improve impaired arterial wall characteristics in type 1 diabetes mellitus patients. A total of 44 type 1 diabetes mellitus patients were randomised into the treatment group [n = 22; received a low-dose combination of fluvastatin (10 mg daily) and valsartan (20 mg daily)] and the control group (n = 22; received placebo), both for 30 days. Brachial artery flow mediated dilation (FMD), pulse wave velocity (PWV) and carotid artery beta stiffness were measured. Significant improvements in FMD (+73.2%), PWV (-7.5%) and beta-stiffness (-10.0%) were achieved after 1-month treatment compared to the control group (all p values < 0.001). Three months after therapy discontinuation, important residual improvement in measured parameters was still present. No changes in lipids and blood pressure accompanied the beneficial improvements. We conclude that relatively simple intervention (low-dose, short-term fluvastatin/valsartan combination) produces substantial, long-term improvement of arterial wall characteristics in type 1 diabetes mellitus patients. PMID- 23811604 TI - Effect of IL-10 on LOX-1 expression, signalling and functional activity: an atheroprotective response. AB - The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) has gained attention for its pro-inflammatory potential in atherogenesis. This study evaluates LOX-1 receptor modulation in the presence of an atheroprotective cytokine, interleukin-10 (IL-10). Both oxidized low-density lipoprotein (oxLDL) and IL-10 stimulated LOX-1 cell surface expression on THP-1 macrophages. However, our study demonstrates differential roles of oxLDL and IL-10 on LOX-1 functionality. Seemingly, oxLDL-induced LOX-1 promoted pro-inflammatory signalling by increasing intracellular NO, a substrate for pro-inflammatory peroxynitrite. In contrast, IL-10-induced LOX-1 facilitated scavenging of extracellular oxLDL without any effect on pro-inflammatory signalling. The atheroprotective effects of IL-10 were demonstrated by both facilitation of cellular oxLDL uptake and expression of LOXIN, an atheroprotective haplotype of the LOX-1 gene. Thus, increased expression of IL-10 may help to attenuate the risk of atherosclerosis developed by pro-inflammatory signal(s) generated through the interaction of oxLDL with its cognate receptor LOX-1 on macrophages. PMID- 23811606 TI - Rostock Glare Perimeter: a distinctive method for quantification of glare. AB - PURPOSE: Disability glare induced by headlights of oncoming cars has been associated with reduced quality of vision. This study aimed at developing the Rostock Glare Perimeter to quantify dysphotopsia effects under simulated realistic conditions. METHODS: Sixty phakic subjects of different ages were dazzled by a bright light source centered at a projection screen 3.30 m away from the subject's eye. Using a projected marker moving outward from the screen center with angular steps of 0.25 degrees in 12 directions, the area where the subject cannot distinguish the white spot from the glare effects of the light source was determined. A corresponding mean radius in a field angle relative to the subject's eye was defined as a measure for disability glare. Monocular and binocular measurements were performed, and a separate repeatability and reproducibility study was executed to determine the precision of the Rostock Glare Perimeter. RESULTS: A significant mean positive correlation of disability glare with age (r = 0.534, p < 0.001) was found. The disability glare ranged from 0.33 degrees to 1.8 degrees , and a strong (r = 0.93, p < 0.0002) binocular summation effect was found. The repeatability and reproducibility limit of the Rostock Glare Perimeter method is 0.14 degrees for 95% confidence interval. CONCLUSIONS: The Rostock Glare Perimeter method is sensitive to detect age related disability glare differences and to find binocular summation for disability glare in a healthy population for small field angles with high angular resolution. These findings suggest that the Rostock Glare Perimeter method is a helpful device to quantify symptoms of glare. PMID- 23811605 TI - Self-organized and cu-coordinated surface linear polymerization. AB - We demonstrate a controllable surface-coordinated linear polymerization of long chain poly(phenylacetylenyl)s that are self-organized into a "circuit-board" pattern on a Cu(100) surface. Scanning tunneling microscopy/spectroscopy (STM/S) corroborated by ab initio calculations, reveals the atomistic details of the molecular structure, and provides a clear signature of electronic and vibrational properties of the poly(phenylacetylene)s chains. Notably, the polymerization reaction is confined epitaxially to the copper lattice, despite a large strain along the polymerized chain that subsequently renders it metallic. Polymerization and depolymerization reactions can be controlled locally at the nanoscale by using a charged metal tip. This control demonstrates the possibility of precisely accessing and controlling conjugated chain-growth polymerization at low temperature. This finding may lead to the bottom-up design and realization of sophisticated architectures for molecular nano-devices. PMID- 23811607 TI - Patient and public preferences for health states associated with AMD. AB - PURPOSE: Health utility values suitable for calculating quality-adjusted life years are increasingly used to assess the cost-effectiveness of treatments for age-related macular degeneration (AMD). In the United States, health utilities are usually derived from the patients' own valuation or modeled using visual acuity as a surrogate outcome. In the United Kingdom and throughout Europe, health utilities are derived from public valuations. Our aim was to test if utility values for health states associated with AMD elicited directly from patients were different from those calculated from public tariffs for health related quality of life (HRQoL) questionnaires. METHODS: Generic preference-based HRQoL questionnaires (EQ-5D and SF-6D) and the time trade-off (TTO) and visual analog scale (VAS) valuation techniques were administered to a sample of UK patients with AMD (N = 60). Health utilities were calculated using standard general population tariffs for the patient EQ-5D and SF-6D health states and directly from patient TTO and VAS scores. RESULTS: Mean utilities derived from the public tariffs were significantly higher than from patients' valuation (mean [+/-SD], 0.613 (+/-0.275) for the EQ-5D and 0.628 (+/-0.114) for the SF-6D compared with 0.481 [+/-0.411] for the TTO and 56.7 [+/-21.8] for the VAS score; p < 0.001). The EQ-5D was not significantly different from the SF-6D (p > 0.6). Visual acuity in the better seeing eye was not associated with any utility measure (all r < 0.08; p > 0.2). CONCLUSIONS: Patient and public preferences for health states associated with AMD are different, with patients valuing their health state more severely than the public tariffs of commonly used HRQoL questionnaires. Visual acuity did not predict health utility using any measure, and therefore, care should be taken when using visual acuity as a surrogate measure for utility in health economic analyses. PMID- 23811608 TI - Intravitreal bevacizumab for ocular metastasis of multiple myeloma. AB - PURPOSE: Multiple myeloma is the most common plasma cell tumor; however, ocular plasmacytomas are rare. Few cases of binocular metastasis have been reported. The authors review a case study using intraocular bevacizumab to treat secondary glaucoma and binocular metastasis from multiple myeloma. CASE REPORT: A 59-year old woman with a 13-month history of multiple myeloma was found to have a suspected masquerade syndrome OS and subsequently developed a neovascular glaucoma within 2 months. Intravitreal bevacizumab injection OS controlled the intraocular pressure and inhibited ocular metastasis. The methods of therapy administration in this case are consistent with procedures commonly used in clinical practice when using bevacizumab to treat other etiologies, such as choroidal neovascular membranes. Lost to follow-up until 2 months later, the patient presented with ocular metastasis OD with the same changes as observed OS. Conjunctival biopsy revealed subconjunctival plasmoma OD. After intravitreal bevacizumab injection, neovascular glaucoma OD was partly controlled. CONCLUSIONS: Secondary ocular plasmacytoma, despite its rarity, should be considered in patients with multiple myeloma. Intravitreal bevacizumab injection may be a promising treatment for ocular metastases and associated secondary or neovascular glaucoma. PMID- 23811609 TI - Association between cataract and the degree of obesity. AB - PURPOSE: To investigate the association between the degree of obesity and cataract. METHODS: We examined 3248 subjects (1421 men and 1827 women) aged 50 years and older who did not have a previous cataract operation. Data were derived from the fourth Korea National Health and Nutrition Examination Survey (2009). Cataract was evaluated by using Lens Opacities Classification System III. Body mass index was categorized into four groups (underweight, <18.5 kg/m(2); normal weight, 18.5 to 22.9 kg/m(2); overweight, 23.0 to 24.9 kg/m(2); and obese, >=25.0 kg/m(2)). Association between the degree of obesity and cataract was evaluated using logistic regression analyses with adjustments of age, the total pack-years of cigarettes smoked, the amount of pure alcohol (g) consumed per day, daily time spent in vigorous physical activity, diabetes mellitus, sunlight exposure, education level, and income. RESULTS: Compared with the normal-weight group, the overweight group had significantly lower risk of any type of cataract (odds ratio, 0.70; 95% confidence interval, 0.50 to 0.97) in men and (odds ratio, 0.70; 95% confidence interval, 0.51 to 0.97) in women in the multiple logistic regression analyses. We could not find any unusual lifestyles or metabolic risks for explaining this low cataract prevalence in the overweight groups. However, nutrient intakes (e.g., vitamin B2, niacin, vitamin C, and vitamin A) were highest in the overweight group. CONCLUSIONS: The overweight group had significantly lower risk of cataract formation than the normal-weight group in Korean population. PMID- 23811610 TI - Field seasonal influenza vaccine effectiveness: evaluation of the screening method using different sources of data during the 2010/2011 French influenza season. AB - Thanks to the screening method, we estimated among target groups the 2010/2011 field vaccine effectiveness (FVE) against laboratory confirmed influenza cases seen in general practice. We also compared the values of FVE estimations obtained by using three sources of the population vaccination coverage (VC) based on three different methodologies: (1) administrative data from the main social security scheme (Caisse Nationale d'Assurance Maladie des Travailleurs Salaries--CNAMTS) covering about 85% of the French population, (2) a cross-sectional national telephone survey in the general population, and (3) a declarative survey in the population seen in a one-day general practitioner (GP) consultations. The FVE estimates among target groups were stratified by age (< 65 y old with reported chronic illness; >=65 y old and overall). Using the VC of the CNAMTS, the FVE of the 2010/2011 seasonal trivalent vaccine against laboratory confirmed infection with any influenza virus was 59% (95% Confidence Interval, 17 to 81). It was 85% (17 to 99) and 50% (-16 to 80) for A(H1N1)pdm09 and B influenza infections, respectively. The values of FVE using the influenza VC obtained in a sample of the general population and of the population of GPs' patients were 73% (45 to 87) and 82% (63 to 92), respectively. We estimated a moderate influenza FVE in preventing confirmed influenza viruses in target groups by using the VC of the CNAMTS. We also observed that the screening method generates FVE values dependent on the choice of the source of VC and thus should be used cautiously. PMID- 23811612 TI - The development of the tobacco tactics website. AB - BACKGROUND: Web-based cessation interventions have been shown to reduce tobacco use, be more efficacious than self-help booklets, be more efficacious if they provide tailored messages, and enhance quit rates in conjunction with nicotine replacement therapy. OBJECTIVE: The objective of this study was to usability test and pilot test the Tobacco Tactics website for veterans. METHODS: Both formative and summative evaluations were used across three small successive studies to develop and test the Tobacco Tactics website for veterans, which was based on a prior face-to-face smoking cessation intervention. Once the website was developed, the research team and Web developers usability tested the website with 5 veteran smokers and former smokers. Feedback from the veterans was collected as they navigated each webpage, then used to revise the website. In pilot study 1, 9 veteran smokers were provided access to the website, and given a baseline and 30 day follow-up survey. In pilot study 2, 18 veteran smokers, who were also motivated to quit smoking, were recruited and randomized to either the Tobacco Tactics website plus nicotine replacement therapy or to the 1-800-QUIT-NOW telephone line. RESULTS: As a result of usability testing, more than 27 modifications were made to improve the website. In pilot study 1, 50% (3/6) veterans who entered the website had cut down on the number of cigarettes and 83% (5/6) found the website enjoyable, easy to read, easy to navigate, and would recommend the website to others. In pilot study 2, which included only smokers motivated to quit and also offered nicotine replacement therapy, seven-day point prevalence abstinence at 30-day follow-up was 40% (4/10) in the intervention group compared to 13% (1/8) in the control group. CONCLUSIONS: These preliminary results are promising and suggest the need for wider-scale testing of the Tobacco Tactics website for veterans. PMID- 23811613 TI - Men older than 50 yrs are more likely to fall than women under similar conditions of health, body composition, and balance. AB - OBJECTIVE: The aim of this study was to analyze the contribution of sex to the occurrence of falls, accounting for comorbidities and differences in physical fitness. DESIGN: This was a cross-sectional study of 587 community-dwelling adults who were older than 50 yrs. Falls, comorbidities (number of diseases and physical impairments), and physical fitness (body composition, lower and upper body strength and flexibility, agility, aerobic endurance, and balance) were evaluated via questionnaires, bioimpedance, and Fullerton batteries, respectively. RESULTS: Compared with the men, the women presented a 10% higher fall prevalence, 1.7 more diseases/impairments, 10% more body fat, 26% less lean body mass, and poorer physical capacity (P < 0.05). Multivariate logistic regression revealed that male sex (odds ratio [OR], 2.723; 95% confidence interval [CI], 1.190-6.230) increased the likelihood of falling, after adjustment for comorbidities (OR, 1.213; 95% CI, 1.109-1.328), lean mass (OR, 0.958; 95% CI, 0.927-0.989), fat mass (OR, 1.053; 95% CI, 1.021-1.086), and balance (OR, 0.942; 95% CI, 0.914-0.971), which were the main risk factors of falls. CONCLUSIONS: Women are more susceptible to falling, presumably because they have poorer health and physical fitness than do men. However, when the values for comorbidities, lean and fat body mass, and balance were similar, the men demonstrated a higher probability of falling. Age is not a significant risk factor of falls under favorable conditions of health, body composition, and balance. PMID- 23811614 TI - Validation of the comprehensive international classification of functioning, disability and health core set for diabetes mellitus: physical therapists' perspectives. AB - OBJECTIVE: The Comprehensive International Classification of Functioning, Disability and Health (ICF) Core Set for Diabetes Mellitus (DM) is an application of the ICF and represents the typical spectrum of problems in functioning in patients with diabetes. The aims of this study were to explore the content validity of this Core Set from the perspectives of physical therapists (PTs) and to identify the most common problems of patients with DM from the perspectives of PTs using the ICF. DESIGN: In this observational study, PTs experienced in DM treatment were asked about patients' problems, patients' resources, and aspects of environment treated by PTs in their practices. The survey was conducted in three rounds using the Delphi technique. Responses were linked to the ICF by two persons. The degree of agreement was calculated using the kappa statistic. RESULTS: Twenty-four PTs, from 11 countries, answered in the first round; 23 PTs completed the second and third Delphi rounds. The PTs reached consensus on 49 ICF categories; 73% of the ICF categories are represented in the ICF Core Set for DM, whereas 27% of the categories are not represented in the ICF Core Set for DM. Five concepts were linked to the ICF component personal factors, which is not yet classified into detailed categories. CONCLUSIONS: The validity of the ICF Core Set for DM from the perspective of PTs was supported. From the perspective of the PTs, some additional categories qualified for future inclusion in the ICF Core Set for DM. The ICF seems to provide an effective framework describing functioning and disability in DM from the perspective of PTs. PMID- 23811615 TI - Comparing a new ultrasound approach with electrodiagnostic studies to confirm clinically defined carpal tunnel syndrome: a prospective, blinded study. AB - OBJECTIVE: The aims of this study were to compare electrodiagnostic (EDX) confirmation of clinical diagnosis of carpal tunnel syndrome (CTS) with ultrasonography (US), using a new set of normal values taking wrist circumference of subjects into account, and to determine whether EDX examination can be replaced by US to confirm CTS. DESIGN: A prospective cohort of 156 patients with idiopathic CTS underwent US and EDX studies. Upper levels of normal cross sectional area of the median nerve were established by taking wrist circumference into account and using linear regression equations. RESULTS: Of the selected patients, 83.3% met the EDX criteria for CTS. The findings from the US were normal in 67 (42.9%) of 156 patients, and within this group, the findings from the EDX were abnormal in 44 patients (65.7%). Of 89 patients with abnormal findings from the US, only 3 patients had normal findings from the EDX. CONCLUSIONS: US cannot replace EDX for confirmation of clinical diagnosis of CTS. However, an abnormal US test result has a high positive predictive value for abnormal EDX result in clinically defined CTS. US might reveal relevant anatomic information preoperatively that rarely has a direct influence on treatment management of patients with CTS. US testing, taking morphometric data into account, does not have the same diagnostic value as EDX does in confirming CTS. PMID- 23811611 TI - Age-related changes in brain support cells: Implications for stroke severity. AB - Stroke is one of the leading causes of adult disability and the fourth leading cause of mortality in the US. Stroke disproportionately occurs among the elderly, where the disease is more likely to be fatal or lead to long-term supportive care. Animal models, where the ischemic insult can be controlled more precisely, also confirm that aged animals sustain more severe strokes as compared to young animals. Furthermore, the neuroprotection usually seen in younger females when compared to young males is not observed in older females. The preclinical literature thus provides a valuable resource for understanding why the aging brain is more susceptible to severe infarction. In this review, we discuss the hypothesis that stroke severity in the aging brain may be associated with reduced functional capacity of critical support cells. Specifically, we focus on astrocytes, that are critical for detoxification of the brain microenvironment and endothelial cells, which play a crucial role in maintaining the blood brain barrier. In view of the sex difference in stroke severity, this review also discusses studies of middle-aged acyclic females as well as the effects of the estrogen on astrocytes and endothelial cells. PMID- 23811616 TI - Effects of exercise training on endothelial progenitor cells in cardiovascular disease: a systematic review. AB - This review aimed to examine the effects of exercise training on mobilization of endothelial progenitor cells (EPCs) in patients with cardiovascular disease and to discuss the possible mechanisms involved in the process. A computer-aided search on PubMed and PEDro was conducted to identify relevant studies published up to June 2012. Two reviewers independently selected studies for inclusion and extracted data, namely, quantitative assessment of circulating EPCs. Of the 88 identified studies, 13 met the inclusion criteria. The 13 studies enrolled 648 participants, including patients with chronic heart failure, peripheral artery disease, and coronary artery disease. The exercise characteristics varied largely across the studies: exercise duration ranged from 2 wks to 6 mos, session duration ranged from 20 to 60 mins, and exercise intensity was usually calculated using the maximal heart rate (ranging from 75% to 85%) or the peak/maximum oxygen consumption (60%-70%). All studies used aerobic exercise. The great majority of the 13 studies reported significant effects of different exercise regimens on the number of circulating EPCs. In summary, exercise training seems to increase the number of circulating EPCs, which could contribute to vascular regeneration and angiogenesis. These positive effects of chronic exercise seem to be closely related to the bioavailability of nitric oxide, including increased activity of endothelial nitric oxide synthase and antioxidant enzymes, and activation of matrix metalloproteinase 9. PMID- 23811617 TI - Ultrasound-guided vs. blind steroid injections in carpal tunnel syndrome: A single-blind randomized prospective study. AB - OBJECTIVE: The aim of this study was to compare the efficacy and the safety of ultrasound (US)-guided vs. blind steroid injections in patients with carpal tunnel syndrome (CTS). DESIGN: This prospective randomized single-blind clinical trial included 46 patients with CTS (46 affected median nerves). The subjects were randomized-to either the US-guided or the blind injection group-before they received 40 mg of methylprednisolone. They were evaluated using the Boston Carpal Tunnel Questionnaire symptom/function at baseline and at 6 wks and 12 wks after injection, and the side effects were noted. RESULTS: The symptom severity and functional status scores improved significantly in both groups at 6 wks after treatment, and these improvements persisted at 12 wks after treatment (all P < 0.05). The improvement in symptom severity scores in the US-guided group at 12 wks was higher than in the palpation-guided group (P < 0.05). Average time to symptom relief was shorter in the US-guided group (P < 0.05). There was no significant difference between the two groups in terms of side effects (P > 0.05). CONCLUSIONS: Although both US-guided and blind steroid injections were effective in reducing the symptoms of CTS and improving the function, an earlier onset/better improvement of symptom relief suggests that US-guided steroid injection may be more effective than are blind injections in CTS. PMID- 23811618 TI - A solid AND logic stimuli-responsive material with bright nondestructive performance designed by sensitive cuprophilicity. AB - A stimuli-responsive material with AND logic function was realized by modulating sensitive Cu-Cu interactions, which is quite different from traditional photoinduced electron transfer (PET) strategies. The obtained material not only gets rid of fluid media, but also displays nondestructive, high intensity optical signals and environmentally friendly performances. PMID- 23811619 TI - Molecular classification of prostate cancer progression: foundation for marker driven treatment of prostate cancer. AB - Recently, many therapeutic agents for prostate cancer have been approved that target the androgen receptor and/or the prostate tumor microenvironment. Each of these therapies has modestly increased patient survival. A better understanding of when in the course of prostate cancer progression specific therapies should be applied, and of what biomarkers would indicate when resistance arises, would almost certainly improve survival due to these therapies. Thus, applying the armamentarium of therapeutic agents in the right sequences in the right combination at the right time is a major goal in prostate cancer treatment. For this to occur, an understanding of prostate cancer evolution during progression is required. In this review, we discuss the current understanding of prostate cancer progression, but challenge the prevailing view by proposing a new model of prostate cancer progression, with the goal of improving biologic classification and treatment strategies. We use this model to discuss how integrating clinical and basic understanding of prostate cancer will lead to better implementation of molecularly targeted therapeutics and improve patient survival. PMID- 23811620 TI - Epidemiology and outcome of sepsis syndromes in Italian ICUs: a muticentre, observational cohort study in the region of Piedmont. AB - BACKGROUND: Sepsis is an important cause of mortality and morbidity in the intensive care unit (ICU). We performed a study to describe the epidemiology of sepsis syndromes in patients admitted to ICUs of the Piedmont region. METHODS: In this prospective, multicentre, observational study, all 3902 patients admitted to a network of 24 ICUs from 17 hospitals during a 180 day period (April 3-September 29, 2006) were included. Patients were followed from the first day of admission until death or ICU discharge. RESULTS: The incidence of sepsis during the ICU stay was 11.4% (N.=446), corresponding to an incidence of 25 cases/100,000 inhabitants/year; 141 (31.6%) patients had only sepsis, 160 patients had severe sepsis (35.9%) and 145 patients (32.5%) had septic shock In 227 patients (50.9%), sepsis was observed within 48 hours after admission to the ICU, and 219 patients (49.1%) developed ICU-acquired sepsis. The main sources of infection were the lungs, abdomen, and urinary tract. ICU mortality was higher (41.3 vs. 17.3%, P<0.0001) and the median ICU length of stay longer (15 vs. 2 days, P<0.0001) in patients with sepsis than in those without sepsis. The mortality rate increased with the severity of sepsis. ICU-acquired sepsis was associated with higher ICU mortality rates than sepsis occurring within 48 hours of ICU admission (49.8 vs. 33.0%, P<0.0001). CONCLUSION: Sepsis is a common occurrence in critically ill patients. Our data underscore the regional variability in the epidemiology and outcome of sepsis syndromes and may be useful to guide appropriate resource allocation. PMID- 23811621 TI - LACTATE or ScvO2 as an endpoint in resuscitation of shock states? AB - In the current management of critically ill patients, variables such as blood pressure, urine output or central venous pressure guide resuscitative efforts. Unfortunately, global tissue hypoxia may persist leading to multiple organ failure and death. To address tissue well-being, indices such as central venous oxygen saturation (ScvO2) and lactataemia are widely used and are strongly linked to outcome. Implementing these indices in haemodynamic optimization protocols have been shown to reduce morbidity and mortality in numerous studies especially in septic shock. Nevertheless, choosing one index over the other remains controversial. Herein, we review the physiology and rationale for ScvO2 and lactate monitoring. Clinical uses, evidence-based outcome implications and limitations are also examined to aid the clinician in daily practice. Key words: lactate, central venous oxygen saturation, shock, goal-directed therapy. PMID- 23811622 TI - Albumin: physiologic and clinical effects on lung function. AB - Fluid resuscitation is one of the most frequent and necessary practices in clinical medicine and is an integral part of the initial stabilization of critically ill, hypovolemic patients. Longstanding debate and conflicting evidence surround the use of both colloid and crystalloid fluid resuscitation in these patients. The basis of this debate is heavily rooted in the physiological understanding of Starling's forces. In this review, we aim to highlight the ongoing debate of albumin versus crystalloid resuscitation both broadly and as it relates to lung function, and will discuss the current state-of-the-art, starting from an historic perspective and progressing through a review of both physiologic and clinical evidence. Despite the biologic and physiologic plausibility of therapeutic benefit, the current evidence base does not support the routine use of albumin administration to improve patient survival or prevent respiratory dysfunction. PMID- 23811623 TI - Global and regional parameters to visualize the 'best' PEEP during a PEEP trial in a porcine model with and without acute lung injury. AB - BACKGROUND: Setting the optimal level of positive end-expiratory pressure (PEEP) in critically ill patients remains a matter of debate. "Best" PEEP is regarded as minimal lung collapse and overdistention to prevent lung injury. In this study, global and regional variables were evaluated in a porcine model to identify which variables should be used to visualize "best" PEEP. METHODS: Eight pigs (28-31 kg) were studied during an incremental and decremental PEEP trial before and after the induction of acute lung injury (ALI) with oleic acid. Arterial oxygenation, compliance, lung volume, dead space, esophageal pressure and electrical impedance tomography (EIT) were recorded at the end of each PEEP step. RESULTS: After ALI, "best" PEEP was comparable at 15 cmH2O between regional compliance of the dorsal lung region by EIT and the global indicators: dynamic compliance, arterial oxygenation, alveolar dead space and venous admixture. After ALI, the intratidal gas distribution was able to detect regional overdistention at 15 cmH2O PEEP. "Best" PEEP based on transpulmonary pressure was lower and no optimal level could be found based on lung volume measurements alone. In addition, the recruitment phase significantly improved end-expiratory lung volume, PaO2, venous admixture and regional and global compliance, both in ALI and the "healthy" lung. CONCLUSION: Most of the evaluated parameters indicate comparable 'best' PEEP levels. However, a combination of these parameters, and especially EIT-derived intratidal gas distribution, might provide additional information. The application of lung recruitment was beneficial in both ALI and the "healthy" lung. PMID- 23811624 TI - Ultrasound-guided single shot caudal block anesthesia reduces postoperative urinary catheter-induced discomfort. AB - BACKGROUND: Urinary catheter-induced discomfort during the postoperative period can be distressing, and sometimes results in severe restlessness and agitation, especially in middle-aged and elderly male patients. Recent advances in ultrasound technology have increased the consistency, safety, and ease of a caudal block even in older patients. We speculated that an ultrasound-guided caudal block would be reliable and safe as treatment for such postoperative discomfort. METHODS: Adult male patients (ASA I-II) undergoing cervical laminoplasty were allocated to either the caudal block (CB, N.=24) or non-block (NB, N.=24) group. Following anesthesia induction, urinary catheterization was performed using a 16 French Foley catheter. Thereafter, an ultrasound-guided caudal block was performed with 8 ml of 0.3% ropivacaine and 100 ug of fentanyl for patients in group CB, while group NB did not receive a caudal block. We assessed urinary catheter-induced discomfort as mild, moderate, or severe at 0, 2, 6, 10, and 18 hours after surgery, and compared the incidence and severity of discomfort between the groups using a randomized double-blind design. RESULTS: All caudal blocks were successfully performed with 1 or 2 needle insertions. The incidence of urinary catheter-induced discomfort was significantly reduced in group CB as compared to NB at 0, 2, and 6 hours, while severity was also reduced at 0 and 2 hours. No patient required re-catheterization due to urinary retention after catheter removal. There were no other complications related to the caudal block. CONCLUSION: Preoperative ultrasound-guided single shot caudal block anesthesia safely reduced postoperative urinary catheter-induced discomfort in our male patients. PMID- 23811625 TI - Neurogenic pulmonary edema and variations of hemodynamic volumetric parameters in children following head trauma. AB - BACKGROUND: Currently there is no clear evidence of how changes in hemodynamic parameters are involved in the onset of neurogenic pulmonary edema. Aim of the study has been to correlate the principal variations of the intracranial pressure and volumetric hemodynamic parameters with the variations of extravascular lung water following severe head trauma in children. METHODS: We studied 28 children, 16 males and 12 females, mean +/- SD age 71+/-29 months (range 24-130 months), admitted for traumatic head injury with Glasgow Coma scale <=8. All patients received volumetric hemodynamic, and intracranial pressure monitoring following initial resuscitation and every four hours thereafter or whenever a hemodynamic deterioration was suspected. All readings were divided in 2 groups: with intracranial pressure (ICP) >15 mmHg or <=15 mmHg. RESULTS: During the cumulative in hospital stay a total 508 sets of measurements were done. In the group with ICP >15 mmHg vs. that with ICP <=15 mmHg we observed increased Extravascular Lung Water Index (EVLWi) (11.05+/-2.28 vs. 6.96+/-0.87 P<0.0001) and pulmonary permeability (8.50+/-1.19 vs. 5.08+/-0.90, P<0.0001), and decreased systemic vascular resistances, (1,451+/-371 vs. 1,602+/-447 P<0.0001) cerebral perfusion (48.87+/-18.67 vs. 69.72+/-11.36 P<0.0001) and PaO2/FiO2 ratio (349+/-122 vs. 490+/-96 P<0.0001). There was a significant correlation between EVLWi and pulmonary permeability (R2=0.83, P<0.0001). Fluid overload and cardiac functional index did not change significantly. CONCLUSION: The increased EVLWi observed in children following severe head trauma seems mainly related with pulmonary vascular permeability which is significantly increased when ICP is >15 mmHg. PMID- 23811626 TI - Glide video laryngoscope for the management of foreign bodies impacted at the hypopharyngeal level in adults. AB - BACKGROUND: Cricopharyngeal foreign bodies (FBs) impaction in adults is a common clinical problem; without treatment, the sequelae may be lethal due to local and/or mediastinal infection. When direct laryngoscopy and flexible fiberoptic endoscopy are ineffective, rigid endoscopy is the method of choice requiring general anesthesia. The new video laryngoscopes represent a great advancement in the assessment of the laryngeal inlet. Aim of the study was to assess the feasibility of identifying and removing FBs impacted at crycofaringeal and upper oesophageal sphincter by the video laryngoscope. METHODS: In a period of 30 months, on an urgent basis, we systematically assessed by GlideScope(r) video laryngoscope all adult patients with a diagnosis of impacted crycofaringeal upper esophageal FB, after unsuccessful removal attempts in the otolaryngology or gastroenterology unit. RESULTS: Twenty-six consecutive patients were evaluated. In conscious sedation by video laryngoscope 17 FBs were identified and removed from the hypopharynx or upper esophageal sphincter. In 9 patients rigid endoscopy in general anesthesia and tracheal intubation was necessary to remove FBs impacted beyond the upper esophageal sphincter. CONCLUSION: In our experience video laryngoscope, because of the magnified vision, the better patient comfort and no requirement of general anesthesia, represents a great improvement in identifying and removing in conscious sedation even small and thin foreign bodies not recognized by radiological and otolaryngology examination and not readily detected by direct endoscopy. PMID- 23811627 TI - Comparing propofol versus sevoflurane anesthesia for epileptogenic focus detection during positron emission tomography in pediatric patients. AB - BACKGROUND: Fluoro-D-deoxyglucose positron emission tomography (FDG-PET) is a standard procedure for interictal assessment and accurate pre-surgical evaluation of presumed epileptogenic zone localization. Profound sedation or general anesthesia is frequently required to reduce movement artefacts in young or cognitively impaired patients during image acquisition. This study compares the impact of propofol and sevoflurane anesthesia on overall quality of PET images, detectability of a hypometabolic lesion and demarcation of the detected lesion in pediatric patients suffering from focal epilepsia. METHODS: Pediatric patients with focal epilepsia were anesthesized using propofol (N.=37) or sevoflurane (N.=43). Two independent blinded investigators rated the PET-scans on a 3-point Likert scale with respect to overall quality of PET images, detectability of a hypometabolic lesion and demarcation of the detected lesion. Mann-Whitney-U-Test was conducted to compare the rating results between the two anesthesia regimes. Inter-rater reliability was calculated using Cohen's Kappa. RESULTS: Anesthesia was throughout uneventful and there was no clinical evidence for peridiagnostic seizures. Differences in neither single dimension ratings nor in sum scores (mean 5.8 +/- SD 1.5 for propofol, and 5.7 +/- SD 1.5 for sevoflurane; P=0.567) were statistically significant. Cohen's Kappa was between 0.428 and 0.499. CONCLUSION: For surgical planning in patients with epilepsy, FDG-PET imaging is an indispensable functional imaging technique to detect hypometabolism. We conclude that both, sevoflurane and propofol based anesthetic regimes are suitable to detect hypometabolic cerebral lesions during FDG-PET. PMID- 23811628 TI - Mechanical and electrical equipment interference provokes a misleading Neurally Adjusted Ventilatory Assist (NAVA) EAdi signal. AB - BACKGROUND: Neurally Adjusted Ventilatory Assist (NAVA) offers synchronized proportional pressure in accordance with the electrical activity of the diaphragm (EAdi). NAVA relies on the EAdi to trigger the respiratory cycle and then adjusts the ventilatory assist to the neural drive. The technique necessitates a catheter with bipolar microelectrodes positioned near the crural diaphragm where this signal can be captured. Capturing a reliable EAdi signal is a condition sine qua non for using NAVA as a mode of ventilation. The displayed signal represents the sum of the electrical activity of the muscle action potential of the diaphragm and is expressed in microvolts. METHODS: A technical note illustrated by a case series in the intensive care unit (ICU) of a tertiary referral hospital with experience using NAVA. RESULTS: Here, we report on three separate cases in which the use of an intra-aortic balloon catheter, a pacemaker and a heating device all resulted in a distortion of the EAdi signal, despite good positioning of the catheter. In a fourth case, we observed internal interference from leaking cardiac electrical activity due to the malpositioning of the EAdi catheter in a patient with atrial fibrillation. CONCLUSION: We illustrate that the detection and therefore interpretation of the EAdi signal during NAVA can be influenced by mechanical and electrical interference by other equipment used in the ICU or from endogenous leaking cardiac activity. PMID- 23811630 TI - Dexmedetomidine and the quality of recovery: Yet another indication for its use? PMID- 23811629 TI - Perioperative administration of colloids: far from good? PMID- 23811631 TI - Comparative alternative materials assessment to screen toxicity hazards in the life cycle of CIGS thin film photovoltaics. AB - Copper-indium-gallium-selenium-sulfide (CIGS) thin film photovoltaics are increasingly penetrating the market supply for consumer solar panels. Although CIGS is attractive for producing less greenhouse gas emissions than fossil-fuel based energy sources, CIGS manufacturing processes and solar cell devices use hazardous materials that should be carefully considered in evaluating and comparing net environmental benefits of energy products. Through this research, we present a case study on the toxicity hazards associated with alternative materials selection for CIGS manufacturing. We applied two numeric models, The Green Screen for Safer Chemicals and the Toxic Potential Indicator. To improve the sensitivity of the model outputs, we developed a novel, life cycle thinking based hazard assessment method that facilitates the projection of hazards throughout material life cycles. Our results show that the least hazardous CIGS solar cell device and manufacturing protocol consist of a titanium substrate, molybdenum metal back electrode, CuInS2 p-type absorber deposited by spray pyrolysis, ZnS buffer deposited by spray ion layer gas reduction, ZnO:Ga transparent conducting oxide (TCO) deposited by sputtering, and the encapsulant polydimethylsiloxane. PMID- 23811632 TI - NF-TiO2 photocatalysis of amitrole and atrazine with addition of oxidants under simulated solar light: emerging synergies, degradation intermediates, and reusable attributes. AB - In order to investigate sustainable alternatives to current water treatment methods, the effect of NF-titania film thickness and subsequent photocatalysis in combination with oxidants was examined under simulated solar light. Such a combination presents a theoretical possibility for a synergistic interaction between the photocatalyst and the oxidant (activation of the oxidant by the catalyst under conditions under which it may not conventionally be activated). To investigate, peroxymonosulfate (PMS) and persulfate (PS) were used as oxidants, and two pesticides, amitrole and atrazine, were used as target contaminants. In the absence of a film, activation of PMS under simulated solar conditions is demonstrated by removal of atrazine, whereas PS provided minimal removal, suggesting inefficient activation. Combining photocatalytic films with PMS and PS manifested synergies for both oxidants. The effect was most pronounced for PS since PMS already underwent significant activation without the photocatalyst. Amitrole degradation results indicated a lack of removal of amitrole by activated PS alone, suggesting that this sulfate radical-based treatment technology may be ineffective for the removal of amitrole. The NF-TiO2 films demonstrated reusability under solar light both with and without oxidants. Finally, the degradation intermediates were analyzed, and a new intermediate appeared upon incorporating oxidants into the system. PMID- 23811633 TI - Degradation pathway of malachite green in a novel dual-tank photoelectrochemical catalytic reactor. AB - A novel dual-tank photoelectrochemical catalytic reactor was designed to investigate the degradation pathway of malachite green. A thermally formed TiO2/Ti thin film electrode was used as photoanode, graphite was used as cathode, and a saturated calomel electrode was employed as the reference electrode in the reactor. In the reactor, the anode and cathode tanks were connected by a cation exchange membrane. Results showed that the decolorization ratio of malachite green in the anode and cathode was 98.5 and 96.5% after 120 min, respectively. Malachite green in the two anode and cathode tanks was oxidized, achieving the bipolar double effect. Malachite green in both the anode and cathode tanks exhibited similar catalytic degradation pathways. The double bond of the malachite green molecule was attacked by strong oxidative hydroxyl radicals, after which the organic compound was degraded by the two pathways into 4,4 bis(dimethylamino) benzophenone, 4-(dimethylamino) benzophenone, 4 (dimethylamino) phenol, and other intermediate products. Eventually, malachite green was degraded into oxalic acid as a small molecular organic acid, which was degraded by processes such as demethylation, deamination, nitration, substitution, addition, and other reactions. PMID- 23811634 TI - Spatial distribution of 214Po ions in the electrostatic collection. AB - A low cost Si-PIN photodiode-based radon monitor was successfully designed and produced to monitor precursory earthquake indicators in the Northern Anatolian Fault Line. The spatial distribution of (214)Po ions was determined by comparing the 7.69 MeV (214)Po peak in the MCA spectrum and the Geant4 energy distribution of alpha particles at various detector source distances. PMID- 23811635 TI - Procedure time and the determination of polypoid abnormalities with experience: implementation of a chromoendoscopy program for surveillance colonoscopy for ulcerative colitis. AB - BACKGROUND: Procedure length and agreement in detection of abnormalities may limit implementation of chromoendoscopy (CE) for dysplasia surveillance in ulcerative colitis (UC). We investigated these factors among endoscopists inexperienced in this technique. METHODS: Six investigators performed surveillance colonoscopy with white light endoscopy (WLE) followed by CE on 75 patients with long-standing UC. Interobserver agreement for WLE and CE images of polyps and nonpolypoid mucosa was determined. Withdrawal times from the cecum were compared based on number of colonoscopies performed. Dysplasia detection rate with WLE was compared with CE. RESULTS: The analysis of 586 images (266 WLE and 320 CE) from 57 patients included images of 160 polyps (64 flat) with 29 dysplastic lesions. All investigators identified 10/11 WLE images of dysplasia and 4 identified all 18 CE dysplasia images, 1 missed 1 and 1 missed 3. Four dysplastic lesions were not identified by 1 or more investigators and all measured <5 mm. Interobserver agreement for lesions was high with kappa scores of 0.91 and 0.86 for WLE and CE, respectively. Among the 75 patients enrolled, dysplasia was found in 9.3% with WLE compared with 21.3% with WLE and CE (P = 0.007). Median colonoscopy withdrawal time improved from 31 minutes for endoscopists performing fewer than 5 procedures to 18 minutes for 5 to 14 and 19 minutes for more than 15 procedures. CONCLUSIONS: Indigo carmine CE for UC surveillance resulted in high rates of interobserver agreement for polyp detection, acceptable withdrawal times, and enhanced dysplasia detection. These results are encouraging for the implementation of CE programs for chronic UC. PMID- 23811636 TI - Myeloid-derived suppressor cells in the inflammatory bowel diseases. AB - BACKGROUND: Myeloid cells are the most abundant and heterogeneous population of leukocytes. They are rapidly recruited from the blood to areas of inflammation and perform a number of important biological functions. Chronic inflammatory conditions contribute to generation of myeloid-derived suppressor cells (MDSCs). These pathologically activated cells are increasingly recognized as important players in cancer, transplantation, and autoimmunity for their abilities to modulate innate and adaptive immune responses. METHODS: Since clinical data on MDSC accumulation in human patients affected with inflammatory bowel diseases (IBD) are relatively scarce, most of the information described in this review came from studies using experimental mouse models of IBD. RESULTS: In this review, we discuss possible roles of these cells in chronic immune-mediated disorders focusing on studies conducted in IBD. We will review the available evidence on how MDSCs are involved in modulating T cell responses and look into the complex relationship between Th1, Th17 cells, and myeloid cells. Finally, we will review some recent successes and failures resulted from therapies aimed at manipulating myeloid cell numbers and/or their function. CONCLUSIONS: Although MDSCs have been described in animal models of experimental colitis and in patients with IBD, their exact role in IBD pathogenesis is unclear and needs to be studied further. Information obtained from these studies will be useful to better understand the cross talk between myeloid cells in T cells during chronic inflammation and may identify novel pathways to be targeted therapeutically. PMID- 23811637 TI - Miltefosine suppresses inflammation in a mouse model of inflammatory bowel disease. AB - BACKGROUND: The repertoire of immunomodulators that can be used for the treatment of inflammatory bowel disease is limited. The use of these drugs is further restricted by the occurrence of side effects in a proportion of patients. Miltefosine (hexadecylphosphocholine) is a lipid drug developed in the 1980s for the treatment of cancer but is nowadays best known for its application in the oral treatment of leishmaniasis. Although the exact mechanism of action of miltefosine has yet to be elucidated, the drug has previously been shown to inhibit phospholipases and protein kinase C, both key components of proproliferative signal transduction in T cells. METHODS: Stimulated peripheral blood lymphocyte were treated with miltefosine, and proliferation was measured. We use the CD45RB T-cell transfer colitis model to investigate the effect of miltefosine treatment on intestinal inflammation. Effects on the severity of colitis were studied by histochemical and immunohistochemical staining, and cytokine levels were determined using a cytokine bead array. RESULTS: Miltefosine inhibited T-cell proliferation in vitro. In the transfer model, miltefosine significantly ameliorated the severity of colitis as measured by clinical, (immuno)histochemical, and biochemical parameters. CONCLUSIONS: Miltefosine inhibits T-cell proliferation and effectively reduces inflammation in the T-cell transfer model. The drug may therefore be a candidate immunomodulator for inflammatory bowel disease. PMID- 23811638 TI - Are there any differences in the efficacy and safety of different formulations of Oral 5-ASA used for induction and maintenance of remission in ulcerative colitis? evidence from cochrane reviews. AB - BACKGROUND: We systematically reviewed and compared the efficacy and safety of oral mesalamine formulations (sustained release, delayed release, and prodrugs) used for induction and maintenance of remission in ulcerative colitis. The main objective of this review was to determine if there are any differences in efficacy or safety among the oral 5-ASA drugs. METHODS: A literature search in February 2013 identified all applicable randomized trials. Study quality was evaluated using the Cochrane risk of bias tool. The Grading of Recommendations Assessment, Development and Evaluation criteria were used to assess the overall quality of the evidence. Studies were subgrouped by common mesalamine comparators for meta-analysis. Studies were pooled for analysis if they compared equimolar doses of oral 5-ASA. RESULTS: Seventeen studies that evaluated 2925 patients were identified. The risk of bias was low for most factors, although 1 study was single blind and 3 were open label. No difference was observed between oral 5-ASA and comparator 5-ASA formulations in the proportion of patients with clinical remission (relative risk, 0.94; 95% confidence interval, 0.86-1.02), clinical improvement (relative risk, 0.89; 95% confidence interval, 0.77-1.01), or relapse at 12 months (relative risk, 1.01; 95% confidence interval, 0.80-1.28). Subgroup analyses showed no important differences in efficacy. No significant difference was demonstrated in rates of adverse events or withdrawal due to adverse events. CONCLUSIONS: There does not seem to be any difference in efficacy or safety among the various formulations of oral 5-ASA. Oral mesalamine is an effective and safe treatment of mild-to-moderate or quiescent ulcerative colitis regardless of the chosen formulation. PMID- 23811639 TI - An in vivo study to determine the effects of early preflaring on the working length in curved mesial canals of mandibular molars. AB - AIM: To evaluate the effects of a preflaring method on the determination of working length in the curved mesial canals of mandibular molars. MATERIALS AND METHODS: Ninety mandibular molars with apical curvature of 30 to 40 degrees were selected and randomly divided into two groups; each containing 45 teeth. In the first group, the initial instrumentation was performed with preflaring on the mesiobuccal canal (preflared group), and in the second group; the instrumentation was performed without preflaring on the mesiobuccal canal (nonpreflared group). A size 15 K-file was inserted in the mesiobuccal canals until the apical constriction could be felt by tactile sensation and a radiograph was taken to identify the distance between the file tip and radiographic apex. The location of the tip was classified as (a) within 1 mm of the radiographic apex, (b) more than 1 mm of the radiographic apex, or (c) overextended beyond the radiographic apex. The collected data was statistically analyzed and probability value was set to be <=0.05. RESULTS: The file tip was significantly closer to the true working length in the canals with early preflaring compared to the canals without early preflaring (p < 0.005). In the preflared group; 75.5% of the cases had the file tip in location 'a', 13.3% in location 'b', and 11.1% in location 'c'. In the nonpreflared group; 33.3% of the cases had the file tip in location 'a', 53.3% in location 'b' and 13.3% in location 'c'. CONCLUSION: Preflaring the coronal portion of curved canals greatly improved the access to the apical constriction, and thus enhanced correct working length determination. If the coronal portion of the curved canals is not preflared, the clinician cannot discern the accuracy of what they feel apically. Thus, preflaring is a highly recommended procedure especially in curved canals for better determination of correct working length. PMID- 23811640 TI - Association between obesity and chronic periodontitis: a cross-sectional study. AB - AIM: Chronic periodontitis is multifactorial and numerous risk factors have been identified to contribute in the disease progression. Current study aimed to conduct a cross-sectional study in a population of patients with cardiovascular diseases in order to correlate the association between obesity [body mass index (BMI) and waist circumference (WC)] and periodontal disease parameters. MATERIALS AND METHODS: The study was of a cross-sectional design and a total of 201 patients were examined after obtaining their informed consent. Subjects who had a history of cardiovascular diseases and under treatment were included in the study. Two indicators of obesity were used: BMI and WC. The following periodontal parameters were assessed: Probing depth, clinical attachment level. The oral hygiene status of the subjects was assessed by the oral hygiene index (OHI, simplified) given by John C Greene and Jack R Vermillion. The influence of the BMI and other confounding variables on periodontitis severity was assessed by multivariate logistic regression analysis. Data were analyzed using SPSS. RESULTS: Significant association was seen with low density lipoproteins (LDL) and severity of periodontitis (p < 0.005), triglyceride levels (TGL) and severity of periodontitis (p < 0.005), cholesterol and severity of periodontitis (p < 0.005), BMI and severity of periodontitis (p < 0.001), OHI and severity of periodontitis (p < 0.001). Significant association was seen with smoking and severity of periodontitis (p < 0.005), BMI and severity of periodontitis (p < 0.001), WC and severity of periodontitis (p < 0.001), cholesterol and severity of periodontitis (p < 0.001), OHI and severity of periodontitis (p < 0.001). CONCLUSION: Obesity has been implicated as a risk factor for several conditions including cardiovascular disease, diabetes, etc. In our study the relation between measures of overall and abdominal obesity (BMI and WC) and periodontal disease showed significant association in the multivariate logistic regression analysis independent of other confounding factors. CLINICAL SIGNIFICANCE: Obesity can act as a significant risk factor in progression of periodontitis. PMID- 23811641 TI - Prevalence of oral mucosal lesions in a group of Iranian dependent elderly complete denture wearers. AB - AIM: Oral mucosal lesions are frequently observed in institutionalized elderly patients more than other age groups. The aim of this study was to determine the prevalence of epulis fissuratum and denture stomatitis and their associated causes in dependent elderly complete denture wearers. MATERIALS AND METHODS: This study was conducted in dependent elderly complete denture's wearers living in four randomly selected nursing homes located in Tehran. Associated factors such as gender, age, use of medication, site of nursing home, denture quality and denture-wearing habit were studied. RESULTS: Overall, 674 patients were examined; 201 had complete denture. The prevalence of denture stomatitis was 36%. There was significant relationship among the prevalence of denture stomatitis with gender and denture wearing period (p < 0.05). The prevalence of epulis fissuratum was 16.4%. There was significant relationship among the prevalence of epulis fissuratum with gender, denture quality and denture wearing habit (p < 0.05). CONCLUSION: In this particular dependent age group, the prevalence of oral mucosal lesions is high and the mentioned associated factors should be noticed. CLINICAL SIGNIFICANCE: Dependent elderly complete denture wearers need more support and motivation for reducing the prevalence of these particular denture associated oral mucosal lesions. PMID- 23811642 TI - Evaluation of periodontal status in alcoholic liver cirrhosis patients: a comparative study. AB - AIM: Bacterial infections are common complicating findings in course of liver cirrhosis, most of them being Gram-negative. Similarly periodontal pathogens are also mostly Gram-negative bacteria hence the objective was to evaluate the periodontal status in alcoholic liver cirrhosis patients and to compare the periodontal status of alcoholic liver cirrhosis patients in: a. Smokers with periodontitis and b. Nonsmokers with periodontitis. MATERIALS AND METHODS: A total of 150 patients made up the sample of this study. The sample size was divided into four groups. The first two groups comprised of 50 patients each comprising of patients with periodontitis who were nonsmokers and patients with periodontitis who were smokers respectively and the next two groups comprised of 25 patients each, which included patients diagnosed as suffering from alcoholic liver cirrhosis who are nonsmokers and patients diagnosed as suffering from alcoholic liver cirrhosis who are smokers. Screening examination included a proper medical history, dental history and Russell's periodontal index was done to evaluate and compare the periodontal status among the selected groups. RESULTS: The data obtained was subjected to statistical analysis using the ANOVA Fisher's F-test. Multiple group comparisons were made using the Tukey's HSD test. CONCLUSION: Conclusions that can be drawn from this study are: 1. Alcoholic liver cirrhosis patients demonstrated greater alveolar bone loss and increased periodontal destruction. 2. There is very high statistically significant difference on periodontal destruction in alcoholic liver cirrhosis patients (with or without smokers) when compared to the control group. CLINICAL SIGNIFICANCE: Periodontal diseases are bacterial infections associated with a bacterial load or insult to the host that elicits a strong inflammatory response cumulating to produce significant pathologic alterations in the systemic status of the host. Alcoholic liver cirrhosis patients as a consequence of liver dysfunction have elevated levels of serum cytokines. These are involved in the destructive process of periodontal disease probably through enhancement of collagenase and metalloproteinase activity. Hence, a study has been planned to evaluate periodontal status in patients with alcoholic liver cirrhosis. PMID- 23811643 TI - An in vitro evaluation of microtensile bond strength of resin-based sealer with dentin treated with diode and Nd:YAG laser. AB - BACKGROUND: Smear layer is a negative factor which prevents adhesion of the filling material to the dentinal walls. Recent advances in dental research have incorporated lasers as a potential adjunct in root canal treatment by removing the smear layer before filling the root canal system, enhancing the adhesion of sealers to dentin and improving the sealing ability. AIM: To evaluate the microtensile bond strength of AH-Plus resin-based sealer to dentin after treatment with 980 nm diode and 1,064 nm neodymium-doped:yttrium aluminum garnet (Nd:YAG) laser in vitro. MATERIALS AND METHODS: Thirty specimens prepared for three groups namely group I (control), group II (980 nm diode-lased specimens) and group III (Nd:YAG-lased specimens). One tooth from each group was observed under scanning electron microscope for evaluation of intracanal root dentin morphology. Remaining specimens were used for making microsections by hard tissue microtome. Specimens for groups II and III were lased with 980 nm diode and 1,064 nm Nd:YAG laser. AH Plus sealer was applied onto specimens and mounted onto Instron universal testing machine for microtensile bond strength testing. Results were subjected to statistical analysis using one-way analysis of variance (ANOVA) and Tukey's test. RESULTS: Group III Nd:YAG had maximum mean microtensile bond strength values (11.558 +/- 0.869), followed by group II diode (9.073 +/- 0.468) and group I control (6.05 +/- 0.036). Statistically significant differences were seen among all the groups. SEM analysis shows removal of smear layer in both groups II and III. CONCLUSION: Both Nd:YAG and diode laser were more effective than control group in improving the microtensile bond strength of AH Plus sealer to dentin. CLINICAL SIGNIFICANCE: Lasers have the potential to increase the adhesiveness of root canal sealer to dentin surface, thereby improving the quality of root canal obturation. PMID- 23811644 TI - Removal efficiency of calcium hydroxide dressing from the root canal without chemically active adjuvant. AB - AIM: Compare the efficiency in removing two calcium hydroxide [Ca(OH)2] preparations from root canal and apical third using single use syringe, ultrasonics and RinsEndo(((r))) with saline solution. MATERIALS AND METHODS: One hundred and eighty human singlerooted teeth were instrumented using ProTaper(((r))) rotary system, divided into two groups according to Ca(OH)2 filling. A: Powder mixed with water, B: Pulpdent(((r))). Each group was divided into three subgroups for the irrigation: A1, B1: Single use syringe; A2, B2: Ultrasonics; A3, B3: RinsEndo(((r))). Teeth were split longitudinally, photographed and imported into Adobe Photoshop. The percentage ratios of Ca(OH)2 remaining in the canal and in the apical third were calculated. Data were statistically analyzed using 'ANOVA two-way' and 'univariate tests'. RESULTS: (a) Remnants of medicament were found in all teeth, (b) no statistically significant difference in the elimination of both Ca(OH)2 from the entire canal (p = 0.436), however, mixed powder was better eliminated from the apical third (p = 0.005), (c) no statistically significant difference among the irrigation techniques in the whole canal (p = 0.608), though, RinsEndo(((r))) and ultrasonics were the most effective in cleaning the apical third (p = 0.032) when mixed powder was used. CONCLUSION: None of the techniques removed completely Ca(OH)2 from the canal. In the apical third, RinsEndo(((r))) and ultrasonics were the most effective when mixed powder was used. CLINICAL SIGNIFICANCE: Ca(OH)2, the most commonly used intracanal dressing, should be completely eliminated before the obturation to assure a good endodontic sealing. Based on the results of this study, RinsEndo(((r))) and ultrasonics were the most effective in removal of Ca(OH)2 especially the powder mixed with water presentation. PMID- 23811645 TI - Evaluation of relative efficacy of beta-tricalcium phosphate with and without type I resorbable collagen membrane in periodontal infrabony defects: a clinical and radiographic study. AB - BACKGROUND AND OBJECTIVES: To compare clinically and radiographically, the regenerative potential of a beta-tricalcium phosphate bone graft, Cerasorb((r)) with and without a bioresorbable type I collagen membrane, BioMend ExtendTM, in treating periodontal infrabony osseous defects. MATERIALS AND METHODS: A total of 20 sites from 10 patients showing bilateral infrabony defects were selected and selected sites were randomly divided into experimental site A (Cerasorb((r))) and experimental site B (Cerasorb((r)) and BioMend ExtendTM) by using split mouth design. The clinical parameters like plaque index, gingival index, probing pocket depth, clinical attachment level and gingival recession were recorded at baseline, 6 weeks, 3, 6 and 9 months. Radiographic evaluation (Linear CADIA) at 6 and 9 months; and intrasurgical measurements at baseline and 9 months were carried out to evaluate the defect fill, change in alveolar crest height and defect resolution. RESULTS: Significant reduction in all clinical parameters was observed in both the groups. On comparison no statistical significance was observed between the two groups. Radiographically, in site A there was significant defect fill of 78.4 and 97.2% at 6 and 9 months respectively. Whereas in site B reduction was 78.4 and 97.2% at 6 and 9 months respectively. After surgical re-entry, there was significant defect fill of 89.2 and 74% in both groups. INTERPRETATION AND CONCLUSION: Individually both the graft and membrane have shown promising results in the management of periodontal intrabony defects. But the added benefit by combining Cerasorb((r)) with BioMend ExtendTM was not observed statistically in both clinical radiographic findings. PMID- 23811646 TI - Cephalometric assessment of effect of head rotation toward focal spot on lateral cephalometric radiographs. AB - INTRODUCTION: The patient's head can be slightly rotated sagittally vertically or transversely with the head holding device. Because of such improper positions due to head rotation, an error can occur in cephalometric measurements. The purpose of this study was to identify the projection errors of lateral cephalometric radiograph due to head rotation in the vertical Z-axis toward the focal spot. MATERIALS AND METHODS: Ten human dry skulls with permanent dentition were collected. Each dry skull was rotated from 0 degrees to +20 degrees at 5 degrees intervals. A vertical axis, the Z-axis, was used as a rotational axis to have 50 lateral cephalometric radiographs exposed. Four linear (S-N, Go-Me, N-Me, S-Go) and six angular measurements (SNA, SNB, N-S-Ar, S-Ar-Go, Ar-Go-Me, AB mandibular plane angle) were calculated manually. RESULTS: The findings were that: (1) Angular measurements have fewer projection errors than linear measurements. (2) The greater the number of landmarks on the midsagittal plane that are included in angular measurements, the fewer the projection errors occurring. (3) Horizontal linear measurements have more projection errors than vertical linear measurements. CONCLUSION: The angular measurements of lateral cephalometric radiographs are more useful than linear measurements in minimizing the projection errors associated with head rotation on a vertical axis toward the focal spot. PMID- 23811647 TI - Use of clinical bleaching with 35% hydrogen peroxide in esthetic improvement of fluorotic human incisors in vivo. AB - AIM: The aim of the study was to evaluate esthetic improvement with the use of 35% hydrogen peroxide clinical bleaching as related to the different grades of enamel fluorosis in vivo and to study adverse effect of clinical bleaching with 35% hydrogen peroxide on teeth and gingiva. MATERIALS AND METHODS: A total of 60 children of different grades of fluorosis were included in the study. With 35% hydrogen peroxide-based dual activated bleaching system, in-office vital teeth bleaching was carried out for each subject. Clinical evaluation for improvement in esthetics, effect on teeth and gingiva were performed for each child during preoperative, immediate postoperative and later 6 months postoperative period. For evaluation and comparison, all the collected data were subjected to statistical analysis. RESULTS: Although in all the subjects, partial shade relapse was seen over a period of time, good homogeneous and esthetic results were seen in very mild and mild cases. A total of 35% hydrogen peroxide in-office bleaching has no adverse effect on teeth and gingiva. CONCLUSION: Comparing all the three groups who participated in the study, 35% hydrogen peroxide in-office bleaching seems to be very effective in very mild and mild forms of fluorosis. CLINICAL SIGNIFICANCE: In very mild and mild forms of fluorosis, in-office vital tooth bleaching with 35% hydrogen peroxide is the most conservative and effective approach in esthetic improvement. PMID- 23811648 TI - Evaluation of efficacy of different gingival displacement materials on gingival sulcus width. AB - AIM: The purpose of the present in vivo study was to measure the efficacy of different gingival displacement materials in achieving gingival tissue displacement and to compare the efficacy of Expasyl displacement paste (Pierre Rolland, France) and gingival displacement cord for gingival displacement. MATERIALS AND METHODS: Sixteen subjects were included in the study. Premolars were prepared to receive full veneer crown, gingival displacement was carried using gingival retraction cord and gingival displacement paste. Impression of the gingival sulcus was made. Sulcus width after displacement was measured under magnification. RESULTS: The mean displacement value of sulcus width was 0.21 +/- 0.01 mm for the gingival retraction cord and 0.26 +/- 0.02 mm for the gingival displacement paste. 'F' test was used for statistical analysis. Difference among the two test agents was statistically significant (p < 0.01). CONCLUSION: Gingival displacement paste showed better response in achieving horizontal displacement of the gingival sulcus than gingival retraction cord. CLINICAL SIGNIFICANCE: Gingival displacement helps in recording the unprepared tooth surface adjacent to the finish line in the impression being made, thereby helping a better marginal adaptation and emergence profile in the extracoronal restoration. PMID- 23811649 TI - Efficacy of locking plates/screw system in mandibular fracture surgery. AB - PURPOSE: The purpose of this study was to determine the efficiency of locking plates and screw system in the treatment of mandibular fracture surgery, by comparing them with the conventional system. PATIENTS AND METHODS: A protocol for selection of patients with mandibular fractures was developed. One hundred patients were treated by locking plates and screw system and another 100 patients were treated with the conventional system. The patients were prospectively evaluated for the duration of surgery, difficulties encountered during surgery, neurologic changes, postsurgical occlusal relationship, adequacy of reduction and postsurgical complications. Data were compared for statistical significance with Chi-square test and Z-test. RESULTS: There was statistically significant difference in postoperative infection, postoperative occlusal discrepancy, postoperative plate fracture and postoperative screw loosening and mobility of the fractured fragments and also the working time between the two systems. CONCLUSION: The results of the present study are comparable with other published data and support the notion that the locking miniplate system is a valid alternative to conventional miniplates with several advantages, the only drawback being the additional working time required during adaptation of this hardware. PMID- 23811650 TI - Observer strategy and radiographic classification of healing after grafting of cystic defects in maxilla: a radiological appraisal. AB - AIM: The aim is to radiographically quantify the bone density and relate the same with observer strategy in the bone healing. OBJECTIVES: To assess pattern of bone regeneration following grafting of defects with hydroxyapatite after apicoectomy/cystic enucleation. MATERIALS AND METHODS: An observer strategy involving trained and experienced examiners used in large series of cases, evaluated radiographically over a period of 1 year with intervals. The cases were grouped into different categories depending on (1) surgical site outline merging with material margin, (2) internal portion of surgical site (i.e. bone formation characteristics) and (3) density of surgical site. The radiographs examined by blind process and the findings were tabulated. Operating surgeon (oral surgeon) has done the interpretation of data to create observer strategy of grafting cases. OBSERVATIONS AND RESULTS: The outline of the defect was changed, partly reduced and completely absent along with remodeling, which showed ground glass, specular or trabecular pattern of bone over a time with increasing density correlating bone regeneration within a short duration. The applied strategy and classification are recommended for follow-up studies. In this study the characteristics of the new bone formation were also delineated. This strategy is helpful for follow-up studies; implant procedures and so; to know quality and condition of bone after treatment. PMID- 23811651 TI - Effect of periodontal therapy on serum C-reactive protein levels in patients with gingivitis and chronic periodontitis: a clinicobiochemical study. AB - AIM: The aim of the present study was to evaluate the effect of periodontal therapy on serum C-reactive protein (CRP) levels in patients with gingivitis and chronic periodontitis. MATERIALS AND METHODS: A total of 60 subjects (30 males and 30 females) were included in the study with 20 subjects in each of the groups classified based on community periodontal index (CPI) scores: I: Healthy, II: Gingivitis, III: Mild periodontitis. Periodontal therapy was performed on groups II and III patients. Venous blood was collected from each subject at baseline and 3 months after periodontal therapy. The collected sample was subjected to biochemical analysis to detect CRP levels by using immunoturbidimetric method. RESULTS: The present study demonstrated that the periodontitis group had a higher mean CRP levels (2.49 +/- 0.47 ng/ml) as compared to the gingivitis group (1.40 +/- 0.32 ng/ml) and healthy group (0.56 +/- 0.20 ng/ml). The mean CRP values after periodontal therapy were found to be reduced to 0.44 +/- 0.23 ng/ml in group II and 1.30 +/- 0.36 ng/ml in group III patients. CONCLUSION: Within the limitations of this study, it can be concluded that CRP level progressively increases from periodontal health to disease. A decrease in CRP levels with periodontal treatment was also observed. CLINICAL SIGNIFICANCE: Due to its opsonizing abilities CRP plays an important role in the innate host defence. It can be hypothesized that CRP is a potential biomarker of periodontal disease. A number of studies have reported elevated serum CRP levels in periodontitis subjects. Long standing periodontal disease and raised CRP levels enhance the risk of cardiovascular disease, cerebrovascular accidents and preterm low birth weight infants. There is also evidence that effective periodontal therapy can lower serum CRP levels. However, the data of interventional studies on CRP in gingivitis and periodontitis is scarce. PMID- 23811652 TI - A cephalometric evaluation of pretreatment and post-treatment outcome using Tetragon analysis: a retrospective study. AB - STATEMENT OF PROBLEM: Few cephalometric analyses have been put forward to assess the treatment outcome after orthodontic treatment. However, these analyses are somewhat complicated and time consuming. The Tetragon analysis is introduced with measurement of treatment outcome as one of its objectives. PURPOSE OF STUDY: The study was undertaken to evaluate the treatment outcome by checking the skeletal and dental changes using pretreatment and post-treatment radiographs and to evaluate the efficiency of treatment in the Department of Orthodontics, College of Dental Sciences, Davangere, using the Tetragon analysis. MATERIALS AND METHODS: Records of 35 finished patients with fixed orthodontic therapy using preadjusted edgewise appliance were selected. The samples were analyzed separately for the skeletal parameters consisting of skeletal class I, II and III using Tetragon analysis. RESULTS: The post-treatment reduction of upper incisor palatal plane angle was found to be statistically significant in skeletal class I (p < 0.01) and skeletal class II patients (p < 0.05). The post-treatment increase in interincisal angle was found to be statistically significant in skeletal class I (p < 0.01) class II patients (p < 0.05). CONCLUSION: Fixed appliance therapy reduced the proclination of upper incisors and increased the interincisal angle in skeletal class I and II cases but not in skeletal class III cases. The lower incisal angulation and the maxilla-mandibular plane angle did change significantly and so were the angles of the Trigon. The Tetragon analysis proved easy to measure the treatment outcome. PMID- 23811653 TI - Degree of conversion and hardness of two different systems of the VitrebondTM glass ionomer cement light cured with blue LED. AB - This study investigated the physicochemical properties of the new formulation of the glass ionomer cements through hardness test and degree of conversion by infrared spectroscopy (FTIR). Forty specimens (n = 40) were made in a metallic mold (4 mm diameter x 2 mm thickness) with two resin-modified glass ionomer cements, VitrebondTM and VitrebondTM Plus (3M/ ESPE). Each specimen was light cured with blue LED with power density of 500 mW/cm(2) during 30 s. Immediately after light curing, 24h, 48h and 7 days the hardness and degree of conversion was determined. The Vickers hardness was performed by the MMT-3 microhardness tester using load of 50 gm force for 30 seconds. For degree of conversion, the specimens were pulverized, pressed with KBr and analyzed with FT-IR (Nexus 470). The statistical analysis of the data by ANOVA showed that the VitrebondTM and VitrebondTM Plus were no difference significant between the same storage times (p > 0.05). For degree of conversion, the VitrebondTM and VitrebondTM Plus were statistically different in all storage times after light curing. The VitrebondTM showed higher values than VitrebondTM Plus (p < 0.05). The performance of VitrebondTM had greater results for degree of conversion than VitrebondTM Plus. The correlation between hardness and degree of conversion was no evidence in this study. PMID- 23811654 TI - Influence of two different bracket base cleaning procedures on shear bond strength reliability. AB - PURPOSE: To search if the shear bond strengths of brackets would change after two different base-cleaning procedures such as sandblasting or carbide bur cleaning, and to determine if a previously bonded tooth surface had any effect on bond strength. MATERIALS AND METHODS: A total of 120 new brackets were first bonded to 120 extracted premolars and then debonded and bond strength was recorded. The debonded brackets were divided into two groups and recycled either by sandblasting or tungsten-carbide bur cleaning. Sixty recycled brackets were divided into two subgroups: In each group; 30 recycled brackets were bonded to unused 30 extracted premolars. The remaining brackets were bonded to 30 previously used premolars. The brackets were debonded again and their bond strengths were remeasured. RESULTS: Bond strength of rebonded brackets after sandblasting was not significantly different from that of new brackets while the bond strength of rebonded brackets after carbide bur cleaning group significantly decreased. The previously bonded tooth surface did not affect the bond strength significantly. CLINICAL SIGNIFICANCE: This study showed that rebonding the brackets after sandblasting supplies sufficient bond strength. Previously bonded tooth surface did not cause a decreasing effect on bond strength. However, when carbide bur cleaning procedure is chosen, the clinician should proceed cautiously. PMID- 23811655 TI - Effect of base metal alloys recasting on marginal integrity of castable crowns. AB - INTRODUCTION: Base metals have a wide use in casting methods. Sometimes they are reused in laboratories which may have an adverse effect on the restoration marginal integrity. This study aimed to investigate the effect of recasting of alloys on marginal integrity of restorations. MATERIALS AND METHODS: Models with two types of finishing lines shoulder bevel 45 degrees and shoulder 135 degrees were produced and 15 wax copings were formed on each one of them. Each group containing 15 copings was divided into three subgroups A, B and C. Group A was casted with 100% new alloy, group B with 50% new and 50% recasted alloy and group C with 100% recasted alloy. Obtained metal copings were placed on dies and marginal gap size between restoration margin and the dies finishing line was measured using metric microscope and Moticam camera in four points, buccal, lingual, mesial and distal. RESULTS: A significant difference in mean marginal gap size exists among three types of alloys used (p-value = 0.036). A significant difference is observed between mean marginal gap size of two types of finishing lines for different alloys (p-value = 0.001). CONCLUSION: Using 100% recasted alloy is not recommended for any of the two types of finishing lines. PMID- 23811656 TI - Influence of acrylic resin polymerization methods on residual monomer release. AB - AIM: The aim of this study was to quantify and compare the amount of methyl methacrylate (MMA) monomer released from three different denture base acrylic material processed by different polymerization methods and storage conditions. MATERIALS AND METHODS: Microwave-cured, conventional heat and injection-technique acrylic polymerized materials were stored in neutral (pH = 7) and acidic (pH = 4.5) artificial saliva for 24 hours at the room temperature, separately. The residual MMA content was determined by high performance liquid chromatography (HPLC). RESULTS: The MMA leaching from resins showed that microwave-cured material has lower residual MMA leach compared both conventional and injection technique on neutral saliva storage conditions. CONCLUSION: The all data's exhibited higher MMA release into an acidic saliva environment than neutral artificial saliva and there were no significant differences between the materials groups on acidic saliva storage conditions. CLINICAL SIGNIFICANCE: Microwave polymerization method might has some advantages on reducing release of MMA concentration and may contributory effect upon polymerization reaction on neutral pH storage condition, therefore methods of polymerization should be considered as amount of monomer release. PMID- 23811657 TI - Evaluation and comparison of dimensional accuracy of newly introduced elastomeric impression material using 3D laser scanners: an in vitro study. AB - AIM: Aim of the present study was to comparatively evaluate dimensional accuracy of newely introduced elastomeric impression material after repeated pours at different time intervals. MATERIALS AND METHODS: In the present study a total of 20 (10 + 10) impressions of master model were made from vinyl polyether silicone and vinyl polysiloxane impression material. Each impression was repeatedly poured at 1, 24 hours and 14 days. Therefore, a total of 60 casts were obtained. Casts obtained were scanned with three-dimensional (3D) laser scanner and measurements were done. RESULTS: Vinyl polyether silicone produced overall undersized dies, with greatest change being 0.14% only after 14 days. Vinyl polysiloxane produced smaller dies after 1 and 24 hours and larger dies after 14 days, differing from master model by only 0.07% for the smallest die and to 0.02% for the largest die. CONCLUSION: All the deviations measured from the master model with both the impression materials were within a clinically acceptable range. CLINICAL SIGNIFICANCE: In a typical fixed prosthodontic treatment accuracy of prosthesis is critical as it determines the success, failure and the prognosis of treatment including abutments. This is mainly dependent upon fit of prosthesis which in turn is dependent on dimensional accuracy of dies, poured from elastomeric impressions. PMID- 23811658 TI - A new solvent-free one-step self-etch adhesive: bond strength to tooth structures. AB - INTRODUCTION: In recent years some new solvent-free dental adhesives have been marketed. This study evaluated bonding effectiveness of a new one-step solvent free self-etch adhesive in comparison with a common two-step self-etch adhesive used as gold standard. MATERIALS AND METHODS: Flat enamel and dentin surfaces were prepared on 60 incisors using silicon carbide papers. Clearfil SE Bond (CSEB) and Bond 1SF (B1SF) adhesives were applied on enamel/dentin surfaces in four groups (n = 15): (1) Enamel surface and CSEB, (2) dentin surface and CSEB, (3) enamel surface and B1SF, (4) dentin surface and B1SF. Composite resin buildups were carried out using Z100 composite resin. All the specimens were stored for 24 hours at 37 degrees C and 100% relative humidity. After 500 rounds of thermocycling, shear bond strength (SBS) test was performed using a universal testing machine at 1 mm/min crosshead speed. Data were analyzed with one-way ANOVA and a post hoc Tukey test (alpha = 0.05). In each experimental group, two additional specimens were prepared for scanning electron microscopy evaluation. RESULTS: Significant differences were observed between the study groups (p < 0.001). The highest enamel/dentin bond strengths were recorded in group 1 (CSEB) (p < 0.001). The SBS of the two-step self-etch adhesive to enamel and dentin was significantly higher than that of the one-step self-etch adhesive (p < 0.001). There was no significant difference between enamel and dentin SBS with B1SF (p = 0.559). CONCLUSION: Within the limitations of the present study, when bonded to enamel and dentin the solvent-free adhesive B1SF underperforms as compared to CSEB as the control gold standard. PMID- 23811659 TI - Evaluation of effect of different cavity disinfectants on shear bond strength of composite resin to dentin using two-step self-etch and one-step self-etch bonding systems: a comparative in vitro study. AB - AIM AND OBJECTIVES: To evaluate the effect of 2% chlorhexidine, 2% sodium hypochlorite, 3% hydrogen peroxide on shear bond strength of composite resin to dentin using two-step and onestep self-etch bonding systems and to study the mode of failure of specimens under stereomicroscope. MATERIALS AND METHODS: Eighty extracted sound human posterior teeth were used. The occlusal surfaces were ground to expose the dentin and were then randomly divided into 4 main groups. In group I, no cavity disinfectant was used and served as control. In groups II, III, IV, 2% chlorhexidine, 2% sodium hypochlorite and 3% hydrogen peroxide were used as cavity disinfectants respectively. Each group was then divided into two subgroups of 10 teeth each according to the bonding agent used, two-step self etch (Adper SE Plus) and one-step self-etch (Adper Easy One) respectively. A transparent cylindrical plastic tube was loaded with microhybrid composite and placed over the dentin and light cured for 40 seconds. The specimens were subjected to shear stress in the universal testing machine. RESULTS: Pretreatment with 2% chlorhexidine, 2% sodium hypochlorite and 3% hydrogen peroxide, had a negative effect on the shear bond strength of self-etching bonding systems. CONCLUSION: The highest bond strength was found in 2% chlorhexidine group followed by 2% sodium hypochlorite group and the lowest bond strength was found in 3% hydrogen peroxide group. CLINICAL SIGNIFICANCE: All three cavity disinfectants used in this study reduced the shear bond strength and hence should be used with caution. PMID- 23811661 TI - Quantitative evaluation and comparison of stress transmission characteristics of bar-clip and short coping overdenture attachments under dynamic loading: a photoelastic stress analysis. AB - STATEMENT OF PROBLEM: When two canine abutment teeth are used to support an overdenture prosthesis, optimal stress distribution to minimize forces to abutments is desired. PURPOSE: This study used photoelastic stress analysis to compare the stress patterns generated around canine abutments using two different overdenture retainer designs. MATERIALS AND METHODS: Two canine abutments were anchored in the photoelastic mandible and overdentures were fabricated using two different overdenture attachments. The fitting surface of dentures were lined with resilient layer of light bodied silicon rubberbase impression material to simulate oral mucosa. The attachments used were Bar-Clip and Short coping type. Verticalload of 5 to 50 lb was applied by jaw simulator. Resultant stress fringes were photographed and evaluated quantitatively. RESULTS: Bar-Clip type of attachment transmitted more amount of stress than short coping type transmitted. There was gross difference in magnitude of stresses between two types of retainers. CONCLUSION: As the retentivity of the attachment increased there was more stress concentration around the abutments. PMID- 23811660 TI - Mineral oil--a biofriendly substitute for xylene in deparaffinization: a novel method. AB - BACKGROUND: In routine histopathology, xylene has been used in tissue processing and staining. Presently health hazards of xylene are well documented and a safer substitute is an absolute necessity. AIM: The present study was conducted to evaluate the efficacy of mineral oil as a deparaffinizing agent when compared to that of xylene by using hematoxylin and eosin (H&E) staining. MATERIALS AND METHODS: Thirty paraffin-embedded tissue blocks were randomly selected and two sections were taken from each block. Thirty sections were stained with conventional H&E method (group A) using xylene as deparaffinizing agent and 30 were stained with xylene free method using refined mineral oil (group B). Sections were blinded and analyzed by two pathologists using the parameters of uniformity, clarity and intensity of nuclear and cytoplasmic staining respectively (satisfactory = score 1, unsatisfactory = score 0). Score >= 4 was considered to be adequate for diagnosis. RESULTS: 100% of sections in group A and 93.3% of sections in group B were adequate for diagnosis (p-value 0.150). CONCLUSION: The study recommends refined mineral oil as a biofriendly and effective xylene substitute in deparaffinization of tissue sections. PMID- 23811662 TI - A survey of endodontic practices among dentists in Nigeria. AB - AIM: To investigate the pattern of routine endodontic practices among Nigerian dentists. MATERIALS AND METHODS: This study was a questionnaire-based survey of samples of dentists in the Nigerian cities of Enugu and Benin. The self administered questionnaire contained 25 close-ended questions with multiple choice options. The data collected included demographic details of respondents, root canal preparation techniques, irrigants and intracanal medicaments used, the number of appointments, method of working length determination, root filling techniques, cements used, and the scope of treatment performed. RESULTS: Most respondents used sodium hypochlorite as the irrigant, the step back technique for canal preparation, and lateral condensation with a zinc oxide-eugenol-based sealer for obturation. Most respondents did root canal treatment on all types of teeth and used radiographs to determine the working length 70% of the time. Most respondents followed up their patients for less than 12 months and most treated teeth with periapical areas larger than 10 mm by root canal therapy combined with apical surgery. CONCLUSION: Most Nigerian dentists use step back technique for canal preparation and lateral condensation for obturation. CLINICAL SIGNIFICANCE: Endodontic practice by Nigerian dentists differs from some established practice quality guidelines in many other countries, particularly in nonperfusion of modern techniques into practice, popularity of antibiotic use for endodontic emergencies and a high rate of perforations. PMID- 23811663 TI - Ergonomics and musculoskeletal disorder: as an occupational hazard in dentistry. AB - OBJECTIVE: Musculoskeletal disorders (MSDs) are commonly experienced in dentistry. The objective of this study is to determine the prevalence of ergonomics and MSDs among dental professionals. MATERIALS AND METHODS: A cross sectional survey was conducted among 170 dentists of different specialties. The questionnaire gathered information regarding demographic details, MSDs, work duration, working status, awareness of ergonomics, etc. Data was analyzed using SPSS version 15.0. Student's t-test and analysis of variance (ANOVA) test was used for comparison in mean scores. Stepwise multiple linear regression analysis was used to assess the independent variables that significantly influenced the variance in the dependent variable (pain). RESULTS: It was found that 73.9% of the participants reported musculoskeletal pain and most common painful sites were neck and back. More than half of the participants, i.e. 232 (59.3%) were aware of correct ergonomic posture regarding dental. Almost percentage of pain increased significantly with increase in age and working time. Among all specialties, prosthodontics were found to have more prevalence of MSDs. CLINICAL SIGNIFICANCE: The appearance of musculoskeletal symptoms among dental professionals was quite common. It suggested that ergonomics should be covered in the educational system to reduce risks to dental practitioners. PMID- 23811664 TI - Heritability of thirty cephalometric parameters on monozygotic and dizygotic twins: twin study method. AB - Genetic mechanisms are already predominant during embryonic craniofacial morphogenesis, but environment is also thought to influence dentofacial morphology postnatally, particularly during facial growth. A better understanding of the relative effects of genes and environment on dentofacial and occlusal parameters should improve our knowledge on the etiology of orthodontic disorders and therefore also on the possibilities and limitations of the orthodontic treatment and treatment planning. The aim of the present study is to explore the genetic and environmental influence on craniofacial dimensions in a group of 19 pairs of twins using the twin study method. The twin study carried out here clearly indicates that craniofacial matrix is under substantial genetic control and the redirection of a basic growth pattern may be modified only within biological limits which are harmonious for the patient. PMID- 23811665 TI - Arch widths after extraction and nonextraction treatment in class I patients. AB - AIM: To compare pretreatment and post-treatment dental arches in relation to intercanine and intermolar width changes in extraction and nonextraction treatment in class I patients. MATERIALS AND METHODS: In this retrospective study pretreatment and post-treatment dental casts of 60 patients (30 extractions of first premolars and 30 nonextractions) were selected. Anterior and posterior arch widths in the canine and molar regions from the most labial aspect of buccal surfaces, the canines and the molars were measured with the help of digital caliper on the study models and compared statistically to determine whether the dental arches were narrower after extraction treatment. RESULTS: At the start of the treatment there were no statistically significant differences in maxillary and mandibular intercanine widths in both groups. At the end of treatment in both the groups anterior and posterior arch width changes were not significant except for the intercanine dimension which was 0.82 mm larger (p < 0.05) in the extraction group. CONCLUSION: The extraction treatment does not result in narrower dental arches than nonextraction treatment in intercanine and intermolar region. CLINICAL SIGNIFICANCE: It is documented that the arch widths determine smile esthetics and treatment stability. According to the findings of the present study the arch widths in extraction treatments are not narrower than nonextraction so there will not be any compromising effects on esthetics and treatment stability. PMID- 23811666 TI - Influence of artificial aging in marginal adaptation of mixed class V cavities. AB - The aim of this study was to investigate whether the artificial aging by thermal cycling had influenced the marginal adaptation of class V restorations with/without chlorhexidine application in the bond process. Twelve intact human third molars were used. Class V cavity preparations were performed on the buccal surface and the teeth received 35% phosphoric acid-etching procedure (Ultradent Products Inc., South Jordan, Utah, USA). Subsequently, the samples were divided in two groups: Untreated acid-etched dentin and chlorhexidine application as an adjunct in the bond process. The adhesive Single Bond 2 (3M ESPE, St. Paul, MN, USA) was used after 2% chlorhexidine application, and the restorations were performed with FiltekTM Z350 XT (3M ESPE) composite resin. The specimens were submitted to artificial aging by thermal cycling with 3,000 cycles. Analyzes were performed on scanning electron microscopy using replicas of marginal adaptation in percentage of continuous margin before and after the artificial aging. The data were analyzed by paired test and the results showed statistically significant differences in the percentage of continuous margin with/without chlorhexidine treatment before and after thermal cycling. This study concluded that the artificial aging by thermal cycling influenced the marginal adaptation of mixed class V composite restorations. PMID- 23811667 TI - Multidisciplinary management of a child with severe open bite and amelogenesis imperfecta. AB - AIM: To present a case of multidisciplinary management and fixed rehabilitation of a young girl with amelogenesis imperfecta (AI), a severe open bite and occlusal instability. BACKGROUND: AI is a genetic disorder characterized by enamel malformations, disturbances in tooth eruption and significant attrition. Early diagnosis is essential, since rapid breakdown of tooth structure may occur, giving rise to acute symptoms and complicated treatment. As AI is frequently accompanied by unesthetic appearance, open bite deformity and malocclusion, a multidisciplinary approach is often required. CASE REPORT: This clinical report describes the condition and presents the case of a 10-year-old girl with hypocalcified form of AI. Orthodontic treatment and orthognathic surgery were performed as part of the prosthetic treatment plan to achieve acceptable and durable results. They consisted of correcting class II, posterior crossbite and anterior open bite with a fixed orthodontic appliance, Lefort I osteotomy, bilateral mandibular ramus osteotomy and genioplasty. Prosthodontics treatment consisted of metal-ceramic crowns with low-fusing ceramic for good long-term results. No deterioration in the rehabilitation was found after 5 years of follow up. CONCLUSION: Complete restoration of severe AI is a long and complex process generally extending over several years. CLINICAL SIGNIFICANCE: This article shows the important role of interdisciplinary approach to treating a patient with AI over a period of 8 years. PMID- 23811668 TI - Oral manifestations of systemic alterations in early childhood. AB - AIM: This study aimed to describe certain common oral manifestations during early childhood that should be known by the pediatric dental surgeon. BACKGROUND: The correct diagnosis and treatment of oral manifestations during early childhood is important for children's development. The pediatric dentist is responsible for maintaining oral health in children, since they change constantly during their development and growth. CASE REPORT: Four cases of oral lesions are described, in which the diagnosis and related approach for each one is reported. The first was an acute primary herpetic gingivostomatitis, the second, pseudomembranous candidiasis, the third, chickenpox and the last was molluscum. CONCLUSION: Professionals who treat children in this age group must be able to diagnose and treat common oral manifestations when necessary and should refer the child to a pediatrician for effective treatment if the presence of any systemic alteration is suspected. CLINICAL SIGNIFICANCE: Pathognomonic signs of the most common oral manifestations in early childhood should be known by dentists to improve early diagnosis and proper management. PMID- 23811669 TI - Interdisciplinary treatment of an adolescent with unilateral cleft lip and palate. AB - AIM: The present case report describes the importance of interdisciplinary approach and gives an understanding on management of an adolescent with unilateral cleft lip and palate. BACKGROUND: Failure of fusion between medial nasal process and maxillary process or between the palatal process leads to the formation of clefts. Clefts are result of genetic or environmental factors or a combination of both. Common dental problems associated with clefts includes anterior and posterior crossbites, hypodontia, malformation and abnormal eruption pattern. CASE REPORT: A girl, aged 15 years reported with a chief complaint of unesthetic appearance of her maxillary anterior teeth. She had unilateral cleft lip and palate and had received cheiloplasty and palatoplasty when she was in young age and rhinoplasty when she was 14 years of age. At pretreatment evaluation, she had concave profile with maxillary arch constriction and oroantral fistula and mesially tipped maxillary left canine. CONCLUSION: This patient's treatment was unconventional, but it was successful in significantly improving her masticatory function and smile, along with favorable dental and facial results. Generalized esthetics and function were significantly improved in this patient without orthognathic surgery, and treatment results were stable 3 years after the appliance removal. Clinical considerations, sequencing of treatment phases as shown in this case report can be utilized while treating an adolescent with cleft lip and palate. CLINICAL SIGNIFICANCE: If the skeletal discrepancy is mild and esthetic concerns are minimal, dental compensation by orthodontic treatment alone might be recommended. The cephalometric analysis and prediction tracings provide further information for deciding whether a patient can be treated by orthodontics alone, or by orthodontics and an orthognathic surgical procedure. A change in axial inclination of the teeth can camouflage the skeletal relationship adequately. However, one should be cautious in a growing patient, because he or she might outgrow the dental correction so that ultimately skeletal surgery would be indicated. PMID- 23811670 TI - Sialolithiasis in the duct of submandibular gland: a case report in patient with epidermolysis bullosa. AB - AIM: To describe the options of treatment to remove a sialolith associated with the submandibular gland duct in a patient with epidermolysis bullosa (EB). BACKGROUND: Treatment of patients with EB is very complex and involves a multidisciplinary team. This condition is characterized by a spectrum of blistering and mechanical fragility of the skin. One main feature of this disease is the esophageal constriction and possible constriction to the submandibular duct. This alteration may induce the formation of calculi in this duct, which is called sialolith. Once the sialolith obliterates the trajectory of the duct this will lead to a sialolithiasis. The calculi have to be removed. CASE REPORT: Seventeen years old female patient with dystrophic EB developed a sialolith at the submandibular duct. She has a limited mouth opening and her tongue was collapsed with mouth floor. The first choice of treatment was the lithotripsy, once this procedure is less invasive and a surgical remove could worse the collapsed tongue. She was with acute pain and with a great augmentation in the submandibular area. Once the patient was debilitated and has difficult to swallow she invariably needed to be hospitalized in order to receive intravenous medication. During the hospitalization the sialolith could be seen through the opening of the duct and the calculi was removed with local anesthesia. CONCLUSION: The treatment of sialolithiasis usually does not present major challenges, nevertheless if the sialolithiasis is associated with EB, the treatment became an extremely challenge. In this particular case the option of treatment was the less invasive. CLINICAL RELEVANCE: This case report has an enormous clinical relevance once there is no protocol to treat patients with EB and buccal diseases. PMID- 23811671 TI - Endodontic treatment of a maxillary central incisor with two roots. AB - AIM: This clinical report presents a rare case of maxillary central incisor with two separate roots. BACKGROUND: Unusual morphology of the roots and root canals may exist in any tooth. Recognition of the dental anatomy and its variations is necessary for successful endodontic therapy. It is well known that maxillary incisors are usually single-rooted teeth. CASE REPORT: The root canals were instrumented with conventional hand files and Gates Glidden and obturated by using the lateral technique. Recall radiograph after 1 year shows the healing process of the preoperative apical periodontitis. CONCLUSION AND CLINICAL SIGNIFICANCE: Clinicians should be aware of unexpected root canal morphology when performing root canal therapy. The present case demonstrated the importance of accurate preoperative radiograph and adequate access preparation. PMID- 23811672 TI - Esthetic dentistry in patients with bilaterally missing maxillary lateral incisors: a multidisciplinary case report. AB - Congenitally missing maxillary lateral incisors pose a difficult esthetic and treatment planning problem for clinicians. Age, location, space limitations, alveolar ridge deficiencies, uneven gingival margins, occlusion and periodontal factors often necessitate an interdisciplinary approach. Over the last several decades, dentistry has focused various treatment modalities for replacement of missing teeth. Treatment plans for patients with missing maxillary lateral incisors have traditionally included either space closure or space reopening. To remove healthy tooth structure of adjacent teeth to replace a tooth, for some patients and dentists, is a very aggressive treatment option which eliminates the option of three unit bridges. Removable partial dentures are also not preferred for its bulkiness and reduced esthetics. Presently, the single implant supported crown is a predictable method of tooth replacement in adolescents. The aim of this case report is to provide a conservative method for the management of bilateral missing lateral incisor. PMID- 23811673 TI - Collision lesion of mandible--coexistence of keratocystic odontogenic tumor with central giant cell granuloma: a rare case report. AB - AIM AND BACKGROUND: An odontogenic keratocyst (OKC) or keratocystic odontogenic tumor (KCOT) and giant cell granuloma (GCG) in the jaws are common lesions which have been studied extensively in detail over the years. However, a lesion showing features of both is exceptionally rare and is reported only twice in the literature till date. CASE DESCRIPTION: A rare case of OKC in mandible showing foci of GCG like areas is reported in a 29 years old male patient. CONCLUSION: It seems to be a collision lesion, though the possibility of KCOT showing a reactive response to form giant cells or it being a rare variant cannot be totally ruled out. CLINICAL SIGNIFICANCE: This entity requires aggressive treatment since biological behavior of this unique lesion is difficult to predict unless more of such lesions are reported and followed up in future. PMID- 23811674 TI - Abnormal odontogenesis following management of childhood cancer (retinoblastoma): review and a new variant. AB - A young child being diagnosed with cancer naturally generates a pretty melancholy reaction. Each cancer can be managed with a vast array of treatment options that are available either individually or as a combination, the final goal of which is total eradication of the condition in the affected individual. Since, most of these treatments are administered during the age of tooth formation, they may affect stages of odontogenesis. Most common treatment of childhood cancers includes--chemotherapy and radiotherapy. With recent advancements in cancer therapy additional treatment options like laser therapy, radiation in the form of brachytherapy or teletherapy, cryotherapy, thermochemotherapy, etc. are available. As treatment of childhood cancers starts at a very young age coinciding with dental development, a number of dental malformations have been reported in childhood cancer survivors. The most common ocular cancer in children is retinoblastoma. This is the first such reported case and unique one where microdontia has affected all the first premolars. PMID- 23811675 TI - Review and update: advanced investigation methods for diagnosis of tongue lesions. AB - Various specialized imaging modalities and guided microscopic methods developed in recent years, having proven value for the evaluation of tongue disorders. The list of which includes cineradiography, pulsed ultrasound, computer-assisted tomography, isotopic scanning, electromyography, magnetic resonance, video microscopy and stereo microscopy. The basic aim of the article is to review and throw light on the importance of complete examination of the tongue and application of advanced investigations for the proper diagnosis of the tongue lesions and its usefulness to the clinician. PMID- 23811677 TI - Rashmdeep's method: a novel method to confirm nasal breathing. AB - Mouth breathing has been a very prevalent oral habit, especially among children. Common etiologies behind this common occurrence can be physiologic enlargement of lymphoid tissue like adenoids leading to decrease nasopharyngeal airway or allergic rhinitis. The traditional or the latest methods used for diagnosing mouth breathing either are too subjective or cannot be performed in usual dental setups. This article presents an innovative method to confirm whether patient can breathe through the nose. This can also be used to diagnose any unilateral nasal blockade. PMID- 23811678 TI - Ipsilateral circumferential radiofrequency ablation of atrial fibrillation with irrigated tip catheter: long-term outcome and pre-procedural predictors. AB - BACKGROUND: Predictors of long-term outcome of atrial fibrillation (AF) ablation are unknown. The predictors of 5-year follow-up (FU) after single ipsilateral circumferential antrum pulmonary vein isolation (PVI) with irrigated tip catheter were investigated. METHODS AND RESULTS: In 356 patients (74% male) with AF (44% paroxysmal AF [PAF]) PVI was performed. Success was defined as absence of AF, atrial flutter or tachycardia (AFLAT) recurrence. A total of 161 patients (45%) were free of AFLAT. The univariate predictors of AFLAT recurrence were: type of AF (non-PAF vs. PAF, P=0.0001), size of LA (normalized left atrium area [NLA] >=11.5 vs. NLA <11.5, P=0.0001), renal function (glomerular filtration rate [GFR] <68ml/min vs. GFR >=68ml/min, P=0.001) and hypertension (HT vs. no HT, P=0.025). The independent predictors of AFLAT-free survival were non-PAF (hazard ratio [HR], 1.67; 95% confidence interval [CI]: 1.23-2.26, P=0.0005), NLA >=11.5 (HR, 1.40; 95% CI: 1.03-1.90, P=0.007) and GFR <68ml/min (HR, 1.70; 95% CI: 1.21-2.37, P=0.008). CONCLUSIONS: Single PVI results in a moderate success rate in patients with AF during 5-year FU without the use of a 3-D mapping system. Higher success was observed in patients with PAF, non-enlarged LA and good renal function. PMID- 23811679 TI - Endothelial progenitor cells and long-term prognosis in patients with stable angina treated with percutaneous coronary intervention. PMID- 23811680 TI - Endothelial progenitor cells and long-term prognosis in patients with stable angina treated with percutaneous coronary intervention--reply. PMID- 23811681 TI - Clinical characteristics of heart failure with preserved ejection fraction in children. PMID- 23811682 TI - Highly purified eicosapentaenoic acid may increase low-density lipoprotein particle size by improving triglyceride metabolism in patients with hypertriglyceridemia. AB - BACKGROUND: The purpose of this study was to evaluate the effect of highly purified eicosapentaenoic acid (EPA) in increasing low-density lipoprotein (LDL) particle size, as one of the possible mechanisms by which intake of EPA may prevent coronary events. METHODS AND RESULTS: Hypertriglyceridemic subjects were randomly assigned to a control group (n=72) or an EPA group (n=72; EPA regimen 1,800mg/day for 6 months). In the EPA group, the serum LDL-cholesterol and high density lipoprotein cholesterol levels remained unchanged, but there was a significant increase in LDL particle size based on LDL-relative mobility measured on lipoprotein polyacrylamide-gel electrophoresis, and a significant decrease in serum triglyceride-rich lipoproteins (TRLs) level. None of these changes were observed in the control group. After adjustments for coronary risk factors, multivariate logistic regression analysis identified elevation of serum EPA related markers (6-month EPA, 6-month EPA/arachidonic acid [AA] ratio, change in [Delta] EPA, and EPA/AA), and treatment with statins and EPA as independent variables associated with increase in LDL particle size. Negative correlations were found between DeltaTRLs and DeltaLDL particle size, suggesting that improvement in triglyceride metabolism was associated with an increase in LDL particle size. CONCLUSIONS: EPA increases LDL particle size by improving triglyceride metabolism; and serum EPA level and EPA/AA ratio after EPA treatment may be useful markers of increased LDL particle size. PMID- 23811683 TI - Prognostic impact of nutritional status in asymptomatic patients with cardiac diseases: a report from the CHART-2 Study. AB - BACKGROUND: The prognostic impact of nutritional status is poorly understood in asymptomatic patients with structural and/or functional heart diseases, classified as stage B in the ESC/AHA/ACC chronic heart failure (HF) guidelines. METHODS AND RESULTS: We evaluated the impact of nutrition, using the controlling nutritional status (CONUT) score, calculated by the serum albumin and total cholesterol levels,and lymphocyte number, in 3,421 stage B patients from the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 Study (mean age: 66.9+/-12.7 years, male: 71.6%). During a median follow-up of 2.89 years, 224 patients died from cardiovascular (45%, n=102) and noncardiovascular (55%, n=123) causes and 139 experienced hospitalization for HF. Survival at 3 years in patients with CONUT 0-1 (reference, n=2,121), 2 (n=693) and >=3 (n=607) was 95.5, 92.3, and 73.2%, respectively (P<0.001). The adjusted Cox hazard analyses revealed that the CONUT score was significantly associated with increased incidence of all-cause death (hazard ratio 1.27 per point increase; 95% confidence interval, 1.16-1.39, P<0.001). Subgroup analysis showed that per point increase in the CONUT score was significantly associated with a 17% increase in HF hospitalization in patients >=70 years old (P=0.049), but not in those aged <70 years. CONCLUSIONS: In the current stage B patients, poor nutritional status was associated with increased incidence of death for the overall population and of HF hospitalization for the elderly proportion. PMID- 23811684 TI - Synaptic transmission and the susceptibility of HIV infection to anti-viral drugs. AB - Cell-to-cell viral transmission via virological synapses has been argued to reduce susceptibility of the virus population to anti-viral drugs through multiple infection of cells, contributing to low-level viral persistence during therapy. Using a mathematical framework, we examine the role of synaptic transmission in treatment susceptibility. A key factor is the relative probability of individual virions to infect a cell during free-virus and synaptic transmission, a currently unknown quantity. If this infection probability is higher for free-virus transmission, then treatment susceptibility is lowest if one virus is transferred per synapse, and multiple infection of cells increases susceptibility. In the opposite case, treatment susceptibility is minimized for an intermediate number of virions transferred per synapse. Hence, multiple infection via synapses does not simply lower treatment susceptibility. Without further experimental investigations, one cannot conclude that synaptic transmission provides an additional mechanism for the virus to persist at low levels during anti-viral therapy. PMID- 23811685 TI - MUS81 promotes common fragile site expression. AB - Fragile sites are chromosomal loci with a propensity to form gaps or breaks during early mitosis, and their instability is implicated as being causative in certain neurological disorders and cancers. Recent work has demonstrated that the so-called common fragile sites (CFSs) often impair the faithful disjunction of sister chromatids in mitosis. However, the mechanisms by which CFSs express their fragility, and the cellular factors required to suppress CFS instability, remain largely undefined. Here, we report that the DNA structure-specific nuclease MUS81 EME1 localizes to CFS loci in early mitotic cells, and promotes the cytological appearance of characteristic gaps or breaks observed at CFSs in metaphase chromosomes. These data indicate that CFS breakage is an active, MUS81-EME1 dependent process, and not a result of inadvertent chromatid rupturing during chromosome condensation. Moreover, CFS cleavage by MUS81-EME1 promotes faithful sister chromatid disjunction. Our findings challenge the prevailing view that CFS breakage is a nonspecific process that is detrimental to cells, and indicate that CFS cleavage actually promotes genome stability. PMID- 23811686 TI - ERCC1 and MUS81-EME1 promote sister chromatid separation by processing late replication intermediates at common fragile sites during mitosis. AB - Chromosomal instability (CIN) is a hallmark of tumour initiation and progression. Some genomic regions are particularly unstable under replication stress, notably common fragile sites (CFSs) whose rearrangements in tumour cells contribute to cancer development. Recent work has shown that the Fanconi anaemia (FANC) pathway plays a role in preventing defective chromosome segregation and CIN under conditions of replication stress. Strikingly, FANCD2 is recruited to regions hosting CFSs on metaphase chromosomes. To decipher the mechanisms protecting CFSs in G2/M, we searched for proteins that co-localize with FANCD2 on mitotic chromosomes, and identified XPF-ERCC1 and MUS81-EME1, two structure-specific endonucleases. We show that depletion of either ERCC1 or MUS81-EME1 affects accurate processing of replication intermediates or under-replicated DNA that persist at CFSs until mitosis. Depletion of these endonucleases also leads to an increase in the frequency of chromosome bridges during anaphase that, in turn, favours accumulation of DNA damage in the following G1 phase. PMID- 23811687 TI - TAp73 enhances the pentose phosphate pathway and supports cell proliferation. AB - TAp73 is a structural homologue of the pre-eminent tumour suppressor p53. However, unlike p53, TAp73 is rarely mutated, and instead is frequently overexpressed in human tumours. It remains unclear whether TAp73 affords an advantage to tumour cells and if so, what the underlying mechanism is. Here we show that TAp73 supports the proliferation of human and mouse tumour cells. TAp73 activates the expression of glucose-6-phosphate dehydrogenase (G6PD), the rate limiting enzyme of the pentose phosphate pathway (PPP). By stimulating G6PD, TAp73 increases PPP flux and directs glucose to the production of NADPH and ribose, for the synthesis of macromolecules and detoxification of reactive oxygen species (ROS). The growth defect of TAp73-deficient cells can be rescued by either enforced G6PD expression or the presence of nucleosides plus an ROS scavenger. These findings establish a critical role for TAp73 in regulating metabolism, and connect TAp73 and the PPP to oncogenic cell growth. PMID- 23811689 TI - Poor kidney allograft survival associated with positive B cell - Only flow cytometry cross matches: a ten year single center study. AB - The presence of donor specific antibody (DSA) to class 1 or class 2 HLA as detected respectively in T cell or B cell - only flow cytometry cross matches (FCXMs) are risk factors for renal allograft survival, though the comparative risk of these XMs has not been definitively established. Allograft survival and FCXM data in 624 microcytotoxicity (CDC) XM negative kidney transplants were evaluated. Short and long term allograft survival was significantly less in recipients with T(-) B(+) FCXMs (1 year, 74%, 10 year, 58%) compared to T(+) B(+) FCXMs (1 year, 84%, 10 year, 68%) and to T(-) B(-) FCXM (1 year, 90%, 10 year, 85%). Risk factors were positive FCXM, deceased donor (DD) transplantation and donor age, but not race, gender, recipient age or previous transplant. Recipients with T(-) B(+) and T(+) B(+) FCXMs were at 4.5 and 2.5 fold greater risk, respectively, of DD allograft failure compared to patients with T(-) B(-) FCXMs. The quantitative value of FCXM did not correlate with the duration of graft survival. We conclude that patients with DSA to class 2 HLA have a greater risk of early and late allograft failure compared to patients with DSA to class 1 HLA. PMID- 23811688 TI - The Lin28b-let-7-Hmga2 axis determines the higher self-renewal potential of fetal haematopoietic stem cells. AB - Mouse haematopoietic stem cells (HSCs) undergo a postnatal transition in several properties, including a marked reduction in their self-renewal activity. We now show that the developmentally timed change in this key function of HSCs is associated with their decreased expression of Lin28b and an accompanying increase in their let-7 microRNA levels. Lentivirus-mediated overexpression of Lin28 in adult HSCs elevates their self-renewal activity in transplanted irradiated hosts, as does overexpression of Hmga2, a well-established let-7 target that is upregulated in fetal HSCs. Conversely, HSCs from fetal Hmga2(-/-) mice do not exhibit the heightened self-renewal activity that is characteristic of wild-type fetal HSCs. Interestingly, overexpression of Hmga2 in adult HSCs does not mimic the ability of elevated Lin28 to activate a fetal lymphoid differentiation program. Thus, Lin28b may act as a master regulator of developmentally timed changes in HSC programs with Hmga2 serving as its specific downstream modulator of HSC self-renewal potential. PMID- 23811690 TI - Noise-induced hearing loss in workers exposed to urban stressors. AB - The technological and industrial progress together with the intensification of vehicular traffic and the adoption of new social habits are the cause of an increasing noise pollution with possible negative effects on the auditory system. This study aims to assess the noise exposure levels and the effects on the hearing threshold in outdoor and indoor male workers of a big Italian city. The study was carried out on 357 outdoor male workers, exposed to urban noise and on a control group of 357 unexposed indoor workers. Noise levels were measured in 30 outdoor and indoor areas. The subjects underwent tonal liminal audiometry in order to determine the value of their hearing threshold. During their working activity, outdoor and indoor workers are exposed to different noise levels LEX<80 dB(A). At mid-low frequencies (250-2000 Hz), the results show significant differences in the average values of hearing threshold between the two groups in both ears and for all age classes; there are no significant differences between the two groups at higher frequencies. The outdoor noise levels measured are not usually ototoxic and the hearing loss at mid-low frequencies is not characteristic of the exposure to industrial noise. For these reasons the Authors hypothesize that the results may be due to the combined effect of the exposure to noise and to ototoxic air pollutants. The impairment of speech frequencies is disabling and involves the risk of missed forensic recognition. PMID- 23811691 TI - Do special occasions trigger psychological distress among older bereaved spouses? An empirical assessment of clinical wisdom. AB - OBJECTIVES: Mental health professionals have suggested that widowed persons experience heightened psychological distress on dates that had special meaning for them and their late spouse, such as a wedding anniversary or the late spouse's birthday. This study examined the effects of such occasions on grief, anxiety, and depressive symptoms in a community sample of older widowed persons. METHODS: OLS regression models were estimated using data from the Changing Lives of Older Couples (CLOC) study, a large prospective probability study of late-life widowhood. Participants were interviewed prior to and both 6 and 18 months after spousal loss; married matched controls were interviewed at comparable times. RESULTS: Widowed persons reported heightened psychological distress when interviewed during the month of their late spouse's birthday, a post-holiday period (January), and in June, a month associated with wedding anniversaries and graduations in the United States. The distressing effects of special occasions on psychological symptoms were evidenced only within the first 6 months postloss, and were not apparent at the 18-month follow-up. DISCUSSION: Our results support the clinical observation that persons in the early stages of spousal bereavement are at increased risk of psychological distress at times with special significance to the couple. We highlight methodological and clinical implications. PMID- 23811692 TI - Do afterlife beliefs affect psychological adjustment to late-life spousal loss? AB - OBJECTIVES: We explore whether beliefs about the existence and nature of an afterlife affect 5 psychological symptoms (anxiety, anger, depression, intrusive thoughts, and yearning) among recently bereaved older spouses. METHOD: We conduct multivariate regression analyses using data from the Changing Lives of Older Couples (CLOC), a prospective study of spousal loss. The CLOC obtained data from bereaved persons prior to loss and both 6 and 18 months postloss. All analyses are adjusted for health, sociodemographic characteristics, and preloss marital quality. RESULTS: Bleak or uncertain views about the afterlife are associated with multiple aspects of distress postloss. Uncertainty about the existence of an afterlife is associated with elevated intrusive thoughts, a symptom similar to posttraumatic distress. Widowed persons who do not expect to be reunited with loved ones in the afterlife report significantly more depressive symptoms, anger, and intrusive thoughts at both 6 and 18 months postloss. DISCUSSION: Beliefs in an afterlife may be maladaptive for coping with late-life spousal loss, particularly if one is uncertain about its existence or holds a pessimistic view of what the afterlife entails. Our findings are broadly consistent with recent work suggesting that "continuing bonds" with the decedent may not be adaptive for older bereaved spouses. PMID- 23811693 TI - Racial, Income, and Marital Status Disparities in Hospital Readmissions Within a Veterans-Integrated Health Care Network. AB - Hospital readmission is an important indicator of health care quality and currently used in determining hospital reimbursement rates by Centers for Medicare & Medicaid Services. Given the important policy implications, a better understanding of factors that influence readmission rates is needed. Racial disparities in readmission have been extensively studied, but income and marital status (a postdischarge care support indicator) disparities have received limited attention. By employing three Poisson regression models controlling for different confounders on 8,718 patients in a veterans-integrated health care network, this study assessed racial, income, and martial disparities in relation to total number of readmissions. In contrast to other studies, no racial and income disparities were found, but unmarried patients experienced significantly more readmissions: 16%, after controlling for the confounders. These findings render unique insight into health care policies aimed to improve race and income disparities, while challenging policy makers to reduce readmissions for those who lack family support. PMID- 23811694 TI - Modulation of ethylene biosynthesis by ACC and AIB reveals a structural and functional relationship between the K15NO3 uptake rate and root absorbing surfaces. AB - The modification of root traits in relation to nitrate uptake represents a source for improvement of nitrogen uptake efficiency. Because ethylene signalling modulates growth of exploratory and root hair systems more rapidly (minutes to hours) than nitrate signalling (days to weeks), a pharmacological approach was used to decipher the relationships between root elongation and N uptake. Rape seedlings were grown on agar plates supplied with 1mM K(15)NO3 and treated with different concentrations of either the ethylene precursor, ACC (0.1, 1, and 10 MUM) or an inhibitor of ethylene biosynthesis, AIB (0.5 and 1 MUM). The results showed that rapid modulation of root elongation (up to 8-fold) is more dependent on the ethylene than the nitrate signal. Indeed, ACC treatment induced a partial compensatory increase in (15)N uptake associated with overexpression of the BnNRT2.1 and BnNRT1.1 genes. Likewise, daily root elongation between treatments was not associated with daily nitrate uptake but was correlated with N status. This suggested that a part of the daily root response was modulated by cross talks between ethylene signalling and N and C metabolisms. This was confirmed by the reduction in C allocation to the roots induced by ACC treatment and the correlations of changes in the root length and shoot surface area with the aspartate content. The observed effects of ethylene signalling in the root elongation and NRT gene expression are discussed in the context of the putative role of NRT2.1 and NRT1.1 transporters as nitrate sensors. PMID- 23811695 TI - Functions of the lethal leaf-spot 1 gene in wheat cell death and disease tolerance to Puccinia striiformis. AB - Pheophorbide a oxygenase (PaO) is a key enzyme in chlorophyll catabolism that is known to suppress cell death in maize and Arabidopsis. The catalytic activity of PaO in chlorophyll degradation has been clearly demonstrated, but the function of PaO in the regulation of cell death and plant-microbe interactions is largely unknown. In this study, we characterized a PaO homologue in wheat of the lethal leaf-spot 1 gene, TaLls1, that was induced in leaves infected by Puccinia striiformis f.sp. tritici (Pst) and wounding treatment. The TaLls1 protein contains a conserved Rieske [2Fe-2S] motif and a mononuclear iron-binding site typical of PaOs. Silencing of TaLls1 by virus-induced gene silencing in wheat led to leaf cell death without pathogen attacks, possibly due to the accumulation of pheophorbide a (upstream substrate of PaO), indicating a suppressor role of TaLls1, while overexpression of TaLls1 also triggered cell death in both tobacco and wheat leaves, probably owing to the accumulation of the red chlorophyll catabolite (downstream product of PaO). Further deletion mutant analysis showed that the conserved Rieske domain, but not the iron-binding site, was essential for cell death induction. These results thus suggest a threshold for TaLls1 in maintaining cell homeostasis to adapt in various stresses, and shed new light on the role of TaLls1 in cell death regulation. Furthermore, silencing of TaLls1 in wheat did not change the disease symptoms but enhanced tolerance to Pst via an significant increase in H2O2 generation, elevated cell death occurrence, and upregulation of pathogenesis-related genes. PMID- 23811697 TI - Realizing improved patient care through human-centered operating room design: a human factors methodology for observing flow disruptions in the cardiothoracic operating room. AB - BACKGROUND: Human factors engineering has allowed a systematic approach to the evaluation of adverse events in a multitude of high-stake industries. This study sought to develop an initial methodology for identifying and classifying flow disruptions in the cardiac operating room (OR). METHODS: Two industrial engineers with expertise in human factors workflow disruptions observed 10 cardiac operations from the moment the patient entered the OR to the time they left for the intensive care unit. Each disruption was fully documented on an architectural layout of the OR suite and time-stamped during each phase of surgery (preoperative [before incision], operative [incision to skin closure], and postoperative [skin closure until the patient leaves the OR]) to synchronize flow disruptions between the two observers. These disruptions were then categorized. RESULTS: The two observers made a total of 1,158 observations. After the elimination of duplicate observations, a total of 1,080 observations remained to be analyzed. These disruptions were distributed into six categories such as communication, usability, physical layout, environmental hazards, general interruptions, and equipment failures. They were further organized into 33 subcategories. The most common disruptions were related to OR layout and design (33%). CONCLUSIONS: By using the detailed architectural diagrams, the authors were able to clearly demonstrate for the first time the unique role that OR design and equipment layout has on the generation of physical layout flow disruptions. Most importantly, the authors have developed a robust taxonomy to describe the flow disruptions encountered in a cardiac OR, which can be used for future research and patient safety improvements. PMID- 23811696 TI - Controlling the mechanical properties of three-dimensional matrices via non enzymatic collagen glycation. AB - The mechanical properties of the extracellular matrix play an important role in maintaining cellular function and overall tissue homeostasis. Recently, a number of hydrogel systems have been developed to investigate the role of matrix mechanics in mediating cell behavior within three-dimensional environments. However, many of the techniques used to modify the stiffness of the matrix also alter properties that are important to cellular function including matrix density, porosity and binding site frequency, or rely on amorphous synthetic materials. In a recent publication, we described the fabrication, characterization and utilization of collagen gels that have been non enzymatically glycated in their unpolymerized form to produce matrices of varying stiffness. Using these scaffolds, we showed that the mechanical properties of the resulting collagen gels could be increased 3-fold without significantly altering the collagen fiber architecture. Using these matrices, we found that endothelial cell spreading and outgrowth from multi-cellular spheroids changes as a function of the stiffness of the matrix. Our results demonstrate that non-enzymatic collagen glycation is a tractable technique that can be used to study the role of 3D stiffness in mediating cellular function. This commentary will review some of the current methods that are being used to modulate matrix mechanics and discuss how our recent work using non-enzymatic collagen glycation can contribute to this field. PMID- 23811698 TI - Gifting and sharing cigarettes in a rural Chinese village: a cross-sectional study. AB - OBJECTIVES: Quantitative measurement of the prevalence of cigarette sharing and gifting in a town in rural China and evaluation of the impact of these practices on individual smoking habits and family expenditures. METHODS: An interview-based cross-sectional study of 105 households in rural Hunan, China tabulated household cigarette gifting and expenditures. Individual smoking and cigarette sharing activities were also recorded among 198 household members aged >15 years who were resident for at least 6 months. RESULTS: With regard to sharing cigarettes, 92% of men and 19% of women reported being offered a cigarette within the past week. Among previous and current smokers who had attempted to quit smoking, 90% reported that their friends had tried to dissuade them from quitting by tempting them with cigarettes. Concerning gifting cigarettes, 74% of households reported sending packaged cigarettes as gifts during the Chinese New Year Festival at an average expense of 2.8% of household annual income. Although households received an average of 12.4% of their annual cigarette consumption in the form of gifts during the Chinese New Year Festival, no association was found between the amount of cigarettes received by a household and the annual cigarette consumption for that household. CONCLUSIONS: Both gifting and sharing cigarettes are common in rural China. Gifting of cigarettes during the New Year Festival is a significant expenditure affecting both smoking and non-smoking households and may be an opportunity for additional mass media marketing. Among current and former smokers, sharing cigarettes in China is a major impediment to smoking cessation. PMID- 23811699 TI - The improving landscape of urologic oncology. PMID- 23811700 TI - Imaging of prostate carcinoma. AB - BACKGROUND: Imaging of prostate carcinoma is an important adjunct to clinical evaluation and prostate specific antigen measurement for detecting metastases and tumor recurrence. In the past, the ability to assess intraprostatic tumor was limited. METHODS: Pertinent literature was reviewed to describe the capabilities and limitations of the currently available imaging techniques for assessing prostate carcinoma. Evaluation of primary tumor and metastatic disease by ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), and nuclear medicine techniques is discussed. RESULTS: Ultrasonography and MRI have limited usefulness for local staging of prostate cancer because of suboptimal sensitivity and specificity for identifying tumor extent and capsular penetration. Additional MRI techniques such as magnetic resonance-based perfusion imaging, diffusion imaging, and spectroscopy may provide incremental benefit. CT and bone scanning provide an assessment of metastatic disease but are also limited by the poor sensitivity of lymph node size as a criterion for detecting metastases. Novel imaging techniques such as hybrid imaging devices in the form of single-photon emission CT/CT gamma cameras, positron emission tomography/CT cameras, and, in the near future, positron emission tomography/MRI combined with tumor specific imaging radiotracers may have a significant impact on tumor staging and treatment response. CONCLUSIONS: Cross-sectional imaging and scintigraphy have an important role in assessing prostate carcinoma metastases and treatment response. Increasingly, the incremental value of primary tumor imaging through MRI is being realized. PMID- 23811701 TI - Focal cryotherapy in the treatment of localized prostate cancer. AB - BACKGROUND: The management choice for newly diagnosed localized prostate cancer presents a challenge to both the physician and the patient. Traditionally, surgery and radiation therapy have been the most commonly recommended options. More recently, active surveillance is recommended as the preferred management choice for a subset of men with localized, low-risk cancer. Recent reports also suggest that focal cryotherapy may be considered as a management option for selected cases of clinically localized prostate cancer. METHODS: A review of the literature on focal cryotherapy from 2002 to 2012 was performed. Outcomes on cancer control, complications, and quality of life were extracted and assessed. RESULTS: The biochemical disease-free survival at 5 years is comparable to whole gland treatment modalities. Complications are minimal and comparable with other local treatment modalities. CONCLUSIONS: Focal cryotherapy is safe and effective, and it may improve failure rates in men who initially pursue active surveillance protocols. Early outcomes with cancer control are encouraging. PMID- 23811702 TI - Sequencing systemic therapies in metastatic castration-resistant prostate cancer. AB - BACKGROUND: Men with prostate cancer will not die of the disease until it progresses to the metastatic castration resistant stage. At that stage, the median survival is 9 to 30 months. METHODS: Recently approved and emerging treatments for metastatic castration-resistant prostate cancer (mCRPC) were reviewed based on their mechanisms of action, as well as sequencing and combining these treatments with existing options. RESULTS: Advances in androgen deprivation therapy, immunotherapy, bone-targeted therapy, and chemotherapy have led to approvals of abiraterone acetate, sipuleucel-T, denosumab, and cabazitaxel for the treatment of mCRPC. Despite improvements in patient survival and quality of life, mCRPC remains incurable. CONCLUSIONS: With the emerging new therapies, this is an unprecedented time in treating mCRPC. A better understanding of their mechanisms of action, the genetic makeup of each mCRPC, and the development of new prognostic and predictive biomarkers will help determine sequencing or different combination treatments for each individual patient. PMID- 23811703 TI - Primary bladder preservation treatment for urothelial bladder cancer. AB - BACKGROUND: Significant advancements have occurred in surgical procedures and chemoradiation therapy for bladder preservation. METHODS: This review addresses primary treatment options for bladder cancer, including an overview of bladder sparing strategies. RESULTS: Surgical series demonstrate that highly selected patients with cT2N0M0 urothelial bladder cancers can be managed with partial cystectomy and bilateral pelvic lymphadenectomy. For patients with cT2N0M0 to cT4aN0M0 urothelial bladder cancers, neoadjuvant chemotherapy followed by radical cystectomy or maximal transurethral resection of the bladder tumor (TURBT) followed by chemoradiation therapy results in equivalent survival rates. However, each treatment option has a different impact on quality of life. Current chemoradiation therapy trials are evaluating novel approaches to improve outcomes. CONCLUSIONS: Maximal TURBT followed by chemoradiation therapy demonstrated equivalent survival with radical cystectomy while preserving bladder function in the majority of patients. Future efforts will be directed toward improving survival and quality of life. PMID- 23811704 TI - Role of systemic chemotherapy in urothelial urinary bladder cancer. AB - BACKGROUND: Radical cystectomy is the standard of care for patients with localized muscle-invasive bladder cancer; however, 50 percent of patients still relapse in distant sites following surgery. A systemic approach is needed to improve outcomes in bladder cancer in the metastatic and perioperative settings. METHODS: We reviewed the literature for use of systemic chemotherapy in bladder cancer and its role in metastatic, neoadjuvant, and adjuvant settings, including patients with comorbidities and renal dysfunction. Current controversies on the role of chemotherapy in neoadjuvant and adjuvant settings as well as the role of novel agents are discussed. RESULTS: First-line cisplatin-based polychemotherapy improves survival in the metastatic setting and is the standard of care. Approved regimens for subsequent-line therapy do not exist. Chemotherapy has a modest benefit in the neoadjuvant setting, but evidence is insufficient to justify its role in the adjuvant setting despite a possible benefit. Carboplatin cannot be substituted for cisplatin in fit patients, and the addition of taxane to a standard regimen cannot be recommended. CONCLUSIONS: Systemic chemotherapy plays a central role in the management of invasive bladder cancer in the metastatic and neoadjuvant settings, but its role in the adjuvant setting remains undefined. Neoadjuvant chemotherapy is underutilized and should be routinely used. Pathological downstaging strongly correlates with improved outcomes and may serve as a surrogate end point for survival. An urgent need exists for the development of novel therapeutic agents to improve outcomes. PMID- 23811705 TI - Current management considerations for the incidentally detected small renal mass. AB - BACKGROUND: Nephron-sparing treatments remain underutilized for the management of small renal masses despite a rise in incidentally detected renal cell carcinoma and a downward stage migration. METHODS: Historical publications representative of currently accepted paradigms were reviewed, and the results of a contemporary scientific literature search conducted in PubMed focusing on studies involving humans, published in English, and inclusive of clinical trials, meta-analyses, randomized controlled trials, and practice guidelines are included. Results from contemporary retrospective trials augment the data when level I or II evidence is absent. RESULTS: Phase III clinical trial results substantiate the long-held tenet that partial nephrectomy is equivalent to radical nephrectomy with respect to safety and oncologic efficacy. Further, minimally invasive techniques using laparoscopy and robotic assistance to achieve partial nephrectomy appear equally effective to traditional open techniques. Although no prospective randomized studies are available, large retrospective studies support the notion that active surveillance and thermal ablative techniques are viable options for carefully selected patients. CONCLUSIONS: The management of small renal masses encompasses a host of therapeutic options, all of which must be considered and discussed with the individual patient. PMID- 23811706 TI - Targeted therapy of kidney cancer: keeping the art around the algorithms. AB - BACKGROUND: Therapy for metastatic kidney cancer is actively evolving, particularly in the results of registration drug trials that have led to the approval of vascular endothelial growth factor pathway drugs such as sorafenib, sunitinib, pazopanib, bevacizumab, and axitinib, with focus on patients with good or intermediate-risk criteria and clear cell histology. Mammalian target of rapamycin (mTOR) drugs such as everolimus and temsirolimus pivotal trials emphasize experiences in the setting of prior treatment or high-risk features. Interferon and interleukin 2 also are part of the treatment algorithms. METHODS: The results of pivotal trials and the underlying context for the development of a cogent, cohesive treatment plan for an individual are reviewed, touching on decision points such as nephrectomy, metastasectomy, and medical initiation and discontinuation time points. RESULTS: To the extent that these drug therapies are essential for achieving best outcomes for patients, these pivotal trial results and associated guidelines exist within a multidimensional, multidisciplinary context of many other disease features, comorbid features, and non-drug treatment decisions. Other dimensions include investigational targeted therapies, patient selection strategies, surgical strategies, and immunotherapies, some of which are in active development. CONCLUSIONS: Clinicians should work toward the best use of drug sequencing and selection strategies based on core data derived from prospective randomized trials. To address individual patient needs, they should also recognize and emphasize individualized goals, to the extent that these are different from issues that were directly addressed in the trials. PMID- 23811707 TI - Infections in oncology: urosepsis due to fluoroquinolone-resistant Escherichia coli after ultrasonographic-guided transrectal implantation of fiducial markers. PMID- 23811708 TI - The role of doctors in the slave trade during the fourteenth and fifteenth centuries within the Kingdom of Valencia (Crown of Aragon). AB - Slavery had become increasingly widespread throughout the entire Mediterranean region during the late Middle Ages. At the same time, a new form of medicine (based upon the Galenism to which the universities gave voice), together with the practice thereof and its practitioners, had gained ground. Detailed evidence from the Kingdom of Valencia enables us to study these two topics, namely slavery and the new medicine. This article illustrates how doctors came to play a highly active role in the slave trade through the assistance they provided in preventing and rectifying any instances of fraud therein. PMID- 23811709 TI - Negotiating technologies in surgery: the controversy about surgical gloves in the 1890s. AB - This article examines the controversial discussions about surgical gloves in the German-language countries in the 1890s. Analyzing the controversy as a contradiction between two important strategies of modern surgery, manual control and aseptic control, it looks at the various ways surgeons dealt with the conflict. Most important, they tried to resolve the problem by designing gloves that reconciled the two conflicting control strategies. This perspective helps to better understand the lengthy process of negotiation and the detailed discussions in the decades before surgical gloves became a standard element of modern operating equipment. PMID- 23811710 TI - Divining and knowing: Karl Sudhoff's historical method. AB - This article investigates the historical method of Karl Sudhoff (1853- 1938), Germany's first professor of medical history. It argues that in order to understand his ideas more fully, we need to step outside the historiography of medical history and assess his methodology in relation to the norms and ideals of German academic history writing in general. The article demonstrates that the philology-based "critical method" of Leopold von Ranke (1795-1886) was central to Sudhoff's methodological thinking. It investigates the underlying philosophical and epistemological assumptions of Ranke's method, which tend to be less appreciated than his overt empiricism and explores how Sudhoff applied these to the new professionalizing subdiscipline of the history of medicine. The article argues that Sudhoff's concerns with the methodology of history, which involved a particular conception of the relationship between the human sciences and the medical sciences, offers compelling addresses to our times. PMID- 23811711 TI - Repositioning the patient: patient organizations, consumerism, and autonomy in Britain during the 1960s and 1970s. AB - This article explores how and why the patient came to be repositioned as a political actor within British health care during the 1960s and 1970s. Focusing on the role played by patient organizations, it is suggested that the repositioning of the patient needs to be seen in the light of growing demands for greater patient autonomy and the application of consumerist principles to health. Examining the activities of two patient groups-the National Association for the Welfare of Children in Hospital (NAWCH) and the Patients Association (PA) indicates that while such groups undoubtedly placed more emphasis on individual autonomy, collective concerns did not entirely fall away. The voices of patients, as well as the patient, continued to matter within British health care. PMID- 23811712 TI - Psychiatry, authoritarianism, and revolution: the politics of mental illness during military dictatorships in Argentina, 1966-1983. AB - From 1966 to 1983, Argentina underwent a period of political radicalization as fascist regimes used terror to control its citizens and leftist guerrillas resorted to violence to spark revolution. During this politically volatile period, psychiatry transformed from an apolitical clinical specialty into an ideological tool used for both leftist resistance and military oppression. The largest psychiatric organization at the time, the Federacion Argentina de Psiquiatras (FAP), became the center for a new politically committed brand of psychiatry in Argentina that united psychoanalysis and community psychiatry with Marxist theory. Though the military targeted and eventually dismantled the FAP and its leftist brand of psychoanalysis and community psychiatry, sectors of the government also paradoxically appropriated and reframed community-based psychiatric perspectives to pathologize leftist subversion and advance their own conservative ideology. PMID- 23811715 TI - Potential 129Xe-NMR biosensors based on secondary and tertiary complexes of a water-soluble pillar[5]arene derivative. AB - We report on the first secondary and tertiary complexes of the pillar[5]arene derivative with xenon in water. We show that the chemical shift of the encapsulated xenon provides information on the type of the formed complex suggesting that has the potential to be used as a platform for NMR biosensors. PMID- 23811716 TI - Active structuring of colloidal armour on liquid drops. AB - Adsorption and assembly of colloidal particles at the surface of liquid droplets are at the base of particle-stabilized emulsions and templating. Here we report that electrohydrodynamic and electro-rheological effects in leaky-dielectric liquid drops can be used to structure and dynamically control colloidal particle assemblies at drop surfaces, including electric-field-assisted convective assembly of jammed colloidal 'ribbons', electro-rheological colloidal chains confined to a two-dimensional surface and spinning colloidal domains on that surface. In addition, we demonstrate the size control of 'pupil'-like openings in colloidal shells. We anticipate that electric field manipulation of colloids in leaky dielectrics can lead to new routes of colloidosome assembly and design for 'smart armoured' droplets. PMID- 23811717 TI - Controlling the morphology and pore size of mesostructured silica nanoparticles: the role of the iron oxidation state. AB - We demonstrate morphology and pore size dependence of silica nanoparticles (SNPs) synthesized via control of the iron oxidation state. In the absence of any Fe species, only spherical SNPs are produced, whereas in the presence of Fe3+ and Fe2+ ions, SNPs with rod-like and nanosheet morphologies, respectively, are formed. The average pore size increases from 1.7 nm in the absence of iron to 3.2 and 5.9 nm as Fe3+ and Fe2+, respectively, were used during the synthesis. Both samples of SNPs synthesized in the presence of Fe2+ and Fe3+ have 0.2 wt% of tetrahedral iron in the silica framework, whereas most of the iron is in the silica extraframework, as verified by Mossbauer spectroscopy, UV-vis diffuse reflectance, FTIR, XRD data and TPR analysis. These Fe2+ and Fe3+ cations play a fundamental role in controlling these properties because they change the curvature and the surface charge density of CTAB micelles, thus favoring the spherical to rod-like transition. The rod-like shape was retained in Fe containing samples, whereas a nanosheet-like morphology was produced in Fe2+ containing samples due to the breakage of silica walls during the thermal treatment to remove the template. The control of the textural properties is interesting to allow the fabrication of selective photocatalysts for oxidation of different organic substrates. PMID- 23811718 TI - Risk of surgery for subacromial impingement syndrome in relation to neck-shoulder complaints and occupational biomechanical exposures: a longitudinal study. AB - OBJECTIVES: The aim of this longitudinal study was to evaluate the risk of surgery for subacromial impingement syndrome (SIS) in relation to neck-shoulder complaints and occupational biomechanical shoulder exposures. METHODS: The study was based on the Musculoskeletal Research Database at the Danish Ramazzini Centre. We linked baseline questionnaire information from 1993-2004 on neck shoulder complaints, job titles, psychosocial work factors, body mass index, and smoking with register information on first-time surgery for SIS from 1996-2008. Biomechanical exposure measures were obtained from a job exposure matrix based on expert judgment. We applied multivariable Cox regression. RESULTS: During 280 125 person-years of follow-up among 37 402 persons, 557 first-time operations for SIS occurred. Crude surgery rates increased from 1.1 to 2.5 per 1000 person-years with increasing shoulder load. Using no neck-shoulder complaints and low shoulder load at baseline as a reference, no neck-shoulder complaints and high shoulder load showed an adjusted hazard ratio (HR(adj)) of 2.55 [95% confidence interval (95% CI) 1.59-4.09], while neck-shoulder complaints in combination with high shoulder load showed an HR(adj) of 4.52 (95% CI 2.87-7.13). Subanalyses based on 18 856 persons showed an HR(adj) of 5.40 (95% CI 2.88-10.11) for complaints located specifically in the shoulder in combination with high shoulder load. CONCLUSIONS: Based on these findings, persons with neck-shoulder and especially shoulder complaints in combination with high shoulder load seem an obvious target group for interventions aimed at reducing exposures to prevent surgery for SIS. PMID- 23811719 TI - Implant diameter and length influence on survival: interim results during the first 2 years of function of implants by a single manufacturer. AB - OBJECTIVES: The aim of the present study was to evaluate the influence of implant length and diameter on implant survival. METHODS: A retrospective cohort of 787 consecutive patients from 2 private practices between the years 2008 and 2011 had been evaluated. Patient demographics, site and implant characteristics, and time of follow-up were recorded from the medical files. RESULTS: Overall, 3043 implants were investigated. Overall survival rate was 98.7% with 39 implant failures recorded. Survival rates for narrow- (<3.75 mm), regular- (3.75-5 mm), and wide- (>5 mm) diameter implants were 98.2%, 98.7%, and 98.5%, respectively (P = 0.89). Survival rates of short (<10 mm) and regular (10 mm and above) implants were 97% and 98.7%, respectively (P = 0.22). CONCLUSIONS: Implant length and diameter were not found to be significant factors affecting implant survival during the first 2 years of function in the present investigation of this specific implant system by a single manufacturer. Further long-term follow-up studies are warranted because 2-years are only interim short-term results when dealing with dental implants. PMID- 23811720 TI - The correlation between crestal bone resorption and implant stability during healing period using resonance frequency analysis. AB - PURPOSE: To detect the correlation between crestal bone resorption and implant stability during healing period using resonance frequency analysis (RFA). MATERIALS AND METHODS: Twenty-two International Team for Implantology Straumann implants were placed in the posterior maxilla or mandible in 9 patients. RFA reading was taken immediately after implant placement. Periapical radiographs were taken, and the distance from the shoulder of the healing cap to the first bone-implant contact was measured, and the average mesial and distal distances were taken. Patients were followed up at 6 and 12 weeks for data collection. RESULTS: At 6 weeks, the correlation between crestal bone resorption and implant stability was significant (Spearman correlation test, P < 0.05) and negative correlation coefficient (r) was -0.522. At 12 weeks, the correlation between crestal bone resorption and implant stability was not significant (Spearman correlation test, P > 0.05) and negative correlation coefficient (r) was -0.119. CONCLUSIONS: There was a significant negative correlation between the crestal bone resorption and implant stability at 6 weeks, whereas the negative correlations between the crestal bone resorption and implant stability at 12 weeks were nonsignificant. PMID- 23811721 TI - Failure analysis of an abutment fracture on single implant restoration. AB - PURPOSE: This study evaluated the mechanism of an abutment fracture by means of a case-based finite element (FE) stress analysis. MATERIALS AND METHODS: A patient presented with a complaint of fracture of an implant-retained single posterior restoration that had been in place for 6 years. The retrieved restoration was examined on the original working cast and subjected to microscopic observation for fracture surface analysis. A case-based FE analysis was conducted to detect the location and magnitude of stress concentration in the implant structures. RESULTS: The fracture occurred at the concave neck of the abutment, with an evidence of fatigue fracture on the titanium surface. Ratchet marks were shown at the distal lingual edge, indicating that the crack proceeded from distolingual to mesial direction. The highest maximum tensile stress at the distolingual concave neck of the abutment was shown when the load was directed on the internal and external surfaces of the mesial buccal cusp. CONCLUSIONS: It is suggested that an offset loading because of the cantilever structure caused a high tensile stress on the distolingual edge, resulting in the fatigue fracture of the abutment. PMID- 23811722 TI - Alveolar distraction osteogenesis in posterior atrophic mandible: a case report on a new technical approach. AB - PURPOSE: To report a clinical case of dental implant rehabilitation of an atrophic posterior mandible with the usage of a new alveolar distraction protocol. MATERIALS AND METHODS: A posterior atrophic mandible was treated with distraction osteogenesis; after the first phase of latency (10 days), the activation phase (24 days), and the consolidation phase (30 days), the distractor was removed, and 2 implants were placed; 4 months thereafter, the fixtures were provisionally loaded. RESULTS: No complications were recorded during the treatment. At the end of the activation phase, a mean of 5 mm of vertical bone augmentation was obtained, and it allowed the placement of two 10-mm long fixtures. No periimplant bone resorption was detected at the time of definitive prosthetic loading. CONCLUSIONS: The proposed protocol secured a sound prosthetic rehabilitation on an otherwise atrophied posterior mandible so as to avoid grafting procedures. PMID- 23811723 TI - Emodin induces human T cell apoptosis in vitro by ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction. AB - AIM: To elucidate the molecular mechanisms underlying the immunosuppressive effects of emodin isolated from Rheum palmatum L. METHODS: Human T cells were isolated from the peripheral venous blood of 10 healthy adult donors. Cell viability was analyzed with MTT assay. AO/EB and Annexin V/PI staining and DNA damage assay were used to detect cell apoptosis. Fluorescence staining was used to detect the levels of ROS, the mitochondrial membrane potential and intracellular Ca(2+). Colorimetry was used to detect the levels of MDA and total SOD and GSH/GSSG ratio. The expression and activity of caspase-3, -4, and -9 were detected with Western blotting and a fluorometric assay. Western blotting was also used to detect the expression of Bcl-2, Bax, cytochrome C, and endoplasmic reticulum (ER) markers. RESULTS: Emodin (1, 10, and 100 MUmol/L) inhibited the growth of human T cells and induced apoptosis in dose- and time dependent manners. Emodin triggered ER stress and significantly elevated intracellular free Ca(2+) in human T cells. It also disrupted mitochondrial membrane potential, and increased cytosolic level of cytochrome C, and the levels of activated cleavage fragments of caspase-3, -4, and -9 in human T cells. Furthermore, emodin significantly increased the levels of ROS and MDA, inhibited both SOD level and GSH/GSSG ratio in human T cells, whereas co-incubation with the ROS scavenger N acetylcysteine (NAC, 20 MUmol/L) almost completely blocked emodin-induced ER stress and mitochondrial dysfunction in human T cells, and decreased the caspase cascade-mediated apoptosis. CONCLUSION: Emodin exerts immunosuppressive actions at least partly by inducing apoptosis of human T cells, which is triggered by ROS mediated ER stress and mitochondrial dysfunction. PMID- 23811724 TI - 6-Shogaol, an active compound of ginger, protects dopaminergic neurons in Parkinson's disease models via anti-neuroinflammation. AB - AIM: 6-Shogaol [1-(4-hydroxy-methoxyphenyl)-4-decen-one], a pungent compound isolated from ginger, has shown various neurobiological and anti-inflammatory effects. The aim of this study was to examine the effects of 6-shogaol on neuroinflammatory-induced damage of dopaminergic (DA) neurons in Parkinson's disease (PD) models. METHODS: Cultured rat mesencephalic cells were treated with 6-shogaol (0.001 and 0.01 MUmol/L) for 1 h, then with MPP(+)(10 MUmol/L) for another 23 h. The levels of TNF-alpha and NO in medium were analyzed spectrophotometrically. C57/BL mice were administered 6-shogaol (10 mg.kg(-1).d( 1), po) for 3 d, and then MPTP (30 mg/kg, ip) for 5 d. Seven days after the last MPTP injection, behavioral testings were performed. The levels of tyrosine hydroxylase (TH) and macrophage antigen (MAC)-1 were determined with immunohistochemistry. The expression of iNOS and COX-2 was measured using RT PCR. RESULTS: In MPP(+)-treated rat mesencephalic cultures, 6-shogaol significantly increased the number of TH-IR neurons and suppressed TNF-alpha and NO levels. In C57/BL mice, treatment with 6-shogaol reversed MPTP-induced changes in motor coordination and bradykinesia. Furthermore, 6-shogaol reversed MPTP-induced reductions in TH-positive cell number in the substantia nigra pars compacta (SNpc) and TH-IR fiber intensity in stratum (ST). Moreover, 6-shogaol significantly inhibited the MPTP-induced microglial activation and increases in the levels of TNF-alpha, NO, iNOS, and COX-2 in both SNpc and ST. CONCLUSION: 6 Shogaol exerts neuroprotective effects on DA neurons in in vitro and in vivo PD models. PMID- 23811725 TI - In vivo and real-time monitoring of secondary metabolites of living organisms by mass spectrometry. AB - Secondary metabolites are compounds that are important for the survival and propagation of animals and plants. Our current understanding on the roles and secretion mechanism of secondary metabolites is limited by the existing techniques that typically cannot provide transient and dynamic information about the metabolic processes. In this manuscript, by detecting venoms secreted by living scorpion and toad upon attack and variation of alkaloids in living Catharanthus roseus upon stimulation, which represent three different sampling methods for living organisms, we demonstrated that in vivo and real-time monitoring of secondary metabolites released from living animals and plants could be readily achieved by using field-induced direct ionization mass spectrometry. PMID- 23811726 TI - [Dimitrij Oscarovic Ott (1855-1929) "Ventroscopy" : His contribution to development of laparoscopy]. AB - Dimitri Oscarovic Ott (1855-1929) can be justified in calling himself one of the true pioneers of laparoscopy and especially of natural orifices transluminal endoscopic surgery (NOTES). As early as 1901 he performed abdominal examinations via a transvaginal access and called this procedure ventroscopy. The publication of his first results and a description of the method and equipment were released in 1902. He was one of the pioneers of present day laparoscopy in addition to Georg Kelling (1866-1945) and Hans Christian Jacobaeus (1879-1937).While Kelling published and presented his first results of animal trials in 1901 and 9 years later in 1910 Jacobaeus performed his first interventions on human beings, Ott had already used the new method developed by him in clinical practice since 1901. Through a single incision in the cul-de-sac and using a head lamp system similar to reflector lamps used by otolaryngologists, he inspected the abdominal cavity with the aid of a gynecological speculum. The patient was positioned in an extreme head-down position and for better lighting he used an additional light source which was connected to the speculum. Even today Prof. Ott is a legend in Russia and especially in St. Petersburg. He was director of the National Institute of Obstetrics and personal physician to Tsarina Aleksandra Fedorovna (1874-1918). He is regarded as the father of the Russian school of obstetrics and gynecology as well as founder of endoscopic surgery and laparoscopy in Russia. PMID- 23811727 TI - Periesophageal vagal nerve injury complicating atrial fibrillation ablation. PMID- 23811728 TI - Force coordination during bimanual task performance in Parkinson's disease. AB - We investigated within- and between-hand grip-load force coordination in medically managed Parkinson's disease (PD) patients during bimanual tasks involving realistic actions. Increased grip force production and evidence of bradykinesia were expected in PD patients. Force coordination indices were also expected to be reduced in PD, due to impaired anticipatory force control. Increased grip force, bradykinesia, and abnormal load force production were exhibited in PD patients as compared to healthy controls. Indices of between-hand load force coordination, but not between-hand grip force coordination, were reduced in PD patients. Discrepancies in the strength of within-hand force coordination with respect to hand action were also noted in PD patients. Increased grip force production, in conjunction with abnormal load force production, may result in reduced fine motor control in PD patients during daily activities. Integrating quantitative analyses of realistic motor function in clinic may assist clinicians in evaluating the effectiveness of medical intervention in PD patients. PMID- 23811730 TI - Outsider interference: no role for motor lateralization in determining the strength of avoidance responses during reaching. AB - When reaches are performed toward target objects, the presence of other non target objects influences kinematic parameters of the reach. A typical observation has been that non-targets positioned ipsilaterally to the acting limb interfere more with the trajectory of the hand than contralateral non-targets. Here, we investigate whether this effect is mediated by motor lateralization or by the relative positioning of the objects with reference to the acting limb. Participants were asked to perform reaches toward physical target objects with their preferred or non-preferred hands while physical non-targets were present in different possible positions in the workspace. We tested both left-handers and right-handers. Our results show that a participant's handedness does not influence reaching behavior in an obstacle avoidance paradigm. Furthermore, no statistically significant differences between the use of the preferred and non preferred hand were observed on the kinematic parameters of the reaches. We found evidence that non-targets positioned on the outside of the reaching limb influenced the reaching behavior more strongly than non-targets on the inside. Moreover, the type of movement also appeared to play a role, as reaches that crossed the workspace had a stronger effect on avoidance behavior than reaches that were 'uncrossed.' We interpret these results as support for the hypothesis that the avoidance response is determined by keeping a preferred distance between the acting limb in all stages of its reach toward the target and the non-target position. This process is not biased by hand dominance or the hand preference of the actor. PMID- 23811729 TI - Action semantics and movement characteristics engage distinct processing streams during the observation of tool use. AB - The cortical motor system follows a modular organization in which different features of executed movements are supported by distinct streams. Accordingly, different levels of action recognition, such as movement characteristics or action semantics may be processed within distinct networks. The present study aimed to differentiate areas related to the analysis of action features involving semantic knowledge from regions concerned with the evaluation of movement characteristics determined by structural object properties. To this end, the assessment of (i) tool-associated actions in relation to semantically, but not functionally inappropriate recipients (factor "Semantics"), and the evaluation of (ii) tool-associated movements performed with awkward versus correct hand postures (factor "Hand") were experimentally manipulated in an fMRI study with an event-related 2 * 2 factorial design. The videos used as stimuli displayed actions performed with the right hand in third-person perspective. Conjunction analysis of all four experimental conditions showed that observing videos depicting tool-related actions compared to rest was associated with widespread bilateral activity within the frontal lobes, inferior and superior parietal lobules, parts of the temporal lobes, as well as the occipital lobes. Viewing actions executed with incorrect compared to correct hand postures (factor "Hand") elicited significantly more activity within right primary sensory cortex (Brodmann area 2) and superior parietal lobule. Conversely, tool-associated actions displayed after semantically incorrect compared to correct recipients elicited higher activation within a left-lateralized network comprising the ventro-lateral prefrontal cortex (VLPFC), parts of the intraparietal sulcus and the angular gyrus (AG), as well as the supplementary motor area (SMA) and pre SMA. Probabilistic diffusion tensor imaging-based tractography revealed two distinct fiber connections between AG and the frontal activation: A dorsal pathway via the superior longitudinal fascicle to the caudal part of VLPFC and a ventral pathway reaching the more rostral parts of VLPFC via the extreme capsule. The task-dependent relative modulation of activity within these brain networks composed of activated cortical areas connected by specific white matter tracts may indicate that the assessment of semantic action features relies on both dorso ventral and ventral processing streams, whereas the analysis of hand postures with respect to objects depends on areas within the dorso-dorsal stream. PMID- 23811731 TI - Imagined actions in multiple sclerosis patients: evidence of decline in motor cognitive prediction. AB - Motor imagery is a mental process during which subjects internally simulate a movement without any motor output. Mental and actual movement durations are similar in healthy adults (isochrony) while temporal discrepancies (anisochrony) could be an expression of neurological deficits on action representation. It is unclear whether patients with multiple sclerosis (PwMS) preserve the capacity to simulate their own movements. This study investigates the ability of PwMS to predict their own actions by comparing temporal features of dominant and non dominant actual and mental actions. Fourteen PwMS and nineteen healthy subjects (HS) were asked to execute and to imagine pointing arm movements among four pairs of targets of different sizes. Task duration was calculated for both actual and mental movements by an optoelectronic device. Results showed temporal consistency and target-by-target size modulation in actual movements through the four cycles for both groups with significantly longer actual and mental movement durations in PwMS with respect to HS. An index of performance (IP) was used to examine actual/mental isochrony properties in the two groups. Statistical analysis on IP showed in PwMS significantly longer actual movement durations with respect to mental movement durations (anisochrony), more relevant for the non-dominant than dominant arm. Mental prediction of motor actions is not well preserved in MS where motor and cognitive functional changes are present. Differences in performing imagined task with dominant and non-dominant arm could be related to increased cognitive effort required for performing non-dominant movements. PMID- 23811732 TI - The context dependence of grasping movements: an evaluation of possible reasons. AB - Laboratory experiments typically examine grasping movements as isolated motor acts executed for their own sake. In real life, however, grasping is often part of complex and meaningful movement sequences. We have shown before that grasping characteristics differ substantially between these two behavioral contexts and that these differences can be reduced to five orthogonal factors. Now we evaluate the role of focused attention, movement speed and/or embedding in other behavior as possible causes for the observed context differences. Subjects grasped in three variants, which deviated from our standard laboratory condition in one of the above three ways: In one, subjects' attention was withdrawn from grasping by a concurrent visual memory task; in a second, subjects were pre-trained to grasp as slowly as in our standard everyday-like condition; and in the third variant, grasping was part of a more complex behavioral sequence. Grasping kinematics, grip forces and eye movements were registered across 20 repetitions of each variant, the outcome was normalized with respect to our standard laboratory and standard everyday-like conditions, and the normalized data were reduced to the underlying orthogonal factors. We found that the three variants of the laboratory condition had a non-uniform effect on grasping: decreasing the difference to the standard everyday-like condition for some factors, increasing it for others and leaving it unchanged for yet others. We interpret this finding as evidence that none of the three variants successfully reduced the difference between standard laboratory and standard everyday-like context; differences between contexts are therefore probably related to factors other than focusing of attention, movement speed and embedding in other behavior. PMID- 23811733 TI - Frontal cerebral oxygen response as an indicator of initial attention effort during perceptual learning. AB - Perceptual learning is critical in many settings. In the present study, we investigated the role of individual differences in attention effort in perceptual learning by having participants learn to detect rare cryptic figures. We employed both functional near-infrared spectroscopy measures of frontal cortical activity and self-reports of pre-task motivation in order to assess individual differences in attention effort. We also manipulated performance feedback and the amount of background information provided to the participants regarding the task. Twelve men and 28 women participated in the experiment. Performance metrics were indicative of perceptual learning occurring. Overall performance on the task was correlated significantly with pre-task levels of self-reported motivation and the rate of learning was correlated with initial oxygen response in the frontal cortex. The initial spike in frontal oxygen response declined with time on task, perhaps due to shifts towards automaticity. The results suggest perceptual learning is influenced by individual differences in attention effort. PMID- 23811736 TI - Role of peripheral vision in rapid perturbation-evoked reach-to-grasp reactions. AB - Onset and execution of compensatory reaches are faster than the most rapid voluntary reaches. With onset latencies near 100 ms, it is proposed that initial control of compensatory reaches cannot rely on visual information obtained after perturbation onset; rather, they rely on a visuospatial map acquired prior to instability. In natural conditions, it is not practical to direct gaze toward every potential support surface in preparation for a perturbation, suggesting that peripheral vision may be uniquely important. This study aimed to determine whether visuospatial mapping achieved using only peripheral visual information could be used to control reach-to-grasp reactions. Participants sat in an unstable chair. Whole body perturbations were used to evoke rapid reach-to-grasp reactions. A handle was positioned at midline or to the right of the participant. Gaze was directed toward the center or right to view the handle in peripheral or central visual fields. Electromyographic and kinematic data were recorded. Peripheral information acquired prior to perturbation was sufficient for successful execution of reach-to-grasp without delay. Differences in reach kinematics, however, did exist between vision conditions (e.g., maximum lateral wrist displacement and magnitude of hand overshoot relative to the handle were greater for peripheral vs. central vision). Handle location led to target specific differences in initial muscle recruitment revealing information acquired prior to perturbation were used to guide initial limb trajectory. Results reveal the capacity to rely on a visuospatial map constructed from peripheral visual information for compensatory reaching but also highlight limitations leading to more conservative reach trajectories. PMID- 23811735 TI - Functional significance of serotonin receptor dimerization. AB - The original model of G-protein activation by a single G-protein-coupled receptor (GPCR) is giving way to a new model, wherein two protomers of a GPCR dimer interact with a single G-protein. This article will review the evidence suggesting that 5-HT receptors form dimers/oligomers and will compare the findings with the results obtained from the studies with other biogenic amine receptors. Topics to be covered include the origin or biogenesis of dimer formation, potential dimer interface(s), and oligomer size (dimer vs. tetramer or higher order). The functional significance will be discussed in terms of G protein activation following ligand binding to one or two protomers in a dimeric structure, the formation of heterodimers, and the development of bivalent ligands. PMID- 23811734 TI - The serotonergic system in motor and non-motor manifestations of Parkinson's disease. AB - The understanding of Parkinson's disease (PD) classically revolves around dopamine depletion within the striatum. However, PD is a multi-systemic disease in which extra-dopaminergic systems are affected. The serotonergic (5-HT) system is one of these and has been extensively studied in PD. Although the 5-HT system uses one transporter (SERT) and 14 receptor sub-types, most of the studies in PD have focussed on SERT and serotonergic type 1A and 2A receptors (5-HT1A and 5 HT2A). Post-mortem autoradiographic binding studies and in vivo imaging studies have suggested an involvement of the 5-HT system in PD-related anxiety, depression, psychosis and L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia. Pre-clinical and clinical pharmacological studies have shown that SERT blockade might effectively alleviate depression and dyskinesia and, more recently, might exert disease-modifying effects. Enhancing the physiological activity of 5-HT1A receptors with 5-HT1A agonists might alleviate anxiety, dyskinesia and tremor, although a deleterious effect on the anti-parkinsonian efficacy of L-DOPA may ultimately limit the use of this class of compounds. Enhanced 5-HT2A-mediated neurotransmission has been associated with depression, dyskinesia, psychosis and tremor. The current article critically reviews studies assessing the SERT, as well as 5-HT1A and 5-HT2A receptors in idiopathic PD and animal models of PD, and discusses unmet challenges to effectively treat manifestations of PD using SERT antagonists, 5-HT1A agonists and 5-HT2A antagonists. PMID- 23811737 TI - Two-phase strategy of neural control for planar reaching movements: II--relation to spatiotemporal characteristics of movement trajectory. AB - In the companion paper utilizing a quantitative model of optimal motor coordination (Part I, Rand and Shimansky, in Exp Brain Res 225:55-73, 2013), we examined coordination between X and Y movement directions (XYC) during reaching movements performed under three prescribed speeds, two movement amplitudes, and two target sizes. The obtained results indicated that the central nervous system (CNS) utilizes a two-phase strategy, where the initial and the final phases correspond to lower and higher precision of information processing, respectively, for controlling goal-directed reach-type movements to optimize the total cost of task performance including the cost of neural computations. The present study investigates how two different well-known concepts used for describing movement performance relate to the concepts of optimal XYC and two-phase control strategy. First, it is examined to what extent XYC is equivalent to movement trajectory straightness. The data analysis results show that the variability, the movement trajectory's deviation from the straight line, increases with an increase in prescribed movement speed. In contrast, the dependence of XYC strength on movement speed is opposite (in total agreement with an assumption of task performance optimality), suggesting that XYC is a feature of much higher level of generality than trajectory straightness. Second, it is tested how well the ballistic and the corrective components described in the traditional concept of two-component model of movement performance match with the initial and the final phase of the two-phase control strategy, respectively. In fast reaching movements, the percentage of trials with secondary corrective submovement was smaller under larger-target shorter-distance conditions. In slower reaching movements, meaningful parsing was impossible due to massive fluctuations in the kinematic profile throughout the movement. Thus, the parsing points determined by the conventional submovement analysis did not consistently reflect separation between the ballistic and error-corrective components. In contrast to the traditional concept of two-component movement performance, the concept of two phase control strategy is applicable to a wide variety of experimental conditions. PMID- 23811738 TI - A guide to performing difficult bimanual coordination tasks: just follow the yellow brick road. AB - Both discrete and continuous bimanual coordination patterns are difficult to effectively perform when the two limbs are required to perform different movements patterns, move at different velocities and/or move different amplitudes unless some form of integrated feedback is provided. The purpose of the present experiment was to determine the degree to which a complex bimanual coordination pattern could be performed when integrated feedback and movement template are provided. The complex bimanual coordination pattern involved reciprocal movements of the two limbs under different difficulty requirements. As defined by Fitts' index of difficulty (ID), the left arm (ID = 3, A = 16 degrees , W = 4 degrees ) task was of lower difficulty than the right arm task (ID = 5, A = 32 degrees , W = 2 degrees ). Note that the left and right limb movements are also different in terms of movement time, movement velocity, accuracy requirements and amplitude as well as one movement was continuous and the other intermittent. Participants were provided 2 blocks of 9 trials in the bimanual condition (30 s/trial). Following the bimanual phase, participants performed two unimanual test trials-one with each limb. The results demonstrated that the performance for each limb in the bimanual condition was similar to the performance for the same limb and conditions in the unimanual control conditions. The similarity was indicated by the same movement speed, movement structure, endpoint variability and hit rates for the bimanual and unimanual conditions. The results support our hypothesis that people can overcome the intrinsic difficulties associated with performing complex bimanual coordination patterns when provided appropriate perceptual information feedback that allows them to detect and correct coordination errors. PMID- 23811739 TI - Instruction-dependent modulation of the long-latency stretch reflex is associated with indicators of startle. AB - Long-latency responses elicited by postural perturbation are modulated by how a subject is instructed to respond to the perturbation, yet the neural pathways responsible for this modulation remain unclear. The goal of this study was to determine whether instruction-dependent modulation is associated with activity in brainstem pathways contributing to startle. Our hypothesis was that elbow perturbations can evoked startle, indicated by activity in the sternocleidomastoid muscle (SCM). Perturbation responses were compared to those elicited by a loud acoustic stimulus, known to elicit startle. Postural perturbations and startling acoustic stimuli both evoked SCM activity, but only when a ballistic elbow extension movement was planned. Both stimuli triggered SCM activity with the same probability. When SCM activity was present, there was an associated early onset of triceps electromyographic (EMG), as required for the planned movement. This early EMG onset occurred at a time often attributed to long-latency stretch reflexes (75-100 ms). The nature of the perturbation triggered EMG (excitatory or inhibitory) was independent of the perturbation direction (flexion or extension) indicating that it was not a feedback response appropriate for returning the limb to its original position. The net EMG response to perturbations delivered after a movement had been planned could be explained as the sum of a stretch reflex opposing the perturbation and a startle-evoked response associated with the prepared movement. These results demonstrate that rapid perturbations can trigger early release of a planned ballistic movement, and that this release is associated with activity in the brainstem pathways contributing to startle reflexes. PMID- 23811740 TI - Pharmacokinetics and pharmacodynamics of oral cephalexin in children with osteoarticular infections. AB - BACKGROUND: Osteoarticular infections lead to significant morbidity in children. Cephalexin has in vitro activity against methicillin-susceptible Staphylococcus aureus, a predominant pathogen in osteoarticular infection. However, cephalexin pharmacokinetics (PK) and pharmacodynamics (PD) are poorly described in children. This study described cephalexin PK in children treated for osteoarticular infection and assessed the proportion of children achieving surrogate PK/PD target for efficacy in methicillin-susceptible S. aureus infection. METHODS: Children with osteoarticular infection, 1 to 18 years of age, were eligible for this study if they were receiving oral cephalexin per standard of care. PK plasma samples were collected at specified times after multiple doses. PK parameters were estimated using noncompartmental analysis. PK/PD target for efficacy was calculated using the child's PK parameters, minimum inhibitory concentration (MIC) of the isolate when available and previously described MIC of 2 and 4 mg/L. RESULTS: Twelve children were enrolled and PK profiles were obtained from 11 of them. Median age was 7 years, and median cephalexin dose was 40 mg/kg/dose every 8 hours. Median apparent oral clearance, apparent oral volume of distribution and elimination half-life (T1/2) were 0.29 L/h/kg, 0.44 L/kg and 1.1 h, respectively. Time above MIC (T>MIC) was greater than 40% of the dosing interval in 100%, 90% and 80% of the children when MICs were 0.25, 2 and 4 mg/L, respectively. CONCLUSIONS: Oral cephalexin achieved optimal plasma exposure and was well tolerated in children with osteoarticular infection. Correlation between osteoarticular infection clinical outcome and PK/PD parameters needs further evaluation. PMID- 23811741 TI - A comparison of characteristics and outcomes in severe human metapneumovirus and respiratory syncytial virus infections in children treated in an intensive care unit. AB - BACKGROUND: Human metapneumovirus (HMPV) and respiratory syncytial virus (RSV) are among the leading causes of respiratory tract infections requiring admission to the pediatric intensive care unit (PICU). We evaluated the risk factors, clinical courses and outcomes of severe HMPV disease relative to severe RSV in children admitted to the PICU. METHODS: Retrospective chart review of children <=18 years old admitted to a tertiary PICU between October 2008 through July 2010 with acute respiratory tract infection and positive direct antigen stain or polymerase chain reaction for RSV or HMPV. RESULTS: One hundred thirty-three patients met inclusion criteria: 107 (80.5%) with RSV and 26 (19.5%) with HMPV. HMPV-infected patients were older than RSV children (3.4 vs. 1.5 years, P = 0.002) and more likely to have congenital heart disease (34.6% vs. 10.3%, P = 0.002). Although HMPV children required longer duration of mechanical ventilation (11 vs. 7 days, P = 0.01), there were no other differences in hospital course. HMPV patients were more likely to be discharged receiving inhaled steroids (53.8% vs. 30.8%, P = 0.03), but there were no differences in other outcome assessments. CONCLUSIONS: Children admitted to the PICU with HMPV are significantly older and more likely to have congenital heart disease than those with RSV. The course of illness was similar between the 2 groups, but HMPV-infected children were more likely to be discharged with inhaled steroid therapy. PMID- 23811742 TI - Hoarseness as a presenting sign in children with Kawasaki disease. AB - We noted that many patients with Kawasaki disease (KD) were hoarse at presentation and thus evaluated the frequency of hoarseness in children with acute KD. New onset hoarseness was noted in 86 of 287 (30%) prospectively assessed KD patients. Laryngoscopic examination of 3 hoarse patients with acute KD revealed edema and erythema of the larynx. PMID- 23811743 TI - Pharmacokinetics, safety and antiviral activity of fosamprenavir/ritonavir containing regimens in HIV-infected children aged 4 weeks to 2 years-48-week study data. AB - BACKGROUND: Pharmacokinetics, safety and antiviral activity of fosamprenavir (FPV) with ritonavir (RTV) twice daily were evaluated in HIV-1-infected infants and children 4 weeks to <2 years over 48 weeks. METHODS: Results from intensive pharmacokinetic sampling of subjects enrolled in single dose visits was used to determine individualized dosing for the first 6-10 subjects in each of 2 cohorts (4 weeks to <6 months, 6 months to <2 years); steady state pharmacokinetic data were then used to select the dosage regimen for the remaining subjects recruited to the cohort. Intensive pharmacokinetic sampling was performed at week 2 or 8; predose samples were collected every 4-12 weeks thereafter. Safety and plasma HIV 1 RNA were monitored every 4-12 weeks. RESULTS: Fifty-nine subjects received study medication. FPV 45 mg/kg boosted with RTV 7 to 10 mg/kg BID achieved average plasma amprenavir area under curve(0-tau) values 26% to 28% lower and Cmax similar to historical adult data for FPV/RTV 700/100 mg BID; amprenavir Ctau values were lower in the subjects <6 months of age. At week 48, 35 of 54 (65%) subjects had achieved plasma HIV-1 RNA <400 copies/mL and 33 of 54 (61%) had plasma HIV-1 RNA values <50 copies/mL. The most common adverse events were diarrhea, upper respiratory tract infection, gastroenteritis and otitis media. CONCLUSIONS: Final FPV/RTV dosing regimens achieved plasma amprenavir exposures comparable with those from regimens approved in adults, with the exception of trough exposures in the <6-month-old infants. The FPV/RTV regimens led to viral suppression in 61% of patients and were generally well tolerated. PMID- 23811744 TI - Pharmacokinetics and 48-week safety and antiviral activity of fosamprenavir containing regimens in HIV-infected 2- to 18-year-old children. AB - BACKGROUND: Pharmacokinetics, safety and antiviral activity of twice-daily fosamprenavir with or without ritonavir were evaluated in 2- to 18-year-old protease inhibitor-naive and -experienced HIV-1-infected children. METHODS: Serial pharmacokinetic samples were collected at week 2 and predose samples every 4-12 weeks. Safety and plasma HIV-1 RNA were monitored every 4-12 weeks. RESULTS: Twenty protease inhibitor-naive 2- to <6-year-old subjects received antiretroviral treatment including unboosted fosamprenavir twice-daily, whereas 89 protease inhibitor-naive and -experienced 2- to 18-year-old subjects received fosamprenavir/ritonavir-containing therapy twice-daily. Median fosamprenavir exposure was 891 days (range 15-1805 days), with 88% exposed >48 weeks. Twice daily doses of fosamprenavir/ritonavir 23/3 mg/kg in 2- to <6-year olds, 18/3 mg/kg in >=6-year olds and 700/100 mg in adolescents achieved plasma amprenavir exposures comparable with or higher than 700/100 mg twice-daily in adults while fosamprenavir 30 mg/kg twice-daily in 2- to <6-year olds led to exposures higher than 1400 mg twice-daily in adults. The proportion of subjects with HIV-1 RNA <400 copies/mL at week 48 was 60% for fosamprenavir and 53-74% for fosamprenavir/ritonavir (intent-to-treat [exposed], snapshot analysis). Median increases in absolute and relative (percentage) CD4 counts from baseline to week 48 occurred in both the fosamprenavir (340 cells/mm; 8%) and fosamprenavir/ritonavir group (190 cells/mm; 8%). The most common adverse events were vomiting, cough, and diarrhea; 18 subjects experienced serious adverse events, including 9 with suspected abacavir hypersensitivity. CONCLUSIONS: Fosamprenavir regimens administered to HIV-1-infected children aged 2-18 years were generally well-tolerated and provided sustained antiviral activity over 48 weeks, with plasma amprenavir exposures comparable with or higher than adults. PMID- 23811746 TI - Effectiveness of Haemophilus influenzae type b vaccines administered according to various schedules: systematic review and meta-analysis of observational data. AB - BACKGROUND: Conjugate vaccines against Haemophilus influenzae type b (Hib) are widely used. The full implications of Hib vaccination schedule for vaccine effectiveness (VE) are unclear. METHODS: We searched the literature for observational studies reporting the effectiveness of conjugate Hib vaccines administered according to different schedules. We summarized dose-specific VE estimates, where appropriate, using random effects meta-analysis. RESULTS: Thirty one eligible articles (reporting 30 studies conducted in 17 countries) were identified. Meta-analysis of case-control studies using community controls produced VE estimates against Hib meningitis of 55% (95% confidence interval: 2 80%, based on 3 studies), 96% (86-99%, 3 studies) and 96% (86-99%, 4 studies) after 1, 2 and 3 doses of vaccines other than the polyribosyl ribitol phosphate outer membrane protein vaccine. Estimates were similar using hospital controls. VE against invasive Hib disease in case-control studies was estimated as 59% (30 76%, 3 studies) and 97% (87-99%, 3 studies) for 1 and 3 doses (insufficient data were identified to estimate 2-dose VE). Point estimates from 2 studies suggested VE>90% after 1 dose of the polyribosyl ribitol phosphate outer membrane protein vaccine, but meta-analysis was not possible. Using data from 4 cohort studies, 3 dose VE was estimated as 94% (88-97%). There was some evidence that Hib vaccine was less effective when administered with acellular (rather than whole cell) pertussis vaccine. Weak evidence from 2 studies suggested that a booster confers some additional protection following full primary vaccination and may compensate for an incomplete primary series. CONCLUSIONS: Observational data suggest that >=2 doses of Hib vaccine are required for high effectiveness, but do not strongly favor any particular schedule. PMID- 23811745 TI - Invasive pneumococcal disease among children with and without sickle cell disease in the United States, 1998 to 2009. AB - BACKGROUND: Children with sickle cell disease (SCD) are at increased risk of illness and death from invasive pneumococcal disease (IPD). The introduction in 2000 of the 7-valent pneumococcal conjugate vaccine and penicillin prophylaxis for children with SCD has greatly reduced the incidence of IPD in this population. However, a recent report suggested an increase in cases of IPD in children with SCD. METHODS: Using data from Active Bacterial Core surveillance, we analyzed trends in hospitalizations, mortality and serotype among children with SCD compared with other children. We used neonatal screening data to estimate SCD population denominators for each Active Bacterial Core surveillance site. RESULTS: From 1998 to 2009, 3069 cases of IPD occurred among African American children less than 18 years of age in the Active Bacterial Core surveillance catchment area. Of these, 127 (4.1%) had SCD identified by medical chart review and 185 (6.0%) had 1 or more IPD risk factors, excluding SCD. Rates of IPD among children with SCD declined by 53% (1118 vs. 530 per 100,000) whereas the overall rates among African-American children declined by 74% (54 to 14 per 100,000). For all time periods, children with SCD and IPD were more likely to be hospitalized (84%-92% vs. 31%-56%) and more likely to die (6%-17% vs. 1%-2%) than children with no risk factors. CONCLUSIONS: Although the rate of IPD in children with SCD has dropped dramatically since 7-valent pneumococcal conjugate vaccine introduction, the rate of IPD in children with SCD remains higher than that of the general population of African-American children, pointing to the need for more effective prevention efforts to prevent IPD in children with SCD. PMID- 23811747 TI - Utility of surveillance cultures for antimicrobial resistant organisms in infants transferred to the neonatal intensive care unit. AB - BACKGROUND: Infections with antibiotic resistant organisms (AROs) are an important source of morbidity and mortality among infants hospitalized in the neonatal intensive care unit (NICU). To identify potential reservoirs of AROs in the NICU, active surveillance strategies have been adopted by many NICUs to detect infants colonized with AROs. However, the yield, risks, benefits and costs of different strategies have not been fully evaluated. METHODS: We conducted a retrospective study in 2 level III NICUs from 2004 to 2010 to investigate the yield of surveillance cultures obtained from infants transferred to the NICU from other hospitals. Cultures were processed for methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci and antibiotic-resistant gram-negative rods. Risk factors, selected outcomes and laboratory costs associated with ARO colonization were assessed. RESULTS: Among 1751 infants studied, the rate of colonization for methicillin-resistant S. aureus, vancomycin-resistant enterococci and antibiotic-resistant gram-negative rods was 3%, 1.7% and 1%, respectively. Age at transfer was the strongest predictor of ARO colonization; infants transferred at >= 7 days of life had 5.8 increased odds of ARO colonization compared with infants <7 days of age. Transferred infants who were colonized had similar rates of mortality, ARO infection and duration of hospitalization compared with those who were not colonized. The laboratory cost of surveillance cultures during the study period was $58,425. CONCLUSIONS: The rate of colonization with AROs at transfer was low particularly in infants <7 days old. Future studies should examine the safety of targeted surveillance strategies focused on older infants. PMID- 23811748 TI - Identification of nodal tissue in the living heart using rapid scanning fiber optics confocal microscopy and extracellular fluorophores. AB - BACKGROUND: Risks associated with pediatric reconstructive heart surgery include injury of the sinoatrial node (SAN) and atrioventricular node (AVN), requiring cardiac rhythm management using implantable pacemakers. These injuries are the result of difficulties in identifying nodal tissues intraoperatively. Here we describe an approach based on confocal microscopy and extracellular fluorophores to quantify tissue microstructure and identify nodal tissue. METHODS AND RESULTS: Using conventional 3-dimensional confocal microscopy we investigated the microstructural arrangement of SAN, AVN, and atrial working myocardium (AWM) in fixed rat heart. AWM exhibited a regular striated arrangement of the extracellular space. In contrast, SAN and AVN had an irregular, reticulated arrangement. AWM, SAN, and AVN tissues were beneath a thin surface layer of tissue that did not obstruct confocal microscopic imaging. Subsequently, we imaged tissues in living rat hearts with real-time fiber-optics confocal microscopy. Fiber-optics confocal microscopy images resembled images acquired with conventional confocal microscopy. We investigated spatial regularity of tissue microstructure from Fourier analysis and second-order image moments. Fourier analysis of fiber-optics confocal microscopy images showed that the spatial regularity of AWM was greater than that of nodal tissues (37.5 +/- 5.0% versus 24.3 +/- 3.9% for SAN and 23.8 +/- 3.7% for AVN; P<0.05). Similar differences of spatial regularities were revealed from second-order image moments (50.0 +/- 7.3% for AWM versus 29.3 +/- 6.7% for SAN and 27.3 +/- 5.5% for AVN; P<0.05). CONCLUSIONS: The study demonstrates feasibility of identifying nodal tissue in living heart using extracellular fluorophores and fiber-optics confocal microscopy. Application of the approach in pediatric reconstructive heart surgery may reduce risks of injuring nodal tissues. PMID- 23811749 TI - Coronary endothelium-dependent vasoreactivity and atheroma volume in subjects with stable, minimal angiographic disease versus non-ST-segment-elevation myocardial infarction: an intravascular ultrasound study. AB - BACKGROUND: Epicardial plaque burden and endothelial function are recognized predictors of coronary events. We aimed to investigate mechanistic relationships between atheroma volume and endothelial function in patients with non-ST-segment elevation myocardial infarction (NSTEMI) using intravascular ultrasound. METHODS AND RESULTS: In coronary vessels of patients with near-normal or minimal angiographic disease (n=23) and NSTEMI (n=24), intravascular ultrasound-derived measures (percent atheroma volume), arterial remodeling index, and segmental lumen volumes were performed in contiguous 5-mm epicardial segments. Repeat intravascular ultrasound imaging was performed after consecutive 5-minute intracoronary infusions (vehicle solution, 0.30 MUg/min and 0.60 MUg/min intracoronary salbutamol) to measure changes in segmental lumen volume (endothelium-dependent function). Male sex, diabetes mellitus, smoking, higher triglycerides, and lower high-density lipoprotein cholesterol were more prevalent in the NSTEMI group. Patients with NSTEMI demonstrated greater segmental percent atheroma volume (40.4 +/- 12 versus 27.5 +/- 14%, P<0.001), remodeling index (1.2 [1.0-1.5] versus 1.0 [0.9-1.0], P<0.001), and displayed less endothelium dependent vasomotion (% change segmental lumen volume: 2.1 +/- 0.89 versus 5.1 +/ 0.89%, P=0.02) compared to patients with minimal angiographic disease. No significant difference in endothelial function between both groups was observed when controlling for plaque burden. Multivariate analysis for change in segmental lumen volume identified percent atheroma volume (beta=-0.18, P=0.0004), high sensitivity C-reactive protein >2 mg/L (beta=-3.1, P=0.03), diabetes mellitus (beta=-6.9, P<0.0001), low-density lipoprotein cholesterol levels (beta=-0.04, P=0.01), and smoking (beta=-3.2, P=0.01) as independent associates. CONCLUSIONS: Although coronary endothelial vasoreactivity is blunted in the setting of NSTEMI, this is a reflection of the greater volume of atherosclerosis and cardiovascular risk factors. Thus, the relationship between coronary endothelium-dependent vasomotor reactivity and atheroma volume remains constant irrespective of the nature of the clinical presentation. PMID- 23811750 TI - Outcome prediction by quantitative right ventricular function assessment in 575 subjects evaluated for pulmonary hypertension. AB - BACKGROUND: Although right ventricular (RV) dysfunction is a major determinant of outcome in patients with pulmonary hypertension (PH), the optimal measure of RV function is poorly defined. We hypothesized that RV strain measured by speckle tracking echocardiography predicts outcome in PH over a broad range of pulmonary pressures. METHODS AND RESULTS: Prospective peak RV longitudinal systolic strain measurement was performed on 575 patients (mean age, 56 +/- 18 years; 63% women) referred for echocardiography for known or suspected PH. Survival status was assessed over a median of 16.5 (interquartile range, 7.6-20.0) months. There were 406 patients with PH (71%) (74% group 1, 14% group 3, and 12% group 4) and 169 patients without evidence of PH (29%). Among patients with PH, 46% were World Health Organization functional class III-IV. The mean RV strain was -21.2 +/- 6.7% for all patients. RV strain declined with worse functional class, shorter 6 minute walk distances, higher N-terminal pro-B-type natriuretic peptide levels, and the presence of right heart failure. RV strain predicted outcome across pulmonary pressures and groups of PH. Eighteen-month survival was 92%, 88%, 85%, and 71% according to RV strain quartile (P<0.001), with a 1.46 higher risk of death (95% confidence interval, 1.05-2.12) per 6.7% decline in RV strain. RV strain predicted survival when adjusted for pulmonary pressure, pulmonary vascular resistance, and right atrial pressure and provided incremental prognostic value over conventional clinical and echocardiographic variables. CONCLUSIONS: Quantitative assessment of RV free-wall systolic strain is feasible and is a powerful predictor of the clinical outcome of patients with known or suspected PH. PMID- 23811751 TI - Individual common carotid artery wall layer dimensions, but not carotid intima media thickness, indicate increased cardiovascular risk in women with preeclampsia: an investigation using noninvasive high-frequency ultrasound. AB - BACKGROUND: Preeclampsia (PE) is associated with increased risk of cardiovascular disease later in life. Ultrasound assessment of the common carotid artery intima media thickness (IMT) during or after PE has not indicated any increased cardiovascular risk. METHODS AND RESULTS: We used high-frequency ultrasound (22 MHz) to estimate the individual common carotid artery IMTs in 55 women at PE diagnosis and in 64 women with normal pregnancies at a similar stage. All were re examined about 1 year postpartum. A thick intima, thin media, and high intima/media (I/M) ratio are signs of a less healthy artery wall. PE was associated with a significantly thicker mean common carotid artery intima, thinner media, and higher I/M ratio than in normal pregnancy (mean I/M difference, 0.21; 95% confidence interval, 0.17-0.25; P<0.0001). After adjustment for first trimester body mass index and mean arterial pressure, differences in intima thickness and I/M remained significant. About 1 year postpartum, these values had improved in both groups, but group differences remained significant (all adjusted P<0.0001). There were no significant differences in IMT between groups. In receiver-operating characteristic curve analysis, intima thickness and I/M were strongly predictive of prevalent PE (area under the curve, ~0.95), whereas IMT was not (area under the curve, 0.49). CONCLUSIONS: The arteries of women with PE were negatively affected during pregnancy and 1 year postpartum compared with women with normal pregnancies, indicating increased cardiovascular risk. Estimation of intima thickness and I/M ratio seem preferable to estimation of common carotid artery IMT in imaging cardiovascular risk in PE. Results from this pilot study warrant further confirmation. PMID- 23811752 TI - Age-, body size-, and sex-specific reference values for right ventricular volumes and ejection fraction by three-dimensional echocardiography: a multicenter echocardiographic study in 507 healthy volunteers. AB - BACKGROUND: Right ventricular (RV) volumes and ejection fraction (EF) vary significantly with demographic and anthropometric factors and are associated with poor prognosis in several cardiovascular diseases. This multicenter study was designed to (1) establish the reference values for RV volumes and EF using transthoracic three-dimensional (3D) echocardiography; (2) investigate the influence of age, sex, and body size on RV anatomy; (3) develop normative equations. METHODS AND RESULTS: RV volumes (end-diastolic volume and end-systolic volume), stroke volume, and EF were measured by 3D echocardiography in 540 healthy adult volunteers, prospectively enrolled, evenly distributed across age and sex. The relation of age, sex, and body size parameters was investigated using bivariate and multiple linear regression. Analysis was feasible in 507 (94%) subjects (260 women; age, 45 +/- 16 years; range, 18-90). Age, sex, height, and weight significantly influenced RV volumes and EF. Sex effect was significant (P<0.01), with RV volumes larger and EF smaller in men than in women. Older age was associated with lower volumes (end-diastolic volume, -5 mLdecade; end systolic volume, -3 mL/decade; EF, -2 mL/decade) and higher EF (+1% per decade). Inclusion of body size parameters in the statistical models resulted in improved overall explained variance for volumes (end-diastolic volume, R(2)=0.43; end systolic volume, R(2)=0.35; stroke volume, R(2)=0.30), while EF was unaffected. Ratiometric and allometric indexing for age, sex, and body size resulted in no significant residual correlation between RV measures and height or weight. CONCLUSIONS: The presented normative ranges and equations could help standardize the 3D echocardiography assessment of RV volumes and function in clinical practice, considering the effects of age, sex, and body size. PMID- 23811753 TI - Caregiving, perceptions of maternal favoritism, and tension among siblings. AB - PURPOSE: Studies of later-life families have revealed that sibling tension often increases in response to parents' need for care. Both theory and research on within-family differences suggest that when parents' health declines, sibling relations may be affected by which children assume care and whether siblings perceive that the parent favors some offspring over others. In the present study, we explore the ways in which these factors shape sibling tension both independently and in combination during caregiving. DESIGN AND METHODS: In this article, we use data collected from 450 adult children nested within 214 later life families in which the offspring reported that their mothers needed care within 2 years prior to the interview. RESULTS: Multilevel analyses demonstrated that providing care and perceiving favoritism regarding future caregiving were associated with sibling tension following mothers' major health events. Further, the effects of caregiving on sibling tension were greater when perceptions of favoritism were also present. IMPLICATIONS: These findings shed new light on the conditions under which adult children are likely to experience high levels of sibling tension during caregiving. Understanding these processes is important because siblings are typically the individuals to whom caregivers are most likely to turn for support when assuming care of older parents, yet these relationships are often a major source of interpersonal stress. PMID- 23811754 TI - Antitumor effects of Endostar on non-Hodgkin's lymphoma by regulating endothelial progenitor cells through protein kinase B-dependent pathway. AB - Endothelial progenitor cells (EPCs) play an important role in non-Hodgkin's lymphoma (NHL) development. Endostar is an anti-angiogenic drug designed to stop cancer by nullifying a tumor's ability to obtain oxygen and nutrients. In this study, we examined the anti-angiogenic activities of Endostar on NHL cell lines and murine xenograft model of NHL in vitro and in vivo, respectively, and explored the underlying antiangiogenic mechanism of Endostar. Results showed that Endostar may inhibit the EPC proliferation by reducing the expression of p protein kinase B, but not p-ERK expression. Our finding could lead to a better understanding of the effects of Endostar on NHL. PMID- 23811755 TI - Evaluation of potential reference genes for qRT-PCR studies in human hepatoma cell lines treated with TNF-alpha. AB - In this study, the expression of eight candidate reference genes, B2M, ACTB, GAPDH, HMBS, HPRT1, TBP, UBC, and YWHAZ, was examined to identify optimal reference genes by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis in two human hepatoma cell lines, BEL-7402 and SMMC-7721, treated with tumor necrosis factor-alpha (TNF-alpha) for different time periods. The expression stability of these genes was analyzed by three independent algorithms: geNorm, NormFinder, and BestKeeper. Results showed that TBP was the most stably expressed gene in BEL-7402 and SMMC-7721 cell lines under current experimental conditions, and that the optimal set of reference genes required for accurate normalization was TBP and HMBS, based on the pairwise variation value determined with geNorm. UBC and ACTB were ranked as the least stable genes by same algorithms. Our findings provide evidence that using TBP alone or in combination with HMBS as endogenous controls could be a reliable method for normalizing qRT-PCR data in human hepatoma cell lines treated with TNF-alpha. PMID- 23811756 TI - RNAi functionalized scaffold for scarless skin regeneration. AB - Combination of a 3-D scaffold with the emerging RNA interference (RNAi) technique represents the latest paradigm of regenerative medicine. In our recent paper "RNAi functionalized collagen-chitosan/silicone membrane bilayer dermal equivalent for full-thickness skin regeneration with inhibited scarring" in the journal Biomaterial, we not only demonstrated a 3-D system for siRNA sustained delivery, but also presented a comprehensive in vivo study by targeting a vital problem in skin regeneration: scarring. It is expected that further development of this kind of RNAi functionalized scaffold can provide a better platform for directing cell fates by integrating the "down-regulating" biomolecular cues into the cellular microenvironment, leading to the complete functional regeneration of skin. PMID- 23811757 TI - Nutritional policy changes in the supplemental nutrition assistance program: a microsimulation and cost-effectiveness analysis. AB - BACKGROUND: Some experts have proposed limiting the use of Supplemental Nutrition Assistance Program (SNAP) benefits, for calorie-dense foods or subsidizing SNAP purchases of healthier foods. OBJECTIVE: To estimate health effects and cost effectiveness of banning or taxing sugar-sweetened beverages (SSBs) or subsidizing fruits and vegetables purchased with SNAP. DESIGN: . Microsimulation. Data Sources. National Health and Nutrition Examination Survey, US Department of Agriculture Quarterly Food-at-Home Price Database, and SNAP program data. TARGET POPULATION: US adults aged 25 to 64 y. Time Horizon. 10 y. Perspective. Governmental. OUTCOME MEASURES: Incremental costs, quality-adjusted life-years (QALYs), body mass index, Alternative Healthy Eating Index, Food Security Score, diabetes person-years, and deaths from myocardial infarctions (MIs) and strokes. RESULTS: of Base-Case Analysis. Banning SSB purchases using SNAP benefits would be expected to avert 510,000 diabetes person-years and 52,000 deaths from MIs and strokes over the next decade, with a savings of $2900 per QALY saved. A penny-per ounce tax on SSBs purchased with SNAP dollars would produce higher cost savings due to tax revenues but avert fewer chronic disease deaths. However, some SNAP participants are likely to preferentially purchase SSBs through their disposable income, indirectly reducing their food security. A 30% produce subsidy would be expected to avert 39,000 diabetes person-years and 4600 cardiovascular deaths over 10 y without effects on food security. Results of Sensitivity Analysis. Results are sensitive to the intake elasticities of SSBs and produce. Limitations. Input data did not provide information on heterogeneity in response to price changes within the SNAP-using POPULATION: CONCLUSIONS: SNAP restrictions on SSBs could lower chronic disease mortality, but further testing should examine indirect effects on disposable income and food security. Subsidizing produce could confer fewer benefits or risks but at higher cost. PMID- 23811758 TI - Linear regression metamodeling as a tool to summarize and present simulation model results. AB - BACKGROUND / OBJECTIVE: Modelers lack a tool to systematically and clearly present complex model results, including those from sensitivity analyses. The objective was to propose linear regression metamodeling as a tool to increase transparency of decision analytic models and better communicate their results. METHODS: We used a simplified cancer cure model to demonstrate our approach. The model computed the lifetime cost and benefit of 3 treatment options for cancer patients. We simulated 10,000 cohorts in a probabilistic sensitivity analysis (PSA) and regressed the model outcomes on the standardized input parameter values in a set of regression analyses. We used the regression coefficients to describe measures of sensitivity analyses, including threshold and parameter sensitivity analyses. We also compared the results of the PSA to deterministic full-factorial and one-factor-at-a-time designs. RESULTS: The regression intercept represented the estimated base-case outcome, and the other coefficients described the relative parameter uncertainty in the model. We defined simple relationships that compute the average and incremental net benefit of each intervention. Metamodeling produced outputs similar to traditional deterministic 1-way or 2-way sensitivity analyses but was more reliable since it used all parameter values. CONCLUSIONS: Linear regression metamodeling is a simple, yet powerful, tool that can assist modelers in communicating model characteristics and sensitivity analyses. PMID- 23811759 TI - Determining the length of posttherapeutic follow-up for cancer patients using competing risks modeling. AB - BACKGROUND/OBJECTIVE: After a curative treatment for cancer, patients enter into a posttherapeutic surveillance phase. This phase aims to detect relapses as soon as possible to improve the outcome. Mould and others predicted with a simple formula, using a parametric mixture cure model, how long early-stage breast cancer patients should be followed after treatment. However, patients in posttherapeutic surveillance phase are at risk of different events types with different responses according to their prognostic factors and different probabilities to be cured. This paper presents an adaptation of the method proposed by Mould and others, taking into account competing risks. Our loss function estimates, when follow-up is stopped at a given time, the proportion of patients who will fail after this time and who could have been treated successfully. METHOD: We use the direct approach for cumulative incidence modeling in the presence of competing risks with an improper Gompertz probability distribution as proposed by Jeong and Fine. Prognostic factors can be taken into account, leading to a proportional hazards model. In a second step, the estimates of the Gompertz model are combined with the probability for a patient to be treated successfully in case of relapse for each event type. The method is applied to 2 examples, a numeric fictive example and a real data set on soft tissue sarcoma. RESULTS: and CONCLUSION: The model presented is a good tool for decision making to determine the total length of posttherapeutic surveillance. It can be applied to all cancers regardless of the localizations. PMID- 23811760 TI - A framework for evaluating markers used to select patient treatment. AB - There is growing interest in markers that can be used to identify which patients are most likely to benefit from a treatment. For example, the Gail breast cancer risk prediction model may be useful for identifying a subset of older women for whom the benefit of tamoxifen for breast cancer prevention is likely to outweigh the harm. Two general classes of approaches to evaluating treatment selection markers have been developed. The first uses data on a cohort of untreated subjects to develop a risk prediction model, such as the Gail model, which is used to identify a high-risk subset of subjects. This model is paired with a measure of treatment effect to assess the impact of identifying and treating the high-risk subset. The second approach uses data from a randomized trial to model the treatment effect on a composite outcome that includes all effects of treatment (positive and negative). The treatment effect model is used to identify a subset of subjects with positive treatment effects and to assess the impact of identifying and treating this subset. We describe a framework that includes both existing approaches as special cases. In doing so, we review the existing approaches, clarify their underlying assumptions, and facilitate the evaluation of markers under less restrictive assumptions. PMID- 23811761 TI - Exploring the impact of expertise, clinical history, and visual search on electrocardiogram interpretation. AB - BACKGROUND: The primary aim of this study is to understand more about the perceptual-cognitive mechanisms underpinning the expert advantage in electrocardiogram (ECG) interpretation. While research has examined visual search processes in other aspects of medical decision making (e.g., radiology), this is the first study to apply the paradigm to ECG interpretation. The secondary aim is to explore the role that clinical history plays in influencing visual search behavior and diagnostic decision making. While clinical history may aid diagnostic decision making, it may also bias the visual search process. METHODS: Ten final-year medical students and 10 consultant emergency medics were presented with 16 ECG traces (8 with clinical history that was not manipulated independently of case) while wearing eye tracking equipment. The ECGs represented common abnormalities encountered in emergency departments and were among those taught to final-year medical students. Participants were asked to make a diagnosis on each presented trace and report their level of diagnostic confidence. RESULTS: Experts made significantly faster, more accurate, and more confident diagnoses, and this advantage was underpinned by differences in visual search behavior. Specifically, experts were significantly quicker at locating the leads of critical importance. Contrary to our hypothesis, clinical history had no significant effect on the readers' ability to detect the abnormality or make an accurate diagnosis. CONCLUSIONS: Accurate ECG interpretation appears dependent on the perceptual skill of pattern recognition and specifically the time to fixate the critical lead(s). Therefore, there is potential clinical utility in developing perceptual training programs to train novices to detect abnormalities more effectively. PMID- 23811762 TI - Hierarchical tube-in-tube structures prepared by electrophoretic deposition of nanostructured titanates into a TiO2 nanotube array. AB - Multiwalled nanotubular titanates have been incorporated inside the pores of a wide TiO2 nanotube array using electrophoretic deposition under vigorous stirring. The resulting hierarchical electrodes combine both benefits of open channels for rapid transport of ions and high specific surface area. PMID- 23811763 TI - Homoleptic 'sandwich' complexes of substituted tris(methimazolyl)borate ligands with ruthenium, rhodium and palladium. AB - The pursuit of heteroleptic 'half-sandwich' complexes of boron substituted anionic and charge-neutral tris(methimazolyl)borate ligands is described. The formation of the homoleptic 'sandwich' complexes was found to be favoured when the metal precursor contains labile ligands. When unable to form these homoleptic complexes Tm is shown to preferentially coordinate in a kappa2-[S,S] fashion. This study reinforces previous assertions that the Tm ligand preferentially adopts the kappa2-[S,S] mode when coordinated to electron rich metal centres and demonstrates the strong electron donor properties of substituted Tm ligands. PMID- 23811764 TI - [A memoir of my researches on xenobiotic metabolism for 48 years--researches on Kanemi Yusho and endocrine disrupting chemicals]. AB - The author started a research on xenobiotic metabolism at Graduate School of Pharmaceutical Sciences, Kyushu University in 1965. In 1968, an epidemic of a "strange disease", called Yusho, occurred in western Japan. The epidemic was soon identified to be a food poisoning caused by the ingestion of commercial Kanemi rice bran oil which had been accidentally contaminated with large amounts of polychlorinated biphenyls (PCBs) and their related compounds such as polychlorinated dibenzofurans (PCDFs.) At first, in this review, our toxicological studies on Yusho during the early thirty years were briefly described. Next, the studies on aldehyde oxidase, a molybdenum hydroxylase, which is involved in the lactam formation reaction such as 1-phenyl-2-(2 oxopyrrolidine)pentane(oxoprolintane) from 1-phenyl-2 pyrrolidinopentane(prolintane) and 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine(MPTP) lactam from 1-methyl-4-phenyl-2,3-dihydropyridinium ion (MPDP+) were also presented. Finally, we investigated how the xenobiotic metabolism of endocrine disrupting chemicals such as bisphenol A (BPA) and some isoflavones affects their estrogenic activities. In this study, we demonstrated that BPA is converted to 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), an active metabolite as estrogen, by rat liver S9. In the cases of isoflavones, although genistein was inactivated, biochanin A, 4'-methoxy analogue of genistein, was activated to genistein by O-demethylation with rat liver S9. PMID- 23811765 TI - [The production of mouse model of slowly progressive diabetes mellitus and the preventive effect of low molecular weight chitosan on the progression of the diabetes mellitus]. AB - The aim of our study was to produce a new diabetic model by a single i.p. injection of various doses of streptozotocin (STZ) to 8-week-old male Institute of Cancer Research (ICR) mice. When STZ was i.p. injected at doses rainging from 75 to 200 mg/kg, in the group injected 200 mg/kg STZ, the non-fasting serum glucose levels markedly rose from 1 week after STZ administration and the high glucose levels were maintained for 9 weeks. The serum glucose levels in the group administered 100 mg/kg STZ were within a normal range at 1 week after STZ administration, but thereafter continued to increase gradually till 9 weeks. In contrast with the serum glucose levels, a marked reduction in the percentage of the relative numbers of beta-cells in the islets of pancreas from 1 week in mice injected 200 mg/kg STZ was observed. On the other hand, in 100 mg/kg STZ mice, the number of beta-cells was almost normal percentage at 1 week and then continued to gradually decrease as the time went on throughout 24-week observation. These results indicate that only the 100 mg/kg STZ injection produces slowly progressive diabetes mellitus in mice. Low molecular weight (LMW) chitosan (chitosan lactate, average of molecular weight: 20000) was administered as drinking water from prediabetic stage (from 2 weeks after 100 mg/kg STZ injection). The 0.2% or 0.8% LMW chitosan administration prevented the progression of 100 mg/kg STZ-induced slowly progressive diabetes mellitus. The mechanisms, which LMW chitosan is effective in this model may be discussed on beta-cells. PMID- 23811766 TI - [Overview of study on Bacillus subtilis spores]. AB - This review documents my research for the past 29 years in the work of bacterial sporulation. The Gram-positive bacterium Bacillus subtilis forms spores when conditions are unsuitable for growth. The mature spores remain for long periods of starvation and are resistant to harsh environment. This property is attributed mainly to the unique figures of spore's outer layers, spore coat. The protein composition of the spores was comprehensively analyzed by a combination of SDS PAGE and LC-MS/MS. The total of 154 proteins were identified and 69 of them were novel. The expression of the genes encoding them was dependent on sporulation specific sigma factors, sigmaF, sigmaE, sigmaG and sigmaK. The expression of a coat protein gene, cotS, was dependent on sigmaK and GerE. CotE is essential for the assembly of CotS in the coat layer. Many coat genes were identified by reverse genetics and the regulation of the gene expression was studied in detail. Some cot genes are functioned in the resistance to heat and lysozyme, and some of the coat proteins are involved in the specificity of germinants. The yrbA is essential in spore development, yrbA deficient cells revealed abnormal figures of spore coat structure and changed the response to germinants. The location of 16 coat proteins was determined by the observation of fluorescence microscopy using fluorescence-labelled proteins. One protein was assigned to the cortex, nine to the inner coat, and four to the outer coat. In addition, CotZ and CgeA appeared in the outermost layer of the spore coat. PMID- 23811767 TI - [Regulatory mechanisms of skeletal tissues by amino acid signaling]. AB - In this review, we would outline the possible signaling system for three types of amino acids including glutamate (Glu), gamma-aminobutyric acid (GABA) and D serine (D-Ser) to play a role as an extracellular signal mediator in mechanisms underlying maintenance of the cellular homeostasis in skeletal tissues. Although Glu and GABA has been thought to be an excitatory/inhibitory amino acid neurotransmitter in the mammalian central nervous system, our molecular biological analyses give rise to a novel function for Glu and GABA as an autocrine and/or paracrine factor in three types of distinct cell types including osteoblasts, osteoclasts and chondrocytes in bone tissues. Moreover, D-Ser plays a pivotal role in osteoclastogenesis through a mechanism related to the incorporation of serine enantiomers in osteoclasts after the synthesis and subsequent release from adjacent osteoblasts. Accordingly, bone formation and maintenance seems to be under control by amino acid signaling in skeletal tissues as seen with neurotransmission in the brain. PMID- 23811768 TI - [Novel redox molecular imaging "ReMI" with dual magnetic resonance]. AB - Free radicals, reactive oxygen species (ROS), and redox status are known to be involved in cell signaling, proteomics, etc. in homeostasis and oxidative disease. Electron spin resonance (ESR) spectroscopy is a very sensitive and selective technique for detecting free radicals, and we have developed an in vivo ESR spectroscopy/imaging system combined with a nitroxyl probe for noninvasive assessment of free radical reactions in various disease models such as diabetes, cancer, liver/lung damage, gastric lesions, brain injury, etc. The systematic measurement with probes having different degrees of membrane permeability make it possible to clarify the location of free radical generation in blood vessels, cell membranes, and the cytoplasm. Our findings strongly indicate the great advantage of the in vivo ESR spectroscopy/imaging/nitroxyl probe technique in biomedical sciences. However, the spatial resolution of the ESR spectroscopy imaging system is insufficient due to the short T2 of probes. Proton magnetic resonance imaging (MRI) has significant clinical utility in the diagnosis of disease. Dynamic nuclear polarization (DNP)-MRI yields highly resolved images of free radical distribution in small animals by enhancing the water proton signal intensity via the Overhauser effect. We developed a new sequence for DNP-MRI and succeeded in obtaining simultaneous dual images using radicals labeled with 14N and 15N nuclei. This technique can visualize individual redox processes and the individual redox status of inner and/or outer cells in a dose-dependent manner. More recently, we have developed a novel DNP-MRI scanner and enables the use of DNP-MRI in different disease models. PMID- 23811769 TI - [Role of ABC efflux transporters in the oral bioavailability and drug-induced intestinal toxicity]. AB - The gastrointestinal tract is the organ that absorbs nutrients and water from foods and drinks. This organ is often exposed to various harmful xenobiotics, and therefore possesses various detoxification/barrier systems, including metabolizing enzymes and efflux transporters. Intestinal epithelial cells express ATP-binding cassette (ABC) efflux transporters such as P-glycoprotein, multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein, in addition to various solute carrier (SLC) influx transporters. These transporters are expressed site- and membrane-specifically in enterocytes, which affects the bioavailability of ingested substrate drugs. Expression and/or function of transporters can be modulated by various compounds, including therapeutic drugs, herbal products, some foods, and by disease states. The modulation of transporters could cause unexpectedly higher or lower blood concentrations, marked inter- and intra-individual variations in pharmacokinetics, and unreliable pharmacological actions in association with toxicities of substrates. Recently, we found that hyperbilirubinemia, which occurs in some disease states, increased intestinal accumulation and toxicity of methotrexate, an MRP substrate, because of the suppression of MRP function by high plasma concentrations of conjugated bilirubin. We also attempted to ameliorate the intestinal toxicity of irinotecan hydrochloride by modulating the hepatic and intestinal functions of MRP2. This review summarizes our findings regarding the role of ABC transporters, especially MRPs, in oral bioavailability and in drug-induced intestinal toxicity. Our approach to treat intestinal toxicity using an MRP2 modulator is also described. PMID- 23811771 TI - Vegetation response to western juniper slash treatments. AB - The expansion of pinon-juniper woodlands the past 100 years in the western United States has resulted in large scale efforts to kill trees and recover sagebrush steppe rangelands. It is important to evaluate vegetation recovery following woodland control to develop best management practices. In this study, we compared two fuel reduction treatments and a cut-and-leave (CUT) treatment used to control western juniper (Juniperus occidentalis spp. occidentalis Hook.) of the northwestern United States. Treatments were; CUT, cut-and-broadcast burn (BURN), and cut-pile-and-burn the pile (PILE). A randomized complete block design was used with five replicates of each treatment located in a curl leaf mahogany (Cercocarpus ledifolius Nutt. ex Torr. & A. Gray)/mountain big sagebrush (Artemisia tridentata Nutt. spp. vaseyana (Rydb.) Beetle)/Idaho fescue (Festuca idahoensis Elmer) association. In 2010, 4 years after tree control the cover of perennial grasses (PG) [Sandberg's bluegrass (Poa secunda J. Pres) and large bunchgrasses] were about 4 and 5 % less, respectively, in the BURN (7.1 +/- 0.6 %) than the PILE (11.4 +/- 2.3 %) and CUT (12.4 +/- 1.7 %) treatments (P < 0.0015). In 2010, cover of invasive cheatgrass (Bromus tectorum L.) was greater in the BURN (6.3 +/- 1.0 %) and was 50 and 100 % greater than PILE and CUT treatments, respectively. However, the increase in perennial bunchgrass density and cover, despite cheatgrass in the BURN treatment, mean it unlikely that cheatgrass will persist as a major understory component. In the CUT treatment mahogany cover increased 12.5 % and density increased in from 172 +/- 25 to 404 +/- 123 trees/ha. Burning, killed most or all of the adult mahogany, and mahogany recovery consisted of 100 and 67 % seedlings in the PILE and BURN treatments, respectively. After treatment, juniper presence from untreated small trees (<1 m tall; PILE and CUT treatments) and seedling emergence (all treatments) represented 25-33 % of pre-treatment tree density. To maintain recovery of herbaceous, shrub, and mahogany species additional control of reestablished juniper will be necessary. PMID- 23811770 TI - [Mass spectrometric determination of polyfunctionalized nucleoside phosphoramidites using LSI/FAB]. AB - Nucleoside phosphoramidites (PAs) are the most widely used building blocks in the contemporary solid-phase synthesis of oligonucleotides. Accurate molecular weight measurements of such acid-labile compounds may be easily determined in a matrix system comprising triethanolamine (TEOA)-NaCl by liquid secondary ionization mass spectrometry (LSIMS) or fast atom bombardment mass spectrometry (FABMS), using a double-focusing mass spectrometer. The present method rapidly and easily measures the accurate MWs of various PAs as adduct ions [M+Na]+, affording molecular formulas in place of elemental analysis. Further, the intensities by LSIMS of [M+Na]+ were found to be enhanced to the highest degree by adjustment of the mole ratio of PA and NaCl, fixing the amount of TEOA. In addition, the effects of the metal ion in the matrix were investigated. The present method is a powerful tool for the mass spectral identification of polyfunctionalized nucleoside PAs. PMID- 23811772 TI - Evaluation and selection of indicators for land degradation and desertification monitoring: types of degradation, causes, and implications for management. AB - Indicator-based approaches are often used to monitor land degradation and desertification from the global to the very local scale. However, there is still little agreement on which indicators may best reflect both status and trends of these phenomena. In this study, various processes of land degradation and desertification have been analyzed in 17 study sites around the world using a wide set of biophysical and socioeconomic indicators. The database described earlier in this issue by Kosmas and others (Environ Manage, 2013) for defining desertification risk was further analyzed to define the most important indicators related to the following degradation processes: water erosion in various land uses, tillage erosion, soil salinization, water stress, forest fires, and overgrazing. A correlation analysis was applied to the selected indicators in order to identify the most important variables contributing to each land degradation process. The analysis indicates that the most important indicators are: (i) rain seasonality affecting water erosion, water stress, and forest fires, (ii) slope gradient affecting water erosion, tillage erosion and water stress, and (iii) water scarcity soil salinization, water stress, and forest fires. Implementation of existing regulations or policies concerned with resources development and environmental sustainability was identified as the most important indicator of land protection. PMID- 23811773 TI - Success factors for community-based natural resource management (CBNRM): lessons from Kenya and Australia. AB - Recent concerns over a crisis of identity and legitimacy in community-based natural resource management (CBNRM) have emerged following several decades of documented failure. A substantial literature has developed on the reasons for failure in CBNRM. In this paper, we complement this literature by considering these factors in relation to two successful CBNRM case studies. These cases have distinct differences, one focusing on the conservation of hirola in Kenya on community-held trust land and the other focusing on remnant vegetation conservation from grazing pressure on privately held farm land in Australia. What these cases have in common is that both CBNRM projects were initiated by local communities with strong attachments to their local environments. The projects both represent genuine community initiatives, closely aligned to the original aims of CBNRM. The intrinsically high level of "ownership" held by local residents has proven effective in surviving many challenges which have affected other CBNRM projects: from impacts on local livelihoods to complex governance arrangements involving non-government organizations and research organizations. The cases provide some signs of hope among broader signs of crisis in CBNRM practice. PMID- 23811774 TI - Assessment of vegetation establishment on tailings dam at an iron ore mining site of suburban Beijing, China, 7 years after reclamation with contrasting site treatment methods. AB - Strip-mining operations greatly disturb soil, vegetation and landscape elements, causing many ecological and environmental problems. Establishment of vegetation is a critical step in achieving the goal of ecosystem restoration in mining areas. At the Shouyun Iron Ore Mine in suburban Beijing, China, we investigated selective vegetation and soil traits on a tailings dam 7 years after site treatments with three contrasting approaches: (1) soil covering (designated as SC), (2) application of a straw mat, known as "vegetation carpet", which contains prescribed plant seed mix and water retaining agent (designated as VC), on top of sand piles, and (3) combination of soil covering and application of vegetation carpet (designated as SC+VC). We found that after 7 years of reclamation, the SC+VC site had twice the number of plant species and greater biomass than the SC and VC sites, and that the VC site had a comparable plant abundance with the SC+VC site but much less biodiversity and plant coverage. The VC site did not differ with the SC site in the vegetation traits, albeit low soil fertility. It is suggested that application of vegetation carpet can be an alternative to introduction of topsoil for treatment of tailings dam with fine-structured substrate of ore sands. However, combination of topsoil treatment and application of vegetation carpet greatly increases vegetation coverage and plant biodiversity, and is therefore a much better approach for assisting vegetation establishment on the tailings dam of strip-mining operations. While application of vegetation carpet helps to stabilize the loose surface of fine-structured mine wastes and to introduce seed bank, introduction of fertile soil is necessary for supplying nutrients to plant growth in the efforts of ecosystem restoration of mining areas. PMID- 23811775 TI - The race for space: tracking land-cover transformation in a socio-ecological landscape, South Africa. AB - Biosphere Reserves attempt to align existing biodiversity conservation with sustainable resource use, specifically for improving socio-economic circumstances of resident communities. Typically, the Biosphere Reserve model is applied to an established landscape mosaic of existing land uses; these are often socio ecological systems where strict environmental protection and community livelihoods are in conflict, and environmental degradation frequently accompanies "use". This raises challenges for successful implementation of the model, as the reality of the existing land-use mosaic undermines the theoretical aspirations of the Biosphere concept. This study focuses on the Kruger to Canyons Biosphere Reserve (K2C), South Africa; a socio-ecological landscape where formal conservation is juxtaposed against extensive impoverished rural communities. We focus on land-cover changes of the existing land-use mosaic (1993-2006), specifically selected land-cover classes identified as important for biodiversity conservation and local-level resource utilization. We discuss the implications of transformation for conservation, sustainable resource-use, and K2C's functioning as a "Biosphere Reserve". Spatially, changes radiated outward from the settlement expanse, with little regard for the theoretical land-use zonation of the Biosphere Reserve. Settlement growth tracked transport routes, transforming cohesive areas of communal-use rangelands. Given the interdependencies between the settlement population and local environmental resources, the Impacted Vegetation class expanded accordingly, fragmenting the Intact Vegetation class, and merging rangelands. This has serious implications for sustainability of communal harvesting areas, and further transformation of intact habitat. The distribution and magnitude of Intact Vegetation losses raise concerns around connectivity and edge effects, with long-term consequences for ecological integrity of remnant habitat, and K2C's existing network of protected areas. PMID- 23811777 TI - Bioassay-guided fractionation of extracts from Hypericum perforatum in vitro roots treated with carboxymethylchitosans and determination of antifungal activity against human fungal pathogens. AB - The aim of this study was to individuate, by bioassay-guided fractionation, promising antifungal fractions and/or constituents from Hypericum perforatum subsp. angustifolium in vitro roots. Treatments with chitosan, O carboxymethylchitosan (CMC) and its derivatives were used to improve xanthone production in the roots. The bioassay-guided fractionation of CMC-treated roots led to the individuation of an ethyl acetate fraction, containing the highest amount of xanthones (6.8%) and showing the best antifungal activity with minimal inhibitory concentration (MIC) values of 53.82, 14.18, and 36.52 MUg/ml, against Candida spp., Cryptococcus neoformans and dermatophytes, respectively. From this fraction the prenylated xanthone, biyouxanthone D has been isolated and represented the 44.59% of all xanthones detected. For the first time in the present paper biyouxanthone D has been found in H. perforatum roots and tested against C. neoformans, dermatophytes, and Candida species. The xanthone showed the greatest antifungal activity against C. neoformans and dermatophytes, with MIC values of 20.16, 22.63 MUg/ml. In conclusion, the results obtained in the present study demonstrated that CMC-treated Hpa in vitro root extracts represent a tool for the obtainment of promising candidates for further pharmacological and clinical studies. PMID- 23811776 TI - Occurrence of the PsbS and LhcSR products in the green alga Ulva linza and their correlation with excitation pressure. AB - To avoid photoinhibition, plants have developed diverse photoprotection mechanisms. One of the short-term high light protection mechanisms in plants is non-photochemical quenching (NPQ), which dissipates the absorbed light energy as thermal energy. In the green alga, Ulva linza, the kinetics of NPQ starts with an initial, quick rise followed by a decline, and then a second and higher rise at longer time periods. During the whole phase, NPQ is triggered and controlled by DeltapH, then strengthened and modulated by zeaxanthin. Light-harvesting complex (LHC) family members are known to play crucial roles in this mechanism. The PSBS protein, a member of the LHC family that was thought to be present exclusively in higher plants, has been identified for the first time in U. linza. The expression of both PSBS and LHCSR was up-regulated during high light conditions, and LHCSR increased more than PSBS. Both LHCSR and PSBS-dependent NPQ may be important strategies for adapting to the environment, and they have undoubtedly played a role in their evolution. PMID- 23811778 TI - Hormone profiles in microalgae: gibberellins and brassinosteroids. AB - Endogenous gibberellins and brassinosteroids were quantified in 24 axenic microalgae strains from the Chlorophyceae, Trebouxiophyceae, Ulvophyceae and Charophyceae microalgae strains after 4 days in culture. This is the first report of endogenous gibberellins being successfully detected in microalgae. Between 18 and 20 gibberellins were quantified in all strains with concentrations ranging from 342.7 pg mg(-1) DW in Raphidocelis subcapitata MACC 317-4746.1 pg mg(-)(1) DW in Scotiellopsis terrestris MACC 44. Slower growing strains (S. terrestris MACC 44, Gyoerffyana humicola MACC 334, Nautococcus mamillatus MACC 716 and Chlorococcum ellipsoideum MACC 712) exhibited the highest gibberellin contents while lowest levels of gibberellins were found in faster growing strains (R. subcapitata MACC 317 and Coelastrum excentrica MACC 504). In all strains, the active gibberellin detected in the highest concentration was GA6, the predominant intermediates were GA15 and GA53 and the main biosynthetic end products were GA13 and GA51. Gibberellin profiles were similar in all strains except for the presence/absence of GA12 and GA12ald. To date this is the second report of endogenous brassinosteroids in microalgae. Brassinosteroids were detected in all 24 strains with concentrations ranging from 117.3 pg mg(-)(1) DW in R. subcapitata MACC 317-977.8 pg mg(-)(1) DW in Klebsormidium flaccidum MACC 692. Two brassinosteroids, brassinolide and castasterone were determined in all the strains. Generally, brassinolide occurred in higher concentrations than castasterone. PMID- 23811779 TI - Experimental signature of programmable quantum annealing. AB - Quantum annealing is a general strategy for solving difficult optimization problems with the aid of quantum adiabatic evolution. Both analytical and numerical evidence suggests that under idealized, closed system conditions, quantum annealing can outperform classical thermalization-based algorithms such as simulated annealing. Current engineered quantum annealing devices have a decoherence timescale which is orders of magnitude shorter than the adiabatic evolution time. Do they effectively perform classical thermalization when coupled to a decohering thermal environment? Here we present an experimental signature which is consistent with quantum annealing, and at the same time inconsistent with classical thermalization. Our experiment uses groups of eight superconducting flux qubits with programmable spin-spin couplings, embedded on a commercially available chip with >100 functional qubits. This suggests that programmable quantum devices, scalable with current superconducting technology, implement quantum annealing with a surprising robustness against noise and imperfections. PMID- 23811781 TI - The utility of the zebrafish model in conditioned place preference to assess the rewarding effects of drugs. AB - Substance abuse is a significant public health concern both domestically and worldwide. The persistent use of substances regardless of aversive consequences forces the user to give higher priority to the drug than to normal activities and obligations. The harmful and hazardous use of psychoactive substances can lead to a dependence syndrome. In this regard, the genetic and neurobiological underpinnings of reward-seeking behavior need to be fully understood in order to develop effective pharmacotherapies and other methods of treatment. Animal models are often implemented in preclinical screening for testing the efficacy of novel treatments. Several paradigms exist that model various facets of addiction including sensitization, tolerance, withdrawal, drug seeking, extinction, and relapse. Self-administration and, most notably, conditioned place preference (CPP) are relatively simple tests that serve as indicators of the aforementioned aspects of addiction by means of behavioral quantification. CPP is a commonly used technique to evaluate the motivational effects of compounds and experiences that have been associated with a positive or negative reward, which capitalizes on the basic principles of Pavlovian conditioning. During training, the unconditioned stimulus is consistently paired with a neutral set of environmental stimuli, which obtain, during conditioning, secondary motivational properties that elicit approach behavior in the absence of the unconditioned stimulus. For over 50 years, rodents have been the primary test subjects. However, the zebrafish (Danio rerio) is gaining favor as a valuable model organism in the fields of biology, genetics, and behavioral neuroscience. This paper presents a discussion on the merits, advantages, and limitations of the zebrafish model and its utility in relation to CPP. PMID- 23811780 TI - A dynamically reconfigurable Fano metamaterial through graphene tuning for switching and sensing applications. AB - We report on a novel electrically tunable hybrid graphene-gold Fano resonator. The proposed metamaterial consists of a square graphene patch and a square gold frame. The destructive interference between the narrow- and broadband dipolar surface plasmons, which are induced respectively on the surfaces of the graphene patch and the gold frame, leads to the plasmonic equivalent of electromagnetically induced transparency (EIT). The response of the metamaterial is polarization independent due to the symmetry of the structure and its spectral features are shown to be highly controllable by changing a gate voltage applied to the graphene patch. Additionally, effective group index of the device is retrieved and is found to be very high within the EIT window suggesting its potential use in slow light applications. Potential outcomes such as high sensing ability and switching at terahertz frequencies are demonstrated through numerical simulations with realistic parameters. PMID- 23811782 TI - Zinc complexes supported by methyl salicylato ligands: synthesis, structure, and application in ring-opening polymerization of L-lactide. AB - Two novel zinc alkoxides supported by chelating methyl salicylato (MesalO; MesalOH = methyl salicylate) ligands were successfully synthesized and characterized. Reaction of MesalOH with ZnEt2 (2:1) gives a tetranuclear cluster [Zn(MesalO)2]4 (1), which by addition of pyridine is transformed to the mononuclear compound [Zn(MesalO)2(py)2] (2). Compounds 1 and 2 were characterized by elemental analysis, NMR, IR, and single crystal X-ray diffraction. The catalytic activity of both compounds was tested for the ring-opening polymerization (ROP) of L-lactide (L-LA). It was found that compounds 1 and 2 are efficient initiators of the ROP of L-LA, yielding cyclic PLLA with weight average molecular weights up to 100 kDa for 2. The treatment of 2 with 1 equiv. of BnOH in toluene afforded a dimeric compound [Zn(OBn)(MesalO)(py)]2 (3). The addition of L-LA to a combination of 1 and 4 equiv. of BnOH in THF or 2 and 1 equiv. of BnOH in toluene led to the rapid and efficient generation of PLLA with end-capped BnO groups. PMID- 23811783 TI - Effect of ligand geometry on selective gas-adsorption: the case of a microporous cadmium metal organic framework with a V-shaped linker. AB - A microporous cadmium metal organic framework is synthesized and structurally characterized. The material possesses a 3-D framework with a 1-D sinusoidal chain and shows high selectivity for CO2 over N2. The selectivity is attributed to CO2 interacting with two phenyl rings of a V-shaped linker as estimated by the in situ XRD-DSC study. PMID- 23811784 TI - The effect of clozapine on mRNA expression for genes encoding G protein-coupled receptors and the protein components of clathrin-mediated endocytosis. AB - OBJECTIVES: Clathrin-mediated endocytosis (CME) is an intracellular trafficking mechanism for packaging cargo, including G protein-coupled receptors (GPCRs), into clathrin-coated vesicles (CCVs). The antipsychotic chlorpromazine inhibits CCV assembly of adaptor protein AP2 whereas clozapine increases serotonin2A receptor internalization. We hypothesized that clozapine alters the expression of CME genes modulating vesicle turnover and GPCR internalization. MATERIALS AND METHODS: SH-SY5Y human neuroblastoma cells were incubated with clozapine (1-20 umol/l) for 24-72 h. GPCR and CME-related gene mRNA expression was measured using RT-PCR. We quantified changes in the same genes using expression data from a microarray study of mice brains after 12 weeks of treatment with 12 mg/kg/day clozapine. RESULTS: The expression of genes encoding adaptor and clathrin assembly proteins, AP2A2, AP2B1, AP180, CLINT1, HIP1, ITSN2, and PICALM, increased relative to the control in SH-SY5Y cells incubated with 5-10 umol/l clozapine for 24-72 h. The microarray study showed significantly altered expression of the above CME-related genes, with a marked 641-fold and 17-fold increase in AP180 and the serotonin1A GPCR, respectively. The expression of three serotonergic receptor and lysophosphatidic acid receptor 2 (EDG4) GPCR genes was upregulated in SH-SY5Y cells incubated with 5 umol/l clozapine for 24 h. EDG4 expression was also increased with 10-20 umol/l clozapine treatment at 48-72 h. Clozapine significantly decreased the expression of beta-arrestin, involved in GPCR desensitization, both in vitro and vivo. CONCLUSION: The changes we report in CME and GPCR mRNAs implicate CCV-mediated internalization of GPCRs and the serotonergic system in clozapine's mechanism of action, which may be useful in the design of more effective and less toxic antipsychotic therapies. PMID- 23811785 TI - Patterns of second primary malignancy risk in multiple myeloma patients before and after the introduction of novel therapeutics. AB - Recent studies have reported an increased risk of second primary malignancies (SPM) following multiple myeloma (MM) diagnosis associated with novel anti myeloma treatments. We evaluated the risk of SPM among 36 491 MM cases reported to the Surveillance, Epidemiology, and End Results program (SEER) between 1973 and 2008. We calculated overall and site-specific standardized incidence ratio (SIR) and 95% confidence intervals (CI) for 2012 SPM cases diagnosed within the 35-year follow-up. There was no significant overall risk of SPM (SIR=0.98; 95% CI=0.94-1.02); however, there were multiple site-specific risk patterns. The risk of breast and prostate cancer was significantly decreased overall and across age, latency and the year of diagnosis strata. There was an ~50% increased risk of colorectal cancer 5 years after MM diagnosis (Ptrend<0.001). The risk of hematological malignancies was significantly increased, notably for acute myeloid leukemia (AML; SIR=6.51; 95% CI=5.42-7.83). There was a significant decreasing trend for AML over time, particularly for patients ?65. However, no significant change in risk was noted after the introduction of autologous stem cell transplant among younger patients (<65 years). On the basis of observed trends for overall SPM as well as AML, no association between the introduction of novel therapies and SPM following MM has emerged in this large population-based study. PMID- 23811786 TI - Story and science: how providers and parents can utilize storytelling to combat anti-vaccine misinformation. AB - With little or no evidence-based information to back up claims of vaccine danger, anti-vaccine activists have relied on the power of storytelling to infect an entire generation of parents with fear of and doubt about vaccines. These parent accounts of perceived vaccine injury, coupled with Andrew Wakefield's fraudulent research study linking the MMR vaccine to autism, created a substantial amount of vaccine hesitancy in new parents, which manifests in both vaccine refusal and the adoption of delayed vaccine schedules. The tools used by the medical and public health communities to counteract the anti-vaccine movement include statistics, research, and other evidence-based information, often delivered verbally or in the form of the CDC's Vaccine Information Statements. This approach may not be effective enough on its own to convince vaccine-hesitant parents that vaccines are safe, effective, and crucial to their children's health. Utilizing some of the storytelling strategies used by the anti-vaccine movement, in addition to evidence-based vaccine information, could potentially offer providers, public health officials, and pro-vaccine parents an opportunity to mount a much stronger defense against anti-vaccine messaging. PMID- 23811787 TI - Seeing the body: a new mechanism for acupuncture analgesia? AB - The use of visual illusions to study how the brain gives rise to a representation of the body has produced surprising results, particularly in relation to modulation of pain. It seems likely that this research has relevance to how we understand acupuncture analgesia. Acupuncture supplies several different kinds of signal to the brain: touch in the preliminary examination for tender areas; needle stimulation, mainly of Adelta fibres; and sometimes visual input from the patient's sight of the needle insertion. In the light of recent research, all these are likely to modulate pain. There are implications here for clinical practice and for research. Acupuncture may be more effective if patients can see the needles being inserted. The use of non-penetrating stimuli to the skin or minimal needle insertion at non-acupuncture points as control procedures becomes more than ever open to question and this, in turn, has relevance for claims that acupuncture is indistinguishable from placebo. PMID- 23811788 TI - Burn disaster special interest group: bridging the gap. PMID- 23811789 TI - Successful skin homografting from an identical twin in a severely burned patient. AB - Flame burns are a serious condition and usually have high morbidity and mortality because they affect large areas of the body surface as well as the lungs. In these patients, it is especially difficult to find healthy skin for grafting if they have more than 70% third-degree burns. Repeated autografting or synthetic wound care materials are the only treatment options to cover burned areas. Partial-thickness skin grafting from the patient's identical twin sibling may be an alternative treatment option, if possible. Here, we report a patient with severe flame injury treated with skin from his identical twin. The patient had third-degree burns covering 70% of his body surface. Initial treatment consisted of fluid and electrolyte replacement, daily wound care, and surgical debridements, as well as nutritional support. After initial treatment, we performed a successful skin grafting from his identical twin. Skin grafting between identical twins might be an alternate method for severely burned patients. PMID- 23811790 TI - The blue man: burn from muriatic acid combined with chlorinated paint in an adult pool construction worker. AB - Muriatic acid (hydrochloric acid), a common cleaning and resurfacing agent for concrete pools, can cause significant burn injuries. When coating a pool with chlorinated rubber-based paint, the pool surface is initially cleansed using 31.45% muriatic acid. Here we report a 50-year-old Hispanic male pool worker who, during the process of a pool resurfacing, experienced significant contact exposure to a combination of muriatic acid and blue chlorinated rubber-based paint. Confounding the clinical situation was the inability to efficiently remove the chemical secondary to the rubber-based nature of the paint. Additionally, vigorous attempts were made to remove the rubber paint using a variety of agents, including bacitracin, chlorhexidine soap, GOOP adhesive, and Johnson's baby oil. Resultant injuries were devastating fourth-degree burns requiring an immediate operative excision and amputation. Despite aggressive operative intervention and resuscitation, he continued to have severe metabolic derangements and ultimately succumbed to his injuries. We present our attempts at debridement and the system in place to manage patients with complex chemical burns. PMID- 23811791 TI - Costs of caring for adults with long-term neurological conditions. AB - OBJECTIVES: To estimate and compare the costs of informal and formal care provided to adults with long term neurological conditions and to identify characteristics associated with these costs. DESIGN: Cross-sectional postal questionnaire survey. PARTICIPANTS: Family carers of 282 adults with sudden onset, progressive and stable/intermittent conditions were recruited through UK wide voluntary organisations and neuroscience centres. METHODS: Carers provided demographic and condition specific information about the adults cared for. Informal care was measured with the Caregiver Activity Survey and formal service use with the Client Service Receipt Inventory. Costs were calculated and regression analyses identified demographic and clinical characteristics associated with cost. RESULTS: Annual informal care costs mean L82,620 (standard deviation 58,493) were 4 times higher than formal costs mean L18,117 (standard deviation 28,990). Caring for adults with sudden onset conditions and hidden/mixed impairments were both significantly associated with informal costs. Healthcare costs were significantly associated with having a sudden onset condition, greater dependency in activities of daily living and longer condition duration. Greater dependency was significantly associated with increased social care costs. CONCLUSIONS: The cost of caring for adults with long term neurological conditions is largely borne by families. Both health and social costs are higher for more dependent patients, endorsing the importance of developing specialist rehabilitation services that reduce dependency. PMID- 23811792 TI - Hepatic resection for hepatocellular carcinoma patients on hemodialysis for uremia: a nationwide cohort study. AB - BACKGROUND: The association between uremia and survival outcomes of patients undergoing hepatic resection for hepatocellular carcinoma (HCC) has not been well investigated, particularly for perioperative complications. This nationwide cohort study aimed to compare survival outcomes as well as perioperative mortality and complications between uremia-HCC patients and non-uremia-HCC patients who underwent hepatic resection. METHODS: Using Taiwan's National Health Institute Research Database, 149 uremia-HCC patients who underwent hepatic resection between 1996 and 2008 were enrolled. The control group comprised 596 HCC patients who also received hepatic resection during the same time period. The two groups were matched for age, gender, viral hepatitis status, and underlying liver cirrhosis. Disease-free survival, overall survival, and perioperative complications were compared between the two groups. RESULTS: For the uremia-HCC cohort, the 1-, 5-, and 10-year overall and disease-free survival rates were 86, 52, and 38 %, as well as 77, 27, and 18 %, respectively. The survival outcomes were comparable between uremia-HCC cohort and the HCC cohort, regardless of extent of hepatic resection. As for perioperative complications, the uremia-HCC cohort had a higher risk of postoperative infections requiring invasive interventions as well as an increased risk of life-threatening heart-associated complications, compared to the HCC cohort. CONCLUSIONS: Uremia did not influence survival outcomes between the uremia-HCC and the HCC cohorts, irrespective of extent of hepatic resection. This study urges a better perioperative care strategy to avoid potential cardiac and infectious complications in uremia-HCC patients. PMID- 23811793 TI - Gunshot wounds to the face: emergency interventions and outcomes. AB - BACKGROUND: Gunshot wounds to the face (GSWF) may produce life-threatening injuries. Our objective is to describe outcomes of and factors related to interventions for urgent airway control (UAC) and urgent bleeding control (UBC) as well as to analyze complications associated with GSWF. METHODS: This was a retrospective study of 155 GSWF patients who were admitted to two Level 1 academic trauma centers over an 11-year period. Demographic details, injuries sustained, interventions performed, and timing of the interventions were recorded. Morbidity and mortality data were evaluated. RESULTS: Overall, 115 (74 %) patients suffered isolated GSWF, and none died. Of the 90 (58 %) patients requiring UAC, only three had a cricothyroidotomy. Of the 41 (26 %) patients requiring UBC, only four had angiographic embolization. Intraoral involvement and extrafacial injuries were associated with both UAC and UBC. Overall, 75 patients (48 %) required operations on the bones, eyes, or both. Complications developed in 14 and were treated successfully. CONCLUSIONS: UAC and UBC are required frequently after GSWF and are associated with intraoral involvement and injuries beyond the face. Simple methods, such as orotracheal intubation and packing, are typically sufficient for successful management. About half of the patients need further surgery, with infrequent morbidity. PMID- 23811794 TI - Risk factors of hospital mortality after re-laparotomy for post-hepatectomy hemorrhage. AB - BACKGROUND: Post-hepatectomy hemorrhage (PHH) requiring re-laparotomy is a life threatening situation and is associated with a considerably high hospital mortality rate. However, risk factors of hospital mortality in patients with this condition have not yet been investigated. METHODS: The perioperative data of 258 patients with hepatocellular carcinoma who underwent re-laparotomy for PHH from 1997 to 2011 were retrospectively reviewed and evaluated by univariate and multivariate analyses to identify risk factors of hospital mortality. RESULT: Hospital death occurred in 43 patients between 16 h and 40 days after re laparotomy, and the overall mortality rate was 16.7 %. The median time lag between first recognition of active bleeding and re-laparotomy was 6 h (range 0.5 34 h). The mortality of patients undergoing late re-laparotomy (>=6 h) was much higher than those undergoing early re-laparotomy (<6 h) (25 vs 8.6 %; P = 0.001). Multivariate analysis showed early time period (1997-2004) (P = 0.040), liver cirrhosis (P = 0.025), ineffective hemostasis during re-laparotomy due to coagulopathy (P = 0.038), late re-laparotomy (>=6 h) (P = 0.032), postoperative liver failure (P = 0.001), and postoperative acute renal failure requiring hemodialysis (P = 0.024) were independent risk factors of hospital mortality. CONCLUSION: Immediate re-laparotomy is a key factor to reduce hospital mortality for patients with active bleeding after partial hepatectomy. More care should be taken in those patients who develop acute liver failure and/or serious acute renal failure after re-laparotomy. PMID- 23811795 TI - N-acetylglucosaminyltransferase V confers hepatoma cells with resistance to anoikis through EGFR/PAK1 activation. AB - Elevated expression and activity of N-acetylglucosaminyltransferase V (Mgat5) in hepatocellular carcinoma (HCC) is a common early event involved in tumor invasion during hepatocarcinogenesis. A better understanding of the functional role and the molecular mechanism for Mgat5-targeted protein and downstream signaling pathway behind hepatoma invasion and metastasis is urgently needed. Here, we show that Mgat5 overexpression promoted anchorage-independent growth and inhibited anoikis in hepatoma cells. This effect was reversed by glycosyltransferase inactive mutant Mgat5 L188R transfection, alpha-mannosidase II inhibitor swainsonine treatment and N-acetyl glucosamine (GlcNAc) phosphotransferase (GPT) inhibitor tunicamycin administration. Mgat5 overexpression increased p21 activated kinase 1 (PAK1) expression and shRNA-mediated PAK1 knockdown and kinase inactivation with kinase dead mutant PAK1 K299R coexpression or allosteric inhibitor P21-activated kinase inhibitor III (IPA3) treatment reversed anoikis resistance in Mgat5-overexpressed hepatoma cells. Furthermore, Mgat5 overexpression upregulated beta-1-6-GlcNAc branched N-glycosylation and following phosphorylation of epidermal growth factor receptor (EGFR) in hepatoma cells. EGFR tyrosine kinase inhibitors AG1478 and Iressa treatment declined anchorage independent growth and anoikis resistance, which could be rescued by constitutive active mutant PAK1 T423E coexpression in Mgat5-overexpressed hepatoma cells. Conversely, knockdown of Mgat5 reduced EGFR/PAK1-dependent anoikis resistance, which could be reversed by PAK1 T423E. These results identified Mgat5-mediated beta-1-6-GlcNAc branched N-glycosylation and following activation of EGFR as a potential novel upstream molecular event for PAK1-induced anoikis resistance in hepatoma cells, implicating that molecular targeted therapeutics against Mgat5/EGFR/PAK1 might open a new avenue for personalized medicine in advanced stage HCC patients. PMID- 23811797 TI - Valley spin polarization by using the extraordinary Rashba effect on silicon. AB - The addition of the valley degree of freedom to a two-dimensional spin-polarized electronic system provides the opportunity to multiply the functionality of next generation devices. So far, however, such devices have not been realized due to the difficulty to polarize the valleys, which is an indispensable step to activate this degree of freedom. Here we show the formation of 100% spin polarized valleys by a simple and easy way using the Rashba effect on a system with C3 symmetry. This polarization, which is much higher than those in ordinary Rashba systems, results in the valleys acting as filters that can suppress the backscattering of spin-charge. The present system is formed on a silicon substrate, and therefore opens a new avenue towards the realization of silicon spintronic devices with high efficiency. PMID- 23811796 TI - Fluorescence quenching of the phycobilisome terminal emitter LCM from the cyanobacterium Synechocystis sp. PCC 6803 detected in vivo and in vitro. AB - The fluorescence emission of the phycobilisome (PBS) core-membrane linker protein (L(CM)) can be directly quenched by photoactivated orange carotenoid protein (OCP) at room temperature both in vitro and in vivo, which suggests the crucial role of the OCP-L(CM) interaction in non-photochemical quenching (NPQ) of cyanobacteria. This implication was further supported (i) by low-temperature (77K) fluorescence emission and excitation measurements which showed a specific quenching of the corresponding long-wavelength fluorescence bands which belong to the PBS terminal emitters in the presence of photoactivated OCP, (ii) by systematic investigation of the fluorescence quenching and recovery in wild type and L(CM)-less cells of the model cyanobacterium Synechocystis sp. PCC 6803, and (iii) by the impact of dephosphorylation of isolated PBS on the quenching. The OCP binding site within the PBS and the most probable geometrical arrangement of the OCP-allophycocyanin (APC) complex was determined in silico using the crystal structures of OCP and APC. Geometrically modeled attachment of OCP to the PBS core is not at variance with the OCP-L(CM) interaction. It was concluded that besides being a very central element in the PBS to reaction center excitation energy transfer and PBS assembly, L(CM) also has an essential role in the photoprotective light adaptation processes of cyanobacteria. PMID- 23811798 TI - Fluorescent single-ion magnets: molecular hybrid (HNEt3)[DyxYb1-x(bpyda)2] (x = 0.135-1). AB - Four single-phase isostructural mononuclear complexes (HNEt3)[DyxYb1 x(bpyda)2].3H2O (x = 1 (1), 0 (2), 0.367 (3), 0.135 (4), bpyda = 2,2'-bipyridine 6,6'-dicarboxylate) show characteristics of controllable slow relaxation and photoluminescence. The molecular hybrids 3 and 4 exhibit the Orbach process for the DyIII component and a mixture of direct and Raman processes for the YbIII component. The presence of paramagnetic YbIII enhances the relaxation time of the DyIII component, originating from the suppression of the direct process/QTM. The correlation between photoluminescence, static susceptibilities and dynamic magnetic relaxation in the hybrid species was also analysed by comparing the energy gap between the ground and first excited states to the energy barrier. PMID- 23811800 TI - A facile strategy to fabricate large-scale uniform brookite TiO2 nanospindles with high thermal stability and superior electrical properties. AB - A facile strategy was initiated to fabricate large-scale uniform brookite TiO2 nanospindles preferentially grown along the [001] direction, which were highly thermally stable and exhibited superior electrical conductivity, about two orders of magnitude higher than those of anatase and rutile counterparts. PMID- 23811799 TI - Role of huge geometric circular structures in the reproduction of a marine pufferfish. AB - We report that male pufferfishes (Torquigener sp., Tetraodontidae) constructed large geometric circular structures on the seabed that played an important role in female mate choice. Males dug valleys at various angles in a radial direction, constructing nests surrounded by radially aligned peaks and valleys. Furthermore, they created irregular patterns in the nest comprising fine sand particles. The circular structure not only influences female mate choice but also functions to gather fine sand particles in nests, which are important in female mate choice. Strangely enough, the males never reuse the nest, always constructing a new circular structure at the huge cost of construction. This is because the valleys may not contain sufficient fine sand particles for multiple reproductive cycles. PMID- 23811801 TI - Mean platelet volume in patients with obstructive sleep apnea syndrome and its relationship with cardiovascular diseases. AB - Obstructive sleep apnea syndrome (OSAS) is an independent risk factor for the development of cardiovascular events and hypertension. Mean platelet volume (MPV), an indicator of platelet activation and aggregation, is closely related with cardiovascular diseases (CVDs). We aimed to show the relationship between OSAS and MPV with CVD. The medical records of 205 patients who were admitted to the sleep study were evaluated. OSAS was diagnosed by polysomnography if the apnea-hypopnea index (AHI) was greater than 5. MPV was calculated from blood samples. According to AHI, individuals in whom AHI was less than 5 were recruited as the control group, those in whom AHI was 5-15 as the mild OSAS group, those in whom AHI was equal to 15-30 as the moderate OSAS group, and those in whom AHI was greater than 30 as the severe OSAS group. Of the patients, 137 (67%) were men and 68 (33%) were women; the mean age was 53.0+/-14.1 years. There were 35 (17%), 20 (10.2%), 42 (20.4%), and 108 (52.6%) participants in groups 1, 2, 3, and 4, respectively. There were significant differences in terms of coronary artery disease and hypertension between all groups (P<0.05). There was a significant association between the severity of OSAS and MPV in groups 3 and 4, whereas there was not any association in groups 1 and 2 (group 1=9.3+/-0.7, group 2=9.4+/-0.8, group 3=9.5+/-1.1, group 4=10.2+/-1.2; P for trend 0.03). We showed that MPV was significantly increased in patients with OSAS, which is an independent risk factor for CVD. Therefore, MPV could be used as a marker to predict CVD in OSAS. PMID- 23811802 TI - May-Hegglin anomaly and pregnancy: a systematic review. AB - May-Hegglin anomaly (MHA) is an autosomal dominant disorder, characterized by a variable degree of thrombocytopaenia, large platelets and inclusion bodies in white blood cells. Bleeding manifestations are generally mild, but severe bleeding episodes have been reported. This is a systematic review of literature for MHA during pregnancy. The review revealed 26 articles (25 case reports and one case series) including 75 pregnancies (five twin pregnancies) in 40 women. In 11 women, first presentation was incidental thrombocytopaenia during routine antenatal blood test. Of these, five women were misdiagnosed as idiopathic thrombocytopenic purpura (ITP), including three who underwent splenectomy for resistant ITP. Postpartum haemorrhage (PPH) and bleeding after miscarriage were presenting symptoms in two women. Antiplatelet antibody was found in three pregnancies. Only one of them required intervention with intravenous immunoglobulin (IVIG) to prevent neonatal alloimmune thrombocytopaenia. PPH was reported in four pregnancies; three were primary PPH, of which one had blood transfusion, one had platelet and cryoprecipitate transfusion and the third was managed conservatively. There was one secondary PPH that was treated conservatively. Neonatal outcome included 78 live neonates and two intrauterine fetal deaths. Thirty-four neonates had thrombocytopaenia and subsequently were diagnosed with MHA, three of them required platelet transfusion prophylactically as they developed very low platelet counts and one neonate with platelet count of 29 * 10 cells/l and received IVIG, as the mother had a positive antiplatelet antibody during pregnancy. No obvious bleeding complications were reported among the neonates. MHA can present challenges during pregnancy and be associated with adverse maternal and neonatal outcome because of bleeding complications. Joint management by obstetrician and haematologists is required to minimize these risks. PMID- 23811803 TI - Latency of intracranial germ cell tumors and diagnosis delay. AB - BACKGROUND: Intracranial germ cell tumors (GCTs) frequently take an insidious clinical course before diagnosis. To date, clinical latency has been discussed in the context of germinoma in the suprasellar area and basal ganglia. OBJECTIVE: In this study, we classified the clinical latency of intracranial GCTs into three categories and described their characteristics in order to understand the full spectrum of the phenomenon. METHODS: In a cohort of 181 patients with intracranial GCTs, 17 patients had a delayed diagnosis of more than 3 months (90 days) from the initial brain magnetic resonance imaging to the definitive GCT diagnosis. Clinical records and radiological data of the patients were reviewed. RESULTS: The patients with a delayed diagnosis were categorized into three groups according to their tumor location: suprasellar (nine patients), basal ganglia (six patients), and pineal (two patients). Initial symptomatology corresponded with the tumor location: central diabetes insipidus for the suprasellar group, hemiparesis for the basal ganglia group, and precocious puberty for the pineal group. The overall survival of patients with germinoma and delayed diagnosis was significantly shorter than that of patients who were diagnosed within 3 months (P = 0.002). CONCLUSIONS: Clinical latency and delayed diagnosis are not restricted to germinomas in the suprasellar area and basal ganglia; they are canonical features of intracranial GCTs including pineal non-germinomatous GCTs. Early detection and proactive diagnosis of these tumors are required because diagnosis delay may negatively influence patient survival. PMID- 23811804 TI - Persistence of antibodies in adolescents 18-24 months after immunization with one, two, or three doses of 4CMenB meningococcal serogroup B vaccine. AB - We previously demonstrated the immunogenicity and tolerability of the serogroup B meningococcal vaccine, 4CMenB (Bexsero), in 11-17 y-olds randomized to receive 1, 2, or 3 doses at 1, 2, or 6 mo intervals. Participants in this extension study provided an additional blood sample 18-24 mo after last vaccine dose, to assess persistence of serum bactericidal activity with human complement (hSBA), and to compare with age-matched 4CMenB-naive controls. In the original study, one month after one 4CMenB dose, 93% of subjects had seroprotective hSBA titers (>=4) against indicator serogroup B strains for individual vaccine antigens (fHbp, NadA and NZOMV), increasing to ~100% after two or three doses. After 18-24 mo, 62-73% of subjects given one dose had titers >=4 against the three antigens, significantly lower rates than after two (77-94%) or three (86-97%) doses. Only proportions with titers >= 4 against NZOMV were significantly different between the two (77%) and three (90%, p < 0.0001) dose groups. These results confirm that two doses of 4CMenB, administered 1 to 6 mo apart, provide good levels of bactericidal activity against serogroup B meningococci, which were sustained at least 18-24 mo in over 64% of adolescents for all three tested vaccine-related antigens. PMID- 23811805 TI - Desmoplastic melanoma: recent advances and persisting challenges. AB - Desmoplastic melanoma is an uncommon variant of melanoma which presents significant challenges to the clinician and histopathologist. In particular, many cases show a bland 'fibroblastic' appearance, mimicking scar and a range of other benign proliferations. This diagnosis can be particularly problematic in small biopsy specimens, a difficulty exacerbated by an immunoprofile which is typically negative for a number of conventional melanocytic markers. The clinical and histological features of desmoplastic melanoma are reviewed, as are the differential diagnoses and some newer techniques which may contribute to assessment of these lesions. In recent years it has become clear that subclassification of desmoplastic melanoma into pure and mixed variants has clinical significance and it is suggested that this classification be employed in routine practice. PMID- 23811806 TI - Risk prediction for malignant conversion of oral epithelial dysplasia by hypoxia related protein expression. AB - AIMS: Increased aerobic glycolysis is a unique finding in cancers and hypoxia related proteins are associated with aerobic glycolysis. Therefore, we aimed to investigate whether hypoxia-related proteins can be predictive markers for malignant conversion of oral premalignant lesions with epithelial dysplasia (OED). METHODS: Expression of HIF-1alpha, Glut-1 and CA9 were detected in clinical samples of eight normal oral mucosa, 85 transitional areas of oral squamous cell carcinoma (OSCC) and 28 OED with or without malignant conversion using immunohistochemistry and were also comparatively detected in immortalised human oral keratinocyte (IHOK) and OSCC cell lines under hypoxia using immunoblotting. RESULTS: Sequential expression of HIF-1alpha, Glut-1 and CA9 was found both in transitional areas of OSCC and cell lines of IHOK and OSCC under hypoxia, supporting hypoxia-aerobic glycolysis-acidosis axis. Expression of all proteins showed significant association with malignant conversion of OED and CA9 was an independent risk factor of malignant transformation of OED. But the predictability of malignant transformation was improved when all three proteins were applied together. CONCLUSION: High expression of CA9 was an independent predictive marker of malignant conversion. Moreover, the combined application of these three proteins may be useful to assess the risk of malignant conversion of OED. PMID- 23811807 TI - MRI-guided biopsy: a valuable procedure alternative to avoid the risks of ionizing radiation from diagnostic imaging methods. PMID- 23811808 TI - Acute reduction of lipolysis reduces adiponectin and IL-18: evidence from an intervention study with acipimox and insulin. AB - AIMS/HYPOTHESIS: Low-grade inflammation is a feature of chronic diseases such as type 2 diabetes and lipodystrophy. It is associated with abdominal adiposity, increased levels of NEFA, hyperinsulinaemia and low adiponectin levels. However, the causal relationship between impaired metabolism and inflammation is not understood. We explored the anti-lipolytic effect of acipimox and insulin on adiponectin and adipocyte-associated cytokines in patients with lipodystrophy. METHODS: In a randomised placebo-controlled crossover design using nine patients with non-diabetic, HIV-associated lipodystrophy, we assessed whether (1) overnight administration of a low dose of acipimox and/or (2) insulin-induced suppression of NEFA flux altered circulating plasma levels of adiponectin, IL-18, TNF-alpha and IL-6 in the basal condition and in a two-stage euglycaemic hyperinsulinaemic clamp combined with stable isotopes (insulin infusion rates 20 mU m(-2) min(-1) and 50 mU m(-2) min(-1)). RESULTS: Insulin decreased plasma NEFA in a dose-dependent manner (p < 0.0001). Acipimox reduced basal plasma NEFAs and plasma NEFAs during the low-dose insulin infusion compared with placebo (p < 0.0001 for acipimox effect). Plasma adiponectin and plasma IL-18 were reduced during both situations where lipolysis was inhibited (p < 0.0001 for acipimox effect; p < 0.0001 and p < 0.05 for insulin effect on plasma adiponectin and plasma IL-18, respectively). In contrast, plasma IL-6 and plasma TNF-alpha did not change during low NEFA concentrations. CONCLUSIONS/INTERPRETATION: Using two different tools to manipulate lipolysis, the present study found that acute inhibition of lipolysis reduces levels of adiponectin and IL-18 in patients with HIV-associated lipodystrophy. PMID- 23811809 TI - Lower cardiorespiratory fitness contributes to increased insulin resistance and fasting glycaemia in middle-aged South Asian compared with European men living in the UK. AB - AIMS/HYPOTHESIS: This study aimed to determine the extent to which increased insulin resistance and fasting glycaemia in South Asian men, compared with white European men, living in the UK, was due to lower cardiorespiratory fitness (maximal oxygen uptake [VO(2max)]) and physical activity. METHODS: One hundred South Asian and 100 age- and BMI-matched European men without diagnosed diabetes, aged 40-70 years, had fasted blood taken for measurement of glucose concentration, HOMA-estimated insulin resistance (HOMA(IR)), plus other risk factors, and underwent assessment of physical activity (using accelerometry), VO(2max), body size and composition, and demographic and other lifestyle factors. For 13 South Asian and one European man, HbA1c levels were >6.5% (>48 mmol/mol), indicating potential undiagnosed diabetes; these men were excluded from the analyses. Linear regression models were used to determine the extent to which body size and composition, fitness and physical activity variables explained differences in HOMA(IR) and fasting glucose between South Asian and European men. RESULTS: HOMA(IR) and fasting glucose were 67% (p < 0.001) and 3% (p < 0.018) higher, respectively, in South Asians than Europeans. Lower VO(2max), lower physical activity and greater total adiposity in South Asians individually explained 68% (95% CI 45%, 91%), 29% (11%, 46%) and 52% (30%, 80%), respectively, and together explained 83% (50%, 119%) (all p < 0.001) of the ethnic difference in HOMA(IR). Lower VO(2max) and greater total adiposity, respectively, explained 61% (9%, 111%) and 39% (9%, 76%) (combined effect 63% [8%, 115%]; all p < 0.05) of the ethnic difference in fasting glucose. CONCLUSIONS/INTERPRETATION: Lower cardiorespiratory fitness is a key factor associated with the excess insulin resistance and fasting glycaemia in middle-aged South Asian, compared with European, men living in the UK. PMID- 23811811 TI - Secondary analysis of electronic databases: potentials and limitations. PMID- 23811810 TI - SDF-1-CXCR4 differentially regulates autoimmune diabetogenic T cell adhesion through ROBO1-SLIT2 interactions in mice. AB - AIMS/HYPOTHESIS: We had previously reported that stromal cell-derived factor 1 (SDF-1) mediates chemorepulsion of diabetogenic T cell adhesion to islet microvascular endothelium through unknown mechanisms in NOD mice. Here we report that SDF-1-mediated chemorepulsion occurs through slit homologue (SLIT)2 roundabout, axon guidance receptor, homologue 1 (Drosophila) (ROBO1) interactions. METHODS: C-X-C receptor (CXCR)4 and ROBO1 protein expression was measured in mouse and human T cells. Parallel plate flow chamber adhesion and detachment studies were performed to examine the molecular importance of ROBO1 and SLIT2 for SDF-1-mediated T cell chemorepulsion. Diabetogenic splenocyte transfer was performed in NOD/LtSz Rag1(-/-) mice to examine the effect of the SDF-1 mimetic CTCE-0214 on adoptive transfer of diabetes. RESULTS: CXCR4 and ROBO1 protein expression was elevated in diabetic NOD/ShiLtJ T cells over time and coincided with the onset of hyperglycaemia. CXCR4 and ROBO1 expression was also increased in human type 1 diabetic T cells, with ROBO1 expression maximal at less than 1 year post diagnosis. Cell detachment studies revealed that immunoneutralisation of ROBO1 prevented SDF-1-mediated chemorepulsion of NOD T cell firm adhesion to TNFalpha-stimulated islet endothelial cells. SDF-1 increased NOD T cell adhesion to recombinant adhesion molecules, a phenomenon that was reversed by recombinant SLIT2. Finally, we found that an SDF-1 peptide mimetic prevented NOD T cell adhesion in vitro and significantly delayed adoptive transfer of autoimmune diabetes in vivo. CONCLUSIONS/INTERPRETATION: These data reveal a novel molecular pathway, which regulates diabetogenic T cell recruitment and may be useful in modulating autoimmune diabetes. PMID- 23811813 TI - Benzene adsorption on binary Pt3M alloys and surface alloys: a DFT study. AB - Benzene adsorption on Pt3M/Pt(111) surfaces and Pt3M(111) bulk alloys (M = Fe, Co, Ni, Cu, Pd, Ag, Au) is analyzed using density functional theory calculations on 4-layered slabs in the framework of catalyst development for aromatics hydrogenation. Segregation in the top layers was allowed for, accounting for the actual stoichiometric composition of the top layers rather than using simplified 'skin' or 'sandwich' structures. On the surfaces that do not segregate (M = Pd, Ag, Au), the preferred benzene adsorption site is the hollow Pt3-hcp(0) site. On antisegregated "Pt-skin" surfaces (M = Fe, Co, Ni, Cu, Pd), which have a top layer composed entirely of Pt, benzene prefers bridge sites with a maximized number of solute atoms M in the subsurface layers. Benzene adsorption is weaker than on pure Pt(111), by 0.1-0.5 eV on the surface alloys and by 0.6-1.0 eV on bulk alloys, except for Pt3Pd alloys, which behave similarly to pure Pt. On the fully segregated Pt3Ag and Pt3Au alloys, which have a Ag resp. Au monolayer on top, only physisorption occurs. Benzene adsorption does not change the segregation state of the catalyst. From various DOS-based catalyst descriptors, the occupied d-band center of the clean catalyst slab shows the best correlation with benzene adsorption energies, allowing the prediction of benzene adsorption energies on a range of other Pt-based bimetallic alloys. PMID- 23811814 TI - Epidemiological, clinical and pathological features of primary cardiac hemangiosarcoma in dogs: a review of 51 cases. AB - In the study presented here, we aimed to describe the epidemiological, clinical and pathological findings of 51 canine cases with histologically-verified diagnoses of primary cardiac hemangiosarcoma (HSA). The medical data for each dog, including signalment, presenting complaints, physical examination findings, results of various diagnostic testing performed and method of treatment, were checked. In addition, all 51 cases were re-examined pathologically. The tumor occurred most frequently in older Golden Retrievers, followed by Maltese dogs and Miniature Dachshunds. Mass lesions of HSA were found more commonly in the right auricle (RAu) (25/51) and right atrium (RA) (21/51), and the RA masses were significantly (P<0.001) larger than the RAu masses. The echocardiographic detection rate of masses in the RAu group (60%; 15/25) was significantly lower than that in the RA group (95%; 20/21). Survival time was significantly (P<0.05) longer for 5 dogs that received adjuvant chemotherapy after tumor resection than for 12 dogs that did not. In this series, the Maltese (9/51) and Miniature Dachshund (7/51), as well as the Golden Retriever, were represented more frequently than other breeds. The lower echocardiographic detection rate of RAu masses compared with RA masses may be related to tumor size and/or location. The significantly longer survival time for dogs receiving adjuvant chemotherapy indicates that postoperative chemotherapy could be useful for dogs with cardiac HSA. PMID- 23811815 TI - Translating the HLA-DPB1 T-cell epitope-matching algorithm into clinical practice. PMID- 23811816 TI - Risk factors and containment of respiratory syncytial virus outbreak in a hematology and transplant unit. AB - Respiratory syncytial virus (RSV) usually causes self-limiting upper respiratory tract infections, but can be associated with severe lower respiratory tract infection disease (LRTID) in infants and in patients with hematologic malignancies. We have analyzed the risk factors and the measures for containment within an outbreak of nosocomial RSV infections in a hematology and SCT unit. A total of 56 patients were affected (53 RSV-A and 3 RSV-B) including 32 transplant patients (16 allogeneic and 16 autologous). Forty (71%) of the 56 patients suffered from LRTID and 14 (35%) of the patients with LRTID subsequently died. However, because of concomitant infections with fungal and bacterial pathogens, the impact of RSV on the fatal outcome was difficult to assess. Multivariate analysis showed that low levels of IgG were significantly associated with fatal outcome (P=0.007), treatment with oral ribavirin represented a protective factor (P=0.02). An extremely protracted viral shedding was observed in this cohort of patients (median=30.5 days, range: 1-162 days), especially pronounced in patients after allogeneic transplantation (P=0.002). Implementation of rigorous isolation and barrier measures, although challenged by long-term viral carriers, was effective in containment of the outbreak. PMID- 23811817 TI - An update to the HLA Nomenclature Guidelines of the World Marrow Donor Association, 2012. AB - For more than two decades, international cooperation and information technology have been playing key roles in the identification of suitable unrelated donors and cord blood units for hematopoietic SCT. To ensure consistent coding and interpretation of HLA data among the linked computer systems, the World Marrow Donor Association has standardized the extensions of the World Health Organization (WHO) Nomenclature for factors of the HLA system applied in practice. The first version of this report published in 2007 has become the reference for the technical validation of HLA information on donors and patients in the context of search and matching and is used by registries of volunteer unrelated hematopoietic stem cell donors and umbilical cord blood banks throughout the world. The present update became necessary after the major revision of the WHO HLA nomenclature in April 2010. It now covers issues arising when alleles are withdrawn or renamed because of the continuous updating of the WHO HLA nomenclature. In addition, formal validation and interpretation rules for the so-called 'multiple allele codes' have been added. PMID- 23811818 TI - Step by step: a proof of concept study of C-Mill gait adaptability training in the chronic phase after stroke. AB - OBJECTIVE: To evaluate the concept of C-Mill gait adaptability training. DESIGN: Pre- and post-intervention assessments. SUBJECTS: Sixteen community-dwelling persons in the chronic phase after stroke (mean age 54.8 years). METHODS: Participants received 10 sessions (1 h per session, for 5-6 weeks) of gait adaptability training on an instrumented treadmill augmented with visual targets and obstacles (C-Mill). Pre- and post-intervention assessments included: (i) clinical assessments of balance and gait: 10-m walking test, Timed Up-and-Go test, Berg Balance Scale, obstacle sub-task of the Emory Functional Ambulation Profile, and the Trunk Impairment Scale; (ii) physical activity level, assessed with a pedometer; (iii) success rate of accurate step adjustments towards a displacing target, assessed with an instrumented Target-Stepping Task; (iv) participant's experience with the training. RESULTS: All clinical assessments improved significantly after training (all p < 0.05), except for the Trunk Impairment Scale (p = 0.584). Physical activity increased by 19.6% (p < 0.05). Improvements in Target-Stepping Task success rates depended on the specific testing condition (time * body support * step direction, chi2(1) = 3.884, p < 0.05). All participants appreciated the training. CONCLUSION: The concept of C Mill gait adaptability training in the chronic phase after stroke is promising and warrants future research involving a randomized controlled trial. PMID- 23811819 TI - Histology and postural change during the growth of the ceratopsian dinosaur Psittacosaurus lujiatunensis. AB - A few dinosaurs are inferred to have undergone an ontogenetic shift from quadrupedal-to-bipedal posture, or vice versa, based on skeletal allometry. The basal ceratopsian Psittacosaurus lujiatunensis is considered to have been mainly bipedal as an adult. Here we infer a postural shift in this species based on a novel combination of limb measurements and histological data. The forelimb is strongly negatively allometric relative to the hindlimb, and patterns of vascular canal orientation provide evidence that growth of the hindlimb was particularly rapid during the middle part of ontogeny. Histology also makes it possible to determine the ontogenetic ages of individual specimens, showing that the forelimb to-hindlimb ratio changed rapidly during the first or second year of life and thereafter decreased gradually. Occurrence of an ontogenetic shift from quadrupedality to bipedality was evidently widespread in dinosaurs, and may even represent the ancestral condition for the entire group. PMID- 23811820 TI - Formation of an iron phosphine-borane complex by formal insertion of BH3 into the Fe-P bond. AB - A unique hydrido phosphine-borane iron(II) complex [(dppa)(Ph2P-N P(BH3)Ph2)Fe(H)] (1) was obtained by the reaction of iron(II) chloride and two equivalents of bis(diphenylphosphino)amine (dppa) with an excess of sodium borohydride in acetonitrile-ethanol mixtures. Detailed investigations of the reaction revealed that a mixture of cis- and trans-[(dppa)2Fe(NCMe)2]2+ is formed prior to the reduction by sodium borohydride. Depending on the solvent, different products were obtained by the reduction: in acetonitrile-ethanol mixtures the hydrido phosphine-borane complex 1 is formed by formal insertion of BH3, while the reduction in pure acetonitrile results in the formation of the cationic complex trans-[(dppa)2Fe(H)(NCMe)](BH4) (4). Complex 4 is remarkably stable in ethanol and does not undergo phosphine-borane formation, even in the presence of excess sodium borohydride. This observation suggests that the phosphine-borane complex is generated by the reaction with the first equivalent of sodium borohydride with the participation of ethanol, followed by deprotonation or dihydrogen elimination. Experiments with similar diphosphine ligands, such as bis(diphenylphosphino)methane, did not yield a phosphine-borane complex, indicating the crucial role of the amine group in the observed reactivity. PMID- 23811821 TI - Role of outer-pore residue Y380 in U-type inactivation of KV2.1 channels. AB - The interpretation of slow inactivation in potassium channels has been strongly influenced by work on C-type inactivation in Shaker channels. Slow inactivation in Shaker and some other potassium channels can be dramatically modulated by the state of the pore, including mutations at outer pore residue T449, which altered inactivation kinetics up to 100-fold. KV2.1, another voltage-dependent potassium channel, exhibits a biophysically distinct inactivation mechanism with a U-shaped voltage-dependence and preferential closed-state inactivation, termed U-type inactivation. However, it remains to be demonstrated whether U-type and C-type inactivation have different molecular mechanisms. This study examines mutations at Y380 (homologous to Shaker T449) to investigate whether C-type and U-type inactivation have distinct molecular mechanisms, and whether C-type inactivation can occur at all in KV2.1. Y380 mutants do not introduce C-type inactivation into KV2.1 and have little effect on U-type inactivation of KV2.1. Interestingly, two of the mutants tested exhibit twofold faster recovery from inactivation compared to wild-type channels. The observation that mutations have little effect suggests KV2.1 lacks C-type inactivation as it exists in Shaker and that C-type and U-type inactivation have different molecular mechanisms. Kinetic modeling predicts that all mutants inactivate preferentially, but not exclusively, from partially activated closed states. Therefore, KV2.1 exhibits a single U-type inactivation process including some inactivation from open as well as closed states. PMID- 23811822 TI - Differential and isomer-specific modulation of vitamin A transport and the catalytic activities of the RBP receptor by retinoids. AB - Retinoids are vitamin A derivatives with diverse biological functions. Both natural and artificial retinoids have been used as therapeutic reagents to treat human diseases, but not all retinoid actions are understood mechanistically. Plasma retinol binding protein (RBP) is the principal and specific carrier of vitamin A in the blood. STRA6 is the membrane receptor for RBP that mediates cellular vitamin A uptake. The effects of retinoids or related compounds on the receptor's vitamin A uptake activity and its catalytic activities are not well understood. In this study, we dissected the membrane receptor-mediated vitamin A uptake mechanism using various retinoids. We show that a subset of retinoids strongly stimulates STRA6-mediated vitamin A release from holo-RBP. STRA6 also catalyzes the exchange of retinol in RBP with certain retinoids. The effect of retinoids on STRA6 is highly isomer-specific. This study provides unique insights into the RBP receptor's mechanism and reveals that the vitamin A transport machinery can be a target of retinoid-based drugs. PMID- 23811823 TI - Identification of 2-piperidone as a biomarker of CYP2E1 activity through metabolomic phenotyping. AB - Cytochrome P450 2E1 (CYP2E1) is a key enzyme in the metabolic activation of many low molecular weight toxicants and also an important contributor to oxidative stress. A noninvasive method to monitor CYP2E1 activity in vivo would be of great value for studying the role of CYP2E1 in chemical-induced toxicities and stress related diseases. In this study, a mass spectrometry-based metabolomic approach was used to identify a metabolite biomarker of CYP2E1 through comparing the urine metabolomes of wild-type (WT), Cyp2e1-null, and CYP2E1-humanized mice. Metabolomic analysis with multivariate models of urine metabolites revealed a clear separation of Cyp2e1-null mice from WT and CYP2E1-humanized mice in the multivariate models of urine metabolomes. Subsequently, 2-piperidone was identified as a urinary metabolite that inversely correlated to the CYP2E1 activity in the three mouse lines. Backcrossing of WT and Cyp2e1-null mice, together with targeted analysis of 2-piperidone in mouse serum, confirmed the genotype dependency of 2-piperidone. The accumulation of 2-piperidone in the Cyp2e1-null mice was mainly caused by the changes in the biosynthesis and degradation of 2-piperidone because compared with the WT mice, the conversion of cadaverine to 2-piperidone was higher, whereas the metabolism of 2-piperidone to 6-hydroxy-2-piperidone was lower in the Cyp2e1-null mice. Overall, untargeted metabolomic analysis identified a correlation between 2-piperidone concentrations in urine and the expression and activity of CYP2E1, thus providing a noninvasive metabolite biomarker that can be potentially used in to monitor CYP2E1 activity. PMID- 23811824 TI - Early dioxin exposure causes toxic effects in adult zebrafish. AB - The acute effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure have been well documented in many vertebrate species. However, less is known about the consequences in adulthood from sublethal exposure during development. To address this, we exposed zebrafish to sublethal levels of TCDD (1h; 50 pg/ml), either in early embryogenesis (day 0) or during sexual determination (3 and 7 weeks), and assessed the effects later in adulthood. We found that exposure during embryogenesis produced few effects on the adults themselves but did affect the offspring of these fish: Malformations and increased mortality were observed in the subsequent generation. Zebrafish exposed during sexual development showed defects in the cranial and axial skeleton as adults. This was most clearly manifested as scoliosis caused by malformation of individual vertebrae. These fish also showed defects in reproduction, producing fewer eggs with lower fertilization success. Both males and females were affected, with males contributing to the decrease in egg release from the females and exposed females contributing to fertilization failure. TCDD exposure at 3 and 7 weeks produced feminization of the population. Surprisingly, part of this was due to the appearance of fish with clearly female bodies, yet carrying testes in place of ovaries. Our results show that exposures that produce little if any impact during development can cause severe consequences during adulthood and present a model for studying this process. PMID- 23811825 TI - Impact of manganese neurotoxicity on MMP-9 production and superoxide dismutase activity in rat primary astrocytes. Effect of resveratrol and therapeutical implications for the treatment of CNS diseases. AB - Manganese (Mn) is an environmental contaminant and its overexposure contributes to the pathophysiological processes of numerous disorders of the central nervous system in humans with mechanisms of action not completely understood. Activation of astrocytes and the subsequent release of neurotoxic factors have been implicated to contribute to neurodegeneration. Here, we assessed the molecular basis of the effects of Mn on modulation of matrix metalloproteinases-2 (MMP-2) and -9 (MMP-9) in rat astrocyte cultures. Primary cultures of rat astrocytes were exposed to different doses of MnCl2. Culture supernatants and cell lysates were used for the detection of MMP-2 and MMP-9 levels and mRNA expression, respectively. The exposure of astrocytes to MnCl2 induced the levels and expression of MMP-9 in a dose-dependent manner. The addition of resveratrol (RSV) inhibited both levels and expression of MMP-9 in astrocytes, whereas N acetylcysteine (NAC) and quercetin (QRC) were ineffective in inhibiting MMP-9. As a possible mechanism of Mn-induced MMP-9, we determined intracellular redox state in Mn-treated astrocytes by assessing superoxide dismutase (SOD) activity and intracellular reactive oxygen species (ROS) and found a significant increase of ROS and a decrease of SOD activity. RSV, NAC, and QRC restored the redox state. The study of the mitogen-activated protein kinase signaling pathway demonstrated that MMP-9 transcription is mainly regulated by extracellular-regulated protein kinases (ERK). Pretreatment with RSV significantly reduced ERK activation suggesting that its ability to counteract MMP-9 overexpression is due not only to a general redox balance phenomenon but also to the modulation of ERK signaling pathway. PMID- 23811826 TI - Assessment of the genotoxic potential of azidothymidine in the comet, micronucleus, and Pig-a assay. AB - The genotoxic potential of azidothymidine (Zidovudine, AZT), chosen as a model compound for nucleotide analogs, was comprehensively assessed in vivo for gene mutation, clastogenicity, and DNA breakage endpoints. Male Wistar rats were treated by oral gavage over 7 days with AZT at dose levels of 2*0 (control), 2*250, 2*500, and 2*1000mg/kg/day with a final single dose given on day 8. DNA damage was then evaluated with the comet assay in liver, stomach, and peripheral blood and with the micronucleus test in bone marrow and peripheral blood (by flow cytometry) in the same animals. After a treatment-free period of upto 42 days, the Pig-a gene mutation assay was performed in peripheral blood of the high-dose animals. In the comet assay as well as the micronucleus test, AZT caused a considerable dose-dependent increase in DNA damage in all tissues evaluated and was highly cytotoxic to bone marrow and peripheral blood cells. These data are well in line with published results. Surprisingly, AZT did not significantly increase the number of Pig-a mutant cells. We speculate that two factors likely contributed to this negative result: a predominance of large deletions caused by AZT, and the relatively low statistical power of the first-generation scoring method used for this study. PMID- 23811827 TI - Genotoxicity profile of azidothymidine in vitro. AB - Azidothymidine (Zidovudine, AZT) is part of the standard care of treatment for acquired immunodeficiency syndrome since many years. A great number of studies on the genotoxic potential of AZT have been published, but no comprehensive hypothesis yet explains all observations. We investigated a multitude of genotoxic endpoints, both in vitro and in vivo, with the goal to complete the picture. The mutagenic potential of AZT in bacteria was found to be restricted to strains with an "ochre" target sequence and could be abrogated both by thymidine supplementation and rat liver S9 mix. Single-strand breaks in mammalian cells were detected in the comet assay after short-term treatment (3h) with AZT, which did not induce micronuclei. The latter were mainly seen after prolonged exposure (24 and 48h) and are probably not directly related to AZT incorporation into DNA. Our data demonstrate that short-term exposure to low AZT concentrations does not induce biologically relevant micronucleation. Only treatment with high concentrations of AZT for prolonged time periods manifests in substantial micronucleus induction. Furthermore, we found that high concentrations of thymidine have no effect in the comet assay but increase micronucleus frequency in a manner very similar to AZT. These results lead us to the following hypothesis: AZT is triphosphorylated and then incorporated into DNA strands, leading to mutations and cytotoxicity. Cellular attempts to repair these DNA lesions as well as stalled replication forks due to chain termination are detectable with the comet assay. Increased micronucleus frequency is likely related to nucleotide pool imbalance. PMID- 23811828 TI - Structural foundations for the O2 resistance of Desulfomicrobium baculatum [NiFeSe]-hydrogenase. AB - This study shows how the NiFeSe site of an anaerobically purified O2-resistant hydrogenase reacts with air to give a seleninate as the first product. Less oxidized states of the active site are readily reduced in the presence of X-rays. Reductive enzyme activation requires an efficient pathway for water escape. PMID- 23811830 TI - The effects of socioeconomic status and race on pediatric neurosurgical shunting. AB - PURPOSE: It is established in the literature that disparities exist in the quality of healthcare for patients from disadvantaged backgrounds and lower socioeconomic status. There may be roadblocks within the field of neurosurgery preventing equal access and quality of care. Our goal was to study the similarities between pediatric patients with shunted hydrocephalus of different insurance types and race. METHODS: A retrospective chart review was performed on all pediatric patients who underwent ventriculoperitoneal shunting from 1990-2010 at our institution. Race and insurance type were recorded and assessed against specific outcome measures to statistically compare complication rates. RESULTS: A complete record was found for 373 patients who received 849 shunting procedures at our institution. No differences were found between racial groups and insurance type for overall shunt survival, total revision number, or average time to failure. However, nonwhite patients spent an average of 3 days longer in the hospital at initial shunting (p = 0.04), and those with public insurance stayed for 5 days longer (p = 0.002). Patients with public insurance were more likely to present with shunt failure from outside hospitals (p = 0.005) and be born prematurely (p < 0.001). Private patients were more likely to have a neoplasm present at time of initial shunt placement (p = 0.003). CONCLUSION: While overall revision rate was not affected by race or insurance status, there were significant delays in discharge for patients with public insurance. Moreover, potential disparities in outpatient access to primary physicians and specialists may be affecting care. PMID- 23811831 TI - A rare case of split pons with double encephalocoele, dermal sinus tract, and lipomeningomyelocele: a case report and review of literature. AB - INTRODUCTION: Multiple neural tube defects and pontine anomalies are relatively rare. Cases of split pons and double encephalocoeles in combination with other spinal anomalies are even rarer. CASE REPORT: Here, we present a very rare case of split pons, twin encephalocoeles (one of which was atretic), lumbar dermal sinus tract, lumbosacral lipomeningomyelocele, thickened filum, and syringomyelia that was managed successfully at our institute. CONCLUSION: Cases of split pons and double encephalocoeles in combination with other spinal anomalies are very rare, and to the best of author's knowledge, this is the first case report of these multiple anomalies in world literature. PMID- 23811829 TI - Chronic inflammation and oxidative stress: the smoking gun for Helicobacter pylori-induced gastric cancer? AB - Helicobacter pylori is the leading risk factor associated with gastric carcinogenesis. H. pylori leads to chronic inflammation because of the failure of the host to eradicate the infection. Chronic inflammation leads to oxidative stress, deriving from immune cells and from within gastric epithelial cells. This is a main contributor to DNA damage, apoptosis and neoplastic transformation. Both pathogen and host factors directly contribute to oxidative stress, including H. pylori virulence factors, and pathways involving DNA damage and repair, polyamine synthesis and metabolism, and oxidative stress response. Our laboratory has recently uncovered a mechanism by which polyamine oxidation by spermine oxidase causes H 2O 2 release, DNA damage and apoptosis. Our studies indicate novel targets for therapeutic intervention and risk assessment in H. pylori induced gastric cancer. More studies addressing the many potential contributors to oxidative stress, chronic inflammation, and gastric carcinogenesis are essential for development of therapeutics and identification of gastric cancer biomarkers. PMID- 23811832 TI - Enlarging photovoltaic effect: combination of classic photoelectric and ferroelectric photovoltaic effects. AB - Converting light energy to electrical energy in photovoltaic devices relies on the photogenerated electrons and holes separated by the built-in potential in semiconductors. Photo-excited electrons in metal electrodes are usually not considered in this process. Here, we report an enhanced photovoltaic effect in the ferroelectric lanthanum-modified lead zirconate titanate (PLZT) by using low work function metals as the electrodes. We believe that electrons in the metal with low work function could be photo-emitted into PLZT and form the dominant photocurrent in our devices. Under AM1.5 (100 mW/cm2) illumination, the short circuit current and open-circuit voltage of Mg/PLZT/ITO are about 150 and 2 times of those of Pt/PLZT/ITO, respectively. The photovoltaic response of PLZT capacitor was expanded from ultraviolet to visible spectra, and it may have important impact on design and fabrication of high performance photovoltaic devices based on ferroelectric materials. PMID- 23811833 TI - Evaluation of coronary microvascular function and nitric oxide synthase intron 4a/b polymorphism in patients with coronary slow flow. AB - OBJECTIVE: Slow coronary flow (SCF) is reported to be associated with increased risk of cardiovascular disease. We have used coronary flow reserve measurement by transthoracic Doppler echocardiography to determine coronary microvascular function in patients with SCF and to determine whether the intron 4a/b polymorphism of the eNOS gene influences coronary endothelial function. METHODS: Overall, 96 patients with SCF and 79 controls were enrolled in the study. Coronary flow was quantified according to the thrombolysis in myocardial infarction (TIMI) frame count (TFC) on angiogram. Coronary diastolic peak flow velocities (DPFV) were measured with color Doppler flow mapping at baseline and after dipyridamole infusion. Coronary flow reserve was calculated as the ratio of hyperemic to baseline DPFV. The eNOS 4a/b polymorphism was detected by PCR. Patients with diabetes were excluded from the study. RESULTS: The SCF group was comparable to the control group in terms of demographic and clinical characteristics, except for hemoglobin and HDL-cholesterol levels, TFC of the left anterior descending artery, the circumflex artery, and the right coronary artery; the mean TFC was higher in the SCF group. Hyperemic DPFV and the hyperemic/baseline DPFV ratio were significantly lower in the SCF group when compared with the control group. However, baseline DPFV were similar in both groups. The number of patients with eNOS4 a/a and eNOS4 a/b phenotypes was statistically higher in SCF groups. The frequency of allele 'a' of the eNOS4 gene was also statistically higher in the SCF group. When patients were grouped according to the presence or absence of allele 'a' of the eNOS4 gene, statistically significant differences were found in the TFC of the left anterior descending artery, the circumflex artery; mean TFC; baseline DPFV; and hyperemic/baseline DPFV. Univariate analysis in which eNOS4 b/b was used as the referent group showed that the presence of allele 'a' of the eNOS4 gene significantly predicted SCF (odds ratio: 2.79, 95% confidence interval: 1.32 5.89; P=0.007). In multivariate analysis using a model adjusted for variables with a P value lower than 0.10 in univariate analyses, the presence of allele 'a' of the eNOS4 gene was found to be an independent predictor of SCF (odds ratio: 3.22, 95% confidence interval: 1.28-8.82; P=0.013). CONCLUSION: The presence of allele 'a' may be a risk factor for microvascular endothelial dysfunction and higher TFCs in SCF patients. PMID- 23811834 TI - Coronary calcifications and plaque characteristics in patients with end-stage renal disease: a computed tomographic study. AB - BACKGROUND: We examined the association between coronary artery calcifications, atherosclerotic burden, and plaque morphology in end-stage renal disease (ESRD) and non-ESRD patients undergoing 64-slice multidetector coronary computed tomographic angiography. METHODS: The prevalence, extent, and severity of coronary atherosclerosis, calcium burden, and plaque morphology were determined in ESRD patients (n=48), and calcium score-matched (n=39) and unmatched non-ESRD controls (n=29) undergoing computed tomographic angiography using dedicated plaque imaging software. RESULTS: ESRD was associated with a higher prevalence of calcified plaques (55.9% vs. 38.3 and 26.9% in the non-ESRD groups, P=0.005) and higher plaque calcium content (43.7 vs. 34.5% and 33.9%; P=0.003). Nonetheless, the calcium score correlated well with plaque burden (r=0.403 in ESRD vs. r=0.433 in non-ESRD, P<0.001 for both), and the diagnostic association between the calcium score and atherosclerotic lesions was good irrespective of ESRD (area under the curve 0.771 vs. 0.804; P=0.574). CONCLUSION: ESRD is associated with diffuse atherosclerosis and calcific plaque morphology. Nonetheless, the association between the calcium score and atherosclerotic burden is not affected by the presence of ESRD. PMID- 23811836 TI - Erythropoietin in cardiac disease: effective or harmful? AB - Discovered as the primary regulator of erythropoiesis, erythropoietin (EPO) is involved in a broad variety of processes that play a major role in cardiovascular diseases. In particular, the antiapoptotic and pro-angiogenic properties of EPO have prompted a growing interest in the use of EPO for the treatment of myocardial infarction and heart failure. In a variety of myocardial ischemic injury animal models, EPO administration has been shown to acutely reduce infarct size, thereby preserving ventricular function. In addition, cardiac long-term effects of EPO, such as prevention of ventricular remodeling and heart failure, have been described. In recent years, several trials have tested the effects of recombinant human erythropoietin (rhEPO) administration in patients with myocardial infarction and chronic heart failure, in the attempt to translate the cardioprotection found in experimental models to human patients. In view of the generally controversial findings, in this updated review we provide an overview of the results of the most recent trials that investigated the role of erythropoiesis-stimulating agents (ESAs), including rhEPO and its analogue darbepoetin, in the treatment of acute myocardial infarction and heart failure. The problems related to safety and tolerability of ESA therapy are also discussed. Our analysis of the available literature demonstrates that the results of clinical studies in patients with cardiac disease are not uniform and the conclusions are contradictory. Further larger prospective studies are required to test clinical efficacy and safety of EPO. PMID- 23811837 TI - Unexpected death from cardiac involvement in acute granulomatosis with polyangiitis (Wegener's): clinical and histopathologic features. PMID- 23811838 TI - Cardiac resynchronization therapy in cardiomyopathies. AB - Cardiomyopathies are a heterogeneous group of diseases of the myocardium that represent a major cause of morbidity and mortality due to progressive heart failure or sudden death. Cardiac resynchronization therapy has become an essential therapeutic tool in the treatment of heart failure patients today. It is an optimal choice in patients with dilated cardiomyopathy; however, its role in the management of patients with other forms of cardiomyopathies is still under investigation. This article discusses the most recent evidence for the use of cardiac resynchronization therapy in cardiomyopathies. PMID- 23811839 TI - Integrating the knowledge: strength and limitations of echo techniques to diagnose and stage heart failure with preserved ejection fraction. AB - Assessment of diastolic function is nowadays done noninvasively; such an approach provides unambiguous information in a large, albeit not complete, proportion of patients suffering from heart failure with preserved ejection fraction (HFpEF). In this review, echocardiography is used in order to diagnose and stage diastolic dysfunction, including abnormal hemodynamic features that can be elicited under stress, three-dimensional echocardiography implementation and most recent 'diastolic indexes'. It must be admitted, however, that there is still uncertainty in diagnosing borderline cases, where a return to invasive data can contribute to a definitive characterization of the HFpEF patients. PMID- 23811840 TI - Prevalence of ventricular arrhythmias in patients with cardiac resynchronization therapy without back-up ICD: a single-center experience. AB - AIMS: Current guidelines recommend cardiac resynchronization therapy (CRT) in selected heart failure patients, but do not precisely clarify when a back-up implantable cardioverter defibrillator (ICD) should be associated (CRT-D). In this study we evaluate the occurrence of ventricular arrhythmias in a population of patients implanted with biventricular pacemaker without a back-up ICD (CRT-P). METHODS: We performed a retrospective analysis on 84 patients (55 men, mean age 74 +/- 7 years), implanted with a CRT-P since April 2000. Patients had in 31% an underlying coronary artery disease, in 56% an idiopatic dilated cardiomyopathy and in 13% a valvular disease. An upgrade to CRT-P was performed from previous conventional pacemakers in 36% of cases. Baseline New York Heart Association (NYHA) functional class was II in 25%, III in 63% and IV in 12%. Mean left ventricular ejection fraction was 29.8 +/- 8.8% with two-dimensional echo. During follow-up, occurrence of ventricular arrhythmias was assessed clinically and through the pacemaker stored data at the scheduled check-up. RESULTS: During a mean follow-up of 29 months (range 2-127 months), telemetry interrogation revealed unsustained ventricular tachyarrhythmias in 11 of 84 patients (13.1%). Only one patient experienced an episode of sustained ventricular tachycardia. An upgrading to a CRT-D was performed in two patients; one of these patients died suddenly 15 months after the upgrade. Death occurred in 20 of 84 patients (23.8%): 15 for refractory heart failure and five for noncardiac causes. CONCLUSION: Our data show that CRT-P may be well tolerated in selected patients even during a long-term follow-up; and that an upgrade to CRT-D may not be enough to prevent sudden death. PMID- 23811842 TI - Refining the assessment of contrast-induced acute kidney injury: the load-to damage relationship. AB - AIMS: Comparing the nephrotoxicity of individual contrast agents is challenging, as contrast-induced acute kidney injury (CI-AKI), a widely used trial endpoint, is unable to discriminate between contrast-related and contrast-unrelated causes of renal damage. We established a quantitative method to selectively evaluate the dose-dependent nephrotoxic effect of different contrast agents. METHODS: We randomized 113 patients undergoing coronary procedures to either iodixanol 320 mg/ml or iobitridol 350 mg/ml. We calculated baseline creatinine clearance (CrCl) and postprocedural change in serum creatinine. We then calculated the regression of the individual iodine load against the creatinine maximum change [load-to damage relationship (LDR)]. We assumed that its R estimates the predictive accuracy of contrast dose-dependent effects on renal function changes, and that the slope of the LDR characterizes the intrinsic nephrotoxicity of the contrast. We also performed a semi-quantitative evaluation of procedural complexity to assess its complementary role in postprocedural AKI. RESULTS: We found significant correlations between contrast load and creatinine changes for both iobitridol (R: 0.29; P <0.0001) and iodixanol (R: 0.15; P = 0.00028). The LDR slope was, however, significantly steeper for iobitridol compared with iodixanol (19.03 +/- 4.02 vs. 14.50 +/- 4.63 Cr*CrCl/I; P <0.001) and in diabetic compared with nondiabetic patients (24.35 +/- 4.96 vs. 4.59 +/- 3.25 Cr*CrCl/I; P <0.001). Adding the procedural complexity score to the contrast load significantly increased the predictive ability of the regression model for postprocedural renal function changes (P < 0.02 for the R increase in overall population), suggesting a role for procedural complexity in postprocedural renal function damage. CONCLUSION: The LDR slope is a promising method to evaluate the specific contrast related fraction of postprocedural AKI. PMID- 23811843 TI - Synthesis of hierarchical TiO2 nanoflower with anatase-rutile heterojunction as Ag support for efficient visible-light photocatalytic activity. AB - Hierarchical flower-like TiO2 with an anatase-rutile heterojunction was prepared by a hydrothermal process in the presence of titanium trichloride and poly(sodium p-styrenesulfonate) (PSS). The morphology evolution process and formation mechanism of the as-obtained products were investigated in detail. It was found that morphology and crystalline phase can be easily adjusted by changing the reaction time or solution system. On the basis of this hierarchical nanoflower structure, a visible light sensitive Ag/hierarchical flower-like TiO2 plasmonic photocatalyst was fabricated. The obtained composite exhibited significantly visible-light photocatalytic activity, which could be attributed to the existence of a large number of uniformly distributed Ag-TiO2 effective nanojunctions, enhanced visible light-harvesting and improved charge separation due to the migration across the anatase-rutile interface. PMID- 23811841 TI - Cardiac resynchronization therapy: implant rates, temporal trends and relationships with heart failure epidemiology. AB - BACKGROUND: Consensus guidelines define indications for cardiac resynchronization therapy (CRT), but the variability in implant rates in 'real world' clinical practice, as well as the relationship with the epidemiology of heart failure are not defined. METHODS AND RESULTS: In Emilia-Romagna, an Italian region with around 4.4 million inhabitants, a registry was instituted to collect data on implanted devices for CRT, with (CRT-D) or without defibrillation (CRT-P) capabilities. Data from all consecutive patients resident in this region who underwent a first implant of a CRT device in years 2006-2010 were collected and standardized (considering each of the nine provinces of the region). The number of CRT implants increased progressively, with a 71% increase in 2010 compared to 2006. Between 84 and 90% of implants were with CRT-D devices. The variability in standardized implant rates among the provinces was substantial and the ratio between the provinces with the highest and the lowest implant rates was always greater than 2. Considering prevalent cases of heart failure in the period 2006 2010, the proportion of patients implanted with CRT per year ranged between 0.23 and 0.30%. CONCLUSIONS: The application in 'real world' clinical practice of CRT in heart failure is quite heterogeneous, with substantial variability even among areas belonging to the same region, with the need to make the access to this treatment more equitable. Despite the increased use of CRT, its overall rate of adoption is low, if a population of prevalent heart failure patients is selected on the basis of administrative data on hospitalizations. PMID- 23811844 TI - Synapse elimination in the developing cerebellum. AB - Neural circuits in neonatal animals contain numerous redundant synapses that are functionally immature. During the postnatal period, unnecessary synapses are eliminated while functionally important synapses become stronger and mature. The climbing fiber (CF) to the Purkinje cell (PC) synapse is a representative model for the analysis of postnatal refinement of neuronal circuits in the central nervous system. PCs are initially innervated by multiple CFs with similar strengths around postnatal day 3 (P3). Only a single CF is selectively strengthened during P3-P7 (functional differentiation), and the strengthened CF undergoes translocation from soma to dendrites of PCs from P9 on (dendritic translocation). Following the functional differentiation, supernumerary CF synapses on the soma are eliminated, which proceeds in two distinct phases: the early phase from P7 to around P11 and the late phase from around P12 to P17. Here, we review our current understanding of cellular and molecular mechanisms of CF synapse elimination in the developing cerebellum. PMID- 23811845 TI - Double deficiency of cathepsins B and L results in massive secretome alterations and suggests a degradative cathepsin-MMP axis. AB - Endolysosomal cysteine cathepsins functionally cooperate. Cathepsin B (Ctsb) and L (Ctsl) double-knockout mice die 4 weeks after birth accompanied by (autophago-) lysosomal accumulations within neurons. Such accumulations are also observed in mouse embryonic fibroblasts (MEFs) deficient for Ctsb and Ctsl. Previous studies showed a strong impact of Ctsl on the MEF secretome. Here we show that Ctsb alone has only a mild influence on extracellular proteome composition. Protease cleavage sites dependent on Ctsb were identified by terminal amine isotopic labeling of substrates (TAILS), revealing a prominent yet mostly indirect impact on the extracellular proteolytic cleavages. To investigate the cooperation of Ctsb and Ctsl, we performed a quantitative secretome comparison of wild-type MEFs and Ctsb (-/-) Ctsl (-/-) MEFs. Deletion of both cathepsins led to drastic alterations in secretome composition, highlighting cooperative functionality. While many protein levels were decreased, immunodetection corroborated increased levels of matrix metalloproteinase (MMP)-2. Re-expression of Ctsl rescues MMP-2 abundance. Ctsl and to a much lesser extent Ctsb are able to degrade MMP-2 at acidic and neutral pH. Addition of active MMP-2 to the MEF secretome degrades proteins whose levels were also decreased by Ctsb and Ctsl double deficiency. These results suggest a degradative Ctsl-MMP-2 axis, resulting in increased MMP-2 levels upon cathepsin deficiency with subsequent degradation of secreted proteins such as collagen alpha-1 (I). PMID- 23811846 TI - Role of host xanthine oxidase in infection due to enteropathogenic and Shiga toxigenic Escherichia coli. AB - Xanthine oxidase (XO) has been recognized as an important host defense enzyme for decades. In our recent study in Infection and Immunity, we found that enteropathogenic and Shiga-toxigenic E. coli (EPEC and STEC) were far more resistant to killing by the XO pathway than laboratory E. coli strains used in the past. Although XO plus hypoxanthine substrate rarely generated enough H 2O 2 to kill EPEC and STEC, the pathogens were able to sense the H2O2 and react to it with an increase in expression of virulence factors, most notably Shiga toxin (Stx). H 2O 2 produced by XO also triggered a chloride secretory response in T84 cell monolayers studied in the Ussing chamber. Adding exogenous XO plus its substrate in vivo did not decrease the number of STEC bacteria recovered from ligated intestinal loops, but instead appeared to worsen the infection and increased the amount of Stx2 toxin produced. XO plus hypoxanthine also increases the ability of Stx2 to translocate across intestinal monolayers. With regard to EPEC and STEC, the role of XO appears more complex and subtle than what has been reported in the past, since XO also plays a role in host-pathogen signaling, in regulating virulence in pathogens, in Stx production and in toxin translocation. Uric acid produced by XO may also be in itself an immune modulator in the intestinal tract. PMID- 23811847 TI - Identification of PTEN at the ER and MAMs and its regulation of Ca(2+) signaling and apoptosis in a protein phosphatase-dependent manner. AB - The tumor suppressor activity of PTEN (phosphatase and tensin homolog deleted on chromosome 10) is thought to be largely attributable to its lipid phosphatase activity. PTEN dephosphorylates the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate to directly antagonize the phosphoinositide 3-kinase-Akt pathway and prevent the activating phosphorylation of Akt. PTEN has also other proposed mechanisms of action, including a poorly characterized protein phosphatase activity, protein-protein interactions, as well as emerging functions in different compartment of the cells such as nucleus and mitochondria. We show here that a fraction of PTEN protein localizes to the endoplasmic reticulum (ER) and mitochondria-associated membranes (MAMs), signaling domains involved in calcium ((2+)) transfer from the ER to mitochondria and apoptosis induction. We demonstrate that PTEN silencing impairs ER Ca(2+) release, lowers cytosolic and mitochondrial Ca(2+) transients and decreases cellular sensitivity to Ca(2+) mediated apoptotic stimulation. Specific targeting of PTEN to the ER is sufficient to enhance ER-to-mitochondria Ca(2+) transfer and sensitivity to apoptosis. PTEN localization at the ER is further increased during Ca(2+) dependent apoptosis induction. Importantly, PTEN interacts with the inositol 1,4,5-trisphosphate receptors (IP3Rs) and this correlates with the reduction in their phosphorylation and increased Ca(2+) release. We propose that ER-localized PTEN regulates Ca(2+) release from the ER in a protein phosphatase-dependent manner that counteracts Akt-mediated reduction in Ca(2+) release via IP3Rs. These findings provide new insights into the mechanisms and the extent of PTEN tumor suppressive functions, highlighting new potential strategies for therapeutic intervention. PMID- 23811849 TI - Defective immunogenic cell death of HMGB1-deficient tumors: compensatory therapy with TLR4 agonists. AB - Immunogenic cell death induced by anticancer chemotherapy is characterized by a series of molecular hallmarks that include the exodus of high-mobility group box 1 protein (HMGB1) from dying cells. HMGB1 is a nuclear nonhistone chromatin binding protein. It is secreted at the late stages of cellular demise and engages Toll-like receptor4 (TLR4) on dendritic cells (DCs) to accelerate the processing of phagocytic cargo in the DC and to facilitate antigen presentation by DC to T cells. The absence of HMGB1 expression by dying tumor cells exposed to anthracyclines or oxaliplatin compromises DC-dependent T-cell priming by tumor associated antigens. Here, we show that transplantable tumors exhibiting weak expression of nuclear HMGB1 respond to chemotherapy more effectively if the treatment is combined with the local or systemic administration of a highly purified and physiochemically defined and standardized lipopolysaccharide solution, which acts as a high-potency and exclusive TLR4 agonist, called Dendrophilin (DEN). The synergistic antitumor effects mediated by the combination of chemotherapy and immunotherapy relied upon the presence of the MyD88 (myeloid differentiation primary response gene) adapter of TLR4 (but not that of the TIR domain-containing adapter-inducing interferon-beta adapter), in line with the well-characterized action of DEN on the MyD88 signaling pathway. DEN and anthracyclines synergized to induce intratumoral accumulation of interferon-gamma producing CD4(+) and CD8(+) T lymphocytes. Moreover, DEN could restore the immunogenicity of dying tumor cells from which HMGB1 had been depleted by RNA interference. These findings underscore the potential clinical utility of combination regimens involving immunogenic chemotherapy and certain TLR4 agonists in advanced HMGB1-deficient cancers. PMID- 23811851 TI - Yeast between life and death: a summary of the Ninth International Meeting on Yeast Apoptosis in Rome, Italy, 17-20 September 2012. PMID- 23811850 TI - Caspase-2 as a tumour suppressor. AB - Ever since its discovery 20 years ago, caspase-2 has been enigmatic and its function somewhat controversial. Although many in vitro studies suggested that caspase-2 was important for apoptosis, demonstrating an in vivo cell death role for this caspase has been more problematic, with caspase-2-deficient mice showing limited, tissue-specific cell death defects. Recent results from different laboratories suggest that at least one of its physiological roles in animals is to protect against cellular stress and transformation. As such, loss of caspase-2 augments tumorigenesis in some mouse models of cancer, assigning a tumour suppressor function to this enigmatic caspase. This review focuses on this seemingly non-apoptotic function of caspase-2 as a tumour suppressor and reconciles some of the recent findings in the field. PMID- 23811852 TI - Low temperature synthesis of silicon carbide nanomaterials using a solid-state method. AB - Silicon carbide (SiC) nanomaterials have been prepared via the solid-state metathesis reaction of various silica sources, magnesium and carbon. This approach enables synthesis of crystalline beta-SiC nanomaterials of varied morphologies at 600 degrees C - the lowest temperature reported to date. The resulting materials were characterized using XRD, FTIR, XPS, TEM and SEM techniques. PMID- 23811854 TI - Development and evaluation of a novel in-clinic automated hematology analyzer, ProCyte Dx, for canine erythrocyte indices, leukogram, platelet counts and reticulocyte counts. AB - A novel hematology analyzer for small animal medicine, ProCyte Dx, was developed from combination of the fluorescence laser flow cytometry and laminar flow impedance technologies, and its accuracy was evaluated by comparing with the conventional impedance-based hematology analyzer, pocH-100iV Diff, or microscopic manual cell counting methods with staining blood smears in the canine blood. Blood samples of 59 dogs were hematologically analyzed and compared by Pearson's correlation coefficients. Analyses between the two analyzers showed excellent correlation in RBC (r=0.998), HGB (r=0.999), HCT (r=0.998), MCV (r=0.994), MCH (r=0.974), MCHC (r=0.906), WBC (r=0.998) and PLT (r=0.993). Analyses between ProCyte Dx and microscopic manual counting results showed excellent correlation in neutrophils (r=0.920), lymphocytes (r=0.913) and reticulocyte percentages (r=0.924), good correlation in eosinophils (r=0.815) and reticulocyte numbers (r=0.850) and fair correlation in monocytes (r=0.770). The present study indicates that ProCyte Dx is acceptably accurate and can be a powerful tool for canine clinical medicine. PMID- 23811855 TI - The emergency department in China: status and challenges. PMID- 23811856 TI - Screening methods to detect child maltreatment: high variability in Dutch emergency departments. AB - BACKGROUND: In the Netherlands, screening for child maltreatment is mandatory in all emergency departments but it is unclear which screening methods are being used. As a first step towards implementation of a universal screening method across all emergency departments, we assessed the currently used screening methods. OBJECTIVE: To provide an overview of the screening methods for child maltreatment across all emergency departments in the Netherlands and to assess their empirical substantiation. METHODS: We surveyed all emergency departments in the Netherlands using a questionnaire on screening methods. All screening checklists used in emergency departments were assembled and compared with the literature. RESULTS: 85 hospitals with an emergency department were approached, 80 of which completed the questionnaire and 77 provided copies of their screening checklists. All participating hospitals use a screening checklist, 41% a screening physical examination, 60% a screening based on parental risk factors and 3% a retrospective review of all charts. The empirical substantiation for these screening methods is largely lacking, and at least 73% of the hospitals use a checklist that has not been reported in the literature. CONCLUSIONS: Large variations in screening methods exist across emergency departments in the Netherlands, most of which are not based on empirical evidence. PMID- 23811853 TI - Pioglitazone improves glucose metabolism and modulates skeletal muscle TIMP-3 TACE dyad in type 2 diabetes mellitus: a randomised, double-blind, placebo controlled, mechanistic study. AB - AIMS/HYPOTHESIS: Pioglitazone (PIO) is a peroxisome proliferator-activated receptor (PPAR)gamma agonist insulin-sensitiser with anti-inflammatory and anti atherosclerotic effects. Our objective was to evaluate the effect of low-dose PIO (15 mg/day) on glucose metabolism and inflammatory state in obese individuals with type 2 diabetes. METHODS: A randomised, double-blind, placebo-controlled, mechanistic trial was conducted on 29 patients with type 2 diabetes treated with metformin and/or sulfonylurea. They were randomised to receive PIO or placebo (PLC) for 6 months, in a 1:1 ratio. Participants were allocated to interventions by central office. All study participants, investigators and personnel performing measurements were blinded to group assignment. At baseline and after 6 months patients underwent: (1) OGTT; (2) muscle biopsy to evaluate expression of TNF alpha, tissue inhibitor of metalloproteases 3 (TIMP-3) levels, TNF-alpha converting enzyme (TACE) expression and enzymatic activity; (3) euglycaemic hyperinsulinaemic clamp; (4) measurement of plasma high-sensitivity C-reactive protein (hsCRP), plasminogen activator inhibitor type-1 (PAI-1), TNF-alpha, IL-6, monocyte chemotactic protein-1 (MCP-1), adiponectin and fractalkine (FRK). The interventions were PIO 15 mg/day vs placebo and the main outcomes measured were absolute changes in whole-body insulin sensitivity, insulin secretion and inflammatory state. RESULTS: Fifteen participants were randomized to receive PIO and 14 participants were randomized to receive PLC. Eleven participants completed the study in the PIO group and nine participants completed the study in the PLC group and were analysed. Fasting plasma glucose and HbA1c decreased modestly (p < 0.05) after PIO and did not change after PLC. M/I (insulin-stimulated whole-body glucose disposal), adipose tissue insulin resistance (IR) index, insulin secretion/IR (disposition) index and insulinogenic index improved significantly after PIO, but not after PLC. Circulating MCP-1, IL-6, FRK, hsCRP and PAI-1 levels decreased in PIO- as compared with PLC-treated patients, while TNF-alpha did not change. TNF-alpha protein expression and TACE enzymatic activity in muscle were significantly reduced by PIO but not PLC. Adiponectin levels increased significantly after PIO as compared with PLC treatment. Given that the mean TACE enzymatic activity level at baseline in the PIO group was 0.29 +/- 0.07 (fluorescence units [FU]), and at end of study decreased to 0.05 vs 0.14 in the PLC group, the power to reject the null hypothesis that the population means of the PIO and PLC groups are equal after 6 months is greater than 0.80. Given that M/I was 2.41 +/- 0.35 MUmol kg(-1) min(-1) (pmol/l)(-1) at baseline and increased by 0.55 in the PIO and 0.17 in the PLC groups, the power to reject the null hypothesis that the population means of the PIO and PLC groups are equal after 6 months is greater than 0.85. The type I error probability associated with this test of this null hypothesis is 0.05. No serious adverse events occurred in either group. CONCLUSIONS/INTERPRETATION: Low-dose PIO (15 mg/day) improves glycaemic control, beta cell function and inflammatory state in obese patients with type 2 diabetes. TRIAL REGISTRATION: Clinical.Trial.gov NCT01223196. FUNDING: This study was funded by TAKEDA. PMID- 23811857 TI - A population based study on the night-time effect in trauma care. AB - BACKGROUND: The so-called off hour effect-that is, increased mortality for patients admitted outside normal working hours-has never been demonstrated in trauma care. However, most of the studies excluded transferred cases. Because these patients are a special challenge for trauma systems, we hypothesised that their processes of care could be more sensitive to the off hour effect. METHODS: The study design was retrospective, cohort and population based. We compared the mortality of all patients by daytime and night-time admittance to hospitals in an Italian region, with 4.5 million inhabitants, following a major injury in 2011. Logistic regression was used, adjusted for demographics and severity of injury (TMPM-ICD9), and stratified by transfer status. RESULTS: 1940 major trauma cases were included; 105 were acutely transferred. Night-time admission had a significant pejorative effect on mortality in the adjusted analysis (OR=1.49; 95% CI 1.05 to 2.11). This effect was most evident in transferred cases (OR=3.71; 95% CI 1.11 to 12.43). CONCLUSIONS: The night-time effect in trauma care was demonstrated for the first time and was maximal in transferred cases. This may explain why it was not found in previous studies where these patients were mostly excluded. Also, the use of population based data-whereby patients not accessing trauma centre care and presumably receiving poorer care were included-may have contributed to the findings. PMID- 23811859 TI - Biomechanical analysis of spinal immobilisation during prehospital extrication: a proof of concept study. AB - BACKGROUND: In most countries, road traffic collisions (RTCs) are the main cause of cervical spine injuries. There are several techniques in use for spinal immobilisation during prehospital extrication; however, the evidence for these is currently poor. OBJECTIVE: The objective of this study is to establish which technique provides the minimal deviation of the cervical spine from the neutral inline position during the extrication of the RTC patient using biomechanical analysis techniques. METHODS: A crew of two paramedics and four fire-fighter first responders extricated a simulated patient from a prepared motor vehicle using nine different extrication techniques. The patient was marked with biomechanical sensors and relative movement between the sensors was captured via high speed infrared motion analysis cameras. A 3D mathematical model was developed from the recorded movement. RESULTS: Control measurements were taken from the patient during self-extrication and movement was recorded of 4.194 degrees left of midline (LOM) to 2.408 degrees right of midline (ROM) resulting in a total movement of 6.602 degrees . The least deviation recorded during equipment aided extrication was movement of 3.365 degrees LOM and 8.352 degrees ROM resulting in a total movement of 11.717 degrees . The most deviation recorded during equipment aided extrication was movement of 1.588 degrees LOM and 24.498 degrees ROM resulting in a total movement of 26.086 degrees . CONCLUSIONS: Conventional extrication techniques record up to four times more cervical spine movement during extrication than controlled self-extrication. This proof of concept study demonstrates the need for further evaluation of current rescue techniques and the requirement to investigate the clinical and operational significance of such movement. PMID- 23811860 TI - Infected urachal cyst in an adult. PMID- 23811858 TI - Substituting community children's nursing services for inpatient care: a case study of costs and effects. AB - OBJECTIVE: To compare children's pathways to and through Community Children's Nursing Team (CCNT) care, and NHS costs, before and after relocation of inpatient services and extension of a paediatric Emergency Department and Observation and Assessment Unit (ED/OAU). DESIGN: Case study. Routinely collected data on activity and staffing were provided by the CCNT. Parents completed questionnaires about their child's use of healthcare services and satisfaction with care preservice reconfiguration (n=221) or postreconfiguration (n=210). The cost of service use was compared prereconfiguration and postreconfiguration. PATIENTS: Children referred to CCNT care. MAIN OUTCOME MEASURES: Healthcare service use and associated costs, satisfaction with CCNT care. RESULTS: The mean number of services used before referral to the CCNT reduced from 2.8 to 1.6, and the proportion using only one service increased from 26% (n=58) to 61% (n=128). Inpatient admission during CCNT care reduced from 6% (n=13) to 2% (n=4), and ED attendance from 37% (n=79) to 16% (n=31). There was a considerable fall (25%) in the cost of CCNT care, and a sharp fall (55%) in the average overall NHS cost of care. CCNT care was rated 'excellent' or 'very good' by 85% of respondents both prereconfiguration and postreconfiguration. CONCLUSIONS: A CCNT provided an alternative to hospitalisation when acute general paediatric services were reconfigured to substitute for a relocated hospital. Children's pathways to CCNT care were shortened. The average cost of CCNT care and overall NHS cost were lower following reconfiguration. Satisfaction remained high throughout. PMID- 23811861 TI - Salt or sugar for your injured brain? A meta-analysis of randomised controlled trials of mannitol versus hypertonic sodium solutions to manage raised intracranial pressure in traumatic brain injury. AB - BACKGROUND: Rising intracranial pressure (ICP) is a poor prognostic indicator in traumatic brain injury (TBI). Both mannitol and hypertonic sodium solutions are used to treat raised ICP in patients with TBI. OBJECTIVE: This meta-analysis compares the use of mannitol versus hypertonic sodium solutions for ICP control in patients with TBI. DATA SOURCES AND STUDY ELIGIBILITY: Randomised clinical trials in adults with TBI and evidence of raised ICP, which compare the effect on ICP of hypertonic sodium solutions and mannitol. METHODS: The primary outcome measure is the pooled mean reduction in ICP. Studies were combined using a Forest plot. RESULTS: Six studies were included, comprising 171 patients (599 episodes of raised ICP). The weighted mean difference in ICP reduction, using hypertonic sodium solutions compared with mannitol, was 1.39 mm Hg (95% CI -0.74 to 3.53). LIMITATIONS: Methodological differences between studies limit the conclusions of this meta-analysis. CONCLUSIONS: The evidence shows that both agents effectively lower ICP. There is a trend favouring the use of hypertonic sodium solutions in patients with TBI. PMID- 23811862 TI - Can first aid training encourage individuals' propensity to act in an emergency situation? A pilot study. AB - OBJECTIVE: To explore the effect that different activities included in first aid training can have on an individual's propensity to act in a medical emergency. DESIGN: Additional pilot-developed activities were added to a core first aid training session to create six unique groups, including a control group where no activities were added. Participants rated their agreement to pre-identified fears following the course and scored their self-efficacy and willingness to act before, immediately after and 2 months after the course. Change values were compared between groups. SETTING: Three locations in the UK (community halls, schools). PARTICIPANTS: 554 members of the public were recruited using advertising and community groups. A deliberately broad demographic was sought and achieved using targeted approaches where a particular demographic was deficient. INTERVENTION: Each participant attended one British Red Cross first aid course lasting 2 h. MAIN OUTCOME MEASURES: The same questionnaire was completed by all participants before and after each course. Two months later all participants were asked a series of follow-up questions. RESULTS: All courses showed an increase in self-efficacy and willingness to act immediately following the course. The course, which included both factual information relevant to helping in an emergency and 'helper' identity activities, produced significantly more positive responses to pre-identified fears. CONCLUSIONS: Activities which allow the learner to explore and discuss behaviour in an emergency situation can effectively increase the learner's propensity to act. First aid education should be expanded to support the learner to develop both the skill and the will to help. PMID- 23811863 TI - Generation of 120 GW mid-infrared pulses from a widely tunable noncollinear optical parametric amplifier. AB - We demonstrate a noncollinear optical parametric chirped-pulse amplification scheme for generating high-peak-power tunable mid-infrared (IR) pulses. The high gain LiNbO(3)-based noncollinear parametric amplifier, seeded by a tunable femtosecond optical parametric amplifier, provides a wide wavelength tuning range from 3.3 to 3.95 MUm and a large saturated gain of over 4000 in a single-stage amplifier. The compressed mid-IR pulse has a pulse energy of 13.3 mJ and pulse duration of 111 fs, with a peak power as high as 120 GW. To the best of our knowledge, this is the highest peak power ever reported for 3-5 MUm tunable mid IR lasers. PMID- 23811864 TI - SBS-managed high-peak-power nanosecond-pulse fiber-based master oscillator power amplifier. AB - We report on a compactly packaged Yb-doped fiber-based laser architecture featuring an actively pulse controlled, single-longitudinal-mode seeder and multistage amplifier chain terminated by a "folded" rod-type photonic crystal fiber. In this laser source, stimulated Brillouin scattering (SBS) is the power limiting factor, but is managed by phase modulating the seeder with a pseudo random noise signal. Pulse energy/peak power of ~2 mJ/1.5 MW at 10 kHz repetition rate are thus obtained within ~1.55 ns pulses of peak spectral brightness >20 kW cm(-2) sr(-1) Hz(-1). PMID- 23811865 TI - Microsecond fiber laser pumped, single-frequency optical parametric oscillator for trace gas detection. AB - We report on the first microsecond doubly resonant optical parametric oscillator (OPO). It is based on a nested cavity OPO architecture allowing single longitudinal mode operation and low oscillation threshold (few microjoule). The combination with a master oscillator-power amplifier fiber pump laser provides a versatile optical source widely tunable in the 3.3-3.5 MUm range with an adjustable pulse repetition rate (from 40 to 100 kHz), high duty cycle (~10(-2)) and mean power (up to 25 mW in the idler beam). The potential for trace gas sensing applications is demonstrated through photoacoustic detection of atmospheric methane. PMID- 23811866 TI - Convolution-variation separation method for efficient modeling of optical lithography. AB - We propose a general method called convolution-variation separation (CVS) to enable efficient optical imaging calculations without sacrificing accuracy when simulating images for a wide range of process variations. The CVS method is derived from first principles using a series expansion, which consists of a set of predetermined basis functions weighted by a set of predetermined expansion coefficients. The basis functions are independent of the process variations and thus may be computed and stored in advance, while the expansion coefficients depend only on the process variations. Optical image simulations for defocus and aberration variations with applications in robust inverse lithography technology and lens aberration metrology have demonstrated the main concept of the CVS method. PMID- 23811867 TI - Photon-number-resolved detection of photon-subtracted thermal light. AB - We examine the photon statistics of photon-subtracted thermal light using photon number-resolved detection. We demonstrate experimentally that the photon number distribution transforms from a Bose-Einstein distribution to a Poisson distribution as the number of subtracted photons increases. We also show that second- and higher-order photon correlation functions can be directly determined from the photon-number-resolved detection measurements of a single optical beam. PMID- 23811868 TI - Neuronal beacon. AB - The controlled navigation of the axonal growth cone of a neuron toward the dendrite of its synaptic partner neuron is the fundamental process in forming neuronal circuitry. While a number of technologies have been pursued for axonal guidance over the past decades, they are either invasive or not controllable with high spatial and temporal resolution and are often limited by low guidance efficacy. Here, we report a neuronal beacon based on light for highly efficient and controlled guidance of cortical primary neurons. PMID- 23811869 TI - Solitary vortices supported by localized parametric gain. AB - We demonstrate the existence and stability of bright vortex solitons sustained by a ring-shaped parametric gain, for both focusing and defocusing Kerr nonlinearities in lossy optical media. With the defocusing nonlinearity, the vortices are stable at all values of the detuning parameter, while under the focusing nonlinearity their stability region is limited to some positive values of the detuning. Unstable vortices in the focusing medium transform into stable rotating azimuthons. PMID- 23811870 TI - Multiobjective optimization in integrated photonics design. AB - We propose the use of the parallel tabu search algorithm (PTS) to solve combinatorial inverse design problems in integrated photonics. To assess the potential of this algorithm, we consider the problem of beam shaping using a two dimensional arrangement of dielectric scatterers. The performance of PTS is compared to one of the most widely used optimization algorithms in photonics design, the genetic algorithm (GA). We find that PTS can produce comparable or better solutions than the GA, while requiring less computation time and fewer adjustable parameters. For the coherent beam shaping problem as a case study, we demonstrate how PTS can tackle multiobjective optimization problems and represent a robust and efficient alternative to GA. PMID- 23811871 TI - Determination of flow orientation of an optically active turbulent field by means of a single beam. AB - The cross-flow orientation of an optically active turbulent field was determined by Fourier transforming the wander of a laser beam propagating in the ocean. A simple physical model for the measured effect is offered, and numerical simulations are performed. The simulations are in good agreement with measurements, validating the assumptions made in the model. PMID- 23811872 TI - Frequency chirp linearization for ultraflat optical frequency comb generation based on group velocity dispersion. AB - We propose to insert group velocity dispersion between cascaded phase and amplitude modulation for ultraflat optical frequency comb (OFC) generation. With the dispersion, the sinusoidally varied chirp of the continuous wave light induced by phase modulation becomes linear within a relatively wide time interval. This is useful to improve the flatness of the generated OFC by directly cascaded phase and amplitude modulation. Simulation shows a flat comb of 37 tones within 0.88 dB power variation when the modulation index of the phase modulation reaches 20. An ultraflat comb generator with 10 GHz frequency spacing is also demonstrated. The flatness of the 15 tones around the center wavelength has been improved to 0.98 dB. PMID- 23811873 TI - Multiresolution foveated laparoscope with high resolvability. AB - A key limitation of the state-of-the-art laparoscopes for minimally invasive surgery is the tradeoff between the field of view and spatial resolution in a single-view camera system. As such, surgical procedures are usually performed at a zoomed-in view, which limits the surgeon's ability to see much outside the immediate focus of interest and causes a situational awareness challenge. We proposed a multiresolution foveated laparoscope (MRFL) aiming to address this limitation. The MRFL is able to simultaneously capture wide-angle overview and high-resolution images in real time; it can scan and engage the high-resolution images to any subregion of the entire surgical field in analogy to the fovea of human eye. The MRFL is able to render equivalently 10 million pixel resolution with a low data bandwidth requirement. The system has a large working distance (WD) from 80 to 180 mm. The spatial resolvability is about 45 MUm in the object space at an 80 mm WD, while the resolvability of a conventional laparoscope is about 250 MUm at a typically 50 mm surgical distance. PMID- 23811874 TI - Efficient mid-infrared Cr:ZnSe channel waveguide laser operating at 2486 nm. AB - We report a Cr:ZnSe channel waveguide laser operating at 2486 nm. A maximum power output of 285 mW is achieved and slope efficiencies as high as 45% are demonstrated. Ultrafast laser inscription is used to fabricate the depressed cladding waveguide in a polycrystalline Cr:ZnSe sample. Waveguide structures are proposed as a compact and robust solution to the thermal lensing problem that has so far limited power scaling of transition metal doped II-VI lasers. PMID- 23811875 TI - Fluidic lens of floating oil using round-pot chamber based on electrowetting. AB - This study presents a liquid lens using electrowetting that employs an oil phase floating in between the conducting fluids. The lens shape has double-sided surfaces and operates with a bias of 0-60 V. The focal length of the lens, with an aperture size of 2 mm, is ~5.8 mm, and it is converted into an optical power of 172. The lens is sufficient to suppress the fluctuation of fluids due to the external vibration. An image seen through the lens clearly resolves the element better than 6.35 LP/mm on USAF 1951 1*. PMID- 23811876 TI - Resonant THz sensor for paper quality monitoring using THz fiber Bragg gratings. AB - We report fabrication of THz fiber Bragg gratings (TFBG) using CO(2) laser inscription on subwavelength step-index polymer fibers. A fiber Bragg grating with 48 periods features a ~4 GHz-wide stop band and ~15 dB transmission loss in the middle of a stop band. The potential of such gratings in the design of resonant sensors for the monitoring of paper quality is demonstrated. Experimental spectral sensitivity of the TFBG-based paper thickness sensor was found to be ~-0.67 GHz/10 MUm. A 3D electromagnetic model of a Bragg grating was used to explain experimental findings. PMID- 23811877 TI - Investigation of composite materials using SLM-based phase retrieval. AB - We present a robust method to inspect a typical composite material constructed of carbon fiber reinforced plastic (CFRP). It is based on optical surface contouring using the spatial light modulator (SLM)-based phase retrieval technique. The method utilizes multiple intensity observations of the wave field, diffracted by the investigated object, captured at different planes along the optical axis to recover the phase information across the object plane. The SLM-based system allows for the recording of the required consecutive intensity measurements in various propagation states across a common recording plane. This overcomes the mechanical shifting of a camera sensor required within the capturing process. In contrast to existing phase retrieval approaches, the measuring time is considerably reduced, since the switching time of the SLM is less than 50 ms. This enables nondestructive testing under thermal load. Experimental results are presented that demonstrate the approach can be used to assess structural properties of technical components made from CFRP. PMID- 23811878 TI - Nonlinear characterization of materials using the D4sigma method inside a Z-scan 4f-system. AB - We show that direct measurement of the beam radius in Z-scan experiments using a CCD camera at the output of a 4f-imaging system allows higher sensitivity and better accuracy than Baryscan. One of the advantages is to be insensitive to pointing instability of pulsed lasers because no hard (physical) aperture is employed as in the usual Z-scan. In addition, the numerical calculations involved here and the measurement of the beam radius are simplified since we do not measure the transmittance through an aperture and it is not subject to mathematical artifacts related to a normalization process, especially when the diffracted light intensity is very low. PMID- 23811879 TI - Effective light bending and controlling in a chamber-channel waveguide system. AB - A novel chamber-channel system is proposed to achieve the bending of light at a 90 deg angle with relatively high transmission efficiencies. An ultrathin film is introduced into the chamber to couple more light into the system, which makes the chamber as a light absorber, while the channel serves as an output pathway to guide the light through the system. We show that the light propagation is significantly affected by the output position of the channels. By setting the output to specific positions, the device can be considered as a light switch, amplifier, or filter. This work holds great potential for controlling light in nanoscale photonic devices. PMID- 23811880 TI - Fabrication of polarization-dependent light attenuator in fused silica using a low-repetition-rate femtosecond laser. AB - In this Letter, we have demonstrated the direct writing of polarization-dependent light attenuator inside fused silica by tailoring 1 kHz femtosecond (fs) laser induced self-organized nanogratings. Optical birefringence was observed to vary with the polarization plane azimuth of the fs laser and scanning direction. The formation of self-organized nanogratings was confirmed by scanning electron microscopy observation. A polarization-dependent light attenuator was fabricated by forming a plane consisting of nanograting lines inside fused silica by scanning the fs laser. The attenuation efficiency was improved by forming a multilayer nanograting structure. The technique may find important applications in micro-optical devices. PMID- 23811881 TI - Five-ring hollow-core photonic crystal fiber with 1.8 dB/km loss. AB - A 19-cell hollow-core photonic crystal fiber reaching 1.8+/-0.5 dB/km loss at 1530 nm is reported. Despite expanded corner holes in the first ring adjacent to the core, and only five cladding rings, the minimum loss is close to the previously published record of 1.7 dB/km at a comparable wavelength, achieved in a fiber with seven cladding rings. Since each additional cladding ring requires a significant increase in fabrication time and complexity, it is highly desirable to use as few as possible while still achieving low loss. Modeling results confirm that further reducing cladding deformations would yield only a small decrease in loss. This demonstrates that loss comparable to the previously demonstrated lowest-loss bandgap fibers can be achieved with fiber structures that are significantly simpler and faster to fabricate. PMID- 23811882 TI - Arbitrary nonparaxial accelerating periodic beams and spherical shaping of light. AB - We report the observation of arbitrary accelerating beams (ABs) designed using a nonparaxial description of optical caustics. We use a spatial light modulator based setup and techniques of Fourier optics to generate circular and Weber beams subtending over 95 deg of arc. Applying a complementary binary mask also allows the generation of periodic ABs taking the forms of snake-like trajectories, and the application of a rotation to the caustic allows the first experimental synthesis of optical ABs upon the surface of a sphere in three dimensions. PMID- 23811883 TI - Silicon-on-insulator-based adiabatic splitter with simultaneous tapering of velocity and coupling. AB - We propose and experimentally demonstrate a 2*2 3 dB adiabatic splitter based on silicon-on-insulator technology, with simultaneous tapering of the phase velocity and coupling. The advantages of the proposed splitter are indicated by analyzing the effective index evolution of the system modes and comparing them with the simulated performances. The experimental results are in good agreement with the simulations. Over the 100 nm wavelength range measured, the output uniformity is better than 0.2 dB. A low and flat excess loss of about 0.3 dB per splitter is obtained, with a variation below 0.2 dB. PMID- 23811884 TI - Fiber Bragg grating inscription in few-mode highly birefringent microstructured fiber. AB - In this Letter, we present the technology of fiber Bragg grating (FBG) inscription in highly birefringent (HB) few-mode microstructured fibers (MSFs) with two different (nanosecond and femtosecond) lasers in a Talbot interferometer setup. The spectral characteristics of FBGs written in the core region of the investigated fiber, with particular modes represented by dual peaks, are presented and discussed. Furthermore, we calculate the fundamental fiber parameters (mode effective refractive index and phase modal birefringence) from the spectral characteristics and show very good agreement with the performed numerical fiber characterization. We expect the results of our experiments to be very useful in future development of FBG sensors based on novel HB MSFs, with enhanced strain sensitivity of higher-order modes. PMID- 23811886 TI - 75 W 40% efficiency single-mode all-fiber erbium-doped laser cladding pumped at 976 nm. AB - Optimization of Yb-free Er-doped fiber for lasers and amplifiers cladding pumped at 976 nm was performed in this Letter. The single-mode fiber design includes an increased core diameter of 34 MUm and properly chosen erbium and co-dopant concentrations. We demonstrate an all-fiber high power laser and power amplifier based on this fiber with the record slope efficiency of 40%. To the best of our knowledge, the achieved output power of 75 W is the highest power reported for such lasers. PMID- 23811885 TI - Time-resolved photoluminescence of Zn(OH)2 and its composites with graphite oxides. AB - Time-resolved photoluminescence is used to determine carrier recombination through radiative and nonradiative processes in zinc hydroxide Zn(OH)(2) and its porous composites with graphite oxide (GO). The decay times, measured by a streak camera, are found to be larger for zinc hydroxide (~1215+/-156 ps) than its composites (~976+/-81 ps for ZnGO-2 and 742+/-59 ps for ZnGO-5), but no significant changes in rise times (from 4.0 to 5.0 ps) are recorded. The dominant mechanism for the radiative process is attributed to free carrier recombination, while microporous networks present in these materials are found to be pathways for the nonradiative recombination process via multiphonon emission. PMID- 23811887 TI - Spectral Gaussian Schell-model beams. AB - A generalization of the classic Gaussian Schell-model source is considered for which the rms width of the beam sigma and the rms width of the spectral degree of coherence delta are assumed to depend on wavelength. It is shown that the functional form sigma(lambda) and delta(lambda) of such a source can affect the behavior of the spectral density, the degree of coherence, and the degree of polarization of the propagating beam. PMID- 23811888 TI - Polarization-insensitive photonic microwave downconversion. AB - A polarization-insensitive photonic microwave downconverter is proposed and demonstrated, which is comprised of a polarization beam splitter, two Mach Zehnder modulators (MZMs), and a balanced photodetector. By biasing the MZMs at the quadrature bias points with opposing modulation slopes, the performance of the proposed photonic microwave downconverter is almost independent of the polarization state of the optical microwave signal for down conversion. An experiment is performed, which shows that the polarization dependent loss of the proposed downconverter is less than 0.06 dB. The downconverter is also evaluated in a radio-over-fiber link. A 20 GHz RF signal with 20 MBaud 16 quadrature amplitude modulation baseband data is successfully downconverted to a 1 GHz IF signal. When the polarization state of the input optical microwave signal is adjusted, the variation of the error vector magnitude of the downconverted signal is less than 0.4%. PMID- 23811889 TI - Preparation of a YAG:Ce phosphor glass by screen-printing technology and its application in LED packaging. AB - A simple and practical method for preparing phosphor glass is proposed. Phosphor distribution and element analysis are investigated by optical microscope and field emission scanning electron microscope (FE-SEM). The phosphor particles dispersed in the matrix are vividly observed, and their distributions are uniform. Spectrum distribution and color coordinates dependent on the thickness of the screen-printed phosphor layer coupled with a blue light emitting diode (LED) chip are studied. The luminous efficacy of the 75 MUm printed phosphor layer phosphor glass packaged white LED is 81.24 lm/W at 350 mA. This study opens up many possibilities for applications using the phosphor glass on a selected chip in which emission is well absorbed by all phosphors. The screen-printing technique also offers possibilities for the design and engineering of complex phosphor layers on glass substrates. Phosphor screen-printing technology allows the realization of high stability and thermal conductivity for the phosphor layer. This phosphor glass method provides many possibilities for LED packing, including thin-film flip chip and remote phosphor technology. PMID- 23811890 TI - Direct eigenmode analysis of plasmonic modes in metal nanoparticle chain with layered medium. AB - Using the dyadic Green function (GF) with a multilayer medium, we propose an eigendecomposition (ED) analysis of a plasmonic system composed of a one dimensional periodic metal nanoparticle chain and planar layered structure. An effective eigenpolarizability involving the collective effects of both the chain and the layered structure is well defined to characterize the dispersion relation and the mode quality of the plasmonic modes. Applying this method, we demonstrate that the interplay between the surface plasmon polaritons (SPPs) at the metal dielectric interface and the localized plasmon in the chain enables strong mode splitting. In particular, for the polarization perpendicular to layer surface, high-quality modes can be present inside the light cone even if the chain is open to the surrounding air. A slow-light band is also predicted to exist as long as the layered medium supports a SPP mode that can couple to the chain mode. PMID- 23811891 TI - Near-infrared broadband absorber with film-coupled multilayer nanorods. AB - Turning the surfaces of noble metals (metasurfaces) into black (highly absorptive) surfaces can be potentially applied in thermophotovoltaics, sensing, tailoring thermal emissivity, etc. Here we demonstrate an extremely broadband absorber for the 900-1600 nm wavelength range with robust high absorption efficiency. The inexpensive droplet evaporation method is implemented to create patterns of nanoparticles dispersed on a gold film spaced by a thin dielectric layer. The diversity of the complicated random stacking of the chemically synthesized gold nanorods is the major factor for the broad absorption band. Such a metamaterial absorber may pave the way for cost-effective manufacture of large area black metasurfaces. PMID- 23811892 TI - Multifunctional bowtie-shaped ridge aperture for overlay alignment in plasmonic direct writing lithography using a contact probe. AB - We propose a scheme of overlay alignment for plasmonic lithography using a scanning contact probe. Using two resonances of a ridge aperture in a metal film, we introduce the aperture's multifunctional characteristics for patterning and alignment at different wavelengths. To verify this idea, we measure an image of an alignment mark using a scanning ridge aperture and determine the reference point for the alignment. We then analyze the uncertainty of the alignment method with respect to the image data noise and compare the numerical results with the experimental results. The uncertainty of the overlay alignment method is shown to be less than approximately 2 nm. PMID- 23811893 TI - Disorder-mediated enhancement of fiber numerical aperture. AB - The numerical aperture (NA) of a multimode optical fiber sets the limit of the information transport capacity along the spatial degree of freedom. In this Letter, we report that the application of a highly disordered medium can overcome the capacity limit set by the fiber NA. Specifically, we coated the input surface of a multimode fiber with a disordered medium made of ZnO nanoparticles and transported a wide-field image through the fiber with a spatial resolution beyond the diffraction limit given by the fiber NA. This was made possible because multiple scatterings induced by the disordered medium physically increased the NA of the entire system. Our study will lead to enhancing the spatial resolution of fiber-based endoscopic imaging and also improving the information transport capacity in optical communications. PMID- 23811894 TI - Nanostripe length dependence of plasmon-induced material deformations. AB - Following the impact of a single femtosecond light pulse on nickel nanostripes, material deformations-or "nanobumps"-are created. We have studied the dependence of these nanobumps on the length of nanostripes and verified the link with plasmons. More specifically, local electric currents can melt the nanostructures in the hotspots, where hydrodynamic processes give rise to nanobumps. This process is further confirmed by independently simulating local magnetic fields, since these are produced by the same local electric currents. PMID- 23811895 TI - Engineering band structure in nanoscale quantum-dot supercrystals. AB - Supercrystals made of periodically arranged semiconductor quantum dots (QDs) are promising structures for nanophotonics applications due to almost unlimited degrees of freedom enabling fine tuning of their optical responses. Here we demonstrate broad engineering opportunities associated with the possibility of tailoring the energy bands of excitons in two-dimensional quantum-dot supercrystals through the alteration in the QD arrangement. These opportunities offer an unprecedented control over the optical properties of the supercrystals, which may be used as a versatile material base for advanced photonics devices on the nanoscale. PMID- 23811896 TI - Optical fiber interferometer array for scanless Fourier-transform spectroscopy. AB - We report a spatial heterodyne Fourier-transform spectrometer implemented with an array of optical fiber interferometers. This configuration generates a wavelength dependent stationary interferogram from which the input spectrum is retrieved in a single shot without scanning elements. Furthermore, fabrication and experimental deviations from the ideal behavior of the device are corrected by spectral inversion algorithms. The spectral resolution of our system can be readily scaled up by incorporating longer optical fiber delays, providing a pathway toward surpassing current spectroscopy resolution limits. PMID- 23811897 TI - Path length modulation technique for scatter noise immunity in squeezing measurements. AB - We present a technique for frequency shifting scattering induced noise on squeezed light beams, providing immunity from scattered light while preserving the squeezed states. Using a 500 Hz pre and postsqueezing apparatus path length modulation, we show up to a 20 dB reduction in scattering induced noise while recovering squeezing measurement below the shot noise level. Such a technique offers immunity to spurious scattering sources without the need for optically lossy isolation optics. PMID- 23811898 TI - Wave shape recovery for terahertz pulse field detection via photoconductive antenna. AB - For photoconductive (PC) antennae used as terahertz (THz) detectors, traditional data processing methods should be improved because the space-charge and radiation field screening effects and the time dependence of photocarriers density have not been considered. Through developing a double-probe-pulse THz detection technique and using an equivalent-circuit model to describe PC antennae, we present a new method to restore the THz-field wave shape from the measurement data of currents between two electrodes on the antenna. This method is verified to be effective through building a special THz time-domain spectroscopy system with double probes. This work is significant for the accurate determination of pulse THz fields. PMID- 23811899 TI - Coherent correlator and equalizer using a reconfigurable all-optical tapped delay line. AB - We experimentally demonstrate a reconfigurable optical tapped delay line in conjunction with coherent detection to search multiple patterns among quadrature phase shift keying (QPSK) symbols in 20 Gbaud data channel and also to equalize 20 and 31 Gbaud QPSK, 20 Gbaud 8 phase shift keying (PSK), and 16 QAM signals. Multiple patterns are searched successfully on QPSK signals, and correlation peaks are obtained at the matched patterns. QPSK, 8 PSK, and 16 QAM signals are also successfully recovered after 25 km of SMF-28 with average EVMs of 8.3%, 8.9%, and 7.8%. A penalty of <1 dB optical signal to noise penalty is achieved for a 20 Gbaud QPSK signal distorted by up to 400 ps/nm dispersion. PMID- 23811901 TI - Helical-core fiber analog of a quarter-wave plate for orbital angular momentum. AB - We have studied the effect of a twist defect on the conversion of the fundamental mode (FM) into an optical vortex (OV) in a helical-core fiber (HCF). We have shown that if such a twist defect is situated in the middle of the HCF, which converts the FM into an OV, such a fiber system can continuously change the orbital angular momentum (OAM) of the output field from 0 to 1 (in a.u.). This control of the OAM is achieved by variation of the twist angle. In this action upon the OAM, this system has analogy with the quarter-wave plate, which is able to change the spin angular momentum. We also introduced the generalized Stokes parameters (SPs) and Poincare sphere to visualize evolution of the superposition of states with zero and nonzero OAM. Connection of SPs with geometric characteristics of the location of singularity is made. PMID- 23811900 TI - Subwavelength light localization based on optical nonlinearity and light polarization. AB - We propose and experimentally realize subwavelength light localization based on the optical nonlinearity of a single nonlinear element in nanoplasmonics-a split hole resonator (SHR). The SHR is composed of two basic elements of nanoplasmonics, a nanohole, and a nanorod. A peak field intensity occurs at the single spot of the SHR nanostructure. We demonstrate the use of the SHR as a highly efficient nonlinear optical element for (i) the construction of a polarization-ultrasensitive nanoelement and, as a practical application, (ii) the building up of an all-optical display. PMID- 23811902 TI - Yb(3+)-doped GeS(2)-Ga2S(3)-CsCl glass with broad and adjustable absorption/excitation band for near-infrared luminescence. AB - The luminescent property of Yb(3+) ions in GeS(2)-Ga(2)S(3)-CsCl glasses with different CsCl contents has been studied. All the samples demonstrate a broad excitation band in the UV or/and visible range, depending on the composition, which is attributed to the charge transfer of the Yb(3+)-S(2-)/Cl(-) couple. The width of the excitation/absorption band can be as large as 150 nm. Moreover, with the increase of CsCl content, the peak position of the band can be continuously adjusted from 458 to 380 nm, due to the increase of the local average electronegativity around Yb(3+) ions. The broad and adjustable excitation band makes the Yb(3+)doped GeS(2)-Ga(2)S(3)-CsCl glass interesting for modifying the solar spectrum by absorbing strongly in the UV/blue region for emission around 1 MUm. This kind of material is the key to adapting the solar spectrum to the response of silicon photovoltaic solar cells. PMID- 23811903 TI - 530 W, 1.3 mJ, four-channel coherently combined femtosecond fiber chirped-pulse amplification system. AB - We report on a femtosecond fiber laser system comprising four coherently combined large-pitch fibers as the main amplifier. With this system, a pulse energy of 1.3 mJ and a peak power of 1.8 GW are achieved at 400 kHz repetition rate. The corresponding average output power is as high as 530 W. Additionally, an excellent beam quality and efficiency of the combination have been obtained. To the best of our knowledge, such a parameter combination, i.e., gigawatt pulses with half a kilowatt average power, has not been demonstrated so far with any other laser architecture. PMID- 23811904 TI - Spatially resolved measurement of singlet delta oxygen by radar resonance enhanced multiphoton ionization. AB - Coherent microwave Rayleigh scattering (Radar) from resonance-enhanced multiphoton ionization (REMPI) was demonstrated to directly and nonintrusively measure singlet delta oxygen, O(2)(a(1)Delta(g)), with high spatial resolution. Two different approaches, photodissociation of ozone and microwave discharge plasma in an argon and oxygen flow, were utilized for O(2)(a(1)Delta(g)) generation. The d(1)Pi(g)<-a(1)Delta(g) (3-0) and d(1)Pi(g)<-a(1)Delta(g) (1-0) bands of O(2)(a(1)Delta(g)) were detected by Radar REMPI for two different flow conditions. Quantitative absorption measurements using sensitive off-axis integrated cavity output spectroscopy (ICOS) was used simultaneously to evaluate the accuracy and sensitivity of the Radar REMPI technique. The detection limit of Radar REMPI was found to be comparable to the ICOS technique with a detection threshold of approximately 10(14) molecules/cm(3) but with a spatial resolution that was 8 orders of magnitude smaller than the ICOS technique. PMID- 23811905 TI - Mode-locked VECSEL emitting 5 ps pulses at 675 nm. AB - A picosecond GaInP/AlGaInP/GaAs vertical external-cavity surface-emitting laser (VECSEL) at 675 nm is reported. The laser is mode-locked with a GaInP/AlGaInP/GaAs saturable absorber mirror and emitted ~5.1 ps pulses at a 973 MHz repetition rate and an average power of 45 mW. To our knowledge, this is the first demonstration of a passively mode-locked VECSEL emitting fundamental laser radiation at the visible part of the spectrum. PMID- 23811906 TI - Power scalable >25 W supercontinuum laser from 2 to 2.5 MUm with near-diffraction limited beam and low output variability. AB - A power scalable thulium-doped fiber-amplifier-based supercontinuum (SC) laser covering the shortwave infrared region from 2 to 2.5 MUm is demonstrated. The SC laser has an average power up to 25.7 W and a spectral density of >12 dBm/nm. Power scalability of the laser is proven by showing that the SC laser maintains a nearly constant spectral output, beam quality (M(2) measurements), and output spectral stability as the SC average power is scaled from 5 to 25.7 W average output power. We verify that the SC laser beam is nearly diffraction limited with an M(2)<1.2 for all power levels. Output spectral stability measurements with power scaling show a radiometric variability of <0.8% across the entire SC spectrum. PMID- 23811907 TI - Limits to superweak amplification of beam shifts. AB - The magnitudes of beam shifts (Goos-Hanchen and Imbert-Fedorov, spatial and angular) are greatly enhanced when a reflected light beam is postselected by an analyzer, by analogy with superweak measurements in quantum theory. Particularly strong enhancements can be expected close to angles at which no light is transmitted for fixed initial and final polarizations. We derive a formula for the angular and spatial shifts at such angles (which includes the Brewster angle), and we show that their maximum size is limited by higher-order terms from the reflection coefficients occurring in the Artmann shift formula. PMID- 23811908 TI - Spatial modulation of second-harmonic generation via nonlinear Raman-Nath diffraction in an aperiodically poled lithium tantalite. AB - We propose and experimentally demonstrate a colorful nonlinear Raman-Nath second harmonic generation by engineering the quadratic nonlinearity chi((2)) in an aperiodically poled lithium tantalite. The engineered nonlinear structure allows multicolored Raman-Nath second-harmonic signal outputs along a uniform direction, which cannot be achieved in a uniform nonlinear grating. The diffraction angles are independent of the beam waist and the position of incidence. This verifies that nonlinear Raman-Nath diffraction does not depend on the local superlattice structure where the fundamental frequency beam locates, but on the whole nonlinear chi((2)) crystal. PMID- 23811909 TI - Van Cittert-Zernike theorem with Stokes parameters. AB - We formulate the van Cittert-Zernike theorem for spatially incoherent partially polarized sources in terms of the traditional polarization (one-point) Stokes parameters and the coherence (two-point) Stokes parameters. This leads to a physically insightful connection between the source polarization and the field coherence. We show that the far-zone coherence is given by a Fourier relation of the source-plane polarization and apply the results to investigate the far-zone properties of a field emitted by an incoherent source limited by an annular aperture. PMID- 23811910 TI - Temporal ringdown of silicon-on-insulator racetrack resonators. AB - Ring-down temporal measurements of silicon-on-insulator wire racetrack resonators are performed with 150 fs input pulses using a parametric process in a nonlinear crystal to gate and amplify the weak output pulses. We measure the cavity round trip time and the quality factor of these all-pass filters and find excellent agreement with continuous wave spectroscopic measurements as well as with an analytic model built using numerical solutions for the fully vectorial waveguide modes. PMID- 23811911 TI - Continuous-wave terahertz field imaging based on photonics-based self-heterodyne electro-optic detection. AB - We demonstrate a photonics-based self-heterodyne electro-optic field imaging technique at terahertz (THz) frequency. An optical intensity beat generated by mixing two frequency-detuned free-running lasers is used for both the generation and the detection. The frequency of the beat for detection is shifted by an optical frequency shifter to realize coherent heterodyne measurement with free running lasers. Neither mechanical delay lines nor phase-locked synthesizers are required for the amplitude and the phase imaging of the THz field, and the system simplicity is thus improved. The amplitude and phase of the THz field (125 GHz) radiated from a horn antenna are simultaneously imaged, and the standard deviation of the phase measurement is found to be 0.18 rad. PMID- 23811912 TI - Broadband converging plano-concave lens. AB - A plano-concave lens with source-tailored geometric profile and transformational gradient index is proposed for broadband illumination. Such a design, capable of focusing and collimating the electromagnetic fields, fulfils the functionality of a converging lens and can also achieve a steerable beam and multiple beams efficiently. Nonresonant synthesis with a perforated dielectric plate and dielectric rod arrays is demonstrated for the lensing realization, promising a wide operating frequency band in the practical implementation. PMID- 23811913 TI - High-resolution optical spectrum characterization using optical channel estimation and spectrum stitching technique. AB - A technique is proposed to measure the high-resolution and wide-band characterization of amplitude, phase responses, and polarization property of optical components. This technique combines the optical spectrum stitching and optical channel estimation methods. Two kinds of fiber Bragg grating based Fabry Perot cavities with ultrafine structures have been characterized based on this technique. By using 1024 point fast Fourier transform and a narrow linewidth, wavelength-tunable laser source, a frequency resolution of ~10 MHz is realized with an optical measurement range beyond 250 GHz. PMID- 23811914 TI - Rotation-managed dissipative solitons. AB - We show that when spatially localized gain landscape performs accelerated motion in the transverse plane, i.e., when it rotates or oscillates around the light propagation axis, the effective gain experienced by the light beam considerably reduces with an increase of the amplitude of oscillations or frequency of rotation of the localized gain. In the presence of uniform background losses and defocusing nonlinearity, such gain landscapes may support dynamically oscillating gain-managed solitons, but if the amplitude of oscillations or the frequency of rotation of the localized gain exceeds a threshold, stable attractors disappear and any input beam decays. PMID- 23811915 TI - Development of a beveled fiber-optic confocal Raman probe for enhancing in vivo epithelial tissue Raman measurements at endoscopy. AB - We report on the development of a beveled fiber-optic confocal Raman probe coupled with a ball lens for enhancing in vivo epithelial tissue Raman measurements at endoscopy. Our Monte Carlo simulations show that by selecting a proper fiber-ball lens distance and beveled angle of collection fibers, the confocal Raman probe design can be optimized for maximizing shallower tissue Raman measurements in epithelial tissue; in addition, the ratio of epithelium to stromal Raman photons collected using an optimized confocal Raman probe is approximately 19-fold higher than that using a volume-type Raman probe. Further experiments confirm that the confocal Raman endoscopic probe developed is in favor of probing superficial tissue Raman signals from a two-layer tissue phantom as well as esophagus tissue in vivo during endoscopy. This work suggests the great potential of applying the beveled fiber-optic confocal Raman probe for improving in vivo diagnosis of precancer occurring in epithelial tissue at endoscopy. PMID- 23811916 TI - Compression of Born ratio for fluorescence molecular tomography/x-ray computed tomography hybrid imaging: methodology and in vivo validation. AB - The 360 degrees rotation geometry of the hybrid fluorescence molecular tomography/x-ray computed tomography modality allows for acquisition of very large datasets, which pose numerical limitations on the reconstruction. We propose a compression method that takes advantage of the correlation of the Born normalized signal among sources in spatially formed clusters to reduce the size of system model. The proposed method has been validated using an ex vivo study and an in vivo study of a nude mouse with a subcutaneous 4T1 tumor, with and without inclusion of a priori anatomical information. Compression rates of up to two orders of magnitude with minimum distortion of reconstruction have been demonstrated, resulting in large reduction in weight matrix size and reconstruction time. PMID- 23811917 TI - Recovering a fiber Bragg grating axial strain distribution from its reflection spectrum. AB - A processing scheme able to obtain any arbitrary intragrating strain distribution of a fiber Bragg grating (FBG) is proposed and demonstrated. The processing method employs just the intensity of the FBG reflection spectrum to obtain its deformation profile by combining a geometrical processing scheme with the particle swarm optimization technique. The technique has been evaluated using several spectra generated from very heterogeneous strain distributions and with a real spectrum obtained from a 5 mm length FBG under an asymmetric perturbation. The achieved results exhibit a good spatial resolution (Delta~0.5 mm) and repeatability. PMID- 23811918 TI - Effects of trigger laser pulse width on the jitter time of GaAs photoconductive semiconductor switch. AB - The effects of trigger laser pulse width on the jitter time of a GaAs photoconductive semiconductor switch (PCSS) is investigated in the experiment. The laser is split into two optical beams by a cross grating to excite two 3 mm gap GaAs PCSSs in parallel at the same time. This work reveals that the jitter time of the GaAs PCSS is reduced as the trigger laser pulse width decreases. Our results overcome a significant obstacle that hinders the testing and theory of GaAs PCSSs in high-time-precision synchronous control. PMID- 23811919 TI - High net modal gain (>100 cm(-1)) in 19-stacked InGaAs quantum dot laser diodes at 1000 nm wavelength band. AB - An InGaAs quantum dot (QD) laser diode with 19-stacked QDs separated by 20 nm thick GaAs spacers was fabricated using an ultrahigh-rate molecular beam epitaxial growth technique, and the laser characteristics were evaluated. A 19 stacked simple broad area QD laser diode was lased at the 1000 nm waveband. A net modal gain of 103 cm(-1) was obtained at 2.25 kA/cm(2), and the saturated modal gain was 145.6 cm(-1); these are the highest values obtained to our knowledge. These results indicate that using this technique to highly stack QDs is effective for improving the net modal gain of QD lasers. PMID- 23811920 TI - Adaptive liquid iris based on electrowetting. AB - We report a tunable iris using two immiscible liquids. One liquid is opaque and conductive, while the other liquid is clear and insulating. The opaque liquid forms an iris-like opening in its central area on one glass substrate surface. The clear liquid is used to fill the outside space of the opaque liquid. In the voltage-off state, the opening presents the smallest aperture. When a voltage is applied to the liquids, the diameter of the iris is enlarged due to the electrowetting effect. Our results show that the aperture of the iris can be tuned from ~2.3 to ~6.1 mm as the applied voltage is changed from 0 to ~65 V. The response time and the transmittance in the opening area were measured to be ~200 ms and ~85%, respectively. Our adaptive iris has potential applications in beam controls, light shutters, and lab-on-a-chip devices. PMID- 23811922 TI - Optically tunable and rewritable diffraction grating with photoaligned liquid crystals. AB - An optically tunable and rewritable liquid crystal (LC) diffraction grating cell has been revealed that consists of an optically active and an optically passive alignment layer. The grating profile is created by confining the LC director distribution in alternate planar and twisted alignment domains by means of photoalignment of the LCs. The proposed grating is optically tunable for diffractive and nondiffractive states with a small response time that depends on the exposure energy and LC parameters. In addition, the grating can be erased and rewritten for different diffracting characteristics. These optically tunable diffractive elements could find application in various photonic devices. PMID- 23811921 TI - X-ray luminescence optical tomography imaging: experimental studies. AB - We present a hybrid imaging modality, x-ray luminescence optical tomography (XLOT), in which collimated x-ray beams are used to excite phosphor-based contrast agents. Images are reconstructed from the optical signals, using the known x-ray beam location and spatial extent as priors. We demonstrate XLOT using phantom experiments with deep targets and show that the reconstructed signal varies by <12% when the depth changes from 4.2 to 7.7 mm. For simple source distributions, we find as few as two orthogonal projection measurements are sufficient for XLOT reconstruction. PMID- 23811923 TI - Bidirectional 16-QAM OFDM in-building network over SMF and free-space VLC transport. AB - A bidirectional 16-quadrature amplitude modulation (QAM) orthogonal frequency division multiplexing (OFDM) in-building network over 20 km single-mode fiber (SMF) and 15 m free-space visible light communication (VLC) transport is proposed and experimentally demonstrated. Good bit error rate performances and clear constellation maps are obtained for 16-QAM OFDM applications in our proposed in building networks. PMID- 23811924 TI - Phase-shift interference-based wavefront characterization for orbital angular momentum modes. AB - Wavefront characterization for orbital angular momentum (OAM) modes is demonstrated using quadrature phase-shift interference. The phase fronts and intensity profiles of OAM(-2), OAM(-4), OAM(-6), and OAM(-8) are measured. Wavefront correlations between the experimental results and the pure Laguerre Gaussian modes are calculated to evaluate the measurement. The measured results are in reasonable agreement with the anticipated results based on simulations. PMID- 23811925 TI - Experimental demonstration of coherent OCDMA using heterodyne detection. AB - We present the first experimental demonstration of a practical, fully coherent, optical code division multiple access (OCDMA) scheme that can fully suppress multiple access interference (MAI) and speckle noise without phase locking or thresholding and gating. The scheme is sourced from an optical comb generator and uses spectral phase encoding and a heterodyne receiver with balanced detection. Here we present results for a four-user configuration at 50% load. At 4.5 Gbits/s per user, the system achieves a signal to MAI ratio of 648 at a bit error rate of 10(-7). PMID- 23811926 TI - Femtosecond laser-induced apodized Bragg grating waveguides. AB - We report on the inscription of apodized Bragg grating waveguides (BGWs) in fused silica using a modulated high repetition rate fs laser system. Tailoring of the grating's coupling strength is facilitated by appropriately substructuring the modulation of the inscribing laser radiation. The proposed alteration delivers an unchanged constant mean refractive index entailing homogeneous guiding properties along the entire waveguide. The BGWs fabricated using a Gaussian apodized modulation profile exhibit a 10 dB improvement in sideband suppression compared to waveguide gratings written with a uniform modulation profile. PMID- 23811927 TI - Maximum likelihood tomographic reconstruction of extremely sparse solutions in diffuse fluorescence flow cytometry. AB - We apply reparameterization and the maximum likelihood method to a specific fluorescence-mediated tomography problem where the solution is known a priori to be extremely sparse (i.e., all image values are zero except for one). Our algorithm performs significantly better than a standard image reconstruction method, particularly for deep-seated targets, and achieves close to 150 MUm accuracy in a 3 mm diameter cross-sectional area with only 12 measurements. Moreover, results do not depend on the selection of a regularization parameter or other ad hoc values, and since reconstructions can be computed very quickly, the algorithm is also suitable for real-time implementation. PMID- 23811928 TI - High-power mid-infrared frequency comb source based on a femtosecond Er:fiber oscillator. AB - We report on a high-power mid-infrared (MIR) frequency comb source based on a femtosecond (fs) Er:fiber oscillator with a stabilized repetition rate of 250 MHz. The MIR frequency comb is produced through difference frequency generation in a periodically poled MgO-doped lithium niobate crystal. The output power is about 120 mW, with a pulse duration of about 80 fs and spectrum coverage from 2.9 to 3.6 MUm, and the single comb mode power is larger than 0.3 MUW over the range of 700 nm. The coherence properties of the produced high-power broadband MIR frequency comb are maintained, which was verified by heterodyne measurements. As the first application, the spectrum of a ~200 ppm methane-air mixture in a short 20 cm glass cell at ambient atmospheric pressure and temperature was measured. PMID- 23811929 TI - Hybrid quantum-well system for wavelength-channel selection. AB - We consider a hybrid quantum-well structure consisting of regions whose properties alternate between active Raman gain and electromagnetically induced transparency. We present both analytical and numerical results that indicate a large light beam defection using spatially inhomogeneous pump and control lasers. We show well-isolated on-chip wavelength selection or channeling capabilities without light field attenuation or distortion, demonstrating the advantages of the system for possible important applications in integrated circuits for optical telecommunications. PMID- 23811930 TI - Experimental demonstration of the full-wave iterative compensation in free space optical communications. AB - Long-range free space optical communications suffer from atmospheric turbulence effects. To mitigate them, a bidirectional full-wave compensation technique seems promising. We present an experimental implementation and characterization of this concept on a laboratory breadboard. Experimental results confirm former numerical results for similar propagation conditions. The effects of measurement and control errors are analyzed by numerical modeling. PMID- 23811931 TI - Laser cooling of beryllium ions using a frequency-doubled 626 nm diode laser. AB - We demonstrate laser cooling of trapped beryllium ions at 313 nm using a frequency-doubled extended cavity diode laser operated at 626 nm, obtained by cooling a ridge waveguide diode laser chip to -31 degrees C. Up to 32 mW of narrowband 626 nm laser radiation is obtained. After passage through an optical isolator and beam shaping optics, 14 mW of 626 nm power remains of which 70% is coupled into an external enhancement cavity containing a nonlinear crystal for second-harmonic generation. We produce up to 35 MUW of 313 nm radiation, which is subsequently used to laser cool and detect 6*10(2) beryllium ions, stored in a linear Paul trap, to a temperature of about 10 mK, as evidenced by the formation of Coulomb crystals. Our setup offers a simple and affordable alternative for Doppler cooling, optical pumping, and detection to presently used laser systems. PMID- 23811932 TI - DNA repair choice defines a common pathway for recruitment of chromatin regulators. AB - DNA double-strand break repair is essential for maintenance of genome stability. Recent work has implicated a host of chromatin regulators in the DNA-damage response, and although several functional roles have been defined, the mechanisms that control their recruitment to DNA lesions remain unclear. Here we find that efficient double-strand break recruitment of the INO80, SWR-C, NuA4, SWI/SNF and RSC enzymes is inhibited by the non-homologous end-joining machinery, and that their recruitment is controlled by early steps of homologous recombination. Strikingly, we find no significant role for H2A.X phosphorylation in the recruitment of chromatin regulators, but rather their recruitment coincides with reduced levels of H2A.X phosphorylation. Our work indicates that cell cycle position has a key role in DNA repair pathway choice and that recruitment of chromatin regulators is tightly coupled to homologous recombination. PMID- 23811933 TI - Position of the greater palatine foramen: an anatomical study through cone beam computed tomography images. AB - PURPOSE: The block anesthesia of the greater palatine foramen (GPF) is largely used in minor oral surgeries, periodontics and general dentistry. Furthermore, the area of the GPF serves as a donor of soft tissue graft. So, the aim of this study was to evaluate the position and characteristics of the GPF in Brazilian patients using cone beam computed tomography (CBCT) providing anatomical information for the greater palatine nerve block anesthesia and indicate site to collect palatal donor tissue. METHODS: Fifty CBCT exams of Brazilian patients with a mean age of 35.8 years (27 male/23 female) were evaluated. All patients had erupted first, second and third upper molars. A total of 100 GPF were evaluated bilaterally. The GPFs were assessed regarding position, diameter and distances to the midline maxillary suture (MMS) and to alveolar ridge (AR). Guidelines were drawn in the CBCT axial image depicting all molar interproximal surfaces, bilaterally. The guidelines were located between first, second and third molar and in the center of the second and third, performing five guidelines in each side. These guidelines and the molars were landmarks to assess the GPF anatomic position. RESULTS: From the 100 GPF analyzed, 92 were located in the third molar region (24 male/22 female). The 92 GPF were distributed as 47 in the left side and 45 in the right side. The average GPF diameter and the distance to both the AR and the MMS were 3.1 mm; 7.9 and 15.3 mm, respectively. CONCLUSIONS: Within the limits of this study, we concluded that the in Brazilian patients studied, the GPF location was more closely related to third molar. Therefore, whenever the third molar is erupted, it could be used as landmark for successful GPN block anesthesia. Moreover, harvesting palatal mucosa graft around the third molar should be done cautiously to prevent damage to the GPF vascular-nerve complex. PMID- 23811934 TI - Temporomandibular joint model: anatomic and radiologic comparison between rat and human. AB - PURPOSE: The temporomandibular joint (TMJ) is a complex anatomic structure with various pathologies as fractures, ankylosis or degenerative diseases. Few animal models already exist and the current study aims at demonstrating that rats' TMJ could be considered as a model, using anatomic dissection and radiology. METHODS: Five adult Wistar rats were dissected to explore the soft and bone anatomy of the TMJ. Five more adult Wistar rats underwent a CT scan to measure size and angles of the condyle. RESULTS: The angles between the condyle and the mandible corpus were observed to be different both in the sagittal plane (150 degrees vs. 125 degrees in human) and the transversal plane (140 degrees vs. 180 degrees ). The condyle axis is sagittal and drop-shaped and there is no anterior eminence in rats' temporal fossa. However, the other anatomic structures proved to be quite similar. CONCLUSIONS: The temporomandibular joints in human and rat are close and only few anatomic differences have been reported. Rats thus appear as an interesting and cheap alternative to model TMJ. PMID- 23811935 TI - Isolated splenic abscess in children, role of splenic preservation. AB - PURPOSE: Splenic abscess (SA) is rare life threatening clinical condition in children. Diagnosis is delayed because of its non-specific clinical presentation. It has a high mortality rate even in the era of antibiotics. This study aim to determine the role of splenic preservation in the management of isolated splenic abscess in children, and to compare different treatment modalities for it. METHODS: A retrospective cross-sectional study of 20 years was conducted including all children <14 years of age with the principal diagnosis of "Splenic abscess". We have excluded all splenic abscesses occurring after penetrating or blunt abdominal trauma. RESULTS: Total of 17 children were managed during the study period. Most of our patients were older than 10 years of age. Majority of patients had a significant delay in presentation. Fever, abdominal pain, and vomiting were the main mode of presentation. Splenomegaly on abdominal examination was present in 12 patients. 15 (88 %) children were managed conservatively; however, 2 children required surgical intervention. CONCLUSION: Splenic abscess in children is a rare disease and its diagnosis is often delayed. Delay in diagnosis of SA in children can lead to life threatening complications. A high index of suspicion is needed to reduce delay in diagnosis. Children presenting with non-specific high grade fever vomiting and abdominal pain should be evaluated for SA. Timely ultrasound and CT scan will lead to earlier diagnosis. A conservative approach with intravenous antibiotics and early percutaneous drainage especially in immunocompetent children can preserve spleen to continue immune function. PMID- 23811937 TI - MiR-126 promotes coxsackievirus replication by mediating cross-talk of ERK1/2 and Wnt/beta-catenin signal pathways. AB - Coxsackievirus B3 (CVB3) is one of the most prevalent causes of viral myocarditis and is associated with many other pathological conditions. CVB3 replication relies on host cellular machineries and causes direct damage to host cells. MicroRNAs have been found to regulate viral infections but their roles in CVB3 infection are still poorly understood. Here we describe a novel mechanism by which miR-126 regulates two signal pathways essential for CVB3 replication. We found that CVB3-induced ERK1/2 activation triggered the phosphorylation of ETS-1 and ETS-2 transcription factors, which induced miR-126 upregulation. By using both microRNA mimics and inhibitors, we proved that the upregulated miR-126 suppressed sprouty-related, EVH1 domain containing 1 (SPRED1) and in turn enhanced ERK1/2 activation. This positive feedback loop of ERK1/2-miR-126-ERK1/2 promoted CVB3 replication. Meanwhile, miR-126 expression stimulated GSK-3beta activity and induced degradation of beta-catenin through suppressing LRP6 and WRCH1, two newly identified targets in the Wnt/beta-catenin pathway, which sensitized the cells to virus-induced cell death and increased viral progeny release to initiate new infections. Our results demonstrate that upregulated miR 126 upon CVB3 infection targets SPRED1, LRP6, and WRCH1 genes, mediating cross talk between ERK1/2 and Wnt/beta-catenin pathways, and thus promoting viral replication and contributes to the viral cytopathogenicity. PMID- 23811938 TI - Risk assessment of liver-related events using transient elastography in patients with chronic hepatitis B receiving entecavir. AB - GOALS: We investigated whether liver stiffness (LS) values can predict liver related events (LREs) development in patients with chronic hepatitis B (CHB). BACKGROUND: LS values using transient elastography provides accurate assessment of liver fibrosis in patients with chronic liver disease. METHODS: Between June 2007 and May 2010, a total of 162 patients with CHB who completed 2-year entecavir (ETV) treatment were evaluated. The primary endpoint was LRE development (hepatic decompensation, hepatocellular carcinoma, or liver-related death) during the 2-year ETV treatment. RESULTS: The median age of the patients (99 men, 63 women) was 51 years, and the median LS value was 14.8 kPa. During the 2-year ETV treatment, 15 (9.3%) patients experienced LREs. On univariate analysis, age, the proportion of patients with liver cirrhosis, platelet counts, and baseline LS values were significantly associated with LRE development (all P<0.05). Together with age, multivariate analysis identified baseline LS values as an independent predictor of LRE development (P=0.046; hazard ratio, 1.040; 95% confidence interval, 1.101-1.084). The cutoff LS value maximizing the sum of sensitivity and specificity was 12.0 kPa (area under the receiver operating characteristics curve, 0.736; P=0.003; sensitivity, 93.3%; specificity, 42.2%). In addition, the changes in LS values between baseline and 1-year ETV treatment showed significant correlations with LRE development (P=0.030). CONCLUSIONS: Our data suggest that LS values are predictive of LRE development during 2-year ETV treatment in patients with CHB. The potential role of LS value as a monitoring tool for predicting dynamic changes in the risk of LRE development during long term ETV treatment should be investigated further. PMID- 23811939 TI - In response. PMID- 23811936 TI - Joining S100 proteins and migration: for better or for worse, in sickness and in health. AB - The vast diversity of S100 proteins has demonstrated a multitude of biological correlations with cell growth, cell differentiation and cell survival in numerous physiological and pathological conditions in all cells of the body. This review summarises some of the reported regulatory functions of S100 proteins (namely S100A1, S100A2, S100A4, S100A6, S100A7, S100A8/S100A9, S100A10, S100A11, S100A12, S100B and S100P) on cellular migration and invasion, established in both culture and animal model systems and the possible mechanisms that have been proposed to be responsible. These mechanisms involve intracellular events and components of the cytoskeletal organisation (actin/myosin filaments, intermediate filaments and microtubules) as well as extracellular signalling at different cell surface receptors (RAGE and integrins). Finally, we shall attempt to demonstrate how aberrant expression of the S100 proteins may lead to pathological events and human disorders and furthermore provide a rationale to possibly explain why the expression of some of the S100 proteins (mainly S100A4 and S100P) has led to conflicting results on motility, depending on the cells used. PMID- 23811941 TI - AC1MMYR2, an inhibitor of dicer-mediated biogenesis of Oncomir miR-21, reverses epithelial-mesenchymal transition and suppresses tumor growth and progression. AB - The extensive involvement of miRNAs in cancer pathobiology has opened avenues for drug development based on oncomir inhibition. Dicer is the core enzyme in miRNA processing that cleaves the terminal loop of precursor microRNAs (pre-miRNAs) to generate mature miRNA duplexes. Using the three-dimensional structure of the Dicer binding site on the pre-miR-21 oncomir, we conducted an in silico high throughput screen for small molecules that block miR-21 maturation. By this method, we identified a specific small-molecule inhibitor of miR-21, termed AC1MMYR2, which blocked the ability of Dicer to process pre-miR-21 to mature miR 21. AC1MMYR2 upregulated expression of PTEN, PDCD4, and RECK and reversed epithelial-mesenchymal transition via the induction of E-cadherin expression and the downregulation of mesenchymal markers, thereby suppressing proliferation, survival, and invasion in glioblastoma, breast cancer, and gastric cancer cells. As a single agent in vivo, AC1MMYR2 repressed tumor growth, invasiveness, and metastasis, increasing overall host survival with no observable tissue cytotoxicity in orthotopic models. Our results offer a novel, high-throughput method to screen for small-molecule inhibitors of miRNA maturation, presenting AC1MMYR2 as a broadly useful candidate antitumor drug. PMID- 23811942 TI - Acquired expression of NFATc1 downregulates E-cadherin and promotes cancer cell invasion. AB - NFATc1 is a transcription factor that regulates T-cell development, osteoclastogenesis, and macrophage function. Given that T cells, osteoclasts, and macrophages in the tumor microenvironment are thought to modulate tumor progression, tumor cells may acquire NFATc1 expression through fusion with these NFATc1-expressing normal cells. We here revealed that a small proportion of tumor cells in human carcinoma specimens expressed NFATc1. To investigate the consequences of NFATc1 acquisition by tumor cells, we established A549 and MCF7 cell lines expressing a constitutively active form of NFATc1 (NFATc1CA) in an inducible manner. The expression of NFATc1CA promoted cancer cell invasion in association with changes in cell morphology. Analysis of gene expression and RNA interference experiments revealed that NFATc1CA suppressed E-cadherin expression by upregulating the transcriptional repressors Snail and Zeb1 in a manner independent of TGF-beta signaling. Induced expression of NFATc1CA also downregulated E-cadherin expression and increased invasive activity in tumor xenografts in vivo. Our results thus suggest that the acquisition of NFATc1 expression contributes to tumor progression. PMID- 23811940 TI - Targeting ERBB receptors shifts their partners and triggers persistent ERK signaling through a novel ERBB/EFNB1 complex. AB - Most squamous cell carcinomas of the head and neck (HNSCC) overexpress ERBB1/EGFR, but EGF receptor (EGFR)-targeted therapies have yielded disappointing clinical results in treatment of this cancer. Here, we describe a novel interaction between EGFR and the ligand EphrinB1 (EFNB1), and we show that EFNB1 phosphorylation and downstream signaling persists in the presence of cetuximab. Mechanistically, cetuximab drives a shift in EGFR dimerization partners within the signaling complex, suggesting that targeted drugs may trigger partner rearrangements that allow persistent pathway activation. EFNB1 attenuation slowed tumor growth and increased survival in a murine model of HNSCC, suggesting a substantial contribution of EFNB1 signaling to HNSCC development. Together, our findings suggest that EFNB1 is part of the EGFR signaling complex and may mediate drug resistance in HNSCC as well as other solid tumors. PMID- 23811943 TI - Critical tumor suppressor function mediated by epithelial Mig-6 in endometrial cancer. AB - Endometrial cancer is preceded by endometrial hyperplasia, unopposed estrogen exposure, and genetic alterations, but the precise causes of endometrial cancer remain uncertain. Mig-6, mainly known as a negative regulator of the EGF receptor, is an important mediator of progesterone signaling in the uterus, where it mediates tumor suppression by modulating endometrial stromal-epithelial communications. In this study, we investigated the function of Mig-6 in the uterine epithelium using a tissue-specific gene knockout strategy, in which floxed Mig-6 (Mig-6(f/f)) mice were crossed to Wnt7a-Cre mice (Wnt7a(cre+)Mig 6(f/f)). Wnt7a(cre+)Mig-6(f/f) mice developed endometrial hyperplasia and estrogen-dependent endometrial cancer, exhibiting increased proliferation in epithelial cells as well as apoptosis in subepithelial stromal cells. We documented increased expression of NOTCH1 and BIRC3 in epithelial cells of Wnt7a(cre+)Mig-6(f/f) mice and decreased expression of the progesterone receptor (PR) in stromal cells. Progesterone therapy controls endometrial growth and prevents endometrial cancer, but the effectiveness of progesterone as a treatment for women with endometrial cancer is less clear. We noted that the hyperplasic phenotype of Wnt7a(cre+)Mig-6(f/f) mice was prevented by progesterone treatment, whereas this treatment had no effect in PR(cre/+)Mig-6(f/f) mice where Mig-6 was deleted in both the epithelial and stromal compartments of the uterus. In contrast, activation of progesterone signaling in the stroma regulated proliferation and apoptosis in the epithelium via suppression of ERalpha signaling. In summary, our results establish that epithelial Mig-6 functions as a critical tumor suppressor that mediates the ability of progesterone to prevent the development of endometrial cancer. PMID- 23811944 TI - PPARdelta induces estrogen receptor-positive mammary neoplasia through an inflammatory and metabolic phenotype linked to mTOR activation. AB - The peroxisome proliferator-activated receptor-delta (PPARdelta) regulates a multitude of physiological processes associated with glucose and lipid metabolism, inflammation, and proliferation. One or more of these processes are potential risk factors for the ability of PPARdelta agonists to promote tumorigenesis in the mammary gland. In this study, we describe a new transgenic mouse model in which activation of PPARdelta in the mammary epithelium by endogenous or synthetic ligands resulted in progressive histopathologic changes that culminated in the appearance of estrogen receptor- and progesterone receptor positive and ErbB2-negative infiltrating ductal carcinomas. Multiparous mice presented with mammary carcinomas after a latency of 12 months, and administration of the PPARdelta ligand GW501516 reduced tumor latency to 5 months. Histopathologic changes occurred concurrently with an increase in an inflammatory, invasive, metabolic, and proliferative gene signature, including expression of the trophoblast gene, Plac1, beginning 1 week after GW501516 treatment, and remained elevated throughout tumorigenesis. The appearance of malignant changes correlated with a pronounced increase in phosphatidylcholine and lysophosphatidic acid metabolites, which coincided with activation of Akt and mTOR signaling that were attenuated by treatment with the mTOR inhibitor everolimus. Our findings are the first to show a direct role of PPARdelta in the pathogenesis of mammary tumorigenesis, and suggest a rationale for therapeutic approaches to prevent and treat this disease. PMID- 23811946 TI - Retrocalcaneal pain after the repair of acute Achilles tendon rupture. AB - Pain in the posterosuperior portion of the calcaneus can be caused by a retrocalcaneal bursitis, enlargement of the superior bursal prominence of the calcaneus, insertional Achilles tendinopathy, stress fracture of the calcaneus, or inflammation of an adventitious bursa between the Achilles tendon and the skin. Hypertrophied tendon impinging on the posterosuperior calcaneal tuberosity can be a cause of retrocalcaneal pain after repair of acute rupture of the Achilles tendon. This can be effectively treated by endoscopic calcaneoplasty. LEVELS OF EVIDENCE: Therapeutic, Level IV, Case Report. PMID- 23811947 TI - The diagnosis and management of Morton's neuroma: a literature review. AB - Morton's neuroma is a common condition mainly affecting middle aged women, and there are many proposed etiological theories involving chronic repetitive trauma, ischemia, entrapment, and intermetatarsal bursitis. Incorrect terminology suggests that the underlying pathological process is a nerve tumor, although histological examination reveals the presence of inflammatory tissue-that is, perineural fibrosis. The common digital nerve and its branches in the third planter webspace are most commonly affected. Diagnosis is usually made through history taking and clinical examination but may be aided by ultrasonography and magnetic resonance imaging. Current nonoperative treatment strategies include shoe-wear modifications, custom made orthoses, and injections of local anesthetic agents, sclerosing agents, and steroids. Operative management options primarily involve either nerve decompression or neurectomy. We have reviewed the published literature to evaluate the outcomes of the available diagnostic modalities and treatment options and present an algorithm for clinical practice. PMID- 23811945 TI - Early phosphoproteomic changes in the mouse spleen during deoxynivalenol-induced ribotoxic stress. AB - The trichothecene mycotoxin deoxynivalenol (DON) targets the innate immune system and is of public health significance because of its frequent presence in human and animal food. DON-induced proinflammatory gene expression and apoptosis in the lymphoid tissue have been associated with a ribotoxic stress response (RSR) that involves rapid phosphorylation of mitogen-activated protein kinases (MAPKs). To better understand the relationship between protein phosphorylation and DON's immunotoxic effects, stable isotope dimethyl labeling-based proteomics in conjunction with titanium dioxide chromatography was employed to quantitatively profile the immediate (<= 30min) phosphoproteome changes in the spleens of mice orally exposed to 5mg/kg body weight DON. A total of 90 phosphoproteins indicative of novel phosphorylation events were significantly modulated by DON. In addition to critical branches and scaffolds of MAPK signaling being affected, DON exposure also altered phosphorylation of proteins that mediate phosphatidylinositol 3-kinase/AKT pathways. Gene ontology analysis revealed that DON exposure affected biological processes such as cytoskeleton organization, regulation of apoptosis, and lymphocyte activation and development, which likely contribute to immune dysregulation associated with DON-induced RSR. Consistent with these findings, DON impacted phosphorylation of proteins within diverse immune cell populations, including monocytes, macrophages, T cells, B cells, dendritic cells, and mast cells. Fuzzy c-means clustering analysis further indicated that DON evoked several distinctive temporal profiles of regulated phosphopeptides. Overall, the findings from this investigation can serve as a template for future focused exploration and modeling of cellular responses associated with the immunotoxicity evoked by DON and other ribotoxins. PMID- 23811948 TI - Aquatic training for ankle instability. AB - The aim of the present study was to evaluate balance deficits after an ankle sprain in collegiate students and to examine the effectiveness of 2 different balance rehabilitation programs on balance ability. Thirty collegiate students with functional ankle instability were randomly divided into 2 groups. Both groups followed an intervention balance program for 6 weeks, 3 times per week, 20 minutes per session, using balance boards. One of the 2 training groups performed the exercises on the ground-the "Land" group (n = 15), and the other in a swimming pool-the "Aquatic" group (n = 15). Balance ability was assessed before and after the 6-week intervention program. Balance assessments included static (stability indices: total, anterior-posterior, medial-lateral) and dynamic (dynamic moving the cursor) stability tests on the Biodex Stability System (Biodex, Inc, Shirley, NY). The results showed that in both training groups balance ability of the injured leg was significantly improved after the training period. In the final measurements, no statistically significant differences between the injured and healthy limb were found. The present study indicates that the performance of balance exercises in or out of water by collegiate students with functional ankle instability improves their balance ability. LEVEL OF EVIDENCE: Therapeutic, Level 1. PMID- 23811949 TI - The total ankle arthroplasty learning curve with third-generation implants: a single surgeon's experience. AB - BACKGROUND: Renewed interest in total ankle arthroplasty (TAA) has developed globally as a result of recent literature supporting new-generation implants as a viable alternative to arthrodesis. The literature also demonstrates a learning curve among surgeons adopting TAA. The purpose of this study is to better define this learning curve for surgeons using third-generation implants. METHODS: Charts and radiographs were reviewed for the initial 26 TAA procedures performed by the senior author. Three third-generation implants were used: SBi (Small Bone Innovations) STAR, Salto Talaris, and Wright Medical INBONE. We report perioperative and early postoperative complications. RESULTS: Two perioperative fractures occurred in the first 9 cases, and the incidence subsequently dropped to 0 (P = .0431). Two cases of component malalignment occurred in the first 3 patients receiving the STAR implant, and the incidence then dropped to 0 (P = .0034). Five wound complications (4 minor and 1 major) occurred, all in the final 14 patients. No cases of nerve injury, tendon laceration, or deep vein thrombosis occurred. Two patients returned to the operating room as a result of complications, and the total perioperative and early postoperative complication rate was 27%. CONCLUSION: The observed rate of perioperative and early postoperative complications in this case series was low relative to other similar sized studies, suggesting that third-generation implants can reduce adverse events. Our results demonstrate that some common complications could be avoided altogether (nerve/tendon injuries), some decreased quickly with experience (intraoperative fractures and component malpositioning), and some persisted unchanged throughout this study (wound complications). These findings should influence surgical training, surgeon willingness to adopt this procedure, and patient counseling. LEVELS OF EVIDENCE: Therapeutic, Level IV, Retrospective Case Series. PMID- 23811950 TI - Ultrasound-guided first metatarsophalangeal joint injections: description of an in-plane, gel standoff technique in a cadaveric study. AB - OBJECTIVE: To describe a longitudinal ultrasound-guided in-plane approach for injection into the first metatarsophalangeal (MTP) joint and assess its accuracy in a cadaveric model. DESIGN: A prospective anatomical cadaver study model was used. A total of 10 first MTP joints using the described technique were injected with 0.5 mL of dye under ultrasound guidance. The joints were later dissected, and accuracy was classified as accurate, accurate with overflow, or inaccurate with no injectate in the target area. RESULTS: Of the injections, 9 were classified as accurate injections, and 1 was classified accurate with overflow. CONCLUSION: This cadaveric study suggests that ultrasound-guided injections of the first MTP joint can be accurately and reproducibly performed with a gel standoff, long-axis in-plane approach. This technique attempts to minimize the collateral damage to the surrounding tissue, specifically the articular cartilage. Clinicians should consider using this technique when performing ultrasound-guided injections to the first MTP joint. LEVEL OF EVIDENCE: Cadaveric, Level V. PMID- 23811951 TI - HLA-E variants are associated with sustained virological response in HIV/hepatitis C virus-coinfected patients on hepatitis C virus therapy. AB - OBJECTIVES: To analyze whether human leukocyte antigen (HLA)-E allelic variants are associated with and may predict response to peg-interferon (IFN) alpha and ribavirin treatment in HIV/hepatitis C virus (HCV)-coinfected patients. DESIGN: Retrospective follow-up study. METHODS: We studied 321 naive patients who started HCV treatment. HLA-E genotyping was performed by restriction fragment length polymorphism. A sustained virological response (SVR) was defined as undetectable plasma HCV-RNA up through 24 weeks after the end of HCV treatment. RESULTS: The HLA-E*0101 allele increased the odds of achieving SVR for all patients [adjusted odds ratio (aOR) = 2.03 (95% confidence interval, 95% CI = 1.35-3.06); P = 0.001], for HCV genotype (GT) 1/4 patients (aOR = 1.62 (95% CI = 1.03-2.54), P = 0.035), and for GT2/3 patients [aOR = 9.87 (95% CI = 2.47-31.89), P = 0.001]. For decision tree analysis, the SVR rate increased from 0 to 82.6% and then to 92.5% in GT2/3 patients when the count of HLA-E*0101 alleles increased. In GT1/4 patients with rs8099917 TT genotype, the SVR rate increased from 33.3 to 54.8% and then to 61.8% when the count of HLA-E*0101 alleles increased. In GT1/4 patients with rs8099917 GT/GG genotype, the SVR rate increased from 15.4 to 22% and then to 44% when the count of HLA-E*0101 alleles increased. The overall percentage of patients correctly classified was 73.2% and the area under the receiver operating characteristic curve (AUROC) was 0.803 +/- 0.024. CONCLUSION: The HLA-E*0101 allele was associated with increased odds of HCV clearance and could help to predict SVR among HIV/HCV-coinfected patients on HCV therapy. This would be helpful to avoid treatment in those less likely to respond to pegylated interferon-alpha and ribavirin treatment. PMID- 23811952 TI - Photo-regenerable multi-walled carbon nanotube membranes for the removal of pharmaceutical micropollutants from water. AB - Pharmaceutical micropollutants fall in the category of "emerging contaminants" in water because of their prevalence and persistence in the aqueous environment, and because of a poor understanding of their low-dose exposure effects on human and animal populations. In this study, photo-regenerable multiwalled carbon nanotube membranes with variable water permeabilities were produced by embedding hierarchical TiO2 structures (having porous, spherical morphology) onto a pre deposited bed of multi-walled carbon nanotubes (MWNTs) using a modified sol-gel technique. These MWNT-TiO2 composites and their constituent materials were characterized by analytical electron microscopy, surface charge measurement, thermogravimetric analysis, and hydrophobicity determination. The adsorption removal potential of MWNT-TiO2 membranes was demonstrated for three representative pharmaceuticals: acetaminophen, carbamazepine and ibuprofen. The peak initial removal percentages of the pharmaceuticals by the MWNT-TiO2 membranes were 80%, 45%, and 24% for carbamazepine, ibuprofen, and acetaminophen, respectively. The ability of the membranes to be regenerated, once they were saturated with the pharmaceutical compounds, was verified by repeating the adsorption removal experiment on the same membranes after exposure to UV light at 254 nm. Peak removal efficiencies after regeneration were 55%, 32%, and 19% for carbamazepine, ibuprofen, and acetaminophen, respectively, indicating some loss in sorptive capacity upon regeneration. Furthermore, the effect of pH on adsorption of ibuprofen, the pharmaceutical that attained the highest mass loading on the sorbent at equilibrium saturation, was studied and its mechanism of adsorption was proposed at pH below pKa. PMID- 23811953 TI - Stressful psychosocial school environment and suicidal ideation in Chinese adolescents. AB - PURPOSE: Suicide is one of the leading causes of death during adolescence worldwide. This study, using a sample of Chinese adolescents, examines associations of a stressful psychosocial school environment with suicidal ideation, which were rarely investigated so far. METHODS: A total of 1,004 Chinese students (468 boys and 536 girls) from Grade 7-12 were recruited into our questionnaire survey. Psychosocial school environment was measured by the effort reward imbalance questionnaire adapted to the school setting, and suicidal ideation was assessed by a standardized question. Multivariate logistic regression was applied, adjusting odds ratios for age, gender, grade, smoking, alcohol drinking, physical activity, family wealth, and self-rated health. RESULTS: In school settings, 10.86% students reported suicidal ideation during the last 6 months, which was found to be significantly related to both effort and reward. Remarkably, effort-reward imbalance was associated with elevated risk of suicidal ideation (odds ratio = 1.77, 95% confidence interval = 1.34-2.35). CONCLUSIONS: This study finds significant associations between a stressful psychosocial school environment in terms of effort-reward imbalance and suicidal ideation in Chinese adolescents. Preventive actions aiming at reducing this imbalance may define a promising approach towards a healthy psychosocial school environment. PMID- 23811954 TI - The characteristics of ascites in patients with POEMS syndrome. AB - The characteristics of ascites in patients with POEMS syndrome, which comprise polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes, are unknown. We described the frequency of ascites at presentation of POEMS syndrome and further evaluated for the pathogenesis and nature of the ascites. One hundred and six consecutive patients with POEMS syndrome in Chinese PLA General Hospital were evaluated for the presence of ascites, and the cellular and biochemical characteristics of the ascitic fluids were assessed. Serum levels of complement, cytokines, and clinical chemistry parameters were analyzed in peripheral blood samples of the patients with POEMS syndrome. Ascites was observed in 42 of 106 (39.6 %) patients with POEMS syndrome. Patients with ascites had significantly high serum levels of C3 and C4 complement components and TNF-alpha (all p < 0.01). In 31 (73.8 %) patients who underwent paracentesis, the ascitic fluids had low serum ascites albumin gradients (SAAG), indicating non-portal hypertension. Spontaneous bacterial peritonitis was not observed. Ascites is a common complication of POEMS syndrome and has characteristics of non-portal hypertension, based on low SAAG. Increased immune activation and inflammatory status could contribute to the pathogenesis of ascites in POEMS syndrome. PMID- 23811955 TI - Phosphorylation of BLUS1 kinase by phototropins is a primary step in stomatal opening. AB - Opening of stomata in the plant facilitates photosynthetic CO2 fixation and transpiration. Blue-light perception by phototropins (phot1, phot2) activates the plasma membrane H(+)-ATPase, causing stomata to open. Here we describe a regulator that connects these components, a Ser/Thr protein kinase, BLUS1 (BLUE LIGHT SIGNALING1), which mediates a primary step for phototropin signalling in guard cells. blus1 mutants identified by infrared thermography result in a loss of blue light-dependent stomatal opening. BLUS1 encodes a protein kinase that is directly phosphorylated by phot1 in vitro and in vivo at Ser-348 within its C terminus. Both phosphorylation of Ser-348 and BLUS1 kinase activity are essential for activation of the H(+)-ATPase. blus1 mutants show lower stomatal conductance and CO2 assimilation than wild-type plants under decreased ambient CO2. Together, our analyses demonstrate that BLUS1 functions as a phototropin substrate and primary regulator of stomatal control to enhance photosynthetic CO2 assimilation under natural light conditions. PMID- 23811956 TI - Acute interventional recanalisation of vertebrobasilar stenoses by angioplasty: complications and 12 months follow up. AB - INTRODUCTION: In acute symptomatic vertebrobasilar artery stenosis, the use of mechanical recanalisation remains controversial. The complication rate of acute interventional recanalisation (aIR) has to be considered, as evidence from randomised trials is lacking. In a single centre retrospective case series, we here describe complications and outcome after aIR. METHODS: We retrospectively assessed aIR in a tertiary care centre and included the following parameters: indication for aIR, national institute of health stroke scale (NIHSS) score on admission, recanalisation by thrombolysis in myocardial infarction score (TIMI) grades, post-interventional complications, mortality, NIHSS and modified Rankin scale at follow-up and rate of restenosis. RESULTS: We identified 14 aIR (14 percutaneous transluminal angioplasty with or without stent implantation in 12 patients; 6/12 with thrombolysis; n = 6 vertebral artery, n = 8 basilar artery; 4 women, mean age 67 years). Mortality was 25 % (3/12) after 7 days and 42 % (5/12) after 12 months. In 12/14, interventions are complete (TIMI 3, 86 %), in 2/14, a partial recanalisation (TIMI 2, 14 %) was achieved. In one case, a peri interventional fatal intracerebral haemorrhage occurred (1/12, 8 %). At late follow-up (mean 342 days), one re-occlusion (1/7, 14 %) and one recurrent stroke (1/12, 8 %) were observed. CONCLUSIONS: In our single centre series of vertebrobasilar aIR recanalisation rate was high. However, procedural safety and clinical outcome varied considerably. The results of aIR need to be assessed in multicentric registers to define the procedural risk and outcome in the clinical setting. PMID- 23811957 TI - Periprocedural aspects in mechanical recanalization for acute stroke: data from the ENDOSTROKE registry. AB - INTRODUCTION: The ENDOSTROKE registry aims to accompany the spreading use of endovascular stroke treatment (EVT) in academic and non-academic hospitals. This analysis focuses on preprocedural imaging, patient handling and referral, as well as on different treatment modalities in mechanical recanalization. METHODS: Data for this study were from observational registry study in 12 stroke centers in Germany and Austria with online assessment of prespecified variables concerning endovascular stroke therapy. RESULTS: Data from 734 patients undergoing EVT were analyzed. Preferred imaging modality prior to EVT was CT (83 %) and CTA (78 %). In 95 %, EVT was performed under general anesthesia. In 55 % of patients, a combination of intravenous (IV) thrombolysis and EVT was used, followed by pure EVT (25 %), intra-arterial (IA) thrombolysis plus EVT (13 %) and IV + IA thrombolysis plus EVT (7 %). Intrahospital time delay until start of EVT was 91 and 99 min in anterior and vertebrobasilar circulation stroke, respectively. Average duration of EVT was 60 min. Overall thrombolysis in myocardial infarction grade 2/3 recanalization rate was 85 %. Stent retrievers were used in 75 %, being associated with higher recanalization rates than non-stent retrievers. Hemorrhagic complications (symptomatic and asymptomatic) occurred in 12 %. Overall vessel occlusion time was approximately 60 min longer in patients being referred from a primary care hospital for EVT. CONCLUSION: This study gives an overview of procedure-related factors in current EVT practice. It gives estimates on preprocedural imaging modalities, periprocedural handling, and treatment combinations used for EVT. Patient referral for EVT from primary care hospitals is associated with longer vessel occlusion times. PMID- 23811958 TI - Relationship between diabetes mellitus with dural arteriovenous fistula. AB - INTRODUCTION: The aetiology of dural arteriovenous fistula (DAVF) is not well known, but it has been suggested that abnormality in angiogenesis plays a pathological role. Abnormality in angiogenesis is also involved in diabetes mellitus (DM). The purpose of this study was to quantify the relation between DAVF and DM in a Korean population. METHODS: Medical records of 192 patients with DAVF between 2002 and 2011 were reviewed. Age, sex and the presence of DM, hypertension, hyperlipidaemia, stroke, coronary artery disease and cancers were compared between DAVF and control subjects. Data for control were obtained from the Korean National Health and Nutrition Examination Survey. The relationship of DM and DAVF location, presenting symptoms (benign vs. aggressive) and classification (Borden and Geibprasert) were assessed using the Pearson's chi square test. RESULTS: Prevalence of DM was higher in DAVF patients (19.8 %) than in controls (9.5 %; p = 0.004). Univariate analysis showed that DM (odds ratio (OR), 2.356; 95 % confidence interval (CI), 1.634-3.399; p < 0.001) and age (OR, 1.022; 95 % CI, 1.012-1.032; p < 0.001) increased the odds of DAVF. This was supported by multivariate analysis (DM: OR, 2.092; 95 % CI, 1.391-3.145; p = 0.0004 and Age: OR, 1.021; 95 % CI, 1.009-1.033; p = 0.001). When these analyses were repeated after stratification by sex, there was no relation between age and DAVF in men. Borden II and III (p = 0.038) and aggressive symptoms (p = 0.023) were related to DM. CONCLUSION: There was a positive relation between DM and DAVF in a Korean population. DAVFs with aggressive symptoms and behaviour were more commonly related to DM. PMID- 23811959 TI - The characteristics and outcomes of penetrating thoracic and abdominal trauma among children. AB - PURPOSE: Trauma is the most important etiology of morbidity and mortality among children. Penetrating injuries to the thorax and abdomen are extremely rare in children. In the present study, we compared the characteristics of patients, management, and outcomes of penetrating thoracic and abdominal trauma in children. MATERIALS AND METHODS: Data from children who were hospitalized for penetrating injuries of the thorax and abdomen from 2006 to 2012 were evaluated retrospectively. These injuries were evaluated with respect to patient details, clinical presentation, circumstances of trauma, management, and outcomes. RESULTS: Eighty-four patients were hospitalized for penetrating injuries to the thorax and abdomen. The mean age was 10.3 +/- 3.79 years. Patient injuries comprised 26 gunshots injuries and 58 stabbing injuries. Thirty-one patients were wounded in the thorax, 43 were wounded in the abdomen, and 10 were wounded in both the thorax and abdomen. Thirty-one patients had undergone surgical interventions, while the other 53 were managed conservatively. The mean hospital stay was 4.41 +/- 6.84 days. CONCLUSIONS: The incidences of penetrating abdominal and thoracic trauma did not differ significantly. Penetrating injuries may be successfully managed by conservative therapy. PMID- 23811960 TI - Arbor: comparative analysis workflows for the tree of life. AB - We describe our efforts to develop a software package, Arbor, that will enable scientific research in all aspects of comparative biology. This software will enable developmental biologists, geneticists, ecologists, geographers, paleobiologists, educators, and students to analyze diverse types of comparative data at multiple phylogenetic and spatiotemporal scales using an intuitive visual interface. Arbor's user-defined workflows will be exported and shared so that entire analyses can be quickly replicated with new or updated data. Arbor will also be designed to easily and seamlessly expand to include novel analytical tools as they are developed. Here we describe the core components of Arbor, as well as provide details of one proposed test case to illustrate the software's key functionality. PMID- 23811961 TI - Sensing of the concentration and enantiomeric excess of chiral compounds with tropos ligand derived metal complexes. AB - Palladium(II) complexes carrying chromophoric tropos ligands show a characteristic UV change and strong Cotton effects upon coordination of amino alcohols or diamines. The distinct (chir)optical responses can be used for instantaneous in situ determination of the concentration and ee of diamines and amino alcohols at low concentrations. PMID- 23811962 TI - Postdischarge outcomes in heart failure are better for teaching hospitals and weekday discharges. AB - BACKGROUND: It is unclear whether teaching status or day of discharge influences outcomes after a heart failure hospitalization. METHODS AND RESULTS: We evaluated adults discharged after a heart failure hospitalization between 1999 and 2009 in Alberta, Canada. The primary outcome was death or nonelective readmission 30 days postdischarge. Of 12 216 patients discharged from teaching hospitals and 12 157 patients from nonteaching hospitals, 20 524 (84%) discharges occurred on weekdays. Although they had greater comorbidity and used more healthcare resources before their heart failure hospitalization, patients discharged from teaching hospitals exhibited shorter lengths of stay (adjusted ratio, 0.83; 95% confidence interval [CI], 0.80-0.86) and significantly lower rates of death or readmission in the 30 days after discharge than those discharged from nonteaching hospitals (17.4% versus 22.1%; adjusted hazard ratio [aHR], 0.83; 95% CI, 0.77 0.89). Patients discharged on weekdays were older and had greater comorbidity, yet exhibited significantly lower rates of death or readmission at 30 days than those discharged on weekends (19.5% versus 21.1%; aHR, 0.87; 95% CI, 0.80-0.94). Compared with weekend discharge from a nonteaching hospital, 30-day death/readmission rates were lower for weekday discharge from a nonteaching hospital (aHR, 0.85; 95% CI, 0.77-0.94), weekend discharge from a teaching hospital (aHR, 0.80; 95% CI, 0.69-0.92), and weekday discharge from a teaching hospital (aHR, 0.71, 95% CI, 0.63-0.79). CONCLUSIONS: Patients discharged from teaching hospitals or on weekdays exhibited better outcomes despite having higher risk profiles. Future studies should focus on distinguishing which discharge processes differ between teaching and nonteaching hospitals and between weekdays and weekends to define those that optimize patient outcomes. PMID- 23811963 TI - Longitudinal changes in left ventricular stiffness: a community-based study. AB - BACKGROUND: Cross-sectional studies suggest that left ventricular (LV) and arterial elastance (stiffness) increase with age, but data examining longitudinal changes within human subjects are lacking. In addition, it remains unknown whether age-related LV stiffening is merely a reaction to arterial stiffening or caused by other processes. METHODS AND RESULTS: Comprehensive echo-Doppler cardiography was performed in 1402 subjects participating in a randomly selected community-based study at 2 examinations separated by 4 years. From this population, 788 subjects had adequate paired data to determine LV end-systolic elastance (Ees), end-diastolic elastance (Eed), and effective arterial elastance. Throughout 4 years, blood pressure, arterial elastance, and LV mass decreased, coupled with significantly greater use of antihypertensive medications. However, despite reductions in arterial load, Ees increased by 14% (2.10+/-0.67-2.26+/ 0.70 mm Hg/mL; P<0.0001) and Eed increased by 8% (0.13+/-0.03-0.14+/-0.04 mm Hg/mL; P<0.0001). Increases in Eed were greater in women than men, whereas Ees changes were similar. Age-related increases in Ees and Eed were correlated with changes in body weight, but were similar in subjects with or without cardiovascular disease. Changes in Ees were correlated with Eed (r=0.5; P<0.0001), but not with other measures of contractility, indicating that the increase in Ees was reflective of passive stiffening rather than enhanced systolic function. CONCLUSIONS: Despite reductions in arterial load with medical therapy, LV systolic and diastolic stiffness increase over time in humans, particularly in women. In addition to blood pressure control, therapies targeting load-independent ventricular stiffening may be effective to treat and prevent age associated cardiovascular diseases, such as heart failure. PMID- 23811964 TI - Hydrogen sulfide attenuates cardiac dysfunction after heart failure via induction of angiogenesis. AB - BACKGROUND: Hydrogen sulfide (H2S) has been shown to induce angiogenesis in in vitro models and to promote vessel growth in the setting of hindlimb ischemia. The goal of the present study was to determine the therapeutic potential of a stable, long-acting H2S donor, diallyl trisulfide, in a model of pressure overload heart failure and to assess the effects of chronic H2S therapy on myocardial vascular density and angiogenesis. METHODS AND RESULTS: Transverse aortic constriction was performed in mice (C57BL/6J; 8-10 weeks of age). Mice received either vehicle or diallyl trisulfide (200 ug/kg) starting 24 hours after transverse aortic constriction and were followed up for 12 weeks using echocardiography. H2S therapy with diallyl trisulfide improved left ventricular remodeling and preserved left ventricular function in the setting of transverse aortic constriction. H2S therapy increased the expression of the proangiogenic factor, vascular endothelial cell growth factor, and decreased the angiogenesis inhibitor, angiostatin. Further studies revealed that H2S therapy increased the expression of the proliferation marker, Ki67, as well as increased the phosphorylation of endothelial NO synthase and the bioavailability of NO. Importantly, these changes were associated with an increase in vascular density within the H2S-treated hearts. CONCLUSIONS: These results suggest that H2S therapy attenuates left ventricular remodeling and dysfunction in the setting of heart failure by creating a proangiogenic environment for the growth of new vessels. PMID- 23811965 TI - Clinical profile and underdiagnosis of pulmonary hypertension in US veteran patients. AB - BACKGROUND: Pulmonary hypertension (PH) is a key contributor to cardiovascular morbidity and early mortality; however, reports are lacking on the epidemiology of PH in at-risk patient populations. METHODS AND RESULTS: The echocardiography registries from 2 major Veterans Affairs hospitals were accessed to identify patients with at least moderate PH, defined here as a pulmonary artery systolic pressure >=60 mm Hg detected echocardiographically. From a total of 10 471 individual patient transthoracic echocardiograms, we identified moderate or severe PH in 340 patients (332 men; mean, 77 years; mean pulmonary artery systolic pressure, 69.4+/-10.5 mm Hg), of which PH was listed as a diagnosis in the medical record for only 59 (17.3%). At a mean of 832 days (0-4817 days) following echocardiography diagnosing PH, 150 (44.1%) patients were deceased. PH was present without substantial left heart remodeling: the mean left ventricular ejection fraction was 0.50+/-0.16, left ventricular end-diastolic dimension was 5.0+/-0.9 cm, and left atrial dimension was 4.4+/-0.7 cm. Cardiac catheterization (n=122, 36%) demonstrated a mean pulmonary artery pressure of 40.5+/-11.4 mm Hg, pulmonary capillary wedge pressure of 22.6+/-8.9 mm Hg, and pulmonary vascular resistance of 4.6+/-2.9 Wood units. Diagnostic strategies for PH were variable and often incomplete; for example, only 16% of appropriate patients were assessed with a nuclear ventilation/perfusion scan for thromboembolic causes of PH. CONCLUSIONS: in an at-risk patient population, PH is underdiagnosed and associated with substantial mortality. Enhanced awareness is necessary among practitioners regarding contemporary PH diagnostic strategies. PMID- 23811966 TI - Validity and reliability of a novel slow cuff-deflation system for noninvasive blood pressure monitoring in patients with continuous-flow left ventricular assist device. AB - BACKGROUND: Doppler ultrasound is the clinical gold standard for noninvasive blood pressure (BP) measurement among continuous-flow left ventricular assist device patients. The relationship of Doppler BP to systolic BP (SBP) and mean arterial pressure (MAP) is uncertain and Doppler measurements require a clinic visit. We studied the relationship between Doppler BP and both arterial-line (A line) SBP and MAP. Validity and reliability of the Terumo Elemano BP Monitor, a novel slow cuff-deflation device that could potentially be used by patients at home, were assessed. METHODS AND RESULTS: Doppler and Terumo BP measurements were made in triplicate among 60 axial continuous-flow left ventricular assist device (HeartMate II) patients (30 inpatients and 30 outpatients) at 2 separate exams (360 possible measurements). A-line measures were also obtained among inpatients. Mean absolute differences (MADs) and correlations were used to determine within device reliability (comparison of second and third BP measures) and between device validity. Bland-Altman plots assessed BP agreement between A-line, Doppler BP, and Terumo Elemano. Success rates for Doppler and Terumo Elemano were 100% and 91%. Terumo Elemano MAD for repeat SBP and MAP were 4.6+/-0.6 and 4.2+/-0.6 mm Hg; repeat Doppler BP MAD was 2.9+/-0.2 mm Hg. Mean Doppler BP was lower than A-line SBP by 4.1 (MAD=6.4+/-1.4) mm Hg and higher than MAP by 9.5 (MAD=11.0+/ 1.2) mm Hg; Terumo Elemano underestimated A-line SBP by 0.3 (MAD=5.6+/-0.9) mm Hg and MAP by 1.7 (MAD=6.0+/-1.0) mm Hg. CONCLUSIONS: Doppler BP more closely approximates SBP than MAP. Terumo Elemano was successful, reliable, and valid when compared with A-line and Doppler. PMID- 23811967 TI - Individual- and area-level effects on mortality risk in Germany, both East and West, among male Germans aged 65+. AB - OBJECTIVES: This study investigates whether mortality inequalities based on individual- and area-level deprivation exist at older ages in Germany, and whether there are differences between eastern and western Germany. METHODS: Data on population and death counts according to the individual-level socioeconomic status of male German pensioners aged 65+ years in Germany in 2002-2004 were obtained from the German Federal Pension Fund. Area-level characteristics for the 439 German districts were incorporated. Multilevel Poisson models were fitted. RESULTS: Individual-level socioeconomic mortality inequalities exist among elderly men in Germany. After controlling for differential population composition in the districts, we found that district-level factors contribute to the explanation of mortality inequalities in (western) Germany. The analysis further indicated that mortality and mortality inequalities tend to be higher in more economically deprived districts, and that minor mortality differences attributable to regional conditions exist in eastern Germany. CONCLUSIONS: The results showed that regional conditions have moderate effects on health inequalities at older ages in (western) Germany, when the differential population composition in the districts is controlled for. PMID- 23811969 TI - Prenatal phenotype of Nager syndrome and Rodriguez syndrome: variable expression of the same entity? PMID- 23811968 TI - Clinical, genetic, and brain sonographic features related to Parkinson's disease in Gaucher disease. AB - Homozygous or compound heterozygous mutations in the glucocerebrosidase gene cause Gaucher disease. Moreover, heterozygous glucocerebrosidase gene mutations represent the most common genetic risk factor for Parkinson's disease (PD) known so far. Substantia nigra (SN) hyperechogenicity, a sonographic feature thought to reflect iron accumulation, has been described in both PD and Gaucher disease patients. Here we studied how clinical, genetic, and brain sonographic findings relate to the occurrence of PD in Gaucher disease. Sixteen Gaucher disease patients, 12 PD patients, and 32 control subjects were enrolled. The glucocerebrosidase genotypes were identified by DNA sequencing. All subjects underwent transcranial ultrasound, and eight Gaucher disease patients additionally MRI for comparison with SN ultrasound findings. SN hyperechogenicity and reduced echogenicity of brainstem raphe were more frequent in Gaucher disease patients (62, 37 %) than in controls (12, 12 %; p < 0.001, p < 0.05). SN hyperechogenicity in Gaucher disease patients was unrelated to type or severity of glucocerebrosidase gene mutation, but correlated with iron-sensitive MRI-T2 hypointensity of SN pars compacta, and with age at start of enzyme replacement therapy. While none of the five Gaucher disease patients with signs of PD (definite PD, n = 4; early PD, n = 1) had severe glucocerebrosidase gene mutations known to cause neuronopathic Gaucher disease, all carried a N370S allele, previously reported to predict non-neuronopathic Gaucher disease. Hyposmia, higher non-motor symptoms score (constipation, depression, executive dysfunction), and SN hyperechogenicity were characteristic features of Gaucher disease-related PD. We conclude that the combined clinical, genetic, and transcranial sonographic assessment may improve the PD risk evaluation in Gaucher disease. PMID- 23811970 TI - Fast 4D flow MRI re-emerges as a potential clinical tool for neuroradiology. PMID- 23811971 TI - Alphabet soup: our government "in-action". PMID- 23811972 TI - Incidental findings in youths volunteering for brain MRI research. AB - BACKGROUND AND PURPOSE: MRIs are obtained in research in healthy and clinical populations, and incidental findings have been reported. Most studies have examined adults with variability in parameters of image acquisition and clinical measures available. We conducted a prospective study of youths and documented the frequency and concomitants of incidental findings. MATERIALS AND METHODS: Youths (n = 1400) with an age range from 8-23 years were imaged on the same 3T scanner, with a standard acquisition protocol providing 1.0 mm(3) isotropic resolution of anatomic scans. All scans were reviewed by an experienced board-certified neuroradiologist and were categorized into 3 groups: 1) normal: no incidental findings; 2) coincidental: incidental finding(s) were noted, further reviewed with an experienced pediatric neuroradiologist, but were of no clinical significance; 3) incidental findings that on further review were considered to have potential clinical significance and participants were referred for appropriate clinical follow-up. RESULTS: Overall, 148 incidental findings (10.6% of sample) were noted, and of these, 12 required clinical follow-up. Incidental findings were not related to age. However, whites had a higher incidence of pineal cysts, and males had a higher incidence of cavum septum pellucidum, which was associated with psychosis-related symptoms. CONCLUSIONS: Incidental findings, moderated by race and sex, occur in approximately one-tenth of participants volunteering for pediatric research, with few requiring follow-up. The incidence supports a 2-tiered approach of neuroradiologic reading and clinical input to determine the potential significance of incidental findings detected on research MR imaging scans. PMID- 23811974 TI - Sex differences in resting-state functional connectivity in multiple sclerosis. AB - BACKGROUND AND PURPOSE: Multiple studies have demonstrated evidence of sex differences in patients with MS, including differences in disease progression, cognitive decline, and biologic markers. This study used functional connectivity MRI to investigate sex differences in the strength of functional connectivity of the default mode network in patients with MS and healthy control subjects. MATERIALS AND METHODS: A total of 16 men and 16 women with MS and 32 age- and sex matched healthy control subjects underwent a whole-brain resting-state functional connectivity MRI scan. A group-based seed in the posterior cingulate was used to create whole-brain correlation maps. A 2 * 2 ANOVA was used to assess whether disease status and sex affected the strength of connectivity to the posterior cingulate. RESULTS: Patients with MS showed significantly stronger connectivity from the posterior cingulate to the bilateral medial frontal gyri, the left ventral anterior cingulate, the right putamen, and the left middle temporal gyrus (P < .0005). In the left dorsal lateral prefrontal cortex, female patients showed significantly stronger connectivity to the posterior cingulate cortex compared with female control subjects (P = 3 * 10(4)), and male control subjects showed stronger posterior cingulate cortex-left dorsal lateral prefrontal cortex connectivity in comparison to female control subjects (P = .002). Male patients showed significantly weaker connectivity to the caudate compared with female patients (P = .004). CONCLUSIONS: Disease status and sex interact to produce differences in the strength of functional connectivity from the posterior cingulate to the caudate and the left dorsal lateral prefrontal cortex. PMID- 23811973 TI - Potential role of preoperative conventional MRI including diffusion measurements in assessing epidermal growth factor receptor gene amplification status in patients with glioblastoma. AB - BACKGROUND AND PURPOSE: Epidermal growth factor receptor amplification is a common molecular event in glioblastomas. The purpose of this study was to examine the potential usefulness of morphologic and diffusion MR imaging signs in the prediction of epidermal growth factor receptor gene amplification status in patients with glioblastoma. MATERIALS AND METHODS: We analyzed pretreatment MR imaging scans from 147 consecutive patients with newly diagnosed glioblastoma and correlated MR imaging features with tumor epidermal growth factor receptor amplification status. The following morphologic tumor MR imaging features were qualitatively assessed: 1) border sharpness, 2) cystic/necrotic change, 3) hemorrhage, 4) T2-isointense signal, 5) restricted water diffusion, 6) nodular enhancement, 7) subependymal enhancement, and 8) multifocal discontinuous enhancement. A total of 142 patients had DWI available for quantitative analysis. ADC maps were calculated, and the ADCmean, ADCmin, ADCmax, ADCROI, and ADCratio were measured. RESULTS: Epidermal growth factor receptor amplification was present in 60 patients (40.8%) and absent in 87 patients (59.2%). Restricted water diffusion correlated with epidermal growth factor receptor amplification (P = .04), whereas the other 7 morphologic MR imaging signs did not (P > .12). Quantitative DWI analysis found that all ADC measurements correlated with epidermal growth factor receptor amplification, with the highest correlations found with ADCROI (P = .0003) and ADCmean (P = .0007). CONCLUSIONS: Our results suggest a role for diffusion MR imaging in the determination of epidermal growth factor receptor amplification status in glioblastoma. Additional work is necessary to confirm these results and isolate new imaging biomarkers capable of noninvasively characterizing the molecular status of these tumors. PMID- 23811975 TI - Incidence of microemboli and correlation with platelet inhibition in aneurysmal flow diversion. AB - Flow-diverting stents have been associated with embolic and hemorrhagic complications, but the rate of procedure-related microemboli is unknown. Using transcranial Doppler sonography, we measured the rate of microemboli in 23 patients treated with flow-diverting stents. Patients received preprocedural dual antiplatelet medications and intraprocedural heparinization. Point-of-care platelet reactivity testing was performed before the procedure, and nonresponders (>213 P2Y12/ADP receptor reactivity units) received additional thienopyridine. Transcranial Doppler sonography was performed within 12-24 hours. Microemboli were detected in 3 patients (13%), 2 of whom were initially nonresponders. There was no association between the presence of microemboli and procedural or neurologic complications, aneurysm size, number of stents, or procedure time. Eight procedures (34.8%) required additional thienopyridine for inadequate platelet inhibition, and 3 required further treatment for persistent nonresponse to point-of-care platelet reactivity testing. There were 6 technical and 2 postoperative complications; none were associated with inadequate platelet inhibition or microemboli. The combination of routine point-of-care platelet reactivity testing and postprocedural microembolic monitoring may help identify patients at risk for thromboembolic complications after flow-diverting stents. PMID- 23811976 TI - Structural abnormalities in patients with insular/peri-insular epilepsy: spectrum, frequency, and pharmacoresistance. AB - SUMMARY: Between 2002 and 2010, a total of 48 patients were seen at our epilepsy clinic with insular/peri-insular cortex epilepsy. Review of their MR imaging scans revealed a neoplastic lesion in 27% of patients, a malformation of cortical development in 21%, a vascular malformation in 19%, and atrophy/gliosis from an acquired insult in 17%. MR imaging results were normal in 4 patients. Other miscellaneous findings included a case of Rasmussen encephalitis, a nonspecific insular millimetric T2 signal abnormality, a neuroepithelial cyst, and hippocampal sclerosis without MR imaging evidence of dual insular pathologic features (despite depth electrode-proven insular seizures). Refractoriness to antiepileptic drug treatment was present in 56% of patients: 100% for patients with malformations of cortical development (1.0; 95% CI, 0.72-1.0), 50.0% (0.5; 95% CI, 0.21-0.78) in the presence of atrophy/gliosis from acquired insults, 39% (0.39; 95% CI, 0.14-0.68) for neoplastic lesions, and 22.2% (0.22; 95% CI, 0.06 0.55) for vascular malformations. PMID- 23811977 TI - Intracranial-derived atherosclerosis assessment: an in vitro comparison between virtual histology by intravascular ultrasonography, 7T MRI, and histopathologic findings. AB - BACKGROUND AND PURPOSE: Atherosclerotic plaque composition and structure contribute to the risk of plaque rupture and embolization. Virtual histology by intravascular ultrasonography and high-resolution MR imaging are new imaging modalities that have been used to characterize plaque morphology and composition in peripheral arteries. MATERIALS AND METHODS: The objectives of this study were 1) to determine the correlation between virtual histology-intravascular ultrasonography and histopathologic analysis (reference standard) and 2) to explore the comparative results of 7T MR imaging (versus histopathologic analysis), both to be performed in vitro by use of intracranial arterial segments with atherosclerotic plaques. Thirty sets of postmortem samples of intracranial circulation were prepared for the study. These samples included the middle cerebral artery (n = 20), basilar artery (n = 8), and anterior cerebral artery (n = 2). Virtual histology-intravascular ultrasonography and 7T MR imaging were performed in 34 and 10 points of interest, respectively. The formalin-fixed arteries underwent tissue processing and hematoxylin-eosin staining. The plaques were independently categorized according to revised Stary classification after review of plaque morphology and characteristics obtained from 3 modalities. The proportion of fibrous, fibrofatty, attenuated calcium, and necrotic components in the plaques were determined in histology slides and compared with virtual histology-intravascular ultrasonography and MR imaging. RESULTS: Of 34 points of interest in the vessels, 32 had atherosclerotic plaques under direct visualization. Plaques were visualized in gray-scale intravascular ultrasonography as increased wall thickness, outer wall irregularity, and protrusion. The positive predictive value of virtual histology-intravascular ultrasonography for identifying fibroatheroma was 80%. Overall, virtual histology intravascular ultrasonography accurately diagnosed the type of the plaque in 25 of 34 samples, and kappa agreement was 0.58 (moderate agreement). The sensitivity and specificity of virtual histology-intravascular ultrasonography readings for fibroatheroma were 78.9% and 73.3%, respectively. The overall sensitivity and specificity for virtual histology-intravascular ultrasonography were 73.5% and 96.6%, respectively. Plaques were identified in 7T MR imaging as increased wall thickness, luminal stenosis, or outer wall protrusion. The positive predictive value of 7T MR imaging for detecting fibrous and attenuated calcium deposits was 88% and 93%, respectively. CONCLUSIONS: This in vitro study demonstrated that virtual histology-intravascular ultrasonography and high-resolution MR imaging are reliable imaging tools to detect atherosclerotic plaques within the intracranial arterial wall, though both imaging modalities have some limitations in accurate characterization of the plaque components. Further clinical studies are needed to determine the clinical utility of plaque morphology and composition assessment by noninvasive tests. PMID- 23811978 TI - Differentiation of recurrent tumor and posttreatment changes in head and neck squamous cell carcinoma: application of high b-value diffusion-weighted imaging. AB - BACKGROUND AND PURPOSE: High b-value DWI has been expected to have an additional diagnostic role and demonstrated some promising results in head and neck cancer. The aim of this study was to evaluate the diagnostic performance of DWI at a high b-value (b=2000 s/mm(2)) compared with a standard b-value (b=1000 s/mm(2)) and the ratio of ADC values of high and standard b-values for their ability to differentiate between recurrent tumor and posttreatment changes after the treatment of head and neck squamous cell carcinoma. MATERIALS AND METHODS: A total of 33 patients diagnosed with head and neck squamous cell carcinoma were enrolled in the present study; all had contrast-enhancing lesions on follow-up MR imaging. All patients underwent single-shot echo-planar DWI at b=1000 s/mm(2) and b=2000 s/mm(2), and corresponding ADC maps were generated (ADC1000 and ADC2000, respectively). The mean ADC1000, ADC2000, and ADCratio (ADCratio = ADC2000/ADC1000 * 100) values were evaluated within a manually placed ROI with contrast-enhanced T1-weighted images as references. For the statistical analysis, we performed a Student t test and multivariate logistic regression. RESULTS: The mean ADC1000 in recurrent tumor was significantly lower than that in posttreatment changes (P < .001), whereas the mean ADC2000 resulted in no significant difference (P = .365). The mean ADCratio was significantly higher in recurrent tumor than that in posttreatment changes (73.5 +/- 7.2% vs 56.9 +/- 8.8%, respectively; P < .001). Multivariate logistic regression analysis revealed that the ADCratio was the only independently differentiating variable (P = .024). The sensitivity, specificity, and accuracy of ADCratio were 95.0%, 69.2%, and 84.8%, respectively, by use of the optimal cutoff value of 62.6%. CONCLUSIONS: We suggest that the ADCratio calculated from the ADC1000 and ADC2000 is a promising value for the differentiation of recurrent tumor and posttreatment changes in head and neck squamous cell carcinoma. PMID- 23811979 TI - Spontaneous delayed migration/shortening of the pipeline embolization device: report of 5 cases. AB - Five patients were found to have spontaneous delayed migration/shortening of their Pipeline Embolization Devices on follow-up angiography. The device migrated proximally in 4 patients and distally in 1 patient. One patient had a subarachnoid hemorrhage and died as a result of migration of the Pipeline Embolization Device, and another patient presented with complete MCA occlusion and was left severely disabled. Mismatch in arterial diameter between inflow and outflow vessels was a constant finding. Migration of the Pipeline Embolization Device was managed conservatively, with additional placement of the device, or with parent vessel occlusion. Obtaining complete expansion of the embolization device by using a longer device, increasing vessel coverage, using adjunctive aneurysm coiling, and avoiding dragging and stretching of the device are important preventive measures. Neurointerventionalists should be aware of this potentially fatal complication and take all necessary preventive measures. PMID- 23811980 TI - Morphologic, distributional, volumetric, and intensity characterization of periventricular hyperintensities. AB - BACKGROUND AND PURPOSE: White matter hyperintensities are characteristic of old age and identifiable on FLAIR and T2-weighted MR imaging. They are typically separated into periventricular or deep categories. It is unclear whether the innermost segment of periventricular white matter hyperintensities is truly abnormal or is imaging artifacts. MATERIALS AND METHODS: We used FLAIR MR imaging from 665 community-dwelling subjects 72-73 years of age without dementia. Periventricular white matter hyperintensities were visually allocated into 4 categories: 1) thin white line; 2) thick rim; 3) penetrating toward or confluent with deep white matter hyperintensities; and 4) diffuse ill-defined, labeled as "subtle extended periventricular white matter hyperintensities." We measured the maximum intensity and width of the periventricular white matter hyperintensities, mapped all white matter hyperintensities in 3D, and investigated associations between each category and hypertension, stroke, diabetes, hypercholesterolemia, cardiovascular disease, and total white matter hyperintensity volume. RESULTS: The intensity patterns and morphologic features were different for each periventricular white matter hyperintensity category. Both the widths (r = 0.61, P < .001) and intensities (r = 0.51, P < .001) correlated with total white matter hyperintensity volume and with each other (r = 0.55, P < .001) for all categories with the exception of subtle extended periventricular white matter hyperintensities, largely characterized by evidence of erratic, ill-defined, and fragmented pale white matter hyperintensities (width: r = 0.02, P = .11; intensity: r = 0.02, P = .84). The prevalence of hypertension, hypercholesterolemia, and neuroradiologic evidence of stroke increased from periventricular white matter hyperintensity categories 1 to 3. The mean periventricular white matter hyperintensity width was significantly larger in subjects with hypertension (mean difference = 0.5 mm, P = .029) or evidence of stroke (mean difference = 1 mm, P < .001). 3D mapping revealed that periventricular white matter hyperintensities were discontinuous with deep white matter hyperintensities in all categories, except only in particular regions in brains with category 3. CONCLUSIONS: Periventricular white matter hyperintensity intensity levels, distribution, and association with risk factors and disease suggest that in old age, these are true tissue abnormalities and therefore should not be dismissed as artifacts. Dichotomizing periventricular and deep white matter hyperintensities by continuity from the ventricle edge toward the deep white matter is possible. PMID- 23811983 TI - Colon transit time and anorectal manometry in children and young adults with spina bifida. AB - PURPOSE: This study evaluates colon transit time (CTT) and anorectal manometry (ARM) in spina bifida (SB) patients in relation to the level of lesion, mobility, constipation, and continence status. METHODS: SB patients between 6 and 19 years, who are not using antegrade continence enemas and followed at the SB Reference Centre UZ Ghent, were asked to participate. Medical history was retrospectively retrieved from the medical file. Stool habits were prospectively collected using standardized questionnaires. CTT was measured using the 6-day pellet abdominal X ray method. ARM was performed in non-sedated children with a water-perfused, latex-free catheter. RESULTS: Forty out of 52 eligible patients consented to perform CTT, of which 19 also performed the ARM. Fifteen (37 %) SB patients were constipated despite treatment. Twenty-six (65 %) were (pseudo) continent. The total CTT was significantly prolonged in SB patients (median CTT 86.4 vs. 36 h controls). The CTT was significantly prolonged in constipated SB patients compared to non-constipated SB patients (122.4 vs. 52.8 h). Spontaneously continent patients had a normal CTT (33.6 h) as well as a significantly higher resting pressure compared to the pseudo-continent and incontinent SB patients (resting pressure 56.5 vs. 32.5 mmHg). An abnormal CTT was associated with a treatment necessity to achieve pseudo-continence (p = 0.006). CONCLUSION: CTT in SB patients was significantly prolonged, indicating a neurogenic involvement of the bowel and slow transit constipation. SB patients with a normal CTT and a normal ARM spontaneously achieved fecal continence. CTT can help tailor the continence therapy in SB patients. PMID- 23811982 TI - Risk of hemoptysis in patients with resected squamous cell and other high-risk lung cancers treated with adjuvant bevacizumab. AB - PURPOSE: Bevacizumab improves survival in lung adenocarcinomas. The potential anti-tumor benefit of bevacizumab in squamous cell lung cancers (SQCLCs) is unknown because bevacizumab is contraindicated in patients with advanced SQCLC due to an increased risk of hemoptysis. The risk of hemoptysis may be eliminated in patients with resected SQCLCs. We evaluated the safety of adjuvant bevacizumab in patients with resected SQCLCs and other lung cancers at high risk of hemoptysis. METHODS: As part of a prospective, phase II trial, patients with lung cancers at high risk of hemoptysis (defined by SQCLC histology, tumor near the central blood vessels, or history of hemoptysis) were treated with adjuvant bevacizumab following neo-adjuvant chemotherapy and complete surgical resection. Bevacizumab 15 mg/kg was given once every 3 weeks for up to 1 year. Patients were followed for safety and survival. RESULTS: Thirteen patients with high-risk features were treated: 7 patients had SQCLC, 3 had central tumors, and 3 had previous hemoptysis. No hemoptysis of any grade was seen following treatment with bevacizumab. Five of 13 patients experienced grade 1 bleeding (epistaxis, gum bleeding). Hypertension and lymphopenia were seen. CONCLUSIONS: In a cohort of patients with resected lung cancers at high risk of hemoptysis, including those with SQCLC, treatment with adjuvant bevacizumab did not result in hemoptysis of any grade. PMID- 23811984 TI - A randomized crossover open trial of the adenoma miss rate for narrow band imaging (NBI) versus flexible spectral imaging color enhancement (FICE). AB - PURPOSE: Narrow band imaging (NBI) and flexible spectral imaging color enhancement (FICE) allow improved contrasted evaluation of the mucosal surface. However, no study has compared the utility of these two modalities. Therefore, the aim of this study was to compare the adenoma miss rate (AMR) between NBI and FICE. METHODS: A total of 55 patients (38 men, 17 women) were enrolled in this study. Patients were randomly assigned to the NBI-FICE group (NBI followed by FICE) or the FICE-NBI group (FICE followed by NBI). NBI and FICE total colonic observations were tandemly performed for each patient during the scope withdrawal with white light following cecal intubation. All detected polyps with the NBI or FICE observation were categorized into three groups according to the size and number of polyps missed. RESULTS: Twenty-nine patients were assigned to the NBI FICE group, and 26 patients were assigned to the FICE-NBI group. There was no significant difference in the overall AMR when comparing the image-enhanced endoscopy technologies (17.9 % for NBI, 26 % for FICE, p = 0.159). AMR was lower for NBI than for FICE for adenomas <5 mm in diameter (5.7 % for NBI, 12.6 % for FICE, p = 0.036). AMR was not significantly different when comparing NBI and FICE for lesions 5 to 10 mm (p = 0.967) or for lesions >=10 mm (p = 0.269). CONCLUSIONS: This study demonstrated that overall AMR was not different when comparing NBI and FICE. PMID- 23811985 TI - Arrays of microelectrodes: technologies for environmental investigations. AB - Within this work it is our intention to provide an overview of the use of arrays or microelectrodes in the characterisation of environmental samples. Electrochemical methods are often a relatively simple and inexpensive alternative to spectroscopic or chromatographic methods for the analysis of a wide range of analytes. Arrays of microelectrodes display a number of advantages over simple planar macroelectrodes and the reasons for this will be detailed within this work. We will also describe some of the most common methods for constructing microarrays. The application of these arrays for analysis of environmental samples such as soil and water for heavy metal contamination has been the major focus of research in this field and comprises much of this review. However other systems will also be detailed such as determination of various anions or other samples such as pesticides. PMID- 23811986 TI - Evaluation of second phase insulin secretion with simple surrogates derived from the mixed meal tolerance test in patients with type 2 diabetes. AB - The major contributors to the pathogenesis of type 2 diabetes are impaired insulin action and insulin secretion, including second phase insulin secretion (2nd ISEC). This study aimed to compare surrogates derived from the mixed meal tolerance test (MTT) with 2nd ISEC derived from modified low-dose graded glucose infusion (M-LDGGI) in patients with type 2 diabetes. We were subsequently able to decide which surrogate would be performed easily and accurately. Twenty type 2 diabetes patients were enrolled. They received both MTT and M-LDGGI. The standardized MTT meals were provided at 8:00 A.M. and 12:00 P.M. The M-LDGGI was a simplified version of the Polonsky method; only two 80-min stages of glucose infusion (2 and 6 mg/kg/min) were given. The slopes of the insulin to glucose curve during the test were regarded as the 2nd ISEC. First, we used the area under the insulin curve (AUC(IN)) during MTT to quantify the 2nd ISEC. The best correlated AUC(IN) was from 60-240 min. Second, the slopes between any two time points of the plasma insulin to glucose level (SLOPE(I/G)) were also assessed. The time period best correlated with 2nd ISEC was from 0-120 min (SLOPE0-120). Finally, the insulin-to-glucose ratio (IGr) of each time point was used to estimate the 2nd ISEC, and the best correlation was observed at 180 min. In conclusion, estimating 2nd ISEC surrogates derived from MTT proved to be possible. The most accurate surrogate is the SLOPE0-120, while IG(r180) is another less precise but more convenient method. PMID- 23811987 TI - Efficacy and safety of desmopressin orally disintegrating tablet in patients with central diabetes insipidus: results of a multicenter open-label dose-titration study. AB - Central diabetes insipidus (CDI) is associated with arginine vasopressin (AVP) deficiency with resultant polyuria and polydipsia. Intranasal desmopressin provides physiological replacement but oral formulations are preferred for their ease of administration. This study aimed to demonstrate the efficacy and safety of desmopressin orally disintegrating tablet (ODT) in the treatment of Japanese patients with CDI, and confirm that antidiuresis is maintained on switching from intranasal desmopressin to desmopressin ODT. A total of 20 patients aged 6-75 years with CDI were included in this 4-week multicenter, open-label study. Following observation, patients switched from intranasal desmopressin to desmopressin ODT with titration to optimal dose over <=5 days at the study site. Following three consecutive doses with stable patient fluid balance, patients were discharged with visits at Weeks 2 and 4. Following titration from intranasal desmopressin to ODT, the mean 24-hour urine volume was unchanged, indicating similar antidiuresis with both formulations. The proportion of patients with endpoint measurements (urine osmolality, 24-hour urine volume, hourly diuresis rate and urine-specific gravity) within normal range at Days 1-2 (intranasal desmopressin) and Week 4 (desmopressin ODT) was similar. The mean daily dose ratio of intranasal desmopressin to desmopressin ODT (Week 4) was 1:24 but a wide range was observed across individuals to maintain adequate antidiuretic effect. Hyponatraemia was generally mild and managed by dose titration. Desmopressin ODT achieved sufficient antidiuretic control compared to intranasal therapy and was well tolerated over long-term treatment. The wide range of intranasal:ODT dose ratios underline the importance of individual titration. PMID- 23811988 TI - Gestational changes of thyroid function and urinary iodine in thyroid antibody negative Japanese women. AB - Iodine is an essential nutrient for thyroid hormone synthesis, and iodine deficiency especially in pregnant and lactating women results in serious damage to their infants. To characterize iodine nutrition throughout gestation by using a food frequency questionnaire (FFQ) and urinary iodine concentration (UIC) measurement, and to establish appropriate gestational age-specific reference ranges for serum TSH and FT4 in thyroid autoantibody (ThAb) negative euthyroid Japanese women, a total number of 563 pregnant women including 422 subjects with negative ThAbs, 105 postpartum women and their 297 newborn infants were included in the study. Dietary iodine intake (DII) was evaluated by FFQ. Serum TSH, FT4 and UIC were sequentially determined in the three trimesters of pregnancy and at the 31st postpartum day. The overall median UICs throughout pregnancy and in the postpartum period were 224.0 and 135.0 MUg/L, respectively, suggesting sufficient iodine nutrition. The median DII was 842.4 MUg/day in pregnant women. The median UIC in the first trimester (215.9 MUg/L) significantly decreased in the second trimester (136.0 MUg/L). The prevalence of pregnant women with a UIC below 150 MUg/L was 31.6% and that in lactating women with a UIC below 100 MUg/L was 33.3%. The pattern of gestational change in serum TSH and FT4 was comparable to that in iodine-sufficient areas. A substantial percentage of women might be at risk for iodine deficiency if there is a restriction of iodine-rich foods. However, iodine supplementation for pregnant women must be carefully balanced against the risk of iodine excess particularly in Japan. Further research in larger samples is needed. PMID- 23811989 TI - Benzimidazole-embedded N-fused aza-indacenes: synthesis and deprotonation assisted optical detection of carbon dioxide. AB - N-fused aza-indacene-based fluorophores 1 and 2 were prepared via a three component condensation involving benzimidazole-carbinol, trifluoroacetic acid, and either pyrrole or indole, respectively. The N-fused aza-indacenes act as optical-based chemosensors for dissolved carbon dioxide gas following fluoride anion-mediated deprotonation. PMID- 23811990 TI - Different sensitivities of biomarker responses in two epigeic earthworm species after exposure to pyrethroid and organophosphate insecticides. AB - In many studies that investigate the toxic effects of pollutants on earthworms, experiments are performed using only one species of earthworms, most commonly the Eisenia species. However, the differences in sensitivities of different earthworm species could potentially lead to an underestimation of environmental aspects of pollutants. Therefore, the aim of this study was to compare the sensitivity of biomarker responses of Eisenia andrei, an epigeic compost species commonly used in laboratory experiments, with those of Lumbricus rubellus, an epigeic species widely distributed in temperate regions. The earthworms were exposed to the three commonly used insecticides: organophosphates dimethoate (0.03, 0.3, and 3 mg kg( 1)) and pirimiphos-methyl (0.02, 0.2, and 2 mg kg(-1)), as well as pyrethroid deltamethrin (0.01, 0.1, and 0.5 mg kg(-1)), for 1 and 15 days using an artificial soil test. The effects of the pesticides were assessed by measuring the activities of acetylcholinesterase (AChE), carboxylesterase (CES), catalase (CAT), glutathione S-transferase (GST) as well as the concentration of glutathione (GSH). The pesticides caused a significant inhibition of AChE and CES activities and significant changes in activities of CAT, GST, and GSH concentration in both earthworm species. A comparison of biomarker responses between E. andrei and L. rubellus showed significant differences; E. andrei proved to be less susceptible to pesticide exposure than L. rubellus. In addition, the results from the filter-paper contact test mortality experiments showed that lethal concentrations were lower for L. rubellus compared with the E. andrei, further showing a greater sensitivity of L. rubellus. The difference in sensitivities of these epigeic species should be taken into account when conducting toxicity studies. PMID- 23811993 TI - Microwave synthesizer using an on-chip Brillouin oscillator. AB - Low-phase-noise microwave oscillators are important to a wide range of subjects, including communications, radar and metrology. Photonic-based microwave-wave sources now provide record, close-to-carrier phase-noise performance, and compact sources using microcavities are available commercially. Photonics-based solutions address a challenging scaling problem in electronics, increasing attenuation with frequency. A second scaling challenge, however, is to maintain low phase noise in reduced form factor and even integrated systems. On this second front, there has been remarkable progress in the area of microcavity devices with large storage time (high optical quality factor). Here we report generation of highly coherent microwaves using a chip-based device that derives stability from high optical quality factor. The device has a record low electronic white-phase-noise floor for a microcavity-based oscillator and is used as the optical, voltage-controlled oscillator in the first demonstration of a photonic-based, microwave frequency synthesizer. The synthesizer performance is comparable to mid-range commercial devices. PMID- 23811991 TI - A modified Hartmann-Shack aberrometer for measuring stray light in the anterior segment of the human eye. AB - PURPOSE: To examine the use of a modified Hartmann-Shack wave front aberrometer (WASCA; Carl Zeiss Meditec AG, Germany) to measure objective stray light caused by forward light scatter from the anterior segment of the human eye. SETTING: HELIOS Klinikum Erfurt/Institute of Biomedical Engineering and Informatics, Ilmenau University of Technology, Germany. METHOD: Scatter parameters, including the Michelson contrast and cross-sectional area at half height (CAHM) were examined in Hartmann-Shack images from ten subjects with a cataract in one eye and an intraocular lens (IOL) in the other. The parameters were compared between each eye. Light scatter was then measured in 40 healthy subjects (age range, 23 75 years) with spherical ametropia ranging from -0.25 to 0.25 diopters. The subjects were divided into three age groups; 23-35, 36-50, and 51-75 years. Light scatter was also measured using four alternative methods. RESULTS: CAHM and contrast were significantly different between the eyes with the cataract and the IOL (P = 0.007 and P = 0.004, respectively). CAHM (r = 0.557, P < 0.001) and contrast (r = -0.467, P < 0.001) were both significantly correlated with age. There were significant differences in CAHM and contrast between the age groups. CONCLUSION: The modified wave front aberrometer can be used to measure stray light, although its diagnostic sensitivity in individual patients must be improved. PMID- 23811994 TI - Cerebral magnetic resonance imaging findings in adults with haemolytic uraemic syndrome following an infection with Escherichia coli, subtype O104:H4. AB - PURPOSE: Infections with Enterohaemorrhagic Escherichia coli typically occur in children causing haemolytic uraemic syndrome (HUS) and neurological symptoms in 20-50 %. Little information is available on the morphology of brain manifestations in adults. The purpose of this study was to identify a characteristic magnetic resonance imaging (MRI) pattern during the outbreak of a novel mutation of Escherichia coli O104:H4. METHODS: Patients were recruited from two hospitals between May and July 2011. The MRI protocol included standard anatomical, diffusion-weighted, and susceptibility-sensitive sequences. RESULTS: A total of 104 MRIs of 57 (32 female, 25 male) patients (mean 45.5 +/- 18.4 years) showed abnormal signal intensity on 51 MRIs (49 %). Bilateral thalamus (39 %), bilateral pons (35 %), centrum semiovale and splenium of corpus callosum (33 %) were most often involved. Acute lesions were reversible in 81 % of cases. There was no statistically significant association between symptom onset and the MRI findings (P = 0.2). CONCLUSIONS: Neuroimaging findings in this adult patient cohort were non-specific and similar to previous findings in children. A characteristic neuroimaging pattern of an infection with Escherichia coli O104:H4 was not identified. However, bilateral symmetric T2 hyperintense lesions of the thalami and dorsal pons characterized by restricted diffusion suggest a metabolic toxic effect of the disease on the brain. PMID- 23811995 TI - Blood pressure levels and brain volume reduction: a systematic review and meta analysis. AB - OBJECTIVE: High blood pressure (BP) levels may be associated with brain volume reduction and may contribute to brain atrophy in key brain regions involved in cognition and susceptible to neurodegeneration in Alzheimer's disease. The purpose of this work was to systematically review and quantitatively synthesize the association of BP levels with brain volume reduction in humans. METHODS: An English Medline, Cochrane Library and PsycINFO search was conducted in June 2012 using the Medical Subject Heading terms 'Blood pressure', 'Hypertension', 'Brain mapping' and 'Brain atrophy'. RESULTS: Of the 609 screened abstracts, 28 studies (4.6%) were included in the qualitative analysis. Twenty-six studies (92.9%) showed a significant association of higher BP levels and/or hypertension with total and/or regional brain volume reduction, the frontal and temporal lobes being particularly affected. In addition, four other studies reported an association between lower BP levels and brain volume reduction. Due to the heterogeneity of methodology and outcomes, random-effects meta-analyses of the mean difference of brain volume could be performed on only seven studies, with a total of 709 cases with hypertension and 1001 controls without hypertension. The findings showed no between-group difference regarding the whole-gray matter volume (summary mean difference = 2.42 cm [95% confidence interval (CI): -2.13 to 6.96]). Conversely, cases with hypertension exhibited lower hippocampus volume compared with controls [summary mean difference = -0.10 cm (95% CI: -0.17 to 0.02)]. CONCLUSION: These findings provide evidence that high BP levels lead to brain volume reduction, specifically in hippocampus, and may be an important factor that contributes to neurodegeneration in Alzheimer's disease. PMID- 23811996 TI - Renal myogenic constriction protects the kidney from age-related hypertensive renal damage in the Fawn-Hooded rat. AB - INTRODUCTION: Intact myogenic constriction plays a role in renal blood flow autoregulation and protection against pressure-related (renal) injury. However, to what extent alterations in renal artery myogenic constriction are involved in development of renal damage during aging is unknown. Therefore, we studied two strains of fawn-hooded rats, which differ in expression of hypertension and chronic renal failure. METHODS: Ten-week-old fawn-hooded hypertensive (FHH) and fawn-hooded low blood pressure (FHL) rats were followed for SBP and proteinuria for 1 year. At 52 weeks of age, the kidney was removed and studied for focal glomerulosclerosis (FGS) and glomerular cross-sectional area, and myogenic constriction of isolated small renal arteries in a vessel perfusion set up. Renal myogenic constriction and FGS were additionally determined in 10-week-old fawn hooded rats. RESULTS: At young age, fawn-hooded rats did not differ in SBP, FGS, and urinary protein excretion, but renal artery myogenic constriction already was significantly smaller (~50%) in FHH compared with FHL rats. Aging in fawn-hooded rats was associated with increase in SBP and urinary protein excretion and loss of renal artery myogenic constriction. These changes occurred in both fawn-hooded strains, although that in FHH rats the onset of hypertension occurred earlier and the increase in proteinuria by far exceeded (>4 times) that observed in FHL rats, and came along with 5.5 times increase in FGS and 1.3 times increase in glomerular cross-sectional area and significantly less preserved renal artery myogenic constriction in FHH rats. CONCLUSION: Better preservation of renal myogenic constriction protects the kidney from age-related hypertensive renal damage in the fawn-hooded rat. PMID- 23811997 TI - Increased short-term blood pressure variability is associated with early left ventricular systolic dysfunction in newly diagnosed untreated hypertensive patients. AB - BACKGROUND AND AIM: Twenty-four-hour blood pressure (BP) variability, by ambulatory BP monitoring (ABPM), has been related to left ventricular hypertrophy, independent of mean BP values. We tested the hypothesis that short term BP variability (BPV) is also related to subclinical left ventricular systolic dysfunction. METHODS: We assessed 24-h SBP and DBP variabilities, quantified as standard deviation (SD) of daytime (awake) BP values and as weighted SD of 24-h BP (24-h-weighted BPV), in 309 recently (<6 months) diagnosed, prospectively recruited, and untreated hypertensive patients. Patients were included only if with normal (>=55%) left ventricular ejection fraction (LVEF). Left ventricular systolic function was assessed by echocardiography measuring midwall fractional shortening (MFS), circumferential end-systolic stress (cESS), MFS/cESS, peak systolic wall stress, left ventricular fractional shortening (LVFS), and LVEF. RESULTS: At multivariate analysis, awake and 24-h weighted SBP variabilities (directly, P = 0.038 and P = 0.002, respectively) as well as relative wall thickness (RWT) (inversely, P = 0.001) were significantly related to cESS. Awake and 24-h SBP average values (inversely, P = 0.011 and P = 0.002, respectively), awake and 24-h-weighted SBP variabilities (inversely, P = 0.017 and P = 0.024, respectively), and RWT (directly, P = 0.001) were all significantly related to MFS/cESS. Finally, awake and 24-h average SBP (directly, P = 0.01 for both), awake and 24-h-weighted SBP variability (directly, P = 0.001 and P = 0.032, respectively), and RWT (inversely, P = 0.001) were all significantly and independently related to peak systolic wall stress. CONCLUSION: In newly diagnosed never-treated hypertensive patients, in the absence of LVEF changes and independent of left ventricular mass index, higher awake, or 24-h weighted short-term SBP variabilities are associated with early depressed left ventricular systolic function. PMID- 23811998 TI - Association of metabolic risk factors with uncontrolled hypertension: comparison of the several definitions of metabolic syndrome. AB - AIMS: To evaluate the influence of metabolic syndrome in the effectiveness of antihypertensive treatment and to compare it using the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) (2001 and 2004), International Diabetes Federation (IDF) and American Heart Association/National Heart, Lung and Blood Institute (AHA-NHLBI) definitions. METHODS: The VALSIM (Estudo de Prevalencia da Sindrome Metabolica) survey was designed as an observational cross-sectional study performed in a primary healthcare setting in Portugal. The first two adult patients scheduled for an appointment on a given day were invited to participate. The treatment effectiveness was evaluated by the occurrence of uncontrolled hypertension (>=140/90 mmHg) in patients taking antihypertensive drugs. Logistic regression analysis was used to determine the association between uncontrolled hypertension and metabolic risk factors, with adjustments for age, sex, and pattern of antihypertensive treatment. RESULTS: Among the 16,856 individuals evaluated, 8925-treated hypertensive patients were identified. Only 35.8% of them had controlled hypertension. The risk of poor blood pressure control increased with age, waist circumference, serum levels of triglycerides and HDL-cholesterol. Among treatable risk factors, metabolic syndrome as defined by NCEP-ATP III 2001 diagnostic criteria was the strongest independent predictor of uncontrolled hypertension (odds ratio: 1.23; 95% CI: 1.08-1.41; P=0.002). In opposition, the IDF or AHA-NHLBI definitions of metabolic syndrome failed to identify patients at risk of poor blood pressure control. CONCLUSION: Metabolic syndrome is associated with lower effectiveness of antihypertensive therapy and the NCEP-ATP III 2001 definition of metabolic syndrome is the one that better identifies patients at risk of poor blood pressure control. PMID- 23811999 TI - Inhibition of prolyl hydroxylase domain-containing protein on hypertension/renal injury induced by high salt diet and nitric oxide withdrawal. AB - BACKGROUND: Nitric oxide just as prolyl hydroxylase domain-containing protein (PHD) is a regulator of hypoxia inducible factor-1 alpha (HIF-1alpha), a transcription factor complex that controls the expression of most genes involved in hypoxia and cardiovascular diseases. In the absence of nitric oxide, it is not clear how HIF-1alpha and PHD are regulated and to what extent they contribute to the ensuing disorder. METHOD: Using the nitric oxide withdrawal/high salt diet model of hypertensive renal injury, this study tested the hypothesis that removal of the inhibition by nitric oxide on PHD predisposes to increased PHD but reduced HIF-1alpha expression, hypertension and renal injury. RESULTS: In animals treated with N-nitro-L-arginine (L-NNA; 250 mg/l in drinking water for 14 days) and high salt diet (4% NaCl), there was hypertension (41+/-5%, P<0.05), proteinuria (three fold, P<0.05), kidney (22+/-3%, P<0.05) and heart enlargement (24+/-3%, P<0.05), as well as increased renal osteopontin (21+/-3%, P<0.05) and collagen IV (24+/ 4%, P<0.05) expression. Accompanying these effects were increased expression of PHD1 (24+/-4%, P<0.05) and PHD2 (36+/-4%, P<0.05) but reduced HIF-1alpha (35+/ 6%, P < 0.05) expression. Dimethyloxallyl glycine (5mg/kg), a PHD inhibitor, paradoxically exacerbated hypertension (46+/-7%, P<0.05), proteinuria (two-fold, P <0.05), and increased osteopontin (15+/-2%, P<0.05) and HIF-1alpha (31+/-5%, P<0.05) expression with no change in PHD1/2 expression or kidney and heart enlargement. CONCLUSION: These data suggest that the protective effect of physiological levels of nitric oxide may be by virtue of inhibition of PHD or increased HIF-1alpha expression, hence, the pathological changes produced following its withdrawal was accompanied by increased PHD or decreased HIF-1alpha expression. Exacerbation of hypertension and renal injury following PHD inhibition suggests a deleterious effect in the chronic setting and challenges the dogma that inhibition of PHD is useful in cardiovascular diseases. PMID- 23812000 TI - Elderly Algerian women lose their sex-advantage in terms of arterial stiffness and cardiovascular profile. AB - OBJECTIVES: Several studies have shown lower carotid-femoral pulse wave velocity (cfPWV) levels in women compared to men, a difference that could partially explain the increased longevity in women. However, these studies have been performed in industrial countries while few data are available in emerging populations. We studied arterial stiffness, as evaluated by cfPWV, in elderly Algerian men and women. METHODS: cfPWV was studied in 321 Algerian men (81.2 +/- 5.3 years) and women (81.1 +/- 4.4 years). An age-matched and sex-matched cohort of European individuals (n = 321) was used as a control group. RESULTS: Comparatively to men, Algerian women exhibited higher BMI and heart rate (HR), higher prevalence of hypertension, and were more frequently treated for hypertension. cfPWV was not different between Algerian men (14.8 +/- 3.3 m/s) and women (14.9 +/- 3.4 m/s). By contrast, in Europeans, women had lower cfPWV (12.7 +/- 2.7 m/s) than men (14.0 +/- 3.3 m/s; P <0.001). Comparatively to European women, Algerian women had a higher cfPWV (P <0.01). In both ethnic groups, multivariate analyses revealed that age, mean blood pressure (BP), HR, and diabetes were positively associated with cfPWV, whereas female sex was associated with lower cfPWV only in Europeans. CONCLUSION: Elderly Algerian women exhibit arterial stiffness similar to men, whereas European women display lower arterial stiffness than men. This loss of 'arterial sex advantage' in Algerians may be explained by higher BP, HR, and a worse metabolic profile in Algerian women. Interventions in emerging populations, especially in women, should be a priority in order to address these risk factors by acting on current lifestyle. PMID- 23812001 TI - Calcium and osteoprotegerin levels predict the progression of the abdominal aortic calcifications after kidney transplantation. AB - BACKGROUND: Vascular calcifications (VCs) are a cardiovascular risk factor in patients affected by chronic kidney disease and after kidney transplantation (KTx). We evaluated the prevalence of VCs at the abdominal aortic site in KTx patients at the time of transplantation and 1 year after KTx, exploring the possibly associated factors. METHODS: In 107 transplanted patients, the following parameters were evaluated at the first and twelfth month after KTx: the aortic calcification index (ACI), fibroblast growth factor 23, osteoprotegerin (OPG), fetuin A, and clinical and biochemical parameters. Patients were followed up for 2 years after KTx. RESULTS: At the time of KTx, 60% of patients had some degree of VC (ACI>0), whereas 40% had no VC. One year after KTx, VCs worsened in 26% of patients, whereas in 74%, VCs remained stable or improved. The progression of VC was observed almost exclusively in patients with a positive ACI score at the first month. At the multivariate analysis, serum calcium, OPG, and estimated glomerular filtration rate were the only variables independently associated with the progression of VC. CONCLUSIONS: VCs at the aortic site are frequent in KTx patients, and in a significant percentage of them, they tend to progress even in the short time. High levels of serum calcium and OPG are significantly associated with the progression of VCs. Whether these associations are based on a cause effect relationship and their correction might impact on the calcification process could be ascertained by prospective interventional studies. PMID- 23812002 TI - Prevalence and relevance of pediatric spinal fractures in suspected child abuse. AB - BACKGROUND: Spinal fractures are uncommon manifestations of child abuse and elimination of the lateral views of the spine from the initial skeletal survey protocol has been recommended. OBJECTIVE: To establish the prevalence of spinal fractures detected on skeletal surveys performed for suspected child abuse and their association with intracranial injury (ICI). MATERIALS AND METHODS: The ACR standardized skeletal surveys and neuroimaging studies of 751 children (ages 0-4 years) were reviewed. A positive skeletal survey was defined as having one or more clinically unsuspected fractures. RESULTS: Fourteen children had a total of 22 definite spinal fractures. This constituted 1.9% (14/751) of the total cohort, and 9.7% (14/145) of children with a positive skeletal survey. Advanced imaging confirmed the fractures in 13 of the 14 children and demonstrated 12 additional spinal fractures. In five cases, spinal fractures were the only positive skeletal findings. In 71% (10/14) of the children, the spinal fractures were accompanied by ICI. Children with spinal fractures were at significantly greater risk for ICI than those without spinal injury (P < 0.05). CONCLUSION: Spinal fractures are not rare in children with positive skeletal surveys performed for suspected abuse and they may be the only indication of skeletal trauma. There is an association between spinal fractures and ICI. PMID- 23812003 TI - Anisotropy barrier enhancement via ligand substitution in tetranuclear {Co(III)2Ln(III)2} single molecule magnets. AB - The replacement of coordinated acetylacetonate for nitrate around a Dy(III) ion results in the enhancement of the single molecule magnet properties of a {Co(III)2Dy(III)2} complex, resulting in a large thermal energy barrier and reduced quantum tunnelling at low temperatures. The analogous Tb(III) complex displays field induced SMM behaviour. PMID- 23812004 TI - A predictive pharmacokinetic-pharmacodynamic model of tumor growth kinetics in xenograft mice after administration of anticancer agents given in combination. AB - PURPOSE: In clinical oncology, combination treatments are widely used and increasingly preferred over single drug administrations. A better characterization of the interaction between drug effects and the selection of synergistic combinations represent an open challenge in drug development process. To this aim, preclinical studies are routinely performed, even if they are only qualitatively analyzed due to the lack of generally applicable mathematical models. METHODS: This paper presents a new pharmacokinetic-pharmacodynamic model that, starting from the well-known single agent Simeoni TGI model, is able to describe tumor growth in xenograft mice after the co-administration of two anticancer agents. Due to the drug action, tumor cells are divided in two groups: damaged and not damaged ones. The damaging rate has two terms proportional to drug concentrations (as in the single drug administration model) and one interaction term proportional to their product. Six of the eight pharmacodynamic parameters assume the same value as in the corresponding single drug models. Only one parameter summarizes the interaction, and it can be used to compute two important indexes that are a clear way to score the synergistic/antagonistic interaction among drug effects. RESULTS: The model was successfully applied to four new compounds co-administered with four drugs already available on the market for the treatment of three different tumor cell lines. It also provided reliable predictions of different combination regimens in which the same drugs were administered at different doses/schedules. CONCLUSIONS: A good and quantitative measurement of the intensity and nature of interaction between drug effects, as well as the capability to correctly predict new combination arms, suggest the use of this generally applicable model for supporting the experiment optimal design and the prioritization of different therapies. PMID- 23812005 TI - A multi-institutional phase II trial of hepatic arterial infusion chemotherapy with cisplatin for advanced hepatocellular carcinoma with portal vein tumor thrombosis. AB - PURPOSE: The objective of this study was to evaluate the response rate, survival, and adverse effects of hepatic arterial infusion chemotherapy (HAIC) using cisplatin in patients with advanced hepatocellular carcinoma (HCC) and portal vein tumor thrombosis (PVTT). METHODS: Twenty-five patients of advanced HCC with PVTT in the main or first branch, having no prior history of chemotherapy, measurable lesions, adequate liver and renal function, and adequate bone marrow reserve, were enrolled. Cisplatin was administered at the dose of 65 mg/m(2) via the proper hepatic artery. Treatment was repeated every 4-6 weeks for a maximum of six courses until the appearance of evidence of tumor progression or unacceptable toxicity. RESULTS: The median number of treatments was 3 (range 1 6). Among the 25 enrolled patients, complete response was achieved in 1 (4 %) patient and partial response in 6 (24 %), corresponding to a response rate of 28 % (95 % CI 12-49 %). The median progression-free and overall survival times and the 1-, 2-, and 3-year survival rates in the enrolled patients were 3.6 and 7.6 months and 40.3, 36.0, 20 %, respectively. Four of the seven patients who showed complete or partial response survived for more than 3 years. The main grade 3/4 non-hematological adverse events of this treatment were elevation of the serum aspartate aminotransferase (44 %) and alanine aminotransferase (24 %). CONCLUSION: HAIC with cisplatin exerts moderate activity with mild toxicity in advanced HCC patients with PVTT. Especially, markedly prolonged survival can be expected in patients who respond to this treatment. PMID- 23812006 TI - Size- and concentration-dependent deposition of fluorescent silica colloids in saturated sand columns: transport experiments and modeling. AB - This study investigates the size and concentration effects on the transport of silica colloids in columns of sandy aquifer material. Colloid transport experiments were performed with specifically developed fluorescent labeled silica colloids in columns of a repacked natural porous medium under hydro-geochemical conditions representative of sandy aquifers. Breakthrough curves and vertical deposition profiles of colloids were measured for various colloid concentrations and sizes. The results showed that for a given colloid concentration injected, deposition increased when increasing the size of the colloids. For a given colloid size, retention was also shown to be highly concentration-dependent with a non-monotonous pattern presenting low and high concentration specificities. Deposition increases when increasing both size and injected concentration, until a threshold concentration is reached, above which retention decreases, thus increasing colloid mobility. Results observed above the threshold concentration agree with a classical blocking mechanism typical of a high concentration regime. Results observed at lower colloid concentrations were not modeled with a classical blocking model and a depth- and time-dependent model with a second order kinetic law was necessary to correctly fit the experimental data in the entire range of colloid concentrations with a single set of parameters for each colloidal size. The colloid deposition mechanisms occuring at low concentrations were investigated through a pore structure analysis carried out with Mercury Intrusion Porosimetry and image analysis. The determined pore size distribution permitted estimation of the maximal retention capacity of the natural sand as well as some low flow zones. Altogether, these results stress the key role of the pore space geometry of the sand in controlling silica colloids deposition under hydro-geochemical conditions typical of sandy aquifers. Our results also showed originally that colloid mobility in porous media is not only favored at high colloid concentrations, but also at very low concentrations, which are more likely to be observed in groundwater. PMID- 23812007 TI - Impact of rectopexy on sexual function: a cohort analysis. AB - PURPOSE: Laparoscopic ventral rectopexy (LVR) is an established surgical technique for the treatment of both rectal prolapse and symptomatic rectoceles. It is, however, not known whether LVR influences sexual function (SF). The aim of this study was, therefore, to determine the impact of this procedure on the SF of patients. METHODS: All female patients after LVR procedure in a single institution were identified and were sent a questionnaire concerning SF. This addressed sexual activity, satisfaction, preoperative SF, and the impact of surgery on SF. Furthermore, the PISQ-12 validated sexual functioning questionnaire was sent to all female patients. RESULTS: A total of 217 patients were sent a questionnaire. These patients underwent LVR for rectal prolapse, symptomatic rectocele, or enterocele between 2004 and 2011. Mean age was 62 years (range 22-89). Mean follow-up was 30 months (range 5-83). Response rate was 64 % (139 patients). The number of sexual active patients dropped from 71 to 54 % after surgery. The number of patients being satisfied with their SF remained relatively equal; 91 % of patients before and 85 % of patients after surgery. Forty-three percent of patients stated that the LVR procedure did not influence their sexual function, in 16 % of patients, the procedure positively influenced their SF, and in 13 % of respondents, SF decreased after surgery. The mean PISQ 12 score postoperatively was 34 out of 48. CONCLUSIONS: The impact of LVR on SF of patients seems limited in this cross-sectional study in a large cohort of patients. PMID- 23812008 TI - KIF16B delivers for transcytosis. PMID- 23812011 TI - Atomic scale study of the life cycle of a dislocation in graphene from birth to annihilation. AB - Dislocations, one of the key entities in materials science, govern the properties of any crystalline material. Thus, understanding their life cycle, from creation to annihilation via motion and interaction with other dislocations, point defects and surfaces, is of fundamental importance. Unfortunately, atomic-scale investigations of dislocation evolution in a bulk object are well beyond the spatial and temporal resolution limits of current characterization techniques. Here we overcome the experimental limits by investigating the two-dimensional graphene in an aberration-corrected transmission electron microscope, exploiting the impinging energetic electrons both to image and stimulate atomic-scale morphological changes in the material. The resulting transformations are followed in situ, atom-by-atom, showing the full life cycle of a dislocation from birth to annihilation. Our experiments, combined with atomistic simulations, reveal the evolution of dislocations in two-dimensional systems to be governed by markedly long-ranging out-of-plane buckling. PMID- 23812009 TI - Ral mediates activity-dependent growth of postsynaptic membranes via recruitment of the exocyst. AB - Remodelling neuronal connections by synaptic activity requires membrane trafficking. We present evidence for a signalling pathway by which synaptic activity and its consequent Ca(2+) influx activate the small GTPase Ral and thereby recruit exocyst proteins to postsynaptic zones. In accord with the ability of the exocyst to direct delivery of post-Golgi vesicles, constitutively active Ral expressed in Drosophila muscle causes the exocyst to be concentrated in the region surrounding synaptic boutons and consequently enlarges the membrane folds of the postsynaptic plasma membrane (the subsynaptic reticulum, SSR). SSR growth requires Ral and the exocyst component Sec5 and Ral-induced enlargement of these membrane folds does not occur in sec5(-/-) muscles. Chronic changes in synaptic activity influence the plastic growth of this membrane in a manner consistent with activity-dependent activation of Ral. Thus, Ral regulation of the exocyst represents a control point for postsynaptic plasticity. This pathway may also function in mammals as expression of activated RalA in hippocampal neurons increases dendritic spine density in an exocyst-dependent manner and increases Sec5 in spines. PMID- 23812012 TI - Mucophagocytizing histiocytes in a low-grade appendiceal mucinous neoplasm mimicking signet-ring mucosecreting adenocarcinoma cells. PMID- 23812010 TI - Combined clear cornea phacoemulsification in the treatment of pseudoexfoliative glaucoma associated with cataract: significance of trabecular aspiration and ab interno trabeculectomy. AB - BACKGROUND: In the present study, the effectiveness of combined cataract surgery and ab interno trabeculectomy (Trabectome) in exfoliation glaucoma (PEX) was compared with combined cataract surgery and trabecular aspiration. METHODS: In this retrospective comparative cohort outcome study, 27 consecutive patients (mean age 73.41 years +/- 10.78) in group 1 suffering from visually significant cataract and PEX glaucoma (mean preoperative IOP 23.41 mmHg +/- 5.86) were treated with phacoemulsification combined with Trabectome; and 28 consecutive patients (73.83 years +/- 8.94) were treated with phacoemulsification combined with trabecular aspiration (mean preoperative IOP 22.22 mmHg +/- 6.33). The intraocular pressure (IOP) and the number of antiglaucoma eyedrops before and after surgery were evaluated. RESULTS: Examinations were performed prior to surgery, 1 day, 6 weeks, 3 months, 6 months, and 1 year after surgery. In both groups there was a statistically significant decrease in postoperative IOP during the whole follow-up period. Comparing the two groups, there was a statistically significant lower IOP in the Trabectome group 1 day (p = 0.019), 6 months (p = 0.025), and 1 year (p = 0.019) after surgery. Between the two groups, there was no statistically significant difference in the number of antiglaucoma eyedrops at any time. CONCLUSIONS: Both procedures have the ability to significantly lower the postoperative IOP during the first year. However, clear cornea phacoemulsification combined with Trabectome seems to be more effective in IOP reduction in cases of PEX glaucoma associated with cataract. PMID- 23812013 TI - Nitrofurantoin-Induced Granulomatous Interstitial Pneumonia. AB - Nitrofurantoin-induced lung toxicity is relatively common, but rare histologic patterns sometimes occur that may make diagnosis difficult. We present the case of a 69-year-old woman taking prophylactic nitrofurantoin for urinary tract infections, who developed granulomatous interstitial pneumonia. She improved with cessation of nitrofurantoin, without other therapy. To our knowledge, this is the fourth reported case of granulomatous interstitial pneumonia associated with nitrofurantoin, and the first to show complete resolution with cessation of the drug alone, without steroids. It is important to recognize that idiosyncratic reactions to nitrofurantoin can produce a wide spectrum of histologic patterns. Of these patterns, granulomatous interstitial pneumonia is a rarely evidenced manifestation (possibly because few cases undergo a confirmatory lung biopsy). Recognition of granulomatous interstitial pneumonia as a manifestation of nitrofurantoin toxicity can aid in early identification of the reaction and prompt withdrawal of the drug, both of which are essential to prevent long-term complications. PMID- 23812014 TI - Controversy in urinary tract infection management in children: a review of new data and subsequent changes in guidelines. AB - Controversy and lack of consensus have been encountered in the management of pediatric urinary tract infection (UTI), including its diagnosis, radiological investigations and the use of antibiotic therapy. In this review, we discuss the need for radiological investigations and the extent of their use as well as the need for prophylactic antibiotics in children with UTI and vesicoureteral reflux. Only a small proportion of children with first UTI and no history of antenatal renal abnormalities have clinically important malformations. Renal ultrasound should be performed in febrile infants and young children with UTI; a micturating cystourethrogram should not be performed routinely after the first febrile UTI. Long-term antibiotics appear to reduce the risk of recurrent symptomatic UTI in susceptible children, although the clinical benefit is marginal. Current recommendations encourage performing radiological investigations only in children at risk and discourage routine prophylactic antibiotic use. PMID- 23812015 TI - Toddler's diarrhea: is it an under-recognized entity in developing countries? AB - AIM: As there is no report of toddler's diarrhea (TD) from the developing world, we have analyzed our experience of 191 children (<5 years) with chronic diarrhea over 7 years. METHODS: Clinical details, investigations and outcome were retrieved and recorded in a proforma. TD was ascribed in those who had normal growth and no evidence of malabsorption or enteric infections. RESULTS: The etiology of chronic diarrhea was TD 16%, celiac disease (CD) 37%, cow's milk protein allergy (CMPA) 35% and others 12%. The mean age of 30 children with TD was 2.7 +/- 1.2 years (22 boys). While comparing TD with CD and CMPA, weight z score (>-2.2) and hemoglobin (>10 or 10.9 g/dL for CD and CMPA, respectively) were independent variables to discriminate TD from CD and CMPA. CONCLUSIONS: TD is common in developing countries like India too. Anthropometry and hemoglobin can differentiate it from CD and CMPA. PMID- 23812016 TI - [Letter to the editor concerning the article "Hyperglycemic crisis in patients with diabetes mellitus"]. PMID- 23812017 TI - Neurofibroma with numerous lymphoid aggregates simulating spindle cell melanoma: utilization of CD34 fingerprint for diagnosis. PMID- 23812019 TI - Localized post-radiation Kaposi sarcoma in a renal transplant immunosuppressed patient. AB - Organ transplant recipients are at high risk to develop secondary cutaneous neoplasms because of immunosuppression. However, little is known about secondary neoplasms developing within a skin area exposed to radiation therapy in these patients. We report a case of a 45-year-old man with history of kidney transplantation in 2005 and rectal adenocarcinoma in 2006 for which he underwent 2 cycles of chemotherapy and a cycle of radiotherapy. In February 2010, he presented with clustered erythematous-violaceous plaques and nodules of 2-month duration, located on the left buttock in the area previously exposed to radiations. Histological examination revealed a poorly demarcated dermal and subcutaneous proliferation of spindle and partly pleomorphic cells, associated with irregularly shaped vessels that dissected through dermal collagen. Immunohistochemistry showed expression of CD31 and podoplanin. Although a moderate expression of the c-Myc protein was found by immunostaining, no amplification of c-myc gene was detected by fluorescence in situ hybridization. Human herpes virus 8 was positive both on immunohistochemistry and PCR. Based on clinicopathologic findings a diagnosis of iatrogenic Kaposi sarcoma localized in the area treated with radiotherapy was made. Clinical and histopathological features of vascular neoplasms may be overlapping, and correct diagnosis may be difficult, particularly in organ transplant recipients. Only the combination of all available information, including histopathological, immunohistochemical, fluorescence in situ hybridization, and PCR data, permit to achieve a correct diagnosis in particularly difficult setting. PMID- 23812018 TI - Immunohistochemical expression of hormone receptors in melanoma of pregnant women, nonpregnant women, and men. AB - The survival advantage of women over men with cutaneous melanoma and the reports of accelerated progression of melanoma during pregnancy have led to studies of the effect of hormones and hormone receptors on the development and progression of melanoma. However, the results are inconclusive. We therefore evaluated the expression of estrogen receptor alpha, estrogen receptor beta, and androgen receptor in melanomas of stage- and age-matched pregnant women, nonpregnant women, and men by immunohistochemical analysis of formalin-fixed, paraffin embedded archival tissues. In addition, we also assessed the mitotic rate using the antiphosphohistone H3 antibody by immunohistochemistry. Our data showed a trend of more frequent expression of estrogen receptor beta in the melanomas of pregnant patients than in the melanomas of male patients, without a significant difference observed between pregnant and nonpregnant women. However, no association between the expression of estrogen receptor beta and survival was observed. The small cohort may have limited the statistical power of the study, and large-scale studies are needed to elucidate the potential role of estrogen receptor beta as a prognostic marker of melanoma. PMID- 23812020 TI - Cutaneous neurocristic hamartoma presenting as cutis verticis gyrata. AB - Cutaneous neurocristic hamartoma is a rare developmental complex melanocytic lesion of neural crest origin in the dermis and subcutis with diverse histological differentiation including melanocytic, neurosustentacular, and mesenchymal elements. Cutis verticis gyrata is a cerebriform thickening of the scalp manifesting as folds, ridges, or creases. We report a case of cutaneous neurocristic hamartoma of the scalp in a 20-year-old woman presenting as cutis verticis gyrata. Microscopically, the lesion involved the dermis and the subcutis. Dendritic pigmented melanocytes were seen in between the collagen bands. Plexiform islands consisting of cords and palisades of spindled cells were also apparent. Immunohistochemically, HMB-45 positivity was observed in the dendritic melanocytic cells. S-100 protein was positive in dendritic melanocytes and in the Schwannian cells. The stromal cells showed CD34 staining. This lesion is presented because of its rarity, unusual clinical appearance, and resemblance to both a neurocristic hamartoma and large plaque type of blue nevus. PMID- 23812021 TI - Primary adenoid cystic carcinoma of the skin metastatic to the lymph nodes: immunohistochemical study of a new case and literature review. AB - Primary cutaneous adenoid cystic carcinoma (PCACC) is a rare adnexal skin tumor first described in 1975, of which merely 62 cases have so far been studied in detail and reported in the English literature. PCACC is usually regarded as apocrine in origin/differentiation, but its precise histogenesis is still not well known. PCACC has in most cases a rather indolent course but can produce local recurrences and, more rarely, regional (lymph node) and distant (pulmonary) metastases. We report herein a Greek woman with a long-standing PCACC that grew slowly over several years and produced metastasis in the regional lymph nodes, highlighting the potentially aggressive course of this tumor. The primary and metastatic tumors were studied immunohistochemically and proved to express several (sweat gland-related) antigens (such as keratin 7, epithelial membrane antigen, CD10, and CD117) but neither hormonal receptors nor p63 or Gross Cystic disease Fluid Protein 15. The salient clinicopathologic features of this rare cutaneous adnexal tumor are reviewed. PMID- 23812022 TI - Does rocuronium-sugammadex reduce myalgia and headache after electroconvulsive therapy in patients with major depression? AB - BACKGROUND: We aimed to compare the effects of succinylcholine and rocuronium sugammadex on development of myalgia and headache after electroconvulsive therapy (ECT). METHODS: Forty-five patients undergoing ECT were enrolled in the study. Anesthesia induction was provided with propofol 1 mg/kg intravenously (IV) + succinylcholine 1 mg/kg IV in group S (n = 24) and propofol 1 mg/kg IV + rocuronium 0.3 mg/kg IV in group R (n = 21). Sugammadex 4 mg/kg IV was administered to group R after the motor seizure. The first 3 ECT sessions were evaluated on the basis of time to onset of spontaneous respiration following the induction, time to eye-opening response to verbal stimuli, and visual analog scale (VAS) scores for myalgia and headache at hours 2, 6, 12, and 24 following the ECT for all patients. RESULTS: The times to onset of spontaneous respiration and eye-opening response to verbal stimuli were significantly shorter in all the 3 sessions in group R compared with group S (P < 0.002). Myalgia VAS scores at hours 2, 6, and 12 and the headache VAS scores at hours 2 and 6 were significantly higher in group S versus group R (P < 0,015). CONCLUSIONS: We concluded that the rates of myalgia and headache after ECT were significantly lower in group R than in group S, and also the awakening time (spontaneous respiration and opening the eyes in response to verbal stimuli) was significantly shorter in group R compared with group S. PMID- 23812023 TI - Stability of intraocular pressure after retinal reattachment surgery during electroconvulsive therapy for intractable self-injury in a 12-year-old autistic boy. AB - We present a 12-year-old autistic boy who underwent electroconvulsive therapy (ECT) for intractable self-injury toward his head and eyes in the context of acute bilateral retinal detachment and reparative surgery. The patient received 3 ECTs before retinal reattachment surgery, and resumed ECT 2 weeks postoperatively. Bilateral intraocular pressures were monitored before and after the first 7 ECTs and intermittently after ECT for 10 months of maintenance ECT. There was no evidence of sustained intraocular pressure elevation or instability. This report supports the safety of ECT for repetitive self-injury in youth before and after emergent ophthalmologic surgery for trauma-related injury. PMID- 23812025 TI - Evaluation of ecotoxicological risks related to the Discharge of Combined Sewer Overflows (CSOs) in a periurban River. AB - Discharges of Combined Sewer Overflows (CSOs) into periurban rivers present risks for the concerned aquatic ecosystems. In this work, a specific ecotoxicological risk assessment methodology has been developed as management tool to municipalities equipped with CSOs. This methodology comprises a detailed description of the spatio-temporal system involved, the choice of ecological targets to be preserved, and carrying out bioassays adapted to each compartment of the river receiving CSOs. Once formulated, this methodology was applied to a river flowing through the outskirts of the city of Lyon in France. The results obtained for the scenario studied showed a moderate risk for organisms of the water column and a major risk for organisms of the benthic and hyporheic zones of the river. The methodology enabled identifying the critical points of the spatio temporal systems studied, and then making proposals for improving the management of CSOs. PMID- 23812026 TI - Detection of beta-lactamase residues in milk by sandwich ELISA. AB - beta-Lactamase residues in milk represent a public health risk. The cylinder plate detection method, which is based on bacterial growth, is laborious and time consuming. In this study, 15 monoclonal antibodies (mAbs) were selected against Temoneira (TEM) 1 beta-lactamase. A sandwich enzyme-linked immunosorbent assay (ELISA) based on an optimum mAb pair was developed and validated for the detection of beta-lactamase. The limit of detection and linear dynamic range of the method were 4.17 ng/mL and 5.5-100 ng/mL, respectively. beta-Lactamase recovery in pure milk was 96.82-103.13%. The intra- and inter-assay coefficients of variation were 6.21-7.38% and 12.96-13.74%, respectively. Our developed sandwich ELISA can be used as a rapid detection method of beta-lactamase in milk. PMID- 23812024 TI - Antimicrobial resistance in the food chain: a review. AB - Antimicrobial resistant zoonotic pathogens present on food constitute a direct risk to public health. Antimicrobial resistance genes in commensal or pathogenic strains form an indirect risk to public health, as they increase the gene pool from which pathogenic bacteria can pick up resistance traits. Food can be contaminated with antimicrobial resistant bacteria and/or antimicrobial resistance genes in several ways. A first way is the presence of antibiotic resistant bacteria on food selected by the use of antibiotics during agricultural production. A second route is the possible presence of resistance genes in bacteria that are intentionally added during the processing of food (starter cultures, probiotics, bioconserving microorganisms and bacteriophages). A last way is through cross-contamination with antimicrobial resistant bacteria during food processing. Raw food products can be consumed without having undergone prior processing or preservation and therefore hold a substantial risk for transfer of antimicrobial resistance to humans, as the eventually present resistant bacteria are not killed. As a consequence, transfer of antimicrobial resistance genes between bacteria after ingestion by humans may occur. Under minimal processing or preservation treatment conditions, sublethally damaged or stressed cells can be maintained in the food, inducing antimicrobial resistance build-up and enhancing the risk of resistance transfer. Food processes that kill bacteria in food products, decrease the risk of transmission of antimicrobial resistance. PMID- 23812028 TI - Hepatitis screening in Japanese individuals of working age and prejudice against infected persons in the workplace. AB - BACKGROUND: Laboratory confirmation of viral hepatitis infection represents an important issue for working age populations, as early detection and treatment can help ameliorate clinical progression of the disease. On the other hand, prejudice may occur in the workplace against those identified by a positive hepatitis test. This study investigated attitudes towards viral hepatitis testing in Japanese people of working age, including their desire to undergo such testing, and prejudice against persons infected with hepatitis virus. METHODS: A total of 3,129 working age individuals were recruited from a company that conducts Internet surveys in Japan. RESULTS: Of the respondents, 21.3% had previously undergone viral hepatitis testing, most frequently when it was an additional option during a health checkup or health screening for local residents (36.2%) and when it was included in regular health checkups in their workplace (19.2%). Among the respondents with no history of testing, 68.7% expressed a desire to undergo testing, of whom 74.8% wanted to have the test as part of their regular health checkups in the workplace. According to the respondents, if a coworker tested positive for hepatitis, 36.0% reported that they would be anxious about it, 32.0% would try to avoid contact with the infected person as long as circumstances permitted, and 23.7% said they might harbor some kind of bias. CONCLUSIONS: Although further promotion of viral hepatitis testing is needed and this might be achieved during regular health checkups in Japanese workplaces, educational strategies will also be essential to help reduce bias against those who test positive. PMID- 23812027 TI - Land-use change and emerging infectious disease on an island continent. AB - A more rigorous and nuanced understanding of land-use change (LUC) as a driver of emerging infectious disease (EID) is required. Here we examine post hunter gatherer LUC as a driver of infectious disease in one biogeographical region with a compressed and documented history--continental Australia. We do this by examining land-use and native vegetation change (LUCC) associations with infectious disease emergence identified through a systematic (1973-2010) and historical (1788-1973) review of infectious disease literature of humans and animals. We find that 22% (20) of the systematically reviewed EIDs are associated with LUCC, most frequently where natural landscapes have been removed or replaced with agriculture, plantations, livestock or urban development. Historical clustering of vector-borne, zoonotic and environmental disease emergence also follows major periods of extensive land clearing. These advanced stages of LUCC are accompanied by changes in the distribution and density of hosts and vectors, at varying scales and chronology. This review of infectious disease emergence in one continent provides valuable insight into the association between accelerated global LUC and concurrent accelerated infectious disease emergence. PMID- 23812029 TI - Occupational injury proneness in young workers: a survey in stone quarries. AB - OBJECTIVES: Workplace injuries are of concern in adolescent and child workers. The factors of such injuries are important for injury prevention. This study explored the predictors of injury in such workers. METHODS: This study was carried out in stone quarries and included 147 children and adolescent workers (81 males and 66 females). The mean age of the subjects was 11.3 years. An interviewer-administered questionnaire survey was performed to collect personal, occupational, morbidity and injury details. Descriptive analysis followed by logistic regression was undertaken to obtain the contribution of different factors on workplace injury occurrence. RESULTS: Age (OR: 0.73 95% CI: 0.53 0.99), nature of work (OR: 29.4 95% CI: 2.5-340.7), work hours per day (OR: 1.77 95% CI: 1.3-2.3), musculoskeletal complaint (OR: 15.8 95% CI: 4.8-52.2) and education (OR: 0.24 95% CI: 0.08-0.7) showed significant effects on workplace injuries. However, duration of employment and body mass index had no significant contribution. CONCLUSIONS: This study stresses the need to strictly stop employment of child labor in such occupations in accordance with the national law. It shows that apart from nature of job, age of worker, work hours/day, musculoskeletal morbidity and education are significant predictors of occupational injuries and that training of such workers with regard to safe practices, provision for education, alleviation of musculoskeletal morbidity, suitable restriction of work hours/day and awareness generation among parents regarding the imminent danger of such labor in their children will ensure a positive impact in protecting young and child workers from occupational injuries. PMID- 23812030 TI - Changes in psychosocial work conditions in Taiwanese employees by gender and age from 2001 to 2010. AB - OBJECTIVE: The aim of this study was to examine changes in working hours, shift work, psychological and physical job demands, job control and job insecurity in Taiwanese employees by gender and age during the period of 2001 to 2010. METHODS: The study subjects were 36,750 men and 27,549 women, aged 25-64, from 4 rounds of cross-sectional surveys of representative employees. Psychosocial work conditions were assessed by a validated questionnaire. RESULTS: Regression analyses with adjustment of education and employment grade showed that from 2001 to 2010, the proportions of workers with long working hours (>48 hours/week) (OR=1.4 in men and 1.5 in women) and workers with short working hours (<40 hours/week) (OR=1.3 in both genders) both increased over time, indicating an increasing polarization in the distribution of working hours. Furthermore, the proportions of nonstandard work shifts (OR=1.7 in men and 2.1 in women) and work with high physical demands (OR=1.5 for both gender) increased. There were signs of decreasing levels of job control from 2001 to 2007, which seemed to be more apparent in younger workers than in older workers. However, a slight recovery in decision latitude and opportunity for learning was noticed in later years. The trend in job insecurity was not linear, with the highest prevalence found in 2004. CONCLUSIONS: Our findings suggested that certain aspects of psychosocial work environment had deteriorated in Taiwan. There is a need to raise public awareness about the changing patterns of psychosocial health risks at work as well as their causes and their potential impacts on worker well-being. PMID- 23812031 TI - Placebo, nocebo, and expectations: leveraging positive outcomes. PMID- 23812033 TI - 1914-2014: never again. PMID- 23812032 TI - Sex differences in patients with systemic lupus erythematosus from Northwest Spain. AB - To further establish potential differences according to sex in systemic lupus erythematosus (SLE) patients from Southern Europe. We assessed clinical and epidemiological data of patients diagnosed with SLE according to the 1982 American College of Rheumatology classification criteria at the single hospital for a well-defined population of Northwest Spain, between 1987 and 2006. Prevalence in December 2006 and age-standardized incidence rates in the whole period were estimated. Kaplan-Meier method was used in order to estimate the probability of survivorship. Women outnumbered men [127 (84.7%) vs. 23 (15.3%)]. The median age at the time of disease diagnosis in men was 54 years versus 43 in women (p < 0.001). Annual incidence rates were higher in women [5.9 (95% confidence interval--CI 4.9-7.0) per 100,000 population] than in men [1.1 (95% CI 0.7-1.7) per 100,000 population; p < 0.001]. Raynaud's phenomenon was more common in women (40.9 vs. 3.0%; p = 0.01). While the frequency of secondary Sjogren's syndrome was increased in women (p = 0.02), renal disease at the time of diagnosis (39.1 vs. 15.0%; p < 0.01) and over the course of the disease was more common in men (43.5 vs. 24.4%; p = 0.06). Higher frequency of thrombocytopenia (39.1 vs. 16.5%; p = 0.01) and lower frequency of anti-SSA (13.0 vs. 31.5%; p = 0.08) and anti-SSB (0 vs. 17.7%; p = 0.03) were observed in men. The 5- and 10 year survival probabilities were nonsignificantly reduced in men (91.3 and 78.3 3% vs. 94.6 and 89.2% in women). The frequency of some clinical manifestations is different in men and women with SLE. Higher awareness of these peculiarities may help to establish appropriate diagnosis and management of SLE in men. PMID- 23812034 TI - Structures and nonlinear optical properties of the endohedral metallofullerene superhalogen compounds Li@C60-BX4 (X = F, Cl, Br). AB - It has recently been demonstrated that superatoms, which can exhibit behaviors reminiscent of atoms in the periodic table, might have synthetic utility, and represent potential building blocks for the assembly of novel, nanostructured materials [Science 2004, 304, 84-87; Science 2005, 307, 231-235; J. Phys. Chem. C 2009, 113, 2664]. In this work, a new type of endohedral metallofullerene superhalogen compound, Li@C60-BX4 (X = F, Cl, Br), is proposed and characterized using density functional theory. The electron transfer from Li@C60 to BX4 contributes greatly to the Li@C60-BX4 compound formation. Such compounds exhibit considerable stabilities with large binding energies and ionization potentials, as well as large HOMO-LUMO gaps. The investigation of the nonlinear optical (NLO) properties of Li@C60-BX4 reveals a strong dependence of the static first hyperpolarizability, beta0, on the atomic number of the involved halogen atom X. This means that one can enhance the first hyperpolarizabilities of the endohedral metallofullerene by introducing superhalogens. The present investigation may promote the development of novel nanomaterials with unusual properties (i.e. NLO properties), and enrich the knowledge of chemical bonds (for example, long-range interactions between trapped atoms in a C60 cage and the outside superatom motif). PMID- 23812036 TI - RNase non-sensitive and endocytosis independent siRNA delivery system: delivery of siRNA into tumor cells and high efficiency induction of apoptosis. AB - To date, RNase degradation and endosome/lysosome trapping are still serious problems for siRNA-based molecular therapy, although different kinds of delivery formulations have been tried. In this report, a cell penetrating peptide (CPP, including a positively charged segment, a linear segment, and a hydrophobic segment) and a single wall carbon nanotube (SWCNT) are applied together by a simple method to act as a siRNA delivery system. The siRNAs first form a complex with the positively charged segment of CPP via electrostatic forces, and the siRNA-CPP further coats the surface of the SWCNT via hydrophobic interactions. This siRNA delivery system is non-sensitive to RNase and can avoid endosome/lysosome trapping in vitro. When this siRNA delivery system is studied in Hela cells, siRNA uptake was observed in 98% Hela cells, and over 70% mRNA of mammalian target of rapamycin (mTOR) is knocked down, triggering cell apoptosis on a significant scale. Our siRNA delivery system is easy to handle and benign to cultured cells, providing a very efficient approach for the delivery of siRNA into the cell cytosol and cleaving the target mRNA therein. PMID- 23812035 TI - Golgi tubules: their structure, formation and role in intra-Golgi transport. AB - Tubules are common Golgi elements that can form extensive networks associated with the cis-, lateral and trans-Golgi sides, but despite this, they have almost been forgotten for decades. The molecular mechanisms involved in their formation, elongation and fission are only just beginning to be understood. However, the role of these membranes is not well understood. In the present review, we analyze the mechanisms that induce Golgi tubulation or, conversely, disrupt tubules in order to throw some lights on the nature of these elements. The putative role of these elements in the framework of current models for intra-Golgi transport is also discussed. PMID- 23812037 TI - CXCL12 induces hepatic stellate cell contraction through a calcium-independent pathway. AB - Liver fibrosis, with subsequent development of cirrhosis and ultimately portal hypertension, results in the death of patients with end-stage liver disease if liver transplantation is not performed. Hepatic stellate cells (HSCs), central mediators of liver fibrosis, resemble tissue pericytes and regulate intrahepatic blood flow by modulating pericapillary resistance. Therefore, HSCs can contribute to portal hypertension in patients with chronic liver disease (CLD). We have previously demonstrated that activated HSCs express functional chemokine receptor, CXCR4, and that receptor engagement by its ligand, CXCL12, which is increased in patients with CLD, leads to further stellate cell activation in a CXCR4-specific manner. We therefore hypothesized that CXCL12 promotes HSC contraction in a CXCR4-dependent manner. Stimulation of HSCs on collagen gel lattices with CXCL12 led to gel contraction and myosin light chain (MLC) phosphorylation, which was blocked by addition of AMD3100, a CXCR4 small molecule inhibitor. These effects were further mediated by the Rho kinase pathway since both Rho kinase knockdown or Y-27632, a Rho kinase inhibitor, blocked CXCL12 induced phosphorylation of MLC and gel contraction. BAPTA-AM, a calcium chelator, had no effect, indicating that this pathway is calcium sensitive but not calcium dependent. In conclusion, CXCL12 promotes stellate cell contractility in a predominantly calcium-independent fashion. Our data demonstrates a novel role of CXCL12 in stellate cell contraction and the availability of small molecule inhibitors of the CXCL12/CXCR4 axis justifies further investigation into its potential as therapeutic target for portal hypertension. PMID- 23812038 TI - Lipid-rich enteral nutrition regulates mucosal mast cell activation via the vagal anti-inflammatory reflex. AB - Nutritional stimulation of the cholecystokinin-1 receptor (CCK-1R) and nicotinic acetylcholine receptor (nAChR)-mediated vagal reflex was shown to reduce inflammation and preserve intestinal integrity. Mast cells are important early effectors of the innate immune response; therefore modulation of mucosal mast cells is a potential therapeutic target to control the acute inflammatory response in the intestine. The present study investigates intestinal mast cell responsiveness upon nutritional activation of the vagal anti-inflammatory reflex during acute inflammation. Mucosal mast cell degranulation was induced in C57/Bl6 mice by administration of Salmonella enterica LPS. Lipid-rich enteral feeding prior to LPS significantly decreased circulatory levels of mouse mast cell protease at 30 min post-LPS compared with isocaloric low-lipid nutrition or fasting. CCK-1R blockage reversed the inhibitory effects of lipid-rich feeding, whereas stimulation of the peripheral CCK-1R mimicked nutritional mast cell inhibition. The effects of lipid-rich nutrition were negated by nAChR blockers chlorisondamine and alpha-bungarotoxin and vagal intestinal denervation. Accordingly, release of beta-hexosaminidase by MC/9 mast cells following LPS or IgE-ovalbumin complexes was dose dependently inhibited by acetylcholine and nicotine. Application of GSK1345038A, a specific agonist of the nAChR alpha7, in bone marrow-derived mast cells from nAChR beta2-/- and wild types indicated that cholinergic inhibition of mast cells is mediated by the nAChR alpha7 and is independent of the nAChR beta2. Together, the present study reveals mucosal mast cells as a previously unknown target of the nutritional anti-inflammatory vagal reflex. PMID- 23812040 TI - Multiple Factors Underlying Haptic Perception of Length and Orientation. AB - Information about the shape and spatial orientation of an object can be gathered during exploratory hand and arm movements, and then must be synthesized into a unified percept. During the robotically guided exploration of virtual polygons or triangles, the perception of the lengths of two adjoining segments is not always geometrically consistent with the perception of the internal angles between these segments. The present study further characterized this established inconsistency, and also found that subjects' internal angle judgments were influenced by the spatial orientations of the segments, especially the segment that was explored last in the sequence. Internal angle judgments were also biased by the subjects' own active forces, applied in the direction perpendicular to the programmed handle motion. For the last segment, but not for the earlier segments, subjects produced more outward force when they reported larger angles and more inward force when they reported smaller angles. Thus, the haptic synthesis of object shape is influenced by multiple geometric, spatial, and self-produced factors. PMID- 23812039 TI - Genome-wide transcriptome analysis identifies novel gene signatures implicated in human chronic liver disease. AB - The molecular mechanisms behind human liver disease progression to cirrhosis remain elusive. Nuclear receptor small heterodimer partner (SHP/Nr0b2) is a hepatic tumor suppressor and a critical regulator of liver function. SHP expression is diminished in human cirrhotic livers, suggesting a regulatory role in human liver diseases. The goal of this study was to identify novel SHP regulated genes that are involved in the development and progression of chronic liver disease. To achieve this, we conducted the first comprehensive RNA sequencing (RNA-seq) analysis of Shp(-/-) mice, compared the results with human hepatitis C cirrhosis RNA-seq and nonalcoholic steatohepatitis (NASH) microarray datasets, and verified novel results in human liver biospecimens. This approach revealed new gene signatures associated with chronic liver disease and regulated by SHP. Several genes were selected for validation of physiological relevance based on their marked upregulation, novelty with regard to liver function, and involvement in gene pathways related to liver disease. These genes include peptidoglycan recognition protein 2, dual specific phosphatase-4, tetraspanin 4, thrombospondin 1, and SPARC-related modular calcium binding protein-2, which were validated by qPCR analysis of 126 human liver specimens, including steatosis, fibrosis, and NASH, alcohol and hepatitis C cirrhosis, and in mouse models of liver inflammation and injury. This RNA-seq analysis identifies new genes that are regulated by the nuclear receptor SHP and implicated in the molecular pathogenesis of human chronic liver diseases. The results provide valuable transcriptome information for characterizing mechanisms of these diseases. PMID- 23812041 TI - Types and outcomes of cardioversion in patients admitted to hospital for atrial fibrillation: results of the German RHYTHM-AF Study. AB - BACKGROUND: Atrial fibrillation (AF) accounts for approximately one-third of hospitalizations for cardiac rhythm disturbances. Little is known about the characteristics of current use of cardioversion (CV) and its success rates in clinical practice in Germany. METHODS: As part of the international RHYTHM-AF Study, 655 consecutive patients with documented AF (mean age 68.3 +/- 10.5 years, 64.9 % males) who were considered candidates for CV were prospectively enrolled in 22 German hospitals (21 academic/teaching and 1 non-teaching). CV was considered successful if sinus rhythm or atrial rhythm was obtained within 1 day after start of pharmacological CV (PCV) or if sinus rhythm was achieved and maintained for at least 10 min after electrical CV (ECV). RESULTS: Patients with AF considered for CV had ECG in 94.4 %, Holter ECG in 25.8 %, and transesophageal echocardiography (TEE) in 73.1 % of cases. They underwent ECV (after mean 16 h, range 4-48), in 65.3 % and PCV in 6.7 % of patients (amiodarone in 47.7 %, flecainide in 27.3 %, propafenone in 2.3 %) as first CV procedure. No CV was performed in 27.9 %, mainly due to spontaneous CV or pathologic TEE. Primary success rates were 86.7 % for electrical CV and 54.5 % for pharmacological CV. More patients in the ECV group compared to the PCV group received oral anticoagulation at discharge (79.2 vs. 59.1 %, p < 0.001), and at 60 days (77.5 vs. 56.8 %, p < 0.001). Further, at 60 days the proportion of patients in sinus rhythm was not different between groups (ECV 76.8 % vs. PCV 77.3 %). CONCLUSIONS: In large academic centres in Germany, the preferred CV method is electrical, mainly due to its easy access and to its higher success rate for the initial restoration of sinus rhythm. Considering the limitations of the open-label, non randomised study design, overall short-term success rates appeared higher after ECV compared to PCV during hospitalisation, but not after 60 days. PMID- 23812042 TI - Functional MRI pain studies in children? Yes, we (s)can! PMID- 23812043 TI - Robust cyclometallated Ir(III) catalysts for the homogeneous hydrogenation of N heterocycles under mild conditions. AB - Cyclometallated Cp*Ir(N^C)Cl complexes derived from N-aryl ketimines are highly active catalysts for the reduction of N-heterocycles under ambient conditions and 1 atm H2 pressure. The reaction tolerates a broad range of other potentially reducible functionalities and does not require the use of specialised equipment, additives or purified solvent. PMID- 23812045 TI - Ribavirin for upper respiratory tract infections. PMID- 23812044 TI - Regulation of the DNA damage response on male meiotic sex chromosomes. AB - During meiotic prophase in males, the sex chromosomes partially synapse to form the XY body, a unique structure that recruits proteins involved in the DNA damage response, which is believed to be important for silencing of the sex chromosomes. It remains elusive how the DNA damage response in the XY body is regulated. Here we show that H2AX-MDC1-RNF8 signaling, which is well characterized in somatic cells, is dispensable for the recruitment of proteins to the unsynapsed axes in the XY body. On the other hand, the DNA damage response that spreads over the sex chromosomes is largely similar to that in somatic cells. This analysis shows that there are important differences between the regulation of the DNA damage response at the XY body and at DNA damage sites in somatic cells. PMID- 23812047 TI - Sustaining the gains: moving evidence-based practice forward. PMID- 23812046 TI - Reply to Robinson. PMID- 23812048 TI - Significant practice pattern variations associated with intracranial pressure monitoring. AB - PURPOSE: The purpose of this study was to describe nursing practice in the care of patients with intracranial pressure monitoring. Although standards for care of such patients have been established, there continue to be variations in the nursing practice. METHODS: This was an observational study in which data were collected from 28 nurse-patient dyads at 16 different hospitals across the United States. Each dyad was observed for 2 hours; nursing actions and patient responses including intracranial pressure readings were documented. RESULTS: Differences in the care of patients with intracranial pressure monitoring were prevalent. Variations in practice were prompted by healthcare provider prescriptions as well as nursing decisions. Prescriptions and interventions were often not supported by the available scientific evidence. VIDEO ABSTRACT: For more insights from the authors, see Supplemental Digital Content 1, at http://links.lww.com/JNN/A7. PMID- 23812049 TI - Malnutrition and risk of malnutrition in patients with stroke: prevalence during hospital stay. AB - BACKGROUND: Although various studies have shown high prevalence of malnutrition in hospitalized patients with stroke, recent studies on how the nutritional status of patients with acute stroke develops during the first weeks of hospital stay are scarce. Information is lacking concerning the identification of patients with stroke who are at risk of malnutrition during an acute hospital stay, because these patients may have a significant chance to improve their nutritional status. PURPOSE: This study aimed to investigate the prevalence of malnutrition and risk of malnutrition of patients with acute stroke during the first 10 days of hospitalization. METHODS: A prospective, descriptive study was conducted in a neurological department of a university hospital in The Netherlands. Seventy three patients with acute stroke were included, of which 23 patients could be followed up after 10 days. The nutritional status was determined with the Mini Nutritional Assessment at admission and after 10 days. RESULTS: At admission, 5% of the patients (n = 73) were malnourished, 14% were at risk of malnutrition, and 81% were well nourished. Of the patients who could be followed up (n = 23), at admission, no patients were malnourished, 9% were at risk of malnutrition, and 91% were well nourished; whereas 10 days later, 26% of these patients were malnourished, 39% were at risk of malnutrition, and 35% were well nourished. This means that, within the followed-up group, the proportion of patients with malnutrition or risk of malnutrition increased significantly during hospital stay from 9% to 65%. CONCLUSIONS: Our study shows that the prevalence of malnutrition and risk of malnutrition in patients with acute stroke increases strongly during the first 10 days of admission. Therefore, screening of the nutritional status of these patients throughout this period is highly recommended to enable timely nutritional intervention and nutritional management of these patients. PMID- 23812050 TI - The Chiari Symptom Profile: development and validation of a Chiari-/syringomyelia specific questionnaire. AB - OBJECTIVE: The Chiari Symptom Profile (CSP) was developed to provide a quantitative assessment of self-reported Chiari (CMI)-related symptoms and their impact on the individual's quality of life. METHODS: The instrument was developed in three phases. Phase I consisted of instrument development using exploratory item analysis from the literature and direct patient evaluations. The item pool was then analyzed and tested on a convenience sample of eight CMI patients. Interitem correlation matrix suggested redundancy of 13 questions. These items were discarded, resulting in a final questionnaire consisting of 57 items, measuring four realms: physical, functional, psychological, and social. Phases II and III tested the reliability and validity of the instrument using a large sample of patients diagnosed with Chiari/syringomyelia. RESULTS: Statistical analysis confirmed that the CSP has excellent validity and reliability with a Cronbach's alpha of .958 (p = .0001) and factor loadings ranging from .784 to .321. CONCLUSION: The CSP is a self-reported, Chiari-/syringomyelia-specific instrument intended to provide a quantitative analysis of symptoms and their impact on the individual's quality of life. The CSP has shown statistically significant content validity, internal consistency, and test-retest reliability. The CSP will enhance the provider's understanding of Chiari-/syringomyelia related symptoms, quantify the impact of self-reported symptoms on quality of life, help to determine if interventions are of benefit, and allow comparison of symptomatic improvement/outcome following different surgical techniques. PMID- 23812051 TI - Caregivers' beliefs associated with medication adherence among children and adolescents with epilepsy. AB - The purpose of this study was to determine the association between adherence to prescribed antiepileptic medication in a convenience sample of caregivers (n = 100) of children diagnosed with epilepsy, ages 2-14 years, and caregivers' beliefs about the medication. Using the Beliefs about Medication Questionnaire and Medication Adherence Report Scale, caregivers were questioned about beliefs of necessity and concerns associated with medication adherence. Using bivariate linear regression, no significant correlation was found between necessity for antiepileptic drug treatment or caregiver's concerns and medication adherence. Nevertheless, although only 28% of the respondents reported complete adherence, the majority of caregivers perceived their child's medication was necessary to maintain good health. Educational aspects and social desirability in this setting may have contributed to the discordance between adherence and caregivers' beliefs. PMID- 23812052 TI - Nursing implications for the lifelong management of tuberous sclerosis complex. AB - Tuberous sclerosis complex (TSC) is a genetic disorder that can affect multiple organ systems, including the brain, heart, skin, kidney, and lung, by formation of benign hamartomas. It can be associated with autism, epilepsy, and other neurocognitive and behavioral disabilities. The incidence of TSC is approximately 1 in 6,000 live births, but it may be underdiagnosed. Mutations to either the TSC1 (coding for hamartin) or TSC2 (coding for tuberin) genes are present in 85% of patients with TSC. The TSC1/TSC2 protein dimer complex is a crucial inhibitory element in the mammalian target of rapamycin (mTOR) complex 1 pathway that regulates cell growth and proliferation. The manifestations of TSC usually require management over the entire life of the patient. Until recently, there were few options, other than surgical removal, for treating the symptoms of TSC related to growth of hamartomas. Increased understanding of the genetic cause of the disease and the underlying dysregulation of the mTOR pathway has led to clinical trials of mTOR inhibitors including sirolimus and everolimus. This article will review the various manifestations of TSC and describe treatment strategies, recommendations for surveillance, and use of mTOR inhibitors in their management. PMID- 23812054 TI - A nurse-coached exercise program to increase muscle strength, improve quality of life, and increase self-efficacy in people with tetraplegic spinal cord injuries. AB - A nurse-coached exercise intervention for 10 people with tetraplegic spinal cord injuries was conducted over a period of 2 years at an accessible, community-based YMCA using an equipment especially designed for people with mobility issues and neurological deficits. In this single-subject design study, each participant completed three 3-hour exercise sessions a week for over 6 months. The purpose of the study was to determine what effects the program would have on increasing muscle strength, improving quality of life, and increasing self-efficacy after traditional outpatient therapy sessions were no longer available or affordable. The Sheehy Spinal Cord Injury Functional Improvement via Exercise Model was constructed at the conclusion of an unpublished pilot study and was tested in this study. Expectations of the model were that, if a person with a tetraplegic spinal cord injury participated in a coached program of exercise, muscle strength would increase and functional ability would improve, resulting in greater independence, a higher sense of self-efficacy, and a higher quality of life. Study results using a single-subject design of graph-trend analysis showed upward trajectories in muscle strength, quality of life, and self-efficacy in all study participants regardless of the length of time since his or her original injury. The results support the efficacy of this nurse-coached program for people with tetraplegic spinal cord injuries and validate the Sheehy Spinal Cord Injury Functional Improvement via Exercise Model. PMID- 23812055 TI - Taking care of you. PMID- 23812056 TI - Should parents be present during their child's resuscitation? PMID- 23812057 TI - "Try not to judge": mothers of substance exposed infants. AB - PURPOSE: To describe the hospital experiences of mothers who give birth to substance-exposed infants. STUDY DESIGN AND METHODS: Secondary analysis of data from a larger study that was focused on the experiences of Mexican-American mothers in the neonatal intensive care unit (NICU) was conducted. Semistructured interviews with five women who were recovering addicts on methadone were analyzed. Each of their infants spent time in an NICU following birth. The transcribed interviews were analyzed using qualitative content analysis. RESULTS: Four themes were identified: (a) "try not to judge," (b) "scoring" the baby, (c) "share with me," and (d) "I'm the mother here!" CLINICAL IMPLICATIONS: The quality of the relationship between the mothers and the nurses in the NICU was a crucial aspect of the mothers' experiences and may have an effect on long-term outcomes. Women with addictions often have other significant risk factors that may further jeopardize their ability to mother; therefore, it is essential to develop a strong support network. Nurses can be instrumental in organizing resources for this population of women. Judging behaviors may have a detrimental effect on women with addictions. Maternal adaptation to the mothering role can be enhanced by making reasonable efforts to include the mother in the care of the infant. PMID- 23812059 TI - Maternal depression and rapid subsequent pregnancy among first time mothers. AB - PURPOSE: To examine differences in prenatal depression among first-time mothers who had a subsequent pregnancy within 6 months of first birth and those who did not. Mothers with depression symptoms were expected to have a greater likelihood of rapid subsequent pregnancy. STUDY DESIGN: The Parenting for the First Time study is a longitudinal multisite prospective descriptive study designed to identify and understand the dynamics of subthreshold neglectful parenting behaviors among first-time mothers. Data were collected from the prenatal period through the child's first 3 years of life. The Parenting for the First Time sample consisted of 684 first-time mothers between 15 and 36 years. Data were available on prenatal depression and subsequent pregnancy at 6 months for 279 participants (n = 279). METHODS: Multiple logistic regression analysis was conducted to determine the odds of subsequent pregnancy within 6 months of first birth. RESULTS: Twelve mothers (5.9%) became pregnant within 6 months of first birth. The odds of subsequent pregnancy were 7.24 greater (95% confidence interval [CI]: 2.18-24.04) among mothers with moderate-to-severe depression. White versus non-White race did not influence subsequent pregnancy (0.91, 95% CI: 0.18-4.49). Pregnancy was not significantly different between teen and adult mothers (odds ratio: 0.92, 95% CI: 0.24-3.68). CLINICAL IMPLICATIONS: In this sample of first time mothers, moderate-to-severe depression symptoms were associated with subsequent pregnancy within 6 months of first birth. Routine depression screening by nurses during the prenatal period offers opportunities for intensive contraceptive counseling and may help mothers achieve optimal birth spacing. PMID- 23812060 TI - Defining hazards of supplemental oxygen therapy in neonatology using the FMEA tool. AB - PURPOSE: To prospectively evaluate hazards in the process of supplemental oxygen therapy in very preterm infants hospitalized in a Dutch NICU. METHODS: A Failure Mode and Effects Analysis (FMEA) was conducted by a multidisciplinary team. This team identified, evaluated, and prioritized hazards of supplemental oxygen therapy in preterm infants. After accrediting "hazard scores" for each step in this process, recommendations were formulated for the main hazards. RESULTS: Performing the FMEA took seven meetings of 2 hours. The top 10 hazards could all be categorized into three main topics: incorrect adjustment of the fraction of inspired oxygen (FiO2), incorrect alarm limits for SpO2, and incorrect pulse oximetry alarm limits on patient monitors for temporary use. The FMEA culminated in recommendations in both educational and technical directions. These included suggestions for (changes in) protocols on alarm limits and manual FiO2 adjustments, education of NICU staff on hazards of supplemental oxygen, and technical improvements in respiratory devices and patient monitors. CONCLUSIONS: The FMEA prioritized flaws in the process of supplemental oxygen therapy in very preterm infants. Thanks to the structured approach of the analysis by a multidisciplinary team, several recommendations were made. These recommendations are currently implemented in the study's center. PMID- 23812061 TI - African American women's views of factors impacting preterm birth. AB - PURPOSE: To explore pregnant African American women's views of factors that may impact preterm birth. STUDY DESIGN AND METHODS: Qualitative descriptive exploratory cross-sectional design. A convenience sample of 22 low-risk pregnant African American women participated in focus group interviews. Women were asked questions regarding their belief about why women have preterm birth and factors impacting preterm birth. Data were analyzed using content analysis. RESULTS: Pregnant African American women encounter multiple physical, psychological, and social stressors. The four themes included knowledge of preterm birth, risk factors for preterm birth, protective factors for preterm birth, and preterm birth inevitability. The risk factors for preterm birth were health-related conditions, stressors, and unhealthy behaviors. Stressors included lack of social and financial support, interpersonal conflicts, judging, dangerous neighborhoods, racism, and pregnancy- and mothering-related worries. Protective factors for preterm birth included social support and positive coping/self-care. CLINICAL IMPLICATIONS: Clinicians may use the results of this study to better understand women's perceptions of factors that affect preterm birth, to educate women about risk factors for preterm birth, and to develop programs and advocate for policies that have the potential to decrease health disparities in preterm birth. PMID- 23812063 TI - Barriers to breastfeeding in the WIC population. AB - BACKGROUND: Breastfeeding (BF) initiation rates in the United States have increased over the past 11 years by 3.6%. However, women who participate in the Women, Infants, and Children (WIC) program are almost 12% less likely to initiate BF than the general population, and less likely to continue for a year. PURPOSE: To identify barriers to BF in order to recommend guidelines for the WIC population. STUDY DESIGN AND METHODS: A systematic review using the search words WIC and BF was conducted using the CINAHL, PubMed, and Cochrane Library databases. Inclusion criteria were articles studying the WIC population alone and/or relative to other populations. Twenty-four articles from the last 5 years were reviewed and graded according to the Evans' hierarchy of evidence. RESULTS: Barriers to BF in the WIC population were sorted into five categories: lack of support inside/outside the hospital, returning to work, practical issues, WIC related issues, and social/cultural barriers. Factors predisposing to lower BF rates include non-Hispanic ethnicity, obesity, depression, younger age, or an incomplete high school education. Interventions trialed with positive outcomes include peer counseling, improved communication between hospital lactation consultants and WIC staff, breast-pump programs, and discouraging routine formula provision in the hospital and by WIC. CLINICAL IMPLICATIONS: Reasons for low BF rates in the WIC population are complex. More research is needed into interventions tailored for WIC participants. Recommendations for clinicians include initiating peer-counseling programs, prenatal/ postpartum education, in hospital BF support, and changing the focus of WIC from formula to BF promoting. PMID- 23812064 TI - Food safety: the discussion continues. PMID- 23812065 TI - Pediatric capsule endoscopy: the pill camera. PMID- 23812066 TI - Caring: that's what we're here for. PMID- 23812068 TI - "Visitors" during childbirth. PMID- 23812069 TI - [Lupus nephritis associated with nephrotic syndrome]. AB - Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease that is characterized by the production of multiple autoantibodies and immune complex formation. Lupus nephritis (LN), which has various histological patterns and variable clinical outcomes, is one of the most important complications of SLE. Although this pathogenetic mechanism in each histologically different type of nephritis remains unclear, recent findings in LN elucidate an essential role for the Th1, IL-17 producing T cells and Th17 cells in the development of diffuse lupus nephritis (DLN), and Th2 cytokine in that of membranous lupus nephritis (MLN). These data support the hypothesis that individual Th1/Th2 balance is one of the critical determinants for histopathology of LN. Therefore the suppression of pivotal role cytokines in each pathological condition may support immunosuppressant strategy for LN. PMID- 23812070 TI - [Recent clinical trials of tumor immunotherapy]. AB - Many recent clinical trials of immunotherapy for advanced tumors have reported remarkable results. For example, blockade of cytotoxic T-lymphocyte antigen 4 (CTLA-4) significantly improved median overall survival of melanoma patients. Blockade of programmed cell death 1 (PD-1) or programmed cell death 1 ligand 1 (PD-L1) induced durable tumor regression and prolonged disease stabilization in patients with advanced cancers, including melanoma, non-small-cell lung cancer, and renal cell cancer. In addition, adoptive cell transfer of tumor infiltrating lymphocytes (TILs) and T cells transduced with high avidity T cell receptor (TCR) genes have been reported to elicit marked durable tumor regression in melanoma patients. Further, clinical trials of cancer vaccines targeting various tumors have been conducted to prolong overall survival. In this review, some remarkable results achieved in recent clinical trials are summarized. PMID- 23812071 TI - [Autoantibodies and their clinical characteristics in systemic sclerosis]. AB - Systemic sclerosis (SSc) is a connective tissue disorder characterized by microvascular damage and excessive fibrosis of the skin and internal organs with autoimmune background. One representative feature of the immunological abnormalities in SSc patients is the presence of antinuclear antibodies (ANA). More than 90% of patients with SSc are positive for ANA. Although a role of ANA in the pathogenesis in SSc remains unclear, the particular ANA are often indicative of clinical feature, disease course, and overall severity. Therefore, subgrouping patients based on the type of autoantibodies present can be useful in diagnosis and management. Anticentromere antibody (ACA), anti-DNA topoisomerase I antibody (Ab), and anti-RNA polymerase Ab are the representative autoAbs found in patients with SSc. Other serum ANA found in SSc include anti-Th/To Ab, anti-U3RNP Ab, anit-human upstream-binding protein (hUBF) Ab, anti-centriole Ab, anti-U1RNP Ab, anti-Ku Ab, and anti-PM-Scl Ab. It is documented that the prevalence of SSc related Abs and clinical characteristics of patients with SSc are influenced by ethnicity. Identifying several SSc-related Abs requires a complicated technique that include immunoprecipitation assay. Establishment of a system routinely available to screen ANA specificities such as enzyme-linked immunosorbent assay is needed. PMID- 23812072 TI - [Current status and future prospects of stem cell gene therapy for primary immunodeficiency]. AB - Patients affected by primary immunodeficiency (PID) can be cured by allogeneic hematopoietic stem cell transplantation (HSCT). In the absence of HLA-matched donors, however, incidence of HSCT-related complications is observed. Therefore, gene therapy has been developed as a highly desirable alternative treatment for patients lacking suitable donors. Retrovirus-based gene therapy was begun in 1990 for the patients of adenosine deaminase deficiency, followed by X-linked severe combined immunodeficiency, Wiskott-Aldrich syndrome and chronic granulomatous disease. Although treated patients have had excellent immune reconstitution and resolution of ongoing infections, complications such as a lymphoproliferative syndrome and a disappearance of gene-modified cells were observed in some clinical trials. To overcome these, ongoing and upcoming clinical trials use some new strategies. The use of preconditioning chemotherapy makes space in the bone marrow for the gene-treated stem cells and allows engraftment of multi lineage stem/progenitor cells. Self-inactivating vectors in which strong enhancers of long terminal repeat are eliminated may reduce the risk of insertional activation of proto-oncogene resulting in leukemia. These modifications will surely increase the safety and efficacy of stem cell gene therapy for PID. PMID- 23812073 TI - [Resolving factors of inflammation - a bridge between innate immunity and adaptive immunity]. AB - Acute inflammation, a physiologic response to protect cells from microbial infection and other stimuli, is automatically terminated by endogenous anti inflammatory and pro-resolving mediators to restore homeostatic conditions. However, if timely resolution of inflammation is failed, inflammation persists and can progress to a chronic inflammation such as rheumatoid arthritis, interstitial pneumonitis. To prevent chronic inflammation, understanding the process that resolves inflammation is essential. Resolution of inflammation is an active coordinated process regulated by distinct anti-inflammatory and pro resolving endogenous lipid mediators, such as lipoxins/ALX, chemerin/chemR23. In resolution of inflammation these resolving factors contribute a bridge between innate and adaptive immunity. PMID- 23812074 TI - [Development and pharmacological effects of anti-RANKL monoclonal antibody drug denosumab]. AB - Denosumab (called RANMARK((r)) in Japan), an anti-bone resorptive drug, is a complete human type monoclonal antibody that targets the osteoclast differentiation factor receptor activator of NF-kappaB ligand (RANKL). Using advanced gene-engineering techniques, Amgen Inc. (USA) has developed the drug, and it is now utilized in Japan for treatment of cancerous bone lesions associated with multiple myeloma and bone metastasis. On the other hand, denosumab has also shown inhibitory effects on bone resorption seen in patients with osteoporosis, rheumatoid arthritis, and Paget's disease, thus its range of use for medical treatment is expected to widen. Because of its long half-life in the body, subcutaneous denosumab administrations every 6 months are sufficient to obtain inhibitory effects on bone resorption, suggesting that this agent is more efficacious than bisphosphonates, which are presently used as anti-bone resorptive drugs. However, hypocalcemia might develop in patients with massive renal dysfunction. Denosumab binds to a specific loop structure of the RANKL molecule and inhibits its interaction with its receptor RANK. When labeled with radioactivity, denosumab was detected in lymph nodes and the spleen after subcutaneous administration, indicating its binding to RANKL expressed in those tissues. Thus, many medical doctors and investigators are interested in the inhibitory effects of denosumab on bone resorption as well as its mode of action. PMID- 23812075 TI - [Rapidly progressive pulmonary arterial hypertension associated with systemic sclerosis : a case report]. AB - A 68-year-old female who had Raynaud phenomenon for a decade was admitted to our hospital in January 2012. She complained of sclerodactyly and scleroderma that did not extend past the elbows. She also had fingertip ulcers that repeatedly disappeared and recurred for several years. Blood tests showed that she was anti centromere antibody positive. Therefore, she was diagnosed with limited cutaneous systemic sclerosis. Two months after diagnosis, she returned to our hospital because she experienced dyspnea on exertion and exacerbation of her fingertip ulcers. Chest X-rays revealed cardiac enlargement, an echocardiography showed tricuspid regurgitation with an increased tricuspid pressure gradient (91 mmHg) and right heart catheterization showed a mean pulmonary arterial pressure of 59 mmHg. Chest computed tomography and lung perfusion scintigraphy showed no abnormalities. She was then diagnosed with pulmonary arterial hypertension associated with systemic sclerosis. She improved rapidly with daily treatments of prednisolone in addition to warfarin, bosentan and beraprost sodium. This is a rare case of rapidly progressive pulmonary arterial hypertension associated with systemic sclerosis that can be markedly improved with early diagnosis and treatment. PMID- 23812076 TI - [Diagnostic value of brain biopsy in a pediatric multiple sclerosis mimicking brain stem glioma]. AB - Diagnosis of multiple sclerosis (MS) is difficult when the lesion mimics glioma or cerebral enchephalitis. We report a case of pediatric MS initially suspected as brain stem glioma. An 11-year-old boy developed left foot joint pain followed by progressive symptoms such as left arm and leg weakness, dysarthria, paraplegia, and decreased level of consciousness. He subsequently developed respiratory distress requiring endotracheal intubation and mechanical ventilation. Magnetic resonance imaging showed a mass measuring 2 cm in the medulla oblongata. Although this mass was initially suspected as a glioma, the patient's acutely progressive disease course was not consistent with this diagnosis. Open biopsy revealed inflammation and demyelination, but no malignant cells were detected. He was treated with steroid pulse therapy, which showed dramatic effects. Nine months later, he developed another episode characterized by several neurological symptoms, and the diagnosis of MS was clinically confirmed. Open brain stem biopsy is technically demanding, but this case demonstrates that appropriate neurosurgical evaluation can play an important role in diagnosis by ruling out glioma and confirming MS. PMID- 23812078 TI - In vitro antimetastatic effect of phosphatidylinositol 3-kinase inhibitor ZSTK474 on prostate cancer PC3 cells. AB - Tumor metastasis is the main cause of lethality of prostate cancer, because conventional therapies like surgery and hormone treatment rarely work at this stage. Tumor cell migration, invasion and adhesion are necessary processes for metastasis. By providing nutrition and an escape route from the primary site, angiogenesis is also required for tumor metastasis. Phosphatidylinositol 3 kinases (PI3Ks) are well known to play important roles in tumorigenesis as well as metastasis. ZSTK474 is a specific PI3K inhibitor developed for solid tumor therapy. In the present report, antimetastatic activities of ZSTK474 were investigated in vitro by determining the effects on the main metastatic processes. ZSTK474 exhibited inhibitory effects on migration, invasion and adhesive ability of prostate cancer PC3 cells. Furthermore, ZSTK474 inhibited phosphorylation of Akt substrate-Girdin, and the secretion of matrix metalloproteinase (MMP), both of which were reported to be closely involved in migration and invasion. On the other hand, ZSTK474 inhibited the expression of HIF-1alpha and the secretion of vascular endothelial growth factor (VEGF), suggesting its potential antiangiogenic activity on PC3 cells. Moreover, we demonstrated the antiangiogenesis by determining the effect of ZSTK474-reduced VEGF on tube formation of human umbilical vein endothelial cells (HUVECs). In conclusion, ZSTK474 was demonstrated to have potential in vitro antimetastatic effects on PC3 cells via dual mechanisms: inhibition of metastatic processes including cell migration, invasion and adhesion, and antiangiogenesis via blockade of VEGF secretion. PMID- 23812079 TI - Complexes of silver(I) ions and silver phosphate nanoparticles with hyaluronic acid and/or chitosan as promising antimicrobial agents for vascular grafts. AB - Polymers are currently widely used to replace a variety of natural materials with respect to their favourable physical and chemical properties, and due to their economic advantage. One of the most important branches of application of polymers is the production of different products for medical use. In this case, it is necessary to face a significant disadvantage of polymer products due to possible and very common colonization of the surface by various microorganisms that can pose a potential danger to the patient. One of the possible solutions is to prepare polymer with antibacterial/antimicrobial properties that is resistant to bacterial colonization. The aim of this study was to contribute to the development of antimicrobial polymeric material ideal for covering vascular implants with subsequent use in transplant surgery. Therefore, the complexes of polymeric substances (hyaluronic acid and chitosan) with silver nitrate or silver phosphate nanoparticles were created, and their effects on gram-positive bacterial culture of Staphylococcus aureus were monitored. Stages of formation of complexes of silver nitrate and silver phosphate nanoparticles with polymeric compounds were characterized using electrochemical and spectrophotometric methods. Furthermore, the antimicrobial activity of complexes was determined using the methods of determination of growth curves and zones of inhibition. The results of this study revealed that the complex of chitosan, with silver phosphate nanoparticles, was the most suitable in order to have an antibacterial effect on bacterial culture of Staphylococcus aureus. Formation of this complex was under way at low concentrations of chitosan. The results of electrochemical determination corresponded with the results of spectrophotometric methods and verified good interaction and formation of the complex. The complex has an outstanding antibacterial effect and this effect was of several orders higher compared to other investigated complexes. PMID- 23812080 TI - The effect of a silver nanoparticle polysaccharide system on streptococcal and saliva-derived biofilms. AB - In this work, we studied the antimicrobial properties of a nanocomposite system based on a lactose-substituted chitosan and silver nanoparticles: Chitlac-nAg. Twofold serial dilutions of the colloidal Chitlac-nAg solution were both tested on Streptococcus mitis, Streptococcus mutans, and Streptococcus oralis planktonic phase and biofilm growth mode as well as on saliva samples. The minimum inhibitory and bactericidal concentrations of Chitlac-nAg were evaluated together with its effect on sessile cell viability, as well as both on biofilm formation and on preformed biofilm. In respect to the planktonic bacteria, Chitlac-nAg showed an inhibitory/bactericidal effect against all streptococcal strains at 0.1% (v/v), except for S. mitis ATCC 6249 that was inhibited at one step less. On preformed biofilm, Chitlac-nAg at a value of 0.2%, was able to inhibit the bacterial growth on the supernatant phase as well as on the mature biofilm. For S. mitis ATCC 6249, the biofilm inhibitory concentration of Chitlac-nAg was 0.1%. At sub-inhibitory concentrations, the Streptococcal strains adhesion capability on a polystyrene surface showed a general reduction following a concentration dependent-way; a similar effect was obtained for the metabolic biofilm activity. From these results, Chitlac-nAg seems to be a promising antibacterial and antibiofilm agent able to hinder plaque formation. PMID- 23812081 TI - Early phenylpropanoid biosynthetic steps in Cannabis sativa: link between genes and metabolites. AB - Phenylalanine ammonia-lyase (PAL), Cinnamic acid 4-hydroxylase (C4H) and 4 Coumarate: CoA ligase (4CL) catalyze the first three steps of the general phenylpropanoid pathway whereas chalcone synthase (CHS) catalyzes the first specific step towards flavonoids production. This class of specialized metabolites has a wide range of biological functions in plant development and defence and a broad spectrum of therapeutic activities for human health. In this study, we report the isolation of hemp PAL and 4CL cDNA and genomic clones. Through in silico analysis of their deduced amino acid sequences, more than an 80% identity with homologues genes of other plants was shown and phylogenetic relationships were highlighted. Quantitative expression analysis of the four above mentioned genes, PAL and 4CL enzymatic activities, lignin content and NMR metabolite fingerprinting in different Cannabis sativa tissues were evaluated. Furthermore, the use of different substrates to assay PAL and 4CL enzymatic activities indicated that different isoforms were active in different tissues. The diversity in secondary metabolites content observed in leaves (mainly flavonoids) and roots (mainly lignin) was discussed in relation to gene expression and enzymatic activities data. PMID- 23812082 TI - Ectopic overexpression of an AUXIN/INDOLE-3-ACETIC ACID (Aux/IAA) gene OsIAA4 in rice induces morphological changes and reduces responsiveness to Auxin. AB - Auxin has pleiotropic effects on plant growth and development. AUXIN/INDOLE-3 ACETIC ACID (Aux/IAA) proteins are short-lived transcriptional regulators that mediate auxin responses through interaction with an auxin receptor, the F-box protein transport inhibitor response 1 (TIR1). Most functions of Aux/IAA proteins have been identified in Arabidopsis by studying the gain-of-function mutants in domain II. In this study, we isolated and identified an Aux/IAA protein gene from rice, OsIAA4, whose protein contains a dominant mutation-type domain II. OsIAA4 has very low expression in the entire life cycle of rice. OsIAA4-overexpressing rice plants show dwarfism, increased tiller angles, reduced gravity response, and are less sensitive to synthetic auxin 2,4-dichlorophenoxyacetic acid (2,4-D). PMID- 23812083 TI - The interstitial interface within the renal stem/progenitor cell niche exhibits an unique microheterogeneous composition. AB - Repair of parenchyma by stem/progenitor cells is seen as a possible alternative to cure acute and chronic renal failure in future. To learn about this therapeutic purpose, the formation of nephrons during organ growth is under focus of present research. This process is triggered by numerous morphogenetic interactions between epithelial and mesenchymal cells within the renal stem/progenitor cell niche. Recent data demonstrate that an astonishingly wide interstitial interface separates both types of stem/progenitor cells probably controlling coordinated cell-to-cell communication. Since conventional fixation by glutaraldehyde (GA) does not declare in transmission electron microscopy the spatial separation, improved contrasting procedures were applied. As a consequence, the embryonic cortex of neonatal rabbit kidneys was fixed in solutions containing glutaraldehyde in combination with cupromeronic blue, ruthenium red or tannic acid. To obtain a comparable view to the renal stem/progenitor cell niche, the specimens had to be orientated along the cortico medullary axis of lining collecting ducts. Analysis of tissue samples fixed with GA, in combination with cupromeronic blue, demonstrates demasked extracellular matrix. Numerous braces of proteoglycans cover, as well, the basal lamina of epithelial stem/progenitor cells as projections of mesenchymal stem/progenitor cells crossing the interstitial interface. Fixation with GA containing ruthenium red or tannic acid illustrates strands of extracellular matrix that originate from the basal lamina of epithelial stem/progenitor cells and line through the interstitial interface. Thus, for the first time, improved contrasting techniques make it possible to analyze in detail a microheterogeneous composition of the interstitial interface within the renal stem/progenitor cell niche. PMID- 23812085 TI - New treatment option for sclerosing osteomyelitis of Garre. AB - Sclerosing osteomyelitis of Garre continues to be a puzzling entity, with a nonspecific clinical description and course, an obscure pathogenesis, and no consensus on a predictable and helpful method of treatment. The proposed treatment options according to the literature are observation, analgesics and NSAIDs, and bone curettage. Here we present a 15-year-old girl treated by resection of a 12 cm-long lesion after failed conservative treatment, followed by bone transport using a circular external fixator. This treatment method has not been described previously for this condition. The duration of bone transport was 3 months, and the total duration of the frame treatment was 12 months. After hardware removal, and at 2.5-year follow-up, the patient was asymptomatic and achieved good functional results. To the best of our knowledge, this is the first description of bone resection and transport for the treatment of this condition, even though it is well described for the treatment of chronic osteomyelitis and other conditions necessitating bone resection. On the basis of this case we suggest that resection and bone transport using a circular external fixator for the treatment of sclerosing osteomyelitis of Garre might be an effective and safe method. Of course, being a rare entity, large cohorts are difficult to obtain, and more data and longer follow-up are required to form a convincing recommendation. Level IV evidence. PMID- 23812086 TI - Surveillance after treatment of children with developmental dysplasia of the hip: current UK practice and the proposed Stanmore protocol. AB - Monitoring of a patient with developmental dysplasia of the hip (DDH) is required after initial treatment to ensure early detection and correction of complications or poor progression. We established the current practice of surveillance in DDH in the UK. A protocol has been designed at this unit with the aim of identifying the stages in the progression of DDH when imaging of the hip is necessary to detect failure or possible complications of treatment. The outcomes and secondary procedure rates under the surveillance protocol used at this unit, for a UK population, have been reviewed with a minimum of 5 years of follow-up. Frequency of follow-up has been reported as yearly or more frequently until skeletal maturity by 70% of respondents. Ninety patients presenting with DDH were managed under the protocol developed at this unit, with equivalent outcomes as those in patients who reported yearly follow-up. Following our proposed protocol we believe it is possible to limit disruption to the patient's life, reduce costs and maintain compliance and ensure timely detection of any complications, without significant increase in secondary procedure rates. PMID- 23812087 TI - Transient synovitis of the hip: a comprehensive review. AB - Transient synovitis is a benign, self-limiting condition that is diagnosed after the exclusion of more serious causes of acute hip pain in children. Although its etiology remains unclear, it is largely believed to be viral in nature. Transient synovitis typically presents as an acute onset of thigh pain with a limp or an unwillingness to bear weight. It can be distinguished from similar conditions by the absence of fever, as well as unremarkable bloodwork (WBC, CRP, ESR), radiographs, and hip aspiration. Conservative treatment and observation are the mainstay of management. Resolution of symptoms generally occurs by 1 week and may be accelerated by NSAIDs. Although numerous papers have emerged over the years with an effort to advance our understanding, many questions remain about its pathomechanics, etiology, and how to exclude other more serious conditions that present similarly. PMID- 23812084 TI - Stem cells behind the barrier. AB - Epidermal stem cells sustain the adult skin for a lifetime through self-renewal and the production of committed progenitors. These stem cells generate progeny that will undergo terminal differentiation leading to the development of a protective epidermal barrier. Whereas the molecular mechanisms that govern epidermal barrier repair and renewal have been extensively studied, pathways controlling stem cell differentiation remain poorly understood. Asymmetric cell divisions, small non-coding RNAs (microRNAs), chromatin remodeling complexes, and multiple differentiation factors tightly control the balance of stem and progenitor cell proliferation and differentiation, and disruption of this balance leads to skin diseases. In this review, we summarize and discuss current advances in our understanding of the mechanisms regulating epidermal stem and progenitor cell differentiation, and explore new relationships for maintenance of skin barrier function. PMID- 23812088 TI - Response of testosterone to prolonged aerobic exercise during different phases of the menstrual cycle. AB - PURPOSE: To examine the androgen response to exercise in women under conditions of high (H) and low (L) estrogen (E2) levels. METHODS: Ten exercise trained eumenorrheic women (mean +/- SD: 20.0 +/- 2.2 years, 58.7 +/- 8.3 kg, 22.3 +/- 4.9 % body fat, VO2max = 50.7 +/- 9.0 mL/kg/min) completed a 60 min treadmill run at ~70 % of VO2max during both the mid-follicular (L-E2, 69.7 +/- 7.3 % VO2max) and mid-luteal (H-E2, 67.6 +/- 7.9 % VO2max) phases of their menstrual cycle. Blood samples were taken pre-exercise (PRE), immediately post (POST), and 30 min into recovery (30R) from exercise and analyzed for total testosterone using ELISA assays. Results were analyzed using repeated measures ANOVA. RESULTS: Testosterone responses were (mean +/- SD: L-E2, pre = 1.41 +/- 0.21, post = 1.86 +/- 0.21, 30R = 1.75 +/- 0.32 nmol/L; H-E2, pre = 1.27 +/- 0.23, post = 2.43 +/- 0.56, 30R = 1.69 +/- 0.34 nmol/L). Statistical analysis indicated no significant interaction existed between high and low estrogen conditions across the blood sampling times (p = 0.138). However, a main effect occurred for exercise (p < 0.004) with the post-testosterone concentration being greater than pre, although pre vs. 30R was not different (p > 0.05). All testosterone hormonal concentrations immediately post-exercise greatly exceeded the level of hemoconcentration observed during the L-E2 and H-E2 exercise sessions. CONCLUSIONS: Prolonged aerobic exercise induces short-term elevations in testosterone in trained eumenorrheic women, which appears unrelated to estrogen levels and menstrual cycle phase. These increases may occur due to either increased androgen production and/or decreased degradation rates of the hormone, and are not solely the result of plasma fluid shifts from the exercise. PMID- 23812091 TI - Nanoscale free-standing magnetoelectric heteropillars. AB - Nanocomposites with a film-on-substrate geometry usually suffer from a large clamping effect from the substrate, inhibiting the elastic-interaction-mediated "product" property such as the magnetoelectric response in piezoelectric magnetostrictive systems. Here we report a self-assembling strategy to synthesize nanoscaled free-standing magnetoelectric heteropillars. The degree of clamping from the substrate has been greatly reduced, which is manifested by enhanced piezoelectricity and isotropic magnetic behaviors. A combination of techniques such as transmission electron microscopy, Raman spectroscopy and X-ray diffraction provide additional evidence of stress release in the as-prepared nanocomposite. Moreover, as a benefit of this unconstrained structure, we are able to observe a large magnetic-field-induced polarization change of up to 11.5% at room temperature, demonstrating its potential application in future magnetoelectronic devices at the nanoscale. PMID- 23812089 TI - Experimentally induced deep cervical muscle pain distorts head on trunk orientation. AB - PURPOSE: We wanted to explore the specific proprioceptive effect of cervical pain on sensorimotor control. Sensorimotor control comprises proprioceptive feedback, central integration and subsequent muscular response. Pain might be one cause of previously reported disturbances in joint kinematics, head on trunk orientation and postural control. However, the causal relationship between the impact of cervical pain on proprioception and thus on sensorimotor control has to be established. METHODS: Eleven healthy subjects were examined in their ability to reproduce two different head on trunk targets, neutral head position (NHP) and 30 degrees target position, with a 3D motion analyser before, directly after and 15 min after experimentally induced neck pain. Pain was induced by hypertonic saline infusion at C2/3 level in the splenius capitis muscle on one side (referred to as "injected side"). RESULTS: All subjects experienced temporary pain and the head repositioning error increased significantly during head repositioning to the 30 degrees target to the injected side (p = 0.011). A post hoc analysis showed that pain interfered with proprioception to the injected side during acute pain (p < 0.001), but also when the pain had waned (p = 0.002). Accuracy decreased immediately after pain induction for the 30 degrees target position to the side where pain was induced (3.3 -> 5.3 degrees , p = 0.033), but not to the contralateral side (4.9 -> 4.1 degrees , p = 0.657). There was no significant impact of pain on accuracy for NHP. A sensory mismatch appeared in some subjects, who experienced dizziness. CONCLUSIONS: Acute cervical pain distorts sensorimotor control with side-specific changes, but also has more complex effects that appear when pain has waned. PMID- 23812090 TI - Swimming exercise training-induced left ventricular hypertrophy involves microRNAs and synergistic regulation of the PI3K/AKT/mTOR signaling pathway. AB - PURPOSE: Swimming exercise leads to a nonpathological, physiological left ventricular hypertrophy. However, the potential molecular mechanisms are unknown. We investigated the role of microRNAs (miRNA) regulating the cardiac signal cascades were studied in exercised rats. METHODS: Female Wistar rats were assigned into two groups: (1) sedentary control (SC), (2) swimming exercise (SE). The rats in the SE group completed a 1-h swimming exercise, 5 times/week/8-week with 5 % body overload. miRNA, phosphoinositide-3-kinase catalytic alpha polypeptide (PIK3alpha), phosphatase and tensin homolog (PTEN) and tuberous sclerosis complex 2 (TSC2) gene expression analysis were performed by real-time PCR in heart muscle. Moreover, we assessed cardiac protein expression of ERK1/2, PI3K/AKT/mTOR, PTEN and TSC2. RESULTS: Cardiac phospho(ser473)-AKT and phospho(Ser2448)-mTOR were, respectively, increased by 46 and 38 % in the SE group when compared with SC group. miRNAs-21, 144, and 145 were, respectively, up regulated in the SE group (152 %, 128, and 101 % relative increases), but miRNA 124 was decreased by 38 %. In SE group, PIK3alpha (targeted by miRNA-124) gene expression increased by 213 %, and Pten (targeted by miRNAs-21 and 144), and TSC2 (targeted by miRNA-145) were, respectively, decreased by 51 and 55 %. In addition, the swimming exercise increased protein levels of PIK3alpha (36 %) and phospho(Thr1462)-TSC2 (48 %), while it decreased PTEN (37 %) and TSC2 (22 %), which induced activation of PI3K/AKT/mTOR signaling pathway. CONCLUSION: These findings are consistent with a model in which exercise may induce left ventricular hypertrophy, at least in part, changing the expression of specific miRNAs targeting the PIK3/AKT/mTOR signaling pathway and its negative regulators. PMID- 23812092 TI - Anti-cyclic citrullinated peptide antibodies do not reflect self-reported disability and physical health in patients with rheumatoid arthritis of less than 5 years of duration. AB - It is well accepted that patients with antibodies against cyclic citrullinated peptides (anti-CCP) and rheumatoid arthritis (RA) suffer from more severe forms of RA in terms of clinical presentation and radiographic destruction at long term compared to anti-CCP-negative patients. The purpose of this cross-sectional study was to investigate whether the measures of self-reported health among patients with RA of <5 years of duration are influenced by anti-CCP status. Additionally, we aimed to determine whether the measures of self-reported health among the two patient groups differ from those of a control group. Telephone interviews were conducted with 464 patients with RA and 637 population controls, who reported educational level, income, smoking habits and lifestyle 10 years before the interview and completed the Health Assessment Questionnaire and the Short-Form Health Survey Questionnaire, version 2 (SF-36v2); 424 (91%) patients submitted a blood sample for analysis. Patients with anti-CCP-positive and anti-CCP-negative RA showed no significant differences in self-reported disability and physical health after adjustment for age, gender, socioeconomic factors, lifestyle and disease-related variables (p > 0.05). Both groups of RA patients reported significantly more physical disabilities in everyday life and significantly poorer physical health than the controls (both p < 0.001). A similar pattern was seen for self-reported mental health (both p < 0.05). Patients with RA of <5 years of duration report significantly more disability and poorer physical health than the general population of Denmark, but these reports were independent of anti-CCP status. PMID- 23812093 TI - Identification of cut-points in commonly used hip osteoarthritis-related outcome measures that define the patient acceptable symptom state (PASS). AB - To determine patient acceptable symptom state (PASS) estimates in outcome measures commonly used in hip osteoarthritis (OA). Identification of cut-points on commonly used outcome measures associated with patient satisfaction with their current state of health. As part of a randomized controlled trial, 70 patients with a clinical diagnosis of hip OA undergoing a 9-session physiotherapy treatment program completed four physical performance measures and three self report measures at 9 weeks and 1 year. Upon completion of treatment, patients assessed their current health status according to the PASS question. Cut-points were estimated using receiver operating characteristic curves (anchor-based method), based on the patient's response to the PASS question. At 9 weeks and 1 year, identified cut-points were, respectively, <=10 and <=11 for the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale; <=35 and <=40 on the WOMAC physical function subscale; >=+5 and >=+6 on the global rating of change score; <=6.05 and <=5.30 s for the timed-up-and-go; <=28.3 and <=24.9 for the 40-m self-paced walk test; >=11 and >=12 repetitions for the 30-s chair stand test; and >=46 repetitions for the 20-cm step test. Initial target cut-points signaling patient satisfaction with their current symptom state following physiotherapy in patients with hip osteoarthritis were determined for seven outcome measures over 1 year. PMID- 23812094 TI - Weight maintenance and additional weight loss with liraglutide after low-calorie diet-induced weight loss: the SCALE Maintenance randomized study. AB - OBJECTIVE: Liraglutide, a once-daily human glucagon-like peptide-1 analog, induced clinically meaningful weight loss in a phase 2 study in obese individuals without diabetes. The present randomized phase 3 trial assessed the efficacy of liraglutide in maintaining weight loss achieved with a low-calorie diet (LCD). METHODS: Obese/overweight participants (>=18 years, body mass index >=30 kg m(-2) or >=27 kg m(-2) with comorbidities) who lost >=5% of initial weight during a LCD run-in were randomly assigned to liraglutide 3.0 mg per day or placebo (subcutaneous administration) for 56 weeks. Diet and exercise counseling were provided throughout the trial. Co-primary end points were percentage weight change from randomization, the proportion of participants that maintained the initial >=5% weight loss, and the proportion that lost >=5% of randomization weight (intention-to-treat analysis). ClinicalTrials.gov identifier: NCT00781937. RESULTS: Participants (n=422) lost a mean 6.0% (s.d. 0.9) of screening weight during run-in. From randomization to week 56, weight decreased an additional mean 6.2% (s.d. 7.3) with liraglutide and 0.2% (s.d. 7.0) with placebo (estimated difference -6.1% (95% class intervals -7.5 to -4.6), P<0.0001). More participants receiving liraglutide (81.4%) maintained the >=5% run-in weight loss, compared with those receiving placebo (48.9%) (estimated odds ratio 4.8 (3.0; 7.7), P<0.0001), and 50.5% versus 21.8% of participants lost >=5% of randomization weight (estimated odds ratio 3.9 (2.4; 6.1), P<0.0001). Liraglutide produced small but statistically significant improvements in several cardiometabolic risk factors compared with placebo. Gastrointestinal (GI) disorders were reported more frequently with liraglutide than placebo, but most events were transient, and mild or moderate in severity. CONCLUSION: Liraglutide, with diet and exercise, maintained weight loss achieved by caloric restriction and induced further weight loss over 56 weeks. Improvements in some cardiovascular disease-risk factors were also observed. Liraglutide, prescribed as 3.0 mg per day, holds promise for improving the maintenance of lost weight. PMID- 23812095 TI - Transcription factor EBF1 is essential for the maintenance of B cell identity and prevention of alternative fates in committed cells. AB - The transcription factors EBF1 and Pax5 have been linked to activation of the B cell lineage program and irreversible loss of alternative lineage potential (commitment), respectively. Here we conditionally deleted Ebf1 in committed pro-B cells after transfer into alymphoid mice. We found that those cells converted into innate lymphoid cells (ILCs) and T cells with variable-diversity-joining (VDJ) rearrangements of loci encoding both B cell and T cell antigen receptors. As intermediates in lineage conversion, Ebf1-deficient CD19(+) cells expressing Pax5 and transcriptional regulators of the ILC and T cell fates were detectable. In particular, genes encoding the transcription factors Id2 and TCF-1 were bound and repressed by EBF1. Thus, both EBF1 and Pax5 are required for B lineage commitment by repressing distinct and common determinants of alternative cell fates. PMID- 23812096 TI - Origin of monocytes and macrophages in a committed progenitor. AB - Monocytes, macrophages and dendritic cells (DCs) are developmentally related regulators of the immune system that share the monocyte-macrophage DC progenitor (MDP) as a common precursor. Unlike differentiation into DCs, the distal pathways for differentiation into monocytes and monocyte-derived macrophages are not fully elucidated. We have now demonstrated the existence of a clonogenic, monocyte- and macrophage-restricted progenitor cell derived from the MDP. This progenitor was a Ly6C(+) proliferating cell present in the bone marrow and spleen that generated the major monocyte subsets and macrophages, but not DCs or neutrophils. By in depth quantitative proteomics, we characterized changes in the proteome during monocyte differentiation, which provided insight into the molecular principles of developing monocytes, such as their functional maturation. Thus, we found that monocytes and macrophages were renewed independently of DCs from a committed progenitor. PMID- 23812097 TI - MicroRNAs of the miR-17~92 family are critical regulators of T(FH) differentiation. AB - Follicular helper T cells (T(FH) cells) provide critical help to B cells during humoral immune responses. Here we report that mice with T cell-specific deletion of the miR-17~92 family of microRNAs (miRNAs) had substantially compromised T(FH) differentiation, germinal-center formation and antibody responses and failed to control chronic viral infection. Conversely, mice with T cell-specific expression of a transgene encoding miR-17~92 spontaneously accumulated T(FH) cells and developed a fatal immunopathology. Mechanistically, the miR-17~92 family controlled the migration of CD4(+) T cells into B cell follicles by regulating signaling intensity from the inducible costimulator ICOS and kinase PI(3)K by suppressing expression of the phosphatase PHLPP2. Our findings demonstrate an essential role for the miR-17~92 family in T(FH) differentiation and establish PHLPP2 as an important mediator of their function in this process. PMID- 23812100 TI - A flexible, bolaamphiphilic template for mesoporous silicas. AB - A novel symmetrical bolaamphiphile, containing two N-methylimidazolium head groups bridged by a 32-methylene linker, was synthesized and characterized. A variety of mesoporous silicas was prepared using the bolaamphiphile as a "soft template". The effects of absolute surfactant concentration and synthesis conditions upon the morphologies of these silicas were investigated. For a given surfactant concentration, particle morphology; pore size; and pore ordering were modified through control of the template to silica-precursor ratio and synthesis conditions. Observed morphologies included: lenticular core-shell nanoparticles and decorticated globules, truncated hexagonal plates, and sheets. In all cases the mesopores are aligned along the shortest axis of the nanomaterial. Decorticated materials displayed surface areas of up to 1200 m(2) g(-1) and pore diameters (D(BJH)) of 24-28 A. Small-angle X-ray diffraction and transmission electron microscopy measurements revealed that the majority of the materials has elliptical pores arranged in rectangular lattices (c2mm). Adoption of this symmetry group is a result of the template aggregate deformation from a regular hexagonal phase of cylindrical rods to a ribbon phase under the synthetic conditions. PMID- 23812098 TI - The microRNA cluster miR-17~92 promotes TFH cell differentiation and represses subset-inappropriate gene expression. AB - Follicular helper T cells (TFH cells) are the prototypic helper T cell subset specialized to enable B cells to form germinal centers (GCs) and produce high affinity antibodies. We found that expression of microRNAs (miRNAs) by T cells was essential for TFH cell differentiation. More specifically, we show that after immunization of mice with protein, the miRNA cluster miR-17~92 was critical for robust differentiation and function of TFH cells in a cell-intrinsic manner that occurred regardless of changes in proliferation. In a viral infection model, miR 17~92 restrained the expression of genes 'inappropriate' to the TFH cell subset, including the direct miR-17~92 target Rora. Removal of one Rora allele partially 'rescued' the inappropriate gene signature in miR-17~92-deficient TFH cells. Our results identify the miR-17~92 cluster as a critical regulator of T cell dependent antibody responses, TFH cell differentiation and the fidelity of the TFH cell gene-expression program. PMID- 23812099 TI - CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. AB - Particulate ligands, including cholesterol crystals and amyloid fibrils, induce production of interleukin 1beta (IL-1beta) dependent on the cytoplasmic sensor NLRP3 in atherosclerosis, Alzheimer's disease and diabetes. Soluble endogenous ligands, including oxidized low-density lipoprotein (LDL), amyloid-beta and amylin peptides, accumulate in such diseases. Here we identify an endocytic pathway mediated by the pattern-recognition receptor CD36 that coordinated the intracellular conversion of those soluble ligands into crystals or fibrils, which resulted in lysosomal disruption and activation of the NLRP3 inflammasome. Consequently, macrophages that lacked CD36 failed to elicit IL-1beta production in response to those ligands, and targeting CD36 in atherosclerotic mice resulted in lower serum concentrations of IL-1beta and accumulation of cholesterol crystals in plaques. Collectively, our findings highlight the importance of CD36 in the accrual and nucleation of NLRP3 ligands from within the macrophage and position CD36 as a central regulator of inflammasome activation in sterile inflammation. PMID- 23812101 TI - Factors related to tooth loss among community-dwelling middle-aged and elderly Japanese men. AB - BACKGROUND: Using data from a large-scale community-based Japanese population, we attempted to identify factors associated with tooth loss in middle-aged and elderly men. METHODS: A total of 8352 men aged 40 to 79 years who lived in the north of the main island of Japan and underwent health checkups were enrolled between 2002 and 2005. Number of teeth was assessed by the question, "How many teeth do you have (0, 1-9, 10-19, or >=20)?". On the basis of the answer to this question, participants were classified into 2 groups (<=19 teeth or >=20 teeth). Using multivariate logistic regression, factors related to having 19 or fewer teeth were estimated. RESULTS: The numbers (percentages) of participants who had 0, 1 to 9, 10 to 19, and 20 or more teeth were 1764 (21.1%), 1779 (21.3%), 1836 (22.0%), and 2973 (35.6%), respectively. Among the participants overall and those aged 65 to 79 years, having 19 or fewer teeth was significantly associated with older age, smoking status (current smoking and ex-smoking), and low education level. In addition, men with 19 or fewer teeth were more likely to have a low body mass index and low serum albumin level and less likely to be current alcohol drinkers. Among men aged 40 to 64 years, but not men aged 65 to 79 years, those with 19 or fewer teeth were more likely to have a low serum high-density lipoprotein cholesterol level and high glycosylated hemoglobin (HbA1c) level. CONCLUSIONS: Smoking, low education level, and poor nutritional status were associated with tooth loss among middle-aged and elderly Japanese men. PMID- 23812102 TI - Intake of soy products and other foods and gastric cancer risk: a prospective study. AB - BACKGROUND: Gastric cancer, the most common cancer in the world, is affected by some foods or food groups. We examined the relationship between dietary intake and stomach cancer risk in the Korean Multi-Center Cancer Cohort (KMCC). METHODS: The KMCC included 19 688 Korean men and women who were enrolled from 1993 to 2004. Of those subjects, 9724 completed a brief 14-food frequency questionnaire at baseline. Through record linkage with the Korean Central Cancer Registry and National Death Certificate databases, we documented 166 gastric cancer cases as of December 31, 2008. Cox proportional hazard models were used to estimate relative risks (RRs) and 95% CIs. RESULTS: Frequent intake of soybean/tofu was significantly associated with reduced risk of gastric cancer, after adjustment for age, sex, cigarette smoking, body mass index, alcohol consumption, and area of residence (P for trend = 0.036). We found a significant inverse association between soybean/tofu intake and gastric cancer risk among women (RR = 0.41, 95% CI: 0.22-0.78). Men with a high soybean/tofu intake had a lower risk of gastric cancer, but the reduction was not statistically significant (RR = 0.77, 95% CI: 0.52-1.13). There was no interaction between soybean/tofu intake and cigarette smoking in relation to gastric cancer risk (P for interaction = 0.268). CONCLUSIONS: Frequent soybean/tofu intake was associated with lower risk of gastric cancer. PMID- 23812103 TI - Effect of age on the association between waist-to-height ratio and incidence of cardiovascular disease: the Suita study. AB - BACKGROUND: Waist-to-height ratio (WHtR) has been shown to be a useful screening tool for metabolic syndrome and cardiovascular disease (CVD). We investigated the association of WHtR with CVD incidence by age group. METHODS: We conducted a 13.0 year cohort study of Japanese adults (2600 men and 2888 women) with no history of CVD. WHtR was calculated as waist circumference (cm) (WC) divided by height (cm). We stratified participants by sex and age group (30-49, 50-69, >=70 years). Using the Cox proportional hazards model, we calculated hazard ratios (HRs) and 95% CIs for CVD in relation to WHtR quartile for participants aged 50 to 69 years and 70 years or older. RESULTS: Men aged 50 to 69 years in the highest quartile had significantly increased risks of CVD and coronary heart disease as compared with the lowest quartile; the HRs (95% CI) were 1.82 (1.13-2.92) and 2.42 (1.15-5.12), respectively. Women aged 50 to 69 years in the highest quartile had a significantly increased risk of stroke (HR, 2.43; 95% CI, 1.01-5.85). No significant results were observed in men or women aged 70 years or older. The likelihood ratio test showed that the predictive value of WHtR was greater than that of WC among men aged 50 to 69 years. CONCLUSIONS: The association between WHtR and CVD risk differed among age groups. WHtR was useful in identifying middle-aged Japanese at higher risk of CVD and was a better predictor than WC of CVD, especially in men. PMID- 23812104 TI - Expression analysis of the impact of culture filtrates from the biocontrol agent, Phlebiopsis gigantea on the conifer pathogen, Heterobasidion annosum s.s. Transcriptome. AB - Phlebiopsis gigantea has been routinely used as the biological control agent for the conifer pathogen Heterobasidion annosum sensu lato, but the actual mechanism for the biocontrol process is not known. To investigate the effect of secreted molecules from culture filtrate produced by P. gigantea on the gene expression profile of H. annosum s.s., microarray analysis was used. Analysis of the differentially expressed genes led to the identification of genes with diverse functions. A major proportion of the up- and downregulated genes were either uncharacterized or genes whose functions were not known. A number of genes coding for proteins involved in metabolism, transport, and signal transduction were differentially downregulated; comparatively lower number of such genes were upregulated. Some genes involved in transport (polyamine transporters, 2573-fold, P = 0.002) and metabolism (endoglucanase, 622.5-fold, P = 0.002, cytochrome P450, 133.2-fold, P = 0.05) showed high transcript fold changes and were statistically significantly upregulated. Genes encoding defense-related proteins such as hydrophobins were either downregulated or expressed at relatively low levels. Further analysis of the effect of the culture filtrate on glucose metabolism showed downregulation of some key enzymes at the early stage of the glycolytic pathway while some genes were upregulated at the later stage of the pathway. A subset of the genes were selected and used to validate the micro-array result by quantitative real time polymerase chain reaction (qPCR) method. Generally, the high transcript levels of genes encoding several biochemically important genes (protein kinases, major facilitator superfamily polyamine transporters, endoglucanase, cytochrome P450, endoglucanase) suggests their potential functional relevance in signal perception, stress tolerance, cell defenses, and detoxification of toxic molecules during competitive interaction. These results have provided further insights into possible molecular and genetic factors underlying the response of H. annosum to metabolites from P. gigantea during interspecific interaction. PMID- 23812105 TI - Stability of bacterial composition and activity in different salinity waters in the dynamic Patos Lagoon estuary: evidence from a lagrangian-like approach. AB - We employed a Lagrangian-like sampling design to evaluate bacterial community composition (BCC--using temporal temperature gel gradient electrophoresis), community-level physiological profiles (CLPP--using the EcoPlateTM assay), and influencing factors in different salinity waters in the highly dynamic Patos Lagoon estuary (southern Brazil) and adjacent coastal zone. Samples were collected monthly by following limnetic-oligohaline (0-1), mesohaline (14-16), and polyhaline (28-31) waters for 1 year. The BCC was specific for each salinity range, whereas the CLPPs were similar for mesohaline and polyhaline waters, and both were different from the limnetic-oligohaline samples. The limnetic oligohaline waters displayed an oxidation capacity for almost all organic substrates tested, whereas the mesohaline and polyhaline waters presented lower numbers of oxidized substrates, suggesting that potential activities of bacteria increased from the polyhaline to oligohaline waters. However, the polyhaline samples showed a higher utilization of some simple carbohydrates, amino acids, and polymers, indicating a shortage of inorganic nutrients (especially nitrogen) and organic substrates in coastal saltwater. The hypothesis of bacterial nitrogen limitation was corroborated by the higher Nuse index (an EcoPlateTM-based nitrogen limitation indicator) in the polyhaline waters and the importance of NO(2)(-), NO(3)(-), low-molecular-weight substances, and the low-molecular weight:high-molecular-weight substances ratio, indicated by the canonical correspondence analyses (CCAs). Our results demonstrate the important stability of microbial community composition and potential metabolic activity in the different water salinity ranges, which are independent of the region and time of the year of sample collection in the estuary. This is a quite unexpected result for a dynamic environment such as the Patos Lagoon estuary. PMID- 23812106 TI - Quantum-state transfer from an ion to a photon. AB - One model for quantum networks1,2 is based on the probabilistic measurement of two photons, each entangled with a distant node, e.g., an atom or atomic ensemble3-7. A second, deterministic model transfers information directly from an atom onto a cavity photon, which carries it to a second node8, as recently demonstrated with neutral atoms9. In both cases, the challenge is to transfer information efficiently while preserving coherence. Here, following the second scheme, we map the quantum state of an ion onto a photon within an optical cavity. Using an ion enables deterministic state initialization10,11, while the cavity provides coherent coupling to a well-defined output mode12-15. Although it is often assumed that a cavity-based quantum interface requires the strong coupling regime, we show transfer fidelities of 92% in the presence of non negligible decoherence and characterize the interplay between fidelity and efficiency. Our time-independent mapping process offers a promising route toward ion-based quantum networks. PMID- 23812107 TI - Ankle sprains: combination of manual therapy and supervised exercise leads to better recovery. AB - Ankle sprains often occur when running, walking on uneven ground, or jumping. Usually, people are told to rest, elevate the foot, apply ice, and use an elastic wrap to reduce swelling. This treatment is typically followed by exercises that can be performed at home. Although the pain and swelling usually improve quickly, more than 70% of people who sprain their ankles continue to have problems with them and up to 80% will sprain their ankles again. This suggests that it is important to better care for ankle sprains. One option is manual therapy, where the therapist moves the ankle and surrounding joints to help restore normal joint movement. A research report published in the July 2013 issue of JOSPT examines and compares the outcomes of a home exercise program with a more involved treatment program that includes manual therapy and supervised exercises. PMID- 23812108 TI - Preference for different inorganic nitrogen forms among plant functional types and species of the Patagonian steppe. AB - We have explored species-specific preferences for nitrate (NO3(-)) and ammonium (NH4(+)) as an alternative niche separation in ecosystems where nitrogen (N) is present mostly in inorganic forms. The Patagonian steppe is dominated by shrubs and grasses. Shrubs absorb water and nutrients from deep soil layers, which are poor in N, while grasses have the opposite pattern, absorbing most of their water and nutrients from the upper layers of the soil. We hypothesized that the preferences of shrub and grass for inorganic N forms are different and that the rate of potential N uptake is greater in shrubs than in grasses. To test this hypothesis, we grew individuals of six dominant species in solutions of different NH4(+):NO3(-) concentration ratios. Nitrate uptake was found to be higher in shrubs, while ammonium uptake was similar between plant functional types. The NH4(+):NO3(-) uptake ratio was significantly lower for shrubs than grasses. Shrubs, which under field conditions have deeper rooting systems than grasses, showed a higher N absorption capacity than grasses and a preference for the more mobile N form, nitrate. Grasses, which had lower N uptake rates than shrubs, preferred ammonium over nitrate. These complementary patterns between grasses and shrubs suggest a more thorough exploitation of resources by diverse ecosystems than those dominated by just one functional type. The loss of one plant functional group or a significant change in its abundance would therefore represent a reduction in resource use efficiency and ecosystem functioning. PMID- 23812109 TI - Mechanisms driving the density-area relationship in a saproxylic beetle. AB - Mechanisms underlying density-area relationships (correlations between population density and patch size) have rarely been tested experimentally. It is often assumed that higher density on large patches is evidence that large patches are high quality (i.e. have greater survival and reproduction), but the same pattern could result from disproportionate movement from small to large patches. Movement based and within-patch processes must be experimentally separated to show that large patches are indeed of higher quality, but few studies have done so. We experimentally tested movement-based and within-patch hypotheses to explain the positive density-area relationship observed for a saproxylic (decayed wood dependent) beetle, Odontotaenius disjunctus Illiger (Coleoptera: Passalidae). In separate experiments we quantified (1) immigration into and (2) finite growth rate within logs (=patches) that varied in size and density of conspecific beetles. A log was 11.7-fold [95 % confidence interval (CI) 3.4-40.8) and 10.5 fold (95 % CI 2.7-40.9) more likely to contain a new immigrant if it was large or contained a conspecific pair of beetles, respectively. Neither log size nor conspecific density was associated with changes in finite growth rate that would lead to higher density: decreased log size and increased conspecific density reduced finite growth rate in direct proportion to the loss in available resources per mating pair. We conclude that movement behavior rather than habitat quality is responsible for the positive density-area relationship for O. disjunctus. An important implication of our results is that population density is an imperfect indicator of habitat quality. PMID- 23812110 TI - Evaluating delta(15)N-body size relationships across taxonomic levels using hierarchical models. AB - Ecologists routinely set out to estimate the trophic position of individuals, populations, and species composing food webs, and nitrogen stable isotopes (delta(15)N) are a widely used proxy for trophic position. Although delta(15)N values are often sampled at the level of individuals, estimates and confidence intervals are frequently sought for aggregations of individuals. If individual delta(15)N values are correlated as an artifact of sampling design (e.g., clustering of samples in space or time) or due to intrinsic groupings (e.g., life history stages, social groups, taxonomy), such estimates may be biased and exhibit overly optimistic confidence intervals. However, these issues can be accommodated using hierarchical modeling methods. Here, we demonstrate how hierarchical models offer an additional quantitative tool for investigating delta(15)N variability and we explicitly evaluate how delta(15)N varies with body size at successively higher levels of taxonomic aggregation in a diverse fish assemblage. The models take advantage of all available data, better account for uncertainty in parameters estimates, may improve inferences on coefficients corresponding to groups with small to moderate sample sizes, and partition variation across model levels, which provides convenient summaries of the 'importance' of each level in terms of unexplained heterogeneity in the data. These methods can easily be applied to diet-based studies of trophic position. Although hierarchical models are well-understood and established tools, their benefits have yet to be fully reaped by stable isotope and food web ecologists. We suggest that hierarchical models can provide a robust framework for conceptualizing and statistically modeling trophic position at multiple levels of aggregation. PMID- 23812111 TI - Successful correction of D-lactic acid neurotoxicity (drunken lamb syndrome) by bolus administration of oral sodium bicarbonate. AB - Drunken lamb syndrome (DLS) has recently been described as lamb D-lactic acidosis syndrome (LDLAS). In 2012, 18 lambs aged between 7 days and 28 days with LDLAS were identified. Biochemically, each lamb had a metabolic acidosis characterised by D-lactic acidosis and exhibited clinical signs including: not hyperthermic, no evidence of dehydration, demonstrating an ataxic gait tending to recumbency (DLS) and possibly somnolence. These lambs received 50 mmol of sodium bicarbonate as an 8.4 per cent solution given orally, together with parenteral long-acting amoxicillin. All 18 cases made a full clinical recovery. This study demonstrates a novel effective treatment for a disease that is usually fatal, and also demonstrates a strong correlation between venous plasma bicarbonate concentrations and venous plasma D-lactate concentrations (R(2)=0.49). PMID- 23812112 TI - Age and season affect serum testosterone concentrations in cryptorchid stallions. PMID- 23812113 TI - Retrospective analysis of 102 cases of solid pseudopapillary neoplasm of the pancreas in China. AB - OBJECTIVE: Clinicopathological features and surgical outcomes in patients with solid pseudopapillary neoplasm (SPN) of the pancreas were analysed. METHODS: Data regarding clinicopathological features, surgery and outcome for patients with SPN were retrospectively collected and analysed. Patients were followed-up by telephone interview. RESULTS: The study included 102 patients (89 females/13 males), 99 of whom underwent surgical resection. A total of 89 patients (87.3%) were followed-up (mean duration 26.98 months, range 2-95 months); 86 (96.6%) had no relapse or metastasis. CONCLUSIONS: Surgical resection is the primary therapy for SPN, and results in a good prognosis. PMID- 23812114 TI - Comparative study of pregnancy outcomes between day 3 embryo transfer and day 5 blastocyst transfer in patients with progesterone elevation. AB - OBJECTIVE: To explore the effects of progesterone (P) elevation on pregnancy outcomes of day 3 embryo and day 5 blastocyst transfer. METHODS: Clinical outcomes (pregnancy and ectopic pregnancy rates) following day 3 embryo and day 5 blastocyst transfer cycles were retrospectively analysed. Day 3 embryo and day 5 blastocyst transfer cycles were divided into normal P level (P <= 1.5 ng/ml) and P elevation group (P > 1.5 ng/ml), based on the serum P level on the day of human chorionic gonadotropin (hCG) administration. RESULTS: A total of 2868 cycles were analysed. In day 3 embryo transfer cycles (n = 2345), the clinical pregnancy rate was significantly higher in the normal P level group compared with the P elevation group (55.4% versus 46.7%, respectively) and the ectopic pregnancy rate was significantly lower in the normal P level group compared with the P elevation group (2.8% versus 7.9%, respectively). In day 5 blastocyst transfer cycles (n = 523), there were no significant differences in the clinical pregnancy and ectopic pregnancy rates between the two groups, based on the P level. CONCLUSION: These preliminary findings suggest that day 5 blastocyst transfer should be adopted for patients with P elevation on the day of hCG administration. PMID- 23812115 TI - Dissipation and residue of spinosad in zucchini under field conditions. AB - The dissipation and residue of the insecticide spinosad in zucchini were investigated. An ultra-performance liquid chromatography-tandem mass spectrometry analytical method was developed for spinosad analysis. The half-lives of spinosad were 3.5-3.9 days in zucchini and 3.6-4.1 days in soil. The results showed that the dissipation rate of spinosad was fast, and it is suggested that a combination of rapid growth of zucchini, photodecomposition and the activity of soil microorganisms affected the dissipation rate of spinosad. The terminal residues of spinosad in zucchini were all below the quantification limit. No residue limit currently exists for spinosad in zucchini in China and other countries. Thus, the results can be useful in establishing a maximum residue limit. PMID- 23812116 TI - Thirty years on: the past is our future. PMID- 23812117 TI - Expert witness reflections. PMID- 23812118 TI - Liability of the police for the medical protection of persons in custody. AB - The following is a transcript of a talk relating to aspects of the medical protection given to those in custody by the domestic legislation, by the common law and by the European Convention on Human Rights. So far as domestic legislation is concerned, consideration is given to the provisions of the Prison Act 1962 as amended by the Offender Management Act 2007, and the Prison Rules. The protection afforded at common law is considered by reference to some of the leading cases including Leigh v Gladstone (1909) TLR 139, Secretary of State for the Home Office v Robb [1995] 1 All ER 677 and Brooks v Home Office [1999] 2 FLR 33. The question of whether a lower standard of care in law is to be applied to those in custody compared with that applied to those who are not in custody is addressed. Cases involving suicide in prison and liability for negligent release from custody are discussed. The extent to which there may be liability for breaching a patient's confidence is considered. Lastly the talk touches upon the circumstances in which the authorities might be liable for breaches of Articles 2 and 3 of the European Convention on Human Rights by reference to the ECtHR decision in Tarariyeva v Russia [2009] 48 EHRR 26. PMID- 23812119 TI - The ethics of paediatric trials: questions of procedure and of substance. AB - One of the more frequently debated questions about the ethics of research with children is that of informed consent. This raises a twofold problem: the legally valid consent given by the person or persons exercising parental authority, and the consent of the minor when he or she has adequate decision-making capacity. Another ethically important issue is the weighing of risks and benefits. Any assessment of the benefits will embrace the controversial problem of balancing the direct benefits to the individual and the social benefits to other children in similar medical circumstances deriving from increased knowledge. The highly significant questions of risk and of the advancement of knowledge are often - perhaps too emphatically - taken together with that of consent, as though the existence of legally valid consent and, where possible, the assent of the minor were sufficient to justify exposing a child to serious or probable risks. PMID- 23812120 TI - The whistleblower. PMID- 23812121 TI - A rare case of large organized thrombus of the tricuspid valve in a normal heart. AB - Thrombosis of the tricuspid valve is a very rare cardiac pathological condition, characterized by the location and formation of thrombus near the valve edges. Clinically it can be very easy to mistake it for a myxoma or an infective endocarditis. The aetiology of this condition is an alteration of coagulation, deep venous thrombosis, cardiac structural anomalies or idiopathic forms of hearts that appear structurally normal. From a clinical point of view, the thrombosis of the tricuspid, if it is not totally occlusive, causes the development of symptoms related to the reduced flow and to cardiac congestion: easy fatigue, distension of jugular veins, hepatomegaly and pulmonary congestion with dyspnoea and haemoptysis. The case we studied is of an unexpected death in a subject whose preliminary case history did not show any cardiovascular or pulmonary pathology. It was caused by a thrombosis in the tricuspid valve, originating from a deep venous thrombosis of right iliofemoral axis. In conclusion this case highlights the importance of defining precise anatomical abnormalities in forensic pathological cases. PMID- 23812122 TI - Liability for failure to warn of a risk that does not materialize? AB - Doctors in the UK may be reconciled to the fact that they can be held liable for failing to warn patients about complications associated with procedures. They nevertheless might reasonably assume that their liability will be confined to situations where there has been a failure to warn about an inherent complication that subsequently occurred. It might therefore also be assumed that, where a doctor has properly warned the patient about the risk of the complication, the patient cannot seek to recover but this short paper describes several overseas cases where doctors have been held liable in these situations and postulates why courts in the UK may be attracted to this extension of liability. PMID- 23812123 TI - The ethical dilemmas associated with working in an immigration removal centre. AB - The purpose of this paper is to share with colleagues some of the ethical problems encountered in working in an environment unfamiliar to the vast majority of psychiatrists. The author, a consultant psychiatrist with 17 plus years' experience in the NHS, spent a year working part-time in Colnbrook Immigration Removal Centre; an institution holding just over 300 men who are held in administrative detention for periods of time ranging from days to years pending decisions on their immigration status. About 50% of these men have criminal records and the turnover of detainees is fast and unpredictable. The paper describes some of the everyday ethical problems encountered by the author together with some background to the working environment and attempts to tease out some of the key pillars upon which the doctor's work is based in order to inform the limitations and challenges she/he faces. PMID- 23812124 TI - New rules to control compensation claims: which will cut off access to lawyers for many. PMID- 23812125 TI - Prevention is better than cure - reflections of a long-practising GP. PMID- 23812126 TI - Winter weather and disease. PMID- 23812128 TI - Photo-illuminated diamond as a solid-state source of solvated electrons in water for nitrogen reduction. AB - The photocatalytic reduction of N2 to NH3 is typically hampered by poor binding of N2 to catalytic materials and by the very high energy of the intermediates involved in this reaction. Solvated electrons directly introduced into the reactant solution can provide an alternative pathway to overcome such limitations. Here we demonstrate that illuminated hydrogen-terminated diamond yields facile electron emission into water, thus inducing reduction of N2 to NH3 at ambient temperature and pressure. Transient absorption measurements at 632 nm reveal the presence of solvated electrons adjacent to the diamond after photoexcitation. Experiments using inexpensive synthetic diamond samples and diamond powder show that photocatalytic activity is strongly dependent on the surface termination and correlates with the production of solvated electrons. The use of diamond to eject electrons into a reactant liquid represents a new paradigm for photocatalytic reduction, bringing electrons directly to reactants without requiring molecular adsorption to the surface. PMID- 23812129 TI - Electron-pinned defect-dipoles for high-performance colossal permittivity materials. AB - The immense potential of colossal permittivity (CP) materials for use in modern microelectronics as well as for high-energy-density storage applications has propelled much recent research and development. Despite the discovery of several new classes of CP materials, the development of such materials with the required high performance is still a highly challenging task. Here, we propose a new electron-pinned, defect-dipole route to ideal CP behaviour, where hopping electrons are localized by designated lattice defect states to generate giant defect-dipoles and result in high-performance CP materials. We present a concrete example, (Nb+In) co-doped TiO2 rutile, that exhibits a largely temperature- and frequency-independent colossal permittivity (> 10(4)) as well as a low dielectric loss (mostly < 0.05) over a very broad temperature range from 80 to 450 K. A systematic defect analysis coupled with density functional theory modelling suggests that 'triangular' In2(3+)Vo(**)Ti(3+) and 'diamond' shaped Nb2(5+)Ti(3+)A(Ti) (A = Ti(3+)/In(3+)/Ti(4+)) defect complexes are strongly correlated, giving rise to large defect-dipole clusters containing highly localized electrons that are together responsible for the excellent CP properties observed in co-doped TiO2. This combined experimental and theoretical work opens up a promising feasible route to the systematic development of new high performance CP materials via defect engineering. PMID- 23812130 TI - Photocatalysis: a source of energetic electrons. PMID- 23812131 TI - Hyperactivity and the psychological burden of Perthes disease: a case-control study. AB - BACKGROUND: Legg-Calve-Perthes Disease (LCPD) is a childhood precursor to hip osteoarthritis, for which the etiology is unknown. There is a widespread belief that affected individuals are "hyperactive," propagating a theory that such children may have sustained an epiphyseal injury that precipitated the onset of LCPD. This study seeks to quantify the association with hyperactivity, and the wider psychological burden of the disease. METHODS: A case-control study was conducted among 146 cases of LCPD and 142 hospital controls, frequency matched by age and sex. Psychological domains were measured using the Strength and Difficulties Questionnaire. Adjustment was made for age, sex, and socioeconomic deprivation. Results were stratified by the time elapsed since LCPD was diagnosed. RESULTS: Significant associations (P<0.05) existed with the majority of the psychological domains captured by the Strength and Difficulties Questionnaire [odds ratio (OR) for "high" level of difficulties-Emotion OR 3.2, Conduct OR 2.1, Inattention-Hyperactivity OR 2.7, Prosocial Behavior OR 1.9]. Hyperactivity was especially marked among individuals within 2 years of diagnosis (OR 8.6; P<0.001), but not so among individuals over 4 years from diagnosis. Emotional symptoms persisted long after resolution of the active phase of disease. CONCLUSIONS: There was a marked psychological burden among individuals with LCPD, which was most marked amongst individuals with a recent diagnosis. The breadth and inferred temporality of these disturbances may be a function of the disease process, through restriction of activities and disability, or may be a fundamental disease characteristic related directly to disease or to its etiological determinant. PMID- 23812133 TI - Valgus femoral osteotomy for noncontainable Perthes hips: prognostic factors of remodeling. AB - BACKGROUND: The authors have performed valgus femoral osteotomy (VFO) with rotational and sagittal components for Legg-Calve-Perthes disease hips with hinge abduction. We analyzed skeletally mature patients to determine: (1) whether VFO improved hip function; (2) whether favorable radiographic remodeling of the hip occurred; and (3) whether any clinical or radiographic factors were associated with remodeling of femoral head deformity. METHODS: Thirty-one patients (31 hips, 25 boys and 6 girls) who underwent VFO between 1986 and 2007, and subsequently followed until skeletal maturity constituted the study cohort. The mean age at surgery was 9.4 years (range, 3.5 to 15 y) and the mean age at the most recent follow-up was 20.2 years (range, 14.6 to 28.3 y). Clinical outcomes were evaluated using Iowa Hip Scores and ranges of hip motion. Radiographic outcomes were assessed with respect to the radiographic indices for femoral head deformity and subluxation. Clinical and radiographic parameters were analyzed to find correlations with the femoral head remodeling (preoperative to final follow-up changes in deformity index). RESULTS: Iowa Hip Score improved from 71 (30 to 91) to 92 (76 to 100). Ranges of hip abduction, internal rotation, and external rotation increased. At last follow-up evaluations, mean Mose sphericity index of the femoral head was 4.2 mm (range, 0 to 13 mm) and femoral heads had 4 Stulberg type II, 21 type III, and 6 type IV deformity. Overall radiographic indices for femoral head deformity and subluxation did not change during follow-up period except decreased medial joint space, but greater amount of preoperative to final follow-up changes in deformity index was associated with younger age (<10 y) and earlier disease stages (fragmentation and early reossification stage) at time of surgery. CONCLUSIONS: VFO modified to accommodate the various hinging patterns of Legg-Calve-Perthes disease hips was found to beneficially improve hip function at skeletal maturity. Although overall radiographic remodeling was not definite, favorable remodeling of the femoral head can be expected when younger patients undergo this procedure at the fragmentation or early reossification stage. PMID- 23812132 TI - Acute compartment syndrome after intramedullary nailing of isolated radius and ulna fractures in children. AB - BACKGROUND: There exist varying reports in the literature regarding the incidence of compartment syndrome (CS) after intramedullary (IM) fixation of pediatric forearm fractures. A retrospective review of the experience with this treatment modality at our institution was performed to elucidate the rate of postoperative CS and identify risk factors for developing this complication. METHODS: In this retrospective case series, we reviewed the charts of all patients treated operatively for isolated radius and ulnar shaft fractures from 2000 to 2009 at our institution and identified 113 patients who underwent IM fixation of both bone forearm fractures. There were 74 closed fractures and 39 open fractures including 31 grade I fractures, 7 grade II fractures, and 1 grade IIIA fracture. If the IM nail could not be passed easily across the fracture site, a small open approach was used to aid reduction. RESULTS: CS occurred in 3 of 113 patients (2.7%). CS occurred in 3 of 39 (7.7%) of the open fractures compared with none of 74 closed fractures (P=0.039), including 45 closed fractures that were treated within 24 hours of injury. An open reduction was performed in all of the open fractures and 38 (51.4%) of the closed fractures. Increased operative time was associated with developing CS postoperatively (168 vs. 77 min, P<0.001). CS occurred within the first 24 postoperative hours in all 3 cases. CONCLUSION: CS was an uncommon complication after IM fixation of pediatric diaphyseal forearm fractures in this retrospective case series. Open fractures and longer operative times were associated with developing CS after surgery. None of 45 patients who underwent IM nailing of closed fractures within 24 hours of injury developed CS; however, 51.4% of these patients required a small open approach to aid reduction and nail passage. We believe that utilizing a small open approach for reduction of one or both bones, thereby avoiding the soft-tissue trauma of multiple attempts to reduce the fracture and pass the nail, leads to decreased soft-tissue trauma and a lower rate of CS. We recommend a low threshold for converting to open reduction in cases where closed reduction is difficult. PMID- 23812134 TI - Operatively treated type IV tibial tubercle apophyseal fractures. AB - BACKGROUND: Displaced tibial tubercle apophyseal fractures in children and adolescents are typically treated with closed reduction or open reduction with anterior to posterior screw fixation. Since the original classification by Watson Jones and Ogden, an important variant with a posterior metaphyseal fracture line (type IV) was later described. However, there has been a lack of information regarding type IV tibial tubercle apophyseal fractures and its implications for surgical fixation. METHODS: Twenty-four type IV tibial tubercle fractures in 23 children and adolescents were reviewed. Operative reports and clinic records were used to identify the patient demographics, fracture type, and clinical results. Available imaging was also used to characterize these fractures. Minimum follow up was 2 years. RESULTS: Type IV fractures accounted for 18.5% (24/130) of all tibial tubercle apophyseal fractures. Three type IV fractures were identified that had an additional epiphyseal split. These were categorized as type IV-B, whereas the rest were considered type IV-A. There were 19 males and 4 females (average age, 14.8 y; range, 11.8 to 16 y). The most common mechanism was an eccentric quadriceps contraction during basketball. Three patients were initially treated with closed reduction and casting and were noted to have loss of reduction. All patients were treated definitively with open reduction and internal fixation or percutaneous screw placement. In addition to AP compression screws, 4 patients required supplemental plate fixation to stabilize the proximal tibia. Major complications included 1 compartment syndrome and 1 large DVT. All fractures healed and there were no growth disturbances. CONCLUSIONS: Type IV tibial tubercle apophyseal fractures are an important variant that requires careful assessment to ensure adequate stabilization of the proximal tibia when surgery is warranted. LEVEL OF EVIDENCE: IV (prognostic case series). PMID- 23812135 TI - Citation classics in pediatric orthopaedics. AB - BACKGROUND: The purpose of this study was to identify the clinical pediatric orthopaedic articles with at least 100 citations published in all orthopaedic journals and to examine their characteristics. METHODS: All journals dedicated to orthopaedics and its subspecialties were selected from the Journal Citation Report 2001 under the subject category "orthopedics." Articles cited 100 times or more were identified using the database of the Science Citation Index Expanded (SCI-EXPANDED, 1900 to present). The articles were ranked in a comprehensive list. Two authors independently reviewed the full text of each article and applied the inclusion and exclusion criteria to the list of articles. The 2 lists were then compared. All disagreements were resolved by consensus with input from the senior author. The final list of pediatric orthopaedic articles was then compiled. RESULTS: There were a total of 49 journals under the search category "orthopedics." Five journals were excluded as they were non-English journals. The remaining 44 journals were screened for articles with at least 100 citations. A total of 135 clinical pediatric orthopaedic articles cited at least 100 times were included. The most cited article was cited 692 times. The mean number of citations per article was 159 (95% confidence interval, 145-173). All the articles were published between 1949 and 2001, with 1980 and 1989 producing the most citation classics (34). The majority (90) originated from the United States, followed by the United Kingdom (12) and Canada (11). Scoliosis/kyphosis was the most common topic with 26 papers. The second most common subject was hip disorders (24). Therapeutic studies were the most common study type (71). Ninety seven papers were assigned a 4 for level of evidence. CONCLUSIONS: The list of citation classics in pediatric orthopaedic articles is useful for several reasons. It identifies important contributions to the field of pediatric orthopaedics and their originators; it facilitates the understanding and discourse of modern pediatric orthopaedic history and reveals trends in pediatric orthopaedics. PMID- 23812136 TI - Does a preoperative bowel preparation reduce bowel morbidity and length of stay after scoliosis surgery? A randomized prospective study. AB - BACKGROUND: Constipation is a common problem after surgery for adolescent idiopathic scoliosis (AIS), with bowel morbidity being reported as high as 78%. The purpose of this study was to determine if a preoperative bowel preparation reduces the incidence of bowel morbidity after surgery for AIS. METHODS: This is an IRB-approved randomized, prospective study of 60 consecutive patients who underwent surgery for AIS. After consent to participate was signed by the patients' family, patients were randomized to either a preoperative bowel preparation (group A) or no bowel preparation (group B). Bowel morbidity data were then collected and compared postoperatively. RESULTS: Complete data were available for 27 patients in group A and 28 in group B. Postoperatively, we found that group A had less weight gain (P<0.09), fewer postoperative bowel medications (P<0.023), and a shorter time to first bowel movement (P<0.03) when compared with group B. Two patients in group B had persistent constipation after discharge, one requiring readmission to the hospital. One patient in group B developed a postoperative wound infection. There were no adverse events in group A postoperatively. CONCLUSIONS: This study did show a modest reduction in some aspects of bowel morbidity when patients had a preoperative bowel preparation before scoliosis surgery. However, these differences did not reach statistical significance. Therefore, we do not recommend routine preoperative bowel preparations for AIS patients. LEVEL OF EVIDENCE: Level II. PMID- 23812137 TI - Effects of the fusionless instrumentation on the disks and facet joints of the unfused segments: a pig model. AB - BACKGROUND: Growing rod (GR) is a state-of-the-art procedure favored when curvatures of the spine cannot be managed nonoperatively in early-onset scoliosis. Although some postulate that multiple distractions and/or relative immobilization of the unfused segments affect the health of disk and facet joint (FJ) and cause degeneration and/or spontaneous fusion, this has not thoroughly been investigated. In this study, changes in the unfused segment after a spine based fusionless instrumentation (SBFI) are investigated and compared with the control (CG) and instrumented fusion (IF) groups. METHODS: A total of 13 piglets, 10 to 14 weeks of age, were used. SBFI and IF were performed on 7 and 3 piglets, respectively, and 3 formed the CG. In SBFI, lengthening procedures of 5 mm were applied once monthly for 3 months, and, after 4 months, all piglets were euthanized. Histologic sections of the unfused disks and FJ were analyzed, and morphometric histologic analysis was performed. RESULTS: On the basis of the Gries criteria, unfused disk median grades were 1, 2, and 4 for control, SBFI, and IF, respectively, that revealed a statistical difference (P<0.001). Unfused FJ median grades were 1 and 2 for control and SBFI, respectively, that revealed a statistical difference (P<0.001). The mean hypertrophic zone (HZ) heights were 69.78, 84.20, and 66.14 MUm; HZ chondrocyte cell widths were 19.03, 18.76, and 17.36 MUm; and HZ chondrocyte cell heights were 15.01, 15.04, and 12.42 MUm in the CG, SBFI, and IF groups, respectively. Statistically, for HZ heights, SBFI was different compared with CG and IF (P<0.001), and, for HZ chondrocyte cell widths and heights, IF was different compared with CG and SBFI (P<0.001). CONCLUSIONS: Morphometric analysis in this study supports the findings that SBFI preserves the growth potential of the spine. Furthermore, changes in the HZ heights show that distractive forces stimulate the apophyseal growth of the axial skeleton describing how the growth rate of the spine in GR might surpass the normal growth rate. Overall, although some degenerative changes are observed, SBFI and repeated distractions alone are not solely responsible for FJ arthrosis and disk degeneration, given that they are structurally preserved. CLINICAL RELEVANCE: GR and regular lengthening procedures do not impair disk health and preserve the growth potential of the spine if it is applied with a meticulous technique. PMID- 23812138 TI - Re: Biomechanical comparison between 2 guided-growth constructs. PMID- 23812139 TI - Hematogenous osteoarticular infections of the hand and the wrist in children with sickle cell anemia: preliminary report. AB - BACKGROUND: Hematogenous osteoarticular infections of the hand and the wrist in children with sickle cell anemia are rare and no specific studies for this location have been published. METHODS: This retrospective and comparative study reviewed 34 children who carry the diagnosis of osteoarticular infections of the wrist and the hand at our institution during a 10-year period extending from January 2000 to December 2010. The first group included 8 patients with sickle cell anemia (Hg SS). The second group or control group included 26 children without sickle cell disease or any immune deficiency. Differences between groups were established by chi tests. RESULTS: The most common site of osteomyelitis for the sickle cell group was the metacarpals and the fingers phalanx (87.5%) whereas the most common site for the control group was the wrist and the carpus (96.2%; P<0.005).The most common pathogens responsible for osteomyelitis was Salmonella sp. (37.5%) for children with SCD, whereas it was Staphylococcus aureus (70%) for the nonsicklers. There was a significant difference between both groups regarding the treatment. Indeed, a surgical procedure was needed for the sickle cell group in all cases (100%) whereas a surgical debridement was needed in only 19.2% patients in the control group (P<0.001). At long-term follow-up, there were more long-term complications in the sickle cell group (62.5%) with epiphysiodesis of the metacarpals and metacarpophalangeal joint destruction whereas only 11.5% cases with complications were present in the control group including distal ulna epiphysiodesis, proximal interphalangeal joint stiffness, and a central radius epiphysiodesis (P<0.004). CONCLUSIONS: Our results confirm the severity of hand osteomyelitis in patients with sickle cell disease. A systematic approach is needed to perform early diagnosis and treatment. Identification of the causative organism is required (blood culture, bone aspiration). With antibiotic therapy, surgical treatment is the rule. Parents have to be advised about frequent complications like shortening or deformation due to premature fusion. LEVEL OF EVIDENCE: Level III. PMID- 23812140 TI - Exploring the link between dystonia genes and idiopathic scoliosis. AB - BACKGROUND: Adolescent idiopathic scoliosis (AIS) is characterized by a complex curvature of the spine of unknown etiology. Unknown genetic factors likely play a role in disease pathogenesis. Recent studies suggest that AIS could result from central nervous system dysfunction and be related to dystonia. On the basis of this information, we hypothesized that genes linked to dystonia contribute to the pathogenesis of AIS. METHODS: To test this hypothesis, we evaluated the potential association between sequence variants in candidate dystonia genes and AIS. We sequenced the coding region of 5 selected dystonia-causing genes in 24 subjects with AIS, followed by targeted confirmation in additional 89 patients and 73 controls. RESULTS: No mutations were identified in any of the dystonia genes studied. CONCLUSIONS: We found no genetic link between dystonia and AIS. CLINICAL RELEVANCE: This investigation is a genetic evaluation of the association between dystonia and AIS. Despite the support in the literature for a pathogenic link between both the disorders, we have not identified any mutations in dystonia genes in patients with AIS. PMID- 23812141 TI - Hip dysplasia in patients with Hurler syndrome (mucopolysaccharidosis type 1H). AB - BACKGROUND: Hip dysplasia is common in patients with Hurler syndrome (HS). However, its prevalence and optimal management is not yet clear because of the rarity of the disease and the prior short life span of these patients. Recent advances in the management of these children using allogeneic hematopoietic cell transplant (HCT) has significantly increased their life expectancy, with many surviving into adulthood. This review was conducted to describe the experience of a single center with hip dysplasia in HS after HCT. METHODS: We performed a retrospective review of hip dysplasia in a consecutive series of patients with HS treated with HCT from 1985 to 2008. RESULTS: At 4.5 (+/- 2.9) years after HCT all 51 children (102 hips) with HS showed acetabular dysplasia and proximal femur valgus deformity. Mean age at HCT was 1.6 +/- 0.9 years. Forty hips (39%) underwent hip reconstructive osteotomies at mean age of 6.8 +/- 3.1 years. Significant radiographic improvement was noted in all radiographic parameters at 5.4 +/- 3.7 years after hip surgery (P<0.001). Acetabular index improved from 33.3 degrees (+/- 7.9) preoperative to 24.7 degrees (+/- 8) after surgery, lateral center edge angle improved from -5.3 degrees (+/- 10.9) to 35.2 degrees (+/- 17.8), migration index from 50.7% (+/- 15.7) to 9.6% (+/- 13.6), and femoral neck-shaft angle from 150.9 degrees (+/- 5.8) to 130.8 degrees (+/- 12.4). Ten of the 40 hips underwent only proximal femoral varus derotation osteotomy and 30 underwent combined proximal femoral varus derotation osteotomy+pelvic osteotomy. CONCLUSIONS: This study reports high prevalence of hip dysplasia (100%) in patients with HS. As significant radiographic improvement was achieved in those patients treated with surgical interventions we recommend annual orthopaedic evaluation of hips in patients with HS after HCT and intervention with reconstructive femoral and pelvic osteotomies for their hip dysplasia. PMID- 23812142 TI - Simple steps to minimize spine infections in adolescent idiopathic scoliosis. AB - BACKGROUND: To examine the surgical site infection (SSI) rates in patients undergoing posterior spinal fusion surgery for adolescent idiopathic scoliosis (AIS) after implementation of a change in antibiotic prophylaxis and intraoperative irrigation. METHODS: A retrospective review of all consecutive spinal fusions for AIS from 1996 to 2008 was performed. In 2003, 2 changes in our protocol were implemented: (1) routine antibiotic prophylaxis was changed from cefazolin alone to vancomycin and ceftazidime; (2) intraoperative irrigation technique was changed from bulb syringe to pulse lavage irrigation. We compared the rates of deep SSI requiring irrigation and debridement before institution of these changes (1996 to 2002) to the rates after these changes (2003 to 2008). RESULTS: Before the change in the antibiotic and lavage regimen, 261 spinal fusions were performed. Of these, 28/261 (11%) patients underwent irrigation and debridement for SSI. The most common infecting pathogen was coagulase-negative Staphylococcus aureus (47%). Between the years 2003 and 2008, 263 spinal fusions were performed. Only 2/263 (0.7%) patients underwent irrigation and debridement for SSI. This decrease in infection rate is highly significant (P<0.001). CONCLUSIONS: Routine use of vancomycin and ceftazidime and pulsatile lavage for posterior spinal fusion in AIS patients decreased the rates of postoperative infection by 10 fold. As 2 variables were changed, it is impossible to know the relative effect of each. However, as spine infections can be so devastating, and the potential risks of these changes are small, we recommend both the new antibiotic and irrigation protocol. LEVEL OF EVIDENCE: Level III. PMID- 23812143 TI - Long-term outcome of gradual reduction using overhead traction for developmental dysplasia of the hip over 6 months of age. AB - BACKGROUND: In children over 6 months of age with developmental dysplasia of the hip (DDH), achieving a concentrically reduced hip while avoiding avascular necrosis (AVN) is challenging. The utility of gradual reduction (GR) using traction has insufficient evidence. We therefore report the long-term outcome of GR using overhead traction (OHT). METHODS: We retrospectively reviewed 67 patients with DDH (75 hips) treated with GR using OHT over 6 months of age. The age at reduction ranged from 7 months to 4 years. All patients were followed up until skeletal maturity with a mean duration of 15.6 years. Pelvic radiographs were used to assess AVN, acetabular development, and the Severin classification. We determined the factors affecting the outcome at skeletal maturity. RESULTS: Seventy-two hips (96%) were successfully reduced, 2 required subsequent closed reduction and 1 underwent open reduction. AVN occurred in 2 hips (2.7%). Among 48 hips (64%) with residual acetabular dysplasia, 31 were treated with Salter innominate osteotomy (SIO) between 5 and 6 years of age. Finally, 62 hips (82.7%) showed satisfactory outcome (56 in Severin class I and 6 in class II), whereas 13 showed unsatisfactory outcome (class III). Although we found no significant factors affecting the outcome, most of the hips treated with SIO were included in the satisfactory group. CONCLUSIONS: GR using OHT could effectively minimize the risk of developing AVN in patients with DDH over 6 months of age at presentation. SIO at preschool age may play a beneficial role in the long-term outcome of GR using OHT. PMID- 23812144 TI - National access to care for children with fractures. AB - BACKGROUND: Access to health care for many pediatric orthopaedic patients is becoming more difficult. In some communities, children with fractures have limited access to care regardless of insurance status. The purpose of this study was to determine the level of difficulty in obtaining access to care for children with fractures nationally and compare our results to the published results of a national survey in 2006. METHODS: Five orthopaedic offices were identified in each state using an internet search with Google maps by typing "general orthopedics" under the search heading for each state. Each office was contacted with a scripted phone call describing a fracture in a 10-year-old boy that does not involve the growth plate. The office was then told the patient has Medicaid insurance. If no appointment was given, the reason was recorded and the office was asked to refer us to another orthopaedic surgeon. A second phone call was made to the same office a few days later using the same script but the office was told the patient has a private preferred-provider organization insurance. If no appointment was given, the reason was recorded. RESULTS: Of the 250 (23.6%) offices across the country, 59 would see a pediatric fracture patient with Medicaid. 41.3% (79/191) of the offices refusing the patient stated that they do not accept Medicaid patients. Of the 250, 205 (82%) of the offices across the country would see a pediatric fracture patient with a private preferred-provider organization insurance. The 10 states with lowest Medicaid reimbursement offered an appointment 6% of the time, whereas the 10 best reimbursing states offered an appointment 44% of the time. DISCUSSION AND CONCLUSIONS: The access to care for children with fractures is becoming more difficult across the country. Compared with the published data in 2006, the number of offices willing to see a child with private insurance has decreased from 92% to 82%. The number of offices willing to see a child with a fracture and Medicaid insurance has decreased from 62% to 23% over the same time span. PMID- 23812145 TI - Biomechanical analysis of posterior intrafocal pin fixation for the pediatric supracondylar humeral fracture. AB - BACKGROUND: Controversy remains regarding the optimal fixation for displaced pediatric supracondylar humeral fractures. The clinical results of a recently described technique using a posterior intrafocal pin have been good to excellent. The aim of our study was to compare, in a cadaveric model, the stiffness provided by posterior intrafocal pin fixation versus crossed medial and lateral pin fixation and divergent lateral entry pin fixation for the treatment of Gartland Wilkins type 3 supracondylar humeral fractures. METHODS: In 15 pairs of nonosteoporotic adult cadaver specimens, simulated Gartland-Wilkins type 3 supracondylar fractures were created and stabilized using: (1) the posterior intrafocal pin method; (2) medial and lateral crossed pins; or (3) 2 divergent lateral entry pins. Specimens were then subjected to internal rotation to measure the fixation stiffness of each construct. The effects of treatment and cycle number on torsional stiffness and peak torque were assessed for significance using a linear regression model with random effects to account for specimen pairing. Significance was set at P<0.05. RESULTS: The stiffest fixation was provided by crossed pins (2.4 N m/degree), followed by divergent lateral pins (1.9 N m/degree) and the posterior intrafocal pin (1.9 N m/degree), but none of the differences was statistically significant (P>0.9). Peak torque was not significantly different between fixations, although the trend suggested that crossed pins were strongest (34.6 N m), followed by divergent lateral pins (30.3 N m) and then posterior intrafocal pin fixation (26.1 N m). CONCLUSIONS: Our results suggest that posterior intrafocal pin fixation offers resistance to internal rotation equivalent to that of crossed medial and lateral pins and divergent lateral entry pins. CLINICAL RELEVANCE: The current biomechanical study supports the use of the posterior intrafocal posterior Kirschner pin for rotationally unstable supracondylar fractures because it is not significantly more compliant than standard techniques. LEVEL OF EVIDENCE: Level III. PMID- 23812146 TI - Precise resection and biological reconstruction under navigation guidance for young patients with juxta-articular bone sarcoma in lower extremity: preliminary report. AB - BACKGROUND: It is a challenge to perform a joint-preserving resection for young patients with juxta-articular bone sarcomas. We determined whether osteotomy under image-guided navigation make joint-saving resection possible for juxta articular lesions while adhering oncological principles. METHODS: Between June 2008 and July 2010, joint-preserving limb salvage surgeries were performed on 9 patients with juxta-articular bone sarcomas under navigation guidance. Computed tomography/magnetic resonance imaging fusion images were used for real-time navigation. Eight lesions located around the knee and 1 in hip. Six tumors extend to and 3 beyond the epiphyseal line. Planned osteotomy under image-guided navigation was employed for achieving clear surgical margin while maximizing host tissue preservation. All tumors were en bloc removed and intercalary defect were reconstructed by combination of allograft with vascularized fibula graft. All specimens were examined for resection margin. Patients were followed up for an average of 25.2 months for evaluating of functional and oncology outcomes. RESULTS: Entire joint were preserved in 6 patients and part of joint were saved in another 3 patients. The mean registration error for navigation was 0.40 mm (range, 0.31 to 0.62 mm). Clear surgical margin was obtained in all specimens. The average closest distance between the osteotomy line and tumor edge was 9.6 mm (range, 6 to 14 mm). Entire joint cartilage was preserved in 6 patients and portion of joint were saved in 3 patients (2 in proximal tibia, 1 in distal femur). No patient experienced local recurrence. Two patients developed lung metastasis. One died of disease and the other underwent metastasectomy and had no evidence of disease at the most recent follow-up. All reconstruction was in situ with the Musculoskeletal Tumor Society average score of 26.7 at final follow-up. CONCLUSIONS: With careful patient selection, image navigation-assisted surgery made it possible to resect the bone exactly as planned in length and orientation in the magnetic resonance imaging image, yielding a clear margin and preserving the entire or part of the articular cartilage in joint-sparing limb salvage procedures for treating skeletally immature patients with juxta-articular bone sarcomas. LEVEL OF EVIDENCE: Level IV--therapeutic study. PMID- 23812147 TI - Selective epiphysiodesis of the triradiate cartilage for treatment of residual experimental acetabular dysplasia. AB - BACKGROUND: The purpose of the study is to evaluate the effect of a selective epiphysiodesis of the ilioischial limb of the triradiate cartilage (TC) in an experimental dysplastic hip. MATERIALS AND METHODS: A hip dysplasia was obtained in 23 New Zealand rabbits 3 weeks old by immobilizing the knee in extension with a K-wire, in 4 groups: (1) control group; (2) K-wire maintained until sacrifice; (3) K-wire removed 1 week later without epiphysiodesis; and (4) K-wire removed 1 week later with selective epiphysiodesis of the ilioischial limb of the TC. Radiographic evaluation was performed previous to knee immobilization, after K wire removal and after sacrifice. Acetabular index (AI), Sharp's angle, ACM angle, acetabular floor thickness ratio (AFTR) were measured and presence of dysplasia, subluxation, or dislocation was noted. The acetabular version, the acetabular sector angles, and the pelvis rotation were obtained using CT evaluation. A morphology score was developed and a morphometric study of both proximal femur and acetabulum was performed. RESULTS: No differences between groups in the radiographic assessment before immobilization or K-wire removal were found. All cases in group 2 showed dysplasia, subluxation, or dislocation of the hip. The radiographic assessment of group 4, compared with group 3, showed a lower AI (P=0.027), Sharp's angle (P=0.005), ACM angle (0.049), and AFTR (P=0.017). No differences between groups 1 and 4 regarding AI (P=0.08), Sharp's angle (P=0.484), and AFTR (P=0.639) were obtained. The morphology score was lower in group 4 than in groups 2 and 3. Group 4 showed a deeper acetabulum than group 2 (P=0.008) and group 3 (P=0.033), while it was similar to group 1 (P=0.364). CONCLUSIONS: A selective epiphysiodesis of the ilioischial limb of the TC in a dysplastic hip normalized the radiographic measurements of the acetabulum and the acetabular deepness, and it improved the previous gross morphology of the capsule, labrum, and ligamentum teres in rabbits. LEVEL OF EVIDENCE: Level II therapeutic study. PMID- 23812148 TI - Results of cement versus bone graft reconstruction after intralesional curettage of bone tumors in the skeletally immature patient. AB - BACKGROUND: Resection of periphyseal tumors in children presents several unique challenges and complications. Injury to the adjacent physis during resection and adjuvant application has been associated with adverse growth-related outcomes including angular deformities and physeal arrest. The appropriate method of reconstructing bone defects after resection is also controversial. To date there is scant literature on the use of polymethylmethacrylate (PMMA) bone cement as a method of reconstruction in children, and few long-term studies exist on the incidence of growth-related complications after reconstruction. The objective of this study is to evaluate the mechanical, oncological, and developmental outcomes of PMMA use in children. METHODS: The authors retrospectively reviewed the medical records and radiographs of 36 skeletally immature patients who underwent intralesional resections of locally aggressive bone tumors. These patients were divided into 17 patients who received reconstruction with PMMA cement, and 19 patients who were reconstructed with bone graft. Follow-up clinical and radiographic evaluations performed after skeletal maturity were reviewed to assess the structural durability, local tumor recurrence rates, reoperation rates, and the incidence of postoperative complications such as deformity, adjacent joint arthrosis, growth arrest, pain, and functional limitation. RESULTS: The average patient age at the time of surgery was 11.79 years (range, 6 to 15 y). The average length of patient follow-up was 5.3 years (range, 2 to 11.5 y). There were no statistically significant differences observed in the rates of reoperation, local tumor recurrence, growth-related complications, adjacent joint arthrosis, or postoperative pain between the 2 groups. There were no postoperative fractures in the cement group, compared to 3 fractures in the bone graft group, although this was not statistically significant. CONCLUSIONS: PMMA cement as a structural augment after resection may be used in the pediatric population for improving the mechanical stability of bone. Cement use is associated with complication rates of arthrosis, local recurrence, and growth complications comparable to those observed with bone grafting. LEVEL OF EVIDENCE: Level III: Retrospective comparison study. PMID- 23812149 TI - Clinical characteristics of severe supracondylar humerus fractures in children. AB - BACKGROUND: The safety of delayed surgical treatment of severe supracondylar elbow fractures in children remains debated. No large studies have evaluated complications of injury and surgery evaluating only type 3 fractures. Our aim was to review the results of our experience treating children with severe supracondylar elbow fractures at various time points after injury. METHODS: All children treated operatively for supracondylar humerus fractures from 2004 to 2007 at a single pediatric trauma center were identified. A total of 1296 children had operative treatment, of which 872 had type 3 fractures. Clinical records were reviewed to identify time to surgery from presentation at our institution. Patients were grouped into 4 cohorts [<6 h (n=325), 6 to 12 h (n=224), 12 to 24 h (n=295), and >24 h (n=28)]. Emergency, operative, inpatient, and outpatient records were reviewed to determine morbidity at presentation as well as operative and postoperative complications. RESULTS: There was no difference in sex, age, or energy mechanism between children in the various time groups. An absent pulse was found in 54 children (6%) at presentation, of which only 5 ultimately required a vascular intervention. Nerve injury occurred in 105 patients (12%). Use of a medial entry pin was not associated with ulnar nerve injury. Increased time from presentation to surgery was not associated with increased morbidity from the injury or treatment complications. In contrast, there was a trend to steady decrease in morbidity and complication rates with increased time to surgery. CONCLUSIONS: This is the largest single-center study of severe supracondylar humerus fractures and describes rates of vascular compromise, nerve injury, infection, and other complications of these injuries. Most children with type 3 supracondylar humerus fractures can be treated safely in a delayed manner. Appropriate clinical judgment is imperative to optimize outcomes. LEVEL OF EVIDENCE: Level III--retrospective comparative study. PMID- 23812150 TI - Hemiepiphysiodesis for correction of angular deformity in pediatric amputees. AB - BACKGROUND: Angular deformities at the knee are common in children with congenital or acquired below-knee or Syme amputations. These deformities can be well compensated and accommodated with prosthetic modifications. However, as children grow, these prosthetic modifications become more difficult and mechanical axis correction becomes necessary. These deformities have previously been treated with osteotomies and internal or external fixation devices, which necessitate prolonged periods without use of their prosthesis. This study examines the results of hemiepiphysiodesis to correct the mechanical axis and improve prosthetic fitting in a pediatric amputee population. METHODS: Mechanical axis correction using hemiepiphysiodesis in 22 pediatric Symes or transtibial amputees with 22 involved limbs were retrospectively reviewed. Hemiepiphysiodesis was performed with 8-plates (10), staples (6), or drilling and curetting (6). Postoperatively, children were allowed to resume prosthetic use after their wounds healed and they indicated no pain while wearing their prosthesis. Seventeen patients presented with valgus and 5 with varus deformity of their residual limb. Mean age at time of surgery was 11 years and 11 months (range, 7 y and 11 mo to 15 y and 8 mo). Mechanical axis deviation (MAD) was measured before initial surgery and again after hardware removal or physis closure. RESULTS: The mean preoperative MAD was -29.6 mm for the valgus deformities and +10.6 mm for the varus deformities. The mean postoperative MAD was +3.1 mm for the varus knees and -6.0 mm for the valgus knees The mean total mechanical axis correction was 21.8 mm. One patient failed to achieve any mechanical axis correction and 1 hardware failure (broken 8-plate) occurred. Most patients had the staples or 8 plates removed, either after correction was achieved and physes were still open, or due to hardware prominence after physeal closure. CONCLUSIONS: Hemiepiphysiodesis provides reliable correction of angular deformity in pediatric amputees. Surgical intervention while skeletally immature allows for correction using guided growth, without the need for osteotomy with internal or external fixation and the resultant disruptions in prosthetic wear. LEVEL OF EVIDENCE: Case Series, Level IV. PMID- 23812151 TI - Continued growth after limited physeal bridging. AB - BACKGROUND: After any physeal injury, the primary concern is the possibility of some pattern of growth alteration, particularly transphyseal bridging that may cause lasting deformities and impact subsequent patient care. Small areas of physeal bridging, however, may be associated with continued growth, rather than impairment. METHODS: Seven patients with small central physeal bridges of the distal femur were identified. Demographic data and imaging studies were reviewed. RESULTS: Radiography identified small, relatively centrally located transphyseal osseous bridging that was associated with a linear (longitudinal) region of osseous density extending from the physeal bridge proximally into the metaphysis. This linear striation disappeared at the metaphyseal/diaphyseal gradation, an area of progression proximally from metaphysis to diaphysis. Only 1 patient had a significant leg length inequality. Magnetic resonance imaging confirmed the intrametaphyseal linear sclerotic bone and its disappearance with diaphyseal remodeling. CONCLUSIONS: Small, central transphyseal osseous bridges may form after radiologically confirmed acute physeal injury. Normal physiological (hydrostatic) growth forces can be sufficient to overcome such limited central bridging and allow continued, essentially normal, longitudinal growth. LEVEL OF EVIDENCE: Level IV (retrospective case series); anatomic study. PMID- 23812152 TI - Elastic stable intramedullary nailing for displaced pediatric clavicle midshaft fractures: a prospective study of the results and patient satisfaction in 24 children and adolescents aged 10 to 15 years. AB - BACKGROUND: Whereas displaced clavicle fractures in young children are treated nonoperatively, older children are more likely to suffer persistent pain and misalignments during a longer period of treatment. This study presents the outcomes of elastic stable intramedullary nailing for displaced clavicle fractures in children over the age of 10. METHODS: Prospectively, this study evaluates elastic stable intramedullary nailing for displaced clavicle midshaft fractures in children and adolescents, aged 10 to 15 years, from July 2004 to June 2010. We analyzed all complications, patient pain and long-term results, measured using the Constant & Murley Shoulder Score, the Client Satisfaction Questionnaire-8, and ultrasound. RESULTS: Eight girls and 16 boys (aged 10 to 15 y), 1 with bilateral fracture, were recruited. Sixteen mini-open reductions were necessary. All adolescents reported full mobilization from the first postoperative day, full activity after 1 week, and sporting activity after 1 month. Self-reported pain was very low. Five complications occurred: 1 implant breakage (kick-boxing); 2 nail deformations (fall during football, collision in ice-hockey); and 2 imminent skin perforations. The mean Constant & Murley Shoulder Score at follow-up after 1 year was 99.5 of 100 points; the mean patient satisfaction in the Client Satisfaction Questionnaire-8 was 30.6 of 32 points. Axial deviation of the clavicle was always <10 degrees; shortening <0.5 cm. CONCLUSIONS: Elastic stable intramedullary nailing can be offered for displaced midshaft clavicle fractures in children older than 10 years. They benefit from little pain, early mobilization, and fast full range of motion. To avoid complications the maximum projection of the ends of the nails must be 5 mm; no sports should be allowed for 4 weeks, contact sports for 8 weeks. PMID- 23812153 TI - Supramalleolar osteotomy: a comparison of fixation methods. AB - BACKGROUND: For children with persistent tibial torsion, a wide variety of osteotomies and fixation methods have been proposed. We set out to compare the outcomes of percutaneous pin fixation versus a plate and screw construct. Our hypothesis was that the pin fixation group would have comparable outcomes without the need for a secondary procedure for implant removal. METHODS: A retrospective chart review was performed. Data were evaluated on patients undergoing a rotational supramalleolar osteotomy over a 10-year span with follow-up to union. Patient's age, underlying condition, degree of torsion, length of procedure, length of hospital stay, concomitant procedures, complications, recurrence, and secondary procedures were recorded. Statistical analysis utilized the Mann Whitney U test for evaluation of independent samples. RESULTS: A total of 125 patients met the selection criteria with 186 tibias operated. Sixty-one cases were bilateral. Pin fixation was performed in 61 patients (87 tibias) and plate fixation in 64 patients (99 tibias). Age ranged from 2.5 to 19.6 (average 10.6) years. Surgical time, length of stay, and recurrence did not demonstrate a statistically significant difference between the pin fixation and the plate fixation groups. Forty-seven patients had secondary surgical procedures for removal of implants, 44 in the plate group and 3 in the pin group. Complications were considered major if they required reoperation or fracture care. In the plate group, 16 patients (12.8%) had complications with 5 major complications. In the pins group 3 patients (2.4%) had complications, which were minor. Recurrence was seen in 4 patients in the pin group and 2 patients in the plate group. Recurrence correlated with underlying neuromuscular disease and age younger than 11 years at the time of surgery. CONCLUSIONS: The numbers of complications, both major and minor, were significantly greater in the plate group. Therefore, the results of this study did not support our hypothesis that percutaneous pin fixation of supramalleolar osteotomies would have comparable outcomes to plate and screw fixation. PMID- 23812154 TI - VEPTR to treat nonsyndromic congenital scoliosis: a multicenter, mid-term follow up study. AB - BACKGROUND: Traditional surgical management of multiple congenital vertebral anomalies in young children, including fusion in situ and hemiepiphyseodesis, do not promote spinal growth nor address the associated thoracic insufficiency syndrome. We hypothesize that vertical expandable prosthetic titanium rib (VEPTR) with expansion thoracoplasty may control spinal deformity, allow spinal growth, and address thoracic insufficiency syndrome in children with nonsyndromic complex congenital spinal deformities. METHODS: Eight pediatric spine centers prospectively entered clinical and radiographic data into a database on every congenital spinal deformity treated with VEPTR as part of an Food and Drug Administration study. We retrospectively reviewed these data and excluded patients with spina bifida, Jarcho-Levin, or other syndromes. Data analysis focused on surgical technique and expansion frequency, change in Cobb angle and thoracic heights, and adverse events for a consecutive series of patients with at least 2 years of follow-up. RESULTS: Twenty-four children with an average age at surgery of 3.3 years (range, 1.0 to 12.5 y) were treated with VEPTR insertion and expansion thoracostomy and were followed for an average of 40.7 months (range, 25 to 78 mo). Twenty-three (95.8%) had associated rib fusions. All patients had subsequent expansion surgery; 50% had 5 or more expansions. Twenty patients (83.3%) had an improvement in Cobb angle during treatment with an average improvement of 8.9 degrees. All had an increase in thoracic height, with a mean increase of 3.41 cm. The most common adverse events were device migration in 7 patients and infection or skin problems in 6 patients. CONCLUSIONS: VEPTR insertion with expansion thoracoplasty represents a successful treatment paradigm for nonsyndromic congenital spinal deformities. We report multicenter data with midterm follow-up of children without syndromic diagnoses, in which the vast majority had an improvement in Cobb angle and thoracic height over the treatment period. Challenges include the demands of multiple procedures, skin problems, and device migration. LEVEL OF EVIDENCE: Level IV-prognostic study. PMID- 23812156 TI - Venous thromboembolism in children: details of 46 cases based on a follow-up survey of POSNA members. AB - INTRODUCTION: On the basis of a recent survey of Pediatric Orthopedic Society of North America members, 59% of the respondents acknowledged having encountered at least 1 child with the diagnosis of venous thromboembolism (VTE). The current survey sought further information including patient demographics, underlying diagnosis, presence of certain risk factors for VTE, and the clinical outcome. METHODS: A follow-up web-based questionnaire was sent to 121 active members of Pediatric Orthopedic Society of North America who had provided their contact information in the prior survey. Thirty-eight respondents provided clinical details on 46 children. RESULTS: The mean age of the affected patients was 14.3 (95% confidence interval, 13.3-15.3) years and 61% were males. The average body mass index was 28 (95% confidence interval, 25-31). Forty-four percent of the patients were diagnosed with deep venous thrombosis (DVT) only, 26% with pulmonary embolism (PE) only, and 30% with both DVT and PE. Majority of the children had DVT involving the popliteal area or thigh (16 cases each). Lower extremity surgery (29 cases, including proximal femoral/tibial osteotomies, internal fixation of long bone fractures, anterior cruciate ligament reconstruction, and resection of osteochondroma around the knee) and adolescence (28 cases) were the 2 most commonly cited associations. Other cases were noted with spinal surgery (8 children) and musculoskeletal infections (7 children). Three patients developed a postphlebitic syndrome, 1 had recurrent DVT and 2 children died. Both deceased children were diagnosed with DVT and PE including a 9-year-old child with a positive family history of antithrombin-3 deficiency that was not noted preoperatively. CONCLUSIONS: Although uncommon, potentially fatal VTE can occur among children with a variety of musculoskeletal ailments. Obtaining a family history suggestive of thrombophilia preoperatively should be encouraged. Further investigation is warranted to ascertain the role of prophylaxis against VTE among children in an orthopaedic practice. LEVEL OF EVIDENCE: Level IV-case series. PMID- 23812155 TI - An anatomic study of the distal femoral epiphysis. AB - BACKGROUND: The anatomy of the undulating distal femoral physis may be relevant to growth disturbance after physeal fractures and screw fixation about the physis. The surface anatomy of this physis has not been well described. METHODS: We performed an anatomic study on 26 cadaveric distal femoral epiphyses in specimens 3 to 18 years of age. High-resolution 3-dimensional surface scans were obtained and analyzed to determine the heights, approximate surface areas, and locations of the major undulations. RESULTS: Gross examination revealed lateral and anteromedial peripheral notches at the metaphyseal-epiphyseal junction, which deepen with advancing skeletal maturity. Within the epiphysis, there are 3 major undulations: a central ridge, lateral ridge, and medial peak, with mean heights of 5.5 mm (range, 2.9 to 9.8 mm), 2.5 mm (1.0 to 5.7 mm), and 2.9 mm (0.9 to 4.7 mm), respectively. The normalized height and surface area of each undulation decreased with increasing age, most dramatically in the central ridge. With respect to a line connecting the medial and lateral aspects of the physis, we found that the central peak passes more superior with younger age, and tends to be more posteriorly located. The lowest point of the physis is located either anteromedial or posterolateral. CONCLUSIONS: The central ridge, lateral ridge, and medial peak are the 3 major undulations in the distal femoral physis. The central ridge has the greatest height and most dramatic decrease in relative size with increasing age, suggesting structural importance. This anatomic data can guide metaphyseal and epiphyseal screw fixation. CLINICAL RELEVANCE: This study provides quantitative data on the topographic anatomy of the distal femoral physis, which can guide screw placement about the physis. These data may help identify fractures patterns with a greater risk of growth disturbance and key radiographic landmarks for guiding fracture reduction. PMID- 23812157 TI - Abduction bracing for residual acetabular dysplasia in infantile DDH. AB - BACKGROUND: Abduction bracing is often used to treat residual acetabular dysplasia in infants whose acetabular indices (AI) exceed 30 degrees after 6 months of age. However, little data exist to support this practice. The purpose of this study was to determine the efficacy of part-time abduction bracing in treating residual acetabular dysplasia by comparing a cohort of braced infants with a cohort of unbraced infants. METHODS: We performed a retrospective review of a consecutive series of patients with developmental dysplasia of the hip (DDH) treated at our institution over 4 years. Children with stable, treated DDH but residual acetabular dysplasia at 6 months of age were identified; those with available anteroposterior pelvic radiographs at 6 months and 1 year of age were included. Patients who required open surgical reduction and those with syndromic or neuromuscular diagnoses were excluded. On the basis of practice variations at our institution, some orthopaedists start bracing when the 6-month radiograph demonstrates an AI>=30 degrees, whereas others do not; we compared these 2 cohorts. Braced patients were instructed to wear an abduction orthosis during nights and naps until follow-up at 1 year of age. The AI at 6 months and 1 year of age for both cohorts were then measured by a single observer and the differences compared. RESULTS: Seventy-six hips in 52 patients were identified with residual dysplasia on the 6-month radiograph. Thirty-nine hips (27 patients) were unbraced, 31 hips (21 patients) were braced, and 6 hips (4 patients) were excluded for cross-over. Over a 6-month period, the braced cohort had significantly better improvement in the AI of 5.3 degrees (95% confidence interval, 4.3 to 6.3 degrees) compared to the unbraced cohort which had an improvement in the AI of only 1.1 degrees (95% confidence interval 0.6 to 1.6 degrees) (P<0.001). CONCLUSIONS: In this comparative analysis of infants with residual acetabular dysplasia treated with abduction bracing or observation, part time bracing significantly improved the acetabular index between 6 and 12 months of age. Part-time use of an abduction orthosis is effective for improving residual acetabular dysplasia in infants with DDH. LEVEL OF EVIDENCE: Level III retrospective comparative study. PMID- 23812158 TI - Bipolar sealer device reduces blood loss and transfusion requirements in posterior spinal fusion for adolescent idiopathic scoliosis. AB - BACKGROUND: Reducing perioperative blood loss and transfusion requirements is important in the operative treatment of idiopathic scoliosis. This can be achieved with special frames, cell saver systems, pharmacologic aspects, and other techniques. Recently there has been interest in bipolar sealer devices as an adjunct to traditional monopolar electrocautery. However, there is limited information on this device in pediatric spinal deformity surgery. We reviewed our experience with this device in a setting of a standard institutional operative carepath. METHODS: Perioperative blood loss and transfusion requirements of 50 consecutive patients with adolescent idiopathic scoliosis undergoing a posterior spinal fusion and segmental spinal instrumentation and who had a bipolar sealer device used during their surgery was compared with a control group of the 50 preceding consecutive patients who did not. Anesthesia, surgical technique, use of intraoperative epsilon aminocaproic acid (Amicar), postoperative protocol, and indications for transfusions (hemoglobin<=7.0 g/dL) were identical in both groups. RESULTS: The preoperative demographics for the patients in both groups were statistically the same. The bipolar sealer group demonstrated a significant reduction in intraoperative estimated blood loss, total perioperative blood loss, volume of blood products transfused, and overall transfusion rate when compared with the control group. When subgroups consisting of only hybrid or all-pedicle screw constructs were considered individually, these findings remained consistent. There were no complications associated with the use of this device. CONCLUSIONS: Using the bipolar sealer device is a significant adjunct in decreasing perioperative blood loss and transfusion requirements in patients undergoing surgery for adolescent idiopathic scoliosis. LEVEL OF EVIDENCE: Level III-retrospective comparative study. PMID- 23812159 TI - Localized acquired hypertrichosis after cast treatment in pediatric and adolescent patients: a natural history study. AB - BACKGROUND: Localized acquired hypertrichosis (LAH) is a condition characterized by increased hair growth and is frequently seen after cast removal in children and adolescents. The purpose of this study was to examine the natural history of LAH and its potential impact on patients' quality of life. METHODS: Patients between the ages of 5 and 16 years, in whom hypertrichosis was detected after the removal of a cast were enrolled in a prospective study. Each patient completed the Children's Dermatology Life Quality Index after cast removal and at follow up. Each patient was followed up until complete resolution of hypertrichosis. Statistical analyses were performed to determine any relation between the time to resolution of hypertrichosis and potential contributing variables including age, sex, initial diagnosis, type of cast, type of cast liner, and duration of cast. RESULTS: Of the 25 enrolled patients, 3 were lost during follow-up and 1 girl was excluded. The mean Children's Dermatology Life Quality Index total score was 1.1+/-1.4, with the majority of patients (68%) scoring 0 or 1. The hypertrichosis was completely resolved within 6 months in 17 of the 21 patients and within 6 to 12 months in the remaining 4. Although duration of cast showed a statistically significant correlation to time to resolution (P=0.008), the other variables studied showed no significant relationship. CONCLUSIONS: According to this study, LAH is typically resolved within 6 months in 80% of patients. It was not found to negatively impact the quality of life in any of the patients. The study determined that the longer the cast was applied, the longer was the time for hypertrichosis to resolve. LEVEL OF EVIDENCE: Level II, prognostic study. PMID- 23812160 TI - Synthesis and electronic properties of 3,7-dianilino substituted N-hexyl phenothiazines. AB - 3,7-Diaminophenothiazine derivatives are readily synthesized via two-fold Buchwald-Hartwig coupling of 10-hexyl 3,7-dibromo-10H-phenothiazine with a series of primary and secondary anilines and amines. All derivatives possess two reversible oxidations at low potentials with remarkable semiquinone formation constants. The electronic structure of this novel class of phenothiazinyl oligoanilines is additionally studied and rationalized by DFT computations and correlation studies between selected experimental and computational electronic data. PMID- 23812161 TI - A correlated ab initio quantum chemical study of the interaction of the Na+, Mg2+, Ca2+ and Zn2+ ions with the tautomers of cytosine in the presence of polar solvent. AB - The interactions of the metal ions Na(+), Mg(2+), Ca(2+) and Zn(2+) with cytosine have been investigated with inclusion of solvent effects. Computations have been performed at the density functional and Moller-Plesset levels of theory within the IEFPCM solvent model. It has been found that the inclusion of the solvent environment is essential for giving more biologically realistic results. Earlier gas-phase findings of the stabilisation of rare tautomeric forms by the metal ions have been reproduced, with the presence of the solvent further affecting the relative stabilities. PMID- 23812162 TI - Intracerebral hematoma extends via perivascular spaces and perineurium. AB - Intracerebral hemorrhage (ICH) is a devastating disorder associated with high morbidity and mortality. ICH results in the formation of hematoma that affects not only the primary site of injury but also the remote regions. In fact, hematoma can extend via perivascular spaces (also called Virchow-Robin spaces, VRS) and perineurium in an animal model of ICH. In the present study, we used magnetic resonance imaging (MRI) with susceptibility-weighted imaging (SWI) to investigate the characteristics of the perivascular and perineural extensions of hematomas in patients with ICH. A total of 20 ICH patients without secondary subarachnoid and secondary intraventricular hemorrhages were recruited. Brain MRI scans, including SWI, T1, and T2-weighted images, were performed between 17 h to 7 days after the onset of ICH. MRI with SWI revealed that paramagnetic substances spread along the VRS or the perineurium. Such distribution could cause the formation of cerebral microbleeds (CMBs). However, the distribution of remote hemorrhagic lesions varied, depending on the size and location of the original hematoma. The unenhanced CT scans of the 20 patients did not show any hyperdensity around the blood vessels and nerve tracts outside the hematoma. These results indicate the perivascular and perineural extensions of hematomas in patients with ICH, which is formed by the leakage of the original hematoma via the VRS or perineurium. We also provide a new explanation for the series of pathological processes involved in ICH, including the remote effects of hematoma and the formation of CMBs in patients with ICH. PMID- 23812163 TI - Cationic uremic toxins affect human renal proximal tubule cell functioning through interaction with the organic cation transporter. AB - Several organic cations, such as guanidino compounds and polyamines, have been found to accumulate in plasma of patients with kidney failure due to inadequate renal clearance. Here, we studied the interaction of cationic uremic toxins with renal organic cation transport in a conditionally immortalized human proximal tubule epithelial cell line (ciPTEC). Transporter activity was measured and validated in cell suspensions by studying uptake of the fluorescent substrate 4 (4-(dimethylamino)styryl)-N-methylpyridinium-iodide (ASP(+)). Subsequently, the inhibitory potencies of the cationic uremic toxins, cadaverine, putrescine, spermine and spermidine (polyamines), acrolein (polyamine breakdown product), guanidine, and methylguanidine (guanidino compounds) were determined. Concentration-dependent inhibition of ASP(+) uptake by TPA, cimetidine, quinidine, and metformin confirmed functional endogenous organic cation transporter 2 (OCT2) expression in ciPTEC. All uremic toxins tested inhibited ASP(+) uptake, of which acrolein required the lowest concentration to provoke a half-maximal inhibition (IC50 = 44 +/- 2 MUM). A Dixon plot was constructed for acrolein using three independent inhibition curves with 10, 20, or 30 MUM ASP(+), which demonstrated competitive or mixed type of interaction (K i = 93 +/- 16 MUM). Exposing the cells to a mixture of cationic uremic toxins resulted in a more potent and biphasic inhibitory response curve, indicating complex interactions between the toxins and ASP(+) uptake. In conclusion, ciPTEC proves a suitable model to study cationic xenobiotic interactions. Inhibition of cellular uptake transport was demonstrated for several uremic toxins, which might indicate a possible role in kidney disease progression during uremia. PMID- 23812164 TI - Layer- and cell-type-specific tonic GABAergic inhibition of pyramidal neurons in the rat visual cortex. AB - Tonic inhibition mediated by persistent activation of gamma-aminobutyric acidA (GABAA) receptors by ambient GABA plays a crucial role in the regulation of network excitability and neuronal signal processing. Varying degrees in the strength of tonic inhibition were detected across different cell types throughout the brain. Since sensory information flows through cortical layers in a specific order, the characteristics of tonic inhibition in different cortical layers are of interest. Therefore, we examined the properties of tonic inhibition in pyramidal neurons (PyNs) throughout the rat visual cortex. Layer 2/3 PyNs and burst-spiking PyNs in layers 5 and 6 showed prominent tonic GABAA currents. Tonic GABAA currents in layer 4 star PyNs and regular-spiking PyNs in layers 5 and 6 were much weaker. The magnitude of tonic currents correlated well with the inhibition of spike generation. The amplitude of tonic GABAA currents measured with bicuculline and gabazine, the two different GABAA receptor blockers, did not differ. The differences in the expression levels of extrasynaptic GABAA receptors might be the major contributor to the differences in tonic GABAA currents among cell types. Furthermore, alpha5 subunits might contribute significantly to tonic currents in infragranular burst-spiking PyNs, especially in layer 5. These results suggest that ambient GABA might exert differential effects on the neuronal integration in a layer- and cell-type-specific manner and thus contribute to the processing of sensory properties by selectively tuning the signals flowing through the visual cortex. PMID- 23812165 TI - G protein modulation of K2P potassium channel TASK-2 : a role of basic residues in the C terminus domain. AB - TASK-2 (K2P5.1) is a background K(+) channel opened by extra- or intracellular alkalinisation that plays a role in renal bicarbonate handling, central chemoreception and cell volume regulation. Here, we present results that suggest that TASK-2 is also modulated by Gbetagamma subunits of heterotrimeric G protein. TASK-2 was strongly inhibited when GTP-gamma-S was used as a replacement for intracellular GTP. No inhibition was present using GDP-beta-S instead. Purified Gbetagamma introduced intracellularly also inhibited TASK-2 independently of whether GTP or GDP-beta-S was present. The effects of GTP-gamma-S and Gbetagamma subunits were abolished by neutralisation of TASK-2 C terminus double lysine residues K257-K258 or K296-K297. Use of membrane yeast two hybrid (MYTH) experiments and immunoprecipitation assays using tagged proteins gave evidence for a physical interaction between Gbeta1 and Gbeta2 subunits and TASK-2, in agreement with expression of these subunits in proximal tubule cells. Co immunoprecipitation was impeded by mutating C terminus K257-K258 (but not K296 K297) to alanines. Gating by extra- or intracellular pH was unaltered in GTP gamma-S-insensitive TASK-2-K257A-K258A mutant. Shrinking TASK-2-expressing cells in hypertonic solution decreased the current to 36 % of its initial value. The same manoeuvre had a significantly diminished effect on TASK-2-K257A-K258A- or TASK-2-K296-K297-expressing cells, or in cells containing intracellular GDP-beta S. Our data are compatible with the concept that TASK-2 channels are modulated by Gbetagamma subunits of heterotrimeric G protein. We propose that this modulation is a novel way in which TASK-2 can be tuned to its physiological functions. PMID- 23812167 TI - Magnetic resonance imaging in systemic lupus erythematosus: where do we stand? PMID- 23812166 TI - Polymorphisms of killer immunoglobulin-like receptors (KIRs) and HLA ligands in northeastern Thais. AB - Killer cell immunoglobulin-like receptors (KIRs) are cell surface receptors on natural killer (NK) cells and subsets of T cells. The functions of NK cells are partly regulated by interactions between KIRs and HLA ligands on target cells. In this study, the presence or absence of 17 KIR genes and their known HLA ligands have been investigated in 235 unrelated individuals living in northeastern Thailand (NET). Subtypes of KIR2DS4 including full length (KIR2DS4F) and deleted forms (KIR2DS4D) have also been determined. Framework genes (KIR2DL4, 3DL2, 3DL3, and 3DP1) were found in all individuals and KIR genes belonging to the A haplotype (KIR2DL1, 2DL3, 3DL1, and 2DS4) were present in more than 90% of NET. KIR2DS4D (61.7%) was more common than KIR2DS4F (52.8%). A total of 33 different KIR genotypes were observed. Of these, three new genotypes were identified. The most common genotype (AA) was observed in 35.7% of NET, and HLA-C alleles bearing the C1 epitope (HLA-C1) had the highest frequency (97%). All individuals had at least one inhibitory KIR and its corresponding HLA ligand; 40.9% of NET had three pairs of receptor-ligand combinations, and 18.3% had all three receptor-ligand combinations of KIR2DL3+C1, 3DL1+Bw4, and 3DL2+A11. Surprisingly, the patterns of KIR gene frequencies in NET are more similar to those of Caucasians than Japanese, Korean, and Chinese. This is the first report on complete analysis of KIR and known HLA ligands in Thais. These data provide basic knowledge on KIR for further studies on disease associations and transplantation in northeastern Thais. PMID- 23812168 TI - Akinetic mutism without a structural prefrontal lesion. AB - Akinetic mutism is characterized by profound apathy and a lack of verbal and motor output for action, despite preserved alertness. The condition usually follows bilateral damage to the medial frontal subcortical circuits. We report a 59-year-old right-handed woman who was admitted to the neurology ward with sudden onset akinetic mutism. Her medical history included an ischemic stroke 3 years earlier, with residual anomia and mild agraphia but no motor dysfunction. On this admission, a cranial computed tomography scan disclosed an acute left superior cerebellar infarction embracing the vermis, and a prior left inferior parietal infarct. Electroencephalogram showed bilateral frontal delta-wave activity. Four weeks later, we performed a technetium-99m hexamethylpropyleneamine oxime single photon emission computed tomography (Tc-HMPAO SPECT) scan to study the patient's frontal lobe function. The SPECT scan revealed the causative bifrontal hypoperfusion, more prominent on the right, while the structurally evident cerebellar infarction was predictably masked by subacute hyperperfusion phenomenon. Contralateral frontal diaschisis is an established sequela of cerebellar infarction. Because this patient also had lesions in the left parietal region, her left prefrontal area was critically deprived of its major reciprocally connected cortical counterparts (right prefrontal and left parietal), and also became dysfunctional. Her resulting bilateral frontal dysfunction is a common cause of akinetic mutism. PMID- 23812169 TI - White matter abnormalities and working memory impairment in systemic lupus erythematosus. AB - OBJECTIVE/BACKGROUND: Many patients with systemic lupus erythematosus (SLE) have working memory deficits. Few studies have evaluated working memory performance and neurometabolite profile using magnetic resonance spectroscopy in SLE. METHODS: We gave the Paced Auditory Serial Addition Test (PASAT), a measure of working memory, to 73 patients with SLE. We calculated total score, dyads, chunking, and cognitive fatigue. Using magnetic resonance spectroscopy, we determined the ratio of choline to creatine (Ch/Cr) in normal-looking right and left frontal lobe white matter. RESULTS: Twenty-nine percent of patients showed impaired working memory on the PASAT. Total PASAT score inversely correlated with right and left frontal white matter Ch/Cr. Left frontal white matter Ch/Cr correlated with percent chunking and inversely correlated with total and percent dyads. Right frontal white matter Ch/Cr correlated with percent chunking and inversely correlated with total and percent dyads. There was no relationship between cognitive fatigue and either left or right frontal white matter Ch/Cr. Longer disease duration was associated with higher left frontal white matter Ch/Cr. Correlations remained significant when we considered disease duration and left frontal white matter Ch/Cr against total PASAT score and total dyads. CONCLUSIONS: Patients with SLE were impaired on the PASAT. Lower total PASAT score and fewer dyads correlated with higher left frontal microstructural white matter damage, while cognitive fatigue did not. This pattern suggests that early white matter damage interferes with working memory in SLE and provides further insight into the neurobiological basis of mild cognitive dysfunction related to microstructural white matter injury. PMID- 23812170 TI - Guilty by suspicion? Criminal behavior in frontotemporal lobar degeneration. AB - OBJECTIVE: Our aim was to compare the frequency of criminal conduct in patients with behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD), and Alzheimer disease. BACKGROUND: A few small-scale studies of antisocial and criminal behavior in patients with frontotemporal lobar degeneration have focused on the clinical subtype bvFTD. It is not yet known whether antisocial behavior affects patients with other clinical subtypes of frontotemporal lobar degeneration, like SD, and patients with other dementing disorders, like Alzheimer disease. METHODS: We used a standardized caregiver interview to assess criminal behavior in 83 outpatients: 32 with bvFTD, 18 with SD, and 33 with Alzheimer disease. RESULTS: We found criminal behavior (theft, willful damage to property, housebreaking, assault, or indecent behavior) in 54% of the patients with bvFTD and 56% of those with SD, but only 12% of those with Alzheimer disease. CONCLUSIONS: Just over half of our patients with bvFTD or SD had committed crimes. When middle-aged or older patients commit minor crimes, frontotemporal lobar degeneration should be considered as a possible cause. If an affected person faces criminal charges, the court might take incapability or diminished responsibility into account in reaching a verdict. PMID- 23812171 TI - Task demand influences relationships among sex, clustering strategy, and recall: 16-word versus 9-word list learning tests. AB - OBJECTIVE: We compared the relationships among sex, clustering strategy, and recall across different task demands using the 16-word California Verbal Learning Test-Second Edition (CVLT-II) and the 9-word Philadelphia (repeatable) Verbal Learning Test (PrVLT). BACKGROUND: Women generally score higher than men on verbal memory tasks, possibly because women tend to use semantic clustering. This sex difference has been established via word-list learning tests such as the CVLT II. METHODS: In a retrospective between-group study, we compared how 2 separate groups of cognitively healthy older adults performed on a longer and a shorter verbal learning test. The group completing the CVLT-II had 36 women and 26 men; the group completing the PrVLT had 27 women and 21 men. RESULTS: Overall, multiple regression analyses revealed that semantic clustering was significantly associated with total recall on both tests' lists (P<0.001). Sex differences in recall and semantic clustering diminished with the shorter PrVLT word list. CONCLUSIONS: Semantic clustering uniquely influenced recall on both the longer and shorter word lists. However, serial clustering and sex influenced recall depending on the length of the word list (ie, the task demand). These findings suggest a complex nonlinear relationship among verbal memory, clustering strategies, and task demand. PMID- 23812172 TI - Suicidal behavior and loss of the future self in semantic dementia. AB - Semantic dementia impairs semantic autobiographical memory, but tends to spare its episodic components that are critical for the sense of self. Investigators have recently discovered disturbances in the "future self" in semantic dementia. We report a 63-year-old man with semantic dementia who was hospitalized after suicide attempts that he attributed to his loss of a sense of future self. He complained of a decreased sense of being human, because he could not imagine doing things in the future that he had done in the past. Suicidal thinking and inability to place himself in future tasks persisted despite resolution of depression. Clinical assessment revealed a crossmodal loss of semantic knowledge, and neuroimaging showed bilateral anterior temporal atrophy and hypometabolism. On specific tests of autobiographical memory, identity, attribute knowledge, and future projection, the patient could return to the past and visualize himself in familiar scenarios, but he could not visualize himself even passively in these scenarios in the future. His future self was impaired not from seeing himself disabled; it was from an absence of semantic details of potential experiences, associated with impaired semantic autobiographical memory. His self representations were concrete and specific rather than abstract and generalizable. This patient and recent publications indicate that semantic dementia impairs the ability to imagine oneself as capable in the future, leading some patients to suicidal behavior. We discuss possible mechanisms for these findings, including the potential role of abstract construals for future thinking. PMID- 23812173 TI - A case of Wernicke encephalopathy combined with disulfiram intoxication. AB - There have been several reports of disulfiram intoxication, but little evidence of neurologic conditions resulting from disulfiram-induced brain damage combined with Wernicke encephalopathy-associated lesions. We report a rare patient with both Wernicke encephalopathy and disulfiram intoxication. This 50-year-old woman, who was taking disulfiram for chronic alcohol abuse, presented with an acute confusional state, dysarthria, nystagmus, supranuclear ophthalmoplegia, and paraparesis. Biochemical serum and cerebrospinal fluid analyses were normal. An electromyogram detected a motor polyneuropathy. Cognitive assessment revealed severe impairment of memory, attention, and logical and executive abilities. Magnetic resonance imaging with gadolinium enhancement showed brain lesions consistent with Wernicke encephalopathy, but also symmetric hyperintensities on T2-weighted images in the globus pallidus. Stopping the disulfiram and treating with hydration, high-dose thiamine supplements, and benzodiazepines significantly improved the patient's consciousness and oculomotor function. A magnetic resonance imaging scan after 1 month of treatment showed complete disappearance of the brain lesions and the hyperintensities in the globus pallidus. After a further month of intensive neurorehabilitation, the patient was able to interact with the medical staff, and her neuropsychological tests showed only mild memory impairment. Patients with alcoholism who present at emergency departments are at high risk for misdiagnosis, especially because there is no specific routine laboratory test for detecting asymptomatic disulfiram intoxication. Although uncommon, the combination of Wernicke encephalopathy and disulfiram intoxication should be suspected in patients with alcoholism. The disorder can be detected through a careful history and prompt clinical evaluation, together with characteristic magnetic resonance imaging findings. PMID- 23812174 TI - Strategies for the development of conotoxins as new therapeutic leads. AB - Peptide toxins typically bind to their target ion channels or receptors with high potency and selectivity, making them attractive leads for therapeutic development. In some cases the native peptide as it is found in the venom from which it originates can be used directly, but in many instances it is desirable to truncate and/or stabilize the peptide to improve its therapeutic properties. A complementary strategy is to display the key residues that make up the pharmacophore of the peptide toxin on a non-peptidic scaffold, thereby creating a peptidomimetic. This review exemplifies these approaches with peptide toxins from marine organisms, with a particular focus on conotoxins. PMID- 23812176 TI - Food resource effects on diel movements and body size of cisco in north-temperate lakes. AB - The movement patterns and body size of fishes are influenced by a host of physical and biological conditions, including temperature and oxygen, prey densities and foraging potential, growth optimization, and predation risk. Our objectives were to (1) investigate variability in vertical movement patterns of cisco (Coregonus artedi) in a variety of inland lakes using hydroacoustics, (2) explore the causal mechanisms influencing movements through the use of temperature/oxygen, foraging, growth, and predation risk models, and (3) examine factors that may contribute to variations in cisco body size by considering all available information. Our results show that cisco vertical movements vary substantially, with different populations performing normal diel vertical migrations (DVM), no DVM, and reverse DVM in lakes throughout Minnesota and northern Wisconsin, USA. Cisco populations with the smallest body size were found in lakes with lower zooplankton densities. These smaller fish showed movements to areas of highest foraging or growth potential during the day and night, despite moving out of preferred temperature and oxygen conditions and into areas of highest predation risk. In lakes with higher zooplankton densities, cisco grew larger and had movements more consistent with behavioral thermoregulation and predator avoidance, while remaining in areas with less than maximum foraging and growth potential. Furthermore, the composition of potential prey items present in each lake was also important. Cisco that performed reverse DVM consumed mostly copepods and cladocerans, while cisco that exhibited normal DVM or no migration consumed proportionally more macro-zooplankton species. Overall, our results show previously undocumented variation in migration patterns of a fish species, the mechanisms underlying those movements, and the potential impact on their growth potential. PMID- 23812175 TI - Elucidating hormonal/ROS networks during seed germination: insights and perspectives. AB - While authors have traditionally emphasized the deleterious effects of reactive oxygen species (ROS) on seed biology, their role as signaling molecules during seed dormancy alleviation and germination is now the focus of many studies around the world. Over the last few years, studies using "-omics" technologies together with physiological and biochemical approaches have revealed that seed germination is a very complex process that depends on multiple biochemical and molecular variables. The pivotal role of phytohormones in promoting germination now appears to be interdependent with ROS metabolism, involving mitogen-activated protein kinase cascade activation, gene expression and post-translational protein modifications. This review is, thus, an attempt to summarize the new discoveries involving ROS and seed germination. The study of these interactions may supply markers of seed quality that might eventually be used in breeding programs to improve crop yields. PMID- 23812178 TI - Disease patterns in 32,486 insured German shepherd dogs in Sweden: 1995-2006. AB - The aims of this retrospective study were to describe the morbidity and mortality in German shepherd dogs (GSD) in Sweden, based on insurance data, and to test the hypothesis that GSDs are predisposed to immune-related diseases. Morbidity was defined as incidence rates and based on veterinary care events. Mortality was defined as mortality rates and based on life insurance data. The study included 445,336 dogs, 7.3 per cent GSDs, covered by both veterinary care and life insurance between 1995 and 2006 in the Swedish insurance company Agria (Agria Insurance Company, Stockholm, Sweden). For veterinary care events (morbidity) GSDs were most over-represented for immunological disease, with a relative risk (RR) of 2.7, compared with the risk in all other breeds combined. The most common disease category (morbidity) in GSDs was skin disorders with an incidence rate of 346.8 cases per 10,000 dog years at risk. The highest RR for cause of death in GSDs compared with all other breeds was for skin conditions (RR=7.8). Locomotor disorders were the most common cause of death in GSDs. The GSD is predisposed to immune-related disorders, such as allergies, circumanal fistulae and exocrine pancreatic atrophy, with significantly increased risk compared with all other breeds. PMID- 23812180 TI - Thrombolytic therapy for the treatment of prosthetic heart valve thrombosis in pregnancy with low-dose, slow infusion of tissue-type plasminogen activator. AB - BACKGROUND: Prosthetic valve thrombosis during pregnancy is life-threatening for mother and fetus, and the treatment of this complication is unclear. Cardiac surgery in pregnancy is associated with very high maternal and fetal mortality and morbidity. Thrombolytic therapy has rarely been used in these patients. The aim of this study is to evaluate the safety and efficacy of low-dose (25 mg), slow infusion (6 hours) of tissue-type plasminogen activator for the treatment of prosthetic valve thrombosis in pregnant women. METHODS AND RESULTS: Between 2004 and 2012, tissue-type plasminogen activator was administered to 24 consecutive women in 25 pregnancies with 28 prosthetic valve thrombosis episodes (obstructive, n=15; nonobstructive, n=13). Mean age of the patients was 29+/-6 years. Thrombolytic therapy sessions were performed under transesophageal echocardiography guidance. The mean dose of tissue-type plasminogen activator used was 48.7+/-29.5 mg (range, 25-100 mg). All episodes resulted in complete thrombus lysis after thrombolytic therapy. One patient had placental hemorrhage with preterm live birth at the 30th week, and 1 patient had minor bleeding. CONCLUSIONS: Low-dose, slow infusion of tissue-type plasminogen activator with repeated doses as needed is an effective therapy with an excellent thrombolytic success rate for the treatment of prosthetic valve thrombosis in pregnant women. This protocol also seems to be safer than cardiac surgery or any alternative medical strategies published to date. Thrombolytic therapy should be considered first-line therapy in pregnant patients with prosthetic valve thrombosis. PMID- 23812179 TI - Cocaine-induced vasoconstriction in the human coronary microcirculation: new evidence from myocardial contrast echocardiography. AB - BACKGROUND: Cocaine is a major cause of acute coronary syndrome, especially in young adults; however, the mechanistic underpinning of cocaine-induced acute coronary syndrome remains limited. Previous studies in animals and in patients undergoing cardiac catheterization suggest that cocaine constricts coronary microvessels, yet direct evidence is lacking. METHODS AND RESULTS: We used myocardial contrast echocardiography to test the hypothesis that cocaine causes vasoconstriction in the human coronary microcirculation. Measurements were performed at baseline and after a low, nonintoxicating dose of intranasal cocaine (2 mg/kg) in 10 healthy cocaine-naive young men (median age, 32 years). Postdestruction time-intensity myocardial contrast echocardiography kinetic data were fit to the equation y=A(1-e(-betat)) to quantify functional capillary blood volume (A), microvascular flow velocity (beta), and myocardial perfusion (A*beta). Heart rate, mean arterial pressure, and left ventricular work (2 dimensional echocardiography) were measured before and 45 minutes after cocaine. Cocaine increased mean arterial pressure (by 14+/-2 mm Hg [mean+/-SE]), heart rate (by 8+/-3 bpm), and left ventricular work (by 50+/-18 mm Hg.mL(-1).bpm(-1)). Despite the increases in these determinants of myocardial oxygen demand, myocardial perfusion decreased by 30% (103.7+/-9.8 to 75.9+/-10.8 arbitrary units [AU]/s; P<0.01) mainly as a result of decreased capillary blood volume (133.9+/ 5.1 to 111.7+/-7.7 AU; P<0.05) with no significant change in microvascular flow velocity (0.8+/-0.1 to 0.7+/-0.1 AU). CONCLUSIONS: In healthy cocaine-naive young adults, a low-dose cocaine challenge evokes a sizeable decrease in myocardial perfusion. Moreover, the predominant effect is to decrease myocardial capillary blood volume rather than microvascular flow velocity, suggesting a specific action of cocaine to constrict terminal feed arteries. PMID- 23812181 TI - Prosthetic valve thrombosis in pregnancy: a promising treatment for a rare and mostly preventable complication. PMID- 23812182 TI - Association between maternal chronic conditions and congenital heart defects: a population-based cohort study. AB - BACKGROUND: This study quantifies the association between maternal medical conditions/illnesses and congenital heart defects (CHDs) among infants. METHODS AND RESULTS: We carried out a population-based study of all mother-infant pairs (n=2,278,838) in Canada (excluding Quebec) from 2002 to 2010 using data from the Canadian Institute for Health Information. CHDs among infants were classified phenotypically through a hierarchical grouping of International Statistical Classification of Diseases and Related Health Problems, 10th Revision, Canada codes. Maternal conditions such as multifetal pregnancy, diabetes mellitus, hypertension, and congenital heart disease were defined by use of diagnosis codes. The association between maternal conditions and CHDs and its subtypes was modeled using logistic regression with adjustment for maternal age, parity, residence, and other factors. There were 26 488 infants diagnosed with CHDs at birth or at rehospitalization in infancy; the overall CHD prevalence was 116.2 per 10,000 live births, of which the severe CHD rate was 22.3 per 10,000. Risk factors for CHD included maternal age >=40 years (adjusted odds ratio [aOR], 1.48; 95% confidence interval [CI], 1.39-1.58), multifetal pregnancy (aOR, 4.53; 95% CI, 4.28-4.80), diabetes mellitus (type 1: aOR, 4.65; 95% CI, 4.13-5.24; type 2: aOR, 4.12; 95% CI, 3.69-4.60), hypertension (aOR, 1.81; 95% CI, 1.61-2.03), thyroid disorders (aOR, 1.45; 95% CI, 1.26-1.67), congenital heart disease (aOR, 9.92; 95% CI, 8.36-11.8), systemic connective tissue disorders (aOR, 3.01; 95% CI, 2.23-4.06), and epilepsy and mood disorders (aOR, 1.41; 95% CI, 1.16-1.72). Specific CHD subtypes were associated with different maternal risk factors. CONCLUSIONS: Several chronic maternal medical conditions, including diabetes mellitus, hypertension, connective tissue disorders, and congenital heart disease, confer an increased risk of CHD in the offspring. PMID- 23812183 TI - Symptomatic low-gradient severe aortic stenosis with preserved left ventricular ejection fraction: now less of a clinical conundrum. PMID- 23812184 TI - Impact of aortic valve replacement on outcome of symptomatic patients with severe aortic stenosis with low gradient and preserved left ventricular ejection fraction. AB - BACKGROUND: The optimal management of low-gradient "severe" aortic stenosis (mean gradient <40 mm Hg, indexed aortic valve area <=0.6 cm2/m2) with preserved left ventricular ejection fraction remains controversial because gradients may be similar after aortic valve replacement (AVR). We compared outcomes of low gradient severe aortic stenosis with AVR or medical therapy. METHODS AND RESULTS: Comprehensive echocardiographic measurements including hemodynamic calculations were completed in 260 prospectively identified patients with symptomatic low gradient severe aortic stenosis. Patients were followed up for mortality over 28+/-24 months. AVR was performed in 123 patients (47%). Compared with AVR patients, medically treated patients had a higher prevalence of diabetes mellitus (25% versus 41%, P=0.009), lower stroke volume index (36.4+/-8.4 versus 34.4+/ 8.7 mL/m2, P=0.02), higher pulmonary artery pressure (38+/-11 versus 48+/-21 mm Hg, P=0.001), and higher creatinine level (1.1+/-0.4 versus 1.22+/-0.5 mg/dL, P=0.02). These and other clinically relevant variables were entered into a propensity model that reflected likelihood of referral to AVR. This score and other variables were entered into a Cox model to explore the independent effect of AVR on outcome. During follow-up, 105 patients died (40%): 32 (30%) in the AVR group and 73 (70%) in the medical treatment group. AVR (hazard ratio, 0.54; 95% confidence interval, 0.32-0.94; P<0.001) was independently associated with outcome and remained a strong predictor of survival after adjustment for propensity score. Medical therapy was associated with 2-fold greater all-cause mortality than AVR. The protective effect of AVR was similar in 125 patients with normal flow (stroke volume index >35 mL/m2; P=0.22). CONCLUSIONS: AVR is associated with better survival than medical therapy in patients with symptomatic low-gradient severe AS and preserved left ventricular ejection fraction. PMID- 23812185 TI - Bright, long-lived and coherent excitons in carbon nanotube quantum dots. AB - Carbon nanotubes exhibit a wealth of unique physical properties. By virtue of their exceptionally low mass and extreme stiffness they provide ultrahigh-quality mechanical resonances, promise long electron spin coherence times in a nuclear spin free lattice for quantum information processing and spintronics, and feature unprecedented tunability of optical transitions for optoelectronic applications. Excitons in semiconducting single-walled carbon nanotubes could facilitate the upconversion of spin, mechanical or hybrid spin-mechanical degrees of freedom to optical frequencies for efficient manipulation and detection. However, successful implementation of such schemes with carbon nanotubes has been impeded by rapid exciton decoherence at non-radiative quenching sites, environmental dephasing and emission intermittence. Here we demonstrate that these limitations may be overcome by exciton localization in suspended carbon nanotubes. For excitons localized in nanotube quantum dots we found narrow optical lines free of spectral wandering, radiative exciton lifetimes and effectively suppressed blinking. Our findings identify the great potential of localized excitons for efficient and spectrally precise interfacing of photons, phonons and spins in novel carbon nanotube-based quantum devices. PMID- 23812186 TI - Observation of room-temperature ballistic thermal conduction persisting over 8.3 um in SiGe nanowires. AB - In ballistic thermal conduction, the wave characteristics of phonons allow the transmission of energy without dissipation. However, the observation of ballistic heat transport at room temperature is challenging because of the short phonon mean free path. Here we show that ballistic thermal conduction persisting over 8.3 um can be observed in SiGe nanowires with low thermal conductivity for a wide range of structural variations and alloy concentrations. We find that an unexpectedly low percentage (~0.04%) of phonons carry out the heat conduction process in SiGe nanowires, and that the ballistic phonons display properties including non-additive thermal resistances in series, unconventional contact thermal resistance, and unusual robustness against external perturbations. These results, obtained in a model semiconductor, could enable wave-engineering of phonons and help to realize heat waveguides, terahertz phononic crystals and quantum phononic/thermoelectric devices ready to be integrated into existing silicon-based electronics. PMID- 23812187 TI - When thermoelectrics reached the nanoscale. PMID- 23812188 TI - Silicon chips detect intracellular pressure changes in living cells. AB - The ability to measure pressure changes inside different components of a living cell is important, because it offers an alternative way to study fundamental processes that involve cell deformation. Most current techniques such as pipette aspiration, optical interferometry or external pressure probes use either indirect measurement methods or approaches that can damage the cell membrane. Here we show that a silicon chip small enough to be internalized into a living cell can be used to detect pressure changes inside the cell. The chip, which consists of two membranes separated by a vacuum gap to form a Fabry-Perot resonator, detects pressure changes that can be quantified from the intensity of the reflected light. Using this chip, we show that extracellular hydrostatic pressure is transmitted into HeLa cells and that these cells can endure hypo osmotic stress without significantly increasing their intracellular hydrostatic pressure. PMID- 23812190 TI - Is proton pump inhibitor therapy for reflux esophagitis sufficient?: a large real world survey of Japanese patients. AB - OBJECTIVE: Proton pump inhibitors (PPIs) are widely used as the mainstay of treatment for erosive reflux esophagitis, based on the excellent results obtained in clinical trials. However, the endoscopic remission rates in patients treated with PPIs in actual clinical settings have not been fully assessed. We conducted a nationwide survey to evaluate the effectiveness of PPIs based on endoscopic findings in real-world clinical settings. METHODS: This was a multicenter retrospective study conducted among 41 Japanese institutions. Endoscopic findings before and after PPI therapy were collected from the medical records of patients diagnosed with Los Angeles grade A-D reflux esophagitis who had been treated with a PPI for at least eight weeks before undergoing a second endoscopy. The remission rates of erosive esophagitis, defined as the percentage of patients with grade N or M findings following PPI therapy, were calculated. RESULTS: Data for 541 patients were analyzed. At first endoscopy, 45.5%, 30.3%, 15.9% and 8.3% of patients were diagnosed with grade A, B, C and D esophagitis, respectively. The mean duration of PPI therapy was 410 days, and the mean remission rate was 61.6%. The remission rate was significantly lower in the patients with more severe erosive esophagitis based on the LA grade before PPI therapy. CONCLUSION: This study revealed that approximately 40% of the patients did not achieve remission of erosive esophagitis following PPI therapy for a mean of 1.1 years. This suggests the necessity of providing careful follow-up using periodic endoscopy and appropriately selecting PPI therapy. PMID- 23812189 TI - Rapid detection of bacterial resistance to antibiotics using AFM cantilevers as nanomechanical sensors. AB - The widespread misuse of drugs has increased the number of multiresistant bacteria, and this means that tools that can rapidly detect and characterize bacterial response to antibiotics are much needed in the management of infections. Various techniques, such as the resazurin-reduction assays, the mycobacterial growth indicator tube or polymerase chain reaction-based methods, have been used to investigate bacterial metabolism and its response to drugs. However, many are relatively expensive or unable to distinguish between living and dead bacteria. Here we show that the fluctuations of highly sensitive atomic force microscope cantilevers can be used to detect low concentrations of bacteria, characterize their metabolism and quantitatively screen (within minutes) their response to antibiotics. We applied this methodology to Escherichia coli and Staphylococcus aureus, showing that live bacteria produced larger cantilever fluctuations than bacteria exposed to antibiotics. Our preliminary experiments suggest that the fluctuation is associated with bacterial metabolism. PMID- 23812191 TI - Assessment of track microbubble flow signals on contrast-enhanced ultrasound with perflubutane following percutaneous liver biopsy. AB - OBJECTIVE: It is important to detect post-liver biopsy hemorrhage early and confirm hemostasis in the clinical setting. Contrast-enhanced ultrasound (CEUS) is a sensitive and highly specific tool for detecting active bleeding. The aim of this study was to investigate the rate of detection of track microbubble flow signals on CEUS with perflubutane following liver biopsy and to assess the disappearance of these signals. METHODS: Microbubble flow signals along the needle track on CEUS were examined in 100 patients who underwent percutaneous US guided liver biopsies. The microbubble flow signals were examined repeatedly until their disappearance. The patients were followed up with clinical and laboratory data to detect clinically significant hemorrhaging. RESULTS: Microbubble flow signals on CEUS following percutaneous liver biopsy were seen in 33% of the patients. There were no significant differences in the platelet count, prothrombin time or length of the biopsy specimen between the patients with and those without microbubble flow signals on CEUS. The microbubble flow signals disappeared over time in all patients. There were no cases of clinically significant hemorrhaging in the present study. CONCLUSION: Track microbubble flow signals on CEUS are frequently observed after biopsies. The disappearance of a microbubble flow signal is a useful index for confirming hemostasis of postbiopsy hemorrhaging. PMID- 23812192 TI - Liver dysfunction in patients with systemic lupus erythematosus. AB - OBJECTIVE: We aimed to define the clinical features of liver dysfunction in patients with systemic lupus erythematosus (SLE). METHODS: The frequency and causes of liver dysfunction were examined in 206 patients with SLE. RESULTS: Liver dysfunction was evident in 123 (59.7%) of the 206 patients. Liver dysfunction in patients with SLE can be drug-induced (30.9%) or caused by SLE itself (28.5%), fatty liver (17.9%), autoimmune hepatitis (AIH) (4.9%), primary biliary cirrhosis (2.4%), cholangitis (1.6%), alcohol (1.6%) or viral hepatitis (0.8%), and it tends to be mild except when caused by AIH. Values for aminotransferase were significantly increased when AIH was the cause, whereas alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (gamma-GTP) were significantly increased when AIH or drugs were the cause. The liver was already dysfunctional at the time of SLE onset in 56 (45.5%) of 123 patients with liver dysfunction. Neurological involvement was more common among patients with than without liver dysfunction, whereas SLE activity and prognosis did not significantly differ between the two groups. CONCLUSION: Liver dysfunction in the presence of SLE can be caused by many factors, but when extant at the time of SLE onset, either SLE itself or drugs can be the cause. Autoimmune hepatitis should be considered when liver dysfunction is relatively severe. PMID- 23812193 TI - Increased uric acid promotes decline of the renal function in hypertensive patients: a 10-year observational study. AB - OBJECTIVE: Uric acid (UA) has shown to be a causal risk factor for the development and progression of renal disease. The aim of this study was to investigate the relationship between changes in the level of UA and trends in the renal function among hypertensive patients during a 10-year observation period. METHODS: The subjects included 104 hypertensive outpatients (60 women and 44 men, mean age 60+/-9 (SD) years at the first visit) who had undergone at least five instances of successful 24-hour home urine collection, with the first examination completed between 1998 and 2000 and the last examination completed between 2008 and 2010. RESULTS: The estimated glomerular filtration rate (eGFR) significantly decreased over the 10.4-year observation period, with an average change in eGFR of -0.66/mL/min/year. The uric acid clearance at the last examination was significantly lower than that observed at the first visit, while there were no significant differences in the serum UA levels during this period. The change in serum UA exhibited a significant negative correlation with the change in eGFR (r= 0.34, p<0.01). The patients whose UA level decreased more than 0.5 mg/dL during the observation period demonstrated significantly smaller declines in eGFR compared to those whose UA level increased more than 0.5 mg/dL. In the multivariate analysis, the change in serum UA and the average urinary salt excretion during the observation period were found to be significantly associated with the change in eGFR, independent of age, sex, BP changes or an increased number of antihypertensive drugs. CONCLUSION: Based on the findings observed over a 10-year observation period, increased UA is suggested to promote decline of the renal function in hypertensive patients. Controlling the level of UA as well as intensively restricting salt intake is required in order to preserve the renal function. PMID- 23812194 TI - Echoic features of lymph nodes with sarcoidosis determined by endobronchial ultrasound. AB - OBJECTIVE: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS TBNA) is a minimally invasive technique with a high diagnostic yield used in the investigation of mediastinal diseases including sarcoidosis. Although previous reports have discussed the echoic features of metastatic mediastinal lymph nodes in lung cancer, few have addressed those features of mediastinal lymph nodes with sarcoidosis. We therefore investigated whether the echoic features of lymph nodes with sarcoidosis are distinct when compared to those of metastatic lymph nodes in lung cancer. METHODS: This retrospective analysis was held in one university hospital between April 2007 and June 2011. EBUS-guided biopsies were performed on 219 patients, and thus resulting in sarcoidosis diagnoses in 53 patients. We quantitatively analyzed the echoic morphologic features of 42 lymph nodes from 34 sarcoidosis patients and 59 lymph nodes from 44 patients with lung cancer using digital image analyzing software. RESULTS: In patients with sarcoidosis, 64.3% of the lymph nodes had a round shape, 71.4% had a distinct margin, and 88.1% exhibited homogeneous echogenicity. A germinal center structure was observed in 71.4% of the cases. In the context of shape and margin, no significant difference could be observed between sarcoidosis and lung cancer metastasis. However, homogeneous low echogenicity and the presence of a germinal center structure were observed in sarcoidosis more frequently than in lung cancer. CONCLUSION: Homogeneous low echogenicity and the presence of a germinal central structure may be distinctive echoic features of lymph nodes with sarcoidosis. Analyzing the echogenicity of the mediastinal lymph nodes may help to distinguish sarcoidosis from lung cancer. PMID- 23812195 TI - Environmental characteristics and oxidative stress of inhabitants and patients with amyotrophic lateral sclerosis in a high-incidence area on the Kii Peninsula, Japan. AB - OBJECTIVE: Although Oshima, in the Kii Peninsula of Japan, is located within a high incidence area of amyotrophic lateral sclerosis (ALS) (Koza/Kozagawa/Kushimoto area, K area), no patients with ALS were detected between 1960 and 1999. However, the incidence recently increased between 2000 and 2009. On Oshima, the source of drinking water was changed from a regional river/wells to the Kozagawa River in the K area in 1975. We speculate that this change in water source may have played a role in the recent increase in the incidence of ALS. The aim of this study is to find contributing factors that may have triggered the locally high incidence of ALS. METHODS: We investigated a possible association between the mineral content of drinking water and serum and oxidative stress markers among patients with ALS in the K area (K-ALS), residents of Oshima and controls. RESULTS: We found that the levels of Ca and Zn in the recent drinking water in Oshima are low and that the serum levels of Ca and Zn in the Oshima residents and patients with K-ALS were significantly lower, while the oxidative stress markers were significantly higher, than those of the controls. The serum Zn and urinary 8-OHdG/creatinine levels explained 60% and 58% of the variations among the three groups, respectively. The serum Zn levels were negatively correlated with the serum Cu levels in the patients with K-ALS, and the serum Cu levels exhibited a tendency to be positively correlated with the 8 OHdG/creatinine levels in both the patients with K-ALS (r: 0.64) and the residents free from K-ALS (r: 0.32, p<0.01). CONCLUSION: Taken together, we suggest that the low levels of Ca and Zn in the drinking water are possibly associated with an imbalance of metal metabolism in Oshima residents and an increase in oxidative stress markers in patients with K-ALS, although the causative relationship is not clear. This is a cross-sectional study, and a prospective study is needed in the future. PMID- 23812196 TI - Changes in the mean platelet volume levels after bloodstream infection have prognostic value. AB - OBJECTIVE: Thrombocytopenia is frequently observed during bloodstream infection (BSI); however, little is known about the trends in platelet size during BSI. The aim of this study was to investigate trends in platelet indices during BSI and to determine the relationship between the mean platelet volume (MPV) levels and the prognosis of BSI patients. METHODS: We conducted a four-year retrospective study to assess the trends in the platelet indices and the clinical features of BSI. We enrolled 350 patients with positive blood cultures and measured the platelet indices during five periods: 30 to seven days before onset (1st period); within one day of onset (2nd period); three to five days after onset (3rd period); seven to 10 days after onset (4th period); and 14 to 19 days after onset (5th period). The end point was defined as 30-day mortality. RESULTS: Among the BSI patients, the average platelet count decreased during BSI (29.4 *10(9)/L to 24.0 *10(9)/L, p<0.001), while the average MPV level increased (7.33 fL to 7.89 fL, p<0.001). The degree of MPV elevation in the nonsurvivors (n=25) was lower than that observed in the survivors (n=325) between the 1st and 2nd periods (0.00 fL vs. 0.35 fL, p=0.006), whereas between the 2nd and 3rd periods, the degree of MPV elevation in the nonsurvivors was higher than that observed in the survivors (0.74 fL vs. 0.19 fL, p=0.03). MPV elevation after BSI was identified to be a negative prognostic factor for BSI (odds ratio: 1.82; 95% confidence interval: 1.00-3.32; p=0.027). CONCLUSION: Changes in the MPV levels after BSI may therefore be a useful prognostic marker for BSI. PMID- 23812197 TI - Clostridium difficile infection associated with antituberculous agents in a patient with tuberculous pericarditis. AB - Clostridium difficile can cause pseudomembranous colitis (PMC). Antimicrobial agent exposure is a risk factor for Clostridium difficile-associated disease, whereas the use of antituberculous (anti-TB) agents is not. We herein report a case of PMC-associated with antituberculous therapy. A 63-year-old woman with tuberculous pericarditis treated with anti-TB agents was admitted for abdominal pain and diarrhea. On colonoscopy, mucoid exudate and yellowish plaque lesions were observed. The anti-TB agents were discontinued, and the patient was treated with metronidazole and clostridium butyricum. Her symptoms were relieved and did not recur when the anti-TB agents were restarted. In this report, we review the literature and discuss the pathogenesis, clinical manifestations, diagnosis and treatment of this case. PMID- 23812198 TI - Spontaneously remitted pulmonary arterial hypertension associated with the herbal medicine "bofutsushosan". AB - Although the link between pulmonary arterial hypertension (PAH) and exposure to certain drugs has already been identified, we herein present the first case of herbal medicine-associated PAH in which the patient demonstrated spontaneous remission. A 38-year-old woman took the herbal medicine "bofutsushosan" for two weeks then stopped taking it due to exertional dyspnea. However, her dyspnea continued, and right heart catheterization revealed a mean pulmonary arterial pressure of 41 mmHg with a normal wedge pressure. Several months after treatment with oxygen therapy, the patient's dyspnea disappeared, and her pulmonary arterial pressure normalized. Further studies focusing on susceptibility factors to drug-induced pulmonary arterial hypertension are needed. PMID- 23812199 TI - Successful treatment of a patient with multicentric Castleman's disease who presented with thrombocytopenia, ascites, renal failure and myelofibrosis using tocilizumab, an anti-interleukin-6 receptor antibody. AB - We herein describe an unusual case of multicentric Castleman's disease accompanied by thrombocytopenia, ascites, renal failure and myelofibrosis in a Japanese woman. The patient was initially diagnosed as having myelodysplastic syndrome with myelofibrosis. The general condition of the patient deteriorated rapidly; however, treatment with tocilizumab, an anti-interleukin-6 receptor antibody, together with corticosteroids dramatically improved her symptoms. The clinical features of this case were similar to those of three cases previously reported by Takai et al. (Rinsho Ketsueki, 2010, 51:320-5), which were determined to be thrombocytopenia, anasarca, fever, reticulin myelofibrosis and organomegaly (TAFRO) syndrome, a possibly distinct clinical entity. PMID- 23812200 TI - Two cases of acute erythroid leukemia presenting with marked macrocytic anemia, reticulocytosis and hemolysis. AB - Case 1. The laboratory findings of a hematological analysis of a 53-year-old woman with palpitations and dyspnea revealed the following: red blood cell (RBC) count: 9.4*10(5)/MUL with 60.00/00 reticulocytes; Hb: 3.7 g/dL; mean corpuscular volume (MCV): 124.5 fL; white blood cell (WBC) count: 2,800/MUL with 10.0% myeloblasts. Case 2. Similarly, a 42-year-old man with dizziness had a RBC count of 1.63*10(6)/MUL with 24.0% reticulocytes, an Hb level of 6.0 g/dL, an MCV of 120.2 fL and a WBC count of 3,100/MUL with 4.0% myeloblasts. Bone marrow aspirates in both patients confirmed a diagnosis of acute erythroid leukemia (AEL), which can present as marked macrocytic anemia with an MCV in excess of 120 fL and hemolysis. PMID- 23812201 TI - POEMS syndrome presenting with acute demyelinating polyneuropathy: increased terminal latency indices and uniform demyelination. AB - We herein report a case of polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes (POEMS) syndrome presenting with acute Guillain-Barre syndrome (GBS)-like features. The patient was healthy, except for mild dilated cardiomyopathy. She was unable to walk within ten days of the onset of weakness. A nerve conduction study (NCS) showed length-dependent, symmetric and non-focal demyelinating features with increased terminal latency indices (TLIs) in the lower limbs. Following the administration of intravenous immunoglobulin infusion, the proximal weakness of the lower extremities improved; however, the pleural effusion was aggravated and ascites newly developed. On further work-ups, splenomegaly, M-protein and sclerotic bone changes were observed. This case suggests that, although rare, POEMS syndrome can present with acute demyelinating polyneuropathy resembling GBS and that characteristic NCS features such as increased TLI and uniform demyelination are helpful for the early diagnosis of POEMS syndrome. PMID- 23812202 TI - Anti-aquaporin-4 antibody-seronegative NMO spectrum disorder with Balo's concentric lesions. AB - A 34-year-old woman developed simultaneous bilateral severe optic neuritis and subsequent myelitis. Two months after the first attack, she developed a headache and dysesthesia in the left arm. Brain magnetic resonance imaging revealed multiple hyperintense lesions in the white matter of the right hemisphere, some of which were Balo-like concentric lesions. Our diagnosis was neuromyelitis optica spectrum disorder with Balo's concentric sclerosis (BCS), although the patient was negative for anti-aquaporin-4 (anti-APQ4) antibodies. Our case suggests that Balo's concentric sclerosis overlaps with neuromyelitis optica spectrum disorder and that this overlapping is caused by a mechanism that does not involve anti-AQP4 antibodies. PMID- 23812203 TI - Recurrent transient hemiparesis in a patient with a giant persisting Eustachian valve and patent foramen ovale: atypical hemiplegic migraine or paradoxical cerebral embolism? AB - We encountered a patient with the overlapping disorders of migraine with aura, migraine-triggered seizures and recurrent transient hemiparesis caused by atypical hemiplegic migraines with motor weakness during headache attacks, but not during the aura period, or paradoxical cerebral embolism. The patient displayed a giant Eustachian valve and patent foramen ovale, through which a spontaneous right-to-left shunt was revealed on transesophageal echocardiography. We considered that the overlapping disorders in the present case were closely related to the spontaneous right-to-left shunt caused by the giant Eustachian valve. PMID- 23812204 TI - Effectiveness of oral iron chelator treatment with deferasirox in an aceruloplasminemia patient with a novel ceruloplasmin gene mutation. AB - A 59-year-old man presented with refractory anemia, choreoathetosis in the left upper extremity, an unsteady gait and cognitive dysfunction. The laboratory findings showed a marked decrease in ceruloplasmin. Magnetic resonance images revealed iron deposition in the brain and visceral organs. Iron accumulation was also observed in hepatocytes. Genetic analyses of the ceruloplasmin gene revealed a novel homozygous mutation of c.2185 delC in exon 12. The oral chelator deferasirox was effective in treating the left-side choreoathetosis and unsteady gait. Providing early treatment using deferasirox may be useful for preventing the progression of symptomatic neurological dysfunction. PMID- 23812205 TI - Necrotizing pneumonia due to femoral osteomyelitis caused by community-acquired methicillin-resistant Staphylococcus aureus. AB - A chest X-ray of a young healthy African-American man with acute respiratory failure revealed bilateral multiple nodular shadows in the lungs, while community acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) was detected in blood and sputum cultures. Magnetic resonance imaging showed osteomyelitis of the left thigh, and computed tomography revealed bilateral cavitary lesions in the chest, indicating necrotizing pneumonia with pulmonary embolism caused by osteomyelitis as a result of infection with CA-MRSA. CA-MRSA should be suspected as a causative agent of severe community-acquired pneumonia, even in Japan, among patients who belong to communities at high risk of CA-MRSA infection. PMID- 23812206 TI - Mucoid impaction of the bronchi caused by Mycobacterium avium. AB - A 25-year-old woman with a past history of congenital adrenal cortex hypertrophy visited our hospital complaining of a continuous cough. On chest CT, a localized bronchiectatic lesion was recognized with mucoid impaction in the right lower lobe. Because we obtained a positive smear test for acid-fast bacilli and polymerase chain reaction (PCR) of the bronchoscopic specimens was positive for M. avium, we administered combined chemotherapy; however, the clinical effect was poor and video-assisted thoracoscopic surgery (VATS) was performed. As the histological findings revealed a granuloma with caseating necrosis and mucous plugs containing M. avium in the respiratory bronchioles, we diagnosed the patient with mucoid impaction of the bronchi (MIB) due to M. avium. PMID- 23812207 TI - Intracranial hypotension with positional hearing loss. PMID- 23812208 TI - [Dupuytren's contracture associated with silicone wear reaction in late failure of lunate bone spacer prosthesis]. AB - The pathophysiological mechanisms of palmar fibromatosis (Dupuytren's contracture) are still not yet fully understood. In the vast majority of cases, however, reactive changes and reparative processes of tendon tissue can easily be ruled out by clinical and histopathological investigations. This article presents the case of a 62-year-old male patient suffering from palmar fibromatosis associated with a failed silicon spacer of the lunate bone 30 years after index surgery. Although silicon wear particles were observed in distal locations, proximal tendon tissues showed changes consistent with a degenerative palmar fibromatosis in the absence of a pathological wear reaction. The findings are discussed in the light of the current literature on Dupuytren's contracture. PMID- 23812209 TI - [Early results of gender-specific posterior stabilized total knee arthroplasty without patella resurfacing]. AB - INTRODUCTION: To address anatomical gender differences in total knee arthroplasty (TKA) specific total knee prostheses have been developed for women. Potential benefits of these modified prostheses are currently under debate. The present study investigated whether the modified design features bring benefits compared to uni-sex TKA. METHODS: A total of 80 prospectively blinded and randomized patients underwent implantation of unilateral TKAs with NexGen LPS Gender Solutions (Zimmer, Warsaw, USA, group gender-specific GS prosthesis, n = 40) or NexGen LPS Flex (Zimmer, Warsaw, USA, control group standard prosthesis ST, n = 40) The follow-up was carried out 10 days and 6 weeks postoperatively. Clinical data and the subjective assessment of quality of life were evaluated using the Knee Society Clinical Rating System (KSS), the short form 36-item health survey (SF-36) and the Western Ontario and McMaster Universities OA Index (WOMAC). RESULTS: The two groups showed equal values in KSS, SF-36 and WOMAC preoperatively and ten days postoperatively the GS group reached an average KSS knee score of 62.6 +/- 16.1 points (ST group 56.9 +/- 14.7, p = 0.184) and a functional score of 28.5 +/- 12.1 (ST group 24.3 +/- 15.3, p = 0.082). In the overall score the GS group reached 91.1 +/- 24.1 points (ST group 81.0 +/- 27.1, p = 0.104). The GS group reached a knee score of 85.5 +/- 14.4 points (ST group 77.8 +/- 16.8, p = 0.03) and a functional score of 68.1 +/- 20.7 points (ST group 62.3 +/- 18.5, p = 0.185) 6 weeks postoperatively. In the overall score the GS group reached 153.7 +/- 30.7 points (ST group 139.6 +/- 32.4, p = 0.048). The analysis of SF-36 and WOMAC showed no significant differences at all time points. No evidence of loosening or migration was observed in both groups. CONCLUSIONS: Based on the data presented, gender-specific TKA type NexGen LPS Gender Solutions has advantages in terms of early functional outcome. This result is not reflected in the patient satisfaction and is not considered to be clinically relevant. PMID- 23812210 TI - Polymorphisms and tissue expression of the feline leukocyte antigen class I loci FLAI-E, FLAI-H, and FLAI-K. AB - Cytotoxic CD8+ T-cell immunosurveillance for intracellular pathogens, such as viruses, is controlled by classical major histocompatibility complex (MHC) class Ia molecules, and ideally, these antiviral T-cell populations are defined by the specific peptide and restricting MHC allele. Surprisingly, despite the utility of the cat in modeling human viral immunity, little is known about the feline leukocyte antigen class I complex (FLAI). Only a few coding sequences with uncertain locus origin and expression patterns have been reported. Of 19 class I genes, three loci--FLAI-E, FLAI-H, and FLAI-K--are predicted to encode classical molecules, and our objective was to evaluate their status by analyzing polymorphisms and tissue expression. Using locus-specific, PCR-based genotyping, we amplified 33 FLAI-E, FLAI-H, and FLAI-K alleles from 12 cats of various breeds, identifying, for the first time, alleles across three distinct loci in a feline species. Alleles shared the expected polymorphic and invariant sites in the alpha1/alpha2 domains, and full-length cDNA clones possessed all characteristic class Ia exons. Alleles could be assigned to a specific locus with reasonable confidence, although there was evidence of potentially confounding interlocus recombination between FLAI-E and FLAI-K. Only FLAI-E, FLAI-H, and FLAI K origin alleles were amplified from cDNAs of multiple tissue types. We also defined hypervariable regions across these genes, which permitted the assignment of names to both novel and established alleles. As predicted, FLAI-E, FLAI-H, and FLAI-K fulfill the major criteria of class Ia genes. These data represent a necessary prerequisite for studying epitope-specific antiviral CD8+ T-cell responses in cats. PMID- 23812211 TI - Increased longevity of hematopoiesis in continuous marrow cultures and radiation resistance of marrow stromal and hematopoietic progenitor cells from caspase-1 homozygous recombinant-negative (knockout) mice. AB - AIM: We determined whether absence of caspase-1 altered the stress response of hematopoietic and bone marrow stromal cells in vitro. MATERIALS AND METHODS: Long term bone marrow cultures from caspase-1 -/- and control caspase-1 +/+ mice were established and the derived bone marrow stromal and interleukin-3 (Il-3) dependent hematopoietic progenitor cell lines were evaluated for radiosensitivity. RESULTS: Long-term bone marrow cultures from caspase-1 -/- mice generated hematopoietic cells for over 30 weeks in vitro, significantly longer than controls did (p=0.0018). Bone marrow stromal (mesenchymal stem cell) and Il 3-dependent hematopoietic progenitor cell lines from caspase-1-/- marrow cultures compared to caspase-1 +/+ were radioresistant (p=0.0486 and p=0.0235 respectively). Total-body irradiated caspase-1 -/- mice were not significantly radioresistant compared to controls (p=0.6542). CONCLUSION: Caspase-1 deletion increases hematopoiesis and radioresistance of bone marrow cells in vitro. PMID- 23812212 TI - Targeting cancer with a bi-functional peptide: in vitro and in vivo results. AB - BACKGROUND: Current therapies to treat cancer, although successful for some patients, have significant side-effects and a high number of patients have disease that is either non-responsive or which develops resistance. Our goal was to design a small peptide that possesses similar functions to an antibody drug conjugate with regard to targeting and killing cancer cells, but that overcomes size restrictions. MATERIALS AND METHODS: We designed a novel cancer-specific killer peptide created by fusion of the toxic peptide (KLAKLAK)2 with the cancer recognition peptide LTVSPWY. RESULTS: This bi-functional peptide showed toxicity to breast cancer, prostate cancer, and neuroblastoma cell lines. Only low toxicity to non-cancer cells, colon cancer, lung cancer, and lymphoma cell lines was observed. In vivo injections of the bi-functional peptide caused tumor growth retardation compared to mice treated with control peptides. The bi-functional peptide caused retardation of MDA-MB-435S tumors in vivo and increased survival to 80% at day 100 after tumor implantation, whereas all control animals died at day 70. Previous reports showed that the recognition moiety LTVSPWY targets the tumor-associated antigen HER2. Here we found that our new peptide TP-Tox also excerts toxic effects on HER2-negative cell lines. Therefore, we searched for the molecular target of the bi-specific peptide using immunoprecipitation and mass spectrometry. Our data suggest a possible interaction with RAS GTPase-activating protein binding protein 1 (G3BP1). CONCLUSION: We designed a bi-functional peptide of 23 amino acids and demonstrated its ability to bind and kill several cancer cell lines in vitro and to strongly increase survival in breast cancer bearing mice in vivo. This novel toxin could be used in future cancer therapies and warrants further pre-clinical and clinical exploration. PMID- 23812213 TI - Intraluminal gel ultrasound and eco-color doppler: new tools for the study of colorectal cancer in mice. AB - AIM: Azoxymethane (AOM) is a potent carcinogen that induces colorectal cancer in mice. Intraluminal gel ultrasound is a technique based on the injection of gel into the rectum. This technique allows the colon to be straightened and to visualize and identify tumours. MATERIALS AND METHODS: Twenty female C57Bl/6J mice were injected intraperitoneally with 10 mg/kg of AOM one time per week for six weeks. The mice were monitored by ultrasound with a Vevo 2100 system. We evaluated the tumour area and tumour vasculature with Ecocolor-Doppler (ECD). Histological examination of sacrificed mice was employed as the standard protocol. RESULTS: After 40 weeks from the injection, ultrasound analysis revealed the presence of tumours in 50% of all mice. Ex vivo analysis revealed the presence of 57% true-positives and only one false-positive. In two mice, ultrasound did not reveale the presence of tumour due to its small dimension. This indicates that ultrasound is able to detect only tumours with sizes >=3 mm2. CONCLUSION: Ultrasound is a rapid examination compared to other diagnostic techniques. It has a good sensitivity when the tumours reach the dimensions of 3 mm2 or more. Intraluminal gel allows for the tumour area to be evaluated when mice are still alive, while ECD allows for vasculature of intestinal walls and colorectal tumour to be evaluated. PMID- 23812214 TI - Inhibitory effects of tocopherols on expression of the cyclooxygenase-2 gene in RAW264.7 cells stimulated by lipopolysaccharide, tumor necrosis factor-alpha or Porphyromonas gingivalis fimbriae. AB - BACKGROUND: Tocopherols, which include alpha-, beta-, gamma-, and delta tocopherol, protect cells against harmful free radicals and play an important role in preventing many human diseases such as cancer, inflammatory disorders, and ageing itself. However, the causal relationships between periodontal or oral chronic diseases and tocopherols have not been sufficiently studied. The present study investigated the inhibitory effects of these compounds on the expression of cyclooxygenase-2 (COX2) mRNA in RAW264.7 cells stimulated with lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNFalpha) or fimbriae of Poryphyromonas gingivalis (Pg), an oral anaerobe. MATERIALS AND METHODS: The cytotoxicity (EC50) of tocopherols toward RAW cells was determined using a cell counting kit (CCK-8). The regulatory effect of these compounds on the expression of COX2 mRNA stimulated with LPS, TNFalpha or Pg fimbriae was investigated using real-time polymerase chain reaction (PCR). RESULTS: Each tocopherol had similarly low cytotoxicity. COX2 gene expression in RAW cells after exposure to the three different macrophage activators was inhibited by the tocopherols (p<0.01). Compared to alpha-tocopherol, beta-, gamma- and delta-tocopherol exhibited greater inhibitory effects (p<0.05). CONCLUSION: Tocopherols exhibit anti inflammatory activity, and beta-, gamma- and delta-tocopherol have particularly more potent anti-inflammatory activity than alpha-tocopherol. Tocopherols may have potential utility for prevention of periodontal and chronic oral diseases. PMID- 23812215 TI - Hypothermia inhibits expression of CD11b (MAC-1) and CD162 (PSGL-1) on monocytes during extracorporeal circulation. AB - AIM: The aim of the present study was to investigate the effect of different hypothermic temperatures on the expression of cellular adhesion molecules on leukocytes. MATERIALS AND METHODS: Circulation of blood from six volunteers was performed in an extracorporeal circulation model at 36 degrees C, 28 degrees C and 18 degrees C for 30 minutes. Expression of CD11b, CD54 and CD162 on monocytes was measured using flow cytometry. RESULTS: Expression of CD11b significantly decreased at 18 degrees C and at 28 degrees C compared to 36 degrees C. A significant reduction of CD162 expression was found at 18 degrees C compared to 28 degrees C and 36 degrees C and at 28 degrees C compared to 36 degrees C. No association was found between temperature and expression of CD54. CONCLUSION: Expression of CD11b and CD162 on monocytes has a temperature-dependent regulation, with decreased expression during hypothermia, which may result in an inhibition of leukocyte-endothelial and leukocyte-platelet interaction. This beneficial effect may influence the extracorporeal circulation-related inflammatory response and tissue damage. PMID- 23812216 TI - Morphological characterization of systemic changes in KK-Ay mice as an animal model of type 2 diabetes. AB - BACKGROUND: KK-Ay mice, a relevant model of human type 2 diabetes mellitus, are used worldwide for the assessment of pharmacological effects of new anti-diabetes drugs. MATERIALS AND METHODS: KK-Ay mice were examined at five weeks of age (non hyperglycemic condition) and at 10 and 14 weeks of age (hyperglycemic condition). RESULTS: Islet cell hypertrophy was observed in 10- and 14-week-old mice. The area ratio of islet cells to total pancreas significantly increased compared to that of age-matched C57BL/6J mice. Plasma insulin concentration increased in 14 week-old KK-Ay mice. Enlargement of mesangial matrix and increased glomerular area were seen in kidneys of KK-Ay mice. Fatty changes were observed in the liver. Total plasma cholesterol and triglyceride levels increased compared to that of five-week-old KK-Ay mice. CONCLUSION: The present results on young/adult KK-Ay mice indicate that the hyperglycemic state developing at the early stage of diabetes mellitus is due to related changes in systemic organs. PMID- 23812218 TI - Rat hepatic and splanchnic vascular responses to anaphylactic shock, compared with hemorrhagic or vasodilator-induced shock. AB - BACKGROUND: Hemodynamics during anaphylactic shock remain unclear. We determined hepatic and splanchnic responses to anaphylactic hypotension, compared with hemorrhage or sodium nitroprusside (SNP)-induced hypotension, in anesthetized rats. MATERIALS AND METHODS: Portal pressure, systemic arterial pressure (SAP), central venous pressure, portal and hepatic arterial blood flow were measured. Splanchnic (Rspl), portal venous (Rpv), and hepatic arterial (Rha) resistances were determined. RESULTS: In rats with anaphylaxis induced by an intravenous injection of the ovalbumin antigen (n=6), hemorrhage (n=6), and SNP (2 mg/kg, n=6), SAP decreased similarly. During anaphylaxis, Rha and Rspl decreased only at 30 s after the antigen injection. Notably, Rpv increased markedly. During hemorrhage, Rspl and Rha increased and decreased, respectively, with Rpv not changing. After SNP, Rha and Rspl decreased with Rpv not changing. CONCLUSION: Hepatic and splanchnic vascular responses differ according to the type of shock. Anaphylactic hypotension is characterized by markedly increased portal venous resistance. Splanchnic and hepatic artery dilatation occurs only at the beginning of hypotension in anesthetized rats. PMID- 23812217 TI - Comparable molecular alterations in 4-nitroquinoline 1-oxide-induced oral and esophageal cancer in mice and in human esophageal cancer, associated with poor prognosis of patients. AB - BACKGROUND: The murine model of 4-nitroquinoline 1-oxide (4-NQO)-induced oral and esophageal cancer is frequently used to assess the effects of different cancer prevention/ therapy agents in vivo, but the molecular mechanisms in those 4-NQO induced carcinogenesis are unknown. This study investigated aberrant expression of cell growth-critical genes in 4-NQO-induced oral and esophageal cancer tissues in mice compared to those present in the human disease for association with survival of patients. MATERIALS AND METHODS: C57LB6/129Sv mice were given 4-NQO in their drinking water to induce oral and esophageal cancer. Quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blot, and immunohistochemistry were used to detect gene expression in the cancer tissues from mice and in 4-NQO-treated human esophageal cancer cell lines and esophageal cancer tissues. Methylation-specific PCR and DNA sequencing were performed to assess methylation of the Rarb2 promoter in murine tissues. Kaplan-Meier analysis was performed to associate gene expression in esophageal cancer tissues with survival data for patients with esophageal cancer. RESULTS: 4-NQO dose dependently induced pre-malignant and malignant lesions in the oral cavity and esophagus in mice that pathologically and morphologically mimicked human oral and esophageal cancer. Molecularly, 4-NQO inhibited Rarbeta2 but induced expression of phosphorylated extracellular-signal-regulated kinase-1 and -2 (p-ERK1/2) and Cox2 proteins and Rarbeta2 gene promoter methylation in murine tumors. In vitro treatment with 4-NQO altered expression of RARbeta2, p-ERK1/2, and COX2 in human esophageal cancer cells. In tissues from 90 patients with esophageal cancer, expression of p-ERK1/2 and COX2 was up-regulated, and p-ERK1/2 expression was associated with advanced clinical tumor stage and consumption of hot beverages, while COX2 expression was associated with tumor de-differentiation in esophageal cancer. Furthermore, expression of p-ERK1/2 was associated with a worse overall survival rate of patients (p=0.014), whereas the association of COX2 expression with worse overall survival rate did not reach statistical significance (p=0.19). Knockdown of COX2 expression using transient transfection of a COX2 antisense expression vector inhibited Ki67 expression, an indicator of cell proliferation, in human esophageal cancer cells. CONCLUSION: 4-NQO-induced cancer in oral cavity and esophagus of mice not only pathologically and morphologically mimicked human oral and esophageal cancer, but also shared some molecular alterations (e.g. aberrant expression of Rarb2, p-ERK1/2, and Cox2). This study further demonstrated that targeting of the altered RARbeta2-led gene pathway could effectively suppress the development of this deadly type of cancer. PMID- 23812219 TI - Differentiation of human umbilical cord-derived mesenchymal stem cells, WJ-MSCs, into chondrogenic cells in the presence of pulsed electromagnetic fields. AB - During cartilage regeneration, proliferation and differentiation of new chondrocytes are required and towards this goal, in humans electromagnetic stimulation has been used in order to increase the spontaneous regenerative capacity of bone and cartilage tissue. In vivo tissue engineering has pointed out that the absence of an abundant source of cells accelerating the healing process is a limiting factor in the ability to repair articular cartilage. Considering that the umbilical cord is a viable alternative source of mesenchymal stem cells (MSC), our study evaluated the possibility of a combined use of Wharton's jelly - mesenchymal stem cells (WJ-MSCs) and pulsed electromagnetic field (PMEF). The first effect observed was that compared with the untreated cells, when the WJ MSCs were treated with PMEF, there was an increase in the division of cells and a rapid increase in cell density and the morphological and biochemical data showed that the treatment with PMEF reduced the time to obtain chondrocyte cell differentiation and deposition of extracellular matrix. Taken together these data indicate the capacity of PEMF to induce early differentiation of WJ-MSCs cells towards cartilaginous tissue. PMID- 23812220 TI - Localization and modulation of NEDD8 protein in the human placenta. AB - BACKGROUND: Neural precursor cell-expressed, developmentally down-regulated-8 (NEDD8) is a 76-amino-acid ubiquitin-like polypeptide. NEDD8 affects the signaling of various molecules but the major cellular target proteins are cullins. The neddylation process is correlated closely with apoptosis, cell-cycle regulation, embryogenesis and development. AIM: The purpose of the present work was to investigate NEDD8 distribution and expression in the human placenta during gestation. MATERIALS AND METHODS: A total of 30 samples, 15 chorionic villous samples from first trimester and 15 from full-term placentae, were used for the immunohistochemical analysis of NEDD8 expression. The gestation period ranged from 5 to 40 weeks. RESULTS: NEDD8 was highly expressed in the cytotrophoblast of the first trimester of gestation, whereas in the third trimester, it was localized in the endothelial cells and stroma of placental villi. CONCLUSION: Our results suggest that NEDD8 may play an important role in the control of proliferation and differentiation of human placenta throughout pregnancy. PMID- 23812221 TI - Cytotoxic activity of benzo[b]cyclohept[e][1,4]oxazines. AB - BACKGROUND: Although numerous articles have dealt with the biological activities of azulenes, studies of benzo[b]cyclohept[e][1,4]oxazines are limited. In the present study, we investigated a total of 14 newly-synthesized benzo[b]cyclohept[e][1,4]oxazines for their growth stimulation at low concentrations (so-called 'hormesis'), cytotoxicity at higher concentrations and apoptosis-inducing activity. MATERIALS AND METHODS: Cytotoxicity of these compounds against human normal gingival fibroblast (HGF) and human oral squamous cell carcinoma cell lines derived from gingival tissue (Ca9-22), was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. The tumor specificity (TS) was determined by the ratio of the 50% cytotoxic concentration (CC50) value for HGF cells to that for Ca9-22 cells. Apoptosis induction was evaluated by DNA fragmentation and caspase-3 activation. RESULTS: Compounds 10-(2-methoxyethylamino)benzo[b] cyclohept[e][1,4]oxazine and 10-(3 methoxypropylamino) benzo[b]cyclohept[e][1,4] oxazine, but not other compounds, induced hormesis only in HGF cells. Compound 10-(6-hydroxyhexylamino)benzo[b] cyclohept[e][1,4]oxazine [4] showed the highest cytotoxicity against Ca9-22 cells, followed by 10-(4-hydroxybutylamino) benzo[b]cyclohept[e] [1,4]oxazine and 10-(5-hydroxypentylamino)benzo[b]cyclo-hept[e][1,4]oxazine. Compound [4] did not induce apoptosis markers, but rather induced necrotic cell death (characterized by a smear pattern of DNA fragmentation). CONCLUSION: The present study suggests that the OH group and a certain length of methylene group are necessary for maximal cytotoxicity, and substitution of fluoride in the benzene ring enhances cytotoxicity. PMID- 23812222 TI - Inhibition of nitric oxide synthesis enhances teratogenic effects induced by valproic Acid. AB - BACKGROUND/AIM: The mechanism of valproic acid (VPA)-induced teratogenicity is poorly known. This study was carried out to probe into the potential consequences of nitric oxide (NO) deprivation on VPA teratogenicity. MATERIALS AND METHODS: On gestation day 8, mice were injected with a non-teratogenic dose (20 mg/kg) of the nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl esther (L NAME). Thirty minutes later, animals received a teratogenic dose of VPA (400 or 500 mg/kg). Developmental end-points were evaluated near the end of gestation. RESULTS: After treatment with VPA at 400 mg/kg, 35.2% of fetuses exhibited skeletal teratogenesis. The rate of skeletally affected fetuses significantly increased to 53.7% after L-NAME co-administration. In the group treated with VPA at 500 mg/kg group, L-NAME pre-treatment increased the incidence of exencephaly from 5.4% to 22.2%. CONCLUSION: Inhibition of NO synthesis can result in an enhancement of VPA-induced teratogenesis. PMID- 23812223 TI - Painless angioleiomyoma of the first web space of the hand. AB - Angioleiomyoma is a benign dermal or subcutaneous tumor originating from the tunica media of small veins and arteries, and rarely occurs in the hand. Because of its non-specific imaging features, a definite preoperative diagnosis is quite difficult. We present an unusual case of angioleiomyoma arising in the first web space of the right hand of a 56-year-old male. Physical examination showed a 3 cm, elastic-soft, mobile, non-tender mass. Magnetic resonance imaging (MRI) revealed a well-demarcated, subcutaneous, soft tissue mass with iso- to slightly high signal intensity relative to skeletal muscle on T1-weighted sequences and heterogenous high signal intensity with scattered foci of low signal intensity on T2-weigthed sequences. Contrast-enhanced fat-suppressed T1-weighted sequences demonstrated heterogenous, strong enhancement throughout the mass. There was no vascular structure closely abutting the mass. Simple excision of the mass was performed, and the histology was characteristic of an angioleiomyoma. The patient had no evidence of local recurrence within four months of follow-up. Angioleiomyoma should be considered in the differential diagnosis of a well defined, oval soft tissue mass in the first web space of the hand even when an adjacent tortuous vascular structure is not seen on MRI. PMID- 23812224 TI - A new gelatine-based hemostat for sinonasal surgery: a clinical survey. AB - BACKGROUND: To ensure more effective hemostasis in surgical procedures, a novel sponge of pharmaceutical-grade chemically cross-linked gelatine, characterized by a high pore density, reduced ligaments and a high nanoscale roughness of the surface has been developed. PATIENTS AND METHODS: A questionnaire-based survey was carried out at seven ENT centers in Germany to collect clinical data. A total of 62 patients undergoing nasal and sinus surgery were treated with the new product to test its efficacy as a hemostat, its absorptive capacity, its handling in general, and its subsequent biodegradation. RESULTS: In summary, performance regarding the above parameters was very good. No adverse events were observed. The major advantages of this sponge in comparison with other available products were fast hemostasis and that there was no need for removal of the dressing because of its biodegradation. PMID- 23812225 TI - Concomitant interferon-alpha and chemotherapy in hepatitis C and colorectal cancer: a case report. AB - Hepatitis C virus (HCV) infection is one of the main causes of liver disease worldwide. Patients undergoing surgery are at risk of acquiring acute HCV infection and those undergoing surgical eradication of a neoplasia may be indicated for adjuvant treatment. Therefore, unlike chronic infection, these patients may simultaneously need antiviral therapy with interferon for acute hepatitis C and cytotoxic chemotherapy. To date, no data are available regarding the efficacy and tolerability of concomitant interferon treatment and antineoplastic chemotherapy in the setting of acute hepatitis C treatment. Here, we report the case of a 60-year-old man who developed acute hepatitis C after left hemicolectomy for an adenocarcinoma. He received concomitant antiviral treatment with interferon-alpha and adjuvant chemotherapy with capecitabine and oxaliplatin. Both treatments were well-tolerated and the patient completed the scheduled therapies. HCV infection was eradicated and the patient is free of neoplastic disease two years and 6 months after surgery. PMID- 23812226 TI - Bolus 5-fluorouracil as an alternative in patients with cardiotoxicity associated with infusion 5-fluorouracil and capecitabine: a case series. AB - BACKGROUND: 5-Fluorouracil (5-FU) is the backbone of chemotherapy regimens approved for treatment of colorectal cancer. The incidence of cardiotoxicity associated with 5-FU ranges from 1.5% to 18%; 48% as anginal symptoms and 2% as cardiogenic shock. Cardiotoxicity is unpredictable and no alternative chemotherapeutics have been defined so far. PATIENTS AND METHODS: We present a case series of six patients who developed cardiotoxicity on infusional fluorouracil and/or capecitabine and were challenged with bolus 5-FU for the treatment of their malignancies. Four patients were tested for polymorphic abnormality of the human dihydropyrimidine dehydrogenase gene (DPYD) with the TheraGuide 5-FUTM (Myriad Genetic Laboratories, Inc., Salt Lake City, UT, USA) pharmacogenetic test. RESULTS: Five patients were challenged with oral capecitabine that reproduced clinical and/or diagnostic concerns. All six patients tolerated bolus 5-FU either as a radiosensitizing agent or as chemotherapy without recurrence of a cardiac insult. DPYD was normal in the four patients tested. CONCLUSION: Cardiotoxicity induced by 5-FU seems to be schedule dependent. Bolus 5-FU can be used in patients developing cardiotoxicity due to 5 FU infusion or capecitabine with vigilance. PMID- 23812227 TI - First reported case of primary basal cell carcinoma of the right caruncle: a case report and review of the literature. AB - AIM: The clinical and histopathological characteristics of a patient with a primary basal cell carcinoma (BCC) of the right caruncle without seeding of the tumor to the conjunctiva are described. Primary basal cell carcinoma of the caruncle is an extremely rare but distinct entity. CASE REPORT: A 24-year-old female presented with a lesion of the medial caruncle of the right eye. Clinical examination revealed a 5*2 mm, oval-shaped, brown coloured, lesion without local skin involvement. No associated cutaneous lesion was present. The tumour was completely excised. One year later, no evidence of recurrence has been noticed. CONCLUSION: This case describes a primary BCC of the right caruncle without seeding to the conjunctiva. It represents the first case of right caruncle BCC documented in photographs. PMID- 23812228 TI - Fibrolipoma of the ring finger: MR imaging and histological correlation. AB - Fibrolipoma is characterized by the presence of prominent bundles of mature fibrous tissue traversing the fatty lobules. We present a case of a pathologically-proven fibrolipoma arising in the right ring finger of a 66-year old female. Physical examination showed a 2-cm, soft, mobile, nontender mass. Neurovascular examinations including Tinel sign were normal. Plain radiographs revealed a well-defined radiolucent area with no calcification. Magnetic resonance imaging showed a lipomatous tumor with an unusual biphasic pattern. The patient underwent an excisional biopsy. Histologically, the tumor consisted of mature adipocytes with sclerotic fibrous elements as well as myxoid changes. The patient has had no evidence of local recurrence within seven months of follow-up. To the best of our knowledge, this is the first report of fibrolipoma without nerve involvement in the finger. Although nonspecific, clinicians should know the various imaging features of fibrolipoma to avoid an unnecessarily extensive surgery. PMID- 23812229 TI - Persistence of primary MALT lymphoma of the urinary bladder after rituximab with CHOP chemotherapy and radiotherapy. AB - We present a case of a patient with primary extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue of the urinary bladder that persisted after chemotherapy, immunotherapy and radiotherapy. CASE REPORT: A 48-year-old male underwent a routine ultrasound examination. A tumour mass in the urinary bladder was found and a transurethral biopsy was performed. Pathohistological examination revealed MALT lymphoma. Results of computed tomographic scan, positron emission tomography scan and bone marrow biopsy defined the tumour as primary malignant lymphoma of the urinary bladder. The patient received eight cycles of chemo immunotherapy (CHOP) and radiotherapy. Five months after therapy, there is a partial radiological remission, but with metabolic progression of the tumour. To our knowledge, this is the first case of MALT lymphoma of the urinary bladder with chemo-immunotherapy and radiotherapy resistance. PMID- 23812230 TI - Enhanced podoplanin expression in chronic maxillary sinusitis. AB - Podoplanin expression has been reported in oral squamous epithelium, myoepithelia of the salivary glands, and odontogenic lesions, and has been linked with inflammatory and neoplastic conditions. We hypothesized that inflamed respiratory mucosa of the maxillary sinus also express podoplanin, especially in cases with odontogenic sinusitis. We retrospectively investigated podoplanin expression in biopsies from maxillary sinus with inflammatory changes. Cases with chronic rhinosinusitis with polyp formation (n=5), chronic rhinosinusitis without polyps (n=5), chronic rhinosinusitis with eosinophilia (n=5), and odontogenic chronic rhinosinusitis (n=5) were investigated immunohistochemically using an established antibody for podoplanin (D2-40). Respiratory epithelium in chronic maxillary sinusitis with polyp formation did not exhibit enhanced podoplanin expression. However, D2-40 positivity was detected in the basal cells in all cases with chronic sinusitis associated with inflammatory infiltrations as well as in the parabasal epithelial layer in chronic sinusitis without polyp formation. We observed podoplanin expression in non-neoplastic maxillary sinus epithelium exhibiting inflammatory changes. We suggest that podoplanin is involved in the pathogenesis of chronic rhinosinusitis, particularly in the intraepithelial migration of inflammatory infiltrates. PMID- 23812231 TI - Imaging features of desmoid-type fibromatosis in the teres major muscle. AB - Desmoid-type fibromatosis is a locally aggressive fibroblastic neoplasm with a tendency for local recurrence, despite adequate surgical resection. Its clinical presentation, biological behavior, and natural history can vary considerably. We present a unique case of desmoid-type fibromatosis arising in the left teres major muscle of a 62-year-old female. Physical examination showed a 7-cm, elastic hard, immobile, tender mass. Magnetic resonance imaging (MRI) revealed a partially ill-defined mass, with intermediate signal intensity on T1-weighted sequences and heterogenous high signal intensity on T2-weighted sequences. Contrast-enhanced fat-suppressed T1-weighted sequences demonstrated intense and homogenous enhancement throughout the mass. Integrated positron-emission tomographic (PET)/computed tomographic (CT) images showed moderate focal 18F fluorodeoxyglucose uptake corresponding to the clinically palpable and MRI described soft tissue mass, with a maximal standardized uptake value of 4.85. The possibility of a malignant lesion was raised. Following an open biopsy, wide resection of the tumor was performed. Histological examination confirmed the diagnosis of desmoid-type fibromatosis. Finally, we discuss the imaging features of this peculiar neoplasm on MRI and PET/CT. PMID- 23812232 TI - Compression stockings limit the incidence of postoperative lymphocele in kidney transplantation. AB - BACKGROUND: Lymphoceles account for considerable morbidity rates after kidney transplantation. As yet, there is no therapeutic strategy to prevent the formation of lymphoceles. The lower limb provides a large reservoir for lymphatic tissue. Prophylactic compression therapy limits tissue volume and edema formation and may therefore reduce postoperative lymph flow. PATIENTS AND METHODS AND RESULTS: In a non-randomized prospective study using a historical control group prior to 2006 as comparison from our center (2004-2008: total n=126), we found that lymphoceles are significantly diminished on the ipsilateral lower limb of the operative side when patients wear class II compression stockings (n=69) for four weeks after transplantation compared to patients achieving standard antithrombotic therapy by compression class I stockings (n=57) for thrombosis prophylaxis until full mobilization (33% versus 15%, p-value<0.05). Furthermore, a significantly lower percentage of patients needed surgical treatment of the lymphoceles for obstructive complications after class II compression (4% versus 18%, p-value<0.01). These findings were independent of the recipients' demographics, the duration of the surgical procedure, and the operating surgeon. CONCLUSION: Further studies are needed to demonstrate the usefulness of compressing stockings for the reduction of lymphoceles after kidney transplantation. This approach would not only reduce post-transplantation morbidity, but also provide an easy and cost-effective treatment without side effects. PMID- 23812233 TI - Coupling physical chemical techniques with hydrotalcite-like compounds to exploit their structural features and new multifunctional hybrids with luminescent properties. AB - Hydrotalcite-like compounds (HTlc), belonging to the large class of Layered Double Hydroxides (LDH), have excited wide interest owing to the incredible number of their potential and achieved applications in physical, chemical and bio chemical fields. This perspective review deals with recent advances in the application of physical-chemical techniques for the study of HTlc structure and for the design and synthesis, using intercalation chemistry routes, of new hybrid materials. Firstly, a rapid survey on the most common synthetic strategies for the attainment of HTlc with different crystallinity degree and crystal size and for their modification to obtain hybrids has been made, and the use of coupled techniques (XRPD, luminescence, Solid State MAS NMR and Molecular Dynamics) to gain structural information is reported. Then, the design, synthesis and photophysical characterization of azoic dyes-intercalated and co-intercalated HTlc hybrid materials are described. Hybrids constituted of ZnAl-HTlc, co intercalated with stearate anions and methyl orange or methyl yellow dyes, have been used as nanofillers of hydrophobic polymers. The polymeric nano-composites obtained have been characterized by means of XRPD patterns, Thermo-Gravimetric Analysis and Confocal Fluorescence Microscopy. This latter technique has been found to be an excellent, complementary and non-invasive tool to probe the dispersion degree of the fluorescent fillers into the polymeric matrices and their stability in the compounding process. Finally, the synthesis and spectroscopic characterization of nanoparticle (NP) decorated HTlc for advanced antimicrobial and photo-catalytic applications are also reported. The review terminates with a concluding short note and future trends. PMID- 23812234 TI - Tuning the kinetics of cadherin adhesion. AB - Cadherins are Ca(2+)-dependent cell-cell adhesion proteins that maintain the structural integrity of the epidermis; their principle function is to resist mechanical force. This review summarizes the biophysical mechanisms by which classical cadherins tune adhesion and withstand mechanical stress. We first relate the structure of classical cadherins to their equilibrium binding properties. We then review the role of mechanical perturbations in tuning the kinetics of cadherin adhesion. In particular, we highlight recent studies that show that cadherins form three types of adhesive bonds: catch bonds, which become longer lived and lock in the presence of tensile force; slip bonds, which become shorter lived when pulled; and ideal bonds, which are insensitive to tugging. PMID- 23812235 TI - The Cinderella effect: searching for the best fit between mouse models and human diseases. AB - A recent publication questions the suitability of mice as a model for the human inflammatory response and has fueled the continuing debate about the suitability of mice as models for human disease. We discuss recent advances in disease modeling using mice, and the genetic factors that need to be considered when trying to recapitulate aspects of human disease. Failure to appreciate the important differences between human and mouse biology and genetics underlying attempts to generate faithful models frequently leads to poor outcomes. Closely coordinated human and model organism studies are essential to provide traction for translational research. PMID- 23812236 TI - Posterior labral tear with a paralabral cyst causing suprascapular nerve compression. AB - The patient was a 21-year-old man who was currently enrolled in a military academy. He was seen by a physical therapist in a direct-access capacity for a chief complaint of right shoulder fatigue and discomfort that was present for the past week. Due to marked atrophy and weakness with no history of injury, an orthopaedic surgeon was consulted and diagnostic imaging was requested. Magnetic resonance imaging revealed a posterior labral tear with a large paralabral cyst, likely resulting in significant compression of the suprascapular nerve. PMID- 23812237 TI - Challenges in preparing contrast media for videofluoroscopy. PMID- 23812238 TI - Age-associated cross-reactive antibody-dependent cellular cytotoxicity toward 2009 pandemic influenza A virus subtype H1N1. AB - BACKGROUND: During the 2009 pandemic of influenza A virus subtype H1N1 (A[H1N1]pdm09) infection, older individuals were partially protected from severe disease. It is not known whether preexisting antibodies with effector functions such as antibody-dependent cellular cytotoxicity (ADCC) contributed to the immunity observed. METHODS: We tested serum specimens obtained from 182 individuals aged 1-72 years that were collected either immediately before or after the A(H1N1)pdm09 pandemic for ADCC antibodies to the A(H1N1)pdm09 hemagglutinin (HA) protein. RESULTS: A(H1N1)pdm09 HA-specific ADCC antibodies were detected in almost all individuals aged >45 years (28/31 subjects) before the 2009 A(H1N1) pandemic. Conversely, only approximately half of the individuals aged 1-14 years (11/31) and 15-45 years (17/31) had cross-reactive ADCC antibodies before the 2009 A(H1N1) pandemic. The A(H1N1)pdm09-specific ADCC antibodies were able to efficiently mediate the killing of influenza virus infected respiratory epithelial cells. Further, subjects >45 years of age had higher ADCC titers to a range of seasonal H1N1 HA proteins, including from the 1918 virus, compared with younger individuals. CONCLUSIONS: ADCC antibodies may have contributed to the protection exhibited in older individuals during the 2009 A(H1N1) pandemic. This work has significant implications for improved vaccination strategies for future influenza pandemics. PMID- 23812239 TI - Emergence of colistin-resistance in extremely drug-resistant Acinetobacter baumannii containing a novel pmrCAB operon during colistin therapy of wound infections. AB - BACKGROUND: Colistin resistance is of concern since it is increasingly needed to treat infections caused by bacteria resistant to all other antibiotics and has been associated with poorer outcomes. Longitudinal data from in vivo series are sparse. METHODS: Under a quality-improvement directive to intensify infection control measures, extremely drug-resistant (XDR) bacteria undergo phenotypic and molecular analysis. RESULTS: Twenty-eight XDR Acinetobacter baumannii isolates were longitudinally recovered during colistin therapy. Fourteen were susceptible to colistin, and 14 were resistant to colistin. Acquisition of colistin resistance did not alter resistance to other antibiotics. Isolates had low minimum inhibitory concentrations of an investigational aminoglycoside, belonged to multi-locus sequence type 94, were indistinguishable by pulsed-field gel electrophoresis and optical mapping, and harbored a novel pmrC1A1B allele. Colistin resistance was associated with point mutations in the pmrA1 and/or pmrB genes. Additional pmrC homologs, designated eptA-1 and eptA-2, were at distant locations from the operon. Compared with colistin-susceptible isolates, colistin resistant isolates displayed significantly enhanced expression of pmrC1A1B, eptA 1, and eptA-2; lower growth rates; and lowered fitness. Phylogenetic analysis suggested that colistin resistance emerged from a single progenitor colistin susceptible isolate. CONCLUSIONS: We provide insights into the in vivo evolution of colistin resistance in a series of XDR A. baumannii isolates recovered during therapy of infections and emphasize the importance of antibiotic stewardship and surveillance. PMID- 23812240 TI - Reactivation of herpes simplex virus type 2 after initiation of antiretroviral therapy. AB - BACKGROUND: The association between initiation of antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection and possible herpes simplex virus type 2 (HSV-2) shedding and genital ulcer disease (GUD) has not been evaluated. METHODS: GUD and vaginal HSV-2 shedding were evaluated among women coinfected with HIV and HSV-2 (n = 440 for GUD and n = 96 for HSV-2 shedding) who began ART while enrolled in a placebo-controlled trial of HSV-2 suppression with acyclovir in Rakai, Uganda. Monthly vaginal swabs were tested for HSV-2 shedding, using a real-time quantitative polymerase chain reaction assay. Prevalence risk ratios (PRRs) of GUD were estimated using log binomial regression. Random effects logistic regression was used to estimate odds ratios (ORs) of HSV-2 shedding. RESULTS: Compared with pre-ART values, GUD prevalence increased significantly within the first 3 months after ART initiation (adjusted PRR, 1.94; 95% confidence interval [CI], 1.04-3.62) and returned to baseline after 6 months of ART (adjusted PRR, 0.80; 95% CI, .35-1.80). Detection of HSV-2 shedding was highest in the first 3 months after ART initiation (adjusted OR, 2.58; 95% CI, 1.48-4.49). HSV-2 shedding was significantly less common among women receiving acyclovir (adjusted OR, 0.13; 95% CI, .04-.41). CONCLUSIONS: The prevalence of HSV-2 shedding and GUD increased significantly after ART initiation, possibly because of immune reconstitution inflammatory syndrome. Acyclovir significantly reduced both GUD and HSV-2 shedding and should be considered to mitigate these effects following ART initiation. PMID- 23812241 TI - Diagnostic performance of computed tomography coronary angiography to detect and exclude left main and/or three-vessel coronary artery disease. AB - OBJECTIVES: To determine the diagnostic performance of CT coronary angiography (CTCA) in detecting and excluding left main (LM) and/or three-vessel CAD ("high risk" CAD) in symptomatic patients and to compare its discriminatory value with the Duke risk score and calcium score. MATERIALS AND METHODS: Between 2004 and 2011, a total of 1,159 symptomatic patients (61 +/- 11 years, 31 % women) with stable angina, without prior revascularisation underwent both invasive coronary angiography (ICA) and CTCA. All patients gave written informed consent for the additional CTCA. High-risk CAD was defined as LM and/or three-vessel obstructive CAD (>=50 % diameter stenosis). RESULTS: A total of 197 (17 %) patients had high risk CAD as determined by ICA. The sensitivity, specificity, positive predictive value, negative predictive value, positive and negative likelihood ratios of CTCA were 95 % (95 % CI 91-97 %), 83 % (80-85 %), 53 % (48-58 %), 99 % (98-99 %), 5.47 and 0.06, respectively. CTCA provided incremental value (AUC 0.90, P < 0.001) in the discrimination of high-risk CAD compared with the Duke risk score and calcium score. CONCLUSIONS: CTCA accurately excludes high-risk CAD in symptomatic patients. The detection of high-risk CAD is suboptimal owing to the high percentage (47 %) of overestimation of high-risk CAD. CTCA provides incremental value in the discrimination of high-risk CAD compared with the Duke risk score and calcium score. KEY POINTS: * Computed tomography coronary angiography (CTCA) accurately excludes high-risk coronary artery disease. * CTCA overestimates high risk coronary artery disease in 47 %. * CTCA discriminates high-risk CAD better than clinical evaluation and coronary calcification. PMID- 23812242 TI - Locally advanced rectal cancer: diffusion-weighted MR tumour volumetry and the apparent diffusion coefficient for evaluating complete remission after preoperative chemoradiation therapy. AB - OBJECTIVE: To evaluate DW MR tumour volumetry and post-CRT ADC in rectal cancer as predicting factors of CR using high b values to eliminate perfusion effects. METHODS: One hundred rectal cancer patients who underwent 1.5-T rectal MR and DW imaging using three b factors (0, 150, and 1,000 s/mm(2)) were enrolled. The tumour volumes of T2-weighted MR and DW images and pre- and post-CRT ADC150-1000 were measured. The diagnostic accuracy of post-CRT ADC, T2-weighted MR, and DW tumour volumetry was compared using ROC analysis. RESULTS: DW MR tumour volumetry was superior to T2-weighted MR volumetry comparing the CR and non-CR groups (P < 0.001). Post-CRT ADC showed a significant difference between the CR and non-CR groups (P = 0.001). The accuracy of DW tumour volumetry (Az = 0.910) was superior to that of T2-weighed MR tumour volumetry (Az = 0.792) and post-CRT ADC (Az = 0.705) in determining CR (P = 0.015). Using a cutoff value for the tumour volume reduction rate of more than 86.8 % on DW MR images, the sensitivity and specificity for predicting CR were 91.4 % and 80 %, respectively. CONCLUSION: DW MR tumour volumetry after CRT showed significant superiority in predicting CR compared with T2-weighted MR images and post-CRT ADC. PMID- 23812243 TI - Radiation dose to procedural personnel and patients from an X-ray volume imaging system. AB - OBJECTIVE: To evaluate the radiation dose received by procedural personnel and patients from an X-ray volume imaging (XVI) system during interventional procedures. METHODS: Forty patients were examined using catheter angiography (group A), digital subtraction angiography (group B) and cone-beam CT (CBCT, group C). Doses to procedural personnel (using thermo-luminescent dosimeters, TLDs) and patients were estimated. Image quality and lesion delineation were assessed using objective and subjective methods. Shapiro-Wilk, two-sided Student's t and Wilcoxon matched-pairs tests were used to test statistical significance. RESULTS: Doses (milligrays) measured in the hands and left knee of the interventionist were higher than those in an assistant physician (P < 0.05). Doses (dose-area product and skin entry dose) were lower in group A and higher in C compared with other groups; moreover, comparison among the groups were significant (all P = 0.0001). Subjective and objective lesion delineation showed significant results (all P < 0.05) among the tumour types considered. Image quality estimation showed the opposite results for objective and subjective analysis. CONCLUSION: More doses were obtained for hands of the procedural personnel compared to other anatomical regions measured. Catheter angiography showed lower dose compared with other imaging groups examined. Lesion delineation was clearly possible using CBCT. Objective and subjective analysis showed the opposite results regarding image quality because of higher noise levels and artefacts. PMID- 23812244 TI - MR-guided facet joint injection therapy using an open 1.0-T MRI system: an outcome study. AB - OBJECTIVES: To evaluate the accuracy, safety and efficacy of magnetic resonance imaging (MRI)-guided facet joint injection therapy using a 1.0-T open MRI. METHODS: One hundred and sixty-six facet joint blocks in 45 patients with lower back pain were performed under MR fluoroscopic guidance using a proton-density weighted turbo-spin-echo sequence. An in-room monitor, wireless MR-mouse for operator-controlled multiplanar navigation, a flexible surface coil and MR compatible 20-G needle were used. Clinical outcome was evaluated by questionnaire before intervention and after 1 week, 3, 6 and 12 months using a numerical visual analogue scale (VAS). RESULTS: All facet joint blocks were considered technically successful with distribution of the injectant within and/or around the targeted facet joint. No major complications occurred. The final outcome analysis included 38 patients. An immediate effect was reported by 63 % of the patients. A positive mid-/long-term effect was seen in 13 patients (34 %) after 6 months and in 9 patients (24 %) after 12 months. Mean VAS was reduced from 7.1 +/- 1.7 (baseline) to 3.5 +/- 2.2, 4.1 +/- 3.0, 3.8 +/- 2.9 and 4.6 +/- 2.9 at 1 week, 3, 6 and 12 months (P < 0.01). CONCLUSIONS: MR-guided facet joint injection therapy of the lumbosacral spine is accurate, safe and efficient in the symptomatic treatment of lower back pain. PMID- 23812245 TI - Spinal bone defects in neurofibromatosis type I with dural ectasia: stress fractures or dysplastic? A case series. AB - OBJECTIVES: Neurofibromatosis type I (NF1) is a multisystem neurocutaneous disorder with varied musculoskeletal manifestations. Dural ectasia is a known association, whilst pedicular anomalies have been described, although not as frequently as other skeletal manifestations. However, reports of pedicular and other spinal clefts or fractures in combination with dural ectasia in NF1 are scarce. We aimed to identify osseous defects in the posterior elements of NF1 patients with dural ectasia. METHODS: Images of patients with NF1 and back pain were reviewed for osseous defects in the posterior elements. RESULTS: Four patients were identified with NF1, back pain, dural ectasia and bone defects. The imaging appearances of the defects are illustrated. CONCLUSIONS: Defects in the spinal posterior elements of patients with NF1, back pain and dural ectasia may be dysplastic, stress fractures or, most probably, multifactorial in origin. Computed tomography demonstrates these defects most clearly. PMID- 23812247 TI - Phenotyping and outcome on contemporary management in a German cohort of patients with peripartum cardiomyopathy. AB - Peripartum cardiomyopathy (PPCM) is a life-threatening heart disease developing towards the end of pregnancy or in the months following delivery in previously healthy women in terms of cardiac disease. Enhanced oxidative stress and the subsequent cleavage of the nursing hormone Prolactin into an anti-angiogenic 16 kDa subfragment emerged as a potential causal factor of the disease. We established a prospective registry with confirmed PPCM present in 115 patients (mean baseline left ventricular ejection fraction, LVEF: 27 +/- 9 %). Follow-up data (6 +/- 3 months) showed LVEF improvement in 85 % and full recovery in 47 % while 15 % failed to recover with death in 2 % of patients. A positive family history of cardiomyopathy was present in 16.5 %. Pregnancy-associated hypertension was associated with a better outcome while a baseline LVEF <= 25 % was associated with a worse outcome. A high recovery rate (96 %) was observed in patients obtaining combination therapy with beta-blocker, angiotensin-converting enzyme (ACE) inhibitors/angiotensin-receptor-blockers (ARBs) and bromocriptine. Increased serum levels of Cathepsin D, the enzyme that generates 16 kDa Prolactin, miR-146a, a direct target of 16 kDa Prolactin, N-terminal-pro-brain natriuretic peptide (NT-proBNP) and asymmetric dimethylarginine (ADMA) emerged as biomarkers for PPCM. In conclusion, low baseline LVEF is a predictor for poor outcome while pregnancy-induced hypertensive disorders are associated with a better outcome in this European PPCM cohort. The high recovery rate in this collective is associated with a treatment concept using beta-blockers, ACE inhibitors/ARBs and bromocriptine. Increased levels of Cathepsin D activity, miR 146a and ADMA in serum of PPCM patients support the pathophysiological role of 16 kDa Prolactin for PPCM and may be used as a specific diagnostic marker profile. PMID- 23812248 TI - 5-Lipoxygenase facilitates healing after myocardial infarction. AB - Early healing after myocardial infarction (MI) is characterized by a strong inflammatory reaction. Most leukotrienes are pro-inflammatory and are therefore potential mediators of healing and remodeling after myocardial ischemia. The enzyme 5-lipoxygenase (5-LOX) has a key role in the transformation of arachidonic acid in leukotrienes. Thus, we tested the effect of 5-LOX on healing after MI. After chronic coronary artery ligation, early mortality was significantly increased in 5-LOX(-/-) when compared to matching wildtype (WT) mice due to left ventricular rupture. This effect could be reproduced in mice treated with the 5 LOX inhibitor Zileuton. A perfusion mismatch due to the vasoactive potential of leukotrienes is not responsible for left ventricular rupture since local blood flow assessed by magnetic resonance perfusion measurements was not different. However, after MI, there was an accentuation of the inflammatory reaction with an increase of pro-inflammatory macrophages. Yet, mortality was not changed in chimeric mice (WT vs. 5-LOX(-/-) bone marrow in 5-LOX(-/-) animals), indicating that an altered function of 5-LOX(-/-) inflammatory cells is not responsible for the phenotype. Collagen production and accumulation of fibroblasts were significantly reduced in 5-LOX(-/-) mice in vivo after MI. This might be due to an impaired migration of 5-LOX(-/-) fibroblasts, as shown in vitro to serum. In conclusion, a lack or inhibition of 5-LOX increases mortality after MI because of healing defects. This is not mediated by a change in local blood flow, but through an altered inflammation and/or fibroblast function. PMID- 23812246 TI - Proton-density fat fraction and simultaneous R2* estimation as an MRI tool for assessment of osteoporosis. AB - OBJECTIVE: To investigate multi-echo chemical shift-encoded MRI-based mapping of proton density fat fraction (PDFF) and fat-corrected R2* in bone marrow as biomarkers for osteoporosis assessment. METHODS: Fifty-one patients (28 female; mean age 69.7 +/- 9.0 years) underwent dual energy X-ray absorptiometry (DXA). On the basis of the t score, 173 valid vertebrae bodies were divided into three groups (healthy, osteopenic and osteoporotic). Three echo chemical shift-encoded MRI sequences were acquired at 3 T. PDFF and R2* with correction for multiple peak fat (R2*MP) were measured for each vertebral body. Kruskal-Wallis test and post hoc analysis were performed to evaluate differences between groups. Further, the area under the curve (AUC) for each technique was calculated using logistic regression analysis. RESULTS: On the basis of DXA, 92 samples were normal (53 %), 47 osteopenic (27 %) and 34 osteoporotic (20 %). PDFF was increased in osteoporosis compared with healthy (P = 0.007). R2*MP showed significant differences between normal and osteopenia (P = 0.004), and between normal and osteoporosis (P < 0.001). AUC to differentiate between normal and osteoporosis was 0.698 for R2*MP, 0.656 for PDFF and 0.74 for both combined. CONCLUSION: PDFF and R2*MP are moderate biomarkers for osteoporosis. PDFF and R2*MP combination might improve the prediction in differentiating healthy subjects from those with osteoporosis. PMID- 23812249 TI - Hepatotoxicity evaluation of aqueous extract from Scutia buxifolia. AB - Nowadays there is an increase in the number of people taking herbals worldwide. Scutia buxifolia is used for the treatment of hypertension, but little is known about its action on liver. Thirty-two Wistar rats were divided into four groups: control and groups treated during 30 days with 100, 200 and 400 mg of lyophilized aqueous extract of S. buxifolia (SBSB)/kg of body weight. This study was planned to explore hepatotoxic effect of SBSB, which was assessed by serum transaminases (ALT and AST). Thiobarbituric acid reactive substances (TBARS) levels were determined in liver, along with thiols content (NPSH), catalase (CAT) activity and, superoxide dismutase (SOD) enzymes. Histopathological studies of liver tissue were performed. Flavonoids and phenolics were quantified in SBSB by high performance liquid chromatography with diode array detection (HPLC/DAD). We did not observe alterations on redox status (TBARS, NPSH, CAT and, SOD) in the control and experimental groups. An increase on AST activity was only observed at 200 mg of SBSB, whereas ALT score was not affected by SBSB. Moreover, no morphological alterations were observed on the hepatocytes, matching the analysed biochemical parameters. This way, we conclude that SBSB was not toxic. PMID- 23812250 TI - Anxiolytic-like and antinociceptive effects of 2(S)-neoponcirin in mice. AB - STUDY AIMS: 2(S)-neopincirin (NEO) is a constituent from of Clinopodium mexicanum, which is used in traditional Mexican herbal medicine for its tranquilizing and analgesic properties. This study investigated the anxiolytic like, sedative and antinociceptive effects of NEO in several mice models. MATERIAL AND METHODS: The anxiolytic-like effect was evaluated in the hole-board (HBT) and Open Field Tests (OFT); sedative effect was evaluated in sleeping time induced by sodium pentobarbital, and its antinociceptive actions were measured in the hot plate test. To evaluate if the GABA receptor could be involved in the anxiolytic-like effect produced by NEO, in independent experiments, the effects produced by co-administration of NEO plus muscimol (MUS) and NEO plus Pitrotoxin (PTX) were evaluated in the HBT. RESULTS: NEO was isolated from Clinopodium mexicanum leaves. The NMR, MS and optic rotation data helped establish its identity as (2S)-5-hydroxy-4'-methoxyflavanone-7-O-{beta-glucopyranosyl-(1->6) beta-rhamnoside}. NEO showed an anxiolytic-like effect and was able to counter the nociception induced by a thermal stimulus in a dose-dependent manner. PTX blocked the anxiolytic-like effect of NEO, while MUS was able to enhance it. CONCLUSIONS: The findings of present work demonstrated that NEO possesses anxiolytic-like and antinociceptive effects in mice. Such effects are not associated with changes in the locomotor activity. These results supported the notion that anxiolytic-like effect of NEO involves the participation of GABAergic system. PMID- 23812251 TI - Isolation and synthesis of a bioactive benzenoid derivative from the fruiting bodies of Antrodia camphorata. AB - A new enynyl-benzenoid, antrocamphin O (1,4,7-dimethoxy-5-methyl-6-(3'-methylbut 3-en-1-ynyl)benzo[d][1,3]dioxide), and the known benzenoids antrocamphin A and 7 dimethoxy-5-methyl-1,3-benzodioxole, were isolated from the fruiting bodies of Antrodia camphorata (Taiwanofungus camphoratus). The structure of antrocamphin O was unambiguously assigned by the analysis of spectral data (including 1D and 2D NMR, high-resolution MS, IR, and UV) and total synthesis. Compound 1 was prepared through the Sonogashira reaction of 5-iodo-4,7-dimethoxy-6-methylbenzene and 2 methylbut-1-en-3-yne as the key step. The benzenoids were tested for cytotoxicity against the HT29, HTC15, DLD-1, and COLO 205 colon cancer cell lines, and activities are reported herein. PMID- 23812253 TI - In vitro inflammatory responses elicited by isolates of Alloiococcus otitidis obtained from children with otitis media with effusion. AB - Alloiococcus otitidis is usually detected in children with otitis media (OM) by PCR as it is not often detected by routine culture. Our improved method for its isolation obtained A. otitidis from nearly 50% of 78 children with OM with effusion. The role of A. otitidis in pathogenesis of OM is unclear. This study tested two hypothesis: (1) that fresh isolates of A. otitidis would elicit pro inflammatory cytokines from THP-1 monocytic cells equivalent to those induced by Streptococcus pneumoniae; (2) priming THP-1 cells with interferon-gamma (IFN gamma) a surrogate for virus infection, would enhance pro-inflammatory responses. Recent clinical isolates of A. otitidis, S. pneumoniae (ATCC 49619) and a blood culture isolate of S. pneumoniae (SP2) were used in the assays. Cytokines were quantified by BioRad bead assay and Luminex 200. IFN-gamma priming enhanced cytokine responses. S. pneumoniae ATCC 49619 induced lower responses than SP2 for IL-1beta, IL-6, TNF-alpha. A. otitidis LW 27 elicited higher IL-1beta and TNF alpha responses than either pneumococcal isolate. Small green colony types of A. otitidis induced higher responses than large white colony types for IL-8 and IL 1beta. The hypothesis that A. otitidis elicits cytokines observed in middle ear effusions was supported; the need to use recent clinical isolates in studies of pathogenesis was highlighted. PMID- 23812252 TI - Site-specific acylation changes in the lipid A of Escherichia coli lpxL mutants grown at high temperatures. AB - LPS is a major component of the outer membrane of Gram-negative bacteria. The lipid A region of LPS mediates stimulation of the immune system. In E. coli, the gene (formerly htrB) codes for a late lauroyltransferase (LpxL) in lipid A biosynthesis. E. coli lpxL mutants have been described previously with impaired growth above 33 degrees C in rich media. However, we were able to grow lpxL mutants at 30 degrees C, 37 degrees C and 42 degrees C, and investigate their lipid A moieties to gain insight into changes and regulatory effects in lipid A biosynthesis. Multiple-stage mass spectrometry was used to decipher unusual lipid A structures produced by lpxL mutant bacteria at high temperatures that rescue the temperature-sensitive phenotype. At 37 degrees C and 42 degrees C, E. coli lpxL mutants appear to activate different acyltransferases or biosynthetic pathways that generate atypical penta- and hexaacyl lipid A structures by incorporating longer fatty acids, such as a secondary palmitoleic acid (2'-O position, distal) and a secondary palmitic acid (2-O-position, proximal) respectively. However, we observed no changes in these structures through various growth curve stages. This study indicates that E. coli (lpxL) lipid A biosynthesis, and specifically the 'late' acylation of lipid A, is temperature dependent, thus suggesting a highly regulated process. PMID- 23812256 TI - New checkpoint inhibitors ride the immunotherapy tsunami. PMID- 23812255 TI - Optimizing the use of CROs by academia and small companies. PMID- 23812257 TI - First-in-class insomnia drug on the brink of approval nod. PMID- 23812261 TI - Market watch: Upcoming market catalysts in Q3 2013. PMID- 23812262 TI - Deal watch: AbbVie invests in pioneering celiac disease therapy. PMID- 23812264 TI - New hope for dry AMD? PMID- 23812265 TI - Cardiovascular disease: Rejuvenating the ageing heart. PMID- 23812266 TI - Anticancer drugs: Cracking the combination. PMID- 23812272 TI - Propofol sedation in total knee replacement : effects on oxidative stress and ischemia-reperfusion damage. AB - PURPOSE: This study aimed to show the effect of propofol sedation on oxidative stress and inflammation resulting from ischemia-reperfusion. METHODS: After having obtained written informed consent from the patients and ethics committee approval, 36 patients were randomly allocated to 2 groups: group C, control and group P, propofol. Spinal anesthesia was administered to both groups with 15 mg bupivacaine. Patients in group P received a propofol infusion of 2 mg/kgBW/h and the patients in group C received a placebo infusion in an equal dose. Malondialdehyde (MDA), superoxide dismutase (SOD) and the total antioxidative capacity (TAC) levels were measured in venous blood samples prior to propofol or placebo administration (preischemia T0), 30 min after placing the tourniquet (ischemia T1) and 2 h after deflation of the tourniquet (reperfusion T2). High sensitivity C-reactive protein (hsCRP) and neutrophil levels were measured before propofol was administered (T0) and 12 h after reperfusion (T3). RESULTS: While serum MDA and SOD levels were significantly higher during the reperfusion period than the preischemic period, TAC levels were found to be low in the control group (p < 0.05). In the propofol group there were no differences between the preischemia-reperfusion periods with respect to MDA, SOD and TAC levels (p > 0.05). The neutrophil and hsCRP levels were observed to be increased to a lesser extent in the propofol group compared to the control group (p < 0.05). CONCLUSIONS: Propofol infusion in addition to spinal anesthesia may reduce oxidative damage and the inflammatory response developing due to the tourniquet in total knee replacement surgery. PMID- 23812273 TI - [Hot topics in neuroanesthesia : the five most important publications from the previous year]. PMID- 23812274 TI - ["Blood is thicker than water"]. PMID- 23812275 TI - Synthesis of a C1-C11 fragment of Zincophorin using planar chiral, neutral pi allyl iron complexes. AB - A key step in the synthesis of a C1-C11 fragment of the ionophore antibiotic Zincophorin involves the addition of an alpha-alkoxyalkylcopper(I) reagent to a planar chiral, neutral pi-allyl iron complex. The key allylic alkylation reaction is highly regio- and stereoselective with addition taking place at the gamma position anti to the metal centre. PMID- 23812276 TI - Production of ginsenoside aglycons and Rb1 deglycosylation pathway profiling by HPLC and ESI-MS/MS using Sphingobacterium multivorum GIN723. AB - Using enrichment culture, Sphingobacterium multivorum GIN723 (KCCM80060) was isolated as having activity for deglycosylation of compound K and ginsenoside F1 to produce ginsenoside aglycons such as S-protopanaxadiol (PPD(S)) and S protopanaxatriol (PPT(S)). Through BLAST search, purified enzyme from S. multivorum GIN723 was revealed to be the outer membrane protein. The purified enzyme from S. multivorum GIN723 has unique specificity for the glucose moiety. However, it has activity with PPD and PPT group ginsenosides such as ginsenosides Rb1, Rb2, Rb3, Rc, F2, CK, Rh2, Re, and F1. From these results, it was predicted that the enzyme has activity on several ginsenosides. Therefore, the biotransformation pathway from Rb1, which is a major, highly glycosylated compound of ginseng, was analyzed using high-performance liquid chromatography and electrospray ionization mass spectrometry/mass spectrometry. The dominant biotransformation pathway from Rb1 to PPD(S) was determined to be Rb1 -> Gp-XVII > Gp-LXXV -> CK -> PPD(S). S. multivorum GIN723 can be used as a whole cell biocatalyst because its activity as whole cells is nine times higher than its activity as cell extracts. The specific activity of whole cells is 2.89 nmol/mg/min in the production of PPD(S). On the other hand, the specific activity of cell extracts is 0.32 nmol/mg/min. The productivity of this enzyme in whole cell form is 500 mg/1 l of cultured cell. Its optimum reaction condition is 10 mM of calcium ions added to a phosphate buffer with a pH of 8.5. PMID- 23812277 TI - Colonization of Alcaligenes faecalis strain JBW4 in natural soils and its detoxification of endosulfan. AB - Alcaligenes faecalis strain JBW4, a strain of bacteria that is capable of degrading endosulfan, was inoculated into sterilized and natural soils spiked with endosulfan. JBW4 degraded 75.8 and 87.0 % of alpha-endosulfan and 58.5 and 69.5 % of beta-endosulfan in sterilized and natural soils, respectively, after 77 days. Endosulfan ether and endosulfan lactone were the major metabolites that were detected by gas chromatography-mass spectrometry. This result suggested that A. faecalis strain JBW4 degrades endosulfan using a non-oxidative pathway in soils. The ability of strain JBW4 to colonize endosulfan-contaminated soils was confirmed by polymerase chain reaction-denaturing gradient gel electrophoresis. This result suggested that strain JBW4 competed with the original inhabitants in the soil to establish a balance and successfully colonize the soils. In addition, the detoxification of endosulfan by strain JBW4 was evaluated using single-cell gel electrophoresis and by determining the soil microbial biomass carbon and enzymatic activities. The results showed that the genotoxicity and ecotoxicity of endosulfan in soil were reduced after degradation. The natural degradation of endosulfan in soil is inadequate; therefore, JBW4 shows potential for the bioremediation of industrial soils that are contaminated with endosulfan residues. PMID- 23812278 TI - Activity assessment of microbial fibrinolytic enzymes. AB - Conversion of fibrinogen to fibrin inside blood vessels results in thrombosis, leading to myocardial infarction and other cardiovascular diseases. In general, there are four therapy options: surgical operation, intake of antiplatelets, anticoagulants, or fibrinolytic enzymes. Microbial fibrinolytic enzymes have attracted much more attention than typical thrombolytic agents because of the expensive prices and the side effects of the latter. The fibrinolytic enzymes were successively discovered from different microorganisms, the most important among which is the genus Bacillus. Microbial fibrinolytic enzymes, especially those from food-grade microorganisms, have the potential to be developed as functional food additives and drugs to prevent or cure thrombosis and other related diseases. There are several assay methods for these enzymes; this may due to the insolubility of substrate, fibrin. Existing assay methods can be divided into three major groups. The first group consists of assay of fibrinolytic activity with natural proteins as substrates, e.g., fibrin plate methods. The second and third groups of assays are suitable for kinetic studies and are based on the determination of hydrolysis of synthetic peptide esters. This review will deal primarily with the microorganisms that have been reported in literature to produce fibrinolytic enzymes and the first review discussing the methods used to assay the fibrinolytic activity. PMID- 23812279 TI - Immobilization of defined laccase combinations for enhanced oxidation of phenolic contaminants. AB - Immobilization is an important method to increase enzyme stability and allow enzyme reuse. One interesting application in the field of environmental biotechnology is the immobilization of laccase to eliminate phenolic contaminants via oxidation. Fumed silica nanoparticles have interesting potential as support material for laccase immobilization via sorption-assisted immobilization in the perspective of applications such as the elimination of micropollutants in aqueous phases. Based on these facts, the present work aimed to formulate laccase nanoparticle conjugates with defined laccase combinations in order to obtain nanobiocatalysts, which are active over a broad range of pH values and possess a large substrate spectrum to suitably address pollution by multiple contaminants. A multi-enzymatic approach was investigated by immobilizing five different types of laccases originating from a Thielavia genus, Coriolopsis polyzona, Cerrena unicolor, Pleurotus ostreatus, and Trametes versicolor onto fumed silica nanoparticles, separately and in combinations. The laccases differed concerning their pH optima and substrate affinity. Exploiting their differences allowed the formulation of tailor-made nanobiocatalysts. In particular, the production of a nanobiocatalyst could be achieved that retained a higher percentage of its relative activity over the tested pH range (3-7) compared to the dissolved or separately immobilized enzymes. Furthermore, a nanobiocatalyst could be formulated able to oxidize a broader substrate range than the dissolved or separately immobilized enzymes. Thereby, the potential of the nanobiocatalyst for application in biochemical oxidation applications such as the elimination of multiple target pollutants in biologically treated wastewater has been illustrated. PMID- 23812271 TI - Strategies for optimizing the response of cancer and normal tissues to radiation. AB - Approximately 50% of all patients with cancer receive radiation therapy at some point during the course of their treatment, and the majority of these patients are treated with curative intent. Despite recent advances in the planning of radiation treatment and the delivery of image-guided radiation therapy, acute toxicity and potential long-term side effects often limit the ability to deliver a sufficient dose of radiation to control tumours locally. In the past two decades, a better understanding of the hallmarks of cancer and the discovery of specific signalling pathways by which cells respond to radiation have provided new opportunities to design molecularly targeted therapies to increase the therapeutic window of radiation therapy. Here, we review efforts to develop approaches that could improve outcomes with radiation therapy by increasing the probability of tumour cure or by decreasing normal tissue toxicity. PMID- 23812280 TI - Production of 10(S)-hydroxy-8(E)-octadecenoic and 7,10(S,S)-hydroxy-8(E) octadecenoic ethyl esters by Novozym 435 in solvent-free media. AB - Novozym 435, lipase B from Candida antarctica, was used in this study for the production of ethyl esters. For the first time, trans-hydroxy-fatty acid ethyl esters were synthesized in vitro in solvent-free media. We studied the effects of the substrate-ethanol molar ratio and enzyme synthetic stability of the biocatalyst. To determine the structure of the formed compounds, Fourier transformed infrared spectroscopy, nuclear magnetic resonance, and matrix assisted laser desorption/ionization-time-of-flight mass spectrometry were used, three less time-consuming structural techniques. trans-Hydroxy-fatty acid ethyl esters were synthesized with a reaction yield of 90 % or higher with optimal reaction conditions. PMID- 23812281 TI - Single-molecule observations for determining the orientation and diffusivity of dye molecules in lipid bilayers. AB - The molecular orientation and diffusion of dye molecules in artificial lipid bilayers were observed using total internal reflection fluorescence microscopy. An artificial lipid bilayer composed of a ternary lipid mixture of 1,2-dilauroyl sn-glycero-3-phosphocholine (DLPC), 1,2-dipalmitoyl-sn-glycero-3 phosphatidylcholine (DPPC), and cholesterol was used. The molecular orientation, which was obtained through defocused imaging, clarified the microscopic features, including cholesterol-induced changes in the local packing structure. Diffusion analysis gave insights into the macroscopic aspects of phase distribution in the heterogeneous bilayer system. Combining these two independent investigations, we revealed the effect of cholesterol addition on microscopic local packing and macroscopic phase structures. Our observations showed a transition from a DLPC network-like structure to a DPPC-network-like structure upon the addition of cholesterol, which was not evident from previous domain shape observations. The present single-molecule observations yielded the actual phase structure that controls the motion of molecules in the membrane. The results imply that the orientation and diffusivity of molecules offer useful information regarding the phase distribution, which may be hindered by the apparent phase structure in a heterogeneous lipid bilayer that contains cholesterol. PMID- 23812282 TI - Elaboration, activity and stability of silica-based nitroaromatic sensors. AB - Functionalized silica-based thin films, modified with hydrophobic groups, were synthesized and used as sensors for nitroaromatic compound (NAC) specific detection. Their performance and behavior, in terms of stability, ageing and regeneration, have been fully characterized by combining chemical characterization techniques and electron microscopy. NAC was efficiently and specifically detected using these silica-based sensors, but showed a great degradation in the presence of humidity. Moreover, the sensor sensitivity seriously decreases with storage time. Methyl- and phenyl-functionalization helped to overcome this humidity sensitivity. Surface characterization enabled us to establish a direct correlation between the appearance, and increasing amount, of adsorbed carbonyl-containing species, and sensor efficiency. This contamination, appearing after only one month, was particularly important when sensors were stored in plastic containers. Rinsing with cyclohexane enables us to recover part of the sensor performance but does not yield a complete regeneration of the sensors. This work led us to the definition of optimized elaboration and storage conditions for nitroaromatic sensors. PMID- 23812283 TI - Magnetic resonance imaging correlates of physical disability in relapse onset multiple sclerosis of long disease duration. AB - BACKGROUND: Understanding long-term disability in multiple sclerosis (MS) is a key goal of research; it is relevant to how we monitor and treat the disease. OBJECTIVES: The Magnetic Imaging in MS (MAGNIMS) collaborative group sought to determine the relationship of brain lesion load, and brain and spinal cord atrophy, with physical disability in patients with long-established MS. METHODS: Patients had a magnetic resonance imaging (MRI) scan of their brain and spinal cord, from which we determined brain grey (GMF) and white matter (WMF) fractional volumes, upper cervical spinal cord cross-sectional area (UCCA) and brain T2 lesion volume (T2LV). We assessed patient disability using the Expanded Disability Status Scale (EDSS). We analysed associations between EDSS and MRI measures, using two regression models (dividing cohort by EDSS into two and four sub-groups). RESULTS: In the binary model, UCCA (p < 0.01) and T2LV (p = 0.02) were independently associated with the requirement of a walking aid. In the four category model UCCA (p < 0.01), T2LV (p = 0.02) and GMF (p = 0.04) were independently associated with disability. CONCLUSIONS: Long-term physical disability was independently linked with atrophy of the spinal cord and brain T2 lesion load, and less consistently, with brain grey matter atrophy. Combinations of spinal cord and brain MRI measures may be required to capture clinically relevant information in people with MS of long disease duration. PMID- 23812284 TI - Influence of the topography of brain damage on depression and fatigue in patients with multiple sclerosis. AB - OBJECTIVES: Involvement of selected central nervous system (CNS) regions has been associated with depression and fatigue in MS. We assessed whether specific regional patterns of lesion distribution and atrophy of the gray (GM) and white matter (WM) are associated with these symptoms in MS. METHODS: Brain dual-echo and 3D T1-weighted images were acquired from 123 MS patients (69 depressed (D), 54 non-depressed (nD), 64 fatigued, 59 non-fatigued) and 90 controls. Lesion distribution, GM and WM atrophy were estimated using VBM and SPM8. RESULTS: Gender, age, disease duration and conventional MRI characteristics did not differ between D-MS and nD-MS patients. Fatigued patients experienced higher EDSS and depression than non-fatigued ones. Lesion distribution and WM atrophy were not related to depression and fatigue. Atrophy of regions in the frontal, parietal and occipital lobes had a combined effect on depression and fatigue. Atrophy of the left middle frontal gyrus and right inferior frontal gyrus were selectively related to depression. No specific pattern of GM atrophy was found to be related to fatigue. CONCLUSIONS: Depression in MS is linked to atrophy of cortical regions located in the bilateral frontal lobes. A distributed pattern of GM atrophy contributes to the concomitant presence of depression and fatigue in these patients. PMID- 23812285 TI - AXIN genetic analysis in adrenocortical carcinomas updated. AB - BACKGROUND: Wnt/beta-catenin signaling pathway activation plays an important role in adrenocortical tumorigenesis, but is only in part related to beta-catenin activating somatic mutations. Recently, genetic alteration in AXIN2, a key component of the Wnt/beta-catenin signaling pathway, has been described in adrenocortical tumors and specifically in adrenocortical carcinoma (ACC). AIM: To assess frequency and consequences of AXIN genes alteration on a large cohort of ACC. PATIENTS AND METHODS: Forty-nine adult sporadic ACC, with expression data available, in addition to both ACC cell lines H295 and H295R were studied. AXIN2 exon 8 hot-spot sequencing was performed on the entire cohort. AXIN1 entire coding region was studied on the 8 ACC with nuclear beta-catenin staining. RESULTS: The previously described AXIN2 in-frame heterozygous 12bp deletion c2013_2024del12 was found in 1 of the 49 ACC studied (2%), in a tumor with pSer45del activating CTNNB1 mutation and nuclear beta-catenin staining. This heterozygous deletion was also found in the patient's germline DNA, extracted from peripheral blood leukocytes. This genetic alteration was also present in H295 and H295R cell lines. The single-nucleotide polymorphism rs35415678 was found with an allele frequency similar to those found in reference populations. No correlation between AXIN2 expression, AXIN2 genetic variant or nuclear beta- catenin staining was observed. No AXIN1 alterations were found in the 8 ACC studied. CONCLUSIONS: AXIN genes do not play a major role in ACC tumorigenesis and Wnt/beta-catenin signaling pathway activation. AXIN2 germline variant c2013_2024del12 is likely to be a non-pathogenic polymorphism. PMID- 23812286 TI - Prospective, randomized clinical trial comparing the use of a single-port device with that of a flexible endoscope with no other device for transumbilical cholecystectomy: LLATZER-FSIS pilot study. AB - BACKGROUND: Natural orifice transumbilical endoscopic surgery (NOTES) is a technique still in experimental development that requires clinical trials to assess its safety and efficacy. We present a pilot prospective, randomized, three arm clinical trial of 1-year duration that was conducted as a noninferiority trial comparing single-incision laparoscopic surgery (SILS) and flexible single incision surgery (FSIS) with conventional laparoscopy for elective cholecystectomy (NCT01558414). METHODS: Sixty patients between aged 18 and 65 years who were eligible for elective cholecystectomy were randomly assigned in a 1:1:1 ratio (n = 20 per group): group A (SILS), single-incision endoscopic surgery using a transumbilical SILSTM device; group B (FSIS), single-incision transumbilical surgery using a flexible endoscope; and group C (CL), conventional laparoscopy. The main outcome variable of the study was "parietal complications" (wound infection, bleeding, and ventral hernia). The analysis was by intention to treat and attritions were not replaced. RESULTS: Cholecystectomy was performed in 100 % of the cases; perioperative complications occurred in only 1.6 % of the cases, and umbilical surgical wound infection in 3.33 %, with no differences between groups. After a minimum follow-up of 1 year, no differences were noted in the frequency of parietal complications and no ventral hernias occurred. Postoperative pain, hospital length of stay, and downtime from work were similar in all three groups. Surgical time was longer in cases in which a single-incision transumbilical approach was used (58.95 min for SILS and 54.15 for FSIS vs. 49.21 for laparoscopy). CONCLUSIONS: Single-incision transumbilical approaches are not inferior for safety or effectiveness compared with conventional laparoscopy. The transumbilical approach using a flexible endoscope is just as effective and safe as the other two procedures and is a promising single-incision approach. PMID- 23812288 TI - HPA axis activity in multiple sclerosis correlates with disease severity, lesion type and gene expression in normal-appearing white matter. AB - The hypothalamus-pituitary-adrenal (HPA) axis is activated in most, but not all multiple sclerosis (MS) patients and is implicated in disease progression and comorbid mood disorders. In this post-mortem study, we investigated how HPA axis activity in MS is related to disease severity, neurodegeneration, depression, lesion pathology and gene expression in normal-appearing white matter (NAWM). In 42 MS patients, HPA axis activity was determined by measuring cortisol in cerebrospinal fluid (CSF) and counting hypothalamic corticotropin-releasing hormone (CRH)-expressing neurons. Degree of neurodegeneration was based on levels of glutamate, tau and neurofilament in CSF. Duration of MS and time to EDSS 6 served as indicators of disease severity. Glutamate levels correlated with numbers of CRH-expressing neurons, most prominently in primary progressive MS patients, suggesting that neurodegeneration is a strong determinant of HPA axis activity. High cortisol levels were associated with slower disease progression, especially in females with secondary progressive MS. Patients with low cortisol levels had greater numbers of active lesions and tended towards having less remyelinated plaques than patients with high cortisol levels. Interestingly, NAWM of patients with high cortisol levels displayed elevated expression of glucocorticoid-responsive genes, such as CD163, and decreased expression of pro inflammatory genes, such as tumor necrosis factor-alpha. Thus, HPA axis hyperactivity in MS coincides with low inflammation and/or high neurodegeneration, and may impact on lesion pathology and molecular mechanisms in NAWM and thereby be of great importance for suppression of disease activity. PMID- 23812289 TI - Sporadic ALS with compound heterozygous mutations in the SQSTM1 gene. AB - Accumulating evidence suggests that heterozygous mutations in the SQSTM1 gene, which encodes p62 protein, are associated with amyotrophic lateral sclerosis (ALS). Here, we report a Japanese patient with sporadic, late-onset ALS who harbored compound heterozygous SQSTM1 mutations (p.[Val90Met];[Val153Ile]). Autopsy examination revealed that although TDP-43 pathology was rather widespread, the selective occurrence of p62-positive/TDP-43-negative cytoplasmic inclusions in the lower motor neurons (LMNs) was a characteristic feature. No Bunina bodies were found. Ultrastructurally, p62-positive cytoplasmic inclusions observed in the spinal anterior horn cells were composed of aggregates of ribosome-like granules and intermingled bundles of filamentous structures. Another feature of interest was concomitant Lewy body pathology. The occurrence of distinct p62 pathology in the LMNs in this patient indicates the pathogenic role of SQSTM1 mutations in the development of a subset of ALS. PMID- 23812290 TI - [Paul Grammont : 1940-2013]. PMID- 23812291 TI - [Osteoarthritis]. PMID- 23812292 TI - Impaction fracture of the medial femoral condyle. AB - The patient was a 20-year-old man who sustained a noncontact left knee hyperextension injury while playing soccer. In reviewing left knee radiographs that had previously been interpreted as normal, the physical therapist noted an abnormally deep depression of the medial condylopatellar sulcus, which was concerning for a possible impacted osteochondral fracture. After discussing the radiographic findings with a radiologist, the physical therapist ordered magnetic resonance imaging, which revealed a focal indentation of the anterior portion of the medial femoral condyle with adjacent bone marrow edema that was consistent with an impaction fracture of the medial femoral condyle. PMID- 23812296 TI - UPA promotes lipid-loaded vascular smooth muscle cell migration through LRP-1. AB - AIM: Migration of vascular smooth muscle cells (VSMCs) is a crucial event in atherosclerosis and vascular repair. Low-density lipoprotein (LDL) infiltrated in the vessel wall become aggregated (agLDL) and internalized by VSMC through the LDL receptor-related protein LRP1, deriving in lipid-loaded cells with reduced motility capacity. The urokinase-plasminogen activator (UPA)/UPA receptor (UPAR) system plays a relevant role in vascular remodelling. Here, we investigated whether UPA-ligand binding is involved in the detrimental effects of lipid loading in VSMC migration. METHODS AND RESULTS: Animals fed a high-fat diet had 10-fold higher cholesterol-LDL plasma levels, >60% decrease in aortic UPA-protein expression, and VSMC showed impaired outgrowth from aortic explants. Angiotensin II infusion significantly increased aortic UPA expression and accelerated VSMC migration. Using an in vitro model of wound repair, we showed that agLDL inhibits UPA-mediated VSMC migration. UPA silencing reduced migration in control cells to levels observed in lipid-loaded VSMC. UPA silencing did not affect migration in lipid-loaded VSMC. UPA expression was significantly decreased in agLDL-exposed VSMC. agLDL also induced changes in the subcellular localization of UPA, with a reduction in colocalization with UPAR strongly evident at the front edge of agLDL treated migrating cells. Rescue experiments showed that UPA acting as UPAR ligand restored migration capacity of agLDL-VSMC to control levels. The effects of UPA/UPAR on migration of lipid-loaded cells occurred through the binding to LRP 1. CONCLUSION: UPA-ligand binding regulates VSMC migration, a process that is interfered by LDL. Thus, tissue infiltrated LDL through the abrogation of UPA function reduces VSMC-regulated vascular repair. PMID- 23812298 TI - Inflammation impairs eNOS activation by HDL in patients with acute coronary syndrome. AB - AIMS: The aim of the present study was to evaluate the high-density lipoprotein (HDL) structure and endothelial NO synthase (eNOS) activation capacity in ST elevation myocardial infarction (STEMI) patients with different acute-phase inflammatory response (APR). METHODS AND RESULTS: Forty-five STEMI patients were stratified in quartiles according to the delta CRP level, calculated by subtracting the CRP value at admission from the CRP peak value (APR peak). The HDL structure and HDL capacity to stimulate NO production were evaluated at admission and at APR peak. STEMI patients with a low APR had a completely preserved HDL structure and HDL ability to activate eNOS and promote NO production, which did not change during STEMI. On the contrary, HDL from STEMI patients developing a significant APR had compromised ability to stimulate eNOS and promote NO production, and underwent a significant particle remodelling during STEMI. The defective capacity to stimulate NO production of HDL isolated from STEMI patients with high APR was explained, at least in part, by the reduced PON-1 and S1P content. The HDL ability to promote cell cholesterol efflux through different pathways was preserved in ACS patients independently of the inflammatory response. CONCLUSION: The present results extend previous studies reporting an impaired eNOS-activating capacity of HDL from ACS patients, showing that only a subset of patients undergoing STEMI, and in particular those developing an important inflammatory response, have circulating HDL defective in stimulating endothelial eNOS and NO production. PMID- 23812297 TI - Blood flow suppresses vascular Notch signalling via dll4 and is required for angiogenesis in response to hypoxic signalling. AB - AIMS: The contribution of blood flow to angiogenesis is incompletely understood. We examined the effect of blood flow on Notch signalling in the vasculature of zebrafish embryos, and whether blood flow regulates angiogenesis in zebrafish with constitutively up-regulated hypoxic signalling. METHODS AND RESULTS: Developing zebrafish (Danio rerio) embryos survive via diffusion in the absence of circulation induced by knockdown of cardiac troponin T2 or chemical cardiac cessation. The absence of blood flow increased vascular Notch signalling in 48 h post-fertilization old embryos via up-regulation of the Notch ligand dll4. Despite this, patterning of the intersegmental vessels is not affected by absent blood flow. We therefore examined homozygous vhl mutant zebrafish that have constitutively up-regulated hypoxic signalling. These display excessive and aberrant angiogenesis from 72 h post-fertilization, with significantly increased endothelial number, vessel diameter, and length. The absence of blood flow abolished these effects, though normal vessel patterning was preserved. CONCLUSION: We show that blood flow suppresses vascular Notch signalling via down regulation of dll4. We have also shown that blood flow is required for angiogenesis in response to hypoxic signalling but is not required for normal vessel patterning. These data indicate important differences in hypoxia-driven vs. developmental angiogenesis. PMID- 23812299 TI - Blocking von Willebrand factor for treatment of cutaneous inflammation. AB - Von Willebrand factor (VWF), a key player in hemostasis, is increasingly recognized as a proinflammatory protein. Here, we found a massive accumulation of VWF in skin biopsies of patients suffering from immune complex (IC)-mediated vasculitis (ICV). To clarify the impact of VWF on cutaneous inflammation, we induced experimental ICV either in mice treated with VWF-blocking antibodies or in VWF(-/-) mice. Interference with VWF led to a significant inhibition of the cutaneous inflammatory response. We confirmed the major findings in irritative contact dermatitis, a second model of cutaneous inflammation. In vivo imaging of cutaneous inflammation in the dorsal skinfold chamber revealed unaffected leukocyte rolling on anti-VWF treatment. However, we identified that reduced leukocyte recruitment is accompanied by reduced vascular permeability. Although VWF-mediated neutrophil recruitment to the peritoneum was described to require the VWF receptor on platelets (glycoprotein Ibalpha (GPIbalpha)), the VWF/GPIbalpha axis was dispensable for cutaneous inflammation. As assessed in tail bleeding assays, we could exclude interference of VWF blockade with hemostasis. Of particular importance, anti-VWF treatment was effective both in prophylactic and therapeutic administration. Thus, VWF represents a promising target for the treatment of cutaneous inflammation, e.g., leukocytoclastic vasculitis. PMID- 23812300 TI - Nonpathogenic bacteria alleviating atopic dermatitis inflammation induce IL-10 producing dendritic cells and regulatory Tr1 cells. AB - The beneficial effects of nonpathogenic bacteria are increasingly being recognized. We reported in a placebo-controlled study with atopic dermatitis (AD) patients that cutaneous exposure to lysates of nonpathogenic bacteria alleviates skin inflammation. To now unravel underlying mechanisms, immune consequences of sensing nonpathogenic bacterium Vitreoscilla filiformis lysate (Vf) were characterized analyzing (1) differentiation of dendritic cells (DCs) and, consecutively, (2) effector functions of DCs and T helper (Th) cells in vitro and in a murine model of AD in NC/Nga mice in vivo. Topical treatment with Vf significantly reduced AD-like inflammation in NC/Nga mice. Importantly, cutaneous exposure to Vf in combination with the allergen FITC significantly also reduced subsequent allergen-induced dermatitis indicating active immune modulation. Indeed, innate sensing of Vf predominantly induced IL-10-producing DCs, which was dependent on Toll-like receptor 2 (TLR2) activation. Vf-induced IL-10+ DCs primed naive CD4+ T helper cells to become regulatory IFN-gamma(low) IL-10(high) Tr1 (type 1 regulatory T) cells. These IL-10(high) Tr1 cells were also induced by Vf in vivo and strongly suppressed T effector cells and inflammation. In conclusion, we show that innate sensing of nonpathogenic bacteria by TLR2 induces tolerogenic DCs and regulatory Tr1 cells suppressing T effector cells and cutaneous inflammation. These findings indicate a promising therapeutic strategy for inflammatory skin diseases like AD. PMID- 23812301 TI - Regeneration of human dermis by a multi-headed peptide. AB - Skin aging is characterized by deterioration of the dermal collagen fiber network due to both decreased collagen expression and increased collagenolytic activity. We designed and evaluated in vitro and ex vivo the efficacy of a trifunctional peptide (TFP) to restore collagen and elastin fibers. TFP was constituted of an elastokine motif (VGVAPG)3, able to increase matrix constituent expression through the stimulation of the elastin-binding protein receptor, a GIL tripeptide occupying matrix metalloproteinase-1 subsites, and a RVRL linker domain acting as a competitive substrate for urokinase. The effects of TFP on type I, type III collagens, and elastin expression in dermal fibroblasts were determined by quantitative real-time reverse-transcriptase-PCR and western blotting. TFP's inhibitory capacity against MMP-1, plasmin, and urokinase was assessed using synthetic substrates, immunohistochemistry, and skin tissue sections as natural substrates. A skin explant model was used to recapitulate aging-induced dermal changes along culture extent. Collagen and elastin fiber structure was analyzed by two-photon fluorescence, second harmonic generation, and confocal microscopies. Compared with the different sections constituting the full peptide, we found that TFP activated the production of matrix constituents while inhibiting MMP-1 in vitro and ex vivo. It also induced a proper fiber network organization, reflecting the potency of TFP in skin remodeling and regeneration. PMID- 23812302 TI - Increased levels of circulating microparticles are associated with increased procoagulant activity in patients with cutaneous malignant melanoma. AB - Microparticles (MPs) are known to be increased in various malignancies and are involved in tumor invasion, angiogenesis, coagulation, and metastasis. We investigated the plasma levels of annexin-V MPs (AV(+)MPs), platelet-derived MPs (PMPs), and endothelial-derived MPs (EMPs) in patients with melanoma (n=129) and in healthy controls (n=49). A functional coagulation test STA Procoag-PPL measuring the clotting time was performed on samples containing MPs to evaluate their procoagulant potential. The plasma levels of PMPs, EMPs, and AV(+)MPs were significantly higher, and the clotting time-PPL was significantly lower in melanoma patients than in healthy controls. The plasma levels of PMPs, EMPs, and AV(+)MPs were higher in stage IV than in the other stages of melanoma, but with no significant difference. In addition, we observed an inverse correlation between PMPs, AV(+)MPs, and clotting times. Our data suggest that MPs are involved in the progression of melanoma and may be associated to melanoma associated thrombogenesis. PMID- 23812303 TI - Treatment-related restoration of Langerhans cell migration in psoriasis. PMID- 23812304 TI - Modulation of immune function by polyphenols: possible contribution of epigenetic factors. AB - Several biological activities have been described for polyphenolic compounds, including a modulator effect on the immune system. The effects of these biologically active compounds on the immune system are associated to processes as differentiation and activation of immune cells. Among the mechanisms associated to immune regulation are epigenetic modifications as DNA methylation of regulatory sequences, histone modifications and posttranscriptional repression by microRNAs that influences the gene expression of key players involved in the immune response. Considering that polyphenols are able to regulate the immune function and has been also demonstrated an effect on epigenetic mechanisms, it is possible to hypothesize that there exists a mediator role of epigenetic mechanisms in the modulation of the immune response by polyphenols. PMID- 23812306 TI - Cortical imaging in multiple sclerosis: recent findings and 'grand challenges'. AB - PURPOSE OF REVIEW: This review summarizes recent advancements in cortical imaging in multiple sclerosis (MS). RECENT FINDINGS: New and advanced imaging techniques have been developed to improve cortical lesion detection, measure cortical atrophy and depict diffuse gray matter damage. New pulse sequences have been developed and (ultra) high-field strength has been proven to be advantageous in the visualization of cortical lesions. Unfortunately, there are still many cortical lesions that remain undetected on MR sequences, especially subpial lesions. Combining histopathological findings with MR imaging has provided us with more insight into MS pathogenesis. Cortical atrophy, deep gray matter atrophy and cortical lesions all have diagnostic and prognostic value. SUMMARY: New and advanced imaging techniques continue to play a pivotal role in the visualization and quantification of cortical damage in MS. It provides us with a better understanding of cognitive functioning and functional reorganization. PMID- 23812307 TI - Huntington's disease and Huntington's disease-like syndromes: an overview. AB - PURPOSE OF REVIEW: The differential diagnosis of chorea syndromes may be complex and includes various genetic disorders such as Huntington's disease and mimicking disorders called Huntington's disease-like (HDL) phenotypes. To familiarize clinicians with these (in some cases very rare) conditions we will summarize the main characteristics. RECENT FINDINGS: HDL disorders are rare and account for about 1% of cases presenting with a Huntington's disease phenotype. They share overlapping clinical features, so making the diagnosis purely on clinical grounds may be challenging, however presence of certain characteristics may be a clue (e.g. prominent orofacial involvement in neuroferritinopathy etc.), Information of ethnic descent will also guide genetic work-up [HDL2 in Black Africans; dentatorubral-pallidoluysian atrophy (DRPLA) in Japanese etc.], Huntington's disease, the classical HDL disorders (except HDL3) and DRPLA are repeat disorders with anticipation effect and age-dependent phenotype in some, but genetic underpinnings may be more complicated in the other chorea syndromes. SUMMARY: With advances in genetics more and more rare diseases are disentangled, allowing molecular diagnoses in a growing number of choreic patients. Hopefully, with better understanding of their pathophysiology we are moving towards mechanistic therapies. PMID- 23812305 TI - Intestinal iron homeostasis and colon tumorigenesis. AB - Colorectal cancer (CRC) is the third most common cause of cancer-related deaths in industrialized countries. Understanding the mechanisms of growth and progression of CRC is essential to improve treatment. Iron is an essential nutrient for cell growth. Iron overload caused by hereditary mutations or excess dietary iron uptake has been identified as a risk factor for CRC. Intestinal iron is tightly controlled by iron transporters that are responsible for iron uptake, distribution, and export. Dysregulation of intestinal iron transporters are observed in CRC and lead to iron accumulation in tumors. Intratumoral iron results in oxidative stress, lipid peroxidation, protein modification and DNA damage with consequent promotion of oncogene activation. In addition, excess iron in intestinal tumors may lead to increase in tumor-elicited inflammation and tumor growth. Limiting intratumoral iron through specifically chelating excess intestinal iron or modulating activities of iron transporter may be an attractive therapeutic target for CRC. PMID- 23812308 TI - Atypical parkinsonism: an update. AB - PURPOSE OF REVIEW: This update discusses novel aspects on genetics, diagnosis, and treatments of atypical parkinsonism published over the past 2 years. RECENT FINDINGS: A genome-wide association study identified new genetic risk factors for progressive supranuclear palsy and new genetic conditions presenting with atypical parkinsonism have been described. The clinical criteria for diagnosis of corticobasal degeneration have been revised, and for progressive supranuclear palsy are under revision. Novel molecular techniques to identify possible biomarkers, as in other neurodegenerative disorders, have started being studied on atypical parkinsonian conditions, and although preliminary results seem promising, further studies are urgently warranted. Therapeutic trials based on disease-specific targets have shown no clinical improvement. SUMMARY: The knowledge obtained recently on atypical parkinsonian conditions points out the major deficits in this field. With the expanding phenotypical spectrum of atypical parkinsonian conditions, the early identification of patients has become difficult. The inability of conventional methods to identify these disorders earlier and better than clinicians, and the recent failure of promising therapeutic compounds, highlight the fact that the lack of biomarkers is probably the greatest limitation for developing treatments for these disorders. Thus, current and future research in this direction will be crucial. PMID- 23812309 TI - Probing the effect of charge transfer enhancement in off resonance mode SERS via conjugation of the probe dye between silver nanoparticles and metal substrates. AB - The charge transfer-mediated surface enhanced Raman scattering (SERS) of crystal violet (CV) molecules that were chemically conjugated between partially polarized silver nanoparticles and optically smooth gold and silver substrates has been studied under off-resonant conditions. Tyrosine molecules were used as a reducing agent to convert silver ions into silver nanoparticles where oxidised tyrosine caps the silver nanoparticle surface with its semiquinone group. This binding through the quinone group facilitates charge transfer and results in partially oxidised silver. This establishes a chemical link between the silver nanoparticles and the CV molecules, where the positively charged central carbon of CV molecules can bind to the terminal carboxylate anion of the oxidised tyrosine molecules. After drop casting Ag nanoparticles bound with CV molecules it was found that the free terminal amine groups tend to bind with the underlying substrates. Significantly, only those CV molecules that were chemically conjugated between the partially polarised silver nanoparticles and the underlying gold or silver substrates were found to show SERS under off-resonant conditions. The importance of partial charge transfer at the nanoparticle/capping agent interface and the resultant conjugation of CV molecules to off resonant SERS effects was confirmed by using gold nanoparticles prepared in a similar manner. In this case the capping agent binds to the nanoparticle through the amine group which does not facilitate charge transfer from the gold nanoparticle and under these conditions SERS enhancement in the sandwich configuration was not observed. PMID- 23812310 TI - Wall shear stress distribution at the carotid bifurcation: influence of eversion carotid endarterectomy. AB - OBJECTIVES: To test the feasibility of four-dimensional (4D) flow MRI to quantify the systolic wall shear stress (WSSsystole) and oscillatory shear index (OSI) in high-grade internal carotid artery (ICA) stenosis before and after endarterectomy (CEA). METHODS: Twenty patients with >=60 % ICA stenosis were prospectively and consequently included. Four-dimensional flow MRI was used to measure individual time-resolved 3D blood flow velocities. Segmental WSSsystole and OSI were derived at eight wall segments in analysis planes positioned along the ICA, common (CCA) and external carotid artery (ECA). RESULTS: Regional WSSsystole of all patients decreased after CEA (P < 0.05). Changes were most prominent at the ICA bulb but remained unchanged in the CCA and ECA. OSI was significantly lower after CEA in the lateral vessel walls (P < 0.05). For analysis planes at the stenosis in- and outlet, a reduction of mean WSSsystole by 32 % and 52 % (P < 0.001) and OSI distal to the stenosis (40 %, P = 0.01) was found after CEA. CONCLUSIONS: Our findings show the potential of in vivo 4D flow MRI to quantify haemodynamic changes in wall shear stress even in patients with complex flow conditions. PMID- 23812311 TI - The effects of 1,4-cyclohexanediol on frozen ram spermatozoa. AB - In order to improve the quality of frozen spermatozoa of Yunnan semi-fine wool sheep, 1, 4-cyclohexanediol (1, 4-CHD) as a synthetic ice blocker was used for cryopreservation of ram spermatozoa in this study. Briefly, following collection by electric stimulation, equilibration at 5C following dilution with the freezing extender, and pre-freezing in liquid nitrogen vapor, the ram spermatozoa were preserved in liquid nitrogen for one month. In addition, the effects of osmolarity of the diluting extenders used for evaluation of frozen spermatozoa quality were also assessed. The results indicated addition of 1, 4-CHD could not increase the motility of ram spermatozoa after cryopreservation and thawing. With the elevation of the concentrations of 1, 4-CHD, the motility and moving velocity of frozen ram spermatozoa showed a steady decrease. Additionally, the presence of 1, 4-CHD cannot increase the percentage of frozen spermatozoa with intact acrosome and membrane. When the isotonic binding buffer was used to dilute the thawed spermatozoa, the percentage of cells labeled with propidium iodide (PI) after cryopreservation in the presence of 1, 4-CHD was significantly higher than that of spermatozoa frozen in the absence of 1, 4-CHD (P < 0.05). However, the percentage of frozen-thawed spermatozoa with exposed PS in the presence of 1, 4 CHD was significantly less than that of spermatozoa frozen in the absence of 1, 4 CHD (P < 0.01). When the basic extenders with an osmolarity of 404mOsm, 528mOsm, 648mOsm, or 853mOsm were used to dilute the frozen-thawed spermatozoa respectively, there is no significant difference between the four groups with respect to the moving velocity and membrane integrity (P > 0.05). In conclusion, the presence of 1, 4-CHD cannot improve the motility, moving velocity, acrosome staus, and membrane integrity of frozen ram spermatozoa. However, 1, 4-CHD may inhibit apoptosis caused by freezing and thawing. PMID- 23812312 TI - Effects of different cryoprotectant combinations on primordial follicle survivability and apoptosis incidence after vitrification of whole rat ovary. AB - This study was aimed at obtaining best vitrification conditions for preservation of primordial follicles after vitrification of whole ovarian tissue of rats. Ovaries of prepubertal ~5-week old female Wistar rats were divided randomly into 7 groups: Control (non-vitrified), V1 (EG+DMSO), V2 (EG+PROH), V3 (DMSO+PROH), V4 (EG+DMSO+Sucrose), V5 (EG+PROH+Sucrose) and V6 (DMSO+PROH+Sucrose). Control and vitrified-warmed samples were sectioned serially and stained either with HE or anti and pro active caspase-3 kit. The number of intact follicles in different stages of development was lower and the number of atretic and apoptotic follicles was higher in vitrification groups than those of the control group. Cryoprotectant combinations in V4 group showed better follicular preservation especially for primordial follicle. V3, V4 and V5 were best cryoprotectant mixtures, after the control group, according to the number of atretic follicles but the incidence of apoptotic primordial follicles was lowest in V3, V4 and V6. Incidence of apoptosis and the number of atretic follicles were lowest in V3 and V4 groups, and there was better primordial follicle preservation and survivability in VIV group. Thus, the combination of EG + DMSO with sucrose appears to be better suited for vitrification of whole ovarian tissue of rats. PMID- 23812313 TI - Immediate induction of heat shock proteins is not protective against cryopreservation in normal human fibroblasts. AB - Heat shock proteins (HSPs) were first identified as proteins whose synthesis was enhanced by stresses, such as increased temperature. HSPs can protect cells from various cytotoxic factors by stabilizing proteins. Thus, it could be hypothesized that heat induced HSPs can provide protective effects against cryopreservation induced cell death. The aim of this study was to determine whether induction of HSPs can increase the cell viability of normal human fibroblasts after cryopreservation. Cytotoxic effects of heat treatment were tested and the induction of HSPs was assessed by examining time-dependent HSP expression. A cell counting method using fluorescence microscopy was used to determine the viability of cells. In addition, the effects of geranylgeranylacetone were evaluated in terms of HSP expression and cytoskeleton changes. The results of this study showed that immediate induction of HSPs does not protect normal human fibroblasts against cryopreservation-induced cell death possibly by inducing cytoskeleton changes. PMID- 23812314 TI - Confocal raman microscopy as a non-invasive tool to investigate the phase composition of frozen complex cryopreservation media. AB - Various cryoprotective agents (CPA) are added to cell media in order to avoid cell injury during cryo preservation. The resulting complex environment of the preserved cell, consisting of crystalline and liquid phases can however not be investigated non-invasively by established methods in cryobiology. This study shows how scanning confocal Raman microscopy can non-invasively extract information on chemical composition, phase domain and distribution at cryogenic temperatures. The formation of the salt hydrate, hydrohalite NaCl?H2O, in solutions comprised of phosphate buffered saline (PBS) and dimethyl sulphoxide (DMSO) is studied in particular. Scanning confocal Raman microscopy can be used to unambiguously identify hydrohalite in a medium containing DMSO and saline. The confocal Raman microscopy imaging along with differential scanning calorimetric measurements further show that the hydrohalite is formed without eutectic formation. This method also allows for discrimination between closely packed hydrohalite crystals that are oriented differently. PMID- 23812315 TI - Heat transfer coefficient of cryotop during freezing. AB - Cryotop is an efficient vitrification method for cryopreservation of oocytes. It has been widely used owing to its simple operation and high freezing rate. Recently, the heat transfer performance of cryotop was studied by numerical simulation in several studies. However, the range of heat transfer coefficient in the simulation is uncertain. In this study, the heat transfer coefficient for cryotop during freezing process was analyzed. The cooling rates of 40 percent ethylene glycol (EG) droplet in cryotop during freezing were measured by ultra fast measurement system and calculated by numerical simulation at different value of heat transfer coefficient. Compared with the results obtained by two methods, the range of the heat transfer coefficient necessary for the numerical simulation of cryotop was determined, which is between 9000 W/(m(2).K) and 10000 W/(m (2).K). PMID- 23812316 TI - Thermocouple design for measuring temperatures of small insects. AB - Contact thermocouples often are used to measure surface body temperature changes of insects during cold exposure. However, small temperature changes of minute insects can be difficult to detect, particularly during the measurement of supercooling points. We developed two thermocouple designs, which use 0.51 mm diameter or 0.127 mm diameter copper-constantan wires, to improve our ability to resolve insect exotherms. We tested the designs with adults from three parasitoid species: Tetrastichus planipennisi, Spathius agrili, and S. floridanus. These species are <3 mm long and <0.1 mg. Mean exotherms were greater for fine-gauge thermocouples than thick-gauge thermocouples for the smallest species tested, T. planipennisi. This difference was not apparent for larger species S. agrili and S. floridanus. Thermocouple design did not affect the mean supercooling point for any of the species. The cradle thermocouple design developed with the fine gauge wire was reusable and allowed for easy insect recovery after cold exposure. PMID- 23812317 TI - A refinement to the liquidus-tracking method for vitreous preservation of articular cartilage. AB - The recent liquidus-tracking method developed by Pegg et al. (2006a), as an alternative pathway to vitrification, achieved reasonable survival of post thawing chondrocytes in situ. One of the main drawbacks of this method is the long duration of the cryoprotectant addition/removal process. This study was conducted to investigate the possibility of reducing the time by rationalizing the final dimethyl sulfoxide (Me2SO) concentration loaded in tissue before being plunged into liquid nitrogen. Using the differential scanning calorimetric technique, the critical cooling and warming rates for solutions of Me2SO in CPTes2 (a potassium-rich medium, modified slightly from Taylor's original formulation by Pegg et al.) were obtained. The critical cooling and warming rates for 47.5 percent (w/w) solution are < 2.5 degree C per min and < 10 degree C per min, respectively, which could be readily realized for 4 ml solution samples held in polypropylene cryovials as demonstrated by experiments. For articular cartilage, 47.5 percent (w/w) may be recommended as the final concentration of Me2SO loaded in the tissue, which will lead to a time cut of about one-third compared with the original protocol of Pegg et al. (2006a). PMID- 23812318 TI - Translating cryobiology principles into trans-disciplinary storage guidelines for biorepositories and biobanks: a concept paper. AB - Low temperatures are used routinely to preserve diverse biospecimens, genetic resources and non-viable or viable biosamples for medical and clinical research in hospital-based biobanks and non-medical biorepositories, such as genebanks and culture, scientific, museum, and environmental collections. However, the basic knowledge underpinning preservation can sometimes be overlooked by practitioners who are unfamiliar with fundamental cryobiological principles which are more usually described in research literature rather than in quality and risk management documents. Whilst procedures vary, low temperature storage is a common requirement and reaching consensus as to how best it is applied could facilitate the entire biopreservation sector. This may be achieved by encouraging an understanding of cryoprotection theory and emphasizing the criticality of thermal events (glass transitions, ice nucleation, thawing) for sample integrity, functionality and stability. The objective of this paper is to inspire diverse biopreservation sectors to communicate more clearly about low temperature storage and, raise awareness of the importance of cryobiology principles to field newcomers and biopreservation practitioners, by considering how the principles may be translated into evidence-based guidelines for biobank and biorepository operations. PMID- 23812319 TI - CSF alpha-synuclein improves diagnostic and prognostic performance of CSF tau and Abeta in Alzheimer's disease. AB - Alzheimer's disease (AD) and Lewy body diseases (LBD), e.g., Parkinson's disease (PD) dementia and dementia with Lewy bodies (DLB), are common causes of geriatric cognitive impairments. In addition, AD and LBD are often found in the same patients at autopsy; therefore, biomarkers that can detect the presence of both pathologies in living subjects are needed. In this investigation, we report the assessment of alpha-synuclein (alpha-syn) in cerebrospinal fluid (CSF) and its association with CSF total tau (t-tau), phosphorylated tau181 (p-tau181), and amyloid beta1-42 (Abeta1-42) in subjects of the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 389), with longitudinal clinical assessments. A strong correlation was noted between alpha-syn and t-tau in controls, as well as in patients with AD and mild cognitive impairment (MCI). However, the correlation is not specific to subjects in the ADNI cohort, as it was also seen in PD patients and controls enrolled in the Parkinson's Progression Markers Initiative (PPMI; n = 102). A bimodal distribution of CSF alpha-syn levels was observed in the ADNI cohort, with high levels of alpha-syn in the subjects with abnormally increased t tau values. Although a correlation was also noted between alpha-syn and p-tau181, there was a mismatch (alpha-syn-p-tau181-Mis), i.e., higher p-tau181 levels accompanied by lower alpha-syn levels in a subset of ADNI patients. We hypothesize that this alpha-syn-p-tau181-Mis is a CSF signature of concomitant LBD pathology in AD patients. Hence, we suggest that inclusion of measures of CSF alpha-syn and calculation of alpha-syn-p-tau181-Mis improves the diagnostic sensitivity/specificity of classic CSF AD biomarkers and better predicts longitudinal cognitive changes. PMID- 23812320 TI - Longitudinal change in CSF Tau and Abeta biomarkers for up to 48 months in ADNI. AB - The dynamics of cerebrospinal fluid (CSF) tau and Abeta biomarkers over time in Alzheimer's disease (AD) patients from prodromal pre-symptomatic to severe stages of dementia have not been clearly defined and recent studies, most of which are cross-sectional, present conflicting findings. To clarify this issue, we analyzed the longitudinal CSF tau and Abeta biomarker data from 142 of the AD Neuroimaging Initiative (ADNI) study subjects [18 AD, 74 mild cognitive impairment (MCI), and 50 cognitively normal subjects (CN)]. Yearly follow-up CSF collections and studies were conducted for up to 48 months (median = 36 months) for CSF Abeta1 42, phosphorylated tau (p-tau181), and total tau (t-tau). An unsupervised analysis of longitudinal measurements revealed that for Abeta1-42 and p-tau181 biomarkers there was a group of subjects with stable longitudinal CSF biomarkers measures and a group of subjects who showed a decrease (Abeta1-42, mean = -9.2 pg/ml/year) or increase (p-tau181, mean = 5.1 pg/ml/year) of these biomarker values. Low baseline Abeta1-42 values were associated with longitudinal increases in p-tau181. Conversely, high baseline p-tau181 values were not associated with changes in Abeta1-42 levels. When the subjects with normal baseline biomarkers and stable concentrations during follow-up were excluded, the expected time to reach abnormal CSF levels and the mean AD values was significantly shortened. Thus, our data demonstrate for the first time that there are distinct populations of ADNI subjects with abnormal longitudinal changes in CSF p-tau181 and Abeta1-42 levels, and our longitudinal results favor the hypothesis that Abeta1-42 changes precede p-tau181 changes. PMID- 23812321 TI - Crypt dysplasia on Barrett's oesophagus. PMID- 23812322 TI - 5-Methylcytosine hydroxylation-mediated LINE-1 hypomethylation: a novel mechanism of proto-oncogenes activation in colorectal cancer? PMID- 23812324 TI - Endoscopic versus histological characterisation of polyps during screening colonoscopy. AB - BACKGROUND: As screening colonoscopy becomes more widespread, the costs for histopathological assessment of resected polyps are rising correspondingly. Reference centres have published highly accurate results for endoscopic polyp classification. Therefore, it has been proposed that, for smaller polyps, the differential diagnosis that guides follow-up recommendations could be based on endoscopy alone. OBJECTIVE: The aim was to prospectively assess whether the high accuracy for endoscopic polyp diagnosis as reported by reference centres can be reproduced in routine screening colonoscopy. DESIGN: Ten experienced private practice endoscopists had initial training in pit patterns. Then they assessed all polyps detected during 1069 screening colonoscopies. Patients (46% men; mean age 63 years) were randomly assigned to colonoscopy with conventional or latest generation HDTV instruments. The main outcome measure was diagnostic accuracy of in vivo polyp assessment (adenomatous vs hyperplastic). Secondary outcome measures were differences between endoscopes and reliability of image-based follow-up recommendations; a blinded post hoc analysis of polyp photographs was also performed. RESULTS: 675 polyps were assessed (461 adenomatous, 214 hyperplastic). Accuracy, sensitivity and specificity of in vivo diagnoses were 76.6%, 78.1% and 73.4%; size of adenomas and endoscope withdrawal time significantly influenced accuracy. Image-based recommendations for post polypectomy surveillance were correct in only 69.5% of cases. Post hoc analysis of polyp photographs did not improve accuracy. CONCLUSIONS: In everyday practice, endoscopic classification of polyp type is not accurate enough to abandon histopathological assessment and use of latest generation colonoscopes does not improve this. Image-based surveillance recommendations after polypectomy would consequently not meet guideline requirements. TRIALREGNO: NCT01297712. PMID- 23812323 TI - Gastric colonisation with a restricted commensal microbiota replicates the promotion of neoplastic lesions by diverse intestinal microbiota in the Helicobacter pylori INS-GAS mouse model of gastric carcinogenesis. AB - OBJECTIVES: Gastric colonisation with intestinal flora (IF) has been shown to promote Helicobacter pylori (Hp)-associated gastric cancer. However, it is unknown if the mechanism involves colonisation with specific or diverse microbiota secondary to gastric atrophy. DESIGN: Gastric colonisation with Altered Schaedler's flora (ASF) and Hp were correlated with pathology, immune responses and mRNA expression for proinflammatory and cancer-related genes in germ-free (GF), Hp monoassociated (mHp), restricted ASF (rASF; 3 species), and specific pathogen-free (complex IF), hypergastrinemic INS-GAS mice 7 months postinfection. RESULTS: Male mice cocolonised with rASFHp or IFHp developed the most severe pathology. IFHp males had the highest inflammatory responses, and 40% developed invasive gastrointestinal intraepithelial neoplasia (GIN). Notably, rASFHp colonisation was highest in males and 23% developed invasive GIN with elevated expression of inflammatory biomarkers. Lesions were less severe in females and none developed GIN. Gastritis in male rASFHp mice was accompanied by decreased Clostridum species ASF356 and Bacteroides species ASF519 colonisation and an overgrowth of Lactobacillus murinus ASF361, supporting that inflammation driven atrophy alters the gastric niche for GI commensals. Hp colonisation also elevated expression of IL-11 and cancer-related genes, Ptger4 and Tgf-beta, further supporting that Hp infection accelerates gastric cancer development in INS-GAS mice. CONCLUSIONS: rASFHp colonisation was sufficient for GIN development in males, and lower GIN incidence in females was associated with lower inflammatory responses and gastric commensal and Hp colonisation. Colonisation efficiency of commensals appears more important than microbial diversity and lessens the probability that specific gastrointestinal pathogens are contributing to cancer risk. PMID- 23812325 TI - Fungal genetics: Candida chooses its code. PMID- 23812327 TI - The role of viruses in autoreactive B cell activation within tertiary lymphoid structures in autoimmune diseases. AB - TLS, characterized by the formation of ectopic B/T cell follicles with FDCs supporting an ectopic GC response, have been described in the target organs of several autoimmune diseases, including MS, RA, SS, and autoimmune thyroiditis. These structures represent functional niches, whereby autoreactive B cells undergo in situ affinity maturation and differentiation to autoantibody-producing cells, thus contributing to the progression and persistence of autoimmunity. Increasing evidence demonstrates that TLS can also develop in the context of cancer, as well as chronic infections. In this review, we collect recent evidences that highlights the relationship between persistent viral infection and the development of ectopic lymphoid structures in animal models and patients. Furthermore, we shall discuss the concept that whereas in physiological conditions, inducible TLS are critical for viral clearance and the establishment of protective immunity, but in the context of susceptible individuals, persistent viral infections may contribute, directly or indirectly, to the development of breach of tolerance against self-antigens and the development of autoimmunity through the formation of TLS. PMID- 23812326 TI - Cyclic di-AMP: another second messenger enters the fray. AB - Nucleotide signalling molecules contribute to the regulation of cellular pathways in all forms of life. In recent years, the discovery of new signalling molecules in bacteria and archaea, as well as the elucidation of the pathways they regulate, has brought insights into signalling mechanisms not only in bacterial and archaeal cells but also in eukaryotic host cells. Here, we provide an overview of the synthesis and regulation of cyclic di-AMP (c-di-AMP), one of the latest cyclic nucleotide second messengers to be discovered in bacteria. We also discuss the currently known receptor proteins and pathways that are directly or indirectly controlled by c-di-AMP, the domain structure of the enzymes involved in its production and degradation, and the recognition of c-di-AMP by the eukaryotic host. PMID- 23812329 TI - Critical assessment of patient-reported outcome measures. PMID- 23812328 TI - Innate immune responses against Epstein Barr virus infection. AB - EBV persists life-long in >95% of the human adult population. Whereas it is perfectly immune-controlled in most infected individuals, a minority develops EBV associated diseases, primarily malignancies of B cell and epithelial cell origin. In recent years, it has become apparent that the course of primary infection determines part of the risk to develop EBV-associated diseases. Particularly, the primary symptomatic EBV infection or IM, which is caused by exaggerated T cell responses, resulting in EBV-induced lymphocytosis, predisposes for EBV-associated diseases. The role of innate immunity in the development of IM remains unknown. Therefore, it is important to understand how the innate immune response to this virus differs between symptomatic and asymptomatic primary EBV infection. Furthermore, the efficiency of innate immune compartments might determine the outcome of primary infection and could explain why some individuals are susceptible to IM. We will discuss these aspects in this review with a focus on intrinsic immunity in EBV-infected B cells, as well as innate immune responses by DCs and NK cells, which constitute promising immune compartments for the understanding of early immune control against EBV and potential targets for EBV specific immunotherapies. PMID- 23812330 TI - Clinical significance of serum M30 and M65 levels in melanoma. AB - M30 and M65 are relatively new assays that detect different circulating forms of the epithelial cell structural protein cytokeratin 18. This study was carried out to investigate the serum levels of M30 and M65 in patients with melanoma and the relationship with tumor progression and known prognostic parameters. Fifty-two patients with cutaneous melanoma were investigated. Serum samples were obtained on first admission before adjuvant and metastatic treatment were provided and at follow-up. Both serum M30 and M65 levels were determined using an enzyme-linked immunosorbent assay. The median age of patients at diagnosis was 54 years, range 16-88 years; 30 patients were men. Over half of the patients (58%) were in the metastatic stage and most (63%) had M1c. The baseline serum M65 levels were significantly higher in patients with melanoma than in the control group (P < 0.001). For the serum M30 levels, no difference was found (P = 0.76). Both the serum M30 and M65 levels were significantly higher in the patients with leukocytosis (P = 0.02 and 0.007, respectively). In addition, the serum M30 levels were also elevated in young (P = 0.02) and female patients (P = 0.01). A significant relationship was found between the serum levels of M30 and M65 (rs = 0.408, P = 0.003, Spearman's correlation). As expected, distant metastasis (P < 0.001), advanced metastatic stage (M1c) (P = 0.03), elevated erythrocyte sedimentation rate (P = 0.001), higher serum lactate dehydrogenase levels (P < 0.001), and unresponsiveness to chemotherapy (P < 0.001) had worse survival. However, neither serum M30 nor serum M65 had a significantly adverse effect on survival (P = 0.23 and 0.68, respectively). In conclusion, although only serum M65 levels were found to be of diagnostic value, neither M30 nor M65 serum levels played a prognostic role in the outcome in melanoma patients. PMID- 23812331 TI - A comparison of strategies for multiple-gene co-transformation via hairy root induction. AB - Hairy root is a transformed root tissue in which transfer DNA (T-DNA) is inserted in the genome by Agrobacterium rhizogenes. To establish a system for multiple gene co-transformation in hairy roots, we evaluated four different strategies using A. rhizogenes. The genes gusA and mgfp5 were located in separate plasmids, which were transformed into two different batches of A. rhizogenes (strategy 2AR) or a single batch (strategy 2BV). The two reporter genes were also inserted in one T-DNA (strategy 1TD) or two different T-DNAs (strategy 2TD) in a binary vector. Over 90 % of infected Nicotiana tabacum leaf discs formed hairy roots in all four groups, which was not significantly different from the infection efficiency of wild-type A. rhizogenes. Proportions of co-transformed hairy roots with strategies 2AR, 2BV, 1TD, and 2TD were 65.4, 40.0, 78.6, and 82.1 %, respectively, which indicated that all of the strategies were suitable for co transformation of multiple genes. High variation in growth rate and heterologous protein expression indicated that further screening is required to identify the clone with the highest productivity. Our results indicated that strategies 1TD and 2TD achieved the highest co-transformation efficiency. Combination with strategy 2AR or 2BV provides additional options for co-transformation of multiple transgenes. PMID- 23812332 TI - Functional characterization of the twin ZIP/SLC39 metal transporters, NpunF3111 and NpunF2202 in Nostoc punctiforme. AB - The ZIP family of metal transporters is involved in the transport of Zn(2+) and other metal cations from the extracellular environment and/or organelles into the cytoplasm of prokaryotes, eukaryotes and archaeotes. In the present study, we identified twin ZIP transporters, Zip11 (Npun_F3111) and Zip63 (Npun_F2202) encoded within the genome of the filamentous cyanobacterium, Nostoc punctiforme PCC73120. Sequence-based analyses and structural predictions confirmed that these cyanobacterial transporters belong to the SLC39 subfamily of metal transporters. Quantitative real-time (QRT)-PCR analyses suggested that the enzymes encoded by zip11 and zip63 have a broad allocrite range that includes zinc as well as cadmium, cobalt, copper, manganese and nickel. Inactivation of either zip11 or zip63 via insertional mutagenesis in N. punctiforme resulted in reduced expression of both genes, highlighting a possible co-regulation mechanism. Uptake experiments using (65)Zn demonstrated that both zip mutants had diminished zinc uptake capacity, with the deletion of zip11 resulting in the greatest overall reduction in (65)Zn uptake. Over-expression of Zip11 and Zip63 in an E. coli mutant strain (ZupT736::kan) restored divalent metal cation uptake, providing further evidence that these transporters are involved in Zn uptake in N. punctiforme. Our findings show the functional role of these twin metal uptake transporters in N. punctiforme, which are independently expressed in the presence of an array of metals. Both Zip11 and Zip63 are required for the maintenance of homeostatic levels of intracellular zinc N. punctiforme, although Zip11 appears to be the primary zinc transporter in this cyanobacterium, both ZIP's may be part of a larger metal uptake system with shared regulatory elements. PMID- 23812333 TI - Improved thermostability of a Bacillus subtilis esterase by domain exchange. AB - A moderately thermostable esterase from Geobacillus stearothermophilus (BsteE) and its homolog from Bacillus subtilis (BsubE) show a high structural similarity with more than 95% homology and 74% amino acid identity. Interestingly, their thermal stability differs significantly by 30 degrees C in their melting temperature. In order to identify the positions that are responsible for this difference, most of the flexible amino acids assumed to confer instability were found to be in the cap region. For this reason, a 30 amino acid long cap domain fragment containing ten differing positions derived from BsteE was incorporated into the homologous gene encoding for the more labile BsubE by spliced overlap extension PCR. The melting temperature of the two wild-type esterases and the mutant was evaluated by circular dichroism spectroscopy, while the kinetic parameters and the stability were determined with a photometric assay. The cap domain mutant maintained its activity, with a catalytic efficiency more similar to BsteE, while it exhibited an increase of the melting temperature by 4 degrees C compared to BsubE. Additional point mutations based on the differences of the parent enzymes gave a further increase of the thermostability up to 11 degrees C compared to BsubE; however, a significant reduction in activity was observed. PMID- 23812334 TI - Development of a markerless gene deletion system for Streptococcus zooepidemicus: functional characterization of hyaluronan synthase gene. AB - Streptococcus zooepidemicus is a bacterial pathogen used for production of hyaluronan in industry. Intensive research has significantly contributed to our understanding of S. zooepidemicus biology and pathogenesis. However, the lack of an effective targeted gene inactivation system in S. zooepidemicus has notably prevented the functional genomics analysis of this gram-positive bacterium. Here, we report the development of a markerless gene deletion system in S. zooepidemicus. We constructed a sacB expression cassette on the thermosensitive suicide vector pSET4s and demonstrated its use as a counterselection marker in S. zooepidemicus. We validated the efficiency of this system by deletion of hasA, which synthesizes the important virulence factor hyaluronic acid (HA) capsule. The genotype of the resultant hasA mutant was confirmed by polymerase chain reaction and sequencing. Deletion of hasA resulted in non-mucoid morphology, loss of HA capsule formation, and HA production. These defects can be rescued by introduction of a plasmid containing wild-type hasA expression cassette. Moreover, compared with wild type, hasA mutant showed no significant difference in expressions of other members of the hasABCDE operon, further suggesting that the loss of hasA contributed to the defects observed with DeltahasA mutant. Our results describe the first establishment of a sacB-based counterselection system in S. zooepidemicus, along with the first demonstration of hasA that is the only gene encoding a functional hyaluronan synthase in this bacterium. PMID- 23812335 TI - Monoxenic liquid culture with Escherichia coli of the free-living nematode Panagrolaimus sp. (strain NFS 24-5), a potential live food candidate for marine fish and shrimp larvae. AB - The free-living, bacterial-feeding nematode Panagrolaimus sp. (strain NFS 24-5) has potential for use as live food for marine shrimp and fish larvae. Mass production in liquid culture is a prerequisite for its commercial exploitation. Panagrolaimus sp. was propagated in monoxenic liquid culture on Escherichia coli and parameters, like nematode density, population dynamics and biomass were recorded and compared with life history table data. A mean maximum nematode density of 174,278 mL(-1) and a maximum of 251,000 mL(-1) were recorded on day 17 after inoculation. Highest average biomass was 40 g L(-1) at day 13. The comparison with life history table data indicated that the hypothetical potential of liquid culture is much higher than documented during this investigation. Nematode development is delayed in liquid culture and egg production per female is more than five times lower than reported from life history trait analysis. The latter assessed a nematode generation time of 7.1 days, whereas the process time at maximum nematode density in liquid culture was 16 days indicating that a reduction of the process time can be achieved by further investigating the influence of nematode inoculum density on population development. The results challenge future research to reduce process time and variability and improve population dynamics also during scale-up of the liquid culture process. PMID- 23812336 TI - Swerving away from diabetic nephropathy by means of divine guidance. PMID- 23812337 TI - Antibiotic prescription for respiratory tract infections in ventilated patients: where are we heading? PMID- 23812338 TI - Research to inform the consent-to-research process. PMID- 23812339 TI - Pre-emptive broad-spectrum treatment for ventilator-associated pneumonia in high risk patients. AB - PURPOSE: Patients requiring mechanical ventilation (MV) for >48 h after major heart surgery (MHS) are at a high risk of acquiring ventilator-associated pneumonia (VAP) and tracheobronchitis (VAT). Most non-pharmacological interventions to prevent VAP in such patients are usually already implemented. The objective of this study was to evaluate the efficacy in preventing lower respiratory infections of antibiotics active against multidrug-resistant pathogens in this very high-risk population. METHODS: We performed a prospective randomized open-label study of MHS patients requiring MV for >48 h. Patients were randomly allocated to one of two groups: the intervention group, which received a 3-day course of linezolid and meropenem, and the control group, which received the standard of care. The main outcome was the development of VAP or VAT. RESULTS: Overall, of the 78 patients included in the study, 40 were in the intervention group and 38 in the control group. Both groups were comparable. Data for the intervention and control groups respectively were as follows: VAP + VAT/1,000 days was 31.79 vs 64.78 (p = 0.03), median length of MV before the first episode of VAP or VAT 9 vs 4.5 days (p = 0.02). No significant differences were observed in median length of stay in the intensive care unit, median length of hospital stay, antibiotic use, Clostridium difficile infection, and overall mortality rate. We detected linezolid-resistant coagulase-negative and coagulase positive staphylococci in the MHS intensive care unit after the study period. CONCLUSIONS: A pre-emptive approach with broad-spectrum antibiotics may be effective in reducing the incidence and delaying the onset of VAP + VAT after MHS. The ecological consequences have to be carefully evaluated in future trials. PMID- 23812340 TI - Resuscitation of patients with septic shock: please "mind the gap"! PMID- 23812341 TI - Evolution of haemodynamics and outcome of fluid-refractory septic shock in children. AB - BACKGROUND: Maintaining threshold values of cardiac output (CO) and systemic vascular resistance (SVR) when used as part of the American College of Critical Care Medicine (ACCM) haemodynamic protocol improves the outcomes in paediatric septic shock. OBJECTIVE: We observed the evolution of CO and SVR during the intensive care admission of children with fluid-refractory septic shock and report this together with the eventual outcomes. DESIGN: Prospective observational study. SETTING: Tertiary care Paediatric Intensive Care Unit (PICU) in London. METHODS: Children admitted in fluid refractory septic shock to the Intensive Care Unit over a period of 36 months were studied. Post liver re transplant children and delayed septic shock admissions were excluded. A non invasive ultrasound cardiac output monitor device (USCOM) was used to measure serial haemodynamics. Children were allocated at presentation into one of two categories: (1) hospital-acquired infection and (2) community-acquired infection. Vasopressor, inotrope or inodilator therapies were titrated to maintain threshold cardiovascular parameters as per the ACCM guidelines. RESULTS: Thirty-six children [19 male, mean age (SD) 6.78 (5.86) years] were admitted with fluid refractory septic shock and studied. At presentation, all 18 children with hospital-acquired (HA) sepsis and 3 from among the community-acquired (CA) sepsis group were in 'warm shock' (SVRI < 800 dyne s/cm(5)/m(2)) whereas 15 of the 18 children with community-acquired sepsis and none in the hospital-acquired group were in 'cold shock' [cardiac index (CI) < 3.3 l/min/m(2)]. All 21 children in 'warm shock' were initially commenced on a vasopressor (noradrenaline). Despite an initial good response, four patients developed low CI and needed adrenaline. Similarly, all 15 children in cold shock were initially commenced on adrenaline. However, two of them subsequently required noradrenaline. Five others needed milrinone as an inodilator. In general, both groups of children had normalised SVRI and CI within 42 h of therapy but required variable doses of vasopressors, inotropes or inodilators in a heterogeneous manner. The overall 28-day survival rate was 88.9 % in both groups. Central venous oxygen saturation (ScvO2) was significantly (p = 0.003) lower in the community-acquired group (mean 51.72 % +/- 4.26) when compared to the hospital-acquired group (mean 58.72 % +/- 1.36) at presentation but showed steady improvement during therapy. Gram-positive organisms were predominant in blood cultures, 61 % in HA and 56 % in CA groups. CONCLUSIONS: In general, we found children with community-acquired septic shock presented in cold shock whereas hospital-acquired septic shock children manifested warm shock. Both types evolved in a heterogeneous manner needing frequent revision of cardiovascular support therapy. However the 28-day survival in both groups was the same at 89 %. Frequent measurements of haemodynamics using non-invasive ultrasound helped in fine tuning cardiovascular therapies. PMID- 23812342 TI - Accuracy of plasma neutrophil gelatinase-associated lipocalin in the early diagnosis of contrast-induced acute kidney injury in critical illness. PMID- 23812343 TI - Paleopathology of the juvenile Pharaoh Tutankhamun-90th anniversary of discovery. AB - Modern paleopathology is a multidisciplinary field of research which involves archaeology, medicine and biology. The most common diseases of Ancient Egypt were traumatic injuries, malaria and tuberculosis. Exemplarily, an internistic and trauma surgery case of that time is reviewed: Pharaoh Tutankhamun (ca. 1330-1324 B.C.). Summarising all findings which have been collected between 1922 and 2010, including computed tomography and molecular pathology, a diversity of disease is verifiable: (1) chronic/degenerative diseases (mild kyphoscoliosis, pes planus and hypophalangism of the right foot, bone necrosis of metatarsal bones II-III of the left foot); (2) inflammatory disease (malaria tropica, verified by PCR analysis) and (3) acute trauma (complex fracture of the right knee shortly before death). The most likely cause of death is the severe acute knee fracture and/or the malaria, while a suspected eighteenth dynasty syndrome cannot be proven. PMID- 23812344 TI - Sex hormone binding globulin, but not testosterone, is associated with the metabolic syndrome in overweight and obese women with polycystic ovary syndrome. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism and an increased risk of Type 2 diabetes and cardiovascular disease. Decreased SHBG and elevated testosterone are associated with metabolic syndrome and glucose intolerance in women. AIM: The aim of this study was to assess the relationship between SHBG and testosterone and metabolic syndrome and glucose intolerance in PCOS. MATERIAL/SUBJECTS AND METHODS: Cross-sectional study in overweight and obese premenopausal non-diabetic women with PCOS (no.=178: no.=55 metabolic syndrome, no.=16 glucose intolerance). Data were analyzed by multiple regression with metabolic syndrome, oral glucose tolerance test (OGTT) glucose or SHBG as dependent variables and reproductive hormones, insulin resistance, glucose tolerance, lipids or C-reactive protein as independent variables. RESULTS: Metabolic syndrome was independently associated with body mass index [odds ratio (OR) 1.084 95% confidence interval (CI) 1.034-1.170, p=0.015] and SHBG (OR 0.961 95% CI 0.932-0.995, p=0.018). Glucose tolerance was independently associated with OGTT insulin (beta=0.418, p<0.001), age (beta=0.154, p=0.033) and PRL (beta= 0.210, p=0.002). SHBG was independently associated with OGTT insulin (beta= 0.216, p=0.014) and PCOS diagnostic criteria (beta=0.197, p=0.010). CONCLUSIONS: SHBG, but not testosterone, is independently associated with metabolic syndrome in overweight women with PCOS and is associated with insulin resistance and PCOS diagnostic criteria. PMID- 23812346 TI - Organic plasmon-emitting diodes for detecting refractive index variation. AB - A photo-excited organic layer on a metal thin film with a corrugated substrate was used to generate surface plasmon grating coupled emissions (SPGCEs). Directional emissions corresponded to the resonant condition of surface plasmon modes on the Au/air interface. In experimental comparisons of the effects of different pitch sizes on the plasmonic band-gap, the obtained SPGCEs were highly directional, with intensity increases as large as 10.38-fold. The FWHM emission spectrum was less than 70 nm. This method is easily applicable to detecting refractive index changes by using SP-coupled fluorophores in which wavelength emissions vary by viewing angle. The measurements and calculations in this study confirmed that the color wavelength of the SPGCE changed from 545.3 nm to 615.4 nm at certain viewing angles, while the concentration of contacting glucose increased from 10 to 40 wt%, which corresponded to a refractive index increase from 1.3484 to 1.3968. The organic plasmon-emitting diode exhibits a wider linearity range and a resolution of the experimental is 1.056 * 10-3 RIU. The sensitivity of the detection limit for naked eye of the experimental is 0.6 wt%. At a certain viewing angle, a large spectral shift is clearly distinguishable by the naked eye unaided by optoelectronic devices. These experimental results confirm the potential applications of the organic plasmon-emitting diodes in a low-cost, integrated, and disposable refractive-index sensor. PMID- 23812347 TI - A child's battle with Alagille syndrome. PMID- 23812348 TI - Evidence-based recommendations for GERD treatment. AB - Gastroesophageal reflux disease (GERD) is a common presentation in primary care. New research findings have implications for the diagnosis and management of GERD. The purpose of this article is to synthesize current research related to the diagnosis and management of GERD in adults and to make practice recommendations. PMID- 23812345 TI - Improving photosynthesis. AB - Photosynthesis is the basis of plant growth, and improving photosynthesis can contribute toward greater food security in the coming decades as world population increases. Multiple targets have been identified that could be manipulated to increase crop photosynthesis. The most important target is Rubisco because it catalyses both carboxylation and oxygenation reactions and the majority of responses of photosynthesis to light, CO2, and temperature are reflected in its kinetic properties. Oxygenase activity can be reduced either by concentrating CO2 around Rubisco or by modifying the kinetic properties of Rubisco. The C4 photosynthetic pathway is a CO2-concentrating mechanism that generally enables C4 plants to achieve greater efficiency in their use of light, nitrogen, and water than C3 plants. To capitalize on these advantages, attempts have been made to engineer the C4 pathway into C3 rice (Oryza sativa). A simpler approach is to transfer bicarbonate transporters from cyanobacteria into chloroplasts and prevent CO2 leakage. Recent technological breakthroughs now allow higher plant Rubisco to be engineered and assembled successfully in planta. Novel amino acid sequences can be introduced that have been impossible to reach via normal evolution, potentially enlarging the range of kinetic properties and breaking free from the constraints associated with covariation that have been observed between certain kinetic parameters. Capturing the promise of improved photosynthesis in greater yield potential will require continued efforts to improve carbon allocation within the plant as well as to maintain grain quality and resistance to disease and lodging. PMID- 23812349 TI - Keeping pace with HIV: a clinical overview for nurse practitioners. AB - Improved treatment options, advances in prevention, and changes in health policy have transformed HIV into a chronic disease. This article reviews issues relevant for primary care clinicians, including advances in HIV testing, treatment, a review of comorbidities, and the latest information on HIV prevention strategies. PMID- 23812350 TI - Deuterium isotope effects in the polyatomic reaction of O(1D2)+CH4->OH+CH3. AB - The scattering distributions of state-selected CH3 products are measured for the O((1)D2) reaction with CH4 using a crossed molecular beam ion imaging method at collision energies of 0.9-6.8 kcal mol(-1). The results are compared with the reaction with CD4 to examine the isotope effects. The scattering distributions exhibit contributions from both the insertion and abstraction pathways, respectively, on the ground- and excited-state potential energy surfaces. Insertion is the main pathway, and it provides a strongly forward-enhanced angular distribution of methyl radicals. Abstraction is a minor pathway, causing backward scattering of methyl radicals with a discrete speed distribution. From the collision energy dependence of the abstraction/insertion ratio, the barrier height for the abstraction pathway is estimated to be 0.7 +/- 0.3 and 0.8 +/- 0.1 kcal mol(-1) for O((1)D2) with CH4 and CD4, respectively. The insertion pathway of the O((1)D2) reaction with CH4 has a narrower angular width in the forward scattering and a larger insertion/abstraction ratio than the reaction with CD4, which indicates that the insertion reaction with CH4 has a larger cross section and a shorter reaction time than the reaction with CD4. Additionally, while the insertion reaction with CD4 exhibits strong angular dependence of the CD3 speed distribution, CH3 exhibits considerably smaller dependence. The result suggests that, although intramolecular vibrational redistribution (IVR) within the lifetime of the methanol intermediate is restrictive in both isotopomers, relatively more extensive IVR occurs in CD3OD than CH3OH, presumably due to the higher vibrational state density. PMID- 23812352 TI - Venous thromboembolism in pediatric nephrotic syndrome. AB - Childhood nephrotic syndrome (NS) is one of the most common pediatric kidney diseases, with an incidence of 2-7 per 100,000. Venous thromboembolism (VTE) is associated with significant morbidity and mortality, and occurs in ~3 % of children with NS, though incidence approaches 25 % in high-risk groups. VTE etiology is multifactorial, with disease-associated coagulopathy thought to be a significant contributor. Other risks include age, disease severity, and treatment related hazards, such as the presence of central venous catheters. Non pharmacologic preventive measures such as ambulation and compression stockings are recommended for patients with identified VTE risks. Central venous catheters should be avoided whenever possible. Symptoms of VTE include venous catheter dysfunction, unilateral extremity symptoms, respiratory compromise, flank pain, and gross hematuria. When VTE is suspected, confirmatory imaging studies should be obtained, followed by appropriate laboratory evaluation and treatment. Therapeutic goals include limiting thrombus growth, extension, and embolization by early institution of anticoagulant therapy. Anticoagulation is recommended for a minimum of 3 months, but should be continued until NS remission is achieved. Further studies are necessary to identify VTE-risk biomarkers and optimal therapeutic regimens. Observational cohort studies are needed to identify VTE risk groups who may benefit from thromboprophylaxis and to define disease specific treatment algorithms. PMID- 23812351 TI - Therapeutic plasma exchange for the treatment of pediatric renal diseases in 2013. AB - Therapeutic plasma exchange is an extracorporeal treatment modality that removes systemic circulating pathologic factors or replaces absent plasma components and plays a role in many nephrologic conditions. It presents a number of technical challenges in the pediatric population but has become an increasingly common practice in pediatric nephrology over the past several decades. While prospective evidence is often lacking, our increased understanding of the molecular pathogenesis underlying many pediatric renal diseases provides sound reasoning for the use of plasma exchange in treating these conditions. This review will present the currently accepted indications for plasma exchange in children, the technical aspects of the procedure and its potential complications. PMID- 23812353 TI - High frequency of kidney and urinary tract anomalies in asymptomatic first-degree relatives of patients with CAKUT. AB - BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) commonly cause chronic kidney disease in children. While most CAKUT cases are sporadic, observed familial clustering suggests that the pathogenesis is influenced by genetic factors. METHODS: The purpose of the present study is to determine the frequency of the kidney and urinary tract anomalies in asymptomatic first-degree relatives of patients with CAKUT. A total of 218 index patients and their families followed at an academic hospital in Ankara, Turkey, were enrolled in the study. RESULTS: Family histories revealed at least one other member with a known kidney or urinary tract disease in 50% and CAKUT in 22.9% of the families. All asymptomatic first-degree relatives of 180 index patients were screened for kidney and urinary tract anomalies using ultrasound. New anomalies were diagnosed in 116 asymptomatic first-degree relatives (23%) in 87 families (48.3%). When family histories and ultrasound findings of 180 index patients were evaluated together, 129 first-degree relatives in 92 families (51.1%) had CAKUT. CONCLUSIONS: This study suggests that genetic mechanisms might be very important in the pathogenesis of apparently sporadic CAKUT. Identification of the underlying gene mutations will provide further insights into the knowledge of the kidney and urinary tract development and pathogenesis of CAKUT. PMID- 23812354 TI - The use of posterior vertebral column resection in the management of severe posttuberculous kyphosis: a retrospective study and literature review. AB - PURPOSE: We present a retrospective study of 15 cases with severe posttuberculous kyphosis of thoracolumbar region that underwent posterior vertebral column resection. METHODS: From 2004 to 2009, 15 consecutive patients with posttubercular kyphotic deformity underwent posterior vertebral resection osteotomy. Six subjects were females and nine were males with an average age of 35.8 years (range 20-60 years) at the time of surgery. None of the patients had neurological deficits. The mean preoperative visual analogue scale was 8.7 (range 3-9), and the average preoperative Oswestry Disability Index was 46.5 (range 40 56). RESULTS: The average duration of postoperative follow-up was 36.1 +/- 10.7 months (range 24-62 months). The number of vertebra resected was 1.3 (range 1-2) on average. There were ten patients with one-level osteotomy and five patients with two-level osteotomy. The average operation time was 446.0 +/- 92.5 min (range 300-640 min) with an average blood loss of 1,653.3 +/- 777.9 ml (range 800 3000 ml). The focal kyphosis before surgery averaged 92.3 +/- 8.9 degrees (range 74-105 degrees ), and the kyphotic angle decreased to 34.5 +/- 8.7 degrees on average after the surgical correction. The average kyphotic angle at the last follow-up was 36.9 +/- 8.5 degrees , loss of correction was 2.4 +/- 1.4 degrees on average. All patients postoperatively received bony fusion within 6-9 months. CONCLUSIONS: Our results showed that although posterior vertebral resection is a highly technical procedure, it can be used safely and effectively in the management of severe posttuberculous kyphosis. It is imperative that operations be performed by an experienced surgical team to prevent operation-related complications. PMID- 23812355 TI - Genome-scale gene expression characteristics define the follicular initiation and developmental rules during folliculogenesis. AB - The ovarian follicle supplies a unique dynamic system for gametes that ensures the propagation of the species. During folliculogenesis, the vast majority of the germ cells are lost or inactivated because of ovarian follicle atresia, resulting in diminished reproductive potency and potential infertility. Understanding the underlying molecular mechanism of folliculogenesis rules is essential. Primordial (P), preantral (M), and large antral (L) porcine follicles were used to reveal their genome-wide gene expression profiles. Results indicate that primordial follicles (P) process a diverse gene expression pattern compared to growing follicles (M and L). The 5,548 differentially expressed genes display a similar expression mode in M and L, with a correlation coefficient of 0.892. The number of regulated (both up and down) genes in M is more than that in L. Also, their regulation folds in M (2-364-fold) are much more acute than in L (2-75-fold). Differentially expressed gene groups with different regulation patterns in certain follicular stages are identified and presumed to be closely related following follicular developmental rules. Interestingly, functional annotation analysis revealed that these gene groups feature distinct biological processes or molecular functions. Moreover, representative candidate genes from these gene groups have had their RNA or protein expressions within follicles confirmed. Our study emphasized genome-scale gene expression characteristics, which provide novel entry points for understanding the folliculogenesis rules on the molecular level, such as follicular initiation, atresia, and dominance. Transcriptional regulatory circuitries in certain follicular stages are expected to be found among the identified differentially expressed gene groups. PMID- 23812358 TI - Vitamin D and cardiovascular risk in postmenopausal women: how to translate preclinical evidence into benefit for patients. AB - Preclinical work indicates that calcitriol restores vascular function by normalizing the endothelial expression of cyclooxygenase-2 and thromboxane prostanoid receptors in conditions of estrogen deficiency and thus prevents the thromboxane-prostanoid receptor activation-induced inhibition of nitric oxide synthase. Since endothelial dysfunction is a key factor in the pathogenesis of cardiovascular diseases, this finding may have an important translational impact. It provides a clear rationale to use endothelial function in clinical trials aiming to find the optimal dose of vitamin D for the prevention of cardiovascular events in postmenopausal women. PMID- 23812359 TI - New wrinkles in old receptors: core fucosylation is yet another target to inhibit TGF-beta signaling. AB - Shen et al. exploit glycobiology to dampen transforming growth factor-beta (TGF beta) signaling and ameliorate renal fibrosis after ureteral obstruction. Core fucosylation of N-linked oligosaccharides in TGF-beta receptors is required for receptor function. Adenoviruses expressing Fut8-fucosyl transferase-shRNA inhibited receptor fucosylation, decreased tubule TGF-beta signaling, and reduced fibrosis. Fut8-shRNA interferes with core fucosylation of other receptors also. Regardless, this first attempt to capitalize on a new aspect of TGF-beta receptor function provides a basis for further research. PMID- 23812360 TI - The contentious ontogeny of fibrosis in the kidney. AB - Arguably, no cell biology related to the loss of renal function is more debated than the ontogeny of fibrosis in the kidney. Recent studies suggest that the fibroblasts depositing most of the excess extracellular matrix in diseased kidneys derive from epithelial cells versus pericytes resident within the kidney. Reich et al. now contend that circulating bone marrow-derived fibrocytes independent of monocyte lineages are an important source of fibrogenic cells recruited to the kidney following injury. PMID- 23812361 TI - The conundrum of protection from AKI by adenosine in rodent clamp ischemia models. AB - Kim et al. show that isoflurane uses a tubule-based transforming growth factor beta/CD73-dependent process that generates adenosine to protect mice from ischemic acute kidney injury (AKI) with effects to prevent the 'no-reflow phenomenon' and decrease inflammation. While direct cytoprotection occurred in culture, extensive research suggests that in vivo adenosine protection from rodent ischemic AKI is mediated by a mutually cooperative mechanism involving blood flow, inflammation, and innate immunity through multiple adenosine receptors with promiscuous actions on diverse cell types. PMID- 23812362 TI - The dynamics of prognostic indicators: toward earlier identification of dialysis patients with a high risk of dying. AB - Mortality remains stubbornly high in patients receiving chronic dialysis treatment. Identifying at-risk patients is essential for implementation of supportive therapies. The Monitoring Dialysis Outcomes (MONDO) database shows that in 40,000 dialysis patients worldwide who died, systolic blood pressure, interdialytic weight gain, and serum albumin declined progressively, and C reactive protein increased more than 12 months before death, indicating that predictive models may be developed to enable nephrologists to improve the clinical outcome of dialysis patients. PMID- 23812363 TI - Hemostasis in acute liver and kidney failure: nothing is as it seems. AB - Very little is known about the behavior of the hemostatic system in patients with acute kidney injury (AKI) associated with acute liver failure (ALF). Agarwal and colleagues show that patients who suffer from both ALF and AKI exhibit a higher degree of hemostasis impairment than those with normal renal function. Both anticoagulant and procoagulant factors were impaired. The development of AKI appears to displace the hemostatic equilibrium toward a more prothrombotic pattern. PMID- 23812364 TI - The authors reply. PMID- 23812365 TI - Role of mast cells in renal fibrosis. PMID- 23812366 TI - Angiotensin receptor blocker and calcium channel blocker combination prevents cardiovascular events in CKD better than high-dose ARB alone. PMID- 23812367 TI - The authors reply. PMID- 23812368 TI - The author replies. PMID- 23812369 TI - The value of urinary neutrophil gelatinase-associated lipocalin in risk prediction of renal decline in patients with chronic kidney disease. PMID- 23812370 TI - The authors reply. PMID- 23812371 TI - Cryptococcus within a urinary cast. PMID- 23812372 TI - The case | Reversible rapidly progressive renal failure with loss of vision. PMID- 23812373 TI - Structure and function of Hip, an attenuator of the Hsp70 chaperone cycle. AB - The Hsp70-interacting protein, Hip, cooperates with the chaperone Hsp70 in protein folding and prevention of aggregation. Hsp70 interacts with non-native protein substrates in an ATP-dependent reaction cycle regulated by J-domain proteins and nucleotide exchange factors (NEFs). Hip is thought to delay substrate release by slowing ADP dissociation from Hsp70. Here we present crystal structures of the dimerization domain and the tetratricopeptide repeat (TPR) domain of rat Hip. As shown in a cocrystal structure, the TPR core of Hip interacts with the Hsp70 ATPase domain through an extensive interface, to form a bracket that locks ADP in the binding cleft. Hip and NEF binding to Hsp70 are mutually exclusive, and thus Hip attenuates active cycling of Hsp70-substrate complexes. This mechanism explains how Hip enhances aggregation prevention by Hsp70 and facilitates transfer of specific proteins to downstream chaperones or the proteasome. PMID- 23812374 TI - Single-molecule reconstitution of mRNA transport by a class V myosin. AB - Molecular motors are instrumental in mRNA localization, which provides spatial and temporal control of protein expression and function. To obtain mechanistic insight into how a class V myosin transports mRNA, we performed single-molecule in vitro assays on messenger ribonucleoprotein (mRNP) complexes reconstituted from purified proteins and a localizing mRNA found in budding yeast. mRNA is required to form a stable, processive transport complex on actin--an elegant mechanism to ensure that only cargo-bound motors are motile. Increasing the number of localizing elements ('zip codes') on the mRNA, or configuring the track to resemble actin cables, enhanced run length and event frequency. In multi-zip code mRNPs, motor separation distance varied during a run, thus showing the dynamic nature of the transport complex. Building the complexity of single molecule in vitro assays is necessary to understand how these complexes function within cells. PMID- 23812375 TI - Structurally encoded intraclass differences in EphA clusters drive distinct cell responses. AB - Functional outcomes of ephrin binding to Eph receptors (Ephs) range from cell repulsion to adhesion. Here we used cell collapse and stripe assays, showing contrasting effects of human ephrinA5 binding to EphA2 and EphA4. Despite equivalent ligand binding affinities, EphA4 triggered greater cell collapse, whereas EphA2-expressing cells adhered better to ephrinA5-coated surfaces. Chimeric receptors showed that the ectodomain is a major determinant of cell response. We report crystal structures of EphA4 ectodomain alone and in complexes with ephrinB3 and ephrinA5. These revealed closed clusters with a dimeric or circular arrangement in the crystal lattice, contrasting with extended arrays previously observed for EphA2 ectodomain. Localization microscopy showed that ligand-stimulated EphA4 induces smaller clusters than does EphA2. Mutant Ephs link these characteristics to interactions observed in the crystal lattices, suggesting a mechanism by which distinctive ectodomain surfaces determine clustering, and thereby signaling, properties. PMID- 23812376 TI - Crystal structure of peroxisomal targeting signal-2 bound to its receptor complex Pex7p-Pex21p. AB - Appropriate targeting of matrix proteins to peroxisomes is mainly directed by two types of peroxisomal targeting signals, PTS1 and PTS2. Although the basis of PTS1 recognition has been revealed by structural studies, that of PTS2 recognition remains elusive. Here we present the crystal structure of a heterotrimeric PTS2 recognition complex from Saccharomyces cerevisiae, containing Pex7p, the C terminal region of Pex21p and the PTS2 of the peroxisomal 3-ketoacyl-CoA thiolase. Pex7p forms a beta-propeller structure and provides a platform for cooperative interactions with both the amphipathic PTS2 helix and Pex21p. The C terminal region of Pex21p directly covers the hydrophobic surfaces of both Pex7p and PTS2, and the resulting hydrophobic core is the primary determinant of stable complex formation. Together with in vivo and in vitro functional assays of Pex7p and Pex21p variants, our findings reveal the molecular mechanism of PTS2 recognition. PMID- 23812377 TI - Ductal closure using the Amplatzer duct occluder type two: experience in Port Elizabeth hospital complex, South Africa: cardiovascular topic. AB - OBJECTIVE: To report outcomes in percutaneous ductal closure using the Amplatzer duct occluder type two (ADO II). METHODS: Records of patients admitted for percutaneous closure of patent ductus arteriosus (PDA) were reviewed. RESULTS: From May 2009 to July 2012, 36 patients were assigned to closure using the ADO II. There were 21 females and 15 males. The median age was 16.5 (2-233) months; median weight, 8 (3.94-39.2) kg; and median height, 75 (55-166) cm. The mean pulmonary artery pressure was 24.4 (+/- 10.4) mmHg, the pulmonary blood flow:systemic blood flow (Qp:Qs) ratio was 2.25 (+/- 1.97), and mean pulmonary resistance (Rp) was 1.87 (+/- 1.28) Wood units. The mean ductal size was 2.74 (+/ 1.3) mm. In 30 patients the device was delivered through the pulmonary artery. Thirty-three patients achieved complete closure by discharge (day one). CONCLUSION: The ADO II is capable of closing a wide range of ducts in carefully selected patients. Our findings are comparable with other studies regarding ductal closure rates. PMID- 23812378 TI - Measured symptomatic and psychological outcomes in women undergoing laparoscopic surgery for endometriosis: a prospective study. PMID- 23812379 TI - The role of the robot in treating urinary tract endometriosis. AB - PURPOSE OF REVIEW: To detail the recent advances in the use of computer-enhanced robotic technology to surgically treat urinary tract endometriosis. RECENT FINDINGS: Few studies have been published in this field. The studies are severely limited in scope. Further study is warranted. SUMMARY: Robotic-assisted laparoscopic techniques have proven useful in the treatment of extensive endometriosis and may prove useful in the treatment of urinary tract endometriosis. PMID- 23812380 TI - Surgical techniques and outcome in the management of submucous fibroids. AB - PURPOSE OF REVIEW: Hysteroscopic myomectomy was a revolution for surgical treatment of symptomatic submucosal myoma. RECENT FINDINGS: A new International Federation of Gynecology and Obstetrics classification for myoma was recently described. Type 0, 1 and 2 are submucosal like in the European Society for Human Reproduction and Embryology. An intraoperative ultrasound control should be done to avoid bowel lesion when the margin between the deepest part of the myoma and the serosa is less than 5-8 mm. For monopolar resection, glycine is used as distension medium and a high frequency current is required. The bipolar system is a newer electrosurgical system. The distension medium used is isotonic saline. The advantage of this energy is that with the same safety and efficacy as the monopolar system, isotonic saline as a distension medium instead of glycine seems to reduce the risk of metabolic complications. For bleeding outcome, a success rate from 70 to 99% has been reported by different studies; the success rate seems to decline as the follow-up period increases for fertility outcome, submucosal fibroids have negative impact on pregnancy rates in the case of spontaneous fertility as in the case of assisted reproduction technologies. SUMMARY: Hysteroscopic resection of submucous myoma is a well tolerated procedure. Bipolar resection should be studied for safe diffusion. Fertility outcome and menorragia are both enhanced by hysteroscopic myomectomy. PMID- 23812381 TI - Mullerian anomalies and recurrent miscarriage. AB - PURPOSE OF REVIEW: To review the prevalence of congenital uterine anomalies and pregnancy outcomes in patients with these anomalies. RECENT FINDINGS: Women with a history of recurrent miscarriage have been estimated to have a 3.2-10.4% likelihood of having a major uterine anomaly except arcuate uterus. Hysterosalpingography and/or 2D ultrasound can be used as the initial screening tools. The American Fertility Society classification of Mullerian anomalies is the most commonly utilized standardized classification. However, there is still no international consensus to distinguish between septate and bicornuate uteri. A total of 35.1-65.9% of patients with bicornuate or septate uteri give live births after correctional surgery. In regard to the live birth rate in the absence of surgery, it has been reported that 33.3-59.5% of patients with such anomalies had a successful first pregnancy after the examination, as compared to 71.7% of individuals with normal uteri (P=0.084), with no significant difference in the cumulative live birth rate (78.0 and 85.5%, respectively) between the two groups. SUMMARY: Randomized controlled trials comparing the pregnancy outcomes between cases treated and not treated by surgery among patients with a history of recurrent miscarriage are needed because it is not established whether surgery could improve live birth rate. PMID- 23812382 TI - Lichen sclerosus in children and adolescents. AB - PURPOSE OF REVIEW: This review of lichen sclerosus in children and adolescents will discuss the disease and highlight the most recent literature. RECENT FINDINGS: Lichen sclerosus continues to be poorly recognized and misdiagnosed by clinicians. There is growing support for an autoimmune component in the cause of this disease. Recent studies confirm that lichen sclerosus does not resolve after puberty but usually improves. In small case series, topical calcineurin inhibitors are effective as second-line therapy. SUMMARY: Lichen sclerosus is an uncommon, poorly recognized disease in girls and adolescents and is likely to have a chronic course requiring long-term follow-up and treatment. There needs to be increased awareness among providers of this disease as a cause of vulvar itching. Because of the lack of knowledge of the natural course and treatment outcomes, prospective, multicenter studies are needed. PMID- 23812384 TI - Termination of dobutamine infusion causes transient rebound left heart diastolic dysfunction in healthy elderly women but not in men: a cardiac magnetic resonance study. AB - Men and women are known to react differently to stress. Thus, stress cardiomyopathy almost solely strikes women. Stress cardiomyopathy is suggested to relate to sex differences in catecholamine reaction. Left heart function during dobutamine stress is well described, but sex-specific inotropic and lusitropic response to abrupt termination of dobutamine stress is not. We aimed to investigate sex differences in left ventricular (LV) and atrial (LA) function during and after dobutamine stress. We enrolled 20 healthy elderly subjects (60 70 yr, 10 females) and measured their LV and LA volumes throughout the cardiac cycle by cardiac magnetic resonance imaging at rest, during dobutamine stress (15 MUg.kg(-1).min(-1)), 15 min after termination (T15), and 30 min after termination (T30) of dobutamine stress. We calculated LV ejection fractions, LV stroke volumes, LV peak filling rates, and LA passive, active, and conduit volumes. Sex differences were not observed at rest or during dobutamine stress. Compared with prestress values, at T15 a rebound decrease in LV peak filling rate was observed in women (-22 +/- 3%, P < 0.001) but not in men. This was reflected in reduced LA passive emptying volume (-40 +/- 3%, P < 0.001) and a corresponding increase in LA active emptying volume (36 +/- 2%, P < 0.001). At T30 there were no differences between the sexes. We conclude that dobutamine causes greater stress to the female heart. This is revealed after termination of dobutamine stress where the left heart recovers in men, whereas women experience rebound LV stiffening with reduced diastolic relaxation. This is the first report of a sex specific transient rebound phenomenon in cardiovascular response to catecholamines. PMID- 23812383 TI - Identifying cellular mechanisms of zinc-induced relaxation in isolated cardiomyocytes. AB - We tested several molecular and cellular mechanisms of cardiomyocyte contraction relaxation function that could account for the reduced systolic and enhanced diastolic function observed with exposure to extracellular Zn(2+). Contraction relaxation function was monitored in isolated rat and mouse cardiomyocytes maintained at 37 degrees C, stimulated at 2 or 6 Hz, and exposed to 32 MUM Zn(2+) or vehicle. Intracellular Zn(2+) detected using FluoZin-3 rose to a concentration of ~13 nM in 3-5 min. Peak sarcomere shortening was significantly reduced and diastolic sarcomere length was elongated after Zn(2+) exposure. Peak intracellular Ca(2+) detected by Fura-2FF was reduced after Zn(2+) exposure. However, the rate of cytosolic Ca(2+) decline reflecting sarcoplasmic reticulum (SR) Ca(2+)-ATPase (SERCA2a) activity and the rate of Na(+)/Ca(2+) exchanger activity evaluated by rapid Na(+)-induced Ca(2+) efflux were unchanged by Zn(2+) exposure. SR Ca(2+) load evaluated by rapid caffeine exposure was reduced by ~50%, and L-type calcium channel inward current measured by whole cell patch clamp was reduced by ~70% in cardiomyocytes exposed to Zn(2+). Furthermore, ryanodine receptor (RyR) S2808 and phospholamban (PLB) S16/T17 were markedly dephosphorylated after perfusing hearts with 50 MUM Zn(2+). Maximum tension development and thin-filament Ca(2+) sensitivity in chemically skinned cardiac muscle strips were not affected by Zn(2+) exposure. These findings suggest that Zn(2+) suppresses cardiomyocyte systolic function and enhances relaxation function by lowering systolic and diastolic intracellular Ca(2+) concentrations due to a combination of competitive inhibition of Ca(2+) influx through the L type calcium channel, reduction of SR Ca(2+) load resulting from phospholamban dephosphorylation, and lowered SR Ca(2+) leak via RyR dephosphorylation. The use of the low-Ca(2+)-affinity Fura-2FF likely prevented the detection of changes in diastolic Ca(2+) and SERCA2a function. Other strategies to detect diastolic Ca(2+) in the presence of Zn(2+) are essential for future work. PMID- 23812385 TI - Central endogenous angiotensin-(1-7) protects against aldosterone/NaCl-induced hypertension in female rats. AB - In comparison to male rodents, females are protected against angiotensin (ANG) II and aldosterone (Aldo)-induced hypertension. However, the mechanisms underlying this protective effect are not well understood. ANG-(1-7) is formed from ANG II by angiotensin-converting enzyme 2 (ACE2) and has an antihypertensive effect in the central nervous system (CNS). The present study tested the hypothesis that central ANG-(1-7) plays an important protective role in attenuating the development of Aldo/NaCl-hypertension in female rats. Systemic infusion of Aldo into intact female rats with 1% NaCl as their sole drinking fluid resulted in a slight increase in blood pressure (BP). Intracerebroventricular (icv) infusion of A-779, an ANG-(1-7) receptor (Mas-R) antagonist, significantly augmented the pressor effects of Aldo/NaCl. In contrast, systemic Aldo/NaCl induced a significant increase in BP in ovariectomized (OVX) female rats, and central infusion of ANG-(1-7) significantly attenuated this Aldo/NaCl pressor effect. The inhibitory effect of ANG-(1-7) on the Aldo/NaCl pressor effect was abolished by concurrent infusion of A-779. RT-PCR analyses showed that there was a corresponding change in mRNA expression of several renin-angiotensin system components, estrogen receptors and an NADPH oxidase subunit in the lamina terminalis. Taken together these results suggest that female sex hormones regulate an antihypertensive axis of the brain renin-angiotensin system involving ACE2/ANG-(1-7)/Mas-R that plays an important counterregulatory role in protecting against the development of Aldo/NaCl-induced hypertension. PMID- 23812386 TI - A mathematical evaluation of hemodynamic parameters after carotid eversion and conventional patch angioplasty. AB - Carotid endarterectomy has a long history in stroke prevention, yet controversy remains concerning optimal techniques. Two methods frequently used are endarterectomy with patch angioplasty (CEAP) and eversion endarterectomy (CEE). The objective of this study was to compare hemodynamics-related stress and strain distributions between arteries repaired using CEAP and CEE. Mathematical models were based on in vivo three-dimensional arterial geometry, pulsatile velocity profiles, and intraluminal pressure inputs obtained from 16 patients with carotid artery disease. These data were combined with experimentally derived nonlinear, anisotropic carotid artery mechanical properties to create fluid-structure interaction models of CEAP and CEE. These models were then used to calculate hemodynamic parameters thought to promote recurrent disease and restenosis. Combining calculations of stress and strain into a composite risk index, called the integral abnormality factor, allowed for an overall comparison between CEAP and CEE. CEE demonstrated lower mechanical stresses in the arterial wall, whereas CEAP straightened the artery and caused high stress and strain concentrations at the suture-artery interface. CEAP produced a larger continuous region of oscillatory, low-shear, vortical flow in the carotid bulb. There was a more than two-fold difference in the integral abnormality factor, favoring CEE. In conclusion, in a realistically simulated carotid artery, fluid-structure interaction modeling demonstrated CEE to produce less mechanical wall stress and improved flow patterns compared with CEAP. Clinical validation with larger numbers of individual patients will ultimately be required to support modeling approaches to help predict arterial disease progression and comparative effectiveness of reconstruction methods and devices. PMID- 23812387 TI - Chronic atrial fibrillation causes left ventricular dysfunction in dogs but not goats: experience with dogs, goats, and pigs. AB - Structural remodeling in chronic atrial fibrillation (AF) occurs over weeks to months. To study the electrophysiological, structural, and functional changes that occur in chronic AF, the selection of the best animal model is critical. AF was induced by rapid atrial pacing (50-Hz stimulation every other second) in pigs (n = 4), dogs (n = 8), and goats (n = 9). Animals underwent MRIs at baseline and 6 mo to evaluate left ventricular (LV) ejection fraction (EF). Dogs were given metoprolol (50-100 mg po bid) and digoxin (0.0625-0.125 mg po bid) to limit the ventricular response rate to <180 beats/min and to mitigate the effects of heart failure. The pacing leads in pigs became entirely encapsulated and lost the ability to excite the heart, often before the onset of sustained AF. LV EF in dogs dropped from 54 +/- 11% at baseline to 33 +/- 7% at 6 mo (P < 0.05), whereas LV EF in goats did not drop significantly (69 +/- 8% at baseline vs. 60 +/- 9% at 6 mo, P = not significant). After 6 mo of AF, fibrosis levels in dog atria and ventricles increased, whereas only atrial fibrosis levels increased in goats compared with control animals. In our experience, the pig model is not appropriate for chronic rapid atrial pacing-induced AF studies. Rate-controlled chronic AF in the dog model developed HF and LV fibrosis, whereas the goat model developed only atrial fibrosis without ventricular dysfunction and fibrosis. Both the dog and goat models are representative of segments of the patient population with chronic AF. PMID- 23812388 TI - Primacy of angiotensin converting enzyme in angiotensin-(1-12) metabolism. AB - Angiotensin-(1-12) [ANG-(1-12)], a new member of the renin-angiotensin system, is recognized as a renin independent precursor for ANG II. However, the processing of ANG-(1-12) in the circulation in vivo is not fully established. We examined the effect of angiotensin converting enzyme (ACE) and chymase inhibition on angiotensin peptides formation during an intravenous infusion of ANG-(1-12) in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). WKY and SHR were assigned to a short ANG-(1-12) infusion lasting 5, 15, 30, or 60 min (n = 4-10 each group). In another experiment WKY and SHR were assigned to a continuous 15-min ANG-(1-12) infusion with pretreatment of saline, lisinopril (10 mg/kg), or chymostatin (10 mg/kg) (n = 7-13 each group). Saline or lisinopril were infused intravenously 15 min before the administration of ANG-(1-12) (2 nmol.kg(-1).min(-1)), whereas chymostatin was given by bolus intraperitoneal injection 30 min before ANG-(1-12). Infusion of ANG-(1-12) increased arterial pressure and plasma ANG-(1-12), ANG I, ANG II, and ANG-(1-7) levels in WKY and SHR. Pretreatment with lisinopril caused increase in ANG-(1-12) and ANG I and large decreases in ANG II compared with the other two groups in both strains. Pretreatment of chymostatin had no effect on ANG-(1-12), ANG I, and ANG II levels in both strains, whereas it increased ANG-(1-7) levels in WKY. We conclude that ACE acts as the primary enzyme for the conversion of ANG-(1-12) to smaller angiotensin peptides in the circulation of WKY and SHR and that chymase may be an ANG-(1-7) degrading enzyme. PMID- 23812389 TI - Eukaryotic elongation factor 2 kinase regulates the development of hypertension through oxidative stress-dependent vascular inflammation. AB - Eukaryotic elongation factor 2 kinase (eEF2K) is a Ca2+/calmodulin-dependent protein kinase. We recently demonstrated that eEF2K protein increases in mesenteric artery from spontaneously hypertensive rats (SHR). Pathogenesis of hypertension is regulated in part by vascular inflammation. We tested the hypothesis whether eEF2K mediates vascular inflammatory responses and development of hypertension. In vascular endothelial cells, small interfering RNA (siRNA) against eEF2K inhibited induction of VCAM-1 and endothelial-selectin as well as monocyte adhesion by TNF-alpha (10 ng/ml). eEF2K siRNA inhibited phosphorylation of JNK and NF-kappaB p65 as well as reactive oxygen species (ROS) production by TNF-alpha. In vascular smooth muscle cells, eEF2K siRNA also inhibited VCAM-1 induction and phosphorylation of JNK and NF-kappaB by TNF-alpha. In vivo, increased blood pressure in SHR and ROS production, induction of inflammatory molecules, and hypertrophy in SHR superior mesenteric artery were reduced by an eEF2K inhibitor NH125 (500 MUg.kg(-1).day(-1)). In SHR superior mesenteric artery, impairment of ACh-induced relaxation was normalized by NH125. The present results for the first time demonstrate that eEF2K mediates TNF-alpha-induced vascular inflammation via ROS-dependent mechanism, which is at least partly responsible for the development of hypertension in SHR. PMID- 23812390 TI - Periaortic adipose tissue-specific activation of the renin-angiotensin system contributes to atherosclerosis development in uninephrectomized apoE-/- mice. AB - Chronic kidney disease (CKD) is an independent risk factor for the development of cardiovascular disease. The perivascular adipose tissue is closely implicated in the development of atherosclerosis; however, the contribution to CKD-associated atherogenesis remains undefined. Eight-week-old apoE-deficient mice were uninephrectomized and fed a high-cholesterol diet starting at 12 wk of age. The atherosclerotic lesion area in the thoracic aorta was comparable in 16-wk-old uninephrectomized (UNX) mice and sham control mice; however, the lesion area was markedly exaggerated in 20-wk-old UNX mice compared with the control (54%, P < 0.05). While the accumulation of monocytes/macrophages and the mRNA expression levels of inflammatory cytokines/chemokines in the thoracic periaortic adipose tissue (PAT) did not differ between the two groups, angiotensinogen (AGT) mRNA expression and the angiotensin II (ANG II) concentration in the PAT were significantly higher in 16-wk-old UNX mice than in the control (1.9- and 1.5-fold increases vs. control, respectively; P < 0.05). ANG II concentrations in both the plasma and epididymal white adipose tissue (WAT) were comparable between the two groups, suggesting that PAT-specific activation of the renin-angiotensin system (RAS) is primarily involved in CKD-associated atherogenesis. The homeostasis model assessment-insulin resistance (HOMA-IR) index and plasma insulin level after glucose loading were significantly elevated in 16-wk-old UNX mice. In vitro stimulation of preadipocytes with insulin exaggerated the AGT mRNA expression along with increased mRNA expression of PPARgamma. These findings suggest that PAT-specific RAS activation probably primarily contributes in accelerating atherosclerotic development in UNX mice and could thus represent a therapeutic target for preventing CKD-associated atherogenesis. PMID- 23812392 TI - Cardiovascular effects of nose-only water-pipe smoking exposure in mice. AB - Water-pipe smoking (WPS) is a major type of smoking in Middle Eastern countries and is increasing in popularity in Western countries and is perceived as relatively safe. However, data on the adverse cardiovascular effects of WPS are scarce. Here, we assessed the cardiovascular effects of nose-only exposure to mainstream WPS generated by commercially available honey-flavored "moasel" tobacco in BALB/c mice. The duration of the session was 30 min/day for 1 mo. Control mice were exposed to air. WPS caused a significant increase of systolic blood pressure (SBP) in vivo (+13 mmHg) and plasma concentrations of IL-6 (+30%) but not that of TNF-alpha. Heart concentrations of IL-6 (+184%) and TNF-alpha (+54%) were significantly increased by WPS. Concentrations of ROS (+95%) and lipid peroxidation (+27%) were significantly increased, whereas those of GSH were decreased (-21%). WPS significantly shortened the thrombotic occlusion time in pial arterioles (-46%) and venules (40%). Plasma von Willebrand factor concentrations were significantly increased (+14%) by WPS. Erythrocyte numbers (+15%) and hematocrit (+17%) were significantly increased. Blood samples taken from mice exposed to WPS and exposed to ADP showed significant platelet aggregation compared with air-exposed mice. WPS caused a significant shortening of activated partial thromboplastin time (-45%) and prothrombin time (-13%). We conclude that 1-mo nose-only exposure to WPS increased SBP and caused cardiac inflammation, oxidative stress, and prothrombotic events. Our findings provide plausible elucidation that WPS is injurious to the cardiovascular system. PMID- 23812391 TI - The bone morphogenic protein inhibitor, noggin, reduces glycemia and vascular inflammation in db/db mice. AB - Vascular diseases frequently accompany diabetes mellitus. Based on the current understanding of atherosclerosis as an inflammatory disorder of the vascular wall, it has been speculated that diabetes may accelerate atherosclerosis by inducing a proinflammatory milieu in the vasculature. ANG II and bone morphogenic proteins (BMPs) have been implicated in vascular inflammation. We evaluated the effect of angiotensin receptor blockade by valsartan and BMP inhibition by noggin on markers of vascular inflammation in a mouse model of diabetes. Noggin had no effect on blood pressure but decreased serum glucose levels, whereas valsartan significantly decreased blood pressure, but not serum glucose. Both inhibitors reduced reactive oxygen species production in the aorta. Additionally, noggin and valsartan diminish gene transcription and protein expression of various inflammatory molecules in the vascular wall. These observations indicate that although both inhibitors block superoxide production and have similar effects on inflammatory gene expression, glycemia and blood pressure may represent a secondary target differentially affected by noggin and valsartan. Our data clearly identify the BMP pathway as a potentially potent therapeutic target in diabetic inflammatory vascular disease. PMID- 23812393 TI - Design and synthesis of some 3-substituted-2-[(2,4-dichlorophenoxy) methyl]quinazolin-4(3H)-one derivatives as potential anticonvulsant agents. AB - Series of 2,3-disubstituted quinazolinone derivatives and a [1,2,4]triazino[2,3 c]quinazolinone featuring the pharmacophoric elements of anticonvulsant drugs were designed and synthesized. Target compounds were screened for their anticonvulsant activity using the subcutaneous pentylenetetrazole (s.c. PTZ) and maximal electroshock (MES) models. The s.c. PTZ test showed that the most active compound was the amide derivative 9c having a protective dose 50 (PD50) of 200.53 umol/kg (PD50 of phenobarbitone=62.18 umol/kg); nevertheless, this low potency is outweighed by the much higher safety profile of 9c (LD50 >3000 mg/kg). In the MES screening, seven compounds were equal to or more active than phenytoin; some of these compounds were less neurotoxic than phenytoin. Few compounds such as 9c and 10 were effective in both models. LD50 for the most active compounds was calculated. PMID- 23812394 TI - Fasudil inhibits epithelial-myofibroblast transdifferentiation of human renal tubular epithelial HK-2 cells induced by high glucose. AB - Renal fibrosis is a crucial pathologic process underlying diabetic nephropathy (DN). Central to this process is the epithelial-mesenchymal transformation (EMT) of tubular epithelial cells. Fasudil, a Rho-associated coiled-coil forming protein serine/threonine kimase (ROCK) inhibitor, protects against renal fibrosis in a variety of renal injury models. However, fasudil's effects on renal fibrosis in DN remain unknown. The aim of the present study was to investigate the effects of fasudil on high glucose-induced EMT in human renal tubular epithelial (HK-2) cells. HK-2 cells were exposed to 5.5 or 60 mmol/L D-glucose for 72 h, or to mannitol (osmotic control). RhoA activity was assessed using a RhoA pull-down assay, and ROCK activity was determined by myosin phosphatase target subunit-1 (MYPT1) phosphorylation. Myofibroblast (vimentin and alpha-smooth muscle actin [alpha-SMA]) and epithelial (E-cadherin) markers expressions were detected by immunocytochemistry and Western blotting. Transforming growth factor (TGF)-beta1 and fibronectin secretion were detected with enzyme-linked immunosorbent assay (ELISA), and connective tissue growth factor (CTGF) was analyzed by Western blotting. Results showed that high glucose levels induced morphological changes, reduced E-cadherin expression (-73%), increased expression of vimentin (+148%) and alpha-SMA (+226%), increased TGF-beta1 (from 116.0+/-5.2 ug/g to 351.0+/-3.2 ug/g) and CTGF (from 0.26+/-0.01 to 0.92+/-0.03) secretion, and increased RhoA and ROCK activation (p<0.05 for all). All these effects of high glucose stimulation were suppressed or abolished by fasudil. In conclusion, fasudil may attenuate EMT through reduced activation of RhoA/ROCK signaling, and decreased expression of TGF-beta1 and CTGF. Thus, fasudil may be a renoprotective agent for the treatment of DN. PMID- 23812395 TI - Cyclic sulfoxides garlicnins B2, B3, B4, C2, and C3 from Allium sativum. AB - Several novel sulfides, called garlicnins B2 (1), B3 (2), B4 (3), C2 (4), and C3 (5), were isolated from acetone extracts of garlic, Allium sativum L. and characterized. These garlicnins are capable of suppressing M2 macrophage activation and they have a novel skeleton of cyclic sulfoxide. The structures of the former 3 and latter of 2 were deduced to be 2-(sulfenic acid)-5-(allyl)-3,4 dimethyltetrahydrothiophene-S-oxides and 2-(allyldithiine)-5-(propenylsulfoxide) 3,4-dimethyltetrahydrothiophene-S-oxides, respectively. The mechanism of the proposed production of these compounds is discussed. The identification of these novel sulfoxides from garlic accumulates a great deal of new chemistry in the Allium sulfide field, and future pharmacological investigations of these compounds will aid the development of natural, healthy foods and anti-cancer agents that may prevent or combat disease. PMID- 23812396 TI - Synthesis, crystal structures and DNA-cleaving activities of [Cemp]2[MCl4] (Cemp = N-carbethoxymethyl-1,10-phenanthrolinium, M = Cu(II), Zn(II), Co(II), Ni(II) and Mn(II)). AB - N-Carbethoxymethyl-1,10-phenanthrolinium bromide (CempBr) and its five ionic metal complexes, [Cemp]2[MCl4] where M = Cu(II) (1), Zn(II) (2), Co(II) (3), Ni(II) (4) and Mn(II) (5) were synthesized and fully characterized. Complexes 1-5 have similar structures, and consist of isolated [Cemp](+) cations and [MCl4](2-) anions in which there are no obvious interactions between the oxygen or nitrogen donor atoms in [Cemp](+) and the metal center in [MCl4](2-). Agarose gel electrophoresis studies on the cleavage of plasmid pBR322 DNA by complexes 1-5 indicated that complex 1 was capable of efficiently cleaving DNA under physiological conditions, most probably via an oxidative mechanism. Kinetic assay of complex 1 afforded the maximal catalytic rate constant kmax of 0.55 h(-1) and Michaelis constant KM of 47.6 uM, respectively, which gives about 1.5*10(7)-fold rate acceleration over uncatalyzed cleavage of supercoiled DNA. Ethidium bromide displacement experiments indicated that complex 1 had a binding affinity of (1.58+/-1.12)*10(6) M(-1) toward calf-thymus DNA, 20-100-fold higher than those shown by CempBr and complexes 2-5. The high cleaving efficacy of complex 1 is thought to be due to the efficient catalysis of the copper(II)-coordinated center and the efficient binding of the quaternized 1,10-phenanthroline cation to DNA. PMID- 23812397 TI - Synthesis, antimicrobial and cytotoxic activities of sulfonamidomethane linked heterocycles. AB - A new class of sulfonamidomethane pyrrolyl-oxadiazoles/thiadiazoles and pyrazolyl oxadiazoles/thiadiazoles was prepared from arylsulfonylaminoacetic acid hydrazides and E-cinnamic acid. The lead compounds were tested for antimicrobial and cytotoxic activities. The thiadiazole compounds having chloro substituent on the aromatic ring 4c, 8c and 10c exhibited comparable antibacterial activity against Pseudomonas aeruginosa and also antifungal activity against Penicillium chrysogenum. The styryl oxadiazole compound 3c showed appreciable cytotoxic activity on A549 lung carcinoma cells which can be used as a lead compound in the future studies. PMID- 23812398 TI - Hydroxynaphthoic acids identified in a high throughput screening potently ameliorate endoplasmic reticulum stress as novel chemical chaperones. AB - Folding of newly synthesized protein occurs in endoplasmic reticulum (ER) and is assisted by chaperone molecules. In ER stress conditions, misfolded proteins are enriched in a lumen of ER perturbing its normal function, which triggers cellular self-defense mechanism, the unfolded protein response (UPR). It was reported that tunicamycin-induced ER stress can be modulated with high concentration of chemicals such as 4-phenylbutyric acid and salicylate. In search of assay systems to identify such compounds, we have developed a cell-based reporter assay where renilla luciferase activity is driven by glucose-regulated protein 78 (GRP78) promoter. Using our reporter assay, we have screened chemical libraries and found that hydroxynaphthoic acids, especially 1-, 3-, and 6-hydroxy-2-naphthoic acids, potently decrease the ER stress signal, showing an order of magnitude better activity than salicylate. UPR markers such as GRP78, C/EBP homology protein (CHOP) and phosphorylated protein kinase RNA-activated (PKR)-like ER kinase (PERK) were significantly down-regulated with hydroxynaphthoic acids in western blot. Among the analogues, 1-hydroxy-2-naphthoic acid was the most potent in down regulating those UPR markers. Further, both phosphorylated inositol-requiring enzyme 1alpha (IRE1alpha) and spliced form of X-box binding protein 1 (XBP1) were decreased in the protein and the mRNA level, implying both PERK and IRE1alpha branches in UPR mechanism are controlled with hydroxynaphthoic acids. Taken together, it was suggested that hydroxynaphthoic acids exert their ER stress reducing activity prior to the UPR activation as chemical chaperones do. In summary, we report a cell-based assay system for the screening of ER stress reducing compounds and hydroxynaphthoic acids as novel series of chemical chaperones. PMID- 23812400 TI - Saponins esculeosides B-1 and B-2 in Italian canned tomatoes. AB - Italian canned tomatoes contain the tomato glycosides esculeosides B-1 (1, 0.0052%) and B-2 (2, 0.0068%) without esculeoside A. Herein, the structure of esculeoside B-1 (1) is characterized to be 3-O-beta-lycotetraosyl (5S,22R,23S,25S)-22,26-epimino-16beta,23-epoxy-3beta,23,27-trihydroxycholestane 27-O-beta-D-glucopyranoside. We hypothesized that these substances might be derived from esculeoside A when the cans are prepared with treatment in boiling water. To confirm that hypothesis, we refluxed esculeoside A with water for 6.5 h, providing esculeosides B-1 (1) and B-2 (2) in yields of 25.8% and 31.0%, respectively. PMID- 23812399 TI - Novel quinolinylaminoisoquinoline bioisosteres of sorafenib as selective RAF1 kinase inhibitors: design, synthesis, and antiproliferative activity against melanoma cell line. AB - Design and synthesis of a new series of quinolinylaminoisoquinoline derivatives as conformationally restricted bioisosteres of Sorafenib are described. Their in vitro antiproliferative activity against A375P melanoma cell line was tested. Compounds 1b, 1d, 1g, and 1j showed the highest potency against A375P cell line with IC50 values in sub-micromolar scale. In addition, compound 1d exerted high selectivity towards RAF1 serine/threonine kinase with 96.47% inhibition at 10 uM, and IC50 of 0.96 uM. This compound can possess antiproliferative activity against melanoma cells through inhibition of RAF1 kinase. PMID- 23812401 TI - One-pot synthesis of phenol derivatives by the novel intramolecular Alder-Rickert reaction: effects of aryl substituent at the 3-position of cyclohexenone derivatives on reactivity. AB - We examined In(OTf)3-catalyzed enolization and intramolecular Alder-Rickert reactions of cyclohexenone derivatives. The 3-aryl substituted cyclohexenone derivatives bearing an ethoxycarbonyl-substituted alkyne moiety could be converted into the corresponding phenols in comparatively good yield. PMID- 23812402 TI - First synthesis of saponarin, 6-C- and 7-O-di-beta-D-glucosylapigenin. AB - Saponarin, apigenin 6-C- and 7-O-bis-beta-D-glucoside, was synthesized in an overall yield of 37% via 11 steps, which included the C-glycosylation of 2,4-O dibenzylphloroacetophenone, the introduction of a cinnamoyl residue by aldol condensation, the formation of a flavone by regioselective deprotection, and oxidative ring-closure to the final regioselective deprotection and stereoselective O-glycosylation. PMID- 23812403 TI - In silico analysis of pathways affected by differentially expressed microRNA in adrenocortical tumors. AB - BACKGROUND: MicroRNA are involved in the pathogenesis of several tumors, and several studies have been performed on the microRNA profile of adrenocortical tumors to date. The pathways affected by these microRNA, however, have not been analyzed yet by a systematic approach. AIM: To perform an in silico bioinformatics analysis of microRNA commonly altered in at least two studies and to decipher the pathways affected by microRNA in adrenocortical tumors. METHODS: Datasets on microRNA and mRNA expression have been retrieved from 5 and 3 studies, respectively. MicroRNA mRNA targets have been identified by our tissue specific target prediction pipeline, and mRNA have been subjected to Ingenuity Pathway Analysis. RESULTS: Thirty- nine microRNA were identified as commonly altered in two studies. Altogether 49,817 mRNA targets have been found for these microRNA. One-hundred and seventy-eight significant pathways associating with these have been identified and were found in all studies. We have selected 12 pathways involving retinoic acid signaling (lipopolysaccharide/ interleukin-1 mediated inhibition of retinoic X receptor (RXR) function, peroxisome proliferator-activated receptor (PPAR)alpha/RXRalpha activation, retinoic A receptor activation and PPAR signaling pathways) and cell cycle alterations (aryl hydrocarbon receptor signaling, growth arrest and DNA damage-inducible 45 signaling, integrin signaling, G2/M DNA damage checkpoint regulation, cyclins and cell cycle regulation and cell cycle control of chromosomal replication pathways) as these have been also established in our previous study on the functional genomics meta-analysis of adrenocortical tumors. Several microRNA have been identified that could affect these pathways. CONCLUSIONS: MicroRNA might affect several pathogenic pathways in adrenocortical tumors. Validation studies are required to confirm the biological relevance of these findings. PMID- 23812405 TI - Glutathione peroxidase 7 prevents cancer in the oesophagus. PMID- 23812406 TI - Temporal and regional variations in accidental deaths of elderly people in Japan. AB - To ascertain the characteristics of accidental deaths of elderly people in urban and rural areas, we analyzed the deaths of elderly people over the 10-year period from 2000 to 2009, in three geographic areas: nationwide, in the 23 wards of the metropolis of Tokyo, and in Saga prefecture. In addition, to assess the regional variation in accidental deaths of the elderly, we aggregated the numbers of accidental deaths of elderly people for each of Japan's prefectures in the year 2009 and categorized the deaths by accident type. The results showed that nationwide, deaths due to threats to breathing, falls, and drowning and submersion are increasing, while deaths due to transport accidents are decreasing, indicating a need for measures to prevent deaths from accidents other than transport accidents. In the urban areas of Tokyo's 23 wards, there is an increasing incidence of deaths due to falls, which is likely due to the high number of structures such as buildings and railway stations that elderly people need to negotiate. In urban areas, measures to reduce the incidence of accidental deaths need to focus on improving the physical environment to help prevent falls. In the rural locality of Saga prefecture, increasing numbers of elderly people are dying by drowning and submersion. The results of analysis of accidents in all prefectures of Japan by accident type show that the causes of accidental deaths of elderly people vary regionally, suggesting that accident prevention measures for elderly people need to consider the characteristics of the locality. PMID- 23812404 TI - Alternative lipid emulsions in the critically ill: a systematic review of the evidence. AB - PURPOSE: Parenteral lipid emulsions (LEs) are commonly rich in long-chain triglycerides derived from soybean oil (SO). SO-containing emulsions may promote systemic inflammation and therefore may adversely affect clinical outcomes. We hypothesized that alternative oil-based LEs (SO-sparing strategies) may improve clinical outcomes in critically ill adult patients compared to products containing SO emulsion only. The purpose of this systematic review was to evaluate the effect of parenteral SO-sparing strategies on clinical outcomes in intensive care unit (ICU) patients. METHODS: We searched computerized databases from 1980 to 2013. We included randomized controlled trials (RCTs) conducted in critically ill adult patients that evaluated SO-sparing strategies versus SO based LEs in the context of parenteral nutrition. RESULTS: A total of 12 RCTs met the inclusion criteria. When the results of these RCTs were statistically aggregated, SO-sparing strategies were associated with clinically important reductions in mortality (risk ratio, RR 0.83; 95 % confidence intervals, CI 0.62, 1.11; P = 0.20), in duration of ventilation (weighted mean difference, WMD -2.57; 95 % CI -5.51, 0.37; P = 0.09), and in ICU length of stay (LOS) (WMD -2.31; 95 % CI -5.28, 0.66; P = 0.13) but none of these differences were statistically significant. SO-sparing strategies had no effect on infectious complications (RR 1.13; 95 % CI 0.87, 1.46; P = 0.35). CONCLUSION: Alternative oil-based LEs may be associated with clinically important reductions in mortality, duration of ventilation, and ICU LOS but lack of statistical precision precludes any clinical recommendations at this time. Further research is warranted to confirm these potential positive treatment effects. PMID- 23812407 TI - Microbial ethanol production in postmortem urine sample. AB - We present a case in which postmortem blood ethanol concentration was 0.02 g/kg and acetone concentration was 0.51 g/kg, while urine ethanol concentration was 6.0 g/kg and acetone concentration was 0.63 g/kg. In the urine sample, sodium fluoride was not added. The urinary ethanol concentration continued to increase without any remarkable increase of isopropanol concentration and external contamination was excluded. Species of bacteria and yeasts, including Candida glabrata, were isolated from urine and blood samples. A few days after the collection of samples, we received the information that the patient was diabetic and did not receive insulin therapy regularly. To prevent postmortem microbial ethanol production and incorrect diagnosis of the cause of death, it is necessary to add sodium fluoride to blood and urine samples collected from diabetic patients. PMID- 23812408 TI - Degradation of aflatoxin B1 during the fermentation of alcoholic beverages. AB - Aflatoxin B1 (AFB1) is a contaminant of grain and fruit and has one of the highest levels of carcinogenicity of any natural toxin. AFB1 and the fungi that produce it can also contaminate the raw materials used for beer and wine manufacture, such as corn and grapes. Therefore, brewers must ensure strict monitoring to reduce the risk of contamination. In this study, the fate of AFB1 during the fermentation process was investigated using laboratory-scale bottom and top beer fermentation and wine fermentation. During fermentation, cool wort beer samples and wine must samples were artificially spiked with AFB1 and the levels of AFB1 remaining after fermentation were analyzed. AFB1 levels were unchanged during both types of fermentation used for beer but were reduced to 30% of their initial concentration in wine. Differential analysis of the spiked and unspiked wine samples showed that the degradation compound was AFB2a, a hydrated derivative of AFB1. Thus, the results showed that the risk of AFB1 carryover was still present for both types of beer fermentation but was reduced in the case of wine fermentation because of hydration. PMID- 23812409 TI - Gallium-68: a systematic review of its nononcological applications. AB - The increased availability of PET facilities worldwide has sparked renewed interest in the use of generator-produced tracers such as gallium-68 (Ga). Imaging with Ga provides exciting opportunities in terms of new ligand-labelling possibilities and the exploration of novel clinical applications. The aim of the study was to summarize and appraise what has been published on the clinical applications of Ga outside oncology practice. This systematic review was based on the PRISMA guidelines. Databases searched include PubMed, Medline, Scopus, Web of Science and Google Scholar. The following search strategy was used: 'Ga' OR 'Gallium' (all fields) NOT the following (title and abstract): Oncology/NET/neuroendocrine tumour/tumor/DOTATOC, DOTATATE, DOTANOC. These results were further limited to English publications, which resulted in 205 publications on PubMed. After duplicates and irrelevant articles were removed, 72 publications remained for inclusion. Only those studies in which compounds were labelled with Ga for applications other than in oncology-related indications were included. Publications in which the focus was on oncology-related applications of Ga imaging or in which the emphasis was on aspects relating to generators, radiochemistry or physics were excluded. Although a multitude of tracers have been labelled with Ga over several decades, it has not been established in routine clinical practice yet. In addition, neuroendocrine and other oncological applications have dominated the field until relatively recently following reports of applications in infection and inflammation. The majority of publications to date involve small numbers of subjects in mainly preclinical settings. Differences in methodology preclude grouping of studies to reach a clear conclusion. There is wide scope for Ga tracer application outside oncological practice, which remains greatly underutilized. Larger clinical trials are needed to validate these applications. PMID- 23812410 TI - Mortality and psychiatric disorders among public mental health care clients in Utrecht: a register-based cohort study. AB - BACKGROUND: Different studies have shown similar or even lower mortality among homeless persons with compared to homeless persons without a severe mental disorder. AIMS: To clarify the association between presence of a psychiatric diagnosis and mortality among the socially marginalized. METHODS: The Public Mental health care (PMHc) is a legal task of the municipal authority aiming at prevention and intervention in case of (imminent) homelessness among persons with a serious shortage of self-sufficiency. The data of PMHc clients (N=6,724) and personally matched controls (N=66,247) were linked to the registries of Statistics Netherlands and analysed in a Cox model. RESULTS: The increased mortality among PMHc clients, compared to the general population (HR=2.99, 95% CI: 2.63-3.41), was associated with a broad range of death causes. Clients with a record linkage to the Psychiatric Case Registry Middle Netherlands ('PMHc+') had an increased risk of suicide (HR=2.63, 0.99-7.02, P=0.052), but a lower risk of natural death causes (HR=0.71, 0.54-0.92, P=0.011), compared to clients without this record linkage ('PMHc-'). Compared to controls, however, 'PMHc-' clients experienced substantially increased risks of suicide (HR=3.63, 1.42-9.26, P=0.007) and death associated with mental and behavioural disorders (ICD-10 Ch.V) (HR=7.85, 3.54-17.43, P<0.001). CONCLUSION: Psychiatric services may deliver an important contribution to the prevention of premature natural death among the socially marginalized. KEYPHRASES: The earlier observed lower mortality among vulnerably housed and homeless persons with a psychiatric diagnosis compared to vulnerably housed and homeless persons without a psychiatric diagnosis appears to be due to a significantly lower risk of natural causes of death. Compared to controls from the general population, vulnerably housed and homeless persons without registered diagnosis at a local psychiatric service have a significantly increased mortality associated both with natural death causes and with suicide and death due to mental and behavioural disorders. Services for mental health care may deliver an important contribution to the prevention of premature death due to somatic disorders among the socially marginalized. PMID- 23812411 TI - Experiences from the implementation of a comprehensive development plan for user involvement in a mental health hospital: A qualitative case study. AB - BACKGROUND: Few studies have investigated user involvement initiatives in whole organizations. The aim was to explore the experiences of professionals and user representatives taking part in the implementation of a user involvement plan. MATERIALS: A qualitative study in a mental health hospital included interviews and observational data. DISCUSSION: Three different stories emerged. The first described the implementation as a success. The second described the implementation as a success, but after overcoming several obstacles. The third described that the development plan had limited impact. CONCLUSIONS: Close attention should be made to decision-making and resource allocation when implementing user involvement. PMID- 23812412 TI - Fir honeydew honey flavonoids inhibit TNF-alpha-induced MMP-9 expression in human keratinocytes: a new action of honey in wound healing. AB - Matrix metalloproteinase-9 (MMP-9) appears to be a major protease responsible for the degradation of matrix and growth-promoting agents in chronic wounds. Honey has been successfully used for treating non-healing wounds associated with infections. However, the mechanisms of its action at the cellular level have remained poorly understood. The aim of this study was to investigate the effect of fir honeydew honey on TNF-alpha-induced MMP-9 expression and secretion from human keratinocytes (HaCaT) and to identify the honey component(s) responsible for a discovered effect. A C18 solid-phase column was used for preparation of honey aqueous extract (HAE). Expression and production of MMP-9 by HaCaT cells were determined by reverse transcription-PCR, gelatine zymography and Western blot analysis using a polyclonal antibody against MMP-9. We found that HAE inhibited TNF-alpha-induced production of MMP-9 in keratinocytes in a dose dependent manner at both the mRNA and protein levels. Apigenin and kaempferol, identified flavonoids in HAE, markedly inhibited MMP-9 production from HaCaT and epidermal keratinocytes. Taken together, fir honeydew honey, which contains certain flavonoids, prevents TNF-alpha-induced proteolytic activity in cutaneous inflammation. Thus, our findings provide clear evidence that honey may serve as a natural treatment for dermatological problems associated with a persistent inflammation. PMID- 23812413 TI - Intrinsic ligament and triangular fibrocartilage complex tears of the wrist: comparison of MDCT arthrography, conventional 3-T MRI, and MR arthrography. AB - PURPOSE: This study compares the diagnostic performance of multidetector CT arthrography (CTA), conventional 3-T MR and MR arthrography (MRA) in detecting intrinsic ligament and triangular fibrocartilage complex (TFCC) tears of the wrist. MATERIALS AND METHODS: Ten cadaveric wrists of five male subjects with an average age 49.6years (range 26-59years) were evaluated using CTA, conventional 3 T MR and MRA. We assessed the presence of scapholunate ligament (SLL), lunotriquetral ligament (LTL), and TFCC tears using a combination of conventional arthrography and arthroscopy as a gold standard. All images were evaluated in consensus by two musculoskeletal radiologists with sensitivity, specificity, and accuracy being calculated. RESULTS: Sensitivities/specificity/accuracy of CTA, conventional MRI, and MRA were 100%/100%/100%, 66%/86%/80%, 100%/86%/90% for the detection of SLL tear, 100%/80%/90%, 60%/80%/70%, 100%/80%/90% for the detection of LTL tear, and 100%/100%/100%, 100%/86%/90%, 100%/100%/100% for the detection of TFCC tear. Overall CTA had the highest sensitivity, specificity, and accuracy among the three investigations while MRA performed better than conventional MR. CTA also had the highest sensitivity, specificity, and accuracy for identifying which component of the SLL and LTL was torn. Membranous tears of both SLL and LTL were better visualized than dorsal or volar tears on all three imaging modalities. CONCLUSION: Both CT and MR arthrography have a very high degree of accuracy for diagnosing tears of the SLL, LTL, and TFCC with both being more accurate than conventional MR imaging. PMID- 23812415 TI - Understanding chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). PMID- 23812416 TI - How the pulmonary veins 'talk' to the sinoatrial node: new insights into an old mystery. PMID- 23812417 TI - Activin A impairs insulin action in cardiomyocytes via up-regulation of miR-143. AB - AIMS: Enhanced activin A release from epicardial adipose tissue (EAT) has been linked to the development of cardiac dysfunction in type 2 diabetes (T2D). This study examined whether the inhibition of insulin action induced by epicardial adipokines in cardiomyocytes can be ascribed to alterations in miRNA expression. METHODS AND RESULTS: Expression levels of miRNAs were assessed by real-time PCR in primary adult rat cardiomyocytes (ARC) exposed to conditioned media generated from EAT biopsies (CM-EAT) from patients with and without T2D. CM-EAT-T2D altered the expression of eight miRNAs in ARC vs. CM-EAT from patients without T2D. Of these, only expression of the miR-143/145 cluster was affected by activin A in the same direction as CM-EAT-T2D. Accordingly, activin A neutralizing antibodies prevented the induction of the miR-143/145 cluster by CM-EAT-T2D. Subsequently, the impact of the miR-143/145 cluster on insulin action was investigated. Transfection of HL-1 cells with precursor-miR-143 (pre-miR-143), but not pre-miR 145, blunted the insulin-mediated phosphorylation of Akt and its substrate proline-rich Akt substrate of 40 kDa (PRAS40), and reduced insulin-stimulated glucose uptake. Also lentivirus-mediated expression of pre-miR-143 in ARC reduced insulin-induced Akt phosphorylation. These effects were ascribed to down regulation of the miR-143 target and regulator of insulin action, the oxysterol binding protein-related protein 8 (ORP8) in both ARC and HL-1 cells. Finally, LNA anti-miR-143 protected against the detrimental effects of CM-EAT-T2D on insulin action in ARC. CONCLUSION: Activin A released from EAT-T2D inhibits insulin action via the induction of miR-143 in cardiomyocytes. This miRNA inhibits the Akt pathway through down-regulation of the novel regulator of insulin action, ORP8. PMID- 23812418 TI - Functional characterization of Foxp3-specific spontaneous immune responses. AB - Tumor-infiltrating CD4+CD25+ regulatory T cells (Tregs) are associated with an impaired prognosis in several cancers. The transcription factor forkhead box P3 (Foxp3) is generally expressed in Tregs. Here, we identify and characterize spontaneous cytotoxic immune responses to Foxp3-expressing cells in peripheral blood of healthy volunteers and cancer patients. These immune responses were directed against a HLA-A2-restricted peptide epitope derived from Foxp3. Foxp3 reactive T cells were characterized as cytotoxic CD8+ T cells. These cells recognized dendritic cells incubated with recombinant Foxp3 protein indicating that this protein was indeed internalized, processed and cross-presented in the context of HLA-A2. More importantly, however, Foxp3-specific T cells were able to specifically recognize Tregs. Similarly, Foxp3+ malignant T cells established from a Cutaneous T-cell lymphomas (CTCL) patient were readily killed by the Foxp3 specific cytotoxic T lymphocytes. The spontaneous presence of Foxp3-specific cytotoxic T-cell responses suggest a general role of such T cells in the complex network of immune regulation as such responses may eliminate Tregs, that is, suppression of the suppressors. Consequently, induction of Foxp3-specific cytotoxic T-cell responses appears as an attractive tool to boost spontaneous or therapeutically provoked immune responses, for example, for the therapy of cancer. PMID- 23812419 TI - Hyperdiploidy with 49-65 chromosomes represents a heterogeneous cytogenetic subgroup of acute myeloid leukemia with differential outcome. AB - Chromosome gain is frequent in acute myeloid leukemia (AML) and is counted alongside structural abnormalities when determining karyotype complexity. However, there are few studies investigating the cytogenetic profile and outcome of patients with a hyperdiploid karyotype (49-65 chromosomes, HK). We identified 221 (14%) patients with HK out of 1563 patients with three or more chromosomal abnormalities. HK was not associated with sex, white cell count and secondary disease status, but was more prevalent among children (22% vs 13%). The pattern of chromosomal gain and loss was non-random and chromosomes 8, 13 and 21 were the most frequently gained. Three distinct subgroups (numerical, structural and adverse) were identified with differential outcome: 5-year cumulative incidence of relapse of 52%, 68% and 76%, respectively (P=0.008). Patients in the adverse subgroup had poorer survival compared with patients with only numerical abnormalities (adjusted hazard ratio: 2.01 (95% confidence interval: 1.43-2.83), P=0.0002). This outcome heterogeneity was similar among children and adults. In conclusion, AML patients with a HK should not automatically be assigned to the adverse cytogenetic risk group on the basis of complexity. Instead they should be assessed for the presence of specific chromosomal abnormalities, which are known to harbour an adverse effect. PMID- 23812420 TI - JAK inhibitors suppress t(8;21) fusion protein-induced leukemia. AB - Oncogenic mutations in components of the JAK/STAT pathway, including those in cytokine receptors and JAKs, lead to increased activity of downstream signaling and are frequently found in leukemia and other hematological disorders. Thus, small-molecule inhibitors of this pathway have been the focus of targeted therapy in these hematological diseases. We previously showed that t(8;21) fusion protein acute myeloid leukemia (AML)1-ETO and its alternatively spliced variant AML1 ETO9a (AE9a) enhance the JAK/STAT pathway via downregulation of CD45, a negative regulator of this pathway. To investigate the therapeutic potential of targeting JAK/STAT in t(8;21) leukemia, we examined the effects of a JAK2-selective inhibitor TG101209 and a JAK1/2-selective inhibitor INCB18424 on t(8;21) leukemia cells. TG101209 and INCB18424 inhibited proliferation and promoted apoptosis of these cells. Furthermore, TG101209 treatment in AE9a leukemia mice reduced tumor burden and significantly prolonged survival. TG101209 also significantly impaired the leukemia-initiating potential of AE9a leukemia cells in secondary recipient mice. These results demonstrate the potential therapeutic efficacy of JAK inhibitors in treating t(8;21) AML. PMID- 23812421 TI - Modified wind chill temperatures determined by a whole body thermoregulation model and human-based facial convective coefficients. AB - Wind chill equivalent temperatures (WCETs) were estimated by a modified Fiala's whole body thermoregulation model of a clothed person. Facial convective heat exchange coefficients applied in the computations concurrently with environmental radiation effects were taken from a recently derived human-based correlation. Apart from these, the analysis followed the methodology used in the derivation of the currently used wind chill charts. WCET values are summarized by the following equation:[Formula: see text]Results indicate consistently lower estimated facial skin temperatures and consequently higher WCETs than those listed in the literature and used by the North American weather services. Calculated dynamic facial skin temperatures were additionally applied in the estimation of probabilities for the occurrence of risks of frostbite. Predicted weather combinations for probabilities of "Practically no risk of frostbite for most people," for less than 5 % risk at wind speeds above 40 km h(-1), were shown to occur at air temperatures above -10 degrees C compared to the currently published air temperature of -15 degrees C. At air temperatures below -35 degrees C, the presently calculated weather combination of 40 km h(-1)/-35 degrees C, at which the transition for risks to incur a frostbite in less than 2 min, is less conservative than that published: 60 km h(-1)/-40 degrees C. The present results introduce a fundamentally improved scientific basis for estimating facial skin temperatures, wind chill temperatures and risk probabilities for frostbites over those currently practiced. PMID- 23812422 TI - A novel bispecific EGFR/Met antibody blocks tumor-promoting phenotypic effects induced by resistance to EGFR inhibition and has potent antitumor activity. AB - Simultaneous targeting of epidermal growth factor receptor (EGFR) and Met in cancer therapy is under pre-clinical and clinical evaluation. Here, we report the finding that treatment with EGFR inhibitors of various tumor cells, when stimulated with hepatocyte growth factor (HGF) and EGF, results in transient upregulation of phosphorylated AKT. Furthermore, EGFR inhibition in this setting stimulates a pro-invasive phenotype as assessed in Matrigel-based assays. Simultaneous treatment with AKT and EGFR inhibitors abrogates this invasive growth, hence functionally linking signaling and phenotype. This observation implies that during treatment of tumors a balanced ratio of EGFR and Met inhibition is required. To address this, we designed a bispecific antibody targeting EGFR and Met, which has the advantage of a fixed 2:1 stoichiometry. This bispecific antibody inhibits proliferation in tumor cell cultures and co cultures with fibroblasts in an additive manner compared with treatment with both single agents. In addition, cell migration assays reveal a higher potency of the bispecific antibody in comparison with the antibodies' combination at low doses. We demonstrate that the bispecific antibody inhibits invasive growth, which is specifically observed with cetuximab. Finally, the bispecific antibody potently inhibits tumor growth in a non-small cell lung cancer xenograft model bearing a strong autocrine HGF-loop. Together, our findings strongly support a combination treatment of EGFR and Met inhibitors and further evaluation of resistance mechanisms to EGFR inhibition in the context of active Met signaling. PMID- 23812423 TI - Crosstalk of Ras and Rho: activation of RhoA abates Kras-induced liver tumorigenesis in transgenic zebrafish models. AB - RAS and Rho small GTPases are key molecular switches that control cell dynamics, cell growth and tissue development through their distinct signaling pathways. Although much has been learnt about their individual functions in both cell and animal models, the physiological and pathophysiological consequences of their signaling crosstalk in multi-cellular context in vivo remain largely unknown, especially in liver development and liver tumorigenesis. Furthermore, the roles of RhoA in RAS-mediated transformation and their crosstalk in vitro remain highly controversial. When challenged with carcinogens, zebrafish developed liver cancer that resembles the human liver cancer both molecularly and histopathologically. Capitalizing on the growing importance and relevance of zebrafish (Danio rerio) as an alternate cancer model, we have generated liver-specific, Tet-on-inducible transgenic lines expressing oncogenic Kras(G12V), RhoA, constitutively active RhoA(G14V) or dominant-negative RhoA(T19N). Double-transgenic lines expressing Kras(G12V) with one of the three RhoA genes were also generated. Based on quantitative bioimaging and molecular markers for genetic and signaling aberrations, we showed that the induced expression of oncogenic Kras during early development led to liver enlargement and hepatocyte proliferation, associated with elevated Erk phosphorylation, activation of Akt2 and modulation of its two downstream targets, p21Cip and S6 kinase. Such an increase in liver size and Akt2 expression was augmented by dominant-negative RhoA(T19N), but was abrogated by the constitutive-active RhoA(G14V). Consequently, induced expression of the oncogenic Kras in adult transgenic fish led to the development of hepatocellular carcinomas. Survival studies further revealed that the co-expression of dominant negative RhoA(T19N) with oncogenic Kras increased the mortality rate compared with the other single or double-transgenic lines. This study provides evidence of the previously unappreciated signaling crosstalk between Kras and RhoA in regulating liver overgrowth and liver tumorigenesis. Our results also implicate that activating Rho could be beneficial to suppress the Kras-induced liver malignancies. PMID- 23812424 TI - LXRalpha-mediated downregulation of FOXM1 suppresses the proliferation of hepatocellular carcinoma cells. AB - Liver X receptors (LXRs), including LXRalpha and LXRbeta isoforms, have important roles in the metabolic regulation of glucose, cholesterol and lipid. Moreover, activation of LXRs also represses the expression of cyclin D1 and cyclin B1, and thus suppresses the proliferation of multiple cancer cells, but the relevant mechanism is not well known. Forkhead box M1 (FOXM1) is a proliferation-specific member of forkhead box family, which is highly expressed in proliferating normal cells and numerous cancer cells. FOXM1 directly activates transcription of cyclin D1 and cyclin B1, resulting in the enhancement of cell cycle progression and cell proliferation. However, it is unclear whether LXRs are involved in the regulation of FOXM1. In this study, we demonstrated that specific LXRs agonists downregulated expression of FOXM1, cyclin D1 and cyclin B1 in hepatocellular carcinoma (HCC) cells, which led to cell cycle and cell proliferation arrest. Knockdown of FOXM1 significantly alleviated LXRs activation-mediated cell cycle arrest and cell growth suppression. Reporter assays showed that the activation of LXRs significantly reduced the transcriptional activity of FOXM1 promoter. Electrophoretic mobility shift assay and chromatin immunoprecipitation assays demonstrated that LXRalpha but not LXRbeta could bind to an inverted repeat IR2 ( 52CCGTCAcgTGACCT-39) in the promoter region of FOXM1 gene. Moreover, the xenograft tumor growth and the corresponding FOXM1 expression in nude mice were dramatically repressed by LXRs agonists. Taken together, we conclude that LXRalpha but not LXRbeta functions as a transcriptional repressor for FOXM1 expression. The pathway 'LXRalpha-FOXM1-cyclin D1/cyclin B1' is a novel mechanism by which LXRs suppress the proliferation of HCC cells, suggesting that the pathway may be a novel target for HCC treatment. PMID- 23812426 TI - Post-transcriptional regulation of cyclins D1, D3 and G1 and proliferation of human cancer cells depend on IMP-3 nuclear localization. AB - RNA-binding proteins of the IMP family (insulin-like growth factor 2 (IGF2) mRNA binding proteins 1-3) are important post-transcriptional regulators of gene expression. Multiple studies have linked high expression of IMP proteins, and especially of IMP-3, to an unfavorable prognosis in numerous types of cancer. The specific importance of IMP-3 for cancer transformation remains poorly understood. We here show that all three IMPs can directly bind the mRNAs of cyclins D1, D3 and G1 (CCND1, D3 and G1) in vivo and in vitro, and yet only IMP-3 regulates the expression of these cyclins in a significant manner in six human cancer cell lines of different origins. In the absence of IMP-3, the levels of CCND1, D3 and G1 proteins fall dramatically, and the cells accumulate in the G1 phase of the cell cycle, leading to almost complete proliferation arrest. Our results show that, compared with IMP-1 and IMP-2, IMP-3 is enriched in the nucleus, where it binds the transcripts of CCND1, D3 and G1. The nuclear localization of IMP-3 depends on its protein partner HNRNPM and is indispensable for the post transcriptional regulation of expression of the cyclins. Cytoplasmic retention of IMP-3 and HNRNPM in human cancer cells leads to significant drop in proliferation. In conclusion, a nuclear IMP-3-HNRNPM complex is important for the efficient synthesis of CCND1, D3 and G1 and for the proliferation of human cancer cells. PMID- 23812427 TI - Histone deacetylase 5 blocks neuroblastoma cell differentiation by interacting with N-Myc. AB - The N-Myc oncoprotein induces neuroblastoma, which arises from undifferentiated neuroblasts in the sympathetic nervous system, by modulating gene and protein expression and consequently causing cell differentiation block and cell proliferation. The class IIa histone deacetylase 5 (HDAC5) represses gene transcription, and blocks myoblast, osteoblast and leukemia cell differentiation. Here we showed that N-Myc upregulated HDAC5 expression in neuroblastoma cells. Conversely, HDAC5 repressed the ubiquitin-protein ligase NEDD4 gene expression, increased Aurora A gene expression and consequently upregulated N-Myc protein expression. Genome-wide gene expression analysis and protein co immunoprecipitation assays revealed that HDAC5 and N-Myc repressed the expression of a common subset of genes by forming a protein complex, whereas HDAC5 and the class III HDAC SIRT2 independently repressed the expression of another common subset of genes without forming a protein complex. Moreover, HDAC5 blocked differentiation and induced proliferation in neuroblastoma cells. Taken together, our data identify HDAC5 as a novel co-factor in N-Myc oncogenesis, and provide the evidence for the potential application of HDAC5 inhibitors in the therapy of N-Myc-induced neuroblastoma and potentially other c-Myc-induced malignancies. PMID- 23812425 TI - KLF8 and FAK cooperatively enrich the active MMP14 on the cell surface required for the metastatic progression of breast cancer. AB - Kruppel-like factor 8 (KLF8) regulates critical gene transcription associated with cancer. The underlying mechanisms, however, remain largely unidentified. We have recently demonstrated that KLF8 expression enhances the activity but not expression of matrix metalloproteinase-2 (MMP2), the target substrate of MMP14. Here, we report a novel KLF8 to MMP14 signaling that promotes human breast cancer invasion and metastasis. Using cell lines for inducible expression and knockdown of KLF8, we demonstrate that KLF8 promotes MMP14 expression at the transcriptional level. Knocking down KLF8 expression inhibited the breast cancer cell invasion both in vitro and in vivo as well as the lung metastasis in mice, which could be rescued by ectopic expression of MMP14. Promoter reporter assays and oligonucleotide and chromatin immunoprecipitations determined that KLF8 activates the human MMP14 gene promoter by both directly acting on the promoter and indirectly via promoting the nuclear translocation of beta-catenin, the expression of T-cell factor-1 (TCF1) and subsequent activation of the promoter by the beta-catenin/TCF1 complex. Inhibition of focal adhesion kinase (FAK) using pharmacological inhibitor, RNA interference or knockout showed that the cell surface presentation of active MMP14 downstream of KLF8 depends on FAK expression and activity. Taken together, this work identified novel signaling mechanisms by which KLF8 and FAK work together to promote the extracellular activity of MMP14 critical for breast cancer metastasis. PMID- 23812428 TI - Rare insights into cancer biology. AB - Cancer-associated mutations have been identified in the metabolic genes succinate dehydrogenase (SDH), fumarate hydratase (FH) and isocitrate dehydrogenase (IDH), advancing and challenging our understanding of cellular function and disease mechanisms and providing direct links between dysregulated metabolism and cancer. Some striking parallels exist in the cellular consequences of the genetic mutations within this triad of cancer syndromes, including accumulation of oncometabolites and competitive inhibition of 2-oxoglutarate-dependent dioxygenases, particularly, hypoxia-inducible factor (HIF) prolyl hydroxylases, JmjC domain-containing histone demethylases (part of the JMJD family) and the ten eleven translocation (TET) family of 5methyl cytosine (5mC) DNA hydroxylases. These lead to activation of HIF-dependent oncogenic pathways and inhibition of histone and DNA demethylation. Mutations in FH, resulting in loss of enzyme activity, predispose affected individuals to a rare cancer, hereditary leiomyomatosis and renal cell cancer (HLRCC), characterised by benign smooth muscle cutaneous and uterine tumours (leiomyomata) and an aggressive form of collecting duct and type 2 papillary renal cancer. Interestingly, loss of FH activity results in the accumulation of high levels of fumarate that can lead to the non-enzymatic modification of cysteine residues in multiple proteins (succination) and in some cases to their disrupted function. Here we consider that the study of rare diseases such as HLRCC, combining analyses of human tumours and cell lines with in vitro and in vivo murine models has provided novel insights into cancer biology associated with dysregulated metabolism and represents a useful paradigm for cancer research. PMID- 23812429 TI - As an independent prognostic factor, FAT10 promotes hepatitis B virus-related hepatocellular carcinoma progression via Akt/GSK3beta pathway. AB - FAT10 is an oncogene that is localized at 6q21.3, a region frequently amplified in hepatocellular carcinoma (HCC). Recently, growing attention has been paid to its effect in the initiation of various cancers. However, there has been little research into the influence of FAT10 on the progression and prognosis of HCC, especially in hepatitis B virus (HBV)-related HCC. Here, we aimed at investigating clincopathological significance of FAT10 in HBV-related HCC and its underlying mechanisms. Based on the analysis of FAT10 expression in a reliable and large number of cases with 5-year follow-up, we showed that FAT10 was significantly increased in 260 samples from HBV-related HCC patients, compared with 30 normal tissue, 50 cirrhosis and matched adjacent nontumor tissues. FAT10 expression is correlated with recurrence and poor prognosis in HBV-related HCC. In addition, ectopic expression of FAT10 enhanced cell proliferation, inhibited apoptosis and induced cell cycle progression, whereas silencing FAT10 expression suppressed cell proliferation and induced apoptosis. FAT10 also induced the epithelial-mesenchymal transition (EMT) and promoted invasion of HCC cells. Furthermore, we found Akt/GSK3beta pathway contributed to the effects of FAT10 in HCC cells. Blocking the Akt pathway significantly inhibited the actions of FAT10. Taken together, the ubiquitin-like protein FAT10 has a central role in regulating diverse aspects of the pathogenesis of HCC, indicating that it might be a potential therapeutic target. PMID- 23812430 TI - Expression of the antimicrobial peptide cathelicidin in myeloid cells is required for lung tumor growth. AB - Antimicrobial peptides, such as the cathelicidin LL-37/hCAP-18 and its mouse homolog cathelicidin-related antimicrobial peptide (CRAMP), are important effectors of the innate immune system with direct anti-bacterial activity. Cathelicidin is possibly involved in the regulation of tumor cell growth. The aim of this study was to characterize the role of cathelicidin expressed in non tumorous cells in a preclinical mouse model of tumor growth. Wild-type and CRAMP deficient animals were exposed to cigarette smoke (CS) and Lewis lung carcinoma cells were injected to initiate the growth of tumors in the lung. CS exposure significantly increased the proliferation of lung tumors in wild-type mice, but not in CRAMP-deficient mice. CS exposure induced the recruitment of myeloid cell into tumor tissue in a CRAMP-dependent manner. Mice lacking RelA/p65 specifically in myeloid cells showed impaired recruitment of CRAMP-positive cells into the lung. In vitro studies with human cells showed that LL-37/hCAP-18 in macrophages is induced by soluble factors derived from cancer cells. Taken together, these data indicate that cathelicidin expressed from myeloid cells promotes CS-induced lung tumor growth by further recruitment of inflammatory cells. The regulation of cathelicidin expression involves myeloid p65/RelA and soluble factor from tumor cells. PMID- 23812432 TI - The antipsychotic olanzapine induces apoptosis in insulin-secreting pancreatic beta cells by blocking PERK-mediated translational attenuation. AB - Patients with schizophrenia receive medication to alleviate various symptoms, but some efficacious second generation antipsychotics, particularly olanzapine, can cause obesity, dyslipidemia, and diabetes mellitus. It has been generally considered that olanzapine contributes to the development of diabetes by inducing obesity and subsequent insulin resistance. In this study, we examined the effect of olanzapine and risperidone, another second generation antipsychotic, on a hamster pancreatic beta cell line, and found that both evoked mild endoplasmic reticulum (ER) stress, as evidenced by mild activation of the ER stress sensor molecule PERK. Surprisingly, only olanzapine induced marked apoptosis. Phosphorylation of the alpha subunit of eukaryotic initiation factor 2, an event immediately downstream of PERK activation, was not observed in cells treated with olanzapine, protein synthesis continued despite PERK activation, and ER stress was thereby sustained. Secretion of insulin was markedly inhibited, and both proinsulin and insulin accumulated inside olanzapine-treated cells. Inhibition of protein synthesis and knockdown of insulin mRNA, which result in less unfolded protein burden, both attenuated subsequent olanzapine-induced apoptosis. Given clinical observations that some patients taking olanzapine exhibit hyperlipidemia and hyperglycemia without gaining weight, our observations suggest that damage to pancreatic beta cells may contribute to the undesirable metabolic consequences of olanzapine treatment in some cases. PMID- 23812431 TI - PPM1A is a RelA phosphatase with tumor suppressor-like activity. AB - Nuclear factor-kappaB (NF-kappaB) signaling contributes to human disease processes, notably inflammatory diseases and cancer. NF-kappaB has a role in tumorigenesis and tumor growth, as well as promotion of metastases. Mechanisms responsible for abnormal NF-kappaB activation are not fully elucidated; however, RelA phosphorylation, particularly at serine residues S536 and S276, is critical for RelA function. Kinases that phosphorylate RelA promote oncogenic behaviors, suggesting that phosphatases targeting RelA could have tumor-inhibiting activities; however, few RelA phosphatases have been identified. Here, we identified tumor inhibitory and RelA phosphatase activities of the protein phosphatase 2C (PP2C) phosphatase family member, PPM1A. We show that PPM1A directly dephosphorylated RelA at residues S536 and S276 and selectively inhibited NF-kappaB transcriptional activity, resulting in decreased expression of monocyte chemotactic protein-1/chemokine (C-C motif) ligand 2 and interleukin 6, cytokines implicated in cancer metastasis. PPM1A depletion enhanced NF-kappaB dependent cell invasion, whereas PPM1A expression inhibited invasion. Analyses of human expression data revealed that metastatic prostate cancer deposits had lower PPM1A expression compared with primary tumors without distant metastases. A hematogenous metastasis mouse model revealed that PPM1A expression inhibited bony metastases of prostate cancer cells after vascular injection. In summary, our findings suggest that PPM1A is a RelA phosphatase that regulates NF-kappaB activity and that PPM1A has tumor suppressor-like activity. Our analyses also suggest that PPM1A inhibits prostate cancer metastases and as neither gene deletions nor inactivating mutations of PPM1A have been described, increasing PPM1A activity in tumors represents a potential therapeutic strategy to inhibit NF-kappaB signaling or bony metastases in human cancer. PMID- 23812433 TI - Enhanced xylose fermentation capacity related to an altered glucose sensing and repression network in a recombinant Saccharomyces cerevisiae. AB - The co-fermentation of glucose and xylose is one of the issues in decreasing the price of biofuel or chemicals produced from lignocellulosic materials. A glucose and xylose co-utilizing Saccharomyces cerevisiae was obtained through rational genetic manipulation. Non-rational evolution in xylose was performed, and the xylose utilization efficiency of the engineered strain was significantly enhanced. The results of transcriptome study suggested that Snf1/Mig1-mediated regulation, a part of glucose sensing and repression network, was altered in the evolved strain and might be related to the enhancement of xylose utilization. PMID- 23812434 TI - Graphene-based 3D composite hydrogel by anchoring Co3O4 nanoparticles with enhanced electrochemical properties. AB - Three-dimensional (3D) graphene-based composite materials have attracted increasing attention, owing to their specific surface area, high conductivity and electronic interactions. Here, we report a convenient route to fabricate a 3D Co3O4/Graphene Hydrogel (CGH) composite as an electrode material for supercapacitors. Utilizing the gelation of a graphene oxide dispersion enables the anchoring of Co3O4 nanoparticles on the graphene sheet surfaces and formation of the hydrogel simultaneously. Remarkably, the spherical Co3O4 particles can serve as spacers to keep the neighboring graphene sheets separated. The CGH exhibits a high specific capacitance (Cs) of 757.5 F g(-1) at a current density of 0.5 A g(-1), indicating its potential application as an electrode material for supercapacitors. PMID- 23812435 TI - Prevalence of antibodies against hepatitis A virus among children and adolescents in Germany. AB - Since hepatitis A virus (HAV) infection during childhood is mostly asymptomatic, only seroprevalence studies can provide reliable information on incidence of HAV infection in children. The prevalence of anti-HAV antibodies was determined in sera taken in 2008 to 2010 from 1,645 children aged 0-17 years and in sera taken in 2010-2011 from 400 adult blood donors in Germany. For examination of trend over time, 715 sera collected between 1999 and 2006 from children at the age of 0 17 years within the federal state Thuringia were included. Antibody testing was carried out using the test kits ETI-AB-HAVK PLUS and ETI-HA-IGMK PLUS from DiaSorin. In children, the overall prevalence of antibodies was 10.8 %. After the seroprevalence declined from 8.8 % among the 0-2 year-olds to 2.4 % among the 3-4 year-olds, there was a significant increase to 20.5 % in the group of the 15-17 year-olds. Boys had with 12.7 % a significantly higher seroprevalence of anti-HAV antibodies compared to 8.8 % among girls. In adult blood donors, there was a HAV seroprevalence of 19.3 %. The likelihood of past infection or immunization within the age groups of children from 0 to 12 years differed significantly from that of adults. In conclusion, in Germany, only a small number of HAV infections occur in children, especially up to the age of 12 years. The proportion of susceptible children is greater than the proportion of susceptible adults. Thus, during outbreaks, the rate of infection among children would usually be higher than the rate among adults. PMID- 23812437 TI - Silk sericin and burn wound. PMID- 23812438 TI - Quadriceps function following ACL reconstruction and rehabilitation: implications for optimisation of current practices. AB - PURPOSE: To determine the most effective practices for quadriceps strengthening after ACL reconstruction. METHODS: An electronic search has been performed for the literature appearing from January 1990 to January 2012. Inclusion criteria were articles written in English, German or Dutch with unilateral ACL reconstructed patients older than 13 years, RCT rehabilitation programmes containing muscle strengthening, protocol described in detail and time frame of measurements reported. Quadriceps muscle strength and patient-reported outcomes were the endpoints. Included studies were assessed on their methodological quality using the CONSORT Checklist. RESULTS: From 645 identified studies, 10 met the inclusion criteria. Seven studies found an increase in quadriceps strength after intervention programmes regardless of type of training. An eccentric exercise programme showed significantly better values for isometric quadriceps strength compared to a concentric exercise programme. The Tegner activity scale showed a significant increase in activity level for all training programmes. The Cincinnati Knee Rating System showed significant improvements in particular for the neuromuscular training group. CONCLUSIONS: The evidence from this review indicates that eccentric training may be most effective to restore quadriceps strength, but full recovery may not be achieved with current rehabilitation practices. Neuromuscular training incorporating motor learning principles should be added to strengthening training to optimise outcome measurements. LEVEL OF EVIDENCE: II. PMID- 23812439 TI - Minimum thickness of all-poly tibial component unicompartmental knee arthroplasty in patients younger than 60 years does not increase revision rate for aseptic loosening. AB - PURPOSE: Management of unicompartmental knee osteoarthritis in middle-aged patients is a challenging problem. Despite its functional advantages, UKA still raises questions concerning implant survivorship and an increased revision risk for aseptic loosening mainly due to polyethylene wear. The main purpose of the present study was to investigate whether using the minimum thickness of an all poly tibial UKA in patients under 60 years of age increases the revision rate for aseptic loosening. The secondary purposes were to compare implant survivorship with data reported in literature and to prospectively evaluate the clinical outcome in this selected group of patients. METHODS: Thirty-three consecutive patients under 60 years of age at the time of surgery with isolated medial compartment osteoarthritis underwent a unilateral medial UKA from 2002 to 2005 and were prospectively followed. A Kaplan-Meier analysis was performed to determine the 8-year implant survivorship with revision for any reason as endpoint. KSS, WOMAC, Tegner-Lysholm, Tegner and VAS scores were prospectively evaluated at 3- to 8-year follow-up. Weight-bearing radiographs were collected pre-operatively and at 3- to 8-year follow-up to prospectively evaluate hip-knee ankle angle (HKA), femoro-tibial angle (FTA), tibial plateau angle and posterior tibial slope. RESULTS: The 8-year Kaplan-Meier survivorship with revision for any reason as endpoint was 83 %. Five failures were reported, and in 3 patients' aseptic loosening of the tibial component was the reason for failure. All clinical scores significantly improved at 3-year follow-up, and no further modification was demonstrated up to 8-year follow-up. HKA, FTA and TPA had a significant difference at 3-year follow-up with respect to pre-operative values (p < 0.01) and no further difference at 8-year follow-up was found. CONCLUSIONS: The present study failed to demonstrate an increased revision rate for aseptic loosening of the implant in patients under 60 years of age, who received an all poly tibial component UKA using the minimum thickness of the implant in all cases. PMID- 23812440 TI - Femoroacetabular impingement: is hyaluronic acid effective? AB - PURPOSE: Femoroacetabular impingement may predispose to the development of hip osteoarthritis. Conservative treatments are effective in the short term, but surgery is often required. Aim of this paper was to report the short-term results on hip pain and function after ultrasound-guided injections of hyaluronic acid. METHODS: In this open prospective trial, twenty patients suffering from mild femoroacetabular impingement were enrolled. Each patient received a 2-ml intra articular ultrasound-guided injection of hyaluronic acid at baseline and after 40 days; the same dosing schedule was repeated after 6 months. The clinical evaluation was performed at baseline and after 6 and 12 months of follow-up. Pain score, Lequesne Index, Harris Hip Score and anti-inflammatory medication consumption were measured. Adverse events were also registered. RESULTS: Twenty three hips (3 bilateral cases) were treated. Pain decreased from 6.7 +/- 1.3 to 3.7 +/- 1.8 and to 1.7 +/- 1.8 after 6 and 12 months, respectively; Lequesne Index was reduced and the mean Harris Hip Score improved from 83.3 +/- 6 before treatment to 88.2 +/- 4.7 at 12 months. Consumption of anti-inflammatory drugs was also reduced, from 14 to 4 subjects and from 3.6 +/- 2.2 to 1.3 +/- 1.3 tablets/week. Local side effects after injection were observed only in 2 cases. CONCLUSIONS: Hyaluronic acid is safe and effective in the treatment of mild femoroacetabular impingement, with significant pain reduction and function improvement. PMID- 23812441 TI - [Humeral head replacement in acute proximal humerus fractures]. AB - Complex proximal humerus fractures with an avascular head fragment and unreconstructable fracture types represent indications for humeral head replacement. Special prosthetic designs allow modular anatomical restoration of the centre of rotation and alignment and stable fixation of the tuberosities. These play a key role with respect to the functional outcome and are often prone to complete or partial osteolysis with secondary rotator cuff deficiency. Because the operational procedure is technically demanding, attention must be paid to correct implantation. The functional results which can be expected are reliable with a moderate Constant score of 50 to 60 points and a low pain level. In elderly patients with poor bone quality and an associated increased tuberosity related complication rate, a primary inverse prosthetic design has to be considered as a reasonable alternative. The overall revision rate is approximately 11 %. PMID- 23812442 TI - [Pediculated deltoid muscle flap: an alternative for coverage of chronic radionecrotic lesions in the shoulder region]. AB - Soft tissue lesions in the clavicular region may be the result of trauma, infections or oncological resection and necessitate plastic surgery coverage. A case of an 85-year-old woman is presented with non-union of the mid-portion of the left clavicle with an overlying skin defect and a brachial plexus lesion after radiation therapy for breast cancer. The left arm was functionless so after partial resection of the medial part of the clavicle coverage of the defect was conducted by a proximally pediculated anterior part of the deltoid muscle with a split thickness skin graft. PMID- 23812443 TI - [Patient rights act. Effect on clinical rourtine]. PMID- 23812445 TI - Nonsurgical treatment of endometrial hyperplasia: is the road less traveled the one we should be taking more? PMID- 23812446 TI - Bed rest in pregnancy: time to put the issue to rest. PMID- 23812447 TI - Health information technology. PMID- 23812448 TI - Prediction of regression and relapse of endometrial hyperplasia with conservative therapy. AB - OBJECTIVE: To identify predictors and to estimate their prognostic accuracy for regression and relapse of endometrial hyperplasia treated with levonorgestrel releasing intrauterine system or oral progestogens. METHODS: This was a cohort study of women treated with levonorgestrel-releasing intrauterine system or oral progestogens for complex hyperplasia or atypical complex hyperplasia for women wishing to preserve their fertility or those who were unfit for surgery. Hazard ratios (HRs) with the Cox proportional hazards model and Kaplan-Meier survival estimates for independent predictors were calculated. RESULTS: Regression was evaluated in 344 women over a 12-year period, with a median follow-up of 58.8 months (interquartile range 38.4-96.4, range 12-148.2) for levonorgestrel releasing intrauterine system compared with 95.1 months (interquartile range 41.6 124.6, range 13.2-162) for oral progestogens. In women treated with levonorgestrel-releasing intrauterine system for complex hyperplasia, we found that 221 women regressed (96.5%, 221/229) and body mass index (BMI) 35 or higher was associated with failure to regress (HR 5.51, 95% confidence interval [CI] 1.05-28.87; P=.043). Relapse was evaluated in 219 women over a 9-year period, with median follow-up of 67 months (interquartile range 50.4-103.5, range 14.5 146.4) for levonorgestrel-releasing intrauterine system and 96.8 months (interquartile range 62.3-122, range 6-151.5) for oral progestogens. In women treated with levonorgestrel-releasing intrauterine system for complex hyperplasia, we found that 18 women experienced relapse (12.7%, 18/142) and BMI 35 or higher was found to be a strong independent predictor of relapsed endometrial hyperplasia (HR 18.93, 95% CI 3.93-91.15; P<.001). Only 3.3% of women with complex hyperplasia treated with levonorgestrel-releasing intrauterine system and with BMI less than 35 experienced relapse during long-term follow-up compared with 32.6% of women with BMI 35 or higher. CONCLUSION: Body mass index 35 or higher is strongly associated with failure to regress and relapse of complex hyperplasia treated with levonorgestrel-releasing intrauterine system. PMID- 23812449 TI - Systemic and local hormone therapy for endometrial hyperplasia and early adenocarcinoma. AB - OBJECTIVE: To estimate disease regression, persistence, and progression in women with complex endometrial hyperplasia and stage I endometrial carcinoma treated with a levonorgestrel-releasing-intrauterine system or oral progesterone. METHODS: Records of all patients who received progestin therapy for endometrial hyperplasia or early-stage endometrioid cancer between January 1999 and July 2011 were reviewed. Demographic data (age, body mass index), presentation, treatment modality and rationale, rates of response, recurrence, and salvage surgery were collected and compared using Student's t and chi tests. Fertility outcomes when available were analyzed. RESULTS: One hundred eighty-six women received primary hormone therapy for endometrial hyperplasia or cancer. Of these, 153 had adequate follow-up without surgery or radiation as part of primary treatment. Average age at diagnosis was 49.6 years (range 22-92 years). The most common reasons cited for hormone therapy were medical comorbidities (46%) and fertility (21%). Patients with hyperplasia compared with cancer had significantly different complete response (66-70% compared with 6-13%), initial response with recurrence (11-23% compared with 19-30%), and no response rates (11-19% compared with 57 75%), respectively (P<.001). Outcomes were not significantly different between the levonorgestrel-releasing intrauterine system and oral progesterone among patients with cancer at all time points. In patients with hyperplasia, outcomes were not significantly different except during the 9-month to 12-month assessment where those who received systemic hormones were less likely to have disease persistence or progression compared with patients who had levonorgestrel releasing intrauterine systems. Three patients achieved pregnancy. CONCLUSIONS: Hormone therapy has varied response rates among women with endometrial hyperplasia or cancer who do not undergo surgery. Close patient monitoring remains paramount given the high recurrence and high percentage of patients who will not respond. PMID- 23812451 TI - Effect of bidet toilet use on preterm birth and vaginal flora in pregnant women. AB - OBJECTIVE: To estimate the association between bidet toilet use and preterm birth, as well as the effect of bidet toilet use on bacterial vaginosis, in pregnant women. METHODS: Questionnaires about bidet toilet usage were sent to 2,545 women who gave birth between 2006 and 2010 in Tokyo. Crude and multivariable adjusted odds ratios (ORs) for the incidence of preterm birth (delivery at less than 37 completed weeks of gestation) and the prevalence of bacterial vaginosis between users and nonusers of the bidet toilet were calculated using data from the questionnaire and delivery records. Bacterial vaginosis was estimated by the balance of lactobacilli and nonlactobacillus microbes based on routine prenatal microbiologic test results. RESULTS: Of 1,293 women who responded to the questionnaire, 63.3% were users of the bidet toilet. The incidence of preterm birth was 15.8% among bidet users and 16.0% among nonusers (adjusted OR 1.04, 95% confidence interval [CI] 0.72-1.48). Additionally, no association was found between bidet toilet use and bacterial vaginosis (adjusted OR 0.96, 95% CI 0.70-1.33). CONCLUSION: Normal use of the bidet toilet by pregnant women poses no clinical health risk for preterm birth and bacterial vaginosis. PMID- 23812452 TI - Health outcomes for vaginal compared with cesarean delivery of appropriately grown preterm neonates. AB - OBJECTIVE: To examine the association between route of delivery and neonatal outcomes in a large, diverse cohort of preterm, appropriate-for-gestational-age neonates. METHODS: This is a retrospective cohort study examining New York City birth data for 1995-2003 linked to hospital discharge data. Data were limited to singleton, live-born, cephalic neonates delivered between 24 and 34 weeks of gestation. Exclusion criteria included congenital anomalies, forceps or vacuum assistance, birth weight missing, less than 500 g, or not appropriate for gestational age. Any neonatal diagnosis of intraventricular hemorrhage, seizure, sepsis, subdural hemorrhage, respiratory distress, 5-minute Apgar score less than 7, or neonatal death was considered significant. Associations between method of delivery and neonatal morbidities were estimated using logistic regression. RESULTS: Of 20,231 neonates meeting study criteria, 69.3% were delivered vaginally and 30.7% were delivered by cesarean. After controlling for maternal age, ethnicity, education, primary payer, prepregnancy weight, gestational age, diabetes, and hypertension, cesarean delivery compared with vaginal delivery was associated with increased odds of respiratory distress (39.2% compared with 25.6%, adjusted odds ratio [OR] 1.74, 95% confidence interval [CI] 1.61-1.89) and 5-minute Apgar score less than 7 (10.7% compared with 5.8%, adjusted OR 2.04, 95% CI 1.77-2.35). CONCLUSION: In this preterm cohort, cesarean delivery was not protective against poor outcomes and in fact was associated with increased risk of respiratory distress and low Apgar score compared with vaginal delivery. PMID- 23812450 TI - Activity restriction among women with a short cervix. AB - OBJECTIVE: To estimate determinants of and outcomes associated with activity restriction among women with a short cervix. METHODS: This was a secondary analysis of a randomized trial of 17-alpha hydroxyprogesterone caproate for prevention of preterm birth among nulliparous women with singleton gestations and cervices less than 30 mm by midtrimester ultrasonography. Women were asked weekly whether they had been placed on pelvic, work, or nonwork rest. "Any activity restriction" was defined as being placed on any type of rest. Factors associated with any activity restriction were determined and the association between preterm birth and activity restriction was estimated with multivariable logistic regression. RESULTS: Of the 657 women in the trial, 646 (98%) responded to questions regarding activity restriction. Two hundred fifty-two (39.0%) were placed on any activity restriction at a median of 23.9 weeks (interquartile range 22.6-27.9 weeks). Women on activity restriction were older, more likely to have private insurance, less likely to be Hispanic, had a shorter cervical length, and were more likely to have funneling and intra-amniotic debris. Preterm birth at less than 37 weeks of gestation was more common among women placed on activity restriction (37% compared with 17%, P<.001). After controlling for potential confounding factors, preterm birth remained more common among those placed on activity restriction (adjusted odds ratio 2.37, 95% confidence interval 1.60 3.53). Results were similar for preterm birth at less than 34 weeks of gestation. CONCLUSION: Activity restriction did not reduce the rate of preterm birth in asymptomatic nulliparous women with a short cervix. PMID- 23812453 TI - Paradoxical trends and racial differences in obstetric quality and neonatal and maternal mortality. AB - OBJECTIVE: To evaluate trends by race in Agency for Healthcare Research and Quality obstetric-related quality and safety indicators and their relationships to trends in inpatient maternal and neonatal mortality. METHODS: We used the Nationwide Inpatient Sample from 2000 through 2009 and calculated obstetric hospital quality and patient safety indicators and inpatient maternal and neonatal mortality stratified by race. We examined differences in age and comorbidity-adjusted trends in black compared with white women over time in the United States and by geographic region. Proportions were analyzed by chi2 and trends by regression analysis. RESULTS: Obstetric quality indicators varied by geographic region, but changes over time were consistent for both races. Cesarean deliveries increased similarly for black and white women, and vaginal births after cesarean delivery declined for both races but more rapidly for white women than for black women. Obstetric safety indicators improved over the study period for black and white women, with obstetric trauma decreasing significantly for both groups (28% compared with 35%, respectively) and birth trauma-injury to neonates declining for both, but changes were not significant. In striking contrast, inpatient maternal and neonatal mortality remained relatively constant during the study period, with persistently higher rates of both seen among black compared with white women (12.0 compared with 4.6 per 100,000 deliveries, P<.001 and 6.6 compared with 2.5 per 1,000 births, P<.001, respectively, in 2009). CONCLUSION: Improvements in Agency for Healthcare Research and Quality quality indicators for obstetrics are not reflected in improvements in maternal and neonatal morbidity and mortality and do not explain continued racial disparities for outcomes in pregnancies in black and white women. Quality measures that are related to pregnancy outcomes are needed and these should elucidate obstetric health disparities. PMID- 23812454 TI - Overtreatment in a see-and-treat approach to cervical intraepithelial lesions. AB - OBJECTIVE: To determine the overtreatment rate at colposcopy in women who underwent a see-and-treat protocol. METHODS: We identified 3,192 patients (mean age 36 years, standard deviation 8.7) who underwent a see-and-treat protocol in Radboud University Nijmegen Medical Center between January 1981 and December 2010. Overtreatment, defined as cervical intraepithelial neoplasia 1 or less at final histopathology analysis, was investigated in relation to the age of the women, time of referral, cervical smear result, colposcopic impression, and histopathology result. RESULTS: A total of 579 women (18.1%, 95% confidence interval [CI] 16.7-19.5) were overtreated. The lowest overtreatment rate (4.5%, 95% CI 3.5-5.5) was seen in women with both a high-grade cervical smear result and a high-grade colposcopic impression. Women aged younger than 40 years were less likely to be overtreated (13.1%, 95% CI 11.7-14.5) than women aged 40-49 years (24.2% 95% CI 21.2-27.4, number needed to harm nine) and aged 50 years and older (42.2%, 95% CI 36.5-47.7, number needed to harm three). CONCLUSIONS: The overtreatment rate is low for patients with both a high-grade smear result and a high-grade colposcopic impression, justifying a see-and-treat approach for these patients. In women with either a high-grade smear result or a high-grade impression on colposcopy, a see-and-treat approach may still be preferable but has higher overtreatment rates. Given the side effects of cervical surgery on pregnancy outcome, young women, in particular those who have either a low-grade smear result or low-grade impression on colposcopy, are better served by a two step approach. In older women, a see-and-treat policy may be preferable. PMID- 23812456 TI - Adherence to treatment guidelines for ovarian cancer as a measure of quality care. AB - OBJECTIVES: To validate National Comprehensive Cancer Network ovarian cancer guideline adherence as a quality process measure associated with improved survival, and to identify structural health care characteristics predictive of adherence to National Comprehensive Cancer Network guideline care. METHODS: Consecutive patients with epithelial ovarian cancer diagnosed between 1 January 1999 and 31 December 2006 were identified from the California Cancer Registry. Adherence to National Comprehensive Cancer Network guideline care was defined by stage-appropriate surgical procedures and recommended chemotherapy. Multivariable logistic regression models were used to identify characteristics predictive of National Comprehensive Cancer Network guideline adherence and ovarian cancer specific survival. RESULTS: A total of 13,321 patients were identified. Overall, 37.2% of patients received National Comprehensive Cancer Network guideline adherent care. Guideline-adherent care was associated with high-volume hospitals (20 or more cases per year; 50.8% compared with 34.1%; P<.001) and high-volume physicians (10 or more cases per year; 47.6% compared with 34.5%; P<.001). After controlling for other factors, both low-volume hospitals (odds ratio [OR] 1.83, 95% confidence interval [CI] 1.66-2.01) and low-volume physicians (OR 1.19, 95% CI 1.07-1.32) were independently associated with deviation from National Comprehensive Cancer Network guidelines. On multivariable survival analysis, nonadherence to National Comprehensive Cancer Network guideline care was associated with decreased disease-specific survival (hazard ratio [HR] 1.33, 95% CI 1.26-1.41). Both low-volume hospitals (HR 1.08, 95% CI 1.01-1.16) and low volume physicians (HR 1.18, 95% CI 1.09-1.28) were associated with decreased disease-specific survival after adjusting for National Comprehensive Cancer Network guideline-adherent care. CONCLUSIONS: Adherence to National Comprehensive Cancer Network guidelines for treatment of ovarian cancer is correlated with improved survival and may be a useful process measure of quality cancer care. Ovarian cancer case volume correlates with a higher likelihood of recommended care and improved survival and may be a useful structural quality measure. Increased efforts to concentrate ovarian cancer care are warranted. PMID- 23812455 TI - Trends in hospital volume and patterns of referral for women with gynecologic cancers. AB - OBJECTIVE: To estimate trends in hospital volume and referral patterns for women with uterine and ovarian cancer. METHODS: The Surveillance, Epidemiology, and End Results-Medicare database was used to identify women aged 65 years or older with ovarian and uterine cancer who underwent surgery from 2000 to 2007. "Volume creep," when a greater number of patients undergo surgery at the same hospitals, and "market concentration," when a similar overall number of patients undergo a procedure but at a smaller number of hospitals, were analyzed. RESULTS: Among 4,522 patients with ovarian cancer, mean hospital volume increased from 3.1 cases during 2000-2001 to 3.4 cases during 2006-2007 (P=.62) suggesting minimal volume creep. Similarly, there was little evidence of market concentration. In 2000 2001, 37.8% of women were treated at the top decile by volume hospitals compared with 41.4% in 2006-2007 (P=.14). In 2006-2007, 201 (63.2%) of the hospitals had an ovarian cancer surgery volume of two or fewer cases. Among 9,908 women with uterine cancer, the mean hospital volume increased slightly from 4.5 in 2000-2001 to 5.4 in 2006-2007 (P=.10). The percentage of patients treated at the top decile by volume of hospitals increased from 40.4% in 2000-2001 to 44.7% in 2006-2007 (P<.001). In 2006-2007, 243 (49.3%) of the hospitals had a uterine cancer surgery volume of two or fewer cases. CONCLUSION: There have been only modest changes in the referral patterns of women with ovarian and uterine cancer. A large number of hospitals have a very low procedural volume. PMID- 23812457 TI - Breast cancer in women aged 25 years and younger. AB - OBJECTIVE: To evaluate breast cancer characteristics in women aged 25 years and younger. METHODS: This was a retrospective, nested, within-cases matched study. The study design was based on a two-phase protocol. In the first phase, stage, grade, histologic subtype, estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status were compared between 28 patients (aged 25 years and younger) and 685 older premenopausal women (aged older than 25 years) with breast cancer. The second phase aimed to determine whether young patients exhibited worse prognosis when compared with older premenopausal women. RESULTS: Young patients presented at a more advanced stage (P=.012) and exhibited a higher grade (P=.018). No significant differences were noted regarding histologic subtype, estrogen receptor, and progesterone receptor status. Genetic testing for BRCA1 and BRCA2 mutations was performed in 12 of 28 young patients and mutations were found in 25% of them. Moreover, young women presented poorer overall survival (hazard ratio [HR] 4.30, 95% confidence interval [CI] 1.09 17.03) than their older counterparts, matched by histologic subtype, stage, and grade; a similar pattern was noted regarding relapse-free survival (HR 8.28, 95% CI 2.24-30.60). CONCLUSION: Breast cancer diagnosis in women aged 25 years and younger is uncommon; however, these patients present at a more advanced stage, with a higher grade, and exhibit poorer survival. PMID- 23812459 TI - Global gene expression analysis of term amniotic fluid cell-free fetal RNA. AB - OBJECTIVE: To identify the tissue expression patterns and biological pathways enriched in term amniotic fluid cell-free fetal RNA by comparing functional genomic analyses of term and second-trimester amniotic fluid supernatants. METHODS: This was a prospective whole genome microarray study comparing eight amniotic fluid samples collected from women at term who underwent prelabor cesarean delivery and eight second-trimester amniotic fluid samples from routine amniocenteses. A functional annotation tool was used to compare tissue expression patterns in term and second-trimester samples. Pathways analysis software identified physiologic systems, molecular and cellular functions, and upstream regulators that were significantly overrepresented in term amniotic fluid. RESULTS: There were 2,871 significantly differentially regulated genes. In term amniotic fluid, tissue expression analysis showed enrichment of salivary gland, tracheal, and renal transcripts as compared with brain and embryonic neural cells in the second trimester. Functional analysis of genes upregulated at term revealed pathways that were highly specific for postnatal adaptation such as immune function, digestion, respiration, carbohydrate metabolism, and adipogenesis. Inflammation and prostaglandin synthesis, two key processes involved in normal labor, were also activated in term amniotic fluid. CONCLUSIONS: Transcriptomic analysis of amniotic fluid cell-free fetal RNA detects fetal maturation processes activated in term pregnancy. These findings further develop the concept of amniotic fluid supernatant as a real-time gene expression "summary fluid" and support its potential for future studies of fetal development. PMID- 23812460 TI - Risk of large-for-gestational-age newborns in women with gestational diabetes by race and ethnicity and body mass index categories. AB - OBJECTIVE: To compare the prevalence of large-for-gestational-age (LGA) newborns across categories of body mass index (BMI) in five racial and ethnic groups. METHODS: This cohort study examined 7,468 women with gestational diabetes mellitus (GDM) who delivered a live newborn between 1995 and 2006 at Kaiser Permanente Northern California. The racial and ethnic groups were non-Hispanic white, African American, Hispanic, Asian, and Filipina. The BMI was classified using the World Health Organization International guidelines (normal, 18.50 24.99; overweight, 25.00-29.99; obese, 30.00-34.99; obese class II, 35.00 or higher). Having an LGA newborn was defined as birth weight more than 90th percentile for the study population's race or ethnicity and gestational age- specific birth weight distribution. Logistic regression was used to estimate odds of having an LGA newborn by BMI and race and ethnicity. RESULTS: Overall prevalence of LGA newborns was highest in African American women (25.1%), lowest in Asians (13.9%), and intermediate among Hispanic (17.3%), white (16.4%), and Filipina women (15.3%). The highest increased risk of LGA newborns was observed among women with class II obesity in most racial and ethnic groups, and African American and Asian women with class II obesity had a four-fold increased risk of LGA newborns compared with women of normal weight in the same racial and ethnic group. CONCLUSIONS: African American women with GDM have a greater risk of LGA newborns at a lower BMI than other racial and ethnic groups. Clinicians should be aware that among women with GDM, there may be significant racial and ethnic differences in the risk of LGA newborns by BMI threshold. PMID- 23812458 TI - Relationship between 1-hour glucose challenge test results and perinatal outcomes. AB - OBJECTIVE: To estimate the relationship between 1-hour 50 g glucose challenge test values and perinatal outcomes. METHODS: This was a secondary analysis of data from a multicenter treatment trial of mild gestational diabetes mellitus. Women with glucose challenge test values of 135-199 mg/dL completed a 3-hour oral glucose tolerance test. Mild gestational diabetes mellitus was defined as fasting glucose less than 95 mg/dL and two or more abnormal oral glucose tolerance test values: 1-hour 180 mg/dL or more; 2-hour 155 mg/dL or more; and 3-hour 140 mg/dL or more. Our study included untreated women with glucose challenge test values of 135-139 mg/dL and 140-199 mg/dL and a comparison group with values less than 120 mg/dL. Primary outcomes included a perinatal composite (stillbirth, neonatal death, hypoglycemia, hyperbilirubinemia, neonatal hyperinsulinemia, and birth trauma), large for gestational age (LGA, birth weight above the 90 percentile based on sex-specific and race-specific norms), and macrosomia (greater than 4,000 g). RESULTS: There were 436 women with glucose challenge test values less than 120 mg/dL and 1,403 with values of 135 mg/dL or more (135-139, n=135; 140 199, n=1,268). The composite perinatal outcome occurred in 25.6% of those with glucose challenge test values less than 120 mg/dL compared with 21.1% for values of 135-139 mg/dL and 35.3% for values of 140-199 mg/dL. Rates of LGA by group were 6.6%, 6.8%, and 12.4%, respectively. Rates of macrosomia by group were 7.8%, 6.1%, and 12.1%, respectively. Compared with glucose challenge test values less than 120 mg/dL, the adjusted odds ratios (ORs) (95% confidence intervals [CIs]) for values of 140-199 mg/dL were 1.48 (1.14-1.93) for the composite outcome, 1.97 (1.29-3.11) for LGA, and 1.61 (1.07-2.49) for macrosomia. For glucose challenge test values of 135-139 mg/dL, adjusted ORs and 95% CIs were 0.75 (0.45-1.21), 1.04 (0.44-2.24), and 0.75 (0.30-1.66), respectively. The subcategories with glucose challenge test values of 140-144 mg/dL and 145-149 mg/dL also were associated with an increase in selected outcomes when compared with those with values less than 120 mg/dL. CONCLUSIONS: Glucose challenge test values of 135-139 mg/dL were not associated with adverse outcomes compared with values less than 120 mg/dL; however, glucose challenge test values of 140 mg/dL or more were associated with an increase in odds of the composite perinatal outcome, LGA, and macrosomia. PMID- 23812462 TI - Vaginal dilators for prevention of dyspareunia after prolapse surgery: a randomized controlled trial. AB - OBJECTIVE: To compare rates of de novo dyspareunia in women with and without vaginal dilator use after posterior colporrhaphy. METHODS: This randomized controlled trial included sexually active patients with prolapse and no bothersome baseline dyspareunia undergoing posterior colporrhaphy. Patients were randomized to daily vaginal dilator use from postoperative weeks 4 through 8 or to no dilator use. Pelvic organ prolapse quantification examination and vaginal caliber were measured at baseline, 8 weeks, and 6 months postoperatively. Sexual function was evaluated at baseline, 3 months, and 6 months postoperatively using the Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire-12. Participants completed a Patient Global Impression of Improvement at 3 months and 6 months postoperatively. RESULTS: Sixty patients were randomized: 30 in the dilator group and 30 in the control group. There were no differences in baseline characteristics and postoperative vaginal caliber between groups. At 3 months, 9.5% of patients reported de novo dyspareunia in the dilator group compared with 19.2% of control patients (P=.44). At 6 months, 12.5% of patients in the dilator group reported de novo dyspareunia compared with 3.8% of control patients (P=.34). There was a 13% loss-to-follow-up rate, and therefore we did not meet appropriate power to detect a difference. There were no differences in overall sexual function or Patient Global Impression of Improvement scores between groups at 3 months and 6 months. CONCLUSION: There were no significant differences in de novo dyspareunia rates, overall postoperative sexual function scores, or global improvement scores between those using vaginal dilators compared with control patients. PMID- 23812461 TI - Tubal factor infertility and perinatal risk after assisted reproductive technology. AB - OBJECTIVE: To assess trends of tubal factor infertility and to evaluate risk of miscarriage and delivery of preterm or low birth weight (LBW) neonates among women with tubal factor infertility using assisted reproductive technology (ART). METHODS: We assessed trends of tubal factor infertility among all fresh and frozen, donor, and nondonor ART cycles performed annually in the United States between 2000 and 2010 (N=1,418,774) using the National ART Surveillance System. The data set was then limited to fresh, nondonor in vitro fertilization cycles resulting in pregnancy to compare perinatal outcomes for cycles associated with tubal compared with male factor infertility. We performed bivariate and multivariable analyses controlling for maternal characteristics and calculated adjusted risk ratios (RRs) and 95% confidence intervals (CI). RESULTS: The percentage of ART cycles associated with tubal factor infertility diagnoses decreased from 2000 to 2010 (26.02-14.81%). Compared with male factor infertility, tubal factor portended an increased risk of miscarriage (14.0% compared with 12.7%, adjusted RR 1.08, 95% CI 1.04-1.12); risk was increased for both early and late miscarriage. Singleton neonates born to women with tubal factor infertility had an increased risk of preterm birth (15.8% compared with 11.6%, adjusted RR 1.27, 95% CI 1.20-1.34) and LBW (10.9% compared with 8.5%, adjusted RR 1.28, 95% CI 1.20-1.36). Significant increases in risk persisted for early and late preterm delivery and very low and moderately LBW delivery. A significantly elevated risk was also detected for twin, but not triplet, pregnancies. CONCLUSION: Tubal factor infertility, which is decreasing in prevalence in the United States, is associated with an increased risk of miscarriage, preterm birth, and LBW delivery as compared with couples with male factor infertility using ART. PMID- 23812463 TI - Lack of transparency of clinical trials on endometriosis. AB - OBJECTIVE: To estimate patterns of publication of clinical trials of endometriosis registered in ClinicalTrials.gov and their associated characteristics. METHODS: Information on interventional clinical trials on endometriosis that were registered at ClinicalTrials.gov and updated as having been completed by October 25, 2012, was retrieved and the publication status and time to publication in Medline-indexed journals were ascertained by searching PubMed and by sending e-mail inquiries to the principal investigators listed by the registry. RESULTS: Seventy-one interventional trials of endometriosis, testing various drugs and biologicals, were identified. Among them, 49.3% (35/71) were completed by October 25, 2012, 21.1% were either stopped or inactive in the past 2 years, and the remaining 29.6% were ongoing. Among the 35 completed trials, 25 (71.4%) were sponsored by industry and results were published for only 11 (31.4%; five industry-sponsored, and six nonindustry-sponsored). Trials sponsored by industry were nearly four times less likely to publish their results than nonindustry-sponsored trials, even though these trials typically had larger sample sizes and were completed faster. Compared with the publication rate of 20% found 4 years ago, the current rate has increased only marginally but still lies significantly below the reported 66.3% surveyed recently among 546 completed nonendometriosis trials registered at ClinicalTrials.gov (P<.001). CONCLUSION: Despite mounting pressure on more transparency of clinical trials, the current state of transparency or lack thereof of clinical trials on endometriosis is worrisome and does not benefit the trial sponsor or the public. Thus, we again call for more transparency for endometriosis trials. PMID- 23812464 TI - Denosumab compared with ibandronate in postmenopausal women previously treated with bisphosphonate therapy: a randomized open-label trial. AB - OBJECTIVE: To compare the efficacy and safety of denosumab to ibandronate in postmenopausal women with low bone mineral density (BMD) previously treated with a bisphosphonate. METHODS: In a randomized, open-label study, postmenopausal women received 60 mg denosumab subcutaneously every 6 months (n=417) or 150 mg ibandronate orally every month (n=416) for 12 months. End points included percentage change from baseline in total hip, femoral neck, and lumbar spine BMD at month 12 and percentage change from baseline in serum C-telopeptide at months 1 and 6 in a substudy. RESULTS: At month 12, significantly greater BMD gains from baseline were observed with denosumab compared with ibandronate at the total hip (2.3% compared with 1.1%), femoral neck (1.7% compared with 0.7%), and lumbar spine (4.1% compared with 2.0%; treatment difference P<.001 at all sites). At month 1, median change in serum C-telopeptide from baseline was -81.1% with denosumab and -35.0% with ibandronate (P<.001); the treatment difference remained significant at month 6 (P<.001). Adverse events occurred in 245 (59.6%) denosumab treated women and 230 (56.1%) ibandronate-treated women (P=.635). The incidence of serious adverse events was 9.5% for denosumab-treated women and 5.4% for ibandronate-treated women (P=.046). No clustering of events in any organ system accounted for the preponderance of these reports. The incidence rates of serious adverse events involving infection and malignancy were similar between treatment groups. CONCLUSION: In postmenopausal women previously treated with a bisphosphonate and low BMD, denosumab treatment resulted in greater BMD increases than ibandronate at all measured sites. No new safety risks with denosumab treatment were identified. PMID- 23812465 TI - Leveraging the Affordable Care Act to improve the health of mothers and newborns. AB - Health insurance in the United States is a patchwork system whereby opportunities for coverage are strongly associated with life circumstances (ie, age, income, pregnancy, parental status). For pregnant women, this situation contributes to unstable coverage before, between, and after pregnancies. The Affordable Care Act has the potential to make coverage for women of reproductive age more stable and create new opportunities to intervene on conditions associated with maternal and neonatal morbidity. In this article, we discuss the health economics of the Affordable Care Act, its implications for maternal and neonatal health, specific challenges associated with implementation, and opportunities for obstetricians to leverage the Affordable Care Act to improve the care of women. PMID- 23812466 TI - "Therapeutic" bed rest in pregnancy: unethical and unsupported by data. AB - "Therapeutic" bed rest continues to be used widely, despite evidence of no benefit and known harms. In this commentary, we summarize the Cochrane reviews of bed rest and propose an ethical argument for discontinuing this practice. Cochrane systematic reviews do not support "therapeutic" bed rest for threatened abortion, hypertension, preeclampsia, preterm birth, multiple gestations, or impaired fetal growth. This assessment has been echoed in other comprehensive reviews. Prescribing bed rest is inconsistent with the ethical principles of autonomy, beneficence, and justice. Hence, if bed rest is to be used, it should be only within a formal clinical trial. PMID- 23812467 TI - A pharmacologic approach to the use of glyburide in pregnancy. AB - Despite widespread use of glyburide to treat pregnancy-related hyperglycemia, the dosing regimen is based in large part on pharmacokinetic and pharmacodynamic studies in men and nonpregnant women. Like many medications used by pregnant women, adequate pharmacokinetic and pharmacodynamic data in pregnancy have been sorely lacking. This lack of information can lead to both overdosing with excessive side effects and underdosing with an inadequate therapeutic response. Both of these problems may apply to glyburide use in pregnancy. This commentary provides a pharmacologic basis for altering the glyburide administration regimen. Taking glyburide 1 hour before a meal may improve efficacy in patients with pregnancy-related hyperglycemia. PMID- 23812468 TI - The 2013 review of the Children's Health Insurance Program Reauthorization Act: a call to action. AB - In September 2013, Congress again will review the Children's Health Insurance Program Reauthorization Act of 2009. Fourteen states cover the fetus only (and not the pregnant woman) under the "unborn child" provision of the current law. That the Children's Health Insurance Program Reauthorization Act continues to make it possible for states to provide health insurance coverage to the fetus only has been critiqued for unnecessarily politicizing the law, dragging abortion and personhood debates into the matter of children's health insurance and creating unacceptable tensions between maternal and fetal health. Although the 2009 reauthorization attempted to remedy this issue by also providing coverage for the pregnant mother, it is imperative to review these changes and their effect before the 2013 reauthorization. To ensure optimum health care for both the fetus and the woman, we urge for removal of the "unborn child" pathway and promote coverage of both the fetus and the pregnant woman. PMID- 23812469 TI - Increased stillbirth in uncomplicated monochorionic twin pregnancies: a systematic review and meta-analysis. AB - OBJECTIVE: To estimate the risk of stillbirth in apparently uncomplicated monochorionic-diamniotic twin pregnancies by systematic review and meta-analysis and compare it with that in uncomplicated dichorionic pregnancies. DATA SOURCES: We performed an electronic search (January 1985 to April 2012) of Medline, PubMed, Embase, and ClinicalTrials.gov databases. METHODS OF STUDY SELECTION: Studies detailing gestational-age specific stillbirth rates after 24 weeks of gestation in monochorionic-diamniotic twin pregnancies uncomplicated by twin-twin transfusion syndrome, growth restriction, or major anomalies. The rate and risk of stillbirth were calculated in 2-week gestational age blocks and compared in controlled studies with dichorionic pregnancies. TABULATION, INTEGRATION, AND RESULTS: We evaluated 361 studies to include nine informative studies, four after additional data from the investigators. The rate of stillbirth per 1,000 uncomplicated monochorionic-diamniotic pregnancies at 32-33, 34-35, and 36-37 weeks of gestation was 5.1, 6.8, and 6.2, respectively. The risk of stillbirth per pregnancy at 32, 34, and 36 weeks of gestation was 1.6%, 1.3% and 0.9%, respectively. Compared with uncomplicated dichorionic pregnancies, the odds ratio for stillbirth per pregnancy at 32, 34, and 36 weeks of gestation was 4.2 (95% confidence interval [CI] 1.4-12.6), 3.7 (CI 1.1-12.0), and 8.5 (CI 1.6-44.7), respectively. CONCLUSION: Uncomplicated monochorionic twin pregnancies are at substantial risk of stillbirth throughout the third trimester, which is severalfold higher than in dichorionic twin pregnancies. Given the risk of fetal death to the cotwin, these data should inform decisions around timing of delivery in seemingly normal monochorionic twin pregnancies. PMID- 23812470 TI - Early oral intake and gastrointestinal function after cesarean delivery: a systematic review and meta-analysis. AB - OBJECTIVE: To evaluate whether early oral intake after cesarean delivery has an effect on gastrointestinal outcomes during postpartum recovery. DATA SOURCES: Electronic searches of published studies between 1980 and 2011 were conducted using PubMed, Medline, CINAHL, ClinicalTrials.gov, and Airiti databases. METHODS OF STUDY SELECTION: Randomized controlled trials (RCTs) and nonrandomized trials were included. Data were extracted in a systematic manner and the quality of each study was appraised independently by two reviewers. Meta-analyses were conducted only for RCTs using the RevMan5. TABULATION, INTEGRATION, AND RESULTS: Seventeen studies met eligible criteria and were retrieved, including 14 RCTs and three non RCTs. The majority of early oral intake was provided within 6-8 hours after cesarean delivery. Early oral intake was significantly related to the return of gastrointestinal functions compared with delayed oral intake (bowel sounds -9.2 hours; passage of flatus -10 hours; bowel evacuation -14.6 hours). Early oral intake did not significantly increase the occurrence of gastrointestinal complications compared with delayed oral intake after cesarean delivery (ileus symptoms 18.7% compared with 18%, odds ratio [OR] 0.98; vomiting 5% compared with 5.5%, OR 0.9; nausea 10.3% compared with 10.3%, OR 1.03; abdominal distention 9.3% compared with 11.6%, OR 0.82; diarrhea 3.4% compared with 5%, OR 0.62). CONCLUSION: Early oral intake after cesarean delivery improves the return of gastrointestinal function and does not increase the occurrence of gastrointestinal complications. A clinical implication based on the findings of the current evidence is proposed. PMID- 23812471 TI - Mifepristone-misoprostol dosing interval and effect on induction abortion times: a systematic review. AB - OBJECTIVE: To examine the effect of the interval between mifepristone and misoprostol administration on induction time (first misoprostol dose to abortion), total procedure time (mifepristone administration to abortion), and safety and efficacy in second-trimester induction abortion (13-24 weeks). DATA SOURCES: We searched MEDLINE (1966-2012), ClinicalTrials.gov, POPLINE, and the Cochrane Controlled Trials Register using search terms for second trimester, abortion, misoprostol, and mifepristone and reviewed reference lists of published reports. METHODS OF STUDY SELECTION: Our search revealed 138 articles of which 29 met inclusion criteria: 20 randomized controlled trials and nine observational studies. Studies were included if, in any study arm, mifepristone and misoprostol were used for medical abortion in the second trimester. TABULATION, INTEGRATION, AND RESULTS: Two authors independently reviewed the articles and abstracted the data using standardized data abstraction templates to summarize data. Discrepancies were resolved by consensus. Three studies directly compared a 1-day to 2-day mifepristone-misoprostol interval; they showed small differences in median induction times (weighted average 7.3 hours, range 7-8.5 for a 1-day interval; weighted average 6.8 hours, range 6.3-7.2 for a 2-day interval) and no significant difference in percent expelled by 12 hours or 24 hours. When all randomized studies using mifepristone and misoprostol were pooled by comparable mifepristone-misoprostol interval and misoprostol dose, induction times (first misoprostol dose to expulsion) were only 1-2 hours longer for a 12- to 24-hour interval compared with a 36-48-hour interval, whereas total abortion times (mifepristone to expulsion) were at least 18 hours longer in the 36- to 48-hour group. Induction times varied by misoprostol dosing, with 400-microgram misoprostol protocols resulting in shorter induction times than 200-microgram protocols. CONCLUSION: Shortening the mifepristone-misoprostol interval, thereby reducing total abortion time, does not compromise the safety or efficacy of second-trimester medication abortion and may be used to accommodate patient or health care provider preference. PMID- 23812472 TI - Predictions: the future of our specialty. PMID- 23812473 TI - What is new in ultrasonography? Best articles from the past year. PMID- 23812474 TI - Dextrose saline compared with normal saline rehydration of hyperemesis gravidarum: a randomized controlled trial. PMID- 23812475 TI - In reply. PMID- 23812476 TI - Association of abnormal ovarian reserve parameters with a higher incidence of aneuploid blastocysts. PMID- 23812477 TI - In reply. PMID- 23812478 TI - Notice of retraction: "Dexamethasone for the prevention of nausea and vomiting after dilatation and curettage: a randomized controlled trial" (Fujii and Uemura) and "Dose-range effects of propofol for reducing emetic symptoms during cesarean delivery" (Fujii and Numazaki). PMID- 23812485 TI - ACOG Practice Bulletin No. 135: Second-trimester abortion. PMID- 23812486 TI - ACOG Committee Opinion No. 565: Hormone therapy and heart disease. AB - Menopausal hormone therapy should not be used for the primary or secondary prevention of coronary heart disease at the present time. Evidence is insufficient to conclude that long-term estrogen therapy or hormone therapy use improves cardiovascular outcomes. Nevertheless, recent evidence suggests that women in early menopause who are in good cardiovascular health are at low risk of adverse cardiovascular outcomes and should be considered candidates for the use of estrogen therapy or conjugated equine estrogen plus a progestin for relief of menopausal symptoms. There is some evidence that lends support to the "timing hypothesis," which posits that cardiovascular benefit may be derived when estrogen therapy or hormone therapy is used close to the onset of menopause, but the relationship of duration of therapy to cardiovascular outcomes awaits further study. Clinicians should encourage heart-healthy lifestyles and other strategies to reduce cardiovascular risk in menopausal women. Because some women aged 65 years and older may continue to need systemic hormone therapy for the management of vasomotor symptoms, the American College of Obstetricians and Gynecologists recommends against routine discontinuation of systemic estrogen at age 65 years. As with younger women, use of hormone therapy and estrogen therapy should be individualized based on each woman's risk-benefit ratio and clinical presentation. PMID- 23812487 TI - ACOG Committee Opinion No. 566: Update on immunization and pregnancy: tetanus, diphtheria, and pertussis vaccination. AB - In the face of dramatic and persistent increases in pertussis disease in the United States, the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices has updated its guidelines for the use of the tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap) for pregnant women. The new guidance was issued based on an imperative to minimize the significant burden of pertussis disease in vulnerable newborns, the reassuring safety data on the use of Tdap in adults, and the evolving immunogenicity data that demonstrate considerable waning of immunity after immunization. The revised Advisory Committee on Immunization Practices guidelines recommend that health care personnel administer a dose of Tdap during each pregnancy, irrespective of the patient's prior history of receiving Tdap. To maximize the maternal antibody response and passive antibody transfer and levels in the newborn, optimal timing for Tdap administration is between 27 weeks and 36 weeks of gestation, although Tdap may be given at any time during pregnancy. However, there may be compelling reasons to vaccinate earlier in pregnancy. There is no evidence of adverse fetal effects from vaccinating pregnant women with an inactivated virus or bacterial vaccines or toxoids, and a growing body of robust data demonstrates safety of such use. For women who previously have not received Tdap, if Tdap was not administered during pregnancy it should be administered immediately postpartum to the mother in order to reduce the risk of transmission to the newborn. Additionally, other family members and planned direct caregivers also should receive Tdap as previously recommended (sustained efforts at cocooning). Given the rapid evolution of data surrounding this topic, immunization guidelines are likely to change over time and the American College of Obstetricians and Gynecologists will continue to issue updates accordingly. PMID- 23812488 TI - Technology assessment No. 9: Digital breast tomosynthesis. AB - Mammography has been the primary screening test for early breast cancer for more than five decades, but conventional mammography imaging continues to have limitations in sensitivity and specificity. Digital mammography detects some cases of cancer that are not identified by film mammography, but overall detection is similar for many women. Digital breast tomosynthesis offers the potential to overcome one of the primary limitations of mammography, which is the inability to image overlapping dense normal breast tissue. Clinical data suggest that digital mammography with tomosynthesis produces a better image, improved accuracy, and lower recall rates compared with digital mammography alone. Further study will be necessary to confirm whether digital mammography with tomosynthesis is a cost-effective approach, capable of replacing digital mammography alone as the first-line screening modality of choice for breast cancer screening. PMID- 23812489 TI - Chromatin, non-coding RNAs, and the expression of HIV. AB - HIV is a chronic viral infection affecting an estimated 34 million people worldwide. Current therapies employ the use of a cocktail of antiretroviral medications to reduce the spread and effects of HIV, however complete eradication from an individual currently remains unattainable. Viral latency and regulation of gene expression is a key consideration when developing effective treatments. While our understanding of these processes remains incomplete new developments suggest that non-coding RNA (ncRNA) mediated regulation may provide an avenue to controlling both viral expression and latency. Here we discuss the importance of known regulatory mechanisms and suggest directions for further study, in particular the use ncRNAs in controlling HIV expression. PMID- 23812490 TI - CXCR5 polymorphisms in non-Hodgkin lymphoma risk and prognosis. AB - CXCR5 [chemokine (C-X-C motif) receptor 5; also known as Burkitt lymphoma receptor 1 (BCR1)] is expressed on mature B-cells, subsets of CD4+ and CD8+ T cells, and skin-derived migratory dendritic cells. Together with its ligand, CXCL13, CXCR5 is involved in guiding B-cells into the B-cell zones of secondary lymphoid organs as well as T-cell migration. This study evaluated the role of common germline genetic variation in CXCR5 in the risk and prognosis of non Hodgkin lymphoma (NHL) using a clinic-based study of 1,521 controls and 2,694 NHL cases including 710 chronic lymphocytic leukemia/small lymphocytic lymphoma, 586 diffuse large B-cell lymphoma (DLBCL), 588 follicular lymphoma (FL), 137 mantle cell lymphoma (MCL), 230 marginal zone lymphoma (MZL), and 158 peripheral T-cell lymphoma (PTCL). Of the ten CXCR5 tag SNPs in our study, five were associated with risk of NHL, with rs1790192 having the strongest association (OR 1.19, 95% CI 1.08-1.30; p = 0.0003). This SNP was most strongly associated with the risk of FL (OR 1.44, 95 % CI 1.25-1.66; p = 3.1 * 10(-7)), with a lower degree of association with DLBCL (OR 1.16, 95% CI 1.01-1.33; p = 0.04) and PTCL (OR 1.29, 95 % CI 1.02-1.64; p = 0.04) but no association with the risk of MCL or MZL. For FL patients that were observed as initial disease management, the number of minor alleles of rs1790192 was associated with better event-free survival (HR 0.64; 95% CI 0.47-0.87; p = 0.004). These results provide additional evidence for a role of host genetic variation in CXCR5 in lymphomagenesis, particularly for FL. PMID- 23812491 TI - Regulation of iNOS expression by NF-kappaB in human lens epithelial cells treated with high levels of glucose. AB - PURPOSE: To explore the regulation of inducible nitric oxide synthase (iNOS) expression by nuclear factor kappa B (NF-kappaB) in human lens epithelial cells (LECs) treated with high levels of glucose, and to elucidate the impact of this in the pathogenesis of cataracts associated with diabetes. METHODS: LECs (SRA01/04) were cultured in vitro. NF-kappaB nuclear translocation and iNOS expression were measured at different glucose concentrations and at various time points, and the optimal concentration for detecting changes in the patterns of NF kappaB nuclear translocation and iNOS expression was chosen. As a specific NF kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC) was used to assess the effect of inhibiting NF-kappaB. Western blotting and inverted fluorescence microscopy were used to monitor the nuclear translocation of NF-kappaB. PCR and Western blotting were used to measure iNOS expression. Using the University of California, Santa Cruz database and the TFSEARCH program, we searched the DNA sequence upstream of iNOS for the core binding sequence for NF-kappaB. Chromatin immunoprecipitation (ChIP) was used to measure the binding of NF-kappaB. RESULTS: The nuclear translocation of NF-kappaB was measured upon glucose treatment, and the concentration of NF-kappaB in the nucleus was found to peak at 25 to 30 minutes of treatment with 25 mM glucose. iNOS mRNA and protein levels also increased significantly in a time- and concentration-dependent manner and iNOS mRNA and protein reached their peak values after 8 hours of treatment with 25 mM glucose. The binding of NF-kappaB to the promoter of the iNOS gene was enhanced in the 25 mM glucose group compared with the 5.5 mM glucose group or the 25 mM glucose + 100 MUL PDTC group, and this difference was statistically significant (P < 0.05). CONCLUSIONS: NF-kappaB regulates iNOS expression in a time- and concentration-dependent manner. Under high glucose conditions, NF-kappaB is activated and rapidly translocates to the nucleus, leading to increased binding to the iNOS promoter and a consequent increase in iNOS expression. The findings of this study provide important experimental evidence that clarifies the pathogenesis of cataracts associated with diabetes and contributes to the search for therapeutic targets of these cataracts. PMID- 23812492 TI - Effect of instillation of eyedrops for dry eye on optical quality. AB - PURPOSE: To investigate the effects of viscosity and suspensibility of eyedrops for dry eye by evaluating an eyedrop with one of the solutions or no solution (0.3% sodium hyaluronate ophthalmic solution, 3% diquafosol ophthalmic solution, and 2% rebamipide ophthalmic suspension) on ocular higher-order aberrations (HOAs) and forward light scatter. METHODS: We evaluated ocular HOAs and forward light scatter before and 1, 5, and 10 minutes after instillation of three eyedrops for dry eye in 15 healthy subjects. Saline served as the control. The HOAs were measured for a 4-mm pupil using a wavefront sensor. The obtained aberration data were analyzed in the central 4-mm diameter for total HOAs up to the sixth-order Zernike polynomials. Forward light scatter was quantified with a straylight meter. RESULTS: A significant increase was seen in the HOAs 1 minute after instillation of the three eyedrops for dry eye; the HOAs recovered to the baseline level thereafter. When 0.3% sodium hyaluronate was compared with 2% rebamipide and 3% diquafosol, the HOAs increased significantly (P < 0.01 for both comparisons) immediately after instillation. A significant increase in forward light scatter occurred 1 minute after instillation of rebamipide suspension and returned to the preinstillation level 5 minutes after instillation. No significant changes in forward light scatter occurred after instillation of 3% diquafosol or 0.3% sodium hyaluronate. CONCLUSIONS: Quantitative serial measurement of HOAs and forward light scatter showed that the temporal reduction in optical quality may be attributed mainly to increased HOAs after instillation of highly viscous 0.3% sodium hyaluronate ophthalmic solution and to increased forward light scatter after instillation of 2% rebamipide ophthalmic suspension in healthy subjects. PMID- 23812493 TI - Sulforaphane can protect lens cells against oxidative stress: implications for cataract prevention. AB - PURPOSE: Protecting the lens against oxidative stress is of great importance in delaying the onset of cataract. Isothiocyanates, such as sulforaphane (SFN), are proposed to provide cytoprotection against oxidative stress. We therefore tested the ability of SFN to perform this role in lens cells and establish its ability to delay the onset of cataract. METHODS: The human lens epithelial cell line FHL124 and whole porcine lens culture systems were used. The ApoTox-Glo Triplex Assay was used to assess FHL124 cell survival, cytotoxicity, and apoptosis. The MTS assay was used to assess cell populations. To determine levels of DNA strand breaks, the alkaline comet assay was performed and quantified. Lactate dehydrogenase levels in the medium were evaluated to reflect cell damage/death. To assess level of gene expression, an Illumina whole-genome HT-12 v4 beadchip was used. Protein expression was determined by Western blot and immunocytochemistry. RESULTS: Exposures of 30 MUM H2O2 to FHL124 cells caused a reduction in cell viability and increased cytotoxicity/apoptosis; these effects were significantly inhibited by 24-hour pretreatment with 1 MUM SFN. In addition, 1 MUM SFN significantly reduced H2O2-induced DNA strand breaks. When applied to cultured porcine lenses, SFN protected against H2O2-induced opacification. Illumina whole-genome HT-12 v4 beadchip microarray data revealed eight genes upregulated following 24-hour exposure to 1- and 2-MUM SFN, which included NQO1 and TXNRD1. This pattern was confirmed at the protein level. Nrf2 translocated to the nucleus in response to 0.5- to 2.0-MUM SFN exposure CONCLUSIONS: The dietary component SFN demonstrates an ability to protect human lens cells against oxidative stress and thus could potentially delay the onset of cataract. PMID- 23812494 TI - Associations between self-rated vision score, vision tests, and self-reported visual function in the Salisbury Eye Evaluation Study. AB - PURPOSE: We attempt to understand the determinants of self-rated vision status by examining associations with vision tests, self-reported visual function, demographic, and health-status characteristics. METHODS: Participants included 2467 individuals, aged 65 to 84 years, in a longitudinal, population-based cohort study. Participants rated their vision status from 0 to 10. Visual acuity, contrast sensitivity, stereoacuity, and visual fields were assessed. The Activities of Daily Vision Scale (ADVS) questionnaire was administered. Multivariate ordinal and multinomial logistic-regression models examined the association of demographic, health-status characteristics, vision tests, and ADVS subscales with self-rated vision status score. Odds ratios described the association of these characteristics with reporting better vision status. RESULTS: Better visual acuity, contrast sensitivity, stereoacuity, and visual fields were associated with increased odds of reporting better vision status. Among the vision tests, a 2-line increase in visual acuity was most likely to result in an individual reporting better vision status (odds ratio, 1.49; 95% confidence interval [CI], 1.30-1.70). A 5-point increase in the near vision and far vision ADVS subscale scores was associated with increased odds of reporting good versus poor vision status. A 5-point increase in the near vision subscale was most likely to result in an individual reporting good versus poor vision status (odds ratio, 1.38; 95% CI, 1.28-1.50). CONCLUSIONS: Self-rated vision status is a multidimensional measure. Near-vision visual function, visual acuity, and contrast sensitivity are important determinants of self-rated vision status in an elderly population. This understanding may improve the ability of eye care providers to maximize self-rated vision status among their patients. PMID- 23812495 TI - Supporting patients with low health literacy: what role do radiation therapists play? AB - PURPOSE: Health literacy plays a key role in a patient's ability to use health information and services, and can affect health outcomes. This study aimed to explore radiation therapists' perspectives on how they support people with lower health literacy who are undergoing radiotherapy. METHODS: Semi-structured interviews were conducted with 25 radiation therapists working in radiation oncology departments in New South Wales, Australia. RESULTS: The four key themes were (1) the process of identifying a patient with low health literacy, (2) the perceived consequences of low health literacy, (3) managing and responding to the needs of different health literacy groups and (4) recommendations to address low health literacy in radiotherapy. Radiation therapists appeared to make an informal, intuitive judgment about a patient's health literacy, using a variety of verbal and non-verbal cues as well as impromptu conversations with the multi disciplinary team. Patients perceived to have lower health literacy were described as having greater difficulties assimilating knowledge and engaging in self-care. Although participants reported communicating to patients at a basic level initially, they subsequently tailored their communication to match a patient's health literacy. Strategies reported to communicate to low health literacy groups ranged from using lay language with minimal medical terminology, using visual aids (photos), using analogies, reiterating information and asking family members with higher literacy to attend consultations. CONCLUSION: A more structured approach to supporting patients with low health literacy and integrating health literacy training in radiation oncology departments may help to minimise the adverse outcomes typically experienced by this population. PMID- 23812496 TI - Lower limb lymphedema in gynecological cancer survivors--effect on daily life functioning. AB - PURPOSE: Lower limb lymphedema (LLL) is a common condition after pelvic cancer treatment but few studies have evaluated its effect on the quality of life and its consequences on daily life activities among gynecological cancer survivors. METHODS: We identified a cohort of 789 eligible women, treated with pelvic radiotherapy alone or as part of combined treatment of gynecological cancer, from 1991 to 2003 at two departments of gynecological oncology in Sweden. As a preparatory study, we conducted in-depth interviews with gynecological cancer survivors and constructed a study-specific questionnaire which we validated face to-face. The questionnaire covered physical symptoms originating in the pelvis, demographic, psychological, and quality of life factors. In relation to the lymph system, 19 questions were asked. RESULTS: Six hundred sixteen (78 %) gynecological cancer survivors answered the questionnaire and participated in the study. Thirty-six percent (218/606) of the cancer survivors reported LLL. Overall quality of life was significantly lower among cancer survivors with LLL. They were also less satisfied with their sleep, more worried about recurrence of cancer, and more likely to interpret symptoms from the body as recurrence. Cancer survivors reported that LLL kept them from physical activity (45 %) and house work (29 %) and affected their ability to partake in social activities (27 %) or to meet friends (20 %). CONCLUSION: Lower limb lymphedema has a negative impact on quality of life among gynecological cancer survivors, affecting sleep and daily life activities, yet only a few seek professional help. PMID- 23812497 TI - Risk stratification of metastatic recurrence in invasive upper urinary tract carcinoma after radical nephroureterectomy without lymphadenectomy. AB - PURPOSE: To assess the risk factors of metastasis relapse in pT2-3 upper tract urothelial carcinomas (UTUCs) treated by radical nephroureterectomy (RNU) without lymphadenectomy (LN). METHODS: A multicentric retrospective study was performed for pT2-3 pNx UTUCs treated by RNU between 1995 and 2010. The following criteria were retrieved: age, gender, American Society of Anaesthesiologists physical status, surgical approach, preoperative hydronephrosis, stage, grade, tumor location, surgical margin, lymphovascular invasion (LVI) status and outcomes. Metastasis-free survival (MFS) was measured by Kaplan-Meier method with the log rank test. RESULTS: Overall, 151 patients were included. The median follow-up was 18.5 months (IQR 9.5-37.9). The 2- and 5-year MFS were 69 % +/- 4.5 and 54.1 % +/ 5.8, respectively. In univariate analysis, ureteral location, pT3 stage, positive LVI status and positive surgical margin were significantly associated with worse MFS (p = 0.03; 0.02; 0.01 and 0.006, respectively). In the multivariate analysis of ureteral location and pT3 stage were independent prognostic factors (p = 0.03 and 0.03, respectively). Based on the results of the univariate analysis, we proposed a risk model predicting MFS, which classifies patients into 3 categories with different overall survival (p < 0.001). CONCLUSION: In view of our data, tumor location, T stage, LVI and surgical margin status are mandatory to predict survival in case of RN without LN. Contingent upon external validation, our risk model based on these variables could be useful to provide relevant information concerning metastasis relapse probability and necessity of close follow-up for these patients. PMID- 23812498 TI - Molecular cloning and identification of the transcriptional regulatory domain of the goat neurokinin B gene TAC3. AB - Neurokinin B (NKB), encoded by TAC3, is thought to be an important accelerator of pulsatile gonadotropin-releasing hormone release. This study aimed to clarify the transcriptional regulatory mechanism of goat TAC3. First, we determined the full length mRNA sequence of goat TAC3 from the hypothalamus to be 820 b, including a 381 b coding region, with the putative transcription start site located 143-b upstream of the start codon. The deduced amino acid sequence of NKB, which is produced from preproNKB, was completely conserved among goat, cattle, and human. Next, we cloned 5'-upstream region of goat TAC3 up to 3400 b from the translation initiation site, and this region was highly homologous with cattle TAC3 (89%). We used this goat TAC3 5'-upstream region to perform luciferase assays. We created a luciferase reporter vector containing DNA constructs from -2706, -1837, -834, 335, or -197 to +166 bp (the putative transcription start site was designated as +1) of goat TAC3 and these were transiently transfected into mouse hypothalamus derived N7 cells and human neuroblastoma-derived SK-N-AS cells. The luciferase activity gradually increased with the deletion of the 5'-upstream region, suggesting that the transcriptional suppressive region is located between -2706 and -336 bp and that the core promoter exists downstream of -197 bp. Estradiol treatment did not lead to significant suppression of luciferase activity of any constructs, suggesting the existence of other factor(s) that regulate goat TAC3 transcription. PMID- 23812499 TI - Oxidic materials: an endless frontier. AB - Selected areas of heterogeneous catalysis involving nanoporous oxides in the context of clean technology, green chemistry and sustainability are highlighted in this overview. So also is the potential of oxidic membranes in the context of producing hydrogen from water at high temperatures; and a brief survey is given of strategies that are required for the design of better oxidic photocatalysts for the conversion of visible light to H2 and O2. Aspects of physico-chemical characterization of advanced oxidic materials are also outlined. PMID- 23812500 TI - Modified LeFort colpocleisis: clinical outcome and patient satisfaction. AB - OBJECTIVES: The purpose of this study was to determine the anatomical and functional outcomes, as well as patients' satisfaction and morbidity associated with modified LeFort colpocleisis. STUDY DESIGN: Between 7/2007 and 6/2011 58 patients underwent a modified LeFort colpocleisis. Thirty-eight were available for follow-up visit. Records were reviewed for patients' characteristics, operative data and incidence of complications. The follow-up visit comprised a medical history and a gynecological examination. A visual-analog-scale to assess patients' quality of life after surgery was used. The patients were asked: "Would you again choose to have this surgery performed?" and "Do you regret choosing to have a vaginal closure procedure?" Statistical analysis was performed using R version 2.12.1, R Foundation for Statistical Computing, Vienna, Austria. RESULTS: There were no treatment failures within a mean follow-up of 14 months (range 3-41 months). 89% of patients reported an improved quality of life postoperatively. No complications occurred intraoperatively and none of the patients regretted the loss of sexual function. All patients stated that they would choose to have the colpocleisis procedure again. Postoperatively 8 urinary tract infections, 2 hematomas and 1 pyometra occurred. Two patients complained about stress urinary incontinence and another one about an overactive bladder. CONCLUSION: The study highlights an additional safe and effective option for an individualized treatment of pelvic organ prolapse. PMID- 23812501 TI - Unexpected labor and successful twin birth to a pure gonadal dysgenetic woman. PMID- 23812502 TI - Trigonometric regressive spectral analysis: an innovative tool for evaluating the autonomic nervous system. AB - Biological rhythms, describing the temporal variation of biological processes, are a characteristic feature of complex systems. The analysis of biological rhythms can provide important insights into the pathophysiology of different diseases, especially, in cardiovascular medicine. In the field of the autonomic nervous system, heart rate variability (HRV) and baroreflex sensitivity (BRS) describe important fluctuations of blood pressure and heart rate which are often analyzed by Fourier transformation. However, these parameters are stochastic with overlaying rhythmical structures. R-R intervals as independent variables of time are not equidistant. That is why the trigonometric regressive spectral (TRS) analysis--reviewed in this paper--was introduced, considering both the statistical and rhythmical features of such time series. The data segments required for TRS analysis can be as short as 20 s allowing for dynamic evaluation of heart rate and blood pressure interaction over longer periods. Beyond HRV, TRS also estimates BRS based on linear regression analyses of coherent heart rate and blood pressure oscillations. An additional advantage is that all oscillations are analyzed by the same (maximal) number of R-R intervals thereby providing a high number of individual BRS values. This ensures a high confidence level of BRS determination which, along with short recording periods, may be of profound clinical relevance. The dynamic assessment of heart rate and blood pressure spectra by TRS allows a more precise evaluation of cardiovascular modulation under different settings as has already been demonstrated in different clinical studies. PMID- 23812504 TI - On the chemical bonding features in boron containing compounds: a combined QTAIM/ELF topological analysis. AB - The nature of chemical bonding in four classes of boron-containing compounds has been investigated using two topological approaches: the "quantum theory of atoms in molecules (QTAIM)" and "electron localization function (ELF)". It has been shown that the bonding in these compounds could be described in terms of familiar schemes (covalent single, double or triple bonds, dative bond, etc.) and be rationalized from the QTAIM tools. The ELF analysis is the bridge between two worlds: classical donor-acceptor and delocalization in the one hand, and the quantum chemical concepts obtained from the charge and its Laplacian topology. Particularly, we have shown that: (1) in the case of boron-boron bonding, although the V(B,B) basins are similar to the V(C,C) ones, but the V(B,B) population is always smaller than the corresponding V(C,C). (2) In the planar tetracoordinate boron species, each boron atom is characterized by three chemical bonds despite four neighboring atoms. (3). In the [RuH2(eta(2):eta(2) H2BMes)(PCy3)2] compound, the B-Ru bonding belongs to the closed-shell interaction, and there is no BCP between the hydrogen bridge atoms (H(B)) and the ruthenium center despite the close contact of the atoms. (4) In the case of the XH...M...HX hydrogen bonding, we found a complex bonding mode involving not only the two hydrogen atoms, but also the two boron atoms. The presence of an RCP in the center of the B-H-Cr-H-B five-membered cycle confers to the compound the potential to evolve under perturbation. PMID- 23812503 TI - MICE models: superior to the HERG model in predicting Torsade de Pointes. AB - Drug-induced block of the cardiac hERG (human Ether-a-go-go-Related Gene) potassium channel delays cardiac repolarization and increases the risk of Torsade de Pointes (TdP), a potentially lethal arrhythmia. A positive hERG assay has been embraced by regulators as a non-clinical predictor of TdP despite a discordance of about 30%. To test whether assaying concomitant block of multiple ion channels (Multiple Ion Channel Effects or MICE) improves predictivity we measured the concentration-responses of hERG, Nav1.5 and Cav1.2 currents for 32 torsadogenic and 23 non-torsadogenic drugs from multiple classes. We used automated gigaseal patch clamp instruments to provide higher throughput along with accuracy and reproducibility. Logistic regression models using the MICE assay showed a significant reduction in false positives (Type 1 errors) and false negatives (Type 2 errors) when compared to the hERG assay. The best MICE model only required a comparison of the blocking potencies between hERG and Cav1.2. PMID- 23812505 TI - Long-term liposteroid therapy for idiopathic pulmonary hemosiderosis. AB - Control of refractory bleeding in idiopathic pulmonary hemosiderosis (IPH) is challenging. Based on the effect of liposteroid (dexamethasone palmitate) for acute bleeding in two reported cases, the long-term utility was assessed in all nine IPH children (including the first two cases) treated in a tertiary center for 20 years. The median at disease onset was 2.3 years (range, 1.2 to 8.6). All had life-threatening and/or repetitive bleeding on prednisolone (PSL) therapy. Liposteroid was intravenously infused at 0.8 mg/kg/day for three consecutive days at the time of acute bleeding. Single infusion was followed by a longer interval from weekly to monthly accompanied by low-dose PSL (less than 0.3 mg/kg/day). Monthly infusion as maintenance therapy was continued for prophylaxis of bleeding. Treatment outcomes were retrospectively analyzed. During the observation period of a median of 11.0 years (range 2.4-16.9 years), no one died. Five patients were weaned and the other one was being weaned from liposteroid for the cure or long remission (median, 5.5 years). Three others were on liposteroid therapy because of active disease. Neither patient had respiratory symptoms, although three showed subnormal %vital capacity. Serum levels of KL-6 and ferritin were normal in all and all but one patient(s), respectively. Four patients (three on liposteroid therapy) showed low bone mineral density. There were no obese patients. Height SD score did not significantly decrease except for one patient. CONCLUSION: The liposteroid therapy might improve the survival of IPH patients with reducing the adverse effects of steroids, although prospective control studies are needed. PMID- 23812506 TI - Clinical efficacy of gabexate mesilate for acute pancreatitis in children. AB - Children with acute pancreatitis have been treated by fasting and parenteral nutritional support, and to date, the efficacy of drugs for acute pancreatitis in children is unclear. Gabexate mesilate is a synthetic serine protease inhibitor used to prevent or treat acute pancreatitis in adult patients. The purpose of this study was to evaluate the clinical efficacy of gabexate for acute pancreatitis in children. Fifty-three children hospitalized with acute pancreatitis between 2004 and 2012 were divided between a gabexate-treated group (n = 26) and a control group without gabexate infusion (n = 27). The severity of acute pancreatitis was graded according to Balthazar scoring of computed tomography images. All subjects had a Balthazar score of <4 without pancreatic necrosis or organ failure. The median age of the patients was 11.8 years (range, 18 months-17 years). The durations of hospitalization, abdominal pain, and parenteral nutrition in the gabexate-treated group were significantly shorter than in control subjects (P = 0.032, P = 0.000, and P = 0.016, respectively). Serum levels of amylase and lipase were significantly lower in gabexate-infused children than in control subjects on day 7 (median amylase, 81 vs. 137 IU/L, P = 0.001; median lipase, 273 vs. 523 IU/L, P = 0.031). CONCLUSION: The present study showed that gabexate infusion has some clinical benefits for acute pancreatitis in children. The clinical application of gabexate for managing acute pancreatitis in children may be appropriate beyond conventional therapy. PMID- 23812507 TI - Retinal haemorrhage in an infant following an accidental fall--a case report. PMID- 23812508 TI - Dyssynchronous ventricular contraction in Wolff-Parkinson-White syndrome: a risk factor for the development of dilated cardiomyopathy. AB - Emerging evidence suggests that significant left ventricular dysfunction may arise in right-sided septal or paraseptal accessory pathways (APs) with Wolff Parkinson-White syndrome, even in the absence of recurrent or incessant tachycardia. During 1 year and 9 months, we identified four consecutive female children with median age of 8 years diagnosed as having dilated cardiomyopathy (DCM) combined with overt right-sided APs several years ago. Incessant or recurrent tachycardia as the cause of DCM could be excluded. Anti-heart failure chemotherapy did not produce satisfactory effects. The patients underwent radiofrequency ablations (RFCAs). This report describes the clinical and echocardiographic characteristics of the cases before and after the ablation. Dyssynchronous ventricular contraction was observed in all patients. The locations of the APs were the right-sided anteroseptum and the free wall (n = 2 each). All patients received successful RFCAs. Their physical activities and growth improved greatly, and the echocardiographic data demonstrated that their left ventricular (LV) contraction recovered to synchrony shortly after the ablation and that their LV function recovered to normal gradually during the follow-up. CONCLUSIONS: A causal relationship between overt ventricular preexcitation and the development of DCM is supported by the complete recovery of LV function and reversed LV remodeling after the loss of ventricular preexcitation. Preexcitation-related dyssynchrony was probably the crucial mechanism. Not only right-sided septal or paraseptal but also free wall overt APs may induce LV dysfunction and even DCM. AP-induced DCM is an indication for ablation with a good prognosis. PMID- 23812509 TI - Blood parameters changes in cord blood of newborns of hypertensive mothers. AB - The aim of this study was to investigate the changes in the peripheral blood of newborns of hypertensive mothers. The umbilical cord blood from newborns of 31 hypertensive mothers and 32 healthy mothers were examined. In all subjects, complete blood count, peripheral blood smear, reticulocyte count, vitamin B12, folate, ferritin levels and hemoglobin electrophoresis were performed. The subjects were followed up on for 1 year in terms of infections. RBC, hemoglobin, reticulocyte count and normoblast count were higher in the newborns of hypertensive mothers compared to the control group, and total leukocytes, neutrophil, lymphocyte, monocyte, eosinophil, and thrombocyte counts were lower. The number of neutropenic and thrombocytopenic subjects in newborns of hypertensive mothers was higher compared to the control group. On peripheral smears, dysplastic changes in neutrophils and erythrocytes were observed with a higher rate in newborns of hypertensive mothers compared to the control group. HbF levels were found to be higher in newborns of hypertensive mothers compared to the control group. During the follow-up period of 1 year, the number of infections in newborns of hypertensive mothers was found to be higher than the control group. CONCLUSION: Newborns of hypertensive mothers should be carefully evaluated and monitored in terms of hematologic abnormalities. Complete blood counts and peripheral blood smears can be used as significant parameters for early diagnosis of possible complications. PMID- 23812511 TI - Leishman-Donovan bodies at bone marrow examination. AB - Leishmaniasis is a parasitic disease and often seen in developing countries and tropic areas. Visceral leishmaniasis (VL) is the most severe form of this disease, which is fatal if left untreated. In this report, we describe an 11 month-old infant with poor growth, pancytopenia, and splenomegaly. Microscopic examination of bone marrow revealed intracellular and extracellular Leishmania amastigotes. VL should be considered when a child presents with fever, failure to thrive, organomegaly, and pancytopenia. PMID- 23812510 TI - Myocardial performance in children with autoimmune hepatitis: Doppler tissue imaging study. AB - Autoimmune hepatitis (AIH) is a member of autoimmune diseases family which can increase risk of cardiovascular morbidity and mortality. This study aimed to assess subclinical impact of AIH on global myocardial performance in affected children using Doppler tissue imaging (DTI) and to correlate it with total serum immunoglobulin-G (IgG). Thirty children with AIH (mean age = 12.67 +/- 2.9 years) was included as the study group and 20 age- and sex-matched healthy children (mean age = 11.93 +/- 2.66 years) as the control group. Conventional two dimensional echocardiography was performed to both groups and DTI were used to determine right ventricular (RV) and left ventricular (LV) Tei indexes. Total serum IgG levels at initial diagnosis of AIH were correlated to the cardiac functions of AIH patients. RV and LV Tei indexes were significantly higher in AIH group (mean +/- SD: 0.46 +/- 0.088 vs. 0.26 +/- 0.01, P < 0.0001 and 0.45 +/- 0.086 vs. 0.31 +/- 0.02, P < 0.0001, respectively). Also, total IgG concentrations were correlated positively with the LV Tei index (r = 0.69, P < 0.0001) and with the RV Tei index (r = 0.61, P < 0.0003) and correlated negatively with the mitral systolic (Sm) velocity (r = -0.76, P < 0.0001) and with tricuspid systolic (Sm) velocity (r = -0.66, P < 0.0001). On the other hand, fractional shortening did not correlate with serum IgG concentrations (r = -0.04, P = 0.821). In conclusion, the DTI technique appears to be more sensitive than conventional echocardiography in the early detection of myocardial dysfunction in AIH children. PMID- 23812512 TI - Propranolol is more effective than pulsed dye laser and cryosurgery for infantile hemangiomas. AB - Propranolol hydrochloride is a nonselective beta-blocker that is used for the treatment of hypertension, arrhythmia, and angina pectoris. In Japan, it was recently approved for the treatment of childhood arrhythmia. It has been observed to produce drastic involution of infantile hemangiomas. The aim of this prospective study was to examine propranolol's superiority to classical therapy with pulsed dye laser and/or cryosurgery in treating proliferating infantile hemangiomas. Fifteen patients between the ages of 1 and 4 months with proliferating infantile hemangiomas received grinded propranolol tablets 2 mg/kg per day divided in three doses. Twelve patients with proliferating infantile hemangiomas receiving pulsed dye laser and/or cryosurgery were enrolled as controls. Baseline electrocardiogram, echocardiogram, and chest x-ray were performed. Monitoring of heart rate, blood pressure, and blood glucose was performed every 2 weeks. Efficacy was assessed by performing blinded volume measurements and taking photographs at every visit. Propranolol induced significantly earlier involution and redness reduction of infantile hemangiomas, compared to pulsed dye laser and cryosurgery. Adverse effects such as hypoglycemia, hypotension, or bradycardia did not occur. CONCLUSION: The dramatic response of infantile hemangiomas to propranolol and few side effects suggest that early treatment of infantile hemangiomas could result in decreased disfigurement. Propranolol should be considered as a first-line treatment of infantile hemangiomas. PMID- 23812513 TI - Randomized controlled trial of topical EMLA and breastfeeding for reducing pain during wDPT vaccination. AB - The primary objective was to evaluate the analgesic effect of a eutectic mixture of local anesthetics (EMLA) during whole cell DPT vaccination. The secondary objective was to evaluate if the analgesic effect of EMLA was synergistic to breastfeeding. A randomized, placebo-controlled trial was done to include infants of up to 3 months of age who came for their first DPT vaccination. The outcome variables were duration of cry, latency of onset of cry, and Modified Facial Coding Score. Thirty babies were enrolled in each of three groups. The groups did not differ significantly in baseline characteristics. Median (interquartile range) of duration of cry was least [34.6 (24.1-72.2) s] in babies receiving EMLA cream with breastfeeding (EB group), followed by 94.2 (46.1-180) s in babies receiving EMLA cream with oral distilled water (EW group), as compared to 180.0 (180-180) s in babies receiving placebo cream with oral distilled water (PCW group) (p < 0.05). Mean (SD) of latency of cry was significantly greater in EB group [2.4 (1.14) s] and EW group [1.9 (0.62) s] as compared to babies in PCW group [1.5 (0.47) s] (p < 0.05), but the difference between EB and EW groups was not significant. Modified Facial Coding Score was significantly lower in EB group as compared to the other groups (p < 0.05). CONCLUSIONS: Topical EMLA is effective in reducing pain and has a synergistic effect in analgesia when combined with breastfeeding during vaccination in infants. PMID- 23812514 TI - Parental TV viewing, parental self-efficacy, media equipment and TV viewing among preschool children. AB - This study examined if parental TV viewing, parental self-efficacy or access to media equipment were associated with TV viewing among UK preschool-aged children. Data were derived from a cross-sectional survey of 252 parents of 3-5-year-old children. Parents reported child and parent TV viewing and the number of TVs, DVDs, computers, games consoles, hand-held games consoles, music players and laptop computers in the home. Parents also completed scales which assessed their self-efficacy to limit the screen viewing (SV) and promote the physical activity (PA) and their own PA self-efficacy. Analysis indicated that around two thirds of the children spent two or more hours per day watching TV while 75 % of parents watched >= 2 h of TV per day. Logistic regression models showed that children who had a parent who watched >= 2 h of TV per day were over five times more likely to also watch >= 2 h of TV per day. Each unit increase in parental self-efficacy to limit SV was associated with a 77 % reduction in the likelihood that the child watched >= 2 h of TV per day. Each additional piece of media equipment in the home was associated with a 28 % increase in the likelihood that parents watched >= 2 h of TV per day. CONCLUSION: Family-based interventions focusing on changing access to home media equipment and building parental self-efficacy to reduce child TV viewing could form part of efforts to reduce TV viewing among preschool children. PMID- 23812515 TI - Epidermal inclusion cyst of the soft palate and uvula in an infant. AB - Congenital epidermal inclusion cysts of the soft palate or the uvula are uncommon mass lesions, and there have been only limited case reports of these in the literature. Although epidermal cysts are benign in nature and develop slowly, mass lesions growing near the soft palate or the uvula can result in velopharyngeal insufficiency, affecting both speech and swallowing. We present such a condition in a 7-month-old male infant with an epidermal inclusion cyst involving both the soft palate and the uvula. PMID- 23812516 TI - Effects of infant cereals with different carbohydrate profiles on colonic function--randomised and double-blind clinical trial in infants aged between 6 and 12 months--pilot study. AB - Infant cereals are often the elected foodstuff for beginning complementary feeding and provide carbohydrates which are different to those found in maternal milk. The objective of this preliminary study was to ascertain the colonic effects of two infant cereals, with different carbohydrate profiles, in a randomised and double-blind trial in healthy infants. Nineteen term infants between 6.3 and 9.8 months of age were enrolled, after written informed consent was obtained from parents. Ten subjects were allocated to take infant cereal A and nine, infant cereal B. An intervention period was 2 months, with five visits every 15 days, to take anthropometric measurements and faeces samples for the analysis of microbiota, short-chain fatty acids concentration (SCFA), pH value and secretory immunoglobulin A (sIgA). An adequate growth and stool frequency was registered in both intervention groups. Faecal counts of Bifidobacterium, Lactobacillus, Enterobacteriaceae, Enterococcus, Clostridium and Bacteroides did not show any statistical differences. However, a significantly (P < 0.05) higher butyric acid and sIgA, and lower faecal pH were observed in infants who had ingested infant cereal A, with a higher ratio complex/simple carbohydrates. In conclusion, small changes in the carbohydrate profile of infant cereals could lead to significant differences in parameters related to fermentative activity of intestinal microbiota. PMID- 23812517 TI - [Increased VEGFR-1 immunoreactivity in the choroid-scleral complex in hypercholesterolemia experimental model]. AB - PURPOSE: The aim of this study is to investigate the expression of vascular endothelial growth factor (VEGF) in the choroid and sclera using hypercholesterolemia experimental model. METHODS: New Zealand rabbits were divided into two groups: 8 rabbits (8 eyes), in the normal diet group (NG), were fed by a standard diet for 4 weeks; and 13 rabbits (13 eyes), in the hypercholesterolemic group (HG), were fed by a 1% cholesterol-enriched diet for 8 weeks. Total serum cholesterol, triglyceride, HDL cholesterol and fasting blood glucose exams were performed at the initiation of the experiment and at the euthanasia time. After hypercholesterolemic group 8th week and NG 4th week, animals were euthanized and their eyes underwent immunohistochemical analysis with the RAM-11 and VEGFR-1). RESULTS: The diet has induced a significant increase in total cholesterol and triglyceride levels in HG when compared with NG (p<0.001). There was a significant increase in the RAM-11 and VEGFR-1 expressions in hypercholesterolemic group choroid and sclera in relation to NG (p<0,001). CONCLUSION: This study has revealed that the hypercholesterolemic diet in rabbits induces an increase in the macrophage concentration and immunoreactivity to VEGFR 1 in the choroid and sclera, resembling human age-related macular degeneration (ARMD). PMID- 23812518 TI - The need for artificial tears in glaucoma patients: a comparative, retrospective study. AB - PURPOSE: To evaluate the need for artificial tears by glaucoma patients under topical hypotensive treatment and to identify risk factors associated with it. METHODS: The charts of 175 glaucoma patients under medical treatment and 175 age matched controls were reviewed. Age, gender, use of artificial tears, number of glaucoma medications used, and duration of treatment were recorded. RESULTS: Significantly more glaucoma patients (n=92; 52.6%) used artificial tears compared to age-matched controls (n=31; 17.7%) (p<0.001). Significantly more females (n=81; 39%) than males (n=42; 28.9%) used artificial tears (p=0.036). When the whole population was analyzed, female gender (OR=1.63) and the presence of glaucoma (OR= 5.14) were risk factors for the use of artificial tears (p<0.05). When the glaucoma population was analyzed, female gender (OR=2.57), number of medications >2 (OR=1.92), and duration of treatment >5 years (OR=2.93) were risk factors for the use of artificial tears (p<0.05). CONCLUSIONS: Topical treatment with antiglaucoma medication is a risk factor for the use of artificial tears. Female gender and long-term treatment of glaucoma with two or more medications were aggravating factors for the need for artificial tears. PMID- 23812519 TI - The correlation between body mass index and intraocular pressure in children. AB - PURPOSE: There is evidence from some studies that support an association between obesity in adults and higher intraocular pressure (IOP). However, this association has not been completely studied in children. Our aim is to evaluate the association between child body mass index (BMI) and IOP. METHODS: Ninety-six children attending the Instituto de Medicina Integral Prof. Fernando Figueira (IMIP) in Brazil were studied. Thirty-three were overweight/obese with a mean BMI of 29.7 +/- 5.2 and 63 with a mean BMI of 20.8 +/- 3.3. IOP was measured using the Goldmann applanation tonometer and was corrected for corneal thickness. The coefficient of correlation between BMI and IOP was calculated. RESULTS: There was no significant difference in the IOP of children with or without overweight/obesity. The mean IOP was 13.5 and 13.0 mmHg for the right eye and 13.1 and 12.9 mmHg for left eye, respectively (p=0.38 and p=0.71). The results remained the same after correction by pachymetry; 13.0 and 13.1 mmHg for the right eye and 12.4 and 12.9 mmHg for the left eye, respectively (p=0.88 and p=0.41). The coefficient of correlation between BMI and IOP was 0.070 (p=0.496). CONCLUSION: These results do not show a correlation between body mass index and IOP in children. Further studies are warranted to clarify the association between BMI and IOP in children. PMID- 23812520 TI - Composition of intraocular foreign bodies: experimental study of ultrasonographic presentation. AB - PURPOSE: To investigate the reliability of ultrasound in determining the size and identify the sonographic features and artifacts generated by intraocular foreign bodies of different materials. METHODS: Experimental study using 36 enucleated porcine eyes. Fragments of nine different compositions (wood, glass, plastic, cardboard, iron, aluminum, lead, powder and concrete) and similar dimensions (4 mm) were implanted via scleral incision into the vitreous cavity of 36 porcine eyes, four eyes were used for each material. Ultrasound examination was performed in all eyes using the contact technique, conductive gel and 10-MHz transducer (EZScan, Sonomed). RESULTS: Considering the material fragments of gunpowder, lead, concrete, aluminum, wood and glass, the size determined by ultrasound was considered statistically similar to the actual size. The material iron presented ultrasound-determined dimension statistically smaller than its actual size. Cardboard and plastic materials showed ultrasound-determined measurements far greater than the actual. All fragments of intraocular foreign bodies demonstrated hyper-reflective interfaces, irrespective of their composition. Whereas the artifacts generated by different materials, it was found that the materials iron, aluminum and lead showed reverberation of great extent. The material wood showed no reverberation. The length of the reverberation artifact for the materials iron, glass, aluminum and cardboard was lower when compared to other materials. All materials presented posterior shadowing artifact, with the exception of aluminum. CONCLUSION: Ultrasonography was considered a reliable technique to determine the size of intraocular foreign bodies in pigs, with little influence caused by its composition. Ultrasound artifacts generated were considered material-dependent and can assist the examiner to identify the nature of a foreign body of unknown etiology. Ultrasonography aided the surgeon to identify, locate and measure the intraocular foreign body, directing appropriate surgical planning. PMID- 23812521 TI - Panretinal photocoagulation versus intravitreal injection retreatment pain in high-risk proliferative diabetic retinopathy. AB - PURPOSE: To compare pain related to intravitreal injection and panretinal photocoagulation in the management of patients with high-risk proliferative diabetic retinopathy. METHODS: Prospective study including patients with high risk proliferative diabetic retinopathy and no prior laser treatment randomly assigned to receive panretinal photocoagulation (PRP group) or panretinal photocoagulation plus intravitreal ranibizumab (PRPplus group). In all patients, panretinal photocoagulation was administered in two sessions (weeks 0 and 2), and intravitreal ranibizumab was administered at the end of the first laser session in the PRPplus group. Retreatment was performed at weeks 16 and 32 if active new vessels were detected at fluorescein angiography. Patients in the PRPplus group received intravitreal ranibizumab and patients in the PRP group received 500-um additional spots per quadrant of active new vessels. After the end of retreatment, a 100-degree Visual Analog Scale was used for pain score estimation. The patient was asked about the intensity of pain during the whole procedure (retinal photocoagulation session or intravitreal ranibizumab injection). Statistics for pain score comparison were performed using a non-parametric test (Wilcoxon rank sums). RESULTS: Seventeen patients from PRPplus and 14 from PRP group were evaluated for pain scores. There were no significant differences between both groups regarding gender, glycosylated hemoglobin and disease duration. Mean intravitreal injection pain (+/-SEM) was 4.7 +/- 2.1 and was significantly lower (p<0.0001) than mean panretinal photocoagulation pain (60.8 +/- 7.8). Twelve out of 17 patients from the PRPplus group referred intensity pain score of zero, while the minimal score found in PRP group was found in one patient with 10.5. CONCLUSION: In patients with high-risk proliferative diabetic retinopathy who needed retreatment for persistent new vessels, there was more comfort for the patient when retreatment was performed with an intravitreal injection in comparison with retinal photocoagulation. Further larger studies are necessary to confirm our preliminary findings. PMID- 23812522 TI - Clinical trials in Brazilian journals of ophthalmology: where we are. AB - PURPOSE: To compare clinical trials published in Brazilian journals of ophthalmology and in foreign journals of ophthalmology with respect to the number of citations and the quality of reporting [by applying the Consolidated Standards for Reporting Trials (CONSORT) statement writing standards]. METHODS: The sample of this systematic review comprised the two Brazilian journals of ophthalmology indexed at Science Citation Index Expanded and six of the foreign journals of ophthalmology with highest Impact Factor(r) according ISI. All clinical trials (CTs) published from January 2009 to December 2010 at the Brazilians journals and a 1:1 randomized sample of the foreign journals were included. The primary outcome was the number of citations through the end of 2011. Subgroup analysis included language. The secondary outcome included likelihood of citation (cited at least once versus no citation), and presence or absence of CONSORT statement indicators. RESULTS: The citation counts were statistically significantly higher (P<0.001) in the Foreign Group (10.50) compared with the Brazilian Group (0.45). The likelihood citation was statistically significantly higher (P<0.001) in the Foreign Group (20/20 - 100%) compared with the Brazilian Group (8/20 - 40%). The subgroup analysis of the language influence in Brazilian articles showed that the citation counts were statistically significantly higher in the papers published in English (P<0.04). Of 37 possible CONSORT items, the mean for the Foreign Group was 20.55 and for the Brazilian Group was 13.65 (P<0.003). CONCLUSION: The number of citations and the quality of reporting of clinical trials in Brazilian journals of ophthalmology still are low when compared with the foreign journals of ophthalmology with highest Impact Factor(r). PMID- 23812523 TI - Influence of English language in the number of citations of articles published in Brazilian journals of ophthalmology. AB - PURPOSE: To determine the association between language and number of citations of ophthalmology articles published in Brazilian journals. METHODS: This study was a systematic review. Original articles were identified by review of documents published at the two Brazilian ophthalmology journals indexed at Science Citation Index Expanded - SCIE ["Arquivos Brasileiros de Oftalmologia (ABO)" and "Revista Brasileira de Oftalmologia (RBO)"]. All document types ("articles" and "reviews") listed at SCIE in English (English Group) or in Portuguese (Portuguese Group) from January 1, 2008 to December 31, 2009 were included, except: "editorial materials"; "corrections"; "letters"; and "biographical items". The primary outcome was the number of citations through the end of second year after publication date. Subgroup analysis included likelihood of citation (cited at least once versus no citation), journal, and year of publication. RESULTS: The search at the web of science revealed 382 articles [107 (28%) in the English Group and 275 (72%) in the Portuguese Group]. Of those, 297 (77.7%) were published at the ABO and 85 (23.3%) at the RBO. The citation counts were statistically significantly higher (P<0.001) in the English Group (1.51 - SD 1.98 - range 0 to 11) compared with the Portuguese Group (0.57 - SD 1.06 - range 0 to 7). The likelihood citation was statistically significant higher (P<0.001) in the English Group (70/107 - 65.4%) compared with the Portuguese Group (89/275 - 32.7%). There were more articles published in English at the ABO (98/297 - 32.9%) than at the RBO (9/85 - 10.6%) [P<0.001]. There were no significant difference (P=0.967) at the proportion of articles published in English at the years 2008 (48/172 - 27.9%) and 2009 (59/210 - 28.1%). CONCLUSION: The number of citations of articles published in Portuguese at Brazilian ophthalmology journals is lower than the published in English. The results of this study suggest that the editorial boards should strongly encourage the authors to adopt English as the main language in their future articles. PMID- 23812524 TI - [Brazilian trends in refractive surgery]. AB - PURPOSE: To determine preferences and practices of refractive surgeons in Brazil. METHODS: A cross-sectional study was conducted based on the data collected from a questionnaire applied during the VI Brazilian Congress of Cataract and Refractive Surgery and by e-mail sent to all members of that society. Refractive surgery techniques, use of emerging technologies, surgical volume, type of excimer laser and microkeratomes, mitomycin C, postoperative medications were analyzed among others questions. RESULTS: Two hundred ninety-two surgeons replied to the questions. The majority has a surgical volume between 2 and 4 eyes per week (57.60%). Most of the surgeons (64.50%) perform corneal tomography routinely and 22.00% of them do never customize their surgeries. The laser in situ keratomileusis (LASIK) is the main technique performed and when the photorefractive keratectomy (PRK) is applied; most of the surgeons uses mitomycin C (52.60%) in these patients. The excimer laser of choice was the Nidek (26.12%). CONCLUSION: LASIK is the preferred surgical procedure and the majority customizes their refractive surgeries. When photorefractive keratectomy is performed, mitomycin C is used by most of the surgeons (52.60%). Bilateral surgery is routinely performed and the femtosecond laser is still used by few refractive surgeons. PMID- 23812525 TI - [Progressive addition lenses--analysis of intermediate and near vision zones by deflectometry]. AB - PURPOSE: To determine near and intermediate vision areas of progressive addition lenses by means of a deflectometer. METHODS: Twenty-two progressive addition lenses with +1.00 SD far power and two different additions (add 1.00 and 2.00; eleven subjects in each addition) were studied. Near and intermediate vision areas within 0.50 CD isoastigmatic lines were determined. RESULTS: There are significant differences between near and intermediate vision areas of the studied lenses. There is also an inverse correlation between the addition and intermediate areas as well as direct relation between the vertical length of the corridor and its area. CONCLUSION: Based on those findings, progressive addition lenses can be selected to suit the wearer's visual requirements. PMID- 23812526 TI - Assessment of ocular surface toxicity after topical instillation of nitric oxide donors. AB - PURPOSE: To evaluate the ocular surface toxicity of two nitric oxide donors in ex vivo and in vivo animal models: S-nitrosoglutathione (GSNO) and S-nitroso-N acetylcysteine (SNAC) in a hydroxypropyl methylcellulose (HPMC) matrix at final concentrations 1.0 and 10.0 mM. METHODS: Ex vivo GSNO and SNAC toxicities were clinically and histologically analyzed using freshly excised pig eyeballs. In vivo experiments were performed with 20 albino rabbits which were randomized into 4 groups (5 animals each): Groups 1 and 2 received instillations of 150 uL of aqueous HPMC solution containing GSNO 1.0 and 10.0 mM, respectively, in one of the eyes; Groups 3 and 4 received instillations of 150 uL of aqueous HPMC solution-containing SNAC 1.0 and 10.0 mM, respectively, in one of the eyes. The contralateral eyes in each group received aqueous HPMC as a control. All animals underwent clinical evaluation on a slit lamp and the eyes were scored according to a modified Draize eye test and were histologically analyzed. RESULTS: Pig eyeballs showed no signs of perforation, erosion, corneal opacity or other gross damage. These findings were confirmed by histological analysis. There was no difference between control and treated rabbit eyes according to the Draize eye test score in all groups (p>0.05). All formulations showed a mean score under 1 and were classified as "non-irritating". There was no evidence of tissue toxicity in the histological analysis in all animals. CONCLUSION: Aqueous HPMC solutions containing GSNO and SNAC at concentrations up to 10.0 mM do not induce ocular irritation. PMID- 23812527 TI - Bilateral acute depigmentation of the iris (BADI): first reported case in Brazil. AB - Bilateral acute depigmentation of the iris (BADI) is a recently described entity characterized by acute onset of pigment dispersion in the anterior chamber, depigmentation of the iris, and heavy pigment deposition in the anterior chamber angle. Involvement is always bilateral, simultaneous, and symmetrical. We report the case of a 61-year-old man who presented with bilateral ocular pain, red eyes, and severe photophobia. Examination revealed a dense Krukenberg spindle, heavy pigment dispersion in the anterior chamber, extensive transillumination iris defects, and a heavy pigment deposition in the trabecular meshwork bilaterally. Intraocular pressure increased to 48 mmHg in both eyes. The patient received topical steroids, maximum hypotensive treatment and oral valacyclovir. Intraocular pressure gradually decreased throughout the second and third months, and medications were gradually tapered. The time to complete resolution of pigment dispersion was 18 weeks. Visual acuity and visual fields remained normal, but the photophobia was permanent. PMID- 23812528 TI - Idiopathic dilated episcleral vessels (Radius-Maumenee syndrome): case report. AB - Radius-Maumenee syndrome comprises idiopathic dilated episcleral vessels that are usually associated with glaucoma. The case described herein is of a male patient, 69 years old, with chronic dilation of the episcleral vessels and glaucoma in his left eye, with no history of systemic disease. Visual acuity and fundoscopy were normal in both eyes. Tonometry measured 14 mmHg in the right eye and 25 mmHg in the left. Computed tomography angiography (CTA) was negative for carotid cavernous fistula. The intraocular pressure of the left eye decreased to 20 mmHg with clinical treatment without regression of episcleral venous dilation. Trabeculectomy normalized the intraocular pressure and reduced the vessels. There was choroidal effusion on day 16 of the postoperative period, which resolved with corticosteroids. Although choroidal effusion can occur, the efficacy of trabeculectomy in controlling glaucoma and the reduction of episcleral vessels are clearly demonstrated. PMID- 23812529 TI - Topiramate-associated acute, bilateral, angle-closure glaucoma: case report. AB - This paper describes a topiramate induced acute bilateral angle-closure glaucoma. This rare adverse effect is an idiosyncratic reaction characterized by uveal effusion and lens forward displacement, leading to increased intraocular pressure and vision loss. We describe a 55 year-old white woman with migraine, spasmodic torticollis and essential tremor, who developed bilateral acute angle-closure glaucoma, one week after starting topiramate 25 mg/day. She was seen at the Ophthalmology Emergency Department of the Fundacao Joao Penido Burnier (Campinas, SP, Brazil) with a 4 hours history of blurry vision, ocular pain and bright flashes vision. Slit lamp examination revealed moderate conjunctival injection and corneal edema, and shallow anterior chambers. Intraocular pressure was 48 mmHg in both eyes. Fundoscopic examination findings were normal. She was treated with timolol, brimonidine, dorzolamide, pilocarpine, prednisone acetate eye drops and acetazolamide. One hour after those measures, as the intraocular pressure was 30 mmHg, she received a manitol intravenous injection and the intraocular pressure normalized. After 24 hours an iridotomy with Yag laser was performed. Topiramate was discontinued and she was totally recovered after one week. PMID- 23812530 TI - Essential trichomegaly: case report. AB - The present study reports two cases of symptomatic essential trichomegaly. Trichomegaly may develop in various diseases, including anorexia nervosa, hypothyroidism, pregnancy, pretibial myxedema, systemic lupus erythematosus, vernal keratoconjunctivitis, and uveitis. The exact incidence trichomegaly is unknown, and the condition remains sporadically reported. Two cases of symptomatic trichomegaly without any associated systemic disorder are presented in this paper. PMID- 23812531 TI - [Fungal keratitis: review of diagnosis and treatment]. AB - Fungal keratitis is a characteristic infection upon tropical zones, associated with vegetal trauma. Doubt exists about the best diagnostic test and the effectiveness of available treatment. Which is the best diagnostic method for fungal keratitis? And, which is the best management? Fungal culture remains as diagnostic gold standard of fungal elements. As of treatment, natamycin and amphotericin B are the most popular drugs for fungal keratitis and they have not shown effectiveness in randomized controlled trials or systematic reviews. Voriconazole showed effectiveness and security in multiple fungal infections. It may be the drug of choice in optimal conditions, because of its better ocular penetration and wider coverage. However, its high price difficult general application. This review establishes management recommendations and the need to perform studies that address cost-effectiveness analysis of voriconazole for fungal keratitis. PMID- 23812532 TI - Abnormal vascular regulation in the ophthalmic artery of chronic heart failure patients. PMID- 23812533 TI - The language issue in Brazilian ophthalmological journals. PMID- 23812534 TI - Autonomic changes in young smokers: acute effects of inspiratory exercise. AB - PURPOSE: One of the most important consequences of smoking is the development of cardiovascular diseases. However, little is known about the early consequences of smoking and the acute effects of a single inspiratory muscle exercise session (IME). We evaluated the acute effects of an IME on cardiac parameters of young smokers. METHODS: Twelve nonsmokers (C) and fifteen smokers [S; 2.08 (1.0-3.2) pack-years] underwent an acute IME. We evaluated blood pressure (BP) and lactate, and we recorded RR interval for posterior analysis of heart rate variability (HRV), before and after IME. RESULTS: At baseline, systolic BP and HRV parameters in time and frequency domains were changed in S group in comparison with the C. Following IME, S group reduced systolic BP (-8 %), low frequency band (LF) (-21.4 %), LF/high frequency (HF) (-57 %), as well as increased RR variance (+105 %) and HF band. CONCLUSIONS: Our findings indicate that a single session of inspiratory muscle exercise was able to both reduce systolic BP and improve parasympathetic and sympathetic modulations in young smokers. The results of the current study highlight the importance of furthering research on this area to better elucidate the acute and chronic effects of inspiratory muscle training on early cardiovascular and pulmonary changes of cigarette smoking. PMID- 23812535 TI - Extraordinary expansion of a Sorangium cellulosum genome from an alkaline milieu. AB - Complex environmental conditions can significantly affect bacterial genome size by unknown mechanisms. The So0157-2 strain of Sorangium cellulosum is an alkaline adaptive epothilone producer that grows across a wide pH range. Here, we show that the genome of this strain is 14,782,125 base pairs, 1.75-megabases larger than the largest bacterial genome from S. cellulosum reported previously. The total 11,599 coding sequences (CDSs) include massive duplications and horizontally transferred genes, regulated by lots of protein kinases, sigma factors and related transcriptional regulation co-factors, providing the So0157-2 strain abundant resources and flexibility for ecological adaptation. The comparative transcriptomics approach, which detected 90.7% of the total CDSs, not only demonstrates complex expression patterns under varying environmental conditions but also suggests an alkaline-improved pathway of the insertion and duplication, which has been genetically testified, in this strain. These results provide insights into and a paradigm for how environmental conditions can affect bacterial genome expansion. PMID- 23812536 TI - Evaluation of the coracoclavicular reconstruction using LARS artificial ligament in acute acromioclavicular joint dislocation. AB - PURPOSE: The most appropriate procedure for surgical treatment of severe acromioclavicular (AC) joint dislocation was still not clear. The purpose of this study is to evaluate the outcomes of coracoclavicular (CC) reconstruction with ligament augmentation and reconstruction system (LARS) artificial ligaments for the treatment of acute complete AC joint dislocation. METHODS: Twenty-four patients (16 male and 8 female, ages ranged from 21 to 45) with acute complete AC joint dislocations were treated with CC reconstruction using LARS artificial ligaments. All these dislocations were unstable injuries. Clinical evaluation was used by the Constant scores and VAS. The radiographic evaluation consisted of Zanca radiographs for bilateral AC joint and axillary radiographs for the injured shoulder. RESULTS: All patients had follow-up times of 36 months (range 6-60). The Constant scores rose from 62.3 +/- 6.9 preoperatively to 94.5 +/- 9.3 at final evaluation (P < 0.05). Preoperative VAS scores were 5.1 +/- 1.7, and the VAS scores at the last review were 0.7 +/- 1.4 (P < 0.05). Follow-up radiographs showed anatomical reduction in 20 patients and slight loss of reduction in 4 patients. Calcification of CC ligament in 4 patients, degenerative change around the AC joint in 2 patient and clavicular osteolysis around screws in one patient were found. CONCLUSIONS: LARS artificial ligament for reconstruction of CC can provide immediate stability and allow early shoulder mobilization with good functional results and few complications. This procedure was an effective and safe method to treat grade III and more AC joint dislocations. LEVEL OF EVIDENCE: IV. PMID- 23812537 TI - Tbc1d15-17 regulates synaptic development at the Drosophila neuromuscular junction. AB - Members of the Tre-2/Bub2/Cdc16 (TBC) family of proteins are believed to function as GTPase-activating proteins (GAPs) for Rab GTPases, which play pivotal roles in intracellular membrane trafficking. Although membrane trafficking is fundamental to neuronal morphogenesis and function, the roles of TBC-family Rab GAPs have been poorly characterized in the nervous system. In this paper, we provide genetic evidence that Tbc1d15-17, the Drosophila homolog of mammalian Rab7-GAP TBC1d15, is required for normal presynaptic growth and postsynaptic organization at the neuromuscular junction (NMJ). A loss-of-function mutation in Tbc1d15-17 or its presynaptic knockdown leads to an increase in synaptic bouton number and NMJ length. Tbc1d15-17 mutants are also defective in the distribution of the postsynaptic scaffold Discs-large (Dlg) and in the level of the postsynaptic glutamate subunit GluRIIA. These postsynaptic phenotypes are recapitulated by postsynaptic knockdown of Tbc1d15-17. We also show that presynaptic overexpression of a constitutively active Rab7 mutant in a wild-type background causes a synaptic overgrowth phenotype resembling that of Tbc1d15-17 mutants, while a dominant-negative form of Rab7 has the opposite effect. Together, our findings establish a novel role for Tbc1d15-17 and its potential substrate Rab7 in regulating synaptic development. PMID- 23812538 TI - Cosmic-ray astrochemistry. AB - Gas-phase chemistry in the interstellar medium is driven by fast ion-molecule reactions. This, of course, demands a mechanism for ionization, and cosmic rays are the ideal candidate as they can operate throughout the majority of both diffuse and dense interstellar clouds. Aside from driving interstellar chemistry via ionization, cosmic rays also interact with the interstellar medium in ways that heat the ambient gas, produce gamma rays, and produce light element isotopes. In this paper we review the observables generated by cosmic-ray interactions with the interstellar medium, focusing primarily on the relevance to astrochemistry. PMID- 23812539 TI - Anterior cruciate ligament reconstruction with LARSTM artificial ligament results at a mean follow-up of eight years. AB - PURPOSE: The aim of this study was to review patients that underwent ACL reconstruction with the LARSTM ligament in the First Orthopaedic Division of Pisa University during the period between January 2003 and December 2005. METHODS: Twenty-six patients were reviewed with an average follow-up of 95.3 months (7.9 years). The review protocol was articulated in three phases: (1) a subjective evaluation using three grading scales: VAS, KOOS and the Cincinnati knee rating scale, (2) a clinical and objective evaluation, and (3) a biomechanical evaluation of the knee stability. RESULTS: A global positive result was obtained in 92.3 % of the patients (16 optimal results and eight good results), with a fast functional recovery and a high knee stability. A global poor result was reported in two cases. In our series we did not record cases of infection or knee synovitis. We recorded only one case of mechanical graft failure. The results obtained from our study are encouraging and similar to those in the literature. CONCLUSIONS: We conclude that the LARSTM ligament can be considered a suitable option for ACL reconstruction in carefully selected cases, especially for older patients needing a fast functional recovery. PMID- 23812540 TI - [Fusion criteria for cages as vertebral body replacement in thoracolumbar fractures]. AB - BACKGROUND: No commonly accepted criteria to evaluate bony incorporation of cages as vertebral body replacement in thoracolumbar fractures exist. The goal of this study was a thorough radiological evaluation of the fusion process in posterior anterior stabilized fractures. PATIENTS AND METHODS: In this study 35 patients were evaluated radiologically including computed tomography (CT) scanning and bone mineral density measurement inside the cages. Correction loss, cage subsidence and tilting, bone growth in and around the cages as well as bone mineral density were assessed. Fusion grading was assessed with defined criteria (i.e. bridging bone, bone growth through the cage, stability in functional X-rays and no radiolucent lines). RESULTS: After 12 months minor subsidence and tilting of the cages had caused significant correction loss of the basal plate angle of 2.4 degrees on average. Of the patients 20 (57%) fulfilled the criteria for complete or incomplete fusion and 5 (14%) showed no signs of bony fusion. Bone mineral density measurements were unreliable due to metallic artefacts. CONCLUSIONS: The advocated criteria allow accurate assessment of bony incorporation of cages. Bony incorporation can be detected in and around the cages over time; however, only 57% of patients showed signs of bony fusion after 1 year. PMID- 23812542 TI - Suspected intraoperative formation of left atrial thrombus in a patient with atrial fibrillation receiving bridging anticoagulation therapy. AB - We present a patient with atrial fibrillation (AF) in whom a left atrial (LA) thrombus might have formed during laparotomy despite bridging anticoagulation therapy. No evidence of thrombus was detected by transesophageal echocardiography (TEE) at the start of surgery; however, a thrombus measuring 13 * 10 mm was found in the LA appendage by the end of the procedure, suggesting that thrombus might develop intraoperatively in patients with AF even when bridging anticoagulation is properly established. Intraoperative TEE can assist in detecting intracardiac thrombus in patients with AF regardless of their anticoagulation status and provides a tool for intervention to prevent systemic embolization. PMID- 23812541 TI - [Posterocentral approach to the posterior tibial plateau. Reconstruction of tibial plateau fractures and avulsions of the posterior cruciate ligament]. AB - BACKGROUND: For surgical treatment of posterior shearing tibial plateau fractures and avulsion fractures of the posterior cruciate ligament (PCL) a posterocentral approach without dissection or separation of the heads of the gastrocnemius muscle is used. The aim of this study was an evaluation of this approach. PATIENTS AND METHODS: From 2001-2012 a total of 33 patients were surgically treated using a posterocentral approach to the dorsal knee joint. Of these patients 22 had a posterior shearing tibial plateau fracture and 11 had an avulsion fracture of the PCL. The fracture type, complications, expertise of the surgeon, fracture healing, implant position and irritation, nerve lesions, scar tissue and range of motion were documented. RESULTS: Hypesthesia around the scar, at the lateral foot and lower lateral leg were observed in one each of three patients. Despite two ventral implant infections no infection of the dorsal implant occurred. All scar tissue was without pathological findings and scar contracture was not observed. In three cases the screw tips at the anterior proximal tibia were palpable but without complaints from the patients. CONCLUSIONS: The posterocentral approach showed a low complication rate in the hands of experienced surgeons. The soft tissue cover seems to prevent implant infections. PMID- 23812546 TI - Generation and homing of iPSC-derived hematopoietic cells in vivo. PMID- 23812547 TI - Exosome-like nanoparticles from food: protective nanoshuttles for bioactive cargo. PMID- 23812549 TI - Effects of dietary fibre and protein on urea transport across the cecal mucosa of piglets. AB - In ruminants, gastrointestinal recycling of urea is acutely enhanced by fibre rich diets that lead to high ruminal concentration of short chain fatty acids (SCFA), while high ammonia has inhibitory effects. This study attempted to clarify if urea flux to the porcine cecum is similarly regulated. Thirty-two weaned piglets were fed diets containing protein (P) of poor prececal digestibility and fibre (F) at high (H) or low levels (L) in a 2 * 2 factorial design. After slaughter, cecal content was analyzed and the cecal mucosa incubated in Ussing chambers to measure the effect of pH, SCFA and NH4 (+) on the flux rates of urea, short-circuit current (I sc) and tissue conductance (G t). NH4 (+) significantly enhanced I sc (from 0.5 +/- 0.2 to 1.2 +/- 0.1 MUEq cm(-2) h(-1)). No acute effects of SCFA or ammonia on urea flux were observed. Tissue conductance was significantly lower in the high dietary fibre groups irrespective of the protein content. Only the HP-LF group emerged as different from all others in terms of urea flux (74 +/- 6 versus 53 +/- 3 nmol cm(-2) h(-1)), associated with higher cecal ammonia concentration and reduced fecal consistency. The data suggest that as in the rumen, uptake of ammonia by the cecum may involve electrogenic transport of the ionic form (NH4 (+)). In contrast to findings in the rumen, neither a high fibre diet nor acute addition of SCFA enhanced urea transport across the pig cecum. Instead, a HP-LF diet had stimulatory effects. A potential role for urea recycling in stabilizing luminal pH is discussed. PMID- 23812550 TI - A large prospective study of risk factors for adenocarcinomas and malignant carcinoid tumors of the small intestine. AB - PURPOSE: Small intestinal cancer is increasing in the U.S.A, yet little is known about its etiology. Our aim was to prospectively evaluate risk factors for this malignancy by the two main histologic subtypes (adenocarcinomas and carcinoids). METHODS: Hazard ratios and 95% confidence intervals (CI) were estimated for all incident small intestinal cancers (n = 237), adenocarcinomas (n = 84), and malignant carcinoids (n = 124), by demographic and lifestyle factors among 498,376 men and women. RESULTS: Age was the only risk factor for adenocarcinomas (HR for >= 65 vs. 50-55 years = 3.12, 95% CI 1.33, 7.31). Age (HR for >= 65 vs. 50-55 years = 3.31, 95% CI 1.51, 7.28), male sex (HR = 1.44, 95% CI 1.01, 2.05), body mass index (BMI, HR for >= 35 vs. 18.5-< 25 kg/m2 = 1.95, 95% CI 1.06, 3.58), and current menopausal hormone therapy use (HR = 1.94, 95% CI 1.07, 3.50) were positively associated with malignant carcinoids. A family history of any cancer or colorectal cancer (HR = 1.42, 95% CI 0.99, 2.03; 1.61, 0.97, 2.65, respectively), or a personal history of colorectal polyps (HR = 1.51, 95% CI 0.92, 2.46) produced elevated, but not statistically significant, risks for malignant carcinoids. Race, education, diabetes, smoking, physical activity, and alcohol intake were not associated with either histologic subtype. CONCLUSIONS: Risk factors differed according to cancer subtype; only age was associated with adenocarcinomas, whereas age, male sex, BMI, and menopausal hormone therapy use were positively associated with malignant carcinoids. PMID- 23812551 TI - Randomized clinical trial of arginine-supplemented enteral nutrition versus standard enteral nutrition in patients undergoing gastric cancer surgery. AB - PURPOSE: Significant malnutrition exists in a high percentage of patients with gastric cancer. It is, therefore, crucial to establish an effective means to provide nutrition for these patients. This prospective, randomized, double blinded clinical trial aims to assess the long-term survival of arginine supplementation enteral nutrition versus standard enteral nutrition in malnourished patients with gastric cancer. METHODS: The control group (36 cases) received postoperative standard enteral nutrition. Meanwhile, the arginine supplementation group (37 cases) adopted the same nutrition product but enriched with arginine (9.0 g/L). The primary study objective was overall survival (OS). Secondary endpoints were progression-free survival (PFS); serum parameters including total protein, albumin, proalbumin, and transferrin obtained on preoperative day 1, postoperative day 2, and day 12; CD4(+) and CD8(+) T cells, natural killer (NK) cells, immunoglobulin M (IgM), and immunoglobulin G (IgG) obtained on preoperative day 1 and postoperative day 7. RESULTS: No significant differences in baseline characteristics were observed between groups. The group receiving arginine-enriched nutrition had a significantly better OS (P = 0.03, 41 vs. 30.5 months) and better PFS (P = 0.02, 18 vs. 11.5 months). On postoperative day 7, CD4(+) T cells, NK cells, IgM and IgG levels of the arginine-supplemented group increased prominently and were significantly higher than those of the control group and those on preoperative day 1. There is no significant difference in the serum total protein, albumin, proalbumin, and transferrin levels between the two arms. CONCLUSIONS: Arginine-supplemented enteral nutrition significantly improves long-term survival and restores immunity in malnourished gastric cancer. PMID- 23812552 TI - Open mini-incision parathyroidectomy for solitary parathyroid adenoma: surgical limitations. PMID- 23812553 TI - The effects of air pollutants on nasal functions of outdoor runners. AB - Nowadays road running is becoming more and more popular in our country. Road running is mostly done under improper conditions. The aim of this study was to investigate the effects of running on nasal response combined with the effects of air pollutants. Twenty road runners were enrolled in the study. All subjects were male and between 20 and 41 years of age. They ran for 60 min on the right side of an avenue in the center of the city. It is in a residential area but has heavy traffic. One week later they were invited to run for 60 min through a running course away from traffic that is located outside the city center. Nasal resistances were measured by active anterior rhinomanometry. Nasal transport time was also measured by saccharin transport method. There was a reduction in nasal resistance, which was statistically significant in city center runners but was not statistically significant in those running outside of the city center after the exercise. Although nasal transport times were statistically shorter in both groups, there were no differences between two groups. Nowadays, everyone is advised to do sports. Due to increase in the number of breaths, the depth of breathing, and the reduction in nasal resistance in outdoor runners during exercise, harmful air pollution particles can easily reach the lower respiratory tract. Exercise is important for our health, but it should be noted that the environment in which we run is as important as doing sports for our health, especially in outdoor runners. PMID- 23812554 TI - Evaluation of early hearing damage in personal listening device users using extended high-frequency audiometry and otoacoustic emissions. AB - Although sound exposure from personal listening devices (PLDs) could potentially lead to noise-induced hearing loss (NIHL), the actual hearing risk associated with the use of these devices is still unclear. In this study, early hearing effects related to PLD usage were evaluated in 35 young adult PLD users (listening for >1 h/day, at >50% of the maximum volume setting of their devices) and their age- and sex-matched controls using a combination of conventional and extended high-frequency audiometry as well as transient-evoked otoacoustic emission (TEOAE) and distortion product of otoacoustic emission (DPOAE) measurements. The mean listening duration of the PLD users was 2.7 +/- 1.0 h/day while their estimated average listening volume was 81.3 +/- 9.0 dBA (free-field corrected). Typical signs of NIHL were not detected in the audiogram of PLD users and their audiometric thresholds at most of the conventional test frequencies (0.25-8 kHz) were comparable with those obtained from controls. However, compared with the controls, mean hearing thresholds of PLD users at many of the extended high-frequencies (9-16 kHz) were significantly higher. In addition, TEOAE and DPOAE amplitudes in users were reduced compared with controls. The deterioration of extended high-frequency thresholds and the decrease in DPOAE amplitudes were more evident in the users' right ears. These results indicate the presence of an early stage of hearing damage in the PLD user group. Preventive steps should be taken as the initial hearing damage in these users could eventually progress into permanent NIHL after many years of PLD use. PMID- 23812555 TI - Identification of D179H, a novel missense GJB2 mutation in a western Sicily family. AB - The main purpose of this study was to describe a novel missense mutation (p.D179H) found in a Western Sicily family and to examine the genetic and audiologic profiles of all family members by performing a GJB2 and GJB6 mutations analysis and a complete audiologic assessment. The proband was a 3-month-old infant with a congenital profound sensorineural hearing loss; direct sequencing of the GJB2 revealed the presence of a c.35delG mutation in the heterozygous state and a heterozygous G>C transition at nucleotide 535 in trans; this novel mutation, called p.D179H, resulted in an aspartic acid to histidine change at codon 179. It was also evidenced in the heterozygous state in two members of this family, both with normal hearing. No GJB6 mutations were evidenced in all subjects studied. Considering the genotypic and phenotypic analysis of all family members, we suggest, differently from the p.D179 N mutation previously reported, a recessive mode of inheritance. Functional studies on p.D179H have to be performed to confirm our hypothesis. PMID- 23812556 TI - Differing rates of cholesterol absorption among inbred mouse strains yield differing levels of HDL-cholesterol. AB - Inbred strains of mice with differing susceptibilities to atherosclerosis possess widely varying plasma HDL levels. Cholesterol absorption and lipoprotein formation were compared between atherosclerosis-susceptible, low-HDL C57BL6/J mice and atherosclerosis-resistant, high-HDL FVBN/J mice. [(3)H]cholesterol and triglyceride appeared in the plasma of FVB mice gavaged with cholesterol in olive oil at a much higher rate than in C57 mice. The plasma cholesterol was found almost entirely as HDL-cholesterol in both strains. Inhibition of lipoprotein catabolism with Tyloxapol revealed that the difference in the rate of [(3)H]cholesterol appearance in the plasma was due entirely to a greater rate of chylomicron secretion from the intestine of the FVB mice. Lipid absorption into the 2nd quarter of the small intestine is greater in the FVB mice and indicates that this region may contain the factors that give rise to the differences in absorption observed between the two mouse strains. Additionally, ad libitum feeding prior to cholesterol gavage accentuates the absorption rate differences compared with fasting. The resultant remodeling of the increased levels of chylomicron in the plasma may contribute to increased plasma HDL. Intestinal gene expression analysis reveals several genes that may play a role in these differences, including microsomal triglyceride transfer protein and ABCG8. PMID- 23812557 TI - Lipid transfer particle from the silkworm, Bombyx mori, is a novel member of the apoB/large lipid transfer protein family. AB - Lipid transfer particle (LTP) is a high-molecular-weight, very high-density lipoprotein known to catalyze the transfer of lipids between a variety of lipoproteins, including both insects and vertebrates. Studying the biosynthesis and regulation pathways of LTP in detail has not been possible due to a lack of information regarding the apoproteins. Here, we sequenced the cDNA and deduced amino acid sequences for three apoproteins of LTP from the silkworm (Bombyx mori). The three subunit proteins of the LTP are coded by two genes, apoLTP-II/I and apoLTP-III. ApoLTP-I and apoLTP-II are predicted to be generated by posttranslational cleavage of the precursor protein, apoLTP-II/I. Clusters of amphipathic secondary structure within apoLTP-II/I are similar to Homo sapiens apolipoprotein B (apoB) and insect lipophorins. The apoLTP-II/I gene is a novel member of the apoB/large lipid transfer protein gene family. ApoLTP-III has a putative conserved juvenile hormone-binding protein superfamily domain. Expression of apoLTP-II/I and apoLTP-III genes was synchronized and both genes were primarily expressed in the fat body at the stage corresponding to increased lipid transport needs. We are now in a position to study in detail the physiological role of LTP and its biosynthesis and assembly. PMID- 23812559 TI - Concept determination of human dignity. AB - This study presents findings from an ontological and contextual determination of the concept of dignity. The study had a caritative and caring science perspective and a hermeneutical design. The aim of this study was to increase caring science knowledge of dignity and to gain a determination of dignity as a concept. Eriksson's model for conceptual determination is made up of five part-studies. The ontological and contextual determination indicates that dignity can be understood as absolute dignity, the spiritual dimension characterized by responsibility, freedom, duty, and service, and relative dignity, characterized by the bodily, external aesthetic dimension and the psychical, inner ethical dimension. Dignity exists in human beings both as absolute and relative dignity. PMID- 23812560 TI - Patients' perspectives on person-centred participation in healthcare: a framework analysis. AB - The aim of this article was to critically analyse the concept of person-centred participation in healthcare from patients' perspectives through a review of qualitative research findings. In accordance with the integrative review method of Broom, data were retrieved from databases, but 60 studies were finally included in the study. The diverse attributes of person-centred participation in healthcare were identified and contrasted with participation that was not person centred and analysed through framework analysis. Person-centred participation in healthcare was found to be based on patients' experiences, values, preferences and needs in which respect and equality were central. It manifested itself via three intertwined phases: the human-connection phase, the phase of information processing and the action phase. The results challenge in many aspects earlier concept analyses of patient participation in addition to illuminating patient participation that is not positively valued by patients. PMID- 23812558 TI - Cardioprotective functions of HDLs. AB - Multiple human population studies have established the concentration of high density lipoprotein (HDL) cholesterol as an independent, inverse predictor of the risk of having a cardiovascular event. Furthermore, HDLs have several well documented functions with the potential to protect against cardiovascular disease. These include an ability to promote the efflux of cholesterol from macrophages in the artery wall, inhibit the oxidative modification of low density lipoproteins (LDLs), inhibit vascular inflammation, inhibit thrombosis, promote endothelial repair, promote angiogenesis, enhance endothelial function, improve diabetic control, and inhibit hematopoietic stem cell proliferation. There are undoubtedly other beneficial functions of HDLs yet to be identified. The HDL fraction in human plasma is heterogeneous, consisting of several subpopulations of particles of varying size, density, and composition. The functions of the different HDL subpopulations remain largely unknown. Given that therapies that increase the concentration of HDL cholesterol have varying effects on the levels of specific HDL subpopulations, it is of great importance to understand how distribution of different HDL subpopulations contribute to the potentially cardioprotective functions of this lipoprotein fraction. This review summarizes current understanding of the relationship of HDL subpopulations to their cardioprotective properties and highlights the gaps in current knowledge regarding this important aspect of HDL biology. PMID- 23812561 TI - Vanadium(IV/V)-p-dioxolene temperature induced electron transfer associated with ligation/deligation of solvent molecules. AB - Reaction of an aqueous solution of NaVO3 or a methanol solution of [VO(acac)2] with 2,5-bis((bis(2-hydroxyethyl)amino)methyl)hydroquinone, H6bdeah, results in the formation of two major vanadium species characterized by X-ray crystallography: the [(V(5+)O)2(bdeah)] and the [(V(4.5+)O)2(bdeas)S2] (S = DMSO or MeOH). The vanadium ions in the two species have a trigonal pyramidal and an octahedral coordination sphere respectively. Variable temperature UV-Vis and (51)V NMR spectroscopy as well as EPR and electrochemistry showed a temperature induced electron transfer. The diamagnetic [(V(5+)O)2(bdeah)] is the main species at high temperature. At low temperature one electron is transferred from the bdeah(6-) to the two vanadium centers resulting in the [(V(4.5+)O)2(bdeas)S2] species [H5bdeas = 2,5-bis((bis(2-hydroxyethyl)amino)methyl)-1,4-semiquinone]. The thermodynamic parameters of this intramolecular electron transfer were calculated by UV-Vis (DeltaH = -36 +/- 2 kJ mol(-1) and DeltaS = -129 +/- 5 J mol(-1) K(-1)) and (51)V NMR spectroscopy (DeltaH = -37 +/- 2 kJ mol(-1) and DeltaS = -109 +/- 5 J mol(-1) K(-1)). The electron transfer is a result of the large change of entropy which is associated with the ligation of the solvent molecules and the geometry change. EPR spectroscopy shows that most of the electron density in [(V(4.5+)O)2(bdeas)S2] is mainly located on the two vanadium ions. PMID- 23812562 TI - The periaqueductal grey area and control of blood pressure in neurodegeneration. AB - The periaqueductal/periventricular grey area (PAG/PVG) is a midbrain nucleus with an important role in pain signalling and autonomic control. We present the case of an initially hypertensive man who developed a presumed neurodegenerative disorder over a decade, characterised by progressive right-sided chronic pain, extra-pyramidal symptoms and autonomic dysfunction including postural hypotension, sleep apnoea, and bladder instability. He underwent a variety of treatments for his symptoms, including deep brain stimulation (DBS) of the PAG/PVG. 24-h blood pressure monitoring was carried out 1 and 5 years after implantation. Although the DBS initially produced a significant reduction in blood pressure, the effect was significantly reversed when the same tests were repeated 5 years after surgery. This may imply a functional involvement of the PAG/PVG in the neurodegenerative process. PMID- 23812563 TI - Factors associated with the quality of life of adults subjected to hemodialysis in a city in northeast Brazil. AB - INTRODUCTION: There is a known association between low scores for quality of life (QOL) and higher rates of hospitalization, mortality in hemodialysis vascular access catheter, older age, lack of regular occupation, presence of comorbidities and hypoalbuminemia. There is still no agreement about the influence of sex, educational level, socioeconomic status and treatment time on the worst levels of QOL. OBJECTIVE: Identify socioeconomic, demographic, clinical, nutritional and laboratory factors associated with worse QOL in adults undergoing hemodialysis in Sao Luis, Maranhao, Brazil. METHODS: A cross-sectional study which evaluated the QOL of patients with chronic renal disease, aged 20-59 years, undergoing hemodialysis. Two instruments were used: the Kidney Disease Quality of Life Short Form 1.3 (KDQOL-SFTM 1.3) and a questionnaire on socioeconomic, demographic, clinical, nutritional and laboratory data. The reliability of KDQOL SFTM 1.3 was assessed by Cronbach's alpha. For the multivariable analysis a Poisson regression model with robust adjustment of the standard error was used. RESULTS: The reliability assessment of KDQOL-SFTM 1.3 showed a Cronbach's alpha test greater than 0.8 in all areas. The areas with the worst levels of QOL were "work situation", "burden of kidney disease", "patient satisfaction", "physical function" and "general health". Having less than 8 years of schooling, coming from the countryside and having cardiovascular disease were associated to the areas with the worst levels of QOL. CONCLUSIONS: KDQOL-SFTM 1.3 is a reliable instrument to measure quality of life of hemodialysis patients. Demographic and clinical conditions can negatively influence QOL in chronic renal failure patients. PMID- 23812564 TI - Factors associated to salt intake in chronic hemodialysis patients. AB - INTRODUCTION: Salt intake increases fluid intake and, consequently, blood pressure (BP) and interdialytic weight gain (IDWG), known as morbi-mortality risk factors for hemodialysis (HD) patients. OBJECTIVE: Evaluate salt intake and food sources, as well as its relationship with demographics, clinical and nutritional parameters. METHODS: Cross-sectional study with 109 patients (66% women, age = 49.0 +/- 12.6 years) from five dialysis centers. For total salt intake, a validated food frequency questionnaire (FFQ) and the use of discretionary salt were estimated. The relationship of salt intake with many factors was studied. RESULTS: Salt intake was high (8.6 +/- 5.4 g/day) and 72% came from discretionary salt. Only literacy was significantly correlated total salt intake (r = -0.29, p < 0.01) and discretionary salt (r = -0.30, p < 0.01). With FFQ food items, there was a positive correlation with the %IDWG (r = 0.26, p < 0.01) and negative with age (r = -0.35, p < 0.001). Direct relationship between salt intake with %IDWG was found in the anuric subgroup (r = 0.26, p < 0.05) and with medium BP in those with no prescription of hypotensive drugs (r = 0.35, p < 0.05). CONCLUSION: Salt intake was high mainly due to discretionary salt. It was associated with education and adversely affected %IDWG in anuric patients and medium BP in those not taking hypotensive drugs. PMID- 23812565 TI - Community-acquired urinary tract infection: age and gender-dependent etiology. AB - INTRODUCTION: Choosing the antimicrobial agent for initial therapy of urinary tract infection (UTI) is usually empirical and should consider the prevalence of uropathogens in different age groups and gender. OBJECTIVE: To establish prevalence rates of uropathogens in community-acquired UTI in relation to age and gender. METHODS: Cross-sectional study conducted in the emergency department (ED) of a general hospital, from January to December, 2010, in patients younger than 15 years old who had clinical suspicion of UTI and collected quantitative urine culture. UTI was defined as urine culture with growth of a single agent > 100.000 colony forming units (cfu)/mL in a midstream collection or >= 50.000 cfu/mL in urethral catheterization. RESULTS: There were 63.464 visits to ED. 2577 urine cultures were obtained, of whom 291 were positive for UTI (prevalence = 11.3% of clinical suspicion and 0.46% of visits), 212 cases (72.8%) in females, median age = 2.6 years. The predominant uropathogen was E. coli (76.6%), followed by Proteus mirabilis (10.3%) and Staphylococcus saprophyticus (4.1%). Among infants < 3 months, prevalence rates of E. coli were significantly lower (50% vs 78.4%; OR = 0.276; p = 0.006). Higher prevalences of Staphylococcus saprophyticus occurred among patients > 10 years (24.4% vs 0.4%; OR = 79.265; p < 0.0001). Proteus mirabilis was significantly more prevalent in boys than girls (24.0% vs 5.2%; OR = 5.786; p < 0.001). CONCLUSIONS: E. coli was the most prevalent community acquired uropathogen. Nevertheless, initial empiric antimicrobial treatment of UTI should consider the significant prevalence of other agents different from E. coli in infants < 3 months, the high prevalence of Staphylococcus saprophyticus in patients > 10 years and Proteus mirabilis in males. PMID- 23812566 TI - Progression of chronic kidney disease: ambulatory experience in Santarem - Para. AB - INTRODUCTION: Chronic kidney disease (CKD) is a growing public health problem. Nevertheless there is a little data about CKD in Brazil, mainly in its non dialytic stages. OBJECTIVE: To know about demographic, clinical and laboratory features of patients with CKD non-dialytic, and evaluate the impact of these variables on disease progression. METHODS: A retrospective cohort study comprised of 65 adult patients with stages CKD 2-4, followed-up for 28.24 +/- 13.3 months. RESULTS: Mean age was 64.6 +/- 12.6 years. The main causes of the CKD were diabetic kidney disease (DRD) (47.7%) and hypertensive nephrosclerosis (34.2%). Most patients were on stage 3 CKD (44.6%) and the minority reached therapeutic targets in control of their co-morbidities, 40% for arterial pressure and 38.7% for glycemic control. The mean annual loss of glomerular filtration rate (GFR) was 3.1 +/- 7.3 mL/min/1; 73 m2 (median 1.4 mL/min/1; 73 mL/min/1; 73 m2) 21.5% of patients developed progressive CKD. Diastolic blood pressure (DBP) >= 90 mmHg increased 2.7 times the risk of developing progressive CKD (95% CI 1.14 to 6.57; p = 0.0341) as well as systolic blood pressure (SBP) > 160 mmHg (RR = 3.64, 95% CI 1.53 to 8.65; p = 0.0053) and proteinuria (RR = 4.05, 95% CI; 1.55 to 10.56; p = 0.0031). It was also observed higher SBP mean (p = 0.0359) and lower HDL-c median (p = 0.0047) in patients with CKD Progressive. CONCLUSION: In this study, hypertension and proteinuria were risk factors for evolution with progressive CKD, in spite of the difficult clinical control a minority of patients had the progressive form of CKD. PMID- 23812567 TI - Evaluation of knowledge of the term "nephrology" in a population sample. AB - INTRODUCTION: The consolidation of nephrology as a medical specialty is relatively new and its denomination does not intuitively reflects its true scope. OBJECTIVE: To assess the degree of knowledge from a population sample regarding the term "nephrology". METHODS: We carried out a cross-sectional study in Niteroi, RJ, with adult passerby individuals answering to the question "Do you know what nephrology is?". The variables recorded included: gender, age, skin color, residence, income, educational level and kidney-disease history in the family. p values < 0.05 were considered significant. RESULTS: Of the 564 individuals asked, 504 were willing to answer. Of those who refused, 64% were males, 58% caucasians--from whom 85% were aged > 30 years. The mean age among participants was 39 (22-56) years, 49% were males and 56% caucasians. Twenty eight percent of the interviewees knew the term "nephrology". Their knowledge came from school (39%) and family (30%). Those who knew about the term "nephrology" were older (42 +/- 17 vs. 39 +/- 17 years, p < 0.05), had higher income (R$ 4,522 vs. R$ 2,934, p < 0.05) and higher education (27% vs. 12% with complete higher education, p < 0.001). They were predominantly caucasians (64% vs. 53%, p = 0.001), and had a higher rate of renal disease in the family (55% vs. 36%, p < 0.001). In the multivariate analysis, associations were maintained for age (OR 1.02; 95% CI 1.00 to 1.03, p = 0.004); higher education (OR 10.60, 95% CI, 4.20 to 26.86, p < 0.001) and kidney disease in the family (OR 2.2, 95% CI, 1.40 to 3.41, p < 0.001). CONCLUSIONS: Only 28% knew the term "nephrology", illustrating the specialty's low penetration. We must strive to popularize this field of medicine aiming at better educating the population concerning the prevention and care of kidney diseases. PMID- 23812568 TI - Histologic variants of primary focal segmental glomerulosclerosis: presentation and outcome. AB - INTRODUCTION: The clinical significance of histologic variants of primary focal segmental glomerulosclerosis (FSGS) remains unclear. With the aim to determine presentation and outcome of the variants of FSGS in a hispanic population, we studied our cases of this glomerulopathy. METHODS: In this retrospective study, all renal biopsies with FSGS (1998-2009), were classified according to the Columbia's classification. We analyzed histological, clinical and follow-up data and compared among variants. RESULTS: Among 291 cases, 224 (77.0%) corresponded to NOS variant, 40 cases (13.7%) to tip variant (TIP), 14 cases (4.8%) to perihilar (PH), 10 cases (3.4%) to collapsing (COLL) and three cases (1.0%) to cellular variant (CELL). Median age: 26 years (range 1 to 79); 74 patients (25.4%) were < 15 years of age. Hypertension and renal dysfunction were more frequent in PH and COLL cases. PH presented frequently as nonnephrotic proteinuria. There were fewer histologic chronic lesions in TIP cases. There was remission in 23.5% of patients with NOS, 57.7% of patients with TIP, 22.2% of patients with COLL and 0 patients with PH (p < 0.01). Chronic kidney disease (CKD) was less frequent in TIP than in the other variants (p = 0.03). There were not statistical differences for end-stage renal disease among variants. CONCLUSIONS: Glomerular histological appearance is not a good indicator of outcome. COLL is a disease with many differences to the other variants and bad prognosis; PH is a variant mainly of adults, with frequent evolution to CKD. TIP appears as a less aggressive, although not benign, variant. PMID- 23812569 TI - Is there association between acyl-ghrelin and inflammation in hemodialysis patients? AB - INTRODUCTION AND OBJECTIVES: Patients with chronic kidney disease (CKD) present anorexia, which may be related with the chronic inflammatory process. Thus the objective of this study was to evaluate if there is association between inflammation and the orexigenic hormone, acyl-ghrelin, in CKD patients undergoing hemodialysis (HD). METHODS: Thirty-six patients were studied (61.1% men, 46.7 +/- 14.9 years, BMI 22.9 +/- 3.9 kg/m2) in regular HD program (65.0 +/- 46.8 months). Plasma levels of acyl-ghrelin and inflammatory markers TNF-alpha, IL-6 and CRP were measured by enzyme immunoassay (ELI-SA, Enzyme Linked Immunosorbent Assay). Anthropometric parameters were collected for assessment of nutritional status and dietary intake was assessed by food recall. RESULTS: The patients presented elevated plasma levels of IL-6 (83 +/- 10 pg/mL), TNF-alpha (21.06 pg/mL [20.6 40.0]) and CRP (2.7 pg/mL [1.73.4]) compared to normal values. Acylghrelin plasma levels were (18.0 [1.3 to 77.7 pg/mL]) low when compared to healthy individuals. However, patients with high BMI (> 25 kg/m2) presented lower acyl-ghrelin plasma levels (13.6 [1.3 to 30.5] pg/mL) when compared to patients with BMI < 25 kg/m2 (21.7 [7.4 to 77.7] pg/mL) (p < 0.05). Acylghrelin and BMI were negatively correlated (r = -0.38, p = 0.02) and there was no significant correlation between acyl-ghrelin and inflammatory markers. CONCLUSIONS: Hemodialysis patients showed low acyl-ghrelin levels and seem to present an acyl-ghrelin resistance and there was no correlation between inflammation and this orexigenic hormone. PMID- 23812570 TI - Risk factors for injury acute renal in patients with severe trauma and its effect on mortality. AB - The studies which associated acute kidney injury (AKI) and trauma emerged during the Second World War, and since then we have seen a progressive evolution of healthcare aiming at AKI prevention. However, establishing the risk factors for post-trauma AKI development remains crucial and may help reduce this complication. OBJECTIVE: This study aims at identifying risk factors vis-a-vis the development of AKI in patients with severe trauma and its impact on mortality. This is a retrospective study of 75 patients with severe trauma. Six were taken off because they arrived at the hospital past the point of resuscitation. METHOD: The variables considered were age, gender, trauma severity according to the Injury Severity Score (ISS) and the Glasgow Coma Scale (GCS), trauma mechanism, mean blood pressure upon admission, fluid replacement in the first 24 hours, serum creatinine levels, use of nephrotoxic antibiotics, length of hospital stay, need for ICU admission and mortality. RESULTS: The prevalence of AKI in severe trauma patients was 17.3%, and the factors associated with ARF in this sample were Head Injury and GCS < 10. Mortality, length of hospital stay and the need for ICU were significantly higher in patients who developed AKI. CONCLUSIONS: The identification of these risk factors is of paramount importance for the development of care strategies for patients suffering from severe trauma, for the prevention of acute kidney injury and the associated high mortality. PMID- 23812571 TI - Dialysis in the elderly patient: a challenge of the XXI century--narrative review. AB - With the increase in life expectancy, the improvement of therapeutic arsenal, knowledge and control of chronic degenerative diseases, the world population has reached older age groups. As advanced age is a risk factor for chronic kidney disease (CKD), along with the bonus of increased survival, today we are experiencing the greatest burden of progressive incidence of elderly patients on renal replacement therapy (RRT). Dialysis in elderly patients, which for three decades was considered out of question, today is a routine for nephrologists, who face the challenge of providing care to elderly patients with CKD stage 5 with dialysis indication. In fact, what we see nowadays are dialysis incidents elderly patients as the fastest growing group on RRT. Although without reaching a consensus, it seems indisputable that for elderly patients with CKD, the most important is the quality of life. In this paper we discuss the dialysis in the elderly patient. PMID- 23812572 TI - Extended hemodialysis in acute kidney injury. AB - About 10% of patients in the intensive care unit which develop acute renal failure will depend on renal replacement therapy. Although there are no data showing reduction in mortality when compared with intermittent therapy, continuous therapies provide higher cumulative doses of dialysis and greater hemodynamic stability. However, have high costs and are not available in many centers. In this context the Extended Hemodialysis gaining ground in clinical practice because it combines the hemodynamic tolerability, slow and sustained solute control and effective doses of continuous dialysis therapies associated with reduced costs and logistics facilities of intermittent therapy. PMID- 23812573 TI - Vascular calcification in chronic kidney disease: a review. AB - Vascular calcification (VC), an independent and strong predictor of cardiovascular risk, is often found in CKD patients. The degree of VC is providing incremental prognostic value over traditional risk markers. There is interest in improving our understanding of mechanisms, establishing diagnostic methods and effective prevention and treatment modalities. The abnormal mineral metabolism of CKD is known to facilitate the progression of VC, in concert with altered activities of VC inhibitors. Possible measures to prevent VC include the control of serum calcium and phosphate as well as other factors involved in its progression, including vitamin D sterols, parathyroid hormone, fibroblast growth factor-23, klotho, and VC inhibitors. In addition, we discuss new possible therapeutic approaches to halt VC or reverse its progression. The principal aim of this review is to provide an updated overview of VC in patients with CKD, with particular focus on pathophysiology, diagnosis, prevention and treatment. PMID- 23812574 TI - [Spontaneous perirenal hematoma in a lupic patient on haemodialysis treatment and with renal cysts]. AB - The spontaneous perirenal hemorrhage usually presents as sudden pain in the side ipsilateral, no history of trauma. Acquired cystic kidney disease is a common finding in chronic hemodialysis patients. However, spontaneous bleeding from the rupture of the cyst is a rare clinical entity. We describe the case of a female patient, 45 years old, with controlled hypertension for 8 years, chronic renal failure for 15 years and lupus nephritis 2 years ago, undergoing hemodialysis three times a week since 2006, and who presented concurrently acquired cystic kidney disease. She was admitted to the emergency department complaining of sudden onset of pain in the thoraco-abdominal left. Perirenal hematoma was diagnosed by ultrasound and computed tomography of the abdomen. The patient underwent embolization of left renal artery, with good evolution. PMID- 23812575 TI - [Hadju-Cheney syndrome: kidney disturbs in a case report]. AB - Hajdu-Cheney disease is characterized by craniofacial dimorphisms and skeletal changes. Renal disturbs; such as renal cortical cysts, vesico-ureteral reflux and renal failure are rarely related but it is included as a less common feature. The diagnosis is not yet available and the pathogenesis it is related with mutations in the NOTCH gene. The authors report a case of a 26-years-old boy; but with phenotypic characteristics of a pediatric patient. He presented nephrotic syndrome, hypertension, renal cortical cysts, nephrotic range proteinuria and acute renal failure requiring hemodialysis. The renal tissue showed global and segmental glomerulosclerosis and the treatment to this patient it was supporting with hemodialysis. The diagnosis of Hadju-Cheney disease was given during investigation of renal function. PMID- 23812576 TI - Patterns of isotope uptake in sequential postoperative bone scan in undisplaced femoral-neck fractures. AB - PURPOSE: We aimed to investigate the changing pattern of isotope uptake in the sequential bone scan test for the prediction of osteonecrosis of the femoral head in patients with an undisplaced femoral-neck fracture. METHODS: Fifty-four cases of sequential bone scan for nondisplaced femoral-neck fracture treated by internal fixation with cannulated screws between 2000 and 2009 were retrospectively studied. The mean follow-up period was 4.2 years. The first postoperative bone scan was performed two weeks postoperatively in all patients. Second, third, and fourth follow-up bone scans were performed at one to six months, 12-18 months, and 18-24 months postoperatively. RESULTS: Mean femoral head ratio (FHR) in the first postoperative bone scan was 0.99. Although it was under 1.0 in 38 patients (70.4 % of the 54 patients), only one patient developed osteonecrosis of the femoral head. The others showed hot uptake in their second follow-up bone scan. Mean FHRs in the second, third, and fourth postoperative bone scans were 1.69, 1.29, and 1.05, respectively, and there were significant statistical differences in each follow-up period (P = 0.035). In addition, there were unique patterns of isotope uptake with the passage of time, such as cold uptake in the early stage, hot uptake in a couple of months, and iso-uptake in the late stage. CONCLUSIONS: Early postoperative bone scan results should not be over interpreted when predicting osteonecrosis of the femoral head. PMID- 23812577 TI - Pregnancy, childbirth, and sexual function: perceptions and facts. AB - INTRODUCTION AND HYPOTHESIS: Data on the effect of pregnancy and mode of delivery on postpartum sexual function are very heterogenic and inconclusive. The aim of this review is to examine the current literature for reliable data on the role of pregnancy and the route of delivery on sexual health and different dysfunctions. METHODS: A Medline search was performed for the terms "sexuality," "sexual function," "sexual dysfunction," and "pregnancy," "childbirth," "mode of delivery," "delivery," "cesarean section," "puerperium," and "postpartum." Randomized, prospective, and retrospective studies in published in the English language from 1960 to November 2012 were evaluated. RESULTS: Sexual function decreases throughout pregnancy, getting worse as the pregnancy progresses. Decreasing desire and orgasm, increasing pain and other sexual dysfunction problems in the first 3 months gradually improved within 6 months after delivery. This process is affected by many factors such as socio-cultural, age, parity, breastfeeding, depression, tiredness, sexual inactivity during the first trimester, postpartum body image, worries about getting pregnant again, and concomitant urinary tract infections are reported as independent risk factors for sexual dysfunction. CONCLUSIONS: In this review there is no clear evidence of a relationship between the mode of delivery and changes in sexual function. Quality of sexual life should be part of history taking because of the possible sequelae of pregnancy and delivery. More adequately powered studies are necessary to answer the many open questions. PMID- 23812578 TI - Evaluation of xenogenic extracellular matrices as adjuvant scaffolds for the treatment of stress urinary incontinence. AB - INTRODUCTION AND HYPOTHESIS: Tissue-engineered biomaterials have shown recent promise as adjuvant scaffolds for treating stress urinary incontinence (SUI). The objective of the present study was to compare their mechanical and regenerative properties with synthetic biomaterials in this urogynaecological setting. METHODS: The biomechanical properties of polypropylene (Serasis(r); n = 12), four ply urinary bladder matrix (UBM; n = 12) and four-ply small intestinal submucosa (SIS; n = 12) were determined with uni-axial tensile testing protocols and compared with stress-strain curves. Subsequently, human dermal fibroblasts (2.5 * 10(4)cells/cm(2)) were cultured onto each biomaterial under conventional laboratory growth conditions for 12 consecutive days. Attachment, viability, and proliferative activity of fibroblasts were evaluated and compared using quantitative viability indicators and scanning electron microscopy. RESULTS: There were no significant differences in the biomechanical properties of each biomaterial assessed. Incremental stiffness at 0-10 % strain measured 5.73 +/- 0.36 MPa for polypropylene compared with 8.23 +/- 0.92 MPa and 6.81 +/- 0.83 MPa for SIS and UBM respectively (p > 0.05). Viability and proliferative activity of fibroblasts differed significantly on all three biomaterials with the luminal and abluminal surfaces of the UBM demonstrating significantly greater rates of fibroblast proliferation compared with polypropylene and SIS (p < 0.01). CONCLUSION: This is the first comparative study on porcine UBM, porcine SIS, and synthetic polypropylene as adjuvant scaffolds for the treatment of SUI. Our results demonstrate that porcine UBM may provide an attractive alternative owing to its superior remodelling potential. PMID- 23812579 TI - Pelvic organ prolapse surgery with and without tension-free vaginal tape in women with occult or asymptomatic urodynamic stress incontinence: a randomised controlled trial. AB - INTRODUCTION: We set out to determine if insertion of a retropubic tension-free vaginal tape (TVT) sling at the time of pelvic organ prolapse surgery improves continence outcomes in women with pre-operative occult stress incontinence (OSI) or asymptomatic urodynamic stress incontinence (USI). METHODS: We conducted a randomised controlled study of prolapse surgery with or without a TVT midurethral sling. The pre- and post-operative assessment at 6 months included history, physical examination and urodynamic testing. Quality of life (QOL) and treatment success was assessed with the UDI-6 SF, IIQ-7 SF and a numerical success score. The primary outcome was symptomatic stress urinary incontinence (SUI) requiring continence surgery (TVT) at 6 months. Long-term follow-up continued to a minimum of 24 months. Secondary outcomes were quality of life parameters. RESULTS: Eighty women received prolapse surgery alone (n = 43) or prolapse surgery with concurrent TVT (n = 37). Six months following prolapse surgery 3 out of 43 (7 %) patients in the no TVT group requested sling surgery compared with 0 out of 37 (0 %) in the TVT group (ARR 7 % [95 %CI: 3 to 19 %], p = 0.11). After 24 months there was one further participant in the no TVT group who received a TVT for treatment of SUI compared with none in the TVT group (4 out of 43, 9.3 % versus 0 out of 37; ARR 9.3 % [95 %CI: -1 to 22 %], p = 0.06). Both groups showed improvement in QOL difference scores for within-group analysis, without difference between groups. CONCLUSION: These results support a policy that routine insertion of a sling in women with OSI at the time of prolapse repair is questionable and should be subject to shared decision-making between clinician and patient. PMID- 23812580 TI - A review of sternal closure techniques. AB - Sternotomy and sternal closure occur prior to and post cardiac surgery, respectively. Although post-operative complications associated with poor sternal fixation can result in morbidity, mortality, and considerable resource utilization, sternotomy is preferred over other methods such as lateral thoracotomy. Rigid sternal fixation is associated with stability and reduced incidence of post-operative complications. This is a comprehensive review of the literature evaluating in vivo, in vitro, and clinical responses to applying commercial and experimental surgical tools for sternal fixation after median sternotomy. Wiring, interlocking, plate-screw, and cementation techniques have been examined for closure, but none have experienced widespread adoption. Although all techniques have their advantages, serious post-operative complications were associated with the use of wiring and/or plating techniques in high-risk patients. A fraction of studies have analyzed the use of sternal interlocking systems and only a single study analyzed the effect of using kryptonite cement with wires. Plating and interlocking techniques are superior to wiring in terms of stability and reduced rate of post-operative complications; however, further clinical studies and long-term follow-up are required. The ideal sternal closure should ensure stability, reduced rate of post-operative complications, and a short hospitalization period, alongside cost-effectiveness. PMID- 23812581 TI - Comparison of intubation performance between the King Vision and Macintosh laryngoscopes in novice personnel: a randomized, crossover manikin study. AB - PURPOSE: The King Vision laryngoscope is a newly developed video laryngoscope. We conducted a simulation study to evaluate the efficacy of the King Vision in novice personnel. METHODS: Thirty-one registered nurses with no previous experience with tracheal intubation were enrolled. Participants made 6 consecutive attempts at intubation of the manikin's trachea with a Macintosh laryngoscope (MAC) and the King Vision with channeled blade (KVC) and non channeled blade (KVNC) in a randomized cross-over fashion. The Grading Scale of Intubation Difficulty (GSID) was rated on a 5-point scale. RESULTS: Overall median (range) intubation times (sec) were 16.9 (8.0-60.0) with the MAC, 20.5 (7.2-60.0) with the KVC, and 60.0 (11.0-60.0) with the KVNC. The KVNC required significantly longer intubation time compared with the MAC or the KVC (p < 0.001). Success rate with the KVNC was 47.3 %, which was significantly inferior to that with the MAC (91.4 %) or KVC (86.6 %). Median GSID was 2 (range 1-5) with the KVC and 3 (1-4) with the MAC, which were both significantly lower than the 4 (2-5) with the KVNC (p < 0.001). Esophageal intubation with the MAC occurred in 18 of 186 attempts, whereas no incidents of esophageal intubation occurred with the KVC or KVNC. CONCLUSION: The KVC facilitated intubation by novice personnel without incidence of esophageal intubation. However, intubation times, success rates, and GSID scores were similar to the values obtained with the MAC. These findings suggest that the KVC, but not the KVNC, could be used as an alternative device for intubation by novice personnel. PMID- 23812582 TI - Dual-source computed tomography coronary angiography in patients with high heart rate. AB - Although single-source 64-multislice computed tomography coronary angiography (SSCTA) needs to reduce heart rate (HR), dual-source computed tomography coronary angiography (DSCTA) can acquire images even in tachycardia. The accuracy of DSCTA during tachycardia is compared to the accuracy of SSCTA at reduced HR. Patients who received invasive coronary angiography and either SSCTA or DSCTA were included. In the SSCTA group, HR was reduced to <65 beats per minute (bpm) with beta-blocker (n = 27), while in the DSCTA group patients whose HR was >65 bpm were selected (n = 27). The diagnostic accuracy for significant coronary stenosis was calculated by comparing the invasive coronary angiography. Using dual-Doppler echocardiography, isovolumic relaxation time (IRT) and diastasis time (DT) were evaluated in these patients. In SSCTA, sensitivity was 89 %, specificity 99 %, the positive predictive value (PPV) 94 %, and the negative predictive value (NPV) was 98 %. In DSCTA, sensitivity was 96 %, the specificity was 99 %, PPV was 91 %, and NPV was 99 % (all NS compared to SSCTA). When HR was >75 bpm, DT was markedly shortened (<83 ms), however IRT was maintained >85 ms. Thus, the image reconstruction at the phase of IRT is feasible in DSCTA because of its temporal resolution of 83 ms. High temporal resolution of DSCTA shows equivalent accuracy of coronary stenosis detection to SSCTA, without reducing heart rate, because of its image reconstruction at IRT. PMID- 23812583 TI - "Wedge effect" in stenosed coronary artery assessed using a PressureWire: change in pressure waveform during percutaneous coronary intervention in a patient with a coronary artery-left ventricular fistula. AB - In this case report, we describe the recovery of abnormal coronary pressure waveform using a PressureWire Certus during percutaneous coronary intervention in a patient with severe stenosis in the proximal segment of the left anterior descending coronary artery. Since the diastolic pressure in the distal left anterior descending coronary artery was lower than that in the aorta, the pressure waveform before percutaneous coronary intervention represented the left ventricular pressure through a fistula due to a "wedge effect" in the stenosis as if the pulmonary artery wedge pressure determined by a Swan-Ganz catheter reflected the pressure in the distal portion (left atrium). We diagnosed this case coronary artery-left ventricular fistula based on the above findings. PressureWire Certus may be a valuable tool with which to estimate the hemodynamics in a patient with a coronary anomaly. PMID- 23812584 TI - Serum uric acid is an independent predictor of metabolic syndrome in a Japanese health screening population. AB - Serum levels of uric acid (UA) are associated with metabolic syndrome (MetS). However, no study has been aimed to investigate whether baseline UA is a predictor of MetS in a Japanese population. The multivariable adjusted hazard ratios (HRs) of MetS through 3 years were calculated for each 1 SD increase in baseline UA, for the higher quartiles of baseline UA compared with the lowest quartile, and for baseline hyperuricemia defined as >=7.0 mg/dl for men and >=6.0 mg/dl for women in apparently healthy 1,606 men aged 51.7 +/- 9.4 years and 953 women aged 51.6 +/- 9.4 years who visited a medical check-up center in Japan. The HRs (95 % confidence interval; p value) were 1.282 (1.097-1.499; 0.002) in men and 1.354 (1.041-1.762; 0.024) in women for 1 SD increase in baseline UA, 2.206 (1.344-3.620; 0.002) in men and 3.110 (1.121-8.627; 0.029) in women for the highest quartile of baseline UA compared with the lowest quartile, and 1.900 (1.376-2.622; <0.001) in men and 2.088 (1.040-4.190; 0.038) in women for baseline hyperuricemia adjusting for the pre-existing components of MetS, age, smoking, drinking, physical activity, use of antihypertensive, antihyperlipidemic, and antidiabetic medications and histories of coronary heart disease and stroke. However, no significant association was found between longitudinal changes in UA and incident MetS. Baseline UA is an independent predictor of MetS in a Japanese health screening population. PMID- 23812585 TI - Are modern voice prostheses better? A lifetime comparison of 749 voice prostheses. AB - The aim of the study was to compare device life of more recent indwelling voice prostheses Provox Vega and Blom-Singer Dual Valve to device life of well-known standard devices (Provox 2, Blom-Singer Classic). In a prospective, non randomised study, device life of Blom-Singer Classic, Blom-Singer Dual Valve, Provox2, Provox Vega and Provox ActiValve voice prostheses was recorded in a group of 102 laryngectomised patients. In total 749 voice prosthesis were included. Average overall life time was 108 days, median 74 days. The prosthesis with the longest dwell time was the Provox ActiValve (median 291 days). Provox Vega had longer device life compared with Provox2 (median 92 days vs 66 days; p = 0.006) and compared with Blom-Singer Classic (median 92 days vs 69 days; p = 0.004). In conclusion, device lifetimes of Provox Vega and ActiValve were better than those of Provox2 and the Blom-Singer Classic. New voice prostheses, with a defined valve opening pressure (Provox Vega, Provox ActiValve, Blom-Singer Dual Valve) had longer lifetimes than prostheses without a defined opening pressure (Blom-Singer Classic and Provox 2). PMID- 23812586 TI - Structural basis for the inhibition of bacterial multidrug exporters. AB - The multidrug efflux transporter AcrB and its homologues are important in the multidrug resistance of Gram-negative pathogens. However, despite efforts to develop efflux inhibitors, clinically useful inhibitors are not available at present. Pyridopyrimidine derivatives are AcrB- and MexB-specific inhibitors that do not inhibit MexY; MexB and MexY are principal multidrug exporters in Pseudomonas aeruginosa. We have previously determined the crystal structure of AcrB in the absence and presence of antibiotics. Drugs were shown to be exported by a functionally rotating mechanism through tandem proximal and distal multisite drug-binding pockets. Here we describe the first inhibitor-bound structures of AcrB and MexB, in which these proteins are bound by a pyridopyrimidine derivative. The pyridopyrimidine derivative binds tightly to a narrow pit composed of a phenylalanine cluster located in the distal pocket and sterically hinders the functional rotation. This pit is a hydrophobic trap that branches off from the substrate-translocation channel. Phe 178 is located at the edge of this trap in AcrB and MexB and contributes to the tight binding of the inhibitor molecule through a pi-pi interaction with the pyridopyrimidine ring. The voluminous side chain of Trp 177 located at the corresponding position in MexY prevents inhibitor binding. The structure of the hydrophobic trap described in this study will contribute to the development of universal inhibitors of MexB and MexY in P. aeruginosa. PMID- 23812587 TI - Unusual base pairing during the decoding of a stop codon by the ribosome. AB - During normal translation, the binding of a release factor to one of the three stop codons (UGA, UAA or UAG) results in the termination of protein synthesis. However, modification of the initial uridine to a pseudouridine (Psi) allows efficient recognition and read-through of these stop codons by a transfer RNA (tRNA), although it requires the formation of two normally forbidden purine purine base pairs. Here we determined the crystal structure at 3.1 A resolution of the 30S ribosomal subunit in complex with the anticodon stem loop of tRNA(Ser) bound to the PsiAG stop codon in the A site. The PsiA base pair at the first position is accompanied by the formation of purine-purine base pairs at the second and third positions of the codon, which show an unusual Watson Crick/Hoogsteen geometry. The structure shows a previously unsuspected ability of the ribosomal decoding centre to accommodate non-canonical base pairs. PMID- 23812588 TI - A stable transcription factor complex nucleated by oligomeric AML1-ETO controls leukaemogenesis. AB - Transcription factors are frequently altered in leukaemia through chromosomal translocation, mutation or aberrant expression. AML1-ETO, a fusion protein generated by the t(8;21) translocation in acute myeloid leukaemia, is a transcription factor implicated in both gene repression and activation. AML1-ETO oligomerization, mediated by the NHR2 domain, is critical for leukaemogenesis, making it important to identify co-regulatory factors that 'read' the NHR2 oligomerization and contribute to leukaemogenesis. Here we show that, in human leukaemic cells, AML1-ETO resides in and functions through a stable AML1-ETO containing transcription factor complex (AETFC) that contains several haematopoietic transcription (co)factors. These AETFC components stabilize the complex through multivalent interactions, provide multiple DNA-binding domains for diverse target genes, co-localize genome wide, cooperatively regulate gene expression, and contribute to leukaemogenesis. Within the AETFC complex, AML1-ETO oligomerization is required for a specific interaction between the oligomerized NHR2 domain and a novel NHR2-binding (N2B) motif in E proteins. Crystallographic analysis of the NHR2-N2B complex reveals a unique interaction pattern in which an N2B peptide makes direct contact with side chains of two NHR2 domains as a dimer, providing a novel model of how dimeric/oligomeric transcription factors create a new protein-binding interface through dimerization/oligomerization. Intriguingly, disruption of this interaction by point mutations abrogates AML1-ETO-induced haematopoietic stem/progenitor cell self-renewal and leukaemogenesis. These results reveal new mechanisms of action of AML1-ETO, and provide a potential therapeutic target in t(8;21)-positive acute myeloid leukaemia. PMID- 23812589 TI - mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function. AB - The mechanistic target of rapamycin (mTOR) pathway integrates diverse environmental inputs, including immune signals and metabolic cues, to direct T cell fate decisions. The activation of mTOR, which is the catalytic subunit of the mTORC1 and mTORC2 complexes, delivers an obligatory signal for the proper activation and differentiation of effector CD4(+) T cells, whereas in the regulatory T-cell (T(reg)) compartment, the Akt-mTOR axis is widely acknowledged as a crucial negative regulator of T(reg)-cell de novo differentiation and population expansion. However, whether mTOR signalling affects the homeostasis and function of T(reg) cells remains largely unexplored. Here we show that mTORC1 signalling is a pivotal positive determinant of T(reg)-cell function in mice. T(reg) cells have elevated steady-state mTORC1 activity compared to naive T cells. Signals through the T-cell antigen receptor (TCR) and interleukin-2 (IL-2) provide major inputs for mTORC1 activation, which in turn programs the suppressive function of T(reg) cells. Disruption of mTORC1 through Treg-specific deletion of the essential component raptor leads to a profound loss of T(reg) cell suppressive activity in vivo and the development of a fatal early onset inflammatory disorder. Mechanistically, raptor/mTORC1 signalling in T(reg) cells promotes cholesterol and lipid metabolism, with the mevalonate pathway particularly important for coordinating T(reg)-cell proliferation and upregulation of the suppressive molecules CTLA4 and ICOS to establish Treg-cell functional competency. By contrast, mTORC1 does not directly affect the expression of Foxp3 or anti- and pro-inflammatory cytokines in T(reg) cells, suggesting a non-conventional mechanism for T(reg)-cell functional regulation. Finally, we provide evidence that mTORC1 maintains T(reg)-cell function partly through inhibiting the mTORC2 pathway. Our results demonstrate that mTORC1 acts as a fundamental 'rheostat' in T(reg) cells to link immunological signals from TCR and IL-2 to lipogenic pathways and functional fitness, and highlight a central role of metabolic programming of T(reg)-cell suppressive activity in immune homeostasis and tolerance. PMID- 23812590 TI - Dual-mode operation of neuronal networks involved in left-right alternation. AB - All forms of locomotion are repetitive motor activities that require coordinated bilateral activation of muscles. The executive elements of locomotor control are networks of spinal neurons that determine gait pattern through the sequential activation of motor-neuron pools on either side of the body axis. However, little is known about the constraints that link left-right coordination to locomotor speed. Recent advances have indicated that both excitatory and inhibitory commissural neurons may be involved in left-right coordination. But the neural underpinnings of this, and a possible causal link between these different groups of commissural neurons and left-right alternation, are lacking. Here we show, using intersectional mouse genetics, that ablation of a group of transcriptionally defined commissural neurons--the V0 population--leads to a quadrupedal hopping at all frequencies of locomotion. The selective ablation of inhibitory V0 neurons leads to a lack of left-right pattern at low frequencies, mixed coordination at medium frequencies, and alternation at high locomotor frequencies. When ablation is targeted to excitatory V0 neurons, left-right alternation is present at low frequencies, and hopping is restricted to medium and high locomotor frequencies. Therefore, the intrinsic logic of the central control of locomotion incorporates a modular organization, with two subgroups of V0 neurons required for the existence of left-right alternating modes at different speeds of locomotion. The two molecularly distinct sets of commissural neurons may constrain species-related naturally occurring frequency-dependent coordination and be involved in the evolution of different gaits. PMID- 23812592 TI - Nifedipine enhances cholesterol efflux in RAW264.7 macrophages. AB - PURPOSE: Studies have shown that nifedipine protects against atherosclerotic progression, but its underlying mechanisms remain unclear. In this study, we examined if nifedipine increases macrophage cholesterol efflux, a pathway known to inhibit atherogenesis. METHODS: We evaluated the ability of different doses of nifedipine to affect cholesterol efflux in RAW264.7 macrophages and its relationship with mRNA and protein levels of several well-characterized proteins involved in cholesterol efflux, including ABCA1, ABCG1, SR-BI and LXRalpha, using quantitative real-time PCR, Western blotting, and siRNA techniques. RESULTS: Nifedipne at 1, 10, and 100 nmol/L increased apoA-I-mediated cholesterol efflux from 2.55 % to 5.65 %, 6.20 %, and 6.10 %, as well as HDL-mediated cholesterol efflux from 31.0 % to 42.5 %, 46.0 %, and 43.5 %, respectively, in RAW264.7 macrophages (p < 0.05), which was associated with increased mRNA expression levels of ABCA1, ABCG1, SR-BI, and LXRalpha (405 %, 381 %, 336 %; 890 %, 960 %, 1002 %; 285 %, 325 %, 336 %; 482 %, 445 %, 405 %, respectively, p < 0.05), and with increased protein levels of ABCA1, ABCG1, SR-BI, and LXRalpha (428 %, 492 %, 361 %; 288 %, 331 %, 365 %; 283 %, 320 %, 505 %; 581 %, 678 %, 608 %, respectively, p < 0.05). SiRNA-mediated silencing of LXRalpha revealed that LXRalpha was involved in these increases and the enhanced cholesterol efflux. CONCLUSION: Nifedipine may protect against atherosclerosis partly by promoting macrophage cholesterol efflux through the stimulation of LXRalpha-dependent expression of ABCA1, ABCG1, and SR-BI. PMID- 23812591 TI - Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. AB - DNA methylation is a heritable epigenetic modification involved in gene silencing, imprinting, and the suppression of retrotransposons. Global DNA demethylation occurs in the early embryo and the germ line, and may be mediated by Tet (ten eleven translocation) enzymes, which convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Tet enzymes have been studied extensively in mouse embryonic stem (ES) cells, which are generally cultured in the absence of vitamin C, a potential cofactor for Fe(II) 2-oxoglutarate dioxygenase enzymes such as Tet enzymes. Here we report that addition of vitamin C to mouse ES cells promotes Tet activity, leading to a rapid and global increase in 5hmC. This is followed by DNA demethylation of many gene promoters and upregulation of demethylated germline genes. Tet1 binding is enriched near the transcription start site of genes affected by vitamin C treatment. Importantly, vitamin C, but not other antioxidants, enhances the activity of recombinant Tet1 in a biochemical assay, and the vitamin-C-induced changes in 5hmC and 5mC are entirely suppressed in Tet1 and Tet2 double knockout ES cells. Vitamin C has a stronger effect on regions that gain methylation in cultured ES cells compared to blastocysts, and in vivo are methylated only after implantation. In contrast, imprinted regions and intracisternal A particle retroelements, which are resistant to demethylation in the early embryo, are resistant to vitamin-C induced DNA demethylation. Collectively, the results of this study establish vitamin C as a direct regulator of Tet activity and DNA methylation fidelity in ES cells. PMID- 23812593 TI - The unique and interactive contributions of peer victimization and teacher-child relationships to children's school adjustment. AB - The present study tested whether a close relationship with the teacher would reduce, or a conflictual relationship would amplify, links between peer victimization and school maladjustment. Data on 352 3rd- and 4th-grade children (166 boys; 186 girls) were collected over a two-year period. Teachers provided data on their relationships with students and students' academic performance. Children completed measures assessing peer victimization and school liking. Latent growth curve analyses revealed that at high levels of peer victimization declines in school liking were reduced when student shared a close, low conflict, relationship with their teacher. Furthermore, a combination of peer victimization and poor teacher-child relationship quality predicted trajectories of sustained, low academic performance. These findings highlight the benefits of a close relationship with the teacher for victimized children and the cumulative impact stress within peer- and teacher-relationships can have on students. PMID- 23812594 TI - Impacts of age on coronary atherosclerosis and vascular response to statin therapy. AB - Age is a well-established risk factor for cardiovascular disease. Recent trials using intravascular ultrasound (IVUS) have shown that lipid-lowering therapy with statins halts the progression or induces the regression of coronary artery plaques. However, impacts of age on coronary atherosclerosis and vascular response to statin therapy have not been fully evaluated. The effects of 8-month statin therapy on coronary atherosclerosis were evaluated using virtual histology IVUS. IVUS data were analyzed from 119 patients who were divided into two groups according to age: elderly patients (>=65 years, n = 72) and non-elderly patients (<65 years, n = 47). No patients were taking statins or other lipid-lowering therapies at baseline. At baseline, external elastic membrane (EEM) volume (17.27 vs. 14.95 mm(3)/mm, p = 0.02) and plaque volume (9.49 vs. 8.11 mm(3)/mm, p = 0.03) in the elderly patients were significantly greater than in the non-elderly patients. The EEM volume (-2.4 %, p = 0.007) and plaque volume (-3.1 %, p = 0.007) after 8-month of statin therapy had significantly decreased in the non elderly patients but not in the elderly patients. A significant positive correlation was observed between age and percentage change in plaque volume (r = 0.265, p = 0.004). A multivariate regression analysis showed that age was a significant predictor of the percentage change in plaque volume during statin therapy (beta = 0.223, p = 0.02). Coronary atherosclerosis was more advanced and vascular responses to statin therapy were attenuated in the elderly patients compared to the non-elderly patients. PMID- 23812595 TI - Exploring the determinants of fracture risk among individuals with spinal cord injury. AB - In this cross-sectional study, we found that areal bone mineral density (aBMD) at the knee and specific tibia bone geometry variables are associated with fragility fractures in men and women with chronic spinal cord injury (SCI). INTRODUCTION: Low aBMD of the hip and knee regions have been associated with fractures among individuals with chronic motor complete SCI; however, it is unclear whether these variables can be used to identify those at risk of fracture. In this cross sectional study, we examined whether BMD and geometry measures are associated with lower extremity fragility fractures in individuals with chronic SCI. METHODS: Adults with chronic [duration of injury >= 2 years] traumatic SCI (C1-L1 American Spinal Cord Injury Association Impairment Scale A-D) reported post injury lower extremity fragility fractures. Dual-energy X-ray absorptiometry (DXA) was used to measure aBMD of the hip, distal femur, and proximal tibia regions, while bone geometry at the tibia was assessed using peripheral quantitative computed tomography (pQCT). Logistic regression and univariate analyses were used to identify whether clinical characteristics or bone geometry variables were associated with fractures. RESULTS: Seventy individuals with SCI [mean age (standard deviation [SD]), 48.8 (11.5); 20 females] reported 19 fragility fractures. Individuals without fractures had significantly greater aBMD of the hip and knee regions and indices of bone geometry. Every SD decrease in aBMD of the distal femur and proximal tibia, trabecular volumetric bone mineral density, and polar moment of inertia was associated with fracture prevalence after adjusting for motor complete injury (odds ratio ranged from 3.2 to 6.1). CONCLUSION: Low knee aBMD and suboptimal bone geometry are significantly associated with fractures. Prospective studies are necessary to confirm the bone parameters reported to predict fracture risk in individuals with low bone mass and chronic SCI. PMID- 23812596 TI - Fracture prevention in patients with cognitive impairment presenting with a hip fracture: secondary analysis of data from the HORIZON Recurrent Fracture Trial. AB - Patients with cognitive impairment (CI) often do not receive secondary fracture prevention. Use of zoledronic acid led to a similar reduction in re-fracture risk but the survival benefit was limited to those without CI. INTRODUCTION: We tested whether the effects of zoledronic acid (Zol) on re-fracture and mortality differed in patients presenting with a hip fracture by cognitive status. METHODS: We used data from the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Recurrent Fracture Trial, of yearly intravenous 5 mg Zol vs. placebo in patients presenting with a hip fracture. Primary outcome was new fracture and secondary outcome mortality. Short Portable Mental Status Questionnaire (SPMSQ) with a cut-point of >2 was used to identify CI. Fine-Gray models for competing events were fitted to study the effect of Zol on re-fracture and Cox regression for death. A multiplicative term was introduced to study a potential interaction between treatment and cognitive status on outcomes. RESULTS: Baseline SPMSQ of 1,966/2,127 (92.4%) patients was measured. Three hundred fifty (17.8%) had CI, balanced between treatment arms. In the placebo arm, there was similar fracture incidence between those with and without CI (15.4 vs. 12.3%, p = 0.26). There was no significant interaction for the effect of CI on Zol and re-fracture (p = 0.66). CI was associated with higher 1-year mortality (12.6 vs. 4.3%, p < 0.001) and the interaction was bordering significance (interaction, p = 0.066). Zol prolonged survival only in patients with normal cognitive status [HR 0.56 (95% CI 0.40-0.80)] and not in those with CI [HR 0.90 (95% CI 0.59-1.38)]. CONCLUSIONS: While these results require confirmation, the findings support the use of bisphosphonates in patients with osteoporotic fracture and CI expected to live for more than 6 months. PMID- 23812597 TI - An algorithm using the early changes in PINP to predict the future BMD response for patients treated with daily teriparatide. AB - About two thirds of patients with a procollagen type I N-terminal propeptide (PINP) increase of >80 MUg/l at 1 month after starting teriparatide therapy showed a >=10 % increase in lumbar spine (LS) bone mineral density (BMD) from baseline at 12 months. We recommend this algorithm as an aid in the clinical management of patients treated with daily teriparatide. INTRODUCTION: An algorithm using PINP is provided in osteoporotic patients with teriparatide treatment. The correlations between the early changes in PINP and the subsequent BMD changes after daily teriparatide therapy were studied to develop an algorithm to monitor patients. METHODS: We evaluated whether early changes in PINP correlated with the changes in BMD at 12 months and developed an algorithm using the early changes in PINP to predict the upcoming BMD increases. RESULTS: The highest correlation coefficient for the relationship between PINP and LS BMD response was determined for the absolute change in PINP at 1 month and the percent change in LS BMD at 12 months (r = 0.36, p <0.01). Using a receiver operator curve analysis, we determined that an 80 MUg/l increase in PINP was the most convenient predictor of a 10% increase in LS BMD from baseline (area under curve = 0.72). Using a cut-off value of 80 MUg/l, the positive predictive value for predicting a 10% increase in LS BMD from baseline to 12 months was 65%. CONCLUSION: Greater short-term changes in PINP with teriparatide therapy are associated with greater 12-month increases in LS BMD. About two thirds of patients with a PINP increase of >80 MUg/l at 1 month after starting treatment showed a >=10 % increase in LS BMD from baseline at 12 months. We recommend this algorithm as an aid in the clinical management of patients treated with teriparatide. PMID- 23812598 TI - Physical activity as determinant of femoral neck strength relative to load in adult women: findings from the hip strength across the menopause transition study. AB - Our objective was to examine associations of physical activity in different life domains with peak femoral neck strength relative to load in adult women. Greater physical activity in each of the domains of sport, active living, home, and work was associated with higher peak femoral neck strength relative to load. INTRODUCTION: Our objective was to examine the associations of physical activity in different life domains with peak femoral neck strength relative to load in adult women. Composite indices of femoral neck strength integrate body size with femoral neck size and bone mineral density to gauge bone strength relative to load during a fall, and are inversely associated with incident fracture risk. METHODS: Participants were 1,919 pre- and early perimenopausal women from the Study of Women's Health Across the Nation. Composite indices of femoral neck strength relative to load in three failure modes (compression, bending, and impact) were created from hip dual-energy X-ray absorption scans and body size. Usual physical activity within the past year was assessed with the Kaiser Physical Activity Survey in four domains: sport, home, active living, and work. We used multiple linear regression to examine the associations. RESULTS: Greater physical activity in each of the four domains was independently associated with higher composite indices, adjusted for age, menopausal transition stage, race/ethnicity, Study of Women's Health Across the Nation study site, smoking status, smoking pack-years, alcohol consumption level, current use of supplementary calcium, current use of supplementary vitamin D, current use of bone-adverse medications, prior use of any sex steroid hormone pills or patch, prior use of depo-provera injections, history of hyperthyroidism, history of previous adult fracture, and employment status: standardized effect sizes ranged from 0.04 (p < 0.05) to 0.20 (p < 0.0001). CONCLUSIONS: Physical activity in each domain examined was associated with higher peak femoral neck strength relative to load in pre- and early perimenopausal women. PMID- 23812599 TI - Consequences of musculoskeletal disorders on occupational events: a life-long perspective from a national survey. AB - INTRODUCTION: Musculoskeletal disorders (MSDs) are among the most frequent causes of disability, with potentially important consequences. Our objective was to investigate from a lifelong perspective the factors associated with these consequences, including permanent withdrawal from the workforce, focusing especially on factors at the start of working life. METHODS: The data come from the SIP national survey (Sante et Histoire Professionnelle, health and occupational history). Three groups of subjects were compared with multinomial logistic models: group 1 (G1), who had MSDs that caused an important event in their working life; group 2, who had MSDs without any such consequence; and group 3 (G3), who had no MSD. RESULTS: In multivariate models, MSDs with consequences on occupational events were strongly associated with a low educational level for both sexes, and with some working conditions. In the comparison G1/G3, the odds ratio (OR) for "no diploma" compared to "university level" was 4.41 and the confidence interval (95 % CI) 2.31-8.40 for men. For women the OR was 2.02 (95 % CI 1.32, 3.10). Group 2's educational level was between G1 and G3, closer to G3. For men, another risk factor was a first job in construction or farming (OR = 2.95 for construction, 2.23 for farming, comparison G1/G3). Comparisons focusing on "permanent withdrawal from the workforce" yielded similar results. CONCLUSIONS: Associations between occupational history and health are complex; the results strongly suggest that factors at the beginning of working life, including level of education, have important delayed consequences, especially for workers with health disorders such as MDSs. In order to reduce the frequency of negative consequences, a better knowledge on causal mechanisms would be needed. PMID- 23812600 TI - Unicapsula species (Myxosporea: Trilosporidae) of Australian marine fishes, including the description of Unicapsula andersenae n. sp. in five teleost families off Queensland, Australia. AB - A survey of the myxosporean fauna of Australian marine fishes revealed the presence of three previously unreported species of Unicapsula (Multivalvulida: Trilosporidae) from sites off Southeast Queensland, off Lizard Island on the Great Barrier Reef, Queensland, and from Jurien Bay in Western Australia. Morphometric data (spore, polar capsule and caudal appendage dimensions) combined with Bayesian inference and maximum likelihood analyses of small subunit (SSU) and large subunit (LSU) ribosomal DNA (rDNA) were used for species identification and to explore relationships among these taxa. The four species of Unicapsula for which DNA data are now available for comparative purposes (Unicapsula andersenae n. sp., Unicapsula pflugfelderi, Unicapsula seriolae and Unicapsula pyramidata) formed a well-supported monophyletic sister clade to the other major multivalvulidan group, the Kudoidae. The combined morphometric and genetic diagnostic approach identified an undescribed taxon, U. andersenae n. sp., from the muscle of Argyrosomus japonicus, Acanthopagrus australis and Eleutheronema tetradactylum off the Southeast Queensland coast and in Lutjanus russellii and Sillago ciliata off Lizard Island. Intra-specific variation within U. andersenae n. sp. varied from 2-4 (0.2-0.4%) nucleotides over the SSU region to 2-20 (0.3 3.2%) over the LSU region. Inter-specific variation between U. andersenae n. sp. and the other three species for which genetic sequence data are now available ranged from 15-66 (3-6.5%) nucleotides over the SSU region to 103-120 (17.6 21.2%) nucleotides over the LSU region. The host distribution observed here for U. andersenae n. sp. (five fish species from five different fish families) represents the broadest specificity known for a single species of Unicapsula. U. pyramidata Naidjenova & Zaika 1970, whose spore morphology and presence of caudal appendages immediately distinguish it from other species, was recovered from the nemipterid, Scolopsis monogramma, off Lizard Island. U. seriolae Lester 1982 is reported here from Yellowtail Kingfish, Seriola lalandi, from sites off Queensland and from Jurien Bay, Western Australia. Comparative genetic analyses also revealed that an unidentified species of Unicapsula from Epinephelus septemfasciatus off Japan whose rDNA sequence data are available on GenBank is consistent with U. seriolae. This suggests that U. seriolae may also exhibit low host specificity and may be distributed widely throughout the Indo-West Pacific region. In comparison to other myxozoan genera, it is clear that the species richness of Unicapsula spp. falls well below that displayed by either Ceratomyxa spp. or Kudoa spp. The discovery of a further new species of Unicapsula in Australia now brings the total worldwide number of formally described Unicapsula species to a modest 11. Nonetheless, this taxon remains of significant interest to commercial and recreational fisheries through the potential production of macroscopic pseudocysts in fish muscle and post-mortem muscle liquefaction, both of which can render fish fillets unpalatable and unmarketable. PMID- 23812601 TI - Prevalence and diversity of Hepatozoon canis in naturally infected dogs in Japanese islands and peninsulas. AB - Canine hepatozoonosis is a worldwide protozoal disease caused by Hepatozoon canis and Hepatozoon americanum and is transmitted by ixodid ticks, Rhipicephalus and Amblyomma spp., respectively. H. canis infection is widespread in Africa, Europe, South America, and Asia, including Japan. The objective of this study was to study the distribution pattern and diversity of H. canis in naturally infected dogs in nine Japanese islands and peninsulas. Therefore, 196 hunting dogs were randomly sampled during the period from March to September 2011 and the ages and sexes were identified. Direct microscopy using Giemsa-stained blood smears revealed H. canis gametocytes in the peripheral blood of 45 (23.6%) dogs. Polymerase chain reaction (PCR) was performed on EDTA-anticoagulated blood, initially with the common primer set (B18S-F and B18S-R) amplifying the 1,665-bp portion of the 18S rRNA gene, and then with the specific primer set (HepF and HepR) amplifying about 660 bp fragments of the same gene. Based on PCR, 84 (42.9%) dogs were positive using the common primer and 81 (41.3%) were positive using the specific primer. The current investigation indicated that all screened areas, except for Sado Island and Atsumi Peninsula, were infected. Yaku Island had the highest infection rate (84.6% in males and 100.0% in females), while Ishigaki Island showed the lowest infection rates (8.3% in males and 17.7% in females). Both sexes were infected with no significant difference. However, diversity of infection among the surveyed islands and peninsulas was significantly different (P < 0.05). Although H. canis has previously been reported in dogs in Japan, the higher infection rate described in the current study and the diversity of infection in a wide range of islands strongly encourage prospective studies dealing with the prevention and treatment of the infection in dogs, as well as control of ticks. PMID- 23812603 TI - Natal departure timing from spatially varying environments is dependent of individual ontogenetic status. AB - Natal departure timing represents one of the first crucial decisions for juveniles born in spatially varying environments that ultimately disappear, but our knowledge on its determinants is limited. The present study aimed at understanding the determinants of juvenile natal departure by releasing individually tagged juvenile pike (Esox lucius L.) with variable body size and trophic position in a temporary flooded grassland. Specifically, we investigated whether natal departure depends on individual competitive status ('competition hypothesis'), physiological tolerance to environmental conditions ('physiological hypothesis') or individual trophic position and the spatial heterogeneity of trophic resources ('trophic hypothesis'). The results indicated that departure timing was negatively correlated with body size at release, showing that the dominance status among competing individuals was not the main trigger of juvenile departure. A positive correlation between departure timing and individual body size at departure was observed, suggesting that inter-individual variability in physiological tolerance did not explain departure patterns. While individual growth performances were similar irrespective of the timing of natal departure, stable isotope analyses revealed that juveniles with higher trophic position departed significantly earlier than individuals with lower trophic position. Therefore, the trade-off driving the use of spatially varying environments was most likely dependent upon the benefits associated with energetic returns than the costs associated with inter-individual competition or physiological stress. This result highlighted how ontogeny, and particularly ontogenetic niche shift, can play a central role in juvenile's decision to depart from natal habitats in a predatory species. PMID- 23812602 TI - Starting and stopping SUMOylation. What regulates the regulator? AB - A large number of proteins are modified post-translationally by the ubiquitin like protein (Ubl) SUMO. This process, known as sumoylation, regulates the function, localisation and activity of target proteins as part of normal cellular metabolism, e.g., during development, and through the cell cycle, as well as in response to a range of stresses. In order to be effective, the sumoylation pathway itself must also be regulated. This review describes how the SUMOylation process is regulated. In particular, regulation of the SUMO conjugation and deconjugation machinery at the level of transcription and by post-translational modifications is discussed. PMID- 23812604 TI - Scouts behave as streakers in honeybee swarms. AB - Harmonic radar tracking was used to record the flights of scout bees during takeoff and initial flight path of two honeybee swarms. One swarm remained intact and performed a full flight to a destination beyond the range of the harmonic radar, while a second swarm disintegrated within the range of the radar and most of the bees returned to the queen. The initial stretch of the full flight is characterized by accelerating speed, whereas the disintegrating swarm flew steadily at low speed. The two scouts in the swarm displaying full flight performed characteristic flight maneuvers. They flew at high speed when traveling in the direction of their destination and slowed down or returned over short stretches at low speed. Scouts in the disintegrating swarm did not exhibit the same kind of characteristic flight performance. Our data support the streaker bee hypothesis proposing that scout bees guide the swarm by traveling at high speed in the direction of the new nest site for short stretches of flight and slowing down when reversing flight direction. PMID- 23812605 TI - Neuroprotective, neuroplastic, and neurobehavioral effects of daily treatment with levetiracetam in experimental traumatic brain injury. AB - BACKGROUND: Prophylactic treatment with antiepileptic drugs (AEDs) has been recommended to prevent early seizure onset in patients with traumatic brain injury (TBI). However, the potential neuroprotective and/or detrimental effects of prophylactic AED treatment on behavioral and cognitive function after TBI are not well studied. OBJECTIVE: To investigate the effects of a novel AED, levitiracetam (LEV), on behavioral and cognitive function after experimental TBI in rats. METHODS: Adult male rats were administered LEV (intraperitoneal 50 mg/kg) or vehicle (saline; SL) daily for 20 days beginning 1 day after controlled cortical impact (CCI; 2.8 mm; 4 m/s) or sham surgery. Beam performance (days 1 6), Y-maze (day 7), and Morris water maze (days 14-19) postinjury testing was assessed. RESULTS: Daily LEV treatment improved motor function, increased novel arm exploration in the Y-maze, elicited greater hippocampal cell sparing, and decreased contusion volumes compared with CCI/SL rats. Daily LEV administration also reversed a TBI-induced decrease in regional glutamate transporter expression and neuroplastic marker proteins present 20 days post-CCI. Also, daily LEV treatment decreased regional IL-1beta expression after TBI. CONCLUSIONS: These results suggest that daily LEV treatment has beneficial effects on histological, molecular, and behavioral elements of neurological recovery after TBI, in part, via modulation of neuroinflammatory and excitatory pathways. PMID- 23812606 TI - Intravital multiphoton microscopy can model uptake and excretion of fluorescein in hepatic ischemia-reperfusion injury. AB - The liver is important in the biotransformation of various drugs, where hepatic transporters facilitate uptake and excretion. Ischemia-reperfusion (I/R) injury is a common occurrence in liver surgery, and the developing oxidative stress can lead to graft failure. We used intravital multiphoton tomography, with fluorescence lifetime imaging, to characterize metabolic damage associated with hepatic I/R injury and to model the distribution of fluorescein as a measure of liver function. In addition to measuring a significant increase in serum alanine transaminase levels, characteristic of hepatic I/R injury, a decrease in the averaged weighted lifetime of reduced nicotinamide adenine dinucleotide phosphate was observed, which can be attributed to a changed metabolic redox state of the hepatocytes. I/R injury was associated with delayed uptake and excretion of fluorescein and elevated area-under-the-curve within the hepatocytes compared to sham (i.e., untreated control) as visualized and modeled using images recorded by intravital multiphoton tomography. High-performance liquid chromatography analysis showed no differences in plasma or bile concentrations of fluorescein. Finally, altered fluorescein distribution was associated with acute changes in the expression of liver transport proteins. In summary, multiphoton intravital imaging is an effective approach to measure liver function and is more sensitive in contrasting the impact of I/R injury than measuring plasma and bile concentrations of fluorescein. PMID- 23812607 TI - Quantitative observation of focused-ultrasound-induced vascular leakage and deformation via fluorescein angiography and optical coherence tomography. AB - Focused ultrasound (FUS) is a recently discovered noninvasive technique for local and temporal enhancement of vascular permeability, which facilitates drug delivery from the vessels into the surrounding tissue. However, exposure to FUS at a high intensity may cause permanent damage. To investigate the effects of the FUS treatment on blood vessels, we propose to use fluorescein angiography (FA) and optical coherence tomography (OCT) for real-time observation of the diffusion of fluorescence dye from blood vessels and to evaluate the morphological changes of the vessels in vivo. With time-resolved FA imaging, the relationship between the exposed power and the improved permeability of the vessels can be assessed according to the enhancement of the fluorescent intensity due to the dye leakage. Furthermore, the variation of the time-resolved fluorescent intensities can be used to identify the occurrence of dye leakage. In contrast, OCT can be implemented for the reconstruction of tissue microstructures. To quantitatively evaluate the morphological changes of the vessels after the FUS exposure with OCT, a new algorithm was proposed to estimate the vessel area based on the comparison of backscattering properties resulting from the tissue and vascular structures. Results showed that the vessel area increased as the exposed power increased, and the area became significantly larger at a higher FUS exposure power of 10 W. In conclusion, integrated FA and OCT observation can be potentially effective for monitoring the outcome and investigating the effects of FUS treatment. PMID- 23812608 TI - Do jasmonates play a role in arbuscular mycorrhiza-induced local bioprotection of Medicago truncatula against root rot disease caused by Aphanomyces euteiches? AB - Bioprotective effects of mycorrhization with two different arbuscular mycorrhizal (AM) fungi, Funneliformis mosseae and Rhizophagus irregularis, against Aphanomyces euteiches, the causal agent of root rot in legumes, were studied in Medicago truncatula using phenotypic and molecular markers. Previous inoculation with an AM-fungus reduced disease symptoms as well as the amount of pathogen within roots, as determined by the levels of A. euteiches rRNA or transcripts of the gene sterol C24 reductase. Inoculation with R. irregularis was as efficient as that with F. mosseae. To study whether jasmonates play a regulatory role in bioprotection of M. truncatula by the AM fungi, composite plants harboring transgenic roots were used to modulate the expression level of the gene encoding M. truncatula allene oxide cyclase 1, a key enzyme in jasmonic acid biosynthesis. Neither an increase nor a reduction in allene oxide cyclase levels resulted in altered bioprotection by the AM fungi against root infection by A. euteiches. These data suggest that jasmonates do not play a major role in the local bioprotective effect of AM fungi against the pathogen A. euteiches in M. truncatula roots. PMID- 23812609 TI - Single-site bismuth alkoxide catalysts for the ring-opening polymerization of lactide. AB - Salen bismuth alkoxides, where the salen ligand contains 2,4-di-tert-butylphenoxy groups and one of ethylene, cyclohexane or ortho-phenyl as a backbone have been prepared from reactions involving Bi[N(SiMe3)2]3 and the free salen ligand followed by alcoholysis (ButOH, PriOH and 2,6-But2C6H3OH). The molecular structures of the salen ligand with the cyclohexyl back-bone have been determined for the complexes salenBiCl and salenBiOC6H3-2,6-But2. The chloro compound is a dimer with chloride bridges while the phenoxide is monomeric with an unusually distorted five-coordinate geometry. The phenoxide and tert-butoxide complexes have been employed in the ring-opening polymerization of lactides (L- and rac-) to give polylactides, PLAs. With rac-LA heterotactic PLA is formed preferentially, Pr = ~0.9, in dichloromethane or toluene at room temperature. The reaction is first order in [Bi] and is notably faster than most aluminum and zinc initiators as well as tin(II) octanoate. These results are discussed in terms of a recent report on the polymerization of LA by Peptobismol(r) and bismuth subsalicylate. PMID- 23812610 TI - Oncologic surveillance of breast cancer patients after lipofilling. AB - BACKGROUND: The regenerative effects of fat injections are based on the same hormones, growth factors, and stem cells that stimulate neoplastic angiogenesis and cancer progression in basic research. Few studies have analyzed the oncologic risk. No report has covered 5 years of oncologic surveillance, and no long-term risk has been estimated. The in vivo relationship between lipofilling and breast cancer remains unclear and controversial. This observational study focused on locoregional recurrence (LR) risk after lipofilling. METHODS: The study enrolled 60 patients after breast cancer surgery (total mastectomy) from 2000 to 2007 treated by lipofilling (82 single-surgeon procedures with the same fat-decanting technique). The study ended when follow-up observation reached 10 years. RESULTS: The study included invasive carcinoma (55 cases), in situ carcinoma (five cases), T1 (71.6 %) and T2 (23.3 %) carcinoma, N+ carcinoma (45 %), and stages 1 (43.3 %) and 2 (45 %) carcinoma. The overall 12-year incidence of LR was 5 % (1.6 % before and 3.3 % after lipofilling). The incidence of local relapse per 100 person-years was 0.36 in the first observation period and 0.43 after lipofilling. All LRs were stage 2, and the same rate, limited to stage 2, was 1.04. The crude cumulative incidence after lipofilling was 7.25 % (95 % confidence interval [CI], 0-15.4 %) for LR and 7.6 % (95 % CI, 0.2-15 %) for distant metastases. DISCUSSION: Clinical data and recurrence incidences were compared with those of prior publications concerning lipofilling oncologic risk and discussed in relation to the inherent cancer literature. CONCLUSIONS: Lipofilling may be used safely to treat tumor node metastasis stage 1 subjects after mastectomy. The local risk is low. For stage 2 patients, local failure was not significantly higher. Compared with institutional data and prior publications, the risk still is reliable. Breast conservative treatment must be investigated further because of the high risk for local relapse. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 23812611 TI - Surgical management of silicone mastitis: case series and review of the literature. AB - BACKGROUND: Free silicone injection for breast augmentation, which became widespread in the 1960s and continues illicitly to this day, has well-known adverse effects. In this retrospective chart review of 14 patients treated for silicone mastitis from 1990 to 2002, we present our experience with the surgical management of patients with silicone mastitis. METHODS: All the patients were women, ranging in age from 49 to 76 years old (mean age = 58.8). Patients presented to us a mean of 29.9 years after their free silicone breast injection. Treatment modalities were analyzed, and, specifically, methods of breast reconstruction involving autologous tissue transfers, implants, or a combination were evaluated. RESULTS: The majority of patients (12 of 14) required mastectomies for extensive silicone-infiltrated tissues. The remaining two patients had focal areas of disease and were successfully treated with excision and local breast parenchyma flaps. Autologous reconstruction was performed with a total of 20 flaps, including 12 free transverse rectus abdominis myocutaneous flaps, 4 free superior gluteal artery perforator (SGAP) flaps, and 4 pedicled latissimus dorsi (LD) flaps. Two patients had bilateral implant-based breast reconstruction. CONCLUSION: A variety of reconstructive options are available for patients presenting with silicone mastitis. Once an appropriate breast cancer workup has been performed, the surgical goal is to excise as much of the silicone infiltrated tissues as possible before reconstruction. To our knowledge, this is the first reported series that incorporates the use of SGAP and LD flaps as a means of autologous tissue reconstruction for silicone-infiltrated breasts. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23812612 TI - Fractional carbon dioxide laser and acoustic-pressure ultrasound for transepidermal delivery of cosmeceuticals: a novel method of facial rejuvenation. AB - BACKGROUND: This study aimed to determine the efficacy and safety of a new facial rejuvenation procedure that combines a fractional carbon dioxide (CO2) laser, an ultrasound emitter, and a cosmeceutical preparation to be applied intraoperatively. METHODS: A split-face, double-blind randomized prospective study of 14 patients was designed, in which one half of the face was treated with a fractional CO2 laser, with the other half receiving the same laser and acoustic pressure ultrasound for transepidermal delivery of cosmeceuticals. Two semiquantitative scales and two visual analog scales were completed to evaluate the efficacy of each treatment. The results were assessed on the basis of photographs taken before treatment and then after 1, 2, and 6 months afterward. Potential adverse effects and complications were recorded. RESULTS: Both treatments achieved significant improvements in all parameters evaluated (p < 0.001). The combined ultrasound and cosmeceutical treatment had better scores for reduced fine lines and wrinkles as well as for overall facial aging at 6 months (p < 0.01), with nearly 80 % overall improvement in facial aging. The treatment was well tolerated, and no unexpected adverse effects were observed. The majority of the patients (86 %) stated that they were satisfied or very satisfied with their results. CONCLUSION: One session of fractional ablative CO2 laser and acoustic pressure ultrasound technology for transepidermal delivery of cosmeceuticals is an effective method for treating facial rejuvenation. PMID- 23812613 TI - Facial rejuvenation with fine-barbed threads: the simple Miz lift. AB - BACKGROUND: Since the invention of the first barbed (short) suture by Sulamanidze in the late 1990s, different techniques have been described including Woffles (long) thread lifting, Waptos suture lifting, Isse unidirectional barbed-threads lifting, and silhouette lifting. The authors have implemented a newly developed type of thread integrating more small cogs and a soft and fragile feeling of the material (medical grade polypropylene: 16.5 cm long, 15 cm of length covered with cogs, and 0.40 mm in diameter). This study aimed to describe the authors' thread and the surgical techniques they have adopted to counteract the descent and laxity of facial soft tissues. METHODS: A retrospective chart review was performed during a period of 2 years, from March 2010 to February 2012. The procedure was performed with the patient under local anesthesia and intravenous sedation. The face was marked preoperatively to determine the appropriate vector of the thread and its five end fixation points. The superior border of the incision was approximately at the level of the lateral brow, and the lower border was about 2 cm above the superior margin of the helical root. After the temporal incision was made, the dissection was carried all the way down to the deep temporal fascia to create a plane between the superficial and deep temporal fascias. Using blunt cannulas, the dissection was continued in an inferomedial direction from the temporal incision to the lower face through the sub-submucosal aponeurotic system (sub-SMAS) plane, which was marked preoperatively. This sub SMAS dissection could easily proceed to the premasseteric space (PMS). The face lift sutures (Gusan Inc., Seoul, Republic of Korea) then were inserted through the cannula from the lower face to the temporal incision line. The sutures were trimmed, and the proximal ends were secured on the deep temporal fascia reinforced with Vicryl interrupted sutures. The results were assessed objectively using serial photography and subjectively according to patient assessment. Complications also were recorded. RESULTS: All but two patients (100/102, 98.1 %) were satisfied with the outcomes after surgery. Consensus ratings by two independent plastic surgeons found that objective outcomes were divided among "excellent," "good," and "fair." The postoperative course was uneventful except for one patient (1/102, 1 %) who presented with minor skin dimpling and another patient (1/102, 1 %) who had a temporary facial weakness. These two complicated cases were resolved spontaneously without any surgical interventions. CONCLUSIONS: The reported technique has several advantages over current approaches. First, the use of nonabsorbable sutures with sufficient maintenance potential can produce long-lasting, satisfying results. Second, use of the authors' fine thread can avoid complications such as extruded or visible thread, which often have been complaints with thread lifting. Third, use of a loose areolar plane, including sub-SMAS and PMS free of vital structures, which is deeper than the traditional lift procedure, can avoid any traction line during rest or animation without any significant complications. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23812614 TI - The complete S RNA and M RNA nucleotide sequences of a hippeastrum chlorotic ringspot virus (HCRV) isolate from Hymenocallis littoralis (Jacq.) Salisb in China. AB - An isolate of hippeastrum chlorotic ringspot virus (HCRV) named HLS1-2, causing necrotic spots on leaves of spider lily, was obtained and characterized in China. The complete S RNA and M RNAs of the HLS1-2 isolate are 2724 nt and 4741 nt in length, respectively. The HLS1-2 S RNA sequence is most closely related to that of HCRV, with 99 % identity. Viral proteins encoded by the M RNA are closely related to those of tomato yellow ring virus (TYRV), polygonum ringspot virus (PolRSV) and iris yellow spot virus (IYSV). Phylogenetic trees for the four viral proteins encoded by the S and M RNAs placed HCRV-HLS1-2 in a distinct cluster with IYSV, TYRV and PolRSV and provided further support for the subdivision of tospoviruses into American and Eurasian groups. PMID- 23812616 TI - Complete nucleotide sequence of Rosa rugosa leaf distortion virus, a new member of the family Tombusviridae. AB - This report describes the complete nucleotide sequence and genome organization of Rosa rugosa leaf distortion virus (RrLDV), the causal agent of a previously undescribed virus disease of Rosa rugosa. The RrLDV genome is a positive-sense ssRNA, 3971 nucleotides in length, containing five open reading frames (ORFs). ORF1 encodes a 27-kDa peptide (p27). ORF2 shares a common start codon with ORF1 and continues through the amber stop codon of p27 to produce an 87-kDa protein (p87) with amino acid sequence similarity to the RNA-dependent RNA polymerases (RdRp) of members of the family Tombusviridae. ORF3 encodes a protein of 8 kDa with no significant similarity to known viral sequences. ORF4 encodes a 6-kDa protein (p6) with similarity to the p13 movement proteins of members of the family Tombusviridae. ORF5 has no conventional start codon and overlaps with p6. A putative +1 frame shift mechanism allows p6 translation to continue through the stop codon and results in a 12-kDa protein with high homology to the carmovirus p13 movement protein. The 37-kDa protein encoded by ORF6 has amino acid sequence similarity to coat proteins (CPs) of members of the family Tombusviridae. Phylogenetic analyses of the RdRp and CP amino acid sequences placed RrLDV in a subgroup close to members of the genus Carmovirus of the family Tombusviridae. PMID- 23812617 TI - "Megavirales", a proposed new order for eukaryotic nucleocytoplasmic large DNA viruses. AB - The nucleocytoplasmic large DNA viruses (NCLDVs) comprise a monophyletic group of viruses that infect animals and diverse unicellular eukaryotes. The NCLDV group includes the families Poxviridae, Asfarviridae, Iridoviridae, Ascoviridae, Phycodnaviridae, Mimiviridae and the proposed family "Marseilleviridae". The family Mimiviridae includes the largest known viruses, with genomes in excess of one megabase, whereas the genome size in the other NCLDV families varies from 100 to 400 kilobase pairs. Most of the NCLDVs replicate in the cytoplasm of infected cells, within so-called virus factories. The NCLDVs share a common ancient origin, as demonstrated by evolutionary reconstructions that trace approximately 50 genes encoding key proteins involved in viral replication and virion formation to the last common ancestor of all these viruses. Taken together, these characteristics lead us to propose assigning an official taxonomic rank to the NCLDVs as the order "Megavirales", in reference to the large size of the virions and genomes of these viruses. PMID- 23812618 TI - Mortality in systemic sclerosis-a single centre study from the UK. AB - This study aims to determine the cause and predictors of mortality in a cohort of patients with systemic sclerosis (SSc) and assess whether the mortality rate differs significantly from the general population. Patients enrolled onto the Royal National Hospital for Rheumatic Diseases Connective Tissue Disease database between 1999 and 2010 were included in this study. The NHS Strategic Tracing Service and UK Registry of Births, Marriages and Deaths were used to establish date and cause of deaths. A retrospective case note review collected information on clinical phenotype and serology. A standardised mortality ratio (SMR) was calculated and survival was determined using Kaplan-Meier estimates. Univariate and multivariate predictors of survival were assessed using proportional hazards regression modelling. Amongst this cohort of 204 patients (25 males, 40 diffuse SSc), the mean age at diagnosis was 51.6 years (SD13.7) and the mean duration of follow-up was 12.5 years (SD 8.8 years). In the deceased group (53 patients), the mean age of death was 72.0 years (SD 12.3 years). The mean disease duration at death was 14.2 years (SD 8.5 years). The overall SMR was 1.34 (95 % confidence interval (CI) 1.00-1.75). The SMR was higher in males (1.54 [95 % CI 0.67-3.04] vs. 1.30 [95 % CI 0.95-1.74]). The leading causes of death in this cohort were infection, respiratory disease and malignancy. The most common cause of SSc related mortality was pulmonary complications. Factors adversely affecting survival were older age at diagnosis, male gender, interstitial lung disease (ILD) and anti-RNA polymerase III antibody. The mortality rate of our cohort, who had predominantly limited disease, was higher than that of the general population; although not as high as reported in previous retrospective studies. PMID- 23812619 TI - Does enthesopathy relate to M694V gene mutation in patients with Familial Mediterranean fever? AB - Familial Mediterranean fever (FMF) is a systemic hereditary autoinflammatory disorder. The present study aimed to investigate the relationship of enthesitis to FMF and to search the potential association between enthesitis and MEFV gene missense variations in patients with FMF. The study consisted of 72 FMF patients (mean age 29.12 +/- 11.47 years, 32 females), 29 patients with ankylosing spondylitis (AS) (mean age 34.14 +/- 11.73 years, 16 females), and 34 healthy volunteers (mean age 23.06 +/- 6.41 years, 8 females). FMF patients were classified according to the kind of MEFV gene mutation. Doppler ultrasound was used to determine enthesitis based on the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) scoring system. OMERACT score was significantly different between FMF patients and control group (p < 0.001 in all patients, p = 0.009 in men, and p = 0.002 in women). However, it was not significantly different between FMF and AS patients in both sexes. OMERACT score did not differ between FMF patients with and without M694V gene mutation. The best cutoff point of OMERACT score to predict enthesitis was found as >=0.5 with sensitivity of 29 %, specificity of 100 %, positive predictive value of 100 %, and negative predictive value of 40 %. PMID- 23812620 TI - Decreased interleukin-20 level in patients with systemic sclerosis: are they related with angiogenesis? AB - In this study, we aimed to evaluate the relation between angiogenesis indicators and T helper 17 cytokine group in patients with systemic sclerosis (SSc) which is a disease characterized by impaired angiogenesis and autoimmune response. In our study, patients with SSc are compared with patients with primary Raynaud's phenomenon (RP) and healthy controls. Forty SSc patients, 18 primary RP cases, and 20 healthy controls were included in our study. The demographic and clinical features of patients with SSc were recorded. The serum levels of vascular endothelial growth factor (VEGF), vascular endothelial (VE)-cadherin, interleukin (IL)-20, IL-22, and IL-23 were assessed. In the SSc group, IL-20 level was significantly lower than in both primary RP group and controls (p values <0.001). VE-cadherin level in SSc was significantly higher than in primary RP (p = 0.016). The IL-22 and IL-23 and VEGF levels of SSc, primary RP, and control groups were similar (p values >0.05). In SSc patients, IL-23 correlated negatively with VEGF (r = -0.36, p = 0.025) and positively with VE-cadherin (r = 0.55, p < 0.001). IL 20 levels in SSc patients correlated with disease duration (r = 0.32, p = 0.044). SSc patients with limited involvement had significantly higher VE-cadherin levels than SSc patients with diffuse involvement (p = 0.044). We observed that IL-20 which is an IL-10 group angiogenesis indicator was observed to be suppressed in SSc, suggesting abnormal angiogenesis. PMID- 23812621 TI - Anaesthesiological support in a cardiac electrophysiology laboratory: a single centre prospective observational study. AB - BACKGROUND: Implantation of cardiovascular implantable electronic devices (CIEDs) has greatly increased during the last decade and anaesthetic management of these patients remains an open question. OBJECTIVE: This study describes anaesthetic management and risk factors associated with complications occurring during these procedures. DESIGN: A single-centre prospective observational study. SETTING: Grenoble University Hospital, France, from May 2010 to October 2010. PATIENTS: All patients admitted to the cardiac electrophysiology laboratory were included. INTERVENTION: None. MAIN OUTCOME MEASURES: Clinical data, anaesthetic and medical characteristics as well as complications (respiratory or cardiovascular) and treatment were recorded by the anaesthetic nurse at the end of each procedure. RESULTS: Two hundred and sixty-nine patients were included, 229 (85%) with an American Society of Anaesthesiologists (ASA) status of 3 or 4, 103 (38%) with a New York Heart Association (NYHA) functional class of 3 or 4 and 136 (51%) with a left ventricular ejection fraction of less than 40%. Two hundred and forty-seven (92%) of the patients underwent deep sedation and 12 (8%) general anaesthesia. Seventy-eight (29%) patients had at least one complication, among whom 21 (27%) had at least one considered as severe. Fifty (19%) of the patients had a respiratory complication and 46 (17%) a cardiovascular complication; the latter was more frequently severe (41 vs. 12%; P=0.001). Lead extraction [odds ratio (OR) 13.7, 95% confidence interval (CI) 3.5 to 53.3; P<0.001], NYHA status of 4 (OR 11.8, 95% CI 1.8 to 74.8; P<0.001), implantable cardioverter-defibrillator (ICD) testing by T-wave shock (OR 3.9, 95% CI 1.53 to 10.2; P=0.005) and length of procedure (OR 1.01, 95% CI 1.004 to 1.031; P=0.013) were identified as independent risk factors for cardiovascular complications. CONCLUSION: Patients requiring cardiovascular implantable electronic device (CIED) implantation were fragile with a high complication rate and a high rate of severe complications even with anaesthesiological support. These complications, as well as the need for deep sedation or general anaesthesia, clearly justify the involvement of a qualified anaesthesiologist. PMID- 23812622 TI - Bilateral passive leg raising attenuates and delays tourniquet deflation-induced hypotension and tachycardia under spinal anaesthesia: a randomised controlled trial. AB - BACKGROUND: The pneumatic tourniquet is frequently used in total knee arthroplasty. Tourniquet deflation may result in hypotension and tachycardia caused by the rapid shift of blood volume back to the ischaemic limb and a decrease in cardiac preload. Passive leg raising (PLR) represents a 'self-volume challenge' that can result in an increase in preload. Such a PLR-induced increase in preload was hypothesised to attenuate the decrease in preload resulting from tourniquet deflation. OBJECTIVE: To evaluate the effect of PLR on hypotension and tachycardia following tourniquet deflation. DESIGN: A randomised controlled trial. SETTING: Single medical centre. PATIENTS: Seventy patients who underwent unilateral total knee arthroplasty were randomised into two groups: tourniquet deflation with PLR (n = 35) or without PLR (control group, n = 35). INTERVENTION(S): Patients in both groups were administered a single dose of plain bupivacaine for spinal anaesthesia. The pneumatic tourniquet was inflated on the thigh and the surgery was performed. The study composed of four steps: for the PLR group, step 1 - inflation of the tourniquet while the patient was supine; step 2 - the patient's legs were raised to a 45 degrees angle; step 3 - the tourniquet was deflated while the patient's legs were still raised; and step 4 - the legs were returned to the supine position. In the control group, the same perioperative procedure was used, but PLR was not conducted. MAIN OUTCOME MEASURES: The patients' blood pressure and heart rate were measured before, during and after tourniquet deflation. RESULTS: After tourniquet deflation, the magnitude of the changes in blood pressure and heart rate was less in the PLR group than that in the control group. In addition, the blood pressure nadir also occurred later in the PLR group than in the controls. CONCLUSION: Bilateral PLR is a simple, reversible manoeuvre that mimics rapid fluid loading. Bilateral PLR attenuates the severity of, and delays the time to, hypotension and tachycardia following deflation of a lower limb tourniquet. TRIAL REGISTRATION: ClinicalTrials.gov number NCT01592669. PMID- 23812623 TI - Accidental intra-arterial injection of paracetamol: different preparations, different results. PMID- 23812624 TI - Reply to: An alternative way of managing acute pain in patients who are in buprenorphine opioid substitution therapy programmes. PMID- 23812625 TI - Scavenger receptor-BI is a receptor for lipoprotein(a). AB - Scavenger receptor class B type I (SR-BI) is a multi-ligand receptor that binds a variety of lipoproteins, including high density lipoprotein (HDL) and low density lipoprotein (LDL), but lipoprotein(a) [Lp(a)] has not been investigated as a possible ligand. Stable cell lines (HEK293 and HeLa) expressing human SR-BI were incubated with protein- or lipid-labeled Lp(a) to investigate SR-BI-dependent Lp(a) cell association. SR-BI expression enhanced the association of both (125)I- and Alexa Fluor-labeled protein from Lp(a). By confocal microscopy, SR-BI was also found to promote the internalization of fluorescent lipids (BODIPY cholesteryl ester (CE)- and DiI-labeled) from Lp(a), and by immunocytochemistry the cellular internalization of apolipoprotein(a) and apolipoprotein B. When dual labeled ((3)H-cholesteryl ether,(125)I-protein) Lp(a) was added to cells expressing SR-BI, there was a greater relative increase in lipid uptake over protein, indicating that SR-BI mediates selective lipid uptake from Lp(a). Compared with C57BL/6 control mice, transgenic mice overexpressing human SR-BI in liver were found to have increased plasma clearance of (3)H-CE-Lp(a), whereas mouse scavenger receptor class B type I knockout (Sr-b1-KO) mice had decreased plasma clearance (fractional catabolic rate: 0.63 +/- 0.08/day, 1.64 +/- 0.62/day, and 4.64 +/- 0.40/day for Sr-b1-KO, C57BL/6, and human scavenger receptor class B type I transgenic mice, respectively). We conclude that Lp(a) is a novel ligand for SR-BI and that SR-BI mediates selective uptake of Lp(a) associated lipids. PMID- 23812626 TI - Stability in the metamemory realism of eyewitness confidence judgments. AB - The stability of eyewitness confidence judgments over time in regard to their reported memory and accuracy of these judgments is of interest in forensic contexts because witnesses are often interviewed many times. The present study investigated the stability of the confidence judgments of memory reports of a witnessed event and of the accuracy of these judgments over three occasions, each separated by 1 week. Three age groups were studied: younger children (8-9 years), older children (10-11 years), and adults (19-31 years). A total of 93 participants viewed a short film clip and were asked to answer directed two alternative forced-choice questions about the film clip and to confidence judge each answer. Different questions about details in the film clip were used on each of the three test occasions. Confidence as such did not exhibit stability over time on an individual basis. However, the difference between confidence and proportion correct did exhibit stability across time, in terms of both over/underconfidence and calibration. With respect to age, the adults and older children exhibited more stability than the younger children for calibration. Furthermore, some support for instability was found with respect to the difference between the average confidence level for correct and incorrect answers (slope). Unexpectedly, however, the younger children's slope was found to be more stable than the adults. Compared to the previous research, the present study's use of more advanced statistical methods provides a more nuanced understanding of the stability of confidence judgments in the eyewitness reports of children and adults. PMID- 23812627 TI - Isolation of tumor spheres and mesenchymal stem-like cells from a single primitive neuroectodermal tumor specimen. AB - PURPOSE: It has been reported that cancer stem cells (CSCs) can be isolated from primitive neuroectodermal tumor (PNET) specimens. Moreover, mesenchymal stem-like cells (MSLCs) have been isolated from Korean glioma specimens. Here, we tested whether tumor spheres and MSLCs can be simultaneously isolated from a single PNET specimen, a question that has not been addressed. METHODS: We isolated single cell suspensions from PNET specimens, then cultured these cells using methods for MSLCs or CSCs. Cultured cells were analyzed for surface markers of CSCs using immunocytochemistry and for surface markers of bone marrow-derived mesenchymal stem cells (BM-MSCs) using fluorescence-activated cell sorting (FACS). Tumor spheres were exposed to neural differentiation conditions, and MSLCs were exposed to mesenchymal differentiation conditions. Possible locations of MSLCs within PNET specimens were determined by immunofluorescence analysis of tumor sections. RESULTS: Cells similar to tumor spheres and MSLCs were independently isolated from one of two PNET specimens. Spheroid cells, termed PNET spheres, were positive for CD133 and nestin, and negative for musashi and podoplanin. PNET spheres were capable of differentiation into immature neural cells and astrocytes, but not oligodendrocytes or mature neural cells. FACS analysis revealed that adherent cells isolated from the same PNET specimen, termed PNET MSLCs, had surface markers similar to BM-MSCs. These cells were capable of mesenchymal differentiation. Immunofluorescence labeling indicated that some CD105(+) cells might be closely related to endothelial cells and pericytes. CONCLUSION: We showed that both tumor spheres and MSLCs can be isolated from the same PNET specimen. PNET-MSLCs occupied a niche in the vicinity of the vasculature and could be a source of stroma for PNETs. PMID- 23812628 TI - Desmoplastic fibroma of the pediatric cranium: case report and review of the literature. AB - PURPOSE: Desmoplastic fibromas are primary bone tumors that seldom occur in the cranial bones. Furthermore, reports of desmoplastic fibromas of the skull in children are exceedingly rare. Although desmoplastic fibromas are histologically benign, they are locally aggressive and have a propensity to reoccur. Their radiographic appearance may mimic other more common central nervous system and bone neoplasms. There are only 19 reported cases of desmoplastic fibroma of the cranium in the literature, and only seven occurred in the pediatric age group. We present a case report of an 11-year-old female patient with a desmoplastic fibroma of the parieto-occipital region and review the literature. CASE REPORT: An 11-year-old female presented to the craniofacial clinic complaining of intermittent pain and a soft mass in the occipital region. There was a distant history of trauma to the region that did not require medical intervention. Computed tomography imaging revealed a lytic bone lesion overlying the sagittal sinus in the parieto-occipital region. Surgical resection with wide margins and immediate autologous reconstruction was performed. Pathological analysis revealed a desmoplastic fibroma. At 4 months of follow-up, no recurrence has been noted. CONCLUSION: Desmoplastic fibroma of the cranium is rare. Complete surgical resection with careful follow-up is the treatment of choice. PMID- 23812629 TI - Spontaneous spinal epidural hematoma secondary to extradural arteriovenous malformation in a child: a case-based update. AB - INTRODUCTION: The aim of this study was to report a rare pediatric case of spontaneous spinal epidural hematoma (SSEH) mimicking Guillain-Barre syndrome (GBS), secondary to an epidural arteriovenous malformation (AVM). Furthermore, a case-based update and insight into the entity is attempted. METHODS: An 8-year old male presented with progressing severe lower limb weakness and no traumatic history. Presentation was mimicking GBS with ascending symptoms. Magnetic resonance (MR) scan revealed a dorsal epidural mass, extending from C6-C7 to T2, compressing the spinal cord. Emergency laminoplasties and surgical evacuation of the hematoma were performed. An up-to-date review of reported SSEH cases in children was conducted, with emphasis on underlying vascular malformations (epidural AVMs in particular). Pathogenesis, predisposing factors, imaging, diagnosis, treatment and outcome are discussed. RESULTS: The hematoma was successfully evacuated. A vascular membrane on the dura was peeled off and sent for histopathology. There was no evidence of intradural vascular penetration. The patient improved postoperatively and was able to walk with support 7 months later. Histology revealed closely packed thin-walled angiomatous structures with wide lumens (filled with red blood cells) with walls composed of collagen and smooth muscle fibers, findings consistent with AVM. CONCLUSIONS: Non-traumatic SSEH is rare in the pediatric population. Although vascular malformations are suspected, they are extremely rarely identified histopathologically. This case represents one of the very few reports of pediatric SSEH caused by a histologically proven, purely epidural AVM. High index of clinical suspicion and low threshold for MR can lead to timely diagnosis and prompt treatment with good functional outcome. PMID- 23812630 TI - Olaquindox-induced apoptosis is suppressed through p38 MAPK and ROS-mediated JNK pathways in HepG2 cells. AB - We investigated mitogen-activated protein kinase (MAPK) pathways as well as reactive oxygen species (ROS) in olaquindox-induced apoptosis. Exposure of HepG2 cells to olaquindox resulted in the phosphorylation of p38 MAPK and c-Jun N terminal kinases (JNK). To confirm the role of p38 MAPK and JNK, HepG2 cells were pretreated with MAPKs-specific inhibitors prior to olaquindox treatment. Olaquindox-induced apoptosis was significantly potentiated by the JNK inhibitor (SP600125) or the p38 MAPK inhibitor (SB203580). Furthermore, we observed that olaquindox treatment led to ROS generation and that olaquindox-induced apoptosis and ROS generation were both significantly reduced by the antioxidants, superoxide dismutase and catalase. In addition, the levels of phosphorylation of JNK, but not p38 MAPK, were significantly suppressed after pretreatment of the antioxidants, while inhibition of the activations of JNK or p38 MAPK had no effect on ROS generation. This result suggested that ROS may be the upstream mediator for the activation of JNK. Conclusively, our results suggested that apoptosis in response to olaquindox treatment in HepG2 cells might be suppressed through p38 MAPK and ROS-JNK pathways. PMID- 23812631 TI - Factors controlling vascular permeability: transmitting mechanical signals. Focus on "Mechanical induction of group V phospholipase A2 causes lung inflammation and acute lung injury". PMID- 23812632 TI - Curcumin protects the developing lung against long-term hyperoxic injury. AB - Curcumin, a potent anti-inflammatory and antioxidant agent, modulates peroxisome proliferator-activated receptor-gamma signaling, a key molecule in the etiology of bronchopulmonary dysplasia (BPD). We have previously shown curcumin's acute protection against neonatal hyperoxia-induced lung injury. However, its longer term protection against BPD is not known. Hypothesizing that concurrent treatment with curcumin protects the developing lung against hyperoxia-induced lung injury long-term, we determined if curcumin protects against hyperoxic neonatal rat lung injury for the first 5 days of life, as determined at postnatal day (PND) 21. One day-old rat pups were exposed to either 21 or 95% O2 for 5 days with or without curcumin treatment (5 mg/kg) administered intraperitoneally one time daily, following which the pups grew up to PND21 in room air. At PND21 lung development was determined, including gross and cellular structural and functional effects, and molecular mediators of inflammatory injury. To gain mechanistic insights, embryonic day 19 fetal rat lung fibroblasts were examined for markers of apoptosis and MAP kinase activation following in vitro exposure to hyperoxia for 24 h in the presence or absence of curcumin (5 MUM). Curcumin effectively blocked hyperoxia-induced lung injury based on systematic analysis of markers for lung injury (apoptosis, Bcl-2/Bax, collagen III, fibronectin, vimentin, calponin, and elastin-related genes) and lung morphology (radial alveolar count and alveolar septal thickness). Mechanistically, curcumin prevented the hyperoxia-induced increases in cleaved caspase-3 and the phosphorylation of Erk1/2. Molecular effects of curcumin, both structural and cytoprotective, suggest that its actions against hyperoxia-induced lung injury are mediated via Erk1/2 activation and that it is a potential intervention against BPD. PMID- 23812634 TI - Wt1-expressing progenitors contribute to multiple tissues in the developing lung. AB - Lungs develop from paired endodermal outgrowths surrounded by a mesodermal mesenchyme. Part of this mesenchyme arises from epithelial-mesenchymal transition of the mesothelium that lines the pulmonary buds. Previous studies have shown that this mesothelium-derived mesenchyme contributes to the smooth muscle of the pulmonary vessels, but its significance for lung morphogenesis and its developmental fate are still little known. We have studied this issue using the transgenic mouse model mWt1/IRES/GFP-Cre (Wt1cre) crossed with the Rosa26R-EYFP reporter mouse. In the developing lungs, Wt1, the Wilms' tumor suppressor gene, is specifically expressed in the embryonic mesothelium. In the embryos obtained from the crossbreeding, the Wt1-expressing cell lineage produces the yellow fluorescent protein (YFP), allowing for colocalization with differentiation markers. Wt1cre-YFP cells were very abundant from the origin of the lung buds to postnatal stages, contributing significantly to pulmonary endothelial and smooth muscle cells, bronchial musculature, tracheal and bronchial cartilage, as well as CD34+ fibroblast-like interstitial cells. Thus Wt1cre-YFP mesenchymal cells show the very same differentiation potential as the splanchnopleural mesenchyme surrounding the lung buds. FSP1+ fibroblast-like cells were always YFP-; they expressed the common leukocyte antigen CD45 and were apparently recruited from circulating progenitors. We have also found defects in pulmonary development in Wt1-/- embryos, which showed abnormally fused lung lobes, round-shaped and reduced pleural cavities, and diaphragmatic hernia. Our results suggest a novel role for the embryonic mesothelium-derived cells in lung morphogenesis and involve the Wilms' tumor suppressor gene in the development of this organ. PMID- 23812633 TI - Agonists of MAS oncogene and angiotensin II type 2 receptors attenuate cardiopulmonary disease in rats with neonatal hyperoxia-induced lung injury. AB - Stimulation of MAS oncogene receptor (MAS) or angiotensin (Ang) receptor type 2 (AT2) may be novel therapeutic options for neonatal chronic lung disease (CLD) by counterbalancing the adverse effects of the potent vasoconstrictor angiotensin II, consisting of arterial hypertension (PAH)-induced right ventricular hypertrophy (RVH) and pulmonary inflammation. We determined the cardiopulmonary effects in neonatal rats with CLD of daily treatment during continuous exposure to 100% oxygen for 10 days with specific ligands for MAS [cyclic Ang-(1-7); 10-50 MUg.kg(-1).day(-1)] and AT2 [dKcAng-(1-7); 5-20 MUg.kg(-1).day(-1)]. Parameters investigated included lung and heart histopathology, fibrin deposition, vascular leakage, and differential mRNA expression in the lungs of key genes involved in the renin-angiotensin system, inflammation, coagulation, and alveolar development. We investigated the role of nitric oxide synthase inhibition with N(omega)-nitro-l-arginine methyl ester (25 mg.kg(-1).day(-1)) during AT2 agonist treatment. Prophylactic treatment with agonists for MAS or AT2 for 10 days diminished cardiopulmonary injury by reducing alveolar septum thickness and medial wall thickness of small arterioles and preventing RVH. Both agonists attenuated the pulmonary influx of inflammatory cells, including macrophages (via AT2) and neutrophils (via MAS) but did not reduce alveolar enlargement and vascular alveolar leakage. The AT2 agonist attenuated hyperoxia-induced fibrin deposition. In conclusion, stimulation of MAS or AT2 attenuates cardiopulmonary injury by reducing pulmonary inflammation and preventing PAH-induced RVH but does not affect alveolar and vascular development in neonatal rats with experimental CLD. The beneficial effects of AT2 activation on experimental CLD were mediated via a NOS-independent mechanism. PMID- 23812635 TI - Thioredoxin-1 mediates hypoxia-induced pulmonary artery smooth muscle cell proliferation. AB - Pathological pulmonary artery smooth muscle cell (PASMC) proliferation contributes to pulmonary vascular remodeling in pulmonary hypertensive diseases associated with hypoxia. Both the hypoxia-inducible factor (HIF) and phosphatidylinositol 3-kinase (PI3K)/serine/threonine kinase (Akt) pathways have been implicated in hypoxia-induced PASMC proliferation. Thioredoxin-1 (Trx1) is a ubiquitously expressed protein that is involved in redox-dependent signaling via HIF and PI3K-Akt in cancer. The role of Trx1 in PASMC proliferation has not been elucidated. The present studies tested the hypothesis that Trx1 regulates hypoxia induced PASMC proliferation via HIF and/or PI3K- and Akt-dependent mechanisms. Following exposure to chronic hypoxia, our data indicate that Trx1 activity is increased in adult murine lungs. Furthermore, hypoxia-induced increases in cellular proliferation are correlated with increased Trx1 expression, HIF activation, and Akt activation in cultured human PASMC. Both small-interfering RNA-mediated knockdown and pharmacological Trx1 inhibition attenuated hypoxia induced PASMC proliferation, HIF activation, and Akt activation. While Trx1 knockdown suppressed hypoxia-induced PI3K-Akt activation in PASMC, PI3K-Akt inhibition prevented hypoxia-induced proliferation but had no effect on hypoxia induced increases in Trx1 or HIF activation. Thus, our findings indicate that Trx1 contributes to hypoxia-induced PASMC proliferation by modulating HIF activation and subsequent PI3K-Akt activation. These novel data suggest that Trx1 might represent a novel therapeutic target to prevent hypoxic PASMC proliferation. PMID- 23812636 TI - The Fas/FasL pathway impairs the alveolar fluid clearance in mouse lungs. AB - Alveolar epithelial damage is a critical event that leads to protein-rich edema in acute lung injury (ALI), but the mechanisms leading to epithelial damage are not completely understood. Cell death by necrosis and apoptosis occurs in alveolar epithelial cells in the lungs of patients with ALI. Fas activation induces apoptosis of alveolar epithelial cells, but its role in the formation of lung edema is unclear. The main goal of this study was to determine whether activation of the Fas/Fas ligand pathway in the lungs could alter the function of the lung epithelium, and the mechanisms involved. The results show that Fas activation alters the alveolar barrier integrity and impairs the ability of the lung alveolar epithelium to reabsorb fluid from the air spaces. This result was dependent on the presence of a normal Fas receptor and was not affected by inflammation induced by Fas activation. Alteration of the fluid transport properties of the alveolar epithelium was partially restored by beta-adrenergic stimulation. Fas activation also caused apoptosis of alveolar endothelial cells, but this effect was less pronounced than the effect on the alveolar epithelium. Thus, activation of the Fas pathway impairs alveolar epithelial function in mouse lungs by mechanisms involving caspase-dependent apoptosis, suggesting that targeting apoptotic pathways could reduce the formation of lung edema in ALI. PMID- 23812637 TI - Epigenetic regulation of organic anion transporting polypeptide 1B3 in cancer cell lines. AB - PURPOSE: The expression of a multispecific organic anion transporter, OATP1B3/SLCO1B3, is associated with clinical prognosis and survival of cancer cells. The aims of present study were to investigate the involvement of epigenetic regulation in mRNA expression of a cancer-type variant of OATP1B3 (Ct OATP1B3) in cancer cell lines. METHODS: The membrane localization and transport functions of Ct-OATP1B3 were investigated in HEK293 cells transiently expressing Ct-OATP1B3. DNA methylation profiles around the transcriptional start site of Ct OATP1B3 in cancer cell lines were determined. The effects of a DNA methyltransferase inhibitor and siRNA knockdown of methyl-DNA binding proteins (MBDs) on the expression of Ct-OATP1B3 mRNA were investigated. RESULTS: 5'-RACE identified the TSS of Ct-OATP1B3 in PK-8 cells. Ct-OATP1B3 was localized on the plasma membrane, and showed the transport activities of E217betaG, fluvastatin, rifampicin, and Gd-EOB-DTPA. The CpG dinucleotides were hypomethylated in Ct OATP1B3-positive cell lines (DLD-1, TFK-1, PK-8, and PK-45P) but were hypermethylated in Ct-OATP1B3-negative cell lines (HepG2 and Caco-2). Treatment with a DNA methyltransferase inhibitor and siRNA knockdown of MBD2 significantly increased the expression of Ct-OATP1B3 mRNA in HepG2 and Caco-2. CONCLUSIONS: Ct OATP1B3 is capable of transporting its substrates into cancer cells. Its mRNA expression is regulated by DNA methylation-dependent gene silencing involving MBD2. PMID- 23812638 TI - Fathers' challenging parenting behavior prevents social anxiety development in their 4-year-old children: a longitudinal observational study. AB - Recent models on parenting propose different roles for fathers and mothers in the development of child anxiety. Specifically, it is suggested that fathers' challenging parenting behavior, in which the child is playfully encouraged to push her limits, buffers against child anxiety. In this longitudinal study, we explored whether the effect of challenging parenting on children's social anxiety differed between fathers and mothers. Fathers and mothers from 94 families were separately observed with their two children (44 % girls), aged 2 and 4 years at Time 1, in three structured situations involving one puzzle task and two games. Overinvolved and challenging parenting behavior were coded. Child social anxiety was measured by observing the child's response to a stranger at Time 1, and half a year later at Time 2, and by parental ratings. In line with predictions, father's challenging parenting behavior predicted less subsequent observed social anxiety of the 4-year-old child. Mothers' challenging behavior, however, predicted more observed social anxiety of the 4-year-old. Parents' overinvolvement at Time 1 did not predict change in observed social anxiety of the 4-year-old child. For the 2-year-old child, maternal and paternal parenting behavior did not predict subsequent social anxiety, but early social anxiety marginally did. Parent-rated social anxiety was predicted by previous parental ratings of social anxiety, and not by parenting behavior. Challenging parenting behavior appears to have favorable effects on observed 4-year-old's social anxiety when displayed by the father. Challenging parenting behavior emerges as an important focus for future research and interventions. PMID- 23812639 TI - Willingness score obtained after a short CPAP trial predicts CPAP use at 1 year. AB - PURPOSE: To predict continuous positive airway pressure (CPAP) adherence at 1 year. METHODS: We followed consecutive OSA patients scheduled for CPAP initiation for 1 year. Patients completed a self-efficacy questionnaire (5 = low, 25 = high score) before CPAP initiation. After CPAP initiation, we enquired about patients' satisfaction in CPAP trial and their eagerness and willingness to continue CPAP therapy (0 = unsatisfied, uneager, or refused CPAP; 100 = satisfied, eager, or willing to continue CPAP treatment). RESULTS: Of the 580 patients we followed, 377 continued CPAP therapy beyond 1 year. A low willingness score (<50) was expressed by 77 patients but only 7 of them used CPAP >4 h daily at 1 year, yielding a specificity of 97 % in predicting CPAP failure. At 1 year, patients with a self-efficacy score >20, expressed prior to CPAP initiation, used CPAP more often than the patients with a score <20 (average use 4.4 +/- 2.2 h vs. 3.7 +/- 2.3 h, p<0.001). CONCLUSIONS: A low score of willingness to continue CPAP therapy after a short trial predicts CPAP failure and poor CPAP adherence at 1 year. PMID- 23812641 TI - Targeted next generation sequencing in SPAST-negative hereditary spastic paraplegia. AB - Molecular characterization is important for an accurate diagnosis in hereditary spastic paraplegia (HSP). Mutations in the gene SPAST (SPG4) are the most common cause of autosomal dominant forms. We performed targeted next generation sequencing (NGS) in a SPAST-negative HSP sample. Forty-four consecutive HSP patients were recruited from an adult neurogenetics clinic in Sydney, Australia. SPAST mutations were confirmed in 17 subjects, and therefore 27 SPAST-negative patients were entered into this study. Patients were screened according to mode of inheritance using a PCR-based library and NGS (Roche Junior 454 sequencing platform). The screening panel included ten autosomal dominant (AD) and nine autosomal recessive (AR) HSP-causing genes. A genetic cause for HSP was identified in 25.9 % (7/27) of patients, including 1/12 classified as AD and 6/15 as AR or sporadic inheritance. Several forms of HSP were identified, including one patient with SPG31, four with SPG7 (with one novel SPG7 mutation) and two with SPG5 (including two novel CYP7B1 frameshift mutations). Additional clinical features were noted, including optic atrophy and ataxia for patients with SPG5 and ataxia and a chronic progressive external ophthalmoplegia-like phenotype for SPG7. This protocol enabled the identification of a genetic cause in approximately 25 % of patients in whom one of the most common genetic forms of HSP (SPG4) was excluded. Targeted NGS may be a useful method to screen for mutations in multiple genes associated with HSP. More studies are warranted to determine the optimal approach to achieve a genetic diagnosis in this condition. PMID- 23812643 TI - Nematode parasites of Chelidae (Testudines) from southern Brazil. AB - The presence of helminths associated with freshwater turtles is rarely reported. There are no records of nematodes parasitizing Acanthochelys spixii, and for Hydromedusa tectifera, there is only the report of unidentified nematodes found in this species in Argentina. This is the first report of nematodes (Spiroxys contortus and Camallanus sp.) in A. spixii and the first record of Spiroxys contortus and Camallanus sp. in H. tectifera. This is the southernmost record of S . contortus because this nematode was previously recorded only in Mexico. PMID- 23812642 TI - Intracerebral haemorrhage in a population-based stroke registry (LuSSt): incidence, aetiology, functional outcome and mortality. AB - Data on incidence of intracerebral haemorrhage (ICH) vary widely. Population based data on predictors of ICH survival and functional outcome are rare. The Ludwigshafen Stroke Study is a prospective, population-based stroke registry which started in January 2006. All residents of the city of Ludwigshafen, Germany, who suffer from acute stroke or transient ischaemic attack are registered. Patients with first-ever primary intracerebral haemorrhage (FE-pICH) between 2006 and 2010 were included in the present analysis. Between January 1st, 2006 and December 31st, 2010, 152 patients suffered a FE-pICH. Crude and age adjusted incidence rates per 100,000 for FE-pICH were 18.7 (95 % CI 15.9-21.9) and 11.9 (95 % CI 10.2-14.0), respectively, and remained stable over time. Case fatality rates for FE-pICH were 27.0, 34.9 and 44.1 % at days 28, 90 and 365, respectively. In 21 patients, an (21.3 %) early do-not resuscitate-order was documented. Excluding these patients from multivariate analyses, National Institute of Health Stroke Scale (NIHSS) (OR 1.22, 95 % CI 1.08-1.36), hypercholesterolemia (OR 0.16, 95 % CI 0.05-0.55) and modified Rankin Scale (mRS) prior to stroke (OR 1.56, 95 % CI 1.06-2.3) were independently associated with risk of 1-year mortality, whereas NIHSS (OR 1.41, 95 % CI 1.20-1.66) and leukocyte count on admission (OR 1.48, 95 % CI 1.16-1.89) were independently associated with good or moderate functional outcome (mRS <= 3) after 1 year. Incidence of FE-ICH is in the lower range of those reported from other registries and remained stable over the observation period. Higher treatment rates for hypertension might partly account for this. Stroke severity as indicated by NIHSS was independently associated with mortality and functional outcome after 1 year. We found no association between aetiology and outcome in ICH patients. PMID- 23812644 TI - Activation of Leishmania spp. leishporin: evidence that dissociation of an inhibitor not only improves its lipid-binding efficiency but also endows it with the ability to form pores. AB - We have previously shown that various species of Leishmania produce a lytic activity, which, in Leishmania amazonensis, is mediated by a pore-forming cytolysin, called leishporin. It is toxic for macrophages in vitro and optimally active at pH 5.0 to 5.5 and at 37 degrees C, suggesting that it might be active inside phagolysosomes. Leishporin from both L. amazonensis (a-leishporin) and Leishmania guyanensis (g-leishporin) can be activated by proteases, suggesting either a limited proteolysis of an inactive precursor or a proteolytic degradation of a non-covalently linked inhibitor. Here, we show that both a- and g-leishporin are also activated in dissociating conditions, indicating the second hypothesis as the correct one. In fact, we further demonstrated that inactive leishporin is non-covalently associated with an inhibitor, possibly more than one oligopeptide that, when removed, renders leishporin hemolytically active. This activation was shown to be the result of both the improvement of leishporin's ability to bind to phospholipids and the emergence of its pore-forming ability. In vitro results demonstrate that leishporin can be released by the parasites, as they evolve in axenic cultures, in an inactive form that can be activated. These results are compatible with our hypothesis that leishporin can be activated in the protease-rich, low pH, and dissociating environment of parasitophorous vacuoles, leading to disruption of both vacuoles and plasma membranes with the release of amastigotes. PMID- 23812645 TI - Simplified models for heterobivalent ligand binding: when are they applicable and which are the factors that affect their target residence time. AB - Bivalent ligands often display high affinity/avidity for and long residence time at their target. Thereto responsible is the synergy that emanates from the simultaneous binding of their two pharmacophores to their respective target sites. Thermodynamic cycle models permit the most complete description of the binding process, and thereto, corresponding differential equation-based simulations link the "microscopic" rate constants that govern the individual binding steps to the "macroscopic" bivalent ligand's binding properties. Present simulations of heterobivalent ligand binding led to an appreciably simpler description thereof. The thermodynamic cycle model can be split into two pathways/lanes that the bivalent ligand can solicit to reach fully bound state. Since the first binding event prompts the still free pharmacophore to stay into "forced proximity" of its target site, such lanes can be looked into by the equations that also apply to induced fit binding mechanisms. Interestingly, the simplest equations apply when bivalency goes along with a large gain in avidity. The overall bivalent ligand association and dissociation will be swifter than via each lane apart, but it is the lane that allows the fastest bidirectional "transit" between the free and the fully bound target that is chiefly solicited. The bivalent ligand's residence time is governed not only by the stability of the fully bound complex but also by the ability of freshly dissociated pharmacophores to successfully rebind. Hence, the presence of a slow-associating pharmacophore could be counterproductive. Yet, a long residence time is unfortunately also responsible for the slow attainment of binding equilibrium. PMID- 23812647 TI - Raman spectroscopic documentation of Oligocene bladder stone. AB - Discovery of a fossil (30-35 million-year-old) urolith from Early Oligocene deposits in northeastern Colorado provides the earliest evidence for the antiquity of bladder stones. These are spherical objects with a layered phosphatic structure and a hollow center. Each layer is composed of parallel crystals oriented perpendicular to the surface. Macroscopic and microscopic examination and X-ray diffraction analysis, along with comparison with 1,000 contemporary uroliths, were used as evidence in the confirmation of this diagnosis. Raman microspectroscopy verified the presence of organic material between layers, confirming its biologic origin. PMID- 23812646 TI - In vitro pharmacological profile of the A2A receptor antagonist istradefylline. AB - Adenosine A2A receptors are suggested to be a promising non-dopaminergic target for the treatment of Parkinson's disease (PD). Istradefylline is an adenosine A2A receptor antagonist that has been reported to exhibit antiparkinsonian activities in PD patients as well as both rodents and nonhuman primate models of PD. The aim of this study was to evaluate the in vitro pharmacological profile of istradefylline as an A2A receptor antagonist. Istradefylline exhibited high affinity for A2A receptors in humans, marmosets, dogs, rats, and mice. The affinities for the other subtypes of adenosine receptors (A1, A2B, and A3) were lower than that for A2A receptors in each species. Istradefylline demonstrated no significant affinity for other neurotransmitter receptors, including dopamine receptors (D1, D2, D3, D4, and D5). In addition, istradefylline hardly inhibited monoamine oxidase-A, monoamine oxidase-B, or catechol-O-methyl transferase. A kinetic analysis indicated that istradefylline reversibly binds to the human A2A receptors: The association reached equilibrium within 1 min, and the binding was also almost completely dissociated within 1 min. Istradefylline inhibited the A2A agonist CGS21680-induced accumulation of cAMP in the cultured cells and then shifted the concentration-response curve of CGS21680 to the right without affecting the maximal response of the agonist. These results indicate that istradefylline is a potent, selective, and competitive A2A receptor antagonist. The in vitro pharmacological profile of istradefylline helps to explain the in vivo profile of istradefylline and may be useful for clinical pharmacokinetic pharmacodynamic considerations of efficacy and safety. PMID- 23812649 TI - Optical methods of imaging in the skin. PMID- 23812648 TI - Domestic dogs' (Canis familiaris) choices in reference to information provided by human and artificial hands. AB - Even young humans show sensitivity to the accuracy and reliability of informants' reports. Children are selective in soliciting information and in accepting claims. Recent research has also investigated domestic dogs' (Canis familiaris) sensitivity to agreement among human informants. Such research utilizing a common human pointing gesture to which dogs are sensitive in a food retrieval paradigm suggests that dogs might choose among informants according to the number of points exhibited, rather than the number of individuals indicating a particular location. Here, we further investigated dogs' use of information from human informants using a stationary pointing gesture, as well as the conditions under which dogs would utilize a stationary point. First, we explored whether the number of points or the number of individuals more strongly influenced dogs' choices. To this end, dogs encountered a choice situation in which the number of points exhibited toward a particular location and the number of individuals exhibiting those points conflicted. Results indicated that dogs chose in accordance with the number of points exhibited toward a particular location. In a second experiment, we explored the possibility that previously learned associations drove dogs' responses to the stationary pointing gesture. In this experiment, dogs encountered a choice situation in which artificial hands exhibited a stationary pointing gesture toward or away from choice locations in the absence of humans. Dogs chose the location to which the artificial hand pointed. These results are consistent with the notion that dogs may respond to a human pointing gesture due to their past-learning history. PMID- 23812650 TI - Modulation of testicular and whole blood trace element concentrations in conjunction with testosterone release following kisspeptin administration in male rabbits (Oryctolagus cuniculus). AB - The present study investigated the role of kisspeptin-10 on reproductively significant trace elements in relation to testosterone release in male rabbits, Oryctolagus cuniculus. Groups of rabbits were exposed to single 1 MUg kisspeptin dose (i.v., saphenous vein), while simultaneous groups were pretreated with a kisspeptin antagonist, peptide-234 (50 MUg) 20 min before administering kisspeptin. Sequential blood sampling was done through marginal ear vein puncture at staggered time intervals: 0, 0.5, 1, 2, 4, and 24 h to determine serum testosterone. Testes and whole blood were collected at 4 and 24 h post dosage to determine trace element concentrations through atomic absorption spectrophotometry. In testes, zinc (Zn), manganese (Mn), and Fe concentrations showed significant increases at 24 h, while copper (Cu) concentration was found elevated at 4 and 24 h both (P < 0.001). In whole blood, Zn and Cu concentrations were significantly elevated at 4 and 24 h, while Mn and cobalt (Co) concentrations showed increases only at 24 h (P < 0.001). Blood iron concentration was not altered in the blood. In contrast, no change occurred in testicular Co, and chromium or nickel concentrations in either testes or blood. Compared to control and predose groups, serum testosterone levels increased gradually and peaked at 2 h (P < 0.001) post kisspeptin treatment but declined thereafter. Pretreatment with antagonist abolished all increases in trace elements and testosterone concentrations. The present study provides first evidence that reproduction- and fertility-related peptide "kisspeptin" modulates testicular and blood trace elements and that this action is likely GPR54 dependent. PMID- 23812651 TI - Regional differences in elements of human peroneus longus tendons. AB - Many studies have been performed on the structure, molecular composition, and biochemical properties of tendons. However, comparatively little research has been conducted on the content of various trace elements within tendons. Six elements were analyzed in four regions of the peroneus longus tendon: the tensional part of the tendon immediately proximal to the lateral malleolus (region A), the compressive region of the tendon in contact with the lateral malleolus (region B), the compressive region of the tendon in contact with the deep surface of the cuboid (region C), and the tensional part of the tendon between the cuboid and first metatarsal, to which the tendon is attached (region D). Regions B and C are wraparound regions. The calcium content was higher in region C (2.10 +/- 0.93 mg/g) than in both regions A (1.25 +/- 0.51 mg/g) and D (1.43 +/- 0.41 mg/g) (p < 0.05), indicating that it is likely related to regional differences in cartilage degeneration. The phosphorus content was also higher in region C, possibly because of low alkaline phosphatase activity in this region. The sulfur content was higher in the wraparound regions (region B: 0.98 +/- 0.09 mg/g, region C: 1.24 +/- 0.19 mg/g) than in both regions A (0.83 +/- 0.11 mg/g) and D (0.83 +/- 0.1 mg/g) (p < 0.01); sulfur content is thought to be influenced by tendon-bone compression. Finally, the magnesium content in the wraparound regions was also higher, which is probably related to a higher level of fibrocartilage. No significant relationships were found with regard to zinc or iron. Overall, the findings of the present study indicate that element contents are related to function and anatomical differences in tendons, and that they may even vary within the same tendon. PMID- 23812652 TI - Risk factors for diabetes mellitus in women with primary ovarian insufficiency. AB - Primary ovarian insufficiency (POI) is not only a gynecological problem but also has serious effects on women's health such as changes in hormone levels that can trigger fluctuations in blood sugar level and inflammation status. The present study was designed to determine vitamin D, copper, zinc, metabolic parameters [insulin, homeostasis model of assessment-insulin resistance (HOMA-IR)], inflammation parameters such as procalcitonin and high sensitivity C reactive protein (hs-CRP), and lipid profile in POI patients and control subjects with normal menstrual cycles. A total of 43 patients with nondiabetic POI were studied in order to evaluate and compare the findings with those of the control group, which comprised 33 women with normal menstrual cycles. The women with POI had higher levels of serum copper, serum insulin, glucose, LDL-cholesterol, total cholesterol, HOMA-IR, hs-CRP, and procalcitonin, whereas serum vitamin D and zinc levels were lower compared with the healthy control group. Follicle-stimulating hormone (FSH) levels were positively correlated with insulin, glucose, HOMA-IR, hs-CRP, procalcitonin, and copper and negatively correlated with vitamin D and zinc levels. In multivariate statistic analyses with body mass index and FSH as dependent variables, FSH was positively associated with copper and HOMA-IR negatively with vitamin D levels. The present study demonstrated that women with POI have traditional risk factors for diabetes mellitus, including lower levels of vitamin D, whereas higher levels of copper and HOMA-IR. PMID- 23812655 TI - Endophytic and mycorrhizal fungi associated with roots of endangered native orchids from the Atlantic Forest, Brazil. AB - The composition and diversity of fungal communities associated with three endangered orchid species, Hadrolaelia jongheana, Hoffmannseggella caulescens, and Hoffmannseggella cinnabarina, found in different vegetation formations of the Atlantic Forest were determined by constructing clone libraries and by applying diversity and richness indices. Our results demonstrated the presence of Basidiomycetes. Sebacinales (81.61%) and Cantharellales (12.10%) were the dominant orders and are potential candidates for orchid mycorrhizal fungi. The Ascomycetes identified included the Helotiales (29.31%), Capnodiales (18.10%), and Sordariales (10.34%), among others. These orders may represent potentially endophytic fungi. A Shannon-Wiener diversity index (H') analysis showed a relatively high fungal community diversity associated with these tropical orchids. This diversity may offer greater flexibility in terms of the adaptation of the plants to changing environmental conditions and the potential facilitation of reintroduction programs. The Simpson diversity index values showed that all of the libraries included dominant species, and a LIBSHUFF analysis showed that the fungal communities were structurally different from each other, suggesting an influence of local factors on this diversity. This study offers important information for the development of conservation strategies for threatened and endemic species of Brazilian flora in an important and threatened hotspot. PMID- 23812656 TI - Molecular and biological characterization of corchorus mottle virus, a new begomovirus from Brazil. AB - A begomovirus infecting Orinoco jute (Corchorus hirtus) from Brazil was characterized. Molecular analysis revealed a bipartite genomic organization, which is typical of the New World begomoviruses. Sequence analysis and phylogenetic data showed that both genomic components have the closest relationship with abutilon mosaic Brazil virus, with an identity of 87.3 % for DNA-A, indicating that this virus is a member of a new begomovirus species for which the name "Corchorus mottle virus" (CoMoV) is proposed. Sida rhombifolia plants inoculated by biolistics with an infectious clone of CoMoV showed systemic vein chlorosis, mottling and leaf deformation symptoms, while Nicotiana benthamiana and tomato plants had symptomless infection. CoMoV is the first corchorus-infecting begomovirus reported in Brazil. PMID- 23812657 TI - Malignant fibrous histiocytoma/undifferentiated high-grade pleomorphic sarcoma of the maxillary sinus: report of a case and review of the literature. AB - Malignant fibrous histiocytoma (MFH) also known as undifferentiated high-grade pleomorphic sarcoma (UHPS) is a soft tissue sarcoma, composed of undifferentiated mesenchymal tumors possessed fibrohistiocytic morphology without definite true histiocytic differentiation. Head and neck localization is very rare, showing an incidence ranging from 4 % to 10 % in different series of investigations. The most frequent involved sites in UHPS are the neck and parotid, followed by the scalp, face, anterior skull base and orbit. Upper aerodigestive tract, lateral skull base and ear are rare locations. The incidence of the lymphatic metastases is also rare. The aim of this article is to report a case of UHPS in the maxillary sinus with palatal, orbital and ethmoidal involvement, with lymphatic metastasis and its surgical treatment. In addition, we review the literature of similar cases of the past 12 years. PMID- 23812658 TI - Human chorionic gonadotropin increases beta-cleavage of amyloid precursor protein in SH-SY5Y cells. AB - Elevated levels of amyloid-beta (Abeta) peptides, the main component of amyloid plaques in Alzheimer's disease, are the result of excessive beta- and gamma cleavage of the amyloid precursor protein (APP) and/or impaired Abeta clearance in the brain. It has been suggested that high concentrations of luteinizing hormone (LH) in women contribute to increased Abeta generation after menopause, but the mechanism for this is incompletely understood. We investigated the effect of human chorionic gonadotropin (hCG), an LH receptor agonist, on APP beta cleavage in the SH-SY5Y neuroblastoma cell line. Treatment of these cells with hCG-induced elevated beta-cleavage in a dose-dependent manner: administration of 30 mIU but not 10 mIU/ml of hCG significantly increased sAPPbeta levels in the cell medium 1.7-fold as measured by ELISA. These results support the notion that LH contributes to elevated Abeta levels at least in part by increasing beta cleavage of APP by beta-site APP cleaving enzyme. PMID- 23812659 TI - Primary intrapulmonary thymoma. AB - Primary intrapulmonary thymoma (PIT), which is an intrapulmonary tumor without an associated mediastinal component, is rare. We herein report a resected case of PIT in a 55-year-old female who presented with a 2.5 * 2.4 cm mass in the left upper lobe. We also summarize the clinicopathological features and discuss the diagnosis, pathogenesis, and treatment of PIT. PMID- 23812660 TI - Development of a new strategy of visual field testing for macular dysfunction in patients with open angle glaucoma. AB - PURPOSE: To explore methods of automated visual field (VF) examination for the assessment of macular function. METHOD: We used a VF examination (AP-7000 automatic perimeter, Kowa, Japan) to examine macular function in 53 eyes from 29 patients with open angle glaucoma. We measured the mean total deviation (c-MD) of 16 points in the central VF located in a 2-degree-interval 4 * 4 array with various stimulus sizes (Goldmann sizes III, II, and I). The retinal nerve fiber layer (RNFL) thickness, ganglion cell complex (GCC), and ganglion cell layer plus inner plexiform layer (GCL + IPL) were measured with the 3D OCT-2000 System (Topcon, Japan). The c-MDs of various stimulus sizes were compared with the OCT parameters using the Spearman rank correlation. RESULTS: The average examination time was 93.5 +/- 23.5 s and the c-MD values were -11.8 +/- 8.2 (stimulus size III), -11.9 +/- 9.5 (stimulus size II), and -12.3 +/- 9.6 dB (stimulus size I). The c-MD (stimulus size III) and averaged total deviations of the Humphrey Field Analysis 10-2 program were significantly correlated (rho = 0.91). The C-MD values for stimulus size III were significantly correlated with the OCT parameters (RNFL: rho = 0.59; GCC: rho = 0.65; and GCL + IPL: rho = 0.64). The correlation coefficient between the c-MD and the GCC was better for stimulus sizes II and I (rho = 0.69) than for stimulus size III (rho = 0.65). CONCLUSION: The C-MD values for the 16 measured central VF points were significantly correlated with macular structure, and the smaller stimulus sizes of the automated VF test had a higher correlation coefficient of within 8 degrees . PMID- 23812661 TI - Comparative efficacy of LEAP, TEACCH and non-model-specific special education programs for preschoolers with autism spectrum disorders. AB - LEAP and TEACCH represent two comprehensive treatment models (CTMs) that have been widely used across several decades to educate young children with autism spectrum disorders. The purpose of this quasi-experimental study was to compare high fidelity LEAP (n = 22) and TEACCH (n = 25) classrooms to each other and a control condition (n = 28), in which teachers in high quality special education programs used non-model-specific practices. A total of 198 children were included in data analysis. Across conditions, children's performances improved over time. This study raises issues of the replication of effects for CTMs, and whether having access to a high quality special education program is as beneficial as access to a specific CTM. PMID- 23812662 TI - The clinical utility of the modified checklist for autism in toddlers with high risk 18-48 month old children in Singapore. AB - The modified checklist for autism in toddlers (M-CHAT) is a tool developed for 16 30 month old children to screen for autism spectrum disorders (ASD). It is a well researched tool, but little is known about its utility with Singaporean toddlers and with older children referred for developmental concerns. This study investigated the M-CHAT's performance with 18-30 month old (N = 173) and >30-48 month old (N = 407) developmentally at-risk Singaporean children, when used with three recommended scoring methods i.e., the total, critical and Best7 scoring methods. The results indicate that the critical and Best7 scoring methods detected most true cases of ASD without inflating the false positive rates in toddlers, and that only the total scoring method performed acceptably for the older children. PMID- 23812663 TI - iSocial: delivering the Social Competence Intervention for Adolescents (SCI-A) in a 3D virtual learning environment for youth with high functioning autism. AB - One consistent area of need for students with autism spectrum disorders is in the area of social competence. However, the increasing need to provide qualified teachers to deliver evidence-based practices in areas like social competence leave schools, such as those found in rural areas, in need of support. Distance education and in particular, 3D Virtual Learning, holds great promise for supporting schools and youth to gain social competence through knowledge and social practice in context. iSocial, a distance education, 3D virtual learning environment implemented the 31-lesson social competence intervention for adolescents across three small cohorts totaling 11 students over a period of 4 months. Results demonstrated that the social competence curriculum was delivered with fidelity in the 3D virtual learning environment. Moreover, learning outcomes suggest that the iSocial approach shows promise for social competence benefits for youth. PMID- 23812664 TI - Brief report: DSM-5 "levels of support:" a comment on discrepant conceptualizations of severity in ASD. AB - Proposed DSM-5 revisions to the diagnosis of autism spectrum disorder (ASD) include a "severity" marker based on degree of impairment. Although qualitative differences between support levels are described, quantitative methods or practice recommendations for differentiating between levels remain undetermined. This leaves the field vulnerable to potential discrepancies between severity categorizations that may have inadvertent service implications. We examined overlap between mild, moderate, and severe impairment classifications based on autism symptoms, cognitive skills, and adaptive functioning in 726 participants (15 months-17 years) with ASD. Participants with mild, moderate, and severe autism symptoms demonstrated varying levels of adaptive and cognitive impairment. These discrepancies highlight the need for a clearly elucidated method of classifying level of support in ASD diagnosis. PMID- 23812666 TI - Physico-chemical stability of eribulin mesylate containing concentrate and ready to-administer solutions. AB - OBJECTIVES: The aim of this study was to determine the stability of commercially available eribulin mesylate containing injection solution as well as diluted ready-to-administer solutions stored under refrigeration or at room temperature. METHODS: Stability was studied by a novel developed stability-indicating reversed phase high-performance liquid chromatography (RP-HPLC) assay with ultraviolet detection (detection wavelength 200 nm). Triplicate test solutions of eribulin mesylate containing injection concentrate (0.5 mg/mL) and with 0.9% sodium chloride solution diluted ready-to-administer preparations (0.205 mg/mL eribulin mesylate in polypropylene (PP) syringes, 0.020 mg/mL eribulin mesylate in polypropylene/polyethylene (PE) bags) were stored protected from light either at room temperature (25) or under refrigeration (2-8). Samples were withdrawn on day 0 (initial), 1, 3, 5, 7, 14, 21 and 28 of storage and assayed. Physical stability was determined by measuring the pH value once a week and checking for visible precipitations or colour changes. RESULTS: The stability tests revealed that concentrations of eribulin mesylate remained unchanged over a period of 28 days irrespective of concentration, container material or storage temperature. Neither colour changes nor visible particles have been observed. The pH value varied slightly over time but remained in the stability favourable range of 5-9. CONCLUSION: Eribulin mesylate injection (0.5 mg/mL) is physico-chemically stable over a period of 28 days after first puncture of the vial. After dilution with 0.9% NaCl vehicle solution, ready-to-administer eribulin mesylate injection solutions (0.205 mg/mL in PP syringe) and infusion solutions (0.02 mg/mL in prefilled PP/PE bags) are physico-chemically stable for a period of at least four weeks either refrigerated or stored at room temperature. For microbiological reasons storage under refrigeration is recommended. PMID- 23812665 TI - Measuring the plasticity of social approach: a randomized controlled trial of the effects of the PEERS intervention on EEG asymmetry in adolescents with autism spectrum disorders. AB - This study examined whether the Program for the Education and Enrichment of Relational Skills (PEERS: Social skills for teenagers with developmental and autism spectrum disorders: The PEERS treatment manual, Routledge, New York, 2010a) affected neural function, via EEG asymmetry, in a randomized controlled trial of adolescents with Autism spectrum disorders (ASD) and a group of typically developing adolescents. Adolescents with ASD in PEERS shifted from right-hemisphere gamma-band EEG asymmetry before PEERS to left-hemisphere EEG asymmetry after PEERS, versus a waitlist ASD group. Left-hemisphere EEG asymmetry was associated with more social contacts and knowledge, and fewer symptoms of autism. Adolescents with ASD in PEERS no longer differed from typically developing adolescents in left-dominant EEG asymmetry at post-test. These findings are discussed via the Modifier Model of Autism (Mundy et al. in Res Pract Persons Severe Disabl 32(2):124, 2007), with emphasis on remediating isolation/withdrawal in ASD. PMID- 23812667 TI - Clinical significance and prognostic value of microRNA expression signatures in hepatocellular carcinoma. AB - PURPOSE: MicroRNAs (miRNAs) play important roles in the development and progression of cancer. The aim of this study is to identify miRNA expression signatures in hepatocellular carcinoma and delineate their clinical significance for hepatocellular carcinoma. EXPERIMENTAL DESIGN: Patients with hepatocellular carcinoma, undergoing hepatectomy were randomly divided into training set (60 patients) and test set (50 patients). Other 56 patients were used as an independent cohort. The miRNA expression levels were detected by microarray and verified by quantitative real-time reverse transcription-PCR (qRT-PCR). RESULTS: A 30-miRNA signature consisting of 10 downregulated and 20 upregulated miRNAs was established for distinguishing hepatocellular carcinoma from noncancerous liver tissues in the training set with 99.2% accuracy. The classification accuracies of this signature were 97% and 90% in the test set and independent cohort, respectively. The expression level of four miRNAs in the 30-miRNA signature was verified by qRT-PCR in the training set. Twenty miRNAs were then selected to construct prognostic signature in the training set. Of the 20 miRNAs, six were risk factors and 14 were protective factors. A formula based on the 20 miRNAs was built to compute prognostic index. Kaplan-Meier analysis showed that patients with a higher prognostic index had a significantly lower survival than those with a low index. This was verified in the test and independent sets. Multivariate analysis indicated that the 20-miRNA signature was an independent prognostic predictor. CONCLUSIONS: The 30- and 20-miRNA signatures identified in this study should provide new molecular approaches for diagnosis and prognosis of patients with hepatocellular carcinoma and clues for elucidating molecular mechanism of hepatocarcinogenesis. PMID- 23812668 TI - A novel aldehyde dehydrogenase-3 activator (Alda-89) protects submandibular gland function from irradiation without accelerating tumor growth. AB - PURPOSE: To determine the effect of Alda-89 (an ALDH3 activitor) on (i) the function of irradiated (radiotherapy) submandibular gland (SMG) in mice, (ii) its toxicity profile, and (iii) its effect on the growth of head and neck cancer (HNC) in vitro and in vivo. EXPERIMENTAL DESIGN: Adult mice were infused with Alda-89 or vehicle before, during, and after radiotherapy. Saliva secretion was monitored weekly. Hematology, metabolic profile, and postmortem evaluation for toxicity were examined at the time of sacrifice. Alda-89 or vehicle was applied to HNC cell lines in vitro, and severe combined immunodeficient (SCID) mice transplanted with HNC in vivo with or without radiation; HNC growth was monitored. The ALDH3A1 and ALDH3A2 protein expression was evaluated in 89 patients with HNC and correlated to freedom from relapse (FFR) and overall survival (OS). RESULTS: Alda-89 infusion significantly resulted in more whole saliva production and a higher percentage of preserved acini after radiotherapy compared with vehicle control. There was no difference in the complete blood count, metabolic profile, and major organ morphology between the Alda-89 and vehicle groups. Compared with vehicle control, Alda-89 treatment neither accelerated HNC cell proliferation in vitro, nor did it affect tumor growth in vivo with or without radiotherapy. Higher expression of ALDH3A1 or ALDH3A2 was not significantly associated with worse FFR or OS in either human papillomavirus (HPV)-positive or HPV-negative group. CONCLUSION: Alda-89 preserves salivary function after radiotherapy without affecting HNC growth or causing measurable toxicity in mice. It is a promising candidate to mitigate radiotherapy-related xerostomia. PMID- 23812670 TI - Ki67 measured after neoadjuvant chemotherapy for primary breast cancer. AB - PURPOSE: The value of Ki67 measured on residual disease after neoadjuvant chemotherapy is not sufficiently described. EXPERIMENTAL DESIGN: Participants of the GeparTrio study with primary breast cancer randomly received neoadjuvant response-guided [8 cycles TAC (docetaxel/doxorubicin/cyclophosphamide) in responding and TAC-NX (vinorelbine/capecitabine) in nonresponding patients] or conventional (6 cycles TAC) chemotherapy according to interim response assessment. Ki-67 levels were centrally measured immunohistochemically after neoadjuvant treatment if tumor tissue was available. Here, we analyze 1,151 patients having a pathologic complete response (pCR; n, 484), or residual disease with low (0-15%), intermediate (15.1-35%), or high (35.1-100%) posttreatment Ki67 levels in 488, 77, and 102 patients, respectively. RESULTS: Patients with high posttreatment Ki67 levels showed higher risk for disease relapse (P < 0.0001) and death (P < 0.0001) compared with patients with low or intermediate Ki67 levels. Patients with low Ki67 levels showed a comparable outcome to patients with a pCR (P = 0.211 for disease-free and P = 0.779 for overall survival). Posttreatment Ki67 levels provided more prognostic information than pretreatment Ki67 levels or changes of Ki67 from pre- to posttreatment. Information on pCR plus posttreatment Ki67 levels surmount the prognostic information of pCR alone in hormone-receptor positive disease [hazard ratios (HR), 1.82-5.88] but not in hormone-receptor negative disease (HR: 0.61-1.73). Patients with conventional and response-guided treatment did not show a different distribution of posttreatment Ki67 (P = 0.965). CONCLUSIONS: Posttreatment Ki67 levels provide prognostic information for patients with hormone-receptor-positive breast cancer and residual disease after neoadjuvant chemotherapy. Levels were not prognostic for outcome after response guided chemotherapy. High posttreatment Ki67 indicates the need for innovative postneoadjuvant treatments. PMID- 23812669 TI - Development and preclinical characterization of a humanized antibody targeting CXCL12. AB - PURPOSE: Our goal was to develop a potent humanized antibody against mouse/human CXCL12. This report summarized its in vitro and in vivo activities. EXPERIMENTAL DESIGN: Cell surface binding and cell migration assays were used to select neutralizing hamster antibodies, followed by testing in several animal models. Monoclonal antibody (mAb) 30D8 was selected for humanization based on its in vitro and in vivo activities. RESULTS: 30D8, a hamster antibody against mouse and human CXCL12alpha, CXCL12beta, and CXCL12gamma, was shown to dose-dependently block CXCL12alpha binding to CXCR4 and CXCR7, and CXCL12alpha-induced Jurkat cell migration in vitro. Inhibition of primary tumor growth and/or metastasis was observed in several models. 30D8 alone significantly ameliorated arthritis in a mouse collagen-induced arthritis model (CIA). Combination with a TNF-alpha antagonist was additive. In addition, 30D8 inhibited 50% of laser-induced choroidal neovascularization (CNV) in mice. Humanized 30D8 (hu30D8) showed similar in vitro and in vivo activities as the parental hamster antibody. A crystal structure of the hu30D8 Fab/CXCL12alpha complex in combination with mutational analysis revealed a "hot spot" around residues Asn(44)/Asn(45) of CXCL12alpha and part of the RFFESH region required for CXCL12alpha binding to CXCR4 and CXCR7. Finally, hu30D8 exhibited fast clearance in cynomolgus monkeys but not in rats. CONCLUSION: CXCL12 is an attractive target for treatment of cancer and inflammation-related diseases; hu30D8 is suitable for testing this hypothesis in humans. PMID- 23812671 TI - Vemurafenib synergizes with nutlin-3 to deplete survivin and suppresses melanoma viability and tumor growth. AB - PURPOSE: For patients with advanced melanoma, primary and secondary resistance to selective BRAF inhibition remains one of the most critically compelling challenges. One rationale argues that novel biologically informed strategies are needed to maximally cripple melanoma cells up front before compensatory mechanisms emerge. As p53 is uncommonly mutated in melanoma, restoration of its function represents an attractive adjunct to selective BRAF inhibition. EXPERIMENTAL DESIGN: Thirty-seven BRAF(V600E)-mutated melanoma lines were subjected to synergy studies in vitro using a combination of vemurafenib and nutlin-3 (Nt-3). In addition, cellular responses and in vivo efficacy were also determined. We also analyzed changes in the levels of canonical apoptotic/survival factors in response to vemurafenib. RESULTS: Dual targeting of BRAF(V600E) and Hdm2 with vemurafenib and Nt-3, respectively, synergistically induced apoptosis and suppressed melanoma viability in vitro and tumor growth in vivo. Suppression of p53 in melanoma cells abrogated Nt-3's effects fully and vemurafenib's effects partially. A survey of canonical survival factors revealed that both vemurafenib and Nt-3 independently attenuated levels of the antiapoptotic protein, survivin. Genetic depletion of survivin reproduces the cytotoxic effects of the combination strategy. CONCLUSION: These results show preclinical feasibility for overcoming primary vemurafenib resistance by restoring p53 function. Moreover, it identifies survivin as one downstream mediator of the observed synergism and a potential secondary target. PMID- 23812673 TI - Enhanced beta-turn conformational stability of tripeptides containing DeltaPhe in cis over trans configuration. AB - Conformations of three pairs of dehydropeptides with the opposite configuration of the DeltaPhe residue, Boc-Gly-Delta(Z/E)Phe-Phe-p-NA (Z- p -NA and E- p -NA), Boc-Gly-Delta(Z/E)Phe-Phe-OMe (Z-OMe and E-OMe), and Boc-Gly-Delta(Z/E)Phe-Phe-OH (Z-OH and E-OH) were compared on the basis of CD and NMR studies in MeOH, TFE, and DMSO. The CD results were used as the additional input data for the NMR-based calculations of the detailed solution conformations of the peptides. It was found that Z- p -NA, E- p -NA, Z-OMe, and Z-OH adopt the beta-turn conformations and E OMe and E-OH are unordered. There are two overlapping type III beta-turns in Z- p -NA, type II' beta-turn in E- p -NA, and type II beta-turn in Z-OMe and Z-OH. The results obtained indicate that in the case of methyl esters and peptides with a free carboxyl group, Delta(Z)Phe is a much stronger inducer of ordered conformations than Delta(E)Phe. It was also found that temperature coefficients of the amide protons are not reliable indicators of intramolecular hydrogen bonds donors in small peptides. PMID- 23812672 TI - RNA editing events in mitochondrial genes by ultra-deep sequencing methods: a comparison of cytoplasmic male sterile, fertile and restored genotypes in cotton. AB - Cytoplasmic male sterility (CMS) is a maternally inherited trait resulting in failure to produce functional pollen and is widely used in the production of hybrid seed. Improper RNA editing is implicated as the molecular basis for some CMS systems. However, the mechanism of CMS in cotton is unknown. This study compared RNA editing events in eight mitochondrial genes (atp1, 4, 6, 8, 9, and cox1, 2, 3) among three lines (maintainer B, CMS A, and restorer R). These events were quantified by ultra-deep sequencing of mitochondrial transcripts and sequencing of cloned versions of these genes as cDNAs. A comparison of genomic PCR and RT-PCR products detected 72 editing sites in coding sequences in the eight genes and four partial editing sites in the 3'-untranslated region of atp6. The most frequent alteration (61.4 %) resulted in changes of hydrophilic amino acids to hydrophobic amino acids and the most common alteration was proline (P) to leucine (L) (26.7 %). In atp6, RNA editing created a stop codon from a glutamine in the genomic sequence. Statistical analysis of the frequencies of RNA editing events detected differences between mtDNA genes, but no differences between cotton cytoplasms that could account for the CMS phenotype or restoration. This study represents the first work to use next-generation sequencing to identify RNA editing positions and efficiency, and possible association with CMS and restoration in plants. PMID- 23812674 TI - Leucine treatment enhances oxidative capacity through complete carbohydrate oxidation and increased mitochondrial density in skeletal muscle cells. AB - Leucine has been largely implicated for increasing muscle protein synthesis in addition to stimulating mitochondrial biosynthesis. Limited evidence is currently available on the effects and potential benefits of leucine treatment on skeletal muscle cell glycolytic and oxidative metabolism. This work identified the effects of leucine treatment on oxidative and glycolytic metabolism as well as metabolic rate of human and murine skeletal muscle cells. Human rhabdomyosarcoma cells (RD) and mouse myoblast cells (C2C12) were treated with leucine at either 100 or 500 MUM for 24 or 48 h. Glycolytic metabolism was quantified by measuring extracellular acidification rate (ECAR) and oxidative metabolism was quantified by measuring oxygen consumption rate. Peroxisome proliferator-activated receptor coactivator 1 alpha (PGC-1alpha), an important stimulator of mitochondrial biosynthesis, was quantified using flow cytometry and verified by immunofluorescent confocal microscopy. Mitochondrial content was quantified using mitochondrial and cytochrome C staining measured by flow cytometry and confirmed with confocal microscopy. Treatment with leucine significantly increased both basal and peak oxidative metabolism in both cell models. Leucine treated cells also exhibited significantly greater mitochondrial proton leak, which is associated with heightened energy expenditure. Basal ECAR was significantly reduced in both cell models following leucine treatment, evidence of reduced lactate export and more complete carbohydrate oxidation. In addition, both PGC 1alpha and cytochrome C expression were significantly elevated in addition to mitochondrial content following 48 h of leucine treatment. Our observations demonstrated few dose-dependent responses induced by leucine; however, leucine treatment did induce a significant dose-dependent expression of PGC-1alpha in both cell models. Interestingly, C2C12 cells treated with leucine exhibited dose dependently reduced ATP content, while RD ATP content remain unchanged. Leucine presents a potent dietary constituent with low lethality with numerous beneficial effects for increasing oxidative preference and capacity in skeletal muscle. Our observations demonstrate that leucine can enhance oxidative capacity and carbohydrate oxidation efficiency, as well as verify previous observations of increased mitochondrial content. PMID- 23812675 TI - Prognostic value and clinical pathology of MACC-1 and c-MET expression in gastric carcinoma. AB - This study was to assess the expression of MACC-1 and c-MET in gastric cancer, and to correlate this expression with clinicohistological parameters and patient prognosis. Total RNA was extracted from cancer tissue and adjacent normal mucosa from frozen biopsy specimens of 30 patients with gastric cancer, and MACC-1 expression was assessed by RT-PCR. MACC-1 and c-MET protein expression were also assessed in paraffin-embedded tissues obtained from 436 tumor mucosa and 92 normal mucosa specimens by immunohistochemistry. The correlation between MACC-1 and c-MET expression and clinicopathological factors (age, sex, histology, tumor depth, lymph node status and vessel invasion) were also evaluated. RT-PCR analysis revealed that MACC-1 expression was significantly higher in cancerous mucosa compared with normal tissue. Immunohistochemical analysis indicated that MACC-1 and c-MET were moderately or strongly expressed in gastric cancer tissue, whereas expression was weak or absent in non-cancer tissue. Expression of MACC-1 or c-MET was significantly associated with larger tumor size, deeper tumor invasion, presence of lymph node metastasis, lymphatic involvement, venous invasion, distant metastasis and advanced clinical stage. However, only MACC-1 exhibited significantly greater expression in carcinomas from the higher age group. The intensity of MACC-1 and c-MET expression was also positively correlated. Survival analysis of the 436 gastric cancer patients revealed that patients in clinical stages I, II and III exhibiting lower MACC-1 and c-MET expression had a higher 5-year survival rate compared with patients expressing high levels of these proteins. Multivariate analysis revealed that MACC-1 and c MET may be independent prognostic indexes of gastric carcinoma (P < 0.01). Our findings confirm that MACC-1 and c-MET expression is strongly related to gastric cancer stage and degree of malignancy, and is inversely correlated to patient prognosis. Thus, MACC-1 and c-MET may interact to promote tumorigenesis and their expression may be used as independent prognostic markers in gastric cancer. PMID- 23812676 TI - Rhynchophylline-induced vasodilation in human mesenteric artery is mainly due to blockage of L-type calcium channels in vascular smooth muscle cells. AB - Rhynchophylline (Rhy) is a pharmacologically active substance isolated from Uncaria rhynchophylla which has been used to treat cardiovascular diseases and has drawn considerable attention in recent years for its antihypertensive activities. We investigated the actions of Rhy on endothelium-denuded human mesenteric artery by tension measurement and its actions on high conductance Ca(2+)-activated K(+) channels (BKCa) currents and calcium currents (ICa) in freshly isolated smooth muscle cells using perforated patch clamp technique. Intracellular Ca(2+) level was measured in Fura-2-loaded cells. Rhy inhibited both the KCl and BayK-evoked mesenteric artery constrictions in a dose-dependent manner. K(+) channel blockers (TEA, glibenclamide, IbTX, and 4-AP) did not affect the vasorelaxing effect of Rhy. Rhy inhibited L-type voltage-gated Ca(2+) current (ICa,L) but had no significant effect on macroscopic BKCa current. Rhy preincubation markedly reduced the elevation of [Ca(2+)]i level induced by KCl depolarization. Caffeine-stimulated [Ca(2+)]i elevation was also decreased to some extent by pretreatment with Rhy for 20 min. Our results show that Rhy relaxes smooth muscles of human mesenteric resistance arteries, mainly due to inhibition of Ca(2+) influx by blockage of L-type Ca(2+) channels and thereby the decrease in [Ca(2+)]i. PMID- 23812677 TI - Retrospective and prospective metacognitive judgments in rhesus macaques (Macaca mulatta). AB - A growing body of research suggests that some non-human animals are capable of making accurate metacognitive judgments. In previous studies, non-human animals have made either retrospective or prospective judgments (about how they did on a test or how they will do on a test, respectively). These two types of judgments are dissociable in humans. The current study tested the abilities of two rhesus macaque monkeys to make both retrospective and prospective judgments about their performance on the same memory task. Both monkeys had been trained previously to make retrospective confidence judgments. Both monkeys successfully demonstrated transfer of retrospective metacognitive judgments to the new memory task. Furthermore, both monkeys transferred their retrospective judgments to the prospective task (one, immediately, and one, following the elimination of a response bias). This study is the first to demonstrate both retrospective and prospective monitoring abilities in the same monkeys and on the same task, suggesting a greater level of flexibility in animals' metacognitive monitoring abilities than has been reported previously. PMID- 23812679 TI - Potentially inappropriate prescribing and drug-drug interactions among elderly Chinese nursing home residents in Macao. AB - BACKGROUND: The ageing of the population has become a concern all over the world, including Macao. In general, older people are more prone to adverse drug events which can result from potentially inappropriate medication (PIM) use and drug drug interactions (DDIs). OBJECTIVE: This study was designed to evaluate the prevalence of PIM use and DDIs among elderly nursing home residents in Macao, and to find out the factors associated with these drug-related problems. SETTING: This study was conducted in the largest nursing home in Macao, with a bed capacity of 168. METHOD: All data of this cross-sectional study were collected from medical charts and medication administration records. PIM use was determined by the screening tool of older person's prescription (STOPP) criteria and potential DDIs were detected using the preset criteria of two compendia, Drug Reax and Lexi-Interact. Multivariate logistic regression analysis was performed to identify the independent factors associated with each drug-related problem. MAIN OUTCOME MEASURES: The proportions of elderly nursing home residents who regularly used PIMs and who were exposed to DDIs. RESULTS: A total of 114 elderly residents were eligible for PIM analysis. They consumed an average of 6.9 +/- 3.1 different medications. About 46.5 % of them regularly used one or more PIMs. The prevalence of DDIs was 37.8 % among the 111 elderly residents who consumed at least two different medications. An increased number of drugs used was identified as the independent factor associated with PIM use and DDIs (p < 0.05). However, the use of STOPP-related PIMs did not appear to raise the likelihood of DDIs among the study population. CONCLUSION: Both PIM use and DDIs are common among elderly nursing home residents in Macao. Further studies should be conducted to evaluate the clinical outcomes of pharmacist-led interventions for elderly residents in the local nursing home setting. PMID- 23812678 TI - Intravenous phenytoin: a retrospective analysis of Bayesian forecasting versus conventional dosing in patients. AB - BACKGROUND: In the hospital, medication management for effective antiepileptic therapy with phenytoin (PHT) often needs rapid IV loading and subsequent dose adjustment according to therapeutic drug monitoring (TDM). OBJECTIVE: To investigate PHT performance in reaching therapeutic target serum concentration rapidly and sustainably, a Bayesian forecasting (BF) regimen was compared to conventional dosing (CD), according to the official summary of product characteristics. SETTING: A 500-600 bed acute care teaching hospital in Switzerland, serving as a referral centre for neurology and neurosurgery. METHOD: In a retrospective, single centre, long-term analysis of hospitalized in- and out patients, all PHT serum tests from the central hospital laboratory from 1997 to 2007 were assessed. The BF regimen consisted of a guided, body weight-adapted rapid IV PHT loading over 5 days with pre-defined TDM time points. The conventional dosage was performed without written guidance. Assuming non-normally distributed data, non-parametric statistical methods for analysis were applied. MAIN OUTCOME MEASURE: The extent of target therapeutic PHT serum levels (40-80 MUmol/L) was measured and compared between the two regimens. Also, the influence of gender and age was analysed. RESULTS: A total of 6,120 PHT serum levels (2,819 BF and 3,301 conventionally dosed) from 2,589 patients (869 BF and 1,720 conventionally dosed) were evaluated and compared. 63.6 % of the PHT serum levels from the BF group were within the therapeutic range, compared with only 34.0 % in the conventional group (p < 0.0001). The mean BF serum level was 52.0 +/- 22.1 MUmol/L (within target range) (n = 2,819), whereas the mean serum level of the CD was 39.8 +/- 28.2 MUmol/L (sub-target range) (n = 3,301). In the BF group, men had small but significantly lower PHT serum levels compared to women (p < 0.0001). The conventionally dosed group showed no significant gender differences (p = 0.187). A comparative sub-analysis of age-related groups (children, adolescents, adults, seniors, and elderly) showed significantly lower target levels (p < 0.0001) for each group in the conventional dosed group, compared to BF. CONCLUSION: Comparing the two cohorts, BF with the well-defined dose regimen showed significantly better performance in reaching therapeutic PHT serum levels rapidly and for longer duration. PMID- 23812680 TI - Communicating medication changes to community pharmacy post-discharge: the good, the bad, and the improvements. AB - BACKGROUND: Communication between hospital and community pharmacists when a patient is discharged from hospital can improve the accuracy of medication reconciliation, thus preventing unintentional changes and ensuring continuity of supply. It allows problems to be resolved before a patient requires a further supply of medication post-discharge. Despite evidence demonstrating the benefits of sharing information, community pharmacists' willingness to receive information and advances in information technology (particularly electronic discharge medication summaries), there is little published evidence to indicate whether communication has improved over the last 15 years. This study aimed to explore community pharmacists' experience of information sharing by and with their local hospital and GP practices. OBJECTIVES: (1) To establish the extent to which community pharmacies currently receive discharge medication information, and for which patients.(2)To determine community pharmacy staff opinion on where and how current communication practice could be improved. SETTING: Community Pharmacies in one Primary Care Organisation (PCO) in England. METHOD: Semi-structured interviews conducted during visits to community pharmacies. MAIN OUTCOME MEASURE: Reported receipt of discharge medication information from hospitals and general practices. RESULTS: A total of 14 community pharmacies participated. Current provision of information to community pharmacies from hospitals regarding medication changes at discharge was reported to be inconsistent and lacking in quality. Where information was received it was predominantly for patients who receive their medicines in monitored dosage systems (MDS) rather than for the general population of patients. Some examples of "notable practice" were reported. CONCLUSION: Community pharmacists received post-discharge information rarely and mainly for patients where the hospital perceived the patient's medication issues as "complex". Practice was inconsistent overall. These findings suggest that the potential of community pharmacists to improve patient safety after discharge from hospital is not being utilised. PMID- 23812681 TI - Trans-translation mediates tolerance to multiple antibiotics and stresses in Escherichia coli. AB - BACKGROUND: Trans-translation mediated by SsrA (tmRNA) and its associated protein SmpB plays an important role in rescuing stalled ribosomes and detoxifying toxic protein products under stress conditions. However, the role of SsrA and SmpB in bacterial persister survival has not been studied. The recent finding that pyrazinamide as a unique persister drug inhibits trans-translation in Mycobacterium tuberculosis prompted us to examine the role of trans-translation in persister survival. METHODS: Using Escherichia coli as a model, we constructed SsrA and SmpB mutants and assessed the susceptibility of the mutants to various antibiotics and stress conditions in MIC/MBC and persister assays. RESULTS: We found that mutations in SsrA and SmpB caused a defect in persister survival as shown by their increased susceptibility to a variety of antibiotics, including gentamicin, streptomycin, amikacin, norfloxacin, trimethoprim and tetracycline, and also stresses, such as acid, weak acid salicylate, heat and peroxide. Additionally, the SsrA and SmpB mutants were 2-8-fold more susceptible than the parent strain to various antibiotics in MIC and MBC tests. The SmpB mutant was more susceptible to antibiotics and stresses than the SsrA mutant. A particularly interesting finding is the hypersusceptibility of the SmpB mutant and the SsrA mutant to trimethoprim. The defect of various SsrA and SmpB mutant phenotypes could be complemented by functional ssrA and smpB, respectively. CONCLUSIONS: We conclude that SsrA and SmpB are important for persister survival and may serve as a good target for developing new antibiotics that kill persister bacteria for improved treatment of persistent bacterial infections. PMID- 23812682 TI - Plasma fibroblast growth factor 23 and osteocalcin serum levels are associated with cardiovascular risk in HIV-1-infected patients receiving antiretroviral treatment. PMID- 23812683 TI - Lincosamide resistance mediated by lnu(C) (L phenotype) in a Streptococcus anginosus clinical isolate. AB - OBJECTIVES: Unique resistance to lincosamides (L phenotype) due to the production of nucleotidyltransferases (Lnu) is uncommon among Gram-positive bacteria. The aim of the study was to characterize the L phenotype in a clinical isolate of the Streptococcus milleri group. METHODS: The strain UCN93 was recovered from neonatal specimens and from the mother's vaginal swab. Identification was confirmed by sequencing of the sodA gene. Antimicrobial susceptibility testing was carried out by the disc diffusion method, while MICs were determined using the agar dilution method. Screening for lnu(A), lnu(B), lnu(C) and lnu(D) genes was performed by PCR. Genetic environment and support were determined by thermal asymmetric interlaced PCR and PCR mapping. The transfer of lincomycin resistance was also attempted by conjugation. RESULTS: UCN93 was unambiguously identified as Streptococcus anginosus. It was susceptible to all tested antibiotics, except lincomycin (MIC, 8 mg/L) and tetracycline (2 mg/L). The lnu(C) gene was found to be responsible for the L phenotype. It was shown that lnu(C) was associated with a gene coding for a transposase within a structure similar to the transposon MTnSag1, described once in Streptococcus agalactiae. Since MTnSag1 was found to be mobilized by Tn916 and S. anginosus UCN93 harboured a Tn916 transposon, several attempts at transfer were performed but they all failed. The lnu(C) containing genetic element was inserted into a chromosomal intergenic sequence of S. anginosus. CONCLUSIONS: Since lnu(C) has been detected in only one S. agalactiae clinical isolate so far, this is its second description among clinically relevant streptococci. PMID- 23812684 TI - Expert's comment concerning Grand Rounds case entitled "synovial sarcoma of the spine: a case involving paraspinal muscle with extensive calcification and the surgical consideration in treatment" (by Junhyung Kim, Sun-Ho Lee, Yoon-La Choi, Go Eun Bae, Eun-Sang Kim, Whan Eoh). PMID- 23812686 TI - Reviewer's comment concerning "The percutaneous stabilization of the sacroiliac joint with hollow modular anchorage screws: a prospective outcome study" (ESJO-D 12-01011R1 by Lyndon W. Mason, Iqroop Chopra and Khitish Mohanty, doi:10.1007/s00586-013-2825-2). PMID- 23812687 TI - The science of sustainability. PMID- 23812685 TI - 3D analysis of brace treatment in idiopathic scoliosis. AB - PURPOSE: We have evaluated the effect of bracing in scoliosis on coronal alignment in a cohort of patients. Current literature has not described the specific effect of bracing on the 3D shape of the scoliotic curves. The purpose of this study was to analyze the variability of the 3D effect of bracing on idiopathic scoliosis. MATERIALS AND METHODS: The spines of 30 patients with adolescent idiopathic scoliosis were reconstructed using biplanar stereoradiography with and without the brace. The Cobb angle, sagittal and pelvic parameters and transverse plane parameters were calculated. The variability and the mean values of each parameter, with and without a brace, were analyzed and compared using a student t test. RESULTS: The Cobb angle improved in 50% of patients but remained unchanged in 50% cases. In 90% of the cases lordosis was decreased. The thoracic kyphosis was decreased in 26% cases, unchanged in 57% of cases and increased in 17% cases. The AVR was improved (>5 degrees ) in 26% cases, worsened in 23% and unchanged in 50%. Only the differences of Cobb angle and the lordosis were statistically significant. CONCLUSIONS: Global statistics of this study concur with the literature. The Cobb angle was significantly improved. It also showed a significant hypolordotic effect. However, the results showed a high variability of the brace treatment effect in almost every parameter. Analysis of this variability by means of 3D reconstructions instead of global statistics should help characterize the mechanisms of correction of brace treatment. PMID- 23812693 TI - Stem cell research. Chimeric embryos may soon get their day in the sun. PMID- 23812692 TI - Influenza. Dueling reviews for controversial flu drug. PMID- 23812695 TI - Optics. Light beams with a twist could give a turbo boost to fiber-optic cables. PMID- 23812694 TI - U.S. graduate education. Minorities run up significant debt in earning STEM Ph.D.s. PMID- 23812697 TI - Canada. Scientists bristle at Canadian leader's applied research push. PMID- 23812696 TI - The dizzying journey to a new cancer arsenal. PMID- 23812698 TI - Coral diseases cause reef decline. PMID- 23812699 TI - Reversing excess atmospheric CO2. PMID- 23812700 TI - Reversing excess atmospheric CO2--response. PMID- 23812701 TI - Good grades for dual education. PMID- 23812703 TI - Neuroscience. Garbage truck of the brain. PMID- 23812704 TI - Chemistry. More can be better in N2 activation. PMID- 23812705 TI - Microbiology. Eliminating malaria. PMID- 23812706 TI - Microbiology. Some like it hot, some not. PMID- 23812707 TI - Biochemistry. Translocation in action. PMID- 23812708 TI - IBI series winner. Investigating ecosystems as a blended learning experience. PMID- 23812709 TI - Terabit-scale orbital angular momentum mode division multiplexing in fibers. AB - Internet data traffic capacity is rapidly reaching limits imposed by optical fiber nonlinear effects. Having almost exhausted available degrees of freedom to orthogonally multiplex data, the possibility is now being explored of using spatial modes of fibers to enhance data capacity. We demonstrate the viability of using the orbital angular momentum (OAM) of light to create orthogonal, spatially distinct streams of data-transmitting channels that are multiplexed in a single fiber. Over 1.1 kilometers of a specially designed optical fiber that minimizes mode coupling, we achieved 400-gigabits-per-second data transmission using four angular momentum modes at a single wavelength, and 1.6 terabits per second using two OAM modes over 10 wavelengths. These demonstrations suggest that OAM could provide an additional degree of freedom for data multiplexing in future fiber networks. PMID- 23812710 TI - Dinitrogen cleavage and hydrogenation by a trinuclear titanium polyhydride complex. AB - Both the Haber-Bosch and biological ammonia syntheses are thought to rely on the cooperation of multiple metals in breaking the strong N=N triple bond and forming an N-H bond. This has spurred investigations of the reactivity of molecular multimetallic hydrides with dinitrogen. We report here the reaction of a trinuclear titanium polyhydride complex with dinitrogen, which induces dinitrogen cleavage and partial hydrogenation at ambient temperature and pressure. By (1)H and (15)N nuclear magnetic resonance, x-ray crystallographic, and computational studies of some key reaction steps and products, we have determined that the dinitrogen (N2) reduction proceeds sequentially through scission of a N2 molecule bonded to three Ti atoms in a MU-eta(1):eta(2):eta(2)-end-on-side-on fashion to give a MU2-N/MU3-N dinitrido species, followed by intramolecular hydrogen migration from Ti to the MU2-N nitrido unit. PMID- 23812711 TI - Continuous permeability measurements record healing inside the Wenchuan earthquake fault zone. AB - Permeability controls fluid flow in fault zones and is a proxy for rock damage after an earthquake. We used the tidal response of water level in a deep borehole to track permeability for 18 months in the damage zone of the causative fault of the 2008 moment magnitude 7.9 Wenchuan earthquake. The unusually high measured hydraulic diffusivity of 2.4 * 10(-2) square meters per second implies a major role for water circulation in the fault zone. For most of the observation period, the permeability decreased rapidly as the fault healed. The trend was interrupted by abrupt permeability increases attributable to shaking from remote earthquakes. These direct measurements of the fault zone reveal a process of punctuated recovery as healing and damage interact in the aftermath of a major earthquake. PMID- 23812712 TI - Supercomplex assembly determines electron flux in the mitochondrial electron transport chain. AB - The textbook description of mitochondrial respiratory complexes (RCs) views them as free-moving entities linked by the mobile carriers coenzyme Q (CoQ) and cytochrome c (cyt c). This model (known as the fluid model) is challenged by the proposal that all RCs except complex II can associate in supercomplexes (SCs). The proposed SCs are the respirasome (complexes I, III, and IV), complexes I and III, and complexes III and IV. The role of SCs is unclear, and their existence is debated. By genetic modulation of interactions between complexes I and III and III and IV, we show that these associations define dedicated CoQ and cyt c pools and that SC assembly is dynamic and organizes electron flux to optimize the use of available substrates. PMID- 23812713 TI - Intrinsically disordered protein threads through the bacterial outer-membrane porin OmpF. AB - Porins are beta-barrel outer-membrane proteins through which small solutes and metabolites diffuse that are also exploited during cell death. We have studied how the bacteriocin colicin E9 (ColE9) assembles a cytotoxic translocon at the surface of Escherichia coli that incorporates the trimeric porin OmpF. Formation of the translocon involved ColE9's unstructured N-terminal domain threading in opposite directions through two OmpF subunits, capturing its target TolB on the other side of the membrane in a fixed orientation that triggers colicin import. Thus, an intrinsically disordered protein can tunnel through the narrow pores of an oligomeric porin to deliver an epitope signal to the cell to initiate cell death. PMID- 23812714 TI - Temperature drives the continental-scale distribution of key microbes in topsoil communities. AB - Global warming will likely force terrestrial plant and animal species to migrate toward cooler areas or sustain range losses; whether this is also true for microorganisms remains unknown. Through continental-scale compositional surveys of soil crust microbial communities across arid North America, we observed a latitudinal replacement in dominance between two key topsoil cyanobacteria that was driven largely by temperature. The responses to temperature of enrichment cultures and cultivated strains support this contention, with one cyanobacterium (Microcoleus vaginatus) being more psychrotolerant and less thermotolerant than the other (M. steenstrupii). In view of our data and regional climate predictions, the latter cyanobacterium may replace the former in much of the studied area within the next few decades, with unknown ecological consequences for soil fertility and erodibility. PMID- 23812715 TI - Mechanism of eukaryotic RNA polymerase III transcription termination. AB - Gene expression in organisms involves many factors and is tightly controlled. Although much is known about the initial phase of transcription by RNA polymerase III (Pol III), the enzyme that synthesizes the majority of RNA molecules in eukaryotic cells, termination is poorly understood. Here, we show that the extensive structure of Pol III-synthesized transcripts dictates the release of elongation complexes at the end of genes. The poly-T termination signal, which does not cause termination in itself, causes catalytic inactivation and backtracking of Pol III, thus committing the enzyme to termination and transporting it to the nearest RNA secondary structure, which facilitates Pol III release. Similarity between termination mechanisms of Pol III and bacterial RNA polymerase suggests that hairpin-dependent termination may date back to the common ancestor of multisubunit RNA polymerases. PMID- 23812716 TI - Transcription under torsion. AB - In cells, RNA polymerase (RNAP) must transcribe supercoiled DNA, whose torsional state is constantly changing, but how RNAP deals with DNA supercoiling remains elusive. We report direct measurements of individual Escherichia coli RNAPs as they transcribed supercoiled DNA. We found that a resisting torque slowed RNAP and increased its pause frequency and duration. RNAP was able to generate 11 +/- 4 piconewton-nanometers (mean +/- standard deviation) of torque before stalling, an amount sufficient to melt DNA of arbitrary sequence and establish RNAP as a more potent torsional motor than previously known. A stalled RNAP was able to resume transcription upon torque relaxation, and transcribing RNAP was resilient to transient torque fluctuations. These results provide a quantitative framework for understanding how dynamic modification of DNA supercoiling regulates transcription. PMID- 23812717 TI - Fe-S cluster biosynthesis controls uptake of aminoglycosides in a ROS-less death pathway. AB - All bactericidal antibiotics were recently proposed to kill by inducing reactive oxygen species (ROS) production, causing destabilization of iron-sulfur (Fe-S) clusters and generating Fenton chemistry. We find that the ROS response is dispensable upon treatment with bactericidal antibiotics. Furthermore, we demonstrate that Fe-S clusters are required for killing only by aminoglycosides. In contrast to cells, using the major Fe-S cluster biosynthesis machinery, ISC, cells using the alternative machinery, SUF, cannot efficiently mature respiratory complexes I and II, resulting in impendence of the proton motive force (PMF), which is required for bactericidal aminoglycoside uptake. Similarly, during iron limitation, cells become intrinsically resistant to aminoglycosides by switching from ISC to SUF and down-regulating both respiratory complexes. We conclude that Fe-S proteins promote aminoglycoside killing by enabling their uptake. PMID- 23812718 TI - Deep cortical layers are activated directly by thalamus. AB - The thalamocortical (TC) projection to layer 4 (L4) is thought to be the main route by which sensory organs communicate with cortex. Sensory information is believed to then propagate through the cortical column along the L4->L2/3->L5/6 pathway. Here, we show that sensory-evoked responses of L5/6 neurons in rats derive instead from direct TC synapses. Many L5/6 neurons exhibited sensory evoked postsynaptic potentials with the same latencies as L4. Paired in vivo recordings from L5/6 neurons and thalamic neurons revealed substantial convergence of direct TC synapses onto diverse types of infragranular neurons, particularly in L5B. Pharmacological inactivation of L4 had no effect on sensory evoked synaptic input to L5/6 neurons. L4 is thus not an obligatory distribution hub for cortical activity, and thalamus activates two separate, independent "strata" of cortex in parallel. PMID- 23812719 TI - From gas to stars over cosmic time. AB - From the time the first stars formed over 13 billion years ago to the present, star formation has had an unexpectedly dynamic history. At first, the star formation rate density increased dramatically, reaching a peak 10 billion years ago of more than 10 times the present-day value. Observations of the initial rise in star formation remain difficult, poorly constraining it. Theoretical modeling has trouble predicting this history because of the difficulty in following the feedback of energy from stellar radiation and supernova explosions into the gas from which further stars form. Observations from the ground and space with the next generation of instruments should reveal the full history of star formation in the universe, and simulations appear poised to accurately predict the observed history. PMID- 23812720 TI - Elongation factor G bound to the ribosome in an intermediate state of translocation. AB - A key step of translation by the ribosome is translocation, which involves the movement of messenger RNA (mRNA) and transfer RNA (tRNA) with respect to the ribosome. This allows a new round of protein chain elongation by placing the next mRNA codon in the A site of the 30S subunit. Translocation proceeds through an intermediate state in which the acceptor ends of the tRNAs have moved with respect to the 50S subunit but not the 30S subunit, to form hybrid states. The guanosine triphosphatase (GTPase) elongation factor G (EF-G) catalyzes the subsequent movement of mRNA and tRNA with respect to the 30S subunit. Here, we present a crystal structure at 3 angstrom resolution of the Thermus thermophilus ribosome with a tRNA in the hybrid P/E state bound to EF-G with a GTP analog. The structure provides insights into structural changes that facilitate translocation and suggests a common GTPase mechanism for EF-G and elongation factor Tu. PMID- 23812721 TI - Control of ribosomal subunit rotation by elongation factor G. AB - Protein synthesis by the ribosome requires the translocation of transfer RNAs and messenger RNA by one codon after each peptide bond is formed, a reaction that requires ribosomal subunit rotation and is catalyzed by the guanosine triphosphatase (GTPase) elongation factor G (EF-G). We determined 3 angstrom resolution x-ray crystal structures of EF-G complexed with a nonhydrolyzable guanosine 5'-triphosphate (GTP) analog and bound to the Escherichia coli ribosome in different states of ribosomal subunit rotation. The structures reveal that EF G binding to the ribosome stabilizes switch regions in the GTPase active site, resulting in a compact EF-G conformation that favors an intermediate state of ribosomal subunit rotation. These structures suggest that EF-G controls the translocation reaction by cycles of conformational rigidity and relaxation before and after GTP hydrolysis. PMID- 23812722 TI - Crystal structures of EF-G-ribosome complexes trapped in intermediate states of translocation. AB - Translocation of messenger and transfer RNA (mRNA and tRNA) through the ribosome is a crucial step in protein synthesis, whose mechanism is not yet understood. The crystal structures of three Thermus ribosome-tRNA-mRNA-EF-G complexes trapped with beta,gamma-imidoguanosine 5'-triphosphate (GDPNP) or fusidic acid reveal conformational changes occurring during intermediate states of translocation, including large-scale rotation of the 30S subunit head and body. In all complexes, the tRNA acceptor ends occupy the 50S subunit E site, while their anticodon stem loops move with the head of the 30S subunit to positions between the P and E sites, forming chimeric intermediate states. Two universally conserved bases of 16S ribosomal RNA that intercalate between bases of the mRNA may act as "pawls" of a translocational ratchet. These findings provide new insights into the molecular mechanism of ribosomal translocation. PMID- 23812723 TI - Values of MMP-2 and MMP-9 in tumor tissue of basal-like breast cancer patients. AB - Gelatinase A (MMP-2) and gelatinase B (MMP-9) are proteolytic enzymes involved in process of tumor invasion, and they are considered as possible tumor markers in breast cancer patients. In this study, we measured activity of latent and active form of MMP-2 and MMP-9 in tumor and adjacent tissue of 60 breast cancer patients by SDS-PAGE zymography. The activity of both form of gelatinases significantly increased with each advancing clinical stage of disease. ProMMP-9 and aMMP-9 activity in tumor tissue shows a positive association with tumor size. Patients with lymph node involvement have higher proMMP-2, aMMP-2 and aMMP-9 activity than node negative patients. Steroid receptor-negative tumors had enhanced aMMP-2 and aMMP-9 activity. Patients with basal-like cancers had higher proMMP-2 tumor activity and aMMP-2 adjacent tissue activity compared to patients with luminal A tumors. Patients with negative hormone receptors are associated with increased activity of both form of gelatinases in adjacent tissue. Reported increased activity of MMP-2 in tumor and adjacent tissue of basal-like tumors implicates that MMP-2 might have a role in aggressive biology of basal-like cancers. Additional investigations regarding molecular pathways in adjacent tissue could give better insight into aggressive nature of basal-like carcinomas. PMID- 23812724 TI - Graphically characterizing the movement of a rabid striped skunk epizootic across the landscape in northwestern Wyoming. AB - A striped skunk (Mephitis mephitis) rabies epizootic in northwestern Wyoming was studied from the Index Case in 1988 to the last case in 1993, and possibly is the first rabies epizootic in a previously rabies-free zone monitored from beginning to end. The 843 km(2) study area comprised skunk habitat along 90 km of Shoshone River's floodplain from Bighorn Lake upstream to Cody. Of 1,015 skunks tested, 215 were rabies-positive. Integrating spatial and temporal data from positive cases, we analyzed the epizootic's movements and dynamics at 6-month intervals using multivariate movement maps, a new multivariate descriptive methodology presented here to demonstrate the epizootic's directional flow, while illustrating areas with higher case densities (i.e., wave crests). This approach should help epidemiologists and public health officials to better understand future rabies epizootics. PMID- 23812725 TI - P53 codon 72 Arg/Pro polymorphism and lung cancer risk in Asians: an updated meta analysis. AB - The polymorphism of p53 codon 72, a transversion of G to C (Arg to Pro), has been demonstrated to be associated with the risk for lung cancer. However, individual studies conducted in Asians have provided conflicting and inconclusive findings. Thus, we performed a meta-analysis by pooling all currently available case control studies to estimate the effect of p53 codon 72 Arg/Pro polymorphism on the development of lung cancer. The pooled odds ratios (ORs) with the corresponding 95 % confidence intervals (95 %CIs) were calculated to assess this effect. A total of 14 individual studies involving 7,929 cases and 5,924 controls were included into this meta-analysis according to the inclusion criteria. The overall OR for the dominant genetic model indicated that the p53 codon 72 Arg/Pro variant was positively correlated with lung cancer risk (ORArg/Pro + Pro/Pro vs. Arg/Arg = 1.14, 95 %CI 1.07-1.23, P OR < 0.001). Similar results were found in the stratified analysis of population-based studies. The histological types of lung cancer and smoking status seemed to exert no effect on the lung cancer risk. Sensitivity analysis confirmed the stability of the above findings. The updated meta-analysis suggests that the p53 codon 72 Arg/Pro polymorphism is a risk factor for lung cancer in the Asian population. However, the potential role of gene-environment interaction in lung cancer susceptibility needs further investigation in future studies with high quality. PMID- 23812726 TI - Survey of activated kinase proteins reveals potential targets for cholangiocarcinoma treatment. AB - Improving therapy for patients with cholangiocarcinoma (CCA) presents a significant challenge. This is made more difficult by a lack of a clear understanding of potential molecular targets, such as deregulated kinases. In this work, we profiled the activated kinases in CCA in order to apply them as the targets for CCA therapy. Human phospho-receptor tyrosine kinases (RTKs) and phospho-kinase array analyses revealed that multiple kinases are activated in both CCA cell lines and human CCA tissues that included cell growth, apoptosis, cell to cell interaction, movement, and angiogenesis RTKs. Predominately, the kinases activated downstream were those in the PI3K/Akt, Ras/MAPK, JAK/STAT, and Wnt/beta-catenin signaling pathways. Western blot analysis confirms that Erk1/2 and Akt activation were increased in CCA tissues when compared with their normal adjacent tissue. The inhibition of kinase activation using multi-targeted kinase inhibitors, sorafenib and sunitinib led to significant cell growth inhibition and apoptosis induction via suppression of Erk1/2 and Akt activation, whereas drugs with specificity to a single kinase showed less potency. In conclusion, our study reveals the involvement of multiple kinase proteins in CCA growth that might serve as therapeutic targets for combined kinase inhibition. PMID- 23812727 TI - AdHu5-apoptin induces G2/M arrest and apoptosis in p53-mutated human gastric cancer SGC-7901 cells. AB - The use of anticancer therapeutic agents is limited largely by their severe toxicity to normal tissues. The development of novel agents with tumor-specific cell-killing and effective gene delivery properties is thus very desirable. We used human adenovirus serotype 5 (AdHu5) as a vehicle to deliver the apoptin gene to specifically target gastric cancer in a recombinant gene delivery approach. AdHu5-apoptin is a safe and efficacious agent for the treatment of gastric cancer (GC). Our results show that apoptin protein encoded by the apoptin gene delivered via AdHu5 significantly inhibited the proliferation of SGC-7901 GC cells. Apoptin reduced the clone number by more than 75% and resulted in cell cycle arrest in the G2/M phase for 48% of the GC cells. It also induced cleavage of caspase-3, caspase-7, and caspase-9 in the GC cells. Intratumoral and peritumoral in vivo injection of AdHu5-apoptin significantly suppressed tumor growth and induced apoptosis in xenogeneic tumors in mice. The apoptosis induced by AdHu5-apoptin was independent of anti-apoptotic Bcl-2 and Bcl-xL proteins and the p53 pathway. Taken together, our results show that AdHu5-apoptin has great potential as a therapeutic agent for effective treatment of gastric tumors. PMID- 23812728 TI - Methylenetetrahydrofolate reductase gene polymorphisms association with the risk of diffuse large B cell lymphoma: a meta-analysis. AB - To date, case-control studies on the association between methylenetetrahydrofolate reductase (MTHFR) and diffuse large B cell lymphoma (DLBCL) have provided either controversial or inconclusive results. To clarify the effect of MTHFR on the risk of diffuse large B cell lymphoma, a meta-analysis of all case-control observational studies was performed. The fixed effects and random effects model showed that the C677T polymorphism was associated with a risk of DLBCL among East Asian populations, and A1298C polymorphism was not associated with a risk of DLBCL among Caucasian and East Asian populations. Our pooled data suggest evidence for a major role of MTHFR C677T polymorphism in the carcinogenesis of DLBCL among East Asian populations. PMID- 23812729 TI - Tropomyosin-4 correlates with higher SBR grades and tubular differentiation in infiltrating ductal breast carcinomas: an immunohistochemical and proteomics based study. AB - The aim of this study is to evaluate tropomyosin-4 (TM4) expression in infiltrating ductal breast carcinomas (IDCAs), as well as its prognostic significance. Using a 2-DE/MALDI-TOF mass spectrometry investigation coupled with an immunohistochemical approach, we have assessed the expression of TM4 in IDCAs, as well as in other types of breast tumors. Proteomic analyses revealed an increased expression of tropomyosin-4 in IDCA tumors. Using immunohistochemistry, overexpression of tropomyosin-4 was confirmed in 51 additional tumor specimens. Statistical analyses revealed, however, no significant correlations between tropomyosin-4 expression and clinicopathological parameters of the disease including tumor stage, patient age, estrogen and progesterone receptor status, and lymph node metastasis occurrence. A significant association was found, however, with a high Scarf-Bloom-Richardson (SBR) grade, a known marker of tumor severity. Additionally, the SBR component showing a correlation with TM4 expression was the tubular differentiation status. This study demonstrates the upregulation of tropomyosin-4 in IDCA tissues, which may highlight its involvement in breast cancer development. Our findings also support a link between tropomyosin-4 expression and aggressiveness of IDCA tumors. PMID- 23812730 TI - HtrA3 is negatively correlated with lymph node metastasis in invasive ductal breast cancer. AB - Breast cancer is the most common cancer in women worldwide. Studies have shown that the high temperature requirement factor A3 (HtrA3) is involved in important physiological processes including maintenance of mitochondrial homeostasis, cell death, and cell signaling. HtrA3 is reported to be downregulated in several cancers and has been correlated with advancing cancer stage. We performed a retrospective study using our breast cancer tissue bank to investigate whether the expression of HtrA3 correlated with lymphatic metastasis in breast cancer and whether the expression of HtrA3 was correlated with estrogen receptor (ER) and progesterone receptor (PR) expression in breast cancer. Breast cancer tissues from 156 invasive ductal breast cancer patients with or without lymphatic metastasis were collected and the levels of HtrA3 were measured by immunohistochemistry and western blotting. The expression of HtrA3 was lower in breast cancer. In particular, HtrA3 expression in breast cancer with lymphatic metastasis was lower than that in breast cancer without lymphatic metastasis. In breast cancers with no lymphatic metastasis, the expression of HtrA3 was lower in patients with ER- and PR-positive tumors, but when breast cancers with lymphatic metastasis were analyzed, there was no difference in HtrA3 expression between ER- and PR-positive or ER- and PR-negative tumors. These data suggest that the expression of HtrA3 was negatively correlated with lymphatic metastasis in breast cancer but not correlated with ER and PR positivity or negativity. A better understanding of the mechanism of HtrA3 may provide the basis for future development of a novel therapeutic target in breast cancer. PMID- 23812732 TI - Relationship of extinction coefficient, air pollution, and meteorological parameters in an urban area during 2007 to 2009. AB - Light extinction, which is the extent of attenuation of light signal for every distance traveled by light in the absence of special weather conditions (e.g., fog and rain), can be expressed as the sum of scattering and absorption effects of aerosols. In this paper, diurnal and seasonal variations of the extinction coefficient are investigated for the urban areas of Tehran from 2007 to 2009. Cases of visibility impairment that were concurrent with reports of fog, mist, precipitation, or relative humidity above 90% are filtered. The mean value and standard deviation of daily extinction are 0.49 and 0.39 km(-1), respectively. The average is much higher than that in many other large cities in the world, indicating the rather poor air quality over Tehran. The extinction coefficient shows obvious diurnal variations in each season, with a peak in the morning that is more pronounced in the wintertime. Also, there is a very slight increasing trend in the annual variations of atmospheric extinction coefficient, which suggests that air quality has regressed since 2007. The horizontal extinction coefficient decreased from January to July in each year and then increased between July and December, with the maximum value in the winter. Diurnal variation of extinction is often associated with small values for low relative humidity (RH), but increases significantly at higher RH. Annual correlation analysis shows that there is a positive correlation between the extinction coefficient and RH, CO, PM10, SO2, and NO2 concentration, while negative correlation exists between the extinction and T, WS, and O3, implying their unfavorable impact on extinction variation. The extinction budget was derived from multiple regression equations using the regression coefficients. On average, 44% of the extinction is from suspended particles, 3% is from air molecules, about 5% is from NO2 absorption, 0.35% is from RH, and approximately 48% is unaccounted for, which may represent errors in the data as well as contribution of other atmospheric constituents omitted from the analysis. Stronger regression equation is achieved in the summer, meaning that the extinction is more predictable in this season using pollutant concentrations. PMID- 23812731 TI - RTEL1 and TERT polymorphisms are associated with astrocytoma risk in the Chinese Han population. AB - Common variants of multiple genes play a role in glioma onset. However, research related to astrocytoma, the most common primary brain neoplasm, is rare. In this study, we chose 21 tagging SNPs (tSNPs), previously reported to be associated with glioma risk in a Chinese case-control study from Xi'an, China, and identified their contributions to astrocytoma susceptibility. We found an association with astrocytoma susceptibility for two tSNPs (rs6010620 and rs2853676) in two different genes: regulator of telomere elongation helicase 1 (RTEL1) and telomerase reverse transcriptase (TERT), respectively. We confirmed our results using recessive, dominant, and additive models. In the recessive model, we found two tSNPs (rs2297440 and rs6010620) associated with increased astrocytoma risk. In the dominant model, we found that rs2853676 was associated with increased astrocytoma risk. In the additive model, all three tSNPs (rs2297440, rs2853676, and rs6010620) were associated with increased astrocytoma risk. Our results demonstrate, for the first time, the potential roles of RTEL1 and TERT in astrocytoma development. PMID- 23812733 TI - Occurrence and distribution of veterinary antibiotics and tetracycline resistance genes in farmland soils around swine feedlots in Fujian Province, China. AB - Six antibiotics, tetracyclines (TCs), and quinolones (QNs) in farmland soils from four coastal cities in Fujian Province of China were investigated. Oxytetracycline was most frequently detected, followed by enrofloxacin, ciprofloxacin, chlorotetracycline, ofloxacin, and tetracycline, with maximum concentrations of 613.2, 637.3, 237.3, 2668.9, 205.7, and 189.8 MUg kg(-1), respectively. Samples from Putian City contained the highest maximum concentration of ?TCs (3,064.2 MUg kg(-1)), whereas those from Fuzhou City contained the highest maximum concentration of ?QNs (897.8 MUg kg(-1)). It is noteworthy that the ?TCs and ?QNs in 46.4 and 28.6 % of samples exceeded the ecotoxic effect trigger value (100 MUg kg(-1)), respectively. The concentrations of these antibiotics and five tetracycline resistance genes in four soil plots at depth profiles were quantified thereafter. In most cases, both antibiotics and resistance genes decreased with the increase of depth. Some antibiotics can be detected at a depth of 60-80 cm where the abundance of tetO, tetM, and tetX reached up to 10(7) copies g(-1). Additionally, the sum of all tet genes (normalized to 16S rRNA genes) correlated with ?TCs significantly (r=0.676). Our results suggest that resistance determinants can migrate to deeper soil layers and would probably contaminate groundwater by vertical transport. PMID- 23812734 TI - Uranium contents in plants and mushrooms grown on a uranium-contaminated site near Ronneburg in Eastern Thuringia/Germany. AB - Uranium concentrations in cultivated (sunflower, sunchoke, potato) and native plants, plant compartment specimens, and mushrooms, grown on a test site within a uranium-contaminated area in Eastern Thuringia, were analyzed and compared. This test site belongs to the Friedrich-Schiller University Jena and is situated on the ground of a former but now removed uranium mine waste leaching heap. For determination of the U concentrations in the biomaterials, the saps of the samples were squeezed out by using an ultracentrifuge, after that, the uranium concentrations in the saps and the remaining residue were measured, using ICP-MS. The study further showed that uranium concentrations observed in plant compartment and mushroom fruiting bodies sap samples were always higher than their associated solid residue sample. Also, it was found that the detected uranium concentration in the root samples were always higher than were observed in their associated above ground biomass, e.g., in shoots, leaves, blossoms etc. The highest uranium concentration was measured with almost 40 ppb U in a fruiting body of a mushroom and in roots of butterbur. However, the detected uranium concentrations in plants and mushrooms collected in this study were always lower than in the associated surface and soil water of the test site, indicating that under the encountered natural conditions, none of the studied plant and mushroom species turned out to be a hyperaccumulator for uranium, which could have extracted uranium in sufficient amounts out of the uranium-contaminated soil. In addition, it was found that the detected uranium concentrations in the sap samples, despite being above the sensitivity limit, proved to be too low-in combination with the presence of fluorescence quenching substances, e.g., iron and manganese ions, and/or organic quenchers-to extract a useful fluorescence signal, which could have helped to identify the uranium speciation in plants. PMID- 23812735 TI - Occurrence and sources of antibiotics and their metabolites in river water, WWTPs, and swine wastewater in Jiulongjiang River basin, south China. AB - In this study, the occurrence and sources of five cataloged antibiotics and metabolites were studied in Jiulongjiang River basin, south China. Nineteen antibiotics and 13 metabolites were detected in water samples from 16 river sampling sites, wastewater from 5 swine-raising facilities, and effluent from 5 wastewater treatment plants (WWTPs). The results showed that 12 antibiotics and 6 metabolites were detected in river water samples. Sulfonamides (SAs) and their metabolites were detected at high concentrations (8.59-158.94 ng/L). Tetracyclines (TCs) and their metabolites were frequently detected in swine wastewater, and the maximum concentration was up to the level in milligram per liter. Macrolides (MLs) and beta-lactams (beta-Ls) were found in all WWTP effluent samples and some river samples, while they were never found in any of the swine wastewater samples. SAs and quinolones (QNs) were detected in all samples. Hierarchical cluster analysis of 16 surface water samples was applied to achieve the spatial distribution characteristics of antibiotics in the Jiulongjiang River. As a result, two categories were obviously obtained. Principal component analysis and redundancy analysis showed that TCs and SAs as well as their metabolites were the major antibiotics in Jiulongjiang River, and they mainly originated from swine wastewater, while the QNs, MLs, and beta-Ls in the Jiulongjiang River came from WWTP effluent. PMID- 23812736 TI - Survival of Escherichia coli O157:H7 in soils under different land use types. AB - Laboratory studies on Escherichia coli O157:H7 survival in soils from four different land use types: forest, tea plantation, bamboo grove, and vegetable garden were investigated at 25 +/- 1 degrees C with the field capacity (soil water content at -33 kPa). Results showed that E. coli O157:H7 declined quickly in the test soils, but its survival dynamics varied in the soils under different land use types. The survival time needed to reach the detection limit (t d) in the test soils ranged from 2.1 to 3.6 days, with slightly longer t d values being observed in soils from the bamboo grove. Stepwise multiple regression analysis revealed that the t d values were shorter in sandy, lower pH, and lower organic carbon content soils. Different E. coli O157:H7 survival time in the soils under different land uses suggests that it is important to adapt proper management practices for reducing the potential risks of pathogen contamination when diary manure is applied to agricultural land. PMID- 23812737 TI - Involvement of abscisic acid in regulating antioxidative defense systems and IAA oxidase activity and improving adventitious rooting in mung bean [Vigna radiata (L.) Wilczek] seedlings under cadmium stress. AB - In vitro experiments were conducted to investigate the effects of abscisic acid (ABA) and Cd on antioxidative defense systems and indole-3-acetic acid (IAA) oxidase during adventitious rooting in mung bean [Vigna radiata (L.) Wilczek] seedlings. The exogenous ABA significantly enhanced the number and fresh weight of the adventitious roots. CdCl2 strongly inhibited adventitious rooting. Pretreatment with 10 MUM ABA clearly alleviated the inhibitory effect of Cd on rooting. ABA significantly reduced superoxide dismutase (SOD), ascorbate peroxidase (APX), peroxidase (POD), and catalase (CAT) activities, as well as the levels of glutathione (GSH) and ascorbic acid (ASA) during adventitious rooting. ABA strongly increased IAA-oxidase activity during the induction (0-12 h) and expression (after 48 h) phases and increased the phenols levels. Cd treatment significantly reduced the activities of SOD, APX, POD, and IAA oxidase, as well as GSH level. Cd strongly increased ASA levels. ABA pretreatment counteracted Cd induced alterations of certain antioxidants and antioxidative enzymes, e.g., remarkably rescued APX and POD activities, reduced the elevated SOD and CAT activities and ASA levels, and recovered the reduced GSH levels, caused by Cd stress. Thus, the physiological effects of the combination of ABA and Cd treatments were opposite of those obtained with Cd treatment alone, suggesting that ABA involved in the regulation of antioxidative defense systems and the alleviation of wounding- and Cd-induced oxidative stress. PMID- 23812739 TI - Women's perspectives on postpartum depression screening in pediatric settings: a preliminary study. AB - This preliminary study is the first to identify mothers' perspectives on barriers and facilitators to addressing postpartum depression (PPD) in pediatric settings. We conducted four 90-min focus groups with women (n = 27) who self-identified a history of perinatal depression and/or emotional complications. Barriers reported included stigma and fear among women and lack of provider knowledge/skills regarding depression. Participants recommended non-stigmatizing approaches to depression screening/referral. Future PPD screening efforts should leverage the pediatrician-mother relationship to mitigate mothers' fears and encourage help seeking. PMID- 23812738 TI - The balance between stress and personal capital during pregnancy and the relationship with adverse obstetric outcomes: findings from the 2007 Los Angeles Mommy and Baby (LAMB) study. AB - Stress during pregnancy is a salient risk factor for adverse obstetric outcomes. Personal capital during pregnancy, defined as internal and social resources that help women cope with or decrease their exposure to stress, may reduce the risk of poor obstetric outcomes. Using data from the 2007 Los Angeles Mommy and Baby study (N = 3,353), we examined the relationships between the balance of stress and personal capital during pregnancy, or the stress-to-capital ratio (SCR), and adverse obstetric outcomes (i.e., pregnancy complications, preterm birth (PTB), low birth weight (LBW), and small for gestational age (SGA)). Women with a higher SCR (i.e., greater stress relative to personal capital during pregnancy) were significantly more likely to experience at least one pregnancy complication, PTB, and lower gestational age, but not LBW or SGA. Accounting for pregnancy complications completely mediated the association between the SCR and PTB. Our findings indicate that experiencing greater stress relative to personal capital during pregnancy is associated with an increased risk for pregnancy complications, PTB, and lower gestational age and that pregnancy complications may be a mechanism by which the SCR is related to adverse obstetric outcomes. PMID- 23812740 TI - TMEM43 mutations associated with arrhythmogenic right ventricular cardiomyopathy in non-Newfoundland populations. AB - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a myocardial disease characterized by fibro-fatty replacement of right ventricular free wall myocardium and life-threatening ventricular arrhythmias. A missense mutation, c.1073C>T (p.S358L) in the transmembrane protein 43 (TMEM43) gene, has been genetically identified to cause ARVC type 5 in a founder population from Newfoundland. It is unclear whether this mutation occurs in other populations outside of this founder population or if other variants of TMEM43 are associated with ARVC disease. We sought to identify non-Newfoundland individuals with TMEM43 variants among patient samples sent for genetic assessment for possible ARVC. Of 195 unrelated individuals with suspected ARVC, mutation of desmosomal proteins was seen in 28 and the p.S358L TMEM43 mutation in six. We identified a de novo p.S358L mutation in a non-Newfoundland patient and five separate rare TMEM43 (four novel) sequence variants in non-Newfoundland patients, each occurring in an evolutionarily conserved amino acid. TMEM43 mutations occur outside of the founder population of the island of Newfoundland where it was originally described. TMEM43 sequencing should be incorporated into clinical genetic testing for ARVC patients. PMID- 23812741 TI - Characterization of a novel missense mutation in the prodomain of GDF5, which underlies brachydactyly type C and mild Grebe type chondrodysplasia in a large Pakistani family. AB - All TGF-beta family members have a prodomain that is important for secretion. Lack of secretion of a TGF-beta family member GDF5 is known to underlie some skeletal abnormalities, such as brachydactyly type C that is characterized by a huge and unexplained phenotypic variability. To search for potential phenotypic modifiers regulating secretion of GDF5, we compared cells overexpressing wild type (Wt) GDF5 and GDF5 with a novel mutation in the prodomain identified in a large Pakistani family with Brachydactyly type C and mild Grebe type chondrodyslplasia (c527T>C; p.Leu176Pro). Initial in vitro expression studies revealed that the p.Leu176Pro mutant (Mut) GDF5 was not secreted outside the cells. We subsequently showed that GDF5 was capable of forming a complex with latent transforming growth factor binding proteins, LTBP1 and LTBP2. Furthermore, secretion of LTBP1 and LTBP2 was severely impaired in cells expressing the Mut GDF5 compared to Wt-GDF5. Finally, we demonstrated that secretion of Wt-GDF5 was inhibited by the Mut-GDF5, but only when LTBP (LTBP1 or LTBP2) was co-expressed. Based on these findings, we suggest a novel model, where the dosage of secretory co-factors or stabilizing proteins like LTBP1 and LTBP2 in the microenvironment may affect the extent of GDF5 secretion and thereby function as modifiers in phenotypes caused by GDF5 mutations. PMID- 23812742 TI - The impact of emotional disturbances on the arrest trajectories of youth as they transition into young adulthood. AB - This article identifies the arrest trajectories of youth from ages 12 through 24 years old and tests hypotheses derived from Moffitt's developmental taxonomic theory of crime concerning the impact of various emotional disturbances on the specific trajectories of the youth involved. The study uses exclusively administrative data sets and includes a gender and racially diverse sample of 10,360 youth (30.7% females) who were arrested at least once between ages 12 and 24 in the early 2000s. Latent class growth analysis was employed in order to identify distinct arrest trajectories of youth in the sample. Multinomial logistic regression was used to identify diagnostic and other characteristics associated with membership in the specific trajectories predicted by Moffitt's theory. Five trajectory classes were identified, 3 of which were consistent with taxonomic theory including high and classic adolescence limited trajectory classes and a "snared adolescence limited class" described more recently by Moffitt. The distribution of youth among the 5 classes was very different for those with and without emotional disturbances. Youth with emotional disturbances in their late adolescent years were more likely to fall into the high arrest trajectory class and much less likely to fall into the low arrest trajectory class. Compared to youth without an emotional disturbance, youth with psychotic disorders were more than twice as likely to fall into the high as into the low arrest trajectory class. Youth with disruptive behavior disorders were more than twice as likely to fall into the high and intermediate classes as into the low trajectory class. Anxiety and depressive disorders were not associated with significantly greater likelihood of falling into any one of the trajectory classes. Youth in the snared adolescence limited class were more likely than those in the classic adolescence limited class to be male, black versus white and in the foster care enrollment category lending some support to Moffitt's conceptualization of this class as an adolescence limited class composed of youth who are snared by involvement in the criminal justice and or social services systems. Implications of these results for public policy and the study of adolescence are discussed. PMID- 23812743 TI - Cultural orientations, parental beliefs and practices, and latino adolescents' autonomy and independence. AB - Despite the salience of behavioral autonomy and independence to parent-child interactions during middle adolescence, little is known about parenting processes pertinent to youth autonomy development for Latino families. Among a diverse sample of 684 Latino-origin parent-adolescent dyads in Houston, Texas, this study examines how parents' cultural orientations are associated directly and indirectly, through parental beliefs, with parenting practices giving youth behavioral autonomy and independence. Informed by social domain theory, the study's parenting constructs pertain to youth behaviors in an "ambiguously personal" domain-activities that adolescents believe are up to youth to decide, but which parents might argue require parents' supervision, knowledge, and/or decision-making. Results for latent profile analyses of parents' cultural identity across various facets of acculturation indicate considerable cultural heterogeneity among Latino parents. Although 43% of parents have a Latino cultural orientation, others represent Spanish-speaking/bicultural (21%), bilingual/bicultural (15%), English-speaking/bicultural (15%), or US (6%) cultural orientations. Structural equation modeling results indicate that bilingual/bicultural, English-speaking/bicultural, and US-oriented parents report less emphasis on the legitimacy of parental authority and younger age expectations for youth to engage in independent behaviors than do Latino-oriented parents. Parental beliefs endorsing youth's behavioral independence and autonomy, in turn, are associated with less stringent parental rules (parental report), less parental supervision (parental and youth report), and more youth autonomy in decision-making (parental and youth report). Evidence thus supports the idea that the diverse cultural orientations of Latino parents in the US may result in considerable variations in parenting processes pertinent to Latino adolescents' development. PMID- 23812744 TI - Changes in histological features of nasal polyps in a Korean population over a 17 year period. AB - OBJECTIVE: Nasal polyps can be categorized as eosinophilic or non-eosinophilic, depending on inflammatory cell infiltration. There are geographical differences in the prevalence of types of pathologic polyps. The aim of this study was to evaluate the change in the prevalence of histological subtypes of polyps over time in a Korean population. STUDY DESIGN: A retrospective cross-sectional study with histologic analysis. SETTING: A single academic medical center. SUBJECTS AND METHODS: A total of 230 patients with nasal polyps were enrolled between 1993 1994 (group A) and 2010-2011 (group B). Specimens were fixed in formalin and embedded into paraffin blocks. Slides were stained with hematoxylin-eosin (H&E) and were subsequently reviewed by 2 of the authors. The numbers of eosinophils per high power field (HPF), as well as other cellular, epithelial, and stromal markers, were recorded. RESULTS: We compared nasal polyp eosinophil counts according to time period. The average eosinophil count/HPF increased from 6.8 in group A to 19.3 in group B (P = .006). The prevalence of eosinophilic polyps also increased from 24.0% in group A to 50.9% in group B (P < .001). Among other histologic markers, lymphocytes, basement membrane thickening, and gland hyperplasia showed significant differences between groups. CONCLUSION: After comparison of histopathologic findings of nasal polyps from 1993 and 2011 at 1 academic medical center in Korea, the prevalence of eosinophilic nasal polyps, which are known to be rare among Asians, has significantly increased. PMID- 23812745 TI - MicroRNAs in endothelial senescence and atherosclerosis. AB - Aging is an important risk factor for the development of many cardiovascular diseases as atherosclerosis and is accompanied by the decline of endothelial function. Senescence of endothelial cells has been proposed to be involved in endothelial dysfunction and atherogenesis. Therefore, the study of new target therapies to prevent or reverse this process represents a field of great interest. MicroRNAs (miRNAs), a class of short RNAs, play key roles in various biological processes and in the development of human disease through specific posttranscriptional downregulation of gene expression. In particular, miRNAs that are highly expressed by endothelial cells can be detected in high concentration in human atherosclerotic plaques and in the circulation, suggesting their potential translation to bedside to determine the dysfunction of specific signaling pathways which play a role in coronary artery disease in the individual patient, a path towards a stratified medicine approach for early preventive treatment of disease. Here, we review the most recent advances in the field of atherosclerosis that implicate a role for miRNAs with a special emphasis on endothelial senescence and its involvement in the atherosclerotic process. Finally, we briefly discuss the potential use of miRNAs signatures to map atherosclerosis progression and in particular underlying the relevance of circulating plasma miRNAs that can be used clinically as biomarkers of vascular pathology. PMID- 23812747 TI - Theory of mass-independent fractionation of isotopes, phase space accessibility, and a role of isotopic symmetry. AB - Key experimental and theoretical features of mass-independent fractionation (MIF) of isotopes, also known as the eta-effect, are summarized, including its difference from the exit channel zero-point energy difference effect. The latter exactly cancels in the MIF. One key experimental result is that the MIF for O3 formation is a low-pressure phenomenon and, moreover, that it decreases with increasing pressure of third bodies at pressures far below the "Lindemann fall off" pressures for three-body recombination of O and O2. A possible origin of the MIF is discussed in terms of a role for isotopologue symmetry in intramolecular energy sharing. An explanation is suggested for the large difference in the fall off pressure for recombination and the pressure for a large decrease in MIF, in terms of a difference between deactivating collisions and what we term here "symmetry-changing collisions". It is noted that the theory of the MIF involves four recombination rate constants and an equilibrium constant, for each trace isotope, seven rate constants in all and two equilibrium constants. A conceptual shortcut is noted. Experimental and computational information that may provide added insight into the MIF mechanism and tests is described. PMID- 23812746 TI - Signaling through hepatocellular A2B adenosine receptors dampens ischemia and reperfusion injury of the liver. AB - Ischemia and reperfusion significantly contributes to the morbidity and mortality of liver surgery and transplantation. Based on studies showing a critical role for adenosine signaling in mediating tissue adaptation during hypoxia, we hypothesized that signaling events through adenosine receptors (ADORA1, ADORA2A, ADORA2B, or ADORA3) attenuates hepatic ischemia and reperfusion injury. Initial screening studies of human liver biopsies obtained during hepatic transplantation demonstrated a selective and robust induction of ADORA2B transcript and protein following ischemia and reperfusion. Subsequent exposure of gene-targeted mice for each individual adenosine receptor to liver ischemia and reperfusion revealed a selective role for the Adora2b in liver protection. Moreover, treatment of wild type mice with an Adora2b-selective antagonist resulted in enhanced liver injury, whereas Adora2b-agonist treatment was associated with attenuated hepatic injury in wild-type, but not in Adora2b(-/-) mice. Subsequent studies in mice with Adora2b deletion in different tissues--including vascular endothelia, myeloid cells, and hepatocytes--revealed a surprising role for hepatocellular-specific Adora2b signaling in attenuating nuclear factor NF-kappaB activation and thereby mediating liver protection from ischemia and reperfusion injury. These studies provide a unique role for hepatocellular-specific Adora2b signaling in liver protection during ischemia and reperfusion injury. PMID- 23812748 TI - RNA splicing regulates the temporal order of TNF-induced gene expression. AB - When cells are induced to express inflammatory genes by treatment with TNF, the mRNAs for the induced genes appear in three distinct waves, defining gene groups I, II, and III, or early, intermediate, and late genes. To examine the basis for these different kinetic classes, we have developed a PCR-based procedure to distinguish pre-mRNAs from mRNAs. It shows that the three groups initiate transcription virtually simultaneously but that delays in splicing characterize groups II and III. We also examined the elongation times, concluding that pre mRNA synthesis is coordinate but splicing differences directly regulate the timing of mRNA production. PMID- 23812749 TI - Maturation, not initiation, is the major roadblock during reprogramming toward pluripotency from human fibroblasts. AB - Pluripotency can be induced in somatic cells by forced expression of POU domain, class 5, transcription factor 1 (OCT3/4), sex determining region Y-box 2 (SOX2), Kruppel-like factor 4 (KLF4), myelocytomatosis oncogene (c-MYC) (OSKM). However, factor-mediated direct reprogramming is generally regarded as an inefficient and stochastic event. Contrary to this notion, we herein demonstrate that most human adult dermal fibroblasts initiated the reprogramming process on receiving the OSKM transgenes. Within 7 d, ~20% of these transduced cells became positive for the TRA-1-60 antigen, one of the most specific markers of human pluripotent stem cells. However, only a small portion (~1%) of these nascent reprogrammed cells resulted in colonies of induced pluripotent stem cells after replating. We found that many of the TRA-1-60-positive cells turned back to be negative again during the subsequent culture. Among the factors that have previously been reported to enhance direct reprogramming, LIN28, but not Nanog homeobox (NANOG), Cyclin D1, or p53 shRNA, significantly inhibited the reversion of reprogramming. These data demonstrate that maturation, and not initiation, is the limiting step during the direct reprogramming of human fibroblasts toward pluripotency and that each proreprogramming factor has a different mode of action. PMID- 23812751 TI - Metabolic rates and sulfur cycling in the geologic record. PMID- 23812750 TI - Highly potent, synthetically accessible prostratin analogs induce latent HIV expression in vitro and ex vivo. AB - Highly active antiretroviral therapy (HAART) decreases plasma viremia below the limits of detection in the majority of HIV-infected individuals, thus serving to slow disease progression. However, HAART targets only actively replicating virus and is unable to eliminate latently infected, resting CD4(+) T cells. Such infected cells are potentially capable of reinitiating virus replication upon cessation of HAART, thus leading to viral rebound. Agents that would eliminate these reservoirs, when used in combination with HAART, could thus provide a strategy for the eradication of HIV. Prostratin is a preclinical candidate that induces HIV expression from latently infected CD4(+) T cells, potentially leading to their elimination through a virus-induced cytopathic effect or host anti-HIV immunity. Here, we report the synthesis of a series of designed prostratin analogs and report in vitro and ex vivo studies of their activity relevant to induction of HIV expression. Members of this series are up to 100-fold more potent than the preclinical lead (prostratin) in binding to cell-free PKC, and in inducing HIV expression in a latently infected cell line and prostratin-like modulation of cell surface receptor expression in primary cells from HIV-negative donors. Significantly, selected members were also tested for HIV induction in resting CD4(+) T cells isolated from infected individuals receiving HAART and were found to exhibit potent induction activity. These more potent agents and by extension related tunable analogs now accessible through the studies described herein should facilitate research and preclinical advancement of this strategy for HIV/AIDS eradication. PMID- 23812752 TI - Aneuploidy underlies a multicellular phenotypic switch. AB - Although microorganisms are traditionally used to investigate unicellular processes, the yeast Saccharomyces cerevisiae has the ability to form colonies with highly complex, multicellular structures. Colonies with the "fluffy" morphology have properties reminiscent of bacterial biofilms and are easily distinguished from the "smooth" colonies typically formed by laboratory strains. We have identified strains that are able to reversibly toggle between the fluffy and smooth colony-forming states. Using a combination of flow cytometry and high throughput restriction-site associated DNA tag sequencing, we show that this switch is correlated with a change in chromosomal copy number. Furthermore, the gain of a single chromosome is sufficient to switch a strain from the fluffy to the smooth state, and its subsequent loss to revert the strain back to the fluffy state. Because copy number imbalance of six of the 16 S. cerevisiae chromosomes and even a single gene can modulate the switch, our results support the hypothesis that the state switch is produced by dosage-sensitive genes, rather than a general response to altered DNA content. These findings add a complex, multicellular phenotype to the list of molecular and cellular traits known to be altered by aneuploidy and suggest that chromosome missegregation can provide a quick, heritable, and reversible mechanism by which organisms can toggle between phenotypes. PMID- 23812753 TI - High-resolution view of bacteriophage lambda gene expression by ribosome profiling. AB - Bacteriophage lambda is one of the most extensively studied organisms and has been a primary model for understanding basic modes of genetic regulation. Here, we examine the progress of lambda gene expression during phage development by ribosome profiling and, thereby, provide a very-high-resolution view of lambda gene expression. The known genes are expressed in a predictable fashion, authenticating the analysis. However, many previously unappreciated potential open reading frames become apparent in the expression analysis, revealing an unexpected complexity in the pattern of lambda gene function. PMID- 23812754 TI - Interpreting China's carbon flows. PMID- 23812755 TI - CYP76AH1 catalyzes turnover of miltiradiene in tanshinones biosynthesis and enables heterologous production of ferruginol in yeasts. AB - Cytochrome P450 enzymes (CYPs) play major roles in generating highly functionalized terpenoids, but identifying the exact biotransformation step(s) catalyzed by plant CYP in terpenoid biosynthesis is extremely challenging. Tanshinones are abietane-type norditerpenoid naphthoquinones that are the main lipophilic bioactive components of the Chinese medicinal herb danshen (Salvia miltiorrhiza). Whereas the diterpene synthases responsible for the conversion of (E,E,E)-geranylgeranyl diphosphate into the abietane miltiradiene, a potential precursor to tanshinones, have been recently described, molecular characterization of further transformation of miltiradiene remains unavailable. Here we report stable-isotope labeling results that demonstrate the intermediacy of miltiradiene in tanshinone biosynthesis. We further use a next-generation sequencing approach to identify six candidate CYP genes being coregulated with the diterpene synthase genes in both the rhizome and danshen hairy roots, and demonstrate that one of these, CYP76AH1, catalyzes a unique four-electron oxidation cascade on miltiradiene to produce ferruginol both in vitro and in vivo. We then build upon the previous establishment of miltiradiene production in Saccharomyces cerevisiae, with incorporation of CYP76AH1 and phyto-CYP reductase genes leading to heterologous production of ferruginol at 10.5 mg/L. As ferruginol has been found in many plants including danshen, the results and the approaches that were described here provide a solid foundation to further elucidate the biosynthesis of tanshinones and related diterpenoids. Moreover, these results should facilitate the construction of microbial cell factories for the production of phytoterpenoids. PMID- 23812756 TI - Axon position within the corpus callosum determines contralateral cortical projection. AB - How developing axons in the corpus callosum (CC) achieve their homotopic projection to the contralateral cortex remains unclear. We found that axonal position within the CC plays a critical role in this projection. Labeling of nearby callosal axons in mice showed that callosal axons were segregated in an orderly fashion, with those from more medial cerebral cortex located more dorsally and subsequently projecting to more medial contralateral cortical regions. The normal axonal order within the CC was grossly disturbed when semaphorin3A/neuropilin-1 signaling was disrupted. However, the order in which axons were positioned within the CC still determined their contralateral projection, causing a severe disruption of the homotopic contralateral projection that persisted at postnatal day 30, when the normal developmental refinement of contralateral projections is completed in wild-type (WT) mice. Thus, the orderly positioning of axons within the CC is a primary determinant of how homotopic interhemispheric projections form in the contralateral cortex. PMID- 23812757 TI - Context-dependent signaling defines roles of BMP9 and BMP10 in embryonic and postnatal development. AB - Many important signaling pathways rely on multiple ligands. It is unclear if this is a mechanism of safeguard via redundancy or if it serves other functional purposes. In this study, we report unique insight into this question by studying the activin receptor-like kinase 1 (ALK1) pathway. Despite its functional importance in vascular development, the physiological ligand or ligands for ALK1 remain to be determined. Using conventional knockout and specific antibodies against bone morphogenetic protein 9 (BMP9) or BMP10, we showed that BMP9 and BMP10 are the physiological, functionally equivalent ligands of ALK1 in vascular development. Timing of expression dictates the in vivo requisite role of each ligand, and concurrent expression results in redundancy. We generated mice (Bmp10(9/9)) in which the coding sequence of Bmp9 replaces that of Bmp10. Surprisingly, analysis of Bmp10(9/9) mice demonstrated that BMP10 has an exclusive function in cardiac development, which cannot be substituted by BMP9. Our study reveals context-dependent significance in having multiple ligands in a signaling pathway. PMID- 23812759 TI - Comparison among children with children with autism spectrum disorder, nonverbal learning disorder and typically developing children on measures of executive functioning. AB - It has been suggested that children with nonverbal learning disabilities (NLD) or Asperger's Syndrome (AS) may show difficulties with executive functioning. There were 3 groups in this study who completed a neuropsychological battery of visual spatial, executive functioning, and reasoning tasks; AS (n = 37), NLD (n = 31), and controls (n = 40). Results indicated that children in both clinical groups scored within average limits on measures of spatial reasoning and verbal ability. Fluid reasoning was also found to be within average ranges for all groups. The AS group experienced significant problems with cognitive flexibility compared to the other two groups. In contrast the NLD group showed fewer difficulties with cognitive flexibility but more problems with visual sequencing. These findings suggest that performance on executive function measures for children with AS or NLD is remarkably similar with subtle differences present. PMID- 23812758 TI - Protective effect of Bajijiasu against beta-amyloid-induced neurotoxicity in PC12 cells. AB - Beta-amyloid peptide (Abeta), a major protein component of senile plaques associated with Alzheimer's disease (AD), is also directly neurotoxic. Mitigation of Abeta-induced neurotoxicity is thus a possible therapeutic approach to delay or prevent onset and progression of AD. This study evaluated the protective effect of Bajijiasu (beta- D-fructofuranosyl (2-2) beta- D-fructofuranosyl), a dimeric fructose isolated from the Chinese herb Radix Morinda officinalis, on Abeta-induced neurotoxicity in pheochromocytoma (PC12) cells. Bajijiasu alone had no endogenous neurotoxicity up to 200 MUM. Brief pretreatment with 10-40 MUM Bajijiasu (2 h) significantly reversed the reduction in cell viability induced by subsequent 24 h exposure to Abeta25-35 (21 MUM) as measured by MTT and LDH assays, and reduced Abeta25-35-induced apoptosis as indicated by reduced annexin V-EGFP staining. Bajijiasu also decreased the accumulation of intracellular reactive oxygen species and the lipid peroxidation product malondialdehyde in PC12 cells, upregulated expression of glutathione reductase and superoxide dismutase, prevented depolarization of the mitochondrial membrane potential (Psim), and blocked Abeta25-35-induced increases in [Ca(2+)] i . Furthermore, Bajijiasu reversed Abeta25-35-induced changes in the expression levels of p21, CDK4, E2F1, Bax, NF-kappaB p65, and caspase-3. Bajijiasu is neuroprotective against Abeta25-35-induced neurotoxicity in PC12 cells, likely by protecting against oxidative stress and ensuing apoptosis. PMID- 23812760 TI - Thermal acclimation of photosynthesis: on the importance of adjusting our definitions and accounting for thermal acclimation of respiration. AB - While interest in photosynthetic thermal acclimation has been stimulated by climate warming, comparing results across studies requires consistent terminology. We identify five types of photosynthetic adjustments in warming experiments: photosynthesis as measured at the high growth temperature, the growth temperature, and the thermal optimum; the photosynthetic thermal optimum; and leaf-level photosynthetic capacity. Adjustments of any one of these variables need not mean a concurrent adjustment in others, which may resolve apparently contradictory results in papers using different indicators of photosynthetic acclimation. We argue that photosynthetic thermal acclimation (i.e., that benefits a plant in its new growth environment) should include adjustments of both the photosynthetic thermal optimum (T opt) and photosynthetic rates at the growth temperature (A growth), a combination termed constructive adjustment. However, many species show reduced photosynthesis when grown at elevated temperatures, despite adjustment of some photosynthetic variables, a phenomenon we term detractive adjustment. An analysis of 70 studies on 103 species shows that adjustment of T opt and A growth are more common than adjustment of other photosynthetic variables, but only half of the data demonstrate constructive adjustment. No systematic differences in these patterns were found between different plant functional groups. We also discuss the importance of thermal acclimation of respiration for net photosynthesis measurements, as respiratory temperature acclimation can generate apparent acclimation of photosynthetic processes, even if photosynthesis is unaltered. We show that while dark respiration is often used to estimate light respiration, the ratio of light to dark respiration shifts in a non-predictable manner with a change in leaf temperature. PMID- 23812761 TI - Abstinence-related expectancies predict smoking withdrawal effects: implications for possible causal mechanisms. AB - RATIONALE: Despite the decades-long emphasis on withdrawal in leading models of addiction, the causal mechanisms driving smoking withdrawal effects are not well known. This gap in the knowledge base has stalled theory and treatment development for smoking dependence. OBJECTIVES: As cognitive factors have been largely neglected as predictors of withdrawal, the current study sought to examine how smokers' abstinence-related expectancies relate to withdrawal symptomatology. METHODS: Adult smokers (N = 180; >=10 cigarettes/day) participated in two counterbalanced experimental sessions involving either 16 h of abstinence or smoking as usual. At baseline, participants completed three withdrawal-related scales of the Smoking Abstinence Questionnaire (Withdrawal, Optimistic Outcomes, and Weight Gain scales), a self-report measure of smokers' abstinence-related expectancies. During experimental sessions, participants completed a number of instruments that covered the range of smoking withdrawal effects (i.e., negative affect, urge/craving to smoke, diminished positive affect, concentration difficulty, hunger, and physiological symptoms). RESULTS: Even after controlling for the influence of demographic characteristics and cigarette dependence, smokers' abstinence-related expectancies were meaningful predictors of abstinence-induced changes in various withdrawal symptoms (mean adjusted standardized beta = 0.22). Stronger expectancies for withdrawal and weight gain predicted more severe withdrawal effects, whereas stronger expectancies for optimistic outcomes predicted less severe withdrawal effects. CONCLUSIONS: These findings are consistent with the notion that expectancies actively shape future experience and are the first to support the suggestion that smokers' abstinence-related expectancies may be causal agents of withdrawal symptomatology. Future research is required to more conclusively determine whether abstinence-related expectancies mold withdrawal effects. PMID- 23812762 TI - Effects of acute alcohol intoxication on saccadic conflict and error processing. AB - RATIONALE: Flexible behavior optimization relies on cognitive control which includes the ability to suppress automatic responses interfering with relevant goals. Extensive evidence suggests that the anterior cingulate cortex (ACC) is the central node in a predominantly frontal cortical network subserving executive tasks. Neuroimaging studies indicate that the ACC is sensitive to acute intoxication during conflict, but such evidence is limited to tasks using manual responses with arbitrary response contingencies. OBJECTIVES: The present study was designed to examine whether alcohol's effects on top-down cognitive control would generalize to the oculomotor system during inhibition of hardwired saccadic responses. METHODS: Healthy social drinkers (N = 22) underwent functional magnetic resonance imaging (fMRI) scanning and eye movement tracking during alcohol (0.6 g/kg ethanol for men, 0.55 g/kg for women) and placebo conditions in a counterbalanced design. They performed visually guided prosaccades (PS) towards a target and volitional antisaccades (AS) away from it. To mitigate possible vasoactive effects of alcohol on the BOLD (blood oxygenation level-dependent) signal, resting perfusion was quantified with arterial spin labeling (ASL) and used as a covariate in the BOLD analysis. RESULTS: Saccadic conflict was subserved by a distributed frontoparietal network. However, alcohol intoxication selectively attenuated activity only in the ACC to volitional AS and erroneous responses. CONCLUSIONS: This study provides converging evidence for the selective ACC vulnerability to alcohol intoxication during conflict across different response modalities and executive tasks, confirming its supramodal, high-level role in cognitive control. Alcohol intoxication may impair top-down regulative functions by attenuating the ACC activity, resulting in behavioral disinhibition and decreased self-control. PMID- 23812763 TI - Traumatic stress in rats induces noradrenergic-dependent long-term behavioral sensitization: role of individual differences and similarities with dependence on drugs of abuse. AB - RATIONALE: The aim of this paper is to provide evidence for the hypothesis that posttraumatic stress disorder (PTSD) and drug addiction rely on common processes. OBJECTIVE: Our objective is to show that a noradrenergic-dependent behavioral sensitization occurs after the development of PTSD, in a way similar to that recently demonstrated after repeated drug injections. METHODS: Rats classified into high and low responders to novelty (HR/LR) were subjected to a single prolonged stress (SPS). Cross-sensitization was evaluated after d-amphetamine injection (1.0 mg/kg) in a locomotor activity test given either 4, 15, or 90 days later. To determine the involvement of the noradrenergic system, rats were injected with the alpha2-receptor agonist, clonidine (20 MUg/kg), during the SPS. Subsequently, their auditory startle response (ASR) and cross-sensitization were assessed. RESULTS: SPS affected both the hypothalamic-pituitary-adrenal axis and the ASR, replicating some PTSD-like symptoms. Behavioral sensitization was found after 15, 21, and 90 days after the SPS in LR rats, and a behavioral desensitization in HR rats after 15 days. Clonidine delivered during the SPS prevented the behavioral sensitization in LR rats, as well as the effects on ASR in HR and LR rats. CONCLUSIONS: Exposure to SPS is shown to affect behavior and induce a behavioral sensitization to d-amphetamine that is modulated by individual differences. Both of these effects depend on the noradrenergic system. Altogether, the present results (1) replicate findings obtained after repeated drug exposure and (2) strengthen our hypothesis of a common physiological basis between PTSD and drug addiction. PMID- 23812764 TI - Role of GABAA receptors in dorsal raphe nucleus in stress-induced reinstatement of morphine-conditioned place preference in rats. AB - RATIONALE: The serotonin (5-hydroxytryptamine, 5-HT) system plays an important role in stress-related psychiatric disorders and substance abuse. Our data indicate that stress inhibits the dorsal raphe nucleus (DRN)-5-HT system via stimulation of GABA synaptic activity by the stress neurohormone corticotropin releasing factor and, more recently, that morphine history sensitizes DRN-5-HT neurons to GABAergic inhibitory effects of stress. OBJECTIVES: We tested the hypothesis that DRN GABAA receptors contribute to stress-induced reinstatement of morphine-conditioned place preference (CPP). METHODS: First, we tested if activation of GABAA receptors in the DRN would reinstate morphine CPP. Second, we tested if blockade of GABAA receptors in the DRN would attenuate swim stress induced reinstatement of morphine CPP. CPP was induced by morphine (5 mg/kg) in a 4-day conditioning phase followed by a conditioning test. Upon acquiring conditioning criteria, subjects underwent 4 days of extinction training followed by an extinction test. Upon acquiring extinction criteria, animals underwent a reinstatement test. For the first experiment, the GABAA receptor agonist muscimol (50 ng) or vehicle was injected into the DRN prior to the reinstatement test. For the second experiment, the GABAA receptor antagonist bicuculline (75 ng) or vehicle was injected into the DRN prior to a forced swim stress, and then, animals were tested for reinstatement of CPP. RESULTS: Intraraphe injection of muscimol reinstated morphine CPP, while intraraphe injection of bicuculline attenuated swim stress-induced reinstatement. CONCLUSIONS: These data provide evidence that GABAA receptor-mediated inhibition of the serotonergic DRN contributes to stress-induced reinstatement of morphine CPP. PMID- 23812765 TI - Vestibular hemispatial neglect: patterns and possible mechanism. AB - Recent reports have suggested that hemispatial neglect may be a vestibular disorder at the cortical level, based on the similarities of symptoms and neural correlates between the two phenomena. If this is the case, peripheral vestibulopathy may lead to hemispatial neglect. However, the etiology of hemispatial neglect in patients with unilateral peripheral vestibulopathy remains unclear. The aims of the present study were to investigate the following: (1) if unilateral peripheral vestibulopathy might cause hemispatial neglect, and if so, (2) whether hemispatial neglect in unilateral peripheral vestibulopathy might be induced by horizontal bias for eye position and body orientation or whether it is secondary to vestibular cortical dysfunction following unilateral peripheral vestibulopathy. Twenty-five consecutive patients with acute vestibular neuritis were recruited at the Dizziness Clinic of Pusan National University Hospital. All participants underwent neglect testing and measurements of horizontal bias for eye position and head and body orientation. Hemispatial neglect occurred in 32 % of patients with unilateral peripheral vestibulopathy. The frequency of contralesional neglect was equal to that of ipsilesional neglect. All patients with hemispatial neglect showed abnormal performance in bisection tasks. The incidence and severity of the horizontal bias of eye position and head and body orientation did not differ between patients with or without hemispatial neglect. Our study demonstrates that hemispatial neglect can develop after acute unilateral peripheral vestibulopathy. Hemispatial neglect after acute unilateral peripheral vestibulopathy may be attributed to damaged vestibular subnuclei, which receive afferents from both peripheral vestibular end organs and the vestibulocerebellum and project to the ipsilateral or contralateral thalamus and vestibular cortex. PMID- 23812767 TI - Reproducibility and validity of the Japanese version of the Western Ontario Rotator Cuff Index. AB - BACKGROUND: The Western Ontario Rotator Cuff Index (WORC) is a self-report, disease-specific, quality-of-life assessment tool. Good reliability and validity have been demonstrated with several language versions of the WORC. In this study, the WORC was translated into Japanese, and its reproducibility and validity for use in Japanese patients with rotator cuff disorder were determined. MATERIALS AND METHODS: The translated version of the WORC was certified by the developer of the original version. Of 78 consecutive Japanese patients with rotator cuff disorder, 75 completed the following questionnaires: the WORC; the Disabilities of the Arm, Shoulder, and Hand (DASH); and the Short Form 36 (SF-36). In total, 50 patients completed the WORC twice within 2-14 days. Internal consistency, test retest reliability, absolute reliability, and construct validity were assessed. RESULTS: Cronbach's alpha coefficients ranged from 0.78-0.95, and intraclass correlation coefficients ranged from 0.72-0.84 for the total score as well as scores on all WORC domains. A fixed bias was revealed between the test and retest for the total score and scores of some domains. Limits of agreement (LOA) ranged from -19.0-27.9% for the total score on the WORC. Furthermore, the WORC scores correlated with those of DASH (r = 0.63-0.78) and SF-36 (r = -0.24 to -0.69). CONCLUSIONS: Good test-retest reliability and construct validity were demonstrated for the Japanese WORC, but relatively high absolute measurement errors were observed. LOA values must be considered when using the WORC for individual patients with rotator cuff disorder. PMID- 23812766 TI - Tumor suppressor in lung cancer 1 (TSLC1), a novel tumor suppressor gene, is implicated in the regulation of proliferation, invasion, cell cycle, apoptosis, and tumorigenicity in cutaneous squamous cell carcinoma. AB - Tumor suppressor in lung cancer 1 (TSLC1) is tightly implicated in a variety of biological processes and plays critical roles in tumor development and progression. However, the roles of TSLC1 in cutaneous squamous cell carcinoma (CSCC) remain to be unraveled. Here, we reported the TSLC1 gene that was significantly downregulated in CSCC tissues and cells, and survival times of patients with TSLC1 at a low level were markedly lower than that at a high level (P = 0.0070). A stepwise investigation demonstrated that an elevated TSLC1 level evoked obvious proliferation and invasion inhibitions and arrested cell cycle at G0/G1 phase in A431 cells. Moreover, increase of caspase-3 activity mediated by elevated TSLC1 level induced cell apoptosis in A431 cells. Most notably, upregulation of TSLC1 expression reduced the numbers of colony formation and tumorigenicity. Collectively, our results presented herein suggest that TSLC1 as tumor suppressor may play prominent roles in development and progression of CSCC via regulation of different biological processes. PMID- 23812768 TI - The Pavlik harness in the treatment of developmentally dislocated hips: results of Japanese multicenter studies in 1994 and 2008. AB - BACKGROUND: It has already been more than 50 years since the Pavlik harness was introduced in Japan, and today the Pavlik harness is widely recognized as the standard initial treatment modality for developmental dysplasia of the hip. We performed a multicenter nationwide questionnaire study concerning the results of Pavlik harness treatment twice in 1994 and 2008. METHODS: In 1994 and in 2008, we sent questionnaires to 12 institutes in Japan specializing mainly in pediatric orthopedics. We compare the results of these two studies and discuss differences in reduction rates, incidence of avascular necrosis in the femoral epiphysis and the percentage of joints with acceptable morphology (Severin grade I + II/total) at skeletal maturity. We statistically assessed these results to see whether there were changes in the treatment outcomes over this 14-year period. RESULTS: Reduction of the dislocated hips was obtained by the Pavlik harness in 80.2% (1990/2481 hips; 1994) and 81.9% (1248/1523 hips; 2008). The incidences of avascular necrosis of the proximal femoral epiphysis in the dysplastic hips were 14.3% (119/835 hips; 1994) and 11.5% (76/663 hips; 2008). The type of avascular necrosis in hips from the 2008 study was determined according to the classification of Kalamchi and MacEwen: 24/69 hips (34.8%) were classified as group I; 20/69 hips (29.0%) as group II; 11/69 hips (15.9%) as group Ill; 14/69 hips (20.3%) as group IV. The percentages of hips with acceptable outcomes at skeletal maturity discerned from Severin X-ray changes (grade I + II/total) were 72.3% (604/835 hips; 1994) and 77.7% (488/628 hips; 2008). CONCLUSION: Reduction rates and the incidence of avascular necrosis in 2008 were statistically similar to the results in 1994. The rate of acceptable outcome (Severin grade I + II/total) in 2008 was statistically higher than that of 1994. PMID- 23812769 TI - Cost-effectiveness analysis of intraoperative radiation therapy for early-stage breast cancer. AB - BACKGROUND: Shortened courses of radiation therapy have been shown to be similarly effective to whole-breast external-beam radiation therapy (WB-EBRT) in terms of local control. We sought to analyze, from a societal perspective, the cost-effectiveness of two radiation strategies for early-stage invasive breast cancer: single-dose intraoperative radiation therapy (IORT) and the standard 6 week course of WB-EBRT. METHODS: We developed a Markov decision-analytic model to evaluate these treatment strategies in terms of life expectancy, quality-adjusted life years (QALYs), costs, and the incremental cost-effectiveness ratio over 10 years. RESULTS: IORT single-dose intraoperative radiation therapy was the dominant, more cost-effective strategy, providing greater quality-adjusted life years at a decreased cost compared with 6-week WB-EBRT. The model was sensitive to health state utilities and recurrence rates, but not costs. IORT was either the preferred or dominant strategy across all sensitivity analyses. The two-way sensitivity analyses demonstrate the need to accurately determine utility values for the two forms of radiation treatment and to avoid indiscriminate use of IORT. CONCLUSIONS: With less cost and greater QALYs than WB-EBRT, IORT is the more valuable strategy. IORT offers a unique example of new technology that is less costly than the current standard of care option but offers similar efficacy. Even when considering the capital investment for the equipment ($425 K, low when compared with the investments required for robotic surgery or high-dose-rate brachytherapy), which could be recouped after 3-4 years conservatively, these results support IORT as a change in practice for treating early-stage invasive breast cancer. PMID- 23812770 TI - Identification of the NEDD4L gene as a prognostic marker by integrated microarray analysis of copy number and gene expression profiling in non-small cell lung cancer. AB - PURPOSE: The purpose of this study was to identify prognostic genes by integrated microarray analysis between comparative genomic hybridization and gene expression with laser microdissection in non-small cell lung cancer (NSCLC). METHODS: Integrated microarray analysis in 11 lung adenocarcinomas was performed, and several genes were identified. Among them, neural precursor cell-expressed developmentally down-regulated 4-like (NEDD4L) was chosen for further characterization. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was used to explore the clinicopathological significance of NEDD4L expression in 84 NSCLC patients. RESULTS: 18q was more frequently lost in advanced lung cancer. Therefore, we selected the NEDD4L gene, located on chromosome 18q, for which reduced expression was significantly correlated with copy number loss. NEDD4L mRNA expression in paired tumor/normal samples from 79 cases of lung cancer was evaluated using real-time PCR analysis. NEDD4L mRNA expression was significantly lower in tumor tissues than in normal lung tissues (p < 0.0001). Clinicopathological factors, such as excessive smoking history, histological grade (moderately and poorly), T stage (T2-4), lymph node metastasis, and pathological stage (stage II-IV), were significantly associated with low NEDD4L expression (p < 0.05). In the low expression group, prognoses were significantly poorer than in the high expression group (p < 0.05). CONCLUSIONS: Low NEDD4L expression may be a marker of prognosis. This is the first report to describe NEDD4L expression in NSCLC. NEDD4L may be considered a key gene in the progression of NSCLC, and its expression is likely affected by genomic alterations. PMID- 23812771 TI - Indeterminate pulmonary nodules at colorectal cancer staging: a systematic review of predictive parameters for malignancy. AB - BACKGROUND: This study aimed to estimate the prevalence of indeterminate pulmonary nodules and specific radiological and clinical characteristics that predict malignancy of these at initial staging chest computed tomography (CT) in patients with colorectal cancer. A considerable number of indeterminate pulmonary nodules, which cannot readily be classified as either benign or malignant, are detected at initial staging chest CT in colorectal cancer patients. METHODS: A systematic review based on a search in EMBASE, Medline, the Cochrane library and science citation index, PubMed databases, Google scholar, and relevant conference proceedings was performed in cooperation with the Cochrane Colorectal Cancer Group. RESULTS: A total of 2,799 studies were identified, of which 12 studies met the inclusion criteria. The studies primarily consisted of case series and included a total of 5,873 patients. Of these patients, 9% (95% confidence interval [95% CI] 8.9-9.2%) had indeterminate pulmonary nodules at chest CT, of which 10.8% (95% CI 10.3-11.2%) turned out to be colorectal cancer metastases at follow-up. Generally, regional lymph node metastasis, and multiple numbers of indeterminate pulmonary nodules were reported to predict malignancy, whereas calcification of the nodules indicated benign lesions. CONCLUSION: It was found that 1 in 100 colorectal cancer patients subjected to preoperative staging chest CT will have an indeterminate pulmonary nodule that proves to be metastatic disease. Such a low risk suggests that indeterminate pulmonary nodules should not cause further preoperative diagnostic workup or follow-up besides routine regimens. PMID- 23812772 TI - The role of lymphadenectomy in cervical cancer patients: the significance of the number and the status of lymph nodes removed in 526 cases treated in a single institution. AB - PURPOSE: To investigate whether the total number of removed lymph nodes (LNs) and the number of metastatic LNs would prove to be independent prognostic factors for survival in patients with cervical cancer (CC). METHODS: Data from patients with CC who underwent radical surgery between March 1980 and September 2009 were reviewed. A total of 526 patients were included in the statistical analysis. Full pathologic evaluation was performed. The total number of examined LNs and their histopathological status were analyzed for their prognostic effect on survival by means of multivariable Cox proportional hazard regression models. RESULTS: The median number (interquartile range) of total, pelvic, and para-aortic nodes removed was 37 (29-47), 34 (27-42), and 19 (14-24), respectively. Positive pelvic nodes were found in 102 of 526 (19%) patients. All 8 patients with para-aortic metastases had also pelvic node metastases. At multivariable analysis, vaginal involvement, type of lymphadenectomy and LN status all significantly negatively affected disease-free survival and overall survival, whereas the number of total LNs removed did not affect survival. CONCLUSIONS: LN metastasis and number of LN metastases confer an independent risk for worse survival in patients with CC. Pelvic lymphadenectomy is important for staging and regional disease control when LNs are involved. If a standardized complete lymphadenectomy is performed, the number of LNs is not a significant factor per se. PMID- 23812773 TI - Does bethesda category predict aggressive features in malignant thyroid nodules? AB - BACKGROUND: It has been speculated that the Bethesda Classification System for thyroid fine-needle aspirate (FNA) may be used to predict aggressive features among histologically proven malignancies. We sought to evaluate whether malignancies that were characterized as Bethesda category V or VI have more aggressive features than malignancies that were category III or IV. METHODS: A prospectively maintained database was reviewed to identify thyroid malignancies treated at a single center from 2004 to 2009. Only cancers that could be definitively matched to a preoperative FNA were included. Associations between Bethesda category, patient demographics, histopathologic findings, and outcomes were examined. RESULTS: A total of 360 cancers were analyzed: 73 (20 %) were Bethesda category III or IV and 287 (80 %) were category V or VI. The majority of Bethesda III and IV cancers were follicular variants of papillary thyroid carcinoma (fvPTC), whereas the majority of Bethesda V and VI cancers were classic PTC (52 and 67 %, respectively, p < 0.01). Extrathyroidal extension (30 vs. 16 %, p = 0.02), lymph node metastases (50 vs. 31 %, p = 0.05), and multifocality (51 vs. 37 %, p = 0.03) were more common among Bethesda V and VI nodules. However, when Bethesda III or IV classic PTC and fvPTC were compared to Bethesda V or VI cancers of the same histologic subtype, there were no differences in any features. Recurrence and overall survival were the same in all groups. CONCLUSIONS: Bethesda category may help to predict the most likely histologic subtype of thyroid cancer, but it does not have any prognostic significance once the histologic diagnosis is known. PMID- 23812774 TI - Anti-melanogenic effect of (Z)-5-(2,4-dihydroxybenzylidene) thiazolidine-2,4 dione, a novel tyrosinase inhibitor. AB - We synthesized (Z)-5-(2,4-dihydroxybenzylidene)thiazolidine-2,4-dione (MHY498) as a potential tyrosinase inhibitor. MHY498 potently inhibited mushroom tyrosinase activity (mean IC50 = 3.55 MUM) in a dose-dependent manner. MHY498 was more potent than the well-known tyrosinase inhibitor, kojic acid (mean IC50 = 22.79 MUM). When tested in B16F10 melanoma cells treated with alpha-melanocyte stimulating hormone (alpha-MSH), MHY498 inhibited murine tyrosinase activity and decreased melanin production without inducing cytotoxicity. Docking models showed that the binding affinity of MHY498 to tyrosinase was higher than that of kojic acid, and docking simulation results indicated that the tyrosinase binding moieties of MHY498 and kojic acid were similar. Western blotting showed that tyrosinase inhibition by MHY498 partly resulted from the expressional modulations of tyrosinase and its transcription factor, microphthalmia-associated transcription factor, via the cAMP-PKA-CREB pathway. These findings suggest that MHY498 could be useful as an antimelanogenic agent for the prevention and treatment of diseases associated with skin pigmentation. PMID- 23812775 TI - Antioxidant activity of 3,4,5-trihydroxyphenylacetamide derivatives. AB - A series of amide derivatives of 3,4,5-trihydroxyphenylacetic acid was synthesized in two steps. The antioxidant activities were evaluated by using four different in vitro models such as ABTS and DPPH radical scavenging activity and FTC and TBA anti-lipid peroxidation activity. Most of compounds were more powerful radical scavengers than vitamin C and were comparable to Trolox. It was found that there were no direct correlations between radical scavenging and anti peroxidation activities. The inhibitory activity of compound on lipid peroxidation showed remarkable dependency on both the number of phenolic hydroxyl group and the length of methylene linker in N-arylalkyl group of amide. Compound 14, a conjugate of 3,4,5-trihydroxyphenylacetic acid and dopamine, was found as powerful antioxidant as propyl gallate in all four antioxidant assays. PMID- 23812776 TI - Effect of pressure sensitive adhesive and vehicles on permeation of terbinafine across porcine hoof membrane. AB - The purpose of this study was to investigate characteristics of transungual drug delivery and the feasibility of developing a drug-in-adhesive formulation of terbinafine. The permeation of terbinafine from a PSA matrix across porcine hoof membrane was determined using a plate containing poloxamer gel. The permeation rate of terbinafine across hairless mouse skin was evaluated using a flow-through diffusion cell system. The permeation of terbinafine across the hoof membranes was the highest from the silicone adhesive matrix, followed by PIB, and most of the acrylic adhesives, SIS, and SBS. The rank order of permeation rate across mice skin was different from the rank order across porcine hooves. The amount of terbinafine permeated across the porcine hoof membranes poorly correlated with the amount of terbinafine remaining inside the hooves after 20 days, however, the ratio between rate of terbinafine partitioning into the hoof membrane and its rate of diffusion across the membrane was relatively constant within the same type of PSA. For influence of various vehicles in enhancing permeation of terbinafine across the hoof membrane, all vehicles except Labrasol((r)) showed tendency to improve permeation rate. However, the enhancement ratio of a given vehicle differed from one adhesive to another with a moderate correlation between them. The infrared spectrum of the hoof treated with NMP, PPG 400 or PEG 200 indicated that the conformation of keratin changed from a non-helical to a helical structure. PMID- 23812777 TI - Current status of PET-imaging probes of beta-amyloid plaques. AB - Alzheimer's disease (AD) is the most common form of dementia and is characterized by progressive cognitive decline and memory loss. One of pathological hallmarks of AD is the accumulation and deposition of beta-amyloid (Abeta) plaques which is a potential target for the early diagnosis of AD. Positron emission tomography (PET), a sensitive radionuclide imaging technique, has provided opportunities to detect Abeta plaques of AD. PET-imaging probes of Abeta plaques have been extensively developed during the last decade. [(18)F]Florbetapir, the (18)F labeled PET-imaging probe of Abeta plaques, was recently approved by US Food and Drug Administration. A number of follow-on PET-imaging probes are currently being developed in academia and pharmaceutical companies. This article will discuss the recent development of PET-imaging probes from [(11)C]PIB to [(18)F]Florbetapir, which are in clinic trials, and several follow-on probes in preclinical stage. PMID- 23812778 TI - Protective effect of hydrogen sulfide against cold restraint stress-induced gastric mucosal injury in rats. AB - Hydrogen sulfide (H2S) is an endogenous gaseous mediator plays a potential role in modulating gastric inflammatory responses. However, its putative protective role remains to be defined. The present study aimed to evaluate role of the exogenously released and endogenously synthesized H2S in cold restraint stress (CRS)-induced oxidative gastric damage in rats. Rats were restrained, and maintained at 4 degrees C for 3 h. The H2S donor, sodium hydrosulfide (NaHS) (60 MUmol/kg) was injected intraperitoneally (i.p.) before CRS. Our results revealed that NaHS pretreatment significantly attenuated ulcer index, free and total acid output, and pepsin activity in gastric juice along with decreased gastric mucosal carbonyl content and reactive oxygen species production. This was accompanied by increased gastric juice pH and mucin concentration in addition to restoring the deficits in the gastric reduced glutathione, catalase as well as superoxide dismutase enzyme activities. NaHS pretreatment markedly reduced the serum level of tumor necrosis factor (TNF-alpha) and myeloperoxidase activity compared to CRS non-treated. Moreover, NaHS preadministration significantly abrogated the inflammatory and the deleterious responses of gastric mucosa in CRS. The protective effects of H2S were confirmed by gastric histopathological examination. However, pretreatment with the H2S-synthesizing enzyme, cystathionine-gamma-lyase inhibitor, beta-cyano-L-alanine (50 mg/kg, i.p.) reversed the gastroprotection afforded by the endogenous H2S. Collectively, our results suggest that H2S can protect rat gastric mucosa against CRS-induced gastric ulceration possibly through mechanisms that involve anti-oxidant and anti inflammatory actions alongside enhancement of gastric mucosal barrier and reduction in acid secretory parameters. PMID- 23812779 TI - Antiproliferative activities of Garcinia bracteata extract and its active ingredient, isobractatin, against human tumor cell lines. AB - In our cell based screening of antitumor ingredients from plants, the EtOH extract of Garcinia bracteata displayed antiproliferative effect against human lung adenocarcinoma A549 cells, human breast cancer MCF-7 cells, and human prostate cancer PC3 cells. Phytochemical investigation of this active extract produced nine ingredients, and their structures were established by analysis of MS and NMR spectra. Antiproliferative evaluation of isolated ingredients on A549, MCF-7 and PC3 cells indicated that a xanthone named isobractatin (1) exhibited potent antiproliferative activity against the above three human cancer cell lines with IC50 values ranging from 2.90 to 4.15 MUM. Treatment of PC3 cells with 1 led to an enhancement of the cell apoptosis, and arrested cell cycle in the G0/G1 phase. The G0/G1 phase cycle-related proteins analysis showed that the expressions of cyclins D1 and E were reduced by 1, whereas the protein level of cyclin dependent kinase (CDK) inhibitor P21 was induced. Additionally, 1 enhanced PC3 cell apoptosis by activations of Bax, caspases 3 and 9, and by inhibition of Bcl-2. Our combined data illustrated that isobractatin (1) was the antiproliferative ingredient of G. bracteata against three human cancer cell lines, which exerted its antiproliferatrive effect via cell cycle arrest and induction of apoptosis. PMID- 23812780 TI - Novel deletion of RPL15 identified by array-comparative genomic hybridization in Diamond-Blackfan anemia. AB - Diamond-Blackfan anemia (DBA) is an inherited red blood cell aplasia that usually presents during the first year of life. The main features of the disease are normochromic and macrocytic anemia, reticulocytopenia, and nearly absent erythroid progenitors in the bone marrow. The patients also present with growth retardation and craniofacial, upper limb, heart and urinary system congenital malformations in ~30-50 % of cases. The disease has been associated with point mutations and large deletions in ten ribosomal protein (RP) genes RPS19, RPS24, RPS17, RPL35A, RPL5, RPL11, RPS7, RPS10, RPS26, and RPL26 and GATA1 in about 60 65 % of patients. Here, we report a novel large deletion in RPL15, a gene not previously implicated to be causative in DBA. Like RPL26, RPL15 presents the distinctive feature of being required both for 60S subunit formation and for efficient cleavage of the internal transcribed spacer 1. In addition, we detected five deletions in RP genes in which mutations have been previously shown to cause DBA: one each in RPS19, RPS24, and RPS26, and two in RPS17. Pre-ribosomal RNA processing was affected in cells established from the patients bearing these deletions, suggesting a possible molecular basis for their pathological effect. These data identify RPL15 as a new gene involved in DBA and further support the presence of large deletions in RP genes in DBA patients. PMID- 23812781 TI - Alterations in axial curvature of the cervical spine with a combination of rotation and extension in the conventional anterior cervical approach. AB - PURPOSE: Alterations of three-dimensional cervical curvature in conventional anterior cervical approach position are not well understood. The purpose of this study was to evaluate alignment changes of the cervical spine in the position. In addition, simulated corpectomy was evaluated with regard to sufficiency of decompression and perforation of the vertebral artery canal. METHODS: Fifty patients with cervical spinal disorders participated. Cervical CT scanning was performed in the neutral and supine position (N-position) and in extension and right rotation simulating the conventional anterior approach position (ER position). Rotation at each vertebral level was measured. With simulation of anterior corpectomy in a vertical direction with a width of 17 mm, decompression width at the posterior wall of the vertebrae and the distance from each foramen of the vertebral artery (VA) were measured. RESULTS: In the ER-position, the cervical spine was rotated rightward by 37.2 degrees +/- 6.2 degrees between the occipital bone and C7. While the cervical spine was mainly rotated at C1/2, the subaxial vertebrae were also rotated by several degrees. Due to the subaxial rotation, the simulated corpectomy resulted in smaller decompression width on the left side and came closer to the VA canal on the right side. CONCLUSIONS: In the ER-position, the degrees of right rotation of subaxial vertebrae were small but significant. Therefore, preoperative understanding of this alteration of cervical alignment is essential for performing safe and sufficient anterior corpectomy of the cervical spine. PMID- 23812782 TI - Phosphorylation of tropomyosin in striated muscle. AB - An historical perspective of the phosphorylation of tropomyosin is provided. The effects of this covalent modification on the properties of striated muscle tropomyosin are summarised. Technical hurdles and findings in other systems are also discussed. PMID- 23812783 TI - Gangrene of the oesophago-gastric junction caused by strangulated hiatal hernia: operative challenge or surgical dead end. AB - BACKGROUND: Gangrene of the oesophago-gastric junction due to incarcerated hiatal hernia is an extremely uncommon emergency situation which was first recognized in the late nineteenth century. Early symptoms are mainly unspecific and so diagnosis is often considerably delayed. Aim of the study is to share experience in dealing with this devastating condition. MATERIAL: We encountered three male patients with gangrene of the oesophago-gastric junction caused by strangulated hiatal hernia within the last years. Clinical symptoms, surgical procedures and outcomes were retrospectively analyzed. Furthermore, we provide a history outline on the evolving surgical management from the preliminary reports of the nineteenth century up to modern times. RESULTS: Early symptoms were massive vomiting accompanied by retrosternal and epigastric pain. Hiatal hernia was already known in all patients. Nevertheless, clinical presentation was initially misdiagnosed as cardiovascular disorders. Upon emergency laparotomy gangrene of the oesophago-gastric junction was obvious while in one case even necrosis of the whole stomach occurred after considerable delayed diagnosis. Transmediastinal esophagectomy with resection of the proximal stomach and gastric pull up with cervical anastomosis was performed in two cases. Oesophago-gastrectomy with delayed reconstruction by retrosternal colonic interposition was mandatory in the case of complete gastric gangrene. Finally all sufferers recuperated well. CONCLUSIONS: Strangulation of hiatal hernia with subsequent gangrene of the oesophago-gastric junction is a life-threatening condition. Straight diagnosis is mandatory to avoid further necrosis of the proximal gastrointestinal tract as well as severe septic disease. Surgical strategies have considerably varied throughout the last 100 years. In our opinion transmediastinal oesophagectomy with interposition of a gastric tube and cervical anastomosis should be the procedure of choice if the distal stomach is still viable. Otherwise oesophago gastrectomy is unavoidable. Delayed cervical anastomosis or reconstruction is advisable in instable, septic patients. PMID- 23812785 TI - Spectral properties of a divinyl chlorophyll a harboring mutant of Synechocystis sp. PCC6803. AB - A divinyl chlorophyll (DV-Chl) a harboring mutant of Synechocystis sp. PCC 6803, in which chlorophyll species is replaced from monovinyl(normal)-Chl a to DV-Chl a, was characterized. The efficiency of light utilization for photosynthesis was decreased in the mutant. Absorption spectra at 77 K and their fourth derivative analyses revealed that peaks of each chlorophyll forms were blue-shifted by 1-2 nm, suggesting lowered stability of chlorophylls at their binding sites. This was also true both in PSI and PSII complexes. On the other hand, fluorescence emission spectra measured at 77 K were not different between wild type and the mutant. This indicates that the mode of interaction between chlorophyll and its binding pockets responsible for emitting fluorescence at 77 K is not altered in the mutant. P700 difference spectra of thylakoid membranes and PSI complexes showed that the spectrum in Soret region was red-shifted by 7 nm in the mutant. This is a characteristic feature of DV-Chl a. Microenvironments of iron-sulfur center of a terminal electron acceptor of PSI complex, P430, were practically the same as that of wild type. PMID- 23812784 TI - Human placental mesenchymal stem cells (pMSCs) play a role as immune suppressive cells by shifting macrophage differentiation from inflammatory M1 to anti inflammatory M2 macrophages. AB - BACKGROUND: Mesenchymal stem cells (MSCs) have a therapeutic potential in tissue repair because of capacity for multipotent differentiation and their ability to modulate the immune response. In this study, we examined the ability of human placental MSCs (pMSCs) to modify the differentiation of human monocytes into macrophages and assessed the influence of pMSCs on important macrophage functions. METHODS: We used GM-CSF to stimulate the differentiation of monocytes into the M1 macrophage pathway and then co-cultured these cells with pMSCs in the early stages of macrophage differentiation. We then evaluated the effect on differentiation by microscopic examination and by quantification of molecules important in the differentiation and immune functions of macrophages using flow cytometry and ELISA. The mechanism by which pMSCs could mediate their effects on macrophage differentiation was also studied. RESULTS: The co-culture of pMSCs with monocytes stimulated to follow the inflammatory M1 macrophage differentiation pathway resulted in a shift to anti-inflammatory M2-like macrophage differentiation. This transition was characterized by morphological of changes typical of M2 macrophages, and by changes in cell surface marker expression including CD14, CD36, CD163, CD204, CD206, B7-H4 and CD11b, which are distinctive of M2 macrophages. Co-culture with pMSCs reduced the expression of the costimulatory molecules (CD40, CD80 and CD86) and increased the expression of co-inhibitory molecules (CD273, CD274 and B7-H4) as well as the surface expression of major histocompatibility complex (MHC-II) molecules. Furthermore, the secretion of IL-10 was increased while the secretion of IL-1beta, IL-12 (p70) and MIP-1alpha was decreased; a profile typical of M2 macrophages. Finally, pMSCs induced the phagocytic activity and the phagocytosis of apoptotic cells associated with M2- like macrophages; again a profile typical of M2 macrophages. We found that the immunoregulatory effect of pMSCs on macrophage differentiation was mediated by soluble molecules acting partially via glucocorticoid and progesterone receptors. CONCLUSIONS: We have shown that pMSCs can transition macrophages from an inflammatory M1 into an anti-inflammatory M2 phenotype. Our findings suggest a new immunosuppressive property of pMSCs that may be employed in the resolution of inflammation associated with inflammatory diseases and in tissue repair. PMID- 23812786 TI - Fate of para-toluenesulfonamide (p-TSA) in groundwater under anoxic conditions: modelling results from a field site in Berlin (Germany). AB - This article reports on a field modelling study to investigate the processes controlling the plume evolution of para-toluenesulfonamide (p-TSA) in anoxic groundwater in Berlin, Germany. The organic contaminant p-TSA originates from the industrial production process of plasticisers, pesticides, antiseptics and drugs and is of general environmental concern for urban water management. Previous laboratory studies revealed that p-TSA is degradable under oxic conditions, whereas it appears to behave conservatively in the absence of oxygen (O2). p-TSA is ubiquitous in the aquatic environment of Berlin and present in high concentrations (up to 38 MUg L(-1)) in an anoxic aquifer downgradient of a former sewage farm, where groundwater is partly used for drinking water production. To obtain refined knowledge of p-TSA transport and degradation in an aquifer at field scale, measurements of p-TSA were carried out at 11 locations (at different depths) between 2005 and 2010. Comparison of chloride (Cl(-)) and p-TSA field data showed that p-TSA has been retarded in the same manner as Cl(-). To verify the transport behaviour under field conditions, a two-dimensional transport model was setup, applying the dual-domain mass transfer approach in the model sector corresponding to an area of high aquifer heterogeneity. The distribution of Cl(-) and p-TSA concentrations from the site was reproduced well, confirming that both compounds behave conservatively and are subjected to retardation due to back diffusion from water stagnant zones. Predictive simulations showed that without any remediation measures, the groundwater quality near the drinking water well galleries will be affected by high p-TSA loads for about a hundred years. PMID- 23812787 TI - Some technical issues in managing PCBs. AB - Polychlorinated biphenyls (PCBs) were important industrial chemicals featuring high thermal and chemical stability and low flammability. They were widely used as dielectric and thermal fluid in closed electro-technical applications (transformers, capacitors...) and also in numerous dispersive uses, ranking from auto-copying paper to sealant or coatings. During the 1960s, severe environmental consequences started becoming apparent. The stability of PCBs contributed to their persistence in the environment, their lipophilic character to bio magnification. Fish-eating species seemed threatened in their existence. In Japan and in Taiwan, thousands of people consumed PCB-contaminated oil. The production of PCBs stopped completely during the 1980s. Usage could continue in closed applications only. In this paper, particular attention is given to two issues: the cleaning of PCB electric transformers and the potential impact of PCB containing building materials. Other contributions will cover the management and treatment of PCB-contaminated soil, sludge or fly ash. The complete survey is being prepared by request of the Knowledge Center for Engineers and Professionals. PMID- 23812788 TI - Environmentally friendly system for the degradation of multipesticide residues in aqueous media by the Fenton's reaction. AB - A Fenton oxidation system employing zero-valent iron (whose source was swarf, a residue of metallurgical industries, in powder form) and hydrogen peroxide for the treatment of an aqueous solution with six pesticides was developed, and the effect of the iron metal content, pH, and hydrogen peroxide concentration was evaluated. The characterization of the aqueous solution resulted in: pH 5.6, 105 mg L(-1) of dissolved organic carbon, and 44.6 NTU turbidity. In addition, the characterization of the swarf by FAAS and ICP-MS showed 98.43 +/- 7.40 % of zero valent iron. The removal was strongly affected by the content of iron metal, pH, and hydrogen peroxide concentration. The best degradation conditions were 2.0 g swarf, pH 2.0, and 5 mmol L(-1) H2O2. At the end of the treatment, the pesticide degradation ranged from 60 to 100%, leading to 55% mineralization. Besides, all hydrogen peroxide was consumed and the determination of total dissolved iron resulted in 2 mg L(-1). Thus, the advantages of this system are rapid degradation (up to 20 min), high-degradation rates, simple handling, and low cost. PMID- 23812790 TI - Identification and source apportionment of polycyclic aromatic hydrocarbons in ambient air particulate matter of Riyadh, Saudi Arabia. AB - In an effort to assess the occurrence and sources of polycyclic aromatic hydrocarbons (PAHs) in the ambient air of Riyadh, Saudi Arabia, PM10 samples were collected during December 2010. Diagnostic PAH concentration ratios were used as a tool to identify and characterize the PAH sources. The results reflect high PM10 and PAH concentrations (particulate matter (PM) = 270-1,270 MUg/m(3)). The corresponding average PAH concentrations were in the range of 18 +/- 8 to 1,003 +/- 597 ng/m(3) and the total concentrations (total PAHs (TPAHs) of 17 compounds) varied from 1,383 to 13,470 ng/m(3) with an average of 5,871 +/- 2,830 ng/m(3). The detection and quantification limits were 1-3 and 1-10 ng/ml, respectively, with a recovery range of 42-80%. The ratio of the sum of the concentrations of the nine major non-alkylated compounds to the total (CPAHs/TPAHs) was 0.87 +/- 0.10, and other ratios were determined to apportion the PM sources. The PAHs found are characteristic for emissions from traffic with diesel being a predominant source. PMID- 23812789 TI - Biosorption of Cr(VI) and Zn(II) ions from aqueous solution onto the solid biodiesel waste residue: mechanistic, kinetic and thermodynamic studies. AB - In this present study, the biosorption of Cr(VI) and Zn(II) ions from synthetic aqueous solution on defatted J atropha oil cake (DJOC) was investigated. The effect of various process parameters such as the initial pH, adsorbent dosage, initial metal ion concentration and contact time has been studied in batch stirred experiments. Maximum removal of Cr(VI) and Zn(II) ions in aqueous solution was observed at pH 2.0 and pH. 5.0, respectively. The removal efficiency of Cr(VI) and Zn(II) ions from the aqueous solution was found to be 72.56 and 79.81%, respectively, for initial metal ion concentration of 500 mg/L at 6 g/L dosage concentration. The biosorbent was characterized by Fourier transform infrared, scanning electron microscopy and zero point charge. Equilibrium data were fitted to the Langmuir, Freundlich, Temkin and Dubinin-Radushkevich isotherm models and the best fit is found to be with the Freundlich isotherm for both Cr(VI) and Zn(II) metal ions. The kinetic data obtained at different metal ion concentration have been analysed using the pseudo-first-order, pseudo-second order and intraparticle diffusion models and were found to follow the pseudo second-order kinetic model. The values of mass transfer diffusion coefficients (De) were determined by Boyd model and compared with literature values. Various thermodynamic parameters, such as DeltaG degrees , DeltaH degrees and DeltaS degrees , were analysed using the equilibrium constant values (Ke) obtained from experimental data at different temperatures. The results showed that biosorption of Cr(VI) and Zn(II) ions onto the DJOC system is more spontaneous and exothermic in nature. The results indicate that DJOC was shown to be a promising adsorbent for the removal of Cr(VI) and Zn(II) ions from aqueous solution. PMID- 23812791 TI - In vitro cytogenetic assessment of trichloroacetic acid in human peripheral blood lymphocytes. AB - Trichloroacetic acid (TCA), a common water disinfection byproduct and a persistent metabolite of trichloroethylene (TCE), has been examined for its genotoxic potential in human lymphocytes. Chromosomal aberration (CA) and cytokinesis-block micronucleus (CBMN) assay were employed to assess the toxicity of TCA. Lymphocytes obtained from three healthy donors were exposed to 25, 50, and 100 MUg/ml concentration of TCA separately. TCA exposure resulted in chromosomal anomalies and the formation of micronuclei in lymphocytes. Chromosome analysis revealed the dose-dependent and significant induction of CA. Chromatid break/chromosome break, fragments, and chromatid exchanges were commonly observed. Exposure of higher concentration (50 and 100 MUg/ml) significantly inhibited mitotic index. Data obtained with CBMN assay indicated that the induction of micronucleus (MN) formation was greater than that of CA. At 25 MUg/ml, TCA induced significant frequencies of MN as compared to control cells. Significant induction of MN at the lowest concentration indicates TCA may also interact with mitotic spindles. Lower percentage of CA and MN at 100 MUg/ml as compared to 50 MUg/ml indicates occurrence of severe cytotoxicity on exposure of 100 MUg/ml TCA in lymphocytes. Collectively, results of both cytogenetic assays indicate that exposure of TCA can induce significant genotoxic and cytotoxic effects. PMID- 23812792 TI - Specificity of LSU rRNA-targeted oligonucleotide probes for Pseudo-nitzschia species tested through dot-blot hybridisation. AB - In the scope of the development of a microarray PhyloChip for the detection of toxic phytoplankton species, we designed a large series of probes specific against targets in the nuclear large subunit (LSU) rRNA of a range of Pseudo nitzschia species and spotted these onto the microarray. Hybridisation with rRNA extracted from monoclonal cultures and from plankton samples revealed many cross reactions. In the present work, we tested the functionality and specificity of 23 of these probes designed against ten of the species, using a dot-blot procedure. In this case, probe specificity is tested against the target region in PCR products of the LSU rRNA gene marker region blotted on nitrocellulose filters. Each filter was incubated with a species-specific oligoprobe. Eleven of the tested probes showed specific responses, identifying seven Pseudo-nitzschia species. The other probes showed non-specific responses or did not respond at all. Results of dot-blot hybridisations are more specific than those obtained with the microarray approach and the possible reasons for this are discussed. PMID- 23812793 TI - Lifetime trauma, subjective distress, substance use, and PTSD symptoms in people with severe mental illness: comparisons among four diagnostic groups. AB - The current study examines correlations among trauma, high risk behaviors, subjective distress from both trauma and high risk behaviors, and substance use in community mental health clients diagnosed with a severe mental illness, and tests the following key hypothesis: clients with major mood disorders (major depression, bipolar I) will show higher rates of posttraumatic stress disorder (PTSD) symptoms than clients with either schizophrenia or schizoaffective disorder when trauma, high risk behaviors, subjective distress, substance use and gender are controlled. Linear regression demonstrated that only major depression and bipolar disorder varied significantly with PTSD symptoms when controlling for other key factors. PMID- 23812794 TI - Hepatitis B vaccination of men who have sex with men in the Netherlands: should we vaccinate more men, younger men or high-risk men? AB - OBJECTIVES: The selective vaccination programme against hepatitis B virus (HBV) was introduced in the Netherlands in 2002 targeting high-risk groups, including men who have sex with men (MSM). Despite the high average age of vaccination in MSM, the number of notifications of acute HBV recently declined. We investigate whether this can be attributed to the selective vaccination programme. We examine how vaccination strategies could be improved and the impact of universal infant vaccination introduced in 2011. METHODS: We use a mathematical model for HBV transmission among MSM. The incidence of HBV was calculated from the model and from notification data of acute HBV. RESULTS: A decline was observed in the incidence of HBV since 2006, as calculated from the model; this decline was smaller than that observed in data if all MSM were equally likely to be vaccinated. Assuming that high-risk MSM were more likely to be vaccinated than low-risk MSM resulted in a steeper decline in modelled incidence and better agreement with observed incidence. Vaccinating MSM at a younger age or doubling the vaccination rate would increase the impact of selective vaccination, but is less effective than vaccinating high-risk MSM. CONCLUSIONS: Selective HBV vaccination of MSM in the Netherlands has had a substantial impact in reducing HBV incidence. The reduction suggests that vaccination rates among high-risk MSM were higher than those among low-risk MSM. Countries that have not yet reached 35 year cohorts with universal childhood vaccination should actively implement or continue selective high-risk MSM vaccination. PMID- 23812795 TI - Gloria R. Smith, 1934-2013. PMID- 23812797 TI - Isolated plasma cell granuloma of the meninges. PMID- 23812796 TI - Risperidone, QTc interval prolongation, and torsade de pointes: a systematic review of case reports. AB - RATIONALE: A recent publication asserted that even low-dose risperidone may induce corrected QT (QTc) interval prolongation up to 500 ms without drug-induced IKr blockade. We seek to better understand the complexity of any link between risperidone-induced/associated QTc interval prolongation and torsade de pointes (TdP). OBJECTIVES: The objective of this study is to systematically analyze all available case reports of risperidone, QTc interval prolongation, and/or TdP. METHOD: We identify case reports using PubMed, Medline, EMBASE, and Cochrane. RESULTS: Of the 15 cases found, nine were adult women (ages 31, 33, 34, 37, 47, "elderly", 77, 84, and 87 years) and one was a teenager. There were four men (ages 28, 29, 29, and 46 years) and one preadolescent boy. Besides risperidone administration or overdose, traditional risk factors for QTc interval prolongation and TdP included female sex (n = 10), older age (n = 4), heart disease (n = 3), hypokalemia (n = 2), bradycardia (n = 1), liver disease (n = 1), QTc interval prolonging drugs other than risperidone (n = 8), and metabolic inhibitors (n = 2). TdP occurred in four cases. Six patients died, and three deaths were probably related to TdP. CONCLUSION: Risperidone (when properly prescribed in patients free of other risk factors for QTc interval prolongation and TdP) is a relatively safe drug. Conventional statistics can neither predict the individual patient who will experience TdP nor determine the relationship of drug dose to QTc interval prolongation and TdP. Narrative medicine using a case report format appears to be an alternative and valuable additional approach to advance our understanding of this relationship and to reduce risks. PMID- 23812798 TI - Maintenance of smoking cessation in the postpartum period: which interventions work best in the long-term? AB - Smoking during pregnancy has been linked to a variety of adverse outcomes for both maternal and child health. Decades of studies have sought to increase cessation antepartum and reduce relapse postpartum. A number of effective interventions exist to significantly reduce smoking rates during pregnancy; however, less is known about how to prevent relapse in the postpartum period. This review investigates interventions to prevent relapse in the long-term postpartum period. We focus specifically on nonspontaneous quitters (individuals who quit smoking as a result of an external intervention) to reveal differences in long-term response to interventions for this population compared to spontaneous quitters. A systematic literature search yielded 32 relevant studies of pharmacological, behavioral, and incentives-based interventions. Results were compiled, analyzed, and compared in order to evaluate success factors in maintaining cessation postpartum. Though intervention groups showed consistently higher quit rates during pregnancy than control groups, none of the intervention types were effective at preventing relapse in the longer-term postpartum period. One study maintained significantly higher abstinence in the longer-term period postpartum using a mix of behavioral and incentives strategies. Additional research in this area is needed to identify optimal intervention strategies to reduce long-term postpartum relapse, particularly for nonspontaneous quitters. PMID- 23812799 TI - Medical care transition planning and dental care use for youth with special health care needs during the transition from adolescence to young adulthood: a preliminary explanatory model. AB - The aims of the study were to test the hypotheses that youth with special health care needs (YSHCN) with a medical care transition plan are more likely to use dental care during the transition from adolescence to young adulthood and that different factors are associated with dental utilization for YSHCN with and YSHCN without functional limitations. National Survey of CSHCN (2001) and Survey of Adult Transition and Health (2007) data were analyzed (N = 1,746). The main predictor variable was having a medical care transition plan, defined as having discussed with a doctor how health care needs might change with age and having developed a transition plan. The outcome variable was dental care use in 2001 (adolescence) and 2007 (young adulthood). Multiple variable Poisson regression models with robust standard errors were used to estimate covariate-adjusted relative risks (RR). About 63 % of YSHCN had a medical care transition plan and 73.5 % utilized dental care. YSHCN with a medical care transition plan had a 9 % greater RR of utilizing dental care than YSHCN without a medical care transition plan (RR 1.09; 95 % CI 1.03-1.16). In the models stratified by functional limitation status, having a medical care transition plan was significantly associated with dental care use, but only for YSHCN without functional limitations (RR 1.11; 95 % CI 1.04-1.18). Having a medical care transition plan is significantly associated with dental care use, but only for YSHCN with no functional limitation. Dental care should be an integral part of the comprehensive health care transition planning process for all YSHCN. PMID- 23812800 TI - Does it really matter where women live? A multilevel analysis of the determinants of postnatal care in Nigeria. AB - Although postnatal care is one of the major interventions recommended for the reduction of maternal and newborn deaths worldwide, almost two-third (56 %) of women in Nigeria do not receive postnatal care. Attempts to explain this situation have focused on individual and household level factors, but the role of community characteristics has received less attention.This study examines community factors associated with the receipt of postnatal care in Nigeria and the moderating effects of community factors on the association between individual factors and postnatal care. Data was drawn from the 2008 Nigeria Demographic and Health Survey, and a sample of 17,846 women aged 15-49 years was selected. We employed a multilevel logistic regression analysis to identify community factors associated with postnatal care. Our findings showed that significant variations in receiving postnatal care exist across communities. Specifically, Nigerian women's likelihood of receiving postnatal care is a function of where they reside. Living in communities with a high proportion of educated women (OR = 2.04; 95 % CI = 1.32-3.16; p < 0.001) and a high proportion of those who have had a health facility delivery (OR = 17.86; 95 % CI = 8.34-38.24; p < 0.001) was significantly associated with an increased likelihood of receiving postnatal care. Community women's education moderated the association between ethnic origin and postnatal care. Community variance in postnatal care was significant (tau = 10.352, p = 0.001). Community interventions aimed at improving postnatal care should take into account the community context in which women live. To close the gap in community variations in postnatal care, secondary and higher education for women, and health facility delivery should be increased in disadvantaged communities. PMID- 23812801 TI - Effect of seminal plasma application to the vaginal vault in in vitro fertilization or intracytoplasmic sperm injection treatment cycles-a double blind, placebo-controlled, randomized study. AB - PURPOSE: To study whether intravaginal application of seminal plasma after follicle aspiration has the potential to increase implantation and clinical pregnancy rates after IVF-ET. METHODS: We conducted a prospective, double-blind, placebo-controlled randomized study of 230 patients undergoing IVF-ET cycles. 500 MUL of Fresh seminal plasma from the patient's partner or culture medium (placebo) were injected in the vaginal vault just after follicle aspiration. The main outcome measured was ongoing clinical-pregnancy rate. RESULTS: After ET cancellation in ten patients due to lack of fertilization or embryo cleavage, 220 embryo transfers (103 and 117 in the study and control groups) resulted in a clinical pregnancy rate of 36.9 % and 29.1 % for the study and control groups, corresponding to a relative increase of 26.8 %. After an early pregnancy loss of 13.1 % (5/38) and 23.5 % (8/34) in the study and control groups respectively an ongoing pregnancy rate of 32.0 % (33/103) and 22.2 % (26/117) was achieved corresponding to a relative increase of 44.1 %. Multivariate logistic regression analysis adjusted for study group, age, infertility, and cycle characteristics did not demonstrate any parameter that could predict occurrence of clinical pregnancy rates after IVF-ET. CONCLUSIONS: Patients who underwent SP intravaginal insemination after oocyte pick-up reached higher implantation and clinical pregnancy rates following ET compared to controls, although the difference did not reach statistical significance. More studies and variable methodologies may clarify the potential clinical effect of SP in improving live birth rates after ART. PMID- 23812802 TI - Efficacy and tolerability of perospirone in schizophrenia: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Perospirone is a second-generation antipsychotic (SGA) used only in Japan, and acts as a serotonin (5-HT)1A receptor partial agonist, 5-HT2A receptor inverse agonist, and dopamine (D)2, D4, and alpha1-adrenergic receptor antagonist. To our knowledge, no meta-analysis addressing the efficacy and effectiveness of perospirone in schizophrenia has been published to date. OBJECTIVE: The aim of the study was to identify the characteristics of perospirone by assessing the efficacy, discontinuation rate, and side effects of perospirone versus other antipsychotics in the treatment of patients with schizophrenia. METHODS: Using information obtained from the PubMed, PsycINFO, Google Scholar and Cochrane Library databases without language restrictions published up to 10 June 2013, we conducted a systematic review and meta-analysis of patient data from randomized controlled trials comparing perospirone with other antipsychotic medications. Risk ratio (RR), standardized mean difference (SMD) and 95% confidence intervals were calculated. All studies used the Positive and Negative Syndrome Scale (PANSS) for the evaluation of the schizophrenia psychopathology. RESULTS: The search in PubMed, Cochrane Library databases, Google Scholar and PsycINFO yielded 69 hits. We included three studies in the current meta-analysis and excluded 66 studies based on title, abstract, and full text review. Moreover, two additional studies were identified from a review article. Across the five studies (mean duration 9.6 weeks), 562 adult patients with schizophrenia were randomized to perospirone (n = 256), olanzapine (n = 20), quetiapine (n = 28), risperidone (n = 53), aripiprazole (n = 49), haloperidol (n = 75), or mosapramine (n = 81). Perospirone was not different from other pooled antipsychotics regarding reduction in PANSS negative (SMD = 0.38, p = 0.09) and general (SMD = 0.28, p = 0.06) subscale scores, and discontinuation due to any cause (RR = 1.03, p = 0.83), inefficacy (RR = 0.99, p = 0.98) and side effects (RR = 0.72, p = 0.25). However, perospirone was inferior to other pooled antipsychotics in the reduction of PANSS total scores (SMD = 0.36, p = 0.04) and positive subscale scores (SMD = 0.34, p = 0.03). Moreover, excluding the comparison of perospirone with the first-generation antipsychotic (haloperidol), perospirone was inferior to other pooled SGAs in the reduction of PANSS total scores (SMD = 0.46, p = 0.02), positive (SMD = 0.42, p = 0.03), negative (SMD = 0.52, p = 0.02) and general subscale scores (SMD = 0.37, p = 0.03). However, perospirone was superior to haloperidol in the reduction of PANSS negative subscale scores (SMD = -0.41, p = 0.01). Perospirone also had lower scores related to extrapyramidal symptoms than other pooled antipsychotics (SMD = -0.30, p = 0.01). CONCLUSIONS: Our results suggest that although perospirone seems to be a well tolerated treatment, perospirone does not reduce PANSS score as much as other SGAs. PMID- 23812803 TI - The exon 3 polymorphism of the growth hormone receptor is a severity-related factor for osteoporosis. AB - The purpose of this study was to investigate the association between the GHR exon 3 fl/d3 polymorphism and body composition traits in Brazilian cohorts of normal post-menarche adolescent girls and in post-menopausal women with and without osteoporosis. First, multiplex PCR and quantitative PCR (TaqMan) were used with 105 DNA samples from the general Brazilian population to validate the SNP rs6873545 as a surrogate marker for the GHR polymorphism. Subsequently, genotyping was carried out to evaluate associations for this polymorphism in 136 post-menarche adolescents and 175 post-menopausal women, who were evaluated for body composition traits such as bone mineral density and fat-free mass. Statistical analysis used an independent sample t test, one-way ANOVA test and post hoc Tukey HSD test. Significant values were assumed by p < 0.05. Genotyping indicated complete linkage disequilibrium between the GHR polymorphism and the SNP alleles (r(2) = 1.0). Adolescents and healthy post-menopausal women showed no genotype associations for body composition traits or osteoporosis. However, a lower total body bone mineral density was observed in fl/fl post-menopausal women with osteoporosis (p = 0.0004). These results suggest that the SNP rs6873545 can be used as a surrogate for the GHR fl/d3 polymorphism due to linkage disequilibrium in the Brazilian population and that the fl/fl genotype is a severity-related risk factor for osteoporosis, but did not appear to be associated with disease status. PMID- 23812804 TI - Less than 12 nodes in the surgical specimen after total mesorectal excision following neoadjuvant chemoradiation: it means more than you think! AB - BACKGROUND: A minimum of 12 examined lymph nodes (LN) is recommended to ensure adequate staging and oncologic resection of patients undergoing proctectomy for rectal adenocarcinoma. However, a decreased number of LN is not unusual in patients receiving neoadjuvant chemoradiation. PURPOSE: We hypothesized that a decreased number of LN in the proctectomy specimen of these patients may be an indicator of tumor response and be associated with improved prognosis. METHODS: A single-center colorectal cancer database was queried for c-stage II-III rectal cancer patients undergoing neoadjuvant chemoradiation followed by proctectomy between 1997 and 2007. Patients were categorized into two groups according to the number of LN retrieved from the proctectomy specimen: <12 LN versus >=12 LN. Groups were compared with respect to demographics, tumor and treatment characteristics, and the following oncologic outcomes: overall-survival (OS), cancer-specific-mortality (CSM), cancer-free-survival (CFS), distant (DR), and local recurrences (LR). RESULTS: The query returned 237 patients. There were 173 (73 %) males, and the median age was 57 years [interquartile range (IQR) 49-66 years]. The median number of LN retrieved was 15 (IQR 10-23) and 70 (30 %) patients had less than 12 nodes examined. The <12 nodes group was older [60 (IQR 51-71 years) vs. 55 (IQR 48-65 years), p = 0.009] and had more pathologic complete responders (36 vs. 19 %, p = 0.01). No <12 nodes patient experienced a LR, whereas the 5-year LR rate was 11 % in the >=12 nodes group (p = 0.004). Other oncologic outcomes were not significantly different. CONCLUSIONS: Retrieval of less than 12 nodes in the proctectomy specimen of rectal cancer patients treated with neoadjuvant chemoradiation does not affect OS, CSM, CFS, or DR and may be a marker of higher tumor response and, consequently, decreased LR rate. PMID- 23812805 TI - The impact of the Harmonic FOCUSTM on complications in thyroid surgery: a prospective multicenter study. AB - In recent years, newer tools have been developed and used in thyroid surgery. This study compared patients with multinodular goiter undergoing thyroidectomy using the Harmonic FOCUSTM with patients undergoing the clamp-and-tie technique. Medical records of 268 patients with multinodular goiter undergoing thyroidectomy from December 2006 to July 2011 in two centers in Italy, the Department of Surgery of Pisa and the General Surgery Unit of Grosseto, were prospectively evaluated. Patients were divided into group A (Harmonic FOCUSTM Shear), and group B (clamp-and-tie technique). Patient demographics and specific end points analyzed included age, sex, diagnosis, thyroid gland volume, operative time, complications, need for clips and hemostatic agents, need for suction balloon, postoperative blood loss, and postoperative hospital length of stay. 141 patients were included in group A, and 127 patients were included in group B. The two groups were similar in age, sex ratio, indication for surgery, and thyroid volume. Mean operative time was significantly shorter with the Harmonic FOCUSTM Shear (51.8 min) than with the clamp-and-tie technique (70.9 min). The mean postoperative amount obtained from the suction balloon was similar. Vascular clips were needed significantly more frequently in group A (26.2 %) than in group B (12.5 %), whereas the need for hemostatic agents was significantly reduced in group A (4.2 %) compared with group B (14.9 %). The decision to leave a suction drain at the end of the operation occurred significantly more frequently in group B (96 %) than in group A (78 %). Mean postoperative hospital length of stay was 2.02 days in group A compared with 3.1 days in group B, which was significant. No definitive postoperative complications were documented in either group, except a higher rate, but not statistically significant, of permanent hypoparathyroidism in group B versus Group A. Transient laryngeal nerve injury was similar in both groups, whereas transient hypoparathyroidism occurred more frequently in Group B (4.7 %) than in Group A (2.4 %). Harmonic FOCUS device was significantly associated with lower rate of postoperative transient hypocalcemia, decreased operative time, shorter hospitalization, and lesser need for hemostatic agents and postoperative drain balloon. These results might be considered "indirect" money-saving factors, despite the cost of the device, especially in countries where the cost of thyroidectomy is influenced also by the hospital length of stay. PMID- 23812806 TI - Development of diagnostic and vaccine markers through cloning, expression, and regulation of putative virulence-protein-encoding genes of Aeromonas hydrophila. AB - Aeromonas hydrophila is an opportunistic bacterial pathogen that is associated with a number of diseases in fish, amphibians, reptiles, and humans. In fish it causes several disease symptoms including tail and skin rot, and haemorrhagic septicemia; in human it causes soft-tissue wound infection and diarrhoea. The pathogenesis of A. hydrophila is multifactorial, but the mechanism is unknown so far. It is considered to be mediated by expression and secretion of extracellular proteins such as aerolysin, lipase, chitinase, amylase, gelatinase, hemolysins, and enterotoxins. A number of the putative virulence-protein-encoding genes that are present in the genome of A. hydrophila have been targeted by PCR for molecular diagnosis. These significant genes are also targeted for over production of proteins by cloning and expression methods. In this review, we emphasize recent progress in the cloning, expression, and regulation of putative virulence-protein-encoding genes of A. hydrophila for a better understanding of the pathogenesis and also help to provide effective strategies for control of diseases. PMID- 23812807 TI - Lysinibacillus tabacifolii sp. nov., a novel endophytic bacterium isolated from Nicotiana tabacum leaves. AB - A Gram-positive, catalase- and oxidase-positive, strictly aerobic, endospore forming rod bacterium, designated K3514(T), was isolated from the leaves of Nicotiana tabacum. The strain was able to grow at temperatures of 8-40 degrees C, pH 5.0-10.0 and NaCl concentrations of 0-7%. The predominant quinones (>30%) of this strain were MK-7(H2) and MK-7. Phylogenetic analysis of 16S rRNA gene sequence showed that strain K3514(T) was affiliated to the genus Lysinibacillus, with its closest relatives being Lysinibacillus mangiferihumi (98.3% sequence similarity), Lysinibacillus sphaericus (97.9% sequence similarity), Lysinibacillus fusiformis (97.4% sequence similarity), and Lysinibacillus xylanilyticus (97.3% sequence similarity). However, low levels of DNA-DNA relatedness values suggested that the isolate was distinct from the other closest Lysinibacillus species. Additionally, based on analysis of morphological, physiological, and biochemical characteristics, the isolate could be differentiated from the closest known relatives. Therefore, based on polyphasic taxonomic data, the novel isolate likely represents a novel species, for which the name Lysinibacillus tabacifolii sp. nov. and the type strain K3514(T) (=KCTC 33042(T) =CCTCC AB 2012050(T)) are proposed. PMID- 23812808 TI - Changes in arbuscular mycorrhizal fungus community along an exotic plant Eupatorium adenophorum invasion in a Chinese secondary forest. AB - Knowledge of the changes in arbuscular mycorrhizal (AM) fungi is fundamental for understanding the success of exotic plant invasions in natural ecosystems. In this study, AM fungal colonization and spore community were examined along an invasive gradient of the exotic plant Eupatorium adenophorum in a secondary forest in southwestern China. With increasing E. adenophorum invasion, the density of arbuscules in the roots of E. adenophorum significantly increased, but the AM root colonization rate and the densities of vesicles and hyphal coils in roots of E. adenophorum were not significantly different. A total of 29 AM fungi belonging to nine genera were identified based on spore morphology. Claroideoglomus etunicatum, Funneliformis geosporus, and Glomus aggregatum were the most common AM fungal species. The E. adenophorum invasion significantly decreased the AM fungal spore density in the soil. Furthermore, with increasing of E. adenophorum invasion the spore densities of C. etunicatum, G. aggregatum, and G. arenarium significantly decreased, whereas F. geosporus significantly increased. Nonmetric multidimensional scaling demonstrated that the AM fungus community composition was significantly different (P=0.003) in the different invasive levels of E. adenophorum, and significantly correlated with plant species richness, soil total P, and soil NO3 (-)-N. The results suggest that the alteration in AM fungus community might be caused by E. adenophorum invasion via changing the local plant community and soil properties in a Chinese secondary forest ecosystem. PMID- 23812809 TI - Rhodopirellula rosea sp. nov., a novel bacterium isolated from an ark clam Scapharca broughtonii. AB - A novel Gram-negative, motile, and ovoid-shaped strain, LHWP3(T), which belonged to the family Planctomycetaceae in the phylum Planctomycetes, was isolated from a dead ark clam Scapharca broughtonii collected during a mass mortality event on the south coast of Korea. Phylogenetic analysis based on the 16S rRNA gene sequences indicated that the isolate was most closely related to the type strain of Rhodopirellula baltica, with a shared 16S rRNA gene sequence similarity of 94.8%. The isolate grew optimally at 30 degrees C in 4-6% (w/v) NaCl, and at pH 7. The major isoprenoid quinone was menaquinone-6 (MK-6). The dominant polar lipids were phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine, and unidentified polar lipids. The predominant cellular fatty acids were C16:0, C18:1 omega9c, and C18:0. The genomic DNA G+C content of strain LHWP3(T) was 53.0 mol%. Based on polyphasic taxonomic analyses, strain LHWP3(T) should be classified as a novel species in the genus Rhodopirellula in the family Planctomycetaceae, for which the name Rhodopirellula rosea sp. nov. is proposed. The type strain is LHWP3(T) (=KACC 15560(T) =JCM 17759(T)). PMID- 23812810 TI - Deinococcus swuensis sp. nov., a gamma-radiation-resistant bacterium isolated from soil. AB - Strain DY59(T), a Gram-positive non-motile bacterium, was isolated from soil in South Korea, and was characterized to determine its taxonomic position. Phylogenetic analysis based on the 16S rRNA gene sequence of strain DY59(T) revealed that the strain DY59(T) belonged to the family Deinococcaceae in the class Deinococci. The highest degree of sequence similarities of strain DY59(T) were found with Deinococcus radiopugnans KACC 11999(T) (99.0%), Deinococcus marmoris KACC 12218(T) (97.9%), Deinococcus saxicola KACC 12240(T) (97.0%), Deinococcus aerolatus KACC 12745(T) (96.2%), and Deinococcus frigens KACC 12220(T) (96.1%). Chemotaxonomic data revealed that the predominant fatty acids were iso-C15:0 (19.0%), C16:1 omega7c (17.7%), C15:1 omega6c (12.6%), iso-C17:0 (10.3%), and iso-C17:1 omega9c (10.3%). A complex polar lipid profile consisted of a major unknown phosphoglycolipid. The predominant respiratory quinone is MK 8. The cell wall peptidoglycan contained D-alanine, L-glutamic acid, glycine, and L-ornithine (di-amino acid). The novel strain showed resistance to gamma radiation, with a D10 value (i.e. the dose required to reduce the bacterial population by 10-fold) in excess of 5 kGy. Based on the phylogenetic, chemotaxonomic, and phenotypic data, strain DY59(T) (=KCTC 33033(T) =JCM 18581(T)) should be classified as a type strain of a novel species, for which the name Deinococcus swuensis sp. nov. is proposed. PMID- 23812811 TI - Paenibacillus marinisediminis sp. nov., a bacterium isolated from marine sediment. AB - A Gram-negative, nonmotile, endospore-forming, rod-shaped bacterial strain LHW35(T), which belonged to the genus Paenibacillus, was isolated from marine sediment collected from the south coast of the Republic of Korea. A phylogenetic analysis of 16S rRNA gene sequences indicated that strain LHW35(T) was most closely related to Paenibacillus taiwanensis G-soil-2-3(T) (97.2% similarity). The optimal growth conditions for strain LHW35(T) were 37 degrees C, pH 6.0, and 0% (w/v) NaCl. The main isoprenoid quinone was menaquinone-7 (MK-7) and the major polyamine was spermidine. The diamino acid present in the cell-wall peptidoglycan was meso-diaminopimelic acid. The major fatty acids were anteiso-C15:0 and C16:0. The polar lipids were phosphatidylethanolamine, phosphatidylglycerol, unidentified amino-hospholipids, unidentified phospholipids, and unidentified polar lipids. A DNA-DNA hybridization experiment using the type strain of P. taiwanensis indicated <40% relatedness. The DNA G+C content was 45.0 mol%. Based on these phylogenetic, genomic, and phenotypic analyses, strain LHW35(T) should be classified as a novel species within the genus Paenibacillus, for which the name Paenibacillus marinisediminis sp. nov. is proposed. The type strain is LHW35(T) (=KACC 16317(T) =JCM 17886(T)). PMID- 23812812 TI - A novel retron of Vibrio parahaemolyticus is closely related to retron-Vc95 of Vibrio cholerae. AB - Some bacteria produce a satellite RNA-DNA complex termed msDNA, multicopy single stranded DNA. In this report, msDNA from Vibrio parahaemolyticus, a cause of acute gastroenteritis, was identified and named msDNA-Vp96. The retron element containing the ret gene, encoding the reverse transcriptase (RT) that is responsible for msDNA production, was cloned and characterized. Comparison of msDNA-Vp96 and msDNA-Vc95, from Vibrio cholerae, showed a high level of sequence similarity. We exchanged the two ret genes to examine whether msDNA was produced by the RT from different sources. We found that RT-Vp96 of V. parahaemolyticus was able to synthesize msDNA-Vc95 of V. cholerae and vice versa. To the best of our knowledge, this is the first report that RT from different bacterial species can synthesize msDNA. PMID- 23812813 TI - Cloning and functional characterization of endo-beta-1,4-glucanase gene from metagenomic library of vermicompost. AB - In the vermicomposting of paper mill sludge, the activity of earthworms is very dependent on dietetic polysaccharides including cellulose as energy sources. Most of these polymers are degraded by the host microbiota and considered potentially important source for cellulolytic enzymes. In the present study, a metagenomic library was constructed from vermicompost (VC) prepared with paper mill sludge and dairy sludge (fresh sludge, FS) and functionally screened for cellulolytic activities. Eighteen cellulase expressing clones were isolated from about 89,000 fosmid clones libraries. A short fragment library was constructed from the most active positive clone (cMGL504) and one open reading frame (ORF) of 1,092 bp encoding an endo-beta-1,4-glucanase was indentified which showed 88% similarity with Cellvibrio mixtus cellulase A gene. The endo-beta-1,4-glucanase cmgl504 gene was overexpressed in Escherichia coli. The purified recombinant cmgl504 cellulase displayed activities at a broad range of temperature (25-55 degrees C) and pH (5.5-8.5). The enzyme degraded carboxymethyl cellulose (CMC) with 15.4 U, while having low activity against avicel. No detectable activity was found for xylan and laminarin. The enzyme activity was stimulated by potassium chloride. The deduced protein and three-dimensional structure of metagenome-derived cellulase cmgl504 possessed all features, including general architecture, signature motifs, and N-terminal signal peptide, followed by the catalytic domain of cellulase belonging to glycosyl hydrolase family 5 (GHF5). The cellulases cloned in this work may play important roles in the degradation of celluloses in vermicomposting process and could be exploited for industrial application in future. PMID- 23812814 TI - Saccharomyces cerevisiae can secrete Sapp1p proteinase of Candida parapsilosis but cannot use it for efficient nitrogen acquisition. AB - Secreted aspartic proteinase Sapp1p of Candida parapsilosis represents one of the factors contributing to the pathogenicity of the fungus. The proteinase is synthesized as an inactive pre-pro-enzyme, but only processed Sapp1p is secreted into extracellular space. We constructed a plasmid containing the SAPP1 coding sequence under control of the ScGAL1 promoter and used it for proteinase expression in a Saccharomyces cerevisiae kex2Delta mutant. Because Sapp1p maturation depends on cleavage by Kex2p proteinase, the kex2Delta mutant secreted only the pro-form of Sapp1p. Characterization of this secreted proteinase form revealed that the Sapp1p signal peptide consists of 23 amino acids. Additionally, we prepared a plasmid with the SAPP1 coding sequence under control of its authentic CpSAPP1 promoter, which contains two GATAA motifs. While in C. parapsilosis SAPP1 expression is repressed by good low molecular weight nitrogen sources (e.g., ammonium ions), S. cerevisiae cells harboring this plasmid secreted a low concentration of active proteinase regardless of the type of nitrogen source used. Quantitative real-time PCR analysis of a set of genes related to nitrogen metabolism and uptake (GAT1, GLN3, STP2, GAP1, OPT1, and PTR2) obtained from S. cerevisiae cells transformed with either plasmid encoding SAPP1 under control of its own promoter or empty vector and cultivated in media containing various nitrogen sources also suggested that SAPP1 expression can be connected with the S. cerevisiae regulatory network. However, this regulation occurs in a different manner than in C. parapsilosis. PMID- 23812815 TI - Candida albicans ENO1 null mutants exhibit altered drug susceptibility, hyphal formation, and virulence. AB - We previously showed that the expression of ENO1 (enolase) in the fungal pathogen Candida albicans is critical for cell growth. In this study, we investigate the contribution of the ENO1 gene to virulence. We conducted our functional study of ENO1 in C. albicans by constructing an eno1/eno1 null mutant strain in which both ENO1 alleles in the genome were knockouted with the SAT1 flipper cassette that contains the nourseothricin-resistance marker. Although the null mutant failed to grow on synthetic media containing glucose, it was capable of growth on media containing yeast extract, peptone, and non-fermentable carbon sources. The null mutant was more susceptible to certain antifungal drugs. It also exhibited defective hyphal formation, and was avirulent in BALB/c mice. PMID- 23812816 TI - Identification and characterization of an anti-fungi Fusarium oxysporum f. sp. cucumerium protease from the Bacillus subtilis strain N7. AB - A newly discovered alkaline antifungal protease named P6 from Bacillus subtilis N7 was purified and partially characterized. B. subtilis N7 culture filtrates were purified by 30-60% (NH4)2SO4 precipitation, anion-exchange chromatography and gel filtration chromatography. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) revealed a single band of 41.38 kDa. Peptide sequence of protease P6 was determined using a 4800 Plus MALDI TOF/TOFTM Analyzer System. Self-Formed Adaptor PCR (SEFA-PCR) was used to amplify the 1,149 bp open read frame of P6. Dimensional structure prediction using Automatic Modeling Mode software showed that the protease P6 consisted of two beta-barrel domains. Purified P6 strongly inhibited spore and mycelium growth of Fusarium oxysporum f. sp. cucumerium (FOC) by causing hypha lysis when the concentration was 25 MUg/ml. Characterization of the purified protease indicated that it had substrate specificity for gelatin and was highly active at pH 8.0-10.6 and 70 degrees C. The P6 protease was inhibited by EDTA (2 mmol/L), phenyl methyl sulfonyl fluoride (PMSF, 1 mmol/L), Na(+), Fe(3+), Cu(2+), Mg(2+) (5 mmol/L each) and H2O2 (2%, v/v). However, protease activity was activated by Ca(2+), K(+), Mn(2+) (5 mmol/L each), mercaptoethanol (2%, v/v) and Tween 80 (1%, v/v). In addition, activity was also affected by organic solvents such as acetone, normal butanol and ethanol, but not hexane (25%, v/v each). PMID- 23812817 TI - Live and dead GFP-tagged bacteria showed indistinguishable fluorescence in Caenorhabditis elegans gut. AB - Caenorhabditis elegans has been used for studying host-pathogen interactions since long, and many virulence genes of pathogens have been successfully identified. In several studies, fluorescent pathogens were fed to C. elegans and fluorescence observed in the gut was considered an indicator for bacterial colonization. However, the grinder in the pharynx of these nematodes supposedly crushes the bacterial cells, and the ground material is delivered to the intestine for nutrient absorption. Therefore, it remains unclear whether intact bacteria pass through the grinder and colonize in the intestine. Here we investigated whether the appearance of fluorescence is indicative of intact bacteria in the gut using both fluorescence microscopy and transmission electron microscopy. In wild-type N2 C. elegans, Escherichia coli DH5alpha, and Vibrio vulnificus 93U204, both of which express the green fluorescence protein, were found intact only proximal to the grinder, while crushed bacterial debris was found in the post-pharyngeal lumen. Nevertheless, the fluorescence was evident throughout the lumen of worm intestines irrespective of whether the bacteria were intact or not. We further investigated the interaction of the bacteria with C. elegans phm-2 mutant, which has a dysfunctional grinder. Both strains of bacteria were found to be intact and accumulated in the pharynx and intestine owing to the defective grinder. The fluorescence intensity of intact bacteria in phm-2 worms was indistinguishable from that of crushed bacterial debris in N2 worms. Therefore, appearance of fluorescence in the C. elegans intestine should not be directly interpreted as successful bacterial colonization in the intestine. PMID- 23812818 TI - Influence of culture conditions and medium composition on the production of antibacterial compounds by marine Serratia sp. WPRA3. AB - This study was undertaken to investigate the influence of culture conditions and medium components on production of antibacterial compounds by Serratia sp. WPRA3 (JX020764) which was isolated from marine water of Port Dickson, Malaysia. Biochemical, morphological, and molecular characteristics suggested that the isolate is a new candidate of the Serratia sp. The isolate showed strong antimicrobial activity against fungi, Gram-negative and Gram-positive bacteria. This bacterium exhibited optimum antibacterial compounds production at 28 degrees C, pH 7 and 200 rev/min aeration during 72 h of incubation period. Highest antibacterial activity was obtained when sodium chloride (2%), yeast extract (0.5%), and glucose concentration (0.75%) were used as salt, nitrogen, and carbon sources respectively. Different active fractions were obtained by Thin-Layer Chromatography (TLC) and Flash Column Chromatography (FCC) from ethyl acetate crude extracts namely OCE and RCE in different culture conditions, OCE (pH 5, 200 rev/min) and RCE (pH 7/without aeration). In conclusion, the results suggested different culture conditions have a significant impact on the types of secondary metabolites produced by the bacterium. PMID- 23812819 TI - Quantification of rice sheath blight progression caused by Rhizoctonia solani. AB - Rhizoctonia solani has a wide host range, including almost all cultivated crops and its subgroup anastomosis group (AG)-1 IA causes sheath blight in rice. An accurate measurement of pathogen's biomass is a convincing tool for enumeration of this disease. Mycological characteristics and molecular diagnosis simultaneously supported that all six strains in this study were R. solani AG-1 IA. Heterokaryons between strains Rs40104, Rs40105, and Rs45811 were stable and viable, whereas Rs40103 and Rs40106 did not form viable fused cells, except for the combination of Rs40106 and Rs40104. A primer pair was highly specific to RsAROM gene of R. solani strains and the amplified fragment exists as double copies within fungal genome. The relationship between crossing point (CP) values and the amount of fungal DNA was reliable (R (2) >0.99). Based on these results, we determined R. solani's proliferation within infected stems through real time PCR using a primer pair and a Taqman probe specific to the RsAROM gene. The amount of fungal DNA within the 250 ng of tissue DNA from rice cv. Dongjin infected with Rs40104, Rs40105, and Rs45811 were 7.436, 5.830, and 5.085 ng, respectively. In contrast, the fungal DNAs within the stems inoculated with Rs40103 and Rs40106 were 0.091 and 0.842 ng. The sheath blight symptom progression approximately coincided with the amount of fungal DNA within the symptoms. In summary, our quantitative evaluation method provided reliable and objective results reflecting the amount of fungal biomass within the infected tissues and would be useful for evaluation of resistance germplasm or fungicides and estimation of inoculum potential. PMID- 23812820 TI - Mucilaginibacter ginsenosidivorax sp. nov., with ginsenoside converting activity isolated from sediment. AB - A Gram-reaction-negative, strictly aerobic, non-motile, non-spore-forming, and rod-shaped bacterial strain designated KHI28(T) was isolated from sediment in Gapcheon (river) and its taxonomic position was investigated using a polyphasic approach. Strain KHI28(T) grew at 10-42 degrees C and at pH 5.5-8.5 on R2A and nutrient agar without additional NaCl as a supplement. Strain KHI28(T) possessed beta-glucosidase activity, which was responsible for its ability to transform ginsenosides Rb1 and Re (ones of the dominant active components of ginseng) to C K and Rg2, respectively. On the basis of 16S rRNA gene sequence similarity, strain KHI28(T) was shown to belong to the family Sphingobacteriaceae and to be related to Mucilaginibacter dorajii DR-f4(T) (97.9% sequence similarity), M. polysacchareus DRP28(T) (97.3%), and M. lappiensis ANJLI2(T) (97.2%). The G+C content of the genomic DNA was 45.8%. The predominant respiratory quinone was MK 7 and the major fatty acids were summed feature 3 (comprising C16:1 omega6c and/or C16:1 omega7c), iso-C15:0 and C16:0. DNA and chemotaxonomic data supported the affiliation of strain KHI28(T) to the genus Mucilaginibacter. Strain KHI28(T) could be differentiated genotypically and phenotypically from the recognized species of the genus Mucilaginibacter. The isolate therefore represents a novel species, for which the name Mucilaginibacter ginsenosidivorax sp. nov. is proposed, with the type strain KHI28(T) (=KACC 14955(T) =LMG 25804(T)). PMID- 23812821 TI - Lysinibacillus chungkukjangi sp. nov., isolated from Chungkukjang, Korean fermented soybean food. AB - One bacterial strain 2RL3-2(T) was isolated from Chungkukjang, a traditional Korean fermented food made from soybeans, and determined to be a Gram-positive, aerobic, spore-forming rod. Growth of the novel strain was optimal at 30 degrees C and pH 7.0. The 16S rRNA gene of strain 2RL3-2(T) showed the highest level of sequence similarity to Lysinibacillus sinduriensis BLB-1(T) (99.0%), Lysinibacillus massiliensis 4400831(T) (97.1%), Lysinibacillus xylanilyticus XDB9(T) (97.0%), and Lysinibacillus odysseyi 34hs-1(T) (96.8%). Phylogenetic analysis showed that strain 2RL3-2(T) formed a robust cluster with L. sinduriensis BLB-1(T), L. massiliensis 4400831(T), and L. odyssey 34hs-1(T). The major fatty acids were anteiso-C15:0 (47.3%), iso-C16:0 (16.3%), and anteiso C17:0 (11.3%), and the only menaquinone was MK-7. Diphosphatidylglycerol, phosphatidylglycerol, and phosphatidylethanolamine were the major polar lipids, along with an unknown phospholipid and two unknown lipids. The peptidoglycan type was A4alpha, with an interpeptide bridge of l-Lys-d-Asp. DNA-DNA hybridization values between strain 2RL3-2(T) and closely related Lysinibacillus species were below 43+/-4%. Therefore, based on phenotypic, chemotaxonomic, and phylogenetic characteristics, it was determined that strain 2RL3-2(T) represents a novel species of the genus Lysinibacillus, for which the name Lysinibacillus chungkukjangi sp. nov. is proposed. The type strain is 2RL3-2(T) (=KACC 16626(T) =NBRC 108948(T)). PMID- 23812823 TI - Neuroprotection in glaucoma. PMID- 23812822 TI - Effect of sonic application mode on the resin-dentin bond strength and nanoleakage of simplified self-etch adhesive. AB - OBJECTIVES: This study aims to evaluate the effect of different application modes on the immediate and 6-month resin-dentin bond strength (MUTBS) and nanoleakage in the hybrid and adhesive layers. MATERIALS AND METHODS: Three 1-step self-etch adhesives (One Coat 7.0 (OC), Clearfil S(3) Bond (CS), and FuturaBond NR (FB)) were applied on a flat superficial dentin surface of 30 human molars under manual mode or sonic vibration at a frequency of 170 Hz (SV). Composite build-ups were constructed incrementally; specimens were sectioned to obtain resin-dentin sticks with cross-sectional area of 0.8 mm(2) and tested in tension (0.5 mm/min) immediately (IM) or after 6 months (6M) of water storage. Two bonded sticks, from each tooth at each storage time, were immersed in a silver nitrate solution, photo-developed, and analyzed under scanning electron microscopy. The amount of nanoleakage was measured using the ImageTool 3.0 software. Data, from each adhesive, were analyzed by two-way ANOVA and Tukey's test (alpha = 0.05). RESULTS: OC and CS showed higher MUTBS and lower nanoleakage in the IM period when applied with SV groups. For FB, no significant difference was observed between the two modes of application. All materials showed lower nanoleakage in the SV groups. Higher nanoleakage was observed after 6M for OC and FB. CONCLUSIONS: The sonic application mode at an oscillating frequency of 170 Hz can improve the resin-dentin MUTBS, reduce the nanoleakage, and retard the degradation of the resin-dentin MUTBS of Clearfil S(3) Bond and One Coat 7.0 adhesives. CLINICAL SIGNIFICANCE: Sonic application mode at an oscillating frequency of 170 Hz can be helpful and easy to use in dental practice to guaranty long-lasting restorations. PMID- 23812824 TI - Comparison of platelet count in tuberculosis spine to other spine pathology. AB - PURPOSE: Haematological markers currently used to investigate TB spine vary from WCC, Anaemia, ESR and CRP. Platelet count in TB spine as a marker has been inadequately investigated. METHOD: In this retrospective review, Platelet count in TB spondylitis on admission was compared to patients undergoing other elective spinal surgery (control) preoperatively. Comparisons of the platelets with ESR and the effect of HIV on platelet count in TB spine were also evaluated. RESULTS: 160 TB spine patients showed statistically significant higher platelet count when compared to 210 patients in the control group (p < 0.001). 52.5 % patients had a raised platelet count in the TB spondylitis group. Raised Platelet count had a sensitivity and specificity of 52.5 % and 86.2 %, respectively in TB spondylitis. ESR and platelet count had a Pearson correlation r = 0.31 (p < 0.001). HIV however did not statistically show any difference in the platelet count (p = 0.12). CONCLUSION: A raised platelet count in spinal pathology may be used as an inflammatory marker of TB spondylitis. PMID- 23812825 TI - A systematic review with meta-analysis of posterior interbody fusion versus posterolateral fusion in lumbar spondylolisthesis. AB - PURPOSE: To compare the clinical effectiveness of posterior lumbar interbody fusion (PLIF) and posterolateral fusion (PLF) for lumbar spondylolisthesis and to collect scientific evidence for determining which fusion method is better. METHODS: After systematic search, comparative studies were selected according to eligibility criteria. Checklists by Furlan and by Cowley were used to evaluate the risk of bias of the included randomized controlled trials (RCTs) and nonrandomized controlled studies, respectively. Weighed mean differences (WMDs) and risk differences were calculated for common outcomes. The final strength of evidence was expressed as different levels recommended by the GRADE Working Group. RESULTS: Four RCTs and five comparative observational studies were identified. Moderate-quality evidence indicated that PLIF was more effective than PLF for clinical satisfaction [odds ratios (OR) 0.49, 95 % confidence limits (95 % CI): (0.28, 0.88, P = 0.02)]. Moderate-quality evidence showed that no significant difference was found for the complication rate [OR 2.28, 95 % CI (0.97, 5.35), P = 0.06]. In secondary outcomes, moderate-quality evidence indicated that PLIF improved fusion rate [OR 0.32, 95 % CI (0.17, 0.61), P = 0.0006]. Low-quality evidence showed that PLIF resulted in a lower reoperation rate than PLF [OR 5.30, 95 % CI (1.47, 19.11), P = 0.01]. No statistical difference was found between the two groups with regard to blood loss [WMD = 76.52, 95 % CI (-310.68, 463.73), P = 0.70] and operating time [WMD = -1.20, 95 % CI (-40.36, 37.97), P = 0.95]. CONCLUSIONS: Moderate-quality evidence indicates that PLIF can improve the clinical satisfaction and increase the fusion rate compared to PLF. No superiority was found between the two fusion methods in terms of complication rate, amount of blood loss, and operating time for the treatment of lumbar spondylolisthesis. PMID- 23812826 TI - Peritoneal fluid bilirubin to serum bilirubin ratio for the diagnosis of bile leaks in orthotopic liver transplant recipients. AB - BACKGROUND: A peritoneal fluid-to-serum bilirubin ratio (FSBR) of >5 has been shown to be accurate for the detection of bile leaks in post-cholecystectomy and trauma patients; however, there are no studies evaluating the accuracy of this threshold ratio in orthotopic liver transplant (OLT) recipients. METHODS: We performed a nested case-control analysis to determine the optimal FSBR threshold for diagnosing bile leaks in OLT recipients and the relationship between FSBR and likelihood of bile leak. Adult OLT patients undergoing ERCP for suspected bile leak were divided into 2 groups: those with cholangiographic evidence of a bile leak and those without evidence of leak. Of 57 included patients, 37 were found to have a bile leak on cholangiogram (64.9 %). RESULTS: We found a relationship between higher FSBR and the presence of a bile leak (OR 2.84, 95 % CI 1.37-5.88, p = 0.005). A FSBR of >3.25 produced the optimal sensitivity and specificity for identifying bile leaks in OLT recipients (area under ROC curve 0.8865, sensitivity 72.97 %, specificity 95.00 %). CONCLUSIONS: We conclude FSBR is an easily accessible, moderately accurate test to diagnose bile leaks in liver transplant recipients. This test can inform clinical decision-making with regard to the utilization of ERCP in lower suspicion transplant recipients with a suspected bile leak. PMID- 23812827 TI - Pathogen-specific risk of celiac disease following bacterial causes of foodborne illness: a retrospective cohort study. AB - BACKGROUND: The US CDC recently estimated over 2 million foodborne illnesses annually are caused by 4 major enteropathogens: non-typhoid Salmonella spp., Campylobacter spp., Shigella spp., and Yersinia enterocolitica. While recent data suggest functional gastrointestinal disorders are associated with these infections, studies linking foodborne illness to celiac disease (CD) are limited. We utilized a US Department of Defense medical encounter database to evaluate the risk of CD following select foodborne infections. METHODS: We identified subjects with acute gastroenteritis between 1998 and 2009 attributed to Salmonella (nontyphoidal) spp., Shigella spp., Campylobacter spp., or Y. enterocolitica and matched each with up to 4 unexposed subjects. Exposed and unexposed subjects were followed for incident CD diagnosis for their entire military record duration (or a minimum of 1 year). Relative risks were calculated using modified Poisson regression to determine the relationship between pathogen-attributable gastroenteritis and CD while controlling for covariates. RESULTS: A total of 1,753 pathogen-specific gastroenteritis cases (Campylobacter: 738; Salmonella: 624; Shigella: 376; Yersinia: 17) were identified and followed for a median of 3.8 years. The incidence (per 100,000 person-years) of CD was 0.05. We found a suggested risk of CD after Campylobacter, but not other foodborne infection etiologies. CONCLUSIONS: These data support a previous study demonstrating increased risk of CD following Campylobacteriosis and highlight the need for additional research into how infections might trigger CD in susceptible individuals. PMID- 23812828 TI - Obliterative portal venopathy: a clinical and histopathological review. AB - Non-cirrhotic portal hypertension (NCPH) is characterized by the elevation of the portal pressure in the absence of cirrhosis. Obliterative portal venopathy (OPV) as a cause of NCPH is being increasingly diagnosed, especially after recent reports of its occurrence in patients with HIV using didanosine. Patients usually present with episodes of variceal hemorrhage and other features of portal hypertension including jaundice, ascites, encephalopathy and hepatopulmonary syndrome. Hepatic synthetic function is typically well preserved and the laboratory evaluation in OPV patients typically reveals only mild nonspecific hematological abnormalities chiefly related to hypersplenism. Its diagnosis remains a challenge and patients are often mistakenly diagnosed as having cirrhosis. Despite the increasing recognition of OPV, its etiology and pathogenesis are still unclear. A number of etiologies have been proposed including genetic predisposition, recurrent bacterial infections, HIV infection and highly active antiretroviral therapy, an altered immune response, hypercoagulability, and exposure to chemicals and certain medications. Histopathological evaluation remains critical in excluding cirrhosis and other causes of portal hypertension, and is the only way of definitively establishing the diagnosis of OPV. Clinicians should have a high index of suspicion for OPV in patients who present with variceal bleeding and splenomegaly and who do not have other features of cirrhosis. The purpose of this review is to summarize the known etiologies for OPV and its associated clinical aspects and correlations, and to also provide ample histophotomicrographs of OPV to aid in the diagnosis. It will also help raise awareness of this entity amongst pathologists and clinicians alike. PMID- 23812829 TI - Body mass index, age, and gender affect prep quality, sedation use, and procedure time during screening colonoscopy. AB - BACKGROUND: Body mass index (BMI), age, and gender influence colorectal cancer (CRC) and adenoma risk. Their effects on colonoscopy characteristics are unclear, but might inform the screening approach in patient subgroups. AIMS: The aims of this study were to assess the effect of BMI, age, and gender on prep quality, amount of sedation, procedure time, and adenoma prevalence for screening colonoscopy. METHODS: We conducted a review of 773 eligible colonoscopies performed for average-risk CRC screening. We performed multivariable regression analyses to assess the outcomes of prep quality, amount of fentanyl and midazolam used, procedure time, and the adenoma prevalence rate (APR). RESULTS: Obese patients were less likely (p = 0.01) to have a good or excellent prep, had similar procedure times, and received similar amounts of fentanyl and midazolam. Increasing age had no effect on prep quality or procedure time, but was associated with decreased fentanyl and midazolam (both p <= 0.001). Women had similar prep quality, longer procedure times (increased by 2.8 +/- 0.7 min, p < 0.001) for colonoscopies in which no polyps were detected, and received more fentanyl and midazolam (both p = 0.01). Increasing BMI, increasing age, and male gender were associated with an increased APR. The APR for women aged 50-59 with a normal BMI was 17.9 %. CONCLUSIONS: Normal-weight females, particularly those under age 60, have the lowest APR but have longer procedure times and require higher amounts of sedation. Screening options other than colonoscopy might be well-suited to this population. PMID- 23812830 TI - Meditations on bowel preps. PMID- 23812831 TI - Role-playing as a tool for hiring, training, and supervising peer providers. AB - This article presents role-playing as an activity that can help managers in hiring, evaluating, and supervising peer providers. With the increasing employment of peers in mental health care systems, supervisors have had to face dilemmas related to peer employment more frequently and with little guidance and direction. In response, this article presents role-playing as a practical tool to hire, train, and supervise peer providers. The effectiveness of role-playing depends largely on context and execution, and so this article also offers direction on how to maximize the utility and benefits of role-playing to enhance the performance of peer providers. PMID- 23812832 TI - Statewide implementation of recovery support groups for people with serious mental illness: a multidimensional evaluation. AB - This study evaluated a statewide demonstration project to implement a group-based intervention called Procovery in selected inpatient and community mental health centers. Procovery is a facilitated mutual support group designed to build hope and a sense of social inclusion by raising consciousness and helping people develop an understanding of the ways one can move toward recovery in their own lives. This evaluation sought to determine both consumer outcomes and perceptions of the program and implementation efforts held by consumers and the facilitators of the intervention. A multidimensional approach was used, including a quasi experimental design with consumers, questionnaires and focus groups with the intervention facilitators, and individual interviews with administrators. The Procovery model was shown to have a positive impact on consumers' recoveries and was viewed favorably by consumers, facilitators, and administrators. Several barriers to effective implementation were identified. These findings and their implications for future practice and research are discussed. PMID- 23812833 TI - Temporal and spectral characterization of the photosynthetic reaction center from Heliobacterium modesticaldum. AB - A time-resolved spectroscopic study of the isolated photosynthetic reaction center (RC) from Heliobacterium modesticaldum reveals that thermal equilibration of light excitation among the antenna pigments followed by trapping of excitation and the formation of the charge-separated state P800 (+)A0 (-) occurs within ~25 ps. This time scale is similar to that reported for plant and cyanobacterial photosystem I (PS I) complexes. Subsequent electron transfer from the primary electron acceptor A0 occurs with a lifetime of ~600 ps, suggesting that the RC of H. modesticaldum is functionally similar to that of Heliobacillus mobilis and Heliobacterium chlorum. The (A0 (-) - A0) and (P800 (+) - P800) absorption difference spectra imply that an 8(1)-OH-Chl a F molecule serves as the primary electron acceptor and occupies the position analogous to ec3 (A0) in PS I, while a monomeric BChl g pigment occupies the position analogous to ec2 (accessory Chl). The presence of an intense photobleaching band at 790 nm in the (A0 (-) - A0) spectrum suggests that the excitonic coupling between the monomeric accessory BChl g and the 8(1)-OH-Chl a F in the heliobacterial RC is significantly stronger than the excitonic coupling between the equivalent pigments in PS I. PMID- 23812834 TI - Assessment of novel binocular colour, motion and contrast tests in glaucoma. AB - The effects of glaucoma on binocular visual sensitivity for the detection of various stimulus attributes are investigated at the fovea and in four paracentral retinal regions. The study employed a number of visual stimuli designed to isolate the processing of various stimulus attributes. We measured absolute contrast detection thresholds and functional contrast sensitivity by using Landolt ring stimuli. This psychophysical Landolt C-based contrast test of detection and gap discrimination allowed us to test parafoveally at 6 degrees from fixation and foveally by employing interleaved testing locations. First order motion perception was examined by using moving stimuli embedded in static luminance contrast noise. Red/green (RG) and yellow/blue (YB) colour thresholds were measured with the Colour Assessment and Diagnosis (CAD) test, which utilises random dynamic luminance contrast noise (+/- 45 %) to ensure that only colour and not luminance signals are available for target detection. Subjects were normal controls (n = 65) and glaucoma patients with binocular visual field defects (n = 15) classified based on their Humphrey Field Analyzer mean deviation (MD) scores. The impairment of visual function varied depending on the stimulus attribute and location tested. Progression of loss was noted for all tests as the degree of glaucoma increased. For subjects with mild glaucoma (MD -0.01 dB to -6.00 dB) significantly more data points fell outside the normal age-representative range for RG colour thresholds than for any other visual test, followed by motion thresholds. This was particularly the case for the parafoveal data compared with the foveal data. Thus, a multifaceted measure of binocular visual performance, incorporating RG colour and motion test at multiple locations, might provide a better index for comparison with quality of life measures in glaucoma. PMID- 23812835 TI - Dipeptidyl peptidase-4 inhibitors and their effects on the cardiovascular system. AB - It is well known that patients with type 2 diabetes mellitus (T2DM) are at increased risk of cardiovascular (CV) disease. Elevated plasma glucose levels that independently lead to increased cardiovascular risk, combined with associated co-morbidities such as obesity, hypertension, and dyslipidemia, further contribute to the development of CV complications. Dipeptidyl peptidase 4 inhibitors (DPP-4 inhibitors) are a relatively new class of drugs used for the treatment of diabetes and recently have been widely used in clinical practice. They exert their actions through degradation inhibition of endogenous glucagon like peptides (GLP-1) and glucose-dependent insulinotropic peptides (GIP), with a resulting increase in glucose mediated insulin secretion and a suppression of glucagon secretion. Since GLP-1 is known to have an impact not only on plasma glucose levels but also to have cardiovascular protective effects there is increased speculation of whether DPP-4 inhibitors will have similar effects. Though many short-term studies have been encouraging, ongoing long-term clinical trials on humans are needed to provide further clarity to the complete safety profiles of these agents in terms of cardiovascular risk, and whether they may exert potential cardiovascular benefit. This review includes available data on the cardiovascular effects of DPP-4 inhibitors as well as their overall safety profile. PMID- 23812836 TI - Quantification of mitral valve regurgitation: new solutions provided by 3D echocardiography. AB - The accurate quantification of mitral regurgitation (MR) using 2D imaging tools is difficult due to its structural complexity; however, it is crucially important in clinical medicine as MR severity has prognostic consequences. Novel 3 dimensional (3D) echocardiography and 3-dimensional (3D) color Doppler methods can provide quantitative and qualitative classification of MR including measurement of the vena contracta area, regurgitant volume, regurgitant fraction, and effective regurgitant orifice area (EROA). Nevertheless, with so many conventional and developing techniques it can be difficult to decide which technique to use for selected patients. We suggest using an approach that is focused not only on the techniques and measurements but also combines imaging portability, availability, clinical efficiency, and accurate and reproducible assessments. In this review we discuss the established and emerging applications of 3D color Doppler for the quantification of MR severity. PMID- 23812837 TI - Percutaneous treatment of aortic and mitral valve paravalvular regurgitation. AB - Percutaneous paravalvular leak closure represents a small but important niche in structural interventions in the current era of interventional cardiology. It is estimated that paravalvular regurgitation affects 5-17 % of all surgically implanted prosthetic heart valves (which equates to 500 to 10,200 cases annually). Patients may present with clinical signs and evidence of heart failure, hemolysis or both. Due to the increased morbidity and mortality, reoperation is often best avoided, especially if the underlying perivalvular tissue is friable or heavily calcified. Perimitral defects are usually approached in an antegrade approach via a transeptal puncture; periaortic defects usually in a retrograde approach. Depending on the number, size and shape of the defect(s) - as determined by 2D and 3D echocardiography - one or multiple closure devices are deployed using various wiring and anchor techniques. This brief review provides a summary of the currently applied paravalvular leak closure techniques. PMID- 23812838 TI - Genetic etiology and evaluation of sudden cardiac death. AB - A wide range of inherited syndromes can result in ventricular arrhythmias and sudden cardiac death (SCD). The natural histories of inherited arrhythmia syndromes are highly variable and current risk stratification techniques are limited. Thus, the management of these conditions can be difficult and often involves a combination of risk assessment, lifestyle modification, cardiac interventions, counselling, and family screening. Recent advances in high throughput sequencing have enabled routine testing in patients with a high clinical index of suspicion for an inherited arrhythmia condition, and cascade screening in relatives of mutation carriers. Given the complexity in screening and data interpretation that has been introduced by recent genomic advances, individuals with inherited arrhythmia syndromes are encouraged to seek care at specialized centers with cardiovascular genetics expertise. In this review, we discuss the etiologies of SCD syndromes and discuss strategies for the evaluation of patients at risk for SCD with a focus on the role of genetic testing and family screening. PMID- 23812839 TI - Targeting left ventricular lead placement to improve cardiac resynchronization therapy outcomes. AB - Although cardiac resynchronization therapy (CRT) has been established as an important treatment modality for heart failure patients, at least one third of CRT recipients do not respond to this therapy or derive minimal benefit from it. The impact of the site of left ventricular (LV) pacing on outcome after CRT has been examined extensively. Initial studies suggested benefit of posterior or lateral sites but subsequent work has yielded conflicting results. There also remain conflicting results of apical vs basal pacing sites. Avoiding LV lead placement at sites of transmural scar is however a viable strategy. In addition, The TARGET and STARTER trials, 2 independent, randomized, prospective studies, have demonstrated that targeting LV lead placement to sites of latest LV mechanical activation as defined by speckle tracking echocardiography remains the most promising method to improve clinical outcome after CRT. PMID- 23812840 TI - The need for combination drug therapies in patients with complex dyslipidemia. AB - Statins are first line therapy for the prevention of cardiovascular disease (CVD). Only 30 %-70 % of high risk patients will attain standard low-density lipoprotein cholesterol targets. Patients with familial hypercholesterolemia and genetic mixed hyperlipidemias do not meet goals with standard therapy. Patients with mixed hyperlipidemia secondary to the metabolic syndrome, diabetes, renal, or HIV infection are at high residual risk due to low HDL-cholesterol or high triglycerides. Newer therapies can be added to statins. The use of ezetimibe has CVD outcomes evidence in chronic renal disease. Adding omega-3 fatty acids, fibrates, or niacin to statins has failed to show any benefit except possibly with fibrates in patients with diabetes and low HDL-C/high triglycerides. Additional benefits on lipid profiles have been shown with pro-protein convertase subtilisin/kexin-9 (PCSK9), mipomersen, lomitapide, and cholesterol ester transfer protein inhibitors (CETPIs). Two CETPIs have failed to show benefit in hard outcomes trials but others remain under investigation. It remains unclear whether additional therapies add to statins for the prevention of CVD in most patients. They may have some added benefit in patients with complex dyslipidemias. PMID- 23812841 TI - Tumor necrosis factor-alpha-mediated suppression of dual-specificity phosphatase 4: crosstalk between NFkappaB and MAPK regulates endothelial cell survival. AB - We investigated the effects of tumor necrosis factor-alpha (TNF-alpha) exposure on mitogen-activated protein kinase signaling in human microvascular endothelial cells. TNF-alpha caused a significant suppression of a dual specificity phosphatase, DUSP4, that regulates ERK1/2 activation. Thus, we hypothesized that suppression of DUSP4 enhances cell survival by increasing ERK1/2 signaling in response to growth factor stimulation. In support of this concept, TNF-alpha pre exposure increased growth factor-mediated ERK1/2 activation, whereas overexpression of DUSP4 with an adenovirus decreased ERK1/2 compared to an empty adenovirus control. Overexpression of DUSP4 also significantly decreased cell viability, lessened recovery in an in vitro wound healing assay, and decreased DNA synthesis. Pharmacological inhibition of NFkappaB activation or a dominant negative construct of the inhibitor of kappaB significantly lessened TNF-alpha mediated suppression of DUSP4 expression by 70-84% and attenuated ERK activation, implicating NFkappaB-dependent pathways in the TNF-alpha-mediated suppression of DUSP4 that contributes to ERK1/2 signaling. Taken together, our findings show that DUSP4 attenuates ERK signaling and reduces cell viability, suggesting that the novel crosstalk between NFkappaB and MAPK pathways contributes to cell survival. PMID- 23812842 TI - Kinetic regulation of the binding of prothrombin to phospholipid membranes. AB - A wide range of equilibrium and kinetic constants exist for the interaction of prothrombin and other coagulation factors with various model membranes from a variety of techniques. We have investigated the interaction of prothrombin with pure dioleoylphosphatidylcholine (DOPC) membranes and dioleoylphosphatidlyserine (DOPS)-containing membranes (DOPC:DOPS, 3:1) using surface plasmon resonance (SPR, with four different model membrane presentations) in addition to isotheral titration calorimetry (ITC, with suspensions of phospholipid vesicles) and ELISA methods. Using ITC, we found a simple low-affinity interaction with DOPC:DOPS membranes with a K(D) = 5.1 MUM. However, ELISA methods using phospholipid bound to microtitre plates indicated a complex interaction with both DOPC:DOPS and DOPC membranes with K(D) values of 20 and 58 nM, respectively. An explanation for these discrepant results was developed from SPR studies. Using SPR with low levels of immobilised DOPC:DOPS, a high-affinity interaction with a K(D) of 18 nM was obtained. However, as phospholipid and prothrombin concentrations were increased, two distinct interactions could be discerned: (i) a kinetically slow, high-affinity interaction with K(D) in the 10(-8) M range and (ii) a kinetically rapid, low-affinity interaction with K(D) in the 10(-6 )M range. This low affinity, rapidly equilibrating, interaction dominated in the presence of DOPS. Detailed SPR studies supported a heterogeneous binding model in agreement with ELISA data. The binding of prothrombin with phospholipid membranes is complex and the techniques used to measure binding will report K D values reflecting the mixture of complexes detected. Existing data suggest that the weaker rapid interaction between prothrombin and membranes is the most important in vivo when considering the activation of prothrombin at the cell surface. PMID- 23812844 TI - Exosomes from human adipose-derived mesenchymal stem cells promote migration through Wnt signaling pathway in a breast cancer cell model. AB - Human mesenchymal stem cell (MSC)-conditioned medium (CM) was previously reported to affect the biology of tumor cells; however, the precise mechanisms remain unclear. Here, we show that MSCs secreted 40-100 nm particles, which have the typical characteristics of exosomes, and these MSC-derived exosomes promoted migration of the breast cancer cell line MCF7. Global gene expression profiling revealed that several cancer-related signaling pathways were upregulated after exosome treatment in MCF7, and the Wnt signaling pathway was further confirmed to be activated. Our findings demonstrated a new mechanism through which MSC-CM may contribute to tumor cell migration. PMID- 23812845 TI - Uterine fibroids are characterized by an impaired antioxidant cellular system: potential role of hypoxia in the pathophysiology of uterine fibroids. AB - PURPOSE: Fibroids are the most common smooth muscle overgrowth in women. This study determined the expression and the effect of hypoxia on two potent antioxidant enzymes, superoxide dismutase (SOD) and catalase (CAT) on human fibroid cells. METHODS: Immortalized human leiomyoma (fibroid) and myometrial cells were subjected to hypoxia (2 % O2, 24 h). Total RNA and cell homogenate were obtained from control and treated cells; CAT and SOD mRNA and activity levels were determined by real-time RT-PCR and ELISA, respectively. RESULTS: Fibroid cells have significantly lower antioxidant enzymes, SOD and CAT mRNA and activity levels than normal myometrial cells (p < 0.05). Hypoxia treatment significantly increased SOD activity in myometrial cells while significantly decreasing CAT activity in fibroid cells (p < 0.05). There was no significant difference in CAT mRNA levels or activity in response to hypoxia in myometrial cells. Also, there was no significant difference in SOD mRNA levels in response to hypoxia in myometrial cells. CONCLUSION: This is the first report to show that uterine fibroids are characterized by an impaired antioxidant cellular enzymatic system. More importantly, our results indicate a role for hypoxia in the modulation of the balance of those enzymes in fibroid and myometrial cells. Collectively, these results shed light on the pathophysiology of fibroids thereby providing potential targets for novel fibroid treatment. PMID- 23812846 TI - Low utilization of extra embryos in donor oocyte in vitro fertilization cycles: an ethical dilemma to donor management. AB - PURPOSE: To explore outcomes of donor In Vitro Fertilization (IVF) cycles with regards to cryopreservation and utilization of extra embryos after fresh transfer. METHODS: A database search was performed to identify all consecutive fresh donor oocyte cycles from January 1, 2000 to December 31, 2010 at a private fertility laboratory. Parameters analyzed included: number of oocytes retrieved, number of patients choosing embryo cryopreservation, number of patients returning for frozen embryo transfer (FET), and pregnancy outcomes. RESULTS: A total of 1070 fresh oocyte donor cycles were identified. Average number of oocytes retrieved was 16.9 +/- 7.9, and average number of embryos transferred was 2.3 +/- 0.96. Sixty-six percent of patients cryopreserved excess embryos following fresh transfer, and only 40 % of these patients ultimately returned for FET. Patients who conceived in their fresh cycle were much less likely to return for FET than those who did not (25 % v 65 %, p < 0.001), however chance of conceiving with FET was no different between these two groups (38 % v 38 %, NS). CONCLUSIONS: An unexpectedly low number of patients undergoing a donor oocyte IVF cycle will ultimately return to utilize extra embryos from their fresh cycle. This is concerning considering the high numbers of oocytes retrieved and the known complications from hyperstimulation, especially in light of the relatively high pregnancy rates associated with donor cycles. This raises concerns not only for donor management, but also raises ethical dilemmas when considering the large numbers of remaining embryos that will never be utilized. PMID- 23812847 TI - HERMES: towards an integrated toolbox to characterize functional and effective brain connectivity. AB - The analysis of the interdependence between time series has become an important field of research in the last years, mainly as a result of advances in the characterization of dynamical systems from the signals they produce, the introduction of concepts such as generalized and phase synchronization and the application of information theory to time series analysis. In neurophysiology, different analytical tools stemming from these concepts have added to the 'traditional' set of linear methods, which includes the cross-correlation and the coherency function in the time and frequency domain, respectively, or more elaborated tools such as Granger Causality.This increase in the number of approaches to tackle the existence of functional (FC) or effective connectivity (EC) between two (or among many) neural networks, along with the mathematical complexity of the corresponding time series analysis tools, makes it desirable to arrange them into a unified-easy-to-use software package. The goal is to allow neuroscientists, neurophysiologists and researchers from related fields to easily access and make use of these analysis methods from a single integrated toolbox.Here we present HERMES ( http://hermes.ctb.upm.es ), a toolbox for the Matlab(r) environment (The Mathworks, Inc), which is designed to study functional and effective brain connectivity from neurophysiological data such as multivariate EEG and/or MEG records. It includes also visualization tools and statistical methods to address the problem of multiple comparisons. We believe that this toolbox will be very helpful to all the researchers working in the emerging field of brain connectivity analysis. PMID- 23812848 TI - A 635-nm light-emitting diode (LED) therapy inhibits bone resorptive osteoclast formation by regulating the actin cytoskeleton. AB - Bone diseases such as osteoporosis are mainly caused by upregulated activity of osteoclasts. The present study was designed to examine the effects of light emitting diode (LED) irradiation on the formation and activity of multinucleated osteoclasts, specifically "round-shaped" osteoclast cells (ROC) in different cell types derived from mouse. After 635-nm LED irradiation, the cell viability was evaluated by MTT assay. The amount of total tartrate-resistant acid phosphatase (TRAP) + osteoclast and the number of ROC cells were also estimated by TRAP solution assay and TRAP staining, respectively. Actin rings were stained with rhodamine-conjugated phalloidin, and resorption assay was performed by dentin slices. In addition, gene expression levels between the control and irradiation groups were evaluated by RT-PCR. In a morphological analysis, the formation of ROC was significantly inhibited by 635-nm LED irradiation in the different cell types. Actin rings were seen at cell peripheries in most ROC cells of the control group, but patches containing disorganized actin were found in the irradiation group. Both the number of ROCs and bone resorption activity were much lower in the irradiation group than in the control group. Also, the gene expression levels involved in actin ring formation such as integrin beta3 and c-Src decreased in RT PCR analysis. Overall, 635-nm LED therapy may play a pivotal role in regulating bone remodeling, and it may prove to be a valuable tool to prevent bone loss in osteoporosis and other resorptive bone diseases. PMID- 23812849 TI - What is the best treatment to decrease pro-inflammatory cytokine release in acute skeletal muscle injury induced by trauma in rats: low-level laser therapy, diclofenac, or cryotherapy? AB - Currently, treatment of muscle injuries represents a challenge in clinical practice. In acute phase, the most employed therapies are cryotherapy and nonsteroidal anti-inflammatory drugs. In the last years, low-level laser therapy (LLLT) has becoming a promising therapeutic agent; however, its effects are not fully known. The aim of this study was to analyze the effects of sodium diclofenac (topical application), cryotherapy, and LLLT on pro-inflammatory cytokine levels after a controlled model of muscle injury. For such, we performed a single trauma in tibialis anterior muscle of rats. After 1 h, animals were treated with sodium diclofenac (11.6 mg/g of solution), cryotherapy (20 min), or LLLT (904 nm; superpulsed; 700 Hz; 60 mW mean output power; 1.67 W/cm(2); 1, 3, 6 or 9 J; 17, 50, 100 or 150 s). Assessment of interleukin-1beta and interleukin-6 (IL-1beta and IL-6) and tumor necrosis factor-alpha (TNF-alpha) levels was performed at 6 h after trauma employing enzyme-linked immunosorbent assay method. LLLT with 1 J dose significantly decreased (p < 0.05) IL-1beta, IL-6, and TNF alpha levels compared to non-treated injured group as well as diclofenac and cryotherapy groups. On the other hand, treatment with diclofenac and cryotherapy does not decrease pro-inflammatory cytokine levels compared to the non-treated injured group. Therefore, we can conclude that 904 nm LLLT with 1 J dose has better effects than topical application of diclofenac or cryotherapy in acute inflammatory phase after muscle trauma. PMID- 23812850 TI - Influence of CO2 (10.6 MUm) and Nd:YAG laser irradiation on the prevention of enamel caries around orthodontic brackets. AB - One possible undesirable consequence of orthodontic therapy is the development of incipient caries lesions of enamel around brackets. The aim of this study was to compare the effects of CO2 (lambda = 10.6 MUm) and Nd:YAG (lambda = 1,064 nm) lasers associated or not with topical fluoride application on the prevention of caries lesions around brackets. Brackets were bonded to the enamel of 65 premolars. The experimental groups (n = 13) were: G1--application of 1.23% acidulated fluoride phosphate gel (AFP, control); G2--Nd:YAG laser irradiation (0.6 W, 84.9 J/cm(2), 10 Hz, 110 MUs, contact mode); G3--Nd:YAG laser irradiation associated with AFP; G4--CO2 laser irradiation (0.5 W, 28.6 J/cm(2), 50 Hz, 5 MUs, and 10 mm focal distance); and G5--CO2 laser irradiation associated with AFP. Quantitative light-induced fluorescence was used to assess enamel demineralization. The data were statistically compared (alpha = 5%). The highest demineralization occurred in the Nd:YAG laser group (G2, 26.15% +/- 1.94). The demineralization of all other groups was similar to that of the control group. In conclusion, CO2 laser alone was able to control enamel demineralization around brackets at the same level as that obtained with topical fluoride application. PMID- 23812852 TI - In situ spectroscopic ellipsometry of pH-responsive polymer brushes on gold substrates. AB - The dynamic and reversible switching behaviour of polyelectrolyte brushes of poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) toward changes of the pH value was studied by in situ VIS-spectroscopic ellipsometry (SE). For this, PDMAEMA brushes with three different molecular weights were synthesized via the "grafting from" method using surface initiated atom transfer radical polymerization. In detail, the applicability of different SE data modelling to describe the optical properties of the different brush layers in the swollen and collapsed state was investigated. Especially for the PDMAEMA brushes with a high molecular weight, an improved optical modelling of the experimental data could be achieved and revealed an exponential distribution of the PDMAEMA fraction in the brush layer. PMID- 23812851 TI - Arthroscopic versus mini-open rotator cuff repair: a prospective, randomized study with 24-month follow-up. AB - This prospective, randomized study was performed to evaluate the results of mini open and arthroscopic rotator cuff repair in a comparative case series of patients followed for 24 months. A total of 125 patients were randomized to mini open (Group I) or arthroscopic (Group II) rotator cuff repair at the time of surgical intervention. The University of California Los Angeles (UCLA) score, the American Shoulder and Elbow Surgeons (ASES) index, and muscle strength were measured to evaluate the clinical results, while magnetic resonance arthrography was used at 24-month follow-up to investigate the postoperative rotator cuff integrity. Fifty-three patients in Group I and 55 patients in Group II were available for evaluation at 24-month follow-up. At 24-month follow-up, the UCLA score, the ASES index, and muscle strength were statistically significantly increased in both groups postoperatively, while no significant difference was detected between the 2 groups. Intact rotator cuffs were investigated in 42 patients in Group I and 35 in Group II, and there was a significant difference in postoperative structural integrity between the two groups (P < 0.05). When analysis was limited to the patients with full-thickness tear, the muscle strength of the shoulder was significantly better in Group II, and the retearing rate was significantly higher in Group II. Based on the results obtained from this study, it can be indicated that arthroscopic and mini-open rotator cuff repair displayed substantially equal outcomes, except for higher retearing rate in the arthroscopic repair group. While for patients with full-thickness tear, arthroscopic rotator cuff repair displayed better shoulder strength and significantly higher retearing rate as compared to mini-open rotator cuff repair at 24-month follow-up. PMID- 23812853 TI - Chemometric evaluation of the column classification system during the pharmaceutical analysis of lamotrigine and its related substances. AB - This paper investigates the performance of a column classification system developed at the Katholieke Universiteit Leuven applied to pharmaceutical chromatographic analyses. The liquid chromatography assay of lamotrigine and related compounds was carried out according to the method prescribed in the European Pharmacopoeia monograph, using 28 brands of stationary phases. A ranking was built based on the F KUL value calculated against the selected reference column, then compared with the column test performance established for the stationary phases studied. Therefore, the system suitability test prescribed by the European Pharmacopoeia in order to distinguish between suitable or unsuitable columns for this analysis was evaluated. Moreover, it was examined whether the classes of the stationary phases, determined using test parameter results, contain either suitable or unsuitable supports for the lamotrigine separation. This assay was performed using chemometric a technique, namely factor analysis. PMID- 23812854 TI - In-syringe magnetic-stirring-assisted liquid-liquid microextraction for the spectrophotometric determination of Cr(VI) in waters. AB - A fully automated method for the determination of chromate is described. It is based on the selective reaction of Cr(VI) with diphenylcarbazide in acidic media to form a colored complex of Cr(III) with the oxidation product diphenylcarbazone. The reaction was performed within the syringe of an automatic burette containing a magnetic stirrer for homogenization of the sample and the required reagents. In-syringe stirring was made possible using a specially designed driving device placed around the syringe barrel to achieve a rotating magnetic field in the syringe, forcing the stirrer to spin. In a second step, the reaction mixture in the syringe was neutralized to allow in-syringe magnetic stirring-assisted dispersive liquid-liquid microextraction of the complex into 125 MUL of n-hexanol. After phase separation by droplet flotation over 30 s, the organic phase was propelled into a coupled spectrophotometric detection cell. The entire multistep procedure including in-system standard preparation was done within 270 s. The method was used for the analysis of natural waters, achieving average analyte recovery of 103%, a limit of detection of 0.26 MUg L(-1), and a repeatability of less than 4% relative standard deviation. PMID- 23812855 TI - Enantioseparation of 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate tagged amino acids and other zwitterionic compounds on cinchona-based chiral stationary phases. AB - The fluorescent tag 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC; AccQ Fluor reagent kit from Waters) is a commercial N-terminal label for proteinogenic amino acids (AAs), designed for reversed-phase separation and quantification of the AA racemates. The applicability of AQC-tagged AAs and AA-type zwitterionic compounds was tested for enantiomer separation on the tert-butyl carbamate modified quinine and quinidine based chiral stationary phases, QN-AX and QD-AX employing polar-organic elution conditions. The investigated test analytes included the enantiomers of the positional isomers of isoleucine (Ile), threonine, homoserine, and 4-hydroxyproline. Furthermore, beta-AAs, cyclic, and heterocyclic AAs including trans-2-amino-cyclohexane carboxylic acid and trans-2 aminocyclohexyl sulfonic acid, phenylalanine derivatives substituted with halides with increasing electronegativity and 3,4-dihydroxyphenylalanine, cysteine related derivatives including homocysteic acid, methionine sulfone, cysteine-S acetic acid, and cysteine-S-acetamide as well as a small range of aminophosphonic acids were enantioseparated. A mechanistic interaction study of AQC-AAs in comparison with fluoresceine isothiocyanate-labeled AAs was performed. The chiral and chemoselective recognition processes involved in enantiomer separation and retention was systematically discussed. Special emphasis was set on the influential factors exhibited by the chemistry, branching position, and spatial properties of the investigated zwitterionic analytes. The general interest to separate and distinguish between different types of branched-chained AAs and metabolic side products thereof lies in the toxicity of some of these compounds, which makes for instance allo-Ile an attractive candidate in disease-related biomarker research. PMID- 23812856 TI - Increasing physical activity for the treatment of hypertension: a systematic review and meta-analysis. AB - BACKGROUND: Low physical activity has been identified as a major risk factor for cardiovascular disease. Medical societies therefore recommend increased physical activity be part of any antihypertensive therapy. OBJECTIVE: Focusing on patient relevant outcomes such as mortality and cardiovascular events, this review was conducted to assess the long-term effects of interventions aiming at increasing physical activity in comparison with no such interventions on adult patients with essential hypertension. DATA SOURCES: We searched for high-quality systematic reviews in MEDLINE, EMBASE, Cochrane Database of Systematic Reviews (Cochrane Reviews), Database of Abstracts of Reviews of Effects (Other Reviews) and Health Technology Assessment Database (Technology Assessments) published between 1997 and February 2009 and for randomized controlled trials (RCTs) in MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials (Clinical Trials) published before September 2012. Additional studies were identified by hand searching reference lists of reviews. STUDY SELECTION: RCTs with at least 24 weeks' follow up that evaluated the effect of increased physical activity on the blood pressure of adults with essential hypertension were included in our review. Primary outcomes were all-cause mortality, cardiovascular morbidity and mortality, end stage renal disease, quality of life and adverse events. STUDY APPRAISAL AND SYNTHESIS METHODS: When appropriate, we used random effects meta-analyses to determine mean difference with 95 % confidence intervals for each endpoint. All data were analysed using the Review Manager software version 5.0.24 from the Cochrane Collaboration. RESULTS: None of the included nine trials, covering 891 patients with hypertension, provided sufficient data on patient-relevant outcomes such as mortality, cardiovascular events or injuries related to physical activity. Information on changes in systolic and diastolic blood pressure was provided for all included trials. The majority of the included RCTs reported that increased physical activity led to a decrease in systolic and diastolic blood pressure of 5-10 and 1-6 mmHg, respectively, but due to marked heterogeneity in the meta-analyses both for systolic and diastolic blood pressure (I2 = 70.0 and 73.0 %), no effect estimates were provided. LIMITATIONS: About 50 % of the included trials were small, evaluating at most 20 participants per study group, and more than twothirds were deemed to have a high risk of bias. CONCLUSIONS: Although a decrease in blood pressure is shown to be a consequence of increased physical activity, RCTs of appropriate study size and quality that examine potential patient-relevant benefits or harms still need to be conducted to evaluate whether physical activity really improves the health of patients with essential hypertension. PMID- 23812857 TI - Global positioning systems (GPS) and microtechnology sensors in team sports: a systematic review. AB - BACKGROUND: Use of Global positioning system (GPS) technology in team sport permits measurement of player position, velocity, and movement patterns. GPS provides scope for better understanding of the specific and positional physiological demands of team sport and can be used to design training programs that adequately prepare athletes for competition with the aim of optimizing on field performance. OBJECTIVE: The objective of this study was to conduct a systematic review of the depth and scope of reported GPS and microtechnology measures used within individual sports in order to present the contemporary and emerging themes of GPS application within team sports. METHODS: A systematic review of the application of GPS technology in team sports was conducted. We systematically searched electronic databases from earliest record to June 2012. Permutations of key words included GPS; male and female; age 12-50 years; able bodied; and recreational to elite competitive team sports. RESULTS: The 35 manuscripts meeting the eligibility criteria included 1,276 participants (age 11.2-31.5 years; 95 % males; 53.8 % elite adult athletes). The majority of manuscripts reported on GPS use in various football codes: Australian football league (AFL; n = 8), soccer (n = 7), rugby union (n = 6), and rugby league (n = 6), with limited representation in other team sports: cricket (n = 3), hockey (n = 3), lacrosse (n = 1), and netball (n = 1). Of the included manuscripts, 34 (97 %) detailed work rate patterns such as distance, relative distance, speed, and accelerations, with only five (14.3 %) reporting on impact variables. Activity profiles characterizing positional play and competitive levels were also described. Work rate patterns were typically categorized into six speed zones, ranging from 0 to 36.0 km.h-1, with descriptors ranging from walking to sprinting used to identify the type of activity mainly performed in each zone. With the exception of cricket, no standardized speed zones or definitions were observed within or between sports. Furthermore, speed zone criteria often varied widely within (e.g. zone 3 of AFL ranged from 7 to 16 km.h-1) and between sports (e.g. zone 3 of soccer ranged from 3.0 to <13 km.h-1 code). Activity descriptors for a zone also varied widely between sports (e.g. zone 4 definitions ranged from jog, run, high velocity, to high-intensity run). Most manuscripts focused on the demands of higher intensity efforts (running and sprint) required by players. Body loads and impacts, also summarized into six zones, showed small variations in descriptions, with zone criteria based upon grading systems provided by GPS manufacturers. CONCLUSION: This systematic review highlights that GPS technology has been used more often across a range of football codes than across other team sports. Work rate pattern activities are most often reported, whilst impact data, which require the use of microtechnology sensors such as accelerometers, are least reported. There is a lack of consistency in the definition of speed zones and activity descriptors, both within and across team sports, thus underscoring the difficulties encountered in meaningful comparisons of the physiological demands both within and between team sports. A consensus on definitions of speed zones and activity descriptors within sports would facilitate direct comparison of the demands within the same sport. Meta-analysis from systematic review would also be supported. Standardization of speed zones between sports may not be feasible due to disparities in work rate pattern activities. PMID- 23812858 TI - United States women receive more curative treatment for hepatocellular carcinoma than men. AB - BACKGROUND: Previous database studies have found gender disparities favoring men in rates of liver transplantation, which resolve in cohorts examining only patients with hepatocellular carcinoma (HCC). AIMS: Our study aims to use two large, multicenter United States (US) databases to assess for gender disparity in HCC treatment regardless of transplant listing status. METHODS: We performed a retrospective database analysis of inpatient admission data from the University Health Consortium (UHC) and the Nationwide Inpatient Sample (NIS), over a 9- and 10-year period, respectively. Adults with a primary discharge diagnosis of HCC, identified using the International Classification of Diseases 9th Edition (ICD-9) code, were included. Series of univariate and multivariate analyses were performed to examine gender disparities in metastasis, liver decompensation, treatment type, and inpatient mortality after controlling for other possible predictors. RESULTS: We included 26,054 discharges from the NIS database and 25,671 patients from the UHC database in the analysis. Women with HCC appear to present less often with decompensated liver disease (OR = 0.79, p < 0.001). Furthermore they are more likely to receive invasive HCC treatment, with significantly higher rates of resection across race and diagnoses (OR = 1.34 and 1.44, p < 0.001). Univariate analyses show that US women have lower unadjusted rates of transplant; however, the disparity resolves after controlling for other clinical and demographic factors. CONCLUSIONS: US women more often receive invasive treatment for HCC (especially resection) than US men with no observed disparity in transplantation rates when adjusted for pre-treatment variables. PMID- 23812860 TI - Analysis of adverse events associated with endoscopic papillary large-balloon dilation. PMID- 23812859 TI - Downregulation of Beclin 1 and impairment of autophagy in a small population of colorectal cancer. AB - BACKGROUND: Autophagy is a highly conserved mechanism for degradation and recycling of long-lived proteins and damaged organelle to maintain cell homeostasis. Deregulation of autophagy has been associated with tumorigenesis. Beclin 1 is an essential autophagy protein and its upregulation has been observed in most colorectal cancer tissues. However, there is a small population of colorectal cancers with downregulation of Beclin 1. AIM: The purpose of this study was to investigate the role autophagy plays in colorectal cancers with downregulation of Beclin 1. METHODS: LC3 protein, an autophagosome marker, was assessed by ICH and WB in colorectal cancers tissues. An anti-tumor effect of Beclin 1 was examined by introducing exogenous Beclin 1 in vitro. Colony formation assay, growth curves and mouse xenograft were analysed. RESULTS: Our results showed that LC3 was suppressed in the colorectal cancers (9.86 %) with downregulation of Beclin 1. Moreover, overexpression of Beclin 1 inhibited colorectal cancer cell growth and enhanced the rapamycin-induced antitumor effect in vitro. CONCLUSION: Downregulation of Beclin 1 and autophagy inhibition play an important role in a part of colorectal cancers. Activating autophagy or overexpression of Beclin 1 may be an effective treatment for some colorectal cancers. Detection of expression profile of Beclin 1 in colorectal cancers could be a strategy for new diagnostic and therapeutic methods. PMID- 23812861 TI - Prevalence of corticosteroids use and disease course after initial steroid exposure in ulcerative colitis. AB - BACKGROUND: Limited nationwide data currently exists regarding corticosteroid (CS) use and long-term outcome after CS initiation in ulcerative colitis (UC). AIMS: The purpose of this study was to assess CS use prevalence and long-term outcomes after the index CS exposure. Our outcomes of interest were CS use level (reintroduction, dependency, and refractoriness), thiopurine use, and colectomy. METHODS: Nationwide data was obtained from the Veterans Affairs (VA) healthcare system for the period 2001-2011. Patients with UC were included if they had been diagnosed in the VA system and if they had filled CS for the first time during the observation period. A retrospective cohort design and time-to-event survival analysis was used to track outcomes of interest. RESULTS: A total of 1,038 newly diagnosed patients with UC were identified. The prevalence of CS use over the observation period was 45 %. Four hundred sixty-four CS users with median follow up of 3.4 years were included. Among the included patients, 65 % required CS reintroduction, 38 % were classified as CS dependent, and 11 % were classified as CS refractory mostly within 2 years after the index CS course. Respectively, 8.6 and 38 % had colectomy and received thiopurine. Colectomy and thiopurine use rates varied significantly according to CS use level. CONCLUSIONS: Approximately half of newly-diagnosed patients with UC required CS. Among CS users, one third of the patients had a sustained response after the initial CS course while two thirds required further CS therapy. We observed a trend towards higher than previously reported thiopurine use accompanied by marked reduction in colectomy rates. PMID- 23812862 TI - Intravenous interferon administered during liver transplantation is not effective in preventing hepatitis C reinfection. AB - BACKGROUND: Post-transplant hepatitis C is a major challenge after liver transplantation (LT). Antiviral therapy is associated with lower efficacy in the post-transplant setting. AIMS: The purpose of this study was to determine the safety and effect of intravenous interferon (IFN) during the anhepatic phase of LT on hepatitis C viral load. METHODS: Fifteen consecutive subjects undergoing liver transplant for hepatitis C cirrhosis were enrolled in the study, ten of which received study drug and five subjects served as controls. Cases received weight-based ribavirin and subcutaneous IFN at time of incision followed by intravenous IFN at the start of the anhepatic phase. Adverse events and viral levels were recorded. Repeated measures ANOVA was employed to test for differences over time, between the groups, and time by group interaction. RESULTS: All subjects had genotype 1 virus. Hepatitis C viral load was lower at week 4 in cases compared to controls (769,004 +/- 924,082 IU/ml and 2,329,896 +/- 3,731,749 IU/ml, respectively), but did not reach statistical significance (p = 0.50). Three subjects developed adverse events related to IFN including pulmonary edema, rejection, and neutropenia. CONCLUSIONS: Intravenous IFN administered during the anhepatic phase of liver transplant did not prevent graft reinfection and was associated with manageable adverse events. This regimen could be further studied if direct acting antiviral agents alone are insufficient for treating post-transplant hepatitis C. PMID- 23812863 TI - Visceral hypersensitivity in non-erosive reflux disease: neurogenic overwhelming in esophagus? PMID- 23812864 TI - Open channels for functional bowel disorders: guanylate cyclase C agonists in IBS and CC. PMID- 23812866 TI - Serum brain-derived neurotrophic factor (BDNF) levels in attention deficit hyperactivity disorder (ADHD). AB - It has been proposed that the neurotrophin brain-derived neurotrophic factor (BDNF) may be involved in attention deficit-hyperactivity disorder (ADHD) etiopathogenesis. Alterations in BDNF serum levels have been observed in childhood/adulthood neurodevelopmental pathologies, but no evidence is available for BDNF serum concentrations in ADHD. The study includes 45 drug-naive ADHD children and 45 age-sex matched healthy subjects. Concentration of serum BDNF was determined by the ELISA method. BDNF serum levels in patients with ADHD were not different from those of controls (mean +/- SD; ADHD: 39.33 +/- 10.41 ng/ml; controls: 38.82 +/- 8.29 ng/ml, t = -0.26, p = 0.80). Our findings indicate no alteration of serum BDNF levels in untreated patients with ADHD. A further stratification for cognitive, neuropsychological and psychopathological assessment in a larger sample could be useful to clarify the role of BDNF in the endophenotype characterization of ADHD. PMID- 23812865 TI - Psychophysiological arousal and biased perception of bodily anxiety symptoms in socially anxious children and adolescents: a systematic review. AB - Cognitive models of social anxiety [Clark and Wells, Social phobia: Diagnosis, assessment, and treatment, Guilford Press, New York, 1995], diagnostic criteria and studies on adult samples suggest that both an overestimation of bodily anxiety symptoms and psychophysiological abnormalities play an important role in social anxiety. To date, less is known about such a perception bias and physiological characteristics in children and adolescents with social anxiety. We performed a systematic review of the literature in the electronic databases Medline, PsycINFO, and PSYNDEX. Additional studies were identified by hand search using the ancestry approach. We identified 1,461 studies, screened their titles and abstracts, viewed 94 papers, and included 28 of these. Study samples were heterogeneous and consisted of socially phobic, high socially anxious, shy and test anxious children and adolescents. Regarding a biased perception, most studies in the review suggest that bodily symptoms of anxiety were overestimated by children and adolescents across the social anxiety spectrum when compared with control groups. An elevated psychophysiological reactivity to social stress was present in samples of high social anxiety, shyness, and test anxiety. In clinical samples with social phobia, by contrast, no differences or an even lower physiological responding compared with healthy control groups were reported. In addition, some evidence for a chronic psychophysiological hyperarousal was found across all sample types. The results are discussed with regard to current models of social anxiety, psychophysiological theories, and treatment implications. PMID- 23812867 TI - A forgotten lethal psychosis: a case report. AB - Homocystinuria due to cystathionine beta-synthase deficiency is an inborn error of metabolism first described almost 50 years ago, which involves the accumulation of plasma homocysteine and other metabolites. Without early detection and appropriate treatment, common and sometimes lethal consequences include ocular abnormalities, osteoporosis, developmental delays, marfanoid phenotype, vascular disease, and mental retardation. Almost 50% of subjects develop a psychiatric disorder during their life, but only 2.8% present a psychiatric symptom as the initial manifestation. Among this group, psychotic disorders are infrequent. We describe the case of a 17-year-old boy presenting with a first episode psychosis and an unknown homocystinuria due to cystathionine beta-synthase deficiency, which led to a lethal outcome. PMID- 23812868 TI - Levels of reflective thinking and patient safety: an investigation of the mechanisms that impact on student learning in a single cohort over a 5 year curriculum. AB - Existing research into learning about patient safety focuses on identifying how educational interventions improve educational outcomes but few studies offer evidence that inform educators about the mechanisms involved in learning about patient safety. The current evidence based in undergraduates is also limited to outcomes that relate to knowledge and skills. A realist approach involving three cycles of data collection in a single cohort of students over 5 years used different outcomes in Kirkpatrick's framework to identify the mechanisms that influence students learning about patient safety. Data source 1. Focus groups identified an overarching theoretical model of the mechanisms that influence patient safety learning for medical students. Data source 2 Identified if the mechanisms from data source 1 could be demonstrated at the outcome level of knowledge and attitudes. Data source 3 Established associations between mechanisms and outcomes at skills and behavioural level, in a standardised simulated ward setting. Data source 1: The interpretation of data from seven focus groups involving sixty students identified reflection at two levels of Mezirow's descriptions; reflection and critical reflection as mechanisms that influence learning about error. Data source 2: Sixty-one students participated. The associations found, reflection and knowledge of actions to take for patient safety, r = 0.44 (P = 0.00) and critical reflection and intentions regarding patient safety, r = 0.40 (P = 0.00) Data source 3: Forty-eight students participated. The correlation identified associations between critical reflection and planned changes following feedback was, r = 0.48 (P = 0.00) and reflection and knowledge based errors r = -0.30 (P = 0.03). A realist approach identified two different levels of reflection were associated with different patient safety outcomes for this cohort of students. Critical reflection was associated with attitudes and reflection was associated with knowledge of actions and error behaviours. These findings give educators greater depth of information about the role of reflection in patient safety. PMID- 23812870 TI - Atmospheric pressure ion source development: experimental validation of simulated ion trajectories within complex flow and electrical fields. AB - Three-dimensionally (3D) resolved ion trajectory calculations within the complex viscous flow field of an atmospheric pressure ion source are presented. The model calculations are validated with spatially resolved measurements of the relative sensitivity distribution within the source enclosure, referred to as the distribution of ion acceptance (DIA) of the mass analyzer. In previous work, we have shown that the DIA shapes as well as the maximum signal strengths strongly depend on ion source operational parameters such as gas flows and temperatures, as well as electrical field gradients established by various source electrode potentials (e.g., capillary inlet port potential and spray shield potential). In all cases studied, distinct, reproducible, and, to some extent, surprising DIA patterns were observed. We have thus attempted to model selected experimental operational source modes (called operational points) using a validated computational flow dynamics derived 3D-velocity field as an input parameter set for SIMION/SDS, along with a suite of custom software for data analysis and parameter set processing. Despite the complexity of the system, the modeling results reproduce the experimentally derived DIA unexpectedly well. It is concluded that SIMION/SDS in combination with accurate computational fluid dynamics (CFD) input data and adequate analysis software is capable of successfully modeling operational points of an atmospheric pressure ion (API) source. This approach should be very useful in the computer-aided design of future API sources. PMID- 23812869 TI - Lithium chloride alleviates neurodegeneration partly by inhibiting activity of GSK3beta in a SCA3 Drosophila model. AB - Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG trinucelotide repeat that encodes an abnormal polyglutamine (PolyQ) tract in the disease protein, ataxin-3. The formation of neuronal intranuclear inclusions in the specific brain regions is one of the pathological hallmarks of SCA3. Acceleration of the degradation of the mutant protein aggregates is proven to produce beneficial effects in SCA3 and other PolyQ diseases. Lithium is known to be neuroprotective in various models of neurodegenerative disease and can reduce the mutant protein aggregates by inducing autophagy. In this study, we explored the therapeutic potential of lithium in a SCA3 Drosophila model. We showed that chronic treatment with lithium chloride at specific doses notably prevented eye depigmentation, alleviated locomotor disability, and extended the median life spans of SCA3 transgenic Drosophila. By means of genetic approaches, we showed that co-expressing the mutant S9E, which mimicked the phosphorylated S9 state of Shaggy as done by lithium, also partly decreased toxicity of gmr-SCA3tr-Q78. Taken together, our findings suggest that lithium is a promising therapeutic agent for the treatment of SCA3 and other PolyQ diseases. PMID- 23812871 TI - Unusual analyte-matrix adduct ions and mechanism of their formation in MALDI TOF MS of benzene-1,3,5-tricarboxamide and urea compounds. AB - Analyte-matrix adducts are normally absent under typical matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI TOF MS) conditions. Interestingly, though, in the analysis of several types of organic compounds synthesized in our laboratory, analyte-matrix adduct ion peaks were always recorded when common MALDI matrices such as 4-hydroxy-alpha-cyanocinnamic acid (CHCA) were used. These compounds are mainly those with a benzene-1,3,5 tricarboxamide (BTA) or urea moiety, which are important building blocks to make new functional supramolecular materials. The possible mechanism of the adduct formation was investigated. A shared feature of the compounds studied is that they can form intermolecular hydrogen bonding with matrices like CHCA. The intermolecular hydrogen bonding will make the association between analyte ions and matrix molecules stronger. As a result, the analyte ions and matrix molecules in MALDI clusters will become more difficult to be separated from each other. Furthermore, it was found that analyte ions were mainly adducted with matrix salts, which is probably due to the much lower volatility of the salts compared with that of their corresponding matrix acids. It seems that the analyte-matrix adduct formation for our compounds are caused by the incomplete evaporation of matrix molecules from the MALDI clusters because of the combined effects of enhanced intermolecular interaction between analyte-matrix and of the low volatility of matrix salts. Based on these findings, strategies to suppress the analyte-matrix adduction are briefly discussed. In return, the positive results of using these strategies support the proposed mechanism of the analyte-matrix adduct formation. PMID- 23812872 TI - Treatment of adolescents with aggressive B-cell malignancies: the pediatric experience. AB - Non-Hodgkin lymphoma (NHL) is amongst the most frequent cancer subtypes in children and in adults. However, there are major differences in the distribution of NHL subtypes between the pediatric and adult patient populations. At least for diffuse large B-cell lymphoma (DLBCL) recent data indicate that patient age at diagnosis correlates with molecular features of the lymphoma. Concerning treatment, in common pediatric protocols the same therapy is used for DLBCL and Burkitt lymphoma/leukemia (BL/B-AL). In adult patients, there is an established gold standard treatment for DLBCL, while the optimal treatment of BL/B-AL is under evaluation. Importantly, the correct diagnosis of the NHL subtype plays a crucial role in the treatment decision in adults with aggressive B-cell lymphoma. Adolescent and young adult patients are caught between the two age groups of children on the one hand and adults on the other. Whether the lymphoma biology and subtypes found in this age group resemble rather their pediatric or their adult counterparts is not yet answered. Also, systematic data on the optimal treatment for adolescents with lymphoma are lacking. Therefore, this article reviews current data on patient characteristics, biology, treatment and outcome, mainly in pediatric patients. These data are compared to those published for adult patients with B-cell NHL aiming to look for hints on optimal classification and treatment in adolescents and young adults with B-NHL. PMID- 23812874 TI - Miroestrol, a phytoestrogen from Pueraria mirifica, improves the antioxidation state in the livers and uteri of beta-naphthoflavone-treated mice. AB - Oxidative stress is involved in the progression of several diseases such as diabetes, hypertension, and age-related diseases. Miroestrol (MR) is a potent phytoestrogen from the tuberous root of Pueraria mirifica, a plant used in traditional Thai medicine that is claimed to have rejuvenating effects. In this study, the effects of MR on the antioxidation system, including anti-lipid peroxidation; on the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase; and on glutathione content in the livers and uteri of beta-naphthoflavone (BNF)-treated mice were determined. BNF-treated mice are a model of procarcinogen-exposed mice. The results showed that MR improved the antioxidant activities of SOD and CAT in the livers and uteri of both normal and BNF-treated mice, while estradiol (E2) increased SOD activity in the uteri of normal mice and CAT activity in the livers of both normal and BNF-treated mice. In the liver, MR increased the levels of several forms of glutathione, whereas in the uteri E2 and MR reduced the level of lipid peroxidation by decreasing the level of malondialdehyde. Therefore, the use of MR as an alternative hormone replacement therapy might be beneficial due to its ability to improve antioxidation systems. PMID- 23812873 TI - Obesity, growth hormone and exercise. AB - Growth hormone (GH) is regulated, suppressed and stimulated by numerous physiological stimuli. However, it is believed that obesity disrupts the physiological and pathological factors that regulate, suppress or stimulate GH release. Pulsatile GH has been potently stimulated in healthy subjects by both aerobic and resistance exercise of the right intensity and duration. GH modulates fuel metabolism, reduces total fat mass and abdominal fat mass, and could be a potent stimulus of lipolysis when administered to obese individuals exogenously. Only pulsatile GH has been shown to augment adipose tissue lipolysis and, therefore, increasing pulsatile GH response may be a therapeutic target. This review discusses the factors that cause secretion of GH, how obesity may alter GH secretion and how both aerobic and resistance exercise stimulates GH, as well as how exercise of a specific intensity may be used as a stimulus for GH release in individuals who are obese. Only five prior studies have investigated exercise as a stimulus of endogenous GH in individuals who are obese. Based on prior literature, resistance exercise may provide a therapeutic target for releasing endogenous GH in individuals who are obese if specific exercise programme variables are utilized. Biological activity of GH indicates that this may be an important precursor to beneficial changes in body fat and lean tissue mass in obese individuals. However, additional research is needed including what molecular GH variants are acutely released and involved at target tissues as a result of different exercise stimuli and what specific exercise programme variables may serve to stimulate GH in individuals who are obese. PMID- 23812875 TI - Insulin degludec once-daily in type 2 diabetes: simple or step-wise titration (BEGIN: once simple use). AB - INTRODUCTION: Insulin degludec (IDeg) is a new basal insulin in development with a flat, ultra-long action profile that may permit dosing using a simplified titration algorithm with less frequent self-measured blood glucose (SMBG) measurements and more simplified titration steps than currently available basal insulins. METHODS: This 26-week, multi-center, open-label, randomized, treat-to target study compared the efficacy and safety of IDeg administered once-daily in combination with metformin in insulin-naive subjects with type 2 diabetes using two different patient-driven titration algorithms: a "Simple" algorithm, with dose adjustments based on one pre-breakfast SMBG measurement (n = 111) versus a "Step-wise" algorithm, with adjustments based on three consecutive pre-breakfast SMBG values (n = 111). IDeg was administered using the FlexTouch(r) insulin pen (Novo Nordisk A/S, Bagsvaerd, Denmark), with once-weekly dose titration in both groups. RESULTS: Glycosylated hemoglobin (HbA1c) decreased from baseline to week 26 in both groups (-1.09%, IDegSimple; -0.93%, IDegStep-wise). IDegSimple was non inferior to IDegStep-wise in lowering HbA1c [estimated treatment difference (IDegSimple - IDegStep-wise): -0.16% points (-0.39; 0.07)95% CI]. Fasting plasma glucose was reduced (-3.27 mmol/L, IDegSimple; -2.68 mmol/L, IDegStep-wise) with no significant difference between groups. Rates of confirmed hypoglycemia [1.60, IDegSimple; 1.17, IDegStep-wise events/patient year of exposure (PYE)] and nocturnal confirmed hypoglycemia (0.21, IDegSimple; 0.10, IDegStep-wise events/PYE) were low, with no significant differences between groups. Daily insulin dose after 26 weeks was 0.61 U/kg (IDegSimple) and 0.50 U/kg (IDegStep wise). No significant difference in weight change was seen between groups by week 26 (+1.6 kg, IDegSimple; +1.1 kg, IDegStep-wise), and there were no clinically relevant differences in adverse event profiles. CONCLUSION: IDeg was effective and well tolerated using either the Simple or Step-wise titration algorithm. While selection of an algorithm must be based on individual patient characteristics and goals, the ability to attain good glycemic control using a simplified titration algorithm may enable patient empowerment through self titration, improved convenience, and reduced costs. PMID- 23812876 TI - Arthroscopic findings in the recurrent anterior instability of the shoulder. AB - BACKGROUND: A recurrent anterior shoulder dislocation consists of a variety of lesion types. OBJECTIVES: To evaluate the pathological classification of recurrent anterior dislocation of the shoulder joint under arthroscopy. METHODS: Thirty-one patients with recurrent anterior shoulder dislocation were inspected by arthroscopy, including 23 males and 8 females, with a mean age of 35.1 (18-46) years. The patients were divided into two groups: 17 with shoulder dislocation and hyper-laxity (the hyper-laxity group) and 14 with only traumatic shoulder dislocation (the trauma group). All the patients were assessed by arthroscopy for pathological changes, and the differences in the pathological changes were compared between the two groups. RESULTS: All these 31 patients suffered from anteroinferior labrum injury. Twenty-five had Hill-Sachs injury; 27, bone or cartilage injury of anteroinferior glenoid; 16, SLAP injury; and 5, rotator cuff injury. Bankart injury occurred more in the trauma group, and anterior labroligamentous periosteal sleeve avulsion injury and glenolabral articular disruption injury were more in the hyper-laxity group. Bone or cartilage injury of anteroinferior glenoid was more noticed in the trauma group. CONCLUSIONS: Significant differences are found under arthroscopy in the pathological changes of recurrent anterior shoulder dislocation between the purely traumatic group and the hyper-laxity group. The pathological changes in the trauma group were more severe than in the hyper-laxity group. PMID- 23812877 TI - Development and single laboratory validation of an optical biosensor assay for tetrodotoxin detection as a tool to combat emerging risks in European seafood. AB - Tetrodotoxin (TTX) is a potent neurotoxin emerging in European waters due to increasing ocean temperatures. Its detection in seafood is currently performed as a consequence of using the Association of Analytical Communities (AOAC) mouse bioassay (MBA) for paralytic shellfish poisoning (PSP) toxins, but TTX is not monitored routinely in Europe. Due to ethical and performance-related issues associated with this bioassay, the European Commission has recently published directives extending procedures that may be used for official PSP control. An AOAC-accredited high-performance liquid chromatography (HPLC) method has now been accepted by the European Union as a first action screening method for PSP toxins to replace the MBA. However, this AOAC HPLC method is not capable of detecting TTX, so this potent toxin would be undetected; thereby, a separate method of analysis is required. Surface plasmon resonance (SPR) optical biosensor technology has been proven as a potential alternative screening method to detect PSP toxins in seafood. The addition of a similar SPR inhibition assay for TTX would complement the PSP assay in removing the MBA. The present report describes the development and single laboratory validation in accordance with AOAC and IUPAC guidelines of an SPR method to be used as a rapid screening tool to detect TTX in the sea snail Charonia lampas lampas, a species which has been implicated in 2008 in the first case of human TTX poisoning in Europe. As no current regulatory limits are set for TTX in Europe, single laboratory validation was undertaken using those for PSP toxins at 800 MUg/kg. The decision limit (CCalpha) was 100 MUg/kg, with the detection capability (CCbeta) found to be <=200 MUg/kg. Repeatability and reproducibility were assessed at 200, 400, and 800 MUg/kg and showed relative standard deviations of 8.3, 3.8, and 5.4% and 7.8, 8.3, and 3.7% for both parameters at each level, respectively. At these three respective levels, the recovery of the assay was 112, 98, and 99%. PMID- 23812878 TI - Characterization of oat proteins and aggregates using asymmetric flow field-flow fractionation. AB - The soluble proteins and protein aggregates in Belinda oats were characterized using asymmetric flow field-flow fractionation (AF4) coupled with online UV-vis spectroscopy and multiangle light-scattering detection (MALS). Fractions from the AF4 separation were collected and further characterized by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The AF4 fractogram of the oat extracts revealed three peaks which were determined to be monomeric forms of soluble proteins, globulin aggregates, and beta-glucan, respectively. The early eluting monomeric proteins ranged in molar mass (MM) between 5 and 90 kg/mol and in hydrodynamic diameter (D h) from 1.6 to 13 nm. The MM at peak maximum of the globulin aggregate peak was found to be ~300 kg/mol and the D h was measured to be ~20 nm. SDS-PAGE of the collected fraction across this peak revealed two bands with MM of 37 and 27 kg/mol which correspond to the alpha and beta subunits of globulin indicating the elution of globulin aggregates. A third peak at long retention time was determined to be beta-glucan through treatment of the oat extract with beta-glucanase and by injection of beta-glucan standards. The amount of soluble protein was measured to be 83.1 +/- 2.3 wt.%, and the amount of albumin proteins was measured to be 17.6 +/- 5.7 wt.% of the total protein in the oats. The results for Belinda oat extracts show that the AF4-MALS/UV platform is capable of characterizing the physicochemical properties such as MM and hydrodynamic size distribution of proteins and protein aggregates within a complicated food matrix environment and without the need to generate protein isolates. PMID- 23812879 TI - Off-chip passivated-electrode, insulator-based dielectrophoresis (OpiDEP). AB - In this study, we report the first off-chip passivated-electrode, insulator-based dielectrophoresis microchip (OpiDEP). This technique combines the sensitivity of electrode-based dielectrophoresis (eDEP) with the high-throughput and inexpensive device characteristics of insulator-based dielectrophoresis (iDEP). The device is composed of a permanent, reusable set of electrodes and a disposable, polymer microfluidic chip with microposts embedded in the microchannel. The device operates by capacitively coupling the electric fields into the microchannel; thus, no physical connections are made between the electrodes and the microfluidic device. During operation, the polydimethylsiloxan (PDMS) microfluidic chip fits onto the electrode substrate as a disposable cartridge. OpiDEP uses insulting structures within the channel as well as parallel electrodes to create DEP forces by the same working principle that iDEP devices use. The resulting devices create DEP forces which are larger by two orders of magnitude for the same applied voltage when compared to off-chip eDEP designs from literature, which rely on parallel electrodes alone to produce the DEP forces. The larger DEP forces allow the OpiDEP device to operate at high flow rates exceeding 1 mL/h. In order to demonstrate this technology, Escherichia coli (E. coli), a known waterborne pathogen, was trapped from water samples. Trapping efficiencies of 100% were obtained at flow rates as high as 400 MUL/h and 60% at flow rates as high as 1200 MUL/h. Additionally, bacteria were selectively concentrated from a suspension of polystyrene beads. PMID- 23812880 TI - A high-throughput screening assay for assessing the viability of Cryptococcus neoformans under nutrient starvation conditions. AB - Cryptococcus neoformans causes an estimated 600,000 AIDS-related deaths annually that occur primarily in resource-limited countries. Fluconazole and amphotericin B are currently available for the treatment of cryptococcal-related infections. However, fluconazole has limited clinical efficacy and amphotericin B requires intravenous infusion and is associated with high renal toxicity. Therefore, there is an unmet need for a new orally administrable anti-cryptococcal drug. We have developed a high-throughput screening assay for the measurement of C. neoformans viability in 1,536-well plate format. The signal-to-basal ratio of the ATP content assay was 21.9 fold with a coefficient of variation and Z' factor of 7.1% and 0.76, respectively. A pilot screen of 1,280 known compounds against the wild type C. neoformans (strain H99) led to the identification of four active compounds including niclosamide, malonoben, 6-bromoindirubin-3'-oxime, and 5-[(4 ethylphenyl)methylene]-2-thioxo-4-thiazolidinone. These compounds were further tested against nine clinical isolates of C. neoformans, and their fungicidal activities were confirmed. The results demonstrate that this miniaturized C. neoformans assay is advantageous for the high-throughput screening of large compound collections to identify lead compounds for new anti-cryptococcal drug development. PMID- 23812881 TI - A simple method to identify ether lipids in spermatozoa samples by MALDI-TOF mass spectrometry. AB - Plasmalogens (alkenylacyl glycerophospholipids) are important lipid constituents of many tissues and cells (e.g., selected spermatozoa). Since the molecular weights of plasmalogens overlap with that of diacyl- or alkyl acyl lipids, sophisticated mass spectrometry (MS; including MS/MS) analysis is normally used for the unequivocal identification of plasmalogens. We will show here that a simple matrix-assisted laser desorption/ionization time-of-flight mass spectrometer (without MS/MS capability) in combination with acidic hydrolysis and subsequent derivatization with 2,4-dinitrophenylhydrazine (DNPH) and/or digestion with phospholipase A2 (PLA2) is sufficient to determine the contributions of ether lipids in spermatozoa extracts. As neither diacyl nor alkylacyl lipids are sensitive to acids and do not react with DNPH, the comparison of the mass spectra before and after treatment with acids and/or DNPH addition readily provides unequivocal information about the plasmalogen content. Additionally, the released aldehydes are readily converted into the 2,4-dinitrophenylhydrazones and can be easily identified in the corresponding negative ion mass spectra. Finally, PLA2 digestion is very useful in confirming the presence of plasmalogens. The suggested method was validated by analyzing roe deer, bovine, boar, and domestic cat spermatozoa extracts and comparing the results with isolated phospholipids. PMID- 23812882 TI - Flow injection of liquid samples to a mass spectrometer with ionization under vacuum conditions: a combined ion source for single-photon and electron impact ionization. AB - Electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI), and atmospheric pressure photo-ionization (APPI) are the most important techniques for the ionization of liquid samples. However, working under atmospheric pressure conditions, all these techniques involve some chemical rather than purely physical processes, and therefore, side reactions often yield to matrix-dependent ionization efficiencies. Here, a system is presented that combines both soft single-photon ionization (SPI) and hard 70 eV electron impact ionization (EI) of dissolved compounds under vacuum conditions. A quadrupole mass spectrometer was modified to enable direct EI, a technique developed by Cappiello et al. to obtain library-searchable EI mass spectra as well as soft SPI mass spectra of sample solutions. An electron beam-pumped rare gas excimer lamp working at 126 nm was used as well as a focusable vacuum UV light source for single-photon ionization. Both techniques, EI and SPI, were applied successfully for flow injection experiments providing library-matchable EI fragment mass spectra and soft SPI mass spectra, showing dominant signals for the molecular ion. Four model compounds were analyzed: hexadecane, propofol, chlorpropham, and eugenol, with detection limits in the picomolar range. This novel combination of EI and SPI promises great analytical benefits, thanks to the possibility of combining database alignment for EI data and molecular mass information provided by SPI. Possible applications for the presented ionization technology system are a matrix-effect-free detection and a rapid screening of different complex mixtures without time-consuming sample preparation or separation techniques (e.g., for analysis of reaction solutions in combinatorial chemistry) or a switchable hard (EI) and soft (SPI) MS method as detection step for liquid chromatography. PMID- 23812883 TI - EC-SPE-stripline-NMR analysis of reactive products: a feasibility study. AB - Flow-through electrochemical conversion (EC) of drug-like molecules was hyphenated to miniaturized nuclear magnetic resonance spectroscopy (NMR) via on line solid-phase extraction (SPE). After EC of the prominent p38alpha mitogen activated protein kinase inhibitor BIRB796 into its reactive products, the SPE step provided preconcentration of the EC products and solvent exchange for NMR analysis. The acquisition of NMR spectra of the mass-limited samples was achieved in a stripline probe with a detection volume of 150 nL offering superior mass sensitivity. This hyphenated EC-SPE-stripline-NMR setup enabled the detection of the reactive products using only minute amounts of substrate. Furthermore, the integration of conversion and detection into one flow setup counteracts incorrect assessments caused by the degradation of reactive products. However, apparent interferences of the NMR magnetic field with the EC, leading to a low product yield, so far demanded relatively long signal averaging. A critical assessment of what is and what is not (yet) possible with this approach is presented, for example in terms of structure elucidation and the estimation of concentrations. Additionally, promising routes for further improvement of EC-SPE-stripline-NMR are discussed. PMID- 23812884 TI - Acute peritoneal dialysis in the newborn period: a 7-year single-center experience at tertiary neonatal intensive care unit in Turkey. AB - OBJECTIVE: To evaluate the underlying causes and outcomes of neonates who underwent acute peritoneal dialysis (APD). STUDY DESIGN: This report describes a 7-year experience with APD in 77 neonates. RESULTS: Underlying causes requiring APD were acute tubular necrosis (ATN; n = 53), inborn error of metabolism (n = 18), bilateral renal vein thrombosis (n = 3), obstructive uropathy (n = 2; posterior urethral valve and neurogenic bladder), and bilateral renal artery thrombosis (n = 1). Fifteen of the 53 patients developed post-cardiac surgery ATN. The mean dialysis duration was 6.2 +/- 10.7 days (range 1 to 90 days). Complications of procedure were hyperglycemia (n = 35), leaking of dialysate (n = 13), peritonitis (n = 10), catheter obstruction (n = 3), bleeding when inserting the catheter (n = 3), exit site infection (n = 2), and bowel perforation (n = 1). There were 57 deaths (74%) in this high-risk group due to underling causes. Of the 20 survivors, 16 patients showed a full renal recovery, but mild chronic renal failure developed in 1 patient and proteinuria with/without hypertension in 3 patients. CONCLUSION: Peritoneal dialysis is an effective means of renal replacement therapy in the neonatal period in the management of metabolic disturbances as well as renal failure. Although major complications of procedure are not so common, these patients have high mortality rates due to the serious nature of the primary causes. PMID- 23812885 TI - Viability inhibition effect of gambogic acid combined with cisplatin on osteosarcoma cells via mitochondria-independent apoptotic pathway. AB - We previously demonstrated that gambogic acid (GA) is a promising chemotherapeutic compound for human osteosarcoma treatment. The aim of this study was to detect whether the combination of lower-dose GA (0.3 mg/L) and cisplatin (CDDP) (1 mg/L) could perform a synergistic effect on inhibiting tumor in four osteosarcoma cell lines. Our results showed that the combination between GA at lower dose and CDDP significantly exerts a synergistic effect on inhibiting the cellular viability in MG63, HOS, and U2OS cells. In contrast, an antagonistic character was detected in SAOS2 cells exposed to the combined use of lower-dose GA (0.3 mg/L) and CDDP (1 mg/L). Then, analysis of cell cycle showed the combination of both drugs significantly induced the G2/M phase arrest, without any difference relative to GA treatment alone, in MG63 cells. Flow-cytometric analysis of cell apoptosis displayed that the apoptotic rate in the combination group is higher than that in GA treatment alone in MG63, HOS, and U2OS cells. The combined use of both drugs had no effect on mitochondrial membrane potential, but promoted the apoptosis-inducing function through triggering of CDDP in the three cell lines. By measurement of mitochondrial membrane potential, the activity of caspase-3 and the expressions of caspase-8 and caspase-9, it was showed that the apoptosis-promoting effect of the combined use of both drugs could be dependent on the death receptor apoptosis pathway, not dependent on the mitochondria apoptosis mechanism. This research, for the first time, demonstrates that GA could increase the chemotherapeutic effect of CDDP in human osteosarcoma treatment through inducing the cell cycle arrest and promoting cell apoptosis. PMID- 23812886 TI - Predictors of onset for non-suicidal self-injury within a school-based sample of adolescents. AB - This paper reports on a prospective study exploring risk factors specifically related to the onset of non-suicidal self-injury (NSSI) during adolescence. We examined cumulative incidence and predictors of onset of NSSI over 1 year among 1,973 school-based adolescents (13-19 years old; M = 14.9, SD = 0.96) from five states in Australia. Data showed cumulative incidence of 3.8 % (95 % CI [3.0-4.7 %]) over 1 year. Multiple socio-demographic and psychosocial factors were assessed using sequential logistic regression models. Onset of NSSI was associated with being female (OR = 3.47, 95 % CI [1.48-8.18]), being born outside of Australia (OR = 3.05, 95 % CI [1.10-8.47]), not identifying as religious or spiritual (OR = 1.80, 95 % CI [1.04-3.10]), increased psychological distress (OR = 1.12, 95 % CI [1.08-1.16]), poor social support from family (OR = 0.89, 95 % CI [0.83-0.95]), poor self-esteem (OR = 0.90, 95 % CI [0.83-0.98]), and poor problem solving coping (OR = 0.90, 95 % CI [0.82-0.99]). These findings may assist to better identify young people more likely to start self-injuring and also highlight issues to provide a focus for prevention initiatives. PMID- 23812887 TI - Prevalence and community variation in harmful levels of family conflict witnessed by children: implications for prevention. AB - Children's reports of high family conflict consistently predict poor outcomes. The study identified criteria for high family conflict based on prospective prediction of increased risk for childhood depression. These criteria were subsequently used to establish the prevalence of high family conflict in Australian communities and to identify community correlates suitable for targeting prevention programs. Study 1 utilised a longitudinal design. Grade 6 and 8 students completed a family conflict scale (from the widely used Communities That Care survey) in 2003 and depression symptomotology were evaluated at a 1-year follow-up (International Youth Development Study, N = 1,798). Receiver-operating characteristic analysis yielded a cut-off point on a family conflict score with depression symptomatology as a criterion variable. A cut-off score of 2.5 or more (on a scale of 1 to 4) correctly identified 69 % with depression symptomology, with a specificity of 77.2 % and sensitivity at 44.3 %. Study 2 used data from an Australian national survey of Grade 6 and 8 children (Healthy Neighbourhoods Study, N = 8,256). Prevalence estimates were calculated, and multivariate logistic regression with multi-level modelling was used to establish factors associated with community variation in family conflict levels. Thirty-three percent of Australian children in 2006 were exposed to levels of family conflict that are likely to increase their future risk for depression. Significant community correlates for elevated family conflict included Indigenous Australian identification, socioeconomic disadvantage, urban and state location, maternal absence and paternal unemployment. The analysis provides indicators for targeting family-level mental health promotion programs. PMID- 23812888 TI - Changing the conversation: the influence of emotions on conversational valence and alcohol consumption. AB - Health campaign effects may be improved by taking interpersonal communication processes into account. The current study, which employed an experimental, pretest-posttest, randomized exposure design (N = 208), investigated whether the emotions induced by anti-alcohol messages influence conversational valence about alcohol and subsequent persuasion outcomes. The study produced three main findings. First, an increase in the emotion fear induced a negative conversational valence about alcohol. Second, fear was most strongly induced by a disgusting message, whereas a humorous appeal induced the least fear. Third, a negative conversational valence elicited healthier binge drinking attitudes, subjective norms, perceived behavioral control, intentions, and behaviors. Thus, health campaign planners and health researchers should pay special attention to the emotional characteristics of health messages and should focus on inducing a healthy conversational valence. PMID- 23812889 TI - Bio-removal of cadmium by growing deep-sea bacterium Pseudoalteromonas sp. SCSE709-6. AB - Effective bio-removal of heavy metals is important for water treatment. Although a number of microorganism species demonstrated the ability of living cells to remove cadmium, most of them were tested at fixed concentration of metals, salinity, and temperature. This paper reported a research on the screening and performance of a newly developed deep-sea bacterium, Pseudoalteromonas sp. SCSE709-6, for Cd(II) removal by growing cells under a range of experimental conditions: 0-50 mg/L of Cd(II), 15-30 degrees C of incubation temperatures, 6.5 8.0 of initial pH, and 1.5-5.0 % of salinity. Study results revealed that Pseudoalteromonas sp. SCSE709-6 could remove more than 96 % of Cd(II) on growth. The Cd(II) bioremoval was in correlation but not in accordance with biomass. As cadmium concentrations increased, the Cd(II) removal by cell adsorption played an increasingly important role compared with that of intracellular accumulation. For the removal mechanism, Fourier transform infrared spectroscopy revealed that carboxyl, amido and hydroxyl of saccharides, and proteins in the extracellular polymeric substances are the most active groups for Cd(II) absorption. The bacterium reported in this study offers a new microbe strain for Cd(II) bioremediation. PMID- 23812890 TI - Spatial pattern in Antarctica: what can we learn from Antarctic bacterial isolates? AB - A range of small- to moderate-scale studies of patterns in bacterial biodiversity have been conducted in Antarctica over the last two decades, most suggesting strong correlations between the described bacterial communities and elements of local environmental heterogeneity. However, very few of these studies have advanced interpretations in terms of spatially associated patterns, despite increasing evidence of patterns in bacterial biogeography globally. This is likely to be a consequence of restricted sampling coverage, with most studies to date focusing only on a few localities within a specific Antarctic region. Clearly, there is now a need for synthesis over a much larger spatial to consolidate the available data. In this study, we collated Antarctic bacterial culture identities based on the 16S rRNA gene information available in the literature and the GenBank database (n > 2,000 sequences). In contrast to some recent evidence for a distinct Antarctic microbiome, our phylogenetic comparisons show that a majority (~75 %) of Antarctic bacterial isolates were highly similar (>=99 % sequence similarity) to those retrieved from tropical and temperate regions, suggesting widespread distribution of eurythermal mesophiles in Antarctic environments. However, across different Antarctic regions, the dominant bacterial genera exhibit some spatially distinct diversity patterns analogous to those recently proposed for Antarctic terrestrial macroorganisms. Taken together, our results highlight the threat of cross-regional homogenisation in Antarctic biodiversity, and the imperative to include microbiota within the framework of biosecurity measures for Antarctica. PMID- 23812891 TI - An ICEBs1-like element may be associated with the extreme radiation and desiccation resistance of Bacillus pumilus SAFR-032 spores. AB - Comparisons of the genomes of Bacillus pumilus SAFR-032 and the closely related type strain, B. pumilus ATCC7061(T), exposed an extended region of non-homologous genes. A detailed examination of this region revealed the presence of an ICEBs1 like integrative conjugative element in SAFR-032. A similar element was subsequently located elsewhere in the ATCC7061(T) genome. A detailed comparison of these elements and the ICEBs1 of B. subtilis revealed extremely rapid flux in gene content, genome organization and sequence similarity. It is not clear if the B. pumilus elements as they are currently structured are functional. However, it is clear that the past involvement of these elements has brought multiple genes of unknown function to the SAFR-032 genome and these genes may be responsible for the rapid evolution that led to the extreme radiation and desiccation resistance of this organism's spores. PMID- 23812892 TI - A preliminary RCT of CBT-AD for adherence and depression among HIV-positive Latinos on the U.S.-Mexico border: the Nuevo Dia study. AB - We conducted a preliminary RCT among 40 HIV-positive Latinos of Mexican descent on the U.S.-Mexico border who indicated imperfect adherence and depressive symptomatology. Participants were randomly assigned to culturally adapted cognitive-behavioral therapy for adherence and depression with an alarmed pillbox or usual care. Outcomes were depressive symptoms (self-report and blind clinician ratings), adherence (self-report and electronic pillbox), and biological markers. The intervention, delivered in English and Spanish, proved feasible and acceptable. Generalized estimating equations in intent-to-treat analyses showed some effects of "moderate" to "large" size, with maintenance over time. For example, intervention (vs. control) participants demonstrated at post intervention a greater drop in BDI scores (OR = -3.64, p = 0.05) and greater adherence according to the electronic pillbox (OR = 3.78, p = 0.03). Biological markers indicated some relative improvement for CD4 count but not VL. The promising results suggest a larger trial to determine efficacy is warranted. PMID- 23812893 TI - The association between beta-glucocerebrosidase mutations and parkinsonism. AB - Mutations in the beta-glucocerebrosidase gene (GBA), which encodes the lysosomal enzyme beta-glucocerebrosidase, have traditionally been implicated in Gaucher disease, an autosomal recessive lysosomal storage disorder. Yet the past two decades have yielded an explosion of epidemiological and basic-science evidence linking mutations in GBA with the development of Parkinson disease (PD) as well. Although the specific contribution of mutant GBA to the pathogenesis of parkinsonism remains unknown, evidence suggests that both loss of function and toxic gain of function by abnormal beta-glucocerebrosidase may be important, and implicates a close relationship between beta-glucocerebrosidase and alpha synuclein. Furthermore, multiple lines of evidence suggest that although GBA associated PD closely mimics idiopathic PD (IPD), it may present at a younger age, and is more frequently complicated by cognitive dysfunction. Understanding the clinical association between GBA and PD, and the relationship between beta glucocerebrosidase and alpha-synuclein, may enhance understanding of the pathogenesis of IPD, improve prognostication and treatment of GBA carriers with parkinsonism, and furthermore inform therapies for IPD not due to GBA mutations. PMID- 23812894 TI - Technological advances in the surgical treatment of movement disorders. AB - Technological innovations have driven the advancement of the surgical treatment of movement disorders, from the invention of the stereotactic frame to the adaptation of deep brain stimulation (DBS). Along these lines, this review will describe recent advances in inserting neuromodulation modalities, including DBS, to the target, and in the delivery of therapy at the target. Recent radiological advances are altering the way that DBS leads are targeted and inserted, by refining the ability to visualize the subcortical targets using high-field strength magnetic resonance imaging and other innovations, such as diffusion tensor imaging, and the development of novel targeting devices enabling purely anatomical implantations without the need for neurophysiological monitoring. New portable computed tomography scanners also are facilitating lead implantation without monitoring, as well as improving radiological verification of DBS lead location. Advances in neurophysiological mapping include efforts to develop automatic target verification algorithms, and probabilistic maps to guide target selection. The delivery of therapy at the target is being improved by the development of the next generation of internal pulse generators (IPGs). These include constant current devices that mitigate the variability introduced by impedance changes of the stimulated tissue and, in the near future, devices that deliver novel stimulation patterns with improved efficiency. Closed-loop adaptive IPGs are being tested, which may tailor stimulation to ongoing changes in the nervous system, reflected in biomarkers continuously recorded by the devices. Finer-grained DBS leads, in conjunction with new IPGs and advanced programming tools, may offer improved outcomes via current steering algorithms. Finally, even thermocoagulation-essentially replaced by DBS-is being advanced by new minimally invasive approaches that may improve this therapy for selected patients in whom it may be preferred. Functional neurosurgery has a history of being driven by technological innovation, a tradition that continues into its future. PMID- 23812896 TI - Preanalytical stringency: what factors may confound interpretation of thiopurine S-methyl transferase enzyme activity? AB - BACKGROUND: Measurement of red blood cell thiopurine S-methyl transferase (TPMT) enzyme activity before commencing thiopurine therapy is recommended to avoid severe bone marrow suppression in TPMT-deficient patients. Patient's samples go through preanalytical transportation and storage steps before measurement. We studied patient's TPMT activity sample data to assess the effect of preanalytical variables including transportation time. METHODS: A total of 8524 TPMT enzyme activity analyses were conducted from 2002 to 2010 in a single laboratory, with samples sent from seven centres throughout New Zealand. TPMT activity was correlated with time of arrival at the reference laboratory, patient gender and age and centre of sample collection. RESULTS: The 6348 (74%) selected TPMT measurements that fulfilled selection criteria ranged from 0 to 25.8 IU/mL. Median delay to sample analysis was 42 h. Median TPMT activity was significantly lower for all centres compared with the reference centre (P < 0.001). Delay in sample arrival was significantly and independently correlated with TPMT enzyme activity (ANCOVA; P < 0.001), which showed a 0.011 (95% CI, 0.008-0.014) IU/mL decrease per extra hour of delay. After correcting for these data, one centre still had a significantly lower TPMT enzyme activity compared with the reference centre. CONCLUSIONS: There was a significant negative correlation between TPMT enzyme activity and delay from sample collection to analysis. Transportation time is therefore an important preanalytical variable influencing TPMT activity. Samples from one centre had a lower TPMT activity after correcting for transportation delay, suggesting that other factors related to sample processing may also be relevant. PMID- 23812898 TI - Deterioration of left ventricular ejection fraction and contraction synchrony during right ventricular pacing in patients with left bundle branch block. AB - BACKGROUND: Electrocardiographic left bundle branch block (LBBB) may be intrinsic, due to ventricular conduction system disease, or induced by right ventricular pacing. Prior reports clearly delineate the derogatory impact of LBBB on left ventricular (LV) mechanical synchrony and global function, and suggest that the intrinsic and induced varieties are equivalent. This study sought to determine the difference in LV synchrony and global function between intrinsic LBBB and right ventricular apical pacing induced LBBB. METHODS: Ten patients with heart failure, diminished ejection fraction (EF) (33 +/- 11%), intrinsic LBBB and an implanted cardiac pacing device were studied. In each patient, separate gated SPECT acquisitions were performed during intrinsic ventricular activation (atrial pacing) and during induced LBBB (atrial and right ventricular pacing). During each condition, LVEF, contraction synchrony (phase standard deviation, PSD), and spatial pattern of activation were measured. RESULTS: Compared to intrinsic, induced LBBB was associated with decreased EF (30 +/- 11% vs 33 +/- 11%, P = .007), contraction synchrony (PSD 49.7 +/- 23.2 degrees vs 41.6 +/- 19.8, P = .02), and a disparate spatial pattern of activation. CONCLUSIONS: Induced LBBB is associated with significantly worse global and regional LV mechanical function than intrinsic LBBB. PMID- 23812895 TI - Innate immune responses in the CNS: role of toll-like receptors, mechanisms, and therapeutic opportunities in multiple sclerosis. AB - Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), which is considered immune-mediated. Our knowledge of innate immune mechanisms in the CNS and their implications for pathogenesis and treatment of multiple sclerosis (MS) are limited, particularly if compared with the body of literature on adaptive immune mechanisms. There is, however, growing understanding of the workings of the innate immune system and accordingly, of its potential role in driving immune-mediated pathology. Such mechanisms will be discussed in this review along with potential therapeutic opportunities. These may require blocking pathogenic innate immunity and in some cases, promoting its protective effects. PMID- 23812899 TI - Effects of phenylephrine and noradrenaline on coronary artery motion in an open chest porcine beating heart model. AB - PURPOSE: During off-pump coronary artery bypass (OPCAB), surgeons are required to perform a precise anastomosis on the beating heart. The hypotension caused by vertical displacement of the heart during OPCAB is usually treated with vasopressors, such as noradrenaline and phenylephrine. However, the effects of these agents on coronary artery motion are unknown. The present study analyzed the motion of the target coronary arteries during noradrenaline or phenylephrine infusion using three-dimensional motion capture and reconstruction technology. METHODS: The left anterior descending (LAD) artery, left circumflex (LCX) artery and right coronary artery (RCA) of 12 female landrace pigs (weight 50 +/- 1 kg) were stabilized using a tissue stabilizer. The motions in the regions were captured before and during noradrenaline (n = 5) and phenylephrine (n = 7) infusion. RESULTS: Noradrenaline (0.15 MUg/kg/min) and phenylephrine (1.1 MUg/kg/min) significantly increased the blood pressure. Noradrenaline significantly increased the motion parameters, such as the distance moved, maximum velocity, acceleration and deceleration at the LAD (4.2 vs. 7.9 mm, P = 0.025; 95.7 vs. 215.5 mm/s, P = 0.0074; 35.3 vs. 83.6 m/s(2), P = 0.0096 and 35.6 vs. -83.6 m/s(2), P = 0.005, respectively). The values during phenylephrine infusion did not change except for the distance moved at the LAD (3.8 vs. 7.7 mm, P = 0.042). The motion parameters at the LCX and RCA during noradrenaline and phenylephrine infusion did not change significantly. CONCLUSIONS: The effect of phenylephrine on the coronary artery motion was less dramatic than that of noradrenaline. PMID- 23812900 TI - Controlling massive hemorrhage from the retropancreatic portal vein as a complication of thromboendovenectomy during liver transplantation with balloon catheter tamponade: how to do it. AB - We herein describe two cases of liver transplantation with portal vein thrombosis. In both cases, a tear advancing to the retropancreatic area occurred during portal vein thrombectomy. Hemorrhage from the limited visibility retropancreatic area made it impossible to stop the bleeding by clamping or direct suturing, and the clamping and suturing efforts actually increased the hemorrhage, possibly due to the damaged and thin portal vein wall. First, finger compression over the retropancreatic area was employed to stop the bleeding, then a Foley urinary catheter was introduced into the portal vein under the finger. The balloon of the catheter was inflated with 8 cc of normal saline, and the finger was released. The bleeding was stopped temporarily, and two different venous conduits were sutured to the trimmed portal vein stump in a bloodless surgical area. The venous conduits were easily controlled with vascular clamps after deflating the balloon catheters, and implantation of the liver was then done in a standard manner. Balloon tamponade can be a lifesaving technique that can temporarily stop a hemorrhage to allow for definitive repair in cases of retropancreatic portal vein hemorrhage. PMID- 23812901 TI - Modified LigaSure hemorrhoidectomy for the treatment of hemorrhoidal crisis. AB - PURPOSE: This study aimed at reporting a modified LigaSure technique for the treatment of acute hemorrhoidal crisis. METHODS: Consecutive patients with an acute hemorrhoidal crisis received a modified LigaSure hemorrhoidectomy. After removing the hemorrhoidal tissues above the welding line, scissors were used to undermine the anoderm to excise residual thrombosed hemorrhoidal tissue. The wound was approximated with a continuous 4-0 vicryl suture. RESULTS: Forty patients (mean age, 47.5 years; range 22.0-76.0 years) were included. The mean duration of the crisis, length of the operation, and follow-up were 2.0 days (range 1.0-5.0 days), 35.6 min (range 15.0-60.0 min), and 13.2 months (range 6-24 months), respectively. At the final follow-up, all patients were continent and there were no cases with anal stenosis, recurrent bleeding, prolapse, or thrombus. The mean pain score before surgery was 8.3, and was 4.4 and 3.2 on postoperative days 1 and 7, respectively. Complications within 30 days of surgery included two cases of urine retention, two cases bleeding, one wound infection and one case of fecal impaction, which all resolved with conservative treatment. The only late complication was one case of residual skin tags. CONCLUSIONS: The modified LigaSure hemorrhoidectomy offers rapid pain relief, early recovery, and low morbidity for patients with an acute hemorrhoidal crisis. PMID- 23812902 TI - Enhanced incorporation of docosahexaenoic acid in serum, heart, and brain of rats given microemulsions of fish oil. AB - Long-chain n-3 fatty acids are essential for the development of cognitive functions and reducing the risk factor for cardiovascular diseases. The present study was undertaken to prepare fish oil (FO) microemulsion and explore the possibility of enhancing the enrichment of long-chain n-3 PUFA in the heart and brain lipids. The bioavailability of encapsulated FO was compared with that of native oil in rats by utilizing the intestinal sac method and by an in vivo study giving microemulsions of FO through intubation for a period of 30 days. Microemulsions were prepared using chitosan, gum acacia, whey protein, and lipoid. The bioavailability of eicosapentaenoic acid and docosahexaenoic acid (DHA) from FO encapsulated in chitosan, gum acacia, whey protein, and lipoid was increased by 7, 9, 23, and 68%, respectively, as compared to oil given without encapsulation in the everted intestinal sacs model. The DHA levels in serum lipids when FO was given as lipoid emulsion to rats were found to be 56 MUg/ml, while rats given FO without encapsulation had a DHA level of 22 MUg/ml. In the heart and brain lipids, the DHA levels were increased by 77 and 41%, respectively, in rats given FO encapsulated with lipoid compared to those given native oil. These studies indicated that DHA from FO was taken up in a more efficient manner when given in an encapsulated form with lipoid. Thus, phospholipid-based binding materials such as Lipoid provide a good delivery system for FO and significantly enhance DHA levels in the serum, liver, heart, and brain tissues. PMID- 23812903 TI - Treatment selection for gastric cancer with portal hypertension: clinical management. AB - BACKGROUND: Treatment for gastric cancer with portal hypertension must consider the eradication of the tumor and the change of hemodynamics in portal hypertension (PHT). Few reports have described the surgical procedures and postoperative complications of surgery for gastric cancer associated with PHT. METHODS: The clinical data of 22 patients with PHT undergoing curative surgery for gastric cancer during 5 years were retrospectively analyzed. For 12 patients classified in Child's class A, D2 lymph node (LN) dissection was performed, and 10 patients classified into Child's class B were treated with D1 LN dissection. Surgical treatment included total gastrectomy combined with pericardial devascularization, distal subtotal gastrectomy, distal subtotal gastrectomy combined with splenectomy, and distal subtotal gastrectomy combined with pericardial devascularization with posterior gastric artery and left inferior phrenic artery preserved. A liver biopsy was analyzed in all patients. RESULTS: Postoperative complications developed in 50 % (11/22 patients) and the mortality rate was 9 % (2/22). The rate of postoperative ascites in patients with Child's class A was much lower than in those with Child's class B (P < 0.05). "Operation time," "volume of hemorrhage," "platelet count," and "treatment of PHT" are all risk factors of liver function deterioration. However, there was no significant difference in liver function deterioration rate between patients with Child's class A and Child's class B (P > 0.05). The occurrence rate of complications in patients with PHT was much higher compared to those without with PHT (P < 0.05). CONCLUSIONS: Individualized selection of surgical approaches is crucial for treatment of gastric carcinoma accompanied by PHT. Surgical treatment should be based on preoperative TNM stage, liver function, and degree of PHT. PMID- 23812904 TI - Aberrant expression of SOX9 is associated with gastrokine 1 inactivation in gastric cancers. AB - BACKGROUND: SOX9 belongs to the SOX [sry-related high-mobility group (HMG) box] family and acts as a transcription factor that plays a central role in the development and differentiation of multiple cell lineages. The aim of this study was to determine whether the GKN1 gene is involved in the development of gastric cancer by regulating SOX9. METHODS: The effect of GKN1 and beta-catenin on SOX9 expression was examined in GKN1 and beta-catenin-transfected AGS and MKN-1 gastric cancer cells. SOX9 expression was also determined in gastric cancer tissues and cell lines by Western blot analysis and immunohistochemistry. RESULTS: Ectopic expression of beta-catenin induced increased expression of SOX9 in AGS cells, whereas GKN1 decreased expression of SOX9 in AGS and MKN-1 cells. In addition, we found an inverse correlation between expression of SOX9 and GKN1 in gastric cancer tissues and cell lines. In immunohistochemistry, nuclear SOX9 expression was detected in 64 (34.6 %) of 185 gastric carcinomas and its expression was closely associated with GKN1 immunonegativity. There was no significant relationship between altered expression of SOX9 protein and clinicopathological parameters including overall survival. CONCLUSION: These data suggest that aberrant SOX9 expression by GKN1 inactivation may be involved in the development of sporadic gastric cancers as an early event. PMID- 23812905 TI - A phase II study of combined VEGF inhibitor (bevacizumab+sorafenib) in patients with metastatic breast cancer: Hoosier Oncology Group Study BRE06-109. AB - PURPOSE: Angiogenesis plays an essential role in tumor development, invasion and metastasis. We evaluated the efficacy and safety of dual angiogenesis blockade with bevacizumab and sorafenib in patients with metastatic breast cancer. PATIENTS AND METHODS: Patients who had received no more than 2 prior chemotherapy regimens in any setting were treated with sorafenib 200 mg as a single oral dose daily plus bevacizumab intravenously 5 mg/kg every other week. Response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST). The primary endpoint was progression free survival (PFS). RESULTS: Eighteen patients were enrolled. Median age was 56 yo, all had good performance status KPS of 0 or 1, and 17 patients had received 1 or 2 prior chemotherapy regimens. Median PFS was 2.8 months. There were no complete or partial responses; 3 patients had stable disease for >6 months. Toxicity was substantial with 9 (50 %) patients reporting Grade 3 toxicity. Seven (39 %) patients discontinued therapy due to adverse events including hypertension (N=2), GI toxicity (N=1), sensory neuropathy (N=1), rash (N=1), pain (N=1) and wound complication (N=1). Given the lack of clear efficacy and increased toxicity, accrual was terminated. CONCLUSION: The combination of sorafenib and bevacizumab has substantial toxicity and minimal efficacy in patients with previously treated metastatic breast cancer. Further study of this combination is not recommended. PMID- 23812906 TI - Collective efficacy as a task specific process: examining the relationship between social ties, neighborhood cohesion and the capacity to respond to violence, delinquency and civic problems. AB - In the neighborhood effects literature, collective efficacy is viewed as the key explanatory process associated with the spatial distribution of a range of social problems. While many studies usefully focus on the consequences of collective efficacy, in this paper we examine the task specificity of collective efficacy and consider the individual and neighborhood factors that influence residents' perceptions of neighborhood collective efficacy for specific tasks. Utilizing survey and administrative data from 4,093 residents nested in 148 communities in Australia, we distinguish collective efficacy for particular threats to social order and assess the relative importance of social cohesion and neighborhood social ties to the development of collective efficacy for violence, delinquency and civic/political issues. Our results indicate that a model separating collective efficacy for specific problems from social ties and the more generalized notions of social cohesion is necessary when understanding the regulation potential of neighborhoods. PMID- 23812907 TI - Predictors of psychological well-being and stress among Jordanian menopausal women. AB - PURPOSE: The aim of this study was to investigate purpose in life, self acceptance, perceived stress levels, and menopausal symptoms among Jordanian women. METHODS: A descriptive, correlational design with a convenience sample of 193 women aged 40-55 years was employed. RESULTS: The average age at menopause for the current sample was 47.4 years, and menopausal status did not significantly affect purpose in life, self-acceptance, or perceived stress levels. Negative correlations were found between purpose in life and perceived stress, and between self-acceptance and perceived stress (r = -0.49; p = 0.01 and r = -0.58; p = 0.01, respectively). Menopausal symptoms were found to be a strong negative predictor of purpose in life, self-acceptance, and perceived stress levels. In addition, higher health rating was significantly associated with higher psychological well-being and lower perceived stress levels. Perimenopause was found to be a vulnerable stage for severe menopausal symptoms particularly psychological complaints. However, vasomotor symptoms and loss of sexual interest became more intense among postmenopausal women. Although women in the current study had low psychological well-being and high perceived stress, these were not affected by their menopausal status. CONCLUSION: The study showed the importance of including both physical and psychological symptoms during encounters with health professionals, besides considering women's expectations about menopause to help ease their menopausal transition and improve their well-being. PMID- 23812908 TI - On homology modeling of the M2 muscarinic acetylcholine receptor subtype. AB - Twelve homology models of the human M2 muscarinic receptor using different sets of templates have been designed using the Prime program or the modeller program and compared to crystallographic structure (PDB:3UON). The best models were obtained using single template of the closest published structure, the M3 muscarinic receptor (PDB:4DAJ). Adding more (structurally distant) templates led to worse models. Data document a key role of the template in homology modeling. The models differ substantially. The quality checks built into the programs do not correlate with the RMSDs to the crystallographic structure and cannot be used to select the best model. Re-docking of the antagonists present in crystallographic structure and relative binding energy estimation by calculating MM/GBSA in Prime and the binding energy function in YASARA suggested it could be possible to evaluate the quality of the orthosteric binding site based on the prediction of relative binding energies. Although estimation of relative binding energies distinguishes between relatively good and bad models it does not indicate the best one. On the other hand, visual inspection of the models for known features and knowledge-based analysis of the intramolecular interactions allows an experimenter to select overall best models manually. PMID- 23812910 TI - Can the diagnosis of NF1 be excluded clinically? A lack of pigmentary findings in families with spinal neurofibromatosis demonstrates a limitation of clinical diagnosis. AB - BACKGROUND: Consensus clinical diagnostic criteria for neurofibromatosis type I (NF1) include cafe-au-lait macules and skinfold freckling. The former are frequently the earliest manifestation of NF1, and as such are of particular significance when assessing young children at risk of the condition. A phenotype of predominantly spinal neurofibromatosis has been identified in a small minority of families with NF1, often in association with a relative or absolute lack of cutaneous manifestations. An association with splicing and missense mutations has previously been reported for spinal neurofibromatosis, but on the basis of molecular results in only a few families. METHOD: Patients with spinal NF1 were identified through the Manchester nationally commissioned service for complex NF1. RESULTS: Five families with spinal NF1 were identified, with a broad spectrum of NF1 mutations, providing further evidence that this phenotype may arise in association with any genre of mutation in this gene. Pigmentary manifestations were absent or very mild in affected individuals. Several further affected individuals, some with extensive spinal root tumours, were ascertained when additional family members were assessed. CONCLUSIONS: Clinical NF1 consensus criteria cannot be used to exclude the diagnosis of spinal NF1, especially in childhood. This emphasises the importance of molecular confirmation in individuals and families with atypical presentations of NF1. PMID- 23812911 TI - Comparison of the clinical scoring systems in Silver-Russell syndrome and development of modified diagnostic criteria to guide molecular genetic testing. AB - BACKGROUND: About half of all children with a clinical diagnosis of Silver Russell syndrome (SRS) have a detectable molecular genetic abnormality (maternal uniparental disomy of chromosome upd(7)mat or hypomethylation of H19 differentially methylated region (DMR). The selection of children for molecular genetic testing can be difficult for non-specialists because of the broad phenotypic spectrum of SRS and the tendency of the facial features to mitigate during late childhood. Several clinical scoring systems for SRS have been developed by specialist researchers, but the utility of these for guiding molecular genetic testing in routine clinical practice has not been established. OBJECTIVES: To evaluate the utility of four published clinical scoring systems for genetic testing in a cohort of patients referred to a clinical service laboratory. PATIENTS: Individuals with suspected SRS referred for molecular genetic testing of H19 DMR methylation status or upd(7)mat. RESULTS: 36 of 139 (25.9%) patients referred for testing had a genetic abnormality identified. Comparison of four published clinical scoring systems demonstrated that all included subjective criteria that could be difficult for the general clinician to assess. We developed a novel, simplified, scoring system utilising four objective, easily measured parameters that performed similarly to the most sensitive and specific published scoring system. DISCUSSION: Effective utilisation of genetic testing by clinicians without specialist clinical genetics training will be facilitated by the development of targeted testing protocols that are based on robust objective clinical features and are designed for use in a busy clinical practice rather than a research setting. PMID- 23812909 TI - FGFR1 mutations cause Hartsfield syndrome, the unique association of holoprosencephaly and ectrodactyly. AB - BACKGROUND: Harstfield syndrome is the rare and unique association of holoprosencephaly (HPE) and ectrodactyly, with or without cleft lip and palate, and variable additional features. All the reported cases occurred sporadically. Although several causal genes of HPE and ectrodactyly have been identified, the genetic cause of Hartsfield syndrome remains unknown. We hypothesised that a single key developmental gene may underlie the co-occurrence of HPE and ectrodactyly. METHODS: We used whole exome sequencing in four isolated cases including one case-parents trio, and direct Sanger sequencing of three additional cases, to investigate the causative variants in Hartsfield syndrome. RESULTS: We identified a novel FGFR1 mutation in six out of seven patients. Affected residues are highly conserved and are located in the extracellular binding domain of the receptor (two homozygous mutations) or the intracellular tyrosine kinase domain (four heterozygous de novo variants). Strikingly, among the six novel mutations, three are located in close proximity to the ATP's phosphates or the coordinating magnesium, with one position required for kinase activity, and three are adjacent to known mutations involved in Kallmann syndrome plus other developmental anomalies. CONCLUSIONS: Dominant or recessive FGFR1 mutations are responsible for Hartsfield syndrome, consistent with the known roles of FGFR1 in vertebrate ontogeny and conditional Fgfr1-deficient mice. Our study shows that, in humans, lack of accurate FGFR1 activation can disrupt both brain and hand/foot midline development, and that FGFR1 loss-of-function mutations are responsible for a wider spectrum of clinical anomalies than previously thought, ranging in severity from seemingly isolated hypogonadotropic hypogonadism, through Kallmann syndrome with or without additional features, to Hartsfield syndrome at its most severe end. PMID- 23812912 TI - West syndrome, microcephaly, grey matter heterotopia and hypoplasia of corpus callosum due to a novel ARFGEF2 mutation. AB - West syndrome (WS) is an epileptic encephalopathy of childhood, defined by the presence of clustered spasms usually occurring before the age of 1 year, hypsarrhythmia on EEG that is notoriously difficult to define, and developmental arrest or regression. The incidence of WS is 1:3200 live births with an aetiology dependent prognosis. Up to 80% of children with symptomatic WS suffer from mental retardation, and approximately 50% develop Lennox-Gastaut syndrome. Using homozygosity mapping followed by exome sequencing, we identified a ADP ribosylation factor (ARF) guanine nucleotide-exchange factor two (brefeldin A inhibited) (ARFGEF2) mutation in five related infants with WS. ARFGEF2 is involved in the activation of ARFs by accelerating replacement of bound guanosine diphosphate (GDP) with Guanosine triphosphate (GTP), and is involved in Golgi transport. A mutation in ARFGEF2 has been previously described only once, causing microcephaly and periventricular heterotopia. Here, we describe a novel ARFGEF2 mutation in five related patients presenting with WS, microcephaly, periventricular heterotopia and thin corpus callosum. PMID- 23812913 TI - The interaction between alerting and executive control: dissociating phasic arousal and temporal expectancy. AB - In recent years, studies have revealed an interaction between two systems of attention-alerting and executive control. Specifically, warning cues increase the influence of cognitive conflict under certain conditions. One of the problems of interpreting this effect is that warning cues can trigger two processes simultaneously-a high arousal state and strategic temporal expectancy. The goal of the present study was to clarify which process underlies the increased congruency effects following a warning event. In two experiments, the influence of warning cues on flanker congruency was examined while controlling for the effects of temporal expectancy and arousal. Experiment 1 revealed a strong effect of warning cues on congruency, even when the warning cues were not temporally predictive. This effect was evident at two short cue-to-target intervals of 100 and 500 ms, but not following a 900-ms interval. Experiment 2 revealed that this effect was not altered even when the warning cues predicted with high certainty that the target would appear at long cue-to-target intervals (e.g., 900 ms). We suggest that the interaction between alerting and executive control reflects the involvement of a subcortical mechanism responsible for increasing arousal. PMID- 23812914 TI - A state dependent pulse control strategy for a SIRS epidemic system. AB - With the consideration of mechanism of prevention and control for the spread of infectious diseases, we propose, in this paper, a state dependent pulse vaccination and medication control strategy for a SIRS type epidemic dynamic system. The sufficient conditions on the existence and orbital stability of positive order-1 or order-2 periodic solution are presented. Numerical simulations are carried out to illustrate the main results and compare numerically the state dependent vaccination strategy and the fixed time pulse vaccination strategy. PMID- 23812915 TI - Segmentectomy for c-T1N0M0 non-small cell lung cancer. AB - While the use of segmentectomy to treat lung cancer remains controversial, it has recently gained status as a radical surgery for cT1aN0M0 non-small cell lung cancer. I herein review the literature regarding segmentectomy and present my data to discuss the following issues: the prognosis after segmentectomy; local recurrence; the area required for lymph node dissection at the hilum and mediastinum; the technique used to cut the intersegmental plane; the selection of the lymph nodes for frozen sections; the postoperative pulmonary function; the role of completion lobectomy after radical segmentectomy for cT1N0M0/pN1-2; expectations and concerns regarding the randomized controlled trial JCOG0802; and the future of segmentectomy. PMID- 23812917 TI - ["We have to talk"]. PMID- 23812916 TI - Surgical treatment of gastric cancer in a community hospital in Brazil: who are we treating and how? AB - PURPOSE: Surgical treatment of gastric cancer has risks, and the current trend in developed countries is to centralize cases in high-volume centers. Many countries, however, particularly the developing ones, have to rely in low-volume centers for the most part of gastric cancer operations. We aimed to verify the characteristics of the patients and tumors as well as the in-hospital outcomes in a community hospital in Brazil treating gastric cancer. METHODS: This is a retrospective study on patients undergoing surgical treatment of gastric adenocarcinoma at a community hospital in Brazil. The authors reviewed demographic, clinical, pathological, and perioperative data. RESULTS: A total of 28 patients were operated on during the study period. Mean age was 69.5 years, 53.6% were male, 67.9% had anemia, 78.5% had ASA score >= 3, 89.3% were at nutritional risk, intestinal/diffuse ratio was 1.6, 68.5% had tumor >= 6 cm, involvement of lower/middle third of the stomach occurred in 96.4%, 73.7% had serosal invasion, 79% had stage III disease, median number of dissected nodes was 23, median operative time was 255 min, 21.4% had urgent procedures, 67.8% had curative surgery, 50% had distal gastrectomy, 43.5% had a Billroth I, median length of stay was 17 days, 53.6% had some admission to the intensive care unit, 21.4% required relaparotomy, 25% had wound infection/dehiscence, and mortality was 66.7/18.2% (urgent/non-urgent surgery). CONCLUSION: We treat elderly malnourished patients with multiple comorbidities and advanced cancer. Improvement is required in lymph node dissection, non-surgical therapies, and critical care. PMID- 23812918 TI - [Maternal-placental interactions and fetal programming]. AB - Pregnancy-related complications not only represent a risk for maternal and fetal morbidity and mortality, but are also a risk for several diseases later in life. Many epidemiological studies have shown clear associations between an adverse intrauterine environment and an increased risk of diabetes, hypertension, cardiovascular disease, depression, obesity, and other chronic diseases in the adult. Some of these syndromes could be prevented by avoiding adverse stimuli or insults including psychological stress during pregnancy, intake of drugs, insufficient diet and substandard working conditions. Hence, all of these stimuli have the potential to alter health later in life. The placenta plays a key role in regulating the nutrient supply to the fetus and producing hormones that control the fetal as well as the maternal metabolism. Thus, any factor or stimulus that alters the function of the hormone producing placental trophoblast will provoke critical alterations of placental function and hence could induce programming of the fetus. The factors that change placental development may interfere with nutrient and oxygen supply to the fetus. This may be achieved by a direct disturbance of the placental barrier or more indirectly by, e. g., disturbing trophoblast invasion. For both path-ways, the respective pathologies are known: while preeclampsia is caused by alterations of the villous trophoblast, intra-uterine growth restriction is caused by insufficient invasion of the extravillous trophoblast. In both cases the effect can be undernutrition and/or fetal hypoxia, both of which adversely affect organ development, especially of brain and heart. However, the mechanisms responsible for disturbances of trophoblast differentiation and function remain elusive. PMID- 23812919 TI - [Individual neonatal end-of-life care and family-centred bereavement support]. AB - Neonatal end-of-life care and family-centred bereavement support in perinatal medicine are a multiprofessional challenge directed to the dying newborn and the parents as well as to the care-givers. Clinical experience shows that many aspects of individual neonatal end-of-life care and family-centred bereavement support are not well known to the health-care providers. This is especially true for a standardised quality management and the components of bereavement support offered to parents. An interdisciplinary concept for an individual neonatal end of-life care and famlily-centred bereavement support has been developed at the Center of Perinatal Medicine at the Charite, Berlin. The concept aims for two main aspects: (1) meeting the individual medical, psychological, emotional and spiritual needs of the dying newborn, the parents and family, and (2) facilitating standardised and process-orientated preparation, evaluation and reflexion of every case of end-of-life care. In this article some recommendations for implementing a basic care concept for families and their dying newborns are presented. PMID- 23812920 TI - [Psychosocial child development after successful infertility treatment]. AB - The long-term development of children after assisted reproduction, especially the physical, mental and social development, has attracted increasing interest. Most studies are focused on singletons after ART compared to those after spontaneous conception. A distinction is made between health, cognitive and psychosocial development. Studies report on hospital admissions of children after ART without a specific reason. ART children exhibit an increased manifestation of malformations, especially in the urogenital tract of the boys. The cognitive development of children does not differ fundamentally in singleton preschool children. Child behaviour and parental stress at the of age 5-8 years after ART did not differ significantly to those after spontaneous conception. In a small sample (n=87) after ICS some children were found to have an autistic spectrum disorder. Adolescents after ART were compared to adolescents after SC, no differences in psychosocial adjustment were apparent. Recent studies confirm that there are no fundamental differences in the development of children after ART in comparison to spontaneously conceived children. PMID- 23812921 TI - [Changes in the somatic classification according to birth weight and duration of pregnancy of newborn girls when maternal height is considered]. AB - This study examines the quantitative changes in the somatic classification according to birth weight and duration of pregnancy of German neonates when maternal height is considered (5 maternal height groups). Our calculations were performed using data of 319 884 girls born in 2010. Overall, about 6% (18 792 girls) are classified differently (more appropriately) when group-specific norm values were used. PMID- 23812922 TI - Early-onset diffuse gastric cancer associated with a de novo large genomic deletion of CDH1 gene. AB - A 41-year-old man with no familial history of gastric cancer was diagnosed as with intramucosal early gastric cancer. Two months after the first endoscopic submucosal dissection for signet-ring cell carcinoma (SRCC), the appearance of previously unrecognized multiple erosions of SRCC was noticed. Pathological examination after a total gastrectomy and Roux-en-Y reconstruction with D2 lymph node dissection were performed. Postoperative pathological examination revealed 90 and more lesions, which tempted the attending pathologist to refer to genetic tests for the predisposition though the patient had no familial history of gastric cancer. There were no mutations in all the exons of CDH1 with conventional DNA sequencing, but multiplex ligation-dependent probe amplification, and reverse transcription-polymerase chain reaction analyses disclosed a large genomic deletion (c.1566-?_1711+?del), leading to the mRNA with loss of the exon 11. Among family members, his son was found to be a carrier of this change, while his parents were negative for the familial CDH1 mutation, implying that this change is a de novo event in the proband. The present report is the first description of a de novo large genomic deletion of CDH1 gene associated with early-onset diffuse gastric cancer. When the clinician finds a relatively-young patient who has multiple SRCCs, CDH1 germline mutation should be considered, even for patients with no familial history. PMID- 23812923 TI - Efficacy and safety of new oral anticoagulants for extended treatment of venous thromboembolism: systematic review and meta-analyses of randomized controlled trials. AB - INTRODUCTION: Currently available anticoagulants have limitations for long term treatment of venous thromboembolism (VTE). OBJECTIVE: A meta-analysis was performed to evaluate the efficacy and safety of new oral anticoagulants (NOACs) for extended treatment of VTE. METHODS: PubMed, Cochrane Library, EMBASE, Web of Science and CINAHL databases were searched from January 01, 2001 through February 28, 2013. Randomized controlled trials (RCTs) comparing NOACs (apixaban, rivaroxaban and dabigatran) with placebo or warfarin for extended treatment of VTE were selected. Primary efficacy outcome was recurrent VTE or VTE related death, and primary safety outcome was major bleeding. We used random-effects models. RESULTS: Four RCTs included 7,877 participants. NOACs significantly lowered the risk of recurrent VTE or VTE-related death compared to placebo/warfarin (odds ratio [OR] 0.25, 95 % confidence interval [CI] 0.07 to 0.86; number needed to treat [NNT] = 30). All-cause mortality was significantly lower in NOACs group compared to placebo (OR 0.38, 95 % CI 0.18 to 0.80). Risk of major bleeding was not different with NOACs compared to placebo/warfarin (OR 0.88, 95 % CI 0.27 to 2.91). However, NOACs caused significantly higher rate of major or clinically relevant bleeding compared to placebo (OR 2.69, 95 % CI 1.25 to 5.77; number needed to harm [NNH] = 39). All three NOACs (apixaban, rivaroxaban and dabigatran) individually significantly reduced recurrent VTE or VTE-related death compared to placebo. Major or clinically relevant bleeding was higher with dabigatran and rivaroxaban but not with apixaban. CONCLUSION: NOACs are effective for the extended treatment of venous thromboembolism and may reduce the risk of all-cause mortality. Dabigatran and rivaroxaban may cause more major or clinically relevant bleeding. PMID- 23812925 TI - Feeling entitled to more: ostracism increases dishonest behavior. AB - Five experiments tested whether ostracism increases dishonesty through increased feelings of entitlement. Compared with included and control participants, ostracized participants indicated higher levels of dishonest intentions (Experiments 1-3) and cheated more to take undeserved money in a behavioral task (Experiments 4 and 5). In addition, increased feelings of entitlement mediated the effect of ostracism on dishonesty (Experiments 3-5). Framing ostracism as beneficial weakened the connection between ostracism, entitlement, and dishonest behavior (Experiment 5). Together, these findings highlight the significance of entitlement in explaining when and why ostracism increases dishonest behavior and how to weaken this relationship. PMID- 23812926 TI - When suppressing one stereotype leads to rebound of another: on the procedural nature of stereotype rebound. AB - A known consequence of stereotype suppression is post-suppressional rebound (PSR), an ironic activation of the suppressed stereotype. This is typically explained as an unintended by-product from a dual-process model of mental control. Relying on this model, stereotype rebound is believed to be conceptual. Alternative accounts predict PSR to be featural or procedural. According to the latter account, stereotype rebound would not be limited to the suppressed social category, but could occur for a target from any social category. The occurrence of procedural stereotype rebound was examined across five experiments. Suppression of one particular stereotype consistently led to rebound for social targets belonging to the same or a different stereotype in an essay-writing task (Experiments 1-3) and led to facilitation in recognition of stereotype-consistent words (Experiment 4). Finally, stereotype suppression was shown to impact on assessments of stereotype use but not on heuristic thinking (Experiment 5). PMID- 23812924 TI - Omalizumab: a review of its use in patients with severe persistent allergic asthma. AB - Omalizumab (Xolair((r))) is a subcutaneously administered monoclonal antibody that targets circulating free IgE and prevents its interaction with the high affinity IgE receptor (FCepsilonRI), thereby interrupting the allergic cascade. In the EU, the drug is approved as add-on therapy in adults, adolescents and children aged >=6 years with severe persistent allergic asthma. In well designed clinical trials, add-on omalizumab significantly reduced the asthma exacerbation rate (primary endpoint) compared with placebo in adults, adolescents and children with severe persistent allergic asthma. Furthermore, add-on omalizumab reduced the need for inhaled corticosteroids in adults and adolescents, and improved asthma control and symptoms, and asthma-related quality of life in all age groups. The efficacy of omalizumab was also demonstrated in the real-world setting, with add-on therapy leading to reduced rates of hospitalizations, emergency room visits and unscheduled doctor's visits, as well as improvements in asthma symptom scores and the physician's overall assessment of treatment response. More data are needed to determine the optimum duration of treatment, and currently the duration is at the discretion of the treating physician. Omalizumab was generally well tolerated in clinical trials; the most common adverse event was transient injection-site reactions. In cost-utility analyses modelled over a life-time horizon, add-on omalizumab was cost effective compared with standard therapy, with incremental cost-effectiveness ratios falling within generally accepted willingness-to-pay thresholds. Thus, in difficult-to-treat patients with severe persistent allergic asthma, omalizumab provides a valuable treatment option. PMID- 23812927 TI - Changing me to keep you: state jealousy promotes perceiving similarity between the self and a romantic rival. AB - Individuals sometimes alter their self-views to be more similar to others- traditionally romantic partners--because they are motivated to do so. A common motivating force is the desire to affiliate with a partner. The current research examined whether a different motivation--romantic jealousy--might promote individuals to alter their self-views to be more similar to a romantic rival, rather than a partner. Romantic jealousy occurs when individuals perceive a rival as a threat to their relationship and motivates individuals to defend their relationship. We proposed that one novel way that individuals might defend their relationship is by seeing themselves as more similar to a perceived romantic rival. We predicted individuals would alter their self-views to be more similar to a rival that they believed their partner found attractive. Importantly, we predicted that state romantic jealousy would motivate these self-alterations. Three studies confirmed these hypotheses. PMID- 23812928 TI - Getting it on versus getting it over with: sexual motivation, desire, and satisfaction in intimate bonds. AB - Across three studies, we demonstrate that pursuing sex for approach goals, such as to enhance intimacy, fuels satisfaction and pursuing sex for avoidance goals, such as to avoid disappointing a partner, detracts from satisfaction. In Study 1, we use hypothetical scenarios to provide experimental support for the associations between sexual goals and sexual and relationship satisfaction. In Study 2, a dyadic daily experience study of dating couples, we demonstrate that daily sexual goals are associated with both partners' daily relationship and sexual satisfaction. In Study 3, a dyadic daily experience study, we replicate the daily associations between sexual goals and satisfaction in a sample of long term couples, and demonstrate that sexual goals impact partner's relationship and sexual quality 4 months later. In all studies, the associations between sexual goals and enhanced satisfaction as reported by both partners were mediated by sexual desire. Implications for research on sexual motivation and close relationships are discussed. PMID- 23812929 TI - Attachment and parental divorce: a test of the diffusion and sensitive period hypotheses. AB - One of the assumptions of attachment theory is that disruptions in parental relationships are prospectively related to insecure attachment patterns in adulthood. The majority of research that has evaluated this hypothesis, however, has been based on retrospective reports of the quality of relationships with parents-research that is subject to retrospective biases. In the present research, the authors examined the impact of parental divorce-an event that can be assessed relatively objectively-on attachment patterns in adulthood across two samples. The data indicate that parental divorce has selective rather than diffuse implications for insecure attachment. Namely, parental divorce was more strongly related to insecure relationships with parents in adulthood than insecure relationships with romantic partners or friends. In addition, parental insecurity was most pronounced when parental divorce took place in early childhood. This finding is consistent with hypotheses about sensitive periods in attachment development. PMID- 23812930 TI - Lenalidomide plus cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab is safe and effective in untreated, elderly patients with diffuse large B-cell lymphoma: a phase I study by the Fondazione Italiana Linfomi. AB - Despite improvements in standard therapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone for patients with untreated, diffuse large B-cell lymphoma, up to 40% of these patients relapse. Lenalidomide alone or in combination with rituximab has been shown to be active in relapsed/refractory aggressive lymphomas. In this phase I study we determined the maximum tolerated dose of lenalidomide plus rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone in untreated, elderly (median age 68 years) patients with diffuse large B-cell lymphoma. Four lenalidomide doses (5, 10, 15, and 20 mg/day on days 1-14) allocated using the continual reassessment method were planned to be administered for 14 days in combination with each course of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone for a total of six courses. Seven cohorts of patients (n=3 in each cohort) were treated (total n=21) at 10, 20, 15, 15, 15, 10, and 10 mg of lenalidomide. Dose-limiting toxicities occurred in seven patients during the first three courses of treatment. The third dose-level of lenalidomide (15 mg/day) was selected as the maximum tolerated dose, with an estimated probability of dose-limiting toxicities of 0.345 (95% credibility interval 0.164-0.553). Grade 3-4 hematologic adverse events were: neutropenia in 28% of the courses, thrombocytopenia in 9%, and anemia in 3%. Non hematologic toxicities were moderate: grade 4 increase of creatinine phosphokinase (n=1), grade 3 cardiac (n=2), grade 3 neurological (n=3), and grade 3 gastrointestinal (n=1). In this phase I study, the overall response rate was 90%, with 81% achieving complete remission. This combination regimen appears safe in elderly patients with diffuse large B-cell lymphoma and its efficacy will be assessed in the ongoing phase II trial. This trial was registered at www.clinicaltrials.gov as NCT00907348. PMID- 23812931 TI - Schnitzler syndrome: an under-diagnosed clinical entity. AB - Schnitzler syndrome is considered to be a rare disorder characterized by a monoclonal IgM protein and chronic urticaria that is associated with considerable morbidity. We hypothesized that the syndrome may be under-recognized and patients may be deprived of highly effective therapy in the form of anakinra. We performed a retrospective search of the dysproteinemia database at Mayo Clinic as well as the medical records of all patients with chronic urticaria to determine the true incidence of the disease. We compared patients with the diagnosis of Schnitzler syndrome and those who met the criteria but in whom the syndrome was not recognized. Comparisons between groups were performed and survival curves determined. We identified 16 patients with diagnosed Schnitzler syndrome and an additional 46 patients who met diagnostic criteria. The monoclonal protein was IgMkappa in 94% of patients. Therapy with anakinra in 4 patients led to rapid and complete resolution of symptoms. The median overall survival for this syndrome is over 12.8 years. Progression to lymphoma was only observed in 8% of patients; this is lower than previous reports. Schnitzler syndrome may be present in up to 1.5% of patients with a monoclonal IgM in their serum and likely under-recognized as a clinical syndrome. PMID- 23812932 TI - Single agent bevacizumab for myelofibrosis: results of the Myeloproliferative Disorders Research Consortium Trial. AB - The myeloproliferative neoplasm, myelofibrosis, is a morbid and frequently fatal illness encompassing primary myelofibrosis, and end-stage essential thrombocythemia and polycythemia. Bevacizumab (15 mg/kg intravenous (i.v.) every 21 days) was tested in a phase II international trial conducted by the Myeloproliferative Disorders Research Consortium. Thirteen patients were enrolled in the first stage of this 2-stage trial. Among the 11 patients who received therapy, only 3 received more than 4 cycles of therapy; none of the patients achieved an objective response. Furthermore, significant toxicity, not directly related to the vascular or gastrointestinal events typically associated with the anti-VEGF monoclonal antibody preparation in other disease states, was observed. Lack of objective responses coupled with toxicity led to the decision to terminate the study early. If future studies incorporate bevacizumab in combination therapy for myelofibrosis, more modest doses should be considered. (clinicaltrials.gov Identifier 00667277). PMID- 23812933 TI - Population-based incidence of myeloid malignancies: fifteen years of epidemiological data in the province of Girona, Spain. PMID- 23812934 TI - BubR1 is frequently repressed in acute myeloid leukemia and its re-expression sensitizes cells to antimitotic therapy. AB - Spindle poison-based therapy is of only limited benefit in acute myeloid leukemia while lymphoblastic leukemia/lymphoma responds well. In this study, we demonstrated that the spindle assembly checkpoint protein BubR1 was down regulated in the vast majority of cases of acute myeloid leukemia whereas its expression was high in lymphoblastic cells. Correct function of the spindle assembly checkpoint is pivotal in mediating mitotic delay in response to spindle poisons. Mitotic delay by the spindle assembly checkpoint is achieved by inhibition of anaphase-promoting complex-dependent proteolysis of cyclin B and securin. We demonstrated a link between the repression of the spindle assembly checkpoint protein BubR1 in acute myeloid leukemia and the limited response to spindle poison. In accordance with its established role as an anaphase-promoting complex-inhibitor, we found that repression of BubR1 was associated with enhanced anaphase-promoting complex activity and cyclin B and securin degradation, which leads to premature sister-chromatid separation and failure to sustain a mitotic arrest. This suggests that repression of BubR1 in acute myeloid leukemia renders the spindle assembly checkpoint-mediated inhibition of the anaphase-promoting complex insufficient, which facilitates completion of mitosis in the presence of spindle poison. As both direct and BubR1-mediated restoration of cyclin B expression enhanced response to spindle poison, we propose that the downstream axis of the spindle assembly checkpoint is a promising target for tailored therapies for acute myeloid leukemia. PMID- 23812935 TI - Subsequent donation requests among 2472 unrelated hematopoietic progenitor cell donors are associated with bone marrow harvest. AB - Approximately 1 in 20 unrelated donors are asked to make a second donation of hematopoietic progenitor cells, the majority for the same patient. Anthony Nolan undertook a study of subsequent hematopoietic progenitor cell donations made by its donors from 2005 to 2011, with the aims of predicting those donors more likely to be called for a second donation, assessing rates of serious adverse reactions and examining harvest yields. This was not a study of factors predictive of second allografts. During the study period 2591 donations were made, of which 120 (4.6%) were subsequent donations. The median time between donations was 179 days (range, 21-4016). Indications for a second allogeneic transplant included primary graft failure (11.7%), secondary graft failure (53.2%), relapse (30.6%) and others (1.8%). On multivariate analysis, bone marrow harvest at first donation was associated with subsequent donation requests (odds ratio 2.00, P=0.001). The rate of serious adverse reactions in donors making a subsequent donation appeared greater than the rate in those making a first donation (relative risk=3.29, P=0.005). Harvest yields per kilogram recipient body weight were equivalent between donations, although females appeared to have a lower yield at the subsequent donation. Knowledge of these factors will help unrelated donor registries to counsel their donors. PMID- 23812936 TI - Erythroid cells generated in the absence of specific beta1-integrin heterodimers accumulate reactive oxygen species at homeostasis and are unable to mount effective antioxidant defenses. AB - We have previously reported that beta1(Delta/Delta) mice have a markedly impaired response to hemolytic stress, but the mechanisms of this were unclear. In the present study we explored in detail quantitative, phenotypic and functional aspects of erythropoiesis at homeostasis in a large number of animals for each of 3 murine models with specific beta1 heterodimer integrin deficiencies. We found that, at homeostasis, beta1-deficient mice have a modest uncompensated anemia with ineffective erythropoiesis and decreased red blood cell survival. Mice lacking only alpha4 integrins (alpha4beta1/alpha4beta7) do not share this phenotype. There is an increased tendency for reactive oxygen species accumulation in beta1(Delta/Delta) erythroid cells with decreased anti-oxidant defenses at homeostasis which are exaggerated after stress. Furthermore, expansion of erythroid cells in spleen post-stress is dependent on alpha5beta1, likely through mechanisms activating focal adhesion kinase complexes that are distinct from alpha4beta1-mediated responses. In vivo inhibition of focal adhesion kinase activation partially recapitulates the beta1(Delta/Delta) stress response. Mice lacking all alpha4 and beta1 integrins (double knockouts) had, at homeostasis, the most severe phenotype with selective impairment of erythroid responses. The fact that integrins participate in mitigating stress in erythroid cells through redox activation of distinct signaling pathways by specific integrin heterodimers is a link that has not been appreciated until now. PMID- 23812937 TI - Cytoplasmic localization of wild-type survivin is associated with constitutive activation of the PI3K/Akt signaling pathway and represents a favorable prognostic factor in patients with acute myeloid leukemia. AB - Survivin is over-expressed in most hematologic malignancies but the prognostic significance of the subcompartmental distribution of wild-type or splicing variants in acute myeloid leukemia has not been addressed yet. Using western blotting, we assessed the expression of wild-type survivin and survivin splice variants 2B and Delta-Ex3 in nuclear and cytoplasmic protein extracts in samples taken from 105 patients at the time of their diagnosis of acute myeloid leukemia. Given that survivin is a downstream effector of the PI3K/Akt signaling pathway, survivin expression was also correlated with pSer473-Akt. Wild-type survivin and the 2B splice variant were positive in 76.3% and 78.0% of samples in the nucleus, cytoplasm or both, whereas the Delta-Ex3 isoform was only positive in the nucleus in 37.7% of samples. Cytoplasmic localization of wild-type survivin was significantly associated with the presence of high levels of pSer473-Akt (P<0.001). Inhibition of the PI3K/Akt pathway with wortmannin and Ly294002 caused a significant reduction in the expression of cytoplasmic wild-type survivin. The presence of cytoplasmic wild-type survivin and pSer473-Akt was associated with a lower fraction of quiescent leukemia stem cells (P=0.02). The presence of cytoplasmic wild-type survivin and pSer473-Akt were favorable independent prognostic factors. Moreover, the activation of the PI3K/Akt pathway with expression of cytoplasmic wild-type survivin identified a subgroup of acute myeloid leukemia patients with an excellent outcome (overall survival rate of 60.0+/-21.9% and relapse-free survival of 63.0+/-13.5%). Our findings suggest that cytoplasmic wild-type survivin is a critical downstream effector of the PI3K/Akt pathway leading to more chemosensitive cells and a more favorable outcome in acute myeloid leukemia. PMID- 23812938 TI - South-Italy beta degrees -thalassemia: a novel deletion not removing the gamma globin silencing element and with 3' breakpoint in a hsRTVL-H element, associated with beta degrees -thalassemia and high levels of HbF. PMID- 23812939 TI - International survey of T2* cardiovascular magnetic resonance in beta-thalassemia major. AB - Accumulation of myocardial iron is the cause of heart failure and early death in most transfused thalassemia major patients. T2* cardiovascular magnetic resonance provides calibrated, reproducible measurements of myocardial iron. However, there are few data regarding myocardial iron loading and its relation to outcome across the world. A survey is reported of 3,095 patients in 27 worldwide centers using T2* cardiovascular magnetic resonance. Data on baseline T2* and numbers of patients with symptoms of heart failure at first scan (defined as symptoms and signs of heart failure with objective evidence of left ventricular dysfunction) were requested together with more detailed information about patients who subsequently developed heart failure or died. At first scan, 20.6% had severe myocardial iron (T2*<= 10 ms), 22.8% had moderate myocardial iron (T2* 10-20 ms) and 56.6% of patients had no iron loading (T2*>20 ms). There was significant geographical variation in myocardial iron loading (24.8-52.6%; P<0.001). At first scan, 85 (2.9%) of 2,915 patients were reported to have heart failure (81.2% had T2* <10 ms; 98.8% had T2* <20 ms). During follow up, 108 (3.8%) of 2,830 patients developed new heart failure. Of these, T2* at first scan had been less than 10 ms in 96.3% and less than 20 ms in 100%. There were 35 (1.1%) cardiac deaths. Of these patients, myocardial T2* at first scan had been less than 10 ms in 85.7% and less than 20 ms in 97.1%. Therefore, in this worldwide cohort of thalassemia major patients, over 43% had moderate/severe myocardial iron loading with significant geographical differences, and myocardial T2* values less than 10 ms were strongly associated with heart failure and death. PMID- 23812940 TI - Blinatumomab induces autologous T-cell killing of chronic lymphocytic leukemia cells. AB - Chronic lymphocytic leukemia is an incurable B-cell malignancy that is associated with tumor cell-mediated T-cell dysfunction. It therefore represents a challenging disease for T-cell immunotherapeutics. The CD19/CD3 bi-specific antibody construct blinatumomab (AMG103 or MT103) has been tested clinically in non-Hodgkin's lymphoma and acute lymphoblastic leukemia but has not been assessed in chronic lymphocytic leukemia. We investigated whether blinatumomab could overcome T-cell dysfunction in chronic lymphocytic leukemia in vitro. Blinatumomab was tested on peripheral blood mononuclear cells from 28 patients (treatment naive and previously treated). T-cell activation and function, as well as cytotoxicity against leukemic tumor cells were measured. Blinatumomab induced T-cell activation, proliferation, cytokine secretion and granzyme B release in a manner similar to that occurring with stimulation with anti-CD3/anti-CD28 beads. However, only blinatumomab was able to induce tumor cell death and this was found to require blinatumomab-mediated conjugate formation between T cells and tumor cells. Cytotoxicity of tumor cells was observed at very low T-cell:tumor cell ratios. A three-dimensional model based on confocal microscopy suggested that up to 11 tumor cells could cluster round each T cell. Importantly, blinatumomab induced cytotoxicity against tumor cells in samples from both treatment-naive and treated patients, and in the presence of co-culture pro-survival signals. The potent cytotoxic action of blinatumomab on tumor cells appears to involve conjugation of T cells with tumor cells at both the activation and effector stages. The efficacy of blinatumomab in vitro suggests that the bi-specific antibody approach may be a powerful immunotherapeutic strategy in chronic lymphocytic leukemia. PMID- 23812941 TI - Downregulation of PPP2R5E is a common event in acute myeloid leukemia that affects the oncogenic potential of leukemic cells. PMID- 23812942 TI - Specific and global coagulation assays in the diagnosis of discrepant mild hemophilia A. AB - The activity of the factor VIII coagulation protein can be measured by three methods: a one or two-stage clotting assay and a chromogenic assay. The factor VIII activity of most individuals with mild hemophilia A is the same regardless of which method is employed. However, approximately 30% of patients show marked discrepancies in factor VIII activity measured with the different methods. The objective of this study was to investigate the incidence of assay discrepancy in our center, assess the impact of alternative reagents on factor VIII activity assays and determine the usefulness of global assays of hemostasis in mild hemophilia A. Factor VIII activity was measured in 84 individuals with mild hemophilia A using different reagents. Assay discrepancy was defined as a two fold or greater difference between the results of the one-stage and two-stage clotting assays. Rotational thromboelastometry and calibrated automated thrombography were performed. Assay discrepancy was observed in 31% of individuals; 12% with lower activity in the two-stage assay and 19% with lower activity in the one-stage assay. The phenotype could not always be predicted from the individual's genotype. Chromogenic assays were shown to be a suitable alternative to the two-stage clotting assay. Thromboelastometry was found to have poor sensitivity in hemophilia. Calibrated automated thrombography supported the results obtained by the two-stage and chromogenic assays. The current international guidelines do not define the type of assay to be used in the diagnosis of mild hemophilia A and some patients could be misclassified as normal. In our study, 4% of patients would not have been diagnosed on the basis of the one-stage factor VIII assay. Laboratories should use both one stage and chromogenic (or two-stage) assays in the diagnosis of patients with possible hemophilia A. PMID- 23812944 TI - Infrequent occurrence of mutations in the PH domain of LNK in patients with JAK2 mutation-negative 'idiopathic' erythrocytosis. PMID- 23812943 TI - Assessment at 6 months may be warranted for patients with chronic myeloid leukemia with no major cytogenetic response at 3 months. AB - Response to tyrosine kinase inhibitors at three months is a predictor for long term outcome in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. We analyzed 456 newly diagnosed chronic myeloid leukemia patients treated with tyrosine kinase inhibitors to determine their outcome based on their response at six months. Forty-four (10%) patients did not achieve major cytogenetic response at three months: 18 of 67 (27%) patients treated with imatinib 400; 18 of 196 (9%) with imatinib 800; and 8 of 193 (4%) with 2nd generation tyrosine kinase inhibitors. Among them, 19 (43%) achieved major cytogenetic response at six months and subsequently had an overall outcome similar to the patients who achieved a major cytogenetic response at three months. In conclusion, the response to tyrosine kinase inhibitors at three months is a static, one-time measure. Assessing the response at six months of patients with poor response at three months may provide a better predictor for long-term outcome. PMID- 23812945 TI - Physicochemical and biological characterization of nanocomposites made of segmented polyurethanes and Cloisite 30B. AB - Nanocomposites were prepared with segmented polyurethanes and Cloisite 30B by either solution mixing or in situ polymerization and characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, thermogravimetric analysis and X-ray diffraction. Cytotoxicity and genotoxicity were assessed with lymphocytes while cell viability was measured by the methyl tetrazolium assay using fibroblasts. It was found that in situ polymerization rendered exfoliated nanocomposites with higher glass transition temperature, tensile modulus and thermal stability compared to nanocomposites obtained by solution mixing. The mitotic index of lymphocytes was significantly reduced at high clay concentrations (6 wt% and 10 wt%), while fibroblast viability improved in the presence of extract obtained after days 2 and 7. PMID- 23812946 TI - A dual-modal magnetic nanoparticle probe for preoperative and intraoperative mapping of sentinel lymph nodes by magnetic resonance and near infrared fluorescence imaging. AB - The ability to reliably detect sentinel lymph nodes for sentinel lymph node biopsy and lymphadenectomy is important in clinical management of patients with metastatic cancers. However, the traditional sentinel lymph node mapping with visible dyes is limited by the penetration depth of light and fast clearance of the dyes. On the other hand, sentinel lymph node mapping with radionucleotide technique has intrinsically low spatial resolution and does not provide anatomic details in the sentinel lymph node mapping procedure. This work reports the development of a dual modality imaging probe with magnetic resonance and near infrared imaging capabilities for sentinel lymph node mapping using magnetic iron oxide nanoparticles (10 nm core size) conjugated with a near infrared molecule with emission at 830 nm. Accumulation of magnetic iron oxide nanoparticles in sentinel lymph nodes leads to strong T2 weighted magnetic resonance imaging contrast that can be potentially used for preoperative localization of sentinel lymph nodes, while conjugated near infrared molecules provide optical imaging tracking of lymph nodes with a high signal to background ratio. The new magnetic nanoparticle based dual imaging probe exhibits a significant longer lymph node retention time. Near infrared signals from nanoparticle conjugated near infrared dyes last up to 60 min in sentinel lymph node compared to that of 25 min for the free near infrared dyes in a mouse model. Furthermore, axillary lymph nodes, in addition to sentinel lymph nodes, can be also visualized with this probe, given its slow clearance and sufficient sensitivity. Therefore, this new dual modality imaging probe with the tissue penetration and sensitive detection of sentinel lymph nodes can be applied for preoperative survey of lymph nodes with magnetic resonance imaging and allows intraoperative sentinel lymph node mapping using near infrared optical devices. PMID- 23812947 TI - Health-related quality of life and physical, mental, and cognitive disabilities among nursing home residents in Jordan. AB - PURPOSE: To describe the physical, cognitive, psychological, and medical status of nursing home residents in Jordan. We also investigated the perceived health related quality of life of this population. METHODS: A sample of 221 nursing home residents in Jordan was recruited to participate in this study. Demographic variables and medical history were collected. In addition, all participants were assessed using health-related quality of life items (HRQOL), mini-mental state examination (MMSE), Geriatric Depression Scale (GDS), Tinetti assessment battery for gait and balance (TAB), and disability of arm, shoulder, and hand assessment (DASH). RESULTS: TAB and DASH scores were related to the following HRQOL items: self-reported general health status, the need for personal care, the need for help from others in handling routine needs, the number of days of pain, feeling sad, depressed, worried, and not getting enough sleep, and the number of days feeling very healthy and full of energy. MMSE scores were related to self reported need for personal care, the need for help from others in handling daily routine needs, and the number of days feeling pain, sad, worried, and depressed. GDS scores were related to self-reported general health status, the need for personal care, the need for help from others for handling daily routine needs, the number of pain, sad, worried, and not getting enough sleep days, and the number of days feeling healthy and full of energy. CONCLUSIONS: This study revealed a substantial impact of physical, cognitive, and psychological disabilities on HRQOL of nursing home residents in Jordan. PMID- 23812948 TI - Homology modeling and structural comparison of leucine rich repeats of Toll like receptors 1-10 of ruminants. AB - Toll-like receptors (TLRs) are transmembrane receptors composed of extra cellular leucine rich repeats (LRRs) that identify specific pathogen associated molecular patterns triggering a innate immune cascade. The LRR regions of TLR 1-10 proteins of goat (Capra hircus), sheep (Ovis aries), buffalo (Bubalus bubalis) and bovine (Bos taurus) were modeled using MODELLER 9v7 tool and validated. The similarities and variations of these 10 TLRs extracellular regions of each species were compared using online servers like FATCAT, SSM and SSAP. It was evident that the LRRs of TLRs like 1, 2, 3 and 6 showed structural convergence with <1 % RMSD deviation while TLRs like 5, 7, 8 and 9 had high divergence. Docking analysis showed that TLR 2, 3 and 7 of all the selected four ruminant species were able to bind with their corresponding ligands like Peptidoglycan (PGN), Poly I:C, Resiquimod (R-848) and Imiquimod. However, there were variations in the active site regions, interacting residues and the number of bonded interactions. Variations seen among TLR structures and their ligand binding characteristics is likely to be responsible for species and breed specific genetic resistance observed among species or breeds. PMID- 23812949 TI - Hypothetical in silico model of the early-stage intermediate in protein folding. AB - This paper presents a method for determining the structure of the early stage (ES) intermediate in the multistage protein folding process. ES structure is modeled on the basis of a limited conformational subspace of the Ramachandran plot. The model distinguishes seven structural motifs corresponding to seven local probability maxima within the limited conformational subspace. Three of these are assigned to well-defined secondary structures, while the remaining four are found to represent various types of random coils. The presented heuristic approach also provides insight into the reasons behind incorrect predictions occurring when the folding process depends on external factors (e.g., ligands, ions or other proteins) rather than on the characteristics of the backbone itself. The accuracy of the presented method is estimated at around 48 %. PMID- 23812950 TI - Pharmacogenetic influence of GST polymorphisms on anthracycline-based chemotherapy responses and toxicity in breast cancer patients: a multi-analytical approach. AB - BACKGROUND AND OBJECTIVE: Chemotherapeutic drug treatment outcomes are genetically determined. Polymorphisms in genes encoding phase II drug metabolizing enzyme glutathione-S-transferase (GST) can possibly predict treatment outcomes, and can be of prognostic significance in breast cancer patients. The aim of this study was to determine the role of genetic variations in GST in predicting response to, and toxicity of, anthracycline-based chemotherapy in breast cancer patients. METHOD: Two hundred and seven patients treated with anthracycline-based chemotherapy were genotyped for GSTM1 and GSTT1 deletion polymorphisms, and GSTP1 Ile105Val (rs1695), by polymerase chain reaction (PCR)/ PCR-restriction fragment length polymorphism (RFLP). Genetic variations were correlated with tumor response to neo-adjuvant chemotherapy (NACT) in 100 patients, and with chemo-toxicity in 207 who received adjuvant chemotherapy or NACT, using Chi-square and logistic regression. Higher order gene gene interactions with treatment outcomes were characterized by multifactor dimensionality reduction (MDR) analysis. RESULTS: In single-locus analysis, Ile/Val and Ile/Val+Val/Val genotypes of the GSTP1 Ile105Val (rs1695) polymorphism reached statistical significance with grade 2-4 anemia (P=0.019, P=0.027). On performing gene-gene interaction analysis, GSTM1 null-GSTP1 Ile/Val was significantly associated with response to NACT (P=0.032). On evaluating higher order gene-gene interaction models by MDR analysis, GSTM1 and GSTP1 Ile105Val; GSTM1 and GSTT1; and GSTT1 and GSTP1 Ile105Val showed significant association with treatment response, grade 2-4 anemia, and dose delay/reduction due to neutropenia (P=0.046, P=0.027, P=0.026), respectively. CONCLUSION: Multi analytical strategies may serve as a better tool for characterization of pharmacogenetic-based breast cancer treatment outcomes. PMID- 23812952 TI - Biological risk in the Mexican population at the turn of the 21st century. AB - Mexico has experienced changes in its demographic and epidemiologic profile accompanied by recent changes in nutrition and income. Thus, the old and the young have experienced very different environments. Using data from the Mexican National Health Nutrition Survey 2006, we examine age and sex differences in physiological status and dysregulation and assess how socioeconomic factors associate with variability in biological indicators of health. Results indicate that young people have experienced better physical development as evidenced by their being taller and having less stunting. There is currently little under nutrition in Mexico, but there is evidence of over-nutrition as indicated by high prevalence of overweight across the age range. Physiological dysregulation across multiple systems is higher in Mexicans than Americans across all ages. Mexicans have: higher levels of blood pressure, plasma glucose, and especially for women, dysregulated cholesterol and higher body weight. Low education is associated with both being stunted and overweight, and with adverse levels of HDL cholesterol and more physiological risk factors. Rural dwelling males are less likely to be overweight as are females living in poor states. Living in a poor state among females and having rural residence among males is associated with a higher number of high-risk factors. Overweight is a strong predictor of hypertension. Age differences in indicators of physiological development suggest that the epidemiological and demographic transitions in Mexico were accompanied by improved physical development; however, increases in nutrition may have reached a point of diminishing returns as Mexico switched from a state of under-nutrition to over-nutrition. PMID- 23812953 TI - Patients' perceptions of cosmetic surgery at a time of globalization, medical consumerism, and mass media culture: a French experience. AB - BACKGROUND: The global popularity of cosmetic surgery, combined with mass media attention on medical consumerism, has resulted in misinformation that may have negatively affected the "collective image" of aesthetic practitioners. OBJECTIVES: The authors assess patients' perceptions of cosmetic surgery and analyze their decision-making processes. METHODS: During a 2-year period, 250 consecutive patients presenting to either of 2 public hospitals for cosmetic surgery treatment were asked to complete a 7-item questionnaire evaluating their knowledge of opinions about, and referring practices for, aesthetic procedures. Patients undergoing oncologic, postbariatric, or reconstructive procedures were not included in the study. RESULTS: After exclusion of 71 cases for refusal or incompletion, 179 questionnaires were retained and analyzed (from 162 women and 17 men). Overall, repair (70.4%), comfort (45.3%), and health (40.8%) were the words most frequently associated with cosmetic surgery. Quality of preoperative information (69.3%), patient-physician relationship (65.4%), and results seen in relatives/friends (46.3%) were the most important criteria for selecting a cosmetic surgeon. Moreover, 82.7% of patients knew the difference between cosmetic surgery and cosmetic medicine. CONCLUSIONS: Although potential patients appear to be more educated about cosmetic surgery than they were several years ago, misinformation still persists. As physicians, we must be responsible for disseminating accurate education and strengthening our collaboration with general practitioners to improve not only our results but also the accuracy of information in the mass media. PMID- 23812954 TI - Posterior wedge resection: a more aesthetic labiaplasty. AB - BACKGROUND: Hypertrophy of the labia minora is of concern to a subset of adolescents and adult women. The posterior wedge resection is a new labiaplasty technique with an anatomic approach to yield the optimal aesthetic outcome and yet continue the functional achievement of prior techniques. OBJECTIVE: The authors describe the results of their posterior wedge resection technique in a retrospective series of patients. METHODS: A retrospective chart review was performed of 22 consecutive patients who underwent posterior wedge resection labiaplasty between February 2009 and February 2012. Complications and aesthetic outcomes were reviewed. RESULTS: The average age of the patients in this study was 35 years (median, 33 years). Follow-up ranged from 2 weeks to 1.5 years. Two minor complications occurred without further sequelae. At follow-up, none of the patients reported any paresthesias, pain, or problems with penetrating vaginal intercourse. CONCLUSIONS: An increasing number of labiaplasties are being performed for aesthetic and functional concerns. The posterior wedge resection enables the surgeon to perform labiaplasty easily, safely, and effectively, ensuring symmetry and maintenance of the natural pigment, color, and texture of the defining free edge of the labia minora. PMID- 23812951 TI - Fertility preservation in the male with cancer. AB - This article reviews the current concepts, recommendations, and principles of fertility preservation in men with cancer. Obstacles to sperm banking are addressed, as well as future directions for fertility-preserving technologies. All cancer therapies--chemotherapy, radiation, and surgery--are potential threats to a man's reproductive potential. Additionally, cancer itself can impair spermatogenesis. Thus, sperm cryopreservation prior to initiating life-saving cancer treatment offers men and their families the best chances to father biologically-related children and should be offered to all men with cancer before treatment. Better patient and provider education, as well as deliberate, coordinated strategies at comprehensive cancer care centers, are necessary to make fertility preservation for male cancer patients a priority during pre treatment planning. PMID- 23812956 TI - Leiomyosarcoma of the sigmoid colon: a rare cause of intestinal intussusception. PMID- 23812955 TI - Prediction of late disease recurrence and extended adjuvant letrozole benefit by the HOXB13/IL17BR biomarker. AB - BACKGROUND: Biomarkers to optimize extended adjuvant endocrine therapy for women with estrogen receptor (ER)-positive breast cancer are limited. The HOXB13/IL17BR (H/I) biomarker predicts recurrence risk in ER-positive, lymph node-negative breast cancer patients. H/I was evaluated in MA.17 trial for prognostic performance for late recurrence and treatment benefit from extended adjuvant letrozole. METHODS: A prospective-retrospective, nested case-control design of 83 recurrences matched to 166 nonrecurrences from letrozole- and placebo-treated patients within MA.17 was conducted. Expression of H/I within primary tumors was determined by reverse-transcription polymerase chain reaction with a prespecified cutpoint. The predictive ability of H/I for ascertaining benefit from letrozole was determined using multivariable conditional logistic regression including standard clinicopathological factors as covariates. All statistical tests were two-sided. RESULTS: High H/I was statistically significantly associated with a decrease in late recurrence in patients receiving extended letrozole therapy (odds ratio [OR] = 0.35; 95% confidence interval [CI] = 0.16 to 0.75; P = .007). In an adjusted model with standard clinicopathological factors, high H/I remained statistically significantly associated with patient benefit from letrozole (OR = 0.33; 95% CI = 0.15 to 0.73; P = .006). Reduction in the absolute risk of recurrence at 5 years was 16.5% for patients with high H/I (P = .007). The interaction between H/I and letrozole treatment was statistically significant (P = .03). CONCLUSIONS: In the absence of extended letrozole therapy, high H/I identifies a subgroup of ER-positive patients disease-free after 5 years of tamoxifen who are at risk for late recurrence. When extended endocrine therapy with letrozole is prescribed, high H/I predicts benefit from therapy and a decreased probability of late disease recurrence. PMID- 23812957 TI - Are explanatory trials ethical? Shifting the burden of justification in clinical trial design. AB - Most phase III clinical trials today are explanatory. Because explanatory, or efficacy, trials test hypotheses under "ideal" conditions, they are not well suited to providing guidance on decisions made in most clinical care contexts. Pragmatic trials, which test hypotheses under "usual" conditions, are often better suited to this task. Yet, pragmatic, or effectiveness, trials are infrequently carried out. This mismatch between the design of clinical trials and the needs of health care professionals is frustrating for everyone involved, and explains some of the challenges inherent in attempts to enhance knowledge translation and encourage evidence-based practice. The situation is more than simply frustrating, however; it is potentially unethical. Clinical trials must be socially valuable in order to (1) warrant the risks they impose on human research subjects and (2) fairly and efficiently assess new clinical interventions. Most bioethicists would agree that trials that have no social value, for instance, because their results do not have the potential to advance clinical care, should not be performed. What is less widely appreciated is that given limited research resources, trials that are more socially valuable should be preferred to trials that are less socially valuable when all else is equal. With respect to clinical trial design, I argue that while explanatory trials often have some social value, many have less social value than their pragmatic counterparts. On the basis of this general ethical assessment, I provide a preliminary defense of the position that clinical researchers should aim to conduct pragmatic trials, that is, that researchers face a burden of justification related to any idealizing elements added to trial designs. PMID- 23812958 TI - Approximating optimal controls for networks when there are combinations of population-level and targeted measures available: chlamydia infection as a case study. AB - Using a modified one-dimensional model for the spread of an SIS disease on a network, we show that the behaviour of complex network simulations can be replicated with a simpler model. This model is then used to design optimal controls for use on the network, which would otherwise be unfeasible to obtain, resulting in information about how best to combine a population-level random intervention with one that is more targeted. This technique is used to minimise intervention costs over a short time interval with a target prevalence, and also to minimise prevalence with a specified budget. When applied to chlamydia, we find results consistent with previous work; that is maximising targeted control (contact tracing) is important to using resources effectively, while high intensity bursts of population control (screening) are more effective than maintaining a high level of coverage. PMID- 23812959 TI - Age-related differences in selection by visual saliency. AB - We examined the ability of older adults to select local and global stimuli varying in perceptual saliency-a task requiring nonspatial visual selection. Participants were asked to identify in separate blocks a target at either the global or the local level of a hierarchical stimulus, while the saliency of each level was varied (across different conditions, either the local or the global form was the more salient and relatively easier to identify). Older adults were less efficient than young adults in ignoring distractors that were higher in saliency than were targets, and this occurred across both the global and local levels of form. The increased effects of distractor saliency on older adults occurred even when the effects were scaled by overall differences in task performance. The data provide evidence for an age-related decline in nonspatial attentional selection of low-salient hierarchical stimuli, not determined by the (global or local) level at which selection was required. We discuss the implications of these results for understanding both the interaction between saliency and hierarchical processing and the effects of aging on nonspatial visual attention. PMID- 23812960 TI - Conserved synteny-based anchoring of the barley genome physical map. AB - Gene order is largely collinear in the small-grained cereals, a feature which has proved helpful in both marker development and positional cloning. The accuracy of a virtual gene order map ("genome zipper") for barley (Hordeum vulgare), developed by combining a genetic map of this species with a large number of gene locations obtained from the maps constructed in other grass species, was evaluated here both at the genome-wide level and at the fine scale in a representative segment of the genome. Comparing the whole genome "genome zipper" maps with a genetic map developed by using transcript-derived markers, yielded an accuracy of >94 %. The fine-scale comparison involved a 14 cM segment of chromosome arm 2HL. One hundred twenty-eight genes of the "genome zipper" interval were analysed. Over 95 % (45/47) of the polymorphic markers were genetically mapped and allocated to the expected region of 2HL, following the predicted order. A further 80 of the 128 genes were assigned to the correct chromosome arm 2HL by analysis of wheat-barley addition lines. All 128 gene-based markers developed were used to probe a barley bacterial artificial chromosome (BAC) library, delivering 26 BAC contigs from which all except two were anchored to the targeted zipper interval. The results demonstrate that the gene order predicted by the "genome zipper" is remarkably accurate and that the "genome zipper" represents a highly efficient informational resource for the systematic identification of gene-based markers and subsequent physical map anchoring of the barley genome. PMID- 23812961 TI - Relative bioequivalence evaluation of two oral atomoxetine hydrochloride capsules: a single dose, randomized, open-label, 2-period crossover study in healthy Chinese volunteers under fasting conditions. AB - To evaluate the bioequivalence of a new formulation of atomoxetine hydrochloride (CAS 82248-59-7) capsules (test) and an available branded capsules (reference) after administration of a single 40 mg dose, randomized, open-label, 2-period crossover study was conducted in 22 healthy male Chinese subjects with a 1-week wash-out period. This study was designed for/the Honglin Pharmaceutical Co. Ltd and contracted to be done by the Beijing Anding Hospital in order to satisfy Chinese regulatory requirements to allow marketing of this generic product and performed according to the criteria of SFDA. Blood samples were collected before and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 16 and 24 h after drug administration. Plasma concentrations were determined by high-performance liquid chromatography (HPLC) with UV detection. A non-compartmental method was used to calculate the pharmacokinetic parameters and evaluate bioequivalence of the 2 formulations. The 90% confidence interval (CI) of the ratios (test/reference) of atomoxetine for AUC0-24, AUC0-infinity and Cmax were 100.9% (93.6-108.8%), 103.1% (95.1-111.7%) and 105.2% (92.8-119.4%), respectively, which fell within the interval of 80-125% and 75-133%. No clinically significant changes or abnormalities were noted in laboratory data and vital signs. From these results it can be concluded that the test formulation of atomoxetine capsules met the regulatory criterion for bioequivalence to the reference formulation. PMID- 23812962 TI - Few items in the thyroid-related quality of life instrument ThyPRO exhibited differential item functioning. AB - OBJECTIVE: To evaluate the extent of differential item functioning (DIF) within the thyroid-specific quality of life patient-reported outcome measure, ThyPRO, according to sex, age, education and thyroid diagnosis. STUDY DESIGN AND SETTING: A total of 838 patients with benign thyroid diseases completed the ThyPRO questionnaire (84 five-point items, 13 scales). Uniform and nonuniform DIF were investigated using ordinal logistic regression, testing for both statistical significance and magnitude (?R(2) > 0.02). Scale level was estimated by the sum score, after purification. RESULTS: Twenty instances of DIF in 17 of the 84 items were found. Eight according to diagnosis, where the goiter scale was the one most affected, possibly due to differing perceptions in patients with auto-immune thyroid diseases compared to patients with simple goiter. Eight DIFs according to age were found, of which 5 were in positively worded items, which younger patients were more likely to endorse; one according to gender: women were more likely to report crying, and three according to educational level. The vast majority of DIF had only minor influence on the scale scores (0.1-2.3 points on the 0-100 scales), but two DIF corresponded to a difference of 4.6 and 9.8, respectively. CONCLUSION: Ordinal logistic regression identified DIF in 17 of 84 items. The potential impact of this on the present scales was low, but items displaying DIF could be avoided when developing abbreviated scales, where the potential impact of DIF (due to fewer items) will be larger. PMID- 23812963 TI - Rhabdoid glioblastoma: a recently recognized subtype of glioblastoma. AB - BACKGROUND: Rhabdoid glioblastoma is a rare type of recently described malignant brain tumor. It is characterized by a glioblastoma associated with rhabdoid components. METHODS: Here we report two cases of rhabdoid glioblastoma and a brief literature review. The first patient was a 19-year-old boy who initially presented with a foul-smelling odor and progressive right-side weakness. The second case was a 29-year-old male patient who presented only with a severe headache. RESULTS: Both of these patients were young, and the disease progression was quick despite optimal treatment. CONCLUSION: The diagnosis of rhabdoid glioblastoma was confirmed after microscopic and immunohistochemical findings. PMID- 23812964 TI - Angiographic characteristics of ruptured paraclinoid aneurysms: risk factors for rupture. AB - BACKGROUND: The diagnosis and treatment of unruptured paraclinoid aneurysms has been increasing with the recent advent of diagnostic tools and less invasive endovascular therapeutic options. Considering the low incidence of rupture, investigation of the characteristics of ruptured paraclinoid aneurysm is important to predict rupture risk of the paraclinoid aneurysms. The objective of this study is to evaluate probable factors for rupture by analyzing the characteristics of ruptured paraclinoid aneurysms. METHODS: A total of 2,276 aneurysms (1,419 ruptured and 857 unruptured) were diagnosed and treated endovascularly or microsurgically between 2001 and 2011. Among them, 265 were paraclinoid aneurysms, of which 37 were ruptured. Removing 12 blister-like aneurysms, 25 ruptured and 228 unruptured saccular aneurysms were included and the medical records and radiological images were retrospectively analyzed. RESULTS: Of 25 aneurysms, 16 (64.0%) were located in the superior direction. Five were inferior located lesions (20%) and four were medially located lesions (16.0%). Laterally located lesions were not found. The mean size of aneurysms was 9.4 +/- 5.6 mm. Ten aneurysms (40.0%) were >= 10 mm in size. Thirteen aneurysms (52.0%) were lobulated. The superiorly located aneurysms were larger than the other aneurysms (10.3 +/- 5.8 mm vs. 7.7 +/- 4.9 mm) and more frequently lobulated (ten of 16 vs. three of nine). In a comparative analysis, the ruptured aneurysms were located more in the superior direction compared with unruptured aneurysms (64 vs. 23.2%, p < 0.0001). Large aneurysms (36.0 vs. 7.9%, p < 0.0001), longer fundus diameter (mean 9.4 +/- 5.6 vs. 4.8 +/- 3.3 mm, p = 0.001), dome-to-neck ratio (mean 1.8 +/- 0.9 vs. 1.2 +/- 0.5, p < 0.0001), and lobulated shape aneurysms were more likely to be ruptured aneurysms (13 of 25 ruptured aneurysms, 52.0%, p = 0.001). CONCLUSIONS: Rupture risk of the paraclinoid aneurysm is very low. However, superiorly located paraclinoid aneurysms appear more likely to rupture than other locations. Angiographically, more conservative indication for the treatment of paraclinoid aneurysm should be recommended except for superior located lesions. PMID- 23812965 TI - Awake craniotomies without any sedation: the awake-awake-awake technique. AB - BACKGROUND: Temporary anaesthesia or analgosedation used for awake craniotomies carry substantial risks like hemodynamic instabilities, airway obstruction, hypoventilation, nausea and vomiting, agitation, and interference with test performances. We tested the actual need for sedatives and opioids in 50 patients undergoing awake craniotomy for brain tumour resection in eloquent or motoric brain areas when cranial nerve blocks, permanent presence of a contact person, and therapeutic communication are provided. METHODS: Therapeutic communication was based on the assumption that patients in such an extreme medical situation enter a natural trance-like state with elevated suggestibility. The anaesthesiologist acted as a continuous guide, using a strong rapport, nonverbal communication, hypnotic suggestions, such as dissociation to a "safe place", and the reframing of disturbing noises, while simultaneously avoiding negative suggestions. Analgesics or sedatives were at hand according to the principle "as much as necessary, but not more than needed". RESULTS: No sedation was necessary for any of the patients besides for the treatment of seizures. Only two-thirds of the patients requested remifentanil, with a mean dosage of 96 MUg before the end of tumour resection and a total of 156 MUg. Hemodynamic reactions indicative of stress were mainly seen during nerve blockades and neurological testing. Postoperative vigilance tests showed equal or higher scores than preoperative tests. CONCLUSIONS: The main challenges for patients undergoing awake craniotomies include anxiety and fears, terrifying noises and surroundings, immobility, loss of control, and the feeling of helplessness and being left alone. In such situations, psychological support might be more helpful than the pharmacological approach. With adequate therapeutic communication, patients do not require any sedation and no or only low-dose opioid treatment during awake craniotomies, leaving patients fully awake and competent during the entire surgical procedure without stress. This approach can be termed "awake-awake-awake technique". PMID- 23812966 TI - Histone H1.0--a potential molecular marker with prognostic value for patients with malignant gliomas. AB - BACKGROUND: Histones are proteins closely associated with the DNA molecules and serve as a structural scaffold for the organization of chromatin. They play an important role in the regulation of gene expression by changing the level of DNA compaction. The special subtype of the linker histone family-H1 zero (H1.0) is generally expressed in non-dividing, terminally differentiated cells. The aim of our study is to investigate the correlation between the quantities of histone H1.0 in human gliomas, the histopathological grade and the overall survival. MATERIAL AND METHOD: Twenty-nine (N = 29) patients with intraaxial lesions underwent a microsurgical tumor resection. Tumor samples were snap-frozen in liquid nitrogen immediately after resection. Following a specific protocol, linker histones were extracted from the tumor specimens and the quantities of histone H1.0 were assessed. All patients were followed up prospectively. RESULTS: Of the 29 patients in our study (M:F = 17:12), five had a grade II astrocytoma, seven had a grade III, and 17 had a grade IV, according to the World Health Organization (WHO) classification. At the end of the study, three patients were still alive. The mean quantities of H1.0 were: 23.3 for grade II tumors, 13.9 for grade III and 11.3 for grade IV tumors. The statistical analysis demonstrated that the histological grade, age and Karnofsky performance status (KPS) remain among the most reliable predictive factors for the survival of patients with gliomas. Grade III-IV gliomas had significantly less histone H1.0 than grade II gliomas. Conformably, in a multivariate Cox regression analysis, H1.0 made a small but significant contribution (p < 0.05) to survival rates. CONCLUSION: Our study confirmed that histone H1.0 is a potential biological marker with prognostic value for the survival of patients with gliomas. The quantities of histone H1.0 are correlated to the histopathological grade of the tumor. The more aggressive and malignant gliomas tend to have lower quantities of histone H1.0. PMID- 23812968 TI - Bacterial siderophores efficiently provide iron to iron-starved tomato plants in hydroponics culture. AB - Iron is one of the essential elements for a proper plant development. Providing plants with an accessible form of iron is crucial when it is scant or unavailable in soils. Chemical chelates are the only current alternative and are highly stable in soils, therefore, posing a threat to drinking water. The aim of this investigation was to quantify siderophores produced by two bacterial strains and to determine if these bacterial siderophores would palliate chlorotic symptoms of iron-starved tomato plants. For this purpose, siderophore production in MM9 medium by two selected bacterial strains was quantified, and the best was used for biological assay. Bacterial culture media free of bacteria (S) and with bacterial cells (BS), both supplemented with Fe were delivered to 12-week-old plants grown under iron starvation in hydroponic conditions; controls with full Hoagland solution, iron-free Hoagland solution and water were also conducted. Treatments were applied twice along the experiment, with a week in between. At harvest, plant yield, chlorophyll content and nutritional status in leaves were measured. Both the bacterial siderophore treatments significantly increased plant yield, chlorophyll and iron content over the positive controls with full Hoagland solution, indicating that siderophores are effective in providing Fe to the plant, either with or without the presence of bacteria. In summary, siderophores from strain Chryseobacterium C138 are effective in supplying Fe to iron-starved tomato plants by the roots, either with or without the presence of bacteria. Based on the amount of siderophores produced, an effective and economically feasible organic Fe chelator could be developed. PMID- 23812967 TI - Understanding clinic options for overactive bladder. AB - Overactive bladder (OAB) is a symptom complex of urinary frequency, nocturia and urgency with or without urgency incontinence that adversely impacts patient's quality of life. Conservative management begins in the outpatient clinic, often with significant improvement and patient satisfaction. In this review we will discuss the evaluation of OAB and review treatment options focusing on behavioral modification, medical therapy, and neuromodulation. These treatment options are offered in a stepwise fashion, remembering that more than one may be needed and can be used concomitantly. PMID- 23812969 TI - Molecular signatures for the phylum Aquificae and its different clades: proposal for division of the phylum Aquificae into the emended order Aquificales, containing the families Aquificaceae and Hydrogenothermaceae, and a new order Desulfurobacteriales ord. nov., containing the family Desulfurobacteriaceae. AB - We report here detailed phylogenetic and comparative analyses on 11 sequenced genomes from the phylum Aquificae to identify molecular markers that are specific for the species from this phylum or its different families (viz. Aquificaceae, Hydrogenothermaceae and Desulfurobacteriaceae). In phylogenetic trees based on 16S rRNA gene or concatenated sequences for 32 conserved proteins, species from the three Aquificae families formed distinct clades. These trees also supported a strong relationship between the Aquificaceae and Hydrogenothermaceae families. In parallel, comparative analyses on protein sequences from Aquificae genomes have identified 46 conserved signature indels (CSIs) in broadly distributed proteins that are either exclusively or mainly found in members of the phylum Aquificae or its different families and subclades. Four of these CSIs, which are found in all sequenced Aquificae species, provide potential molecular markers for this phylum. Twelve, six and thirteen other CSIs that respectively are specific for the sequenced Aquificaceae, Hydrogenothermaceae and Desulfurobacteriaceae species provide molecular markers and novel tools for the identification of members of these families and for genetic and biochemical studies on them. Lastly, these studies have identified 11 CSIs in divergent proteins that are uniquely shared by members of the Aquificaceae and Hydrogenothermaceae families providing strong evidence that these two groups of bacteria shared a common ancestor exclusive of all other Aquificae (bacteria). The species from these two families are also very similar in their metabolic and physiological properties and they consist of aerobic or microaerophilic bacteria, which generally obtain energy by oxidation of hydrogen or reduced sulfur compounds by molecular oxygen. Based upon their strong association in phylogenetic trees, unique shared presence of large numbers of CSIs in different proteins, and similarities in their metabolic and physiological properties, it is proposed that the order Aquificales should be emended to include only the members of the families Aquificaceae and Hydrogenothermaceae. The members of the family Desulfurobacteriaceae, which are obligate anaerobes that strictly use hydrogen as electron donor, are now transferred to a new order Desulfurobacteriales ord. nov. The emended descriptions of the phylum Aquificae and its three families incorporating information for different molecular signatures are also provided. PMID- 23812970 TI - Resolving complex mixtures: trilinear diffusion data. AB - Complex mixtures are at the heart of biology, and biomacromolecules almost always exhibit their function in a mixture, e.g., the mode of action for a spider venom is typically dependent on a cocktail of compounds, not just the protein. Information about diseases is encoded in body fluids such as urine and plasma in the form of metabolite concentrations determined by the actions of enzymes. To understand better what is happening in real living systems we urgently need better methods to characterize such mixtures. In this paper we describe a potent way to disentangle the NMR spectra of mixture components, by exploiting data that vary independently in three or more dimensions, allowing the use of powerful algorithms to decompose the data to extract the information sought. The particular focus of this paper is on NMR diffusion data, which are typically bilinear but can be extended by a third dimension to give the desired data structure. PMID- 23812971 TI - Out-and-back 13C-13C scalar transfers in protein resonance assignment by proton detected solid-state NMR under ultra-fast MAS. AB - We present here (1)H-detected triple-resonance H/N/C experiments that incorporate CO-CA and CA-CB out-and-back scalar-transfer blocks optimized for robust resonance assignment in biosolids under ultra-fast magic-angle spinning (MAS). The first experiment, (H)(CO)CA(CO)NH, yields (1)H-detected inter-residue correlations, in which we record the chemical shifts of the CA spins in the first indirect dimension while during the scalar-transfer delays the coherences are present only on the longer-lived CO spins. The second experiment, (H)(CA)CB(CA)NH, correlates the side-chain CB chemical shifts with the NH of the same residue. These high sensitivity experiments are demonstrated on both fully protonated and 100%-H(N) back-protonated perdeuterated microcrystalline samples of Acinetobacter phage 205 (AP205) capsids at 60 kHz MAS. PMID- 23812973 TI - Two new areas were defined: "Metabolic Networks" and "RNA Bioinformatics. PMID- 23812972 TI - Quantitative one- and two-dimensional 13C spectra of microcrystalline proteins with enhanced intensity. AB - We recorded quantitative, uniformly enhanced one- and two-dimensional (13)C spectra of labelled microcrystalline proteins. The approach takes advantage of efficient equilibration of magnetization by low-power proton irradiation using Phase Alternated Recoupling Irradiation Schemes and benefits simultaneously from uniform sensitivity enhancement due to efficient spin exchange that can overcome T1((13)C) constraints and the presence of heteronuclear Overhauser effects. PMID- 23812974 TI - Genome-wide identification and predictive modeling of tissue-specific alternative polyadenylation. AB - MOTIVATION: Pre-mRNA cleavage and polyadenylation are essential steps for 3'-end maturation and subsequent stability and degradation of mRNAs. This process is highly controlled by cis-regulatory elements surrounding the cleavage/polyadenylation sites (polyA sites), which are frequently constrained by sequence content and position. More than 50% of human transcripts have multiple functional polyA sites, and the specific use of alternative polyA sites (APA) results in isoforms with variable 3'-untranslated regions, thus potentially affecting gene regulation. Elucidating the regulatory mechanisms underlying differential polyA preferences in multiple cell types has been hindered both by the lack of suitable data on the precise location of cleavage sites, as well as of appropriate tests for determining APAs with significant differences across multiple libraries. RESULTS: We applied a tailored paired-end RNA-seq protocol to specifically probe the position of polyA sites in three human adult tissue types. We specified a linear-effects regression model to identify tissue-specific biases indicating regulated APA; the significance of differences between tissue types was assessed by an appropriately designed permutation test. This combination allowed to identify highly specific subsets of APA events in the individual tissue types. Predictive models successfully classified constitutive polyA sites from a biologically relevant background (auROC = 99.6%), as well as tissue specific regulated sets from each other. We found that the main cis-regulatory elements described for polyadenylation are a strong, and highly informative, hallmark for constitutive sites only. Tissue-specific regulated sites were found to contain other regulatory motifs, with the canonical polyadenylation signal being nearly absent at brain-specific polyA sites. Together, our results contribute to the understanding of the diversity of post-transcriptional gene regulation. AVAILABILITY: Raw data are deposited on SRA, accession numbers: brain SRX208132, kidney SRX208087 and liver SRX208134. Processed datasets as well as model code are published on our website: http://www.genome.duke.edu/labs/ohler/research/UTR/. CONTACT: uwe.ohler@duke.edu. PMID- 23812975 TI - Stability selection for regression-based models of transcription factor-DNA binding specificity. AB - MOTIVATION: The DNA binding specificity of a transcription factor (TF) is typically represented using a position weight matrix model, which implicitly assumes that individual bases in a TF binding site contribute independently to the binding affinity, an assumption that does not always hold. For this reason, more complex models of binding specificity have been developed. However, these models have their own caveats: they typically have a large number of parameters, which makes them hard to learn and interpret. RESULTS: We propose novel regression-based models of TF-DNA binding specificity, trained using high resolution in vitro data from custom protein-binding microarray (PBM) experiments. Our PBMs are specifically designed to cover a large number of putative DNA binding sites for the TFs of interest (yeast TFs Cbf1 and Tye7, and human TFs c-Myc, Max and Mad2) in their native genomic context. These high throughput quantitative data are well suited for training complex models that take into account not only independent contributions from individual bases, but also contributions from di- and trinucleotides at various positions within or near the binding sites. To ensure that our models remain interpretable, we use feature selection to identify a small number of sequence features that accurately predict TF-DNA binding specificity. To further illustrate the accuracy of our regression models, we show that even in the case of paralogous TF with highly similar position weight matrices, our new models can distinguish the specificities of individual factors. Thus, our work represents an important step toward better sequence-based models of individual TF-DNA binding specificity. AVAILABILITY: Our code is available at http://genome.duke.edu/labs/gordan/ISMB2013. The PBM data used in this article are available in the Gene Expression Omnibus under accession number GSE47026. PMID- 23812977 TI - Supervised de novo reconstruction of metabolic pathways from metabolome-scale compound sets. AB - MOTIVATION: The metabolic pathway is an important biochemical reaction network involving enzymatic reactions among chemical compounds. However, it is assumed that a large number of metabolic pathways remain unknown, and many reactions are still missing even in known pathways. Therefore, the most important challenge in metabolomics is the automated de novo reconstruction of metabolic pathways, which includes the elucidation of previously unknown reactions to bridge the metabolic gaps. RESULTS: In this article, we develop a novel method to reconstruct metabolic pathways from a large compound set in the reaction-filling framework. We define feature vectors representing the chemical transformation patterns of compound-compound pairs in enzymatic reactions using chemical fingerprints. We apply a sparsity-induced classifier to learn what we refer to as 'enzymatic reaction likeness', i.e. whether compound pairs are possibly converted to each other by enzymatic reactions. The originality of our method lies in the search for potential reactions among many compounds at a time, in the extraction of reaction-related chemical transformation patterns and in the large-scale applicability owing to the computational efficiency. In the results, we demonstrate the usefulness of our proposed method on the de novo reconstruction of 134 metabolic pathways in Kyoto Encyclopedia of Genes and Genomes (KEGG). Our comprehensively predicted reaction networks of 15 698 compounds enable us to suggest many potential pathways and to increase research productivity in metabolomics. AVAILABILITY: Softwares are available on request. Supplementary material are available at http://web.kuicr.kyoto-u.ac.jp/supp/kot/ismb2013/. PMID- 23812976 TI - Predicting drug-target interactions using restricted Boltzmann machines. AB - MOTIVATION: In silico prediction of drug-target interactions plays an important role toward identifying and developing new uses of existing or abandoned drugs. Network-based approaches have recently become a popular tool for discovering new drug-target interactions (DTIs). Unfortunately, most of these network-based approaches can only predict binary interactions between drugs and targets, and information about different types of interactions has not been well exploited for DTI prediction in previous studies. On the other hand, incorporating additional information about drug-target relationships or drug modes of action can improve prediction of DTIs. Furthermore, the predicted types of DTIs can broaden our understanding about the molecular basis of drug action. RESULTS: We propose a first machine learning approach to integrate multiple types of DTIs and predict unknown drug-target relationships or drug modes of action. We cast the new DTI prediction problem into a two-layer graphical model, called restricted Boltzmann machine, and apply a practical learning algorithm to train our model and make predictions. Tests on two public databases show that our restricted Boltzmann machine model can effectively capture the latent features of a DTI network and achieve excellent performance on predicting different types of DTIs, with the area under precision-recall curve up to 89.6. In addition, we demonstrate that integrating multiple types of DTIs can significantly outperform other predictions either by simply mixing multiple types of interactions without distinction or using only a single interaction type. Further tests show that our approach can infer a high fraction of novel DTIs that has been validated by known experiments in the literature or other databases. These results indicate that our approach can have highly practical relevance to DTI prediction and drug repositioning, and hence advance the drug discovery process. AVAILABILITY: Software and datasets are available on request. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23812978 TI - CAMPways: constrained alignment framework for the comparative analysis of a pair of metabolic pathways. AB - MOTIVATION: Given a pair of metabolic pathways, an alignment of the pathways corresponds to a mapping between similar substructures of the pair. Successful alignments may provide useful applications in phylogenetic tree reconstruction, drug design and overall may enhance our understanding of cellular metabolism. RESULTS: We consider the problem of providing one-to-many alignments of reactions in a pair of metabolic pathways. We first provide a constrained alignment framework applicable to the problem. We show that the constrained alignment problem even in a primitive setting is computationally intractable, which justifies efforts for designing efficient heuristics. We present our Constrained Alignment of Metabolic Pathways (CAMPways) algorithm designed for this purpose. Through extensive experiments involving a large pathway database, we demonstrate that when compared with a state-of-the-art alternative, the CAMPways algorithm provides better alignment results on metabolic networks as far as measures based on same-pathway inclusion and biochemical significance are concerned. The execution speed of our algorithm constitutes yet another important improvement over alternative algorithms. AVAILABILITY: Open source codes, executable binary, useful scripts, all the experimental data and the results are freely available as part of the Supplementary Material at http://code.google.com/p/campways/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23812980 TI - IBD-Groupon: an efficient method for detecting group-wise identity-by-descent regions simultaneously in multiple individuals based on pairwise IBD relationships. AB - MOTIVATION: Detecting IBD tracts is an important problem in genetics. Most of the existing methods focus on detecting pairwise IBD tracts, which have relatively low power to detect short IBD tracts. Methods to detect IBD tracts among multiple individuals simultaneously, or group-wise IBD tracts, have better performance for short IBD tracts detection. Group-wise IBD tracts can be applied to a wide range of applications, such as disease mapping, pedigree reconstruction and so forth. The existing group-wise IBD tract detection method is computationally inefficient and is only able to handle small datasets, such as 20, 30 individuals with hundreds of SNPs. It also requires a previous specification of the number of IBD groups, or partitions of the individuals where all the individuals in the same partition are IBD with each other, which may not be realistic in many cases. The method can only handle a small number of IBD groups, such as two or three, because of scalability issues. What is more, it does not take LD (linkage disequilibrium) into consideration. RESULTS: In this work, we developed an efficient method IBD-Groupon, which detects group-wise IBD tracts based on pairwise IBD relationships, and it is able to address all the drawbacks aforementioned. To our knowledge, our method is the first practical group-wise IBD tracts detection method that is scalable to very large datasets, for example, hundreds of individuals with thousands of SNPs, and in the meanwhile, it is powerful to detect short IBD tracts. Our method does not need to specify the number of IBD groups, which will be detected automatically. And our method takes LD into consideration, as it is based on pairwise IBD tracts where LD can be easily incorporated. PMID- 23812979 TI - Simple topological properties predict functional misannotations in a metabolic network. AB - MOTIVATION: Misannotation in sequence databases is an important obstacle for automated tools for gene function annotation, which rely extensively on comparison with sequences with known function. To improve current annotations and prevent future propagation of errors, sequence-independent tools are, therefore, needed to assist in the identification of misannotated gene products. In the case of enzymatic functions, each functional assignment implies the existence of a reaction within the organism's metabolic network; a first approximation to a genome-scale metabolic model can be obtained directly from an automated genome annotation. Any obvious problems in the network, such as dead end or disconnected reactions, can, therefore, be strong indications of misannotation. RESULTS: We demonstrate that a machine-learning approach using only network topological features can successfully predict the validity of enzyme annotations. The predictions are tested at three different levels. A random forest using topological features of the metabolic network and trained on curated sets of correct and incorrect enzyme assignments was found to have an accuracy of up to 86% in 5-fold cross-validation experiments. Further cross-validation against unseen enzyme superfamilies indicates that this classifier can successfully extrapolate beyond the classes of enzyme present in the training data. The random forest model was applied to several automated genome annotations, achieving an accuracy of ~60% in most cases when validated against recent genome-scale metabolic models. We also observe that when applied to draft metabolic networks for multiple species, a clear negative correlation is observed between predicted annotation quality and phylogenetic distance to the major model organism for biochemistry (Escherichia coli for prokaryotes and Homo sapiens for eukaryotes). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23812981 TI - Efficient network-guided multi-locus association mapping with graph cuts. AB - MOTIVATION: As an increasing number of genome-wide association studies reveal the limitations of the attempt to explain phenotypic heritability by single genetic loci, there is a recent focus on associating complex phenotypes with sets of genetic loci. Although several methods for multi-locus mapping have been proposed, it is often unclear how to relate the detected loci to the growing knowledge about gene pathways and networks. The few methods that take biological pathways or networks into account are either restricted to investigating a limited number of predetermined sets of loci or do not scale to genome-wide settings. RESULTS: We present SConES, a new efficient method to discover sets of genetic loci that are maximally associated with a phenotype while being connected in an underlying network. Our approach is based on a minimum cut reformulation of the problem of selecting features under sparsity and connectivity constraints, which can be solved exactly and rapidly. SConES outperforms state-of-the-art competitors in terms of runtime, scales to hundreds of thousands of genetic loci and exhibits higher power in detecting causal SNPs in simulation studies than other methods. On flowering time phenotypes and genotypes from Arabidopsis thaliana, SConES detects loci that enable accurate phenotype prediction and that are supported by the literature. AVAILABILITY: Code is available at http://webdav.tuebingen.mpg.de/u/karsten/Forschung/scones/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23812982 TI - Automated cellular annotation for high-resolution images of adult Caenorhabditis elegans. AB - MOTIVATION: Advances in high-resolution microscopy have recently made possible the analysis of gene expression at the level of individual cells. The fixed lineage of cells in the adult worm Caenorhabditis elegans makes this organism an ideal model for studying complex biological processes like development and aging. However, annotating individual cells in images of adult C.elegans typically requires expertise and significant manual effort. Automation of this task is therefore critical to enabling high-resolution studies of a large number of genes. RESULTS: In this article, we describe an automated method for annotating a subset of 154 cells (including various muscle, intestinal and hypodermal cells) in high-resolution images of adult C.elegans. We formulate the task of labeling cells within an image as a combinatorial optimization problem, where the goal is to minimize a scoring function that compares cells in a test input image with cells from a training atlas of manually annotated worms according to various spatial and morphological characteristics. We propose an approach for solving this problem based on reduction to minimum-cost maximum-flow and apply a cross entropy-based learning algorithm to tune the weights of our scoring function. We achieve 84% median accuracy across a set of 154 cell labels in this highly variable system. These results demonstrate the feasibility of the automatic annotation of microscopy-based images in adult C.elegans. PMID- 23812983 TI - Inference of historical migration rates via haplotype sharing. AB - SUMMARY: Pairs of individuals from a study cohort will often share long-range haplotypes identical-by-descent. Such haplotypes are transmitted from common ancestors that lived tens to hundreds of generations in the past, and they can now be efficiently detected in high-resolution genomic datasets, providing a novel source of information in several domains of genetic analysis. Recently, haplotype sharing distributions were studied in the context of demographic inference, and they were used to reconstruct recent demographic events in several populations. We here extend the framework to handle demographic models that contain multiple demes interacting through migration. We extensively test our formulation in several demographic scenarios, compare our approach with methods based on ancestry deconvolution and use this method to analyze Masai samples from the HapMap 3 dataset. AVAILABILITY: DoRIS, a Java implementation of the proposed method, and its source code are freely available at http://www.cs.columbia.edu/~pier/doris. PMID- 23812984 TI - Phylogenetic analysis of multiprobe fluorescence in situ hybridization data from tumor cell populations. AB - MOTIVATION: Development and progression of solid tumors can be attributed to a process of mutations, which typically includes changes in the number of copies of genes or genomic regions. Although comparisons of cells within single tumors show extensive heterogeneity, recurring features of their evolutionary process may be discerned by comparing multiple regions or cells of a tumor. A useful source of data for studying likely progression of individual tumors is fluorescence in situ hybridization (FISH), which allows one to count copy numbers of several genes in hundreds of single cells. Novel algorithms for interpreting such data phylogenetically are needed, however, to reconstruct likely evolutionary trajectories from states of single cells and facilitate analysis of tumor evolution. RESULTS: In this article, we develop phylogenetic methods to infer likely models of tumor progression using FISH copy number data and apply them to a study of FISH data from two cancer types. Statistical analyses of topological characteristics of the tree-based model provide insights into likely tumor progression pathways consistent with the prior literature. Furthermore, tree statistics from the resulting phylogenies can be used as features for prediction methods. This results in improved accuracy, relative to unstructured gene copy number data, at predicting tumor state and future metastasis. AVAILABILITY: Source code for software that does FISH tree building (FISHtrees) and the data on cervical and breast cancer examined here are available at ftp://ftp.ncbi.nlm.nih.gov/pub/FISHtrees. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23812985 TI - Minimum curvilinearity to enhance topological prediction of protein interactions by network embedding. AB - MOTIVATION: Most functions within the cell emerge thanks to protein-protein interactions (PPIs), yet experimental determination of PPIs is both expensive and time-consuming. PPI networks present significant levels of noise and incompleteness. Predicting interactions using only PPI-network topology (topological prediction) is difficult but essential when prior biological knowledge is absent or unreliable. METHODS: Network embedding emphasizes the relations between network proteins embedded in a low-dimensional space, in which protein pairs that are closer to each other represent good candidate interactions. To achieve network denoising, which boosts prediction performance, we first applied minimum curvilinear embedding (MCE), and then adopted shortest path (SP) in the reduced space to assign likelihood scores to candidate interactions. Furthermore, we introduce (i) a new valid variation of MCE, named non-centred MCE (ncMCE); (ii) two automatic strategies for selecting the appropriate embedding dimension; and (iii) two new randomized procedures for evaluating predictions. RESULTS: We compared our method against several unsupervised and supervisedly tuned embedding approaches and node neighbourhood techniques. Despite its computational simplicity, ncMCE-SP was the overall leader, outperforming the current methods in topological link prediction. CONCLUSION: Minimum curvilinearity is a valuable non-linear framework that we successfully applied to the embedding of protein networks for the unsupervised prediction of novel PPIs. The rationale for our approach is that biological and evolutionary information is imprinted in the non-linear patterns hidden behind the protein network topology, and can be exploited for predicting new protein links. The predicted PPIs represent good candidates for testing in high throughput experiments or for exploitation in systems biology tools such as those used for network-based inference and prediction of disease-related functional modules. AVAILABILITY: https://sites.google.com/site/carlovittoriocannistraci/home. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23812986 TI - A context-sensitive framework for the analysis of human signalling pathways in molecular interaction networks. AB - MOTIVATION: A major challenge in systems biology is to reveal the cellular pathways that give rise to specific phenotypes and behaviours. Current techniques often rely on a network representation of molecular interactions, where each node represents a protein or a gene and each interaction is assigned a single static score. However, the use of single interaction scores fails to capture the tendency of proteins to favour different partners under distinct cellular conditions. RESULTS: Here, we propose a novel context-sensitive network model, in which genes and protein nodes are assigned multiple contexts based on their gene ontology annotations, and their interactions are associated with multiple context sensitive scores. Using this model, we developed a new approach and a corresponding tool, ContextNet, based on a dynamic programming algorithm for identifying signalling paths linking proteins to their downstream target genes. ContextNet finds high-ranking context-sensitive paths in the interactome, thereby revealing the intermediate proteins in the path and their path-specific contexts. We validated the model using 18 348 manually curated cellular paths derived from the SPIKE database. We next applied our framework to elucidate the responses of human primary lung cells to influenza infection. Top-ranking paths were much more likely to contain infection-related proteins, and this likelihood was highly correlated with path score. Moreover, the contexts assigned by the algorithm pointed to putative, as well as previously known responses to viral infection. Thus, context sensitivity is an important extension to current network biology models and can be efficiently used to elucidate cellular response mechanisms. AVAILABILITY: ContextNet is publicly available at http://netbio.bgu.ac.il/ContextNet. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23812987 TI - Multitask learning for host-pathogen protein interactions. AB - MOTIVATION: An important aspect of infectious disease research involves understanding the differences and commonalities in the infection mechanisms underlying various diseases. Systems biology-based approaches study infectious diseases by analyzing the interactions between the host species and the pathogen organisms. This work aims to combine the knowledge from experimental studies of host-pathogen interactions in several diseases to build stronger predictive models. Our approach is based on a formalism from machine learning called 'multitask learning', which considers the problem of building models across tasks that are related to each other. A 'task' in our scenario is the set of host pathogen protein interactions involved in one disease. To integrate interactions from several tasks (i.e. diseases), our method exploits the similarity in the infection process across the diseases. In particular, we use the biological hypothesis that similar pathogens target the same critical biological processes in the host, in defining a common structure across the tasks. RESULTS: Our current work on host-pathogen protein interaction prediction focuses on human as the host, and four bacterial species as pathogens. The multitask learning technique we develop uses a task-based regularization approach. We find that the resulting optimization problem is a difference of convex (DC) functions. To optimize, we implement a Convex-Concave procedure-based algorithm. We compare our integrative approach to baseline methods that build models on a single host pathogen protein interaction dataset. Our results show that our approach outperforms the baselines on the training data. We further analyze the protein interaction predictions generated by the models, and find some interesting insights. AVAILABILITY: The predictions and code are available at: http://www.cs.cmu.edu/~mkshirsa/ismb2013_paper320.html . SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23812988 TI - Identifying proteins controlling key disease signaling pathways. AB - MOTIVATION: Several types of studies, including genome-wide association studies and RNA interference screens, strive to link genes to diseases. Although these approaches have had some success, genetic variants are often only present in a small subset of the population, and screens are noisy with low overlap between experiments in different labs. Neither provides a mechanistic model explaining how identified genes impact the disease of interest or the dynamics of the pathways those genes regulate. Such mechanistic models could be used to accurately predict downstream effects of knocking down pathway members and allow comprehensive exploration of the effects of targeting pairs or higher-order combinations of genes. RESULTS: We developed methods to model the activation of signaling and dynamic regulatory networks involved in disease progression. Our model, SDREM, integrates static and time series data to link proteins and the pathways they regulate in these networks. SDREM uses prior information about proteins' likelihood of involvement in a disease (e.g. from screens) to improve the quality of the predicted signaling pathways. We used our algorithms to study the human immune response to H1N1 influenza infection. The resulting networks correctly identified many of the known pathways and transcriptional regulators of this disease. Furthermore, they accurately predict RNA interference effects and can be used to infer genetic interactions, greatly improving over other methods suggested for this task. Applying our method to the more pathogenic H5N1 influenza allowed us to identify several strain-specific targets of this infection. AVAILABILITY: SDREM is available from http://sb.cs.cmu.edu/sdrem. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23812989 TI - Predicting protein interactions via parsimonious network history inference. AB - MOTIVATION: Reconstruction of the network-level evolutionary history of protein protein interactions provides a principled way to relate interactions in several present-day networks. Here, we present a general framework for inferring such histories and demonstrate how it can be used to determine what interactions existed in the ancestral networks, which present-day interactions we might expect to exist based on evolutionary evidence and what information extant networks contain about the order of ancestral protein duplications. RESULTS: Our framework characterizes the space of likely parsimonious network histories. It results in a structure that can be used to find probabilities for a number of events associated with the histories. The framework is based on a directed hypergraph formulation of dynamic programming that we extend to enumerate many optimal and near-optimal solutions. The algorithm is applied to reconstructing ancestral interactions among bZIP transcription factors, imputing missing present-day interactions among the bZIPs and among proteins from five herpes viruses, and determining relative protein duplication order in the bZIP family. Our approach more accurately reconstructs ancestral interactions than existing approaches. In cross-validation tests, we find that our approach ranks the majority of the left out present-day interactions among the top 2 and 17% of possible edges for the bZIP and herpes networks, respectively, making it a competitive approach for edge imputation. It also estimates relative bZIP protein duplication orders, using only interaction data and phylogenetic tree topology, which are significantly correlated with sequence-based estimates. AVAILABILITY: The algorithm is implemented in C++, is open source and is available at http://www.cs.cmu.edu/ckingsf/software/parana2. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23812990 TI - ThreaDom: extracting protein domain boundary information from multiple threading alignments. AB - MOTIVATION: Protein domains are subunits that can fold and evolve independently. Identification of domain boundary locations is often the first step in protein folding and function annotations. Most of the current methods deduce domain boundaries by sequence-based analysis, which has low accuracy. There is no efficient method for predicting discontinuous domains that consist of segments from separated sequence regions. As template-based methods are most efficient for protein 3D structure modeling, combining multiple threading alignment information should increase the accuracy and reliability of computational domain predictions. RESULT: We developed a new protein domain predictor, ThreaDom, which deduces domain boundary locations based on multiple threading alignments. The core of the method development is the derivation of a domain conservation score that combines information from template domain structures and terminal and internal alignment gaps. Tested on 630 non-redundant sequences, without using homologous templates, ThreaDom generates correct single- and multi-domain classifications in 81% of cases, where 78% have the domain linker assigned within +/-20 residues. In a second test on 486 proteins with discontinuous domains, ThreaDom achieves an average precision 84% and recall 65% in domain boundary prediction. Finally, ThreaDom was examined on 56 targets from CASP8 and had a domain overlap rate 73, 87 and 85% with the target for Free Modeling, Hard multiple-domain and discontinuous domain proteins, respectively, which are significantly higher than most domain predictors in the CASP8. Similar results were achieved on the targets from the most recently CASP9 and CASP10 experiments. AVAILABILITY: http://zhanglab.ccmb.med.umich.edu/ThreaDom/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23812991 TI - Protein threading using context-specific alignment potential. AB - MOTIVATION: Template-based modeling, including homology modeling and protein threading, is the most reliable method for protein 3D structure prediction. However, alignment errors and template selection are still the main bottleneck for current template-base modeling methods, especially when proteins under consideration are distantly related. RESULTS: We present a novel context-specific alignment potential for protein threading, including alignment and template selection. Our alignment potential measures the log-odds ratio of one alignment being generated from two related proteins to being generated from two unrelated proteins, by integrating both local and global context-specific information. The local alignment potential quantifies how well one sequence residue can be aligned to one template residue based on context-specific information of the residues. The global alignment potential quantifies how well two sequence residues can be placed into two template positions at a given distance, again based on context specific information. By accounting for correlation among a variety of protein features and making use of context-specific information, our alignment potential is much more sensitive than the widely used context-independent or profile-based scoring function. Experimental results confirm that our method generates significantly better alignments and threading results than the best profile-based methods on several large benchmarks. Our method works particularly well for distantly related proteins or proteins with sparse sequence profiles because of the effective integration of context-specific, structure and global information. AVAILABILITY: http://raptorx.uchicago.edu/download/. PMID- 23812992 TI - Predicting protein contact map using evolutionary and physical constraints by integer programming. AB - MOTIVATION: Protein contact map describes the pairwise spatial and functional relationship of residues in a protein and contains key information for protein 3D structure prediction. Although studied extensively, it remains challenging to predict contact map using only sequence information. Most existing methods predict the contact map matrix element-by-element, ignoring correlation among contacts and physical feasibility of the whole-contact map. A couple of recent methods predict contact map by using mutual information, taking into consideration contact correlation and enforcing a sparsity restraint, but these methods demand for a very large number of sequence homologs for the protein under consideration and the resultant contact map may be still physically infeasible. RESULTS: This article presents a novel method PhyCMAP for contact map prediction, integrating both evolutionary and physical restraints by machine learning and integer linear programming. The evolutionary restraints are much more informative than mutual information, and the physical restraints specify more concrete relationship among contacts than the sparsity restraint. As such, our method greatly reduces the solution space of the contact map matrix and, thus, significantly improves prediction accuracy. Experimental results confirm that PhyCMAP outperforms currently popular methods no matter how many sequence homologs are available for the protein under consideration. AVAILABILITY: http://raptorx.uchicago.edu. PMID- 23812993 TI - Automated annotation of gene expression image sequences via non-parametric factor analysis and conditional random fields. AB - MOTIVATION: Computational approaches for the annotation of phenotypes from image data have shown promising results across many applications, and provide rich and valuable information for studying gene function and interactions. While data are often available both at high spatial resolution and across multiple time points, phenotypes are frequently annotated independently, for individual time points only. In particular, for the analysis of developmental gene expression patterns, it is biologically sensible when images across multiple time points are jointly accounted for, such that spatial and temporal dependencies are captured simultaneously. METHODS: We describe a discriminative undirected graphical model to label gene-expression time-series image data, with an efficient training and decoding method based on the junction tree algorithm. The approach is based on an effective feature selection technique, consisting of a non-parametric sparse Bayesian factor analysis model. The result is a flexible framework, which can handle large-scale data with noisy incomplete samples, i.e. it can tolerate data missing from individual time points. RESULTS: Using the annotation of gene expression patterns across stages of Drosophila embryonic development as an example, we demonstrate that our method achieves superior accuracy, gained by jointly annotating phenotype sequences, when compared with previous models that annotate each stage in isolation. The experimental results on missing data indicate that our joint learning method successfully annotates genes for which no expression data are available for one or more stages. PMID- 23812994 TI - Automated target segmentation and real space fast alignment methods for high throughput classification and averaging of crowded cryo-electron subtomograms. AB - MOTIVATION: Cryo-electron tomography allows the imaging of macromolecular complexes in near living conditions. To enhance the nominal resolution of a structure it is necessary to align and average individual subtomograms each containing identical complexes. However, if the sample of complexes is heterogeneous, it is necessary to first classify subtomograms into groups of identical complexes. This task becomes challenging when tomograms contain mixtures of unknown complexes extracted from a crowded environment. Two main challenges must be overcomed: First, classification of subtomograms must be performed without knowledge of template structures. However, most alignment methods are too slow to perform reference-free classification of a large number of (e.g. tens of thousands) of subtomograms. Second, subtomograms extracted from crowded cellular environments, contain often fragments of other structures besides the target complex. However, alignment methods generally assume that each subtomogram only contains one complex. Automatic methods are needed to identify the target complexes in a subtomogram even when its shape is unknown. RESULTS: In this article, we propose an automatic and systematic method for the isolation and masking of target complexes in subtomograms extracted from crowded environments. Moreover, we also propose a fast alignment method using fast rotational matching in real space. Our experiments show that, compared with our previously proposed fast alignment method in reciprocal space, our new method significantly improves the alignment accuracy for highly distorted and especially crowded subtomograms. Such improvements are important for achieving successful and unbiased high throughput reference-free structural classification of complexes inside whole cell tomograms. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23812995 TI - Compressive genomics for protein databases. AB - MOTIVATION: The exponential growth of protein sequence databases has increasingly made the fundamental question of searching for homologs a computational bottleneck. The amount of unique data, however, is not growing nearly as fast; we can exploit this fact to greatly accelerate homology search. Acceleration of programs in the popular PSI/DELTA-BLAST family of tools will not only speed-up homology search directly but also the huge collection of other current programs that primarily interact with large protein databases via precisely these tools. RESULTS: We introduce a suite of homology search tools, powered by compressively accelerated protein BLAST (CaBLASTP), which are significantly faster than and comparably accurate with all known state-of-the-art tools, including HHblits, DELTA-BLAST and PSI-BLAST. Further, our tools are implemented in a manner that allows direct substitution into existing analysis pipelines. The key idea is that we introduce a local similarity-based compression scheme that allows us to operate directly on the compressed data. Importantly, CaBLASTP's runtime scales almost linearly in the amount of unique data, as opposed to current BLASTP variants, which scale linearly in the size of the full protein database being searched. Our compressive algorithms will speed-up many tasks, such as protein structure prediction and orthology mapping, which rely heavily on homology search. AVAILABILITY: CaBLASTP is available under the GNU Public License at http://cablastp.csail.mit.edu/ CONTACT: bab@mit.edu. PMID- 23812996 TI - GeneScissors: a comprehensive approach to detecting and correcting spurious transcriptome inference owing to RNA-seq reads misalignment. AB - MOTIVATION: RNA-seq techniques provide an unparalleled means for exploring a transcriptome with deep coverage and base pair level resolution. Various analysis tools have been developed to align and assemble RNA-seq data, such as the widely used TopHat/Cufflinks pipeline. A common observation is that a sizable fraction of the fragments/reads align to multiple locations of the genome. These multiple alignments pose substantial challenges to existing RNA-seq analysis tools. Inappropriate treatment may result in reporting spurious expressed genes (false positives) and missing the real expressed genes (false negatives). Such errors impact the subsequent analysis, such as differential expression analysis. In our study, we observe that ~3.5% of transcripts reported by TopHat/Cufflinks pipeline correspond to annotated nonfunctional pseudogenes. Moreover, ~10.0% of reported transcripts are not annotated in the Ensembl database. These genes could be either novel expressed genes or false discoveries. RESULTS: We examine the underlying genomic features that lead to multiple alignments and investigate how they generate systematic errors in RNA-seq analysis. We develop a general tool, GeneScissors, which exploits machine learning techniques guided by biological knowledge to detect and correct spurious transcriptome inference by existing RNA seq analysis methods. In our simulated study, GeneScissors can predict spurious transcriptome calls owing to misalignment with an accuracy close to 90%. It provides substantial improvement over the widely used TopHat/Cufflinks or MapSplice/Cufflinks pipelines in both precision and F-measurement. On real data, GeneScissors reports 53.6% less pseudogenes and 0.97% more expressed and annotated transcripts, when compared with the TopHat/Cufflinks pipeline. In addition, among the 10.0% unannotated transcripts reported by TopHat/Cufflinks, GeneScissors finds that >16.3% of them are false positives. AVAILABILITY: The software can be downloaded at http://csbio.unc.edu/genescissors/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23812998 TI - The RNA Newton polytope and learnability of energy parameters. AB - MOTIVATION: Computational RNA structure prediction is a mature important problem that has received a new wave of attention with the discovery of regulatory non coding RNAs and the advent of high-throughput transcriptome sequencing. Despite nearly two score years of research on RNA secondary structure and RNA-RNA interaction prediction, the accuracy of the state-of-the-art algorithms are still far from satisfactory. So far, researchers have proposed increasingly complex energy models and improved parameter estimation methods, experimental and/or computational, in anticipation of endowing their methods with enough power to solve the problem. The output has disappointingly been only modest improvements, not matching the expectations. Even recent massively featured machine learning approaches were not able to break the barrier. Why is that? APPROACH: The first step toward high-accuracy structure prediction is to pick an energy model that is inherently capable of predicting each and every one of known structures to date. In this article, we introduce the notion of learnability of the parameters of an energy model as a measure of such an inherent capability. We say that the parameters of an energy model are learnable iff there exists at least one set of such parameters that renders every known RNA structure to date the minimum free energy structure. We derive a necessary condition for the learnability and give a dynamic programming algorithm to assess it. Our algorithm computes the convex hull of the feature vectors of all feasible structures in the ensemble of a given input sequence. Interestingly, that convex hull coincides with the Newton polytope of the partition function as a polynomial in energy parameters. To the best of our knowledge, this is the first approach toward computing the RNA Newton polytope and a systematic assessment of the inherent capabilities of an energy model. The worst case complexity of our algorithm is exponential in the number of features. However, dimensionality reduction techniques can provide approximate solutions to avoid the curse of dimensionality. RESULTS: We demonstrated the application of our theory to a simple energy model consisting of a weighted count of A-U, C-G and G-U base pairs. Our results show that this simple energy model satisfies the necessary condition for more than half of the input unpseudoknotted sequence-structure pairs (55%) chosen from the RNA STRAND v2.0 database and severely violates the condition for ~ 13%, which provide a set of hard cases that require further investigation. From 1350 RNA strands, the observed 3D feature vector for 749 strands is on the surface of the computed polytope. For 289 RNA strands, the observed feature vector is not on the boundary of the polytope but its distance from the boundary is not more than one. A distance of one essentially means one base pair difference between the observed structure and the closest point on the boundary of the polytope, which need not be the feature vector of a structure. For 171 sequences, this distance is larger than two, and for only 11 sequences, this distance is larger than five. AVAILABILITY: The source code is available on http://compbio.cs.wayne.edu/software/rna-newton polytope. PMID- 23812999 TI - A weighted sampling algorithm for the design of RNA sequences with targeted secondary structure and nucleotide distribution. AB - MOTIVATIONS: The design of RNA sequences folding into predefined secondary structures is a milestone for many synthetic biology and gene therapy studies. Most of the current software uses similar local search strategies (i.e. a random seed is progressively adapted to acquire the desired folding properties) and more importantly do not allow the user to control explicitly the nucleotide distribution such as the GC-content in their sequences. However, the latter is an important criterion for large-scale applications as it could presumably be used to design sequences with better transcription rates and/or structural plasticity. RESULTS: In this article, we introduce IncaRNAtion, a novel algorithm to design RNA sequences folding into target secondary structures with a predefined nucleotide distribution. IncaRNAtion uses a global sampling approach and weighted sampling techniques. We show that our approach is fast (i.e. running time comparable or better than local search methods), seedless (we remove the bias of the seed in local search heuristics) and successfully generates high-quality sequences (i.e. thermodynamically stable) for any GC-content. To complete this study, we develop a hybrid method combining our global sampling approach with local search strategies. Remarkably, our glocal methodology overcomes both local and global approaches for sampling sequences with a specific GC-content and target structure. AVAILABILITY: IncaRNAtion is available at csb.cs.mcgill.ca/incarnation/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23813000 TI - Poly(A) motif prediction using spectral latent features from human DNA sequences. AB - MOTIVATION: Polyadenylation is the addition of a poly(A) tail to an RNA molecule. Identifying DNA sequence motifs that signal the addition of poly(A) tails is essential to improved genome annotation and better understanding of the regulatory mechanisms and stability of mRNA. Existing poly(A) motif predictors demonstrate that information extracted from the surrounding nucleotide sequences of candidate poly(A) motifs can differentiate true motifs from the false ones to a great extent. A variety of sophisticated features has been explored, including sequential, structural, statistical, thermodynamic and evolutionary properties. However, most of these methods involve extensive manual feature engineering, which can be time-consuming and can require in-depth domain knowledge. RESULTS: We propose a novel machine-learning method for poly(A) motif prediction by marrying generative learning (hidden Markov models) and discriminative learning (support vector machines). Generative learning provides a rich palette on which the uncertainty and diversity of sequence information can be handled, while discriminative learning allows the performance of the classification task to be directly optimized. Here, we used hidden Markov models for fitting the DNA sequence dynamics, and developed an efficient spectral algorithm for extracting latent variable information from these models. These spectral latent features were then fed into support vector machines to fine-tune the classification performance. We evaluated our proposed method on a comprehensive human poly(A) dataset that consists of 14 740 samples from 12 of the most abundant variants of human poly(A) motifs. Compared with one of the previous state-of-the-art methods in the literature (the random forest model with expert-crafted features), our method reduces the average error rate, false-negative rate and false-positive rate by 26, 15 and 35%, respectively. Meanwhile, our method makes ~30% fewer error predictions relative to the other string kernels. Furthermore, our method can be used to visualize the importance of oligomers and positions in predicting poly(A) motifs, from which we can observe a number of characteristics in the surrounding regions of true and false motifs that have not been reported before. AVAILABILITY: http://sfb.kaust.edu.sa/Pages/Software.aspx. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23813001 TI - IDBA-tran: a more robust de novo de Bruijn graph assembler for transcriptomes with uneven expression levels. AB - MOTIVATION: RNA sequencing based on next-generation sequencing technology is effective for analyzing transcriptomes. Like de novo genome assembly, de novo transcriptome assembly does not rely on any reference genome or additional annotation information, but is more difficult. In particular, isoforms can have very uneven expression levels (e.g. 1:100), which make it very difficult to identify low-expressed isoforms. One challenge is to remove erroneous vertices/edges with high multiplicity (produced by high-expressed isoforms) in the de Bruijn graph without removing correct ones with not-so-high multiplicity from low-expressed isoforms. Failing to do so will result in the loss of low expressed isoforms or having complicated subgraphs with transcripts of different genes mixed together due to erroneous vertices/edges. Contributions: Unlike existing tools, which remove erroneous vertices/edges with multiplicities lower than a global threshold, we use a probabilistic progressive approach to iteratively remove them with local thresholds. This enables us to decompose the graph into disconnected components, each containing a few genes, if not a single gene, while retaining many correct vertices/edges of low-expressed isoforms. Combined with existing techniques, IDBA-Tran is able to assemble both high expressed and low-expressed transcripts and outperform existing assemblers in terms of sensitivity and specificity for both simulated and real data. AVAILABILITY: http://www.cs.hku.hk/~alse/idba_tran. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23813003 TI - Using state machines to model the Ion Torrent sequencing process and to improve read error rates. AB - MOTIVATION: The importance of fast and affordable DNA sequencing methods for current day life sciences, medicine and biotechnology is hard to overstate. A major player is Ion Torrent, a pyrosequencing-like technology which produces flowgrams--sequences of incorporation values--which are converted into nucleotide sequences by a base-calling algorithm. Because of its exploitation of ubiquitous semiconductor technology and innovation in chemistry, Ion Torrent has been gaining popularity since its debut in 2011. Despite the advantages, however, Ion Torrent read accuracy remains a significant concern. RESULTS: We present FlowgramFixer, a new algorithm for converting flowgrams into reads. Our key observation is that the incorporation signals of neighboring flows, even after normalization and phase correction, carry considerable mutual information and are important in making the correct base-call. We therefore propose that base-calling of flowgrams should be done on a read-wide level, rather than one flow at a time. We show that this can be done in linear-time by combining a state machine with a Viterbi algorithm to find the nucleotide sequence that maximizes the likelihood of the observed flowgram. FlowgramFixer is applicable to any flowgram-based sequencing platform. We demonstrate FlowgramFixer's superior performance on Ion Torrent Escherichia coli data, with a 4.8% improvement in the number of high quality mapped reads and a 7.1% improvement in the number of uniquely mappable reads. AVAILABILITY: Binaries and source code of FlowgramFixer are freely available at: http://www.cs.tau.ac.il/~davidgo5/flowgramfixer.html. PMID- 23813002 TI - A graph kernel approach for alignment-free domain-peptide interaction prediction with an application to human SH3 domains. AB - MOTIVATION: State-of-the-art experimental data for determining binding specificities of peptide recognition modules (PRMs) is obtained by high throughput approaches like peptide arrays. Most prediction tools applicable to this kind of data are based on an initial multiple alignment of the peptide ligands. Building an initial alignment can be error-prone, especially in the case of the proline-rich peptides bound by the SH3 domains. RESULTS: Here, we present a machine-learning approach based on an efficient graph-kernel technique to predict the specificity of a large set of 70 human SH3 domains, which are an important class of PRMs. The graph-kernel strategy allows us to (i) integrate several types of physico-chemical information for each amino acid, (ii) consider high-order correlations between these features and (iii) eliminate the need for an initial peptide alignment. We build specialized models for each human SH3 domain and achieve competitive predictive performance of 0.73 area under precision-recall curve, compared with 0.27 area under precision-recall curve for state-of-the-art methods based on position weight matrices. We show that better models can be obtained when we use information on the noninteracting peptides (negative examples), which is currently not used by the state-of-the art approaches based on position weight matrices. To this end, we analyze two strategies to identify subsets of high confidence negative data. The techniques introduced here are more general and hence can also be used for any other protein domains, which interact with short peptides (i.e. other PRMs). AVAILABILITY: The program with the predictive models can be found at http://www.bioinf.uni freiburg.de/Software/SH3PepInt/SH3PepInt.tar.gz. We also provide a genome-wide prediction for all 70 human SH3 domains, which can be found under http://www.bioinf.uni-freiburg.de/Software/SH3PepInt/Genome-Wide Predictions.tar.gz. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23813004 TI - Haplotype assembly in polyploid genomes and identical by descent shared tracts. AB - MOTIVATION: Genome-wide haplotype reconstruction from sequence data, or haplotype assembly, is at the center of major challenges in molecular biology and life sciences. For complex eukaryotic organisms like humans, the genome is vast and the population samples are growing so rapidly that algorithms processing high throughput sequencing data must scale favorably in terms of both accuracy and computational efficiency. Furthermore, current models and methodologies for haplotype assembly (i) do not consider individuals sharing haplotypes jointly, which reduces the size and accuracy of assembled haplotypes, and (ii) are unable to model genomes having more than two sets of homologous chromosomes (polyploidy). Polyploid organisms are increasingly becoming the target of many research groups interested in the genomics of disease, phylogenetics, botany and evolution but there is an absence of theory and methods for polyploid haplotype reconstruction. RESULTS: In this work, we present a number of results, extensions and generalizations of compass graphs and our HapCompass framework. We prove the theoretical complexity of two haplotype assembly optimizations, thereby motivating the use of heuristics. Furthermore, we present graph theory-based algorithms for the problem of haplotype assembly using our previously developed HapCompass framework for (i) novel implementations of haplotype assembly optimizations (minimum error correction), (ii) assembly of a pair of individuals sharing a haplotype tract identical by descent and (iii) assembly of polyploid genomes. We evaluate our methods on 1000 Genomes Project, Pacific Biosciences and simulated sequence data. AVAILABILITY AND IMPLEMENTATION: HapCompass is available for download at http://www.brown.edu/Research/Istrail_Lab/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23813005 TI - FuncISH: learning a functional representation of neural ISH images. AB - MOTIVATION: High-spatial resolution imaging datasets of mammalian brains have recently become available in unprecedented amounts. Images now reveal highly complex patterns of gene expression varying on multiple scales. The challenge in analyzing these images is both in extracting the patterns that are most relevant functionally and in providing a meaningful representation that allows neuroscientists to interpret the extracted patterns. RESULTS: Here, we present FuncISH--a method to learn functional representations of neural in situ hybridization (ISH) images. We represent images using a histogram of local descriptors in several scales, and we use this representation to learn detectors of functional (GO) categories for every image. As a result, each image is represented as a point in a low-dimensional space whose axes correspond to meaningful functional annotations. The resulting representations define similarities between ISH images that can be easily explained by functional categories. We applied our method to the genomic set of mouse neural ISH images available at the Allen Brain Atlas, finding that most neural biological processes can be inferred from spatial expression patterns with high accuracy. Using functional representations, we predict several gene interaction properties, such as protein-protein interactions and cell-type specificity, more accurately than competing methods based on global correlations. We used FuncISH to identify similar expression patterns of GABAergic neuronal markers that were not previously identified and to infer new gene function based on image-image similarities. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23813006 TI - Short read alignment with populations of genomes. AB - SUMMARY: The increasing availability of high-throughput sequencing technologies has led to thousands of human genomes having been sequenced in the past years. Efforts such as the 1000 Genomes Project further add to the availability of human genome variation data. However, to date, there is no method that can map reads of a newly sequenced human genome to a large collection of genomes. Instead, methods rely on aligning reads to a single reference genome. This leads to inherent biases and lower accuracy. To tackle this problem, a new alignment tool BWBBLE is introduced in this article. We (i) introduce a new compressed representation of a collection of genomes, which explicitly tackles the genomic variation observed at every position, and (ii) design a new alignment algorithm based on the Burrows Wheeler transform that maps short reads from a newly sequenced genome to an arbitrary collection of two or more (up to millions of) genomes with high accuracy and no inherent bias to one specific genome. AVAILABILITY: http://viq854.github.com/bwbble. PMID- 23813008 TI - A method for integrating and ranking the evidence for biochemical pathways by mining reactions from text. AB - MOTIVATION: To create, verify and maintain pathway models, curators must discover and assess knowledge distributed over the vast body of biological literature. Methods supporting these tasks must understand both the pathway model representations and the natural language in the literature. These methods should identify and order documents by relevance to any given pathway reaction. No existing system has addressed all aspects of this challenge. METHOD: We present novel methods for associating pathway model reactions with relevant publications. Our approach extracts the reactions directly from the models and then turns them into queries for three text mining-based MEDLINE literature search systems. These queries are executed, and the resulting documents are combined and ranked according to their relevance to the reactions of interest. We manually annotate document-reaction pairs with the relevance of the document to the reaction and use this annotation to study several ranking methods, using various heuristic and machine-learning approaches. RESULTS: Our evaluation shows that the annotated document-reaction pairs can be used to create a rule-based document ranking system, and that machine learning can be used to rank documents by their relevance to pathway reactions. We find that a Support Vector Machine-based system outperforms several baselines and matches the performance of the rule based system. The success of the query extraction and ranking methods are used to update our existing pathway search system, PathText. AVAILABILITY: An online demonstration of PathText 2 and the annotated corpus are available for research purposes at http://www.nactem.ac.uk/pathtext2/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23813009 TI - Information-theoretic evaluation of predicted ontological annotations. AB - MOTIVATION: The development of effective methods for the prediction of ontological annotations is an important goal in computational biology, with protein function prediction and disease gene prioritization gaining wide recognition. Although various algorithms have been proposed for these tasks, evaluating their performance is difficult owing to problems caused both by the structure of biomedical ontologies and biased or incomplete experimental annotations of genes and gene products. RESULTS: We propose an information theoretic framework to evaluate the performance of computational protein function prediction. We use a Bayesian network, structured according to the underlying ontology, to model the prior probability of a protein's function. We then define two concepts, misinformation and remaining uncertainty, that can be seen as information-theoretic analogs of precision and recall. Finally, we propose a single statistic, referred to as semantic distance, that can be used to rank classification models. We evaluate our approach by analyzing the performance of three protein function predictors of Gene Ontology terms and provide evidence that it addresses several weaknesses of currently used metrics. We believe this framework provides useful insights into the performance of protein function prediction tools. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23813010 TI - Learning subgroup-specific regulatory interactions and regulator independence with PARADIGM. AB - High-dimensional '-omics' profiling provides a detailed molecular view of individual cancers; however, understanding the mechanisms by which tumors evade cellular defenses requires deep knowledge of the underlying cellular pathways within each cancer sample. We extended the PARADIGM algorithm (Vaske et al., 2010, Bioinformatics, 26, i237-i245), a pathway analysis method for combining multiple '-omics' data types, to learn the strength and direction of 9139 gene and protein interactions curated from the literature. Using genomic and mRNA expression data from 1936 samples in The Cancer Genome Atlas (TCGA) cohort, we learned interactions that provided support for and relative strength of 7138 (78%) of the curated links. Gene set enrichment found that genes involved in the strongest interactions were significantly enriched for transcriptional regulation, apoptosis, cell cycle regulation and response to tumor cells. Within the TCGA breast cancer cohort, we assessed different interaction strengths between breast cancer subtypes, and found interactions associated with the MYC pathway and the ER alpha network to be among the most differential between basal and luminal A subtypes. PARADIGM with the Naive Bayesian assumption produced gene activity predictions that, when clustered, found groups of patients with better separation in survival than both the original version of PARADIGM and a version without the assumption. We found that this Naive Bayes assumption was valid for the vast majority of co-regulators, indicating that most co-regulators act independently on their shared target. AVAILABILITY: http://paradigm.five3genomics.com. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23813011 TI - Design of shortest double-stranded DNA sequences covering all k-mers with applications to protein-binding microarrays and synthetic enhancers. AB - MOTIVATION: Novel technologies can generate large sets of short double-stranded DNA sequences that can be used to measure their regulatory effects. Microarrays can measure in vitro the binding intensity of a protein to thousands of probes. Synthetic enhancer sequences inserted into an organism's genome allow us to measure in vivo the effect of such sequences on the phenotype. In both applications, by using sequence probes that cover all k-mers, a comprehensive picture of the effect of all possible short sequences on gene regulation is obtained. The value of k that can be used in practice is, however, severely limited by cost and space considerations. A key challenge is, therefore, to cover all k-mers with a minimal number of probes. The standard way to do this uses the de Bruijn sequence of length . However, as probes are double stranded, when a k mer is included in a probe, its reverse complement k-mer is accounted for as well. RESULTS: Here, we show how to efficiently create a shortest possible sequence with the property that it contains each k-mer or its reverse complement, but not necessarily both. The length of the resulting sequence approaches half that of the de Bruijn sequence as k increases resulting in a more efficient array, which allows covering more longer sequences; alternatively, additional sequences with redundant k-mers of interest can be added. AVAILABILITY: The software is freely available from our website http://acgt.cs.tau.ac.il/shortcake/. PMID- 23813012 TI - Hard-wired heterogeneity in blood stem cells revealed using a dynamic regulatory network model. AB - MOTIVATION: Combinatorial interactions of transcription factors with cis regulatory elements control the dynamic progression through successive cellular states and thus underpin all metazoan development. The construction of network models of cis-regulatory elements, therefore, has the potential to generate fundamental insights into cellular fate and differentiation. Haematopoiesis has long served as a model system to study mammalian differentiation, yet modelling based on experimentally informed cis-regulatory interactions has so far been restricted to pairs of interacting factors. Here, we have generated a Boolean network model based on detailed cis-regulatory functional data connecting 11 haematopoietic stem/progenitor cell (HSPC) regulator genes. RESULTS: Despite its apparent simplicity, the model exhibits surprisingly complex behaviour that we charted using strongly connected components and shortest-path analysis in its Boolean state space. This analysis of our model predicts that HSPCs display heterogeneous expression patterns and possess many intermediate states that can act as 'stepping stones' for the HSPC to achieve a final differentiated state. Importantly, an external perturbation or 'trigger' is required to exit the stem cell state, with distinct triggers characterizing maturation into the various different lineages. By focusing on intermediate states occurring during erythrocyte differentiation, from our model we predicted a novel negative regulation of Fli1 by Gata1, which we confirmed experimentally thus validating our model. In conclusion, we demonstrate that an advanced mammalian regulatory network model based on experimentally validated cis-regulatory interactions has allowed us to make novel, experimentally testable hypotheses about transcriptional mechanisms that control differentiation of mammalian stem cells. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23813013 TI - Integrating sequence, expression and interaction data to determine condition specific miRNA regulation. AB - MOTIVATION: MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post-transcriptionally. MiRNAs were shown to play an important role in development and disease, and accurately determining the networks regulated by these miRNAs in a specific condition is of great interest. Early work on miRNA target prediction has focused on using static sequence information. More recently, researchers have combined sequence and expression data to identify such targets in various conditions. RESULTS: We developed the Protein Interaction based MicroRNA Modules (PIMiM), a regression-based probabilistic method that integrates sequence, expression and interaction data to identify modules of mRNAs controlled by small sets of miRNAs. We formulate an optimization problem and develop a learning framework to determine the module regulation and membership. Applying PIMiM to cancer data, we show that by adding protein interaction data and modeling cooperative regulation of mRNAs by a small number of miRNAs, PIMiM can accurately identify both miRNA and their targets improving on previous methods. We next used PIMiM to jointly analyze a number of different types of cancers and identified both common and cancer-type-specific miRNA regulators. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23813015 TI - A framework for scalable parameter estimation of gene circuit models using structural information. AB - MOTIVATION: Systematic and scalable parameter estimation is a key to construct complex gene regulatory models and to ultimately facilitate an integrative systems biology approach to quantitatively understand the molecular mechanisms underpinning gene regulation. RESULTS: Here, we report a novel framework for efficient and scalable parameter estimation that focuses specifically on modeling of gene circuits. Exploiting the structure commonly found in gene circuit models, this framework decomposes a system of coupled rate equations into individual ones and efficiently integrates them separately to reconstruct the mean time evolution of the gene products. The accuracy of the parameter estimates is refined by iteratively increasing the accuracy of numerical integration using the model structure. As a case study, we applied our framework to four gene circuit models with complex dynamics based on three synthetic datasets and one time series microarray data set. We compared our framework to three state-of-the-art parameter estimation methods and found that our approach consistently generated higher quality parameter solutions efficiently. Although many general-purpose parameter estimation methods have been applied for modeling of gene circuits, our results suggest that the use of more tailored approaches to use domain-specific information may be a key to reverse engineering of complex biological systems. AVAILABILITY: http://sfb.kaust.edu.sa/Pages/Software.aspx. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23813014 TI - A high-throughput framework to detect synapses in electron microscopy images. AB - MOTIVATION: Synaptic connections underlie learning and memory in the brain and are dynamically formed and eliminated during development and in response to stimuli. Quantifying changes in overall density and strength of synapses is an important pre-requisite for studying connectivity and plasticity in these cases or in diseased conditions. Unfortunately, most techniques to detect such changes are either low-throughput (e.g. electrophysiology), prone to error and difficult to automate (e.g. standard electron microscopy) or too coarse (e.g. magnetic resonance imaging) to provide accurate and large-scale measurements. RESULTS: To facilitate high-throughput analyses, we used a 50-year-old experimental technique to selectively stain for synapses in electron microscopy images, and we developed a machine-learning framework to automatically detect synapses in these images. To validate our method, we experimentally imaged brain tissue of the somatosensory cortex in six mice. We detected thousands of synapses in these images and demonstrate the accuracy of our approach using cross-validation with manually labeled data and by comparing against existing algorithms and against tools that process standard electron microscopy images. We also used a semi-supervised algorithm that leverages unlabeled data to overcome sample heterogeneity and improve performance. Our algorithms are highly efficient and scalable and are freely available for others to use. AVAILABILITY: Code is available at http://www.cs.cmu.edu/~saketn/detect_synapses/ PMID- 23813016 TI - A suite of new genes defining salinity stress tolerance in seedlings of contrasting rice genotypes. AB - Salinity is one of the major constraints adversely influencing crop productivity. Saltol QTL is a major QTL associated with Na+-K+ ratio and seedling stage salinity tolerance in rice. With an aim to understand the contribution of individual genes localized within saltol towards salinity tolerance, we analysed the transcript abundance of a set of these genes in seedlings of contrasting genotypes of rice. We hypothesize that this approach may be helpful in identifying new 'candidate genes' for improving salinity tolerance in crops. For this purpose, seedlings of Oryza sativa cv. IR64 (sensitive) and the landrace Pokkali (tolerant) were subjected to short/long durations of salinity. qRT-PCR analysis clearly exhibited differential regulation of genes encoding signaling related protein (SRPs), where higher transcript abundance for most of them was observed in Pokkali than IR64 under non-stress conditions, thereby indicating towards well preparedness of the former to handle stress, in anticipation. Genes encoding proteins of unknown function (PUFs), though, constitute a considerable portion of plant genome, have so far been neglected in most studies. Time course analysis of these genes showed a continuous increase in their abundance in Pokkali, while in IR64, their abundance increased till 24 h followed by a clear decrease, thereby justifying their nomenclature as 'salinity induced factors' (SIFs). This is the first report showing possible involvement of SIFs localized within salinity related QTL towards salinity stress response. Based on the phenotypes of insertional mutants, it is proposed that these SIFs may have a putative function in vegetative growth (SIFVG), fertility (SIFF), viability (SIFV) or early flowering (SIFEF). PMID- 23813017 TI - Reproducibility of functional network metrics and network structure: a comparison of task-related BOLD, resting ASL with BOLD contrast, and resting cerebral blood flow. AB - Network analysis is an emerging approach to functional connectivity in which the brain is construed as a graph and its connectivity and information processing estimated by mathematical characterizations of graphs. There has been little to no work examining the reproducibility of network metrics derived from different types of functional magnetic resonance imaging (fMRI) data (e.g., resting vs. task related, or pulse sequences other than standard blood oxygen level dependent [BOLD] data) or of measures of network structure at levels other than summary statistics. Here, we take up these questions, comparing the reproducibility of graphs derived from resting arterial spin-labeling perfusion fMRI with those derived from BOLD scans collected while the participant was performing a task. We also examine the reproducibility of the anatomical connectivity implied by the graph by investigating test-retest consistency of the graphs' edges. We compare two measures of graph-edge consistency both within versus between subjects and across data types. We find a dissociation in the reproducibility of network metrics, with metrics from resting data most reproducible at lower frequencies and metrics from task-related data most reproducible at higher frequencies; that same dissociation is not recapitulated, however, in network structure, for which the task-related data are most consistent at all frequencies. Implications for the practice of network analysis are discussed. PMID- 23813018 TI - Bone metastasis from breast cancer involves elevated IL-11 expression and the gp130/STAT3 pathway. AB - To evaluate the relationship between IL-11 and bone metastasis in patients with breast cancer and explore the potential molecular mechanism, total serum samples were collected from 180 breast cancer patients and 20 women without breast cancer. The serum expression level of interleukin (IL)-11, connective tissue growth factor (CTGF), transforming growth factor-beta, and Tracp5b was determined by enzyme-linked immunosorbent assay, and mRNA expression of IL-11 in fresh breast cancer tissue was determined by RT-PCR. Immunohistochemical staining was used to detect the expression of IL-11 and CTGF in breast cancer tissue, and Western blot was used to detect the expression of p-38, p-C-JUN, p-STAT3, and p gp130 in fresh breast cancer tissue. DNA-binding activity of AP-1 was examined by electrophoretic mobility shift assay. Differences were statistically analyzed between the group with breast cancer metastatic to bone (MBC-B) and the group with only primary breast cancer (PBC). Serum level and mRNA expression of IL-11 in the MBC-B group were significantly higher than those in the PBC group. IL-11 immunohistochemical staining showed that the percentage of positively stained cells in the MBC-B group (57.5 %) was significantly higher than that in the PBC group (14.29 %). Western blot analysis showed higher expression of p-p38, p-C JUN, p-STAT3, and p-gp130 in the MBC-B group than in the PBC group. DNA-binding activity of AP-1 was significantly higher in the MBC-B group than in the PBC group. These data suggest that IL-11 is associated with bone metastasis and may be of value for predicting bone metastasis from breast cancer. PMID- 23813019 TI - Non-cancer-related mortality after cisplatin-based adjuvant chemotherapy for non small cell lung cancer: a study-level meta-analysis of 16 randomized trials. AB - Adjuvant chemotherapy is associated with increased overall survival in non-small cell lung cancer (NSCLC), but is associated with high-grade toxicity. The effect of cisplatin-based adjuvant chemotherapy on non-lung cancer-related mortality is not well investigated. We conducted a systematic review and a study-level meta analysis of published randomized controlled trials (RCTs) in order to determine the overall risk of non-lung cancer-related mortality associated with adjuvant cisplatin-based chemotherapy in NSCLC. PubMed was searched to identify relevant studies. Eligible publications included prospective RCTs in which cisplatin-based adjuvant chemotherapy plus local therapy was compared with local therapy alone in NSCLC. Summary incidence rates, relative risks (RRs), and 95 % confidence intervals (CIs) were calculated using fixed- or random-effects models. Primary endpoint was non-lung cancer-related mortality risk (due to cardiovascular, respiratory or second malignancy deaths for example), and secondary endpoints were chemotherapy-related, second primary tumor-related, cardiovascular-related, and unknown cause mortalities. A total of 6,430 patients with NSCLC from 16 RCTs were included in the analysis. Compared with no chemotherapy, the use of cisplatin-based adjuvant chemotherapy was associated with an increased risk of non-lung cancer-related death, with an RR of 1.30 (95 % CI 1.1-1.53; P = 0.002; incidence, 9.3 vs. 7.2 %; absolute difference 2 %). Cisplatin-based adjuvant chemotherapy was also associated with a greater risk of chemotherapy-related mortality (RR 2.16, 95 % CI 1.15-4.06; P = 0.02). Second primary tumor-related mortality and cardiovascular-related mortality were similar. In this meta analysis of RCTs in NSCLC, cisplatin-based adjuvant chemotherapy was associated with a 30 % increase in non-lung cancer-related mortality compared with local therapy alone. PMID- 23813020 TI - Alterations of the subchondral bone in osteochondral repair--translational data and clinical evidence. AB - Alterations of the subchondral bone are pathological features associated with spontaneous osteochondral repair following an acute injury and with articular cartilage repair procedures. The aim of this review is to discuss their incidence, extent and relevance, focusing on recent knowledge gained from both translational models and clinical studies of articular cartilage repair. Efforts to unravel the complexity of subchondral bone alterations have identified (1) the upward migration of the subchondral bone plate, (2) the formation of intralesional osteophytes, (3) the appearance of subchondral bone cysts, and (4) the impairment of the osseous microarchitecture as potential problems. Their incidence and extent varies among the different small and large animal models of cartilage repair, operative principles, and over time. When placed in the context of recent clinical investigations, these deteriorations of the subchondral bone likely are an additional, previously underestimated, factor that influences the long-term outcome of cartilage repair strategies. Understanding the role of the subchondral bone in both experimental and clinical articular cartilage repair thus holds great promise of being translated into further improved cell- or biomaterial-based techniques to preserve and restore the entire osteochondral unit. PMID- 23813021 TI - Human rhinovirus VPg uridylylation AlphaScreen for high-throughput screening. AB - As an obligate step for picornaviruses to replicate their genome, the small viral peptide VPg must first be specifically conjugated with uridine nucleotides at a conserved tyrosine hydroxyl group. The resulting VPg-pUpU serves as the primer for genome replication. The uridylylation reaction requires the coordinated activity of many components, including the viral polymerase, a conserved internal RNA stem loop structure, and additional viral proteins. Formation of this complex and the resulting conjugation reaction catalyzed by the polymerase, offers a number of biochemical targets for inhibition of an essential process in the viral life cycle. Therefore, an assay recapitulating uridylylation would provide multiple opportunities for discovering potential antiviral agents. Our goal was to identify inhibitors of human rhinovirus (HRV) VPg uridylylation, which might ultimately be useful to reduce or prevent HRV-induced lower airway immunologic inflammatory responses, a major cause of asthma and chronic obstructive pulmonary disease exacerbations. We have reconstituted the complex uridylylation reaction in an AlphaScreen suitable for high-throughput screening, in which a rabbit polyclonal antiserum specific for uridylylated VPg serves as a key reagent. Assay results were validated by quantitative mass spectrometric detection of uridylylation. PMID- 23813022 TI - Thrombosis on a mechanical mitral valve anticoagulated with dabigatran. PMID- 23813023 TI - Small hepatic veins Budd-Chiari syndrome. AB - Budd-Chiari syndrome is a rare disorder characterized by hepatic venous outflow obstruction at any level from the small hepatic veins to the atrio-caval junction, in the absence of heart failure or constrictive pericarditis. Various imaging modalities are available for investigating the gross hepatic vascular anatomy but there are rare forms of this disease where the obstruction is limited to the small intrahepatic veins, with normal appearance of the large hepatic veins at imaging. In this cases only a liver biopsy can demonstrate the presence of a small vessels outflow block. We report two cases of small hepatic veins Budd Chiari syndrome. PMID- 23813024 TI - RCVS seeks views on creating a new learned society. PMID- 23813026 TI - FVE adopts Day 1 competences for animal welfare. PMID- 23813027 TI - Scottish Government to consult on compulsory microchipping of dogs. PMID- 23813028 TI - Call for a more streamlined system for regulating veterinary medicines. PMID- 23813032 TI - Do your homework before you travel, says charity. PMID- 23813033 TI - Veterinary cardiology: a journey through time. PMID- 23813034 TI - Ensuring correct use of technology on farm. PMID- 23813036 TI - Dried manure solids as a bedding material for dairy cows. PMID- 23813037 TI - Reduction, refinement and replacement. PMID- 23813038 TI - Career choices made by vets and vet nurses. PMID- 23813039 TI - A vet not by any other name. PMID- 23813040 TI - Diagnostic imaging: reflecting on the past. PMID- 23813041 TI - Detection of sexual orientation ("gaydar") by homosexual and heterosexual women. AB - Although there has been considerable research investigating the ability to identify sexual orientation from static images, or "gaydar," few studies have considered the role of female sexual orientation or sexual interest (for example, sociosexual orientation) in judgment accuracy. In two studies, we investigated the sexuality detection ability, and masculinity and femininity as cues used in judgment. In Study 1, we recruited heterosexual (N = 55) and homosexual (N = 71) women to rate the sexual orientation of homosexual and heterosexual male and female targets (N = 80: 20 heterosexual men, 20 homosexual men, 20 heterosexual women, and 20 homosexual women). We found that detection accuracy was better than chance levels for both male and female targets and that male targets were more likely to be falsely labeled as homosexual than female targets were. Overall, female faces were more accurately identified as heterosexual or homosexual than male faces and homosexual female raters were biased towards labeling targets as homosexual. Sociosexuality did not influence the accuracy with which targets were identified as heterosexual or homosexual. In Study 2, 100 heterosexual and 20 homosexual women rated the stimulus for masculinity and femininity. Heterosexual women were rated as more feminine and less masculine than homosexual women and homosexual men were rated as more feminine and less masculine than heterosexual men. Sexual orientation of the judges did not affect the ratings. The results were discussed with a reference to evolutionary and cultural influences affecting sexual orientation judgment accuracy. PMID- 23813042 TI - Status of endovascular interventions to treat acute ischemic stroke. AB - OPINION STATEMENT: Acute stroke is a major component of neurology and one of few neurologic emergencies. Despite many efforts to increase treatment of acute ischemic stroke, we are still not able to treat a significant percentage of patients with intravenous tPA, typically because of time restrictions. Unfortunately, many patients do not present to medical attention within the short window for tPA administration. In addition, there are numerous contraindications for tPA, which make more patients ineligible. Endovascular treatment for acute ischemic stroke may help to expand the number of patients treated by extending the time window beyond the 3 to 4.5 hour constraints of IV tPA, and including patients with tPA contraindications such as use of oral anticoagulants. However, several recent studies have raised questions regarding the utility and efficacy of these procedures. These studies should not discourage endovascular treatment of acute stroke, but should lead us to ask more questions and be proactive in seeking answers, and should make us carefully select the patient population to receive the treatment. Future studies should take advantage of the lessons learned from these recent trials, including the importance of using vascular imaging for inclusion criteria, and of utilizing the latest and most advanced devices and techniques. Endovascular therapy will continue to evolve into what will hopefully be a clinically significant alternative therapy for acute ischemic stroke. PMID- 23813043 TI - Improvement of prognosis in patients with metastatic renal cell carcinoma and Memorial Sloan-Kettering Cancer Center intermediate risk features by modern strategy including molecular-targeted therapy in clinical practice. AB - OBJECTIVES: To identify the patient subgroups benefitting the most from the modern strategy including molecular-targeted therapy among patients with metastatic renal cell carcinoma (mRCC) in clinical practice. METHODS: Retrospective analysis of 144 patients with mRCC diagnosed between 1992 and 2011 at Kyoto University Hospital was conducted. Multivariate analysis using the Cox proportional hazards model was conducted to identify prognostic factors associated with overall survival (OS). Subgroup analysis was conducted to identify patients who benefitted the most from molecular-targeted therapy. RESULTS: Independent factors associated with worse OS are: tumors of histological type other than clear-cell, decreased hemoglobin (Hb), elevated lactate dehydrogenase (LDH), elevated C-reactive protein (CRP), and metastases at >= 3 sites. Median OS of patients treated with molecular-targeted therapy alone or with prior immunotherapy and those treated with immunotherapy alone was 57, 45 and 28 months, respectively. Molecular-targeted therapy had more effect on OS than immunotherapy alone among female patients, patients with Memorial Sloan Kettering Cancer Center (MSKCC) intermediate risk features, and patients with metastatic progression less than 1 year after initial diagnosis of RCC, compared with their counterparts. CONCLUSIONS: The modern strategy including molecular targeted therapy may improve OS in patients with mRCC and MSKCC intermediate risk features in clinical practice, relative to those with other risk features. However, the prognosis for patients with tumors of histological type other than clear-cell, decreased Hb, elevated LDH, elevated CRP, or metastases at >= 3 sites remains poor even in the modern molecular-targeted era. Novel treatment strategies are necessary to improve prognosis in these patients. PMID- 23813044 TI - Carcinoma of unknown primary with gastrointestinal profile: immunohistochemistry and survival data for this favorable subset. AB - BACKGROUND: Carcinoma of unknown primary with a "gastrointestinal profile" is an emerging, favorable entity. Distinguishing this entity is of increasing significance given the progress in the treatment of colorectal cancer. PATIENTS AND METHODS: 74 carcinoma of unknown primary (CUP) patients with CDX2+ tumors were chosen from the databases at M.D. Anderson and Sarah Cannon Cancer Centers between 2004 and 2010. Data on clinical and pathological characteristics including therapy and survival were recorded. RESULTS: 20 patients had ascites on presentation; the predominant sites of metastases included liver (30 %), carcinomatosis (50 %), and nodes (51 %). Based on immunohistochemistry, 2 cohorts were created: Cohort 1-"consistent with lower GI profile" included 34 patients [CDX-2+, CK20+, CK7-] and Cohort 2-"probable lower GI profile" included 40 patients [CDX2+, irrespective of CK7/CK20 status]. Excluding 6 outliers, Cohorts 1 and 2 had 32 and 36 patients, respectively; their median survivals were 37 and 21 months, respectively. On multivariate Cox regression analysis, only liver metastases were found to negatively influence survival. CONCLUSIONS: Our retrospective study provides encouraging indications that CUP patients with gastrointestinal profiles benefit from site-specific therapy. We recommend all CUP patients, especially those with abdominal nodes, isolated carcinomatosis or liver metastases, to undergo optimal immunohistochemistry (IHC) to check for a gastrointestinal profile of CUP. PMID- 23813045 TI - Synthesis and structure-activity relationship of mono-indole-, bis-indole-, and tris-indole-based sulfonamides as potential anticancer agents. AB - A series of arylsulfonyl mono-indoles (10-15), bis-indoles (16-27), and tris indoles (28-32) have been synthesized and evaluated for their cytotoxicity toward four human cancer cell lines including HuCCA-1 (cholangiocarcinoma), HepG2 (hepatocellular carcinoma), A-549 (lung carcinoma), and MOLT-3 (lymphoblastic leukemia). Most of the synthesized indoles displayed cytotoxicity against the MOLT-3 cell line except for analogs 16, 17, and 32. Significantly, the [Formula: see text]-sulfonylphenolic bis-indole series (18-27) and the [Formula: see text] chlorobenzenesulfonyl tris-indole (30) showed higher antiproliferative activity against HepG2 cell than the reference drug, etoposide. Promisingly, the [Formula: see text]-chlorobenzenesulfonyl bis-indole (20) and tris-indole (30) provided 3 fold and 2-fold stronger activity, respectively, against HepG2 cell than etoposide. Moreover, the phenolic bis-indole (20) was also shown to be the most potent cytotoxic agent against HuCCA-1 and A-549 cell lines with [Formula: see text] values of 7.75 and [Formula: see text], respectively. The tris-indole analogs 28, 29, and 31 also exhibited selectivity against MOLT-3 cell. The findings disclosed that [Formula: see text]-arylsulfonyl bis-indoles-bearing phenolic groups are potentially interesting lead pharmacophores of anticancer agents that should be further investigated in more detail. PMID- 23813047 TI - Predictors of recurrence in intraductal papillary mucinous neoplasm: experience with 183 pancreatic resections. AB - OBJECTIVES: We examined long-term outcomes in patients with surgically treated intraductal papillary mucinous neoplasm (IPMN) to determine if any clinical or histologic features could predict risk of recurrent disease. METHODS: We reviewed 183 margin-negative surgical resections performed for IPMN between 1994 and 2011 with documented postoperative abdominal imaging. We calculated time to recurrent disease as indicated by radiographic change and created a multivariable Cox proportional hazards model to assess the relationship between patient characteristics and histopathologic tumor features and disease recurrence. RESULTS: Among patients with margin-negative resections and adequate imaging follow-up, we observed a recurrence rate of 13% over a median follow-up of 32.0 months. Individuals with invasive tumors on original pathology were more likely to recur (HR 5.2, 95% CI 2.2-12.2); however, original pathology did not predict disease severity on recurrence. Controlling for invasive pathology, no other histologic feature of the original tumor, including dysplasia at the surgical margin, predicted recurrence. Among non-invasive IPMN, pancreatitis was associated with disease recurrence (HR 3.6, 95% CI 1.2-10.7). CONCLUSIONS: The frequency of recurrent disease in this population and the inability to predict recurrence argues for universal and continuous surveillance after resection for IPMN. The relationship between pancreatitis and disease recurrence should be investigated further. PMID- 23813048 TI - Postoperative detection of circulating tumor cells predicts tumor recurrence in colorectal cancer patients. AB - INTRODUCTION: Circulating tumor cells are thought to play a crucial role in the development of distant metastases. Their detection in the blood of colorectal cancer patients may be linked to poor outcome, but current evidence is controversial. MATERIALS AND METHODS: Pre- and postoperative flow cytometric analysis of blood samples was carried out in 76 colorectal cancer patients undergoing surgical resection. The EpCAM/CD326 epithelial surface antigen was used to identify circulating tumor cells. RESULTS: Fifty-four (71%) patients showed circulating tumor cells preoperatively, and all metastatic patients showed high levels of circulating tumor cells. Surgical resection resulted in a significant decrease in the levels of circulating tumor cells. Among 69 patients undergoing radical surgery, 16 had high postoperative levels of circulating tumor cells, and 12 (75%) experienced tumor recurrence. High postoperative level of circulating tumor cells was the only independent variable related to cancer relapse. In patients without circulating tumor cells, the progression-free survival rate increased from 16 to 86%, with a reduction in the risk of tumor relapse greater than 90%. CONCLUSIONS: High postoperative levels of circulating tumor cells accurately predicted tumor recurrence, suggesting that assessment of circulating tumor cells could optimize tailored management of colorectal cancer patients. PMID- 23813050 TI - Headache and co-morbid pains associated with TMD pain in adolescents. AB - This case-control study evaluated the association of headache and other co-morbid pain with temporomandibular disorder (TMD) pain in adolescents and explored the temporal co-variance of headache and TMD pain. In a population-based sample of 12 to 19-year-olds, 350 patients with self-reported TMD pain and 350 healthy age- and sex-matched individuals were mailed questionnaires. Descriptive statistics, 95% CI, and OR analyses--logistic regression models with TMD pain as the outcome variable and adjusted for age and gender--were used for the analysis of individuals' responses. Headache, whether defined as once a week or more (OR = 6.6) or as moderate or severe (categorical), was significantly related to TMD pain. Severe headache (vs. mild) showed stronger associations with TMD (OR = 10.1) than between moderate and mild headache (OR = 5.5). Neck (OR = 4.0) and back (OR = 2.6) pain was also significantly related to TMD pain. When participants were grouped according to headache onset and TMD pain, the highest association between headache and TMD pain was found in the subgroup "Headache onset before TMD pain" (OR 9.4). In conclusion, headache appears to be independently and highly associated with TMD pain in adolescents. Neck pain and somatic complaints were also significantly associated with TMD pain. Headache seems to precede TMD pain in many adolescents with pain. PMID- 23813049 TI - Molecular cloning, expression, and in silico structural analysis of guinea pig IL 17. AB - Interleukin-17A (IL-17A) is a potent proinflammatory cytokine and the signature cytokine of Th17 cells, a subset which is involved in cytokine and chemokine production, neutrophil recruitment, promotion of T cell priming, and antibody production. IL-17 may play an important role in tuberculosis and other infectious diseases. In preparation for investigating its role in the highly relevant guinea pig model of pulmonary tuberculosis, we cloned guinea pig IL-17A for the first time. The complete coding sequence of the guinea pig IL-17A gene (477 nucleotides; 159 amino acids) was subcloned into a prokaryotic expression vector (pET-30a) resulting in the expression of a 17 kDa recombinant guinea pig IL-17A protein which was confirmed by mass spectrometry analysis. Homology modeling of guinea pig IL-17A revealed that the three-dimensional structure resembles that of human IL-17A. The secondary structure predicted for this protein showed the presence of one extra helix in the N-terminal region. The expression profile of IL-17A was analyzed quantitatively in spleen, lymph node, and lung cells from BCG vaccinated guinea pigs by real-time PCR. The guinea pig IL-17A cDNA and its recombinant protein will serve as valuable tools for molecular and immunological studies in the guinea pig model of pulmonary TB and other human diseases. PMID- 23813051 TI - Awake endotracheal retrograde intubation in restricted mouth opening: a 'J' tipped guide wire technique--a retrospective study. AB - INTRODUCTION: Airway management in patient with restricted mouth opening is a great challenge, owing to the difficulty in laryngoscopy and visualisation of the vocal cords during the procedure of intubation. The term retrograde intubation refers to a technique in which a guide wire is passed into the trachea and then into the mouth or nose. A tracheal tube is then passed down over the guide until it enters the trachea. MATERIAL AND METHOD: A retrospective audit was undertaken to determine the success and complication associated with retrograde intubation. RESULTS: The results show that in a sample of 20 patients in which retrograde intubation was done, only three developed sore throat and cough, one had bronchospasm and one developed infection at the site of insertion of a J-tipped catheter. CONCLUSION: Retrograde tracheal intubation was easy to perform and had a high success rate and a low incidence of complications. PMID- 23813052 TI - Preserved antibody levels and loss of memory B cells against pneumococcus and tetanus after splenectomy: tailoring better vaccination strategies. AB - Splenectomized patients are exposed to an increased risk of septicemia caused by encapsulated bacteria. Defense against infection is ensured by preformed serum antibodies produced by long-lived plasma cells and by memory B cells that secrete immunoglobulin in response to specific antigenic stimuli. Studying a group of asplenic individuals (57 adults and 21 children) without additional immunologic defects, we found that spleen removal does not alter serum anti-pneumococcal polysaccharide (PnPS) IgG concentration, but reduces the number of PnPS-specific memory B cells, of both IgM and IgG isotypes. The number of specific memory B cells was low in splenectomized adults and children that had received the PnPS vaccine either before or after splenectomy. Seven children were given the 13 valent pneumococcal conjugated vaccine after splenectomy. In this group, the number of PnPS-specific IgG memory B cells was similar to that of eusplenic children, suggesting that pneumococcal conjugated vaccine administered after splenectomy is able to restore the pool of anti-PnPS IgG memory B cells. Our data further elucidate the crucial role of the spleen in the immunological response to infections caused by encapsulated bacteria and suggest that glycoconjugated vaccines may be the most suitable choice to generate IgG-mediated protection in these patients. PMID- 23813053 TI - Authorship matrix: a rational approach to quantify individual contributions and responsibilities in multi-author scientific articles. AB - We propose a rational method for addressing an important question-who deserves to be an author of a scientific article? We review various contentious issues associated with this question and recommend that the scientific community should view authorship in terms of contributions and responsibilities, rather than credits. We propose a new paradigm that conceptually divides a scientific article into four basic elements: ideas, work, writing, and stewardship. We employ these four fundamental elements to modify the well-known International Committee of Medical Journal Editors (ICMJE) authorship guidelines. The modified ICMJE guidelines are then used as the basis to develop an approach to quantify individual contributions and responsibilities in multi-author articles. The outcome of the approach is an authorship matrix, which can be used to answer several nagging questions related to authorship. PMID- 23813054 TI - Cell cytoskeletal changes effected by static compressive stress lead to changes in the contractile properties of tissue regenerative collagen membranes. AB - Static compressive stress can influence the matrix, which subsequently affects cell behaviour and the cell's ability to further transform the matrix. This study aimed to assess response to static compressive stress at different stages of osteoblast differentiation and assess the cell cytoskeleton's role as a conduit of matrix-derived stimuli. Mouse bone marrow mesenchymal stem cells (MSCs) (D1 ORL UVA), osteoblastic cells (MC3T3-E1) and post-osteoblast/pre-osteocyte-like cells (MLO-A5) were seeded in hydrated and compressed collagen gels. Contraction was quantified macroscopically, and cell morphology, survival, differentiation and mineralisation assessed using confocal microscopy, alamarBlue(r) assay, real time quantitative reverse transcription polymerase chain reaction (RT-qPCR) and histological stains, respectively. Confocal microscopy demonstrated cell shape changes and favourable microfilament organisation with static compressive stress of the collagen matrix; furthermore, cell survival was greater compared to the hydrated gels. The stage of osteoblast differentiation determined the degree of matrix contraction, with MSCs demonstrating the greatest amount. Introduction of microfilament disrupting inhibitors confirmed that pre-stress and tensegrity forces were under the influence of gel density, and there was increased survival and differentiation of the cells within the compressed collagen compared to the hydrated collagen. There was also relative stiffening and differentiation with time of the compressed cell-seeded collagen, allowing for greater manipulation. In conclusion, the combined collagen chemistry and increased density of the microenvironment can promote upregulation of osteogenic genes and mineralisation; MSCs can facilitate matrix contraction to form an engineered membrane with the potential to serve as a 'pseudo-periosteum' in the regeneration of bone defects. PMID- 23813055 TI - Atypical indications for transanal endoscopic microsurgery to avoid major surgery. AB - BACKGROUND: Transanal endoscopic microsurgery (TEM) was originally designed for the removal of rectal tumors, principally incipient adenomas, and adenocarcinomas up to 20 cm from the anal verge. However, with the evolution of the technique and the increase in surgeons' experience, new indications have emerged and TEM may now be used in place of other surgical procedures which are associated with higher morbidity. The aim of our study was to evaluate our group's use of TEM or transanal endoscopic operations (TEO) for conditions other than rectal tumors. METHODS: An observational study of TEM (using Wolf equipment) or TEO (using Storz equipment) for indications other than excision of rectal tumors was conducted from June 2004 to July 2012. RESULTS: Four hundred twenty-four procedures were performed using TEM/TEO: removal of adenocarcinomas in 148 (34.9 %) patients, adenomas in 236 (55.7 %), post-polypectomy excision in 12 (2.8 %), removal of neuroendocrine tumors in 8 (1.9 %), and atypical indications in 20 (4.7 %). Atypical indications were pelvic abscess (3), benign rectal stenoses (2), rectourethral fistula after prostatectomy (3), gastrointestinal stromal tumor (3), endorectal condylomata acuminata (1), rectal prolapse (2), extraction of impacted fecaloma in the rectosigmoid junction (1), repair of traumatic and iatrogenic perforation of the rectum (2), and presacral tumor (3). CONCLUSIONS: The use of TEM/TEO in atypical indications may benefit patients by avoiding surgical procedures associated with greater morbidity. PMID- 23813056 TI - Nonreinforced flavor exposure attenuates the effects of conditioned taste aversion on both flavor consumption and cue palatability. AB - Nonreinforced exposure to a cue tends to attenuate subsequent conditioning with that cue-an effect referred to as latent inhibition (LI). In the two experiments reported here, we examined LI effects in the context of conditioned taste aversion by examining both the amount of consumption and the microstructure of the consummatory behavior (in terms of the mean size of lick clusters). The latter measure can be taken to reflect affective responses to, or the palatability of, the solution being consumed. In both experiments, exposure to a to-be-conditioned flavor prior to pairing the flavor with nausea produced by lithium chloride attenuated both the reduction in consumption and the reduction in lick cluster sizes typically produced by taste aversion learning. In addition, we observed a tendency (especially in the lick cluster measure) for nonreinforced exposure to reduce neophobic responses to the test flavors. Taken together, these results reinforce the suggestion from previous experiments using taste reactivity methods that LI attenuates the effects of taste aversion on both consumption and cue palatability. The present results also support the suggestion that the failure in previous studies to see concurrent LI effects on consumption and palatability was due to a context specificity produced by the oral taste infusion methods required for taste reactivity analyses. Finally, the fact that the pattern of extinction of conditioned changes in consumption and in lick cluster sizes was not affected by preexposure to the cue flavors suggests that LI influenced the quantity but not the quality of conditioned taste aversion. PMID- 23813057 TI - Transcriptional regulation of human MUC4 gene: identification of a novel inhibitory element and its nuclear binding protein. AB - The human mucin 4 (MUC4) is aberrantly expressed in pancreatic adenocarcinoma and tumor cell lines, while remaining undetectable in normal pancreas, indicating its important role in pancreatic cancer development. Although its transcriptional regulation has been investigated in considerable detail, some important elements remain unknown. The aim of the present study was to demonstrate the existence of a novel inhibitory element in the MUC4 promoter and characterize some of its binding proteins. By luciferase reporter assay, we located the inhibitory element between nucleotides -2530 and -2521 in the MUC4 promoter using a series of deletion and mutant reporter constructs. Electrophoretic mobility shift assay (EMSA) with Bxpc-3 cell nuclear extracts revealed that one protein or protein complex bind to this element. The proteins binding to this element were purified and identified as Yin Yang 1 (YY1) by mass spectrometry. Supershift assay and chromatin immunoprecipitation (ChIP) assay confirmed that YY1 binds to this element in vitro and in vivo. Moreover, transient YY1 overexpression significantly inhibited MUC4 promoter activity and endogenous MUC4 protein expression. In conclusion, we reported here a novel inhibitory element in the human MUC4 promoter. This provides additional data on MUC4 gene regulation and indicates that YY1 may be a potential target for abnormal MUC4 expression. PMID- 23813058 TI - A novel chloroplast transformation vector compatible with the Gateway((r)) recombination cloning technology. AB - To analyze the suitability of Gateway((r)) vectors for transformation of chloroplasts, we converted a standard plastid transformation vector into a Gateway((r)) destination vector containing the necessary recombination sites attR1 and attR2. Insertion of the green fluorescent protein (GFP) coding sequence with associated T7g10 ribosome binding site into this destination vector created the expression vector for transformation of tobacco chloroplasts with the biolistic method. Correct integration of the transgene into the plastid genome was verified by PCR and the homoplasmic nature of the transformed plants was confirmed by Southern Blot analysis. Expression of the GFP reporter protein was monitored by confocal laser scanning microscopy (CLSM) and quantification by western blot analysis showed a GFP accumulation level of 3% total soluble protein (TSP). The presented results clearly demonstrate that the Gateway((r)) recombination sites are compatible with all steps of plastid transformation, from generation of transplastomic plants to expression of GFP. This is the first report of a plastid transformation vector made by the Gateway((r)) recombinant cloning technology, which proves the suitability of this system for use in chloroplasts. PMID- 23813059 TI - Long-term clinical outcome and routine angiographic follow-up after successful recanalization of complex coronary true chronic total occlusion with a long stent length: a single-center experience. AB - OBJECTIVES: To evaluate clinical and angiographic outcomes after successful recanalization of chronic total coronary occlusion (CTO) with implantation of a long total stent length (SL). BACKGROUND: Routine follow-up angiogram (RFUA) data after successful recanalization of CTO with a long SL are lacking. METHODS: RFUAs were performed at 6 months after successful recanalization of 106 CTOs using drug eluting stents (DESs) with a long SL (>= 20 mm) in 102 consecutive patients. RESULTS: Mean number of stents was 3.9 +/- 1.8 and mean total SL was 78 +/- 32 mm (range, 23-174 mm). Sirolimus-eluting stents (SESs) were used in 100 lesions. In stent total reocclusion occurred in 2 cases (1 SES and 1 non-SES DES). Restenosis rate was 18% in the 100 SES subgroup (total SL, 79 +/- 33 mm; range, 23-174 mm; mean number of stents, 3.9 +/- 1.8); younger age and longer total SL were found to be independent predictors of restenosis (longer age: hazard ratio, 0.939; 95% confidence interval, 0.885-0.996; P=.035; longer total SL: hazard ratio, 1.017; 95% confidence interval, 1.00-1.03; P=.045). Restenosis type was diffuse in only 11% and 89% were successfully treated by repeat percutaneous coronary intervention. During a median follow-up of 2 years (interquartile range, 1-4.3 years), major cardiac events other than those angiographically driven at RFUA occurred in 2 patients. CONCLUSION: Angiographic restenosis rate remains acceptable in patients with complex CTO successfully treated by DES despite a long SL. PMID- 23813060 TI - Stent thrombosis with second- versus first-generation drug-eluting stents in real world percutaneous coronary intervention: analysis of 3806 consecutive procedures from a large-volume single-center prospective registry. AB - BACKGROUND AND AIMS: When compared to their first-generation (1stGEN) counterparts, second-generation (2ndGEN) drug-eluting stents (DESs) have been associated with better clinical outcomes in randomized clinical trials, namely by reducing the rates of stent thrombosis (ST). Our goal was to investigate whether or not the broad use of newer devices would translate into higher safety in a real-world population. For that purpose, we compared the occurrence of definite ST at 12 months between two patient subsets from a large-volume single-center registry, according to the type of DES used. Total mortality was a secondary endpoint. METHODS AND RESULTS: Between January 2003 and December 2010, a total of 3806 patients were submitted to percutaneous coronary intervention (PCI) with only 1stGEN or 2ndGEN DES: 2388 patients (62.7%) were treated with 1stGEN DES only (sirolimus-eluting stent [SES] = 1295 [34.0%]; paclitaxel-eluting stent [PES] = 943 [24.8%]; both stent types were used in 150 patients) and 1418 patients (37.3%) were treated with 2ndGEN DESs only. The total incidence of definite ST (as defined by the Academic Research Consortium) at 12 months was 1.2% (n = 46). After correction for baseline differences between study groups and other variables deemed to influence the occurrence of ST, the use of 1stGEN DES was associated with a significant 2.4-fold increase in the risk of definite ST (95% confidence interval [CI], 1.05-5.42; P=.039) at 12 months; adjusted risk was higher with PES (hazard ratio [HR], 3.6; 95% CI, 1.48-8.70; P=.005) than with SES (HR, 2.3; 95% CI, 0.92-5.65; P=.074). Total mortality (3.7% vs 3.5%) did not differ significantly between groups (adjusted HR, 1.2; 95% CI, 0.81-1.84, P=.348). CONCLUSIONS: Our data suggest that in the real-world setting of contemporary PCI, the unrestricted use of newer 2ndGEN DESs translates into an improvement in PCI safety (relative to 1stGEN DESs), with a significantly lower risk of definite ST at 12 months. PMID- 23813061 TI - Stent thrombosis through the generations. PMID- 23813062 TI - Evolution in the management of postinfarct ventricular septal defects from surgical to percutaneous approach: a single-center experience. AB - BACKGROUND: Postinfarction ventricular septal defect (VSD) is an uncommon but serious complication of myocardial infarction associated with high mortality. While traditionally postinfarct VSDs were only closed surgically, percutaneous closure is a newer treatment strategy that has been introduced with success in recent years. We sought to assess trends in treatment choice at our center. METHODS AND RESULTS: A single-center, retrospective study design included all patients treated for postinfarction VSDs, either surgically or percutaneously, from January 1992 to December 2012. Percutaneous closure was performed using the self-expandable, double-disc Amplatzer closure device. Over the 20-year study period, a total of 25 patients were treated for postinfarct VSDs, with 18 managed surgically and 7 managed percutaneously. Two patients with an initial surgical repair experienced patch dehiscence and were subsequently treated percutaneously, bringing the number in this group to 9. The use of surgical closure declined over time, with percutaneous closure being the only treatment strategy used from 2004 onward. Mortality rates were 44% and 75% for those with final percutaneous and surgical closure, respectively (P<.13). Mortality rates in patients presenting with and without cardiogenic shock were 80% and 46%, respectively (P<.05). CONCLUSION: Percutaneous closure has become the preferred treatment of postinfarct VSDs at our center. Percutaneous closure may be a viable and non inferior treatment strategy compared to traditional surgical closure. PMID- 23813063 TI - Safety and efficacy of the frontrunner XP catheter for recanalization of chronic total occlusion of the femoropopliteal arteries. AB - OBJECTIVE: The purpose of this study was to examine the safety and efficacy of the Frontrunner XP CTO (chronic total occlusion) catheter (Cordis Corporation) for recanalization of CTO of femoropopliteal arteries. METHODS: A retrospective analysis of consecutive patients with critical limb ischemia (CLI) who underwent femoropopliteal angioplasty for TransAtlantic Inter-Society Consensus (TASC) class D lesions between 2009 and 2011 was performed. Twenty-two patients were enrolled with a mean age of 58.9 +/- 11.5 years. Patients were enrolled with totally occluded arteries (mean occlusion length, 18.0 +/- 10.1 cm) that were treated with the Frontrunner XP CTO catheter. All lesions were complex (TASC D) and 86.4% of the lesions were mildly calcified. A Frontrunner catheter was used to treat 22 CTOs after guidewire failure. RESULTS: Twenty-two of the 33 cases (66.7%) had failed previous attempts of percutaneous intervention with conventional guidewire. The Frontrunner catheter was used to treat 22 CTOs after guidewire failure. The Frontrunner catheter successfully facilitated the placement of a guidewire into the distal true lumen in 21 cases (95.5%). Thrombolysis in Myocardial Infarction 3 flow was achieved in all target vessels after further balloon angioplasty or stenting. CONCLUSIONS: The Frontrunner XP CTO catheter is safe and effective for successful recanalization of CTO of femoropopliteal arteries and it should be an alternative method after guidewire failure. PMID- 23813064 TI - Decrease in coronary flow after consecutive injections of contrast media during coronary angiography. AB - BACKGROUND: TIMI frame count (TIMIfc) is widely used to assess coronary flow during angiography and there are studies showing the effects of contrast media on blood cells. In this study, we investigate changes in coronary flow and in red blood cells following contrast injections. METHODS AND RESULTS: Coronary flow was assessed by TIMIfc in the left anterior descending and circumflex coronary arteries of patients undergoing elective angiography. Changes in the morphology of red blood cells and in the mean corpuscular volume (MCV) were evaluated by optical microscopy. We enrolled 24 patients with a mean age of 61.9 +/- 12 years. In 45 coronary arteries, the mean baseline-corrected TIMIfc was 19.4 +/- 3.46 frames and the final one was 24.3 +/- 3.2 frames (P=.001) with a mean increase of 4.92 +/- 0.25 frames (frame range, 0-10), indicating significant impairment of coronary flow. There was an increase in the number of crenated red cells per camp (4.3 +/- 3.4%; P=.001). The MCV changed from 86.6 +/- 4.7 fL to 86.8 +/- 4.6 fL (P=.011). There was no association of the TIMIfc increase with changes in either crenated red cells (P=NS) or MCV (P=NS). CONCLUSION: There was significant impairment of coronary artery flow following contrast injections during angiography. These findings indicate that the TIMIfc is affected by the timing of assessment during angiography, with implications for clinical trial design and for the use of TIMIfc as a surrogate endpoint. In addition, this impairment of coronary flow may have implications for slow flow observed during coronary interventions. PMID- 23813065 TI - Angiographic evaluation of the radial artery diameter in patients who underwent coronary angiography or coronary intervention. AB - OBJECTIVES: The aim of this study was to determine the radial artery diameter of patients through angiography and evaluate the feasibility of using wider sheaths for radial interventions. In addition, any parameters that could affect the radial artery diameter were also evaluated. BACKGROUND: The radial artery is a suitable, beneficial route for coronary procedures and is considered a good alternative to transfemoral access. However, a small radial artery diameter may make complicated coronary and peripheral procedures even more difficult. Therefore, an evaluation of the radial artery diameter may help the interventional cardiologist to select the instruments and techniques that are the most appropriate for the patient. METHODS: Radial artery diameters were calculated in 93 consecutive patients who underwent a transradial coronary procedure along with simultaneous radial angiography, and the anthropometric parameters that might affect the diameter and the association between vessel diameter and pain experienced by the patient during sheath removal were investigated. RESULTS: A total of 97 patients (69 males [71.1%]; 28 females [28.9%]) between 30-89 years of age (mean age, 59.0 +/- 10.6 years) were included in the study. Four patients were excluded due to the failure of the radial procedure. The radial artery diameters were measured angiographically in the remaining 93 patients, and the procedural success rate was 95.8%. The mean radial artery diameters were 2.3 +/- 0.38 mm in males, 2.1 +/- 0.42 mm in females, and 2.3 +/- 0.40 mm for the entire study population. Body weight and distal and proximal wrist diameters showed positive and significant correlations with the radial artery diameter (P=.025, P=.013, and P=.032, respectively). CONCLUSION: In this cross-sectional study, since the mean radial artery diameter was 2.3 +/- 0.40 mm, the coronary procedures performed via the radial route can be deemed successful. Moreover, we found no independent predictors of radial artery diameter. Among the patients, 74% had coronary artery diameters of 6 Fr or larger. As long as the ulnar collateral circulation is sufficient, the transradial procedure can be safely performed without considering any other anthropometric parameters. PMID- 23813066 TI - Treatment of recurrent radial artery pseudoaneurysms by prolonged mechanical compression. AB - As radial artery pseudoaneurysm (PA) is a rare complication of transradial catheterization, data on their management are sparse. Here, we report the case of a 77-year-old woman who underwent right transradial diagnostic cardiac catheterization, and subsequently developed a symptomatic PA. She underwent initial treatment with 20 minutes of mechanical compression with a Hemoband (Hemoband Corporation) with initial success. Three weeks later, she developed recurrence of her PA, and was treated with 24 hours of mechanical compression, wearing the Hemoband as an outpatient, with sustained resolution of the PA confirmed by ultrasound 1 month later, and no neurologic or further vascular complications. In addition to demonstrating that an initial PA as well as its recurrence can be treated with prolonged mechanical compression, we review the literature regarding radial artery PAs and their treatment. PMID- 23813067 TI - Coronary angioplasty after self-expandable transcatheter aortic valve implantation. AB - Aortic stenosis and coronary artery disease share comorbidities/risk factors; thus, it is not surprising they occur concomitantly. With increased life expectancy of patients who undergo transcatheter aortic valve implantation (TAVI), the rate of post-TAVI percutaneous coronary intervention (PCI) is expected to rise. In the current report, we present two cases using PCI following CoreValve (Medtronic) implantation. Our cases indicated that the procedure is feasible and safe, but requires careful planning and understanding of the three dimensional geometry of the prosthetic valve and its relation to the coronary ostia. PMID- 23813068 TI - Histopathologic validation of optical coherence tomography findings of non apposed side-branch struts in porcine arteries. AB - BACKGROUND: The presence of uncovered struts overlying side branch is considered to be a potential risk of stent thrombosis. The accuracy in detection of neointimal strut coverage at branch point by optical coherence tomography (OCT) has not been validated in comparison with histology. METHODS: A total of 5 stents (3 drug-eluting stents and 2 bare-metal stents) were implanted in the bifurcation segment of normal coronary arteries in 4 domestic swine (weight, 25-40 kg). The animals underwent follow-up OCT at 30 days after stent implantation and were then sacrificed for histologic evaluation. The neointimal coverage of the non-apposed struts over the side branch was assessed by light microscopy. Every millimeter of the stent was specified by the OCT frame rate, and comparisons between OCT and pathologic findings were performed through precise histological-OCT frame matching. RESULTS: OCT images at the side branch corresponded well with histological cross-sections. The tissues covering struts as assessed by OCT contained smooth muscle cells with proteoglycan-collagen matrix, but platelets are attached above the neointima in one of them on histologic examination, suggesting that most of the struts were well healed, with normal neointimal coverage. CONCLUSION: This study demonstrated the accuracy of OCT for the detection of neointimal coverage of non-apposed struts over the side branch. PMID- 23813069 TI - Optical frequency domain imaging for guidance of optimal stenting in the setting of recanalization of chronic total occlusion. AB - We present an interesting case illustrating how coronary optical frequency domain imaging (OFDI) examination can be used to guide revascularization of a complex chronic total occlusion (CTO) in a patient presenting to our hospital with a 2 year history of angina, dyspnea, and a positive treadmill test. This case demonstrates the potential clinical role of high-resolution OFDI to optimize coronary stent implantation. OFDI may help to limit the coronary area covered by stents to the true coronary lesion. PMID- 23813070 TI - Letter to the editor: X-ray dose delivered during coronary angioplasty. PMID- 23813071 TI - Successful IVUS-guided reentry from iatrogenic coronary arteriovenous fistula related to wire perforation following wiring of a totally occluded vessel. AB - We experienced a rare case in which a guidewire was advanced into a coronary vein through an arteriovenous fistula caused by wire perforation. The patient, who had chronic total occlusion (CTO) of the left circumflex coronary artery, was treated successfully with a procedure guided by intravascular ultrasound (IVUS). The IVUS guided parallel-wire technique allowed recrossing of the guidewire into the distal true lumen of the CTO by identifying the anatomy of the occluded segment and the appropriate re-entry point. Angiography demonstrated that the fistula was completely sealed after stent deployment, and there was no extravasation. PMID- 23813072 TI - Transvenous IVUS-guided percutaneous coronary intervention for chronic total occlusion: a novel strategy. AB - The major obstacle to successful recanalization of a chronic total occlusion (CTO) is difficulty in passing the guidewire through the occlusion. We report successful transvenous intravascular ultrasound (IVUS)-guided percutaneous coronary intervention for CTO of the coronary artery in two patients, one with CTO of the left circumflex artery and the other with CTO of the left anterior descending artery. The procedure involved the passage of a guidewire through the CTO lesion under fluoroscopic guidance and insertion of an IVUS catheter into the cardiac vein parallel to the target artery. Angiography after 8 months revealed no restenosis in either patient. PMID- 23813073 TI - Coronary stenting in a patient with single coronary artery and double-vessel disease! AB - A 52-year-old female with exertional angina of class II severity was referred to us. Her coronary angiogram revealed an anomalous single coronary artery from left coronary sinus. Its circumflex branch continued in the right AV groove to supply the right coronary artery territory. Significant stenoses were found in the left anterior descending and circumflex arteries. In view of her persistent angina despite optimal antianginals, percutaneous intervention of the stenosed arteries was done, after which the symptoms abated. Single coronary artery is a rare coronary anomaly, with reported prevalence of 0.024%-0.066%. It is usually asymptomatic. Coronary angioplasty of such rare anomalous vessels for atherosclerotic disease has been reported previously. We describe stenting of both the major branches of an anomalous single coronary artery in a patient with atherosclerotic coronary artery disease with a brief review and discuss the issues with intervention on single coronary artery. PMID- 23813074 TI - Transcatheter right ventricular outflow tract stenting in children with postoperative infundibular stenosis and preserved pulmonary valve function. AB - Recurrent or residual right ventricular outflow tract obstruction after early surgical repair of congenital heart disease is one of the most frequent indications for either surgical or transcatheter reintervention. Transcatheter stent implantation across the stenotic right ventricular outflow tract or conduit is a safe and effective alternative to surgical reintervention. However, chronic deleterious effects of pulmonary regurgitation can potentially counterbalance the early improvement in clinical and hemodynamic parameters, sometimes necessitating further intervention. While there are several studies documenting safe and effective palliation by transcatheter right ventricular outflow tract stenting in infants with tetralogy of Fallot, literature on isolated infundibular stent implantation sparing the normal pulmonary valve in postoperative infundibular restenosis is very scant. We report our experience of safety and feasibility of transcatheter right ventricular outflow tract stent implantation while preserving the native pulmonary valve function in two children with infundibular stenosis after surgical repair of congenital heart disease. PMID- 23813075 TI - Stingray balloon used in slender percutaneous coronary intervention for chronic total occlusion. AB - Slender chronic total occlusion (CTO) percutaneous coronary intervention (PCI) using 5 Fr radial Ikari catheter is possible in simple CTO cases. We report a case where we initially thought the LAD CTO was short and easy, but we found that the CTO had a considerable amount of calcium and also some tortuosity, making simple wire crossing impossible. We used a Stingray balloon to perform re-entry by tracking the balloon over an Ultimate Bros 3 gram wire using an extension wire. We successfully punctured into true lumen and completed stenting through a slender 5 Fr system. This case demonstrates the beauty of combining the advances in CTO PCI from the East and the West together and also demonstrates the possibility of using the Stingray system in a 5 Fr guiding catheter. PMID- 23813076 TI - Spontaneous coronary artery dissection: a case series highlighting diagnostic challenges and the potential for underestimating the incidence of this presumed rare disorder. AB - Spontaneous coronary artery dissection (SCAD) is an uncommon condition with a variety of clinical presentations. Our knowledge base for SCAD is limited and derives from case reports and retrospective reviews. Several aspects of this disorder, including its rarity, heterogeneity of its presentation, and lack of identification during initial assessment, propose obstacles to reliably secure an accurate diagnosis and consequently we believe that the incidence of this disorder is likely underestimated in the literature. We present a case series of 5 patients with SCAD who exhibit features of this disorder that pose diagnostic challenges and outline the aspects of their history, presentation, and work-up. We propose that this condition is more than rare and may be underestimated; improved awareness of this disorder and associated trends might improve a clinician's index of suspicion and lead to a better diagnostic approach. Case reports and reviews remain vital to our understanding of this disorder and its true prevalence. PMID- 23813077 TI - A microfluidic localized, multiple cell culture array using vacuum actuated cell seeding: integrated anticancer drug testing. AB - In this study, we introduced a novel and convenient approach to culture multiple cells in localized arrays of microfluidic chambers using one-step vacuum actuation. In one device, we integrated 8 individually addressable regions of culture chambers, each only requiring one simple vacuum operation to seed cell lines. Four cell lines were seeded in designated regions in one device via sequential injection with high purity (99.9 %-100 %) and cultured for long-term. The on-chip simultaneous culture of HuT 78, Ramos, PC-3 and C166-GFP cells for 48 h was demonstrated with viabilities of 92 %+/-2 %, 94 %+/-4 %, 96 %+/-2 % and 97 %+/-2 %, respectively. The longest culture period for C166-GFP cells in this study was 168 h with a viability of 96 %+/-10 %. Cell proliferation in each individual side channel can be tracked. Mass transport between the main channel and side channels was achieved through diffusion and studied using fluorescein solution. The main advantage of this device is the capability to perform multiple cell-based assays on the same device for better comparative studies. After treating cells with staurosporine or anti-human CD95 for 16 h, the apoptotic cell percentage of HuT 78, CCRF-CEM, PC-3 and Ramos cells were 36 %+/-3 %, 24 %+/-4 %, 12 %+/-2 %, 18 %+/-4 % for staurosporine, and 63 %+/-2 %, 45 %+/-1 %, 3 %+/-3 %, 27 %+/-12 % for anti-human CD95, respectively. With the advantages of enhanced integration, ease of use and fabrication, and flexibility, this device will be suitable for long-term multiple cell monitoring and cell based assays. PMID- 23813078 TI - Emerging micro- and nanotechnologies in cancer diagnosis and therapy. PMID- 23813079 TI - The silent physician. PMID- 23813080 TI - Cancer cell bioenergetics and pH regulation influence breast cancer cell resistance to paclitaxel and doxorubicin. AB - The multidrug resistance (MDR) phenotype, frequently observed during cancer treatment, is often associated with drug efflux pump activity. However, many other factors are also known to be involved. Cancer cells often rely on aerobic glycolysis for energy production; this is known as the "Warburg effect" and is used as a survival mechanism. Associated to this event, a reverse pH gradient across the cell membrane occurs, leading to cytosol alkalinization and extracellular acidification. In the present study, we investigated the role of different mechanisms involved in MDR, such as altered tumor microenvironment and energetic metabolism. The breast cancer cell line MCF-7, used as model, was exposed to two widely used antitumor drugs, paclitaxel (antimitotic agent) and doxorubicin (alkylating agent). Cancer pH regulation was shown to be crucial for malignant characteristics such as cell migration and drug resistance. Our results showed that a lower extracellular pH induced a higher migratory capacity and higher resistance to the studied chemotherapeutical compounds in MCF-7 cells. Besides the influence of the extracellular pH, the role of the tumor metabolism in the MDR phenotype was also investigated. Pre-treatment with different bioenergetic modulators led to cell ATP depletion and altered lactic acid production and glucose consumption, resulting in increased sensitivity to paclitaxel and doxorubicin. Overall, this study supports the potential use of compounds targeting cell metabolism and tumor microenvironment factors such as pH, as co-adjuvants in conventional chemotherapy. PMID- 23813081 TI - Discriminative validity of metabolic and workload measurements for identifying people with chronic fatigue syndrome. AB - BACKGROUND: Reduced functional capacity and postexertion fatigue after physical activity are hallmark symptoms of chronic fatigue syndrome (CFS) and may even qualify for biomarker status. That these symptoms are often delayed may explain the equivocal results for clinical cardiopulmonary exercise testing in people with CFS. Test reproducibility in people who are healthy is well documented. Test reproducibility may not be achievable in people with CFS because of delayed symptoms. OBJECTIVE: The objective of this study was to determine the discriminative validity of objective measurements obtained during cardiopulmonary exercise testing to distinguish participants with CFS from participants who did not have a disability but were sedentary. DESIGN: A prospective cohort study was conducted. METHODS: Gas exchange data, workloads, and related physiological parameters were compared in 51 participants with CFS and 10 control participants, all women, for 2 maximal exercise tests separated by 24 hours. RESULTS: Multivariate analysis showed no significant differences between control participants and participants with CFS for test 1. However, for test 2, participants with CFS achieved significantly lower values for oxygen consumption and workload at peak exercise and at the ventilatory or anaerobic threshold. Follow-up classification analysis differentiated between groups with an overall accuracy of 95.1%. LIMITATIONS: Only individuals with CFS who were able to undergo exercise testing were included in this study. Individuals who were unable to meet the criteria for maximal effort during both tests, were unable to complete the 2-day protocol, or displayed overt cardiovascular abnormalities were excluded from the analysis. CONCLUSIONS: The lack of any significant differences between groups for the first exercise test would appear to support a deconditioning hypothesis for CFS symptoms. However, the results from the second test indicated the presence of CFS-related postexertion fatigue. It might be concluded that a single exercise test is insufficient to reliably demonstrate functional impairment in people with CFS. A second test might be necessary to document the atypical recovery response and protracted fatigue possibly unique to CFS, which can severely limit productivity in the home and workplace. PMID- 23813082 TI - Participation following knee replacement: the MOST cohort study. AB - BACKGROUND: Participation is an important, yet seldom studied, outcome after total knee replacement (TKR). OBJECTIVE: The purpose of this study was to investigate the extent and predictors of participation and participation restriction among people after TKR. MATERIALS AND METHODS: This study investigated the changes in pain, function, and participation scores (measured using a subscale of the Late-Life Function and Disability Instrument) from pre TKR to >=1 year post-TKR among a subsample of participants from the Multicenter Osteoarthritis Study (MOST) longitudinal cohort (MOST is funded by the National Institutes of Health). The proportions of individuals with participation restriction pre-TKR and >=1 and >=2 years post-TKR were calculated for all participants and for important demographic subgroups. The association between demographic and clinical factors and participation was estimated using linear regression. The association between demographic and clinical factors and participation restriction was estimated using logistic regression. RESULTS: There were 292 individuals with outcome data >=1 year post-TKR. Of these, 218 (75%) had data pre-TKR and >=1 year post-TKR and 160 (55%) had data >=2 years post-TKR. There were mean improvements in pain, function, and participation at >=1 and 2 years. However, approximately 30% of the study sample had participation restriction pre-TKR and post-TKR, and the proportion decreased significantly only for those <65 years old. Non-whites had a higher proportion of participation restriction than any other subgroup (41% >=1 year, 48% >=2 years). Female sex and non-white race were associated with a worse participation score, and several demographic and modifiable factors were associated with participation restriction following TKR. LIMITATIONS: The time between pre-TKR and post-TKR assessment varied across study participants, and data were not available on their rehabilitation utilization. CONCLUSIONS: Although there was a mean increase in participation >=1 year following TKR, participation restriction was common. The likelihood of low participation was increased among women, non-whites, and those with depressive symptoms, severe pain in either knee, or worse pre-TKR function. PMID- 23813083 TI - Factors associated with paraspinal muscle asymmetry in size and composition in a general population sample of men. AB - BACKGROUND: Paraspinal muscle asymmetry in cross-sectional area (CSA) and composition have been associated with low back pain and pathology. However, substantial multifidus muscle asymmetry also has been reported in men who were asymptomatic, and little is known about other factors influencing asymmetry. OBJECTIVE: The goal of this study was to identify behavioral, environmental, and constitutional factors associated with paraspinal muscle asymmetry. DESIGN: A cross-sectional study of 202 adult male twins was conducted. METHODS: Data were collected through a structured interview, physical examination, and magnetic resonance imaging. Measurements of multifidus and erector spinae muscle CSA and the ratio of fat-free CSA to total CSA were obtained from T2-weighted axial images at L3-L4 and L5-S1. RESULTS: In multivariable analyses, greater asymmetry in multifidus CSA at L3-L4 was associated with lower occupational physical demands and less disk height narrowing. Handedness was the only factor associated with multifidus muscle CSA asymmetry at L5-S1. For the erector spinae muscle, greater age, handedness, and disk height narrowing were associated with CSA asymmetry at L3-L4, and sports activity, handedness, disk height narrowing, and familial aggregation were associated with CSA asymmetry at L5-S1. In multivariable analyses of asymmetry in muscle composition, familial aggregation explained 7% to 20% of the variance in multifidus and erector spinae muscle side to-side differences at both levels measured. In addition, handedness and pain severity entered the model for erector spinae muscle asymmetry at L5-S1, and disability, handedness, and disk height narrowing entered the model for multifidus muscle asymmetry at L5-S1. LIMITATIONS: Reliance on participants' recall for low back pain history, occupation, and physical activity levels was a limitation of this study. CONCLUSIONS: Few of the factors investigated were associated with paraspinal muscle asymmetry, and associations were inconsistent and modest, explaining little of the variance in paraspinal muscle asymmetry. PMID- 23813084 TI - Physical fitness training after stroke. PMID- 23813085 TI - Exercise for prevention of recurrences of nonspecific low back pain. PMID- 23813087 TI - Perspectives of academic faculty and clinical instructors on entry-level DPT preparation for pediatric physical therapist practice. AB - BACKGROUND: To prepare students for pediatric practice, the professional (entry level) curriculum must reflect the essential knowledge, skills, and abilities (KSA) required for pediatric physical therapist practice. OBJECTIVES: The aim of this study was to develop consensus concerning the pediatric-specific KSA that should be expected of doctor of physical therapy (DPT) students at various points in the curriculum: prior to a pediatric clinical education experience, after a pediatric clinical education experience, and at the end of a DPT program. DESIGN AND METHODS: The study was conducted using the Delphi method. Purposive and snowball sampling were used to recruit pediatric academic faculty and pediatric clinical instructors. Three Web-based survey rounds were used to achieve consensus, defined as agreement among >=70% of informants. The first round identified pediatric-specific KSA that were essential for DPT students to demonstrate at the identified points in the curriculum. In the second round, informants indicated their level of agreement with each item identified in the first round. Items that achieved consensus were included in the third round, in which informants rated the level of proficiency that DPT students should demonstrate related to pediatric-specific KSA. RESULTS: Consensus revealed the informants' perspectives concerning pediatric-specific KSA that a DPT student should be able to demonstrate at the identified curricular points. Consensus was reached on items in the curricular categories of basic science and foundations for practice; common pediatric diagnoses/pathologies, examination, interventions/plan of care/documentation; and general skills and abilities. LIMITATIONS: Limitations included the small sample size and the potential for informants to feel uncomfortable prioritizing KSA. CONCLUSIONS: This study is an initial step toward identifying pediatric-specific KSA that should be demonstrated by DPT students. PMID- 23813086 TI - A Rasch-validated version of the upper extremity functional index for interval level measurement of upper extremity function. AB - BACKGROUND: The original 20-item Upper Extremity Functional Index (UEFI) has not undergone Rasch validation. OBJECTIVE: The purpose of this study was to determine whether Rasch analysis supports the UEFI as a measure of a single construct (ie, upper extremity function) and whether a Rasch-validated UEFI has adequate reproducibility for individual-level patient evaluation. DESIGN: This was a secondary analysis of data from a repeated-measures study designed to evaluate the measurement properties of the UEFI over a 3-week period. METHODS: Patients (n=239) with musculoskeletal upper extremity disorders were recruited from 17 physical therapy clinics across 4 Canadian provinces. Rasch analysis of the UEFI measurement properties was performed. If the UEFI did not fit the Rasch model, misfitting patients were deleted, items with poor response structure were corrected, and misfitting items and redundant items were deleted. The impact of differential item functioning on the ability estimate of patients was investigated. RESULTS: A 15-item modified UEFI was derived to achieve fit to the Rasch model where the total score was supported as a measure of upper extremity function only. The resultant UEFI-15 interval-level scale (0-100, worst to best state) demonstrated excellent internal consistency (person separation index=0.94) and test-retest reliability (intraclass correlation coefficient [2,1]=.95). The minimal detectable change at the 90% confidence interval was 8.1. LIMITATIONS: Patients who were ambidextrous or bilaterally affected were excluded to allow for the analysis of differential item functioning due to limb involvement and arm dominance. CONCLUSION: Rasch analysis did not support the validity of the 20-item UEFI. However, the UEFI-15 was a valid and reliable interval-level measure of a single dimension: upper extremity function. Rasch analysis supports using the UEFI-15 in physical therapist practice to quantify upper extremity function in patients with musculoskeletal disorders of the upper extremity. PMID- 23813088 TI - Effect of selected manual therapy interventions for mechanical neck pain on vertebral and internal carotid arterial blood flow and cerebral inflow. AB - BACKGROUND: Manual therapy of the cervical spine has occasionally been associated with serious adverse events involving compromise of the craniocervical arteries. Ultrasound studies have shown certain neck positions can alter craniocervical arterial blood flow velocities; however, findings are conflicting. Knowledge about the effects of neck position on blood flow may assist clinicians in avoiding potentially hazardous practices. OBJECTIVE: The purpose of this study was to examine the effects of selected manual therapeutic interventions on blood flow in the craniocervical arteries and blood supply to the brain using magnetic resonance angiography (MRA). DESIGN: This was an experimental, observational magnetic resonance imaging study. METHOD: Twenty adult participants who were healthy and had a mean age of 33 years were imaged using MRA in the following neck positions: neutral, rotation, rotation/distraction (similar to a Cyriax manipulation), C1-C2 rotation (similar to a Maitland or osteopathic manipulation), and distraction. RESULTS: The participants were imaged using 3T MRA. All participants had normal vascular anatomy. Average inflow to the brain in neutral was 6.98 mL/s and was not significantly changed by any of the test positions. There was no significant difference in flow in any of the 4 arteries in any position from neutral, despite large individual variations. LIMITATIONS: Only individuals who were asymptomatic were investigated, and a short section of the arteries only were imaged. CONCLUSIONS: Blood flow to the brain does not appear to be compromised by positions commonly used in manual therapy. Positions using end-range neck rotation and distraction do not appear to be more hazardous to cerebral circulation than more segmentally localized techniques. PMID- 23813089 TI - Using a treadmill intervention to promote the onset of independent walking in infants with or at risk for neuromotor delay. PMID- 23813090 TI - Expanding the scoring system for the Dynamic Gait Index. AB - BACKGROUND: The Dynamic Gait Index (DGI) measures the capacity to adapt gait to complex tasks. The current scoring system combining gait pattern (GP) and level of assistance (LOA) lacks clarity, and the test has a limited range of measurement. OBJECTIVE: This study developed a new scoring system based on 3 facets of performance (LOA, GP, and time) and examined the psychometric properties of the modified DGI (mDGI). DESIGN: A cross-sectional, descriptive study was conducted. METHODS: Nine hundred ninety-five participants (855 patients with neurologic pathology and mobility impairments [MI group] and 140 patients without neurological impairment [control group]) were tested. Interrater reliability was calculated using kappa coefficients. Internal consistency was computed using the Cronbach alpha coefficient. Factor analysis and Rasch analysis investigated unidimensionality and range of difficulty. Internal validity was determined by comparing groups using multiple t tests. Minimal detectable change (MDC) was calculated for total score and 3 facet scores using the reliability estimate for the alpha coefficients. RESULTS: Interrater agreement was strong, with kappa coefficients ranging from 90% to 98% for time scores, 59% to 88% for GP scores, and 84% to 100% for LOA scores. Test-retest correlations (r) for time, GP, and LOA were .91, .91, and .87, respectively. Three factors (time, LOA, GP) had eigenvalues greater than 1.3 and explained 79% of the variance in scores. All group differences were significant, with moderate to large effect sizes. The 95% minimal detectable change (MDC95) was 4 for the mDGI total score, 2 for the time and GP total scores, and 1 for the LOA total score. LIMITATIONS: The limitations included uneven sample sizes in the 2 groups. The MI group were patients receiving physical therapy; therefore, they may not be representative of this population. CONCLUSIONS: The mDGI, with its expanded scoring system, improves the range, discrimination, and facets of measurement related to walking function. The strength of the psychometric properties of the mDGI warrants its adoption for both clinical and research purposes. PMID- 23813091 TI - Tools for observational gait analysis in patients with stroke: a systematic review. AB - BACKGROUND: Stroke severely affects walking ability, and assessment of gait kinematics is important in defining diagnosis, planning treatment, and evaluating interventions in stroke rehabilitation. Although observational gait analysis is the most common approach to evaluate gait kinematics, tools useful for this purpose have received little attention in the scientific literature and have not been thoroughly reviewed. OBJECTIVES: The aims of this systematic review were to identify tools proposed to conduct observational gait analysis in adults with a stroke, to summarize evidence concerning their quality, and to assess their implementation in rehabilitation research and clinical practice. METHODS: An extensive search was performed of original articles reporting on visual/observational tools developed to investigate gait kinematics in adults with a stroke. Two reviewers independently selected studies, extracted data, assessed quality of the included studies, and scored the metric properties and clinical utility of each tool. Rigor in reporting metric properties and dissemination of the tools also was evaluated. RESULTS: Five tools were identified, not all of which had been tested adequately for their metric properties. Evaluation of content validity was partially satisfactory. Reliability was poorly investigated in all but one tool. Concurrent validity and sensitivity to change were shown for 3 and 2 tools, respectively. Overall, adequate levels of quality were rarely reached. The dissemination of the tools was poor. CONCLUSIONS: Based on critical appraisal, the Gait Assessment and Intervention Tool shows a good level of quality, and its use in stroke rehabilitation is recommended. Rigorous studies are needed for the other tools in order to establish their usefulness. PMID- 23813092 TI - Empirical voriconazole therapy for febrile neutropenic patients with hematological disorders: a prospective multicenter trial in Japan. AB - An open-label, prospective, multicenter study was conducted between October 2006 and March 2010 to assess the efficacy and safety of intravenous voriconazole (VRCZ) as empirical therapy for antibiotic-refractory febrile neutropenia in Japanese patients with hematological disorders. In addition, to find the patient groups that may benefit from antifungal therapy, the definition of invasive fungal infection proposed by EORTC/MSG (2002) was assessed in this study. Plasma (1-3)-beta-D-glucan and Aspergillus PCR in blood were also measured to improve the diagnostic accuracy. A total of 103 patients (median age, 59 years), including 25 undergoing induction chemotherapies and 19 allogeneic hematopoietic cell transplants, were evaluable. Sixty-nine percent of the patients achieved resolution of clinical symptoms and 31% achieved treatment success, defined as fulfilling the previously described five-part composite endpoint. Although VRCZ was discontinued in 9.7% of the patients because of adverse effects, all the patients recovered soon after discontinuation of VRCZ. The treatment success rate of VRCZ appeared to be higher in patients categorized as "not classified" compared with "possible invasive fungal disease" according to the EORTC/MSG criteria. Moreover, six "not classified" patients were positive for either plasma (1-3)-beta-D-glucan (n = 5) or Aspergillus PCR in blood (n = 2). The present study demonstrates that empirical VRCZ therapy is safe and effective in Japanese patients. Additionally, (1-3)-beta-D-glucan and Aspergillus PCR tests were expected to provide additional information on the diagnosis of invasive fungal infections. PMID- 23813094 TI - Prediction of AMD generation potential in mining waste piles, in the Sarcheshmeh porphyry copper deposit, Iran. AB - This study investigates the possibility of acid mine drainage (AMD) generation in active and derelict mine waste piles in Sarcheshmeh Copper Mine produced in several decades, using static tests including acid-base accounting (ABA) and net acid-generating pH (NAGpH). In this study, 51 composite samples were taken from 11 waste heaps, and static ABA and NAGpH tests were carried out on samples. While some piles are acid producing at present and AMD is discharging from the piles, most of them do not show any indication on their AMD potential, and they were investigated to define their acid-producing potential. The analysis of data indicates that eight waste piles are potentially acid generating with net neutralization potentials (NNPs) of -56.18 to -199.3, net acid generating of 2.19 3.31, and NPRs from 0.18 to 0.44. Other waste piles exhibited either a very low sulfur, high carbonate content or excess carbonate over sulfur; hence, they are not capable of acid production or they can be considered as weak acid producers. Consistency between results of ABA and NAGpH tests using a variety of classification criteria validates these tests as powerful means for preliminary evaluation of AMD/ARD possibilities in any mining district. It is also concluded that some of the piles with very negative NNPs are capable to produce AMD naturally, and they can be used in heap leaching process for economic recovery of trace amounts of metals without applying any biostimulation methods. PMID- 23813093 TI - Nationwide surveillance of the antimicrobial susceptibility of Neisseria gonorrhoeae from male urethritis in Japan. AB - Neisseria gonorrhoeae is one of the most important pathogens causing sexually transmitted infection, and strains that are resistant to several antimicrobials are increasing. To investigate the trends of antimicrobial susceptibility among N. gonorrhoeae strains isolated from male patients with urethritis, a Japanese surveillance committee conducted the first nationwide surveillance. The urethral discharge was collected from male patients with urethritis at 51 medical facilities from April 2009 to October 2010. Of the 156 specimens, 83 N. gonorrhoeae strains were tested for susceptibility to 18 antimicrobial agents. The prevalence of beta-lactamase-producing strains and chromosomally mediated resistant strains were 7.2 % and 16.5 %, respectively. None of the strains was resistant to ceftriaxone, but the minimum inhibitory concentration (MIC) of ceftriaxone for 7 strains (8.4 %) was 0.125 MUg/ml. One strain was resistant to cefixime (MIC 0.5 MUg/ml). The MICs of fluoroquinolones, such as ciprofloxacin, levofloxacin, and tosufloxacin, showed a bimodal distribution. The MIC of sitafloxacin was lower than those of the three fluoroquinolones listed here, and it was found that the antimicrobial activity of sitafloxacin was stronger than that of the fluoroquinolones. The MIC of azithromycin in 2 strains was 2 MUg/ml, but no high-level resistance to macrolides was detected. PMID- 23813095 TI - Monitoring of nitrates in drinking water from agricultural and residential areas of Podravina and Prigorje (Croatia). AB - Nitrates are the most common chemical pollutant of groundwater in agricultural and suburban areas. Croatia must comply with the Nitrate Directive (91/676/EEC) whose aim is to reduce water pollution by nitrates originating from agriculture and to prevent further pollution. Podravina and Prigorje are the areas with a relatively high degree of agricultural activity. Therefore, the aim of this study was, by monitoring nitrates, to determine the distribution of nitrates in two different areas, Podravina and Prigorje (Croatia), to determine sources of contamination as well as annual and seasonal trends. The nitrate concentrations were measured in 30 wells (N = 382 samples) in Prigorje and in 19 wells (N = 174 samples) in Podravina from 2002 to 2007. In Podravina, the nitrate content was 24.9 mg/l and 6% of the samples were above the maximum available value (MAV), and in Prigorje the content was 53.9 mg/l and 38% of the samples above MAV. The wells were classified as correct, occasionally incorrect and incorrect. In the group of occasionally incorrect and incorrect wells, the point sources were within 10 m of the well. There is no statistically significant difference over the years or seasons within the year, but the interaction between locations and years was significant. Nitrate concentrations' trend was not significant during the monitoring. These results are a prerequisite for the adjustment of Croatian standards to those of the EU and will contribute to the implementation of the Nitrate Directive and the Directives on Environmental Protection in Croatia and the EU. PMID- 23813096 TI - Mapping afforestation and deforestation from 1974 to 2012 using Landsat time series stacks in Yulin District, a key region of the Three-North Shelter region, China. AB - The Three-North Shelter Forest Program is the largest afforestation reconstruction project in the world. Remote sensing is a crucial tool to map land use and land cover change, but it is still challenging to accurately quantify the change in forest extent from time-series satellite images. In this paper, 30 Landsat MSS/TM/ETM+ epochs from 1974 to 2012 were collected, and the high-quality ground surface reflectance (GSR) time-series images were processed by integrating the 6S atmosphere transfer model and a relative reflectance normalization algorithm. Subsequently, we developed a vegetation change tracking method to reconstruct the forest change history (afforestation and deforestation) from the time-series Landsat GSR images based on the integrated forest z-score (IFZ) model by Huang et al. (2009a), which was improved by multi-phenological IFZ models and the smoothing processing of IFZ data for afforestation mapping. The mapping result showed a large increase in the extent of forest, from 380,394 ha (14.8% of total district area) in 1974 to 1,128,380 ha (43.9%) in 2010. Finally, the land cover and forest change map was validated with an overall accuracy of 89.1% and a kappa coefficient of 0.858. The forest change time was also successfully retrieved, with 22.2% and 86.5% of the change pixels attributed to the correct epoch and within three epochs, respectively. The results confirmed a great achievement of the ecological revegetation projects in Yulin district over the last 40 years and also illustrated the potential of the time-series of Landsat images for detecting forest changes and estimating tree age for the artificial forest in a semi-arid zone strongly influenced by human activities. PMID- 23813097 TI - Temporal regulation of apoptotic and anti-apoptotic molecules after middle cerebral artery occlusion followed by reperfusion. AB - A tremendous effort has been expended to elucidate the role of apoptotic molecules in ischemia. However, many agents that target apoptosis, despite their proven efficacy in animal models, have failed to translate that efficacy and specificity in clinical settings. Therefore, comprehensive knowledge of apoptotic mechanisms involving key apoptotic regulatory molecules and the temporal expression profiles of various apoptotic molecules after cerebral ischemia may provide insight for the development of better therapeutic strategies aimed at cerebral ischemia. The present study investigates the extent of apoptosis and the regulation of apoptotic molecules both at mRNA and protein levels at various time points after focal cerebral ischemia in a rat model of middle cerebral artery occlusion. In this study, we performed various techniques, such as TTC (2,3,5 triphenyltetrazolium chloride), H&E (hematoxylin and eosin), and TUNEL (terminal deoxy nucleotidyl transferase-mediated nick-end labeling) staining, along with polymerase chain reaction (PCR) microarray, antibody microarray, reverse transcription (RT)-PCR, immunofluorescence, and immunoblot analyses. Our research provided a large list of pro-apoptotic and anti-apoptotic molecules and their temporal expression profiles both at the mRNA and protein levels. This information could be very useful for designing future stroke therapies and aid in targeting the right molecules at critical time to obtain maximum therapeutic benefit. PMID- 23813099 TI - Redox mechanism of S-nitrosothiol modulation of neuronal CaV3.2 T-type calcium channels. AB - T-type calcium channels in the dorsal root ganglia (DRG) have a central function in tuning neuronal excitability and are implicated in sensory processing including pain. Previous studies have implicated redox agents in control of T channel activity; however, the mechanisms involved are not completely understood. Here, we recorded T-type calcium currents from acutely dissociated DRG neurons from young rats and investigated the mechanisms of CaV3.2 T-type channel modulation by S-nitrosothiols (SNOs). We found that extracellular application of S-nitrosoglutathione (GSNO) and S-nitroso-N-acetyl-penicillamine rapidly reduced T-type current amplitudes. GSNO did not affect voltage dependence of steady-state inactivation and macroscopic current kinetics of T-type channels. The effects of GSNO were abolished by pretreatment of the cells with N-ethylmaleimide, an irreversible alkylating agent, but not by pretreatment with 1H-(1,2,4) oxadiazolo (4,3-a) quinoxalin-1-one, a specific soluble guanylyl cyclase inhibitor, suggesting a potential effect of GSNO on putative extracellular thiol residues on T-type channels. Expression of wild-type CaV3.2 channels or a quadruple Cys-Ala mutant in human embryonic kidney cells revealed that Cys residues in repeats I and II on the extracellular face of the channel were required for channel inhibition by GSNO. We propose that SNO-related molecules in vivo may lead to alterations of T-type channel-dependent neuronal excitability in sensory neurons and in the central nervous system in both physiological and pathological conditions such as neuronal ischemia/hypoxia. PMID- 23813098 TI - Glia and mast cells as targets for palmitoylethanolamide, an anti-inflammatory and neuroprotective lipid mediator. AB - Glia are key players in a number of nervous system disorders. Besides releasing glial and neuronal signaling molecules directed to cellular homeostasis, glia respond also to pro-inflammatory signals released from immune-related cells, with the mast cell being of particular interest. A proposed mast cell-glia communication may open new perspectives for designing therapies to target neuroinflammation by differentially modulating activation of non-neuronal cells normally controlling neuronal sensitization-both peripherally and centrally. Mast cells and glia possess endogenous homeostatic mechanisms/molecules that can be upregulated as a result of tissue damage or stimulation of inflammatory responses. Such molecules include the N-acylethanolamines, whose principal family members are the endocannabinoid N-arachidonoylethanolamine (anandamide), and its congeners N-stearoylethanolamine, N-oleoylethanolamine, and N palmitoylethanolamine (PEA). A key role of PEA may be to maintain cellular homeostasis when faced with external stressors provoking, for example, inflammation: PEA is produced and hydrolyzed by microglia, it downmodulates mast cell activation, it increases in glutamate-treated neocortical neurons ex vivo and in injured cortex, and PEA levels increase in the spinal cord of mice with chronic relapsing experimental allergic encephalomyelitis. Applied exogenously, PEA has proven efficacious in mast cell-mediated experimental models of acute and neurogenic inflammation. This fatty acid amide possesses also neuroprotective effects, for example, in a model of spinal cord trauma, in a delayed post glutamate paradigm of excitotoxic death, and against amyloid beta-peptide-induced learning and memory impairment in mice. These actions may be mediated by PEA acting through "receptor pleiotropism," i.e., both direct and indirect interactions of PEA with different receptor targets, e.g., cannabinoid CB2 and peroxisome proliferator-activated receptor-alpha. PMID- 23813100 TI - Progress in dodecafluoropentane emulsion as a neuroprotective agent in a rabbit stroke model. AB - Dodecafluoropentane emulsion (DDFPe) in 250 nm nanodroplets seems to swell modestly to accept and carry large amounts of oxygen in the body at >29 degrees C. Small particle size allows oxygen delivery even into hypoxic tissue unreachable by erythrocytes. Using permanent cerebral embolic occlusion in rabbits, we assessed DDFPe dose response as a neuroprotectant at 7 and 24 h post embolization without lysis of arterial obstructions and investigated blood pharmacokinetics. New Zealand White rabbits (N = 56) received cerebral angiography and embolic spheres (diameter = 700-900 MUm) occluded middle and/or anterior cerebral arteries. Intravenous DDFPe dosing (2 % w/v emulsion) began at 60 min and repeated every 90 min until sacrifice at 7 or 24 h post-embolization. Seven-hour groups: (1) control (embolized without treatment, N = 6), and DDFPe treatment: (2) 0.1 ml/kg (N = 7), (3) 0.3 ml/kg (N = 9), (4) 0.6 ml/kg (N = 8). Twenty-four-hour groups: (5) control (N = 16), and DDFPe treatment: (6) 0.1 ml/kg (N = 10). Infarcts as percent of total brain volume were determined using vital stains on brain sections. Other alert normal rabbits (N = 8) received IV doses followed by rapid arterial blood sampling and GC-MS analysis. Percent infarct volume means significantly decreased for all DDFPe-treated groups compared with controls, p = <0.004 to <0.03. Blood DDFP (gas) half-life was 1.45 +/- 0.17 min with R = 0.958. Mean blood clearance was 78.5 +/- 24.9 ml/min/kg (mean +/- SE). Intravenous DDFPe decreases ischemic stroke infarct volumes. Blood half-life values are very short. The much longer therapeutic effect, >90 min, suggests multiple compartments. Lowest effective dose and maximum effective therapy duration are not yet defined. Rapid development is warranted. PMID- 23813101 TI - Insulin resistance and dysregulation of tryptophan-kynurenine and kynurenine nicotinamide adenine dinucleotide metabolic pathways. AB - Insulin resistance (IR) underlines aging and aging-associated medical (diabetes, obesity, dyslipidemia, hypertension) and psychiatric (depression, cognitive decline) disorders. Molecular mechanisms of IR in genetically or metabolically predisposed individuals remain uncertain. Current review of the literature and our data presents the evidences that dysregulation of tryptophan (TRP)-kynurenine (KYN) and KYN-nicotinamide adenine dinucleotide (NAD) metabolic pathways is one of the mechanisms of IR. The first and rate-limiting step of TRP-KYN pathway is regulated by enzymes inducible by pro-inflammatory factors and/or stress hormones. The key enzymes of KYN-NAD pathway require pyridoxal-5-phosphate (P5P), an active form of vitamin B6, as a cofactor. Deficiency of P5P diverts KYN-NAD metabolism from production of NAD to the excessive formation of xanthurenic acid (XA). Human and experimental studies suggested that XA and some other KYN metabolites might impair production, release, and biological activity of insulin. We propose that one of the mechanisms of IR is inflammation- and/or stress induced upregulation of TRP-KYN metabolism in combination with P5P deficiency induced diversion of KYN-NAD metabolism towards formation of XA and other KYN derivatives affecting insulin activity. Monitoring of KYN/P5P status and formation of XA might help to identify subjects at risk for IR. Pharmacological regulation of the TRP-KYN and KYN-NAD pathways and maintaining of adequate vitamin B6 status might contribute to prevention and treatment of IR in conditions associated with inflammation/stress-induced excessive production of KYN and deficiency of vitamin B6, e.g., type 2 diabetes, obesity, cardiovascular diseases, aging, menopause, pregnancy, and hepatitis C virus infection. PMID- 23813102 TI - Food, nutrigenomics, and neurodegeneration--neuroprotection by what you eat! AB - Diet in human health is no longer simple nutrition, but in light of recent research, especially nutrigenomics, it is linked via evolution and genetics to cell health status capable of modulating apoptosis, detoxification, and appropriate gene response. Nutritional deficiency and disease especially lack of vitamins and minerals is well known, but more recently, epidemiological studies suggest a role of fruits and vegetables, as well as essential fatty acids and even red wine (French paradox), in protection against disease. In the early 1990s, various research groups started considering the use of antioxidants (e.g., melatonin, resveratrol, green tea, lipoic acid) and metabolic compounds (e.g., nicotinamide, acetyl-L-carnitine, creatine, coenzyme Q10) as possible candidates in neuroprotection. They were of course considered on par with snake oil salesman (women) at the time. The positive actions of nutritional supplements, minerals, and plant extracts in disease prevention are now mainstream and commercial health claims being made are subject to regulation in most countries. Apart from efficacy and finding, the right dosages, the safety, and especially the level of purification and lack of contamination are all issues that are important as their use becomes widespread. From the mechanistic point of view, most of the time these substances replenish the body's deficiency and restore normal function. However, they also exert actions that are not sensu stricto nutritive and could be considered pharmacological especially that, at times, higher intake than recommended (RDA) is needed to see these effects. Free radicals and neuroinflammation processes underlie many neurodegenerative conditions, even Parkinson's disease and Alzheimer's disease. Curcumin, carotenoids, acetyl-L carnitine, coenzyme Q10, vitamin D, and polyphenols and other nutraceuticals have the potential to target multiple pathways in these conditions. In summary, augmenting neuroprotective pathways using diet and finding new natural substances that can be more efficacious, i.e., induction of health-promoting genes and reduction of the expression of disease-promoting genes, could be incorporated into neuroprotective strategies of the future. PMID- 23813103 TI - An elemental model of retrospective revaluation without within-compound associations. AB - When retrospective revaluation phenomena (e.g., unovershadowing: AB+, then A-, then test B) were discovered, simple elemental models were at a disadvantage because they could not explain such phenomena. Extensions of these models and novel models appealed to within-compound associations to accommodate these new data. Here, we present an elemental, neural network model of conditioning that explains retrospective revaluation apart from within-compound associations. In the model, previously paired stimuli (say, A and B, after AB+) come to activate similar ensembles of neurons, so that revaluation of one stimulus (A-) has the opposite effect on the other stimulus (B) through changes (decreases) in the strength of the inhibitory connections between neurons activated by B. The ventral striatum is discussed as a possible home for the structure and function of the present model. PMID- 23813105 TI - Intravitreal Ranibizumab for myopic choroidal neovascularization after pars plana vitrectomy and silicone oil tamponade. AB - PURPOSE: To report on intravitreal Ranibizumab for intervening myopic choroidal neovascularization (CNV) in a case of retinal detachment successfully repaired with pars plana vitrectomy and silicone oil tamponade. METHODS: Intravitreal ranibizumab was performed in a 67-year-old woman with CNV complicating pathologic myopia. The patient had previously undergone vitrectomy and silicone oil tamponade for retinal detachment. RESULTS: At 2 months from intravitreal ranibizumab, best-corrected visual acuity (BCVA) improved from count fingers to 20/100, and intraocular pressure (IOP) was 16 mm Hg. Fluorescein angiography (FA) and spectral-domain optical coherence tomography (SD-OCT) showed resolution of late leakage and subretinal/intraretinal fluid, respectively. CONCLUSIONS: Administration of intravitreal anti-V EGF in patients with silicone oil as intraocular tamponade may represent an intriguing treatment option. Our results suggest that intravitreal injections of Ranibizumab may lead to a rapid improvement in both functional (BCVA) and morphologic (FA and SD-OCT) parameters of CNV activity, without significant rise in IOP, in eyes with silicone oil as intraocular tamponade. PMID- 23813106 TI - Clinical analysis of macular edema with new software for SD-OCT imaging. AB - PURPOSE: To evaluate the clinical efficacy of user-friendly software for the measurement of intraretinal hyporeflective spaces expression of macular edema. METHODS: Fifteen consecutive patients with diabetic retinopathy with clinically significant macular edema were examined using conventional spectral domain optical coherence tomography (OCT). A new composite software application, OCT measurement analysis tool (OCT-MAT), was developed to automatically process and analyze OCT B-scans by means of image acquisition, filtering, and elaboration, together with hyporeflective area recognition and measurement in um2. The same macular areas were measured manually, and then compared to the measurements obtained by the automated OCT-MAT software. A statistical t test analysis was applied (statistical significance level at p<0.05). The repeatability and reproducibility coefficient for the automated software was computed using the Wilcoxon matched pair test (5% significance level). RESULTS: In all patients, the software effectively measured the number and extension of intraretinal hyporeflective spaces in um2. The comparison between mean manual measurements and OCT-MAT measurements (0.478 +/- 0.300 * 10(6) um2 vs 0.471 +/- 0.321 * 10(6) um2) showed correct correspondence (p>0.05). Moreover, the OCT-MAT software showed good repeatability and reproducibility (coefficient below 3%). CONCLUSIONS: OCT MAT allows the precise measurement of macular edema in terms of the number of empty spaces and their size in all patients. Its daily clinical application might give precise information regarding the evolution of macular edema and the efficacy of therapy. PMID- 23813107 TI - Mean platelet volume in pseudoexfoliation syndrome and glaucoma. AB - PURPOSE: Pseudoexfoliation (PEX) syndrome (PES) is characterized by the widespread deposition of abnormal extracellular fibrillary material on many ocular and extraocular tissues. The objective of this study was to evaluate the association among PES, PEX glaucoma (PEG), and mean platelet volume (MPV). METHODS: Forty patients with PES (mean age 62.6 +/- 7.8 years), 31 with PEG (mean age 65.9 +/- 6.6 years), and 37 healthy individuals (control group) (mean age 64.0 +/- 7.1 years) were included in the study. The MPV of the 3 groups were compared. RESULTS: Age and sex distribution were similar among groups (p>0.05). Mean MPV in PES, PEG, and control groups were 9.59 +/- 0.94 fl, 9.53 +/- 0.80 fl, and 7.7 +/- 0.67 fl, respectively. In the PEX group, MPV values were significantly higher than in the control group (p<0.05). However, there was no difference between the PES and PEG groups (p>0.05). CONCLUSIONS: The MPV values in both groups with PEX were higher than those in the healthy group. PMID- 23813108 TI - Pattern electroretinogram assessment during ibopamine test in ocular hypertension. AB - PURPOSE: To determine the change in pattern electroretinogram (PERG) amplitude during the ibopamine test in patients with ocular hypertension (OHT). METHODS: A total of 32 eyes (16 patients) with OHT (8 male, 8 female), mean age 54.19 years (range 22-76 years), mean baseline intraocular pressure (IOP) 23 +/- 2 mm Hg, received a PERG assessment in both eyes every 5 minutes from baseline to 60 minutes. All the patients were pretreated by thymoxamine eyedrops to avoid the mydriatic effect of ibopamine. All the data were evaluated by descriptive statistics and paired t test. The results were considered with a significance level of p<0.05. RESULTS: All the patients enrolled matched the inclusion criteria and they did not have any local or systemic effects with the ibopamine test. The mean PERG amplitude decreased significantly from baseline after 45 minutes during the ibopamine test (paired t test = 0.05). The results were statistically not correlated with the positivity to the ibopamine test (p = 0.5). CONCLUSIONS: These data stress that, even in presence of a moderate and transient IOP increase, inner retinal function of patients with OHT may be transiently affected. PMID- 23813109 TI - High-dose (2.0 mg) intravitreal ranibizumab for recalcitrant radiation retinopathy. AB - PURPOSE: To evaluate the safety and tolerability and treatment efficacy of high dose (2.0 mg) intravitreal ranibizumab for recalcitrant radiation retinopathy. METHODS: A phase I to II open-label, nonrandomized prospective clinical trial was performed on 10 eyes of 10 patients with recalcitrant radiation retinopathy who were failing standard dose anti-vascular endothelial growth factor (VEGF) therapy. External beam or plaque brachytherapy-associated retinopathy was characterized by persistent macular edema or leakage on optical coherence tomography or fluorescein angiography. Intravitreal 2.0 mg ranibizumab was given monthly up to 12 months and monitored for tolerability and change in best corrected visual acuity (BCVA), central foveal thickness, and clinical signs of radiation retinopathy. RESULTS: Seven patients completed the 1-year study and received all 12 injections; 3 withdrew from the study due to worsening retinopathy (1 after external beam, 2 following plaque). Treatment was well tolerated with no severe adverse reactions. A total of 70% had stable (n = 3) or improved (n = 4) BCVA. Mean change in BCVA was +3.3 letters at 6 months and +0.7 letters at 1 year. Mean improvement in central foveal thickness (CFT) was -19.3% (range -57 to +15%) at 1 year. Initial mean CFT was 428 um (range 192-776); final mean CFT was 333 um (range 190-532). A total of 80% demonstrated a statistically significant (p<0.05) reduction in CFT. CONCLUSIONS: Regardless of radiation source, intravitreal injections of 2.0 ranibizumab induced significant reductions in macular edema and maintained or improved BCVA in most patients who were failing standard dose anti-VEGF therapy. PMID- 23813110 TI - Intermediate uveitis: comparison between childhood-onset and adult-onset disease. AB - PURPOSE: To compare demographic and clinical data, systemic disease association, visual prognosis, and complications found in childhood and adult onset of intermediate uveitis (IU). METHODS: Retrospective cohort study of 287 patients with IU: 122 (42.5%) children at onset (<16 years), 165 (57.5%) adults. The data were entered on a computer-based standardized data entry form for statistical analysis. Student t test was used regarding differences in means. To assess significance of differences in proportions, we used the chi2 test, but when the population in the subgroup was <= 5 patients, we used the Fisher exact test (p<0.05 were deemed to be statistically significant and as reported were not corrected for multiple testing and so should be viewed as nominal). RESULTS: A total of 61% of childhood-onset cases occurred in boys (44% in the adult group), while adult onset was more common in women (56% vs 39%) (p = 0.004, odds ratio [OR] 2.06). Regardless of the onset age, IU was frequently bilateral and idiopathic. The most frequent complication was cystoid macular edema (27.5%, p = 0.469, OR 0.85), which was also the most frequent cause of visual loss. Optic disc edema was more prevalent in children (15.5% vs 9.2%; p = 0.027, OR 1.81), ocular hypertension in adults (15.6% vs 7.5%, p = 0.007, OR 0.44). A total of 25 patients had non-idiopathic IU. A total of 14 patients had multiple sclerosis. CONCLUSIONS: Intermediate uveitis was mostly idiopathic and bilateral in both groups. Visual prognosis was good and it was not age-related. Childhood onset was more frequent in boys, adult onset in women. Endocrinal factors could be involved. PMID- 23813111 TI - Presumed herpetic anterior uveitis: a study with retrospective analysis of 79 cases. AB - PURPOSE: To describe the clinical features, visual outcome, medical treatment, and complications of presumed herpetic anterior uveitis. METHODS: We retrospectively analyzed the clinical data related to 79 eyes of 77 patients with presumed herpetic anterior uveitis seen at the Uveitis Unit of the Ulucanlar Eye Training and Research Hospital from 1996 to 2011. Age at onset of disease, sex, follow-up duration, existence of corneal involvement, posterior synechiae, distorted pupil, iris atrophy, characteristic of keratic precipitates, elevated intraocular pressure (IOP), medical treatment, recurrence rate, complications, visual acuities (VA), and surgery for complications were recorded. The complication rates in patients with and without corneal involvement were compared. RESULTS: There were 38 (49.4%) female and 39 (50.6%) male patients. The mean age at presentation was 48.5 +/- 14.8 (20-82) years. The follow-up period was 26.5 (2-127) months. Two patients had bilateral involvement. Ocular findings were a corneal scar or active keratitis in 37 (46.8%) eyes, secondary glaucoma in 14 (17.7%), iris atrophy in 39 (49.4%), distorted pupil in 16 (20.3%), posterior synechiae in 23 (29.1%), and granulomatous anterior uveitis in 30 (40%) eyes. Eight (10.1%) eyes had a posterior subcapsular cataract. Glaucoma surgery was required for uncontrolled IOP with maximum medical treatment in 2 (2.4%) eyes. Long-term oral acyclovir was used in 9 (11.3%) patients. Final VA was <= 0.1 in 8 (10.1%) eyes; of these, 6 had either corneal scarring or cataract and 2 preexisting amblyopia. CONCLUSIONS: Presumed herpetic anterior uveitis with or without keratitis has characteristic clinical findings that enable the diagnosis. Long-term prophylactic antiviral therapy should be considered especially in patients <50 years old. PMID- 23813112 TI - The influence of compliance with the use of refractive correction in hyperopic children on accommodation. AB - PURPOSE: To indicate the relationship between constant, correct use of hyperopic spectacles and relaxation of accommodation in children. METHODS: After thorough ophthalmic examination (cycloplegia included), 52 children 2.5 to 9 years old were detected with hyperopia >3 D, out of all examined within a year. These children were fully or partially corrected, with hyperopic glasses, depending on whether accommodative esotropia was or was not present. Constant and correct use of spectacles was strongly suggested to all children. During follow-up 3 and 6 months later, the amount of manifest hyperopia was measured in each case by an autorefractometer (without the use of cycloplegic factor). RESULTS: Out of the 52 children, 37 who participated in our study fully complied with hyperopic spectacle treatment, wearing their glasses constantly and correctly. The 15 others wore their glasses partially or not at all or made incorrect use of them. During follow-up 3 and 6 months later, refractive measurements of manifest hyperopia in the first group of children were identical or similar to the refractive power of their glasses. On the contrary, in the second group of children, strong accommodation did not allow the expression of hyperopia, and in a few cases myopic refractive measurements appeared (similar to those on the first examination, before spectacle treatment was prescribed). CONCLUSIONS: Constant and correct use of hyperopic spectacles leads to relaxation of accommodation in children and is thus an accurate indicator of compliance. PMID- 23813113 TI - Comparison of far and near contrast sensitivity in patients symmetrically implanted with multifocal and monofocal IOLs. AB - PURPOSE: A prospective, randomized, double-masked, clinical trial was designed to evaluate distance and near contrast sensitivity (CS) in patients symmetrically, and randomly, implanted with 4 different multifocal intraocular lens (MIOL) designs (ReSTOR SN6AD1, ReSTOR SN60D3, ReZoom NXG, and Tecnis ZMA00) and a monofocal control group (Tecnis ZA9003), 6 months after cataract intervention. METHODS: Photopic, mesopic, and mesopic with glare distance CS, as well as photopic near CS, was evaluated with the CSV-1000 CS test and the Vistech VCTS 6000 system, respectively, in a group of 180 patients attending the ophthalmology department of Sant Pau Hospital, Barcelona, for cataract intervention and lens implantation. RESULTS: Statistically and clinically significant differences were found between the monofocal and multifocal lens groups at all spatial frequencies and illumination conditions, both during distance and near CS evaluation (all p<0.05), with the monofocal lens offering the best performance in all cases. Contrast sensitivity was similarly compromised in all MIOL models at distance, although MIOLs with diffractive optics and aspheric profiles showed a non statistically significant trend to perform better in mesopic conditions. Near CS was lower for refractive, distance dominant lens designs, particularly at medium to high spatial frequencies. CONCLUSIONS: The present results, which reflect intraocular lens (IOL) characteristics in optics, profile, and add power, may contribute to help surgeons decide on the type of IOL most suitable for each patient by taking into consideration the individual needs for critical distance and near vision, both in terms of visual acuity and contrast sensitivity. PMID- 23813114 TI - Science is a gateway for democracy. AB - The Arab Spring of 2011 has highlighted an unprecedent fact in the region: it was the young and educated population who established the spearheading of change, and led their countries to democracy. In this paper, we try to analyze how science has been a key factor in these moves, in Tunisia as well as in Egypt, and how it can help to anchor democracy in these countries. PMID- 23813115 TI - Electronic health records and the increasing complexity of medical practice. PMID- 23813116 TI - Methohexital in total intravenous anesthesia during intraoperative neurophysiological monitoring. AB - Total intravenous anesthesia (TIVA) is usually recommended during spinal surgery when transcranial motor evoked potentials (tcMEPs) are used to monitor. A shortage of propofol has prompted a search for an alternative sedative-hypnotic agent. We explored the use of methohexital as an alternative. TIVA was provided for two adult patients having spinal surgery using an infusion of methohexital. TcMEPs and somatosensory evoked potentials were acquired to monitor neurological function and electroencephalogram was used to titrate the methohexital dose. Two cases are presented in which the anesthesia and monitoring that was provided were successful. These cases indicate that methohexital can be a suitable alternative to propofol in some patients. PMID- 23813117 TI - Tools (Viewer, Library and Validator) that facilitate use of the peptide and protein identification standard format, termed mzIdentML. AB - The Proteomics Standards Initiative has recently released the mzIdentML data standard for representing peptide and protein identification results, for example, created by a search engine. When a new standard format is produced, it is important that software tools are available that make it straightforward for laboratory scientists to use it routinely and for bioinformaticians to embed support in their own tools. Here we report the release of several open-source Java-based software packages based on mzIdentML: ProteoIDViewer, mzidLibrary, and mzidValidator. The ProteoIDViewer is a desktop application allowing users to visualize mzIdentML-formatted results originating from any appropriate identification software; it supports visualization of all the features of the mzIdentML format. The mzidLibrary is a software library containing routines for importing data from external search engines, post-processing identification data (such as false discovery rate calculations), combining results from multiple search engines, performing protein inference, setting identification thresholds, and exporting results from mzIdentML to plain text files. The mzidValidator is able to process files and report warnings or errors if files are not correctly formatted or contain some semantic error. We anticipate that these developments will simplify adoption of the new standard in proteomics laboratories and the integration of mzIdentML into other software tools. All three tools are freely available in the public domain. PMID- 23813118 TI - Modified Kugel herniorrhaphy using standardized dissection technique of the preperitoneal space: long-term operative outcome in consecutive 340 patients with inguinal hernia. AB - PURPOSE: The aim of this study was to evaluate the outcome, with a special reference to recurrence and postoperative chronic pain, of the modified Kugel herniorrhaphy (MKH) using standardized dissection of the preperitoneal space. PATIENTS AND METHODS: Operative results were examined based on medical records and questionnaire surveys in 340 consecutive cases of MKH performed at a single institution. The operation was performed with an original 3-stage dissection of the preperitoneal space only via the internal inguinal ring. RESULTS: The mean follow-up period was 50.5 +/- 24.3 months. The mean operating time was 42.2 +/- 13.1 min, and by Nyhus classification, significant difference was observed between types IIIA and IIIB (39.5 +/- 10.8 vs. 45.6 +/- 15.6 min, P = 0.0279). Eight surgeons performed 10 or more operations, and no significant difference was found in their operating time. Thirty-one patients used additional analgesics postoperatively (9.1 %) and the length of postoperative stay was 1.2 +/- 0.7 days. Seven patients (2.1 %) developed complications related to the hernia operation, but none of them required re-operation. The period required to return to normal daily activities was 3 +/- 3.2 days. Questionnaire forms were returned from 77.7 % of all the patients, in which 12 patients reported chronic pain (4.7 %). Visual analog scale for patients with chronic pain scored 3.8 +/- 2.4, with no patient indicating restrictions on daily life. Recurrence was observed in only one case (0.3 %). CONCLUSION: MKH using standardized dissection of the preperitoneal space is a highly reproducible procedure with acceptable rate of postoperative chronic pain and recurrence. PMID- 23813119 TI - Survey of mycotic mastitis in dairy cows from Heilongjiang Province, China. AB - A survey of the prevalence rate, pathogenic subspecies, and risk factors of mycotic mastitis in dairy cows from Heilongjiang Province, China, was conducted. Milk samples from 412 cows with chronic mastitis were collected and cultured on 8 % sheep blood agar, MacConkey agar, and Sabouraud agar with chloramphenicol. Counting of the morphologically distinct colonies was performed, as well as the isolation and identification of organisms through phenotypical and physiological criteria. Four hundred seventy-eight aerobic microorganisms were isolated. Yeasts and yeast-like fungi 35.6 % (170/478) and bacteria 64.4 % (308/478) were isolated. The fungal isolates were identified as Candida (79.4 %), Trichosporon (5.9 %), Aspergillus (7.1 %), Cryptococcus (2.4 %), and Rhodotorula (4.1 %). More than ten species of yeast were isolated including Candida krusei 50/135 (37 %), Candida rugosa 16/135 (11.9 %), and Candida lusitaniae 15/135 (11.1 %). A higher positivity (18.5 and 56.3 %) (P <=0.05) was observed in cows from environmental temperatures of 0-15 and 15-35 degrees C than those at <0 degrees C and in cows affected by the disease for >45 and 30-45 days compared with cows suffering 10-30 days. Meanwhile, a statistically significant difference (44.9 vs. 31.4 %) (P <=0.05) was observed under extensive raising systems vs. intensive raising systems. It appears that Candida is a major pathogen of mycotic mastitis of dairy cows. Extensive raising system, high environmental temperature (15-35 degrees C), and the duration of the disease (>30 days) were important risk factors of the incidence of mycotic mastitis. Here, we provide a theoretical foundation for research into preventing and treating mycotic mastitis of dairy cows in China. PMID- 23813120 TI - Tinea capitis in the paediatric population in Milan, Italy: the emergence of Trichophyton violaceum. AB - Tinea capitis (TC) is the most common type of dermatophytosis in children. The epidemiology of TC depends on the geographical areas, and it changes over time. The aim of the study is to determine the incidence of TC and to identify the causative species in children observed at Dermatology Outpatient Department of the University of Milan, Italy, between January 2004 and December 2011. Four hundred and eighty-six children with suspected dermatomycosis were observed; TC was the most prevalent dermatomycoses with 86 cases. The most common isolated dermatophyte in scalp lesions was Trichophyton violaceum with 33 cases. The most recent epidemiological Italian studies still show zoophilic fungi as primary cause of TC. We are the first medical team in Italy to demonstrate a dominance of anthropophilic fungi, in particular T. violaceum. PMID- 23813121 TI - Surgical management of thoracolumbar kyphosis in mucopolysaccharidosis type 1 in a reference center. AB - PURPOSE: Mucopolysaccharidosis (MPS) I is a rare autosomal recessive lysosomal storage disease. Thoracolumbar kyphosis is an early characteristic feature of the disease. Ossification failure in the anterosuperior quadrant of the vertebral body results in anterior dislocation. This study describes the surgical management of thoracolumbar kyphosis in MPS IH (Hurler syndrome) in a national reference center. METHODS: Among 72 MPS I patients followed in our institution, we treated surgically 14 MPS IH patients with severe thoracolumbar kyphosis. The decision was made after documented deformity progression. Mean age at surgery was 8 (3.5-15) years. Sagittal imbalance of the trunk was constant. One patient underwent extended fusion for associated scoliosis. We retrospectively reviewed 13 patients who underwent selective circumferential fusion at the thoracolumbar level. RESULTS: Average preoperative kyphosis was +57.5 degrees (+30 degrees ; +90 degrees ). Surgical correction of the kyphosis was about 66 % and maintained at final follow-up. Fusion was obtained in all patients. Two patients required revision surgery consecutively to a previous posterior-only fusion, as a significant loss of correction occurred. One patient presented delayed neurologic deficit secondarily to cardiac embolism. One patient died postoperatively from cardiorespiratory failure. CONCLUSION: Surgery is necessary when kyphosis is progressive despite orthopedic management, aggravating the multifactorial trunk imbalance. Regarding our experience, circumferential arthrodesis should be recommended to achieve stable correction. Surgical management requires a multidisciplinary approach due to multisystemic failure and neurological risks specific to metabolic disorders. PMID- 23813122 TI - Paying the piper: additional considerations of the theoretical, ethical and moral basis of financial incentives for health behaviour change. AB - Lynagh, Sanson-Fisher and Bonevski's article entitled "What's good for the goose is good for the gander. Guiding principles for the use of financial incentives in health behaviour change" (Int J Behav Med 20:114-120, 2012) reviews evidence for the use of financial incentives for encouraging health behaviour change. Their discussion of the practical and moral issues involved is a timely contribution which will encourage consideration of the implications of such interventions. In this response to their paper, I suggest that there are also broader aspects that we must consider before developing principles for public policy intervention. First, we must include good theories that explain in a great deal more depth what we mean by health-related behaviours, and secondly, we need to understand the location of these behaviours in social life and within structural inequalities. To ignore these fundamental aspects of health is to risk increasing social injustice and worsening health inequalities, a facet of the morality of health promotion activities which is not touched upon by the Lynagh et al. paper. PMID- 23813123 TI - Correlates of 15-year maintenance of physical activity in middle-aged women. AB - BACKGROUND: Interventions to increase sustained physical activity are needed and should be based on proven theories. PURPOSE: To gain a better understanding of the correlates of sustained physical activity in midlife women, we used longitudinal epidemiologic data to investigate links between sustained physical activity and constructs advocated by three basic behavioral and social science theories: (1) self-determination, (2) social cognitive, and (3) social networks. A random sample of 90 midlife women, stratified by level of physical activity over 15 years, was selected from the Chicago cohort of the Longitudinal Study of Women's Health Across the Nation (SWAN). METHODS: Using data on self-reported physical activity collected over 15 years, women were categorized into consistently active, sporadically active, and sedentary. New data were collected on theory-relevant constructs, i.e., autonomous motivation (assessed by the Treatment Self-Regulation Questionnaire) and self-efficacy (assessed by the Self Efficacy and Exercise Habits Survey). Every SWAN woman identified a close female friend who also completed the physical activity questionnaire. RESULTS: SWAN women with higher autonomous motivation (p = 0.002) and higher self-efficacy (p < 0.001) were more likely to be consistently physically active in analyses adjusted for age, race, and socioeconomic status. Sixty-one percent of SWAN women with a history of consistent physical activity had a friend who is currently highly active, versus 38 and 23 % for sporadically active and sedentary women, respectively (test for trend p = 0.008). CONCLUSION: In midlife women, constructs advocated by basic behavioral and social science theories were consistent with long-term patterns of physical activity behavior. Special focus should be given to these basic theories in the design of interventions to promote sustained physical activity in mid-life women. PMID- 23813124 TI - The role of self-monitoring and response inhibition in improving sleep behaviours. AB - BACKGROUND: Young adults tend to have poor sleep, which may be a result of poor self-regulation. PURPOSE: This study investigated whether manipulating two aspects of self-regulation: self-monitoring and response inhibition could improve sleep behaviours. METHOD: University students (N = 190) were randomly allocated to complete (1) a self-monitoring sleep diary and response inhibition training, (2) a sleep diary only, or (3) a control questionnaire daily for a period of 7 days. RESULTS: Outcome measures were three sleep hygiene behaviours previously found to be particularly important in this population: avoiding going to bed hungry and thirsty, avoiding anxiety and stress-provoking activity before bed, and making the bedroom and sleep environment restful. Those who completed diary based self-monitoring successfully avoided anxiety and stress-provoking activity before bed more frequently than control participants, corresponding to a medium effect size, and further development may provide a simple intervention to improve aspects of sleep and other health behaviours. CONCLUSION: There was no incremental effect of response inhibition training. Modified response inhibition training tasks may be worth investigating in future research. PMID- 23813125 TI - Dissipation kinetics of tetraconazole in three types of soil and water under laboratory condition. AB - Laboratory experiment was conducted to understand the persistence behavior of tetraconazole in three soils of West Bengal (alluvial, red lateritic, and coastal saline) and also in water maintained at three different pH (4.0, 7.0, and 9.2) conditions. Processed soil samples (100 g) were spiked at two treatment doses: 2.5 MUg/g (T1) and 5.0 MUg/g (T2). Double distilled buffered water (200 ml) was spiked at two treatment doses: 1.0 MUg/ml (T1) and 2.00 MUg/ml (T2). The tetraconazole dissipation followed first-order reaction kinetics and the residual half-life (T1/2) values in soil were found to be in the range of 66.9-77.2 days for T1 and 73.4-86.0 days for T2. The persistence increased in the order red lateritic > new alluvial > coastal saline. Interestingly, the red lateritic soil exhibited the lowest pH (5.56) and organic carbon (0.52%) content as compared to other two soils. However, the dissipation of tetraconazole in case of water was not pH dependant. The T1/2 values in water were in the range of 94 to 125 days. The study indicated the persistent nature of tetraconazole in soil and water. PMID- 23813127 TI - The Annals of Hepatology welcomes the Canadian Association for the Study of the Liver (CASL). PMID- 23813126 TI - A screening procedure for selecting the most suitable dredged material placement site at the sea. The case of the South Euboean Gulf, Greece. AB - The selection of the best site for the placement of dredged sedimentary material (~7,000 m(3)) from the Aliveri coastal area in the adjacent South Euboean Gulf (Greece) was accomplished through a screening procedure. The initial stage comprised the determination of physical, chemical, and biological characteristics of the dredged sediment before the commencement of any dredging operation. Grain size measurements, geochemical analyses together with the use of pollution/toxicity indices and empirical sediment quality guidelines, and the conduct of an acute toxicity test showed that the dredged material consisted of "unpolluted to slightly polluted" silty sands and sandy silts. However, the local authorities planned to place this sediment in the neighboring open sea area, i.e., the South Euboean Gulf, due to the absence of any beneficial use or alternative dumping option (i.e., dumping on public lands). Therefore, the next stage of the screening procedure, based on criteria such as the national legislation, seabed and seawater column characteristics, influence of the water mass circulation pattern on the post-placement migration of dredged sediment, impact on living resources and human activities (i.e., aquaculture and fishing), effect on significant marine sites (i.e., sites of scientific, ecological, and historical importance, navigation routes, military zones), and seafloor engineering uses, led to the evaluation of the suitability of the South Euboean Gulf as a potential dumping area. Then, the identification of the appropriate dredged material placement sites in the South Euboean Gulf was based on a cluster analysis, which tested the physicochemical resemblance of the dredged material and the surface sediments of 19 potential placement locations in the gulf. After the statistical process, only four sites situated near the north shoreline of the South Euboean Gulf were qualified as the best dredged material placement locations. PMID- 23813129 TI - Occult hepatitis B in patients on hemodialysis: a review. AB - The hepatitis B virus (HBV) is one of the most frequently transmitted agents in dialysis units. Occult hepatitis B is characterized by HBV infection without detectable surface antigen (HBsAg) in the patient's serum, a positive or negative HBV DNA marker result in the serum and a positive result in the liver tissue, which leads to the potential risk of transmission during renal replacement therapy service. There is variation in occult hepatitis B prevalence rates in this population across various studies that may be related to numerous factors. The presence of occult hepatitis B in individuals undergoing renal replacement therapy is important with regard to both the possibility of transmission and the consequences for the patient, especially the development of chronic liver disease and reactivation of the disease after renal transplantation. PMID- 23813130 TI - Efficacy and safety of interferon-based therapy in the treatment of adult thalassemic patients with chronic hepatitis C: a 12 years audit. AB - BACKGROUND: HCV infection and transfusional iron overload in Thalassemic patients may result in liver disease. HCV treatment in Thalassemia has raised safety concerns. AIM: Estimate effectiveness and tolerability of interferon-based therapy in HCV-infected Thalassemic patients. MATERIAL AND METHODS: Over a 12 year period, consecutive patients with beta Thalassemia major (TM) and chronic hepatitis C received treatment. Liver biopsy, HCV-RNA and genotyping were performed beforehand. Sustained virological response (SVR) was defined as negative HCV-RNA 6 months post-treatment. Forty eight patients (26 M-22 F, mean age 39.8) were enrolled. Twenty nine patients were treated with conventional interferon alpha (IFNa) for 48 weeks (group A). Nineteen patients (10 naive-9 previously IFNa experienced) received pegylated interferon (PEGIFN) (group B). RESULTS: HCV-1 was found in 44%, HCV-2 in 14%, HCV-3 in 23% and HCV-4 in 19%. Group A: ten patients (38.5%) achieved SVR, 2 (7.5%) relapsed and 17 (54%) were non responders. Group B: five (28%) achieved SVR, 8 (44%) relapsed and 6 (28%) never responded. High HCV-RNA levels, genotype 1 and advanced liver fibrosis were independently associated with no response. Four patients (3 treated with IFNalpha, 1 with PEG-IFN) had to discontinue treatment due to complications. CONCLUSIONS: The response rate of IFN monotherapy in multi-transfused, HCV infected Thalassemic patients is not inferior to that in non-multitransfused patients. IFNa administration is well-tolerated and should be recommended as initial treatment schedule in this setting. PMID- 23813131 TI - High frequencies of CD158b+ NK cells are associated with persistent hepatitis C virus infections. AB - BACKGROUND: During the early phases of a hepatitis C virus (HCV) infection, NK cell activation appears to be critical to the induction of adaptive immune responses that have the potential of clearing the infection. This study aimed to investigate the phenotype and function of NK cells in chronic HCV (CHC) patients, particularly patients who cleared HCV infections spontaneously (SR-HCV). MATERIAL AND METHODS: Peripheral blood NK cells were compared between 36 CHC patients, 12 SR-HCV patients, and 14 healthy controls (HC). The phenotype and function of NK cells were characterized by flow cytometry. In addition, the potential associations between the frequency of NK cell subsets and ALT, AST and HCV viral loads were also analyzed. RESULTS: Our data revealed that the population of CD3 CD56+ NK cells was significantly decreased in CHC and SR-HCV patients compared to levels in HC (P = 0.031, P = 0.014). Interestingly, we found that the levels of the CD158b inhibitory receptor were higher in CHC patients compared to levels observed in HCand SR-HCV subjects (P = 0.018, P = 0.036). In addition, the percentages of the activation receptors NKp30 and NKp46 were significantly decreased in CHC and SR-HCV patients compared to their expression levels in HC (P < 0.05). Moreover, the frequencies of inducible CD107a (but not IFN-gamma secreting) NK cellsfrom both CHC and SR-HCV patients were significantly lower than frequencies observed in controls (P = 0.018, P = 0.027). CONCLUSION: Our data indicated that the higher frequency of inhibitory NK cells combined with fewer activated NK cells may be associated with HCV-related chronic inflammation involved in CHC pathogenesis. PMID- 23813132 TI - Association of plasma visfatin with hepatic and systemic inflammation in nonalcoholic fatty liver disease. AB - BACKGROUND: Visfatin is a proinflammatory and insulin-mimetic adipokine contributing to whole body glucose and lipid metabolism. Studies to date are conflicting regarding the relationship between visfatin and non-alcoholic fatty liver disease (NAFLD). The aim of the present study was to evaluate the relationship of circulating visfatin with NAFLD. MATERIAL AND METHODS: The study included 114 NAFLD patients and 60 healthy non-diabetic controls. Plasma visfatin, adiponectin, tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) levels were measured by ELISA. High sensitive C-reactive protein (hsCRP) levels were measured by immunoturbidimetric fixed rate method. Insulin sensitivity determined by homeostasis model assessment (HOMA-IR) index. RESULTS: TNF-alpha, IL-6 and hsCRP levels were higher and, Adiponectin levels were lower in NAFLD group when compared to healthy controls (p < 0.001, for all). However, no difference was found regarding to visfatin levels between two groups. Different histologic subgroups of NAFLD had a significantly higher TNF-alpha, IL 6 and hsCRP, and lower adiponectin levels than those with controls (p < 0.001, for all). On the other hand, no statistically significant difference was found regarding to visfatin levels among different histologic groups. Visfatin was found to be negatively correlated with TNF-alpha (r = -0.236, p = 0.011) in NAFLD group. However, no association was found between visfatin and histological findings. CONCLUSION: Our findings show that plasma visfatin levels are not altered in the early stages of NAFLD. However, it is inversely associated with TNF-alpha. These findings suggest a role for visfatin in protection against liver injury in this widespread disease. PMID- 23813133 TI - Predicting the prognosis in acute liver failure: results from a retrospective pilot study using the LiMAx test. AB - BACKGROUND: Acute liver failure (ALF) is a rare but potentially life-threatening condition and liver transplantation (LTX) remains frequently the only effective therapy. Nevertheless, some patients recover without LTX but the individual indication for or against LTX remains difficult. AIM: To evaluate maximal liver function capacity (LiMAx) for predicting the prognosis of ALF. Material and methods. Clinic data of 12 patients was retrospectively analyzed to compare the different liver function test results with the patients' clinical outcome. Patients were assessed by the LiMAx test, a non-invasive breath test determining cytochrome P450 1A2 capacity using intravenous 13C-methacetin. Statistical analysis compared patients with spontaneous recovery versus non-recovery (LTX or death). RESULTS: Twelve patients (6 male, 6 female; 49 [11-72] years) with viral hepatitis (n = 2), toxic liver injury (n = 3), or cryptogenic liver failure (n = 7) were analyzed. Seven patients fully recovered from ALF and were discharged without LTX. Three patients died and two underwent LTX. The King's College Criteria (KCC) was fulfilled in only one out of five patients without recovery. The LiMAx was 19 +/- 19 (16-62) for non-recovery vs. 94 +/- 119 (39-378) MUg/kg/h for recovery (P = 0.018). In contrast, all biochemical parameters [bilirubin (P = 0.106), creatinine (P = 0.343), AST (P = 0.53), ALT (P = 0.876) and INR (P = 0.876) were statistically indistinct. Also the Model for End-Stage Liver Disease (MELD) score did not show a difference [35 +/- 4.3 (29-40) vs. 30 +/- 11.5 (6 40); P = 0.27]. CONCLUSIONS: Maximal liver function capacity determined by LiMAx test is severely impaired in patients with ALF. The LiMAx test might be effective in predicting the individual prognosis and the need for LTX in ALF. PMID- 23813134 TI - Sirolimus based immunosuppression is associated with need for early repeat therapeutic ERCP in liver transplant patients with anastomotic biliary stricture. AB - INTRODUCTION: Sirolimus has inhibitory effects on epithelial healing and cholangiocyte regeneration. In liver transplantation (LT) patients, these effects may be greatest at the biliary anastomosis. We therefore investigated whether sirolimus use is associated with need for early or emergent repeat therapeutic endoscopic retrograde cholangiography (ERC) in LT patients with anastomotic biliary stricture (ABS). MATERIAL AND METHODS: Medical records of patients who underwent LT from 1998-2009 at Johns Hopkins were reviewed and patients with ABS identified. Primary outcome was early repeat ERC, defined as need for unscheduled (i.e. unplanned) or emergent repeat therapeutic ERC. Univariate and multivariate logistic regression analyses (adjusting for age, sex, LT to ERC time, and stent number) were performed to assess association between sirolimus and early repeat ERC. RESULTS: 45 patients developed ABS and underwent 156 ERCs total. Early (median 26 days) repeat ERC occurred in 14/56 (25%) and 6/100 (6%) ERCs performed with and without concomitant sirolimus-based immunosuppression, respectively (OR 1.22; 95% CI 1.02-1.45; p = 0.03). In multivariate analysis, sirolimus use was associated with early repeat ERC (OR 1.24; 95% CI 1.04-1.47; p = 0.015); this association remained significant when sirolimus dose was modeled as a continuous variable (OR 1.04 for each mg of sirolimus per day; 95% CI 1.02-1.08; p = 0.038). CONCLUSIONS: Sirolimus-based immunosuppression appears to be associated with a modest but significantly increased, dose-dependent risk of early repeat ERC in LT patients with ABS. Prospective studies are needed to further investigate these findings and determine if sirolimus use or dose should potentially be reconsidered once ABS is diagnosed. PMID- 23813135 TI - Non-invasive assessment of liver fibrosis with transient elastography (FibroScan(r)): applying the cut-offs of M probe to XL probe. AB - BACKGROUND AND RATIONALE FOR THE STUDY: Limited studies have aimed to define the cut-offs of XL probe (XL cut-offs) for different stages of liver fibrosis, whereas those of M probe (M cut-offs) may not be applicable to XL probe. We aimed to derive appropriate XL cut-offs in overweight patients. Patients with liver stiffness measurement (LSM) by both probes were recruited. XL cut-offs probe for corresponding M cut-offs were derived from an exploratory cohort, and subsequently validated in a subgroup patients also underwent liver biopsy. The diagnostic accuracy of XL cut-offs to diagnose advanced fibrosis was evaluated. RESULTS: Total 517 patients (63% male, mean age 58) who had reliable LSM by both probes were included in the exploratory cohort. There was a strong correlation between the LSM by M probe (LSM-M) and LSM by XL probe (LSM-XL) (r2 = 0.89, p < 0.001). A decision tree using LSM-XL was learnt to predict the 3 categories of LSM-M (< 6.0kPa, 6.0-11.9kPa and >= 12.0kPa), and XL cut-offs at 4.8kPa and 10.7kPa were identified. These cut-offs were subsequently validated in a cohort of 147 patients who underwent liver biopsy. The overall accuracy was 89% among 62 patients whose LSM-XL < 4.8kPa or >= 10.7kPa. These cut-offs would have avoided under-staging of fibrosis among patients with body mass index (BMI) > 25-30 kg/m2 but not > 30 kg/m2. CONCLUSIONS: XL cut-offs at 4.8kPa and 10.7kPa were the best estimates of 6.0kPa and 12.0kPa of M probe for patients with BMI > 25-30 kg/m2. Patients with BMI > 30 kg/m2 might use M probe cut-offs for XL probe. PMID- 23813136 TI - Serum cholesterol is a significant and independent mortality predictor in liver cirrhosis patients. AB - BACKGROUND AND AIM: Accurate assessment of cirrhotic patient's prognosis is essential for decisions regarding the course of treatment. Therefore we aimed to confirm and quantify the predictive value of serum cholesterol and serum triglycerides in liver cirrhosis patients. MATERIAL AND METHODS: We performed a retrospective observational cohort study on consecutive patients with liver cirrhosis (n = 191). Relevant clinical and laboratory variables were obtained from patients' charts and patients were followed for two months. Mortality was the main outcome. RESULTS: Thirty-eight patients died in the follow-up period. Significant difference was observed in the level of total serum cholesterol between surviving and deceased patients (2.27 +/- 1.02 mmol/L vs. 2.97 +/- 1.00 mmol/L, P < 0.0001 respectively). Cholesterol was confirmed as a significant predictor of mortality in univariate logistic regression analysis, and independent predictor beside bilirubin, creatinine and MELD score in multivariate logistic regression analysis. Addition of serum cholesterol level to a prognostic model based on total bilirubin, creatinine and INR increased its accuracy by 4%. Adding cholesterol to the MELD score improved prediction accuracy by 3%. There was no significant difference in serum levels of triglycerides between surviving and deceased patients. CONCLUSION: Serum cholesterol is a routinely measured parameter, which has independent prognostic value in patients with liver cirrhosis. PMID- 23813137 TI - Predicting portal hypertension and variceal bleeding using non-invasive measurements of metabolic variables. AB - BACKGROUND & AIM: This study assessed the involvement of metabolic factors (anthropometric indices, insulin resistance (IR) and adipocytokines) in the prediction of portal hypertension, esophageal varices and risk of variceal bleeding in cirrhotic patients. MATERIAL AND METHODS: Two prospective and retrospective cohorts of cirrhotic patients were selected (n = 357). The first prospective cohort (n = 280) enrolled consecutively in three centers, underwent upper gastrointestinal endoscopy, seeking evidence of esophageal varices. Clinical, anthropometric, liver function tests, ultrasonographic, and metabolic features were recorded at the time of endoscopy, patients were followed-up every 6 months until death, liver transplantation or variceal bleeding. The second retrospective cohort (n = 48 patients) had measurements of the hepatic venous pressure gradient (HVPG). Statistical analyses of the data were with the SPSS package. RESULTS: The presence of esophageal varices was independently associated with lower platelet count, raised HOMA index and adiponectin levels. This relationship extended to subset analysis in patients with Child A cirrhosis. HOMA index and adiponectin levels significantly correlated with HVPG. Beside Child Pugh class, variceal size and glucagonemia, HOMA index but not adiponectin and leptin plasma levels were associated with higher risk of variceal bleeding. CONCLUSION: In patients with cirrhosis, HOMA score correlates with HVPG and independently predict clinical outcomes. Three simple markers i.e. platelet count, IR assessed by HOMA-IR and adiponectin significantly predict the presence of esophageal varices in cirrhotic patients. PMID- 23813138 TI - Acute phase proteins for the diagnosis of bacterial infection and prediction of mortality in acute complications of cirrhosis. AB - INTRODUCTION: Bacterial infection is a frequent complication in patients with decompensated liver cirrhosis and is related to high mortality rates during follow-up of these individuals. We sought to evaluate the diagnostic value of C reactive protein (CRP) and procalcitonin (PCT) in diagnosing infection and to investigate the relationship between these biomarkers and mortality after hospital admission. MATERIAL AND METHODS: Prospective study that included cirrhotic patients admitted to the hospital due to complications of the disease. The diagnostic accuracy of CRP and PCT for the diagnosis of infection was evaluated by estimating the sensitivity and specificity and by measuring the area under the receiver operating characteristics curve (AUROC). RESULTS: A total of 64 patients and 81 hospitalizations were analyzed during the study. The mean age was 54.31 +/- 11.87 years with male predominance (68.8%). Significantly higher median CRP and PCT levels were observed among infected patients (P < 0.001). The AUROC of CRP and PCT for the diagnosis of infection were 0.835 +/- 0.052 and 0.860 +/- 0.047, respectively (P = 0.273). CRP levels > 29.5 exhibited sensitivity of 82% and specificity of 81% for the diagnosis of bacterial infection. Similarly, PCT levels > 1.10 showed sensitivity of 67% and specificity of 90%. Significantly higher levels of CRP (P = 0.026) and PCT (P = 0.001) were observed among those who died within three months after admission. CONCLUSION: CRP and PCT were reliable markers of bacterial infection in subjects admitted due to complications of liver cirrhosis and higher levels of these tests are related to short-term mortality in those patients. PMID- 23813139 TI - Non-invasive assessment of liver fibrosis using ARFI with pathological correlation, a prospective study. AB - INTRODUCTION: ARFI is a new technique that uses acoustic push pulse to generate tissue displacement resulting in shear wave propagation, can be used to measure elasticity of tissue. We aim to assess feasibility of ARFI as a non-invasive method to measure liver fibrosis compared to histological fibrosis scores and to compare our results with the published pooled-meta-analysis cut off values. MATERIAL AND METHODS: Prospective study to compare median velocities of ARFI shear wave measurements (Virtual Touch ImagingTM ACUSON S2000, Siemens, Mountain View CA) with Batts and Ludwig liver fibrosis scoring system F0-F4. RESULTS: 70 patients (mean = 49 years) were included. Etiologies were chronic hepatitis C (n = 43), chronic hepatitis B (n = 7) and others (n = 20). Median ARFI values (m/sec) for fibrosis stages and inflammatory stages measured were F0: 1.52, 1.42; F1: 1.50, 1.37; F3: 2.36, 2.41 and F4: 2.61. Areas under the curve for grade 3 = 0.875, stage 3 = 0.867; grade 2 = 0.4, stage 2 = 0.3.Using the cut-off ARFI value of 1.34 m/s for F >= 2 suggested in the meta-analysis, we found sensitivity of detecting true F >= 2 is 68%, specificity 66%, PPV 74% and NPV 59%. For F >= 3 using the cut-off ARFI value of 1.55 m/s, we found sensitivity of 95%, specificity 86%, PPV 74% and NPV 98%. No stage 4 was compared due to insufficient cases. CONCLUSION: ARFI has strong correlation with higher fibrosis scores compared to lower. When compared to the pooled meta-analysis cut off values, the sensitivity and specificity for detecting true F >= 3 are higher than that of F >= 2. PMID- 23813140 TI - Pegylated interferon-alpha2b and ribavirin decrease claudin-1 and E-cadherin expression in HepG2 and Huh-7.5 cells. AB - BACKGROUND: Hepatitis C virus (HCV) infection usually results in long-term viremia. Entry of HCV into the hepatocyte requires claudin-1, -6, -9 and occludin. The efficacy of Pegylated interferon-alpha (PEG-IFN) treatment against HCV infection increased when ribavirin (RBV) was added to the therapeutic scheme. Our aim was to investigate if PEG-IFN plus RBV regulate claudin expression. MATERIAL AND METHODS: HepG2, Huh-7 and Huh-7.5 cells were treated with PEG-IFN alpha2a or alpha2b and/or RBV at different times before obtaining the cytosolic, membrane and cytoskeletal fractions. Claudin-1, 3, 4, 6, and 9, E-cadherin and occludin expression was evaluated by Western blot analysis. Transepithelial electrical resistance (TER) was also determined. RESULTS: Claudin-1, 3, 4, 6, E cadherin and occludin are constitutively expressed mainly in HepG2 cell membrane. Claudin-1 and E-cadherin cell membrane expression diminished after exposure to PEGIFNalpha2b (50 ng) + RBV(50 MUg); the maximal decrease was observed with 200 ng of PEG-IFNalpha2b + 200 MUg of RBV. The effect was less intense with PEG IFNalpha2a. The inhibition of claudin-1 and E-cadherin expression in Huh-7 and Huh-7.5 cells was only observed with 200 ng of PEG-IFNalpha2b + 200 MUg of RBV. TER diminished marginally in the HCV containing hepatoma cells with 200 ng of PEG IFNalpha2b + 200 MUg of RBV. Claudin-1 mRNA expression level was not affected by the combined treatment. CONCLUSION: The increased therapeutic efficacy of the PEG IFNalpha2b plus RBV treatment could be secondary to the inhibition of claudin-1 and E-cadherin cell membrane expression. PMID- 23813141 TI - Hepatocellular carcinoma arising in a telangiectatic hepatocellular adenoma. AB - Telangiectatic hepatocellular adenoma is a rare, recently recognized subtype of benign liver tumor that may very rarely undergo transformation into hepatocellular carcinoma. We report an unusual case of a 75-year-old woman with no history of oral contraceptive use that underwent malignant transformation of a telangiectactic hepatocellular adenoma. No risk factors for adenoma development were identified in this otherwise healthy woman. Radiological characteristics, gross features and histopathology are herein described. In conclusion, telangiectatic hepatocellular adenoma can undergo malignant transformation. Further studies are needed to better clarify the factors associated with malignant progression. PMID- 23813142 TI - Pulmonary complications of treatment with pegylated interferon for hepatitis C infection-two case reports. AB - Pegylated interferon (Peg-IFN) in combination with ribavirin is the standard of care in the treatment of chronic hepatitis C (HCV). Peg-IFN is known to have a number of side effects but severe respiratory complications are uncommon. We report two cases, one of Peg-IFN induced interstitial pneumonitis (IP) and the other of bronchiolitis obliterans organising pneumonia (BOOP) in patients with chronic hepatitis C infection. In general, respiratory complications of Peg-IFN are mild and resolve with withdrawal of Peg-IFN. However, as illustrated in our first case fatal interstitial pneumonitis can occur. We present a review of the available literature on Peg-IFN induced lung toxicity. In conclusion, pulmonary toxicity with Peg-IFN is rare but fatality can occur. We highlight the importance of maintaining a high index of suspicion for early diagnosis and prompt treatment, which includes withdrawal of Peg-IFN and consideration of corticosteroid treatment. PMID- 23813143 TI - Unexpected discovery of massive liver echinococcosis. A clinical, morphological, and functional diagnosis. AB - We report a case of symptomatic massive liver echinococcosis due to Echinococcus granulosus, unexpectedly found in a 34 year old woman living in Apulia, Italy. Based on size (max diameter 18 cm), clinical presentation, geographical area, and natural history of echinococcosis, we estimate that the initial infection should have occurred 9-20 yrs before. Presenting symptoms were those of typical mass effect with RUQ pain, pruritus, malaise, and recent weight loss. Abdominal ultrasound diagnosis of probable echinococcal cyst was subsequentely confirmed by positive serology and further detailed by radiological imaging. The cyst was massively occupying subdiaphragmatic liver segments and extending to the omentum and the stomach. The characteristics of the lesion were compatible with the WHO 2003 classification type CE2l, indicating a large active fertile cyst with daughter cysts. The cyst was successfully treated with medical therapy followed by surgery. The prevalence, diagnostic workup, management, and costs of echinococcosis are discussed in this case presentation. PMID- 23813144 TI - The fate of fatty liver disease: of bile and fatty acids. PMID- 23813147 TI - Comparison of high-definition oscillometry -- a non-invasive technology for arterial blood pressure measurement -- with a direct invasive method using radio telemetry in awake healthy cats. AB - This study compared indirect blood pressure measurements using a non-invasive method, high-definition oscillometry (HDO), with direct measurements using a radio-telemetry device in awake cats. Paired measurements partitioned to five sub ranges were collected in six cats using both methods. The results were analysed for assessment of correlation and agreement between the two methods, taking into account all pressure ranges, and with data separated in three sub-groups, low, normal and high ranges of systolic (SBP) and diastolic (DBP) blood pressure. SBP data displayed a mean correlation coefficient of 0.92 +/- 0.02 that was reduced for low SBP. The agreement level evaluated from the whole data set was high and slightly reduced for low SBP values. The mean correlation coefficient of DBP was lower than for SBP (ie, 0.81 +/- 0.02). The bias for DBP between the two methods was 22.3 +/- 1.6 mmHg, suggesting that HDO produced lower values than telemetry. These results suggest that HDO met the validation criteria defined by the American College of Veterinary Internal Medicine consensus panel and provided a faithful measurement of SBP in conscious cats. For DBP, results suggest that HDO tended to underestimate DBP. This finding is clearly inconsistent with the good agreement reported in dogs, but is similar to outcomes achieved in marmosets and cynomolgus monkeys, suggesting that this is not related to HDO but is species related. The data support that the HDO is the first and only validated non invasive blood pressure device and, as such, it is the only non-invasive reference technique that should be used in future validation studies. PMID- 23813149 TI - Evaluation of serum ischemia modified albumin levels in acute rheumatic fever before and after therapy. AB - OBJECTIVE: To investigate ischemia modified albumin (IMA) levels in children with acute rheumatic fever (ARF) before and after therapy and compare them with those of controls. METHODS: Twenty seven patients with ARF and 18 healthy, age and sex matched children were included in the study. The diagnosis of ARF was established according to the modified Jones criteria. Follow-up studies were made when acute phase reactants [erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)] levels returned normal. IMA levels were measured using the rapid and colorimetric method with the albumin cobalt binding test. RESULTS: IMA levels were significantly higher in ARF group (p < 0.001) compared with controls at the time on admission. IMA (absorbance units) was measured as 0.41 +/- 0.10 in the control group, 0.55 (0.44-1.13) in the study group before treatment and 0.48 +/- 0.12 in the study group after treatment. After treatment, statistically important decrements were determined in the levels of ESR (p<0.001), CRP (p<0.001) and IMA (p<0.01). There was no significant difference for IMA levels between after treatment and control group. IMA levels at the time on admission correlated positively with ESR (r = 0.605, p < 0.01) and CRP (r = 0.543, p < 0.01). CONCLUSIONS: The present study shows that increased serum IMA levels in patients with ARF at the time of diagnosis is a sign of increased inflammation. Thus, serum IMA levels may be used as a follow-up marker like CRP and ESR for evaluating the efficacy of treatment in ARF. PMID- 23813150 TI - Common endocrine problems in children (hypothyroidism and type 1 diabetes mellitus). AB - Hypothyroidism and type 1 diabetes mellitus (T1DM) constitute two common endocrine disorders of children. Both these are chronic conditions which require long term follow-up for optimum control, can be missed on initial presentation unless a high index of suspicion is maintained and may be associated with adverse outcome if not properly managed. This article deals with basic pathology, recognition, initial investigations, and principles of treatment of these conditions from the perspective of a general pediatrician. It also describes the role of a practitioner in management of these disorders. PMID- 23813151 TI - Coping strategies of parents of Down syndrome children in India. PMID- 23813152 TI - Fusarium falciforme infection of foot in a patient with type 2 diabetes mellitus: a case report and review of the literature. AB - Fungal infections of foot in patients with diabetes are not uncommon; however, foot infection due to Fusarium species has been rarely reported. We report here a case of a 50-year-old male with type 2 diabetes who developed multiple spontaneous nodular lesions on right foot without any systemic symptoms and signs for 6 months. The lesions were unresponsive to broad-spectrum antibacterial treatment. Fine needle aspiration cytology of nodular lesions revealed the presence of fungal hyphae, and Fusarium species was isolated from the same sample which was identified as Fusarium solani species complex: Fusarium falciforme. Radiological investigations and blood culture ruled out any dissemination of the disease. The lesions healed after voriconazole therapy for 3 months. No relapse was noted at the end of the next 6-month follow-up. All reported cases of Fusarium infection of foot in patients with diabetes in English and non-English literature since 1970 have been reviewed. PMID- 23813153 TI - Disseminated fusariosis secondary to neuroblastoma with fatal outcome. AB - Disseminated fusariosis is an uncommon clinical condition in immunocompromised patients. We report a fatal case of disseminated fusariosis secondary to neuroblastoma in a male patient, 15 years old, who underwent a bone marrow transplant. The patient was admitted to the pediatric intensive care unit (PICU) of a public hospital in Recife-PE, Brazil, presenting bone marrow aplasia, severe leukopenia, and thrombocytopenia. After 15 days, the patient developed right knee effusion. Synovial fluid and blood samples were analyzed at the Medical Mycology Laboratory of the Federal University of Pernambuco. Mycological diagnosis was based on the presence of hyaline septate hyphae on direct examination and the isolation of Fusarium oxysporum in culture, confirming the case of disseminated fusariosis. In vitro, the isolate showed fluconazole resistance and sensitivity to amphotericin B, anidulafungin, and voriconazole. Therapy with voriconazole in combination with liposomal amphotericin B led to an improved clinical response; however, due to underlying disease complications, the patient progressed to death. PMID- 23813154 TI - Cardiac device-related endocarditis in the patient with end-stage renal failure in the course of Fabry disease. PMID- 23813155 TI - Topography of the periacetabular bone in Chinese patients - do current cages fit? AB - BACKGROUND: Understanding the anatomy of the periacetabular bone is critical for designing and implanting cages, as well as reconstruction of lost periacetabular bone. We aimed to study the topography of periacetabular bone and compare it with current cages to examine their fit in a Chinese population. METHODS: We performed three-dimensional measurement on computed tomography images of 105 hemipelves to delineate the topography of the periacetabular bone. We compared the bone with digital models of commercially available cages, and divided the results into three scenarios (fit, mismatch and unfit) according to absence or existence of overhang and the extent of contouring needed after implanting the cages to the pelves. RESULTS: Our measurement provided a representation of normal topography of the periacetabular bone. Only 21% of the patients studied had commercially available cages which fit their pelves, whilst there was no cage that fitted 59% of the patients even after extensive contouring. CONCLUSION: Current acetabular cages have low fit rates for the periacetabular bone in Chinese patients. PMID- 23813156 TI - Revision hip arthroplasty with an extensively ?porous-coated stem - excellent long-term ?results also in severe femoral bone stock loss. AB - During the last 25 years uncemented hip stem revision relying on diaphyseal fixation has shown improving clinical results and stem survival. The purpose of this study was to present the long-term results of hip revision with the SOLUTION stem (DePuy, Warsaw Indiana).?Ninety-three consecutive SOLUTION hip stem revisions in 84 patients with a mean age of 69 years (range 33-86 years) were reviewed. Of these, clinical and radiographic follow-up examination by an independent observer was possible in 36 hips/29 patients after mean 14 years (range 10-18 years). Stem re-revision was documented by our own files and by the Danish Hip Arthroplasty Registry. ?Stem re-revision had been performed in two hips for aseptic loosening, one due to deep infection and in one patient due to stem fracture. The 18 years cumulative survival, free of re-revision for any reason was calculated as 94.4% (88.9-99.8)% and for aseptic loosening to 97.6% (94.3-100%). Intraoperative complications were frequent with incidence of shaft fractures (14/93) and perforations (9/93) showing a significant learning curve. Mean Harris Hip Score was 85 (range 53-99). Osseointegration was seen in 34/36 stems with two stems fibrous fixated. Stress shielding was significant associated with stem diameters >=15 mm. Severe preoperative bone deficiency had no negative bearing on stem survival and no significant influence on osseointegration of the stem or on Harris Hip Score. ? CONCLUSION: Femoral stem revision with an extensively porous-coated monoblock chrome-cobalt stem seems to be a reliable and reproducible technique resulting in excellent long-term survivorship and clinical outcome. It can be used in femurs with deficient bone stock. PMID- 23813158 TI - Revealing the "Secrets" of the Medici family--no proof as yet for hip dysplasia. Commentary on "Developmental hip dysplasia in the Medici family", Hip Int. 2013;23(1):108-9. PMID- 23813157 TI - Clinical manifestations in ten patients with asymptomatic metal-on-metal hip arthroplasty with very high cobalt levels. AB - Reports of adverse reactions to metal particle debris with metal-on-metal (MoM) hip arthroplasty have increased recently. Apart from the formation of pseudotumours and higher revision rates, another major cause for concern are the systemic effects of metal ions. Several effects of elevated systemic cobalt ions have been reported (e.g., myocardial and neurological effects, hypothyroidism). All 643 patients who underwent a stemmed large head MoM total hip replacement in our clinic were screened with repeated whole blood samples of metal ions (cobalt, chromium). We included ten asymptomatic unrevised patients with the highest cobalt concentrations, determined at a minimum of three years after implantation. These patients were subjected to an extensive neurological and cardiological screening protocol. In addition, blood samples were taken to assess renal and thyroid function. Ten patients with a cobalt level of 18-153 ug/L (mean 46.8 ug/L) were included. Nine patients were female, mean age was 65 years (range 56 75). The mean follow-up period was 4.2 years (range 3.0-6.1). Seven patients had bilateral stemmed MoM hip arthroplasty. No signs or symptoms of neurological dysfunction, cardiomyopathy, or renal or thyroid dysfunction could be identified or attributed to elevated cobalt levels. The clinical relevance of this study is that after short-term follow-up highly elevated blood cobalt levels do not cause systemic effects in our population. Hence in asymptomatic patients metal ions appear not to be a significant factor in the decision of when to revise a MoM large head total hip replacement. PMID- 23813159 TI - Psychosocial aspects of hip disease in the young adult. AB - The psychosocial impact of hip disease on the young adult has not been elucidated. This study aimed to identify the functional and psychosocial characteristics of a cohort of young patients (age less than 40 years) presenting to our tertiary care complex hip clinic. A postal questionnaire comprising of a Visual Analogue Scale (VAS) for Pain, the Oswestry Disability Index (ODI) and the Hospital Anxiety and Depression Scale (HADS) was posted to 63 patients. Forty nine (n = 49) patients (79%) responded to the questionnaire. Mean age was 20 years (range 16-38) with a gender ratio of 2:1 (female: male). More than half of our patients had moderate to severe pain based on the VAS and at least moderate disability on the ODI. HADS showed that 32% and 49% of patients were classified as having borderline to abnormal levels of depression and anxiety respectively. Multiple regression showed ODI scores to be a significant predictor of anxiety and depression. Comparison with asymptomatic controls shows that these patients have significantly worse ODI and HADS scores compared to normal population. This study quantifies the degree of functional and psychosocial compromise present in young patients with hip problems. PMID- 23813160 TI - Results using Trabecular MetalTM augments in combination with acetabular impaction bone grafting in deficient acetabula. AB - We examined whether the use of trabecular metal wedges to fill segmental defects is an effective method of socket reconstruction when used in combination with impaction grafting and implantation of a cemented socket. Fifteen hips in 14 patients underwent impaction grafting in combination with a TM wedge with a minimum of two years follow-up. All patients had their defects assessed using the Paprosky classification. Patients were reviewed with x-rays and migration of the implant was measured. Outcome scores were also collected. Mean follow-up was 39 months (25-83). The mean age at surgery was 67.8 (49-85) years. Seven of the patients had previously undergone impaction grafting with the use of a stainless steel rim mesh to constrain the graft. None of the patients had failed either clinically or radiologically. PMID- 23813161 TI - Hip arthroscopy for femoroacetabular impingement: results of 118 consecutive cases in a district general hospital. AB - Femoroacetabular impingement (FAI) is an increasingly recognised cause of hip symptoms in the young active adult and can lead to labral tears and chondral damage. FAI can be treated with open surgery or arthroscopically: aiming to stabilise labral tears and remove bony impingement. We report the results of a single surgeon series of arthroscopic labral debridement and cam resection in 118 consecutive cases during a two-year period, with a minimum follow-up of one year. Quantitative assessment was undertaken using the Non-Arthritic Hip Score (NAHS) calculated preoperatively and at two, four and 12 months postoperatively. Mean NAHS in all patient groups at two and four months, and at one year showed improvement (p<0.05). These results compare favourably with previous patients treated with open osteochondroplasty by the same surgeon, as well as with the published results from other larger centres. The faster improvement and the shorter hospital stay and lower morbidity make arthroscopic surgery for FAI a favourable option, and a feasible treatment modality in the non-specialist setting. PMID- 23813162 TI - Anterior dislocation after total hip replacement - effects of pelvic rotation and femoral head size. AB - We investigated the effects of pelvic rotation and femoral head diameter on the anterior stability of the hip joint after total hip replacement. Computer navigation and cadaveric bone were used to simulate the range of motion after total hip replacement. The hip was put at 0 degrees of flexion and it was gradually externally rotated until the hip dislocated. The degree of external rotation when the hip was dislocated was recorded. The test was repeated with the hip at +10, -10, -20, -30, -40 and -50 degrees of flexion. The acetabular component was positioned with abduction of 45 degrees and anteversion at 20 degrees. There was a significant difference amongst each group of pelvic rotation from 0 to -50 degrees in the degree of external rotation when the hip was dislocated. The degree became insignificant when pelvic rotation was increased from 0 to 10 degrees. From -10 to -50 degree of pelvic rotation, 36mm head had significant better stability compared with 32mm and 28mm femoral heads. The presence of significant pelvic sagittal malrotation can increase the risk of anterior dislocation. A larger femoral head is more stable than smaller heads. When pelvic sagittal malrotation is not present, there is no difference in stability between large and small femoral heads. PMID- 23813163 TI - Bone allograft in the U.K.: perceptions and realities. AB - Bone allografts are widely used in the U.K. in joint revision surgery. Despite this widespread usage, there remain concerns among the surgical community regarding the safety of allografts, in terms of the risk of transmission of infection, together with a persistent misconception that allografts are in limited availability. In this paper we discuss the precautions taken to ensure that allografts are safe, and review the residual risks. We also demonstrate that the availability of allograft in the U.K., both actual and potential, greatly exceeds the current clinical demand. PMID- 23813164 TI - Periprosthetic fractures around polished collarless cemented stems: the effect of stem design on fracture pattern. AB - BACKGROUND: Predictable patterns of periprosthetic fracture have been observed around polished double tapered stems. Finite element studies have suggested that triple-tapered stems cause less cement strain in torsion compared to double tapered stems. Hence, we hypothesised that the in vitro behaviour of implanted double- and triple-tapered polished stems, like the CPT (Zimmer, Warsaw, USA) or C-Stem (DePuy, Leeds, U.K.) when subjected to pathological torsional loads may cause different patterns of periprosthetic fractures. METHODS: Ten double-tapered stems (CPT) and ten triple-tapered stems (C-Stem) were cemented into synthetic femur bones. A constant axial compression load of 100 N and a torsional pre-load of 0.1 N.m were applied using a biaxial testing machine. The distal femur was then loaded in external rotation at 45 degrees until failure. RESULTS: Seven of the 10 CPT stems fractured at the level of the stem body while fracturing the cement mantle at the same level. In three of ten of the CPT stems and all ten C Stems, the synthetic bone fractured at the tip of the prosthesis while the cement mantle remained intact. This was significant for the resulting fracture pattern (P=0.001). There was no significant difference between the groups for either torque (P=0.13) or angle at failure (P=0.49). INTERPRETATION: This biomechanical study indicates that the CPT and C-Stem create a different fracture pattern under the same loading condition. The C-Stem (a triple tapered stem) may produce lower strain in torsion to the cement mantle of a cemented THA. However, fractures that do occur may be more difficult to treat than those produced around a stem like the CPT subjected to comparable loading. PMID- 23813165 TI - The efficacy of a "double-D-shaped" wire marker for radiographic measurement of acetabular cup orientation and wear. AB - Historically, wire markers were attached to cemented all-plastic acetabular cups to demarcate the periphery and to measure socket wear. The wire shape was either a semi-circle passing over the pole of the cup, or a circle around the cup equator. More recently, "double-D" shaped markers were introduced with a part circular aspect passing over the pole and a semi-circular aspect parallel to the equatorial plane. This configuration enabled cup retroversion to be distinguished from anteversion. In this study, the accuracy of radiographic measurement of cup orientation and wear was assessed for cups with "double-D" and circular markers. Each cup was attached to a measurement jig which could vary the anteversion/retroversion and internal/external rotation of the cup. A metal femoral head was fixed within the socket and radiographic images were created for all combinations of cup orientation settings. The images were measured using software with automatic edge detection, and cup orientation and zero-wear accuracies were determined for each setting. The median error for cup version measurements was similar for both types of wire marker (0.2 degrees double-D marker, -0.24 degrees circular marker), but measurements of the circular marker were more repeatable. The median inclination errors were 2.05 degrees (double-D marker) and 0.23 degrees (circular marker). The median overall "zero wear" errors were 0.19 mm (double-D marker) and 0.03 mm (circular marker). Measurements of the circular wire marker were much more repeatable. PMID- 23813166 TI - Acetabular revision in THA using tantalum augments combined with impaction bone grafting. AB - INTRODUCTION: Acetabular revision with associated bone loss in uncontained defects can be difficult. We report preliminary results utilising a novel technique, combining tantalum-augments with allograft bone and cemented cups. PATIENTS AND METHODS: Forty-six patients undergoing cup revision with a tantalum augment and allografting were clinically (HHS) and radiographically reviewed at an average of 46 months postoperatively. There were 28 type-2B and 18 type-3A Paprosky defects. Postoperative images were assessed for osteointegration, bone remodelling and recreation of the native hip centre. RESULTS: The average patient age at time of acetabular revision was 65 years, with 18 male and 28 female patients. The HHS improved on average from 44 to 82 points. Correction of the high hip centre was possible in all patients with average medialisation of 10 mm and lowering of the hip centre by 14 mm. Four patients (four hips) sustained a hip dislocation postoperatively and one required revision. Two acetabular revisions were necessary after implantation, because of early cup loosening and failure of the construct. In one of these, the tantalum augment was found to be well fixed. Of the remaining hips, at latest radiographic follow-up, 44 tantalum implants were radiographically stable and osteointegrated. Non-progressive radiolucent lines were present around the acetabular component in two other hips. CONCLUSION: The combination of tantalum-augmentation with impaction allografting is a promising technique to manage severe uncontained acetabular defects. PMID- 23813167 TI - Resurfacing hip replacement and cemented total hip replacement have equivalent outcome at one year in a disease matched population: a case-control study of patient reported outcome measures. AB - Resurfacing hip replacement has demonstrated good survival and outcomes for cohorts of younger male patients, but few controlled studies exist. In this study we compared patient reported outcome measures and satisfaction scores at one year following resurfacing hip replacement in 69 male patients with two control groups of equal numbers undergoing cemented total hip replacement: aged-matched patients and disease matched patients. At one year we found no difference in improvement in patient reported outcome measures between patients undergoing resurfacing hip replacement and disease matched patients, whereas patients undergoing resurfacing hip replacement had a statistically significant improvement in Oxford Hip Score compared to the age-matched controls (p<0.047) although this was below the minimally clinically detectable difference. Resurfacing hip replacement and total ?hip replacement both confer increase in patient reported outcome scores and high patient satisfaction at one year. The results of this study will allow better counselling of patients and help inform ?treatment decisions. PMID- 23813168 TI - Cementless total hip arthroplasty in patients with Crowe type-4 developmental dysplasia. AB - BACKGROUND: Developmental dysplasia of the hip is one of the most common causes of secondary osteoarthritis. The purpose of our study was to review clinical and radiological outcomes of reconstruction surgery using cementless total hip arthroplasty in patients with Crowe type-IV dysplastic hips. METHODS: This study included eighty-seven primary total hip arthroplasties performed between January 2005 and January 2010 at our clinic in 74 patients who had Crowe type-IV developmental dysplasia of the hip. Cementless total hip arthroplasty was applied in all hips. At the clinical status analysis, any limping, the Harris hip score, surgical approach, the use of bone grafts, the presence of femoral osteotomy, any component migration, union status of the osteotomy site (if present), and any osteolysis or heterotopic ossification were noted. Mean follow-up time was 4.8 years. RESULTS: Mean Harris hip score was improved from 41.8 points preoperatively to 86.2 points postoperatively (p<0.001). At the final clinical examination, none of the patients had severe limping. Restoration of the anatomical hip centre was achieved in all hips. Pseudoarthrosis of the femoral osteotomy site was seen in two hips (3.6%). Twelve hips (13.8%) underwent revision surgery. Neurological complications were seen in two hips (2.3%). Heterotopic ossification was detected in one hip. CONCLUSION: Cementless total hip arthroplasty with restoration of the anatomic hip centre resulted in satisfactory clinical outcomes in patients with secondary coxarthrosis due to Crowe type IV developmental dysplasia of the hip joint. PMID- 23813169 TI - Surgeon records in the public domain. PMID- 23813170 TI - Proximal femoral canal shape is more accurately assessed on AP hip radiographs than AP pelvis radiographs in primary hip osteoarthritis. AB - The objectives of the present study were to determine whether differences in the radiographic appearance of the of the proximal femoral canal exist on corresponding AP pelvis and AP hip radiographs, and whether radiographic assessment of canal shape is accurate with reference to computed tomography (CT). In a retrospective study, corresponding radiographs and CT scans of 100 consecutive patients with primary hip OA were evaluated. Active shape modelling (ASM) was performed to assess the variation in proximal femoral canal shape and to identify differences between AP hip and AP pelvis views. Differences in the medial cortical flare between radiographs and CT were quantified using least squares curve fitting. ASM identified significant differences in the assessment of canal shape on corresponding AP hip and AP pelvis views. Curve fitting demonstrated a good agreement between AP hip radiographs and CT. Agreement between AP pelvis radiographs and CT was less good. In contrast to AP pelvis radiographs, AP hip radiographs allow a more accurate and reliable assessment of proximal femoral canal shape in the frontal plane in primary hip OA. Our findings may improve stem fit in total hip arthroplasty without the routine use of CT. PMID- 23813171 TI - Assessment of range of motion and contact zones with commonly performed physical exam manoeuvers for femoroacetabular impingement (FAI): what do these tests mean? AB - Recognition of the magnitude and location of mechanical conflicts is critical to reliably and reproducibly improve functional range of motion and outcomes after surgical treatment of femoroacetabular impingement (FAI). The purpose of this study was to assess the ROM and location of intra-articular and extra-articular mechanical conflict with seven commonly performed physical exam manoeuvers in a cohort of hips with symptomatic FAI. Internal rotation in flexion results in mechanical contact between the anterolateral and anterior femoral head-neck junction with the acetabulum, most commonly at a 1:15 o'clock position. Associated adduction, however, significantly reduces the available internal rotation secondary to contact in the same locations. Straight abduction results in mechanical conflict between the superior femoral head-neck junction and the 12:00 o'clock position of the acetabulum. With external rotation of the hip in various degrees of hip flexion, the potential mechanical impingement is extra articular between the greater trochanter and ischium or pubic ramus. The zones of proximal femoral and acetabular contact are not intuitive, and may extend significantly more laterally and distally on the femoral head-neck junction than previously appreciated. PMID- 23813172 TI - The use of Gamma-irradiated proximal femoral allografts for bone stock reconstruction in complex revision hip arthroplasty. AB - We have followed a consecutive series of 49 revision hip arthroplasties, performed for severe femoral bone loss using Gamma-irradiated anatomic-specific proximal femoral allografts longer than five centimetres. The patients were followed for a median 10.2 years, with a five year minimum follow-up. The median preoperative Harris Hip Score (HHS) improved from 42 points to 77 points postoperatively. In four hips the femoral component was further revised for non union of the allograft and aseptic failure. In one hip the allograft and the femoral component were removed because of infection. In one hip the allograft and the femoral component were re-revised for host step-cut fracture. Junctional union was observed in 44/49 hips. By defining success as an increase of HHS by 20 points or more, a stable implant and no need for any subsequent re-operations related to the allograft and /or the implant, a success rate of 76% was observed. Kaplan-Meier survivorship analysis predicted 79% rate of survival at 10 years and 75% rate of survival at 17 years, with the need for further revision of the allograft and/or implant as the end point. Three hips underwent re-attachment of the greater trochanter for trochanteric escape. Asymptomatic non-union of the greater trochanter was noticed in another three hips. Moderate allograft resorption was observed in four hips. Two fractures of the host step-cut occurred. There were four dislocations. Good long-term results with the use of large anatomic-specific femoral allografts justify their continued use in cases of revision hip arthroplasty complicated with severe femoral bone loss. PMID- 23813173 TI - A comparison of reversed locking compression-distal femoral plates and blade plates in osteotomies for young adult hip pathology. AB - The aim of this study was to compare fixation of proximal femoral osteotomies using reverse contralateral LCP-Distal Femoral Plates (LCP-DF) with the more traditional blade plate technique. This was a retrospective review over six years of a single surgeon's practice within a tertiary orthopaedic unit. Patient demographics were collected, along with indication for surgery. Radiological outcomes, fixation failures and the need for revision surgery were recorded. Forty-six patients were identified; 23 patients in the LCP-DF plate group (7 females, 16 males. Mean age 18.3 years old) and 23 patients in the blade plate group (6 females, 17 males. Mean age 19.1 years old). The patients' presenting conditions were; 26 Perthes'; eight hip dysplasia; 11 slipped capital femoral epiphysis; one fibrous dysplasia. Osteotomy type included; 13 Double osteotomy, 11 Imhauser; 13 pure valgus; eight valgus + rotation; There was one revision for implant failure in the LCP-DF group. In the blade plate group, there were four implant failures--three requiring revision operations (p = 0.155). In the LCP-DF group the mean neck-shaft angle difference compared to the contralateral side (if normal) or 135 degrees (if abnormal) was 0.58 degrees . In the condylar plate group the mean difference was 4.37 degrees . The use of a contralateral LCP-DF plate in the reverse contralateral position to stabilise proximal femoral osteotomies in our cohort confers advantages over blade plate technology. We have found that the plate is stiffer, is easier to use and provides increased screw placement options over standard proximal femoral locking plates. PMID- 23813174 TI - Predictors of blood loss and haematocrit after periacetabular osteotomy. AB - BACKGROUND: Acetabular dysplasia is a common cause of hip pain that can lead to osteoarthritis. Periacetabular osteotomy (PAO) is an effective procedure to treat symptomatic dysplasia in properly selected patients. PURPOSE: This study aims to determine patient or perioperative variables that are predictive of blood loss (EBL) and postoperative haematocrit (HCT) with PAO. PATIENTS AND METHODS: Between March 2009 and October 2011, 169 PAOs in 141 patients were performed. Associations with EBL (log-transformed) and lowest postoperative haematocrit (post-HCT, <26 vs. >=26) were assessed by regression analysis, adjusting for surgeon and for within-patient correlations. RESULTS: Geometric mean EBL was 925 mL (range 200-3900 mL; 95% CI: 851.3, 1005.1). There was 11.1% greater blood loss per hour of surgery (p = 0.02). Preoperative HCT averaged (+/-SD) 36.1 (+/-3.3). In 119 cases (71%), the post-HCT was <26. Lower preoperative HCT correlated with post-HCT <26 (p<0.001); the median ratio of the lowest postoperative HCT to the preoperative HCT was 0.687 (5th, 95th percentiles: 0.538, 0.781). Age, body mass index (BMI), arthrotomy, and anaesthesia-type showed no association with EBL or post-HCT. CONCLUSIONS: Longer duration of surgery correlated with increased blood loss during PAO. Current guidelines recommend considering transfusion at haemoglobin <=8 g/dL for postoperative patients. The median nadir post-HCT was 31% lower than the preoperative value, a ratio that may help determine the need for preoperative blood donation. This information facilitates future investigation of blood management with PAO. PMID- 23813175 TI - Highly-porous metal option for primary cementless acetabular fixation. What is the evidence? AB - The purported improvement in the initial stability and enhanced osseointegration has stimulated a recent increase in the use of highly-porous interfaces for acetabular fixation in cementless hip arthroplasty. The aim of this study was to comprehensively review the literature and report the clinical outcomes of highly porous metals in primary cementless acetabular fixation. Aseptic survivorship, osteolysis, Harris hip scores, cup migration and the incidence of peri-acetabular gaps, and peri-prosthetic fractures were assessed. A search of four electronic databases yielded 16 level IV studies that reported on the use of these newer highly-porous metals in primary cementless acetabular fixation. The mean cup survivorship for aseptic loosening with the use of these modern interfaces was 100% and the mean acetabular component revision rate for any reason at 100 component years was 0.14 (range 0 to 0.55) at a mean follow-up of five years. The functional outcomes were also noted to be excellent with significant improvement in Harris Hip scores from a mean of 46 points pre-operatively (15 to 85 points) to 91 points (range, 80 to 97 points) post-operatively. Cup-stability was found to be excellent with a mean incidence of migration of less than 2% at mean follow up of five years (range, 0.6 to 12 years). None of the studies on primary arthroplasty had any evidence of progressive peri-acetabular osteolysis in their study population at final follow-up. In summary, randomised controlled trials and long-term evaluation of these highly-porous implants will be needed in future to determine their potential superiority and to justify the increased cost. PMID- 23813176 TI - Total hip arthroplasty with porous metal cups following acetabular fracture. AB - Total hip arthroplasty (THA) after acetabular fracture presents unique challenges, including acetabular fixation. Twelve patients with a history of acetabular fracture underwent THA with porous metal cups. The average age was 57 years (range 24-88). THA was performed at an average 20 months from initial fracture. Average follow-up was 39 months (range 24-49). Average WOMAC scores improved from 32 to 79; UCLA scores improved from 1.75 to 5.25. There was one case of acetabular loosening in a renal transplant patient with rheumatoid arthritis. No other patients showed progressive radiolucent lines. At average three-year follow-up, porous metal components afforded improved clinical and radiographic outcomes in the majority of patients. Longer follow-up will determine whether porous metal is a durable option in the management of prior acetabular fracture. PMID- 23813177 TI - Delirium in older postoperative hip fracture patients. PMID- 23813178 TI - Two-stage revision of an infected total hip arthroplasty: a follow-up of 136 patients. AB - BACKGROUND AND PURPOSE: Periprosthetic infection of a total hip arthroplasty (THA) is commonly treated with a two-stage revision procedure. After resection of the infected THA and placement of a cement spacer loaded with antibiotics, a THA is inserted at a second procedure to restore hip function and mobility. Revision surgery carries a significant risk of complications. This study focuses on hip function, rate of complications and reinfection after two-stage revision surgery for an infected THA. PATIENTS AND METHODS: From January 1996 to April 2010, 136 patients underwent revision surgery after removal of an infected THA. Follow-up ranged from 2 years to more than 15 years. Hip function was evaluated using the modified Harris Hip Score (mHHS) and the Hip disability and Osteoarthritis Outcome Score (HOOS). Visual Analogue Scale (VAS) measured pain. Annual follow-up included radiographs of the affected hip and blood sampling for inflammatory parameters. RESULTS: After revision surgery, average mHHS was 63% and average HOOS was 54%. VAS pain averaged 26.8 on a 100-point scale and 40% of patients had no pain. Prosthesis-related complications unrelated to sepsis occurred in 32%. Most common were periprosthetic fractures, leg length discrepancy and dislocation. Reinfection occurred in 13% of these patients and Coagulase Negative Staphylococcus (CNS) was isolated in 67%. CONCLUSION: Two-stage evision surgery is an accepted treatment for infected THAs. However, complications are common and hip function afterwards is modest. As previous studies have shown, CNS is an important microorganism in reinfection. PMID- 23813179 TI - Blood levels of cobalt and chromium are inversely correlated to head size after metal-on-metal resurfacing arthroplasty. AB - Resurfacing arthroplasty has fallen out of favour in recent years due to unfavourable survivorship in joint registries and alarming reports of soft tissue reactions around metal on metal prostheses. Our aim was to assess the effect of head size, implant design and component positioning on metal production by resurfacing arthroplasties. We measured whole blood cobalt and chromium and component position in matched populations implanted with two designs of resurfacing arthroplasty over a two-year period. Both implants resulted in a significant increase in blood metal levels (p<0.001) though the ASR design generated significantly higher metal levels (p = 0.041). A significant inverse correlation was seen between component size and blood cobalt levels (p = 0.032) and blood chromium levels (p<0.001). No correlation was identified between component position and blood metal levels. Small diameter metal resurfacing components result in increased metal generation compared with larger components. As increased metal generation has been correlated to wear and therefore failure, caution must be used on implantation of smaller components and indeed, in those who require smaller components, alternative bearing materials should be considered. These results contrast with recent findings which have demonstrated early failure for larger diameter stemmed metal-on-metal prostheses. PMID- 23813180 TI - Inter- and intraobserver reliability of two-dimensional CT scan for total knee arthroplasty component malrotation. AB - BACKGROUND: Rotational malalignment of total knee arthroplasty (TKA) has been correlated with patellofemoral maltracking, knee instability, and stiffness. CT is the most accurate method to assess rotational alignment of prosthetic components after TKA, but inter- and intraobserver reliability of CT scans for this use has not been well documented. QUESTIONS/PURPOSES: The objective of this study was to determine the inter- and intraobserver reliability and the repeatability of the measurement of TKA component rotation using two-dimensional CT scans. METHODS: Fifty-two CT scans of TKAs being evaluated for revision surgery were measured by three different physicians. An orthopaedic resident and attending measured the same scans twice (more than 2 weeks apart) and a musculoskeletal radiologist measured them once. To assess interobserver reliability, intraclass correlation coefficients (ICCs) with two-way mixed effects analysis of variance models as well as 95% confidence intervals for each were done. The repeatability coefficient was calculated as well, which is defined as the difference in measurements that include 95% of the values. This indicates the magnitude of variability among measurements in the same scale, which in this study is degrees. RESULTS: The interobserver ICC measurement for the femoral component was 0.386 (poor), and it was 0.670 (good) for the tibial component. The interobserver ICC for the combined rotation measurements was 0.617 (good). The intraobserver ICC for the femoral component was 0.606 (good), and it was 0.809 (very good) for the tibial component. The intraobserver ICC for combined rotation was 0.751 (good). The intraobserver repeatability coefficient for the femoral component was 0.49 degrees , 10.64 degrees for the tibial component, and 12.29 degrees for combined rotation. CONCLUSIONS: In this study, the inter- and intraobserver reliability, and the repeatability, of TKA component rotation were variable. This raises concern about whether CT scan is diagnostic in the assessment of component malrotation after TKA. PMID- 23813181 TI - CORR Insights(r): does proximal rectus femoris release influence kinematics in patients with cerebral palsy and stiff knee gait? PMID- 23813182 TI - Chronic knee pain in an 80-year-old woman. PMID- 23813184 TI - Extracorporeal shock wave therapy is effective in treating chronic plantar fasciitis: a meta-analysis of RCTs. AB - BACKGROUND: Plantar fasciitis is the most common cause of heel pain. It may remain symptomatic despite conservative treatment with orthoses and analgesia. There is conflicting evidence concerning the role of extracorporeal shock wave therapy (ESWT) in the management of this condition. QUESTIONS/PURPOSES: We investigated whether there was a significant difference in the change of (1) VAS scores and (2) Roles and Maudsley scores from baseline when treated with ESWT and placebo. Specifically we compared overall improvement from baseline composite VAS, reduction in overall VAS pain, success rate of improving overall VAS pain by 60%, success rate of improving VAS pain by 60% when taking first steps, doing daily activities, and during application of a pain pressure meter. METHODS: MEDLINE, Embase, and CINAHL databases were searched from January 1980 to January 2013 and a double extraction technique was used to obtain relevant studies. Studies had to be prospective randomized controlled trials on adults and must not have used local anesthesia as part of their treatment protocol. Studies must have specifically recruited patients who continued to be symptomatic despite a minimum of 3 months of conservative treatments. All papers were assessed regarding their methodologic quality and a meta-analysis performed. Seven prospective randomized controlled trials were included in this study. There were 369 patients included in the placebo group and 294 in the ESWT group. RESULTS: After ESWT, patients had better composite VAS scores (random effects model, standardized mean difference [SMD] = 0.38; 95% CI, 0.05, 0.72; z = 2.27). They also had a greater reduction in their absolute VAS scores compared with placebo (random effects model, SMD = 0.60; 95% CI, 0.34, 0.85; z = 4.64). Greater success of improving heel pain by 60% was observed after ESWT when taking first steps (random effects model, risk ratio [RR] = 1.30; 95% CI, 1.04, 1.62; z = 2.29) and during daily activities (random effects model, RR = 1.44; 95% CI, 1.13, 1.84; z = 2.96). Subjective measurement of pain using a pressure meter similarly favored ESWT (random effects model, RR = 1.37, 95% CI, 1.06, 1.78; z = 2.41). There was a significant difference in the change to "excellent - good" Roles and Maudsley scores in favor of the ESWT group. CONCLUSIONS: ESWT is a safe and effective treatment of chronic plantar fasciitis refractory to nonoperative treatments. Improved pain scores with the use of ESWT were evident 12 weeks after treatment. The evidence suggests this improvement is maintained for up to 12 months. We recommend the use of ESWT for patients with substantial heel pain despite a minimum of 3 months of nonoperative treatment. PMID- 23813183 TI - Risk factors for significant wound complications following wide resection of extremity soft tissue sarcomas. AB - BACKGROUND: Wound complications following resection of a localized soft tissue sarcoma have been associated with lower extremity location, large tumor volume, and use of preoperative radiation. Some of these wounds, however, show the potential for healing with local wound care and nonsurgical techniques. We are unaware of any published data establishing factors associated with nonhealing wounds that ultimately are treated with local or free vascularized tissue transfer. QUESTIONS/PURPOSES: The purpose of this study was to determine the variables associated with development of a significant wound complication defined as one that underwent a secondary procedure using local or free tissue transfer after resection of a localized soft tissue sarcoma. METHODS: Using our institution's cancer center database, we identified 140 patients who underwent resection of a localized extremity soft tissue sarcoma at our institution between 1997 and 2010. Thirty-two patients were excluded who underwent immediate planned vascularized tissue transfer, along with 26 patients who did not receive radiation, and an additional three patients were excluded who were followed for less than 1 month. This left 79 patients, including 18 treated with postoperative external beam radiotherapy and 61 with preoperative external beam radiotherapy. Of patients receiving radiation treatment before surgery, 13 received no additional radiation treatment, 33 underwent intraoperative radiation with electrons (IOERT) to sites considered at high risk for local recurrence, and an additional 15 had perioperative brachytherapy. Univariate and multiple regression analyses were performed using frequency of local or free tissue transfer at 3 weeks or greater postoperatively owing to wound-related complications as a dependent variable. RESULTS: Lower extremity location and vascular involvement were associated with use of delayed vascularized tissue coverage for wound healing problems. Patients in this series who underwent preoperative external beam radiotherapy coupled with dose-escalated IOERT or chemotherapy had a similar rate of flap use compared with patients treated with postoperative radiation. CONCLUSIONS: Patients with tumors of the lower extremity involving major neurovascular structures and for whom radiation therapy is planned should be counseled specifically because they appear to be at increased risk for use of delayed local or free vascularized tissue transfer for a nonhealing wound following resection of a localized extremity soft tissue sarcoma. PMID- 23813185 TI - Culture of amelanotic melanocytes derived from human fetal hair follicles. AB - Human melanocyte stem cells (MSCs) or melanoblasts are not well-investigated owing to the devoid of suitable culture system. Establishing cell lines of MSCs and/or their progenies from human hair follicles will provide a better opportunity to satisfy clinical needs and to enable a deeper understanding of hair-related diseases. In the present study, we cultured melanocytes derived from human fetal hair follicles, perform immunocytochemistry and Fontana Masson staining on them, and employed atomic force microscopy (AFM) and scanning electron microscopy to observe their subtle morphologies. The results show that the cultured melanocytes have a bipolar or tripolar appearance, which obviously differ from cultured epidermal melanocytes. Compared to cells derived from adult human hair follicles, these cells display a high proliferative capability and exhibit a clonal growth behavior. At the second passage, all these cells were positive for immunocytochemical staining with the NKI/beteb monoclonal antibody and Fontana Masson staining. Under AFM, the cells exhibited rounded, oval, triangular, or quadrangular perikarya, from which two or three dendrites arose. The dendritic arbor was not homogeneous but appeared as spindle-shaped dendritic swellings, knob-like processes, without any filopodia arising from the dendrites or the cell body. Without using a feeder layer, we successfully obtained the clonal growth of melanocytes from human fetal HFs, suggesting that the medium was suitable for the growth of MSCs and their progenies. PMID- 23813186 TI - Establishment of a Chinese bladder cancer cell line (T921) with high metastatic activity. AB - Muscle-invasive bladder cancer is prone to metastasis without a standard organ preference. The current cell lines used to study bladder cancer have primarily been derived from individuals in Western populations, and no human bladder cancer cell line has been established from the Chinese population. A bladder cancer cell line was derived from a female Chinese patient with muscle-invasive bladder cancer, and these cells were then xenografted into the bladders of three nude mice. Five weeks later, these mice were killed to observe local invasion and distant metastasis. The metastatic tumors were also removed and analyzed to assess the metastatic mechanism. This bladder cancer cell line, named T921, was successfully established, as evidenced by karyotype and immunohistochemistry analyses. Multi-organ metastases were observed in all three of the nude mice 5 wk after the orthotopic transfer of the cell line. In addition, epithelial mesenchymal transition (EMT)-related genes were involved in the tumor metastases. The T921 bladder cancer cell line was successfully established, and EMT was observed to play a role in bladder cancer metastasis. PMID- 23813187 TI - Hypoxia increases the release of salmon cardiac peptide (sCP) from the heart of rainbow trout (Oncorhynchus mykiss) under constant mechanical load in vitro. AB - Our aim was to study the effects of hypoxia on the release of salmon cardiac peptide (sCP) from an isolated heart ventricle of trout during a constant mechanical load. Trout heart ventricles were studied in vitro. The ventricle was placed in an organ bath at 12 degrees C in which a constant mechanical load could be imposed on the ventricle while buffer solution was circulating. Ventricles were field-stimulated with a supramaximal voltage pulse at a rate of about 0.3 s-1. Samples of 1 ml were collected at an interval of 10 min for 200 min from the organ bath and assessed with a radioimmunoassay for sCP. After a control period of 20 min, ventricles were exposed to hypoxia produced with N2 gassing (n = 9) or to hypoxia with 20 mM BDM, a nonselective myosin ATPase inhibitor locking cross-bridges in a pre-power-stroke state inhibiting force production with normal electrical activity (n = 10). In this model and setup, hypoxia stimulated the release of sCP, but the interindividual variation in the response was large. At the end of hypoxia exposure, the concentration of sCP in the organ bath was about sixfold higher than at the start of the exposure (P < 0.05, one-way ANOVA for repeated measurements, followed by Dunnett's multiple comparison test). When BDM was introduced into the bath, the ventricle still secreted sCP but the hypoxic response was smaller than in the experiments without BDM. In the trout heart ventricle, there is a hypoxia-sensitive component in the release mechanism of sCP which is independent of contraction. PMID- 23813188 TI - Probing the microscopic aspects of 1-butyl-3-methylimidazolium trifluoroacetate ionic liquid and its mixture with water and methanol: a photophysical and theoretical (DFT) study. AB - Considering the potential of mixed ionic liquid-cosolvent systems in wide range of applications, photophysical and theoretical studies on an industrially important ionic liquid, 1-butyl-3-methylimidazolium trifluoroacetate (BMIMTFA), and also its mixture with water and methanol have been investigated. Two organic dipolar solutes coumarin 153 (C153) and 2-aminonitrofluorene (ANF) have been used as the probe molecule for the present study. Steady-state absorption and emission spectral behavior of C153 has not been significantly influenced by both the cosolvents. However, excitation wavelength dependent measurements with ANF in the BMIMTFA-water and BMIMTFA-methanol show entirely different photophysical response. For BMIMTFA-methanol system the average solvation and rotational time is found to be less than that in BMIMTFA-water system. Quite interestingly, time resolved fluorescence anisotropy measurements reveal two different solute-solvent coupling constant (C(obs)) even if same mole fraction of water and methanol is used for the mixed solvent systems. Theoretical calculations also reveal stronger intermolecular interaction between IL and methanol than that between IL and water. The present combined photophysical and theoretical calculations seem to suggest different microscopic structural organization in the two binary systems. PMID- 23813189 TI - Closing the gap: medialization of fascia with laparoscopic incisional hernia repair. AB - PURPOSE: Laparoscopic incisional hernioplasty (LIH) bridges the fascial gap between the rectus muscles with a posteriorly placed mesh, and is a low recurrence alternative to other reconstructions. It is unclear if this repair optimizes the function of the abdominal wall. We hypothesize that significant medialization of the fascial edges occurs in patients who undergo LIH. METHODS: Two hundred fifty-eight patients underwent LIH by a single surgeon between 2004 and 2012. 44 of these had pre- and postoperative CT scans that illustrated the gap between the rectus muscles. All 44 patients underwent LIH with polyester composite mesh, with suture and tack fixation. The distance between the fascial edges on the pre- and postoperative CT scans was compared. Percent medialization was calculated for each defect. RESULTS: Average fascial separation reduction was 0.8 cm (6.56-5.76 cm, 12.2 % medialization, p < 0.0001). 36 of 44 patients demonstrated a reduction in hernia defect width (81.8 %): these defects reduced 1.09 cm (6.47-5.38 cm, 16.9 % medialization, p < 0.0001). In defects wider than 5 cm, the width reduced by 0.94 cm (8.48-7.54 cm, n = 26, 10.6 % medialization, p = 0.004). The use of meshes >=500 cm(2) reduced the defect by 0.95 cm (8.42-7.47 cm, 11.23 % medialization, n = 22, p = 0.005). CONCLUSIONS: Significant medialization of the rectus muscles is evident in most patients undergoing LIH. Although the rectus muscles are not ideally approximated, this may help improve the function of the anterior abdominal wall. Further technical refinements and material improvements may improve the reconstructive results of the LIH. PMID- 23813190 TI - A bottom-up view of toddler word learning. AB - A head camera was used to examine the visual correlates of object name learning by toddlers as they played with novel objects and as the parent spontaneously named those objects. The toddlers' learning of the object names was tested after play, and the visual properties of the head camera images during naming events associated with learned and unlearned object names were analyzed. Naming events associated with learning had a clear visual signature, one in which the visual information itself was clean and visual competition among objects was minimized. Moreover, for learned object names, the visual advantage of the named target over competitors was sustained, both before and after the heard name. The findings are discussed in terms of the visual and cognitive processes that may depend on clean sensory input for learning and also on the sensory-motor, cognitive, and social processes that may create these optimal visual moments for learning. PMID- 23813191 TI - Protective effects of antioxidants on deoxynivalenol-induced damage in murine lymphoma cells. AB - As contradictory results have been reported on the immunotoxic properties of deoxynivalenol (DON) in animal studies, we introduced a lymphoblast cell culture model in order to examine the effects of DON on lymphoblastic cell growth and metabolism as well as the preventive properties of free radical scavenger molecules against the DON-induced cell damage. Murine YAC-1 lymphoma cells were used because lymphoblasts have been shown to be sensitive to DON-induced immunotoxicity. Cells were quantified and their proliferative activity was measured by a proliferation test. Lipid peroxidation and protein oxidation were determined using assays quantifying thiobarbituric acid reactive substances (TBARS) and carbonylated proteins. Severely reduced cell counts were detected in DON-treated samples, confirmed by a 5-10 times lower proliferative activity. Significant increases in lipid peroxidation and protein oxidation were found in parallel incubated samples. The pre-incubation with free radical scavengers significantly reduced DON-induced changes to proteins and lipids as well as the tarnished cell viability and cell proliferation. These results suggest that YAC-1 lymphoma cells are a suitable model to investigate and elucidate the basic molecular and cellular mechanisms for possible immunotoxic effects of DON. With regard to the impact of free radical scavengers, the applied in-vitro model might enable the investigation of potential prophylactic and therapeutic effects before or even without harmful animal experiments and cost- and time-intensive expenses. PMID- 23813192 TI - Speech sound disorders in a community study of preschool children. AB - PURPOSE: To undertake a community (nonclinical) study to describe the speech of preschool children who had been identified by parents/teachers as having difficulties "talking and making speech sounds" and compare the speech characteristics of those who had and had not accessed the services of a speech language pathologist (SLP). METHOD: Stage 1: Parent/teacher concern regarding the speech skills of 1,097 4- to 5-year-old children attending early childhood centers was documented. Stage 2a: One hundred forty-three children who had been identified with concerns were assessed. Stage 2b: Parents returned questionnaires about service access for 109 children. RESULTS: The majority of the 143 children (86.7%) achieved a standard score below the normal range for the percentage of consonants correct (PCC) on the Diagnostic Evaluation of Articulation and Phonology (Dodd, Hua, Crosbie, Holm, & Ozanne, 2002). Consonants produced incorrectly were consistent with the late-8 phonemes ( Shriberg, 1993). Common phonological patterns were fricative simplification (82.5%), cluster simplification (49.0%)/reduction (19.6%), gliding (41.3%), and palatal fronting (15.4%). Interdental lisps on /s/ and /z/ were produced by 39.9% of the children, dentalization of other sibilants by 17.5%, and lateral lisps by 13.3%. Despite parent/teacher concern, only 41/109 children had contact with an SLP. These children were more likely to be unintelligible to strangers, to express distress about their speech, and to have a lower PCC and a smaller consonant inventory compared to the children who had no contact with an SLP. CONCLUSION: A significant number of preschool-age children with speech sound disorders (SSD) have not had contact with an SLP. These children have mild-severe SSD and would benefit from SLP intervention. Integrated SLP services within early childhood communities would enable earlier identification of SSD and access to intervention to reduce potential educational and social impacts affiliated with SSD. PMID- 23813193 TI - Line spread as a visual clinical tool for thickened liquids. AB - PURPOSE: Preparing modified liquids to a target level of consistency is critical to patients' nutritional care. This study examined the relationship of line spread (i.e., the distance a liquid flows) to viscometer measurements for a variety of product/liquid combinations and determined if flow distance visually differentiated nectar-thick versus honey-like consistency. METHOD: Combinations of 4 thickening products (3 starch-based and 1 gum-based thickener) prepared with 6 serving-temperature liquids that had various levels of fat, fiber, and added nutrients were tested. A total of 32 product/liquid combinations tested within the target range of 80-800 centipoise (cP). Measurements were recorded using line spread and a Brookfield RVDV-II+ viscometer. RESULTS: Nectar-thick and honey-like consistencies significantly differed in their degree of line spread. Using our line spread apparatus, a value of 4.5 cm differentiated between nectar-thick and honey-like consistencies. There was an inverse correlation (-.75) between viscometer data and line spread results. That is, high viscosity values represented samples with less flow distance (line spread), and low viscosity values represented samples with more flow distance. CONCLUSION: Line spread appears to be a quick, objective, and visual method that might be used to help patients and their caregivers achieve more accurate and consistent thickened liquid preparation. PMID- 23813194 TI - Treating speech subsystems in childhood apraxia of speech with tactual input: the PROMPT approach. AB - PURPOSE: Prompts for Restructuring Oral Muscular Phonetic Targets (PROMPT; Hayden, 2004; Hayden, Eigen, Walker, & Olsen, 2010)-a treatment approach for the improvement of speech sound disorders in children-uses tactile-kinesthetic- proprioceptive (TKP) cues to support and shape movements of the oral articulators. No research to date has systematically examined the efficacy of PROMPT for children with childhood apraxia of speech (CAS). METHOD: Four children (ages 3;6 [years;months] to 4;8), all meeting the American Speech-Language Hearing Association (2007) criteria for CAS, were treated using PROMPT. All children received 8 weeks of 2 * per week treatment, including at least 4 weeks of full PROMPT treatment that included TKP cues. During the first 4 weeks, 2 of the 4 children received treatment that included all PROMPT components except TKP cues. This design permitted both between-subjects and within-subjects comparisons to evaluate the effect of TKP cues. Gains in treatment were measured by standardized tests and by criterion-referenced measures based on the production of untreated probe words, reflecting change in speech movements and auditory perceptual accuracy. RESULTS: All 4 children made significant gains during treatment, but measures of motor speech control and untreated word probes provided evidence for more gain when TKP cues were included. CONCLUSION: PROMPT as a whole appears to be effective for treating children with CAS, and the inclusion of TKP cues appears to facilitate greater effect. PMID- 23813195 TI - A multidimensional investigation of children's /r/ productions: perceptual, ultrasound, and acoustic measures. AB - PURPOSE: This study explored relationships among perceptual, ultrasound, and acoustic measurements of children's correct and misarticulated /r/ sounds. Longitudinal data documenting changes across these parameters were collected from 2 children who acquired /r/ over a period of intervention and were compared with data from children with typical speech. METHOD: Participants were 3 children with typical speech, recorded once, and 2 children with /r/ misarticulation, recorded over 7-8 months. The following data from /r/ produced in nonwords were collected: perceptually rated accuracy, ultrasound measures of tongue shape, and F3 - F2 distance. RESULTS: Regression models revealed significant associations among perceptual, ultrasound, and acoustic measures of /r/ accuracy. The inclusion of quantitative tongue-shape measurements improved the match between the ultrasound and perceptual/acoustic data. Perceptually incorrect /r/ productions were found to feature posteriorly located peaked tongue shapes. Of the children who were seen longitudinally, 1 developed a bunched /r/ and 1 demonstrated retroflexion. The children with typical speech also differed in their tongue shapes. CONCLUSION: Results support the validity of using qualitative and quantitative ultrasound measures to characterize the accuracy of children's /r/ sounds. Clinically, findings suggest that it is important to encourage pharyngeal constriction while allowing children to find the /r/ tongue shape that best fits their individual vocal tract. PMID- 23813196 TI - Lexical diversity and omission errors as predictors of language ability in the narratives of sequential Spanish-English bilinguals: a cross-language comparison. AB - PURPOSE: This study explored the utility of language sample analysis for evaluating language ability in school-age Spanish-English sequential bilingual children. Specifically, the relative potential of lexical diversity and word/morpheme omission as predictors of typical or atypical language status was evaluated. METHOD: Narrative samples were obtained from 48 bilingual children in both of their languages using the suggested narrative retell protocol and coding conventions as per Systematic Analysis of Language Transcripts (SALT; Miller & Iglesias, 2008) software. An additional lexical diversity measure, VocD, was also calculated. A series of logistical hierarchical regressions explored the utility of the number of different words, VocD statistic, and word and morpheme omissions in each language for predicting language status. RESULTS: Omission errors turned out to be the best predictors of bilingual language impairment at all ages, and this held true across languages. Although lexical diversity measures did not predict typical or atypical language status, the measures were significantly related to oral language proficiency in English and Spanish. CONCLUSION: The results underscore the significance of omission errors in bilingual language impairment while simultaneously revealing the limitations of lexical diversity measures as indicators of impairment. The relationship between lexical diversity and oral language proficiency highlights the importance of considering relative language proficiency in bilingual assessment. PMID- 23813197 TI - A case for the implementation of cognitive-communication screenings in acute stroke. AB - PURPOSE: The purpose of this article was to illustrate the importance of the implementation of cognitive-communication screenings in acute stroke and to discuss the need for further research on whether and how these screenings are implemented. Cognitive-communication screenings after stroke are the subject of existing practice guidelines and are supported by accumulated evidence. METHOD: The author uses an autoethnographic narrative--a tool founded in phenomenology- to provide an in-depth description of the experiences of a family in which one member experienced right-hemispheric stroke. She uses systematic introspection to produce a narrative using literary techniques. RESULTS: The narrative illustrates the experiences of one family when one of their members has a right-hemisphere stroke, and cognitive-communication impairments are never formally identified by professionals involved in the patient's care. CONCLUSIONS: The narrative is linked to the published literature and the importance of identifying and managing cognitive-communication impairments after stroke. A model of implementation science is presented as one way to consider the challenges clinicians face when attempting to implement evidence-based practices. The model and examples from other fields show avenues for further research. PMID- 23813198 TI - Lexical and phonological variability in preschool children with speech sound disorder. AB - PURPOSE: The authors of this study examined relationships between measures of word and speech error variability and between these and other speech and language measures in preschool children with speech sound disorder (SSD). METHOD: In this correlational study, 18 preschool children with SSD, age-appropriate receptive vocabulary, and normal oral motor functioning and hearing were assessed across 2 sessions. Experimental measures included word and speech error variability, receptive vocabulary, nonword repetition (NWR), and expressive language. Pearson product-moment correlation coefficients were calculated among the experimental measures. RESULTS: The correlation between word and speech error variability was slight and nonsignificant. The correlation between word variability and receptive vocabulary was moderate and negative, although nonsignificant. High word variability was associated with small receptive vocabularies. The correlations between speech error variability and NWR and between speech error variability and the mean length of children's utterances were moderate and negative, although both were nonsignificant. High speech error variability was associated with poor NWR and language scores. CONCLUSION: High word variability may reflect unstable lexical representations, whereas high speech error variability may reflect indistinct phonological representations. Preschool children with SSD who show abnormally high levels of different types of speech variability may require slightly different approaches to intervention. PMID- 23813199 TI - Language comprehension profiles of young adolescents with fragile X syndrome. AB - PURPOSE: In this study, the authors sought to characterize the language phenotype of fragile X syndrome (FXS), focusing on the extent of impairment in receptive syntax, within-syndrome variability in those impairments in relation to gender, and the syndrome specificity of those impairments. METHOD: The Test for Reception of Grammar, Version 2 ( Bishop, 2003), was used to examine the overall receptive syntactic skills of adolescents with FXS ( n = 35; 30 males, 5 females), adolescents with Down syndrome (DS; n = 28; 18 males, 10 females), and younger typically developing (TD) children ( n = 23; 14 males, 9 females) matched on nonverbal cognition. Performance on specific grammatical constructions and error types was examined for a subset of matched participants. RESULTS: Participants with FXS had overall receptive syntax scores that were lower than those of the TD participants but higher than those of the participants with DS; however, there was no difference in performance between the FXS and DS groups when females were excluded. Grammatical constructions that were especially difficult for participants with FXS and those with DS were identified, especially relative clause constructions and reversible constructions requiring attention to word order encoded by syntactic features. CONCLUSION: The current findings have implications for understanding the nature of the language learning difficulties of individuals with FXS and for language interventions. PMID- 23813200 TI - Validating dynamic assessment of triadic gaze for young children with severe disabilities. AB - PURPOSE: This research investigated the use of a dynamic assessment (DA) to identify differences among young children with severe disabilities, which would predict progress in learning behaviors indicating coordinated joint attention (CJA). METHOD: Six children 10-24 months of age were enrolled in a 16-week treatment for behaviors indicating CJA, specifically triadic gaze (TG), which is a 3-point gaze shift between object and adult. An initial static assessment documented the children's eligibility for the study and their baseline performance of TG. DA procedures were then implemented to determine each child's performance with examiner support in producing behaviors suggesting joint attention (i.e., tracking, gaze toward an object or an adult, scanning between objects, scanning an object and adult, and TG). RESULTS: Results demonstrated differences among children during the DA via a DA score and a behavioral profile. These results were predictive of differences among children in subsequent learning of TG. CONCLUSION: These data support the validity of DA for describing heterogeneity among young children with severe disabilities who look similar on static assessment but appear differentially ready to learn behaviors associated with joint attention. This knowledge will assist clinicians in planning more efficacious services for young children who struggle to communicate and are at risk for extended therapeutic needs. PMID- 23813201 TI - Factors that enhance English-speaking speech-language pathologists' transcription of Cantonese-speaking children's consonants. AB - PURPOSE: To investigate speech-language pathology students' ability to identify errors and transcribe typical and atypical speech in Cantonese, a nonnative language. METHOD: Thirty-three English-speaking speech-language pathology students completed 3 tasks in an experimental within-subjects design. RESULTS: Task 1 (baseline) involved transcribing English words. In Task 2, students transcribed 25 words spoken by a Cantonese adult. An average of 59.1% consonants was transcribed correctly (72.9% when Cantonese-English transfer patterns were allowed). There was higher accuracy on shared English and Cantonese syllable initial consonants /m,n,f,s,h,j,w,l/ and syllable-final consonants. In Task 3, students identified consonant errors and transcribed 100 words spoken by Cantonese-speaking children under 4 additive conditions: (1) baseline, (2) +adult model, (3) +information about Cantonese phonology, and (4) all variables (2 and 3 were counterbalanced). There was a significant improvement in the students' identification and transcription scores for conditions 2, 3, and 4, with a moderate effect size. Increased skill was not based on listeners' proficiency in speaking another language, perceived transcription skill, musicality, or confidence with multilingual clients. CONCLUSION: Speech-language pathology students, with no exposure to or specific training in Cantonese, have some skills to identify errors and transcribe Cantonese. Provision of a Cantonese-adult model and information about Cantonese phonology increased students' accuracy in transcribing Cantonese speech. PMID- 23813202 TI - Nasalance scores of children with repaired cleft palate who exhibit normal velopharyngeal closure during aerodynamic testing. AB - PURPOSE: To determine if children with repaired cleft palate and normal velopharyngeal (VP) closure as determined by aerodynamic testing exhibit greater acoustic nasalance than control children without cleft palate. METHOD: Pressure flow procedures were used to identify 2 groups of children based on VP closure during the production of /p/ in the word hamper: (a) children with repaired cleft palate and normal VP closure ( n = 23) and (b) controls without cleft palate and with normal VP closure ( n = 16). Acoustic nasalance scores were obtained for all children during the production of syllables with high-pressure consonants and sentences with low-pressure consonants (i.e., low-pressure sentences). RESULTS: Nasalance scores were generally higher for children with repaired cleft palate and normal VP function as compared to controls; however, a significant difference occurred only for low-pressure sentences ( p = .005). CONCLUSION: Results partially support a pressure-sensitive theory of VP function in that some children with repaired cleft palate may achieve VP closure during the production of high-pressure consonants but fail to do so during the production of vowels and low-pressure consonants. Clinical implications are discussed. PMID- 23813203 TI - Beginning to talk like an adult: increases in speech-like utterances in young cochlear implant recipients and typically developing children. AB - PURPOSE: Speech-like utterances containing rapidly combined consonants and vowels eventually dominate the prelinguistic and early word productions of typically developing (TD) toddlers. It seems reasonable to expect a similar phenomenon in young recipients of cochlear implants (CIs). The authors of this study sought to determine the number of months of robust hearing experience needed to achieve a majority of speech-like utterances in both of these groups. METHOD: Speech samples were recorded from CI recipients at 3-month intervals during the first 2 years of CI experience, and from TD children at time points between 6 and 24 months of age. Speech-like utterances were operationally defined as those belonging to the basic canonical syllables (BCS) or advanced forms (AF) levels of the Consolidated Stark Assessment of Early Vocal Development-Revised ( Ertmer, Young, & Nathani, 2007). RESULTS: On average, the CI group achieved a majority of speech-like utterances after 12 months of robust hearing experience and the TD group after 18 months. The CI group produced greater percentages of speech-like utterances at each interval until 24 months, when both groups approximated 80%. CONCLUSION: Auditory deprivation did not limit progress in vocal development as young CI recipients showed more-rapid-than-typical speech development during the first 2 years of device use. Implications for the infraphonological model of speech development are considered. PMID- 23813204 TI - Reading and listening in people with aphasia: effects of syntactic complexity. AB - PURPOSE: The purpose of this study was to compare online effects of syntactic complexity in written and spoken sentence comprehension in people with aphasia (PWA) and adults with no brain damage (NBD). METHOD: The participants in Experiment 1 were NBD older and younger adults (n = 20 per group). The participants in Experiment 2 were 10 PWA. In both experiments, the participants read and listened to sentences in self-paced reading and listening tasks. The experimental materials consisted of object cleft sentences (e.g., It was the girl who the boy hugged.) and subject cleft sentences (e.g., It was the boy who hugged the girl.). RESULTS: The predicted effects of syntactic complexity were observed in both Experiments 1 and 2: Reading and listening times were longer for the verb in sentences with object compared to subject relative clauses. The NBD controls showed exaggerated effects of syntactic complexity in reading compared to listening. The PWA did not show different modality effects from the NBD participants. CONCLUSION: Although effects of syntactic complexity were somewhat exaggerated in reading compared with listening, both the PWA and the NBD controls showed similar effects in both modalities. PMID- 23813205 TI - Children's marking of verbal -s by nonmainstream English dialect and clinical status. AB - PURPOSE: Children's marking of verbal -s was examined by their dialect (African American English [AAE] vs. Southern White English [SWE]) and clinical status (specific language impairment [SLI] vs. typically developing [TD]) and as a function of 4 linguistic variables (verb regularity, negation, expression of a habitual activity, and expression of historical present tense). METHOD: The data were language samples from 57 six-year-olds who varied by their dialect and clinical status (AAE: SLI = 14, TD = 12; SWE: SLI = 12, TD = 19). RESULTS: The AAE groups produced lower rates of marking than did the SWE groups, and the SWE SLI group produced lower rates of marking than did the SWE TD group. Although low numbers of verb contexts made it difficult to evaluate the linguistic variables, there was evidence of their influence, especially for verb regularity and negation. The direction and magnitude of the effects were often (but not always) consistent with what has been described in the adult dialect literature. CONCLUSION: Verbal -s can be used to help distinguish children with and without SLI in SWE but not in AAE. Clinicians can apply these findings to other varieties of AAE and SWE and other dialects by considering rates of marking and the effects of linguistic variables on marking. PMID- 23813206 TI - Phonological processing skills of children adopted internationally. AB - PURPOSE: In recent years, large numbers of children have been adopted from abroad into the United States. This has prompted an interest in understanding and improving the developmental outcomes for these children. Although a growing number of studies have investigated the early language development of children who have been adopted internationally, few have focused specifically on the phonological processing development of this group of children, even though it is widely acknowledged that phonological processing skills are important in language and literacy acquisition. The purpose of this study was to examine the phonological processing skills of a group of children who had been adopted from China into the United States. METHOD: The participants were 45 children who had been adopted from China ( M age at adoption = 13.09 months). The children were assessed between the ages of 6;10 (years;months) and 9;4. Their phonological processing skills, spoken language skills, and reading comprehension skills were assessed using norm-referenced measures. RESULTS: Overall, the majority of children scored at or above the average ranges across measures of phonological awareness, phonological memory, and rapid naming. The children's reading comprehension scores were moderately to highly correlated with their phonological processing scores, but age at the time of adoption was not highly correlated with phonological processing or reading comprehension. CONCLUSION: The findings of the current study provide a basis for an optimistic view regarding the later language and literacy development of school-age children who were internationally adopted by the age of 2 years. PMID- 23813207 TI - Ultrasound biofeedback treatment for persisting childhood apraxia of speech. AB - PURPOSE: The purpose of this study was to evaluate the efficacy of a treatment program that includes ultrasound biofeedback for children with persisting speech sound errors associated with childhood apraxia of speech (CAS). METHOD: Six children ages 9-15 years participated in a multiple baseline experiment for 18 treatment sessions during which treatment focused on producing sequences involving lingual sounds. Children were cued to modify their tongue movements using visual feedback from real-time ultrasound images. Probe data were collected before, during, and after treatment to assess word-level accuracy for treated and untreated sound sequences. As participants reached preestablished performance criteria, new sequences were introduced into treatment. RESULTS: All participants met the performance criterion (80% accuracy for 2 consecutive sessions) on at least 2 treated sound sequences. Across the 6 participants, performance criterion was met for 23 of 31 treated sequences in an average of 5 sessions. Some participants showed no improvement in untreated sequences, whereas others showed generalization to untreated sequences that were phonetically similar to the treated sequences. Most gains were maintained 2 months after the end of treatment. The percentage of phonemes correct increased significantly from pretreatment to the 2-month follow-up. CONCLUSION: A treatment program including ultrasound biofeedback is a viable option for improving speech sound accuracy in children with persisting speech sound errors associated with CAS. PMID- 23813208 TI - Increasing social interaction using prelinguistic milieu teaching with nonverbal school-age children with autism. AB - PURPOSE: Children with autism display marked deficits in initiating and maintaining social interaction. Intervention using play routines can create a framework for developing and maintaining social interaction between these children and their communication partners. METHOD: Six nonverbal 5- to 8-year olds with autism were taught to engage in social interaction within salient play routines. Prelinguistic milieu teaching (PMT) techniques were used to teach the children to communicate intentionally during these routines. Intervention focused on the children's social interaction with an adult. The effects of intervention were evaluated using a multiple baseline design across participants. RESULTS: At study onset, the participants demonstrated few consistent interaction with others. With intervention, all of the children improved their ability to sustain social interactions, as evidenced by an increase in the number of communicative interactions during play routines. Participants also increased their overall rate of initiated intentional communication. CONCLUSION: Development of intentional prelinguistic communication within salient social routines creates opportunities for an adult to teach social and communication skills to young school-age children with autism who function at a nonverbal level. PMID- 23813209 TI - Individual trial analysis for 7T fMRI data by a data-driven multi scale approach. AB - An important interest in event-related single trial fMRI is the possibility of studying cognitive processes that vary in time (e.g. learning or adaptation). Region-specific modelling and the inter-trial variability of the evoked response play an important role. We showed how the use of the iterated multigrid priors (iMGP) method, a previously introduced data-driven multi scale Bayesian iterative approach, may be extended for a trial-by-trial analysis on ultra-high magnetic field data. We used both artificial (present real physiological noise) and real (unilateral finger tapping experiment) data at 7T and compared to other methods. Since the iMGP does not need to spatially smooth the data, avoiding a loss of sensitivity, we take advantage of the high SNR available at 7T. For artificial data, we showed receiver operating characteristic curves parametrized by the activity threshold and by the addition of extra thermal noise and compared with correlation technique results.The method showed be very robust in terms of specificity for very noisy data and capable of capturing the temporal variability imposed artificially across regions. For real data, we examined the inter-trial spatial relationships for four subjects and the time-to-peak of the evoked response estimated by the iMGP across trials, regions and subjects. To stress the reliability of the iMGP in single trial studies, an illustrative comparison with the variational Bayes approach (implemented in the very popular Statistical Parametric Mapping software) was done for a single subject. Despite the extravascular signals are still present at 7T and the confounds of physiological noise and hemodynamic variability affecting single trial approaches, we showed that with the iMGP method it is possible to detect individual HR robustly. PMID- 23813210 TI - Resilient actions in the diagnostic process and system performance. AB - OBJECTIVES: Systemic issues can adversely affect the diagnostic process. Many system-related barriers can be masked by 'resilient' actions of frontline providers (ie, actions supporting the safe delivery of care in the presence of pressures that the system cannot readily adapt to). We explored system barriers and resilient actions of primary care providers (PCPs) in the diagnostic evaluation of cancer. METHODS: We conducted a secondary data analysis of interviews of PCPs involved in diagnostic evaluation of 29 lung and colorectal cancer cases. Cases covered a range of diagnostic timeliness and were analysed to identify barriers for rapid diagnostic evaluation, and PCPs' actions involving elements of resilience addressing those barriers. We rated these actions according to whether they were usual or extraordinary for typical PCP work. RESULTS: Resilient actions and associated barriers were found in 59% of the cases, in all ranges of timeliness, with 40% involving actions rated as beyond typical. Most of the barriers were related to access to specialty services and coordination with patients. Many of the resilient actions involved using additional communication channels to solicit cooperation from other participants in the diagnostic process. DISCUSSION: Diagnostic evaluation of cancer involves several resilient actions by PCPs targeted at system deficiencies. PCPs' actions can sometimes mitigate system barriers to diagnosis, and thereby impact the sensitivity of 'downstream' measures (eg, delays) in detecting barriers. While resilient actions might enable providers to mitigate system deficiencies in the short run, they can be resource intensive and potentially unsustainable. They complement, rather than substitute for, structural remedies to improve system performance. Measures to detect and fix system performance issues targeted by these resilient actions could facilitate diagnostic safety. PMID- 23813211 TI - Human factors and ergonomics as a patient safety practice. AB - BACKGROUND: Human factors and ergonomics (HFE) approaches to patient safety have addressed five different domains: usability of technology; human error and its role in patient safety; the role of healthcare worker performance in patient safety; system resilience; and HFE systems approaches to patient safety. METHODS: A review of various HFE approaches to patient safety and studies on HFE interventions was conducted. RESULTS: This paper describes specific examples of HFE-based interventions for patient safety. Studies show that HFE can be used in a variety of domains. CONCLUSIONS: HFE is a core element of patient safety improvement. Therefore, every effort should be made to support HFE applications in patient safety. PMID- 23813212 TI - APOL1 and progression of nondiabetic nephropathy. PMID- 23813213 TI - Maintaining mitochondrial morphology in AKI: looks matter. PMID- 23813214 TI - IL-11 is required for A1 adenosine receptor-mediated protection against ischemic AKI. AB - A1 adenosine receptor activation ameliorates ischemic AKI through the induction of renal proximal tubular sphingosine kinase-1. However, systemic adverse effects may limit A1 adenosine receptor-based therapy for ischemic AKI, indicating a need to identify alternative therapeutic targets within this pathway. Here, we evaluated the function of renal proximal tubular IL-11, a clinically approved hematopoietic cytokine, in A1 adenosine receptor-mediated induction of sphingosine kinase-1 and renal protection. Treatment of human proximal tubule epithelial (HK-2) cells with a selective A1 adenosine receptor agonist, chloro N(6)-cyclopentyladenosine (CCPA), induced the expression of IL-11 mRNA and protein in an extracellular signal-regulated kinase-dependent manner, and administration of CCPA in mice induced renal synthesis of IL-11. Pretreatment with CCPA protected against renal ischemia-reperfusion injury in wild-type mice, but not in IL-11 receptor-deficient mice. Administration of an IL-11-neutralizing antibody abolished the renal protection provided by CCPA. Similarly, CCPA did not induce renal IL-11 expression or protect against renal ischemia-reperfusion injury in mice lacking the renal proximal tubular A1 adenosine receptor. Finally, treatment with CCPA induced sphingosine kinase-1 in HK-2 cells and wild-type mice, but not in IL-11 receptor-deficient or renal proximal tubule A1 adenosine receptor-deficient mice. Taken together, these results suggest that induction of renal proximal tubule IL-11 is a critical intermediary in A1 adenosine receptor mediated renal protection that warrants investigation as a novel therapeutic target for the treatment of ischemic AKI. PMID- 23813215 TI - The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin. AB - Ischemia causes AKI as a result of ATP depletion, and rapid recovery of ATP on reperfusion is important to minimize tissue damage. ATP recovery is often delayed, however, because ischemia destroys the mitochondrial cristae membranes required for mitochondrial ATP synthesis. The mitochondria-targeted compound SS 31 accelerates ATP recovery after ischemia and reduces AKI, but its mechanism of action remains unclear. Here, we used a polarity-sensitive fluorescent analog of SS-31 to demonstrate that SS-31 binds with high affinity to cardiolipin, an anionic phospholipid expressed on the inner mitochondrial membrane that is required for cristae formation. In addition, the SS-31/cardiolipin complex inhibited cytochrome c peroxidase activity, which catalyzes cardiolipin peroxidation and results in mitochondrial damage during ischemia, by protecting its heme iron. Pretreatment of rats with SS-31 protected cristae membranes during renal ischemia and prevented mitochondrial swelling. Prompt recovery of ATP on reperfusion led to rapid repair of ATP-dependent processes, such as restoration of the actin cytoskeleton and cell polarity. Rapid recovery of ATP also inhibited apoptosis, protected tubular barrier function, and mitigated renal dysfunction. In conclusion, SS-31, which is currently in clinical trials for ischemia reperfusion injury, protects mitochondrial cristae by interacting with cardiolipin on the inner mitochondrial membrane. PMID- 23813217 TI - Vascular access for hemodialysis in older adults: a "patient first" approach. PMID- 23813216 TI - Fistula first is not always the best strategy for the elderly. AB - Whether placing a fistula first is the superior predialysis approach among octogenarians is unknown. We analyzed data from a cohort of 115,425 incident hemodialysis patients >=67 years old derived from the US Renal Data System with linked Medicare claims, which allowed us to identify the first predialysis vascular access placed rather than the first access used. We used proportional hazard models to evaluate all-cause mortality outcomes based on first vascular access placed, considering the fistula group as the reference. In the study population, 21,436 patients had fistulas as the first predialysis access placed, 3472 had grafts, and 90,517 had catheters. Those patients with a catheter as the first predialysis access placed had significantly inferior survival compared with those patients with a fistula (HR=1.77; 95% CI=1.73 to 1.81; P<0.001). However, we did not detect a significant mortality difference between those patients with a graft as the first access placed and those patients with a fistula (HR=1.05; 95% CI=1.00 to 1.11; P=0.06). Analyzing mortality stratified by age groups, grafts as the first predialysis access placed had inferior mortality outcomes compared with fistulas for the 67 to <=79-years age group (HR=1.10; 95% CI=1.02 to 1.17; P=0.007), but differences between these groups were not statistically significant for the 80 to <=89- and the >90-years age groups. In conclusion, fistula first does not seem to be clearly superior to graft placement first in the elderly, because each strategy associates with similar mortality outcomes in octogenarians and nonagenarians. PMID- 23813218 TI - Mycophenolate mofetil versus cyclosporin A in children with frequently relapsing nephrotic syndrome. AB - The severe side effects of long-term corticosteroid or cyclosporin A (CsA) therapy complicate the treatment of children with frequently relapsing steroid sensitive nephrotic syndrome (FR-SSNS). We conducted a randomized, multicenter, open-label, crossover study comparing the efficacy and safety of a 1-year treatment with mycophenolate mofetil (MMF; target plasma mycophenolic acid trough level of 1.5-2.5 ug/ml) or CsA (target trough level of 80-100 ng/ml) in 60 pediatric patients with FR-SSNS. We assessed the frequency of relapse as the primary endpoint and evaluated pharmacokinetic profiles (area under the curve [AUC]) after 3 and 6 months of treatment. More relapses per patient per year occurred with MMF than with CsA during the first year (P=0.03), but not during the second year (P=0.14). No relapses occurred in 85% of patients during CsA therapy and in 64% of patients during MMF therapy (P=0.06). However, the time without relapse was significantly longer with CsA than with MMF during the first year (P<0.05), but not during the second year (P=0.36). In post hoc analysis, patients with low mycophenolic acid exposure (AUC <50 ug?h/ml) experienced 1.4 relapses per year compared with 0.27 relapses per year in those with high exposure (AUC>50 ug?h/ml; P<0.05). There were no significant differences between groups with respect to BP, growth, lipid levels, or adverse events. However, cystatin clearance, estimated GFR, and hemoglobin levels increased significantly with MMF compared with CsA. These results indicate that MMF is inferior to CsA in preventing relapses in pediatric patients with FR-SSNS, but may be a less nephrotoxic treatment option. PMID- 23813220 TI - 1H, 13C and 15N resonance assignments of Ca2+-bound human S100A15. AB - S100A15 (koebnerisin) is overexpressed in psoriatic skin and displays distinct localizations in skin and breast with divergent functions in inflammation. Here we report the backbone and side-chain resonance assignments for the Ca(2+)-bound human S100A15. PMID- 23813219 TI - Interaction between PLA2R1 and HLA-DQA1 variants associates with anti-PLA2R antibodies and membranous nephropathy. AB - Risk alleles at genome loci containing phospholipase A2 receptor 1 (PLA2R1) and HLA-DQA1 closely associate with idiopathic membranous nephropathy (IMN) in the European population, but it is unknown whether a similar association exists in the Chinese population and whether high-risk alleles promote the development of anti-PLA2R antibodies. Here, we genotyped 2132 Chinese individuals, including 1112 patients with IMN and 1020 healthy controls, for three single nucleotide polymorphisms (SNPs) within PLA2R1 and three SNPs within HLA genes. We also selected 71 patients, with varying genotypes, to assess for circulating anti PLA2R antibody and for PLA2R expression in glomeruli. Three SNPs within PLA2R1 and one SNP within HLA-DQA1 strongly associated with IMN, and we noted gene-gene interactions involving these SNPs. Furthermore, these risk alleles strongly associated with the presence of anti-PLA2R antibodies and glomerular PLA2R expression. Among individuals who carried risk alleles for both genes, 73% had anti-PLA2R antibodies and 75% expressed PLA2R in glomeruli. In contrast, among individuals who carried protective genotypes of both genes, none had anti-PLA2R antibodies and glomerular expression of PLA2R was weak or absent. In conclusion, the interaction between PLA2R1 and HLA-DQA1 risk alleles associates with the development of IMN in the Chinese population. Individuals carrying risk alleles are predisposed to the generation of circulating anti-PLA2R autoantibodies, which may contribute to the development of IMN. PMID- 23813221 TI - Canal shaping with WaveOne reciprocating files: influence of operator experience on instrument breakage and canal preparation time. AB - The aim of this study was to determine the fracture incidence of WaveOne Primary reciprocating files and the time required for shaping of curved canals based on the experience of the operator. A total of 109 mesiobuccal canals of permanent molars extracted with an angle of curvature of >25 degrees -45 degrees according to Schneider were randomly assigned to four groups. An experienced operator (endodontist) and an inexperienced operator (student) each shaped one of two groups: one with the instrument WaveOne Primary to WL and the other after creation of a glide path with PathFile 1, 2 and 3 at the WL. Any fractures or visible deformations of the instruments during the shaping phase and the effective time required to prepare the canals for each instrument were recorded. No visible deformation or fracture was observed. The experienced operator tended to finish their shape faster than the inexperienced operator regardless of the technique applied. For the inexperienced operator, the usage time with only WaveOne Primary was significantly lower when the canals were preliminarily instrumented with the PathFile than when these instruments were not used (average time, 22.03 vs. 36.22 s, respectively; p < 0.001). The experience of the operator did not influence fracture of the WaveOne Primary instruments. The time required to prepare the canals was instead inversely proportional to the experience of the operator. However, the creation of a glide path with PathFile instruments reduced the time required by the inexperienced operator to prepare the canal. PMID- 23813222 TI - Carboxyl terminus heterogeneity of type IV fimbrial subunit protein of Pasteurella multocida isolates. AB - Pasteurella multocida, a Gram-negative bacterial pathogen, known to affect a wide range of domestic as well as wild animal and avian species throughout the world by causing either systemic or localized infections termed as 'pasteurellosis'. P. multocida isolates are known to possess type IV fimbriae (pili) as one of the major virulence factors based on their role in adhesion to host surfaces and subsequent pathogenesis. In the present study, ptfA gene of Indian P. multocida isolates (n = 8) originated from different animal (buffalo, sheep, goat, pig) and avian host species (chicken, turkey, duck, quail) were amplified, cloned, sequenced and compared with available ptfA/fimbrial protein sequences in GenBank/publications (n = 22) to understand its variability with respect to geography/host/serogroup/disease specific patterns. Multiple sequence alignment revealed highly conserved N-terminus alpha-1 helix region and heterogeneous C terminus (68-137 aa) comprised of beta-strand regions (beta1, beta2, beta3, beta4) with conserved two pairs of cysteine residues. Interestingly, an existence of absolute homogeneity among the P. multocida isolates that caused haemorrhagic septicaemia in bovines and septicaemic pasteurellosis in sheep and goats was noticed. Pig isolates had 99.3% homogeneity. On contrary, more diversity (35.8%) was observed among isolates that caused fowl cholera in avians irrespective of identical capsular/somatic serogroup and similar host species. Phylogenetic analysis based on nucleotide sequences of ptfA gene revealed formation of mixed clusters with isolates representing different disease conditions as well as serogroups irrespective of country of origin which indicated the possible role of cross-species transmission among different animal/avian species. The study indicated highly conserved and host specific fimbriae among animal species than relatively divergent fimbriae among avian species. PMID- 23813224 TI - [All doors into the healthcare system should be the right doors for the alcohol- and drug addict]. PMID- 23813223 TI - Contrast-enhanced ultrasound detects perfusion defects in an ex vivo porcine liver model: a useful tool for the study of hepatic reperfusion. AB - Following transplantation, areas of hypoperfusion can be associated with metabolic changes and poor organ recovery. Our study evaluated contrast-enhanced ultrasound (CEUS) agents for the detection of such areas. Livers were collected from ten pigs, connected to extracorporeal circuits and perfused using autologous blood. After 1 and 4 h livers were scanned with an ultrasound machine following the administration of CEUS agents. Biopsies from perfused and non-perfused areas were collected. The entire parenchyma enhanced strongly on non-contrast ultrasound at 1 h with no perfusion defects. Four hours later multiple perfusion defects manifested not evident with non-contrast ultrasound. Histology confirmed non-perfused areas corresponded to ischemic zones. In our model the addition of CEUS revealed perfusion defects after 4 h. This might facilitate detection and characterization of perfusion defects in transplanted livers. PMID- 23813225 TI - [To screen or no to screen? That is the question. The answer should not be 42]. PMID- 23813226 TI - [Prevalence of abnormal electrocardiographic patterns in Icelandic soccer players and relationship with echocardiographic findings]. AB - An abnormal electrocardiogram (ECG) is common among young athletes but the underlying cause is unclear. Therefore it is hard to predict how accurate ECG is when screening for sudden cardiac death (SCD) in elite athletes. OBJECTIVE: 1) to determine the prevalence of abnormal ECG patterns, among soccer players, especially in relation to age and 2) to link ECG patterns with echocardiographic findings in order to find out whether the ECG can predict disease and/or physiological changes. MATERIALS AND METHODS: A total of 159 male soccer players (16-45 years, mean age 25.5 years) that participated in the UEFA cup competition 2008-2010 were studied. They underwent both an ECG and echocardiography along with routine history and cardiologic examination, according to UEFA protocol. RESULTS were classified and grouped according to standards set by The European Society of Cardiology and The American Society of Echocardiography. RESULTS: 84 (53%) had abnormal ECG patterns. The prevalence of abnormal ECG patterns decreased with age. Echocardiographic findings showed that left ventricular wall thickness, mass and diameter increased with age, along with left atrial diameter. Left ventricular wall thickness, diameter and mass were similar among those with an abnormal ECG and those with a normal ECG. CONCLUSION: The prevalence of abnormal ECG's is high in Icelandic soccer players, a finding that usually does not indicate underlying heart disease. There was no relationship between ECG changes and echocardiographic findings. High prevalance of abnormal ECG patterns in young athletes reduces the usefulness of ECG in screening for SCD. PMID- 23813227 TI - [Acoustic neuroma in Iceland for 30 years (1979-2009)]. AB - INTRODUCTION: Acoustic neuroma (AN) is a tumor of the 8th cranial nerve. The goal of this study was to find the incidence of AN in Iceland from 1979 - 2009 as well as investigate other epidemiological factors. MATERIAL AND METHODS: The group of patients with the AN diagnosis was gathered retrospectively through medical records. We looked at several epidemiological factors including age and symptoms at diagnosis, and the treatment chosen for each individual. RESULTS: The incidence rate of AN in Iceland is 1.24/100,000. About 10% of diagnosed tumors were found incidentally. Most of those were found in the last 10 years of the investigation and in that period fewer large and giant tumors at diagnosis. Present complaints of patients at diagnosis were hearing loss (69%), dysequilibrium/dizziness (47%) and tinnitus (43%). Treatments were surgery (n=47), observation (n=30) and gamma knife radiosurgery (n=16). We had information concerning postoperative hearing loss and facial paralysis in 39 patients who underwent surgery. Loss of hearing postoperatively occurred in 69% (n=27) and 44% (n=17) had facial paralysis. For an average of 3.5 years, 17% of tumors followed by imaging grew. CONCLUSION: The incidence of AN is similar to that in Europe and is increasing. More tumors are found incidentally. Small tumors can be followed by regular imaging, at least for the short term. Larger tumors are treated by surgery or gamma knife radiosurgery. A high percentage of patients receiving surgery lost their hearing postoperatively. PMID- 23813228 TI - A multi-center retrospective analysis of treatment effects and quality of life in adult patients with cranial ependymomas. AB - Long term quality of life data of adult patients harboring intracranial ependymomas have not been reported. The role of adjuvant radiation therapy in Grade II ependymomas is unclear and differs from study to study. We therefore sought to retrospectively analyze outcome and quality of life of adult patients that were operated on intracranial ependymomas at four different surgical centers in two countries. All patients were attempted to be contacted via telephone to assess quality of life (QoL) at the time of the telephone interview. The standard EORTC QoL Questionnaire C30 (EORTC QLQ-C30) and the EORTC QLQ-Brain Cancer Module (QLQ-BN20) were used. 64 adult patients with intracranial ependymomas were included in the study. The only factor that was associated with increased survival was age <55 years (p < 0.001). Supratentorial location was correlated with shorter progression free survival than infratentorial location (PFS; p = 0.048). In WHO Grade II tumors local irradiation did not lead to increased PFS (p = 0.888) or overall survival (p = 0.801). Even for incompletely resected Grade II tumors local irradiation did not lead to a benefit in PFS (p = 0.911). In a multivariate analysis of QoL, irradiated patients had significantly worse scores in the item "fatigue" (p = 0.037) than non-irradiated patients. Here we present QoL data of adult patients with intracranial ependymomas. Our data show that local radiation therapy may have long-term effects on patients' QoL. Since in the incompletely resected Grade II tumors local irradiation did not lead to a benefit in PFS in this retrospective study, prospective randomized studies are necessary. In addition to age, supratentorial tumor location is associated with a worse prognosis in adult ependymoma patients. PMID- 23813229 TI - Clinico-radiologic characteristics of long-term survivors of diffuse intrinsic pontine glioma. AB - Diffuse intrinsic pontine glioma (DIPG) is the deadliest central nervous system tumor in children. The survival of affected children has remained poor despite treatment with radiation therapy (RT) with or without chemotherapy. We reviewed the medical records of all surviving patients with DIPG treated at our institution between October 1, 1992 and May 31, 2011. Blinded central radiologic review of the magnetic resonance imaging at diagnosis of all surviving patients and 15 controls with DIPG was performed. All surviving patients underwent neurocognitive assessment during follow-up. Five (2.6 %) of 191 patients treated during the study period were surviving at a median of 9.3 years from their diagnosis (range 5.3-13.2 years). Two patients were younger than 3 years, one lacked signs of pontine cranial nerve involvement, and three had longer duration of symptoms at diagnosis. One patient had a radiologically atypical tumor and one had a tumor originating in the medulla. All five patients received RT. Chemotherapy was variable among these patients. Neurocognitive assessments were obtained after a median interval of 7.1 years. Three of four patients who underwent a detailed evaluation showed cognitive function in the borderline or mental retardation range. Two patients experienced disease progression at 8.8 and 13 years after diagnosis. A minority of children with DIPG experienced long-term survival with currently available therapies. These patients remained at high risk for tumor progression even after long follow-ups. Four of our long-term survivors had clinical and radiologic characteristics at diagnosis associated with improved outcome. PMID- 23813230 TI - Clinical outcomes of patients treated with a second course of stereotactic radiosurgery for locally or regionally recurrent brain metastases after prior stereotactic radiosurgery. AB - Patients with metastatic disease are living longer and may be confronted with locally or regionally recurrent brain metastases (BM) after prior stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT). This study analyzes outcomes in patients without prior whole brain radiotherapy (WBRT) who were treated with a second course of SRS/FSRT for locally or regionally recurrent BM. We identified 32 patients at our institution who were treated with a second course of SRS/FSRT after initial SRS/FSRT for newly diagnosed BM. We report clinical outcomes including local control, survival, and toxicities. Control rates and survival were calculated using Kaplan-Meier analysis and the multivariate proportional hazards model. The Kaplan-Meier estimate of local control at 6 months was 77 % for targets treated by a second course of SRS/FSRT with 11/71 (15 %) targets experiencing local failure. Multivariate analysis shows that upon re-treatment, local recurrences were more likely to fail than regional recurrences (OR 8.8, p = 0.02). Median survival for all patients from first SRS/FSRT was 14.6 months (5.3-72.2 months) and 7.9 months (0.7-61.1 months) from second SRS/FSRT. Thirty-eight percent of patients ultimately received WBRT as salvage therapy after the second SRS/FSRT. Seventy-one percent of patients died without active neurologic symptoms. The present study demonstrates that the majority of patients who progress after SRS/FSRT for newly diagnosed BM are candidates for salvage SRS/FSRT. By reserving WBRT for later salvage, we believe that a significant proportion of patients can avoid WBRT all together, thus putting fewer patients at risk for neurocognitive toxicity. PMID- 23813232 TI - Accessory liver lobe attached to the wall of the gallbladder: a cadaveric case report. AB - Accessory liver lobe is found incidentally during laparoscopy, laparotomy or autopsy performed for unrelated reasons. The occurrence of accessory liver lobe attached to the gallbladder is reported rarely in the literature. During regular dissection classes, we came across an accessory liver lobe in the wall of the gallbladder in an adult male cadaver. On its left, it was connected to the quadrate lobe by a short fold of peritoneum. On the right, it was attached to the wall of the gallbladder. The fragment was triangular in shape, and was 20 mm in length, 11 mm in width and 6 mm thick. The histology of the fragment revealed the unusual architecture of hepatic tissue with the absence of the classical hexagonal lobule pattern. Cords of hepatocytes surrounding the central vein, with an absence of portal canals, were observed. There were branches of hepatic artery, portal vein and hepatic duct in its peritoneal fold. Smooth muscle fibers were also observed along its attachment on the wall of the gallbladder. Awareness of the incidence of accessory liver lobe in the wall of the gallbladder is of clinical importance during the diagnosis and treatment of gallstones. PMID- 23813231 TI - Stereotactic radiosurgery for brain metastases from hepatocellular carcinoma. AB - The purpose of this study is to investigate the possible role of stereotactic radiosurgery (SRS) in the management of patients with brain metastases from hepatocellular carcinoma (HCC). Thirty-two consecutive patients with 80 brain metastases from HCC were treated with SRS. Twenty-eight (87.5 %) patients were male, and the mean age of the patients was 54 +/- 12 years (range 22-73). Twenty seven (84.4 %) patients were classified as RTOG RPA Class 2. The mean tumor volume was 6.14 +/- 11.3 cm(3) (range 0.01-67.3). The mean marginal dose prescribed was 20.1 +/- 3.6 Gy (range 10.0-25.0). The median overall survival time after SRS was 11.3 +/- 5.8 weeks (95 % CI 0-22.7). A greater total volume of brain metastases (>14 cm(3)) was the only independent prognostic factor (HR = 2.419; 95 % CI 1.040-5.624; p = 0.040). The actuarial control rate of brain metastases was 51.3 % at 4 months after SRS. The prescribed marginal dose (>18 Gy) was significantly related with the actuarial tumor control (HR = 0.254; 95 % CI 0.089-0.725; p = 0.010). The prognosis of patients with brain metastases from HCC is dismal even with the modern technology of radiosurgery. The marginal dose prescribed should be reevaluated to improve upon the current poor local control rates. PMID- 23813233 TI - Excited state structural changes of 10-cyano-9-tert-butyl-anthracene (CTBA) in polymer matrices. AB - Two main deactivation processes are suggested to be present in the electronic excited state of 10-cayano-9-tert-butyl-anthracene (CTBA): one leading to the Dewar strucure resulted from photochemical effect, similar to the case of 9-tert butyl-anthracene (TBA), which is enhanced in solution, and another leads to a more planar structure leading to a Charge Transfer (CT) state and is enhanced in polymers. The presence of donor (tert-butyl group) and an acceptor (cyano group) along the line of 9,10 positions in CTBA confirm our hypothesis of CT state. Our suggestions were supported by steady state and time resolved fluorescence spectra results. PMID- 23813234 TI - Sensitized near-infrared luminescence from Nd(III), Yb(III) and Er(III) complexes by energy-transfer from ruthenium 1,3-Bis([1,10]phenanthroline-[5,6-d]-imidazol-2 -yl)benzene. AB - The luminescent ruthenium 1,3 -bis([1,10]phenanthroline-[5,6 -d]- imidazol-2 yl)benzene (bpibH2) complex, a potentially useful bridging ligand with a vacant diimine site, has been used as 'metallo ligand' to make heterodinuclear d-f complexes by attachment of a {Ln(dik)3} fragment (dik = 1,3-diketonate) at the vacant site. When Ln = Nd, Yb, or Er the lanthanide centre has low-energy f-f excited states capable of accepting energy from the (3)MLCT excited state of the Ru(II) centre, there is quenching in the (3)MLCT luminescence of the Ru(II) centre, that affords sensitized lanthanide(III) based luminescence in the near-IR region. Nd(III) was found to be the most effective at quenching the (3)MLCT luminescence of the ruthenium component because of the high density of f-f excited states of the appropriate energy which make it as effective energy acceptor compared to Er and Yb complexes. PMID- 23813235 TI - Applications of fluorescent sensor based on 1H-pyrazolo[3,4-b]quinoline in analytical chemistry. AB - Fluorescent dye 2-[(2-Hydroxyethyl)-(1,3-diphenyl-1H-pyrazolo[3,4-b]quinolin-6 ylmethyl)-amino]ethanol (LL1) was examined for its efficiency in the detection of small inorganic cations (lithium, sodium, barium, calcium, magnesium, cadmium, lead and zinc). The dye was synthesized in the laboratory and investigated by means of both, steady-state and time-resolved fluorescence techniques. This compound acts as a fluorescent sensor suitable for detection of small inorganic cations (lithium, sodium, barium, calcium, magnesium, cadmium, lead and zinc) in strongly polar solvent (acetonitrile). An electron transfer from the electro donative part (receptor) of the molecule to the acceptor part (fluorophore) is thought to be the main mechanism that underlies functionality of the compound as a sensor. This process can be retarded upon complexation of the receptor moiety by inorganic cations. Relatively high sensitivity but poor selectivity of the amino alcohol that contains indicator towards the two-valued cations was observed. However, upon addition of some amounts of water the selectivity of this sensor has been enhanced (especially towards lead cation). The preliminary results in analytical application of the sensor are discussed. PMID- 23813236 TI - Numerical and structural chromosome variation in the swarm-founding wasp Metapolybia decorata Gribodo 1896 (Hymenoptera, Vespidae). AB - The Neotropical Polistinae wasps are diverse in taxonomy, social behavior, and nesting founding characteristics. Although some species in this group have been used as models for studies on wasp's biology, they are poorly known in terms of cytogenetics. Here we reported an intraspecific numerical-structural chromosome variation in the swarm-founding wasp Metapolybia decorata from the Brazilian Atlantic Rainforest using conventional and molecular cytogenetic techniques. The observed structural chromosome change involved a telomeric fusion that resulted in a chromosome number range of 2n = 34-36. The origin and geographic distribution of the variant chromosome forms as well as their frequency and maintenance in the studied populations are discussed. In addition, we reported a novel and geographically restricted deletion in the fused chromosomes indicating that the species is undergoing a continued process of karyotype evolution leading to fused chromosome stabilization by elimination of inactive centromeric sequences. Evidence of differences in the telomeric sequences of this wasp was also found by in situ hybridization using the motif (T2AG2)7 as probe. PMID- 23813237 TI - The Chinese Lexicon Project: a repository of lexical decision behavioral responses for 2,500 Chinese characters. AB - The Chinese language has more native speakers than any other language, but research on the reading of Chinese characters is still not as well-developed as it is for the reading of words in alphabetic languages. Two areas notably lacking are the paucity of megastudies in Chinese and the relatively infrequent use of the lexical decision paradigm to investigate single-character recognition. The Chinese Lexicon Project, described in this article, is a database of lexical decision latencies for 2,500 Chinese single characters in simplified script, collected from a sample of native mainland Chinese (Mandarin) speakers (N = 35). This resource will provide a valuable adjunct to influential mega-databases, such as the English, French, and Dutch Lexicon Projects. Using two separate analyses, some advantages associated with megastudies are exemplified. These include the selection of the strongest measure to represent Chinese character frequency (Cai & Brysbaert's (PLoS ONE 5(6): e10729, 2010) subtitle contextual diversity frequency count), and the conducting of virtual studies to replicate and clarify existing findings. The unique morpho-syllabic nature of the Chinese writing system makes it a valuable case study for functional language contrasts. Moreover, this is the first publicly available large-scale repository of behavioral responses pertaining to Chinese language processing (the behavioral dataset is attached to this article, as a supplemental file available for download). For these reasons, the data should be of substantial interest to psychologists, linguists, and other researchers. PMID- 23813238 TI - ArduiPod Box: a low-cost and open-source Skinner box using an iPod Touch and an Arduino microcontroller. AB - This article introduces the ArduiPod Box, an open-source device built using two main components (i.e., an iPod Touch and an Arduino microcontroller), developed as a low-cost alternative to the standard operant conditioning chamber, or "Skinner box." Because of its affordability, the ArduiPod Box provides an opportunity for educational institutions with small budgets seeking to set up animal laboratories for research and instructional purposes. A pilot experiment is also presented, which shows that the ArduiPod Box, in spite of its extraordinary simplicity, can be effectively used to study animal learning and behavior. PMID- 23813239 TI - Local alendronic acid elution increases net periimplant bone formation: a micro CT analysis. AB - BACKGROUND: Fixation of cementless orthopaedic implants is not always achieved, particularly in challenging scenarios such as revision surgery, trauma, and tumor reconstruction. An adjunct therapy for improving implant fixation would improve the reliability and durability of certain reconstructive procedures. QUESTIONS/PURPOSES: The purpose of this study was to determine the effect of local elution of the bisphosphonate alendronic acid on bone formation around porous titanium implants in an animal model. METHODS: Porous-coated cylindrical rods were coated with either 0.2 mg or 1.0 mg alendronic acid before bilateral surgical implantation into the femoral intramedullary canals of 10 experimental dogs. Twelve weeks after surgery, the femora were harvested and scanned with micro-CT to quantify the percentage volume of bone within the immediate periimplant space. Four femora from two dogs were also processed for undecalcified thin-section histology and analysis with backscattered scanning electron microscopy. Three histologic sections from each of these four femora were anatomically matched with transverse micro-CT sections to enable direct comparison of the area fraction of bone within the periimplant space. RESULTS: Compared with paired controls, micro-CT analysis showed that local elution of alendronic acid increased periimplant bone at both doses of 0.2 mg (+52%, p = 0.01) and 1.0 mg (+152%, p = 0.004) with 1.0 mg resulting in a 2.9-fold greater mean relative increase compared with 0.2 mg (p = 0.002). Micro-CT measurements of periimplant bone formation correlated very strongly with the backscattered scanning electron microscopy measurements (R = 0.965, p < 0.001). CONCLUSIONS: Local elution of alendronic acid causes a dose-dependent net increase in periimplant bone formation in an animal model. CLINICAL RELEVANCE: This concept has potential to improve the biologic fixation of porous reconstructive implants. PMID- 23813240 TI - Silver negative pressure dressing with vacuum-assisted closure of massive pelvic and extremity wounds. AB - BACKGROUND: Massive soft tissue loss involving the pelvis and extremities from trauma, infections, and tumors remains a challenging and debilitating problem. Although vacuum-assisted closure (VAC) technology is effective in the management of soft tissue loss, the adjunct of a silver dressing in the setting of massive wounds has not been as well tested. QUESTIONS/PURPOSES: Does a silver negative pressure dressing used in conjunction with a wound VAC decrease (1) the length of acute hospital stay and overall length of treatment; (2) the number of surgical debridements the patients underwent as part of their care; and (3) the likelihood of wound closure without soft tissue transposition? METHODS: We evaluated 42 patients with massive (> 200 cm(2)) pelvic and extremity wounds from trauma, infection, or tumor who were treated with the wound VAC with or without a silver negative pressure dressing between January 2003 and January 2010; the first 26 patients were treated with the wound VAC alone, and in the final 16 consecutively treated patients, the silver dressing was added to the regimen. We reviewed medical records to determine length of treatment as well as the number and type of surgical interventions these patients underwent. We compared the group treated with the wound VAC alone with those patients treated with the wound VAC and silver negative pressure dressing. RESULTS: Hospital stay averaged 19 days in the VAC only group and 7.5 days in the VAC with silver dressing group (p < 0.041), length of overall treatment averaged 33 days in the VAC only group and 14.3 days in the VAC with silver dressing group (p < 0.022), number of operative debridements averaged 7.9 in the VAC alone group and 4.1 in the VAC with silver dressing group (p < 0.001), and success of wound closure without soft tissue transposition was 16 of 26 patients in the VAC alone group and three of 16 patients in the VAC with silver dressing group (p < 0.033). CONCLUSIONS: Based on the reduced length of care and the number of surgical procedures these patients with massive wounds of the pelvis and extremities underwent, we now use the silver negative pressure dressing in combination with the wound VAC as part of routine care of such patients. These results may be used as hypothesis-generating data for future randomized studies. LEVEL OF EVIDENCE: Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 23813241 TI - Adverse local tissue reaction associated with a modular hip hemiarthroplasty. AB - BACKGROUND: The local and systemic effects of wear debris and corrosion products remain a concern in arthroplasty and reaction to corrosion or wear products from modular junctions has been reported in primary and revision total joint arthroplasties. These effects have not been reported previously for unipolar hemiarthroplasties where there is no prosthetic bearing surface to contribute to the phenomenon. This may have implications for clinical surveillance and implant design. CASE DESCRIPTION: We report the case of a 72-year-old man who had symptomatic pseudotumor formation, confirmed by pathologic examination of the excised pseudotumor, with a large-head modular hip hemiarthroplasty. Metallosis and corrosion of the modular head/neck taper junction were noted at the time of revision surgery. LITERATURE REVIEW: To our knowledge, this is the first report of pseudotumor formation where the corrosion or wear products arose from the modular junction of the implant with no bearing couple present to contribute wear debris that may influence the formation of the pseudotumor. PURPOSES AND CLINICAL RELEVANCE: Adverse tissue reactions to wear debris generated at prosthetic articulating surfaces and corrosion and wear products from nonarticulating prosthetic junctions have been reported. The problem has been reported to be higher in metal-on-metal bearing couples and in large-diameter hip arthroplasties. Mixed-alloy junctions appear to be more susceptible to corrosion. We believe that corrosion should be considered a possible diagnostic entity when investigating persistent symptoms after hemiarthroplasty and may be avoided with the use of monoblock components. PMID- 23813242 TI - Do psychiatric comorbidities influence inpatient death, adverse events, and discharge after lower extremity fractures? AB - BACKGROUND: Psychiatric comorbidity is known to contribute to illness (the state of feeling unwell/unable to rely on one's body) and increased use of healthcare resources, but the effect on inpatient outcomes in fracture care is relatively unexplored. QUESTIONS/PURPOSES: Our primary null hypothesis is that a concomitant diagnosis of depression, anxiety, dementia, or schizophrenia is not associated with (1) discharge to another care facility rather than home after lower extremity fractures. Secondary study questions address the associations between psychiatric comorbidity and (2) longer inpatient stay and inpatient (3) adverse events; (4) blood transfusion; and (5) mortality after lower extremity fractures. METHODS: Using the National Hospital Discharge Survey database, we analyzed a total estimated number of 10,669,449 patients with lower limb fractures from 1990 to 2007. Sixty-four percent were women, and the mean+/-SD age was 67+/-22 years. The prevalence in the study population was 3.2% for depression, 1.6% for anxiety, 0.6% for schizophrenia, and 2.9% for dementia. RESULTS: A discharge diagnosis of psychiatric comorbidity was associated with a lower rate of discharge to home after accounting for an association with greater medical comorbidity (schizophrenia: odds ratio [OR], 5.6, 95% confidence interval [CI], 5.5-5.8; dementia: OR, 1.3, 95% CI, 1.2-1.3; depression: OR, 1.2, 95% CI, 1.2-1.3; anxiety: OR, 1.04, 95% CI, 1.02-1.06). Hospital stay was longer for patients with schizophrenia and dementia but shorter in patients with depression or anxiety compared with patients without any mental disorders. Schizophrenia was associated with more in-hospital adverse events and depression and anxiety with fewer events. A diagnosis of depression was associated with blood transfusion. Psychiatric comorbidity was not associated with a higher risk of in-hospital death. CONCLUSIONS: Optimal inpatient management of patients with lower extremity fractures should account for the influence of psychiatric comorbidities, dementia and schizophrenia in particular. PMID- 23813243 TI - Immortalized mouse dental papilla mesenchymal cells preserve odontoblastic phenotype and respond to bone morphogenetic protein 2. AB - Odontogenesis is the result of the reciprocal interactions between epithelial mesenchymal cells leading to terminally differentiated odontoblasts. This process from dental papilla mesenchymal cells to odontoblasts is regulated by a complex signaling pathway. When isolated from the developing tooth germs, odontoblasts quickly lose their potential to maintain the odontoblast-specific phenotype. Therefore, generation of an odontoblast-like cell line would be a good surrogate model for studying the dental mesenchymal cell differentiation into odontoblasts and the molecular events of dentin formation. In this study, immortalized dental papilla mesenchymal cell lines were generated from the first mouse mandibular molars at postnatal day 3 using pSV40. These transformed cells were characterized by RT-PCR, immunohistochemistry, Western blot, and analyzed for alkaline phosphatase activity and mineralization nodule formation. One of these immortalized cell lines, iMDP-3, displayed a high proliferation rate, but retained the genotypic and phenotypic characteristics similar to primary cells as determined by expression of tooth-specific markers and demonstrated the ability to differentiate and form mineralized nodules. Furthermore, iMDP-3 cells had high transfection efficiency as well as were inducible and responded to BMP2 stimulation. We conclude that the establishment of the stable murine dental papilla mesenchymal cell line might be used for studying the mechanisms of dental cell differentiation and dentin formation. PMID- 23813244 TI - Human identity and the evolution of societies. AB - Human societies are examined as distinct and coherent groups. This trait is most parsimoniously considered a deeply rooted part of our ancestry rather than a recent cultural invention. Our species is the only vertebrate with society memberships of significantly more than 200. We accomplish this by using society specific labels to identify members, in what I call an anonymous society. I propose that the human brain has evolved to permit not only the close relationships described by the social brain hypothesis, but also, at little mental cost, the anonymous societies within which such alliances are built. The human compulsion to discover or invent labels to "mark" group memberships may originally have been expressed in hominins as vocally learned greetings only slightly different in function from chimpanzee pant hoots (now known to be society-specific). The weight of evidence suggests that at some point, conceivably early in the hominin line, the distinct groups composed of several bands that were typical of our ancestors came to be distinguished by their members on the basis of multiple labels that were socially acquired in this way, the earliest of which would leave no trace in the archaeological record. Often overlooked as research subjects, these sizable fission-fusion communities, in recent egalitarian hunter-gatherers sometimes 2,000 strong, should consistently be accorded the status of societies, in the same sense that this word is used to describe tribes, chiefdoms, and other cultures arising later in our history. The capacity of hunter-gatherer societies to grow sufficiently populous that not all members necessarily recognize one another would make the transition to larger agricultural societies straightforward. Humans differ from chimpanzees in that societal labels are essential to the maintenance of societies and the processes giving birth to new ones. I propose that anonymous societies of all kinds can expand only so far as their labels can remain sufficiently stable. PMID- 23813245 TI - Household and kin provisioning by Hadza men. AB - We use data collected among Hadza hunter-gatherers between 2005 and 2009 to examine hypotheses about the causes and consequences of men's foraging and food sharing. We find that Hadza men foraged for a range of food types, including fruit, honey, small animals, and large game. Large game were shared not like common goods, but in ways that significantly advantaged producers' households. Food sharing and consumption data show that men channeled the foods they produced to their wives, children, and their consanguineal and affinal kin living in other households. On average, single men brought food to camp on 28% of days, married men without children at home on 31% of days, and married men with children at home on 42% of days. Married men brought fruit, the least widely shared resource, to camp significantly more often than single men. A model of the relationship between hunting success and household food consumption indicates that the best hunters provided 3-4 times the amount of food to their families than median or poor hunters. These new data fill important gaps in our knowledge of the subsistence economy of the Hadza and uphold predictions derived from the household and kin provisioning hypotheses. Key evidence and assumptions backing prior claims that Hadza hunting is largely a form of status competition were not replicated in our study. In light of this, family provisioning is a more viable explanation for why good hunters are preferred as husbands and have higher fertility than others. PMID- 23813246 TI - Activation of elements in HERV-W family by caffeine and aspirin. AB - Caffeine and aspirin have been suggested to be involved in neurologic diseases, such as schizophrenia, and previous data have revealed that abnormal expression of HERV-W elements may be an important factor in the etiopathogenesis of those diseases. In this article, we reported that caffeine and aspirin contributed to the expression of HERV-W env and gag in Human SH-SY5Y neuroblastoma cells. Semi quantitative RT-PCR and quantitative Real-time PCR were used to detect the mRNA of HERV-W env and gag in cells exposed to caffeine or aspirin. Western blotting was used to detect the protein of HERV-W env. Luciferase activity assay was employed to detect the activity of HERV-W env promoter. It was found that both caffeine and aspirin could increase the expression of HERV-W env and gag in human SH-SY5Y neuroblastoma cells. Caffeine could activate the HERV-W env promoter, while aspirin could not. With previous studies we can conjecture that HERVs might play a bridging role between environmental factors, such as drugs and neurologic diseases. PMID- 23813247 TI - Analysis of the biological and molecular variability of the Polish isolates of Tomato black ring virus (TBRV). AB - Tomato black ring virus (TBRV) is an important pathogen infecting many plant species worldwide. The biological and molecular variability of the Polish isolates of TBRV was analyzed. The analysis was performed based on the symptoms induced by various isolates on test plant species as well as on phylogenetic relationships between isolates. Isolates differed in their host range and symptomatology. In addition, genetic variation among isolates was characterized by restriction fragment length polymorphism analysis and confirmed by sequencing. The phylogenetic analysis revealed that the Polish isolates differ from each other and do not form a monophyletic cluster. Finally, we identified and analyzed sequences of defective RNA forms arising from the TBRV genome. PMID- 23813248 TI - Molecular characteristics and evolutionary analysis of field Marek's disease virus prevalent in vaccinated chicken flocks in recent years in China. AB - Marek's disease is a highly contagious, oncogenic, and immunosuppressive avian viral disease. Surveillance of newly registered Marek's disease virus (MDV) isolates is meaningful for revealing the potential factors involved in increased virulence. Presently, we have focused on the molecular characteristics of all available MDVs from China, including 17 new Henan isolates. Based on Meq, gE, and gI genes, we found that most Chinese isolates contain conserved amino acid point mutations in Meq, such as E(77), A(115), A(139), R(176), and A(217), compared to USA virulent MDVs. However, the 59-aa or 60-aa insertions are only found in a few mild MDVs rather than virulent MDVs in China. Further phylogenetic analysis has demonstrated that a different genotype of MDV has been prevalent in China, and for virulent MDVs, their recent evolution has possibly been geographically restricted. Our study has provided more detailed information regarding the field MDVs circulating in China. PMID- 23813249 TI - Identification of a conserved B-cell epitope in the equine arteritis virus (EAV) N protein using the pepscan technique. AB - The nucleocapsid (N) gene of equine arteritis virus (EAV) is highly conserved between isolates, and the N protein is an important antigen that induces immunity when horses are infected with EAV. This study describes the identification of a linear B-cell epitope on the N protein using the pepscan technique with a monoclonal antibody (mAb) 2B1 directed against the N protein. The N protein was divided into 11 overlapping peptides, each containing 16 amino acids associated with six overlapping amino acids. The fragments were expressed as MBP fusion proteins that were then used to probe the 2B1 mAb. The minimal epitope sequence was confirmed step-by-step using single amino acid residue deletion. One completely conserved linear epitope ((38)KPPAQP(43)) was identified that matched with EAV-positive serum in Western blots, thereby revealing the importance of these six amino acids of the epitope for antibody-epitope binding activity. This finding not only contributes to our understanding of the antigenic structure of the N protein of EAV but also has potential for the development of diagnostic techniques. PMID- 23813250 TI - Complete genome sequence of a novel Plum pox virus strain W isolate determined by 454 pyrosequencing. AB - The near-complete (99.7 %) genome sequence of a novel Russian Plum pox virus (PPV) isolate Pk, belonging to the strain Winona (W), has been determined by 454 pyrosequencing with the exception of the thirty-one 5'-terminal nucleotides. This region was amplified using 5'RACE kit and sequenced by the Sanger method. Genomic RNA released from immunocaptured PPV particles was employed for generation of cDNA library using TransPlex Whole transcriptome amplification kit (WTA2, Sigma Aldrich). The entire Pk genome has identity level of 92.8-94.5 % when compared to the complete nucleotide sequences of other PPV-W isolates (W3174, LV-141pl, LV 145bt, and UKR 44189), confirming a high degree of variability within the PPV-W strain. The isolates Pk and LV-141pl are most closely related. The Pk has been found in a wild plum (Prunus domestica) in a new region of Russia indicating widespread dissemination of the PPV-W strain in the European part of the former USSR. PMID- 23813251 TI - Periodontitis: the canary in the coal mine. PMID- 23813252 TI - Human dentition. PMID- 23813253 TI - Sealants and caries. PMID- 23813254 TI - Authors' response. PMID- 23813255 TI - Tissue management. PMID- 23813256 TI - Author's response. PMID- 23813257 TI - Pointing the way to better oral health. PMID- 23813258 TI - A practitioner's guide to developing critical appraisal skills: what is the difference between clinical and statistical significance? AB - BACKGROUND: It is common to find published studies in which the authors claim to have found significant results. However, many times these results are only statistically significant with no meaningful impact in clinical settings. METHODS: The authors aim to clarify and differentiate the concepts of statistical and clinical significance, as well as to provide guidance on how to interpret research results to determine whether an observed difference is meaningful. RESULTS: Study results are considered to be statistically significant if statistical tests that examine the null hypothesis of no difference yield P values that are smaller than the significance level prespecified by the authors. In this way, researchers can use hypothesis testing to assess the possibility that observed results could have arisen by chance. However, hypothesis testing cannot establish the clinical implications of these results. Rather, clinical significance can be established once the magnitude of results is larger than the minimal clinically important difference. Clinical significance then would encompass not only statistical significance, but also the importance of the outcomes to patients, clinicians and policymakers. CONCLUSION: The values for statistical significance alone cannot convey the complete picture of the effectiveness of an intervention or of a difference between two groups. Both clinical and statistical significance are important measures for interpretation of clinical research results and should complement each other. PRACTICAL IMPLICATIONS: Any benefit in terms of improved health outcomes must be both clinically and statistically significant. If there is no benefit at the threshold of both clinical and statistical improvement, then the intervention should not be used for that purpose. PMID- 23813259 TI - Dietary supplement interactions with medications used commonly in dentistry. AB - BACKGROUND: Because nearly 70 percent of prescription drug users do not discuss their dietary supplement use with their health care providers, clinicians must be proactive in questioning patients about their use of these agents. A complete and accurate pharmacological history will help clinicians avoid potential interactions between dietary supplements and drugs. METHODS: The authors reviewed the literature regarding interactions between popular dietary supplements and medications used commonly in dentistry. They used clinical databases and decision support tools to classify interactions according to their level of risk for the patient. The authors address the interactions of greatest clinical concern with a high-quality evidence-based foundation in either randomized controlled clinical trials or meta-analyses. CONCLUSIONS: Provided that patients are not taking ginkgo, St. John's wort, evening primrose or valerian, oral health care providers can prescribe or administer any of the medications used commonly in dentistry without concern about possible dietary supplement-drug interactions. PRACTICAL IMPLICATIONS: Recognition and avoidance of potential interactions between dietary supplements and drugs will help clinicians optimize treatment while emphasizing patients' safety. PMID- 23813260 TI - Dysesthesia of the mandible. PMID- 23813261 TI - In vitro demineralization of tooth enamel subjected to two whitening regimens. AB - BACKGROUND: The resistance of bleached enamel to demineralization has not been elucidated fully. In this study, the authors aimed to examine the level of in vitro demineralization of human tooth enamel after bleaching by using two common bleaching regimens: home bleaching (HB) and office bleaching (OB) with photoirradiation. METHODS: The authors bleached teeth to equivalent levels by means of the two bleaching regimens. They used fluorescence spectroscopy to measure the reduction in enamel density and the release of calcium into solution after storing the treated teeth in a demineralizing solution for two weeks. They also visualized and quantified mineral distribution in demineralized bleached enamel over time by using a desktop microcomputed-tomographic analyzer. RESULTS: Enamel subjected to HB or to photoirradiation without bleaching showed increased demineralization. In contrast, enamel treated with OB was more resistant to demineralization. This resistance to demineralization in teeth treated with OB presumably is due to peroxide's permeating to deeper layers of enamel before being activated by photoirradiation, which enhances mineralization. CONCLUSIONS: The mineral distribution pattern of enamel after treatment plays a critical role in providing resistance to demineralization in whitened teeth. PRACTICAL IMPLICATIONS: OB confers to enamel significant resistance to in vitro demineralization. Dentists should supervise the nightguard HB process. PMID- 23813262 TI - An adverse event trigger tool in dentistry: a new methodology for measuring harm in the dental office. AB - BACKGROUND: There is a dearth of knowledge about the type and frequency of adverse events (AEs) in dentistry. Current approaches to obtaining information rely on reviews of randomly selected records, which may not be the most efficient or effective methodology. METHODS: Inspired by the Institute for Healthcare Improvement's (IHI) global and outpatient trigger tools, which identifies records with characteristics ("triggers") that are associated with AEs, the authors created the dental clinic trigger tool. The triggers included procedures for incision and drainage, failed implants and selected treatment patterns. The authors ran the trigger tool against six months of electronic health records data and compared its performance with that of a review of 50 randomly selected patient records. RESULTS: In total, 315 records were triggered, 158 (50 percent) of which were positive for one or more AEs; 17 (34 percent) of the 50 randomly selected records were positive for at least one AE. The authors assigned each AE an IHI severity ranking. Most AEs caused temporary harm, but nine were considered to have caused permanent harm according to a modified IHI severity ranking. CONCLUSIONS: The study results demonstrate the promise of a directed records review approach, as the dental clinic trigger tool was more effective in identifying AEs than was a review of randomly selected records. PRACTICAL IMPLICATIONS: All dental practices should proactively monitor the safety of the care they provide. Use of the trigger tool will help make this process more efficient and effective. PMID- 23813263 TI - The effects of beverages on plaque acidogenicity after a sugary challenge. AB - BACKGROUND: Caries prevention traditionally has emphasized the restriction of cariogenic foods and beverages, but it has placed less emphasis on how the choice, combination and sequence of consumed foods and beverages may help reduce plaque acidogenicity. The authors conducted a study to examine whether whole milk, 100 percent apple juice or tap water affect dental plaque acidity in people after a sugary challenge. METHODS: Twenty adults participated in a randomized controlled crossover study. Participants consumed four combinations of foods: 20 grams of dry sugary Froot Loops (FL) (Kellogg's, Battle Creek, Mich.) cereal, 20 g of FL followed by 50 milliliters of milk (FL/milk), 20 g of FL followed by 50 mL of juice (FL/juice) and 20 g of FL followed by 50 mL of water (FL/water). The authors used a touch microelectrode to take plaque pH readings at the interproximal space just below the contact area between the maxillary premolars on both left and right sides at two and five minutes after FL consumption and at two to 30 minutes after milk, juice or water consumption. RESULTS: Consumption of FL plaque pH (standard deviation [SD]) was 5.83 (0.68) at 30 minutes, whereas plaque pH (SD) in the FL/milk group was 6.48 (0.30), which was significantly higher than that for FL/juice (5.83 [0.49]) or FL/water (6.02 [0.41]) (P < .005) at 35 minutes. CONCLUSION: Drinking milk after a sugary cereal challenge significantly reduced plaque pH drop due to the sugary challenge. PRACTICAL IMPLICATIONS: When discussing the cariogenicity of foods and beverages with patients, dentists and other health care professionals should emphasize that the order of ingesting sugary and nonsugary foods is important and may affect their oral health. PMID- 23813264 TI - Complete regeneration of peri-implantitis-induced bony defects using guided bone regeneration is unpredictable. PMID- 23813266 TI - Taking control of practice overhead. PMID- 23813265 TI - Racial and ethnic variations in waiting times for emergency department visits related to nontraumatic dental conditions in the United States. AB - BACKGROUND: Researchers have documented an association between waiting times in emergency departments (EDs) and quality of care for medical conditions, but little is known about trends and factors associated with waiting times for ED visits related to nontraumatic dental conditions (NTDCs). The authors examined trends in waiting time and associated factors for NTDC-related ED visits in the United States. METHODS: The authors analyzed data from the National Hospital Ambulatory Medical Care survey for 1997 to 2007, excluding 2001 and 2002 owing to lack of information about waiting times. The authors used a survey-weighted linear regression of log-transformed waiting-time model to determine the waiting time for NTDC-related visits. RESULTS: The geometric mean (standard error) waiting times for NTDC- and non-NTDC-related visits were 29 (1.0) and 25 (0.6) minutes, respectively (P < .01). The geometric mean waiting time for NTDC-related visits increased by 6 percent annually and from 20 minutes in 1997 to 37 minutes in 2007. Compared with whites, Hispanics and African Americans had significantly longer waiting times for NTDC-related visits (adjusted fold-difference [R] = 1.2, 95 percent confidence interval [CI] = 1.13-1.31) and [R] = 1.3, [CI] = 1.29 1.38). Age, payer type, reason for visit and triage category were significant predictors of waiting time (R = 2.3 and 2.4 for NTDC-related visits in the triage categories of more than one to two hours and more than two to 24 hours, respectively). CONCLUSION: Nationally, waiting times in EDs for NTDC-related visits increased over time. Compared with whites, Hispanics and blacks waited longer to receive care for NTDCs in EDs. PRACTICAL IMPLICATIONS: Prolonged waiting times associated with NTDC-related ED visits reinforce the need for dental professionals to continue to advise patients regarding the need to implement oral health preventive strategies and to avoid the use of the ED for preventable common dental conditions. PMID- 23813267 TI - Is it ethical to raffle off prizes in exchange for referrals? PMID- 23813268 TI - Disposable handpieces: a laboratory evaluation of two new products: American Dental Association Council on Scientific Affairs. PMID- 23813269 TI - For the dental patient. Gum disease can raise your blood sugar level. PMID- 23813270 TI - High and low stimulus-driven conflict engage segregated brain networks, not quantitatively different resources. AB - Task-irrelevant information is constantly present in our environment and may interfere with the processing of the information necessary to achieve goal directed behavior. While task goals determine which information must be suppressed, the demand for inhibitory control depends on the strength of the interference induced by incoming, task-irrelevant information. Whether the same or distinct inhibitory processes are engaged to suppress various degrees of interference from task-irrelevant information remains largely unresolved. We investigated this question by manipulating the strength of the conflict induced by automatic word reading in a classical color Stroop task. High conflict was induced by presenting words in participant's native language and low conflict by presenting words in a less familiar language. Behavioral performance and electrical neuroimaging analyses of event-related potentials to the words were analyzed following a two-by-two within-subject design with factors conflict strength (high; low) and color word/word ink congruency (congruent; incongruent). Behaviorally, we observed a significant conflict strength * congruency driven by a smaller Stroop effect in the low- than high conflict condition. Electrophysiologically, we observed a significant conflict strength * congruency interaction at the topographic level during the period of the N450 components, indicative of the engagement of distinct configurations of brain networks. No such interaction was found at the level of response strength. Electrical sources analyses localized the topographic effect within the anterior cingulate cortex and basal ganglia, left middle frontal and occipital areas. We interpret our results in terms of qualitatively distinct executive mechanisms for reactive inhibitory control in conditions of high versus low stimulus-driven conflict. PMID- 23813271 TI - Alpha- and theta-range cortical synchronization and corticomuscular coherence during joystick manipulation in a virtual navigation task. AB - Previous studies have reported that multiple brain regions are activated during spatial navigation, but it remains unclear how this activation is converted to motor commands for navigation. This study was aimed to investigate synchronization across different brain regions and between cortical areas and muscles during spatial navigation. This synchronization has been suggested to be essential for integrating activity in the multiple brain areas to support higher cognitive functions and for conversion of cortical activity to motor commands. In the present study, the subjects were required to sequentially trace ten checkpoints in a virtual town by manipulating a joystick and to perform this three times while electroencephalograms and electromyograms from the right arm were monitored. Time spent on the task in the third trial was significantly lesser than that in the first trial indicating an improvement in task performance. This repeated learning was associated with an increase in alpha power at the electrodes over the contralateral sensorimotor region and in theta power at the electrodes over the bilateral premotor and frontotemporal regions. Alpha- and theta-range corticocortical coherences between these regions and other brain areas were also increased in the third trial compared to the first trial. Furthermore, alpha- and theta-range corticomuscular coherence was significantly increased in the second and third trials compared to the first trial. These results suggest that alpha- and theta-range synchronous activity across multiple systems is essential for the integrated brain activity required in spatial navigation and for the conversion of this activity to motor commands. PMID- 23813272 TI - The migration pathway of an extracted maxillary third molar into the buccal fat pad. AB - The migration of the maxillary third molar is one of the most critical complications that can occur during extraction, and the most frequent site of migration is the maxillary sinus. We herein report an extremely rare case in which the migrated maxillary third molar became displaced into the buccal fat pad. The pathway of migration from the original site of the tooth into the buccal space is therefore considered from the anatomical perspective in this paper. PMID- 23813273 TI - A parametric study on mathematical formulation and geometrical construction of a stentless aortic heart valve. AB - This study presents a novel methodology for constructing an accurate geometrical model of a stentless aortic heart valve replacement (AVR). The main objective is to propose an optimized AVR model that can be used as an ideal scaffold for tissue engineering applications or a biocompatible prosthesis. Current techniques available for creating heart valve geometry, including leaflets, are very complicated and are not precise, due to the extensive use of various complicated parameters. This paper introduces an alternative design procedure that uses limited and effective numbers of controlling parameters to construct the whole valve including the sinus of valsalva. In doing so the hyperbolic curves for multithickness leaflets are used and a 3D elliptical formulation is incorporated for the surface geometry of the sinus of valsalva. Still, the feasibility and the precision of the mathematical method are established by performing standard deviation analysis on the constructed surfaces. The surface fitting residuals are found as low as error 0.2351 mm with standard deviation of 8.83e-5 over the commissural lines. Preliminary validation to the proposed AVR model performance is achieved by testing the generated AVR model under quasi static condition while obtaining the mesh independent setup. The numerical model showed a rapid response of the leaflets to the transvalvular pressure where adequate values of stress are measured over the commissural lines. PMID- 23813274 TI - Human impact on the microbiological water quality of the rivers. AB - Microbiological contamination is an important water-quality problem worldwide. Human impact on this category of contamination is significant and several human related activities, and also the population explosion, have affected and are still affecting dramatically the aquatic environment. Extensive industrialization and agriculture have led to increased pollution and hydromorphological changes in many river basins. The Danube river is one of the most affected by these changes where human involvement is undeniable, and subsequently, the Danube Delta Biosphere Reserve became one of the most vulnerable ecosystems. This review is an attempt to analyse the microbiological contamination and to identify the major role human activities play in altering the water quality of the rivers. PMID- 23813275 TI - Lysins: the arrival of pathogen-directed anti-infectives. AB - Lysins represent a novel class of anti-infectives derived from bacteriophage. Lysins are bacterial cell-wall hydrolytic enzymes that selectively and rapidly kill (>=3 log c.f.u. in 30 min) specific Gram-positive bacteria providing a targeted therapeutic approach with minimal impact on unrelated commensal flora. The potential for bacterial resistance to lysins is considered low due to targeting of highly conserved peptidoglycan components. Through cutting-edge genetic engineering, lysins can be assembled into large libraries of anti infective agents tailored to any bacterium of interest including drug-resistant Gram-positive pathogens such as meticillin- and vancomycin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecalis and Enterococcus faecium, and penicillin-resistant Streptococcus pneumoniae. Lysins can eliminate bacteria systemically and topically from mucosal surfaces and biofilms, as evidenced by experimental models of sepsis, endocarditis, pneumonia, meningitis, and nasopharyngeal, skin and vaginal decolonization. Furthermore, lysins can act synergistically with antibiotics and, in the process, resensitize bacteria to non-susceptible antibiotics. Clinical trials are being prepared to assess the safety and pharmacokinetic properties of lysins in humans. PMID- 23813276 TI - Use of a high-throughput screen to identify Leptospira mutants unable to colonize the carrier host or cause disease in the acute model of infection. AB - The molecular basis for leptospirosis infection and colonization remains poorly understood, with no efficient methods available for screening libraries of mutants for attenuation. We analysed the attenuation of leptospiral transposon mutants in vivo using a high-throughput method by infecting animals with pooled sets of transposon mutants. A total of 95 mutants was analysed by this method in the hamster model of acute infection, and one mutant was identified as attenuated (M1233, lb058 mutant). All virulence factors identified in Leptospira to date have been characterized in the acute model of infection, neglecting the carrier host. To address this, a BALB/c mouse colonization model was established. The lb058 mutant and two mutants defective in LPS synthesis were colonization deficient in the mouse model. By applying the high-throughput screening method, a further five colonization-deficient mutants were identified for the mouse model; these included two mutants in genes encoding proteins with a predicted role in iron uptake (LB191/HbpA and LB194). Two attenuated mutants had transposon insertions in either la0589 or la2786 (encoding proteins of unknown function). The final attenuated mutant had an unexpected deletion of genes la0969-la0975 at the point of transposon insertion. This is the first description of defined, colonization-deficient mutants in a carrier host for Leptospira. These mutants were either not attenuated or only weakly attenuated in the hamster model of acute leptospirosis, thus illustrating that different factors that may be required in the carrier and acute models of leptospiral infection. High throughput screening can reduce the number of animals used in virulence studies and increase the capacity to screen mutants for attenuation, thereby enhancing the likelihood of detecting unique virulence factors. A comparison of virulence factors required in the carrier and acute models of infection will help to unravel colonization and dissemination mechanisms of leptospirosis. PMID- 23813277 TI - IB-367 pre-treatment improves the in vivo efficacy of teicoplanin and daptomycin in an animal model of wounds infected with meticillin-resistant Staphylococcus aureus. AB - Antimicrobial peptides are known as immunomodulators and antibiotic enhancers. We report that administration of an antimicrobial peptide, IB-367, was efficacious in increasing the antimicrobial activity of daptomycin and teicoplanin in a mouse model of wound infection caused by meticillin-resistant Staphylococcus aureus (MRSA). Mice were assigned to seven groups: an IB-367 pre-treated group with no antibiotics given after challenge, two IB-367 pre-treated groups plus daptomycin or teicoplanin given after challenge, two groups treated with daptomycin or teicoplanin only after challenge, and two control groups without infection or that did not receive any treatment. The main outcome measures were quantitative bacterial culture and analysis of natural killer (NK) cytotoxicity and leukocyte phenotype. The wound, established through the panniculus carnosus muscle of mice, was infected by MRSA. Bacterial cultures of mice receiving antibiotics alone showed a -2 log decrease, whilst those for IB-367 plus daptomycin or teicoplanin showed a -4 log decrease. IB-367 plus daptomycin showed the highest efficacy. The higher antimicrobial effect exerted by IB-367 was associated with increased levels of NK cytotoxicity but not of NK cell number. IB-367 increased the number of both CD11b and Gr-1 cells 3 days after MRSA challenge, whereas both of these leukocyte populations were reduced at 10 days after challenge. Our data suggest that a combination of IB-367 with antibiotic exerts a therapeutic effect and may be useful for the management of staphylococcal wounds. PMID- 23813278 TI - [The first Icelandic physician, Hrafn Sveinbjarnarson. In memoriam -- 800 years later]. PMID- 23813279 TI - [Back pain and antibiotics]. PMID- 23813280 TI - [The effects of 6 months' multimodal training on functional performance, strength, endurance, and body mass index of older individuals. Are the benefits of training similar among women and men?]. AB - INTRODUCTION: Good functional performance in elderly people greatly improves their changes of independence and well-being. Conversely, bad functional performance can impair their capability of managing the activities of daily life.. The main goal of this study was to investigate the effects of a 6-months' multimodal training intervention on the physical performance of males and females, possible gender differences and the outcome 6 and 12 months after its completion. MATERIAL AND METHODS: This study examined 71-90 year old healthy seniors (n=117) participating in the AGES Reykjavik Study. It was a randomized and controlled cross-over trial, conducted in three 6-months' phases (time points). After enrollment and baseline assessments, the study group was divided in two. Group 1 received 6-months' training while group 2 served as a control. In the second 6 months' phase, group 1 received no formal training while group 2 did. In the third phase, neither group received training. The groups' physical conditions were assessed after each phase. RESULTS: After 6-months' training, 32% improvement was seen in physical activity among males (p<0.001) and 39% among females (p<0.001). In physical performance, 5% improvement was seen for males (p<0.01) and 7% for females (p<0.001). Strength increased by 8% for males (p<0.001) and 13% for females (p<0.001). For both sexes, about 10% increase was seen in dynamic balance in the 8-foot up-and-go test (p<0.001) and 5-6% in walking distance for both sexes in the six minutes walking test (p<0.001). For both sexes, body mass index decreased by about 2% (p<0.001). No difference was seen between the sexes.in the training results. Both sexes retained long-term effects of the training on physical performance and dynamic balance for at least 12 months. CONCLUSIONS: Multimodal training intervention has positive effects on physical performance in older individuals, the sexes respond similarly to the training and retain achieved improvement for at least 12 months. The research indicates that moderate and systemic training for this age group could be a part of conventional health service for this age group. PMID- 23813281 TI - [Diabetes of type 1, pregnancy and glycemic control]. AB - INTRODUCTION: Type 1 diabetes has wide-ranging effects for expectant mothers and their unborn children. Optimal blood sugar control minimizes complications for both. We assessed maternal and neonatal outcome in relation to glycemic control. MATERIAL AND METHODS: Retrospective evaluation of pregnancies among type 1 diabetic women in Iceland during 1999-2010, with information collected from maternity and newborn records on disease severity, HbA1c values before and during pregnancy, delivery mode and complications. RESULTS: There were 93 pregnancies among 68 women (47% primigravid). Mean age was 29 years and mean time from diabetes diagnosis 16 years (median 19, range <1-35 years). Retinal changes affected 57%, chronic hypertension and thyroid disease 13%, kidney disease and neuropathy <10%. Mean HbA1c before pregnancy was 7.8% declining to 7.5% in first and 6.3% by third trimester. Women <25 had worse first trimester blood sugar control compared to those 25-35 (p<0.04) and >35 years (p=0.02). Delivery was induced in 40% and the cesarean section rate was 65%. Mean gestation was 37+2 weeks. There were two stillbirths. Preterm deliveries were 28%. Congenital anomalies affected 9% of newborns (mostly cardiac). One-third of newborns developed diabetic fetopathy, one-quarter jaundice, both associated with worse maternal bloodsugars. CONCLUSIONS: Most women with type 1 diabetes improved blood sugar control during pregnancy, which became good or acceptable by the last trimester by HbA1c values. Cesarean section was over three times more frequent than in the general population. Neonatal complications and congenital anomalies were also more common. To minimize complications improved control of bloodsugar is needed before and throughout pregnancy. PMID- 23813282 TI - Associations of baseline characteristics with evolution of eGFR in a referred chronic kidney disease cohort. AB - BACKGROUND: Currently, most chronic kidney disease (CKD) classifications identify patients at different stages of CKD but do not identify risk of progression or adverse outcome. This analysis aims to describe associations between baseline characteristics and the evolution of estimated glomerular filtration rate (eGFR) and identify threshold values for clinical parameters that maximally discriminate progression to renal replacement therapy (RRT) in a referred cohort of patients with CKD stages 3-5. DESIGN AND METHODS: A longitudinal mixed-effect model was used to determine annualized estimated change in eGFR and classification tree analysis to identify threshold values that maximally discriminate progression to RRT. RESULTS: A total of 1316 patients were available for analysis with median follow-up of 33 months (interquartile range 20-60). Mixed model analysis suggested that the underlying diagnoses of autosomal dominant polycystic kidney disease and diabetic nephropathy exhibited on average a 2.7 (0.3) and 0.7 (0.3) ml/min/year faster rate of decline in eGFR, respectively, compared to those patients with biopsy-proven glomerulonephritis. In the regression tree analysis, we attempted to identify threshold values for clinical parameters that maximally discriminate progression to RRT. eGFR <=24 ml/min was the first ranked discriminator, diastolic blood pressure appeared in the second and fourth rounds, eGFR appeared again in the third round together with cholesterol and systolic blood pressure, with basal metabolic index in the fourth. CONCLUSION: This analysis highlights risk factors for progressive kidney disease and demonstrates the variability in evolution of eGFR across the cohort as well as the importance of underlying renal disease type on the progression of CKD. PMID- 23813283 TI - Case-only method for cause-specific hazards models with application to assessing differential vaccine efficacy by viral and host genetics. AB - Cause-specific proportional hazards models are commonly used for analyzing competing risks data in clinical studies. Motivated by the objective to assess differential vaccine protection against distinct pathogen types in randomized preventive vaccine efficacy trials, we present an alternative case-only method to standard maximum partial likelihood estimation that applies to a rare failure event, e.g. acquisition of HIV infection. A logistic regression model is fit to the counts of cause-specific events (infecting pathogen type) within study arms, with an offset adjusting for the randomization ratio. This formulation of cause specific hazard ratio estimation permits immediate incorporation of host-genetic factors to be assessed as effect modifiers, an important area of vaccine research for identifying immune correlates of protection, thus inheriting the estimation efficiency, and cost benefits of the case-only estimator commonly used for assessing gene-treatment interactions. The method is used to reassess HIV genotype-specific vaccine efficacy in the RV144 trial, providing nearly identical results to standard Cox methods, and to assess if and how this vaccine efficacy depends on Fc-gamma receptor genes. PMID- 23813284 TI - Prostate biopsy after abdominoperineal resection: a diagnostic challenge. AB - Prostate biopsy in patients who underwent abdominoperineal resection (APR) of the rectum is commonly considered a technical challenge even for experienced urologists, although tissue diagnosis is essential in prostate cancer management. Transperitoneal, transperineal and transgluteal approaches have been reported, under US, CT or MRI guidance. Transperineal biopsy seems to be the safest and most cost-effective technique. At our institution we developed a modified transperineal biopsy approach with combined transperineal and suprapubic US guidance. Here we report the cases of two patients who came to our institution for PSA raise years after APR procedure, describing in detail the modified transperineal technique and the results of tissue sampling. PMID- 23813285 TI - Cheek metastasis from a bladder tumor: unusual presentation of an aggressive disease. AB - Transitional cell carcinoma (TCC) has been well described for its propensity to metastasize to distant sites. Metastases to the soft tissues of the oral cavity from a bladder cancer are extremely rare. We present the case of a 65-year-old man who presented with history of hematuria for 1 month and was found to have high-grade TCC of the bladder. He developed a cheek lesion after 3 weeks, which was diagnosed as metastatic nodule along with pulmonary metastases from high grade bladder TCC. The patient received chemotherapy followed by the radiotherapy of the cheek lesion, but he succumbed after 3 months due widespread metastatic disease. We also presented a review of the literature regarding this rare presentation. PMID- 23813286 TI - [Fournier's Gangrene: a fifteen-year survey. Three cases treated by aggressive surgical management]. AB - OBJECTIVES: To analyze our data with regard to the treatment of Fournier's Gangrene, a necrotizing subcutaneous infection of the male genitalia. This disease needs a pharmacological antibiotic and surgical treatment. Hyperbaric oxygen therapy is useful too. METHODS: Our case record of fifteen years consists of 23 male patients. RESULTS: The present article describes the last three cases that required an aggressive surgical management. CONCLUSIONS: We have observed a probable worsening of the prognosis of Fournier's Gangrene related to a possible increase of drug resistance. PMID- 23813287 TI - Innovations in the endoscopic management of bladder cancer: is the era of white light cystoscopy over. AB - Bladder cancer is the most common tumor of the urinary tract, with a worldwide incidence of 8.6 x 100000 in men and 2.6 x 100000 in women (1). The majority of patients (75-85%) present as non-muscle invasive bladder cancer (NMIBC); within this category the most represented stage is Ta (70%), followed by T1 (20%) and, less frequently, carcinoma in situ (CIS) (10%) (2). The diagnosis of NMIBC and, more generally, of bladder cancer, depends on urine cytology and endoscopic examination with histological evaluation of the resected tissue. Clearly, an optimal cystoscopy with accurate transurethral resection (TUR) is of great importance in order to improve the detection rate and to reduce the probability of recurrence and progression. Today the cystoscopy is routinely performed with the white light technique (WLC), the same of about 80 years ago (3). Several studies have demonstrated that an initial TUR with WLC can miss small papillary lesions and, particularly, flat lesions such as CIS. Moreover, recurrence rates of non-muscle invasive bladder cancer (NMIBC) are directly related to the possibility of achieving a complete resection: residual cancer is present in a large percentage of re-TUR, showing a not so good performance of resection with this method. For these reasons new methodologies have been investigated in order to improve the sensitivity and specificity of WLC, such as photodynamic diagnosis (PDD), narrow band imaging (NBI), optical coherence tomography (OCT) and CT virtual cystoscopy. Some of them have been well established and supported by consistent literature while others are still to be viewed as experimental. The purpose of this review is to investigate the state of the art of these new techniques. PMID- 23813288 TI - A prospective observational study of chronic prostatitis with emphasis on epidemiological and microbiological features. AB - OBJECTIVES: Despite the progress made in recent years in understanding and diagnosing chronic prostatitis (CP) many cases are still underdiagnosed and undertreated for unknown reasons. The purpose of this study is to investigate the epidemiological data of patients with symptoms of CP and to associate data from medical history and clinical examination with the results of laboratory tests. METHODS: The study population consisted of individuals with reported pelvic discomfort and genital pain with or without lower urinary tract symptoms and sexual dysfunction visiting our department from 03/2009 to 03/2011. Patients underwent Meares-Stamey test (a few cases underwent the two-glass test). Depending on history and specific symptoms, urethral smear and sperm cultures were additionally obtained from several patients. The processes and reading of the samples were performed by a specialist microbiologist, who has not notified the patient record. RESULTS: 114 out of 155 patients who finally enrolled into the study had a medical history, 69 had sexual behavior and 72 sexual habits that predispose to chronic prostatitis. The clinical examination was not diagnostic in 43.8% of cases. The urethral smear and sperm culture diagnosed coexistent urethral infection in 22 cases. 54 out of the 72 positive EPS/VB3/PPM cultures grew one, 11 two to three and 5 cultures grew more than three different organisms. CONCLUSIONS: Findings of this study debate some widely accepted considerations on the etiology and diagnosis of chronic prostatitis and highlight the uncertainties and controversies regarding chronic prostatitis etiology, pathophysiology, presentation and diagnosis. PMID- 23813289 TI - The Revised Cardiac Risk Index in the new millennium: a single-centre prospective cohort re-evaluation of the original variables in 9,519 consecutive elective surgical patients. AB - PURPOSE: Cardiac complications following non-cardiac surgery are major causes of morbidity and mortality. The Revised Cardiac Risk Index (RCRI) has become a standard for predicting post-surgical cardiac complications. This study re examined the original six risk factors to confirm their validity in a large modern prospective database. METHODS: Using the definitions in the original risk index, this study included 9,519 patients aged >= 50 undergoing elective non cardiac surgery with an expected length of stay >= two days at two major tertiary care teaching hospitals. The validity of the original predictors was tested in this population using binomial logistic regression modelling, area under the receiver operator curve (ROC) analysis, and the net reclassification index. RESULTS: Rates of major cardiac complications with 0, 1, 2, >= 3 of the predictors were 0.5%, 2.6%, 7.2%, and 14.4%, respectively, in our patient cohort compared with 0.4%, 1.1%, 4.6%, and 9.7%, respectively, in the original cohort. Similar to the original report, binary logistic regression analysis showed that both preoperative treatment with insulin (odds ratio [OR] 1.4; 95% confidence interval [CI] 0.7 to 2.6) and preoperative creatinine > 176.8 mmol.L(-1) (OR 1.7; 95% CI 0.8 to 3.6) did not improve the predictive ability of the index. Analysis of the remaining four factors resulted in an area under the curve (AUC) identical to that seen for the reconstructed six-factor RCRI (AUC = 0.79). We found that a glomerular filtration rate (GFR) < 30 mL.min(-1) was a better predictor of major cardiac complications (OR 2.2; 95% CI 1.2 to 4.3) than creatinine > 176.8 mmol.L( 1). The receiver operating characteristic analysis of this resultant 5-Factor model resulted in an AUC of 0.79, with 0, 1, 2, >= 3 of the predictors representing 0.5%, 2.9%, 7.4%, and 17.0% risk, respectively, among our patient cohort. CONCLUSION: Compared with the RCRI, a simplified 5-Factor model using a high-risk type of surgery, a history of ischemic heart disease, congestive heart failure, cerebrovascular disease, and a preoperative GFR < 30 mL.min(-1) results in superior prediction of major cardiac complications following elective non cardiac surgery. PMID- 23813290 TI - Butorphanol prevents morphine-induced pruritus without increasing pain and other side effects: a systematic review of randomized controlled trials. AB - PURPOSE: Pruritus is a frequent adverse event after administration of morphine. Butorphanol has been used to prevent morphine-induced pruritus, but its efficacy is still controversial. The aim of this systematic review was to evaluate the efficacy of using butorphanol to prevent morphine-induced pruritus. SOURCE: We searched PubMed, Cochrane Library, EMBASE, and China's BioMedical Disc for full reports of randomized controlled trials that compared the use of butorphanol with either placebo or no treatment for preventing morphine-induced pruritus. The number of patients experiencing pruritus or other side effects was analyzed using relative risk (RR) with 95% confidence intervals (CI). PRINCIPAL FINDINGS: Sixteen trials (795 patients) were analyzed. Continuous intravenous and epidural butorphanol reduced pruritus with RR 0.22 (95% CI 0.10 to 0.45) and RR 0.24 (95% CI 0.16 to 0.36), respectively. Use of epidural butorphanol decreased the number of patients requesting rescue treatment for pruritus (RR 0.57; 95% CI 0.41 to 0.81). Butorphanol decreased postoperative pain intensity at four, eight, and 12 hr with standardized mean differences of -0.29 (95% CI -0.52 to -0.05), -0.30 (95% CI -0.56 to -0.04), and -0.23 (95% CI -0.46 to -0.01), respectively. Epidural but not intravenous butorphanol reduced postoperative nausea and vomiting (PONV) (RR 0.35; 95% CI 0.19 to 0.66). Butorphanol did not increase respiratory depression (RR 0.71; 95% CI 0.31 to 1.63), somnolence (RR 0.71; 95% CI 0.22 to 2.37), or dizziness (RR 2.45; 95% CI 0.35 to 17.14). CONCLUSION: Butorphanol administered with morphine may be an effective strategy for preventing morphine-induced pruritus as it decreases pain intensity and PONV without increasing other side effects. Thus, it can be recommended for preventing morphine-induced pruritus during the perioperative period. PMID- 23813291 TI - The role of pre-treatment white matter abnormalities in developing white matter changes following whole brain radiation: a volumetric study. AB - White matter injury is a known complication of whole brain radiation (WBRT). Little is known about the factors that predispose a patient to such injury. The current study used MR volumetrics to examine risk factors, in particular the influence of pre-treatment white matter health, in developing white matter change (WMC) following WBRT. Thirty-four patients with unilateral metastatic disease underwent FLAIR MRI pre-treatment and at several time points following treatment. The volume of abnormal FLAIR signal in the white matter was measured in the hemisphere contralateral to the diseased hemisphere at each time point. Analyses were restricted to the uninvolved hemisphere to allow for the measurement of WBRT effects without the potential confounding effects of the disease on imaging findings. The relationship between select pre-treatment clinical variables and the degree of WMC following treatment was examined using correlational and regression based analyses. Age when treated and volume of abnormal FLAIR prior to treatment were significantly associated with WMC following WBRT; however, pre treatment FLAIR volume was the strongest predictor of post-treatment WMCs. Age did not add any predictive value once white matter status was considered. No significant relationships were found between biological equivalent dose and select cerebrovascular risk factors (total glucose, blood pressure, BMI) and development of WMCs. The findings from this study identify pre-treatment white matter health as an important risk factor in developing WMC following WBRT. This information can be used to make more informed decisions and counsel patients on their risk for treatment effects. PMID- 23813292 TI - The fate of spinal schwannomas following subtotal resection: a retrospective multicenter study by the Korea spinal oncology research group. AB - The fate of residual spinal schwannomas needs to be estimated in order to plan further management after subtotal removal. Our aim was to evaluate the growth rate of residual spinal schwannomas and compare results in regrowth and no regrowth groups by using data collected from the Korea Spinal Oncology Research Group database. From January 1989 to August 2011, 27 patients with residual spinal schwannomas were selected. Patients with at least two follow-up magnetic resonance image (MRI) studies after subtotal resection were included. The mean period of MRI follow-up was 62.4 months. A tumor size increase of over 2 mm in the maximal diameter was considered indicative of regrowth. Age, sex, size at initial diagnosis, postoperative tumor size, and Ki-67 labeling index were compared between regrowth and no regrowth groups. Eight residual schwannomas regrew (29.6 %), and 19 (70.4 %) did not regrow. Average growth rate of the regrowing tumors was 1.0 +/- 4.4 mm/year. The mean percentage increase in tumor size during follow-up was 10.0 +/- 28.8 %. The Ki-67 labeling indices were significantly different between regrowth and no regrowth groups (P = 0.014). Two patients underwent a revision operation for significant tumor regrowth. Nineteen cases (70.4 %) among 27 residual spinal schwannomas did not regrow significantly, but further surgical treatments were necessary in 2 patients due to significant regrowth. The Ki-67 labeling index was higher in the regrowth group. Earlier follow-up MRI is recommended for patients whose tumors have higher Ki-67. PMID- 23813293 TI - Stimulation of human peripheral blood mononuclear cells by the sialic acid precursor N-propanoylmannosamine. AB - N-Propanoylmannosamine is an unnatural precursor of sialic acid, which is taken up by a variety of animal cells and metabolized to N-propanoylneuraminic acid. In several studies it has been demonstrated that application of unnatural precursors of sialic acids such as N-propanoylmannosamine (ManNProp) and homologues interfere with cell differentiation and proliferation of neuronal cells or embryonic stem cells. Since the function of the immune system is known to rely on the presence of sialic acid, we applied ManNProp to human peripheral blood mononuclear cells (PBMC). When culturing those lymphocytes with ManNProp 10 % of the natural sialic acid N-acetylneuraminic acid could be replaced by the newly formed N-propanoylneuraminic acid. This procedure resulted (a) in a marked stimulation in the rate of proliferation of PBMC, (b) a 10-fold increase of IL-2 production coupled with an up-regulation of its receptor CD25 on the cell surface and (c) a concomitant expression and regulation of the transferrin receptor with cell growth. The stimulation of PBMC by ManNProp might therefore introduce a new approach of immunomodulation. PMID- 23813294 TI - Comment on Minamimoto: incidental focal FDG uptake in heart is a lighthouse for considering cardiac screening. PMID- 23813295 TI - Combining medical treatment and CBT in treating alcohol-dependent patients: effects on life quality and general well-being. AB - AIMS: The aim of the study was to examine how the combination of medication and a brief cognitive behavioral intervention for alcohol dependency can affect patients' quality of life (QL), symptoms of depression and smoking habits. METHODS: We conducted a randomized, open-label, multicenter naturalistic study for 243 voluntary-treatment-seeking alcohol-dependent adult outpatients in two phases: first, 12 weeks with continuous medication followed by targeted medication for up to 52 weeks, and second, a follow-up period of 67 weeks (altogether 2.5 years). The subjects were randomized 1:1:1 to receive supervised naltrexone, acamprosate or disulfiram, plus a brief manual-based cognitive behavioral intervention (CBT). RESULTS: All three study groups showed a significant reduction in drinking from baseline to the end of the study. In the QL test EQ-5D, patients exhibited significant positive changes in sleeping, action, pain and mood dimensions. Severity of depression decreased during the whole study. Smoking decreased more in the disulfiram group than in the naltrexone and acamprosate groups. CONCLUSION: A combination of medical treatment (naltrexone, acamprosate or disulfiram) with the CBT-booklet (patient guide) appears to help reduce patients' symptoms of depression and improve their QL. Treatment is also associated with success at quitting smoking, especially among patients using disulfiram. PMID- 23813296 TI - Quantification of ethyl glucuronide in hair: effect of milling on extraction efficiency. AB - AIM: The objective of the study was to provide conclusive evidence for the effect of particle size reduction as by milling on the extractable content of ethyl glucuronide (EtG) of hair samples. METHODS: A number of real case hair samples and two pooled hair materials with EtG contents in the range of 10-30 pg/mg were systematically compared with regard to the extraction yield of EtG after cutting to 2-3 mm length and pulverization with a ball mill. After the respective treatment the samples were submitted to aqueous extraction followed by quantification of EtG using HPLC-MS/MS. RESULTS: It was unequivocally demonstrated that milling of hair samples prior to aqueous extraction significantly increases the extractable EtG content compared with cut hair. The effect ranged between 137 and 230% and was seen to occur regardless of the extent of pulverization. Cooling of samples was not necessary to prevent partial degradation of EtG during the grinding procedure. CONCLUSION: The options currently employed at choice in analytical practice (cutting or milling) were seen to significantly affect the extractable amount of EtG in hair. This is suspected to influence the degree of equivalence of quantification results obtained in different laboratories as well as their respective classification of a test subject's drinking behaviour on the basis of currently recommended cut-off values. PMID- 23813297 TI - In response to Accuracy of fine-needle aspiration and imaging in the preoperative workup of salivary gland mass lesions treated surgically. PMID- 23813298 TI - Large normal and intermediate alleles in the context of SCA2 prenatal diagnosis. AB - In 2001 a program for predictive testing of Spinocerebellar Ataxia type 2 was developed in Cuba, based on the detection of an abnormal CAG trinucleotide repeat expansion in the ATXN2 gene. A descriptive study was designed to assess the implications of ATXN2 large normal and intermediate alleles in the context of the SCA2 Prenatal Diagnosis Program. Four clinical scenarios were selected based upon the behaviour of large normal and intermediate alleles when passing from one generation to the next, showing expansions, contractions, or stability in the CAG repeat size. In some populations, traditional Mendelian risk figures of 0 % or 50 % may not be applicable due to the high frequency of unstable large normal alleles. Couples with no family history of SCA2 may have a >0 % risk of having an affected offspring. Similarly, couples in which there is both an expanded and a large normal allele may have a recurrence risk >50 %. It is imperative that these issues be addressed with these couples during genetic counseling. These recurrence risks have to be carefully estimated in the presence of such alleles (particularly alleles >=27 CAG repeats), carriers need to be aware of the potential risk for their descendants, and programs for prenatal diagnosis must be available for them. PMID- 23813299 TI - Peering into a Chilean black box: parental storytelling in pediatric genetic counseling. AB - While genetic counseling has expanded to multiple international settings, research about providing culturally sensitive services to non-U.S. patients is limited. To gain insights, we utilized a process study to explore parental communication in pediatric genetics clinics in Chile. We utilized a phenomenological hermeneutic approach to assess storytelling in six pediatric sessions that were conducted in Spanish, and translated into English. The majority of the sessions focused on information gathering (35 %), and providing medical (20 %) and genetics education (18 %). The 14 instances of storytelling we identified usually emerged during information gathering, genetics education, and the closing of the session. Stories illustrated parental efforts to create a cognitive and emotional context for their child's genetic diagnosis. Parents emerged as competent caregivers who discussed the role of the child as a social being in the family and the larger community. Our analysis found that genetic counseling sessions in the U.S. and Chile are structured similarly and although communication is not a balanced process, parents use storytelling to participate as active agents in the session. Via storytelling, we learned that parents are working to understand and gain control over their child's genetic diagnosis by relying on mechanisms that extend beyond the genetics appointment. PMID- 23813300 TI - Young adults' pre-existing knowledge of cystic fibrosis and sickle cell diseases: implications for newborn screening. AB - Parental distress following newborn screening is thought to result from inadequate preparation for screening results which can result in maladjustment to screening results after birth. Although prior awareness of relevant genetic disorders such as cystic fibrosis and sickle cell diseases, and preparedness for screening is suggested to enhance information uptake and reduce parental distress, little is known about how young adults' prior knowledge prepares them for screening or affects the assimilation and retention of screening information. Thirty-four young adults, without familial genetic disease or screening experience took part in one of seven focus groups which examined knowledge of cystic fibrosis and sickle cell diseases and ability to assimilate new disease information. Thematic analysis revealed that adults had limited understanding of how cystic fibrosis and sickle cell diseases were inherited or how symptoms manifest, leaving them inadequately prepared for screening results if they do not engage with information interventions. Further, they selectively assimilated new disease information and had difficulty understanding new information in the absence of prior disease knowledge. Young adults' prior disease knowledge should be considered within a newborn screening context and written materials should consider the inclusion of carrier statistics to improve information relevance. PMID- 23813301 TI - Highly efficient factorial designs for cDNA microarray experiments: use of approximate theory together with a step-up step-down procedure. AB - A general method for obtaining highly efficient factorial designs of relatively small sizes is developed for cDNA microarray experiments. It allows the main effects and interactions to be of possibly unequal importance. First, the approximate theory is employed to get an optimal design measure which is then discretized. It is, however, observed that a naive discretization may fail to yield an exact design of the stipulated size and, even when it yields such an exact design, there is often scope for improvement in efficiency. To address these issues, we propose a step-up/down procedure which is seen to work very well. The resulting designs turn out to be quite robust to possible dye-color effects and heteroscedasticity. We focus on the baseline and all-to-next parametrizations but our method works equally well also for hybrids of the two and other parametrizations. PMID- 23813302 TI - First clinical experience with TRV027: pharmacokinetics and pharmacodynamics in healthy volunteers. AB - TRV027 is a novel beta-arrestin biased peptide ligand of the angiotensin II type 1 receptor (AT1R). The compound antagonizes G protein coupling while simultaneously stimulating beta-arrestin-mediated signaling. In preclinical studies, TRV027 reversibly reduced blood pressure while preserving renal function in a dog tachypaced heart failure model and stimulating cardiomyocyte contractility in vitro. This profile suggests that TRV027 may have unique benefits in acute heart failure, a condition associated with renin-angiotensin system activation. A first-time-in-human study was conducted with ascending doses of TRV027 to explore its tolerability, pharmacokinetics and pharmacodynamics in healthy volunteers. Subjects' salt intake was restricted to stimulate RAS activation. In this study TRV027 was safe and well tolerated with a short-half life (ranging between 2.4 and 13.2 minutes) and dose-proportional increases in systemic exposure. Consistent with the pre-clinical findings, TRV027 reduced blood pressure to a greater degree in subjects with RAS activation, measured as elevated plasma renin activity, than in those with normal PRA levels. This study in sodium-restricted healthy subjects suggests that TRV027 will successfully target a core mechanism of acute heart failure pathophysiology. Further clinical studies with TRV027 in patients with heart failure are underway. PMID- 23813304 TI - Cording following treatment for breast cancer. AB - Treatment for breast cancer may result in the formation of palpable cords in the axillary region. Our aim was to evaluate cording incidence, risk factors, and association with upper extremity functional impairment and measured arm volume change. We included 308 patients with unilateral breast cancer prospectively screened for upper extremity lymphedema, symptoms and function. Patients were assessed pre- and post-operatively and at 3-8-month intervals with perometer arm measurements and the LEFT-BC questionnaire. Cording was determined by patient self-report. The cumulative incidence of cording and its association with clinicopathologic factors, upper extremity functional impairment, and measured arm volume change were analyzed. 31.5 % (97/308) of patients reported cording, with a cumulative incidence of 36.2 % at 24 months post-operative. Clinicopathologic factors significantly associated with cording by multivariate analysis included axillary lymph node dissection (p < 0.0001) and younger age at diagnosis (p = 0.0005). Cording was associated with increased functional impairment (p = 0.0018) and an arm volume increase of >=5 % (p = 0.028). Cording following breast cancer treatment is common, and may occur beyond the post operative period. Our findings emphasize the importance of identifying patients at high risk for cording, and developing strategies to minimize functional impairment and arm volume elevation associated with cording. Future studies should investigate the effectiveness of interventions for cording following breast cancer treatment. PMID- 23813303 TI - Clinical-pathologic significance of cancer stem cell marker expression in familial breast cancers. AB - Human breast cancer cells with a CD44(+)/CD24(-/low) or ALDH1+ phenotype have been demonstrated to be enriched for cancer stem cells (CSCs) using in vitro and in vivo techniques. The aim of this study was to determine the association between CD44(+)/CD24(-/low) and ALDH1 expression with clinical-pathologic tumor characteristics, tumor molecular subtype, and survival in a well characterized collection of familial breast cancer cases. 364 familial breast cancers from the Ontario Familial Breast Cancer Registry (58 BRCA1-associated, 64 BRCA2 associated, and 242 familial non-BRCA1/2 cancers) were studied. Each tumor had a centralized pathology review performed. TMA sections of all tumors were analyzed for the expression of ER, PR, HER2, CK5, CK14, EGFR, CD44, CD24, and ALDH1. The Chi square test or Fisher's exact test was used to analyze the marker associations with clinical-pathologic tumor variables, molecular subtype and genetic subtype. Analyses of the association of overall survival (OS) with marker status were conducted using Kaplan-Meier plots and log-rank tests. The CD44(+)/CD24(-/low) and ALDH1+ phenotypes were identified in 16% and 15% of the familial breast cancer cases, respectively, and associated with high-tumor grade, a high-mitotic count, and component features of the medullary type of breast cancer. CD44(+)/CD24(-/low) and ALDH1 expression in this series were further associated with the basal-like molecular subtype and the CD44(+)/CD24(-/low) phenotype was independently associated with BRCA1 mutational status. The currently accepted breast CSCs markers are present in a minority of familial breast cancers. Whereas the presence of these markers is correlated with several poor prognostic features and the basal-like subtype of breast cancer, they do not predict OS. PMID- 23813305 TI - Pesticide tolerant Azotobacter isolates from paddy growing areas of northern Karnataka, India. AB - A total of 14 Azotobacter strains were isolated from different paddy cultivating soils with pH ranging from 6.5 to 9.5 by using serial dilution agar plate method. The strains were Gram negative, rod shaped, cyst forming and developed brown to black colored colonies, which were glistening, smooth, slimy on Ashby's agar plates. Biochemically they were positive for biochemical tests namely, indole production, citrate, catalase, carbohydrate fermentation and Voges-Proskauer test. Further, sequence analysis of PCR amplicons obtained from these cultures revealed the presence of five different Azotobacter species viz., Azotobacter vinelandii, Azotobacter salinestris, Azotobacter sp., Azotobacter nigricans subsp. nigricans and Azotobacter tropicalis. Phylogenetically these strains were grouped into two distinct clusters. These strains were tested for their ability to grow on a media containing four different pesticides such as pendimethalin, glyphosate, chloropyrifos and phorate, which are commonly used for the paddy. Out of 14 strains tested, 13 strains were able to grow on a media containing herbicides such as pendimethalin, glyphosate and insecticides like chloropyrifos and phorate. However, five Azotobacter strains were able to grow at higher concentration of 5% pesticides, without affecting their growth rate. Further, the effect of pesticides on the indole acetic acid (IAA) production by Azotobacter strains was also estimated. Azotobacter-16 strain was found to produce 34.4 MUg ml(-l) of IAA in a media supplemented with 1,000 mg of tryptophan and 5% of pendimethalin. Present study reveals that species of Azotobacter are able to grow and survive in the presence of pesticides and no significant effects were observed on the metabolic activities of Azotobacter species. PMID- 23813306 TI - Supplemental oxygen for caesarean section during regional anaesthesia. AB - BACKGROUND: Supplementary oxygen is routinely administered to low-risk pregnant women during an elective caesarean section under regional anaesthesia; however, maternal and foetal outcomes have not been well established. OBJECTIVES: The primary objective was to determine whether supplementary oxygen given to low-risk term pregnant women undergoing elective caesarean section under regional anaesthesia can prevent maternal and neonatal desaturation. The secondary objective was to compare the mean values of maternal and neonatal blood gas levels between mothers who received supplementary oxygen and those who did not (control group). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 2, 2012), MEDLINE (1948 to February 2012) and EMBASE (1980 to February 2012). We did not apply language restrictions. SELECTION CRITERIA: We included randomized controlled trials of low risk pregnant women undergoing an elective caesarean section under regional anaesthesia and compared outcomes with, and without, oxygen supplementation. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data, assessed methodological quality and performed subgroup and sensitivity analyses. MAIN RESULTS: We included 10 trials with a total of 683 participants. Supplementary oxygen administration varied widely in dose and duration between trials. No cases of maternal desaturation were reported, although none of the 10 trials focused on maternal desaturation. Significant differences were noted in maternal oxygen saturation (higher with oxygen, N = three trials; mean difference (MD) 1.6%, 95% confidence interval (CI) 0.8 to 2.3, P < 0.0001), maternal PaO2 (oxygen pressure in the blood; higher with oxygen, N = six trials; MD 141.8 mm Hg, 95% CI 109.3 to 174.3, P < 0.00001), neonatal UaPO2 (foetal umbilical arterial blood; higher with oxygen, N = eight trials; MD 3.3 mm Hg, 95% CI 1.8 to 4.9, P < 0.0001) and UvPO2 (foetal umbilical venous blood; higher with oxygen, N = 10 trials; MD 5.9 mm Hg, 95% CI 3.2 to 8.5, P < 0.0001). No significant differences were reported in neonatal UapH (N = eight trials; MD 0.00, 95% CI 0.01 to 0.00, P = 0.26) and in average Apgar scores at one minute (N = five trials; MD 0.07, 95% CI -0.20 to 0.34, P = 0.6) and at five minutes (N = five trials; MD 0.00, 95% CI -0.06 to 0.05, P = 0.91).Only two out of 10 trials had a low risk of bias in all categories. When we separated the studies into low risk and high risk for bias, we found substantial statistical heterogeneity. None of the low-risk studies showed a significant difference in neonatal UaPO2 between the two intervention groups, whereas the high-risk studies showed a benefit for the neonatal oxygen group.The level of oxygen free radicals (malondialdehyde (MDA) and 8-isoprostane) was higher in participants who received supplementary oxygen (N = two trials; MD 0.2 umol/L, 95% CI 0.1 to 0.4, P = 0.0002; MD 64.3 pg/mL, 95% CI 51.7 to 76.8, P < 0.00001, respectively). AUTHORS' CONCLUSIONS: Current evidence suggests that supplementary oxygen given to healthy term pregnant women during elective caesarean section under regional anaesthesia is associated with higher maternal and neonatal oxygen levels (maternal SpO2, PaO2, UaPO2 and UvPO2) and higher levels of oxygen free radicals. However, the intervention was neither beneficial nor harmful to the neonate's short-term clinical outcome as assessed by Apgar scores. PMID- 23813307 TI - Wake-up call by breathomics in sleep apnoea. PMID- 23813308 TI - Tuberculosis: are we making it incurable? PMID- 23813309 TI - Getting risks right on inhaled corticosteroids and adrenal insufficiency. PMID- 23813310 TI - Ventilator-induced diaphragm dysfunction: time for (contr)action! PMID- 23813311 TI - Can phrenic stimulation protect the diaphragm from mechanical ventilation-induced damage? PMID- 23813312 TI - Quality of life after lung resection is not associated with functional objective measures. PMID- 23813313 TI - Inhalational anthrax in a vaccinated soldier. PMID- 23813314 TI - Linezolid to treat extensively drug-resistant TB: retrospective data are confirmed by experimental evidence. PMID- 23813315 TI - In vitro susceptibility testing and totally drug-resistant tuberculosis. PMID- 23813316 TI - In vitro susceptibility testing and totally drug-resistant tuberculosis. PMID- 23813317 TI - Recovery of left ventricular function and sleep apnoea after acute myocardial infarction. PMID- 23813319 TI - A nutrigenomic framework to identify time-resolving responses of hepatic genes in diet-induced obese mice. AB - Obesity and its related complications have emerged as global health problems; however, the pathophysiological mechanism of obesity is still not fully understood. In this study, C57BL/6J mice were fed a normal (ND) or high-fat diet (HFD) for 0, 2, 4, 6, 8, 12, 20, and 24 weeks and the time course was systemically analyzed specifically for the hepatic transcriptome profile. Genes that were differentially expressed in the HFD-fed mice were clustered into 49 clusters and further classified into 8 different expression patterns: long-term up-regulated (pattern 1), long-term downregulated (pattern 2), early up-regulated (pattern 3), early down-regulated (pattern 4), late up-regulated (pattern 5), late down-regulated (pattern 6), early up-regulated and late down-regulated (pattern 7), and early down-regulated and late up-regulated (pattern 8) HFD responsive genes. Within each pattern, genes related with inflammation, insulin resistance, and lipid metabolism were extracted, and then, a protein-protein interaction network was generated. The pattern specific sub-network was as follows: pattern 1, cellular assembly and organization, and immunological disease, pattern 2, lipid metabolism, pattern 3, gene expression and inflammatory response, pattern 4, cell signaling, pattern 5, lipid metabolism, molecular transport, and small molecule biochemistry, pattern 6, protein synthesis and cell to cell signaling and interaction and pattern 7, cell-to cell signaling, cellular growth and proliferation, and cell death. For pattern 8, no significant sub networks were identified. Taken together, this suggests that genes involved in regulating gene expression and inflammatory response are up-regulated whereas genes involved in lipid metabolism and protein synthesis are down-regulated during diet-induced obesity development. PMID- 23813320 TI - Behavioral mediators of treatment effects in the weight loss maintenance trial. AB - BACKGROUND: The Weight Loss Maintenance Trial tested strategies for maintenance of weight loss. Personal contact was superior to interactive technology and self directed conditions. PURPOSE: We aimed to identify behavioral mediators of the superior effect of personal contact vs. interactive technology and of personal contact vs. self-directed arms. METHODS: Overweight/obese adults at risk for cardiovascular disease (n = 1,032) who lost at least 4 kg were randomized to personal contact, interactive technology, or self-directed. After 30 months, 880 participants had data on weight and behavioral strategies. RESULTS: Reported increase of intake of fruits and vegetables and physical activity and more frequent self-weighing met criteria as mediators of the better outcome of personal contact vs. interactive technology. Increased intake of fruits and vegetables, more frequent self-weighing, and decreased dessert consumption were mediators of the difference between personal contact vs. self-directed. CONCLUSION: Inducing changes in the identified behaviors might yield better outcomes in future weight loss maintenance trials. PMID- 23813321 TI - Practice policy and quality initiatives: using lean principles to improve screening mammography workflow. AB - The "lean" approach is a quality improvement method that focuses on maximizing activities that are valued by the customer and eliminating waste that impedes efficiency in the workplace. The unique philosophy of the lean approach encourages all members of the team to be directly involved in identifying areas of waste and generating solutions to eliminate them. When the breast imaging section at the authors' institution became part of a multispecialty breast care center, the result was escalating examination volumes, more complex cases, and overall increased demand on radiologists' time. After several unsuccessful attempts to improve the efficiency of the section, including evaluation by outside consultants, the decision was made to embark on a comprehensive quality improvement program using the lean approach. A team of radiologists, technologists, file room personnel, information technology (IT) representatives, and administrators from the breast imaging section met twice a month to learn about lean principles and how to apply them to screening mammography workflows. Sources of inefficiency (waste) were identified, and potential solutions were generated. Multiple trials were performed to test these solutions. Throughout the process, all team members were engaged in identifying the problems, suggesting solutions, and implementing change. Most of the tested solutions were successful and resulted in decreased patient wait times, improved efficiency for the technologists and radiologists, faster report turnaround, and advances in IT. In addition, staff members were introduced to the lean philosophy and became actively involved in improving their workplace, resulting in a more cohesive section. PMID- 23813322 TI - A randomized-controlled, pilot intervention on diabetes prevention and healthy lifestyles in the New York City Korean community. AB - Asian Americans experience diabetes at a higher rate than non-Hispanic whites. Diabetes prevention programs using lifestyle interventions have been shown to produce beneficial results, yet there have been no culturally-tailored programs for diabetes prevention in the Korean community. We explore the impact and feasibility of a pilot Community Health Worker (CHW) intervention to improve health behaviors and promote diabetes prevention among Korean Americans using a randomized controlled trial. Between 2011 and 2012, a total of 48 Korean Americans at risk for diabetes living in New York City (NYC) participated in the intervention. Participants were allocated to treatment or control groups. A community-based participatory research approach guided development of the intervention, which consisted of 6 workshops held by CHWs on diabetes prevention, nutrition, physical activity, diabetes complications, stress and family support, and access to health care. Changes over 6 months were examined for clinical measurements (weight, BMI, waist circumference, blood pressure, glucose, and cholesterol); health behaviors (physical activity, nutrition, food behaviors, diabetes knowledge, self-efficacy, and mental health); and health access (insurance and self-reported health). In this small pilot study, changes were seen in weight, waist circumference, diastolic blood pressure, physical activity nutrition, diabetes knowledge, and mental health. Qualitative findings provide additional contextual information that inform ways in which CHWs may influence health outcomes. These findings demonstrate that a diabetes prevention program can be successful among a Korean American population in NYC, and important insight is provided for ways that programs can be tailored to meet the needs of vulnerable populations. PMID- 23813323 TI - Knowledge and beliefs regarding human papillomavirus among college nursing students at a minority-serving institution. AB - Cervical cancer is a leading cause of death in US women, with Hispanic women at higher risk of mortality than non-Hispanic white women. While the human papillomavirus (HPV) vaccine represents substantial progress towards cervical cancer prevention, little is currently known about Hispanic student's beliefs regarding the HPV vaccine. To assess the knowledge, attitudes, behaviors, and beliefs of college students in the US-Mexico border region following the release of the HPV vaccine for both males and females. This survey was conducted using a convenience sample were participants were recruited from pre-nursing and nursing courses. The self-administered questionnaire ascertained HPV vaccination status, and knowledge and beliefs regarding the HPV vaccine. 202 male and female students responded. 28.9% of respondents reported having received the HPV vaccine. Of the non-vaccinated students under age 27, 27.3% Hispanic students reported an intention to receive the vaccine. Misinformation about HPV was common and was associated with intention to get vaccinated among non-Hispanic white students. We found a relatively small proportion of unvaccinated Hispanic and non-Hispanic nursing students intend to be vaccinated for HPV. Findings indicate an intervention to increase vaccination rates among college-aged students may not be as straightforward as increasing knowledge of HPV. Nurses are in a unique position to educate and recommend HPV to underserved patients. Thus, educating nursing students regarding HPV and the associated cancers is paramount if we are to encourage ethnic minorities to receive the HPV vaccine. PMID- 23813325 TI - Assessment of damages for wrongful birth and consolidation in advance care directives. PMID- 23813324 TI - Coercion, incarceration, and chemical castration: an argument from autonomy. AB - In several jurisdictions, sex offenders may be offered chemical castration as an alternative to further incarceration. In some, agreement to chemical castration may be made a formal condition of parole or release. In others, refusal to undergo chemical castration can increase the likelihood of further incarceration though no formal link is made between the two. Offering chemical castration as an alternative to further incarceration is often said to be partially coercive, thus rendering the offender's consent invalid. The dominant response to this objection has been to argue that any coercion present in such cases is compatible with valid consent. In this article, we take a different tack, arguing that, even if consent would not be valid, offering chemical castration will often be supported by the very considerations that underpin concerns about consent: considerations of autonomy. This is because offering chemical castration will often increase the offender's autonomy, both at the time the offer is made and in the future. PMID- 23813326 TI - Ghrelin inhibits high glucose-induced PC12 cell apoptosis by regulating TLR4/NF kappaB pathway. AB - Ghrelin has a protective effect on diabetic encephalopathy. To expound the protective mechanism, we investigated the effects of ghrelin on high glucose induced cell apoptosis and intracellular signaling in cultured PC12, which is a suitable model for studying neuronal cell death. High glucose-induced PC12 apoptosis was significantly inhibited by co-treatment of ghrelin. Sustaining inflammatory response is one of the molecular mechanisms of diabetic encephalopathy and TLR4 signaling has close relationship with inflammatory response. But there is no report about the biologic role of toll-like receptor 4/nuclear factor-kappaB (TLR4/NF-kappaB) signaling in controlling high glucose induced PC12 apoptosis by ghrelin. In this study, we found that TLR4/NF-kappaB pathway was activated by high glucose stimulation in PC12 and significantly alleviated by the co-treatment of ghrelin. From these findings, we made the conclusion that ghrelin could attenuate the symptoms of diabetic encephalopathy, which alleviates inflammatory reaction of diabetic encephalopathy by regulating TLR4/NF-kappaB pathway. PMID- 23813327 TI - 1,25(OH)2D3-mediated amelioration of aortic injury in streptozotocin-induced diabetic rats. AB - In this study, a single tail vein injection of streptozotocin (STZ)-induced rat model was employed to study the effects of 1,25(OH)2D3 supplementation, the active form of vitamin D, on diabetes-induced aortic injury. Aortas from different groups were assessed for histopathology, toll-like receptor 4 (TLR4), myeloid differentiation primary response gene 88 (MyD88), and nuclear factor kappa B (NF-kappaB) p65 expression by hematoxylin and eosin staining, immunohistochemistry staining, reverse transcription polymerase chain reaction, and Western blot analysis. High-dose 1,25(OH)2D3 (0.3 MUg/kg/day) significantly prevented diabetes-induced aortic pathological changes and collagen deposition and decreased the expression of TLR4, MyD88, and NF-kappaB at both mRNA and protein levels in the aorta of STZ-induced diabetic rats (P < 0.01). In vitro studies in A7r5 cells (a rat embryonic thoracic aortic smooth muscle cell line) showed that high-dose glucose (25 mmol/L) enhanced TLR4 expression at both mRNA and protein levels by fourfold and twofold, respectively, at 24 h, which were significantly diminished by 1,25(OH)2D3 (1 * 10(-7) mol/L) by 50 and 36 %, respectively. Similar effects of high-dose 1,25(OH)2D3 on the expression of MyD88 were observed. Our results indicate that vitamin D has protective effects on diabetes-induced aortic injury and attenuates the expressions of TLR4, MyD88, and NF-kappaB in diabetic rats. PMID- 23813328 TI - CD4+CD25+Foxp3+ regulatory T cells contribute in liver fibrosis improvement with interferon alpha. AB - The aim of this study is to investigate the optimal dose, treatment time, and possible immunologic mechanisms of interferon alpha (IFN-alpha) in the treatment of liver fibrosis. Mice were injected intraperitoneally with 10 % carbon tetrachloride to induce liver fibrosis, except in the normal control group. The experimental mice were randomly divided into four groups: physiological saline group, 20 U/gb wt IFN-alpha group, 40 U/gb wt IFN-alpha group, and 60 U/gb wt IFN alpha group. After 3 and 6 weeks, type I collagen was detected in liver by hematoxylin and eosin (HE) stain, Masson's trichrome stain, and immunohistochemical staining. The number of CD8(+) T cells, the number of CD4(+)CD25(+)Foxp3(+) Tregs and the activation of CD4(+) T cells were detected in liver and spleen. Beneficial effects were observed in the 40 U/gb wt IFN-alpha group by pathological analysis. The number of CD8(+) T cells in the liver was significantly lower in mice receiving middle-dose IFN-alpha therapy as compared to mice receiving physiological saline (P < 0.05), while CD4(+)CD25(+)Foxp3(+) Tregs and activation of CD4(+) T cells in the liver were significantly higher in the therapeutic group than in the physiological saline group (P < 0.05). CD8(+) T cells (r = 0.3796) and activated CD4(+) T cells (r = 0.2437) were found to be positively correlated with the degree of liver fibrosis. CD4(+)CD25(+)Foxp3(+) Tregs (r = -0.7932) was found to be negatively correlated with the degree of liver fibrosis. IFN-alpha can inhibit liver fibrosis following 6 weeks of middle dose IFN-alpha therapy by upregulating CD4(+)CD25(+)Foxp3(+) Tregs and suppressing CD8(+) T cells. PMID- 23813329 TI - Interaction of aromatic amines with iron oxides: implications for prebiotic chemistry. AB - The interaction of aromatic amines (aniline, p-chloroaniline, p-toludine and p anisidine) with iron oxides (goethite, akaganeite and hematite) has been studied. Maximum uptake of amines was observed around pH 7. The adsorption data obtained at neutral pH were found to follow Langmuir adsorption. Anisidine was found to be a better adsorbate probably due to its higher basicity. In alkaline medium (pH > 8), amines reacted on goethite and akaganeite to give colored products. Analysis of the products by GC-MS showed benzoquinone and azobenzene as the reaction products of aniline while p-anisidine afforded a dimer. IR analysis of the amine iron oxide hydroxide adduct suggests that the surface acidity of iron oxide hydroxides is responsible for the interaction. The present study suggests that iron oxide hydroxides might have played a role in the stabilization of organic molecules through their surface activity and in prebiotic condensation reactions. PMID- 23813330 TI - Contribution of renal and non-renal clearance on increased total clearance of adalimumab in glomerular disease. AB - The contribution of renal and non-renal clearance toward targeted concentrations and/or effects of therapeutic proteins in nephrotic patients are unknown. This study dissected the contribution of clearance pathways to adalimumab elimination in patients with focal segmental glomerulosclerosis (FSGS). Urine was collected from seven patients treated with adalimumab. Renal clearance (ClR ) was measured and non-renal clearance (ClNR ) was calculated as the difference between total clearance and ClR . Differences in cumulative amount in urine, ClR, and ClNR between study weeks 1 and 16 and relationships between proteinuria (protein:creatinine ratio (Up/c)), and ClR and ClNR were evaluated. Up to 13% of the adalimumab dose was lost in urine. ClNR contributed more than ClR to enhanced total clearance. There was a nonlinear relationship between Up/c and ClR (R(2) 0.7059); an increase in ClR beginning at Up/c of 12 mg/mg [slope 1.755, (C.I. 7.825 to 11.34)]. There was a linear relationship between Up/c and ClNR (R(2) 0.5039); for every one unit increase in Up/c, ClNR would increase by 3.5 mL/hr (P = 0.01). Both ClR and ClNR contribute to enhanced total clearance of adalimumab in glomerular disease secondary to FSGS. Additional research is needed to identify mechanisms for the increased ClNR pathways. PMID- 23813331 TI - Ultrasound-guided fine-needle aspiration of suspicious nodes in breast cancer patients; selecting patients with extensive nodal involvement. AB - The aim of this study was to evaluate the value of Ultrasonography (US) guided fine-needle aspiration (FNA) of the axilla to identify breast cancer patients with extensive nodal involvement. A prospective database of breast cancer patients who underwent US-guided FNA of suspicious nodes, diagnosed between 2000 and 2007 was analyzed. Patients with a negative axillary US or C2 (benign) FNA result underwent SLNB. Patients with C5 (malignant) FNA result underwent axillary lymph node dissection (ALND). All SLNB positive patients underwent completion ALND. The number of positive nodes after ALND was documented and analyzed. A total of 1,448 patients were included. US sensitivity was 34.2 %, specificity was 96.2 % and the accuracy was 71.7 %. For US-guided FNA this was 89, 100 and 90.4 %, respectively. In 234/1,448 patients (16.2 %) US-guided FNA was performed. A total of 19/41 C2 patients (46.3 %) had a positive SLNB. A median of 1 (range 1 6) positive node was found. A median of 4 (range 1-30) positive nodes were found in 158 C5 patients. In 376/1,214 patients with a negative US, SLNB was positive. A median of 2 (range 1-38) positive nodes were found. There was a significant difference in nodal involvement between C5 and SLNB positive patients (p = 0.043 and p < 0.0001, respectively). Ultrasound-guided FNA is a highly specific technique for detecting axillary metastases in breast cancer patients. Patients with US-guided FNA-diagnosed axillary metastases have significantly more involved nodes compared to SLNB positive patients. PMID- 23813332 TI - Methodological considerations in quantification of 3'-deoxy-3' [18F]fluorothymidine uptake measured with positron emission tomography in patients with non-small cell lung cancer. AB - PURPOSE: To investigate the effect of image-derived input functions (IDIF), input function corrections and volume of interest (VOI) size in quantification of [(18)F]FLT uptake in non-small cell lung cancer (NSCLC) patients. PROCEDURES: Twenty-three NSCLC patients were scanned on a HR+ scanner. IDIFs were defined over the aorta and left ventricle. Activity concentration and metabolite fraction were measured in venous blood samples. Venous blood samples at 30, 40 and 60 min after injection were used to calibrate the IDIF time-activity curves. Adaptive thresholds were used for VOI definition. Full kinetic analysis and simplified measures were performed. RESULTS: Non-linear regression analysis showed better fits for the irreversible model compared to the reversible model in the majority. Calibrated and metabolite corrected plus plasma-to-blood ratio corrected input function resulted in high correlations between SUV and Patlak K i (Pearson correlation coefficients 0.86-0.96, p value < 0.001). No significant differences in correlation between SUV and Patlak K i were observed with variation of IDIF structure or VOI size. CONCLUSIONS: Plasma-to-blood ratio correction, metabolite correction and calibration improved the correlation between SUV and Patlak K i significantly, indicating the need for these corrections when K i is used to validate semi-quantitative measures, such as SUV. PMID- 23813333 TI - Response to the letter to the editor regarding the manuscript entitled "positron emission tomography with [(18)F]-3'-deoxy-3'fluorothymidine (FLT) as a predictor of outcome in patients with locally advanced resectable rectal cancer: a pilot study". PMID- 23813334 TI - Interactive learning research: application of cognitive load theory to nursing education. AB - The purpose of this research was to investigate the effectiveness of interactive self-paced computerized case study compared to traditional hand-written paper case study on the outcomes of student knowledge, attitude, and retention of the content delivered. Cognitive load theory (CLT) provided the theoretical framework for the study. A quasi-experimental pre-test post-test design with random group assignment was used to measure by self-report survey student cognitive load and interactivity level of the intervention. Student scores on quizzes in semester 1 and post-test follow-up quizzes in semester 3 were assessed for the intervention's effects on knowledge retention. While no significant statistical differences were found between groups, the students in the interactive case study group rated their case study as more fun and interactive. These students also scored consistently higher on the post-test quiz items in their third semester, showing the viability of using CLT to improve student retention of nursing curricula information. PMID- 23813335 TI - The relevance of indigenous knowledge for nursing curriculum. AB - Indigenous knowledge (IK) has the potential to complement the dominant epistemologies central to nursing curricula. Acknowledging IK as a thriving set of worldviews, we discuss how nursing educators might access and integrate IK in ways that are respectful and sustainable. IK is highlighted as an entry point for understanding concepts such as cultural safety, ethical space, and relational practice and as a strength-based approach to learning about Aboriginal people's health. As with any use of knowledge, consideration must be given to issues of ownership, misappropriation, institutional responsibility, Indigenous protocol, and the creation of partnerships. Recommendations are provided for educators wishing to explore how to incorporate IK into nursing curriculum. With appropriate partnerships, protocols, and processes in place, the incorporation of IK may provide educators and students an opportunity to explore divergent epistemologies, philosophies, and worldviews, thereby encouraging broader perspectives about the world, ways of being, various types of knowledge, and nursing care. PMID- 23813336 TI - Maintenance chemotherapy for ovarian cancer. AB - BACKGROUND: Epithelial ovarian cancer accounts for about 90% of all cases of ovarian cancer. Debulking surgery and six courses of platinum-based chemotherapy results in complete clinical remission (CCR) in up to 75% of cases. However, 75% of the responders will relapse within a median time of 18 to 28 months and only 20% to 40% of women will survive beyond five years. It has been suggested that maintenance chemotherapy could assist in prolonging remission. To date, there has not been a systematic review on the impact of maintenance chemotherapy for epithelial ovarian cancer. OBJECTIVES: To assess the effectiveness and toxicity of maintenance chemotherapy for epithelial ovarian cancer and to evaluate the impact on quality of life (QoL). SEARCH METHODS: In the original review we searched the Cochrane Gynaecological Cancer Review Group Specialised Register, The Cochrane Central Register of Controlled Trails (CENTRAL, The Cochrane Library 2009, Issue 1), MEDLINE, EMBASE, PubMed, CBMdisc, CNKI and VIP (to May 2009). We collected information from ongoing trials, checked reference lists of published articles and consulted experts in the field. For this update, the searches were extended to October 2012. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing maintenance chemotherapy with no further intervention, maintenance radiotherapy or other maintenance therapy. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for eligibility and quality and extracted data. We analysed overall survival (OS) and progression-free survival (PFS) rates as dichotomous variables. Toxicity and QoL data were extracted where present. All analyses were based on intention-to-treat (ITT) on the endpoint of survival. We also analysed data by subgroups of drugs. MAIN RESULTS: We included eight trials (1644 women). When all chemotherapy regimens were combined, meta analysis indicated no significant difference in three-, five- and 10-year OS or PFS. For five-year OS, the combined risk ratio (RR) was 1.03 (95% confidence interval (CI) 0.96 to 1.10) and for the five-year PFS, the combined RR was 1.06 (95% CI 0.97 to 1.17). Results were very similar when trials of different regimens were analysed. Comparing chemotherapy with radiotherapy, only the RR for 10-year PFS in pathological complete remission (PCR) was in favour of whole abdominal radiotherapy 0.51 (95% CI 0.27 to 1.00), while three- and five-year OS rates have no significant difference between the two groups. AUTHORS' CONCLUSIONS: There is no evidence to suggest that the use of platinum agents, doxorubicin or paclitaxel used as maintenance chemotherapy is more effective than observation alone. Further investigations regarding the effect of paclitaxel used as maintenance chemotherapy are required. PMID- 23813338 TI - Kinetic properties of two Rhizopus exo-polygalacturonase enzymes hydrolyzing galacturonic acid oligomers using isothermal titration calorimetry. AB - The kinetic characteristics of two Rhizopus oryzae exo-polygalacturonases acting on galacturonic acid oligomers (GalpA) were determined using isothermal titration calorimetry (ITC). RPG15 hydrolyzing (GalpA)2 demonstrated a K m of 55 MUM and k cat of 10.3 s(-1) while RPG16 was shown to have greater affinity for (GalpA)2 with a K m of 16 MUM, but lesser catalytic activity with a k cat of 3.9 s(-1). Both enzymes were inhibited by the product, galacturonic acid, with app K i values of 886 and 501 MUM for RPG15 and RPG16, respectively. RPG15 exhibited greater affinity for (GalpA)3 with a K m of 9.2 MUM and a similar k cat at 10.7 s(-1) relative to (GalpA)2. Catalytic constants for RPG16 hydrolyzing (GalpA)3 could not be determined; however, single-injection ITC assays suggest a distinct preference and catalytic rate for (GalpA)3 relative to (GalpA)2. Thermodynamic parameters of a series of galacturonic acid oligomers binding to RPG15 were determined and exhibited some distinct differences from RPG16 binding thermodynamics, providing potential clues to the differing kinetic characteristics of the two exo-polygalacturonase enzymes. PMID- 23813337 TI - Community leaders' perspectives on engaging African Americans in biobanks and other human genetics initiatives. AB - There is limited information about what African Americans think about biobanks and the ethical questions surrounding them. Likewise, there is a gap in capacity to successfully enroll African Americans as biobank donors. The purposes of this community-based participatory study were to: (a) explore African Americans' perspectives on genetics/genomic research, (b) understand facilitators and barriers to participation in such studies, and (c) enlist their ideas about how to attract and sustain engagement of African Americans in genetics initiatives. As the first phase in a mixed methods study, we conducted four focus groups with 21 African American community leaders in one US Midwest city. The sample consisted of executive directors of community organizations and prominent community activists. Data were analyzed thematically. Skepticism about biomedical research and lack of trust characterized discussions about biomedical research and biobanks. The Tuskegee Untreated Syphilis Study and the Henrietta Lacks case influenced their desire to protect their community from harm and exploitation. Connections between genetics and family history made genetics/genomics research personal, pitting intrusion into private affairs against solutions. Participants also expressed concerns about ethical issues involved in genomics research, calling attention to how research had previously been conducted in their community. Participants hoped personalized medicine might bring health benefits to their people and proposed African American communities have a "seat at the table." They called for basic respect, authentic collaboration, bidirectional education, transparency and prerogative, and meaningful benefits and remuneration. Key to building trust and overcoming African Americans' trepidation and resistance to participation in biobanks are early and persistent engagement with the community, partnerships with community stakeholders to map research priorities, ethical conduct of research, and a guarantee of equitable distribution of benefits from genomics discoveries. PMID- 23813339 TI - Molecular dynamic and docking interaction study of Heterodera glycines serine proteinase with Vigna mungo proteinase inhibitor. AB - Many plants do produce various defense proteins like proteinase inhibitors (PIs) to protect them against various pests. PIs function as pseudosubstrates of digestive proteinase, which inhibits proteolysis in pests and leads to amino acid deficiency-based mortality. This work reports the structural interaction studies of serine proteinase of Heterodera glycines (SPHG) with Vigna mungo proteinase inhibitor (VMPI). 3D protein structure modeling, validation of SPHG and VMPI, and their putative protein-protein binding sites were predicted. Protein-protein docking followed by molecular dynamic simulation was performed to find the reliable confirmation of SPHG-VMPI complex. Trajectory analysis of each successive conformation concludes better interaction of first loop in comparison with second loop. Lysine residues of first loop were actively participating in complex formation. Overall, this study discloses the structural aspects and interaction mechanisms of VMPI with SPHG, and it would be helpful in the development of pest-resistant genetically modified crops. PMID- 23813340 TI - Purification and characterization of a new metallo-neutral protease for beer brewing from Bacillus amyloliquefaciens SYB-001. AB - The increased additive amount of adjuncts in the raw materials of Chinese beer requires the usage of protease to release more water-soluble proteins. Here, a metallo-neutral protease suited for brewing industry was purified from Bacillus amyloliquefaciens SYB-001. A 5.6-fold purification of the neutral protease was achieved with a 4-step procedure including ammonium sulfate precipitation, ion exchange, hydrophobic interaction, and gel-filtration chromatography. The molecular mass of the enzyme was estimated to be 36.8 kDa. The protease was active and stable at a wide range of pH from 6.0-10.0 with an optimum at pH 7.0. The highest activity of the purified enzyme was found at 50 degrees C. The existence of manganese ion would specifically enhance the protease activity. Comparing with other commercial neutral proteases in China, adding the new neutral protease during mashing process would release more amino acids from wort such as aspartic acid, arginine, methione, and histidine, resulting in a better amino acid profile in wort. Moreover, the wort processed with the new neutral protease had a higher alpha-amino nitrogen concentration, which would ensure a vigorous yeast growth and better flavor. The study of the enzyme could lay a foundation for its industrial application and further research. PMID- 23813341 TI - A protein from Aloe vera that inhibits the cleavage of human fibrin(ogen) by plasmin. AB - A protease inhibitor protein with the molecular mass of 11,804.931 Da (analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry) was isolated from Aloe vera leaf gel and designated as AVPI-12. The isoelectric point of the protein is about 7.43. The first ten amino acid sequence from the N terminal was found to be R-D-W-A-E-P-N-D-G-Y, which did not match other protease inhibitors in database searches and other publications, indicating AVPI-12 is a novel protease inhibitor. The band protein of AVPI-12 migrated further on nonreducing sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) than reducing SDS-PAGE. This result indicated that the molecule of AVPI-12 did not contain interchain disulfide bonds, but appeared to have intrachain disulfide bonds instead. AVPI-12 strongly resisted digestion by the serine proteases human plasmin and bovine trypsin. The protein could protect the gamma-subunit of human fibrinogen from plasmin and trypsin digestion, similar to the natural plasma serine protease inhibitor alpha2-macroglobulin. The protein also could protect the gamma-subunit of fibrinogen from the cysteine protease papain. AVPI-12 also exhibited dose-dependent inhibition of the fibrinogenolytic activity of plasmin, similar to alpha2-macroglobulin. The fibrinolytic inhibitory activity of AVPI-12 and the small-angle X-ray scattering showed that the protein could protect human fibrin clot from complete degradation by plasmin. The inhibition of the fibrinogenolytic and fibrinolytic activities of plasmin by AVPI-12 suggests that the inhibitor has potential for use in antifibrinolytic treatment. PMID- 23813342 TI - A dynamic scanning method based on signal-statistics for scanning electron microscopy. AB - A novel dynamic scanning method for noise reduction in scanning electron microscopy and related applications is presented. The scanning method dynamically adjusts the scanning speed of the electron beam depending on the statistical behavior of the detector signal and gives SEM images with uniform and predefined standard deviation, independent of the signal value itself. In the case of partially saturated images, the proposed method decreases image acquisition time without sacrificing image quality. The effectiveness of the proposed method is shown and compared to the conventional scanning method and median filtering using numerical simulations. PMID- 23813344 TI - Laser-assisted subepithelial keratomileusis with mitomycin C for myopic astigmatism >=2.00 diopters using a Zeiss MEL 80 Excimer. AB - To examine the refractive and visual outcome of laser-assisted subepithelial keratomileusis (LASEK) with mitomycin C(MMC) in eyes with myopic astigmatism >=2.00 diopters (D). This study comprised 82 eyes of 82 consecutive patients (37 male, 45 female; mean age at surgery 34.7 +/- 9.0 years) with preoperative topographic astigmatism >=2.00 D and mean preoperative spherical equivalent (SE) 4.50 +/- 1.13 D. To assess whether the refractive results differed with the amount of corrected sphere, the data were separated by preoperative SE thereby defining two groups with SE < -5.00 D (-2.00 to -4.75 D) and >=-5.00 D (-5.00 to 7.75 D). Mean manifest refraction spherical equivalent (MRSE) of -0.39 +/- 0.52 D was obtained at the 6-months (5.4 +/- 1.6 months) follow-up. The results were within +/-1.00 D of the attempted correction in 89 % of patients. The mean postoperative corrected distant visual acuity was -0.02 +/- 0.065 logMAR (range 0.10 to 0.15 logMAR). Sixty-seven (81.7 %) of all eyes did not change lines in safety. There was no statistically significant difference (P = 0.262) in safety between the SE groups. Mean efficacy was 0.89 +/- 0.27. There was a statistically significant difference in efficacy (P = 0.024) between the preoperative SE groups. Larger ablation zones were associated with better visual outcome, confirmed by safety, efficacy and predictability. The data reported here demonstrated that LASEK using a Zeiss MEL 80 excimer laser with an additional application of MMC is a safe and efficient technique with predictable results for the correction of eyes with myopic astigmatism >=2.00 D. PMID- 23813346 TI - Determination of protoapigenone in rat plasma by high-performance liquid chromatography with UV detection and its application in pharmacokinetic studies. AB - A simple and sensitive HPLC method using UV detection was developed to determine the concentration of protoapigenone in rat plasma. Chromatographic separation was conducted on a C18 column with a mobile phase consisting of an acetonitrile methanol-aqueous phase (containing 0.2% acetic acid, pH 3.0) system at a flow rate of 1.0 mL/min. The UV detector was set at 248 nm. The calibration curve was linear over the range of 0.031-10.0 ug/mL. The lower limit of quantification was 31 ng/mL. The recoveries for plasma samples ranged from 70.3 to 82.5%. The intra- and inter-day accuracy and precision fulfilled the international standards. This method was successfully applied to a pharmacokinetic study of protoapigenone in rats after oral administration of protoapigenone. It was shown that protoapigenone could be absorbed rapidly after oral administration and could reach the maximum concentration within 1 h. PMID- 23813347 TI - Stress and sociocultural factors related to health status among US-Mexico border farmworkers. AB - This study examines factors relating to farmworkers' health status from sociocultural factors, including stress embedded within their work and community contexts. A cross-sectional household survey of farmworkers (N = 299) included social-demographics, immigration status descriptors, and a social-ecologically grounded, community-responsive, stress assessment. Outcomes included three standard US national surveillance measures of poor mental, physical, and self rated health (SRH). Logistic regression models showed that higher levels of stress were significantly associated (Ps < .001) with increased risk for poor mental health and poor physical health considering all variables. Stress was not associated with SRH. Regarding two of the three outcomes, mental health and physical health, stress added explanatory power as expected. For poor SRH, a known marker for mortality risk and quite high in the sample at 38%, only age was significantly associated. Clinical and systems-level health promotion strategies may be required to mitigate these stressors in border-residing farmworkers. PMID- 23813348 TI - Immigration policy and access to health services. PMID- 23813349 TI - Investigating the relation between striatal volume and IQ. AB - The volume of the input region of the basal ganglia, the striatum, is reduced with aging and in a number of conditions associated with cognitive impairment. The aim of the current study was to investigate the relation between the volume of striatum and general cognitive ability in a sample of 303 healthy children that were sampled to be representative of the population of the United States. Correlations between the WASI-IQ and the left striatum, composed of the caudate nucleus and putamen, were significant. When these data were analyzed separately for male and female children, positive correlations were significant for the left striatum in male children only. This brain structure-behavior relation further promotes the increasingly accepted view that the striatum is intimately involved in higher order cognitive functions. Our results also suggest that the importance of these brain regions in cognitive ability might differ for male and female children. PMID- 23813350 TI - Delayed plaque protrusion after carotid artery stenting for the patient with symptomatic bi-lateral carotid artery stenosis. AB - Carotid artery stenting (CAS) has been developed as an alternative therapeutic strategy for carotid endarterectomy (CEA) for the past several decades. One of the remaining issues of CAS is the relatively higher incidence of ipsi-lateral stroke after the procedure compared with CEA. Ischemic stroke after CAS sometimes occurred after catheterization, and a major cause of delayed stroke has been hypothesized to be stent-thrombosis. In this report, we present a case of a delayed plaque protrusion observed by contrast enhanced computed tomography and intravascular ultrasound, which could be the cause of the delayed recurrence of ischemic symptom. The lesion required an additional endovascular treatment to relieve the patient of the recurrence. This phenomenon might be a possible reason for the delayed ischemic stroke after CAS. PMID- 23813351 TI - Diagnosis of septo-optic dysplasia in a neonate with hypernatremia, hypoglycemia, and persistent hypothermia. AB - A term neonate was diagnosed with septo-optic dysplasia (SOD) on the 11th day of life. The patient had hypernatremia, hypoglycemia, and hypothermia. The patient's persistent hypothermia prompted a head ultrasound to examine for abnormalities of the central nervous system, which suggested an absent septum pellucidum. A subsequent brain magnetic resonance imaging confirmed an absent septum pellucidum, and coupled with pituitary dysfunction and bilateral optic nerve hypoplasia, the diagnosis of SOD was made. The authors argue that persistent hypothermia in a neonate may raise the index of suspicion for SOD and thereby facilitate an earlier diagnosis of SOD. PMID- 23813352 TI - Successful subcutaneous glucagon use for persistent hypoglycaemia in congenital hyperinsulinism. AB - Abstract Congenital hyperinsulinism (CHI) results from inappropriate excessive insulin secretion by the beta cells in the pancreas. A wide clinical spectrum of disease exists and a genetic diagnosis is now possible for approximately 50% of affected children. We describe a patient with atypical diffuse CHI caused by mosaic ABCC8 mutation inheritance, unmasked by paternal uniparental disomy. Hypoglycaemia persisted despite two subtotal pancreatectomies and trials of diazoxide and nifedipine were unsuccessful. Octreotide resulted in anaphylaxis, precluding its use. Continuous subcutaneous glucagon infusion was successful in restoring normoglycaemia and attenuating weight gain, with concomitant improvement of developmental milestones. No adverse effects have been encountered after >12 months of therapy. Administration problems (e.g., line crystallisation) may complicate continuous glucagon therapy; hence a practical description of infusion constitution is included. We recommend consideration of continuous subcutaneous glucagon infusion as a therapeutic option for persistent refractory hypoglycaemia in CHI. PMID- 23813353 TI - Could GSD type I expand the spectrum of disorders with elevated plasma chitotriosidase activity? AB - Glycogen storage disease type I (GSDI) is characterized by accumulation of glycogen and fat in the liver and kidneys, resulting in hepatomegaly and renomegaly. Human chitotriosidase is a recently described fully active chitinase expressed by activated macrophages. Marked elevation of chitotriosidase activity was initially observed in plasma of patients with Gaucher disease. Subsequently, elevation was also observed in various lysosomal storage disorders such as fucosidosis, galactosialidosis and glycogen storage disease type IV. The aim of the present study was to evaluate plasma chitotriosidase activity in 19 children with glycogen storage disease type I. Plasma chitotriosidase levels were found to be significantly higher in children with GSD type I than healthy age-matched controls (21.3 +/- 16.4 vs. 12.3 +/- 8.9 nmol/h/mL, p=0.04). All the patients reported here presented with hepatomegaly. Our report expands the spectrum of disorders that should be included in the differential diagnosis of patients with increased plasma chitotriosidase activity, irrespective of the mechanisms involved. PMID- 23813354 TI - PHEX gene mutation in a Chinese family with six cases of X-linked hypophosphatemic rickets. AB - OBJECTIVE: X-linked hypophosphatemic (XLH) rickets is caused by inactivating mutations in the PHEX gene, which encodes a metalloprotease that cleaves small peptide hormone. So far there are only a few reports on XLH patients from China. In the present study, we report on six XLH patients from one family. A PHEX missense mutation was found in exon 22, and a literature review on the mutations of Chinese patients was undertaken. CASE DESCRIPTION: The family included six XLH patients with five females and one male (the proband). All the patients showed a low serum phosphorus, increased blood alkaline phosphatase and normal calcium levels. Mutation analysis revealed a PHEX mutation in exon 22 (c.2237G>A). In total, 15 PHEX mutations have been reported in Chinese populations at this time. CONCLUSION: These data extend the spectrum of mutations in the PHEX gene in Chinese populations. PMID- 23813355 TI - A case of SCNN1A splicing mutation presenting as mild systemic pseudohypoaldosteronism type 1. AB - Systemic pseudohypoaldosteronism type 1 (PHA1) is characterized by excessive salt loss from the renal tubulus, colon, sweat and salivary glands. Here we present a case of systemic PHA1 whose genetic analysis revealed a homozygous splicing mutation in intron 4 of SCNN1A (c.684+2 T>A) and discuss with the patient's phenotype. Previously described systemic PHA cases show varying degrees of severity dependent on the mutation. Most of the SCNN1A gene mutations present with a severe phenotype. The long-term follow-up and phenotype of the two reported cases with splicing mutation of the SCNN1A gene are unknown. Our case, with a new splicing mutation of SCNN1A, presented with a severe phenotype in the neonatal period. Since then she has been well without any hospitalization and respiratory illness. Her requirement for medication also decreased gradually. After early infancy she presented a mild systemic PHA1 phenotype up to the age of 39 months. In conclusion, the mutation in the patient is located at the splicing site and is definitely a new and pathogenic one, and the phenotype of the patient was milder as observed in a patient with missense mutation. PMID- 23813356 TI - Adaptation of glucose metabolism to fasting in young children with infectious diseases: a perspective. AB - Hypoglycemia is a frequently encountered complication in young children with infectious diseases and may result in permanent neurological damage or even death. Mortality rate in young children under 5 years of age is increased four- to six-fold when severe infectious disease is complicated by hypoglycemia. Young age, prolonged fasting and severity of disease are considered important risk factors. This perspective describes the combined results of recently conducted studies on the effect of these risk factors on glucose metabolism in children with different infectious diseases. The results of these studies have nutritional implications for the approach in clinical practice towards young children with infectious diseases and specific recommendations are made. A unique finding is the existence of infectious disease-related differences in the adaptation of glucose metabolism during fasting in young children. PMID- 23813357 TI - Type 1 diabetes mellitus in a patient with homozygous sickle cell anemia. AB - In children with sickle cell disease, reports of type 1 diabetes mellitus (T1D) are extremely rare. Several studies failed to show the co-existence of the two conditions. In the few cases reported, the diagnosis has been made solely based on the clinical presentation. Here we report the case of an adolescent with sickle cell anemia who presented with hyperglycemia and positive T1D-specific auto-antibodies. PMID- 23813358 TI - The Elecsys(r) Vitamin B12 assay is not affected by anti-intrinsic factor antibodies. PMID- 23813359 TI - Analytical performance and method comparison study of the total homocysteine immunoassay on the AIA 600II analyser. PMID- 23813360 TI - Multicenter reference intervals studies: a promising perspective for the future? PMID- 23813361 TI - Intralesional antigen immunotherapy for the treatment of warts: current concepts and future prospects. AB - Many destructive and immunotherapeutic modalities have been used for the management of warts; however, an optimal treatment with high efficacy and absent or low recurrence has not been explored to date. Recently, the use of intralesional immunotherapy with different antigens has shown promising efficacy in the treatment of warts. We review the different aspects of this new modality, including candidates, types of warts treated, dosage, number and interval between treatment sessions, mode of action, efficacy, adverse effects, recurrence rate, advantages, disadvantages, current place and future prospects. A literature review revealed that healthy immune subjects are the best candidates, and a pre sensitization test is usually done before the start of therapy. The dosage, the number and interval between sessions, and the success rates varied among the different studies. The mode of action is still uncertain, but is essentially mediated through stimulation of T helper-1 cell cytokine response. Adverse effects are mild and generally insignificant, and the recurrence rate is absent or low. Intralesional antigen immunotherapy seems to be a promising, effective and safe treatment modality for viral warts. Future well-designed and controlled studies would help to more clearly define its place in the challenging field of wart therapy. PMID- 23813362 TI - Limited sampling strategy of mycophenolic acid in adult kidney transplant recipients: influence of the post-transplant period and the pharmacokinetic profile. AB - We aimed to develop an accurate and convenient LSS for predicting MPA-AUC(0-12 hours) in Tunisian adult kidney transplant recipients whose immunosuppressive regimen consisted of MMF and tacrolimus combination with regards to the post transplant period and the pharmacokinetic profile. Each pharmacokinetic profile consisted of eight blood samples collected during the 12-hour dosing interval. The AUC(0-12 hours) was calculated according to the linear trapezoidal rule. The MPA concentrations at each sampling time were correlated by a linear regression analysis with the measured AUC(0-12). We analyzed all the developed models for their ability to estimate the MPA-AUC(0-12 hours). The best multilinear regression model for predicting the full MPA-AUC(0-12 hours) was found to be the combination of C1, C4, and C6. All the best correlated models and the most convenient ones were verified to be also applicable before 5 months after transplantation and thereafter. These models were also verified to be applicable for patients having or not the second peak in their pharmacokinetic profiles. For practical reasons we recommend a LSS using C0, C1, and C4 that provides a reasonable MPA-AUC(0-12 hours) estimation. PMID- 23813363 TI - A brief overview of multitalented microglia. AB - Microglia are the resident immune cells of the central nervous system, and accumulating data demonstrates a vast array of tasks in the healthy and injured brain. Microglia participate in both innate and adaptive immune responses. These cells contribute to the brain homeostasis, including the regulation of cell death, synapse elimination, neurogenesis, and neuronal surveillance. However, microglia can also become activated and/or deregulated in the context of neurodegenerative diseases, brain injuries, and cancer and thereby contribute to disease severity. As a consequence of these developments, microglia have attracted substantial attention on themselves. PMID- 23813364 TI - Cell culturing of human and murine microglia cell lines. AB - Despite the fact that microglia cells were first described almost a century ago, microglia-derived immortalized cell lines have only been established in the last two decades. One should be aware of their limitations but also of their advantages. Cell lines offer a potentially powerful tool to investigate some functional aspects of microglia. Cell culturing of human and murine microglia cell lines will be described in this chapter. It includes a presentation of equipment needed, cell culture medium and supplements, cell culture monitoring, and a protocol describing the steps for subculturing of microglia cell lines. PMID- 23813365 TI - Microglia isolation from adult mouse brain. AB - Although microglia isolation from embryonic or postnatal mouse brain is possible using a number of different protocols, microglia isolation from adult brain is more challenging and often results in low yields. Here, we describe a protocol to isolate intact microglia from adult mouse brain for functional assays, immunocytochemistry, and/or flow cytometry analysis. This protocol involves enzymatic dissociation in medium supplemented with dispase II, papain, and DNase I followed by mechanical dissociation. Cell separation is achieved via percoll gradients of various densities. Microglia isolated using this protocol is suitable for flow cytometry analysis, RNA isolation for gene expression by real time PCR or microarrays, and for functional assays including cytokine production, chemotaxis, and phagocytosis. PMID- 23813366 TI - Preparation of primary microglia cultures from postnatal mouse and rat brains. AB - Microglia are the inflammatory cells of the brain and are activated in neuropathological conditions. To study the biology of microglia, these cells can be isolated from the brain and analyzed in terms of pro- and anti-inflammatory cytokine production, involvement of intracellular signaling pathways upon inflammatory stimuli, phagocytosis, and several more biological aspects to understand their role in the brain. In this book chapter, I will discuss microglial cells and describe how these cells can be cultured from a postnatal mouse and rat brain. PMID- 23813367 TI - Isolation of murine postnatal brain microglia for phenotypic characterization using magnetic cell separation technology. AB - To shorten the time between brain harvesting and microglia isolation, and characterization, we utilized the MACS((r)) neural dissociation kit followed by OctoMACS((r)) CD11b magnetic bead isolation technique to positively select for brain microglia expressing the pan-microglial marker CD11b, a key subunit of the membrane attack complex (MAC). This protocol yields a viable and highly pure (>95%) microglial population of approximately 500,000 cells per pup that is amenable for in vitro characterization within hours or days after being harvested from brain tissue. Primary microglia from C57Bl/6 mice were plated for next-day analyses of morphology and cellular markers by immunocytochemistry or for analysis of gene expression under resting or LPS-stimulated conditions. The ease of isolation enables investigators to perform molecular and cellular analyses without having to wait 1-2 weeks to isolate microglia by conventional methods involving mechanical agitation to dislodge these from astrocyte beds. PMID- 23813368 TI - Isolation and culture of adult human microglia within mixed glial cultures for functional experimentation and high-content analysis. AB - Microglia are thought to be involved in diseases of the adult human brain as well as normal aging processes. While neonatal and rodent microglia are often used in studies investigating microglial function, there are important differences between rodent microglia and their adult human counterparts. Human brain tissue provides a unique and valuable tool for microglial cell and molecular biology. Routine protocols can now enable use of this culture method in many laboratories. Detailed protocols and advice for culture of human brain microglia are provided here. We demonstrate the protocol for culturing human adult microglia within a mixed glial culture and use a phagocytosis assay as an example of the functional studies possible with these cells as well as a high-content analysis method of quantification. PMID- 23813369 TI - Depletion of microglia from primary cellular cultures. AB - Primary cultures are an important in vitro tool to study cellular processes and interactions. These cultures are complex systems, composed of many cell types, including neurons, astrocytes, oligodendrocytes, microglia, NG2 cells, and endothelial cells. For some studies it is necessary to be able to study a pure culture of one cell type, or eliminate a particular cell type, to better understand its function. There exist cell culture protocols for making pure astrocyte or microglia cultures. Here we present two protocols to produce cultures depleted for microglia: in the first case, from a mixed astrocyte microglia culture and, in the second, for eliminating microglia from neuronal cultures. PMID- 23813370 TI - Lentiviral transduction of cultured microglia. AB - Microglial cells are the resident immune-related glial cells of the central nervous system (CNS) that are crucial for maintaining homeostasis and sensing pathological alterations in the nervous system. To improve our understanding of the biological function of microglia, gene-transfer techniques have been improved and become widely used over the past several years. Here, we describe lentiviral mediated transduction as a valuable tool for transduction of cultured microglial cells. PMID- 23813371 TI - Microglial activation: measurement of cytokines by flow cytometry. AB - Cytokine measurement is a prerequisite to understand the inflammatory state of the body. Quantitative analysis of cytokines by Western blotting and ELISA is a daunting task as these are time-consuming and error-prone protocols. With the advent of flow cytometry, the estimation of cytokines using the classical antigen antibody reaction has become a popular choice with researchers/clinicians. Here, we describe a protocol for multiple cytokine analysis using flow cytometry. PMID- 23813372 TI - In situ hybridization of cytokine mRNA using alkaline phosphatase-labelled oligodeoxynucleotide probes. AB - In situ hybridization is a powerful tool for visualizing cellular gene expression in morphologically preserved brain tissue giving precise information on the regional expression of specific mRNA sequences in cells of diverse phenotype. Here, we describe a sensitive, simple, and robust method using alkaline phosphatase (AP)-labelled oligodeoxynucleotide probes to detect cytokine mRNA in the acutely injured or inflamed mouse CNS. PMID- 23813373 TI - Use of meso-scale discoveryTM to examine cytokine content in microglia cell supernatant. AB - Cytokine production by activated microglia is one of the hallmarks of inflammatory response in the CNS. The cytokines released by microglia cells can be very different depending on the proinflammatory stimulus. Traditionally, to quantify these different cytokines, the "Sandwich"-enzyme-linked immunosorbent assay (Sandwich-ELISA) has been used. In this chapter we will discuss and describe an improved protocol of the Sandwich-ELISA developed by Meso-Scale Discovery based on an electrochemiluminescence detection system, which allows the ultralow detection of multiple cytokines in microglia cell supernatant. PMID- 23813374 TI - Analysis of microglial production of reactive oxygen and nitrogen species. AB - Reactive oxygen and nitrogen species are both regulators and effectors of microglial activation, and assays of these oxidants can be used as a measure of acute and chronic activation of microglial cells. Here we describe quick methods to assess the production of superoxide, hydrogen peroxide, nitric oxide, and peroxynitrite by microglia. PMID- 23813375 TI - Quantification of active caspase-3 and active caspase-8 in microglia cells. AB - During microglia activation the levels of active caspase-3, caspase-7 and caspase 8 are increased, which leads to the transcription of proinflammatory cytokines and factors. As such, the induction of caspase activity in microglia can be used as a marker for activation. The use of sensitive and quantitative techniques has made it possible to reproducibly detect these low levels of active caspases. This chapter outlines the materials and methodology for three different ways to detect caspase activation in microglia. PMID- 23813376 TI - Quantification of microglial phagocytosis by a flow cytometer-based assay. AB - Microglia represent the largest population of phagocytes in the CNS and have a principal role in immune defense and inflammatory responses in the CNS. Their phagocytic activity can be studied by a variety of techniques, including a flow cytometry-based approach utilizing polystyrene latex beads. The flow cytometry based microglial phagocytosis assay, which is presented here, offers the advantage of rapid and reliable analysis of thousands of cells in a quantitative fashion. PMID- 23813377 TI - Quantification of microglial proliferation and apoptosis by flow cytometry. AB - Microglia are innate immune cells that survey the central nervous system (CNS) and respond almost immediately to any disturbance in CNS homeostasis. They are derived from primitive yolk sac myeloid progenitors and in the mouse colonize the CNS during fetal development. As a population, microglia have the potential to expand rapidly in response to inflammatory stimuli, injury, or any other pathological changes, due to a high capacity for proliferation. In addition, apoptotic mechanisms can be evoked to retract the microglial population, as reactivity declines. In the normal CNS, a low rate of proliferation and apoptosis maintain a low rate of microglial turnover. Here, we describe quantitative analysis of proliferation and apoptosis of microglial cells isolated from individual adult mice by flow cytometry, which allows distinction from perivascular or infiltrating macrophages, based on differential expression of CD45. These methods can be applied to analyze microglial turnover in various models of neuroinflammation. PMID- 23813378 TI - Fluorescence imaging of intracellular Ca2+, Na+, and H+ in cultured microglia. AB - The behavior of microglial cells involves the activity of a variety of ion channels and ion transporters, which are implicated in the regulation of ion concentrations, membrane potential, and cell volume of microglia. Fluorescence imaging has been proven to be an elegant method to study ion concentration changes in intact microglial cells under physiological and pathophysiological conditions. The development of highly specific ion indicators has made it possible to detect changes in intracellular Ca(2+), Na(+), and H(+) concentrations of microglial cells as a result of ion channel or ion transporter activity. Fluorescence signals of isolated dye-loaded microglial cells can be detected via a CCD camera equipped to a conventional microscope. This chapter summarizes protocols of loading of microglial cells with small-molecule ion indicators as well as protocols optimal for measurement and analysis of intracellular Ca(2+), Na(+), and H(+) concentrations in microglia in vitro. PMID- 23813379 TI - Patch clamp protocols to study ion channel activity in microglia. AB - Microglia express a variety of ion channels, which can be distinguished based on their ion selectivity into K(+), H(+), Na(+), Ca(2+), nonselective cation, and Cl(-) channels. With respect to their activation mode, voltage-, Ca(2+)-, calcium release-, G protein-, swelling-, and stretch-activated ion channels have been described in microglia. The best method to study the activity of microglial ion channels is the patch clamp technique. The activity of microglial ion channels under physiological conditions is best explored using the perforated patch clamp technique, which allows recordings of membrane potential or ion currents, while the intracellular milieu of the cells remains intact. In whole-cell patch clamp recordings, application of specific voltage protocols with defined intra- and extracellular solutions allows precise identification of a certain ion channel type in microglia as well as the investigation of the channel's biophysical and pharmacological properties. This chapter summarizes patch clamp protocols optimal for recording and analysis of microglial ion channel activity in vitro and in situ. PMID- 23813380 TI - Studying M1 and M2 states in adult microglia. AB - Microglial cell function receives increasing interest. To date, the majority of experiments are performed by using immortalized microglia-like cells or primary microglia prepared from pre- or postnatal rodent brain. As those may not adequately reflect the microglial biology in the adult brain, this protocol advocates a procedure which allows for the isolation, purification, and subsequent analysis of microglial cells. Once isolated, the principal state of activation, M1 or M2, can be determined in adult microglia using fluorescence activated cell sorting, quantitative PCR, and/or Western blotting. Likewise, adult microglia generated by this protocol can be used for functional analysis through cell cultivation for a limited time. PMID- 23813381 TI - Isolating, culturing, and polarizing primary human adult and fetal microglia. AB - Microglia are an important component of the innate immune system within the central nervous system (CNS). Isolation and in vitro culturing of microglia can provide insight towards the basic biology of these cells as well as their interactions with neurons, astrocytes, and oligodendrocytes. While studies of rodent microglia and microglial cell lines have provided a basis for our understanding of these cells, human adult microglia exhibit distinct properties when compared to rodent cells. Furthermore, the study of human fetal microglia provides a window into the developing CNS. This chapter describes the protocols used to isolate, purify, and culture both human adult and fetal microglia. Under basal culture conditions, human microglia survive for extended periods in the absence of growth factors, thus allowing their properties to be investigated under resting conditions. In addition, both human adult and fetal microglia can be used to study how they respond to different polarization conditions. As is the case with macrophages, it is also possible to polarize microglia towards the pro inflammatory "M1" and the anti-inflammatory "M2" phenotypes, as described in this chapter. PMID- 23813382 TI - Understanding microglia-neuron cross talk: relevance of the microglia-neuron cocultures. AB - Microglia-neuron interaction is a complex process involving a plethora of ligands and receptors. The outcome of this intricate process will depend on the prevailing signals (i.e., whether the microglial cells will produce pro inflammatory cytokines and/or phagocyte a dying neuron or whether it will produce neurotrophic factors and support neuronal growth, among other possible scenarios). In order to study this complex process, several tools have been developed, ranging from in vivo models (knockout and knock-in mice, conditional transgenic mice, imaging techniques) to in vitro models (microglia-neuron cocultures, transwell cell cultures). Here we describe a protocol for primary microglia-neuron coculture. this coculture allows to combine neurons and microglial cells coming from wild-type and KO mice, making this coculture a useful method to study in vitro the interaction of different sets of ligand receptor. PMID- 23813383 TI - Preparation of rodent primary cultures for neuron-glia, mixed glia, enriched microglia, and reconstituted cultures with microglia. AB - Microglia, neurons, and macroglia (astrocytes and oligodendrocytes) are the major cell types in the central nervous system. In the past decades, primary microglia enriched cultures have been widely used to study the biological functions of microglia in vitro. In order to study the interactions between microglia and other brain cells, neuron-glia, neuron-microglia, and mixed glia cultures were developed. The aim of this chapter is to provide basic and adaptable protocols for the preparation of these microglia-containing primary cultures from rodent. Meanwhile, we also want to provide a collection of tips from our collective experiences doing primary brain cell cultures. PMID- 23813384 TI - Microglia detection by enzymatic histochemistry. AB - Visualization of microglia by means of histochemistry has been for years a reliable method to demonstrate this population of cells in the central nervous system (CNS). Wide range of data on microglia has been published using lectin and enzymatic histochemistry. While at present, in most laboratories, the use of specific antibodies is the first choice, histochemical detection of microglia remains a powerful method as it has certain advantages upon immunohistochemical methods because it is faster, cheaper, and can be used in different species including human. In this chapter we want to present the detailed methodology for microglial staining using the histoenzymatic demonstration of the enzyme nucleoside-diphosphatase (NDPase), a phosphatase found in the plasma membrane of microglia that is absent in the plasma membrane of other glial cells and neurons. With this technique it is possible to visualize amoeboid microglia during development, ramified microglia in the adult brain, and also reactive microglia. As the technique also stains the blood vessels, it allows the analysis of the relationship between microglia and vasculature. This method can be performed in either histological sections or cell cultures for light microscopy analysis. Furthermore, we described how to combine this histochemical method with conventional immunohistochemistry for double labelling using other markers, and finally we give details to perform the procedure not only for optical microscopic studies but also for transmission electron microscopy (TEM). PMID- 23813385 TI - Tomato lectin histochemistry for microglial visualization. AB - The use of different lectins for the study of microglial cells in the central nervous system (CNS) is a valuable tool that has been extensively used in the last years for the selective staining of this glial cell population, not only in normal physiological conditions, but also in a wide range of pathological situations where the normal homeostasis of the parenchyma is disturbed. In this chapter we accurately describe the methodology for the selective labelling of microglial cells by using the tomato lectin (TL), a protein lectin obtained from Lycopersicum esculentum with specific affinity for poly-N-acetyl lactosamine sugar residues which are found on the plasma membrane and in the cytoplasm of microglia. Here we describe how to perform this technique on vibratome, frozen, and paraffin sections for optical microscopy, as well as for transmission electron microscopy (TEM) studies. Using this methodology it is possible to visualize amoeboid microglia in the developing brain, ramified microglia in the adult, and activated/reactive microglia in the experimentally damaged brain. In addition, as TL also recognized sugar residues in endothelial cells, this technique is very useful for the study of the relationship established between microglia and the CNS vasculature. PMID- 23813386 TI - Immunohistochemical detection of microglia. AB - Immunohistochemistry (IHC) is a technique that allows the localization of antigens or proteins in tissue sections using the high specificity and affinity of antibodies to recognize molecules and join them. The commercial offer and the standardization of protocols make this technique a simple, fast, and powerful method. Microglia, the resident macrophage cells of the central nervous system, can exist in three different forms that can be identified using different antibodies. The aim of this chapter is to describe the methods to perform IHC using these different antibodies. PMID- 23813387 TI - Intrathecal infusion of microglia cells. AB - Spinal microglia have been implicated in the pathogenesis of neuropathic pain after peripheral nerve injury concomitant with diseases such as diabetes and cancer. To reveal the etiological roles of microglia in behavioral pain hypersensitivity or neuronal excitability, technical approaches have been used. Here, we describe a technique for intrathecal transfer of cultured microglial cells through a catheter surgically implanted into the spinal subarachnoid space. PMID- 23813388 TI - Intracranial injection of LPS in rat as animal model of neuroinflammation. AB - Animal models of neuroinflammatory processes are needed to study the involvement of inflammation in neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. One of the models used is based on lipopolysaccharide (LPS) as brain inflammation-inducing agent. This toxin is a potent inducer of inflammation and has different effects on cells of the immune system, as microglial cells. This chapter describes a protocol for the model of brain inflammation in rats based on the unilateral stereotaxic injection of LPS, which mimics the inflammatory milieu produced in some brain diseases. PMID- 23813389 TI - Analyses of microglia effector function using CX3CR1-GFP knock-in mice. AB - The generation of bone marrow radiation chimeric mice is a beneficial tool to utilize when studying inflammation of the central nervous system (CNS). It is widely accepted that blood-derived progenitors are capable of populating the CNS during chronic diseases and severe injuries; however, they are neither consistent nor efficient in doing so. The lack of the appropriate recruitment could explain delays in recovery and repair after an increase of toxic proteins in chronic neurodegenerative diseases. With the ingenious development of bone marrow chimeric mice, some of these concerns can be addressed and allow us to hypothesize about further implications and possible mechanisms that may lead to medicinal applications. Bone marrow chimeric mice are often used to distinguish the intrinsic versus extrinsic effects of specific mutations. In our case, chimeras help us to better understand the role of CX3CR1 in microglia and peripheral myeloid cells. To detect cell autonomous effects on myeloid cell differentiation, CX3CR1-deficient mice are used as donors and wild-type mice are used as recipients. In order to detect effects on the "immune cell environment," wild-type donors are used for the transfer into Cx 3 cr1 (-/-) recipients. The resulting chimeric mice can then be used for the analysis of microglial motility, regulation of neuroinflammation, and persistence. This technique can be applied to a broad spectrum of research ranging from neurodegenerative diseases to viral and parasitic pathogenicity and everything in between. This protocol describes the approach to generate chimeric mice and analyze the role of CX3CR1 in CNS inflammation in bone marrow radiation chimeras. PMID- 23813390 TI - In vivo two-photon microscopy of microglia. AB - In vivo imaging with two-photon microscopy is becoming an indispensable technique to investigate cellular and subcellular phenomenon in living tissues including the central nervous system. This microscopy enables to image dynamics of molecules, morphology, and excitability with minimal invasion to tissues. Microglia are residual immune-responsive cells in the central nervous system and show highly dynamic response to the environmental alterations. Diverse roles of microglial functions in the intact and pathological brain are still largely unknown. In this chapter we describe the detailed method to image the dynamics of microglia in the mouse brain in vivo. PMID- 23813391 TI - Use of confocal microscopy in the study of microglia in a brain metastasis model. AB - Confocal imaging of brain slices is a worthwhile analysis method to study the structure and function of resting and activated microglia with submicrometer resolution. This chapter will focus on acquisition of high-resolution confocal image stacks where we will discuss the technical aspects of confocal imaging in brain sections as well as some of the currently suitable fluorescent markers for this type of work. PMID- 23813393 TI - Surgical resection versus liver transplant for patients with hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma is a major worldwide health problem, involving more than half a million new patients yearly, with a different incidence in different parts of the world. Hepatocellular carcinoma develops in about 80% of cirrhotic patients, and cirrhosis is considered the strongest predisposing factor for it. Surgical resection and liver transplantation are conventional treatment modalities that can offer long-term survival for patients with hepatocellular carcinoma. OBJECTIVES: To assess the benefits and harms of surgical resection compared with those of liver transplantation in patients with hepatocellular carcinoma. SEARCH METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded (SCI-EXPANDED) at ISI Web of Science (last search February 2013). We also searched the abstracts from annual meetings of the American Society of Clinical Oncology, the American Association for the Study of Liver Diseases (AASLD), and the European Association for the Study of the Liver (EASL), provided through The Cochrane Hepato-Biliary Group until February 2013. SELECTION CRITERIA: Randomised clinical trials comparing surgical resection and hepatic transplantation. DATA COLLECTION AND ANALYSIS: The search strategies were run and two authors individually evaluated whether the retrieved studies fulfilled the inclusion criteria. MAIN RESULTS: No randomised clinical trials comparing surgical resection and liver transplantation as the major methods of treating hepatocellular carcinoma were found. AUTHORS' CONCLUSIONS: There are no randomised clinical trials comparing surgical resection and liver transplantation for hepatocellular carcinoma treatment. PMID- 23813392 TI - Atypical mitogen-activated protein kinase phosphatase implicated in regulating transition from pre-S-Phase asexual intraerythrocytic development of Plasmodium falciparum. AB - Intraerythrocytic development of the human malaria parasite Plasmodium falciparum appears as a continuous flow through growth and proliferation. To develop a greater understanding of the critical regulatory events, we utilized piggyBac insertional mutagenesis to randomly disrupt genes. Screening a collection of piggyBac mutants for slow growth, we isolated the attenuated parasite C9, which carried a single insertion disrupting the open reading frame (ORF) of PF3D7_1305500. This gene encodes a protein structurally similar to a mitogen activated protein kinase (MAPK) phosphatase, except for two notable characteristics that alter the signature motif of the dual-specificity phosphatase domain, suggesting that it may be a low-activity phosphatase or pseudophosphatase. C9 parasites demonstrated a significantly lower growth rate with delayed entry into the S/M phase of the cell cycle, which follows the stage of maximum PF3D7_1305500 expression in intact parasites. Genetic complementation with the full-length PF3D7_1305500 rescued the wild-type phenotype of C9, validating the importance of the putative protein phosphatase PF3D7_1305500 as a regulator of pre-S-phase cell cycle progression in P. falciparum. PMID- 23813394 TI - MR imaging of the spine and sacroiliac joints for spondyloarthritis: influence on clinical diagnostic confidence and patient management. AB - PURPOSE: To quantify the effect of magnetic resonance (MR) imaging of the spine and sacroiliac joints on clinical diagnostic confidence and to determine if MR imaging affects treatment of patients with axial spondyloarthritis. MATERIALS AND METHODS: This prospective observational study was approved by the research ethics board and included 55 consecutive patients referred by three rheumatologists for MR imaging of the spine and sacroiliac joints. Measures of diagnostic confidence for clinical features (inflammatory back pain, mechanical back pain, muscular back pain, radicular back pain, spondylitis, sacroiliitis, and other) and overall diagnoses were made by using a Likert scale both before and after MR imaging. Proposed treatment was similarly recorded before and after MR imaging interpretation. The McNemar test was performed to determine the change in diagnostic confidence and consequent effect on patient treatment. RESULTS: Diagnostic confidence for specific clinical features improved significantly after MR imaging for inflammatory back pain (14% vs 76%, before vs after; P < .001), mechanical back pain (4% vs 49%, P < .001), spondylitis (7% vs 76%, P < .001) and sacroiliitis (9% vs 87%, P < .001). Confidence for overall diagnoses also improved significantly after MR imaging for ankylosing spondylitis (29% vs 80%, P < .001), undifferentiated spondyloarthritis (58% vs 93%, P < .001) and osteoarthritis (29% vs 64%, P < .001). Of the 23 patients for whom tumor necrosis factor-alpha inhibitor (TNFi) therapy was recommended before MR imaging, 12 (52%) were prescribed TNFi therapy after MR imaging. Of the 32 patients for whom TNFi therapy was not recommended before MR imaging, 10 (31%) patients were prescribed TNFi therapy after MR imaging. Overall, 22 (40%) patients had a change in treatment recommendation regarding TNFi therapy after MR imaging. CONCLUSION: MR imaging of the spine and sacroiliac joints significantly influences the diagnostic confidence of rheumatologists regarding clinical features and overall diagnoses of axial spondyloarthritis, and consequently significantly affects treatment plans. PMID- 23813395 TI - Facial rejuvenation with staged injections of cryopreserved fat and tissue cocktail: clinical outcomes in the past 10 years. AB - BACKGROUND: Facial rejuvenation by autologous fat transfer is common in aesthetic plastic surgery. The main drawback is progressive resorption, requiring repeated harvesting and microfat grafting. OBJECTIVE: The authors present a method for cryopreservation of excess harvested fat and tissue to enable subsequent use of previously harvested excess material. METHODS: Fat grafts were harvested using a 50-mL syringe and a 3- or 4-mm cannula. A tissue "cocktail" composed of dermis, fascia, and fat was prepared from excised scar tissue, tissue from abdominoplasty, or tissue from reduction mammaplasty. Cocktail specimens were placed in sterile tubes, immersed in a liquid nitrogen tank (-196 degrees C), and stored at -80 degrees C. At 3- to 6-month intervals, repeated cryopreserved fat graft injections were performed. Patients were evaluated by comparing preoperative and postoperative photographs. RESULTS: Between 2000 and 2010, a total of 5199 cryopreserved fat or tissue injections were performed in 2439 consecutive patients (age range, 19-80 years). Nasolabial folds and lips were the most common injection sites. Clinical outcomes were satisfactory, and improved contour was achieved in most patients after repeated injections. CONCLUSIONS: Cryopreservation of excess tissue for future injection is promising since repetitive injections are often required after resorption of microfat grafts. In our study, the survival of cryopreserved tissue cocktail or fat was comparable to that of fresh fat grafts and is therefore an effective adjuvant method for facial rejuvenation. PMID- 23813396 TI - Commentary on: Correction of cleft lip nose deformity with rib cartilage. PMID- 23813397 TI - Use of porcine acellular dermal matrix in revisionary cosmetic breast augmentation. AB - BACKGROUND: Aesthetic breast augmentation can be fraught with postoperative complications, particularly capsular contracture (CC), skin surface irregularities, and implant or inframammary fold malposition. Similar complications have been addressed successfully in reconstructive breast surgery with acellular dermal matrix (ADM) products. OBJECTIVE: The authors present their initial experience with porcine ADM (PADM) in aesthetic breast augmentation. METHODS: Retrospective chart review was performed for 93 consecutive patients (179 breasts) who underwent revisionary cosmetic breast augmentation with or without mastopexy between May 2009 and September 2012. Porcine ADM (Strattice; Lifecell Corp, Branchburg, New Jersey) was placed bilaterally in 74 patients and unilaterally in 19 patients. All patients were operated upon by 1 surgeon (J.N.P.). Product use description and complications were recorded, including infection, extrusion, CC, and implant malposition. RESULTS: Average follow-up was 12 months (range, 1-39 months). There were 2 major complications (1.6% of breasts): an infection in 1 breast that required implant explantation approximately 2 weeks postoperatively and an extrusion that required PADM removal. Two additional patients had high-riding implants resulting from folded PADM that required revision; both cases were corrected by excising the folded PADM segment. Seven other patients required office procedures to correct minor imperfections. Two CC recurrences were suspected (1 patient) in the 76 breasts that underwent capsulectomy and PADM placement. CONCLUSIONS: Porcine ADM demonstrated great utility as an adjunct in revisionary cosmetic breast surgery. The product helped to provide good aesthetic outcomes with low complication rates. Prospective, randomized trials may prove helpful in defining the role of PADM further in these challenging cases. PMID- 23813398 TI - A lot to learn from ASAPS 2012 statistics. PMID- 23813399 TI - Taking evidence-based plastic surgery to the next level: report of the second Summit on Evidence-based Plastic Surgery. AB - Applying the principles of evidence-based medicine has the potential to drastically improve quality of care and patient outcomes. For this reason, evidence-based medicine has been held as one of the 15 most important developments in medicine within the past 100 years. In August of 2010, a broad coalition of leaders from numerous organizations representing societies, boards, journals, foundations, and academic institutions met in Colorado Springs, Colorado, for the first Evidence-Based Plastic Surgery Summit. The summit signaled a sea change in the approach of organized plastic surgery to the promotion of evidence-based medicine within the specialty. It was determined that a strategic, coordinated, and sustained effort to drive an evidence-based medicine culture would accelerate adoption and advance quality of care and patient safety. Over the past 2 years, many of the goals of the initial summit have been met. In order to take our evidence-based medicine efforts to the next level, a second summit was recently held to redefine goals, focus efforts, address barriers, and launch new initiatives with broad consensus. This article documents the outcomes of the second Evidence-Based Plastic Surgery Summit. PMID- 23813400 TI - Does quiescence exist in subcutaneous abscesses? A case of a 10-year-old abdominoplasty abscess. PMID- 23813401 TI - Breast ecology assessment in the study of local microflora. PMID- 23813402 TI - I am not a medical provider; I am a doctor. PMID- 23813403 TI - Enhancing (L)-isoleucine production by thrABC overexpression combined with alaT deletion in Corynebacterium glutamicum. AB - L-isoleucine is synthesized from 2-ketobutyrate and pyruvate in Corynebacterium glutamicum, and the supplies of these two precursors are important for L isoleucine synthesis. C. glutamicum YILWDeltaalaT with alaT gene deletion (encoding alanine aminotransferase, a principal enzyme for L-alanine synthesis) was constructed to increase intracellular pyruvate availability, and the thrABC genes from Escherichia coli (encoding bifunctional aspartate kinase I-homoserine dehydrogenase I, homoserine kinase, and threonine synthetase) were overexpressed in C. glutamicum YILW and YILWDeltaalaT to increase the supply of intracellular 2 ketobutyrate. In the fed-batch fermentation, YILWpXMJ19thrABC, YILWDeltaalaT, and YILWDeltaalaTpXMJ19thrABC exhibited 5.3, 17.6, and 8.4 % higher L-isoleucine production than the original strain, respectively. Both YILWpXMJ19thrABC and YILWDeltaalaT excreted lower concentrations of L-lysine, L-alanine, and L-valine. YILWDeltaalaTpXMJ19thrABC exhibited a cumulative reduction of these by-products excretion, which indicated that thrABC overexpression combined with alaT deletion resulted in the metabolic flux redistribution from 2-ketobutyrate and pyruvate to L-isoleucine synthesis, and decreased the fluxes to by-products synthesis accordingly. PMID- 23813404 TI - Predictions of enzymatic parameters: a mini-review with focus on enzymes for biofuel. AB - Enzymatic reactions are very basic processes in biological systems, and parameters related to enzymatic reactions always provide good indicators for understanding of mechanisms underlined in enzymatic reactions, for better controlling of enzymatic reactions, and for comparison of different enzymes. In this mini-review: first, parameters in enzymatic reactions were briefly reviewed from three different standpoints; second, predictions of parameters in enzymatic reactions without information on enzyme structure were shortly reviewed from viewpoints of geometric approach, graphic approach and compartmental approach; third, predictions of parameters in enzymatic reaction with information on enzyme structure were reviewed from the points of view of modeling, with 19 currently available databases, and 17 software packages and web servers; fourth, the current state of prediction on parameters in enzymatic reaction in biofuel industry with respect to cellulolytic enzymes were reviewed; fifth, the pros and cons for future development were discussed; and finally, a worked example was given in the Appendix to describe the whole procedures of prediction of enzymatic parameters in reactions. PMID- 23813405 TI - "Malonate uptake and metabolism in Saccharomyces cerevisiae". AB - Malonyl-CoA plays an important role in the synthesis and elongation of fatty acids in yeast Saccharomyces cerevisiae. Malonyl-CoA is at a low concentration inside the cell and is produced mainly from acetyl-CoA through the enzyme acetyl CoA carboxylase. It would be beneficial to find an alternative source of malonyl CoA to increase its intracellular concentration and overall synthesis of the fatty acids. MatB gene from the bacteria Rhizobium leguminosarium bv. trifolii encodes for a malonyl-CoA synthetase which catalyzes the formation of the malonyl CoA directly from malonate and CoA. However, results from high-performance liquid chromatography (HPLC) proved that Saccharomyces cerevisiae itself does not contain enough cytoplasmic malonate within them and is unable to uptake exogenously supplied malonate in the form of malonic acid. A dicarboxylic acid plasma membrane transporter with the ability to uptake exogenous malonic acid was identified from another species of yeast known as Schizosaccharomyces pombe and the gene encoding this transporter is identified as the mae1 gene. From the experiments thus far, the mae1 gene had been successfully cloned and transformed into Saccharomyces cerevisiae. The expression and functional ability of the encoded plasma membrane dicarboxylic acid transporter were also demonstrated and verified using specialized technologies such as RT-PCR, yeast immunofluorescence, HPLC, and LC-MS. PMID- 23813406 TI - Expression, purification, and partial in vitro characterization of biologically active human coagulation factor VIII light chain (A3-C1-C2) in Pichia pastoris. AB - Recombinant coagulation factor VIII (FVIII) expressed in mammalian expression systems is used extensively in the treatment of hemophilia A. It is reported that the heavy (A1-A2) and light chains (A3-C1-C2) of factor VIII purified from plasma regained the coagulation activity by dimerization in vitro. In this work, cDNA coding for the light chain of human coagulation factor VIII (FVIII-LC) was cloned into pPICZalpha-A expression vector downstream of alcohol oxidase promoter and alpha-mating signal sequence from Saccharomyces cerevisiae in order to express the protein with a native N-terminus. The methylotrophic yeast, Pichia pastoris X 33, was transformed with this cassette, and transformants were selected for production of human factor VIII light chain into culture media. SDS-PAGE and Western blot analysis confirmed the expression of factor VIII light chain protein. The expressed protein was purified to near homogeneity using histidine ligand affinity chromatography (2.342 mg/L). The biological activity of FVIII-LC was confirmed by analyzing the interaction between FVIII-LC and phospholipid vesicles. The data presented here indicate the possibilities of exploring cost effective systems to express complex proteins of therapeutic value. PMID- 23813407 TI - Production and properties of two novel exopolysaccharides synthesized by a thermophilic bacterium Aeribacillus pallidus 418. AB - Synthesis of innovative exocellular polysaccharides (EPSs) was reported for few thermophilic microorganisms as one of the mechanisms for surviving at high temperature. Thermophilic aerobic spore-forming bacteria able to produce exopolysaccharides were isolated from hydrothermal springs in Bulgaria. They were referred to four species, such as Aeribacillus pallidus, Geobacillus toebii, Brevibacillus thermoruber, and Anoxybacillus kestanbolensis. The highest production was established for the strain 418, whose phylogenetic and phenotypic properties referred it to the species A. pallidus. Maltose and NH4Cl were observed to be correspondingly the best carbon and nitrogen sources and production yield was increased more than twofold in the process of culture condition optimization. After purification of the polymer fraction, a presence of two different EPSs, electroneutral EPS 1 and negatively charged EPS 2, in a relative weight ratio 3:2.2 was established. They were heteropolysaccharides consisting of unusual high variety of sugars (six for EPS 1 and seven for EPS 2). Six of the sugars were common for both EPSs. The main sugar in EPS 1 was mannose (69.3 %); smaller quantities of glucose (11.2 %), galactosamine (6.3 %), glucosamine (5.4 %), galactose (4.7 %), and ribose (2.9 %) were also identified. The main sugar in EPS 2 was also mannose (33.9 %), followed by galactose (17.9 %), glucose (15.5 %), galactosamine (11.7 %), glucosamine (8.1 %), ribose (5.3 %), and arabinose (4.9 %). Both polymers showed high molecular weight and high thermostability. PMID- 23813408 TI - An efficient method for Agrobacterium-mediated genetic transformation and plant regeneration in cumin (Cuminum cyminum L.). AB - Cumin is an annual herbaceous medicinally important plant having diverse applications. An efficient and reproducible method of Agrobacterium-mediated genetic transformation was herein established for the first time. A direct regeneration method without callus induction was optimised using embryos as explant material in Gamborg's B5 medium supplemented with 0.5-MUM 6-benzyladenine and 2.0-MUM alpha-naphthalene acetic acid. About 1,020 embryos (a mean of 255 embryos per batch) were used for the optimisation of transformation conditions. These conditions were an Agrobacterium cell suspension of 0.6 OD600, a co cultivation time of 72 h, 300-MUM acetosyringone and wounding of explants using a razor blade. Pre-cultured elongated embryos were treated using optimised conditions. About 720 embryos (a mean of 180 embryos per batch) were used for transformation and 95 % embryos showed transient beta-glucuronidase expression after co-cultivation. Putative transformed embryos were cultured on B5 medium for shoot proliferation and 21 regenerated plants were obtained after selection and allowed to root. T0 plantlets showed beta-glucuronidase expression and gene integration was confirmed via PCR amplification of 0.96 and 1.28 kb fragments of the hygromycin-phosphotransferase II and beta-glucuronidase genes, respectively. In this study, a transformation efficiency of 1.5 % was demonstrated and a total of 11 transgenic plants were obtained at the hardening stage, however, only four plants acclimatised during hardening. Gene copy number was analysed by Southern blot analysis of hardened plants and single-copy gene integration was observed. This is the first successful attempt of Agrobacterium-mediated genetic transformation of cumin. PMID- 23813409 TI - Inhibition of myosin light chain kinase can be targeted for the development of new therapies against herpes simplex virus type-1 infection. AB - BACKGROUND: Herpes simplex virus type-1 (HSV-1) is the leading cause of infectious blindness worldwide. Through a multistep process, HSV-1 enters into naturally susceptible human corneal epithelial (HCE) cells where it establishes an optimal environment for viral replication and spread. HSV-1 employment of cytoskeletal proteins, kinases, and cell signalling pathways is crucial for the entry process. METHODS: Here we demonstrate that non-muscle myosin IIA (NM-IIA) and/or a myosin activating kinase, myosin light chain kinase (MLCK), can be targeted for the development of new and effective therapies against HSV-1. HCE cells were incubated with MLCK inhibitors ML-7 and ML-9 and NM-IIA inhibitor blebbistatin. Following the application of inhibitors, HSV-1 entry and spread to neighbouring HCE cells was evaluated. RESULTS: Upon application of MLCK inhibitors ML-7 and ML-9 and NM-IIA inhibitor blebbistatin, HSV-1 entry into HCE cells was significantly decreased. Furthermore, dramatic impairment of glycoprotein-mediated membrane fusion was seen in cells treated with MLCK inhibitors, thus establishing a role for MLCK activation in cell-to-cell fusion and multinucleated syncytial cell formation. These results also indicate that the activation of motor protein NM-IIA by MLCK is crucial for cytoskeletal changes required for HSV-1 infection of corneal cells. CONCLUSIONS: We provide new evidence that NM-IIA and MLCK can be used as effective antiviral targets against ocular herpes. PMID- 23813410 TI - A retrospective clinical analysis of Japanese patients with peripheral T-cell lymphoma not otherwise specified: Hokkaido Hematology Study Group. AB - Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) comprises a group of heterogeneous lymphomas that do not fit any other identified PTCL-subgroup and show poor prognosis. To clarify clinical aspects of Japanese PTCL-NOS patients, the Hokkaido Hematology Study Group conducted a multicenter retrospective analysis. The median age of the 107 patients (male 65.4 %) was 67 years. The majority (82.4 %) had stage III/IV disease. Following the international prognostic index, 65.7 % were categorized as high intermediate or high risk. Primary chemotherapy was selected in 96 (90 %) patients, 86 of whom received anthracycline regimens. Sixteen patients received high-dose chemotherapy with autologous stem cell transplantation. Forty-eight (52 %) of the 92 evaluable patients achieved complete remission (CR) or CR/unconfirmed after the primary treatment, in which 22 (46 %) relapsed. The estimated 5-year overall survival (OS) of all patients was 35 %. Three independent risk factors (RFs) associated with OS, bulky disease (hazard ratio HR = 5.324; p = 0.019), age >60 years (HR = 3.015; p = 0.025), and platelet count less than 10 * 10(4)/MUL (HR = 3.999; p = 0.036), were identified in a multivariate analysis. Using these three RFs, the OS curves were significantly stratified into three risk groups (low risk, 0 RFs, 3 year-OS 72 %; intermediate risk, one RF, 30 %; high risk, two or three RFs, 0 %; p = 0.0005). These findings may provide valuable information for the management of Japanese PTCL-NOS patients. PMID- 23813411 TI - Glucocorticoids in the management of systemic juvenile idiopathic arthritis. AB - Glucocorticoids have been the mainstay of treatment for many years in systemic onset juvenile idiopathic arthritis (sJIA), causing important side effects and some difficulties in the management of this disease. Until the introduction of biologic agents, oral glucocorticoids were used to control fever and other systemic features for several months or even years if systemic manifestations persisted. Nowadays, clinicians have valid alternatives that have revolutionized the natural history of sJIA. Biologic agents, such as the interleukin-1 inhibitors anakinra and the more recent canakinumab, or the interleukin-6 inhibitor tocilizumab, have improved the prognosis of this debilitating disease. Glucocorticoids still have to be considered at the onset of disease when a non steroidal anti-inflammatory drug therapy fails or when there are life-threatening complications such as severe anemia or pericarditis, or macrophage activation syndrome. Local (intra-articular) triamcinolone hexacetonide is the treatment of choice for arthritis limited to one joint or a few joints in patients without systemic activity. To date, there is still great heterogeneity in the management of sJIA patients, but in recent years there have been attempts to design algorithms and treatment protocols for glucocorticoids, disease-modifying anti rheumatic drugs, and biologic agents. This review provides an overview of the current knowledge of glucocorticoid therapy in sJIA, comments on recently published recommendations, and gives practical support to the clinician for management of this disease. PMID- 23813413 TI - Determination of 3-alpha-hydroxytibolone in human plasma by LC-MS/MS: application for a pharmacokinetic study after administration of a tibolone formulation. AB - A new method was developed for the quantitation of 3-alpha-hydroxy tibolone, in human plasma, after oral administration of a tablet formulation containing tibolone (2.5 mg). 3-alpha-Hydroxy tibolone was extracted by a liquid-liquid procedure, using cyproterone acetate as internal standard and chlorobutane as extraction solvent. After extraction, samples were submitted to a derivatization step with p-toluenesulfonyl isocyanate. A mobile phase consisting of acetonitrile and water (72:28 v/v) was used and chromatographic separation was achieved using Agilent XDB C18 column (100 * 4.6 mm i.d.; 5 um particle size), at 40 degrees C. Mass spectrometric detection was performed using atmospheric pressure chemical ionization in negative mode for 3-alpha-hydroxy tibolone and in positive mode for cyproterone acetate. The fragmentation transitions were m/z 510.2 -> m/z 170.1 and m/z 417.0 -> m/z 357.1 for 3-alpha-hydroxy tibolone and cyproterone acetate, respectively. Calibration curves were constructed over the range 100-30,000 pg/mL and the method was shown to be specific, precise and accurate, with a mean recovery rate of 94.2% for 3-alpha-hydroxy tibolone. No matrix effect or carry over was detected in the samples. The validated method was applied in a pharmacokinetic study with a tibolone formulation in healthy female volunteers. PMID- 23813414 TI - Successful percutaneous thrombectomy in an elderly patient with massive pulmonary embolism with cardiogenic shock. AB - We report on an 80-year-old woman with cardiogenic shock due to massive pulmonary embolism who was successfully treated with percutaneous thrombectomy using a conventional angiographic guide wire and catheters combined with systemic thrombolysis. We successfully treated the patient without a ventilator or extracorporeal life support. We report that percutaneous thrombectomy can provide rapid improvement of hemodynamic instability and can be used as an effective adjuvant therapy for systemic thrombolysis in patients with massive pulmonary embolism. Percutaneous thrombectomy is a less invasive and reasonable alternative to surgical embolectomy for patients with massive pulmonary embolism with cardiogenic shock. PMID- 23813412 TI - Long-term consequences of membership in trajectory groups of delinquent behavior in an urban sample: violence, drug use, interpersonal, and neighborhood attributes. AB - Research on stability and change in delinquent behavior over time has important implications for both the individual and the criminal justice system. The present research looks at this issue by examining the associations between the trajectories of delinquent behavior in adolescence and adult functioning. Data for the present study are from a four-wave longitudinal study of African American and Hispanic participants. Participants provided information at mean ages 14, 19, 24, and 29. We used growth mixture modeling to extract trajectory groups of delinquent behavior in adolescence and young adulthood. Regression analyses were conducted to examine whether memberships in the trajectory groups of delinquent behavior from mean age 14 to mean age 24 were associated with violence, substance abuse and dependence, partner discord, peer substance use, and residence in a high-crime neighborhood at mean age 29 when compared with the reference trajectory group of participants with low or no delinquent behavior. Four trajectory groups of delinquent behavior were identified: the no/low, the decreasing, the moderate, and the high persistent trajectory groups. Memberships in the trajectory groups were significantly correlated with variations in adult functioning. Memberships in some trajectory groups of delinquent behavior are significant predictors of later violent behavior, substance abuse and dependence, partner discord, peer substance use, and residence in a high-crime neighborhood. The findings reinforce the importance of investing in interventions to address different patterns of delinquent behavior. Findings are discussed in relation to previous investigations with non-Hispanic White samples. PMID- 23813415 TI - Labeling of cancer cells with magnetic nanoparticles for magnetic resonance imaging. AB - PURPOSE: The process of invasion and metastasis formation of tumor cells can be studied by following the migration of labeled cells over prolonged time periods. This report investigates the applicability of iron oxide nanoparticles as a magnetic resonance imaging (MRI) contrast agent for cell labeling. METHODS: gammaFe2 O3 nanoparticles prepared with direct flame spray pyrolysis are biofunctionalized with poly-l-lysine (PLL). The nanoparticles within the cells were observed with transmission electron microscopy, bright-field microscopy, and magnetorelaxometry. MRI of labeled cells suspended in agarose was used to estimate the detection limit. RESULTS: PLL-coated particles are readily taken up, stored in intracellular clusters, and gradually degraded by the cells. During cell division, the nanoparticle clusters are divided and split between daughter cells. The MRI detection limit was found to be 25 cells/mm(3) for R2*, and 70 cells/mm(3) for R2. The iron specificity, however, was higher for R2 images. Due to the degradation of intracellular gammaFe2 O3 to paramagnetic iron ions within 13 days, the R1, R2, and R2* contrast gradually decreased over this time period to approximately 50% of its initial value. CONCLUSIONS: These results suggest that PLL-coated gammaFe2 O3 nanoparticles can be used as an MRI contrast agent for long-term studies of cell migration. Magn Reson Med 71:1896-1905, 2014. (c) 2013 Wiley Periodicals, Inc. PMID- 23813416 TI - First experience of high-intensity focused ultrasound combined with transcatheter arterial embolization as local control for hepatoblastoma. AB - The purpose of this study was to assess the effectiveness of high-intensity focused ultrasound (HIFU) combined with transarterial chemoembolization (TACE) in treating pediatric hepatoblastoma. Twelve patients with initially unresectable hepatoblastoma were enrolled in the study. All patients received chemotherapy, TACE, and HIFU ablation. Follow-up materials were obtained in all patients. The tumor response, survival rate, and complications were analyzed. Complete ablation was achieved in 10 patients (83.3%), and the alpha-fetoprotein level was also decreased to normal in these patients. The mean follow-up time was 13.3 +/- 1.8 months (range, 2-25 months). At the end of follow-up, two patients died from tumor progression, the other 10 patients were alive. One patient was found to have lung metastasis after HIFU and had an operation to remove the lesion. The median survival time was 14 months, and the 1- and 2-year survival rates were 91.7% and 83.3%, respectively. Complications included fever, transient impairment of hepatic function, and mild malformation of ribs. CONCLUSION: HIFU combined with TACE is a safe and promising method with a low rate of severe complications. As a noninvasive approach, it may provide a novel local therapy for patients with unresectable hepatoblastoma. PMID- 23813417 TI - Objective image analysis of the meibomian gland area. AB - AIMS: To evaluate objectively the meibomian gland area using newly developed software for non-invasive meibography. METHODS: Eighty eyelids of 42 patients without meibomian gland loss (meiboscore=0), 105 eyelids of 57 patients with loss of less than one-third total meibomian gland area (meiboscore=1), 13 eyelids of 11 patients with between one-third and two-thirds loss of meibomian gland area (meiboscore=2) and 20 eyelids of 14 patients with two-thirds loss of meibomian gland area (meiboscore=3) were studied. Lid borders were automatically determined. The software evaluated the distribution of the luminance and, by enhancing the contrast and reducing image noise, the meibomian gland area was automatically discriminated. The software calculated the ratio of the total meibomian gland area relative to the total analysis area in all subjects. Repeatability of the software was also evaluated. RESULTS: The mean ratio of the meibomian gland area to the total analysis area in the upper/lower eyelids was 51.9+/-5.7%/54.7+/-5.4% in subjects with a meiboscore of 0, 47.7+/-6.0%/51.5+/ 5.4% in those with a meiboscore of 1, 32.0+/-4.4%/37.2+/-3.5% in those with a meiboscore of 2 and 16.7+/-6.4%/19.5+/-5.8% in subjects with a meiboscore of 3. CONCLUSIONS: The meibomian gland area was objectively evaluated using the developed software. This system could be useful for objectively evaluating the effect of treatment on meibomian gland dysfunction. PMID- 23813418 TI - Understanding of and attitudes to genetic testing for inherited retinal disease: a patient perspective. AB - BACKGROUND/AIMS: The views of people with inherited retinal disease are important to help develop health policy and plan services. This study aimed to record levels of understanding of and attitudes to genetic testing for inherited retinal disease, and views on the availability of testing. METHODS: Telephone questionnaires comprising quantitative and qualitative items were completed with adults with inherited retinal disease. Participants were recruited via postal invitation (response rate 48%), approach at clinic or newsletters of relevant charitable organisations. RESULTS: Questionnaires were completed with 200 participants. Responses indicated that participants' perceived understanding of genetic testing for inherited retinal disease was variable. The majority (90%) considered testing to be good/very good and would be likely to undergo genetic testing (90%) if offered. Most supported the provision of diagnostic (97%) and predictive (92%) testing, but support was less strong for testing as part of reproductive planning. Most (87%) agreed with the statement that testing should be offered only after the individual has received genetic counselling from a professional. Subgroup analyses revealed differences associated with participant age, gender, education level and ethnicity (p<0.02). Participants reported a range of perceived benefits (eg, family planning, access to treatment) and risks (eg, impact upon family relationships, emotional consequences). CONCLUSIONS: Adults with inherited retinal disease strongly support the provision of publicly funded genetic testing. Support was stronger for diagnostic and predictive testing than for testing as part of reproductive planning. PMID- 23813419 TI - Microvascular autologous transplantation of partial submandibular gland for severe keratoconjunctivitis sicca. AB - OBJECTIVE: To evaluate the feasibility of microvascular autologous transplantation of partial submandibular gland (SMG) to prevent or reduce epiphora in severe keratoconjunctivitis sicca (KCS). METHODS: A total of 39 patients with KCS, covering 42 eyes, were randomised to undergo transplantation of partial or total SMG from January 2006 to December 2009. Clinical data of survival rate of transplanted SMG, ophthalmologic features of best-corrected visual acuity, Schirmer test results, break-up time (BUT) of tear film, fluorescence staining, incidence of postoperative epiphora and frequency of subsequent surgery were compared between two groups. RESULTS: Total SMG transplantation was performed in 22 eyes, and partial SMG transplantation was performed in the other 20 eyes. All transplanted SMGs survived. Microvascular crisis occurred in one case of partial SMG transplantation, but the gland survived after exploration to remove the venous thrombus. Obstruction of the ductal orifice in one case of partial SMG transplantation was resolved by reconstruction of the ductal orifice. Symptoms of dry eyes disappeared, and patients were able to discontinue use of artificial tears. Severe epiphora occurred in 6 eyes undergoing partial SMG transplantation and in 19 eyes undergoing total SMG transplantation (p<0.01). Surgical reduction was performed in 6 eyes undergoing partial SMG transplantation and 18 eyes undergoing total SMG transplantation (p<0.01). CONCLUSIONS: Microvascular transplantation of partial SMG is feasible and effective for severe KCS and does not decrease the survival rate of transplanted SMG. For ample SMGs with normal function, transplantation of partial SMG alleviates the symptoms of dry eye and significantly reduces the incidence of severe postoperative epiphora. PMID- 23813420 TI - Incidence and baseline clinical characteristics of treated neovascular age related macular degeneration in a well-defined region of the UK. AB - AIMS: To analyse the incidence and baseline clinical characteristics of patients with neovascular age-related macular degeneration (nAMD) treated with intravitreal anti-vascular endothelial growth factor (VEGF) injections in a defined UK region. METHODS: A standardised dataset was collected prospectively using an electronic medical record (EMR) system from 1 January 2008 to 21 June 2012 for all patients living in Gloucestershire who received intravitreal anti VEGF injections for nAMD. RESULTS: Over the study period, 1207 eyes from 1033 patients began intravitreal anti-VEGF injections for nAMD. The annual incidence in the years after National Institute for Health and Care Excellence (NICE) technology appraisal 155 implementation was stable at 120 (95% CI 110 to 138) eyes or 100 (89 to 115) people per 100 000 population. The most common indication was occult choroidal neovascularisation (51%). Median baseline visual acuity (VA) was significantly higher for second treated than first treated eyes (66 and 56 letters, respectively; p<0.0001). Median baseline VA of fellow eyes increased from 47 (2008) to 67 letters (2012; p<0.005). The proportion of patients with baseline VA in the better eye >=70 letters increased from 27.6% (2008) to 51.4% (2012; p<0.0001), while the proportion eligible at baseline for full or partial certificate of visual impairment decreased from 13.8% (2008) to 7.1% (2012; p<0.05). CONCLUSIONS: The incidence of patients undergoing anti-VEGF therapy for nAMD increased substantially following NICE approval of ranibizumab (August 2008), and has been stable since 2009. This equates to an annual UK incidence of 26 850 (21 320 to 32 440) eyes, similar to NICE estimates. Patients eligible for blindness certification before treatment decreased by half from 2008-2012. Prospective data collection using an EMR system is invaluable for efficient monitoring of real-world clinical care. PMID- 23813423 TI - "I guess what he said wasn't that bad": dissonance in nonconfronting targets of prejudice. AB - Although confrontations can be an effective means of reducing prejudicial responding, individuals often do not confront others due to the interpersonal costs. In the present research, we examined the intrapersonal implications of not confronting prejudice. In three studies, female participants were exposed to a confederate who made a sexist remark. Consistent with self-justification theories, in Study 1, participants who valued confronting and were given the opportunity to confront-but did not-subsequently made more positive evaluations of the confederate. Study 2 found that when participants were given a chance to affirm an important aspect of the self prior to evaluating the confederate, these inflated evaluations of the confederate did not occur. Finally, in Study 3, participants who initially valued confronting but did not confront a sexist partner reduced the amount of importance they placed on confronting. These data reveal that there are important intrapersonal consequences of not confronting prejudice. PMID- 23813422 TI - Is it really self-control? Examining the predictive power of the delay of gratification task. AB - This investigation tests whether the predictive power of the delay of gratification task (colloquially known as the "marshmallow test") derives from its assessment of self-control or of theoretically unrelated traits. Among 56 school-age children in Study 1, delay time was associated with concurrent teacher ratings of self-control and Big Five conscientiousness-but not with other personality traits, intelligence, or reward-related impulses. Likewise, among 966 preschool children in Study 2, delay time was consistently associated with concurrent parent and caregiver ratings of self-control but not with reward related impulses. While delay time in Study 2 was also related to concurrently measured intelligence, predictive relations with academic, health, and social outcomes in adolescence were more consistently explained by ratings of effortful control. Collectively, these findings suggest that delay task performance may be influenced by extraneous traits, but its predictive power derives primarily from its assessment of self-control. PMID- 23813424 TI - Self-compassionate reactions to health threats. AB - Four studies investigated the relationship between self-compassion, health behaviors, and reactions to illness. Participants completed measures of self compassion, health-related thoughts and feelings, reactions to actual and hypothetical illnesses, and self-regulation. Study 1 revealed that self compassion was related to health-related cognitions and affect for healthy and unhealthy participants. In Study 2, self-compassion predicted participants' reactions to actual illnesses beyond the influence of illness severity and other predictors of health behaviors. Self-compassionate people also indicated they would seek medical attention sooner when experiencing symptoms than people lower in self-compassion. Study 3 demonstrated that self-compassion is related to health-promoting behaviors even after accounting for self-regulatory capabilities and illness cognitions. Study 4 revealed that the relationship between self compassion and health reactions is partially explained by a proactive approach to health, benevolent self-talk, and a motivation toward self-kindness. Overall, these studies demonstrate that self-compassion has important implications for health-promoting behaviors and reactions to illness. PMID- 23813425 TI - Chinese medicinal herbs for cholelithiasis. AB - BACKGROUND: Cholelithiasis is a common disease of the biliary tract. Chinese medicinal herbs are being used widely as an alternative treatment in people with cholelithiasis, but their beneficial or harmful effects have not been assessed systematically. OBJECTIVES: To assess the beneficial and harmful effects of Chinese medicinal herbs in people with cholelithiasis. SEARCH METHODS: We conducted searches in the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, Chinese Medicine Conference Disc, and Chinese Bio-Medicine Disc to January 2013. We handsearched four Chinese journals. No language or year of publication restrictions were applied. SELECTION CRITERIA: Randomised clinical trials studying Chinese medicinal herbs for treatment of cholelithiasis. DATA COLLECTION AND ANALYSIS: Two review authors (SJ, TG) independently extracted data. For dichotomous data, we estimated the risk ratio (RR), and for continuous data, we calculated the mean difference. We also calculated 95% confidence intervals (CI). MAIN RESULTS: Eleven randomised trials with 1205 participants with asymptomatic or mild-to-moderate cholelithiasis were included. None of the randomised clinical trials compared a single Chinese medicinal herb with a Western medicine or with surgery. No placebo-controlled trials were identified. In the trials comparing one Chinese herbal medicine (Gandanxiaoshi tablet) versus another (Aihuodantong tablet), there was no significant difference in the improvement of upper abdominal pain after the end of treatment (RR 1.21; 95% CI 0.71 to 2.05), and the heterogeneity among trials was not substantial. No other outcomes could be assessed. The remaining trials of Chinese medicinal herbs (Qingdan capsule, Danshu capsule, Paishi capsule, Rongdanpaishi capsule), did not offer specific data on symptoms, signs, or change in gallstones that would permit assessment of significant differences in curative effects between the treatment and control groups. No serious adverse events were reported. AUTHORS' CONCLUSIONS: This review reveals no strong evidence that the analysed Chinese medicinal herbs have any beneficial effects on asymptomatic or mild-to-moderate cholelithiasis. Definitive conclusions will require much better designed randomised trials to reduce risk of bias and allow detailed assessment of clinical outcomes. PMID- 23813426 TI - Manganese-induced effects on cerebral trace element and nitric oxide of Hyline cocks. AB - Exposure to Manganese (Mn) is a common phenomenon due to its environmental pervasiveness. To investigate the Mn-induced toxicity on cerebral trace element levels and crucial nitric oxide parameters on brain of birds, 50-day-old male Hyline cocks were fed either a commercial diet or a Mn-supplemented diet containing 600, 900, 1,800 mg kg(-1). After being treated with Mn for 30, 60, and 90 days, the following were determined: the changes in contents of copper (Cu), iron (Fe), zinc (Zn), calcium (Ca), selenium (Se) in brain; inducible nitric oxide synthase-nitric oxide (iNOS-NO) system activity in brain; and histopathology and ultrastructure changes of cerebral cortex. The results showed that Mn was accumulated in brain and the content of Cu and Fe increased. However, the levels of Zn and Se decreased and the Ca content presented no obvious regularity. Exposure to Mn significantly elevated the content of NO and the expression of iNOS mRNA. Activity of total NO synthase (T NOS) and iNOS appeared with an increased tendency. These findings suggested that Mn exposure resulted in the imbalance of cerebral trace elements and influenced iNOS in the molecular level, which are possible underlying nervous system injury mechanisms induced by Mn exposure. PMID- 23813427 TI - Poor response to thiopurine in inflammatory bowel disease: how to overcome therapeutic resistance? PMID- 23813428 TI - Commentary. PMID- 23813429 TI - Commentary. PMID- 23813430 TI - It's not that crystal clear. PMID- 23813431 TI - Detecting in the dark. PMID- 23813434 TI - Art and science: interacting universes. PMID- 23813437 TI - Ophthalmic delivery of brinzolamide by liquid crystalline nanoparticles: in vitro and in vivo evaluation. AB - Brinzolamide (BLZ) is a drug used to treat glaucoma; however, its use is restricted due to some unwanted adverse events. The goal of this study was to develop BLZ-loaded liquid crystalline nanoparticles (BLZ LCNPs) and to figure out the possibility of LCNPs as a new therapeutic system for glaucoma. BLZ LCNPs were produced by a modified emulsification method and their physicochemical aspects were estimated. In vitro release study revealed BLZ LCNPs displayed to some extent prolonged drug release behavior in contrast to that of BLZ commercial product (Azopt(r)). The ex vivo apparent permeability coefficient of BLZ LCNP systems demonstrated a 3.47-fold increase compared with that of Azopt(r). The pharmacodynamics was checked over by calculating the percentage fall in intraocular pressure and the pharmacodynamic test showed that BLZ LCNPs had better therapeutic potential than Azopt(r). Furthermore, the in vivo ophthalmic irritation was evaluated by Draize test. In conclusion, BLZ LCNPs would be a promising delivery system used for the treatment of glaucoma, with advantages such as lower doses but maintaining the effectiveness, better ocular bioavailability, and patient compliance compared with Azopt(r). PMID- 23813436 TI - Treatment of graft-versus-host disease with naturally occurring T regulatory cells. AB - A significant body of evidence suggests that treatment with naturally occurring CD4(+)CD25(+) T regulatory cells (Tregs) is an appropriate therapy for graft versus-host disease (GvHD). GvHD is a major complication of bone marrow transplantation in which the transplanted immune system recognizes recipient tissues as a non-self and destroys them. In many cases, this condition significantly deteriorates the quality of life of the affected patients. It is also one of the most important causes of death after bone marrow transplantation. Tregs constitute a population responsible for dominant tolerance to self-tissues in the immune system. These cells prevent autoimmune and allergic reactions and decrease the risk of rejection of allotransplants. For these reasons, Tregs are considered as a cellular drug in GvHD. The results of the first clinical trials with these cells are already available. In this review we present important experimental facts which led to the clinical use of Tregs. We then critically evaluate specific requirements for Treg therapy in GvHD and therapies with Tregs currently under clinical investigation, including our experience and future perspectives on this kind of cellular treatment. PMID- 23813435 TI - Emerging targets and novel approaches to Ebola virus prophylaxis and treatment. AB - Ebola is a highly virulent pathogen causing severe hemorrhagic fever with a high case fatality rate in humans and non-human primates (NHPs). Although safe and effective vaccines or other medicinal agents to block Ebola infection are currently unavailable, a significant effort has been put forth to identify several promising candidates for the treatment and prevention of Ebola hemorrhagic fever. Among these, recombinant adenovirus-based vectors have been identified as potent vaccine candidates, with some affording both pre- and post exposure protection from the virus. Recently, Investigational New Drug (IND) applications have been approved by the US Food and Drug Administration (FDA) and phase I clinical trials have been initiated for two small-molecule therapeutics: anti-sense phosphorodiamidate morpholino oligomers (PMOs: AVI-6002, AVI-6003) and lipid nanoparticle/small interfering RNA (LNP/siRNA: TKM-Ebola). These potential alternatives to vector-based vaccines require multiple doses to achieve therapeutic efficacy, which is not ideal with regard to patient compliance and outbreak scenarios. These concerns have fueled a quest for even better vaccination and treatment strategies. Here, we summarize recent advances in vaccines or post-exposure therapeutics for prevention of Ebola hemorrhagic fever. The utility of novel pharmaceutical approaches to refine and overcome barriers associated with the most promising therapeutic platforms are also discussed. PMID- 23813438 TI - Validation of a new HPLC-UV method for determination of the antibiotic linezolid in human plasma and in bronchoalveolar lavage. AB - A rapid and selective HPLC-UV method was developed for the quantification of linezolid (LNZ) in human plasma and bronchoalveolar lavage (BAL) at the concentrations associated with therapy. Plasma samples were extracted by solid phase extraction followed by evaporation to dryness and reconstitution in mobile phase solution. The chromatographic separation was carried out on a C18 column with an isocratic mobile phase consisting of dihydrogen phosphate buffer 50 mm (pH 3.5) and acetonitrile (60:40 v/v). The detection was performed using a photodiode array. Under these conditions, a single chromatographic run could be completed within 12 min. The method was validated by estimating the precision and the accuracy for inter- and intra-day analysis in the concentration range of 25 25600 ng/mL. The method was linear over the investigated range with all the correlation coefficients R > 0.999. The intra- and inter-day precision was within 8.90% and the accuracy ranged from -4.76 to +5.20%. This rapid and sensitive method was fully validated and could be applied to pharmacokinetic study for the determination of LNZ levels in human plasma and BAL samples. PMID- 23813439 TI - Knockdown of core binding factorbeta alters sphingolipid metabolism. AB - Core binding factor (CBF) is a heterodimeric transcription factor containing one of three DNA-binding proteins of the Runt-related transcription factor family (RUNX1-3) and the non-DNA-binding protein, CBFbeta. RUNX1 and CBFbeta are the most common targets of chromosomal rearrangements in leukemia. CBF has been implicated in other cancer types; for example RUNX1 and RUNX2 are implicated in cancers of epithelial origin, including prostate, breast, and ovarian cancers. In these tumors, CBF is involved in maintaining the malignant phenotype and, when highly over-expressed, contributes to metastatic growth in bone. Herein, lentiviral delivery of CBFbeta-specific shRNAs was used to achieve a 95% reduction of CBFbeta in an ovarian cancer cell line. This drastic reduction in CBFbeta expression resulted in growth inhibition that was not associated with a cell cycle block or an increase in apoptosis. However, CBFbeta silencing resulted in increased autophagy and production of reactive oxygen species (ROS). Since sphingolipid and ceramide metabolism regulates non-apoptotic cell death, autophagy, and ROS production, fumonsin B1 (FB1), an inhibitor of ceramide synthase, was used to alter ceramide production in the CBFbeta-silenced cells. FB1 treatment inhibited the CBFbeta-dependent increase in autophagy and provided a modest increase in cell survival. To document alterations to sphingolipids in the CBFbeta-silenced cells, ceramide, and lactosylceramide levels were directly examined by mass spectrometry. Substantial increases in ceramide species and decreases in lactosylceramides were identified. Altogether, this report provides evidence that CBF transcriptional pathways control cellular survival, at least in part, through sphingolipid metabolism. PMID- 23813440 TI - Does economic incentive matter for rational use of medicine? China's experience from the essential medicines program. AB - BACKGROUND: Before the new round of healthcare reform in China, primary healthcare providers could obtain a fixed 15 % or greater mark-up of profits by prescribing and selling medicines. There were concerns that this perverse incentive was a key cause of irrational medicine use. China's new Essential Medicines Program (EMP) was launched in 2009 as part of the national health sector reform initiatives. One of its core policies was to eliminate primary care providers' economic incentives to overprescribe or prescribe unnecessarily expensive drugs, which were regarded as consequences of China's traditional financing system for health institutions. OBJECTIVES: The objective of the study was to measure changes in prescribing patterns in primary healthcare facilities after the removal of the economic incentives for physicians to overprescribe as a result of the implementation of the EMP. METHODS: A comparison design was applied to 8,258 prescriptions in 2007 and 8,278 prescriptions in 2010, from 83 primary healthcare facilities nationwide. Indicators were adopted to evaluate medicine utilization, which included overall number of medicines, average number of Western and traditional Chinese medicines, pharmaceutical expenditure per outpatient prescription, and proportion of prescriptions that contained two or more antibiotics. We further assessed the use of medicines (antibiotics, infusion, hormones, and intravenous injection) per disease-specific prescription for hypertension, diabetes, coronary artery heart disease, bronchitis, upper respiratory tract infection, and gastritis. A difference-in-difference analysis was employed to evaluate the net policy effect. RESULTS: Overall changes in indicators were not found to be statistically significant between the 2 years. The results varied for different diseases. The number of Western drugs per outpatient prescription decreased while that of traditional Chinese medicines increased. Overuse of antibiotics remained an extensive problem in the treatment of many diseases, though there was some significant improvement in certain diseases, like diabetes in rural areas. Medicine expenditure per prescription also decreased. CONCLUSIONS: It seems that the removal of a perverse economic incentive alone would not lead to improvement of healthcare providers' prescribing patterns. The rationality of the Essential Medicines List and the lack of payers' and providers' meaningful involvement in the development of the policy possibly contribute to the lack of significant changes in prescribing behaviors. It is suggested that China should adopt more comprehensive policies for healthcare facilities, physicians, patients, and payers, rather than just relying on economic incentives to improve rational use of medicines. PMID- 23813441 TI - Seven-tesla phase imaging of acute multiple sclerosis lesions: a new window into the inflammatory process. AB - OBJECTIVE: In multiple sclerosis (MS), accurate, in vivo characterization of dynamic inflammatory pathological changes occurring in newly forming lesions could have major implications for understanding disease pathogenesis and mechanisms of tissue destruction. Here, we investigated the potential of ultrahigh-field magnetic resonance imaging (MRI; 7T), particularly phase imaging combined with dynamic contrast enhancement, to provide new insights in acute MS lesions. METHODS: Sixteen active MS patients were studied at 7T. Noncontrast, high-resolution T2* magnitude and phase scans, T1 scans before/after gadolinium contrast injection, and dynamic contrast-enhanced (DCE) T1 scans were acquired. T2*/phase features and DCE pattern were determined for acute and chronic lesions. When possible, 1-year follow-up 7T MRI was performed. RESULTS: Of 49 contrast enhancing lesions, 44 could be analyzed. Centrifugal DCE lesions appeared isointense or hypointense on phase images, whereas centripetal DCE lesions showed thin, hypointense phase rims that clearly colocalized with the initial site of contrast enhancement. This pattern generally disappeared once enhancement resolved. Conversely, in 43 chronic lesions also selected for the presence of hypointense phase rims, the findings were stable over time, and the rims were typically thicker and darker. These considerations suggest different underlying pathological processes in the 2 lesion types. INTERPRETATION: Ultrahigh-field MRI and, especially, phase contrast, are highly sensitive to tissue changes in acute MS lesions, which differ from the patterns seen in chronic lesions. In acute lesions, the hypointense phase rim reflects the expanding inflammatory edge and may directly correspond to inflammatory byproducts and sequelae of blood-brain barrier opening. PMID- 23813442 TI - Bone remodelling is reduced by recovery from iron-deficiency anaemia in premenopausal women. AB - Iron-deficiency anaemia (IDA), one of the most common and widespread health disorders worldwide, affects fundamental metabolic functions and has been associated with deleterious effects on bone. Our aim was to know whether there are differences in bone remodelling between a group of premenopausal IDA women and a healthy group, and whether recovery of iron status has an effect on bone turnover markers. Thirty-five IDA women and 38 healthy women (control group) were recruited throughout the year. IDA women received pharmacological iron treatment. Iron biomarkers, aminoterminal telopeptide of collagen I (NTx), procollagen type 1 N-terminal propeptide (P1NP), 25-hydroxyvitamin D, and parathormone (PTH) were determined at baseline for both groups and after treatment with pharmacological iron for the IDA group. IDA subjects were classified as recovered (R) or non recovered (nR) from IDA after treatment. NTx levels were significantly higher (p <0.001), and P1NP levels tended to be lower in IDA women than controls after adjusting for age and body mass index (BMI), with no differences in 25 hydroxyvitamin D or PTH. After treatment, the R group had significantly lower NTx and P1NP levels compared to baseline (p <0.05 and p <0.001 respectively), whilst no significant changes were seen in the nR group. No changes were seen in 25 hydroxyvitamin D or PTH for either group. IDA is related to higher bone resorption independent of age and BMI. Recovery from IDA has a concomitant beneficial effect on bone remodelling in premenopausal women, decreasing both bone resorption and formation. PMID- 23813443 TI - Positive influence of a natural product as propolis on antioxidant status and lipid peroxidation in senescent rats. AB - Given the importance of oxidative stress associated to aging, it would be interesting to assess the effect of oral supplementation with antioxidant substances capable of diminishing oxidative aggression and free radicals generation associated to this condition. This study investigated the effects of AIN-93 M diet supplemented either with 2 % of propolis, or with 4 % of a natural product obtained from lyophilizate vegetables, selected by its antioxidant properties, in senescent healthy Wistar rats fed ad libitum over 3 months. Propolis supplementation leads to a lower level of glucose and cholesterol concentrations together with a reduction in protein oxidation. Plasma thiobarbituric acid-reactive substance levels were lower in the rats consuming the natural vegetable product and propolis possibly due to its antioxidant components, neutralizing the free radical produced, and thus preventing cellular damage. The results of the present study suggest a synergic effect of overall propolis compounds reducing the oxidative stress and glucose and cholesterol plasma levels associated with aging. PMID- 23813444 TI - Prospective motion correction using inductively coupled wireless RF coils. AB - PURPOSE: A novel prospective motion correction technique for brain MRI is presented that uses miniature wireless radio-frequency coils, or "wireless markers," for position tracking. METHODS: Each marker is free of traditional cable connections to the scanner. Instead, its signal is wirelessly linked to the MR receiver via inductive coupling with the head coil. Real-time tracking of rigid head motion is performed using a pair of glasses integrated with three wireless markers. A tracking pulse-sequence, combined with knowledge of the markers' unique geometrical arrangement, is used to measure their positions. Tracking data from the glasses is then used to prospectively update the orientation and position of the image-volume so that it follows the motion of the head. RESULTS: Wireless-marker position measurements were comparable to measurements using traditional wired radio-frequency tracking coils, with the standard deviation of the difference < 0.01 mm over the range of positions measured inside the head coil. Wireless-marker safety was verified with B1 maps and temperature measurements. Prospective motion correction was demonstrated in a 2D spin-echo scan while the subject performed a series of deliberate head rotations. CONCLUSION: Prospective motion correction using wireless markers enables high quality images to be acquired even during bulk motions. Wireless markers are small, avoid radio-frequency safety risks from electrical cables, are not hampered by mechanical connections to the scanner, and require minimal setup times. These advantages may help to facilitate adoption in the clinic. PMID- 23813445 TI - Degrading magnesium screws ZEK100: biomechanical testing, degradation analysis and soft-tissue biocompatibility in a rabbit model. AB - Magnesium alloys are promising implant materials for use in orthopaedic applications. In the present study, screws made of the Mg-alloy ZEK100 (n = 12) were implanted in rabbit tibiae for four and six weeks, respectively. For degradation analysis, in vivo u-computed tomography (uCT), a determination of the weight changes and SEM/EDX examinations of the screws were performed. Screw retention forces were verified by uniaxial pull-out tests. Additionally, soft tissue biocompatibility was estimated using routine histological methods (H&E staining) and the immunohistological characterization of B- and T-cells. After six weeks, a 7.5% weight reduction occurred and, in dependence of the implant surrounding, the volume loss (uCT) reached 9.6% (screw head) and 5.0% for the part of the thread in the marrow cavity. Pull-out forces significantly decreased to 44.4% in comparison with the origin value directly after implantation. Soft tissue reactions were characterized by macrophage and lymphocyte infiltration, whereas T-cells as well as B-cells could be observed. In comparison to MgCa0.8 screws, the degradation rate and inflammatory tissue response were increased and the screw holding power was decreased after six weeks. In conclusion, ZEK100 screws seem to be inferior to MgCa0.8-screws, although their initial strength was more appropriate. PMID- 23813446 TI - Physiologically based pharmacokinetic and pharmacodynamic modeling of an antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in a mouse xenograft model of human breast cancer. AB - The inhibitors of apoptosis proteins (IAPs) are a class of key apoptosis regulators overexpressed or dysregulated in cancer. SM-406/AT-406 is a potent and selective small molecule mimetic of Smac that antagonizes the inhibitor of apoptosis proteins (IAPs). A physiologically based pharmacokinetic and pharmacodynamic (PBPK-PD) model was developed to predict the tissue concentration time profiles of SM-406, the related onco-protein levels in tumor, and the tumor growth inhibition in a mouse model bearing human breast cancer xenograft. In the whole body physiologically based pharmacokinetic (PBPK) model for pharmacokinetics characterization, a well stirred (perfusion rate-limited) model was used to describe SM-406 pharmacokinetics in the lung, heart, kidney, intestine, liver and spleen, and a diffusion rate-limited (permeability limited) model was used for tumor. Pharmacodynamic (PD) models were developed to correlate the SM-406 concentration in tumor to the cIAP1 degradation, pro-caspase 8 decrease, CL-PARP accumulation and tumor growth inhibition. The PBPK-PD model well described the experimental pharmacokinetic data, the pharmacodynamic biomarker responses and tumor growth. This model may be helpful to predict tumor and plasma SM-406 concentrations in the clinic. PMID- 23813447 TI - Involvement of miRNAs in equine follicle development. AB - Previous evidence from in vitro studies suggests specific roles for a subset of miRNAs, including miR-21, miR-23a, miR-145, miR-503, miR-224, miR-383, miR-378, miR-132, and miR-212, in regulating ovarian follicle development. The objective of this study was to determine changes in the levels of these miRNAs in relation to follicle selection, maturation, and ovulation in the monovular equine ovary. In Experiment 1, follicular fluid was aspirated during ovulatory cycles from the dominant (DO) and largest subordinate (S) follicles of an ovulatory wave and the dominant (DA) follicle of a mid-cycle anovulatory wave (n=6 mares). Follicular fluid levels of progesterone and estradiol were lower (P<0.01) in S follicles than in DO follicles, whereas mean levels of IGF1 were lower (P<0.01) in S and DA follicles than in DO follicles. Relative to DO and DA follicles, S follicles had higher (P<=0.01) follicular fluid levels of miR-145 and miR-378. In Experiment 2, follicular fluid and granulosa cells were aspirated from dominant follicles before (DO) and 24 h after (L) administration of an ovulatory dose of hCG (n=5 mares/group). Relative to DO follicles, L follicles had higher follicular fluid levels of progesterone (P=0.05) and lower granulosa cell levels of CYP19A1 and LHCGR (P<0.005). Levels of miR-21, miR-132, miR-212, and miR-224 were increased (P<0.05) in L follicles; this was associated with reduced expression of the putative miRNA targets, PTEN, RASA1, and SMAD4. These novel results may indicate a physiological involvement of miR-21, miR-145, miR-224, miR-378, miR-132, and miR-212 in the regulation of cell survival, steroidogenesis, and differentiation during follicle selection and ovulation in the monovular ovary. PMID- 23813448 TI - The senescence-accelerated mouse prone 8 as a model for oxidative stress and impaired DNA repair in the male germ line. AB - The discovery of a truncated base excision repair pathway in human spermatozoa mediated by OGG1 has raised questions regarding the effect of mutations in critical DNA repair genes on the integrity of the paternal genome. The senescence accelerated mouse prone 8 (SAMP8) is a mouse model containing a suite of naturally occurring mutations resulting in an accelerated senescence phenotype largely mediated by oxidative stress, which is further enhanced by a mutation in the Ogg1 gene, greatly reducing the ability of the enzyme to excise 8-hydroxy,2' deoxyguanosine (8OHdG) adducts. An analysis of the reproductive phenotype of the SAMP8 males revealed a high level of DNA damage in caudal epididymal spermatozoa as measured by the alkaline Comet assay. Furthermore, these lesions were confirmed to be oxidative in nature, as demonstrated by significant increases in 8OHdG adduct formation in the SAMP8 testicular tissue (P<0.05) as well as in mature spermatozoa (P<0.001) relative to a control strain (SAMR1). Despite this high level of oxidative DNA damage in spermatozoa, reactive oxygen species generation was not elevated and motility of spermatozoa was found to be similar to that for the control strain with the exception of progressive motility, which exhibited a slight but significant decline with advancing age (P<0.05). When challenged with Fenton reagents (H2O2 and Fe2+), the SAMP8 spermatozoa demonstrated a highly increased susceptibility to formation of 8OHdG adducts compared with the controls (P<0.001). These data highlight the role of oxidative stress and OGG1-dependent base excision repair mechanisms in defining the genetic integrity of mammalian spermatozoa. PMID- 23813449 TI - Differential effects of docosahexaenoic acid on preterm and term placental pro oxidant/antioxidant balance. AB - Docosahexaenoic acid (DHA) supplementation in pregnancy may confer some clinical benefits; however, this compound can exert pro-oxidant effects. In this study, we investigated the effects of DHA on pro-oxidant/antioxidant balance in term and preterm placental explants, assessing oxidative stress marker concentrations, antioxidant capacity and pro-inflammatory cytokine production. Term (n=8) and preterm (n=9) placental explants were exposed to lipopolysaccharide (LPS, 1 ng/ml), DHA (1, 10 and 100 MUM), and DHA and LPS simultaneously or pre-treated with DHA for 24 h prior to LPS treatment. The production of malondialdehyde (MDA, lipid peroxidation), 8-hydroxy-2-deoxy guanosine (8-OHdG, oxidative DNA damage) and pro-inflammatory cytokines (tumour necrosis factor alpha (TNFalpha), interleukin 6 and interferon-gamma) and total antioxidant capacity were measured. DHA at a concentration of 100 MUM induced oxidative stress in term placentas, while at all the three concentrations, it induced oxidative stress in preterm placentas. DHA and LPS resulted in reduced MDA levels in term (P<0.005) and preterm (P=0.004) placentas and reduced 8-OHdG levels in preterm placentas (P=0.035). DHA pre-treatment, but not co-treatment with LPS, reduced 8-OHdG levels (P<0.001) in term placentas. DHA increased antioxidant capacity only in term placentas (P<0.001), with lower antioxidant capacity being observed overall in preterm placentas compared with term placentas (P<=0.001). In term placentas, but not in preterm ones, DHA co-treatment and pre-treatment reduced LPS-induced TNFalpha levels. The ability of DHA to alter placental pro-oxidant/antioxidant balance is dependent on the DHA concentration used and the gestational age of the placental tissue. DHA has a greater capacity to increase oxidative stress in preterm placentas, but it offers greater protection against inflammation-induced oxidative stress in term placentas. This appears to be a result of DHA altering placental antioxidant capacity. These data have implications for the timing and concentration of DHA supplementation in pregnancy. PMID- 23813450 TI - A historical perspective of pacemaker infections: 40-years single-centre experience. AB - AIMS: The approach to infected cardiac devices has changed during recent decades. Optimal treatment is still a matter of debate, especially in pacemaker-dependent patients. Therefore, we investigated the management and outcome of patients with pacemaker infections in a single centre over four decades. METHODS AND RESULTS: We conducted a retrospective analysis of 4212 patients and extracted those with pacemaker infections admitted to Rostock Heart Center between 1973 and 2012. One hundred and thirty-one consecutive patients (median age 69.6 +/- 14.9 years) were admitted for device infections. Two-stage exchange was performed in 42 patients (32.8%). In 72 patients (55%), explantation and implantation on the contralateral side was performed simultaneously. In 17 cases the device was not replaced. Mean follow-up was 63 +/- 81 months. Reinfection rate was 12.2%, which declined from 24% (1980s) to 2.6% (after 2000). Complete device removal (in 57.3%) reduced the risk for reinfection by 75% (P = 0.02), as well as increasing age (0.049% per year, P = 0.001). One-stage exchange increased the risk of reinfection six-fold (P = 0.021). Cultured bacteria after initiation of antibiotic therapy predicted a four-fold increase in risk of a recurrent infection (P = 0.01). CONCLUSION: Continuous assimilation of guidelines for pacemaker infection improved the outcome over time: complete extraction of the infected device seems to be highly desirable. A one-stage exchange increased the risk of recurrent device infection and should probably be avoided, but complete extraction seems to be more important than timing. PMID- 23813451 TI - Passive-fixation lead failure rates and long-term patient mortality in subjects implanted with Sprint Fidelis electrodes. AB - AIMS: To evaluate passive-fixation lead failure rates and long-term patient survival in subjects implanted with Sprint Fidelis electrodes. METHODS AND RESULTS: We identified 748 subjects who received a Sprint Fidelis (n = 429; Medtronic models 6948: 94.8%, 6949: 2.6%, 6930: 1.9%, 6931: 0.7%) or a Sprint 'non-Fidelis' implantable cardioverter defibrillator lead (n = 319, Medtronic models 6944: 68.6%, 6947: 17.9%, 6942: 7.8%, 6943: 3.4%, 6945: 2.2%) at our centre between 1998 and 2008. Kaplan-Meier patient survival was lower in the Fidelis group than in the Control cohort (68.4 vs. 77.0% at 5 years, P = 0.0061), but multivariate analyses revealed no significant association between mortality and implanted lead type. Passive-fixation lead failure rate at 5 years was 14.4% (95% confidence interval (CI) [9.2, 19.3]) in the Fidelis (n = 414) group and 1.8% (95% CI [0.0-3.8]) in the Control (n = 241) cohort (P < 0.001 upon multivariate comparison). CONCLUSION: Failure rates of passive-fixation Sprint Fidelis leads are increased and similar to those previously reported for active fixation Fidelis electrodes. Despite the elevated risk for lead failure and its potential sequelae, the Sprint Fidelis has no obvious impact on long-term mortality. PMID- 23813452 TI - CHADS2 and CHA2DS2-VASc scores as predictors of left atrial ablation outcomes for paroxysmal atrial fibrillation. AB - AIMS: The selection of patients with atrial fibrillation (AF) that will benefit most by left atrial ablation remains suboptimal. CHADS2 score has been shown to be associated with post-ablation AF recurrences. However, data regarding the CHA2DS2-VASc score are lacking. In addition, there is paucity of data regarding the exact predictive value, in terms of sensitivity and specificity, of each of these scores as to AF recurrence. This study aimed to evaluate the merit of the CHADS2 and CHA2DS2-VASc scores in predicting arrhythmia recurrence after a single ablation procedure for paroxysmal AF. METHODS AND RESULTS: One hundred and twenty six patients (78 males, median age 61 years) with symptomatic paroxysmal AF underwent left atrial ablation. Over 16 months (interquartile range: 10.8-26.0), 89 patients were recurrence-free (70.6%). Larger left atrial volume (P: 0.039), diabetes (P: 0.001), dyslipidemia (P: 0.003), coronary artery disease (P: 0.003), class III antiarrhythmic drugs (P: 0.017), CHADS2 (P: 0.006), and CHA2DS2-VASc (P: 0.016) scores were univariately associated with recurrence. In the multivariate analysis, both CHADS2 (hazard ratio: 1.91, 95% confidence interval 1.09-3.36, P: 0.023) and CHA2DS2-VASc (hazard ratio: 1.97, 95% confidence interval 1.16-3.33, P: 0.012) were independently associated with AF recurrence. Cut-off analysis showed that a score >=2 for both the CHADS2 (sensitivity = 46% and specificity = 79%, area under the Receiver's operating characteristic curve, AUC = 0.644) and CHA2DS2-VASc score (sensitivity = 57% and specificity = 65%, AUC = 0.627) showed the highest predictive value for AF recurrence. CONCLUSIONS: CHA2DS2-VASc score is an independent predictor of left atrial ablation outcomes for paroxysmal AF, with a similar predictive value to CHADS2. However, the predictive accuracy of both is mediocre. PMID- 23813453 TI - One-year adjustable intragastric balloons: do they offer more than two consecutive nonadjustable 6-month balloons? A response to Genco et al. PMID- 23813454 TI - Progesterone receptor membrane component 1 as the mediator of the inhibitory effect of progestins on cytokine-induced matrix metalloproteinase 9 activity in vitro. AB - Progesterone (P4) and the progestin, 17alpha-hydroxyprogesterone caproate, are clinically used to prevent preterm births (PTBs); however, their mechanism of action remains unclear. Cytokine-induced matrix metalloproteinase 9 (MMP-9) activity plays a key role in preterm premature rupture of the membranes and PTB. We demonstrated that the primary chorion cells and the HTR8/SVneo cells (cytotrophoblast cell line) do not express the classical progesterone receptor (PGR) but instead a novel progesterone receptor, progesterone receptor membrane component 1 (PGRMC1), whose role remains unclear. Using HTR8/SVneo cells in culture, we further demonstrated that 6 hours pretreatment with medroxyprogesterone acetate (MPA) and dexamethasone (Dex) but not P4 or 17alpha hydroxyprogesterone hexanoate significantly attenuated tumor necrosis factor alpha-induced MMP-9 activity after a 24-hour incubation period. The inhibitory effect of MPA, but not Dex, was attenuated when PGRMC1 expression was successfully reduced by PGRMC1 small interfering RNA. Our findings highlight a possible novel role of PGRMC1 in mediating the effects of MPA and in modulating cytokine-induced MMP-9 activity in cytotrophoblast cells in vitro. PMID- 23813455 TI - Beta-lactam versus beta-lactam-aminoglycoside combination therapy in cancer patients with neutropenia. AB - BACKGROUND: Continued controversy surrounds the optimal empirical treatment for febrile neutropenia. New broad-spectrum beta-lactams have been introduced as single treatment, and classically, a combination of a beta-lactam with an aminoglycoside has been used. OBJECTIVES: To compare beta-lactam monotherapy versus beta-lactam-aminoglycoside combination therapy for cancer patients with fever and neutropenia. SEARCH METHODS: The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 7, 2012), LILACS (August 2012), MEDLINE and EMBASE (August 2012) and the Database of Abstracts of Reviews of Effects (DARE) (Issue 3, 2012). We scanned references of all included studies and pertinent reviews and contacted the first author of each included trial, as well as the pharmaceutical companies. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing any beta-lactam antibiotic monotherapy with any combination of a beta-lactam and an aminoglycoside antibiotic, for the initial empirical treatment of febrile neutropenic cancer patients. All cause mortality was the primary outcome assessed. DATA COLLECTION AND ANALYSIS: Data concerning all cause mortality, infection related mortality, treatment failure (including treatment modifications), super-infections, adverse effects and study quality measures were extracted independently by two review authors. Risk ratios (RRs) with their 95% confidence intervals (CIs) were estimated. Outcomes were extracted by intention-to-treat (ITT) analysis whenever possible. Individual domains of risk of bias were examined through sensitivity analyses. Published data were complemented by correspondence with authors. MAIN RESULTS: Seventy-one trials published between 1983 and 2012 were included. All cause mortality was lower with monotherapy (RR 0.87, 95% CI 0.75 to 1.02, without statistical significance). Results were similar for trials comparing the same beta-lactam in both trial arms (11 trials, 1718 episodes; RR 0.74, 95% CI 0.53 to 1.06) and for trials comparing different beta-lactams-usually a broad-spectrum beta-lactam compared with a narrower-spectrum beta-lactam combined with an aminoglycoside (33 trials, 5468 episodes; RR 0.91, 95% CI 0.77 to 1.09). Infection related mortality was significantly lower with monotherapy (RR 0.80, 95% CI 0.64 to 0.99). Treatment failure was significantly more frequent with monotherapy in trials comparing the same beta-lactam (16 trials, 2833 episodes; RR 1.11, 95% CI 1.02 to 1.20), and was significantly more frequent with combination therapy in trials comparing different beta-lactams (55 trials, 7736 episodes; RR 0.92, 95% CI 0.88 to 0.97). Bacterial super-infections occurred with equal frequency, and fungal super infections were more common with combination therapy. Adverse events were more frequent with combination therapy (numbers needed to harm 4; 95% CI 4 to 5). Specifically, the difference with regard to nephrotoxicity was highly significant. Adequate trial methods were associated with a larger effect estimate for mortality and smaller effect estimates for failure. Nearly all trials were open-label. No correlation was noted between mortality and failure rates and these trials. AUTHORS' CONCLUSIONS: Beta-lactam monotherapy is advantageous compared with beta-lactam-aminoglycoside combination therapy with regard to survival, adverse events and fungal super-infections. Treatment failure should not be regarded as the primary outcome in open-label trials, as it reflects mainly treatment modifications. PMID- 23813456 TI - A selective M1 and M3 receptor antagonist, penehyclidine hydrochloride, prevents postischemic LTP: involvement of NMDA receptors. AB - Our previous and other studies have confirmed that a selective M1 and M3 receptor antagonist, Penehyclidine hydrochloride (PHC), has neuroprotection activity in cerebral ischemia. However, the precise mechanisms of protection of PHC are still elusive. In this study we analyzed PHC-mediated neuroprotection on a model of brain ischemia (oxygen and glucose deprivation), named postischemic LTP (i-LTP). We found that the activation of NMDA receptor was required for the induction of i LTP. Compared with scopolamine, PHC could prevent it due to selectively blocking M1 receptor, not M2 receptor, to decrease NMDAR activation. Our findings further showed that the inhibition of SK2 channels occluded the prevention of PHC on NMDAR activation. Furthermore, we confirmed that PHC exerted its roles through directly disinhibition of SK2 channels by blocking M1 receptor and subsequent restricting PKC activation. Moreover, our studies further revealed the critical roles of SK2 channels in i-LTP. Thus, the mechanisms of PHC in brain protection may be involved in suppression of NMDAR by regulation of SK2 channels. Our results obtained in effects of PHC on i-LTP further provided a better understanding of the therapy strategy during stroke and identified potential therapeutic targets to prevent development of ischemia. PMID- 23813457 TI - Build a better mouse model, and the world will beat a path to your door. PMID- 23813458 TI - Oxidative stress in breath-hold divers after repetitive dives. AB - INTRODUCTION: Hyperoxia causes oxidative stress. Breath-hold diving is associated with transient hyperoxia followed by hypoxia and a build-up of carbon dioxide (CO2), chest-wall compression and significant haemodynamic changes. This study analyses variations in plasma oxidative stress markers after a series of repetitive breath-hold dives. METHODS: Thirteen breath-hold divers were asked to perform repetitive breath-hold dives to 20 metres' depth to a cumulative breath hold time of approximately 20 minutes over an hour in the open sea. Plasma nitric oxide (NO), peroxinitrites (ONOO-) and thiols (R-SH) were measured before and after the dive sequence. RESULTS: Circulating NO significantly increased after successive breath-hold dives (169.1 +/- 58.26% of pre-dive values; P = 0.0002). Peroxinitrites doubled after the dives (207.2 +/- 78.31% of pre-dive values; P = 0.0012). Thiols were significantly reduced (69.88 +/- 19.23% of pre-dive values; P = 0.0002). CONCLUSION: NO may be produced by physical effort during breath-hold diving. Physical exercise, the transient hyperoxia followed by hypoxia and CO2 accumulation would all contribute to the increased levels of superoxide anions (O22-). Since interaction of O22- with NO forms ONOO-, this reaction is favoured and the production of thiol groups is reduced. Oxidative stress is, thus, present in breath-hold diving. PMID- 23813459 TI - Oxygen exposure and toxicity in recreational technical divers. AB - INTRODUCTION: Central nervous system oxygen toxicity is a recognised risk in recreational open-circuit scuba diving with the use of nitrox (oxygen-enriched air mixtures), but other forms of oxygen toxicity in other diving settings are poorly understood. However, divers using constant partial pressure of oxygen closed-circuit rebreathers (CCRs) for multi-day, multi-dive expeditions could potentially experience cumulative oxygen exposures above the current recommended limits. METHODS: We followed a number of technical recreational diving expeditions using CCRs and recorded the cumulative oxygen exposures of the individual divers. Lung function and visual acuity were recorded at intervals during the expeditions. RESULTS: Over several 8- to 12-day expeditions, divers either approached or exceeded the recommended maximum repetition excursion oxygen exposure (REPEX) limits. Lung function did not show any significant decrement. Changes in visual acuity were reported in several divers but were difficult to quantify. Formal testing of one diver's visual acuity on return home demonstrated a myopic change that resolved over the subsequent eight weeks. CONCLUSIONS: Recreational CCR divers conducting multi-dive expeditions of eight days or more may approach or exceed the REPEX oxygen limits. Despite this, there does not appear to be any significant decrement in lung function. Hyperoxic myopia occurs in some individuals. Changes in acuity appear to resolve spontaneously post exposure. Despite the lack of significant changes in respiratory function, divers should be cautious of such exposures as, should they require recompression therapy for decompression illness, this may result in significant pulmonary oxygen toxicity. PMID- 23813461 TI - Analysis of recreational closed-circuit rebreather deaths 1998-2010. AB - INTRODUCTION: Since the introduction of recreational closed-circuit rebreathers (CCRs) in 1998, there have been many recorded deaths. Rebreather deaths have been quoted to be as high as 1 in 100 users. METHODS: Rebreather fatalities between 1998 and 2010 were extracted from the Deeplife rebreather mortality database, and inaccuracies were corrected where known. Rebreather absolute numbers were derived from industry discussions and training agency statistics. Relative numbers and brands were extracted from the Rebreather World website database and a Dutch rebreather survey. Mortality was compared with data from other databases. A fault tree analysis of rebreathers was compared to that of open-circuit scuba of various configurations. Finally, a risk analysis was applied to the mortality database. RESULTS: The 181 recorded recreational rebreather deaths occurred at about 10 times the rate of deaths amongst open-circuit recreational scuba divers. No particular brand or type of rebreather was over-represented. Closed-circuit rebreathers have a 25-fold increased risk of component failure compared to a manifolded twin-cylinder open-circuit system. This risk can be offset by carrying a redundant 'bailout' system. Two-thirds of fatal dives were associated with a high-risk dive or high-risk behaviour. There are multiple points in the human machine interface (HMI) during the use of rebreathers that can result in errors that may lead to a fatality. CONCLUSIONS: While rebreathers have an intrinsically higher risk of mechanical failure as a result of their complexity, this can be offset by good design incorporating redundancy and by carrying adequate 'bailout' or alternative gas sources for decompression in the event of a failure. Designs that minimize the chances of HMI errors and training that highlights this area may help to minimize fatalities. PMID- 23813460 TI - Rescue of drowning victims and divers: is mechanical ventilation possible underwater? A pilot study. AB - INTRODUCTION: In-water resuscitation has recently been proposed in the European resuscitation guidelines. Initiation of mechanical ventilation underwater might be considered when an immediate ascent to the surface is impossible or dangerous. The present study evaluated the feasibility of such ventilation underwater. METHODS: A resuscitation manikin was ventilated using an Interspiro(r) MK II full face mask or with an Oxylator(r) ventilator via a facemask or a laryngeal tube, or with mouth-to-tube inflation. Tidal volumes achieved by the individual methods of ventilation were assessed. The ventilation tests were performed during dives in the wet compartment of a recompression chamber and in a lake. Ventilation was tested at 40, 30, 20, 12, 9 and 6 metres' depth. RESULTS: Ventilation was impossible with the cuffed mask and only sufficient after laryngeal intubation for a small number of breaths. Laryngeal tube ventilation was associated with the aspiration of large amounts of water and the Oxylator failed during the ascent. Efficient ventilation with the MK II full-face mask was also possible only for a short period. An absolutely horizontal position of the manikin was required for successful ventilation, which is likely to be difficult to achieve in open water. Leakage at the sealing lip of the full-face mask and the cuff of the laryngeal tube led to intrusion of water and resulted in subsequent complete failure of ventilation. CONCLUSIONS: The efficacy of underwater ventilation seems to be poor with any of the techniques trialed. Water aspiration frequently makes ventilation impossible and might foster emphysema aquosum-like air trapping and, therefore, increase the risk of pulmonary barotrauma during ascent. Because the limitations of underwater ventilation are substantial even under ideal conditions, it cannot be recommended presently for real diving conditions. PMID- 23813462 TI - Recreational technical diving part 1: an introduction to technical diving methods and activities. AB - Technical divers use gases other than air and advanced equipment configurations to conduct dives that are deeper and/or longer than typical recreational air dives. The use of oxygen-nitrogen (nitrox) mixes with oxygen fractions higher than air results in longer no-decompression limits for shallow diving, and faster decompression from deeper dives. For depths beyond the air-diving range, technical divers mix helium, a light non-narcotic gas, with nitrogen and oxygen to produce 'trimix'. These blends are tailored to the depth of intended use with a fraction of oxygen calculated to produce an inspired oxygen partial pressure unlikely to cause cerebral oxygen toxicity and a nitrogen fraction calculated to produce a tolerable degree of nitrogen narcosis. A typical deep technical dive will involve the use of trimix at the target depth with changes to gases containing more oxygen and less inert gas during the decompression. Open-circuit scuba may be used to carry and utilise such gases, but this is very wasteful of expensive helium. There is increasing use of closed-circuit 'rebreather' devices. These recycle expired gas and potentially limit gas consumption to a small amount of inert gas to maintain the volume of the breathing circuit during descent and the amount of oxygen metabolised by the diver. This paper reviews the basic approach to planning and execution of dives using these methods to better inform physicians of the physical demands and risks. PMID- 23813463 TI - Recreational technical diving part 2: decompression from deep technical dives. AB - Technical divers perform deep, mixed-gas 'bounce' dives, which are inherently inefficient because even a short duration at the target depth results in lengthy decompression. Technical divers use decompression schedules generated from modified versions of decompression algorithms originally developed for other types of diving. Many modifications ostensibly produce shorter and/or safer decompression, but have generally been driven by anecdote. Scientific evidence relevant to many of these modifications exists, but is often difficult to locate. This review assembles and examines scientific evidence relevant to technical diving decompression practice. There is a widespread belief that bubble algorithms, which redistribute decompression in favour of deeper decompression stops, are more efficient than traditional, shallow-stop, gas-content algorithms, but recent laboratory data support the opposite view. It seems unlikely that switches from helium- to nitrogen-based breathing gases during ascent will accelerate decompression from typical technical bounce dives. However, there is evidence for a higher prevalence of neurological decompression sickness (DCS) after dives conducted breathing only helium-oxygen than those with nitrogen oxygen. There is also weak evidence suggesting less neurological DCS occurs if helium-oxygen breathing gas is switched to air during decompression than if no switch is made. On the other hand, helium-to-nitrogen breathing gas switches are implicated in the development of inner-ear DCS arising during decompression. Inner-ear DCS is difficult to predict, but strategies to minimize the risk include adequate initial decompression, delaying helium-to-nitrogen switches until relatively shallow, and the use of the maximum safe fraction of inspired oxygen during decompression. PMID- 23813465 TI - Moving from acceptance toward transformation with Internal Family Systems Therapy (IFS). AB - Clients come to psychotherapy intent on changing, rather than accepting, their unwanted behaviors, emotions, or thoughts. The problem often is, however, that their lack of self-acceptance is the primary obstacle to change. This article describes how one approach, the Internal Family Systems (IFS) model, fosters clients' acceptance of all parts of themselves no matter how destructive, and how that acceptance can lead to the transformation of those parts and, in turn, of other people. PMID- 23813464 TI - Risk of colonic cancer is not higher in the obese Lep(ob) mouse model compared to lean littermates. AB - Epidemiological data suggest that obesity increases the risk of colorectal cancer in humans. Given that diet-induced obesity mouse models verified the epidemiological data, the present study aimed to determine whether obese C57BL/6J Lep(ob) male mice (a different obesity in vivo model) were at greater risk of colonic cancer than their lean male littermates. Risk of colonic tumorigenesis was assessed by numbers of aberrant crypts, aberrant crypt foci and colonic tumors. Proliferation of the colonic epithelia was assessed histochemically following administration of BrdU. Availability of the procarcinogen, azoxymethane (AOM) to target tissues was assessed by quantifying via HPLC plasma AOM concentrations during the 60 min period following AOM injection. When obese and lean mice were injected with azoxymethane (AOM) at doses calculated to provide equivalent AOM levels per kg lean body mass, obese animals had significantly fewer aberrant crypts/colon and fewer aberrant crypt foci/colon than the lean animals. Tumors were identified in the colonic mucosa of lean (4 tumors in 14 mice) but not obese (0 tumors in 15 mice) mice. Colonic cell proliferation was not significantly different for obese and lean mice. Because these results were unexpected, plasma AOM concentrations were measured and were found to be lower in the obese than lean mice. When plasma AOM levels were comparable for the lean and obese mice, the Lep(ob) mice continued to have significantly fewer aberrant crypt foci/colon than the lean mice, but differences were not statistically different for aberrant crypts/colon. Interestingly, obese Lep(ob) mice did not exhibit increased risk of colonic cancer as expected. Instead, Lep(ob) mice exhibited equivalent or lower risk of colon cancer when compared to the lean group. These results taken together with in vivo results from diet-induced obesity studies, imply that leptin may be responsible for the increased risk of colon cancer associated with obesity. PMID- 23813466 TI - Computational analysis shows why transcranial alternating current stimulation induces retinal phosphenes. AB - OBJECTIVE: Transcranial alternating current stimulation (tACS), which is a novel technique for the manipulation of cortical oscillations, can generate subjective visual sensations (phosphenes). In this work, we computationally investigate the current that reaches the eyes from tACS electrodes in order to show that phosphenes induced by tACS are retinal in origin. APPROACH: The finite-element method is used for modelling the path of the current in an anatomically realistic model of the head for various electrode montages. The computational results are used for analysing previous experimental data to investigate the sensitivity of the eye to electrical stimulation. MAIN RESULTS: Depending on the locations of both the stimulating and reference electrodes, a small portion of the stimulation current chooses a path that goes through the eyes. Due to the sensitivity of the retina to electrical stimulation, even distant electrodes can produce a sufficiently strong current at the eyes for inducing retinal phosphenes. SIGNIFICANCE: The interference from retinal phosphenes needs to be considered in the design of tACS experiments. The occurrence of phosphenes can be reduced by optimizing the locations of the electrodes, or potentially increasing the number of reference electrodes to two or more. Computational modelling is an effective tool for guiding the electrode positioning. PMID- 23813467 TI - High mobility N-type transistors based on solution-sheared doped 6,13 bis(triisopropylsilylethynyl)pentacene thin films. AB - An N-Type organic thin-film transistor (OTFT) based on doped 6,13 Bis(triisopropylsilylethynyl)pentacene is presented. A transition from p-type to n-type occurrs with increasing doping concentrations, and the highest performing n-channel OTFTs are obtained with 50 mol% dopant. X-ray diffraction, scanning Auger microscopy, and secondary ionization mass spectrometry are used to characterize the morphology of the blends. The high performance of the obtained transistors is attributed to the highly crystalline and aligned nature of the doped thin films. PMID- 23813469 TI - Efficient chromatographic separation of intact proteins derivatized with a fluorogenic reagent for proteomics analysis. AB - To achieve more efficient separation of intact proteins for proteomics applications, three columns of differing diameters (4.0, 4.6 and 6.0 mm internal diameter) were chosen for comparison and investigated to identify optimal conditions. The column with the largest diameter gave the largest peak capacity, showing the efficient separation of intact proteins, such as two protein standards, glutathione S-transferase and beta-lactoglobulin. On the other hand, a low-molecular-weight compound was separated effectively on the smaller diameter column, demonstrating that the separation mechanism seems to differ between high- and low-molecular-weight compounds. Finally, using the 6.0 mm i.d. column, 680 protein peaks were observed in mouse liver extracts, demonstrating that a wider diameter separation column is effective for intact protein separations. PMID- 23813468 TI - Correlations of noninvasive BOLD and TOLD MRI with pO2 and relevance to tumor radiation response. AB - PURPOSE: To examine the potential use of blood oxygenation level dependent (BOLD) and tissue oxygenation level dependent (TOLD) contrast MRI to assess tumor oxygenation and predict radiation response. METHODS: BOLD and TOLD MRI were performed on Dunning R3327-AT1 rat prostate tumors during hyperoxic gas breathing challenge at 4.7 T. Animals were divided into two groups. In Group 1 (n = 9), subsequent (19) F MRI based on spin lattice relaxation of hexafluorobenzene reporter molecule provided quantitative oximetry for comparison. For Group 2 rats (n = 13) growth delay following a single dose of 30 Gy was compared with preirradiation BOLD and TOLD assessments. RESULTS: Oxygen (100%O2 ) and carbogen (95%O2 /5%CO2 ) challenge elicited similar BOLD, TOLD and pO2 responses. Strong correlations were observed between BOLD or R2* response and quantitative (19) F pO2 measurements. TOLD response showed a general trend with weaker correlation. Irradiation caused a significant tumor growth delay and tumors with larger changes in TOLD and R1 values upon oxygen breathing exhibited significantly increased tumor growth delay. CONCLUSION: These results provide further insight into the relationships between oxygen sensitive (BOLD/TOLD) MRI and tumor pO2 . Moreover, a larger increase in R1 response to hyperoxic gas challenge coincided with greater tumor growth delay following irradiation. PMID- 23813471 TI - Synthesis, structural characterization, and thermoresponsivity of hybrid supramolecular dendrimers bearing a polyoxometalate core. AB - A series of cationic dendrons bearing triethylene glycol monomethyl ether terminal groups of different generations have been synthesized and used to encapsulate an inorganic polyanionic cluster [K(12.5)Na(1.5)(NaP5W30O110)] through electrostatic interactions. The resulting dendritic cation-encapsulated polyoxometalate (POM) complexes, cluster-dendrimers, are soluble in water and exhibit lower critical solution temperatures (LCST). The thermoresponsivities of these complexes in aqueous solutions were studied by turbidimetry and variable temperature (1)H NMR spectroscopy. The observed cloud points show a remarkable dependence on the generation of the dendrons. Complexes composed of first generation dendrons exhibit no obvious thermoresponsive properties, but for complexes bearing second-generation dendrons, the LCST decreases as the number of dendritic cations around the POM cluster increases. Complexes composed of third generation cations underwent reversible aggregation and disaggregation upon heating and cooling, respectively. This thermally induced self-aggregation was characterized by DLS and TEM. In addition, the effects of salt and solvent on the LCST were investigated. This research demonstrates a new type of thermoresponsive dendritic organic-inorganic hybrid complex and provides a general route to the endowment of POMs with temperature-sensitive properties through electrostatic interactions. PMID- 23813470 TI - AICAR inhibits oxygen consumption by intact skeletal muscle cells in culture. AB - Activation of 5' adenosine monophosphate-activated protein kinase (AMPK) with aminoimidazole carboxamide ribonucleotide (AICAR) increases skeletal muscle glucose uptake and fatty acid oxidation. The purpose of these experiments was to utilize AICAR to enhance palmitate consumption by mitochondria in cultured skeletal muscle cells. In these experiments, we treated C2C12 myotubes or adult single skeletal muscle fibers with varying concentrations of AICAR for different lengths of time. Surprisingly, acute AICAR exposure at most concentrations (0.25 1.5 mM), but not all (0.1 mM), modestly inhibited oxygen consumption even though AICAR increased AMPK phosphorylation. The data suggest that AICAR inhibited oxygen consumption by the cultured muscle in a non-specific manner. The results of these experiments are expected to provide valuable information to investigators interested in using AICAR in cell culture studies. PMID- 23813472 TI - Clinical and epidemiological features of hepatitis C virus infection in South Korea: a prospective, multicenter cohort study. AB - The epidemiological and clinical features of hepatitis C virus (HCV) infection in South Korea were examined in a prospective, multicenter cohort study that included 1,173 adult patients with positive results for anti-HCV antibody who completed a questionnaire survey on the risk factors for HCV infection from January 2007 to December 2011 at five university hospitals. The HCV cohort had a mean age of 55.4 years with 48.3% men, and diagnostic categories of acute hepatitis (n = 63, 5.3%), past infection (n = 37, 3.2%), chronic hepatitis (n = 777, 66.2%), cirrhosis of the liver (n = 179, 15.3%), and hepatocellular carcinoma (n = 117, 10.0%). The major HCV genotypes were genotype 1 (52.7%) and genotype 2 (45.3%). Liver biopsy was performed in 301 patients (25.7%), and 42.8% of the subjects received antiviral therapy against HCV. The behavioral risk factors possibly related to HCV infection were intravenous drug use (5%), needle stick injury (7%), blood transfusion before 1995 (19%), sexual relationship with more than three partners (28%), piercings (35%), tattoos (36%), surgery (43%), acupuncture (83%), diagnostic endoscopy (85%), and dental procedures (93%). Age, intravenous drug use, needle stick injury, transfusion before 1995, and tattoos were the independent risk factors of HCV infection. PMID- 23813474 TI - Selective peptide inhibitors of bifunctional thymidylate synthase-dihydrofolate reductase from Toxoplasma gondii provide insights into domain-domain communication and allosteric regulation. AB - The bifunctional enzyme thymidylate synthase-dihydrofolate reductase (TS-DHFR) plays an essential role in DNA synthesis and is unique to several species of pathogenic protozoans, including the parasite Toxoplasma gondii. Infection by T. gondii causes the prevalent disease toxoplasmosis, for which TS-DHFR is a major therapeutic target. Here, we design peptides that target the dimer interface between the TS domains of bifunctional T. gondii TS-DHFR by mimicking beta strands at the interface, revealing a previously unknown allosteric target. The current study shows that these beta-strand mimetic peptides bind to the apo enzyme in a species-selective manner to inhibit both the TS and distal DHFR. Fluorescence spectroscopy was used to monitor conformational switching of the TS domain and demonstrate that these peptides induce a conformational change in the enzyme. Using structure-guided mutagenesis, nonconserved residues in the linker between TS and DHFR were identified that play a key role in domain-domain communication and in peptide inhibition of the DHFR domain. These studies validate allosteric inhibition of apo-TS, specifically at the TS-TS interface, as a potential target for novel, species-specific therapeutics for treating T. gondii parasitic infections and overcoming drug resistance. PMID- 23813476 TI - Electrophysiological and behavioral effects of group III metabotropic glutamate receptors on pallidal neurons in normal and parkinsonian rats. AB - The globus pallidus plays a critical role in movement regulation. Glutamate being an important excitatory neurotransmitter modulates the activity of pallidal neurons through both ionotropic and metabotropic glutamate receptors (mGluRs). Morphological studies have shown that group III mGluRs are generally located presynaptically in the globus pallidus. Up to now, little is known about the in vivo electrophysiological effects of group III mGluRs on the pallidal neurons. This study investigated the electrophysiological and behavioral effects of group III mGluRs on pallidal neurons in both normal and 6-hydroxydopamine (6-OHDA) lesioned parkinsonian rats. Micropressure ejection of group III mGluR agonist, L 2-amino-4-phosphonobutyrate (L-AP4), increased or decreased the firing rate of pallidal neurons in both normal and parkinsonian rats. The L-AP4-induced excitatory effects on the lesioned side of parkinsonian rats (117.4 +/- 17.2%) were stronger than that in normal rats (64.3 +/- 10.1%). While the proportion of neurons that were unresponsive to L-AP4 on the lesioned side of parkinsonian rats (50%) was more than that of normal rats (13%). Unilateral microinjection of L-AP4 into the globus pallidus induced a contralateral dystonic posturing in the presence of systemic haloperidol administration. The selective group III mGluRs antagonist, (RS)-alpha-cyclopropyl-4-phosphonophenylglycine, had no effect on pallidal neurons when used alone and could block both L-AP4-induced electrophysiological and behavioral effects. Combining electrophysiological and behavioral findings, we concluded that activation of group III mGluRs modulate the activity of pallidal neurons under both normal and parkinsonian state. PMID- 23813475 TI - Overactivation of the TGF-beta pathway confers a mesenchymal-like phenotype and CXCR4-dependent migratory properties to liver tumor cells. AB - Transforming growth factor-beta (TGF-beta) is an important regulatory suppressor factor in hepatocytes. However, liver tumor cells develop mechanisms to overcome its suppressor effects and respond to this cytokine by inducing other processes, such as the epithelial-mesenchymal transition (EMT), which contributes to tumor progression and dissemination. Recent studies have placed chemokines and their receptors at the center not only of physiological cell migration but also of pathological processes, such as metastasis in cancer. In particular, CXCR4 and its ligand, stromal cell-derived factor 1alpha (SDF-1alpha) / chemokine (C-X-C motif) ligand 12 (CXCL12) have been revealed as regulatory molecules involved in the spreading and progression of a variety of tumors. Here we show that autocrine stimulation of TGF-beta in human liver tumor cells correlates with a mesenchymal like phenotype, resistance to TGF-beta-induced suppressor effects, and high expression of CXCR4, which is required for TGF-beta-induced cell migration. Silencing of the TGF-beta receptor1 (TGFBR1), or its specific inhibition, recovered the epithelial phenotype and attenuated CXCR4 expression, inhibiting cell migratory capacity. In an experimental mouse model of hepatocarcinogenesis (diethylnitrosamine-induced), tumors showed increased activation of the TGF-beta pathway and enhanced CXCR4 levels. In human hepatocellular carcinoma tumors, high levels of CXCR4 always correlated with activation of the TGF-beta pathway, a less differentiated phenotype, and a cirrhotic background. CXCR4 concentrated at the tumor border and perivascular areas, suggesting its potential involvement in tumor cell dissemination. CONCLUSION: A crosstalk exists among the TGF-beta and CXCR4 pathways in liver tumors, reflecting a novel molecular mechanism that explains the protumorigenic effects of TGF-beta and opens new perspectives for tumor therapy. PMID- 23813473 TI - Epigenetics and chromatin remodeling in adult cardiomyopathy. AB - The manipulation of chromatin structure regulates gene expression and the flow of genetic information. Histone modifications and ATP-dependent chromatin remodeling together with DNA methylation are dynamic processes that modify chromatin architecture and profoundly modulate gene expression. Their coordinated control is key to ensuring proper cell commitment and organ development, as well as adaption to environmental cues. Recent studies indicate that abnormal epigenetic status of the genome, in concert with alteration of transcriptional networks, contribute to the development of adult cardiomyopathy such as pathological cardiac hypertrophy. Here we consider the emerging role of different classes of chromatin regulators and how their dysregulation in the adult heart alters specific gene programs with subsequent development of major cardiomyopathies. Understanding the functional significance of the different epigenetic marks as points of genetic control may represent a promising future therapeutic tool. PMID- 23813477 TI - Early versus delayed laparoscopic cholecystectomy for people with acute cholecystitis. AB - BACKGROUND: Gallstones are present in about 10% to 15% of the adult western population. Between 1% and 4% of these adults become symptomatic in a year (the majority due to biliary colic but a significant proportion due to acute cholecystitis). Laparoscopic cholecystectomy for acute cholecystitis is mainly performed after the acute cholecystitis episode settles because of the fear of higher morbidity and of need for conversion from laparoscopic to open cholecystectomy. However, delaying surgery exposes the people to gallstone related complications. OBJECTIVES: The aim of this systematic review was to compare early laparoscopic cholecystectomy (less than seven days of clinical presentation with acute cholecystitis) versus delayed laparoscopic cholecystectomy (more than six weeks after index admission with acute cholecystitis) with regards to benefits and harms. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, and World Health Organization International Clinical Trials Registry Platform until July 2012. SELECTION CRITERIA: We included all randomised clinical trials comparing early versus delayed laparoscopic cholecystectomy in participants with acute cholecystitis. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We identified seven trials that met the inclusion criteria. Out of these, six trials provided data for the meta analyses. A total of 488 participants with acute cholecystitis and fit to undergo laparoscopic cholecystectomy were randomised to early laparoscopic cholecystectomy (ELC) (244 people) and delayed laparoscopic cholecystectomy (DLC) (244 people) in the six trials. Blinding was not performed in any of the trials and so all the trials were at high risk of bias. Other than blinding, three of the six trials were at low risk of bias in the other domains such as sequence generation, allocation concealment, incomplete outcome data, and selective outcome reporting. The proportion of females ranged between 43.3% and 80% in the trials that provided this information. The average age of participants ranged between 40 years and 60 years. There was no mortality in any of the participants in five trials that reported mortality. There was no significant difference in the proportion of people who developed bile duct injury in the two groups (ELC 1/219 (adjusted proportion 0.4%) versus DLC 2/219 (0.9%); Peto OR 0.49; 95% CI 0.05 to 4.72 (5 trials)). There was no significant difference between the two groups (ELC 14/219 (adjusted proportion 6.5%) versus DLC 11/219 (5.0%); RR 1.29; 95% CI 0.61 to 2.72 (5 trials)) in terms of other serious complications. None of the trials reported quality of life from the time of randomisation. There was no significant difference between the two groups in the proportion of people who required conversion to open cholecystectomy (ELC 49/244 (adjusted proportion 19.7%) versus DLC 54/244 (22.1%); RR 0.89; 95% CI 0.63 to 1.25 (6 trials)). The total hospital stay was shorter in the early group than the delayed group by four days (MD -4.12 days; 95% CI -5.22 to -3.03 (4 trials; 373 people)). There was no significant difference in the operating time between the two groups (MD -1.22 minutes; 95% CI -3.07 to 0.64 (6 trials; 488 people)). Only one trial reported return to work. The people belonging to the ELC group returned to work earlier than the DLC group (MD -11.00 days; 95% CI -19.61 to -2.39 (1 trial; 36 people)). Four trials did not report any gallstone-related morbidity during the waiting period. One trial reported five gallstone-related morbidities (cholangitis: two; biliary colic not requiring urgent operation: one; acute cholecystitis not requiring urgent operation: two). There were no reports of pancreatitis during the waiting time. Gallstone-related morbidity was not reported in the remaining trials. Forty (18.3%) of the people belonging to the delayed group had either non resolution of symptoms or recurrence of symptoms before their planned operation and had to undergo emergency laparoscopic cholecystectomy in five trials. The proportion with conversion to open cholecystectomy was 45% (18/40) in this group of people. AUTHORS' CONCLUSIONS: We found no significant difference between early and late laparoscopic cholecystectomy on our primary outcomes. However, trials with high risk of bias indicate that early laparoscopic cholecystectomy during acute cholecystitis seems safe and may shorten the total hospital stay. The majority of the important outcomes occurred rarely, and hence the confidence intervals are wide. It is unlikely that future randomised clinical trials will be powered to measure differences in bile duct injury and other serious complications since this might involve performing a trial of more than 50,000 people, but several smaller randomised trials may answer the questions through meta-analyses. PMID- 23813478 TI - Early versus delayed laparoscopic cholecystectomy for uncomplicated biliary colic. AB - BACKGROUND: Uncomplicated biliary colic is one of the commonest indications for laparoscopic cholecystectomy. Laparoscopic cholecystectomy involves several months of waiting if performed electively. However, people can develop life threatening complications during this waiting period. OBJECTIVES: To assess the benefits and harms of early versus delayed laparoscopic cholecystectomy for people with uncomplicated biliary colic due to gallstones. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until March 2013. SELECTION CRITERIA: We included only randomised clinical trials, irrespective of language and publication status. DATA COLLECTION AND ANALYSIS: Two authors independently extracted the data. We sought to include data on short-term mortality (30-day mortality or in-hospital mortality), bile duct injury, other serious adverse events, quality of life, conversion to open cholecystectomy, length of hospital stay, operating time, and return to work. We planned to calculate the risk ratio with 95% confidence interval (CI) for dichotomous outcomes and mean difference (MD) with 95% CI for continuous outcomes using RevMan and based on intention-to-treat analysis when data were available. Since only one trial contributed data to this review, Fisher's exact test was used for binary outcomes. A P value of < 0.05 was considered statistically significant. MAIN RESULTS: Only one trial including 75 participants (average age: 43 years; females: 65% of participants), randomised to early laparoscopic cholecystectomy (less than 24 hours after diagnosis) (n = 35) or delayed laparoscopic cholecystectomy (mean waiting period of 4.2 months) (n = 40), contributed information to this review. The trial had a high risk of bias. Information on the outcome mortality was available for the 75 participants. Information on serious adverse events was available for 68 participants (28 people in the early group and 40 people in the delayed group). The other outcomes were available for 28 participants in the early laparoscopic cholecystectomy group and 35 participants in the delayed laparoscopic cholecystectomy group. There were no deaths in the early group (0/35) (0%) versus 1/40 (2.5%) in the delayed laparoscopic cholecystectomy group (P > 0.9999). There was no bile duct injury in either group. There were no serious adverse events related to the surgery in either group. During the waiting period, complications developed in the delayed laparoscopic cholecystectomy group. The complications that the participants suffered included pancreatitis (n = 1), empyema of the gallbladder (n = 1), gallbladder perforation (n = 1), acute cholecystitis (n = 2), cholangitis (n = 2), obstructive jaundice (n = 2), and recurrent biliary colic (requiring hospital visits) (n = 5). In total, 14 participants required hospital admissions for the above symptoms. All of these admissions occurred in the delayed group as all the participants were operated on within 24 hours in the early group. The proportion of people who developed serious adverse events was 0/28 (0%) in the early group, which was significantly lower than in the delayed laparoscopic cholecystectomy group 9/40 (22.5%) (P = 0.0082). This trial did not report quality of life or return to work. There was no significant difference in the proportion of people who required conversion to open cholecystectomy in the early group 0/28 (0%) compared with the delayed group (6/35 or 17.1%) (P = 0.0743). There was a statistically significant shorter hospital stay in the early group than in the delayed group (MD -1.25 days, 95% CI -2.05 to -0.45). There was a statistically significant shorter operating time in the early group than the delayed group (MD 14.80 minutes, 95% CI -18.02 to -11.58). AUTHORS' CONCLUSIONS: Based on evidence from only one high-bias risk trial, it appears that early laparoscopic cholecystectomy (less than 24 hours after diagnosis of biliary colic) decreases the morbidity during the waiting period for elective laparoscopic cholecystectomy (mean waiting time 4.2 months), the hospital stay, and operating time. Further randomised clinical trials are necessary to confirm or refute these findings, and to determine if early laparoscopic cholecystectomy is better than the delayed laparoscopic cholecystectomy if the waiting time is shortened further. PMID- 23813479 TI - The advances of electromigration techniques applied for alkaloid analysis. AB - Alkaloids are natural products of metabolism found mainly in plants. Their diversified pharmacological activities as medical agents and extensive occurrence in nutritional products demand the development of reliable and sensitive analytical tools. This review presents the developments in the field of electromigration techniques and specifically capillary and microchip electrophoresis. We include the main aspects of interest to researches over the past 12 years. The scope of this review covers detection, on- and off-line preconcentration techniques, chiral separation and developments in the field of microchip electrophoresis. Their applications in alkaloid determination, capillary electrochromatography and inter-molecular interactions are also examined. PMID- 23813480 TI - Expression of insulin-like growth factor binding proteins during mouse cochlear development. AB - BACKGROUND: Insulin-like growth factor (IGF) signaling plays important roles in growth and cellular differentiation in the cochlear sensory epithelium. However, the roles of IGF binding proteins (IGFBPs), a family of IGF modulators, remain to be elucidated in this system. To begin to examine the role of IGFBPs, we used reverse transcription polymerase chain reaction (RT-PCR) and in situ hybridization to determine the temporal and spatial patterns of expression for Igfbps within the developing mouse cochlea. RESULTS: RT-PCR analysis indicates that Igfpb2-5 are expressed in the cochlea between embryonic day (E) 13.5 and postnatal day (P) 0. In addition, the expression of each Igfbp significantly increased between E13.5 and P0. In situ hybridization indicates that Igfbp2, 3, 4, and 5 have distinct and complementary expression patterns in the developing cochlea. Moreover, expression patterns of Igfbp3 and 5 demonstrate contrasting gradients along the basal-to-apical axis of the cochlea. CONCLUSIONS: Igfbp2-5 are expressed in distinct and complementary patterns during cochlear development. These data suggest that IGFBPs may act to precisely regulate activation of IGF signaling in the developing cochlea in a cell type-specific manner, contributing to cellular patterning and differentiation in the cochlea. PMID- 23813481 TI - Bioinspired superhydrophobic carbonaceous hairy microstructures with strong water adhesion and high gas retaining capability. AB - Various hydrophobic hairy carbonaceous fibers are obtained by a low-temperature CVD process on catalyst-patterned surface patches which are selectively coated with silica to make the surface superhydrophobic and yet allow strong water adhesion for the "Salvinia effect". The versatility of the functional hairy fiber surfaces is demonstrated with a liquid barrier grid for cell microarray, a gas retaining capability under water/liquid for a membrane-free microfluidic chemical process, and functionalized papillae for cell immobilization with green algae. PMID- 23813482 TI - Examination of the protective effects of heparin and recombinant tissue plasminogen activator (rtPA) in compromised adipocutaneous free flaps in the rat model using intravital video microscopy. AB - BACKGROUND: The purpose of this study was to determine whether the focused delivery of heparin or recombinant tissue plasminogen activator (rtPA) by rinsing accords protective effects which increases the survival of free groin flaps following fatal secondary venous stasis. METHODS: Free microvascular groin flaps (n = 40) were transplanted to the necks of adult Sprague-Dawley rats 20 hours before the experiment. The study groups (each n = 10 animals) were: No adjunctive treatment (Group I), Ringer's solution (Group II), heparin solution (100 IU/kg, group III) and rtPA (2 mg/kg, group IV), respectively. The flap vein was then clamped for 35 minutes. Intravital video microscopy was applied and flap viability was assessed 14 days later. RESULTS: Mean flap necrosis was 90% in group I and II, whereas the rate of flap survival was 80% in group III and 60% in group IV, respectively. CONCLUSIONS: Even though clinical and microvascular flap perfusion parameters in both the rtPA-group and heparin group were initially similar, it has been demonstrated here in our investigations that the flaps treated with heparin showed a higher viability rate. Therefore, we can conclude that the focused delivery of heparin and rtPA resulted in a significantly improved flap salvage. PMID- 23813484 TI - Sport medicine research needs funding: the International football federations are leading the way. PMID- 23813483 TI - Variable delay multi-pulse train for fast chemical exchange saturation transfer and relayed-nuclear overhauser enhancement MRI. AB - PURPOSE: Chemical exchange saturation transfer (CEST) imaging is a new MRI technology allowing the detection of low concentration endogenous cellular proteins and metabolites indirectly through their exchangeable protons. A new technique, variable delay multi-pulse CEST (VDMP-CEST), is proposed to eliminate the need for recording full Z-spectra and performing asymmetry analysis to obtain CEST contrast. METHODS: The VDMP-CEST scheme involves acquiring images with two (or more) delays between radiofrequency saturation pulses in pulsed CEST, producing a series of CEST images sensitive to the speed of saturation transfer. Subtracting two images or fitting a time series produces CEST and relayed-nuclear Overhauser enhancement CEST maps without effects of direct water saturation and, when using low radiofrequency power, minimal magnetization transfer contrast interference. RESULTS: When applied to several model systems (bovine serum albumin, crosslinked bovine serum albumin, l-glutamic acid) and in vivo on healthy rat brain, VDMP-CEST showed sensitivity to slow to intermediate range magnetization transfer processes (rate < 100-150 Hz), such as amide proton transfer and relayed nuclear Overhauser enhancement-CEST. Images for these contrasts could be acquired in short scan times by using a single radiofrequency frequency. CONCLUSIONS: VDMP-CEST provides an approach to detect CEST effect by sensitizing saturation experiments to slower exchange processes without interference of direct water saturation and without need to acquire Z-spectra and perform asymmetry analysis. PMID- 23813485 TI - Implementation of the FIFA 11+ football warm up program: how to approach and convince the Football associations to invest in prevention. AB - In the last decade, injury prevention has received a lot of attention in sports medicine, and recently international sports-governing bodies, such as the International Olympic Committee, declared the protection of the athletes' health as one of their major objectives. In 1994, the Federation Internationale de Football Association (FIFA) established its Medical Assessment and Research Centre (F-MARC) with the aim 'to prevent football injuries and to promote football as a health-enhancing leisure activity, improving social behaviour'. Since then, FIFA has developed and evaluated its injury-prevention programmes 'The 11' and 'FIFA 11+' have demonstrated in several scientific studies how simple exercise-based programmes can decrease the incidence of injuries in amateur football players. This paper summarises 18 years of scientific and on field work in injury prevention by an international sports federation (FIFA), from formulating the aim to make its sport safer to the worldwide dissemination of its injury-prevention programme in amateur football. PMID- 23813486 TI - Time-trends and circumstances surrounding ankle injuries in men's professional football: an 11-year follow-up of the UEFA Champions League injury study. AB - BACKGROUND: Ankle injury is common in football, but the circumstances surrounding them are not well characterised. AIM: To investigate the rates, especially time trends, and circumstances of ankle injuries in male professional football. METHODS: 27 European clubs with 1743 players were followed prospectively between 2001/2002 and 2011/2012. Time loss injuries and individual-player exposure during training sessions and matches were recorded. Injury rate was defined as the number of injuries/1000 h. RESULTS: A total of 1080 ankle injuries were recorded (13% of all injuries) with lateral ligament ankle sprain being the most common injury subtype (51% of all ankle injuries). The rates of ankle injury and ankle sprain were 1/1000 h and 0.7/1000 h, respectively. The ankle sprain rate declined slightly over time during the 11-year study period (on average 3.1%/season) with a statistically significant seasonal trend (p=0.041). Foul play according to the referee was involved in 40% of the match-related ankle sprains. Syndesmotic sprains and ankle impingement were uncommon causes of time loss (3% each of all ankle injuries). CONCLUSIONS: Lateral ligament ankle sprain constituted half of all ankle injuries in male professional football, whereas ankle impingement syndromes were uncommon. The ankle sprain rate decreased slightly over time, but many ankle sprains were associated with foul play. Our data extend the body of literature that provides football policy makers with a foundation to review existing rules and their enforcement. PMID- 23813487 TI - The Seattle Criteria increase the specificity of preparticipation ECG screening among elite athletes. AB - BACKGROUND: In 2010, the European Society of Cardiology (ESC) released recommendations for the interpretation of the 12-lead ECG in athletes, dividing changes into group 1 (training related) and group 2 (training unrelated). Recently, the 'Seattle Criteria', a series of revisions to these recommendations, was published, with the aim of improving the specificity of ECG screening in athletes. OBJECTIVES: First, to assess the prevalence of ECG abnormalities in a cohort of elite Australian athletes using the 2010 ESC recommendations and determine how often group 2 ECG changes correlate with the evidence of significant cardiac pathology on further investigation. Second, to assess the impact of the 'Seattle Criteria' in reducing the number of athletes with ECG abnormalities in whom further cardiac testing is unremarkable ('false positives'). DESIGN: 1197 elite athletes underwent cardiovascular screening between 2011 and 2012, of whom 1078 aged 16-35 years volunteered and were eligible to participate. RESULTS: 186 (17.3%) had an abnormal ECG according to ESC recommendations and a further 30 (2.8)% had unclassified changes. Three athletes (0.3%) were found to have a cardiac abnormality on further investigation. Using the Seattle Criteria, the number of athletes classified as abnormal fell to 48 (4.5%, p<0.0001) and the three with an underlying cardiac abnormality were still identified. The improved specificity was due to reclassification of 71 athletes (6.6%) with an equivocal QTc interval, 42 (3.9%) with T wave inversion isolated to V1-2 and 22 (2%) with either isolated right axis deviation or right ventricular hypertrophy on voltage criteria. CONCLUSIONS: The 'Seattle Criteria' reduced the false-positive rate of ECG screening from 17% to 4.2%, while still identifying the 0.3% of athletes with a cardiac abnormality. PMID- 23813488 TI - Testicular cancer knowledge among deaf and hearing men. AB - Testicular cancer typically affects young and middle-aged men. An educational video about prostate and testicular cancer was created in American Sign Language, with English open captioning and voice overlay, so that it could be viewed by audiences of diverse ages and hearing characteristics. This study recruited young Deaf (n = 85) and hearing (n = 90) adult males to help evaluate the educational value of the testicular cancer portion of this video. Participants completed surveys about their general, testicular, and total cancer knowledge before and after viewing the video. Although hearing men had higher pre-test scores than Deaf men, both Deaf and hearing men demonstrated significant increases in General, Testicular, and Total Cancer Knowledge scores after viewing the intervention video. Overall, results demonstrate the value of the video to Deaf and hearing men. PMID- 23813489 TI - Fatalistic cancer beliefs and information sources among rural and urban adults in the USA. AB - Fatalistic beliefs about cancer prevention can be a significant deterrent to one's likelihood of engaging in cancer prevention behaviors. Lower education and less access to cancer information among rural residents may influence their level of cancer fatalism. The purpose of this study was to examine rural-urban differences in fatalistic beliefs about cancer prevention and cancer information sources using data from the 2007 Health Information National Trends Survey (n = 1,482 rural and 6,192 urban residents). Results showed that rural residents were more likely to endorse multiple fatalistic beliefs about cancer prevention than urban residents even after controlling for other significant demographic correlates. Urban residents were more likely to use the internet as their primary cancer information source, whereas rural residents were more likely to rely on print material and healthcare providers. Future educational work to communicate relevant and accurate cancer prevention information to rural residents should consider not only information access but also rural culture and fatalistic perspectives. PMID- 23813490 TI - Breast cancer screening perceptions among American Indian women under age 40. AB - Breast cancer mortality rates are the second leading cause of cancer death in American Indian (AI) women. AI breast cancer screening rates have been decreasing, and AI women have some of the lowest screening rates compared to other racial/ethnic groups. Our research team investigated breast cancer and breast cancer screening education prior to recommended age for screening. It is imperative to examine the perspectives of young AI women toward breast cancer screening to better understand screening perceptions among AI women. Following a community-based participatory research approach, we conducted five focus groups and four interviews with AI women aged 25-39 (N = 48) in Kansas and Missouri. Nine themes emerged from the focus groups and relate to topics such as the following: knowledge of breast cancer and breast cancer screening, barriers to screening and treatment, suggestions to improve access, and perceptions and use of health-care systems. Specifically, we found that AI women lacked knowledge of details about screenings and their risks for getting breast cancer, cost was cited as a primary barrier to screening, additional education was needed (particularly materials that were AI focused), breast health was generally not discussed with others, and more instruction was requested for techniques used to identify bodily changes or abnormalities. Understanding attitudes of AI women not of recommended screening age may provide an insight into low screening rates among AI women. Furthermore, the results may inform outreach strategies to improve current and future screening rates. PMID- 23813491 TI - From adolescent daughter to mother: exploring message design strategies for breast and cervical cancer prevention and screening. AB - Early detection of breast and cervical cancers is one preventive behavior that may provide the adolescent daughter with a unique opportunity to provide encouragement to her mother or guardian to obtain screening. This study explored the design strategies necessary for developing an effective daughter-initiated message about screening for breast and cervical cancers. Thirty-two (N = 64) African-American mother-daughter dyads were interviewed about parenting style, goodwill, and daughters' credibility and risk behaviors that might influence receptivity toward a screening appeal. Mothers indicated that a tailored, emotional appeal combined with cancer facts delivered in a private setting would be most effective. Daughters were perceived as highly credible messengers and were perceived to have high levels of goodwill toward their mothers, regardless of risk behaviors. PMID- 23813492 TI - Criminal history and future offending of juveniles convicted of the possession of child pornography. AB - Most child pornography is distributed online. It is estimated that 3% to 15% of child pornography consumers are juveniles. The present study analyzed a consecutive sample of 54 male juveniles convicted of the possession of child pornography. Demographic characteristics, criminal history, and subsequent offending were assessed from criminal files and official reports. Juvenile possessors of child pornography were compared to three different groups of juveniles: Juvenile possessors of other illegal pornography (n = 42), juveniles who committed a sexual contact offense against a child (n = 64), and juveniles who committed a sexual contact offense against a peer or adult (n = 104). Juvenile possessors of child pornography were found to have downloaded the illegal material more frequently and over a longer time period than juvenile possessors of other illegal pornography. Furthermore, juvenile possessors of child pornography differed from juveniles who had committed a sexual contact offense in terms of demographics and showed fewer previous and subsequent offending than juveniles who sexually offended against a peer or adult. We conclude that juvenile possessors of child pornography need a specific target intervention focusing on dysfunctional Internet use and sexually deviant arousal. PMID- 23813493 TI - Pharmacokinetics of afatinib, a selective irreversible ErbB family blocker, in patients with advanced solid tumours. AB - BACKGROUND AND OBJECTIVE: Afatinib is a potent, irreversible, ErbB family blocker in clinical development for the treatment of a variety of solid tumours. This study evaluated the pharmacokinetics of afatinib (10-100 mg once daily) in cancer patients. METHODS: Data from 221 patients with advanced solid tumours in four phase I and one phase II trial were analysed using non-compartmental methods. RESULTS: Within each dose group, the shape of the geometric mean plasma concentration-time profiles after single and multiple doses were comparable. Maximum plasma concentration (C(max)) values were achieved 2-5 h after dosing and thereafter declined at least bi-exponentially. Steady-state plasma concentrations were attained within 8 days after the start of dosing. The geometric mean terminal elimination half-life at steady state was about 37 h. Repeated dosing resulted in a 2.77-fold accumulation based on the area under the plasma concentration-time curve (AUC), and 2.11-fold accumulation based on C(max) values. A slightly more than dose-proportional increase in afatinib exposure was observed. There was moderate intra-individual variability in afatinib trough concentration values (the geometric coefficient of variation (gCV) ranged from 22.2 to 67.5 %). The inter-patient variability in plasma concentrations was moderate to high (e.g. at the 40 mg dose, the gCVs ranged from 35.6 to 221 %). The exposure to afatinib (as measured by AUC and C(max)) correlated with the severity of the most common adverse events of afatinib--diarrhoea and rash. CONCLUSION: The pharmacokinetic profile of afatinib supports a once-daily dosage regimen. As expected for this patient population, the pharmacokinetic parameters of afatinib showed moderate to high inter-patient variability. Afatinib exhibits non-linear pharmacokinetics. PMID- 23813494 TI - H63D HFE polymorphisms are associated with increased disease duration and decreased muscle superoxide dismutase-1 expression in amyotrophic lateral sclerosis patients. AB - INTRODUCTION: H63D HFE polymorphisms increase the risk of neurodegenerative disorders and, specifically, may increase amyotrophic lateral sclerosis (ALS) risk. Investigating the physiological alterations induced by H63D polymorphisms in ALS patients may elucidate mechanisms by which this genotype alters disease. METHODS: Clinical measures and muscle biopsies were available from patients previously diagnosed with ALS who underwent HFE genotyping. Clinical outcomes and SOD1 protein expression were analyzed using standard statistical analyses. RESULTS: ALS patients harboring H63D HFE (n = 16) had 28.1 months longer average disease duration and 39.3% lower muscle SOD1 protein than ALS patients with wild type HFE (n = 22). CONCLUSIONS: Combined with previous reports suggesting the H63D polymorphism is associated with ALS, these results support a model wherein the H63D polymorphism is involved in ALS by means of pathways involving SOD1 but may limit cellular damage in individuals who develop disease. The association between HFE genotype and disease duration has important implications for clinical care and treatment trials. PMID- 23813495 TI - Cannabinoid receptor 2 counteracts interleukin-17-induced immune and fibrogenic responses in mouse liver. AB - Interleukin (IL)-17 is a proinflammatory and fibrogenic cytokine mainly produced by T-helper (Th)17 lymphocytes, together with the hepatoprotective and antifibrogenic cytokine, IL-22. Cannabinoid receptor 2 (CB2) is predominantly expressed in immune cells and displays anti-inflammatory and antifibrogenic effects. In the present study, we further investigated the mechanism underlying antifibrogenic properties of CB2 receptor and explored its effect on the profibrogenic properties of IL-17. After bile duct ligation (BDL), the hepatic expression of Th17 markers and IL-17 production were enhanced in CB2(-/-) mice, as compared to wild-type (WT) counterparts, and correlated with increased fibrosis in these animals. In contrast, IL-22-induced expression was similar in both animal groups. Inhibition of Th17 differentiation by digoxin lowered Th17 marker gene expression and IL-17 production and strongly reduced liver fibrosis in CB2(-/-) BDL mice. In vitro, differentiation of CD4(+) naive T cells into Th17 lymphocytes was decreased by the CB2 agonist, JWH-133, and was associated with reduced Th17 marker messenger RNA expression and IL-17 production, without modification of IL-22 release. The inhibitory effect of JWH-133 on IL-17 production relied on signal transducer and activator of transcription (STAT)5 phosphorylation. Indeed, STAT5 phosphorylation and translocation into the nucleus was enhanced in JWH133-treated Th17 lymphocytes, and the addition of a STAT5 inhibitor reversed the inhibitory effect of the CB2 agonist on IL-17 production, without affecting IL-22 levels. Finally, in vitro studies also demonstrated that CB2 receptor activation in macrophages and hepatic myofibroblasts blunts IL-17 induced proinflammatory gene expression. CONCLUSION: These data demonstrate that CB2 receptor activation decreases liver fibrosis by selectively reducing IL-17 production by Th17 lymphocytes via a STAT5-dependent pathway, and by blunting the proinflammatory effects of IL-17 on its target cells, while preserving IL-22 production. PMID- 23813496 TI - MicroRNA-203 down-regulation is associated with unfavorable prognosis in human glioma. AB - BACKGROUND AND OBJECTIVES: MicroRNA-203 (miR-203) serves as a tumor suppressor or a tumor promoter in different human malignancies. However, its involvement in human gliomas is still unclear. The aim of this study was to investigate the clinical significance of miR-203 expression in gliomas. METHODS: Real-time quantitative PCR was employed to measure the expression level of miR-203 in clinical glioma tissues. RESULTS: The expression of miR-203 was reduced in high WHO grade glioma tissues compared with that in low WHO grade and normal brain tissues, and decreased with ascending tumor WHO grades (P < 0.001). The reduced miR-203 expression in gliomas was significantly associated with higher WHO grade (P < 0.001), lower KPS score (P = 0.008) and poorer disease-specific survival of patients (P = 0.001). More importantly, subgroup analyses according to tumor WHO grade revealed that the disease-specific survival of patients with low miR-203 expression in high WHO grades (III-IV) subgroup was significantly shorter than those with high miR-203 expression (P < 0.001), but no significant difference was found for patients in WHO grades I-II subgroup (P = 0.08). CONCLUSION: Our data validate an important clinical significance of miR-203 in gliomas, and reveal that it might be an intrinsic regulator of tumor progression and a potential prognostic factor for this dismal disease. PMID- 23813498 TI - Self-assembled pi-extended condensed benzothiophene nanoribbons for field-effect transistors. AB - Nanostructures: A new air-stable pi-extended condensed benzothiophene was prepared by starting from 4,8-dioctyl-oxybenzo[1,2-b:4,5-b']dithiophene in about 54 % overall yield. Highly ordered 1D organic nanoribbons of the resultant compound were formed by molecular self-assembly. An individual nanoribbon-based organic field-effect transistor (see figure) exhibited an average mobility of 0.05 cm(2) V(-1) s(-1). PMID- 23813497 TI - Urea-temperature phase diagrams capture the thermodynamics of denatured state expansion that accompany protein unfolding. AB - We have analyzed the thermodynamic properties of the von Willebrand factor (VWF) A3 domain using urea-induced unfolding at variable temperature and thermal unfolding at variable urea concentrations to generate a phase diagram that quantitatively describes the equilibrium between native and denatured states. From this analysis, we were able to determine consistent thermodynamic parameters with various spectroscopic and calorimetric methods that define the urea temperature parameter plane from cold denaturation to heat denaturation. Urea and thermal denaturation are experimentally reversible and independent of the thermal scan rate indicating that all transitions are at equilibrium and the van't Hoff and calorimetric enthalpies obtained from analysis of individual thermal transitions are equivalent demonstrating two-state character. Global analysis of the urea-temperature phase diagram results in a significantly higher enthalpy of unfolding than obtained from analysis of individual thermal transitions and significant cross correlations describing the urea dependence of DeltaH0 and DeltaCP0 that define a complex temperature dependence of the m-value. Circular dichroism (CD) spectroscopy illustrates a large increase in secondary structure content of the urea-denatured state as temperature increases and a loss of secondary structure in the thermally denatured state upon addition of urea. These structural changes in the denatured ensemble make up ~40% of the total ellipticity change indicating a highly compact thermally denatured state. The difference between the thermodynamic parameters obtained from phase diagram analysis and those obtained from analysis of individual thermal transitions illustrates that phase diagrams capture both contributions to unfolding and denatured state expansion and by comparison are able to decipher these contributions. PMID- 23813499 TI - Elevated serotonin and 5-HIAA in the brainstem and lower serotonin turnover in the prefrontal cortex of suicides. AB - Using high pressure liquid chromatography, we find more brainstem 5-HT and 5-HIAA in suicides compared with nonpsychiatric, sudden death controls throughout the rostrocaudal extent of the brainstem DRN and MRN. This suggests that 5-HT synthesis in suicides is greater within all DRN subnuclei and the MRN compared with controls. PMID- 23813500 TI - Analysis of gene expression in wild-type and Notch1 mutant retinal cells by single cell profiling. AB - BACKGROUND: The vertebrate retina comprises sensory neurons, the photoreceptors, as well as many other types of neurons and one type of glial cell. These cells are generated by multipotent and restricted retinal progenitor cells (RPCs), which express Notch1. Loss of Notch1 in RPCs late during retinal development results in the overproduction of rod photoreceptors at the expense of interneurons and glia. RESULTS: To examine the molecular underpinnings of this observation, microarray analysis of single retinal cells from wild-type or Notch1 conditional knockout retinas was performed. In situ hybridization was carried out to validate some of the findings. CONCLUSIONS: The majority of Notch1-mutant cells lost expression of known Notch target genes. These cells also had low levels of RPC and cell cycle genes, and robustly up-regulated rod precursor genes. In addition, single wild-type cells, in which cell cycle marker genes were down-regulated, expressed markers of both rod photoreceptors and interneurons. PMID- 23813501 TI - Characterization and quantification of 10-hydroxycamptothecine in Camptotheca acuminate and its medicinal preparation by liquid chromatography-ion trap mass spectrometry. AB - A rapid and sensitive method for the identification and quantification of 10 hydroxycamptothecine (HCPT) in Camptotheca acuminata Decne is described. The HCPT standard solution was directly infused into the ion trap mass spectrometers (IT/MS) for collecting the MS(n) spectra. The electrospray ionization (ESI) mass spectral fragmentation pathway of HCPT was proposed and the ESI-MS(n) fragmentation behavior of HCPT was deduced in detail. The major fragment ions of HCPT were confirmed by MS(n) in both negative ion and positive ion mode. The possible main cleavage pathway of fragment ions was studied. Quantification of HCPT was assigned in negative-ion mode at a product ion at m/z 363 -> 319 by LC MS. The LC-MS method was validated for linearity, sensitivity, accuracy and precision, and then used to determine the content of the HCPT. Lastly, the LC-MS method was successfully applied to determine HCPT in real samples of Camptotheca acuminate Decne and its medicinal preparation in the first time. PMID- 23813502 TI - Non-volatile control of 2DEG conductivity at oxide interfaces. AB - The functionalization of two-dimensional electron gas (2DEG) at oxide interfaces can be realized integrating 2DEG with multifunctional oxide overlayers by epitaxial growth. Using a ferroelectric Pb(Zr0.2 Ti0.8 )O3 overlayer on 2DEG (LaAlO3 /SrTiO3 ), we demonstrate a model system of the functionalized 2DEG, where electrical conductivity of 2DEG can be reversibly controlled with a large on/off ratio (>1000) in a non-volatile way by ferroelectric polarization switching. PMID- 23813503 TI - Cognitive rehabilitation for spatial neglect following stroke. AB - BACKGROUND: Unilateral spatial neglect causes difficulty attending to one side of space. Various rehabilitation interventions have been used but evidence of their benefit is lacking. OBJECTIVES: To assess whether cognitive rehabilitation improves functional independence, neglect (as measured using standardised assessments), destination on discharge, falls, balance, depression/anxiety and quality of life in stroke patients with neglect measured immediately post intervention and at longer-term follow-up; and to determine which types of interventions are effective and whether cognitive rehabilitation is more effective than standard care or an attention control. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (last searched June 2012), MEDLINE (1966 to June 2011), EMBASE (1980 to June 2011), CINAHL (1983 to June 2011), PsycINFO (1974 to June 2011), UK National Research Register (June 2011). We handsearched relevant journals (up to 1998), screened reference lists, and tracked citations using SCISEARCH. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of cognitive rehabilitation specifically aimed at spatial neglect. We excluded studies of general stroke rehabilitation and studies with mixed participant groups, unless more than 75% of their sample were stroke patients or separate stroke data were available. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, extracted data, and assessed study quality. For subgroup analyses, review authors independently categorised the approach underlying the cognitive intervention as either 'top-down' (interventions that encourage awareness of the disability and potential compensatory strategies) or 'bottom-up' (interventions directed at the impairment but not requiring awareness or behavioural change, e.g. wearing prisms or patches). MAIN RESULTS: We included 23 RCTs with 628 participants (adding 11 new RCTs involving 322 new participants for this update). Only 11 studies were assessed to have adequate allocation concealment, and only four studies to have a low risk of bias in all categories assessed. Most studies measured outcomes using standardised neglect assessments: 15 studies measured effect on activities of daily living (ADL) immediately after the end of the intervention period, but only six reported persisting effects on ADL. One study (30 participants) reported discharge destination and one study (eight participants) reported the number of falls.Eighteen of the 23 included RCTs compared cognitive rehabilitation with any control intervention (placebo, attention or no treatment). Meta-analyses demonstrated no statistically significant effect of cognitive rehabilitation, compared with control, for persisting effects on either ADL (five studies, 143 participants) or standardised neglect assessments (eight studies, 172 participants), or for immediate effects on ADL (10 studies, 343 participants). In contrast, we found a statistically significant effect in favour of cognitive rehabilitation compared with control, for immediate effects on standardised neglect assessments (16 studies, 437 participants, standardised mean difference (SMD) 0.35, 95% confidence interval (CI) 0.09 to 0.62). However, sensitivity analyses including only studies of high methodological quality removed evidence of a significant effect of cognitive rehabilitation.Additionally, five of the 23 included RCTs compared one cognitive rehabilitation intervention with another. These included three studies comparing a visual scanning intervention with another cognitive rehabilitation intervention, and two studies (three comparison groups) comparing a visual scanning intervention plus another cognitive rehabilitation intervention with a visual scanning intervention alone. Only two small studies reported a measure of functional disability and there was considerable heterogeneity within these subgroups (I2 > 40%) when we pooled standardised neglect assessment data, limiting the ability to draw generalised conclusions.Subgroup analyses exploring the effect of having an attention control demonstrated some evidence of a statistically significant difference between those comparing rehabilitation with attention control and those with another control or no treatment group, for immediate effects on standardised neglect assessments (test for subgroup differences, P = 0.04). AUTHORS' CONCLUSIONS: The effectiveness of cognitive rehabilitation interventions for reducing the disabling effects of neglect and increasing independence remains unproven. As a consequence, no rehabilitation approach can be supported or refuted based on current evidence from RCTs. However, there is some very limited evidence that cognitive rehabilitation may have an immediate beneficial effect on tests of neglect. This emerging evidence justifies further clinical trials of cognitive rehabilitation for neglect. However, future studies need to have appropriate high quality methodological design and reporting, to examine persisting effects of treatment and to include an attention control comparator. PMID- 23813504 TI - Maxillofacial prosthesis in a palliative care for terminally ill patient with squamous cell carcinoma. AB - It is the god given right of every human being to appear human. - Ernest L. DaBreo. A 55-year-old man with combined surgical and radiation therapy for buccal mucosa required the prosthetic rehabilitation for full thickness facial cheek defect. Apart from the aesthetics concerns, he had several oral debilities like difficulty in speaking, eating and swallowing. Though the carcinoma is known for high rates of morbidity and mortality, it is an obligation of a prosthodontist to help the patient to have a dignified and normal social life for their remaining lifespan. Palliative dental care's main focus is to re-establish the quality of the remaining life, in addition to the alleviation of physical and psychological suffering of the far-advanced disease patients. This case report summarises the importance of maxillofacial prosthesis in a postoperative malignancy and palliative care. PMID- 23813505 TI - IgG4-related disease with atypical laryngeal presentation and Behcet/granulomatous polyangiitis mimicking features. AB - The following report describes two male patients with an ongoing medical history with a predominant laryngeal focus, who were finally diagnosed with IgG4-related disease (IgG4-RD). Their primary symptoms included hoarseness and pain of the throat, and they had undergone multiple laryngeal surgeries and laser treatments due to tumorous growth with limited success. Due to the onset of additional symptoms, they initially received the diagnoses granulomatous polyangiitis (GPA) and Behcet's disease. However, further analysis showed elevated IgG4 levels in serum and infiltration of IgG4-positive plasma cells upon biopsy of laryngeal and pulmonary tissue. Treatment was started with moderate doses of prednisone, leading to a rapid resolution of symptoms. PMID- 23813506 TI - Crohn's disease unmasked following etanercept treatment for ankylosing spondylitis. AB - We describe the case of a 45-year-old man with ankylosing spondylitis being treated with etanercept who presented with a 1 month history of abdominal pain. CT abdomen revealed an ileocaecal mass associated with an abscess, resulting in a laparotomy and right hemi-colectomy. Histology of the resected specimen showed the classical features of Crohn's disease. Etanercept was stopped and he was started on adalimumab. He is currently in clinical remission from both ankylosing spondylitis and Crohn's disease. PMID- 23813507 TI - How to exhaust your bone marrow. AB - A 32-year-old man was admitted to the hospital because of oedema and 8 kg of gained weight. The oedema decreased spontaneously over weeks and there was no evidence for a nephrotic syndrome; however, the blood tests revealed a moderate pancytopenia. The patient practiced excessive physical activity at work and in his spare time, and kept a very thorough training and weight diary. Owing to a high intake of energy and protein drinks he tried to optimise his physical performance and kept a normal body mass index at 23.7. A bone marrow biopsy showed gelatinous bone marrow transformation, normally seen in critically ill patients or those with severe malnutrition. In this case, the cause is presumed to be excessive physical activity/overtraining in combination with relatively insufficient nutrition. PMID- 23813508 TI - Clinical presentation of left angular gyrus ischaemic lesion: finger agnosia, acalculia, agraphia, left-right disorientation and episodic autoscopia. PMID- 23813509 TI - Tumefactive demyelination: an unusual cause of a spontaneously resolving homonymous hemianopia. AB - A 21-year-old man presented to eye casualty complaining of altered vision associated with headache and vomiting upon waking. Clinical examination was unremarkable except for a right-sided homonymous hemianopia. The MRI scan of the brain revealed a space occupying lesion within the occipital lobe and MR spectroscopy highlighted this to be inflammatory in nature, most likely a tumefactive demyelinating lesion (TDL). Lumbar puncture displayed positive oligoclonal bands. The patient was managed conservatively and made a full recovery, with normal visual fields recorded after a 3 month follow-up. This is a case of a TDL manifesting itself as an unusual cause of homonymous hemianopia; misdiagnosis of TDL is common and potentially damaging to the patient. PMID- 23813510 TI - Low-grade meningioma showing nearly equal density with spinal fluid on radiographic images. AB - A 61-year-old woman had an intracranial tumour that was located on the falx. Meningioma was suspected and the tumour rapidly grew over 1 year. It showed nearly equal density with spinal fluid showing almost no enhancement on radiographic images, like microcystic meningioma. Successful removal of the tumour was achieved. Histopathologically, the tumour was diagnosed as low-grade meningioma. The meningioma had variable sized microcysts and the appearance of solid area was meningothelial meningioma. This is a rare radiographic image for meningothelial meningioma. PMID- 23813511 TI - Primary extraskeletal Ewing's sarcoma/primitive neuroectodermal tumour of breast. AB - Primary primitive neuroectodermal tumour (PNET) and extraskeletal Ewing's sarcoma belongs to the Ewing's family of tumours. Primary tumours arising from breast are very rare. There are only a few case reports published on primary extraskeletal Ewing's sarcoma and PNET arising from breast. We present an extremely rare case of an inoperable primary Ewing's sarcoma arising from left breast with contralateral breast, lymphatic and lung metastasis. PMID- 23813512 TI - Persistent headache in a postpartum patient: the investigation and management. AB - Postdural puncture headache (PDPH) is the most common complication of obstetric regional anaesthesia and the most likely cause of headache in a woman who underwent epidural anaesthesia during delivery. Cerebral venous sinus thrombosis (CVST) is an uncommon cause of postpartum headache. Anaesthesia in obstetrics may lead to long-lasting intracranial hypotension resulting in CVST. CVST is a serious pathology with high mortality if misdiagnosed, but its correct and rapid diagnosis offers the opportunity for early treatment. Cranial magnetic resonance imaging (MRI) is an important modality in the diagnosis of both CVST and intracranial hypotension. The latter condition may be treated either by an epidural blood patch or bed rest and hydration. We report a case of a 36-year-old woman who developed CVST and multiple venous infarcts after an attempted epidural procedure during delivery. She was treated conservatively with bed rest, hydration and low-molecular-weight heparin and the patient recovered completely. PMID- 23813513 TI - Ring chromosome with deletion 7q in acute myeloid leukaemia. AB - Cytogenetic abnormalities can be detected in approximately 50-60% of newly diagnosed adult patients with acute myeloid leukaemia (AML). Monosomy of the chromosome 7 (-7) and deletion of the long arm of the chromosome 7 (7q-) are considered as high cytogenetic-risk AML with a poor prognosis. These abnormalities can occur, as a single chromosomal aberration, in approximately 8% of newly diagnosed AML. We report an elderly patient with AML who had deletion 7q (7q-) along with ring chromosome, which was demonstrated in conventional cytogenetics and fluoresecent in-situ hybridisation techniques. PMID- 23813514 TI - Central pontine myelinolysis with meticulous correction of hyponatraemia in chronic alcoholics. AB - Central pontine myelinolysis is a demyelinating disorder that arises due to osmolar disturbances in the cerebral microenvironment characterised by loss of the myelin sheath of neurons. The diffusion-weighting imaging sequence of MRI is the most sensitive diagnostic imaging modality for myelinolysis. The rapid correction of hyponatraemia by >20-25 mmol/L/48 h has been known for a long time as a prime cause of osmotic demyelination. Various other comorbidities in hyponatraemic patients are well known that can lead to osmotic demyelination such as alcoholism, hypoxaemia, severe liver disease, malignancy, burns, liver transplantation and malnutrition. Chronic alcohol abusers with additional liver disease and malnutrition have altered osmotic equilibrium at baseline that predisposes them to osmotic demyelination. We suggest a more cautious and meticulous approach should be followed in these patients to avoid the dreaded complication. PMID- 23813515 TI - Rare sites of delayed metastasis in renal cell carcinoma. AB - Renal cell carcinoma (RCC) is a lethal malignancy with a propensity for metastatic spread to any part of the body. The common sites of metastases from RCC include lungs, adrenals, intestines and brain and most intra-abdominal organs which may present as synchronous or metachronous to the primary tumour. A long follow-up is advised to deal with the risk of delayed metastases even when the primary has been well controlled. There have been few case reports in regard to rare sites of RCC metastasis. In this series of three cases, we present three rarest sites of metastatic RCC reported after 5 years of the primary malignancy. PMID- 23813516 TI - Concomitant acromioclavicular and miliary tuberculosis. AB - A 48-year-old man was being treated unsuccessfully for miliary tuberculosis for 5 months until he presented with acromioclavicular joint swelling. Imaging of the shoulder revealed destruction of the acromioclavicular joint and the patient was brought to the operating theatre and underwent the excision of the distal end of the clavicle, synovectomy and drainage of the abscess. Surgery was followed by prompt clinical, functional and radiological improvement. Histopathology confirmed the diagnosis of acromioclavicular tuberculosis. Resistance to appropriate antituberculous treatment in patients with miliary tuberculosis can sometimes be a result of undiagnosed extrapulmonary site of infection. PMID- 23813517 TI - Antiglycine receptor antibody and encephalomyelitis with rigidity and myoclonus (PERM) related to small cell lung cancer. AB - A 39-year-old man (a lifetime non-smoker) presented with a locked left jaw and leg myoclonus. Clinical and electromyographic findings were in keeping with progressive encephalomyelitis with rigidity and myoclonus (PERM) syndrome. A thoracic CT scan demonstrated a 19 mm right hilar nodule, which was proven to be small cell lung cancer on bronchoscopic biopsy. Serological evaluation of the patient's plasma revealed antibodies against glycine receptors (serology negative for anti-GAD, anti-Yo, anti-Hu, anti-Ri, antiamphiphysin, anti-Ma2/Ta, anti-CRMP5 and anti-NMDA receptor). After his cancer was treated with chemotherapy and intravenous immunoglobulins (IVIg), neurological symptoms resolved but returned several months later without any evidence of cancer recurrence. Symptoms were refractory to corticosteroids and IVIg therapy. Rituximab was then initiated, which led to a dramatic and sustained resolution of symptoms. To our knowledge, this is the first case of PERM related to antiglycine receptor antibodies from paraneoplastic syndrome, which resolved with rituximab. PMID- 23813518 TI - Beware of gossypibomas. AB - Gossypiboma, a retained surgical sponge, is a rare complication that can occur after any type of surgery. Despite the precautions, the retention of foreign bodies still occurs. We describe a case of a 33-year-old woman with epigastric pain. She was initially diagnosed with acute cholangitis with choledocholithiasis. Although common bile duct stone was successfully removed endoscopically, her epigastric pain did not completely subside. She had undergone an emergency caesarean section at a suburban maternity hospital 6 weeks prior to the referral. A contrast-enhanced CT revealed an encapsulated mass showing a spongiform pattern with fluids and gas bubbles inside, and gossypiboma was suspected. A retained surgical sponge without radiopaque markers was removed surgically. Except for a wound infection, the postoperative course was uneventful. Gossypiboma should always be considered in the differential diagnosis of indeterminate abdominal pain, infection or a mass in patients with a prior surgical history. PMID- 23813519 TI - Multiple long-standing massive oral mandibular granuloma gravidarum (pregnancy tumour). AB - Oral granuloma gravidarum (OGG) is a distinct clinical entity used to describe pyogenic granuloma developing mainly on the gingiva of pregnant women, possibly propagated by gingival high levels of active progesterone and poor oral hygiene. We report herein a 41-year-old woman presented 7 months after childbirth with two painless masses of OGG in mandibular gingiva that developed at the end of first trimester and increased gradually in size even after delivery. Surgical excisional biopsy was performed under general anaesthesia with extraction of periodontally involved mandibular anterior teeth. Proper oral hygiene in pregnant women is mandatory to prevent such oral condition. PMID- 23813520 TI - Mediastinal myelolipoma with leukocytosis. AB - Myelolipoma is a benign tumour consisting of mature fat with scattered foci of haematopoietic elements resembling bone marrow. Extra-adrenal myelolipomas are an infrequent pattern of presentation. We report the case of a 64-year-old woman who presented a heterogeneous 1.4*2.5*3 cm paravertebral thoracic mass detected by chest tomography during the study of a leukocytosis of unknown aetiology. The CT findings and pathology revealed the diagnosis of myelolipoma. PMID- 23813521 TI - Beyond the stained back-drop. PMID- 23813522 TI - 'Bird-beak sign' of left atrial thrombus: a guide to management. PMID- 23813523 TI - Successful management of native-valve Brucella endocarditis with medical therapy alone. AB - A 71-year-old Asian-Indian male agriculturist presented with fever since 3 months. Clinical examination revealed hepatosplenomegaly and an early diastolic murmur in the aortic area. Echocardiography confirmed aortic regurgitation with large vegetations on the aortic valve leaflets, and also showed mild left ventricular dilatation with systolic dysfunction. Although blood cultures were persistently sterile, serology for Brucella was strongly positive. On retrospective questioning, the patient confirmed frequent occupational exposure to cattle. Surgical intervention was offered, but refused by the patient on financial grounds. Medical therapy for brucellosis with rifampicin, doxycycline and streptomycin resulted in complete and durable recovery. PMID- 23813524 TI - Physiological and metabolic responses of late pregnant women to 40 min of steady state exercise followed by an oral glucose tolerance perturbation. AB - We examined the physiological and metabolic responses of 24 active late pregnant women to 40 min of vigorous (95% ventilatory threshold) steady-state treadmill exercise followed by a metabolic perturbation [oral glucose tolerance test (OGTT), 75 g] after exercise. Heart rate and respiratory measures were taken throughout exercise, and blood samples were collected during exercise and every 30 min during the 2-h OGTT. Values were compared with those for a group of physically active nonpregnant women (n = 16) in the luteal phase of the menstrual cycle. Although late pregnant women were heavier, they performed the same work rate (182 vs. 208 W, P > 0.05), with the same oxygen pulse, but responded to the exercise with a blunted heart rate and relative oxygen consumption, with less carbon dioxide expired, possibly due to pregnancy-related adaptations in heart efficiency. Resting glucose concentrations were the same between groups, but by 40 min of exercise (3.8 +/- 0.1 vs. 4.6 +/- 0.1 mmol/l) and into 15 min of recovery (4.3 +/- 0.2 vs. 5.0 +/- 0.1 mmol/l), glucose concentrations were diminished in late pregnant women (P <= 0.05, respectively). The pregnancy induced delay of glucose uptake was seen in response to the postexercise OGTT compared with the nonpregnant women, but insulin sensitivity (ISI) remained (7.4 +/- 0.9 vs. 9.7 +/- 1.4 ISI, P > 0.05, respectively), with the preservation of the sensitivity of lipolysis inhibition of nonesterified free fatty acids to insulin. These adaptations may be fetoprotective, because our research suggests that 40 min of continuous treadmill exercise is well tolerated by physically active pregnant women. No adverse effects on birth outcome (3.53 +/- 0.08 kg birth weight; 39.6 +/- 0.33 wk gestational age) were observed. PMID- 23813525 TI - Electrical stimulation of the hypoglossal nerve: a potential therapy. AB - Obstructive sleep apnea is characterized by recurrent episodes of pharyngeal collapse, which result from a decrease in pharyngeal dilator muscle tone. The genioglossus is a major pharyngeal dilator that maintains airway patency during sleep. Early studies in animal and humans have demonstrated that electrical stimulation of this muscle reduces pharyngeal collapsibility, increases airflow, and mitigates obstructive sleep apnea. These findings impelled the development of fully implantable hypoglossal nerve stimulating systems (HGNS), for which feasibility trial results are now available. These pilot studies have confirmed that hypoglossal nerve stimulation can prevent pharyngeal collapse without arousing patients from sleep. Potentially, a substantial segment of the patient population with obstructive sleep apnea can be treated with this novel approach. Furthermore, the feasibility trial findings suggest that the therapeutic potential of HGNS can be optimized by selecting patients judiciously, titrating the stimulus intensity optimally, and characterizing the underlying function and anatomy of the pharynx. These strategies are currently being examined in ongoing pivotal trials of HGNS. PMID- 23813527 TI - The influence of training status, age, and muscle fiber type on cycling efficiency and endurance performance. AB - The purpose of this study was to assess the influence of age, training status, and muscle fiber-type distribution on cycling efficiency. Forty men were recruited into one of four groups: young and old trained cyclists, and young and old untrained individuals. All participants completed an incremental ramp test to measure their peak O2 uptake, maximal heart rate, and maximal minute power output; a submaximal test of cycling gross efficiency (GE) at a series of absolute and relative work rates; and, in trained participants only, a 1-h cycling time trial. Finally, all participants underwent a muscle biopsy of their right vastus lateralis muscle. At relative work rates, a general linear model found significant main effects of age and training status on GE (P < 0.01). The percentage of type I muscle fibers was higher in the trained groups (P < 0.01), with no difference between age groups. There was no relationship between fiber type and cycling efficiency at any work rate or cadence combination. Stepwise multiple regression indicated that muscle fiber type did not influence cycling performance (P > 0.05). Power output in the 1-h performance trial was predicted by average O2 uptake and GE, with standardized beta-coefficients of 0.94 and 0.34, respectively, although some mathematical coupling is evident. These data demonstrate that muscle fiber type does not affect cycling efficiency and was not influenced by the aging process. Cycling efficiency and the percentage of type I muscle fibers were influenced by training status, but only GE at 120 revolutions/min was seen to predict cycling performance. PMID- 23813526 TI - Mitochondrial function and increased convective O2 transport: implications for the assessment of mitochondrial respiration in vivo. AB - Although phosphorus magnetic resonance spectroscopy (31P-MRS)-based evidence suggests that in vivo peak mitochondrial respiration rate in young untrained adults is limited by the intrinsic mitochondrial capacity of ATP synthesis, it remains unknown whether a large, locally targeted increase in convective O2 delivery would alter this interpretation. Consequently, we examined the effect of superimposing reactive hyperemia (RH), induced by a period of brief ischemia during the last minute of exercise, on oxygen delivery and mitochondrial function in the calf muscle of nine young adults compared with free-flow conditions (FF). To this aim, we used an integrative experimental approach combining 31P-MRS, Doppler ultrasound imaging, and near-infrared spectroscopy. Limb blood flow [area under the curve (AUC), 1.4 +/- 0.8 liters in FF and 2.5 +/- 0.3 liters in RH, P < 0.01] and convective O2 delivery (AUC, 0.30 +/- 0.16 liters in FF and 0.54 +/- 0.05 liters in RH, P < 0.01), were significantly increased in RH compared with FF. RH was also associated with significantly higher capillary blood flow (P < 0.05) and faster tissue reoxygenation mean response times (70 +/- 15 s in FF and 24 +/- 15 s in RH, P < 0.05). This resulted in a 43% increase in estimated peak mitochondrial ATP synthesis rate (29 +/- 13 mM/min in FF and 41 +/- 14 mM/min in RH, P < 0.05) whereas the phosphocreatine (PCr) recovery time constant in RH was not significantly different (P = 0.22). This comprehensive assessment of local skeletal muscle O2 availability and utilization in untrained subjects reveals that mitochondrial function, assessed in vivo by 31P-MRS, is limited by convective O2 delivery rather than an intrinsic mitochondrial limitation. PMID- 23813528 TI - Effects of lung inflation on airway heterogeneity during histaminergic bronchoconstriction. AB - Lung inflation has been shown to dilate airways by altering the mechanical equilibrium between opposing airway and parenchymal forces. However, it is not known how heterogeneously such dilation occurs throughout the airway tree. In six anesthetized dogs, we measured the diameters of five to six central airway segments using high-resolution computed tomography, along with respiratory input impedance (Zrs) during generalized aerosol histamine challenge, and local histamine challenge in which the agonist was instilled directly onto the epithelia of the imaged central airways. Airway diameters and Zrs were measured at 12 and 25 cmH2O. The Zrs spectra were fitted with a model that incorporated continuous distributions of airway resistances. Airway heterogeneity was quantified using the coefficient of variation for predefined airway distribution functions. Significant reductions in average central airway diameter were observed at 12 cmH2O for both aerosolized and local challenges, along with significant increases upon inflation to 25 cmH2O. No significant differences were observed for the coefficient of variation of airway diameters under any condition. Significant increases in effective airway resistance as measured by Zrs were observed only for the aerosolized challenge at 12 cmH2O, which was completely reversed upon inflation. We conclude that the lung periphery may be the most dominant contributor to increases in airway resistance and tissue elastance during bronchoconstriction induced by aerosolized histamine. However, isolated constriction of only a few central airway segments may also affect tissue stiffness via interdependence with their surrounding parenchyma. PMID- 23813529 TI - Combined effects of inspired oxygen, carbon dioxide, and carbon monoxide on oxygen transport and aerobic capacity. AB - We hypothesized that breathing hypoxic, hypercapnic, and CO-containing gases together reduces maximal aerobic capacity (Vo2max) as the sum of each gas' individual effect on Vo2max. To test this hypothesis, goats breathed combinations of inspired O2 fraction (FiO2) of 0.06-0.21 and inspired CO2 fraction of 0.00 or 0.05, with and without inspired CO that elevated carboxyhemoglobin fraction (FHbCO) to 0.02-0.45, while running on a treadmill at speeds eliciting Vo2max. Individually, hypoxia and elevated FHbCO decreased fractional Vo2max (FVo2max, fraction of a goat's Vo2max breathing air) in linear, dose-dependent manners; hypercapnia did not change Vo2max. Concomitant hypoxia and elevated FHbCO decreased Vo2max less than the individual gas effects summed, indicating their combined effects on Vo2max are attenuated, fitting the following regression: FVo2max = 4.24 FiO2 + 0.519 FHbCO - 8.22 (FiO2 * FHbCO) + 0.117, (R(2) = 0.965, P < 0.001). The FVo2max correlated highly with total cardiopulmonary O2 delivery, not peripheral diffusing capacity, and with arterial O2 concentration (CaO2), not cardiac output. Hypoxia and elevated FHbCO decreased CaO2 by different mechanisms: hypoxia decreased arterial O2 saturation (SaO2), whereas elevated FHbCO decreased O2 capacitance {concentration of hemoglobin (Hb) available to bind O2 ([Hbavail])}. When breathing hypoxic gas (FiO2 0.12), CaO2 did not change with increasing FHbCO up to 0.30 because higher SaO2 of Hbavail offset decreased [Hbavail] due to the following: 1) hyperventilation with hypoxia and/or elevated FHbCO; 2) increased Hb affinity for O2 due to both Bohr and direct carboxyhemoglobin effects; and 3) the sigmoid relationship between O2 saturation and partial pressure elevating SaO2 more with hypoxia than normoxia. PMID- 23813530 TI - Hypertrophy in the cervical muscles and thoracic discs in bed rest? AB - The impact of prolonged bed rest on the cervical and upper thoracic spine is unknown. In the 2nd Berlin BedRest Study (BBR2-2), 24 male subjects underwent 60 day bed rest and performed either no exercise, resistive exercise, or resistive exercise with whole body vibration. Subjects were followed for 2 yr after bed rest. On axial cervical magnetic resonance images from the skull to T3, the volumes of the semispinalis capitis, splenius capitis, spinalis cervicis, longus capitis, longus colli, levator scapulae, sternocleidomastoid, middle and posterior scalenes, and anterior scalenes were measured. Disc height, anteroposterior width, and volume were measured from C2/3 to T6/7 on sagittal images. The volume of all muscles, with the exception of semispinalis capitis, increased during bed rest (P < 0.025). There were no significant differences between the groups for changes in the muscles. Increased upper and midthoracic spine disc height and volume (P < 0.001) was seen during bed rest, and disc height increases persisted at least 6 mo after bed rest. Increases in thoracic disc height were greater (P = 0.003) in the resistive vibration exercise group than in control. On radiological review, two subjects showed new injuries to the mid-lower thoracic spine. One of these subjects reported a midthoracic pain incident during maximal strength testing before bed rest and the other after countermeasure exercise on day 3 of bed rest. We conclude that bed rest is associated with increased disc size in the thoracic region and increases in muscle volume at the neck. The exercise device needs to be modified to ensure that load is distributed in a more physiological fashion. PMID- 23813532 TI - Comparison of single- or multifrequency bioelectrical impedance analysis and spectroscopy for assessment of appendicular skeletal muscle in the elderly. AB - Bioelectrical impedance analysis (BIA) is used to assess skeletal muscle mass, although its application in the elderly has not been fully established. Several BIA modalities are available: single-frequency BIA (SFBIA), multifrequency BIA (MFBIA), and bioelectrical impedance spectroscopy (BIS). The aim of this study was to examine the difference between SFBIA, MFBIA, and BIS for assessment of appendicular skeletal muscle strength in the elderly. A total of 405 elderly (74.2 +/- 5.0 yr) individuals were recruited. Grip strength and isometric knee extension strength were measured. Segmental SFBIA, MFBIA, and BIS were measured for the arms and upper legs. Bioelectrical impedance indexes were calculated by squared segment length divided by impedance (L2/Z). Impedance at 5 and 50 kHz (Z5 and Z50) was used for SFBIA. Impedance of the intracellular component was calculated from MFBIA (Z250-5) and BIS (RICW). Correlation coefficients between knee extension strength and L2/Z5, L2/Z50, L2/RICW, and L2/Z250-5 of the upper legs were 0.661, 0.705, 0.790, and 0.808, respectively (P < 0.001). Correlation coefficients were significantly greater for MFBIA and BIS than SFBIA. Receiver operating characteristic curves showed that L2/Z250-5 and L2/RICW had significantly larger areas under the curve for the diagnosis of muscle weakness compared with L2/Z5 and L2/Z50. Very similar results were observed for grip strength. Our findings suggest that MFBIA and BIS are better methods than SFBIA for assessing skeletal muscle strength in the elderly. PMID- 23813531 TI - AltitudeOmics: on the consequences of high-altitude acclimatization for the development of fatigue during locomotor exercise in humans. AB - The development of muscle fatigue is oxygen (O2)-delivery sensitive [arterial O2 content (CaO2) * limb blood flow (QL)]. Locomotor exercise in acute hypoxia (AH) is, compared with sea level (SL), associated with reduced CaO2 and exaggerated inspiratory muscle work (Winsp), which impairs QL, both of which exacerbate fatigue individually by compromising O2 delivery. Since chronic hypoxia (CH) normalizes CaO2 but exacerbates Winsp, we investigated the consequences of a 14 day exposure to high altitude on exercise-induced locomotor muscle fatigue. Eight subjects performed the identical constant-load cycling exercise (138 +/- 14 W; 11 +/- 1 min) at SL (partial pressure of inspired O2, 147.1 +/- 0.5 Torr), in AH (73.8 +/- 0.2 Torr), and in CH (75.7 +/- 0.1 Torr). Peripheral fatigue was expressed as pre- to postexercise percent reduction in electrically evoked potentiated quadriceps twitch force (DeltaQtw,pot). Central fatigue was expressed as the exercise-induced percent decrease in voluntary muscle activation (DeltaVA). Resting CaO2 at SL and CH was similar, but CaO2 in AH was lower compared with SL and CH (17.3 +/- 0.5, 19.3 +/- 0.7, 20.3 +/- 1.3 ml O2/dl, respectively). Winsp during exercise increased with acclimatization (SL: 387 +/- 36, AH: 503 +/- 53, CH: 608 +/- 67 cmH2O.s(-1).min(-1); P < 0.01). Exercise at SL did not induce central or peripheral fatigue. DeltaQtw,pot was significant but similar in AH and CH (21 +/- 2% and 19 +/- 3%; P = 0.24). DeltaVA was significant in both hypoxic conditions but smaller in CH vs. AH (4 +/- 1% vs. 8 +/- 2%; P < 0.05). In conclusion, acclimatization to severe altitude does not attenuate the substantial impact of hypoxia on the development of peripheral fatigue. In contrast, acclimatization attenuates, but does not eliminate, the exacerbation of central fatigue associated with exercise in severe AH. PMID- 23813533 TI - Regional cerebral blood flow in humans at high altitude: gradual ascent and 2 wk at 5,050 m. AB - The interindividual variation in ventilatory acclimatization to high altitude is likely reflected in variability in the cerebrovascular responses to high altitude, particularly between brain regions displaying disparate hypoxic sensitivity. We assessed regional differences in cerebral blood flow (CBF) measured with Duplex ultrasound of the left internal carotid and vertebral arteries. End-tidal Pco2, oxyhemoglobin saturation (SpO2), blood pressure, and heart rate were measured during a trekking ascent to, and during the first 2 wk at, 5,050 m. Transcranial color-coded Duplex ultrasound (TCCD) was employed to measure flow and diameter of the middle cerebral artery (MCA). Measures were collected at 344 m (TCCD-baseline), 1,338 m (CBF-baseline), 3,440 m, and 4,371 m. Following arrival to 5,050 m, regional CBF was measured every 12 h during the first 3 days, once at 5-9 days, and once at 12-16 days. Total CBF was calculated as twice the sum of internal carotid and vertebral flow and increased steadily with ascent, reaching a maximum of 842 +/- 110 ml/min (+53 +/- 7.6% vs. 1,338 m; mean +/- SE) at ~ 60 h after arrival at 5,050 m. These changes returned to +15 +/ 12% after 12-16 days at 5,050 m and were related to changes in SpO2 (R(2) = 0.36; P < 0.0001). TCCD-measured MCA flow paralleled the temporal changes in total CBF. Dilation of the MCA was sustained on days 2 (+12.6 +/- 4.6%) and 8 (+12.9 +/- 2.9%) after arrival at 5,050 m. We observed no significant differences in regional CBF at any time point. In conclusion, the variability in CBF during ascent and acclimatization is related to ventilatory acclimatization, as reflected in changes in SpO2. PMID- 23813534 TI - Muscle metabolism and activation heterogeneity by combined 31P chemical shift and T2 imaging, and pulmonary O2 uptake during incremental knee-extensor exercise. AB - The integration of skeletal muscle substrate depletion, metabolite accumulation, and fatigue during large muscle-mass exercise is not well understood. Measurement of intramuscular energy store degradation and metabolite accumulation is confounded by muscle heterogeneity. Therefore, to characterize regional metabolic distribution in the locomotor muscles, we combined 31P magnetic resonance spectroscopy, chemical shift imaging, and T2-weighted imaging with pulmonary oxygen uptake during bilateral knee-extension exercise to intolerance. Six men completed incremental tests for the following: (1) unlocalized 31P magnetic resonance spectroscopy; and (2) spatial determination of 31P metabolism and activation. The relationship of pulmonary oxygen uptake to whole quadriceps phosphocreatine concentration ([PCr]) was inversely linear, and three of four knee-extensor muscles showed activation as assessed by change in T2. The largest changes in [PCr], [inorganic phosphate] ([Pi]) and pH occurred in rectus femoris, but no voxel (72 cm3) showed complete PCr depletion at exercise cessation. The most metabolically active voxel reached 11 +/- 9 mM [PCr] (resting, 29 +/- 1 mM), 23 +/- 11 mM [Pi] (resting, 7 +/- 1 mM), and a pH of 6.64 +/- 0.29 (resting, 7.08 +/- 0.03). However, the distribution of 31P metabolites and pH varied widely between voxels, and the intervoxel coefficient of variation increased between rest (~10%) and exercise intolerance (~30-60%). Therefore, the limit of tolerance was attained with wide heterogeneity in substrate depletion and fatigue-related metabolite accumulation, with extreme metabolic perturbation isolated to only a small volume of active muscle (<5%). Regional intramuscular disturbances are thus likely an important requisite for exercise intolerance. How these signals integrate to limit muscle power production, while regional "recruitable muscle" energy stores are presumably still available, remains uncertain. PMID- 23813535 TI - Phenotypic variability of familial and sporadic Progranulin p.Gln257Profs*27 mutation. AB - The clinical phenotype of frontotemporal dementia patients carrying progranulin (GRN) mutations is known to be heterogeneous. We present a patient with corticobasal syndrome and a family with progressive aphasia and behavioral features who were found to have the same p.Gln257Profs*27 mutation. These cases depict the variability of GRN mutation carriers regarding clinical presentation and age of onset. In addition to giving a detailed report of a GRN mutation, we highlight the importance of searching for the presence of GRN mutations in selected sporadic cases and suggest a broadening of GRN genetic screening to better understand the clinical spectrum of these mutations. PMID- 23813536 TI - Real-time motion correction in two-dimensional multislice imaging with through plane navigator. AB - PURPOSE: To develop a new real-time strategy to detect and correct for full three dimensional rigid-body motion in two-dimensional multislice magnetic resonance imaging scans. METHODS: Two through-plane navigator echoes collected on each imaging slice are used to reconstruct two orthogonal through-plane navigator projection images both perpendicular to the imaged slices, within each repetition time. Rotation/translation within each through-plane navigator image plane is detected using a regional image correlation measure that is robust against unaccounted orthogonal rotation and noise. An additional orbital navigator is used to detect rotation within the imaging plane and to reject intrarepetition time motion in real time. RESULTS: The efficacy of the proposed method was demonstrated with in vivo brain studies. CONCLUSION: The proposed real-time three dimensional motion correction method does not introduce any additional three dimensional radiofrequency excitation and does not require any additional hardware. PMID- 23813537 TI - Diaphragm muscle atrophy in the mouse after long-term mechanical ventilation. AB - INTRODUCTION: Mechanical ventilation (MV) is a life-saving measure, but full ventilator support causes ventilator-induced diaphragm atrophy (VIDA). Previous studies of VIDA have relied on human biopsies or a rat model. If MV can induce diaphragm atrophy in mice, then mechanistic study of VIDA could be explored via genetic manipulation. RESULTS: We show that 18 hours of MV in mice results in a 15% loss of diaphragm weight and a 17% reduction in fiber cross-sectional area. Important catabolic cascades are activated in this mouse model: transcription of the ubiquitin ligases, atrogin and MuRF1, and the apoptotic marker, Bim, are increased; the marker of autophagy, LC3, is induced at the protein level and shows a punctate distribution in diaphragm muscle fibers. CONCLUSIONS: This mouse model recapitulates the key pathophysiological findings of other models of VIDA, and it will enable the genetic manipulation required to fully explore the mechanisms underlying this important process. PMID- 23813538 TI - Three-dimensional morphological and signal intensity features for detection of intervertebral disc degeneration from magnetic resonance images. AB - BACKGROUND AND OBJECTIVES: Advances in MRI hardware and sequences are continually increasing the amount and complexity of data such as those generated in high resolution three-dimensional (3D) scanning of the spine. Efficient informatics tools offer considerable opportunities for research and clinically based analyses of magnetic resonance studies. In this work, we present and validate a suite of informatics tools for automated detection of degenerative changes in lumbar intervertebral discs (IVD) from both 3D isotropic and routine two-dimensional (2D) clinical T2-weighted MRI. MATERIALS AND METHODS: An automated segmentation approach was used to extract morphological (traditional 2D radiological measures and novel 3D shape descriptors) and signal appearance (extracted from signal intensity histograms) features. The features were validated against manual reference, compared between 2D and 3D MRI scans and used for quantification and classification of IVD degeneration across magnetic resonance datasets containing IVD with early and advanced stages of degeneration. RESULTS AND CONCLUSIONS: Combination of the novel 3D-based shape and signal intensity features on 3D (area under receiver operating curve (AUC) 0.984) and 2D (AUC 0.988) magnetic resonance data deliver a significant improvement in automated classification of IVD degeneration, compared to the combination of previously used 2D radiological measurement and signal intensity features (AUC 0.976 and 0.983, respectively). Further work is required regarding the usefulness of 2D and 3D shape data in relation to clinical scores of lower back pain. The results reveal the potential of the proposed informatics system for computer-aided IVD diagnosis from MRI in large-scale research studies and as a possible adjunct for clinical diagnosis. PMID- 23813539 TI - A sense inventory for clinical abbreviations and acronyms created using clinical notes and medical dictionary resources. AB - OBJECTIVE: To create a sense inventory of abbreviations and acronyms from clinical texts. METHODS: The most frequently occurring abbreviations and acronyms from 352,267 dictated clinical notes were used to create a clinical sense inventory. Senses of each abbreviation and acronym were manually annotated from 500 random instances and lexically matched with long forms within the Unified Medical Language System (UMLS V.2011AB), Another Database of Abbreviations in Medline (ADAM), and Stedman's Dictionary, Medical Abbreviations, Acronyms & Symbols, 4th edition (Stedman's). Redundant long forms were merged after they were lexically normalized using Lexical Variant Generation (LVG). RESULTS: The clinical sense inventory was found to have skewed sense distributions, practice specific senses, and incorrect uses. Of 440 abbreviations and acronyms analyzed in this study, 949 long forms were identified in clinical notes. This set was mapped to 17,359, 5233, and 4879 long forms in UMLS, ADAM, and Stedman's, respectively. After merging long forms, only 2.3% matched across all medical resources. The UMLS, ADAM, and Stedman's covered 5.7%, 8.4%, and 11% of the merged clinical long forms, respectively. The sense inventory of clinical abbreviations and acronyms and anonymized datasets generated from this study are available for public use at http://www.bmhi.umn.edu/ihi/research/nlpie/resources/index.htm ('Sense Inventories', website). CONCLUSIONS: Clinical sense inventories of abbreviations and acronyms created using clinical notes and medical dictionary resources demonstrate challenges with term coverage and resource integration. Further work is needed to help with standardizing abbreviations and acronyms in clinical care and biomedicine to facilitate automated processes such as text-mining and information extraction. PMID- 23813540 TI - Appropriateness of commercially available and partially customized medication dosing alerts among pediatric patients. AB - OBJECTIVES: To evaluate dosing alert appropriateness, categorize orders with alerts, and compare the appropriateness of alerts due to customized and non customized dose ranges at a pediatric hospital. METHODS: This was a retrospective analysis of medication orders causing dosing alerts. Orders for outpatient prescriptions, patients >=18 years of age, and research protocols were excluded. Patient medical records were reviewed and ordered doses compared with a widely used pediatric reference (Lexi-Comp) and institutional recommendations. The alerted orders were categorized and the occurrence of appropriate alerts was compared. RESULTS: There were 47 181 inpatient orders during the studied period; 1935 orders caused 3774 dosing alerts for 369 medications in 573 patients (median age 6.1 years). All alerted orders had an alert overridden by the prescriber. The majority (86.2%) of alerted orders inappropriately caused alerts; 58.0% were justifiable doses and 28.2% were within Lexi-Comp. However, 13.8% of alerted orders appropriately caused alerts; 8.0% were incorrect doses and 5.8% had no dosing recommendations available. Appropriately alerted orders occurred in 19.7% of alerted orders due to customized ranges compared to 12.8% due to non customized ranges (p=0.002). Preterm and term neonates, infants, and children (2 5 years) had higher proportions of inappropriate alerts compared to appropriate alerts (all p<0.01). CONCLUSIONS: The vast majority of dosing alerts were presented to practitioners inappropriately, potentially contributing to alert fatigue. Appropriate alerts occurred more often when alerts were due to customized ranges. Advances in dosing alerts should aim to provide accurate and clinically relevant alerts that minimize excessive inappropriate alerting. Medications requiring dosing adjustments based on clinical parameters must be taken into account when designing and evaluating dosing alerts. PMID- 23813541 TI - Evaluating the accuracy of electronic pediatric drug dosing rules. AB - OBJECTIVE: To determine the accuracy of vendor-supplied dosing eRules for pediatric medication orders. Inaccurate or absent dosing rules can lead to high numbers of false alerts or undetected prescribing errors and may potentially compromise safety in this already vulnerable population. MATERIALS AND METHODS: 7 months of medication orders and alerts from a large pediatric hospital were analyzed. 30 medications were selected for study across 5 age ranges and 5 dosing parameters. The resulting 750 dosing rules from a commercial system formed the study corpus and were examined for accuracy against a gold standard created from traditional clinical resources. RESULTS: Overall accuracy of the rules in the study corpus was 55.1% when the rules were transformed to fit a priori age ranges. Over a pediatric lifetime, the dosing rules were accurate an average of 57.6% of the days. Dosing rules pertaining to the newborn age range were as accurate as other age ranges on average, but exhibited more variability. Daily frequency dosing parameters showed more accuracy than total daily dose, single dose minimum, or single dose maximum. DISCUSSION: The accuracy of a vendor supplied set of dosing eRules is suboptimal when compared with traditional dosing sources, exposing a gap between dosing rules in commercial products and actual prescribing practices by pediatric care providers. More research on vendor supplied eRules is warranted in order to understand the effects of these products on safe prescribing in children. PMID- 23813542 TI - Identifying health literacy and health system navigation needs among rural cancer patients: findings from the Rural Oncology Literacy Enhancement Study (ROLES). AB - Rural residence is associated with disparities in cancer-related outcomes. Guided by the Chronic Care Model (CCM), the Rural Oncology Literacy Enhancement Study (ROLES) assessed health literacy and patient navigation needs among rural cancer patients. A mixed methods (qualitative and quantitative) approach was used, including: in-depth interviews, health literacy assessments, and phone surveys with cancer patients (N = 53) from 5 oncology clinics in rural Wisconsin; focus groups and self-administered surveys with staff (N = 41) in these clinics. Within four dimensions of the CCM (community resources, self-management support, delivery system design, and decision support), this study uncovered multiple unmet navigation needs, health literacy limitations, and barriers to quality cancer care. System-level implementation of patient navigation and health literacy best practices could contribute to improved cancer care and patient outcomes among rural populations. Further research identifying effective interventions that reduce cancer disparities among rural cancer patients is necessary. PMID- 23813543 TI - Fewer ligament injuries but no preventive effect on muscle injuries and severe injuries: an 11-year follow-up of the UEFA Champions League injury study. AB - BACKGROUND: Limited information is available on the variation in injury rates over multiple seasons of professional football. AIM: To analyse time-trends in injury characteristics of male professional football players over 11 consecutive seasons. METHODS: A total of 1743 players comprising 27 teams from 10 countries were followed prospectively between 2001 and 2012. Team medical staff recorded individual player exposure and time loss injuries. RESULTS: A total of 8029 time loss injuries were recorded. The match unavailability due to injury was 14% and constant over the study period. On average, a player sustained two injuries per season, resulting in approximately 50 injuries per team and season. The ligament injury rate decreased during the study period (R(2)=0.608, b=-0.040, 95% CI 0.065 to -0.016, p=0.005), whereas the rate of muscle injury (R(2)=0.228, b= 0.013, 95% CI -0.032 to 0.005, p=0.138) and severe injury (R(2)=0.141, b=0.015, 95% CI -0.013 to 0.043, p=0.255) did not change over the study period. In addition, no changes in injury rates over the 11-year period were found for either training (R(2)=0.000, b=0.000, 95% CI -0.035 to 0.034, p=0.988) or match play (R(2)=0.282, b=-0.015, 95% CI -0.032 to 0.003, p=0.093). CONCLUSIONS: The injury rate has decreased for ligament injuries over the last 11 years, but overall training, match injury rates and the rates of muscle injury and severe injury remain high. PMID- 23813544 TI - Placement education pedagogy as social participation: what are students really learning? AB - BACKGROUND AND PURPOSE: This paper draws on empirical fieldwork data of naturally occurring UK physiotherapy placement education to make visible how education is actually carried out and suggest what students may be learning through their placement interactions. The data challenge everyone involved in placement education design and practice to consider the values and practices students are learning to perpetuate through placement education experiences. METHODS: The researcher undertook an ethnomethodologically informed ethnographic observation of naturally occurring physiotherapy placement education in two UK NHS placement sites. This study adopted a social perspective of learning to focus on the minutiae of placement educator, student and patient interaction practices during student-present therapeutic activities. Two days of placement for each of six senior students were densely recorded in real-time focussing specifically on the verbal, kinesics and proxemics-based elements of the participants' interaction practices. Repeated cycles of data analysis suggested consistent practices irrespective of the placement, educators, students or patients. RESULTS: The data suggest that placement education is a powerful situated learning environment in which students see, experience and learn to reproduce the physiotherapy practices valued by the local placement. Consistently, placement educators and students co produced patient-facing activities as spectacles of physiotherapy-as-science. In each setting, patients were used as person-absent audiovisual teaching aids from which students learnt to make a case for physiotherapy intervention. DISCUSSION: The paper challenges physiotherapists and other professions using work-placement education to look behind the rhetoric of their placement documentation and explore the reality of students' learning in the field. The UK-based physiotherapy profession may wish to consider further the possible implications of its self-definition as a 'science-based healthcare profession' on its in-the presence-of-students interactions with patients. PMID- 23813546 TI - Induction of supramolecular chirality in the self-assemblies of lipophilic pyrimidine derivatives by choice of the amino acid-based chiral spacer. AB - A new family of supramolecular organogelators, based on chiral amino acid derivatives of 2,4,6-trichloro-pyrimidine-5-carbaldehyde, has been synthesized. L alanine was incorporated as a spacer between the pyrimidine core and long hydrocarbon tails to compare the effect of chirality and hydrogen bonding to that of the achiral analogue. The role of aromatic moiety on the chiral spacer was also investigated by introducing L-phenyl alanine moieties. The presence of intermolecular hydrogen-bonding leading to the chiral self-assembly was probed by concentration-dependent FTIR and UV/Vis spectroscopies, in addition to circular dichroism (CD) studies. Temperature and concentration-dependent CD spectroscopy ascribed to the formation of beta-sheet-type H-bonded networks. The morphology and the arrangements of the molecules in the freeze-dried gels were examined by scanning electron microscopy (SEM), transmission electron microscopy (TEM), atomic force microscopy (AFM), and X-ray diffraction (XRD) techniques. Calculation of the length of each molecular system by energy minimization in its extended conformation and comparison with the small-angle XRD pattern reveals that this class of gelator molecules adopts a lamellar organization. Polarized optical microscopy (POM) and differential scanning calorimetry (DSC) indicate that the solid state phase behavior of these molecules is totally dependent on the choice of their amino acid spacers. Structure-induced aggregation properties based on the H-bonding motifs and the packing of the molecule in three dimensions leading to gelation was elucidated by rheological studies. However, viscoelasticity was shown to depend only marginally on the H-bonding interactions; rather it depends on the packing of the gelators to a greater extent. PMID- 23813545 TI - Molecular changes in the phosphatidylinositide 3-kinase (PI3K) pathway are common in gastric cancer. AB - BACKGROUND AND OBJECTIVES: The phosphatidylinositide 3-kinase (PI3K) pathway is an important signalling pathway that is frequently activated in cancer cells. This has led to the emergence of PI3K inhibitors as potential new treatment modalities for many cancers. We have investigated the frequency of molecular changes in the PI3K pathway in gastric cancer. METHODS: A series of sixty one human gastric cancer specimens and nine human gastric cancer cell lines were screened for PIK3CA mutations and copy number gain by direct sequencing and multiplex ligation-dependent probe amplification (MLPA), respectively. PTEN protein levels were assessed by immunohistochemistry. RESULTS: Alterations in the PI3K pathway were found in 33 of 61 (54%) gastric tumours. PIK3CA mutation and copy number gain were detected in 3 (4.9%) and 8 (13.1%), respectively, of 61 gastric cancer samples while PTEN loss was detected in 24 (39%) of the tumours. Two tumours had both PTEN loss and PIK3CA copy number gain. There were no significant associations between these PI3K pathway changes and the clinical features of the tumours. CONCLUSIONS: Alterations in the PI3K pathway are frequent in gastric tumours implicating this pathway as a legitimate therapeutic target in gastric cancer. PMID- 23813547 TI - Controlling Hox gene expression and activity to build the vertebrate axial skeleton. AB - It has long been known that Hox genes are central players in patterning the vertebrate axial skeleton. Extensive genetic studies in the mouse have revealed that the combinatorial activity of Hox genes along the anterior-posterior body axis specifies different vertebral identities. In addition, Hox genes were instrumental for the evolutionary diversification of the vertebrate body plan. In this review, we focus on fundamental questions regarding the intricate mechanisms controlling Hox gene activity. In particular, we discuss the functional relevance of the precise timing of Hox gene activation in the embryo. Moreover, we provide insight into the epigenetic regulatory mechanisms that are likely to control this process and are responsible for the maintenance of spatially restricted Hox expression domains throughout embryonic development. We also analyze how specific features of each Hox protein may contribute to the functional diversity of Hox family. Altogether, the work reviewed here further supports the notion that the Hox program is far more complex than initially assumed. Exciting new findings will surely emerge in the years ahead. PMID- 23813548 TI - Unprotected left main coronary stenting as alternative therapy to coronary bypass surgery in high surgical risk acute coronary syndrome patients. AB - Acute coronary syndrome has a high mortality rate that dramatically increases in the presence of left main coronary artery (LMCA) disease. Over the past decades, coronary artery bypass graft (CABG) surgery has been commonly accepted as the standard of care for patients with LMCA stenosis and is still considered the first-line treatment in current practice guidelines. Percutaneous coronary intervention (PCI) of protected and unprotected LMCA has gained popularity and is increasingly utilized with comparable outcomes to CABG in randomized controlled trials. In-stent restenosis and the need for revascularization provide the main obstacle to LMCA revascularization. The advent of better PCI equipment, stents, ablative devices, intravascular ultrasound, hemodynamic support devices and antithrombotic agents have ignited a renewed interest in the practice of LMCA PCI, especially for high surgical risk patients who are neither candidates nor agreeable to CABG surgery. Herein, we review the studies comparing unprotected LMCA stenting with CABG surgery in regard to 3 main endpoints: mortality, major adverse events and the incidence of repeat revascularization. PMID- 23813549 TI - The increased expression of proteins involved in proliferation, DNA repair and DNA methylation in spleen of mice exposed to E. coli O157:H7 lipopolysaccharide. AB - Previous research showed that the consumption of heat-killed E. coli O157:H7 bacteria resulted in an increase in the level of DNA damage in intestine, liver and spleen cells. We hypothesized that certain bacterial components released from heat-killed bacteria trigger this response. We analysed the possibility that bacterial components [such as lipopolysaccharides (LPS)] could induce changes in the level of proteins involved in cell proliferation, DNA repair and DNA methylation in distal spleen tissues of mice. Four-week-old male mice were provided water supplemented with whole heat-killed E. coli O157:H7 bacteria or components of bacteria (DNA, RNA, proteins and LPS). Spleen cells responded to exposure to whole heat-killed bacteria and LPS with an alteration in the level of PCNA proteins, DNA methylation proteins (DNMT1, DNMT3A, DNMT3B, and MeCP2) and DNA repair proteins (APE1 and KU70). Other bacterial components analysed in this study mostly did not alter protein expression. The data suggest that LPS is a bacterial component capable of inducing molecular changes in naive spleen cells of hosts exposed to it. PMID- 23813550 TI - Bile acids trigger cholemic nephropathy in common bile-duct-ligated mice. AB - Tubular epithelial injury represents an underestimated but important cause of renal dysfunction in patients with cholestasis and advanced liver disease, but the underlying mechanisms are unclear. To address the hypothesis that accumulation and excessive alternative urinary elimination of potentially toxic bile acids (BAs) may contribute to kidney injury in cholestasis, we established a mouse model for detailed in vivo time course as well as treatment studies. Three day common bile duct ligation (CBDL) induced renal tubular epithelial injury predominantly at the level of aquaporin 2-positive collecting ducts with tubular epithelial and basement membrane defects. This was followed by progressive interstitial nephritis and tubulointerstitial renal fibrosis in 3-, 6-, and 8 week CBDL mice. Farnesoid X receptor knockout mice (with a hydrophilic BA pool) were completely protected from CBDL-induced renal fibrosis. Prefeeding of hydrophilic norursodeoxycholic acid inhibited renal tubular epithelial injury in CBDL mice. In addition, we provide evidence for renal tubular injury in cholestatic patients with cholemic nephropathy. CONCLUSION: We characterized a novel in vivo model for cholemic nephropathy, which offers new perspectives to study the complex pathophysiology of this condition. Our findings suggest that urinary-excreted toxic BAs represent a pivotal trigger for renal tubular epithelial injury leading to cholemic nephropathy in CBDL mice. PMID- 23813551 TI - Screening and determination for potential alpha-glucosidase inhibitory constituents from Dalbergia odorifera T. Chen using ultrafiltration-LC/ESI-MS(n). AB - In the present study, it was demonstrated that ethyl acetate soluble fraction partitioned from heartwood of Dalbergia odorifera T. Chen (HEF) had a remarkable inhibitory effect on alpha-glucosidase. Therefore HEF was selected as a starting material for screening the potential alpha-glucosidase inhibitors using ultrafiltration liquid chromatography/mass spectrometry (UF-LC/MS). Twenty-six compounds were identified with analysis of LC/MS. UF assay indicated that 18 compositions might be alpha-glucosidase inhibitors in HEF; eight of them were estimated for their alpha-glucosidase inhibitory activity, and the results showed that (2S)-liquiritigenin, (2S)-4',6-dihydroxy- 7-methoxyflavanone and isoliquiritigenin displayed obvious inhibition of yeast alpha-glucosidase. In addition, in order to control the quality of HEF, the content of five compounds in HEF was simultaneously determined for the first time. These results provide an important theoretical base for the further application of HEF to treat type 2 diabetes in the clinic and development of natural alpha-glucosidase inhibitors with low toxicity. PMID- 23813552 TI - Clean-lifting transfer of large-area residual-free graphene films. AB - A unique "clean-lifting transfer" (CLT) technique that applies a controllable electrostatic force to transfer large-area and high-quality CVD-grown graphene onto various rigid or flexible substrates is reported. The CLT technique without using any organic support or adhesives can produce residual-free graphene films with large-area processability, and has great potential for future industrial production of graphene-based electronics or optoelectronics. PMID- 23813553 TI - Detailing magnetic field strength dependence and segmental artifact distribution of myocardial effective transverse relaxation rate at 1.5, 3.0, and 7.0 T. AB - PURPOSE: Realizing the challenges and opportunities of effective transverse relaxation rate (R2 *) mapping at high and ultrahigh fields, this work examines magnetic field strength (B0 ) dependence and segmental artifact distribution of myocardial R2 * at 1.5, 3.0, and 7.0 T. METHODS: Healthy subjects were considered. Three short-axis views of the left ventricle were examined. R2 * was calculated for 16 standard myocardial segments. Global and mid-septum R2 * were determined. For each segment, an artifactual factor was estimated as the deviation of segmental from global R2 * value. RESULTS: The global artifactual factor was significantly enlarged at 7.0 T versus 1.5 T (P = 0.010) but not versus 3.0 T. At 7.0 T, the most severe susceptibility artifacts were detected in the inferior lateral wall. The mid-septum showed minor artifactual factors at 7.0 T, similar to those at 1.5 and 3.0 T. Mean R2 * increased linearly with the field strength, with larger changes for global heart R2 * values. CONCLUSION: At 7.0 T, segmental heart R2 * analysis is challenging due to macroscopic susceptibility artifacts induced by the heart-lung interface and the posterior vein. Myocardial R2 * depends linearly on the magnetic field strength. The increased R2 * sensitivity at 7.0 T might offer means for susceptibility-weighted and oxygenation level-dependent MR imaging of the myocardium. PMID- 23813554 TI - Socioeconomic measures and CKD in the United States and The Netherlands. AB - BACKGROUND AND OBJECTIVES: According to the cost of health care utilization systems, there may be regional differences in the relative strength of association of income and education-based socioeconomic status measures with CKD. This study investigated the relative strength of the association of income and education with CKD in a United States and a Dutch population. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This cross-sectional study examined individuals who participated in the 1999-2002 National Health and Nutritional Examination Survey (NHANES) and in Prevention of Renal and Vascular End-stage Disease (PREVEND 1997 1998), general population-based cohorts in the United States and The Netherlands, respectively. The main outcome was CKD, defined as estimated GFR <60 ml/min per 1.73 m(2) (using creatinine) or albuminuria >= 30 mg/24 hours or albumin-to creatinine ratio >= 30 mg/g. RESULTS: In NHANES (n=6428), income was strongly associated with CKD (adjusted odds ratio, 2.34 [95% confidence interval (CI), 1.68 to 3.27]; P for trend<0.001) but education was not (adjusted odds ratio, 1.62 [95% CI, 0.87 to 2.25]; P for trend=0.05]. In contrast, in PREVEND (n=7983), low income was weakly associated with CKD whereas low education had a strong association. The fit of the logistic regression model estimating association of income and education with CKD was significantly improved only after income was added in NHANES (P<0.001) and education was added in PREVEND (P=0.01). Sensitivity analyses that used other CKD-defining variables and restricted analyses to participants <65 years of age resulted in similar findings. CONCLUSION: In the United States, where access to health care is traditionally income dependent, income appeared more strongly associated with CKD than in The Netherlands, where education showed a stronger association. PMID- 23813555 TI - The unjustified classification of kidney donors as patients with CKD: critique and recommendations. AB - Unilateral nephrectomy for kidney donation results in loss of about 30% of baseline GFR, leaving some donors with GFR <60 ml/min per 1.73 m(2), the threshold for the diagnosis CKD. This has resulted in insurability problems for some donors. This article reviews the definition of CKD, risks associated with CKD, and large follow-up studies on the vital status and risk of ESRD in kidney donors. It also provides evidence that kidney donors, despite having reduced GFR, are not at increased risk for CKD-associated morbidity and mortality. Epidemiologic studies, most with follow-up <10 years, have shown an association between GFR <60 ml/min per 1.73 m(2) and higher mortality and progression to ESRD. Low GFR in the absence of any other markers for kidney disease, however, conveys attenuated or minimal risk. Of note, studies of long-term kidney donor outcomes (6-45 years) have not shown excess mortality or ESRD. The limitation of the collective evidence is that the increased risks associated with GFR <60 ml/min per 1.73 m(2) were demonstrated in much larger cohorts than those reported for kidney donor outcomes, but donor outcome studies have substantially longer follow-up. On the basis of current findings, kidney donors with low GFR and no other signs of kidney disease should not be classified as having CKD. This is definitely not the reward they deserve, and, more important, the implications of reduced GFR in donors are not associated with unfavorable outcomes. PMID- 23813556 TI - Glomerular diseases: membranous nephropathy--a modern view. AB - Membranous nephropathy (MN) is an autoimmune disease usually associated with a nephrotic syndrome and it may progress to ESRD in the long term. Its etiology is often unknown (idiopathic MN), whereas other cases have a recognizable etiology (secondary MN). In idiopathic MN, the glomerular lesions are mainly caused by autoantibodies against a podocyte membrane protein, the M-type of phospholipase A2 receptor 1. The natural course of idiopathic MN is quite varied with spontaneous complete or partial remissions a relatively common occurrence. Patients with asymptomatic non-nephrotic proteinuria seldom progress and need only conservative management. Those with persistent full-blown nephrotic syndrome and those with declining renal function are candidates for specific treatment with any of several regimens. Cyclical therapy with alternating monthly intravenous and oral glucocorticoids combined with a cytotoxic agent can induce remission and preserve renal function in the long term. Cyclosporine or tacrolimus can induce remission, but relapses are frequent after the drug withdrawal. Mycophenolate mofetil monotherapy seems to be ineffective, but may be beneficial when administered together with steroids. The experience with adrenocorticotropic hormone, natural or synthetic, is limited to a few studies with short-term follow-up, but high rates of remission can be seen after prolonged treatment. A high rate of remission and good tolerance have also been reported with rituximab. Patients with moderate renal insufficiency may also benefit from treatment, but at a price of frequent and serious side effects. With these limitations in mind, idiopathic MN may be considered a treatable disease in many patients. PMID- 23813557 TI - Renal clearance and intestinal generation of p-cresyl sulfate and indoxyl sulfate in CKD. AB - BACKGROUND AND OBJECTIVES: p-Cresyl sulfate and indoxyl sulfate contribute to cardiovascular disease and progression of renal disease. Renal clearance of both solutes mainly depends on tubular secretion, and serum concentrations are widely dispersed for any given stage of CKD. From this information, it is inferred that estimated GFR is not a suitable proxy of the clearance of these solutes. Formal clearance studies have, however, not been performed to date. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study analyzed renal clearances of p-cresyl sulfate and indoxyl sulfate in the Leuven CKD cohort (NCT00441623; inclusion between November of 2005 and September of 2006) and explored their relationship with estimated GFR. Multivariate linear regression models were built to evaluate contributions of estimated GFR, demographics, and generation rates to p-cresyl sulfate and indoxyl sulfate serum concentrations. RESULTS: Renal clearances were analyzed in 203 patients with CKD stages 1-5. Indoxyl sulfate clearances (median=17.7, interquartile range=9.4-33.2 ml/min) exceeded p-cresyl sulfate clearances (median=6.8, interquartile range=3.4-12.0 ml/min) by about threefold. A linear relationship was observed between estimated GFR and clearances of p cresyl sulfate (R(2)=0.50, P<0.001) and indoxyl sulfate (R(2)=0.55, P<0.001). In multivariate regression, p-cresyl sulfate concentrations were associated (R(2)=0.75) with estimated GFR and generation rate (both P<0.001). Indoxyl sulfate concentrations were associated (R(2)=0.74) with estimated GFR, generation rate (both P<0.001), age (P<0.05), and sex (P<0.05). CONCLUSIONS: Estimated GFR provides an acceptable estimate of renal clearance of p-cresyl sulfate and indoxyl sulfate. Remarkably, clearances of indoxyl sulfate exceed clearances of p cresyl sulfate by approximately threefold, suggesting substantial differences between tubular transporter affinities and/or involvement of separate transporter systems for p-cresyl sulfate and indoxyl sulfate. PMID- 23813558 TI - Piecewise analysis of patient survival after onset of AKI. AB - BACKGROUND AND OBJECTIVES: AKI affects approximately 2%-7% of hospitalized patients and >35% of critically ill patients. Survival after AKI may be described as having an acute phase (including an initial hyperacute component) followed by a convalescent phase, which may itself have early and late components. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data from the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network (ATN) study was used to model mortality risk among patients with dialysis-requiring AKI. This study assumed that the mortality hazard can be described by a piecewise log-linear function with change points. Using an average likelihood method, the authors tested for the number of change points in a piecewise log-linear hazard model. The maximum likelihood approach to locate the change point(s) was then adopted, and associated parameters and standard errors were estimated. RESULTS: There were 1124 ATN participants with follow-up to 1 year. The mortality hazard of AKI decreased over time with inflections in the rate of decrease at days 4, 42, and 148, with the sharpest change at day 42. The daily rate of decline in the log of the hazard for death was 0.220 over the first 4 days, 0.046 between day 4 and day 42, 0.017 between day 42 and day 148, and 0.003 between day 148 and day 365. CONCLUSIONS: There appear to be two major phases of mortality risk after AKI: an early phase extending over the first 6 weeks and a late phase from 6 weeks to 1 year. Within the first 42 days, this can be further divided into hyperacute (days 1-4) and acute (days 4-42) phases. After 42 days, there appear to be early (days 42-148) and late (after day 148) convalescent phases. These findings may help to inform the design of AKI clinical trials and assist critical care physicians in prognostic stratification. PMID- 23813559 TI - Preoperative venous intimal hyperplasia, postoperative arteriovenous fistula stenosis, and clinical fistula outcomes. AB - BACKGROUND AND OBJECTIVES: Arteriovenous fistulas often fail to mature, and nonmaturation has been attributed to postoperative stenosis caused by aggressive neointimal hyperplasia. Preexisting intimal hyperplasia in the native veins of uremic patients may predispose to postoperative arteriovenous fistula stenosis and arteriovenous fistula nonmaturation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This work explored the relationship between preexisting venous intimal hyperplasia, postoperative arteriovenous fistula stenosis, and clinical arteriovenous fistula outcomes in 145 patients. Venous specimens obtained during arteriovenous fistula creation were quantified for maximal intimal thickness (median thickness=22.3 MUm). Postoperative ultrasounds at 4-6 weeks were evaluated for arteriovenous fistula stenosis. Arteriovenous fistula maturation within 6 months of creation was determined clinically. RESULTS: Postoperative arteriovenous fistula stenosis was equally frequent in patients with preexisting venous intimal hyperplasia (thickness>22.3 MUm) and patients without hyperplasia (46% versus 53%; P=0.49). Arteriovenous fistula nonmaturation occurred in 30% of patients with postoperative stenosis versus 7% of those patients without stenosis (hazard ratio, 4.33; 95% confidence interval, 1.55 to 12.06; P=0.001). The annual frequency of interventions to maintain arteriovenous fistula patency for dialysis after maturation was higher in patients with postoperative stenosis than patients without stenosis (0.83 [95% confidence interval, 0.58 to 1.14] versus 0.42 [95% confidence interval, 0.28 to 0.62]; P=0.008). CONCLUSIONS: Preexisting venous intimal hyperplasia does not predispose to postoperative arteriovenous fistula stenosis. Postoperative arteriovenous fistula stenosis is associated with a higher arteriovenous fistula nonmaturation rate. Arteriovenous fistulas with hemodynamically significant stenosis frequently mature without an intervention. Postoperative arteriovenous fistula stenosis is associated with an increased frequency of interventions to maintain long-term arteriovenous fistula patency after maturation. PMID- 23813560 TI - Length polymorphism in heme oxygenase-1 and cardiovascular events and mortality in hemodialysis patients. AB - BACKGROUND AND OBJECTIVES: Persistent inflammation and oxidative stress play a pathogenic role in the high cardiovascular morbidity and mortality of hemodialysis patients. Heme oxygenase-1 is considered to have anti-inflammatory and antioxidant properties. This study assessed the association between the length of guanosine thymidine dinucleotide repeats in the heme oxygenase-1 gene microsatellite promoter and cardiovascular events and mortality among hemodialysis patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Study participants were recruited from October 1, 2006 to December 31, 2006. The allelic frequencies of the length of guanosine thymidine dinucleotide repeats (the S allele represents shorter [<27] repeats, and the L allele represents longer [>= 27] repeats) in the heme oxygenase-1 gene promoter were analyzed in 1080 unrelated chronic hemodialysis patients and 365 healthy controls for distribution comparison. Cardiovascular events and mortality were the study outcomes, and the hemodialysis patients were followed until June 30, 2011. RESULTS: The genotype proportions were 20.6%, 48.8%, and 30.6% for S/S, S/L, and L/L, respectively, in the hemodialysis patients and comparable with those proportions in healthy controls. The patients with the L/L genotype had significantly higher baseline serum high-sensitivity C-reactive protein and malondialdehyde levels than the patients with the S/S or S/L genotypes. During a median follow-up of 50 months, 307 patients died. A Kaplan-Meier survival analysis showed the highest cardiovascular events and all-cause mortality in patients with the L/L genotype. The adjusted hazard ratios (95% confidence intervals) for each L allele in additive model were 1.42 (1.20 to 1.67 [P<0.001]) for cardiovascular events and 1.19 (1.01 to 1.40 [P=0.03]) for all-cause mortality. CONCLUSIONS: Chronic hemodialysis patients with longer lengths of guanosine thymidine dinucleotide repeats in the heme oxygenase-1 gene promoter exhibit higher inflammation and oxidative stress. These patients have higher risk of long-term cardiovascular events and mortality. PMID- 23813561 TI - Guillain-Barre syndrome during childhood: particular clinical and electrophysiological features. AB - INTRODUCTION: Guillain-Barre syndrome (GBS) has some specific characteristics in children. METHODS: In this study we reviewed the clinical, laboratory, electrophysiological, and prognosis features of the 19 children diagnosed with GBS at Nantes University Hospital from 2000 to 2011. RESULTS: Gait disturbance and leg pain were the most frequent presenting symptoms. Electrophysiological examinations revealed significant abnormalities even when performed within the first week after onset. Decreased distal CMAP amplitude was noted in 89% of cases. The pattern indicated an acute inflammatory demyelinating polyneuropathy in 95% of cases and acute motor axonal neuropathy in the remaining 5%. About two thirds of the children were treated with intravenous immunoglobulin. After >1 year of follow-up, 17 patients had complete recovery. CONCLUSION: Gait disorder, leg pain, a high rate of distal conduction block, and a good prognosis are among the main specific features of GBS in childhood. PMID- 23813562 TI - Mindfulness-based stress reduction for parents of young children with developmental delays: implications for parental mental health and child behavior problems. AB - BACKGROUND: Parents of children with developmental delays (DD) typically report elevated levels of parental stress compared with parents of typically developing children. Children with DD are also at high risk for exhibiting significant behaviour problems. Parental stress has been shown to impact the development of these behaviour problems; however, it is rarely addressed in interventions aimed at reducing child behaviour problems. The current study examined the efficacy of mindfulness-based stress reduction (MBSR) for parents of children with DD by investigating whether this intervention is effective in reducing parenting stress and whether decreases in parenting stress lead to reductions in behaviour problems among children with DD. MATERIALS AND METHODS: Forty six parents of children with DD were randomly assigned to an immediate treatment or wait list control group. Participants completed questionnaires assessing parental stress and child behaviour problems at intake and at a second assessment, which took place after only the immediate treatment group had received the MBSR. RESULTS: Parents who participated in MBSR reported significantly less stress and depression as well as greater life satisfaction compared with wait list-control parents. Regarding child outcomes, children whose parents participated in MBSR were reported to have fewer behaviour problems following the intervention, specifically in the areas of attention problems and ADHD symptomatology. DISCUSSION: Results indicated that MBSR may be an effective intervention for ameliorating parental stress and mental health problems among parents of children with DD. Additionally, these benefits may 'spill over' and improve behaviour challenges among these children. PMID- 23813563 TI - The reporting of outcomes in studies of fever and neutropenia in children with cancer: time for consensus. PMID- 23813565 TI - Enantioselective syntheses of the proposed structures of kopeolin and kopeolone. AB - The first total syntheses of the proposed structures of kopeolin (1) and kopeolone (3) have been achieved from a common enantiopure chiral building block obtained by a chemoenzymatic enantioconvergent methodology. The syntheses feature two key steps: a one-pot reduction/diastereoselective protonation followed by a highly diastereoselective addition of an organocerate. The synthetic structures were fully characterized and all stereocenters were confirmed. The results show that the two previously reported structures were not assigned correctly, and suggest an initial structural misassignment during the isolation of the natural products. Thus, two revised structures, 1' for kopeolin and 3' for kopeolone, are proposed. PMID- 23813564 TI - Canonical Wnt signaling regulates Nkx3.1 expression and luminal epithelial differentiation during prostate organogenesis. AB - BACKGROUND: The formation of the prostate gland requires reciprocal interactions between the epithelial and mesenchymal components of the embryonic urogenital sinus. However, the identity of the signaling factors that mediate these interactions is largely unknown. RESULTS: Our studies show that expression of the prostate-specific transcription factor Nkx3.1 is regulated by the canonical Wnt signaling pathway. Using mice carrying a targeted lacZ knock-in allele of Nkx3.1, we find that Nkx3.1 is expressed in all epithelial cells of ductal buds during prostate organogenesis. Addition of Wnt inhibitors to urogenital sinus explant culture greatly reduces prostate budding and inhibits Nkx3.1 expression as well as differentiation of luminal epithelial cells. Analyses of a TCF/Lef:H2B-GFP transgene reporter show that canonical Wnt signaling activity is found in urogenital mesenchyme but not urogenital sinus epithelium before prostate formation, and is later observed in the mesenchyme and epithelium of prostate ductal tips. Furthermore, TCF/Lef:H2B-GFP reporter activity is reduced in epithelial cells of Nkx3.1 null neonatal prostates, suggesting that Nkx3.1 functions to maintain canonical Wnt signaling activity in developing prostate bud tips. CONCLUSIONS: We propose that activated canonical Wnt signals and Nkx3.1 function in a positive feedback loop to regulate prostate bud growth and luminal epithelial differentiation. PMID- 23813566 TI - Open source electronic health records and chronic disease management. AB - OBJECTIVE: To study and report on the use of open source electronic health records (EHR) to assist with chronic care management within safety net medical settings, such as community health centers (CHC). METHODS AND MATERIALS: The study was conducted by NORC at the University of Chicago from April to September 2010. The NORC team undertook a comprehensive environmental scan, including a literature review, a dozen key informant interviews using a semistructured protocol, and a series of site visits to CHC that currently use an open source EHR. RESULTS: Two of the sites chosen by NORC were actively using an open source EHR to assist in the redesign of their care delivery system to support more effective chronic disease management. This included incorporating the chronic care model into an CHC and using the EHR to help facilitate its elements, such as care teams for patients, in addition to maintaining health records on indigent populations, such as tuberculosis status on homeless patients. DISCUSSION: The ability to modify the open-source EHR to adapt to the CHC environment and leverage the ecosystem of providers and users to assist in this process provided significant advantages in chronic care management. Improvements in diabetes management, controlled hypertension and increases in tuberculosis vaccinations were assisted through the use of these open source systems. CONCLUSIONS: The flexibility and adaptability of open source EHR demonstrated its utility and viability in the provision of necessary and needed chronic disease care among populations served by CHC. PMID- 23813567 TI - Aberrant DNA methylation of miR-219 promoter in long-term night shiftworkers. AB - The idea that shiftwork may be carcinogenic in humans has gained widespread attention since the pioneering work linking shiftwork to breast cancer over two decades ago. However, the biomolecular consequences of long-term shiftwork exposure have not been fully explored. In this study, we performed a genome-wide CpG island methylation assay of microRNA (miRNA) promoters in long-term night shiftworkers and day workers. This analysis indicated that 50 CpG loci corresponding to 31 miRNAs were differentially methylated in night shiftworkers compared to day workers, including the circadian-relevant miR-219, the expression of which has been implicated in several cancers. A genome-wide expression microarray assay was carried out in a miR-219-overexpressed MCF-7 breast cancer cell line, which identified 319 differentially expressed transcripts. The identified transcriptional targets were analyzed for network and functional interrelatedness using the Ingenuity Pathway Analysis (IPA) software. Overexpression of miR-219 in MCF-7 breast cancer cells resulted in accentuated expression of apoptosis- and proliferation-related anti-viral immunodulators of the Jak-STAT and NF-kappabeta pathways. These findings suggest that long-term night shiftwork exposure may lead to the methylation-dependent downregulation of miR-219, which may in turn lead to the downregulation of immunomediated antitumor activity and increased breast cancer risk. PMID- 23813568 TI - Editorial: Molecular Endocrinology articles in the spotlight for July 2013. PMID- 23813571 TI - Rebuttal: response to letter by Fan and colleagues regarding "impact on fractional flow reserve of donor artery by chronic total obstruction revascularization". PMID- 23813570 TI - A novel role of nucleostemin in maintaining the genome integrity of dividing hepatocytes during mouse liver development and regeneration. AB - During liver development and regeneration, hepatocytes undergo rapid cell division and face an increased risk of DNA damage associated with active DNA replication. The mechanism that protects proliferating hepatocytes from replication-induced DNA damage remains unclear. Nucleostemin (NS) is known to be up-regulated during liver regeneration, and loss of NS is associated with increased DNA damage in cancer cells. To determine whether NS is involved in protecting the genome integrity of proliferating hepatocytes, we created an albumin promoter-driven NS conditional-null (albNS(cko) ) mouse model. Livers of albNS(cko) mice begin to show loss of NS in developing hepatocytes from the first postnatal week and increased DNA damage and hepatocellular injury at 1-2 weeks of age. At 3-4 weeks, albNS(cko) livers develop bile duct hyperplasia and show increased apoptotic cells, necrosis, regenerative nodules, and evidence suggestive of hepatic stem/progenitor cell activation. CCl4 treatment enhances degeneration and DNA damage in NS-deleted hepatocytes and increases biliary hyperplasia and A6(+) cells in albNS(cko) livers. After 70% partial hepatectomy, albNS(cko) livers show increased DNA damage in parallel with a blunted and prolonged regenerative response. The DNA damage in NS-depleted hepatocytes is explained by the impaired recruitment of a core DNA repair enzyme, RAD51, to replication-induced DNA damage foci. CONCLUSION: This work reveals a novel genome protective role of NS in developing and regenerating hepatocytes. PMID- 23813572 TI - Simultaneous quantitative analyses of indole and oxindole alkaloids of Uncaria Hook in rat plasma and brain after oral administration of the traditional Japanese medicine Yokukansan using high-performance liquid chromatography with tandem mass spectrometry. AB - Uncaria Hook (UH) alkaloids are involved in the beneficial effects of Yokukansan. However, the pharmacokinetics of UH alkaloids after oral administration of Yokukansan has not yet been sufficiently investigated. Therefore, we developed and validated a sensitive and specific high-performance liquid chromatography with tandem mass spectrometry (LC/MS/MS) method for the simultaneous quantitation of seven UH alkaloids (corynoxeine, isocorynoxeine, rhynchophylline, isorhynchophylline, hirsutine, hirsuteine and geissoschizine methyl ether) in rat plasma and brain. After protein precipitation with acetonitrile, chromatographic separation was performed using an Ascentis Express RP-amide column, with gradient elution with 0.2% formic acid and acetonitrile at 0.3 mL/min. All analytes in the plasma and brain showed good linearity over a wide concentration range (r > 0.995). Intra-day and inter-day variations of each constituent were 8.6 and 8.0% or less in the plasma, and 14.9 and 15.0% or less in the brain, respectively. The validated LC/MS/MS method was applied in the pharmacokinetic studies of UH alkaloids after oral administration of Yokukansan to rats. In the plasma, rhynchophylline, hirsutine, hirsuteine and geissoschizine methyl ether were detected, but only geissoschizine methyl ether was detected in the brain. These results suggest that geissoschizine methyl ether is an important constituent of the pharmacological effects of Yokukansan. PMID- 23813573 TI - Evaluation of the staging systems for gastric cancer. AB - BACKGROUND: Some staging systems for gastric cancer (GC) have been developed as alternatives to the 6th and 7th TNM staging systems, including the Hybrid, tumor ratio-metastasis (TRM), and Kiel staging systems. This study evaluated the overall performance of these systems for GC. METHODS: A total of 540 GC patients undergoing surgical resection were staged using these five systems. Homogeneity, discrimination power, predictive accuracy, and complexity of these systems were compared. RESULTS: Multivariate analyses showed that all of 7th pT, pN, and pM classifications were independent factors for GC prognosis (P < 0.001 for all). Compared with the other four systems, 7th TNM system had improved stage groups homogeneity (7 of 8 stage groups homogeneous), enhanced discrimination power (4 of 5, 5 of 7, 4 of 7, 3 of 7, and 1 of 4 adjacent stage groups were differentiated by the 6th, 7th TNM, Hybrid, TRM, and Kiel systems, respectively), and better prediction value for GC patients' outcome (AUC = 0.801, P < 0.001). In addition, the 7th TNM system did not increase the staging complexity (9 groups and 21 subgroups). CONCLUSIONS: The 7th TNM staging system represents advancement in GC staging system for better prediction of clinical outcomes. PMID- 23813576 TI - MicroRNAs involved in skeletal muscle development and their roles in rhabdomyosarcoma pathogenesis. AB - MicroRNAs (miRs) are small non-coding RNAs known to fulfill various functions in tissue development, function, and pathogenesis of various diseases, including cancer. Rhabdomyosarcoma (RMS) represents the most common soft tissue tumor in the pediatric population. miRs have been shown to play important roles in RMS pathogenesis and some of the studies suggest their potential as diagnostic, prognostic, and even therapeutic tools facilitating better management of this disease. This review summarizes current information about the role of miRs in the development of normal skeletal muscle and their deregulation in RMS. PMID- 23813578 TI - Formation of the digestive tract in Ciona intestinalis includes two distinct morphogenic processes between its anterior and posterior parts. AB - BACKGROUND: In the ascidian Ciona intestinalis, the digestive tract, an essential system for animals, develops during metamorphosis from the two primordial tissues, the endoderm and endodermal strand, located in the larval trunk and tail, respectively. However, it has been largely unknown how the digestive tract develops from these primordial tissues. We examined the metamorphosing larvae for the tubular formation of the digestive tract, focusing on the epithelial organization of the endoderm, by combined confocal microscopy and computational rendering. RESULTS: The tubular structure of the esophagus to the stomach was formed through the folding and closure of the endodermal epithelia in the central to-right posterior trunk. By contrast, the intestine was formed in the left posterior trunk through the accumulation and rearrangement of the cells originated from the endodermal strand. This was confirmed by the cell-tracing experiment using Kaede expression construct driven in the endodermal strand. Thus, the tubular formation of the digestive tract in C. intestinalis includes distinct morphogenetic processes and cell lineages between its anterior and posterior parts. CONCLUSION: This study provides the first detailed description of the digestive tract morphogenesis in C. intestinalis and serves as an important basis toward thorough understanding of its digestive tract development. PMID- 23813577 TI - Comorbidities are associated with poorer outcomes in community patients with rheumatoid arthritis. AB - OBJECTIVE: To evaluate the impact of comorbidities on achieving remission by examining changes in the clinical disease activity index (CDAI) in RA patients in the community-based Consortium of Rheumatology Researchers of North America (CORRONA) registry. METHODS: A subcohort of 1548 RA subjects with varying disease duration met the following inclusion criteria: started a DMARD/biologic agent, continued therapy >= 3 months, CDAI >= 2.8 at study entry and followed longitudinally from baseline to follow-up (mean time 7.46 months). Patients reported comorbidities according to a standardized list of 33 conditions. Entry characteristics were compared across age categories using one-way analysis of variance. Linear and logistic regression models were constructed to assess characteristics [e.g. age, disease duration, number of previous DMARDs/biologics, baseline modified health assessment questionnaire (MHAQ), baseline CDAI and number of comorbidities] associated with primary outcomes: change in CDAI (baseline to follow-up) and CDAI remission (yes/no). RESULTS: Although disease activity measures at entry were similar across age categories, older patients had more comorbidities, less improvement in CDAI/MHAQ and were less likely to attain remission at follow-up. However, after adjusting covariates an increasing number of patient-reported comorbidities and higher baseline CDAI (but not age) were consistently and independently associated with a lower likelihood of clinical improvement or remission (P < 0.001). CONCLUSION: In this observational cohort of community RA patients an increasing number of patients reported comorbidities, independently correlated with less CDAI improvement over time. These results reaffirm that comorbidities may be an important factor in consideration of treat to-target recommendations and aid in understanding achievable RA therapeutic goals. PMID- 23813579 TI - Ultra-fast steady state free precession and its application to in vivo (1)H morphological and functional lung imaging at 1.5 tesla. AB - PURPOSE: The speed limit for three-dimensional Fourier-encoded steady state free precession (SSFP) imaging is explored on a clinical whole body system and pushed toward a pulse repetition time (TR) close to or even below the 1 ms regime; in the following referred to as ultra-fast SSFP imaging. METHODS: To this end, contemporary optimization strategies, such as efficient gradient switching patterns, partial echoes, ramp sampling techniques, and a target-related design of excitation pulses were applied to explore the lower boundaries in TR for SSFP based Cartesian imaging. RESULTS: Generally, minimal TR was limited in vivo by peripheral nerve stimulation, allowing a TR ~1 ms for isotropic resolutions down to about 2 mm. As a result, ultra-fast balanced SSFP provides artifact-free images even for targets with severe susceptibility variations, and native high resolution structural and functional in vivo (1)H imaging of the human lung is demonstrated at 1.5 T. CONCLUSION: On clinical whole body MRI systems, the TR of SSFP-based Cartesian imaging can be pushed toward the 1 ms regime. As a result, ultra-fast SSFP protocols might represent a promising new powerful approach for SSFP-based imaging, not only for lung but also in a variety of clinical and scientific applications. PMID- 23813580 TI - Hyperparathyroidism caused by a functional parathyroid cyst. AB - A 67-year-old Japanese woman was admitted to our hospital for malaise and loss of appetite. Relevant biochemical examinations showed definite hypercalcaemia and elevated serum levels of intact parathyroid hormone (PTH). We performed thyroid ultrasonography and CT of the neck, which revealed a cystic lesion in the right lower lobe of the thyroid glands. Ultrasound-guided fine-needle aspiration was performed, and PTH level of the cystic fluid was markedly elevated. Technetium 99m-hexakis 2-methoxyisobutyi isonitrile sesta scintigraphy showed intense ring shaped accumulation of radioactivity in the wall of the cyst. The patient underwent a right lobectomy to resect the cystic parathyroid adenoma. After surgery, her serum calcium and PTH level returned to normal ranges. PMID- 23813581 TI - Successful treatment of pain in melorheostosis with zoledronate, with improvement on bone scintigraphy. AB - Melorheostosis is a very rare sclerosing bone disorder that involves frequently one limb. It may be asymptomatic, but pain and limb deformity may occur and can be very debilitating. Different reports have indicated efficacy of bisphosphonates (pamidronate and etidronate) on symptoms. We report an adult patient with a very painful melorheostosis, who improved after treatment with zoledronate, either on symptoms or on bone scans. PMID- 23813582 TI - Preparation of ordered mesoporous alumina-doped titania films with high thermal stability and their application to high-speed passive-matrix electrochromic displays. AB - Ordered mesoporous alumina-doped titania thin films with anatase crystalline structure were prepared by using triblock copolymer Pluronic P123 as structure directing agent. Uniform Al doping was realized by using aluminum isopropoxide as a dopant source which can be hydrolyzed together with titanium tetraisopropoxide. Aluminum doping into the titania framework can prevent rapid crystallization to the anatase phase, thereby drastically increasing thermal stability. With increasing Al content, the crystallization temperatures tend to increase gradually. Even when the Al content doped into the framework was increased to 15 mol %, a well-ordered mesoporous structure was obtained, and the mesostructural ordering was still maintained after calcination at 550 degrees C. During the calcination process, large uniaxial shrinkage occurred along the direction perpendicular to the substrate with retention of the horizontal mesoscale periodicity, whereby vertically oriented nanopillars were formed in the film. The resulting vertical porosity was successfully exploited to fabricate a high-speed and high-quality passive-matrix electrochromic display by using a leuco dye. The vertical nanospace in the films can effectively prevent drifting of the leuco dye. PMID- 23813583 TI - Easy-to-read texts for students with intellectual disability: linguistic factors affecting comprehension. AB - BACKGROUND: The use of 'easy-to-read' materials for people with intellectual disabilities has become very widespread but their effectiveness has scarcely been evaluated. In this study, the framework provided by Kintsch's Construction Integration Model (1988) is used to examine (i) the reading comprehension levels of different passages of the Spanish text that have been designed following easy to-read guidelines and (ii) the relationships between reading comprehension (literal and inferential) and various linguistic features of these texts. METHOD: Sixteen students with mild intellectual disability and low levels of reading skills were asked to read easy-to-read texts and then complete a reading comprehension test. The corpus of texts was composed of a set of forty-eight pieces of news selected from www.noticiasfacil.es, a Spanish digital newspaper that publishes daily journalistic texts following international guidelines for the design of easy-to-read documents (IFLA, Tronbacke B. (1997) Guidelines for Easy-to-read Materials. IFLA, The Hague). RESULTS: Participants correctly answered 80% of the comprehension questions, showing significantly higher scores for literal questions than for inferential questions. The analyses of the texts' linguistic features revealed that the number of coreferences was the variable that best predicted literal comprehension, but contrary to what the previous literature seemed to indicate, the relationship between the two variables was inverse. In the case of inferential comprehension, the number of sentences was a significant negative predictor; that is, the higher the sentence density, the lower the ability of these students to find relationships between them. The effects of the rest of linguistic variables, such as word frequency and word length, on comprehension were null. CONCLUSIONS: These results provide preliminary empirical support for the use of easy-to-read texts but bring into question the validity of some popular design guidelines (e.g. augmenting word frequency) to optimally match texts and reading levels of students with intellectual disability. Two factors are suggested as contributing to the effect of sentence density on inferential comprehension: (i) long texts present higher conceptual density, so there are more ideas to store, retrieve and integrate, which increases the demand on inferential reasoning and (ii) long texts are perceived as difficult, which affects reading motivation and, consequently, induces passive reading strategies. The need for further research to elucidate the origin of our main findings with a larger and more heterogeneous sample of students with intellectual disability is highlighted. PMID- 23813584 TI - Symmetry of paraspinal muscle denervation in clinical lumbar spinal stenosis: support for a hypothesis of posterior primary ramus stretching? AB - INTRODUCTION: Denervation of the paraspinal muscles in spinal disorders is frequently attributed to radiculopathy. Therefore, patients with lumbar spinal stenosis causing asymmetrical symptoms should have asymmetrical paraspinal denervation. METHODS: Seventy-three patients with clinical lumbar spinal stenosis, aged 55-85 years, completed a pain drawing and underwent masked electrodiagnostic testing, including bilateral paraspinal mapping and testing of 6 muscles on the most symptomatic (or randomly chosen) limb. RESULTS: With the exception of 10 subjects with unilateral thigh pain (P = 0.043), there was no relationship between side of pain and paraspinal mapping score for any subgroups (symmetrical pain, pain into 1 calf only). Among those with positive limb EMG (tested on 1 side), no relationship between side of pain and paraspinal EMG score was found. CONCLUSION: Evidence suggests that paraspinal denervation in spinal stenosis may not be due to radiculopathy, but rather due to stretch or damage to the posterior primary ramus. PMID- 23813585 TI - Hyaluronic acid-dependent protection against UVB-damaged human corneal cells. AB - Within ultraviolet radiation, ultraviolet B (UVB) is the most energetic and damaging to humans. At the protein level, UVB irradiation downregulates the expression of antioxidant enzymes leading to the accumulation of reactive oxygen species (ROS). Due to lacking of a global analysis of UVB-modulated corneal proteome, we investigate in vitro the mechanism of UVB-induced corneal damage to determine whether hyaluronic acid (HA) is able to reduce UVB irradiation-induced injury in human corneal epithelial cells. Accordingly, human corneal epithelial cell lines (HCE-2) were irradiated with UVB, followed by incubation with low molecular weight HA (LMW-HA, 100 kDa) or high molecular weight HA (HMW-HA, 1,000 kDa) to investigate the physiologic protection of HMW-HA in UVB-induced corneal injury, and to perform a global proteomic analysis. The data demonstrated that HA treatment protects corneal epithelial cells in the UVB-induced wound model, and that the molecular weight of HA is a crucial factor. Only HMW-HA significantly reduces the UVB-induced cytotoxic effects in corneal cells and increases cell migration and wound-healing ability. In addition, proteomic analysis showed that HMW-HA might modulate cytoskeleton regulation, signal transduction, biosynthesis, redox regulation, and protein folding to stimulate wound healing and to prevent these UVB-damaged cells from cell death. Further studies evidenced membrane associated progesterone receptor component 1 (mPR) and malate dehydrogenase (MDH2) play essential roles in protecting corneal cells from UVB irradiation. This study reports on UVB-modulated cellular proteins that might play an important role in UVB-induced corneal cell injury and show HMW-HA to be a potential substance for protecting corneal cells from UVB-induced injury. PMID- 23813587 TI - Climate affects symbiotic fungal endophyte diversity and performance. AB - PREMISE OF THE STUDY: Fungal endophytes are symbionts that inhabit aboveground tissues of most terrestrial plants and can affect plant physiology and growth under stressed conditions. In a future faced with substantial climate change, endophytes have the potential to play an important role in plant stress resistance. Understanding both the distributions of endophytes and their functioning in symbiosis with plants are key aspects of predicting their role in an altered climate. METHODS: Here we characterized endophytes in grasses across a steep precipitation gradient to examine the relative importance of environmental and spatial factors in structuring endophyte communities. We also tested how 20 endophytes isolated from drier and wetter regions performed in symbiosis with grass seedlings under high and low soil moisture in the greenhouse. KEY RESULTS: Environmental factors related to historical and current precipitation were the most important predictors of endophyte communities in the field. On average, endophytic fungi from western sites also reduced plant water loss in the greenhouse compared to fungi from eastern sites. However, there was substantial variability in how individual endophytic taxa affected plant traits under high and low water availability, with up to two orders of magnitude difference in the plasticity of plant traits conferred by the different fungal taxa. CONCLUSIONS: While species sorting appears to largely explain local endophyte community composition, their function in symbiosis is not predictable from local environmental conditions. The development of a predictive framework for endophyte function will require further study of individual fungal taxa and genotypes across environmental gradients. PMID- 23813588 TI - Recent advances in design and fabrication of upconversion nanoparticles and their safe theranostic applications. AB - Lanthanide (Ln) doped upconversion nanoparticles (UCNPs) have attracted enormous attention in the recent years due to their unique upconversion luminescent properties that enable the conversion of low-energy photons (near infrared photons) into high-energy photons (visible to ultraviolet photons) via the multiphoton processes. This feature makes them ideal for bioimaging applications with attractive advantages such as no autofluorescence from biotissues and a large penetration depth. In addition, by incorporating advanced features, such as specific targeting, multimodality imaging and therapeutic delivery, the application of UCNPs has been dramatically expanded. In this review, we first summarize the recent developments in the fabrication strategies of UCNPs with the desired size, enhanced and tunable upconversion luminescence, as well as the combined multifunctionality. We then discuss the chemical methods applied for UCNPs surface functionalization to make these UCNPs biocompatible and water soluble, and further highlight some representative examples of using UCNPs for in vivo bioimaging, NIR-triggered drug/gene delivery applications and photodynamic therapy. In the perspectives, we discuss the need of systematically nanotoxicology data for rational designs of UCNPs materials, their surface chemistry in safer biomedical applications. The UCNPs can actually provide an ideal multifunctionalized platform for solutions to many key issues in the front of medical sciences such as theranostics, individualized therapeutics, multimodality medicine, etc. PMID- 23813586 TI - DNA damage response: three levels of DNA repair regulation. AB - Genome integrity is challenged by DNA damage from both endogenous and environmental sources. This damage must be repaired to allow both RNA and DNA polymerases to accurately read and duplicate the information in the genome. Multiple repair enzymes scan the DNA for problems, remove the offending damage, and restore the DNA duplex. These repair mechanisms are regulated by DNA damage response kinases including DNA-PKcs, ATM, and ATR that are activated at DNA lesions. These kinases improve the efficiency of DNA repair by phosphorylating repair proteins to modify their activities, by initiating a complex series of changes in the local chromatin structure near the damage site, and by altering the overall cellular environment to make it more conducive to repair. In this review, we focus on these three levels of regulation to illustrate how the DNA damage kinases promote efficient repair to maintain genome integrity and prevent disease. PMID- 23813589 TI - Development of a serum-free defined system employing growth factors for preantral follicle culture. AB - This study was conducted to evaluate if mouse preantral follicles can yield developmentally competent oocytes following culture in serum-free, defined medium. Donor follicles were obtained from 14-day-old B6CBAF1 mice, and cultured in alpha-MEM-Glutamax medium. The replacement of fetal bovine serum with knockout serum replacement (KSR) did not significantly reduce follicle growth or oocyte maturation in vitro, although it significantly reduced the development of oocytes after activation. Regardless of the replacement medium, follicle growth was not influenced by the addition of leukemia inhibitory factor (LIF). The addition of 100 ng/ml stem cell factor (SCF) to the KSR-supplemented serum-free medium significantly stimulated follicle development, which further improved blastocyst formation after oocyte activation. On Day 3 of culture, a significant increase in Bmp7 expression was detected in the SCF-containing medium compared with the serum containing medium, whereas Gdf9 and Amh were increased in the serum-containing medium. A significant increase in estradiol production was detected under serum free conditions, but minimal progesterone secretion was detected throughout the culture period. In conclusion, serum-free media can be used to optimize ovarian follicle cultures, and the addition of SCF is beneficial for deriving developmentally competent oocytes through follicle culture. PMID- 23813590 TI - Hepatic loss of survivin impairs postnatal liver development and promotes expansion of hepatic progenitor cells in mice. AB - Hepatocytes possess a remarkable capacity to regenerate and reconstitute the parenchyma after liver damage. However, in the case of chronic injury, their proliferative potential is impaired and hepatic progenitor cells (HPCs) are activated, resulting in a ductular reaction known as oval cell response. Proapoptotic and survival signals maintain a precise balance to spare hepatocytes and progenitors from hyperplasia and cell death during regeneration. Survivin, a member of the family of inhibitor of apoptosis proteins (IAPs), plays key roles in the proliferation and apoptosis of various cell types. Here, we characterized the in vivo function of Survivin in regulating postnatal liver development and homeostasis using mice carrying conditional Survivin alleles. Hepatic perinatal loss of Survivin causes impaired mitosis, increased genome ploidy, and enlarged cell size in postnatal livers, which eventually leads to hepatocyte apoptosis and triggers tissue damage and inflammation. Subsequently, HPCs that retain genomic Survivin alleles are activated, which finally differentiate into hepatocytes and reconstitute the whole liver. By contrast, inducible ablation of Survivin in adult hepatocytes does not affect HPC activation and liver homeostasis during a long-life period. CONCLUSION: Perinatal Survivin deletion impairs hepatic mitosis in postnatal liver development, which induces HPC activation and reconstitution in the liver, therefore providing a novel HPC induction model. PMID- 23813591 TI - Correlative light-electron fractography for fatigue striations characterization in metallic alloys. AB - The correlative light-electron fractography technique combines correlative microscopy concepts to the extended depth-from-focus reconstruction method, associating the reliable topographic information of 3-D maps from light microscopy ordered Z-stacks to the finest lateral resolution and large focus depth from scanning electron microscopy. Fatigue striations spacing analysis can be precisely measured, by correcting the mean surface tilting with the knowledge of local elevation data from elevation maps. This new technique aims to improve the accuracy of quantitative fractography in fatigue fracture investigations. PMID- 23813592 TI - Impact on fractional flow reserve of donor artery by chronic total obstruction revascularization. PMID- 23813593 TI - Cramps and small-fiber neuropathy. AB - INTRODUCTION: Muscle cramps are a common complaint and are thought to arise from spontaneous discharges of the motor nerve terminal. Polyneuropathy is often causative, but small-fiber neuropathy (SFN) has not been assessed. METHODS: We performed skin biopsies on consecutive patients with cramps but without neuropathic complaints. Twelve patients were biopsied, 8 with normal small-fiber sensation. RESULTS: Seven patients had decreased intraepidermal nerve fiber density (IENFD), 2 with non-length-dependent loss. A cause for neuropathy was found in 1 patient with cramp-fasciculation syndrome. Creatine kinase was elevated in 8 patients, 4 with decreased IENFD. Muscle biopsy, performed in 8 patients, but was diagnostic in only 1, with McArdle disease. CONCLUSIONS: Our data show that 60% of patients with muscle cramps who lack neuropathic complaints have SFN, as documented by decreased IENFD. Cramps may originate as local mediators of inflammation released by damaged small nerve that excite intramuscular nerves. PMID- 23813594 TI - Plasmonics in nanostructures. AB - Plasmonics has developed into one of the rapidly growing research topics for nanophotonics. With advanced nanofabrication techniques, a broad variety of nanostructures can be designed and fabricated for plasmonic devices at nanoscale. Fundamental properties for both surface plasmon polaritons (SPP) and localized surface plasmons (LSP) arise a new insight and understanding for the electro optical device investigations, such as plasmonic nanofocusing, low-loss plasmon waveguide and active plasmonic detectors for energy harvesting. Here, we review some typical functional plasmonic nanostructures and nanosmart devices emerging from our individual and collaborative research works. PMID- 23813595 TI - Quantitative determination of d- and l-threo enantiomers of methylphenidate in brain tissue by liquid chromatography-mass spectrometry. AB - Methylphenidate, a psychostimulant used for the treatment of attention deficit hyperactivity disorder and narcolepsy, is administered as a 50:50 racemic mixture, despite the fact that d-methylphenidate has been shown to have greater pharmacologic activity. This paper presents a validated LC-MS/MS approach to separation and quantification of methylphenidate enantiomers using a vancomycin column and triethylammonium acetate to enhance the chiral separation. The method is applicable to the monitoring of these enantiomers in mouse brain, with a limit of detection of 0.5 ng/mL and a lower limit of quantification of 7.5 ng/mL. PMID- 23813596 TI - Mental disorders associated with subpopulations of women affected by violence and abuse. AB - Violence against women is a major public health problem associated with mental disorders. Few studies have examined the heterogeneity of interpersonal violence and abuse (IVA) among women and associated mental health problems. Latent class analysis was used to identify subpopulations of women with similar lifetime histories of IVA victimization and to examine 10 associated past-year mental disorders. Participants were 19,816 adult women who participated in Wave 2 of the National Epidemiologic Study on Alcohol and Related Conditions (NESARC). The 3 class model was best supported by the data. Class 1 (6.7%) had a high probability of witnessing domestic violence as a child. Class 2 (21.8%) had a low probability of all events except lifetime sexual assault. Class 3 (71.5%) had a low probability for all events. Mental disorders were more common among members of Classes 1 and 2 than Class 3. For example, members in Class 1 were approximately 8 and 9 times more likely than members in Class 3 to have had posttraumatic stress disorder or a drug use disorder, respectively, during the past year. Of the 10 mental disorders, 5 were more common among members of Class 1 than of Class 2. Findings suggest the mental health consequences of IVA among women are extensive and interventions should be tailored for distinct subpopulations affected by IVA. PMID- 23813597 TI - 13C-NMR data of daphnane diterpenoids. AB - Daphnane diterpenoids are mainly distributed in Thymelaeaceae and Euphorbiaceae and have various bioactivities. About 100 daphnane diterpenoids have been isolated from natural plants. In this review, we systematically summarize the (13)C-NMR data of daphnane diterpenoids isolated from natural plants over the past several decades and briefly discussed their biological activities and basic structural-activity relationship. PMID- 23813598 TI - Interchangeability between 24-hour collection and single spot urines for vanillylmandelic and homovanillic acid levels in the diagnosis of neuroblastoma. AB - The determination of the two urinary catecholamine metabolites homovanillic acid (HVA) and vanillylmandelic acid (VMA) is of crucial importance for the diagnosis and follow-up of neuroblastoma (NB). The standard practice for their measurement requires the use of 24-hour collections that are time consuming and difficult to obtain. In this article, we directly demonstrate that 24-hour collections and single spot urines are interchangeable for the determination of HVA and VMA expressed as ratio on creatinine concentration. This study can be useful for a faster management of NB at onset. PMID- 23813599 TI - Multiscale geometric modeling of macromolecules II: Lagrangian representation. AB - Geometric modeling of biomolecules plays an essential role in the conceptualization of biolmolecular structure, function, dynamics, and transport. Qualitatively, geometric modeling offers a basis for molecular visualization, which is crucial for the understanding of molecular structure and interactions. Quantitatively, geometric modeling bridges the gap between molecular information, such as that from X-ray, NMR, and cryo-electron microscopy, and theoretical/mathematical models, such as molecular dynamics, the Poisson Boltzmann equation, and the Nernst-Planck equation. In this work, we present a family of variational multiscale geometric models for macromolecular systems. Our models are able to combine multiresolution geometric modeling with multiscale electrostatic modeling in a unified variational framework. We discuss a suite of techniques for molecular surface generation, molecular surface meshing, molecular volumetric meshing, and the estimation of Hadwiger's functionals. Emphasis is given to the multiresolution representations of biomolecules and the associated multiscale electrostatic analyses as well as multiresolution curvature characterizations. The resulting fine resolution representations of a biomolecular system enable the detailed analysis of solvent-solute interaction, and ion channel dynamics, whereas our coarse resolution representations highlight the compatibility of protein-ligand bindings and possibility of protein-protein interactions. PMID- 23813600 TI - Liver resection for metastatic melanoma: equivalent survival for cutaneous and ocular primaries. AB - BACKGROUND: The value of surgical resection in patients with hepatic metastases from melanoma is poorly documented in the literature. This study sought to determine the clinicopathologic and surgical factors predictive of outcome for melanoma patients who underwent resection of hepatic metastases. METHODS: Thirty three patients who underwent liver resection for melanoma metastases were identified from the Melanoma Institute Australia research database. Univariate and multivariate analyses were performed to identity factors predictive of recurrence and survival following liver resection for melanoma metastasis. RESULTS: The actuarial 2- and 5-year survival rates were 59% and 42%, respectively, with a median survival of 29 months (range 1-139). The 5-year survival rates for cutaneous and ocular primary melanoma were 44% and 39%, respectively. Improved post-hepatic metastasectomy survival was observed in patients with microscopically clear resection margins (R0, 44 months; R1/2, 12 months; P = 0.04). Although major hepatic resection was associated with improved survival (major, 70 months; minor, 23 months; P = 0.07), major hepatectomies were performed almost exclusively in patients with isolated liver metastases. CONCLUSIONS: Hepatic resection for metastatic melanoma is associated with improved survival in selected patients with both primary ocular and cutaneous melanoma. Surgical treatment of hepatic melanoma metastases should be considered when complete resection is feasible. PMID- 23813601 TI - An in vitro atomic force microscopic study of commercially available dental luting materials. AB - OBJECTIVE: The aim of this in vitro study was to compare the surface roughness parameters of four different types of dental luting agents used for cementation of implant restorations. METHOD AND MATERIALS: Five specimens (8 mm high and 1 mm thick) of each cement were made using metal ring steelless molds. Atomic Force Microscope was employed to analyze different surface texture parameters of the materials. Bearing ratio analysis was used to calculate the potential microgap size between the cement and implant material and to calculate the depth of the valleys on the cement surface, while power spectral density (PSD) measurements were performed to measure the percentage of the surface prone to bacterial adhesion. RESULTS: Glass ionomer cement showed significantly lower value of average surface roughness then the other groups of the materials (P < 0.05) which was in line with the results of Bearing ratio analysis. On the other side, PSD analysis showed that zinc phosphate cement experience the lowest percentage of the surface which promote bacterial colonization. CONCLUSION: Glas ionomer cements present the surface roughness parameters that are less favorable for bacterial adhesion than that of zinc phosphate, resin-modified glass ionomer and resin cements. PMID- 23813602 TI - Schistosomiasis chemotherapy. AB - After malaria, schistosomiasis (or bilharzia) is the second most prevalent disease in Africa, and is occurring in over 70 countries in tropical and subtropical regions. It is estimated that 600 million people are at risk of infection, 200 million people are infected, and at least 200,000 deaths per year are associated with the disease. All schistosome species are transmitted through contact with fresh water that is infested with free-swimming forms of the parasite, which is known as cercariae and produced by snails. When located in the blood vessels of the host, larval and adult schistosomes digest red cells to acquire amino acids for growth and development. Vaccine candidates have been unsuccessful up to now. Against such devastating parasitic disease, the antischistosomal arsenal is currently limited to a single drug, praziquantel, which has been used for more than 35 years. Because the question of the reduction of the activity of praziquantel was raised recently, it is thus urgent to create new and safe antischistosomal drugs that should be combined with praziquantel to develop efficient bitherapies. PMID- 23813603 TI - Impact of glomerular filtration rate on clinical outcomes after carotid artery revascularization in 11,832 patients from the CARE registry. AB - OBJECTIVE: The aim of this study was to assess the association of kidney function with carotid artery revascularization outcomes in a large contemporary database. BACKGROUND: Chronic kidney disease (CKD) is associated with increased mortality and adverse cardiovascular events after coronary intervention. There are limited data evaluating the association between CKD and adverse events among patients undergoing carotid artery revascularization procedures. METHODS: The Carotid Artery Revascularization and Endarterectomy (CARE) Registry is a voluntary registry of 168 hospitals. Using data from the CARE Registry, we examined registry patients undergoing carotid artery revascularization by either carotid endarterectomy (CEA) or carotid artery stenting (CAS) from May 2005 through March 2010. Patients were divided into four groups according to their glomerular filtration rate (GFR), as estimated by the Modification of Diet in Renal Disease Study Group equation using preprocedural serum creatinine levels. RESULTS: The analysis included 11,832 patients who underwent carotid revascularization (6,899 CAS and 4,933 CEA). Patients with lower GFR were older, more frequently female, had more comorbidities, including hypertension, dyslipidemia, peripheral arterial disease, diabetes mellitus, chronic lung disease, ischemic heart disease, heart failure, and reduced left ventricular function, and were more likely to undergo CAS than CEA. In the overall population, CKD was associated with higher unadjusted in-hospital and 30-day rates of the combined endpoint of death, stroke, and myocardial infarction and the individual endpoint of stroke. After adjustment for baseline and preprocedural characteristics, CKD was not an independent predictor of adverse events in either CAS or CEA. CONCLUSIONS: Patients with CKD have a greater number of comorbidities and worse unadjusted in hospital and 30-day outcomes; CKD was not, however, an independent predictor of in-hospital and 30-day outcomes after carotid artery revascularization. PMID- 23813604 TI - Renal impairment is frequent in chronic hepatitis C patients under triple therapy with telaprevir or boceprevir. AB - In clinical trials with telaprevir (TLV) and boceprevir (BOC) renal impairment was not reported as a relevant adverse event. The PAN study is a noninterventional study enrolling patients treated with peginterferon alfa 2a/ribavirin (PEG/RBV) with or without TVL or BOC. Here we restrict the analysis to hepatitis C virus genotype 1 patients having completed 12 (n = 895) or 24 weeks (n = 591) of treatment. For estimation of glomerular filtration rate (eGFR) the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula was chosen. Patients on TLV 38/575 (6.6%) and BOC 10/211 (4.7%) more frequently experienced a decrease in eGFR to <60 mL/min compared to patients on PEG/RBV 1/109 (0.9%) (P < 0.05). Risk factors associated with eGFR <60 mL/min in multiple logistic regression analysis were age (P < 0.001), arterial hypertension (P < 0.05), higher serum creatinine at baseline (P < 0.001), and being on triple therapy with TLV or BOC (P < 0.01). Patients with an eGFR of <60 mL/min had a lower absolute mean hemoglobin at week 12 compared to patients with an eGFR >60 mL/min (9.7 g/dL +/- 1.4 g/dL versus 11.0 g/dL +/- 1.7 g/dL) (P < 0.001). Most patients on TLV with a decrease of eGFR <60 mL/min showed a marked improvement in renal function after discontinuation of TLV. CONCLUSION: Renal impairment has not been reported as a safety signal in clinical trials with TVL or BOC. However, in this large cohort including patients with risk factors for renal impairment a marked decline in renal function was observed in about 5% of patients on triple therapy. In addition to being a safety concern, substantial ribavirin dose reductions have to be considered in these patients, as anemia was more pronounced in patients with impaired renal function. PMID- 23813606 TI - Graphene-based materials for hydrogen generation from light-driven water splitting. AB - Hydrogen production from solar water splitting has been considered as an ultimate solution to the energy and environmental issues. Over the past few years, graphene has made great contribution to improving the light-driven hydrogen generation performance. This article provides a comprehensive overview of the recent research progress on graphene-based materials for hydrogen evolution from light-driven water splitting. It begins with a brief introduction of the current status and basic principles of hydrogen generation from solar water splitting, and tailoring properties of graphene for application in this area. Then, the roles of graphene in hydrogen generation reaction, including an electron acceptor and transporter, a cocatalyst, a photocatalyst, and a photosensitizer, are elaborated respectively. After that, the comparison between graphene and other carbon materials in solar water splitting is made. Last, this review is concluded with remarks on some challenges and perspectives in this emerging field. PMID- 23813608 TI - Managing agitation using nonpharmacological interventions for seniors with dementia. AB - Approximately 36 million people have Alzheimer's disease worldwide, and many experience behavioral issues such as agitation. The purpose of this study was to investigate the perceptions of long-term care (LTC) staff regarding the current use of nonpharmacological interventions (NPIs) for reducing agitation in seniors with dementia and to identify facilitators and barriers that guide NPI implementation. Qualitative methods were used to gather data from interviews and focus groups. A total of 44 staff from 5 LTC facilities participated. Findings showed that both medications and NPIs are used for the management of agitation. The use of NPIs was facilitated by consistency in staffing, and the ability of all the staff members to implement them. Common barriers to NPI use included the perceived lack of time, low staff-to-resident ratios, and the unpredictable and short-lasting effectiveness of NPIs. This study offers insight into perceived factors that influence implementation of NPIs and the perceived effectiveness of NPIs. PMID- 23813607 TI - The natural history of sickle cell disease. AB - The term sickle cell disease embraces a group of genetic conditions in which pathology results from the inheritance of the sickle cell gene either homozygously or as a double heterozygote with another interacting gene. The spectrum of resulting conditions is therefore influenced by the geography of individual hemoglobin genes, but in most populations, the commonest genotype at birth is homozygous sickle cell (SS) disease. Because this genotype generally manifests a greater mortality, the relative proportion of sickle cell genotypes is influenced by age as well as the geographical distribution of individual genes. PMID- 23813609 TI - Reduced orexin-A levels in frontotemporal dementia: possible association with sleep disturbance. AB - Sleep disturbances including excessive daytime sleepiness (EDS) are encountered in frontotemporal dementia (FTD). To investigate the relationship between the plasma orexin-A levels and sleep disturbance patterns, we measured the plasma orexin-A levels and performed sleep studies in patients with FTD. The orexin-A levels were measured in 10 consecutive patients with FTD and controls by enzyme linked immunosorbent assay. Nocturnal polysomnography (PSG) and Multiple Sleep Latency Test (MSLT) were performed in 2 patients with FTD. The orexin-A levels were significantly lower in patients with FTD compared to controls. The PSG revealed increased rapid eye movement (REM) latency in patients, whether or not they reported EDS. Mean sleep latency in MSLT was less than 10 minutes in both the patients, being shorter in patient without EDS, but none of them had REM sleep onset. Some patients with FTD may develop narcolepsy-like involuntary sleep attacks, even without complaining of EDS. Involvement of hypothalamus and a subsequent alteration in the orexin levels might be one of the determining factors in this sleep disturbance. PMID- 23813610 TI - Meta-analysis of the association between urokinase-plasminogen activator gene rs2227564 polymorphism and Alzheimer's disease. AB - OBJECTIVE: The association between urokinase-plasminogen activator (PLAU) gene rs2227564 polymorphism and Alzheimer's disease (AD) risk has been widely reported across different ethnic populations, with inconsistent results. Thus, we performed a meta-analysis to assess the association between PLAU rs2227564 polymorphism and AD risk. METHODS: Fixed or random effect model was used as the pooling method to assess the basis of homogeneity test among studies. Summarized estimation of odds ratio (OR) and 95% confidence interval (CI) were calculated. Heterogeneity among studies was evaluated using Q test and I (2). Publication bias was estimated using Harbord's test. RESULTS: A total of 27 studies (comprising 6100 AD cases and 5718 controls) were included in this meta-analysis. The present meta-analysis showed a significant increased effect of T allele on risk of AD in dominant model (fixed effect model [FEM] OR 1.123, 95% CI 1.025 1.231) and heterozygote comparison (CT vs CC; FEM OR 1.126, 95% CI 1.027-1.235). No publication bias was detected. CONCLUSION: This meta-analysis showed that T allele of rs2227564 polymorphism in PLAU gene could increase the effects on risk of AD, and this result needs to be confirmed by further studies. PMID- 23813611 TI - Daily assistance for individuals with dementia via videophone. AB - We previously developed remote reminiscence conversation and schedule prompter systems via the videophone to improve psychological stability and to assist individuals with dementia to perform household tasks. Our results showed that the psychological stability of 1 patient persisted for 3 hours after remote conversations. The task completion rate afforded by the schedule prompter system, which displays a video reminder series automatically, was 52%. In the present study, we also investigated whether psychological stability was sustained in other patients. Furthermore, motivational prompter videos were added to enhance the original schedule prompter system. We found that 1 in 4 patients living at home showed greater stability while conversing with a conversation partner on the videophone than while watching television programs, and that she remained stable for 3 hours after remote conversations. The task completion rate afforded by the revised schedule prompter system was 82%. These 2 remote systems are promising tools for assisting individuals with dementia in their daily lives. PMID- 23813612 TI - Vascular risk factors: a ticking time bomb to Alzheimer's disease. AB - Evidence is growing that vascular risk factors (VRFs) for Alzheimer's disease (AD) affect cerebral hemodynamics to launch a cascade of cellular and molecular changes that initiate cognitive deficits and eventual progression of AD. Neuroimaging studies have reported VRFs for AD to be accurate predictors of cognitive decline and dementia. In regions that participate in higher cognitive function, middle temporal, posterior cingulate, inferior parietal and precuneus regions, and neuroimaging studies indicate an association involving VRFs, cerebral hypoperfusion, and cognitive decline in elderly individuals who develop AD. The VRF can be present in cognitively intact individuals for decades before mild cognitive deficits or neuropathological signs are manifested. In that sense, they may be "ticking time bombs" before cognitive function is demolished. Preventive intervention of modifiable VRF may delay or block progression of AD. Intervention could target cerebral blood flow (CBF), since most VRFs act to lower CBF in aging individuals by promoting cerebrovascular dysfunction. PMID- 23813613 TI - Mast cells can regulate skeletal muscle cell proliferation by multiple mechanisms. AB - INTRODUCTION: Mast cells (MCs) can stimulate cell proliferation, but their specific contribution to skeletal muscle regeneration is not well defined. METHODS: L6 myoblast proliferation was assessed in coculture with MCs or when grown with MC-conditioned media. To address the in vivo implication of MCs in regeneration, rats were treated with cromolyn, and myoblast proliferation, immune cell accumulation, and myogenic factors were assessed in bupivacaine-injured muscles. RESULTS: In vitro, both procedures increased the L6 cell proliferation rate, and this was tryptase-dependent. In vivo, MC stabilization increased myoblast proliferation and accumulation of macrophages CD68 and CD163 after injury. This correlated with a sequential increase in MyoD and myogenin protein level expression. CONCLUSIONS: MCs can directly stimulate muscle cell proliferation via tryptase. MCs can influence myoblast proliferation in vivo, but this effect seems to be predominantly related to their modulation of macrophage recruitment. The MC is a potential actor in the early stages of muscle healing. PMID- 23813614 TI - Note on the autocorrelation coefficient as a test statistic for assessment of the goodness-of-fit of biokinetic models to multiple bioassay data sets. AB - The European Commission project IDEAS has produced guidelines for internal dose assessments from monitoring data. A key stage in the guidelines requires assessment of the goodness-of-fit of biokinetic models to bioassay data. The present note extends the use of an autocorrelation coefficient to assess the fits of multiple types of bioassay quantity simultaneously. PMID- 23813615 TI - The adductor part of the adductor magnus is innervated by both obturator and sciatic nerves. AB - The hip adductor group, innervated predominantly by the obturator nerve, occupies a large volume of the lower limb. However, case reports of patients with obturator nerve palsy or denervation have described no more than minimal gait disturbance. Those facts are surprising, given the architectural characteristics of the hip adductors. Our aim was to investigate which regions of the adductor magnus are innervated by the obturator nerve and by which sciatic nerve and to consider the clinical implications. Twenty-one lower limbs were examined from 21 formalin-fixed cadavers, 18 males and 3 females. The adductor magnus was dissected and was divided into four parts (AM1-AM4) based on the locations of the perforating arteries and the adductor hiatus. AM1 was supplied solely by the obturator nerve. AM2, AM3, and AM4 received innervation from both the posterior branch of the obturator nerve and the tibial nerve portion of the sciatic nerve in 2 (9.5%), 20 (95.2%), and 6 (28.6%) of the cadavers, respectively. The double innervation in more than 90% of the AM3s is especially noteworthy. Generally, AM1 AM3 corresponds to the adductor part, traditionally characterized as innervated by the obturator nerve, and AM4 corresponds to the hamstrings part, innervated by the sciatic nerve. Here, we showed that the sciatic nerve supplies not only the hamstrings part but also the adductor part. These two nerves spread more widely than has generally been believed, which could have practical implications for the assessment and treatment of motor disability. PMID- 23813616 TI - Complete assignments of 1H and 13C NMR data for 21 naphthalenyl-phenyl-pyrazoline derivatives. AB - To find potent new chemotherapy drugs, we designed and synthesized a series of naphthochalcones bearing naphthalenyl-phenyl-pyrazoline moieties. The complete (1)H and (13)C NMR data for these compounds are reported here and can be used to identify further new naphthochalcones bearing the desired pyrazoline moieties. PMID- 23813618 TI - Hybrid semiconductor core-shell nanowires with tunable plasmonic nanoantennas. AB - Multi-segmented nanowires with optically active hybrid core-shell regions are fabricated between two metal nanoantennas. These nanowires generate significant photocurrent under illumination and are solution-dispersible. PMID- 23813617 TI - Therapists' professional and personal characteristics as predictors of working alliance in short-term and long-term psychotherapies. AB - To investigate the determinants of the therapeutic working relationship and better understand its intrapersonal and interpersonal nature, this study investigated therapist characteristics as predictors of the formation and development of patient-rated and therapist-rated working alliances within a clinical trial of short-term versus long-term therapies. Short-term (solution focused and short-term psychodynamic) and long-term (long-term psychodynamic therapy and psychoanalysis) therapies were provided by 70 volunteering, experienced therapists to 333 patients suffering from depressive and/or anxiety disorders. Therapists' professional and personal characteristics, measured prior to the start of the treatments, were assessed with the comprehensive self-report instrument, Development of Psychotherapists Common Core Questionnaire. The Working Alliance Inventory was rated by both therapists and patients at the third session and at the 7 months' follow-up point from the initiation of therapy. Therapists' self-rated basic interpersonal skills were found to predict the formation of better patient-rated alliances in both short-term and long-term therapies. Engaging, encouraging relational style fostered improvement of patients' working alliances especially in the course of short-term therapies. However, it led to patient alliance deterioration in long-term therapies, where constructive coping techniques proved more beneficial. Therapists' professional self-confidence and work enjoyment, along with their self-experiences in personal life, consistently predicted their alliances, but were less salient for patient ratings of alliance. The divergence of therapist and patient viewpoints has implications for therapist training and supervision, as characteristics found detrimental or helpful for the working relationship rated from the perspective of one party may not be predictive of the other therapy participant's experience. PMID- 23813619 TI - Polar and magnetic Mn2FeMO6 (M=Nb, Ta) with LiNbO3-type structure: high-pressure synthesis. PMID- 23813620 TI - Pharmacokinetic properties of isradipine after single-dose and multiple-dose oral administration in Chinese volunteers: a randomized, open-label, parallel-group phase I study. AB - Isradipine could be used for the treatment of high blood pressure or Parkinsonism, yet the study on pharmacokinetics (PK) of isradipine is lacking in the Chinese population. The current study aims to assess the dose proportionality, pharmacokinetics and gender effect of isradipine following oral single and multiple doses in Chinese subjects. A randomized, open-label, parallel group trial was conducted in 30 healthy Chinese volunteers. Subjects randomly received a single dose of 2.5, 5 or 10 mg, and multiple doses (2.5 mg) of isradipine. Blood samples were collected pre-dose (0 h) and 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 9, 12, 24, 36 and 48 h post-dose. Isradipine was rapidly absorbed with the time to maximum concentration <1.27 h for all dosage groups. The maximum concentrations were 2.46, 5.34, 10.93 and 3.32 ng/mL and area under the concentration-time curve from time zero to the last time point (AUClast ) were 7.05, 12.58, 24.68 and 5.31 ng/ml . h for the 2.5, 5 and 10 mg single-dose and 2.5 mg multiple-dose groups, respectively. The half-life ranged from 5.76 to 7.94 h. The maximum concentration and AUC were found to increase linearly and dose dependently for isradipine. No statistical gender differences were found. These findings indicated that the pharmacokinetic parameters of isradipine in Chinese population were dose-proportional and predictable over a range of 2.5-10 mg isradipine oral doses. PMID- 23813621 TI - Deeper insights into the relevance of lymphatic circulation in cirrhosis of the liver: a Trojan horse or the Holy Grail? PMID- 23813622 TI - Sensing chiral drugs by using CdSe/ZnS nanoparticles capped with N-acetyl-L cysteine methyl ester. AB - Chiral quantum dots (QDs), differing in their core or shell size and, consequently, in their optical properties, were synthesized by the treatment of commercially available amine-capped quantum dots with methyl ester N-acetyl-L cysteine (CysP). Interestingly, their colloidal methanol solutions remain stable for several months. Their NMR and IR spectra were in accordance with CysP binding to the QD surface through two anchoring groups; its thiolate (strongly bound) and the carbonyl group of its ester (weaker bound) group, whereas their circular dichroism (CD) spectra showed a new broad redshifted band, suggesting that the attachment to the QD surface modified the conformational equilibrium towards conformer(s) with optical activity in this region. These QDs were sufficiently fluorescent to perform studies of the chiral recognition of drugs, in particular the aryl propionic acids (APAs) ketoprofen (KP), naproxen (NP), flurbiprofen (FP), and ibuprofen (IP). We used different drug concentration ranges, depending on the QD solubility. All the assayed drugs quenched the QD emission in a concentration-dependent mode. Quenching fluorescence assays with the chiral QDs (CS@CysP) showed their extraordinary capacity for the chiral recognition of KP, NP, and FP, and particularly in the case of KP and FP, a remarkable positive allosteric effect was detected for the R enantiomer. By using a drug/CS@CysP molar ratio of 5000:1 and 2500:1, the changes of intensity and the sign of the CD spectrum of the drug evidenced the dissociation of the drug carboxylic group in the presence of the QD. PMID- 23813623 TI - Confirmation of GRHL2 as the gene for the DFNA28 locus. AB - More than 10 years ago, a c.1609_1610insC mutation in the grainyhead-like 2 (GRHL2) gene was identified in a large family with nonsyndromic sensorineural hearing loss, so far presenting the only evidence for GRHL2 being an autosomal dominant deafness gene (DFNA28). Here, we report on a second large family, in which post-lingual hearing loss with a highly variable age of onset and progression segregated with a heterozygous non-classical splice site mutation in GRHL2. The c.1258-1G>A mutation disrupts the acceptor recognition sequence of intron 9, creating a new AG splice site, which is shifted by only one nucleotide in the 3' direction. cDNA analysis confirmed a p.Gly420Glufs*111 frameshift mutation in exon 10. PMID- 23813624 TI - Overexpression of fibroblast activation protein and its clinical implications in patients with osteosarcoma. AB - BACKGROUND AND OBJECTIVES: Fibroblast activation protein (FAP) expression has been detected in fibroblastic component of osteosarcomas. The aim of this study was to analyze the correlation of FAP expression with the clinicopathological features of osteosarcoma. METHODS: FAP mRNA and protein expression levels in human osteosarcoma tissues were, respectively detected by RT-PCR, Western blot, and immunohistochemistry assays. RESULTS: FAP mRNA and protein expression were both higher in osteosarcoma than in corresponding noncancerous bone tissues (both P < 0.001). In addition, the immunohistochemistry assay found that all patients showed positive FAP expression. Higher FAP expression was significantly correlated with advanced clinical stage (P = 0.006), high histological grade (P = 0.02), positive metastatic status (P = 0.01), shorter overall (P < 0.001), and disease-free (P < 0.001) survival in osteosarcoma patients. Furthermore, Cox multivariate analysis showed that FAP overexpression was an independent prognostic factor for predicting both overall and disease-free survival of osteosarcoma patients. CONCLUSION: Expression of FAP in osteosarcoma could be adopted as a candidate biomarker for the diagnosis of clinical stage, histological grade and metastasis, and for assessing prognosis, indicating for the first time that FAP may play an important role in tumor development and progression in osteosarcoma. FAP might be considered as a novel therapeutic target against this cancer. PMID- 23813626 TI - VinaMPI: facilitating multiple receptor high-throughput virtual docking on high performance computers. AB - The program VinaMPI has been developed to enable massively large virtual drug screens on leadership-class computing resources, using a large number of cores to decrease the time-to-completion of the screen. VinaMPI is a massively parallel Message Passing Interface (MPI) program based on the multithreaded virtual docking program AutodockVina, and is used to distribute tasks while multithreading is used to speed-up individual docking tasks. VinaMPI uses a distribution scheme in which tasks are evenly distributed to the workers based on the complexity of each task, as defined by the number of rotatable bonds in each chemical compound investigated. VinaMPI efficiently handles multiple proteins in a ligand screen, allowing for high-throughput inverse docking that presents new opportunities for improving the efficiency of the drug discovery pipeline. VinaMPI successfully ran on 84,672 cores with a continual decrease in job completion time with increasing core count. The ratio of the number of tasks in a screening to the number of workers should be at least around 100 in order to have a good load balance and an optimal job completion time. The code is freely available and downloadable. Instructions for downloading and using the code are provided in the Supporting Information. PMID- 23813625 TI - Sarcomere lengths in human extensor carpi radialis brevis measured by microendoscopy. AB - INTRODUCTION: Second-harmonic generation microendoscopy is a minimally invasive technique to image sarcomeres and measure their lengths in humans, but motion artifact and low signal have limited the use of this novel technique. METHODS: We discovered that an excitation wavelength of 960 nm maximized image signal; this enabled an image acquisition rate of 3 frames/s, which decreased motion artifact. We then used microendoscopy to measure sarcomere lengths in the human extensor carpi radialis brevis with the wrist at 45 degrees extension and 45 degrees flexion in 7 subjects. We also measured the variability in sarcomere lengths within single fibers. RESULTS: Average sarcomere lengths in 45 degrees extension were 2.93+/-0.29 MUm (+/-SD) and increased to 3.58+/-0.19 MUm in 45 degrees flexion. Within single fibers the standard deviation of sarcomere lengths in series was 0.20 MUm. CONCLUSIONS: Microendoscopy can be used to measure sarcomere lengths at different body postures. Lengths of sarcomeres in series within a fiber vary substantially. PMID- 23813627 TI - Association of baseline C-reactive protein levels with periprocedural myocardial injury in patients undergoing percutaneous bifurcation intervention: a CACTUS study subanalysis. AB - OBJECTIVES: To assess the predictive value of C-reactive protein (CRP) on periprocedural myocardial injury (PMI), evaluated by creatine kinase-myocardial band isoform (CK-MB) elevation in patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stent (DES) implantation for the treatment of coronary bifurcation lesions is actually unknown. BACKGROUND: Systemic inflammation as assessed by CRP has been associated with averse events after DES implantation. After PCI, the occurrence of PMI is common and has also been associated with worse outcomes. Finally, bifurcations are frequently encountered anatomically complex lesions which the treatment is associated with higher complication rate compared with simple lesions. METHODS: A total of 96 patients (66 +/- 10 years, 70 men) from the Coronary bifurcations: Application of the Crushing Technique Using Sirolimus-eluting stents (CACTUS) trial who had baseline CRP dosage and both baseline and postprocedural CK-MB measurement were included. RESULTS: A complex bifurcation strategy was implemented in 53 (55%) patients, and angiographic success was achieved in all but two (2%) patients. Periprocedural myocardial necrosis (increase of CK-MB between one and three times the upper limit of normal [ULN]) was observed in 12 (13%) patients, and four (4%) patients had PCI-related myocardial infarction (increase of CK-MB more than three times ULN). Notably, progressively higher CRP levels were observed in patients with different increase in CK-MB (P = 0.041). Moreover, CRP >1 mg/L significantly predicted CK-MB rise (odds ratio 5.6, 95% confidence interval 1.5-4.3, P = 0.011). CONCLUSION: In the setting of true coronary bifurcations treated by DES, baseline CRP levels were significantly associated with both the incidence and the extent of PMI. PMID- 23813628 TI - Origin of the torus mandibularis: an embryological hypothesis. AB - Torus mandibularis, a well-known protuberance in the dental field, has been defined as a hyperostosis in the lingual aspect of the body of the mandible above the mylohyoid line. However, the origin of the torus mandibularis has not yet been clarified. The aim of this study was to provide a better understanding on the origin of the torus in view of the specific development of Meckel's cartilage at the site corresponding to the adult torus. A total of 40 mid-term human fetuses at 7-16 weeks of gestation were examined. The 10-13 weeks stage corresponded to the critical period in which Meckel's cartilage with endochondral ossification underwent a bending at the beginning of the intramandibular course. At the level of mental foramen, which was located between the deciduous canine and the first deciduous molar germs, the medial lamina of the mandible protruded medially to reach Meckel's cartilage. Thus, the medial lamina covered the posterior and superior aspect of the bending Meckel's cartilage just above the attachment of the developing mylohyoid muscle (i.e., in the oral cavity). We considered a bony prominence, which composed the protruding medial lamina and the bending Meckel's cartilage as the fetal origin of the torus mandibularis. A new theory is proposed for the origin of the torus mandibularis based on the existence of an anlage formed during the development of the mandible, variable in morphology and size, but always constant. PMID- 23813629 TI - Emotion-focused therapy for the treatment of social anxiety: an overview of the model and a case description. AB - Emotion-focused therapy (EFT) is an integrative and experiential treatment approach that views emotions as fundamentally adaptive and privileges attention to, and exploration of, emotional experiences. EFT has been demonstrated to be efficacious with depression, interpersonal trauma and marital discord, but application to anxiety disorders is in its initial stages. The purpose of this paper is to present the main principles of using EFT with socially anxious patients and to make the case that EFT is particularly well suited for working with this patient group. The primary change processes in EFT for social anxiety include improving emotion awareness, reducing experiential avoidance and the activation and transformation of shame that underlies the symptomatic anxiety. Such processes lead to less self-criticism, to more self-compassion and self soothing and to a more favourable perception of the self. A case example is used to illustrate how these principles were applied with a socially anxious patient. PMID- 23813630 TI - Spontaneous ripple formation in MoS(2) monolayers: electronic structure and transport effects. AB - The spontaneous formation of ripples in molybdenum disulfide (MoS2 ) monolayers is investigated via density functional theory based tight-binding Born Oppenheimer molecular dynamics. Monolayers with different lengths show spontaneous rippling during the simulations. The density of states reveals a decrease in the bandgap induced by the stretching of the MoS2 units due to ripple formation. Significant quenching in electron conductance was also observed. The ripples in the MoS2 monolayers have an effect on the properties of the material and could impact its application in nanoelectronics. PMID- 23813631 TI - Epidemiology and management of chronic hepatitis E infection in solid organ transplantation: a comprehensive literature review. AB - Hepatitis E virus (HEV) infection has emerged as a global public health issue. Although it often causes an acute and self-limiting infection with low mortality rates in the western world, it bears a high risk of developing chronic hepatitis in immunocompromised patients with substantial mortality rates. Organ transplant recipients who receive immunosuppressive medication to prevent rejection are thought to be the main population at risk for chronic hepatitis E. Therefore, there is an urgent need to properly evaluate the clinical impact of HEV in these patients. This article aims to review the prevalence, infection course, and management of HEV infection after solid organ transplantation by performing a comprehensive literature review. In addition, an in-depth emphasis of this clinical issue and a discussion of future development are also presented. PMID- 23813632 TI - A recurrent mutation in the 5'-UTR of IFITM5 causes osteogenesis imperfecta type V. PMID- 23813633 TI - Ultrafast scanning of exchangeable sites by NMR spectroscopy. PMID- 23813634 TI - A novel hydroxysuberamide derivative potentiates MG132-mediated anticancer activity against human hormone refractory prostate cancers--the role of histone deacetylase and endoplasmic reticulum stress. AB - BACKGROUND: Histone deacetylase (HDAC) inhibitors are successful for treatment of advanced cutaneous T-cell lymphoma but only show modest effect in solid tumors. Approaches for HDAC inhibitors to improve activity against solid tumors are necessary. METHODS: Sulforhodamine B assay and flow cytometric analysis detected cell proliferation and cell-cycle progression, respectively. Protein expression was determined by Western blotting. Comet assay and DNA end-binding activity of Ku proteins detected DNA damage and DNA repair activity, respectively. siRNA technique was used for knockdown of specific cellular target. RESULTS: WJ25591 displayed inhibitory activity against HDAC1 and cell proliferation in human hormone-refractory prostate cancers PC-3 and DU-145. WJ25591 caused an arrest of cell-cycle at both G1- and G2-phase and increased protein expressions of p21 and cyclin E, followed by cell apoptosis. WJ25591-induced Bcl-2 down-regulation and activation of caspase-9, -8, and -3, suggesting apoptotic execution through both intrinsic and extrinsic apoptotic pathways. WJ25591 also significantly inhibited DNA repair activity but not directly induced DNA damage. Moreover, the proteasome inhibitor MG-132 dramatically sensitized WJ25591-induced cell apoptosis. The siRNA technique demonstrated that endoplasmic reticulum (ER) stress, in particular CHOP/GADD153 up-regulation, contributed to the synergistic effect. CONCLUSIONS: The data suggest that WJ25591 inhibited HDAC activity, leading to cell-cycle arrest and inhibition of DNA repair. Caspase cascades are subsequently triggered to execute cell apoptosis. MG-132 dramatically sensitizes WJ25591 mediated apoptosis, at least partly, through ER stress response. The data also reveal that combination of HDAC inhibitors and proteasome inhibitors may be a potential strategy against hormone-refractory prostate cancers. PMID- 23813635 TI - Evaluation of electrostatic descriptors for predicting crystalline density. AB - This study evaluates the importance of electrostatic corrections to earlier quantum-mechanically based methods to predict crystal densities of neutral and ionic molecular energetic materials. Our previous methods (B. M. Rice et al., J. Phys. Chem. A 2007, 111, 10874) use the molecular volumes of the isolated molecule or formula unit to estimate the crystal density; this volume is defined to be that inside the quantum-mechanically determined 0.001 a.u. isosurface of electron density surrounding the isolated molecule. The electrostatic corrections to these volumetric estimates are based on features of the electrostatic potential mapped onto this isosurface of electron density, and have been parameterized using information from 180 neutral and 23 ionic CHNO molecular systems. The quality of the electrostatically corrected methods was assessed through application to 38 neutral and 48 ionic compounds not used in the parameterization. The root mean square (rms) percent deviation and average absolute error of predictions for the 38 neutral species relative to experiment are 2.7% and 0.035 g/cm(3), respectively, decreases of 0.9% and 0.015 g/cm(3) from the earlier predictions (3.6% and 0.050 g/cm(3), respectively). The rms percent deviation and average absolute error of predictions for the 48 ionic compounds relative to experiment are 3.7% and 0.045 g/cm(3), respectively, decreases of 2.6% and 0.043 g/cm(3) from the earlier predictions that used the formula unit volumes only. The results clearly show a significant improvement to the earlier method upon inclusion of electrostatic corrections. PMID- 23813636 TI - Ultra-high-field MR imaging in multiple sclerosis. AB - In multiple sclerosis (MS), MRI is the most important paraclinical tool used to inform diagnosis and for monitoring disease evolution, either natural or modified by treatment. The increased availability of ultra-high-field magnets (7 Tesla or higher) gives rise to questions about the main benefits of and challenges for their use in patients with MS. The main advantages of ultra-high-field MRI are the improved signal-to-noise ratio, greater chemical shift dispersion, and improved contrast due to magnetic susceptibility variations, which lead to increased sensitivity to the heterogeneous pathological substrates of the disease. At present, ultra-high-field MRI is mainly used to improve our understanding of MS pathogenesis. This review discusses the main achievements that have so far come from the use of these scanners, which are: better visualisation of white matter lesions and their morphological characteristics; an improvement in the ability to visualise grey matter lesions and their exact location; the quantification of 'novel' metabolites which may have a role in axonal degeneration; and greater sensitivity to iron accumulation. The application of ultra-high-field systems in standard clinical practice is still some way off since their role in the diagnostic work-up of patients at presentation with clinically isolated syndromes, or in monitoring disease progression or treatment response in patients with definite MS, needs to be established. Additional challenges remain in the development of morphological, quantitative and functional imaging methods at these field strengths, techniques which may ultimately lead to novel biomarkers for monitoring disease evolution and treatment response. PMID- 23813637 TI - A new care paradigm in geriatric head and neck surgical oncology. AB - BACKGROUND AND OBJECTIVES: Perioperative management of elderly patients with head and neck cancer poses unique challenges. Our objective is to describe the implementation and feasibility of a novel intervention designed to improve perioperative care in geriatric head and neck surgery. METHODS: This pilot study was performed in a single-institution, NCI-designated comprehensive cancer center. All surgical patients with head and neck cancer over age 75 were offered perioperative consultation with fellowship-trained geriatricians focusing in geriatric oncology. RESULTS: Between 2010 and 2011, a total of 168 patients requiring head and neck surgery were seen by the geriatric service, of which 94% subsequently underwent surgery. Apart from preoperative medical optimization, geriatricians assisted in complex decision-making regarding the indications for cancer-directed therapy. Postoperatively, they assisted in preventing and treating delirium and poly-pharmacy, facilitating discharge planning, and initiating rehabilitation. Postoperatively, 87% were discharged home, and 13% required placement in skilled nursing facilities. At 24 months, overall survival was 80%. Patients, surgeons and geriatricians alike were enthusiastic about the initiative, which is expanding within the institution. CONCLUSION: Geriatric perioperative support for elderly head and neck cancer patients is well-received with promising potential. The tangible impact and direct benefits of this pilot initiative require additional study. PMID- 23813638 TI - Garments fire: history repeats itself. PMID- 23813639 TI - Acid-base-controlled stereoselective metalation of overhanging carboxylic acid porphyrins: consequences for the formation of heterobimetallic complexes. AB - Overhanging carboxylic acid porphyrins have revealed promising ditopic ligands offering a new entry in the field of supramolecular coordination chemistry of porphyrinoids. Notably, the adjunction of a so-called hanging-atop (HAT) Pb(II) cation to regular Pb(II) porphyrin complexes allowed a stereoselective incorporation of the N-core bound cation, and an allosterically controlled Newton's cradle-like motion of the two Pb(II) ions also emerged from such bimetallic complexes. In this contribution, we have extended this work to other ligands and metal ions, aiming at understanding the parameters that control the HAT Pb(II) coordination. The nature of the N-core bound metal ion (Zn(II), Cd(II)), the influence of the deprotonation state of the overhanging COOH group and the presence of a neutral ligand on the opposite side (exogenous or intramolecular), have been examined through (1)H NMR spectroscopic experiments with the help of radiocrystallographic structures and DFT calculations. Single and bis-strap ligands have been considered. They all incorporate a COOH group hung over the N-core on one side. For the bis-strap ligands, either an ester or an amide group has been introduced on the other side. In the presence of a base, the mononuclear Zn(II) or Cd(II) complexes incorporate the carbonyl of the overhanging carboxylate as apical ligand, decreasing its availability for the binding of a HAT Pb(II). An allosteric effector (e.g., 4-dimethylaminopyridine (DMAP), in the case of a single-strap ligand) or an intramolecular ligand (e.g., an amide group), strong enough to compete with the carbonyl of the hung COO(-), is required to switch the N-core bound cation to the opposite side with concomitant release of the COO(-), thereby allowing HAT Pb(II) complexation. In the absence of a base, Zn(II) or Cd(II) binds preferentially the carbonyl of the intramolecular ester or amide groups in apical position rather than that of the COOH. This better preorganization, with the overhanging COOH fully available, is responsible for a stronger binding of the HAT Pb(II). Thus, either allosteric or acid-base control is achieved through stereoselective metalation of Zn(II) or Cd(II). In the latter case, according to the deprotonation state of the COOH group, the best electron-donating ligand is located on one or the other side of the porphyrin (COO(-)>CONHR>COOR>COOH): the lower affinity of COOH for Zn(II) and Cd(II), the higher for a HAT Pb(II). These insights provide new opportunities for the elaboration of innovative bimetallic molecular switches. PMID- 23813640 TI - Spontaneous electromyographic activity of the tongue in amyotrophic lateral sclerosis. AB - INTRODUCTION: Detection of denervation in muscles in the craniobulbar area is important to assure widespread lower motor neuron involvement in the diagnosis of amyotrophic lateral sclerosis (ALS). The value of spontaneous activity analysis in needle electromyography (EMG) of the tongue has been questioned in the recent literature. METHODS: Spontaneous activity in the tongue and sternocleidomastoid (SCM) muscles was reviewed retrospectively in 17 ALS patients. RESULTS: Needle EMG showed spontaneous activity in the tongue in 14 of 17 patients (82%) and in 6 patients of 17 (35%) in SCM. Spontaneous EMG activity in the tongue was found in patients with and without bulbar symptoms. CONCLUSIONS: Needle EMG is a valuable method for assessing clinical and subclinical involvement of the tongue in patients with bulbar and limb onset ALS. Adequate relaxation of the tongue is a prerequisite for proper spontaneous activity recording. PMID- 23813641 TI - GoSynthetic database tool to analyse natural and engineered molecular processes. AB - An essential topic for synthetic biologists is to understand the structure and function of biological processes and involved proteins and plan experiments accordingly. Remarkable progress has been made in recent years towards this goal. However, efforts to collect and present all information on processes and functions are still cumbersome. The database tool GoSynthetic provides a new, simple and fast way to analyse biological processes applying a hierarchical database. Four different search modes are implemented. Furthermore, protein interaction data, cross-links to organism-specific databases (17 organisms including six model organisms and their interactions), COG/KOG, GO and IntAct are warehoused. The built in connection to technical and engineering terms enables a simple switching between biological concepts and concepts from engineering, electronics and synthetic biology. The current version of GoSynthetic covers more than one million processes, proteins, COGs and GOs. It is illustrated by various application examples probing process differences and designing modifications. Database URL: http://gosyn.bioapps.biozentrum.uni-wuerzburg.de. PMID- 23813642 TI - Mitochondria underlie different metabolism of hematopoietic stem and progenitor cells. PMID- 23813643 TI - Circulating microparticles in children with sickle cell anemia: a heterogeneous procoagulant storm directed by hemolysis and fetal hemoglobin. PMID- 23813644 TI - Are ongoing trials on hematologic malignancies still excluding older subjects? PMID- 23813645 TI - A European strategy for targeted education in hematology. PMID- 23813647 TI - Indications for hematopoietic stem cell transplantation in patients with follicular lymphoma: a consensus project of the EBMT-Lymphoma Working Party. AB - The aim of this project was to define indications for hematopoietic stem cell transplantation in follicular lymphoma in Europe. In the absence of evidence based data, a RAND-modified Delphi procedure was used by an expert panel. After pre-defining statements, these were individually/anonymously scored by each participant using a 9-point scale. Consensus was reached that: 1) high-dose therapy with autologous stem cell rescue is not an appropriate option to consolidate first remission in patients responding to immuno-chemotherapy outside clinical trials; 2) in patients with first chemo-sensitive relapse, high-dose therapy with autologous stem cell rescue is an appropriate option to consolidate remission, especially in patients with a short response after immuno-chemotherapy or with high-risk FLIPI; 3) high-dose therapy with autologous stem cell rescue is also appropriate in second/subsequent chemo-sensitive relapses; 4) allotransplant (preferably a reduced intensity conditioning-allotransplant) should be considered at relapse after high-dose therapy with autologous stem cell rescue. No consensus was reached on the role of high-dose therapy with autologous stem cell rescue in low-risk first relapse, or on when an allotransplant should be preferred over high-dose therapy with autologous stem cell rescue. In the absence of evidence based data, the consensus method used was a valuable tool to define indications for hematopoietic stem cell transplant in follicular lymphoma. PMID- 23813646 TI - Recognizing nodal marginal zone lymphoma: recent advances and pitfalls. A systematic review. AB - The diagnosis of nodal marginal zone lymphoma is one of the remaining problem areas in hematopathology. Because no established positive markers exist for this lymphoma, it is frequently a diagnosis of exclusion, making distinction from other low-grade B-cell lymphomas difficult or even impossible. This systematic review summarizes and discusses the current knowledge on nodal marginal zone lymphoma, including clinical features, epidemiology and etiology, histology, and cytogenetic and molecular features. In particular, recent advances in diagnostics and pathogenesis are discussed. New immunohistochemical markers have become available that could be used as positive markers for nodal marginal zone lymphoma. These markers could be used to ensure more homogeneous study groups in future research. Also, recent gene expression studies and studies describing specific gene mutations have provided clues to the pathogenesis of nodal marginal zone lymphoma, suggesting deregulation of the nuclear factor kappa B pathway. Nevertheless, nodal marginal zone lymphoma remains an enigmatic entity, requiring further study to define its pathogenesis to allow an accurate diagnosis and tailored treatment. However, recent data indicate that it is not related to splenic or extranodal lymphoma, and that it is also not related to lymphoplasmacytic lymphoma. Thus, even though the diagnosis is not always easy, it is clearly a separate entity. PMID- 23813649 TI - Profibrinolytic microparticles are not adequately produced to compensate their prothrombotic effect. PMID- 23813650 TI - Membrane microvesicles: a circulating source for fibrinolysis, new antithrombotic messengers. PMID- 23813651 TI - Inter-observer agreement in myelodysplastic syndromes. PMID- 23813652 TI - Response to "Predictors of survival in thrombotic thrombocytopenic purpura" Haematologica 2013;98(5):e58. PMID- 23813654 TI - Structure of the parallel duplex of poly(A) RNA: evaluation of a 50 year-old prediction. PMID- 23813653 TI - Challenges of using primary care electronic medical records in the UK to study medications in pregnancy. AB - PURPOSE: This paper aimed to assess the prescription of medications during pregnancy by primary care physicians in the UK. METHODS: We identified both completed pregnancies and pregnancies losses (ectopic pregnancies, miscarriages, terminations, and stillbirths) in women aged 13-49 years enrolled in The Health Improvement Network (THIN) between 1996 and 2010 following an algorithm with three sequential cycles that searched for Read Code groups in hierarchical order: (1) indicators of conception; (2) delivery or pregnancy loss; and (3) other codes suggestive of pregnancy. Completed pregnancies were linked to liveborn infants by means of the family identification number and date of birth. Prescription of specific drugs during the first trimester and time trends during the last decade were calculated. RESULTS: A total of 191 000 pregnancies were identified, including 148 544 completed pregnancies and 42 456 (22.2%) pregnancies losses (ectopic pregnancies, miscarriages, terminations, and stillbirths). Of the completed pregnancies, 131670 (88.6%) were successfully linked with the offspring. The most commonly prescribed drugs were antibiotics, antimycotics, asthma/allergy medications, and analgesics. From 1996 to 2010, the proportion of completed pregnancies with at least one prescription during the first trimester increased for antidepressants (1.8% to 4.2%), thyroid hormones (0.7% to 1.6%), and opiods (1.5% to 2.6%), among other drugs. CONCLUSION: In conclusion, the prescription of several medications by primary care physicians during the first trimester of pregnancy has risen in the UK during the last decade. We discuss how, when important challenges are considered, THIN may be a promising resource to study specific therapies during pregnancy. PMID- 23813655 TI - The subparietal and parietooccipital sulci: an anatomical study. AB - The subparietal and parietooccipital sulci are both located on the medial surface of the brain. Both of these sulci reveal significant variability in pattern and complexity. Both subparietal and parietooccipital sulci play an important role as surgical landmarks using posterior interhemispheric parietooccipital approach to lesions located adjacent to the ventricular trigon deep to the cingulate gyrus. The aim of this study is to analyze variations in the patterns of the subparietal and parietooccipital sulci and to emphasize their surgical importance. Fifty-six formalin-fixed cadaveric cerebral hemispheres from 28 adult humans are examined. Subparietal and parietal sulci patterns, variations and their relationship with the cingulate sulcus are studied according to the terminology introduced by Ono et al. The H-pattern was observed in 50% (n = 28) of all hemispheres, being the most common pattern of the subparietal sulcus. The Straight pattern was observed in the 30.4% (n = 17) of all hemispheres, being the most common pattern of the parietooccipital sulcus. Furthermore, more detailed results among the patterns, connections, side branches and the relationship with the adjacent sulci are given. Our study further confirms the complexities in the patterns of the subparietal and parietooccipital sulci and demonstrates that these sulci fall within an expected range of variations. Better knowledge of these variations will further help neurosurgeons to navigate easily during approaches involving the medial surface of the parietal lobe. Clin. Anat. 26:667-674, 2013. (c) 2013 Wiley Periodicals, Inc. PMID- 23813656 TI - Orthopedic manifestations and implications for individuals with Costello syndrome. AB - Costello syndrome is a rare genetic condition caused by heterozygous alterations in HRAS and characterized by multi-system abnormalities. Individuals with Costello syndrome usually present with severe feeding difficulties in infancy, short stature, coarse facial features, increased tumor risks, cardiac and neurological complications, intellectual disability and orthopedic complications. This study further defines the orthopedic manifestations affecting individuals with Costello syndrome. We studied 43 participants and performed medical records review, clinical examinations and orthopedic inquiry forms. In 23 participants, hip and or spinal imaging assessments were completed. Serial radiographs were analyzed when available. A total of 25 orthopedic manifestations were identified. Ten manifestations were seen in the majority of the participants: hypotonia (87%), ligamentous laxity (85%), scoliosis (63%), kyphosis (58%), characteristic hand deformities (85%), ulnar deviation of the wrist (63%), elbow (55%) and shoulder contractures (65%), tight Achilles tendon (73%), and pes planus (53%). Other characteristics of special note were hip dysplasia (45%), foot deformities requiring surgical intervention (38%) and osteopenia/osteoporosis (47%). We also studied the development of the hips and spine. Uni- or bilateral hip dysplasia was congenital in some, while it developed throughout childhood in others. Spinal involvement included scoliosis, kyphosis, lordosis, and curvature reversal (thoracic lordosis and lumbar kyphosis). Based on these findings, we recommend routine referral to an orthopedic surgeon as well as instituting screening protocols for hips and spine for individuals with Costello syndrome. PMID- 23813657 TI - Bladder pain syndrome/interstitial cystitis increase the risk of coronary heart disease. AB - AIM: Vascular factor was proposed as being involved in the etiology of bladder pain syndrome/interstitial cystitis (BPS/IC). However, few studies have attempted to investigate the relationship between BPS/IC and cardiovascular disease. This study aimed to investigate the risk of coronary heart disease (CHD) among BPS/IC subjects during a 3-year follow-up period. METHODS: Data for this retrospective matched-cohort study were retrieved from the Taiwan "Longitudinal Health Insurance Database 2000." There were 752 BPS/IC female subjects in the study cohort and 3,760 randomly selected female subjects in the comparison cohort. We individually tracked each subject for 3 years and identified each subject that received a subsequent diagnosis of CHD during that follow-up period. RESULTS: Results showed that incidence rates of CHD during the 3-year follow-up period were 19.50 (95% confidence interval (CI): 14.35-25.95) and 8.87 (95% CI: 7.25 10.74) per 1,000 person-years for the study and comparison cohorts, respectively. The Cox proportional hazards regression suggested that the hazard ratio for CHD in subjects with BPS/IC was 1.65 (95% CI: 1.09-2.48) within the 3-year follow-up period following the index date compared to the comparison subjects after adjusting for monthly income, geographic region, hypertension, diabetes, hyperlipidemia, chronic kidney disease, bladder outlet obstruction, urinary tract infection, chronic pelvic pain, overactive bladder, and number of physician visits during the 3-year follow up period. CONCLUSIONS: Our study demonstrated an association between BPS/IC and a subsequent CHD diagnosis. We advise clinicians to screen subjects with BPS/IC for modifiable risk factors for CHD. PMID- 23813658 TI - Polymer monoliths as efficient solid phases for enzymatic polynucleotide degradation followed by fast HPLC analysis. AB - Two ribonuclease A bioreactors based on lab-made macroporous monolithic columns and intended for polynucleotide degradation were prepared using in situ free radical polymerization. Different methods of enzyme immobilization were applied. In the first case, the biocatalyst molecule was attached to the solid surface via direct covalent binding, while in the second bioreactor the flexible-chain synthetic polymer was used as an intermediate spacer. The effect of temperature, substrate flow rate, and loaded sample volume on the biocatalytic efficiency of the immobilized enzyme was examined. The kinetic parameters of the enzymatic degradation of synthetic polycytidylic acid were calculated and compared to those found for hydrolysis with soluble ribonuclease A. The monitoring of substrate splitting was carried out by means of fast anion-exchange HPLC on an ultra-short monolithic column (disk) using off- and on-line analytical approaches. PMID- 23813659 TI - Sulfur-infiltrated micro- and mesoporous silicon carbide-derived carbon cathode for high-performance lithium sulfur batteries. AB - Novel nanostructured sulfur (S)-carbide derived carbon (CDC) composites with ordered mesopores and high S content are successfully prepared for lithium sulfur batteries. The tunable pore-size distribution and high pore volume of CDC allow for an excellent electrochemical performance of the composites at high current densities. A higher electrolyte molarity is found to enhance the capacity utilization dramatically and reduce S dissolution in S-CDC composite cathodes during cycling. PMID- 23813660 TI - Integrative analysis of prostate cancer aggressiveness. AB - BACKGROUND: Clinical management of prostate cancer (PC) is still highly demanding on the identification of robust biomarkers which will allow a more precise prediction of disease progression. METHODS: We profiled both mRNA expression and DNA copy number alterations (CNAs) from laser capture microdissected cells from 31 PC patients and 17 patients with benign prostatic hyperplasia using Affymetrix GeneChip(r) technology. PC patients were subdivided into an aggressive (Gleason Score 8 or higher, and/or T3/T4 and/or N+/M+) and non-aggressive (all others) form of PC. Furthermore, we correlated the two datasets, as genes whose varied expression is due to a chromosomal alteration, may suggest a causal implication of these genes in the disease. All statistical analyses were performed in R version 2.15.0 and Bioconductor version 1.8.1., respectively. RESULTS: We confirmed several common altered chromosomal regions as well as recently discovered loci such as deletions on chromosomes 3p14.1-3p13 and 13q13.3-13q14.11 supporting a possible role for RYBP, RGC32, and ELF1 in tumor suppression. Integrative analysis of expression and CN data combined with data retrieved from online databases propose PTP4A3 and ELF1 as possible factors for tumor progression. CONCLUSIONS: Copy number data analysis revealed some significant differences between aggressive and non-aggressive tumors, while gene expression data alone could not define an aggressive group of patients. The assessment of CNA may have diagnostic and prognostic value in PC. PMID- 23813661 TI - Perceiving nonverbal behavior: neural correlates of processing movement fluency and contingency in dyadic interactions. AB - Despite the fact that nonverbal dyadic social interactions are abundant in the environment, the neural mechanisms underlying their processing are not yet fully understood. Research in the field of social neuroscience has suggested that two neural networks appear to be involved in social understanding: (1) the action observation network (AON) and (2) the social neural network (SNN). The aim of this study was to determine the differential contributions of the AON and the SNN to the processing of nonverbal behavior as observed in dyadic social interactions. To this end, we used short computer animation sequences displaying dyadic social interactions between two virtual characters and systematically manipulated two key features of movement activity, which are known to influence the perception of meaning in nonverbal stimuli: (1) movement fluency and (2) contingency of movement patterns. A group of 21 male participants rated the "naturalness" of the observed scenes on a four-point scale while undergoing fMRI. Behavioral results showed that both fluency and contingency significantly influenced the "naturalness" experience of the presented animations. Neurally, the AON was preferentially engaged when processing contingent movement patterns, but did not discriminate between different degrees of movement fluency. In contrast, regions of the SNN were engaged more strongly when observing dyads with disturbed movement fluency. In conclusion, while the AON is involved in the general processing of contingent social actions, irrespective of their kinematic properties, the SNN is preferentially recruited when atypical kinematic properties prompt inferences about the agents' intentions. PMID- 23813662 TI - Alkyl transfer from C-C cleavage. PMID- 23813663 TI - Tuning the Lewis acidity of boranes in frustrated Lewis pair chemistry: implications for the hydrogenation of electron-poor alkenes. AB - An analysis of the metal-free reduction of electron deficient olefins by frustrated Lewis pairs indicates that the rate-determining step might be either the heterolytic cleavage of H2 to form an -onium borohydride salt, or the subsequent transfer of the hydride moiety to the substrate following a Michael type addition reaction. While the use of strong Lewis acids such as B(C6F5)3 facilitates the first of these processes, hydride transfer to the olefin should be contrarily favoured by the use of weak Lewis acids which, for this very same reason, might be unable to promote the prior H2 split. After systematic testing of several boranes of different Lewis acidity (assessed by using the Childs' method) and steric demand, an optimal situation that employs tris(2,4,6 trifluorophenyl)borane was reached. Mixtures of this borane with 1,4 diazabicyclo[2.2.2]octane (DABCO) exhibited excellent catalytic activity for the hydrogenation of alkylidene malonates. In fact, this transformation could be achieved under milder conditions than those we reported previously. Moreover, the reaction scope could be expanded to other electron deficient olefins containing esters, sulfones or nitro functionalities as electron-withdrawing substituents. PMID- 23813664 TI - Discrimination, harassment, abuse, and bullying in the workplace: contribution of workplace injustice to occupational health disparities. AB - BACKGROUND: This paper synthesizes research on the contribution of workplace injustices to occupational health disparities. METHODS: We conducted a broad review of research and other reports on the impact of workplace discrimination, harassment, and bullying on workers' health and on family and job outcomes. RESULTS: Members of demographic minority groups are more likely to be victims of workplace injustice and suffer more adverse outcomes when exposed to workplace injustice compared to demographic majority groups. A growing body of research links workplace injustice to poor psychological and physical health, and a smaller body of evidence links workplace injustice to unhealthy behaviors. Although not as well studied, studies show that workplace injustice can influence workers' health through effects on workers' family life and job-related outcomes. CONCLUSION: Injustice is a key contributor to occupational health injustice and prospective studies with oversample of disadvantaged workers and refinement of methods for characterizing workplace injustices are needed. PMID- 23813665 TI - Atomoxetine for attention deficit hyperactivity disorder in the adulthood: a meta analysis and meta-regression. AB - PURPOSE: Atomoxetine is a non-stimulant drug that could be an alternative to methylphenidate, whose benefit : risk balance for the treatment of adults with attention deficit hyperactivity disorder (ADHD) has recently been shown to be unclear. This study aimed to compare all-cause discontinuation rate between atomoxetine and placebo in adults with ADHD. Secondarily, efficacy and safety were investigated. METHODS: Systematic review and meta-analysis of randomized controlled trials comparing atomoxetine with placebo in adults with ADHD were performed. All-cause treatment discontinuation was the primary endpoint. Efficacy in reducing ADHD symptoms and safety were the secondary endpoints. Odds ratio (OR) and the standardized mean difference (SMD) were calculated for dichotomous and continuous outcomes, respectively. Data were pooled using the fixed and random effects model. The influence of study design-related, intervention-related and patient-related co-variables over the primary endpoint was investigated by means of meta-regression. This study is registered with the international prospective register of systematic reviews (PROSPERO): CRD 42012002042. RESULTS: Twelve studies (3375 patients) were included. Treatment discontinuation was larger with atomoxetine than with placebo (OR = 1.39). No co-variable was found to modify the effect of atomoxetine over treatment discontinuation. Atomoxetine showed modest efficacy in reducing ADHD symptoms irrespective of the assessor: patient (SMD = -0.33); clinician (SMD = -0.40). The rate of adverse events induced discontinuation was higher with atomoxetine than with placebo (OR = 2.57). CONCLUSION: This study suggests that atomoxetine has a poor benefit-risk balance for the treatment of adults with ADHD. The recommendation of atomoxetine use in this population is weak. PMID- 23813666 TI - Dr. Peter Emil Becker and the Third Reich. AB - In 1985 the physician after whom Becker Muscular Dystrophy is named, German neurologist Dr. Peter Emil Becker (1908-2000), published an autobiographical article in the American Journal of Medical Genetics in which he disavowed any association with the Nazi Party. A closer look at the evidence, however, suggests otherwise. Review of war records and related sources raise concern for Dr. Becker's affiliation with the Nazi Party and his contributions to its ideology. PMID- 23813667 TI - Genetics driven interventions for ex situ conservation of red junglefowl (Gallus gallus murghi) populations in India. AB - Genetics driven interventions (GDI) are imperative for ex situ conservation to exhort long-term sustenance of small and isolated populations in captivity as they are more prone to an increased extinction risk due to inbreeding and genetic drift. We investigated constitutive genetic attributes of four captive Red Junglefowl (RJF) populations in India, to facilitate the prioritization of the birds to formulate an effective breeding action plan. All the four RJF populations were found to be evident of significant inbreeding but none of them had exhibited any signature of bottleneck footprints in the recent past. Bayesian cluster analysis revealed three distinct groups among the four captive RJF populations. Interestingly, birds of Kufri population were assigned together with Gopalpur as well as with Morni populations, indicating their shared genetic ancestry. Among the four populations, Morni population displayed the richest genetic attributes and was therefore presumed as a key source of genetic variation. Nine birds of Morni population were relatively pure (q-value >0.98) and carried about 50% of the total private alleles of Morni population. Thus, being the foremost reservoir of allelic diversity, these nine birds may be selected for launching alien alleles to other RJF populations to rescue their loss of genetic diversity arising from inbreeding. PMID- 23813668 TI - Bicycling to university: evaluation of a bicycle-sharing program in Spain. AB - This study examined the change in behavioral stages (e.g. contemplation, action and maintenance) of cycling to university before and after the implementation of a new public bicycle share program (PBSP) and promotion of its use. The study also determined the change in the prevalence, correlates of PBSP use and potential role in the promotion of healthy weight. An 8-month follow-up cross sectional study (September 2010-April 2011) was carried out among undergraduate students during the first season of implementation of the PBSP in Valencia, Spain. The sample was 173 students (68.2% female) with a mean age of 21.3 years (SD 3.06) who attended a PBSP promotional session. The data were collected by questionnaire. Results indicated a significant increase of 14.6% in the action/maintenance stage of change and showed that 19% of the participants were PBSP users 8 months later. The behavioral stage did not change when students always had access to car/motorbike, lived further than 5 km from the university and had no bicycle stations within 250 m from home. Those most likely to start using PBSP were students who were in the contemplation stage, perceived fewer environmental and safety barriers to active commuting and had one or more stations within 250 m of home. PBSP users expended ~257 metabolic equivalent.minutes/week bicycling to university, and there was a small reduction in BMI. Findings suggest that PBSPs can be considered as useful promoters of cycling behavior and may contribute to weight control in university students. PMID- 23813669 TI - Evaluation of continence following 532 nm laser prostatectomy for patients previously treated with radiation therapy or brachytherapy. AB - INTRODUCTION/OBJECTIVE: Urinary complications such as bladder outlet obstruction or urinary retention following radiation therapy or brachytherapy have been reported in up to 15% of men. When conservative therapy has failed, surgical intervention with transurethral resection of the prostate (TURP) may be performed, but carries a significant risk of incontinence, ranging from 18% to 70% in reported literature. We reviewed a cohort of men previously treated with radiation or brachytherapy, who underwent laser prostatectomy. METHODS: From February 2004 to October 2011, 12 patients (Six = brachytherapy and Six = external beam radiation) underwent 532 nm GreenLightTM laser prostatectomy by a single surgeon (BBC) for chronic retention or debilitating obstructive symptoms. Preoperative, intraoperative, and postoperative parameters were collected prospectively and reviewed retrospectively. Statistical analysis was performed with a Wilcox Rank sum test with significance defined as P < 0.05. RESULTS: The median patient age was 77.4 (Interquartile range (IQR) 73.9, 79.1). Prior to surgery, five patients were catheter dependent. Intraopertively, the median operative time was 48 minutes (IQR 35, 67); median lasing time was 28 minutes (IQR 23, 44); median Joules used was 126,873 (IQR 95,030, 222,336) J. Postoperative median follow up was 22.9 (IQR 13.4, 41.7) months. Significant improvements were noted in IPSS, QoL scores, PVR, and Qmax after PVP treatment. At 12 months, the median decrease in IPSS, QoL scores, and PVR was 15 (IQR 14.5, 22) to 10 (IQR 5.5, 13.5), 5 (IQR 3.5, 5) to 2 (IQR 1, 3.5), 200 (IQR 171, 327.5) to 5 (IQR 1.25, 8), respectively (P < 0.05 for all). Similarly, at 12 months, the median increase in Qmax (ml/second) was 4 (IQR 3, 10) to 15.9 (IQR 11, 16) (P = 0.04). There were no reportable complications at 12 months. None of the 12 patients that underwent 532 nm GreenLightTM laser prostatectomy developed stress urinary incontinence. One patient developed metastatic prostate cancer and the remaining patients had no evidence of biochemical recurrence. CONCLUSION: In this pilot study, 532 nm GreenLightTM laser prostatectomy is feasible and safe in patients who have undergone prior radiotherapy for prostate cancer. Laser prostatectomy provides a durable response while maintaining continence in this cohort suffering from severe lower urinary tract symptoms (LUTS) or retention. Larger, randomized trials comparing GreenLightTM laser prostatectomy to traditional TURP are necessary to confirm non-inferiority. PMID- 23813670 TI - Pneumomediastinum and the aortic nipple: the clinical relevance of the left superior intercostal vein. AB - This article discusses the appearance of the "aortic nipple" in chest radiography, and reviews the embryology and anatomy of the left superior intercostal vein which causes the appearance of an "aortic nipple." This radiological sign is useful in differentiating certain thoracic pathologies, such as pneumomediastinum, pneumopericardium, and medial pneumothorax. Pneumomediastinum is an encompassing term describing the presence of air in the mediastinum, and may arise from a wide range of pathological conditions. Despite the well-described imaging of pneumomediastinum, it is sometimes difficult to differentiate from other conditions such as pneumopericardium and medial pneumothorax. A separate finding, "aortic nipple" is the radiographic term used to describe the lateral nipple-like projection from the aortic knob present in a small number of individuals. The aortic nipple corresponds to the end-on appearance of the left superior intercostal vein coursing around the aortic knob, and may be mistaken radiologically for lymphadenopathy or a neoplasm. Despite their relative independence, the aortic nipple is defined by new contours in cases of pneumomediastinum, taking on an "inverted aortic nipple" appearance. In this position, the inverted aortic nipple may facilitate radiographic discrimination of pneumomediastinum from similar conditions. This study aims to review the common clinical and radiographic features of both pneumomediastinum and the aortic nipple. The radiologic appearance of the aortic nipple occurring in unison with pneumomediastinum, and its potential role as a tool in the differentiation of pneumomediastinum from similarly presenting conditions will also be described. PMID- 23813671 TI - The over-expression of Pim-2 promote the tumorigenesis of prostatic carcinoma through phosphorylating eIF4B. AB - BACKGROUND: Cell experiments have found Pim-2 may take part in the tumorigenesis of prostatic carcinoma (PCA). More direct evidences are needed, and the detailed anti-apoptotic mechanism of Pim-2 in PCA cells is still unknown. METHODS: Pim-2 expression levels were compared between benign prostatic hyperplasia (BPH) tissues and PCA tissues using real time PCR and Western blot, respectively. Then Pim-2 expression levels were detected in PCA cell lines DU-145 and LNCaP, as well as in nontumorous prostatic epithelial cell lines RWPE-1 and PNT1a, using real time PCR and Western blot, respectively. The co-expression of Pim-2 and eukaryotic initiation factor 4B (eIF4B) was examined by immunofluorescence cytochemistry using laser scanning confocal microscope. Finally, Pim-2 SiRNA was transfected into DU-145 cells and Pim-2 was transfected into RWPE-1 cells, and the level of Pim-2 and phosphorylated eukaryotic initiation factor 4B (p-eIF4B) were detected, as well as the apoptosis rate. RESULTS: The Pim-2 mRNA and protein level were significantly higher in PCA tissues than those in BPH tissues. The Pim 2 mRNA and protein level in DU-145 and LNCaP cells were significantly higher than those in RWPE-1 and PNT1a cells. Pim-2 and eIF4B could co-express in DU-145 cells. Pim-2 level determined the phosphorylation level of eIF4B and the apoptosis rate of prostatic cells. The higher Pim-2 expressed, the more eIF4B phosphorylated, then the less cell got apoptosis, and vice versa. CONCLUSION: Pim 2 was over-expressed in PCA cell lines and tissues. It may inhibit the apoptosis of PCA cells through phosphorylating eIF4B, thus promote the tumorigenesis of PCA. PMID- 23813672 TI - Parenting stress in parents of children with cochlear implants: relationships among parent stress, child language, and unilateral versus bilateral implants. AB - Little attention has been focused on stress levels of parents of children with cochlear implants (CIs). This study examined the stress experience of 70 parents of children with CIs by comparing stress levels in this group of parents to those in parents of children without disabilities, identifying primary stressors, examining the relationship between parent stress and child language, and comparing stress in parents of children with bilateral and unilateral CIs. Parents completed a parent stress questionnaire, and the receptive vocabulary and language abilities of the children were evaluated. Results indicated that these parents had a higher incidence of stress than the normative population. Parent stress levels and child language outcomes were negatively correlated. Child behavior and lack of spousal and social support were the prime causes of parent stress. Parents of children with bilateral CIs were significantly less stressed than were parents of children with unilateral CIs. PMID- 23813673 TI - Poly(ethylene glycol)-based monolithic capillary columns for hydrophobic interaction chromatography of immunoglobulin G subclasses and variants. AB - Polymer monoliths were prepared in 150 MUm id capillaries by thermally initiated polymerization of PEG diacrylate for rapid hydrophobic interaction chromatography of immunoglobulin G (IgG) subclasses and related variants. Using only one monomer in the polymerization mixture allowed ease of optimization and synthesis of the monolith. The performance of the monolith was demonstrated by baseline resolution of IgG subclasses and variants, including mixtures of the kappa variants of IgG1, IgG2, and IgG3 as well as the kappa and lambda variants associated with IgG1 and IgG2. The effect of eluent concentration and pH on the separation efficiency of studied proteins was also explored, allowing almost baseline resolution to be achieved for mixtures of the kappa variants of IgG1, IgG2, IgG3, and IgG4 but also for the kappa and lambda variants of IgG1 and IgG2. The results showed significant improvement in the separations in terms of the tradeoff between analysis time and resolution, while maintaining a simple methodology, in comparison to previous reports. The synthesized monolith was also used for the separation of isoforms of a therapeutic monoclonal antibody. PMID- 23813674 TI - Patterned deposition of metal-organic frameworks onto plastic, paper, and textile substrates by inkjet printing of a precursor solution. AB - Flexible in many aspects: inkjet printing of metal-organic frameworks permits their larger area, high-resolution deposition in any desired pattern, even in the form of gradients or shades. When flexible substrates are used, many applications can be envisioned, such as sensing and capture of hazardous gases for personal safety measures. PMID- 23813675 TI - Identification and characterization of biofilm formation-defective mutants of Xanthomonas citri subsp. citri. AB - Xanthomonas citri subsp. citri (Xcc) develops a biofilm structure both in vitro and in vivo. Despite all the progress achieved by studies regarding biofilm formation, many of its mechanisms remain poorly understood. This work focuses on the identification of new genes involved in biofilm formation and how they are related to motility, virulence and chemotaxis in Xcc. A Tn5 library of approximately 6000 Xcc (strain 306) mutants was generated and screened to search for biofilm formation defective strains. We identified 23 genes not previously associated with biofilm formation. The analysis of the 23 mutants not only revealed the involvement of new genes in biofilm formation, but also reinforced the importance of exopolysaccharide production, motility and cell surface structures in this process. This collection of biofilm-defective mutants underscores the multifactorial genetic programme underlying the establishment of biofilm in Xcc. PMID- 23813676 TI - Importance of the proline-rich region for the regulatory function of RcsF, an outer membrane lipoprotein component of the Escherichia coli Rcs signal transduction system. AB - The outer membrane lipoprotein RcsF is an essential component of the Rcs phosphorelay signal transduction system in Escherichia coli. It senses stresses imposed on the cell envelope and conveys the information to histidine kinase RcsC in the cytoplasmic membrane. Mislocalization of RcsF to the periplasm, effected by fusing it to the periplasmic maltose-binding protein, or to the cytoplasmic membrane, brought about by changing the lipoprotein sorting signal, leads to high activation of the Rcs system, suggesting that RcsF functions as a ligand for RcsC in activating the system. Here, we focus on the proline-rich region (PRR) in the N-terminal half of RcsF, a region which also contains many basic amino acid residues. Deletion of the PRR in the mislocalized RcsF resulted in even higher activation of the Rcs system. The same deletion in wild-type RcsF lipoprotein that is correctly localized to the outer membrane, however, blocked activation of the system under stresses that normally should activate it. It is highly likely that the PRR plays an important role in the regulation of the function of RcsF in activating the Rcs system. PMID- 23813677 TI - Distribution and diversity of the haemoglobin-haptoglobin iron-acquisition systems in pathogenic and non-pathogenic Neisseria. AB - A new generation of vaccines containing multiple protein components that aim to provide broad protection against serogroup B meningococci has been developed. One candidate, 4CMenB (4 Component MenB), has been approved by the European Medicines Agency, but is predicted to provide at most 70-80 % strain coverage; hence there is a need for second-generation vaccines that achieve higher levels of coverage. Prior knowledge of the diversity of potential protein vaccine components is a key step in vaccine design. A number of iron import systems have been targeted in meningococcal vaccine development, including the HmbR and HpuAB outer-membrane proteins, which mediate the utilization of haemoglobin or haemoglobin-haptoglobin complexes as iron sources. While the genetic diversity of HmbR has been described, little is known of the diversity of HpuAB. Using whole genome sequences deposited in a Bacterial Isolate Genome Sequence Database (BIGSDB), the prevalence and diversity of HpuAB among Neisseria were investigated. HpuAB was widely present in a range of Neisseria species whereas HmbR was mainly limited to the pathogenic species Neisseria meningitidis and Neisseria gonorrhoeae. Patterns of sequence variation in sequences from HpuAB proteins were suggestive of recombination and diversifying selection consistent with strong immune selection. HpuAB was subject to repeat-mediated phase variation in pathogenic Neisseria and the closely related non-pathogenic Neisseria species Neisseria lactamica and Neisseria polysaccharea but not in the majority of other commensal Neisseria species. These findings are consistent with HpuAB being subject to frequent genetic transfer potentially limiting the efficacy of this receptor as a vaccine candidate. PMID- 23813679 TI - Blue-light-dependent inhibition of twitching motility in Acinetobacter baylyi ADP1: additive involvement of three BLUF-domain-containing proteins. AB - Twitching motility in Acinetobacter baylyi ADP1 is inhibited by moderate intensities of blue light in a temperature-dependent manner (maximally at 20 degrees C). We analysed the involvement of four predicted blue-light sensing using flavin (BLUF)-domain-containing proteins encoded in the genome of this strain in the twitching motility phenotype. All four genes were expressed both in light and in darkness. A phylogenetic tree showed that one BLUF domain, ACIAD2110, grouped separately from the other three (ACIAD1499, ACIAD2125 and ACIAD2129). Individual knockout mutants of the latter three, but not of ACIAD2110, fully abolished the light dependency of the twitching motility response. Quantitative analysis of transcript level of the three genes showed a decreased expression in the light, with dark/light ratios of 1.65+/-0.28, 1.79+/ 0.21 and 2.69+/-0.39, for ACIAD2125, ACIAD2129 and ACIAD1499, respectively. Double and triple knockouts of ACIAD1499, ACIAD2125 and ACIAD2129 confirmed the same phenotype as the corresponding single knockouts. Complementation of all the single knockouts and the triple knockout mutants with any of the three BLUF domain-encoding genes fully restored the inhibition of twitching motility by blue light that is observed in the wild-type strain. A. baylyi ADP1 therefore shows a high degree of redundancy in the genes that encode BLUF-containing photoreceptors. Moreover, all plasmid-complemented strains, expressing any of the BLUF proteins irrespective of the specific set of deleted photoreceptors, displayed increased light-dependent inhibition of twitching motility, as compared to the wild-type (P<0.001). We conclude that the three genes ACIAD1499, ACIAD2125 and ACIAD2129 are jointly required to inhibit twitching motility under moderate blue-light illumination. PMID- 23813678 TI - Reversible acetylation regulates acetate and propionate metabolism in Mycobacterium smegmatis. AB - Carbon metabolic pathways are important to the pathogenesis of Mycobacterium tuberculosis, the causative agent of tuberculosis. However, extremely little is known about metabolic regulation in mycobacteria. There is growing evidence for lysine acetylation being a mechanism of regulating bacterial metabolism. Lysine acetylation is a post-translational modification in which an acetyl group is covalently attached to the side chain of a lysine residue. This modification is mediated by acetyltransferases, which add acetyl groups, and deacetylases, which remove the acetyl groups. Here we set out to test whether lysine acetylation and deacetylation impact acetate metabolism in the model mycobacteria Mycobacterium smegmatis, which possesses 25 candidate acetyltransferases and 3 putative lysine deacetylases. Using mutants lacking predicted acetyltransferases and deacetylases we showed that acetate metabolism in M. smegmatis is regulated by reversible acetylation of acetyl-CoA synthetase (Ms-Acs) through the action of a single pair of enzymes: the acetyltransferase Ms-PatA and the sirtuin deacetylase Ms-SrtN. We also confirmed that the role of Ms-PatA in regulating Ms-Acs regulation depends on cAMP binding. We additionally demonstrated a role for Ms-Acs, Ms-PatA and Ms SrtN in regulating the metabolism of propionate in M. smegmatis. Finally, along with Ms-Acs, we identified a candidate propionyl-CoA synthetase, Ms5404, as acetylated in whole-cell lysates. This work lays the foundation for studying the regulatory circuit of acetylation and deacetylation in the cellular context of mycobacteria. PMID- 23813681 TI - Rhodium-catalyzed synthesis of amides from aldehydes and azides by chelation assisted C-H bond activation. PMID- 23813680 TI - Hematological and serum biochemical analytes reflect physiological challenges during gestation and lactation in killer whales (Orcinus orca). AB - Gestation and lactation result in metabolic alterations of the dam because of varying demands of the fetus and offspring during the different stages of development. Despite killer whales (Orcinus orca) having one of the longest gestations and highest birth weights of all mammals in human care, these metabolic alterations, and their impact on the physiology of the dam have not been measured. The objectives of this analysis were to determine if physiologic demands on the killer whale during pregnancy and lactation have measurable effects on hematology and biochemical analytes and if detectable, to compare these changes to those which are observed in other mammalian species. Forty hematologic and biochemical analytes from seven female killer whales (22 pregnancies, 1,507 samples) were compared between the following stages: (1) non pregnant or lactating (control); (2) gestation; and (3) the first 12 months of lactation. Decreased hematocrit, hemoglobin, and red blood cell counts were indicative of plasma volume expansion during mid and late gestation. The killer whales exhibited a progressively increasing physiologic inflammatory state leading up to parturition. Gestation and lactation caused significant shifts in the serum lipid profiles. Gestation and lactation cause significant physiologic changes in the killer whale dam. The last 12 months of gestation had greater physiological impact than lactation, but changes associated with and immediately following parturition were the most dramatic. During this period, killer whales may experience increased susceptibility to illness, and anthropogenic and environmental disturbances. PMID- 23813682 TI - Association between physical activity and risk of fracture. AB - Prospective studies that have examined the association between physical activity and fracture risks have reported conflicting findings. We performed a meta analysis to evaluate this association. We searched MEDLINE (1966 to February 1, 2013), EMBASE (1980 to February 1, 2013), and OVID (1950 to February 1, 2013) for prospective cohort studies with no restrictions. Categorical, heterogeneity, publication bias, and subgroup analyses were performed. There were 22 cohort studies with 1,235,768 participants and 14,843 fractures, including 8874 hip, 690 wrist, and 927 vertebral fractures. The pooled relative risk (RR) of total fractures for the highest versus lowest category of physical activity was 0.71 (95% confidence interval [CI], 0.63-0.80). The analysis of fracture subtypes showed a statistically significant inverse relationship between a higher category of physical activity and risk of hip and wrist fracture. The risk of hip or wrist fracture was 39% and 28% lower, respectively, among individuals with the highest category of physical activity than among those with the lowest category (95% CI, 0.54-0.69 and 0.49-0.96, respectively). The association between physical activity and vertebral fracture risk was not statistically related (RR, 0.87; 95% CI, 0.72 1.03). There was no evidence of publication bias. There was a statistically significant inverse association between physical activity and total fracture risk, especially for hip and wrist fractures. Additional subject-level meta analyses are required for a more reliable assessment of subgroups and types of physical activity. PMID- 23813683 TI - Surface coatings that promote rapid release of peptide-based AgrC inhibitors for attenuation of quorum sensing in Staphylococcus aureus. AB - Staphylococcus aureus is a major human pathogen responsible for a variety of life threatening infections. The pathogenicity of this organism is attributed to its ability to produce a range of virulence factors and toxins, including the superantigen toxic shock syndrome toxin-1 (TSST-1). While many S. aureus infections can be treated using conventional antibiotics, strains resistant to these bactericidal agents have emerged. Approaches that suppress pathogenicity through mechanisms that are nonbactericidal (i.e., antivirulence approaches) could provide new options for treating infections, including those caused by resistant strains. Here, we report a nonbactericidal approach to suppressing pathogenicity based on the release of macrocyclic peptides (1 and 2) that inhibit the agr quorum sensing (QS) circuit in group-III S. aureus. It is demonstrated that these peptides can be immobilized on planar and complex objects (on glass slides, nonwoven meshes, or within absorbent tampons) using the rapidly dissolving polymer carboxymethylcellulose (CMC). Peptide-loaded CMC films released peptide rapidly (<5 min) and promoted strong (>95%) inhibition of the agr QS circuit without inducing cell death when incubated in the presence of a group-III S. aureus gfp-reporter strain. Peptide 1 is among the most potent inhibitors of QS in S. aureus reported to date, and the group-III QS circuit regulates production of TSST-1, the primary cause of toxic shock syndrome (TSS). These results thus suggest approaches to treat the outer covers of tampons, wound dressings, or other objects to suppress toxin production and reduce the severity of TSS in clinical and personal care contexts. Because peptide 1 also inhibits QS in S. aureus groups-I, -II, and -IV, this approach could also provide a pathway for attenuation of QS and associated virulence phenotypes in a broader range of contexts. PMID- 23813684 TI - Air temperature optimisation for humidity-controlled cold storage of the predatory mites Neoseiulus californicus and Phytoseiulus persimilis (Acari: Phytoseiidae). AB - BACKGROUND: Humidity-controlled cold storage, in which the water vapour pressure is saturated, can prolong the survival of the predatory mites Neoseiulus californicus (McGregor) and Phytoseiulus persimilis Athias-Henriot (Acari: Phytoseiidae). However, information on the optimum air temperature for long-term storage by this method is limited. The authors evaluated the survival of mated adult females of N. californicus and P. persimilis at 5.0, 7.5, 10.0 and 12.5 degrees C under saturated water vapour condition (vapour pressure deficit 0.0 kPa). RESULTS: N. californicus showed a longer survival time than P. persimilis at all the air temperatures. The longest mean survival time of N. californicus was 11 weeks at 7.5 degrees C, whereas that of P. persimilis was 8 weeks at 5.0 degrees C. After storage at 7.5 degrees C for 8 weeks, no negative effect on post-storage oviposition was observed in N. californicus, whereas the oviposition of P. persimilis stored at 5.0 degrees C for 8 weeks was significantly reduced. CONCLUSION: The interspecific variation in the response of these predators to low air temperature might be attributed to their natural habitat and energy requirements. These results may be useful for the long-term storage of these predators, which is required for cost-effective biological control. PMID- 23813685 TI - How yawning switches the default-mode network to the attentional network by activating the cerebrospinal fluid flow. AB - Yawning is a behavior to which little research has been devoted. However, its purpose has not yet been demonstrated and remains controversial. In this article, we propose a new theory involving the brain network that is functional during the resting state, that is, the default mode network. When this network is active, yawning manifests a process of switching to the attentional system through its capacity to increase circulation of cerebrospinal fluid (CSF), thereby increasing clearance of somnogenic factors (prostaglandin D(2), adenosine, and others) accumulating in the cerebrospinal fluid. PMID- 23813686 TI - Cortical surface complexity in frontal and temporal areas varies across subgroups of schizophrenia. AB - Schizophrenia is assumed to be a neurodevelopmental disorder, which might involve disturbed development of the cerebral cortex, especially in frontal and medial temporal areas. Based on a novel spherical harmonics approach to measuring complexity of cortical folding, we applied a measure based on fractal dimension (FD) to investigate the heterogeneity of regional cortical surface abnormalities across subgroups of schizophrenia defined by symptom profiles. A sample of 87 patients with DSM-IV schizophrenia was divided into three subgroups (based on symptom profiles) with predominantly negative (n = 31), disorganized (n = 23), and paranoid (n = 33) symptoms and each compared to 108 matched healthy controls. While global FD measures were reduced in the right hemisphere of the negative and paranoid subgroups, regional analysis revealed marked heterogeneity of regional FD alterations. The negative subgroup showed most prominent reductions in left anterior cingulate, superior frontal, frontopolar, as well as right superior frontal and superior parietal cortices. The disorganized subgroup showed reductions in bilateral ventrolateral/orbitofrontal cortices, and several increases in the left hemisphere, including inferior parietal, middle temporal, and midcingulate areas. The paranoid subgroup showed only few changes, including decreases in the right superior parietal and left fusiform region, and increase in the left posterior cingulate cortex. Our findings suggest regional heterogeneity of cortical folding complexity, which might be related to biological subgroups of schizophrenia with differing degrees of altered cortical developmental pathology. PMID- 23813687 TI - Health insurance tax credits, the earned income tax credit, and health insurance coverage of single mothers. AB - The Omnibus Budget Reconciliation Act of 1990 enacted a refundable tax credit for low-income working families who purchased health insurance coverage for their children. This health insurance tax credit (HITC) existed during tax years 1991, 1992, and 1993, and was then rescinded. A difference-in-differences estimator applied to Current Population Survey data suggests that adoption of the HITC, along with accompanying increases in the Earned Income Tax Credit (EITC), was associated with a relative increase of about 4.7 percentage points in the private health insurance coverage of working single mothers with high school or less education. Also, a difference-in-difference-in-differences estimator, which attempts to net out the possible influence of the EITC increases but which requires strong assumptions, suggests that the HITC was responsible for about three-quarters (3.6 percentage points) of the total increase. The latter estimate implies a price elasticity of health insurance take-up of -0.42. PMID- 23813688 TI - Restricted access media as a streamlined approach toward on-line sample preparation: recent advancements and applications. AB - Restricted access media (RAM) as an alternative to traditional sample preparation strategies are reviewed. RAM comprise chromatographic packing materials that combine, typically, a restrictive outer surface to exclude the retention of large biomolecules, which are common interferences in biological fluids, with retentive inner pores or phases to capture analytes of interest. Through the years, a variety of RAM formats have been created, including internal surface phases, semipermeable phases, and molecularly imprinted polymer phases. Many phases are commercially available through a variety of manufacturers. The use of on-line sample preparation using RAM can increase throughput, recovery, and ease of use for sample preparation of complex biological matrices. The state-of-the-art with respect to production and use of these media for a variety of applications is covered. PMID- 23813689 TI - Discriminative analysis of mild Alzheimer's disease and normal aging using volume of hippocampal subfields and hippocampal mean diffusivity: an in vivo magnetic resonance imaging study. AB - BACKGROUND: Studies discovered that the hippocampal subfields are differentially affected by pathological damage, and magnetic resonance (MR) diffusion tensor imaging parameters might be more sensitive measures of early degeneration in Alzheimer's disease (AD) than conventional MR imaging techniques. The purpose of this study was to evaluate the significance of the volume of hippocampal subfields and the mean diffusivity (MD) value of hippocampus in discrimination between mild AD and normal aging. METHODS: A total of 29 patients with mild AD and 30 normal aging were scanned. Binary logistic regression analysis was applied to assess the diagnostic significance of the volumes of hippocampal subfields and the MD value of hippocampus. RESULTS: All hippocampal subfields except right tail atrophied significantly in the mild AD group (P < .05). The relative volumes of right CA1 and subiculum subfields entered the binary logistic regression model. The accuracy was 91.8%, which was improved to 93.9% as the MD value of right hippocampus entered the model. CONCLUSION: Atrophy was present in almost all hippocampal subfields at mild AD stage. The volumes of CA1 and subiculum were of the most diagnostic significance in discrimination of mild AD, which can be improved by the combination of volume and diffusivity analysis. PMID- 23813690 TI - Coping Strategy and Caregiver Burden Among Caregivers of Patients With Dementia. AB - BACKGROUND: This study aims to examine whether coping strategies employed by caregivers are related to distinct symptoms of patients with dementia and to investigate the associations between burden and coping among caregivers of patients with dementia. METHODS: A cross-sectional study design was used. A total of 57 caregivers of patients with dementia were enrolled. Coping strategies were assessed using the Ways of Coping Checklist, and burden was assessed using the Chinese version of Caregiver Burden Inventory. Correlations between coping and patients' behavior or memory problems were examined. Severities of behavior and memory problems were adjusted to examine the correlations between caregiver burden and coping strategies. RESULTS: The patients' disruptive behavior problems were associated with avoidance, and depression problems were associated with avoidance and wishful thinking. After adjusting for severity of behavior problems, coping strategies using avoidance were positively correlated with caregiver burden. CONCLUSIONS: Emotion-focused coping strategies are a marker of caregiver burden. PMID- 23813691 TI - A Control-Based Multidimensional Approach to the Role of Optimism in the Use of Dementia Day Care Services. AB - We examined whether grounded optimism and external locus of control are associated with admission to dementia day care centers (DCCs). A total of 130 informal caregivers were recruited from the Alzheimer's Association in Salamanca (northwest Spain). All caregivers completed an assessment protocol that included the Battery of Generalized Expectancies of Control Scales (BEEGC-20, acronym in Spanish) as well as depression and burden measures. The decision of the care setting at baseline assessment (own home vs DCC) was considered the main outcome measure in the logistic regression analyses. Grounded optimism was a preventive factor for admission (odds ratio [OR]: 0.34 and confidence interval [CI]: 0.15 0.75), whereas external locus of control (OR: 2.75, CI: 1.25-6.03) increased the probabilities of using DCCs. Depression mediated the relationship between optimism and DCCs, but this effect was not consistent for burden. Grounded optimism promotes the extension of care at home for patients with dementia. PMID- 23813692 TI - Clinical Subtypes of Frontotemporal Dementia. AB - Frontotemporal dementia (FTD) was one of the lesser known dementias until the recent advancements revealing its genetic and pathological foundation. This common neurodegenerative disorder has three clinical subtypes- behavioral, semantic and progressive non fluent aphasia. The behavioral variant mostly exhibits personality changes, while the other two encompass various language deficits. This review discusses the basic pathology, genetics, clinical and histological presentation and the diagnosis of the 3 subtypes. It also deliberates the different therapeutic modalities currently available for frontotemporal dementia and the challenges faced by the caregivers. Lastly it explores the scope of further research into the diagnosis and management of FTD. PMID- 23813693 TI - Musculoskeletal disorders among clerical workers in Los Angeles: a labor management approach. AB - BACKGROUND: Musculoskeletal disorders (MSDs) persist among clerical workers despite ergonomic advances. METHODS: A cross-sectional survey among 2,310 clerical workers investigated MSD cases, defined as musculoskeletal discomfort and seeking treatment for that discomfort in the past 12 months. A modified Poisson regression model was adopted to assess the association between work and individual factors and the risk of MSDs. RESULTS: Over half of respondents reported musculoskeletal discomfort. The prevalence of MSD cases was: 37.2% neck/shoulders, 21.7% upper extremities, 18% lower extremities, and 34.3% back region. Elevated risk of MSDs was associated with less workstation adjustability; work schedule, gender, age, and BMI were also significant. Positive trends were observed between computer use and MSDs for the neck/shoulder region and the effect was amplified among those reporting insufficient workstation adjustability and lacking computer ergonomics training. CONCLUSIONS: Results demonstrate the need to limit continuous computer use and to improve the human-machine interface through adjustable workstations and worker training to enhance use of adjustable features. PMID- 23813694 TI - Tungsten oxide buffer layers fabricated in an inert sol-gel process at room temperature for blue organic light-emitting diodes. AB - WO3 deposition from tungsten ethoxide precursor solutions at room temperature is demonstrated. The W(OEt)6 precursor can be converted under inert conditions and hence avoids sample contamination with oxygen, opening a pathway to more stable devices. The stoichiometry of all WO3 layers and the optoelectronic performance of the respective SMOLEDs well match thermally evaporated WO3 and its corresponding SMOLEDs. The solution processed WO3 hole injection layers enable the fabrication of blue phosphorescent OLEDs with low onset voltage and current efficiencies of up to 14 cd A(-1) . PMID- 23813695 TI - A comparison of pragmatic abilities of children who are deaf or hard of hearing and their hearing peers. AB - Pragmatic skills are the key to a satisfying and sustained conversation. Such conversation is critical for the development of meaningful friendships. Previous studies have investigated the conversational skills of deaf children while interacting with adults or when interacting with peers in structured referential tasks. There are few published studies that have compared the pragmatic skills of children who are deaf or hard of hearing (D/HH) in free conversation with their hearing peers. In this study, the conversational skills of 31 children who are D/HH when interacting with a hearing friend were compared with those of 31 pairs of hearing children. Findings suggest that school-aged children (Years 3-6 of study; aged 8-12 years) who are D/HH have a wide range of pragmatic skills that they use effectively when conversing with their hearing peers. Specifically, these children asked more questions, made more personal comments, initiated more topics, and took longer turns in their conversations with a hearing friend. In contrast, the conversations between hearing peers were very balanced with similar topic initiation, length of turn, numbers of questions, personal comments, and minimal answers. These findings will help teachers to provide support for both pragmatic and social skills in children who are D/HH. PMID- 23813696 TI - Bismuth(V)-mediated thioglycoside activation. PMID- 23813697 TI - Prostate cancer cells differ in testosterone accumulation, dihydrotestosterone conversion, and androgen receptor signaling response to steroid 5alpha-reductase inhibitors. AB - BACKGROUND: Blocking 5alpha-reductase-mediated testosterone conversion to dihydrotestosterone (DHT) with finasteride or dutasteride is the driving hypothesis behind two prostate cancer prevention trials. Factors affecting intracellular androgen levels and the androgen receptor (AR) signaling axis need to be examined systematically in order to fully understand the outcome of interventions using these drugs. METHODS: The expression of three 5alpha reductase isozymes, as determined by immunohistochemistry and qRT-PCR, was studied in five human prostate cancer cell lines. Intracellular testosterone and DHT were analyzed using mass spectrometry. A luciferase reporter assay and AR regulated genes were used to evaluate the modulation of AR activity. RESULTS: Prostate cancer cells were capable of accumulating testosterone to a level 15-50 times higher than that in the medium. The profile and expression of 5alpha reductase isozymes did not predict the capacity to convert testosterone to DHT. Finasteride and dutasteride were able to depress testosterone uptake in addition to lowering intracellular DHT. The inhibition of AR activity following drug treatment often exceeded the expected response due to reduced availability of DHT. The ability to maintain high intracellular testosterone might compensate for the shortage of DHT. CONCLUSIONS: The biological effect of finasteride or dutasteride appears to be complex and may depend on the interplay of several factors, which include testosterone turnover, enzymology of DHT production, ability to use testosterone and DHT interchangeably, and propensity of cells for off-target AR inhibitory effect. PMID- 23813698 TI - Empirical research on the ethics of genomic research. PMID- 23813699 TI - Maternal dietary fat intake in association with autism spectrum disorders. AB - Our goal in this study was to determine whether maternal fat intake before or during pregnancy was associated with risk of autism spectrum disorder (ASD) in the offspring. Our primary analysis included 317 mothers who reported a child with ASD and 17,728 comparison mothers from the Nurses' Health Study II (index births in 1991-2007). Dietary information was collected prospectively through a validated food frequency questionnaire. Binomial regression was used to estimate crude and adjusted risk ratios. Maternal intake of linoleic acid was significantly inversely associated with ASD risk in offspring, corresponding to a 34% reduction in risk in the highest versus lowest quartiles of intake. Mothers in the lowest 5% of omega-3 fatty acid intake had a significant increase in offspring ASD risk as compared with the remaining distribution (risk ratio = 1.53, 95% confidence interval: 1.00, 2.32); this association was also seen in the subgroup of women (86 cases and 5,798 noncases) for whom dietary information during pregnancy was available (risk ratio = 2.42, 95% confidence interval: 1.19, 4.91). Thus, variations in intake of polyunsaturated fats within the range commonly observed among US women could affect fetal brain development and ASD risk. Because the number of women with diet assessed during pregnancy was small, however, these results should be interpreted cautiously. PMID- 23813700 TI - Associations of Tai Chi, walking, and jogging with mortality in Chinese men. AB - Moderate-intensity exercise has attracted considerable attention because of its safety and many health benefits. Tai Chi, a form of mind-body exercise that originated in ancient China, has been gaining popularity. Practicing Tai Chi may improve overall health and well-being; however, to our knowledge, no study has evaluated its relationship with mortality. We assessed the associations of regular exercise and specifically participation in Tai Chi, walking, and jogging with total and cause-specific mortality among 61,477 Chinese men in the Shanghai Men's Health Study (2002-2009). Information on exercise habits was obtained at baseline using a validated physical activity questionnaire. Deaths were ascertained through biennial home visits and linkage with a vital statistics registry. During a mean follow-up of 5.48 years, 2,421 deaths were identified. After adjustment for potential confounders, men who exercised regularly had a hazard ratio for total mortality of 0.80 (95% confidence interval: 0.74, 0.87) compared with men who did not exercise. The corresponding hazard ratios were 0.80 (95% confidence interval: 0.72, 0.89) for practicing Tai Chi, 0.77 (95% confidence interval: 0.69, 0.86) for walking, and 0.73 (95% confidence interval: 0.59, 0.90) for jogging. Similar inverse associations were also found for cancer and cardiovascular mortality. The present study provides the first evidence that, like walking and jogging, practicing Tai Chi is associated with reduced mortality. PMID- 23813701 TI - Changes in fish consumption in midlife and the risk of coronary heart disease in men and women. AB - Without data from randomized trials, the long-term effects of fish consumption on coronary heart disease (CHD) need to be inferred from observational studies. We estimated CHD risk under different hypothetical interventions on fish consumption during mid- and later life in 2 prospective US cohorts of 25,797 men in the Health Professionals Follow-Up Study and 53,772 women in the Nurses' Health Study. Participants provided information on risk factors and disease every 2 years and on diet every 4 years. We adjusted for baseline and time-varying risk factors for CHD by using the parametric g-formula (where g stands for "generalized"). We observed 1,865 incident CHD cases among men (in 1990-2008) and 1,891 CHD cases among women (in 1986-2008). The risk ratios for CHD when comparing the risk if everyone had consumed at least 2 servings of fish per week with the risk if no one consumed fish during the follow-up periods were 1.03 (95% confidence interval: 0.90, 1.15) for men and 0.87 (95% confidence interval: 0.76, 0.98) for women. Our results suggest that increasing fish consumption to at least 2 servings per week in mid- or later life may lower CHD risk in women but not in men. Our analytical approach allowed us to explicitly specify hypothetical interventions and to assess the effectiveness of dietary changes in midlife. PMID- 23813702 TI - Estimated kidney function based on serum cystatin C and risk of subsequent coronary artery calcium in young and middle-aged adults with preserved kidney function: results from the CARDIA study. AB - Whether kidney dysfunction is associated with coronary artery calcium (CAC) in young and middle-aged adults who have a cystatin C-derived estimated glomerular filtration rate (eGFRcys) greater than 60 mL/min/1.73 m(2) is unknown. In the Coronary Artery Risk Development in Young Adults (CARDIA) cohort (recruited in 1985 and 1986 in Birmingham, Alabama; Chicago, Illinois; Minneapolis, Minnesota; and Oakland, California), we examined 1) the association of eGFRcys at years 10 and 15 and detectable CAC over the subsequent 5 years and 2) the association of change in eGFRcys and subsequent CAC, comparing those with stable eGFRcys to those whose eGFRcys increased (>3% annually over 5 years), declined moderately (3%-5%), or declined rapidly (>5%). Generalized estimating equation Poisson models were used, with adjustment for age, sex, race, educational level, income, family history of coronary artery disease, diabetes, body mass index, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and tobacco use. Among 3,070 participants (mean age 35.6 (standard deviation, 4.1) years and mean eGFRcys 106.7 (standard deviation, 18.5) mL/min/1.73 m(2)), 529 had detectable CAC. Baseline eGFRcys was not associated with CAC. Moderate eGFRcys decline was associated with a 33% greater relative risk of subsequent CAC (95% confidence interval: 5, 68; P = 0.02), whereas rapid decline was associated with a 51% higher relative risk (95% confidence interval: 10, 208; P = 0.01) in adjusted models. In conclusion, among young and middle-aged adults with eGFRcys greater than 60 mL/min/1.73 m(2), annual decline in eGFRcys is an independent risk factor for subsequent CAC. PMID- 23813703 TI - Risk of pelvic inflammatory disease following Chlamydia trachomatis infection: analysis of prospective studies with a multistate model. AB - Our objective in this study was to estimate the probability that a Chlamydia trachomatis (CT) infection will cause an episode of clinical pelvic inflammatory disease (PID) and the reduction in such episodes among women with CT that could be achieved by annual screening. We reappraised evidence from randomized controlled trials of screening and controlled observational studies that followed untreated CT-infected and -uninfected women to measure the development of PID. Data from these studies were synthesized using a continuous-time Markov model which takes into account the competing risk of spontaneous clearance of CT. Using a 2-step piecewise homogenous Markov model that accounts for the distinction between prevalent and incident infections, we investigated the possibility that the rate of PID due to CT is greater during the period immediately following infection. The available data were compatible with both the homogenous and piecewise homogenous models. Given a homogenous model, the probability that a CT episode will cause clinical PID was 0.16 (95% credible interval (CrI): 0.06, 0.25), and annual screening would prevent 61% (95% CrI: 55, 67) of CT-related PID in women who became infected with CT. Assuming a piecewise homogenous model with a higher rate during the first 60 days, corresponding results were 0.16 (95% CrI: 0.07, 0.26) and 55% (95% CrI: 32, 72), respectively. PMID- 23813704 TI - Association of nocturnal melatonin secretion with insulin resistance in nondiabetic young women. AB - Exogenous melatonin ameliorates insulin resistance in animals, while among humans, polymorphisms in the melatonin receptor gene are associated with insulin resistance. We aimed to investigate the association of endogenous nocturnal melatonin secretion with insulin resistance in humans. We analyzed the association between endogenous nocturnal melatonin secretion, estimated by measuring the main melatonin metabolite, 6-sulfatoxymelatonin, from the first morning urinary void, and the prevalence of insulin resistance based on fasting blood samples collected in a cross-sectional study of 1,075 US women (1997-1999) without diabetes, hypertension, or malignancy. Urinary 6-sulfatoxymelatonin level was standardized to urinary creatinine level; insulin resistance was defined as an insulin sensitivity index value (using the McAuley formula) less than 7.85. Logistic regression models included adjustment for age, body mass index, smoking, physical activity, alcohol intake, dietary glycemic index, family history of diabetes mellitus, blood pressure, plasma total cholesterol, uric acid, and estimated glomerular filtration rate. Higher nocturnal melatonin secretion was inversely associated with insulin levels and insulin resistance. In fully adjusted models, the odds ratio for insulin resistance was 0.45 (95% confidence interval: 0.28, 0.74) among women in the highest quartile of urinary 6 sulfatoxymelatonin:creatinine ratio compared with women in the lowest quartile. Nocturnal melatonin secretion is independently and inversely associated with insulin resistance. PMID- 23813706 TI - Kicking against the pricks: vaccine sceptics have a different social orientation. AB - BACKGROUND: In any country, part of the population is sceptical about the utility of vaccination. To develop successful vaccination programmes, it is important to study and understand the defining characteristics of vaccine sceptics. Research till now mainly focused either on the underlying motives of vaccine refusal, or on socio-demographic differences between vaccine sceptics and non-sceptics. It remained till now unexplored whether both groups differ in terms of basic psychological dispositions. METHODS: We held a population survey in a representative sample of the population in Flanders, Belgium (N = 1050), in which we investigated whether respondents' attitude to vaccination was associated with their basic disposition toward other community members or society in general, as measured by the Triandis and Gelfand social orientation scale. RESULTS: We found that sceptics and non-sceptics have a different social orientation, even when several variables are controlled for. More specifically, vaccine sceptics scored significantly lower on both horizontal individualism and horizontal collectivism, indicating a lower disposition to see others as equals. CONCLUSION: These findings need confirmation in the context of different countries. Such insights can be valuable to optimize the design of effective communication strategies on vaccination programmes. PMID- 23813707 TI - Validity of self-reported utilization of physician services: a population study. AB - BACKGROUND: Health care utilization is of central interest in epidemiology, and most of the studies rely on self-report. The objectives of this study were to assess the validity of self-reported utilization of general practitioner and specialist physician by correlating self-reported utilization with registered services utilization, and to determine the factors related to that validity. METHODS: The 1997 Belgian National Health Interview Survey (BNHIS) was linked with registered medical utilization data provided by the Belgian Health Insurance Funds. Valid information on general practitioner and specialist physician utilization during the past 2 months was found for 5869 participants at the BNHIS who were aged >=25 years. Intra-class correlation coefficients were used to determine the rate of agreement, and multinomial logistic regression to model factors influencing under- and over-reporting. RESULTS: The results demonstrated a substantial agreement between the self-reported and registered general practitioner contacts, and only a minor bias was found towards under-reporting. There was no significant difference between mean self-reported and registered specialist physician utilization, but the agreement was rather moderate. Gender, age, country of birth, self-rated health, number of chronic illnesses, having functional limitations and having mental health problems, were associated with under- and/or over-reporting. CONCLUSION: Studies that aim to compare the utilization of different socio-demographic groups have to take into account that the reporting errors vary by respondents characteristics. PMID- 23813705 TI - Should modest elevations in prostate-specific antigen, International Prostate Symptom Score, or their rates of increase over time be used as surrogate measures of incident benign prostatic hyperplasia? AB - Although surrogate measures of benign prostatic hyperplasia (BPH) are often used in epidemiologic studies, their performance characteristics are unknown. Using data from the Prostate Cancer Prevention Trial (n = 5,986), we evaluated prostate specific antigen (PSA), International Prostate Symptom Score (IPSS), and their rates of change as predictors of incident BPH. BPH (n = 842 cases) was defined as medical or surgical treatment or at least 2 IPSS of 15 or higher. Proportional hazards models were used to measure the associations of baseline PSA, IPSS, and their velocities over 2 years with BPH risk, and time-dependent receiver operating characteristic curves were used to measure their discriminatory performance. Unit increases in PSA, IPSS, and IPSS velocity were associated with 34%, 35%, and 29% (all P < 0.001) increases in BPH risk, respectively. The areas under the receiver-operating characteristic curves were significantly greater than 0.5 for PSA (0.58, 95% confidence interval (CI): 0.56, 0.60), IPSS (0.77, 95% CI: 0.75, 0.78), and IPSS velocity (0.63, 95% CI: 0.61, 0.65); however there were no cut points at which sensitivity and specificity were both above 75%. We concluded that moderate elevations in PSA, IPSS, or their rates of change should not be used as surrogate measures of incident BPH. PMID- 23813708 TI - Prevalence and factors associated with use of smokeless tobacco in young Swiss men. AB - BACKGROUND: Smokeless tobacco is of increasing interest to public health researchers and policy makers. This study aims to measure prevalence of smokeless tobacco use (nasal dry snuff, snus and chewing tobacco) among young Swiss men, and to describe its correlates. METHODS: We invited 13 245 young men to participate in this survey on socio-economic and substance use data. Response rate was 45.2%. We included 5720 participants. Descriptive statistics and multivariable-adjusted logistic regression were performed. RESULTS: Mean age of participants was 19.5 years. Self-reported use once a month or more often was 8% for nasal dry snuff, 3% for snus and negligible for chewing tobacco. In multivariable-adjusted logistic regression, the odds for nasal dry snuff use increased in non daily smokers [odds ratio (OR) 2.41, 95% confidence interval (CI) 1.90-3.05], compared with non smokers, participants reporting risky weekly drinking volume (OR 3.93, 95% CI 1.86-8.32), compared with abstinents, and binge drinking once a month or more often (OR 7.41, 95% CI 4.11-13.38), compared with never binge drinking. Nasal dry snuff use was positively associated with higher BMI, average or above family income and German language, compared with French, and negatively associated with academic higher education, compared with non higher education, and occasional cannabis use, compared with no cannabis use. Correlates of snus were similar to those of nasal dry snuff. CONCLUSION: One in 12 young Swiss men use nasal dry snuff and 3% use snus. Consumption of smokeless tobacco is associated with a cluster of other risky behaviours, especially binge drinking. PMID- 23813709 TI - Trends of overweight and obesity, physical activity and sedentary behaviour in Czech schoolchildren: HBSC study. AB - BACKGROUND: The decline of physical activity (PA) and the increased prevalence of overweight and obese children have been discussed worldwide. This study assessed the trends in the prevalence of overweight and obesity, PA and sedentary behaviour in Czech school-aged children. METHODS: A cross-sectional questionnaire from the Czech Republic was administered in cycles in 2002, 2006 and 2010 under the Health Behaviour in School-Aged Children (HBSC) study. In the study, 14,219 children aged 11-15 years participated. RESULTS: In comparison with 2002, there is a significant increase (P < 0.01) of obese and overweight boys in 2010. The same trend has been recorded in girls, except those in the 13-year-old group. There has been a significant decline (P < 0.05) in meeting PA recommendations in 11-year-old girls and boys and in 13-year-old girls when comparing the 2006 and 2002 data. In 2010, we found a non-significant increase or stagnation of the share of children meeting the PA recommendation compared with 2006. We found an increasing length of sedentary time for children. There were significant associations between>2 h being spent sitting by a TV or PC and consuming fruit and vegetables (negative associations) or sweets and sweetened lemonades (positive associations). CONCLUSIONS: An increasing percentage of obese or overweight children, increased sedentary time and a decline or stagnation of the proportion of children meeting recommendations for PA were found among Czech schoolchildren. Future research should evaluate PA recommendations with respect to gender, age and effective intervention approach to reduce the obesity incidence in childhood. PMID- 23813711 TI - Factors associated with self-cutting as a method of self-harm: findings from the Irish National Registry of Deliberate Self-Harm. AB - BACKGROUND: Research suggests that patients presenting to hospital with self cutting differ from those with intentional overdose in demographic and clinical characteristics. However, large-scale national studies comparing self-cutting patients with those using other self-harm methods are lacking. We aimed to compare hospital-treated self-cutting and intentional overdose, to examine the role of gender in moderating these differences, and examine the characteristics and outcomes of those patients presenting with combined self-cutting and overdose. METHODS: Between 2003 and 2010, the Irish National Registry of Deliberate Self-Harm recorded 42,585 self-harm presentations to Irish hospital emergency departments meeting the study inclusion criteria. Data were obtained on demographic and clinical characteristics by independent data registration officers. RESULTS: Compared with overdose only, involvement of self-cutting (with or without overdose) was significantly more common in males than females, with an overrepresentation of males aged <35 years. Independent of gender, involvement of self-cutting (with or without overdose) was significantly associated with younger age, city residence, repetition within 30 days and repetition within a year (females only). Factors associated with self-cutting as the sole method were no fixed abode/living in an institution, presenting outside 9 a.m. to 5 p.m., not consuming alcohol and repetition between 31 days and 1 year (males only). CONCLUSION: The demographic and clinical differences between self-harm patients underline the presence of different subgroups with implications for service provision and prevention of repeated self-harm. Given the relationship between self-cutting and subsequent repetition, service providers need to ensure that adequate follow-up arrangements and supports are in place for the patient. PMID- 23813710 TI - Awareness and uptake of colorectal, breast, cervical and prostate cancer screening tests in Spain. AB - BACKGROUND: We aim to describe levels of awareness and uptake of colorectal, breast, cervical and prostate cancer screening tests and to analyze the association to socio-demographic and health-related variables. METHODS: Population-based cross-sectional study conducted using a home-based personal interview survey on a nationwide representative sample (n = 7938) of population aged >=18 years (Oncobarometro Survey). Awareness was assessed by asking participants: Now I am going to mention several medical tests for cancer detection, please tell me if you already know about them or if this is the first time you have heard of them? The tests mentioned were faecal occult blood test (FOBT), mammography, Pap smear and prostate-specific antigen (PSA). Cancer screening uptake was assessed by asking participants whether they had received tests within the previous 2 years. RESULTS: Awareness rates of 38.55% for FOBT, 95.03% for mammography, 70.84% for Pap smears and 54.72% for PSA were found. Uptake mammography was 74.46%, Pap smears 65.57%, PSA 35.19% and FOBT 9.40%. Factors such as immigration status, lower educational level or income and not suffering from chronic conditions are negative predictors for uptake. CONCLUSIONS: Awareness and uptake results showed acceptable figures for mammography, moderate for Pap smears and unacceptably low for FOBT. Inequalities exist in uptake of cancer screening. It is necessary to develop public health educational programmes, especially for the vulnerable populations, aiming to inform and motivate them to use screening services on a regular basis. Our data suggest that although PSA is not recommended, this opportunistic screening is frequently used in Spain. PMID- 23813712 TI - Use of informal and formal care among community dwelling dependent elderly in Spain. AB - BACKGROUND: Faced with increased public spending for care, knowledge of the determinants of the choices between informal and formal care is of particular importance for estimating the need for care in the future. METHODS: Using a representative sample of Spanish dependent elderly from the Disabilities, Independence and Dependency Situations Survey (DIDSS) 2008, we compare the factors associated with the reception of informal, formal and mixed care. The study included 10 703 dependent persons living at home aged >= 65 years. RESULTS: Overall, the percentage of those receiving only informal care was high in Spain, 47.5%. Formal care was most often received in combination with informal care (9.8%) than alone (4.9%). Five out of the seven factors analysed were found to influence the reception of all types of care: age, gender, income, self-rated health and suffering a chronic condition. CONCLUSIONS: There is a high coincidence among how factors affect the reception of care although some differences can be noted. Curiously, a high income level and the availability of informal care (as measured by living with a partner) can negatively affect the reception of only formal care. Living in a capital can also have an impact on the type of care a dependent elderly person receives. PMID- 23813713 TI - Widening educational differences in cancer survival in Norway. AB - BACKGROUND: All-cause and cause-specific mortality have long been known to be associated with various indicators of socio-economic status, and social gradients have been shown also for cancer survival. In recent decades, several studies have reported increasing social differentials in mortality rates. This study aims to investigate the development with respect to cancer survival, which has not been done before. METHODS: Discrete-time hazard regression models for cancer deaths among women and men diagnosed with cancer 1970-2007 at age 30-89 were estimated, using register data encompassing the entire Norwegian population. The analysis was based on >200,000 cancer deaths during over 2 million person-years of exposure among >440,000 individuals diagnosed with cancer. RESULTS: There has been an increasing advantage for women of all educational categories when compared with those with only compulsory schooling. No such widening of the educational gap has appeared with respect to cancer survival among men. CONCLUSIONS: Increasing educational differentials in health at the time of diagnosis, health behaviour and cancer treatment seem plausible, and would to some extent accord with the increasing social gaps in all-cause or cause-specific mortality rates that have been reported in other studies. Also, it is not impossible that such trends in the educational gradients in health and treatment are stronger for women than for men, though such sex differences have not been indicated in mortality studies. There is no obvious explanation for the complete absence of change in the education effects among men. PMID- 23813714 TI - Do smoking and fruit and vegetable intake mediate the association between socio economic status and plasma carotenoids? AB - BACKGROUND: The aim was to study whether the association between educational attainment and antioxidant status is mediated by smoking and fruit and vegetable intake. METHODS: Cross-sectional analyses of the Oslo Youth Study 2006 wave were carried out. Information about education, smoking habits and diet was collected by questionnaire for 261 subjects (142 women and 119 men aged 38-42 years). Blood samples, height and weight measurements were taken by the participants' General Practitioner. Blood were analysed for plasma carotenoids. Linear regression analyses were used to examine whether smoking and fruit and vegetable intake mediate the association between education and plasma carotenoids. RESULTS: Educational level was positively associated with beta-cryptoxanthin, alpha carotene and lutein/zeaxanthin, but not with total carotenoids, beta-carotene or lycopene. Education was negatively associated with smoking and positively associated with fruit and vegetable intake. Smoking was negatively associated with beta-cryptoxanthin, and fruit and vegetable intake was positively associated with beta-cryptoxanthin (adjusted for educational level). Moreover, cigarette consumption mediated the association between education and beta-cryptoxanthin by 37%, while fruit and vegetable intake mediated this association by 18%. The total mediation effect was 55%. CONCLUSION: Smoking seemed to be more important as a mediator between education and plasma levels of beta-cryptoxanthin than the intake of fruit and vegetables, but more studies are needed to establish the relative importance of smoking and diet as mediators of the association between education and antioxidant status. PMID- 23813715 TI - Public health, primary care and the 'cluster' model. PMID- 23813716 TI - Immigration and recommended care after a suicide attempt in Europe: equity or bias? AB - This report describes the investigation of care recommendations in the medical system across European countries to immigrants who attempted suicide. Data from seven European countries with 8865 local and 2921 immigrant person-cases were derived from the WHO/EURO Multicentre Study on Suicidal Behaviour and ensuing MONSUE (Monitoring Suicidal Behaviour in Europe) project. The relationship between immigrant status and type of aftercare recommended was analysed with binary logistic regression, adjusting for gender, age, method of attempt and the Centre collecting the data. Clear disparities were identified in the care recommendation practices toward immigrants, compared with hosts, over and above differing policies by the European Centres. PMID- 23813717 TI - Have regional inequalities in life expectancy widened within the European Union between 1991 and 2008? AB - BACKGROUND: Health inequalities have widened within and between many European countries over recent decades, but Europe-wide sub-national trends have been largely overlooked. For regions across the European Union (EU), we assess how geographical inequalities (i.e., between regions) and sociospatial inequalities (i.e., between regions grouped by an area-level measure of average household income) in male and female life expectancy have changed between 1991 and 2008. METHODS: Household income, life expectancy at birth and population count data were obtained for 129 regions (level 2 Nomenclature of Statistical Territorial Units, 'NUTS') in 13 European countries with 1991-2008 data (2008 population = 272 million). We assessed temporal changes in the range of life expectancies, for all regions and for Western and Eastern European regions separately. RESULTS: Between 1991 and 2008, the geographical range of life expectancies found among European regions remained relatively constant, with the exception of life expectancy among male Eastern Europeans, for whom the range widened by 2.8 years. Sociospatial inequalities in life expectancy (1999-2008 data only) remained constant for all regions combined and for Western Europe, but more than doubled in size for male Eastern Europeans. For female Eastern Europeans, life expectancy was unrelated to regional household income. CONCLUSIONS: Regional life-expectancy inequalities in the EU have not narrowed over 2 decades, despite efforts to reduce them. Household income differences across European regions may partly explain these inequalities. As inequalities transcend national borders, reduction efforts may require EU-wide coordination in addition to national efforts. PMID- 23813719 TI - No mutations in CIZ1 in twelve adult-onset primary cervical dystonia families. PMID- 23813718 TI - Is tuberculosis crossing borders at the Eastern boundary of the European Union? AB - BACKGROUND: The Eastern border of the European Union (EU) consists of 10 countries after the expansion of the EU in 2004 and 2007. These 10 countries border to the East to countries with high tuberculosis (TB) notification rates. We analyzed the notification data of Europe to quantify the impact of cross border TB at the Eastern border of the EU. METHODS: We used TB surveillance data of 2010 submitted by 53 European Region countries to the European Centre for Disease Prevention and Control and the World Health Organization Regional Office for Europe. Notified TB cases were stratified by origin of the case (national/foreign). We calculated the contribution of foreign to overall TB notification. RESULTS: In the 10 EU countries located at the EU Eastern border, 618 notified TB cases (1.7% of all notified TB cases) were of foreign origin. Of those 618 TB cases, 173 (28.0%) were from countries bordering the EU to the East. More specifically, 90 (52.0%) were from Russia, 33 (19.1%) from Belarus, 33 (19.1%) from Ukraine, 13 (7.5%) from Moldova and 4 (2.3%) from Turkey. CONCLUSIONS: Currently, migrants contribute little to TB notifications in the 10 EU countries at the Eastern border of the EU, but changes in migration patterns may result in an increasing contribution. Therefore, EU countries at the Eastern border of the EU should strive to provide prompt diagnostic services and adequate treatment of migrants. PMID- 23813720 TI - Captive-housed male cheetahs (Acinonyx jubatus soemmeringii) form naturalistic coalitions: measuring associations and calculating chance encounters. AB - Cheetahs are known to reproduce poorly in captivity and research suggests that the reasons for this are behavioral, rather than physiological. In the wild, male cheetahs remain in stable groups, or coalitions, throughout their lifetime. Appropriate social group housing is important in enhancing welfare and reproductive success in captivity and this study examined the effect of changes in social group composition on the behavior of four male cheetahs: two siblings and two half siblings. During the study, the cheetahs were housed both in pairs and as a group of four, before one male was relocated. The remaining cheetahs were then housed in a trio. Affiliative behaviors were frequently shown within pairs and overt aggression was seldom observed. Association indices were calculated for each cheetah pair and corrected for chance encounters based on data generated from a Monte Carlo simulation. The indices showed that two coalitions existed before the relocated male departed. Following the relocation of one of the half siblings, the remaining cheetahs appeared to form a coalition of three, as the indices of association between the unrelated male and the siblings increased and allogrooming between unrelated individuals was observed. The findings of this study indicate that natural social groupings of male cheetahs can be successfully replicated in captivity, which could potentially improve the chances of reproductive success when they are introduced to female cheetahs. PMID- 23813721 TI - Resistance and behavioural response of Plutella xylostella (Lepidoptera: Plutellidae) populations to Bacillus thuringiensis formulations. AB - BACKGROUND: Insecticide resistance is probably the major cause of control failure of Plutella xylostella (L.) in Brazil. In most production regions, the use of chemicals has been the prevalent method of control, with reduced efficacy through cropping seasons, even for the most recent use of products based on Bacillus thuringiensis (Bt). The current status of the resistance to these products was assessed, as well as the behavioural response of P. xylostella populations to Bt sprays. RESULTS: Most populations of P. xylostella were resistant to Bt products, particularly to Xentari(r)WDG (2-54-fold). Differences in walking characteristics of larvae were variable for most populations, for both Dipel(r)WP and Xentari(r)WDG, but not associated with resistance. Most females preferred to lay eggs on untreated surfaces and showed a reduced proportion of oviposition on treated surfaces that only correlated with resistance to Dipel(r)WP (r = -0.74, P = 0.02). CONCLUSION: Broad and indiscriminate use of Bt-based products has selected Brazilian P. xylostella populations to resistance. Larval movement appears to be a resistance-independent mechanism. Most populations of P. xylostella preferred to lay eggs on Bt-free surfaces, which might be a result of growers' practice of spraying the cabbage head. Reduced oviposition on treated surfaces correlated with physiological resistance, suggesting a behavioural response among the Bt-resistant colonies to Dipel(r)WP. PMID- 23813722 TI - Self-assembly of coronene bisimides: mechanistic insight and chiral amplification. AB - The study of the organization of small pi-conjugated molecules is imperative to understanding and controlling its properties for various applications. Coronene bisimides (CBIs) are potential candidates for novel liquid-crystalline materials and active n-type semiconductor molecules in organic electronics. To understand the self-assembly of this seldom-studied chromophore, we have designed two derivatives of CBIs bearing chiral and achiral 3,4,5-trialkoxyphenyl groups at the imide position, named as CBI-GCH and CBI-GACH, respectively. CBI-GCH self assembles mainly through pi-stacking and van der Waals interactions in nonpolar methylcyclohexane to result in long 1D fibrillar stacks. The mechanism of supramolecular polymerization was probed by using chiroptical studies, which showed an isodesmic pathway for CBI-GCH. The thermodynamic parameters that govern the self-assembly are detailed. CBI-GACH also shows similar self-assembly behavior as its chiral counterpart. X-ray diffraction studies of both molecules reveals a 2D hexagonal columnar arrangement. The coassembly of CBI-GCH and CBI GACH shows chiral amplification (sergeant and soldiers experiment) with saturation at 30-50 % of the chiral derivative, which was further used to study the dynamics of the assembly. Thus, this study presents a rare report of chiral amplification in an isodesmic system. PMID- 23813723 TI - Validation of the Rotterdam MOVE2PC Questionnaire for assessment of nurses' knowledge and opinions on palliative care. AB - The purpose of this study was the psychometric testing of a questionnaire to assess nurses' opinions, subjective norms, perceived difficulties, and knowledge related to palliative care. The 63-item MOVE2PC Questionnaire was tested among 219 nurses in groups differing in education and experience. The intra-rater agreement was moderate to good (k > .5kappamax ), and internal consistency was good (alpha = .77). Construct validity was demonstrated by between-groups differences in knowledge, opinions, and perceived difficulties. Responsiveness was shown by improved scores after an education program. Time of completion was 20 minutes, and 99% skipped at most five items, demonstrating feasibility. Findings support the usefulness of the instrument for assessing nurses' knowledge and views on palliative care. PMID- 23813724 TI - Hemophagocytosis in an adrenal aspirate: histiocytic sarcoma. PMID- 23813725 TI - Blood supply to the human spinal cord: part I. Anatomy and hemodynamics. AB - The arterial network that supplies the human spinal cord, which was once thought to be similar to that of the brain, is in fact much different and more extensive. In this article, the authors attempt to provide a comprehensive review of the literature regarding the anatomy and known hemodynamics of the blood supply to the human spinal cord. Additionally, as the medical literature often fails to provide accurate terminology for the arteries that supply the cord, the authors attempt to categorize and clarify this nomenclature. A complete understanding of the morphology of the arterial blood supply to the human spinal cord is important to anatomists and clinicians alike. PMID- 23813726 TI - The impact of social housing on the labour market status of the disabled. AB - Disability may impact on employment through entitlement to social housing. Estimates of an original dynamic panel data model of disability, labour market and housing tenure transitions in England indicate that up to one-quarter of the lower employment probability of the disabled can be attributed to the effect of qualifying for social housing. Short-lived disabilities can result in long spells in social housing that reduce incentives to participate in the labour market. This suggests that authorities should reform the welfare system and the allocation of social housing to limit the persistent and unfavourable consequences of allocating social housing to the disabled. PMID- 23813727 TI - A case of anorexia nervosa with comorbid Crohn's disease: beneficial effects of anti-TNF-alpha therapy? AB - This case report describes a 26-year-old woman affected by long-lasting anorexia nervosa (AN) and Crohn's disease. Worsening of the bowel illness led to the prescription of immunosuppressive therapy (biologic infliximab for 4 months, followed by adalimumab for 6 months) and referral to our Eating Disorders Unit. Although she initially demonstrated denial of her eating disorder, in a few months she gradually improved her weight and psychopathology. Crohn's disease can worsen AN by modifying hunger and energy expenditure through the effects of TNF alpha and IL-6, pro-inflammatory cytokines which moderate leptin and melanocortin signaling. Previous studies have observed the antidepressant effects of TNF antagonist in patients with treatment-resistant depression with high baseline inflammatory biomarkers. Our case report suggests that future studies are needed to clarify the existence, patterns, and extent of increased inflammatory markers in patients with AN, and whether they determine clinical features or identify subgroups of patients. Potential therapeutic significance of above issues remains to be determined. PMID- 23813728 TI - Effect of the abortive infection mechanism and type III toxin/antitoxin system AbiQ on the lytic cycle of Lactococcus lactis phages. AB - To survive in phage-containing environments, bacteria have evolved an array of antiphage systems. Similarly, phages have overcome these hurdles through various means. Here, we investigated how phages are able to circumvent the Lactococcus lactis AbiQ system, a type III toxin-antitoxin with antiviral activities. Lactococcal phage escape mutants were obtained in the laboratory, and their genomes were sequenced. Three unrelated genes of unknown function were mutated in derivatives of three distinct lactococcal siphophages: orf38 of phage P008, m1 of phage bIL170, and e19 of phage c2. One-step growth curve experiments revealed that the phage mutations had a fitness cost while transcriptional analyses showed that AbiQ modified the early-expressed phage mRNA profiles. The L. lactis AbiQ system was also transferred into Escherichia coli MG1655 and tested against several coliphages. While AbiQ was efficient against phages T4 (Myoviridae) and T5 (Siphoviridae), escape mutants of only phage 2 (Myoviridae) could be isolated. Genome sequencing revealed a mutation in gene orf210, a putative DNA polymerase. Taking these observations together, different phage genes or gene products are targeted or involved in the AbiQ phenotype. Moreover, this antiviral system is active against various phage families infecting Gram-positive and Gram-negative bacteria. A model for the mode of action of AbiQ is proposed. PMID- 23813729 TI - Caffeine junkie: an unprecedented glutathione S-transferase-dependent oxygenase required for caffeine degradation by Pseudomonas putida CBB5. AB - Caffeine and other N-methylated xanthines are natural products found in many foods, beverages, and pharmaceuticals. Therefore, it is not surprising that bacteria have evolved to live on caffeine as a sole carbon and nitrogen source. The caffeine degradation pathway of Pseudomonas putida CBB5 utilizes an unprecedented glutathione-S-transferase-dependent Rieske oxygenase for demethylation of 7-methylxanthine to xanthine, the final step in caffeine N demethylation. The gene coding this function is unusual, in that the iron-sulfur and non-heme iron domains that compose the normally functional Rieske oxygenase (RO) are encoded by separate proteins. The non-heme iron domain is located in the monooxygenase, ndmC, while the Rieske [2Fe-2S] domain is fused to the RO reductase gene, ndmD. This fusion, however, does not interfere with the interaction of the reductase with N1- and N3-demethylase RO oxygenases, which are involved in the initial reactions of caffeine degradation. We demonstrate that the N7-demethylation reaction absolutely requires a unique, tightly bound protein complex composed of NdmC, NdmD, and NdmE, a novel glutathione-S-transferase (GST). NdmE is proposed to function as a noncatalytic subunit that serves a structural role in the complexation of the oxygenase (NdmC) and Rieske domains (NdmD). Genome analyses found this gene organization of a split RO and GST gene cluster to occur more broadly, implying a larger function for RO-GST protein partners. PMID- 23813730 TI - Identification of Coxiella burnetii type IV secretion substrates required for intracellular replication and Coxiella-containing vacuole formation. AB - Coxiella burnetii, the etiological agent of acute and chronic Q fever in humans, is a naturally intracellular pathogen that directs the formation of an acidic Coxiella-containing vacuole (CCV) derived from the host lysosomal network. Central to its pathogenesis is a specialized type IVB secretion system (T4SS) that delivers effectors essential for intracellular replication and CCV formation. Using a bioinformatics-guided approach, 234 T4SS candidate substrates were identified. Expression of each candidate as a TEM-1 beta-lactamase fusion protein led to the identification of 53 substrates that were translocated in a Dot/Icm-dependent manner. Ectopic expression in HeLa cells revealed that these substrates trafficked to distinct subcellular sites, including the endoplasmic reticulum, mitochondrion, and nucleus. Expression in Saccharomyces cerevisiae identified several substrates that were capable of interfering with yeast growth, suggesting that these substrates target crucial host processes. To determine if any of these T4SS substrates are necessary for intracellular replication, we isolated 20 clonal T4SS substrate mutants using the Himar1 transposon and transposase. Among these, 10 mutants exhibited defects in intracellular growth and CCV formation in HeLa and J774A.1 cells but displayed normal growth in bacteriological medium. Collectively, these results indicate that C. burnetii encodes a large repertoire of T4SS substrates that play integral roles in host cell subversion and CCV formation and suggest less redundancy in effector function than has been found in the comparative Legionella Dot/Icm model. PMID- 23813731 TI - Gene ercA, encoding a putative iron-containing alcohol dehydrogenase, is involved in regulation of ethanol utilization in Pseudomonas aeruginosa. AB - Several two-component regulatory systems are known to be involved in the signal transduction pathway of the ethanol oxidation system in Pseudomonas aeruginosa ATCC 17933. These sensor kinases and response regulators are organized in a hierarchical manner. In addition, a cytoplasmic putative iron-containing alcohol dehydrogenase (Fe-ADH) encoded by ercA (PA1991) has been identified to play an essential role in this regulatory network. The gene ercA (PA1991) is located next to ercS, which encodes a sensor kinase. Inactivation of ercA (PA1991) by insertion of a kanamycin resistance cassette created mutant NH1. NH1 showed poor growth on various alcohols. On ethanol, NH1 grew only with an extremely extended lag phase. During the induction period on ethanol, transcription of structural genes exa and pqqABCDEH, encoding components of initial ethanol oxidation in P. aeruginosa, was drastically reduced in NH1, which indicates the regulatory function of ercA (PA1991). However, transcription in the extremely delayed logarithmic growth phase was comparable to that in the wild type. To date, the involvement of an Fe-ADH in signal transduction processes has not been reported. PMID- 23813732 TI - Polyphosphate storage during sporulation in the gram-negative bacterium Acetonema longum. AB - Using electron cryotomography, we show that the Gram-negative sporulating bacterium Acetonema longum synthesizes high-density storage granules at the leading edges of engulfing membranes. The granules appear in the prespore and increase in size and number as engulfment proceeds. Typically, a cluster of 8 to 12 storage granules closely associates with the inner spore membrane and ultimately accounts for ~7% of the total volume in mature spores. Energy dispersive X-ray spectroscopy (EDX) analyses show that the granules contain high levels of phosphorus, oxygen, and magnesium and therefore are likely composed of polyphosphate (poly-P). Unlike the Gram-positive Bacilli and Clostridia, A. longum spores retain their outer spore membrane upon germination. To explore the possibility that the granules in A. longum may be involved in this unique process, we imaged purified Bacillus cereus, Bacillus thuringiensis, Bacillus subtilis, and Clostridium sporogenes spores. Even though B. cereus and B. thuringiensis contain the ppk and ppx genes, none of the spores from Gram positive bacteria had granules. We speculate that poly-P in A. longum may provide either the energy or phosphate metabolites needed for outgrowth while retaining an outer membrane. PMID- 23813733 TI - Cluster of genes that encode positive and negative elements influencing filament length in a heterocyst-forming cyanobacterium. AB - The filamentous, heterocyst-forming cyanobacteria perform oxygenic photosynthesis in vegetative cells and nitrogen fixation in heterocysts, and their filaments can be hundreds of cells long. In the model heterocyst-forming cyanobacterium Anabaena sp. strain PCC 7120, the genes in the fraC-fraD-fraE operon are required for filament integrity mainly under conditions of nitrogen deprivation. The fraC operon transcript partially overlaps gene all2395, which lies in the opposite DNA strand and ends 1 bp beyond fraE. Gene all2395 produces transcripts of 1.35 kb (major transcript) and 2.2 kb (minor transcript) that overlap fraE and whose expression is dependent on the N-control transcription factor NtcA. Insertion of a gene cassette containing transcriptional terminators between fraE and all2395 prevented production of the antisense RNAs and resulted in an increased length of the cyanobacterial filaments. Deletion of all2395 resulted in a larger increase of filament length and in impaired growth, mainly under N2-fixing conditions and specifically on solid medium. We denote all2395 the fraF gene, which encodes a protein restricting filament length. A FraF-green fluorescent protein (GFP) fusion protein accumulated significantly in heterocysts. Similar to some heterocyst differentiation-related proteins such as HglK, HetL, and PatL, FraF is a pentapeptide repeat protein. We conclude that the fraC-fraD-fraE<-fraF gene cluster (where the arrow indicates a change in orientation), in which cis antisense RNAs are produced, regulates morphology by encoding proteins that influence positively (FraC, FraD, FraE) or negatively (FraF) the length of the filament mainly under conditions of nitrogen deprivation. This gene cluster is often conserved in heterocyst-forming cyanobacteria. PMID- 23813734 TI - Residue substitutions near the redox center of Bacillus subtilis Spx affect RNA polymerase interaction, redox control, and Spx-DNA contact at a conserved cis acting element. AB - Spx, a member of the ArsC protein family, is a regulatory factor that interacts with RNA polymerase (RNAP). It is highly conserved in Gram-positive bacteria and controls transcription on a genome-wide scale in response to oxidative stress. The structural requirements for RNAP interaction and promoter DNA recognition by Spx were examined through mutational analysis. Residues near the CxxC redox disulfide center of Spx functioned in RNAP alpha subunit interaction and in promoter DNA binding. R60E and C10A mutants were shown previously to confer defects in transcriptional activation, but both were able to interact with RNAP. R92, which is conserved in ArsC-family proteins, is likely involved in redox control of Spx, as the C10A mutation, which blocks disulfide formation, was epistatic to the R92A mutation. The R91A mutation reduced transcriptional activation and repression, suggesting a defect in RNAP interaction, which was confirmed by interaction assays using an epitope-tagged mutant protein. Protein DNA cross-linking detected contact between RNAP-bound Spx and the AGCA element at -44 that is conserved in Spx-controlled genes. This interaction caused repositioning of the RNAP sigmaA subunit from a -35-like element upstream of the trxB (thioredoxin reductase) promoter to positions -36 and -11 of the core promoter. The study shows that RNAP-bound Spx contacts a conserved upstream promoter sequence element when bound to RNAP. PMID- 23813735 TI - Detection and characterization of miniature inverted-repeat transposable elements in "Candidatus Liberibacter asiaticus". AB - Miniature inverted-repeat transposable elements (MITEs) are nonautonomous transposons (devoid of the transposase gene tps) that affect gene functions through insertion/deletion events. No transposon has yet been reported to occur in "Candidatus Liberibacter asiaticus," an alphaproteobacterium associated with citrus Huanglongbing (HLB, yellow shoot disease). In this study, two MITEs, MCLas A and MCLas-B, in "Ca. Liberibacter asiaticus" were detected, and the genome was characterized using 326 isolates collected in China and Florida. MCLas-A had three variants, ranging from 237 to 325 bp, and was inserted into a TTTAGG site of a prophage region. MCLas-A had a pair of 54-bp terminal inverted repeats (TIRs), which contained three tandem repeats of TGGTAACCAC. Both "filled" (with MITE) and "empty" (without MITE) states were detected, suggesting the MITE mobility. The empty sites of all bacterial isolates had TIR tandem repeat remnants (TRR). Frequencies of TRR types varied according to geographical origins. MCLas-B had four variants, ranging from 238 to 250 bp, and was inserted into a TA site of another "Ca. Liberibacter" prophage. The MITE, MCLas-B, had a pair of 23-bp TIRs containing no tandem repeats. No evidence of MCLas-B mobility was found. An identical open reading frame was found upstream of MCLas-A (229 bp) and MCLas-B (232 bp) and was predicted to be a putative tps, suggesting an in cis tps-MITE configuration. MCLas-A and MCLas-B were predominantly copresent in Florida isolates, whereas MCLas-A alone or MCLas-B alone was found in Chinese isolates. PMID- 23813737 TI - The direct inhibitory effect of dutasteride or finasteride on androgen receptor activity is cell line specific. AB - BACKGROUND: Finasteride and dutasteride were developed originally as 5alpha reductase inhibitors to block the conversion of testosterone to dihydrotestosterone (DHT). These drugs may possess off-target effects on the androgen receptor (AR) due to their structural similarity to DHT. METHODS: A total of four human prostate cancer cell models were examined: LNCaP (T877A mutant AR), 22Rv1 (H874Y mutant AR), LAPC4 (wild-type AR), and VCaP (wild-type AR). Cells were cultured in 10% charcoal-stripped fetal bovine serum, either with or without DHT added to the medium. AR activity was evaluated using the ARE luciferase assay or the expression of AR regulated genes. RESULTS: Dutasteride was more potent than finasteride in interfering with DHT-stimulated AR signaling. Disruption of AR function was accompanied by decreased cell growth. Cells that rely on DHT for protection against death were particularly vulnerable to dutasteride. Different prostate cancer cell models exhibited different sensitivities to dutasteride and finasteride. LNCaP was most sensitive, LAPC4 and VCaP were intermediate, while 22Rv1 was least sensitive. Regardless of the AR genotype, if AR was transfected into drug-sensitive cells, AR was inhibited by drug treatment; and if AR was transfected into drug-resistant cells, AR was not inhibited. CONCLUSIONS: The direct inhibitory effect of dutasteride or finasteride on AR signaling is cell line specific. Mutations in the ligand binding domain of AR do not appear to play a significant role in influencing the AR antagonistic effect of these drugs. Subcellular constituent is an important factor in determining the drug effect on AR function. PMID- 23813739 TI - Role of porosity and pore architecture in the in vivo bone regeneration capacity of biodegradable glass scaffolds. AB - The aim of this work is to shed light on the role of porosity and pore architecture in the in vivo bone regeneration capacity of biodegradable glass scaffolds. A calcium phosphate glass in the system P2O5-CaO-Na2O-TiO2 was foamed using two different porogens, namely albumen and hydrogen peroxide (H2O2); the resulting three-dimensional porous structures were characterized and implanted in New Zealand rabbits to study their in vivo behavior. Scaffolds foamed with albumen displayed a monomodal pore size distribution centered around 150 MUm and a porosity of 82%, whereas scaffolds foamed with H2O2 showed lower porosity (37%), with larger elongated pores, and multimodal size distribution. After 12 weeks of implantation, histology results revealed a good osteointegration for both types of scaffolds. The quantitative morphometric analysis showed the substitution of the biomaterial by new bone in the case of glasses foamed with albumen. In contrast, bone neoformation and material resorption were significantly lower in the defects filled with the scaffolds foamed with H2O2. The results obtained in this study showed that both calcium phosphate glass scaffolds were osteoconductive, biocompatible, and biodegradable materials. However, differences in porosity, pore architecture, and microstructure led to substantially different in vivo response. PMID- 23813736 TI - Forster resonance energy transfer microscopy and spectroscopy for localizing protein-protein interactions in living cells. AB - The fundamental theory of Forster resonance energy transfer (FRET) was established in the 1940s. Its great power was only realized in the past 20 years after different techniques were developed and applied to biological experiments. This success was made possible by the availability of suitable fluorescent probes, advanced optics, detectors, microscopy instrumentation, and analytical tools. Combined with state-of-the-art microscopy and spectroscopy, FRET imaging allows scientists to study a variety of phenomena that produce changes in molecular proximity, thereby leading to many significant findings in the life sciences. In this review, we outline various FRET imaging techniques and their strengths and limitations; we also provide a biological model to demonstrate how to investigate protein-protein interactions in living cells using both intensity- and fluorescence lifetime-based FRET microscopy methods. PMID- 23813740 TI - Purkinje cell loss is the major brain pathology of spinocerebellar ataxia type 10. PMID- 23813738 TI - Neural processing of race during imitation: self-similarity versus social status. AB - People preferentially imitate others who are similar to them or have high social status. Such imitative biases are thought to have evolved because they increase the efficiency of cultural acquisition. Here we focused on distinguishing between self-similarity and social status as two candidate mechanisms underlying neural responses to a person's race during imitation. We used fMRI to measure neural responses when 20 African American (AA) and 20 European American (EA) young adults imitated AA, EA and Chinese American (CA) models and also passively observed their gestures and faces. We found that both AA and EA participants exhibited more activity in lateral frontoparietal and visual regions when imitating AAs compared with EAs or CAs. These results suggest that racial self similarity is not likely to modulate neural responses to race during imitation, in contrast with findings from previous neuroimaging studies of face perception and action observation. Furthermore, AA and EA participants associated AAs with lower social status than EAs or CAs, suggesting that the social status associated with different racial groups may instead modulate neural activity during imitation of individuals from those groups. Taken together, these findings suggest that neural responses to race during imitation are driven by socially learned associations rather than self-similarity. This may reflect the adaptive role of imitation in social learning, where learning from higher status models can be more beneficial. This study provides neural evidence consistent with evolutionary theories of cultural acquisition. PMID- 23813741 TI - Impact of premorbid hypertension on haemorrhage severity and aneurysm rebleeding risk after subarachnoid haemorrhage. AB - OBJECTIVE: Arterial hypertension (HTN) is a risk factor for subarachnoid haemorrhage (SAH). We aimed to assess the impact of premorbid HTN on the severity of initial bleeding and the risk of aneurysm rebleeding after SAH. DESIGN: Retrospective analysis of a prospective cohort study of all SAH patients admitted to Columbia University Medical Center between 1996 and 2012. RESULTS: We enrolled 1312 consecutive patients with SAH; 643 (49%) had premorbid HTN. Patients with premorbid HTN presented more frequently as Hunt-Hess Grade IV or V (36% vs 25%, p<0.001) and World Federation of Neurosurgical Societies (WFNS) Grade 4 or 5 (42.6% vs 28.2%, p<0.001), with larger amounts of subarachnoid (Hijdra Sum Score 17 vs 14, p<0.001) and intraventricular blood (median IVH sum score 2 vs 1, p<0.001), and more often with intracerebral haemorrhage (20% vs 13%, p=0.002). In multivariate analysis, patients with premorbid HTN had a higher risk of in hospital aneurysm rebleeding (11.8% vs 5.5%, adjusted OR 1.67, 95% CI 1.02 to 2.74, p=0.04) after adjusting for age, admission, Hunt-Hess grade, size and site of the ruptured aneurysm. CONCLUSIONS: Premorbid HTN is associated with increased severity of the initial bleeding event and represents a significant risk factor for aneurysm rebleeding. Given that aneurysm rebleeding is a potentially fatal but preventable-complication, these findings are of clinical relevance. PMID- 23813742 TI - Depressive symptoms in Parkinson's disease are related to reduced [123I]FP-CIT binding in the caudate nucleus. AB - BACKGROUND: Depression is a common neuropsychiatric symptom in Parkinson's disease (PD). In previous research, PD-related depression was associated with striatal dopaminergic deficits, presumably due to degeneration of brainstem dopaminergic projections. Segregated areas of the striatum are crucially involved in various parallelly arranged cortical-striatal-thalamocortical circuits and serve functions in, among others, motor control or emotion. This suggests regional specificity of dopaminergic deficits in the striatum in motor and depressive symptoms in PD. METHODS: In this cross-sectional retrospective study, we correlated severity scores of depressive and motor symptoms in 100 non demented PD patients (median Hoehn & Yahr stage: 2) with dopamine loss in specific regions of the striatum as measured by [(123)I]FP-CIT SPECT tracer binding to the dopamine transporter (DaT). RESULTS: Depressive symptoms were related to lower DaT binding in the right caudate nucleus, while motor symptoms were associated with decreased DaT binding in the right putamen. This double dissociation was most pronounced in early-stage PD patients. CONCLUSIONS: These results suggest that depressive symptoms in PD are associated with dopamine loss in the caudate nucleus, possibly related to degeneration of dopaminergic projections from the ventral tegmental area, while motor symptoms are associated with low dopamine signalling to the putamen and loss of nigrostriatal projections. This is consistent with the neuroanatomy of partially segregated cortical-striatal-thalamocortical circuits and supports the role of dysfunctional associative and motivational circuits in PD-related depression. PMID- 23813743 TI - A randomised double-blind, cross-over trial of 4-aminopyridine for downbeat nystagmus--effects on slowphase eye velocity, postural stability, locomotion and symptoms. AB - OBJECTIVE: The effects of 4-aminopyridine (4-AP) on downbeat nystagmus (DBN) were analysed in terms of slow-phase velocity (SPV), stance, locomotion, visual acuity (VA), patient satisfaction and side effects using standardised questionnaires. METHODS: Twenty-seven patients with DBN received 5 mg 4-AP four times a day or placebo for 3 days and 10 mg 4-AP four times a day or placebo for 4 days. Recordings were done before the first, 60 min after the first and 60 min after the last drug administration. RESULTS: SPV decreased from 2.42 deg/s at baseline to 1.38 deg/s with 5 mg 4-AP and to 2.03 deg/s with 10 mg 4-AP (p<0.05; post hoc: 5 mg 4-AP: p=0.04). The rate of responders was 57%. Increasing age correlated with a 4-AP-related decrease in SPV (p<0.05). Patients improved in the 'get-up and-go test' with 4-AP (p<0.001; post hoc: 5 mg: p=0.025; 10 mg: p<0.001). Tandem walk time (both p<0.01) and tandem-walk error (4-AP: p=0.054; placebo: p=0.059) improved under 4-AP and placebo. Posturography showed that some patients improved with the 5 mg 4-AP dose, particularly older patients. Near VA increased from 0.59 at baseline to 0.66 with 5 mg 4-AP (p<0.05). Patients with idiopathic DBN had the greatest benefit from 4-AP. There were no differences between 4-AP and placebo regarding patient satisfaction and side effects. CONCLUSIONS: 4-AP reduced SPV of DBN, improved near VA and some locomotor parameters. 4-AP is a useful medication for DBN syndrome, older patients in particular benefit from the effects of 5 mg 4 AP on nystagmus and postural stability. PMID- 23813744 TI - Headache-related health resource utilisation in chronic and episodic migraine across six countries. AB - OBJECTIVE: To describe headache-related health resource usage in chronic and episodic migraine across six countries. METHODS: A web-based questionnaire eliciting data on several topics, including health resource usage, was administered to panellists with migraine from the USA, Canada, UK, Germany, France and Australia. Respondents were grouped into episodic and chronic migraine, based on reported headache phenotype and headache-day frequency. ORs were calculated, comparing usage in each country to that in the US, controlling for chronic versus episodic migraine and other factors. RESULTS: Relative to the USA, the odds of visiting a provider for headache during the preceding 3 months were significantly higher in all countries, except Germany. Respondents in France were more likely to report having a provider they typically visited for headache related care. The odds of visiting the emergency department for headache were significantly lower in France, the UK and Germany, and hospitalisation for headache was significantly more frequent in Canada and Australia. Respondents from all countries, except Canada, were more likely to report currently using a prescription-acute treatment, and those from France were more likely to report trying more than three acute treatments. Preventive treatment use did not differ significantly. CONCLUSIONS: Headache-related resource usage differed significantly between the USA and other countries. US respondents were generally less likely to report recent provider visits and use of prescription-acute treatments. They were more likely to report emergency department visits than in European countries, but less likely to report hospitalisation than in Canada and Australia. PMID- 23813745 TI - Early predictors of oxaliplatin-induced cumulative neuropathy in colorectal cancer patients. AB - OBJECTIVES: Peripheral neuropathy ranks among the most common dose-limiting and disabling side-effect of oxaliplatin (OXA)-based chemotherapy. The aim of this prospective, multicentre study was to define early clinical and neurophysiological markers that may help to identify patients at risk of developing severe, treatment emergent, cumulative OXA-induced peripheral neuropathy (OXAIPN). METHODS: 200 colorectal cancer patients, scheduled to receive OXA-based chemotherapy, were prospectively followed. Detailed neurological assessment employing the clinical Total Neuropathy Score (TNSc), oncological rating scales (National Common Institute-Common Toxicity Criteria V.3) and nerve conduction studies (NCS) were performed at baseline, mid-treatment and at the end of chemotherapy. Symptoms of OXA-induced acute neurotoxicity were systematically recorded. RESULTS: According to TNSc, 36 (18%) patients developed grade 3 OXAIPN. These patients were predominantly men (p=0.005), presented a significant decrease in all NCS (p<0.001), reported more acute neuropathic symptoms (p<0.001) and received higher OXA cumulative dose (p=0.003). Multivariate analysis showed that three variables obtained at intermediate follow up, namely, the number of acute symptoms (OR 1.9; CI 95% 1.2 to 3.2; p=0.012) and the >30% decrease in sensory nerve action potential amplitude from the baseline value in radial (OR 41.4; CI 95% 4.98 to 343.1; p=0.001) and dorsal sural nerves (OR 24.96; CI 95% 2.6 to 239.4; p=0.005) were independently associated with the risk of developing severe OXAIPN. CONCLUSIONS: High-grade OXA neurotoxicity can be predicted by clinical and neurophysiological information obtained at mid treatment. Neurological assessment of acute neuropathy symptoms and radial and dorsal sural nerves NCS should be carefully monitored to predict and hopefully prevent the induction of severe OXAIPN. PMID- 23813746 TI - Solid-state reversible quadratic nonlinear optical molecular switch with an exceptionally large contrast. AB - Exceptional nonlinear optical (NLO) switching behavior, including an extremely large contrast (on/off) of ~35 and high NLO coefficients, is displayed by a solid state reversible quadratic NLO switch. The favorable results, induced by very fast molecular motion and anionic ordering, provides impetus for the design of a novel second-harmonic-generation switch involving molecular motion. PMID- 23813747 TI - Discount rates and the education gradient in mammography in the UK. AB - I analyse intertemporal decisions on undertaking breast cancer screening by women aged 50-64 years in the UK and provide estimates of the rate of discounting potential future benefits of screening. I also analyse education differences in mammography decisions and examine the underlying mechanisms by which education influences breast cancer screening attendance. I estimate a structural model, which reveals that although there are differences in the disutility of breast cancer screening between education groups, there is no difference in the estimated discount factor. These results suggest that the observed education gradient is mainly due to differences in health behaviours and healthcare attitudes. PMID- 23813749 TI - The evolution of diffusion tensor imaging in Parkinson's disease research. PMID- 23813748 TI - Investigators' successful strategies for working with Institutional Review Boards. AB - This study was designed to identify successful strategies used by investigators for working with their Institutional Review Boards (IRBs) in conducting human subjects research. Telephone interviews were conducted with 46 investigators representing nursing, medicine, and social work. Interview transcripts were analyzed using qualitative descriptive methods. Investigators emphasized the importance of intentionally cultivating positive relationships with IRB staff and members, and managing bureaucracy. A few used evasive measures to avoid conflict with IRBs. Few successful strategies were identified for working with multiple IRBs. Although most investigators developed successful methods for working with IRBs, further research is needed on how differences in IRB culture affect human subjects protection, and on best approaches for obtaining IRB approval of multi site studies. PMID- 23813750 TI - Repair of avascular meniscal injuries using juvenile meniscal fragments: an in vitro organ culture study. AB - We investigated whether the implantation of juvenile allograft and minced meniscal fragments could improve the healing of avascular meniscal injuries, which cannot heal spontaneously. Concentric cylindrical explants were excised from the inner two-thirds of swine medial menisci. The inner cylinder consisted of a "sandwich" structure, with minced juvenile meniscal fragments, juvenile meniscal columns, minced mature meniscal fragments, or mature meniscal columns implanted in the middle. The explants were cultured in vitro for 2, 4, or 6 weeks. Interfacial meniscal repair was assessed by histology, immunohistochemistry, biomechanical testing, and confocal laser scanning microscopy. Histology and confocal microscopy results revealed that tissue repair and cell accumulation at the interface were best at all time points in the juvenile meniscal fragments group, followed by the juvenile columns, minced mature fragments, and mature columns groups, respectively. At 6 weeks, the implantation of juvenile allograft and minced meniscal fragments increased the shear strength, peak force, and energy to failure in the peripheral interface. Picosirius red/polarized light microscopy and immunohistochemistry results showed concurrent expression of type I and II collagen in the interfacial repair tissue. In conclusion, implantation of juvenile allograft and minced meniscal fragments could increase the healing of avascular meniscal injury in vitro. PMID- 23813751 TI - Nocturnal dipping is preserved in children with sleep disordered breathing regardless of its severity. AB - OBJECTIVE: Sleep disordered breathing (SDB) in adults has been associated with a loss of nocturnal dipping in blood pressure (BP) and heart rate, however, there have been limited studies in children. We measured BP non-invasively and continuously overnight in 105 children aged 7-12 with a range of severities of SDB and 36 non-snoring controls to examine nocturnal dipping profiles. STUDY DESIGN: Children with SDB were divided into three severity groups according to their obstructive apnea hypopnea index. Nocturnal dipping profiles across sleep stages were described both as a proportion of children exhibiting a >=10% fall in systolic arterial pressure (SAP) and heart rate (HR) from wake to sleep and according to SAP sleep/SAP wake ratio as extreme dippers (ratio <= 0.8), dippers (ratio < 0.8 and <=0.9), non-dippers (ratio < 0.9 and <=1.0), and reverse dippers (ratio > 1.0). RESULTS: The mean fall in BP between wake and NREM 1/2, SWS, and REM sleep was not different between the groups and there were no differences between the dipping profiles of children in each group. CONCLUSIONS: SDB did not alter nocturnal dipping patterns of BP and HR compared to controls, a finding which may suggest that these young children have not been exposed to the effects of SDB long enough or that SDB severity was not great enough to affect nocturnal dipping profiles. However, further studies are required to determine if the elevated BP previously reported in this group of children will have long-term effects on the cardiovascular system. PMID- 23813752 TI - Synthesis of conjugated dienes via a biomimetic aerobic oxidative coupling of two C(vinyl)-H bonds. PMID- 23813753 TI - The posterior intercostal vein: a thermoregulatory gateway to the internal vertebral venous plexus. AB - The internal vertebral venous plexus (IVVP) plays a putative role in thermoregulation of the spinal cord. Cold cutaneous venous blood may cool, while warm venous blood from muscles and brown fat areas may warm the spinal cord. The regulating mechanisms for both cooling and warming are still unknown. Warm venous blood mainly enters the IVVP via the intervertebral veins. In the thoracic area these veins are connected to the posterior intercostal veins. In this study, anatomical structures were investigated that might support the mechanisms by which warmed venous blood from the intercostal muscles and the recently described paravertebral patches of brown adipose tissue are able to drain into the vertebral venous plexus. Therefore, tissue samples from human cadavers (n = 21) containing the posterior intercostal vein and its connections to the IVVP and the azygos veins were removed and processed for histology. Serial sections revealed that the proximal parts of the posterior intercostal veins contained abundant smooth muscle fibers at their opening into the azygos vein. Furthermore, the walls of the proximal parts of the posterior intercostal veins contain plicae that allow the vessel to dilate, thereby allowing it to serve as a pressure chamber. It is suggested that a cold induced closure of the intercostal/azygos opening can result in retrograde blood flow from the proximal posterior intercostal vein towards the IVVP. This blood flow would be composed of warm blood from the paravertebral brown adipose tissue and blood containing metabolic heat from the muscles draining into the intercostal veins. PMID- 23813754 TI - Transfusion of older red blood cells is associated with decreased graft survival after orthotopic liver transplantation. AB - Investigations have demonstrated conflicting results regarding the influence of the red blood cell (RBC) storage duration on outcomes. We evaluated whether graft failure or mortality after orthotopic liver transplantation (OLT) increased when recipients were transfused with older RBCs. This study included 637 patients who underwent OLT between January 2001 and June 2011. Baseline and perioperative data were obtained from our blood bank, the Unified Transplant Center database, and the United Network for Organ Sharing database. Recipients whose transfused RBCs were all stored for <= 15 days were grouped in a younger group, and recipients who were transfused with RBCs stored for >15 days were placed in an older group. The relationship between graft survival/mortality and the age of intraoperatively transfused RBCs was studied by Kaplan-Meier estimation with a log-rank test and multivariate Cox proportional hazards regression. Three hundred thirty-four patients and 303 patients were grouped in the younger and the older RBC groups, respectively, on the basis of the ages of intraoperatively transfused RBCs. Kaplan-Meier estimates of graft survival/mortality as a function of the posttransplant time were significantly different: the older group experienced the outcome sooner than the younger group [P = 0.02 (log-rank test)]. After covariate adjustments, the risk of graft failure/mortality was significantly different at any given time after transplantation between patients receiving intraoperative transfusions of older RBC units and patients receiving intraoperative transfusions of younger RBC units (hazard ratio = 1.65, 95% confidence interval = 1.18-2.31). In conclusion, patients who received intraoperative transfusions of RBCs with longer storage times had an increased risk of adverse outcomes. PMID- 23813756 TI - OpenNotes: hospitalists' challenge and opportunity. AB - At a time of societal fascination both with transparency and the explosion of health information technologies, a growing number of hospitals are offering, or will soon offer patients and their family instantaneous access to their doctors' and nurses' notes. What will this new opportunity for patient engagement mean for the hospitalist? Today, state and federal government regulations either encourage or require healthcare providers to grant patients access to their clinical information. But despite the rules embedded in the federal Health Insurance Portability and Accountability Act (HIPAA), patients often face time-consuming obstacles in their quest for access, and many providers view compliance as a burden. We suggest an alternative view: Over time, we anticipate that inviting patients to review their medical record will reduce risk, increase knowledge, foster active engagement, and help them take more control of their care. The OpenNotes trial provides clues as to how such practice will affect both patients and providers (1, 2). We anticipate that transparent records will stimulate hospitalists, PCPs, and other caregivers to improve communication throughout the patient's hospital stay. OpenNotes offers a special opportunity for improving the patient experience after leaving the hospital as well. Open notes will be viewed by many as a disruptive change, and the best strategy for adapting will be to move proactively to create policies that establish clear guidelines, for which the authors offer some suggestions. PMID- 23813758 TI - Intrinsically unstructured proteins by design-electrostatic interactions can control binding, folding, and function of a helix-loop-helix heterodimer. AB - Intrinsically disordered proteins that exist as unordered monomeric structures in aqueous solution at pH 7 but fold into four-helix bundles upon binding to recognized polypeptide targets have been designed. NMR and CD spectra of the monomeric polypeptides show the hallmarks of unordered structures, whereas in the bound state they are highly helical. Analytical ultracentrifugation data shows that the polypeptides bind to their targets to form exclusively heterodimers at neutral pH. To demonstrate the relationship between binding, folding, and function, a catalytic site for ester hydrolysis was introduced into an unordered and largely inactive monomer, but that was structured and catalytically active in the presence of a specific polypeptide target. Electrostatic interactions between surface-exposed residues inhibited the binding and folding of the monomers at pH 7. Charge-charge repulsion between ionizable amino acids was thus found to be sufficient to disrupt binding between polypeptide chains despite their inherent propensities for structure formation and may be involved in the folding and function of inherently disordered proteins in biology. PMID- 23813763 TI - Parameter identification of in vivo kinetic models: limitations and challenges. AB - Systems metabolic engineering of metabolic networks by genetic techniques requires kinetic equations for each enzyme present. In vitro studies of singular enzymes have limitations for predicting in vivo behavior, and in vivo experiments are constrained to retain viable cells. The estimation of kinetic parameters in vivo is a challenge due to the complexity of the internal cell environment. This concise review analyzes the limitations of in vitro and in vivo approaches, and shows that not all parameters can be determined and that multicollinearity exists. On the other hand, this review also shows that cell metabolism is adequately described with a smaller number of parameters and with approximative or reduced models. A major hurdle is the identification and quantification of allosteric effectors. Despite limitations, in vivo kinetic experiments are adequate in providing a quantitative description of the cell as a system. PMID- 23813764 TI - Full factorial screening of human embryonic stem cell maintenance with multiplexed microbioreactor arrays. AB - Use of human pluripotent stem cells (hPSCs) in regenerative medicine applications relies on control of cell fate decisions by exogenous factors. This control can be hindered by the use of undefined culture components, poorly understood autocrine/paracrine effects, spatiotemporal variations in microenvironmental composition inherent to static culture formats, and signal cross-talk between multiple factors. We recently described microbioreactor arrays that provide a full factorial spectrum of exogenous factors, and allow gradual accumulation of paracrine factors through serial culture chambers. We combined these with defined biochemical conditions, and in situ reporter gene- and immunofluorescence-based readouts to create an hPSC screening platform with enhanced data throughput and microenvironmental control. HES3-EOS-C(3+)-EiP reporter hESCs were screened against FGF-2, TGF-beta1, and retinoic acid in a modified mTeSR-1 medium background. Differential pluripotency marker expression reflected mTeSR-1's maintenance capacity, and differentiation in response to removal of maintenance factors or addition of retinoic acid. Interestingly, pluripotency marker expression was downregulated progressively through serial chambers. Since downstream chambers are exposed to greater levels of paracrine factors under continuous flow, this effect is thought to result from secreted factors that negatively influence pluripotency. The microbioreactor array platform decodes factor interplay, and has a broad application in deciphering microenvironmental control of cell fate. PMID- 23813768 TI - Risk of emergent bradycardia associated with initiation of immediate- or slow release metoprolol. AB - OBJECTIVES: To estimate and compare the risk of emergent bradycardia associated with starting immediate-release (IR) and slow-release (SR) formulations of metoprolol. DESIGN: Retrospective analysis of administrative claims data. DATA SOURCE: State of California Medicaid program (Medi-Cal) claims database. PATIENTS: A total of 31,574 adults beginning metoprolol between May 1, 2004, and November 1, 2009, without a pharmacy claim for a beta blocker within the previous 6 months of metoprolol initiation; patients with a primary or secondary diagnosis of symptomatic bradycardia, pacemaker, or implantable cardioverter-defibrillator placement before metoprolol initiation were excluded. MEASUREMENTS AND MAIN RESULTS: The study outcome was the time to first occurrence of emergent bradycardia, measured at an emergency department visit or hospitalization due to diagnosis of symptomatic bradycardia, after metoprolol initiation. We calculated the incidence and compared the risk of emergent bradycardia by using a proportional hazards model that included the metoprolol formulation with adjustment for total daily metoprolol dose and the use of other drugs as time varying covariates, as well as demographics and comorbidities. Among 31,574 patients starting metoprolol, 18,516 (58.6%) used the IR formulation. The incidence of emergent bradycardia was 19.1/1000 person-years overall but was nearly twice as common in patients using the IR versus the SR formulation (24.1/1000 person-yrs in the IR group versus 12.9/1000 person-yrs in the SR group, unadjusted hazard ratio [HR] 1.81, 95% confidence interval [CI] 1.28 2.56). Adjustment for other drugs also associated with symptomatic bradycardia (cytochrome P450 2D6 inhibitors, class I or III antiarrhythmics, and atrioventricular node-blocking agents), metoprolol dose, and other participant characteristics somewhat attenuated the association (adjusted HR 1.48, 95% CI 1.03-2.13). CONCLUSION: The risk of emergent bradycardia associated with metoprolol initiation was higher with the IR formulation than the SR formulation, although the absolute risk was low. PMID- 23813769 TI - Relationship between passive smoking exposure and urinary heavy metals and lung functions in preschool children. AB - Environmental tobacco smoke (ETS) exposure is a risk factor for asthma in school age children, but there is limited data of ETS exposure on respiratory health in preschool children. This study investigated the relationship between ETS, lead (Pb), and cadmium (Cd) exposures and asthma symptoms and spirometric indices in Chinese preschoolers. Preschool children from 30 nurseries and kindergartens performed spirometry with incentives of animation programs, and their urinary cotinine, Pb and Cd concentrations were measured by immunoassay and inductively coupled plasma-mass spectrometry, respectively. Two thousand seven hundred sixty three preschoolers participated, and 1,505 and 893 provided valid spirometric data and urine samples, respectively. Current domestic smoking was reported in 37.5% of children, but only 95 (10.6%) had high urinary cotinine-to-creatinine ratio (>=30 ng/mg). Pb was measurable in 3.9% of samples, whereas 406 (45.5%) children had high Cd. Reported ETS exposure was not associated with any spirometric index, whereas cotinine-to-creatinine ratio was inversely associated with forced expiratory volume in 0.5-sec (beta = -0.093, P = 0.003), forced expiratory flow between 25% and 75% of expiration (beta = -0.138, P = 0.002) and peak expiratory flow (beta = -0.106, P = 0.002). Cd exposure was not associated with reported respiratory symptom or spirometric indices. This community study shows that ETS exposure defined by urinary cotinine is a strong risk factor for lung function impairment measured by spirometry in Chinese preschool children. Urinary cotinine is more reliable than questionnaire for assessing ETS exposure in young children. Although high urinary Cd is common in Hong Kong preschoolers, such biomarker is not associated with any clinical or spirometric outcome. PMID- 23813770 TI - Organocatalytic asymmetric synthesis of tetracyclic pyridocarbazole derivatives by using a Diels-Alder/aza-Michael/aldol condensation domino reaction. PMID- 23813772 TI - Reply to: "polychlorinated biphenyls in prospectively collected serum and Parkinson's disease risk". PMID- 23813771 TI - The influence of stem design on critical squeaking friction with ceramic bearings. AB - Ceramic-on-ceramic hip joints have been reported to squeak, a phenomenon that may occur in compromised lubrication conditions. One factor related to the incidence of in vivo squeaking is the stem design. However, it has not yet been possible to relate stem design to squeaking in deteriorating lubrication conditions. The purpose of this study was to determine critical friction factors for different stem designs. A hip simulator was used to measure the friction factor of a ceramic bearing with different stem designs and gradually deteriorating lubrication represented by evaporation of a volatile fluid lubricant. The critical squeaking friction factor was measured at the onset of squeaking for each stem. Critical friction was higher for the long cobalt chrome (0.32 +/- 0.02) and short titanium stems (0.39 +/- 0.02) in comparison with a long titanium stem (0.29 +/- 0.02). The onset of squeaking occurred at a friction factor lower than that measured for dry conditions, in which squeaking is usually investigated experimentally. The results suggest that shorter or heavier stems might limit the possibility of squeaking as lubrication deteriorates. The method developed can be used to investigate the influence of design parameters on squeaking probability. PMID- 23813773 TI - Amplified spontaneous emission in conjugated polyrotaxanes under quasi-CW pumping. AB - Amplified spontaneous emission under millisecond pulsed excitation on a rotaxane insulated conjugated polymer is reported. Pump-probe spectroscopy confirms the absence of polaron-pair absorption in the gain spectral region as the main factor contributing to quasi-steady-state amplified spontaneous emission. The low polaron-pair yield in this compound is the likely result of effective backbone encapsulation provided by the threading ring. PMID- 23813774 TI - 'I know they are distressed. What do I do now?'. AB - Significant advances have been made in our understanding of psychological adjustment to cancer over the last 40 years. Most clinicians now recognise the importance of psychosocial factors and the need for skills in emotional support. In the first phase of psycho-oncology, pioneering work in the 1970s and 1980s mapped the extent of psychological morbidity in cancer. This has been followed by a second phase where clinical trials have demonstrated that psychological treatments are effective. But although clinicians may feel more confident in identifying distress and listening to the patient, they rarely feel confident that they possess the skills to help. This paper will review the progress through the first two phases and argue that we are now in the third phase where we can begin to examine methods for delivering cost-effective psychological care. One of these methods is to equip staff with basic skills to understand and manage psychological distress. This paper will also describe a programme over the last 10 years to evaluate the effectiveness and clinical impact of such training for palliative care professionals. PMID- 23813776 TI - Sirolimus as a calcineurin inhibitor- and renal-sparing agent: all good things come to those who wait versus spare the nephron, spoil the patient. PMID- 23813775 TI - Clinical utility of 18F-FDG PET/CT concurrent with 131I therapy in intermediate to-high-risk patients with differentiated thyroid cancer: dual-center experience with 286 patients. AB - Patients with differentiated thyroid carcinoma (DTC) are treated with (131)I therapy after total thyroidectomy or surgical resection of recurrent tumor. However, some recurrent DTC lesions are not iodine-avid, which affects further treatment planning. The aim of this study was to evaluate the clinical benefit of (18)F-FDG PET/CT performed concurrently with (131)I therapy in DTC patients with intermediate to high risk. METHODS: We retrospectively enrolled 286 DTC patients at 2 Korean medical centers who comprised 2 different patient groups: 28 patients who underwent adjuvant (131)I treatment after curative surgical resection of recurrent tumor and 258 patients with intermediate to high risk who underwent (131)I ablation after total thyroidectomy. (131)I therapy and (18)F-FDG PET/CT scanning were performed on the same day. Administration of l-thyroxine was withheld from all enrollees for 4 wk before (131)I treatment. RESULTS: In 39 patients (14%), (18)F-FDG PET/CT detected additional recurrent or metastatic lesions that were not detected on the posttherapy (131)I scan, and the treatment plan was changed for 30 patients (10%) based on such findings. Among the 28 patients receiving (131)I treatment after resection of recurrent tumor, PET/CT detected additional lesions in 46%, and treatment was changed in 43%. Assessing a subgroup of stage T3-T4N1 patients with tumor size > 2.0 cm, among 258 patients undergoing (131)I ablation after total thyroidectomy, we found that 25% had additional positive PET/CT results, and treatment changed for 17%. In contrast, 8% of stage T3-T4N1 patients with tumor size <= 2.0 cm, 6% of stage T1-T2N1 patients, and 3% of stage T3-T4N0 patients had additional positive PET/CT findings. CONCLUSION: (18)F-FDG PET/CT performed concurrently with (131)I therapy detected additional lesions in 14% of DTC patients and was particularly helpful for detecting additional lesions in patients undergoing (131)I therapy after resection of recurrent tumor or in stage T3-T4N1 patients with tumor size > 2.0 cm. PMID- 23813777 TI - Determination of potential scaffolds for human choline kinase alpha1 by chemical deconvolution studies. AB - Dual binding modes: Combined empirical and computational studies of a series of compounds showed adenine and 1-benzyl-4-(dimethylamino)pyridinium fragments to function most efficiently in binding CHOKalpha1, and also determined how the latter fragment interacts with the choline binding site through two different binding modes. These data provide a basis for the future design of better and more selective inhibitors. PMID- 23813778 TI - Morphological study of the inferior transverse scapular ligament. AB - The suprascapular nerve can be compressed by the inferior transverse scapular ligament (ITSL), also known as the spinoglenoid ligament, and this entrapment results in dysfunction of the external rotation of the upper arm owing to isolated weakness of the infraspinatus muscle. The morphology of the ITSL has not been adequately characterized. The aim of this study was to clarify the morphological characteristics of the ITSL. In total, 110 shoulders from 72 cadavers were dissected in this study. The ITSL was present in 73 (66.4%) of the 110 specimens, and comprised membrane in 40 (36.4%), ligament in 25 (22.7%), and both membrane and ligament in eight (7.3%). This structure could be classified into three types on the basis of its shape: band-like (33.6%, type I), triangular (15.5%, type II), or irregular (17.3%, type III). In the spinoglenoid notch, the suprascapular nerve was always close to the lateral margin of the scapular spine. The length of the ligament between its origin and insertion sites ranged from 8.7 to 23.4 mm at its superior margin and from 8.9 to 17.5 mm at its inferior margin. The ligament width and thickness at its midportion ranged from 1.6 to 10.0 mm and from 0.1 to 1.2 mm, respectively. The results of this study improve understanding of the ITSL and will be helpful for successful diagnoses and treatments for selective suprascapular nerve entrapment. PMID- 23813757 TI - The association of skin intrinsic fluorescence with type 1 diabetes complications in the DCCT/EDIC study. AB - OBJECTIVE: To determine whether skin intrinsic fluorescence (SIF) is associated with long-term complications of type 1 diabetes (T1D) and, if so, whether it is independent of chronic glycemic exposure and previous intensive therapy. RESEARCH DESIGN AND METHODS: We studied 1,185 (92%) of 1,289 active Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) participants from 2010 to 2011. SIF was determined using a fluorescence spectrometer and related cross-sectionally to recently determined measures of retinopathy (stereo fundus photography), cardiac autonomic neuropathy (CAN; R-R interval), confirmed clinical neuropathy, nephropathy (albumin excretion rate [AER]), and coronary artery calcification (CAC). RESULTS: Overall, moderately strong associations were seen with all complications, before adjustment for mean HbA1c over time, which rendered these associations nonsignificant with the exception of sustained AER>30 mg/24 h and CAC, which were largely unaffected by adjustment. However, when examined within the former DCCT treatment group, associations were generally weaker in the intensive group and nonsignificant after adjustment, while in the conventional group, associations remained significant for CAN, sustained AER>30 mg/24 h, and CAC even after mean HbA1c adjustment. CONCLUSIONS: SIF is associated with T1D complications in DCCT?EDIC. Much of this association appears to be related to historical glycemic exposure, particularly in the previously intensively treated participants, in whom adjustment for HbA1c eliminates statistical significance. PMID- 23813779 TI - Tanshinone IIA induces autophagic cell death via activation of AMPK and ERK and inhibition of mTOR and p70 S6K in KBM-5 leukemia cells. AB - Although tanshinone IIA (Tan IIA) from Salviae miltiorrhizae was known to induce apoptosis in various cancers, its underlying mechanism of autophagic cell death was not reported yet. Thus, in the present study, the molecular mechanism of autophagic cell death by Tan IIA was investigated in KBM-5 leukemia cells. Tan IIA significantly increased the expression of microtubule-associated protein light chain 3 (LC3) II as a hallmark of autophagy in western blotting and immunofluorescence staining. Tan IIA augmented the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and attenuated the phosphorylation of mammalian target of rapamycin (mTOR) and p70 S6K in a dose-dependent manner. Conversely, autophagy inhibitor 3-methyladenine partly reversed the cytotoxicity and the phosphorylation of AMPK, mTOR and p70 S6K induced by Tan IIA in KBM-5 leukemia cells. In addition, Tan IIA dramatically activated the extracellular signal regulated kinase (ERK) signaling pathway including Raf, ERK and p90 RSK in a dose-dependent and time-dependent manner. Consistently, ERK inhibitor PD184352 suppressed LC3-II activation induced by Tan IIA, whereas PD184352 and PD98059 did not affect poly (ADP-ribose) polymerase cleavage and sub-G1 accumulation induced by Tan IIA in KBM-5 leukemia cells. Furthermore, Tan IIA could induce autophagy via LC3-II activation in various cancer cells such as prostate (PC-3), multiple myeloma (U266), lung (NCI-H460), and breast (MDA-MB-231) cells. Overall, these findings suggest that Tan IIA induces autophagic cell death via activation of AMPK and ERK and inhibition of mTOR and p70 S6K in KBM-5 cells as a potent natural compound for leukemia treatment. PMID- 23813780 TI - Localization of the anti-cancer peptide EGFR-lytic hybrid peptide in human pancreatic cancer BxPC-3 cells by immunocytochemistry. AB - Cationic lytic-type peptides have been studied for clinical application in various infections and cancers, but their functional cellular mechanisms remain unclear. We generated anti-cancer epithelial growth factor receptor (EGFR)-lytic hybrid peptide, a 32-amino-acid peptide composed of an EGFR-binding sequence and lytic sequence. In this study, we investigated the distribution of EGFR-lytic hybrid peptide in BxPC-3 human pancreatic cancer cells by an immunocytochemical (ICC) method. Distribution of EGFR protein expression was unchanged after treatment with EGFR-lytic peptide compared with non-treated cells. In confocal laser scanning microscopy, immunostaining of EGFR-lytic peptide was observed in the cytoplasm, mostly in the form of granules. Some staining was also localized on the mitochondrial membrane. At the ultrastructure level, cells treated with EGFR-lytic peptide had a low electron density, disappearance of microvilli, and swollen mitochondria. Fragments of cell membrane were also observed in the proximity of the membrane. In immunoelectron microscopy, EGFR-lytic peptide was observed in the cell membrane and cytoplasm. A number of granules were considered swollen mitochondria. Activation of the caspase pathway as a result of mitochondrial dysfunction was also examined to determine the cytotoxic activity of EGFR-lytic peptide; however, no effect on cell death after EGFR-lytic treatment was observed, and moreover, apoptosis was not found to play a critical role in the cell death mechanism. These results suggest that EGFR-lytic peptide is localized on cell and mitochondrial membranes, with disintegration of the cell membrane contributing mainly to cell death. PMID- 23813781 TI - Impact of an immunoglobulin G-specific enzyme-linked immunosorbent assay on the management of heparin-induced thrombocytopenia. AB - STUDY OBJECTIVE: To evaluate whether using an immunoglobulin G (IgG)-specific platelet factor 4 (PF4) test reduces the rate of positive PF4 results and has an impact on prescribing practices of nonheparin anticoagulants (direct thrombin inhibitors and fondaparinux) in patients assessed for heparin-induced thrombocytopenia (HIT). DESIGN: Single-center prospective cohort study with a historical control group. SETTING: Large academic medical center. PATIENTS: A total of 672 patients assessed for HIT. INTERVENTION: Patients were assessed for HIT by using either an IgG-specific PF4 enzyme-linked immunosorbent assay (ELISA; 336 patients) or a nonspecific PF4 ELISA (336 patients; historical control group). MEASUREMENTS AND MAIN RESULTS: No significant difference was noted in the proportion of patients with a low, intermediate, or high risk of HIT based on the 4Ts pretest clinical scoring system. The PF4 ELISA was positive in 6.9% versus 11.3% of patients (p=0.04) in the IgG-specific and nonspecific cohorts, respectively. A smaller proportion of patients were prescribed a direct thrombin inhibitor in the IgG-specific cohort (19.4% vs 25.9%; p=0.04). No significant difference in fondaparinux use was noted between the cohorts. The duration of direct thrombin inhibitor therapy, bleeding events, hospital length of stay, and in-hospital mortality was similar in both cohorts. CONCLUSION: Use of an IgG specific PF4 ELISA was associated with a lower rate of positive PF4 test results. Direct thrombin inhibitor prescribing was also significantly lower during the time period where the IgG-specific PF4 ELISA was used, with no significant differences noted in safety outcomes. PMID- 23813782 TI - Heterologous prime-boost immunization regimens using adenovirus vector and virus like particles induce broadly neutralizing antibodies against H5N1 avian influenza viruses. AB - Highly pathogenic avian influenza (HPAI) H5N1 viruses continue to trigger severe diseases in poultry and humans, prompting efforts to develop an effective vaccine. Toward that goal, we constructed a recombinant adenovirus vector encoding influenza hemagglutin (rAd-HA) and a flagellin-containing virus-like particle (FliC-VLP). Using a murine model, we investigated a heterologous prime boost vaccination regimen combining these two vectors. Our results indicate that priming with the rAd-HA vector followed by a FliC-VLP booster induced the highest HA-specific total IgG, IgG1and IgG2a. Maximum neutralizing antibody titers against homologous and heterologous clades of H5N1 virus strains and hemagglutination inhibition resulted from the heterologous vaccination strategy. Our results are likely to contribute to the development of more effective H5N1 vaccines. PMID- 23813783 TI - In vivo study of the biocompatibility of a novel compressed collagen hydrogel scaffold for artificial corneas. AB - The experiments were designed to evaluate the biocompatibility of a plastically compressed collagen scaffold (PCCS). The ultrastructure of the PCCS was observed via scanning electron microscopy. Twenty New Zealand white rabbits were randomly divided into experimental and control groups that received corneal pocket transplantation with PCCS and an amniotic membrane, respectively. And the contralateral eye of the implanted rabbit served as the normal group. On the 1st, 7th, 14th, 21st, 30th, 60th, 90th, and 120th postoperative day, the eyes were observed via a slit lamp. On the 120th postoperative day, the rabbit eyes were enucleated to examine the tissue compatibility of the implanted stroma. The PCCS was white and translucent. The scanning electron microscopy results showed that fibers within the PCCS were densely packed and evenly arranged. No edema, inflammation, or neovascularization was observed on ocular surface under a slit lamp and few lymphocytes were observed in the stroma of rabbit cornea after histological study. In conclusion, the PCCS has extremely high biocompatibility and is a promising corneal scaffold for an artificial cornea. PMID- 23813784 TI - Surface octahedral distortions and atomic design of perovskite interfaces. AB - Atomic engineering of perovskite films and interfaces is significantly improved by in situ optimization of reflection high-energy electron diffraction (RHEED) features resulting from surface BO6 octahedral rotations seen during molecular beam epitaxy growth. This approach yields Sr-doped manganite films across the phase diagram with magnetotransport properties that are, for the first time, identical to bulk single crystals. Careful structural analysis of manganite/titanate interfaces shows that cation intermixing and unit cell dilations are eliminated, while BO6 rotations and Jahn-Teller-type elongations are nearly completely suppressed at the interface. PMID- 23813785 TI - A comparison of cancer survivors from the PROMIS study selecting telephone versus online questionnaires. PMID- 23813786 TI - Metaphyseal fracture healing in a sheep model of low turnover osteoporosis induced by hypothalamic-pituitary disconnection (HPD). AB - We recently established a large animal model of osteoporosis in sheep using hypothalamic-pituitary disconnection (HPD). As central regulation is important for bone metabolism, HPD-sheep develop severe osteoporosis because of low bone turnover. In this study we investigated metaphyseal fracture healing in HPD sheep. To elucidate potential pathomechanisms, we included a treatment group receiving thyroxine T4 and 17beta-estradiol. Because clinically osteoporotic fractures often occur in the bone metaphysis, HPD-sheep and healthy controls received an osteotomy in the distal femoral condyle. Half of the HPD-sheep were systemically treated with thyroxine T4 and 17beta-estradiol during the healing period. Fracture healing was evaluated after 8 weeks using pQCT, uCT, and histomorphometrical analysis. Bone mineral density (BMD) and bone volume/total volume (BV/TV) were considerably reduced by 30% and 36%, respectively, in the osteotomy gap of the HPD-sheep compared to healthy sheep. Histomorphometry also revealed a decreased amount of newly formed bone (-29%) and some remaining cartilage in the HPD-group, suggesting that HPD disturbed fracture healing. Thyroxine T4 and 17beta-estradiol substitution considerably improved bone healing in the HPD-sheep. Our results indicate that fracture healing requires central regulation and that thyroxine T4 and 17beta-estradiol contribute to the complex pathomechanisms of delayed metaphyseal bone healing in HPD-sheep. PMID- 23813787 TI - Membrane separations for solid-liquid clarification within lignocellulosic biorefining processes. AB - Membrane separations can be integrated into a biorefinery to reduce water and energy consumption. Unfortunately, current membrane materials suffer from severe fouling, which limits their applicability. Here, using analytical characterizations along with fouling models, we correlate membrane properties with performance metrics to provide a framework for optimal membrane selection during solid-liquid clarification of a biomass hydrolysate. Five membranes were evaluated: polyether sulfone, mixed cellulose esters, and three surface modified membranes with weak acid, strong acid, and weak base functionalities. Lignin was the primary component responsible for flux decline, due to physical entrapment and chemical adsorption. The best membrane performance (high and sustained flux, low fouling, and high separation factor) was correlated with higher surface roughness, lower hydrophobicity, neutral or positively charged zeta potential, and a larger number of smaller surface pores. These analyses provide valuable information for designing new materials for biorefining processes to reduce fouling and increase stability. PMID- 23813788 TI - Recurrent hepatitis C: the bane of transplant hepatology. PMID- 23813789 TI - Physical activity and memory complaints in middle-age Americans: results from the MIDUS study. AB - Work-related physical activity (PA; WRPA), household PA (HPA), and leisure-time PA(LTPA) are the 3 important PA domains for most people, but their relationships with cognition functions have not been thoroughly examined, especially the subjective memory complaints (SMCs). We used a data set from the 2005 midlife development in the United States (MIDUS) survey for community-dwelling adults aged 35 to 64 years (mean age = 51.01) to examine the relationship between these 3 PA domains (and 3 levels under the domains) with SMCs (N = 1044). The moderate levels of HPA and LTPA are significantly but oppositely linked to SMCs, with the adjusted odds ratios and 95% confidence intervals of .864 and .764-.978 for HPA and 1.130 and 1.010-1.264 for LTPA, respectively. Neither vigorous or low PA level nor domains of WRPA link to SMCs. The interaction terms were not found to be associated with sex and age. Future works and limitations were also discussed. PMID- 23813790 TI - Peer support for carers: a qualitative investigation of the experiences of carers and peer volunteers. AB - Being a carer of someone with dementia can be rewarding and also challenging. Volunteer peer support schemes for carers are being introduced, little is known about either their impact on carers and volunteers or about volunteers' and carers' experiences. This study investigated peer volunteer and carer recipient experiences of a peer support service. Thematic analysis of 13 in-depth interviews with 9 carers and 4 peer volunteers revealed that peer support helped both carers and peer volunteers through the realization that they were "not alone" in their experiences and emotions. Additional carer benefits included opportunities to talk freely about difficult experiences and learning how others cope. Volunteers found their role rewarding, describing satisfaction from putting their own experiences to good use. These findings highlight the isolation and exclusion experienced by current and former carers of people with dementia and draw attention to the benefits of peer support for both the groups. PMID- 23813791 TI - Brain Metabolic Dysfunction in Capgras Delusion During Alzheimer's Disease: A Positron Emission Tomography Study. AB - Capgras delusion is characterized by the misidentification of people and by the delusional belief that the misidentified persons have been replaced by impostors, generally perceived as persecutors. Since little is known regarding the neural correlates of Capgras syndrome, the cerebral metabolic pattern of a patient with probable Alzheimer's disease (AD) and Capgras syndrome was compared with those of 24-healthy elderly participants and 26 patients with AD without delusional syndrome. Comparing the healthy group with the AD group, the patient with AD had significant hypometabolism in frontal and posterior midline structures. In the light of current neural models of face perception, our patients with Capgras syndrome may be related to impaired recognition of a familiar face, subserved by the posterior cingulate/precuneus cortex, and impaired reflection about personally relevant knowledge related to a face, subserved by the dorsomedial prefrontal cortex. PMID- 23813792 TI - Impact of dementia progression on food-related processes: a qualitative study of caregivers' perspectives. AB - As dementia progresses, one area that can help maintain connection and memories with others is within the food domain. There is little research in this area particularly from the informal caregivers' perspectives. Therefore, a qualitative study was conducted to explore the impact of dementia progression on food-related processes from the perspectives of informal caregivers. The aim of the study was to document the methodology used and to disseminate the findings to researchers, care providers, and policy makers. A total of 10 men and 10 women caregivers of those with dementia underwent a semistructured interview. Transcripts were analyzed using thematic analysis. The caregivers' narratives indicated a set pattern of decline, with food shopping being the first ability to decline, followed by food preparation and the ability to eat. Caregivers adapted to their food roles, for example, by becoming responsible for financial issues. These adaptations were described as stressful yet satisfying as food care was seen as an important social time. Educating caregivers' about the likely adaptations to food processes may increase food satisfaction in both the parties. PMID- 23813793 TI - Impact of hydrostatic pressure on an intrinsically disordered protein: a high pressure NMR study of alpha-synuclein. AB - The impact of pressure on the backbone (15) N, (1) H and (13) C chemical shifts in N-terminally acetylated alpha-synuclein has been evaluated over a pressure range 1-2500 bar. Even while the chemical shifts fall very close to random coil values, as expected for an intrinsically disordered protein, substantial deviations in the pressure dependence of the chemical shifts are seen relative to those in short model peptides. In particular, the nonlinear pressure response of the (1) H(N) chemical shifts, which commonly is associated with the presence of low-lying "excited states", is much larger in alpha-synuclein than in model peptides. The linear pressure response of (1) H(N) chemical shift, commonly linked to H-bond length change, correlates well with those in short model peptides, and is found to be anticorrelated with its temperature dependence. The pressure dependence of (13) C chemical shifts shows remarkably large variations, even when accounting for residue type, and do not point to a clear shift in population between different regions of the Ramachandran map. However, a nearly universal decrease in (3) JHN-Halpha by 0.22 +/- 0.05 Hz suggests a slight increase in population of the polyproline II region at 2500 bar. The first six residues of N-terminally acetylated synuclein show a transient of approximately 15% population of alpha-helix, which slightly diminishes at 2500 bar. The backbone dynamics of the protein is not visibly affected beyond the effect of slight increase in water viscosity at 2500 bar. PMID- 23813794 TI - Blood Supply to the human spinal cord: part II. Imaging and pathology. AB - The blood supply of the spinal cord is a complex system based on multilevel sources and anastomoses. Diseases often affect this vascular supply and imaging has been developed that better investigates these structures. The authors review the literature regarding pathology and imaging modalities for the blood supply of the spinal cord. Knowledge of the disease processes and imaging modalities used to investigate these arterial lesions of the spinal cord will assist the clinician when treating patients with spinal cord lesions. PMID- 23813795 TI - General practitioner involvement in follow-up of childhood cancer survivors: a systematic review. AB - BACKGROUND: An increasing number of childhood cancer survivors need long-term follow-up care. Different models address this problem, including that of follow up by general practitioners (GP). We describe models that involve GPs in follow up for childhood cancer survivors, their advantages and disadvantages, clinics that employ these models, and the elements essential to high-quality, GP-led follow-up care. PROCEDURE: We searched four databases (PubMed [including Medline], Embase, Cochrane, and CINAHL) without language restrictions. RESULTS: We found 26 publications, which explicitly mentioned GP-led follow-up. Two models were commonly described: GP-only, and shared care between GP and pediatric oncology or late effects clinic. The shared care model appears to have advantages over GP-only follow-up. We found four clinics using models of GP-led follow-up, described in five papers. We identified well-organized transition, treatment summary, survivorship care plan, education of GPs and guidelines as necessary components of successful follow-up. CONCLUSION: Scarcity of literature necessitated a review rather than a meta-analysis. More research on the outcomes of GP-led care is necessary to confirm the model for follow-up of childhood cancer survivors in the long term. However, with the necessary elements in place, the model of GP-led follow-up, and shared care in particular, holds promise. PMID- 23813796 TI - Mutations in VLDLR associated with ataxia with secondary vitamin E deficiency. PMID- 23813797 TI - The role of human cytochrome P450 enzymes in the formation of 2 hydroxymetronidazole: CYP2A6 is the high affinity (low Km) catalyst. AB - Despite metronidazole's widespread clinical use since the 1960s, the specific enzymes involved in its biotransformation have not been previously identified. Hence, in vitro studies were conducted to identify and characterize the cytochrome P450 enzymes involved in the formation of the major metabolite, 2 hydroxymetronidazole. Formation of 2-hydroxymetronidazole in human liver microsomes was consistent with biphasic, Michaelis-Menten kinetics. Although several cDNA-expressed P450 enzymes catalyzed 2-hydroxymetronidazole formation at a supratherapeutic concentration of metronidazole (2000 MUM), at a "therapeutic concentration" of 100 MUM only CYPs 2A6, 3A4, 3A5, and 3A7 catalyzed metronidazole 2-hydroxylation at rates substantially greater than control vector, and CYP2A6 catalyzed 2-hydroxymetronidazole formation at rates 6-fold higher than the next most active enzyme. Kinetic studies with these recombinant enzymes revealed that CYP2A6 has a Km = 289 MUM which is comparable to the Km for the high-affinity (low-Km) enzyme in human liver microsomes, whereas the Km values for the CYP3A enzymes corresponded with the low-affinity (high-Km) component. The sample-to-sample variation in 2-hydroxymetronidazole formation correlated significantly with CYP2A6 activity (r >= 0.970, P < 0.001) at substrate concentrations of 100 and 300 MUM. Selective chemical inhibitors of CYP2A6 inhibited metronidazole 2-hydroxylation in a concentration-dependent manner and inhibitory antibodies against CYP2A6 virtually eliminated metronidazole 2 hydroxylation (>99%). Chemical and antibody inhibitors of other P450 enzymes had little or no effect on metronidazole 2-hydroxylation. These results suggest that CYP2A6 is the primary catalyst responsible for the 2-hydroxylation of metronidazole, a reaction that may function as a marker of CYP2A6 activity both in vitro and in vivo. PMID- 23813798 TI - Dynamic motion of Ru-polyoxometalate ions (POMs) on functionalized few-layer graphene. PMID- 23813799 TI - Predicting and assessing fall risk in an acute inpatient rehabilitation facility. AB - PURPOSE: Unintentional falls account for 70% of all hospital accidents. The objective of this study was to identify risk factors for falls and develop an assessment tool specific for an inpatient rehabilitation facility setting. DESIGN/METHOD: Diagnosis and Functional Independence Measure (FIM) scores were collected for 174 patients to assess predictors for fall risk. Independent t tests, chi-square, and logistic regression analysis were conducted to examine differences between fallers and nonfallers. FINDINGS: We identified several risk factors for falls including 4 FIM items: toileting, bed transfer, tub/shower transfer, and stairs; and three diagnoses: right stroke, traumatic brain injury, and amputation. From these findings, we completed initial development of a risk assessment tool. CONCLUSIONS: Evaluation of the tool suggests good specificity with 20%-30% of the patient population identified as high risk and good sensitivity by correctly predicting nearly 90% of patient falls. CLINICAL RELEVANCE: Continued evaluation of this assessment tool is needed to identify effectiveness in predicting patients who are at high risk for falling. PMID- 23813800 TI - Age, graft size, and Tegner activity level as predictors of failure in anterior cruciate ligament reconstruction with hamstring autograft. AB - BACKGROUND: Patient age, Tegner activity level, and graft size could be factors that influence the outcome of anterior cruciate ligament reconstruction (ACLR) with hamstring autografts. HYPOTHESIS: Decreased graft size, higher Tegner activity score, and younger age are associated with an increased failure rate of ACLR, represented by continued knee laxity and revision surgery. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 98 patients who had undergone ACLR with hamstring tendon autografts between 2000 and 2007 were identified from a computerized relational database. Inclusion criteria consisted of a minimum of 2 years of follow-up, all age groups, and all activity levels. Exclusion criteria consisted of treatment with other grafts or previous ligament surgery, previous ACL repairs, bilateral ACL injuries, and associated ligament tears. Failure was defined as a 2+ Lachman result, positive pivot shift, and 5-mm difference or more on KT-1000 arthrometer measurement. RESULTS: Fifteen of the 98 ACLRs (15.3%) were defined as failures. Of the failures, 12 of 48 (25%) occurred in patients aged 25 years and younger, whereas 3 of 50 (6%) occurred in patients older than 25 years. There was a statistically significant association when comparing failure rate and age groups (P = .009); however, a significant association was not found between graft size and failure rate in the entire study population (P = .135) or within the different age groups (age <=25 years vs. >25 years) based on failure rate (P = .390 and P = .165, respectively). No statistical significance was found when Tegner activity level and failure rate were compared in the overall study population (P = .463) or within age groups (<=25 years, P = .707; >25 years, P = .174). CONCLUSION: In this study population, younger patients (<=25 years) demonstrated a higher failure rate compared with the over-25 age group. A statistically significant difference was not found in terms of graft size and activity level correlating with failure rate in ACL reconstruction with hamstring autograft. PMID- 23813801 TI - Diagnosis and management of symptomatic muscle herniation of the extremities: a retrospective review. AB - BACKGROUND: There is a paucity of published literature on diagnosis and surgical management of muscle herniation of the extremities, with most reported cases involving military personnel and men aged 18 to 40 years. Hypothesis/ PURPOSE: The purpose of this study is to describe the presentation, diagnosis, and results of fasciotomy for symptomatic muscle herniation in young athletes. We hypothesize that fasciotomy can be a safe and effective treatment option that allows the majority of athletes to return to sports. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: From 2001 to 2011, 26 athletes (19 women; 11 runners) with a mean age 19.0 +/- 4.0 years (range, 14.2-28.4 years) underwent fasciotomy for symptomatic muscle herniation at the authors' institution. Retrospective chart review recorded pertinent patient data and clinical course. Questionnaires were sent to all patients to assess satisfaction with surgery, ability to return to sports, and residual symptoms. RESULTS: Muscle hernias were classified as primary (n = 8, 31%), postsurgical (n = 8, 31%), and associated with underlying untreated chronic exertional compartment syndrome (n = 10, 38%). The tibialis anterior muscle (n = 12, 46%) was most commonly involved. The mean time from onset of symptoms to surgery was 15.1 +/- 8.6 months (range, 3-38 months). Dynamic ultrasound (5/6 patients, 83%) was more accurate than magnetic resonance imaging (3/18, 17%) at identifying the hernia. At median follow-up of 28 months (range, 12-127 months), 17 patients (65%) had returned to sports. Seventeen patients (65%) completed the postoperative questionnaire; 14 reported being satisfied with their results (82%). Mild residual symptoms were common (9 of 17 respondents, 53%), especially in runners (5 of 7, 71%), all of whom were satisfied with surgery. Patients with a postsurgical muscle herniation took the longest to return to sports and were the least likely to return to sports, had the highest rate of dissatisfaction with surgery, and were most likely to have persistent symptoms not improved by surgery. CONCLUSION: Fasciotomy is a safe surgical option for symptomatic muscle herniation in young athletes. Many patients are able to return to sports and most are satisfied with surgery. Residual symptoms are common, especially in runners. Patients with postsurgical muscle herniations may have the worst clinical outcome. PMID- 23813802 TI - Analysis of 16,192 anterior cruciate ligament reconstructions from a community based registry. AB - BACKGROUND: Orthopaedic registries have shown value in tracking and surveillance of patients, implants, and outcomes associated with procedures. No current anterior cruciate ligament reconstruction registry (ACLRR) exists in the United States. PURPOSE: To describe the current cohort captured by an institutional ACLRR and describe the outcomes observed in the registered patients and how findings from the ACLRR are disseminated. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: The anterior cruciate ligament reconstructions (ACLRs) registered between February 2005 and September 2011 by 244 surgeons in 48 medical centers were evaluated. The ACLRR collected data intra- and postoperatively using paper forms and electronic medical records. The ACLRR cohort was longitudinally followed and outcomes were prospectively ascertained. Outcomes (ie, revisions, subsequent operations, venous thromboembolism, and surgical site infections) were adjudicated via chart review. Descriptive statistics are used to describe the cohort and Kaplan-Meier curves to evaluate survival. RESULTS: During the study period, 16,192 ACLRs (15,101 primary and 1091 revisions) with a median follow-up of 1.6 years (interquartile range, 0.7-2.8 years) were registered. Male patients received 64% of both primary and revision ACLRs. The mean age at surgery was 29.5 years (SD, 11.4 years) for primary and revision reconstructions. Cartilage injuries were noted in 25.2% of primary and 37.5% of revision ACLRs, and meniscal injuries were identified in 60.8% and 53.2%, respectively. Autografts were used in 57.6% of primary ACLRs and 20.9% of revisions. Allografts were used in 42.4% of primaries and 78.8% of revisions. In primary ACLR, the most common femoral and tibial fixation types were interference screws (42.2% and 79.7%, respectively). Fixation type distribution was nearly identical in primaries and revisions. Of the primary ACLRs, 3.7% had subsequent operations on the same knee and 1.7% on the contralateral knee. Deep surgical site infection developed in 0.3% of primaries and 0.8% of revisions. Symptomatic deep vein thromboses were seen in 0.2% of both primaries and revisions. The overall revision rate was 1.7%. Lower rates of graft survival were identified in younger patients and those with allografts. CONCLUSION: Large, community-based ACLRRs are useful in informing participating surgeons of current treatment practices, prevalence of concurrent injuries, and outcomes associated with the procedures. Information from the ACLRR can be used to develop interactive patient and surgeon tools that can be used to optimize patient care. PMID- 23813803 TI - Oxytocin projections to the nucleus of the solitary tract contribute to the increased meal-related satiety responses in primary adrenal insufficiency. AB - Anorexia is a common clinical manifestation of primary adrenal gland failure. Adrenalectomy (ADX)-induced hypophagia is reversed by oxytocin (OT) receptor antagonist and is associated with increased activation of satiety-related responses in the nucleus of the solitary tract (NTS). This study evaluated OT projections from the paraventricular nucleus of the hypothalamus (PVN) to the NTS after ADX and the effect of pretreatment with intracerebroventricular injection of an OT receptor antagonist ([d(CH2)5,Tyr(Me)(2),Orn(8)]-vasotocin; OVT) on the activation of NTS neurons induced by feeding in adrenalectomized rats. Adrenalectomized animals showed higher OT labelling in the NTS than the sham and the ADX with corticosterone replacement (ADX + B) groups. Adrenalectomized animals exhibited co-localization of the anterograde tracer Phaseolus vulgaris leucoagglutinin and OT in axons in the NTS as well as OT fibres apposing NTS neurons activated by refeeding. After vehicle pretreatment, compared with fasting, refeeding increased the numbers of Fos- and Fos + TH-immunoreactive neurons in the NTS in sham, ADX and ADX + B groups, with a higher number of these immunolabelled neurons in adrenalectomized animals. Compared with fasting conditions, refeeding also increased the activation of NTS neurons in OVT pretreated sham, ADX and ADX + B groups, but there was no difference among the three experimental groups. These data demonstrate that OT is upregulated in projections to the NTS following ADX and that OT receptor antagonist reverses the greater activation of NTS neurons induced by feeding after ADX. The data indicate that OT pathways to the NTS contribute to higher satiety-related responses and, thus, to reduce meal size in primary adrenal insufficiency. PMID- 23813804 TI - Cystine dimethylester loading promotes oxidative stress and a reduction in ATP independent of lysosomal cystine accumulation in a human proximal tubular epithelial cell line. AB - Using the cystine dimethylester (CDME) loading technique to achieve elevated lysosomal cystine levels, ATP depletion has previously been postulated to be responsible for the renal dysfunction in cystinosis, a genetic disorder characterized by an excessive accumulation of cystine in the lysosomes. However, this is unlikely to be the sole factor responsible for the complexity of cell stress associated with cystinosis. Moreover, CDME has been shown to induce a direct toxic effect on mitochondrial ATP generation. Using a human-derived proximal tubular epithelial cell line, we compared the effects of CDME loading with small interfering RNA-mediated cystinosin, lysosomal cystine transporter (CTNS) gene silencing on glutathione redox status, reactive oxygen species levels, oxidative stress index, antioxidant enzyme activities and ATP generating capacity. The CDME-loaded cells displayed increased total glutathione content, extensive superoxide depletion, augmented oxidative stress index, decreased catalase activity, normal superoxide dismutase activity and compromised ATP generation. In contrast, cells subjected to CTNS gene inhibition demonstrated decreased total glutathione content, increased superoxide levels, unaltered oxidative stress index, unaltered catalase activity, induction of superoxide dismutase activity and normal ATP generation. Our data indicate that many CDME induced effects are independent of lysosomal cystine accumulation, which further underscores the limited value of CDME loading for studying the pathogenesis of cystinosis. CTNS gene inhibition, which results in intracellular cystine accumulation, is a more realistic approach for investigating biochemical alterations in cystinosis. PMID- 23813806 TI - Adjuvant chemotherapy in elderly women with breast cancer: patients' perspectives on information giving and decision making. AB - BACKGROUND: Decisions about adjuvant chemotherapy in older women with early stage breast cancer (EBC) are often challenging. Uncertainty about benefits due to limited data about treatment efficacy and outcomes complicates decision making. This qualitative study explored older patients' experiences and preferences towards information giving and ultimate decisions about adjuvant chemotherapy. METHODS: Clinicians from 24 UK breast cancer teams reported on adjuvant chemotherapy decisions for women aged >=70 years with EBC from April 2010 to December 2011. Women who were offered chemotherapy were invited to participate in structured interviews. Self-reported quality of life (QoL) and functional ability were assessed. Qualitative methods were used to identify themes associated with information giving and decision making. RESULTS: A total of 58/95 eligible women (61%) participated. Median age was 73 years (range 70-83). Mean total scores for QoL and functional ability were average. The majority of women preferred to make their treatment decisions collaboratively with a clinician (59%) or on their own (19%). The main reasons influencing decisions to accept chemotherapy were categorised as prevention of recurrence and clinician recommendation. Side effects, length of treatment, impact on QoL, low survival benefits and clinician recommendation influenced decisions to decline chemotherapy. The majority (80%) were satisfied with information provision, the communication with their clinician and explanation of treatment. CONCLUSIONS: Older women with EBC preferred to be involved in clinical decision making. Clinician recommendation plays a significant role in either accepting or declining chemotherapy. Well-informed decision making and effective communication between clinicians, older women and their family members are therefore important. PMID- 23813807 TI - Hydrolysis of insoluble cellulose to glucose catalyzed by cellulase-containing liposomes in an aqueous solution of 1-butyl-3-methylimidazolium chloride. AB - The liposome containing cellulase from Trichoderma viride was prepared under the condition that an appreciable amount of cellulase was incorporated in lipid membranes. The liposomal cellulase and free enzyme were examined in their hydrolytic activities to insoluble cellulose powder CC31 in the acetate buffer solution (pH 4.8) of 15 w/w% [Bmim][Cl] (1-butyl-3-methylimidazolium chloride). The mean diameter and size distribution of cellulase-containing liposome were practically unchanged under the above condition. The free cellulase was deactivated more rapidly than the liposomal cellulase in catalyzing the hydrolysis of 2.0 g/l CC31 at 45 degrees C in the presence of [Bmim][Cl] for 48 h. The activities of liposomal and free cellulase to cellobiose as soluble substrate were less susceptible to [Bmim][Cl] than their cellulolytic activities to CC31, meaning that beta-glucosidase is relatively stable among the three enzyme components of cellulase. The rate of glucose production could be appreciably improved by the pretreatment of CC31 with [Bmim][Cl] alone at 120 degrees C for 30 min followed by the liposomal cellulase-catalyzed hydrolysis of the substrate at 45 degrees C at the [Bmim][Cl] concentration of 15 w/w%. PMID- 23813805 TI - Transcriptional impact of dietary methionine restriction on systemic inflammation: relevance to biomarkers of metabolic disease during aging. AB - Calorie restriction (CR) without malnutrition increases lifespan and produces significant improvements in biomarkers of metabolic health. The improvements are attributable in part to effects of CR on energy balance, which limit fat accumulation by restricting energy intake. Normal age-associated increases in adiposity and insulin resistance are associated with development of a systemic proinflammatory state, while chronic CR limits fat deposition and expression of inflammatory markers. Dietary methionine restriction (MR) has emerged as an effective CR mimetic because it produces a comparable extension in lifespan. MR also reduces adiposity through a compensatory increase in energy expenditure that effectively limits fat accumulation, but essentially nothing is known about the effects of MR on systemic inflammation. Here, we review the relationships between these two interventions and discuss their transcriptional impact. In addition, using tissues from rats after long-term consumption of CR or MR diets, transcriptional profiling was used to examine retrospectively the systems biology of 59 networks of molecules annotated to inflammation. Transcriptional effects of both diets occurred primarily in white adipose tissue and liver, and the responses to MR were far more robust than those to CR. The primary transcriptional targets of MR in both liver and white adipose tissue were phagocytes and macrophages, where expression of genes associated with immune cell infiltration and quantity was reduced. These findings support the conclusion that anti-inflammatory responses produced by CR and MR are not strictly dependent upon reduced adiposity but are significantly influenced by the metabolic mechanisms through which energy balance is altered. PMID- 23813809 TI - Venturing further into feline infectious disease. PMID- 23813808 TI - Lipid-modified aminoglycoside derivatives for in vivo siRNA delivery. AB - Rationally designed siRNA delivery materials that are enabled by lipid-modified aminoglycosides are demonstrated. Leading materials identified are able to self assemble with siRNA into well-defined nanoparticles and induce efficient gene knockdown both in vitro and in vivo. Histology studies and liver function tests reveal that no apparent toxicity is caused by these nanoparticles at doses over two orders of magnitude. PMID- 23813810 TI - ABCD: Update of the 2009 guidelines on prevention and management of feline infectious diseases. AB - OVERVIEW: In this article, the ABCD guidelines published in the JFMS Special Issue of July 2009 (Volume 11, Issue 7, pages 527-620) are updated by including previously unavailable and novel information. For a better picture, the reader is advised to consult that issue before focusing on the novel features. PMID- 23813811 TI - Matrix vaccination guidelines: ABCD recommendations for indoor/ outdoor cats, rescue shelter cats and breeding catteries. AB - OVERVIEW: This article presents, in a user-friendly, tabluated form, the ABCD's current vaccination recommendations for four broad categories of cats: outdoor cats (ie, those with access outdoors that come into contact with other cats outdoors); indoor cats (ie, those with no contact with other cats from outdoors); rescue shelter cats; and cats in breeding catteries. Note that it is not always possible to make a clear distinction between these various categories and the definition in any individual case is left up to the veterinary surgeon conducting the vaccination interview. PMID- 23813812 TI - Prevention of infectious diseases in cat shelters: ABCD guidelines. AB - OVERVIEW: Recommendations are given in relation to infectious diseases in rescue shelters. The ABCD recognises that there is a wide variation in the design and management of shelters, and that these largely reflect local pressures. These guidelines are written with this diverse audience in mind; they point to the ideal, and also provide for some level of compromise where this ideal cannot immediately be attained. In addition consideration should be given to general requirements in order to optimise overall health and wellbeing of cats within the shelter. HOUSING: Compartmentalisation of the shelter into at least three individual sections (quarantine area for incoming cats, isolation facilities for sick or potentially infectious cats, and accommodation for clinically healthy, retrovirus-negative cats) can facilitate containment of a disease outbreak, should it occur. STANDARD OF CARE: Incoming cats should receive a full health check by a veterinary surgeon, should be dewormed and tested for retrovirus infections (feline leukaemia virus [FeLV] and/or feline immunodeficiency virus [FIV]) in regions with high prevalence and in shelters that allow contact between cats. Cats which are not rehomed should receive a regular veterinary check-up at intervals recommended by their veterinarian. VACCINATION: Each cat should be vaccinated as soon as possible against feline panleukopenia virus (FPV), feline herpesvirus (FHV-1) and feline calicivirus (FCV) infections. HYGIENE: Adequate hygiene conditions should ensure that contact between shedders of infectious agents and susceptible animals is reduced as efficiently as possible by movement control, hygiene procedures of care workers, barrier nursing, cleaning and disinfection. STRESS REDUCTION: Stress reduction is important for overall health and for minimising the risk of recrudescence and exacerbation of infectious diseases. In general, a special effort should be made to rehome cats as soon as possible. PMID- 23813813 TI - Aujeszky's disease/pseudorabies in cats: ABCD guidelines on prevention and management. AB - OVERVIEW: Although pseudorabies in swine - Aujeszky's disease - has been eradicated from many pork-producing countries, the virus may still lurk in other vertebrate species and cause feline cases. Infection occurs through the ingestion of uncooked meat and organ material and presents as an acute encephalitis with a short incubation period and a rapidly fatal outcome. The ABCD considers this reason enough to include a review of this, now very rare, condition in this Special Issue. PMID- 23813814 TI - Cowpox virus infection in cats: ABCD guidelines on prevention and management. AB - OVERVIEW: The misnomer 'cowpox' has historical roots: cats rather acquire the virus from small rodents. It has a wide host spectrum (including man) and causes skin lesions, predominantly on the head and paws. Progressive proliferative ulcerations in kittens and immunosuppressed cats may take a fatal course. Cat owners should be informed about the zoonotic risk. PMID- 23813815 TI - Feline viral papillomatosis: ABCD guidelines on prevention and management. AB - OVERVIEW: Papillomaviruses are epitheliotropic and cause cutaneous lesions in man and several animal species, including cats. INFECTION: Cats most likely become infected through lesions or abrasions of the skin. Species-specific viruses have been detected but human and bovine related sequences have also been found, suggesting cross-species transmission. CLINICAL SIGNS: In cats, papillomaviruses are associated with four different skin lesions: hyperkeratotic plaques, which can progress into Bowenoid in situ carcinomas (BISCs) and further to invasive squamous cell carcinomas (ISCCs); cutaneous fibropapillomas or feline sarcoids; and cutaneous papillomas. However, papillomaviruses have also been found in normal skin. DIAGNOSIS: Papillomavirus-induced skin lesions can be diagnosed by demonstration of papillomavirus antigen in biopsies of skin lesions, or detection of papillomavirus-like particles by electron microscopy and papillomavirus DNA by polymerase chain reaction (PCR). TREATMENT: Spontaneous regression might be expected. In cases of ISCC, complete excision should be considered if possible. PMID- 23813816 TI - Bartonella species infection in cats: ABCD guidelines on prevention and management. AB - OVERVIEW: Over 22 Bartonella species have been described in mammals, and Bartonella henselae is most common worldwide. Cats are the main reservoir for this bacterium. B henselae is the causative agent of cat scratch disease in man, a self-limiting regional lymphadenopathy, but also of other potentially fatal disorders in immunocompromised people. INFECTION: B henselae is naturally transmitted among cats by the flea Ctenocephalides felis felis, or by flea faeces. A cat scratch is the common mode of transmission of the organism to other animals, including humans. Blood transfusion also represents a risk. DISEASE SIGNS: Most cats naturally infected by B henselae do not show clinical signs but cardiac (endocarditis, myocarditis) or ocular (uveitis) signs may be found in sporadic cases. B vinsonii subspecies berkhoffii infection has reportedly caused lameness in a cat affected by recurrent osteomyelitis and polyarthritis. DIAGNOSIS: Isolation of the bacterium is the gold standard, but because of the high prevalence of infection in healthy cats in endemic areas, a positive culture (or polymerase chain reaction) is not confirmatory. Other compatible diagnoses must be ruled out and response to therapy gives a definitive diagnosis. Serology (IFAT or ELISA) is more useful for exclusion of the infection because of the low positive predictive value (39-46%) compared with the good negative predictive value (87-97%). Laboratory testing is required for blood donors. DISEASE MANAGEMENT: Treatment is recommended in the rare cases where Bartonella actually causes disease. PMID- 23813817 TI - Pasteurella multocida infection in cats: ABCD guidelines on prevention and management. AB - OVERVIEW: Pasteurella species are part of the normal oral flora of cats. They are also a common cause of infection in this species and an important zoonotic agent. INFECTION IN CATS: Pasteurella species are commonly isolated from subcutaneous abscesses and pyothorax in cats. They may also cause secondary lower respiratory tract infection and have been associated with spinal empyema and meningoencephalomyelitis. INFECTION IN HUMANS: Disease in humans mainly occurs after a cat bite or scratch, but may also be transmitted via respiratory secretions from cats in close contact with a person. Signs of local infection after a cat bite appear in a few hours (3-6 h). Severe disease and a fatal outcome mostly occur in immunocompromised people, but have also been reported in immunocompetent healthy individuals. Cat ownership by immunocompromised people may carry a risk. PMID- 23813818 TI - Coxiellosis/Q fever in cats: ABCD guidelines on prevention and management. AB - OVERVIEW: Q fever is a zoonotic disease caused by Coxiella burnetii. Farm animals and pets are the main reservoirs of infection. INFECTION: Cats become infected by ingestion or inhalation of organisms from contaminated carcases of farm animals, or tick bites. Infection is common, as shown by several serological studies. CLINICAL SIGNS: Experimentally, fever, anorexia and lethargy have been noted. In the field, infection usually remains subclinical. Abortion might occur. C burnetii has been isolated from the placenta of aborting cats, but also from cats experiencing normal parturition. DIAGNOSIS: Infection with C burnetii can be diagnosed by isolation of the agent or serology. PREVENTION: Most important is the potential zoonotic risk. Cats suspected of having been exposed to C burnetii might shed organisms during parturition. Wearing gloves and a mask when attending parturient or aborting cats can minimise the risk of infection. Tick prevention is recommended. PMID- 23813819 TI - Leptospira species infection in cats: ABCD guidelines on prevention and management. AB - OVERVIEW: Leptospirosis is a bacterial disease affecting a variety of domestic and wild animals as well as humans worldwide. Leptospirosis has been reported in over 150 mammalian species. It is considered an emerging infectious disease in humans and in dogs. Subclinically infected wild and domestic animals serve as reservoir hosts and are a potential source of infection for incidental hosts and humans. INFECTION: Reports of leptospirosis in cats are rare, but the importance of cats shedding Leptospira species and serving as a source of infection has recently gained attention. Leptospira species antibodies are commonly present in the feline population, and Leptospira species shedding of cats with outdoor exposure has been demonstrated. Cats mostly become infected through transmission from hunting rodents. SIGNIFICANCE: The role of healthy carrier cats as a source of contamination, as well as the role of leptospires as a pathogen in cats, are likely underestimated. PMID- 23813820 TI - Yersinia pestis infection in cats: ABCD guidelines on prevention and management. AB - OVERVIEW: Plague, the medieval 'Black Death', is caused by a Gram-negative coccobacillus, Yersinia pestis, which also infects cats. As in people, it is transmitted from rodents through flea bites; it occurs in Asia, Africa and the Americas in flea-infested regions, all year round, and where rodent reservoirs are abundant. A poor prognosis is associated with high fever, and the pulmonary and septicaemic forms. Antibiotic therapy, flea control and avoidance of rodent contacts have made this infection manageable. PMID- 23813822 TI - Capnocytophaga canimorsus infection in cats: ABCD guidelines on prevention and management. AB - OVERVIEW: Capnocytophaga canimorsus and Capnocytophaga cynodegmi are part of the normal bacterial flora of the oral cavity of dogs and cats. C canimorsus is more pathogenic and causes more severe infections in humans. INFECTION: Disease is less frequently seen after a cat bite, scratch or close contact than after dog contacts. Serious disease has been reported in people, especially associated with immunocompromise and alcoholism. Disease in cats is not well documented; two cases of respiratory infection have been associated with the presence of these bacteria. DIAGNOSIS: Diagnosis is based on culture in specific media, but these are slow growing bacteria; polymerase chain reaction and sequencing may aid in diagnosis and species identification. TREATMENT: Penicillin or beta-lactams are the treatment options of choice. ZOONOTIC POTENTIAL: Based on incidence surveys, the zoonotic potential is low. The risk may be higher for immunocompromised persons, where dog and cat ownership must be discussed. PMID- 23813821 TI - Francisella tularensis infection in cats: ABCD guidelines on prevention and management. AB - OVERVIEW: Disease in cats after infection with the zoonotic bacterium Francisella tularensis has been reported only from North America; rodents and lagomorphs are the more susceptible hosts. Tularaemia is transmitted by ticks, but also acquired by direct contact, bite, scratch, ingestion or inhalation. Clinical signs range from mild chronic localised infections to fatal acute disease; antibiotic therapy is efficient. Acquiring the infection from cats is a risk for owners of outdoor cats, veterinarians and technicians. PMID- 23813823 TI - Mycobacterioses in cats: ABCD guidelines on prevention and management. AB - OVERVIEW: Mycobacterial infections are important in humans and animals. Cats can be infected by several Mycobacterium species, which may cause different syndromes, mainly tuberculosis, atypical or non-tuberculous mycobacteriosis and leprosy. In recent years, awareness has increased about how to recognise and confirm these infections. More cases are diagnosed today, which probably means that the disease has escaped detection in the past. INFECTION: Most cases in cats are cutaneous, presenting as nodules in the skin and draining tracts, ulceration and local lymphadenopathy; however, systemic dissemination may also occur. DIAGNOSIS: Definitive diagnosis is difficult when the bacterium cannot be detected by histology or culture. However, species confirmation is essential for treatment and prognosis, so material for culture and polymerase chain reaction should be submitted in every suspected case. TREATMENT: Treatment is challenging. A combination of two or three antibiotics is needed, and treatment must be continued for some months, which makes owner compliance especially difficult in cats. ZOONOTIC RISK: There is a zoonotic risk associated with some mycobacterial species. Concerns should be communicated in every case of an immunocompromised owner in contact with an infected cat. PMID- 23813824 TI - Dermatophytosis in cats: ABCD guidelines on prevention and management. AB - OVERVIEW: Dermatophytosis, usually caused by Microsporum canis, is the most common fungal infection in cats worldwide, and one of the most important infectious skin diseases in this species. Many adult cats are asymptomatic carriers. Severe clinical signs are seen mostly in kittens or immunosuppressed adults. Poor hygiene is a predisposing factor, and the disease may be endemic in shelters or catteries. Humans may be easily infected and develop a similar skin disease. INFECTION: Infectious arthrospores produced by dermatophytes may survive in the environment for about a year. They are transmitted through contact with sick cats or healthy carriers, but also on dust particles, brushes, clothes and other fomites. DISEASE SIGNS: Circular alopecia, desquamation and sometimes an erythematous margin around central healing ('ringworm') are typical. In many cats this is a self-limiting disease with hair loss and scaling only. In immunosuppressed animals, the outcome may be a multifocal or generalised skin disease. DIAGNOSIS: Wood's lamp examination and microscopic detection of arthrospores on hairs are simple methods to confirm M canis infection, but their sensitivity is relatively low. The gold standard for detection is culture on Sabouraud agar of hairs and scales collected from new lesions. DISEASE MANAGEMENT: In shelters and catteries eradication is difficult. Essential is a combination of systemic and topical treatments, maintained for several weeks. For systemic therapy itraconazole is the drug of choice, terbinafine an alternative. Recommended topical treatment is repeated body rinse with an enilconazole solution or miconazole with or without chlorhexidine. In catteries/shelters medication must be accompanied by intensive decontamination of the environment. VACCINATION: Few efficacy studies on anti-M canis vaccines (prophylactic or therapeutic) for cats have been published, and a safe and efficient vaccine is not available. PMID- 23813825 TI - Aspergillosis in cats: ABCD guidelines on prevention and management. AB - OVERVIEW: Aspergillosis is a sporadic mycosis that occurs worldwide in mammals and birds and leads to a usually chronic, and only rarely acute, disease that mainly affects the nasal cavity and sinuses. INFECTION: Aspergillus species infections are commonly associated with predisposing local or systemic factors. Local disease can spread and involve the central nervous system or the lungs. Some Aspergillus species can also disseminate, causing systemic infections. In contrast to dogs, in which (nasal) aspergillosis is relatively common, aspergillosis is rare in cats, but considered an emerging infection. CLINICAL SIGNS: There are two clinical forms of aspergillosis in cats, the sinonasal form (characterised by signs of chronic nasal infection) and the newly emerging, more invasive sino-orbital form (characterised by signs of orbital and surrounding tissue invasion). Sino-orbital involvement has been described now in approximately half of the reported cases. DISEASE MANAGEMENT: Treatment should consist of local and systemic antifungal therapy. PMID- 23813826 TI - Cryptococcosis in cats: ABCD guidelines on prevention and management. AB - OVERVIEW: Cryptococcosis is worldwide the most common systemic fungal disease in cats; it is caused by the Cryptococcus neoformans- Cryptococcus gattii species complex, which includes eight genotypes and some subtypes (strains) with varying geographical distribution, pathogenicity and antimicrobial susceptibility. Cats acquire the infection from a contaminated environment. The prognosis is favourable in most cases, provided a diagnosis is obtained sufficiently early and prolonged treatment is maintained. INFECTION: Basidiospores are the infectious propagules of Cryptococcus species as they penetrate the respiratory system and induce primary infection. Asymptomatic colonisation of the respiratory tract is more common than clinical disease. Avian guanos, particularly pigeon droppings, offer favourable conditions for the reproduction of C neoformans. Both Cryptococcus species are associated with decaying vegetation. DISEASE SIGNS: Cryptococcosis caused by C neoformans or C gattii is indistinguishable clinically. The disease can present in nasal, central nervous system (which can derive from the nasal form or occur independently), cutaneous and systemic forms. DIAGNOSIS: An easy and reliable test for cryptococcosis diagnosis is antigen detection in body fluids. Only isolation and polymerase chain reaction allow identification of the species genotype. DISEASE MANAGEMENT: Amphotericin B, ketoconazole, fluconazole and itraconazole have all been used to treat cats. Surgical excision of any nodules in the skin, nasal or oral mucosa assists recovery. Continued treatment is recommended until the antigen test is negative. PREVENTION: Efficient preventive measures have not been demonstrated. Vaccines are not available. PMID- 23813827 TI - Sporotrichosis in cats: ABCD guidelines on prevention and management. AB - OVERVIEW: Sporotrichosis is an important subcutaneous fungal infection of humans and animals in some endemic tropical and subtropical areas. Among domestic species, cats are the most frequently infected. INFECTION: The primary mode of transmission is traumatic inoculation of fungal conidia from plants and soil. Contact with infected cats is the major mode of transmission to humans, especially in endemic areas like Brazil, where a large epidemic has occurred in the past decade. DISEASE SIGNS: Most cases in cats are cutaneous, presenting as multiple ulcerated nodules and draining tracts in the skin. Lymphadenopathy, respiratory signs and systemic dissemination may also occur. DIAGNOSIS: Diagnosis is based on fungal detection by cytology and/or histology, and confirmation by culture. TREATMENT: Treatment consists of at least 2 months' systemic antifungal therapy, with itraconazole as the first-choice agent. The prognosis is favourable provided there is good owner compliance and adverse drug effects do not occur. PREVENTION: Contact with infected cats carries a high zoonotic risk. Cat owners travelling to endemic areas should be warned and advised to keep their cats indoors to prevent infection. Professionals must wear gloves when handling cats with skin nodules and ulcers and dealing with diagnostic samples. PMID- 23813828 TI - Rare systemic mycoses in cats: blastomycosis, histoplasmosis and coccidioidomycosis: ABCD guidelines on prevention and management. AB - OVERVIEW: Rare fungal infections, including those hitherto not reported in Europe, may occur sporadically in non-endemic areas, or imported cases may be seen. INFECTIONS: Blastomycosis is mainly seen in North America; no cases have been reported in Europe. Histoplasmosis, which is endemic in the eastern US, Central and South America, has been diagnosed in Japan and Europe. Coccidioidomycosis is endemic in the southwestern US, Central and South America; only one imported case has been reported in Europe. The primary mode of transmission is inhalation of conidia or spores from the environment. DISEASE SIGNS: Most feline cases present with a combination of clinical signs (mainly respiratory, along with skin, eye, central nervous system and bone). Lymphadenopathy and systemic signs may be present. DIAGNOSIS: Diagnosis is based on fungal detection by cytology and/or histology. Commercial laboratories do not routinely perform fungal culture. Diagnosis of coccidioidomycosis, which is more difficult, may be supported by antibody detection. TREATMENT: Treatment consists of prolonged systemic antifungal therapy, with itraconazole as the first-choice agent for histoplasmosis and blastomycosis. The prognosis is good if owner compliance is adequate and adverse drug effects do not occur. PREVENTION: Cat owners travelling to endemic areas should be warned about these diseases. There is no zoonotic risk. PMID- 23813829 TI - Rare opportunistic mycoses in cats: phaeohyphomycosis and hyalohyphomycosis: ABCD guidelines on prevention and management. AB - OVERVIEW: Phaeohyphomycoses and hyalohyphomycoses are rare opportunistic infections acquired from the environment. More cases have been reported in recent years in humans and cats. DISEASE SIGNS: Single or multiple nodules or ulcerated plaques (which may be pigmented) in the skin are the typical lesions. In some cases the infection disseminates or involves the central nervous system (CNS). DIAGNOSIS: Diagnosis is based on fungal detection by cytology and/or histology. Culture provides definitive diagnosis and species identification. TREATMENT: Treatment involves surgical excision in cases of localised skin disease followed by systemic antifungal therapy, with itraconazole as the agent of first choice. Relapses after treatment are common. Itraconazole and other systemic antifungal agents have been used to treat systemic or neurological cases, but the response is unpredictable. The prognosis is guarded to poor in cats with multiple lesions and systemic or neurological involvement. ZOONOTIC RISK: There is no zoonotic risk associated with contact with infected cats. PMID- 23813830 TI - Toxoplasma gondii infection in cats: ABCD guidelines on prevention and management. AB - OVERVIEW: Toxoplasma gondii infection is common in cats, but the clinical disease is rare. Up to 50% of cats, especially free-roaming ones, have antibodies indicating infection and the presence of cystic stages. DISEASE SIGNS: Clinical signs only appear in few cats when they become immunosuppressed - in these situations cystic stages can be reactivated. Commonly affected are the central nervous system (CNS), muscles, lungs and eyes. HUMAN INFECTION: Cats can pose a risk for humans when they shed oocysts. However, this happens only once in their lifetime, usually only for 3-10 days after ingestion of tissue cysts. Thus, cats that have antibodies to T gondii no longer shed oocysts, and do not pose a risk to humans. PMID- 23813831 TI - Leishmaniosis in cats: ABCD guidelines on prevention and management. AB - OVERVIEW: Leishmania infection is less known in cats than in dogs and humans; felids were traditionally considered a resistant species, and canids as the main reservoir. Only sporadic cases of feline disease have been reported worldwide, mainly caused by L infantum. Epidemiological investigations have confirmed, however, that feline infections are not rare and that disease occurrence might be underestimated in endemic areas. INFECTION: Cats are infected by the same Leishmania species that infect dogs and humans in tropical and subtropical areas worldwide. Sand fly vectors take blood meals from cats and are competent vectors for L infantum, as shown experimentally. DISEASE SIGNS: Skin lesions (ulcerative, crusty, nodular or scaly dermatitis) are the most frequent clinical manifestations and sometimes the only findings on physical examination. Lymph node enlargement, weight loss, ocular involvement (nodular blepharitis, uveitis, panophthalmitis), decreased appetite, chronic gingivostomatitis and lethargy are the most frequent non-cutaneous findings, alone or in combination. DIAGNOSIS: Direct confirmation can be obtained by cytology, histology, isolation or polymerase chain reaction (PCR) on samples of skin, lymph nodes, blood or any affected tissue. Serology using a validated immunofluorescence test, ELISA, direct agglutination or Western blot has been used to assess infection frequencies. DISEASE MANAGEMENT: Little information is available about treatment with follow-up reports. Long-term administration of allopurinol (10-20 mg/kg q12h or q24h) is usually clinical effective. Vaccines are licensed for dogs only. PMID- 23813832 TI - Babesiosis in cats: ABCD guidelines on prevention and management. AB - OVERVIEW: Babesiosis is a tick-borne protozoan disease caused by parasites of the genus Babesia that belong to the Piroplasmida. The disease is named after the Romanian bacteriologist Victor Babes. Babesiosis is also known as piroplasmosis (from Latin pirum, meaning 'pear', and plasma, 'image, formation'). INFECTION: Babesiosis affects domestic and wild animals and humans worldwide. While the disease is recognised in dogs around the world, it is found only rarely in cats. HUMAN DISEASE: Babesia species are common blood parasites of mammals. Human babesiosis is uncommon, but more cases in people have been reported recently, most likely because of rising awareness. PMID- 23813833 TI - Tritrichomoniasis in cats: ABCD guidelines on prevention and management. AB - OVERVIEW: Tritrichomonas foetus is a protozoan organism that is specific to cats and can cause large bowel diarrhoea. It is distinct from other Tritrichomonas species and not considered to be zoonotic. Infection is most common in young cats from multicat households, particularly pedigree breeding catteries. DISEASE SIGNS: Affected cats show frequent fetid diarrhoea, often with mucus, fresh blood and straining, but generally remain bright and do not lose weight. DIAGNOSIS: Diagnosis of infection is usually based on direct microscopic examination of freshly voided faeces. Polymerase chain reaction (PCR) testing is more sensitive but may detect infections unrelated to diarrhoea and, therefore, requires care in interpretation. TREATMENT: The treatment of choice is ronidazole, which should be used with care as it is an unlicensed drug for cats with a narrow safety margin. Clinical signs are generally self-limiting in untreated cases, but may take months to resolve. PMID- 23813834 TI - Giardiasis in cats: ABCD guidelines on prevention and management. AB - OVERVIEW: Giardia is a protozoan parasite that infects the small intestine of cats and can cause diarrhoea. The biotypes that affect cats do not appear to infect humans. Infection is most common in young cats, particularly from multicat backgrounds. DISEASE SIGNS: Infected cats that develop clinical signs show small intestinal diarrhoea and there may be associated weight loss. DIAGNOSIS: Diagnosis of infection is usually based on an in-practice ELISA for faecal antigen or zinc sulphate flotation of several pooled faecal samples. Polymerase chain reaction (PCR) tests are available but not used so widely. Infection can be detected in clinically healthy cats so interpretation of a positive result in cats with diarrhoea requires care. TREATMENT: Fenbendazole or metronidazole are regarded as the treatments of choice. Secondary gut changes may be slow to resolve and so diarrhoea may continue for some time after infection has been eliminated. PMID- 23813837 TI - Local cooling reduces regional bone blood flow. AB - Local cooling is very common after bone and joint surgery. Therefore the knowledge of bone blood flow during local cooling is of substantial interest. Previous studies revealed that hypothermia leads to vasoconstriction followed by decreased blood flow levels. The aim of this study was to characterize if local cooling is capable of inducing reduced blood flow in bone tissue using a stepwise reduced temperature protocol in experimental rabbits. To examine bone blood flow we utilized the fluorescent microsphere (FM) method. In New Zealand white rabbits one randomly chosen hind limb was cooled stepwise from 32 to 2 degrees C, whereas the contra lateral hind limb served as control. Injection of microspheres was performed after stabilization of bone and muscle temperature at each temperature level. Bones were removed, dissected and fluorescence intensity was determined to calculate blood flow values. We found that blood flow of all cooled regions decreased relative to the applied external temperature. At maximum cooling blood flow was almost completely disrupted, indicating local cooling as powerful regulatory mechanism for regional bone blood flow (RBBF). Postoperative cooling therefore may lead to strongly decreased bone blood flow values. As a result external cooling has capacity to both diminish bone healing and reduce bleeding complications. PMID- 23813838 TI - Structure-based design of small-molecule ligands of phosphofructokinase-2 activating or inhibiting glycolysis. AB - Glycolysis lies at the basis of metabolism and cell energy supply. The disregulation of glycolysis is involved in such pathological processes as cancer proliferation, neurodegenerative diseases, and amplification of ischemic damage. Phosphofructokinase-2 (PFK-2), a bifunctional enzyme and regulator of glycolytic flux, has recently emerged as a promising anticancer target. Herein, the computer aided design of a new class of aminofurazan-triazole regulators of PFK-2 is described along with the results of their in vitro evaluation. The aminofurazan triazoles differ from other recently described inhibitors of PFK-2 and demonstrate the ability to modulate glycolytic flux in rat muscle lysate, producing a twofold decrease by inhibitors and fourfold increase by activators. The most potent compounds in the series were shown to inhibit the kinase activity of the hypoxia-inducible form of PFK-2, PFKFB3, as well as proliferation of HeLa, lung adenocarcinoma, colon adenocarcinoma, and breast cancer cells at concentrations in the low micromolar range. PMID- 23813839 TI - Towards the accurate and efficient calculation of optical rotatory dispersion using augmented minimal basis sets. AB - It has been recognized that quantum-chemical predictions of dispersive (nonresonant) chiroptical phenomena are exquisitely sensitive to the periphery of the electronic wavefunction. To further elaborate and potentially exploit this assertion, linear-response calculations of specific optical rotation were performed within the framework of density-functional theory (DFT) by augmenting small basis sets (e.g., STO - 3G and 3 - 21G) for the core and valence electrons with diffuse functions taken from substantially larger bases (e.g., aug-cc-pVXZ where X = D, T, or Q). Of particular interest was the ability of such computationally efficient (augmented small-basis) model chemistries to reproduce results derived from more expensive (canonical large-basis) schemes. The results appear to be quite promising, with the augmented minimal-basis ansatz often yielding wavelength-resolved rotatory powers close to those deduced from standard DFT(B3LYP)/aug-cc-pVXZ treatments. Analogous linear-response analyses were performed by means of coupled-cluster singles and doubles (CCSD) theory, once again leading to augmented small-basis estimates of specific rotation in reasonable accord with their large-basis counterparts. Although CCSD predictions were deemed to be slightly worse than those obtained from DFT, they still were of sufficient quality for such reduced-basis calculations to be considered viable for exploratory work. PMID- 23813840 TI - Childhood and adult socio-economic position and social mobility as determinants of low back pain outcomes. AB - BACKGROUND: Low back pain (LBP) is a prevalent problem and tends to be socio economically patterned. Relatively little is known about life-course socio economic circumstances as determinants of different types of LBP. Our aim was to examine whether childhood and adult socio-economic position and social mobility are associated with radiating and non-specific LBP and sciatica. METHOD: Data were derived from the Young Finns Study (n = 2231). Childhood socio-economic position was based on parental education, occupational class and family income at baseline in 1980. Data on own education and LBP outcomes were collected at the end of follow-up in 2007. Social mobility was based on parental and own education. Covariates were composed of age, parental body mass index and smoking. RESULTS: Both childhood and own socio-economic position remained associated with radiating LBP and sciatica after adjustments. However, the associations varied by socio-economic indicator and gender. Stable lower socio-economic position and downward mobility were associated with radiating LBP. CONCLUSION: Childhood socio economic circumstances affect the risk of radiating LBP and sciatica in adulthood. To prevent low back disorders, early socio-economic circumstances need to be considered alongside own socio-economic position. PMID- 23813843 TI - From bench to bar: careers in patent law for molecular biologists. AB - Leaving science to pursue a career in patent law requires a considerable investment of time and energy, and possibly money, with no guarantee of finding a job or of returning to science should the decision prove infelicitous. Yet the large number of former scientists now practicing patent law shows that it can be done. I provide suggestions for investigating the potential opportunities, costs, risks, and rewards of this career path. PMID- 23813841 TI - Synthetic tracheal mucus with native rheological and surface tension properties. AB - In this study, the development of a model tracheal mucus with chemical composition and physical properties (bulk viscoelasticity and surface tension) matched to that of native tracheal mucus is described. The mucus mimetics (MMs) were formulated using components that are abundant in tracheal mucus (glycoproteins, proteins, lipids, ions, and water) at concentrations similar to those found natively. Pure solutions were unable to achieve the gel behavior observed with native mucus. The addition of a bifunctional cross-linking agent enabled control over the viscoelastic properties of the MMs by tailoring the concentration of the cross-linking agent and the duration of cross-linking. Three MM formulations with different bulk viscoelastic properties, all within the normal range for nondiseased tracheal mucus, were chosen for investigation of surfactant spreading at the air-mimetic interface. Surfactant spread quickly and completely on the least viscoelastic mimetic surface, enabling the surface tension of the mimetic to be lowered to match native tracheal mucus. However, surfactant spreading on the more viscoelastic mimetics was hindered, suggesting that the bulk properties of the mimetics dictate the range of surface properties that can be achieved. PMID- 23813842 TI - NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice. AB - Inflammasome activation plays a central role in the development of drug-induced and obesity-associated liver disease. However, the sources and mechanisms of inflammasome-mediated liver damage remain poorly understood. Our aim was to investigate the effect of NLRP3 inflammasome activation on the liver using novel mouse models. We generated global and myeloid cell-specific conditional mutant Nlrp3 knock-in mice expressing the D301N Nlrp3 mutation (ortholog of D303N in human NLRP3), resulting in a hyperactive NLRP3. To study the presence and significance of NLRP3-initiated pyroptotic cell death, we separated hepatocytes from nonparenchymal cells and developed a novel flow-cytometry-based (fluorescence-activated cell sorting; FACS) strategy to detect and quantify pyroptosis in vivo based on detection of active caspase 1 (Casp1)- and propidium iodide (PI)-positive cells. Liver inflammation was quantified histologically by FACS and gene expression analysis. Liver fibrosis was assessed by Sirius Red staining and quantitative polymerase chain reaction for markers of hepatic stellate cell (HSC) activation. NLRP3 activation resulted in shortened survival, poor growth, and severe liver inflammation; characterized by neutrophilic infiltration and HSC activation with collagen deposition in the liver. These changes were partially attenuated by treatment with anakinra, an interleukin-1 receptor antagonist. Notably, hepatocytes from global Nlrp3-mutant mice showed marked hepatocyte pyroptotic cell death, with more than a 5-fold increase in active Casp1/PI double-positive cells. Myeloid cell-restricted mutant NLRP3 activation resulted in a less-severe liver phenotype in the absence of detectable pyroptotic hepatocyte cell death. CONCLUSIONS: Our data demonstrate that global and, to a lesser extent, myeloid-specific NLRP3 inflammasome activation results in severe liver inflammation and fibrosis while identifying hepatocyte pyroptotic cell death as a novel mechanism of NLRP3-mediated liver damage. PMID- 23813844 TI - A systematic review on the safety and efficacy of percutaneous edge-to-edge mitral valve repair with the MitraClip system for high surgical risk candidates. AB - BACKGROUND: MitraClip implantation has emerged as a viable option in high surgical risk patients with severe mitral regurgitation (MR). We performed the present systematic review to assess the safety and efficacy of the MitraClip system for high surgical risk candidates with severe organic and/or functional MR. METHODS: Six electronic databases were searched for original published studies from January 2000 to March 2013. Two reviewers independently appraised studies, using a standard form, and extracted data on methodology, quality criteria, and outcome measures. All data were extracted and tabulated from the relevant articles' texts, tables, and figures and checked by another reviewer. RESULTS: Overall 111 publications were identified. After applying selection criteria and removing serial publications with accumulating number of patients or increased length of follow-up, 12 publications with the most complete dataset were included for quality appraisal and data extraction. All 12 studies were prospective observational studies. Immediate procedural success ranged from 72 100%; 30 day mortality ranged from 0-7.8%. There was a significant improvement in haemodynamic profile and functional status after implantation. One year survival ranged from 75-90%. No long term outcomes have been reported for high surgical risk patients. CONCLUSIONS: MitraClip implantation is an option in managing selected high surgical risk patients with severe MR. The current evidence suggests that MitraClip can be implanted with reproducible safety and feasibility profile in this subgroup of patients. Further prospective trials with mid- to long-term follow-up are required. PMID- 23813845 TI - Prophylactic implantable cardioverter defibrillator treatment in patients with end-stage heart failure awaiting heart transplantation. AB - OBJECTIVES: This study was designed to delineate the role of implantable cardioverter defibrillator (ICD) therapy for the primary and secondary prevention of sudden cardiac death in patients listed for heart transplantation. SETTING: Retrospective observational multicentre study. PATIENTS: 1089 consecutive patients listed for heart transplantation in two tertiary heart transplant centres were enrolled. Of 550 patients (51%) on the transplant list with an ICD, 216 had received their ICD for the primary prevention of sudden cardiac death and 334 for secondary prevention. 539 patients did not receive an ICD. INTERVENTION: Treatment with or without an ICD was left to the discretion of the heart failure specialist. MAIN OUTCOME MEASURE: All-cause mortality. RESULTS: ICDs appear to be associated with a reduction in all-cause mortality in patients implanted with the device for primary and secondary prevention compared to those without an ICD despite a median time on the waiting list of only 8 months (estimated 1-year: 88+/-3% vs. 77+/-3% vs. 67+/-3%; p=0.0001). A Cox regressional hazard model (corrected for age, sex, underlying heart disease, atrial fibrillation, cardiac resynchronisation therapy, New York Heart Association (NYHA) class, ejection fraction, co-medication and year of listing) suggested an independent beneficial effect of ICDs that was most pronounced in patients who had received an ICD for primary prevention (HR 0.4, 95% CI 0.19 to 0.85; p=0.016). CONCLUSIONS: ICD implantation appears to be associated with an immediate and sustained survival benefit for patients awaiting heart transplantation. PMID- 23813846 TI - Effects of antihypertensive treatment in patients over 65 years of age: a meta analysis of randomised controlled studies. AB - CONTEXT: Despite the high incidence of hypertension, the elderly population is not represented in clinical trials as they have upper age limits or do not present age-specific results. OBJECTIVES: The present study was designed to systematically review prospective randomized trials and assess the effects of antihypertensive treatment on cardiovascular, all-cause mortality, stroke and heart failure in patients over 65 years of age. DATA SOURCES: We systematically searched the electronic databases, MEDLINE, PUBMED, EMBASE and Cochrane for prospective randomized studies (1970-2012) in which patients were randomized either to antihypertensive treatment and non-drug control group or to different antihypertensive treatments. STUDY SELECTION: We identified 18 clinical studies, with 19 control arms and 19 treatment arms examining 59285 controls, 55569 hypertensive patients with an average follow up duration of 3.44 years. The mean age of patients on treatment was 71.04 years. DATA EXTRACTION: Included studies were divided and analyzed in 2 subgroups: i) studies comparing treatment group vs non-drug placebo group with a BP decrease of 27.3/11.1 mmHg and ii) studies comparing two anti-hypertensive regimens with baseline BP ~157/86, and BP reduction to less than 140/80. RESULTS: A significant reduction in all four outcomes was found in the first group of studies. In the second group similar BP reduction resulted in equivalent risk reduction in both treatment groups. In the meta-regression analysis mean SBP difference was linearly associated with all cause, cardiovascular, stroke and heart failure risk reduction. CONCLUSION: Reducing BP to a level of 150/80 mmHg is associated with large benefit in stroke, cardiovascular and all-cause mortality as well as heart failure risk in elderly individuals. Different antihypertensive regimens with equal BP reduction have similar effects on cardiovascular outcomes. SBP rather than DBP reduction is significantly related to lower cardiovascular risk in this population. PMID- 23813847 TI - The association of genetic variants of matrix metalloproteinases with abdominal aortic aneurysm: a systematic review and meta-analysis. AB - CONTEXT: Aberrant matrix turnover is believed to play a key role in the pathogenesis of abdominal aortic aneurysm (AAA). Matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitor of metalloproteinases; TIMPs) are important enzymes in the control of extracellular matrix remodelling. OBJECTIVE: The aim of this study was to investigate if single nucleotide polymorphisms (SNPs) within MMP and TIMP gene families are associated with the presence of AAA. DATA SOURCES: We performed a search of MEDLINE and EMBASE databases on the 21st November 2012. STUDY SELECTION: Case-control studies assessing the association of at least one SNP in a MMP or TIMP gene with AAA were included. DATA EXTRACTION: Data were independently extracted by two reviewers. A random effects model was used to calculate combined odds ratios for commonly investigated SNPs according to dominant, recessive and additive inheritance. RESULTS: Thirteen studies examining 58 SNPs within 10 different MMP and TIMP genes were identified. Eight SNPs were assessed in at least 3 studies (combined sample size ranging from 141- 2191 AAA cases and 340-2013 controls) and included in a meta-analysis. Results on 1258 cases and 1406 controls for MMP3 rs3025058 showed an association with AAA presence; best described by a dominant pattern of inheritance (OR=1.48 95%CI 1.23 - 1.78, p=3.95*10-5). No associations with AAA were identified for other SNPs assessed in this study including rs1799750 (MMP1), rs3918242 (MMP9), rs486055 (MMP10), rs2276109 (MMP12), rs2252070 (MMP13), rs4898 (TIMP1) or rs9619311 (TIMP3). CONCLUSION: A common SNP within the MMP3 promoter region, previously suggested to increase MMP3 expression, appears to be a moderate risk factor for AAA. PMID- 23813848 TI - Intra-cardiac echocardiography in mitral valve repair: a novel use of a complimentary imaging modality in a difficult scenario. PMID- 23813849 TI - Cardiac rehabilitation: fit to face the future? PMID- 23813850 TI - Value of D-dimer and C reactive protein in predicting inhospital death in acute aortic dissection. AB - OBJECTIVE: To evaluate the role of D-dimer and C reactive protein (CRP) in predicting inhospital death in acute aortic dissection (AD). DESIGN: A single centre prospective study. SETTING: University hospital in China. PATIENTS: 114 patients with acute AD. INTERVENTION: Admission D-dimer and CRP concentrations were assayed. MAIN OUTCOME MEASURES: To observe the association of D-dimer and CRP with inhospital death. RESULTS: Increased levels of plasma D-dimer (9.84+/ 3.53 vs. 4.28+/-1.99, P < 0.001), CRP (14.08+/-2.81 vs. 11.18+/-1.85, P < 0.001) and aortic diameter (45.2+/-9.5 vs. 40.3+/-6.0, p = 0.007) were found in dead patients compared with those survived. Moreover, plasma D-dimer concentrations in type A were higher than that in type B (6.51+/-4.11 vs. 4.87+/-2.29, p = 0.013). Plasma D-dimer concentrations had positive correlations with CRP levels (r=0.527, P < 0.001) and aortic diameter (r=0.227, p = 0.015), and had negative correlations with the type of AD (r=-0.232, p = 0.013) and the time from onset (r=-0.264, p = 0.005). D-dimer and CRP levels and the type of AD were strongly associated with inhospital mortality. The OR and 95% CI were 3.272, 1.638 to 6.535; 2.322, 1.134 to 4.757; and 0.126, 0.019 to 0.853, respectively. Furthermore, the sensitivity and specificity of D-dimer >=5.67 MUg/mL in predicting inhospital death in acute AD were 90.3% and 75.9% (95% CI 0.85 to 0.96), respectively. Moreover, the sensitivity and specificity of CRP levels >=11.21 mg/L were 100% and 54.2%, respectively (95% CI 0.74 to 0.89). CONCLUSIONS: D-dimer >=5.67 MUg/mL, CRP >=11.21 mg/L and type A acute AD were important risk factors and independently associated with acute AD inhospital death. PMID- 23813851 TI - Effect of a nurse-coordinated prevention programme on cardiovascular risk after an acute coronary syndrome: main results of the RESPONSE randomised trial. AB - OBJECTIVE: To quantify the impact of a practical, hospital-based nurse coordinated prevention programme on cardiovascular risk, integrated into the routine clinical care of patients discharged after an acute coronary syndrome, as compared with usual care only. DESIGN: RESPONSE (Randomised Evaluation of Secondary Prevention by Outpatient Nurse SpEcialists) was a randomised clinical trial. SETTING: Multicentre trial in secondary and tertiary healthcare settings. PARTICIPANTS: 754 patients admitted for acute coronary syndrome. INTERVENTION: A nurse-coordinated prevention programme, consisting of four outpatient nurse clinic visits, focusing on healthy lifestyles, biometric risk factors and medication adherence, in addition to usual care. MAIN OUTCOME MEASURES: The main outcome was 10-year cardiovascular mortality risk as estimated by Systematic Coronary Risk Evaluation at 12 months follow-up. Secondary outcomes included Framingham Coronary Risk Score at 12 months, in addition to changes in individual risk factors. Risk factor control was classified as 'poor' if 0 to 3 factors were on target, 'fair' if 4 to 6 factors were on target, and 'good' if 7 to 9 were on target. RESULTS: The mean Systematic Coronary Risk Evaluation at 12 months was 4.4 per cent (SD 4.5) in the intervention group and 5.4 per cent (SD 6.2) in the control group (p=0.021), representing a 17.4% relative risk reduction. At 12 months, risk factor control classified as 'good' was achieved in 35% of patients in the intervention group compared with 25% in the control group (p=0.003). Attendance to the nurse-coordinated prevention programme was 92%. In the intervention group, 86 rehospitalisations were observed against 132 in the control group (relative risk reduction 34.8%, p=0.023). CONCLUSIONS: The nurse coordinated hospital-based prevention programme in addition to usual care is a practical, yet effective method for reduction of cardiovascular risk in patients with coronary disease. Our data suggest that the counselling component of the programme may lead to a reduction in hospital readmissions. TRIAL REGISTRATION TRIALREGISTERNL IDENTIFIER: TC1290. PMID- 23813852 TI - Urine for plasmonic nanoparticle-based colorimetric detection of mercury ion. AB - Urine for diagnostics: Urine, a "green" natural product, is used as an active component to produce a simple, inexpensive, and portable colorimetric Hg(2+) sensing assay with high selectivity and sensitivity by simply mixing gold nanoparticles (AuNPs) and urine. The synergetic effect of uric acid and creatinine decorated on AuNPs is the reason for selective binding of Hg(2+) , leading to the aggregation of gold nanoparticles and thereby causing a visible color change. PMID- 23813853 TI - Structure and activity of NADPH-dependent reductase Q1EQE0 from Streptomyces kanamyceticus, which catalyses the R-selective reduction of an imine substrate. AB - NADPH-dependent oxidoreductase Q1EQE0 from Streptomyces kanamyceticus catalyzes the asymmetric reduction of the prochiral monocyclic imine 2-methyl-1-pyrroline to the chiral amine (R)-2-methylpyrrolidine with >99% ee, and is thus of interest as a potential biocatalyst for the production of optically active amines. The structures of Q1EQE0 in native form, and in complex with the nicotinamide cofactor NADPH have been solved and refined to a resolution of 2.7 A. Q1EQE0 functions as a dimer in which the monomer consists of an N-terminal Rossman-fold motif attached to a helical C-terminal domain through a helix of 28 amino acids. The dimer is formed through reciprocal domain sharing in which the C-terminal domains are swapped, with a substrate-binding cleft formed between the N-terminal subunit of monomer A and the C-terminal subunit of monomer B. The structure is related to those of known beta-hydroxyacid dehydrogenases, except that the essential lysine, which serves as an acid/base in the (de)protonation of the nascent alcohol in those enzymes, is replaced by an aspartate residue, Asp187 in Q1EQE0. Mutation of Asp187 to either asparagine or alanine resulted in an inactive enzyme. PMID- 23813854 TI - Thymus and mediastinal node involvement in childhood Langerhans cell histiocytosis: long-term follow-up from the French national cohort. AB - BACKGROUND: Mediastinal involvement (MI) in Langerhans cell histiocytosis (LCH) has been rarely reported. Here, we describe the clinical, radiological, and biological presentation, and the outcome of childhood LCH with MI. METHOD: From the French LCH register, which includes 1,423 patients aged less than 18 years, we retrieved the medical charts of patients with mediastinal enlargement detected on chest X-rays. RESULTS: Thirty-seven patients were retrieved, including 18 males; median age of diagnosis was 0.7 years, and median follow-up time was 6.2 years. The prevalence of MI varied with the age at diagnosis, ranging from 7% below 1 year old to less than 1% at >5 years. Thirteen cases (35%) were diagnosed because of MI-related symptoms, including respiratory distress (N = 4), superior venous cava syndrome (N = 2), and/or cough and polypnea (N = 10). CT scans performed in 32 cases at diagnosis showed tracheal compression (N = 5), cava thrombosis (N = 2), and/or calcification (N = 16). All patients presented multi system disease at LCH diagnosis, and 35/37 were initially treated with vinblastine and corticosteroids. Death occurred in five cases, due to MI (N = 1) or hematological refractory involvement (N = 4). The overall 5-year survival was 87.1%, and immunodeficiency was not detected as a sequel. CONCLUSIONS: MI in LCH mainly occurs in young children, and diagnosis was based on CT showing thymus enlargement and calcifications. PMID- 23813855 TI - Identification of Hck inhibitors as hits for the development of antileukemia and anti-HIV agents. AB - Hematopoietic cell kinase (Hck) is a member of the Src family of non-receptor protein tyrosine kinases. High levels of Hck are associated with drug resistance in chronic myeloid leukemia. Furthermore, Hck activity has been connected with HIV-1. Herein, structure-based drug design efforts were aimed at identifying novel Hck inhibitors. First, an in-house library of pyrazolo[3,4-d]pyrimidine derivatives, which were previously shown to be dual Abl and c-Src inhibitors, was analyzed by docking studies within the ATP binding site of Hck to select the best candidates to be tested in a cell-free assay. Next, the same computational protocol was applied to screen a database of commercially available compounds. As a result, most of the selected compounds were found active against Hck, with Ki values ranging from 0.14 to 18.4 MUM, confirming the suitability of the computational approach adopted. Furthermore, selected compounds showed an interesting antiproliferative activity profile against the human leukemia cell line KU-812, and one compound was found to block HIV-1 replication at sub-toxic concentrations. PMID- 23813856 TI - DNA origami directed large-scale fabrication of nanostructures resembling room temperature single-electron transistors. AB - Room temperature single-electron transistor core nanostructures are fabricated on a large scale with DNA origami as a template with an unprecedented yield. The accuracy of DNA origami enables precise positioning of a Coulomb island in the center of a 10 nm gap between the source and the drain electrodes, which can not be realized by using state-of-the-art nanofabrication techniques. PMID- 23813857 TI - The TRAIL of oncogenes to apoptosis. AB - Despite the significant advances in clinical research, surgical resection, radiotherapy and chemotherapy are still used as the primary method for cancer treatment. As compared to conventional therapies that often induce systemic toxicity and eventually contribute to tumor resistance, the TNF-related apoptosis inducing ligand (TRAIL) is a promising anticancer agent that selectively triggers apoptosis in various cancer cells by interacting with its proapoptotic receptors DR4 and KILLER/DR5, while sparing the normal surrounding tissue. The intensive studies of TRAIL signaling pathways over the past decade have provided clues for understanding the molecular mechanisms of TRAIL-induced apoptosis in carcinogenesis and identified an array of therapeutic responses elicited by TRAIL and its receptor agonists. Analysis of its activity at the molecular level has shown that TRAIL improves survival either as monotherapies or combinatorial therapies with other mediators of apoptosis or anticancer chemotherapy. Combinatorial treatments amplify the activities of anticancer agents and widen the therapeutic window by overcoming tumor resistance to apoptosis and driving cancer cells to self-destruction. Although TRAIL sensitivity varies widely depending on the cell type, nontransformed cells are largely resistant to death mediated by TRAIL Death Receptors (DRs). Genetic alterations in cancer can contribute in tumor progression and often play an important role in evasion of apoptosis by tumor cells. Remarkably, RAS, MYC and HER2 oncogenes have been shown to sensitise tumor cells to TRAIL induced cell death. Here, we summarise the cross-talk of oncogenic and apoptotic pathways and how they can be exploited toward efficient combinatorial therapeutic protocols. PMID- 23813858 TI - DIXDC1 increases the invasion and migration ability of non-small-cell lung cancer cells via the PI3K-AKT/AP-1 pathway. AB - DIX domain containing 1 (DIXDC1), is a human homolog of Ccd1, a recently identified DIX domain containing protein in zebrafish. DIXDC1 protein was detected in human colorectal adenocarcinoma tissues and was found to be correlated with a high cell proliferation index. We demonstrated DIXDC1 overexpression in 55% (92/167) of non-small cell lung cancer (NSCLC) cases, compared to adjacent noncancerous lung tissues (P < 0.01). Overexpression of DIXDC1 was associated with lymph node metastasis and more advanced TNM stage (P < 0.001 and P = 0.001, respectively). Kaplan-Meier survival curves and log-rank testing indicated that overexpression of DIXDC1 correlated with worse overall survival in NSCLC (P = 0.031). DIXDC1 was more abundant in seven NSCLC lines than the bronchial cell line HBE, and modulation of its expression regulated AP-1 activity; MMP2, MMP7, and MMP9 protein and mRNA; and invasion ability. Metalloproteinase induction was reversed by PI3K/AKT and AP-1 inhibition. These results suggest DIXDC1 is associated with stage and prognosis in NSCLC, and may promote invasion and migration through PI3K-AKT/AP-1-dependent activation of metalloproteinases. PMID- 23813859 TI - Developing polymer composite materials: carbon nanotubes or graphene? AB - The formation of composite materials represents an efficient route to improve the performances of polymers and expand their application scopes. Due to the unique structure and remarkable mechanical, electrical, thermal, optical and catalytic properties, carbon nanotube and graphene have been mostly studied as a second phase to produce high performance polymer composites. Although carbon nanotube and graphene share some advantages in both structure and property, they are also different in many aspects including synthesis of composite material, control in composite structure and interaction with polymer molecule. The resulting composite materials are distinguished in property to meet different applications. This review article mainly describes the preparation, structure, property and application of the two families of composite materials with an emphasis on the difference between them. Some general and effective strategies are summarized for the development of polymer composite materials based on carbon nanotube and graphene. PMID- 23813860 TI - Improved repair of chondral and osteochondral defects in the ovine trochlea compared with the medial condyle. AB - Associations between topographic location and articular cartilage repair in preclinical animal models are unknown. Based on clinical investigations, we hypothesized that lesions in the ovine femoral condyle repair better than in the trochlea. Full-thickness chondral and osteochondral defects were simultaneously established in the weightbearing area of the medial femoral condyle and the lateral trochlear facet in sheep, with chondral defects subjected to subchondral drilling. After 6 months in vivo, cartilage repair and osteoarthritis development was evaluated by macroscopic, histological, immunohistochemical, and biochemical analyses. Macroscopic and histological articular cartilage repair and type-II collagen immunoreactivity were better in the femoral trochlea, regardless of the defect type. Location-independently, osteochondral defects induced more osteoarthritic degeneration of the adjacent cartilage than drilled chondral lesions. DNA and proteoglycan contents of chondral defects were higher in the condyle, reflecting physiological topographical differences. The results indicate that topographic location dictates the structural patterns and biochemical composition of the repair tissue in sheep. These findings suggest that repair of cartilage defects at different anatomical sites of the ovine stifle joint needs to be assessed independently and that the sheep trochlea exhibits cartilage repair patterns reflective of the human medial femoral condyle. PMID- 23813861 TI - The influence of patient's sex, race and depression on clinician pain treatment decisions. AB - BACKGROUND: Pain treatments often vary across patients' demographic and mental health characteristics. Most research on this topic has been observational, has focused on opioid therapy exclusively and has not examined individual differences in clinician decision making. The current study examined the influence of patient's sex, race and depression on clinicians' chronic pain treatment decisions. METHODS: We used virtual human technology and lens model methodology to enhance study realism and facilitate a richer understanding of treatment decisions. Clinicians and trainees (n = 100) made treatment decisions (opioid, antidepressant, pain specialty referral, mental health referral) for 16 computer simulated patients with chronic low back pain. Patients' sex, race and depression status were manipulated across vignettes (image and text). RESULTS: Individual- and group-level analyses indicated that patient's depression status had the strongest and most consistent influence on treatment decisions. Although less influential overall, patient's sex and race were significantly influential for a subset of participants. Furthermore, the results indicated that participants who were influenced by patient's race had less experience in treating chronic pain than those who were not influenced by patient's race [t(11.59) = 4.75; p = 0.001; d = 1.20]. CONCLUSIONS: The results of this study indicated considerable variability in participants' chronic pain treatment decisions. These data suggest that interventions to reduce variability in treatment decision making and improve pain care should be individually tailored according to clinicians' decision profiles. PMID- 23813862 TI - CD39 expression by hepatic myeloid dendritic cells attenuates inflammation in liver transplant ischemia-reperfusion injury in mice. AB - Hepatic innate immune cells, in particular, interstitial dendritic cells (DCs), regulate inflammatory responses and may promote inherent liver tolerogenicity. After tissue injury, adenosine triphosphate (ATP) is released and acts as a damage-associated molecular pattern that activates innate immune cells by pattern recognition receptors. CD39 (ectonucleoside triphosphate diphosphohydrolase-1) rapidly hydrolyzes extracellular ATP to maintain physiological levels. We hypothesized that CD39 expression on liver DCs might contribute to regulation of their innate immune functions. Mouse liver conventional myeloid DCs (mDCs) were hyporesponsive to ATP, compared with their splenic counterparts. This disparity was ascribed to more efficient hydrolysis of ATP by higher expression of CD39 on liver mDCs. Human liver mDCs expressed greater levels of CD39 than those from peripheral blood. The comparatively high expression of CD39 on liver mDCs correlated strongly with both ATP hydrolysis and adenosine production. Notably, CD39(-/-) mouse liver mDCs exhibited a more mature phenotype, greater responsiveness to Toll-like receptor 4 ligation, and stronger proinflammatory and immunostimulatory activity than wild-type (WT) liver mDCs. To investigate the role of CD39 on liver mDCs in vivo, we performed orthotopic liver transplantation with extended cold preservation using CD39(-/-) or WT donor mouse livers. Compared to WT liver grafts, CD39(-/-) grafts exhibited enhanced interstitial DC activation, elevated proinflammatory cytokine levels, and more-severe tissue injury. Moreover, portal venous delivery of WT, but not CD39(-/-) liver mDCs, to donor livers immediately post-transplant exerted a protective effect against graft injury in CD39(-/-) to CD39(-/-) liver transplantation. CONCLUSIONS: These data reveal that CD39 expression on conventional liver mDCs limits their proinflammatory activity and confers protective properties on these important innate immune cells against liver transplant ischemia/reperfusion injury. PMID- 23813863 TI - A polymorphism in the TYMP gene is associated with the outcome of HLA-identical sibling allogeneic stem cell transplantation. AB - Thymidine phosphorylase (TYMP), an enzyme involved in nucleotide synthesis, has been implicated in critical biological processes such as DNA replication, protection against mutations, and tissue repair. In this work, we retrospectively evaluated the influence of a polymorphism in the TYMP gene (rs112723255; G/A) upon the outcome of 448 patients subjected to allogeneic stem cell transplantation (allo-SCT) from an human leukocyte antigen (HLA)-identical sibling donor. The TYMP genotype of patients correlated with overall survival carriers of the minor allele (A) being at an increased risk of dying after transplantation (hazard ratio, HR = 1.9; P = 0.004). This effect was mostly due to differences in transplant toxicity-related mortality (HR = 2.5; P = 0.029). In addition, the TYMP genotype of donors was associated with the risk of chronic graft-versus-host disease (GVHD)-carriers of the minor allele being at an increased risk of developing this complication ([HR] = 1.7; P = 0.039). The impact of such polymorphism on the risk of chronic GVHD is limited to patients transplanted in early stage disease (HR = 2.2; P = 0.019). The combination of a donor harboring the minor allele with a patient homozygous for the major allele was associated with the highest risk of chronic GVHD (HR = 2.8; P = 0.008). These findings provide the first evidence of the significant impact of the TYMP genotype upon the clinical outcome of patients treated with HLA-identical sibling allo-SCT. PMID- 23813864 TI - Follow-up of long-term survivors of breast cancer in primary care versus specialist attention. AB - BACKGROUND: Hospitals have traditionally been the place where the follow-up of breast cancer patients occurs in Spain. OBJECTIVE: To describe the evolution of long-term survivors of breast cancer according to type of follow-up received (in primary or specialist/hospital care), measuring impact of care type on health, cost, health-related quality of life (HRQL) and satisfaction results. METHOD: Retrospective study of cohorts with disease-free patients followed up for at least 5 years in Oncology. Using personal questionnaires, the type and cost of the follow-up, events, HRQL and satisfaction were analysed. RESULTS: Ninety-eight women were surveyed, 60 in primary and 38 in specialist care. There were no differences between groups in diagnosis of metastasis or new primary tumours. The number of annual visits per patient was 0.98 (0.48) in primary and 1.11 (0.38) in specialist care (P = 0.19). In primary, 44.6% were programmed and 55.4% on demand; in specialist, 94.6% were programmed and 5.4% on demand (P = 0.0001). The costs of follow-up in primary care were lower--?112.86 (77.54) versus ?184.61 (85.87) per patient and year (P = 0.0001). No differences were reported in HRQL. Preference for specialist care was expressed by 80%, versus 10% for primary, with 10% indifferent. Patients showed greater satisfaction with specialist care in all questionnaire dimensions. CONCLUSIONS: Compliance with follow-up protocol was high in both groups. In specialist care nearly all the visits were programmed and in primary almost half were on demand. In our locality, primary is more cost effective than specialist care, but patients express greater satisfaction with specialist follow-up and hence prefer it. PMID- 23813865 TI - Extracellular electron transfer of a highly adhesive and metabolically versatile bacterium. AB - Bacterial adhesion to a solid plays a predominant role in mediating the extracellular electron transfer for genus Acinetobactor, a metabolically versatile bacterium that can couple toluene degradation and electricity generation. PMID- 23813866 TI - Corannulene-fused anion-responsive pi-conjugated molecules that form self assemblies with unique electronic properties. AB - The fusion of bowl-shaped pi-conjugated corannulene units to anion-responsive pi conjugated dipyrrolyldiketone-boron complexes resulted in new molecular materials with a unique self-assembly capability. The bowl-fused receptor with aliphatic tails could form both supramolecular gels and mesophases through pi-stacking interactions and also exhibited anion-responsive characteristics. The presence of the pi-bowl unit not only afforded enhanced self-assembly capability both in solution and in the mesophases, as evidenced by gelation experiments and phase transition profiles, but also enhanced intrinsic charge-carrier mobility. PMID- 23813867 TI - Plasmacytoma-like post-transplant lymphoproliferative disorder seen in pediatric combined liver and intestinal transplant recipients. AB - Post-transplant lymphoproliferative disease (PTLD) is a lymphoproliferative disorder secondary to chronic immunosuppression and is the most common malignancy in transplanted patients [Kamdar et al. Curr Opin Organ Transplant, 2011; 16:274 280]. Although PTLD usually presents as B or T cell lymphoma, plasmacytomas have been reported, mostly in the adult population. Six cases of pediatric plasmacytoma-like PTLD have been reported, all of which were treated with vincristine, adriamycin, and dexamethasone (VAD), high dose dexamethasone alone, or dexamethasone + thalidomide [Tcheng et al. Pediatric Blood Cancer, 2006; 47:218-223; Perry et al. Blood, 2013; 8:1377-1383]. We present two cases of pediatric plasmacytoma-like PTLD in combined liver and small bowel transplant patients both successfully treated with bortezomib and dexamethasone based on multiple myeloma protocols [Kyle and Rajkumar, Clin Lymphoma Myeloma, 2009; 9:278 288; Adams and Kaufmann, Cancer Invest, 2004; 22:304-311]. PMID- 23813868 TI - Growth arrest specific 1 (GAS1) is abundantly expressed in the adult mouse central nervous system. AB - Growth arrest specific 1 (GAS1) is a pleiotropic protein that induces apoptosis and cell arrest in different tumors, but it is also involved in the development of the nervous system and other tissues and organs. This dual ability is likely caused by its capacity to interact both by inhibiting the intracellular signaling cascade induced by glial cell-line derived neurotrophic factor and by facilitating the activity of the sonic hedgehog pathway. The presence of GAS1 mRNA has been described in adult mouse brain, and here we corroborated this observation. We then proceeded to determine the distribution of the protein in the adult central nervous system (CNS). We detected, by western blot analysis, expression of GAS1 in olfactory bulb, caudate-putamen, cerebral cortex, hippocampus, mesencephalon, medulla oblongata, cerebellum, and cervical spinal cord. To more carefully map the expression of GAS1, we performed double-label immunohistochemistry and noticed expression of GAS1 in neurons in all brain areas examined. We also observed expression of GAS1 in astroglial cells, albeit the pattern of expression was more restricted than that seen in neurons. Briefly, in the present article, we report the widespread distribution and cellular localization of the GAS1 native protein in adult mammalian CNS. PMID- 23813869 TI - Functional validation of GWAS gene candidates for abnormal liver function during zebrafish liver development. AB - Genome-wide association studies (GWAS) have revealed numerous associations between many phenotypes and gene candidates. Frequently, however, further elucidation of gene function has not been achieved. A recent GWAS identified 69 candidate genes associated with elevated liver enzyme concentrations, which are clinical markers of liver disease. To investigate the role of these genes in liver homeostasis, we narrowed down this list to 12 genes based on zebrafish orthology, zebrafish liver expression and disease correlation. To assess the function of gene candidates during liver development, we assayed hepatic progenitors at 48 hours post fertilization (hpf) and hepatocytes at 72 hpf using in situ hybridization following morpholino knockdown in zebrafish embryos. Knockdown of three genes (pnpla3, pklr and mapk10) decreased expression of hepatic progenitor cells, whereas knockdown of eight genes (pnpla3, cpn1, trib1, fads2, slc2a2, pklr, mapk10 and samm50) decreased cell-specific hepatocyte expression. We then induced liver injury in zebrafish embryos using acetaminophen exposure and observed changes in liver toxicity incidence in morphants. Prioritization of GWAS candidates and morpholino knockdown expedites the study of newly identified genes impacting liver development and represents a feasible method for initial assessment of candidate genes to instruct further mechanistic analyses. Our analysis can be extended to GWAS for additional disease-associated phenotypes. PMID- 23813870 TI - EGFR-mediated Akt and MAPKs signal pathways play a crucial role in patulin induced cell proliferation in primary murine keratinocytes via modulation of Cyclin D1 and COX-2 expression. AB - Patulin (PAT), a present day major contaminant of commercial apple and apple products is reported to be carcinogenic, embryotoxic, and immunotoxic. While oral and inhalation are considered to be the most prevalent routes of exposure to this toxin, exposure through skin is now being extensively investigated. Our previous study showed that short-term dermal exposure to PAT resulted in toxicological injury to the skin, while long-term exposure induced skin tumorigenesis. In this study, we explore the mechanism involve in proliferation of mouse keratinocytes by PAT. Our study revealed that PAT rapidly induces phosphorylation of EGFR, activation of the Ras/MAPKs, and Akt pathways. This in-turn leads to the activation of NF-kappaB/AP-1 transcription factors which then binds to the promoter region of the cell growth regulatory genes Cyclin D1 and COX-2 inducing their expression leading ultimately to PMKs proliferation. Inhibition of EGFR or the Ras/MAPKs, PI3/Akt pathways with different pharmacological inhibitors or knockdown of NF-kappaB, c-jun, c-fos, Cyclin D1, and COX-2 with siRNA inhibited PAT-induced PMKs proliferation. PMID- 23813871 TI - Fibroblasts cultured on nanowires exhibit low motility, impaired cell division, and DNA damage. AB - Nanowires are commonly used as tools for interfacing living cells, acting as biomolecule-delivery vectors or electrodes. It is generally assumed that the small size of the nanowires ensures a minimal cellular perturbation, yet the effects of nanowires on cell migration and proliferation remain largely unknown. Fibroblast behaviour on vertical nanowire arrays is investigated, and it is shown that cell motility and proliferation rate are reduced on nanowires. Fibroblasts cultured on long nanowires exhibit failed cell division, DNA damage, increased ROS content and respiration. Using focused ion beam milling and scanning electron microscopy, highly curved but intact nuclear membranes are observed, showing no direct contact between the nanowires and the DNA. The nanowires possibly induce cellular stress and high respiration rates, which trigger the formation of ROS, which in turn results in DNA damage. These results are important guidelines to the design and interpretation of experiments involving nanowire-based transfection and electrical characterization of living cells. PMID- 23813872 TI - High-fat and high-sucrose (western) diet induces steatohepatitis that is dependent on fructokinase. AB - Fructose intake from added sugars has been implicated as a cause of nonalcoholic fatty liver disease. Here we tested the hypothesis that fructose may interact with a high-fat diet to induce fatty liver, and to determine if this was dependent on a key enzyme in fructose metabolism, fructokinase. Wild-type or fructokinase knockout mice were fed a low-fat (11%), high-fat (36%), or high-fat (36%) and high-sucrose (30%) diet for 15 weeks. Both wild-type and fructokinase knockout mice developed obesity with mild hepatic steatosis and no evidence of hepatic inflammation on a high-fat diet compared to a low-fat diet. In contrast, wild-type mice fed a high-fat and high-sucrose diet developed more severe hepatic steatosis with low-grade inflammation and fibrosis, as noted by increased CD68, tumor necrosis factor alpha, monocyte chemoattractant protein-1, alpha-smooth muscle actin, and collagen I and TIMP1 expression. These changes were prevented in the fructokinase knockout mice. CONCLUSION: An additive effect of high-fat and high-sucrose diet on the development of hepatic steatosis exists. Further, the combination of sucrose with high-fat diet may induce steatohepatitis. The protection in fructokinase knockout mice suggests a key role for fructose (from sucrose) in this development of steatohepatitis. These studies emphasize the important role of fructose in the development of fatty liver and nonalcoholic steatohepatitis. PMID- 23813873 TI - Accurate and early diagnosis of orthopedic device-related infection by microbial heat production and sonication. AB - Proper and rapid diagnosis of orthopedic device-related infection is important for successful treatment. Sonication has been shown to improve the diagnostic performance. We hypothesized that the combination of sonication with a novel method called microcalorimetry will further improve and accelerate the diagnosis of implant infection. We prospectively included 39 consecutive patients (mean age 59 years, 62% males) at our institution from whom 29 orthopedic prostheses and 10 osteosynthesis material were explanted. The explanted device was sonicated. The resulting sonication fluid was analyzed using microcalorimetry. Using standardized criteria to define orthopedic device-related infection, 12 cases (31%) were defined as infected. In all, positive periprosthetic tissue cultures were found. The sensitivity and specificity of microcalorimetry of sonication fluid were 100% and 97%, respectively. Mean time to detection, defined as time to reach a rising heat flow signal of 20 uW measured after equilibiration needed to get accurate measurement, was 10.9 h. In summary, microcalorimetry of sonication fluid is a reliable and a fast method in detecting the presence of microorganisms in orthopedic device-related infection. PMID- 23813874 TI - Outcomes of patients with relapsed/refractory diffuse large B-cell lymphoma with progression of lymphoma after autologous stem cell transplantation in the rituximab era. AB - Salvage chemotherapy followed by autologous stem cell transplant (ASCT) remains the current standard of care for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) with chemosensitive disease. The addition of rituximab results in improved overall survival (OS) after first-line treatment, but cure rates of salvage therapy with ASCT are inferior when compared to historical controls. Historically, patients with DLBCL with disease progression following ASCT have had an extremely poor prognosis with a median OS of 3 months. However, there are little data regarding outcomes in the rituximab era. We performed a retrospective study of 56 patients with relapsed or refractory DLBCL with prior exposure to rituximab who had disease progression following ASCT. The median OS from progression following ASCT for the cohort was 9.9 months (95% CI: 5.3-13.1 months). Patients who progressed less than 1 year from ASCT had a significantly shorter OS than those who progressed at 1 year or greater from ASCT (8.2 vs. 26.7 months, P = 0.01). Patients with at least stable disease following ASCT had a longer OS than those who progressed immediately after ASCT (12.3 vs. 5.3 months, P = 0.01). Other factors associated with OS were International Prognostic Index (IPI) (P = 0.01) and LDH level (P = 0.0003) at the time of progression following ASCT. In the rituximab era, the prognosis for patients with disease progression following ASCT remains poor, but is improved when compared with historical controls. Ultimately, more work needs to be done to develop novel therapeutic strategies tailored to individual patients in this heterogeneous population. PMID- 23813875 TI - A dense metal-organic framework for enhanced magnetic refrigeration. AB - The three-dimensional metal-organic framework Gd(HCOO)3 is characterized by a relatively compact crystal lattice of weakly interacting Gd(3+) spin centers interconnected via lightweight formate ligands, overall providing a remarkably large magnetic:non-magnetic elemental weight ratio. The resulting magnetocaloric effect per unit volume is decidedly superior in Gd(HCOO)3 than in the best known magnetic refrigerant materials for liquid-helium temperatures and low-moderate applied fields. PMID- 23813877 TI - MicroRNA-146b improves intestinal injury in mouse colitis by activating nuclear factor-kappaB and improving epithelial barrier function. AB - BACKGROUND: The precise role of microRNAs in inflammatory disease is not clear. The present study investigated the effect of microRNA (miR-146b) with respect to improving intestinal inflammation. METHODS: The microRNA profile in interleukin 10 deficient mice was examined using microRNA arrays and miR-146b was selected for the subsequent experiments. The expression vectors containing either the whole sequence of miR-146b or small interfering RNA for miR-146b were intraperitoneally administered to the dextran sodium sulfate (DSS)-induced colitis mouse. The expression levels of inflammation-related mediators were examined by the reverse transcriptase-polymerase chain reaction and western blotting analysis. Intestinal barrier function was evaluated by an ex vivo mannitol flux study. RESULTS: The overexpression of miR-146b activated the NF kappaB pathway, improved epithelial barrier function, relieved intestinal inflammation in the DSS-induced colitis mice, and improved the survival rate of mice with lethal colitis. Furthermore, this amelioration of intestinal inflammation by miR-146b was negated by the inhibitor for the NF-kappaB pathway. The overexpression of miR-146b decreased the expression of siah2, which has a target sequence for miR-146b, and promoted the ubiquitination of TRAF proteins. This suggests that the up-regulation of NF-kappaB by miR-146b was mediated by inhibition of the ubiquitination of TRAF proteins upstream of NF-kappaB. CONCLUSIONS: miR-146b improves intestinal inflammation by up-regulating NF-kappaB as a result of the decreased expression of siah2, which ubiquitinates TRAF proteins. Modulation of the miR-146b expression is a potentially useful therapy for the treatment of intestinal inflammation via activation of the NF-kappaB pathway. PMID- 23813878 TI - Enhancing treatment engagement in sexual offenders: a pilot study to explore the utility of the Personal Aspirations and Concerns Inventory for Offenders (PACI O). AB - BACKGROUND: It is essential to improve the motivation of incarcerated sexual offenders to engage in programmes that help lower reoffending rates. The Personal Aspirations and Concerns Inventory for Offenders (PACI-O) is a semi-structured interview that helps them to identify what they want to achieve or change in their life. It may improve treatment engagement. AIMS: The aims of this study were to test use of the PACI-O as a motivator towards treatment engagement and to test the feasibility of a randomised controlled trial (RCT) of this with sex offenders. METHODS: Thirty-seven convicted sex offenders who were due to participate in an Enhanced Thinking Skills programme were randomly assigned to the 'experimental' group, who completed the PACI-O prior to programme entry, or a control group, who completed the programme but not the PACI-O. All participants completed treatment engagement measures. RESULTS: Small positive changes were observed in indicators of treatment motivation and engagement, which were most marked in the small group of offence deniers. The RCT method proved feasible. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE AND RESEARCH: Although our sample was small, our preliminary finding indicates that the PACI-O may provide a cost effective method of improving treatment engagement for a hard-to-reach group of offenders. Replication with a sample of just over 100 men should offer sufficient power for establishing this technique. PMID- 23813879 TI - ATR controls the UV-related upregulation of the CDKN1A mRNA in a Cdk1/HuR dependent manner. AB - Ultraviolet (UV) light is a carcinogenic agent that upregulates the expression of several genes involved in various cellular processes, including cell cycle checkpoints and apoptosis. The universal cyclin-dependent kinase inhibitor p21(WAF1/Cip1) plays major roles in these processes, and the level of its corresponding message increases several times in response to UV-induced DNA damage. This upregulation is mainly posttranscriptional owing to HuR-dependent mRNA stabilization. Since the protein kinase Atr plays major roles during the cellular response to UV damage, we sought to investigate its possible implication in the stabilization of the p21(WAF1/Cip1) coding mRNA. We have shown that the UV dependent accumulation of the CDKN1A mRNA is indeed under the control of the Atr protein kinase. Upon UV damage, Atr allows nuclear-cytoplasmic shuttling of the HuR protein, which binds the CDKN1A mRNA and reduces its turnover. This ATR dependent effect is mediated through UV-related phosphorylation/inactivation of the Cdk1 protein kinase by Atr, which leads to the dissociation of HuR from Cdk1. Indeed, inhibition or shRNA specific knockdown of CDK1 in ATR-deficient cells enhanced the cytoplasmic level of HuR and restored the CDKN1A mRNA upregulation in response to UV damage. These results show that ATR stabilizes the CDKN1A message in response to UV damage through Cdk1-related cytoplasmic accumulation of HuR. PMID- 23813880 TI - Stable aqueous solutions of naked titanate nanotubes. AB - Aqueous solutions of naked nanotubes with Ti concentration up to 10 mM are obtained by hydrothermal synthesis followed by extensive ultrasound treatment. The morphology, surface characteristics, and solution behavior of the solubilized nanotubes are investigated. The time course of the solubilization process driven by ultrasound follows a first-order kinetic law and is mediated by the competition between Na(+) and H(+) for surface sites. The dynamics of interaction with small cations (i.e. the sodium ion) is studied by nuclear magnetic resonance spectroscopy and is demonstrated to be a multifaced process, since Na(+) is in part free to exchange between the binding sites on nanotubes and the bulk and in part is confined to slowly exchanging nanotube sites. The aqueous titanate nanotube solutions are stable for months, thus opening new perspectives for the use of this material in drug delivery and in homogeneous photocatalysis. PMID- 23813881 TI - Anti-D immunoglobulin therapy for pediatric ITP: before and after the FDA's black box warning. AB - In March 2010, the Food and Drug Administration (FDA) issued a black box warning for anti-D immunoglobulin (anti-D), an approved treatment for immune thrombocytopenia (ITP). It is unknown if and how clinical practice at U.S children's hospitals has since changed. We sought to describe inpatient anti-D usage, laboratory monitoring, and anti-D complications before and after the FDA warning. Using the Pediatric Health Information System, we collected data from 41 children's hospitals. There was a modest but statistically significant decrease in anti-D usage from pre-warning to post-warning. Severe complication rates were very low and did not change appreciably. PMID- 23813882 TI - Phosphine-catalyzed Rauhut-Currier domino reaction: a facile strategy for the construction of carbocyclic spirooxindoles skeletons. AB - Push-over: A novel domino reaction of activated conjugated dienes and methyleneindolinones incorporates a phosphine-catalyzed intermolecular Rauhut Currier to form two C-C bonds and a quaternary carbon center. This method can be used to synthesize spirocyclopenteneoxindoles skeletons, which are potential building blocks for biologically active compounds. PMID- 23813883 TI - Harnessing the influence of reactive edges and defects of graphene substrates for achieving complete cycle of room-temperature molecular sensing. AB - Molecular doping and detection are at the forefront of graphene research, a topic of great interest in physical and materials science. Molecules adsorb strongly on graphene, leading to a change in electrical conductivity at room temperature. However, a common impediment for practical applications reported by all studies to date is the excessively slow rate of desorption of important reactive gases such as ammonia and nitrogen dioxide. Annealing at high temperatures, or exposure to strong ultraviolet light under vacuum, is employed to facilitate desorption of these gases. In this article, the molecules adsorbed on graphene nanoflakes and on chemically derived graphene-nanomesh flakes are displaced rapidly at room temperature in air by the use of gaseous polar molecules such as water and ethanol. The mechanism for desorption is proposed to arise from the electrostatic forces exerted by the polar molecules, which decouples the overlap between substrate defect states, molecule states, and graphene states near the Fermi level. Using chemiresistors prepared from water-based dispersions of single-layer graphene on mesoporous alumina membranes, the study further shows that the edges of the graphene flakes (showing p-type responses to NO2 and NH3) and the edges of graphene nanomesh structures (showing n-type responses to NO2 and NH3) have enhanced sensitivity. The measured responses towards gases are comparable to or better than those which have been obtained using devices that are more sophisticated. The higher sensitivity and rapid regeneration of the sensor at room temperature provides a clear advancement towards practical molecule detection using graphene-based materials. PMID- 23813884 TI - Do clinical parameters predict first planned extubation outcome in the pediatric intensive care unit? AB - CONTEXT: There is absence of evidence-based guidelines to determine extubation readiness in the pediatric intensive care unit (PICU). OBJECTIVE: Evaluate our practice of determining extubation readiness based on physician judgment of preextubation ventilator settings, blood gas analysis, and other factors potentially affecting extubation outcome. DESIGN: Prospective cohort study from August 2010 to April 2012. SETTING: Academic, multidisciplinary PICU. PATIENTS: A total of 319 PICU patients undergoing first planned extubation attempt. INTERVENTIONS: None. MEASUREMENTS: Determine the extubation success rate and evaluate factors potentially affecting extubation outcome. The PICU length of stay (LOS) and cost were also recorded. Subgroup analysis was performed based on days of mechanical ventilation (MV). RESULTS: A total of 319 consecutive patients underwent first planned extubation attempt with a 91% success rate. Factors associated with extubation failure were the length of MV (P < .0001, odds ratio [OR] 2.20); age (P = .02, OR 0.54); preextubation steroids (P = .04, OR 2.40); and postextubation stridor (P < .01, OR 3.40). Ventilator settings and blood gas results had no association with extubation outcome with 1 exception, ventilator rates <= 8 were associated with extubation failure in patients with <=1 day of MV. Extubation failure was associated with prolonged PICU LOS and excess cost, with failures staying 14 days longer (P < .0001) and costing 3.2 time more (P < .0001) than successes. CONCLUSIONS: Physician judgment to determine extubation readiness led to a first planned extubation success rate of 91%. Age and the length of MV were primary risk factors for failed extubation. In patients with <=1 day of MV, our findings suggest that confidence in extubation readiness following weaning to low ventilator rates may not be justified. Furthermore, reliance on preextubation ventilator settings and blood gas results to determine extubation readiness may lead to unnecessary prolongation of MV, thereby increasing the PICU LOS and excess cost. These findings are hypothesis generating and require further study for confirmation. PMID- 23813885 TI - Management of retinopathy of prematurity. AB - While current management of retinopathy of prematurity (ROP) is well evidenced, the recent Neonatal Oxygenation Prospective Meta-analysis (NeoPROM) oxygen therapy trials, and the Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEAT-ROP) trial of intravitreal injection bevacizumab, have reopened debate on optimal management. Early postnatal manipulation of oxygen therapy, nutrition and serum IGF 1 levels may improve early retinal blood vessel development and prevent later severe ROP. While the use of intravitreal injections of antivascular endothelial growth factor (VEGF) agents may appear to be an attractive alternative to laser ablation of the peripheral retina, caution is needed. The optimal choice of agent and dose remain unknown, and suppression of serum VEGF levels might interfere with normal angiogenesis processes in developing tissues. There is a pressing need for good Phase 1 studies of these agents, and safety trials. PMID- 23813886 TI - T1 estimation for aqueous iron oxide nanoparticle suspensions using a variable flip angle SWIFT sequence. AB - PURPOSE: T1 quantification of contrast agents, such as super-paramagnetic iron oxide nanoparticles, is a challenging but important task inherent to many in vivo applications in magnetic resonance imaging. In this work, a sweep imaging with Fourier transformation using variable flip angles (VFAs-SWIFT) method was proposed to measure T1 of aqueous super-paramagnetic iron oxide nanoparticle suspensions. METHODS: T1 values of various iron concentrations (from 1 to 7 mM) were measured using VFA-SWIFT and three-dimensional spoiled gradient-recalled echo with VFAs (VFA-SPGR) sequences on a 7 T MR scanner. For validation, T1 values were also measured using a spectroscopic inversion-recovery sequence on a 7 T spectrometer. RESULTS: VFA-SWIFT demonstrated its advantage for quantifying T1 of highly concentrated aqueous super-paramagnetic iron oxide nanoparticle suspensions, but VFA-SPGR failed at the higher end of iron concentrations. Both VFA-SWIFT and VFA-SPGR yielded linear relationships between the relaxation rate and iron concentrations, with relaxivities of 1.006 and 1.051 s(-1) mM(-1) at 7 T, respectively, in excellent agreement with the spectroscopic measurement of 1.019 s(-1) mM(-1) . CONCLUSION: VFA-SWIFT is able to achieve accurate T1 quantification of aqueous super-paramagnetic iron oxide nanoparticle suspensions up to 7 mM. PMID- 23813887 TI - Procedures to evaluate the efficiency of protective clothing worn by operators applying pesticide. AB - The evaluation of the efficiency of whole-body protective clothing against pesticides has already been carried out through field tests and procedures defined by international standards, but there is a need to determine the useful life of these garments to ensure worker safety. The aim of this article is to compare the procedures for evaluating efficiency of two whole-body protective garments, both new and previously used by applicators of herbicides, using a laboratory test with a mannequin and in the field with the operator. The evaluation of the efficiency of protective clothing used both quantitative and qualitative methodologies, leading to a proposal for classification according to efficiency, and determination of the useful life of protective clothing for use against pesticides, based on a quantitative assessment. The procedures used were in accordance with the standards of the modified American Society for Testing and Materials (ASTM) F 1359:2007 and International Organization for Standardization 17491-4. The protocol used in the field was World Health Organization Vector Biology and Control (VBC)/82.1. Clothing tested was personal water repellent and pesticide protective. Two varieties of fabric were tested: Beige (100% cotton) and Camouflaged (31% polyester and 69% cotton). The efficiency in exposure control of the personal protective clothing was measured before use and after 5, 10, 20, and 30 uses and washes under field conditions. Personal protective clothing was worn by workers in the field during the application of the herbicide glyphosate on weed species in mature sugar cane plantations using a knapsack sprayer. The modified ASTM 1359:2007 procedure was chosen as the most appropriate due to its greater repeatability (lower coefficient of variation). This procedure provides quantitative evaluation needed to determine the efficiency and useful life of individual protective clothing, not just at specific points of failure, but according to dermal protection as a whole. The qualitative assessment, which is suitable for verification of garment design and stitching flaws, does not aid in determining useful life, but does complement the quantitative evaluation. The proposed classification is appropriate and accurate for determining the useful life of personal protective clothing against pesticide materials relative to number of uses and washes after each use. For example, the Beige garment had a useful life of 30 uses and washes, while the Camouflaged garment had a useful life of 5 uses and washes. The quantitative evaluation aids in determining the efficiency and useful life of individual protective clothing according to dermal protection as a whole, not just at specific points of failure. PMID- 23813888 TI - Exposure of wildland firefighters to carbon monoxide, fine particles, and levoglucosan. AB - Wildland firefighters are occupationally exposed to elevated levels of woodsmoke. Eighteen wildland firefighters were monitored for their personal exposure to particulate matter with median aerodynamic diameter of 2.5 microns (PM2.5), levoglucosan (LG), and carbon monoxide (CO) at 30 prescribed burns at the Savannah River Site, South Carolina. Linear mixed effect models were used to investigate the effect on exposure of various factors and to examine whether the firefighters were able to qualitatively estimate their own exposures. Exposure to PM2.5 and CO was higher when firefighters performed 'holding' tasks compared with 'lighting' duties, whereas exposures to CO and LG were higher when burns were in compartments with predominantly pine vegetation (P < 0.05). Exposures to PM2.5 (64-2068 ug m(-3)) and CO (0.02-8.2 p.p.m.) fell within the ranges observed in previous studies. Some recommended shorter term exposure limits for CO were exceeded in a few instances. The very low LG:PM2.5 ratios in some samples suggest that the exposures of wildland firefighters to pollutants at prescribed burns may be substantially impacted by non-woodsmoke sources. The association of the qualitative exposure estimation of the firefighters with actual PM2.5 and CO measurements (P < 0.01) indicates that qualitative estimation may be used to assess exposure in epidemiology studies. PMID- 23813889 TI - Exposure to grain dust and microbial components in the Norwegian grain and compound feed industry. AB - OBJECTIVES: The aim of this study was to extensively characterize grain workers' personal exposure during work in Norwegian grain elevators and compound feed mills, to identify differences in exposures between the workplaces and seasons, and to study the correlations between different microbial components. METHODS: Samples of airborne dust (n = 166) were collected by full-shift personal sampling during work in 20 grain elevators and compound feed mills during one autumn season and two winter seasons. The personal exposure to grain dust, endotoxins, beta-1->3-glucans, bacteria, and fungal spores was quantified. Correlations between dust and microbial components and differences between workplaces and seasons were investigated. Determinants of endotoxin and beta-1->3-glucan exposure were evaluated by linear mixed-effect regression modeling. RESULTS: The workers were exposed to an overall geometric mean of 1.0mg m(-3) inhalable grain dust [geometric standard deviation (GSD) = 3.7], 628 endotoxin units m(-3) (GSD = 5.9), 7.4 ug m(-3) of beta-1->3-glucan (GSD = 5.6), 21 * 10(4) bacteria m(-3) (GSD = 7.9) and 3.6 * 10(4) fungal spores m(-3) (GSD = 3.4). The grain dust exposure levels were similar across workplaces and seasons, but the microbial content of the grain dust varied substantially between workplaces. Exposure levels of all microbial components were significantly higher in grain elevators compared with all other workplaces. The grain dust exposure was significantly correlated (Pearson's r) with endotoxin (rp = 0.65), beta-1->3-glucan (rp = 0.72), bacteria (rp = 0.44) and fungal spore (rp = 0.48) exposure, whereas the explained variances were strongly dependent on the workplace. Bacteria, grain dust, and workplace were important determinants for endotoxin exposure, whereas fungal spores, grain dust, and workplace were important determinants for beta-1 >3-glucan exposure. CONCLUSIONS: Although the workers were exposed to a relatively low mean dust level, the microbial exposure was high. Furthermore, the exposure levels of microbial components varied between workplaces although the dust levels were similar. We therefore recommend that exposure levels at different workplaces should be assessed separately and a task-based assessment should be done for detailed evaluation of efficient dust-reducing measures. The microbial content and knowledge of health effects of the microbial components should be considered in health risk evaluations of these workplaces. PMID- 23813890 TI - Molecular basis of protein S deficiency in China. AB - Protein S (ProS) is a physiological inhibitor of coagulation with an important function in the down-regulation of thrombin generation. ProS deficiency is a major risk factor for venous thrombosis. This study enrolled 40 ProS-deficient probands to investigate the molecular basis of hereditary ProS deficiency in Chinese patients. A mutation analysis was performed by resequencing the PROS1 gene. Large deletions were identified by multiplex ligation-dependent probe amplification (MLPA) analysis. A total of 20 different mutations, including 15 novel mutations, were identified in 21 of the 40 index probands. Small mutations were detected in 18 (45.0%) probands, and large deletions were found in 3 (7.5%) probands, leaving 19 (47.5%) patients without causative variants. To evaluate the functional consequences of 2 novel missense variants, ex vivo thrombin-generation assays, bioinformatics tools, and in vitro expression studies were employed. The p.Asn365Lys ProS variant was found to have moderately impaired secretion and reduced activated protein C cofactor activity. In contrast, the p.Pro410His mutant appeared to have severely impaired secretion but full anticoagulant activity. This study is the largest investigation of ProS deficiency in China and the first investigation of the influence of Type I ProS missense mutations on the global level of coagulation function. The p.K196E mutation, which is common in the neighboring Japanese population, was not found in our Chinese population, and null mutations were common in our Chinese population but not common in Japan. Further genetic analysis is warranted to understand the causes of ProS deficiency in patients without a genetic explanation. PMID- 23813891 TI - Birth of children with severe beta-thalassemia at a tertiary obstetric hospital: what are the reasons behind it? AB - OBJECTIVE: To find reasons for the births of severe beta-thalassemia at a tertiary obstetric hospital in mainland China. METHODS: All cases with confirmed diagnosis of beta-thalassemia major were included from 1 January 2007 to 31 December 2011. The main clinical characteristics of the affected pregnancies were reviewed, including maternal reproductive history, prenatal care in the current pregnancy, the gestation of pregnancy at the time of booking, and availability of husbands for a screen test. RESULTS: A total of nine cases of beta-thalassemia major were identified at birth during the study period. The reasons for no prenatal diagnosis included unavailability of the father for a test in four cases, unacceptability of the invasive procedure in two cases, absence of prenatal care in two cases, and nonpaternity in one case. CONCLUSION: The effectiveness in control of the disease is not only associated with the model itself but also the factors playing against the model. The identification of the main reasons for the birth of severe thalassemia might help to find room for improvement in clinical practice. PMID- 23813892 TI - Scalable manufacture of built-to-order nanomedicine: spray-assisted layer-by layer functionalization of PRINT nanoparticles. AB - Scalable methods, PRINT particle fabrication, and spray-assisted Layer-by-Layer deposition are combined to generate uniform and functional nanotechnologies with precise control over composition, size, shape, and surface functionality. A modular and tunable approach towards design of built-to-order nanoparticle systems, spray coating on PRINT particles is demonstrated to achieve technologies capable of targeted interactions with cancer cells for applications in drug delivery. PMID- 23813894 TI - Characterisation of phenolic compounds by HPLC-TOF/IT/MS in buds and open flowers of 'Chemlali' olive cultivar. AB - INTRODUCTION: Plant phenolics are secondary metabolites that constitute one of the most widely occurring groups of phytochemicals that play several important functions in plants. In olive (Olea europaea L), there is not enough information about the occurrence of these compounds in buds and flowers. OBJECTIVE: To conduct a comprehensive characterisation of buds and open flowers from the olive cultivar 'Chemlali'. METHODS: The polar fraction of buds and open flowers was extracted using solid-liquid extraction with hydro-alcoholic solvent. Then extracts were analysed using high performance liquid chromatography (HPLC) coupled to electrospray ionisation time-of-flight mass spectrometry (ESI/TOF/MS) and electrospray ionisation ion-trap tandem mass spectrometry (ESI/IT/MS2) operating in negative ion mode. RESULTS: Phenolic compounds from different classes including secoiridoids, flavonoids, simple phenols, cinnamic acid derivatives and lignans were tentatively identified in both extracts. Qualitatively, no significant difference was observed between flower buds and open flowers extracts. However, quantitatively the secoiridoids presented higher percentage of total phenols in open flowers (41.7%) than in flower buds (30.5%) in contrast to flavonoids, which decreased slightly from 38.1 to 26.7%. Cinnamic acid derivatives and simple phenols did not show any change. Lignans presented the lowest percentage in both extracts with an increase during the development of the flower bud to open flower. CONCLUSION: The HPLC-TOF/IT/MS allowed the characterisation, for the first time, of the phenolic profile of extracts of 'Chemlali' olive buds and open flowers, proving to be a very useful technique for the characterisation and structure elucidation of phenolic compounds. PMID- 23813893 TI - Efficacy and mechanism of poloxamine-assisted polyplex transfection. AB - BACKGROUND: Amphiphilic block copolymers acting as biological response modifiers provide an attractive approach for improving the transfection efficiency of polycationic polymer/DNA complexes (polyplexes) by altering cellular processes crucial for efficient transgene expression. METHODS: The present study aimed to investigate the effect of the poloxamine Tetronic T904, a four-arm polyethylene oxide/polypropylene oxide block copolymer, on polyplex transfection and to determine its mechanism of action by analyzing the cellular uptake of polyplex, the nuclear localization of plasmid and RNA transcript production. RESULTS: T904 significantly increased the transfection efficiency of polyplexes based on 25-kDa branched polyethylenimine in a dose-dependent manner in the presence of serum in C6 glioma cells, as well as human fibroblasts and mesenchymal stem cells. The activity of T904 was not promoter-dependent, increasing the expression of reporter genes under both cytomegalovirus and SV40 promoters. Although T904 did not affect the internalization or nuclear uptake of plasmid, mRNA expression levels from both promoters showed dose-dependent increases that closely paralleled increases in gene expression. CONCLUSIONS: The present study demonstrates that T904 significantly increases polyplex transfection efficiency and suggests a mechanism of increased transcriptional activity. As a four-arm, hydroxyl-terminated polymer, T904 is amenable to a variety of end group functionalization and covalent cross-linking strategies that have been developed for preparing hydrogels from multi-arm polyethylene glycol, making it particularly attractive for scaffold-mediated gene delivery. PMID- 23813895 TI - Comparison of two editions of Tokyo guidelines for the management of acute cholangitis. AB - BACKGROUND: The Tokyo guidelines from 2007 (TG07) and 2013 (TG13) were compared for the management of acute cholangitis (AC). METHODS: We reviewed patients with clinically-proven AC by detecting purulent biles during biliary drainage. TG07 and TG13 were compared regarding diagnosis, severity grading and prognostic values. New risk factors for 30-day mortality were investigated. RESULTS: Definite diagnosis for 120 eligible patients was made in 104 (86.7%) and 101 (84.2%) cases by TG07 and TG13, respectively (P = 0.36), higher than 61 (50.8%) by Charcot's triad (P < 0.001). Diagnostic overlap and concordance (kappa) are 90.8% (109/120) and 0.63 (P < 0.0001). Patients classified into mild and moderate grades by TG07 and TG13 differed significantly (P = 0.043). Both guidelines could not predict clinical outcomes except the needs for multi ERCP session by TG13. Intrahepatic obstruction (OR = 11.2, 95% CI: 1.55-226.9) and hypoalbuminemia (<= 25.0 g/l; OR = 17.3, 95% CI: 3.5-313.6) were independent risk factors for 30-day mortality in multivariate model. CONCLUSION: Two guidelines are reproducible and reliable in AC diagnosis but different in severity grading. TG13 are more practical for immediate severity grading, enabling planning treatment upon admission. Intrahepatic obstruction is a new candidate predictor of 30-day mortality for further assessment. PMID- 23813896 TI - Plant response to climate change along the forest-tundra ecotone in northeastern Siberia. AB - Russia's boreal (taiga) biome will likely contract sharply and shift northward in response to 21st century climatic change, yet few studies have examined plant response to climatic variability along the northern margin. We quantified climate dynamics, trends in plant growth, and growth-climate relationships across the tundra shrublands and Cajander larch (Larix cajanderi Mayr.) woodlands of the Kolyma river basin (657 000 km(2) ) in northeastern Siberia using satellite derived normalized difference vegetation indices (NDVI), tree ring-width measurements, and climate data. Mean summer temperatures (Ts ) increased 1.0 degrees C from 1938 to 2009, though there was no trend (P > 0.05) in growing year precipitation or climate moisture index (CMIgy ). Mean summer NDVI (NDVIs ) increased significantly from 1982 to 2010 across 20% of the watershed, primarily in cold, shrub-dominated areas. NDVIs positively correlated (P < 0.05) with Ts across 56% of the watershed (r = 0.52 +/- 0.09, mean +/- SD), principally in cold areas, and with CMIgy across 9% of the watershed (r = 0.45 +/- 0.06), largely in warm areas. Larch ring-width measurements from nine sites revealed that year-to year (i.e., high-frequency) variation in growth positively correlated (P < 0.05) with June temperature (r = 0.40) and prior summer CMI (r = 0.40) from 1938 to 2007. An unexplained multi-decadal (i.e., low-frequency) decline in annual basal area increment (BAI) occurred following the mid-20th century, but over the NDVI record there was no trend in mean BAI (P > 0.05), which significantly correlated with NDVIs (r = 0.44, P < 0.05, 1982-2007). Both satellite and tree-ring analyses indicated that plant growth was constrained by both low temperatures and limited moisture availability and, furthermore, that warming enhanced growth. Impacts of future climatic change on forests near treeline in Arctic Russia will likely be influenced by shifts in both temperature and moisture, which implies that projections of future forest distribution and productivity in this area should take into account the interactions of energy and moisture limitations. PMID- 23813897 TI - Programmable imaging amplification via nanoparticle-initiated DNA polymerization. PMID- 23813898 TI - Radiological features of thymic langerhans cell histiocytosis. AB - TI was reported in 18/1,264 (1.4%) LCH patients. All nine patients with TI at initial LCH presentation were below 2 years of age and had multisystem LCH (9/242, 4%). Images (sonography, CT, MRI) for central review were available in 15 cases. Characteristic findings of TI were thymus enlargement (67%), few to many cysts (80%), and few to many calcifications (100%). Sonographic and MRI findings were in excellent agreement. We recommend adding sonography of the thymus to the standard for initial clinical evaluation of LCH patients below the age of 2 years. PMID- 23813899 TI - Remarkable properties of ZnO heavily substituted with nitrogen and fluorine, ZnO(1-x)(N,F)x. PMID- 23813901 TI - Does website-based information add any value in counseling mothers expecting a baby with severe congenital diaphragmatic hernia? AB - OBJECTIVE: We aimed to measure whether website-provided information about congenital diaphragmatic hernia (CDH) and fetal therapy for severe cases provides added value compared with clinical counseling of parents. METHODS: This is a single center study in 102 couples who earlier opted for fetoscopic endoluminal tracheal occlusion (FETO) because of isolated severe CDH. They were asked to fill out an anonymized web-based survey of 12 questions. Then, they were offered access to information on the web pages of the randomized Tracheal Occlusion to Accelerate Lung Growth (TOTAL) trial. One week later, their appreciation was measured again by a second questionnaire. RESULTS: Eighty-two (80%) parents completed the first questionnaire, and 48 (47%) completed the entire survey. Several items became more clear to the parents after reading the website, such as the length of hospital stay (23.2% prior to web information, 60.4% after; P = 0.004), maternal risk, or the requirement of fetal anesthesia for FETO (43.9% resp. 79.2%; P = <0.001). CONCLUSION: Complementing prenatal counseling on CDH and FETO by standardized information via website is perceived by parents as of added value. Maternal risks and the need for fetal medication need more clarification during the verbal counseling prior to prenatal interventions. PMID- 23813900 TI - Rapid donor T-cell engraftment increases the risk of chronic graft-versus-host disease following salvage allogeneic peripheral blood hematopoietic cell transplantation for bone marrow failure syndromes. AB - The risk of graft-rejection after allogeneic hematopoietic cell transplantation using conventional cyclophosphamide-based conditioning is increased in patients with bone marrow failure syndromes (BMFS) who are heavily transfused and often HLA-alloimmunized. Fifty-six patients with BMFS underwent fludarabine-based reduced-intensity conditioning and allogeneic peripheral blood progenitor cell (PBPC) transplantation at a single institution. The conditioning regimen consisted of intravenous cyclophosphamide, fludarabine, and equine antithymocyte globulin. Graft-versus-host disease (GVHD) prophylaxis included cyclosporine A alone or in combination with either mycophenolate mofetil or methotrexate. To reduce the risk of graft-rejection/failure, unmanipulated G-CSF mobilized PBPCs obtained from an HLA-identical or single HLA-antigen mismatched relative were transplanted rather than donor bone marrow. Despite a high prevalence of pretransplant HLA-alloimmunization (41%) and a heavy prior transfusion burden, graft-failure did not occur with all patients having sustained donor lympho hematopoietic engraftment. The cumulative incidence of grade II-IV acute-GVHD and chronic-GVHD was 51.8% and 72%, respectively; with 87.1% surviving at a median follow-up of 4.5 years. A multivariate analysis showed pretransplant alloimmunization and rapid donor T-cell engraftment (>=95% donor by day 30) were both significantly (P < 0.05) associated with the development of chronic-GVHD (adjusted HR 2.13 and 2.99, respectively). These data show fludarabine-based PBPC transplantation overcomes the risk of graft-failure in patients with BMFS, although rapid donor T-cell engraftment associated with this approach appears to increase the risk of chronic-GVHD. (Clinicaltrials.gov identifier: NCT00003838). PMID- 23813903 TI - Porous protein crystals as reaction vessels. AB - Porous protein crystals have the potential to provide new porous materials due to their unique chemical environments composed of amino acid residues periodically exposed at the surface of the solvent channels in the crystal lattice. This enables accumulation of external compounds in special arrangements by metal coordination interactions or by chemical modifications. This article presents a review of advances in the recently established field of porous protein crystals. PMID- 23813904 TI - In situ generation of PhI(+)CF3 and transition-metal-free oxidative sp2 C-H trifluoromethylation. PMID- 23813906 TI - A LC/QTOF-MS/MS application to investigate chemical compositions in a fraction with protein tyrosine phosphatase 1B inhibitory activity from Rosa rugosa flowers. AB - INTRODUCTION: Rosa rugosa flowers used as herbal medicine possess many activities. A fraction extracted by ethyl acetate exhibited strong inhibitive activity against protein tyrosine phosphatase 1B (PTP1B) in vitro. OBJECTIVE: Establish an efficient method of LC coupled to quadrupole time-of-flight (QTOF) with tandem MS/MS to investigate the compositions in the active fraction. METHODS: Chemical compositions were separated and investigated by LC/QTOF-MS/MS in negative electrospray ionisation (ESI) mode at different collision energy (CE) values. The maximal structural information was obtained for the identification of components. RESULTS: A total of 75 compounds including tannins, their related compounds and flavonoids were identified or partially characterised according to accurate mass and the characteristic fragments at low and high CE. Meanwhile, the fragmentation pathways of gallotannins and ellagitannins (hexahydroxydiphenoyl group and lactonised valoneoyl group) were studied and proposed and were used to trace tannins in crude extracts. CONCLUSION: The results suggest that this fraction is a source of PTP1B inhibitory activity with a potential for treating diabetes. PMID- 23813907 TI - Clinical guidance of community physiotherapists regarding people with MS: professional development and continuity of care. AB - BACKGROUND AND PURPOSE: Clinical guidance to community physiotherapists (cPTs) is an integral part of physiotherapy service offered in hospital outpatient (OP) clinics for people with multiple sclerosis (PwMS). There is currently a lack of knowledge on the significance of such guidance. The aims of this study were 1) to identify the features that cPTs perceive to be significant in clinical guidance and 2) how this guidance may affect the cPTs' subsequent treatment of PwMS. METHODS: A phenomenological-hermeneutical framework was selected, and qualitative research interviews were performed and complemented with non-participating observations of a strategic sample of nine cPTs who received clinical guidance for their patients. The interviews were recorded and transcribed, and content analysis was conducted by using systematic text condensation, using theories of practice knowledge as analytic perspectives. RESULTS: The results indicate that cPTs identify participation in authentic movement analysis of a familiar patient as significant for professional development. Vital features are evaluation of the interplay between body parts, exploration of improvement of movement embedded in the OP clinic physiotherapist's explanations, followed by discussion. These elements provide access to dynamic elements in practice knowledge that are available only through first-hand experience and promote clinical reasoning through enhanced reflection during action as well as following action. Such guidance suggests direction for subsequent treatment and may enhance the continuity of care, particularly if the cPTs are experienced. Mutual information flow implementing the cPTs' perspective is requested, as are the use of plain language and supervision of the cPTs handling skills. Professional guidance for cPTs in OP clinics for PwMS should be considered when programmes aiming to develop competency in neurological physiotherapy are designed and when continuity of care for PwMS is discussed. More research regarding potential long-term impact of professional guidance in these clinics is requested. PMID- 23813905 TI - Cell segregation, mixing, and tissue pattern in the spinal cord of the Xenopus laevis neurula. AB - BACKGROUND: During Xenopus laevis neurulation, neural ectodermal cells of the spinal cord are patterned at the same time that they intercalate mediolaterally and radially, moving within and between two cell layers. Curious if these rearrangements disrupt early cell identities, we lineage-traced cells in each layer from neural plate stages to the closed neural tube, and used in situ hybridization to assay gene expression in the moving cells. RESULTS: Our biotin and fluorescent labeling of deep and superficial cells reveals that mediolateral intercalation does not disrupt cell cohorts; in other words, it is conservative. However, outside the midline notoplate, later radial intercalation does displace superficial cells dorsoventrally, radically disrupting cell cohorts. The tube roof is composed almost exclusively of superficial cells, including some displaced from ventral positions; gene expression in these displaced cells must now be surveyed further. Superficial cells also flank the tube's floor, which is, itself, almost exclusively composed of deep cells. CONCLUSIONS: Our data provide: (1) a fate map of superficial- and deep-cell positions within the Xenopus neural tube, (2) the paths taken to these positions, and (3) preliminary evidence of re patterning in cells carried out of one environment and into another, during neural morphogenesis. PMID- 23813908 TI - Eradication of multi-drug resistant bacteria by a novel Zn-doped CuO nanocomposite. AB - Zinc-doped copper oxide nanoparticles are synthesized and simultaneously deposited on cotton fabric using ultrasound irradiation. The optimization of the processing conditions, the specific reagent ratio, and the precursor concentration results in the formation of uniform nanoparticles with an average size of ~30 nm. The antibacterial activity of the Zn-doped CuO Cu0.88Zn0.12O in a colloidal suspension or deposited on the fabric is tested against Escherichia coli (Gram negative) and Staphylococcus aureus (Gram positive) bacteria. A substantial enhancement of 10,000 times in the antimicrobial activity of the Zn CuO nanocomposite compared to the pure CuO and ZnO nanoparticles (NPs) is observed after 10 min exposure to the bacteria. Similar activities are observed against multidrug-resistant bacteria (MDR), (i.e., Methicillin-resistant S. aureus and MDR E. coli) further emphasizing the efficacy of this composite. Finally, the mechanism for this enhanced antibacterial activity is presented. PMID- 23813909 TI - Effect of non-specifically adsorbed ions on the surface oxidation of Pt(111). AB - The oxidation processes of a Pt(111) electrode in alkaline electrolytes depend on non-specifically adsorbed ions according to in situ X-ray diffraction and infrared spectroscopic measurements. In an aqueous solution of LiOH, an OHad adlayer is formed in the first oxidation step of the Pt(111) electrode as a result of the strong interaction between Li(+) and OHad , whereas Pt oxidation proceeds without OHad formation in CsOH solution. Structural analysis by X-ray diffraction indicates that Li(+) is strongly protective against surface roughening caused by subsurface oxidation. Although Cs(+) is situated near the Pt surface, the weak protective effect of Cs(+) results in irreversible surface roughening due to subsurface oxidation. PMID- 23813910 TI - ADAMTS13 content in plasma-derived factor VIII/von Willebrand factor concentrates. AB - Thrombotic thrombocytopenic purpura (TTP) is a microangiopathy syndrome caused by a congenital or acquired deficiency of ADAMTS13, a plasma metalloprotease that cleaves von Willebrand factor (VWF) and thus prevents the formation of platelet rich thrombi in the microcirculation. TTP can be fatal if not appropriately and timely treated with the infusion of fresh frozen plasma (FFP) or exchange plasmapheresis, that reverse the process of microangiopathy by removing anti ADAMTS13 autoantibodies and replacing functional ADAMTS13. The treatment of TTP with FFP is not free from risks and must be administered in hospitals or clinics, owing to the substantial amount of plasma volume infused or exchanged and the frequent need of catheter application. Moreover, most FFPs are not subjected to treatments to remove or inactivate blood-borne infectious agents. A number of recent reports indicate that certain plasma-derived VWF-factor VIII (FVIII) concentrates are clinically effective in the treatment of congenital TTP. In this study, we measured ADAMTS13 levels in various plasma-derived VWF-FVIII concentrates, showing that Koate((r)) -DVI (Grifols), contained relatively high amounts of ADAMTS13 and that Alphanate((r)) (Grifols) was the closest other product in terms of protease content. Koate((r)) -DVI contains, on average (five lots tested), 0.091 +/- 0.007 Units of ADAMTS13 activity per IU of FVIII. On the basis of this analysis and other reports of VWF-FVIII concentrate utilization in congenital TTP, potential dosing, and future clinical developments are discussed. PMID- 23813911 TI - Preoperative prediction of the individualized risk of early fetal death after laser therapy in twin-to-twin transfusion syndrome. AB - OBJECTIVE: The aim of this study is to evaluate the independent and combined value of gestational age, fetal weight, fetoplacental Doppler, and myocardial performance index for the prediction of individual risk of early (<=7 days) intrauterine fetal death (IUFD) after laser therapy in twin-to-twin transfusion syndrome (TTTS). MATERIAL AND METHODS: A consecutive series of 215 cases of TTTS treated with laser therapy in three centers was prospectively studied. Ultrasound evaluation within 24 h of surgery included estimated fetal weight discordance, umbilical artery, pulsatility index (PI) and diastolic flow evaluation, middle cerebral artery PI and middle cerebral artery peak systolic velocity, ductus venosus PI and atrial flow assessment, and modified myocardial performance index. Logistic regression analysis was used to explore the association of preoperative parameters with IUFD. RESULTS: Intrauterine fetal death occurred in 17 (7.9%) of the recipients and 33 (15.3%) donors (p = 0.016). The only independent predictors of IUFD in recipients was the middle cerebral artery peak systolic velocity >1.5 MoM (OR = 22, p = 0.015), but this event was present in only 3% of recipients. In donors, reverse end diastolic flow in the umbilical artery (OR = 14.748, p = 0.033), estimated fetal weight discordance (OR = 1.054, p = 0.036), and gestational age (OR = 0.757, p = 0.046) were independent predictors. CONCLUSION: In TTTS, preoperative fetal assessment can identify independent risk factors for early post-operative IUFD, particularly in donors. PMID- 23813912 TI - Phase I trial of fenretinide delivered orally in a novel organized lipid complex in patients with relapsed/refractory neuroblastoma: a report from the New Approaches to Neuroblastoma Therapy (NANT) consortium. AB - BACKGROUND: A phase I study was conducted to determine the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetics of fenretinide (4 HPR) delivered in an oral powderized lipid complex (LXS) in patients with relapsed/refractory neuroblastoma. PROCEDURE: 4-HPR/LXS powder (352-2,210 mg/m(2) /day) was administered on Days 0-6, in 21-day courses, by standard 3 + 3 design. RESULTS: Thirty-two patients (median age = 8 years, range 3-27 years) enrolled with 30 evaluable for dose escalation. Prior therapies included stem cell transplantation/support (n = 26), 13-cis-retinoic acid (n = 22), (125/131) I-MIBG (n = 13), and anti-GD2 antibody (n = 6). 170+ courses were delivered. Course 1 DLTs were a Grade 3 (n = 1) alkaline phosphatase at 352 mg/m(2) /day. Other major toxicities were Grade 4 (n = 1) alkaline phosphatases on Courses 5 and 6 at 774 mg/m(2) /day, and Grade 3 (n = 1) ALT/AST elevation on Course 2 at 1,700 mg/m(2) /day. Of 29 response-evaluable patients, six had stable disease (SD) (4-26 courses); four with marrow- or bone disease-only had complete responses (CR) (10 46 courses). 4-HPR plasma levels were several folds higher (P < 0.05) than previously reported using capsular fenretinide. The Day 6 mean peak 4-HPR plasma level at 1,700 mg/m(2) /day was 21 uM. An MTD was not reached. CONCLUSIONS: 4 HPR/LXS oral powder obtained higher plasma levels, with minimal toxicity and evidence of anti-tumor activity, than a previous capsule formulation. A recommended phase II schedule of 4-HPR/LXS powder is 1,500 mg/m(2) /day, TID, on Days 0-6, of a 21-day course. PMID- 23813914 TI - Automated image analysis of in vitro angiogenesis assay. AB - Angiogenesis is the biological process of generating new capillary blood vessels. It is a fundamental component of a number of normal (reproduction and wound healing) and pathological processes (diabetic retinopathy, rheumatoid arthritis, tumor growth, and metastasis). In vitro angiogenesis assays provide a platform for evaluating the effects of pro- or antiangiogenic compounds. One of the most informative assays is the endothelial cells capillary tube formation assay performed on a biological matrix. This assay is based on quantification of the stimulatory and inhibitory effects of various agents, which is estimated through the measurement of the pseudo-tubules network length. This standard measurement is usually carried out manually by trained operators but requires time, attention, and dedication to achieve a reasonable degree of accuracy. Moreover, the screening is operator dependent. In this article, we propose an automated procedure to evaluate the pseudo-tubule network lengths. We propose a series of image analysis procedures developed using a freely available image analysis software library. More than 800 images from 12 experiments were analyzed automatically and manually, and their results were compared to improve and validate the proposed image analysis procedure. The resulting image analysis software is currently running on a dedicated server, with comparable accuracy to manual measurements. Using this new automated procedure, we are able to treat 540 images, or three complete assays per hour. PMID- 23813913 TI - The duplication 17p13.3 phenotype: analysis of 21 families delineates developmental, behavioral and brain abnormalities, and rare variant phenotypes. AB - Chromosome 17p13.3 is a gene rich region that when deleted is associated with the well-known Miller-Dieker syndrome. A recently described duplication syndrome involving this region has been associated with intellectual impairment, autism and occasional brain MRI abnormalities. We report 34 additional patients from 21 families to further delineate the clinical, neurological, behavioral, and brain imaging findings. We found a highly diverse phenotype with inter- and intrafamilial variability, especially in cognitive development. The most specific phenotype occurred in individuals with large duplications that include both the YWHAE and LIS1 genes. These patients had a relatively distinct facial phenotype and frequent structural brain abnormalities involving the corpus callosum, cerebellar vermis, and cranial base. Autism spectrum disorders were seen in a third of duplication probands, most commonly in those with duplications of YWHAE and flanking genes such as CRK. The typical neurobehavioral phenotype was usually seen in those with the larger duplications. We did not confirm the association of early overgrowth with involvement of YWHAE and CRK, or growth failure with duplications of LIS1. Older patients were often overweight. Three variant phenotypes included cleft lip/palate (CLP), split hand/foot with long bone deficiency (SHFLD), and a connective tissue phenotype resembling Marfan syndrome. The duplications in patients with clefts appear to disrupt ABR, while the SHFLD phenotype was associated with duplication of BHLHA9 as noted in two recent reports. The connective tissue phenotype did not have a convincing critical region. Our experience with this large cohort expands knowledge of this diverse duplication syndrome. PMID- 23813916 TI - Highly efficient room-temperature photoresponsive DNA tethering azobenzene through backbone-inserted glycerol via ether bond. PMID- 23813917 TI - Molecular evolutionary mechanisms driving functional diversification of the HSP90A family of heat shock proteins in eukaryotes. AB - The ubiquitous and conserved cytosolic heat-shock proteins 90 (HSP90A) perform essential functions in the cell. To understand the evolutionary origin of HSP90A functional diversification, we analyzed the distribution of HSP90A family from 54 species representing the main eukaryotic lineages. Three independent HSP90A duplications led to the paralog subfamilies HSP90AA (heat-stress inducible) and HSP90AB (constitutive) and trace back to key time points during vertebrate, seed plant, and yeast evolution. HSP90AA and HSP90AB present divergent selection pressures, positive selection (PS), and signatures of functional divergence (FD) after duplication. The differential evolutionary patterns support different mechanisms for HSP90A functional diversification in vertebrates and seed plants. Mapping of PS and FD residues onto the HSP90A structure suggests the acquisition of novel and/or specialized client protein and/or cochaperone binding functions. We propose these residues as targets for further experimental studies of HSP90A proteins, reported to be capacitors of rapid evolutionary change, and targets for anticancer therapeutics. PMID- 23813915 TI - Physical methods for intracellular delivery: practical aspects from laboratory use to industrial-scale processing. AB - Effective intracellular delivery is a significant impediment to research and therapeutic applications at all processing scales. Physical delivery methods have long demonstrated the ability to deliver cargo molecules directly to the cytoplasm or nucleus, and the mechanisms underlying the most common approaches (microinjection, electroporation, and sonoporation) have been extensively investigated. In this review, we discuss established approaches, as well as emerging techniques (magnetofection, optoinjection, and combined modalities). In addition to operating principles and implementation strategies, we address applicability and limitations of various in vitro, ex vivo, and in vivo platforms. Importantly, we perform critical assessments regarding (1) treatment efficacy with diverse cell types and delivered cargo molecules, (2) suitability to different processing scales (from single cell to large populations), (3) suitability for automation/integration with existing workflows, and (4) multiplexing potential and flexibility/adaptability to enable rapid changeover between treatments of varied cell types. Existing techniques typically fall short in one or more of these criteria; however, introduction of micro-/nanotechnology concepts, as well as synergistic coupling of complementary method(s), can improve performance and applicability of a particular approach, overcoming barriers to practical implementation. For this reason, we emphasize these strategies in examining recent advances in development of delivery systems. PMID- 23813918 TI - The ancient and widespread nature of the ER-mitochondria encounter structure. AB - Mitochondria are the result of a billion years of integrative evolution, converting a once free-living bacterium to an organelle deeply linked to diverse cellular processes. One way in which mitochondria are integrated with nonendosymbiotically derived organelles is via endoplasmic reticulum (ER) mitochondria contact sites. The ER membrane is physically tethered to the mitochondrial outer membrane by the ER-mitochondria encounter structure (ERMES). However, to date, ERMES has only ever been found in the fungal lineage. Here, we bioinformatically demonstrate that ERMES is present in lineages outside Fungi and validate this inference by mass spectrometric identification of ERMES components in Acanthamoeba castellanii mitochondria. We further demonstrate that ERMES is retained in hydrogenosome-bearing but not mitosome-bearing organisms, yielding insight into the process of reductive mitochondrial evolution. Finally, we find that the taxonomic distribution of ERMES is most consistent with rooting the eukaryotic tree between Amorphea (Animals + Fungi + Amoebozoa) + Excavata and all other eukaryotes (Diaphoratickes). PMID- 23813919 TI - Exploring the validity of assessment in anatomy: do images influence cognitive processes used in answering extended matching questions? AB - Assessment is an important aspect of medical education because it tests students' competence and motivates them to study. Various assessment methods, with and without images, are used in the study of anatomy. In this study, we investigated the use of extended matching questions (EMQs). To gain insight into the influence of images on the validity of test items, we focused on students' cognitive processes while they answered questions with and without images. Seventeen first year medical students answered EMQs about gross anatomy, combined with either labeled images or answer lists, while thinking aloud. The participants' verbal reports were transcribed verbatim and then coded. Initial codes were based on a task analysis and were adapted into final codes during the coding process. Results showed that students used more cues from EMQs with images and visualized more often in EMQs with answer lists. Ready knowledge and verbal reasoning were used equally often in both conditions. In conclusion, EMQs with and without images elicit different results in this think aloud experiment, indicating different cognitive processes. They seem to measure different skills, making them valid for different testing purposes. The take-home message for anatomy teachers is that questions without images seem to test the quality of students' mental images while questions with images test their ability to interpret visual information. It makes sense to use both response formats in tests. Using images from clinical practice instead of anatomical drawings will help to improve test validity. PMID- 23813920 TI - Embryological staging of the Zebra Finch, Taeniopygia guttata. AB - Zebra Finches (Taeniopygia guttata) are the most commonly used laboratory songbird species, yet their embryological development has been poorly characterized. Most studies to date apply Hamburger and Hamilton stages derived from chicken development; however, significant differences in development between precocial and altricial species suggest that they may not be directly comparable. We provide the first detailed description of embryological development in the Zebra Finch under standard artificial incubation. These descriptions confirm that some of the features used to classify chicken embryos into stages are not applicable in an altricial bird such as the Zebra Finch. This staging protocol will help to standardize future studies of embryological development in the Zebra Finch. PMID- 23813921 TI - Ofatumumab for refractory opsoclonus-myoclonus syndrome following treatment of neuroblastoma. AB - Opsoclonus-myoclonus syndrome (OMS) may be associated with ANNA-1 (anti-Hu) autoantibodies. The standard treatment with IVIG, steroids, and anti-CD20 monoclonal antibody may fail, and optimal therapy is unknown. A patient developed OMS with high-titer ANNA-1 following recovery from neuroblastoma. She failed standard therapy and had only transient response to rituximab. Treatment with the humanized anti-CD20 monoclonal antibody ofatumumab combined with methotrexate resulted in transient neurologic improvement and decrease of ANNA-1. This suggests that ofatumumab combined with methotrexate should further be considered OMS patients, particularly in refractory disease. PMID- 23813922 TI - The challenge of mild traumatic brain injury: role of biochemical markers in diagnosis of brain damage. AB - During the past decade there has been an increasing recognition of the incidence of mild traumatic brain injury (mTBI) and a better understanding of the subtle neurological and cognitive deficits that may result from it. A substantial, albeit suboptimal, effort has been made to define diagnostic criteria for mTBI and improve diagnostic accuracy. Thus, biomarkers that can accurately and objectively detect brain injury after mTBI and, ideally, aid in clinical management are needed. In this review, we discuss the current research on serum biomarkers for mTBI including their rationale and diagnostic performances. Sensitive and specific biomarkers reflecting brain injury can provide important information regarding TBI pathophysiology and serve as candidate markers for predicting abnormal computed tomography findings and/or the development of residual deficits in patients who sustain an mTBI. We also outline the roles of biomarkers in settings of specific interest including pediatric TBI, sports concussions and military injuries, and provide perspectives on the validation of such markers for use in the clinic. Finally, emerging proteomics-based strategies for identifying novel markers will be discussed. PMID- 23813923 TI - "Ocular tremor" in Parkinson's disease: a technology-dependent artifact of universal head motion? PMID- 23813926 TI - Severe infantile leigh syndrome associated with a rare mitochondrial ND6 mutation, m.14487T>C. AB - We describe a case of severe infantile-onset complex I deficiency in association with an apparent de novo near-homoplasmic mutation (m.14487T>C) in the mitochondrial ND6 gene, which was previously associated with Leigh syndrome and other neurological disorders. The mutation was near-homoplasmic in muscle by NextGen sequencing (99.4% mutant), homoplasmic in muscle by Sanger sequencing, and it was associated with a severe complex I deficiency in both muscle and fibroblasts. This supports previous data regarding Leigh syndrome being on the severe end of a phenotypic spectrum including progressive myoclonic epilepsy, childhood-onset dystonia, bilateral striatal necrosis, and optic atrophy, depending on the proportion of mutant heteroplasmy. While the mother in all previously reported cases was heteroplasmic, the mother and brother of this case were homoplasmic for the wild-type, m.14487T. Importantly, the current data demonstrate the potential for cases of mutations that were previously reported to be homoplasmic by Sanger sequencing to be less homoplasmic by NextGen sequencing. This case underscores the importance of considering mitochondrial DNA mutations in families with a negative family history, even in offspring of those who have tested negative for a specific mtDNA mutation. PMID- 23813928 TI - Cancer and mental health--a clinical and research unmet need. AB - BACKGROUND: Poor mental health is the largest single source of disability in the UK, and co-morbid health problems, particularly with cancer, raise total health care costs significantly. METHODS: This study examined what research is being conducted into the intersection between cancer and mental health. Research papers captured by the intersection of sub-field filters-'mental disorder' and 'cancer' were studied from the Web of Science over a 10-year period (2002-2011). RESULTS: There were 1463 papers dealing with the dual presence of cancer and mental disorder. They amounted to 0.26% of cancer research and 0.51% of mental health research over the 10-year period, indicating that their intersection receives little research attention. Eighty per cent of papers were concerned with the effects of cancer on mental health rather than the reverse; a few (5%) looked at the post-traumatic stress suffered by carers of cancer patients. Of cancer types, breast dominated (21%), followed by prostate (5%), lung (3%), oral (2%) and colorectal (2%) cancer. The area of mental health most studied in cancer was unipolar depression. CONCLUSIONS: The paucity of research that exists at the intersection of cancer and mental health requires attention from policymakers and funders in order to address an important trans-disciplinary gap in health care research. PMID- 23813927 TI - Integrating men's health and masculinity theories to explain colorectal cancer screening behavior. AB - Colorectal cancer (CRC) is the third most common cause of cancer deaths among men in the United States. Although CRC screening has been found to reduce CRC incidence and mortality, current screening rates among men are suboptimal due to various practical and psychosocial barriers. One potential barrier to CRC screening identified in qualitative studies with men is the threat to masculinity that endoscopic screening methods pose. Indeed, beliefs about masculinity have been predictive of other preventive health behaviors among men. In this review article, we propose a novel conceptual framework to explain men's CRC screening behavior that integrates masculinity norms, gender role conflict, men's health care experiences, behaviors, and beliefs, and social and background variables. This framework has the potential to guide future research on men's CRC screening behaviors and other health behaviors and may inform gender-sensitive interventions that target masculinity beliefs to increase preventive health behaviors. PMID- 23813929 TI - Small-cell lung cancer (SCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. PMID- 23813930 TI - Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. PMID- 23813931 TI - Familial risk-colorectal cancer: ESMO Clinical Practice Guidelines. PMID- 23813932 TI - Cancer, pregnancy and fertility: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. PMID- 23813933 TI - Reflections as near-peer facilitators of an inquiry project for undergraduate anatomy: Successes and challenges from a term of trial-and-error. AB - Near-peer facilitators (senior students serving as facilitators to their more junior peers) bring a unique student-based perspective to teaching. With fewer years of teaching experience however, students who become involved in a facilitator role typically develop related skills quickly through a process of trial-and-error within the classroom. The aim of this paper is to report on the authors' own experiences and reflections as student near-peer facilitators for an inquiry-based project in an undergraduate anatomy course. Three areas of the facilitator experience are explored: (1) offering adequate guidance as facilitators of inquiry, (2) motivating students to engage in the inquiry process, and (3) fostering creativity in learning. A practical framework for providing guidance to students is discussed which offers facilitators a scaffold for asking questions and assisting students through the inquiry process. Considerations for stimulating intrinsic motivations toward inquiry learning are made, paying attention to ways in which facilitators might influence feelings of motivation towards learning. Also, the role of creativity in inquiry learning is explored by highlighting the actions facilitators can take to foster a creative learning environment. Finally, recommendations are made for the development of formalized training programs that aid near-peer facilitators in the acquisition of facilitation skills before entering into a process of trial-and-error within the classroom. PMID- 23813934 TI - Imatinib tackles lymphoma via the PDGFRbeta+ pericyte. PMID- 23813935 TI - Antiviral cell therapy: is this the future? PMID- 23813936 TI - To B1 or not to B1: that really is still the question! PMID- 23813937 TI - The role of RUNX1 isoforms in hematopoietic commitment of human pluripotent stem cells. PMID- 23813938 TI - Response: the role of RUNX1 isoforms in hematopoietic commitment of human pluripotent stem cells. PMID- 23813939 TI - Young adults with acute lymphoblastic leukemia treated with a pediatric-inspired regimen do not need a bone marrow transplant in first remission. PMID- 23813940 TI - Response: chemotherapy versus allogeneic transplantation in adult patients with acute lymphoblastic leukemia in first remission--not a time for dogma. PMID- 23813941 TI - Coordinate expression of transcripts and proteins in platelets. PMID- 23813942 TI - Response: platelet transcriptome and proteome--relation rather than correlation. PMID- 23813943 TI - Early clinical experience with a modified amplatzer ductal occluder for transcatheter arterial duct occlusion in infants and small children. AB - OBJECTIVES: To describe early clinical experience with the amplatzer ductal occluder II additional sizes (ADO II AS) for percutaneous arterial duct occlusion in infants and small children. METHODS: Pre-, intra- and postprocedural data analysis of all patients undergoing arterial duct occlusion with the ADO II AS from three tertiary referral centers. RESULTS: 17 patients (10 female) with a median age of 6 months (range 1.0-48.1 months) and a median weight of 5.7 kg (range 1.7-17.4 kg) underwent attempted transcatheter ductal closure with the ADO II AS. Retrograde arterial approach was used in eight patients with transvenous femoral approach used in nine. The mean minimal ductal diameter was 2.2 +/- 0.7 mm with mean ductal length of 6.8 +/- 1.7 mm. Device sizes used were 5/6 (n = 5), 3/4 (n = 4), 4/4 (n = 3), 4/6 (n = 3), and 5/4 (n = 2) with four French delivery sheaths used in all cases. The median fluoroscopy time was 5.7 +/- 1.8 min. Two patients underwent delivery under exclusive echocardiography guidance. Complete ductal occlusion was achieved by the end of the procedure in 13 patients. Device embolization to the left pulmonary artery occurred in one patient with successful surgical removal and ligation of the arterial duct. Three patients required device resizing following deployment of the initial device. Complete ductal occlusion without aortic arch or left pulmonary artery stenosis has been identified in all 16 remaining patients on transthoracic echocardiographic follow up at median of 4.2 months. CONCLUSIONS: The new amplatzer ductal occluder II AS achieves excellent ductal closure rates through low profile delivery systems in small infants and children with variable ductal anatomy. (c) 2012 Wiley Periodicals, Inc. (c) 147. PMID- 23813944 TI - Light-induced generation of singlet oxygen by naked gold nanoparticles and its implications to cancer cell phototherapy. AB - Generation of singlet oxygen by direct irradiation of naked gold nanoparticles is observed using either continuous wave or pulsed laser sources. The underlying mechanism involves plasmon- and hot-electron-mediated reaction pathways and (1) O2 seems to significantly amplify the overall death rates during photothermal treatment of cancer cell lines in vitro. PMID- 23813945 TI - Nonconvulsive seizures after subarachnoid hemorrhage: Multimodal detection and outcomes. AB - OBJECTIVE: Seizures have been implicated as a cause of secondary brain injury, but the systemic and cerebral physiologic effects of seizures after acute brain injury are poorly understood. METHODS: We analyzed intracortical electroencephalographic (EEG) and multimodality physiological recordings in 48 comatose subarachnoid hemorrhage patients to better characterize the physiological response to seizures after acute brain injury. RESULTS: Intracortical seizures were seen in 38% of patients, and 8% had surface seizures. Intracortical seizures were accompanied by elevated heart rate (p = 0.001), blood pressure (p < 0.001), and respiratory rate (p < 0.001). There were trends for rising cerebral perfusion pressure (p = 0.03) and intracranial pressure (p = 0.06) seen after seizure onset. Intracortical seizure-associated increases in global brain metabolism, partial brain tissue oxygenation, and regional cerebral blood flow (rCBF) did not reach significance, but a trend for a pronounced delayed rCBF rise was seen for surface seizures (p = 0.08). Functional outcome was very poor for patients with severe background attenuation without seizures and best for those without severe attenuation or seizures (77% vs 0% dead or severely disabled, respectively). Outcome was intermediate for those with seizures independent of the background EEG and worse for those with intracortical only seizures when compared to those with intracortical and scalp seizures (50% and 25% death or severe disability, respectively). INTERPRETATION: We replicated in humans complex physiologic processes associated with seizures after acute brain injury previously described in laboratory experiments and illustrated differences such as the delayed increase in rCBF. These real world physiologic observations may permit more successful translation of laboratory research to the bedside. PMID- 23813946 TI - Cytotoxic effects of the quinolone levofloxacin on rabbit meniscus cells. AB - Quinolones have been reported to induce adverse effects on articular cartilage, tendons and ligaments. However, the effects of quinolones on menisci have not been revealed. The present study was to test the effects of levofloxacin on meniscus cells in vitro. Rabbit meniscus cells were administrated with different concentrations of levofloxacin (0, 14, 28, 56, 112 and 224 um) for 24 or 48 h, and cell viability and apoptosis were measured. The mRNA expression levels of matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, tissue inhibitors of metalloproteinase (TIMP)-1, TIMP-3, Col1a1, Bcl-2, caspase-3 and inducible nitric oxide were analyzed by real-time polymerase chain reaction. Active caspase-3 was detected by immunocytochemical assay, while protein expression levels of MMP-3 and MMP-13 were measured by Western blotting assay. After treatment with levofloxacin for 48 h, cell viability was decreased from dose of 28 to 224 um in a concentration-dependent manner. An increase of apoptotic cells was observed by flow cytometry. Active caspase-3 protein expression level was also increased. The mRNA level of Bcl-2 was decreased and levels of MMP-1, MMP-3 and MMP-13 in experimental groups were higher than those of controls. The protein levels of MMP 3 and MMP-13 were increased. Moreover, the mRNA levels of TIMP-3 and col1a1 were decreased. A dose-dependent increase of inducible nitric oxide mRNA expression level was also observed. Our results suggested the cytotoxic effects of levofloxacin on meniscus cells through induction of apoptosis and unbalanced MMPs/TIMPs expression. These side effects might result in meniscus extracellular matrix degradation and meniscal lesion. Thus, quinolones should be used cautiously on patients who perform athletic activities or undergo surgical meniscus repair. PMID- 23813947 TI - The use of a checklist in a pediatric oncology clinic. AB - BACKGROUND: Errors and near misses are common in medicine. Checklists and similar interventions are feasible and can reduce the incidence of errors and improve patient outcomes. This study assessed the feasibility and efficacy of a checklist in a pediatric oncology clinic. PROCEDURE: Errors and near misses of all types were systematically tracked for 1 month in a pediatric oncology clinic. Following the initial 1 month time period (baseline), a 10-item checklist was implemented for each patient encounter during a 4-month period. During month 5 of the study while the checklist was being used, errors and near misses were again systematically tracked for 1 month. RESULTS: The use of a checklist was associated with a significant reduction of errors in our clinic. The total number of errors (including documentation errors) decreased from 133 in month 1 to 39 in month 5 (P < 0.0001). In addition, checklist use decreased the rate of encounters with at least one error from 34% to 15% (P < 0.001). The reduction in errors occurred despite the checklist not being used for each encounter. The majority of practitioners were satisfied with the use of a checklist and think that the use of a checklist is a good way to reduce errors. CONCLUSIONS: A checklist is potentially a feasible, safe, inexpensive, and simple method to lower the rate of medical errors in a pediatric oncology clinic. PMID- 23813948 TI - Effects of low-dose mirtazapine on driving performance in healthy volunteers. AB - OBJECTIVE: This study aimed to assess whether a lower initial dose of mirtazapine can lessen the harmful effect on driving performance or not in a double-blinded, placebo-controlled crossover trial. METHODS: Thirteen healthy men received 8 days of continuous nocturnal doses of mirtazapine at 7.5 mg or 15 mg, or placebo. At baseline and on days 2 and 9, subjects performed three driving tasks (road tracking, car-following, and harsh-braking tasks) using a driving simulator and a Continuous Performance Test. Stanford Sleepiness Scale (SSS) scores were also assessed. In the mirtazapine 7.5 mg series, 15 mg of mirtazapine was additionally administered on day 9, followed by all the same assessments on day 10. RESULTS: Mirtazapine 7.5 mg had no significant effects on any tasks except for SSS compared with placebo. Mirtazapine 15 mg impaired road-tracking task and SSS. The increase in mirtazapine dose also had no significant effects on any tasks compared with those before dose increase. CONCLUSIONS: Mirtazapine 7.5 mg did not cause driving impairment compared with mirtazapine 15 mg, while both doses of mirtazapine produced subjective somnolence. The increase in mirtazapine had no detrimental effects on psychomotor performance. Initial low-dose mirtazapine may be safer for automobile driving than the normal starting dose. PMID- 23813949 TI - Craniosynostosis and radial ray defect: a rare presentation of 22q11.2 deletion syndrome. AB - A newborn with bilateral coronal craniosynostosis, hypoplastic thumbs, imperforate anus, and prenatal growth restriction was evaluated and given the clinical diagnosis of Baller-Gerold syndrome (BGS). While confirmatory testing of RECQL4 was pending, the infant developed unexplained hypocalcemia, prompting testing for a 22q11.2 deletion. Subsequently, the infant was found to have a 22q11.2 deletion, and was negative for an RECQL4 mutation. We therefore conclude that 22q11.2 deletion syndrome can present with findings resembling the BGS phenotype. PMID- 23813950 TI - Effects of environmental enrichment on repetitive behaviors in the BTBR T+tf/J mouse model of autism. AB - Lower order and higher order repetitive behaviors have been documented in the BTBR T+tf/J (BTBR) mouse strain, a mouse model that exhibits all three core behavioral domains that define autism. The purpose of this study was to evaluate the effectiveness of environmental enrichment for reducing repetitive behaviors in BTBR mice. Lower order behaviors were captured by assaying the time and sequence of grooming, while higher order behaviors were measured using pattern analysis of an object exploration task from digital recordings. Baseline scores were established at 7 weeks of age, followed by 30 days of housing in either a standard or enriched cage. As expected, BTBR mice spent significantly more time grooming and had a more rigid grooming sequence than control C57BL/6J mice did at baseline. After 30 days of enrichment housing, BTBR mice demonstrated a significant reduction in time spent grooming, resulting in levels that were lower than those exhibited by BTBR mice in standard housing. However, no changes were noted in the rigidity of their grooming sequence. In contrast to previous findings, there was no difference in repetitive patterns of exploration at baseline between BTBR and C57BL/6J mice in the object exploration test. Subsequently, enrichment did not significantly alter the number of repetitive patterns at posttest. Overall, the results suggest that environmental enrichment may be beneficial for reducing the time spent engaging in lower order repetitive behaviors, but may not change the overall quality of the behaviors when they do manifest. PMID- 23813951 TI - Usefulness of the chaotropic effect in sample preparation for chromatographic analysis of acidic xenobiotics in human plasma. AB - In this study a new RP-HPLC with photo-diode array detection method for the determination of ibuprofen ((RS)-2-(4-isobutylphenyl)propionic acid) in human plasma samples was developed. Samples were prepared by SPE and analyzed by an isocratic elution mode over a C18 column using 80% methanol. A novel sample pretreatment method, based on the addition of ionic liquids possessing chaotropic ions to small human plasma sample (100 MUL), was elaborated. 1-Butyl-3 methylimidazolium chloride and 1-butyl-3-methylimidazolium tetrafluoroborate (BMIM BF4 ) were tested from the point of view of extraction yield. Quantification was based on calibration curve applying diclofenac as the internal standard. Owing to dilution of plasma sample by 2 mM aqueous solution of BMIM BF4 before SPE, appropriate sample purification and extraction yields higher than 95% with precision lower than 2% can be achieved. Linear coefficients of correlation (r(2)) were >0.99 in the range of 0.3-5 MUg/mL ibuprofen concentration in plasma. The limit of quantification was 65 ng/mL and the detection limit for ibuprofen was 19.5 ng/mL. PMID- 23813954 TI - Three-dimensional reconstruction and analysis of the tubular system of vertebrate skeletal muscle. AB - Skeletal muscle fibres are very large and elongated. In response to excitation there must be a rapid and uniform release of Ca(2+) throughout for contraction. To ensure a uniform spread of excitation throughout the fibre to all the Ca(2+) release sites, the muscle internalizes the plasma membrane, to form the tubular (t-) system. Hence the t-system forms a complex and dense network throughout the fibre that is responsible for excitation-contraction coupling and other signalling mechanisms. However, we currently do not have a very detailed view of this membrane network because of limitations in previously used imaging techniques to visualize it. In this study we serially imaged fluorescent dye trapped in the t-system of fibres from rat and toad muscle using the confocal microscope, and deconvolved and reconstructed these images to produce the first three-dimensional reconstructions of large volumes of the vertebrate t-system. These images showed complex arrangements of tubules that have not been described previously and also allowed the association of the t-system with cellular organelles to be visualized. There was a high density of tubules close to the nuclear envelope because of the close and parallel alignment of the long axes of the myofibrils and the nuclei. Furthermore local fluorescence intensity variations from sub-resolution tubules were converted to tubule diameters. Mean diameters of tubules were 85.9+/-6.6 and 91.2+/-8.2 nm, from rat and toad muscle under isotonic conditions, respectively. Under osmotic stress the distribution of tubular diameters shifted significantly in toad muscle only, with change specifically occurring in the transverse but not longitudinal tubules. PMID- 23813953 TI - ZO-1 recruitment to alpha-catenin--a novel mechanism for coupling the assembly of tight junctions to adherens junctions. AB - The formation of a barrier between epithelial cells is a fundamental determinant of cellular homeostasis, protecting underlying cells against pathogens, dehydration and damage. Assembly of the tight junction barrier is dependent upon neighboring epithelial cells binding to one another and forming adherens junctions, but the mechanism for how these processes are linked is poorly understood. Using a knockdown and substitution system, we studied whether ZO-1 binding to alpha-catenin is required for coupling tight junction assembly to the formation of adherens junctions. We found that preventing ZO-1 binding to alpha catenin did not appear to affect adherens junctions. Rather the assembly and maintenance of the epithelial barrier were disrupted. This disruption was accompanied by alterations in the mobility of ZO-1 and the organization of the actin cytoskeleton. Thus, our study identifies alpha-catenin binding to ZO-1 as a new mechanism for coupling the assembly of the epithelial barrier to cell-to-cell adhesion. PMID- 23813952 TI - Rab5 activation promotes focal adhesion disassembly, migration and invasiveness in tumor cells. AB - Migration and invasion are essential steps associated with tumor cell metastasis and increasing evidence points towards endosome trafficking being essential in this process. Indeed, the small GTPase Rab5, a crucial regulator of early endosome dynamics, promotes cell migration in vitro and in vivo. Precisely how Rab5 participates in these events remains to be determined. Considering that focal adhesions represent structures crucial to cell migration, we specifically asked whether Rab5 activation promoted focal adhesion disassembly and thereby facilitated migration and invasion of metastatic cancer cells. Pulldown and biosensor assays revealed that Rab5-GTP loading increased at the leading edge of migrating tumor cells. Additionally, targeting of Rab5 by different shRNA sequences, but not control shRNA, decreased Rab5-GTP levels, leading to reduced cell spreading, migration and invasiveness. Re-expression in knockdown cells of wild-type Rab5, but not the S34N mutant (GDP-bound), restored these properties. Importantly, Rab5 association with the focal adhesion proteins vinculin and paxillin increased during migration, and expression of wild-type, but not GDP bound Rab5, accelerated focal adhesion disassembly, as well as FAK dephosphorylation on tyrosine 397. Finally, Rab5-driven invasiveness required focal adhesion disassembly, as treatment with the FAK inhibitor number 14 prevented Matrigel invasion and matrix metalloproteinase release. Taken together, these observations show that Rab5 activation is required to enhance cancer cell migration and invasion by promoting focal adhesion disassembly. PMID- 23813955 TI - Endoplasmic reticulum stress impairs IL-4/IL-13 signaling through C/EBPbeta mediated transcriptional suppression. AB - Activation of the unfolded protein response (UPR) by endoplasmic reticulum (ER) stress culminates in extensive gene regulation, with transcriptional upregulation of genes that improve the protein folding capacity of the organelle. However, a substantial number of genes are downregulated by ER stress, and the mechanisms that lead to this downregulation and its consequences on cellular function are poorly understood. We found that ER stress led to coordinated transcriptional suppression of diverse cellular processes, including those involved in cytokine signaling. Using expression of the IL-4/IL-13 receptor subunit Il4ra as a sentinel, we sought to understand the mechanism behind this suppression and its impact on inflammatory signaling. We found that reinitiation of global protein synthesis by GADD34-mediated dephosphorylation of eIF2alpha resulted in preferential expression of the inhibitory LIP isoform of the transcription factor C/EBPbeta. This regulation was in turn required for the suppression of Il4ra and related inflammatory genes. Suppression of Il4ra was lost in Cebpb(-/-) cells but could be induced by LIP overexpression. As a consequence of Il4ra suppression, ER stress impaired IL-4/IL-13 signaling. Strikingly, Cebpb(-/-) cells lacking Il4ra downregulation were protected from this signaling impairment. This work identifies a novel role for C/EBPbeta in regulating transcriptional suppression and inflammatory signaling during ER stress. PMID- 23813956 TI - Scribble regulates an EMT polarity pathway through modulation of MAPK-ERK signaling to mediate junction formation. AB - The crucial role the Crumbs and Par polarity complexes play in tight junction integrity has long been established, however very few studies have investigated the role of the Scribble polarity module. Here, we use MCF10A cells, which fail to form tight junctions and express very little endogenous Crumbs3, to show that inducing expression of the polarity protein Scribble is sufficient to promote tight junction formation. We show this occurs through an epithelial-to mesenchymal (EMT) pathway that involves Scribble suppressing ERK phosphorylation, leading to downregulation of the EMT inducer ZEB. Inhibition of ZEB relieves the repression on Crumbs3, resulting in increased expression of this crucial tight junction regulator. The combined effect of this Scribble-mediated pathway is the upregulation of a number of junctional proteins and the formation of functional tight junctions. These data suggests a novel role for Scribble in positively regulating tight junction assembly through transcriptional regulation of an EMT signaling program. PMID- 23813957 TI - The fission yeast beta-arrestin-like protein Any1 is involved in TSC-Rheb signaling and the regulation of amino acid transporters. AB - Rheb GTPase and the Tsc1-Tsc2 protein complex, which serves as a GTPase activating protein for Rheb, have crucial roles in the regulation of cell growth in response to extracellular conditions. In Schizosaccharomyces pombe, Rheb and Tsc1-Tsc2 regulate cell cycle progression, the onset of meiosis and the uptake of amino acids. In cells lacking Tsc2 (Deltatsc2), the amino acid transporter Aat1, which is normally expressed on the plasma membrane under starvation conditions, is confined to the Golgi. Here, we show that the loss of either pub1(+), encoding an E3 ubiquitin ligase, or any1(+), encoding a beta-arrestin-like protein, allows constitutive expression of Aat1 on the plasma membrane in Deltatsc2 cells, suggesting that Pub1 and Any1 are required for localization of Aat1 to the Golgi. Subsequent analysis revealed that, in the Golgi, Pub1 and Any1 form a complex that ubiquitylates Aat1. Physical interaction of Pub1 and Any1 is more stable in Deltatsc2 cells than in wild-type cells and is independent of Tor2 activity. These results indicate that the TSC-Rheb signaling pathway regulates the localization of amino acid transporters via Pub1 and Any1 in a Tor2-independent manner. Our study demonstrates that, unlike in budding yeast (in which Rsp5 and ARTs, a pair of proteins analogous to Pub1 and Any1, respectively, primarily act to reduce expression of the transporters on plasma membrane when nutrients are abundant), the primary role of fission yeast Pub1 and Any1 is to store the transporter in the Golgi under nutrient-rich conditions. PMID- 23813958 TI - The telomere-associated homeobox-containing protein TAH1/HMBOX1 participates in telomere maintenance in ALT cells. AB - The majority of cancer cells rely on elevated telomerase expression and activity for rapid growth and proliferation. Telomerase-negative cancer cells, by contrast, often employ the alternative lengthening of telomeres (ALT) pathway to maintain telomeres. ALT cells are characterized by long and dynamic telomeres and the presence of ALT-associated promyelocytic leukemia (PML) bodies (APBs). Previous work has shown the importance of APBs to the ALT pathway, but their formation and precise role remain unclear. Here, we demonstrate that a homeobox containing protein known as HMBOX1 can directly bind telomeric double-stranded DNA and associate with PML nuclear bodies. Hence, we renamed this protein TAH1 for telomere-associated homeobox-containing protein 1. TAH1 knockdown significantly reduced the number of APBs and led to an increase in DNA damage response signals at telomeres. Importantly, TAH1 inhibition also notably reduced the presence of telomere C-circles, indicating altered ALT activity. Our findings point to TAH1 as a novel link between pathways that regulate DNA damage responses, PML nuclear bodies, and telomere homeostasis in ALT cells, and provide insight into how ALT cells may achieve sustained growth and proliferation independent of the telomerase. PMID- 23813959 TI - Matched miRNA and mRNA signatures from an hESC-based in vitro model of pancreatic differentiation reveal novel regulatory interactions. AB - The differentiation of human pluripotent stem cells (hPSCs) to insulin-expressing beta islet-like cells is a promising in vitro model system for studying the molecular signaling pathways underlying beta cell differentiation, as well as a potential source of cells for the treatment of type 1 diabetes. MicroRNAs (miRNAs) are a class of small non-coding RNAs that regulate many biological processes, including cellular differentiation. We studied the miRNA and mRNA expression profiles of hPSCs at five stages of in vitro differentiation along the pancreatic beta cell lineage (definitive endoderm, primitive gut tube, posterior foregut, pancreatic progenitor and hormone-expressing endocrine cells) in the context of samples of primary human fetal pancreas and purified adult islet cells using microarray analysis. Bioinformatic analysis of the resulting data identified a unique miRNA signature in differentiated beta islet cells, and predicted the effects of key miRNAs on mRNA expression. Many of the predicted miRNA-mRNA interactions involved mRNAs known to play key roles in the epithelial mesenchymal transition process and pancreatic differentiation. We validated a subset of the predictions using qRT-PCR, luciferase reporter assays and western blotting, including the known interaction between miR-200 and ZEB2 (involved in epithelial-mesenchymal transition) and the novel interaction between miR-200 and SOX17 (a key transcription factor in specification of definitive endoderm). In addition, we found that miR-30d and let-7e, two miRNAs induced during differentiation, regulated the expression of RFX6, a transcription factor that directs pancreatic islet formation. These findings suggest that precise control of target mRNA expression by miRNAs ensures proper lineage specification during pancreatic development. PMID- 23813960 TI - Alternative fates of newly formed PrPSc upon prion conversion on the plasma membrane. AB - Prion diseases are fatal neurodegenerative diseases characterised by the accumulation of misfolded prion protein (PrP(Sc)) in the brain. They are caused by the templated misfolding of normal cellular protein, PrP(C), by PrP(Sc). We have recently generated a unique cell system in which epitope-tagged PrP(C) competent to produce bona fide PrP(Sc) is expressed in neuroblastoma cells. Using this system we demonstrated that PrP(Sc) forms on the cell surface within minutes of prion exposure. Here, we describe the intracellular trafficking of newly formed PrP(Sc). After formation in GM1-enriched lipid microdomains at the plasma membrane, PrP(Sc) is rapidly internalised to early endosomes containing transferrin and cholera toxin B subunit. Following endocytosis, PrP(Sc) intracellular trafficking diverges: some is recycled to the plasma membrane via Rab11-labelled recycling endosomes; the remaining PrP(Sc) is subject to retromer mediated retrograde transport to the Golgi. This pathway leads to lysosomal degradation, and we show that this is the dominant PrP(Sc) degradative mechanism in the early stages of prion infection. PMID- 23813961 TI - NDRG1 functions in LDL receptor trafficking by regulating endosomal recycling and degradation. AB - N-myc downstream-regulated gene 1 (NDRG1) mutations cause Charcot-Marie-Tooth disease type 4D (CMT4D). However, the cellular function of NDRG1 and how it causes CMT4D are poorly understood. We report that NDRG1 silencing in epithelial cells results in decreased uptake of low-density lipoprotein (LDL) due to reduced LDL receptor (LDLR) abundance at the plasma membrane. This is accompanied by the accumulation of LDLR in enlarged EEA1-positive endosomes that contain numerous intraluminal vesicles and sequester ceramide. Concomitantly, LDLR ubiquitylation is increased but its degradation is reduced and ESCRT (endosomal sorting complex required for transport) proteins are downregulated. Co-depletion of IDOL (inducible degrader of the LDLR), which ubiquitylates the LDLR and promotes its degradation, rescues plasma membrane LDLR levels and LDL uptake. In murine oligodendrocytes, Ndrg1 silencing not only results in reduced LDL uptake but also in downregulation of the oligodendrocyte differentiation factor Olig2. Both phenotypes are rescued by co-silencing of Idol, suggesting that ligand uptake through LDLR family members controls oligodendrocyte differentiation. These findings identify NDRG1 as a novel regulator of multivesicular body formation and endosomal LDLR trafficking. The deficiency of functional NDRG1 in CMT4D might impair lipid processing and differentiation of myelinating cells. PMID- 23813963 TI - The microtubule end-binding protein EB2 is a central regulator of microtubule reorganisation in apico-basal epithelial differentiation. AB - Microtubule end-binding (EB) proteins influence microtubule dynamic instability, a process that is essential for microtubule reorganisation during apico-basal epithelial differentiation. Here, we establish for the first time that expression of EB2, but not that of EB1, is crucial for initial microtubule reorganisation during apico-basal epithelial differentiation, and that EB2 downregulation promotes bundle formation. EB2 siRNA knockdown during early stages of apico-basal differentiation prevented microtubule reorganisation, whereas its downregulation at later stages promoted microtubule stability and bundle formation. Interestingly, although EB1 is not essential for microtubule reorganisation, its knockdown prevented apico-basal bundle formation and epithelial elongation. siRNA depletion of EB2 in undifferentiated epithelial cells induced the formation of straight, less dynamic microtubules with EB1 and ACF7 lattice association and co alignment with actin filaments, a phenotype that could be rescued by inhibition with formin. Importantly, in situ inner ear and intestinal crypt epithelial tissue revealed direct correlations between a low level of EB2 expression and the presence of apico-basal microtubule bundles, which were absent where EB2 was elevated. EB2 is evidently important for initial microtubule reorganisation during epithelial polarisation, whereas its downregulation facilitates EB1 and ACF7 microtubule lattice association, microtubule-actin filament co-alignment and bundle formation. The spatiotemporal expression of EB2 thus dramatically influences microtubule organisation, EB1 and ACF7 deployment and epithelial differentiation. PMID- 23813962 TI - Protective effects of matrix metalloproteinase-12 following corneal injury. AB - Corneal scarring due to injury is a leading cause of blindness worldwide and results from dysregulated inflammation and angiogenesis during wound healing. Here we demonstrate that the extracellular matrix metalloproteinase MMP12 (macrophage metalloelastase) is an important regulator of these repair processes. Chemical injury resulted in higher expression of the fibrotic markers alpha smooth muscle actin and type I collagen, and increased levels of angiogenesis in corneas of Mmp12(-/-) mice compared with corneas of wild-type mice. In vivo, we observed altered immune cell dynamics in Mmp12(-/-) corneas by confocal imaging. We determined that the altered dynamics were the result of an altered inflammatory response, with delayed neutrophil infiltration during the first day and excessive macrophage infiltration 6 days later, mediated by altered expression levels of chemokines CXCL1 and CCL2, respectively. Corneal repair returned to normal upon inhibition of these chemokines. Taken together, these data show that MMP12 has a protective effect on corneal fibrosis during wound repair through regulation of immune cell infiltration and angiogenesis. PMID- 23813964 TI - Innexins Ogre and Inx2 are required in glial cells for normal postembryonic development of the Drosophila central nervous system. AB - Innexins are one of two gene families that have evolved to permit neighbouring cells in multicellular systems to communicate directly. Innexins are found in prechordates and persist in small numbers in chordates as divergent sequences termed pannexins. Connexins are functionally analogous proteins exclusive to chordates. Members of these two families of proteins form intercellular channels, assemblies of which constitute gap junctions. Each intercellular channel is a composite of two hemichannels, one from each of two apposed cells. Hemichannels dock in the extracellular space to form a complete channel with a central aqueous pore that regulates the cell-cell exchange of ions and small signalling molecules. Hemichannels can also act independently by releasing paracrine signalling molecules. optic ganglion reduced (ogre) is a member of the Drosophila innexin family, originally identified as a gene essential for postembryonic neurogenesis. Here we demonstrate, by heterologous expression in paired Xenopus oocytes, that Ogre alone does not form homotypic gap-junction channels; however, co-expression of Ogre with Innexin2 (Inx2) induces formation of functional channels with properties distinct from Inx2 homotypic channels. In the Drosophila larval central nervous system, we find that Inx2 partially colocalises with Ogre in proliferative neuroepithelia and in glial cells. Downregulation of either ogre or inx2 selectively in glia, by targeted expression of RNA interference transgenes, leads to a significant reduction in the size of the larval nervous system and behavioural defects in surviving adults. We conclude that these innexins are crucially required in glial cells for normal postembryonic development of the central nervous system. PMID- 23813965 TI - A multiscale road map of cancer spheroids--incorporating experimental and mathematical modelling to understand cancer progression. AB - Computational models represent a highly suitable framework, not only for testing biological hypotheses and generating new ones but also for optimising experimental strategies. As one surveys the literature devoted to cancer modelling, it is obvious that immense progress has been made in applying simulation techniques to the study of cancer biology, although the full impact has yet to be realised. For example, there are excellent models to describe cancer incidence rates or factors for early disease detection, but these predictions are unable to explain the functional and molecular changes that are associated with tumour progression. In addition, it is crucial that interactions between mechanical effects, and intracellular and intercellular signalling are incorporated in order to understand cancer growth, its interaction with the extracellular microenvironment and invasion of secondary sites. There is a compelling need to tailor new, physiologically relevant in silico models that are specialised for particular types of cancer, such as ovarian cancer owing to its unique route of metastasis, which are capable of investigating anti-cancer therapies, and generating both qualitative and quantitative predictions. This Commentary will focus on how computational simulation approaches can advance our understanding of ovarian cancer progression and treatment, in particular, with the help of multicellular cancer spheroids, and thus, can inform biological hypothesis and experimental design. PMID- 23813966 TI - Sorting receptor SORLA--a trafficking path to avoid Alzheimer disease. AB - Excessive proteolytic breakdown of the amyloid precursor protein (APP) to neurotoxic amyloid beta peptides (Abeta) by secretases in the brain is a molecular cause of Alzheimer disease (AD). According to current concepts, the complex route whereby APP moves between the secretory compartment, the cell surface and endosomes to encounter the various secretases determines its processing fate. However, the molecular mechanisms that control the intracellular trafficking of APP in neurons and their contribution to AD remain poorly understood. Here, we describe the functional elucidation of a new sorting receptor SORLA that emerges as a central regulator of trafficking and processing of APP. SORLA interacts with distinct sets of cytosolic adaptors for anterograde and retrograde movement of APP between the trans-Golgi network and early endosomes, thereby restricting delivery of the precursor to endocytic compartments that favor amyloidogenic breakdown. Defects in SORLA and its interacting adaptors result in transport defects and enhanced amyloidogenic processing of APP, and represent important risk factors for AD in patients. As discussed here, these findings uncovered a unique regulatory pathway for the control of neuronal protein transport, and provide clues as to why defects in this pathway cause neurodegenerative disease. PMID- 23813967 TI - Intranasal formulation of erythropoietin (EPO) showed potent protective activity against amyloid toxicity in the Abeta25-35 non-transgenic mouse model of Alzheimer's disease. AB - Erythropoietin (EPO) promotes neurogenesis and neuroprotection. We here compared the protection induced by two EPO formulations in a rodent model of Alzheimer's disease (AD): rHu-EPO and a low sialic form, Neuro-EPO. We used the intracerebroventricular administration of aggregated Abeta25-35 peptide, a non transgenic AD model. rHu-EPO was tested at 125-500 ug/kg intraperitoneally and Neuro-EPO at 62-250 ug/kg intranasally (IN). Behavioural procedures included spontaneous alternation, passive avoidance, water-maze and object recognition, to address spatial and non-spatial, short- and long-term memories. Biochemical markers of Abeta25-35 toxicity in the mouse hippocampus were examined and cell loss in the CA1 layer was determined. rHu-EPO and Neuro-EPO led to a significant prevention of Abeta25-35-induced learning deficits. Both EPO formulations prevented the induction of lipid peroxidation in the hippocampus, showing an antioxidant activity. rHu-EPO (250 ug/kg) or Neuro-EPO (125 ug/kg) prevented the Abeta25-35-induced increase in Bax level, TNFalpha and IL-1beta production and decrease in Akt activation. A significant prevention of the Abeta25-35-induced cell loss in CA1 was also observed. EPO is neuroprotective in the Abeta25-35 AD model, confirming its potential as an endogenous neuroprotection system that could be boosted for therapeutic efficacy. We here identified a new IN formulation of EPO showing high neuroprotective activity. Considering its efficacy, ease and safety, IN Neuro-EPO is a new promising therapeutic agent in AD. PMID- 23813968 TI - Plasma levels of interleukin-6 and selective serotonin reuptake inhibitor response in patients with major depressive disorder. AB - OBJECTIVE: We investigated the plasma levels of interleukin (IL)-6 and 5-HTT polymorphisms in patients with major depressive disorder (MDD). This is the first report, to our knowledge, of an investigation into the association between 5-HTT gene polymorphism, plasma IL-6 levels, and responses to selective serotonin reuptake inhibitors (SSRIs) in Japanese patients with MDD. METHOD: One-hundred and eighteen patients (51 male, 67 female) who met the DSM-IV criteria for MDD were enrolled. Their ages ranged from 24 to 78 (mean +/- SD = 44 +/- 12) years. The patients were treated with SSRIs (paroxetine in 66 cases, sertraline in 42 cases) for 8 weeks. RESULTS: The plasma levels of IL-6 were significantly higher in the SSRI responders than in the nonresponders (p = 0.0328), and the changes in plasma IL-6 levels correlated significantly with the changes in severity of depressive state (p = .0.007). No difference was found in baseline and the changes in plasma IL-6 levels between the patients with a 5-HTT gene (5-HTTLPR) L carrier and those with S/S. CONCLUSION: These results suggest that the plasma levels of IL-6 reflect the severity of MDD and that plasma IL-6 levels might be another biological-state marker for the depressive state. In addition, the 5 HTTLPR polymorphism might be independent of plasma IL-6 levels. PMID- 23813969 TI - Asparagine levels in the bone marrow of patients with acute lymphoblastic leukemia during asparaginase therapy. PMID- 23813970 TI - Medulloblastoma in a patient with the PTPN11 p.Thr468Met mutation. AB - Medulloblastoma is the commonest brain tumor in childhood and in a minority of patients is associated with an underlying genetic disorder such as Gorlin syndrome or familial adenomatous polyposis. Increased susceptibility to certain tumors, including neuroblastoma and some hematological malignancies, is recognized in disorders caused by mutations in genes encoding components of the RAS signaling pathway which include Noonan syndrome, Noonan syndrome with multiple lentigines (NSML; formerly called LEOPARD syndrome), Costello syndrome, Cardiofaciocutaneous syndrome, Legius syndrome, and Neurofibromatosis type 1 (NF1), collectively termed RASopathies. Although an association between medulloblastoma and NF1 has been reported, this tumor has not previously been reported in other RASopathies. We present a patient with NSML caused by the recurrent PTPN11 mutation c.1403C > T (p.Thr468Met) in whom medulloblastoma was diagnosed at age 10 years. Medulloblastoma could therefore be part of the tumor spectrum associated with this disorder. PMID- 23813971 TI - A comparative study of matrix metalloproteinase and aggrecanase mediated release of latent cytokines at arthritic joints. AB - BACKGROUND: Latent cytokines are engineered by fusing the latency associated peptide (LAP) derived from transforming growth factor-beta (TGF-beta) with the therapeutic cytokine, in this case interferon-beta (IFN-beta), via an inflammation-specific matrix metalloproteinase (MMP) cleavage site. OBJECTIVES: To demonstrate latency and specific delivery in vivo and to compare therapeutic efficacy of aggrecanase-mediated release of latent IFN-beta in arthritic joints to the original MMP-specific release. METHODS: Recombinant fusion proteins with MMP, aggrecanase or devoid of cleavage site were expressed in CHO cells, purified and characterised in vitro by Western blotting and anti-viral protection assays. Therapeutic efficacy and half-life were assessed in vivo using the mouse collagen induced arthritis model (CIA) of rheumatoid arthritis and a model of acute paw inflammation, respectively. Transgenic mice with an IFN-regulated luciferase gene were used to assess latency in vivo and targeted delivery to sites of disease. RESULTS: Efficient localised delivery of IFN-beta to inflamed paws, with low levels of systemic delivery, was demonstrated in transgenic mice using latent IFN beta. Engineering of latent IFN-beta with an aggrecanase-sensitive cleavage site resulted in efficient cleavage by ADAMTS-4, ADAMTS-5 and synovial fluid from arthritic patients, with an extended half-life similar to the MMP-specific molecule and greater therapeutic efficacy in the CIA model. CONCLUSIONS: Latent cytokines require cleavage in vivo for therapeutic efficacy, and they are delivered in a dose dependent fashion only to arthritic joints. The aggrecanase specific cleavage site is a viable alternative to the MMP cleavage site for the targeting of latent cytokines to arthritic joints. PMID- 23813973 TI - Inhibition of excessive mitochondrial fission reduced aberrant autophagy and neuronal damage caused by LRRK2 G2019S mutation. AB - LRRK2 G2019S mutation is the most common genetic cause of Parkinson's disease (PD). Cellular pathology caused by this mutant is associated with mitochondrial dysfunction and augmented autophagy. However, the underlying mechanism is not known. In this study, we determined whether blocking excessive mitochondrial fission could reduce cellular damage and neurodegeneration induced by the G2019S mutation. In both LRRK2 G2019S-expressing cells and PD patient fibroblasts carrying this specific mutant, treatment with P110, a selective peptide inhibitor of fission dynamin-related protein 1 (Drp1) recently developed in our lab, reduced mitochondrial fragmentation and damage, and corrected excessive autophagy. LRRK2 G2019S directly bound to and phosphorylated Drp1 at Threonine595, whereas P110 treatment abolished this phosphorylation. A site directed mutant, Drp1(T595A), corrected mitochondrial fragmentation, improved mitochondrial mass and suppressed excessive autophagy in both cells expressing LRRK2 G2019S and PD patient fibroblasts carrying the mutant. Further, in dopaminergic neurons derived from LRRK2 G2019S PD patient-induced pluripotent stem cells, we demonstrated that either P110 treatment or expression of Drp1(T595A) reduced mitochondrial impairment, lysosomal hyperactivity and neurite shortening. Together, we propose that inhibition of Drp1-mediated excessive mitochondrial fission might be a strategy for treatment of PD relevant to LRRK2 G2019S mutation. PMID- 23813972 TI - Transmembrane water-flux through SLC4A11: a route defective in genetic corneal diseases. AB - Three genetic corneal dystrophies [congenital hereditary endothelial dystrophy type 2 (CHED2), Harboyan syndrome and Fuchs endothelial corneal dystrophy] arise from mutations of the SLC4a11 gene, which cause blindness from fluid accumulation in the corneal stroma. Selective transmembrane water conductance controls cell size, renal fluid reabsorption and cell division. All known water-channelling proteins belong to the major intrinsic protein family, exemplified by aquaporins (AQPs). Here we identified SLC4A11, a member of the solute carrier family 4 of bicarbonate transporters, as an unexpected addition to known transmembrane water movement facilitators. The rate of osmotic-gradient driven cell-swelling was monitored in Xenopus laevis oocytes and HEK293 cells, expressing human AQP1, NIP5;1 (a water channel protein from plant), hCNT3 (a human nucleoside transporter) and human SLC4A11. hCNT3-expressing cells swelled no faster than control cells, whereas SLC4A11-mediated water permeation at a rate about half that of some AQP proteins. SLC4A11-mediated water movement was: (i) similar to some AQPs in rate; (ii) uncoupled from solute-flux; (iii) inhibited by stilbene disulfonates (classical SLC4 inhibitors); (iv) inactivated in one CHED2 mutant (R125H). Localization of AQP1 and SLC4A11 in human and murine corneal (apical and basolateral, respectively) suggests a cooperative role in mediating trans endothelial water reabsorption. Slc4a11(-/-) mice manifest corneal oedema and distorted endothelial cells, consistent with loss of a water-flux. Observed water flux through SLC4A11 extends the repertoire of known water movement pathways and call for a re-examination of explanations for water movement in human tissues. PMID- 23813974 TI - The large non-coding RNA ANRIL, which is associated with atherosclerosis, periodontitis and several forms of cancer, regulates ADIPOR1, VAMP3 and C11ORF10. AB - The long non-coding RNA ANRIL is the best replicated genetic risk locus of coronary artery disease (CAD) and periodontitis (PD), and is independently associated with a variety of other immune-mediated and metabolic disorders and several forms of cancer. Recent studies showed a correlation of decreased concentrations of proximal ANRIL transcripts with homozygous carriership of the CAD and PD main risk alleles. To elucidate the relation of these transcripts to disease manifestation, we constructed a short hairpin RNA in a stable inducible knock-down system of T-Rex 293 HEK cell lines, specifically targeting the proximal transcripts EU741058 and DQ485454. By genome-wide expression profiling using Affymetrix HG1.0 ST Arrays, we identified the transcription of ADIPOR1, VAMP3 and C11ORF10 to be correlated with decreased ANRIL expression in a time dependent manner. We validated these findings on a transcriptional and translational level in different cell types. Exploration of the identified genes for the presence of disease associated variants, using Affymetrix 500K genotyping and Illumina custom genotyping arrays, highlighted a region upstream of VAMP3 within CAMTA1 to be associated with increased risk of CAD [rs10864294 P = 0.015, odds ratio (OR) = 1.30, 95% confidence interval (CI) = 1.1-1.6, 1471 cases, 2737 controls] and aggressive PD (AgP; P = 0.008, OR = 1.31, 95% CI = 1.1-1.6, 864 cases, 3664 controls). In silico replication in a meta-analysis of 14 genome-wide association studies of CAD of the CARDIoGRAM Consortium identified rs2301462, located on the same haplotype block, as associated with P = 0.001 upon adjustment for sex and age. Our results give evidence that specific isoforms of ANRIL regulate key genes of glucose and fatty acid metabolism. PMID- 23813975 TI - Muscle-specific function of the centronuclear myopathy and Charcot-Marie-Tooth neuropathy-associated dynamin 2 is required for proper lipid metabolism, mitochondria, muscle fibers, neuromuscular junctions and peripheral nerves. AB - The ubiquitously expressed large GTPase Dynamin 2 (DNM2) plays a critical role in the regulation of intracellular membrane trafficking through its crucial function in membrane fission, particularly in endocytosis. Autosomal-dominant mutations in DNM2 cause tissue-specific human disorders. Different sets of DNM2 mutations are linked to dominant intermediate Charcot-Marie-Tooth neuropathy type B, a motor and sensory neuropathy affecting primarily peripheral nerves, or autosomal dominant centronuclear myopathy (CNM) presenting with primary damage in skeletal muscles. To understand the underlying disease mechanisms, it is imperative to determine to which degree the primary affected cell types require DNM2. Thus, we used cell type-specific gene ablation to examine the consequences of DNM2 loss in skeletal muscle cells, the major relevant cell type involved in CNM. We found that DNM2 function in skeletal muscle is required for proper mouse development. Skeletal muscle-specific loss of DNM2 causes a reduction in muscle mass and in the numbers of muscle fibers, altered muscle fiber size distributions, irregular neuromuscular junctions (NMJs) and isolated degenerating intramuscular peripheral nerve fibers. Intriguingly, a lack of muscle-expressed DNM2 triggers an increase of lipid droplets (LDs) and mitochondrial defects. We conclude that loss of DNM2 function in skeletal muscles initiates a chain of harmful parallel and serial events, involving dysregulation of LDs and mitochondrial defects within altered muscle fibers, defective NMJs and peripheral nerve degeneration. These findings provide the essential basis for further studies on DNM2 function and malfunction in skeletal muscles in health and disease, potentially including metabolic diseases such as diabetes. PMID- 23813977 TI - Organic monoliths for high-performance reversed-phase liquid chromatography. AB - RPLC is the most common mode of LC. It is widely used for separations of both small and large molecules. Monolithic columns, which are currently under intensive study by many groups, have the potential of becoming attractive alternatives to particle-packed columns. They are generally easier and faster to fabricate, and they demonstrate a lower pressure drop, less nonspecific adsorption, and richer chemistry (in the case of organic polymer monoliths) for providing broad selectivity. Silica monoliths, as is also true for columns packed with silica particles, are best applied to small-molecule separations. Organic polymer monoliths, on the other hand, have shown advantages for large-molecule separations. Recently, improvements in organic monoliths have led to efficiencies for small molecules that are approaching and even surpassing 100,000 plates/m. While this performance is still far short of what is currently available using modern small particles and silica monoliths in RPLC, steady progress is being made. This review describes recent developments in the synthesis and performance of organic polymer RPLC monoliths, and identifies areas where additional work is needed to significantly improve their performance for both small- and large molecule separations. PMID- 23813978 TI - Less is more in mammalian phylogenomics: AT-rich genes minimize tree conflicts and unravel the root of placental mammals. AB - Despite the rapid increase of size in phylogenomic data sets, a number of important nodes on animal phylogeny are still unresolved. Among these, the rooting of the placental mammal tree is still a controversial issue. One difficulty lies in the pervasive phylogenetic conflicts among genes, with each one telling its own story, which may be reliable or not. Here, we identified a simple criterion, that is, the GC content, which substantially helps in determining which gene trees best reflect the species tree. We assessed the ability of 13,111 coding sequence alignments to correctly reconstruct the placental phylogeny. We found that GC-rich genes induced a higher amount of conflict among gene trees and performed worse than AT-rich genes in retrieving well-supported, consensual nodes on the placental tree. We interpret this GC effect mainly as a consequence of genome-wide variations in recombination rate. Indeed, recombination is known to drive GC-content evolution through GC-biased gene conversion and might be problematic for phylogenetic reconstruction, for instance, in an incomplete lineage sorting context. When we focused on the AT richest fraction of the data set, the resolution level of the placental phylogeny was greatly increased, and a strong support was obtained in favor of an Afrotheria rooting, that is, Afrotheria as the sister group of all other placentals. We show that in mammals most conflicts among gene trees, which have so far hampered the resolution of the placental tree, are concentrated in the GC rich regions of the genome. We argue that the GC content-because it is a reliable indicator of the long-term recombination rate-is an informative criterion that could help in identifying the most reliable molecular markers for species tree inference. PMID- 23813976 TI - Pathogenic rare copy number variants in community-based schizophrenia suggest a potential role for clinical microarrays. AB - Individually rare, large copy number variants (CNVs) contribute to genetic vulnerability for schizophrenia. Unresolved questions remain, however, regarding the anticipated yield of clinical microarray testing in schizophrenia. Using high resolution genome-wide microarrays and rigorous methods, we investigated rare CNVs in a prospectively recruited community-based cohort of 459 unrelated adults with schizophrenia and estimated the minimum prevalence of clinically significant CNVs that would be detectable on a clinical microarray. A blinded review by two independent clinical cytogenetic laboratory directors of all large (>500 kb) rare CNVs in cases and well-matched controls showed that those deemed to be clinically significant were highly enriched in schizophrenia (16.4-fold increase, P < 0.0001). In a single community catchment area, the prevalence of individuals with these CNVs was 8.1%. Rare 1.7 Mb CNVs at 2q13 were found to be significantly associated with schizophrenia for the first time, compared with the prevalence in 23 838 population-based controls (42.9-fold increase, P = 0.0002). Additional novel findings that will facilitate the future clinical interpretation of smaller CNVs in schizophrenia include: (i) a greater proportion of individuals with two or more rare exonic CNVs >10 kb in size (1.5-fold increase, P = 0.0109) in schizophrenia; (ii) the systematic discovery of new candidate genes for schizophrenia; and, (iii) functional gene enrichment mapping highlighting a differential impact in schizophrenia of rare exonic deletions involving diverse functions, including neurodevelopmental and synaptic processes (4.7-fold increase, P = 0.0060). These findings suggest consideration of a potential role for clinical microarray testing in schizophrenia, as is now the suggested standard of care for related developmental disorders like autism. PMID- 23813979 TI - Heterogeneous models place the root of the placental mammal phylogeny. AB - Heterogeneity among life traits in mammals has resulted in considerable phylogenetic conflict, particularly concerning the position of the placental root. Layered upon this are gene- and lineage-specific variation in amino acid substitution rates and compositional biases. Life trait variations that may impact upon mutational rates are longevity, metabolic rate, body size, and germ line generation time. Over the past 12 years, three main conflicting hypotheses have emerged for the placement of the placental root. These hypotheses place the Atlantogenata (common ancestor of Xenarthra plus Afrotheria), the Afrotheria, or the Xenarthra as the sister group to all other placental mammals. Model adequacy is critical for accurate tree reconstruction and by failing to account for these compositional and character exchange heterogeneities across the tree and data set, previous studies have not provided a strongly supported hypothesis for the placental root. For the first time, models that accommodate both tree and data set heterogeneity have been applied to mammal data. Here, we show the impact of accurate model assignment and the importance of data sets in accommodating model parameters while maintaining the power to reject competing hypotheses. Through these sophisticated methods, we demonstrate the importance of model adequacy, data set power and provide strong support for the Atlantogenata over other competing hypotheses for the position of the placental root. PMID- 23813980 TI - Making the impossible possible: rooting the tree of placental mammals. AB - Untangling the root of the evolutionary tree of placental mammals has been nearly an impossible task. The good news is that only three possibilities are seriously considered. The bad news is that all three possibilities are seriously considered. Paleontologists favor a root anchored by Xenarthra (e.g., sloths and anteater), whereas molecular evolutionists have favored the two other possible roots: Afrotheria (e.g., elephants, hyraxes, and tenrecs) and Atlantogenata (Afrotheria + Xenarthra). Now, two groups of researchers have scrutinized the largest available genomic data sets bearing on the question and have come to opposite conclusions, as reported in this issue of Molecular Biology and Evolution. Needless to say, more research is needed. PMID- 23813981 TI - The shared genome is a pervasive constraint on the evolution of sex-biased gene expression. AB - Males and females share most of their genomes, and differences between the sexes can therefore not evolve through sequence divergence in protein coding genes. Sexual dimorphism is instead restricted to occur through sex-specific expression and splicing of gene products. Evolution of sexual dimorphism through these mechanisms should, however, also be constrained when the sexes share the genetic architecture for regulation of gene expression. Despite these obstacles, sexual dimorphism is prevalent in the animal kingdom and commonly evolves rapidly. Here, we ask whether the genetic architecture of gene expression is plastic and easily molded by sex-specific selection, or if sexual dimorphism evolves rapidly despite pervasive genetic constraint. To address this question, we explore the relationship between the intersexual genetic correlation for gene expression (rMF), which captures how independently genes are regulated in the sexes, and the evolution of sex-biased gene expression. Using transcriptome data from Drosophila melanogaster, we find that most genes have a high rMF and that genes currently exposed to sexually antagonistic selection have a higher average rMF than other genes. We further show that genes with a high rMF have less pronounced sex-biased gene expression than genes with a low rMF within D. melanogaster and that the strength of the rMF in D. melanogaster predicts the degree to which the sex bias of a gene's expression has changed between D. melanogaster and six other species in the Drosophila genus. In sum, our results show that a shared genome constrains both short- and long-term evolution of sexual dimorphism. PMID- 23813982 TI - Separation optimization of long porous-layer open-tubular columns for nano-LC-MS of limited proteomic samples. AB - The single-run resolving power of current 10 MUm id porous-layer open-tubular (PLOT) columns has been optimized. The columns studied had a poly(styrene-co divinylbenzene) porous layer (~0.75 MUm thickness). In contrast to many previous studies that have employed complex plumbing or compromising set-ups, SPE-PLOT-LC MS was assembled without the use of additional hardware/noncommercial parts, additional valves or sample splitting. A comprehensive study of various flow rates, gradient times, and column length combinations was undertaken. Maximum resolution for <400 bar was achieved using a 40 nL/min flow rate, a 400 min gradient and an 8 m long column. We obtained a 2.3-fold increase in peak capacity compared to previous PLOT studies (950 versus previously obtained 400, when using peak width = 2sigma definition). Our system also meets or surpasses peak capacities obtained in recent reports using nano-ultra-performance LC conditions or long silica monolith nanocolumns. Nearly 500 proteins (1958 peptides) could be identified in just one single injection of an extract corresponding to 1000 BxPC3 beta catenin (-/-) cells, and ~1200 and 2500 proteins in extracts of 10,000 and 100,000 cells, respectively, allowing detection of central members and regulators of the Wnt signaling pathway. PMID- 23813983 TI - An analysis of the contact between the stent and the artery using tube hydroforming simulation. AB - Stents for angioplasty have been extensively used to treat coronary diseases. The aim of this study is to analyze the expansion of the stent and the contact with the artery using tube hydroforming simulation. In the simulation, the contact stress and the final shape of the artery after stent expansion process using the Stampack ((r);) software will be studied. A model of a commercial stent made of 316L stainless steel was modeled by using an elastic-plastic constitutive law with isotropic hardening. The artery was modeled as a cylinder and made of hyperelastic material. The stent model studied in this work presented a good performance according to the results obtained. After expansion, any region of the stent's structure with strong risk of wrinkling, thinning, or buckling was not observed. In the forming limit diagram, all points were far from the Keeler Goodwin diagram. Furthermore, the expanded stent model has a good conformability. In conclusion, our data show that the proposed methodology is a useful tool to check if the stent model implanted in the artery may cause restenosis after angioplasty; thus, our tests provided a reliable tool to analyze this risk. PMID- 23813984 TI - Effects of noninvasive brain stimulation on language networks and recovery in early poststroke aphasia. AB - BACKGROUND AND PURPOSE: Modulation of activity in language networks using repetitive transcranial magnetic stimulation (rTMS) may possibly support recovery from poststroke aphasia. Case series and feasibility studies seem to indicate a therapeutic effect; however, randomized sham-controlled, proof-of-principle studies relating clinical effects to activation patterns are missing. METHODS: Twenty-four patients with subacute poststroke aphasia were randomized to a 10-day protocol of 20-minute inhibitory 1 Hz rTMS over the right triangular part of the posterior inferior frontal gyrus or sham stimulation, followed by 45 minutes of speech and language therapy. Activity in language networks was measured with O-15 water positron emission tomography during verb generation before and after treatment. Language performance was assessed using the Aachen Aphasia Test battery. RESULTS: The primary outcome measure, global Aachen Aphasia Test score change, was significantly higher in the rTMS group (t test, P=0.003). Increases were largest for subtest naming (P=0.002) and tended to be higher for comprehension, token test, and writing (P<0.1). Patients in the rTMS group activated proportionally more voxels in the left hemisphere after treatment than before (difference in activation volume index) compared with sham-treated patients (t test, P=0.002).There was a moderate but significant linear relationship between activation volume index change and global Aachen Aphasia Test score change (r2=0.25; P=0.015). CONCLUSIONS: Ten sessions of inhibitory rTMS over the right posterior inferior frontal gyrus, in combination with speech and language therapy, significantly improve language recovery in subacute ischemic stroke and favor recruitment of left-hemispheric language networks. PMID- 23813985 TI - Letter by Chen regarding article, "The impact of green tea and coffee consumption on the reduced risk of stroke incidence in Japanese population: the Japan public health center-based study cohort". PMID- 23813986 TI - Risk of subarachnoid hemorrhage and early case fatality associated with outpatient antithrombotic drug use. AB - BACKGROUND AND PURPOSE: Subarachnoid hemorrhage (SAH) accounts for <7% of all strokes, but is an enormous individual and societal burden. We investigated the risk of SAH associated with prior use of antithrombotic drugs and their influence on 30-day case fatality. METHODS: We conducted a nested case-control study in a cohort of 13.4 million members of the German Pharmacoepidemiological Research Database. Ten controls were matched to each case hospitalized for SAH between July 2004 and November 2006 by health insurance, year of birth, and sex using risk set sampling. Exposure was assessed for the warfarin analog phenprocoumon, heparin, clopidogrel/ticlopidine, and acetylsalicylic acid. Multivariable adjusted odds ratios (ORs) for SAH were estimated by conditional logistic regression. Risk factors for 30-day case fatality were assessed in patients with SAH by logistic regression. RESULTS: The nested case-control study included 2065 SAH cases and 20 649 matched controls. The risk of SAH was significantly increased for phenprocoumon (OR, 1.7; 95% confidence interval [CI], 1.3-2.3), clopidogrel/ticlopidine (OR, 1.7; 95% CI, 1.1-2.5), and for acetylsalicylic acid use (OR, 1.5; 95% CI, 1.2-2.0), but not for outpatient heparin use (OR, 1.2; 95% CI, 0.5-2.7). The early case fatality of 22.8% was associated with an age >70 years (OR, 2.3; 95% CI, 1.8-3.1) and arterial hypertension (OR, 1.3; 95% CI, 1.0 1.6), but not with any of the antithrombotic drugs. CONCLUSIONS: Outpatient antithrombotic drug use was associated with an increased risk of SAH, but no association was observed with early case fatality. PMID- 23813987 TI - Response to letter regarding article, "The impact of green tea and coffee consumption on the reduced risk of stroke incidence in Japanese population: the Japan public health center-based study cohort". PMID- 23813988 TI - Differences in outcome and predictors between ischemic and intracerebral hemorrhage: the South London Stroke Register. AB - BACKGROUND AND PURPOSE: Few population-based studies describing functional outcome between ischemic stroke and intracerebral hemorrhage (ICH) in the short- and long-term are available. Knowledge of the natural history and factors associated with poor outcome is important in providing prognostic information and resource allocation. METHODS: Data were collected within the population-based South London Stroke Register between 1995 and 2011. Baseline data were collection of sociodemographic factors, case mix, risk factors before stroke, and acute stroke processes, with outcomes at 7 days, 3 months, 1 year, 5 years, and 10 years after stroke. Logistic regression was used to determine factors associated with poor outcome (dead and dependency: Barthel index<15). RESULTS: Age and incontinence were associated with poor outcome at 3 months, 1 year, 5 years, and 10 years in ICH, whereas age, incontinence, failed swallow, atrial fibrillation, and diabetes mellitus were associated with poor outcome in ischemic stroke. ICH was more likely to have poorer outcomes at 3 months (odds ratio, 2.2; 95% confidence interval [CI], 1.8-2.8) and 1 year (odds ratio, 2.1; 95% CI, 1.7-2.6) but not at 5 years (odds ratio, 1.1; 95% CI, 0.8-1.4) or 10 years (odd ratio, 0.8; 95% CI, 0.57-1.22); however, the improvement of functional outcome from day 7 to 3 months was significantly greater for ICH (regression coefficient: 1.8; 95% CI, 1.1-2.6; P<0.0001). CONCLUSIONS: ICH has poorer outcomes up to 5 years after stroke. The improvement of functional outcome up to 3 months was significantly greater with ICH. Identification of factors associated with poor outcome may be used for clinical predictions. PMID- 23813991 TI - Spontaneous intraperitoneal haemorrhage from short gastric artery avulsion secondary to forceful retching. AB - Spontaneous intraperitoneal haemorrhage can occur in any age group. It is defined as presence of free blood in the peritoneal cavity which can results from a non traumatic and non-iatrogenic cause. Common causes are visceral, coagulopathy related and vascular. The clinical presentation is usually non-specific; it can vary from mild abdominal pain to a shock status. We report a very rare case of a 17-year-old male patient who presented to our institution with spontaneous intraperitoneal bleeding secondary to avulsion of one of the short gastric artery following forceful retching. PMID- 23813992 TI - Streptococcus pneumoniae mycotic aneurysm with contiguous vertebral discitis treated by endovascular aortic repair and antibiotics. AB - A 61-year-old man was admitted with a history of right upper quadrant and left iliac fossa pain and raised inflammatory markers. Initial investigations, including contrast-enhanced CT scan of the abdomen and pelvis, were reported as normal. Following readmission 2 months later with thoracolumbar back pain and recurrent fevers, an MRI showed T11/12 discitis and an adjacent mycotic aneurysm of the aorta. CT angiogram confirmed an 8 cm mycotic aneurysm. A second, more distal aneurysm was found located at the left common femoral artery. The aortic aneurysm was treated by antegrade stenting. The left common femoral artery aneurysm was excised. The patient was also treated with antibiotics. He made a good recovery and was well 8 months later apart from mild residual thoracolumbar spinal pain. To date, he has been followed up for 1 year and remains asymptomatic. PMID- 23813993 TI - Bilateral axillary masses mimicking as accessory breast with multiple fibroadenoma and bilateral gigantomastia in HIV-positive patient. AB - Accessory breast is a rare entity that can present as asymptomatic masses or can cause symptoms like heaviness, pain, restriction of arm movement and limitation in daily pursuits with allied apprehension and anxiety for the patient. We present a case of bilateral axillary masses mimicking as accessory breast with multiple fibroadenoma in a 28 years, nulliparous, Indian woman who is HIV positive, which proves to be a diagnostic dilemma. Excisional biopsy was diagnostic. The rarity of such cases imposes challenges on the management in terms of diagnosis, prognosis and therapeutic options. PMID- 23813994 TI - Rehabilitation of lost vertical dimension with cast post core and cast partial denture. AB - Loss of teeth is sometimes inevitable. But, it is the duty of a restorative dentist to restore the loss of teeth in way keeping in mind the discomfort and agony of the patient. Rehabilitation of these types of patients requires thorough knowledge and great skills on the part of a prosthodontist. This clinical case report describes the management of a 58-year-old male patient with a loss of mandibular posterior teeth and severely attrited anterior teeth opposing natural teeth. The treatment plan was to restore the loss of teeth and the loss of vertical dimension by providing prosthesis keeping in mind the occlusion and stomatognathic system. A novel approach of fixed and removable type of prostheses was implemented and successfully delivered. PMID- 23813995 TI - Bilateral dens evaginatus (talon cusp) in permanent maxillary lateral incisors: a rare developmental dental anomaly with great clinical significance. AB - Talon cusp is an accessory cusp-like structure which projects from the cingulum area or cementoenamel junction. It is important for dentists to be aware of the potential complications that may occur with talon cusp. Early diagnosis and treatment is important, especially to prevent pulpal complications in permanent teeth which may be in developing stage in paediatric patients. The purpose of this paper is to report a case of bilateral talon cusp in permanent maxillary lateral incisors. Associated dental anomalies and clinical problems are discussed along with successful management of the case with conservative therapy. PMID- 23813996 TI - Altered mental status and fever. AB - West Nile virus (WNV) is still the most common cause of neuroinvasive arboviral disease in the USA with a case death of 10-30%. We are reporting a case of a 61 year-old woman with a history of Crohn's disease, fibromyalgia treated with chronic steroid therapy that presented with a day history of fever, confusion and lethargy. She had a lumbar puncture which was notable for lymphocytosis and was positive for WNV. She initially was treated with broad-spectrum antibiotics, which were subsequently discontinued when the diagnosis of WNV neuroinvasive disease (WNND) was made. A high index of suspicion is needed to diagnose WNND, and this should be suspected in elderly immunocompromised patient presenting with altered mental status and lumbar puncture suggestive of aseptic meningitis. Recent study has showed that there is genetic variation in the interferon response pathway which is associated with both risk for symptomatic WNV infection and disease progression. PMID- 23813997 TI - Advanced testicular cancer in a society of racial and socio-economic health disparity. AB - This is the case of an African-American man who presented with a 6 month history of impressive unilateral testicular swelling and abdominal pain. After a thorough workup he was found to have metastatic testicular seminoma causing multiple complex sequelae. This case highlights the essential diagnostic and therapeutic features of a common malignancy seen primarily in young men. His advanced disease presentation, complex management of multiple comorbidities combined with his African-American race and lower socio-economic status (SES) highlight an unusual paradigm shift in testicular cancer epidemiology from the more typical high SES Caucasian to the lower SES, less educated male patient. Beyond the unexpected clinical presentation, this case then presents multiple avenues of discussion regarding the unfortunate effects of racial disparities on disease presentation and progression that are plaguing our healthcare system today. PMID- 23813998 TI - Lead intoxication and knee osteoarthritis after a gunshot: long-term follow-up case report. AB - This case is of a man who suffered gunshots and developed saturnism. Projectiles were removed from the abdomen, but one was left in the knee for 14 years. The patient presented with weight loss, headaches, loss of sight, tiredness, cramps, painful joints and trembling. We identified ataxic movements such as intense trembling of the limbs and anaemia. The abdominal pain caused eight internments in different hospitals, and the patient always received the diagnosis of intestinal subocclusion. We removed the bullet and did a wide synovectomy. The patient did not receive a clinical treatment with chelates. The symptoms of lead poisoning ceased, but he developed knee osteoarthritis, during the 7 years of follow-up. PMID- 23813999 TI - Laparoscopically assisted repair of an acute traumatic diaphragmatic hernia. AB - A 60-year-old man with chronic obstructive pulmonary disease and a heavy smoker and drinker presented to the emergency department with left-sided thoracoabdominal pain after falling down the stairs. Initial clinical findings were left-sided chest tenderness with no clinical evidence of subcutaneous emphysema. Twenty-four hours later the patient's respiratory distress increased repeat chest X-ray showed a left gastrothorax indicative of a ruptured left hemi diaphragm. Diagnostic laparoscopy in the supine position via an umbilical port confirmed the presence of the stomach, spleen and splenic flexure of the colon in the left chest. Laparoscopic reduction of the stomach and colon was performed, but a small upper midline incision was required to reduce the spleen without injury. The diaphragmatic tear was repaired by direct open suture. The patient required a brief period of postoperative ventilation via a tracheostomy. The patient remained well at a 3-month follow-up visit. PMID- 23814000 TI - Lightning can strike twice: an unlucky patient of neurological interest. AB - Poliomyelitis, once a worldwide epidemic, is becoming increasingly rare owing to the introduction of the polio vaccine in the 1950s. It is estimated that the number of cases of polio has reduced by 99% since the Global Polio Eradication Initiative (GPEI) started in 1988. Amyotrophic lateral sclerosis (ALS) is another relatively uncommon condition which also affects anterior horn cells with debilitating neurological, and deadly, consequences. An unusual case of an aggressive form of ALS developing in a 72-year-old patient with paralytic poliomyelitis in childhood is presented. Her initial presentation was puzzling, and our approach to the diagnostic dilemma is discussed. PMID- 23814001 TI - Glomus jugulare: high index of clinical suspicion is important for optimal management. AB - Glomus tumour is a type of extra-adrenal chemodectoma or paraganglioma, originating within the wall of jugular bulb. We report a case of a 60-year-old woman who presented with hearing loss and pulsatile tinnitus. High index of suspicion and appropriate use of imaging led to early diagnosis. However, the patient did not give consent for surgery and was managed satisfactorily with radiotherapy. PMID- 23814002 TI - A rare case of transmigration of mandibular canine associated with an odontoma. AB - Transmigration or intraosseous migration of mandibular canine is a very rare phenomenon. Specific aetiology and mechanism of transmigration is still unclear. Majority of these transmigrated canines are impacted, asymptomatic and involve the left mandible. This article describes a rare case of transmigrated mandibular right permanent canine associated with a retained deciduous right canine and an odontoma in a 25-year-old man with a follow-up of 3 years. The present case report also highlights the importance of early diagnosis and periodic monitoring of impacted teeth with panoramic radiography to avoid the occurrence of any associated pathologies and further allow interceptive treatment for possible better results. PMID- 23814003 TI - Cervical nodular fasciitis in a 17-month-old child. AB - Nodular fasciitis (NF) is an uncommon fibroblastic proliferation that usually arises in the extremities or trunk, less frequently in the head and neck region. It is frequently mistaken for a malignant tumour owing to its rapid growth, but it is ultimately a benign condition with spontaneous regression. We describe a case of a 17-month-old African girl with cervical NF in which spontaneous and complete regression of the lesion occurred following the diagnosis by fine needle aspiration cytology. We emphasise the importance of making an accurate and timely diagnosis, and the imperative role of fine needle aspiration cytology in this process, potentially avoiding further unnecessary surgical procedures. PMID- 23814004 TI - Use of C2 spinous process screw for posterior cervical fixation as substitute for laminar screw in a patient with thin laminae. AB - Rigid screw fixation of C2 including transarticular screw and pedicle screw contain the risk of vertebral artery (VA) injury. On the other hand, translaminar screws are considered to be safer for patients with anomalous VA. But C2 translaminar screw placement was limited in patients who have thin laminas and there is marked variation in C2 laminar thickness. Appropriate C2 fixation method for a patient who has thin laminas and high-riding VA together was controversial. Here, we present a case of an elderly Asian woman who had thin laminas and high riding VA together with progressive myelopathy to report a first case of C2 spinous process screw insertion. Although the stability and safety of C2 spinous process screw was reported in cadaver series, there was no clinical report to our knowledge. Spinous process screw can be an option of C2 fixation for patients with high-riding VA and severe degenerated cervical spines including thin C2 laminas. PMID- 23814005 TI - Diffuse parenchymal lung disease caused by surfactant deficiency: dramatic improvement by azithromycin. AB - Pulmonary surfactant deficiency caused by mutations in ABCA3 (ATP-binding cassette transporter of the A subfamily, member 3) gene results in diffuse parenchymal lung disease (DPLD) in children. So far, systemic steroids are the main treatment, with however limited efficacy. We report the case of a young boy showing a dramatic long-term improvement of respiratory disease by low-dose azithromycin (AZM) with no side effect after 6 years of treatment. Cellular and molecular studies are ongoing to progress in the understanding of the mechanisms involved. On behalf of the National Reference Center for rare lung diseases in France (Respirare, http://www.respirare.fr), clinical studies on AZM in various forms of DPLD in children have been initiated and should provide information on the types of paediatric DPLD that may benefit from this treatment. PMID- 23814006 TI - Adductor longus ruptures in elite sportsmen--pitfalls of surgical repair: a report of two cases. AB - Insertional tendinopathy of the adductor longus is a common and problematic condition in elite athletes and may lead to rupture. Previous literature has reported good outcomes in these patients when these ruptures are treated with both surgical and non-operative management. This paper will discuss the available literature on management of adductor tears and describe two case reports of deep infection following surgical repair of ruptures in soccer players and the effects this had on their profession. We conclude that, given the overall evidence of conservative management of adductor tears and possible complications associated with the surgery that these cases highlight, acute adductor tears in the majority should be treated conservatively. PMID- 23814007 TI - Sinus pauses and high-grade atrioventricular block in Albright's hereditary osteodystrophy with pseudopseudohypoparathyroidism. AB - Albright's hereditary osteodystrophy (AHO) is a rare inherited syndrome involving the molecular defects in the gene encoding the alpha subunit of the stimulatory G protein (Gsalpha). AHO has several variants, mainly pseudohypoparathyroidism (PHP) and pseudopseudohypoparathyroidism (PPHP). We present a family that share the same inactivating GNAS1 mutation, the daughter being affected by PPHP and her late father with PHP. The daughter, in her late teens, presented with a long history of presyncopal and syncopal attacks. Her father died suddenly in his mid 40 s. As expected, her laboratory tests to date have shown normal biochemistry and hormonal levels. Subsequently, an implantable loop recorder was inserted. This demonstrated extreme sinus pauses of >11 s and also high-grade atrioventricular block. A dual-chamber pacemaker was therefore inserted. PMID- 23814008 TI - Perianal hair as an unusual presentation of non-classical congenital adrenal hyperplasia. PMID- 23814009 TI - Massive pulmonary embolus and a precariously positioned thrombus: teetering on a knife edge! AB - Pulmonary embolism (PE) is a common condition seen regularly by emergency physicians. The authors describe a patient who presented with shortness of breath and syncope. He also experienced drowsy, clammy and sweaty episodes. He was tachycardic, tachypnoeic and saturating at 92% on air. A chest X-ray was normal but an ECG showed S1Q3T3. A CT pulmonary angiography performed showed bilateral pulmonary emboli with a large inferior vena cava (IVC) thrombus. Echocardiography revealed severely dilated right ventricle and atrium, severe right ventricular impairment, pulmonary hypertension, large mobile friable clots seen extending into the tricuspid valve. A multidisciplinary team decided the safest management approach was intravenous heparin. The patient recovered and repeat echocardiography 5 days later showed significantly smaller clots. The extension of an IVC thrombus into the heart and prolapsing into the tricuspid valve is an extremely rare presentation. Furthermore this case demonstrates the importance of echocardiography when diagnosing and generating bespoke management plans for PE. PMID- 23814010 TI - Adolescent haematopyocolpos simulating appendicular abscess. PMID- 23814011 TI - Asymptomatic submitral aneurysm: an uncommon complication of a common disease. PMID- 23814012 TI - Prostaglandin F2alpha upregulates Slit/Robo expression in mouse corpus luteum during luteolysis. AB - Prostaglandin F2 alpha (PGF2 alpha) is a key factor in the triggering of the regression of the corpus luteum (CL). Furthermore, it has been reported that Slit/Robo signaling is involved in the regulation of luteolysis. However, the interactions between PGF2 alpha and Slit/Robo in the progression of luteolysis remain to be established. This study was designed to determine whether luteolysis is regulated by the interactions of PGF2 alpha and Slit/Robo in the mouse CL. Real-time PCR and immunohistochemistry results showed that Slit2 and its receptor Robo1 are highly and specifically co-expressed in the mouse CL. Functional studies showed that Slit/Robo participates in mouse luteolysis by enhancing cell apoptosis and upregulating caspase3 expression. Both in vitro and in vivo studies showed that PGF2 alpha significantly increases the expression of Slit2 and Robo1 during luteolysis through protein kinase C-dependent ERK1/2 and P38 MAPK signaling pathways, whereas an inhibitor of Slit/Robo signaling significantly decreases the stimulating effect of PGF2 alpha on luteolysis. These findings indicate that Slit/Robo signaling plays important roles in PGF2 alpha-induced luteolysis by mediating the PGF2 alpha signaling pathway in the CL. PMID- 23814013 TI - Mitotane reduces human and mouse ACTH-secreting pituitary cell viability and function. AB - Medical therapy for Cushing's disease (CD) is currently based on agents mainly targeting adrenocortical function. Lately, pituitary-directed drugs have been developed, with limited efficacy. Mitotane, a potent adrenolytic drug, has been recently investigated for the treatment of CD, but the direct pituitary effects have not been clarified so far. The aim of our study was to investigate whether mitotane may affect corticotroph function and cell survival in the mouse pituitary cell line AtT20/D16v-F2 and in the primary cultures of human ACTH secreting pituitary adenomas, as an in vitro model of pituitary corticotrophs. We found that in the AtT20/D16v-F2 cell line and in primary cultures, mitotane reduces cell viability by inducing caspase-mediated apoptosis and reduces ACTH secretion. In the AtT20/D16v-F2 cell line, mitotane reduces Pomc expression and blocks the stimulatory effects of corticotropin-releasing hormone on cell viability, ACTH secretion, and Pomc expression. These effects were apparent at mitotane doses greater than those usually necessary for reducing cortisol secretion in Cushing's syndrome, but still in the therapeutic window for adrenocortical carcinoma treatment. In conclusion, our results demonstrate that mitotane affects cell viability and function of human and mouse ACTH-secreting pituitary adenoma cells. These data indicate that mitotane could have direct pituitary effects on corticotroph cells. PMID- 23814014 TI - Resveratrol inhibits 11beta-hydroxysteroid dehydrogenase type 1 activity in rat adipose microsomes. AB - It has been suggested that resveratrol, a polyphenol in wine, can regulate adiposity because it decreases adipose deposition in mice and rats; however, the mechanism underlying this effect has not been fully clarified. In humans and rodents, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is expressed in liver and adipose tissue. 11beta-HSD1 converts inactive glucocorticoid into active glucocorticoid in adipocytes. Activated glucocorticoid plays an important role in the pathogenesis of central obesity. The objective of this study was to investigate the effects of resveratrol on 11beta-HSD1 activity in rodent adipose tissue. 11beta-HSD1 activity in microsomes from rat mesenteric adipose depots and 3T3-L1 adipocytes was determined in the presence of 11-dehydrocorticosterone with or without varying concentrations of resveratrol. Significant inhibition of 11beta-HSD1 by resveratrol was observed in rat adipose microsomes and 3T3-L1 adipocytes within 10 min. Time- and dose-dependent effects were also observed. The 11beta-HSD1 activity by resveratrol was also inhibited in rat epididymal adipose tissue, and this inhibition was not recovered by estrogen receptor blockers. The kinetic study revealed that resveratrol acted as a non-competitive inhibitor of 11beta-HSD1. Ki and IC50 values of resveratrol were 39.6 and 35.2 MUM respectively. Further, resveratrol did not affect the activities of 11beta HSD2 and hexose-6-phosphate dehydrogenase. These results suggest that the most likely mechanism of 11beta-HSD1 inhibition by resveratrol is via interaction between resveratrol and 11beta-HSD1 enzyme, rather than via a transcriptional pathway. We demonstrated that the antiobesity effects of resveratrol may partially be attributed to the inhibition of 11beta-HSD1 activity in adipocytes. PMID- 23814015 TI - Duress without stress: Cryptobia infection results in HPI axis dysfunction in rainbow trout. AB - Despite clear physiological duress, rainbow trout (Oncorhynchus mykiss) infected with the pathogenic haemoflagellate Cryptobia salmositica do not appear to mount a cortisol stress response. Therefore, we hypothesized that the infection suppresses the stress response by inhibiting the key effectors of the hypothalamic-pituitary-interrenal (HPI) axis. To test this, we characterized the basal activity of the HPI axis and the cortisol response to air exposure in saline- and parasite-injected fish. All fish were sampled at 4 and 6 weeks post injection (wpi). While both the treatment groups had resting plasma cortisol levels, the parasite-infected fish had lower levels of plasma ACTH than the control fish. Relative to the control fish, the infected fish had higher mRNA levels of brain pre-optic area corticotrophin-releasing factor (CRF) and pituitary CRF receptor type 1, no change in pituitary POMC-A1, -A2 and -B gene expression, higher and lower head kidney melanocortin 2 receptor mRNA levels at 4 and 6 wpi respectively and reduced gene expression of key proteins regulating interrenal steroidogenesis: StAR, cytochrome P450scc and 11beta-hydroxylase. The parasite-infected fish also had a reduced plasma cortisol response to a 60-s air exposure stressor. Superfusion of the head kidney tissues of the parasite infected fish led to significantly lower ACTH-stimulated cortisol release rates than that observed in the control fish. These novel findings show that infection of rainbow trout with C. salmositica results in complex changes in the transcriptional activity of both central and peripheral regulators of the HPI axis and in a reduction in the interrenal capacity to synthesize cortisol. PMID- 23814016 TI - Titanium microbead-based porous implants: bead size controls cell response and host integration. AB - Openly porous structures in implants are desirable for better integration with the host tissue. Sintered microbead-based titanium implants for oto rhinolaryngology applications, which create an environment where the cells can migrate in the areas between the microbeads, are developed. This structure promotes fibrovascular tissue formation within the implant in vivo. In this study, it is determine to what extent these events can be controlled by changing the physical environment of the implants both in vitro and in vivo. By cell tracking, it is observed that the size of the beads and the distance between the neighboring beads significantly affect the ability of cells to develop cell-to cell contacts and to bridge the pores. Live cell staining shows that as the bead size gets smaller, the probability to observe cells that fill the porous areas is higher. This also affects the initial attachment and distribution of the cells and collagen secretion by fibroblasts. Obtaining a fast coverage of the system also enables co-culture systems where, the number and the distribution of the second cell type are boosted by the presence of the first. This concept is utilized to increase the attachment of vascular endothelial cells by an initial layer of fibroblasts. By decreasing the bead diameter, the overall colonization of the implant can be significantly increased in vivo. The effect of bead size has a similar pattern both in rats and rabbits, with faster colonization of smaller bead-based structures. Using smaller beads would improve clinical outcomes as faster integration facilitates the attainment of functionality by the implant. PMID- 23814017 TI - A prospective study of 67 serum immune and inflammation markers and risk of non Hodgkin lymphoma. AB - Although severe immune dysregulation is an established risk factor for non Hodgkin lymphoma (NHL), the importance of subclinical immunologic effects is unclear. We compared baseline serum levels of 67 immune and inflammation markers between 301 patients with NHL diagnosed 5+ years after blood collection and 301 control patients within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. We observed associations with NHL for elevated B-cell-attracting chemokine 1 (BCA-1; fourth quartile vs first: odds ratio [OR], 2.7; 95% confidence interval [CI], 1.7-4.2; Ptrend = 1.0 * 10(-6)), soluble tumor necrosis factor receptor 2 (sTNFR2; OR, 3.4; 95% CI, 2.0-5.8; Ptrend = 1.1 * 10(-6)), and soluble vascular endothelial growth factor receptor 2 (sVEGFR2; OR, 2.3; 95% CI, 1.4-3.9; Ptrend = .0005) that remained significant after Bonferroni correction, simultaneous model adjustment, and restriction to cases diagnosed 8 to 13 years after blood collection. Associations with other markers were observed, although none remained associated with NHL after adjustment for BCA-1, sTNFR2, and sVEGFR2. Our findings suggest that circulating BCA-1, sTNFR2, and sVEGFR2 are associated with NHL risk well in advance of diagnosis. Additional research is needed to replicate these findings and elucidate the underlying biologic mechanisms. PMID- 23814018 TI - PPARalpha and fatty acid oxidation mediate glucocorticoid resistance in chronic lymphocytic leukemia. AB - High-dose glucocorticoids (GCs) can be a useful treatment for aggressive forms of chronic lymphocytic leukemia (CLL). However, their mechanism of action is not well understood, and resistance to GCs is inevitable. In a minimal, serum-free culture system, the synthetic GC dexamethasone (DEX) was found to decrease the metabolic activity of CLL cells, indicated by down-regulation of pyruvate kinase M2 (PKM2) expression and activity, decreased levels of pyruvate and its metabolites, and loss of mitochondrial membrane potential. This metabolic restriction was associated with decreased size and death of some of the tumor cells in the population. Concomitant plasma membrane damage increased killing of CLL cells by DEX. However, the nuclear receptor peroxisome proliferator activated receptor alpha (PPARalpha), which regulates fatty acid oxidation, was also increased by DEX, and adipocyte-derived lipids, lipoproteins, and propionic acid protected CLL cells from DEX. PPARalpha and fatty acid oxidation enzyme inhibitors increased DEX-mediated killing of CLL cells in vitro and clearance of CLL xenografts in vivo. These findings suggest that GCs prevent tumor cells from generating the energy needed to repair membrane damage, fatty acid oxidation is a mechanism of resistance to GC-mediated cytotoxicity, and PPARalpha inhibition is a strategy to improve the therapeutic efficacy of GCs. PMID- 23814019 TI - Integrated phosphoproteomic and metabolomic profiling reveals NPM-ALK-mediated phosphorylation of PKM2 and metabolic reprogramming in anaplastic large cell lymphoma. AB - The mechanisms underlying the pathogenesis of the constitutively active tyrosine kinase nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) expressing anaplastic large cell lymphoma are not completely understood. Here we show using an integrated phosphoproteomic and metabolomic strategy that NPM-ALK induces a metabolic shift toward aerobic glycolysis, increased lactate production, and biomass production. The metabolic shift is mediated through the anaplastic lymphoma kinase (ALK) phosphorylation of the tumor-specific isoform of pyruvate kinase (PKM2) at Y105, resulting in decreased enzymatic activity. Small molecule activation of PKM2 or expression of Y105F PKM2 mutant leads to reversal of the metabolic switch with increased oxidative phosphorylation and reduced lactate production coincident with increased cell death, decreased colony formation, and reduced tumor growth in an in vivo xenograft model. This study provides comprehensive profiling of the phosphoproteomic and metabolomic consequences of NPM-ALK expression and reveals a novel role of ALK in the regulation of multiple components of cellular metabolism. Our studies show that PKM2 is a novel substrate of ALK and plays a critical role in mediating the metabolic shift toward biomass production and tumorigenesis. PMID- 23814020 TI - Multimodal imaging reveals structural and functional heterogeneity in different bone marrow compartments: functional implications on hematopoietic stem cells. AB - Intravital microscopy of the calvarium is the only noninvasive method for high resolution imaging of the bone marrow (BM) and hematopoietic stem cell (HSC) niches. However, it is unclear if the calvarium is representative of all BM compartments. Using the combination of whole body optical imaging, intravital microscopy, and "in vivo fluorescence trapping," a thorough comparison of HSCs and putative HSC niches in the calvaria, epiphyses, and diaphyses, at steady state or after HSC transplantation, can be made. We report substantial heterogeneity between different BM compartments in terms of bone-remodeling activity (BRA), blood volume fraction (BVF), and hypoxia. Although BVF is high in all BM compartments, including areas adjacent to the endosteum, we found that compartments displaying the highest BVF and BRA were preferentially seeded and engrafted upon HSC transplantation. Unexpectedly, the macroanatomical distribution of HSCs at steady state is homogeneous across these 3 areas and independent of these 2 parameters and suggests the existence of "reconstituting niches," which are distinct from "homeostatic niches." Both types of niches were observed in the calvarium, indicating that endochondral ossification, the process needed for the formation of HSC niches during embryogenesis, is dispensable for the formation of HSC niches during adulthood. PMID- 23814021 TI - Abnormalities in the alternative pathway of complement in children with hematopoietic stem cell transplant-associated thrombotic microangiopathy. AB - Hematopoietic stem cell transplant (HSCT)-associated thrombotic microangiopathy (TMA) is a complication that occurs in 25% to 35% of HSCT recipients and shares histomorphologic similarities with hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). The hallmark of all thrombotic microangiopathies is vascular endothelial cell injury of various origins, resulting in microangiopathic hemolytic anemia, platelet consumption, fibrin deposition in the microcirculation, and tissue damage. Although significant advances have been made in understanding the pathogenesis of other thrombotic microangiopathies, post HSCT TMA remains poorly understood. We report an analysis of the complement alternative pathway, which has recently been linked to the pathogenesis of both the Shiga toxin mediated and the atypical forms of HUS, with a focus on genetic variations in the complement Factor H (CFH) gene cluster and CFH autoantibodies in six children with post-HSCT TMA. We identified a high prevalence of deletions in CFH-related genes 3 and 1 (delCFHR3-CFHR1) and CFH autoantibodies in these patients with HSCT-TMA. Conversely, CFH autoantibodies were not detected in 18 children undergoing HSCT who did not develop TMA. Our observations suggest that complement alternative pathway dysregulation may be involved in the pathogenesis of post-HSCT TMA. These findings shed light on a novel mechanism of endothelial injury in transplant-TMA and may therefore guide the development of targeted treatment interventions. PMID- 23814023 TI - Dual inhibition of PI3K and mTOR mitigates compensatory AKT activation and improves tamoxifen response in breast cancer. AB - Everolimus, an mTOR inhibitor, showed great clinical efficacy in combination with tamoxifen, letrozole, or exemestane for the treatment of estrogen receptor positive (ER+) breast cancer. However, its antitumor activity was shown to be compromised by a compensatory process involving AKT activation. Here, it was determined whether combining an additional PI3K inhibitor can reverse this phenomenon and improve treatment efficacy. In breast cancer cells (MCF-7 and BT474), everolimus inhibited the mTOR downstream activity by limiting phosphorylation of p70S6K and 4EBP1, which resulted in p-Ser473-AKT activation. However, addition of a LY294002, a PI3K inhibitor, to tamoxifen and everolimus treatment improved the antitumor effect compared with tamoxifen alone or the other two agents in combination. Moreover, LY294002 suppressed the activity of the PI3K/AKT/mTOR axis and mitigated the p-Ser473-AKT activation feedback loop in both cell lines. Critically, this combination scheme also significantly inhibited the expression of HIF-1a, an angiogenesis marker, under hypoxic conditions and reduced blood vessel sprout formation in vitro. Finally, it was shown that the three-agent cocktail had the greatest efficacy in inhibiting MCF-7 xenograft tumor growth and angiogenesis. Taken together, these results suggest that inhibition of PI3K and mTOR may further improve therapy in ER(+) breast cancer cells. IMPLICATIONS: Combinatorial inhibition of the PI3K/AKT/mTOR signaling axis may enhance endocrine-based therapy in breast cancer. PMID- 23814024 TI - Towards sustained silencing of HER2/neu in cancer by epigenetic editing. AB - The human epidermal growth factor receptor-2 (HER2/neu/ERBB2) is overexpressed in several cancer types. Although therapies targeting the HER2/neu protein result in inhibition of cell proliferation, the anticancer effect might be further optimized by limiting HER2/neu expression at the DNA level. Towards this aim, epigenetic editing was performed to suppress HER2/neu expression by inducing epigenetic silencing marks on the HER2/neu promoter.HER2/neu expression and HER2/neu promoter epigenetic modification status were determined in a panel of ovarian and breast cancer cell lines. HER2/neu-overexpressing cancer cells were transduced to express a zinc finger protein (ZFP), targeting the HER2/neugene, fused to histone methyltransferases (G9a, SUV39-H1)/super KRAB domain (SKD). Epigenetic assessment of the HER2/neu promoter showed that HER2/neu-ZFP fused to G9a efficiently induced the intended silencing histone methylation mark (H3K9me2). Importantly, H3K9me2 induction was associated with a dramatic downregulation of HER2/neu expression in HER2/neu- overexpressing cells. Downregulation by SKD, traditionally considered transient in nature, was associated with removal of the histone acetylation mark (H3ac). The downregulation of HER2/neu by induced H3K9 methylation and/or reduced H3 acetylation was sufficient to effectively inhibit cellular metabolic activity and clonogenicity. Furthermore, genome-wide analysis indicated preferential binding of the ZFP to its target sequence. These results not only show that H3K9 methylation can be induced but also that this epigenetic mark was instructive in promoting downregulation of HER2/neu expression. IMPLICATIONS: Epigenetic editing provides a novel (synergistic) approach to modulate expression of oncogenes. PMID- 23814022 TI - Inhibiting retinoic acid signaling ameliorates graft-versus-host disease by modifying T-cell differentiation and intestinal migration. AB - Graft-versus-host disease (GVHD) is a critical complication after allogeneic bone marrow transplantation. During GVHD, donor T cells are activated by host antigen presenting cells and differentiate into T-effector cells (Teffs) that migrate to GVHD target organs. However, local environmental factors influencing Teff differentiation and migration are largely unknown. Vitamin A metabolism within the intestine produces retinoic acid, which contributes to intestinal homeostasis and tolerance induction. Here, we show that the expression and function of vitamin A-metabolizing enzymes were increased in the intestine and mesenteric lymph nodes in mice with active GVHD. Moreover, transgenic donor T cells expressing a retinoic acid receptor (RAR) response element luciferase reporter responded to increased vitamin A metabolites in GVHD-affected organs. Increasing RAR signaling accelerated GVHD lethality, whereas donor T cells expressing a dominant-negative RARalpha (dnRARalpha) showed markedly diminished lethality. The dnRARalpha transgenic T cells showed reduced Th1 differentiation and alpha4beta7 and CCR9 expression associated with poor intestinal migration, low GVHD pathology, and reduced intestinal permeability, primarily via CD4(+) T cells. The inhibition of RAR signaling augmented donor-induced Treg generation and expansion in vivo, while preserving graft-versus-leukemia effects. Together, these results suggested that reagents blunting donor T-cell RAR signaling may possess therapeutic anti-GVHD properties. PMID- 23814025 TI - PTP1B contributes to calreticulin-induced metastatic phenotypes in esophageal squamous cell carcinoma. AB - Calreticulin (CRT) is a Ca(2+)-binding chaperone protein that alters cellular Ca(2+)-homeostasis in the endoplasmic reticulum (ER). Previously it was shown that CRT was overexpressed in esophageal squamous cell carcinoma (ESCC), and elevated CRT expression promoted the migration and invasion of ESCC cells. In the present study, the mechanisms underlying the role of CRT in esophageal carcinoma progression were investigated. Critically, depletion of CRT or protein-tyrosine phosphatase 1B (PTP1B) reduced ESCC cell migration and metastasis to the lung, whereas restoration of PTP1B protein levels rescued cell migration in CRT silenced cells. Knockdown of CRT decreased PTP1B protein expression by reducing phosphorylation at the Y694 site of STAT5A, whereas knockdown of PTP1B reduced ERK1/2 phosphorylation at T204. Immunohistochemical analysis of CRT and PTP1B expression in ESCC patient tissues was strongly correlated. Importantly, PTP1B expression was associated with poor survival in patients with CRT overexpression. Overall, these data indicate a novel signaling pathway connecting CRT, STAT5A, PTP1B, and ERK1/2 in the regulation of ESCC cell migration. IMPLICATIONS: These findings suggest that PTP1B is a downstream effector of CRT signaling, promotes tumor progression, and can potentially be used as a new drug target for ESCC. PMID- 23814026 TI - The Human Factors Analysis Classification System (HFACS) applied to health care. AB - In spite of efforts to improve patient safety since the 1999 report, To Error Is Human, recent studies have shown limited progress toward preventing serious error. Most hospitals use root cause analysis as a method of serious event investigation. The authors postulate that this method suffers from 4 problems: (a) the use of root cause analysis is neither standardized nor reliable between organizations, (b) hospitals focus on "who" did "what" rather than on "why" the error occurred, (c) the identified causes are often too nonspecific to develop actionable correction plans, and (d) a standardized nomenclature does not exist to allow analysis of recurring errors across the organization. This article describes the modification of the Human Factors Analysis Classification System based on James Reason's theory of error causation for use in health care. This method resolves the 4 deficiencies noted above. The authors' experience investigating 105 serious events over 2 years is described. PMID- 23814027 TI - Rhabdomyosarcoma of spermatic cord in a 65-year-old man presenting as a groin swelling. AB - A 65-year-old man presented with a swelling in the right groin of 6 months duration. The swelling was associated with dull aching pain and the patient reported of increase in size of the swelling during lifting of heavy weights. The swelling was 6*5 cm, hard in consistency, mobile and there was no impulse of cough. Ultrasonography showed a solid mass measuring 5.3*1.5*5.2 cm arising from the spermatic cord. High-inguinal orchiectomy was performed. Histopathology revealed rhabdomyosarcoma (RMS) of the spermatic cord. Patient was advised adjuvant chemotherapy but he refused. Spermatic cord RMS is a rare tumour derived from the undifferentiated mesoderm. It is most often observed in children and adolescents. It rarely appears after the second decade of life. It usually manifests as a painless, firm to hard mass in the inguinal canal or scrotum. Radical high-inguinal orchiectomy is the treatment of choice. PMID- 23814028 TI - Complete Genome Sequence of Phocine Distemper Virus Isolated from a Harbor Seal (Phoca vitulina) during the 1988 North Sea Epidemic. AB - Phocine distemper virus (PDV) was identified as the cause of a large morbillivirus outbreak among harbor seals in the North Sea in 1988. PDV is a member of the family Paramyxoviridae, genus Morbillivirus. Until now, no full genome sequence of PDV has been available. PMID- 23814029 TI - Genome Sequences of a Novel HIV-1 Circulating Recombinant Form (CRF61_BC) Identified among Heterosexuals in China. AB - We report here the first novel HIV-1 second-generation intercirculating recombinant form 61_BC (inter-CRF61_BC), composed of two established CRFs (CRF07_BC and CRF08_BC), in China. CRF61_BC is the first CRF found among the heterosexual population in two different regions in China, suggesting the increasing significance of heterosexual transmission of HIV in China. PMID- 23814030 TI - Draft Genome Sequence of Streptococcus pyogenes Strain 06BA18369, a Human Pathogen Associated with Skin and Soft Tissue Infections in Northern Canada. AB - We report the draft sequence of Streptococcus pyogenes 06BA18369 (emm type 41.2, sequence type 579 [ST579]), isolated from a skin and soft tissue infection (SSTI) mixed with Staphylococcus aureus. This genome provides insight into the genetic composition of S. pyogenes strains associated with mixed SSTIs. PMID- 23814031 TI - Draft Genome Sequence of Methicillin-Susceptible Staphylococcus aureus Strain 06BA18369, a Pathogen Associated with Skin and Soft Tissue Infections in Northern Saskatchewan, Canada. AB - Here, we announce the draft sequence of a representative methicillin-susceptible Staphylococcus aureus (MSSA) isolate (06BA18369) whose strain type (spa type t311) was commonly isolated from skin and soft tissue coinfections with Streptococcus pyogenes. This strain sequence provides insight into a highly successful community-associated MSSA strain type. PMID- 23814032 TI - Draft Genome Sequence of the Ascomycete Phaeoacremonium aleophilum Strain UCR PA7, a Causal Agent of the Esca Disease Complex in Grapevines. AB - Grapevine infections by Phaeoacremonium aleophilum in association with other pathogenic fungi cause complex and economically important vascular diseases. Here we present the first draft of the P. aleophilum genome sequence, which comprises 624 scaffolds with a total length of 47.5 Mb (L50, 45; N50, 336 kb) and 8,926 predicted protein-coding genes. PMID- 23814033 TI - Complete Genome Sequence of Streptococcus suis Serotype 16 Strain TL13. AB - We report here the first complete genome sequence of Streptococcus suis serotype 16, which has been identified to be zoonotic. The sequenced strain TL13 was isolated from a pig in China. The genome is 2,038,146 bp in length, covering 1,950 coding sequences, 53 tRNAs, and 4 rRNA loci. PMID- 23814034 TI - Complete Genome Sequence of Raoultella ornithinolytica Strain B6, a 2,3 Butanediol-Producing Bacterium Isolated from Oil-Contaminated Soil. AB - Here we report the full genome sequence of Raoultella ornithinolytica strain B6, a Gram-negative aerobic bacillus belonging to the family Enterobacteriaceae. This 2,3-butanediol-producing bacterium was isolated from oil-contaminated soil on Backwoon Mountain in South Korea. Strain B6 contains 5,398,151 bp with 4,909 protein-coding genes, 104 structural RNAs, and 55.88% G+C content. PMID- 23814035 TI - Genome Sequencing of Four Strains of Rickettsia prowazekii, the Causative Agent of Epidemic Typhus, Including One Flying Squirrel Isolate. AB - Rickettsia prowazekii is a notable intracellular pathogen, the agent of epidemic typhus, and a potential biothreat agent. We present here whole-genome sequence data for four strains of R. prowazekii, including one from a flying squirrel. PMID- 23814036 TI - Genome Sequence of the Vancomycin-Producing Amycolatopsis orientalis subsp. orientalis Strain KCTC 9412T. AB - Amycolatopsis orientalis is the producer of vancomycin, a glycopeptide antibiotic that is used for the treatment of serious infections with Gram-positive bacteria. Here we present the next-generation sequencing (NGS)-based 9.06-Mb draft genome sequence of the type strain Amycolatopsis orientalis subsp. orientalis KCTC 9412 (DSM 40040; ATCC 19795). PMID- 23814037 TI - Highly fluorescent and photostable probe for long-term bacterial viability assay based on aggregation-induced emission. AB - Long-term tracking of bacterial viability is of great importance for monitoring the viability change of bacteria under storage, evaluating disinfection efficiency, as well as for studying the pharmacokinetic and pharmacodynamic properties of antibacterials. Most of the conventional viability dyes, however, suffer from high toxicity and/or poor photostability, making them unsuitable for long-term studies. In this work, an aggregation-induced emission molecule, TPE 2BA, which can differentiate dead and living bacteria and serve as a highly fluorescent and photostable probe for long-term viability assay. TPE-2BA is a cell-impermeable DNA stain that binds to the groove of double-stranded DNA. Bacteria with compromised membrane open the access for TPE-2BA to reach DNA, endowing it with strong emission. The feasibility of using TPE-2BA for screening effective bactericides is also demonstrated. Plate count experiment reveals that TPE-2BA poses negligible toxicity to bacteria, indicating that it is an excellent probe for long-term bacterial viability assay. PMID- 23814039 TI - Modularization and epistatic hierarchy determine homeostatic actions of multiple blood pressure quantitative trait loci. AB - Hypertension, the most frequently diagnosed clinical condition world-wide, predisposes individuals to morbidity and mortality, yet its underlying pathological etiologies are poorly understood. So far, a large number of quantitative trait loci (QTLs) have been identified in both humans and animal models, but how they function together in determining overall blood pressure (BP) in physiological settings is unknown. Here, we systematically and comprehensively performed pair-wise comparisons of individual QTLs to create a global picture of their functionality in an inbred rat model. Rather than each of numerous QTLs contributing to infinitesimal BP increments, a modularized pattern arises: two epistatic 'blocks' constitute basic functional 'units' for nearly all QTLs, designated as epistatic module 1 (EM1) and EM2. This modularization dictates the magnitude and scope of BP effects. Any EM1 member can contribute to BP additively to that of EM2, but not to those of the same module. Members of each EM display epistatic hierarchy, which seems to reflect a related functional pathway. Rat homologues of 11 human BP QTLs belong to either EM1 or EM2. Unique insights emerge into the novel genetic mechanism and hierarchy determining BP in the Dahl salt-sensitive SS/Jr (DSS) rat model that implicate a portion of human QTLs. Elucidating the pathways underlying EM1 and EM2 may reveal the genetic regulation of BP. PMID- 23814038 TI - Mutations in LYRM4, encoding iron-sulfur cluster biogenesis factor ISD11, cause deficiency of multiple respiratory chain complexes. AB - Iron-sulfur clusters (ISCs) are important prosthetic groups that define the functions of many proteins. Proteins with ISCs (called iron-sulfur or Fe-S proteins) are present in mitochondria, the cytosol, the endoplasmic reticulum and the nucleus. They participate in various biological pathways including oxidative phosphorylation (OXPHOS), the citric acid cycle, iron homeostasis, heme biosynthesis and DNA repair. Here, we report a homozygous mutation in LYRM4 in two patients with combined OXPHOS deficiency. LYRM4 encodes the ISD11 protein, which forms a complex with, and stabilizes, the sulfur donor NFS1. The homozygous mutation (c.203G>T, p.R68L) was identified via massively parallel sequencing of >1000 mitochondrial genes (MitoExome sequencing) in a patient with deficiency of complexes I, II and III in muscle and liver. These three complexes contain ISCs. Sanger sequencing identified the same mutation in his similarly affected cousin, who had a more severe phenotype and died while a neonate. Complex IV was also deficient in her skeletal muscle. Several other Fe-S proteins were also affected in both patients, including the aconitases and ferrochelatase. Mutant ISD11 only partially complemented for an ISD11 deletion in yeast. Our in vitro studies showed that the l-cysteine desulfurase activity of NFS1 was barely present when co-expressed with mutant ISD11. Our findings are consistent with a defect in the early step of ISC assembly affecting a broad variety of Fe-S proteins. The differences in biochemical and clinical features between the two patients may relate to limited availability of cysteine in the newborn period and suggest a potential approach to therapy. PMID- 23814040 TI - Altered 2-thiouridylation impairs mitochondrial translation in reversible infantile respiratory chain deficiency. AB - Childhood-onset mitochondrial encephalomyopathies are severe, relentlessly progressive conditions. However, reversible infantile respiratory chain deficiency (RIRCD), due to a homoplasmic mt-tRNA(Glu) mutation, and reversible infantile hepatopathy, due to tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase (TRMU) deficiency, stand out by showing spontaneous recovery, and provide the key to treatments of potential broader relevance. Modification of mt-tRNA(Glu) is a possible functional link between these two conditions, since TRMU is responsible for 2-thiouridylation of mt-tRNA(Glu), mt-tRNA(Lys) and mt tRNA(Gln). Here we show that down-regulation of TRMU in RIRCD impairs 2 thiouridylation and exacerbates the effect of the mt-tRNA(Glu) mutation by triggering a mitochondrial translation defect in vitro. Skeletal muscle of RIRCD patients in the symptomatic phase showed significantly reduced 2-thiouridylation. Supplementation with l-cysteine, which is required for optimal TRMU function, rescued respiratory chain enzyme activities in human cell lines of patients with RIRCD as well as deficient TRMU. Our results show that l-cysteine supplementation is a potential treatment for RIRCD and for TRMU deficiency, and is likely to have broader application for the growing group of intra-mitochondrial translation disorders. PMID- 23814041 TI - Sterol metabolism regulates neuroserpin polymer degradation in the absence of the unfolded protein response in the dementia FENIB. AB - Mutants of neuroserpin are retained as polymers within the endoplasmic reticulum (ER) of neurones to cause the autosomal dominant dementia familial encephalopathy with neuroserpin inclusion bodies or FENIB. The cellular consequences are unusual in that the ordered polymers activate the ER overload response (EOR) in the absence of the canonical unfolded protein response. We use both cell lines and Drosophila models to show that the G392E mutant of neuroserpin that forms polymers is degraded by UBE2j1 E2 ligase and Hrd1 E3 ligase while truncated neuroserpin, a protein that lacks 132 amino acids, is degraded by UBE2g2 (E2) and gp78 (E3) ligases. The degradation of G392E neuroserpin results from SREBP dependent activation of the cholesterol biosynthetic pathway in cells that express polymers of neuroserpin (G392E). Inhibition of HMGCoA reductase, the limiting enzyme of the cholesterol biosynthetic pathway, reduced the ubiquitination of G392E neuroserpin in our cell lines and increased the retention of neuroserpin polymers in both HeLa cells and primary neurones. Our data reveal a reciprocal relationship between cholesterol biosynthesis and the clearance of mutant neuroserpin. This represents the first description of a link between sterol metabolism and modulation of the proteotoxicity mediated by the EOR. PMID- 23814042 TI - A reappraisal of the diagnostic and therapeutic management of uncommon histologies of primary ocular adnexal lymphoma. AB - Lymphoma is the most common malignancy arising in the ocular adnexa, which includes conjunctiva, lachrymal gland, lachrymal sac, eyelids, orbit soft tissue, and extraocular muscles. Ocular adnexal lymphoma (OAL) accounts for 1%-2% of non Hodgkin lymphoma and 5%-15% of extranodal lymphoma. Histology, stage, and primary localizations are the most important variables influencing the natural history and therapeutic outcome of these malignancies. Among the various lymphoma variants that could arise in the ocular adnexa, marginal zone B-cell lymphoma (OA MZL) is the most common one. Other types of lymphoma arise much more rarely in these anatomical sites; follicular lymphoma is the second most frequent histology, followed by diffuse large B-cell lymphoma and mantle cell lymphoma. Additional lymphoma entities, like T-cell/natural killer cell lymphomas and Burkitt lymphoma, only occasionally involve orbital structures. Because they are so rare, related literature mostly consists of anecdotal cases included within series focused on OA-MZL and sporadic case reports. This bias hampers a global approach to clinical and molecular properties of these types of lymphoma, with a low level of evidence supporting therapeutic options. This review covers the prevalence, clinical presentation, behavior, and histological and molecular features of uncommon forms of primary OAL and provides practical recommendations for therapeutic management. PMID- 23814043 TI - Novel targets in non-small cell lung cancer: ROS1 and RET fusions. AB - The discovery of chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) gene in non-small cell lung cancer (NSCLC) has stimulated renewed interest in oncogenic fusions as potential therapeutic targets. Recently, genetic alterations in ROS1 and RET were identified in patients with NSCLC. Like ALK, genetic alterations in ROS1 and RET involve chromosomal rearrangements that result in the formation of chimeric fusion kinases capable of oncogenic transformation. Notably, ROS1 and RET rearrangements are rarely found with other genetic alterations, such as EGFR, KRAS, or ALK. This finding suggests that both ROS1 and RET are independent oncogenic drivers that may be viable therapeutic targets. In initial screening studies, ROS1 and RET rearrangements were identified at similar frequencies (approximately 1%-2%), using a variety of genotyping techniques. Importantly, patients with either ROS1 or RET rearrangements appear to have unique clinical and pathologic features that may facilitate identification and enrichment strategies. These features may in turn expedite enrollment in clinical trials evaluating genotype-directed therapies in these rare patient populations. In this review, we summarize the molecular biology, clinical features, detection, and targeting of ROS1 and RET rearrangements in NSCLC. PMID- 23814044 TI - Health-related quality of life with adjuvant docetaxel- and trastuzumab-based regimens in patients with node-positive and high-risk node-negative, HER2 positive early breast cancer: results from the BCIRG 006 Study. AB - BACKGROUND: This study aims to describe and compare health-related quality of life (HRQL) in patients with node-positive and high-risk node-negative HER2 positive early breast cancer receiving adjuvant docetaxel and trastuzumab-based or docetaxel-based regimens alone. METHODS: Eligible patients (n = 3,222) were randomly assigned to either four cycles of adjuvant doxorubicin and cyclophosphamide followed by four cycles of docetaxel (AC->T) or one of two trastuzumab-containing regimens: adjuvant doxorubicin and cyclophosphamide followed by docetaxel plus trastuzumab administered for 1 year (AC->TH) or six cycles of docetaxel plus carboplatin combined with trastuzumab administered for 1 year (TCH). The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 and BR-23 were administered at baseline, the start of cycle 4 (mid), and the end of chemotherapy (EOC), as well as at 6, 12, and 24 months after chemotherapy. RESULTS: Compliance rates for the EORTC questionnaires were acceptable at 72%-93% of eligible patients out to the 12-month assessment. Systemic side effect (SE) change scores were significantly improved for TCH-treated patients compared with AC->TH and AC->T at EOC, suggesting improved tolerability. Physical functioning (PF) was only slightly worse at midpoint for those receiving TCH, compared with patients who were just starting on taxane in an AC->TH regimen, but was otherwise similar between arms. All treatment arms recovered from the deterioration in SE, PF, and Global Health Scale scores by 1 year and median future perspective change scores continued to improve throughout treatment and follow-up. CONCLUSION: HRQL outcomes for adjuvant docetaxel and trastuzumab-based regimens are favorable and support TCH as a more tolerable treatment option. PMID- 23814045 TI - Practicing in partnership with Dr. Google: the growing effect of social media in oncology practice and research. PMID- 23814046 TI - Radiolytic mapping of solvent-contact surfaces in Photosystem II of higher plants: experimental identification of putative water channels within the photosystem. AB - Photosystem II uses water as an enzymatic substrate. It has been hypothesized that this water is vectored to the active site for water oxidation via water channels that lead from the surface of the protein complex to the Mn4O5Ca metal cluster. The radiolysis of water by synchrotron radiation produces amino acid residue-modifying OH(*) and is a powerful technique to identify regions of proteins that are in contact with water. In this study, we have used this technique to oxidatively modify buried amino acid residues in higher plant Photosystem II membranes. Fourier transform ion cyclotron resonance mass spectrometry was then used to identify these oxidized amino acid residues that were located in several core Photosystem II subunits (D1, D2, CP43, and CP47). While, as expected, the majority of the identified oxidized residues (~75%) are located on the solvent-exposed surface of the complex, a number of buried residues on these proteins were also modified. These residues form groups which appear to lead from the surface of the complex to the Mn4O5Ca cluster. These residues may be in contact with putative water channels in the photosystem. These results are discussed within the context of a number of largely computational studies that have identified putative water channels in Photosystem II. PMID- 23814047 TI - Protein-tyrosine phosphatase 1B antagonized signaling by insulin-like growth factor-1 receptor and kinase BRK/PTK6 in ovarian cancer cells. AB - Ovarian cancer, which is the leading cause of death from gynecological malignancies, is a heterogeneous disease known to be associated with disruption of multiple signaling pathways. Nevertheless, little is known regarding the role of protein phosphatases in the signaling events that underlie the disease; such knowledge will be essential to gain a complete understanding of the etiology of the disease and how to treat it. We have demonstrated that protein-tyrosine phosphatase 1B (PTP1B) was underexpressed in a panel of ovarian carcinoma-derived cell lines, compared with immortalized human ovarian surface epithelial cell lines. Stable restoration of PTP1B in those cancer cell lines substantially decreased cell migration and invasion, as well as proliferation and anchorage independent survival. Mechanistically, the pro-survival IGF-1R signaling pathway was attenuated upon ectopic expression of PTP1B. This was due to dephosphorylation by PTP1B of IGF-1R beta-subunit and BRK/PTK6, an SRC-like protein-tyrosine kinase that physically and functionally interacts with the IGF 1R beta-subunit. Restoration of PTP1B expression led to enhanced activation of BAD, one of the major pro-death members of the BCL-2 family, which triggered cell death through apoptosis. Conversely, inhibition of PTP1B with a small molecular inhibitor, MSI-1436, increased proliferation and migration of immortalized HOSE cell lines. These data reveal an important role for PTP1B as a negative regulator of BRK and IGF-1Rbeta signaling in ovarian cancer cells. PMID- 23814048 TI - Interaction of glucocorticoid receptor (GR) with estrogen receptor (ER) alpha and activator protein 1 (AP1) in dexamethasone-mediated interference of ERalpha activity. AB - The role of glucocorticoids in the inhibition of estrogen (17-beta-estradiol (E2))-regulated estrogen receptor (ER)-positive breast cancer cell proliferation is well established. We and others have seen that synthetic glucocorticoid dexamethasone (Dex) antagonizes E2-stimulated endogenous ERalpha target gene expression. However, how glucocorticoids negatively regulate the ERalpha signaling pathway is still poorly understood. ChIP studies using ERalpha- and glucocorticoid receptor (GR)-positive MCF-7 cells revealed that GR occupies several ERalpha-binding regions (EBRs) in cells treated with E2 and Dex simultaneously. Interestingly, there was little or no GR loading to these regions when cells were treated with E2 or Dex alone. The E2+Dex-dependent GR recruitment is associated with the displacement of ERalpha and steroid receptor coactivator-3 from the target EBRs leading to the repression of ERalpha-mediated transcriptional activation. The recruitment of GR to EBRs requires assistance from ERalpha and FOXA1 and is facilitated by AP1 binding within the EBRs. The GR binding to EBRs is mediated via direct protein-protein interaction between the GR DNA-binding domain and ERalpha. Limited mutational analyses indicate that arginine 488 located within the C-terminal zinc finger domain of the GR DNA binding domain plays a critical role in stabilizing this interaction. Together, the results of this study unravel a novel mechanism involved in glucocorticoid inhibition of ERalpha transcriptional activity and E2-mediated cell proliferation and thus establish a foundation for future exploitation of the GR signaling pathway in the treatment of ER-positive breast cancer. PMID- 23814049 TI - Transcription factors Sp1 and Hif2alpha mediate induction of the copper transporting ATPase (Atp7a) gene in intestinal epithelial cells during hypoxia. AB - Genes with G/C-rich promoters were up-regulated in the duodenal epithelium of iron-deficient rats including those encoding iron (e.g. Dmt1 and Dcytb) and copper (e.g. Atp7a and Mt1) metabolism-related proteins. It was shown previously that an intestinal copper transporter (Atp7a) was co-regulated with iron transport-related genes by a hypoxia-inducible transcription factor, Hif2alpha. In the current study, we sought to test the role of Sp1 in transcriptional regulation of Atp7a expression during iron deprivation/hypoxia. Initial studies in IEC-6 cells showed that mithramycin, an Sp1 inhibitor, reduced expression of Atp7a and iron transport-related genes (Dmt1, Dcytb, and Fpn1) and blocked their induction by CoCl2, a hypoxia mimetic. Consistent with this, overexpression of Sp1 increased endogenous Atp7a mRNA and protein expression and stimulated Atp7a, Dmt1, and Dcytb promoter activity. Site-directed mutagenesis and functional analysis of a basal Atp7a promoter construct revealed four functional Sp1 binding sites that were necessary for Hif2alpha-mediated induction of promoter activity. Furthermore, chromatin immunoprecipitation (ChIP) assays confirmed that Sp1 specifically interacts with the Atp7a promoter in IEC-6 cells and in rat duodenal enterocytes. This investigation has thus revealed a novel aspect of Atp7a gene regulation in which Sp1 may be necessary for the HIF-mediated induction of gene transcription during iron deficiency/hypoxia. Understanding regulation of Atp7a expression may help further clarify the physiological role of copper in the maintenance of iron homeostasis. Furthermore, this Sp1/Hif2alpha regulatory mechanism may have broader implications for understanding the genetic response of the intestinal epithelium to maintain whole-body iron homeostasis during states of deficiency. PMID- 23814050 TI - Methionine adenosyltransferase 2B, HuR, and sirtuin 1 protein cross-talk impacts on the effect of resveratrol on apoptosis and growth in liver cancer cells. AB - Resveratrol is growth-suppressive and pro-apoptotic in liver cancer cells. Methionine adenosyltransferase 2B (MAT2B) encodes for two dominant variants V1 and V2 that positively regulate growth, and V1 is anti-apoptotic when overexpressed. Interestingly, crystal structure analysis of MAT2B protein (MATbeta) protomer revealed two resveratrol binding pockets, which raises the question of the role of MAT2B in resveratrol biological activities. We found that resveratrol induced the expression of MAT2BV1 and V2 in a time- and dose dependent manner by increasing transcription, mRNA, and protein stabilization. Following resveratrol treatment, HuR expression increased first, followed by SIRT1 and MAT2B. SIRT1 induction contributes to increased MAT2B transcription whereas HuR induction increased MAT2B mRNA stability. MATbeta interacts with HuR and SIRT1, and resveratrol treatment enhanced these interactions while reducing the interaction between MATbeta and MATalpha2. Because MATbeta lowers the Ki of MATalpha2 for S-adenosylmethionine (AdoMet), this allowed steady-state AdoMet level to rise. Interaction among MATbeta, SIRT1, and HuR increased stability of these proteins. Induction of MAT2B is a compensatory response to resveratrol as knocking down MAT2BV1 potentiated the resveratrol pro-apoptotic and growth suppressive effects, whereas the opposite occurred with V1 overexpression. The same effect on growth occurred with MAT2BV2. In conclusion, resveratrol induces HuR, SIRT1, and MAT2B expression; the last may represent a compensatory response against apoptosis and growth inhibition. However, MATbeta induction also facilitates SIRT1 activation, as the interaction stabilizes SIRT1. This complex interplay among MATbeta, HuR, and SIRT1 has not been previously reported and suggests that these proteins may regulate each other's signaling. PMID- 23814051 TI - Dissecting the catalytic mechanism of Trypanosoma brucei trypanothione synthetase by kinetic analysis and computational modeling. AB - In pathogenic trypanosomes, trypanothione synthetase (TryS) catalyzes the synthesis of both glutathionylspermidine (Gsp) and trypanothione (bis(glutathionyl)spermidine (T(SH)2)). Here we present a thorough kinetic analysis of Trypanosoma brucei TryS in a newly developed phosphate buffer system at pH 7.0 and 37 degrees C, mimicking the physiological environment of the enzyme in the cytosol of bloodstream parasites. Under these conditions, TryS displays Km values for GSH, ATP, spermidine, and Gsp of 34, 18, 687, and 32 MUm, respectively, as well as Ki values for GSH and T(SH)2 of 1 mm and 360 MUm, respectively. As Gsp hydrolysis has a Km value of 5.6 mm, the in vivo amidase activity is probably negligible. To obtain deeper insight in the molecular mechanism of TryS, we have formulated alternative kinetic models, with elementary reaction steps represented by linear kinetic equations. The model parameters were fitted to the extensive matrix of steady-state data obtained for different substrate/product combinations under the in vivo-like conditions. The best model describes the full kinetic profile and is able to predict time course data that were not used for fitting. This system's biology approach to enzyme kinetics led us to conclude that (i) TryS follows a ter-reactant mechanism, (ii) the intermediate Gsp dissociates from the enzyme between the two catalytic steps, and (iii) T(SH)2 inhibits the enzyme by remaining bound at its product site and, as does the inhibitory GSH, by binding to the activated enzyme complex. The newly detected concerted substrate and product inhibition suggests that TryS activity is tightly regulated. PMID- 23814052 TI - Essential role for the Mnk pathway in the inhibitory effects of type I interferons on myeloproliferative neoplasm (MPN) precursors. AB - The mechanisms of generation of the antineoplastic effects of interferons (IFNs) in malignant hematopoietic cells remain to be precisely defined. We examined the activation of type I IFN-dependent signaling pathways in malignant cells transformed by Jak2V617F, a critical pathogenic mutation in myeloproliferative neoplasms (MPNs). Our studies demonstrate that during engagement of the type I IFN receptor (IFNAR), there is activation of Jak-Stat pathways and also engagement of Mnk kinases. Activation of Mnk kinases is regulated by the Mek/Erk pathway and is required for the generation of IFN-induced growth inhibitory responses, but Mnk kinase activation does not modulate IFN-regulated Jak-Stat signals. We demonstrate that for type I IFNs to exert suppressive effects in malignant hematopoietic progenitors from patients with polycythemia vera, induction of Mnk kinase activity is required, as evidenced by studies involving pharmacological inhibition of Mnk or siRNA-mediated Mnk knockdown. Altogether, these findings provide evidence for key and essential roles of the Mnk kinase pathway in the generation of the antineoplastic effects of type I IFNs in Jak2V617F-dependent MPNs. PMID- 23814053 TI - Protein phosphatase PPM1G regulates protein translation and cell growth by dephosphorylating 4E binding protein 1 (4E-BP1). AB - Protein translation initiation is a tightly controlled process responding to nutrient availability and mitogen stimulation. Serving as one of the most important negative regulators of protein translation, 4E binding protein 1 (4E BP1) binds to translation initiation factor 4E and inhibits cap-dependent translation in a phosphorylation-dependent manner. Although it has been demonstrated previously that the phosphorylation of 4E-BP1 is controlled by mammalian target of rapamycin in the mammalian target of rapamycin complex 1, the mechanism underlying the dephosphorylation of 4E-BP1 remains elusive. Here, we report the identification of PPM1G as the phosphatase of 4E-BP1. A coimmunoprecipitation experiment reveals that PPM1G binds to 4E-BP1 in cells and that purified PPM1G dephosphorylates 4E-BP1 in vitro. Knockdown of PPM1G in 293E and colon cancer HCT116 cells results in an increase in the phosphorylation of 4E BP1 at both the Thr-37/46 and Ser-65 sites. Furthermore, the time course of 4E BP1 dephosphorylation induced by amino acid starvation or mammalian target of rapamycin inhibition is slowed down significantly in PPM1G knockdown cells. Functionally, the amount of 4E-BP1 bound to the cap-dependent translation initiation complex is decreased when the expression of PPM1G is depleted. As a result, the rate of cap-dependent translation, cell size, and protein content are increased in PPM1G knockdown cells. Taken together, our study has identified protein phosphatase PPM1G as a novel regulator of cap-dependent protein translation by negatively controlling the phosphorylation of 4E-BP1. PMID- 23814054 TI - Substrate specificity of R3 receptor-like protein-tyrosine phosphatase subfamily toward receptor protein-tyrosine kinases. AB - Receptor-like protein-tyrosine phosphatases (RPTPs) are involved in various aspects of cellular functions, such as proliferation, differentiation, survival, migration, and metabolism. A small number of RPTPs have been reported to regulate activities of some cellular proteins including receptor protein-tyrosine kinases (RPTKs). However, our understanding about the roles of individual RPTPs in the regulation of RPTKs is still limited. The R3 RPTP subfamily reportedly plays pivotal roles in the development of several tissues including the vascular and nervous systems. Here, we examined enzyme-substrate relationships between the four R3 RPTP subfamily members and 21 RPTK members selected from 14 RPTK subfamilies by using a mammalian two-hybrid system with substrate-trapping RPTP mutants. Among the 84 RPTP-RPTK combinations conceivable, we detected 30 positive interactions: 25 of the enzyme-substrate relationships were novel. We randomly chose several RPTKs assumed to be substrates for R3 RPTPs, and validated the results of this screen by in vitro dephosphorylation assays, and by cell-based assays involving overexpression and knock-down experiments. Because their functional relationships were verified without exception, it is probable that the RPTKs identified as potential substrates are actually physiological substrates for the R3 RPTPs. Interestingly, some RPTKs were recognized as substrates by all R3 members, but others were recognized by only one or a few members. The enzyme substrate relationships identified in the present study will shed light on physiological roles of the R3 RPTP subfamily. PMID- 23814055 TI - Noncanonical matrix metalloprotease-1-protease-activated receptor-1 signaling triggers vascular smooth muscle cell dedifferentiation and arterial stenosis. AB - Vascular injury that results in proliferation and dedifferentiation of vascular smooth muscle cells (SMCs) is an important contributor to restenosis following percutaneous coronary interventions or plaque rupture. Protease-activated receptor-1 (PAR1) has been shown to play a role in vascular repair processes; however, little is known regarding its function or the relative roles of the upstream proteases thrombin and matrix metalloprotease-1 (MMP-1) in triggering PAR1-mediated arterial restenosis. The goal of this study was to determine whether noncanonical MMP-1 signaling through PAR1 would contribute to aberrant vascular repair processes in models of arterial injury. A mouse carotid arterial wire injury model was used for studies of neointima hyperplasia and arterial stenosis. The mice were treated post-injury for 21 days with a small molecule inhibitor of MMP-1 or a direct thrombin inhibitor and compared with vehicle control. Intimal and medial hyperplasia was significantly inhibited by 2.8-fold after daily treatment with the small molecule MMP-1 inhibitor, an effect that was lost in PAR1-deficient mice. Conversely, chronic inhibition of thrombin showed no benefit in suppressing the development of arterial stenosis. Thrombin-PAR1 signaling resulted in a supercontractile, differentiated phenotype in SMCs. Noncanonical MMP-1-PAR1 signaling resulted in the opposite effect and led to a dedifferentiated phenotype via a different G protein pathway. MMP-1-PAR1 significantly stimulated hyperplasia and migration of SMCs, and resulted in down regulation of SMC contractile genes. These studies provide a new mechanism for the development of vascular intimal hyperplasia and suggest a novel therapeutic strategy to suppress restenosis by targeting noncanonical MMP-1-PAR1 signaling in vascular SMCs. PMID- 23814056 TI - The structure of the ternary complex of Krev interaction trapped 1 (KRIT1) bound to both the Rap1 GTPase and the heart of glass (HEG1) cytoplasmic tail. AB - Loss of function mutation in Krev interaction trapped 1 (KRIT1) causes autosomal dominant familial cerebral cavernous malformations and disrupts cardiovascular development. The biological function of KRIT1 requires that its FERM (band 4.1, ezrin, radixin, moesin) domain physically interact with both the small GTPase Rap1 and the cytoplasmic tail of the Heart of glass (HEG1) membrane anchor. In this study, we show that the KRIT1 FERM domain can bind both Rap1 and HEG1 simultaneously, and we solved the crystal structure of the KRIT1-Rap1-HEG1 ternary complex. Rap1 binds on the surface of the F1 and F2 subdomains, in an interaction that leaves its Switch II region accessible to other potential effectors. HEG1 binds in a hydrophobic pocket at the KRIT1 F1 and F3 interface, and there is no overlap with the Rap1-binding site. Indeed, the affinity of KRIT1 or the KRIT1-Rap1 complex for HEG1 is comparable (Kd = 1.2 and 0.96 MUm, respectively) showing that there is no competition between the two sites. Furthermore, analysis of this structure revealed a specific ionic interaction between the F2 lobe of KRIT1 and Rap1 that could explain the remarkable Rap1 specificity of KRIT1. This structural insight enabled design of KRIT1(K570I), a mutant that binds Rap1 with 8-fold lower affinity and exhibits increased binding to HRas. These data show that HEG1 can recruit the Rap1-KRIT complex to the plasma membrane where Rap1's Switch II region remains accessible and reveals an important determinant of KRIT1's specificity for Rap1. PMID- 23814057 TI - Diacylglycerol kinases terminate diacylglycerol signaling during the respiratory burst leading to heterogeneous phagosomal NADPH oxidase activation. AB - It is commonly assumed that all phagosomes have identical molecular composition. This assumption has remained largely unchallenged due to a paucity of methods to distinguish individual phagosomes. We devised an assay that extends the utility of nitro blue tetrazolium for detection and quantification of NAPDH oxidase (NOX) activity in individual phagosomes. Implementation of this assay revealed that in murine macrophages there is heterogeneity in the ability of individual phagosomes to generate superoxide, both between and within cells. To elucidate the molecular basis of the variability in NOX activation, we employed genetically encoded fluorescent biosensors to evaluate the uniformity in the distribution of phospholipid mediators of the oxidative response. Despite variability in superoxide generation, the distribution of phosphatidylinositol 3,4,5 trisphosphate, phosphatidylinositol 3-phosphate, and phosphatidic acid was nearly identical in all phagosomes. In contrast, diacylglycerol (DAG) was not generated uniformly across the phagosomal population, varying in a manner that directly mirrored superoxide production. Modulation of DAG levels suggested that NOX activation is precluded when phagosomes fail to reach a critical DAG concentration. In particular, forced expression of diacylglycerol kinase beta abrogated DAG accumulation at the phagosome, leading to impaired respiratory burst. Conversely, pharmacological inhibition of DAG kinases or expression of an inactive diacylglycerol kinase beta mutant increased the proportion of DAG positive phagosomes, concomitantly potentiating phagosomal NOX activity. Our data suggest that diacylglycerol kinases limit the extent of NADPH oxidase activation, curtailing the production of potentially harmful reactive oxygen species. The resulting heterogeneity in phagosome responsiveness could enable the survival of a fraction of invading microorganisms. PMID- 23814058 TI - Cyclin-dependent kinase 1-dependent phosphorylation of cAMP response element binding protein decreases chromatin occupancy. AB - The cyclic AMP response element-binding protein (CREB) initiates transcriptional responses to a wide variety of stimuli. CREB activation involves its phosphorylation on Ser-133, which promotes interaction between the CREB kinase inducible domain (KID) and the KID-interacting domain of the transcriptional coactivator, CREB-binding protein (CBP). The KID also contains a highly conserved phosphorylation cluster, termed the ATM/CK cluster, which is processively phosphorylated in response to DNA damage by the coordinated actions of ataxia telangiectasia-mutated (ATM) and casein kinases (CKs) 1 and 2. The ATM/CK cluster phosphorylation attenuates CBP binding and CREB transcriptional activity. Paradoxically, it was recently reported that DNA damage activates CREB through homeodomain-interacting protein kinase 2-dependent phosphorylation of Ser-271 near the CREB bZIP DNA binding domain. In this study we sought to further clarify DNA damage-dependent CREB phosphorylation as well as to explore the possibility that the ATM/CK cluster and Ser-271 synergistically or antagonistically modulate CREB activity. We show that, rather than being induced by DNA damage, Ser-270 and Ser-271 of CREB cophosphorylated in a CDK1-dependent manner during G2/M phase. Functionally, we show that phosphorylation of CREB on Ser-270/Ser-271 during mitosis correlated with reduced CREB chromatin occupancy. Furthermore, CDK1 dependent phosphorylation of CREB in vitro inhibited its DNA binding activity. The combined results suggest that CDK1-dependent phosphorylation of CREB on Ser 270/Ser-271 facilitates its dissociation from chromatin during mitosis by reducing its intrinsic DNA binding potential. PMID- 23814060 TI - Investigations on collectin liver 1. AB - Collectins are pattern recognition molecules of the innate immune system showing binding to carbohydrate structures on microorganisms in a calcium-dependent manner. Recently, three novel collectins, collectin liver 1 (CL-L1), collectin kidney 1 (CL-K1 and CL-11), and collectin placenta 1 (CL-P1), were discovered. The roles of these three collectins remain largely unknown. Here, we present a time-resolved immunofluorometric assay for quantification of CL-L1. The concentration of CL-L1 in donor plasma (n = 210) was distributed log-normally with a median value of 3.0 MUg/ml (range 1.5-5.5 MUg/ml). We observed on average 30% higher concentrations of CL-L1 in plasma as compared with serum. Size analysis by gel-permeation chromatography showed CL-L1 in serum to elute as large 700-800-kDa complexes and smaller 200-300-kDa complexes. CL-L1 showed specific binding to mannose-TSK beads in a Ca(2+)-dependent manner. This binding could be inhibited by mannose and glucose, but not galactose, indicating that CL-L1 binds via its carbohydrate-recognition domain and has ligand specificity similar to that of mannan-binding lectin. Western blot analysis of CL-L1 showed the presence of several oligomeric forms in serum. Ontogeny studies showed CL-L1 to be present at birth at near adult levels. CL-L1 levels exhibit low variation in healthy adults over a 1-year period. During acute-phase responses, the CL-L1 levels display only minor variations. In serum, CL-L1 was found in complexes with mannan binding lectin-associated serine proteases, suggesting a role in the lectin pathway of complement activation. The presented data establish a basis for future studies on the biological role of CL-L1. PMID- 23814059 TI - Direct TFIIA-TFIID protein contacts drive budding yeast ribosomal protein gene transcription. AB - We have previously shown that yeast TFIID provides coactivator function on the promoters of ribosomal protein-encoding genes (RPGs) by making direct contact with the transactivator repressor activator protein 1 (Rap1). Further, our structural studies of assemblies generated with purified Rap1, TFIID, and TFIIA on RPG enhancer-promoter DNA indicate that Rap1-TFIID interaction induces dramatic conformational rearrangements of enhancer-promoter DNA and TFIID-bound TFIIA. These data indicate a previously unknown yet critical role for yeast TFIIA in the integration of activator-TFIID contacts with promoter conformation and downstream preinitiation complex formation and/or function. Here we describe the use of systematic mutagenesis to define how specific TFIIA contacts contribute to these processes. We have verified that TFIIA is required for RPG transcription in vivo and in vitro, consistent with the existence of a critical Rap1-TFIIA-TFIID interaction network. We also identified essential points of contact for TFIIA and Rap1 within the Rap1 binding domain of the Taf4 subunit of TFIID. These data suggest a mechanism for how interactions between TFIID, TFIIA, and Rap1 contribute to the high rate of transcription initiation seen on RPGs in vivo. PMID- 23814061 TI - Polycomb repressive complex 2 (PRC2) protein ESC regulates insect developmental timing by mediating H3K27me3 and activating prothoracicotropic hormone gene expression. AB - The decision made by insects to develop into adults or halt development (enter diapause and prolong lifespan) is commonly based on environmental signals that provide reliable predictors of future seasons of adversity. For example, the short day lengths of early autumn accurately foretell the advent of winter, but little is known about the molecular mechanisms that preside over the hormonal events dictating whether the insect proceeds with development or enters diapause. In Helicoverpa armigera we show that day length affects H3K27me3 by affecting polycomb repressive complex 2 (PRC2) protein extra sex comb (ESC) and regulates the prothoracicotropic hormone (PTTH) gene, thus directly influencing developmental timing. ESC expression in brains of developing (nondiapause) pupae is higher than in brains from diapausing pupae. High ESC expression is localized in two pairs of PTTH neurosecretory cells, and H3K27me3 recruits on the PTTH promoter. Double strand ESC and PRC2 inhibitor (DzNep) treatment in vitro show that ESC triggers PTTH promoter activity, which in turn depends on PRC2 methyltransferase activity. Injection of DzNep into pupae programmed for development reduces the H3K27me3 mark and PTTH gene expression, thereby delaying development. Although ESC is best known as a transcriptional repressor, our results show that ESC prompts development and metamorphosis. We believe this is the first report showing that the PRC2 complex functions as an activator and that a low level of H3K27me3 can prolong lifespan (i.e. induce diapause) by controlling PTTH gene expression in insects. PMID- 23814063 TI - Phosphorylation regulates kinase and microtubule binding activities of the budding yeast chromosomal passenger complex in vitro. AB - The chromosomal passenger complex (CPC) is a key regulator of mitosis in eukaryotes. It comprises four essential and conserved proteins known in mammals/yeasts as Aurora B/Ipl1, INCENP/Sli15, Survivin/Bir1, and Borealin/Nbl1. These subunits act together in a highly controlled fashion. Regulation of Aurora B/Ipl1 kinase activity and localization is critical for CPC function. Although regulation of CPC localization and kinase activity in vivo has been investigated elsewhere, studies on the complete, four-subunit CPC and its basic biochemical properties are only beginning. Here we describe the biochemical characterization of purified and complete Saccharomyces cerevisiae four-subunit CPC. We determined the affinity of the CPC for microtubules and demonstrated that the binding of CPC to microtubules is primarily electrostatic in nature and depends on the acidic C terminal tail (E-hook) of tubulin. Moreover, phosphorylation of INCENP/Sli15 on its microtubule binding region also negatively regulates CPC affinity for microtubules. Furthermore, we show that phosphorylation of INCENP/Sli15 is required for activation of the kinase Aurora B/Ipl1 and can occur in trans. Although phosphorylation of INCENP/Sli15 is essential for activation, we determined that a version of the CPC lacking the INCENP/Sli15 microtubule binding region (residues Glu-91 to Ile-631) is able to form an intact complex that retains microtubule binding activity. Thus, we conclude that this INCENP/Sli15 linker domain plays a largely regulatory function and is not essential for complex formation or microtubule binding. PMID- 23814062 TI - Differential activation of cultured neonatal cardiomyocytes by plasmalemmal versus intracellular G protein-coupled receptor 55. AB - The L-alpha-lysophosphatidylinositol (LPI)-sensitive receptor GPR55 is coupled to Ca(2+) signaling. Low levels of GPR55 expression in the heart have been reported. Similar to other G protein-coupled receptors involved in cardiac function, GPR55 may be expressed both at the sarcolemma and intracellularly. Thus, to explore the role of GPR55 in cardiomyocytes, we used calcium and voltage imaging and extracellular administration or intracellular microinjection of GPR55 ligands. We provide the first evidence that, in cultured neonatal ventricular myocytes, LPI triggers distinct signaling pathways via GPR55, depending on receptor localization. GPR55 activation at the sarcolemma elicits, on one hand, Ca(2+) entry via L-type Ca(2+) channels and, on the other, inositol 1,4,5-trisphosphate dependent Ca(2+) release. The latter signal is further amplified by Ca(2+) induced Ca(2+) release via ryanodine receptors. Conversely, activation of GPR55 at the membrane of intracellular organelles promotes Ca(2+) release from acidic like Ca(2+) stores via the endolysosomal NAADP-sensitive two-pore channels. This response is similarly enhanced by Ca(2+)-induced Ca(2+) release via ryanodine receptors. Extracellularly applied LPI produces Ca(2+)-independent membrane depolarization, whereas the Ca(2+) signal induced by intracellular microinjection of LPI converges to hyperpolarization of the sarcolemma. Collectively, our findings point to GPR55 as a novel G protein-coupled receptor regulating cardiac function at two cellular sites. This work may serve as a platform for future studies exploring the potential of GPR55 as a therapeutic target in cardiac disorders. PMID- 23814064 TI - By ribosome possessed. PMID- 23814065 TI - Niemann-pick type C2 deficiency in human fibroblasts confers robust and selective activation of prostaglandin E2 biosynthesis. AB - Activated fibroblasts, also known as myofibroblasts, are mediators of several major human pathologies including proliferative fibrotic disorders, invasive tumor growth, rheumatoid arthritis, and atherosclerosis. We previously identified Niemann-Pick type C2 (NPC2) protein as a negative regulator of fibroblast activation (Csepeggi, C., Jiang, M., Kojima, F., Crofford, L. J., and Frolov, A. (2011) J. Biol. Chem. 286, 2078-2087). Here we report that NPC2-deficiency leads to a dramatic up-regulation of the arachidonic acid (AA) metabolic pathway in human fibroblasts. The major enzymes in this pathway, cPLA2 type IVA, COX-2, and mPGES-1, were dramatically up-regulated at both the transcriptional and translational levels. The specific phenotypic changes resulted in a >10-fold increase in the production and secretion of a key modulator of inflammation and immunity, prostaglandin E2. More importantly, AA metabolome profiling by liquid chromatography/tandem mass-spectrometry revealed the very specific nature of prostaglandin E2 up-regulation as the other analyzed AA metabolites derived from the COX-2, cytochrome P450, 5/15-lipoxygenase, and non-enzymatic oxidative pathways were mostly down-regulated. Blocking activity of cPLA2 efficiently suppressed expression of inflammatory cytokines, IL-1beta and IL-6, thereby identifying cPLA2 as an important regulator of the inflammatory program in NPC2 null cells. Altogether, these studies highlight NPC2 as a specific regulator of AA metabolism and inflammation that suggests potential for NPC2 protein or its related signaling in the treatment of inflammatory diseases characterized by the presence of activated fibroblasts. PMID- 23814066 TI - Autoactivation of mouse trypsinogens is regulated by chymotrypsin C via cleavage of the autolysis loop. AB - Chymotrypsin C (CTRC) is a proteolytic regulator of trypsinogen autoactivation in humans. CTRC cleavage of the trypsinogen activation peptide stimulates autoactivation, whereas cleavage of the calcium binding loop promotes trypsinogen degradation. Trypsinogen mutations that alter these regulatory cleavages lead to increased intrapancreatic trypsinogen activation and cause hereditary pancreatitis. The aim of this study was to characterize the regulation of autoactivation of mouse trypsinogens by mouse Ctrc. We found that the mouse pancreas expresses four trypsinogen isoforms to high levels, T7, T8, T9, and T20. Only the T7 activation peptide was cleaved by mouse Ctrc, causing negligible stimulation of autoactivation. Surprisingly, mouse Ctrc poorly cleaved the calcium binding loop in all mouse trypsinogens. In contrast, mouse Ctrc readily cleaved the Phe-150-Gly-151 peptide bond in the autolysis loop of T8 and T9 and inhibited autoactivation. Mouse chymotrypsin B also cleaved the same peptide bond but was 7-fold slower. T7 was less sensitive to chymotryptic regulation, which involved slow cleavage of the Leu-149-Ser-150 peptide bond in the autolysis loop. Modeling indicated steric proximity of the autolysis loop and the activation peptide in trypsinogen, suggesting the cleaved autolysis loop may directly interfere with activation. We conclude that autoactivation of mouse trypsinogens is under the control of mouse Ctrc with some notable differences from the human situation. Thus, cleavage of the trypsinogen activation peptide or the calcium binding loop by Ctrc is unimportant. Instead, inhibition of autoactivation via cleavage of the autolysis loop is the dominant mechanism that can mitigate intrapancreatic trypsinogen activation. PMID- 23814068 TI - Reefer madness: doctors need more drugs training. PMID- 23814067 TI - Trimeric Tn antigen on syndecan 1 produced by ppGalNAc-T13 enhances cancer metastasis via a complex formation with integrin alpha5beta1 and matrix metalloproteinase 9. AB - We demonstrated previously that ppGalNAc-T13 (T13), identified as an up-regulated gene with increased metastasis in a DNA microarray, generated trimeric Tn (tTn) antigen (GalNAcalpha1-Ser/Thr)3 on Syndecan 1 in highly metastatic sublines of Lewis lung cancer. However, it is not known how tTn antigen regulates cancer metastasis. Here, we analyzed the roles of tTn antigen in cancer properties. tTn antigen on Syndecan 1 increased cell adhesion to fibronectin in an integrin dependent manner. Furthermore, cell adhesion to fibronectin induced phosphorylation of focal adhesion kinase and paxillin in T13-transfectant cells. In the search of Syndecan 1-interacting molecules, it was demonstrated that tTn antigen-carrying Syndecan 1 interacted with integrin alpha5beta1 and matrix metalloproteinase 9 and that these molecules shifted to a glycolipid-enriched microdomain/rafts along with increased metastatic potential in T13-transfectant cells. We also identified a tTn substitution site on Syndecan 1, demonstrating that tTn on Syndecan 1 is essential for the interaction with integrin alpha5beta1 as well as for the reaction with mAb MLS128. These data suggest that high expression of the ppGalNAc-T13 gene generates tTn antigen on Syndecan 1 under reduced expression of GM1, leading to enhanced invasion and metastasis via the formation of a molecular complex consisting of integrin alpha5beta1, Syndecan 1, and MMP-9 in the glycolipid-enriched microdomain/rafts. PMID- 23814069 TI - Mental health service system improvement: translating evidence into policy. PMID- 23814070 TI - Electroconvulsive therapy in a patient with drug-resistant depression and thyroid hormone imbalance. PMID- 23814071 TI - Willingness to disclose a mental disorder and knowledge of disorders in others: changes in Australia over 16 years. AB - OBJECTIVE: To assess whether willingness to disclose experience of a mental disorder and treatment, and awareness of others' experiences have changed over a 16-year period. METHODS: In 2011, telephone interviews were carried out with 6019 Australians aged 15+. The survey interview used the same questions as those of the 1995 and 2003/4 national mental health literacy surveys, in which participants were presented with a case vignette describing either depression, depression with suicidal thoughts (2003/4 only), early schizophrenia or chronic schizophrenia (2003/4 only). Participants were asked whether they had a close friend or family member who had experienced a problem similar to that described in the vignette and whether the person received professional help. They were also asked whether they had experienced such a problem and whether they received professional help. RESULTS: The numbers of those disclosing experiences of depression and early schizophrenia, and of having received professional help for depression, have increased since 1995. Awareness of a family member or close friend with experiences of depression and early schizophrenia also increased between these years, as did awareness that the person received professional help. CONCLUSIONS: The numbers of those disclosing experiences of and treatment for mental disorders has increased in the last 16 years. This is likely to be due to increased willingness to disclose rather than increased prevalence of disorders or increased rates of help-seeking. PMID- 23814072 TI - Is it just motion that silences awareness of other visual changes? AB - When an array of visual elements is changing color, size, or shape incoherently, the changes are typically quite visible even when the overall color, size, or shape statistics of the field may not have changed. When the dots also move, however, the changes become much less apparent; awareness of them is "silenced" (Suchow & Alvarez, 2011). This finding might indicate that the perception of motion is of particular importance to the visual system, such that it is given priority in processing over other forms of visual change. Here we test whether that is the case by examining the converse: whether awareness of motion signals can be silenced by potent coherent changes in color or size. We find that they can, and with very similar effects, indicating that motion is not critical for silencing. Suchow and Alvarez's dots always moved in the same direction with the same speed, causing them to be grouped as a single entity. We also tested whether this coherence was a necessary component of the silencing effect. It is not; when the dot speeds are randomly selected, such that no coherent motion is present, the silencing effect remains. It is clear that neither motion nor grouping is directly responsible for the silencing effect. Silencing can be generated from any potent visual change. PMID- 23814073 TI - A Bayesian model of lightness perception that incorporates spatial variation in the illumination. AB - The lightness of a test stimulus depends in a complex manner on the context in which it is viewed. To predict lightness, it is necessary to leverage measurements of a feasible number of contextual configurations into predictions for a wider range of configurations. Here we pursue this goal, using the idea that lightness results from the visual system's attempt to provide stable information about object surface reflectance. We develop a Bayesian algorithm that estimates both illumination and reflectance from image luminance, and link perceived lightness to the algorithm's estimates of surface reflectance. The algorithm resolves ambiguity in the image through the application of priors that specify what illumination and surface reflectances are likely to occur in viewed scenes. The prior distributions were chosen to allow spatial variation in both illumination and surface reflectance. To evaluate our model, we compared its predictions to a data set of judgments of perceived lightness of test patches embedded in achromatic checkerboards (Allred, Radonjic, Gilchrist, & Brainard, 2012). The checkerboard stimuli incorporated the large variation in luminance that is a pervasive feature of natural scenes. In addition, the luminance profile of the checks both near to and remote from the central test patches was systematically manipulated. The manipulations provided a simplified version of spatial variation in illumination. The model can account for effects of overall changes in image luminance and the dependence of such changes on spatial location as well as some but not all of the more detailed features of the data. PMID- 23814075 TI - Memory color of natural familiar objects: effects of surface texture and 3-D shape. AB - Natural objects typically possess characteristic contours, chromatic surface textures, and three-dimensional shapes. These diagnostic features aid object recognition, as does memory color, the color most associated in memory with a particular object. Here we aim to determine whether polychromatic surface texture, 3-D shape, and contour diagnosticity improve memory color for familiar objects, separately and in combination. We use solid three-dimensional familiar objects rendered with their natural texture, which participants adjust in real time to match their memory color for the object. We analyze mean, accuracy, and precision of the memory color settings relative to the natural color of the objects under the same conditions. We find that in all conditions, memory colors deviate slightly but significantly in the same direction from the natural color. Surface polychromaticity, shape diagnosticity, and three dimensionality each improve memory color accuracy, relative to uniformly colored, generic, or two dimensional shapes, respectively. Shape diagnosticity improves the precision of memory color also, and there is a trend for polychromaticity to do so as well. Differently from other studies, we find that the object contour alone also improves memory color. Thus, enhancing the naturalness of the stimulus, in terms of either surface or shape properties, enhances the accuracy and precision of memory color. The results support the hypothesis that memory color representations are polychromatic and are synergistically linked with diagnostic shape representations. PMID- 23814074 TI - Contrast magnitude and polarity effects on color filling-in along cardinal color axes. AB - Color filling-in is the phenomenon in which the color of a visual area is perceived as the color that is only presented in an adjacent area. In a stimulus with multiple edges, color filling-in can occur along any edge and in both centripetal and centrifugal directions when maintaining steady fixation. The current study aimed to investigate the role of chromatic contrast magnitude and polarity along the two chromaticity cardinal axes and the interaction of the axes in the color filling-in process. In Experiment 1, the color filling-in process was examined using stimuli with three different regions and two edges. The three regions had chromaticities that varied only in one of the chromaticity axes. In Experiment 2, the regions along both edges differed in chromaticity along both axes. The results showed that the contrast magnitudes and polarity relationship of the two edges worked together to determine the filled-in direction and time course of the filled-in percepts. Further, the results pointed to a common mechanism mediating the color filling-in process along the two cardinal axes, and the two axes did not act independently in this process. PMID- 23814076 TI - A diagnostic intravenous urogram. PMID- 23814077 TI - Preventable diabetes complications are still occurring in hospitals, audit finds. PMID- 23814078 TI - Cell cycle-dependent subcellular translocation of the human DNA licensing inhibitor geminin. AB - Once per cell cycle replication is crucial for maintaining genome integrity. Geminin interacts with the licensing factor Cdt1 to prevent untimely replication and is controlled by APC/C-dependent cell cycle specific proteolysis during mitosis and in G1. We show here that human geminin, when expressed in human cells in culture under a constitutive promoter, is excluded from the nucleus during part of the G1 phase and at the transition from G0 to G1. The N-terminal 30 amino acids of geminin, which contain its destruction box, are essential for nuclear exclusion. In addition, 30 amino acids within the central domain of geminin are required for both nuclear exclusion and nuclear accumulation. Cdt1 overexpression targets geminin to the nucleus, while reducing Cdt1 levels by RNAi leads to the appearance of endogenous geminin in the cytoplasm. Our data propose a novel means of regulating the balance of Cdt1/geminin in human cells, at the level of the subcellular localization of geminin. PMID- 23814080 TI - An overview of respiratory problems in children with Down's syndrome. AB - Respiratory disease is a common cause of morbidity and mortality in children with Down's syndrome (DS). Causes range from those problems common to many children with DS, such as a narrow airway or impaired immunity, to rare structural lesions, such as tracheal bronchus. Additionally, other organ systems or extrinsic factors may play a role. A thorough understanding of the range of potential problems will aid in the evaluation and management of children with DS and respiratory symptoms. PMID- 23814079 TI - Dual roles of the transcription factor grainyhead-like 2 (GRHL2) in breast cancer. AB - Using a retrovirus-mediated cDNA expression cloning approach, we identified the grainyhead-like 2 (GRHL2) transcription factor as novel protooncogene. Overexpression of GRHL2 in NIH3T3 cells induced striking morphological changes, an increase in cell proliferation, anchorage-independent growth, and tumor growth in vivo. By combining a microarray analysis and a phylogenetic footprinting analysis with various biochemical assays, we identified the epidermal growth factor receptor family member Erbb3 as a novel GRHL2 target gene. In breast cancer cell lines, shRNA-mediated knockdown of GRHL2 expression or functional inactivation of GRHL2 using dominant negative GRHL2 proteins induces down regulation of ERBB3 gene expression, a striking reduction in cell proliferation, and morphological and phenotypical alterations characteristic of an epithelial-to mesenchymal transition (EMT), thus implying contradictory roles of GRHL2 in breast carcinogenesis. Interestingly, we could further demonstrate that expression of GRHL2 is directly suppressed by the transcription factor zinc finger enhancer-binding protein 1 (ZEB1), which in turn is a direct target for repression by GRHL2, suggesting that the EMT transcription factors GRHL2 and ZEB1 form a double negative regulatory feedback loop in breast cancer cells. Finally, a comprehensive immunohistochemical analysis of GRHL2 expression in primary breast cancers showed loss of GRHL2 expression at the invasive front of primary tumors. A pathophysiological relevance of GRHL2 in breast cancer metastasis is further demonstrated by our finding of a statistically significant association between loss of GRHL2 expression in primary breast cancers and lymph node metastasis. We thus demonstrate a crucial role of GRHL2 in breast carcinogenesis. PMID- 23814081 TI - Superior mesenteric artery syndrome: a rare complication in a child with Marfan syndrome. PMID- 23814082 TI - Recognition, assessment and management of eosinophilic oesophagitis. AB - Eosinophilic oesophagitis (EO) is a chronic immune/antigen-mediated oesophageal disease, with the immune reaction most likely directed to foods but on occasion also to aeroallergens. Clinically, it is characterised by symptoms of oesophageal dysfunction in subjects who typically have other indicators of an atopic tendency. Older children (and adults) frequently present with dysphagia and can have strictures (which may require dilatation). The diagnosis is dependent on an eosinophil-predominant oesophageal inflammation, with 15 or more eosinophils per high-powered field, now generally accepted as a necessary cut-off level of infiltration, which together with other clinical data (eg, oesophageal pH/impedance studies) can help discriminate EO from other potential causes of symptoms such as gastro-oesophageal reflux disease. Recommended therapies, which may need to be long term, are dietary antigen exclusion (with elemental feeds or an exclusion diet) and/or topical corticosteroids. PMID- 23814083 TI - Breast feeding, causal effects and inequalities. PMID- 23814084 TI - A short guide to understanding behavioural difficulties. AB - An approach to behaviour problems presenting in a paediatric context is described. This model aims to generate a form of understanding that is not only accessible but can also generate management strategies. PMID- 23814085 TI - Management of reflex anoxic seizures in children. AB - Reflex anoxic seizures (RAS) are important in the differential diagnosis of non epileptic paroxysmal events in infants and preschool-aged children. They are classically provoked by a sudden distressing stimulus, which causes loss of consciousness followed by stiffening and brief clonic movements affecting some or all limbs, often misinterpreted as an epileptic seizure. The underlying pathophysiology is a vagal-induced brief cardiac asystole with resultant transient cerebral hypoperfusion. Parents and carers who witness the event are understandably anxious, and the mainstay of management are ensuring the appropriate timely diagnosis of RAS and excluding cardiac arrhythmia. A detailed history from a witness is all that is needed to diagnose this condition and investigations like EEG or neuroimaging should be avoided. Education and reassurance remain the mainstay in the management. Some children benefit from medical treatment with atropine or fluoxetine; however, there is a lack of evidence for pharmacological treatment. Cardiac pacing is the only definitive treatment, and is reserved for frequent, severe cases in joint consultation with the cardiologist. PMID- 23814086 TI - Engaging young people in treatment after self-harm. PMID- 23814087 TI - Hypoxic challenge test applied to healthy children: influence of body positions and exertion on pulse oximetric saturation. AB - BACKGROUND: Commercial aircraft are pressurised to ~2438 m (8000 ft) above sea level that equates breathing 15% oxygen at sea level. A preflight hypoxic challenge test (HCT) is therefore recommended for children with cystic fibrosis or other chronic lung diseases and inflight oxygen is advised if pulse oximetric saturation (SpO2) decreases <90%. OBJECTIVE: Study responses to a modified HCT, encompassing various body positions and light physical activity, reflecting relevant activities of children during flight, with a view to challenge the evidence of the current cut-off. METHODS: Oxygenation, heart rate and ventilation were observed in 34 healthy schoolchildren (17 boys) undergoing a modified HCT, alternating between breathing room air and 15% oxygen in nitrogen while seated, supine, standing and walking at 3 km/h and 5 km/h. RESULTS: Nadir SpO2 <90%, median (range), occurred in 9 subjects sitting, 89% (78-89%); 6 supine, 88.5% (87 89%); 9 standing, 89% (85-89%); 23 walking 3 km/h, 87% (74-89%); and 21 walking 5 km/h, 86% (74-89%). Total time <90% for these subjects in seconds was 20 (10-80) sitting, 30 (10-190) supine, 50 (10-150) standing, 80 (10-260) walking 3 km/h and 125 (10-300) walking 5 km/h. Light exercise in general led to lower SpO2: 91% (77 96%), p<0.0001. CONCLUSIONS: A modified HCT led to moments of desaturation below 90% in various body positions at rest and during light physical activity in healthy schoolchildren. It is questionable whether the international recommended cut-off of 90% for children with chronic lung disease reflects clinical oxygen dependence during flights. PMID- 23814088 TI - Investigating microcephaly. AB - 1. Microcephaly is a clinical finding, not a 'disease', and is a crude but trusted assessment of intracranial brain volume. 2. Developmental processes reducing in utero neuron generation present at birth with 'Primary microcephaly'. 3. 'Secondary microcephaly' develops after birth and predominantly reflects dendritic or white matter diseases. 4. Microcephalic conditions have a heterogeneous aetiology, but increasingly genomic tests are available that allow an exact diagnosis. PMID- 23814090 TI - Nebulised DNase post-therapeutic bronchoalveolar lavage in near fatal asthma exacerbation in an adult patient refractory to conventional treatment. AB - Mucus plugging plays a vital role in the pathophysiology of fatal and near fatal asthma as demonstrated in various postmortem studies. There is a paucity of published literature on how to manage mucus plugging in adult patients with refractory asthma exacerbation not responding to conventional therapies as compared with its paediatric cohort. We describe a dramatic improvement with the use of rhDNase, following bronchoalveolar lavage in an intubated adult female patient, with status asthmaticus refractory to conventional treatment. PMID- 23814089 TI - Acute phenytoin intoxication in a 4-year-old mimicking viral meningoencephalitis. AB - We report here the case of a 4-year-old female preschooler who presented to the emergency department with generalised tonic-clonic convulsions and history of vomiting, irritability and dysarthria of short duration. On examination she was found to be responsive only to painful stimulus, had terminal neck stiffness and bilateral extensor plantars. In view of her clinical presentation, an initial diagnosis of viral meningoencephalitis was made in the emergency room and the child treated accordingly. On subsequent transfer to the intensive care unit (ICU), the parents revealed additional history of an elder sibling taking phenytoin for seizures. Therefore, a suspicion of acute phenytoin toxicity was made and phenytoin levels sent for confirmation. Her serum phenytoin level was 80 MUgm/mL (normal: 10-20). The child was managed conservatively and discharged after 5 days of hospitalisation. We chose to report this case to highlight the unusual presentation of this rare intoxication. PMID- 23814091 TI - Chasing the ACE of hearts. AB - A case study of a patient presenting with acute pulmonary oedema, dynamic ECG changes and a rise in cardiac biomarkers with no evidence of myocardial infarction. The clinical course followed a dynamic and inflammatory disease process with evidence of sarcoidosis on tissue histology. The patient had an excellent clinical response to corticosteroid therapy with minimal evidence of hyperenhancement (focal fibrosis) on cardiac MRI at 6 months. The case highlights the challenges in making a new diagnosis of sarcoidosis where involvement appears limited to the heart and lymphatic system. PMID- 23814092 TI - Osler-Weber-Rendu syndrome during pregnancy. AB - Osler-Weber-Rendu syndrome is a very rare systemic fibrovascular dysplasia. Rupture of angiomas can cause haemorrhages, which sometimes can be severe with difficult bleeding control. The main manifestation is recurrent epistaxis. Treatment of this disorder is symptomatic. During pregnancy, there may be an increased risk of complications. We describe a case of a pregnant woman with Osler-Weber-Rendu syndrome. Besides frequent epistaxis and microcytic hypochromic anaemia that resolved with oral iron treatment, she had a normal pregnancy, vaginal delivery and puerperium without complications. PMID- 23814093 TI - Lymphangioma: surrounding the ovarian vein and ovary. AB - Lymphangiomas are usually benign lesions seen in the head and neck region in children. Intra-abdominal localisation is rare and the majority of these cases are in early childhood. Retroperitoneal lymphangiomas constitute approximately 1% of all lymphangiomas. They are generally diagnosed incidentally, may be asymptomatic or may present with a palpable abdominal mass. A limited number of cases of ovarian lymphangiomas have been reported in women, whereas there are no reported cases of paraovarian localisation. We present a rare case of lymphangioma located in bilateral paraovarian region and along the left ovarian vein with radiological findings. PMID- 23814094 TI - Toxicokinetics/Toxicodynamics of gamma-hydroxybutyrate-ethanol intoxication: evaluation of potential treatment strategies. AB - gamma-Hydroxybutyrate (GHB), a common drug of abuse, is often coingested with ethanol. Increasing renal clearance via monocarboxylate transporter (MCT) inhibition represents a potential therapeutic strategy in GHB overdose, as does inhibition of GABAB receptors. In this study, we investigate toxicokinetic/toxicodynamic interactions between GHB-ethanol and efficacy of treatment options for GHB-ethanol intoxication in rats. Sedation was assessed using the endpoint of return-to-righting reflex. Respiration was assessed using plethysmography. Coadministration of 2.0 g/kg ethanol i.v. with 600 mg/kg GHB i.v. increased sleep time compared with GHB alone. Administration of ethanol to steady-state concentrations of 0.1-0.2% and 0.3-0.4% (w/v) did not affect toxicokinetics of 600 mg/kg GHB i.v., or respiratory rate, but did result in significantly lower peak tidal volumes compared with GHB alone. Oral administration of 2.5 g/kg ethanol had no significant effect on toxicokinetics of 1500 mg/kg orally administered GHB. Pretreatment with specific receptor inhibitors indicated no effect of GABAA receptor inhibition on sleep time or respiratory depression in GHB-ethanol intoxication. GABAB receptor inhibition partially prevented sedation and completely prevented respiratory depression. Ethanol increased fatality when administered at 0.1-0.2% (4 of 10) and 0.3-0.4% (9 of 10) versus 1500 mg/kg GHB i.v. alone (0 of 10). Treatment with the MCT inhibitor, l-lactate, significantly decreased sleep time after GHB-ethanol and decreased fatality at 0.1-0.2% (0 of 10) and 0.3-0.4% ethanol (5 of 10). Treatment with a GABAB receptor antagonist completely prevented fatality at 0.3 0.4% (0 of 10). These data indicate that ethanol potentiates the sedative and respiratory depressant effects of GHB, increasing the risk of fatality. MCT and GABAB receptor inhibition represent potentially effective treatments in GHB ethanol intoxication. PMID- 23814096 TI - Prevalence of polycystic ovary syndrome in women in China: a large community based study. AB - STUDY QUESTION: What is the prevalence of polycystic ovary syndrome (PCOS) in Han Chinese women from different communities? SUMMARY ANSWER: The prevalence of PCOS in Chinese women aged 19-45 years is 5.6%. WHAT IS KNOWN ALREADY: The prevalence of PCOS is reported to range from 5 to 10% but to the best of our knowledge the Han Chinese population has not been studied. STUDY DESIGN, SIZE, DURATION: A large-scale epidemiological study was carried out between October 2007 and September 2011 in 15 924 Han Chinese women of reproductive age (19-45 years) from the 10 provinces and municipalities in China. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 16 886 women from 152 cities and 112 villages were involved in the study. All study participants received a questionnaire and underwent a physical and transvaginal ultrasound examination. Blood samples were collected from a subsample of women (n = 3565) for analysis of metabolic markers and hormones. Based on the Rotterdam PCOS criteria, we assessed hyperandrogenism (H), chronic anovulation (O) and polycystic ovaries (P). Following diagnosis, women with PCOS were assigned to one of four different phenotypes. Finally, the prevalence and related risks of PCOS among Chinese women were estimated based on all the data sources. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 16 886 women were initially involved in the study and 15 924 eligible participants then completed the study; the overall response rate was 94.3% (15 924/16 886). The prevalence of PCOS in the Chinese community population was 5.6% (894/15 924). Blood samples were analyzed from 833 of these women who were assigned to the four PCOS phenotypes as follows: 19% H + O, 37% H + P, 15% O + P and 29% H + O + P. Comparing the 833 women with PCOS to 2732 women without PCOS indicated that PCOS occurs in younger women (P < 0.05) and these women were prone not only to menstrual problems, hyperandrogenism, PCO and infertility but also metabolic syndrome (MS) and insulin resistance (IR). However, there was no significant difference in the rate of hypertension or hyperlipemia between the two groups. Obese patients with PCOS had a higher rate of MS (16 versus 48%), IR (7 versus 28%), hypertension (8 versus 30%) and hyperlipemia (48 versus 73%) compared with non-obese patients (all P < 0.05), respectively. The rates of metabolic complications in patients with PCOS increased with age. LIMITATIONS, REASONS FOR CAUTION: Age and ethnic origin contribute to the differing manifestations of PCOS; therefore, sampling is one of the most important issues in epidemiological research into PCOS. Owing to the mobility of the Chinese population, the survey among resident populations caused a certain deviation in the age distribution. WIDER IMPLICATIONS OF THE FINDINGS: The prevention and treatment of PCOS, particularly in those who are obese, are essential in Chinese women of reproductive age. PMID- 23814097 TI - Higher prevalence of gestational diabetes mellitus following assisted reproduction technology treatment. AB - STUDY QUESTION: Do mothers following assisted reproduction technology (ART) treatment have increased likelihood of gestational diabetes mellitus (GDM) compared with non-ART mothers after controlling for maternal factors and plurality? SUMMARY ANSWER: ART mothers had 28% increased likelihood of GDM compared with non-ART mothers. WHAT IS KNOWN ALREADY: Advanced maternal age and multiple pregnancies are independently associated with increased likelihood of GDM. Given the average age of mothers having ART treatment is higher than non-ART mothers and the higher multiple pregnancy rate following ART treatment, ART treatment might be expected to be associated with increased risk of GDM. STUDY DESIGN, SIZE, DURATION: A population retrospective cohort study of 400 392 mothers who gave birth in Australia between 2007 and 2009, using the Australian National Perinatal Data Collection from five states (Australian Capital Territory, Queensland, Tasmania, Victoria and Western Australia) where a code for ART treatment is available. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study included 13 732 ART mothers and 386 660 non-ART mothers. The prevalence of GDM was compared between ART and non-ART mothers. Logistic regressions were used to assess the association between ART treatment and GDM. Odds ratio (OR), adjusted OR (AOR) and 95% confidence interval (CI) were calculated. MAIN RESULTS AND THE ROLE OF CHANCE: A larger proportion of ART mothers were aged >=40 years compared with non-ART counterpart (11.7 versus 3.4%, P < 0.01). The prevalence of GDM was 7.6% for ART mothers and 5.0% for non-ART mothers (P < 0.01). Mothers who had twins had higher prevalence of GDM than those who gave births to singletons (8.8 versus 7.5%, P = 0.06 for ART mothers; and 7.3 versus 5.0%, P < 0.01 for non-ART mothers). Overall, ART mothers had a 28% increased likelihood of GDM compared with non-ART mothers (AOR 1.28, 95% CI 1.20-1.37). Of mothers who had singletons, ART mothers had higher odds of GDM than non-ART mothers (AOR 1.26, 95% CI 1.18 1.36). There was no significant difference in the likelihood of GDM among mothers who had twins between ART and non-ART (AOR 1.18, 95% CI 0.94-1.48). For mothers aged <40 years, the younger the maternal age, the higher the odds of GDM for ART singleton mothers compared with non-ART singleton mothers. LIMITATIONS, REASONS FOR CAUTION: It was not possible to investigate which ART procedure is associated with increased risk of GDM and how the risk could have been minimized. The information on BMI and smoking during pregnancy was not stated for a large proportion of mothers. These limitations may have reduced the validity of the study. WIDER IMPLICATIONS OF THE FINDINGS: In agreement with other studies, our data suggest that the underlying cause of subfertility and some particular ART procedures might have played an important role in the increased likelihood of GDM. Together with the public education on not delaying motherhood, minimizing multiple pregnancies by applying single embryo transfer may diminish the excess risk of GDM related to ART treatment. PMID- 23814095 TI - Vitamin D3 inhibits expression and activities of matrix metalloproteinase-2 and 9 in human uterine fibroid cells. AB - STUDY QUESTION: Can biologically active vitamin D3 [1,25(OH)2D3] regulate the expression and activity of matrix metalloproteinases (MMPs) in human uterine fibroid cells? SUMMARY ANSWER: 1,25(OH)2D3 effectively reduced the expression and activities of MMP-2 and MMP-9 in cultured human uterine fibroid cells. WHAT IS KNOWN ALREADY: Uterine fibroids (leiomyoma) express higher levels of MMP activity than adjacent normal myometrium, and this is associated with uterine fibroid pathogenesis. However, it is unknown whether 1,25(OH)2D3 can regulate the expression and activities of MMPs in human uterine fibroid cells. STUDY DESIGN, SIZE, DURATION: Surgically removed fresh fibroid tissue was used to generate primary uterine fibroid cells. PARTICIPANTS/MATERIALS, SETTING, METHODS: An immortalized human uterine fibroid cell line (HuLM) and/or primary human uterine fibroid cells isolated from fresh fibroid tissue were used to examine the expression of several MMPs, tissue inhibitors of metalloproteinases (TIMP) 1 and 2 and the activities of MMP-2 and MMP-9 after 1,25(OH)2D3 treatment. Real-time PCR and western blots analyses were used to measure mRNA and protein expression of MMPs, respectively. Supernatant cell culture media were analyzed for MMP-2 and MMP-9 activities using a gelatin zymography assay. MAIN RESULTS AND THE ROLE OF CHANCE: 1-1000 nM 1,25(OH)2D3 significantly reduced mRNA levels of MMP-2 and MMP 9 in HuLM cells in a concentration-dependent manner (P < 0.5 to P < 0.001). The mRNA levels of MMP-1, MMP-3, MMP-13 and MMP-14 in HuLM cells were also reduced by 1,25(OH)2D3. 1,25(OH)2D3 significantly reduced MMP-2 and MMP-9 protein levels in a concentration-dependent manner in both HuLM and primary uterine fibroid cells (P < 0.05 to P < 0.001). Moreover, 1,25(OH)2D3 increased the mRNA levels of vitamin D receptor (VDR) and TIMP-2 in a concentration-dependent manner in HuLM cells (P < 0.05 to P < 0.01). 1,25(OH)2D3 also significantly increased protein levels of VDR and TIMP-2 in all cell types tested (P < 0.05 to P < 0.001). Gelatin zymography revealed that pro-MMP-2, active MMP-2 and pro-MMP-9 were down regulated by 1,25(OH)2D3 in a concentration-dependent manner; however, the active MMP-9 was undetectable. LIMITATIONS, REASONS FOR CAUTION: This study was performed using in vitro uterine fibroid cell cultures and the results were extrapolated to in vivo situation of uterine fibroids. Moreover, in this study the interaction of vitamin D3 with other regulators such as steroid hormone receptors was not explored. WIDER IMPLICATIONS OF THE FINDINGS: This study reveals an important biological function of 1,25(OH)2D3 in the regulation of expression and activities of MMP-2 and MMP-9. Thus, 1,25(OH)2D3 might be a potential effective, safe non-surgical treatment option for human uterine fibroids. PMID- 23814098 TI - The chemokine CXCL6 restricts human trophoblast cell migration and invasion by suppressing MMP-2 activity in the first trimester. AB - STUDY QUESTION: Can the chemokine CXCL6 affect trophoblast cell migration and invasion in human first-trimester placenta? SUMMARY ANSWER: Chemokine CXCL6 inhibits trophoblast cell migration and invasion by suppressing matrix metalloproteinase (MMP)-2 activity in human first-trimester placenta. WHAT IS KNOWN ALREADY: Several chemokines including CXCL8, CXCL12, CXCL14, CXCL16, CX3CL1, CCL14 and CCL4 can promote or inhibit trophoblast cell migration and invasion in human first-trimester placenta. STUDY DESIGN, SIZE, DURATION: We used the trophoblast cell line HTR8/SVneo cells, primary trophoblast cells and villi explants to investigate the effect of rhCXCL6 on trophoblast cell migration and invasion. PARTICIPANTS/MATERIALS, SETTING, METHODS: First, the CXCL6 RNA transcript level was detected in HTR8/SVneo cells derived from human first trimester, second-trimester and third-trimester placenta by RT-PCR. Protein expression of CXCL6 and its receptors was tested in first-trimester placenta by immunohistochemistry. Secreted CXCL6 protein was detected in HTR8/SVneo cell supernatants by enzyme-linked immunosorbent assay. Secondly, the effect of rhCXCL6 on HTR8/SVneo cell proliferation was assessed by the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Thirdly, the effect of rhCXCL6 on cell migration and invasion of HTR8/SVneo cells, primary trophoblast cells and villi explants was tested by transwell migration and invasion assays, respectively. Last, MMP-2 and MMP-9 activity in the supernatants of HTR8/SVneo and primary trophoblast cells treated by rhCXCL6 in the invasion assay was assessed by gelatin zymography. MAIN RESULTS AND THE ROLE OF CHANCE: Abundance of the CXCL6 RNA transcript increased with pregnancy development. CXCL6 and its receptor were expressed in several cells at the human maternal-fetal interface. RhCXCL6 inhibited trophoblast cell migration and invasion by suppressing MMP-2 activity. LIMITATIONS, REASONS FOR CAUTION: These experiments are only in vitro. WIDER IMPLICATIONS OF THE FINDINGS: According to the literature, CXCL6 could promote tumour cell migration and invasion by accelerating MMP-9 activity. However, CXCL6 inhibited trophoblast cell migration and invasion by suppressing MMP-2 activity in human first-trimester interface. These data suggest that strict regulation of CXCL6 is required for normal migration and invasion of cells, such as those involved at the maternal-fetal interface. PMID- 23814100 TI - Better hospital care and women's groups reduced neonatal mortality in Malawi by a quarter. PMID- 23814099 TI - Interleukin (IL)-32beta-mediated CCAAT/enhancer-binding protein alpha (C/EBPalpha) phosphorylation by protein kinase Cdelta (PKCdelta) abrogates the inhibitory effect of C/EBPalpha on IL-10 production. AB - We previously reported that IL-32beta promotes IL-10 production in myeloid cells. However, the underlying mechanism remains elusive. In this study, we demonstrated that IL-32beta abrogated the inhibitory effect of CCAAT/enhancer-binding protein alpha (C/EBPalpha) on IL-10 expression in U937 cells. We observed that the phosphorylation of C/EBPalpha Ser-21 was inhibited by a PKCdelta-specific inhibitor, rottlerin, or IL-32beta knockdown by siRNA and that IL-32beta shifted to the membrane from the cytosol upon phorbol 12-myristate 13-acetate treatment. We revealed that IL-32beta suppressed the binding of C/EBPalpha to IL-10 promoter by using ChIP assay. These data suggest that PKCdelta and IL-32beta may modulate the effect of C/EBPalpha on IL-10 expression. We next demonstrated by immunoprecipitation that IL-32beta interacted with PKCdelta and C/EBPalpha, thereby mediating C/EBPalpha Ser-21 phosphorylation by PKCdelta. We showed that IL-32beta suppressed the inhibitory effect of C/EBPalpha on IL-10 promoter activity. However, the IL-10 promoter activity was reduced to the basal level by rottlerin treatment. When C/EBPalpha serine 21 was mutated to glycine (S21G), the inhibitory effect of C/EBPalpha S21G on IL-10 promoter activity was not modulated by IL-32beta. Taken together, our results show that IL-32beta-mediated C/EBPalpha Ser-21 phosphorylation by PKCdelta suppressed C/EBPalpha binding to IL-10 promoter, which promoted IL-10 production in U937 cells. PMID- 23814101 TI - 'It was just nice to be able to talk to somebody': long-term incapacity benefit recipients' experiences of a case management intervention. AB - BACKGROUND: This paper provides important contextual and service implementation data by exploring participant experiences of a pilot case management intervention for long-term incapacity benefit (IB) recipients. METHODS: Service experiences were assessed via a postal questionnaire and semi-structured qualitative telephone interviews. Data from 77 service user questionnaires and 20 semi structured qualitative interviews were obtained. Questionnaire data were analysed using SPSS and telephone interviews were transcribed, thematically coded and analysed using NVivo. RESULTS: Respondents were generally positive about their experience of the intervention and particularly the benefit gained from the personal support that case managers provided. However, they also made suggestions about how the service could be delivered more effectively particularly in terms of the duration of the treatments and increasing the level of face-to-face support. CONCLUSIONS: Case management approaches may offer a supportive environment in which the health needs of those in the long-term receipt of IB can be addressed. PMID- 23814102 TI - The effects of acupuncture on rates of clinical pregnancy among women undergoing in vitro fertilization: a systematic review and meta-analysis. AB - BACKGROUND Recent systematic reviews of adjuvant acupuncture for IVF have pooled heterogeneous trials, without examining variables that might explain the heterogeneity. The aims of our meta-analysis were to quantify the overall pooled effects of adjuvant acupuncture on IVF clinical pregnancy success rates, and evaluate whether study design-, treatment- and population-related factors influence effect estimates. METHODS We included randomized controlled trials that compared needle acupuncture administered within 1 day of embryo transfer, versus sham acupuncture or no adjuvant treatment. Our primary outcome was clinical pregnancy rates. We obtained from all investigators additional methodological details and outcome data not included in their original publications. We analysed sham-controlled and no adjuvant treatment-controlled trials separately, but since there were no large or significant differences between these two subsets, we pooled all trials for subgroup analyses. We prespecified 11 subgroup variables (5 clinical and 6 methodological) to investigate sources of heterogeneity, using single covariate meta-regressions. RESULTS Sixteen trials (4021 participants) were included in the meta-analyses. There was no statistically significant difference between acupuncture and controls when combining all trials [risk ratio (RR) 1.12, 95% confidence interval (CI), 0.96-1.31; I(2) = 68%; 16 trials; 4021 participants], or when restricting to sham-controlled (RR 1.02, 0.83-1.26; I(2) = 66%; 7 trials; 2044 participants) or no adjuvant treatment-controlled trials (RR 1.22, 0.97-1.52; I(2) = 67%; 9 trials; 1977 participants). The type of control used did not significantly explain the statistical heterogeneity (interaction P = 0.27). Baseline pregnancy rate, measured as the observed rate of clinical pregnancy in the control group of each trial, was a statistically significant effect modifier (interaction P < 0.001), and this covariate explained most of the heterogeneity of the effects of adjuvant acupuncture across all trials (adjusted R(2) = 93%; I(2) residual = 9%). Trials with lower control group rates of clinical pregnancy showed larger effects of adjuvant acupuncture (RR 1.53, 1.28 1.84; 7 trials; 1732 participants) than trials with higher control group rates of clinical pregnancy (RR 0.90, 0.80-1.01; 9 trials; 2289 participants). The asymmetric funnel plot showed a tendency for the intervention effects to be more beneficial in smaller trials. CONCLUSIONS We found no pooled benefit of adjuvant acupuncture for IVF. The subgroup finding of a benefit in trials with lower, but not higher, baseline pregnancy rates (the only statistically significant subgroup finding in our earlier review) has been confirmed in this update, and was not explained by any confounding variables evaluated. However, this baseline pregnancy rate subgroup finding among published trials requires further confirmation and exploration in additional studies because of the multiple subgroup tests conducted, the risk of unidentified confounders, the multiple different factors that determine baseline rates, and the possibility of publication bias. PMID- 23814103 TI - Factors contributing to parental decision-making in disclosing donor conception: a systematic review. AB - BACKGROUND In recent years, changes in attitudes towards (non-)disclosure of donor conception to offspring and/or others have been observed. Studies have started to identify possible factors that contribute to these changes that are relevant for clinics, counsellors and policy-makers in their approach to the disclosure process. The aim of this systematic review was to integrate the existing knowledge on factors that influence the disclosure decision-making process of donor conception to offspring and/or others in heterosexual couples, and to discuss future trends and concerns. METHODS A bibliographic search of English, French, German and Dutch language publications of five computerized databases was undertaken from January 1980 to March 2012. A Cochrane Database systematic review approach was applied. RESULTS A total of 43 studies met the inclusion criteria, and these represented 36 study populations. The review shows that the parents' disclosure decision-making process is influenced by a myriad of intrapersonal, interpersonal, social and family life cycle features. These influences were not necessarily independent but rather were interwoven and overlapping. Theoretical frameworks have not yet been used to explain how the different factors influenced disclosure. Methodological limitations of the original publications (lack of information, several factors included in one study, descriptive character of studies) and this review (multiple factors that may interact) which hindered integration of the findings are outlined. CONCLUSIONS Intrapersonal, interpersonal, social and family life cycle factors influence the parents' disclosure decision-making process. The review has demonstrated the need for the development of a theoretical model to enable integration of the identified influencing factors. Further research is needed on the role of stigma, confrontation efficacy, extended family, donor siblings' characteristics, cross-border treatment, culture, gender and socio-educational factors. PMID- 23814104 TI - Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. AB - OBJECTIVE: To assess whether lithium has a specific preventive effect for suicide and self harm in people with unipolar and bipolar mood disorders. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, CINAHL, PsycINFO, CENTRAL, web based clinical trial registries, major textbooks, authors of important papers and other experts in the discipline, and websites of pharmaceutical companies that manufacture lithium or the comparator drugs (up to January 2013). INCLUSION CRITERIA: Randomised controlled trials comparing lithium with placebo or active drugs in long term treatment for mood disorders. REVIEW METHODS: Two reviewers assessed studies for inclusion and risk of bias and extracted data. The main outcomes were the number of people who completed suicide, engaged in deliberate self harm, and died from any cause. RESULTS: 48 randomised controlled trials (6674 participants, 15 comparisons) were included. Lithium was more effective than placebo in reducing the number of suicides (odds ratio 0.13, 95% confidence interval 0.03 to 0.66) and deaths from any cause (0.38, 0.15 to 0.95). No clear benefits were observed for lithium compared with placebo in preventing deliberate self harm (0.60, 0.27 to 1.32). In unipolar depression, lithium was associated with a reduced risk of suicide (0.36, 0.13 to 0.98) and also the number of total deaths (0.13, 0.02 to 0.76) compared with placebo. When lithium was compared with each active individual treatment a statistically significant difference was found only with carbamazepine for deliberate self harm. Lithium tended to be generally better than the other active comparators, with small statistical variation between the results. CONCLUSIONS: Lithium is an effective treatment for reducing the risk of suicide in people with mood disorders. Lithium may exert its antisuicidal effects by reducing relapse of mood disorder, but additional mechanisms should also be considered because there is some evidence that lithium decreases aggression and possibly impulsivity, which might be another mechanism mediating the antisuicidal effect. PMID- 23814105 TI - Draft Genome Sequence of Methylomicrobium buryatense Strain 5G, a Haloalkaline Tolerant Methanotrophic Bacterium. AB - Robust growth of the gammaproteobacterium Methylomicrobium buryatense strain 5G on methane makes it an attractive system for CH4-based biocatalysis. Here we present a draft genome sequence of the strain that will provide a valuable framework for metabolic engineering of the core pathways for the production of valuable chemicals from methane. PMID- 23814106 TI - Draft Genome Sequence of the Moderately Halophilic Bacterium Marinobacter lipolyticus Strain SM19. AB - Marinobacter lipolyticus strain SM19, isolated from saline soil in Spain, is a moderately halophilic bacterium belonging to the class Gammaproteobacteria. Here, we report the draft genome sequence of this strain, which consists of a 4.0-Mb chromosome and which is able to produce the halophilic enzyme lipase LipBL. PMID- 23814107 TI - Genome Sequence of a Novel H10N9 Avian Influenza Virus Isolated from Chickens in a Live Poultry Market in Eastern China. AB - An H10N9 avian influenza virus (AIV) strain, A/Chicken/Jiangsu/RD5/2013, was isolated in China. The hemagglutinin (HA) and neuraminidase (NA) genes in this strain originated from H10N1 and H7N9 AIVs, respectively, and the other genes derived from H7N3 AIVs. Sequence analysis implies that the H10N9 AIV may be an NA gene donor for the human H7N9 influenza viruses. PMID- 23814108 TI - First draft genome sequence from a member of the genus agrococcus, isolated from modern microbialites. AB - We report the first draft genome sequence from a member of the genus Agrococcus, isolated from cold thrombolytic microbialites within Pavilion Lake, British Columbia, Canada. The draft genome assembly for Agrococcus pavilionensis strain RW-1 has a size of 2,878,403 bp with a G+C content of 72.56%. PMID- 23814109 TI - Genome Sequence of Plesiomonas shigelloides Strain 302-73 (Serotype O1). AB - Plesiomonas shigelloides, the only species of the genus, is an emergent pathogenic bacterium associated with human diarrheal and extraintestinal disease. We present the whole-genome sequence analysis of the representative strain for the O1 serotype (strain 302-73), providing a tool for studying bacterial outbreaks, virulence factors, and accurate diagnostic methods. PMID- 23814110 TI - Draft Genome Sequence of the Basidiomycetous Yeast-Like Fungus Pseudozyma hubeiensis SY62, Which Produces an Abundant Amount of the Biosurfactant Mannosylerythritol Lipids. AB - The basidiomycetous yeast-like fungus Pseudozyma hubeiensis strain SY62 is capable of producing an abundant amount of the glycolipid biosurfactant mannosylerythritol lipids (MELs), which are a major component of monoacetylated MEL (MEL-C). To reveal the synthetic pathway of the MELs of strain SY62, we present the 18.44-Mb draft genome sequence. PMID- 23814111 TI - Draft Genome Sequence of Ammonia-Producing Acinetobacter sp. Strain MCC2139 from Dairy Effluent. AB - We report the draft genome sequence of an ammonia-producing, esculin-hydrolyzing, catalase-positive, gram-negative bacterium, Acinetobacter sp. strain MCC2139. This bacterium, isolated from dairy sludge and with optimum growth at 37 degrees C, has a genome size of 2,967,280 bp with a G+C content of 42.3%. PMID- 23814112 TI - Genome Sequence of the Multiple-beta-Lactam-Antibiotic-Resistant Bacterium Acidovorax sp. Strain MR-S7. AB - Acidovorax sp. strain MR-S7 was isolated from activated sludge in a treatment system for wastewater containing beta-lactam antibiotic pollutants. Strain MR-S7 demonstrates multidrug resistance for various types of beta-lactam antibiotics at high levels of MIC. The draft genome sequence clarified that strain MR-S7 harbors unique beta-lactamase genes. PMID- 23814113 TI - Prognostic factors associated with radiotherapy for cervical cancer with computed tomography-detected para-aortic lymph node metastasis. AB - Patients with cervical cancer diagnosed with a para-aortic lymph node (PALN) metastasis by computed tomography (CT) scan were analyzed to identify associated prognostic factors. A total of 55 patients were reviewed, and 27 of these patients underwent extended-field radiotherapy (EFRT). The median PALN dose in patients receiving EFRT was 45 Gy (range, 27-57.6 Gy). Of the 55 patients, 28 underwent pelvic radiotherapy (RT); concurrent chemoradiotherapy (CCRT) was administered to 41 patients. The Kaplan-Meier method was used to calculate the actuarial rate. Multivariate analysis was performed using the Cox proportional hazards model. Five-year overall survival (OS) rates were 41% and 17.9% in patients undergoing EFRT and pelvic RT (P = 0.030), respectively. Age < 53 years (P = 0.023), FIGO Stage I-II (P = 0.002), and treatment with EFRT (P = 0.003) were independent predictors of better OS. The use of CCRT (P = 0.014), Stage I-II (P = 0.002), and treatment using EFRT (P = 0.036) were independent predictors of distant metastasis. In patients undergoing EFRT plus CCRT, the 5-year OS was 50%. Three-year PALN disease-free rates were 8.8%, 57.9% and 100% (P < 0.001) in CCRT patients who received PALN doses of 0 Gy, <=45 Gy and >=50.4 Gy, respectively. Although PALN metastasis is thought to be distant metastasis in cervical cancer, EFRT plus CCRT shows a good outcome, particularly in younger patients in an early FIGO stage. Cervical cancer with a PALN metastasis should not be considered incurable. Doses >=50.4 Gy for treating PALN may result in better disease control. PMID- 23814114 TI - Alpha-tocopherol succinate- and AMD3100-mobilized progenitors mitigate radiation combined injury in mice. AB - The purpose of this study was to elucidate the role of alpha-tocopherol succinate (TS)- and AMD3100-mobilized progenitors in mitigating combined injury associated with acute radiation exposure in combination with secondary physical wounding. CD2F1 mice were exposed to high doses of cobalt-60 gamma-radiation and then transfused intravenously with 5 million peripheral blood mononuclear cells (PBMCs) from TS- and AMD3100-injected mice after irradiation. Within 1 h after irradiation, mice were exposed to secondary wounding. Mice were observed for 30 d after irradiation and cytokine analysis was conducted by multiplex Luminex assay at various time-points after irradiation and wounding. Our results initially demonstrated that transfusion of TS-mobilized progenitors from normal mice enhanced survival of acutely irradiated mice exposed 24 h prior to transfusion to supralethal doses (11.5-12.5 Gy) of (60)Co gamma-radiation. Subsequently, comparable transfusions of TS-mobilized progenitors were shown to significantly mitigate severe combined injuries in acutely irradiated mice. TS administered 24 h before irradiation was able to protect mice against combined injury as well. Cytokine results demonstrated that wounding modulates irradiation-induced cytokines. This study further supports the conclusion that the infusion of TS mobilized progenitor-containing PBMCs acts as a bridging therapy in radiation combined-injury mice. We suggest that this novel bridging therapeutic approach involving the infusion of TS-mobilized hematopoietic progenitors following acute radiation exposure or combined injury might be applicable to humans. PMID- 23814115 TI - Endothelial cell sensing of flow direction. AB - OBJECTIVE: Atherosclerosis-prone regions of arteries are characterized by complex flow patterns where the magnitude of shear stress is low and direction rapidly changes, termed disturbed flow. How endothelial cells sense flow direction and how it impacts inflammatory effects of disturbed flow are unknown. We therefore aimed to understand how endothelial cells respond to changes in flow direction. APPROACH AND RESULTS: Using a recently developed flow system capable of changing flow direction to any angle, we show that responses of aligned endothelial cells are determined by flow direction relative to their morphological and cytoskeletal axis. Activation of the atheroprotective endothelial nitric oxide synthase pathway is maximal at 180 degrees and undetectable at 90 degrees , whereas activation of proinflammatory nuclear factor-kappaB is maximal at 90 degrees and undetectable at 180 degrees . Similar effects were observed in randomly oriented cells in naive monolayers subjected to onset of shear. Cells aligned on micropatterned substrates subjected to oscillatory flow were also examined. In this system, parallel flow preferentially activated endothelial nitric oxide synthase and production of nitric oxide, whereas perpendicular flow preferentially activated reactive oxygen production and nuclear factor-kappaB. CONCLUSIONS: These data show that the angle between flow and the cell axis defined by their shape and cytoskeleton determines endothelial cell responses. The data also strongly suggest that the inability of cells to align in low and oscillatory flow is a key determinant of the resultant inflammatory activation. PMID- 23814116 TI - Liver ABCA1 deletion in LDLrKO mice does not impair macrophage reverse cholesterol transport or exacerbate atherogenesis. AB - OBJECTIVE: Hepatic ATP binding cassette transporter A1 (ABCA1) expression is critical for maintaining plasma high-density lipoprotein (HDL) concentrations, but its role in macrophage reverse cholesterol transport and atherosclerosis is not fully understood. We investigated atherosclerosis development and reverse cholesterol transport in hepatocyte-specific ABCA1 knockout (HSKO) mice in the low-density lipoprotein (LDL) receptor KO (LDLrKO) C57BL/6 background. APPROACH AND RESULTS: Male and female LDLrKO and HSKO/LDLrKO mice were switched from chow at 8 weeks of age to an atherogenic diet (10% palm oil, 0.2% cholesterol) for 16 weeks. Chow-fed HSKO/LDLrKO mice had HDL concentrations 10% to 20% of LDLrKO mice, but similar very low-density lipoprotein and LDL concentrations. Surprisingly, HSKO/LDLrKO mice fed the atherogenic diet had significantly lower (40% to 60%) very low-density lipoprotein, LDL, and HDL concentrations (50%) compared with LDLrKO mice. Aortic surface lesion area and cholesterol content were similar for both genotypes of mice, but aortic root intimal area was significantly lower (20% to 40%) in HSKO/LDLrKO mice. Although macrophage (3)H cholesterol efflux to apoB lipoprotein-depleted plasma was 24% lower for atherogenic diet-fed HSKO/LDLrKO versus LDLrKO mice, variation in percentage efflux among individual mice was <2-fold compared with a 10-fold variation in plasma HDL concentrations, suggesting that HDL levels, per se, were not the primary determinant of plasma efflux capacity. In vivo reverse cholesterol transport, resident peritoneal macrophage sterol content, biliary lipid composition, and fecal cholesterol mass were similar between both genotypes of mice. CONCLUSIONS: The markedly reduced plasma HDL pool in HSKO/LDLrKO mice is sufficient to maintain macrophage reverse cholesterol transport, which, along with reduced plasma very low-density lipoprotein and LDL concentrations, prevented the expected increase in atherosclerosis. PMID- 23814118 TI - Smad2-dependent protease nexin-1 overexpression differentiates chronic aneurysms from acute dissections of human ascending aorta. AB - OBJECTIVE: Tissue activation of proteolysis is involved in acute intramural rupture (dissections, acute ascending aortic dissection) and in progressive dilation (aneurysms, thoracic aneurysm of the ascending aorta) of human ascending aorta. The translational aim of this study was to characterize the regulation of antiproteolytic serpin expression in normal, aneurysmal, and dissecting aorta. APPROACH AND RESULTS: We explored expression of protease nexin-1 (PN-1) and plasminogen activator inhibitor-1 and their regulation by the Smad2 signaling pathway in human tissue and cultured vascular smooth muscle cells (VSMCs) of aneurysms (thoracic aneurysm of the ascending aorta; n=46) and acute dissections (acute ascending aortic dissection; n=10) of the ascending aorta compared with healthy aortas (n=10). Both PN-1 and plasminogen activator inhibitor-1 mRNA and proteins were overexpressed in medial tissue extracts and primary VSMC cultures from thoracic aneurysm of the ascending aorta compared with acute ascending aortic dissection and controls. Transforming growth factor-beta induced increased PN-1 expression in control but not in aneurysmal VSMCs. PN-1 and plasminogen activator inhibitor-1 overexpression by aneurysmal VSMCs was associated with increased Smad2 binding on their promoters and, functionally, resulted in VSMC self-protection from plasmin-induced detachment and death. This phenomenon was restricted to aneurysms and not observed in acute dissections. CONCLUSIONS: These results demonstrate that epigenetically regulated PN-1 overexpression promotes development of an antiproteolytic VSMC phenotype and might favor progressive aneurysmal dilation, whereas absence of this counter-regulation in dissections would lead to acute wall rupture. PMID- 23814117 TI - 25-Hydroxyvitamin D and parathyroid hormone are not associated with carotid intima-media thickness or plaque in the multi-ethnic study of atherosclerosis. AB - OBJECTIVE: Observational evidence supports independent associations of 25 hydroxyvitamin D (25-OHD) and parathyroid hormone (PTH) with cardiovascular risk. A plausible hypothesis for these associations is accelerated development of atherosclerosis. APPROACH AND RESULTS: We evaluated cross-sectional and longitudinal associations of 25-OHD and PTH with carotid intima-media thickness (IMT) and carotid plaques among 3251 participants free of cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis. 25-OHD and PTH were measured at baseline by mass spectrometry and immunoassay, respectively. All subjects underwent a carotid ultrasound examination at baseline and 9.4 years later (median, range 8-11.1 years). Multivariable linear and logistic regressions were used to test associations of 25-OHD and PTH with the extent and progression of IMT and the prevalence and incidence of carotid plaque. Mean (SD) 25-OHD and PTH were 25.8 ng/mL (10.6) and 44.2 pg/mL (20.2), respectively. No independent associations were found between 25-OHD or PTH and IMT at baseline (increment of 1.9 MUm [95% confidence interval, -5.1 to 8.9] per 10 ng/mL lower 25-OHD; increment of 0.8 MUm [95% confidence interval, -3.2 to 4.8] per 10 pg/mL higher PTH) or progression of IMT (increment of 2.6 MUm [95% confidence interval, -2.5 to 7.8] per 10 ng/mL lower 25-OHD, increment of 1.6 MUm [95% confidence interval, -1.9 to 5.2] per 10 pg/mL higher PTH). No associations were found with the baseline prevalence of carotid plaque or the incidence of new plaques during the study period. We did not observe any interaction by race or ethnicity (White, Chinese, Black, and Hispanic). CONCLUSIONS: The consistent lack of association of vitamin D and PTH with carotid IMT and plaque suggests that these hormones may influence cardiovascular risk through pathways not reflected by carotid atherosclerosis. PMID- 23814120 TI - Intake of fish and marine n-3 polyunsaturated fatty acids and risk of breast cancer: meta-analysis of data from 21 independent prospective cohort studies. AB - OBJECTIVES: To investigate the association between intake of fish and n-3 polyunsaturated fatty acids (n-3 PUFA) and the risk of breast cancer and to evaluate the potential dose-response relation. DESIGN: Meta-analysis and systematic review of prospective cohort studies. DATA SOURCES: PubMed and Embase up to December 2012 and references of retrieved relevant articles. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Prospective cohort studies with relative risk and 95% confidence intervals for breast cancer according to fish intake, n-3 PUFA intake, or tissue biomarkers. RESULTS: Twenty six publications, including 20,905 cases of breast cancer and 883,585 participants from 21 independent prospective cohort studies were eligible. Eleven articles (13,323 breast cancer events and 687,770 participants) investigated fish intake, 17 articles investigated marine n 3 PUFA (16,178 breast cancer events and 527,392 participants), and 12 articles investigated alpha linolenic acid (14,284 breast cancer events and 405,592 participants). Marine n-3 PUFA was associated with 14% reduction of risk of breast cancer (relative risk for highest v lowest category 0.86 (95% confidence interval 0.78 to 0.94), I(2)=54), and the relative risk remained similar whether marine n-3 PUFA was measured as dietary intake (0.85, 0.76 to 0.96, I(2)=67%) or as tissue biomarkers (0.86, 0.71 to 1.03, I(2)=8%). Subgroup analyses also indicated that the inverse association between marine n-3 PUFA and risk was more evident in studies that did not adjust for body mass index (BMI) (0.74, 0.64 to 0.86, I(2)=0) than in studies that did adjust for BMI (0.90, 0.80 to 1.01, I(2)=63.2%). Dose-response analysis indicated that risk of breast cancer was reduced by 5% per 0.1g/day (0.95, 0.90 to 1.00, I(2)=52%) or 0.1% energy/day (0.95, 0.90 to 1.00, I(2)=79%) increment of dietary marine n-3 PUFA intake. No significant association was observed for fish intake or exposure to alpha linolenic acid. CONCLUSIONS: Higher consumption of dietary marine n-3 PUFA is associated with a lower risk of breast cancer. The associations of fish and alpha linolenic acid intake with risk warrant further investigation of prospective cohort studies. These findings could have public health implications with regard to prevention of breast cancer through dietary and lifestyle interventions. PMID- 23814119 TI - Atrial natriuretic peptide-mediated inhibition of microcirculatory endothelial Ca2+ and permeability response to histamine involves cGMP-dependent protein kinase I and TRPC6 channels. AB - OBJECTIVE: Histamine increases microvascular endothelial leakage by activation of complex calcium-dependent and -independent signaling pathways. Atrial natriuretic peptide (ANP) via its cGMP-forming guanylyl cyclase-A (GC-A) receptor counteracts this response. Here, we characterized the molecular mechanisms underlying this interaction, especially the role of cGMP-dependent protein kinase I (cGKI). APPROACH AND RESULTS: We combined intravital microscopy studies of the mouse cremaster microcirculation with experiments in cultured microvascular human dermal endothelial cells. In wild-type mice, ANP had no direct effect on the extravasation of fluorescent dextran from postcapillary venules, but strongly reduced the histamine-provoked vascular leakage. This anti-inflammatory effect of ANP was abolished in mice with endothelial-restricted inactivation of GC-A or cGKI. Histamine-induced increases in endothelial [Ca(2+)]i in vitro and of vascular leakage in vivo were markedly attenuated by the Ca(2+)-entry inhibitor SKF96365 and in mice with ablated transient receptor potential canonical (TRPC) 6 channels. Conversely, direct activation of TRPC6 with hyperforin replicated the hyperpermeability responses to histamine. ANP, via cGKI, stimulated the inhibitory phosphorylation of TRPC6 at position Thr69 and prevented the hyperpermeability responses to hyperforin. Moreover, inhibition of cGMP degradation by the phosphodiesterase 5 inhibitor sildenafil prevented the edematic actions of histamine in wild types but not in mice with endothelial GC-A or cGKI deletion. CONCLUSIONS: ANP attenuates the inflammatory actions of histamine via endothelial GC-A/cGMP/cGKI signaling and inhibitory phosphorylation of TRPC6 channels. The therapeutic potential of this novel regulatory pathway is indicated by the observation that sildenafil improves systemic endothelial barrier functions by enhancing the endothelial effects of endogenous ANP. PMID- 23814121 TI - Intracerebral haemorrhage, anticoagulation and mechanical heart valves: what should I do next? AB - Life-long oral anticoagulant therapy is recommended to all patients with mechanical heart valves to reduce the incidence of thromboembolic events. However, intracerebral haemorrhage is the fatal complication associated with anticoagulation, with an estimated 6-month mortality of 67%. (1) The incidence of cerebral bleeding while on anticoagulation is 0.3-0.7%/year, with as many as 85% of survivors left with permanent neurological deficits. (2) Difficulties in management arise when anticoagulation is temporarily discontinued as mechanical valves, particularly mitral, are exposed to significant thromboembolic and valve dysfunction risk. The decision on when to appropriately restart anticoagulation needs to be balanced with the risk of precipitating further cerebral haemorrhage. There are currently no guidelines on the optimal time to start anticoagulation. We describe a case of the management approach implemented in a patient with a mechanical valve presenting to the emergency department with an acute intracerebral haemorrhage. PMID- 23814122 TI - Diagnostic value of anti-gp210 antibodies in primary biliary cirrhosis: a case based review. AB - Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterised by chronic cholestasis usually associated with antimitochondrial antibodies. Moreover, several types of antinuclear antibodies have been associated with primary biliary cirrhosis. We describe an 83-year-old man, in whom the exploration of a chronic cholestasis led to the diagnosis of primary biliary cirrhosis despite negative antimitochondrial antibodies, regarding the presence of anti-gp210 antibodies. Found in 25% of patients, these antinuclear antibodies must be sought before a strong suspicion of primary biliary cirrhosis with antimitochondrial antibodies negative, as they are highly specific of the disease. They are generally associated with a more aggressive form of PBC. PMID- 23814123 TI - Severe parainfluenza pneumonia in a case of transient hypogammalobulinemia of infancy. AB - Human parainfluenza viruses (HPIVs) infection, largely known to cause self limiting bronchiolitis and pneumonia in immune competent patients, can lead to severe to fatal pulmonary disease in immune disorders, such as primary or acquired-immune deficiencies. We report the case of a 1-year-old child who developed an acute respiratory distress syndrome. Because of a progressive respiratory failure unresponsive to conventional treatment extracorporeal membrane oxygenation (ECMO) was rapidly started. HPIV-3 infection was diagnosed on the rhinopharyngeal fluid and immunological examinations revealed a hypogammaglobulinemia. A combination therapy with ribavirin, intravenous immunoglobulin (IVIG) and steroid under ECMO support was started with considerable improvement. Subsequent analysis and more specific immunological assessment resulted normal confirming the diagnosis of transient hypogammaglobulinemia of infancy (THI). This case highlights the importance of prompt therapy with early ECMO support in combination with ribavirin, IVIG and steroids in patients affected by severe HPIV-3 pneumonia and THI. PMID- 23814124 TI - Lenticulostriate artery aneurysm presenting as primary intraventricular haemorrhage. AB - Isolated or primary intraventricular haemorrhage (PIVH) is rare and usually caused by hypertension, vascular malformations, aneurysms and moyamoya disease. Lenticulostriate artery aneurysm (LSA) is also a rare entity, and LSA aneurysm rupture causing primary intraventricular haemorrhage is extremely rare. There are only a few case reports. LSA aneurysms can occur medially or laterally, proximally or distally, though distal lateral LSA aneurysms are more common. They are usually associated with various vascular conditions. We report two rare cases of LSA aneurysms presenting as PIVH, one being medial and other being lateral distal LSA aneurysm. Both were normotensives, and one was associated with arteriovenous malformation. PMID- 23814125 TI - An unusual posterior fossa tumour in a young child. PMID- 23814126 TI - Von Meyenburg complexes mimicking metastatic disease at laparotomy for focal nodular hyperplasia. AB - A 44-year-old woman presented with symptoms of fatigue and increasing abdominal discomfort. MRI with the hepatobiliary contrast Gd-EOB-DTPA (Primovist) was performed showing a 6 cm lesion in segment 2/3 of the liver typical for focal nodular hyperplasia (FNH). Because of severe complaints attributed to the lesion, the patient was scheduled for resection. At laparotomy multiple small white lesions were found throughout the liver with enlarged locoregional lymph nodes. Macroscopically, the findings could be consistent with widespread metastases and the surgeon felt compelled to determine the nature of these lesions before continuing resection. Final diagnosis revealed multiple bile duct hamartomas and an FNH lesion as was expected. PMID- 23814128 TI - Government clears way for practitioners of traditional Indian medicine to practise modern medicine. PMID- 23814127 TI - Proximal base stress fracture of the second metatarsal in a Highland dancer. AB - A 15-year-old female Highland dancer presented to the accident and emergency department with an ankle inversion injury on a background of several weeks of pain in the right foot. A radiograph of the right foot demonstrated a stress fracture at the base of the second metatarsal. She was treated conservatively with a below knee removable supportive walking boot with a rocker bottom sole. She re-presented to the accident and emergency department 3 weeks later with pins and needles in the right foot; she was given crutches to use along side the supportive walking boot. Radiographs 12 weeks after the first presentation showed healing of the stress fracture. The patient was now asymptomatic of the injury. She was unable to fully train for 12 weeks due to the injury. Conservative management was successful in this patient. PMID- 23814131 TI - Functional genomics of the inflammatory response: where are we now? AB - Inflammation is a tightly regulated process that is achieved through the specific and controlled activation of innate immune system cells, notably neutrophils, macrophages and dendritic cells. Functional genomics studies in the last years have contributed to an integrated picture of the events controlling macrophage specialization and plasticity. Here we will summarize recent advances in the characterization of the molecular determinants of macrophage functional properties, and specifically how the interplay between genomic and epigenomic information, transcription factors and micro-environmental cues results in a fine tuned transcriptional response. PMID- 23814130 TI - Evolutionary rate heterogeneity of core and attachment proteins in yeast protein complexes. AB - In general, proteins do not work alone; they form macromolecular complexes to play fundamental roles in diverse cellular functions. On the basis of their iterative clustering procedure and frequency of occurrence in the macromolecular complexes, the protein subunits have been categorized as core and attachment. Core protein subunits are the main functional elements, whereas attachment proteins act as modifiers or activators in protein complexes. In this article, using the current data set of yeast protein complexes, we found that core proteins are evolving at a faster rate than attachment proteins in spite of their functional importance. Interestingly, our investigation revealed that attachment proteins are present in a higher number of macromolecular complexes than core proteins. We also observed that the protein complex number (defined as the number of protein complexes in which a protein subunit belongs) has a stronger influence on gene/protein essentiality than multifunctionality. Finally, our results suggest that the observed differences in the rates of protein evolution between core and attachment proteins are due to differences in protein complex number and expression level. Moreover, we conclude that proteins which are present in higher numbers of macromolecular complexes enhance their overall expression level by increasing their transcription rate as well as translation rate, and thus the protein complex number imposes a strong selection pressure on the evolution of yeast proteome. PMID- 23814129 TI - Genome-wide patterns of genetic variation in two domestic chickens. AB - Domestic chickens are excellent models for investigating the genetic basis of phenotypic diversity, as numerous phenotypic changes in physiology, morphology, and behavior in chickens have been artificially selected. Genomic study is required to study genome-wide patterns of DNA variation for dissecting the genetic basis of phenotypic traits. We sequenced the genomes of the Silkie and the Taiwanese native chicken L2 at ~23- and 25-fold average coverage depth, respectively, using Illumina sequencing. The reads were mapped onto the chicken reference genome (including 5.1% Ns) to 92.32% genome coverage for the two breeds. Using a stringent filter, we identified ~7.6 million single-nucleotide polymorphisms (SNPs) and 8,839 copy number variations (CNVs) in the mapped regions; 42% of the SNPs have not found in other chickens before. Among the 68,906 SNPs annotated in the chicken sequence assembly, 27,852 were nonsynonymous SNPs located in 13,537 genes. We also identified hundreds of shared and divergent structural and copy number variants in intronic and intergenic regions and in coding regions in the two breeds. Functional enrichments of identified genetic variants were discussed. Radical nsSNP-containing immunity genes were enriched in the QTL regions associated with some economic traits for both breeds. Moreover, genetic changes involved in selective sweeps were detected. From the selective sweeps identified in our two breeds, several genes associated with growth, appetite, and metabolic regulation were identified. Our study provides a framework for genetic and genomic research of domestic chickens and facilitates the domestic chicken as an avian model for genomic, biomedical, and evolutionary studies. PMID- 23814132 TI - Genomics and epigenomics: new promises of personalized medicine for cancer patients. AB - Recent years have brought about a marked extension of our understanding of the somatic basis of cancer. Parallel to the large-scale investigation of diverse tumor genomes the knowledge arose that cancer pathologies are most often not restricted to single genomic events. In contrast, a large number of different alterations in the genomes and epigenomes come together and promote the malignant transformation. The combination of mutations, structural variations and epigenetic alterations differs between each tumor, making individual diagnosis and treatment strategies necessary. This view is summarized in the new discipline of personalized medicine. To satisfy the ideas of this approach each tumor needs to be fully characterized and individual diagnostic and therapeutic strategies designed. Here, we will discuss the power of high-throughput sequencing technologies for genomic and epigenomic analyses. We will provide insight into the current status and how these technologies can be transferred to routine clinical usage. PMID- 23814133 TI - Doctors must explain benefits of reconfiguration to patients, conference hears. PMID- 23814134 TI - Mediastinal infectious complication after endobronchial ultrasound-guided transbronchial needle aspiration. AB - We report here a mediastinal infectious complication after endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) that was successfully treated using intravenous antibiotic therapy. EBUS-TBNA was performed for a 59-year old man with mediastinal adenopathy 8 years after left pneumonectomy for squamous cell carcinoma of the lung. A single-needle pass produced an adequate cytology and histology sample, and the lesion was diagnosed as small-cell lung cancer. The procedure itself was uneventful, but the patient developed a nightly fever after the biopsy. Finally, he was readmitted, and intravenous antibiotic therapy was required for 4 weeks to treat a mediastinal infection after EBUS-TBNA before chemotherapy for small-cell lung cancer. PMID- 23814136 TI - Transcatheter valve used in a bailout technique during complicated open mitral valve surgery. AB - Here, we describe the case of a 62-year old woman who required aortic and mitral valve replacement plus coronary artery bypass grafting. Transoesophageal echocardiogram revealed stenosis of the aortic valve (Ao valve area, 0.9 cm(2); PG, 45 mmHg; MG, 25 mmHg) and a diseased calcified mitral valve with stenosis and regurgitation (mitral valve area, 1.1 cm(2); MG, 10 mmHg; RV, 25 ml; ERO, 12 mm(2)). The mitral annulus calcifications were very deep into the left atrium and the left ventricle muscle, around the full annulus circumference. We decided to avoid complete deep mitral annulus decalcification. The left atrium was surgically exposed, and we deployed a 26-mm Edwards SAPIEN XT endovalve through the left atriotomy. To prevent paravalvular leakage, we then used a pericardial patch to close the gap between the endovalve and the calcified mitral annulus. The postoperative echocardiogram showed perfect anchoring of the endovalve in the mitral annulus without any paravalvular leakage. PMID- 23814135 TI - Remote ischaemic preconditioning down-regulates kinin receptor expression in neutrophils of patients undergoing heart surgery. AB - OBJECTIVES: Remote ischaemic preconditioning (RIPC) may protect distant organs against ischaemia-reperfusion injury. We investigated the impact of RIPC on kinin receptor expression in neutrophils following RIPC in patients undergoing coronary artery bypass grafting (CABG). METHODS: Patients undergoing elective CABG with cardiopulmonary bypass (CPB) were randomized to RIPC (n = 15) or control (n = 15) groups. The study group underwent RIPC by inflation of a blood pressure cuff on the arm. Expression of kinin receptors, plasma concentrations of IL-6, IL-8, IL 10, TNF-alpha and neutrophil elastase were determined at baseline (before RIPC/sham), immediately before surgery (after RIPC/sham) and 30 min and 24 h after surgery. Plasma bradykinin levels were assessed before and after RIPC/sham, and at 30 min, 6, 12 and 24 h after surgery. Serum creatine kinase (CK), troponin I, C-reactive protein (CRP) and lactate levels were measured immediately prior to surgery and 30 min, 6, 12, 24 and 48 h after surgery. RESULTS: Kinin B2 receptor expression did not differ between the groups at baseline (pre-RIPC), but was significantly lower in the RIPC group than in the control group after RIPC/sham (P < 0.05). Expressions of both kinin B1 and B2 receptors were significantly down regulated in the RIPC group, and this persisted to 24 h after surgery (P < 0.001). Neutrophil elastase levels were significantly increased after surgery. There were no differences in CK, CRP, cytokine, lactate or troponin I levels between the groups. CONCLUSIONS: RIPC down-regulated the expression of kinin B1 and B2 receptors in neutrophils of patients undergoing CABG. PMID- 23814137 TI - Fontan operation for the Cantrell syndrome using a clamshell incision. AB - A median sternotomy could be difficult for a child with ectopia cordis and complex congenital cardiac anomalies. We report a patient with ectopia cordis, functionally single ventricle and bilateral superior vena cava, who underwent a staged Fontan procedure through a clamshell incision and the sternothoracotomy approach. PMID- 23814138 TI - Feasibility and safety of minimized cardiopulmonary bypass in major aortic surgery. AB - OBJECTIVES: Conventional cardiopulmonary bypass causes haemodilution and is a trigger of systemic inflammatory reactions, coagulopathy and organ failure. Miniaturized cardiopulmonary bypass has been proposed as a way to reduce these deleterious effects of conventional cardiopulmonary bypass and to promote a more physiological state. The use of miniaturized cardiopulmonary bypass has been reported in low-risk patients undergoing valve and coronary artery bypass graft (CABG) surgery. However, little is known about its application in major aortic surgery. METHODS: From February 2007 to September 2010, 49 patients underwent major aortic surgery using the Hammersmith miniaturized cardiopulmonary bypass (ECCO, Sorin). Data were extracted from medical records to characterize preoperative comorbidities (EuroSCORE), perioperative complications and the use of blood products. The same data were collected and described for 328 consecutive patients having similar surgery with conventional cardiopulmonary bypass at the Bristol Heart Institute, our twinned centre, during the same period. RESULTS: The miniaturized cardiopulmonary bypass group had a median EuroSCORE of 8 [inter quartile range (IQR): 5-11], 13% had preoperative renal dysfunction and 20% of operations were classified as emergency or salvage. Thirty-day mortalities were 6.4; and 69, 67 and 74% had >= 1 unit of red cells, fresh frozen plasma (FFP) and platelets transfused, respectively. Eight percent of patients experienced a renal complication, and 8% a neurological complication. The conventional cardiopulmonary bypass group was similar, with a EuroSCORE of 8 (IQR: 6-10); 30 day mortalities were 9.4; and 68, 62 and 74% had >= 1 unit of red cells, FFP and platelets transfused, respectively. The proportions experiencing renal and neurological complications were 14 and 5%. CONCLUSIONS: Our experience suggests that miniaturized cardiopulmonary bypass is safe and feasible for use in major aortic cardiac surgery. A randomized trial is needed to evaluate miniaturized cardiopulmonary bypass formally. PMID- 23814139 TI - Postgenomic analysis of bacterial pathogens repertoire reveals genome reduction rather than virulence factors. AB - In the pregenomic era, the acquisition of pathogenicity islands via horizontal transfer was proposed as a major mechanism in pathogen evolution. Much effort has been expended to look for the contiguous blocks of virulence genes that are present in pathogenic bacteria, but absent in closely related species that are nonpathogenic. However, some of these virulence factors were found in nonpathogenic bacteria. Moreover, and contrary to expectation, pathogenic bacteria were found to lack genes (antivirulence genes) that are characteristic of nonpathogenic bacteria. The availability of complete genome sequences has led to a new era of pathogen research. Comparisons of genomes have shown that the most pathogenic bacteria have reduced genomes, with less ribosomal RNA and unorganized operons; they lack transcriptional regulators but have more genes that encode protein toxins, toxin-antitoxin (TA) modules, and proteins for DNA replication and repair, when compared with less pathogenic close relatives. These findings questioned the paradigm of virulence by gene acquisition and put forward the notion of genomic repertoire of virulence. PMID- 23814140 TI - Publish all trial results within a year or face disciplinary action, BMA says. PMID- 23814141 TI - SbacHTS: spatial background noise correction for high-throughput RNAi screening. AB - MOTIVATION: High-throughput cell-based phenotypic screening has become an increasingly important technology for discovering new drug targets and assigning gene functions. Such experiments use hundreds of 96-well or 384-well plates, to cover whole-genome RNAi collections and/or chemical compound files, and often collect measurements that are sensitive to spatial background noise whose patterns can vary across individual plates. Correcting these position effects can substantially improve measurement accuracy and screening success. RESULT: We developed SbacHTS (Spatial background noise correction for High-Throughput RNAi Screening) software for visualization, estimation and correction of spatial background noise in high-throughput RNAi screens. SbacHTS is supported on the Galaxy open-source framework with a user-friendly open access web interface. We find that SbacHTS software can effectively detect and correct spatial background noise, increase signal to noise ratio and enhance statistical detection power in high-throughput RNAi screening experiments. AVAILABILITY: http://www.galaxy.qbrc.org/ PMID- 23814142 TI - L3bn of NHS money will go to new pooled fund for health and social care. PMID- 23814143 TI - Surgeon leaders support publishing outcomes but warn of limitations. PMID- 23814144 TI - Ban junk food in hospitals, say doctors. PMID- 23814146 TI - Chief medical officer advises government to allow mitochondrial replacement to prevent disease. PMID- 23814145 TI - All vascular surgeons are performing within expected limits, show individual outcome data. PMID- 23814147 TI - Discussion, debate and some areas for positive action. PMID- 23814148 TI - DSM-5: Il buono, il cattivo, il brutto. PMID- 23814149 TI - EPPIC mirage: cost-effectiveness of early psychosis intervention. PMID- 23814150 TI - Unhealthy scepticism: time for a fair go for best available evidence. PMID- 23814151 TI - Creating a recovery-oriented society: research and action. PMID- 23814152 TI - Biomarkers in DSM-5: lost in translation. PMID- 23814153 TI - Psychodynamic minimalism. PMID- 23814154 TI - Youth consultation-liaison psychiatry: a commentary. PMID- 23814155 TI - Transparency and accountability in early psychosis intervention research. PMID- 23814156 TI - In this issue: personalized medicine. PMID- 23814157 TI - Personalized medicine: hype or reality. PMID- 23814158 TI - Personalized cancer care is not new. PMID- 23814159 TI - Personalized cancer medicine: are we there yet? PMID- 23814160 TI - Cancer clinical trials--do we need a new algorithm in the age of stratified medicine? PMID- 23814161 TI - Personalized medicine: does the molecular suit fit? PMID- 23814162 TI - Preparing for success with comparative effectiveness research. PMID- 23814163 TI - Melanoma: more answers, more questions. PMID- 23814166 TI - Death, time, and psychosis. AB - Working through the awareness of death and the consciousness of time, it is hypothesized, plays a decisive role in the analytic process and in the mental growth of psychotic analysands, as well as in the integration of the psychotic areas in healthier patients. Clinical material is presented from a psychotic woman treated analytically, four sessions a week, for twelve years. The patient suffered several acute relapses, during which the analytic work was not interrupted. Her fourth psychotic episode in the course of analysis, which involved a delusion about gray men and the theft of time, is explored in particular depth. This phase fostered the patient's recognition of the value of time, together with the acquisition of her own center of psychosensory integration, the basis of an ability to learn from experience. PMID- 23814168 TI - Inferring the quality of hospital treatment for COPD by mortality; caution is needed. PMID- 23814167 TI - Increased skeletal muscle-specific microRNA in the blood of patients with COPD. AB - BACKGROUND: Skeletal muscle weakness in chronic obstructive pulmonary disease (COPD) carries a poor prognosis, therefore a non-invasive marker of this process could be useful. Reduced expression of muscle-specific microRNA (myomiRs) in quadriceps muscle in patients with COPD is associated with skeletal muscle weakness and changes in muscle fibre composition. Circulating exosomal miRNAs can be measured in blood, making them candidate biomarkers of biopsy phenotype. To determine whether plasma myomiR levels were associated with fibre size or fibre proportion, we measured myomiRs in plasma from patients with COPD and healthy controls. METHODS AND RESULTS: 103 patients with COPD and 25 age-matched controls were studied. Muscle-specific miRNA was elevated in the plasma of patients with COPD and showed distinct patterns. Specifically, miR-1 was inversely associated with fat-free mass in the cohort, whereas levels of miR-499 were more directly associated with strength and quadriceps type I fibre proportion. Two miRs not restricted to muscle in origin (miR-16 and miR-122) did not differ between patients and controls. Plasma miR-499 was also associated with muscle nuclear factor kappaB p50 but not p65 in patients with early COPD whereas plasma inflammatory cytokines were associated with miR-206 in patients with more advanced disease. CONCLUSIONS: Plasma levels of individual myomiRs are altered in patients with COPD but alone do not predict muscle fibre size or proportion. Our findings are consistent with an increase in muscle wasting and turnover associated with the development of skeletal muscle dysfunction and fibre-type shift in patients with stable COPD. PMID- 23814169 TI - Effect of aqueous extract and fractions of Fagonia arabica on in vitro anticoagulant activity. AB - Fagonia arabica (FA) is a deobstruent and blood purifier, which possesses thrombolytic and antioxidant activities. In this study, the anticoagulant effects of FA and its derived fractions were evaluated. Plasma recalcification was performed with multisolvent extracts of FA and then with extracts prepared successively with increasing polarity of the solvents. Aqueous extract was the most potent anticoagulant extract, which was fractionated by thin-layer chromatography and column chromatography. Five fractions collected were checked for their anticoagulation effect. The most potent fraction was screened for phytoconstituents. Aqueous extract of FA is the most active anticoagulant (31 minutes). Results were statistically significant when compared to heparin (38 minutes) and saline (4.04 minutes; P > .001). The Fifth fraction (FA5), the most potent fraction (27 minutes), was found positive for flavonoids, saponin, tannin, triterpenoids, carbohydrates, reducing sugar, and monosaccharides. Aqueous FA and fraction FA5 were most active in in vitro anticoagulation, and any of the phytochemicals identified could be considered the active component. PMID- 23814171 TI - The role of the nonspecific inflammatory markers in determining the anatomic extent of venous thromboembolism. AB - We aimed to investigate the relationship between the extent of venous thromboembolism (VTE) and nonspecific inflammatory markers such as neutrophil to lymphocyte ratio (NLR) and high-sensitivity C-reactive protein (hs-CRP). We retrospectively enrolled 77 patients with VTE (distal deep vein thrombosis [DVT], n = 19; proximal DVT, n = 32; and pulmonary thromboembolism [PTE], n = 26) and 34 healthy controls. In the performed analysis of variance, the levels of white blood cell, NLR, and hs-CRP were clearly different among the groups (control, distal and proximal DVT, and PTE) (P < .001). Especially, a significant increase from the control group to the DVT and PTE was observed in the analysis made for NLR. In the performed receiver-operating characteristic curve analysis, area under curve (AUC) = 0.849 and P < .001 were detected for NLR > 1.84. For this value, the sensitivity and specificity were determined as 88.2% and 67.6%, respectively. The NLR is an inexpensive and a readily available marker that may be effective in determining the extent of VTE, and it is useful for risk stratification in patients with VTE. PMID- 23814170 TI - Hospitalizations of adults >=60 years of age with venous thromboembolism. AB - We assessed the rates, trends, and factors associated with venous thromboembolism (VTE) diagnosis among hospitalizations of adults >=60 years of age during the period 2001 to 2010. Data from the National Hospital Discharge Survey were used for this study. During the period 2001 to 2010, the estimated annual number of hospitalizations in which a VTE diagnosis was recorded, among adults >= 60 years of age, ranged from approximately 2 70 000 in 2001 to 4 23 000 in 2010. The rate of such hospitalizations per 1 00 000 US population >=60 years of age ranged from 581 in 2001 to 739 in 2010. During the period 2001 to 2004, there was a significant increasing trend in the rate of hospitalizations with VTE among women >=60 years of age. The factors positively associated with an increased risk of VTE diagnosis were female sex, summer and autumn seasons (compared with spring), venous catheterization, cancer, and greater length of hospital stay. PMID- 23814172 TI - Parental behaviour in paediatric chronic pain: a qualitative observational study. AB - OBJECTIVES: Parental behaviour appears to influence the adjustment of children with chronic pain. However, research in this area has failed to produce consistent evidence. Studies have tended to rely on self-report measures derived from adult pain populations. This qualitative, observational research provides descriptive data of parental behaviour in a clinical environment. DESIGN: A qualitative observational study was made of parents and adolescents in a physically stressful setting. Modified grounded theory was used to analyse verbal and non-verbal behaviours. METHODS: Eight parent-adolescent dyads seeking treatment for chronic pain were videoed during physical exercise sessions. Verbal and non-verbal behaviours were recorded and transcribed. RESULTS: Four overarching categories emerged: 'monitoring', 'protecting', 'encouraging' and 'instructing'. These often had both verbal and non-verbal aspects. Within these categories, more precise behavioural groups were also identified. CONCLUSIONS: This research identifies categories of parental behaviour that were derived directly from observation, rather than imposed on the basis of results from different populations. Four categories of behaviour were derived, which clarify and extend dimensions used in existing self-report instruments. Careful description of parental behaviours showed features that past research has neglected, and highlighted potential drawbacks of apparently positive parental actions. PMID- 23814173 TI - Occipital nerve stimulation for intractable chronic cluster headache or migraine: a critical analysis of direct treatment costs and complications. AB - BACKGROUND: Occipital nerve stimulation (ONS) has been shown to be effective for selected patients with intractable headache disorders. We performed a prospective critical evaluation of complications and direct treatment costs. METHODS: Twenty seven patients with chronic cluster headache (CCH, N = 24) or chronic migraine (CM, N = 3) underwent a trial phase with bilateral ONS and subsequent implantation of a permanent generator (IPG), if responsive to treatment according to predefined criteria. Procedural and long-term complications as well as direct treatment costs of neuromodulation therapy of ONS were recorded over a mean follow-up period of 20 months (range 5-47 months). RESULTS: Twenty-five of 27 patients (93%) responded to treatment. Twenty-one complications in 14 patients were identified, necessitating reoperation in 13 cases. Overall treatment costs were ?761,043, including hardware-related costs of ?506,019, costs for primary hospital care of ?210,496, and complications related to hospitalization costs of ?44,528. This results in a per case-based cost of ?9445 for hospitalization and ?18,741 for hardware costs, totaling ?28,186. CONCLUSION: ONS for treatment of refractory CCH and CM is a cost-intensive treatment option with a significant complication rate. Nevertheless, patients with refractory primary headache disorders may experience substantial relief of pain attacks, and headache days, respectively. PMID- 23814174 TI - Physical restraint usage at a teaching hospital: a pilot study. AB - This mixed method study examines the prevalence of restraint usage; perception of nurses and doctors about the practice and whether they were trained to apply physical restraints. The physical restraint prevalence tools were used to observe 172 adult patients and conduct 47 chart audits in the medical-surgical wards and a psychiatric unit in November 2011. Focus group discussions with nurses and doctors were conducted. Quantitative data were analyzed using the SPSS and focus group discussions thematically analyzed. The prevalence of physical restraints between the medical-surgical wards was 75%. Nurses and medical doctors were not formally trained to apply restraint, and had learnt from peer observation. They expressed sadness, guilt, and fear when restraints are used and identified that inadequate institutional support existed. Restraint usage was high, and nurses and doctors experienced moral dilemma when they perceived that lack of formal training and inadequate institutional support may contribute to patient injury. PMID- 23814175 TI - Intensity, chronicity, circumstances, and consequences of HIV-related fatigue: a longitudinal study. AB - HIV-related fatigue remains the most troubling complaint of seropositive people. Researchers often use tools to measure fatigue that were developed for other patient populations; thus, the measurement of fatigue specific to HIV is needed. This article describes results from the HIV-Related Fatigue Scale (HRFS) including: (a) the variability in intensity and chronicity of HIV-related fatigue, (b) the circumstances surrounding changes in fatigue, (c) the impact of fatigue on activities of daily living (ADLs), and (d) the consequences of HIV related fatigue. We collected data every 3 months over a 3-year period from 128 people. HIV-related fatigue was chronic and did not appear to remit spontaneously; those who were the most fatigued at the beginning of the study remained the most fatigued over 3 years. Fatigue interfered more with instrumental activities of daily living than basic ADLs; it also interfered with work, family, and social life. Stress and depression increased fatigue. PMID- 23814176 TI - Gender differences in the predictors of depression among patients with heart failure. AB - BACKGROUND: Depression is common in patients with heart failure. The prevalence of depression is known to differ in male and female patients with heart failure, but little is known about whether these patients differ in predictors of depression. The purposes of this study were to: (1) determine whether the prevalence of depression in patients with heart failure differed by gender: (2) examine if predictors of depression differed by patient gender. METHODS: In this cross-sectional observational study, 147 patients with a primary diagnosis of heart failure completed five self-report questionnaires: demographic and clinical characteristic questionnaire, Mishel Uncertainty in Illness Scale, Beck Depression Inventory-II, Social Support Scale and Minnesota Living with Heart Failure Questionnaire. Data were analyzed with logistic regression. RESULTS: The majority of subjects were male (54.4%), with a mean age of 71.04 +/- 13.29 years and mean ejection fraction of 46.42 +/- 17.02%. About two-thirds of male patients (65%) and of female patients (65.7%) had significant depressive symptoms (Beck Depression Inventory-II score >=14). More female than male patients had moderate or severe depressive symptoms. Stratified analyses revealed that significant independent predictors of depressive symptoms among males were being unemployed (odds ratio=.09, 95% confidence intervals=.02- .54), lower ejection fraction (odds ratio=.96, 95% confidence intervals=.92-1.00), and worse quality of life (odds ratio=1.09, 95% confidence intervals=1.05-1.14); among females, predictors were uncertainty (odds ratio=1.09, 95% confidence intervals=1.04-1.32) and worse quality of life (odds ratio=1.17, 95% confidence intervals=1.08-1.48). CONCLUSIONS: Different variables predicted the presence of significant depressive symptoms in male and female patients with heart failure, but quality of life was an important factor in predicting depression in both genders. PMID- 23814177 TI - The potential role of miR-451 in cancer diagnosis, prognosis, and therapy. AB - MicroRNAs (miRNA) are small noncoding RNAs that converge to maintain an intrinsic balance of various processes, including cell proliferation, differentiation, and apoptosis. Recent research efforts have been devoted to translating these basic discoveries into applications that could improve the early diagnosis and therapeutic outcome of patients with cancer. Early studies have shown that miRNA 451 (miR-451) is widely dysregulated in human cancers and plays a critical role in tumorigenesis and tumor progression. In this review, we summarize the potential use of miR-451 for cancer diagnosis, prognosis, and treatment. In addition, we discuss the possible mechanisms of miR-451 dysregulation and future challenges in development of miR-451 as a noninvasive biomarker and a potential therapeutic target in human cancers. PMID- 23814178 TI - Physical abuse leading to renal failure: a unique case of rhabdomyolysis. PMID- 23814179 TI - Fitwits: preparing residency-based physicians to discuss childhood obesity with preteens. AB - OBJECTIVE: To evaluate the Fitwits MD office tool and games for obesity discussions with 9- to 12-year-olds. METHODS: A nonrandomized intervention study using pre- and posttest assessments in 2 residency programs compared 31 control group and 55 intervention physicians (34 previously trained, 21 newly trained to use Fitwits). Surveys addressed comfort and competence regarding: obesity prevention and treatment, nutrition, exercise, portion size, body mass index (BMI), and the term "obesity." We surveyed all groups at baseline and 5 months (post 1) and new trainees 3 months later (post 2). RESULTS: In post 1, prior trainees reported significantly increased comfort and competence for discussing obesity prevention, portion size, BMI, and "obesity." In post 2, new trainees reported significantly increased comfort and competence discussing obesity prevention and treatment, portion size, and BMI. CONCLUSIONS: Experience using Fitwits improved residency-based physician comfort and competence in obesity prevention and treatment, portion size, BMI, and "obesity" discussions with preadolescents. PMID- 23814180 TI - The role of human equilibrative nucleoside transporter 1 on the cellular transport of the DNA methyltransferase inhibitors 5-azacytidine and CP-4200 in human leukemia cells. AB - The nucleoside analog 5-azacytidine is an archetypical drug for epigenetic cancer therapy, and its clinical effectiveness has been demonstrated in the treatment of myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML). However, therapy resistance in patients with MDS/AML remains a challenging issue. Membrane proteins that are involved in drug uptake are potential mediators of drug resistance. The responsible proteins for the transport of 5-azacytidine into MDS/AML cells are unknown. We have now systematically analyzed the expression and activity of various nucleoside transporters. We identified the human equilibrative nucleoside transporter 1 (hENT1) as the most abundant nucleoside transporter in leukemia cell lines and in AML patient samples. Transport assays using [14C]5-azacytidine demonstrated Na+-independent uptake of the drug into the cells, which was inhibited by S-(4-nitrobenzyl)-6-thioinosine (NBTI), a hENT1 inhibitor. The cellular toxicity of 5-azacytidine and its DNA demethylating activity were strongly reduced after hENT1 inhibition. In contrast, the cellular activity of the 5-azacytidine derivative 5-azacytidine-5'-elaidate (CP-4200), a nucleoside transporter-independent drug, persisted after hENT1 inhibition. A strong dependence of 5-azacytidine-induced DNA demethylation on hENT1 activity was also confirmed by array-based DNA methylation profiling, which uncovered hundreds of loci that became demethylated only when hENT1-mediated transport was active. Our data establish hENT1 as a key transporter for the cellular uptake of 5-azacytidine in leukemia cells and raise the possibility that hENT1 expression might be a useful biomarker to predict the efficiency of 5-azacytidine treatments. Furthermore, our data suggest that CP-4200 may represent a valuable compound for the modulation of transporter-related 5-azacytidine resistances. PMID- 23814181 TI - Influences of histone deacetylase inhibitors and resveratrol on DNA repair and chromatin compaction. AB - Accessibility of DNA is a prerequisite for both DNA damage and repair. Therefore, the chromatin structure is expected to have major impact on both processes, with opposite consequences for the stability of the genome. To analyse the influence of chromatin compaction on the generation and repair of various types of DNA modifications, we modulated the global chromatin structure of AS52 Chinese hamster ovary cells and HeLa cells by treatment with either histone deacetylase inhibitors or resveratrol and measured the repair kinetics of (i) pyrimidine dimers induced by ultraviolet B, (ii) oxidised purines generated by photosensitisation and (iii) single-strand breaks induced by H2O2, using an alkaline elution technique. The decrease of chromatin compaction (detected as reduced DNA accessibility to DNase I) after treatment with trichostatin A or butyrate slightly increased the damage generation but had no significant effect on the global repair rates. In contrast, incubation of AS52 cells with resveratrol at concentrations that caused significant chromatin compaction and that had only moderate influence on cell proliferation gave rise to a strong decrease of the repair rates of all three types of DNA modifications. Similar, but less pronounced effects were observed in HeLa cells. The effects of resveratrol on the repair rates were not antagonised by the sirtuin inhibitor EX 527 or by an increase of the intracellular thiol levels. PMID- 23814182 TI - Tracking a refined eIF4E-binding motif reveals Angel1 as a new partner of eIF4E. AB - The initiation factor 4E (eIF4E) is implicated in most of the crucial steps of the mRNA life cycle and is recognized as a pivotal protein in gene regulation. Many of these roles are mediated by its interaction with specific proteins generally known as eIF4E-interacting partners (4E-IPs), such as eIF4G and 4E-BP. To screen for new 4E-IPs, we developed a novel approach based on structural, in silico and biochemical analyses. We identified the protein Angel1, a member of the CCR4 deadenylase family. Immunoprecipitation experiments provided evidence that Angel1 is able to interact in vitro and in vivo with eIF4E. Point mutation variants of Angel1 demonstrated that the interaction of Angel1 with eIF4E is mediated through a consensus eIF4E-binding motif. Immunofluorescence and cell fractionation experiments showed that Angel1 is confined to the endoplasmic reticulum and Golgi apparatus, where it partially co-localizes with eIF4E and eIF4G, but not with 4E-BP. Furthermore, manipulating Angel1 levels in living cells had no effect on global translation rates, suggesting that the protein has a more specific function. Taken together, our results illustrate that we developed a powerful method for identifying new eIF4E partners and open new perspectives for understanding eIF4E-specific regulation. PMID- 23814183 TI - Quantitative assessment of ratiometric bimolecular beacons as a tool for imaging single engineered RNA transcripts and measuring gene expression in living cells. AB - Recently, we developed an oligonucleotide-based probe, ratiometric bimolecular beacon (RBMB), which generates a detectable fluorescent signal in living cells that express the target RNA. Here, we show that RBMBs can also be used to image single RNA transcripts in living cells, when the target RNA is engineered to contain as few as four hybridization sites. Moreover, comparison with single molecule fluorescence in situ hybridization confirmed that RBMBs could be used to accurately quantify the number of RNA transcripts within individual cells. Measurements of gene expression could be acquired within 30 min and using a wide range of RBMB concentrations. The ability to acquire accurate measurements of RNA copy number in both HT-1080 cells and CHO cells also suggests that RBMBs can be used to image and quantify single RNA transcripts in a wide range of cell lines. Overall, these findings highlight the robustness and versatility of RBMBs as a tool for imaging RNA in live cells. We envision that the unique capabilities of RBMBs will open up new avenues for RNA research. PMID- 23814184 TI - Computational methods to detect conserved non-genic elements in phylogenetically isolated genomes: application to zebrafish. AB - Many important model organisms for biomedical and evolutionary research have sequenced genomes, but occupy a phylogenetically isolated position, evolutionarily distant from other sequenced genomes. This phylogenetic isolation is exemplified for zebrafish, a vertebrate model for cis-regulation, development and human disease, whose evolutionary distance to all other currently sequenced fish exceeds the distance between human and chicken. Such large distances make it difficult to align genomes and use them for comparative analysis beyond gene focused questions. In particular, detecting conserved non-genic elements (CNEs) as promising cis-regulatory elements with biological importance is challenging. Here, we develop a general comparative genomics framework to align isolated genomes and to comprehensively detect CNEs. Our approach integrates highly sensitive and quality-controlled local alignments and uses alignment transitivity and ancestral reconstruction to bridge large evolutionary distances. We apply our framework to zebrafish and demonstrate substantially improved CNE detection and quality compared with previous sets. Our zebrafish CNE set comprises 54 533 CNEs, of which 11 792 (22%) are conserved to human or mouse. Our zebrafish CNEs (http://zebrafish.stanford.edu) are highly enriched in known enhancers and extend existing experimental (ChIP-Seq) sets. The same framework can now be applied to the isolated genomes of frog, amphioxus, Caenorhabditis elegans and many others. PMID- 23814185 TI - An 'open' structure of the RecOR complex supports ssDNA binding within the core of the complex. AB - Efficient DNA repair is critical for cell survival and the maintenance of genome integrity. The homologous recombination pathway is responsible for the repair of DNA double-strand breaks within cells. Initiation of this pathway in bacteria can be carried out by either the RecBCD or the RecFOR proteins. An important regulatory player within the RecFOR pathway is the RecOR complex that facilitates RecA loading onto DNA. Here we report new data regarding the assembly of Deinococcus radiodurans RecOR and its interaction with DNA, providing novel mechanistic insight into the mode of action of RecOR in homologous recombination. We present a higher resolution crystal structure of RecOR in an 'open' conformation in which the tetrameric RecR ring flanked by two RecO molecules is accessible for DNA binding. We show using small-angle neutron scattering and mutagenesis studies that DNA binding does indeed occur within the RecR ring. Binding of single-stranded DNA occurs without any major conformational changes of the RecOR complex while structural rearrangements are observed on double-stranded DNA binding. Finally, our molecular dynamics simulations, supported by our biochemical data, provide a detailed picture of the DNA binding motif of RecOR and reveal that single-stranded DNA is sandwiched between the two facing oligonucleotide binding domains of RecO within the RecR ring. PMID- 23814186 TI - Lighting up left-handed Z-DNA: photoluminescent carbon dots induce DNA B to Z transition and perform DNA logic operations. AB - Left-handed Z-DNA has been identified as a transient structure occurred during transcription. DNA B-Z transition has attracted much attention because of not only Z-DNA biological importance but also their relation to disease and DNA nanotechnology. Recently, photoluminescent carbon dots, especially highly luminescent nitrogen-doped carbon dots, have attracted much attention on their applications to bioimaging and gene/drug delivery because of carbon dots with low toxicity, highly stable photoluminescence and controllable surface function. However, it is still unknown whether carbon dots can influence DNA conformation or structural transition, such as B-Z transition. Herein, based on our previous series work on DNA interactions with carbon nanotubes, we report the first example that photoluminescent carbon dots can induce right-handed B-DNA to left handed Z-DNA under physiological salt conditions with sequence and conformation selectivity. Further studies indicate that carbon dots would bind to DNA major groove with GC preference. Inspired by carbon dots lighting up Z-DNA and DNA nanotechnology, several types of DNA logic gates have been designed and constructed based on fluorescence resonance energy transfer between photoluminescent carbon dots and DNA intercalators. PMID- 23814187 TI - Carcinogenic adducts induce distinct DNA polymerase binding orientations. AB - DNA polymerases must accurately replicate DNA to maintain genome integrity. Carcinogenic adducts, such as 2-aminofluorene (AF) and N-acetyl-2-aminofluorene (AAF), covalently bind DNA bases and promote mutagenesis near the adduct site. The mechanism by which carcinogenic adducts inhibit DNA synthesis and cause mutagenesis remains unclear. Here, we measure interactions between a DNA polymerase and carcinogenic DNA adducts in real-time by single-molecule fluorescence. We find the degree to which an adduct affects polymerase binding to the DNA depends on the adduct location with respect to the primer terminus, the adduct structure and the nucleotides present in the solution. Not only do the adducts influence the polymerase dwell time on the DNA but also its binding position and orientation. Finally, we have directly observed an adduct- and mismatch-induced intermediate state, which may be an obligatory step in the DNA polymerase proofreading mechanism. PMID- 23814190 TI - Chorea gravidarum: a rarity in West still haunts pregnant women in the East. AB - A pregnant woman, in her early 20s, presents with chorea following an emotional outburst. While the family members feel it to be a spirit haunting her, we try to establish the medical diagnosis of the present condition. There is a history of rheumatic fever in the past and examination reveals choreioathetoid jerky movements of her upper limbs with jerky speech, spooning of her limbs and demonstration of milkmaid's grip. Laboratory investigations did not reveal anything interesting. We discuss the diagnosis and management of this patient. PMID- 23814188 TI - Computational identification of novel biochemical systems involved in oxidation, glycosylation and other complex modifications of bases in DNA. AB - Discovery of the TET/JBP family of dioxygenases that modify bases in DNA has sparked considerable interest in novel DNA base modifications and their biological roles. Using sensitive sequence and structure analyses combined with contextual information from comparative genomics, we computationally characterize over 12 novel biochemical systems for DNA modifications. We predict previously unidentified enzymes, such as the kinetoplastid J-base generating glycosyltransferase (and its homolog GREB1), the catalytic specificity of bacteriophage TET/JBP proteins and their role in complex DNA base modifications. We also predict the enzymes involved in synthesis of hypermodified bases such as alpha-glutamylthymine and alpha-putrescinylthymine that have remained enigmatic for several decades. Moreover, the current analysis suggests that bacteriophages and certain nucleo-cytoplasmic large DNA viruses contain an unexpectedly diverse range of DNA modification systems, in addition to those using previously characterized enzymes such as Dam, Dcm, TET/JBP, pyrimidine hydroxymethylases, Mom and glycosyltransferases. These include enzymes generating modified bases such as deazaguanines related to queuine and archaeosine, pyrimidines comparable with lysidine, those derived using modified S-adenosyl methionine derivatives and those using TET/JBP-generated hydroxymethyl pyrimidines as biosynthetic starting points. We present evidence that some of these modification systems are also widely dispersed across prokaryotes and certain eukaryotes such as basidiomycetes, chlorophyte and stramenopile alga, where they could serve as novel epigenetic marks for regulation or discrimination of self from non-self DNA. Our study extends the role of the PUA-like fold domains in recognition of modified nucleic acids and predicts versions of the ASCH and EVE domains to be novel 'readers' of modified bases in DNA. These results open opportunities for the investigation of the biology of these systems and their use in biotechnology. PMID- 23814191 TI - Inadvertent left ventricular pacing through a patent foramen ovale: identification, management and implications for postpacemaker implantation checks. AB - A dual chamber permanent pacemaker was implanted into an asymptomatic man with complete (third degree) heart block because of the risk of asystole. The ventricular lead was thought to have been attached to the right ventricular septum; however, it inadvertently passed through a patent foramen ovale into the left ventricle. Although the postprocedure ECG showed right bundle branch block this was thought to be due to the presumed septal positioning of the pacing lead. Lead misplacement was not detected on posterioanterior chest X-ray but was clearly demonstrated by transthoracic echocardiography, and subsequently on lateral chest X-ray. The lead was successfully removed and repositioned correctly at the next available opportunity without complication or sequelae. PMID- 23814189 TI - DNA motif elucidation using belief propagation. AB - Protein-binding microarray (PBM) is a high-throughout platform that can measure the DNA-binding preference of a protein in a comprehensive and unbiased manner. A typical PBM experiment can measure binding signal intensities of a protein to all the possible DNA k-mers (k=8~10); such comprehensive binding affinity data usually need to be reduced and represented as motif models before they can be further analyzed and applied. Since proteins can often bind to DNA in multiple modes, one of the major challenges is to decompose the comprehensive affinity data into multimodal motif representations. Here, we describe a new algorithm that uses Hidden Markov Models (HMMs) and can derive precise and multimodal motifs using belief propagations. We describe an HMM-based approach using belief propagations (kmerHMM), which accepts and preprocesses PBM probe raw data into median-binding intensities of individual k-mers. The k-mers are ranked and aligned for training an HMM as the underlying motif representation. Multiple motifs are then extracted from the HMM using belief propagations. Comparisons of kmerHMM with other leading methods on several data sets demonstrated its effectiveness and uniqueness. Especially, it achieved the best performance on more than half of the data sets. In addition, the multiple binding modes derived by kmerHMM are biologically meaningful and will be useful in interpreting other genome-wide data such as those generated from ChIP-seq. The executables and source codes are available at the authors' websites: e.g. http://www.cs.toronto.edu/~wkc/kmerHMM. PMID- 23814192 TI - Post-traumatic delayed onset pectoralis myospasm secondary to alpha-gamma dysfunction. AB - A restrained motor vehicle accident victim suffered from delayed onset left pectoralis myospasms refractory to multiple treatments: behavioural, conservative, physical therapy, opiate, muscle relaxer and incomplete response to invasive pain management spinal blocks. After conduction of a literature review, several authors had noted the mechanism of alpha-gamma loop dysfunction resulting in myospams, and also case studies which described painful postsurgical myospasms that were treated with neurectomy and/or botulinum toxin A with successful results. The patient in this case underwent an initial lidocaine injection to observe response to treatment, followed by two treatments with botulinum toxin A treatment with subsequent resolution of symptoms. Successful therapy and previous research supports that botulinum toxin A can be an effective treatment for myospasms secondary to trauma-induced alpha-gamma dysfunction, as suggested by the cellular pathophysiology. PMID- 23814193 TI - Recurrent venous thrombosis in Ehlers-Danlos syndrome type III: an atypical manifestation. AB - Ehlers-Danlos syndrome (EDS) comprises a group of hereditary connective tissue disorders in which collagen synthesis and fibrogenesis are impaired. Patients with EDS type III have a bleeding tendency manifested by ecchymoses and haematomas. However, thrombotic events are rare in this entity. Herein, we present a 48-year-old Hispanic man with EDS type III who had recurrent cephalic vein thrombophlebitis and thrombosis, and brachial vein thrombosis. Tests for hypercoagulable disorders including antithrombin III activity, protein C activity, protein S activity, anticardiolipin antibodies, homocysteine levels, factor V Leiden mutation and prothrombin gene mutation were negative. The patient required long-term anticoagulation with warfarin. After 3 years follow-up, he did not present further thrombotic events. Clinicians should be aware that patients with EDS might be at risk for hypercoagulable disorders. PMID- 23814194 TI - Streptococcus agalactiae endogenous endophthalmitis. AB - Streptococcus agalactiae (SA) is a Group B Streptococcus, which is a common pathogen implicated in neonatal and geriatric sepsis. Endogenous bacterial endophthalmitis (EBE) is a condition that results from haematogenous seeding of the globe, during transient or persistent bacteremia. We document a case of a non septic geriatric patient, who developed EBE after a transient bacteraemia with SA. PMID- 23814195 TI - Diffuse perforated necrotising amoebic colitis with histoplasmosis in an immunocompetent individual presenting as an acute abdomen. AB - Perforated necrotising amoebic colitis associated with intestinal histoplasmosis has rarely been reported in an immunocompetent individual. Radiology and preoperative features are non-specific and requires histopathological examination for a definitive diagnosis. Hence, this condition needs to be considered in the differential diagnosis of complicated infective colitis. PMID- 23814196 TI - Growth of corneal epithelial cells over in situ therapeutic contact lens after simple limbal epithelial transplantation (SLET). AB - An 11-year-old boy underwent simple limbal epithelial transplantation (SLET) from the healthy right eye to his left eye for total limbal stem cell deficiency. One month later, corneal surface epithelialised and whitish plaques overlying the transplants were seen inferiorly. Those plaques were adherent to the surface of the contact lens and underlying corneal surface had smooth elevations. Similar findings were noted in a 23-year man following cyanoacrylate glue application for corneal perforation. On histological and immunohistochemical analysis, cells lining the contact lenses were identified as corneal epithelial cells. These cases illustrate epithelial cell growth on the contact lens and epithelial hyperplasia on corresponding surface of the cornea. Exorbitant proliferation of the epithelial cells may be owing to young age; therefore, early contact lens removal after SLET in young age, can possibly avoid epithelial hyperplasia. This also reiterates the possibility of using contact lens as a scaffold to grow epithelial cells. PMID- 23814197 TI - Aneurysmal bone cyst of thoracic spine: case report and brief review of literature. AB - A 16-year-old girl was admitted with insidious onset, gradually progressive spastic sensori-motor paraparesis, with a sensory level at D10 dermatome without bowel or bladder involvement for the last 2 months following trivial trauma on the lower back. MRI of the spine showed a low-to-intermediate signal intensity, heterogeneous mass with multiple fluid levels. A diagnosis of aneurysmal bone cyst was made. A D8-D9 laminectomy with near total excision of mass was performed. Histopathology of the mass showed cyst cavity filled with haemorrhage surrounded by bony trabeculae confirming the diagnosis. Following excision the patient had excellent recovery. We report this case owing to its rarity and to emphasise the importance of surgery if there is cord compression. PMID- 23814198 TI - Dentin dysplasia type I. AB - Dentin dysplasia type I is a rare hereditary disturbance of dentin formation characterised clinically by nearly normal appearing crowns and hypermobility of teeth that affects one in every 100,000 individuals and manifests in both primary and permanent dentitions. Radiographic analysis shows obliteration of all pulp chambers, short, blunted, and malformed roots, and periapical radiolucencies of non-carious teeth. This paper presents three cases demonstrating classic features of type I dentin dysplasia. PMID- 23814199 TI - Management of refractory irritable bowel syndrome and comorbid mental ill-health: challenges, reflections and patient's perspective of life on the body-mind divide. AB - This complex case illustrates how blurred the divide between body and mind can be. In a patient with refractory irritable bowel symptoms, the emergence of new social problems exacerbate both psychiatric (anxiety and depression) and physical symptoms. Treatment of the physical symptomatology consisted of acute hospital treatments initially and subsequent primary care consultations. Psychiatric treatment consists of psychopharmacological (venlafaxine and mirtazapine) and psychotherapeutic approaches (cognitive behavioural therapy initially, and clinical hypnosis). The objectives of psychiatric treatment were to stabilise symptoms, reduce hospital admissions and foster self-management. The gains of management are presented. Social difficulties encountered over the period of treatment were legal processes to gain custody of son, bereavement, financial difficulties occasioned by stoppage of welfare benefits and legal processes involved in welfare appeal. Importantly, the patient's perceptive of treatment and care is presented. Detrimental effects that current welfare reforms in the UK may have on health are highlighted. PMID- 23814200 TI - A clinically hidden but severely destructive entity. AB - The diagnosis' Aggressive Periodontitis' (AgP), defined by the International workshop for a classification of periodontal diseases and conditions in 1999, refers to the multifactorial, severe and rapidly progressive form of periodontitis, which primarily--but not exclusively--affects younger patients. Direct and indirect bacterial effects influencing the host immune response play a significant part in the aetiology of AgP comparable with chronic periodontitis. In addition to various virulence factors of specific periodontal pathogens, a genetic predisposition influences the outbreak and progression of the disease. This report describes the disciplinary treatment of AgP patient with progressing full-mouth bone resorption. PMID- 23814201 TI - Haemophagocytic lymphohistiocytosis mimicking septic shock after the initiation of chemotherapy for squamous cell carcinoma of the neck. AB - Haemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal disorder resulting from a highly stimulated immune response with uncontrolled accumulation of lymphocytes and macrophages in multiple organs. Both the inherited and acquired forms of this disease exist; the latter can sometimes occur secondary to different malignancies. In this report, we present a middle aged Hispanic man who presented with features of septic shock during the course of chemotherapy for squamous cell carcinoma of the neck. Despite aggressive treatment for septic shock, he rapidly deteriorated and died after 30 h of admission. Autopsy findings confirmed a diagnosis of HLH. HLH should be recognised as a serious adverse event during chemotherapy for different malignancies including squamous cell carcinoma of the neck. PMID- 23814202 TI - Bleomycin-induced flagellate dermatitis. AB - Flagellate dermatitis shows very characteristic lesions: linear erythema or hyperpigmentation in various areas of the skin. It is a side effect of bleomycin, an immunosupressive drug used for several types of cancers. All physicians must be aware of this disease so they can make a rapid diagnosis and interrupt the causative agent. Our patient presented during chemotherapy for a Hodgkin's lymphoma pruritic, erythematous lesions on the lower limbs and the back diagnosed as flagellate dermatitis due to bleomycin. PMID- 23814203 TI - Tubercular thyroid abscess. AB - We encountered a patient who presented with neck swelling, difficulty in swallowing, voice change along with systemic features such as evening rise of temperature, chronic cough and weight loss. Ultrasonography of the thyroid gland revealed two cystic swellings. An ultrasound guided fine needle aspiration cytology was suggestive of tubercular abscess. The patient responded well to antigravity aspiration of the swellings and antitubercular treatment. PMID- 23814204 TI - An asymptomatic orthodontic bracket in the mandibular alveolar bone region. PMID- 23814205 TI - Brugada syndrome with elevated cardiac biomarkers. AB - A 45-year-old man presented to our hospital with a history of palpitations, presyncope and chest pain. Vital signs and physical examination were unremarkable. Initial ECG revealed sinus rhythm with non-specific ST changes. Subsequent ECGs showed rsr' in V1 and saddle-back pattern of ST elevation in lead V2, indicative of type 2 Brugada ECG pattern. Telemetry monitoring revealed multiple runs of asymptomatic non-sustained polymorphic ventricular tachycardia. Ajmaline challenge test confirmed the diagnosis of Brugada syndrome. The subsequent rise and fall of cardiac biomarkers was suggestive of acute myocardial infarction which was refuted by having normal coronaries by cardiac catheterisation. Echocardiogram showed normal cardiac structures and function without any evidence of myopericarditis. Automated intracardiac defibrillator was recommended which the patient declined. PMID- 23814206 TI - Spermatic cord liposarcoma: organ-sparing surgery. AB - The authors report a case of a 53-year-old male patient who came to the urologic clinic with symptoms of a left-sided testicular mass with 4 years of evolution. A left inguinal approach was decided for scrotal exploration. High clamping of the spermatic cord was performed with complete excision of the lesion, which was sent for pathology, preserving the spermatic cord and the testicle. The peroperative result was a well-differentiated liposarcoma of the spermatic cord. We then chose to preserve the ipsilateral testis (organ-sparing surgery). Postoperatively, the final pathology confirmed a well-differentiated spermatic cord liposarcoma, revealing negative surgical margins and no signs of local invasion, namely of the underlying structures. The patient is currently doing well, with no signs of recurrence after one and a half year of follow-up. PMID- 23814208 TI - Eschar: an important clue to diagnosis. PMID- 23814207 TI - Femoral arteriovenous fistula associated with calf pain 2 months after removal of a haemodialysis catheter. AB - Double-lumen catheters are widely used to achieve temporary access to circulation in patients requiring acute haemodialysis (HD); however, several complications are associated with the insertion of these catheters. Arteriovenous fistula (AVF), a rare but significant complication of catheter insertion, has been reported in several cases. In this report, we describe a case of a right femoral AVF that caused calf pain 2 months after HD catheter removal. The right ankle brachial index was 0.46, and the diagnosis of AVF was confirmed using colour Doppler ultrasound and three-dimensional CT. The fistula was managed by surgical vascular repair. The right ABI improved to 1.06, and the absence of fistula was confirmed using three-dimensional CT. Therefore, physicians and nursing staff should be aware of the potential of this complication and should perform clinical and medical examinations at the insertion and removal of temporary HD catheters. PMID- 23814209 TI - Adenomatoid odontogenic tumour. AB - Adenomatoid odontogenic tumour (AOT) is a benign non-invasive odontogenic tumour, having mostly a slow and sustained growth pattern. AOT is an uncommon lesion of odontogenic origin, which affects young individuals, with a female predilection and mostly occurring in the second decade. In the literature, it has been considered as a hamartoma rather than a true neoplasm because of its limited size, minimal growth potential and the lack of recurrence. We present an extrafollicular central variant of AOT with a occurrence rate of 30%, adjacent to the incisors. PMID- 23814210 TI - Pulmonary alveolar microlithiasis: a rare cause of right heart failure. PMID- 23814211 TI - Catatonia and parkinsonism as a sequelae of typhoid fever: a rare experience. AB - Although neurological manifestations of typhoid fever was thought to be obsolete from modern world, emergence of multidrug resistant typhoid bacilli and reporting of outbreak of typhoid fever with a range of early neuropsychiatric manifestations from various parts of world has led clinicians and investigators to re-evaluate the clinical spectrum of this endemic sinister disease. An 18-year old male student was admitted in psychiatry ward with mutism, staring look, posturing and rigidity. There was history of typhoid fever 1 week before for which he was prescribed cefuroxime. Although investigations fail to provide any clue, his catatonic symptoms disappeared 2 weeks later giving way to resting tremor, bradykinesia, cog-wheel rigidity but without gait abnormality. He was successfully treated with lorazepam, amantidine, olanzapine and pramiprexole. The patient was asymptomatic within a month. He had no recurrence of symptoms till last follow-up, 6 months from the illness. PMID- 23814212 TI - Diagnosis demystified: CT as diagnostic tool in endodontics. AB - Diagnosis in endodontics is usually based on clinical and radiographical presentations, which are only empirical methods. The role of healing profession is to apply knowledge and skills towards maintaining and restoring the patient's health. Recent advances in imaging technologies have added to correct interpretation and diagnosis. CT is proving to be an effective tool in solving endodontic mysteries through its three-dimensional visualisation. CT imaging offers many diagnostic advantages to produce reconstructed images in selected projection and low-contrast resolution far superior to that of all other X-ray imaging modalities. This case report is an endeavour towards effective treatment planning of cases with root fracture, root resorption using spiral CT as an adjuvant diagnostic tool. PMID- 23814213 TI - Bilateral knee extensor disruption in severe crouch gait. AB - Crouch gait is one of the most troublesome abnormal gait patterns in ambulant patients with spastic diplegic cerebral palsy (CP). Although CP is a non progressive condition, crouch gait can result in knee extensor disruption (KED) causing deterioration or cessation of ambulation. Diagnosis of KED in crouch gait is often overlooked. We report a seminal case of a 28-year-old active woman with diplegic CP with severe crouch gait who was referred for gait analysis due to subjective decreased walking speed and endurance. Gait analysis showed kinematic features typical of KED and radiology confirmed the diagnosis. PMID- 23814214 TI - Lungs on fire. AB - A 50-year-old man was diagnosed as classical Hodgkin's lymphoma stage III B. He had been a reformed smoker and has had a coronary artery disease as his comorbidity. He was started on adriamycin, bleomycin, vinblastine, dacarbazine (ABVD)-based chemotherapy. An interim disease evaluation was suggestive of metabolic complete response after four cycles of ABVD. After completion of his sixth cycle, he presented with low-grade fever, dry cough, generalised malaise and increasing dyspnoea on exertion. FDG (18 fluoro-deoxyglucose) positron emission tomography (PET)-CT revealed intensely FDG avid diffuse activity in mid and lower zone both lung fields. He was started on intravenous steroids along with broad spectrum antibiotic and antifungal cover. Clinical, radiological and laboratory assays did not reveal any infective pathology. He was diagnosed as bleomycin-induced pulmonary toxicity (BIP). Despite best supportive care, his pulmonary functions deteriorated and he developed cardiac arrhythmias. He finally succumbed to the irreversible chemotherapy toxicity of a curable malignancy. PMID- 23814215 TI - Gorlin-Goltz syndrome: a rare case report. AB - Gorlin-Goltz syndrome (GS), also known as nevoid basal cell carcinoma syndrome, is an infrequent multisystem disease inherited in a dominant autosomal way, which shows a high level of penetrance and variable expressiveness. It is characterised by keratocystic odontogenic tumours (KCOT) in the jaw, multiple basal cell nevi carcinomas and skeletal abnormalities. This syndrome may be diagnosed early by a dentist by routine radiographical examinations in the first decade of life, since the KCOTs are usually one of the first manifestations of the syndrome. This article describes an 11-year-old boy with GS. PMID- 23814216 TI - Florid osseous dysplasia. AB - Florid osseous dysplasia (FOD) is the most dramatic and rare variant of the cemento-osseous lesions in which the normal cancellous bone is replaced by dense, acellular cemento-osseous tissue in a background of fibrous connective tissue. It appears to be a widespread form of periapical cemental dysplasia (PCD). No clear definition indicates that when the multiple lesions of PCD can be termed as FOD. If PCD is identified in three or four quadrants or is extensive in one jaw, then it is considered as FOD. Here, in this article, we report a case of FOD in 35 year-old woman. PMID- 23814217 TI - Urethral tumour: rare images of unaware entity. PMID- 23814218 TI - Metal impaction: an unusual cause of dysphagia. AB - A 41-year-old unemployed construction worker with a background of insulin dependent diabetes mellitus, hypertension, chronic kidney disease stage 3, previous incisor tooth abscess aged 9, for which he was fitted with metal dentures, underwent a right below knee amputation. Postoperative day 8 he experienced episodes of dysphagia and vomiting postparandial. CT thorax revealed a foreign body in the midline region of the mediastinum. After two failed attempts at endoscopic extraction of the metal denture, the patient underwent surgical extraction of his metal denture. PMID- 23814219 TI - Jejuno-jejunal intussusception: an unusual complication of feeding jejunostomy. AB - The jejuno-jejunal intussusception is a rare complication of jejunostomy tube placement. We are reporting a case of 33-year-old man who was suffering from absolute dysphagia due to carcinoma of cricopharynx with advanced metastatic disease, who underwent Stamms feeding jejunostomy as a part of palliative care. After 1 month he presented with colicky type of pain in the abdomen and vomiting. Sonogram of abdomen revealed a target sign and a feeding tube in a dilated jejunum. Abdominal CT proved the sonographic impression of jejuno-jejunal intussusception. He, therefore, underwent exploratory laparotomy and resection and anastomosis of the intussuscepted bowel. New feeding jejunostomy (FJ) was done distally from the anastomotic site. As per the literature this complication has been reported in Witzels jejunostomy. In our case the patient had undergone Stamms jejunostomy with placement of a Ryle's tube. Intussusception should be considered if a patient comes with abdominal pain and vomiting following FJ. PMID- 23814220 TI - Portal pyaemia secondary to open haemorrhoidectomy: need for prophylactic broad spectrum antibiotics. AB - A 70-year-old man presenting with long standing grade 3 Haemorrhoids, underwent open haemorrhoidectomy under spinal anaesthesia. The patient passed stools on subsequent day and there was no bleeding per rectum. On day 5, he complained of dull aching upper abdominal pain. On physical examination, the abdomen was soft and there was mild tenderness in the epigastric region. Subsequently, he developed high temperature with chills and rigors. His condition failed to improve and the abdominal pain increased in severity. There was no pain in the perianal region and per rectum examination was normal. Leucocyte count rose to 12*10(9)/L and there were toxic changes on peripheral smear. Blood culture grew Staphylococcus aureus. Liver enzymes were mildly elevated. Coagulation profile was deranged. Fibrin degradation products were positive. D-dimer was high. CT revealed acute thrombosis of left portal vein and microabscesses suggestive of portal pyaemia. PMID- 23814223 TI - Dancing vegetations: Kocuria rosea endocarditis. PMID- 23814224 TI - Mixed pyogenic and tuberculous liver abscess: clinical suspicion is what matters. AB - Tuberculosis (TB) is a rare cause of liver abscess, even in country like India where it is a very common infection. Moreover, tubercular liver abscess (TLA) is the most unusual pattern of hepatic tuberculosis. We report an unusual case of liver abscess in an immune-competent patient presenting only with weight loss. On investigation, initially it appeared pyogenic, but later turn out to be a mixed infection with tuberculosis. He responded well to antibiotic and antitubercular drugs. A mixed pyogenic and TLA is very uncommon. We conclude that, tuberculosis should be suspected in liver abscess, especially in the absence of typical features and failure to respond to antibiotics. PMID- 23814226 TI - Hypoglycaemia begets hypoglycaemia. AB - Drug-induced (insulin/insulin secretagogue) hypoglycaemia is the most common cause of hypoglycaemia particularly in the elderly. It is estimated that hypoglycaemia of any severity occurs annually in 5-20% of patients taking antihyperglycaemic agents. Although these hypoglycaemic episodes are rarely fatal, they can be associated with serious clinical sequelae. The half-life for most sulfonylurea medications is 14-16 h; they can cause severe, prolonged hypoglycaemia. It is important to recognise, prevent and treat hypoglycaemic episodes secondary to the use of antihyperglycaemic agents. Patient education has become focused on minimising hyperglycaemia but emphasis must be placed on minimising even minor subclinical hypoglycaemia because it will contribute to a vicious cycle of hypoglycaemia begetting hypoglycaemia. Ten per cent dextrose is recommended for the reversal of all hypoglycaemic episodes rather than the conventional 50% dextrose. Octreotide can be an option for recurrent and relapsing hypoglycaemia in an acute setting. PMID- 23814225 TI - Idiopathic intracranial hypertension and transverse sinus stenoses. AB - An 18-year-old woman was diagnosed with idiopathic intracranial hypertension (IIH) and bilateral transverse sinus stenoses (TSS), after presenting with papilledema and decreased visual acuity. Lumbar puncture revealed an opening pressure of >60 cm H2O. MRI showed bilateral TSS believed to be associated with the IIH. Initial treatment consisted of symptom relief by a temporary lumbar drain for cerebrospinal fluid (CSF) diversion, while the pros and cons of a more permanent solution by insertion of a ventriculoperitoneal shunt (VPS) or bilateral transverse sinus stent was discussed. A VPS was inserted since the patient had improved with CSF diversion. MRI verified reopening of the venous sinuses after shunt placement, and the patient remains asymptomatic with no signs of relapse after 3 years of follow-up. PMID- 23814227 TI - A lumpy appendix. AB - A De Garengeot hernia is a rare and interesting presentation of a groin lump, with the diagnosis usually only being identified during surgery. It still presents clinicians with diagnostic and therapeutic challenges, owing to the lack of signs associated with sepsis and so an important case to highlight. We present a case report of a 90-year-old woman who developed a De Garengeot hernia as part of her presentation of bowel obstruction illustrating the importance of careful examination and to ensure prompt diagnosis and initiation of appropriate multidisciplinary management. PMID- 23814228 TI - Surgical intervention for adnexal masses during pregnancy. AB - We aimed to evaluate the influence of surgical intervention on gestational and neonatal outcomes in women who underwent elective surgery in the second trimester of gestation because of an adnexal mass. We retrospectively reviewed the hospital records of women who underwent elective surgery for adnexal masses in the second trimester of gestation between 2006 and 2012. The ages of the women ranged between 17 and 33 years. Eight women underwent a laparotomy, and one woman, who aborted on the day of the operation, underwent a laparoscopy. Dermoid cysts, cystadenoma and borderline ovarian tumours were present in four, two and two of the women, respectively. Eight women had no complications after surgery and delivered healthy newborns at term. We concluded that elective surgery on an adnexal mass in the second trimester of gestation is safe for both the mother and the fetus. PMID- 23814229 TI - Mycotic aneurysm: a rare and dreaded complication of infective endocarditis. AB - Mycotic cerebral aneurysm is a rare and potentially fatal complication of infective endocarditis. A young man was diagnosed with culture negative infective endocarditis of mitral valve with cerebral aneurysm. The patient was started on conservative management, but he died owing to intracerebral haemorrhage. In the absence of large randomised trials, there is a lack of consensus regarding the management of unruptured aneurysms. Since mycotic aneurysms are known to resolve or decrease in size with antimicrobial therapy, several institutions advice the conservative approach. A few case reports like the present case have shown that the risk of aneurysmal rupture and death is considerably high with the conservative approach. Endovascular therapy has shown to reduce the mortality in this subgroup. These patients should be managed aggressively with endovascular or surgical procedure along with antimicrobial therapy. PMID- 23814230 TI - Aggressive fibromatosis (desmoid tumour) of the head and neck: a benign neoplasm with high recurrence. AB - A 50-year-old man presented with a 5-month history of swelling over the right side of neck. The swelling was associated with dull aching pain radiating to the forearm without associated weakness of upper extremity or sensory loss. There was no history of trauma. On examination a fixed mass approximately 8*6 cm in size, smooth, firm in consistency, with ill-defined margins was present in the right posterior triangle. MRI scan of the neck revealed well-defined, lobulated, heterogeneously enhancing altered signal intensity mass at the root of neck. Debulking of the tumour was performed in view of its close proximity to the brachial plexus. Histopathology revealed aggressive fibromatosis (AF). AF is a benign fibrous neoplasm arising from fascia, periosteum and musculoaponeurotic structures of the body. AF in the head and neck region tends to be locally aggressive with a nature to invade bone and soft tissue structures. PMID- 23814231 TI - Acrodermatitis enteropathica-like skin lesions in a neonate. AB - A male neonate was born to a sixth-gravida mother with a history of four early neonatal deaths. On day 21 of life, the patient was admitted for poor feeding, vomiting and encephalopathy. Final diagnosis of propionic acidaemica (propionylcarnitine, 17.67 MUmol/L) was made. He was managed by peritoneal dialysis followed by protein-free and special lipid diet, sodium benzoate and multivitamins. On day 28 of life, he developed acrodermatitis enteropathica-like skin lesions on perioral and diaper area that did not respond to oral zinc or antimicrobials. A possibility of acrodermatitis acidaemica was kept and supplementation with essential amino acids started, following which the skin lesions regressed. PMID- 23814233 TI - Research fraud and The Bone & Joint Journal. PMID- 23814234 TI - Dysphagia following anterior cervical spinal surgery: a systematic review. AB - Dysphagia is a common complication of anterior surgery of the cervical spine. The incidence of post-operative dysphagia may be as high as 71% within the first two weeks after surgery, but gradually decreases during the following months. However, 12% to 14% of patients may have some persistent dysphagia one year after the procedure. It has been shown that female gender, advanced age, multilevel surgery, longer operating time and severe pre-operative neck pain may be risk factors. Although the aetiology remains unclear and is probably multifactorial, proposed causes include oesophageal retraction, prominence of the cervical plate and prevertebral swelling. Recently, pre-operative tracheal traction exercises and the use of retropharyngeal steroids have been proposed as methods of reducing post-operative dysphagia. We performed a systematic review to assess the incidence, aetiology, risk factors, methods of assessment and management of dysphagia following anterior cervical spinal surgery. PMID- 23814235 TI - The cost analysis of cemented versus cementless total hip replacement operations on the NHS. AB - In a time of limited resources, the debate continues over which types of hip prosthesis are clinically superior and more cost-effective. Orthopaedic surgeons increasingly need robust economic evidence to understand the full value of the operation, and to aid decision making on the 'package' of procedures that are available and to justify their practice beyond traditional clinical preference. In this paper we explore the current economic debate about the merits of cemented and cementless total hip replacement, an issue that continues to divide the orthopaedic community. PMID- 23814236 TI - Radiological measurement of femoral stem version using a modified Budin method. AB - Version of the femoral stem is an important factor influencing the risk of dislocation after total hip replacement (THR) as well as the position of the acetabular component. However, there is no radiological method of measuring stem anteversion described in the literature. We propose a radiological method to measure stem version and have assessed its reliability and validity. In 36 patients who underwent THR, a hip radiograph and CT scan were taken to measure stem anteversion. The radiograph was a modified Budin view. This is taken as a posteroanterior radiograph in the sitting position with 90 degrees hip flexion and 90 degrees knee flexion and 30 degrees hip abduction. The angle between the stem-neck axis and the posterior intercondylar line was measured by three independent examiners. The intra- and interobserver reliabilities of each measurement were examined. The radiological measurements were compared with the CT measurements to evaluate their validity. The mean radiological measurement was 13.36 degrees (sd 6.46) and the mean CT measurement was 12.35 degrees (sd 6.39) (p = 0.096). The intra- and interobserver reliabilities were excellent for both measurements. The radiological measurements correlated well with the CT measurements (p = 0.001, r = 0.877). The modified Budin method appears reliable and valid for the measurement of femoral stem anteversion. PMID- 23814237 TI - High rate of revision and a high incidence of radiolucent lines around Metasul metal-on-metal total hip replacements: results from a randomised controlled trial of three bearings after seven years. AB - A total of 397 hips were randomised to receive Metasul metal-on-metal (MoM), metal-on-conventional polyethylene (MoP) or ceramic-on-polyethylene (CoP) bearings using a cemented triple-tapered polished femoral component (MS-30). There were 129 MoM hips in 123 patients (39 male and 84 female, mean age 63.3 years (40.7 to 72.9)), 137 MoP hips in 127 patients (39 male and 88 female, mean age 62.8 years (24.5 to 72.7)) and 131 CoP hips in 124 patients (51 male and 73 female, mean age 63.9 years (30.6 to 73.8)). All acetabular components were cemented Weber polyethylene components with the appropriate inlay for the MoM articulation. Clinical evaluation was undertaken using the Harris hip score (HHS) and radiological assessments were made at two, five and seven years. The HHS and radiological analysis were available for 341 hips after seven years. The MoM group had the lowest mean HHS (p = 0.124), a higher rate of revision (p < 0.001) and a higher incidence of radiolucent lines in unrevised hips (p < 0.001). In all, 12 revisions had been performed in 12 patients: eight in the MoM group (four for infection, four for aseptic loosening, three in the MoP group (one each of infection, dislocation and pain) and one in the CoP group (infection). Our findings reveal no advantage to the MoM bearing and identified a higher revision rate and a greater incidence of radiolucent lines than with the other articulations. We recommend that patients with a 28 mm Metasul MoM bearing be followed carefully. PMID- 23814238 TI - Acetabular reconstruction in patients with low and high dislocation: 20- to 32 year survival of an impaction grafting technique (named cotyloplasty). AB - We report the results at a mean of 24.3 years (20 to 32) of 61 previously reported consecutive total hip replacements carried out on 44 patients with severe congenital hip disease, performed with reconstruction of the acetabulum with an impaction grafting technique known as cotyloplasty. The mean age of the patients at operation was 46.7 years (23 to 68) and all were women. The patients were followed post-operatively for a mean of 24.3 years (20 to 32), using the Merle d'Aubigne and Postel scoring system as modified by Charnley, and with serial radiographs. At the time of the latest follow-up, 28 acetabular components had been revised because of aseptic loosening at a mean of 15.9 years (6 to 26), and one at 40 days after surgery because of repeated dislocations. The overall survival rate for aseptic failure of the acetabular component at ten years was 93.1% (95% confidence interval (CI) 86.5 to 96.7) when 53 hips were at risk, and at 23 years was 56.1% (95% CI 49.4 to 62.8), when 22 hips remained at risk. These long-term results are considered satisfactory for the reconstruction of an acetabulum presenting with inadequate bone stock and circumferential segmental defects. PMID- 23814239 TI - The relevance of the radiological signs of acetabular retroversion among patients with femoroacetabular impingement. AB - Orthopaedic surgeons have accepted various radiological signs to be representative of acetabular retroversion, which is the main characteristic of focal over-coverage in patients with femoroacetabular impingement (FAI). Using a validated method for radiological analysis, we assessed the relevance of these signs to predict intra-articular lesions in 93 patients undergoing surgery for FAI. A logistic regression model to predict chondral damage showed that an acetabular retroversion index (ARI) > 20%, a derivative of the well-known cross over sign, was an independent predictor (p = 0.036). However, ARI was less significant than the Tonnis classification (p = 0.019) and age (p = 0.031) in the same model. ARI was unable to discriminate between grades of chondral lesions, while the type of cam lesion (p = 0.004) and age (p = 0.047) were able to. Other widely recognised signs of acetabular retroversion, such as the ischial spine sign, the posterior wall sign or the cross-over sign were irrelevant according to our analysis. Regardless of its secondary predictive role, an ARI > 20% appears to be the most clinically relevant radiological sign of acetabular retroversion in symptomatic patients with FAI. PMID- 23814240 TI - Double-bundle medial patellofemoral ligament reconstruction with hamstring tendon autograft and mediolateral patellar tunnel fixation: a meta-analysis of outcomes and complications. AB - Medial patellofemoral ligament (MPFL) reconstruction is used to treat patellar instability and recurrent patellar dislocation. Anatomical studies have found the MPFL to be a double-bundle structure. We carried out a meta-analysis of studies reporting outcomes of patellofemoral reconstruction using hamstring tendon autograft in a double-bundle configuration and patellar fixation via mediolateral patellar tunnels. A literature search was undertaken with no language restriction in various databases from their year of inception to July 2012. The primary outcome examined was the post-operative Kujala score. We identified 320 MPFL reconstructions in nine relevant articles. The combined mean post-operative Kujala score was 92.02 (standard error (se) 1.4, p = 0.001) using a fixed effects model and 89.45 (se 37.9, p = 0.02) using random effect modelling. The reported rate of complications with MPFL reconstruction was 12.5% (40 of 320) with stiffness of the knee being the most common. High-quality evidence in assessing double-bundle MPFL reconstruction is lacking. The current literature consists of a mixture of prospective and retrospective case series. High-quality randomised trials evaluating this procedure are still awaited. PMID- 23814241 TI - Comparison of the clinical and radiological outcomes of three minimally invasive techniques for total knee replacement at two years. AB - Minimally invasive total knee replacement (MIS-TKR) has been reported to have better early recovery than conventional TKR. Quadriceps-sparing (QS) TKR is the least invasive MIS procedure, but it is technically demanding with higher reported rates of complications and outliers. This study was designed to compare the early clinical and radiological outcomes of TKR performed by an experienced surgeon using the QS approach with or without navigational assistance (NA), or using a mini-medial parapatellar (MP) approach. In all, 100 patients completed a minimum two-year follow-up: 30 in the NA-QS group, 35 in the QS group, and 35 in the MP group. There were no significant differences in clinical outcome in terms of ability to perform a straight-leg raise at 24 hours (p = 0.700), knee score (p = 0.952), functional score (p = 0.229) and range of movement (p = 0.732) among the groups. The number of outliers for all three radiological parameters of mechanical axis, frontal femoral component alignment and frontal tibial component alignment was significantly lower in the NA-QS group than in the QS group (p = 0.008), but no outlier was found in the MP group. In conclusion, even after the surgeon completed a substantial number of cases before the commencement of this study, the supplementary intra-operative use of computer-assisted navigation with QS-TKR still gave inferior radiological results and longer operating time, with a similar outcome at two years when compared with a MP approach. PMID- 23814242 TI - Changes in tibial bone density measured from standard radiographs in cemented and uncemented total knee replacements after ten years' follow-up. AB - Stress shielding resulting in diminished bone density following total knee replacement (TKR) may increase the risk of migration and loosening of the prosthesis. This retrospective study was designed to quantify the effects of the method of fixation on peri-prosthetic tibial bone density beneath cemented and uncemented tibial components of similar design and with similar long-term survival rates. Standard radiographs taken between two months and 15 years post operatively were digitised from a matched group of TKRs using cemented (n = 67) and uncemented (n = 67) AGC tibial prostheses. Digital radiograph densitometry was used to quantify changes in bone density over time. Age, length of follow-up, gender, body mass index and alignment each significantly influenced the long-term pattern of peri-prosthetic bone density. Similar long-term changes in density irrespective of the method of fixation correlated well with the high rate of survival of this TKR at 20 years, and suggest that cemented and uncemented fixation are both equally viable. PMID- 23814243 TI - Total knee replacement with retention of both cruciate ligaments: a 22-year follow-up study. AB - We report on the long-term results of 163 bicruciate-retaining Hermes 2C total knee replacements in 130 patients at a mean follow-up of 22.4 years (20.3 to 23.5). Even when the anterior cruciate ligament had a partially degenerative appearance it was preserved as long as the knee had a normal anterior drawer and Lachman's test pre-operatively. The description and surgical technique of this minimally constrained prosthesis were published in 1983 and the ten-year clinical results in 1999. A total of 12% of the knees (20 of 163) in this study were revised because of wear of the polyethylene tibial insert. Excellent stability was achieved and the incidence of aseptic component loosening was 4.3% (seven of 163). The survival rate using revision for any reason as the endpoint was 82% (95% confidence interval 76.2 to 88.0). Although this series included a relatively small number of replacements, it demonstrated that the anterior cruciate ligament, even when partially degenerated at the time of TKR, remained functional and provided adequate stability at a long-term follow-up. PMID- 23814244 TI - Use of a strontium-enriched calcium phosphate cement in accelerating the healing of soft-tissue tendon graft within the bone tunnel in a rabbit model of anterior cruciate ligament reconstruction. AB - We investigated whether strontium-enriched calcium phosphate cement (Sr-CPC) treated soft-tissue tendon graft results in accelerated healing within the bone tunnel in reconstruction of the anterior cruciate ligament (ACL). A total of 30 single-bundle ACL reconstructions using tendo Achillis allograft were performed in 15 rabbits. The graft on the tested limb was treated with Sr-CPC, whereas that on the contralateral limb was untreated and served as a control. At timepoints three, six, nine, 12 and 24 weeks after surgery, three animals were killed for histological examination. At six weeks, the graft-bone interface in the control group was filled in with fibrovascular tissue. However, the gap in the Sr-CPC group had already been completely filled in with new bone, and there was evidence of the early formation of Sharpey fibres. At 24 weeks, remodelling into a normal ACL-bone-like insertion was found in the Sr-CPC group. Coating of Sr-CPC on soft tissue tendon allograft leads to accelerated graft healing within the bone tunnel in a rabbit model of ACL reconstruction using Achilles tendon allograft. PMID- 23814245 TI - Metatarsal transfer for the treatment of post-axial metatarsal-type foot synpolydactyly: a new technique that allows for comfortable shoe wearing. AB - We analysed the clinical and radiological outcomes of a new surgical technique for the treatment of heterozygote post-axial metatarsal-type foot synpolydactyly with HOX-D13 genetic mutations with a mean follow-up of 30.9 months (24 to 42). A total of 57 feet in 36 patients (mean age 6.8 years (2 to 16)) were treated with this new technique, which transfers the distal part of the duplicated fourth metatarsal to the proximal part of the fifth metatarsal. Clinical and radiological assessments were undertaken pre- and post-operatively and any complications were recorded. Final outcomes were evaluated according to the methods described by Phelps and Grogan. Forefoot width was reduced and the lengths of the all reconstructed toes were maintained after surgery. Union was achieved for all the metatarsal osteotomies without any angular deformities. Outcomes at the final assessment were excellent in 51 feet (89%) and good in six (11%). This newly described surgical technique provides for painless, comfortable shoe-wearing after a single, easy-to-perform operation with good clinical, radiological and functional outcomes. PMID- 23814246 TI - Is there an association between the individual anatomy of the scapula and the development of rotator cuff tears or osteoarthritis of the glenohumeral joint?: A radiological study of the critical shoulder angle. AB - We hypothesised that a large acromial cover with an upwardly tilted glenoid fossa would be associated with degenerative rotator cuff tears (RCTs), and conversely, that a short acromion with an inferiorly inclined glenoid would be associated with glenohumeral osteoarthritis (OA). This hypothesis was tested using a new radiological parameter, the critical shoulder angle (CSA), which combines the measurements of inclination of the glenoid and the lateral extension of the acromion (the acromion index). The CSA was measured on standardised radiographs of three groups: 1) a control group of 94 asymptomatic shoulders with normal rotator cuffs and no OA; 2) a group of 102 shoulders with MRI-documented full thickness RCTs without OA; and 3) a group of 102 shoulders with primary OA and no RCTs noted during total shoulder replacement. The mean CSA was 33.1 degrees (26.8 degrees to 38.6 degrees ) in the control group, 38.0 degrees (29.5 degrees to 43.5 degrees ) in the RCT group and 28.1 degrees (18.6 degrees to 35.8 degrees ) in the OA group. Of patients with a CSA > 35 degrees , 84% were in the RCT group and of those with a CSA < 30 degrees , 93% were in the OA group. We therefore concluded that primary glenohumeral OA is associated with significantly smaller degenerative RCTs with significantly larger CSAs than asymptomatic shoulders without these pathologies. These findings suggest that individual quantitative anatomy may imply biomechanics that are likely to induce specific types of degenerative joint disorders. PMID- 23814247 TI - Improvement in quality of life after arthroscopic capsular release for contracture of the shoulder. AB - There is little published information on the health impact of frozen shoulder. The purpose of this study was to assess the functional and health-related quality of life outcomes following arthroscopic capsular release (ACR) for contracture of the shoulder. Between January 2010 and January 2012 all patients who had failed non-operative treatment including anti-inflammatory medication, physiotherapy and glenohumeral joint injections for contracture of the shoulder and who subsequently underwent an ACR were enrolled in the study. A total of 100 patients were eligible; 68 underwent ACR alone and 32 had ACR with a subacromial decompression (ASD). ACR resulted in a highly significant improvement in the range of movement and functional outcome, as measured by the Oxford shoulder score and EuroQol EQ-5D index. The mean cost of a quality-adjusted life year (QALY) for an ACR and ACR with an ASD was L2563 and L3189, respectively. ACR is thus a cost-effective procedure that can restore relatively normal function and health-related quality of life in most patients with a contracture of the shoulder within six months after surgery; and the beneficial effects are not related to the duration of the presenting symptoms. PMID- 23814248 TI - Endoscopic versus open release in patients with de Quervain's tenosynovitis: a randomised trial. AB - The purpose of this study was to compare the outcome and complications of endoscopic versus open release for the treatment of de Quervain's tenosynovitis. Patients with this condition were randomised to undergo either endoscopic (n = 27) or open release (n = 25). Visual Analogue Scale (VAS) pain and Disabilities of Arm, Shoulder, and Hand (DASH) scores were measured at 12 and 24 weeks after surgery. Scar satisfaction was measured using a VAS scale. The mean pain and DASH scores improved significantly at 12 weeks and 24 weeks (p < 0.001) in both groups. The scores were marginally lower in the endoscopic group compared to the open group at 12 weeks (p = 0.012 and p = 0.002, respectively); however, only the DASH score showed a clinically important difference. There were no differences between the groups at 24 weeks. The mean VAS scar satisfaction score was higher in the endoscopic group at 24 weeks (p < 0.001). Transient superficial radial nerve injury occurred in three patients in the endoscopic group compared with nine in the open release group (p = 0.033). We conclude that endoscopic release for de Quervain's tenosynovitis seems to provide earlier improvement after surgery, with fewer superficial radial nerve complications and greater scar satisfaction, when compared with open release. PMID- 23814249 TI - A systematic review of the non-operative treatment of nightstick fractures of the ulna. AB - Most patients with a nightstick fracture of the ulna are treated conservatively. Various techniques of immobilisation or early mobilisation have been studied. We performed a systematic review of all published randomised controlled trials and observational studies that have assessed the outcome of these fractures following above- or below-elbow immobilisation, bracing and early mobilisation. We searched multiple electronic databases, related bibliographies and other studies. We included 27 studies comprising 1629 fractures in the final analysis. The data relating to the time to radiological union and the rates of delayed union and nonunion could be pooled and analysed statistically. We found that early mobilisation produced the shortest radiological time to union (mean 8.0 weeks) and the lowest mean rate of nonunion (0.6%). Fractures treated with above- or below-elbow immobilisation and braces had longer mean radiological times to union (9.2 weeks, 9.2 weeks and 8.7 weeks, respectively) and higher mean rates of nonunion (3.8%, 2.1% and 0.8%, respectively). There was no statistically significant difference in the rate of non- or delayed union between those treated by early mobilisation and the three forms of immobilisation (p = 0.142 to p = 1.000, respectively). All the studies had significant biases, but until a robust randomised controlled trial is undertaken the best advice for the treatment of undisplaced or partially displaced nightstick fractures appears to be early mobilisation, with a removable forearm support for comfort as required. PMID- 23814250 TI - Does fusion improve the outcome after decompressive surgery for lumbar spinal stenosis?: A two-year follow-up study involving 5390 patients. AB - Whether to combine spinal decompression with fusion in patients with symptomatic lumbar spinal stenosis remains controversial. We performed a cohort study to determine the effect of the addition of fusion in terms of patient satisfaction after decompressive spinal surgery in patients with and without a degenerative spondylolisthesis. The National Swedish Register for Spine Surgery (Swespine) was used for the study. Data were obtained for all patients in the register who underwent surgery for stenosis on one or two adjacent lumbar levels. A total of 5390 patients fulfilled the inclusion criteria and completed a two-year follow up. Using multivariable models the results of 4259 patients who underwent decompression alone were compared with those of 1131 who underwent decompression and fusion. The consequence of having an associated spondylolisthesis in the operated segments pre-operatively was also considered. At two years there was no significant difference in patient satisfaction between the two treatment groups for any of the outcome measures, regardless of the presence of a pre-operative spondylolisthesis. Moreover, the proportion of patients who required subsequent further lumbar surgery was also similar in the two groups. In this large cohort the addition of fusion to decompression was not associated with an improved outcome. PMID- 23814251 TI - Clinical predictors of surgical outcome in cervical spondylotic myelopathy: an analysis of 248 patients. AB - The purpose of this study was to investigate the clinical predictors of surgical outcome in patients with cervical spondylotic myelopathy (CSM). We reviewed a consecutive series of 248 patients (71 women and 177 men) with CSM who had undergone surgery at our institution between January 2000 and October 2010. Their mean age was 59.0 years (16 to 86). Medical records, office notes, and operative reports were reviewed for data collection. Special attention was focused on pre operative duration and severity as well as post-operative persistence of myelopathic symptoms. Disease severity was graded according to the Nurick classification. Our multivariate logistic regression model indicated that Nurick grade 2 CSM patients have the highest chance of complete symptom resolution (p < 0.001) and improvement to normal gait (p = 0.004) following surgery. Patients who did not improve after surgery had longer duration of myelopathic symptoms than those who did improve post-operatively (17.85 months (1 to 101) vs 11.21 months (1 to 69); p = 0.002). More advanced Nurick grades were not associated with a longer duration of symptoms (p = 0.906). Our data suggest that patients with Nurick grade 2 CSM are most likely to improve from surgery. The duration of myelopathic symptoms does not have an association with disease severity but is an independent prognostic indicator of surgical outcome. PMID- 23814252 TI - The effect of excision of the posterior arch of C1 on C1/C2 fusion using transarticular screws. AB - Transarticular screw fixation with autograft is an established procedure for the surgical treatment of atlantoaxial instability. Removal of the posterior arch of C1 may affect the rate of fusion. This study assessed the rate of atlantoaxial fusion using transarticular screws with or without removal of the posterior arch of C1. We reviewed 30 consecutive patients who underwent atlantoaxial fusion with a minimum follow-up of two years. In 25 patients (group A) the posterior arch of C1 was not excised (group A) and in five it was (group B). Fusion was assessed on static and dynamic radiographs. In selected patients CT imaging was also used to assess fusion and the position of the screws. There were 15 men and 15 women with a mean age of 51.2 years (23 to 77) and a mean follow-up of 7.7 years (2 to 11.6). Stable union with a solid fusion or a stable fibrous union was achieved in 29 patients (97%). In Group A, 20 patients (80%) achieved a solid fusion, four (16%) a stable fibrous union and one (4%) a nonunion. In Group B, stable union was achieved in all patients, three having a solid fusion and two a stable fibrous union. There was no statistically significant difference between the status of fusion in the two groups. Complications were noted in 12 patients (40%); these were mainly related to the screws, and included malpositioning and breakage. The presence of an intact or removed posterior arch of C1 did not affect the rate of fusion in patients with atlantoaxial instability undergoing C1/C2 fusion using transarticular screws and autograft. PMID- 23814253 TI - A radiological and cadaveric study of oblique lumbar interbody fixation in patients with normal spinal anatomy. AB - The purpose of this study was to determine whether it would be feasible to use oblique lumbar interbody fixation for patients with degenerative lumbar disease who required a fusion but did not have a spondylolisthesis. A series of CT digital images from 60 patients with abdominal disease were reconstructed in three dimensions (3D) using Mimics v10.01: a digital cylinder was superimposed on the reconstructed image to simulate the position of an interbody screw. The optimal entry point of the screw and measurements of its trajectory were recorded. Next, 26 cadaveric specimens were subjected to oblique lumbar interbody fixation on the basis of the measurements derived from the imaging studies. These were then compared with measurements derived directly from the cadaveric vertebrae. Our study suggested that it is easy to insert the screws for L1/2, L2/3 and L3/4 fixation: there was no significant difference in measurements between those of the 3-D digital images and the cadaveric specimens. For L4/5 fixation, part of L5 inferior articular process had to be removed to achieve the optimal trajectory of the screw. For L5/S1 fixation, the screw heads were blocked by iliac bone: consequently, the interior oblique angle of the cadaveric specimens was less than that seen in the 3D digital images. We suggest that CT scans should be carried out pre-operatively if this procedure is to be adopted in clinical practice. This will assist in determining the feasibility of the procedure and will provide accurate information to assist introduction of the screws. PMID- 23814254 TI - Under-coracoid-around-clavicle (UCAC) loop in type II distal clavicle fractures. AB - In Neer type II (Robinson type 3B) fractures of the distal clavicle the medial fragment is detached from the coracoclavicular ligaments and displaced upwards, whereas the lateral fragment, which is usually small, maintains its position. Several fixation techniques have been suggested to treat this fracture. The aim of this study was to assess the outcome of patients with type II distal clavicle fractures treated with coracoclavicular suture fixation using three loops of Ethibond. This prospective study included 14 patients with Neer type II fractures treated with open reduction and coracoclavicular fixation. Ethibond sutures were passed under the coracoid and around the clavicle (UCAC loop) without making any drill holes in the proximal or distal fragments. There were 11 men and three women with a mean age of 34.57 years (29 to 41). Patients were followed for a mean of 24.64 months (14 to 31) and evaluated radiologically and clinically using the Constant score. Fracture union was obtained in 13 patients at a mean of 18.23 weeks (13 to 23) and the mean Constant score was 96.07 (91 to 100). One patient developed an asymptomatic fibrous nonunion at one year. This study suggests that open reduction and internal fixation of unstable distal clavicle fractures using UCAC loops can provide rigid fixation and lead to bony union. This technique avoids using metal hardware, preserves the acromioclavicular joint and provides adequate stability with excellent results. PMID- 23814255 TI - Argyria following the use of silver-coated megaprostheses: no association between the development of local argyria and elevated silver levels. AB - The aims of this study were to evaluate the incidence of local argyria in patients with silver-coated megaprostheses and to identify a possible association between argyria and elevated levels of silver both locally and in the blood. Between 2004 and 2011, 32 megaprostheses with silver coatings were implanted in 20 female and 12 male patients following revision arthroplasty for infection or resection of a malignant tumour, and the levels of silver locally in drains and seromas and in the blood were determined. The mean age of the patients was 46 years (10 to 81); one patient died in the immediate post-operative period and was excluded. Seven patients (23%) developed local argyria after a median of 25.7 months (interquartile range 2 to 44.5). Patients with and without local argyria had comparable levels of silver in the blood and aspiration fluids. The length of the implant did not influence the development of local argyria. Patients with clinical evidence of local argyria had no neurological symptoms and no evidence of renal or hepatic failure. Thus, we conclude that the short-term surveillance of blood silver levels in these patients is not required. PMID- 23814256 TI - The accuracy of current methods in determining the timing of epiphysiodesis. AB - We compared the accuracy of the growth remaining method of assessing leg-length discrepancy (LLD) with the straight-line graph method, the multiplier method and their variants. We retrospectively reviewed the records of 44 patients treated by percutaneous epiphysiodesis for LLD. All were followed up until maturity. We used the modified Green-Anderson growth-remaining method (Method 1) to plan the timing of epiphysiodesis. Then we presumed that the other four methods described below were used pre-operatively for calculating the timing of epiphysiodesis. We then assumed that these four methods were used pre-operatively. Method 2 was the original Green-Anderson growth-remaining method; Method 3, Paley's multiplier method using bone age; Method 4, Paley's multiplier method using chronological age; and Method 5, Moseley's straight-line graph method. We compared 'Expected LLD at maturity with surgery' with 'Final LLD at maturity with surgery' for each method. Statistical analysis revealed that 'Expected LLD at maturity with surgery' was significantly different from 'Final LLD at maturity with surgery'. Method 2 was the most accurate. There was a significant correlation between 'Expected LLD at maturity with surgery' and 'Final LLD at maturity with surgery', the greatest correlation being with Method 2. Generally all the methods generated an overcorrected value. No method generates the precise 'Expected LLD at maturity with surgery'. It is essential that an analysis of the pattern of growth is taken into account when predicting final LLD. As many additional data as possible are required. PMID- 23814257 TI - Prolonged incubation time does not increase sensitivity for the diagnosis of implant-related infection using samples prepared by sonication of the implants. AB - We have designed a prospective study to evaluate the usefulness of prolonged incubation of cultures from sonicated orthopaedic implants. During the study period 124 implants from 113 patients were processed (22 osteosynthetic implants, 46 hip prostheses, 54 knee prostheses, and two shoulder prostheses). Of these, 70 patients had clinical infection; 32 had received antibiotics at least seven days before removal of the implant. A total of 54 patients had sonicated samples that produced positive cultures (including four patients without infection). All of them were positive in the first seven days of incubation. No differences were found regarding previous antibiotic treatment when analysing colony counts or days of incubation in the case of a positive result. In our experience, extending incubation of the samples to 14 days does not add more positive results for sonicated orthopaedic implants (hip and knee prosthesis and osteosynthesis implants) compared with a conventional seven-day incubation period. PMID- 23814259 TI - Challenges and controversies in the diagnosis of mesothelioma: Part 1. Cytology only diagnosis, biopsies, immunohistochemistry, discrimination between mesothelioma and reactive mesothelial hyperplasia, and biomarkers. AB - The detection of neoplastic invasion remains the linchpin for a clear diagnosis of malignant mesothelioma. Cytology-only diagnosis of epithelioid mesothelioma on aspirated effusion fluid remains controversial. A major problem is poor sensitivity, although cytodiagnosis is achievable in many cases at a high order of specificity, especially when a large volume of effusion fluid is submitted for cytological evaluation, enabling the preparation of cell-block sections for immunohistochemical investigation and when the cytological findings can be correlated with imaging studies to assess the anatomical distribution of the lesion and evidence of nodularity of the pleural disorder and, in some cases, to demonstrate evidence of invasion. Although 'positive' and 'negative' immunohistochemical markers have proved remarkably effective in distinguishing between epithelioid mesothelioma and secondary carcinoma and other malignant tumours metastatic to serosal membranes, no mesothelial marker has 100% sensitivity and specificity for mesothelioma diagnosis, so that panels of 'positive' antibodies and markers with negative predictive value are required. At present, no tissue or serum marker (including the molecular detection of p16/CDKN2A) has been proved to have sufficient specificity, consistency and reproducibility that it can replace evidence of invasion as the decisive marker for diagnosis when there is any uncertainty concerning a diagnosis of epithelioid mesothelioma and in the case of atypical fibrous lesions of the pleura (especially collagen-rich lesions, namely fibrous pleuritis vs desmoplastic mesothelioma), in which even the assessment of invasion can be problematical as illustrated in part 2 of this review. PMID- 23814260 TI - Matrix-assisted laser desorption ionisation-time of flight mass spectrometry for rapid identification of Laribacter hongkongensis. AB - Laribacter hongkongensis is a Gram-negative, facultative anaerobic, motile, S shaped, urease-positive bacillus associated with invasive infections in liver cirrhosis patients and community-acquired gastroenteritis. Most cases of L hongkongensis infections occur in eastern countries. Information is lacking on the usefulness of matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF MS) for the identification of bacteria important in eastern countries. Using the Bruker database extended with 21 L hongkongensis reference strains, all 240 L hongkongensis isolates recovered from patients, fish, frogs and water were correctly identified, with 224 (93.3%) strains having top match scores >=2.0. Notably, the strain of Chromobacterium violaceum was not reliably identified although it is included in the database. MALDI-TOF MS is useful for the accurate routine identification of L hongkongensis after adding reference L hongkongensis main spectra to the database. The number of strains for each species in MALDI-TOF MS databases should be expanded to cover intraspecies variability. PMID- 23814261 TI - Osteoid osteoma and osteoblastoma: novel histological and immunohistochemical observations as evidence for a single entity. AB - AIMS: Osteoid osteoma and osteoblastoma have, in the past, been variously regarded as both similar and distinct entities. Currently, WHO classifies these tumours separately. We compared archetypal cases to identify novel histomorphological and immunohistochemical features attempting to clarify their mutual relationship. METHODS AND RESULTS: 10 osteoid osteomas and 20 osteoblastomas (10 spinal and 10 non-spinal) were retrieved and reviewed clinically, radiologically and histologically. Immunohistochemistry was performed for: desmin, SMA, neurofilament, S100, vimentin, PGP9.5, GFAP, EMA, caldesmon, CD34, broad-spectrum cytokeratins, claudin-1. We identified features, common to both osteoid osteoma and osteoblastoma, namely, areas of lesional non osteoblastic stroma and the presence of scattered, large cells with smudged/degenerate nuclei. Immunohistochemically, we confirmed the innervated status of osteoid osteomas, and found that osteoblastomas were similarly innervated. The non-osteoblastic lesional stroma was distinctive owing to expression of EMA and NSE by the mesenchymal spindle cells and expression of desmin, PGP9.5 and S100 by the scattered, large cells with 'smudged' nuclei. CONCLUSIONS: Both osteoid osteoma and osteoblastoma are innervated bone-forming lesions which share novel histomorphological and immunohistochemical features supporting the view that separate classification is unjustified, and we offer a pathogenetic explanation for their apparent clinical and radiological variance. PMID- 23814262 TI - Changes in presentation, treatment, and outcomes of adult low-grade gliomas over the past fifty years. AB - BACKGROUND: To identify changes in patient presentation, treatment, and outcomes of low-grade gliomas (LGGs) over the past 50 years. METHODS: Records of 852 adults who received a diagnosis at Mayo Clinic from 1960 through 2011 with World Health Organization grade II LGGs were reviewed and grouped by those who received a diagnosis before (group I: 1960-1989) and after (group II: 1990-2011) the routine use of postoperative MRI. RESULTS: Median follow-up was 23.3 and 8.7 years for groups I and II, respectively. Patients in group I more often presented with seizures, headaches, sensory/motor impairment, and astrocytoma histology. Over time, more gross total resections (GTRs) were achieved, fewer patients received postoperative radiotherapy (PORT), and more received chemotherapy. Median progression-free survival (PFS) and overall survival (OS) were 4.4 and 8.0 years, respectively. Although PFS was similar, 10-year OS was better in group II (47%) than in group I (33%; P < .0001). Improved PFS in multivariate analysis was associated with group I patients, nonastrocytoma histology, small tumor size, successful GTR, or radical subtotal resection (rSTR), PORT, and postoperative chemotherapy. Factors associated with improved OS in multivariate analysis were younger age, nonastrocytoma histology, small tumor size, and GTR/rSTR. CONCLUSIONS: OS for LGG has improved over the past 50 years, despite similar rates of progression. In the modern cohort, more patients are receiving a diagnosis of oligodendroglioma and are undergoing extensive resections, both of which are associated with improvements in OS. Because of risk factor stratification by clinicians, the use of PORT has decreased and is primarily being used to treat high-risk tumors in modern patients. PMID- 23814263 TI - Cooperativity between MAPK and PI3K signaling activation is required for glioblastoma pathogenesis. AB - BACKGROUND: Glioblastoma (GBM) genomes feature recurrent genetic alterations that dysregulate core intracellular signaling pathways, including the G1/S cell cycle checkpoint and the MAPK and PI3K effector arms of receptor tyrosine kinase (RTK) signaling. Elucidation of the phenotypic consequences of activated RTK effectors is required for the design of effective therapeutic and diagnostic strategies. METHODS: Genetically defined, G1/S checkpoint-defective cortical murine astrocytes with constitutively active Kras and/or Pten deletion mutations were used to systematically investigate the individual and combined roles of these 2 RTK signaling effectors in phenotypic hallmarks of glioblastoma pathogenesis, including growth, migration, and invasion in vitro. A novel syngeneic orthotopic allograft model system was used to examine in vivo tumorigenesis. RESULTS: Constitutively active Kras and/or Pten deletion mutations activated both MAPK and PI3K signaling. Their combination led to maximal growth, migration, and invasion of G1/S-defective astrocytes in vitro and produced progenitor-like transcriptomal profiles that mimic human proneural GBM. Activation of both RTK effector arms was required for in vivo tumorigenesis and produced highly invasive, proneural-like GBM. CONCLUSIONS: These results suggest that cortical astrocytes can be transformed into GBM and that combined dysregulation of MAPK and PI3K signaling revert G1/S-defective astrocytes to a primitive gene expression state. This genetically-defined, immunocompetent model of proneural GBM will be useful for preclinical development of MAPK/PI3K-targeted, subtype-specific therapies. PMID- 23814264 TI - Bevacizumab as a treatment for radiation necrosis of brain metastases post stereotactic radiosurgery. AB - BACKGROUND: Cerebral radiation necrosis (RN) is a difficult to treat complication of stereotactic radiosurgery (SRS) that can result in progressive neurologic decline. Currently, steroids are the standard of care treatment for brain RN despite their adverse effect profile and limited efficacy. The purpose of this study was to evaluate the treatment efficacy of cerebral RN to bevacizumab in patients with brain metastases previously treated with SRS. METHODS: We retrospectively reviewed 14 lesions in 11 patients treated with bevacizumab for brain RN secondary to SRS for their brain metastases. Steroid dosing, RN associated symptoms, and magnetic resonance imaging (MRI) scans were examined before, during, and after bevacizumab administration. RESULTS: Of the 11 patients included, 6 had metastatic non-small cell lung cancer, and 5 had metastatic breast cancer. The mean percentage decrease in RN volume seen on T1 post Gadolinium and fluid-attenuated inversion recovery (FLAIR) MRI at first follow up, at a mean of 26 days (range, 15-43 days), was 64.4% and 64.3%, respectively. MRI changes were sustained on follow-up MRI scans, obtained at a mean of 33 days (range, 7-58 days) after bevacizumab discontinuation. After bevacizumab treatment, all patients initially receiving steroids had a reduction in steroid requirement, and all but one had an improvement in or stability of RN-associated symptoms. No patients experienced intratumoral bleeds or other adverse effects related to their bevacizumab treatment. CONCLUSIONS: Bevacizumab is effective and safe for the treatment of RN after SRS for brain metastasis. In this context, bevacizumab offers symptomatic relief, a reduction in steroid requirement, and a dramatic radiographic response. PMID- 23814265 TI - MiR-145 functions as a tumor-suppressive RNA by targeting Sox9 and adducin 3 in human glioma cells. AB - BACKGROUND: MicroRNAs (miRNAs) are increasingly being recognized as being involved in cancer development and progression in gliomas. METHODS: Using a model cell system developed in our lab to study glioma progression comprising human neuroglial culture (HNGC)-1 and HNGC-2 cells, we report here that miR-145 is one of the miRNAs significantly downregulated during malignant transformation in glioblastoma multiforme (GBM). In a study using tumor samples derived from various glioma grades, we show that expression of miR-145 is decreased in a graded manner, with GBM patients showing lowest expression relative to lower grade gliomas (P < .05) and normal brain tissues (P < .0001). Functional studies involving ectopic expression of miR-145 in glioma cells had a negative impact on cell proliferation and tumor development, as well as invasion and induced apoptosis, providing further support to the concept that inactivation of miR-145 is important for glioma disease pathogenesis. More notably, these growth suppressive effects of miR-145 are mediated through its target proteins Sox9 and the cell adhesion-associated molecule adducin 3 (ADD3). RESULTS: Inhibiting Sox9 and ADD3 rescued effects of miR-145 loss. Interestingly, miR-145 loss in glioma cells led to overexpression of molecules involved in cell proliferation, like cyclin D1, c-myc, and N-myc, as well as enhanced expression of cell adhesion- and invasion-related molecules N-cadherin and E-cadherin, an effect which was again restored upon miR-145 overexpression in glioma cells. The miR-145 promoter was methylated at its cytosine-phosphate-guanine (CpG) islands in the glioma cell lines studied. CONCLUSION: Our study demonstrates that miR-145 has a tumor suppressive function in glioblastoma in that it reduces proliferation, adhesion, and invasion of glioblastoma cells, apparently by suppressing the activity of oncogenic proteins Sox9 and ADD3. Reduced levels of miR-145 may lead to neoplastic transformation and malignant progression in glioma due to unregulated activity of these proteins. PMID- 23814266 TI - End-of-life caregivers' perception of medical and psychological support during the final weeks of glioma patients: a questionnaire-based survey. AB - BACKGROUND: The prognosis for glioma remains dismal, and little is known about the final disease phase. To obtain information about this period, we surveyed caregivers of patients who were registered in the German Glioma Network and who died from the disease. METHODS: A questionnaire with 15 items, focusing on medical, logistic, and mental health support and symptom control during the final 4 weeks, was sent to caregivers. For some of the questions, a scale from 1 (inadequate) to 10 (excellent) was used. RESULTS: Of 1655 questionnaires, 605 were returned (36.6%) and evaluated. We found that 67.9% of the patients were taken care of at home for the last 4 weeks; 47.7% died at home, 22.6% died in hospitals, and 19.3% died in hospice facilities. Medical support was provided by general practitioners in 72.3% of cases, by physicians affiliated with a nursing home or hospice in 29.9%, and by general oncologists in 17%. Specialized neuro oncologists were involved in 6%. The caregivers ranked the medical support with a mean of 7.2 (using a 10-point scale), nursing service with 8.1, and mental health support with 5.5. In 22.9% of cases, no support for the caregivers themselves was offered by medical institutions. CONCLUSIONS: Although these data reflect the caregivers' subjective views, they are useful in understanding and improving current patterns of care. While patients and their caregivers are supported mainly by neuro-oncologists for most of the disease phase, the end-of-life phase is managed predominantly by general practitioners and specialists in palliative care. Close cooperation between these specialties is necessary to meet the specific needs of glioma patients. PMID- 23814267 TI - Influence of angioarchitecture on management of pediatric intracranial arteriovenous malformations. PMID- 23814268 TI - Socioeconomic inequalities in oral health in different European welfare state regimes. AB - BACKGROUND: There is very little information about the relationship between welfare regimes and oral health inequalities. We compared socioeconomic inequalities in adults' oral health in five European welfare-state regimes: Scandinavian, Anglo-Saxon, Bismarckian, Southern and Eastern. METHODS: Using data from the oral health module of the Eurobarometer 72.3 survey, we assessed inequalities in two self-reported oral health measures: no functional dentition (less than 20 natural teeth) and edentulousness (no natural teeth). Occupational social class, education and subjective social status (SSS) were included as socioeconomic position indicators. We estimated age-standardised prevalence rates, ORs, the Relative Index of Inequality (RII) and the Slope Index of Inequality (SII). RESULTS: The Scandinavian regime showed the lowest prevalence rates of the two oral health measures while the Eastern showed the highest. In all welfare regimes there was a general pattern of social gradients by occupational social class and education. Relative educational inequalities in no functional dentition were largest in the Scandinavian welfare regime (RII=3.81; 95% CI 2.68 to 5.42). The Scandinavian and Southern regimes showed the largest relative inequalities in edentulousness by occupation and education, respectively. There were larger absolute inequalities in no functional dentition in the Eastern regime by occupation (SII=42.16; 95% CI 31.42 to 52.89) and in the Southern by SSS (SII=27.92; 95% CI 17.36 to 38.47). CONCLUSIONS: Oral health inequalities in adults exist in all welfare-state regimes, but contrary to what may be expected from theory, they are not smaller in the Scandinavian regime. Future work should examine the potential mechanisms linking welfare provision and oral health inequalities. PMID- 23814269 TI - Bias analysis to improve monitoring an HIV epidemic and its response: approach and application to a survey of female sex workers in Iran. AB - BACKGROUND: We present probabilistic and Bayesian techniques to correct for bias in categorical and numerical measures and empirically apply them to a recent survey of female sex workers (FSW) conducted in Iran. METHODS: We used bias parameters from a previous validation study to correct estimates of behaviours reported by FSW. Monte-Carlo Sensitivity Analysis and Bayesian bias analysis produced point and simulation intervals (SI). RESULTS: The apparent and corrected prevalence differed by a minimum of 1% for the number of 'non-condom use sexual acts' (36.8% vs 35.8%) to a maximum of 33% for 'ever associated with a venue to sell sex' (35.5% vs 68.0%). The negative predictive value of the questionnaire for 'history of STI' and 'ever associated with a venue to sell sex' was 36.3% (95% SI 4.2% to 69.1%) and 46.9% (95% SI 6.3% to 79.1%), respectively. Bias adjusted numerical measures of behaviours increased by 0.1 year for 'age at first sex act for money' to 1.5 for 'number of sexual contacts in last 7 days'. CONCLUSIONS: The 'true' estimates of most behaviours are considerably higher than those reported and the related SIs are wider than conventional CIs. Our analysis indicates the need for and applicability of bias analysis in surveys, particularly in stigmatised settings. PMID- 23814270 TI - In defence of (social) democracy: on health inequalities and the welfare state. PMID- 23814271 TI - Inequalities in asthma treatment among children by country of birth and ancestry: a nationwide study in Denmark. AB - BACKGROUND: Investigations in several Western countries have reported ethnic differences in asthma prevalence and treatment among children and in some countries these differences are increasing. The aim of this study was to analyse whether there are inequalities in asthma treatment by country of birth and ancestry among children residing in Denmark, and whether this potential association may vary between different household income groups. METHODS: Data were obtained by linking the Danish Civil Registration System, the Central Taxpayers' Register and the Danish National Prescription Register. POPULATION: the entire population of children in Denmark from 0 to 17 years of age in 2008 (n=1 209 091). Information on asthma treatment was obtained from the National Prescription Register. The analyses included multiple logistic regression models stratified by household income. RESULTS: Compared with ethnic Danes, immigrant children had the lowest OR for redeeming a prescription for asthma medication, both relief (OR 0.37; 95% CIs, 0.20 to 0.68) and preventive (OR 0.37; (0.22 to 0.59)). Similar associations were found among descendant children (OR for relief treatment 0.82 (0.79 to 0.89) and for preventive treatment 0.68 (0.61 to 0.75)). The pattern of the association remained after stratifying for household income. CONCLUSIONS: We found that, inequalities that cannot be explained by household income alone exist in treatments to prevent asthma as well as to relieve symptoms in children residing in Denmark, by country of birth and ancestry. The difference between immigrants and descendants may indicate that unfamiliarity with the Danish healthcare system is a contributory cause of the inadequate treatment of asthma. PMID- 23814272 TI - The effect of childhood socioeconomic position on alcohol-related disorders later in life: a Swedish national cohort study. AB - BACKGROUND: Alcohol use is the third most important global-health risk factor and a main contributor to health inequalities. Previous research on social determinants of alcohol-related disorders has delivered inconsistent results. We aimed to investigate whether socioeconomic position (SEP) in childhood predicts alcohol-related disorders in young adulthood in a Swedish national cohort. METHODS: We studied a register-based national cohort of Swedish citizens born during 1973-1984 (N=948 518) and followed them up to 2009 from age 15. Childhood SEP was defined by a six-category socioeconomic index from the Censuses of 1985 and 1990. HRs of alcohol-related disorders, as indicated by register entries on alcohol-related death and alcohol-related medical care, were analysed in Cox regression models with adjustment for sociodemographic variables and indicators of parental morbidity and criminality. RESULTS: Low childhood SEP was associated with alcohol-related disorders later in life among both men and women in a stepwise manner. Growing up in a household with the lowest SEP was associated with risk for alcohol-related disorders of HR: 2.24 (95% CI 2.08 to 2.42) after adjustment for sociodemographic variables, compared with the highest SEP group. Adjusting the analysis for parental psychosocial problems attenuated the association to HR 1.87 (95% CI 1.73 to 2.01). CONCLUSIONS: The study demonstrates that low SEP in childhood predicts alcohol-related disorders in young adulthood. Alcohol abuse needs to be addressed in policies to bridge the gap of health inequalities. PMID- 23814273 TI - Do labour market status transitions predict changes in psychological well-being? AB - BACKGROUND: The objective of this study was to establish the direction of causality in the relationship between labour market status and psychological well being by investigating how transitions between secure employment, insecure employment, unemployment, permanent sickness and other economic inactivity predict changes in psychological well-being over a 16-year period. METHOD: This study used data from the British Household Panel Survey (1991-2007). Psychological well-being was measured using the 12-item General Health Questionnaire (GHQ-12). Fixed effects models were utilised to investigate how transitions between labour market statuses predicted GHQ-12 score, adjusting for current labour market status and a range of covariates. RESULTS: After taking account of the contemporaneous effects of joblessness on psychological well being, and the impact of a range of confounding factors, experiencing a transition from employment to joblessness was significantly predictive of poorer psychological well-being. Transitions into employment were not found to have equal and opposite effects: the positive effects of moving into work from unemployment were not as large as the negative effects of job loss. Transitions between secure and insecure employment did not independently predict changes in psychological well-being. CONCLUSIONS: A causal relationship between labour market status and psychological well-being is indicated. PMID- 23814274 TI - Valuing social housing needs to take a broader view. PMID- 23814275 TI - Modulation of cellular redox status by thiamine-activated NADPH oxidase confers Arabidopsis resistance to Sclerotinia sclerotiorum. AB - Sclerotinia sclerotiorum can initially suppress host oxidative burst to aid infection establishment, but later promotes reactive oxygen species (ROS) generation as proliferation advances. Here, it was shown that the cellular redox status can be modulated by thiamine to protect Arabidopsis thaliana against Sclerotinia at the early stages of infection. The initial inhibition of host ROS generation by Sclerotinia-secreted oxalate could effectively be alleviated by thiamine. Thiamine pre-treatment and subsequent wild-type Sclerotinia invasion induced an increase of ascorbate peroxidase activity concomitant with decreased ascorbate/dehydroascorbate ratios, which led to the cellular transition towards oxidative status in infected tissues. Particularly, it was observed that wild type Sclerotinia, but not oxalate-deficient A2 mutant, could suppress the activity of NADPH oxidase (NOX), which might be an important mechanism underlying the early inhibition of ROS burst. Nevertheless, thiamine pre-treatment followed by wild-type Sclerotinia infection promoted NOX-derived ROS accumulation. Further studies showed that cytosolic Ca(2+) and staurosporine-sensitive protein kinase(s) participated in thiamine-induced activation of NOX. Moreover, thiamine induced tissue defence responses including callose/lignin deposition and stomatal closure were closely correlated with NOX-derived ROS generation. Additionally, studies with Brassica species indicated that the regulation of thiamine is largely conserved upon Sclerotinia infection. Collectively, it was concluded that thiamine reverses the initial reducing status through activating NOX-dependent ROS signalling to perturb the disease progress of Sclerotinia. PMID- 23814278 TI - Emerging roles of microRNAs in the mediation of drought stress response in plants. AB - Drought is a major environmental stress factor that limits agricultural production worldwide. Plants employ complex mechanisms of gene regulation in response to drought stress. MicroRNAs (miRNAs) are a class of small RNAs that are increasingly being recognized as important modulators of gene expression at the post-transcriptional level. Many miRNAs have been shown to be involved in drought stress responses, including ABA response, auxin signalling, osmoprotection, and antioxidant defence, by downregulating the respective target genes encoding regulatory and functional proteins. This review summarizes recent molecular studies on the miRNAs involved in the regulation of drought-responsive genes, with emphasis on miRNA-associated regulatory networks involved in drought stress response. PMID- 23814277 TI - A thraustochytrid diacylglycerol acyltransferase 2 with broad substrate specificity strongly increases oleic acid content in engineered Arabidopsis thaliana seeds. AB - Diacylglycerol acyltransferase (DGAT) catalyses the last step in acyl-CoA dependent triacylglycerol (TAG) biosynthesis and is an important determinant of cellular oil content and quality. In this study, a gene, designated TaDGAT2, encoding a type 2 DGAT (DGAT2)-related enzyme was identified from the oleaginous marine protist Thraustochytrium aureum. The deduced TaDGAT2 sequence contains a ~460 amino acid domain most closely related to DGAT2s from Dictyostelium sp. (45 50% identity). Recombinant TaDGAT2 restored TAG biosynthesis to the Saccharomyces cerevisiae H1246 TAG-deficient mutant, and microsomes from the complemented mutant displayed DGAT activity with C16 and C18 saturated and unsaturated fatty acyl-CoA and diacylglycerol substrates. To examine its biotechnological potential, TaDGAT2 was expressed under control of a strong seed-specific promoter in wild-type Arabidopsis thaliana and the high linoleic acid fad3fae1 mutant. In both backgrounds, little change was detected in seed oil content, but a striking increase in oleic acid content of seeds was observed. This increase was greatest in fad3fae1 seeds, where relative amounts of oleic acid increased nearly 2-fold to >50% of total fatty acids. In addition, >2-fold increase in oleic acid levels was detected in the triacylglycerol sn-2 position and in the major seed phospholipid phosphatidylcholine. These results suggest that increased seed oleic acid content mediated by TaDGAT2 is influenced in part by the fatty acid composition of host cells and occurs not by enhancing oleic acid content at the TAG sn-3 position directly but by increasing total oleic acid levels in seeds, presumably by limiting flux through phosphatidylcholine-based desaturation reactions. PMID- 23814276 TI - Arabidopsis heterotrimeric G protein beta subunit, AGB1, regulates brassinosteroid signalling independently of BZR1. AB - The Arabidopsis thaliana heterotrimeric G protein beta subunit, AGB1, is involved in both abscisic acid (ABA) signalling and brassinosteroid (BR) signalling, but it is unclear how AGB1 regulates these signalling pathways. A key transcription factor downstream of BR, BZR1, and its gain-of-function mutant, bzr1-1, were overexpressed in an AGB1-null mutant, agb1-1, to examine their effects on the BR hyposensitivity and the ABA hypersensitivity of agb1-1, and to examine whether AGB1 regulates the functions of BZR1. Because the amino acid sequence of AGB1 contains 17 putative modification motifs of glycogen synthase kinase 3/SHAGGY like protein kinases (GSKs), which are known components of BR signalling, the interaction between AGB1 and one of the Arabidopsis GSKs, BIN2, was examined. Expression of bzr1-1 alleviated the effects of a BR biosynthesis inhibitor, brassinazole, in both the wild type and agb1-1, and overexpression of BZR1 alleviated the effects of ABA in both the wild type and agb1-1. AGB1 did not affect the phosphorylation state of BZR1 in vivo. AGB1 interacted with BIN2 in vitro, but did not affect the phosphorylation state of BIN2. The results suggest that AGB1 interacts with BIN2, but regulates the BR signalling in a BZR1 independent manner. PMID- 23814279 TI - School Segregation in Metropolitan Regions, 1970-2000: The Impacts of Policy Choices on Public Education. AB - It has been argued that the effects of the desegregation of public schools from the late 1960s onward were limited and short-lived, in part because of white flight from desegregating districts and in part because legal decisions in the 1990s released many districts from court orders. Data presented here for 1970 2000 show that small increases in segregation between districts were outweighed by larger declines within districts. Progress was interrupted but not reversed after 1990. Desegregation was not limited to districts and metropolitan regions where enforcement actions required it, and factors such as private schooling, district size, and inclusion of both city and suburban areas within district boundaries had stronger effects than individual court mandates. PMID- 23814280 TI - Predators' decisions to eat defended prey depend on the size of undefended prey. AB - Predators that have learned to associate warning coloration with toxicity often continue to include aposematic prey in their diet in order to gain the nutrients and energy that they contain. As body size is widely reported to correlate with energetic content, we predicted that prey size would affect predators' decisions to eat aposematic prey. We used a well-established system of wild-caught European starlings, Sturnus vulgaris, foraging on mealworms, Tenebrio molitor, to test how the size of undefended (water-injected) and defended (quinine-injected) prey, on different coloured backgrounds, affected birds' decisions to eat defended prey. We found that birds ate fewer defended prey, and less quinine, when undefended prey were large compared with when they were small, but that the size of the defended prey had no effect on the numbers eaten. Consequently, we found no evidence that the mass of the defended prey or the overall mass of prey ingested affected the amount of toxin that a predator was willing to ingest, and instead the mass of undefended prey eaten was more important. This is a surprising finding, challenging the assumptions of state-dependent models of aposematism and mimicry, and highlighting the need to understand better the mechanisms of predator decision making. In addition, the birds did not learn to discriminate visually between defended and undefended prey based on size, but only on the basis of colour. This suggests that colour signals may be more salient to predators than size differences, allowing Batesian mimics to benefit from aposematic models even when they differ in size. PMID- 23814281 TI - Lessons learned from compounding tragedies. PMID- 23814282 TI - Validity Evidence for FASTHUG-MAIDENS, a Mnemonic for Identifying Drug-Related Problems in the Intensive Care Unit. AB - BACKGROUND: The mnemonic FASTHUG (Feeding, Analgesia, Sedation, Thromboembolic prophylaxis, Head of bed elevation, stress Ulcer prophylaxis, Glucose control) was developed by intensive care unit (ICU) physicians to ensure that key aspects of care are addressed during each patient encounter. Because this tool does not specifically target pharmacotherapy assessments, a modified version, FASTHUG MAIDENS, was created, by changing the H to mean Hypoactive or Hyperactive delirium and adding M for Medication reconciliation; A for Antibiotics or Anti infectives; I for Indications for medications; D for drug Dosing; E for Electrolytes, hematology, and other laboratory tests; N for No drug interactions, allergies, duplication, or side effects; and S for Stop dates. OBJECTIVE: To validate the use of FASTHUG-MAIDENS as a tool for identifying drug-related problems (DRPs) in the ICU. METHODS: This randomized, prospective validation study took place between January and May 2011 in the ICUs of 4 hospitals: 2 community-level ICUs and 2 tertiary referral ICUs. Each ICU had a dedicated ICU pharmacist and one or more pharmacy residents completing an ICU rotation as part of their pharmacy practice residency (total of 6 residents). The 6 pharmacy residents were randomly assigned to assess patients admitted to the ICU using FASTHUG-MAIDENS or standard monitoring practice. The mean proportion of DRPs per patient encounter identified by the residents (relative to DRPs identified by the ICU pharmacists) was the primary outcome, and the proportion of total DRPs identified in each group was assessed as a secondary end point. RESULTS: Pharmacy residents using the FASTHUG-MAIDENS mnemonic identified a significantly greater mean proportion of DRPs per patient encounter (73.2% versus 52.4%, p = 0.008) and a greater proportion of total DRPs (77.1% versus 52.5%, p < 0.001) than those assessing patients according to standard monitoring practice. CONCLUSION: In this sample, the mnemonic FASTHUG-MAIDENS was a useful tool to facilitate the capture of DRPs by pharmacy residents working in the ICU. PMID- 23814283 TI - Compatibility and stability of morphine sulphate and naloxone hydrochloride in 0.9% sodium chloride for injection. AB - BACKGROUND: Naloxone may be administered in conjunction with morphine to reduce the risk of opioid-induced pruritis. Combining these drugs for coadministration may be beneficial, but little is known about their physical compatibility and stability in combined solutions. OBJECTIVE: To describe the physical compatibility and stability of morphine sulphate and naloxone hydrochloride (at various concentrations) in IV admixtures. METHODS: The physical compatibility and stability of admixtures of morphine 1000 MUg/mL and naloxone 4 MUg/mL, 12.5 MUg/mL, and 25 MUg/mL in 0.9% sodium chloride were studied. For each concentration of naloxone, one bag was stored at room temperature (22 degrees C) for 72 h and one bag was stored under refrigeration (4 degrees C) for 30 days. For all preparations, physical characteristics, including pH, colour, and formation of precipitate, were evaluated. The samples were also analyzed by a stability-indicating high-performance liquid chromatographic method. Stability was defined as the retention of at least 90% of the initial concentration. RESULTS: No notable changes in pH or colour and no macroprecipitation were observed in any of the preparations after storage at 22 degrees C for up to 72 h or at 4 degrees C for up to 30 days. All preparations maintained more than 90% of the initial concentrations of morphine and naloxone at the end of the respective study periods. The calculated lower limit of the 95% confidence interval also indicated that 90% or more of the initial concentration remained at the end of each study period. CONCLUSION: Admixtures of morphine sulphate and naloxone hydrochloride were stable for 72 h at room temperature and for 30 days with refrigeration. PMID- 23814284 TI - Patients' recall of interaction with a pharmacist during hospital admission. AB - BACKGROUND: CSHP 2015 objective 1.5 proposes that at least 50% of recently hospitalized patients or their caregivers will recall speaking with a pharmacist while in the hospital. OBJECTIVE: To determine the baseline prevalence of patients' recall of interaction with a pharmacist during their hospital admission and their level of satisfaction with these encounters, following a major reorganization of health authorities in New Brunswick. METHODS: Former inpatients from 27 units in 9 hospitals in the Horizon Health Network were randomly selected to complete a telephone survey within 5 to 7 months after discharge from hospital. Patients' responses were validated against pharmacists' documentation in the patients' health records. RESULTS: From June 2010 to July 2011, a total of 1028 former inpatients were screened, of whom 399 completed the telephone survey. More than half of the respondents were women (225 [56.4%]), and the mean age was 67 years. Overall, 184 patients (46.1%) recalled speaking with a pharmacist during their recent admission. Of these, 164 (89.1%) were "satisfied" or "very satisfied" with these interactions. In addition, 332 respondents (83.2%) indicated that if the hospital offered the opportunity to talk with a pharmacist who could help answer their questions about medications, they would take advantage of this service. The electronic hospital records of 181 patients (from 15 units at 3 sites) were analyzed to seek evidence of pharmacists' interventions or encounters (e.g., medication history, consultation). Pharmacist documentation was found in the health records of 166 (91.7%) of all patients in this sample. CONCLUSIONS: Almost half of former inpatients recalled speaking with a pharmacist during a recent hospital admission. The majority of patients were satisfied with these interactions and would welcome future services from hospital pharmacists. PMID- 23814285 TI - What patients want: preferences regarding hospital pharmacy services. AB - BACKGROUND: The role of hospital pharmacists has evolved over the past couple of decades from preparation and distribution of medications to active involvement in health care teams, through identification and resolution of patients' medication related issues in an effort to improve patient outcomes. However, patients' preferences about pharmacy services are not well known. OBJECTIVE: To use content analysis of open-ended survey responses from recently discharged patients to determine desired pharmacy services. METHODS: Former inpatients were randomly selected for participation in a telephone survey following discharge from acute care hospitals in the Horizon Health Network in New Brunswick. The survey included the question, "What service or information would you like a pharmacist to provide in the hospital that would most help you in managing your medications?" For responses to this question, 2 raters established response categories, obtained acceptable inter-rater agreement, and independently scored the responses. RESULTS: Four global categories of responses were obtained, each having multiple subcategories. Of the 703 responses (from 325 respondents), 445 (63.3%) were related to the category "information about medications", including purpose, adherence, and side effects. The second most common response category was "self-disclosure" (167 [23.8%]), including experiences with pharmacies, medications, or hospitals. Less frequently, responses pertained to "pharmacy services" (54 [7.7%]), such as medication costs and continuity of care, and to "information source for medications" (37 [5.3%]). CONCLUSIONS: Most respondents to this survey wanted hospital pharmacists to provide a general medication overview, including information about side effects and interactions, during their admission. The results suggest that many patients are unaware of other potential clinical services that pharmacists can provide. A future study could assess patients' willingness to select from a guiding list of potential clinical services. PMID- 23814286 TI - Evaluation of a new hierarchical teaching model for pharmacy students in experiential education. PMID- 23814287 TI - [Not Available]. PMID- 23814288 TI - Should Accreditation Canada's Required Organizational Practices and Standards Lead to Prioritization of Clinical Pharmacy Services over Distribution-Related Medication Safety Strategies? PMID- 23814289 TI - Stability of diluted ketamine packaged in glass vials. PMID- 23814290 TI - [Not Available]. PMID- 23814291 TI - Deprescribing: what is it and what does the evidence tell us? PMID- 23814292 TI - Through the looking glass . . . And what you may find there. PMID- 23814293 TI - Single layer staple versus double layer hand-sewn closures -- a comment. PMID- 23814294 TI - The ethical question on prolonging the life of a cancer patient -- a comment. PMID- 23814295 TI - The ethical question on prolonging the life of a cancer patient -- a reply. PMID- 23814296 TI - The ethical question on prolonging the life of a cancer patient -- a reply. PMID- 23814297 TI - A perfect storm? PMID- 23814298 TI - An ethicist's commentary on the case of a service dog needing fracture fixation. PMID- 23814299 TI - Laparoscopic-assisted cystotomy for urolith removal in dogs and cats - 23 cases. AB - This report describes the outcomes of a modified laparoscopic-assisted cystotomy for urolith removal in dogs and cats. Modifications of the original techniques included a temporary cystopexy to the abdominal wall, utilization of a laparoscope instead of cystoscope, and retrograde flow of saline in the bladder with pressurized saline. The medical records of 23 client-owned animals for which laparoscopic-assisted cystotomy was used for urolith extraction were reviewed. Twenty-six procedures were performed in 23 animals. There were intraoperative complications in 19.2% of cases leading to open conversion in 11.5%. Rate of complications directly related to the procedure was 11.5%. Four cases had documented urolith recurrence with a mean time to recurrence of 335 days. PMID- 23814300 TI - The Ontario Veterinary College Hip Certification Program -- assessing inter- and intra-observer repeatability and comparison of findings to those of the Orthopedic Foundation for Animals. AB - In Canada, the Ontario Veterinary College (OVC) has offered radiographic screening for hip dysplasia for many years, but there are other options for this service including the Orthopedic Foundation for Animals (OFA). There are some differences between the OFA and the OVC methods, and this study compares the OVC and OFA hip certification results in 37 dogs. There was good agreement between the two programs but in some instances there was a difference in the pass/fail status of a dog. Neither the OFA nor the OVC was more likely to fail or pass a given dog. The repeatability of the OVC results was assessed by both inter- and intra-observer comparisons in 100 dogs. There was at least 86% agreement among and within radiologists, but in 5 cases the disagreement resulted in a difference in the pass/fail status of the dog. These results illustrate the inherent variation in radiographic hip evaluation and highlight the importance of consensus grading practices to improve the accuracy of hip evaluation. PMID- 23814301 TI - Nutritional and microbial analysis of bully sticks and survey of opinions about pet treats. AB - The objectives of this study were to measure the caloric density of bully sticks, to analyze the bully sticks for bacterial contamination, and to assess owner opinions about these and other pet treat products. Mean caloric density was 15 kcal/inch (38 kcal/cm) [range: 9 to 22 kcal/inch (23 to 56 kcal/cm), 2.96 to 3.07 kcal/g]. Of 26 bully sticks that were tested for bacterial contamination 1 (4%) was contaminated with Clostridium difficile, 1 was contaminated with methicillin resistant Staphylococcus aureus (MRSA), and 1 with a tetracycline resistant Escherichia coli. PMID- 23814302 TI - Cerebellar granuloprival degeneration in an Australian kelpie and a Labrador retriever dog. AB - A 7-month-old Australian kelpie dog and a 14-month-old Labrador retriever dog were diagnosed with an uncommon form of cerebellar abiotrophy called cerebellar granuloprival degeneration. This was characterized by a loss of the granular neurons with relative sparing of the Purkinje neurons. PMID- 23814303 TI - Acute renal failure in 2 adult llamas after exposure to Oak trees (Quercus spp.). AB - Two adult llamas (Lama glama) previously exposed to oak trees (Quercus spp.) were presented with a history of depression and anorexia. Clinicopathological abnormalities included severe gastroenteritis, acute renal failure, and increased liver enzymes. This is believed to be the first report of oak toxicosis in South American camelids. PMID- 23814304 TI - Jugular thrombophlebitis in horses: a review of fibrinolysis, thrombus formation, and clinical management. AB - Thrombophlebitis of the jugular vein is commonly observed in horses, particularly during intensive care, and leads to local and systemic inflammatory responses as well as head and neck circulatory impairment. Thrombolytic therapy is widely used in human practice with the aim of thrombus dissolution and recanalization of the injured vessels. There are similarities between human and horse coagulation and fibrinolytic processes. This review examines the fibrinolytic system, thrombus formation, and the clinical management of jugular thrombophlebitis, including thrombolytic therapy. There is evidence that early regional thrombolytic therapy for jugular thrombophlebitis in horses may be effective to achieve sustained recanalization. PMID- 23814305 TI - Cholesterol granuloma associated with otitis media and leptomeningitis in a cat due to a Streptococcus canis infection. AB - Cholesterol granuloma in the middle ear is a pathological condition often associated with otitis media in humans. Cholesterol granulomas in cats are rarely described. To our knowledge, this is the first report of middle ear cholesterol granuloma in a cat, associated with otitis media and leptomeningitis due to a Streptococcus canis septicemia. PMID- 23814306 TI - Infiltrative lipoma compressing the spinal cord in 2 large-breed dogs. AB - Two cases of infiltrative lipomas compressing the spinal cord and causing nonambulatory paraparesis in 2 large-breed dogs are reported. Magnetic resonance imaging (MRI) revealed severe extradural spinal cord compression by inhomogenous masses that infiltrated the adjacent tissues and the muscles of the spine in both dogs. The presumptive clinical diagnoses were infiltrative lipomas, which were confirmed by histopathology. In rare cases infiltrative lipomas are able to compress the spinal cord by the agressive growth of invasive adipocytes causing neurological deficits. PMID- 23814307 TI - Respiratory disease outbreak in a veterinary hospital associated with canine parainfluenza virus infection. AB - A cluster of canine parainfluenza virus infections was identified in a veterinary referral hospital. While hospital-associated outbreaks of canine parainfluenza virus infection have not been previously reported, veterinary hospitals possess some of the same risk factors that may be present in traditional high-risk sites such as kennels. Hospital-associated transmission of canine respiratory pathogens, therefore, must be considered. PMID- 23814308 TI - Postsurgical segmental mesenteric ischemic thrombosis in a horse. AB - A 16-year-old, Lusitanian stallion was admitted to the Veterinary Teaching Hospital with a 12-hour history of signs of abdominal pain. Exploratory celiotomy was performed due to an inguinal hernia, and a second celiotomy was performed in response to the abdominal pain. The horse was euthanized and mesenteric venous thrombosis was diagnosed and considered likely due to peritonitis and systemic inflammatory response syndrome (SIRS). PMID- 23814309 TI - Diagnostic ophthalmology. PMID- 23814310 TI - Associate veterinarian salaries continue to rise. PMID- 23814311 TI - An experimental and kinetic investigation of premixed furan/oxygen/argon flames. AB - The detailed chemical structures of three low-pressure (35 Torr) premixed laminar furan/oxygen/argon flames with equivalence ratios of 1.4, 1.8 and 2.2 have been investigated by using tunable synchrotron vacuum ultraviolet (VUV) photoionization and molecular-beam mass spectrometry. About 40 combustion species including hydrocarbons and oxygenated intermediates have been identified by measurements of photoionization efficiency spectra. Mole fraction profiles of the flame species including reactants, intermediates and products have been determined by scanning burner position with some selected photon energies near ionization thresholds. Flame temperatures have been measured by a Pt-6%Rh/Pt 30%Rh thermocouple. A new mechanism involving 206 species and 1368 reactions has been proposed whose predictions are in reasonable agreement with measured species profiles for the three investigated flames. Rate-of-production and sensitivity analyses have been performed to track the key reaction paths governing furan consumption for different equivalence ratios. Both experimental and modeling results indicate that few aromatics could be formed in these flames. Furthermore, the current model has been validated against previous pyrolysis results of the literature obtained behind shock waves and the agreement is reasonable as well. PMID- 23814312 TI - Microscopic probing of two-photon fluorescence for cancer diagnosis. PMID- 23814313 TI - Two-photon fluorescence diagnostics of femtosecond laser tweezers. AB - We show how two-photon fluorescence signal can be used as an effective detection scheme for trapping particles of any size in comparison to methods using back scattered light. Development of such a diagnostic scheme allows us a direct observation of trapping a single nanoparticle, which shows new directions to spectroscopy at the single-molecule level in solution. PMID- 23814314 TI - Calorimetric studies of Cu-Li, Li-Sn, and Cu-Li-Sn. AB - Integral molar enthalpies of mixing were determined by drop calorimetry for Cu-Li Sn at 1073 K along five sections xCu/xSn ~ 1:1, xCu/xSn ~ 2:3, xCu/xSn ~ 1:4, xLi/xSn ~ 1:1, and xLi/xSn ~ 1:4. The integral and partial molar mixing enthalpies of Cu-Li and Li-Sn were measured at the same temperature, for Li-Sn in addition at 773 K. All binary data could be described by Redlich-Kister polynomials. Cu-Li shows an endothermic mixing effect with a maximum in the integral molar mixing enthalpy of ~5300 J . mol-1 at xCu = 0.5, Li-Sn an exothermic minimum of ~ -37,000 J . mol-1 at xSn ~ 0.2. For Li-Sn no significant temperature dependence between 773 K and 1073 K could be deduced. Our measured ternary data were fitted on the basis of an extended Redlich-Kister-Muggianu model for substitutional solutions. Additionally, a comparison of these results to the extrapolation model of Chou is given. PMID- 23814315 TI - A hybrid approach for the simulation of a nearly neutrally buoyant nanoparticle thermal motion in an incompressible Newtonian fluid medium. AB - A hybrid scheme based on Markovian fluctuating hydrodynamics of the fluid and a non-Markovian Langevin dynamics with the Ornstein-Uhlenbeck noise perturbing the translational and rotational equations of motion of a nanoparticle is employed to study the thermal motion of a nearly neutrally buoyant nanoparticle in an incompressible Newtonian fluid medium. A direct numerical simulation adopting an arbitrary Lagrangian-Eulerian based finite element method is employed in simulating the thermal motion of the particle suspended in the fluid contained in a cylindrical vessel. The instantaneous flow around the particle and the particle motion are fully resolved. The numerical results show that (a) the calculated temperature of the nearly neutrally buoyant Brownian particle in a quiescent fluid satisfies the equipartition theorem; (b) the translational and rotational decay of the velocity autocorrelation functions result in algebraic tails, over long time; (c) the translational and rotational mean square displacements of the particle obeys Stokes-Einstein and Stokes-Einstein-Debye relations, respectively; and (d) the parallel and perpendicular diffusivities of the particle closer to the wall are consistent with the analytical results, where available. The study has important implications for designing nanocarriers for targeted drug delivery. PMID- 23814316 TI - Chondroitin Sulfate in Solution: Effects of Mono- and Divalent Salts. AB - Chondroitin sulphate (CS) is a linear sulfated polysaccharide found in cartilage and other tissues in the body. Small angle neutron scattering (SANS) and dynamic light scattering (DLS) measurements are made on semi-dilute CS solutions to determine ion induced changes in the local order of the CS chains and in their dynamic properties. In salt-free CS solutions SANS detects the correlation peak due to local ordering between adjacent chains in which the characteristic interchain distance is d ~ 57 A. In both monovalent and divalent salts (NaCl and CaCl2) aligned linear regions are distinguishable corresponding to distance scales ranging from the length of the monomer unit (8 A) to about 1000 A. With increasing calcium ion concentration, the scattering intensity increases. Even in the presence of 200 mM CaCl2, however, neither phase separation nor cross-linking occurs. DLS in the CS solutions reveals two characteristic relaxation modes, the fast mode corresponding to the thermal concentration fluctuations. The collective diffusion coefficient D decreases with increasing calcium ion concentration and exhibits a power law function of the single variable c/J, where c is the CS concentration and J is the ionic strength of the salt in the solution. This result implies that the effect of the sodium and calcium ions on the dynamic properties of CS solutions is fully accounted for by the ionic strength. PMID- 23814317 TI - Perspectives on creating a balanced approach to organ transplantation safety and availability. PMID- 23814318 TI - The power of organ donation to save lives through transplantation. PMID- 23814321 TI - Substituted 2,2'-bipyrroles and pyrrolylfurans via intermediate isoxazolylpyrroles. AB - We describe a new synthesis of the 3-chloro-(4'-methoxy)-2,2'-pyrrolylfuran segment (3) of (+)- roseophilin. The route exploits a isoxazoylpyrrole intermediate, wherein the isoxazole ring serves as a beta-diketone equivalent and a directing group for palladium catalyzed chlorination of the attached pyrrole. Subsequent reduction of the N-O bond and acid promoted cyclization afords roseophilin segment 3b in five steps and 19% overall yield. This strategy was extended to the synthesis of 3-chloro-(4'-alkoxy)-2,2'-pyrrolylfurans (16a-c) and 4-alkoxy-2,2'-bipyrroles (20a-c), which are building blocks to synthesize bioactive prodiginine natural products and their congeners. PMID- 23814322 TI - A mesoscopic bridging scale method for fluids and coupling dissipative particle dynamics with continuum finite element method. AB - A multiscale procedure to couple a mesoscale discrete particle model and a macroscale continuum model of incompressible fluid flow is proposed in this study. We call this procedure the mesoscopic bridging scale (MBS) method since it is developed on the basis of the bridging scale method for coupling molecular dynamics and finite element models [G.J. Wagner, W.K. Liu, Coupling of atomistic and continuum simulations using a bridging scale decomposition, J. Comput. Phys. 190 (2003) 249-274]. We derive the governing equations of the MBS method and show that the differential equations of motion of the mesoscale discrete particle model and finite element (FE) model are only coupled through the force terms. Based on this coupling, we express the finite element equations which rely on the Navier-Stokes and continuity equations, in a way that the internal nodal FE forces are evaluated using viscous stresses from the mesoscale model. The dissipative particle dynamics (DPD) method for the discrete particle mesoscale model is employed. The entire fluid domain is divided into a local domain and a global domain. Fluid flow in the local domain is modeled with both DPD and FE method, while fluid flow in the global domain is modeled by the FE method only. The MBS method is suitable for modeling complex (colloidal) fluid flows, where continuum methods are sufficiently accurate only in the large fluid domain, while small, local regions of particular interest require detailed modeling by mesoscopic discrete particles. Solved examples - simple Poiseuille and driven cavity flows illustrate the applicability of the proposed MBS method. PMID- 23814323 TI - Towards Using Molecular States as Qubits. AB - Molecular systems are presented as possible qubit systems by exploring non resonant molecular fragmentation of n-propyl benzene with femtosecond laser pulses as a model case. We show that such laser fragmentation process is dependent on the phase and polarization characteristics of the laser. The effect of the chirp and polarization of the femtosecond pulse when applied simultaneously is mutually independent of each other, which makes chirp and polarization as useful 'logic' implementing parameters for such molecular qubits. PMID- 23814319 TI - PHS guideline for reducing human immunodeficiency virus, hepatitis B virus, and hepatitis C virus transmission through organ transplantation. PMID- 23814320 TI - INTEGRATED APPROACHES TO THE CONFIGURATIONAL ASSIGNMENT OF MARINE NATURAL PRODUCTS. PMID- 23814325 TI - Cognitive Adaptations for n-person Exchange: The Evolutionary Roots of Organizational Behavior. AB - Organizations are composed of stable, predominantly cooperative interactions or n person exchanges. Humans have been engaging in n-person exchanges for a great enough period of evolutionary time that we appear to have evolved a distinct constellation of species-typical mechanisms specialized to solve the adaptive problems posed by this form of social interaction. These mechanisms appear to have been evolutionarily elaborated out of the cognitive infrastructure that initially evolved for dyadic exchange. Key adaptive problems that these mechanisms are designed to solve include coordination among individuals, and defense against exploitation by free riders. Multi-individual cooperation could not have been maintained over evolutionary time if free riders reliably benefited more than contributors to collective enterprises, and so outcompeted them. As a result, humans evolved mechanisms that implement an aversion to exploitation by free riding, and a strategy of conditional cooperation, supplemented by punitive sentiment towards free riders. Because of the design of these mechanisms, how free riding is treated is a central determinant of the survival and health of cooperative organizations. The mapping of the evolved psychology of n-party exchange cooperation may contribute to the construction of a principled theoretical foundation for the understanding of human behavior in organizations. PMID- 23814324 TI - Updating Historical Maps of Malaria Transmission Intensity in East Africa Using Remote Sensing. AB - Remotely sensed imagery has been used to update and improve the spatial resolution of malaria transmission intensity maps in Tanzania, Uganda, and Kenya. Discriminant analysis achieved statistically robust agreements between historical maps of the intensity of malaria transmission and predictions based on multitemporal meteorological satellite sensor data processed using temporal Fourier analysis. The study identified land surface temperature as the best predictor of transmission intensity. Rainfall and moisture availability as inferred by cold cloud duration (ccd) and the normalized difference vegetation index (ndvi), respectively, were identified as secondary predictors of transmission intensity. Information on altitude derived from a digital elevation model significantly improved the predictions. "Malaria-free" areas were predicted with an accuracy of 96 percent while areas where transmission occurs only near water, moderate malaria areas, and intense malaria transmission areas were predicted with accuracies of 90 percent, 72 percent, and 87 percent, respectively. The importance of such maps for rationalizing malaria control is discussed, as is the potential contribution of the next generation of satellite sensors to these mapping efforts. PMID- 23814326 TI - Towards controlling molecular motions in fluorescence microscopy and optical trapping: a spatiotemporal approach. AB - This account reviews some recent studies pursued in our group on several control experiments with important applications in (one-photon) confocal and two-photon fluorescence laser-scanning microscopy and optical trapping with laser tweezers. We explore the simultaneous control of internal and external (i.e. centre-of-mass motion) degrees of freedom, which require the coupling of various control parameters to result in the spatiotemporal control. Of particular interest to us is the implementation of such control schemes in living systems. A live cell is a system of a large number of different molecules which combine and interact to generate complex structures and functions. These combinations and interactions of molecules need to be choreographed perfectly in time and space to achieve intended intra-cellular functions. Spatiotemporal control promises to be a versatile tool for dynamical control of spatially manipulated bio-molecules. PMID- 23814327 TI - Negotiating candidacy: ethnic minority seniors' access to care. AB - The 'Barriers to Access to Care for Ethnic Minority Seniors ' (BACEMS) study in Vancouver, British Columbia, found that immigrant families torn between changing values and the economic realities that accompany immigration cannot always provide optimal care for their elders. Ethnic minority seniors further identified language barriers, immigration status, and limited awareness of the roles of the health authority and of specific service providers as barriers to health care. The configuration and delivery of health services, and health-care providers' limited knowledge of the seniors' needs and confounded these problems. To explore the barriers to access, the BACEMS study relied primarily on focus group data collected from ethnic minority seniors and their families and from health and multicultural service providers. The applicability of the recently developed model of 'candidacy', which emphasises the dynamic, multi-dimensional and contingent character of health-care access to ethnic minority seniors, was assessed. The candidacy framework increased sensitivity to ethnic minority seniors' issues and enabled organisation of the data into manageable conceptual units, which facilitated translation into recommendations for action, and revealed gaps that pose questions for future research. It has the potential to make Canadian research on the topic more co-ordinated. PMID- 23814328 TI - Structural Brain Modifications in Primary Insomnia: Myth or Reality? PMID- 23814329 TI - Sleep and Psychological Vulnerability to Traumatic Stress. PMID- 23814330 TI - Nightmares as a Paradigm for Studying the Effects of Stressors. PMID- 23814331 TI - Sleep's Role in Human Spatial Learning. PMID- 23814332 TI - Understanding Airway Tissue Mechanics is a Step Towards Improving Treatments in OSA. PMID- 23814333 TI - Sleep Apnea Cardiovascular Clinical Trials-Current Status and Steps Forward: The International Collaboration of Sleep Apnea Cardiovascular Trialists. AB - : Sleep apnea is a common chronic disease that is associated with coronary heart disease, stroke, heart failure and mortality, although the ability of sleep apnea treatment to reduce cardiovascular morbidity and mortality has not been demonstrated. In contrast to patients seeking treatment in sleep disorders centers, as many as half of individuals with moderate to severe sleep apnea in the general population do not report excessive sleepiness; however, if treatment of sleep apnea were shown to reduce cardiovascular disease risk, this would provide a strong rationale for treatment of sleep apnea even in the absence of daytime sleepiness. This article summarizes the status of clinical trials evaluating the potential cardiovascular benefits of sleep apnea treatment and discusses the challenges of conducting such trials, and introduces the International Collaboration of Sleep Apnea Cardiovascular Trialists (INCOSACT), a clinical research collaboration formed to foster cardiovascular sleep research. CITATION: Gottlieb DJ; Craig SE; Lorenzi-Filho G; Heeley E; Redline S; McEvoy RD; Duran-Cantolla J. Sleep apnea cardiovascular clinical trials- current status and steps forward: the International Collaboration of Sleep Apnea Cardiovascular Trialists. SLEEP 2013;36(7):975-980. PMID- 23814334 TI - Effects of Experimental Sleep Restriction on Weight Gain, Caloric Intake, and Meal Timing in Healthy Adults. AB - STUDY OBJECTIVES: Examine sleep restriction's effects on weight gain, daily caloric intake, and meal timing. DESIGN: Repeated-measures experiments assessing body weight at admittance and discharge in all subjects (N = 225) and caloric intake and meal timing across days following 2 baseline nights, 5 sleep restriction nights and 2 recovery nights or across days following control condition nights in a subset of subjects (n = 37). SETTING: Controlled laboratory environment. PARTICIPANTS: Two hundred twenty-five healthy adults aged 22-50 y (n = 198 sleep-restricted subjects; n = 31 with caloric intake data; n = 27 control subjects; n = 6 with caloric intake data). INTERVENTIONS: Approximately 8-to-1 randomization to an experimental condition (including five consecutive nights of 4 h time in bed [TIB]/night, 04:00-08:00) or to a control condition (all nights 10 h TIB/night, 22:00-08:00). MEASUREMENTS AND RESULTS: Sleep-restricted subjects gained more weight (0.97 +/- 1.4 kg) than control subjects (0.11 +/- 1.9 kg; d = 0.51, P = 0.007). Among sleep-restricted subjects, African Americans gained more weight than Caucasians (d = 0.37, P = 0.003) and males gained more weight than females (d = 0.38, P = 0.004). Sleep-restricted subjects consumed extra calories (130.0 +/- 43.0% of daily caloric requirement) during days with a delayed bedtime (04:00) compared with control subjects who did not consume extra calories (100.6 +/- 11.4%; d = 0.94, P = 0.003) during corresponding days. In sleep-restricted subjects, increased daily caloric intake was due to more meals and the consumption of 552.9 +/- 265.8 additional calories between 22:00-03:59. The percentage of calories derived from fat was greater during late-night hours (22:00-03:59, 33.0 +/- 0.08%) compared to daytime (08:00-14:59, 28.2 +/- 0.05%) and evening hours (15:00-21:59, 29.4 +/- 0.06%; Ps < 0.05). CONCLUSIONS: In the largest, most diverse healthy sample studied to date under controlled laboratory conditions, sleep restriction promoted weight gain. Chronically sleep-restricted adults with late bedtimes may be more susceptible to weight gain due to greater daily caloric intake and the consumption of calories during late-night hours. CITATION: Spaeth AM; Dinges DF; Goel N. Effects of experimental sleep restriction on weight gain, caloric intake, and meal timing in healthy adults. SLEEP 2013;36(7):981-990. PMID- 23814335 TI - Increased Rostral Anterior Cingulate Cortex Volume in Chronic Primary Insomnia. AB - BACKGROUND: Recent studies document alterations in cortical and subcortical volumes in patients with chronic primary insomnia (PI) in comparison with normal sleepers. We sought to confirm this observation in two previously studied PI cohorts. METHODS: Two separate and independent groups of unmedicated patients who met Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition (DSM IV) criteria for PI were compared with two separate, healthy control groups (Study 1: PI = 20, controls = 15; Study 2: PI = 21, controls = 20). Both studies included 2 weeks of sleep diaries supplemented by wrist actigraphy. The 3.0 T MRI derived rostral anterior cingulate cortex (rACC) volumes were measured with FreeSurfer image analysis suite (version 5.0) and results normalized to total intracranial volume (ICV). Unpaired t-tests (two-tailed) were used to compare rACC volumes between groups. Post hoc correlations of rACC volumes to insomnia severity measures were performed (uncorrected for multiplicity). RESULTS: Both studies demonstrated increases in normalized rACC volume in PI compared with control patients (Study 1: right side P = 0.05, left side P = 0.03; Study 2: right side P = 0.03, left side P = 0.02). In PI patients from Study 1, right rACC volume was correlated with sleep onset latency (SOL) by both diary (r = 0.51, P = 0.02) and actigraphy (r = 0.50, P = 0.03), and with sleep efficiency by actigraphy (r = -0.57, P = 0.01); left rACC volume was correlated with SOL by diary (r = 0.48, P = 0.04), and wake after sleep onset (WASO) (r = 0.49, P = 0.03) and sleep efficiency (r = -0.49, P = 0.03) by actigraphy. In Study 2, right rACC volume was correlated with SOL by diary (r = 0.44, P = 0.05) in PI patients. CONCLUSIONS: Rostral ACC volumes are larger in patients with PI compared with control patients. Clinical severity measures in PI correlate with rACC volumes. These data may reflect a compensatory brain response to chronic insomnia and may represent a marker of resilience to depressive illness. CITATION: Winkelman JW; Plante DT; Schoerning L; Benson K; Buxton OM; O'Connor SP; Jensen JE; Renshaw PF; Gonenc A. Increased rostral anterior cingulate cortex volume in chronic primary insomnia. SLEEP 2013;36(7):991-998. PMID- 23814336 TI - Brain Gray Matter Deficits in Patients with Chronic Primary Insomnia. AB - STUDY OBJECTIVE: To investigate the structural changes in patients with chronic primary insomnia and the relationships with clinical features of insomnia. DESIGN: Statistical parametric mapping 8-based voxel-based morphometry was used to identify differences in regional gray and white matter between patients with chronic primary insomnia and normal controls. SETTING: University hospital. PATIENTS AND PARTICIPANTS: Twenty-seven patients and 27 age/sex-matched controls. INTERVENTIONS: Regional differences were compared using two-sample t-tests with age, sex, and intracranial volume as covariates. MEASUREMENTS AND RESULTS: The patients were a mean age of 52.3 y and had a mean history of insomnia of 7.6 y. Patients displayed cognitive deficits in attention, frontal/executive function, and nonverbal memory. Patients also displayed significantly reduced gray matter concentrations (GMCs) in dorsolateral prefrontal and pericentral cortices, superior temporal gyrus, and cerebellum and decreased gray matter volumes in medial frontal and middle temporal gyri compared with control patients with the cluster threshold >= 50 voxels at the level of uncorrected P < 0.001. Negative correlations were found between GMC of the prefrontal cortex and insomnia severity and the wakefulness after sleep onset, and between GMC of pericentral cortex and sleep latencies. None of the findings continued to be significant after correction for multiple comparisons. CONCLUSIONS: We found gray matter deficits in multiple brain regions including bilateral frontal lobes in patients with psychophysiologic insomnia. Gray matter deficit of the pericentral and lateral temporal areas may be associated with the difficulties in sleep initiation and maintenance. It is still unclear whether gray matter reductions are a preexisting abnormality or a consequence of insomnia. CITATION: Joo EY; Noh HJ; Kim JS; Koo DL; Kim D; Hwang KJ; Kim JY; Kim ST; Kim MR; Hong SB. Brain gray matter deficits in patients with chronic primary insomnia. SLEEP 2013;36(7):999 1007. PMID- 23814337 TI - Predeployment Sleep Duration and Insomnia Symptoms as Risk Factors for New-Onset Mental Health Disorders Following Military Deployment. AB - STUDY OBJECTIVES: To evaluate predeployment sleep duration and insomnia symptoms in relation to the development of mental health symptoms. DESIGN: Longitudinal cohort study. SETTING: The Millennium Cohort Study survey is administered via a secure website or US mail. PARTICIPANTS: Data were from 15,204 participants who completed their first deployment between the submissions of 2 consecutive Millennium Cohort questionnaires (2001-2008). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Using self-reported data from the Millennium Cohort Study we evaluated the association of predeployment sleep duration and insomnia symptoms on the development of new-onset mental disorders among deployers. Multivariable logistic regression was used to estimate the odds of developing posttraumatic stress disorder (PTSD), depression, and anxiety, while adjusting for relevant covariates including combat-related trauma. The study outcomes were assessed using validated instruments, including the PTSD checklist-civilian version, and the PRIME-MD Patient Health Questionnaire. We identified 522 people with new onset PTSD, 151 with anxiety, and 303 with depression following deployment. In adjusted models, combat-related trauma and predeployment insomnia symptoms were significantly associated with higher odds of developing posttraumatic stress disorder, depression, and anxiety postdeployment. CONCLUSIONS: Sleep characteristics, especially insomnia symptoms, are related to the development of mental disorders following military deployments. Assessment of insomnia symptoms predeployment may help to better identify those at highest risk for subsequent adverse mental health outcomes. CITATION: Gehrman P; Seelig AD; Jacobson IG; Boyko EJ; Hooper TI; Gackstetter GD; Ulmer CS; Smith TC; for the Millennium Cohort Study Team. Predeployment sleep duration and insomnia symptoms as risk factors for new-onset mental health disorders following military deployment. SLEEP 2013;36(7):1009-1018. PMID- 23814338 TI - The Association of Sleep Duration, Mental Health, and Health Risk Behaviors among U.S. Afghanistan/Iraq Era Veterans. AB - STUDY OBJECTIVES: Short and long sleep duration have been linked with higher rates of comorbid medical and mental health issues, as well as increased mortality. The current study examined the association between sleep duration, mental health problems, and health risk behaviors in a large sample of U.S. Afghanistan/Iraq era veterans. DESIGN: NA. SETTING: Mid-Atlantic VA Medical Center(s). PATIENTS/PARTICIPANTS: The sample (N = 1,640) included 20% women (n = 333) and had an average age of 37 years (SD = 10.0). INTERVENTIONS: NA. MEASUREMENTS AND RESULTS: Results from logistic regression analyses that included age, minority status, gender, military rank, number of deployments, combat exposure, and health risk behaviors as covariates indicated that very short sleep duration (<= 5 h of sleep) and long sleep duration (>= 9 h) were each associated with increased odds of current post traumatic stress disorder (PTSD), major depressive disorder (MDD), and smoking; while poor sleep quality was associated with PTSD, panic disorder (PD), MDD, suicidal ideation (SI), and risky drinking. CONCLUSIONS: Sleep duration may be an important marker for psychiatric and health risk behavior problems, and our results suggest that clinical assessment of sleep disturbance in this veteran group is warranted to assess for both short and long sleep. CITATION: Swinkels CM; Ulmer CS; Beckam JC; Buse N; the VA Mid-Atlantic MIRECC Registry Workgroup; Calhoun PS. The association of sleep duration, mental health, and health risk behaviors among U.S. Afghanistan/Iraq era veterans. SLEEP 2013;36(7):1019-1025. PMID- 23814339 TI - Sleep Fragmentation and the Risk of Incident Alzheimer's Disease and Cognitive Decline in Older Persons. AB - OBJECTIVE: Cross-sectional studies suggest that sleep fragmentation is associated with cognitive performance in older adults. We tested the hypothesis that sleep fragmentation is associated with incident Alzheimer's disease (AD) and the rate of cognitive decline in older adults. DESIGN: Prospective cohort study. SETTING: Community-based. PARTICIPANTS: 737 community dwelling older adults without dementia. MEASUREMENTS AND RESULTS: Sleep fragmentation was quantified from up to 10 consecutive days of actigraphy. Subjects underwent annual evaluation for AD with 19 neuropsychological tests. Over a follow-up period of up to 6 years (mean 3.3 years), 97 individuals developed AD. In a Cox proportional hazards model controlling for age, sex, and education, a higher level of sleep fragmentation was associated with an increased risk of AD (HR = 1.22, 95%CI 1.03-1.44, P = 0.02 per 1SD increase in sleep fragmentation). An individual with high sleep fragmentation (90th percentile) had a 1.5-fold risk of developing AD as compared with someone with low sleep fragmentation (10th percentile). The association of sleep fragmentation with incident AD did not vary along demographic lines and was unchanged after controlling for potential confounders including total daily rest time, chronic medical conditions, and the use of common medications which can affect sleep. In a linear mixed effect analysis, a 0.01 unit increase in sleep fragmentation was associated with a 22% increase in the annual rate of cognitive decline relative to the average rate of decline in the cohort (Estimate = -0.016, SE = 0.007, P = 0.03). CONCLUSIONS: Sleep fragmentation in older adults is associated with incident AD and the rate of cognitive decline. CITATION: Lim ASP; Kowgier M; Yu L; Buchman AS; Bennett DA. Sleep fragmentation and the risk of incident alzheimer's disease and cognitive decline in older persons. SLEEP 2013;36(7):1027-1032. PMID- 23814340 TI - Sleep Disturbances and Risk of Depression in Older Men. AB - INTRODUCTION: Self-reported sleep disturbances are associated with an increased risk of depression in younger and older adults, but associations between objective assessments of sleep/wake disturbances via wrist actigraphy and risk of depression are unknown. METHODS: Depressive symptoms (Geriatric Depression Scale [GDS]), self-reported (questionnaires), and objective (actigraphy) sleep parameters were measured at baseline in 2,510 nondepressed men 67 y or older. Depressive symptoms were reassessed an average of 3.4 +/- 0.5 y later. RESULTS: Of the 2,510 men without evidence of depression at baseline, 116 (4.6%) were depressed (GDS >= 6) at the follow-up examination. After adjusting for multiple potential confounders, including baseline depressive symptoms (GDS 0-5), there was evidence of an association between poor self-reported sleep quality and higher odds of being depressed at follow-up (multivariable odds ratio [MOR] = 1.53, 95% confidence interval (CI) 1.00-2.33). In age- and site-adjusted models, objectively measured reduced sleep efficiency (odds ratio [OR] = 1.88, 95% CI 1.13-3.13), prolonged sleep latency (OR = 1.77, 95% CI 1.04-3.00), greater nighttime wakefulness (OR = 1.48, 95% CI 1.01-2.18) and multiple long-wake episodes (OR = 1.69, 95% CI 1.15-2.47) were associated with increased odds of depression at follow-up, but these associations were attenuated and no longer significant after further adjustment for number of depressive symptoms at baseline. Self-reported excessive daytime sleepiness and objectively measured total sleep time were not associated with depression status at follow-up. Excluding baseline antidepressant users from the analyses did not alter the results. CONCLUSIONS: Among nondepressed older men, poor self-reported sleep quality was associated with increased odds of depression several years later. Associations between objectively measured sleep disturbances (e.g., reduced sleep efficiency, prolonged sleep latency, greater nighttime wakefulness, and greater long-wake episodes) and depression several years later were largely explained by a greater burden of depressive symptoms at baseline. CITATION: Paudel M; Taylor BC; Ancoli-Israel S; Blackwell T; Maglione JE; Stone K; Redline S; Ensrud KE; for the Osteoporotic Fractures in Men Study Group. Sleep disturbances and risk of depression in older men. SLEEP 2013;36(7):1033-1040. PMID- 23814341 TI - Nightmares: Prevalence among the Finnish General Adult Population and War Veterans during 1972-2007. AB - STUDY OBJECTIVES: To investigate the prevalence of nightmares among the Finnish general adult population during 1972-2007 and the association between nightmare prevalence and symptoms of insomnia, depression, and anxiety in World War II veterans. DESIGN: Eight independent cross-sectional population surveys of the National FINRISK Study conducted in Finland in 1972, 1977, 1982, 1987, 1992, 1997, 2002, and 2007. SETTING: Epidemiologic. PARTICIPANTS: A total of 69,813 people (33,811 men and 36,002 women) age 25-74 years. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: The investigation of nightmare prevalence and insomnia, depression, and anxiety symptoms was based on questionnaires completed by the participants. Among the whole sample, 3.5% of the men and 4.8% of the women reported frequent nightmares (P < 0.0001 for sex difference), but the prevalence was affected by the age of participants and the year of the survey. Nightmare prevalence increased with age, particularly among the men. The number of people reporting occasional nightmares increased roughly by 20% for both sexes from 1972 to 2007 (P < 0.0001). Participants with war experiences reported more frequent nightmares and symptoms of insomnia, depression, and anxiety than participants without such experiences (P < 0.0001). CONCLUSIONS: Prevalence of nightmares was affected by the sex and age of the participants, and occasional nightmares have become more common in Finland. Exposure to war elevates nightmare prevalence as well as insomnia, depression, and anxiety symptoms even decades after the war; large numbers of war veterans can affect nightmare prevalence on population level. CITATION: Sandman N; Valli K; Kronholm E; Ollila HM; Revonsuo A; Laatikainen T; Paunio T. Nightmares: prevalence among the Finnish general adult population and war veterans during 1972-2007. SLEEP 2013;36(7):1041-1050. PMID- 23814342 TI - Overnight Sleep Enhances Hippocampus-Dependent Aspects of Spatial Memory. AB - STUDY OBJECTIVES: Several studies have now demonstrated that spatial information is processed during sleep, and that posttraining sleep is beneficial for human navigation. However, it remains unclear whether the effects of sleep are primarily due to consolidation of cognitive maps, or alternatively, whether sleep might also affect nonhippocampal aspects of navigation (e.g., speed of motion) involved in moving through a virtual environment. DESIGN: Participants were trained on a virtual maze navigation task (VMT) and then given a memory test following either a day of wakefulness or a night of sleep. Subjects reported to the laboratory for training at either 10:00am or 10:00pm, depending on randomly assigned condition, and were tested 11 h later. Overnight subjects slept in the laboratory with polysomnography. SETTING: A hospital-based academic sleep laboratory. PATIENTS OR PARTICIPANTS: Thirty healthy college student volunteers. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Point-by-point position data were collected from the VMT. Analysis of the movement data revealed a sleep-dependent improvement in maze completion time (P < 0.001) due to improved spatial understanding of the maze layout, which led to a shortening of path from start to finish (P = 0.01) rather than faster exploration speed through the maze (P = 0.7). CONCLUSIONS: We found that overnight sleep benefitted performance, not because subjects moved faster through the maze, but because they were more accurate in navigating to the goal. These findings suggest that sleep enhances participants' knowledge of the spatial layout of the maze, contributing to the consolidation of hippocampus-dependent spatial information. CITATION: Nguyen ND; Tucker MA; Stickgold R; Wamsley EJ. Overnight sleep enhances hippocampus dependent aspects of spatial memory. SLEEP 2013;36(7):1051-1057. PMID- 23814343 TI - A Systematic Review Assessing Bidirectionality between Sleep Disturbances, Anxiety, and Depression. AB - STUDY OBJECTIVES: To investigate whether sleep disturbances are bidirectionally related to anxiety and depression, and thus identify potential risk factors for each problem. DESIGN: A systematic review was conducted on 9 studies (8 longitudinal, 1 retrospective) that assessed bidirectionality between a sleep disturbance, and anxiety or depression. Treatment studies were excluded, along with those solely based on clinical samples or cohorts at high risk of suffering from a sleep disturbance, anxiety and depression. Eligible studies were identified by searching PubMed, PsychINFO, Embase, and Scopus databases, and reference lists of eligible studies. Publication dates ranged from the beginning of each database to December 2011. MEASUREMENTS AND RESULTS: Syntheses of longitudinal studies suggested insomnia and sleep quality were bidirectionally related to anxiety and depression, and depression/anxiety, respectively. Childhood sleep problems significantly predicted higher levels of depression and a combined depression/anxiety variable, but not vice-versa. A one-way relationship was found where anxiety predicted excessive daytime sleepiness, but excessive daytime sleepiness was not associated with depression. CONCLUSIONS: Definitive conclusions regarding bidirectionality cannot be made for most sleep disturbances due to the small number and heterogeneity of cohort samples used across studies. Nevertheless, best available evidence suggests insomnia is bidirectionally related to anxiety and depression. Clinical and theoretical implications are discussed. CITATION: Alvaro PK; Roberts RM; Harris JK. A systematic review assessing bidirectionality between sleep disturbances, anxiety, and depression. SLEEP 2013;36(7):1059-1068. PMID- 23814344 TI - Respiratory Movement of Upper Airway Tissue in Obstructive Sleep Apnea. AB - STUDY OBJECTIVES: To measure real-time movement of the tongue and lateral upper airway tissues in obstructive sleep apnea (OSA) subjects during wakefulness using tagged magnetic resonance imaging. DESIGN: Comparison of the dynamic imaging of three groups of increasing severity OSA and a control group approximately matched for age and body mass index (BMI). SETTING: Not-for-profit research institute. PARTICIPANTS: 24 subjects (apnea hypopnea index [AHI] range 2-84 events/h, 6 with AHI < 5 events/h). METHODS: The upper airway was imaged awake in two planes using SPAtial Modulation of Magnetization (SPAMM). Tissue displacements were quantified with harmonic phase analysis. MEASUREMENTS AND RESULTS: All subjects had dynamic airway opening in the sagittal plane associated with inspiration. In the nasopharynx, the increase in airway cross-sectional area during inspiration correlated with minimal cross-sectional area of the airway (R = 0.900, P < 0.001). AHI correlated negatively with movement of the nasopharyngeal lateral walls (R = - 0.542, P = 0.006). Four movement patterns were observed during inspiration: "en bloc" anterior movement of the whole posterior tongue; movement of only the oropharyngeal posterior tongue; bidirectional movement; or minimal movement. Some subjects showed different inspiratory movement patterns with different breaths. A low AHI (< 5) was associated with en bloc movement (P = 0.002). CONCLUSIONS: Inspiratory movement of the tongue varied between and within subjects, likely as a result of local and neural factors. However, in severe OSA inspiratory movement was minimal. CITATION: Brown EC; Cheng S; McKenzie DK; Butler JE; Gandevia SC; Bilston LE. Respiratory movement of upper airway tissue in obstructive sleep apnea. SLEEP 2013;36(7):1069-1076. PMID- 23814345 TI - Behavioral Sleep Problems and their Potential Impact on Developing Executive Function in Children. AB - : Bedtime resistance and night waking are common sleep problems throughout childhood, especially in the early years. These sleep problems may lead to difficulties in neurobehavioral functioning, but most research into childhood sleep problems has not emphasized the importance of the developmental context in which disruptions in neurobehavioral and daytime functioning occur. We review the development of sleep as well as executive functioning (EF) in childhood and suggest that EF may be particularly vulnerable to the effects of these common childhood sleep problems because of its prolonged course of maturation. Behavioral problems associated with common sleep problems suggest poor self regulation in the context of sleep loss, and developing EF skills play important roles in self-regulation. A research agenda that considers a developmental approach to sleep and sleep problems in the context of childhood EF performance is outlined to promote future research in this area. CITATION: Turnbull K; Reid GJ; Morton JB. Behavioral sleep problems and their potential impact on developing executive function in children. SLEEP 2013;36(7):1077-1084. PMID- 23814346 TI - Acute Sleep Restriction Reduces Insulin Sensitivity in Adolescent Boys. AB - BACKGROUND: Short sleep duration has been linked to impaired glucose metabolism in many experimental studies. Moreover, studies have reported indications of an increased metabolic stress following sleep restriction. OBJECTIVE: We aimed to investigate the effects of partial sleep deprivation on markers of glucose metabolism. Additionally, we aimed to investigate if short sleep duration induces a state of endocrine stress. DESIGN: A randomized crossover design, with 2 experimental conditions: 3 consecutive nights of short sleep (SS, 4 h/night) and long sleep (LS, 9 h/night) duration. SUBJECTS AND MEASUREMENTS: In 21 healthy, normal-weight male adolescents (mean +/- SD age: 16.8 +/- 1.3 y) we measured pre- and post-prandial glucose, insulin, C-peptide, and glucagon concentrations. Furthermore, we measured fasting cortisol, 24-h catecholamines, and sympathovagal balance. RESULTS: Fasting insulin was 59% higher (P = 0.001) in the SS than the LS condition as was both fasting (24%, P < 0.001) and post-prandial (11%, P = 0.018) C-peptide. Pre- and post-prandial glucose and glucagon were unchanged between conditions. The homeostasis model assessment of insulin resistance (HOMA IR) index was 65% higher (P = 0.002) and the Matsuda index was 28% lower (P = 0.007) in the SS condition compared to the LS condition. The awakening cortisol response and 24-h norepinephrine were not affected by sleep duration, whereas 24 h epinephrine was 24% lower (P = 0.013) in the SS condition. Neither daytime nor 24-h sympathovagal balance differed between sleep conditions. Short wave sleep was preserved in the SS condition. CONCLUSION: Short-term sleep restriction is associated with decreased insulin sensitivity in healthy normal-weight adolescent boys. There were no indications of endocrine stress beyond this. CITATION: Klingenberg L; Chaput JP; Holmback U; Visby T; Jennum P; Nikolic M; Astrup A; Sjodin A. Acute Sleep Restriction Reduces Insulin Sensitivity in Adolescent Boys. SLEEP 2013;36(7):1085-1090. PMID- 23814347 TI - Non-24-Hour Disorder in Blind Individuals Revisited: Variability and the Influence of Environmental Time Cues. AB - STUDY OBJECTIVES: To assess the interindividual and intraindividual variability in the circadian rhythms of blind individuals with non-24-h disorder and to quantify the influence of environmental time cues in blind subjects lacking entrainment (non-24-h individuals or N-24s). DESIGN: An observational study of 21 N-24s (11 females and 10 males, age 9-78 years) who kept a sleep/wake schedule of their choosing. Circadian phase was determined using the melatonin onset (MO) from plasma or saliva samples that were collected every 2 weeks. Melatonin concentrations were measured by radioimmunoassay. A total of 469 MO assessments were conducted over 5,536 days of study. The rate of drift of circadian phase was calculated using a series of MOs (total number of hours the MO drifted divided by the total number of days studied). Stability of the rest/activity rhythm was calculated using chi-squared periodogram analysis of wrist actigraphy data in 19 subjects. SETTING: Academic medical center. PARTICIPANTS: Paid volunteers. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Subjects lacked entrainment such that circadian phase drifted an average (+/- standard deviation) of 0.39 +/- 0.29 h later per day; however, there was notable intersubject and intrasubject variability in the rate of drift including relative coordination and periods of transient entrainment during which there was little to no drift in the circadian phase. A regular, reproducible, and significant oscillation in the rate of drift was detected in 14 of the 21 subjects. A significant non-24-h rest/activity rhythm was detected in 18 of 19 subjects. There was a strong correlation (r = 0.793, P = 0.0001) between the non-24-h rest/activity rhythm and the rate of drift of the circadian phase. CONCLUSIONS: Most N-24s are influenced by unidentified environmental time cues and the non-entrained biological clock in such N-24s is reflected in their rest/activity rhythms. These findings may have diagnostic and treatment implications: this disorder might be diagnosed with actigraphy alone, relative coordination and transient entrainment may result in misdiagnosis and responsiveness to environmental time cues may influence treatment success with oral melatonin. CITATION: Emens JS; Laurie AL; Songer JB; Lewy AJ. Non-24-hour disorder in blind individuals revisited: variability and the influence of environmental time cues. SLEEP 2013;36(7):1091-1100. PMID- 23814348 TI - Validation of the Multiple Suggested Immobilization Test: A Test for the Assessment of Severity of Restless Legs Syndrome (Willis-Ekbom Disease). AB - STUDY OBJECTIVES: To validate the Multiple Suggested Immobilization Test (m-SIT), a symptom-provocation test measuring restless legs syndrome (RLS) severity multiple times a day while the patient is awake and resting under controlled conditions. The m-SIT was designed to overcome some limitations in measuring RLS severity with rating scales. DESIGN: Patients completed two m-SITs on 2 consecutive days while on 24-h dopaminergic medication. After treatment discontinuation, they completed one more m-SIT 3 days later. Controls performed only one m-SIT. SETTING: Sleep laboratory. PARTICIPANTS: Nineteen patients with RLS and 10 healthy controls. INTERVENTIONS: The original m-SIT consisted of seven modified 60-min SITs performed every 2 h between noon and midnight. During each SIT, the subject reclined quietly but could move his or her legs without restriction to alleviate symptoms. Every 10 min, periodic leg movements during wakefulness (PLMW) were evaluated and the m-SIT Disturbance Scale (m-SIT-DS; range 0-10) was completed. MEASUREMENTS AND RESULTS: The m-SIT, composed of 6:00pm, 8:00pm, 10:00pm, and 12:00pm SITs, discriminated patients from controls (mean m-SIT-DS: 2.68 +/- 2.35 versus 0.08 +/- 0.26; mean PLMW/h, P = 0.0001) and between treatment groups (on medication versus taken off medication; mean m-SIT DS, P = 0.0001; mean PLMW/h, P < 0.01). It proved reliable on retest and covariated well with the International Restless Legs Scale (IRLS) and scales measuring daytime symptoms (Spearman rho > 0.4). CONCLUSIONS: The m-SIT is a valid and reliable test to evaluate RLS severity and treatment response, and could be useful in the future to confirm diagnosis and identify daytime symptoms. Although it was primarily designed for clinical trials, it might be useful in clinical settings because it provides a standardized testing condition to measure RLS symptoms. CITATION: Garcia-Borreguero D; Kohnen R; Boothby L; Tzonova D; Larrosa O; Dunkl E. Validation of the Multiple Suggested Immobilization Test: a test for the assessment of severity of restless legs syndrome (Willis-Ekbom disease). SLEEP 2013;36(7):1101-1109. PMID- 23814349 TI - European Data Format Now Supports Video. PMID- 23814350 TI - Predicting preschool effortful control from toddler temperament and parenting behavior. AB - This longitudinal study assessed whether maternal behavior and emotional tone moderated the relationship between toddler temperament and preschooler's effortful control. Maternal behavior and emotional tone were observed during a parent-child competing demands task when children were 2 years of age. Child temperament was also assessed at 2 years of age, and three temperament groups were formed: inhibited, exuberant, and low reactive. At 4.5 years of age, children's effortful control was measured from parent-report and observational measures. Results indicated that parental behavior and emotional tone appear to be especially influential on exuberant children's effortful control development. Exuberant children whose mothers used commands and prohibitive statements with a positive emotional tone were more likely to be rated higher on parent-reported effortful control 2.5 years later. When mothers conveyed redirections and reasoning-explanations in a neutral tone, their exuberant children showed poorer effortful control at 4.5 years. PMID- 23814351 TI - A temporal study of Salmonella serovars from environmental samples from poultry breeder flocks in Ontario between 1998 and 2008. AB - A temporal study was carried out to determine Salmonella prevalence, trends, major serovars, and their clusters from environmental samples, in poultry breeder flocks in Ontario between January 1998 and December 2008. Surveillance data were obtained from the Ontario Hatchery and Supply Flock Policy. Logistic regression with a random effect for flock was used to identify factors [poultry type, year (trend) and season] associated with the prevalence of Salmonella. A cluster detection test was used to identify clusters of common serovars. The period prevalence of Salmonella was 47.4% in broiler-breeder, 25.7% in layer-breeder, and 19.6% in turkey-breeder flocks. The overall trend in the prevalence of Salmonella was decreasing for all breeder types, due primarily to decreasing trends of Salmonella Heidelberg. The seasonal effects varied by year with the highest probability of Salmonella occurring in different seasons. The 4 most common serovars identified were Salmonella Heidelberg, Kentucky, Hadar, and Typhimurium in broiler-breeders; Salmonella Heidelberg, Brandenburg, Thompson, and Typhimurium in layer-breeders; and Salmonella Heidelberg, Saintpaul, Brandenburg, and Muenster in turkey-breeders. Salmonella Enteritidis was infrequently isolated in all poultry breeder types. Temporal clusters of different serovars were identified in all poultry breeder types. Clusters of Salmonella Heidelberg, Typhimurium, and Hadar from environmental samples from breeder flocks were detected during a similar period to clusters from hatchery fluff samples from the same population. Therefore, interventions at the breeder flock-level might help to reduce transmission of Salmonella from breeder flocks to hatcheries and possibly, to lower levels of the poultry production chain. PMID- 23814352 TI - A temporal study of Salmonella serovars from fluff samples from poultry breeder hatcheries in Ontario between 1998 and 2008. AB - The objectives of this study were to determine the prevalence of Salmonella, trends, major serovars, and their clusters from fluff samples, in poultry hatcheries in Ontario between 1998 and 2008. Multi-level logistic regression modelling with random effects for hatchery and sampling visit (day on which samples were collected from a hatchery) was used to identify factors [poultry breeder type, year (trend), and season] associated with the prevalence of Salmonella and a cluster detection test was used to identify clusters of common serovars. The period prevalence of Salmonella in fluff samples was 8.7% in broiler-breeders, 3.1% in layer-breeders, 13.2% in turkey-breeders, and 11.9% in other-breeder birds, such as ducks, geese, quail, partridges, and pheasants. There was an overall increasing trend in Salmonella prevalence in broiler breeders and other-breeder birds, and a decreasing trend in layer-breeders. The 4 most common serovars identified were Salmonella Kentucky, Heidelberg, Enteritidis, and Senftenberg in broiler-breeders; Salmonella Heidelberg, Senftenberg, Braenderup, and Typhimurium in layer-breeders; Salmonella Senftenberg, Heidelberg, Saintpaul, and Montevideo in turkey-breeders; and Salmonella Enteritidis, Thompson, Typhimurium, and Heidelberg in other-breeder birds. Temporal clusters were identified for 12 of 13 serovars examined in broiler-breeders, and 4 of 4 serovars in all other poultry-breeders. The seasonal effects varied by year with the highest probability of Salmonella most often occurring in the summer, followed by the fall season. Variance components suggested that control measures should be directed at the hatchery and the sampling visit levels. Further studies are needed to identify risk factors for Salmonella in broiler-breeder, turkey-breeder, and other-breeder bird hatcheries in order to implement necessary control measures. PMID- 23814353 TI - In vivo evaluation of vaccine efficacy against challenge with a contemporary field isolate from the alpha cluster of H1N1 swine influenza virus. AB - Influenza A virus vaccines currently contain a mixture of isolates that reflect the genetic and antigenic characteristics of the currently circulating strains. This study was conducted to evaluate the efficacy of a trivalent inactivated swine influenza virus vaccine (Flusure XP) in pigs challenged with a contemporary alpha-cluster H1N1 field isolate of Canadian swine origin. Pigs were allocated to vaccinated, placebo, and negative-control groups and monitored for respiratory disease for 5 d after challenge. On the challenge day and 5 d after challenge the serum of the vaccinated pigs had reciprocal hemagglutination inhibition antibody titers 40 for all the vaccine viruses but <= 20 for the challenge virus. Gross lesions were present in the lungs of all pigs that had been inoculated with the challenge virus, but the proportion of lung tissue consolidated did not differ significantly between the placebo and vaccinated pigs. However, the amount of virus was significantly reduced in the nasal secretions, lungs, and bronchoalveolar lavage fluid in the vaccinated pigs compared with the placebo pigs. These results indicate that swine vaccinated with Flusure XP were partially protected against experimental challenge with a swine alpha-cluster H1N1 virus that is genetically similar to viruses currently circulating in Canadian swine. PMID- 23814354 TI - Predicting cumulative risk of bovine respiratory disease complex (BRDC) using feedlot arrival data and daily morbidity and mortality counts. AB - Although bovine respiratory disease complex (BRDC) is common in post-weaning cattle, BRDC prediction models are seldom analyzed. The objectives of this study were to assess the ability to predict cumulative cohort-level BRDC morbidity using on-arrival risk factors and to evaluate whether or not adding BRDC risk classification and daily BRDC morbidity and mortality data to the models enhanced their predictive ability. Retrospective cohort-level and individual animal health data were used to create mixed negative binomial regression (MNBR) models for predicting cumulative risk of BRDC morbidity. Logistic regression models were used to illustrate that the percentage of correctly (within |5%| of actual) classified cohorts increased across days, but the effect of day was modified by arrival weight, arrival month, and feedlot. Cattle arriving in April had the highest (77%) number of lots correctly classified at arrival and cattle arriving in December had the lowest (28%). Classification accuracy at arrival varied according to initial weight, ranging from 17% (< 182 kg) to 91% (> 409 kg). Predictive accuracy of the models improved from 64% at arrival to 74% at 8 days on feed (DOF) when risk code was known compared to 56% accuracy at arrival and 69% at 8 DOF when risk classification was not known. The results of this study demonstrate how the predictive ability of models can be improved by utilizing more refined data on the prior history of cohorts, thus making these models more useful to operators of commercial feedlots. PMID- 23814355 TI - An investigation into the association between cpb2-encoding Clostridium perfringens type A and diarrhea in neonatal piglets. AB - To investigate the possible role of cpb2-positive type A Clostridium perfringens in neonatal diarrheal illness in pigs, the jejunum and colon of matched normal and diarrheic piglets from 10 farms with a history of neonatal diarrhea were examined grossly and by histopathology, and tested for C. perfringens, for C. perfringens beta2 (CPB2) toxin, as well as for Clostridium difficile toxins, Salmonella, enterotoxigenic Escherichia coli, rotavirus, transmissible gastroenteritis (TGE) virus, and coccidia. Clostridium perfringens isolates were tested using a multiplex real-time polymerase chain reaction (PCR) to determine the presence of cpa, consensus and atypical cpb2, and other virulence-associated genes. The numbers of C. perfringens in the intestinal contents were lower in diarrheic piglets (log10 5.4 CFU/g) compared with normal piglets (log10 6.5 CFU/g) (P < 0.05). The consensus cpb2 was present in 93% of isolates in each group, but atypical cpb2 was less common (56% healthy, 32% diarrheic piglets isolates, respectively, P < 0.05). The presence of CPB2 toxin in the intestinal contents of normal and diarrheic piglets did not differ significantly. Clostridium difficile toxins and rotavirus were each detected in 7 of the 21 (33%) diarrheic piglets. Rotavirus, C. difficile toxins, Salmonella, or enterotoxigenic E. coli were concurrently recovered in different combinations in 4 diarrheic piglets. The cause of diarrhea in 8 of the 21 (38%) piglets on 6 farms remained unknown. The etiological diagnosis of diarrhea could not be determined in any of the piglets on 2 of the farms. This study demonstrated that the number of cpb2-positive type A C. perfringens in the intestinal contents was not a useful approach for making a diagnosis of type A C. perfringens enteritis in piglets. Further work is required to confirm whether cpb2-carrying type A C. perfringens have a pathogenic role in enteric infection in neonatal swine. PMID- 23814356 TI - Effects of parturition and dexamethasone on DNA methylation patterns of IFN-gamma and IL-4 promoters in CD4+ T-lymphocytes of Holstein dairy cows. AB - This study investigated epigenetic mechanisms by which DNA methylation affects the function of bovine adaptive immune system cells, particularly during the peripartum period, when shifts in type 1 and type 2 immune response (IR) biases are thought to occur. Stimulation of CD4+ T-lymphocytes isolated from 5 Holstein dairy cows before and after parturition with concanavalin A (ConA) and stimulation of CD4+ T-lymphocytes isolated from 3 Holstein dairy cows in mid lactation with ConA alone or ConA plus dexamethasone (Dex) had significant effects on production of the cytokines interferon gamma (IFN-gamma, type 1) and interleukin 4 (IL-4, type 2) that were consistent with DNA methylation profiles of the IFN-gamma gene promoter region but not consistent for the IL-4 promoter region. ConA stimulation increased the production of both cytokines before and after parturition. It decreased DNA methylation in the IFN-gamma promoter region but increased for IL-4 promoter region. Parturition was associated with an increase in IFN-gamma production in ConA-stimulated cells that approached significance. Overall, DNA methylation in both promoter regions increased between the prepartum and postpartum periods, although this did not correlate with secreted cytokine concentrations. Dexamethasone treated cells acted in a manner consistent with the glucocorticoid's immunosuppressive activity, which mimicked the change at the IFN-gamma promoter region observed during parturition. These results support pregnancy as type 2 IR biased, with increases of IFN-gamma occurring after parturition and an increase in IL-4 production before calving. It is likely that these changes may be epigenetically controlled. PMID- 23814357 TI - Resident lymphocytes in the epidermis and adnexal epithelia of normal dorsolateral thorax of alpacas. AB - A small population of resident T-lymphocytes is present in the normal epidermis of skin from humans, mice, sheep, and cattle. The objective of this study was to determine the prevalence of lymphocytes, CD3+ cells (T-lymphocytes) and CD79a+ cells (B-lymphocytes and plasma cells), in the epidermis and adnexal epithelia of alpacas. Skin-biopsy specimens from the normal skin of the dorsolateral thorax of 31 alpacas were examined histologically and immunohistochemically for the presence of CD3+ cells and CD79a+ cells in the epidermis and adnexal epithelia. CD3+ T-lymphocytes, but not CD79a+ cells, were present in the epidermis and adnexal epithelia. Therefore, in the absence of other signs of inflammation, the presence of lymphocytes in these structures in skin-biopsy specimens should be considered normal. PMID- 23814358 TI - Effect of a diet enriched with green-lipped mussel on pain behavior and functioning in dogs with clinical osteoarthritis. AB - This study aimed to establish the effect of a diet enriched with green-lipped mussel (GLM) on pain and functional outcomes in osteoarthritic dogs. Twenty-three client-owned dogs with osteoarthritis (OA) were fed a balanced control diet for 30 d and then a GLM-enriched balanced diet for the next 60 d. We assessed peak vertical force (PVF), which is considered to be the gold standard method, at Day (D)0 (start), D30 (end of control diet), and D90 (end of GLM-enriched diet). The owners completed a client-specific outcome measure (CSOM), which is a pain questionnaire, once a week. Motor activity (MA) was continuously recorded in 7 dogs for 12 wk. Concentrations of plasma omega-3 fatty acids were quantified as indicative of diet change. Statistical analyses were linear-mixed models and multinomial logistic regression for repeated measures. The GLM diet (from D30 to D90) resulted in an increase in concentrations of plasma omega-3 fatty acids (P < 0.016) and improvement of PVF (P = 0.003). From D0 to D30, PVF did not significantly change (P = 0.06), which suggests that the GLM diet had a beneficial effect on gait function. Moreover, PVF (P = 0.0004), CSOM (P = 0.006), and MA (P = 0.02) improved significantly from D0 to D90. In general, the balanced control diet could have contributed to reduced OA symptoms, an effect that was subsequently amplified by the GLM diet. PMID- 23814359 TI - Effect of synchronization of follicle-wave emergence with estradiol and progesterone and superstimulation with follicle-stimulating hormone on milk estrogen concentrations in dairy cattle. AB - Very little is known about the effects of hormonal synchronization of follicle waves and superovulation on the estrogen content of a cow's milk. The objective of this study was to determine the effect in dairy cows of synchronization with estradiol-17beta (E2) and progesterone (P4) on milk E2 concentrations and to compare these levels with those achieved during superstimulation for 4 d with porcine follicle-stimulating hormone (FSH). The milk E2 concentrations were raised significantly above pretreatment levels (P < 0.05) for 2 d after synchronization, the mean peak being 40.2 +/- 18.5 (standard error) pg/mL and the pretreatment mean 1.5 +/- 0.5 pg/mL. The mean peak E2 concentration during ovarian stimulation was 4.4 +/- 0.7 pg/mL. The mean E2 concentration was significantly higher (P < 0.05) after synchronization than during superstimulation for the 1st milking after synchronization but not subsequent milkings. The milk estrone concentrations were above pretreatment levels for 1 d after synchronization and were not different from those observed during superstimulation. PMID- 23814361 TI - Editorial: verbal behavior and motivating operations. PMID- 23814362 TI - Jack Michael's Motivation. AB - Among many of Jack Michael's contributions to the field of behavior analysis is his behavioral account of motivation. This paper focuses on the concept of motivating operation (MO) by outlining its development from Skinner's (1938) notion of drive. Conceptually, Michael's term helped us change our focus on how to study motivation by shifting its origins from the organism to the environment. Michael's account also served to stimulate applied research and to better understand behavioral function in clinical practice. PMID- 23814363 TI - Thirty Points About Motivation From Skinner's Book Verbal Behavior. AB - Skinner discussed the topic of motivation in every chapter of the book Verbal Behavior (1957), usually with his preferred terminology of "deprivation, satiation, and aversive stimulation." In the current paper, direct quotations are used to systematically take the reader through 30 separate points made by Skinner in Verbal Behavior that collectively provide a comprehensive analysis of his position regarding the role of motivation in behavior analysis. In addition, various refinements and extensions of Skinner's analysis by Jack Michael and colleagues (Laraway, Snycerski, Michael, & Poling, 2003; Michael, 1982, 1988, 1993, 2000, 2004, 2007) are incorporated, along with suggestions for research and applications for several of the points. PMID- 23814364 TI - Comments on Michael (1993): establishing operations. AB - The present comments concern Michael's concept of motivative variables, and the implications of that concept for our understanding of the nature of reinforcement as well as the extinction of responses maintained through positive and negative reinforcement. We note that both extinction and altering motivative variables decrease responding, but they do so differently. The former does so by discontinuing the response-reinforcer relation. The latter does so by altering the motivation to respond. We emphasize that we shouldn't conclude we have extinguished a response just because we have performed some operation that results in decreased responding. The difference is especially important for an understanding of how we might reduce maladaptive avoidance responses, such as found in phobias or obsessive-compulsive disorders. PMID- 23814365 TI - The establishing operation and teaching verbal behavior. AB - Twenty years ago Michael (1993) refined and extended the concept of the conditioned establishing operation (CEO). With this paper he updated his previous treatment of the topic (Michael, 1982) by providing terminological refinements and conceptually clear descriptions of the reflexive and transitive CEOs. In the 20 years since the publication of that paper there has been an increase in the application of CEOs as independent variables in the teaching of verbal behavior in applied setting. The purpose of this paper is to provide a brief overview of clinical applications of the EO to the teaching of verbal behavior during the last 20 years. PMID- 23814366 TI - Teaching children with autism spectrum disorders to mand for the removal of stimuli that prevent access to preferred items. AB - Mand training is often a primary focus in early language instruction and typically includes mands that are positively reinforced. However, mands maintained by negative reinforcement are also important skills to teach. These include mands to escape aversive demands or unwanted items. Another type of negatively reinforced mand important to teach involves the removal of a stimulus that prevents access to a preferred activity. We taught 5 participants diagnosed with autism spectrum disorders to mand for the removal of a stimulus in order to access a preferred item that had been blocked. An evaluation was conducted to determine if participants responded differentially when the establishing operations for the preferred item were present versus absent. All participants learned to mand for the removal of the stimulus exclusively under conditions when the establishing operation was present. PMID- 23814367 TI - Comparing acquisition of exchange-based and signed mands with children with autism. AB - Therapists and educators frequently teach alternative-communication systems, such as picture exchanges or manual signs, to individuals with developmental disabilities who present with expressive language deficits. Michael (1985) recommended a taxonomy for alternative communication systems that differentiated between selection-based systems in which each response is topographically identical (e.g., card selection and exchange systems) and topography-based systems in which each response is topographically distinct (e.g., signed language). We compared the efficiency of training picture exchanges and signs with 3 participants who presented with severe language deficits; all participants acquired the picture-exchange responses more readily. PMID- 23814368 TI - Using a lag reinforcement schedule to increase phonemic variability in children with autism spectrum disorders. AB - Shaping functional vocal language is difficult when an individual has not yet acquired an echoic repertoire and does not emit sufficient phonemes (i.e., speech sounds) for shaping. Few studies have evaluated interventions to increase the frequency and breadth of phonemes. The current study extended Esch, Esch, and Love (2009) by evaluating the effects of a Lag 1 reinforcement schedule on vocal variability and limiting the definition of variability to responses that incorporated a novel phoneme. For 2 of the 3 participants, the cumulative number of novel phonemes, the percentage of trials with variability, and the number of different phonemes emitted per session increased during the Lag 1 intervention phase. PMID- 23814369 TI - Evaluation of verbal behavior in older adults. AB - Approximately 5% of older adults have a dementia diagnosis, and language deterioration is commonly associated with this disorder (Kempler, 2005). Several instruments have been developed to diagnose dementia and assess language capabilities of elderly adults. However, none of these instruments take a functional approach to language assessment as described by Skinner (1957). The purpose of this study was to develop and evaluate a function-based assessment for language deficits of older adults. Thirty-one participants were categorized into a control group (n = 15) and a dementia group (n = 16) based on their score on the Dementia Rating Scale-2. Individuals with dementia performed significantly worse on the tact assessment than those without dementia. Participants from both groups performed better on measures of tacts than intraverbals or mands, even though topographically identical responses were required in these assessments. The data provide support for Skinner's conceptualization of functionally independent verbal operants. PMID- 23814370 TI - Effects of a differential observing response on intraverbal performance of preschool children: a preliminary investigation. AB - Axe (2008) speculated that some instances of intraverbal responding might be associated with limited or delayed acquisition because they require discrimination of multiple components of verbal stimuli. Past studies suggest that acquisition of responses under control of complex, multicomponent antecedent stimuli (e.g., conditional or compound stimulus control) can be facilitated with the introduction of a differential observing response (DOR; Dube & McIlvane, 1999; Gutowski, Geren, Stromer, & Mackay, 1995). The purpose of the current study was to evaluate the effects of a DOR (i.e., repeating the question) on intraverbal responding with six neurotypical preschool children. Findings included that (a) accuracy of intraverbal performance increased when the experimenter prompted a DOR; (b) 1 of 6 participants overtly emitted the DOR for a second relation in the absence of prompts, which was correlated with increased accuracy; and (c) following mastery, response accuracy was variable for 3 participants. Based on these findings, prompted DORs may offer an effective, if temporary, aid to intraverbal instruction for neurotypical preschool children. PMID- 23814371 TI - The relationship between punishment history and skin conductance elicited during swearing. AB - Despite its theoretical importance, the effect of past punishment on verbal behavior is often overlooked in research due to the difficulty of measuring it. The present study explores the relationship between physiological arousal in humans and swearing; a behavior likely to have been punished in the typical conditioning history of an individual. Participants' skin conductance was measured as they read aloud a list of words containing swear words, emotionally salient words, and neutral words. The association between SCR measurements and participants' scores on questionnaires on previous punishment for swearing was then analyzed. Findings suggest that people have significantly higher physiological arousal when saying swear words than neutral words, and that this arousal is higher for participants who have previously received more frequent punishment for swearing, according to self-report. PMID- 23814372 TI - Echoic and self-echoic responses in children. AB - Eleven typically developing children were assessed on the accuracy of prompted self-echoic responses following a 5-s delay from their initial echoic response, replicating procedures in Esch, Esch, McCart, and Petursdottir (2010) that compared discrepancies between echoic and self-echoic scores of autistic and typically developing children following a 2-s delay. We compared the two studies in terms of age, level tested, and echoic/self-echoic discrepancy scores. Age and test level differences were found to be statistically significant. Results are discussed in terms of discrepant self-echoic performance and self-echoic rehearsal as it relates to participant age, test level, motivating variables, and the development of complex behavior. PMID- 23814373 TI - An analysis of verbal stimulus control in intraverbal behavior: implications for practice and applied research. AB - A common characteristic of the language deficits experienced by children with autism (and other developmental disorders) is their failure to acquire a complex intraverbal repertoire. The difficulties with learning intraverbal behaviors may, in part, be related to the fact that the stimulus control for such behaviors usually involves highly complex verbal stimuli. The antecedent verbal control of intraverbal behavior may involve discriminative stimuli (i.e., discriminated operants), conditional stimulus control, and/or control by compound stimuli. Distinctions among these different types of antecedent control are presented, along with recommendations for intervention procedures that may facilitate the acquisition of intraverbal behavior. PMID- 23814374 TI - Language generativity, response generalization, and derived relational responding. AB - Language generativity can be described as the ability to produce sentences never before said, and to understand sentences never before heard. One process often cited as underlying language generativity is response generalization. However, though the latter seems to promise a technical understanding of the former at a process level, an investigation of definitions and approaches to the term "response generalization" that appear in the literature suggests that it does not do so. We argue that a more promising candidate for the role of key process underlying language generativity is derived relational responding. We introduce the latter concept and describe empirical research showing its connection with language. We subsequently present a relational frame theory (RFT) conceptualization of derived relations as contextually controlled generalized relational responding. We then review a series of recent studies on derived manding in developmentally delayed children and adults that arguably demonstrate the applied utility of a derived relations-based approach with respect to the phenomenon of generative language. PMID- 23814375 TI - Constructs and events in verbal behavior. AB - Skinner's (1957) analysis of verbal behavior has been the subject of much controversy in recent years. While criticism has historically come from outside the field of behavior analysis, there are now well-articulated arguments against Skinner's analysis of verbal behavior from within the field as well. Recently, advocates of Skinner's analysis have attempted to respond to the critiques, particularly to those regarding Skinner's definition of verbal behavior articulated by proponents of relational frame theory. Specifically, it has been suggested that talk about definitions equates to making the essentialist error. This paper provides an overview of these issues in the context of understanding the role of constructs in science more generally. It will be argued that definitions are central to scientific progress, and are not only relevant to a functional analysis, but a central prerequisite to the pursuit of such an analysis. PMID- 23814376 TI - The Importance of Form in Skinner's Analysis of Verbal Behavior and a Further Step. AB - A series of quotes from B. F. Skinner illustrates the importance of form in his analysis of verbal behavior. In that analysis, form plays an important part in contingency control. Form and function complement each other. Function, the array of variables that control a verbal utterance, dictates the meaning of a specified form; form, as stipulated by a verbal community, indicates that meaning. The mediational actions that shape verbal utterances do not necessarily encounter their controlling variables. These are inferred from the form of the verbal utterance. Form carries the burden of implied meaning and underscores the importance of the verbal community in the expression of all the forms of language. Skinner's analysis of verbal behavior and the importance of form within that analysis provides the foundation by which to investigate language. But a further step needs to be undertaken to examine and to explain the abstractions of language as an outcome of action at an aggregate level. PMID- 23814377 TI - Effects of Mesoporous Silica Coating and Post-Synthetic Treatment on the Transverse Relaxivity of Iron Oxide Nanoparticles. AB - Mesoporous silica nanoparticles have the capacity to load and deliver therapeutic cargo and incorporate imaging modalities, making them prominent candidates for theranostic devices. One of the most widespread imaging agents utilized in this and other theranostic platforms is nanoscale superparamagnetic iron oxide. Although several core-shell magnetic mesoporous silica nanoparticles presented in the literature have provided high T2 contrast in vitro and in vivo, there is ambiguity surrounding which parameters lead to enhanced contrast. Additionally, there is a need to understand the behavior of these imaging agents over time in biologically relevant environments. Herein, we present a systematic analysis of how the transverse relaxivity (r2) of magnetic mesoporous silica nanoparticles is influenced by nanoparticle diameter, iron oxide nanoparticle core synthesis, and the use of a hydrothermal treatment. This work demonstrates that samples which did not undergo a hydrothermal treatment experienced a drop in r2 (75% of original r2 within 8 days of water storage), while samples with hydrothermal treatment maintained roughly the same r2 for over 30 days in water. Our results suggest that iron oxide oxidation is the cause of the r2 loss, and this oxidation can be prevented both during synthesis and storage by the use of deoxygenated conditions during nanoparticle synthesis. The hydrothermal treatment also provides colloidal stability, even in acidic and highly salted solutions, and a resistance against acid degradation of the iron oxide nanoparticle core. The results of this study show the promise of multifunctional mesoporous silica nanoparticles but will also likely inspire further investigation into multiples types of theranostic devices, taking into consideration their behavior over time and in relevant biological environments. PMID- 23814378 TI - Safety of rapid intravenous of infusion acetaminophen. AB - Intravenous acetaminophen, Ofirmev(r), is approved for management of mild to moderate pain, management of moderate to severe pain with adjunctive opioids, and reduction of fever. The product is supplied as a 100 mL glass vial. As stated in the prescribing information, it is recommended to be infused over 15 minutes. This recommendation is related to the formulation propacetamol, the prodrug to acetaminophen, approved in Europe, which caused pain on infusion, and data from the clinical development of acetaminophen. The objective of this retrospective chart review study was to show the lack of side effects of rapidly infusing intravenous acetaminophen. Charts of American Society of Anesthesiology (ASA) Class I-III ambulatory surgical patients who received only acetaminophen in the preoperative setting were reviewed for any infusion-related side effects. Using standard binomial proportion analyses and employing SAS/JMP software, all vital signs were analyzed for statistically significant changes between pre- and postinfusion values. One hundred charts were reviewed. Only one patient had pain on infusion, which lasted 10 seconds. No reported side effects or erythema was seen at the injection site. No infusions had to be slowed or discontinued. The median infusion time was 3:41 minutes. Of the vital signs monitored, only the systolic (P < 0.0001) and diastolic (P < 0.0099) blood pressures had statistically significant changes from pre- to postinfusion; however, they were of no clinical relevance. Acetaminophen can be administered as a rapid infusion with no significant infusion-related side effects or complications. PMID- 23814379 TI - Effect of postoperative course on midterm outcome after esophageal resection for cancer. AB - Esophageal resections are challenging procedures often associated with postoperative complications and a prolonged hospital stay. This study investigated the impact of postoperative course on midterm survival in 35 patients undergoing esophageal resection for malignancy between January 2002 and November 2007. The impact of preoperative and operative variables, pathology, staging, early postoperative complications, and length of hospital stay on midterm survival was determined with Cox regression analysis. During the follow up period, 17 (48.6%) patients died. Multivariate analysis identified surgical stage and length of stay as independent predictors of midterm survival; in addition, the total number of complications reached statistical significance. In conclusion, in addition to surgical stage, postoperative course has an impact upon midterm survival after esophageal resection. PMID- 23814380 TI - Comparison of fluoroscopic operator eye exposures when working from femoral region, side, or head of patient. AB - Operator radiation exposure is an important occupational hazard compounded over the course of an interventional radiologist's career. This study compared operator radiation dose to the eye and head for different positions around the patient. Compared with cases performed from the femoral region, exposures were 1.8 times higher at the side, and 1.6 times higher at the head, using conventional aprons, table shields, and mobile suspended shields. Exposures were 99% lower when using a suspended personal radiation protection system in all positions. In conclusion, standing at the side or head results in higher head exposures in a conventional setup. PMID- 23814381 TI - Development and evaluation of a treadmill-based exercise tolerance test in cardiac rehabilitation. AB - Cardiac rehabilitation exercise prescriptions should be based on exercise stress tests; however, limitations in performing stress tests in this setting typically force reliance on subjective measures like the Duke Activity Status Index (DASI). We developed and evaluated a treadmill-based exercise tolerance test (ETT) to provide objective physiologic measures without requiring additional equipment or insurance charges. The ETT is stopped when the patient's Borg scale rating of perceived exertion (RPE) reaches 15 or when any sign/symptom indicates risk of an adverse event. Outcomes of the study included reasons for stopping; maximum heart rate, systolic blood pressure, and rate pressure product; and adverse events. We tested equivalence to the DASI as requiring the 95% confidence interval for the mean difference between DASI and ETT metabolic equivalents (METs) to fall within the range (-1, 1). Among 502 consecutive cardiac rehabilitation patients, one suffered a panic attack; no other adverse events occurred. Most (80%) stopped because they reached an RPE of 15; the remaining 20% were stopped on indications that continuing risked an adverse event. Mean maximum systolic blood pressure, heart rate, and rate pressure product were significantly (P < 0.001) below thresholds of the American Association of Cardiovascular and Pulmonary Rehabilitation. Two patients' heart rates exceeded 150 beats per minute, but their rate pressure products remained below 36,000. The mean difference between DASI and ETT METs was -0.8 (-0.98, -0.65), indicating equivalence at our threshold. In conclusion, the ETT can be performed within cardiac rehabilitation, providing a functional capacity assessment equivalent to the DASI and objective physiologic measures for developing exercise prescriptions and measuring progress. PMID- 23814382 TI - Application of cranial bone grafts for reconstruction of maxillofacial deformities. AB - This retrospective study evaluated outcomes with the use of calvarial bone grafts (CBGs) in maxillofacial reconstruction as well as donor and recipient site complications. The records of 50 consecutive patients from a private practice were reviewed; there were 34 women and 16 men, with an average age of 32.4 years (range 16 to 66 years). Among the 50 patients, CBGs were placed in 63 sites: the ramus (10), nasal dorsum (14), maxilla/alveolar ridge (12), glenoid fossa/temporal bone (14), mandibular body/symphysis (3), and orbitozygomatic complex (10). The longest follow-up averaged 22.4 months (range 12 to 48 months). An outer-table CBG harvest technique was utilized. All subjects were evaluated for infection, dehiscence, loss of graft, and any other complications. Three complications occurred (5%) at the recipient sites. Two grafts became infected requiring removal, and one nasal dorsal graft was mobile but remained in position. At 50 donor sites, 2 complications (4%) occurred, resulting in dural tears in two patients that were immediately repaired with no untoward consequence. In conclusion, CBGs are an effective bone source for maxillofacial reconstruction with low donor and recipient site complications. PMID- 23814383 TI - Frequency of adoption of practice management guidelines at trauma centers. AB - Evidence-based management guidelines have been shown to improve patient outcomes, yet their utilization by trauma centers remains unknown. This study measured adoption of practice management guidelines or protocols by trauma centers. A survey of 228 trauma centers was conducted over 1 year; 55 completed the survey. Centers were classified into three groups: noncompliant, partially compliant, and compliant with adoption of management protocols. Characteristics of compliant centers were compared with those of the other two groups. Most centers were Level I (58%) not-for-profit (67%) teaching hospitals (84%) with a surgical residency (74%). One-third of centers had an accredited fellowship in surgical critical care (37%). Only one center was compliant with all 32 management protocols. Half of the centers were compliant with 14 of 32 protocols studied (range, 4 to 32). Of the 21 trauma center characteristics studied, only two were independently associated with compliant centers: use of physician extenders and daily attending rounds (both P < .0001). Adoption of management guidelines by trauma centers is inconsistent, with wide variations in practices across centers. PMID- 23814384 TI - Effectiveness and safety of Gamma Knife radiosurgery for glossopharyngeal neuralgia. AB - Glossopharyngeal neuralgia (GPN) is a rare disorder of the ninth cranial nerve characterized by severe paroxysmal pain affecting the ear, tongue, and throat. GPN can be associated with life-threatening issues such as cardiac arrhythmias, syncope, or malnutrition and weight loss from odynophagia. Though traditional treatment for GPN involves medical management at first and surgery for refractory cases, these therapies are often poorly tolerated in the elderly population. We describe the case of a 99-year-old woman, the oldest reported patient with GPN treated successfully with Gamma Knife radiosurgery. We conclude that Gamma Knife radiosurgery for GPN can be both effective and very well tolerated in the elderly and deserves further study and careful consideration as a treatment option in this population. PMID- 23814385 TI - Herpes simplex virus meningitis complicated by ascending paralysis. AB - A case of herpes simplex virus (HSV) meningitis complicated by ascending paralysis with almost complete recovery following antiviral treatment is reported. We present this case to illustrate the importance of including HSV induced neuropathy in the differential diagnosis of acute neurologic symptoms following the viral illness. PMID- 23814386 TI - Adrenomegaly and septic adrenal hemorrhage (Waterhouse-Friderichsen syndrome) in the setting of congenital adrenal hyperplasia. AB - Congenital adrenal hyperplasia refers to a spectrum of autosomal recessive inherited disorders of steroidogenesis most commonly identified on newborn screenings. We describe a young woman who presented with abdominal pain and on subsequent imaging was found to have features of congenital adrenal hyperplasia. Imaging findings, treatment, and potential complications are discussed. PMID- 23814387 TI - Capsule endoscopy device retention and magnetic resonance imaging. AB - A 55-year-old man was hospitalized for a neurologic and infectious workup after having hallucinations and productive cough for 2 days. During hospitalization, he experienced dark stools with an acute drop in hemoglobin. Upper endoscopy and colonoscopy were negative for an identifiable source of bleed. Capsule endoscopy was later done and subsequently an anteroposterior abdominal radiograph confirmed the presence of a retained capsule near the junction of the descending and distal transverse colon, likely contained within a colonic diverticulum. In the interim, the patient developed acute right-sided lumbar radiculopathy prompting emergent lumbar spine magnetic resonance imaging (MRI). During the scanning process, the retained capsule was seen and the test was immediately terminated without harm to the patient. Device retention is a complication unique to capsule endoscopy, occurring at a rate of 1% to 1.7%; retained devices are considered a danger and contraindication to MRI. PMID- 23814388 TI - Association between congenitally quadricuspid aortic valve and mitral valve prolapse. AB - We describe transthoracic echocardiograms in three patients with combined quadricuspid aortic valve and prolapsing mitral valve. None had symptoms of cardiac dysfunction. Two patients had precordial murmurs. A third patient was referred for evaluation of infective endocarditis. The fact that a quadricuspid aortic valve is clearly a congenital anomaly supports the view that mitral valve prolapse is a congenital anomaly that may be more strongly associated with quadricuspid aortic valves than once thought. PMID- 23814389 TI - Pauses in the electrocardiogram of a woman with chest pain and lightheadedness. PMID- 23814390 TI - Coronary angiographic significance of hyperacute ST-T changes associated with regadenoson stress. AB - An abnormal electrocardiographic stress test is typically characterized by ST segment depression. In rare cases, ST segment elevation is observed, which, in the absence of diagnostic Q waves, has anatomic specificity for localized myocardial ischemia. Most instances of ST elevation occurring during cardiac stress testing have been observed with exercise, with only six cases reported with pharmacologic stress. Despite different physiologic mechanisms for inducing myocardial ischemia, development of ST segment elevation during pharmacologic stress, as illustrated by the present case, may also be indicative of critical coronary stenoses, warranting urgent coronary arteriography. PMID- 23814392 TI - Abnormal origin of the left internal thoracic artery detected only by computed tomography. AB - The origins of the branches of the subclavian artery are known to be variable. We present the case of a 55-year-old man whose coronary artery bypass surgery necessitated the use of the internal thoracic artery as he lacked other suitable venous conduits. The left internal thoracic artery appeared to be absent on subselective subclavian angiography. Computed tomographic angiography revealed a previously undescribed anomaly: origin of the internal thoracic artery from a thyrocervical trunk arising directly from the aortic arch. PMID- 23814391 TI - Chylopericardium following orthotopic lung transplantation. AB - Chylopericardium is an uncommon condition, reported to occur following routine cardiac surgery, orthotopic heart transplantation, cardiac trauma, intrathoracic tumors, or infection. It has not, to date, been reported following uncomplicated orthotopic lung transplantation. This article describes chylopericardium following bilateral orthotopic lung transplantation. PMID- 23814393 TI - Avoidance of lower-limb amputation by surgical implantation of autologous stem cells. AB - A 69-year-old Caucasian man was referred to Baylor University Medical Center at Dallas with resting lower-extremity pain and a nonhealing sore above his right ankle (Rutherford chronic ischemia stage 5 of 6) after having failed multiple attempts at revascularization. He was enrolled in a clinical research trial using adult autologous stem cells for treatment of critical limb ischemia. Autologous stem cells from the patient's pelvic bone marrow were harvested, concentrated in the operating room, and reinjected into the lower leg along the vasculature below the level of complete occlusion of the popliteal artery and around the ulcer. After 3 months, the patient had significant improvement in his ankle brachial index, which increased from 0.10 to 0.40 (normal 0.9-1.01), and early healing. After 12 months, the ulcer was fully healed. Healing of the sore has persisted for 3 years. PMID- 23814394 TI - Eosinophilic small bowel enteritis in response to folinic acid, fluorouracil, and oxaliplatin chemotherapy. AB - A 70-year-old woman being treated with folinic acid, fluorouracil, and oxaliplatin (FOLFOX) therapy for relapsed colon cancer metastatic to the lung presented to the hospital with a 1-week history of abdominal pain, anorexia, a 1 day history of diarrhea, and a fever of 101 degrees F. Neutropenia and a peripheral eosinophilia were present, and computed tomogram of the abdomen showed thickening of the wall of a segment of small bowel with luminal stenosis. Colonoscopy and double-balloon small bowel enteroscopy found a stenosis in the ileum that upon biopsy revealed small bowel eosinophilic enteritis. She improved rapidly with the administration of dexamethasone. A Medline search for reports of small bowel eosinophilic enteritis in response to any of the components of FOLFOX was unrevealing. PMID- 23814395 TI - Pulmonary tumor embolism syndrome from occult colonic adenocarcinoma. AB - Pulmonary tumor embolism syndrome is a rare phenomenon that can occur in patients who have an occult neoplasm that metastasizes. We describe a case of an elderly woman with an undiagnosed colon cancer who suffered from respiratory distress and compromised pulmonary blood flow from micrometastasis in the pulmonary arteries. PMID- 23814396 TI - Signet ring lymphoma: a potential diagnostic mishap. AB - Signet ring lymphomas are proliferations of malignant lymphoid cells containing cytoplasmic inclusions or vacuoles that displace the nucleus to the side, imparting a "signet ring" appearance. These signet ring cells, particularly those with cytoplasmic vacuoles, may be mistaken for an adenocarcinoma rather than a lymphoma, if sufficient material is not available to differentiate the case by immunohistochemical stains or flow cytometry. The pathologist must also be aware of this entity so that appropriate studies may be untaken. PMID- 23814397 TI - Invasive mucinous carcinoma of the breast. AB - Mucinous carcinoma of the breast is one of the rarer forms of intramammary cancer, often presenting as a lobulated, fairly well circumscribed mass on mammography, sonography, and gadolinium-enhanced magnetic resonance imaging. It accounts for 1% to 7% of all breast cancers and generally carries a better prognosis than other types of malignant breast cancers. Metastatic disease occurs at a lower frequency than in other types of invasive carcinoma. We present an atypical case of mucinous carcinoma in a woman who presented with a palpable intramammary lymph node metastasis from an unknown breast primary. Subsequent magnetic resonance imaging and percutaneous biopsy demonstrated histologic findings consistent with a mixed mucinous neoplasm with a micropapillary pattern. PMID- 23814398 TI - Fat necrosis in the breast from methylene blue dye injection. AB - Sentinel lymph node biopsy has become the standard of clinical care in staging axillary lymph nodes for breast carcinoma. While deemed safe and effective, methylene blue dye has been associated with infection, fibrosis, and skin and fat necrosis. The variable appearance of surgical dye-related fibrosis and fat necrosis on imaging studies poses a challenge to both radiologists and clinicians. We present a patient in whom a new enhancing lesion was visualized on follow-up magnetic resonance imaging for known breast carcinoma in the setting of neoadjuvant chemotherapy. PMID- 23814399 TI - Kummell disease. AB - Kummell disease, or avascular necrosis of a vertebral body, presents as vertebral osteonecrosis typically affecting a thoracic vertebra with compression deformity, intravertebral vacuum cleft, and exaggerated kyphosis weeks to months after a minor traumatic injury. This rare disease is increasing in prevalence secondary to an aging population and the associated rise in osteoporosis. Treatment with vertebroplasty or surgical decompression and fusion is often required. We present a classic case of Kummell disease to illustrate the salient features of the condition, with associated imaging findings on computed tomography and magnetic resonance imaging. PMID- 23814400 TI - Saving lives, not sacrificing them: the inevitable clash between medical research and the protection of medical subjects. AB - Throughout history, medical practitioners have been admonished to do nothing in treating their patients that might result in harming them. It was not until the 20th century that such teaching was codified in specific legislation. Spurred on by the perversity of Nazi doctors during the Holocaust, world leaders produced the Nuremberg Code in 1947 and the Declaration of Helsinki in 1964. Revelations about other egregious acts in the guise of legitimate medical research led to other measures to prevent such mistreatment. Regulations to ensure physician competency and responsibility have mushroomed in the succeeding years. While such measures were coming into being, some of the greatest advances in medicine were being achieved, not least among them those in cardiovascular surgery. Ironically, much of this valuable research would likely not have been approved under regulatory measures now firmly in place. Given the nature of medical research, more often than not a certain degree of risk in all patients entering such trials may be unavoidable. There is always a balance to be maintained between risk and potential benefit. PMID- 23814401 TI - Thirty years of innovation in gastroenterology: a personal history. PMID- 23814402 TI - Clinical utility of positron emission mammography. AB - Several imaging modalities have been introduced over recent years to better screen for and stage breast cancer. Positron emission mammography (PEM) has been approved by the US Food and Drug Administration and introduced into clinical use as a diagnostic adjunct to mammography and breast ultrasonography. PEM has higher resolution and a more localized field of view than positron emission tomography computed tomography and can be performed on patients to stage a newly diagnosed malignancy. Review of mammograms together with magnetic resonance or PEM images improves detection of disease. PMID- 23814404 TI - William Leslie Jack Edwards, MD: a conversation with the editor. PMID- 23814403 TI - Renal denervation for resistant hypertension. PMID- 23814406 TI - Facts and ideas from anywhere. PMID- 23814405 TI - Steven John Phillips, PhD: a conversation with the editor with an emphasis on hospital and research safety. PMID- 23814407 TI - Temperature dependence of electric-field-induced domain switching in 0.7Pb(Mg1/3Nb2/3)O3-0.3PbTiO3 single crystal. AB - The influence of temperature on electric-field-induced domain switching of [0 0 1]c oriented 0.7Pb(Mg1/3Nb2/3)O3-0.3PbTiO3 (PMN-0.3PT) single crystal has been studied. The piezoelectric properties of PMN-0.3PT single crystal change drastically at one critical field at 30 degrees C and two critical fields at 90 degrees C corresponding to electric-field-induced domain switching. The domain structures were studied by polarizing light microscopy on the [100]c surface under the electric field applied along [001]c direction. The PMN-0.3PT single crystal exhibits a rapid increase in piezoresponse at 100 V/mm, which is related to R-MA phase transformation. At 90 degrees C, the M and T0 0 1 phases coexist at 100 V/mm, while T001 mono-domain appears at 300 V/mm. The domain switching process here can be identified as (T100 or T010) -> M -> T001. The experimental results show that the phase state and domain structures of the crystal are closely related to the piezoelectric behaviors. PMID- 23814408 TI - Silver Doped 0.9PMN-PT-0.1PZT Composite Films for very High Frequency Ultrasonic Transducer Applications. AB - A series of silver doping concentration into the 0.9PMN-PT-0.1PZT (PMN-PT-PZT) films via the composite sol-gel technique were prepared. The crystallographic properties and microstructures of PMN-PT-PZT films with the silver dopant were investigated. Additionally, the effect of silver doping on dielectric and ferroelectric properties was examined. The results show that in general, the dielectric permittivity and remnant polarization increase as the silver doping concentration is increased. The PMN-PT-PZT+ 2.5 mol% Ag film exhibits a dielectric constant of 3,610 at 1 kHz and a remnant polarization of 57.6 uC/cm2 at room temperature. From this silver doped film, very high frequency ultrasonic needle transducers were fabricated and evaluated. The representative transducer had the center frequency of 225 MHz with a -6 dB bandwidth of 29% (65 MHz) and 62 dB insertion loss. The performance of this transducer is comparable to other composite sol-gel films transducer. The results suggest that this silver-doped PMN-PT-PZT film is a promising candidate as an alternative piezoelectric film for very high frequency transducer applications. PMID- 23814409 TI - Maternal mobility across the rural-urban divide: empirical data from coastal Kenya. AB - This paper describes the mobility patterns, rural-urban linkages and household structures for a low-income neighbourhood on the outskirts of Mombasa, Kenya's main port, and a rural settlement 60 kilometres away. Drawing on interviews with a sample of mothers resident in each location, it documents their perceptions of the advantages and disadvantages of rural and urban life, and shows the continuous interchange between the two areas. It also highlights how most rural to urban migrants are familiar with urban environments before moving and how, having moved, many maintain strong rural ties. The ways in which households are split across rural and urban areas is influenced by intra-household relations and by household efforts to balance the income-earning opportunities in town, the relatively low cost of living in rural areas and future family security. This produces dramatic differences between and among rural and urban mothers and suggests a need for policy makers and planners to recognize diversity and to build upon complex livelihood strategies that span the rural-urban divide. PMID- 23814410 TI - Understanding and Treating Complicated Grief: What Can We Learn from Posttraumatic Stress Disorder? AB - The paper outlines possible parallels between the phenomenology and treatment of complicated grief and PTSD. In particular, it explores how treatment procedures used in Cognitive Therapy for PTSD (Ehlers & Clark, 2000) may be adapted for the treatment of complicated grief. Stimulus Discrimination may be helpful in breaking the link between everyday triggers and "felt presence" memories of the deceased. Memory Updating procedures may help the patient accept that the deceased is no longer alive and no longer suffering. Reclaiming your Life procedures may help the patient access autobiographical memories that are not linked to the deceased and counteract beliefs about the value of life without the deceased. The paper further addresses the necessity of specifying the idiosyncratic beliefs that prevent coming to terms with the death, of understanding the relationship between beliefs and coping strategies, and of distinguishing memories from rumination. PMID- 23814411 TI - Toward establishing a renal biopsy registry: A step in the right direction. PMID- 23814412 TI - Noninvasive assessment of bone health in Indian patients with chronic kidney disease. AB - Abnormalities in mineral and bone disease are common in chronic kidney disease (CKD). Evaluation of bone health requires measurement of parameters of bone turnover, mineralization, and volume. There are no data on bone health in CKD patients from India. In this cross-sectional study, we evaluated serum biomarkers of bone turnover: Bone-specific alkaline phosphatase (BAP) and total deoxypyridinoline (tDPD) along with parathyroid hormone, 25(OH) vitamin D, and bone mineral density (BMD) using dual absorption X-ray absorptiometry in a cohort of 74 treatment-naive patients with newly diagnosed stage 4 and 5 CKD (age 42 +/- 14.5 years, 54 men) and 52 non-CKD volunteers (age 40.2 +/- 9.3 years, 40 men). Compared to the controls, CKD subjects showed elevated intact PTH (iPTH), BAP, and tDPD and lower BMD. There was a strong correlation between iPTH and BAP (r = 0.88, P < 0.0001), iPTH and tDPD (r = 0.51, P < 0.0001), and BAP and tDPD (r = 0.46, P = 0.0004). The iPTH elevation was greater than twice the upper range of normal in 73% cases, and BAP was >40 U/L in 66% cases. The combination of these markers suggests high turnover bone disease in over 60% cases. The prevalence of osteopenia and osteoporosis was 37% and 12%, respectively. Osteoporotic subjects had higher iPTH, BAP, and tDPD, suggesting a role of high turnover in genesis of osteoporosis. Vitamin D deficiency was seen in 80%, and another 13% had insufficient levels. Vitamin D correlated inversely with BAP (r = -0.3, P = 0.009), and levels were lower in those with iPTH >300 pg/ml (P = 0.0.04). In conclusion, over 60% of newly diagnosed Indian stage 4-5 CKD patients show biochemical parameters consistent with high turnover bone disease. High turnover could contribute to the development of osteoporosis in CKD subjects. Deficiency of 25 (OH) vitamin D is widespread and seems to have a role in the genesis of renal bone disease. Studies on the effect of supplementation of native vitamin D are needed. PMID- 23814413 TI - The spectrum of glomerular diseases in a single center: A clinicopathological correlation. AB - We report the spectrum of biopsy-proven glomerular disease (GD) in a single center in Eastern India. Medical records of 666 patients with biopsy-proven GD over a period of 2 years from July 2010 to July 2012 were retrospectively analyzed. The clinical, laboratory, and histological data were recorded. All biopsy specimens were examined by the same pathologist with light and immunofluorescence microscopy. Electron microscopic analysis was performed only in selected cases. Histologic spectrum of various GDs was studied along with its correlation with the clinical and laboratory parameters. The clinical diagnosis was nephrotic syndrome (NS) in 410 (61.56%), rapidly progressive renal failure/glomerulonephritis in 130 (19.52%), subnephrotic proteinuria/asymtomatic urinary abnormalities in 52 (7.81%), acute kidney injury/acute nephritic syndrome in 40 (6.01%), and macroscopic hematuria in 4 (0.6%) patients. Male: Female ratio was 1.05; 27.92% (n = 186) were < 18 years, 68.47% (n = 456) were 18-59 years, and 3.6% (n = 24) were >= 60 years of age. The most common GD was minimal change disease (MCD) (20.12%, n = 134); others were focal segmental glomerulosclerosis (FSGS) (18.02%, n = 15.32%), lupus nephritis (LN) (15.32%, n = 102), membranous nephropathy (MN) (12.01%, n = 80), and IgA nephropathy (IgAN) (8.11%, n = 54). Primary GD was present in 79.13% (n = 527) and common histologies were MCD (25.42%), FSGS (22.58%), MN (14.42%), and IgAN (10.25%). Secondary GD was present in 20.87% (n = 139), with the most common being LN (73.38%, n = 102). Among the NS (n = 410), the most common GD was MCD (31.46%), followed by FSGS (25.6%), MN (15.58%), LN (7.8%), IgAN (6.09%), and membranoproliferative glomerulonephritis (4.88%). FSGS was the most common primary GD in adults, MCD in children, and MN in the elderly patients. The spectrum of GD varies according to the area of study and changes over time. A biopsy registry is needed for documenting this variation. PMID- 23814414 TI - Histological pattern of primary glomerular diseases among adult Sudanese patients: A single center experience. AB - In Sudan, like most developing countries, the incidence and histologic patterns of primary glomerulonephritis (GN) remains undetermined. A cross-sectional hospital-based prospective study was performed to determine the pattern of primary GN among adult Sudanese patients. The study was conducted at Khartoum Teaching Hospital from September 2010 to August 2011. It included all adult patients with suspected primary glomerular disease and who underwent native kidney biopsy. A total of 83 adult patients were biopsied with 71 patients (85.5%) being diagnosed as having primary GN. Among those with primary GN the mean age was 34.6 +/- 18 years and males represent 54.9%. In 46.5% kidney biopsy was indicated by the presence of nephrotic syndrome, whereas in 33.8% biopsies were performed due to unexplained elevations in renal parameters. Primary focal segmental glomerulosclerosis (FSGS) was diagnosed in 29.6% of patients, followed by membrano-proliferative glomerulonephritis (MPGN) in 26.8% and minimal change disease in 16.9%. IgA nephropathy was observed in 5.6%. Complications following kidney biopsies were reported in 9.6% of biopsied patients. Nephrotic syndrome in an adult was the most common indication for kidney biopsy in our unit. A large number of patients were biopsied due to elevated renal parameters, which reflected the increasing awareness toward thoroughly diagnosing patients with suspected reversible kidney damage. In conclusion, FSGS and MPGN make the most common causes of primary GN among Sudanese adults. Creation of a national renal registry is essential for obtaining more specified epidemiological data. PMID- 23814415 TI - Serum cystatin C as a marker of renal function in detection of early acute kidney injury. AB - In patients with acute kidney injury (AKI), serum creatinine level does not increase until moderate to severe reduction in glomerular filtration rate (GFR) occurs. Thus its use for estimating GFR in early AKI delays detection of kidney damage and making important therapeutic decisions. Moreover, serum cystatin C is not affected by gender, age, race, and muscle mass and also does not suffer from lag period for its rise in early AKI. We studied 200 healthy subjects and 130 AKI patients over a period of 2 years at a tertiary care hospital. Serum creatinine and serum cystatin C were studied and analyzed in relevance to early AKI. We found that 56.2% of patients of AKI group had normal levels of serum creatinine in early phase, while all patients had elevated serum cystatin C at same time. Multiple logistic regression analysis revealed cystatin C-based GFR reflecting decline in GFR with worsening AKI in better than creatinine-based GFR. Serum cystatin C is a better marker of renal function in early stages of AKI and is less affected by age, gender, muscle mass, and ethnicity. Its use helps in early therapeutic intervention and possibly favorable outcome. PMID- 23814416 TI - General practitioners' knowledge and approach to chronic kidney disease in Karachi, Pakistan. AB - Due to lack of adequate number of formally trained nephrologists, many patients with chronic kidney disease (CKD) are seen by general practitioners (GPs). This study was designed to assess the knowledge of the GPs regarding identification of CKD and its risk factors, and evaluation and management of risk factors as well as complications of CKD. We conducted a cross-sectional survey of 232 randomly selected GPs from Karachi during 2011. Data were collected on a structured questionnaire based on the kidney disease outcomes and quality initiative recommendations on screening, diagnosis, and management of CKD. A total of 235 GPs were approached, and 232 consented to participate. Mean age was 38.5 +/- 11.26 years; 56.5% were men. Most of the GPs knew the traditional risk factors for CKD, i.e., diabetes (88.4%) and hypertension (80%), but were less aware of other risk factors. Only 38% GPs were aware of estimated glomerular filtration rate in evaluation of patients with CKD. Only 61.6% GPs recognized CKD as a risk factor for cardiovascular disease. About 40% and 29% GPs knew the correct goal systolic and diastolic blood pressure, respectively. In all, 41% GPs did not know when to refer the patient to a nephrologist. Our survey identified specific gaps in knowledge and approach of GPs regarding diagnosis and management of CKD. Educational efforts are needed to increase awareness of clinical practice guidelines and recommendations for patients with CKD among GPs, which may improve management and clinical outcomes of this population. PMID- 23814417 TI - Retrospective analysis of 271 arteriovenous fistulas as vascular access for hemodialysis. AB - This report describes our experience of arteriovenous fistula (AVF) creation as vascular access for hemodialysis (HD). Study has been carried out in Deenanath Mangeshkar Hospital, Pune from January 2004 to December 2009. A total of 271 AVFs were created in 249 patients. Maximum follow up was 7 years and minimum was 1 year. In this study of 271 cases of AVFs, there were 196 (72.3%) successful cases and 75 (27.7%) failures. Basilic vein was used in 77 (28.4%) cases, cephalic vein in 186 (68.6%), and antecubital vein in 8 (3%) cases. End (vein) to side (artery) anastomosis was done in 170 (63%) cases. Side to side anastomosis was done in 100 (37%) cases. On table bruit was present in 244 (90%) and thrill in 232 (85.6%) cases. During dialysis, flow rate >250 ml/min was obtained in 136 (50.4%) cases. In complications, 16 (5.9%) patients developed distal edema, 32 (11.8%) developed steal phenomenon. Presence of on table thrill and bruit are indicators of successful AVF. If vein diameter is <2 mm, chances of AVF failure are high. During proximal side to side fistula between antecubital/basilic vein and brachial artery, breaking of first valve toward wrist helps to develop distal veins in forearm by retrograde flow. This technique avoids requirement of superficialization of basilic vein in arm. PMID- 23814418 TI - Study of CC chemokine receptor 5 in renal allograft rejection. AB - Allospecific recruitment of T cells is primary to the pathogenesis of renal transplant rejection. Chemokines and their receptors inducing a Th1 cytokine response play a central role in this recruitment. Renal allograft biopsies of 28 patients with acute cellular rejection and 10 protocol biopsies (controls) were examined in accordance with Banff grading 2007 schema. Immunohistochemistry for CD3 and CC chemokine receptor 5 (CCR5) in sequential sections was performed and quantitatively assessed in the glomeruli, tubules, and interstitium. Histopathologic and clinical correlations were carried out. CD3- and CCR5 positive cells were observed in significantly higher numbers in rejection cases than in controls (P = 0.010). A larger proportion of CCR5-positive cells were noted in the foci of tubulitis compared to the interstitial infiltrates and glomeruli in all cases, and it correlated with the grade of cellular rejection (P = 0.010). A greater number of CCR5-positive cells were seen in early rejection (<6 months posttransplant) compared to late rejection. No clinical correlation with serum creatinine levels was found. CCR5-positive cells represent the alloaggressive subset of T cells in ACR, and their numbers correlate with rejection severity. CCR5 may be used as a marker of early acute rejection and may be an important target for future antirejection therapies. PMID- 23814419 TI - Prevalence and risk factors of hyperuricemia among kidney transplant recipients. AB - Hyperuricemia is common in renal transplant patients (RTRs), especially those on cyclosporine (CsA)-based therapy. We conducted a retrospective study to determine the prevalence of hyperuricemia and its risk factors among RTRs. A total of 17,686 blood samples were obtained from 4,217 RTRs between April 2008 and January 2011. Hyperuricemia was defined as an uric acid level of >=7.0 mg/dl in men and of >=6 mg/dl in women that persisted for at least two consecutive tests. Majority (68.2%) of RTRs were normouricemic. Hyperuricemia was more frequent in younger and female RTRs. On multivariate logistic regression, we found high trough level of cyclosporine to be a risk factor for hyperuricemia. In addition, female gender, impaired renal function, and dyslipidemia (hypercholesterolemia, hypertriglyceridemia, and elevated LDL) were also associated with higher probability of hyperuricemia. Hyperuricemia is a common complication after renal transplantation. Risk factors implicated in post-transplant hyperuricemia include high trough level of cyclosporine, female gender, renal allograft dysfunction, and dyslipidemia. PMID- 23814420 TI - Retrieval of kidney tissue for light microscopy from frozen tissue processed for immunofluorescence: A simple procedure to avoid repeat kidney biopsies. AB - We highlight a method that is helpful in situations where the tissue sent for LM is inadequate whereas the tissue sent for IF showed glomeruli useful for interpretation. We utilized the leftover frozen tissue after the sections for IF were taken. This tissue was post-fixed in formalin for the purpose of light microscopic diagnosis. The glomerular pathology could be commented upon with a fair degree of accuracy and a repeat biopsy was avoided in 74.7% of the cases. However, the tubules showed marked fixation artefact and tubular pathology was distorted. This procedure can help to reach a correct diagnosis in large percentage of cases otherwise labeled as inadequate biopsy and hence, save the patient from the trauma of a repeat biopsy. PMID- 23814421 TI - Rhabdomyolysis induced acute renal failure secondary to statins. AB - Rhabdomyolysis is a syndrome characterized by muscle necrosis and the release of intracellular muscle contents into the systemic circulation. We report a patient with chronic kidney disease who had deterioration of renal function due to combination of risk factors like hypothyroidism and interaction of amlodipine and clopidogrel with statins. PMID- 23814422 TI - Renal transplantation across ABO barrier. AB - In India, patients without a compatible blood group donor are usually excluded from renal transplantation. For young patients, it is a difficult therapeutic choice to stay on long-term dialysis. We describe the case of a 19-year-old male patient who had blood group O +ve and had no compatible donor in the family. His mother was B +ve and was willing to donate. The patient had an initial anti-B antibody titer of 1:512 and underwent antibody depletion with plasmapheresis (11 sessions) and intravenous immunoglobulin (IVIG) 100 mg/kg after every plasmapheresis. He also received rituximab 500 mg for 3 days prior to transplant and was induced with basiliximab. At the time of transplant, his anti-B titers were <1:8. Post-operatively, he required four sessions of plasmapheresis and IVIG as his titers rebounded to 1:64. The titers then spontaneously subsided to <1:16 and have stayed at the same level for 6 months post-transplant. The patient continues to have normal renal function with a creatinine of 1.4 mg/dl% and has had no episodes of rejection. PMID- 23814423 TI - Congenital anomalies of kidney and urinary tract in siblings: An uncommon condition. AB - Congenital anomalies of kidney and urinary tract (CAKUT) are important causes of chronic kidney disease (CKD) in childhood. Most do not have a definite identifiable genetic defect and occur in isolation. Rarely, familial occurrence of CAKUT has been reported. The burden of CKD to a family in a developing country is enormous, and if more than one child is afflicted with the condition, the situation is almost catastrophic. We present here two families with siblings having upper and lower urinary tract obstruction. PMID- 23814424 TI - An unusual case of "renal failure". AB - Myopathy is common in hypothyroidism, but a very high creatinine kinase (CK) level in the range commonly seen with inflammatory myopathy is rare. Reversible elevation of creatinine is known to occur in hypothyroidism due to a decrease in the glomerular filtration rate, but it can also occur rarely due to enhanced creatinine production. We present a case of severe hypothyroidism with massively elevated CK levels and high creatinine levels, both of which reversed on treatment of hypothyroidism. PMID- 23814425 TI - Syndrome of rapid-onset end-stage renal disease in two consecutive renal transplant recipients. AB - A syndrome of rapid-onset end-stage renal disease (SORO-ESRD) following acute kidney injury (AKI) in native kidneys was described recently. To what extent this syndrome of unanticipated and rapidly irreversible ESRD impacts renal allograft survival is unknown. Over 6 months, we managed two deceased donor renal transplant recipients (RTRs) with rapid acceleration of previously stable allograft chronic kidney disease to abruptly terminate in irreversible ESRD following AKI. These are the first reports of SORO-ESRD in RTRs. More research is needed to ascertain the contribution of SORO-ESRD to renal allograft loss. PMID- 23814426 TI - D-penicillamine-induced glomerulonephritis with crescent formation: Remission following drug discontinuation. AB - We report a 71-year-old female who presented with rheumatoid arthritis complicated by proteinuria. She had been receiving D-penicillamine (D-Pc) for two years prior to presentation. A urinalysis showed proteinuria and hematuria which disappeared within 3 months after D-Pc was stopped. The renal histological findings showed focal proliferative glomerulonephritis with crescent formation. A total of 10 cases of D-Pc-induced glomerulonephritis with crescent formation without alveolar hemorrhage have previously been reported in the literature. To the best of our knowledge, this is the first case report in which the patient did not require any treatment. PMID- 23814427 TI - Successful conservative treatment of bilateral emphysematous pyelonephritis in autosomal dominant polycystic kidney disease. AB - Emphysematous pyelonephritis is a rare, potentially lethal complication of polycystic kidney disease. Treatment mostly includes emergency nephrectomy of the affected kidney. We report a case of bilateral emphysematous pyelonephritis in a 57-year-old diabetic male with autosomal dominant polycystic kidney disease, who recovered with conservative treatment. Escherichia coli was cultured from the cyst aspirate. He was treated with percutaneous needle aspiration of infected cysts and intravenous antibiotics (meropenem and pazufloxacin) for 3 weeks. PMID- 23814428 TI - Native valve Escherichia coli endocarditis following urosepsis. AB - Gram-negative organisms are a rare cause of infective endocarditis. Escherichia coli, the most common cause of urinary tract infection and gram-negative septicemia involves endocardium rarely. In this case report, we describe infection of native mitral valve by E. coli following septicemia of urinary tract origin in a diabetic male; subsequently, he required prosthetic tissue valve replacement indicated by persistent sepsis and congestive cardiac failure. PMID- 23814429 TI - Chromoblastomycosis in a renal allograft recipient. PMID- 23814430 TI - Concurrent renal tuberculosis and renal cell carcinoma: A coincidental finding. PMID- 23814431 TI - Salt substitutes: Are they safe? PMID- 23814432 TI - Renal cortical necrosis in a renal transplant recipient. PMID- 23814433 TI - Proliferative glomerulonephritis causing acute renal failure in a child with Salmonella septicemia. PMID- 23814434 TI - Transcriptional regulations of the genes of starch metabolism and physiological changes in response to salt stress rice (Oryza sativa L.) seedlings. AB - The aim of this investigation was to compare the transcriptional expression of starch metabolism, involving genes and physiological characters, in seedlings of two contrasting salt-tolerant rice genotypes, in response to salt-stress. The soluble sugar content in rice seedlings of both salt-tolerant and salt-sensitive genotypes was enriched, relating to starch degradation, in plants subjected to 200 mM NaCl. In the salt-tolerant cultivar Pokkali, a major source of carbon may be that derived from the photosynthetic system and starch degradation. In starch degradation, only Pho and PWD genes in Pokkali were upregulated in plants subjected to salt stress. In contrast, the photosynthetic abilities of IR29 salt susceptible cultivar dropped significantly, relating to growth reduction. The major source of carbohydrate in salt-stressed seedlings of the IR29 cultivar may be gained from starch metabolism, regulated by ADP-glucose pyrophosphorylase (AGP), starch synthase (SS), starch branching enzyme (SBE), starch debranching enzyme (ISA), glucan-water dikinase (GWD), dispropotionating enzyme (DPE), phospho glucan-water dikinase (PWD) and starch phosphorylase (Pho). Also, the major route of soluble sugar in salt-stressed Pokkali seedlings was derived from photosynthesis and starch metabolism. This was identified as novel information in the present study. PMID- 23814435 TI - Identification of salt treated proteins in sorghum using gene ontology linkage. AB - Sorghum bicolor (L.) is an important crop of arid and semi arid zones with most of its varieties tolerant to drought, heat and salt stress. Functional identification of many salt tolerant proteins has been reported in Arabidopsis, rice and other plants, however only little functional information has been predicted in sorghum till date. A 2-D gel electrophoresis based proteomic approach with MALDI-TOF mass spectrometer was utilized to analyze the salt stress response of sorghum. Major changes in protein complement were observed at 200 mM NaCl in hydroponic culture after 96 h of salt-stress. Highly expressed five proteins were excised for functional identification. We developed shortest path (SP) analysis based method on Gene Ontology (GO) hierarchy using sum of GO-term's semantic similarities. In this study, we observed that majority of expressed proteins belonged to the functional category of energy production and conversion, signal transduction mechanisms and ribosome maturation. These identified functions suggest a distinct mechanism of salt-stress adaptation in sorghum plant. The proposed method in this paper potentially has great importance to further understanding of newly identified proteins that can help in plant development. PMID- 23814436 TI - A comprehensive study on dehydration-induced antioxidative responses during germination of Indian bread wheat (Triticum aestivum L. em Thell) cultivars collected from different agroclimatic zones. AB - To explore the adaptability of bread wheat to dehydration stress, we screened 28 cultivars collected from different agroclimatic zones, on the basis of malonaldehyde content as biochemical marker in roots of wheat seedlings during germination and classified them as highly tolerant, tolerant, sensitive and highly sensitive. From this primary screening, ten cultivars that showed differential responses to dehydration stress were selected to understand the biochemical and physiological basis of stress tolerance mechanisms. The highly tolerant cultivars showed lower levels of lipid peroxidation, less membrane damage, increased levels of antioxidants, enzymes like catalase, ascorbate peroxidase, glutathione reductase activities, and maintained higher relative water content in comparison to sensitive cultivars, indicating better protection mechanism operating in tolerant cultivars. Correspondingly, highly tolerant cultivars exhibited more accumulation of proline and less H2O2 content across different time points of polyethylene glycol treatments in comparison to sensitive ones. The above biochemical and physiological parameters were further validated through northern analysis of catalase (CAT1) gene, that showed differential expression patterns in tolerant and sensitive cultivars largely in confirmation with the biochemical and physiological analyses. Our study positively correlates the differences in the redox status and antioxidant defense system between tolerant and sensitive cultivars for the establishment of wheat seedlings in typical dehydration conditions. PMID- 23814437 TI - Physiological and biochemical effect of 24-epibrassinoslide on cold tolerance in maize seedlings. AB - Germination and early seedling growth are important for establishment of maize because maize is chilling sensitive crop and low temperature during early period of growth can be detrimental to subsequent crop growth and productivity. Therefore, it is important to protect maize seedling from cold stress. A study was conducted on induced cold tolerance by 24-epibrassinoslide (EBR) at the Indian Agricultural Research Institute, New Delhi, India. Maize seedlings were raised in green house condition (25/18 degrees C day-night temperatures). Ten days old seedlings were treated with EBR (0.0, 0.01, 0.1, 1.0 and 10 MUM) and then divided into two sets, one set was kept in greenhouse (25/18 degrees C day night temperatures) and another was transferred to net house (cold stress). Data on various morpho-physiological traits was recorded after 7, 14 and 21 days of treatment. Exogenous application of 1.0 MUM EBR had significant effect on growth and morpho-physiological traits under both conditions. The maize seedlings treated with EBR were more tolerant to cold stress than the untreated one. Significant increase in plant height, dry matter accumulation, chlorophyll content, total soluble proteins and starch contents was observed under both conditions, however, the results were more pronounced under cold stress. 1.0 MU M concentration being the most effective under both conditions. Maintenance of high tissue water content, reduced membrane injury index, increased total chlorophyll, soluble sugar and protein content were taken as the possible indicators of EBR induced chilling tolerance. PMID- 23814438 TI - Molecular analysis of maize cystatin expression as fusion product in Escherichia coli. AB - Nowadays, plant cysteine proteinase inhibitors "namely phytocystatins" have attracted researchers towards the identification of their molecular structures and novel physiological functions. Their important roles in plant developmental processes and different stress responses have been well known. In spite of advances in the understanding of phytocystatins, we lack enough data concerning their heterologous expression especially in the forms of fusion products that are most important whether for biochemical, pharmacological or clinical studies. The present work describes an easy method of expression, purification and functional characterization in Escherichia coli of maize cystatin as a part of maltose binding fusion protein. Assessments revealed that upon expression of fused product the total antioxidation status of the induced recombinant cells is increased. This result leads to question 'Is there any parallel functional correlation between anti-proteolytic and anti-oxidative systems?' However, the present research will open a gate for the new studies regarding the putative communicative roles of these systems that may be existing in the biological world. PMID- 23814439 TI - Asymbiotic seed germination and in vitro conservation of Coelogyne nervosa A. Rich. an endemic orchid to Western Ghats. AB - Coelogyne nervosa is an epiphytic orchid endemic to Western Ghats, South India. The mature seeds of C. nervosa were cultured on 1/2 MS (Murashige and Skoog), MS, Kn (Knudson) and VW (Vacin and Went) media to evaluate the seed germination response. Of the four basal media used, MS medium supported maximum seed germination. Further experiments to enhance seed germination were done on MS medium supplemented with various concentrations (10, 20, 30 and 40 %) of coconut water (CW). Thirty percent CW gave the highest response in terms of percent seed germination (96), fresh weight (7.2 mg/seedling) and protocorm length (15.2 mm). Since CW containing medium did not support further seedling growth, each seedling was isolated and cultured on MS medium supplemented with either BA (6 benzylaminopurine) or Kin (kinetin) alone (1.0-4.0 mg/l each) or in combination with NAA (1-naphthaleneacetic acid; 0.2-1.0 mg/l). Maximum growth was observed on MS medium supplemented with BA (3.0 mg/l) and NAA (0.5 mg/l). On this medium, the seedlings reached an average length of 3.6 cm with 2.8 well expanded green leaves per seedling. Similarly optimum, healthy, white root induction (3.3 roots/seedlings) was also observed on the same medium. The rooted seedlings were successfully transplanted to pots with 91 % success. The 2-year-old tissue culture derived plants produced normal flowers and fruits. PMID- 23814440 TI - Plant regeneration in Chlorophytum borivilianum Sant. et Fernand. from embryogenic callus and cell suspension culture and assessment of genetic fidelity of plants derived through somatic embryogenesis. AB - Efficient in vitro propagation of medicinally important endangered plant C. borivilianum has been achieved through somatic embryogenesis. Solid embryogenic medium [Murashige and Skoog medium containing 1.79 mM NH4NO3, 10.72 mM KNO3, 1.13 MUM 2,4-dichlorophenoxyacetic acid, 7.38 MUM 2-isopentenyladenine and 0.76 mM proline] supplemented with polyethylene glycol and sucrose (3 % each), exhibited 1.88-fold increase in embryo maturation compared to embryogenic medium containing 3 % sucrose. Liquid embryogenic medium supported better somatic embryo production and maturation. Highest total (79) and mature (cotyledonary stage) somatic embryos (38) as well as highest germination (57.5 %) was observed at inoculum density of 0.4 g/40 ml of liquid medium. 5.86 pH level exhibited optimal growth, maturation and germination of somatic embryos. Random amplified polymorphic DNA (RAPD) analysis of C. borivilianum plants regenerated through somatic embryogenesis revealed that they were genetically similar to the mother plant. The protocol established in the present study can be used for rapid mass multiplication of C. borivilianum in bioreactor employing liquid medium. PMID- 23814441 TI - Micropropagation of Araucaria excelsa R. Br. var. glauca Carriere from orthotropic stem explants. AB - The objectives of the present work were in vitro propagation of Araucaria excelsa R. Br. var. glauca Carriere (Norfolk Island pine) with focus on the evaluation of the mean number of shoots per explant (MNS/E) and mean length of shoots per explants (MLS/E) produced by different parts of the orthotropic stem of A. excelsa R. Br. var. glauca in response to plant growth regulators. Norfolk Island pine axillary meristems responded very well to the 2-iso-pentenyl adenine (2iP) and thidiazuron (TDZ) levels. Explants taken from stem upper segments in the media containing 2iP had a higher MNS/E (3.47) and MLS/E (6.27 mm) in comparison to those taken from stem lower segments, which were 0.71 and 0.51 mm, respectively. Using 0.045 MUM TDZ in the MS medium not only resulted in 4.60 MNS/E with 7.08 mm MLS/E but proliferated shoots showed a good performance as well. Investigating the best position of stem explant on mother plant as well as the best concentrations of growth regulators were performed which were useful for efficient micropropagation of this plant. Thirty three percent of explants were rooted in the MS medium containing 3 % sucrose, supplemented with 7.5 MUM of both NAA and IBA for 2 weeks before transferring to a half strength MS medium without any growth regulator. Plantlets obtained were acclimatized and transferred to the greenhouse with less than 20 % mortality. This procedure considered the first successful report for regeneration and acclimatization of A. excelsa R. Br. var. glauca plantlet through main stem explants. PMID- 23814442 TI - In vitro propagation of spine gourd (Momordica dioica Roxb.) and assessment of genetic fidelity of micropropagated plants using RAPD analysis. AB - An efficient protocol for rapid in vitro clonal propagation of spine gourd (Momordica dioica Roxb.) genotype RSR/DR15 (female) and DR/NKB-28 (male) was developed through enhanced axillary shoot proliferation from nodal segments. Maximum shoot proliferation of 6.2 shoots per explant with 100 % shoot regeneration frequency was obtained from the female genotype on Murashige and Skoog's (1962) medium supplemented with 0.9 MUM N6-benzyladenine (BA) and 200 mg l(-1) casein hydrolysate (CH). While from the male genotype the optimum shoot regeneration frequency (86.6 %) and 6.4 shoots per explant was obtained on MS medium supplemented with 2.2 MUM BA. CH induced vigorous shoots, promoted callus formation, and proved inhibitory for shoot differentiation and shoot length, especially in explants from male genotype. Rooting was optimum on half-strength MS medium (male 92.8 %, female 74.6 %) containing 4.9 MUM indole-3-butyric acid (IBA). Plantlets were transferred to plastic cups containing a mixture of cocopit and perlite (1:1 ratio) and then to soil after 2-3 weeks. 84 % female and 81 % male regenerated plantlets survived and grew vigorously in the field. Genetic stability of the regenerated plants was assessed using random amplified polymorphic DNA (RAPD). The amplification products were monomorphic in the in vitro propagated plants and similar to those of mother plant. No polymorphism was detected revealing the genetic integrity of in vitro propagated plants. This micropropagation procedure could be useful for raising genetically uniform planting material of known sex for commercial cultivation or build-up of plant material of a specific sex-type. PMID- 23814443 TI - In vitro propagation of Stemona hutanguriana W.Chuakul, an endangered medicinal plant. AB - In vitro propagation of Stemona hutanguriana W.Chuakul, an endangered species of Stemonaceae, was established. Nodal and internodal explants were cultured on Murashige and Skoog (MS) medium supplemented with thidiazuron (TDZ) alone or in combination with 1-naphthaleneacetic acid (NAA). When cultured on MS medium supplemented with 18.16 MUM TDZ with 0.54 MUM NAA for 8 weeks and then on MS medium without plant growth regulator (PGR) for 8 weeks, nodal explants demonstrated a responding frequency of 91.67 % and a shoot regeneration rate of 5.46 shoots/responding explant. Furthermore, internodal explants demonstrated a responding frequency of 17.17 % with 11.17 shoots/responding explant. The regenerated shoots were rooted using a two-step protocol by culturing for 4 weeks on MS medium supplemented with various concentrations of NAA and Indole-3-butyric acid (IBA) and 8 weeks on MS medium without PGR. When 5.40 MUM NAA was used as a PGR, the maximum root induction rate was 69.45 %. Regenerated plantlets were successfully transferred to soil. PMID- 23814444 TI - Coherent Control in Multiphoton Fluorescence Imaging. AB - In multiphoton fluorescence laser-scanning microscopy ultrafast laser pulses, i.e. light pulses having pulse-width <= 1picosecond (1 ps = 10-12s), are commonly used to circumvent the low multiphoton absorption cross-sections of common fluorophores. Starting with a discussion on how amplitude modulation of ultrashort pulse-train enhances the two-photon fluorescence providing deep insight into laser-induced photo-thermal damage, the effect of controlling time lag between phase-locked laser pulses on imaging is described. In addition, the prospects of laser pulse-shaping in signal enhancement (by temporal pulse compression at the sample) and selective excitation of fluorophores (by manipulating the phase and/or amplitude of different frequency components within the pulse) are discussed with promising future applications lying ahead. PMID- 23814445 TI - Three-dimensional image formation under single-photon ultra-short pulsed illumination. AB - The major thrust of modern day fluorescence laser-scanning microscopy have been towards achieving better and better depth resolution embodied by the invention and subsequent development of confocal and multi-photon microscopic techniques. However, each method bears its own limitations: in having sufficient background fluorescence and photo-damage resulting from out-of-focus illumination for the former, while low multi-photon absorption cross-sections of common fluorophores for the latter. Here we show how the intelligent choice of single-photon ultrashort pulsed illumination can circumvent all these shortcomings by exemplifying the tiny spatial stretch of an ultrashort pulse. Besides achieving a novel way of optical sectioning, this new method offers improved signal-to-noise ratio as well as reduced photo-damage which are crucial for live cell imaging under prolonged exposure to light. PMID- 23814446 TI - Towards Spatio-Temporal Control in Optical Trapping. AB - Using both continuous-wave (CW) and high repetition rate femtosecond lasers, we present stable 3-dimensional trapping of 1MUm polystyrene microspheres. We also stably trapped 100nm latex nanoparticles using the femtosecond mode-locked laser at a very low average power where the CW lasers cannot trap, demonstrating the significance of the fleeting temporal existence of the femtosecond pulses. Trapping was visualized through dark-field microscopy as well as through a noise free detection using two-photon fluorescence as a diagnostics tool owing to its intrinsic 3-dimensional resolution. Comparison between a Gaussian versus a flat top Gaussian beam profile demonstrates the importance of laser spatial mode in optical trapping. PMID- 23814447 TI - Fluorescence advantages with microscopic spatiotemporal control. AB - We present a clever design concept of using femtosecond laser pulses in microscopy by selective excitation or de-excitation of one fluorophore over the other overlapping one. Using either a simple pair of femtosecond pulses with variable delay or using a train of laser pulses at 20-50 Giga-Hertz excitation, we show controlled fluorescence excitation or suppression of one of the fluorophores with respect to the other through wave-packet interference, an effect that prevails even after the fluorophore coherence timescale. Such an approach can be used both under the single-photon excitation as well as in the multi-photon excitation conditions resulting in effective higher spatial resolution. Such high spatial resolution advantage with broadband-pulsed excitation is of immense benefit to multi-photon microscopy and can also be an effective detection scheme for trapped nanoparticles with near-infrared light. Such sub-diffraction limit trapping of nanoparticles is challenging and a two photon fluorescence diagnostics allows a direct observation of a single nanoparticle in a femtosecond high-repetition rate laser trap, which promises new directions to spectroscopy at the single molecule level in solution. The gigantic peak power of femtosecond laser pulses at high repetition rate, even at low average powers, provide huge instantaneous gradient force that most effectively result in a stable optical trap for spatial control at sub-diffraction limit. Such studies have also enabled us to explore simultaneous control of internal and external degrees of freedom that require coupling of various control parameters to result in spatiotemporal control, which promises to be a versatile tool for the microscopic world. PMID- 23814448 TI - Towards Stable Trapping of Single Macromolecules in Solution. AB - The implementation of high instantaneous peak power of a femtosecond laser pulse at moderate time-averaged power (~10 mW) to trap latex nanoparticles, which is otherwise impossible with continuous wave illumination at similar power level, has recently been shown [De, A. K., Roy, D., Dutta, A. and Goswami, D. "Stable optical trapping of latex nanoparticles with ultrashort pulsed illumination", Appd. Opt., 48, G33 (2009)]. However, direct measurement of the instantaneous trapping force/stiffness due to a single pulse has been unsuccessful due to the fleeting existence (~100 fs) of the laser pulse compared with the much slower time scale associated with the available trapping force/stiffness calibration techniques, as discussed in this proceeding article. We also demonstrate trapping of quantum dots having dimension similar to macromolecules. PMID- 23814449 TI - Control of femtosecond laser driven retro-Diels-Alder-like reaction of dicyclopentadiene. AB - Using femtosecond time resolved degenerate pump-probe mass spectrometry coupled with simple linearly chirped frequency modulated pulse, we elucidate that the dynamics of retro-Diels-Alder-like reaction of diclopentadiene (DCPD) to cyclopentadiene (CPD) in supersonic molecular beam occurs in ultrafast time scale. Negatively chirped pulse enhances the ion yield of CPD, as compared to positively chirped pulse. This indicates that by changing the frequency (chirp) of the laser pulse we can control the ion yield of a chemical reaction. PMID- 23814450 TI - Spectrally Resolved Femtosecond Photon Echo Spectroscopy of Astaxanthin. AB - We have studied the coherence and population dynamics of Astaxanthin solution in methanol and acetonitrile by spectrally resolving their photon echo signals. Our experiments indicate that methanol has a much stronger interaction with the ultrafast dynamics of Astaxanthin in comparison to that of acetonitrile. PMID- 23814451 TI - Effects of Bilateral Olivocochlear Lesions on Pure-Tone Intensity Discrimination in Cats. AB - Behavioral experiments examined the effects of olivocochlear efferent lesions on performance in an intensity discrimination task. Five cats were trained with food reinforcement to signal the detection of a change in the intensity of pure tones by releasing a response lever. Intensity cues were conveyed by 1 and 8-kHz tone bursts in quiet and in the presence of continuous broadband noise. After the collection of baseline behavioral data, the olivocochlear bundle (OCB) was sectioned with bilateral knife cuts on the floor of the IVth ventricle. The completeness of OCB lesions was evaluated at the conclusion of post-lesion behavioral testing by light microscopic examination of cochlear acetylcholinesterase staining and electrophysiological measures of contralateral noise suppression of compound action potentials (CAPs). Cats with OCB lesions showed greatest performance deficits for the discrimination of 8-kHz intensity changes in continuous background noise. The subjects' ability to discriminate 1 kHz intensity changes in noise was poor prior to OCB lesioning and did not change after the surgical procedure. Lesioning effects were not observed at either frequency when tests were conducted in quiet. These results suggest that olivocochlear feedback contributes to the auditory processing of mid-frequency acoustic signals in noisy backgrounds. PMID- 23814452 TI - A Self-Synchronized Optoelectronic Oscillator based on an RTD Photo-Detector and a Laser Diode. AB - We propose and demonstrate a simple and stable low-phase noise optoelectronic oscillator (OEO) that uses a laser diode, an optical fiber delay line and a resonant tunneling diode (RTD) free-running oscillator that is monolithic integrated with a waveguide photo-detector. The RTD-OEO exhibits single-side band phase noise power below -100 dBc/Hz with more than 30 dB noise suppression at 10 kHz from the center free-running frequency for fiber loop lengths around 1.2 km. The oscillator power consumption is below 0.55 W, and can be controlled either by the injected optical power or the fiber delay line. The RTD-OEO stability is achieved without using other high-speed optical/optoelectronic components and amplification. PMID- 23814453 TI - Is Approximate Number Precision a Stable Predictor of Math Ability? AB - Previous research shows that children's ability to estimate numbers of items using their Approximate Number System (ANS) predicts later math ability. To more closely examine the predictive role of early ANS acuity on later abilities, we assessed the ANS acuity, math ability, and expressive vocabulary of preschoolers twice, six months apart. We also administered attention and memory span tasks to ask whether the previously reported association between ANS acuity and math ability is ANS-specific or attributable to domain-general cognitive skills. We found that early ANS acuity predicted math ability six months later, even when controlling for individual differences in age, expressive vocabulary, and math ability at the initial testing. In addition, ANS acuity was a unique concurrent predictor of math ability above and beyond expressive vocabulary, attention, and memory span. These findings of a predictive relationship between early ANS acuity and later math ability add to the growing evidence for the importance of early numerical estimation skills. PMID- 23814454 TI - Robust Principal Component Analysis and Geographically Weighted Regression: Urbanization in the Twin Cities Metropolitan Area of Minnesota. AB - In this paper, we present a hybrid approach, robust principal component geographically weighted regression (RPCGWR), in examining urbanization as a function of both extant urban land use and the effect of social and environmental factors in the Twin Cities Metropolitan Area (TCMA) of Minnesota. We used remotely sensed data to treat urbanization via the proxy of impervious surface. We then integrated two different methods, robust principal component analysis (RPCA) and geographically weighted regression (GWR) to create an innovative approach to model urbanization. The RPCGWR results show significant spatial heterogeneity in the relationships between proportion of impervious surface and the explanatory factors in the TCMA. We link this heterogeneity to the "sprawling" nature of urban land use that has moved outward from the core Twin Cities through to their suburbs and exurbs. PMID- 23814455 TI - The Evolution of "Enhanced" Cognitive Behavior Therapy for Eating Disorders: Learning From Treatment Nonresponse. AB - In recent years there has been widespread acceptance that cognitive behavior therapy (CBT) is the treatment of choice for bulimia nervosa. The cognitive behavioral treatment of bulimia nervosa (CBT-BN) was first described in 1981. Over the past decades the theory and treatment have evolved in response to a variety of challenges. The treatment has been adapted to make it suitable for all forms of eating disorder-thereby making it "transdiagnostic" in its scope- and treatment procedures have been refined to improve outcome. The new version of the treatment, termed enhanced CBT (CBT-E) also addresses psychopathological processes "external" to the eating disorder, which, in certain subgroups of patients, interact with the disorder itself. In this paper we discuss how the development of this broader theory and treatment arose from focusing on those patients who did not respond well to earlier versions of the treatment. PMID- 23814456 TI - Increasing Physical Activity Decreases Hepatic Fat and Metabolic Risk Factors. AB - This study assessed the changes in time spent in moderate to vigorous physical activity (MVPA) on fat depots, insulin action, and inflammation. Longitudinal data were generated from 66 Hispanic adolescents (15.6+/-1.1 yr; BMI percentile 97.1+/-3.0) who participated in a 16-wk nutrition or nutrition+exercise intervention. There were no effects of the intervention on PA, but there were inter-individual changes in PA. For purposes of this analysis, all intervention groups were combined to assess how changes in PA during 16 wk affected changes in adiposity, insulin action, and markers of inflammation. MVPA was assessed by 7 day accelerometry, total body fat via DXA, liver fat by MRI, and insulin, glucose and HOMA-IR via a fasting blood draw. A repeated measures ANCOVA was used to assess the effect of MVPA on fat depots, insulin action, and inflammatory markers. Sixty-two percent of participants increased MVPA (mean increase, 19.7+/ 16.5 min/day) and 38% decreased MVPA (mean decrease, 10.7+/-10.1 min/day). Those who increased MVPA by as little as 20 min per day over 16 wk, compared to those who decreased MVPA, had significant reductions in liver fat (-13% vs. +3%; P=0.01), leptin levels (-18% vs. +4%; P=0.02), and fasting insulin (-23% vs. +5%; P=0.05). These findings indicate that a modest increase in MVPA can improve metabolic health in sedentary overweight Hispanic adolescents. PMID- 23814457 TI - Automated grading system for evaluation of ocular redness associated with dry eye. AB - BACKGROUND: We have observed that dry eye redness is characterized by a prominence of fine horizontal conjunctival vessels in the exposed ocular surface of the interpalpebral fissure, and have incorporated this feature into the grading of redness in clinical studies of dry eye. AIM: To develop an automated method of grading dry eye-associated ocular redness in order to expand on the clinical grading system currently used. METHODS: Ninety nine images from 26 dry eye subjects were evaluated by five graders using a 0-4 (in 0.5 increments) dry eye redness (Ora CalibraTM Dry Eye Redness Scale [OCDER]) scale. For the automated method, the Opencv computer vision library was used to develop software for calculating redness and horizontal conjunctival vessels (noted as "horizontality"). From original photograph, the region of interest (ROI) was selected manually using the open source ImageJ software. Total average redness intensity (Com-Red) was calculated as a single channel 8-bit image as R - 0.83G - 0.17B, where R, G and B were the respective intensities of the red, green and blue channels. The location of vessels was detected by normalizing the blue channel and selecting pixels with an intensity of less than 97% of the mean. The horizontal component (Com-Hor) was calculated by the first order Sobel derivative in the vertical direction and the score was calculated as the average blue channel image intensity of this vertical derivative. Pearson correlation coefficients, accuracy and concordance correlation coefficients (CCC) were calculated after regression and standardized regression of the dataset. RESULTS: The agreement (both Pearson's and CCC) among investigators using the OCDER scale was 0.67, while the agreement of investigator to computer was 0.76. A multiple regression using both redness and horizontality improved the agreement CCC from 0.66 and 0.69 to 0.76, demonstrating the contribution of vessel geometry to the overall grade. Computer analysis of a given image has 100% repeatability and zero variability from session to session. CONCLUSION: This objective means of grading ocular redness in a unified fashion has potential significance as a new clinical endpoint. In comparisons between computer and investigator, computer grading proved to be more reliable than another investigator using the OCDER scale. The best fitting model based on the present sample, and usable for future studies, was [Formula: see text] is the predicted investigator grade, and [Formula: see text] and [Formula: see text] are logarithmic transformations of the computer calculated parameters COM-Hor and COM-Red. Considering the superior repeatability, computer automated grading might be preferable to investigator grading in multicentered dry eye studies in which the subtle differences in redness incurred by treatment have been historically difficult to define. PMID- 23814458 TI - Postoperative subconjunctival bevacizumab injection as an adjunct to 5 fluorouracil in the management of scarring after trabeculectomy. AB - PURPOSE: Scarring after glaucoma filtering surgery remains the most frequent cause for bleb failure. The aim of this study was to assess if the postoperative injection of bevacizumab reduces the number of postoperative subconjunctival 5 fluorouracil (5-FU) injections. Further, the effect of bevacizumab as an adjunct to 5-FU on the intraocular pressure (IOP) outcome, bleb morphology, postoperative medications, and complications was evaluated. METHODS: Glaucoma patients (N = 61) who underwent trabeculectomy with mitomycin C were analyzed retrospectively (follow-up period of 25 +/- 19 months). Surgery was performed exclusively by one experienced glaucoma specialist using a standardized technique. Patients in group 1 received subconjunctival applications of 5-FU postoperatively. Patients in group 2 received 5-FU and subconjunctival injection of bevacizumab. RESULTS: Group 1 had 6.4 +/- 3.3 (0-15) (mean +/- standard deviation and range, respectively) 5-FU injections. Group 2 had 4.0 +/- 2.8 (0-12) (mean +/- standard deviation and range, respectively) 5-FU injections. The added injection of bevacizumab significantly reduced the mean number of 5-FU injections by 2.4 +/- 3.08 (P <= 0.005). There was no significantly lower IOP in group 2 when compared to group 1. A significant reduction in vascularization and in cork screw vessels could be found in both groups (P < 0.0001, 7 days to last 5-FU), yet there was no difference between the two groups at the last follow-up. Postoperative complications were significantly higher for both groups when more 5-FU injections were applied. (P = 0.008). No significant difference in best corrected visual acuity (P = 0.852) and visual field testing (P = 0.610) between preoperative to last follow-up could be found between the two groups. CONCLUSION: The postoperative injection of bevacizumab reduced the number of subconjunctival 5-FU injections significantly by 2.4 injections. A significant difference in postoperative IOP reduction, bleb morphology, and postoperative medication was not detected. PMID- 23814459 TI - A combined analysis of five observational studies evaluating the efficacy and tolerability of bimatoprost/timolol fixed combination in patients with primary open-angle glaucoma or ocular hypertension. AB - OBJECTIVE: The aim of this study was to evaluate the safety and efficacy of a fixed combination of bimatoprost 0.03% and timolol (BTFC) in a clinical setting, in a large sample of patients with primary open-angle glaucoma or ocular hypertension and insufficient intraocular pressure (IOP) lowering on prior therapy. METHODS: Patient data were combined (n = 5556) from five multicenter, observational, non-controlled, open-label studies throughout Europe. Patients were identified from 830 sites in Austria, France, Germany, The Netherlands, and Switzerland. Assessments were made at baseline, 6 weeks (in Austrian, German and Swiss centers), and 12 weeks in all centers. RESULTS: BTFC lowered mean IOP from baseline by 5.4 mmHg over the 12-week duration of the studies (P < 0.0001). At study entry, 92.9% of patients were receiving another ocular hypotensive medication. In patients with no previous treatment (n = 311), BTFC reduced IOP by -9.1 mmHg, corresponding to a reduction from baseline of 36.4% (P < 0.0001). In patients receiving prior therapy of a prostaglandin analog, a beta-blocker, or a fixed combination, BTFC reduced IOP by a further 24.5%, 25.9%, and 21.4%, respectively. The majority of patients (90.3%) reported no adverse events. The most common adverse events were conjunctival hyperemia (3.2%) and eye irritation (2.8%). BTFC was rated as "good" or "very good" by 92.5% of physicians and 88.0% of patients. Most patients (96.3%) were equally or more compliant with BTFC than with their previous treatment. CONCLUSION: In routine clinical practice, BTFC achieved consistent IOP lowering in both previously treated and untreated patients with primary open-angle glaucoma or ocular hypertension. BTFC was associated with significant IOP reductions, good tolerability, and good compliance. PMID- 23814460 TI - Periocular capillary hemangioma: management practices in recent years. AB - PURPOSE: To present a case series on the management options for capillary hemangiomas involving the eyelid and orbit. METHODS: This is a retrospective chart review of clinically diagnosed capillary hemangioma cases involving the periocular region treated at two local eye institutions. The patients' demographics and clinical presentation - including visual acuity, refractive error, periorbital and orbital examinations, and ultrasound and magnetic resonance imaging findings - were reviewed. The clinical progression, modalities of treatment, and treatment outcomes were studied. RESULTS: Sixteen cases of capillary hemangiomas involving the eyelid and orbit were studied. The mean age at consultation was 9.6 months (range: 1 month-72 months). The majority were females (75%), with 50% presenting as upper-eyelid hemangiomas and the remaining as lower-eyelid (38%) and glabellar (12%) lesions. Combined superficial and deep involvement was common (64%). Cases whose lesions were located at the upper eyelid or superior orbit led to amblyopia (25%). Fifty-six percent of cases (9/16) were managed conservatively, and 44% (7/16) underwent treatment with either single-agent (n = 4) or combined treatments (n = 3). CONCLUSION: Close monitoring of visual development and prompt institution of amblyopia therapy for children with periocular capillary hemangiomas generally preserve vision. Extensive lesions that affect the visual axis require local and systemic treatments, alone or in combination, in order to reduce the size and impact of lesions on the eyeball, to reduce induced refractive error and visual occlusion, and to prevent the development of amblyopia, in order to achieve good visual outcomes. PMID- 23814461 TI - Medication adherence in patients with type 2 diabetes mellitus treated at primary health clinics in Malaysia. AB - PURPOSE: Diabetes mellitus is a growing global health problem that affects patients of all ages. Even though diabetes mellitus is recognized as a major chronic illness, adherence to antidiabetic medicines has often been found to be unsatisfactory. This study was conducted to assess adherence to medications and to identify factors that are associated with nonadherence in type 2 diabetes mellitus (T2DM) patients at Primary Health Clinics of the Ministry of Health in Malaysia. MATERIALS AND METHODS: The cross-sectional survey was carried out among T2DM patients to assess adherence to medication in primary health clinics. Adherence was measured by using the Medication Compliance Questionnaire that consists of a total of seven questions. Other data, such as patient demographics, treatment, outcome, and comorbidities were also collected from patient medical records. RESULTS: A total of 557 patients were recruited in the study. Approximately 53% of patients in the study population were nonadherent. Logistic regression analysis was performed to predict the factors associated with nonadherence. Variables associated with nonadherence were age, odds ratio 0.967 (95% confidence interval [CI]: 0.948-0.986); medication knowledge, odds ratio 0.965 (95% CI: 0.946-0.984); and comorbidities, odds ratio 1.781 (95% CI: 1.064 2.981). CONCLUSION: Adherence to medication in T2DM patients in the primary health clinics was found to be poor. This is a cause of concern, because nonadherence could lead to a worsening of disease. Improving medication knowledge by paying particular attention to different age groups and patients with comorbidities could help improve adherence. PMID- 23814462 TI - Triple-combination rilpivirine, emtricitabine, and tenofovir (CompleraTM/EvipleraTM) in the treatment of HIV infection. AB - The combination rilpivirine (RPV)/emtricitabine (FTC)/tenofovir (TDF) is a once daily, single-tablet regimen (STR) containing one nonnucleoside reverse transcriptase inhibitor associated with two nucleos(t)ide reverse transcriptase inhibitors. It is approved by regulatory agencies (eg, US Food and Drug Association, European Medicines Agency) in all countries in which it is manufactured, except Switzerland, as first-line highly active antiretroviral therapy (HAART) for the treatment of naive patients with HIV infection and a viral load HIV-RNA level of <=100,000 copies/mL. Two large trials (ECHO and THRIVE) comparing RPV with efavirenz, along with different background regimens, led to approval of the drug, while a more recent trial (STaR) explored the use of STR. RPV showed noninferiority to efavirenz in all the studies, including superiority as an STR in patients with HIV-RNA <=100,000 copies/mL in the STaR study. A positive CD4 cell response was observed in all the studies, both in the RPV and efavirenz groups. The incidence of virologic failures was higher for RPV, but was mostly referred to patients with HIV-RNA >100,000 copies/mL. There were fewer adverse events (AEs) with the RPV-based regimens versus efavirenz-based regimens, with a lower discontinuation rate because of AEs, especially psychiatric-neurological AEs, and a significantly lower rate of blood-lipid abnormalities. In the SPIRIT study (a switch study), significantly greater improvements from baseline in serum total cholesterol, low-density lipoprotein cholesterol, and trygliceride were demonstrated in patients switching to RPV/FTC/TDF from a ritonavir-boosted protease inhibitor (PI/r)-based regimen, than in those who continued treatment with a PI/r regimen. RPV's better tolerability, associated with its once-daily STR formulation, is key to improving patients' adherence and quality of life, which are among the most important factors affecting the therapeutic efficacy of an antiretroviral regimen. In summary, RPV/FTC/TDF STR is a valuable treatment option for the majority of antiretroviral-naive HIV-infected patients. Furthermore, the use of this STR in the therapeutic switch, like in the SPIRIT study, can result in another valuable option by which to reduce AEs and improve patients' quality of life. PMID- 23814463 TI - Dentist-patient communication: what do patients and dentists remember following a consultation? Implications for patient compliance. AB - BACKGROUND: There is a lack of information about the extent to which patients recall key facts of dental consultations. Forgetting health advice undermines adherence with such instructions and is a potential problem. This study assessed the quantity and type of information recalled in a dental consultation, dentist patient agreement over the contents of the consultation, and the relationship of such recall with patient satisfaction. METHODS: Using a cross-sectional design, questionnaire data were obtained from patients recruited through a letter and presenting for a routine dental consultation. General issues discussed, specific information about oral health given, dentist-performed procedures, and agreed future actions were reported independently in writing, by patients and also by the treating dentist immediately postconsultation. Additionally, patients completed a dental visit satisfaction questionnaire. RESULTS: Responses (n = 26, 55% response rate) were content-analyzed, and data on the number and type of information that was recalled were obtained. Interrater reliability was established. Inferential testing showed differences in dentist-patient recall, dentist-patient agreement, and the association between patient recall and satisfaction. Dentists recalled more information than patients (P = 0.001). Dentists further reported giving more dental health education (P = 0.006) and discussing more future actions (P = 0.002) than patients actually remembered. Technical (eg, crowns/bridges) rather than psychosocial (eg, pain/embarrassment) issues were reported more often (P = 0.001) by both dentists and patients. Dentist-patient agreement over issues discussed and procedures performed was higher (kappa = 0.210-0.310) than dental health education agreement and agreed future actions (kappa = 0.060-0.110). There was no relationship between patient recall and patient satisfaction with the consultation (P = 0.240). CONCLUSION: Patients do not recall as much advice and agreed actions about future dental care as dentists believe they have discussed. These results have implications for patient adherence with oral health instructions. PMID- 23814464 TI - Influence of anatomic location of lidocaine patch 5% on effectiveness and tolerability for postherpetic neuralgia. AB - PURPOSE: Lidocaine patch 5% is recommended as a first-line therapy for postherpetic neuralgia pain in neuropathic pain guidelines. Postherpetic neuralgia can occur anywhere on the body but often follows acute herpes zoster occurring in trigeminal and brachial plexus dermatomes. An analysis was conducted to determine whether the anatomic location of lidocaine patch 5% is associated with variations in effectiveness or tolerability in patients with postherpetic neuralgia. METHODS: This was a post hoc analysis by anatomic site of patch placement (head [including neck], trunk [chest, abdomen, back, hips], and extremities [arm, leg]) of a 4-week, multicenter, open-label study that enrolled patients with persistent pain following herpes zoster infection. Effectiveness was measured by Brief Pain Inventory (BPI) average pain intensity (0 [no pain] to 10 [worst imaginable pain]) and the BPI subscale for pain relief (0% [no relief] to 100% [complete relief]). Tolerability was assessed on the basis of patient reported adverse events. RESULTS: Of 332 enrolled patients (59.6% women [n = 198]; 92.5% white [n = 307]; mean [standard deviation] age, 71.2 [13.9] years), those (n = 203) who applied lidocaine patch 5% to a single anatomic site only and had baseline and postbaseline pain score data were analyzed (trunk, n = 130; head, n = 41; extremities, n = 32). The frequency of adverse events differed significantly by anatomic location, with significantly more adverse events reported with patch placement on the head versus the extremities (P = 0.006) or trunk (P = 0.02). BPI average pain improved significantly from baseline in each of the three anatomic areas (mean score decrease, 1.50-2.04; P <= 0.002), with no significant difference in effectiveness by patch location. CONCLUSION: Lidocaine 5% patch was effective and generally well tolerated for each anatomic area evaluated, although application to the head was tolerated less well compared with the trunk and extremities. PMID- 23814465 TI - Perceptions of point-of-care infectious disease testing among European medical personnel, point-of-care test kit manufacturers, and the general public. AB - BACKGROUND: The proper development and implementation of point-of-care (POC) diagnostics requires knowledge of the perceived requirements and barriers to their implementation. To determine the current requirements and perceived barriers to the introduction of POC diagnostics in the field of medical microbiology (MM)-POC a prospective online survey (TEMPOtest-QC) was established. METHODS AND RESULTS: The TEMPOtest-QC survey was online between February 2011 and July 2012 and targeted the medical community, POC test diagnostic manufacturers, general practitioners, and the general public. In total, 293 individuals responded to the survey, including 91 (31%) medical microbiologists, 39 (13%) nonmedical microbiologists, 25 (9%) employees of POC test manufacturers, and 138 (47%) members of the general public. Responses were received from 18 different European countries, with the largest percentage of these living in The Netherlands (52%). The majority (>50%) of medical specialists regarded the development of MM-POC for blood culture and hospital acquired infections as "absolutely necessary", but were much less favorable towards their use in the home environment. Significant differences in perceptions between medical specialists and the general public included the: (1) Effect on quality of patient care; (2) Ability to better monitor patients; (3) Home testing and the doctor patient relationship; and (4) MM-POC interpretation. Only 34.7% of the general public is willing to pay more than a?10 ($13) for a single MM-POC test, with 85.5% preferring to purchase their MM-POC test from a pharmacy. CONCLUSION: The requirements for the proper implementation of MM-POC were found to be generally similar between medical specialists and POC test kit manufacturers. The general public was much more favorable with respect to a perceived improvement in the quality of healthcare that these tests would bring to the hospital and home environment. PMID- 23814466 TI - Health-related quality of life in dialysis patients with constipation: a cross sectional study. AB - OBJECTIVES: To evaluate differences in the health-related quality of life (HRQoL) between patients with constipation receiving hemodialysis (HD) and those receiving peritoneal dialysis (PD). METHODS: In this cross-sectional study, 605 dialysis patients (478 HD cases and 127 PD cases; all patients were older than 18 years) from our hospital were included. A questionnaire was used to evaluate their constipation statuses. The effect of constipation on HRQoL was assessed, using the Chinese version of the 12-item short-form (SF-12) general health survey. Karnofsky score, sociodemographic, and clinical data were also collected. We performed multiple logistic regression analysis to define independent risk factors for constipation and impaired HRQoL. RESULTS: A total of 605 participants (326 men [53.9%] and 279 women [46.1%]) were surveyed. The incidence of constipation was 71.7% in HD patients and 14.2% in PD patients. Dialysis patients with constipation had significantly lower mean SF-12 Physical Component Summary scale and Mental Component Summary scale scores than the nonconstipation group (P < 0.05), whereas HD patients had better SF-12 Physical Component Summary and Mental Component Summary scores than PD patients (P < 0.05). When we performed multivariate logistic regression analysis, dialysis modality, diabetes, and the number of constipation-related medications were three independent risk factors associated with constipation. As for impaired HRQoL in the constipated dialysis population, dialysis modality was found to be another independent risk factor in addition to age and diabetes. CONCLUSION: PD patients with constipation had worse HRQoL than HD control participants. We should pay more attention to the patients with constipation receiving PD, as peritonitis caused by constipation was associated with a higher mortality. PMID- 23814467 TI - Perceptions of diabetes obtained through drawing in childhood and adolescence. AB - OBJECTIVE: To examine whether drawing is useful in the detection of problems of psychosocial adaptation in children and adolescents with type 1 diabetes (T1D) and in improving communication with health professionals. METHODS: We performed an exploratory descriptive study in 199 children and adolescents with T1D aged 4 13 years. The participants were asked to render a drawing on a suggested topic. The variables analyzed were related to the drawing and to clinical and sociodemographic data. RESULTS: Most participants showed evidence of having a well-balanced personality, but there were also signs of affective or psychosocial difficulties. CONCLUSION: Drawing is a useful technique by which to identify children's and adolescents' feelings and possible problems in adapting to T1D, as well as to gain information directly from the children themselves. Future studies should delimit the possibilities of this technique in clinical practice in greater detail. PMID- 23814468 TI - Human epidermal growth factor receptor 2-positive breast cancer: which cytotoxic agent best complements trastuzumab's efficacy in vitro? AB - INTRODUCTION: Despite trastuzumab having enhanced selectivity for human epidermal growth factor receptor 2 (HER-2) overexpressing breast cancer cells, treatment is hampered by interindividual variation and tumors with high mitogenic potential. The lack of significant clinical benefit in certain patient cohorts suggests that HER-2 expression is ineffective as a sole prognostic indicator of response to therapy. Therefore, optimizing the clinical role of trastuzumab in drug combinations remains critical for clinical success. AIM: To investigate the effects of trastuzumab in combination with either doxorubicin or geldanamycin on in vitro cell viability, cell cycling, apoptosis and relative HER-2 expression in HER-2-positive (SK-BR-3) and estrogen receptor-positive (MCF-7) breast adenocarcinoma models. RESULTS: HER-2-rich SK-BR-3 cells demonstrated a greater sensitivity to the effects of doxorubicin than MCF-7 cells. Concurrent trastuzumab exposure resulted in a further reduction in cell viability. This decreased cell viability induced by doxorubicin was associated with activation of executioner caspases as well as with alterations in cell-cycle kinetics, primarily promoting S-phase accumulation. Doxorubicin had no effect on surface HER-2 density expression. Geldanamycin reduced cell viability significantly greater in SK-BR-3 than MCF-7 cells, and was associated with G2 cell-cycle accumulation. The addition of trastuzumab did not augment these effects. Geldanamycin promoted substantial reductions in relative surface HER-2 density in SK-BR-3 cells. CONCLUSION: The in vitro data supported the rationale for using doxorubicin in trastuzumab-based therapies. Therefore, despite the incidence of cardiotoxicity, doxorubicin could retain a fundamental role in treating HER-2 positive breast cancer. While geldanamycin is a potent cytotoxic agent, its concurrent use with trastuzumab requires further research into the transient or permanent nature of alterations in HER-2 status in cell progeny. PMID- 23814469 TI - Sporozoite proteome analysis of Cryptosporidium parvum by one-dimensional SDS PAGE and liquid chromatography tandem mass spectrometry. AB - Despite the development of new technologies, new challenges still remain for large scale proteomic profiling when dealing with complex biological mixtures. Fractionation prior to liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis is usually the preferred method to reduce the complexity of any biological sample. In this study, a gel LC-MS/MS approach was used to explore the stage specific proteome of Cryptosporidium (C.) parvum. To accomplish this, the sporozoite protein of C. parvum was first fractionated using SDS-PAGE with subsequent LC-MS/MS analysis. A total of 135 protein hits were recorded from 20 gel slices (from same gel lane), with many hits occurring in more than one band. Excluding all non-Cryptosporidium entries and proteins with multiple hits, 33 separate C. parvum entries were identified during the study. The overall goal of this study was to reduce sample complexity by protein fractionation and increase the possibility of detecting proteins present in lower abundance in a complex protein mixture. PMID- 23814470 TI - Antiviral effect of dietary germanium biotite supplementation in pigs experimentally infected with porcine reproductive and respiratory syndrome virus. AB - Germanium biotite (GB) is an aluminosilicate mineral containing 36 ppm germanium. The present study was conducted to better understand the effects of GB on immune responses in a mouse model, and to demonstrate the clearance effects of this mineral against Porcine reproductive and respiratory syndrome virus (PRRSV) in experimentally infected pigs as an initial step towards the development of a feed supplement that would promote immune activity and help prevent diseases. In the mouse model, dietary supplementation with GB enhanced concanavalin A (ConA) induced lymphocyte proliferation and increased the percentage of CD3+CD8+ T lymphocytes. In pigs experimentally infected with PRRSV, viral titers in lungs and lymphoid tissues from the GB-fed group were significantly decreased compared to those of the control group 12 days post-infection. Corresponding histopathological analyses demonstrated that GB-fed pigs displayed less severe pathological changes associated with PRRSV infection compared to the control group, indicating that GB promotes PRRSV clearance. These antiviral effects in pigs may be related to the ability of GB to increase CD3+CD8+ T lymphocyte production observed in the mice. Hence, this mineral may be an effective feed supplement for increasing immune activity and preventing disease. PMID- 23814471 TI - Effects of intertrochanteric varus osteotomy on Norberg angle and percent coverage of the femoral head in displastic dogs. AB - This study was conducted to assess the effects of femoral varus osteotomy on joint congruency in dogs affected by early stage hip dysplasia. Preoperative planning to move the femoral head within the acetabulum was carried out. Varisation of the femoral inclination angle (fIA) was achieved by Intertrochanteric Osteotomy (ITO). Norberg angle (NA), percent coverage (PC) of the femoral head by the acetabulum and fIA was measured from preoperative, immediate postoperative and first and second recheck radiographs of seven dogs that underwent an ITO (joint n = 9). There was significant (p < 0.05) improvement of both NA and PC in all patients as indicated by a change in the mean +/- standard deviation of 78.9 degrees +/- 7.5 and 36.9% +/- 5.2 to 92.2 degrees +/ 6.7 and 50.6% +/- 8.3, respectively. No significant difference (p < 0.05) was observed between the values of the planned femoral inclination angle (pfIA) of the femur and the effective femoral inclination angle (efIA) obtained after surgery (115.9 degrees +/- 2.5 and 111.3 degrees +/- 6.4, respectively). These findings could encourage the use of ITO in veterinary practice and indicate that intertrochanteric varus osteotomy should be re-considered for the treatment of early stage hip dysplasia in dogs with radiological signs of joint incongruency. PMID- 23814472 TI - Comparison of techniques for transdiaphragmatic thoracic drainage after diaphragmatic defect closure in dogs: a cadaveric study. AB - Four thoracic evacuation techniques for pneumothorax elimination after diaphragmatic defect closure were compared in 40 canine cadavers. After creating a defect in the left side of the diaphragm, thoracic drainage was performed by thoracostomy tube insertion through the defect and a small (DD-SP) or large (DD LP) puncture created in the caudal mediastinum, or through both the diaphragmatic defect and intact contralateral diaphragm with a small (DI-SP) or large (DI-LP) puncture in made in the caudal mediastinum. Differences in intrapleural pressure (IPP) between the right and left hemithoraxes after air evacuation along with differences in IPP before making a defect and after air evacuation in each hemithorax were calculated. A difference (p <= 0.0011) in IPP between the left and right hemithoraxes after air evacuation as well as before making a defect and after air evacuation in the right hemithorax was detected for the DD-SP group. No significant differences (p >= 0.0835) were observed for the DI-LP, DD-LP, or DI SP groups. Creation of a large mediastinal puncture or thoracic evacuation through both a diaphragmatic defect and intact contralateral diaphragm can facilitate proper pneumothorax elimination bilaterally after diaphragmatic defect closure in dogs with a small puncture in the caudal mediastinum. PMID- 23814473 TI - Clinical use of a ceramide-based moisturizer for treating dogs with atopic dermatitis. AB - In humans, skin barrier dysfunction is thought to be responsible for enhanced penetration of allergens. Similar to conditions seen in humans, canine atopic dermatitis (CAD) is characterized by derangement of corneocytes and disorganization of intercellular lipids in the stratum corenum (SC) with decreased ceramide levels. This study was designed to evaluate the effects of a moisturizer containing ceramide on dogs with CAD. Dogs (n = 20, 3~8 years old) with mild to moderate clinical signs were recruited and applied a moisturizer containing ceramide for 4 weeks. Transepidermal water loss (TEWL), skin hydration, pruritus index for canine atopic dermatitis (PICAD) scores, and canine atopic dermatitis extent and severity index (CADESI) scores of all dogs were evaluated. Skin samples from five dogs were also examined with transmission electron microscopy (TEM) using ruthenium tetroxide. TEWL, PICAD, and CADESI values decreased (p < 0.05) and skin hydration increased dramatically over time (p < 0.05). Electron micrographs showed that the skin barrier of all five dogs was partially restored (p < 0.05). In conclusion, these results demonstrated that moisturizer containing ceramide was effective for treating skin barrier dysfunction and CAD symptoms. PMID- 23814474 TI - Radiation up-regulates the expression of VEGF in a canine oral melanoma cell line. AB - To evaluate radiosensitivity and the effects of radiation on the expression of vascular endothelial growth factor (VEGF) and VEGF receptors in the canine oral melanoma cell line, TLM 1, cells were irradiated with doses of 0, 2, 4, 6, 8 and 10 Gray (Gy). Survival rates were then determined by a MTT assay, while vascular endothelial growth factor receptor (VEGFR)-1 and -2 expression was measured by flow cytometry and apoptotic cell death rates were investigated using an Annexin assay. Additionally, a commercially available canine VEGF ELISA kit was used to measure VEGF. Radiosensitivity was detected in TLM 1 cells, and mitotic and apoptotic cell death was found to occur in a radiation dose dependent manner. VEGF was secreted constitutively and significant up-regulation was observed in the 8 and 10 Gy irradiated cells. In addition, a minor portion of TLM 1 cells expressed vascular endothelial growth factor receptor (VEGFR)-1 intracellularly. VEGFR-2 was detected in the cytoplasm and was down-regulated following radiation with increasing dosages. In TLM 1 cells, apoptosis plays an important role in radiation induced cell death. It has also been suggested that the significantly higher VEGF production in the 8 and 10 Gy group could lead to tumour resistance. PMID- 23814475 TI - Effects of one-time and two-time intra-articular injection of hyaluronic acid sodium salt after joint surgery in dogs. AB - Thirty-one dogs with patellar luxation (grades 2 and 3) were categorized into three groups. Group 1 (G.1; n = 12) had sodium hyaluronate (SHA) intra articularly injected into the stifle joint that received surgery. Group 2 (G.2; n = 10) received SHA twice: first after surgery and then 1 week later. Group 3 (G.3; n = 9) served as a control, without injection. Blood was collected before injection and then once a week for 4 weeks after injection for evaluation of chondroitin sulfate (CS-WF6) and hyaluronan (HA). The results revealed significantly (p < 0.05) improved clinical scores by the end of week 4 in G.1 and G.2 relative to G.3; however, there was no significant difference between G.1 and G.2. There was a significant decrease (p < 0.05) in serum CS-WF6 levels beginning at week 2 in G.1 and G.2. At weeks 3 and 4, serum HA in G.1 and G.2 differed from that in G.3 (p < 0.05). No significant difference (p > 0.05) was observed in serum biomarkers between G.1 and G.2. In conclusion, intra-articular injection with SHA after joint surgery may improve homeostasis of the joint, retarding the process of OA. PMID- 23814476 TI - Analysis of ultrastructural glomerular basement membrane lesions and podocytes associated with proteinuria and sclerosis in Osborne-Mendel rats with progressive glomerulonephropathy. AB - The renal glomeruli of 12 male Osborne-Mendel (OM) rats 3 to 24 weeks old were examined by electron microscopy. Effacement of podocyte foot processes (FPs) developed at 3 weeks of age and became progressively worse over time. Loss or dislocation of the slit membrane was also found. Vacuoles and osmiophilic lysosomes appeared in the podocytes starting at 6 weeks of age. Podocyte detachment from the glomerular basement membrane (GBM) was apparent at 18 weeks of age. Laminated GBM was occasionally observed in all animals. These features might lead to the development of spontaneous proteinuria and glomerulosclerosis in OM rats. PMID- 23814477 TI - Isolation and characterization of orf viruses from Korean black goats. AB - Five cases of orf virus infection in Korean black goats were diagnosed in our laboratory between 2010 and 2011. One orf virus (ORF/2011) was isolated from an ovine testis cell line (OA3.Ts) for use as a vaccine candidate. Sequences of the major envelope protein and orf virus interferon resistance genes were determined and compared with published reference sequences. Phylogenetic analyses revealed that orf viruses from Korean black goats were most closely related to an isolate (ORF/09/Korea) from dairy goats in Korea. This result indicates that the orf viruses might have been introduced from dairy goats into the Korean black goat population. PMID- 23814478 TI - An unusual case of concomitant infection with chicken astrovirus and group A avian rotavirus in broilers with a history of severe clinical signs. AB - A molecular study of intestinal samples from 21 broiler flocks with a history of enteritis revealed that 23.8% and 14.3% were positive for chicken astrovirus (CAstV) and avian rotavirus (ARV), respectively. CAstV and group A ARV were simultaneously detected in only one broiler flock. Birds in this group developed the significant intestinal lesions characterized by frothy contents, paleness, and thin intestinal walls. In this report we present an unusual case of runting stunting syndrome (RSS) with a history of high mortality and growth retardation in broiler chickens. We also make the first identification of CAstV and group A ARV in broiler chickens in Korea. PMID- 23814479 TI - Phototransformations of dinitropyrene isomers on models of the atmospheric particulate matter. AB - The 1,6 and 1,8-dinitropyrenes (DNP) isomers are strong mutagens and carcinogens encountered in diesel exhaust and airborne particles. Relative photodegradation rates were determined and some products were characterized when these isomers were irradiated adsorbed onto models of the atmospheric matter. These are compared to their photochemical behavior in a polar nonprotic solvent. The 1,8 DNP isomer is three times more reactive than the 1,6-DNP when irradiated adsorbed onto silica gel surfaces, while the reverse order is observed in solution, demonstrating the influence of structural differences and environmental effects on the photoreactivity. Oxygen is a key factor in the formation of pyrenediones from 1,8-DNP in solution and on silica gel which is not the case for 1,6-DNP. The average pore diameter (2.5 versus 6.0 nm) of the silica surfaces induces a significant change in the product distribution and relative yields of 1,8-DNP because pyrenediones or 8-hydroxy-1-nitropyrene are not produced in the smaller pore silica. A 6-hydroxy-1-nitropyrene product is observed both in acidic alumina and silica (6.0 nm) surfaces. On acidic alumina the rates of phototransformation of the isomers are equal, a significant increase in the relative yield of the hydroxynitropyrene product is observed compared to the silica and unidentified products in which the absence of NO2 and pyrene absorption bands were observed, demonstrating the surface effect on the photodegradation. Overall, the presence of some products indicates the occurrence of a nitro-nitrite rearrangement on the surface with the participation of a pyrenoxy radical as their precursor. PMID- 23814480 TI - The Environmental Cost of Misinformation: Why the Recommendation to Use Elevated Temperatures for Handwashing is Problematic. AB - Multiple government and health organizations recommend the use of warm or hot water in publications designed to educate the public on best practices for washing one's hands. This is despite research suggesting that the use of an elevated water temperature does not improve handwashing efficacy, but can cause hand irritation. There is reason to believe that the perception that warm or hot water is more effective at cleaning one's hands is pervasive, and may be one factor that is driving up unnecessary energy consumption and greenhouse gas emissions. We examine handwashing practices and beliefs about water temperature using a survey of 510 adults in the United States. The survey included measures of handwashing frequency, duration, the proportion of time an elevated temperature was used, and beliefs about water temperature and handwashing efficacy. We also estimate the energy consumed and resultant carbon dioxide equivalent emissions (CO2eq) in the U.S. due to the use of elevated temperatures during handwashing. Participants used an elevated temperature 64% of the time, causing 6.3 million metric tons (MMt) of CO2eq which is 0.1% of total annual emissions and 0.3% of commercial and residential sector emissions. Roughly 69% of the sample believed that elevated temperatures improve handwashing efficacy. Updating these beliefs could prevent 1 MMt of CO2eq annually, exceeding the total emissions from many industrial sources in the U.S. including the Lead and Zinc industries. In addition to causing skin irritation, the recommendation to use an elevated temperature during handwashing contributes to another major threat to public health-climate change. Health and consumer protection organizations should consider advocating for the use of a "comfortable" temperature rather than warm or hot water. PMID- 23814481 TI - Targeting cathepsin E in pancreatic cancer by a small molecule allows in vivo detection. AB - When resectable, invasive pancreatic ductal adenocarcinoma (PDAC) is most commonly treated with surgery and radiochemotherapy. Given the intricate local anatomy and locoregional mode of dissemination, achieving clean surgical margins can be a significant challenge. On the basis of observations that cathepsin E (CTSE) is overexpressed in PDAC and that an United States Food and Drug Administration (FDA)-approved protease inhibitor has high affinity for CTSE, we have developed a CTSE optical imaging agent [ritonavir tetramethyl-BODIPY (RIT TMB)] for potential intraoperative use. We show nanomolar affinity [half maximal inhibitory concentration (IC50) of 39.9 +/- 1.2 nM] against CTSE of the RIT-TMB in biochemical assays and intracellular accumulation and target-to-background ratios that allow specific delineation of individual cancer cells. This approach should be useful for more refined surgical staging, planning, and resection with curative intent. PMID- 23814482 TI - Multimodal microvascular imaging reveals that selective inhibition of class I PI3K is sufficient to induce an antivascular response. AB - The phosphatidylinositol 3-kinase (PI3K) pathway is a central mediator of vascular endothelial growth factor (VEGF)-driven angiogenesis. The discovery of small molecule inhibitors that selectively target PI3K or PI3K and mammalian target of rapamycin (mTOR) provides an opportunity to pharmacologically determine the contribution of these key signaling nodes in VEGF-A-driven tumor angiogenesis in vivo. This study used an array of micro-vascular imaging techniques to monitor the antivascular effects of selective class I PI3K, mTOR, or dual PI3K/mTOR inhibitors in colorectal and prostate cancer xenograft models. Micro-computed tomography (micro-CT) angiography, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), vessel size index (VSI) MRI, and DCE ultrasound (DCE-U/S) were employed to quantitatively evaluate the vascular (structural and physiological) response to these inhibitors. GDC-0980, a dual PI3K/mTOR inhibitor, was found to reduce micro-CT angiography vascular density, while VSI MRI demonstrated a significant reduction in vessel density and an increase in mean vessel size, consistent with a loss of small functional vessels and a substantial antivascular response. DCE-MRI showed that GDC-0980 produces a strong functional response by decreasing the vascular permeability/perfusion-related parameter, K (trans). Interestingly, comparable antivascular effects were observed for both GDC-980 and GNE-490 (a selective class I PI3K inhibitor). In addition, mTOR-selective inhibitors did not affect vascular density, suggesting that PI3K inhibition is sufficient to generate structural changes, characteristic of a robust antivascular response. This study supports the use of noninvasive microvascular imaging techniques (DCE-MRI, VSI MRI, DCE-U/S) as pharmacodynamic assays to quantitatively measure the activity of PI3K and dual PI3K/mTOR inhibitors in vivo. PMID- 23814483 TI - Targeting stem cell behavior in desmoid tumors (aggressive fibromatosis) by inhibiting hedgehog signaling. AB - Desmoid tumor (also called aggressive fibromatosis) is a lesion of mesenchymal origin that can occur as a sporadic tumor or a manifestation of the preneoplastic syndrome, familial adenomatous polyposis caused by a mutation in adenomatous polyposis coli (APC). This tumor type is characterized by the stabilization of beta-catenin and activation of Tcf-mediated transcription. Cell transplantation data suggest that desmoid tumors are derived from mesenchymal progenitor cells (MSCs). As such, modulating cell signaling pathways that regulate MSC differentiation or proliferation, such as hedgehog (Hh) signaling, could alter the tumor phenotype. Here, we found that Hh signaling is activated in human and murine desmoid tumors. Inhibiting Hh signaling in human cell cultures decreased cell proliferation and beta-catenin protein levels. Apc(+)/Apc(1638N) mice, which develop desmoid tumors, develop smaller and fewer tumors when Hh signaling was inhibited either genetically (by crossing Apc(+)/Apc(1638N) mice with mice lacking one copy of a Hh-activated transcription factor, Gli2 (+/-) mice) or using a pharmacologic inhibitor. Both in mice and in human tumor cell cultures, beta-catenin and Hh-mediated signaling positively regulate each other's activity. These data show that targeting a pathway that regulates MSC differentiation influences desmoid tumor behavior, providing functional evidence supporting the notion that these tumors are derived from mesenchymal progenitors. It also suggests Hh blockade as a therapeutic approach for this tumor type. PMID- 23814484 TI - Novel 5' fusion partners of ETV1 and ETV4 in prostate cancer. AB - Gene fusions involving the erythroblast transformation-specific (ETS) transcription factors ERG, ETV1, ETV4, ETV5, and FLI1 are a common feature of prostate carcinomas (PCas). The most common upstream fusion partner described is the androgen-regulated prostate-specific gene TMPRSS2, most frequently with ERG, but additional 5' fusion partners have been described. We performed 5' rapid amplification of cDNA ends in 18 PCas with ETV1, ETV4, or ETV5 outlier expression to identify the 5' fusion partners. We also evaluated the exon-level expression profile of these ETS genes in 14 cases. We identified and confirmed by fluorescent in situ hybridization (FISH) and reverse transcription-polymerase chain reaction the two novel chimeric genes OR51E2-ETV1 and UBTF-ETV4 in two PCas. OR51E2 encodes a G-protein-coupled receptor that is overexpressed in PCas, whereas UBTF is a ubiquitously expressed gene encoding an HMG-box DNA-binding protein involved in ribosome biogenesis. We additionally describe two novel gene fusion combinations of previously described genes, namely, SLC45A3-ETV4 and HERVK17-ETV4. Finally, we found one PCa with TMPRSS2-ETV1, one with C15orf21 ETV1, one with EST14-ETV1, and two with 14q133-q21.1-ETV1. In nine PCas (eight ETV1 and one ETV5), exhibiting ETS outlier expression and genomic rearrangement detected by FISH, no 5' fusion partner was found. Our findings contribute significantly to characterize the heterogeneous group of ETS gene fusions and indicate that all genes described as 5' fusion partners with one ETS gene can most likely be rearranged with any of the other ETS genes involved in prostate carcinogenesis. PMID- 23814485 TI - A new p53 target gene, RKIP, is essential for DNA damage-induced cellular senescence and suppression of ERK activation. AB - p53, a strong tumor suppressor protein, is known to be involved in cellular senescence, particularly premature cellular senescence. Oncogenic stresses, such as Ras activation, can initiate p53-mediated senescence, whereas activation of the Ras-mitogen-activated protein kinase (MAPK) pathway can promote cell proliferation. These conflicting facts imply that there is a regulatory mechanism for balancing p53 and Ras-MAPK signaling. To address this, we evaluated the effects of p53 on the extracellular signal-regulated kinase (ERK) activation and found that p53 could suppress ERK activation through de novo synthesis. Through several molecular biologic analyses, we found that RKIP, an inhibitor of Raf kinase, is responsible for p53-mediated ERK suppression and senescence. Overexpression of RKIP can induce cellular senescence in several types of cell lines, including p53-deficient cells, whereas the elimination of RKIP by siRNA or forced expression of ERK blocks p53-mediated cellular senescence. These results suggested that RKIP is an essential protein for cellular senescence. Moreover, modification of the p53 serine 46 residue was critical for RKIP induction and ERK suppression as well as cellular senescence. These results indicated that RKIP is a novel p53 target gene that is responsible for p53-mediated cellular senescence and tumor suppressor protein expression. PMID- 23814486 TI - PAX3-FOXO1 induces up-regulation of Noxa sensitizing alveolar rhabdomyosarcoma cells to apoptosis. AB - Alveolar rhabdomyosarcoma (ARMS) has a much poorer prognosis than the more common embryonal subtype. Most ARMS tumors characteristically possess a specific genomic translocation between the genes of PAX3/7 and FOXO1 (FKHR), which forms fusion proteins possessing the DNA binding domains of PAX3/7 and the more transcriptionally potent transactivation domain of FOXO1. We have shown that the proapoptotic BH3-only family member Noxa is upregulated by the PAX3-FOXO1 fusion transcription factor in a p53-independent manner. The increased expression of Noxa renders PAX3-FOXO1-expressing cells more susceptible to apoptosis induced by a gamma-secretase inhibitor (GSI1, Z-LLNle-CHO), the proteasome inhibitor bortezomib, and BH3 mimetic ABT-737. Apoptosis in response to bortezomib can be overcome by shRNA knockdown of Noxa. In vivo treatment with bortezomib reduced the growth of tumors derived from a PAX3-FOXO1-expressing primary myoblast tumor model and RH41 xenografts. We therefore demonstrate that PAX3-FOXO1 up-regulation of Noxa represents an unanticipated aspect of ARMS tumor biology that creates a therapeutic window to allow induction of apoptosis in ARMS cells. PMID- 23814487 TI - Loss of Sh3gl2/endophilin A1 is a common event in urothelial carcinoma that promotes malignant behavior. AB - Urothelial carcinoma (UC) causes substantial morbidity and mortality worldwide. However, the molecular mechanisms underlying urothelial cancer development and tumor progression are still largely unknown. Using informatics analysis, we identified Sh3gl2 (endophilin A1) as a bladder urothelium-enriched transcript. The gene encoding Sh3gl2 is located on chromosome 9p, a region frequently altered in UC. Sh3gl2 is known to regulate endocytosis of receptor tyrosine kinases implicated in oncogenesis, such as the epidermal growth factor receptor (EGFR) and c-Met. However, its role in UC pathogenesis is unknown. Informatics analysis of expression profiles as well as immunohistochemical staining of tissue microarrays revealed Sh3gl2 expression to be decreased in UC specimens compared to nontumor tissues. Loss of Sh3gl2 was associated with increasing tumor grade and with muscle invasion, which is a reliable predictor of metastatic disease and cancer-derived mortality. Sh3gl2 expression was undetectable in 19 of 20 human UC cell lines but preserved in the low-grade cell line RT4. Stable silencing of Sh3gl2 in RT4 cells by RNA interference 1) enhanced proliferation and colony formation in vitro, 2) inhibited EGF-induced EGFR internalization and increased EGFR activation, 3) stimulated phosphorylation of Src family kinases and STAT3, and 4) promoted growth of RT4 xenografts in subrenal capsule tissue recombination experiments. Conversely, forced re-expression of Sh3gl2 in T24 cells and silenced RT4 clones attenuated oncogenic behaviors, including growth and migration. Together, these findings identify loss of Sh3gl2 as a frequent event in UC development that promotes disease progression. PMID- 23814488 TI - Cross modulation between the androgen receptor axis and protocadherin-PC in mediating neuroendocrine transdifferentiation and therapeutic resistance of prostate cancer. AB - Castration-resistant prostate cancers (CRPCs) that relapse after androgen deprivation therapies (ADTs) are responsible for the majority of mortalities from prostate cancer (PCa). While mechanisms enabling recurrent activity of androgen receptor (AR) are certainly involved in the development of CRPC, there may be factors that contribute to the process including acquired neuroendocrine (NE) cell-like behaviors working through alternate (non-AR) cell signaling systems or AR-dependent mechanisms. In this study, we explore the potential relationship between the AR axis and a novel putative marker of NE differentiation, the human male protocadherin-PC (PCDH-PC), in vitro and in human situations. We found evidence for an NE transdifferentiation process and PCDH-PC expression as an early-onset adaptive mechanism following ADT and elucidate AR as a key regulator of PCDH-PC expression. PCDH-PC overexpression, in turn, attenuates the ligand dependent activity of the AR, enabling certain prostate tumor clones to assume a more NE phenotype and promoting their survival under diverse stress conditions. Acquisition of an NE phenotype by PCa cells positively correlated with resistance to cytotoxic agents including docetaxel, a taxane chemotherapy approved for the treatment of patients with metastatic CRPC. Furthermore, knockdown of PCDH-PC in cells that have undergone an NE transdifferentiation partially sensitized cells to docetaxel. Together, these results reveal a reciprocal regulation between the AR axis and PCDH-PC signals, observed both in vitro and in vivo, with potential implications in coordinating NE transdifferentiation processes and progression of PCa toward hormonal and chemoresistance. PMID- 23814489 TI - Chemotherapy of skull base chordoma tailored on responsiveness of patient-derived tumor cells to rapamycin. AB - Skull base chordomas are challenging tumors due to their deep surgical location and resistance to conventional radiotherapy. Chemotherapy plays a marginal role in the treatment of chordoma resulting from lack of preclinical models due to the difficulty in establishing tumor cell lines and valuable in vivo models. Here, we established a cell line from a recurrent clival chordoma. Cells were cultured for more than 30 passages and the expression of the chordoma cell marker brachyury was monitored using both immunohistochemistry and Western blot. Sensitivity of chordoma cells to the inhibition of specific signaling pathways was assessed through testing of a commercially available small molecule kinase inhibitor library. In vivo tumorigenicity was evaluated by grafting chordoma cells onto immunocompromised mice and established tumor xenografts were treated with rapamycin. Rapamycin was administered to the donor patient and its efficacy was assessed on follow-up neuroimaging. Chordoma cells maintained brachyury expression at late passages and generated xenografts closely mimicking the histology and phenotype of the parental tumor. Rapamycin was identified as an inhibitor of chordoma cell proliferation. Molecular analyses on tumor cells showed activation of the mammalian target of rapamycin signaling pathway and mutation of KRAS gene. Rapamycin was also effective in reducing the growth of chordoma xenografts. On the basis of these results, our patient received rapamycin therapy with about six-fold reduction of the tumor growth rate upon 10 month follow-up neuroimaging. This is the first case of chordoma in whom chemotherapy was tailored on the basis of the sensitivity of patient-derived tumor cells. PMID- 23814490 TI - Functional role and therapeutic potential of the pim-1 kinase in colon carcinoma. AB - PURPOSE: The provirus integration site for Moloney murine leukemia virus 1 (Pim 1) kinase is overexpressed in various tumors and has been linked to poor prognosis. Its role as proto-oncogene is based on several Pim-1 target proteins involved in pivotal cellular processes. Here, we explore the functional relevance of Pim-1 in colon carcinoma. EXPERIMENTAL DESIGN: RNAi-based knockdown approaches, as well as a specific small molecule inhibitor, were used to inhibit Pim-1 in colon carcinoma cells. The effects were analyzed regarding proliferation, apoptosis, sensitization toward cytostatic treatment, and overall antitumor effect in vitro and in mouse tumor models in vivo. RESULTS: We demonstrate antiproliferative, proapoptotic, and overall antitumor effects of Pim 1 inhibition. The sensitization to 5-fluorouracil (5-FU) treatment upon Pim-1 knockdown offers new possibilities for combinatorial treatment approaches. Importantly, this also antagonizes a 5-FU-triggered Pim-1 up-regulation, which is mediated by decreased levels of miR-15b, a microRNA we newly identify to regulate Pim-1. The analysis of the molecular effects of Pim-1 inhibition reveals a complex regulatory network, with therapeutic Pim-1 repression leading to major changes in oncogenic signal transduction with regard to p21(Cip1/WAF1), STAT3, c jun-N-terminal kinase (JNK), c-Myc, and survivin and in the levels of apoptosis related proteins Puma, Bax, and Bcl-xL. CONCLUSIONS: We demonstrate that Pim-1 plays a pivotal role in several tumor-relevant signaling pathways and establish the functional relevance of Pim-1 in colon carcinoma. Our results also substantiate the RNAi-mediated Pim-1 knockdown based on polymeric polyethylenimine/small interfering RNA nanoparticles as a promising therapeutic approach. PMID- 23814491 TI - Prostaglandin E2 Promotes UV radiation-induced immune suppression through DNA hypermethylation. AB - Exposure of mice to UV radiation results in suppression of the contact hypersensitivity (CHS) response. Here, we report that the UV-induced suppression of CHS is associated with increases in the levels of cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and PGE2 receptors in the exposed skin. UV radiation induced suppression of CHS was inhibited by topical treatment of the skin with celecoxib or indomethacin (inhibitors of COX-2) or AH6809 (an EP2 antagonist). Moreover, mice deficient in COX-2 were found to be resistant to UV-induced suppression of CHS. The exposure of wild-typemice to UVB radiation resulted in DNA hypermethylation, increased DNA methyltransferase (Dnmt) activity, and elevated levels of Dnmt1, Dnmt3a, and Dnmt3b proteins in the skin, and these responses were downregulated on topical treatment of the site of exposure after irradiation with indomethacin or EP2 antagonist. Topical treatment of UVB-exposed COX-2-deficient mice with PGE2 enhanced the UVB-induced suppression of CHS as well as global DNA methylation and elevated the levels of Dnmt activity and Dnmt proteins in the skin. Intraperitoneal injection of 5-aza-2'-deoxycytidine (5-Aza dc), a DNA demethylating agent, restored the CHS response to 2,4 dinitrofluorobenzene in UVB-exposed skin and this was associated with the reduction in global DNA methylation and Dnmt activity and reduced levels of Dnmt proteins. Furthermore, treatment with 5-Aza-dc reversed the effect of PGE2 on UV induced suppression of CHS in COX-2-deficient mice. These findings reveal a previously unrecognized role for PGE2 in the promotion of UVB-induced immunosuppression and indicate that it is mediated through PGE2 regulation of DNA methylation. PMID- 23814492 TI - Immunochemoradiotherapy for patients with oral squamous cell carcinoma: augmentation of OK-432-induced helper T cell 1 response by 5-FU and X-ray irradiation. AB - Eighty-one patients with oral squamous cell carcinoma (OSCC) received oral fluoropyrimidine UFT and radiotherapy (RT) with or without an immunotherapeutic agent OK-432. Both overall survival and progression-free survival of patients who received RT + UFT + OK-432 were significantly longer than those of patients who received RT + UFT (P = .0075 and P = .0175, respectively). Clinical response was also more favorable in RT + UFT + OK-432 group than in RT + UFT group (P = .0066). Next, in vitro experiments were conducted to examine the effect of 5 fluorouracil (5-FU) and X-ray irradiation in OK-432-induced immunity. Human peripheral blood mononuclear cells stimulated with OK-432 produced helper T cell 1 (Th1)-type cytokines as well as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta), which are produced by Th2 and regulatory T cells (Tregs), respectively, and are inhibitory in antitumor immunity. OK-432-induced IL-10 and TGF-beta but not Th1 cytokines were significantly inhibited by 5-FU and/or X-ray. 5-FU and X-ray also inhibited the expression of mRNAs for GATA-3 and Foxp3, which are transcription factors for Th2 and Tregs, respectively, but not for T-bet, a transcription factor for Th1. In addition, 5-FU and X-ray decreased the expression of mRNAs for suppressor of cytokine signaling 1 (SOCS1) and SOCS3. Antisense oligonucleotides for SOCS1 and SOCS3 markedly reduced OK-432-induced IL 10 and TGF-beta. This is the first report clearly demonstrating that OK-432-based immunotherapy significantly enhanced the therapeutic effects of chemoradiotherapy in patients with OSCC as well as elucidating the mechanism of the synergistic effect of immunochemoradiotherapy in which 5-FU and radiation enhanced OK-432 induced Th1 response mediated by the inhibition of SOCS1 and SOCS3 gene expression. PMID- 23814493 TI - Inhibition of tumor angiogenesis and tumor growth by the DSL domain of human Delta-like 1 targeted to vascular endothelial cells. AB - The growth of solid tumors depends on neovascularization. Several therapies targeting tumor angiogenesis have been developed. However, poor response in some tumors and emerging resistance necessitate further investigations of new drug targets. Notch signal pathway plays a pivotal role in vascular development and tumor angiogenesis. Either blockade or forced activation of this pathway can inhibit angiogenesis. As blocking Notch pathway results in the formation of vascular neoplasm, activation of Notch pathway to prevent tumor angiogenesis might be an alternative choice. However, an in vivo deliverable reagent with highly efficient Notch-activating capacity has not been developed. Here, we generated a polypeptide, hD1R, which consists of the Delta-Serrate-Lag-2 fragment of the human Notch ligand Delta-like 1 and an arginine-glycine-aspartate (RGD) motif targeting endothelial cells (ECs). We showed that hD1R could bind to ECs specifically through its RGD motif and effectively triggered Notch signaling in ECs. We demonstrated both in vitro and in vivo that hD1R inhibited angiogenic sprouting and EC proliferation. In tumor-bearing mice, the injection of hD1R effectively repressed tumor growth, most likely through increasing tumor hypoxia and tissue necrosis. The amount and width of vessels reduced remarkably in tumors of mice treated with hD1R. Moreover, vessels in tumors of mice treated with hD1R recruited more NG2(+) perivascular cells and were better perfused. Combined application of hD1R and chemotherapy with cisplatin and teniposide revealed that these two treatments had additive antitumor effects. Our study provided a new strategy for antiangiogenic tumor therapy. PMID- 23814494 TI - Suppression of antifolate resistance by targeting the myosin Va trafficking pathway in melanoma. AB - Human melanoma is a significant clinical problem. As most melanoma patients relapse with lethal drug-resistant disease, understanding and preventing mechanism(s) of resistance is one of the highest priorities to improve melanoma therapy. Melanosomal sequestration and the cellular exportation of cytotoxic drugs have been proposed to be important melanoma-specific mechanisms that contribute to multidrug resistance in melanoma. Concretely, we found that treatment of melanoma with methotrexate (MTX) altered melanogenesis and accelerated the exportation of melanosomes; however, the cellular and molecular processes by which MTX is trapped into melanosomes and exported out of cells have not been elucidated. In this study, we identified myosin Va (MyoVa) as a possible mediator of these cellular processes. The results demonstrated that melanoma treatment with MTX leads to Akt2-dependent MyoVa phosphorylation, which enhances its ability to interact with melanosomes and accelerates their exportation. To understand the mechanism(s) by which MTX activates Akt2, we examined the effects of this drug on the activity of protein phosphatase 2A, an Akt inhibitor activated by the methylation of its catalytic subunit. Taken together, this study identified a novel trafficking pathway in melanoma that promotes tumor resistance through Akt2/MyoVa activation. Because of these findings, we explored several MTX combination therapies to increase the susceptibility of melanoma to this drug. By avoiding MTX exportation, we observed that the E2F1 apoptotic pathway is functional in melanoma, and its induction activates p73 and apoptosis protease activating factor 1 following a p53-autonomous proapoptotic signaling event. PMID- 23814495 TI - Marker-independent method for isolating slow-dividing cancer stem cells in human glioblastoma. AB - Glioblastoma (GBM) is a devastating brain tumor with a poor survival outcome. It is generated and propagated by a small subpopulation of rare and hierarchically organized cells that share stem-like features with normal stem cells but, however, appear dysregulated in terms of self-renewal and proliferation and aberrantly differentiate into cells forming the bulk of the disorganized cancer tissues. The complexity and heterogeneity of human GBMs underlie the lack of standardized and effective treatments. This study is based on the assumption that available markers defining cancer stem cells (CSCs) in all GBMs are not conclusive and further work is required to identify the CSC. We implemented a method to isolate CSCs independently from cell surface markers: four patient derived GBM neurospheres containing stem, progenitors, and differentiated cells were labeled with PKH-26 fluorescent dye that reliably selects for cells that divide at low rate. Through in vitro and in vivo assays, we investigated the growth and self-renewal properties of the two different compartments of high- and slow-dividing cells. Our data demonstrate that only slow-dividing cells retain the ability of a long-lasting self-renewal capacity after serial in vitro passaging, while high-dividing cells eventually exhaust. Moreover, orthotopic transplantation assay revealed that the incidence of tumors generated by the slow dividing compartment is significantly higher in the four patient-derived GBM neurospheres analyzed. Importantly, slow-dividing cells feature a population made up of homogeneous stem cells that sustain tumor growth and therefore represent a viable target for GBM therapy development. PMID- 23814497 TI - Mass spectrometry contamination from Tinuvin 770, a common additive in laboratory plastics. AB - The superior sensitivity of current mass spectrometers makes them prone to contamination issues, which can have deleterious effects on sample analysis. Here, bis(2,2,6,6-tetramethyl-4-piperidyl) sebacate (marketed under the name Tinuvin 770) is identified as a major contaminant in applications using liquid chromatography coupled with mass spectrometry (LC-MS). Tinuvin 770 is often added to laboratory and medical plastics as a UV stabilizer. One particular lot of microcentrifuge tubes was found to have an excess of this compound that would leach into samples and drastically interfere with LC-MS data acquisition. Further analysis found that Tinuvin 770 readily leached into polar and nonpolar solvents from the contaminated tube lot. Efforts to remove Tinuvin 770 from contaminated samples were unsuccessful. A prescreening method using MALDI-TOF MS is presented to prevent system contamination and sample loss. PMID- 23814496 TI - The IL-6/JAK/Stat3 feed-forward loop drives tumorigenesis and metastasis. AB - We have investigated the importance of interleukin-6 (IL-6) in promoting tumor growth and metastasis. In human primary breast cancers, increased levels of IL-6 were found at the tumor leading edge and positively correlated with advanced stage, suggesting a mechanistic link between tumor cell production of IL-6 and invasion. In support of this hypothesis, we showed that the IL-6/Janus kinase (JAK)/signal transducer and activator of transcription 3 (Stat3) pathway drives tumor progression through the stroma and metastatic niche. Overexpression of IL-6 in tumor cell lines promoted myeloid cell recruitment, angiogenesis, and induced metastases. We demonstrated the therapeutic potential of interrupting this pathway with IL-6 receptor blockade or by inhibiting its downstream effectors JAK1/2 or Stat3. These clinically relevant interventions did not inhibit tumor cell proliferation in vitro but had profound effects in vivo on tumor progression, interfering broadly with tumor-supportive stromal functions, including angiogenesis, fibroblast infiltration, and myeloid suppressor cell recruitment in both the tumor and pre-metastatic niche. This study provides the first evidence for IL-6 expression at the leading edge of invasive human breast tumors and demonstrates mechanistically that IL-6/JAK/Stat3 signaling plays a critical and pharmacologically targetable role in orchestrating the composition of the tumor microenvironment that promotes growth, invasion, and metastasis. PMID- 23814499 TI - Comparison of commercially available target enrichment methods for next generation sequencing. AB - Isolating high-priority segments of genomes greatly enhances the efficiency of next-generation sequencing (NGS) by allowing researchers to focus on their regions of interest. For the 2010-11 DNA Sequencing Research Group (DSRG) study, we compared outcomes from two leading companies, Agilent Technologies (Santa Clara, CA, USA) and Roche NimbleGen (Madison, WI, USA), which offer custom targeted genomic enrichment methods. Both companies were provided with the same genomic sample and challenged to capture identical genomic locations for DNA NGS. The target region totaled 3.5 Mb and included 31 individual genes and a 2-Mb contiguous interval. Each company was asked to design its best assay, perform the capture in replicates, and return the captured material to the DSRG-participating laboratories. Sequencing was performed in two different laboratories on Genome Analyzer IIx systems (Illumina, San Diego, CA, USA). Sequencing data were analyzed for sensitivity, specificity, and coverage of the desired regions. The success of the enrichment was highly dependent on the design of the capture probes. Overall, coverage variability was higher for the Agilent samples. As variant discovery is the ultimate goal for a typical targeted sequencing project, we compared samples for their ability to sequence single-nucleotide polymorphisms (SNPs) as a test of the ability to capture both chromosomes from the sample. In the targeted regions, we detected 2546 SNPs with the NimbleGen samples and 2071 with Agilent's. When limited to the regions that both companies included as baits, the number of SNPs was ~1000 for each, with Agilent and NimbleGen finding a small number of unique SNPs not found by the other. PMID- 23814498 TI - Optimization of data-dependent acquisition parameters for coupling high-speed separations with LC-MS/MS for protein identifications. AB - Recent developments in chromatography, such as ultra-HPLC and superficially porous particles, offer significantly improved peptide separation. The narrow peak widths, often only several seconds, can permit a 15-min liquid chromatography run to have a similar peak capacity as a 60-min run using traditional HPLC approaches. In theory, these larger peak capacities should provide higher protein coverage and/or more protein identifications when incorporated into a proteomic workflow. We initially observed a decrease in protein coverage when implementing these faster chromatographic approaches, due to data-dependent acquisition (DDA) settings that were not properly set to match the narrow peak widths resulting from newly implemented, fast separation techniques. Oversampling of high-intensity peptides lead to low protein-sequence coverage, and tandem mass spectra (MS/MS) from lower-intensity peptides were of poor quality, as automated MS/MS events were occurring late on chromatographic peaks. These observations led us to optimize DDA settings to use these fast separations. Optimized DDA settings were applied to the analysis of Trypanosome brucei peptides, yielding peptide identifications at a rate almost five times faster than previously used methodologies. The described approach significantly improves protein identification workflows that use typical available instrumentation. PMID- 23814500 TI - Best practices for core facilities: handling external customers. AB - This article addresses the growing interest among U.S. scientific organizations and federal funding agencies in strengthening research partnerships between American universities and the private sector. It outlines how core facilities at universities can contribute to this partnership by offering services and access to high-end instrumentation to both nonprofit organizations and commercial organizations. We describe institutional policies (best practices) and procedures (terms and conditions) that are essential for facilitating and enabling such partnerships. In addition, we provide an overview of the relevant federal regulations that apply to external use of academic core facilities and offer a set of guidelines for handling them. We conclude by encouraging directors and managers of core facilities to work with the relevant organizational offices to promote and nurture such partnerships. If handled appropriately, we believe such partnerships can be a win-win situation for both organizations that will support research and bolster the American economy. PMID- 23814501 TI - Fragmentation of genomic DNA using microwave irradiation. AB - An unconventional approach for DNA fragmentation was investigated to explore its feasibility as an alternative to the existing DNA fragmentation techniques for next-generation DNA sequencing application. Current methods are based on strong force liquid shearing or specialized enzymatic treatments. There are shortcomings for these platforms yet to be addressed, including aerosolization of genomic materials, which may result in the cross-contamination and biohazards; the difficulty in multiplexing; and the potential sequence biases. In this proof-of concept study, we investigated the microwave irradiation as a simple, unbiased, and easy-to-multiplex way to fragment genomic DNA randomly. In addition, heating DNA at high temperature was attempted for the same purpose and for comparison. Adaptive focused acoustic sonication was used as the control. The yield and functionality for the DNA fragments and DNA fragment libraries were analyzed to assess the feasibility and use of the proposed approach. Both microwave irradiation and thermal heating can fragment genomic DNA to the size ranges suitable for next-generation sequencing (NGS) shotgun library preparation. However, both treatments caused severe reduction in PCR amplification efficiency, which led to low production in emulsion PCR (emPCR). The result was improved by amplification prior to emPCR. Further improvements, such as DNA strand repairing, are needed for the method to be applied practically in NGS. PMID- 23814503 TI - Can Preoccupation with Alcohol Override the Protective Properties of Mindful Awareness on Problematic Drinking? AB - OBJECTIVES: To assess the mediating role of drinking restraint- specifically preoccupation with drinking- on the associations between mindful awareness and alcohol consumption and alcohol-related problems. METHODS: 390 heavy-drinking, undergraduate, college students (52% male) were assessed on measures of mindfulness, drinking restraint, alcohol consumption (prior 90-days), and alcohol related problems via self-report surveys. RESULTS: Mindfulness was negatively associated with alcohol consumption, problems, and both factors of drinking restraint (emotional preoccupation and behavioral constraint). Emotional preoccupation, but not behavioral constraint, statistically mediated these relationships and demonstrated positive associations with both alcohol consumption and related problems. CONCLUSIONS: Results replicate previous findings documenting a negative association between mindfulness and alcohol consumption and problems. Statistical mediation models suggest that preoccupation with drinking may be a risk factor that over-rides the health-promoting effects of mindfulness. PMID- 23814504 TI - Modeling Study of the Low-Temperature Oxidation of Large Methyl Esters from C11 to C19. AB - The modeling of the low temperature oxidation of large saturated methyl esters really representative of those found in biodiesel fuels has been investigated. Models have been developed for these species and then detailed kinetic mechanisms have been automatically generated using a new extended version of software EXGAS, which includes reactions specific to the chemistry of esters. A model generated for a binary mixture of n-decane and methyl palmitate was used to simulate experimental results obtained in a jet-stirred reactor for this fuel. This model predicts very well the reactivity of the fuel and the mole fraction profiles of most reaction products. This work also shows that a model for a middle size methyl ester such as methyl decanoate predicts fairly well the reactivity and the mole fractions of most species with a substantial decrease in computational time. Large n-alkanes such as n-hexadecane are also good surrogates for reproducing the reactivity of methyl esters, with an important gain in computational time, but they cannot account for the formation of specific products such as unsaturated esters or cyclic ethers with an ester function. PMID- 23814505 TI - A high temperature and atmospheric pressure experimental and detailed chemical kinetic modelling study of 2-methyl furan oxidation. AB - An experimental ignition delay time study for the promising biofuel 2-methyl furan (2MF) was performed at equivalence ratios of 0.5, 1.0 and 2.0 for mixtures of 1% fuel in argon in the temperature range 1200-1800 K at atmospheric pressure. Laminar burning velocities were determined using the heat-flux method for mixtures of 2MF in air at equivalence ratios of 0.55-1.65, initial temperatures of 298-398 K and atmospheric pressure. A detailed chemical kinetic mechanism consisting of 2059 reactions and 391 species has been constructed to describe the oxidation of 2MF and is used to simulate experiment. Accurate reproduction of the experimental data has been obtained over all conditions with the developed mechanism. Rate of production and sensitivity analyses have been carried out to identify important consumption pathways of the fuel and key kinetic parameters under these conditions. The reactions of hydrogen atom with the fuel are highlighted as important under all experimental conditions studied, with abstraction by the hydrogen atom promoting reactivity and hydrogen atom addition to the furan ring inhibiting reactivity. This work, to the authors knowledge, is the first to combine theoretical and experimental work to describe the oxidation of any of the alkylated furans. The mechanism developed herein to describe 2MF combustion should also function as a sub-mechanism to describe the oxidation of 2,5-dimethyl furan whilst also providing key insights into the oxidation of this similar biofuel candidate. PMID- 23814506 TI - A variational linear-scaling framework to build practical, efficient next generation orbital-based quantum force fields. AB - We introduce a new hybrid molecular orbital/density-functional modified divide and-conquer (mDC) approach that allows the linear-scaling calculation of very large quantum systems. The method provides a powerful framework from which linear scaling force fields for molecular simulations can be developed. The method is variational in the energy, and has simple, analytic gradients and essentially no break-even point with respect to the corresponding full electronic structure calculation. Furthermore, the new approach allows intermolecular forces to be properly balanced such that non-bonded interactions can be treated, in some cases, to much higher accuracy than the full calculation. The approach is illustrated using the second-order self-consistent charge density-functional tight-binding model (DFTB2). Using this model as a base Hamiltonian, the new mDC approach is applied to a series of water systems, where results show that geometries and interaction energies between water molecules are greatly improved relative to full DFTB2. In order to achieve substantial improvement in the accuracy of intermolecular binding energies and hydrogen bonded cluster geometries, it was necessary to extend the DFTB2 model to higher-order atom centered multipoles for the second-order self-consistent intermolecular electrostatic term. Using generalized, linear-scaling electrostatic methods, timings demonstrate that the method is able to calculate a water system of 3000 atoms in less than half of a second, and systems of up to one million atoms in only a few minutes using a conventional desktop workstation. PMID- 23814507 TI - Prediction of Long Loops with Embedded Secondary Structure using the Protein Local Optimization Program. AB - Robust homology modeling to atomic-level accuracy requires in the general case successful prediction of protein loops containing small segments of secondary structure. Further, as loop prediction advances to success with larger loops, the exclusion of loops containing secondary structure becomes awkward. Here, we extend the applicability of the Protein Local Optimization Program (PLOP) to loops up to 17 residues in length that contain either helical or hairpin segments. In general, PLOP hierarchically samples conformational space and ranks candidate loops with a high-quality molecular mechanics force field. For loops identified to possess alpha-helical segments, we employ an alternative dihedral library composed of (phi,psi) angles commonly found in helices. The alternative library is searched over a user-specified range of residues that define the helical bounds. The source of these helical bounds can be from popular secondary structure prediction software or from analysis of past loop predictions where a propensity to form a helix is observed. Due to the maturity of our energy model, the lowest energy loop across all experiments can be selected with an accuracy of sub-Angstrom RMSD in 80% of cases, 1.0 to 1.5 A RMSD in 14% of cases, and poorer than 1.5 A RMSD in 6% of cases. The effectiveness of our current methods in predicting hairpin-containing loops is explored with hairpins up to 13 residues in length and again reaching an accuracy of sub-Angstrom RMSD in 83% of cases, 1.0 to 1.5 A RMSD in 10% of cases, and poorer than 1.5 A RMSD in 7% of cases. Finally, we explore the effect of an imprecise surrounding environment, in which side chains, but not the backbone, are initially in perturbed geometries. In these cases, loops perturbed to 3A RMSD from the native environment were restored to their native conformation with sub-Angstrom RMSD. PMID- 23814508 TI - Self-Learning Adaptive Umbrella Sampling Method for the Determination of Free Energy Landscapes in Multiple Dimensions. AB - The potential of mean force describing conformational changes of biomolecules is a central quantity that determines the function of biomolecular systems. Calculating an energy landscape of a process that depends on three or more reaction coordinates might require a lot of computational power, making some of multidimensional calculations practically impossible. Here, we present an efficient automatized umbrella sampling strategy for calculating multidimensional potential of mean force. The method progressively learns by itself, through a feedback mechanism, which regions of a multidimensional space are worth exploring and automatically generates a set of umbrella sampling windows that is adapted to the system. The self-learning adaptive umbrella sampling method is first explained with illustrative examples based on simplified reduced model systems, and then applied to two non-trivial situations: the conformational equilibrium of the pentapeptide Met-enkephalin in solution and ion permeation in the KcsA potassium channel. With this method, it is demonstrated that a significant smaller number of umbrella windows needs to be employed to characterize the free energy landscape over the most relevant regions without any loss in accuracy. PMID- 23814509 TI - Analysis of the Errors in the Electrostatically Embedded Many-Body Expansion of the Energy and the Correlation Energy for Zn and Cd Coordination Complexes with Five and Six Ligands and Use of the Analysis to Develop a Generally Successful Fragmentation Strategy. AB - In the present paper, we apply the electrostatically embedded many-body expansion of the correlation energy (EE-MB-CE) to the calculation of zinc-ligand and cadmium-ligand bond dissociation energies, and we analyze the errors due to various fragmentation schemes in a variety of neutral, positively charged, and negatively charged Zn2+ and Cd2+ coordination complexes. As a result of the analysis, we are able to present a new, simple, and unambiguous fragmentation strategy. Following this strategy, we show that both methods perform well for zinc-ligand and cadmium-ligand bond dissociation energies for all systems studied in the paper, including a model of the catalytic site of the zinc-bearing anthrax toxin lethal factor (LF), which has garnered substantial attention as a target for drug development. To draw general conclusions we consider ten pentacoordinate and hexacoordinate zinc and cadmium containing coordination complexes, each with 10 or 15 different fragmentation schemes. By analyzing errors, we developed a prescription for the optimal fragmentation strategy. With this scheme, and using MP2 correlation energies as a test, we find that the electrostatically embedded three-body expansion of the correlation energy (EE-3B-CE) method is able to reproduce all 53 conventionally calculated bond energies with an average absolute error of only 0.59 kcal/mol. The paper also presents EE-MB-CE calculations using the CCSD(T) level of theory on an LF model system. With CCSD(T), EE-3B-CE has an average error of 0.30 kcal/mol. PMID- 23814510 TI - Insights from the cancer center business summit: preparing for the future. Foreword. PMID- 23814511 TI - Going hospital based: nuts and bolts operational issues. AB - For the past few years, there has been a rising trend to shift outpatient infusion services from the private practice setting to the hospital outpatient setting. Numerous and complex factors are driving this trend. More complex however are the myriad details required to operationalize a change in structure and ensure that all parties are clear and comfortable with the outcome. PMID- 23814512 TI - Analyzing the affordable care act: essential health benefits and implications for oncology. AB - The Patient Protection and Affordable Care Act (ACA) will have lasting effects on oncology coverage and, perhaps, on oncology practice as well. The ACA ushers in a new class of insured individuals; approximately 25 million will purchase insurance through the exchanges, and Medicaid will expand by 12 million beneficiaries over the next 10 years. Essential health benefits (EHBs), which are required in all qualified health plans (QHPs) sold in the exchanges, will define the coverage available to the newly insured population and could lead to the development of new definitions and standards for medical necessity. This article will discuss effects of the ACA EHB requirements on oncology coverage, as well as the state and federal options and responsibilities as they relate to coverage of and access to oncology services within the QHPs in the exchanges. PMID- 23814513 TI - Practical issues in palliative and quality-of-life care. AB - Although palliative care is not new to health care or to oncology, oncologists still struggle to maximize the value of this type of care across the entire care continuum and across the patient's trajectory of illness. When we don't use what may be the best tools for the job, at the right times in the care path, we miss opportunities to optimize patient and family coping, to limit suffering, and to ensure that our care plans are patient centered. In this article, we look at how we define palliative care and how the tools of palliative medicine can be used to enhance patient care in the outpatient oncology practice setting. PMID- 23814514 TI - Payers working collaboratively with providers to adopt clinical pathways and new care delivery models. AB - The authors found that payers were realistic and pragmatic in identifying challenges to implementing new oncology care delivery models, identifying provider alignment and infrastructure/data acquisition as the two most significant challenges, followed by care coordination, provider incentives, and organizational structure. PMID- 23814515 TI - Doing palliative care in the oncology office. AB - Palliative care is cited as providing improved communication, symptom control, treatment knowledge, and survival. The authors feel primary palliative care skills should be part of a physician's armamentarium. PMID- 23814516 TI - Oncology Transactions and the 340B Drug Pricing Program. AB - The authors provide a summary of the 340B program and certain business models that allow participating covered entities to expand to new locations. PMID- 23814517 TI - Adjuvant intravesical bacillus calmette-guerin therapy and survival among elderly patients with non-muscle-invasive bladder cancer. AB - PURPOSE: National guidelines recommend adjuvant intravesical Bacillus Calmette Guerin (BCG) therapy for higher-risk non-muscle-invasive bladder cancer (NMIBC). Although a survival benefit has not been demonstrated, randomized trials have shown reduced recurrence and delayed progression after its use. We investigated predictors of BCG receipt and its association with survival for older patients with NMIBC. PATIENTS AND METHODS: We identified individuals with NMIBC registered in the Surveillance, Epidemiology, and End Results-Medicare database from 1991 to 2003. We used logistic regression to compare those treated with BCG within 6 months of initial diagnosis with those not treated, adjusting for demographic and clinical factors. Cox proportional hazards modeling was used to analyze the association between BCG and overall survival (OS) and bladder cancer-specific survival (BCSS) for the entire cohort and within tumor grades. RESULTS: Of 23,932 patients with NMIBC identified, 22% received adjuvant intravesical BCG. Predictors of receipt were stages Tis and T1, higher grade, and urban residence. Age > 80 years, fewer than two comorbidities, and not being married were associated with decreased use. In the survival analysis, BCG use was associated with better OS (hazard ratio [HR], 0.87; 95% CI, 0.83 to 0.92) in the entire cohort and BCSS among higher-grade cancers (poorly differentiated: HR, 0.78; 95% CI, 0.72 to 0.85; undifferentiated: HR, 0.66; 95% CI, 0.56 to 0.77). CONCLUSION: Despite guidelines recommending its use, BCG is administered to less than one quarter of eligible patients. This large population-based study found improved OS and BCSS were associated with use of adjuvant intravesical BCG among older patients with NMIBC. Better-designed clinical trials focusing on higher-grade cancers are needed to confirm these findings. PMID- 23814518 TI - Collaborative practice models and team-based care in oncology. AB - Team-based care has been promoted as one essential component necessary for meeting the supply and demand imbalance in the workforce, and as well serving as a crucial element of improving health care delivery. PMID- 23814520 TI - Use of continuous infusion pumps during radiation treatment. AB - INTRODUCTION: Despite increasing chemoradiotherapy treatment, there is a paucity of information regarding the effects of radiation exposure on ambulatory infusion pumps used to deliver chemotherapy or other essential medications. The aim of this overview is to present the available evidence on this subject, heighten awareness within the clinical community, provide considerations for minimizing possible negative effects on patient care, and encourage the monitoring of infusion devices after exposure to radiation or electromagnetic interference. METHODS: Published literature was systematically searched using MEDLINE and EMBASE; gray literature was searched using Google and an environmental scan of relevant Web sites. A multidisciplinary working group reviewed the compiled evidence, and a draft of the document was sent to health professionals from various disciplines for an external review. RESULTS: Four reports and three manufacturer device alerts were identified that suggest a risk of pump malfunction as a result of radiation exposure. The estimated cumulative dose at which pump failure has been reported ranges from 28.5 to 42 Gy; however, additional clinical investigations should be undertaken. Pump relocation, pump shielding, and assessment of the pump after radiation exposure are most commonly suggested to minimize pump malfunction related to radiation exposure. A list of additional considerations is offered for those developing institution specific policies and procedures based on the available evidence and expert consensus. CONCLUSION: The varied and unpredictable results of radiation exposure on infusion devices suggest that additional testing should be carried out to determine the limits of dose exposure and to raise awareness around this patient safety issue. PMID- 23814519 TI - Acute kidney injury and bisphosphonate use in cancer: a report from the research on adverse drug events and reports (RADAR) project. AB - PURPOSE: To determine whether acute kidney injury (AKI) is identified within the US Food and Drug Administration's Adverse Events and Reporting System (FDA AERS) as an adverse event resulting from bisphosphonate (BP) use in cancer therapy. METHODS: A search of the FDA AERS records from January 1998 through June 2009 was performed; search terms were "renal problems" and all drug names for BPs. The search resulted in 2,091 reports. We analyzed for signals of disproportional association by calculating the proportional reporting ratio for zoledronic acid (ZOL) and pamidronate. Literature review of BP-associated renal injury within the cancer setting was conducted. RESULTS: Four hundred eighty cases of BP-associated acute kidney injury (AKI) were identified in patients with cancer. Two hundred ninety-eight patients (56%) were female; mean age was 66 +/- 10 years. Multiple myeloma (n = 220, 46%), breast cancer (n = 98, 20%), and prostate cancer (n = 24, 5%) were identified. Agents included ZOL (n = 411, 87.5%), pamidronate (n = 8, 17%), and alendronate (n = 36, 2%). Outcomes included hospitalization (n = 304, 63.3%) and death (n = 68, 14%). The proportional reporting ratio for ZOL was 1.22 (95% CI, 1.13 to 1.32) and for pamidronate was 1.55 (95% CI, 1.25 to 1.65), reflecting a nonsignificant safety signal for both drugs. CONCLUSION: AKI was identified in BP cancer clinical trials, although a safety signal for BPs and AKI within the FDA AERS was not detected. Our findings may be attributed, in part, to clinicians who believe that AKI occurs infrequently; ascribe the AKI to underlying premorbid disease, therapy, or cancer progression; or consider that AKI is a known adverse drug reaction of BPs and thus under-report AKI to the AERS. PMID- 23814521 TI - Ethical challenges: managing oncology drug shortages. AB - This vignette highlights the ethical issues surrounding restricted access to oncology drugs caused by drug shortages. A review of selected literature and a framework for creating institutional guidelines for reacting to shortage is provided. PMID- 23814522 TI - Assessment of risk evaluation and mitigation strategies in oncology: summary of the oncology risk evaluation and mitigation strategies workshop. AB - To address oncology community stakeholder concerns regarding implementation of the Risk Evaluation and Mitigation Strategies (REMS) program, ASCO sponsored a workshop to gather REMS experiences from representatives of professional societies, patient organizations, pharmaceutical companies, and the US Food and Drug Administration (FDA). Stakeholder presentations and topical panel discussions addressed REMS program development, implementation processes, and practice experiences, as well as oncology drug safety processes. A draft REMS decision tool prepared by the ASCO REMS Steering Committee was presented for group discussion with facilitated, goal-oriented feedback. THE WORKSHOP IDENTIFIED SEVERAL UNINTENDED CONSEQUENCES RESULTING FROM CURRENT ONCOLOGY REMS: (1) the release of personal health information to drug sponsors as a condition for gaining access to a needed drug; (2) risk information that is not tailored and therefore not accessible-to all literacy levels; (3) exclusive focus on drug risk, thereby affecting patient-provider treatment discussion; (4) REMS elements that do not consider existing, widely practiced oncology safety standards, professional training, and experience; and (5) administrative burdens that divert the health care team from direct patient care activities and, in some cases, could limit patient access to important therapies. Increased provider and professional society participation should form the basis of ongoing and future REMS standardization discussions with the FDA to work toward overall improvement of risk communication. PMID- 23814524 TI - Establishing a minority-based community clinical oncology program: the University of Medicine and Dentistry of New Jersey, New Jersey Medical School-university Hospital Cancer Center experience. AB - The Minority-Based Community Clinical Oncology Program (MB-CCOP) at University of Medicine and Dentistry of New Jersey, New Jersey Medical School-University Hospital Cancer Center was established to serve an unmet need in a medically, educationally, and socioeconomically underserved community of primarily African American and Latino patients in Newark and Essex County, New Jersey. The MB-CCOP was built on an existing infrastructure of multidisciplinary teams of cancer specialists who collaborated in patient care and an existing clinical research program, which included multilingual staff and a breast cancer navigator. This article highlights some of the unique opportunities and challenges involved in the startup of an MB-CCOP specifically relevant to an academic setting. We present a guide to the necessary infrastructure and institutional support that must be in place before considering such a program and some of the steps an institution can take to overcome barriers preventing successful enrollment of patients onto clinical trials. PMID- 23814523 TI - Enrollment of patients with lung and colorectal cancers onto clinical trials. AB - PURPOSE: Only 2% to 5% of adult patients with cancer enroll onto clinical trials. We assessed simultaneously characteristics of patients and their physicians that may be independently associated with participation. METHODS: CanCORS, a National Cancer Institute (NCI) -funded population-based observational cohort study of newly diagnosed patients with lung and colorectal cancers, sampled patients across five geographic areas, five health care delivery systems, and 15 Veterans Administration hospitals. We linked patient survey and medical record data with physician survey data to examine correlates of trial enrollment. RESULTS: Among 9,901 patients, 5.3% enrolled onto trials. Of the 9,901 patients, we linked 6,506 patients to one medical oncologist, surgeon, or radiation oncologist (physicians, N = 1,325) who responded to the physician survey and was considered their primary cancer clinician decision maker. Patient age, race, disease stage, geographic region, and health insurance were independently associated with trial enrollment. Physician factors independently associated with patient trial enrollment were being a medical oncologist, practicing at an NCI-designated cancer center, taking the lead in discussing trials with patients, and receiving increased income from trial enrollment. After simultaneously adjusting for patient and physician characteristics, only being a physician practicing at an NCI-designated cancer center (odds ratio [OR], 1.65; 95% CI, 1.19 to 2.27) and patient female sex (OR, 1.36; 95% CI, 1.10 to 1.68), age > 70 versus < 50 years (OR, 0.28; 95% CI, 0.16 to 0.48), and advanced disease (OR, 1.85; 95% CI, 1.45 to 2.37) remained independently associated with trial enrollment. CONCLUSION: Both practice environment and patient clinical and demographic characteristics are associated with cancer clinical trial enrollment; simultaneous intervention may be required when trying to increase enrollment rates. PMID- 23814525 TI - Early-phase clinical trials in the community: results from the national cancer institute community cancer centers program early-phase working group baseline assessment. AB - PURPOSE: The National Cancer Institute (NCI) Community Cancer Centers Program (NCCCP) formed an Early-Phase Working Group to facilitate site participation in early-phase (EP) trials. The Working Group conducted a baseline assessment (BA) to describe the sites' EP trial infrastructure and its association with accrual. METHODS: EP accrual and infrastructure data for the sites were obtained for July 2010-June 2011 and 2010, respectively. Sites with EP accrual rates at or above the median were considered high-accruing sites. Analyses were performed to identify site characteristics associated with higher accrual onto EP trials. RESULTS: Twenty-seven of the 30 NCCCP sites participated. The median number of EP trials open per site over the course of July 2010-June 2011 was 19. Median EP accrual per site was 14 patients in 1 year. Approximately half of the EP trials were Cooperative Group; most were phase II. Except for having a higher number of EP trials open (P = .04), high-accruing sites (n = 14) did not differ significantly from low-accruing sites (n = 13) in terms of any single site characteristic. High-accruing sites did have shorter institutional review board (IRB) turnaround time by 20 days, and were almost three times as likely to be a lead Community Clinical Oncology Program site (small sample size may have prevented statistical significance). Most sites had at least basic EP trial infrastructure. CONCLUSION: Community cancer centers are capable of conducting EP trials. Infrastructure and collaborations are critical components of success. This assessment provides useful information for implementing EP trials in the community. PMID- 23814526 TI - What currently defines a breast center? Initial data from the national accreditation program for breast centers. AB - PURPOSE: The definition of a "breast center" varies significantly, ranging from hospital-based or free-standing comprehensive programs to private subspecialty practices with patient resources in close proximity. This study analyzes the 2 year data of the National Accreditation Program for Breast Centers (NAPBC) to assess the demographics of the types of programs seeking breast center (BC) accreditation. The results of a postaccreditation survey are also analyzed. MATERIALS AND METHODS: All data (ie, Survey Application Record, on-site surveyors' reports, postaccreditation survey) for programs applying for accreditation between October 31, 2008, and October 31, 2010, were entered into a database at the American College of Surgeons headquarters. Analysis was conducted with SPSS v.19 and Microsoft Excel 2007. RESULTS: During the initial 2-year period, 238 centers were surveyed across 41 states. With regard to the 27 standards and 17 BC components, 68% of centers had no deficiencies, 28% had <= 10% deficiencies, 3% had deficiencies in 11% to 29% of standards, and 2% had >= 30% deficiencies. The most common standards with noncompliance were accreditation for ultrasound-guided biopsy (standard 11), stereotactic biopsy (standard 10), and accrual onto clinical trials (standard 3.2). The only BC component found to be absent was survivorship program (1%). Desciptive categories were as follows: 81.5% were hospital-based centers, 13.5% were free-standing facilities, 2.5% were group practices, and 3% were "other." There were no significant associations between descriptive category and full accreditation versus contingency or failure, or deficiencies in any one standard (all Ps > .05). On the basis of responses to the postaccreditation survey, 76% admitted making significant changes before the survey process. CONCLUSION: This initial analysis of the NAPBC 2-year data suggests that a wide variety of BC models adequately provide a high level of care and services for patients across the nation. PMID- 23814527 TI - The challenge of quality in breast care: beyond accreditation. PMID- 23814528 TI - Community-Acquired Clostridium Difficile Infection: Awareness and Clinical Implications. AB - The epidemiology of Clostridium difficile infection (CDI) is changing. CDI, usually depicted as a nosocomial infection in the elderly, is now occurring in community-dwelling persons who are younger and otherwise dissimilar. A more virulent isolate (North American Pulsed Field type 1 (NAP1) associated with increased morbidity and mortality, has been identified. In 2005, similar strains were associated with severe disease in community-dwelling patients at a rate of 7.6/100,000. Screening patients with potential CDI symptoms and implementing preventative measures, including judicious use of antibiotics, can reduce disease burden. PMID- 23814529 TI - The Vitamin D Receptor, Inflammatory Bowel Diseases, and Colon Cancer. AB - The nuclear receptor is an emerging therapeutic target in various human diseases. Vitamin D receptor (VDR), a nuclear receptor, mediates the biological functions of vitamin D. Classically, vitamin D is recognized as an essential contributor to mineral and bone homeostasis. Increasing evidence demonstrates that vitamin D is involved in inflammatory responses. Persistent intestinal inflammation is associated with colon cancer. This review focuses on vitamin D and VDR in inflammatory bowel diseases and colon cancer. We place emphasis on the regulatory roles of vitamin D/VDR on in inflammation, enteric bacteria, and tumorigenesis. We summarize the signaling pathways regulated by VDR in intestinal homeostasis. Finally, we discuss the potential application of the insights gleaned from these findings to personalized therapies in chronic inflammation and colon cancer. PMID- 23814532 TI - EDITORIAL: Advances in Dystonia. PMID- 23814531 TI - Gambling in the Iranian-American Community and an Assessment of Motives: A Case Study. AB - Nearly half a million United States residents identify themselves as being of Iranian origin, and many in this population are of high socioeconomic status. Although games of chance have been a notable part of Iranian culture for thousands of years, there is almost no research exploring gambling in this population. The objective of this case study is to explore gambling pathology, gambling behavior, and gambling motives among Iranian-Americans using a convenience sample (N=182) at a September 2010 Iranian festival in Southern California. Of this sample, 20% (n=37) and 7% (n=13) screened positive for problem and pathological gambling, respectively. According to the Gambling Motives Questionnaire, enhancement was the preferred motive for gambling ("because you like the feeling, because it's exciting, to get a high feeling, because it's fun, because it makes you feel good"). Pathological gamblers showed a considerable difference in subscale scores between enhancement and either coping or social motives, and problem gamblers showed a considerable difference between enhancement and coping motives. Possible explanations for the higher prevalence of gambling disorders in this sample are discussed. Our results support the notion that underlying cultural factors play a role in the development of gambling disorders. PMID- 23814530 TI - Prevention and Treatment of Colorectal Cancer by Natural Agents From Mother Nature. AB - Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the United States after cancers of the lung and the breast/prostate. While the incidence of CRC in the United States is among the highest in the world (approximately 52/100,000), its incidence in countries in India is among the lowest (approximately 7/100,000), suggesting that lifestyle factors may play a role in development of the disease. Whereas obesity, excessive alcohol consumption, a high-calorie diet, and a lack of physical activity promote this cancer, evidence indicates that foods containing folates, selenium, Vitamin D, dietary fiber, garlic, milk, calcium, spices, vegetables, and fruits are protective against CRC in humans. Numerous agents from "mother nature" (also called "nutraceuticals,") that have potential to both prevent and treat CRC have been identified. The most significant discoveries relate to compounds such as cardamonin, celastrol, curcumin, deguelin, diosgenin, thymoquinone, tocotrienol, ursolic acid, and zerumbone. Unlike pharmaceutical drugs, these agents modulate multiple targets, including transcription factors, growth factors, tumor cell survival factors, inflammatory pathways, and invasion and angiogenesis linked closely to CRC. We describe the potential of these dietary agents to suppress the growth of human CRC cells in culture and to inhibit tumor growth in animal models. We also describe clinical trials in which these agents have been tested for efficacy in humans. Because of their safety and affordability, these nutraceuticals provide a novel opportunity for treatment of CRC, an "old age" disease with an "age old" solution. PMID- 23814533 TI - Imaging studies in focal dystonias: a systems level approach to studying a systems level disorder. AB - Focal dystonias are dystonias that affect one part of the body, and are sometimes task-specific. Brain imaging and transcranial magnetic stimulation techniques have been valuable in defining the pathophysiology of dystonias in general, and are particularly amenable to studying focal dystonias. Over the past few years, several common themes have emerged in the imaging literature, and this review summarizes these findings and suggests some ways in which these distinct themes might all point to one common systems-level mechanism for dystonia. These themes include (1) the role of premotor regions in focal dystonia, (2) the role of the sensory system and sensorimotor integration in focal dystonia, (3) the role of decreased inhibition/increased excitation in focal dystonia, and (4) the role of brain imaging in evaluating and guiding treatment of focal dystonias. The data across these themes, together with the features of dystonia itself, are consistent with a hypothesis that all dystonias reflect excessive output of postural control/stabilization systems in the brain, and that the mechanisms for dystonia reflect amplification of an existing functional system, rather than recruitment of the wrong motor programs. Imaging is currently being used to test treatment effectiveness, and to visually guide treatment of dystonia, such as placement of deep brain stimulation electrodes. In the future, it is hoped that imaging may be used to individualize treatments across behavioral, pharmacologic, and surgical domains, thus optimizing both the speed and effectiveness of treatment for any given individual with focal dystonia. PMID- 23814534 TI - Invertebrate models of dystonia. AB - The neurological movement disorder dystonia is an umbrella term for a heterogeneous group of related conditions where at least 20 monogenic forms have been identified. Despite the substantial advances resulting from the identification of these loci, the function of many DYT gene products remains unclear. Comparative genomics using simple animal models to examine the evolutionarily conserved functional relationships with monogenic dystonias represents a rapid route toward a comprehensive understanding of these movement disorders. Current studies using the invertebrate animal models Caenorhabditis elegans and Drosophila melanogaster are uncovering cellular functions and mechanisms associated with mutant forms of the well-conserved gene products corresponding to DYT1, DYT5a, DYT5b, and DYT12 dystonias. Here we review recent findings from the invertebrate literature pertaining to molecular mechanisms of these gene products, torsinA, GTP cyclohydrolase I, tyrosine hydroxylase, and the alpha subunit of Na+/K ATPase, respectively. In each study, the application of powerful genetic tools developed over decades of intensive work with both of these invertebrate systems has led to mechanistic insights into these human disorders. These models are particularly amenable to large-scale genetic screens for modifiers or additional alleles, which are bolstering our understanding of the molecular functions associated with these gene products. Moreover, the use of invertebrate models for the evaluation of DYT genetic loci and their genetic interaction networks has predictive value and can provide a path forward for therapeutic intervention. PMID- 23814535 TI - Recent advances in the molecular pathogenesis of dystonia-plus syndromes and heredodegenerative dystonias. AB - The majority of studies investigating the molecular pathogenesis and cell biology underlying dystonia have been performed in individuals with primary dystonia. This includes monogenic forms such as DYT1and DYT6 dystonia, and primary focal dystonia which is likely to be multifactorial in origin. In recent years there has been renewed interest in non-primary forms of dystonia including the dystonia plus syndromes and heredodegenerative disorders. These are caused by a variety of genetic mutations and their study has contributed to our understanding of the neuronal dysfunction that leads to dystonia These findings have reinforced themes identified from study of primary dystonia including abnormal dopaminergic signalling, cellular trafficking and mitochondrial function. In this review we highlight recent advances in the understanding of the dystonia-plus syndromes and heredodegenerative dystonias. PMID- 23814536 TI - Motor and Sensory Dysfunction in Musician's Dystonia. AB - Musicians' dystonia is a task-specific and painless loss of motor control in a previously well-executed task. It is increasingly recognized in the medical and musical community. Recent advances in neuroimaging, transcranial magnetic stimulation and novel techniques in electroencephalography have shed light on its underlying pathophysiology. To date, a deranged cortical plasticity leading to abnormal sensorimotor integration, combined with reduced inhibition across several levels of the motor pathway are likely mechanisms.This paper reviews the various phenomenology of musician's dystonia across keyboard, string, brass, flute and drum players. Treatment is often challenging. Medical therapies like botulinum toxin injection and rehabilitation method with sensorimotor training offer symptomatic relief and return to baseline performance to some musicians. PMID- 23814537 TI - Defining dystonic tremor. AB - A strong association between dystonia and tremor has been known for more than a century. Two forms of tremor in dystonia are currently recognized: 1) dystonic tremor, which is tremor produced by dystonic muscle contraction and 2) tremor associated with dystonia, which is tremor in a body part that is not dystonic, but there is dystonia elsewhere. Both forms of tremor in dystonia frequently resemble essential tremor or another pure tremor syndrome (e.g., isolated head and voice tremors and task-specific writing tremor), and relationships among these tremor disorders have long been debated. Misdiagnosis is common because mild dystonia is frequently overlooked in patients with tremor. It is now clear that essential tremor is a syndrome, not a specific disease, and the use of essential tremor as a specific clinical diagnosis is arguably an impediment to elucidating this and other pure tremor syndromes and their relationship to dystonia. A new classification, primary tremor, is proposed and would be used for any disorder in which tremor is the sole or principal abnormality with no identifiable etiology other than possible genetic inheritance. This classification scheme would facilitate tremor research by moving the focus from the narrow question "Is it essential tremor?" to a broader consideration of what genetic and environmental factors cause primary tremor disorders, and how do they relate to dystonia and other neurological disorders. PMID- 23814538 TI - Animal models for investigating benign essential blepharospasm. AB - The focal dystonia benign essential blepharospasm (BEB) affects as many as 40,000 individuals in the United States. This dystonia is characterized by trigeminal hyperexcitability, photophobia, and most disabling of the symptoms, involuntary spasms of lid closure that can produce functional blindness. Like many focal dystonias, BEB appears to develop from the interaction between a predisposing condition and an environmental trigger. The primary treatment for blepharospasm is to weaken the eyelid-closing orbicularis oculi muscle to reduce lid spasms. There are several animal models of blepharospasm that recreate the spasms of lid closure in order to investigate pharmacological treatments to prevent spasms of lid closure. One animal model attempts to mimic the predisposing condition and environmental trigger that give rise to BEB. This model indicates that abnormal interactions among trigeminal blink circuits, basal ganglia, and the cerebellum are the neural basis for BEB. PMID- 23814541 TI - The Neuropeptide Systems and their Potential Role in the Treatment of Mammalian Retinal Ischemia: A Developing Story. AB - The multiplicity of peptidergic receptors and of the transduction pathways they activate offers the possibility of important advances in the development of specific drugs for clinical treatment of central nervous system disorders. Among them, retinal ischemia is a common clinical entity and, due to relatively ineffective treatment, remains a common cause of visual impairment and blindness. Ischemia is a primary cause of neuronal death, and it can be considered as a sort of final common pathway in retinal diseases leading to irreversible morphological damage and vision loss. Neuropeptides and their receptors are widely expressed in mammalian retinas, where they exert multifaceted functions both during development and in the mature animal. In particular, in recent years somatostatin and pituitary adenylate cyclase activating peptide have been reported to be highly protective against retinal cell death caused by ischemia, while data on opioid peptides, angiotensin II, and other peptides have also been published. This review provides a rationale for harnessing the peptidergic receptors as a potential target against retinal neuronal damages which occur during ischemic retinopathies. PMID- 23814542 TI - Pharmacological Treatment of Mild Cognitive Impairment as a Prodromal Syndrome of Alzheimer's Disease. AB - Mild cognitive impairment (MCI) is a syndrome which, depending on various neurobiological, psychological and social factors, carries a high risk of developing into dementia. As far as diagnostic uncertainty and the heterogeneous underlying pathophysiological mechanisms are concerned, only limited therapeutic options are currently available. Clinical trials involving a wide range of substances have failed to show efficacy on primary and secondary outcome parameters. Most results reflect not only a lack of effectiveness of drug therapy but also methodological constraints in true prodromal Alzheimer's disease (AD) based on clinical criteria. Biomarkers may help to identify MCI as a prodromal phase of dementia, so it is important to use them to improve specificity of case selection in future studies. For MCI as a prodromal syndrome of AD, clinical trials with disease modifying drugs that target underlying pathological mechanisms such as amyloid-beta accumulation and neurofibrillary tangle formation may help develop effective treatment options in the future. Alternative pharmacological approaches are currently being evaluated in ongoing phase 1 and phase 2 studies. Nevertheless, a lack of approved pharmacotherapeutic options has led to specific interventions that focus on patient education and life-style related factors receiving increasing attention. PMID- 23814543 TI - The Effects of Psychopharmacologic and Therapeutic Approaches on Neuro-imaging in Obsessive-compulsive Disorder. AB - The neurobiological etiopathogenesis of OCD is still obscure. Neuroimaging studies have been very influential in shaping neurobiological models of OCD. Investigations performed within last twenty years have revealed some important findings and proposed that specific cortico-striato-thalamic circuits are involved in the mediation of its symptoms. The effects of antiobsessional drugs and cognitive behavioral therapy on structural and functional imaging have been evaluated in limited size of investigations. In structural investigations, in summary, it was found key brain regions in the pathophysiology of OCD and amygdala to change volumetrically by treatment. In functional and neurochemical investigations, by using different treatment modalities, cortico-striatal function disablements and NAA changes in a variety of brain regions were reported. In this paper, these limited data are reviewed. It is clear that there is so many things to be performed in the future researches on the effects of therapy on brains of the patients with OCD. PMID- 23814539 TI - Genetics and Pathophysiology of Neurodegeneration with Brain Iron Accumulation (NBIA). AB - Our understanding of the syndromes of Neurodegeneration with Brain Iron Accumulation (NBIA) continues to grow considerably. In addition to the core syndromes of pantothenate kinase-associated neurodegeneration (PKAN, NBIA1) and PLA2G6-associated neurodegeneration (PLAN, NBIA2), several other genetic causes have been identified (including FA2H, C19orf12, ATP13A2, CP and FTL). In parallel, the clinical and pathological spectrum has broadened and new age dependent presentations are being described. There is also growing recognition of overlap between the different NBIA disorders and other diseases including spastic paraplegias, leukodystrophies and neuronal ceroid lipofuscinosis which makes a diagnosis solely based on clinical findings challenging. Autopsy examination of genetically-confirmed cases demonstrates Lewy bodies, neurofibrillary tangles, and other hallmarks of apparently distinct neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease. Until we disentangle the various NBIA genes and their related pathways and move towards pathogenesis targeted therapies, the treatment remains symptomatic. Our aim here is to provide an overview of historical developments of research into iron metabolism and its relevance in neurodegenerative disorders. We then focus on clinical features and investigational findings in NBIA and summarize therapeutic results reviewing reports of iron chelation therapy and deep brain stimulation. We also discuss genetic and molecular underpinnings of the NBIA syndromes. PMID- 23814540 TI - The effects of locus coeruleus and norepinephrine in methamphetamine toxicity. AB - The activity of locus coeruleus (LC) neurons has been extensively investigated in a variety of behavioural states. In fact this norepinephrine (NE)-containing nucleus modulates many physiological and pathological conditions including the sleep-waking cycle, movement disorders, mood alterations, convulsive seizures, and the effects of drugs such as psychostimulants and opioids. This review focuses on the modulation exerted by central NE pathways on the behavioural and neurotoxic effects produced by the psychostimulant methamphetamine, essentially the modulation of the activity of mesencephalic dopamine (DA) neurons. In fact, although NE in itself mediates some behavioural effects induced by methamphetamine, NE modulation of DA release is pivotal for methamphetamine induced behavioural states and neurotoxicity. These interactions are discussed on the basis of the state of the art of the functional neuroanatomy of central NE- and DA systems. Emphasis is given to those brain sites possessing a remarkable overlapping of both neurotransmitters. PMID- 23814545 TI - Drinking Patterns, Gender and Health II: Predictors of Preventive Service Use. AB - BACKGROUND: Chronic diseases and injuries are elevated among people with substance use problems/dependence, yet heavier drinkers use fewer routine and preventive health services than non-drinkers and moderate drinkers, while former drinkers and abstainers use more than moderate drinkers. Researchers hypothesize that drinking clusters with attitudes and practices that produce better health among moderate drinkers and that heavy drinkers avoid doctors until becoming ill, subsequently quitting and using more services. Gender differences in alcohol consumption, health-related attitudes, practices, and prevention-services use may affect these relationships. METHODS: A stratified random sample of health-plan members (7884; 2995 males, 4889 females) completed a mail survey that was linked to 24 months of health-plan records. Data were used to examine relationships between alcohol use, gender, health-related attitudes/practices, health, and prevention-service use. RESULTS: Controlling for attitudes, practices, and health, female lifelong abstainers and former drinkers were less likely to have mammograms; individuals with alcohol use disorders and positive AUDIT scores were less likely to obtain influenza vaccinations. AUDIT-positive women were less likely to undergo colorectal screening than AUDIT-positive men. Consistent predictors of prevention-services use were: self-report of having a primary care provider (positive); disliking visiting the doctor (negative); smoking cigarettes (negative), and higher BMI (negative). CONCLUSIONS: When factors associated with drinking are controlled, patterns of alcohol consumption have limited effects on preventive service use. Individuals with stigmatized behaviors (e.g., hazardous/harmful drinking, smoking, or high BMIs) are less likely to receive care. Making care experiences positive and carefully addressing stigmatized health practices could increase preventive service use. PMID- 23814546 TI - Struggling with growing bodies within silence and denial: Perspectives of HIV and AIDS among youth in Rural Zimbabwe. AB - Concerns regarding HIV and AIDS were elicited from 546 school youth (51% female, age range 9-25 years) in a Zimbabwean rural district, through a self-generated question writing process. Concerns emerged around how to avoid infection at a time when they were undergoing secondary sexual development, had growing feelings for love and were even engaging in sexual activity, but had limited access to preventive methods due to denial by the adult world. Fears were expressed regarding how to tell one's HIV status, even just after sex. HIV and AIDS were visualised in terms of suffering, loneliness, quarantine and death. The youth stressed they would have difficulties communicating with other people should they suspect or find they are infected with HIV, as this would imply they had been sexually active. They seemed to have knowledge around HIV and AIDS that either was incomplete, or they could not apply given a context of silence and denial around their sexuality. Some of the knowledge was coloured with misconceptions, suggesting contradictory information from multiple sources. After more than two decades, the scenario portrayed raises questions about interventions targeting young people. The question is why is their situation in this state when several stakeholders are actively participating in debates and interventions around their well-being? Campaigns and interventions may need to consider young people's complex social contexts, the factors generating and sustaining their situation, and what role diverse actors and social change processes play in this. PMID- 23814544 TI - Modulation of Immunity and the Inflammatory Response: A New Target for Treating Drug-resistant Epilepsy. AB - Until recently, epilepsy medical therapy is usually limited to anti-epileptic drugs (AEDs). However, approximately 1/3 of epilepsy patients, described as drug resistant epilepsy (DRE) patients, still suffer from continuous frequent seizures despite receiving adequate AEDs treatment of sufficient duration. More recently, with the remarkable progress of immunology, immunity and inflammation are considered to be key elements of the pathobiology of epilepsy. Activation of inflammatory processes in brain tissue has been observed in both experimental seizure animal models and epilepsy patients. Anti-inflammatory and immunotherapies also showed significant anticonvulsant properties both in clinical and in experimental settings. The above emerging evidence indicates that modulation of immunity and inflammatory processes could serve as novel specific targets to achieve potential anticonvulsant effects for the patients with epilepsy, especially DRE. Herein we review the recent evidence supporting the role of inflammation in the development and perpetuation of seizures, and also discuss the recent achievements in modulation of inflammation and immunotherapy applied to the treatment of epilepsy. Apart from medical therapy, we also discuss the influences of surgery, ketogenic diet, and electroconvulsive therapy on immunity and inflammation in DRE patients. Taken together, a promising perspective is suggested for future immunomodulatory therapies in the treatment of patients with DRE. PMID- 23814547 TI - Pushing Back the Origin of Bantu Lexicography: The Vocabularium Congense of 1652, 1928, 2012. AB - In this article, the oldest Bantu dictionary hitherto known is explored, that is the Vocabularium Latinum, Hispanicum, e Congense, handed down to us through a manuscript from 1652 by the Flemish Capuchin Joris van Gheel, missionary in the Kongo (present-day north-western Angola and the southern part of the Lower Congo Province of the DRC). The manuscript was heavily reworked by the Belgian Jesuits Joseph van Wing and Constant Penders, and published in 1928. Both works are currently being digitized, linked and added to an interlingual and multimedia database that revolves around Kikongo and the early history of the Kongo kingdom. In Sections 1 and 2 the origins of Bantu lexicography in general and of Kikongo metalexicography in particular are revisited. Sections 3 and 4 are devoted to a study of Van Gheel's manuscript and an analysis of Van Wing and Penders' rework. In Sections 5 and 6 translation equivalence and lexicographical structure in both dictionaries are scrutinized and compared. In Section 7, finally, all the material is brought together. PMID- 23814548 TI - Prevalence of congenitally missing permanent teeth in Iran. AB - BACKGROUND: Hypodontia or congenitally missing teeth is among dental anomalies with different prevalence in each region. The aim of this study was to evaluate the prevalence of congenitally missing permanent teeth in Iranian population. MATERIALS AND METHODS: A descriptive, retrospective and cross-sectional study was done. Panoramic radiographs of 2422 Iranian patients (1539 girls and 883 boys), 7 25 years old, were collected. The radiographs were studied for evidence of congenitally missing teeth. Data were analyzed using Paired t-test, Mann-Whitney test, Fisher exact test and Chi-square test (alpha = 0.05). RESULTS: Prevalence of congenitally missing teeth was totally 45.7% and 34.8% for third molars. The most frequent congenitally missing teeth was mandibular second premolars (23.34%) followed by maxillary second premolars (22.02%). Upper jaw showed significantly higher number of congenitally missing teeth (P value < 0.001). According to Chi square test, congenital missing teeth was found approximately 10.9% in both females and males and there were no statistically significant difference between sexes (P = 0.19). CONCLUSION: The prevalence of congenitally missing teeth (CMT) in Iranian permanent dentition was 10.9%. The most common congenitally missing teeth were mandibular second premolar fallowed by maxillary second premolars. PMID- 23814549 TI - Ghost cells: A journey in the dark.... AB - Ghost cells have been a topic of controversy since a long time. The appearance of these cells in different lesions has given it varying terms. In lesions like that of Calcifying cystic odontogenic tumor (CCOT), these cells have been termed as 'Ghost cells' whereas similar descriptive cells have been called shadow/translucent cells in non-odontogenic lesions like Craniopharyngiomas of the pituitary gland and Pilomatricomas of skin. Controversy arises because of the fact that there are varying opinions and incomplete knowledge about their origin, nature, significance and relation in different neoplasms. Irrespective of the origin, these cells are seen in odontogenic and non-odontogenic neoplasms, which probably direct us towards a missing link between these differing neoplasms. This article attempts to present a review on the concepts around these peculiar cells and shed some light on these ghosts that are still in dark. PMID- 23814550 TI - Effect of smoking on oral pigmentation and its relationship with periodontal status. AB - BACKGROUND: To assess the effect of smoking on lip and gingival pigmentation and also to assess the relationship of pigmentation with periodontal parameters. MATERIALS AND METHODS: 109 smokers and an equal number of control subjects who were nonsmokers in the age range of 35 - 44 years comprised the study sample. All the participants were assessed for pigmentation on lip and gingiva and a total periodontal status examination was done with measurements on gingival bleeding, probing depth and loss of attachment at six points in each tooth. RESULTS: Melanin pigmentation on lips and gingiva was observed in all the smokers except for one who did not exhibit gingival pigmentation. Significantly greater number of smokers exhibited pigmentation than nonsmokers. Gingival bleeding on probing, probing depth and loss of attachment differed significantly in relation to gingival and lip pigmentation. CONCLUSIONS: Oral pigmentation was widespread and more commonly observed in smokers than nonsmokers and there was a relationship between pigmentation and periodontal deterioration. PMID- 23814551 TI - Adenoid cystic carcinoma of the mobile tongue: A rare case. AB - Adenoid cystic carcinoma (ACC) occurs more commonly in the minor salivary glands of the palate on than the tongue. ACC is a malignant neoplasm that accounts for 1 2% of all head and neck malignancies and 10-15% of all salivary gland malignancies. ACC affects the exocrine glands at any site, but the parotid gland is the most common site in the head and neck region. Many factors should be taken into account in the prognosis of ACC, including the histological and clinical stages of the disease. The most striking feature of ACC is that it is locally aggressive, with a high recurrence level, perineural invasion and distant metastases, especially to the lungs and bones. The most common presentation histologically is the presence of cribriform appearance (Swiss cheese pattern). The present case is a rare one present on the tongue. PMID- 23814552 TI - Mandibular intraosseous schwannoma in a child: Report of a rare case. AB - Intraosseous schwannomas is a very rare neoplasm, and less than 50 cases have been reported in the medical literature. In this article, the clinical, radiographic and histopathologic appearances of a rare case of intraosseous schwannomas are presented. The importance of this case is that other benign central lesions such as odontogenic tumors and cysts might be included in differential diagnosis. This case was recognized in a 9-year-old child, which is a very rare occurrence. The diagnosis was confirmed by immunohistochemical staining with S100 protein. PMID- 23814553 TI - Strawberry gingivitis: A diagnostic feature of gingival Wegener's granulomatosis! AB - Wegener's granulomatosis (WG) is an immunologically mediated inflammatory disease characterized by granulomatous vasculitis of the upper and lower aerodigestive tracts together with glomerulonephritis. We are reporting a rare case of gingival WG that presented with erythematous and painful generalized gingival enlargement. Correlation of histopathology with routine hematoxylin and eosin and special stains [Grocott-Gomori methenamine-silver nitrate and Periodic Acid Schiff (PAS)], Mantoux test, peripheral blood smear and clinical presentation were established in diagnosing this rare entity. By the above-mentioned procedures and methodology, we have arrived at the diagnosis of Wegner's granulomatosis limited to the upper aerodigestive tract. Therefore, the aim of reporting this case was to emphasize that, the dental surgeon often being the first person to examine the oral cavity, should be familiar with the typical appearance of gingival WG as "strawberry gingivitis," its clinical course as well as diagnostic parameters and adequate management. To the best of our knowledge, this is the first reported case of WG manifesting as "strawberry gingivitis" in the Indian population. PMID- 23814554 TI - Metastatic anaplastic large cell lymphoma of the oral cavity. AB - Lymphoma is a malignant neoplasm of lymphoid tissue which is divided into 2 groups: Hodgkin and non-Hodgkin. About 85% of non-Hodgkin lymphomas are B-cell lymphomas, and T-cell lymphomas are unusual. Anaplastic large cell lymphoma (ALCL) is a kind of non-Hodgkin lymphoma with T or NK cell origin that is rarely seen in the oral cavity and only 10 cases have been reported up to now. Here we present a case of ALCL metastasized to the oral cavity in a 32- year- old man with pervious history of ALCL which caused an ulceration in the posterior area of the hard palate. Radiography showed irregular resorption of alveolar bone. Histopathologic examination of the incisional biopsy revealed neoplastic proliferation of large and bizarre cells with hyperchromatic nuclei and numerous giant cells and atypical mitoses. Immunohistochemistry markers (CK, LCA, CD3, CD30, CD20) confirmed the diagnosis of ALCL. PMID- 23814555 TI - Bilateral bifid mandibular canal. AB - One of the normal interesting variations that we may encounter in the mandible is bifid mandibular canal. This condition can lead to difficulties when performing mandibular anesthesia or during extraction of lower third molar, placement of implants, and surgery in the mandible. Therefore diagnosis of this variation is sometimes very important and necessary. PMID- 23814556 TI - Congenital granular cell epulis of a newborn. AB - The congenital granular cell epulis (CGCE) is a rare tumor, which is apparent at birth. The histogenesis is still uncertain, but several theories, including origin from epithelial, undifferentiated mesenchymal cells, pericytes, fibroblasts, smooth muscle cells, and nerve-related cells have been proposed. This case report describes management of a 2-day-old baby girl having a large, round, soft, single 3 * 4 cm, pedunculated swelling, on the lower anterior ridge, which was causing difficulty in feeding. Clinical diagnosis of congenital epulis (CE) was made and lesion was excised under conscious sedation. A vessel running over the surface of the lesion was continuous on the alveolar ridge. To reduce intra-operative hemorrhage transfixion suture was passed around the vessel on the alveolar ridge. Then the lesion was excised from the base of peduncle with a scalpel. Histopathologically, the diagnosis of a congenital granular cell lesion of the jaw was given. Follow up of 3 months shows no signs of recurrence. CGCE may interfere with feeding, requiring a conservative excision as soon as the child is fit to undergo surgery. Tendency for recurrence and malignant transformation has not been documented. PMID- 23814557 TI - Salivary Pacemakers: A review. AB - Xerostomia is the medical term for the subjective complaint of dry mouth due to a lack of saliva. Xerostomia is sometimes colloquially called pasties, cottonmouth, drooth, doughmouth or des (like a desert). Several diseases, treatments and medications can cause xerostomia. It is also common in smokers. Treatment of xerostomia is a common clinical challenge in the oral medicine practice. Although some treatments have been used to improve the symptoms of xerostomia, none is completely satisfactory for the patients who suffer of this alteration. This review is aimed at presenting new developments for the treatment of xerostomia. PMID- 23814558 TI - The relation of pericoronal third molar follicle dimension and bcl-2/ki-67 expression: An immunohistochemical study. AB - BACKGROUND: Most common impacted teeth are the mandibular third molars and decision about extraction of them is usually controversial. The presence of pericoronal pathologic changes is an acceptable reason for removal of impacted teeth. Differences in the proliferation rate and apoptosis of odontogenic epithelial cells may influence on the formation of odontogenic epithelial lesions. Therefore, the aim of the present study is to evaluate the immunohistochemical expression of the bcl-2 apoptosis-inhibiting protein and the cell-cycle-related ki-67 antigen in pericoronal follicle of impacted third molars with >=2.5 mm and <2.5 mm radiolucency. MATERIALS AND METHODS: This was a cross sectional study that 20 follicles with <2.5 mm radiolucency and 20 follicles with >=2.5 mm radiolucency were selected by a professional radiologist in digital panoramic radiographs and then referred to a surgeon. Formalin fixed paraffin embedded tissues were immunohistochemical analyzed for immunoreactivity of bcl-2 protein and ki-67 antigen. The data was analyzed using logistic regression, Spearman correlation coefficient and t-test and Mann-Whitney. P<0.05 was considered significant. RESULTS: The findings showed correlation between size of the third molar's follicles and expression of bcl-2 protein (P < 0.001, r = 0.556) but there was no correlation between size of third molar's follicles and staining with ki-67 antigen (P = 0.546, r = 0.098). The follicles with radiolucency >=2.5 mm showed increased immunoreactivity for bcl-2 protein. CONCLUSION: The results of study suggest that impacted third molars with radiolucency >=2.5 mm may be associated with deregulation of cell death, indicated with increased expression of the anti- apoptotic protein bcl-2, while cell proliferation (ki-67) does not seem to play a significant role. PMID- 23814559 TI - A radiographic evaluation of temporomandibular and hand (Metacarpophalangeal) / wrist joints of patients with adult rheumatoid arthritis. AB - BACKGROUND: A review of literature revealed that, although the involvement of temporomandibular joint (TMJ) in rheumatoid arthritis (RA) patients is not uncommon, variation in presentation persist. Comparative studies of bony changes in the right and left TMJ with the right and left peripheral hand (Metacarpophalangeal-MCP)/wrist joints have not been done, to the best of our knowledge. MATERIALS AND METHODS: In this cross-sectional study, the temporomandibular and hand (MCP) and wrist joints of fifteen rheumatoid arthritis patients were evaluated with questionnaires, clinical and lab assessment and radiographically using conventional radiographs and computed tomography. Students t-test was applied for the statistical analysis of the data obtained and a P value of 0.05 was considered as statistically significant. RESULTS: Comparisons between the right TMJ with right MCP/wrist joint and left TMJ with left MCP/wrist joint did not reveal statistically significant results. Radiographically, flattening and erosions were the common manifestations. MCP joints were more affected than the wrist, but whenever the wrist was involved, it was more likely to be bilaterally affected. CONCLUSIONS: Although the TMJ showed osseous changes of a higher grade than the hand (MCP) and wrist joints radiographically, it was observed that patients were more aware of the peripheral joint discomfort. There were no significant differences between TMJ and peripheral joints on both right and left sides. PMID- 23814560 TI - Comparative study of TGF-alpha and P53 markers' expression in odontogenic keratocyst and orthokeratinaized odontogenic cyst. AB - BACKGROUND: Odontogenic keratocyst (OKC) is an aggressive cyst and its recurrence is higher than other odontogenic cysts, orthokeratinized odontogenic cyst (OOC) is a cyst with moderate biological behavior in comparison with OKC, but with the probability of carcinomatous changes. The present study aims to evaluate the quantity and intensity of the expression of P53 protein and transforming growth factor alpha (TGF-alpha) in OKC and OOC in order to compare the biologic behavior of these two cysts. MATERIALS AND METHODS: This is a cross-sectional study. The samples include 30 cysts (15 OKC and 15 OOC), all stained immunohistochemically for P53 protein and TGF-alpha by the Novolinke polymer method. Then, all the cases were examined with an optical microscope with Chi400 magnification and the stained cells were counted in the basal and parabasal layers. Finally the results were analyzed by the Mann-and Wilcoxon tests (P value < 0.05). RESULTS: The difference between the expression of P53 protein in the basal layer in OKC and OOC was not statistically significant (P value = 0.076). The difference between the expression of P53 protein in the parabasal layer in OKC and OOC was statistically significant (P value = 0.003); moreover, the difference between the expression of TGF-alpha in the basal layer in OKC and OOC was not statistically significant (P value = 0.284). The difference between the expression of TGF-alpha in the parabasal layer in OKC and OOC was statistically significant (P value = 0.015). CONCLUSION: Since there was a higher expression of P53 protein and TGF alpha in OKC compared to those in OOC, the probability of carcinomatous changes was at least theoretically higher in OKC than in OOC. PMID- 23814561 TI - Assessing the anatomical variations of lingual foramen and its bony canals with CBCT taken from 102 patients in Isfahan. AB - BACKGROUND: Some studies have been performed on assessing the anatomical variations of lingual foramen and its bony canals, in many different countries but no study has been performed in Iran yet. The purpose of this study is to assess the anatomical variations of lingual foramen and its bony canals with cone beam computed tomography (CBCT) imaging in Isfahan. MATERIALS AND METHODS: This was a cross-sectional study in which CBCT images taken from 102 patients referred to the Radiology Department of Head and Neck in Esfahan (Iran) University between 2010 and 2011. The presence of the lingual foramen and its bony canals, the locations, sizes, and length were assessed. The distances between the terminal end of lingual canal at the buccal and lingual side from the inferior border of the mandible and alveolar crest were measured. We also evaluated the effect of patient age and gender on the dimensional measurements of the anatomical landmark mentioned above t test, analysis of variance (ANOVA), and pearson's correlation were used for statistical analysis and P value lower than 0.05 was considered significant. RESULT: All of the CBCT images taken showed the presence of lingual foramen. Of all the participants, 52% of them had two foramens in their images. The mean diameters of the upper and lower lingual foramen were 1.12 and 0.9 mm, respectively. CONCLUSION: These anatomical landmarks in Isfahan population vary from previous studies. All of the images had at least one lingual foramen which demonstrates high prevalence of this anatomy among Isfehanian population. Therefore, it is recommended to use CBCT imaging for preoperative evaluation prior to installing dental implants. PMID- 23814562 TI - Relationship between the elongated styloid process in panoramic radiographs and some of the general health conditions in patients over 40 years of age in the Iranian population. AB - BACKGROUND: The styloid process and the attached ligaments have the potential for calcification and ossification in specific conditions. The purpose of this study was to evaluate the relationship between the elongated styloid process (ESP) frequency and some of the systemic health factors of patients over 40 years of age. MATERIALS AND METHODS: In this analytical-descriptive study, 296 panoramic radiographs of patients over 40 years of age (165 female and 131 male) referred to the Dental School of Khorasgan Azad University were selected. The length of the styloid process was measured by a special ruler and recorded in a questionnaire form. Other data such as sex, age, height, weight, blood pressure, heartbeat and the number of teeth present in the mouth were also recorded. The lengths equal to or more than 30 mm on the radiographs were considered as ESP. Data analysis were done by independent t-test, Pearson correlation coefficient and Chi-square test at a significance level of < 0.05. RESULTS: ESP was observed in 135 cases (45.6%). There was a significant relationship between ESP and the body height, weight and the blood pressure, but there was no significant correlation between ESP, the heartbeat and the number of teeth present in the mouth. CONCLUSION: Because of the significant relationship between the length of the styloid process and the blood pressure, height and weight it is reasonable to evaluate a patient's systemic health conditions when radiographic signs of ESP are observed. PMID- 23814563 TI - Analysis of linear measurement accuracy obtained by cone beam computed tomography (CBCT-NewTom VG). AB - BACKGROUND: One of the major uses of cone beam computed tomography (CBCT) is presurgical implant planning. Linear measurement is used for the determination of the quantity of alveolar bone (height and width). Linear measurements are used in orthodontic analysis and definition of jaw tumor size. The objective of this study is to evaluate the accuracy of the linear measurement of CBCT (Newtom VG) in the axial and coronal planes, with two different voxel sizes. MATERIALS AND METHODS: In this accuracy diagnostic study, 22 anatomic landmarks in four dry human skulls were marked by gutta-percha. Fifteen linear measurements were obtained using a digital caliper. These were considered to be the gold standard (real measurement). The skulls were scanned by CBCT (Newtom VG) at two settings: (a) Voxel size 0.3 mm (b) voxel size 0.15 mm High Resolution (HR). The radiographic distance measurements were made in the axial and coronal sections by three observers. The radiographic measurements were repeated two weeks later for evaluation of intraobserver reliability. SPSS software version 17 was used for data analysis. The level of significance was considered to be 5% (P <= 0.05). RESULTS: The mean differences of real and radiographic measurements were -0.10+/ 0.99 mm in the axial sections, -0.27+/-1.07 mm in the coronal sections, +0.14+/ 1.44 mm in the axial (HR) sections, and 0.02+/-1.4 mm in the coronal (HR) sections. The intraclass correlation (ICC) for CBCT measurements in the axial sections was 0.9944, coronal sections 0.9941, axial (HR) sections 0.9935, and coronal (HR) sections 0.9937. The statistical analysis showed high interobserver and intraobserver reliability (P <= 0.05). CONCLUSION: CBCT (Newtom VG) is highly accurate and reproducible in linear measurements in the axial and coronal image planes and in different areas of the maxillofacial region. According to the findings of the present study, a CBCT scan with a larger voxel size (0.3 mm in comparison to 0.15 mm) is recommended when the purpose of the CBCT scan is to measure linear distances. This will result in lower patient radiation dose and faster scan time. PMID- 23814564 TI - Prevalence of zygomatic air cell defect: Panoramic radiographic study of a selected Esfehanian population. AB - BACKGROUND: The mastoid pneumatization begins on the 33(rd) week of embryonic life, and continuous up to 8-9 years of age. This air cells is important for surgical perspective. Inadvertent penetration through this anatomical feature during surgical procedures can be disastrous. Aim of this study is to determine the prevalence of zygomatic air cell defect (ZACD) in the Esfehanian population. MATERIALS AND METHODS: This was a cross-sectional study. 2600 panoramic radiographs of patients aged between 3 and 90 years were evaluated retrospectively to establish dominant laterality, type and grade amongst these patients. The SPSS 11.5 program was used for the statistical analysis. Mean and standard deviation were used for statistical methods in this study. RESULTS: ZACD was found in 94 cases, representing a prevalence of 3.6%. 59 cases occurred in females (62.8%) and 35 cases occurred in males (37.2%). Most cases were in their twenties. Unilateral ZACD was found in 70 patients (74.5%) with the half occurring on the right side. In 24 cases (25.5%) was bilateral. 70 of the cases (59.3%) were multilocular type, while 45 (38.1) and 3 (2.6%) were unilocular and trabecular type, respectively. 59 cases were grade 2 (62.8%) and 35 were grade 3 (37.2%). CONCLUSIONS: The frequency of ZACD amongst Iranian population was more than previous studies. In addition younger population was involved in this group. So it is important for clinicians who are planning to perform temporomandibular joint surgery to assess radiographic imaging thoroughly before the surgery to avoid intraoperative complications. PMID- 23814565 TI - Apoptosis status and proliferative activity in mucopolysaccharidosis type I mice tongue mucosa cells. AB - BACKGROUND: Mucopolysaccharidosis type I (MPS I) is caused by a deficiency of alfa-iduronidase (IDUA), which leads to intralysosomal accumulation of glysosaminoglycans. Evidences point secondary events like oxidative stress on lysosomal storage diseases including MPS I. Patients with MPS I present a wide range of oral clinical manifestations, including tongue hypertrophy, hypertrophyc alveolar process, and carious teeth. However, the mechanisms by which these alterations occur are still not fully understood. The aim of this study was to analyze the proliferative activity as well as apoptosis in tongue mucosa cells from murine model of MPS I. MATERIALS AND METHODS: Protein expression of apoptotic markers such as p53, bcl-2 and bax were evaluated in this setting. Ki 67 was used as a proliferative marker. All analyses were made by immunohistochemistry in tongue cells. Statistical analysis was perfomed by Kruskal-Wallis non-parametric test followed by the Dunn's test. P < 0.05 was considered for statistic significance. RESULTS: Histopathological analysis revealed no remarkable differences in tongue mucosa on MPS I mice when compared to control. By contrast, our results demonstrated that bcl-2 immunoexpression was decreased in mice tongue mucosa cells of MPS I mice. p53, bax and ki-67 immunoexpresssion did not show significant differences among controls and MPS I mice. CONCLUSION: Taken together, our results suggest that IDUA deficiency, which characterizes MPS I, may induce apoptosis in mice tongue cells as a result of bcl 2 down regulation. PMID- 23814566 TI - Histologic and histomorphometric evaluation of the effect of lactoferrin combined with anorganic bovine bone on healing of experimentally induced bony defects on rabbit calvaria. AB - BACKGROUND: Recent studies have shown that lactoferrin promotes the proliferation and differentiation of osteoblasts and inhibits osteoclast-mediated bone resorption. Anorganic bovine bone (ABB) graft has been extensively used as an osteoconductive material in the bone reconstructive surgeries. The purpose of this study was to examine whether the combination of lactoferrin with Bio-Oss would improve ossification in experimentally induced bone defects in rabbit calvaria. MATERIALS AND METHODS: In this randomized, prospective animal study, a total of 32 bone defects with the diameter of 6 mm were created on the calvaria of 8 male New Zealand rabbits (4 defects in each animal). One defect was filled with ABB + Lactoferrin + Vehicle (BLV), the second one with ABB + Lactoferrin (BL), the third defect with ABB + V (BV), and the fourth defect was filled with ABB (B) alone. After 4 weeks, histologic sections were prepared and evaluated histologically and histomorphometrically. The type, percentage and vitality of newly formed bone, inflammation, percentage of residual material, and foreign body reaction were assessed for each specimen. Data were analyzed using Friedman tests. RESULTS: All groups were similar in terms of inflammation and vitality, type, percentage of new bone formation, and residual material. The percentage of new bone formation in BLV, BL, BV, and B groups were 14.73 +/- 3.14%, 15.02 +/- 1.51%, 15.95 +/- 2.24% and 13.44 +/- 2.89% (P = 0.1) and the amount of residual biomaterial were 11.85 +/- 1.50%, 13.73 +/- 1.80%, 13.02 +/- 1.86%, and 15.41 +/- 2.05%, respectively (P = 0.392). CONCLUSION: Based on results of this study, the combination of lactoferrin and ABB did not show any significant improvement in bone regeneration compared with ABB alone in surgically induced bony defects in rabbit calvaria. PMID- 23814567 TI - Effect of object location on the density measurement in cone-beam computed tomography versus multislice computed tomography. AB - BACKGROUND: Bone density measurement in a radiographic view is a valuable method for evaluating the density of bone quality before performing some dental procedures such as, dental implant placements. It seems that Cone-Beam Computed Tomography (CBCT) can be used as a diagnostic tool for evaluating the density of the bone, prior to any treatment, as the reported radiation dose in this method is minimal. The aim of this study is to investigate the effect of object location on the density measurement in CBCT versus Multislice computed tomography (CT). MATERIALS AND METHODS: In an experimental study, three samples with similar dimensions, but different compositions, different densities (Polyethylene, Polyamide, Polyvinyl Chloride), and three bone pieces of different parts of the mandibular bone were imaged in three different positions by CBCT and Multislice CT sets. The average density value was computed for each sample in each position. Then the data obtained from each CBCT was converted to a Hounsfield unit and evaluated using a single variable T analysis. A P value <0.05 was considered to be significant. RESULTS: The density in a Multislice CT is stable in the form of a Hounsfield Number, but this density is variable in the images acquired through CBCT, and the change in the position results in significant changes in the density. In this study, a statistically significant difference (P value = 0.000) has been observed for the position of the sample and its density in CBCT in comparison to Multislice CT. CONCLUSIONS: Density values in CBCT are not real because they are affected by the position of the object in the machine. PMID- 23814568 TI - Trends in oral cancer rates in Isfahan, Iran during 1991-2010. AB - BACKGROUND: There is a variation in trends of oral cancers all over the world. Many investigations have reported evidence of an increasing incidence in oral cancers during recent years. The purpose of this study was to investigate time trend and changes in demographic distribution of oral cancers incidence in Isfahan during 1991-2010. MATERIALS AND METHODS: In this retrospective analytic study archive of Oral Pathology Department of School of Dentistry, Isfahan University of Medical Sciences from 1991 to 2010 were reviewed. A total of 231 Pathology reports were analyzed. Age, sex, primary site, histologic type of cancer, and the referral year were recorded. Data were analyzed by using Jointpoint Regression Program 3 and SPSS 18. P value less than 0.05 consider as significant level. RESULTS: Out of all malignancies, 55% were male and 45% were female. The most frequent cancer was squamous cell carcinoma. Comparing the two time intervals (1991-2000) and (2001-2010) showed that the ratio of carcinomas and salivary gland tumors had decreased while there was an increase in incidence of sarcomas and lymphomas. Among young persons, the occurrence of oral carcinomas (mostly SCC) is rare but sarcomas were more common in younger patients. Gingiva was the most frequently involved in oral cancers with (46%), followed by tongue with (18%). CONCLUSION: : According to this study it revealed that some changes in trends of oral cancer have happened in Isfahan that calls for more study and evaluation of etiologies of these changes. PMID- 23814569 TI - Current concepts in diagnosis of unusual salivary gland tumors. AB - Salivary gland tumors are relatively uncommon and account for approximately 3-6% of all neoplasms of the head and neck. Tumors mostly involve the major salivary glands, 42.9-90% of which occur in the parotid glands and 8-19.5% in the sub mandibular glands; tumors in the sub-lingual glands being uncommon. Despite the plethora of different malignant salivary gland tumor presented to pathologists for diagnosis, there is consensus on a limited number of pathologic observations that determine treatment and outcome. There are few absolutes in salivary gland tumor diagnosis given the marked spectrum and overlap of differentiated cell types that participate in the numerous benign and malignant tumors. Thus, there are enumerating antibodies that may be helpful in resolving difficult differential diagnoses when applied with astute morphologic correlation. In general, immunohistochemistry as an ancillary diagnostic tool should be used sparingly and wisely as a morphologic adjunct because of the lack of specificity of many markers for specific histologic tumor types. The aim of this review is to discuss the molecular profiling of salivary gland neoplasms and correlate this with histogenesis of salivary gland neoplasms. We have elected to discuss and illustrate some of the unusual salivary gland tumors that the practicing pathologist find difficult to diagnose. These have been selected because they readily simulate each other but have very different clinical therapies and, therefore, should be included routinely in differential diagnosis. PMID- 23814570 TI - Oral leukoplakia: Transmission electron microscopic correlation with clinical types and light microscopy. AB - BACKGROUND: Leukoplakia, is a precancerous lesion that is most commonly encountered in the oral cavity. The grade of dysplasia is presumed to be the most important indicator of malignant potential. There are many promising aspects in advanced methods for the evaluation of oral precancer and cancer. Among these methods, electron microscopic examination predicts the true biologic potential more accurately than conventional histology and has some success in the early detection of potentially malignant lesions. It has been reported in the literature that there is some correlation between clinical, histopathological, and transmission electron microscopic features. MATERIALS AND METHODS: In this cohort study (prospective research), from the total of 9 subjects, 3 had homogenous leukoplakia, 3 had ulcerative type of oral leukoplakia, and 3 had nodular type of oral leukoplakia. Two patients were selected as control patients. Transmission electron microscopic examination was carried for all the cases and controls. All the findings were correlated with clinical features and light microscopy. RESULTS: Clinically and histologically, mild leukoplakia showed break in basement membrane, which can only be observed under transmission electron microscope (TEM). Additional dysplastic features were observed under transmission electron microscope, which are indicative of neoplastic process. CONCLUSIONS: Thus, it is finally concluded that nodular leukoplakia seems to be the most severe clinical type of leukoplakia showing highest risk of malignant transformation. Homogenous leukoplakia might show break in basement membrane under TEM. PMID- 23814571 TI - Lab-Test((r)) 4: Dental caries and bacteriological analysis. AB - Dental caries is one of the most common infectious ultifactorial diseases worldwide, characterized by the progressive demineralization of the tooth, following the action of bacterial acid metabolism. The main factors predisposing the onset of the carious process are: 1) the presence of bacterial species able to lower the pH until critical values of 5.5, 2) the absence of adequate oral hygiene, 3) an inefficient immune response anti-caries, 4) the type of alimentary diet and 5) the structure of the teeth. Among the 200 bacterial species isolated from dental plaque the most pathogenic for dental caries are: Streptococcus mutans, Streptococcus sobrinus, Lactobacillus acidophilus, Actinomices viscusus and Bifidobacterium dentium. Our laboratory (LAB((r)) s.r.l., Codigoro, Ferrara, Italy) has developed a test for absolute and relative quantification of the most common oral cariogenic bacteria. The test uses specific primers and probes for the amplification of bacteria genome sequences in Polymerase Chain Reaction Real Time. The results provide a profile of patient infection, helpful for improving the diagnosis and planning of preventive treatment to reduce the bacterial load. PMID- 23814572 TI - Bactercline((r))-coated implants: Clinical results up to 1 year after loading from a controlled clinical trial. AB - BACKGROUND: Titanium dioxide exists in three different crystal lattices, anatase, rutile, and brookite. Anatase coating releases, under ultraviolet (UV) irradiation, free radicals such as .OH, O2 (-), HO2 (-), and H2O2. This potent oxidizing power characteristically results in the lysis of bacteria and other organic substances. The purpose of this study was to evaluate the bone response to implants made of titanium alloy or coated with a new combination of anatase and Bactercline((r)) product. MATERIALS AND METHODS: In the period between July 2009 and June 2010, 26 patients (10 females and 16 males; median age 51 +/- 11 years, min. 27 years, max. 72 years) were operated and 62 implants were inserted. Lost fixtures and peri-implant bone resorption were considered as predictors of clinical outcomes. Pearson chi(2)-test was used. Prosthesis and implant failures, any complications after loading, and peri-implant marginal bone-level changes were assessed by a masked assessor. All patients were followed up to 1 year after loading. RESULTS: No implant was lost. Average bone resorption around implant was 0.33 mm (both for 25 standard and 37 Bactercline-coated implants), and thus no statistical difference was detected. CONCLUSION: These results shown that no adverse effects on osseo-integration were present. PMID- 23814573 TI - Effectiveness of one-piece implants inserted in cuspid sites. AB - BACKGROUND: One-piece implants (OPIs) incorporate the trans-mucosal abutment facing the soft tissues as an integral part of the implant. OPIs are usually welded together and loaded immediately. Since no report focuses specifically on OPIs inserted in cuspid sites, a retrospective study is performed. MATERIALS AND METHODS: Nineteen patients (10 females and 9 males) with a median age of 62 years (range, 43-80) were admitted at the Dental Clinic, University of Chieti (Italy), for evaluation and implant treatment, by one surgeon between January and December 2010. RESULTS: In our series, the survival rate (SVR) and success rate (SCR) were 96.8% and 100%, respectively. Statistical analysis demonstrated that no studied variable had an impact on the survival (i.e., lost implants) and clinical success (i.e., crestal bone resorption). CONCLUSION: OPIs are reliable devices for oral rehabilitation in the cuspid sites. PMID- 23814574 TI - Restoration of incisor area using one-piece implants: Evaluation of crestal bone resorption. AB - BACKGROUND: One-piece implants (OPIs) incorporate the trans-mucosal abutment facing the soft tissues as an integral part of the implant. Since OPIs become more and more popular and no report specifically focuses on OPIs inserted in incisors' area, a retrospective study is performed. MATERIALS AND METHODS: Fifty five OPIs were inserted in incisors' area in a series of patients admitted at the Dental Clinic, University of Chieti (Italy), for evaluation and implant treatment between January and December 2010. RESULTS: In our study, the survival rate and success rate were 96.2% and 96.1%, respectively. Statistical analysis demonstrated that no studied variable had an impact on the survival (i.e., lost implants) and clinical success (i.e., crestal bone resorption). CONCLUSIONS: OPIs are reliable devices for oral rehabilitation in the incisors' area. PMID- 23814575 TI - Survival and success rate of one-piece implant inserted in molar sites. AB - BACKGROUND: Recently, the use of one-piece implants (OPI) has become more popular. Since no reports specifically focus on OPIs inserted in molar areas, a retrospective study has been performed. MATERIALS AND METHODS: A series of 36 OPIs (Diamond; BIOIMPLANT, Milan, Italy) were inserted into the molar area of patients admitted at the Dental Clinic, University of Chieti, Italy, for oral rehabilitation between January and December 2010. RESULTS: In our series survival rate (SVR) and success rate (SCR) were 91.7% and 97%, respectively. Statistical analysis demonstrated that no studied variable has an impact on survival (i.e., lost implants) as well as on clinical success (i.e., crestal bone resorption). CONCLUSION: OPIs are reliable devices for oral rehabilitation in the molar areas. PMID- 23814576 TI - Clinical outcome of one-piece implant used in premolar sites. AB - BACKGROUND: The routine and frequent use of dental implants to replace missing teeth is accompanied by high expectations from patients. These expectations are not limited to function and esthetics but extends to patient comfort and time spent in receiving treatment. Replacement of an unrestorable maxillary premolar can be challenging when considering the concerns of patients. A one-piece implant (OPI) incorporates the trans-mucosal abutment facing the soft tissues as an integral part of the implant. Since no report specifically focused on OPIs inserted in premolar areas, a retrospective study was carried out. MATERIALS AND METHODS: Nineteen patients (10 females and 9 males) with a median age of 62 years (43-80) were enrolled and a total of 176 OPIs (Diamond, BIOIMPLANT, Milan, Italy) were inserted. RESULTS: In our series survival rate (SVR) and success rates (SCR) were 90.6% and 97.9%, respectively. Statistical analysis demonstrated that no studied variable had an impact on survival (i.e., lost implants) as well as on clinical success (i.e., crestal bone resorption). CONCLUSION: OPIs are reliable devices for oral rehabilitation in the premolar areas. PMID- 23814577 TI - Titanium nanotubes activate genes related to bone formation in vitro. AB - BACKGROUND: Titanium is used worldwide to make osseointegrable devices, thanks to its favorable characteristics as mechanical proprieties and biocompatibility, demonstrated by in vivo studies with animal models and clinical trials over a forty-year period. However, the exact genetic effect of the titanium layer on cells is still not well characterized. MATERIALS AND METHODS: To investigate how titanium nanotubes stimulate osteoblasts differentiation and proliferation, some osteoblast genes (SP7, RUNX2, COL3A1, COL1A1, ALPL, SPP1 and FOSL1) were analyzed by quantitative Real Time RT- PCR. RESULTS: After 15 days, osteoblasts cultivated on titanium naotube showed the up-regulation of bone related genes SP7, ENG, FOSL1 and SPP1 and the down-regulation of RUNX2, COL3A1, COL1A1, and ALPL. After 30 days of treatment, the bone related genes SP7, ENG, FOSL1 and RUNX2 were up regulated while COL3A1, COL1A1, ALPL and SPP1 were down-regulated. CONCLUSIONS: Our results, demonstrates that titanium nanotubes can lead to osteoblast differentiation and extracellular matrix deposition and mineralization in dental pulp stem cells by the activation of osteoblast related genes SPP1, FOSL1 and RUNX2. PMID- 23814578 TI - Titanium nanotubes stimulate osteoblast differentiation of stem cells from pulp and adipose tissue. AB - BACKGROUND: Titanium is the gold standard among materials used for prosthetic devices because of its good mechanical and chemical properties. When exposed to oxygen, titanium becomes an oxide, anatase that is biocompatible and able to induce osseointegration. MATERIALS AND METHODS: IN THIS STUDY WE COMPARED THE EXPRESSION PROFILING OF STEM CELLS CULTIVATED ON TWO TYPES OF SURFACE: Pure titanium disk and nanotube titanium disk in order to detect if nanotube titanium instead (NTD) surface stimulates stem cells towards osteoblast differentiation. RESULTS: Stem cells cultivated on nanotube titanium disks showed the upregulation of bone-related genes RUNX2, FOSL1 and SPP1. CONCLUSIONS: Results demonstrated that nanotube titanium disk surface is more osteo-induced surface compared to titanium disk, promoting the differentiation of mesenchymal stem cells in osteoblasts. PMID- 23814579 TI - Dental implants inserted in native bone: Cases series analyses. AB - BACKGROUND: The concept of osseointegration, i.e., the direct anchorage of endosseous implants made of commercially pure or titanium alloy to the bone caused a breakthrough in oral rehabilitation. The identification of factors for long-term survival and success rate are the main goal of the recent literature. Several variables can influence the final result, and in general they are grouped in surgery-, host-, implant-, and occlusion-related factors. MATERIALS AND METHODS: A retrospective analysis on a large series of dental implants was performed to detect those variables influencing the clinical outcome. In the period between January 2007 and December 2009, 157 patients were operated. A total of 429 implants were inserted. Dental implants are reliable devices to be used in oral rehabilitation. RESULTS: Globally, very few implants were lost at the end of the follow-up period. Slight but significant differences existed among different implants types with regard to peri-implant bone resorption. CONCLUSION: A better clinical outcome was revealed for Sweden and Martina global implant. PMID- 23814580 TI - A retrospective study on a series of 556 zimmer dental implants. AB - BACKGROUND: One-stage surgery with immediate loading is possible, with good clinical results. Many types of dental implants are available in the market. Zimmer Dental Implants (ZDIs) have been used since the nineties, but few reports have analyzed the clinical outcome of these fixtures. We planned a retrospective study on a series 566 ZDIs, to evaluate their clinical outcome. MATERIALS AND METHODS: In the period between January 2007 and June 2011, 125 patients were treatetd with ZDIs. The last check-up was performed in June 2012, with a mean follow-up period of 17 +/- 9 months (minimum - maximum, 8-4 months). ZDIs were inserted as follows: 295 (53.1%) in the maxilla and 261 (46.9%) in the mandible. There were 480 (86.3%) Screw-vents, 51 (9.2%) Swiss Plusses, and 25 (4.5%) Splines. Sixteen, 355, 34, 90, 55, and six fixtures had a diameter of 3.25, 3.7, 3.75, 4.1, 4.7, and 4.8 mm, respectively. Twenty-eight, 145, 5, 217, 8, 141, and 12 implants hade a length of 8, 10, 11, 11.5, 12, 13, and 14 mm, respectively. The implants were inserted to replace 136 (24.5%) incisors, 80 (14.4%) cuspids, 198 (35.6%) premolars, and 142 (25.5%) molars. RESULTS: No implants were lost (i.e., SRV = 100%). Among the studied variables, only those for the jaws were statistically significant, with a better outcome for implants inserted in the maxilla (P = 0.017). CONCLUSIONS: ZDIs are reliable devices to be used in implantology, althougth a higher marginal bone loss has to be expected when these implants are inserted in mandible. PMID- 23814581 TI - Periodontal effects with self ligating appliances and laser biostimulation. AB - BACKGROUND: Recently, various biostimulation's effects of low energy laser irradiation have been reported. The present study was designed to examine the effects of low-energy laser irradiation on alveolar bone remodelling during orthodontic tooth movement and finally on formation of new keratinized gingiva. MATERIALS AND METHODS: 22 patients and 27 teeth in vestibular mucosal without keratinized gingiva were selected. Every patient was treated with self ligating appliances. In every orthodontic session the patient was treated with Diode laser biostimulation. At the moment of debonding, 27 teeth involved in the research were evaluated in terms of quality and quantity of attached gingiva. BOP and CAL loss were investigated. RESULTS: EVERY TOOTH CONSIDERED AT THE END OF ORTHODONTIC TREATMENT SHOWED AN ATTACHED GINGIVA AROUND THE CROWN: The average of keratinized gingiva at the end of the study was 3.10 mm and the mean increasing at each month was 0,49 mm. CONCLUSIONS: The combination between self ligating appliances and laser's biostimulation could improve the differentiation of periodontal ligaments stem cells in fibroblasts, able to promote attached gingiva around the crown of the teeth erupted in oral vestibular mucosa. PMID- 23814582 TI - Picibanil (OK-432) in the treatment of head and neck lymphangiomas in children. AB - BACKGROUND: Picibanil (OK-432) is a lyophilized mixture of group A Streptococcus pyogenes with antineoplastic activity. Because of its capacity to produce a selective fibrosis of lymphangiomas (LMs), it has been approved by Japanese administration in 1995 for the treatment of LMs. MATERIALS AND METHODS: We treated 15 children (age range: 6-60 months) affected by head and neck macrocystic LMs with intracystic injections (single dose of 0.2 mL) of Picibanil (1-3 injections). RESULTS: Complete disappearance of the lesion was noticed in eight (53.33%) cases, a marked (>50%) reduction of LMs was found five (33.33%) cases, while a moderate (<50%) response was recorded in two (13.33%) cases. Picibanil side effects included fever, local inflammation, and transitory increase of blood platelets' concentration; a single case of anemia was resolved with concentrated red blood cells transfusion. CONCLUSIONS: Intracystic injection of Picibanil is an effective and safe treatment for macrocystic LMs in pediatric patients and may represent the treatment of choice in such cases, especially where surgical excision is associated with the risk of functional/cosmetic side effects. PMID- 23814583 TI - IL6 and IL10 are genetic susceptibility factors of periodontal disease. AB - BACKGROUND: Periodontitis is a disease mainly caused by a chronic infection of tissues that support the teeth. Several factors, such as diabetes, smoking and oral care, as well as genetic susceptibility can influence both the risk to develop periodontitis and its progression. The aim of the investigation was to test whether alleles of candidate genes were associated with periodontitis. MATERIALS AND METHODS: A case control study was performed with a cohort of 184 patients with chronic periodontitis and 231 healthy controls from the Italian population. A total of six single nucleotide polymorphisms from five candidate genes, i.e., IL1A, IL1B, IL6, IL10 and vitamin D receptor, were investigated. RESULTS: Evidence of association were obtained for rs1800795 mapping in IL6 (P value = 0.01) as well as for the rs1800872 mapping in IL10 (P = 0.04). The rarer variant allele lowered the risk to develop periodontitis at IL6 (Odds Ratio [OR] = 0.69 [95% confidence interval {CI} 0.51-0.93]) and increased the risk at IL10 (OR = 1.38 [95% CI 1.01-1.86]). CONCLUSIONS: The present investigation indicated that polymorphisms of IL6 and IL10 constitute risk factors for chronic periodontitis, while there was no evidence implicating a specific IL1A or IL1B genotype. PMID- 23814584 TI - Microflora and periodontal disease. AB - BACKGROUND: Periodontitis is a disease that affects and destroys the tissues that support teeth. Tissue damage results from a prolonged inflammatory response to an ecological shift in the composition of subgingival biofilms. Three bacterial species that constitute the red complex group, Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola, are considered the main pathogens involved in periodontitis. MATERIALS AND METHODS: In the present study, a real time polymerase chain reaction bases assay was designed to detect and quantify red complex species, then used to investigate 307 periodontal pocket samples from 127 periodontitis patients and 180 controls. RESULTS: Significant higher prevalence of red complex species and increased amount of P. gingivalis and T. denticola were detected in periodontal pocket of periodontitis patients. CONCLUSIONS: Results demonstrated that the test is a valuable tool to improve diagnosis of periodontal disease. PMID- 23814585 TI - Titanium alloys (AoN) and their involvement in osseointegration. AB - BACKGROUND: Osseointegration is essential for a long-term successful and inflammation-free dental implant. Such a result depends on osteoblastic cells growth and differentiation at the tissue-implant interface. The aim of this study was to compare two different AoN titanium layers (GR4 and GR5) to investigate which one had a greater osteoconductive power using human osteoblasts (HOb) culture at two different time-points. MATERIALS AND METHODS: The expression levels of some bone-related (ALPL, COL1A1, COL3A1, SPP1, RUNX2, and SPARC) were analyzed using real time reverse transcription-polymerase chain reaction (real time RT-PCR). RESULTS: Real-time RT-PCR data showed that after 3 days of treatment with TiA4GR, the genes up-regulated were COL3A1, ALPL, SPP1, and RUNX2. Moreover, no difference in gene expression was noticed 4 days later. On the other hand, the genes that overexpressed after 3 days of treatment with AoN5GR were ALPL, SPP1, and RUNX2. In both cases, the expression of COL1A1 and SPARC was negatively regulated. CONCLUSION: Our data showed that both titanium surfaces led to osteoblasts recruitment, maturation, and differentiation, thus promoting osseointegration at the tissue-implant interface. PMID- 23814586 TI - Fibroblast behavior after titanium surfaces exposure. AB - BACKGROUND: The main requirements for a good material are its ability to promote attraction and adhesion of bone precursor cells and their proliferation and differentiation. Different biocompatible materials are currently employed as scaffold. Among these, titanium is considered a gold standard because of its biocompatibility and good corrosion resistance. MATERIALS AND METHODS: The aim of this work was to compare two different AoN titanium layers (GR4 and GR5) to investigate which one had a greater osteoconductive power using human fibroblasts (HFb) culture at two different time-points. The expression levels of some adhesion and traction-resistance related genes (COL11A1, COL2A1, COL9A1, DSP, ELN, HAS1, and TFRC) were analyzed using real time reverse transcription polymerase chain reaction. RESULTS: After 7 days of treatment with TiA 4GR, the only two up-regulated genes were COL2A1 and DSP. After 15 days of treatment, none of genes over expressed. CONCLUSION: Our preliminary results suggest that neither AoN 4GR nor AoN 5GR are able to promote the production of protein involved in cell-cell and cell-matrix adhesion and in stress-resistance, required for a good outcome in dental implantology. PMID- 23814587 TI - Comparison between Herbst appliances with or without miniscrew anchorage. AB - BACKGROUND: Herbst appliance is largely used in orthodontics for the correction of Class II. The aim of this paper was to analyze dental and skeletal effects of a splints Herbst-miniscrews combined device in comparison to a mandibular splints Herbst appliance. MATERIALS AND METHODS: Fifty Class II division 1 patients (27 males and 23 females with a mean age of 11.8 +/- 1.7 years) were included in the study. Lateral headfilms of 25 patients with a mandibular resin splint and a miniscrew anchorage (test group) and of 25 patients with mandibular acrylic resin splints (control group) were analyzed before (T0) and after (T1) the Herbst treatment. The mean and standard deviation (SD) of each variable were calculated; paired t-test was used to evaluate statistical changes before and after the treatment, in each group and Student t-test was used to compare the two groups. RESULTS: Significant differences were observed for P < 0.05. At the end of the Herbst treatment, mandibular incisor proclination was significantly lower in the test group (2.8 degrees ) in comparison to the control group (7.4 degrees ). CONCLUSIONS: The miniscrew-Herbst system, described in the present study, allows correction of Class II malocclusion, with a lower anchorage loss, in form of mandibular incisor proclination, during the treatment, in comparison to mandibular acrylic splints Herbst. PMID- 23814588 TI - A case report of haemorrhagic-aneurismal bone cyst of the mandible. AB - Haemorrhagic-aneurismal bone cysts (HABCs) are quite rare, benign, non neoplastic, expansive, and vascular locally destructive lesions. They are generally considered sequelae of an earlier trauma causing an overflow of blood into the bone. HABCs are classified as pseudocysts and they should be differentiated from true cysts because their treatment is different. Since few of these cysts involve subjective symptoms, most are discovered accidentally during radiography, while a sure diagnosis is likely to be obtained only during surgery, on discovery of a non-epithelialised cavity. Here, we report a typical case of a haemorrhagic-mandibular cyst in a 13-year-old girl, which was treated by opening the cavity and scraping its walls following diagnostic arteriography and post operative transcutaneous intralesional embolization. No further complications were recorded in the post-operative period, although the convalescence lasted for a time longer than expected, because of anemia. No further surgery was performed. She has been disease-free for two years. Evaluation of intralesional blood flow is important for HABCs because of the hemorrhagic risk in surgery. Embolization seems to be a useful procedure in the treatment of HABCs and could be tried as the treatment modality in the standard protocol for the treatment of HABCs. PMID- 23814589 TI - A case of lipoma of lateral anterior neck treated with surgical enucleation. AB - Lipoma arise in almost 50% of all soft tumours. The neck lipomas are rare tumours that may present as painless masses with slow growth, in the lateral portions of the neck. Some lipomas, such as the one studied in our case, grow deep in the subcutaneous tissue, in close contact with muscles. Here, we report a case of lipoma extending from pre-tragal region up to the ascending branch of the mandible in a 62 year old man, treated with enucleation. The inferior margin of lipoma involved the pharyngeal and the superior margin was achieved by the top of the skull base. The mass of lipoma caused breathing difficulties in the patient, preventing regular sleep. No complication was recorded in the post-operative period and no further surgery was performed. The complete resolution after one year's follow-up, together with the rarity of the anatomical site, makes this case worthy of description. A correct diagnosis facilitated removal of this lesion with a surgical method. PMID- 23814590 TI - A rare case of rynopharyngeal melanoma. AB - Primary mucosal melanomas (MM) of the head and neck region constitute 0.5-2% of all malignant melanomas. The rynopharynx is a region that is less often involved by malignant melanomas. Because most of mucosal melanotic lesions are painless in their early stages, the diagnosis is unfortunately often delayed until symptoms resulting from ulceration, growth, and/or bleeding are noted. Here, we document the rare case of a malignant rynopharynx melanoma of a 43 year old woman. Its treatment and the pertinent literature are discussed. No complication was recorded in the post-operative period and no further surgery was performed. The follow up showed no recurrence in the same position and with the same characteristics, even after six years. Mucosal melanomas are aggressive tumours and the prognosis in these patients is poor. Clinicians must use treatment strategies that provide functional benefit, so as to maintain quality of life without excessive toxicity. PMID- 23814591 TI - A case of mandible osteonecrosis after a severe periimplant infection. AB - The term osteonecrosis has been applied to describe the presence of a persistent inflammation of the mouth, osteomyelitis, delayed healing of extraction sockets, development of sequestra or presence of fistulae from the mouth to the lower skin. Here, we document a case of mandible osteonecrosis that developed in a patient after a severe periimplant infection. Osteonecrosis, severe inflammatory osteolysis, and heavy bacterial colonization were found. Surgical toilette and hyperbaric oxygen therapy permitted complete healing of the case. No complication was recorded in the post-operative period and no further surgery was performed. The clinical follow up and the imaging after one year showed a complete 'restitution ad integrum' of the mandible. Although the risk of developing osteonecrosis of the jaw for oral implants is low, the devastating complications still require caution. PMID- 23814592 TI - Dental fragment embedded in the lower lip after facial trauma: Brief review literature and report of a case. AB - Upper incisors are the most frequently involved teeth in traumatic dental injuries. Soft tissues (lips and/or oral mucosa) adjacent to incisal edge can receive direct and/or indirect traumas. Laceration of the lower lip is a not rare eventuality and teeth fragments could be embedded in labial soft tissue. The reattachment of these fragments, if possible, is the elective treatment choice, thanks to the modern adhesive and restorative techniques. The authors present a case of a white Caucasian 10-year-old child, who attended the dental clinic for the treatment of both upper central incisors' crown fractures. The fragment of the left incisor was retrieved embedded in the lower lip. It was successfully surgically removed and reattached using a composite adhesive technique. A careful clinical and radiographic examination with the surgical removal of tooth fragments could prevent undesirable foreign body reaction, infection and scarring. The authors also reviewed the most relevant literature concerning tooth fragment reattachment after removal from oral soft tissues. PMID- 23814593 TI - Bilateral pneumothorax after orthognatic surgery. AB - Among complications in orthognathic surgery, the insurgence of pneumothorax is very rare. Pneumothorax is the presence of air or gas in the pleural cavity and it is rare complications in the postoperative oral and maxillofacial surgery patient. The clinical results are dependent on the degree of collapse of the lung on the affected side. Pneumothorax can impair oxygenation and/or ventilation. If the pneumothorax is significant, it can cause a shift of the mediastinum and compromise haemodynamic stability. While 10% of pneumothoraces are asymptomatic, patients often complain of acute chest pain and difficulty breathing. There is a reduction in vital capacity, tachycardia, tachypnoea and a decrease in partial pressure of oxygen with an inability to maintain oxygen saturations. We observed this unusual surgical consequence in a 28-year-old female with negative clinical history and instrumental evaluation after Le Fort I osteotomy and bilateral sagittal split osteotomy (BSSO). No further consequences, no neurological sequelae, no infections and no other osteotomies sequelae were seen. Sudden post surgical dispnea associated to sub-cutaneous emphysema of the neck and of the thorax must be adequately observed with the aim of monitoring further severe sequelae. The anaesthetic management of the emergency difficult airway in any post-surgical orthognatic treatment can be extremely difficult requiring a multi disciplinary approach. PMID- 23814594 TI - Delayed progressive haematoma after Le Fort I osteotomy: A possible severe complication in orthognatic surgery. AB - Although the Le Fort I osteotomy is a safe surgical technique, many complications have been reported. We present a case of an extended cervico-facial haematoma due to delayed bleeding from the terminal branches of the maxillary artery after orthognatic surgery. A 23-year-old man was referred to our observation for the surgical correction of a class III asymmetric malocclusion. The patient underwent a Le Fort I osteotomy, with impaction of the maxilla, associated with an Epker mandibular bilateral sagittal split osteotomy, with maxillary advancement and rigid internal fixation of the mandible with four miniplates and another four for the upper maxilla as well. The first post-surgery day, the patient developed a gradual dispnea together with neck swelling. By second postoperative day, the patient's general condition improved with a progressive normalization of laboratory tests values. The Computerised Axial Tomography (CAT) scan confirmed a decrease in the parapharyngeal thickening. Total recovery was achieved within two months, the final clinical check showed a healthy appearance with good occlusion. An increased knowledge of the basic biology of the Le Fort I osteotomy, the development of instruments specially designed for the Le Fort I procedure and the use of hypotensive anaesthesia could reduce the morbidity and duration of this procedure. PMID- 23814595 TI - Macrodontic maxillary incisor in alagille syndrome. AB - This case report describes the surgical-orthodontic guided-eruption of a deeply impacted macrodontic maxillary central incisor in a 10-year-old patient with Alagille syndrome (ALGS). In the first stage, orthodontic treatment with fixed appliance on deciduous teeth allowed to create enough space for the eruption of the maxillary right central incisor. The second stage included closed surgical exposure and vertical traction. After impacted tooth erupted in the proper position, accessory periodontal treatment and dental reshaping procedures may be indicated to camouflage macrodontic incisor with the adjacent teeth. This is the first report that presents a patient with ALGS undergoing orthodontic and surgical treatment. PMID- 23814596 TI - Recent advances in tuberculosis and nontuberculous mycobacteria lung disease. AB - Tuberculosis (TB) is one of the largest health problems in the world today. And the incidence of nontuberculous mycobacteria (NTM) lung disease appears to be increasing worldwide. Recently, an automated, nucleic acid amplification assay for the rapid detection of both Mycobacterium tuberculosis and rifampin resistance was developed (Xpert MTB/RIF). And fixed-dose combinations of anti-TB drugs and linezolid have been introduced in the treatment of TB. And new NTM species, named Mycobacterium massiliense, which is very closely related to Mycobacterium abscessus was reported. In this review, these recent advances in the diagnosis and treatment of TB and clinical characteristics of M. massiliense lung disease are discussed. PMID- 23814597 TI - A Validation Study for the Korean Version of Chronic Obstructive Pulmonary Disease Assessment Test (CAT). AB - BACKGROUND: Health status measure is not only important for clinical research studies but also for clinical practices of chronic obstructive pulmonary disease (COPD) patients. The objective of this study is to evaluate the validity of the Korean Version of COPD Assessment Test (CAT) in primary care clinics as well as in referral hospitals. METHODS: Smokers or ex-smokers, aged 40 years or older, with a smoking history of >10 pack-years; and a COPD diagnosis in the past 6 months or more, were recruited from 4 primary care clinics and 2 referral hospitals. Demographic, medical, and spirometry data was collected from patients who completed the CAT and St. George Respiratory Questionnaire (SGRQ), and had their dyspnea been assessed. The primary endpoint was the correlation between of the Korean version of CAT with SGRQ in patients with COPD. RESULTS: A total 100 patients were enrolled. The mean age and smoking amounts were 69.2+/-8.4 years and 40.6+/-22.3 pack-years, respectively. Sixty-seven percent of the patients reported at least one exacerbation in the past year. The mean CAT score was 16.9+/-8.0. The internal consistency assessed by Cronbach's alpha was 0.85. The CAT score was positively correlated with the SGRQ score (r=0.76, p<0.0001) and each component of SGRQ: symptoms, activity and impacts; r=0.68, r=0.61, and r=0.72, respectively (all p<0.0001). These positive correlations were preserved in the different groups (r=0.86, p<0.0001 in primary care clinic group; r=0.69, p<0.0001 in hospital group). The CAT score was also positively correlated to the Medical Research Council dyspnoea scale (r=0.46, p<0.0001). CONCLUSION: The Korean version of CAT had good internal consistency and showed good correlations with SGRQ. It can be used for assessing the impacts of COPD on the patient's health including primary care setting. PMID- 23814598 TI - The clinical assessment of protease-activated receptor-2 expression in inflammatory cells from peripheral blood and bronchoalveolar lavage fluid in idiopathic pulmonary fibrosis. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a lethal pulmonary fibrotic disease. In general, the exaggerated activation of the coagulation cascade has been observed during initiation or maintenance of the fibrotic disease. In our recent study, immunohistochemical expression of protease-activated receptor-2 (PAR-2), which plays a key role in coagulation cascade, was observed in surgical specimen of IPF patients, and associated with poor clinical outcome. The aim of this study was to evaluate the overexpression of PAR-2 in inflammatory cells from peripheral blood and bronchoalveolar lavage fluid in IPF patients. METHODS: From May 2011 to March 2012, IPF patients and controls were enrolled in Seoul National University Hospital. Peripheral blood and bronchoalveolar lavage fluid were collected for analysis of PAR-2 expression. Flow cytometry and reverse transcription polymerase chain reaction were used for PAR-2 receptor and mRNA assessment. RESULTS: Twelve IPF patients and 14 controls were included in this study. Among them, flow cytometry analysis was conducted from 26 peripheral blood (patient group, 11; control group, 13) and 7 bronchoalveolar lavage fluid (patient group, 5; control group, 2). The expression of PAR-2 receptor was not different between patient and control groups (p=0.074). Among all 24 population, PAR-2 mRNA assessment was performed in 19 persons (patient group, 10; control group, 9). The mRNA expression of PAR-2 was not significant different (p=0.633). CONCLUSION: In IPF patients, PAR-2 receptor and mRNA expression were not different from control group. PMID- 23814599 TI - A case of isolated pulmonary mucormycosis in an immunocompetent host. AB - Mucormycosis is a rare fungal disease that holds a fatal opportunistic fungal infection in diabetes mellitus, hematological malignancy, and immunocompromised host. Isolated pulmonary mucormycosis is extremely rare. Optimal therapy is a combined medical-surgical approach and a management of the patient's underlying disease. Herein, we report a case-study of isolated pulmonary mucormycosis which was being presented as multiple lung nodules in a patient with no underlying risk factors. Considering that the patient had poor pulmonary functions, we treated him with only antifungal agent rather than a combined medical-surgical approach. After treatment with antifungal agent for six months, the nodules of pulmonary mucormycosis were improved with the prominent reductions of size on the computed tomography. PMID- 23814600 TI - A case of pulmonary sarcoidosis with endobronchial nodular involvement. AB - Sarcoidosis is a multisystemic disorder of unknown cause that is characterized pathologically by noncaseating granulomas. Diagnosis is based on the exclusion of other infectious, interstitial, and neoplastic diseases and on the typical pathology. Although the lungs and mediastinal lymph nodes are almost involved, endobronchial nodular lesions of sarcoidosis with lung involvements are rare. We report a case of sarcoidosis with lung involvements and endobronchial nodules as confirmed by bronchial biopsy. PMID- 23814601 TI - A Case of Atypical Adenomatous Hyperplasia of Larger Than 2 cm. AB - Atypical adenomatous hyperplasia (AAH) has been considered to be a precursor lesion of bronchioloalveolar carcinoma (BAC) and pulmonary adenocarcinoma. It usually coexists with BAC and/or an adenocarcinoma. Chest computed tomography reveals multiple well-defined nodules with ground-glass opacity. Usually, AAH does not exceed 10 mm in size. AAH with extensive involvement on one side of the lung field or one that is larger than 2 cm has not been previously reported. We herein report a case of a 71-year-old nonsmoking female with lung AAH of larger than 2 cm. PMID- 23814602 TI - Cerebral air embolism following pigtail catheter insertion for pleural fluid drainage. AB - Pigtail catheter drainage is a common procedure for the treatment of pleural effusion and pneumothorax. The most common complications of pigtail catheter insertion are pneumothorax, hemorrhage and chest pains. Cerebral air embolism is rare, but often fatal. In this paper, we report a case of cerebral air embolism in association with the insertion of a pigtail catheter for the drainage of a pleural effusion. A 67-year-old man is being presented with dyspnea, cough and right-side chest pains and was administered antibiotics for the treatment of pneumonia. The pneumonia failed to resolve and a loculated parapneumonic pleural effusion developed. A pigtail catheter was inserted in order to drain the pleural effusion, which resulted in cerebral air embolism. The patient was administered high-flow oxygen therapy and recovered without any neurologic complications. PMID- 23814603 TI - Tripod Amphiphiles for Membrane Protein Manipulation. AB - Integral membrane proteins (IMPs) are crucial biological components, mediating the transfer of material and information between cells and their environment. Many IMPs have proven to be difficult to isolate and study. High-resolution structural information on this class of proteins is limited, largely because of difficulties in generating soluble forms of such proteins that retain native folding and activity, and difficulties in generating high-quality crystals from such preparations. Isolated IMPs typically do not dissolve in aqueous solution, a property that arises from the large patches of hydrophobic surface necessary for favorable interactions with the core of a lipid bilayer. Detergents are generally required for IMP solubilization: hydrophobic segments of detergent molecules cluster around and shield from water the hydrophobic protein surfaces. The critical role played by detergents in membrane protein manipulation, and the fact that many IMPs are recalcitrant to solubilization and/or crystallization with currently available detergents, suggest that it should be valuable to explore new types of amphiphiles for these purposes. This review constitutes a progress report on our long-term effort to develop a new class of organic molecules, collectively designated "tripod amphiphiles," that are intended as alternatives to conventional detergents for membrane protein manipulation. One long-range goal of this research is to identify new types of amphiphiles that facilitate IMP crystallization. This review should help introduce an important biochemical need to organic chemists, and perhaps inspire new approaches to the problem. PMID- 23814604 TI - Evaluation of Origin Ensemble algorithm for image reconstruction for pixelated solid-state detectors with large number of channels. AB - The Voxel Imaging PET (VIP) Pathfinder project intends to show the advantages of using pixelated solid-state technology for nuclear medicine applications. It proposes designs for Positron Emission Tomography (PET), Positron Emission Mammography (PEM) and Compton gamma camera detectors with a large number of signal channels (of the order of 106). For PET scanners, conventional algorithms like Filtered Back-Projection (FBP) and Ordered Subset Expectation Maximization (OSEM) are straightforward to use and give good results. However, FBP presents difficulties for detectors with limited angular coverage like PEM and Compton gamma cameras, whereas OSEM has an impractically large time and memory consumption for a Compton gamma camera with a large number of channels. In this article, the Origin Ensemble (OE) algorithm is evaluated as an alternative algorithm for image reconstruction. Monte Carlo simulations of the PET design are used to compare the performance of OE, FBP and OSEM in terms of the bias, variance and average mean squared error (MSE) image quality metrics. For the PEM and Compton camera designs, results obtained with OE are presented. PMID- 23814605 TI - Speckle-scale focusing in the diffusive regime with time-reversal of variance encoded light (TROVE). AB - Focusing of light in the diffusive regime inside scattering media has long been considered impossible. Recently, this limitation has been overcome with time reversal of ultrasound-encoded light (TRUE), but the resolution of this approach is fundamentally limited by the large number of optical modes within the ultrasound focus. Here, we introduce a new approach, time reversal of variance encoded light (TROVE), which demixes these spatial modes by variance-encoding to break the resolution barrier imposed by the ultrasound. By encoding individual spatial modes inside the scattering sample with unique variances, we effectively uncouple the system resolution from the size of the ultrasound focus. This enables us to demonstrate optical focusing and imaging with diffuse light at unprecedented, speckle-scale lateral resolution of ~ 5 MUm. PMID- 23814606 TI - Prospective histopathologic evaluation of lifestyle modification in nonalcoholic fatty liver disease: a randomized trial. AB - BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is now recognized as part of the metabolic syndrome, and is specifically related to obesity and insulin resistance. Lifestyle modification is advocated for the treatment of NAFLD, but few studies have evaluated its impact on liver histology. The purpose of this study was to investigate which, if any, specific diet and exercise recommendations are associated with histopathologic changes. METHODS: A total of 56 participants were randomly assigned to 1 of 4 lifestyle modification subgroups for 6 months: standard care, low-fat diet and moderate exercise, moderate-fat/low processed-carbohydrate diet and moderate exercise, or moderate exercise only. All subjects had biopsy-proven NAFLD, to include nonalcoholic steatohepatitis (NASH), and received a repeat 6-month biopsy to detect histopathologic changes. Other measures included blood assay of liver enzymes (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase), fasting glucose, serum insulin, lipid panel, body weight, dietary intake, fat mass, and fitness level. RESULTS: Among the 41 participants who completed the study (88% with NASH), a significant change was found in pre- to post-NAFLD activity score in the group as a whole (p < 0.001) with no difference detected between subgroups (p = 0.31). Our results confirm that lifestyle modification is effective in improving NAFLD and NASH. CONCLUSIONS: Regardless of intervention group, lifestyle modification improved liver histology, as verified by repeat biopsy, after a 6-month intervention. This study reinforces the importance of lifestyle modification as the primary treatment strategy for patients with NAFLD. PMID- 23814608 TI - Comprehensive review: antitumor necrosis factor agents in inflammatory bowel disease and factors implicated in treatment response. AB - Antitumor necrosis factor alpha (anti-TNF) agents have dramatically influenced management of refractory inflammatory bowel disease (IBD). However, not all patients respond to treatment and some lose response or become intolerant over time. Immunogenicity, a well established phenomenon with anti-TNF agents, may have important clinical implications in patients with IBD. A comprehensive review of available evidence demonstrating how drug concentrations, immunogenicity, and other factors influence outcomes with anti-TNF agents was performed. PubMed, EMBASE, Biosis, Dialog, and Conference Papers Index were searched from 1 January 1995 to 7 April 2012 to identify clinical trials in adult and pediatric patients with IBD treated with anti-TNF agents for Crohn's disease or ulcerative colitis. Data on serum drug levels and immunogenicity and their relationship with clinical efficacy and safety outcomes were extracted and examined. Serum infliximab concentrations correlated with clinical efficacy and treatment outcomes in patients with IBD; this relationship is less well characterized with adalimumab and certolizumab pegol concentrations. In multiple studies, the presence and level of antibodies to infliximab correlated with loss of clinical efficacy and increased risk of infusion reactions. The incidence and clinical impact of antibody formation with adalimumab or certolizumab in IBD is becoming evident as more data become available. Current, enzyme-linked immunosorbent assay based anti TNF antibody assays are suboptimal in that results are often inconclusive and comparisons between agents cannot be made. Measurement of anti-TNF agent drug concentrations and assessment of immunogenicity has the potential to positively impact clinical decision making during anti-TNF therapy for IBD. As assays are optimized, it is expected that the clinical impact of these determinations will be better characterized. PMID- 23814607 TI - LINX((r)) Reflux Management System in chronic gastroesophageal reflux: a novel effective technology for restoring the natural barrier to reflux. AB - Gastroesophageal reflux disease (GERD) results from incompetency of the lower esophageal sphincter that allows the contents of the stomach to reflux into the esophagus, the airways, and the mouth. The disease affects about 10% of the western population and has a profound negative impact on quality of life. The majority of patients are successfully treated with proton-pump inhibitors, but up to 40% have incomplete relief of symptoms even after dose adjustment. The laparoscopic Nissen fundoplication represents the surgical gold standard, but is largely underused because of the level of technical difficulty and the prevalence of side effects. These factors have contributed to the propensity of patients to continue with medical therapy despite inadequate symptom control and complications of the disease. As a consequence, a significant 'therapy gap' in the treatment of GERD remains evident in current clinical practice. The LINX((r)) Reflux Management System (Torax Medical, St. Paul, MN, USA) is designed to provide a permanent solution to GERD by augmenting the sphincter barrier with a standardized, reproducible laparoscopic procedure that does not alter gastric anatomy and is easily reversible. Two single-group trials confirmed that a magnetic device designed to augment the lower esophageal sphincter can be safely and effectively implanted using a standard laparoscopic approach. The device decreased esophageal acid exposure, improved reflux symptoms and quality of life, and allowed cessation of proton-pump inhibitors in the majority of patients. PMID- 23814609 TI - Role of the gut microbiota in health and chronic gastrointestinal disease: understanding a hidden metabolic organ. AB - The human gut microbiota has become the subject of extensive research in recent years and our knowledge of the resident species and their potential functional capacity is rapidly growing. Our gut harbours a complex community of over 100 trillion microbial cells which influence human physiology, metabolism, nutrition and immune function while disruption to the gut microbiota has been linked with gastrointestinal conditions such as inflammatory bowel disease and obesity. Here, we review the many significant recent studies that have centred on further enhancing our understanding of the complexity of intestinal communities as well as their genetic and metabolic potential. These have provided important information with respect to what constitutes a 'healthy gut microbiota' while furthering our understanding of the role of gut microbes in intestinal diseases. We also highlight recently developed genomic and other tools that are used to study the gut microbiome and, finally, we consider the manipulation of the gut microbiota as a potential therapeutic option to treat chronic gastrointestinal disease. PMID- 23814610 TI - Prophylaxis of hepatitis B infection in solid organ transplant recipients. AB - Rates of transmission of hepatitis B virus (HBV) infection from organ donors with HBV markers to recipients along with reactivation of HBV during immunosuppression following transplantation have fallen significantly with the advent of hepatitis B immune globulin (HBIg) and effective antiviral therapy. Although the availability of potent antiviral agents and HBIg has highly impacted the survival rate of HBV-infected patients after transplantation, the high cost associated with this practice represents a major financial burden. The availability of potent antivirals with high genetic barrier to resistance and minimal side effects have made it possible to recommend an HBIg-free prophylactic regimen in selected patients with low viral burden prior to transplant. Significant developments over the last two decades in the understanding and treatment of HBV infection necessitate a re-appraisal of the guidelines for prophylaxis of HBV infection in solid organ transplant recipients. PMID- 23814612 TI - Low Recognition of Posttraumatic Stress Disorder in Primary Care. AB - Posttraumatic stress disorder (PTSD) is a common and disabling disorder that develops as a consequence of traumatic events and is characterised by distressing re-experiencing of parts of the trauma, avoidance of reminders, emotional numbing and hyperarousal. The NICE guidelines for PTSD (2005) recommend trauma-focused psychological therapy as the first-line treatment. A survey of 129 general practitioners in South London investigated the recognition and treatment of PTSD in primary care. The majority of GPs underestimated the prevalence of PTSD. Most PTSD patients seen in GP surgeries currently do not receive or are not referred for NICE recommended psychological treatments. Medications, especially SSRIs, appear to more commonly prescribed than recommended by NICE. Efforts to disseminate information about PTSD and effective treatments to both patients and GPs are needed to increase recognition rates and prompter access to treatment. The Improving Access to Psychological Therapies (IAPT) programme will make the NICE recommended treatments more widely available and will allow self-referral by adults with PTSD to trauma-focused psychological therapy. PMID- 23814613 TI - Personalized medicine in Type 2 diabetes: what does the future hold? AB - The management of patients with Type 2 diabetes is based on a remarkably robust evidence base. Large clinical trials and lengthy observational cohort studies have clearly established the importance of glycemic, blood pressure and lipid level control. Indeed, most elements of guideline-based diabetes care can be supported by clinical research evidence. While such studies are critical for establishing treatment recommendations, the evidence derived from clinical trial participants applies to populations of patients rather than to the individual sitting before the clinician. An important next step in diabetes care would be to develop and implement a framework for personalizing care. In this article, we highlight the major reasons for personalization and discuss what the future of personalized diabetes care may hold. PMID- 23814611 TI - Pancreatic cancer: why is it so hard to treat? AB - No common malignancy is as rapidly and inevitably fatal as pancreatic ductal adenocarcinoma (PDA). This grim fact has driven substantial research efforts into this disease in recent decades. Unfortunately, the investment has yet to result in a meaningful increase in 5-year survival. This has prompted many pancreatic cancer researchers and advocates to redouble their efforts, but also requires one to step back and ask why the previous efforts were lacking and to consider why pancreatic cancer is so difficult to treat. The difficulties are legion. PDA is characterized by an insidious clinical syndrome, but is rarely diagnosed at a time when surgical resection is feasible. We lack markers of early detection and screening programs remain unproven even in high risk populations. The location of the tumor in the retroperitoneum, the advanced age of patients, and the systemic effects of disease limit the options for local therapy. Chemotherapy may provide a small benefit, but most efforts to improve on the current regimens consistently and stubbornly fail in advanced clinical trials. The molecular and cellular features of ductal pancreatic tumors are aggressive and underlay multiple levels of therapeutic resistance. Non-cell-autonomous features including stromal proliferation, reduced vascular density and immune suppression also contribute to therapeutic resistance. Growing awareness of these the fundamental features of PDA has begun to guide ongoing research efforts. Clinical trials are now specifically targeting these tumor properties and actively focusing on the therapeutic implications of tumor stroma. As reviewed here, reflecting on the fundamental question of why pancreatic cancer is so difficult to treat is a necessary and informative exercise that will aid our efforts to improve patient outcomes. These efforts will lead to improvements in clinical trial design, expand our focus to include the molecular and histologic implications of novel treatment paradigms, and ultimately change the lives of our patients. PMID- 23814616 TI - Reliability of plain radiographic parameters for developmental dysplasia of the hip in children. AB - INTRODUCTION: Few studies have evaluated the reliability and reproducibility of the femoral neck-shaft angle (NSA), center-edge angle (CEA), and acetabular index (AI) in young children with developmental dysplasia of the hip (DDH). We wanted to determine whether these parameters could be used reliably by practitioners. METHODS: Fifty radiographs from 21 children with DDH were reviewed. Analysis was performed by three observers, at two time periods. The intra- and inter-observer reliability for each measure was assessed. RESULTS: At time period one, we noted a "high" level of agreement between observers when measuring the NSA, a "low" level when measuring the CEA, and a "moderate" level when measuring the AI. At time period two, we noted a "very high" level of agreement between observers when measuring the NSA and a "high" level when measuring the CEA and AI. When comparing the measurements of observer 1 at the two different time periods, we noted nearly "very high" agreement when measuring the NSA, a "moderate" agreement when measuring the CEA, and a "high" agreement for the AI. In comparing the measurements of observer 2, we noted "very high" agreement for the NSA and "high" agreement for the CEA and AI. In comparing the measurements for observer 3, we noted nearly "very high" agreement for the NSA, nearly "high" agreement for the CEA, and "high" agreement for the AI. CONCLUSION: It is difficult to reliably measure three-dimensional pelvic morphology on a frontal plane radiograph, especially when important pelvic landmarks have yet to ossify. PMID- 23814615 TI - Hip impingement in slipped capital femoral epiphysis: a changing perspective. AB - BACKGROUND: Femoroacetabular impingement (FAI) as a result of slipped capital femoral epiphysis (SCFE) has recently gained significant attention. Seen as an intermediate step toward the development of early osteoarthritis, symptomatic FAI develops in SCFE patients who have residual hip deformity characterized by relative posterior and medial displacement of the capital femoral epiphysis, leading to an anterolateral prominence of the metaphysis which abuts on the acetabular rim. This results in a decreased range of hip motion as well as progressive labral damage and articular cartilage injury, which cause symptoms of FAI. All degrees of slips from mild to severe can develop impingement. METHODS: The existing literature on the subject was thoroughly reviewed and all levels of studies that have made any meaningful changes to clinical practice were considered. RESULTS: Based on the literature review, current practice trends, and our own institutional practice pattern, all treatment options for SCFE in the impingement era have been presented with an open discussion regarding potential benefits and limitations. CONCLUSIONS: Several surgical options exist for the SCFE patient who develops FAI. These are largely determined by the degree of deformity present and severity of the initial slip. Extraarticular (intertrochanteric, base of the neck) as well as subcapital osteotomies can be utilized with a goal of restoring proximal femoral anatomy in order to minimize the effect of the anterolateral prominence in more severe deformities. Patients with milder deformities can undergo osteochondroplasty of the femoral head and neck to remove impinging structures via either an open or arthroscopic approach. Also, proximal femoral osteotomy and open head-neck recontouring can be combined. Finally, patients who develop pain very early after in situ pinning must also be examined for potential iatrogenic screw-head impingement as a source of their pain and decreased hip motion, in addition to abnormalities in the proximal femoral anatomy. There are many centers that are approaching acute unstable SCFE patients as well as the more displaced stable cases with open reduction techniques that seem to be demonstrating good mid-term results. The goal of treatment is to improve patient function, alleviate hip pain, and to delay or prevent the development of early degenerative changes in adolescents and young adults. Prospective multi-center studies will be necessary so as to determine what methods work best in treatment and delay the onset and progression of osteoarthritis. LEVEL OF EVIDENCE: V. PMID- 23814614 TI - Breast cancer survivorship symptom management: current perspective and future development. AB - Increasing numbers and longevity of cancer survivors has furthered our insight into the factors affecting their health outcomes, suggesting that multiple factors play a role (e.g., effects of cancer treatments and health behaviors). Emotional and physical symptoms may not always receive sufficient attention. In this short narrative review highlighting recent literature, we describe the most common physical and emotional symptoms of breast cancer survivors aged 50 years and older and outline a multidisciplinary symptom management approach, regardless of symptom etiology. PMID- 23814617 TI - Birth-related femoral fracture in newborns: risk factors and management. AB - PURPOSE: Femoral shaft fracture following birth in newborns is a very rare injury. However, the risk factors for, mechanism of and management of these injuries remain a matter of debate. We describe our observations in a tertiary centre. METHODS: Ten cases of femoral shaft fracture encountered during a study period from January 2005 to December 2009 were evaluated. The demographic details, risk factors during birth, systemic illness, mode of delivery, type of fracture and management used were documented, and an analysis was performed. RESULTS: Mean gestational age was 37.2 weeks. Mean time to diagnose was 4 days. Two patients had subtrochanteric fracture, and eight patients had mid-shaft fracture. Most patients had breech presentation and had been born by Caesarean section. All patients showed complete union at the end of 4 weeks. No residual angulation or limb length discrepancy was noted after mean follow-up of 5 years. CONCLUSIONS: Thorough clinical examination and proper orthopaedic consult in the event of doubtful presentation help in early diagnosis and management. These fractures have good prognosis at long-term follow-up. PMID- 23814618 TI - Intramedullary nails for pediatric diaphyseal femur fractures in older, heavier children: early results. AB - PURPOSE: A common treatment for pediatric femur fractures is intramedullary nail (IMN) insertion. Elastic stable intramedullary nails (ESINs) are often used for these procedures in heavier patients, but the potential for complications and malunion is greater. We describe here a rigid IMN specifically designed for adolescents, the adolescent lateral entry femoral nail (ALFN). The purpose of this study was to compare the recovery and complications for patients treated with ESINs to those treated with the ALFN. METHODS: Our study design was a retrospective cohort study. We performed a review of medical records of 22 children ages 10-17 requiring surgical fixation of a femur fracture for a 21/2 year period. Patients selected for the study had traumatic diaphyseal femur fractures and were treated with ESINs without end-caps or ALFNs. Our analyses evaluated injury, surgical, and outcome information for all patients. RESULTS: Twenty-two patients were eligible for inclusion and were divided into two groups according to their treatment: the ESIN group with 7 patients and the ALFN group with 15 patients. We then performed a comparison of complications and recovery for these patients. The mean time to full weight-bearing was significantly less for the ALFN group (4.1 weeks; SD, 2.2), than the ESIN group (9.4 weeks; SD 3.9). There was no statistical difference in the incidence of major or minor complications. CONCLUSIONS: Older, heavier pediatric patients treated for femur fracture with ALFNs had a shorter recovery time than similar patients treated with ESINs. However, the outcomes for both groups were satisfactory. PMID- 23814619 TI - Congenital constriction ring in children: sine plasty combined with removal of fibrous groove and fasciotomy. AB - OBJECTIVE: To evaluate the clinical and functional results of a technical procedure used in the surgical treatment of congenital constriction ring (CCR) in children. MATERIALS AND METHODS: This was a retrospective study undertaken to evaluate the results of surgical techniques performed from January 1995 to December 2005 on 95 patients with 134 congenital constriction bands. Due to the drop-out of nine patients during follow-up, data on 86 patients (121 congenital constriction rings; average age at surgery 1 year 2 months) were analyzed. The extent of the constrictions was classified by according to the Patterson criteria. All patients were treated by two-stage sine plasty combined with removal of the fibrous groove and fasciotomy, with one-half of the ring removed during the first stage and the other half removed 1 week later during the second state. The surgical outcomes were assess according to the Moses criteria. RESULTS: Three types of CCR (Patterson criteria) were identified among the 86 patients (121 constriction rings): types I (5 patients, 4.1 %), II (107, 88.5 %), III (9, 7.4 %). Of the 121 constriction rings, good results were attained in 73.6 % and fair results in 26.4 %. Sensory deficits were seen in six patients immediately after the surgery but all six had improved to a normal condition at the final follow-up examination. There were no skin necrosis or wound healing problems. CONCLUSION: The combined sine plasty/removal of fibrous groove and fasciotomy method reported here is a simple and safe surgical technique for treating CCR in children. PMID- 23814620 TI - Musculoskeletal manifestations of neonatal nonketotic hyperglycinemia. AB - PURPOSE: Neonatal nonketotic hyperglycinemia is an autosomal recessive inborn disorder of glycine metabolism in which large quantities of glycine accumulate in all body tissues. It is characterized by a progressive lethargy, hypotonia, myoclonic jerks, and early death secondary to respiratory problems. As a result of early diagnosis and treatment protocols, more patients survive the critical neonatal period with profound mental retardation, delayed developmental milestones, seizures, and spasticity. There are no reports about the orthopaedic manifestations of neonatal nonketotic hyperglycinemia. The purpose of this study is to evaluate the musculoskeletal findings of neonatal nonketotic hyperglycinemia. METHODS: This is a retrospective IRB-approved study of all patients in our Orthopaedic and Genetics Clinics with the diagnosis of neonatal nonketotic hyperglycinemia during a 10-year period. Demographic, clinical, and imaging data were analyzed. RESULTS: Twelve patients with neonatal nonketotic hyperglycinemia were evaluated, with a mean age of 7 years and 2 months (range: 5 months to 21 years). Seven were male and five were female. Eleven patients (92 %) have evidence of progressive early-onset neuromuscular scoliosis with a mean Cobb angle of 55 degrees (range: 30-95 degrees ). Five children (42 %) presented evidence of progressive hip dislocation secondary to spasticity. All the patients have severe multiple joint contractures. CONCLUSION: Neonatal nonketotic hyperglycinemia is a rare metabolic disorder presented in the past as a lethal condition. Recent advances in early diagnosis and neonatal care improve overall outcome. As pediatric orthopaedic surgeons, we need to establish treatment based on update information of the disease and probability to improve quality of life. PMID- 23814621 TI - Primary obturator-muscle pyomyositis in immunocompetent children. AB - PURPOSE: Primary pyomyositis in immunocompetent children in non-tropical regions (countries with temperate climates) is very uncommon. It is rarely found in the intrapelvic muscles, and even more rarely in the obturator muscles. We try to draw attention to the potential occurrence in these conditions. METHODS: Five new cases of primary obturator-muscle pyomyositis in immunocompetent children aged between 6 and 11 years in a temperate climate are presented. They present with symptoms as follows: fever, pain (thigh, abdominal, inguinal, and/or hip pain), and limp. Three of them had no hip movement limitation. All of them had tenderness in the perineum zone. RESULTS: Laboratory tests may reveal high erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) counts, but depend on the length of diagnostic delay. The evolution time oscillated from 1 to 5 days. Fever and limp disappearance depends on the evolution time previous to the onset of the antibiotics administration. In 4 out of 5 patients, Staphylococcus aureus was present in the blood cultures. In all cases of obturator-muscle pyomyositis, diagnosis was confirmed using computed tomography (CT) scan (one) and/or magnetic resonance imaging (MRI) (four). CONCLUSIONS: Obturator-muscle pyomyositis is aimed at emphasizing the diagnostic difficulties associated with the condition, due to its deep location and to the fact that the disease presents with multiple manifestations that may initially cause confusion, since they mimic other conditions occurring in the abdomen, hip (septic arthritis, osteomyelitis), spine, etc. The diagnosis is only confirmed using CT scan and/or MRI. In the five patients with antibiotics treatment, the condition resolves without sequelae, even at long-term follow-up. PMID- 23814622 TI - Pes planovalgus deformity surgical correction in ambulatory children with cerebral palsy. AB - PURPOSE: Planovalgus foot deformity is common in diplegic and quadriplegic patients. Surgery is the definitive treatment to restore the alignment of the talus, calcaneus, and navicular bones. We aimed, in the current study, to compare the effectiveness of subtalar fusion and calcaneal lengthening, and to assess the recurrence in ambulatory children with cerebral palsy. METHODS: This is a retrospective study of 78 patients (138 feet diagnosed with planovalgus deformity) who underwent surgical correction using subtalar fusion or calcaneal lengthening. Range of motion, radiographic indices, kinematic, and pedobarographic data were used to examine the deformity and the outcome of surgery. A repeated measures analysis of variance (ANOVA) was used to test the study hypothesis. RESULTS: Most of the patients were diplegic (87.2 %) and the mean age at surgery was 11.9 +/- 2.9 years (range from 4.7 to 18.3 years), with a mean follow-up of 5 +/- 4.4 years (range from 1 to 15.4 years). Sixty-three feet were treated with calcaneal lengthening, while 75 were treated with subtalar fusion. The feet treated with subtalar fusion were more severe preoperatively. However, both surgery groups showed improvement postoperatively. Among 12 cases of recurrence, medial column fusion was the main surgery performed to correct the deformity. CONCLUSIONS: Surgery is effective in the treatment of planovalgus deformity in ambulatory children with cerebral palsy. Severe and rigid planovalgus feet can be treated effectively with subtalar fusion. Feet with milder deformity show good results, with calcaneal lengthening. Surgery provides good correction in young patients, but there is a higher recurrence rate. PMID- 23814623 TI - Comparison of hamstring lengthening with hamstring lengthening plus transfer for the treatment of flexed knee gait in ambulatory patients with cerebral palsy. AB - PURPOSE: Children with spastic diplegic and hemiplegic cerebral palsy frequently ambulate with flexed knee gait. There has been concern that hamstring lengthening used to treat this problem may weaken hip extension. This study evaluates the primary outcome of hamstring transfer plus lengthening in comparison with traditional hamstring lengthening in treating flexed knee gait in ambulatory patients with cerebral palsy. METHODS: A total of 47 children (67 lower limbs) ranging in age from 5 to 17 years old were included in this study. All subjects underwent a variety of additional surgeries at the time of the hamstring surgery as part of a multilevel treatment plan. All patients who met the inclusion criteria were divided into two groups, the hamstring lengthening alone group (HSL) and the hamstring transfer plus lengthening group (HST). Full gait analysis studies were done for all subjects pre-operatively and 1 year post-operatively. RESULTS: There were 25 patients (35 limbs) in the HSL group and 22 patients (32 limbs) in the HST group. There was no significant difference in age, gender, or the time from surgery to post-operative gait analysis between groups. On physical examination, both HSL and HST groups showed improvement in passive knee extension, popliteal angle, and straight leg raise. Maximum knee extension in stance phase was improved in both groups. The maximum hip extension in late stance phase was significantly improved only in the HST group. The peak hip extension power in stance phase showed significant improvement only in the HST group and a significant decrease for the HSL group. CONCLUSIONS: The findings of this study demonstrated that both the HSL and HST procedures resulted in similar amounts of improvement in passive range of motion of the knee, as well in knee extension in stance during gait at 1 year post-operatively. However, with the HST procedure, there was better preservation of hip extension power and improved hip extension in stance. The HST procedure should be considered when hamstring surgery is performed. PMID- 23814624 TI - Spondylolysis is frequently missed by MRI in adolescents with back pain. AB - PURPOSE: Magnetic resonance imaging (MRI) is often used in the evaluation of lower back pain in adolescents. The purpose of our study is to report on the frequency of MRI missing spondylolysis in adolescents with back pain in a pediatric orthopaedic practice. METHODS: A retrospective review of all patients with a diagnosis of spondylolysis who presented from January 2000 to March 2010 was performed. All patients were evaluated at a single institution by the senior author. Inclusion criteria were patients with spondylolysis confirmed on computed tomography (CT) or plain film that also received an MRI. RESULTS: Eleven patients with spondylolysis had an MRI performed. The mean age of the study patients was 14.2 years (range 10-17). The diagnosis of spondylolysis was missed in the MRI radiology reading in 7 out of 11 (64 %) studies. CONCLUSIONS: MRI missed a spondylolysis in over half of the adolescents in this consecutive series. In patients with a history or physical findings suggestive of spondylolysis, such as localized pain of the lumbar spine with back extension, further radiographic evaluation should be considered, even if an MRI is negative. LEVEL OF EVIDENCE: III, retrospective review. PMID- 23814625 TI - The modulation of spinal growth with nitinol intervertebral stapling in an established swine model. AB - PURPOSE: Anterior spinal stapling for the treatment of adolescent idiopathic scoliosis has been shown to slow progression in small curves; however, its role in larger curves remains unclear. The purpose of this study was to evaluate the effectiveness of nitinol staples to modulate spinal growth by evaluating the two dimensional and three-dimensional morphological and histological effects of this method in a well-established porcine model. METHODS: Three immature Yucatan miniature pigs underwent intervertebral stapling. Two staples spanned each of three consecutive mid-thoracic discs and epiphyses. Monthly radiographs were obtained. Computed tomography (CT) was conducted at harvest after 6 months of growth. Measurements of wedging and height for each disc and vertebral body were conducted. Micro CT was used to compare physeal closure between stapled and non stapled levels. Histology of the growth plate also compared the hypertrophic zone thickness for control and stapled vertebrae. RESULTS: After 6 months of stapled growth, the average coronal Cobb angle of the stapled segments increased by 7.7 +/- 2.0 degrees and kyphosis increased by 3.3 +/- 0.6 degrees compared to preoperative curves. Increased vertebral wedging and decreased disc height (p < 0.001) were noted in stapled regions. Overall, 26 +/- 23 % of each growth plate was closed in the stapled segments, with 6 +/- 8 % closure in the unstapled levels. No difference was observed regarding the hypertrophic zone height when comparing instrumented to uninstrumented levels, nor was a difference recognized when comparing right versus left regions within stapled levels alone. CONCLUSIONS: Six months of nitinol intervertebral stapling created a mild coronal and sagittal deformity associated with reduced vertebral and disc height, and increased coronal vertebral and sagittal disc wedging. PMID- 23814626 TI - Commentary on the article "Alternative technique for open reduction and fixation of displaced pediatric medial epicondyle fractures" by Michael P. Glotzbecker, Benjamin Shore, Travis Matheney, Meryl Gold, Daniel Hedequist. J Child Orthop doi:10.1007/s11832-012-0395-1. PMID- 23814627 TI - Alternative technique for open reduction and fixation of displaced pediatric medial epicondyle fractures: author response to letter to the editor. PMID- 23814630 TI - Development Policy in Thailand: From Top-down to Grass Roots. AB - Top-down industrial development strategies initially dominated the developing world after the second World War but were eventually found to produce inequitable economic growth. For a decade or more, governments and international development agencies have embraced the idea of participatory grass roots development as a potential solution. Here we review Thailand's experience with development strategies and we examine the current focus on participatory approaches. Thai government planning agencies have adopted "people centred development" and a "sufficiency economy", particularly emphasised since the disruptions caused by the 1997 Asian financial crisis. They aim to address the inequitable sharing of the benefits of decades of rapid growth that was particularly unfair for the rural poor. Thai policies aim to decentralise power to the local level, allowing civil society and Non-Governmental Organisations (NGOs) more of a voice in national decision making and promoting sustainable farming practices aimed at enriching rural communities. An example of this change in Thai government policy is the Community Worker Accreditation Scheme which is aiming to develop human resources at the local level by training community based leaders and supporting networks of community organisations. This enables autonomous local development projects led by trained and accredited individuals and groups. The political tensions notable in Thailand at present are part of this modern transition driven by conflicting models of top-down (industrial) development and the bottom-up (participatory) development ideals described above. Once resolved, Thailand will have few obstacles to moving to a new economic level. PMID- 23814628 TI - The potential for cell-based therapy in perinatal brain injuries. AB - Perinatal brain injuries are a leading cause of cerebral palsy worldwide. The potential of stem cell therapy to prevent or reduce these impairments has been widely discussed within the medical and scientific communities and an increasing amount of research is being conducted in this field. Animal studies support the idea that a number of stem cells types, including cord blood and mesenchymal stem cells have a neuroprotective effect in neonatal hypoxia-ischemia. Both these cell types are readily available in a clinical setting. The mechanisms of action appear to be diverse, including immunomodulation, activation of endogenous stem cells, release of growth factors, and anti-apoptotic effects. Here, we review the different types of stem cells and progenitor cells that are potential candidates for therapeutic strategies in perinatal brain injuries, and summarize recent preclinical and clinical studies. PMID- 23814631 TI - BAYESIAN MODELING LONGITUDINAL DYADIC DATA WITH NONIGNORABLE DROPOUT, WITH APPLICATION TO A BREAST CANCER STUDY. AB - Dyadic data are common in the social and behavioral sciences, in which members of dyads are correlated due to the interdependence structure within dyads. The analysis of longitudinal dyadic data becomes complex when nonignorable dropouts occur. We propose a fully Bayesian selection-model-based approach to analyze longitudinal dyadic data with nonignorable dropouts. We model repeated measures on subjects by a transition model and account for within-dyad correlations by random effects. In the model, we allow subject's outcome to depend on his/her own characteristics and measure history, as well as those of the other member in the dyad. We further account for the nonignorable missing data mechanism using a selection model in which the probability of dropout depends on the missing outcome. We propose a Gibbs sampler algorithm to fit the model. Simulation studies show that the proposed method effectively addresses the problem of nonignorable dropouts. We illustrate our methodology using a longitudinal breast cancer study. PMID- 23814629 TI - Assessment of the Efficacy of New Anti-Tuberculosis Drugs. AB - The pathology of tuberculosis in humans starts with an initial Ghon focus in the lungs followed by transmission of bacilli though the blood and lymph to other regions in the lungs and to other organs. While these bacilli usually lie latent without causing further disease, some 10% start foci of adult type disease usually starting in the sub-apical regions of the lungs. Bacilli multiply, killing tissue by caseation and then forming colonies within the caseum. Cavities form connecting to the air in whose walls vigorous bacillary multiplication occurs. The history of the development of anti-tuberculosis chemotherapy is described, starting with the use of multi-drug regimens to prevent the emergence of drug resistance and continuing with the shortening of the treatment period to 6 months by the incorporation in the regimens of rifampicin and pyrazinamide, which are the two drug responsible for bactericidal activity during treatment. Prospects for further shortening of treatment rest with the introduction of higher dosage with rifamycins and with new anti-tuberculosis drugs. These new drugs include the 8 methoxyfluoroquinolones moxifloxacin and gatifloxacin which inhibit topoisomerases and protein formation, the diarylquinoline TM-207 which inhibits the mycobacterial ATP synthase and thus energy formation, the nitroimidazopyran PA-824 and the closely related OPC-676832 which are pro-drugs with uncertain modes of action and the pyrrole SQ-109, a cell wall inhibitor. Anti-tuberculosis drugs have widely variable pharmacokinetic characteristics but as they work efficiently together, it is unnecessary to match these when giving drug combinations. The effects of drug-drug interactions are usually small though the interactions with anti-retroviral drugs can pose problems. Dose sizes have usually been chosen to minimize side effects while retaining activity and thus tend to have low therapeutic margins, the exception being the margin of about 20 for isoniazid. The role of high plasma binding, important in limiting the efficacy of rifamycins, is uncertain for the newer drugs. Post antibiotic effects are vital to the prevention of drug resistance and need exploration for new drugs. The main aims of current drug development are (1) to shorten treatment, and (2) to make it more convenient, by for instance using widely intermittent regimens. The current techniques for measuring efficacy during drug development start with in vitro models, including the Hu/Coates models, which should contain bacterial populations resembling the bacterial persisters in lesions that are responsible for the long duration of treatment. The next stage is the mouse model of the chemotherapy of established tuberculosis, which has proved remarkably useful in assessing the value of the different drugs. The main problem in clinical assessment arises from the use of relapse after treatment as the main end-point, and the consequent need for very large numbers of patients required to provide measurable relapse rates in final phase III licensing studies. For this reason, surrogate studies are necessary in phase II which require much smaller numbers of patients. The first such investigations are phase IIA studies of early bactericidal activity which establish whether the drug given alone has bactericidal activity on cavitary bacilli and which can estimate the minimal effective dose of the drug, useful for decisions of dose size. The next step should be phase IIB studies which measure the rate of elimination of viable bacilli in sputum during the initial 8-weeks of treatment with various combinations of the new drug with established drugs. Measurement can be as (1) the proportion of patients with positive sputum at the end of the 8-weeks period, the easiest method but the least sensitive, or (2) as the speed with which sputum cultures become negative in a survival analysis, or (3) as the mean regression in modeling of serial sputum collections colony counts (SSCC). The relation between these surrogate estimates and the amoun of treatment shortening that can be obtained has still to be worked out. PMID- 23814632 TI - Electrochemical Protease Biosensor Based on Enhanced AC Voltammetry Using Carbon Nanofiber Nanoelectrode Arrays. AB - We report an electrochemical method for measuring the activity of proteases using nanoelectrode arrays (NEAs) fabricated with vertically aligned carbon nanofibers (VACNFs). The VACNFs of ~150 nm in diameter and 3 to 5 MUm in length were grown on conductive substrates and encapsulated in SiO2 matrix. After polishing and plasma etching, controlled VACNF tips are exposed to form an embedded VACNF NEA. Two types of tetrapeptides specific to cancer-mediated proteases legumain and cathepsin B are covalently attached to the exposed VACNF tip, with a ferrocene (Fc) moiety linked at the distal end. The redox signal of Fc can be measured with AC voltammetry (ACV) at ~1 kHz frequency on VACNF NEAs, showing distinct properties from macroscopic glassy carbon electrodes due to VACNF's unique interior structure. The enhanced ACV properties enable the kinetic measurements of proteolytic cleavage of the surface-attached tetrapeptides by proteases, further validated with a fluorescence assay. The data can be analyzed with a heterogeneous Michaelis-Menten model, giving "specificity constant" kcat /Km as (4.3 +/- 0.8) * 104 M-1s-1 for cathepsin B and (1.13 +/- 0.38) * 104 M-1s-1 for legumain. This method could be developed as portable multiplex electronic techniques for rapid cancer diagnosis and treatment monitoring. PMID- 23814633 TI - Combining clinical studies and analogue experiments to investigate cognitive mechanisms in posttraumatic stress disorder. AB - Research into cognitive mechanisms in posttraumatic stress disorder (PTSD) typically comprises two types of studies. The first group of studies is conducted with survivors of traumatic events and assesses the association between PTSD and cognitive variables with questionnaires and/or information processing paradigms. In the second group of studies, healthy non-traumatized individuals are exposed to an analogue stressor (e.g., a stressful film) and cognitive variables of interest are usually experimentally manipulated to investigate their effects on analogue PTSD symptoms. This review illustrates how studies of trauma survivors and analogue studies with non-traumatized populations can be usefully combined. Two examples for this approach are presented: (1) research into the role of perceptual priming for trauma-related stimuli and (2) research into trauma related rumination. The advantages and limitations of both types of studies are discussed and it is argued that a combination of both approaches is needed to investigate cognitive mechanisms in PTSD. PMID- 23814634 TI - Amnion-derived multipotent progenitor cells improve achilles tendon repair in rats. AB - OBJECTIVE: Tendon injuries produce considerable morbidity, long-lasting disability, and remain a considerable challenge for clinicians and patients. The objective of the study was to assess the effect of amnion-derived multipotent progenitor (AMP) cells and amnion-derived cell cytokine solution on Achilles tendon healing by using a rat model. METHODS: Achilles tendons of Sprague-Dawley rats were exposed and transected. The distal and proximal ends were injected with either saline, amnion-derived cell cytokine solution, or AMP cells in a standardized fashion and then sutured by using a Kessler technique. Tendons from each group (n = 6-13) were collected at weeks 1, 2, and 4 postoperatively and assessed for material properties (ultimate tensile strength, Young modulus, yield strength, and breaking strength). Tendons were also evaluated histologically for cross-sectional area by using hematoxylin-eosin and trichrome stains. RESULTS: Mechanical testing showed that the Young modulus was significantly higher in AMP cells-treated tendons at week 4 compared with both saline-treated and amnion derived cell cytokine solution-treated tendons. Yield strength was significantly higher in the AMP cells-treated group compared with saline-treated controls at week 4. No significant differences were observed between the study groups at weeks 1 and 2. DISCUSSION: Amnion-derived multipotent progenitor cells have a positive effect on healing tendons by improving mechanical strength and elastic modulus during the healing process. The presented findings suggest the clinical utility of AMP cells in facilitating the healing of ruptured tendons. Both the Young modulus and yield strengths of tendons increased significantly following treatment with AMP cells. PMID- 23814635 TI - Salvage of failed prosthetic breast reconstructions by autologous conversion with free tissue transfers. AB - OBJECTIVE: Implant-based breast reconstructions are conceptually simple but prone to surgical revisions. Additional procedures often fail to address the problems associated with the reconstructive outcome, especially in patients who have received radiotherapy. However, conversion to free flaps may improve symptoms and aesthetic results. We reviewed our experience in the United Kingdom with autologous replacement of failed prosthetic reconstructions with the aims of documenting the indications for "tertiary" reconstructions and comparing our outcomes with those of other centers. METHODS: Patients undergoing salvage surgery for suboptimal prosthetic breast reconstructions between 2000 and 2012 were retrospectively reviewed for their original reconstructive operation, previous radiotherapy, indications for revision, corrective procedures undertaken, and final outcomes. RESULTS: Of 14 patients identified, 7 had delayed and 7 had immediate reconstructions. Twelve had received radiotherapy; 6 before the initial delayed prosthetic reconstructions and 6 after immediate reconstructions. Ten patients presented after undergoing previous revisions of their original reconstructions (average 1.6). Indications for autologous conversion were capsular contracture, persistent pain, and poor cosmetic outcomes (often in combination). Salvage comprised explantation, total capsulectomy, and abdominal free flap reconstruction using deep inferior epigastric artery flaps (9) and transverse rectus abdominis myocutaneous flaps (5). The average interval between initial reconstruction and salvage was 8 years (r = 1-14). All flap transfers were successful with satisfactory aesthetic outcomes (average 21 months follow-up). CONCLUSIONS: We recommend early salvage autologous conversion of implant-based reconstructions once initial prosthetic reconstructions become unsatisfactory, particularly in recipients of radiotherapy. Many of these patients may have been better served by initial autologous reconstruction; the challenge is to identify them prospectively. PMID- 23814636 TI - Eyebrow ptosis after blowout fracture indicates impairment of trigeminal proprioceptive evocation that induces reflex contraction of the frontalis muscle. AB - OBJECTIVE: The mixed levator and frontalis muscles lack the interior muscle spindles normally required to induce involuntary contraction of their slow-twitch fibers. To involuntarily move the eyelid and eyebrow, voluntary contraction of the levator nonskeletal fast-twitch muscle fibers stretches the mechanoreceptors in Muller's muscle to evoke trigeminal proprioception, which then induces reflex contraction of the levator and frontalis skeletal slow-twitch muscle fibers. The trigeminal proprioceptive nerve has a long intraorbital course from the mechanoreceptors in Muller's muscle to the superior orbital fissure. Since external force to the globe may cause impairment of trigeminal proprioceptive evocation, we confirmed how unilateral blowout fracture due to a hydraulic mechanism affects ipsilateral eyebrow movement as compared with unilateral zygomatic fracture. METHODS: In 16 unilateral blowout fracture patients, eyebrow heights were measured on noninjured and injured sides in primary and 60 degrees upward gaze and statistically compared. Eyebrow heights were also measured in primary gaze in 24 unilateral zygomatic fracture patients and statistically compared. RESULTS: In the blowout fracture patients, eyebrow heights on the injured side were significantly smaller than on the noninjured side in both gaze. In the zygomatic fracture patients, eyebrow heights on the injured side were significantly larger than on the noninjured side in primary gaze. CONCLUSION: Since 60 degrees upward gaze did not recover the eyebrow ptosis observed in primary gaze in blowout fracture patients, such ptosis indicated impairment of trigeminal proprioceptive evocation and the presence of a hydraulic mechanism that may require ophthalmic examination. PMID- 23814637 TI - A ringed fascia lata graft without peritendinous areolar tissue encircling the levator veli palatini and superior pharyngeal constrictor muscles gradually shrinks to reduce velopharyngeal incompetence, functioning as an intravelar palatal lift. AB - INTRODUCTION: We have previously reported that fascia lata grafts with peritendinous areolar tissue used to treat severe congenital blepharoptosis gradually shrink within 6 weeks postoperatively and maintain long-term shrinkage of 15.5% on average. Accordingly, it seemed possible that a fascia lata graft without peritendinous areolar tissue would shrink more than the one with peritendinous areolar tissue in a clinical setting. We evaluated this possibility in a patient with Klippel-Feil syndrome having postoperative deep atonic nasopharynx. METHODS: In combination with intravelar veloplasty and palatal lengthening with modified bilateral buccinator sandwich pushback, a ringed fascia lata without peritendinous areolar tissue encircling the levator veli palatini and superior constrictor muscles was grafted to cure severe velopharyngeal incompetence. RESULTS: Obstructive sleep apnea did not occur following surgery. Pharyngoscopy, videofluoroscopy, and nasometry showed no amelioration of velopharyngeal incompetence at 1 month postoperatively, but marked velopharyngeal incompetence reduction was evident at 4 months and 2 years after surgery. CONCLUSIONS: The extended recovery period suggests that the anticipated postoperative shrinkage of the ringed fascia lata without peritendinous areolar tissue played a more prominent role than intravelar veloplasty and palatal lengthening, which posteroinferiorly elongated the atonic soft palate. Although the pharyngeal flap procedure is the most popular technique for treatment of velopharyngeal incompetence, it is sometimes accompanied by respiratory complications. Thus, the gradual postoperative shrinkage of a ringed fascia lata graft encircling the velopharyngeal muscles functions as an intravelar palatal lift and may be an additional surgical method with less respiratory complications to narrow atonic nasopharyngeal port. PMID- 23814638 TI - Primary mucinous carcinoma of the skin. PMID- 23814639 TI - Body dysmorphic disorder in plastic surgery. PMID- 23814641 TI - Comparing Two Exponential Distributions Using the Exact Likelihood Ratio Test. AB - The exact two-sided likelihood ratio test for testing the equality of two exponential means is proposed and proved to be the uniformly most powerful unbiased test. This exact test has advantages over two alternative approaches in that it is unbiased and more powerful while maintaining the type I error. The use of the proposed test is demonstrated in a non-small cell lung cancer clinical trial design. PMID- 23814640 TI - Statistical Methods for Proteomic Biomarker Discovery based on Feature Extraction or Functional Modeling Approaches. AB - In recent years, developments in molecular biotechnology have led to the increased promise of detecting and validating biomarkers, or molecular markers that relate to various biological or medical outcomes. Proteomics, the direct study of proteins in biological samples, plays an important role in the biomarker discovery process. These technologies produce complex, high dimensional functional and image data that present many analytical challenges that must be addressed properly for effective comparative proteomics studies that can yield potential biomarkers. Specific challenges include experimental design, preprocessing, feature extraction, and statistical analysis accounting for the inherent multiple testing issues. This paper reviews various computational aspects of comparative proteomic studies, and summarizes contributions I along with numerous collaborators have made. First, there is an overview of comparative proteomics technologies, followed by a discussion of important experimental design and preprocessing issues that must be considered before statistical analysis can be done. Next, the two key approaches to analyzing proteomics data, feature extraction and functional modeling, are described. Feature extraction involves detection and quantification of discrete features like peaks or spots that theoretically correspond to different proteins in the sample. After an overview of the feature extraction approach, specific methods for mass spectrometry (Cromwell) and 2D gel electrophoresis (Pinnacle) are described. The functional modeling approach involves modeling the proteomic data in their entirety as functions or images. A general discussion of the approach is followed by the presentation of a specific method that can be applied, wavelet-based functional mixed models, and its extensions. All methods are illustrated by application to two example proteomic data sets, one from mass spectrometry and one from 2D gel electrophoresis. While the specific methods presented are applied to two specific proteomic technologies, MALDI-TOF and 2D gel electrophoresis, these methods and the other principles discussed in the paper apply much more broadly to other expression proteomics technologies. PMID- 23814642 TI - ABSOLUTE CONFIGURATION AND BIOLOGICAL PROPERTIES OF ENANTIOMERS OF CFTR INHIBITOR BPO-27. AB - We previously reported benzopyrimido-pyrrolo-oxazinedione (BPO) inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel and showed their efficacy in a model of polycystic kidney disease. Here, we separated the enantiomers of lead compound BPO-27, (1), which contains a single chiral center, and determined their absolute configuration, activity and metabolic stability. Following separation by chiral supercritical fluid chromatography, the R enantiomer, as determined by x-ray crystallography, inhibited CFTR chloride conductance with IC50 ~ 4 nM, while S enantiomer was inactive. In vitro metabolic stability in hepatic microsomes showed both enantiomers as stable, with <5 % metabolism in 4 h. Following bolus interperitoneal administration in mice, serum (R)-1 decayed with t1/2 ~ 1.6 h and gave sustained therapeutic concentrations in kidney. PMID- 23814643 TI - Selective inhibition of bacterial and human topoisomerases by N-arylacyl O sulfonated aminoglycoside derivatives. AB - Numerous therapeutic applications have been proposed for molecules that bind heparin-binding proteins. Development of such compounds has primarily focused on optimizing the degree and orientation of anionic groups on a scaffold, but utility of these polyanions has been diminished by their typically large size and non-specific interactions with many proteins. In this study N-arylacyl O sulfonated aminoglycosides were synthesized and evaluated for their ability to selectively inhibit structurally similar bacterial and human topoisomerases. It is demonstrated that the structure of the aminoglycoside and of the N-arylacyl moiety imparts selective inhibition of different topoisomerases and alters mechanism. The results here outline a strategy that will be applicable to identifying small, structurally defined oligosaccharides that bind heparin binding proteins with a high degree of selectivity. PMID- 23814644 TI - Role of Amphiphilicity in the Design of Synthetic Mimics of Antimicrobial Peptides with Gram-negative Activity. AB - Two new series of aryl SMAMPs (synthetic mimics of antimicrobial peptides) with facially amphiphilic (FA) and disrupted amphiphilic (DA) topologies were designed and synthesized to directly assess the role of amphiphilicity on their antimicrobial activity against gram-positive and gram-negative bacteria in closely related structures. The FA SMAMPs displayed broad spectrum antimicrobial activity against both gram-positive S. aureus and gram-negative E. coli, whereas the DA SMAMPs, which contained a polar amide bond in between the hydrophobic moieties, only exhibited activity towards S. aureus with increasing hydrophobicity. The integy moment (IW) was used to quantify the amphiphilicity of the SMAMPs and confirmed that it is critical for the design of SMAMPs with gram negative activity. PMID- 23814645 TI - Competition Between Extinction and Enhancement in Surface Enhanced Raman Spectroscopy. AB - Conjugated metallic nanoparticles are a promising means to achieve ultrasensitive and multiplexed sensing in intact three-dimensional samples, especially for biological applications, via surface enhanced Raman scattering (SERS). We show that enhancement and extinction are linked and compete in a collection of metallic nanoparticles. Counterintuitively, the Raman signal vanishes when nanoparticles are excited at their plasmon resonance, while increasing nanoparticle concentrations at off-resonance excitation sometimes leads to decreased signal. We develop an effective medium theory that explains both phenomena. Optimal choices of excitation wavelength, individual particle enhancement factor and concentrations are indicated. The same processes which give rise to enhancement also lead to increased extinction of both the illumination and the Raman scattered light. Nanoparticles attenuate the incident field (blue) and at the same time provide local enhancement for SERS. Likewise the radiation of the Raman-scattered field (green) is enhanced by the near-by sphere but extinguished by the rest of the spheres in the suspension on propagation. PMID- 23814646 TI - Weaning from cardiopulmonary bypass. PMID- 23814647 TI - Age-related requisite concentration of sevoflurane for adequate sedation with combined epidural-general anesthesia. AB - BACKGROUND: The requisite anesthetic concentration of sevoflurane required to obtain adequate sedation when sufficient analgesics are supplied has not been determined. The purpose of this study was to determine the requisite age associated concentration of sevoflurane to obtain an adequate level of anesthesia during combined epidural-general anesthesia by bispectral index (BIS) monitoring. METHODS: Twenty-seven elective abdominal surgery patients (American Society of Anesthesiologists physical status I-II) were enrolled. The patients were divided into two groups of more or less than 60 years of age. We investigated the concentration of sevoflurane required to obtain an adequate sedation level during combined epidural-general anesthesia, maintaining the BIS value between 40 and 60. RESULTS: The requisite sevoflurane concentration required to keep the BIS value at 40-60 was not stable during surgery. In the younger group, the maximum concentration of sevoflurane needed during surgery was 1.95 +/- 0.14 (95% confidence interval: 1.87-2.10) vol%, while it was 1.54 +/- 0.44 (95% confidence interval: 1.27-1.80) vol% in the older group (P < 0.01). CONCLUSIONS: The requisite concentration of sevoflurane required with combined epidural-general anesthesia was 2.5 vol% for the younger group and 2.0 vol% for the older group as determined by BIS monitoring. We believe that these percentages are sufficient to avoid awareness during surgery with adequate analgesia. PMID- 23814648 TI - Comparison of ultrasound-guided supraclavicular block according to the various volumes of local anesthetic. AB - BACKGROUND: The ultrasound guidance in regional nerve blocks has recently been introduced and gaining popularity. Ultrasound-guided supraclavicular block has many advantages including the higher success rate, faster onset time, and fewer complications. The aim of this study was to examine the clinical data according to the varied volume of local anesthetics in the ultrasound-guided supraclavicular block. METHODS: ONE HUNDRED TWENTY PATIENTS WERE RANDOMIZED INTO FOUR GROUPS, ACCORDING TO THE LOCAL ANESTHETIC VOLUME USED: Group 35 (n = 30), Group 30 (n = 30), Group 25 (n = 30), and Group 20 (n = 30). Supraclavicular blocks were performed with 1% mepivacaine 35 ml, 30 ml, 25 ml, and 20 ml, respectively. The success rate, onset time, and complications were checked and evaluated. RESULTS: The success rate (66.7%) was lower in Group 20 than that of Group 35 (96.7%) (P < 0.05). The average onset times of Group 35, Group 30, Group 25, and Group 20 were 14.3 +/- 6.9 min, 13.6 +/- 4.5 min, 16.7 +/- 4.6 min, and 16.5 +/- 3.7 min, respectively. There were no significant differences. Horner's syndrome was higher in Group 35 (P < 0.05). CONCLUSIONS: In conclusion, we achieved 90% success rate with 30 ml of 1% mepivacaine. Therefore, we suggest 30 ml of local anesthetic volume for ultrasound-guided supraclavicular block. PMID- 23814649 TI - Effect of ketamine and midazolam on oculocardiac reflex in pediatric strabismus surgery. AB - BACKGROUND: The oculocardiac reflex (OCR) can be elicited during manipulation of the orbital structures in the strabismus correction surgery. A sinus bradycardia is the most common manifestation of OCR; and cardiac dysrhythmia and asystole may also occur. Various efforts to reduce OCR have been attempted, but without coherent outcome results. METHODS: Sixty one children, undergoing elective strabismus surgery, were randomly allocated into 2 groups: Group K received ketamine 1.0 mg/kg; and Group M received midazolam 0.15 mg/kg for induction of anesthesia. Anesthesia was maintained with 1-1.3 MAC of sevoflurane with 50% N2O in O2. Heart rate and blood pressure were measured 30 seconds before extraocular muscle (EOM) traction and immediately after traction. The OCR was defined as a decrease in heart rate more than 20% of the baseline heart rate, following manipulating EOM. Postoperative nausea and vomiting (PONV) and emergence agitation (EA) were assessed in postanesthetic care unit (PACU). RESULTS: Blood pressure before tightening EOM in Group K was higher than that in Group M (P < 0.05). However Delta HR (2.7 +/- 15% vs. - 0.9 +/- 16%) and incidence of OCR (10.0% vs. 19.4%) after traction an EOM were not different between the two groups. The occurrence of PONV (6.7 vs. 9.7%) and EA (30.0% vs. 22.6%) were similar. CONCLUSIONS: Ketamine does not reduce the incidence of OCR compared with midazolam in pediatric strabismus surgery. In addition, ketamine does not increase the incidence of PONV and EA. In conclusion, it is reliable to use ketamine in pediatric strabismus surgery. PMID- 23814650 TI - Risk factors of morbidity and mortality following hip fracture surgery. AB - BACKGROUND: The preoperative coexisting chronic systemic illness, delay in surgery, gender, and age were considered as risk factors for the complications after hip fracture surgery. The wider range of surgical delay and immobility related pulmonary morbidity may affect postoperative complications and mortality. This study examined the risk factors for morbidity and mortality following the hip fracture surgery. METHODS: The patient data was collected retrospectively. The consecutive 506 patients with hip fracture surgery, aged 60 years or older, were included. The patients' age, gender, preexisting diseases, American Society of Anesthesiologists (ASA) classification, delay in surgical repair, duration of surgical procedure, and methods of anesthesia were noted. The thirty-day postoperative complications were reviewed, and cardiac complications, pulmonary complications, delirium, and death were recorded. The data was analyzed for postoperative complications and risk factors. RESULTS: Atelectasis was associated with postoperative pulmonary complications. Male gender and age >= 80 years were associated with an increased incidence of postoperative delirium. ASA classification 3 was associated with death. A delay in surgery was not associated with any complications. Preexisting diseases and methods of anesthesia did not affect mortality and postoperative complications. CONCLUSIONS: The results suggest that a delay in surgery did not affect the postoperative complications and morbidity. PMID- 23814651 TI - A comparison of analgesic efficacy between oblique subcostal transversus abdominis plane block and intravenous morphine for laparascopic cholecystectomy. A prospective randomized controlled trial. AB - BACKGROUND: The ultrasound-guided oblique subcostal transversus abdominis plane (OSTAP) block provides a wider area of sensory block to the anterior abdominal wall than the classical posterior approach. We compared the intra-operative analgesic efficacy of OSTAP block with conventional intravenous (IV) morphine during laparoscopic cholecystectomy. METHODS: Forty adult patients undergoing laparoscopic cholecystectomy under standard general anesthesia, were randomly assigned for either bilateral OSTAP block using 1.5 mg/kg ropivacaine on each side (n = 20) or IV morphine 0.1 mg/kg (n = 20). The intra-operative pulse rate, systolic and diastolic blood pressure and mean arterial blood pressure were monitored every five minutes. Repetitive boluses of IV fentanyl 0.5 ug/kg were given as rescue analgesia when any of the above-mentioned parameters rose more than 15% from the baseline values. Time to extubation was documented. Additional boluses of IV morphine 0.05 mg/kg were administered in the recovery room if the recorded visual analogue score (VAS) was more than 4. Nausea and vomiting score, as well as sedation score were recorded. RESULTS: The morphine group required more rescue fentanyl as compared to the OSTAP block group but the difference was not significant statistically. Time to extubation was significantly shorter in the OSTAP block group (mean [SD] 10.4 [2.60] vs 12.4 [2.54] min; P = 0.021). Both methods provided excellent analgesia and did not differ in postoperative morphine requirements. No between-group differences in sedation score and incidence of nausea and vomiting were demonstrated. CONCLUSIONS: Ultrasound-guided OSTAP block has an important role as part of balanced anesthesia. It is as efficacious as IV morphine in providing effective analgesia during laparoscopic cholecystectomy. PMID- 23814652 TI - Palonosetron has superior prophylactic antiemetic efficacy compared with ondansetron or ramosetron in high-risk patients undergoing laparoscopic surgery: a prospective, randomized, double-blinded study. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) continues to be a major problem, because PONV is associated with delayed recovery and prolonged hospital stay. Although the PONV guidelines recommended the use of 5-hydroxy-tryptamine (5 HT3) receptor antagonists as the first-line prophylactic agents in patients categorized as high-risk, there are few studies comparing the efficacies of ondansetron, ramosetron, and palonosetron. The aim of present study was to compare the prophylactic antiemetic efficacies of three 5HT3 receptor antagonists in high-risk patients after laparoscopic surgery. METHODS: In this prospective, randomized, double-blinded trial, 109 female nonsmokers scheduled for elective laparoscopic surgery were randomized to receive intravenous 4 mg ondansetron (n = 35), 0.3 mg ramosetron (n = 38), or 75 ug palonosetron (n = 36) before anesthesia. Fentanyl-based intravenous patient-controlled analgesia was administered for 48 h after surgery. Primary antiemetic efficacy variables were the incidence and severity of nausea, the frequency of emetic episodes during the first 48 h after surgery, and the need to use a rescue antiemetic medication. RESULTS: The overall incidence of nausea/retching/vomiting was lower in the palonosetron (22.2%/11.1%/5.6%) than in the ondansetron (77.1%/48.6%/28.6%) and ramosetron (60.5%/28.9%/18.4%) groups. The rescue antiemetic therapy was required less frequently in the palonosetron group than the other groups (P < 0.001). Kaplan-Meier analysis showed that the order of prophylactic efficacy in delaying the interval to use of a rescue emetic was palonosetron, ramosetron, and ondansetron. CONCLUSIONS: Single-dose palonosetron is the prophylactic antiemetics of choice in high-risk patients undergoing laparoscopic surgery. PMID- 23814653 TI - Opioid sparing effect of low dose ketamine in patients with intravenous patient controlled analgesia using fentanyl after lumbar spinal fusion surgery. AB - BACKGROUND: The opioid sparing effect of low dose ketamine is influenced by bolus dose, infusion rate, duration of infusion, and differences in the intensity of postoperative pain. In this study, we investigated the opioid sparing effect of low dose ketamine in patients with intravenous patient-controlled analgesia (PCA) using fentanyl after lumbar spinal fusion surgery, which can cause severe postoperative pain. METHODS: Sixty patients scheduled for elective lumbar spinal fusion surgery were randomly assigned to receive one of three study medications (K1 group: ketamine infusion of 1 ug/kg/min following bolus 0.5 mg/kg, K2 group: ketamine infusion of 2 ug/kg/min following bolus 0.5 mg/kg, CONTROL GROUP: saline infusion following bolus of saline). Continuous infusion of ketamine began before skin incision intraoperatively, and continued until 48 h postoperatively. For postoperative pain control, patients were administered fentanyl using IV-PCA (bolus dose 15 ug of fentanyl, lockout interval of 5 min, no basal infusion). For 48 h postoperatively, the total amount of fentanyl consumption, postoperative pain score, adverse effects and patients' satisfaction were evaluated. RESULTS: The total amount of fentanyl consumption was significantly lower in the K2 group (474 ug) compared to the control group (826 ug) and the K1 group (756 ug) during the 48 h after surgery. Pain scores at rest or with movement, the incidence of adverse events and patient satisfaction were not significantly different among the groups. CONCLUSIONS: Low-dose ketamine at 2 ug/kg/min following bolus 0.5 mg/kg significantly reduced the total amount of fentanyl consumption during the 48 h after lumbar spinal fusion surgery without increasing adverse effects. PMID- 23814654 TI - Intrauterine fetal bradycardia after accidental administration of the anesthetic agent in the subdural space during epidural labor analgesia -A case report-. AB - Subdural injection of epidural anesthesia is rare and is usually undiagnosed during epidural anesthesia causing severely delayed maternal hypotension, hypoxia, and fetal distress. A 38-year-old primiparous woman was administered epidural labor analgesia at 40(+6) weeks' gestation, and developed progressive maternal respiratory depression, bradycardia, and hypotension after accidental subdural administration of the anesthetic agent. Furthermore, fetal distress occurred soon after administration. The patient was managed with oxygen, position changes, fluid resuscitation, and ephedrine. Intrauterine fetal resuscitation was successfully performed with atropine before cesarean section, and a healthy baby was delivered. Although subdural injection is uncommon, this case emphasizes the importance of anesthesiologists monitoring patients for a sufficient period after epidural labor analgesia, and being prepared to perform maternal or fetal resuscitation. PMID- 23814655 TI - Cardiopulmonary bypass weaning difficulty due to anomalous origin of coronary artery -A case report-. AB - We report a case of hemodynamic instability after aortic valve replacement, due to the anomalous origin of the right coronary artery. During the cardiopulmonary bypass weaning process, hemodynamic instability occurred. The cause was not identified at first, and compression of the anomalous right coronary artery was thought to be the culprit, thereafter. PMID- 23814656 TI - Severe hemodynamic instability in a patient with suspected hepatoadrenal syndrome during liver transplantation -A case report-. AB - Adrenal insufficiency, which is related to hemodynamic instability and increased mortality, has been reported in patients with advanced liver disease regardless of the presence of septic conditions. In this regard, the hepatoadrenal syndrome has been recently proposed as adrenal insufficiency in critically ill patients with liver disease. We describe here a 67-year-old female patient with hepatic failure and adrenal insufficiency. The patient showed stable vital signs and no evidence of sepsis preoperatively. Despite hydrocortisone replacement and inotropics administration, severe intraoperative hemodynamic instability was observed. Hydrocortisone administration was continued postoperatively, nevertheless inotropics could not be tapered. On postoperative day 11, the patient died due to pneumonia and septic shock. Hepatoadrenal syndrome may have played a key role in her severe hemodynamic fluctuation and poor outcome, reinforcing the importance of adrenal function in the liver transplantation surgery. PMID- 23814657 TI - Ultrasound-guided subclavian catheterization in pediatric patients with a linear probe: a case series. AB - Central venous catheterization (CVC) can be difficult, especially with pediatric patients in critical care. Accessing the subclavian vein (SCV) can cause serious complications, including pneumothorax, arterial puncture, and hemothorax. Recently, the ultrasonographic (USG) technique has gained popularity, but its efficiency is not yet confirmed. Subclavian venous catheterization (SCVC) through the supraclavicular approach (SCA) with USG or accessing the brachiocephalic vein through the infraclavicular approach (ICA) has been reported in the past. A useful technique is reported that involves the use of a 40 mm probe rather than the usual 25 mm probe in order to confirm the location of the needle while successfully performing subclavian venous catheterization in pediatric patients weighing 1.1 kg to 15.0 kg. PMID- 23814658 TI - Successful weaning from mechanical ventilation in the quadriplegia patient with C2 spinal cord injury undergoing C2-4 spine laminoplasty -A case report-. AB - In patients with cervical spine injuries, respiratory function requires careful attention. Voluntary respiratory control is usually possible with lesions below C4 level although paralysis of the abdominal musculature results in a decreased ability to cough and to clear secretions, which may later lead to respiratory insufficiency. Therefore, injuries above C5 usually necessitate long term mechanical ventilation. Even though weaning criteria are not definitive for the quadriplegic patient, M-mode ultrasonography of the diaphragm may be useful in identifying patients at high risk of difficulty weaning. Diaphragmatic dysfunction (vertical excursion < 10 mm or paradoxical movements) results in frequent early and delayed weaning failures. We present our clinical experience with successful weaning by using M-mode ultrasonography and a cough-assist device for secretion clearance after extubation in a quadriplegic patient undergoing C2 4 spine laminoplasty. PMID- 23814659 TI - Internal leakage of oxygen flush valve. PMID- 23814660 TI - Tethered spinal cord syndrome detected during ultrasound for caudal block in a child with single urological anomaly. PMID- 23814661 TI - Apnea and unconsciousness after accidental subdural placement of an epidural catheter. PMID- 23814662 TI - Intravascular migration of a previously functioning epidural catheter. PMID- 23814663 TI - Subclavian artery perforation and hemothorax after right internal jugular vein catheterization. PMID- 23814664 TI - Change of respiratory mechanics at different intra-abdominal pressures and position change during laparoscopic surgery. PMID- 23814665 TI - Proving universal common ancestry with similar sequences. AB - Douglas Theobald recently developed an interesting test putatively capable of quantifying the evidence for a Universal Common Ancestry uniting the three domains of life (Eukarya, Archaea and Bacteria) against hypotheses of Independent Origins for some of these domains. We review here his model, in particular in relation to the treatment of Horizontal Gene Transfer (HGT) and to the quality of sequence alignment. PMID- 23814666 TI - Bariatric surgery - can we afford to do it or deny doing it? PMID- 23814667 TI - Genomic background-related activation of microglia and reduced beta-amyloidosis in a mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) is by far the most common neurodegenerative disease. AD is histologically characterized not only by extracellular senile plaques and vascular deposits consisting of beta-amyloid (Abeta) but also by accompanying neuroinflammatory processes involving the brain's microglia. The importance of the microglia is still in controversial discussion, which currently favors a protective function in disease progression. Recent findings by different research groups highlighted the importance of strain-specific and mitochondria-specific genomic variations in mouse models of cerebral beta-amyloidosis. Here, we want to summarize our previously presented data and add new results that draw attention towards the consideration of strain-specific genomic alterations in the setting of APP transgenes. We present data from APP-transgenic mice in commonly used C57Bl/6J and FVB/N genomic backgrounds and show a direct influence on the kinetics of Abeta deposition and the activity of resident microglia. Plaque size, plaque deposition rate and the total amount of Abeta are highest in C57Bl/6J mice as compared to the FVB/N genomic background, which can be explained at least partially by a reduced microglia activity towards amyloid deposits in the C57BL/6J strain. PMID- 23814668 TI - Vacant Properties and Violence in Neighborhoods. AB - OBJECTIVES: Violence remains a significant public health issue in the United States. To determine if urban vacant properties were associated with an increased risk of assaultive violence and if this association was modified by important neighborhood institutions (e.g., schools, parks/playgrounds, police stations, and alcohol outlets). METHODS: Longitudinal ecologic study of all 1816 block groups in Philadelphia. Aggravated assault and vacant property data were compiled yearly from 2002 to 2006 and linked to block groups. A mixed effects negative binomial regression model examined the association of vacant properties and assaults between and within block groups. RESULTS: Among all block groups, 84% experienced at least one vacant property, 89% at least one aggravated assault, and 64% at least one gun assault. Between block groups, the risk of aggravated assault increased 18% for every category shift of vacant properties (IRR 1.18, 95% CI: 1.12, 1.25, P < 0.001). Parks/playgrounds and alcohol outlets potentially modified the association between vacant properties and aggravated assaults but only at low levels of vacancy. CONCLUSIONS: Increasing levels of vacancy were associated with increased risk of assaultive violence in urban block groups. PMID- 23814669 TI - The clinical impact of vitamin d in children with atopic dermatitis. PMID- 23814670 TI - Relationship between atopy and bronchial hyperresponsiveness. AB - Both atopy and bronchial hyperresponsiveness (BHR) are characteristic features of asthma. They are also found among non-asthmatic subjects, including allergic rhinitis patients and the general population. Atopy and BHR in asthma are closely related. Atopy induces airway inflammation as an IgE response to a specific allergen, which causes or amplifies BHR. Moreover, significant evidence of the close relationship between atopy and BHR has been found in non-asthmatic subjects. In this article, we discuss the relationship between atopy and BHR in the general population, asthmatic subjects, and those with allergic rhinitis. This should widen our understanding of the pathophysiology of atopy and BHR. PMID- 23814671 TI - Immunopathogenesis of allergic asthma: more than the th2 hypothesis. AB - Asthma is a chronic obstructive airway disease that involves inflammation of the respiratory tract. Biological contaminants in indoor air can induce innate and adaptive immune responses and inflammation, resulting in asthma pathology. Epidemiologic surveys indicate that the prevalence of asthma is higher in developed countries than in developing countries. The prevalence of asthma in Korea has increased during the last several decades. This increase may be related to changes in housing styles, which result in increased levels of indoor biological contaminants, such as house dust mite-derived allergens and bacterial products such as endotoxin. Different types of inflammation are observed in those suffering from mild-to-moderate asthma compared to those experiencing severe asthma, involving markedly different patterns of inflammatory cells and mediators. As described in this review, these inflammatory profiles are largely determined by the involvement of different T helper cell subsets, which orchestrate the recruitment and activation of inflammatory cells. It is becoming clear that T helper cells other than Th2 cells are involved in the pathogenesis of asthma; specifically, both Th1 and Th17 cells are crucial for the development of neutrophilic inflammation in the airways, which is related to corticosteroid resistance. Development of therapeutics that suppress these immune and inflammatory cells may provide useful asthma treatments in the future. PMID- 23814672 TI - Effects of interleukin-9 blockade on chronic airway inflammation in murine asthma models. AB - PURPOSE: Asthma is a chronic inflammatory disease of the airways associated with structural changes and airway remodeling. Interleukin (IL)-9 has pleiotropic effects on both inflammatory cells and airway structural cells, which are involved in asthma pathogenesis. We evaluated the effects of IL-9 blockade on chronic airway inflammation. METHODS: Acute airway inflammation was induced in Balb/c mice using aerosolized ovalbumin (OVA), whereas chronic asthma was induced by OVA exposure for 5 weeks with anti-IL-9 or isotype-matched antibody (Ab) treatment during the OVA challenge. Inflammatory cells in bronchoalveolar lavage fluid (BALF) were counted and lung tissues were stained to detect cellular infiltration, mucus deposition, and collagen accumulation. The levels of interferon (IFN)-gamma, IL-4, IL-5, IL-9, IL-17, and immunoglobulin E (IgE) in BALF were measured using enzyme linked immunosorbent assays, and profiles of inflammatory cells and subsets of T helper (Th) cells were analyzed using flow cytometry. RESULTS: IL-9, IL-17, and IFN-gamma levels were significantly increased in the chronic group compared to the acute asthma group. However, the number of IL-9-positive cells was not affected, with a decrease in Th17 cells in OVA-challenged caspase-1 knockout mice. Numbers of eosinophils, neutrophils, B cells, mast cells, and Th17 cells decreased after administration of anti-IL-9 Ab. Total IgE, IL-5, IL-9, and IL-17 levels were also lower in the anti-IL-9 group. CONCLUSIONS: Our results suggest that anti-IL-9 Ab treatment inhibits pulmonary infiltration of inflammatory cells and cytokine production, especially IL-17. These results provide a basis for the use of an anti-IL-9 Ab to combat IL-17 mediated airway inflammation. PMID- 23814673 TI - Correlation between serum vitamin d level and the severity of atopic dermatitis associated with food sensitization. AB - PURPOSE: A growing body of literature has linked vitamin D deficiency with allergic diseases, particularly atopic dermatitis (AD). In this study, we investigated the association between serum vitamin D status and the clinical manifestation of AD. We also developed an analytical method for the simultaneous determination of 25-hydroxy vitamin D3 (25(OH)D3), using liquid chromatography (LC) coupled with tandem mass spectrometry (MS/MS). METHODS: This study included 157 patients (79 males and 78 females) with AD, aged 4 months to 56 years. We evaluated disease severity using the SCORing Atopic Dermatitis (SCORAD) index. Serum levels of 25(OH)D3 were determined by LC coupled with MS/MS. Total IgE and specific IgE levels were assayed using the immunoCAP system. ANOVA was used for statistical evaluation. RESULTS: We found mild, moderate, and severe AD in 30 (11.1%), 87 (55.4%), and 40 (25.5%) patients, respectively. There was no significant correlation between serum levels of 25(OH)D3 and AD severity. However, among the 36 patients with food sensitization, the mean+/-SD serum levels of 25(OH)D3 were significantly higher (P<0.05) in patients with mild disease (21.2+/-5.18 ng/mL) compared with the levels in patients with moderate (17.9+/-4.02 ng/mL) or severe AD (13.3+/-5.11 ng/mL) disease. CONCLUSIONS: These results suggest that vitamin D deficiency is related to the severity of AD associated with food sensitization. Thus, these data suggest a role for vitamin D in a select group of AD patients. PMID- 23814674 TI - Mutations in the Filaggrin are Predisposing Factor in Korean Children With Atopic Dermatitis. AB - PURPOSE: Filaggrin (FLG) is a key protein that facilitates the terminal differentiation of the epidermis and the formation of the skin barrier. Recent studies showed that atopic dermatitis (AD) associates closely with loss-of function mutations in the FLG gene. Asian and European populations differ in the frequencies of FLG mutations. Several FLG mutations, including 3321delA, E2422X, K4671X, S2554X, and R501X, occur frequently in Chinese and Japanese populations. The association between three FLG null mutations and AD in Korean children was investigated. METHODS: The FLG mutations in 1,430 children (aged 0-18 years) with AD and 862 control subjects were genotyped by using the TaqMan assay. RESULTS: The FLG null mutation E2422X was not detected in any patients with AD or control subjects. The R501X null mutation was detected in only one child with AD (0.1%). Children with AD had the 3321delA deletion significantly more frequently (2.4%) than the control subjects (0.0%, P<0.001). Children with AD also had a significantly higher combined allele frequency of the three FLG null mutations (2.6%) than the controls (0.0%, P<0.001). The 3321delA null mutation did not associate significantly with AD severity (P=0.842). When the patients with AD were divided into allergic AD and non-allergic AD patient groups, these two groups did not differ in terms of the frequency of 3321delA. CONCLUSIONS: The Korean children had a lower frequency of FLG mutations than European populations. FLG null mutations may be associated with the development of AD in Korean children. PMID- 23814675 TI - Rhinovirus-Infected Epithelial Cells Produce More IL-8 and RANTES Compared With Other Respiratory Viruses. AB - PURPOSE: The environmental factors human rhinoviruses (HRVs) and house dust mites (HDMs) are the most common causes of acute exacerbations of asthma. The aim of this study was to compare the chemokine production induced by HRVs in airway epithelial cells with that induced by other respiratory viruses, and to investigate synergistic interactions between HRVs and HDMs on the induction of inflammatory chemokines in vitro. METHODS: A549 human airway epithelial cells were infected with either rhinovirus serotype 7, respiratory syncytial virus (RSV)-A2 strain, or adenovirus serotype 3 and analyzed for interleukin (IL)-8 and regulated on activation, normal T-cell expressed and secreted (RANTES) release and mRNA expression. Additionally, activation of nuclear factor (NF)-kappaB and activator protein (AP)-1 were evaluated. The release of IL-8 and RANTES was also measured in cells stimulated simultaneously with a virus and the HDM allergen, Der f1. RESULTS: HRV caused greater IL-8 and RANTES release and mRNA expression compared with either RSV or adenovirus. NF-kappaB and AP-1 were activated in these processes. Cells incubated with a virus and Der f1 showed an increased IL-8 release. However, compared with cells incubated with virus alone as the stimulator, only HRV with Der f1 showed a statistically significant increase. CONCLUSIONS: IL-8 and RANTES were induced to a greater extent by HRV compared with other viruses, and only HRV with Der f1 acted synergistically to induce bronchial epithelial IL-8 release. These findings may correspond with the fact that rhinoviruses are identified more frequently than other viruses in cases of acute exacerbation of asthma. PMID- 23814676 TI - Effect of prostaglandin e2 on vascular endothelial growth factor production in nasal polyp fibroblasts. AB - PURPOSE: Angiogenesis is involved in the pathogenesis of chronic rhinosinusitis with nasal polyps. We aimed to investigate the effects of prostaglandin E2 (PGE2) on vascular endothelial growth factor (VEGF) production, the role of E-prostanoid (EP) 4 receptors, and the signal transduction pathway mediating VEGF production in nasal polyp-derived fibroblasts (NPDFs). METHODS: Eight primary NPDF cultures were established from nasal polyps, which were incubated with or without PGE2. Reverse transcription-polymerase chain reaction amplification of EP receptors (EP1, EP2, EP3, and EP4) and immunofluorescence staining for VEGF production were performed. VEGF production via the cyclic adenosine monophosphate (cAMP) dependent protein kinase A (PKA) and phosphatidylinositol 3-kinase (PI3K) pathways was evaluated by enzyme-linked immunosorbent assay. RESULTS: All EP receptors were expressed in NPDFs. PGE2 significantly increased VEGF production concentration- and time dependently, and VEGF production was regulated by an EP4 receptor. Activation of intracellular cAMP regulated VEGF production. VEGF production was decreased by PKA and PI3K inhibitors via intracellular cAMP. CONCLUSIONS: PGE2 stimulates VEGF production via the EP4 receptor in NPDFs. These results indicate that PGE2-induced VEGF production is mediated, at least partially, through cAMP-dependent signaling pathways. Therapies targeting the EP4 receptor may be effective in inhibiting the development of nasal polyps. PMID- 23814677 TI - Rhinitis patients with sputum eosinophilia show decreased lung function in the absence of airway hyperresponsiveness. AB - PURPOSE: Sputum eosinophilia is observed frequently in patients with rhinitis. Sputum eosinophilia in patients with non-asthmatic allergic rhinitis has been suggested to be related to nonspecific airway hyperresponsiveness (AHR). However, the clinical significance of sputum eosinophilia in patients with non-asthmatic rhinitis without AHR has not been determined. We conducted a retrospective study examining the influence of sputum eosinophilia in patients with non-asthmatic rhinitis without AHR on pulmonary function and expression of fibrosis-related mediators. METHODS: Eighty-nine patients with moderate-to-severe perennial rhinitis without AHR were included. All underwent lung function tests (forced expiratory volume in 1 second [FEV1] and forced vital capacity [FVC]), skin tests to inhalant allergens, methacholine bronchial challenge tests, and hypertonic saline-induced sputum to determine eosinophil counts. Sputum mRNA levels for transforming growth factor-beta (TGF-beta), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) were also examined. Patients were divided into two groups according to the presence of sputum eosinophilia (>=3%, eosinophilia-positive [EP] and <3%, eosinophilia-negative [EN] groups). RESULTS: FEV1 was significantly lower (P=0.04) and FEV1/FVC tended to be lower (P=0.1) in the EP group than in the EN group. In sputum analyses, the MMP-9 mRNA level (P=0.005) and the ratio of MMP-9 to TIMP-1 expression (P=0.01) were significantly higher in the EP group than in the EN group. There was no significant difference in TGF-beta mRNA expression between the two groups. CONCLUSIONS: Sputum eosinophilia in patients with moderate-to-severe perennial rhinitis without AHR influenced FEV1 and the expression pattern of fibrosis related mediators. PMID- 23814678 TI - Breastfeeding Might Have Protective Effects on Atopy in Children With the CD14C 159T CT/CC Genotype. AB - Breastfeeding is widely recommended to reduce risk of sensitization, eczema and asthma. However, the role of breastfeeding in prevention of allergic diseases is uncertain. We aimed to investigate whether the relationship between breastfeeding and sensitization to aeroallergens is modified by cluster of differentiation 14 (CD14) genotype. This study included 1,828 school children aged 9-12. We administered a detailed questionnaire and genotyped the CD14C-159T polymorphism. Skin prick tests for 12 aeroallergens were performed. School children who had been breastfed were less likely sensitized to aeroallergens (adjusted odds ratio [aOR] 0.712, 95% confidence interval [CI]: 0.555-0.914). There was no significant association between CD14C-159T genotype and atopy. Breastfeeding was associated with a decreased risk of atopic sensitization in children with CT/CC genotype (aOR 0.667, 95% CI: 0.463-0.960). Our data might identify the gene-environment interaction between the CD14C-159T polymorphism and breastfeeding in relation to aeroallergen sensitization. PMID- 23814679 TI - Acute eosinophilic pneumonia leading to acute respiratory failure in a current systemic corticosteroid user. AB - A 69-year-old female patient visited the emergency room with fever (38.3C) and dyspnea. She had been taking prednisolone (5 mg once per day) and methotrexate (2.5 mg once per week) for rheumatoid arthritis for 2 years. Chest computed tomography (CT) showed bilateral, multifocal ground glass opacity with interlobular septal thickening. Peripheral blood leukocyte count was 6,520/mm(3) (neutrophils, 77.4%; eosinophils, 12.1%). During the night, mechanical ventilation was initiated due to the development of severe hypoxemia. Bronchoalveolar lavage fluid showed a high proportion of eosinophils (49%). Her symptoms improved dramatically after commencement of intravenous methylprednisolone therapy. This is the first report of idiopathic acute eosinophilic pneumonia developing in a current user of systemic corticosteroids. PMID- 23814680 TI - A case of idiopathic anaphylaxis followed by acute liver injury. AB - Idiopathic anaphylaxis is characterized by recurrent anaphylaxis without a known trigger. The coexistence of acute liver injury with idiopathic anaphylaxis is rare, even in cases of severe anaphylaxis such as shock. An unusual case involving repeated episodes of anaphylactic shock accompanied by acute liver injury is described here. A 36-year-old woman who experienced anaphylaxis due to an unknown cause was referred to our hospital because of marked elevations in her liver enzyme levels. After a thorough evaluation to determine the cause of the acute liver injury, viral infection, drug use, and autoimmune hepatitis were excluded. The episodes were accompanied by elevated liver enzymes, which suggested that this was a case of anaphylaxis followed by acute liver injury. The patient will have to use self-injectable epinephrine to prevent future hepatic failure. PMID- 23814681 TI - Association of Biomarkers for Inflammation, Endothelial Dysfunction and Oxidative Stress with Cognitive Impairment. The Epidemiology of Hearing Loss Study (EHLS). AB - BACKGROUND: Individual biomarkers of inflammation, endothelial dysfunction and oxidative stress have been associated with cognitive impairment. This study explored whether a combination of biomarkers could prospectively identify those who developed cognitive decline. METHODS: Biomarkers were obtained during the baseline examination of the Beaver Dam Eye Study (1988-90), and cognitive status was assessed during the 5-year follow-up examination of the Epidemiology of Hearing Loss Study (1998-2000). Cognitive impairment was defined as a score of < 24 points on the Mini-Mental State Examination or self- or proxy report of Alzheimer Disease or dementia. Among those with cognitive data, interleukin-6, isoprostanes, protein carbonyl, soluble inter-cellular adhesion molecule-1 and vascular cell adhesion molecule-1 were available for 950 participants and 2,336 had high sensitivity C-reactive protein. RESULTS: Biomarkers of inflammation and endothelial dysfunction were not associated with cognitive impairment. There was a weak inverse association between higher levels of protein carbonyl content and cognitive impairment (OR, 0.8 per quartile of protein carbonyl content, p=0.045 unadjusted for multiple comparisons). This was not significant on multiple testing and may have been a chance finding. CONCLUSION: We found that many markers of inflammation and endothelial dysfunction were not associated with cognitive impairment. An inverse association with carbonyl protein, a marker of oxidative stress needs further confirmation. PMID- 23814682 TI - What Reasons Might the Other One Have?-Perspective Taking to Reduce Psychological Reactance in Individualists and Collectivists. AB - Previous research has demonstrated a considerable amount of negative consequences resulting from psychological reactance. The purpose of this study was to explore opportunities to reduce the amount of reactance. Using the method of perspective taking as an intervention, the current study of 196 Austrians and 198 Filipinos examined whether reactance could be reduced and whether individualists and collectivists differ concerning reactance and their perspective taking abilities. Our results indicated that participants who took the perspective of the person who threatened them experienced less reactance than participants who did not take this approach. This was the case for people from both cultural backgrounds. Nevertheless, comparisons among the two cultural groups yielded different reactions to restrictions. This indicates that individualists are more sensitive to a self-experienced restriction than collectivists, but less sensitive to a restriction of another person. Consequently, we consider culture to be a crucial determinant in predicting the amount of reactance. PMID- 23814684 TI - Renal cell carcinoma in a horseshoe kidney: radiology and pathology correlation. AB - Renal cell carcinoma (RCC) is encountered in about 3% of all adult neoplasms. Presence of any kidney malformation can change the plan for surgical treatment of RCC with organ preserving surgery. We report a case of clear cell RCC in a horseshoe kidney. Computed tomography scan revealed a horseshoe kidney anomaly with a large mass in the left side. The diagnosis of RCC was confirmed by pathology and histology findings. PMID- 23814683 TI - T Cell-Associated Cytokines in the Pathogenesis of Sjogren's Syndrome. AB - Sjogren's syndrome (SjS) is a systemic autoimmune disease that primarily targets salivary and lacrimal glands. SjS affects 2-4 million people in the US alone and greatly affects the life quality of the afflicted individuals. Autoreactive effector T cells are central executors and orchestrators in the pathogenic processes of SjS by mediating target organ inflammation and destruction and by facilitating B cell responses and autoantibody production. A variety of cytokines that are produced by effector T cells or capable of directly affecting effector T cells are elevated in the target organs and circulations of SjS patients. The recent advancement in the understanding about the functions of these cytokines, achieved by using both human samples and mouse disease models, has generated great insights into the cytokine control of autoimmune responses in the SjS disease setting. In this review, we summarized the recent findings on the expression and functions of cytokines in this disease, with specific focus on those derived from T cells and/or directly affecting T cell responses. PMID- 23814685 TI - Autosomal recessive polycystic kidney disease: antenatal diagnosis and histopathological correlation. AB - Autosomal recessive polycystic kidney disease (ARPKD) is one of the most common inheritable disease manifesting in infancy and childhood with a frequency of 1:6,000 to 1:55,000 births. The patient in her second trimester presented with a history of amenorrhea. Ultrasound examination revealed bilateral, enlarged, hyperechogenic kidneys, placentomegaly, and severe oligohydramnios. The pregnancy was terminated. An autopsy was performed on the fetus. Both the kidneys were found to be enlarged and the cut surface showed numerous cysts. The liver sections showed changes due to fibrosis. The final diagnosis of autosomal recessive polycystic kidney disease was made based on these findings. In this article, we correlate the ante-natal ultrasound and histopathological findings in autosomal recessive polycystic kidney disease. PMID- 23814686 TI - Squamous cell carcinoma of the renal pelvis associated with kidney stones: radiologic imaging features with gross and histopathological correlation. AB - Squamous cell carcinoma (SCC) of the renal pelvis is a rare neoplasm and is usually associated with long standing renal stone disease. This tumor is aggressive in nature and usually has a poor prognosis. We report a case who presented with sudden significant weight loss. During the radiologic investigation, a renal mass and staghorn calculi were detected in the right kidney. The patient subsequently underwent right radical nephrectomy. Pathological diagnosis was SCC of renal pelvis with extensive infiltration in to the renal parenchyma. The radiologic imaging features and histopathologic findings of this rare tumor are discussed in this report. PMID- 23814687 TI - Losing your voice: etiologies and imaging features of vocal fold paralysis. AB - Neurogenic compromise of vocal fold function exists along a continuum encompassing vocal cord hypomobility (paresis) to vocal fold immobility (paralysis) with varying degrees and patterns of reinnervation. Vocal fold paralysis (VFP) may result from injury to the vagus or the recurrent laryngeal nerves anywhere along their course from the brainstem to the larynx. In this article, we review the anatomy of the vagus and recurrent laryngeal nerves and examine the various etiologies of VFP. Selected cases are presented with discussion of key imaging features of VFP including radiologic findings specific to central vagal neuropathy and peripheral recurrent nerve paralysis. PMID- 23814688 TI - Magnetic resonance imaging as an adjunct to ultrasound in evaluating cesarean scar ectopic pregnancy. AB - Cesarean scar pregnancies (CSPs) are a relatively rare form of ectopic pregnancy in which the embryo is implanted within the fibrous scar of a previous cesarean section. A greater number of cases of CSPs are currently being reported as the rates of cesarean section are increasing globally and as detection of scar pregnancy has improved with use of transvaginal ultrasound (TVUS) with color Doppler imaging. Delayed diagnosis and management of this potentially life threatening condition may result in complications, predominantly uterine rupture and hemorrhage with significant potential maternal morbidity. Diagnosis of a cesarean scar pregnancy (CSP) requires a high index of clinical suspicion, as up to 40% of patients may be asymptomatic. TVUS has a reported sensitivity of 84.6% and has become the imaging examination of choice for diagnosis of a CSP. Magnetic resonance imaging (MRI) has been used in a small number of patients as an adjunct to TVUS. In the present report, MRI is highlighted as a problem-solving tool capable of more precisely identifying the relationship of a CSP to adjacent structures, thereby providing additional information critical to directing appropriate patient management and therapy. PMID- 23814689 TI - Imaging of tuberculosis of the abdominal viscera: beyond the intestines. AB - There is an increasing incidence of both intra- and extra-thoracic manifestations of tuberculosis, in part due to the AIDS epidemic. Isolated tubercular involvement of the solid abdominal viscera is relatively unusual. Cross-sectional imaging with ultrasound, multidetector computed tomography (CT), and magnetic resonance imaging (MRI) plays an important role in the diagnosis and post treatment follow-up of tuberculosis. Specific imaging features of tuberculosis are frequently related to caseous necrosis, which is the hallmark of this disease. However, depending on the type of solid organ involvement, tubercular lesions can mimic a variety of neoplastic and nonneoplastic conditions. Often, cross-sectional imaging alone is insufficient in reaching a conclusive diagnosis, and image-guided tissue sampling is needed. In this article, we review the pathology and cross-sectional imaging features of tubercular involvement of solid abdominopelvic organs with a special emphasis on appropriate differential diagnoses. PMID- 23814690 TI - Occurrence of polymelia in a female child. AB - We report a rare case of polymelia in a 6-month-old female child who presented with developed lower limbs and an additional underdeveloped left lower limb. PMID- 23814691 TI - Angiographic patterns of transjugular intrahepatic portosystemic shunt dysfunction and interventional approaches to shunt revision. AB - Transjugular intrahepatic portosystemic shunt (TIPS) is an established and effective treatment for the complications of portal hypertension. The non-trivial rates of shunt dysfunction inherent to TIPS mandate familiarity with the imaging diagnosis and endovascular management of this phenomenon. Herein, we present a pictorial review of the various angiographic patterns of TIPS dysfunction and illustrate traditional and innovative technical approaches to shunt revision. PMID- 23814692 TI - An unusual radiological presentation of a pulmonary hydatid cyst in a child. AB - Giant pulmonary hydatid cyst is usually encountered in adolescents and children who are older than 10 years. A relatively higher elasticity of the lung tissue allows rapid growth of cysts. We present a case of a 15-year-old male who was admitted with complaint of frequent and persistent dry cough for over a month. Computed tomographic scan revealed a giant cyst with thick enhancing rim and an "air bubble" sign. Diagnosis of giant hydatid cyst was confirmed by surgery and histopathological examination. PMID- 23814693 TI - An uncommon case of neurofibromatosis type 2: a tribute to the intracranial calcifications. AB - Neurofibromatosis Type 2 (NF2) is a genetic disorder associated with schwannomas, meningiomas, and ependymomas. Intracranial calcifications, either tumoral or non tumoral, are relatively lesser known features of NF2. Here, we present a case of NF2, in which the diagnosis was suspected due to the presence of choroid plexus and subependymal calcifications, although no obvious schwannoma or meningioma was detected initially on standard computed tomography or magnetic resonance imaging. This case highlights the importance of further evaluation with appropriate imaging techniques. PMID- 23814694 TI - Appearances of von meyenburg complex on cross sectional imaging. AB - The von Meyenburg complex (VMC) is an uncommon congenital malformation and is characterized by benign bile duct hamartomas. These are usually discovered incidentally and may represent a diagnostic dilemma when liver metastases are suspected. MRI of VMC shows distinct imaging characteristics, but reporting of lesional contrast enhancement has been inconsistent, whilst microbubble contrast enhanced ultrasound provides 'real-time' evaluation of soft tissue vascularity. Given the diagnostic uncertainty over imaging in VMC, biopsy is often recommended as the definitive diagnosis. We report a biopsy proven case of VMC on a background of primary colonic malignancy investigated with ultrasound, contrast enhanced ultrasound, computed tomography CT, and magnetic resonance imaging MRI, and review the key imaging features. PMID- 23814695 TI - Diagnostic efficacy of panoramic radiography in detection of osteoporosis in post menopausal women with low bone mineral density. AB - OBJECTIVE: The aim of the study was to evaluate panoramic radiograph, a commonly taken dental radiograph as a screening tool to detect early osseous changes (normal, mildly or severely eroded) of the mandibular inferior cortex and measure the mandibular cortical width (CW) in post-menopausal women and correlate it with the bone mineral density (BMD) measured by the ultrasound bone sonometer at the mid-shaft tibia region. MATERIALS AND METHODS: The study included females between 45 years and 65 years of age in their post-menopausal stage (no menstruation for at least 6-12 months). Mandibular indices (mandibular CW and mandibular cortical shape) were evaluated from panoramic radiographs. The BMD assessment was carried out at the mid-shaft tibia region, exactly half-way between the heel and the knee joint perpendicular to the direction of the bone, using an ultrasound bone sonometer. It is a non-invasive device designed for quantitative measurement of the velocity of ultrasound waves as speed of sound in m/s, capable of measuring bone density at one or more skeletal sites. Using 1994 WHO criteria the study subjects were categorized as Group 1: Normal, Group 2: Osteopenia, Group 3: Osteoporosis. (WHO T score for tibia BMD can be used as a standard). RESULTS: The diagnostic efficacy of the panoramic radiograph in detecting osseous changes in post-menopausal women with low BMD was shown to have 96% specificity and 60% sensitivity with mandibular cortical shape and 58% specificity and 73% sensitivity with mandibular CW measurement. Factorial ANOVA analysis carried out indicated a significant correlation of BMD classification with mandibular cortical shape (F = 29.0, P < 0.001, partial eta squared [eta(2)] =0.85), a non significant correlation with mandibular CW, (F = 1.6, P = 0.23, eta(2) = 0.86), and a more significant correlation with combined cortical shape and width (F = 3.3, P < 0.05, eta(2) = 0.70). CONCLUSION: The study concludes that the combined mandibular cortical findings (P < 0.05) and mandibular cortical shape erosion alone (P < 0.001) on panoramic radiograph are effective indicators of osteoporosis in post-menopausal women. PMID- 23814696 TI - A Recombinant Adenovirus Encoding Multiple HIV-1 Epitopes Induces Stronger CD4+ T cell Responses than a DNA Vaccine in Mice. AB - T-cell based vaccines against SIV/HIV may reduce both transmission and disease progression by inducing broad and functionally relevant T cell responses. Mounting evidence points toward a critical role for CD4+ T cells in the control of immunodeficiency and virus replication. We have previously shown that a DNA vaccine (HIVBr18), encoding 18 HIV CD4 epitopes capable of binding to multiple HLA class II molecules was able to elicit broad, polyfunctional, and long-lived CD4+ and CD8+ T cell responses in BALB/c and multiple HLA class II transgenic mice. By virtue of inducing broad responses against conserved CD4+ T cell epitopes that could be recognized across diverse common HLA class II alleles, this vaccine concept may cope with HIV-1 genetic variability and increase population coverage. Given the low immunogenicity of DNA vaccines in clinical trials, we tested the ability of a recombinant adenovirus serotype 5 encoding the 18 HIV epitopes (Ad5-HIVBr18) to increase specific cellular immune responses. We assessed the breadth and magnitude of HIV-specific proliferative and cytokine responses of CD4+ and CD8+ T cells induced by Ad5-HIVBr18 using different vaccination regimens/routes and compared to DNA immunization. Immunization with Ad5-HIVBr18 induced significantly higher specific CD4+ and CD8+ T cell proliferation, IFN-gamma and TNF-alpha production than HIVBr18. The subcutaneous route of Ad5-HIVBr18 administration was associated with the highest responses. Ad5-HIVBr18 induced higher proliferative and cytokine responses than HIVBr18 up to 28 weeks post-immunization. Our results indicate that a vaccine based on an adenovirus vector encoding the HIVBr18 epitopes shows superior immunogenicity as compared to its DNA counterpart. These results support the possible testing of a vaccine encoding HIVBr18 in non-human primates and future clinical trials. PMID- 23814697 TI - Intramolecular Cyclization for Stimuli-Controlled Depolymerization of Polycaprolactone Particles Leading to Disassembly and Payload Release. AB - Developing polymer chemistries capable of on-demand, controlled depolymerization is an important tool in a broad variety of applications in science, technology, and industry. We report functionalized poly(caprolactone)s (PCL)s designed to allow on-demand and complete depolymerization through incorporation of pendant protected amino groups that, on deprotection, trigger nucleophilic attack and yield a single cyclic product. Two cleavable protecting groups were used to cap PCL: light sensititve o-nitrobenzyl alcohol (ONB) and tert-butyl carbamate (Boc) (for proof of concept). NMR confirmed that PCL-Boc degrades completely into the designed intramolecular cyclization products within a day upon deprotection. TEM visualization of particles made from PCL-ONB encapsulating iron oxide nanoparticles reveals complete disruption of nanoparticles and release of payload. This work demonstrates that intramolecular cyclization within the polymer backbone is an excellent route to accelerate polymer degradation by backbiting reactions into small fragments that should be easily cleared from the circulation. PMID- 23814698 TI - Fusing Gene Interaction to Improve Disease Discrimination on Classification Analysis. AB - It is usually observed that among genes there exist strong statistical interactions associated with diseases of public health importance. Gene interactions can potentially contribute to the improvement of disease classification accuracy. Especially when gene expression differs across different classes are not great enough, it is more important to take use of gene interactions for disease classification analyses. However, most gene selection algorithms in classification analyses merely focus on genes whose expression levels show differences across classes, and ignore the discriminatory information from gene interactions. In this study, we develop a two-stage algorithm that can take gene interaction into account during a gene selection procedure. Its biggest advantage is that it can take advantage of discriminatory information from gene interactions as well as gene expression differences, by using "Bayes error" as a gene selection criterion. Using simulated and real microarray data sets, we demonstrate the ability of gene interactions for classification accuracy improvement, and present that the proposed algorithm can yield small informative sets of genes while leading to highly accurate classification results. Thus our study may give a novel sight for future gene selection algorithms of human diseases discrimination. PMID- 23814699 TI - Imaging of Protein Secretion from a Single Cell Using Plasmonic Substrates. AB - Detecting, imaging, and monitoring cell function on a single cell basis is very important in the field of immunology research where many molecules are secreted from cells in response to external stimuli including immunization. Here we introduce substrates with plasmonic nanoparticles and fluorescence microscopy as promising imaging methods for studies on molecular processes controlling cell behavior, particularly secretion of cytokines. We developed unique composition of silver and silica layers of plasmonic nanostructures which resulted in fluorescence enhancement of more than 200-fold for ensemble of molecules in the immunoassay. For the proof of concept demonstration, we used primary mouse macrophages and imaged tumor necrosis alpha (TNF-alpha) secretion after stimulation of the cells with lipopolysaccharide (LPS). We demonstrate that metal enhanced fluorescence assay provides imaging capability detection of cytokine secretion from a single cell without extensive biochemical procedures as required with standard methods. In addition it is demonstrated that cell viability can be controlled during secretion. PMID- 23814700 TI - A Multitrait-Multimethod Matrix Investigation of Hoarding. AB - Hoarding is a serious and potentially life-threatening mental health problem that, until recently, was considered a subtype of OCD. However, recent research suggests it is distinct and more prevalent than OCD. Three key defining features have emerged in factor analytic studies of hoarding scales: excessive acquisition, difficulty discarding, and excessive clutter. Covariation among these defining features has received limited attention. The primary aim of the current study was to examine the role of the three key features in defining hoarding disorder. Convergent and discriminant validity of the three hoarding factors were examined in a multitrait-multimethod matrix. A secondary aim was to examine the extent to which each hoarding feature distinguished individuals meeting criteria for hoarding from those with OCD and community controls. Although the three-factor model provided an adequate fit for the data and convergent validities were high, the hoarding factors evidenced poor discriminant validity across measures. The findings provide preliminary support for a more parsimonious merging of the clutter, acquisition, and discarding subscales versus parsing out subscale scores. Specifically, the active acquisition of items, buildup of clutter, and difficulty discarding accumulated possessions co-occurred strongly enough to be considered a unidimensional construct. Thus, these symptoms were less attributable to separate phenomena and better conceived as part of a cohesive hoarding phenotype. Each of the three factors discriminated hoarding participants from OCD patients and community controls, but did not discriminate the latter two groups. The findings have implications for treating acquisition as a specifier in DSM-5. PMID- 23814701 TI - Expression of PPAR gamma in intestinal epithelial cells is dispensable for the prevention of colitis by dietary abscisic acid. AB - BACKGROUND & AIMS: Dietary abscisic acid (ABA) has shown efficacy in ameliorating experimental IBD in mice through mechanisms requiring expression of peroxisome proliferator activated-receptor gamma (PPAR gamma) in immune cells. The goal of this study was to determine whether PPAR gamma expression in colonic epithelial cells is required for the anti-inflammatory actions of ABA. METHODS: Conditional knockout mice expressing a transgenic recombinase in intestinal epithelial cells under the control of a villin promoter (PPAR gamma flfl; Villin Cre+ or VC+) with defective expression of PPAR gamma in intestinal cells (IEC) and PPAR gamma expressing wild type (PPAR gamma flfl; Villin Cre- or VC-) mice in a C57BL/6 background were fed diets with and without ABA (0.1 g/kg) for 35 days and challenged with 2.5% dextran sodium sulfate (DSS) in the drinking water for 7 days. Clinical disease severity was assessed daily and colonic lesions on day 7 through macroscopic and histopathological examination. Immune cell phenotypes were examined systemically and at the mesenteric lymph nodes (MLN). Epithelial gene expression was assayed in the colon. RESULTS: Dietary ABA-supplementation prevented colitis, reduced disease severity, improved colonic histopathology, and upregulated epithelial lanthionine synthetase C-like protein 2 (LANCL2) expression in VC+ mice. Dietary ABA significantly increased the percentages of MLN CD4+IL-10+ T cells, and blood CD4+CD25+FoxP3+ T cells and CD8+IL-10+ T cells. CONCLUSION: Expression of PPAR gamma in IECs was not required for the anti inflammatory efficacy of ABA in IBD. LANCL2 in IECs and T cell-derived IL-10 may be implicated in the mechanism underlying ABA's immune modulatory activity in IBD. PMID- 23814702 TI - Aldosterone antagonists and outcomes in real-world older patients with heart failure and preserved ejection fraction. AB - OBJECTIVES: The purpose of this study was to examine the clinical effectiveness of aldosterone antagonists in older patients with heart failure and preserved ejection fraction (HF-PEF). BACKGROUND: Aldosterone antagonists improve outcomes in HF and reduced EF. However, their role in HF-PEF remains unclear. METHODS: Of the 10,570 hospitalized older (65 years of age) HF-PEF (EF 40%) patients in the Medicare-linked OPTIMIZE-HF(Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) trial, 8,013 patients had no prior aldosterone antagonist use and no current contraindications; 492 (6% of these 8,013) patients received new prescriptions for aldosterone antagonists. We assembled a matched cohort of 487 pairs of patients receiving and not receiving aldosterone antagonists, who had a similar propensity to receive these drugs and were balanced on 116 baseline characteristics. RESULTS: Patients had a mean age of 80 years old, a mean EF of 54%, 59% were women, and 8% were African American. During 2.4 year of mean follow-up (through December 2008), the primary composite endpoint of all-cause mortality or HF hospitalization occurred in 392 (81%) and 393 (81%) patients receiving and not receiving aldosterone antagonists, respectively (hazard ratio [HR]: 0.97; 95% confidence interval [CI]: 0.84 to 1.11; p = 0.628). Aldosterone antagonists had no association with all-cause mortality (HR: 1.03; 95% CI: 0.89 to 1.20; p = 0.693) or HF hospitalization (HR: 0.88; 95% CI: 0.73 to 1.07; p = 0.188). Among 8013 prematched patients, multivariable-adjusted HR for the primary composite endpoint associated with aldosterone antagonist use was 0.93 (95% CI: 0.83 to 1.03; p = 0.144). CONCLUSIONS: In older HF-PEF patients, aldosterone antagonists had no association with clinical outcomes. Findings from the ongoing randomized controlled TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial will provide further insights into their effect in HF-PEF. PMID- 23814704 TI - Reader's Forum. PMID- 23814703 TI - CCL3L1 gene copy number in individuals with and without HIV-associated neurocognitive disorder. AB - BACKGROUND: CCL3L1 copy number variation has been implicated as a marker for susceptibility and immunity to human immunodeficiency virus (HIV)-1 infection and its pathogenic sequelae. Some of these findings have been confirmed in several, but not all, subsequent independent cohort studies. A three-fold risk for the development of HIV-associated dementia was reported in individuals possessing a CCL3L1 copy number below the ethnic group median combined with a detrimental CCR5 genotype. With the availability of antiretroviral therapy since 1996, there has been a significant decline in HIV-associated dementia, and milder forms of HIV associated neurocognitive impairment (HAND) are now most prevalent. Moreover, patients are living longer with HIV-1 infection and it is recognized that aging may be a contributory factor to the development of cognitive disorder. Thus, the need for biomarkers that can be used in clinical practice to identify and provide optimal treatment for those at increased risk for HAND is great. HAND affects 20% 30% of HIV-infected individuals, and several genetic loci which have been shown to confer susceptibility to HIV infection may also modulate the development of neurocognitive disorder. The aim of this study was to determine whether CCL3L1 chemokine gene copy number in self-defined ethnic groups could differentiate HIV infected individuals with and without HAND. METHODS: Genomic DNA was isolated from buccal swabs or peripheral blood mononuclear cells obtained from HIV infected patients with or without a diagnoses of neurocognitive dysfunction in the Northeast AIDS Dementia Cohort and National NeuroAIDS Tissue Consortium. To maintain a uniform standard, a quantitative polymerase chain reaction design similar to previous studies using Taqman probes and fixed input DNA between 2 ng and 10 ng was used to determine a CCL3L1 copy number. Standard curves with two fold dilutions from 25 ng to 1.56 ng were generated. CCL3L1 copy number was determined in triplicate in 262 subjects using quantitative polymerase chain reaction and the relative quantitation method. Data were analyzed using analysis of variance, with significance defined as P < 0.05 and Bonferroni post hoc tests. RESULTS: Significant differences as determined by analysis of variance in CCL3L1 copy number between African-Americans and Caucasians (P < 0.0001) were found, highlighting ethnic group differences in the copy number of this gene. However, there were no differences in CCL3L1 copy number across the neurocognitive groups within each ethnic group. The median CCL3L1 copy number in African-Americans of two and Caucasians of one in this study was significantly lower than the previously reported ethnic group means of two and four copies, respectively. A higher prevalence of abnormal cognition with a relative risk of four was seen in African-Americans versus Caucasians. CONCLUSION: Based on this nested case control study, CCL3L1 copy number alone may not be useful for distinguishing between individuals at risk for mild or severe neurocognitive disorder. Additional larger cohort studies are required to determine whether CCL3L1 copy number in combination with polymorphisms in other genes known to contribute to HIV risk will be useful in identifying those at increased risk for HAND. PMID- 23814706 TI - Biologic stability of plasma ion-implanted miniscrews. AB - OBJECTIVE: To gain basic information regarding the biologic stability of plasma ion-implanted miniscrews and their potential clinical applications. METHODS: Sixteen plasma ion-implanted and 16 sandblasted and acid-etched (SLA) miniscrews were bilaterally inserted in the mandibles of 4 beagles (2 miniscrews of each type per quadrant). Then, 250 - 300 gm of force from Ni-Ti coil springs was applied for 2 different periods: 12 weeks on one side and 3 weeks contralaterally. Thereafter, the animals were sacrificed and mandibular specimens including the miniscrews were collected. The insertion torque and mobility were compared between the groups. The bone-implant contact and bone volume ratio were calculated within 800 um of the miniscrews and compared between the loading periods. The number of osteoblasts was also quantified. The measurements were expressed as percentages and analyzed by independent t-tests (p < 0.05). RESULTS: No significant differences in any of the analyzed parameters were noted between the groups. CONCLUSIONS: The preliminary findings indicate that plasma ion implanted miniscrews have similar biologic characteristics to SLA miniscrews in terms of insertion torque, mobility, bone-implant contact rate, and bone volume rate. PMID- 23814705 TI - Three-dimensional evaluation of midfacial asymmetry in patients with nonsyndromic unilateral cleft lip and palate by cone-beam computed tomography. AB - OBJECTIVE: To compare three-dimensionally the midfacial hard- and soft-tissue asymmetries between the affected and the unaffected sides and determine the relationship between the hard tissue and the overlying soft tissue in patients with nonsyndromic complete unilateral cleft lip and palate (UCLP) by cone-beam computed tomography (CBCT) analysis. METHODS: The maxillofacial regions of 26 adults (18 men, 8 women) with nonsyndromic UCLP were scanned by CBCT and reconstructed by three-dimensional dental imaging. The frontal-view midfacial analysis was based on a 3 * 3 grid of vertical and horizontal lines and their intersecting points. Two additional points were used for assessing the dentoalveolar area. Linear and surface measurements from three reference planes (Basion-perpendicular, midsagittal reference, and Frankfurt horizontal planes) to the intersecting points were used to evaluate the anteroposterior, transverse, and vertical asymmetries as well as convexity or concavity. RESULTS: Anteroposteriorly, the soft tissue in the nasolabial and dentoalveolar regions was significantly thicker and positioned more anteriorly on the affected side than on the unaffected side (p < 0.05). The hard tissue in the dentoalveolar region was significantly retruded on the affected side compared with the unaffected side (p < 0.05). The other midfacial regions showed no significant differences. CONCLUSIONS: With the exception of the nasolabial and dentoalveolar regions, no distinctive midfacial hard- and soft-tissue asymmetries exist between the affected and the unaffected sides in patients with nonsyndromic UCLP. PMID- 23814707 TI - Effects of silanation time on shear bond strength between a gold alloy surface and metal bracket. AB - OBJECTIVE: We aimed to investigate the effects of silanation time on the shear bond strength (SBS) of metal brackets on gold alloy in a silicoating procedure and compare the SBS of metal brackets on gold alloy and enamel. METHODS: Type III gold alloy plates were sandblasted with 30-um silicon dioxide. Excess particles were removed with gentle air after silica coating, and silane was applied. Maxillary central-incisor metal brackets were bonded to each conditioned alloy surface with a light curing resin adhesive for 1 s, 30 s, 60 s, or 120 s after applying silane. The brackets were also bonded to 36 upper central incisors with the same adhesive. All samples were cured for 40 s with a light emitting diode curing light. The SBS was tested after 1 h and after 24 h. The adhesive remnant index (ARI) of the samples was also compared. RESULTS: The 60-s and 120-s silanation time groups showed a higher SBS than the other groups (p < 0.05). Samples tested after 24 h showed a significantly higher SBS than did the samples tested after 1 h (p < 0.05). The 1-s group showed higher ARI scores. The one-way analysis of variance and Student-Newman-Keuls test showed that the SBS values of the 60-s and 120-s silanation time groups were not significantly different from the SBS values of enamel. CONCLUSIONS: Adequate silanation time is required to produce sufficient bond strength during silicoating. PMID- 23814708 TI - Alveolar bone thickness and lower incisor position in skeletal Class I and Class II malocclusions assessed with cone-beam computed tomography. AB - OBJECTIVE: To evaluate lower incisor position and bony support between patients with Class II average- and high-angle malocclusions and compare with the patients presenting Class I malocclusions. METHODS: CBCT records of 79 patients were divided into 2 groups according to sagittal jaw relationships: Class I and II. Each group was further divided into average- and high-angle subgroups. Six angular and 6 linear measurements were performed. Independent samples t-test, Kruskal-Wallis, and Dunn post-hoc tests were performed for statistical comparisons. RESULTS: Labial alveolar bone thickness was significantly higher in Class I group compared to Class II group (p = 0.003). Lingual alveolar bone angle (p = 0.004), lower incisor protrusion (p = 0.007) and proclination (p = 0.046) were greatest in Class II average-angle patients. Spongious bone was thinner (p = 0.016) and root apex was closer to the labial cortex in high-angle subgroups when compared to the Class II average-angle subgroup (p = 0.004). CONCLUSIONS: Mandibular anterior bony support and lower incisor position were different between average- and high-angle Class II patients. Clinicians should be aware that the range of lower incisor movement in high-angle Class II patients is limited compared to average- angle Class II patients. PMID- 23814709 TI - Orthodontic bonding to acid- or laser-etched prebleached enamel. AB - OBJECTIVE: Bonding forces of brackets to enamel surfaces may be affected by the procedures used for bleaching and enamel etching. The aim of this study was to investigate the bonding strength of orthodontic brackets to laser-etched surfaces of bleached teeth. METHODS: In a nonbleached control group, acid etching (group A) or Er:YAG laser application (group B) was performed prior to bracket bonding (n = 13 in each group). Similar surface treatments were performed at 1 day (groups C and D; n = 13 in each subgroup) or at 3 weeks (groups E and F; n = 13 in each subgroup) after 38% hydrogen peroxide bleaching in another set of teeth. The specimens were debonded after thermocycling. RESULTS: Laser etching of bleached teeth resulted in clinically unacceptable low bonding strength. In the case of acid-etched teeth, waiting for 3 weeks before attachment of brackets to the bleached surfaces resulted in similar, but not identical, bond strength values as those obtained with nonbleached surfaces. However, in the laser-etched groups, the bonding strength after 3 weeks was the same as that for the nonbleached group. CONCLUSIONS: When teeth bleached with 38% hydrogen peroxide are meant to be bonded immediately, acid etching is preferable. PMID- 23814710 TI - Orthodontic treatment of gummy smile by maxillary total intrusion with a midpalatal absolute anchorage system. AB - This article describes the orthodontic treatment of a 31-year-old Korean female patient with gummy smile and crowding. The patient showed excessive gingival display in both the anterior and posterior areas and a large difference in gingival heights between the anterior and posterior teeth in the maxilla. To correct the gummy smile, we elected to intrude the entire maxillary dentition instead of focusing only on the maxillary anterior teeth. Alignment and leveling were performed, and a midpalatal absolute anchorage system as well as a modified lingual arch was designed to achieve posterosuperior movement of the entire upper dentition. The active treatment period was 18 months. The gummy smile and crowding were corrected, and the results were stable at 21 months post-treatment. PMID- 23814711 TI - Biomechanics of Climbing Coconut Trees and its Implications in Ankle Foot Morphology- A Video Sequence analysis. AB - INTRODUCTION: Few studies regarding foot changes and health of professional coconut tree climbers of south India are reported. Medical emergencies are very common, especially due to accidental fall from coconut trees, while on job. Objective of the present study is to analyze the altered biomechanics of lower limb joints used by the coconut tree climbers. METHOD: Videographs of tree climbing each from a total of 30 male volunteers, all between 30-55 years, engaged in coconut tree climbing profession were collected. RESULTS: The data revealed the coconut tree climbers are using abnormal rages of foot and lower limb joint motions. CONCLUSION: This study establishes an occupationally induced form of altered biomechanics, which leads to professional health hazards. PMID- 23814712 TI - Hyperprolactinaemia and its comparision with hypothyroidism in primary infertile women. AB - AIM AND OBJECTIVE: To study the serum prolactin levels and the serum TSH in primary infertile females. MATERIAL AND METHOD: In this study, we investigated thirty women who were diagnosed cases of primary infertility, who attended the Biochemistry Department, Sir JJ Group of Hospitals, Mumbai, India, for hormonal evaluations. Thirty fertile women with similar ages were enrolled as the controls. The status of the thyroid dysfunction and the levels of serum prolactin were reviewed in infertile women and in the controls. The serum Prolactin and the thyroid stimulating hormone levels were measured by using Siemens kits in IMMULITE 1000 chemiluminescence immunoassays. RESULTS: In our study, the serum prolactin levels in the infertile group were found to be high as compared to those in the control group and they were highly significant (p<0.0001). The serum TSH levels in the infertile group were found to be high, as compared to those of control group and they were highly significant (p<0.0001). CONCLUSION: There is a higher incidence of hyperprolactinaemia in infertile patients. There is also a greater propensity for thyroid disorders in infertile women than in the fertile ones. The incidence of hypothyroidism in the hyperprolactinaemic subjects in the study population was found to be highly significant than the normal controls. PMID- 23814713 TI - Effect of Alcohol Withdrawl on Glutathione S-transferase, Total Antioxidant Capacity and Amylase in Blood and Saliva of Alcohol-Dependent Males. AB - INTRODUCTION: Alcohol biomarkers help in the early detection of alcoholism and its complications. There is a paucity of studies in India on the salivary markers of systemic diseases in general and on salivary alcohol biomarkers in particular. OBJECTIVES: The present study was aimed at assessing the effect of alcohol withdrawal on the antioxidants and amylase in blood and saliva, and at finding the correlation between the blood and the salivary parameters in alcoholics. METHODS: Sixty alcohol-dependent males who were in the age group of 30 - 70 years, who were admitted to the Deaddiction Centre for alcohol withdrawal treatment for one month, were the subjects of this study; age-matched healthy individuals were the controls. In the blood and saliva samples, the activities of Glutathione S-Transferase (GST) and amylase and the Total Antioxidant Capacity (TAC) were assayed. RESULTS: The alcohol-dependent subjects showed significantly lower GST and amylase activities and the TAC in blood and saliva as compared to those in the controls (P<0.001). The alcohol withdrawal caused a significant increase in the GST and amylase activities and the TAC to near-control values. In the alcohol-dependent subjects, there was a significant correlation between the values in blood and saliva with respect to GST and TAC. CONCLUSIONS: Alcoholism causes an impaired antioxidant capacity and a decreased secretion of amylase, which is ameliorated due to the alcohol withdrawal regimen . The strong correlation between blood and saliva with respect to the antioxidants suggests the potential future use of saliva as a laboratory tool in clinical medicine. PMID- 23814714 TI - Evaluation of HS-CRP and Lipid Profile in COPD. AB - INTRODUCTION: COPD is a major public health problem. More than 50 % of the patients of COPD die because of some cardiovascular event. Traditionally, the risk of CVD is assessed by the presence of dyslipidaemia. Recently, HS-CRP has emerged as a novel risk factor for the CVD assessment. In this study, we assessed the patients of COPD for CVD with HS-CRP and lipid indicators. MATERIAL AND METHODS: Forty Five diagnosed patients of COPD and 45 age, sex, and BMI matched healthy controls were enrolled for the study after the institutional ethical committee's clearance was obtained. The fasting serum samples of the study subjects were evaluated for the lipid profile and HS-CRP. RESULTS: There was no statistical difference in the lipid profile in the two groups, while HS-CRP was significantly raised in the COPD patients. On applying kappa statistics, we found a poor agreement between the lipid parameters and HS-CRP in estimating the risk for CVD. This underlines the independent importance of HS-CRP in the CVD assessment of COPD patients. DISCUSSION: GOLD has described COPD as a systemic chronic inflammatory disease which involves the lung and the distant organs by the emissary of the systemic inflammation, which is also an antecedent to cardiovascular diseases. COPD is a systemic inflammatory disease which is underlined by this study. But the derangement of the lipid indicators is not statistically significant. This suggests the addition of HS-CRP in the assessment of the COPD patients for CVD. This further needs to be ascertained in a large prospective model. CONCLUSION: COPD is systemic inflammatory disease, but there is hardly any derangement of the lipid indicators. PMID- 23814715 TI - The clinical assessment of ischaemia modified albumin and troponin I in the early diagnosis of the acute coronary syndrome. AB - BACKGROUND: An early identification of the patients with the Acute Coronary Syndrome (ACS) is of prime importance, due to the associated very high mortality. Only about 22% of the patients who present at the emergency cardiology care centres with chest pain, have coronary disease. Ischaemia modified albumin has already been licensed by the US Food and Drug Administration for the diagnosis of suspected myocardial ischaemia. AIM: The goal of the present study was to assess the diagnostic value of serum ischaemia modified albumin and to compare it with sensitive cardiac troponin I in patients with the acute coronary syndromes like unstable angina and acute myocardial infarction. METHODS: A diagnostic case control study was conducted on 102 patients who presented to the Emergency Department within 6 hrs of having acute chest pain and on 110 healthy age and sex matched volunteers who formed the control group. The serum Ischaemia Modified Albumin level was estimated by the albumin cobalt binding test by using a digital spectrophotometer, while Troponin I was measured by doing an immunofluroscence assay. A receiver operating characteristic curve was established for ischaemia modified albumin, to determine the cut-off point. The sensitivity and the specificity of ischaemia modified albumin and troponin I for the detection of acute coronary syndromes, were analyzed. The results of ischaemia modified albumin and troponin I alone and in combination, were correlated. RESULTS: The ischaemia modified albumin (p<0.05) and the troponin I (p<0.001) concentrations were significantly higher in acute myocardial infarction and in unstable angina than in the healthy controls. The sensitivity and the specificity of ischaemia modified albumin for the detection of acute coronary syndromes was 88% and 93% as compared to 87% and 75% respectively for troponin I. The combined use of ischaemia modified albumin and troponin I significantly enhanced the sensitivity to 96%. The area which was under the Receiver Operating Characteristic (ROC) curve of ischaemia modified albumin in acute coronary syndromes was 0.90. CONCLUSION: Ischaemia modified albumin is a useful biochemical marker for the early diagnosis of acute coronary syndrome. The combined use of ischaemia modified albumin and cardiac troponin I enhances the sensitivity and specificity. Hence, a combination of ischaemia modified albumin and cardiac troponin I can be used as a more precise diagnostic marker for Acute Coronary Syndrome. PMID- 23814716 TI - Blood Arsenic and Cadmium Concentrations in End-Stage Renal Disease Patients who were on Maintenance Haemodialysis. AB - BACKGROUND: In India, there is a rising burden of chronic diseases like hypertension and diabetes. It has been estimated that 25-40% of these patients are likely to develop chronic kidney disease (CKD), with a significant percentage requiring renal replacement therapy. Haemodialysis is the most common method which is used to treat advanced and permanent kidney failure. Derangements in the metabolism of several toxic and trace elements such as antimony, arsenic cadmium, molybdenum, nickel, and selenium have been reported for several decades in patients with chronically reduced renal functions. Overall, the available literature suggests that the blood levels of some elements such as cadmium, chromium, fluorine, iodine, lead, or vanadium are high in end-stage renal disease (ESRD). AIM AND OBJECTIVES: Our aim was to study the levels of blood arsenic and cadmium in ESRD patients who were on maintenance haemodialysis (MHD), and to study whether there was any relationship between their concentrations and the duration of the MHD. METHODS: The blood lead levels were determined in 50 healthy subjects with normal renal functions and in 50 patients with ESRD, who were on MHD. None of them had any history of smoking or any industrial exposure. RESULTS: The results of the study revealed that the blood arsenic and cadmium concentrations were higher in the ESRD patients who were on MHD than in the healthy adults. The blood arsenic and cadmium concentrations were found to increase with the duration of the MHD. CONCLUSION: The mild increase in the blood arsenic and cadmium concentrations, with an increase in the duration of the MHD in the study population, may be viewed in the wider context, that a prolonged exposure to arsenic and cadmium, even at low levels, may result in renal damage and/or progression of an already existing CKD. PMID- 23814717 TI - The association of serum osteocalcin with the bone mineral density in post menopausal women. AB - BACKGROUND: The markers of bone remodelling, such as serum osteocalcin, may be used to assess osteoporosis and to predict the fracture risk in elderly persons, especially in women. The bone mineral density which reflects the bone mass and strength, also predicts osteoporotic related hip fractures. So, this work highlights the association between the bone turnover and the bone mass and strength. AIM: To assess the association between the biochemical markers of bone remodeling and osteocalcin with the bone mineral density in non osteoporotic and osteoporotic women among post menopausal subjects. MATERIALS AND METHODS: Sixty postmenopausal women whose ages ranged from 55-65 years included in this study, were further divided into group 1 (thirty non osteoporotic subjects) and group 2 (thirty osteoporotic subjects). For all the subjects, serum osteocalcin was measured by ELISA. BMD was measured by the Dual Energy X- Ray Absorptiometry (DXA) scan. The women with osteoporosis were diagnosed, based on the T- score of the bone mineral density, by the DXA scan. The Student's "t" test was performed between the variables of both the groups and a correlation test was also performed between osteocalcin and BMD by using SPSS. RESULTS: A negative correlation was found between the osteocalcin level and the bone mineral density in post menopausal women. The mean values of both serum osteocalcin and BMD between the osteoporotic and the non osteoporotic subjects were statistically significant. CONCLUSION: An increased bone turnover coincides with the trabecular deterioration in osteoporotic women of the post menopausal age group. A combination of biochemical markers and BMD may be a better predictor of the fracture risk than when it was assessed by either alone. The biochemical markers of the bone turnover cannot be a substitute for the serial BMD measurement, but they may be useful when they are considered in conjunction with the BMD measurement. PMID- 23814718 TI - The prospect of serum magnesium and an electrolyte panel as an adjuvant cardiac biomarker in the management of acute myocardial infarction. AB - BACKGROUND: Ischemic heart disease accounts 12.2% deaths worldwide. Serum magnesium (Mg+) status is often ignored in Acute Myocardial Infarction (AMI). Studies showed alterations in the levels of serum electrolytes including magnesium in AMI. AIM: To evaluate serum Mg+ and other electrolytes as adjuvant markers in the diagnosis of AMI. DESIGN AND SETTINGS: Case control study was conducted in South Indian male population with AMI within six hours of onset of symptoms. PATIENTS AND METHODS: Study includes sixty patients with AMI and 100 controls. Serum electrolytes were estimated using electrolyte analyzer. Data were compared by using student't' test. ROC was drawn to find out optimum cutoff for diagnosing AMI. Pearson's correlation was done to see the association among the markers. RESULTS: Serum Ca, Mg, K and Na electrolytes were significantly lower ('p'<0.001) in AMI. Ca:Mg, K:Mg, and Na:K ratios were significantly higher when compared to controls ('p'<0.001). There was significant correlation of serum Mg levels with other cardiac markers (Total CK, CK-Mb, Troponin -T) of AMI ('p' <0.05).ROC analysis of Na:Mg (40.9), Ca:Mg (3.43) and K:Mg (2.74) ratios showed optimum cutoffs in diagnosis of AMI. CONCLUSION: Serum Mg, Ca:mg, K:mg and Na:K ratios could be useful adjuvant markers in diagnosis of AMI. PMID- 23814719 TI - Assessment of the effects of pranayama/alternate nostril breathing on the parasympathetic nervous system in young adults. AB - BACKGROUND AND AIM: Pranayama, the art of breath control, is considered to be the heart of yogic exercises. The present study was performed with the aim of evaluating the effect of Pranayama/Alternate Nostril Breathing (A.N.B.) on the parasympathetic nervous system in healthy young adult males. METHODS: A comparative account of the expiratioin: inspiration ratio (E:I ratio) and the orthostatic tolerance test (30:15 ratio) at the basal level, at the start of the study and after the practice of A.N.B for 5 minutes and following a training period of 6 weeks. RESULT AND CONCLUSION: This study showed that the parasympathetic tone was enhanced appreciably in the participants. The observations of this study suggest that the yogic exercise of A.N.B. influences the parasympathetic nervous system significantly. PMID- 23814720 TI - ECG Changes in Smokers and Non Smokers-A Comparative Study. AB - INTRODUCTION: Tobacco consumption is the single most cause of the preventable deaths globally. Tobacco is consumed in the form of cigarettes. It contains nicotine which causes physical and psychological dependencies. Cigarette smoking increases the blood coagulability. Nicotine facilitates conduction block, re entry and it increases the vulnerability to ventricular fibrillation. Hence, Nicotine and other components of cigarette can produce profound changes in the heart, which can be assessed by doing an ECG, which is the, cheapest and the most reliable method for assessing cardiovascular abnormalities. AIM: To compare the ECG changes between smokers and non- smokers. MATERIALS: Eighty eight healthy male volunteers who were in the age group of 18-30 years, who attended the outpatients department of SBMCH were recruited for the study. Among the volunteers, 44 were smokers as per the ICD-10 criteria for substance abuse and the rest of the 44 were non-smoker subjects without any systemic illnesses and a drug and alcohol intake. METHODS: After a thorough examination, all the subjects were asked to abstain from smoking and caffeine beverages, 2 hours prior to the taking of the ECG recording. The ECG was recorded in the lab of the Department of Physiology of SBMCH. The following parameters were assessed, namely, the heart rate, the p- wave, the PR interval and the QRS complex. The QTc (corrected QT interval) was calculated by using Bazet's formula. The QT interval, the ST segment and the T wave duration were evaluated in seconds. The results which were obtained were statistically analyzed by using the Students 't' test. RESULTS: The analysis showed that QTc interval was shortened and that the QRS complex duration was widened in the smokers, although the values did not show any statistical significance. The heart rate was increased in the smokers, which was statistically significant. The RR interval, the QT interval and the ST segment were shortened in the smokers as compared to those in the non smokers, which was highly significant statistically. CONCLUSION: All the above changes in our study were either a result of the acute effects or the chronic effects of smoking, which led to cardiovascular disorders which could be easily identified by the wave duration in electrocardiography. This may be used by physicians as a tool for counselling the smokers to stop smoking as early as possible. Smoking even a sin. PMID- 23814721 TI - The serum C Peptide levels among the offsprings of the people with type 2 diabetes. AB - BACKGROUND: Insulin Resistance (IR) is a condition in which the cells of the body become resistant to the effect of insulin , that is, the normal response to a given amount of insulin is reduced. As a result, levels of insulin are needed in order for insulin to produce its effect. The incidence of diabetes in the offsprings of diabetic couples was more than the incidence of diabetes in the offsprings, of whom only a single parent was diabetic. AIMS AND OBJECTIVES: This study was done to assess the prevalence of insulin resistance in the offsprings of diabetic patients. MATERIAL AND METHODS: The present, cross sectional study conducted in the Teerthanker Mahaveer Medical College and Research Centre, Moradabad, U.P., india. The offsprings of diabetic subjects attended the General Medicine OPD and the Diabetic Clinic and they were also admitted in the indoor wards of the Department of Medicine. The study material consisted of 53 (35 males and 18 females) live offsprings of diabetics from 28 families. RESULTS: The mean c-peptide level in the offsprings of biparental diabetics was significantly higher than that in the offsprings of monoparental diabetics (p<0.01) and in the offsprings of non-diabetics (p<0.01). The frequency of the high c-peptide level was 38.1% in the offsprings of biparental diabetics, it was 21.1% in the offsprings of monoparental diabetics and it was 7.7% in the offsprings of non diabetics. CONCLUSION: This study revealed that during the young ages of the offsprings of biparental diabetics, insulin resistance was common and that insulin resistance was more common in the obese, female offsprings of biparental diabetics. PMID- 23814722 TI - Rigid nasal endoscopy in the diagnosis and treatment of epistaxis. AB - BACKGROUND AND OBJECTIVES: Epistaxis is one of the common symptoms encountered in the Otorhinolaryngology department. Many times the cause for epistaxis is not found on anterior and posterior rhinoscopy. The present study was undertaken to assess the role of rigid nasal endoscope in the diagnosis and treatment of epistaxis, where normal anterior and posterior rhinoscopy did not reveal any specific finding. METHODS: Fifty patients with epistaxis were studied using rigid nasal endoscope under local anaesthesia. Patients who were above 15 years with nasal bleeding and who were willing for rigid nasal endoscopy were included in the study. Patients less than 15 years were not included in the study because nasal endoscopy was difficult in them under local anaesthesia. Only those patients in whom, the cause for epistaxis could not be made out on anterior and posterior rhinoscopy were chosen for the study, this was done in order to remove the bias for nasal endoscopy. RESULTS: The use of the nasal endoscope allowed diagnosis of bleeding points and treating them directly. Epistaxis was more in male patients especially in the 3rd and after the 5th decade. On endoscopic examination,the bleeding points were identified as coming from the crevices of the lateral nasal wall, posterior spur on the septum, posterior deviation of the septum with ulcer, congested polyps, enlarged and congested adenoids, scabs or crusts in the crevices of the lateral nasal wall and angiofibroma. Endoscope also helps in the treatment of epistaxis, which includes endoscopic selective nasal packing using gelfoam, endoscopic cautery or diathermy and endoscopic polypectomy. Other patients with adenoids, scabs and crusts and angiofibroma were managed on their merits. INTERPRETATION AND CONCLUSION: Nasal endoscopy helps not only in the localisation of the bleeding point but also in the treatment of those bleeding areas that are situated in the posterior and lateral part of the nose. PMID- 23814723 TI - Domestic microwave versus conventional tissue processing: a quantitative and qualitative analysis. AB - BACKGROUND: Microwave irradiation has been tried as a replacement for the conventional tissue processing technique in histopathology laboratories for quite some time. Studies have shown that Domestic Microwave Tissue Processing (DMWTP) provides a faster delivery of the tissue sections with a morphology which is similar to that which is seen Conventional Tissue Processing (CTP). But many laboratories still confine the domestic microwave tissue processing method only to the handle selected specimens, for which urgent reports are needed. One of the probable reasons is that, understanding about the number of tissue sections which can be processed using a microwave oven at a time, with the appropriate quality, still remains unclear. AIM: The aim of this study was to quantitatively analyze the optimum number of samples that a domestic microwave could process at a time, as well as to qualitatively analyze the morphological outcome of those tissue sections with that of conventional processing. MATERIALS AND METHODS: This study was approved by the research and ethical committee of Sree Balaji Medical College and Hospital. A total of 135 paired tissue sections were included in the study. Ten tissue sections (which are mentioned hereafter as A10) were processed in a domestic microwave and their paired 10 tissues were processed by a conventional method. Subsequently, the number of tissues which was to be processed was increased to B15, C20, D25, E30 and F35, after ascertaining that the morphological qualities of the previously processed tissue sections were satisfactory. Sections of 4 MUm thickness were taken and they were stained by the Haematoxylin and Eosin method. The slides of the tissues which were processed by the microwave method and the conventional method were randomly numbered, for a blind study, which were independently evaluated by two observers. The qualities of slides were assessed, based on 4 parameters: the cytoplasmic details, the nuclear details, the tissue architecture and the staining characteristics. The statistical analysis was done by using SPSS 15.0. RESULTS: The morphological outcomes (quality) of the DMWTPs were comparable to that of the CTPs, when the sample load (quantity) in the microwave oven was up to 25 samples. CONCLUSION: Domestic microwave processing can be effectively used in laboratories with a maximum sample size of 25 samples per load. This has the advantage of being rapid, with its morphological quality being identical to that of conventional processing. PMID- 23814724 TI - E-cadherin expression: a diagnostic utility for differentiating breast carcinomas with ductal and lobular morphologies. AB - OBJECTIVES: The objective of this study was to evaluate the diagnostic utility of the E-Cadherin (EC) expression in differentiating between an infiltrating ductal carcinoma (IDC) and an infiltrating lobular carcinoma (ILC), the two most common forms of invasive breast carcinomas. METHODS: The authors evaluated the E Cadherin expression by doing immunohistochemistical studies of all the cases of invasive lobular carcinomas (ILC) which were diagnosed in the pathology laboratory during a 3 year period and they compared the expression of E-Cadherin in an equal number of invasive ductal carcinomas (IDC) of the breast. RESULTS: A moderate to strong inter-membranous E-Cadherin expression on immunohistochemistry was seen in all the cases of IDC, while only 1 case of ILC showed a moderate E Cadherin expression. Hence, the E-cadherin expression can be reliably used as a marker to differentiate IDC and ILC. However, an aberrant cytoplasmic expression of E-Cadherin may be seen in some cases of ILC, which should be interpreted with caution. PMID- 23814726 TI - The bacterial biofilms in dialysis water systems and the effect of the sub inhibitory concentrations of chlorine on them. AB - INTRODUCTION: The presence of bacteria in the form of biofilms poses a problem in the fluid pathways of haemodialysis plants and procedures which are aimed to detach and neutralize biofilms are necessary to improve the patient safety and the quality of the healthcare. The present study was therefore aimed at isolating the organisms which colonized dialysis water systems as biofilms, as well as to study the effect of the sub inhibitory concentrations of chlorine on the biofilms which were produced by these isolates. METHODS: Swabs were used to collect the biofilms which were produced on the internal surface of the dialysis tubing from the dialysis units. This study was conducted at the Department of Microbiology, Kasturba Medical College (KMC), Mangalore, India. The cultures were performed on MacConkey's agar and blood agar. The organisms which were isolated were identified and antibiotic sensitivity tests were performed. The biofilm production was done by the microtitre plate method of O'Toole and Kolter. The biofilm production was also studied in the presence of sub inhibitory concentrations of chlorine. RESULTS: Acinetobacter spp and Pseudomonas aeruginosa were the two predominant organisms which colonized the dialysis water systems as biofilms. The sub inhibitory concentrations of chlorine did not bring about any decrease in the biofilm production by the isolates. On the contrary, there was an increase in the biofilm production. CONCLUSION: Our study highlighted the importance of using appropriate methods to improve the quality of the water in dialysis units. This in turn, may help in reducing the biofilm formation in the water systems of dialysis units and thus, contribute to the prevention of hospital acquired infections in the patients who need haemodialysis. PMID- 23814725 TI - Application of WHONET in the Antimicrobial Resistance Surveillance of Uropathogens: A First User Experience from Nepal. AB - INTRODUCTION: WHONET is a freely downloadable, Windows-based database software which is used for the management and analysis of microbiology data, with a special focus on the analysis of antimicrobial susceptibility test results. Urinary Tract Infections (UTI) are a common medical problem and they are responsible for notable morbidity among young and sexually active women. OBJECTIVES: The major objective of this study was the utilization and application of the WHONET program for the Antimicrobial Resistance (AMR) surveillance of uropathogens. METHODS: A total of 3209 urine samples were collected from patients who visited Manipal Teaching Hospital with a clinical suspicion of UTI, during December 2010 to July 2011. The isolation and characterization of the isolates were done by conventional methods. Antimicrobial Susceptibility Testing (AST) was performed by Kirby Bauer's disc diffusion method. The data entry and analysis were done by using the WHONET 5.6 software. RESULTS: Out of the 3209 specimens, 497 bacterial isolates were obtained and they were subjected to AST. Escherichia coli (66.2%) was the commonest bacterial isolate, followed by Enterococcus species (9.3%), Staphylococcus aureus (5.0%), and Klebsiella pneumoniae (4.2%). Among the gram-negative enteric bacilli, a high prevalence of resistance was observed against ampicillin and ciprofloxacin. The gram negative nonfermenters exhibited a high degree of resistance to ceftazidime. Staphylococcus species. showed a moderately high resistance to co-trimoxazole. One isolate was Vancomycin Resistant Enterococci (VRE). CONCLUSION: This study, a first of its kind which was done in Nepal, was carried out by using the WHONET software to monitor, analyze and share the antimicrobial susceptibility data at various levels. This study was also aimed at building a surveillance network in Nepal, with the National Public Health Laboratory, Nepal, acting as a nodal centre. This would help in the formulation of antibiotic policies and in identifying hospital and community outbreaks at the nodal centre, as well as in sharing information with the clinicians at the local level. PMID- 23814727 TI - A study on the acute kidney injury in snake bite victims in a tertiary care centre. AB - INTRODUCTION: Snake bite is a common medical emergency and an occupational hazard, more so in tropical India, where farming is a major source of employment. Viper bites are more common than other poisonous snakebites in humans. The World Health Organization has estimated that there are approximately 1,25,000 deaths among 2,50,000 poisonous snake bites worldwide every year, of which India accounts for 10,000 deaths. Acute kidney Injury (AKI) is an important consequence of a snake bite and its proper supportive management after the anti-venom administration is of utmost importance, for a good patient outcome. AIMS AND OBJECTIVES: 1. To assess the risk factors and the prognostic factors in snake bite induced Acute Kidney Injury.2. To determine the outcome of snake bite patients with AKI in a tertiary care centre in Karnataka, India. METHODOLOGY: This prospective study was carried out at Vijaynagar Institute of Medical Sciences, Bellary, Karnataka, India. This institute is a referral government hospital in north Karnataka, India. STUDY DESIGN: This was a prospective and descriptive type of study. RESULTS: A total of 246 cases of venomous snakebite were included in this study, who were admitted in the hospital from November 2007 to October 2008. Among the AKI and the non-AKI patients, Illiteracy was more among the patients who suffered from AKI (75%). In our study, among all the patients (both AKI and non-AKI patients), viper bite was the commonest and it was seen in 31(91.6%) cases among the AKI patients and in 142 (67.6%) cases among the non-AKI patients. In our study, a majority of the patients who developed AKI had initially visited traditional healers before visiting our hospital, which was found to be statistically significant. In the present study, disseminated intravascular coagulation (DIC) and intravascular haemolysis were found to be predominant among the AKI patients. The "Bite to Needle" time was significantly more in the patients who developed AKI as compared to that in those who developed non-AKI. Out of 36 patients who suffered from AKI, 28 (77.7%) patients survived. Among them, 27(96.7%) patients developed cellulitis, 25(89.5%) had regional lymphadenopathy, 22(81.2%) were bitten at their lower limbs, and 6 (23.8%) patients developed bleeding manifestations. CONCLUSION: This study concludes that acute kidney injury occurs in 14.6% of the victims of snake bite. The common manifestations include cellulitis, bleeding manifestations and gangrene at the site of the bite. PMID- 23814728 TI - Self Care Activities, Diabetic Distress and other Factors which Affected the Glycaemic Control in a Tertiary Care Teaching Hospital in South India. AB - BACKGROUND: Interventions which were made to promote a better self-management have produced improvements in the glycaemic control in patients with Diabetes mellitus. An improved glycaemic control is known to prevent the long term complications. METHOD: This study was conducted at the Dr. Pinnamaneni Siddhartha Institute of Medical Sciences and Research Foundation, which is a rural tertiary health care centre. 546 patients were included in our study and they were assessed for the glycaemic control (HbA1c), diabetes distress (DDs), and self care activities. RESULTS: Of the total 546 patients, 49% had a poor glycaemic control, as was indicated by HbA1c levels of >7%. The factors which are significantly associated with a poor glycaemic control are age (p=0.03 ), sex (p= 0.0415), literacy (p=0.0422), duration of the disease (p=0.0006), diabetic distress (p=0.0001) and self care activities like diet ( p=0.0001), medication (p=0.0001) and exercise (p=0.0001), whereas there was no significant effect of the BM I (p=0.094) on the glycaemic control. CONCLUSION: This study revealed the factors that could predict the glycaemic control in the diabetic patients who attended our tertiary care teaching hospital. The barriers that prevent these patients from meeting their goals must be explored, to improve their health outcomes. PMID- 23814730 TI - 'Single Dose MgSo4 Regimen' for Eclampsia - A Safe Motherhood Initiative. AB - OBJECTIVES: To determine the efficacy and the safety of the single dose MgSo4 ('VIMS') regimen in treating eclamptic seizures and their effect on the maternal and foetal outcomes. METHODS: A prospective, observational study was conducted in the period from 2003 to 2007. 513 eclamptic women who were admitted to the Dept of OBG, VIMS, Bellary, received single doses of 4g diluted 50% Mgso4 intravenously, with simultaneous 4g 50% MgSo4 intramuscularly. The recurrent seizures, maternal mortality and the perinatal mortality were measured. RESULTS: 9.16% of recurrence (11.66%-16.49%), 3.3% of maternal mortality (1.8%-4.9%) and 24.8 % ( 21.1%-28.7%) of perinatal mortality were observed. The statistical analysis was done by using confidence intervals, standard deviations, means and the Standard normal "Z" test. CONCLUSION: The single dose MgSo4 regimen is effective and safe in controlling eclamptic convulsions. The 'VIMS' regimen can be used at First Referral Units, before shifting the patients to tertiary care centres. This approach has special implications in the developing countries, especially at the primary care level, where the standard obstetric care is not widely available. PMID- 23814729 TI - The clinicopathologic manifestations of Plasmodium vivax malaria in children: a growing menace. AB - CONTEXT: Today, India faces increasing morbidity and mortality due to malaria, which is a global health burden. Plasmodium vivax which was once considered to have a benign course, is now being increasingly associated with complicated malaria. Studies which have been done on the increasing virulence of P. Vivax in children, are exceptionally rare. AIMS: This study has addressed some of the hitherto unanswered questions, such as: This study has tried to explore the wide spectrum of severe illnesses which are associated with P.vivax malaria in children.Other co-morbid conditions, which include a co-infection with P.falciparum, have been excluded with great care, to assess the increased virulence of P. Vivax.The present study was focused on the paediatric population with a large sample size of 168 subjects. SETTINGS AND DESIGN: This was an observational retrospective analysis on the clinicopathologic manifestations of the paediatric cases which were admitted with severe malaria due to a mono infection with Plasmodium vivax, in a tertiary-care centre in the national capital region, India. METHODS AND MATERIAL: The diagnosis of the mono-infection with P. Vivax malaria was established by making peripheral blood films (PBFs) and by doing rapid diagnostic tests. The severe forms of malaria were categorized as per the World Health Organization guidelines and the clinical and laboratory findings in these cases of complicated malaria were studied. STATISTICS: A descriptive statistical analysis was done by using the SPSS software and an Excel worksheet. RESULTS: This comprehensive study revealed a multisystem involvement. Abdominal manifestations were observed in 75(45.8%) cases (which included hepatosplenomegaly, hepatomegaly, splenomegaly and ascites) and hepatic dysfunction and jaundice were observed in 28(16.7%) cases. The haematological tests showed moderate to severe anaemia in 151(89.9%) cases and thrombocytopaenia in 138(82.1%) cases. Petechiae were noted in 45(26.8%) cases and a gross bleeding was noted in 9(5.3%) cases. The respiratory findings which included tachypnoea, pleural effusions and ARDS were observed in 22(13.1%) cases. Renal dysfunction was noted clinically in 20(11.9%) cases and biochemically in 16(9.5%) cases. Shock was observed in 7(4.1%) cases, cerebral malaria was observed in 10(5.9%) cases and hypoglycaemia was observed in 5(3%) cases. Multi-organ dysfunction was detected in 11(6.54%) cases. The complications were more severe in the younger children (0-5 years). CONCLUSIONS: A mono-infection with P. Vivax may lead to severe malaria and this increased virulence has resulted in the changing picture of P. Vivax malaria, leading to a spectrum of complications which are similar to those which are traditionally associated with P. Falciparum. PMID- 23814731 TI - Target scan-the experience at saveetha medical college. AB - INTRODUCTION: The identification of foetal anomalies in utero is important. The prenatal detection of such abnormalities, often aids in planning the appropriate obstetrical management. OBJECTIVES: To evaluate the antenatal prevalence of the major congenital anomalies and the malformation patterns which were seen in low risk patients of our hospital population. STUDY DESIGN: This was a cross sectional and an observational study. SETTINGS: This study was done in the Radiology and Obstetrics Department of Saveetha Medical College, India. DURATION: It extended from June 2012 to Aug 2012. SAMPLE SIZE: It was done on 250 patients. RESULTS: The incidence of foetal anomalies in our study was 2.97%. The mean maternal/mean gestational age at diagnosis was 24.5years /20 weeks. Among the 250 cases, five cases had lethal anomalies and two cases had non lethal anomalies. The lethal anomalies were cystic hygroma, body stalk anomaly, multicystic kidney, non immune hydrops and a Dandy Walker variant. All of the patients were primi gravida, without any risk factors. Two non lethal anomalies which were found were a duplication cyst in the foetal abdomen and a single umbilical artery. Foetal kartotyping and foetal autopsies were done in two cases. The parents of the offsprings with the lethal anomalies were counseled and they decided to go for termination of the pregnancies. It was offered to them. For the non- lethal cases, complete postnatal work ups were done by the paediatrician. CONCLUSION: The sonographic demonstration of a lethal foetal anomalies is mandatory, which may dramatically alter the obstetrical management and it also aids in the parental preparation. Future Scope: In our study, all the non compatible with life anomalies were seen in the young primi without any risk factors and hence, the environmental cause has to be studied. PMID- 23814732 TI - The role of fibrin glue in the treatment of high and low fistulas in ano. AB - AIM: The aim of this study was to assess the outcome of fibrin glue in high and low anal fistulas. METHODS: A prospective, non-randomized trial was carried out on 30 patients who were diagnosed to have fistulas in ano. They were evaluated by categorizing them into high (with the internal opening above the anorectal ring)(14/30) and low anal fistulas (with the internal opening below the anorectal ring)(16/30). The fibrin glue was instilled in their anal tracts. The character of the anal tract, whether it was single or multiple and primary or recurrent, was analyzed. The outcome in terms of a postoperative discharge (failure), the incidence of a postoperative perianal pain/abscess and the glue reaction, was noted at 1 week, 1 month, 3 months and 6 months. A success was defined as the absence of any discharge at 6 months. RESULTS: Fourteen patients with high anal fistulas and 16 with low anal fistulas (with a mean age of 48.5yrs) were treated with fibrin glue. 19 patients had primary tracts (7- high group and 12- low group) and 11 had recurrent tracts (7- high group and 4- low group). 20 fistulas were single tracted (8- high and 12- low) and ten were multiple tracted (6- high and 4-low). The success rate at 6 months was 57.14% in the high group and it was 81.25% in the low group. The failure rate was 85.71% in the recurrent high fistula group as compared to 25% in the recurrent low fistula group (p=0.049). 25% of the single tracted high fistulas failed to heal as compared to a 100% healing rate in the single low fistulas group (p=0.90). CONCLUSION: This procedure is thus, superior to the conventional surgical treatment, in terms of the patient comfort, an undisturbed sphincter function, a reduced overall hospital stay, wound pain and the complications and adverse reactions. It showed the best results in the primary, single tracted and the low anal fistulas. PMID- 23814733 TI - The Perforation-Operation time Interval; An Important Mortality Indicator in Peptic Ulcer Perforation. AB - OBJECTIVE: To find out the significance of the Perforation-Operation Interval (POI) with respect to an early prognosis, in patients with peritonitis which is caused by peptic ulcer perforation. STUDY DESIGN: Case series. Place and Duration of the Study: Department of General Surgery, Konaseema Institute of Medical Sciences and RF Amalapuram, Andhra Pradesh, India from 2008-2011. MATERIALS AND METHOD: This study included 150 patients with generalized peritonitis, who were diagnosed to have Perforated Peptic Ulcers (PPUs). The diagnosis of the PPUs was established on the basis of the history , the clinical examination and the radiological findings. The perforation-operation interval was calculated from the time of onset of the symptoms like severe abdominal pain or vomiting till the time the patient was operated. RESULT: Out of the 150 patients 134 were males and 16 were females, with a male : female ratio of 9:1. Their ages ranged between 25 70 years. Out of the 150 patients, 65 patients (43.3%) presented within 24 hours of the onset of severe abdominal pain (Group A), 27 patients (18%) presented between 24-48 hours of the onset of severe abdominal pain (Group B) and 58 patients (38.6%) presented after 48 hours. There was no mortality in Group A and the morbidity was more in Group B and Group C. There were 15 deaths in Group C. CONCLUSION: The problem of peptic ulcer perforation with its complication, can be decreased by decreasing the perforation -operation time interval, which as per our study, appeared to be the single most important mortality and morbidity indicator in peptic ulcer perforation. PMID- 23814734 TI - A qualitative assessment of the small group teaching at hawler college of medicine. AB - CONTEXT: Although the medical schools in Iraq recently started to increasingly use the small group teaching approach, only little is known about the students' perceptions toward this approach. Therefore, the aim of this study was to assess small group teaching as a method of teaching at Hawler College of Medicine, from the students' perspectives. SETTING: This study was a qualitative study which was based on six focus group discussions which involved a sample of students from the three last years at the Hawler College of Medicine. A topic guide was used to lead the discussions and it covered questions on the positive aspects and the problems of small group teaching in the college, in addition to recommendations for its improvement. The qualitative data analysis involved a content analysis, followed by a thematic analysis. RESULTS: The participants were generally happy with the application of the small group teaching approach and they recognized many positive aspects which were related to this experience, which included, increasing the focus on the study subjects, enhancing the student-teacher interaction, building a better student-teacher relationship, encouraging the students' attendance, providing a better opportunity to apply a student-centered learning, enhancing a more efficient use of time and assisting in a better understanding of the subjects. The main problems which were faced, included a poor infrastructure and teaching facilities, problems which were related to examinations and the mark distribution, an improper syllabus preparation and problems which were related to the teachers' commitments and performances. The main suggestions which were put forth to improve this system, included, changing the assessment system with the focus more on the end of the course assessment, the students' involvement in the curriculum design, improving the infrastructure and teaching facilities and a better organization and management of the system. CONCLUSIONS: The concept of the small group teaching approach was well received by the students and many positive aspects of this approach have been highlighted. However, this experience witnessed many problems and faced different challenges that need better preparation, organization of the resources and the orientation of students and teachers, for insuring its success. PMID- 23814735 TI - To study the incidence of heterotopic ossification after anterior cruciate ligament reconstruction. AB - INTRODUCTION: Previous studies have enumerated the advantages of an arthroscopic Anterior Cruciate Ligament (ACL) reconstruction with the use of a Bone Patellar Tendon Bone (BPTB) graft. Complications are extremely rare in such surgeries and one such known complication, which is an extra-articular heterotophic ossification at the femoral tunnel site, is rarely seen only in few patients. AIM: To evaluate the incidence of heterotrophic ossifications at the femoral tunnel site and the efficacy of the preventive measures which were undertaken, in patients who had undergone ACL reconstructions with the use of bone patellar tendon bone grafts. MATERIAL AND METHODS: A total of 285 patients who had ACL tears within a duration of six years, were evaluated prospectively for the incidence of heterotrophic ossifications after they underwent arthroscopic reconstructions with the use of bone patellar tendon bone grafts by the double incision technique. The effect of the efficacy of various preventive measures on the incidence of the heterotophic ossifications post surgery was also studied. RESULTS: The observed incidence of the heterotophic ossifications was 2.58% in patients whom preventive measures were not used. In contrast, an incidence of 1.54% of similar complications was recorded, after preventive measures were undertaken. Our results showed that heterotophic ossifications after arthroscopic reconstructions with the use of bone patellar tendon bone grafts were a rare complication and that their incidence could be further reduced if preventive measures were taken. CONCLUSION: The heterotophic ossification is a rare complication after an ACL reconstruction is done with the use of a bone patellar tendon bone graft by the double incision technique. Its incidence reduces significantly after preventive measures are undertaken. PMID- 23814736 TI - Household salt iodine content estimation with the use of rapid test kits and iodometric titration methods. AB - BACKGROUND: Universal salt iodization remains the best strategy for controlling iodine deficiency disorders in Nepal. AIMS: This study was designed to study the salt types and the household salt iodine content of school aged children in the hilly and the plain districts of eastern Nepal. MATERIAL AND METHODS: This cross sectional study was carried out on school children of seven randomly chosen schools from four districts, namely, Sunsari, Dhankuta, Sankhuwasabha and Tehrathum of eastern Nepal. The school children were requested to bring two teaspoonfuls (approx. 12-15 g) of the salt which was consumed in their households, in a tightly sealed plastic pouch. The salt types were categorized, and the salt iodine content was estimated by using rapid test kits and iodometric titrations. The association of the salt iodine content of the different districts were tested by using the Chi-square test. The sensitivity, specificity, positive predictive values, and negative predictive values of the rapid test kits were compared with the iodometric titrations. RESULTS: Our study showed that mean+/-SD values of the salt iodine content in the four districts, namely, Sunsari, Dhankuta, Sankhuwasabha and Tehrathum were 34.2+/-17.9, 33.2+/-14.5, 27.4+/-15.1 and 48.4+/-15.6 parts per million (ppm). There were 270 (38.2%) households which consumed crystal salt and 437(61.8%) of the households consumed packet salts. CONCLUSIONS: Our study recommends a regular monitoring of the salt iodization programs in these regions. More families should be made aware of the need to ensure that each individual consumes iodized salt. PMID- 23814737 TI - Perforator plus fasciocutaneous flaps in the reconstruction of post-burn flexion contractures of the knee joint. AB - BACKGROUND: A post-burn flexion contracture of the knee joint is a disabling condition which interferes with an upright posture and a bipedal locomotion. Islanded perforator flaps have been used to resurface the tissue defect which is produced as a result of the contracture release. Despite their various advantages, they are limited by an increased tendency to undergo venous congestion. Perforator-plus flaps can be used to overcome this limitation, while retaining the merits of the islanded perforator flaps. METHODS: Ninteen patients with post flame burn flexion contractures of the knee joints underwent surgical releases and coverages by various local fasciocutaneous perforator-plus flaps. The patients were followed up for 6 months and the various aspects of the functional and the aesthetic rehabilitations were assessed. RESULTS: All the local fasciocutaneous perforator-plus flaps resurfaced the tissue defect over popliteal fossa with good colour and texture match and maintenance of the contour. None of the flaps had any significant early or delayed complications (which included venous congestions) which necessitated reoperations. All the patients were satisfied with the functional and aesthetic outcomes. CONCLUSION: Local fasciocutaneous perforator-plus flaps can be considered as one of the primary treatment modalities for the surgical release and reconstruction of post burn flexion contractures of the knee. PMID- 23814738 TI - Perineal bull gore with urinary bladder perforation and pneumoperitoneum. AB - Animal related injuries are frequently reported in India and other countries, where bulls are used for sporting events as well as in places where farming and livestock rearing is practised. The presentation is, many times, atypical and misleading as well. They have unique mechanics of injury. The patterns of the injury are reviewed. An intra-peritoneal urinary bladder injury which is caused by a perineal bull gore with a pneumoperitoneum is unusual and it has not been reported in the literature which was reviewed. We are reporting a successfully treated 25 years old male patient from the slopes of the southern district of Manipur, India, who had presented 40 hours after he was injured. The identification and prompt exploration, keeping in mind the mechanics of bull goring, helps the surgeons to adequately deal such atypical injuries, for optimal outcomes. PMID- 23814739 TI - Misplaced intrauterine contraceptive devices: common errors; uncommon complications. AB - Contraception is essential in a developing country like India. Intrauterine Contraceptive Devices (IUCDs) are amongst the most frequently used methods of contraception. The patients with misplaced IUCDs may present with pregnancies or 'lost strings' or they may remain asymptomatic. PMID- 23814740 TI - Metaplastic ossification in a juvenile rectal polyp: a rare histological finding. AB - An osseous metaplasia is a phenomenon which has been described in a wide variety of tissue types with respect to both neoplastic and non-neoplastic conditions. However, an osseous metaplasia is exceedingly rare in colonic polyps. We are herein representing a case of osseous metaplasia in a juvenile rectal polyp in a six year old boy, with review of the literature on the suggested mechanisms of its aetiology. PMID- 23814741 TI - Primary urachal mucinous adenocarcinoma of the urinary bladder. AB - Urinary bladder cancer is the second most frequent tumour of the genitourinary tract with bladder adenocarcinoma comprising for about 0.5-2% of all malignant bladder tumours. Other primary sites for such tumours include rectum, stomach, endometrium, breast, prostate, seminal vesicles and ovaries. Such non-urothelial bladder tumours with intramural bladder tumour growth may delay the onset of symptoms which may lead to a delay in the diagnosis and thereby adversely affecting the prognosis as compared to urothelial bladder tumours. Traditionally bladder adenocarcinomas were believed to be resistant to both chemotherapy and radiotherapy, but recent advancements have shown encouraging responses with adjuvant chemotherapy and radiotherapy. We present here a case of primary urachal mucinous adenocarcinoma of the urinary bladder highlighting their relative rarity of occurrence and the difficulties encountered in diagnosing primary bladder mucinous adenocarcinoma. PMID- 23814742 TI - Vivax malaria presenting with myelitis: a rare complication. AB - Neurological complications may occur with the Plasmodium falciparum infection. However, the association of neurological manifestations with vivax malaria remains doubtful. Of late, there are isolated case reports/studies which have implicated P. vivax in the pathogenesis of severe malaria which is characterized by the features of different organ dysfunctions, which were previously thought to be caused by P. falciparum alone. Though several case studies have mentioned the association of the P. vivax infection with cerebral malaria, a causal correlation has yet to be established. Dorsal cord myelitis (which leads to paraplegia) during the febrile illness, is rarely described in association with vivax malaria, though there are reports on the Post Malaria Neurological Syndrome (PMNS) and acute disseminated encephalomyelitis following vivax malaria. We are reporting a case of P. Vivax malaria which presented with myelitis, which responded well to the antimalarial treatment. PMID- 23814743 TI - Haematemesis: an uncommon presenting symptom of Plasmodium falciparum malaria. AB - Plasmodium falciparum malaria with complications is a challenge for the clinicians worldwide, especially when it presents with rare manifestations. Haematological abnormalities and coagulopathy are the well documented complications in malaria. Rarely does malaria present with bleeding. We are reporting a 20 years old man who presented with haematemesis as the presenting symptom of falciparum malaria. In the review of literature, there are reports of haematemesis in malaria, but none of it as a presenting symptom. PMID- 23814744 TI - An impacted denture in the oesophagus-an endoscopic or a surgical emergency-a case report. AB - Accidentally swallowed dentures can lead to severe complications in the gastrointestinal tract. Therefore, an early detection and an effective therapeutic management are important. In the era of advanced endoscopy, though the primary treatment of an impacted foreign body in the oesophagus is an endoscopic removal, a primary surgical treatment is advised for dentures with sharp hooks. Also, a prolonged impaction of dentures with sharp hooks leads to an increase in the complication rates. We are reporting a case of accidentally swallowed denture. After the diagnosis of an impacted denture was made, upper GI endoscopy revealed that an endoscopic removal was not feasible and thus, a late surgical removal was performed in the form of a transhiatal oesophagectomy and reconstruction. This case highlights the importance of an early and preferred treatment in the form of a controlled surgical intervention as compared to an endoscopic extraction for patients with impacted dentures with sharp hooks. PMID- 23814745 TI - Livedoid Vasculopathy and Mononeuritis Multiplex, with a Fulminant Hepatic Failure which was caused by Herpes Simplex Hepatitis: A Case Report. AB - Livedoid vasculopathy with mononeuritis multiplex is a rare association. We are presenting a case of an unusual association of livedoid vasculopathy with mononeuritis multiplex, who developed fulminant hepatic failure which was secondary to Herpes simplex virus (HSV) hepatitis, while she was on treatment with immunosuppressants. Her skin biopsy and immunofluorescence studies showed the features of vasculitis. A biopsy from the sural nerve showed the features of chronic vasculitis. PMID- 23814746 TI - A rare case of craniofacial morphology with absent face and neck structures, with its review. AB - The development of the head and the face requires an intimate interaction between two mesenchymal populations, a paraxial mesoderm and neural crest cells for the morphogenesis of the musculoskeletal components of the calvaria, the face and the branchial regions. The disruptions in these interactions can cause foetal fatalities or congenital craniofacial anomalies. We are describing a rarest case with a craniofacial malformation, who was born with complete absence of the facial skeleton and the neck structures, a set of well developed ears in their normal locations and eyelids at the junction between the head and the thorax. PMID- 23814747 TI - Primary genito-urinary tuberculosis with bilateral urolithiasis and renal failure an unusual case. AB - Urolithiasis leading to renal failure is a very common occurrence. But if the patient is co-infected with genitourinary tuberculosis, then it becomes all the more unusual and challenging, especially if the patient is immunocompetent. This patient, who presented to us with bilateral urolithiasis and features of renal failure, underwent left nephrectomy after thorough investigations. The biopsy revealed features of renal tuberculosis. The patient was put on anti-tubercular therapy (ATT) and later, he underwent right ureteroscopic lithotripsy. He completed his course of ATT and is on regular follow-up. His serum creatinine also stabilised with regular hemodialysis. The main aim of this case report is to bring to light this unusual and interesting presentation of bilateral urolithiasis with genito-urinary TB presenting as renal failure, which was successfully managed. PMID- 23814748 TI - Primary bilateral fallopian tube carcinoma the report of a single case with review of the literature. AB - Primary fallopian tube carcinoma is an extremely uncommon neoplasm of the female genital tract. Primary Fallopian Tube Carcinoma (PFTC) has a clinical and a histological resemblance to Epithelial Ovarian Cancer (EOC). We are reporting a case of PFTC in a 55 year old tubectomized, postmenopausal woman with the non specific complaints of a watery vaginal discharge and lower abdominal pain. The clinical and radiological findings suggested a bilateral tubo-ovarian abscess. On laprotomy, a bilateral fallopian tube tumour was seen, with a focal extension to the surface of the right ovary from the right fallopian tube. Total abdominal hysterectomy, bilateral adnexectomy andomentectomy, along with excision of the draining lymph nodes, was done. The histopathological examination revealed a bilateral papillary serous carcinoma of the fallopian tube. The patient was treated with adjuvant chemotherapy with Paclitaxel. There was no evidence of any recurrence, after 2 years of regular follow up. The clinical signs and symptoms of fallopian tube neoplasms are usually non-specific. The primary treatment remains a surgical resection, followed by adjuvant chemotherapy or radiation. The prognosis is poor, although long-term survivors have been reported. PMID- 23814749 TI - The flexor indicis profundus - its morphology and clinical significance. AB - The knowledge on the anatomical variations of the deep flexor muscles is important due to its evolutionary significance. The flexor digitorum profundus is the deep flexor muscle of the forearm. It is a composite muscle with a dual nerve supply. The medial half of muscle is supplied by the ulnar nerve, and lateral half of the muscle is supplied by the anterior interosseous nerve, a branch of the median nerve. It flexes the distal phalanges of the medial four digits. In the present case, we observed the presence of extensive cleavage of belly and tendon of flexor digitorum profundus to form flexor indicis profundus on the right side in an adult male cadaver. Flexor indicis profundus muscle is an example of progressive type of variation and it is usually asymptomatic, but it may cause compression of the anterior interosseous nerve, which can lead to compression neuropathy. If it is enlarged, it may simulate a ganglion. PMID- 23814751 TI - Molecular predictors in the early diagnosis of oral cancer. AB - Human beings are being subjected to a variety of disease processes, a majority of which can be cured. However, cancer remains an endangering disease that affects various body parts. Though cancers can be prevented by various therapeutic modalities, the patient survival and the prognosis are questionable, as they are detected at very late stages. The aim of improving the prognosis lies in an early detection of the cancer, which can be brought about by an analysis of the changes in the cellular biomolecules. PMID- 23814750 TI - The associations of nuchal translucency and fetal abnormalities; significance and implications. AB - This review of literature describes the first-trimester nuchal translucency (NT) which forms the basis of new form of screening which can lead to a significant improvement in detection of congenital anomalies as compared to second trimester screening programs, the so called genetic-sonogram. A growing body of evidence based studies has demonstrated that fetal NT can be a powerful prenatal screening tool and combined with first trimester serum markers, it can be incredibly promising in near future. It should be expressed as Multiple of median (MoM) and maintained and monitored like any laboratory analyte. The aim of this review was to investigate the different hypotheses on the aetiology of increased NT. Using a computerized database (PubMed), articles on the aetiology of first-trimester NT were retrieved. Furthermore, the cited references of the retrieved articles were used to find additional articles. Based on ultrasonography, the associations of increased NT fetuses are described in relation with Down syndrome, Cardiac anomalies, and a diverse range of other anomalies. The review concludes that first trimester NT ultrasound has the potential to be used as an important tool for the detection of various congenital abnormalities and an early management can be implemented to reduce the mental trauma of expecting mothers by proper counseling and early diagnosis. For the precise measurements, it should be implemented in a meticulous and coherent manner. PMID- 23814752 TI - Mystery inside the tooth: the dental pulp stem cells. AB - Stem cells are distinguished by their ability to differentiate into different types of cells in the body and to self-replicate. During the recent years, stem cells have been used extensively in the field of medicine for the repair and regeneration of defective tissues and organs. However, the knowledge on the stem cell technology is increasing quickly in all medical disciplines and it dictates the need for new protective approaches in all fields, which include reparative dentistry. Stem cell therapy constitutes a common challenge for dentists as well as for biotechnologists. The aim of this study was to review the knowledge which was related to stem cells and to consider the possibility of use of stem cell populations and their technology in the future clinical applications, to cure diseases like Parkinsonism, Juvenile diabetes, certain forms of cancer, spinal injuries and heart problems. PMID- 23814753 TI - Dental considerations in pregnancy-a critical review on the oral care. AB - Pregnancy is a dynamic physiological state which is evidenced by several transient changes. These can develop as various physical signs and symptoms that can affect the patients health, perceptions and interactions with others in the environment. The patients may not always understand the relevance of the adaptations of their bodies to the health of their foetuses. A gestational woman requires various levels of support throughout this time, such as medical monitoring or intervention, preventive care and physical and emotional assistance. The dental management of pregnant patients requires special attention. Dentists, for example, may delay certain elective procedures so that they coincide with the periods of pregnancy which are devoted to maturation versus organogenesis. At other times, the dental care professionals need to alter their normal pharmacological armamentarium to address the patients' needs versus the foetal demands. Applying the basics of preventive dentistry at the primary level will broaden the scope of the prenatal care. Dentists should encourage all the patients of the childbearing ages to seek oral health counseling and examinations as soon as they learn that they are pregnant. This article has reviewed some of the physiologic changes and the oral pathologies which are associated with pregnancy, and how these alterations can affect the dental care of the patient. PMID- 23814754 TI - Fibrous dysplasia and central giant cell granuloma: a report of hybrid lesion with its review and hypotheticated pathogenesis. AB - Benign fibro-osseous lesions (BFOLS) of the jaws are a wide array of lesions that actually represent distinct phases of a single benign morphological process. These lesions share certain histopathological features which are in common with giant cell containing lesions, which include central giant cell granulomas (CGCGs). The association of BFOLS and CGCG has to be critically evaluated, pertaining to their clinical, radiologic and histologic features. Many pathologists diagnose these types of lesions, considering only one of the prominent features. Eventually, surgeons end up treating these lesions inadequately. This ambiguity may be because of very small number of cases have been reported in the literature, with uncertain clinical, radiologic and histologic features. We are reporting a case of fibrous dysplasia (FD) which was associated with a central giant cell granuloma (CGCG) and discussing the hypothetical pathogenesis of giant cells. PMID- 23814755 TI - The crouzan syndrome-a case report. AB - The Crouzon syndrome is a genetic disorder which is known as the brachial arch syndrome. It is an autosomal dominant disorder which is one of a rare group of syndromes which is characterized by cranio synostosis or a premature closing of the cranial sutures. The major features are brachiocephaly, occular proptosis, an under developed maxilla, mid face hypoplasia, a rare cleft lip or palate, hypodontia (some teeth missing) and crowding of teeth. Due to the maxillary hypoplasia, the Crouzon syndrome patients generally have a considerable permanent underbite and they subsequently cannot chew by using their incisors. We have presented in this article, a case of the Crouzon syndrome which was seen in a girl who was aged six years, with similar symptoms and the multidisciplinary approach which has to be followed in managing the case. PMID- 23814756 TI - The role of colour Doppler ultrasonography in the diagnosis of fascial space infections - a cross sectional study. AB - AIMS AND OBJECTIVES: (1) To evaluate the role of ultrasonography with colour Doppler in the diagnosis of fascial space infections, (2) To determine the nature, size and extent of the odontogenic infections which involve the primary and secondary fascial spaces of the maxilla and the mandible (3) To evaluate the sensitivity of ultrasonography in determining whether the inflammatory process is in a stage of cellulitis or abscess and to thus determine the appropriate time for a surgical intervention during the course of the infection and to correlate the clinical and radiographic findings with the ultrasonographic findings and (4) to determine the treatment plan. METHODOLOGY: Thirty four patients with odontogenic infections which involved the superficial and the deep fascial spaces of the head and neck were subjected to ultrasonographic examinations over the suspected area in the transverse and axial directions to determine the stage of the infection, its anatomic location and the treatment plan. RESULTS: Ultrasonography showed 95.7% sensitivity and 100% specificity as compared to the clinical and radiographic diagnoses and it proved to be an effective investigation modality in the diagnosis of fascial space infections. PMID- 23814757 TI - The aesthetic management of a 180 degree rotated maxillary central incisor with two root canals- a case report. AB - The success of the root canal treatment is based on a thorough knowledge of the normal tooth, the root and the root canal morphology, which include variations. Tooth rotation is a common finding in the premolar-molar region, but a 180 degree rotation of the maxillary central incisor is extremely rare and it has not documented anywhere in the dental literature. This case report describes the aesthetic correction of a maxillary central incisor with a 180 degree rotation and two root canals. PMID- 23814758 TI - Chvostek's and Trousseau's signs in a Case of Hypoparathyroidism. PMID- 23814759 TI - An 'open-ishihara-book' case of what lies beneath.... PMID- 23814760 TI - The role of the total cholesterol level in the assessment of the severity of myocardial infarction. PMID- 23814761 TI - Hyaluronic Acid: a boon in periodontal therapy. AB - Hyaluronic acid is a naturally occurring linear polysaccharide of the extracellular matrix of connective tissue, synovial fluid, and other tissues. Its use in the treatment of the inflammatory process is established in medical areas such as orthopedics, dermatology, and ophthalmology. The Pubmed/Medline database was searched for keywords "Hyaluronic acid and periodontal disease" and "Hyaluronic acid and gingivitis" which resulted in 89 and 22 articles respectively. Only highly relevant articles from electronic and manual search in English literature were selected for the present review article. In the field of dentistry, hyaluronic acid has shown anti-inflammatory and anti-bacterial effects in the treatment of periodontal diseases. Due to its tissue healing properties, it could be used as an adjunct to mechanical therapy in the treatment of periodontitis. Further studies are required to determine the clinical efficacy of hyaluronic acid in healing of periodontal lesion. The aim of the present review, article is to discuss the role of hyaluronic acid in periodontal therapy. PMID- 23814762 TI - Dysmegakaryocytopoiesis and maintaining platelet count in patients with plasma cell neoplasm. AB - BACKGROUND: Dysmegakaryocytopoiesis in patients with the plasma cell neoplasm (PCN) is rarely discussed in the literature. The puzzling phenomenon, which PCN patients maintaining normal platelet count even when the marrow is mostly replaced by plasma cells, is hardly explored. AIM: This study was aimed to determine the frequency of dysmegakaryocytopoiesis in PCN and the relationships between bone marrow (BM) plasma cell percentage, plasma cell immunomarkers, the severity of dysmegakaryocytopoiesis, and peripheral blood platelet count in PCN. MATERIALS AND METHODS: We randomly selected 16 cases of PCN, among which 4 were with monoclonal gammopathy of undetermined significance and 12 were with plasma cell myeloma. RESULTS: OUR STUDY SHOWED THAT: (1) Dysmegakaryocytopoiesis was present in all the selected cases of PCN and its severity was not correlated with the percentage of the plasma cells in BM; (2) almost all patients maintained normal platelet count even when BM was mostly replaced by plasma cells; (3) immunomarkers of the neoplastic plasma cells were not associated with dysmegakaryocytopoiesis or maintaining of platelet count. The possible mechanisms behind dysmegakaryocytopoiesis and maintaining of platelet count were also discussed. CONCLUSION: Despite the universal presence of dysmegakaryocytopoiesis in PCN, the platelet count is maintained at normal range. PMID- 23814763 TI - Manual khalifa therapy in patients with completely ruptured anterior cruciate ligament in the knee: first results from near-infrared spectroscopy. AB - BACKGROUND: Manual Khalifa therapy has been practiced in Hallein, Austria, for more than 30 years; however, there are no scientific results available on the topic. AIMS: The goal of the present study was to investigate possible acute effects of Khalifa therapy on regional oxygen saturation of knee tissues in patients with completely ruptured anterior cruciate ligament. MATERIALS AND METHODS: We investigated 10 male patients (mean age +/- standard deviation (SD) 35.9 +/- 6.1 year) using a four-channel oximeter. The sensors were applied anterolaterally and anteromedially, beside the patella, on both the injured and the healthy (control) knee. RESULTS: The results of the controlled study showed that values of oxygen saturation on the knee with the ruptured ligament were significantly increased (P < 0.001) immediately after Khalifa therapy, whereas the values on the control knee showed insignificant increases. Baselines values of the anterolateral side of the injured knee were significantly (P < 0.001) different from those of the anterolateral side of the control knee. The same effect was present on the anteromedial side; however, with a lower degree of significance (P < 0.05). CONCLUSIONS: Khalifa therapy was clinically successful in all 10 patients. Further, investigations and analyzes are necessary to explain the underlying mechanism. PMID- 23814765 TI - White willow bark induced acute respiratory distress syndrome. PMID- 23814764 TI - Left ventricular mass formulae and prevalence rates of echocardiographic left ventricular hypertrophy in nigerians with essential hypertension. AB - BACKGROUND: Left ventricular hypertrophy (LVH) as a marker of cardiac damage in hypertension has important prognostic implications. With high prevalence of hypertension in Nigeria and the untoward effect of LVH, it is essential that the prevalence of LVH be determined. AIMS: To determine prevalence of LVH and its severity in clinical practice among hypertensive patients referred for echocardiographic assessment in Nigeria. MATERIALS AND METHODS: Devereux and Troy formulae were used to calculate echocardiographic LV mass (LVM) in 401 subjects and thereafter normalized to body surface area (BSA), heigth(2) (ht(2)) and height(2.7) (ht(2.7)) to define LVH to standard gender-specific thresholds. RESULTS: Mean age was 53.22 +/- 16.56 years (male = 53.18 +/- 15.80; female = 53.27 +/- 17.43; P = 0.958) with a male:female ratio of 1.13:1. Prevalence rates of LVH ranged between 38.9-51.3% using the Devereux Formula and 62.4-71.1% using the Troy formula. LVM/(ht(2.7)) using the Troy formula gave the highest prevalence rate of LVH. Majority of the patients with LVH had severe form of hypertrophy with the prevalence rates ranging from 22.3% (LVM/BSA; Devereux formula) to 47.1% (LVM/ht(2.7); Troy formula). CONCLUSION: Prevalence of LVH by any echocardiographic criteria is high. There is a need to come to a consensus on the best formula and indexing variables, that will unify the reporting of LVH. PMID- 23814766 TI - Hypereosinophilic syndrome induced cystitis mimicking bladder tumor. PMID- 23814767 TI - Severe vitamin d deficiency induced myopathy associated with rhabydomyolysis. PMID- 23814768 TI - Diabetes weds oral infection: An unhappy marriage. PMID- 23814769 TI - Transperineal Sonography Evaluation of Muscles and Vascularity in the Male Pelvic Floor. AB - Idiopathic chronic male pelvic pain is difficult to diagnose and treat. Currently, diagnosis relies on subjective symptoms; objective measures of neuromuscular mechanisms have not been investigated. Sonographic imaging has been used to investigate these neuromuscular mechanisms in the female pelvic floor, but neither research nor books describe sonography evaluation of the male pelvic floor. The purpose of this study was to develop and evaluate a perineal sonographic technique for the examination of the male pelvic floor muscles. Anatomic landmarks were identified with images collected from two subjects, one with intermittent reports of pelvic pain and one with no history of pain in the pelvic region. A description of the equipment settings, the examination protocol, and the resulting comparative image analysis is included. A validated protocol such as this may be useful in documenting differences in the soft tissue structures between asymptomatic individuals and patients with chronic pelvic pain to aid in diagnosis and treatment. This is the first known study to report sonographic findings of the individual muscles in the male pelvic floor, and additional research is needed to validate the techniques that have been deemed feasible. PMID- 23814770 TI - [Hard times]. PMID- 23814771 TI - [An editorial manifesto]. PMID- 23814772 TI - Surgical treatment of non-small cell lung cancer in octogenarians - safety and prognosis. AB - BACKGROUND: Reluctance to recommend surgery for the elderly is partly based on the expectation that the rate of complications and mortality is higher in this group of patients and on the impression that the life expectancy of an octogenarian with lung cancer is limited by death from natural causes. METHODS: Between 2007-2011, we operated on 57 patients over 80 years who underwent thoracotomy with curative intent for lung cancer. Mean age was 82.2 years, 17 were female and 40 male. The presence of preoperative comorbidities in this group of patients was significant: chronic lung disease - 22.8%, cardiovascular disease - 38.6% and a history of other malignancy - 17.5%. However, their respiratory function was very acceptable with an average FVC of 93.6% and an average FEV1 of 83.2%. The predominant location of tumor (mean size of 3.0+/-1.7 cm) was upper lobes (63.2%) and cytological diagnosis was established preoperatively in 61.4% of cases. Preoperative staging was complemented by positron emission tomography in 42.1% of cases and in 12.2% with mediastinoscopy. RESULTS: We performed 35 lobectomies (61.4%), 4 bilobectomies (7.0%), 9 wedge resections (15.8%) and 5 pneumonectomies (8.8%). All surgeries were performed through lateral thoracotomy. In 4 patients (7.0%), anatomic resection was aborted intraoperative due to unexpected metastatic disease and/or unresectable mass discovered during exploratory thoracotomy. Lymph node dissection was complete in 57.8%. Final pathology analysis showed: adenocarcinoma in 50.9% of cases, squamous cell carcinoma in 14.0% and carcinoid tumour in 14.0%. Final staging was T1 (24.4%), T2 (26.7%), T3-4 (11.1%), N0 (35.5%), N1-2 (4.4%), G1 (8.9%), G2 (28.9%), G3 (8.9%). Mean hospital stay was 10.7+/-8.1 days. Main surgical complications recorded were: prolonged air leak (15.8%), atelectasis requiring bronchoscopy (7.0%) and persistent air chamber on chest roentgenography (10.5%). We observed an overall operative mortality of one case - 1.8%, which was an 80 year-old patient submitted to a pneumonectomy. CONCLUSIONS: In conclusion, octogenarians should not be denied surgery exclusively due to age. Surgeons should base their decision first on the stage of the disease, and then on an accurate assessment of the general clinical conditions. Pneumonectomy and extended operations should generally be avoided. PMID- 23814773 TI - Lung cancer surgery in octogenarians: who, when and how? PMID- 23814774 TI - A rare cause of acute heart failure. AB - We describe a rare clinical case of ruptured sinus of Valsalva aneurysm (RSVA) into the right ventricle, complicated with severe aortic regurgitation (AR) and myocardial ischaemia. The AR was caused by a hemodynamic effect solely, in which the shunt of blood flow through the ruptured site pulled the right aortic cusp away from closure. The pathological mechanism of the AR was clearly visualized by transesophageal echocardiography. Early successful primary closure of the RSVA resulted in resolution of the associated AR without any additional procedure. PMID- 23814775 TI - Successful implantation of a CoreValve prosthesis through direct aortic access via ministernotomy. AB - The use of tanscathether aortic valve implantation (TAVI) to treat severe aortic valve disease is increasing exponentially. Peripheral vascular access for TAVI is not always possible, and when transapical approach is contraindicated, other access options can be considered like the central transaortic access. The authors describe a successful implantation of a CoreValve prosthesis through direct aortic access via ministernotomy, addressing particular attention to the implantation procedure, potencial complications, advantages and limitations of the method. PMID- 23814776 TI - [Hemangioma of the right ventricular outflow tract, clinical report]. AB - Cardiac hemangiomas are a rare benign primary tumor with an estimated incidence of no more than 10% of cases of primary cardiac tumors. They can arise in any location but most of them occur predominantly in the right ventricle. Heart hemangiomas are usually asymptomatic and accidentally diagnosed by imaging methods such as echocardiography or nuclear magnetic resonance; however they can cause symptoms resulting from obstruction of blood flow, interference with the heart valves, arrhythmias or embolization. Surgical resection is the treatment of choice and long-term prognosis is favorable after total resection of the tumor. The authors present a case of cardiac hemangioma whose clinical diagnosis was triggered by exertional dyspnea and culminating with complete resection of the tumor. In this context, a review of this entity is made with special emphasis on imaging modalities used for diagnosis. PMID- 23814777 TI - [The use of negative pressure therapy in vascular surgery: experience of a single center]. AB - OBJECTIVE: Prospective and unicentric review of the use of negative pressure wound therapy in patients with acute and chronic vascular pathology. MATERIAL AND METHODS: Between January 2010 and February 2012, there were 26 patients treated with negative pressure therapy, with a mean age of 60 years (+/- 14 years), 69% of which male. The most frequently encountered comorbidities were hypertension (66%), followed by diabetes mellitus (50%) and dyslipidemia (38%). 8% had chronic renal failure. The hospitalization was due to ischemic ulcers in 23%, complicated venous ulcer in 13%, diabetic foot in 8% and ruptured abdominal aortic aneurysm in 8%. The main reason for the application of negative pressure therapy was accelerate healing (62%), followed by infection control (46%). Two patients started application for abdominal compartment syndrome. All patients started treatment after hospitalization, with an average of 26 days after admission, having made application for about 13 days (+/- 8 days), with a medium pressure and number of exchanges, respectively, of 106mmHg (+/- 12 mmHg) and 3 exchanges (+/- 1.5). RESULTS: Therapeutic success was obtained in 23 patients (88%), with 2 submitted to major amputation. There were 3 deaths from causes unrelated to vacuotherapy. The average number of days of hospitalization after-treatment was 15 and 88% of patients underwent secondary procedures, 50% of which were cutaneous plasty. In two cases, the treatment was prolonged to ambulatory. CONCLUSION: Beginning about 15 years ago, the application of negative pressure in wound therapy has been having a growing indication, with positive results in the clinical evolution of patients, as exemplified by the results of the service experience. PMID- 23814778 TI - [Large infectious thoracoabdominal aortic aneurysm in a chronic contained rupture, treated successfully using the "simplified technique"]. AB - The clinical case of a 72-years old male is reported, admitted into a Medical Department through the Emergency Service, with a clinical picture of heavy lumbar pain, with walking compromise and acute urinary retention, lasting for several hours. Laboratory analysis revealed a marked elevation of acute inflammatory parameters and a renal failure, expressed by 108 mg/dl of urea and 4.4 mg/dl of creatinine. The patient was admitted with the provisional diagnosis of acute prostatitis, pos-renal acute renal insufficiency and dorso-lumbar pathology of unknown etiology. Three consecutive and subsequent hemocultures allowed the isolation of a Streptococcus pneumonae strain and a CT dorso lumbar spine evaluation disclosed a D11 to D12 spondylodiscitis, with a partial destruction of the vertebral bodies and an extensive throracoabdominal aortic aneurysm adjacent to those vertebrae, with some characteristic features of an infectious aneurysm. Simultaneously, an hemothorax on the left chest was noticed, consequence of a chronic contained rupture of the aneurysm. Following an intensive and specific antibiotic therapy and with an almost completed recovery of the renal function, he underwent surgical management, consisting in the evacuation and drainage of the hemothorax, followed by resection of the aneurysm and extensive tissular debridmente, culminating in the vascular reconstruction utilizing the "simplified technique", introduced in 1984 by A. Dinis da Gama for the surgical management of thoracoabdominal aortic aneurysms. The patiente tolerated the procedure well, with no intercorrences or complications and the post operative course was unventfull. One month later, a CT-angio control disclosed the revascularization procedure working in excellent condition. Finally, an orthopedic artrodhesis of the injuried vertebrae was performed, allowing an easy and pain-free walking and he was discharged on day 60, under antibiotic treatment. The main features of this clinical case are emphasized and discussed, namely those aspects related to its pathogenesis, clinical presentation, diagnosis and surgical management. PMID- 23814779 TI - ["Ex-vivo" surgical repair of renal artery branches aneurysms]. AB - The authors report the clinical case of complex aneurysms of intra-hilar branches of the renal artery, managed recently through a renal auto-transplantation procedures with "ex-vivo" repair, discussing the technique, the principles and the indications for this kind of procedure. PMID- 23814780 TI - [False aneurysm of the superficial temporal artery. Clinical report and literature review]. AB - Traumatic injuries of the external carotid artery and its branches are relatively rare in clinical practice and they may occur following head injuries. The superficial temporal artery is particularly susceptible to injury, given to its superficial course and the fact that it is overlying the temporal bone. The authors report the clinical case of a 88 years-old female treated of a false aneurysm of the superficial temporal artery and they proceed to a review of the literature. PMID- 23814781 TI - ["Universal" calcification of the hand's arteries]. PMID- 23814782 TI - A novel aptasensor for the ultra-sensitive detection of adenosine triphosphate via aptamer/quantum dot based resonance energy transfer. AB - We designed a novel aptamer based biosensor (aptasensor) for ultrasensitive detection of adenosine triphosphate (ATP) through resonance energy transfer (RET). The ATP aptamer was modified with Cy3 at the 3' end, and a green quantum dot (525) was attached to the 5' end of its complementary sequence respectively. The ATP aptamer and its complementary sequence could assemble into a duplex structure in the absence of target ATP, and then decrease the distance between the quantum dot and Cy3 which could produce significant RET signal. Upon ATP binding, the ATP aptamer could dissociate with its complementary sequence and then increase the distance between the quantum dot and Cy3 which would significantly decrease the RET signal. Therefore, the ATP detection could be easily achieved through detection of the fluorescence intensity ratio between 525 nm and 560 nm. The results show that the emission fluorescence intensity ratio of 525/560 is linearly related to the logarithmic concentration of ATP. The linear range of this aptasensor is from 0.1 nM to 1 MUM, and the detection limit is lower down to 0.01 nM. Excellent selectivity of this aptasensor for ATP has been demonstrated through the detection of thymidine triphosphate (TTP), cytidine triphosphate (CTP), guanosine triphosphate (GTP) and adenosine diphosphate (ADP) respectively as control. The method we described here could easily detect ATP with excellent selectivity, linearity and sensitivity down to the nanomolar range, as well as avoid photobleaching. PMID- 23814783 TI - Multiplexed detection of microRNAs by tuning DNA-scaffolded silver nanoclusters. AB - A universal silver-nanocluster method coupled with target-triggered isothermal exponential amplification reaction (TIEAR) is developed for light-up fluorescent detection of multiple microRNAs (miRNAs) in a label-free format. Taking advantage of the interesting feature of the fine-tuned emission spectrum of fluorescent DNA scaffolded silver nanoclusters (DNA/AgNCs), our proposed assay is designed such that the different miRNA targets are transferred to the different oligonucleotide reporters via the TIEAR, in which unimolecular DNAs designed for different targets are employed as the amplification templates, polymerases and nicking enzymes as mechanical activators and miRNA targets as the trigger. The produced oligonucleotide reporters act as templates for the synthesis of multicolor DNA/AgNC probes, which correspond to different target inputs. This proposed method has been well validated on the multiplex detection of miRNAs and DNAs, as well as in practical application. PMID- 23814784 TI - An enzyme-free and label-free assay for copper(II) ion detection based on self assembled DNA concatamers and Sybr Green I. AB - An enzyme-free and label-free fluorescence turn on biosensor for amplified copper(II) ion (Cu(2+)) detection has been constructed based on self-assembled DNA concatamers and Sybr Green I. This assay is simple, inexpensive and sensitive, enabling quantitative detection of as low as 12.8 pM Cu(2+). PMID- 23814785 TI - Straightforward and highly diastereoselective synthesis of 2,2-di-substituted perhydrofuro[2,3-b]pyran (and furan) derivatives promoted by BiCl3. AB - An effective and facile method for the synthesis of 2,2-di-substituted perhydrofuro[2,3-b]pyran (and furan) derivatives is described. The cyclization of 1,2-cyclopropanated sugars with olefins in the presence of BiCl3 is highly diastereoselective. 2,2-Di-substituted cyclization products were obtained in good to excellent yields. PMID- 23814786 TI - Solid phase click ligation for the synthesis of very long oligonucleotides. AB - Oligonucleotides have been ligated efficiently on solid-phase using CuAAC and SPAAC chemistry to produce up to 186-mer triazole linked DNA products. Multiple sequential ligation reactions can be carried out by using a masked azide approach. This work suggests a novel modular approach to the synthesis of large complex oligonucleotide analogues. PMID- 23814787 TI - Reversible and hydrogen bonding-assisted piezochromic luminescence for solid state tetraaryl-buta-1,3-diene. AB - Reversible piezochromic luminescence and aggregation induced emission properties of 4,4'-((Z,Z)-1,4-diphenylbuta-1,3-diene-1,4-diyl)dibenzoic acid are reported. The photoluminescent color of it changes from blue to yellow-green upon grinding, which can be restored upon exposure to a solvent. Intermolecular hydrogen bonding plays a key role in the altered emission. PMID- 23814788 TI - Reconstitution of the pyridoxal 5'-phosphate (PLP) dependent enzyme serine palmitoyltransferase (SPT) with pyridoxal reveals a crucial role for the phosphate during catalysis. AB - The pyridoxal 5'-phosphate (PLP)-dependent enzyme serine palmitoyltransferase (SPT) is required for de novo sphingolipid biosynthesis. A previous study revealed a novel and unexpected interaction between the hydroxyl group of the l serine substrate and the 5'-phosphate group of PLP. By using pyridoxal (PL), the dephosphorylated analogue of vitamin B6, we show here that this interaction is important for substrate specificity and optimal catalytic efficiency. PMID- 23814789 TI - Colorimetric enantioselective recognition of chiral secondary alcohols via hydrogen bonding to a chiral metallocene containing chemosensor. AB - An operationally simple colorimetric method for enantioselective detection of chiral secondary alcohols via hydrogen bonding interactions using a chiral ferrocene derivative is reported. PMID- 23814790 TI - [Not Available]. PMID- 23814791 TI - [Not Available]. PMID- 23814793 TI - Nursing scholarship and leadership in tobacco control. PMID- 23814794 TI - Resolution: Smoke-free campus policies for schools of nursing and college campuses. PMID- 23814795 TI - Reducing firearm violence. PMID- 23814796 TI - Mental health is an urgent public health concern. PMID- 23814797 TI - Screening and counseling for violence against women in primary care settings. PMID- 23814798 TI - Abstracts of EHRA (European Heart Rhythm Association) EUROPACE 2013. June 23-26, 2013. Athens, Greece. PMID- 23814799 TI - Abstracts of the 73rd Scientific Sessions of the American Diabetes Association. June 21-25, 2013. Chicago, Illinois, USA. PMID- 23814801 TI - Retraction. "Meta-analysis on the comparison between two topical calcineurin inhibitors in atopic dermatitis" by Zhi Qiang Y, Wei Ming Z, Guo Xin S, and Dan L. PMID- 23814800 TI - Beyond sun, sand, and stitches: assigning responsibility for the harms of medical tourism. AB - Medical tourism (MT) can be conceptualized as the intentional pursuit of non emergency surgical interventions by patients outside their nation of residence. Despite increasing popular interest in MT, the ethical issues associated with the practice have thus far been under-examined. MT has been associated with a range of both positive and negative effects for medical tourists' home and host countries, and for the medical tourists themselves. Absent from previous explorations of MT is a clear argument of how responsibility for the harms of this practice should be assigned. This paper addresses this gap by describing both backward looking liability and forward looking political responsibility for stakeholders in MT. We use a political responsibility model to develop a decision making process for individual medical tourists and conclude that more information on the effects of MT must be developed to help patients engage in ethical MT. PMID- 23814802 TI - Has the shift to managed care reduced Medicaid expenditures? Evidence from state and local-level mandates. AB - From 1991 to 2009, the fraction of Medicaid recipients enrolled in HMOs and other forms of Medicaid managed care (MMC) increased from 11 percent to 71 percent. This increase was largely driven by state and local mandates that required most Medicaid recipients to enroll in an MMC plan. Theoretically, it is ambiguous whether the shift from fee-for-service into managed care would lead to an increase or a reduction in Medicaid spending. This paper investigates this effect using a data set on state- and local-level MMC mandates and detailed data from the Centers for Medicare and Medicaid Services (CMS) on state Medicaid expenditures. The findings suggest that shifting Medicaid recipients from fee-for service into MMC did not on average reduce Medicaid spending. If anything, our results suggest that the shift to MMC increased Medicaid spending and that this effect was especially present for risk-based HMOs. However, the effects of the shift to MMC on Medicaid spending varied significantly across states as a function of the generosity of the state's baseline Medicaid provider reimbursement rates. PMID- 23814803 TI - Meta-analysis of coronary CT angiography in the emergency department: reply. PMID- 23814804 TI - [How to biopsy only men with high grade prostate cancer]. AB - INTRODUCTION: Fuzzy logic and Artificial Neural Networks (ANN) are complementary technologies that together generate neuro-fuzzy system. The aim of our study is to compare 2 models for predicting the presence of high-grade prostate cancer (Gleason score 7 or more). METHODS: We evaluated data from 1000 men with PSA less than 50 ng/mL, who underwent prostate biopsy. A prostate cancer was found in 313 (31%), and in 172 (17.2%) we detected high-grade prostate cancer. With those data, we developed 2 Co-Active Neuro-Fuzzy Inference Systems to predict the presence of high-grade prostate cancer. The first model had four input neurons (PSA, free PSA percentage [%freePSA], PSA density, and age) and the second model had three input neurons (PSA, %freePSA, and age). RESULTS: The model with four input neurons (PSA, %freePSA, PSA density, and age) showed better performances than the one with three input neurons (PSA, %freePSA, and age). In fact the average testing error was 0.42 for the model with four input neurons and 0.44 for the other model. CONCLUSIONS: The addition of PSA density to the model has allowed to obtain better results for the diagnosis of high grade prostate cancer. PMID- 23814805 TI - [Laparoendoscopic single-site radical nephrectomy for kidney tumor. Surgical technique, cosmetic and postoperative pain control outcomes]. AB - INTRODUCTION: Over the last few years, many urological laparoscopic operations have been successfully performed by LESS. However, the actual role of LESS in the field of minimally invasive urologic surgery remains to be determined with controversial data about postoperative pain control and almost no results on cosmetic data. The aim of the present study is to describe the technique and report the surgical outcomes of LESS radically nephrectomy (RN) in the treatment of renal cell carcinoma with special emphasis for postoperative pain control and almost no results on cosmetic data. MATERIALS AND METHODS: LESS-RN was performed in 33 patients with renal tumors. The indications to perform a LESS-RN were represented by renal tumors not greater than T2, and without evidence of lymphadenopathy or renal vein involvement. SURGICAL PROCEDURE: The Endocone (Karl Storz, Tuttlingen, Germany) was inserted through a transumbilical incision. A combination of standard laparoscopic instruments and bent grasper and scissors was used. The step sequence of LESS-RN was comparable to standard laparoscopic RN. Demographic data and perioperative and postoperative variables were recorded and analyzed. RESULTS: The mean operative time was 143.7 +/- 24.3 min, with a mean estimated blood loss of 122.3 +/- 34.1 mL and a mean hospital stay of 3.8 +/ 0.8 d. The mean length of skin incision was 4.1 +/- 0.6 cm; all patients were discharged from hospital with minimal discomfort, as demonstrated by their pain assessment scores (visual analogue scale: 1.9 +/- 0.8). The definitive pathologic results revealed a renal cell carcinoma in all cases and a stage distribution of four T1a, 27 T1b, and 2 T2 tumors. All patients were very satisfied with the appearance of the scars, and at a median follow-up period of 13.2 +/- 3.9 mo, all patients were alive without evidence of tumor recurrence or port-site metastasis. CONCLUSIONS: LESS is a safe and feasible surgical procedure for RN in the treatment of renal cell carcinoma and has excellent cosmetic results. PMID- 23814806 TI - Renal mass with caval thrombus as atypical presentation of xantogranulomatous pyelonephritis. A case report and literature review. AB - INTRODUCTION: Xantogranulomatous pyelonephritis is a rare, severe, chronic renal infection typically resulting in diffuse renal destruction. Enlarged kidney is typical radiological finding. In this work we describe an extremely rare case in which a clinically classified cT3b Tumor (level II IVC thrombus) was detected; at specimen analysis to be xantogranulomatous pyelonephritis with IVC extension. MATERIAL AND METHOD: U.V., female, 86 years old, we diagnosed with right renal mass, with extension to IVC. By pathological analysis, it was found that renal mass and the thrombus was not due to RCC, but by xantogranulomatous pyelonephritis. DISCUSSION: Xantogranulomatous pyelonephritis with IVC thrombus is exceptional and has been described in 4 cases. Such a diagnosis could have anesthesiologic importance, in particular related to antimicrobial treatment. Xantogranulomatous pyelonephritis has its own classification, based on extension and organ involvement, but this case fall out of current classification. CONCLUSION: This possibility could be suspected and updating of disease's classification could be suggested. PMID- 23814807 TI - [The complications of cochlear implantation. Overview of the international experience]. AB - The objective of the present study was to analyse potential negative consequences of cochlear implantation (CI) with a view to reducing the possibility of their development Vestibular disorders constitute the most frequent complications of cochlear implantation.Wound infections, acute otitis media (especially among the children), and meningitis are almost equally important.A single episode of otitis in the recipients of cochlear implants may have such serious consequences as meningitis. Approximately 20 new cases of meningitis following Cl are documented annually throughout the world. It emphasizes the paramount importance of prophylaxis of this condition, regular information of the patients, and long-term thorough observation of the children that survived after meningitis. PMID- 23814808 TI - [Laryngeal papillomatosis: problem update]. AB - The objective of the present overview was to analyse the available data on etiology, pathogenesis, diagnostics, and treatment of laryngeal papillomatosis. It is shown that the pathogenetic mechanism underlying the development of this pathology is related to cell proliferation mechanisms. The human papilloma virus is most effectively identified by the polymerase chain reaction technique in combination with in situ hybridization. It is expected that new and more informative criteria for diagnostics, treatment,and prognosis of laryngeal papillomatosis will be proposed based on recent progress in molecular biology, morphology,and immunology. Different variants of the therapeutic strategy for the treatment of laryngeal papillomatosis are described.Modern practice of the management of laryngeal papillomatosis takes advantage of the three main approaches and/or their combination. First, further improvement of surgical techniques, such as the application of endoscopic devices and surgical lasers.Second, the search for new pharmaceutical agents (indole-3-carbinol, cidofovir, antiviral medicines, etc.) most frequently used for adjuvant therapy. Third, the development of new vaccination methods. Besides these three approaches, photodynamic therapy and the use of ionizing radiation are currently being studied as the tools for the treatment of extensive and recurrent laryngeal papillomatosis as well as the methods of laser-induced interstitial thermotherapy. PMID- 23814809 TI - A culture of consent. PMID- 23814810 TI - Family first. PMID- 23814811 TI - How do you sleep? PMID- 23814812 TI - Funding: flirting with disaster. PMID- 23814813 TI - [Immune correction by pancreonecrosis]. PMID- 23814814 TI - Giving sizeable coverage to billing issues. PMID- 23814815 TI - [P.A. Kupriianov -- the outstanding organizator of Russian field surgery. To the 120th anniversary of birth]. PMID- 23814816 TI - The seed remains: a tribute to Linda King Aukett (1943-2013). PMID- 23814817 TI - Response to letter regarding article, "Bridging evidence-based practice and practice-based evidence in periprocedural anticoagulation". PMID- 23814818 TI - Reply: To PMID 23347371. PMID- 23814819 TI - [The normality principle]. PMID- 23814820 TI - Mifepristone as a therapeutic agent in psychiatry. AB - The hypothalamic-pituitary-adrenal (HPA) axis is the body's main stress-response system, and cortisol is the major adrenal glucocorticoid hormone secreted in human beings. HPA axis activity and cortisol secretion is regulated by a negative feedback system involving glucocorticoid receptors. Dysregulation of the HPA axis and increased cortisol levels have been implicated in mood, psychotic, and other psychiatric disorders. Mifepristone, as a potent antagonist of glucocorticoid receptors, has been studied or is currently being investigated as a potential therapeutic agent for psychotic depression, posttraumatic stress disorder, and alcohol and cocaine dependence, as well as for mitigating the weight gain associated with the use of antipsychotic drugs and for improving cognitive dysfunction in schizophrenia and bipolar disorder. This article will review some of the work in these areas. PMID- 23814821 TI - Motivational interviewing: a tool for increasing psychotropic medication adherence for youth. AB - There are serious outcomes to nonadherence to psychotropic medications in children and adolescents, including poor school performance, prolonged duration of illness, increased psychopathology, poor interpersonal relationships, increased psychiatric episodes, and suicide attempts. Medication treatment has demonstrated improved psychiatric functioning and a 50% reduction in suicidal behavior. more than 50% of youth with mental health problems are nonadherent with psychiatric medications. A review of literature examining motivational interviewing (MI) for the problem of treatment adherence in children and adolescents is discussed. MI has great potential to improve psychiatric medication adherence in adolescents. An example of how to implement MI with youth is provided. PMID- 23814822 TI - [Electronic noses: how to "smell" diseases]. PMID- 23814823 TI - [Permeability of the hematoencephalic barrier in normalcy, brain development pathology and neurodegeneration]. PMID- 23814824 TI - [Tension headache and migraine: efficacy of biological feed-back in their treatment]. PMID- 23814825 TI - [New form of a acetylsalicylic acid in the secondary prevention of ischemic stroke]. PMID- 23814826 TI - [The otoneurologic aspects of <>]. AB - This review is focused on the problem of <> encountered by physicians representing different medical disciplines. A total of 9 pathogenic theories are considered with a special reference to the <> theory as the most popular among them. Three major variants of the severity of the clinical course of <> and symptoms of its latent form are described. The diagnostic tools ensuring the objective evaluation of these symptoms including various questionnaires and instrumental studies are discussed. PMID- 23814827 TI - [Minilaparotomic access for surgical treatment of cholelithiasis]. PMID- 23814828 TI - [Specifics of hormonal and energy balance in patients with hyperplasia and endometrial neoplasia with metabolic syndrome in the background]. AB - We conducted a comparative investigation of the hormonal status (LH, FSH, estradiol, progesterone, testosterone, prolactin, SHBG), energy status (leptin, ghrelin, insulin), and carbohydrate and lipid metabolism in patients with endometrial hyperplasia and neoplasia (168 patients) with or without metabolic syndrome in the background. Patients with metabolic syndrome had a high frequency of elevated estrogen (72%), testosterone (65%), insulin (81%), leptin (68%). There was a marked increase in the basal level of luteinizing hormone, prolactin, index, LH/FSH, but decrease in FSH and progesterone. There were significant changes in carbohydrate and lipid metabolism. The possible mechanisms for the contribution of the investigated factors to the development of the pathological processes in the endometrium are presented. PMID- 23814829 TI - [Soluble receptors for tumor necrosis factor and lipid metabolism as potential prognostic factors in patients with prostate cancer]. AB - There was investigated the relationship of lipid metabolism, humoral immunity, high sensitivity C-reactive protein and soluble receptors for TNF-alpha with the presence, severity and prognosis of the disease in 85 patients with morphologically verified diagnosis of prostate cancer. Connection with the dynamics of change in PSA as a major predictor of the disease was observed for concentration sRI and sRII to TNF, PSA baseline, total cholesterol and LDL cholesterol. During follow-up the relative risk of poor prognosis increased by 3 times, and death-in 8.7 times with increasing concentrations of soluble receptors for TNF. The concentration of soluble receptors for TNF may serve as an additional predictor of the presence and clinical course of disease in patients with prostate cancer. PMID- 23814830 TI - [Comparison of results of elastography with hormonal and metabolic status in patients with the diagnosis of thyroid neoplasms]. AB - In order to assess the effectiveness of compression elastography of the thyroid gland as a method for differential diagnosis to studies conducted in the pre operative period, there were involved 34 patients with a mean age 46.6 +/- 2.7 years. Elastography in the real time was characterized, according to the method of estimating, by a relatively high sensitivity (85.2-92.5%) and accuracy (70.6 79.4%), but low (30%) specificity. The specificity of the method, as it turned out, could be improved by taking into account the level of thyroid stimulating hormone (TSH) in the blood or body mass index (BMI) of the patients and, therefore, reducing the number of false-positive findings. Further improvement in the pre-operative diagnosis of malignant tumors of the thyroid gland and the formation of appropriate risk groups could be based on a combination of cytologic, hormonal, genetic and instrumental methods, including the so-called shear wave elastography. PMID- 23814831 TI - [MRI with dynamic contrast enhancement in brain tumors]. AB - Magnetic resonance imaging (MRI) is the leading method of radiation diagnosis of brain tumors. In conditions of the artificial contrast enhancement there are more clearly differentiated the boundaries of the tumor node on the back of peritumorous edema and identified structural features of the tumor. The purpose of this study was to examine indicators of the dynamics of accumulation and removal of contrast agents by brain tumors in MRI technique with dynamic contrast and identify opportunities of this method in the differential diagnosis of various types of tumors. PMID- 23814832 TI - [Effect of plastoquinone derivative SkQ1 on benzo(a)pyrene-induced soft tissue carcinogenesis]. AB - Ninety female SHR mice were subcutaneously injected with a single dose of 2 mg benzo(a)pyrene (BaP) dissolved in 0.2 ml of vegetable oil. Since the next day after BaP injection mice were started to treat with mitochondria-targeted antioxidant SkQ1 at the doses of 5 and 50 nmol/kg/day in drinking water. Control animals received tap water. Study was finished by 358th day. Number of tumor bearing mice increased in all groups exposed to BaP but retarded since 20th week in SkQ1-treated groups in comparison with control. Maximal tumor volume gain was observed in control mice resulting in premature death. By the 30th week of study only 20% of control animals survived, whereas SkQ1 treatment increased survival up to 30% at the dose of 5 nmol and 40% at the dose of 50 nmol. By the 40th week mean tumor volume in 5 and 50 nmol SkQ1-treated mice was 13 and 21 cm3 respectively, whereas in control--40 cm3. In SkQ1-treated mice pneumonia was observed rarely as compared with controls. It could be supposed, SkQ1 at the doses of 5 and 50 nmol/kg/day retarted BaP-induced soft tissue carcinogenesis in SHR mice. PMID- 23814833 TI - [The use of hydroxamic acids and sodium nitrate to enhance the antitumor effect of cyclophosphamide]. AB - It has been showed that the introduction of nitrocompounds (as nitic oxide donors) in to the compositions of cyclophosphamide and hydroxamic acids for curing animals having leukemia P-388 increased duration of life by 290%. Thereby 40% of animals have recovered. The therapeutic dose cyclophosphamide have been reduced by 6 times. PMID- 23814834 TI - [Modification of hematosupressive action of ionizing radiation by dicarbamine]. AB - There was studied the effect of different doses of Dicarbamine by means of oral medical-prophylactic and medical administration on the peripheral blood of rabbits in conditions of experimental radiation damage to the blood system. The drug provided the safety of circulating red blood cells at rather high level, prevented the development of severe post-radiation thrombocytopenia, reduced post radiation leukocytopenia, accelerated processes of recovery of peripheral blood leukocytes to the initial level by segmented neutrophils and lymphocytes. PMID- 23814835 TI - [Advantages of dose calculation by the Monte Carlo method for the treatment of patients with lung, and head and neck tumors with the robotic system CyberKnife ]. AB - This paper analyzes the recalculation of plans for the exposure of patients with tumors of the lung, head and neck by the Monte Carlo method. There are presented the results of calculations with understating the dose by 29% when using the algorithm Ray-Tracing. It is proposed mandatory recalculation of dose by Monte Carlo method in planning exposure for patients with tumors of the lung and head and neck tumors to eliminate significant systematic errors in the values of input dose. PMID- 23814836 TI - [Experience of local radiation therapy and total irradiation of the skin by electron beam in patients with primary B and T-cell lymphomas of the skin]. AB - The problem of the treatment of primary malignant lymphomas of the skin is now becoming increasingly important due to the increase of cases among people of working age and disability of these patients. In most cases lymphomas of the skin have a T-cell origin, the most common of skin lymphoma is mycosis fungoides. It is poorly studied the role of electronic radiation therapy in local and systemic skin lymphomas as well as methodological questions of its application, so research in this field is actual. Therefore the aim of the study is improving of the efficiency of therapy in patients affected by non-Hodgkin's lymphoma with skin lesions by the use of local radiation therapy and total skin irradiation by electron beam. PMID- 23814837 TI - [Clinical course of cutaneous melanoma of the head and neck, and the factors affecting patient survival]. AB - It was found that melanomas of the skin of the head and neck, compared to the trunk and limbs, were characterized by a greater proportion of men, an older average age of the patients, high frequency spindle cell tumors, more frequent synchronous distant metastasis and worse survival. Melanomas, which are localized on the skin of the neck and scalp, have similar aggressive clinical course and are characterized by worse overall and disease-free survival than skin melanomas on the trunk and limbs. However, melanomas of the skin on the ear and face proceed more favorably as compared to skin melanomas of the scalp and neck. Multivariate regression analysis using Cox models showed that the melanoma of the head and neck Breslow tumor thickness was the strongest predictor of overall survival. For skin melanomas of the neck and scalp Breslow tumor thickness was the only significant independent factor for overall survival. In melanoma, skin and ear predictors of survival are: sex, age and tumor thickness. In skin melanomas of the face and ear predictors of survival were sex, age and tumor thickness. PMID- 23814838 TI - [Diagnosis and morphologic verification of tumors detected by mammography screening]. AB - Pre-operative morphological verification of tumors of the breast is a necessary phase of diagnosis. The primary method of obtaining material is a fine needle aspiration biopsy, which in some cases is provides poor information. The use of histological methods of biopsy of non-palpable breast lesions extends possibilities of accurate diagnosis and combined treatment of patients with breast cancer, determines the choice and extent of treatment for benign tumors. The latter, after removing them by means of cryomammotom with urgent histological examination, allow limiting of this manipulation and avoiding segmental resection. PMID- 23814839 TI - [Results of combined treatment of patients with metastatic gastric cancer. Case study]. AB - We present the clinical observation of combined treatment of a patient with metastatic gastric cancer. The patient underwent combined chemotherapy for initially inoperable gastric cancer with metastases to the liver, paragastric lymph nodes, and peritoneal carcinomatosis with complete regression of distant metastases, which allowed radical surgery. The patient is currently under regular team observation without signs of disease. His present survival is 44 months. PMID- 23814840 TI - [Delayed elimination of methotrexate after high-dose infusion]. PMID- 23814841 TI - [A method for reducing suppurative septic complications in the perineal wound after cylindrical extralevatory extirpation of the rectum in cancer patients]. AB - One of frequent postoperative complications of cylindrical extralevatory extirpation of the rectum is suppuration of a perineal wound. It is possible to reduce to a minimum or to prevent completely this complication by application of the passive prolonged drainage of a perineal wound. PMID- 23814842 TI - [Stages of development and main directions of research in primary prevention of cancer at the N.N. Petrov Oncology Research Institute]. PMID- 23814843 TI - [Methods of surgical prevention of breast cancer and of ovarian cancer in BRCA mutation carriers]. PMID- 23814844 TI - [Serum tumor markers CA125 and HE4 in ovarian cancer patients]. PMID- 23814845 TI - [Transcranial magnetic stimulation in the diagnosis of cerebral gliomas]. PMID- 23814846 TI - [Unknown primary neoplasms with isolated metastases to cervical lymph nodes: current questions]. PMID- 23814847 TI - [P73 protein in carcinogenesis and response to anti-tumor therapy]. PMID- 23814848 TI - [Dynamics of observed and relative survival of esophageal cancer patients (population-based study)]. PMID- 23814849 TI - [Capsid protein L1 HPV-16 in a modified cervical epithelium]. AB - The 58 cervical biopsies were studied by cytological, histological, immunomorphological methods, electron microscopy and PCR. Expression of L1 was observed only in the differentiated cells of squamous and metaplastic cervical epithelium. At increase of grade of cervical epithelial lesion decrease expression L1 from 75% of cases of CIN1 up to 28.5% of cases of SCC. Not all capsid structures connect with DNA HPV in case of CIN3. PMID- 23814850 TI - [Interleukin-2 (Ronkoleykin) in the first-line chemotherapy for B-cell non Hodgkin lymphoma]. AB - In this paper we present the results of a randomized prospective study, in which we examined the influence of rIL-2 ("Ronkoleykin ") on the effectiveness of the R CHOP combination in the first-line treatment of patients with B-cell non-Hodgkin lymphomas. From March 2006 to December 2009, the study included 109 newly diagnosed patients. Standard R-CHOP was used in 59 patients, in 50 patients rIL-2 was added, injected subcutaneously in a dose of 1 million IU per day during each course in 1-5th days. It was found that the inclusion of rIL-2 in the R-CHOP regimen increased the effectiveness of the treatment of B-cell NHL with a high risk of poor disease's course. PMID- 23814851 TI - [Effectiveness and toxicity of MOPP, ABVD, BEACOPP chemotherapy in first diagnosed Hodgkin lymphoma with a poor prognosis]. AB - In a retrospective study during the primary mode MOPP to primary patients LH II/IVAB stages with a poor prognosis rate of CR, 5--and 10-year DFS, OS was 69%, 71% and 68%, 74% and 64%, ABVD--76%, 78%, 83% and 68%, BEACOPP-baseline--73%, 97%, 85% and 82%, respectively. When the program ran BEACOPP-baseline it was revealed higher rates of DFS compared with ABVD and MOPP. Higher OS rates were observed in the primary patients treated with BEACOPP-baseline compared with MOPP (p = 0.04). In terms of DFS and OS MOPP regimen did not differ from ABVD. Program ABVD and BEACOPP-baseline had no differences in terms of OS. The frequency of primary refractory forms of LH did not depend on the conducted regimens of PCT. Significantly less recurrences occurred during the regimen of BEACOPP-baseline compared to MOPP and ABVD. BEACOPP-baseline was accompanied by a more pronounced reversible hematologic toxicity. Against the background of the program BEACOPP baseline, neutropenia of III-IV degree was detected in 32%, ABVD--16%, MOPP--13%. PMID- 23814852 TI - [Morphological marker of tumor progression in laryngeal cancer]. AB - Dynamic observation of 32 patients with laryngeal cancer, treated with radiotherapy and combination therapy, was performed using diagnostic technology "Litos-system", including the definition of serum morphotypes by marginal dehydration of biological fluids. In nine of them, on the background of the treatment, there was continued growth of the tumor. In the blood serum seven of nine patients had special microspheroliths, characterized by the presence of "wavy" structures. Such "wavy" microspheroliths could be seen as a harbinger of the continued growth of the tumor, because after their appearance there were detected signs of clinical progression. Apparently, the appearance of mentioned "wavy" structures in the patient's blood is a result of release into the blood of qualitatively new macromolecules produced by a clone of malignant tumor cells. PMID- 23814853 TI - [Comparative study of the hemato-protective effect of Dicarbamine and Leykostime in experimental radiation damage to the blood system]. AB - There was studied the influence Dicarbamine and Leykostime on peripheral blood leukocyte composition of rabbits in experimental radiogenic damage to the blood system. Dicarbamine significantly insured the safety of circulating red blood cells, prevented the development of severe postradiation thrombocytopenia, reduced postradiation leukocytopenia, and accelerated the recovery of peripheral blood leukocytes to the initial level by segmented neutrophils and lymphocytes. Leukostime ensured the safety of peripheral blood leukocytes however was less effective than Dicarbamine to prevent postradiation deficit of circulating red blood cells and thrombocytes. PMID- 23814854 TI - [Biodistribution of the recombinant heat shock protein rhHsp70 in intracranial C6 glioma models in Wistar rats and subcutaneos B16/F10 melanoma in C57BL/6 mice]. AB - For the first time, the biodistribution of recombinant heat shock protein in rhHsp70 rats with grafted intracranial C6 glioma was evaluated. It was assessed using the fluorescent antibody accumulation chaperone rhHsp70 conjugated with fluorochrome Alexa Fluor 555 in tumor cells by intratumoral or intravenous administration. Assessment of the distribution and accumulation of labeled protein was carried out on the model of subcutaneous B16/F10 melanoma in C57BL/6 mice with the use of single-photon emission computer tomography. After 60 minutes after intravenous administration rhHsp70-I123 (20 MBq, 5 mg chaperone) accumulation of the drug mainly in the liver and tumor tissue was showed. The coefficient of the differential accumulation of the labeled protein KDN(tumor/background) was 3.14. It was turned out that comparing the level of fixation of rhHsp70-I123 in the liver and the tumor KDN(tumor/ liver) = 0.76. After 24 hours from the time of injection of rhHsp70-I123 it was observed increase the level of fixation of the labeled protein in the liver and melanoma: KDN(tumor/background) = 3.43; KDN(tumor/liver = 0.78. PMID- 23814855 TI - [Use of local induced hyperthermia in the treatment of malignant tumors]. AB - The way of a local contactless hyperthermal induction heating for biological tissues is developed on the basis of implantation of substituting composite applicator made of a polymeric material with incorporated ferromagnetic particles. The simplified mathematical model of the physical processes proceeding at a sample heating is presented. Model results are used for approximation of the experimental data. PMID- 23814856 TI - [Methodological issues of sentinel lymph nodes biopsy in patients with breast cancer]. AB - Radionuclide imaging of sentinel lymph nodes (SLN) was performed in 122 breast cancer patients, which before the biopsy of lymph nodes it was performed intratumoral injection of colloidal radiopharmaceuticals (RFP): in 89 patients- nanocolloidal (NC) and in 33--colloidal with particle size from 200 to 1000 nm. After the introduction of NC the SLN image was obtained in 83 of 89 women. (93.3%). After the introduction of large colloids (200-1000 nm or more) SLN visualization in this group was achieved in 27 of 33 patients, i.e., in 81.8% of cases (p < 0.05). Along with the axillary SLN, in 55.8% of cases SLN image was obtained in parasternal area and/or lymph nodes of the second and higher orders in axillary as well as under-and supraclavicular regions. On the contrary while using larger colloids, RFP accumulated only in SLN of axillary region in 85.1%. These differences in the topography of the absorption of various diameters radiocolloids were reliable (p = 0.01). Using the NC RFN compared with colloidal RFP of larger diameter can reliably improve SLN visualization till 98.9% however leads to a concomitant accumulation of RFP in lymph nodes of the second order in 55.8% of patients. PMID- 23814857 TI - [Pharmacological correction of the psycho-emotional status in breast cancer patients in the postoperative period]. AB - It was established the presence of psychological disorders in 120 breast cancer patients in postoperative chemotherapy and considered the need for correction of revealed changes in the psychoemotional sphere to improve the quality of life of patients. The use of psychotropic drugs to correct the mental and emotional status in 80 women has improved their status, had a positive effect on the postoperative course, and helped to create the installation for continued treatment. PMID- 23814858 TI - [Endometrial neoplasm similar to ovarian sex cord tumor (clinical and morphologic observations)]. AB - Endometrial tumor, similar to sex cord tumors of the ovary is a rare variant of the tumor with a predominantly favorable clinical course. It can be falsely diagnosed as endometrial stromal sarcoma, which has a pronounced aggressiveness with possible fatal consequences. This tumor is poorly represented in the literature. To correct this deficiency this observation is presented. PMID- 23814860 TI - [Mesonephric (clear cell) cervical cancer]. AB - Mezonefric cervical cancer was more prevalent in younger women (mean age 42.2 +/- 1.2 years) with no classic predisposing factors. In most cases (62.1%) the localized stage of the disease (I, II stages) dominated. Regional metastases correlated with depth of tumor invasion (with a depth of invasion of more than 10 mm--57.8%). There was marked low expression of HER2/neu (only in 1 of 14 samples it was revealed light positive reaction. Proliferation index Ki-67 was 37.5% and the signs of mutation in the p53 gene were found in 28.4% of cases. Estimating that two thirds of patients with clear-cervical cancer revealed localized forms of the disease, and that most of the women had received the combination treatment (51.8%)--a 5-year survival rate was quite high and was 79.3%. PMID- 23814859 TI - [The combination of chronic myeloid leukemia and multiple myeloma in one patient]. AB - The article describes the clinical observation of a patient with simultaneous course of lymphoid and myeloid neoplasms. The patient developed two diseases- chronic myeloid leukemia (CML) and multiple myeloma (MM), which were confirmed by corroborated hemogram, myelogram, immunophenotyping of bone marrow cells, biopsy, immunohistochemical, cytogenetic, biochemical and radiological studies. Target therapy of CML with tyrosine kinase inhibitors (imatinib at the standard dose of 400 mg per day) has provided a complete cytogenetic remission at 6 months and major molecular response at 18 months of treatment. Administration of 2 courses of programmed treatment "BD" > (bortezomib + dexamethasone) resulted in a very good partial response, which was maintained through a year and a half. However, against the background of programmed treatment there were developed complications as polyneuropathy of grade 2, which was treated with thioctacide, milgamy, and anemia of grade 2, successfully treated with epoetin beta. Subsequently, the patient was administered continuously with imatinib 400 mg that kept the major molecular response. Relapsed MM was revealed in 20 months and confirmed by a full clinical and hematological examination. The absence of organ dysfunction allowed choosing a supervisory tactics for the patient. PMID- 23814861 TI - [Attitude to the illness of patients with malignant lymphomas on various stages of disease]. AB - In 138 patients with malignant lymphomas on different stages of the disease there were considered attitude to the illness and treatment, which included relation to the diagnosis, the subjective perception of the disease and attitude to treatment. Using a technique of studying psychological attitude to the disease there were studied details of personal response to the disease. Along with the general trends in relation to the disease, specific to cancer patients of different tumor sites, there have been identified particular features related to attitude of malignant lymphoma patients: a long period of denial of a malignant nature of the disease and their greatest psychological trauma during relapse. The necessity of professional psychological support was showed. PMID- 23814862 TI - [The increase of non-cancerous thyroid tissue in children and adolescents operated for papillary thyroid cancer: related factors]. AB - Comparison of intact thyroid tissue in children and adolescents operated for papillary thyroid carcinoma, with the reference values established for this age group, found that half of the operated patients had this amount exceeded the upper limit of age and gender norms. In multivariate assessment an exceed of the upper limit of norm was associated with a younger age (under 11 years), living in areas with moderate iodine deficiency, radiogenic history, the presence of Hashimoto thyroiditis, variant of tumor growth and the degree of intratumoral fibrosis. PMID- 23814863 TI - [30-year observation of a rectal cancer patient who has undergone resection of abdominal aorta because of metastases a quarter of a century ago]. PMID- 23814864 TI - [Basal cell skin cancer can metastasize to regional lymph nodes]. PMID- 23814865 TI - [Abstracts of the Scientific Meeting of the Annual Congress of the French Society of Diabetes (SFD). March 26-29, 2013. Montpellier, France]. PMID- 23814866 TI - [Graft failure based on immunology? Reply ]. PMID- 23814867 TI - [Graft failure based on immunology? Reply]. PMID- 23814868 TI - Are we predictive engines? Perils, prospects, and the puzzle of the porous perceiver. AB - The target article sketched and explored a mechanism (action-oriented predictive processing) most plausibly associated with core forms of cortical processing. In assessing the attractions and pitfalls of the proposal we should keep that element distinct from larger, though interlocking, issues concerning the nature of adaptive organization in general. PMID- 23814869 TI - Quantum principles in psychology: the debate, the evidence, and the future. AB - The attempt to employ quantum principles for modeling cognition has enabled the introduction of several new concepts in psychology, such as the uncertainty principle, incompatibility, entanglement, and superposition. For many commentators, this is an exciting opportunity to question existing formal frameworks (notably classical probability theory) and explore what is to be gained by employing these novel conceptual tools. This is not to say that major empirical challenges are not there. For example, can we definitely prove the necessity for quantum, as opposed to classical, models? Can the distinction between compatibility and incompatibility inform our understanding of differences between human and nonhuman cognition? Are quantum models less constrained than classical ones? Does incompatibility arise as a limitation, to avoid the requirements from the principle of unicity, or is it an inherent (or essential?) characteristic of intelligent thought? For everyday judgments, do quantum principles allow more accurate prediction than classical ones? Some questions can be confidently addressed within existing quantum models. A definitive resolution of others will have to anticipate further work. What is clear is that the consideration of quantum cognitive models has enabled a new focus on a range of debates about fundamental aspects of cognition. PMID- 23814870 TI - Reply to Jensen et al.: Equitable offers are not rationally maximizing. PMID- 23814871 TI - In memoriam. PMID- 23814872 TI - Response from the authors. PMID- 23814873 TI - Response from the authors. PMID- 23814874 TI - Fabry or Anderson Fabry disease. PMID- 23814875 TI - The strengths and limitations of the health care system in France. PMID- 23814877 TI - [Matrix metalloproteinases in periodontitis]. PMID- 23814876 TI - News update on withdrawal of Kyoto Heart Study research paper. PMID- 23814878 TI - [Basic concepts of facial aging]. PMID- 23814879 TI - Response. PMID- 23814880 TI - [Genetic factors of aggressive periodontitis risk(matrix proteins, matrix proteases and their regulators]. PMID- 23814881 TI - Psychological well-being and mental health among users and non-users of hormone therapy. PMID- 23814882 TI - A single hormonal test predicts breast cancer risk up to 20 years later. PMID- 23814883 TI - Is yoga beneficial for menopausal symptoms? PMID- 23814884 TI - Genetic profiling of fracture risk. PMID- 23814885 TI - Response. PMID- 23814886 TI - Response. PMID- 23814887 TI - Response. PMID- 23814888 TI - The emergent malignant obesity hypoventilation syndrome: a new critical care syndrome. Author reply. PMID- 23814889 TI - [Weather sensitivity of healthy organism]. AB - Healthy organism is featured by keen physiological weather sensitivity. Normally it appears as the brain and behavior responses to the ordinary geophysical factors such as wind conditions, temperature, atmospheric pressure and relative humidity. Based on the comparative evolutionary assessment, behavioral sensitivity to weather grows with its phylogenetic complication within a species, which was demonstrated in rats (Rattus norvegicus), and people. Behavioral response of rats is more acute than of people. In people, correlation between the electroencephalogram rhythms (EEG) and weather fluctuations becomes stronger as frequency of the delta-theta-alpha-beta rhythms increases. This dependence progresses throughout human ontogenesis, i.e. as one matures and advances in age. Number of correlations between the weather and REG or EEG parameters increases nonlinearly within the ontogenetic string from 3 to 72 years of age. Physiological weather sensitivity is manifested by a diversity of reactions enlarging the arsenal of adaptive plasticity of organism. PMID- 23814890 TI - [Heart rate and energy expenditure during extravehicular activity in different time of day]. AB - The article discusses the comparative heart rate (HR) characteristics associated with day and night extravehicular activities (EVA). HR was commonly higher in the night but not in the daytime. Presumably, the reason is psychological and physiological challenges of the night work on the background of natural performance decrement. These circumstances could lead to elevation of psychic tension and, consequently, increase of heartbeats to a greater extent as compared with daytime EVA. According to the correlation analysis data, the pattern of HR relation to physical loads evaluated by energy expenditure in the daytime was other than at night, i.e. it was positive unlike the nighttime correlation. We cannot exclude it that in the daytime increase in cardiac output (CO) in response to physical work was largely due to increase in HR, whereas it was stroke volume that dominated during night work; at least, it could support CO fully in the periods of low loading. PMID- 23814891 TI - [Health, morbidity and injury rate among the north fleet seafaring personnel]. AB - Health analysis of the basic and contractual servicemen of varying age was performed using the data of multi-year observations of personnel of a surface naval unit in the Kola arctic region. The article presents analysis of seamen health, level and structure of primary morbidity, structure and causes of injuries, distribution by the ICD-10 codes of disease, and data of regular medical check-ups. The term of comorbidity has been proposed to analyze morbidity among the servicemen and its dependence on environmental and occupational factors. Effects of the Kola environment on the servicemen health condition were demonstrated. PMID- 23814892 TI - [Hemodynamics variation in hypertensive pilots of polar transport aviation on different flight phases]. AB - The purpose was to study in-flight blood pressure (BP) and heart rate (HR) in polar transport aviation pilots afflicted with essential hypertension. A total of 30 pilots were distributed into 2 groups: hypertensive pilots and those who, though generally healthy were, because of some conditions and lifestyle, predisposed to the cardiovascular risk (CVR). The examination included establishment of personal CVR factors, electrocardiography, bicycle ergometry, echocardiography, off-duty 24-hour BP and HR monitoring, and in-flight BP and HR monitoring. Maximum BP and HR values were higher in hypertensive pilots as compared with the control group. In the first group, maximum systolic BP (sBP) on the rise measured 202 mm Hg vs. 179 mm Hg in the control group. The highest HR on the rise was also registered in the first group (164 beats/min vs. 127 beats/min in the control). At landing, maximum sBP and HR made up 253 and 163 mm Hg, 150 and 141 beats/min values in groups first and second, respectively. To summarize, in the harsh weather conditions of Far North hypertensive pilots experience particularly heavy hemodynamic stresses during flight and, consequently, must be allowed to fly only if their hypertension is under control. PMID- 23814893 TI - [Effectiveness of interrelative operators' work as a criterion for classification of isolated small groups]. AB - The conception of effective interrelative operators' activity (IROA) is substantiated. A method of isolated small groups classification has been developed around an integral IROA index as an attribute. The proposed rough gradation of isolated small groups is governed by the classifier structure. A particular crew classification was undertaken in the chamber experiments within the MARS-500 project. PMID- 23814894 TI - [Vulnerability to atmospheric and geomagnetic factors of the body functions in healthy male dwellers of the Russian North]. AB - In April 2009 through to November 2011, a Mars-500 satellite study of Russian Northerners (Syktyvkar citizens) was performed using the standard ECOSAN-2007 procedure evaluating the atmospheric and geomagnetic susceptibility of the main body functional parameters. Seventeen essentially healthy men at the age of 25 to 46 years were investigated. Statistical data treatment included correlation and single-factor analysis of variance. Comparison of the number of statistical correlations of the sum of all functional parameters for participants showed that most often they were sensitive to atmospheric pressure, temperature, relative humidity and oxygen partial pressure (29-35 %), and geomagnetic activity (28 %). Dependence of the functional parameters on the rate of temperature and pressure change was weak and comparable with random coincidence (11 %). Among the hemodynamic parameters, systolic pressure was particularly sensitive to space and terrestrial weather variations (29 %); sensitivity of heart rate and diastolic pressure were determined in 25 % and 21 % of participants, respectively. Among the heart rate variability parameters (HRV) the largest number of statistically reliable correlations was determined for the centralization index (32 %) and high frequency HRV spectrum (31 %); index of the regulatory systems activity was least dependable (19 %). Life index, maximal breath-holding and Ckibinskaya's cardiorespiratory index are also susceptible. Individual responses of the functional parameters to terrestrial and space weather changes varied with partidpants which points to the necessity of individual approach to evaluation of person's reactions to environmental changes. PMID- 23814895 TI - [Means and methods of personal hygiene in the experiment with 520-day isolation]. AB - Six volunteers (3 Russians, a Frenchman, an Italian and a Chinese) participated in assessment of the input of sanitation and housekeeping provisions to their wellbeing during 520-day isolation and confinement. Subject of the study was quality and sufficiency of housekeeping agents and procedures as well as more than 60 names of personal hygiene items. The sanitation and housekeeping monitoring involved the clinical, hygienic and microbiological methods, and also consideration of crew comments on the items at their disposal and recommended procedures. Based on the analysis of the functional condition of the integument and oral cavity and entries in the questionnaires, i.e. objective data and subjective feelings, all test subjects remained in the invariably good state. Owing to the application of the selected hygienic means and methods the microbial status of the crew was stable throughout 520-day isolation. PMID- 23814896 TI - [Gaseous content regeneration system]. AB - The article presents a possible design of an atmosphere revitalization system (ARS) as a component part of a new generation life support system (LSS). The main goal of the test investigation was to block formation of solid hard-to-remove carbon as a by-product of carbon dioxide and hydrogen processing. The Bosch reaction stage of CO2 conversion into CO and water was chosen as the core one. Beside the C02 and hydrogen conversion unit, other ARS constituents are a palladium membrane to generate ultrapure hydrogen, a water electrolysis unit, a hydrogen accumulator and a hydrogen absorber. To reach the materials balance, ARS was complemented with a system for trace contaminants and CO2 removal, and a Co2 concentrator. Zeolites in the CO2 removal system and concentrator ensure microwave energy absorption. Hydrogen is accumulated and absorbed by a LaNi5 based intermetallide. The palladium membrane serves to separate hydrogen from the CO-CO2 mixture. PMID- 23814897 TI - [Analysis of evolution of the size of decompression gas bubbles in diver tissues during schedules of medical recompression]. AB - The mathematical model of gas bubble dynamics in body tissues was used for the analysis of evolution of their size during the treatment of decompression sickness in divers by means of recompression in accordance with RN table 72 and USN table 6A. It was shown that the duration of the process of bubble dissolution depends on the compression - decompression profile, as well on the initial size of a bubble, the oxygen content in the breathing mixture and the rate of nitrogen diffusion between a bubble and the surrounding tissue. The results of this study give the grounds to assume that the effect of recompression regimes used in the UK, USA and Russia promotes the treatment of DCS as a result of complete dissolution or significant reduction in the bubble sizes as well as due to therapeutic action of moderately hyperoxic breathing mixture on the tissues affected by bubbles. PMID- 23814898 TI - [On the mechanism of ikaron-1 anti-naupathia action]. AB - Pneumomicroinjection of vestibuloprotector ikaron-1 (Russia) in specific neurons of the medial vestibular nucleus (MVN) was studied in cats immobilized by muscle relaxants using microelectrode devices. The original preparation had a direct effect on the majority of MVN neurons (95 %). Thirty four neurons of 37 cells (92 %) developed an inhibitory response, only one cell (3 %) was activated and 2 neurons (5 %) were areactive. Therefore, the inhibitory reaction to the preparation was 34 times more often than excitatory. An investigation of the MVN neurons activity evoked by adequate stimulation of the vestibular apparatus showed that ikaron-1 attenuates the evoked response in 92 % cells. This phenomenon could be behind the ikaron-lantinaupathia action. PMID- 23814899 TI - [Status of the water-soluble component of the antioxidant defense system in the conditions of 520-day isolation]. AB - In the 520-d chamber experiment within the international project Mars-500 blood samples of 6 male test-subjects of 28 to 39 years of age were analyzed for water soluble antioxidants: total bilirubin and uric acid; in addition, total antioxidant capacity of blood plasma was determined. Maximal values of these parameters were associated with the most stressful periods of the experiment, i.e. adaptation to the life in isolation and confinement, simulation of the egress onto Martian surface, and change of the diet. On attainment of the homeostatic equilibrium the parameters stabilized on levels slightly lower relative to baseline (pre-isolation) values. Therefore, dynamics of the water soluble antioxidants reflected adequately the homeostatic reactions to and compensation by organism of the effects of the 520-day life in isolation and confinement. PMID- 23814900 TI - [Organism as a functional unity of oscillation processes of varying frequency]. AB - The present concept of organism as an oscillating system is discussed in light of the biological rhythms theory. The phenomenon of biological rhythm is viewed as a result of unity and mutual confrontation of the fundamental conflicts in the life process - destruction and creation. Consideration is given to the system-making role of diurnal rhythms keeping the organism functioning as integration. Possible mechanisms of interrelationships of rhythms with different frequencies based on the principles of ascending from simple to complicated, biological amortization, level destabilization, multiple ratios and frequency locking are dealt with. Emphasis is placed on the necessity of conceptualizing the physiological norm as a rhythmic phenomenon. PMID- 23814901 TI - [Modeling an invasive brain - computer interface in an experiment with primates]. PMID- 23814903 TI - Questions to ask before purchasing or implementing new software. PMID- 23814902 TI - Implementing ICD-10: enhancing clinical documentation. PMID- 23814904 TI - Excellence through education. PMID- 23814905 TI - Hot horizons: CMIOs look to the near future. PMID- 23814906 TI - Clinton tells HIMSS attendees: you will lead healthcare transformation. PMID- 23814907 TI - ONC's Mostashari talks about health innovation. PMID- 23814908 TI - Mostashari, Tavenner reference New York Times coverage at HIMSS13 events. PMID- 23814909 TI - A new voice on the federal HIT Standards Committee. Interview by Mark Hagland. PMID- 23814910 TI - Gauging the temperature of today's physicians: results of a new survey. Interview by Mark Hagland. PMID- 23814911 TI - New England innovation. Interview by Mark Hagland. PMID- 23814912 TI - Under ACA, employee hours and minutes add up. PMID- 23814913 TI - Reply from the author. PMID- 23814914 TI - The Utah Center for Clinical and Translational Science: transformation through collaboration. PMID- 23814915 TI - Recent NICE guidance of interest to surgeons. PMID- 23814916 TI - Feline small cell lymphosarcoma versus inflammatory bowel disease: treatment and prognosis. AB - Feline inflammatory bowel disease is a diagnosis of exclusion and a common cause of chronic gastrointestinal signs suhc as weight loss, variation in appetite, vomiting, diarrhea, and lethargy. Patients with intestinal small cell lymphosarcoma can present identical clinical signs, and differentiating between these two conditions can be a challenge. A companion article discusses the value of performing immunohistochemistry and polymerase chain reaction testing on intestinal biopsy samples for this purpose. PMID- 23814917 TI - Clinical snapshot: equine lymphoma. PMID- 23814919 TI - It's a great time to be treated by a biomedical engineer. PMID- 23814918 TI - Safety, BME style. PMID- 23814920 TI - On leadership. PMID- 23814921 TI - Risk versus reward. PMID- 23814922 TI - Remembering the human in the technology. PMID- 23814923 TI - Health care: maintenance or repair? PMID- 23814924 TI - Mr. or Ms. Janitor et al. PMID- 23814925 TI - Here comes influenza season. PMID- 23814926 TI - Prevention of anterior cruciate ligament injuries. PMID- 23814927 TI - An 11-year-old boy with seizures and fatigue. PMID- 23814928 TI - 'Unroofing' a rare toddler rash. PMID- 23814929 TI - A 10-year-old boy with ADHD symptoms. PMID- 23814930 TI - Chronic arthritis in children. PMID- 23814932 TI - Systemic juvenile idiopathic arthritis: a review. PMID- 23814931 TI - A review guide to oligoarticular and polyarticular juvenile idiopathic arthritis. PMID- 23814933 TI - Diagnosis and treatment of juvenile spondyloarthropathy and related diseases. PMID- 23814934 TI - Treatment of juvenile idiopathic arthritis. PMID- 23814935 TI - Role of the primary care provider in transitioning patients with juvenile arthritis. PMID- 23814936 TI - Best practices for outpatient procedural sedation. PMID- 23814937 TI - Diagnosis and treatment of pediatric acute transverse myelitis. PMID- 23814938 TI - A conversation with Catherine M. Wilfert, MD by Stanford T. Shulman. PMID- 23814939 TI - What--and whom--we leave behind. AB - Baby boomer's careers are winding down. Are they leaving their organizations in good hands? PMID- 23814940 TI - Innovation in end-of-life care. PMID- 23814941 TI - Eliminating CAUTI: crucial support for your safety improvement journey. PMID- 23814942 TI - Say that again. Clinicians aim to clear up confusing instructions. PMID- 23814943 TI - Let's stay together. Try shared medical appointments to help relieve MD shortage. PMID- 23814944 TI - If that bandage could talk... PMID- 23814945 TI - ED as a portal. Hospitals reshape the emergency department's philosophy. PMID- 23814946 TI - Baby photo. PMID- 23814947 TI - Medical home: health IT's next evolution. PMID- 23814948 TI - Linking patients and care systems. PMID- 23814949 TI - Giving the patient a say. No, really. AB - After decades of slow acceptance, giving patients a say--a real say--in their treatment decisions is finally gaining traction. It's a crucial element of the transition to a value-driven health care system. PMID- 23814950 TI - Fueling change in medical education. Interview by Paul Barr. PMID- 23814951 TI - Who will lead your hospital? AB - As baby boom executives retire at an ever-increasing pace, leading-edge hospitals are using a variety of tactics to find Gen Xers and Gen Yers with leadership potential and help them acquire the skills they'll need. PMID- 23814952 TI - A focus on heart failure. AB - Heart failure patients account for a hefty proportion of readmissions, so hospitals are refining their discharge processes, boosting education for patients and caregivers, and sending community health workers to their homes. PMID- 23814953 TI - Value-based leadership. Is your hospital management team prepared for the future? AB - This foldout section looks at the seven steps to a value-structured hospital, 10 must-do strategies for thriving in the new health care era, and what new skills management, physicians and trustees should have. PMID- 23814954 TI - Investing in value-based health care. PMID- 23814955 TI - A commitment to value, unleashed: hospitals step up. PMID- 23814956 TI - Defining value: how will you quantify excellence? PMID- 23814957 TI - Reducing the cost of care: a multifaceted strategy. PMID- 23814958 TI - Directing capital of value-makers: what investors want. PMID- 23814959 TI - Managing risk in a population. The new economics of health care. PMID- 23814960 TI - IT: key enabler of value-based care: data drives success. PMID- 23814961 TI - Waging a war against childhood obesity. PMID- 23814962 TI - From first phone call to last visit. PMID- 23814963 TI - [Obesity--a public health problem and challenge]. AB - Obesity is a major health problem today that grows into a global epidemic. According to the World Health Organization report, 1.5 billion adults were overweight, over 500 million of them were obese, and the prevalence of obesity is expected to rise in the years to come. A similar situation is recorded in Croatia, where there are 25.3% of obese men and 34.1% of obese women. There are multiple factors that cause obesity. Accelerated lifestyle, fast food, unhealthy eating habits and sedentary lifestyle are considered as the major risk factors of overweight and obesity development. Accumulation of fat tissue, especially visceral fat tissue has been demonstrated to be associated with some chronic changes and diseases of different organ systems. Some anthropometric measurements, especially body mass index, waist circumference and waist-to-hip ratio, have been used to diagnose obesity and estimate the health risk. Developing well-structured prevention programs that would encourage people to become aware of obesity as a disease and that imbalanced dietary habits and physical activity are important for obesity prevention and health, is a major public health challenge. PMID- 23814964 TI - [Mortality rates of circulatory system diseases and malignant neoplasms in Zagreb population younger than sixty-five--call for alarm]. AB - AIMS: The aim of this work was to analyze the public health indicators for circulatory heart diseases and malignant neoplasms in the population younger than 65 in the City of Zagreb, Croatia, and compare them with the European Union (EU) countries. The purpose was to evaluate the situation and propose the public health preventive measures. METHODS: The study population were Zagreb citizens aged 0-64 according to the 2001 census. Total Zagreb population was 779145, making 17.6% of total Croatian population. Data from the Croatian Bureau of Statistics and Dr Andrija Stampar Institute of Public Health were used. The standardized 0-64 mortality rates of the selected diseases 2006-2010 were used in the analysis. RESULTS: In 2010, the standardized mortality rates of all analyzed diseases were significantly higher in Zagreb population aged 0-64 than the EU averages except for cervical cancer. In 2010, the mortality rates in Zagreb population aged 0-64 were as follows: circulatory system diseases 61.22, ischemic heart disease 28.99, cerebrovascular diseases 12.51, malignant neoplasms 94.69, tracheal and lung cancer 24.92, breast cancer 21.08 and cervical cancer 2.05. Standardized mortality rates in Zagreb population aged 0-64 for circulatory system were lower than for Croatia (61.22 vs. 63.25), but higher for malignant neoplasms (94.69 vs. 91.2), except for cervical cancer (2.05 vs. 3.14). CONCLUSION: High standardized mortality rates for the selected diseases in the City of Zagreb, Croatia, were observed. The rates were higher in Zagreb population compared to EU averages except for cervical cancer. This situation urges revision of the public health strategy and implementation of more intensive preventive and screening measures to reduce the risk factors. PMID- 23814965 TI - [Bloodstream infections after liver and hematopoietic stem cell transplantation]. AB - The aim of this retrospective study was to evaluate and compare the incidence, timing and etiology of bloodstream infections (BSIs) in patients treated with liver-(LT) or hematopoietic stem cell transplantation (HSCT) in a single institution. We evaluated 280 consecutive transplantations over a period of 34 months. Our results demonstrated 84 episodes of BSIs (47 in LT patients and 37 in HSCT patients) at a median of 28 days post-transplantation. Relative incidence of 34.6 and 29.4 BSI episodes per 100 LT and HSCT patients, respectively, did not differ significantly between the two groups (p = 0.52). BSIs in HSCT patients occurred significantly earlier (p = 0.003) than in LT patients. The recently described reemergence of gram-negative (GN) pathogens as causative agents of BSIs in these patients was confirmed: GN bacilli were the predominant isolates in the LT group, responsible for 58.5% of BSIs and a very frequent (39%) cause of BSIs in the HSCT group. A higher incidence of resistant enterobacteriaceae producing extended spectrum beta-lactamases was found in isolates from LT patients compared to HSCT patients. In both groups, Pseudomonas aeruginosa was the most difficult to treat organism, with 57% of these isolates in LT patients and 44% in HSCT patients being resistant to carbapenems. To conclude, BSIs were confirmed to be important infectious complications of both LT and HSCT. Surveillance and analysis of bacteria causing bloodstream and other serious infections in transplanted patients remain the main prerequisites for planning interventions regarding prevention and treatment of infections in these patients. PMID- 23814966 TI - [Histamine intolerance--possible dermatologic sequences]. AB - Although histamine intolerance (HIT) is not very frequently encountered, it can have serious consequences. Food intolerance is a non allergic hypersensitivity to food that does not include the immune system even though the symptoms are similar to those of IgE-mediated allergic reactions. HIT apparently develops as a result of an impaired diamine oxidase (DAO) activity due to gastrointestinal disease or through DAO inhibition, as well as through a genetic predisposition which was proven in a number of patients. The intake of histamine-rich foods as well as alcohol or drugs which cause either the release of histamine or the blocking of DAO can lead to various disorders in many organs (gastrointestinal system, skin, lungs, cardiovascular system and brain), depending on the expression of histamine receptors. Dermatologic sequels can be rashes, itch, urticaria, angioedema, dermatitis, eczema and even acne, rosacea, psoriasis, and other. Recognizing the symptoms due to HIT is especially important in treating such patients. The significance of HIT in patients with atopic dermatitis in whom the benefit of a low histamine diet has been proven is becoming increasingly understood recently. Because of the possibility of symptoms affecting numerous organs, a detailed history of symptoms following the intake of histamine-rich foods or drugs that interfere with histamine metabolism is essential for making the diagnosis of HIT. Considering that such symptoms can be the result of multiple factors, the existence of HIT is usually underestimated, but considerable expectations are being made from future studies. PMID- 23814968 TI - [Contemporary management of leg ulcer]. AB - Chronic wounds are becoming an increasing health, economic and social problem worldwide, including Croatia. Most common chronic wounds are the results of venous insufficiency of lower legs, and their incidence is about 75% of all chronic wounds. Costs of treating patients with leg ulcer are not trivial. According to available data from different countries, they range from 1% to 3% of total fund allocated for health care. Expensive, time-consuming, difficult, and often uncertain treatment is still great health, social and economic problem. The paper describes current approach to the treatment of venous leg ulcers, with emphasis on the cost-benefit of this approach. Before hospitalization, the patient was treated without compression therapy, just with local application of various types of coatings for 4 years. There are no precise data on the types of dressings that were used, and no data on the microbiological status of the wound during this period. After admission to the hospital, the first step was approach to preparation and conditioning the bed of leg ulcer. After achieving satisfactory local status, the ulcer was covered by free skin graft. Upon discharge from the hospital, minor residual skin defects were treated with alginate dressings and fully healed within 3 weeks. Total cost of 3-month treatment (one-month preoperative period, hospitalization and time elapsed from discharge from the hospital to complete recovery) was 17,085.95 HRK. An approximate cost estimate of 4-year unsuccessful treatment is more than 100,000.00 HRK. Contemporary and active approach that is consistent with current state-of-the-art can achieve significant cost saving in the treatment of patients with chronic leg ulcer. PMID- 23814967 TI - [Laparoscopic versus open appendectomy: our experience and literature review]. AB - AIM: The controversy of the choice between open and laparoscopic appendectomy still remains. The benefits as well as disadvantages of laparoscopy are well known. METHODS: We designed a prospective 3-year clinical study (January 1, 2008 December 31,2010) with 123 patients operated on for acute appendicitis. They were prospectively divided into laparoscopic appendectomy (LA) group with 42 results and open appendectomy (OA) group with 81 results. The following parameters were analyzed: age, sex, preoperative leukocyte count, C-reactive protein (CRP) value, preoperative ultrasound finding (US), analgesic administration and histopathologic finding. The length of the operation, length of hospitalization (LOS) and complications were compared between the two groups, along with personal postoperative satisfaction estimated by telephone survey after discharge from the hospital. RESULTS: In 90% of cases, histopathology was positive for inflammation. CRP was determined in 42 (34%) patients preoperatively, with a mean value of 59; positive histopathology finding was recorded in 31 (74%) patients with increased preoperative CRP. US was performed in 68 (55%) patients; positive US was consistent with histopathology in 44 (65%) cases. The mean time of LA/ OA was 75/72 minutes. The only statistical difference was found for LOS: 4 versus 6 days (p < 0.01). CONCLUSION: LA and OA are comparable for the number of complications. The slight benefit of LA offers the surgeon free hand in decision when dealing with acute appendicitis needing urgent operation. PMID- 23814969 TI - [Invasive trichosporonosis caused by Trichosporon asahii in a polytraumatized neurosurgical patient: case report]. AB - Trichosporon asahii (formerly T. beigelii) is a rare cause of human infections with very varied clinical manifestations ranging from superficial infections to severe and systemic diseases. T. asahii is a life-threatening opportunistic pathogen especially for granulocytopenic, immunocompromised and immunodeficient patients. It is the possible cause of summer-type hypersensitivity pneumonitis in Japan and systemic infections in transplant patients, patients on corticosteroid therapy, patients with solid tumors and burn patients. Cases of infection in non immunocompromised surgical patients and patients with long-term stay in ICU are described in the literature. We report on T. asahii fungemia in a polytraumatized neurosurgical patient with long-term stay in the hospital. Urinary tract was the source of fungemia, with the same pathogen isolated from urine and blood at the same time. In the Referral Center for Systemic Mycoses, Croatian Institute of Public Health, Zagreb, the strain from the urine and blood culture was identified as T. asahii, with good susceptibility to fluconazole, voriconazole and 5 fluorocytosine, reduced susceptibility to itraconazole and resistance to amphotericin B. The patient responded to fluconazole therapy very well. Since systemic trichosporonoses are generally associated with immunocompromised patients (hematologic, granulocytopenic and AIDS patients), this case confirms the possibility of infection with this pathogen in patients with long-term hospital stay and reduced local immunity, but without classic immunodeficiency. PMID- 23814970 TI - [Isolated central nervous system relapse of diffuse large B-cell lymphoma in the era of immunochemotherapy]. AB - Diffuse large B-cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin's lymphoma. Standard chemotherapy is CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisone). Addition of rituximab to standard chemotherapy regimen significantly increased the success of treatment and overall survival in DLBCL patients. The incidence of isolated relapse of lymphoma in the central nervous system (CNS) occurs in 1.2% to 10.4% of patients, and the outcome is almost always fatal. In this paper, we report the clinical course in a patient with advanced large B-cell lymphoma, who had been treated with immunochemotherapy but developed isolated CNS relapse of lymphoma shortly after achieving complete remission. There is still no consensus regarding the administration of prophylaxis for CNS relapse of lymphoma in patients with DLBCL, hence the question when and how to conduct the prophylaxis remains unresolved. The risk of CNS relapse of lymphoma in young patients with a low risk of death is decreased and it is classified as score 0 and 1 according to the International Prognostic Index (IPI), while the risk is increased in patients with score 2 to 5 according to the same classification. The risk of CNS relapse of lymphoma is increased if the disease is found in the head, neck, bone marrow or testicle. According to the results of some studies, the addition of rituximab to standard chemotherapy as well as intrathecal methotrexate CNS prophylaxis or prophylactic head irradiation do not reduce the risk of relapse of lymphoma in the CNS. Some studies suggest that high-dose intravenous methotrexate may help reduce the risk of CNS relapse in high-risk patients, but it needs to be confirmed in future researches. PMID- 23814971 TI - [Diagnosis and conservative treatment of low back pain: review and guidelines of the Croatian Vertebrologic Society]. AB - Low back pain (LBP) is a very common condition with high costs of patient care. Medical doctors of various specialties from Croatia have brought an up-to-date review and guidelines for diagnosis and conservative treatment of low back pain, which should result in the application of evidence-based care and eventually better outcomes. As LBP is a multifactorial disease, it is often not possible to identify which factors may be responsible for the onset of LBP and to what extent they aggravate the patient's symptoms. In the diagnostic algorithm, patient's history and clinical examination have the key role. Furthermore, most important is to classify patients into those with nonspecific back pain, LBP associated with radiculopathy (radicular syndrome) and LBP potentially associated with suspected or confirmed severe pathology. Not solely a physical problem, LBP should be considered through psychosocial factors too. In that case, early identification of patients who will develop chronic back pain will be helpful because it determines the choice of treatment. In order to make proper assessment of a patient with LBP (i.e. pain, function), we should use validated questionnaires. Useful approach to a patient with LBP is to apply the principles of content management. Generally, acute and chronic LBP cases are treated differently. Besides providing education, in patients with acute back pain, advice seems to be crucial (especially to remain active), along with the use of drugs (primarily in terms of pain control), while in some patients spinal manipulation (performed by educated professional) or/and short-term use of lumbosacral orthotic devices can also be considered. The main goal of treating patients with chronic LBP is renewal of function, even in case of persistent pain. For chronic LBP, along with education and medical treatment, therapeutic exercise, physical therapy and massage are recommended, while in patients with a high level of disability intensive multidisciplinary biopsychosocial approach has proved to be effective. PMID- 23814972 TI - [Primary health care and family medicine--possibilities for treatment of opiate addicts]. AB - The global trend of promoting management and treatment of drug addicts in family physician offices is the result of the success of opioid agonist therapy. Studies have shown favorable results by shifting treatment into the hands of family physician. This process contributes to general health care of drug addicts and their health by linking different areas of health care, thereby providing comprehensive protection. Shifting treatment of addiction to family physician offices contributes to the elimination of treatment isolation and stigmatization, while further benefits are lower barriers to employment, increase in patient privacy and opportunity to provide health care. The aim of this study was to provide a concise overview of the knowledge from new clinical research over the past ten years on heroin addiction treatment in primary care. New research dealing with the approach to treating addicts indicates a direct link between receiving primary health care with a reduced likelihood of using heroin; furthermore, the main concerns of drug addicts for treatment are availability of more therapeutic programs, better functioning of existing programs, and improved staff relations towards them; final results and outcomes achieved by office and hospital treatment of drug addicts are similar and confirm the positive linear relationship between treatment duration and outcome. Studies comparing therapies show a positive effect of the adaptive methadone treatment maintenance model on the psychosocial factors; equal efficiency of treatment regardless of initiation with buprenorphine or with methadone; and equal effectiveness of levo-alpha acetylmethadol treatment compared with methadone and diacetylmorphine as a good alternative for addiction therapy with previously unsatisfactory results. New studies on buprenorphine show equal effectiveness and cost of detoxification whether guided by a family physician or at the hospital; non-supervised therapy does not significantly influence the outcome, but is significantly cheaper; long term therapy with buprenorphine in the doctor's office shows mild retention. PMID- 23814974 TI - [Ankle-brachial pressure index as a predictor of future cardiovascular outcomes]. AB - Peripheral arterial occlusive disease is very common in the general population and it is mostly of atherosclerotic origin. About 50%-75% of patients are asymptomatic. Many studies have shown the ankle-brachial pressure index (ABPI) to be a simple and reliable test with high sensitivity (90%) and specificity (98%) in the diagnosis of hemodynamically relevant stenosis of an arterial segment and also in detection of asymptomatic patients. The values of ABPI < 0.90 suggest widespread atherosclerosis, while the ABPI > 1.40 is associated with arterial calcification and wall stiffening. This test is highly specific (92.7%) in predicting future cardiovascular and cerebrovascular risk and could provide a tool for more focused prevention strategies. PMID- 23814973 TI - [New insights in steroid diabetes]. AB - Glucocorticoids (GC) are the cornerstone in the treatment of numerous chronic autoimmune and inflammatory diseases. GC treatment is accompanied by significant metabolic adverse effects, including insulin resistance, glucose intolerance and diabetes, visceral adiposity, dyslipidemia and skeletal muscle atrophy. GCs are the most common cause of drug-induced diabetes mellitus. However, not everyone treated with glucocorticoids develops diabetes. Predictors of development of diabetes are age, weight, family history of diabetes mellitus, or personal history of gestational diabetes. There is evidence that patients with decreased insulin secretory reserve are much more likely to develop diabetes. Diabetes from topical steroid use is uncommon, but high-dose steroids have been associated with significant hyperglycemia, including development of hyperglycemic hyperosmolar syndrome and even diabetic ketoacidosis in patients with type 1 diabetes mellitus. Several mechanisms contribute to the development of hyperglycemia and steroid-induced diabetes, including decreased peripheral insulin sensitivity, increased hepatic glucose production, and inhibition of pancreatic insulin production and secretion. Physicians treating patients with GCs should be aware of the induction of metabolic disturbances and should not solely rely on fasting measurements. In addition, our review indicates that insulin therapy could be considered when treating patients on GC therapy. PMID- 23814975 TI - [Epidemiology of invasive breast cancer according to histopathologic and immunohistochemistry prognostic factors]. AB - The aim of this study was to analyze the TNM classification factors of invasive breast cancer that can be affected by the national program for early detection of breast cancer in the Republic of Croatia. The other analyzed factors related to histology and immunohistochemistry have no such impact as they are related to biological behavior and aggressiveness of malignant breast tumors, thus providing useful predictive and prognostic information. The study was performed at Department of Oncologic Surgery, Sestre milosrdnice University Hospital Center, and included 75 patients surgically treated for invasive breast cancer during the period of one month in 2011, mean age 64 +/- 11.36 (range 36-86) years. Most of the patients (68%) with malignant breast disease were diagnosed in a localized stage, which is consistent with the reports from developed European countries. The size of the newly discovered tumors showed continuation of a trend of detecting tumors of ever less size and a lower percentage of pT3 pT4 tumors. This result proved superior to those reported from many European countries. The results of correlation analysis, tumor size, estrogen and progesterone receptor, HER-2 protein, Ki-67, and histologic tumor grade, tumor size did not show significant correlation with any of these parameters. Concordant expression of phenotype (ER+, PR+) receptor pairs and negative HER-2 was recorded in most study patients. The second most frequent group had tumors with so-called 'triple negative' immunohistochemistry negative phenotype (ER-, PR-, HER-2). In conclusion, the program of early detection of breast cancer in the Republic of Croatia and at the University Hospital for Tumors justifies its existence for revealing malignant breast tumors at an earlier stage of the disease considering the size local stage of newly diagnosed tumors. PMID- 23814976 TI - [Pyogenic liver abscess caused by Klebsiella pneumoniae]. AB - Pyogenic liver abscess caused by Klebsiella pneumoniae is usually found in Southeast Asia, while in Europe Escherichia coli, Streptococcus or Staphylococcus are most common. In case of a failed ultrasound controlled abscess, aspiration surgical treatment is indicated. This paper reports the clinical case of pyogenic liver abscess caused by Klebsiella pneumoniae, which was treated by operative drainage. A 60-year-old patient was transferred to our institution from the University Hospital for Infectious Diseases with septic temperature, abdominal pain and finding of Klebsiella pneumoniae liver abscess (resistant to antibiotic therapy). Additional laboratory tests and abdominal MSCT scan confirmed the initial diagnosis. The localization of abscesses technically prevented ultrasound controlled abscess aspiration and drainage; after appropriate preparation, operative liver abscess incision and drainage were performed. Microbiological examination of the abscess sample revealed Klebsiella pneumoniae as the cause of liver abscess. PMID- 23814977 TI - [Midwifery ordinance of Joannis Baptiste Lalangue in the context of the historical development midwifery in Croatia]. AB - Joannis Baptiste Lalangue was the author of the first published rules for performance of midwifery activities printed in Croatian language (Nagovorni lizt, Zagreb, Trattner, 1785), which is extremely important information for the study of the history of Croatian midwifery. The work contains the first printed oath of midwifery in Croatian language, and has not been known in the medical professional literature to date. Lalangue was the founder of the Croatian midwifery, who gave us the first tutorial and first printed rulebook for performing midwifery services in Croatian language. He also founded the first Croatian midwifery school in Varazdin in 1776. After successful completion of training in Varazdin, midwives were authorized to perform midwifery services, and after that initial 'licensing', in order to perform midwifery activity they had to undergo mandatory and statutory testing of knowledge and skills as a prerequisite for 'relicensing', which gave them right to perform midwifery services. This is the basis of the training and continuous education of Croatian midwives to the present, which is consistent with the achievements of modern midwifery and Lalangue's tenets. Lalangue's works were used in systematic training and education of midwives and they, along with their author, have place in the history of Croatian midwifery. PMID- 23814978 TI - [Would patients want to be informed and participate in medical decision?]. AB - Significant changes in the patient-physician relationship occurred during the 20th century. Modern health systems are inconceivable without the existence of laws on the protection of patient rights. Although the present trend emphasizes the rights of patients and their participation in decision-making, there are studies that report conflicting conclusions. The fact that some patients are not willing to participate in decisions about their health does not mean that physicians should have a paternalistic attitude toward them. PMID- 23814979 TI - [World Oral Health Day]. PMID- 23814980 TI - [Future music for type 1 diabetics]. PMID- 23814981 TI - [Pertuzumab. Dual strategy for the first-line treatment of metastatic HER2 positive breast cancer]. PMID- 23814983 TI - [Polypharmacy in old age. New guideline for medication management in geriatric patients]. PMID- 23814982 TI - [Atrial fibrillation in Germany--epidemiology, diagnosis, treatment and costs]. AB - Atrial fibrillation is the most common cardiac arrhythmia. It is an independent risk factor for cardiovascular complications and stroke. The treatment options for atrial fibrillation have changed significantly in recent years by new drugs and ablative procedures. It is based on the principal strategies of anticoagulation, rhythm and rate control. Goal is to reduce symptoms and subsequent events. Although the costs of about 700 to pound 800 per patient per year are rather high, new treatment options might be associated with a reduction in event rates and an increase in quality adjusted life years (QALYs). The aim of this review is to give a practical overview of the epidemiology, diagnosis, treatment and costs to pharmacists who have a key role in the implementation of pharmacotherapy of atrial fibrillation. PMID- 23814984 TI - [Another capability required for anesthesiologists]. PMID- 23814985 TI - [Mechanisms underlying the improvement of arterial oxygenation using positive end expiratory pressure during surgery under sevoflurane anesthesia and propofol anesthesia: a retrospective clinical study]. AB - BACKGROUND: The use of positive end-expiratory pressure (PEEP) is a practical intervention to improve oxygenation during anesthetic management; however, the underlying mechanisms have not been elucidated. METHODS: Parameters of ventilator settings and results of arterial blood gas analyses were collected from medical records of adult patients undergoing surgery under general anesthesia with pressure-controlled ventilation in our hospital from January 2009 to March 2010. We analyzed the changes in dynamic compliance (Cdyn) and alveolar-arterial oxygen difference (A-aDo2). RESULTS: A total of 139 patients were enrolled; anesthesia was maintained with sevoflurane in 82 patients, and with propofol in 57 patients. After the application of PEEP, significant decreases in A-aDo2 were accompanied with significant increases in Cdyn under sevoflurane anesthesia. However, significant decreases in A-aDo2 were not always accompanied by significant increases in C(dyn) under propofol anesthesia. CONCLUSIONS: These results suggest that the mechanisms for improved oxygenation by PEEP under sevoflurane anesthesia are different from those under propofol anesthesia. The improved oxygenation after the application of PEEP under sevoflurane anesthesia is mainly due to reduction of atelectasis, whereas reduction of atelectasis as well as reduction of intrapulmonary shunt is associated with the improved oxygenation after the application of PEEP under propofol anesthesia. PMID- 23814986 TI - [Compression of facial skin by headrest in prone position]. AB - The higher body pressures of patients compared to their capillary blood pressures in the limited areas of their skin induced peripheral blood flow disturbances, thus causing skin injuries. Use of horseshoe-shaped headrest for prone positioning during surgeries can induce blood flow occlusion, skin ischemia, and skin injury due to high pressure and shear stress on the forehead and both cheeks, which are protrusions on facial bone. The use of pressure dispersion headrests is preferred, redistributing the body pressure equally and absorbing pressure from the entire head in the prone position for surgery. PMID- 23814987 TI - [Safety and beneficial effects of spinal morphine on the postoperative course of elderly patients undergoing surgical fixation of the femoral neck fracture]. AB - BACKGROUND: We performed a retrospective study of the efficacy and safety of spinal anesthesia with 0.1 mg morphine in the postoperative course of elderly patients with femoral neck fracture. METHODS: Sixty patients with ages averaging 84 years participated in this study. Surgery was performed under spinal anesthesia. Patients were assigned to either a group receiving of 0.1 mg morphine added to isobaric bupivacaine (Group M) or a group receiving of isobaric bupivacaine alone (Group B). The frequency of analgesic use and the occurrence of adverse side effects during the first 48 hours after surgery were compared between the two groups. RESULTS: In the first 24 hours, the patients in Group M needed significantly less analgesics compared to Group B. The incidence of adverse side effects did not differ significantly between the groups, although nausea had a tendency to increase in Group M. One patient in Group M showed a mild decrease in oxygen saturation. CONCLUSIONS: The spinal administration of 0.1 mg morphine had beneficial effects and was safe in the postoperative period of elderly patients with femoral neck fracture provided that sufficient observation was given. PMID- 23814988 TI - [Application of air-Q laryngeal airway and gum elastic bougie in a case of anticipated difficult. Mask ventilation and tracheal intubation in a man with morbid obesity]. AB - A 46-year-old man was diagnosed with descending colon cancer and was planned to undergo left hemicolectomy under general anesthesia. His body mass index was 42.6 and due to his small mouth and jaw, we anticipated difficult mask ventilation and tracheal intubation. To avoid 'can't ventilate, can't intubate', we first inserted a size 3.5 air-Q laryngeal airway under moderate sedation, maintaining spontaneous ventilation. After confirming sufficient assisted ventilation, we used a bronchofiberscope to visualize placement of a gum elastic bougie in the trachea via the air-Q. Then, we replaced the air-Q with an outside diameter 8.5 mm tracheal tube. This case was a successful use of the air-Q under moderate sedation for airway management in the setting of anticipated difficult mask ventilation and tracheal intubation. PMID- 23814989 TI - [Kinking of the endotracheal tube in a prone patient associated with the inadequate withdrawal maneuver of the Pentax-AWS Airway Scope]. AB - We report a case of intraoperative kinking of an endotracheal tube (ETT) in a prone patient during spine surgery. We postulate that one of the risk factors involved with kinking was the inadequate withdrawal maneuver of Pentax-AWS Airway Scope (AWS). Patient was a 69-year-old woman with hypertension, diabetes mellitus, and rheumatoid arthritis, undergoing C4-6 laminoplasty under general anesthesia in the prone position. A 7.0-mm polyvinyl endotracheal tube (Paker Flex-Tip Tube) was placed to 21 cm at the right angle of the mouse without difficulty using the AWS. Both peak inspiratory pressure (PIP) and partial pressure of end-tidal carbon dioxide began to rise gradually from 24 to 28 cmH2O and 38 to 44 mmHg, respectively. Although over 30 cmH2O in PIP repeatedly appeared after that, we did not find any remarkable change of ventilation except for weak breath sound. Thereafter, when we checked the tube with a flexible fiberoptic bronchoscope, it could not pass through the tube. At first, we asked the surgeon to release neck flexion as much as possible. This procedure could not correct the kink completely but allowed the passage of bronchoscope in the ETT. Then, we tried to reposition the ETT by inserting the bronchoscope beyond the point of kinking for maintaining luminal patency and adequate ventilation. The subsequent anesthetic course was uneventful. Kinking of the ETT in the oral cavity is an uncommon problem but we must keep in mind as one of the differential diagnoses. When using the AWS for endotracheal intubation, we recommend the confirmation of the position of the ETT to be normal in the oral cavity by direct laryngoscopy. PMID- 23814990 TI - [Accidental left bronchial intubation with Parker Flex-Tip Tube]. AB - In most cases, an endotracheal tube (ETT) enters the right bronchus due to anatomical features of the trachea. The Parker Flex-Tip Tube (Parker tube) has a centered and tapered tip with a posterior facing bevel. Here, we report a case of accidental left bronchial intubation that may be associated with the tip design of the Parker tube. A 43-year-old woman was scheduled for resection of an ovarian tumor. After induction of general anesthesia, the trachea was intubated using a 6.5-mm Parker tube, which was taped at the 21-cm lip line. Subsequent chest auscultation revealed a decrease in right breath sounds, and fibrotic bronchoscopy confirmed the accidental left bronchial intubation. A preoperative chest radiograph indicates no tracheal distortion. Thus, we speculated that the unusual left bronchial intubation occurred because of the ETT tip design. To test this hypothesis, we conducted a simulation study using a standard airway mannequin. Intubation with a standard left-beveled ETT resulted in right bronchial intubation in all 20 trials, while 4 of the 20 Parker tubes entered the left mainstem bronchus. This investigation suggests that unintentional left bronchus intubation of the Parker tube may occur in the ordinary clinical setting if the tube is advanced beyond the carina. PMID- 23814991 TI - [Cervical spine motion during laryngoscopy with the Pentax-AWS with a new thinner blade (Introck-T)]. AB - BACKGROUND: The Pentax-AWS equipped with a new thinner blade (Introck-T) is an intubation device that provides a non-line-of sight view of the glottis. A non line-of sight view is expected to cause less movement of the cervical spine during laryngeal visualization. We measured the degree of cervical spine movement during laryngoscopy with the device. METHODS: Twenty patients requiring general anesthesia were studied. Each patient underwent laryngoscopy using the Pentax-AWS with the Introck-T. Movements of cervical spine were measured by radiography in the same patient both at neutral head position and during laryngoscopy. RESULTS: The anterior movement of the vertebral bodies from baseline was 16.7 +/- 5.2 mm, 16.5 +/- 4.4 mm, 16.5 +/- 4.7mm and 15.5 +/- 4.7mm at the atlas (C1), C2, C3, and C4 vertebrae, respectively, during laryngoscopy. The change in angle during laryngeal visualization was 8.3 +/- 4.0 degrees, 7.6 +/- 3.7 degrees, 1.7 +/- 2.4 degrees, and 1.6 +/- 3.3 degrees, at Occiput/C1, C1/C2, C2/C3, and C3/C4 motion segments, respectively. The total change in angle between the occiput and C4 was 19.1 +/- 5.1 degrees (95% CI 16.6 degrees - 21.5 degrees). CONCLUSIONS: Laryngeal visualization using the Pentax-AWS with the new thinner Introck-T produces the anterior movement and extension of the cervical spine. PMID- 23814992 TI - [A child with Klippel-Feil syndrome in whom GlideScope was effective for tracheal intubation]. AB - GlideScope videolaryngoscope (GlideScope, herein-after referred to as "GS", Verathon Medical, Bothell, WA, USA), with a high-resolution camera positioned on a blade, enables operators to confirm the position of the larynx and a tube through clear view, thereby conducting intubation safely in a patient whose neck is difficult to be bent back. As the blade is slim, GS is indicated for use in children whose oral cavity is narrow. We herein report safe and smooth intubation with GS in a child with Klippel-Feil syndrome in whom difficult intubation was predicted. PMID- 23814993 TI - [A case of emergency cesarean section complicated with spontaneous spinal epidural hematoma]. AB - Spontaneous spinal epidural hematoma (SSEH) is an especially rare medical condition in pregnancy. We report a case of SSEH in pregnancy. A 29-year-old woman at 39 weeks of pregnancy was transported to our hospital with sudden back pain, incomplete paresis of the right lower extremity and paresthesia of the left lower extremity. Magnetic resonance imaging showed an epidural hematoma at T5-6 vertebral level. Emergency cesarean section and posterior decompression of the thoracic spinal cord were performed under general anesthesia. Vascular malformation and tumor of the spinal cord were not found, and we diagnosed this case as SSEH. The patient and her baby were discharged on the postoperative day 14 without any complications. PMID- 23814994 TI - [The importance of preanesthetic evaluation: malignant tumors discovered on preoperative chest radiography, in patients scheduled for operation of benign tumors]. AB - Preanesthetic evaluation is essential for the perioperative period. We report 2 preoperative patients with benign disease, whose preoperative chest radiography revealed intrathoracic malignant tumors. Case 1: A woman in her eighties with vascular necrosis of the femoral head was scheduled for bipolar hip arthroplasty under general anesthesia. On preanesthetic evaluation, widened mediastinum was detected on preoperative chest radiography. Instead of the scheduled operation, she underwent thoracoscopic surgery under general and epidural anesthesia. She was diagnosed with malignant thymoma. Case 2: A woman in her thirties with bilateral oviduct obstruction was scheduled for laparoscopic surgery. On preanesthetic evaluation, right middle lung lesion was detected. She underwent thoracoscopic biopsy under general and epidural anesthesia, and was diagnosed with malignant lymphoma. The result of preanesthetic chest radiography is reported to change the perioperative treatment only in 0.1%; our cases indicate the importance of preanesthetic evaluation of chest radiography in detecting possible underlying disease in the preoperative patient. PMID- 23814995 TI - [Anesthetic management of total hysterectomy in a patient with pulmonary thromboembolism]. AB - We report anesthetic management of a 38-year-old woman with pulmonary thromboembolism for total hysterectomy. She had been taking oral contraceptives for adenomyosis of the uterus. She had thrombi in the arteries from pulmonary trunk to bilateral main pulmonary arteries. Thrombolytic and anticoagulant therapies did not decrease the thrombi. Removal of the swollen uterus suspected to be the origin of the thrombi, rather than thromboembolectomy, was scheduled. Cannulation for percutaneous cardiopulmonary support was set up just in case of hemodynamic derangement, before the surgery. Cardiac contraction was evaluated with transesophageal echocardiography during the surgery. There was no untoward perioperative event. Pulmonary thromboembolectomy was not done because the postoperative CT revealed shrinkage of the pulmonary thrombi after anticoagulation treatment. PMID- 23814996 TI - [Anesthetic management of organ donation after brain death using continuous total hemoglobin measurement]. AB - A 60-year-old woman declared brain dead was scheduled for organ donation. We continuously measured total hemoglobin values (SpHb) using a Radical-7 monitor (Masimo Co, Irvine, CA, USA) to maintain the functions of organs and oxygen delivery. At the start of surgery, the SpHb value was 9.3 g x dl(-1). Packed red blood cells were transfused immediately No anesthetics or opioids were used during the operation. Blood pressure suddenly decreased to below 80 mmHg because of bleeding, manipulation of organs, and/or compression of the vena cava. Six units of red blood cells and 900 ml of colloids were rapidly transfused with real time monitoring of SpHb values. On cross-clamping of the aorta, the SpHb value increased up to 10.2 g x dl(-1). The heart, lungs, liver, pancreas, and kidneys were donated from the patient without organ dysfunction. The highlight of this case report is that anesthesiologists could use SpHb monitoring for management of hemodynamics in a brain-dead organ donor. PMID- 23814997 TI - [General anesthetic management of a patient with spinal muscular atrophy type III]. AB - We report a 61-year-old woman (weight 49 kg, height 156 cm) with Kugelberg Welander disease who was scheduled for bilateral mastectomy under general anesthesia. We administered rocuronium 10 mg (0.20 mg x kg(-1)) for tracheal intubation. After 80 min, train-of-four ratio (TOFR) was 46%. During the operation, we did not administer rocuronium. After surgery, TOFR was 62%. Therefore, we administered sugammadex 100 mg (2 mg x kg(-1)). After 4 min, TOFR became above 90%, and the patient was extubated. There was no respiratory distress, muscle weakness, or neurologic untoward event after the use of sugammadex in the postoperative period. Sugammadex was effective in reversing rocuronium induced neuromuscular block in a patient with Kugelberg-Welander disease. PMID- 23814998 TI - [Cardiac asystole in the postanesthetic care unit: a case report]. AB - We report a patient without apparent heart disease who developed asystole postoperatively. A 24-year-old woman was scheduled for acetabulectomy under lumbar epidural anesthesia with intravenous propofol infusion. There was no profound hypotension or arrhythmia during anesthesia and surgery. She complained of nausea 50 minutes after the operation. The ECG showed an abrupt decrease in the heart rate followed by cardiac asystole 30 seconds after the onset of nausea. Prompt cardiac massage resumed the heart beats in eight seconds. There was no neurological deficit. PMID- 23814999 TI - [A case of previously undiagnosed methemoglobinemia exhibiting sustained low SpO2 value at the induction of general anesthesia]. AB - A 70-year-old woman was scheduled to undergo surgery for removal of thyroid tumor under general anesthesia. A routine preoperative evaluation confirmed that the patient was stable with no signs of cyanosis and dyspnea. However, during pre oxygenation as well as mechanical ventilation with 100% oxygen, she showed sustained low SpO2 values (i.e., 91%). Arterial blood gas analysis at FIO2 of 1.0 showed an oxygen partial pressure (PaO2) of 297 mmHg. Unexpectedly, the analysis revealed methemoglobinemia (MetHb concentration: 15%) causing a discrepancy between the low SpO2 and normal PaO2 values in this patient. Methemoglobinemia is an uncommon cause of cyanosis; however, anesthesiologists should be aware that some drugs used during perioperative period (e.g., local anesthetics) can cause methemoglobinemia. While our case was a mild one and the patient recovered with no complications, methemoglobinemia levels above 30% could cause tissue hypoxemia and, thereby, requiring a treatment with methylene blue or ascorbic acid. PMID- 23815000 TI - [Perioperative anticoagulant therapy in a patient with congenital antithrombin III deficiency undergoing posterior spinal fusion]. AB - A 22-year-old female was scheduled to undergo posterior thoracolumbar spinal fusion. She had been diagnosed with congenital antithrombin III (AT-III) deficiency by the onset of pulmonary embolism and deep vein thrombosis after the first operation at the age of 18. Thereafter she had taken warfarin, 5 mg daily, until 4 days before the surgery. Preoperatively, we administered AT-III products to regulate AT-III activity. The posterior spinal fusion was performed successfully without surgical complications. Postoperatively, we continued administration of AT-III products to maintain AT-III activity above 75%. We also used low dose unfractionated heparin with AT-III by continuous intravenous infusion. Heparin was administered with dose adjustment to achieve a target activated partial thromboplastin time of 45 to 60 seconds. After the activated partial thromboplastin time was stabilized in the target range, we started warfarin therapy (target international normalized ratio, 1.5 to 2.5) on postoperative day 16 and stopped administration of heparin on postoperative day 19. There was no thrombosis complications during the perioperative period. Good anticoagulant management was achieved in a patient with congenital AT-III deficiency undergoing posterior spinal fusion. PMID- 23815001 TI - [A case report of ultrasound guided peripheral nerve block for lower extremity amputation of a patient with anti-phospholipid syndrome]. AB - A 60-year-old female with anti-phospholipid syndrome underwent amputation of her left lower limb. She had had a history of cerebral infarction, cerebral hemorrhage, coagulation abnormalities, thrombocytopenia, and pneumothorax, and just recovered from disseminated intravascular coagulation. After intravenous fentanyl 25 microg, ultrasound-guided sciatic, femoral and lateral femoral cutaneous nerve blocks were performed. We used 0.75% ropivacaine 15 ml and 1% lidocaine 15 ml for sciatic nerve block, 0.75% ropivacaine 5 ml and 1% lidocaine 5 ml for femoral nerve block and 0.75% ropivacaine 5 ml for femoral cutaneous nerve block. For femoral nerve block, a catheter was inserted and ropivacaine was infused at 4 ml x hr(-1) after surgery. Amputation at the left thigh was successfully performed and postoperative course was uneventful. The sciatic, femoral and lateral femoral cutaneous nerve blocks were useful for amputation of a patient with severe coagulopathy by anti-phospholipid syndrome. PMID- 23815002 TI - [Anesthetic management of a patient with severe aortic stenosis undergoing spine surgery]. AB - An 87-year-old man with severe aortic stenosis (AS), refusing aortic valve surgery, was scheduled to undergo posterior spinal fusion. According to American College of Cardiology/American Heart Association (ACC/AHA) 2008 Guideline, aortic valve surgery is recommended before non-cardiac surgery in a patient with severe AS. Several reports have noted that non-cardiac surgery could be performed safely with careful anesthetic management by adjusting left ventricular preload and systemic arterial pressure, and avoiding tachycardia. We used pulmonary artery catheter to estimate left ventricular preload, which is an especially essential factor for maintaining cardiac output. Transesophageal echocardiography has been proved to be superior to pulmonary artery catheter for evaluating left ventricular preload. However, it is difficult to perform in the prone position. Although pulmonary artery wedge pressure (PAWP) is influenced in prone position due to the chest compression, PAWP combined with cardiac index and their responsiveness to fluid administration is valuable in hemodynamic management in a patient with severe AS. PMID- 23815003 TI - [A case of late drug-eluting stent thrombosis during postoperative period after 5 years of stent implantation]. AB - Stent thrombosis during perioperative period is a critical complication for patients treated with drug-eluting stent (DES). We experienced a case of late DES thrombosis 5 years after initial implantation. A 48-year-old man with familial hyperlipidemia, angina pectoris and chronic pulmonary emphysema, was diagnosed with esophageal carcinoma, and scheduled for esophagectomy. He was first treated with DES 5 years ago, and he underwent repeated revascularization for re stenosis. He had received anti-platelet therapy up to 1 week prior to the current operation, which was replaced by heparin administration. The surgical procedure was uneventful, and he tolerated it well. Immediately after his admission to ICU, sporadic premature ventricular contraction and ST-elevation occurred, leading to ventricular fibrillation. Emergent coronary angiography revealed re-stenosis of the right coronary artery treated with DES 5 years ago. At present, there was no definite guideline, on the management of DES during perioperative period. It is important for us to decide continuing antiplatelet therapy balancing the risk of stent thrombosis with surgical bleeding in each patient. PMID- 23815004 TI - [A case report of a failure to advance a guidewire in an infant from the internal jugular vein to the brachiocephalic vein]. AB - A 2-month-old baby boy, 52 cm in height and weighing 4.6 kg, underwent a Blalock Taussig shunt operation under general anesthesia. The authors checked the internal jugular vein (IJV) using an ultrasound apparatus with a 5/10-MHz probe (TiTAN, SonoSite Co., Tokyo, Japan) at a mid-portion of the neck. We observed a 3.9-mm-wide and 7.6-mm-deep IJV for central venous catheter (CVC) placement. We started to videotape the procedure. The operator punctured the IJV using real time ultrasound guidance with a 24 G plastic puncture needle (Jelco Plus, Smith Medical, Tokyo, Japan), and obtained the back flow of the vein. The operator could not advance a guidewire more than 5 cm into the IJV. We suspected that the straight type guidewire had advanced outside of the IJV, and removed the guidewire. We placed the CVC into the left IJV instead of the right IJV. We speculated that the guidewire had advanced into the IJV; however, we could not advance the tip of the guidewire from the IJV to the brachiocephalic vein because the angle between the IJV and the brachiocephalic vein was 90 degrees. We could have advanced a J-type guidewire from the IJV into the brachiocephalic vein. PMID- 23815005 TI - [A case of transient postoperative median nerve palsy due to the use of the wrist holder to stabilize an intra-arterial catheter]. AB - We experienced a case of right median nerve palsy at the distal forearm following abdominal surgery. We postulate that the cause of the median nerve palsy is overextension of the wrist by the inappropriate fixation with a holder. The patient was a 46-year-old man with habit of smoking receiving low-anterior resection of the rectum under general and epidural anesthesia in lithotomy position. During surgery his upper limbs were placed on padded arm board abducted about 80 degrees and affixed with soft cotton. His forearms were slightly supinated, whereas his elbows were not over-extended. A 22 G cannula was inserted in the right radial artery and the right wrist was fixed with plastic-holder with soft pad. This position was maintained throughout the operation approximetly for 250 minutes. During anesthesia any special events regarding hemodynamic variables were not observed. He complained of numbness in the palmar side of the digits 1-3 on his right hand without motor disturbance 4 hours after the operation. Examination by the anesthesiologist revealed median nerve palsy. Fortunately, this symptom gradually but completely resolved over the next few days. The possible causes of this neuropathy include the overextension of the wrist or the unexpected extension of the elbow beyond the acceptable range by the supination of forearm, which was induced by the attachment used to stabilize an intra arterial catheter. Therefore, in the current case we should have returned the wrists promptly to the neutral position following arterial catheter placement to prevent the median nerve palsy. This case suggests the importance of holding the proper position of the arm during surgery. PMID- 23815006 TI - [Efficacy of Pentax-AWS in difficult airways: a meta-analysis of randomized controlled trials]. AB - BACKGROUND: Increased evidence indicates that the Pentax-AWS (AWS) is useful for difficult airways. The aim of this meta-analysis was to assess the efficacy of the AWS in difficult airways, comparing that of Macintosh laryngoscopy. METHODS: The systematic search, data extraction, critical appraisal, and pooled analysis were performed according to the PRISMA statement. The relative risk (RR), mean difference (MD), and their corresponding 95% confidence intervals (CIs) were calculated by the Comprehensive Meta-analysis version 2.2.040 software for dichotomous and continuous outcomes, respectively. RESULTS: Eighteen randomized controlled trials, performed in simulated difficult airways (published between 2006, October and 2012, May), included 981 tracheal intubations by AWS and 986 tracheal intubations by Macintosh laryngoscopy. AWS showed higher success rate (RR: 1.220, 95% CI: 1.126 to 1.322, P < 0.00001) and shorter duration for instrumentation (MD: -10.319 s, 95% CI: -14.309 s to -6.328 s, P < 0.00001). CONCLUSIONS: There is considerable evidence that AWS has an advantage over Macintosh laryngoscope in difficult airways. PMID- 23815007 TI - [Setting appropriate antibiotic prophylaxis before skin incision]. AB - BACKGROUND: Care should be taken to ensure that antibiotic administration is completed before skin incision during surgery. Therefore, we investigated whether prophylactic antibiotics were being appropriately administered before skin incision in the operating rooms at our institute and whether our discussions with anesthesiologists regarding this issue were effective. METHODS: During anesthesia departmental meetings in April 2009, we requested anesthesiologists to ensure appropriate antibiotic administration before incision. Subsequently, we analyzed operating records for February 2009 (n = 142) and May 2009 (n = 132) regarding the time points at which (1) intubation was performed, (2) prophylactic antibiotic administration was initiated and stopped, and (3) operations were initiated. RESULTS: In approximately 97% of cases, antibiotic administration was initiated before incision. The proportion of cases wherein antibiotic administration was initiated and completed before incision insignificantly increased from 63% to 70% after the discussions with the anesthesiologists. The ratio of cases where antibiotic administration was completed within 30 minutes significantly increased from 79 : 142 to 90 : 132 after the discussions (P = 0.033). This result indicates the importance of administering antibiotics within 30 minutes before incision. CONCLUSIONS: Our discussions for ensuring appropriate antibiotic administration in operating rooms seemed to provide better results for patients. PMID- 23815008 TI - [Use of the gum elastic bougie]. AB - Gum Elastic Bougie (GEB) was originally introduced into clinical practice in 1949 by Sir Robert Macintosh. British anesthesiologists choose this tracheal tube introducer than the malleable stylet to facilitate difficult intubation. However, the bougie may not always be used in an optimal manner in Japan. Especially, it is useful when faced with an unexpected difficult intubation, for example, a Cormack-Lehane grade III view at laryngoscopy. GEB is superior to the stylet for a difficult intubation. It is easy to use, portable, and of relatively low cost. We believe that the GEB is useful in patients with and without difficult airways. PMID- 23815009 TI - [The KINGVISION: clinical assessment of performance in 50 patients]. AB - BACKGROUND: The aim of this study was to evaluate the suitability of the KINGVISION videolaryngoscope for tracheal intubation. METHODS: Endotracheal intubation was performed using the KINGVISION in 50 patients undergoing general anesthesia. We compared the percentage of glottic opening score between Coopdech Videolaryngoscope Portable VLP100 and the KINGVISION with staff anesthesiologist and novice personnel. The time to complete instrumentation and optimizing procedures were also recorded. RESULTS: The KINGVISION allowed visualization of the glottis and successful intubation in all patients, including 11 patients with difficult airway. There were no differences in the time to intubation between staff anesthesiologist and novice personnel. Furthermore, percentage of glottic opening score was higher with KINGVISION than with Coopdech Videolaryngoscope Portable VLP100 among staff anesthesiologist and novice personnel. CONCLUSIONS: The KINGVISION could be an effective aid to airway management in surgical patients. PMID- 23815010 TI - [American contributions to Japanese anesthesiology--a historical view]. AB - The origin of anesthesiology in Japan can be traced back to 1804, when Seishu Hanaoka administered anesthesia. However, the present day anesthesiology in Japan was shaped by two programs in the 1950s supported by the United States (US) Government. The first US program to influence anesthesiology in Japan was the Unitarian Service Committee (USC) Medical Mission. The USC sent three anesthesiologists; Dr. Meyer Saklad in 1950, Dr. Perry Perry Volpitto in 1951 and Dr. Joseph Artusio in 1956. The impact of the program on Japanese anesthesiology has been long-lasting. The second program was called Government Account for Relief in Occupied Area (GARIOA). Under this program, two Japanese physicians finished anesthesiology training in the US. Examining the history of our profession helps us understand the dedication and commitment of our pioneers, and prepares us to take on existing challenges to further the vision and goals set by our pioneers. The past provides us with a framework and understanding for how we pursue future opportunities and aspirations. PMID- 23815011 TI - [Prophylactic surgery in common hereditary cancer syndromes]. AB - Preventive surgery is a mainstay of treatment for persons with genetic risk factors for cancer The indications of preventive surgery are based on a thorough risk assessment, clinical characteristics of the different hereditary cancer susceptibility syndromes, the types of mutation, and the possibility of watchful waiting for early cancer detection. Preventive surgery may either be recommended or represent one possible option. Bilateral prophylactic mastectomy can reduce the risk of breast cancer by up to 95% in BRCA1/BRCA2 mutation carriers. Bilateral prophylactic salpingo-oophorectomy is recommended for BRCA1/ BRCA2 carriers: women who undergo this preventive surgery have a reduced risk of ovarian cancer but also of breast cancer (around 50% for breast cancer). Patients with Lynch syndrome are at high risk of endometrial cancer, and prophylactic hysterectomy may be proposed to women for whom surgery is indicated for a uterine disorder (fibroma). Prophylactic surgery may be proposed to patients at risk of hereditary gastrointestinal malignancies, either on a case-by-case basis (Lynch syndrome) or more systematically for patients with the familial adenomatous polyposis syndrome or hereditary difuse gastric cancer Despite its efficacy, prophylactic surgery in a healthy individual, albeit at high risk of cancer, remains a difficult, multidisciplinary decision. Psychological support is needed to anticipate the possible physical psychological and social complications--and benefits. PMID- 23815012 TI - [Prophylactic thyroidectomy in medullary thyroid cancer]. AB - Medullary thyroid cancer (MTC) is genetically determined in 30% to 35% of cases, notably through multiple mutations in the RET protooncogene located on chromosome 10, for which a genotype-phenotype relationship determines age of onset. There are three phenotypes: MEN 2 A and B, and isolated familial MTC. The type of mutation determines 3 levels of aggressiveness. Current guidelines recommend thyroidectomy during the first months of life for patients with very-high-risk (level 3) mutations and before 5 years of age for high-risk (level 2) mutations. There are no precise recommendations for lower-risk mutations, for which the surgical decision also depends on the calcitonin level and family history. We describe 18 patients who underwent prophylactic surgery. Regardless of the mutation, all patients with a normal preoperative calcitonin level were cured. However, surgery was performed later than recommended, for various reasons, including late genetic diagnosis and parents' opposition. PMID- 23815013 TI - [Pathophysiological advances underlying the biotherapeutic revolution in inflammatory rheumatism]. AB - Major advances have been made in the pathogenesis of rheumatoid arthritis, spondyloarthritis and connective tissue diseases, leading to new biotherapies. In rheumatoid arthritis, the discovery of anti-citrulline antibodies (ACPA, anti citrullinatedpeptide antibodies), whose specificity is between 95% and 98% and may be present before symptom onset, allowed early diagnosis and provided new pathological insights. Studies of the role of cytokines, B cells and co stimulation of T cells revealed novel therapeutic targets. TNF inhibitors are effective in spondyloarthritis. In lupusandSjigren'ssyndrome, genes stimulatedby IFNtypel are hyper-expressed, along with BAFF (or BLyS), a B lymphocyte activating cytokine. PMID- 23815014 TI - [Indications and efficacy of biologics in inflammatory arthritis]. AB - Major advances in our knowledge of the pathogenesis of inflammatory arthritis during the last 20 years, including the identification of precise targets of joint inflammation, led to the development of biologic targeted therapies. TNF inhibitors were the first such agents to be approved in rheumatoid arthritis, followed by ankylosing spondylitis and psoriatic arthritis. Later, rituximab, an anti-CD20 B lymphocyte antibody ; abatacept, which inhibits the T cell co stimulatory CD28-CD80 pathway ; and tocilizumab, an interleukin-6 receptor inhibitor, were launched in rheumatoid arthritis. These biologics have dramatically changed the management and mid- to long-term outcomes of patients with rheumatoid arthritis and spondyloarthritis. Current therapeutic strategies are based on disease activity and severity. International societies such as EULAR and ASAS have published precise recommendations for routine management of these patients. PMID- 23815015 TI - [Medical and economic aspects of rheumatoid arthritis]. AB - Rheumatoid arthritis (RA) is a chronic disabling disease that induces substantial costs in terms of healthcare resources (direct costs) and lost productivity (indirect costs). The main cost drivers used to be disability and hospitalization. Recently, however, the cost of new and expensive therapies has exceeded that of hospitalization. These effective treatments have lowered RA related use of healthcare resources, especially totaljoint replacement, as well as sick leave. In contrast, they have not yet been shown to reduce the number of patients who become disabled, and their cost-effectiveness ratio thus tends to be unfavorable. PMID- 23815016 TI - [Amyloid polyneuropathies--biochemical and genetic aspects]. AB - Familial amyloid polyneuropathies (FAP) are among the most frequent hereditary amyloidoses. These are serious, most often fatal diseases with autosomal dominant inheritance. FAP can be caused by mutations in four genes, namely those encoding transthyretin, Al-apoliprotein, gelsolin, and beta-2 microglobulin. Transthyretin is a tetramer composed of four identical subunits linked by non covalent bonds and bearing binding sites for thyroxine (T4) and retinol-binding protein (RBP). More than 120 transthyretin gene sequence variations have been characterized, of which only 80% seem to be pathogenic. Gene mutations can induce tetramer destabilization, thereby generating misfolded monomers that aggregate into insoluble amyloidfibrils. The mutation spectrum is highly variable across countries. For example, while the Val30Met mutation is found in 95% of the Portuguese and Swedish patient populations, high mutational heterogeneity is observed in France. Age of onset and clinical signs are influenced by numerous factors, especially the mutation type and the country, but the mechanisms underlying this variability are not fully clear. The three-dimensional structure of the normal transthyretin protein and a dozen mutants is now known, providing insights into the deleterious effects of mutations. A better understanding of the mechanisms involved in amyloid fibril formation has led to the development of drugs that inhibit transthyretin tetramer destabilization. It is hoped that, within afew years, such drugs will replace liver transplantation, which is currently the only curative treatment. PMID- 23815017 TI - [Familial amyloidotic polyneuropathies]. AB - Transthyretin familial amyloid polyneuropathy (TTRFAP) is an autosomal dominant neuropathy that is fatal within about 10 years after symptom onset. TTRFAP is observed worldwide, albeit with a higher frequency of the most common variant, Val30met, in Portugal, Sweden and Japan. Various phenotypic differences are observed. TTRFAP should be considered in patients with a progressive axonal polyneuropathy of unknown origin, especially when associated with autonomic nervous system dysfunction. A positive family history is found in most cases when onset begins around 30 years of age, while late-onset FAP is often sporadic and may be confused with chronic inflammatory demyelinating polyneuropathy. Nerve biopsy is often used to confirm the presence of extracellular amyloid deposits in interstitial tissue of the endoneurial space, although amyloid can also befound in muscle, salivary gland and abdominal fat. It is important to stress that biopsy negativity does not rule out amyloidosis. Genetic testing for TTR gene mutations should be performed in case of progressive length-dependent axonal polyneuropathy predominantly involving small nerve fibers. PMID- 23815018 TI - [Familial amyloid polyneuropathies: therapeutic issues]. AB - Patients with familial amyloidpolyneuropathies (FAP) require multidisciplinary neurologic and cardiologic management, including specific treatments to control the progression of systemic amyloidogenesis, symptomatic treatment of peripheral and autonomic neuropathies, and management of severe organ involvement (heart, eyes, kidneys). The first-line specific treatment of choice for met30 TTR-FAP is liver transplantation (LT) which suppresses the main source of mutant TTR, halts the progression of neuropathy in 70% of cases, and doubles the median survival time. Dual kidney-liver or heart-liver transplantation may be appropriate for patients with severe renal or cardiac failure. Tafamidis (Vyndaqel(R), Pfizer), a novel stabilizer of tetrameric TTR, has shown short-term effectiveness in slowing the progression of peripheral neuropathy in very early stages of met30 TTR-FAP This drug should thus be proposed for stage 1 symptomatic polyneuropathy. Other innovative medicines (RNA interference, antisense oligonucleotides) have been developed to block hepatic production of both mutant and wildtype TTR (noxious in late-onset forms of NAH after age 50 years), and to remove amyloid deposits (monoclonal anti-SAP). Clinical trials should first include patients with late onset FAP or non-met30 TTR-FAP who are less responsive to LT7 and patients in whom Vyndaqel(R) is ineffective or inappropriate. Initial and periodic cardiac assessment is necessary, as cardiac impairment is inevitable and largely responsible for mortality. Symptomatic treatment is crucial to improve these patients' quality of life. Familial screening for carriers of the TTR gene mutation and regular clinical examination are essential to detect disease onset and to start specific therapy in a timely manner. PMID- 23815019 TI - [Borderline personality disorders: diagnosis and treatment]. AB - Borderline personality disorders are complex clinical states with highly polymorphic symptoms and signs, leading to delays in their diagnosis and treatment. All international classifications emphasize certain clinical criteria such as unstable identity and interpersonal relationships, feelings of emptiness or boredom, and pathological impulsiveness. The prevalence is about 2%, with a female-male sex ratio of 2 or 3 to 1. Both adolescents and adults may be affected There is a high risk of suicide, addictive behaviors, eating disorders, and criminality. These individuals frequently have a history of trauma in early childhood, such as separation, loss, physical or sexual abuse, or affective privation. Subjective signs and symptoms are particularly important in the diagnostic and therapeutic evaluation, and this requires an empathic and subtle approach. Standardized and semi-structured interviews may help to identify comorbidities such as thymic disorders, anxiety, addiction, eating disorders, and, in some cases, psychotic symptoms. The psychiatric bio-psycho-social model takes into account multiple pathogenic factors, such as trauma during early development, temperamental instability and other emotional disorders, as well as psychosocial, neurobiological (5HT etc.) and genetic vulnerabilities. Treatment requires optimal integration of psychotherapeutic and pharmacotherapeutic approaches. Emergency intervention must be available in case of delirious or suicidal behavior The clinical course is often lengthy and complex, but outcome may be favorable, provided the principal risk--suicide--is correctly managed, PMID- 23815020 TI - [Medical progress exemplified by improvements in the safety coronary angioplasty]. AB - The significant decrease in complications associated with coronary angioplasty is a model of medical progress. Breakthroughs are achieved through individual initiatives, whereas incremental progress results from occasional, anonymous improvements. The two types of improvement are complementary, as pointed out by Claude Bernard as early as 1864. PMID- 23815021 TI - [Future drug targets for Parkinson's disease]. AB - Parkinson's disease is characterized by a triad of cardinal motor symptoms (bradykinesia, rigidity and tremor) resulting from the loss of dopaminergic neurons in the substantia nigra. This synucleinopathy is classified in the larger group of Lewy body disorders. Currently, these symptoms are relatively well alleviated by drugs that restore dopaminergic neurotransmission, andlor by deep brain stimulation. It is not yet possible to halt the underlying degeneration, or to treat symptoms due to non-dopaminergic neuron damage. This review examines the mechanisms of neuronal degeneration in Parkinson's disease, new targets for neuroprotection, and the mechanisms causing symptoms resistant to current treatments. PMID- 23815022 TI - [Elevated coronary mortality in Mauritius: risk factors and genetic analyses]. AB - In 1986, early mortality by acute myocardial infarction was found to be much higher in Mauritius than in the United States, among both males and females. For example, among 40-to-44 year olds there were 109 deaths/100,000 males per year in Mauritius, compared to only 34.5/100,000 in the U S. A study comparing two non hospital populations of Mauritian and U S. residents showed a higher prevalence of diabetes and glucose intolerance in Mauritius. Likewise, a case-control study comparing 60 young patients who had MI before age 45 years and age-matched Mauritian residents showed statistically significant differences in terms of abnormal glucose metabolism (P<0.001), LDL cholesterol (P<0.02), total cholesterol (P<0.04), HDL cholesterol (p<10-9), and triglycerides (P<0.01) in the patients with early MI. A genome-wide scan of Mauritian patients of North Indian origin (Francke et al) who had MI before age 52 years and patients with coronary heart disease occurring before age 60 years showed a significant relation between coronary heart disease and loci in chromosome regions 16p-13 (LOD 3.06), 10q23 (LOD 2,03; also linked to HDL cholesterol and the LDL/HDL ratio), and 3q27 (LOD 2.37). Genomic studies of Indo-Mauritian patients confirm the important role of the metabolic syndrome in the high prevalence of coronary heart disease in Mauritius, and show the polygenic nature of the disease. PMID- 23815023 TI - [Recommendations for the management of patients with severe arterial hypertension. Commission IV. Cardiovascular Diseases]. PMID- 23815024 TI - [Physical activities and sport; implications for health and society]. AB - The practice of physical and sporting activities (PSA) throughout life is now known to increase healthy life expectancy, to delay the onset of dependency, and to be an effective complementary treatment for many disorders, particularly obesity and disability. The notion of a "sedentary death syndrome " [SeDS] has been evoked on the other side of the Atlantic. Although the beneficial effects of PSA have long been known, statistical analyses have only recently confirmed at the group level what was often disputed at the individual level. Knowledge of the impacts of PSA on cellular, tissular and metabolic functions has improved considerably. PSA is no longer seen simply as a leisure activity but is now considered necessary for a healthy body and mind. PSA also has considerable social, educational and integrative implications. Can any society ignore these evident health benefits with impunity? The aims of this article are 1) to provide a quick overview of the advantages of regular, measured and reasonable PSA, as well as the potential risks of excess; 2) to discuss the quantity of PSA providing the optimal balance between benefits and risks, and the means of achieving this balance; 3) to highlight the lack of enthusiasm for PSA among the French population, and to analyze its causes, and 4) to propose a new organization designed to help more of our fellow citizens to adopt PSA, in the interests of their health and well-being. PMID- 23815025 TI - [Healthcare expenditure]. AB - Healthcare expenditure is divided between medical infrastructure and individual patient management. Total healthcare costs in France amount to roughly 175 billion euros, financed through public health insurance (77%), private insurance (14%), and individual expenditure (9%). The principal expenditures are for hospitalization (44%), community medical, dental and paramedical care (28%), drugs (20%) and miscellaneous resources (8%). The main factors of rising costs are medical progress and aging. More controllable costs include healthcare provision, the level of reimbursement, public education and information, and physician training. France devotes 9.2% of its gross national product to healthcare, compared to 7-8% in Sweden, Germany and the United Kingdom, representing a diference of about 18 billion euros. In France there is a chronic imbalance between resources and expenditure, creating a cumulative budget deficit of about 100 billlion euros. Major efforts must be made to improve efficiency, and it will be necessary to choose between preserving our healthcare system or our financial system. If the latter is prioritized, healthcare will inevitably deteriorate. PMID- 23815026 TI - [Screening for visual impairment in children: new tests and the place of the orthoptist]. AB - The fragility and plasticity of visual function in children necessitates early detection and treatment of visual disorders. New approaches such as portable automatic refraction, tonometry and digital fundus examination have improved the quality of screening The problem now is a lack of ophthalmologists. One possible solution is to redefine the role of orthoptists. The waiting time for an ophthalmologist appointment is very long in some parts of France (up to a year), because of a training quota established in the 1980s, as well as retirements (average age 52 years), and a concentration of specialists in the south of France and around medical schools. Today, France trains only 80 specialists per year, whereas twice as many are needed Anglo-Saxon countries (US, Canada, United Kingdom) have created a profession--the optometrist--that is intermediate between the optician and the ophthalmologist. This profession is not recognized in France, yet optometrists are capable of detecting many anomalies and quickly referring a child to a specialist. PMID- 23815027 TI - [Are rare earths used in offshore windpower installations toxic?]. PMID- 23815028 TI - Flexibilities in WTO law to support tobacco control regulation. PMID- 23815029 TI - Commercial speech law and tobacco marketing: a comparative discussion of the United States and Canada. PMID- 23815030 TI - The Trans-Pacific Partnership agreement: a gold-plated gift to the global tobacco industry? PMID- 23815031 TI - Tobacco control and beyond: the broader implications of United States Clove Cigarettes for non-communicable diseases. PMID- 23815032 TI - Regulatory approaches to ending cigarette-caused death and disease in the United States. PMID- 23815033 TI - The First Amendment and public health, at odds. PMID- 23815034 TI - Confronting the vector of tobacco-related disease. PMID- 23815035 TI - Exploring the confines of international investment and domestic health protections--is a general exceptions clause a forced perspective? PMID- 23815036 TI - Plainly constitutional: the upholding of plain tobacco packaging by the High Court of Australia. PMID- 23815037 TI - Safeguards for tobacco control: options for the TPPA. PMID- 23815038 TI - The role of private law in the control of risks associated with tobacco smoking: the Canadian experience. PMID- 23815039 TI - Tobacco control lessons from the Higgs Boson: observing a hidden field behind changing tobacco control norms in Japan. PMID- 23815040 TI - Towards a Framework Convention on Global Health: a transformative agenda for global health justice. AB - Global health inequities cause nearly 20 million deaths annually, mostly among the world's poor. Yet international law currently does little to reduce the massive inequalities that underlie these deaths. This Article offers the first systematic account of the goals and justifications, normative foundations, and potential construction of a proposed new global health treaty, a Framework Convention on Global Health (FCGH), grounded in the human right to health. Already endorsed by the United Nations Secretary-General, the FCGH would reimagine global governance for health, offering a new, post-Millennium Development Goals vision. A global coalition of civil society and academics has formed the Joint Action and Learning Initiative on National and Global Responsibilities for Health (JALI) to advance the FCGH. PMID- 23815041 TI - The origins of American health libertarianism. AB - This Article examines Americans' enduring demand for freedom of therapeutic choice as a popular constitutional movement originating in the United States' early years. In exploring extrajudicial advocacy for therapeutic choice between the American Revolution and the Civil War, this piece illustrates how multiple concepts of freedom in addition to bodily freedom bolstered the concept of a constitutional right to medical liberty. There is a deep current of belief in the United States that people have a right to choose their preferred treatments without government interference. Modern American history has given rise to movements for access to abortion, life-ending drugs, unapproved cancer treatments, and medical marijuana. Recently, cries of "Death Panels" have routinely been directed against health care reform proposals that citizens believe would limit the products and procedures covered by government health insurance. Some of the most prominent contemporary struggles for health freedom have been waged in court. But other important recent battles for freedom of therapeutic choice have taken place in other forums, from legislative hearings to Food and Drug Administration advisory committee meetings to public demonstrations. This attitude of therapeutic libertarianism is not new. Drawing mainly on primary historical sources, this Article examines arguments in favor of freedom of therapeutic choice voiced in antebellum America in the context of battles against state licensing regimes. After considering some anti-licensing arguments made before independence, it discusses the views and statements of Benjamin Rush, an influential founding father who was also the most prominent American physician of the early national period. The Article then analyzes the Jacksonian-era battle against medical licensing laws waged by the practitioners and supporters of a school of botanical medicine known as Thomsonianism. This triumphant struggle was waged in explicitly constitutional terms, even though it occurred entirely outside of the courts. The Thomsonian campaign thus offers one of the most striking examples of a successful popular constitutional movement in American history. This article shows that, at its origin, the American commitment to freedom of therapeutic choice was based on notions of not only bodily freedom, but also economic freedom, freedom of conscience, and freedom of injury. Finally, this Article considers ways in which this early history helps illuminate the nature of current struggles for freedom of therapeutic choice. PMID- 23815042 TI - Innovation incentives or corrupt conflicts of interest? Moving beyond Jekyll and Hyde in regulating biomedical academic-industry relationships. AB - The most contentious, unresolved issue in biomedicine in the last twenty-five years has been how to best address compensated partnerships between academic researchers and the pharmaceutical industry. Law and policy deliberately promote these partnerships through intellectual property law, research funding programs, and drug and device approval pathways while simultaneously condemning them through conflict-of-interest (COI) regulations. These regulations have not been subjected to the close scrutiny that is typically utilized in administrative law to evaluate and improve regulatory systems. This Article suggests that the solution to this standoff in biomedical law and policy lies in an informed, empirical approach. Such an approach must both recognize such partnerships' legal and practical variations, as well as classify them based on their benefit to innovation and their harm to research biases. Ultimately, this approach must facilitate administrative reforms that would convert what is now an inherently arbitrary, yet widespread, regulatory regime into an epistemically rich mechanism for distinguishing between harmful and beneficial partnerships. PMID- 23815043 TI - Are independent pharmacies in need of special care? An argument against an antitrust exemption for collective negotiations of pharmacists. PMID- 23815044 TI - Stability of aspiration status in healthy adults. AB - OBJECTIVES: In multiple separate studies, we consistently found that approximately 30% of asymptomatic healthy older adults silently aspirated liquids during flexible endoscopic evaluation of swallowing (FEES). We subsequently questioned whether aspiration status remained stable in healthy older adults over time. The purpose of this study was to determine the stability of aspiration status in healthy older adults over time. METHODS: Eighteen healthy older participants, comprising of 9 aspirators and 9 nonaspirators whose aspiration status was identified in a previous study, underwent a second FEES approximately 6 to 21 months later. The participants contributed 36 swallows, comprising 5-, 10 , 15-, and 20-mL boluses of milk (ie, 1 bolus of each volume of skim, 2%, whole, and soy milk) and water via cup and straw delivery, during the original FEES. An abbreviated protocol was administered for the repeat FEES. The Penetration Aspiration Scale was used to rate all swallows. RESULTS: A McNemar test demonstrated no change in aspiration status among participants between the initial test and the retest (p > 0.999). CONCLUSIONS: In this cohort, the aspiration status was stable over about 12 months. This finding lends credence to the premise that trace aspiration of liquids may be a normal and consistent finding in some healthy older adults. PMID- 23815045 TI - Surgical management of airway dysfunction in Parkinson's disease compared with Parkinson-plus syndromes. AB - OBJECTIVES: We sought to compare the laryngeal symptoms of Parkinson's disease (PD) with those of multiple system atrophy (MSA), a Parkinson-plus syndrome; to review the differences in surgical management of upper airway dysfunction between patients with PD and those with MSA; and to present a treatment algorithm for management of upper airway disorders in patients with PD and MSA. METHODS: We analyzed the airway manifestations of each disease, including clinical and physiological test results and management outcomes, in a case series of 30 patients (24 with PD and 6 with MSA). RESULTS: Vocal fold atrophy causing bowing with a midfold glottic gap was common in patients with PD. One third of patients with PD underwent vocal fold augmentation with noticeable improvement in vocal volume and phonation time. Tracheostomy was required for life-threatening sleep apnea in 50% of the patients with MSA. Systemic medications and speech therapy were integral components of the management regimen. CONCLUSIONS: Surgical management of laryngeal disorders in patients with PD should focus on restoring bulk to atrophic vocal folds to minimize glottic gaps, thus improving vocalization efficiency even in the presence of impaired respiratory effort. Conversely, the autonomic dysfunction that characterizes MSA results in upper airway obstruction, and thus surgical management focuses primarily on maintaining an adequate airway, which frequently necessitates tracheostomy. PMID- 23815046 TI - Combined optical coherence tomography and endobronchial ultrasonography for laser assisted treatment of postintubation laryngotracheal stenosis. AB - OBJECTIVES: We describe the use of combined optical coherence tomography (OCT) and endobronchial ultrasonography (EBUS) to identify the residual hypertrophic tissues and persistent inflammation that are known contributors to stricture recurrence after laser-assisted mechanical dilation (LAMD) oflaryngotracheal stenosis (LTS). METHODS: Commercially available high-frequency EBUS (approximately 100-microm resolution) and time-domain OCT (approximately 10- to 20-microm resolution) systems were used to visualize airway wall microstructures in the area of hypertrophic tissue formation before and after LAMD in 2 patients with complex circumferential postintubation LTS. RESULTS: Before LAMD, EBUS revealed a homogeneous layer consistent with hypertrophic tissue overlying a hyperechogenic layer corresponding to tracheal cartilage. OCT revealed a homogeneous light backscattering layer and an absence of layered microstructures within hypertrophic tissue. Immediately after LAMD, OCT of the laser-charred tissue showed high backscattering and shadowing artifacts; OCT of noncharred tissue showed bright light backscattering regions that suggested acute inflammation. EBUS revealed thinner but persistent hypertrophic tissue overlying the cartilage. Stenosis recurred in both patients. CONCLUSIONS: Intraoperative use of EBUS and OCT could potentially identify residual hypertrophic tissues and persistent inflammation during or after LAMD. It might help physicians predict stricture recurrence, prompting alternative therapeutic strategies and avoidance of repeated endoscopic treatments for LTS. PMID- 23815047 TI - Impairment of habituation of the auditory brain stem response in migrainous vertigo. AB - OBJECTIVES: We evaluated the auditory brain stem response (ABR) in migrainous vertigo (MV). METHODS: Four subjects who met clinical criteria for definite MV and 4 subjects with non-vertiginous migraine (NVM) underwent ABR testing while asymptomatic and within 16 hours of a symptomatic episode. Four control subjects were also tested. A set of 4 consecutive 750-click series was administered at 50 , 60-, and 70-dB intensities. We compared the groups in terms of habituation of the amplitude of wave IV-V (habituation of IV-V) from the first through fourth series for each set. RESULTS: The habituation of IV-V amplitude to 50-dB stimuli was significantly less (p = 0.047) in the symptomatic MV group (5.08% +/- 22.32%) than in the symptomatic NVM group (-21.44% +/- 13.50%) or the control group ( 26.06% +/- 9.76%). The habituation of IV-V amplitude to 70-dB stimuli in the MV group was significantly less (p = 0.031) during symptomatic testing (-3.43% +/- 8.89%) than during asymptomatic testing (-21.23% +/- 6.41%). CONCLUSIONS: The habituation of IV-V amplitude is reduced during MV attacks. This finding suggests impaired brain stem inhibition at the level of the inferior colliculus, which shares serotonergic connections with the dorsal raphe nucleus, an area hyperactive in migraine. PMID- 23815048 TI - Congenital middle ear cholesteatoma: experience from 26 surgical cases. AB - OBJECTIVES: We analyzed the clinical features and surgical techniques used in cases of childhood congenital cholesteatoma of the middle ear. METHODS: We studied 26 patients (26 ears) who underwent surgery for congenital cholesteatoma between January 1998 and December 2009, focusing on the location and type of cholesteatoma, the surgical procedures involved, and the results obtained. Patients with prior otologic procedures were excluded. A 4-stage system was used to grade the cholesteatomas. RESULTS: The frequency of posterior-quadrant involvement and open-type cholesteatomas increased in the more advanced stages. Second-look operations were performed in 60% of stage III and 75% of stage IV cases; and residual cholesteatomas were found in 20% of stage III and 75% of stage IV cases. Of the cases evaluated both before and after the operation, 100% of stage I and II cases, 86% of stage III cases, and 50% of stage IV cases showed improvement in hearing function. CONCLUSIONS: The staging system is relatively simple, while accurately reflecting clinical results. However, there are many differences between the anterior and posterior types of congenital cholesteatomas in surgical approach and postoperative progression that are not reflected in the classification systems and require further study. In addition, we reviewed the surgical procedures involved in anterior-quadrant cases, and propose a modified surgical procedure. PMID- 23815049 TI - Utility of two-stage laryngotracheal reconstruction in the management of subglottic stenosis in adults. AB - OBJECTIVES: We examined a retrospective case series to evaluate the utility of two-stage laryngotracheal reconstruction (LTR) in the management of subglottic stenosis (SGS) in adults. Operative correction of SGS with LTR has been practiced successfully in the pediatric population. However, in the adult population, cricotracheal resection has been a more common alternative. METHODS: We reviewed the medical records at the Wayne State University Department of Otolaryngology Head and Neck Surgery. We included all adult patients with SGS who underwent LTR and completed the recommended procedures between December 24, 2003, and October 1,2010. RESULTS: Twelve of the 14 patients identified were decannulated (86%). Of the 12 decannulated patients, 1 required a salvage operation, eventually achieving decannulation after cricotracheal resection. Therefore, although our overall decannulation rate was 86%, the rate with LTR alone was 79%. The majority of our patients (71%) had high-grade (grade III or IV) stenosis. CONCLUSIONS: We conclude that LTR is a viable option for adult patients with SGS. In children, LTR is a relatively safe and often-performed procedure. With use of modern techniques, it has the potential to be applicable to adults, as well. It has the added benefit of avoiding the pitfalls and complications associated with cricotracheal resection. PMID- 23815050 TI - Adjunctive procedures after pediatric single-stage laryngotracheoplasty. AB - OBJECTIVES: We report the frequency and success rates of adjunctive airway procedures after pediatric single-stage laryngotracheoplasty (LTP) and review different adjunctive techniques in a prospectively enrolled and retrospectively reviewed case series. METHODS: Of 31 LTP procedures performed from 2008 to 2011 at an academic tertiary care children's hospital, 10 were single-stage LTP procedures. These 10 cases were analyzed to determine the number and type, if any, of adjunctive procedures required after LTP, as well as the subglottic response and decannulation rates. RESULTS: Of the 10 patients with single-stage LTP procedures, 6 patients required a total of 16 postoperative adjunctive airway procedures. The adjunctive procedures included granulation tissue removal with forceps or a carbon dioxide laser, stent placement, mitomycin C application, and triamcinolone acetonide injection. One patient also required tracheotomy placement and, eventually, cricotracheal resection. All 6 patients had significant improvement of subglottic and/ or tracheal stenosis on their most recent endoscopic examination. With a minimum follow-up of 12 months, all 6 patients were decannulated. CONCLUSIONS: In this series, more than half of our pediatric patients who underwent single-stage LTP required 1 or more postoperative adjunctive procedures, and all had successful outcomes. PMID- 23815051 TI - Causes of dysphagia in a tertiary-care swallowing center. AB - OBJECTIVES: Dysphagia can be caused by a myriad of disease processes, and it has significant impacts on patients' quality of life, life expectancy, and economic burden. To date, the most common causes of dysphagia in outpatient tertiary-care swallowing centers are unknown. We undertook this study to determine these prevalences. We also describe the diagnostic techniques utilized to establish the diagnosis. METHODS: The electronic charts of 100 consecutive patients who presented to an outpatient tertiary-care university swallowing center between January 2010 and April 2011 were retrospectively reviewed. Information regarding patient demographics, validated symptom surveys, diagnostic workups, and ultimate diagnoses was abstracted and tabulated into a central database. Descriptive statistics were used to evaluate the association between patient symptoms and diagnoses. RESULTS: The mean age of the entire cohort was 62 +/- 13.5 years, and 58% of the cohort was male. The most common identified causes of dysphagia were reflux (27%), postirradiation dysphagia (14%), and cricopharyngeus muscle dysfunction (11%). In 13% of cases, the cause of dysphagia was undetermined. The diagnostic tests utilized included flexible laryngoscopy (71%; 17% with endoscopic swallow evaluation), modified barium swallow study (45%), esophagoscopy (35%), barium esophagography (21%), manometry (10%), and ambulatory pH testing (2%). CONCLUSIONS: The most common causes of dysphagia in a tertiary care swallowing center are reflux, postirradiation dysphagia, and cricopharyngeus muscle dysfunction. A precise cause for the symptom could not be identified in 13% of our cohort. Endoscopic visualization (laryngoscopy, flexible endoscopic evaluation of swallowing, and transnasal esophagoscopy) and fluoroscopic swallow studies were the investigations most often utilized. These techniques can be used to arrive at a diagnosis in 80% of cases. PMID- 23815052 TI - Optimal level of continuous positive airway pressure: auto-adjusting titration versus titration with a predictive equation. AB - OBJECTIVES: The aims of the present study were twofold. We sought to compare two methods of titrating the level of continuous positive airway pressure (CPAP) - auto-adjusting titration and titration using a predictive equation - with full night manual titration used as the benchmark. We also investigated the reliability of the two methods in patients with obstructive sleep apnea syndrome (OSAS). METHODS: Twenty consecutive adult patients with OSAS who had successful, full-night manual and auto-adjusting CPAP titration participated in this study. The titration pressure level was calculated with a previously developed predictive equation based on body mass index and apnea-hypopnea index. RESULTS: The mean titration pressure levels obtained with the manual, auto-adjusting, and predictive equation methods were 9.0 +/- 3.6, 9.4 +/- 3.0, and 8.1 +/- 1.6 cm H2O,respectively. There was a significant difference in the concordance within the range of +/- 2 cm H2O (p = 0.019) between both the auto-adjusting titration and the titration using the predictive equation compared to the full-night manual titration. However, there was no significant difference in the concordance within the range of +/- 1 cm H2O (p > 0.999). CONCLUSIONS: When compared to full-night manual titration as the standard method, auto-adjusting titration appears to be more reliable than using a predictive equation for determining the optimal CPAP level in patients with OSAS. PMID- 23815053 TI - Bioluminescent imaging of pneumococcal otitis media in chinchillas. AB - OBJECTIVES: Bioluminescent imaging has emerged as a powerful tool for monitoring the pathological process of infections in animals. The purpose of this study was to harness this new tool for objective assessment of acute otitis media (AOM) in animals with and without antibiotic interventions. METHODS: Thirty-six healthy chinchillas, free of middle ear infections, were randomly divided into a control group and a group that received amoxicillin treatment. Bioluminescent Streptococcus pneumoniae (Xen 10) was injected into the epitympanic bullae of chinchillas (50 colony-forming units each) for induction of AOM. The infectious process of Xen 10 in the bullae of living animals with and without antibiotic interventions was monitored in real time with bioluminescence equipment. RESULTS: A dynamic change of bioluminescent signals in the bullae of chinchillas from days 1 to 14 was observed after Xen 10 injection. Amoxicillin treatment reduced the bioluminescent signals in the bullae of chinchillas compared with controls. The AOM persisted for 14 days, and middle ear effusion for 6 weeks, in the control animals, whereas AOM lasted for 2 days, and effusion for 6 to 12 days, in the antibiotic-treated animals. CONCLUSIONS: Bioluminescent imaging provides an innovative method for assessment of the bacterial loads in the middle ear of chinchillas in a real-time manner and is very useful for objective evaluation of the efficacy of therapeutic interventions. PMID- 23815054 TI - [ROL, your journal, a journal with many prizes]. PMID- 23815055 TI - [Hemodialysis on a cruise ship: our logbook]. AB - After a diet and hydric restriction, travelling is one of the most limiting and worrying activities for patients under chronic renal replacement therapy. The vital dependency on the hemodialysis machine makes travelling an extremely difficult experience. In order to prove the legitimacy of our patients' fears, we embarked on to a cruise-liner with them. This confirmed their limitations when travelling thanks to the reliable data input. This study describes our personal and professional experience as nurses, specialized in hemodialysis, embarking onto a cruise-liner with twelve patients suffering from ESRD. Our goal is to share that experience with professional nurses as well as patients who seek information in regards to this type of trip with a specialized nurse. A summary of this work was presented as a communication oral in the XXXVI Congress of the Spanish Society of Nephrology Nursing. PMID- 23815056 TI - [Analisys of nursing diagnosis risk of falls in adults and children]. AB - Falls are a problem for all age groups but it affects children and the elderly in particular. Falls are a major public health problem as they not only have physical, social and economic consequences but also they are associated to high mortality rates. It has been proven that the cause of falls is multifactorial. Therefore, the implementation of a Multifactorial Fall Prevention Program is extremely important. For these reasons, this research study is done based on other studies already published. Falls linked to specific factors are analyzed in order to prove through evidence risk factors established by the NANDA for Risk Fall Diagnosis or if some of them can not be justified and, therefore, should not be classified as risk factors. PMID- 23815057 TI - [Intraprofessional communication during shift change]. AB - INTRODUCTION: Effective communication between professionals is crucial to ensure patient safety. OBJECTIVES: 1) Explore the intraprofessional communication process during nurse shift change; 2) identify improvement strategies to facilitate optimal communication process. METHODS: Exploratory study conducted from January to May 2011 in an intermediate unit. There were performed 16 structured observations of the communication process and 4 semistructured interviews and 16 anonymous surveys (designed by the evidence, interviews and observations) to the nurses who agreed to participate in the study. RESULTS: Strengths: complete process and the usefulness of the computer record. LIMITATIONS: lack of common structure, repetition and forgetfulness of information, numerous interruptions during the process and noise. The 68.75% of nurses said that part of the transmitted information was irrelevant and too long. All of them perceived the need for changes in the existing process. Some strategies were identified to improve the development of a guide based on the mnemonic SBAR. It was adapted to the structure of the software as well as a change in location for the transmission of information. CONCLUSION: We propose to have an effective intraprofessional communication in order to ensure patient safety. In addition the transmission of information during the shift change should be done through a systematic process in a quiet place without interruptions. PMID- 23815058 TI - [The most frequent digestive disorders in the elderly]. AB - Aging is a stage with various changes and physiological modifications. It's a progressive, dynamic and irreversible process. Elderly people are beings fragile, multipathological, and polimedicated. 40 Of the world's population has indigestion. They are the most common digestive disorders: constipation, dysphagia, and dyspepsia, reaching levels of prevalence around the 25, 30 and 25 respectively. The main activity of the nursing professional lies in making a proper assessment of the patient and offer a health education regarding habits hygiene and dietetics, in order to reduce the intake of drugs and increase the quality of life of our elders. We should not forget that the family plays a fundamental role for the treatment of these disorders. PMID- 23815059 TI - [Impact of diffusion of the methodology of evidence-based nursing through Facebook]. AB - AIMS: Evaluate the impact of diffusion of the contents of the blog "Evidence Based Nursing" through Facebook. METHOD: Cross-sectional study carried out via a web link to the online survey (previously tested) to a population of 2132 Facebook profiles that had a "friendship" with the profile studied. The survey had 8 items and a descriptive study of variables was conducted using SPSS 19. RESULTS: 75.9% of the sample has a Facebook profile of a personal character and 94.1% of cases are interested in evidence-based practices. 55.6% of the sample knows the blog, plus 46.5% answered that they read it occasionally, compared with 17.1% who does regularly and 35.7% who say they do not read it. Of all readers, 75.75% say they have improved their knowledge in terms of evidence-based practice after reading it. 88% said they did not follow the blog by other means or social network and in the case that they did, the most used are Google Reader, and Twitter Networked Blogs. CONCLUSIONS: Reading the contents of this blog improve the knowledge about evidence-based practices of the "friends" of the social profile, as they themselves relate. The adequacy of the social profile as a dissemination tool is successful as it is necessary to investigate in depth the functioning of social networks. PMID- 23815060 TI - [Music provides color to life's score. Interview by Maria Jesus Nadal Nadal]. PMID- 23815061 TI - [Life history, accompanied by ROL]. PMID- 23815062 TI - [International development cooperation from the D. Orem self-care theory]. AB - This article aim is to analyze the performance of Spanish cooperation from the perspective of Orem self-care theory, from the next hypothesis: the Spanish international cooperation programs works as total compensation systems. METHODS: cross sectional and descriptive study in which qualitative analysis was performed 3 African countries: Mozambique, Angola and Namibia. The variables were management, focused area and resources used. RESULTS: All countries have a shared management of the cooperation. Mozambique has developed training activities (72%), management support (38%) and direct health care (27%), focused on the area of the fight against infection and tropical diseases. In Angola, the activities are based in training (37%), management support (37%) and health care (75%) in the area of basic health services (25%), fighting against tropical diseases (50%) and improving maternal and child health (25%). Namibia focuses on the health care area (100%) through direct assistance activities and management support. DISCUSSION: Health cooperation programs developed by the Spanish state have probed to work as partial compensation system. PMID- 23815063 TI - [Direct clinical practice: conceptual analysis. Central competence for the development of advanced nursing practice]. AB - The recent implementation in Spain of post degree in nursing has made possible the emergence of new advanced profiles, which direct clinical practice is the core competence. OBJECTIVE: To analyse and clarify the term of direct clinical practice. METHODOLOGY: A conceptual analysis was carried out based on Rogers's evolutionary approach. A review of the literature was made in the following data bases: PubMed, CINAHL, ISI Web of Knowledge, Psych INFO (Ovid) and Cochrane Library. Furthermore, five books about advanced practice nursing were revised. RESULTS: 7 articles and 4 books based on the inclusion criteria were selected. After their analysis the concept of direct clinical practice is defined. CONCLUSIONS: This paper clarifies the concept of direct clinical practice and helps to have a stronger base of knowledge. This will serve as foundation to improve and perfect the conceptualization of this term. PMID- 23815064 TI - [Aging in the rural environment]. PMID- 23815065 TI - [Manager nurses contribute to the sustainability of the health system]. PMID- 23815066 TI - [Promoting research, teaching and continuous training]. PMID- 23815067 TI - Pressure-induced phase transitions and correlation between structure and superconductivity in iron-based superconductor Ce(O(0.84)F(0.16))FeAs. AB - High-pressure angle-dispersive X-ray diffraction experiments on iron-based superconductor Ce(O(0.84)F(0.16))FeAs were performed up to 54.9 GPa at room temperature. A tetragonal to tetragonal isostructural phase transition starts at about 13.9 GPa, and a new high-pressure phase has been found above 33.8 GPa. At pressures above 19.9 GPa, Ce(O(0.84)F(0.16))FeAs completely transforms to a high pressure tetragonal phase, which remains in the same tetragonal structure with a larger a-axis and smaller c-axis than those of the low-pressure tetragonal phase. The structure analysis shows a discontinuity in the pressure dependences of the Fe-As and Ce-(O, F) bond distances, as well as the As-Fe-As and Ce-(O, F)-Ce bond angles in the transition region, which correlates with the change in T(c) of this compound upon compression. The isostructural phase transition in Ce(O(0.84)F(0.16))FeAs leads to a drastic drop in the superconducting transition temperature T(c) and restricts the superconductivity at low temperature. For the 1111-type iron-based superconductors, the structure evolution and following superconductivity changes under compression are related to the radius of lanthanide cations in the charge reservoir layer. PMID- 23815068 TI - Accurate high-N rest frequencies for CO+, an ideal tracer of photon-dominated regions. AB - The submillimeter-wave rotational spectra of CO(+), (13)CO(+) and C(18)O(+) in the v = 0 and 1 vibrational states were measured through a hollow cathode dc discharge in a cryogenic cell cooled to liquid nitrogen temperature. In addition, a few transitions of the main isotopic species have been measured between 1.1 and 1.3 THz. An updated isotopically invariant fit, including Born-Oppenheimer breakdown corrections, is presented: the derived set of independent molecular parameters, valid for all the isotopologues of the molecule included in the fit, allows to predict the rotational spectrum with calculated 1sigma uncertainty of 280 kHz at 2 THz. PMID- 23815069 TI - Charge-based detection of small molecules by plasmonic-based electrochemical impedance microscopy. AB - Charge-based detection of small molecules is demonstrated by plasmonic-based electrochemical impedance microscopy (P-EIM). The dependence of surface plasmon resonance (SPR) on surface charge density is used to detect small molecules (60 120 Da) printed on a dextran-modified sensor surface. Local variations in charge density on an electrode surface are manifest in an optical SPR signal. The SPR response to an applied ac potential measures the sensor surface impedance which is a function of the surface charge density. This optical signal is comprised of a dc and an ac component, and is measured with high spatial resolution. The dc element of the SPR signal represents conventional SPR imaging information. The amplitude and phase of local surface impedance is provided by the ac component. The phase signal of the small molecules is a function of their charge status, which is manipulated by the pH of a solution. Small molecules with positive, neutral, and negative charge are detected by P-EIM. This technique is used to detect and distinguish small molecules based on their charge status, thereby circumventing the mass limitation (~100 Da) of conventional SPR measurement. PMID- 23815070 TI - Agarose hydrogels embedded with pH-responsive diblock copolymer micelles for triggered release of substances. AB - Hybrid agarose hydrogels embedded with pH-responsive diblock copolymers micelles were developed to achieve functional hydrogels capable of stimulus-triggered drug release. Specifically, a well-defined poly(ethylene oxide) (PEO)-based diblock copolymer, PEO-b-poly(2-(N,N-diisopropylamino)ethyl methacrylate) (PEO(113)-b PDPAEMA(31), where the subscripts represent the degrees of polymerization of two blocks), was synthesized by atom transfer radical polymerization. PDPAEMA is a pH responsive polymer with a pKa value of 6.3. The PEO(113)-b-PDPAEMA(31) micelles were formed by a solvent-switching method, and their pH-dependent dissociation behavior was investigated by dynamic light scattering and fluorescence spectroscopy. Both studies indicated that the micelles were completely disassembled at pH = 6.40. The biocompatibility of PEO(113)-b-PDPAEMA(31) micelles was demonstrated by in vitro primary cortical neural culture. Hybrid agarose hydrogels were made by cooling 1.0 wt % agarose solutions that contained various amounts of PEO(113)-b-PDPAEMA(31) micelles at either 2 or 4 degrees C. Rheological measurements showed that the mechanical properties of gels were not significantly adversely affected by the incorporation of diblock copolymer micelles with a concentration as high as 5.0 mg/g. Using Nile Red as a model hydrophobic drug, its incorporation into the core of diblock copolymer micelles was demonstrated. Characterized by fluorescent spectroscopy, the release of Nile Red from the hybrid hydrogel was shown to be controllable by pH due to the responsiveness of the block copolymer micelles. Based on the prominent use of agarose gels as scaffolds for cell transplantation for neural repair, the hybrid hydrogels embedded with stimuli-responsive block copolymer micelles could allow the controlled delivery of hydrophobic neuroprotective agents to improve survival of transplanted cells in tune with signals from the surrounding pathological environment. PMID- 23815071 TI - Isopalhinine A, a unique pentacyclic Lycopodium alkaloid from Palhinhaea cernua. AB - A new pentacyclic (5/6/6/6/7) Lycopodium alkaloid named isopalhinine A (1), which possesses a sterically congested architecture built with a tricyclo[4.3.1.0(3,7)]decane (isotwistane) moiety and a 1-azabicyclo[4.3.1]decane moiety, and palhinines B (2) and C (3) were isolated from Palhinhaea cernua. The structure and absolute configuration of 1 were elucidated by a combination of NMR spectra, optical rotation calculation, and X-ray diffraction experiment. A possible biogenetic pathway was also proposed. PMID- 23815073 TI - Value of Bishop score and ultrasound cervical length measurement in the prediction of cesarean delivery. AB - AIM: The aim of this study was to evaluate the role of Bishop score and cervical length in predicting the outcome of induced labor. MATERIAL AND METHODS: A prospective observational study was performed during a year in women undergoing labor induction. Prior to the procedure, Bishop score was evaluated by transvaginal digital examination and cervical length was measured by transvaginal ultrasound. Demographic data and labor details were recorded. RESULTS: A total of 197 women were analyzed; 166 women had a vaginal delivery (84.3%) and 31 had a cesarean section (15.7%). On univariate analysis, nulliparity, Bishop score >5 and cervical length <30 mm were all associated with cesarean delivery. On multivariate analysis, only nulliparity remained significantly associated with cesarean delivery and the other characteristics did not achieve statistical significance. When women were stratified according to parity, there was a significant association between cesarean delivery and nulliparity, but not multiparity. CONCLUSIONS: Our results suggest that Bishop score and cervical length are good predictors of successful induction of labor, particularly in nulliparous women. PMID- 23815074 TI - An exploratory digital analysis of the early years of G. Stanley Hall's American Journal of Psychology and Pedagogical Seminary. AB - In this article, we present the results of an exploratory digital analysis of the contents of the two journals founded in the late 19th century by American psychologist G. Stanley Hall. Using the methods of the increasingly popular digital humanities, some key attributes of the American Journal of Psychology (AJP) and the Pedagogical Seminary (PS) are identified. Our analysis reaffirms some of Hall's explicit aims for the two periodicals, while also revealing a number of other features of the journals, as well as of the people who published within their pages, the methodologies they employed, and the institutions at which they worked. Notably, despite Hall's intent that his psychological journal be strictly an outlet for scientific research, the journal-like its sister pedagogically focused publication-included an array of methodologically diverse research. The multiplicity of research styles that characterize the content of Hall's journals in their initial years is, in part, a consequence of individual researchers at times crossing methodological lines and producing a diverse body of research. Along with such variety within each periodical, it is evident that the line between content appropriate to one periodical rather than the other was fluid rather than absolute. The full results of this digitally informed analysis of Hall's two journals suggest a number of novel avenues for future research and demonstrate the utility of digital methods as applied to the history of psychology. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 23815075 TI - The History of Psychology Newsletter, 1969-1997: History and index. AB - During 1968-1997, Division 26 of the American Psychological Association, now the Society for the History of Psychology, and its predecessor, the History of Psychology Group, published a series of some 101 newsletters. These are a form of gray literature unfamiliar to some historians of psychology. I provide both an overview of the newsletters and their history and some highlights of the 153 substantive articles appearing in the newsletter through its run. Many issues of both sets include features such as a Notes and News section, a President's Message, Membership Lists, assorted division business items, and other items of potential interest to members of the division. However, many issues, especially the later ones, also contained substantive articles that are of broader interest. These materials provide a potentially valuable source for historians of psychology. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 23815072 TI - Jenner-predict server: prediction of protein vaccine candidates (PVCs) in bacteria based on host-pathogen interactions. AB - BACKGROUND: Subunit vaccines based on recombinant proteins have been effective in preventing infectious diseases and are expected to meet the demands of future vaccine development. Computational approach, especially reverse vaccinology (RV) method has enormous potential for identification of protein vaccine candidates (PVCs) from a proteome. The existing protective antigen prediction software and web servers have low prediction accuracy leading to limited applications for vaccine development. Besides machine learning techniques, those software and web servers have considered only protein's adhesin-likeliness as criterion for identification of PVCs. Several non-adhesin functional classes of proteins involved in host-pathogen interactions and pathogenesis are known to provide protection against bacterial infections. Therefore, knowledge of bacterial pathogenesis has potential to identify PVCs. RESULTS: A web server, Jenner Predict, has been developed for prediction of PVCs from proteomes of bacterial pathogens. The web server targets host-pathogen interactions and pathogenesis by considering known functional domains from protein classes such as adhesin, virulence, invasin, porin, flagellin, colonization, toxin, choline-binding, penicillin-binding, transferring-binding, fibronectin-binding and solute-binding. It predicts non-cytosolic proteins containing above domains as PVCs. It also provides vaccine potential of PVCs in terms of their possible immunogenicity by comparing with experimentally known IEDB epitopes, absence of autoimmunity and conservation in different strains. Predicted PVCs are prioritized so that only few prospective PVCs could be validated experimentally. The performance of web server was evaluated against known protective antigens from diverse classes of bacteria reported in Protegen database and datasets used for VaxiJen server development. The web server efficiently predicted known vaccine candidates reported from Streptococcus pneumoniae and Escherichia coli proteomes. The Jenner Predict server outperformed NERVE, Vaxign and VaxiJen methods. It has sensitivity of 0.774 and 0.711 for Protegen and VaxiJen dataset, respectively while specificity of 0.940 has been obtained for the latter dataset. CONCLUSIONS: Better prediction accuracy of Jenner-Predict web server signifies that domains involved in host-pathogen interactions and pathogenesis are better criteria for prediction of PVCs. The web server has successfully predicted maximum known PVCs belonging to different functional classes. Jenner-Predict server is freely accessible at http://117.211.115.67/vaccine/home.html. PMID- 23815076 TI - "The last possible resort": A forgotten prod and the in situ standardization of Stanley Milgram's voice-feedback condition. AB - This article uses previously unpublished data from Stanley Milgram's obedience experiments to draw attention to a hitherto neglected procedural innovation of the voice-feedback condition. In 3 experimental sessions in this condition, the experimenter responded to a participant's attempted defiance by leaving the room, apparently to speak to the learner, before returning to assure the participant that the learner was willing or able to continue. This article documents the use of this tactic during the voice-feedback condition and highlights the negotiation surrounding the use of the tactic between Milgram and his confederate John Williams, who played the role of the experimenter. It is shown that the subsequent use of this tactic did not conform to the conditions for its use agreed by Milgram and Williams. Moreover, the tactic seems to have been dropped from both subsequent experimental conditions and Milgram's published accounts of his work. These observations are discussed in relation to historical work on experimentation in social psychology, research on standardization in the sociology of scientific knowledge, and in terms of their implications for theory and research on dis/obedience. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 23815077 TI - Shaping and owning the boundaries of a book. AB - Cheryl Logan uses examples from her recent book, Hormones, Heredity, and Race, to discuss the importance of establishing conceptual boundaries, as writers develop book projects. The conceptual clarity of a book's central thesis and transitions to key subthemes that enrich its structure can both benefit from well-crafted edges that exclude some topics. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 23815078 TI - Computed tomographic characteristics of presumed normal canine abdominal lymph nodes. AB - Though identification of lymph nodes is essential in staging cancer patients, little has been reported about the CT features of canine abdominal lymph nodes. The purpose of this retrospective study was to describe the visibility, location, and characteristics of abdominal lymph nodes in abdominal CT studies of dogs considered unlikely to have lymphadenopathy. The relationship between the number of identified lymph nodes and intraabdominal fat ranking, body weight, and slice thickness was also investigated. A total of 19 dogs were included. At least two jejunal lymph nodes and both left and right medial iliac lymph nodes were identified in all dogs. Colic lymph nodes were not identified in any of the dogs. Visualization of all other lymph nodes varied. There were significantly more lymph nodes visible in dogs with more intraabdominal fat (P < 0.0001). No correlation between the number of identified lymph nodes and body weight (P = 0.64) or slice thickness (P = 0.76) was found. Though most of all identified lymph nodes had an elongated shape, a rounded shape was most common in splenic, pancreaticoduodenal, renal, ileocolic and caudal mesenteric lymph nodes. Most lymph nodes had a homogeneous structure before and following the intravenous administration of contrast medium. Some lymph nodes had a slightly irregular structure or were relatively more hyper attenuating in the periphery than centrally before and/or after contrast administration. Mean attenuation before contrast was 37 Hounsfield Units (HU) (range 20-52 HU), and 109 HU after contrast (range 36-223 HU). Findings indicated that the CT visibility, characteristics of different abdominal lymph nodes may be variable in dogs. PMID- 23815079 TI - Environmental persistence of vaccinia virus on materials. AB - Smallpox is caused by the variola virus, and ranks as one of the most serious diseases that could originate from a biological weapon. However, limited data exist on the persistence of variola and related viruses on materials (that may act as fomites), under controlled environmental conditions. To fill these data gaps, we determined the persistence of the vaccinia virus (an established surrogate for the variola virus) as a function of temperature, relative humidity and material. Experiments were conducted with vaccinia virus in a freeze-dried form, using four materials under four sets of environmental conditions. After elapsed times ranging from 1 to 56 days, the virus was extracted from small coupons and quantified via plaque-forming units (PFU). The vaccinia virus was most persistent at low temperature and low relative humidity, with greater than 10(4) PFU recovered from glass, galvanized steel and painted cinder block at 56 days (equivalent to only a c. 2 log reduction). Thus, vaccinia virus may persist from weeks to months, depending on the material and environmental conditions. This study may aid those responsible for infection control to make informed decisions regarding the need for environmental decontamination following the release of an agent such as variola. PMID- 23815080 TI - Helicopter emergency medical services (HEMS) over-triage and the financial implications for major trauma centres in NSW, Australia. AB - BACKGROUND: In NSW Australia, a formal trauma system including the use of helicopter emergency medical services (HEMS) has existed for over 20 years. Despite providing many advantages in NSW, HEMS patients are frequently over triaged; leading to financial implications for major trauma centres that receive HEMS patients. The aim of this study was to investigate the financial implications of HEMS over-triage from the perspective of major trauma centres in NSW. METHODS: The study sample included all trauma patients transported via HEMS to 12 major trauma centres in NSW during the period: 1 July 2008 to 30 June 2009. Clinical data were gathered from individual hospital trauma registries and merged with financial information obtained from casemix units at respective hospitals. HEMS over-triage was estimated based on the local definition of minor to moderate trauma (ISS<=12) and hospital length of stay of less than 24 hrs. The actual treatment costs were determined and compared to state-wide peer group averages to obtain estimates of potential funding discrepancies. RESULTS: A total of 707 patients transported by HEMS were identified, including 72% pre-hospital (PH; n=507) and 28% inter-hospital (IH; n=200) transports. Over-triage was estimated at 51% for PH patients and 29% for IH patients. Compared to PH patients, IH patients were more costly to treat on average (IH: $42,604; PH: $25,162), however PH patients were more costly overall ($12,329,618 [PH]; $8,265,152 [IH]). When comparing actual treatment costs to peer group averages we found potential funding discrepancies ranging between 4% and 32% across patient groups. Using a sensitivity analysis, the potential funding discrepancy increased with increasing levels of over-triage. CONCLUSIONS: HEMS patients are frequently over-triaged in NSW, leading to funding implications for major trauma centres. In general, HEMS patient treatment costs are higher than the peer group average and the potential funding discrepancy varies by injury severity and the type of transport performed. Although severely injured HEMS patients are more costly to treat, HEMS patients with minor injuries make up the majority of HEMS transports and have larger relative potential funding discrepancies. Future episode funding models need to account for the variability of trauma patients and the proportion of patients transported via HEMS. PMID- 23815081 TI - Controlling self-assembly of a peptide-based material via metal-ion induced registry shift. AB - Peptide TZ1C2 can populate two distinct orientations: a staggered (out-of register) fibril and an aligned (in-register) coiled-coil trimer. The coordination of two cadmium ions induces a registry shift that results in a reversible transition between these structural forms. This process recapitulates the self-assembly mechanism of native protein fibrils in which a ligand binding event gates a reversible conformational transition between alternate forms of a folded peptide structure. PMID- 23815082 TI - A review on structure-affinity relationship of dietary flavonoids with serum albumins. AB - Flavonoids are a class of plant secondary metabolites and among thousands of flavonoids few are considered as dietary flavonoids. Serum albumin (SA), the most abundant protein in plasma, functions as the most important carrier of vital drugs, including dietary flavonoids. The binding affinity of dietary flavonoids to SA is demonstrated to be governed by structure-affinity relationship (SAR) and its bioavailability. The present review summarizes the interactions of flavonoids categorized as flavanol, flavonol, flavone, isoflavone, flavanones, and anthocyanidins with SAs (bovine serum albumin and human serum albumin) in light of SAR. The key findings are: (1) the position and degree of hydroxylation highly influence the affinity of flavonoids to SAs, (2) glycosylation decreases and substitution of methoxy group increases the affinity of flavonoids for SAs, (3) catechin gallates have higher binding affinity to SAs than catechins and gallocatechins, (4) inorganic metal ions modulate the binding affinity of flavonoids to SAs, and (5) hydrophobic interaction plays a major role in the interactions of all flavonoids with SAs. PMID- 23815083 TI - iPad-presented social stories for young children with autism. AB - OBJECTIVE: This study investigated the effectiveness of iPad-presented social stories in increasing the on-task behaviour of three young children with autism. METHOD: A single-subject with multiple baseline across participants design was employed with three 4-year-old children to assess intervention effectiveness during structured table top activities. Observational data were digitally recorded, scored, graphed, and interpreted using 10-second interval measures over 5-min periods across baseline, intervention, and withdrawal phases. RESULTS: The combination of the social story together with the iPad proved to be an effective intervention for one of the three child participants. These findings confirm that the intervention may be effective with some children, but not others. CONCLUSION: Overall, this study builds on existing research that supports social stories as a promising practice. Further research into the use of iPad-presented social stories, particularly for children of varying ages, abilities, and learning styles is recommended. PMID- 23815084 TI - Nanostructured nonprecious metal catalysts for oxygen reduction reaction. AB - Platinum-based catalysts represent a state of the art in the electrocatalysis of oxygen reduction reaction (ORR) from the point of view of their activity and durability in harnessing the chemical energy via direct electrochemical conversion. However, because platinum is both expensive and scarce, its widespread implementation in such clean energy applications is limited. Recent breakthroughs in the synthesis of high-performance nonprecious metal catalysts (NPMCs) make replacement of Pt in ORR electrocatalysts with earth-abundant elements, such as Fe, Co, N, and C, a realistic possibility. In this Account, we discuss how we can obtain highly promising M-N-C (M: Fe and/or Co) catalysts by simultaneously heat-treating precursors of nitrogen, carbon, and transition metals at 800-1000 degrees C. The activity and durability of resulting catalysts depend greatly on the selection of precursors and synthesis chemistry. In addition, they correlate quite well with the catalyst nanostructure. While chemists have presented no conclusive description of the active catalytic site for this class of NPMCs, they have developed a designed approach to making active and durable materials, focusing on the catalyst nanostructure. The approach consists of nitrogen doping, in situ carbon graphitization, and the usage of graphitic structures (possibly graphene and graphene oxides) as carbon precursors. Various forms of nitrogen, particularly pyridinic and quaternary, can act as n-type carbon dopants in the M-N-C catalysts, assisting in the formation of disordered carbon nanostructures and donating electrons to the carbon. The CNx structures are likely a crucial part of the ORR active site(s). Noteworthy, the ORR activity is not necessarily governed by the amount of nitrogen, but by how the nitrogen is incorporated into the nanostructures. Apart from the possibility of a direct participation in the active site, the transition metal often plays an important role in the in situ formation of various carbon nanostructures by catalyzing the decomposition of the nitrogen/carbon precursor. We can control the formation of different nanostructures during the synthesis of M-N-C catalysts. For example, in situ formed nitrogen-doped graphene-sheets can only be derived from polyaniline (PANI), probably due to structural similarities between the aromatic structures of PANI and graphene. Highly-graphitized carbon nanostructures may serve as a matrix for the formation of ORR-active groups with improved catalytic activity and durability, containing nitrogen and most probably also metal atoms. In the future, we will likely focus NPMC synthesis approaches on precise control of interactions between precursors of the metal and carbon/nitrogen during the heat treatment. The main purposes will be to maximize the number of active sites, optimize nitrogen doping levels, and generate morphologies capable of hosting active and stable ORR sites. PMID- 23815085 TI - The presence of outer arm fucose residues on the N-glycans of tissue inhibitor of metalloproteinases-1 reduces its activity. AB - Tissue inhibitor of metalloproteinases-1 (TIMP-1) inhibits matrix metalloproteinases (MMPs) by binding at a 1:1 stoichiometry. Here we have shown the involvement of N-glycosylation in the MMP inhibitory ability of TIMP-1. TIMP 1, purified from HEK 293 cells overexpressing TIMP-1 (293 TIMP-1), showed less binding and inhibitory abilities to MMPs than TIMP-1 purified from fibroblasts or SF9 insect cells infected with TIMP-1 baculovirus. Following deglycosylation of TIMP-1, all forms of TIMP-1 showed similar levels of MMP binding and inhibition, suggesting that glycosylation is involved in the regulation of these TIMP-1 activities. Analysis of the N-glycan structures showed that SF9 TIMP-1 has the simplest N-glycan structures, followed by fibroblast TIMP-1 and 293 TIMP-1, in order of increasing complexity in their N-glycan structures. Further analyses showed that cleavage of outer arm fucose residues from the N-glycans of 293 TIMP 1 or knockdown of both FUT4 and FUT7 (which encode for fucosyltransferases that add outer arm fucose residues to N-glycans) enhanced the MMP-binding and catalytic abilities of 293 TIMP-1, bringing them up to the levels of the other TIMP-1. These results demonstrate that the ability of TIMP-1 to inhibit MMPs is at least in part regulated by outer arm fucosylation of its N-glycans. PMID- 23815086 TI - Harvest discrimination of pomegranate fruit: postharvest quality changes and relationships between instrumental and sensory attributes during shelf life. AB - Harvest maturity discrimination was carried out for "Ruby" pomegranate cultivar in simulated handling conditions for long distant supply chains. Fruit were harvested at 3 different maturities along days after full bloom (DAFB); Harvest 1 (H1) at 133 DAFB, H2 at 143 DAFB, and H3 at 157 DAFB. The effects of harvest maturity and storage duration on fruit quality attributes during a 6-wk period of cold storage (5 degrees C, 95% RH) and subsequent 5 d of shelf life (20 degrees C, 75% RH) were investigated. Instrumental evaluation of aril color, juice content, juice absorbance (520 nm), total soluble solids (TSS), pH, titratable acids (TA), and phytochemical components including total phenolics, flavonoids, and anthocyanins were carried out. Textural properties of arils which included hardness, toughness, bioyield point, and Young's modulus were also investigated. During the shelf life period, arils from individual fruit were rated by a trained sensory panel based on appearance, taste, and texture. Relationships between the instrumental and descriptive sensory data were explored and fruit harvest maturities were discriminated using discriminant analysis. Among the attributes evaluated, TSS : TA, sweet taste, and the CIE hue angle (h degrees ) were the most decisive attributes distinguishing the harvest maturities. The optimum time for harvesting was at 143 DAFB (H2) when fruit TSS : TA ratio was > 55, which coincided with significantly higher rating for sweet taste in fruit at H2 than at H1 and H3 during shelf life. The harvest index proposed in the current study could be used as a guide to establish a reliable harvest maturity index to assist in assuring fruit quality in consideration of long supply chains for the investigated cultivar. PMID- 23815087 TI - Robust PCA based method for discovering differentially expressed genes. AB - How to identify a set of genes that are relevant to a key biological process is an important issue in current molecular biology. In this paper, we propose a novel method to discover differentially expressed genes based on robust principal component analysis (RPCA). In our method, we treat the differentially and non differentially expressed genes as perturbation signals S and low-rank matrix A, respectively. Perturbation signals S can be recovered from the gene expression data by using RPCA. To discover the differentially expressed genes associated with special biological progresses or functions, the scheme is given as follows. Firstly, the matrix D of expression data is decomposed into two adding matrices A and S by using RPCA. Secondly, the differentially expressed genes are identified based on matrix S. Finally, the differentially expressed genes are evaluated by the tools based on Gene Ontology. A larger number of experiments on hypothetical and real gene expression data are also provided and the experimental results show that our method is efficient and effective. PMID- 23815088 TI - Interobserver reliability and reproducibility of s.T.o.N.e. Nephrolithometry for renal calculi. AB - PURPOSE: To assess the reliability of the S.T.O.N.E. (stone size [S], tract length [T], obstruction [O], number of involved calices [N], and essence or stone density [E]) nephrolithometry scoring system by testing its reproducibility between different observers. PATIENTS AND METHODS: Preoperative images of 58 patients who underwent percutaneous nephrolithotomy (PCNL) were reviewed. Medical students, urology residents, one fellow, and a urology attending independently reviewed all images and scored the renal stones. Interobserver reliabilities of the total score for all categories and each component were evaluated by the intraclass correlation (ICC) and a kappa coefficient. RESULTS: The interobserver reliability for the total score demonstrated high correlations for all components and total score (ICC=S, T, O, N, E and total 0.80, 0.97, 0.89, 0.84, 0.91, and 0.87, respectively). kappa rates for individual components between two medical students were 0.36, 1, 0.31, 0.45, 0.33, and 0.30 for the S, T, O, N, E components and total score, respectively. kappa values between the two urology residents were 0.71, 1, 0.92, 0.79, 0.93, and 0.67 for S, T, O, N, E components and total score, respectively. kappa values between the urology fellow and an attending physician were 0.95, 1, 0.88, 0.94, 0.89, and 0.87 for S, T, O, N, E components and total score, respectively. P value for all the scoring components was <0.05, indicating that the estimated kappa was not a result of chance. CONCLUSIONS: The S.T.O.N.E. nephrolithometry has excellent interobserver reliability. Quantifying the S and N metrics was the most challenging and least reliable. Standardized protocols to measure these components should be considered to improve accuracy and reproducibility of the scoring system. PMID- 23815089 TI - Titania binding peptides as templates in the biomimetic synthesis of stable titania nanosols: insight into the role of buffers in peptide-mediated mineralization. AB - In this Article, we report the unusual behavior of two peptides (Ti-1 (QPYLFATDSLIK) and Ti-2 (GHTHYHAVRTQT)) with high affinity for titania that efficiently promote titania mineralization from an aqueous titanium bisammonium lactatodihydroxide (TiBALDH) solution, yielding small (ca. 4 nm) titania nanoparticles. As a result, we were able to produce for the first time using a biomimetic approach highly stable sub-10-nm titania sols. Both sequences show a high titania mineralization activity per unit peptide concentration and a capacity to control particle size and stabilize nanoparticles through specific surface interactions. We also show that phosphate ions disrupt the controlled particle formation and stabilization achieved in the presence of the two peptides. The products obtained from phosphate buffered solutions are titanium containing materials (not pure oxide) with poor morphological control similar to those previously reported by others. Our results provide important insights into understanding the mechanism of titania mineralization in a range of different aqueous media (water, Tris, and phosphate buffer). PMID- 23815090 TI - Resource-use strategies of native and invasive plants in Eastern North American forests. AB - Studies in disturbed, resource-rich environments often show that invasive plants are more productive than co-occurring natives, but with similar physiological tradeoffs. However, in resource-limited habitats, it is unclear whether native and invasive plants have similar metabolic constraints or if invasive plants are more productive per unit resource cost - that is, use resources more efficiently. Using a common garden to control for environment, we compared leaf physiological traits relating to resource investments, carbon returns, and resource-use efficiencies in 14 native and 18 nonnative invasive species of common genera found in Eastern North American (ENA) deciduous forest understories, where growth is constrained by light and nutrient limitation. Despite greater leaf construction and nitrogen costs, invaders exhibited greater instantaneous photosynthetic energy-use efficiency (PEUE) and marginally greater photosynthetic nitrogen-use efficiency (PNUE). When integrated over leaf lifespan (LL), these differences were magnified. Differences in efficiency were driven by greater productivity per unit leaf investment, as invaders exhibited both greater photosynthetic abilities and longer LL. Our results indicate that woody understory invaders in ENA forests are not constrained to the same degree by leaf based metabolic tradeoffs as the native understory flora. These strategy differences could be attributable to pre-adaptation in the native range, although other explanations are possible. PMID- 23815091 TI - miR-144 downregulation increases bladder cancer cell proliferation by targeting EZH2 and regulating Wnt signaling. AB - microRNAs (miRNAs) have been proposed to be key regulators of diverse biological processes such as transcriptional regulation, cell growth and tumorigenesis. Wnt signaling plays an important role in the regulation of tumorigenesis and cancer progression. However, little is known about whether miR-144 regulates bladder cancer cell proliferation by controlling Wnt signaling. In this study, we found that the miR-144 expression level is significantly decreased in bladder cancer cell lines as well as in clinical cancer tissues. miR-144 inhibitor blocks the expression of endogenous miR-144 and promotes cancer cell proliferation, whereas miR-144 overexpression is sufficient to inhibit cell proliferation. We further demonstrated that enhancer of zeste homolog 2 (EZH2) is a target gene of miR-144. miR-144 downregulation relieves miR-144-mediated repression of EZH2, which results in activation of Wnt/beta-catenin signaling and subsequent cell proliferation. These data suggest miR-144 is an essential mediator of bladder cancer cell proliferation, thus offering a new target for the development of therapeutic agents against bladder cancer. PMID- 23815093 TI - Dopaminergic medication counteracts conflict adaptation in patients with Parkinson's disease. AB - OBJECTIVE: We tested the role of dopamine in conflict-induced behavioral adjustments by evaluating the effect of dopaminergic medication on conflict adaptation in Parkinson's disease (PD) patients. METHOD: Nine PD patients performed a vocal Stroop task on two separate testing occasions: once on their regular medication and once after overnight withdrawal. RESULTS: In line with previous studies (e.g., Bonnin, Houeto, Gil, & Bouquet, 2010), patients displayed no conflict adaptation when tested on medication. However, the same patients tested off of their medication did display a conflict adaptation effect in that the size of the interference effect was reduced after incongruent trials compared with after congruent trials. CONCLUSIONS: This difference is discussed in terms of an inverted U-shaped relation between dopamine and performance, according to which dopaminergic medication has detrimental effects on PD patients' performance by overdosing brain regions that are relatively spared in the initial stage of the disease, including the ventral striatum and prefrontal cortex. PMID- 23815092 TI - Predictive validity of dynamic factors: assessing violence risk in forensic psychiatric inpatients. AB - There is general consensus that dynamic factors ought to be considered in the assessment of violence risk, but little direct evidence exists to demonstrate that within-individual fluctuations in putative dynamic factors are associated with changes in risk. We examined these issues in a sample of 30 male forensic psychiatric inpatients using a pseudoprospective design. Static and dynamic factors were coded on the basis of chart review using 2 structured measures of violence risk: Version 2 of the Historical-Clinical-Risk Management-20 (HCR-20; C. D. Webster, K. S. Douglas, D. Eaves, & S. D. Hart, 1997, HCR-20: Assessing risk for violence, Version 2, Vancouver, BC, Canada: Mental Health, Law, and Policy Institute, Simon Fraser University) and the Short-Term Assessment of Risk and Treatability (START; C. D. Webster, M. L. Martin, J. Brink, T. L. Nicholls, & S. L. Desmarais, 2009, Short-Term Assessment of Risk and Treatability [START], Version 1.1, Coquitlam, BC, Canada: British Columbia Mental Health and Addiction Services). HCR-20 and START assessments were repeated every 3 months for a period of 1 year. Institutional violence in the 3 months following each assessment was coded using a modified version of the Overt Aggression Scale (S. C. Yudofsky, J. M. Silver, W. Jackson, J. Endicott, & D. W. Williams, 1986, The Overt Aggression Scale for the objective rating of verbal and physical aggression, The American Journal of Psychiatry, Vol. 143, pp. 35-39). Dynamic risk and strength factors showed predictive validity for institutional aggression. Results of event history analyses demonstrated that changes in dynamic risk factors significantly predicted institutional violence, even after controlling for static risk factors. This is one of the first studies to provide clear and direct support for the utility of dynamic factors in the assessment of violence risk. PMID- 23815094 TI - Galactose-decorated reduction-sensitive degradable chimaeric polymersomes as a multifunctional nanocarrier to efficiently chaperone apoptotic proteins into hepatoma cells. AB - Hepatoma-targeting reduction-sensitive chimaeric biodegradable polymersomes were designed and developed based on galactose-poly(ethylene glycol)-poly(epsilon caprolactone) (Gal-PEG-PCL), PEG-PCL-poly(2-(diethylamino)ethyl methacrylate) (PEG-PCL-PDEA, asymmetric), and PEG-SS-PCL for facile loading and triggered intracellular delivery of proteins. The chimaeric polymersomes formed from PEG PCL-PDEA and PEG-SS-PCL had a monodisperse distribution with average sizes ranging from 95.5 to 199.2 nm depending on PEG-SS-PCL contents. Notably, these polymersomes displayed decent loading of bovine serum albumin (BSA), ovalbumin (OVA), and cytochrome C (CC) proteins likely due to presence of electrostatic and hydrogen bonding interactions between proteins and PDEA block located in the interior of polymersomes. The in vitro release studies showed that protein release was largely accelerated under a reductive condition containing 10 mM dithiothreitol (DTT). For example, ca. 77.2 and 22.1% of FITC-BSA were released from CP(SS50) (chimaeric polymersomes containing 50 wt % PEG-SS-PCL) at 37 degrees C in 12 h in the presence and absence of 10 mM DTT, respectively. Confocal microscopy showed that FITC-CC-loaded Gal-decorated CP(SS40) could efficiently deliver and release FITC-CC into HepG2 cells following 24 h treatment, in contrast to little or negligible fluorescence detected in HepG2 cells treated with FITC-CC-loaded nontargeting polymersomes or free CC. MTT assays revealed that CC-loaded Gal-decorated CP(SS40) exhibited apparent targetability and pronounced antitumor activity to HepG2 cells, in which cell viabilities decreased from 81.9, 60.6, 49.5, 42.2 to 31.5% with increasing Gal PEG-PCL contents from 0, 10, 20, 30 to 40 wt %. Most remarkably, granzyme B loaded Gal-decorated chimaeric polymersomes effectively caused apoptosis of HepG2 cells with a markedly low half-maximal inhibitory concentration (IC(50)) of 2.7 nM. These reduction-responsive chimaeric biodegradable polymersomes offer a multifunctional platform for efficient intracellular protein delivery. PMID- 23815095 TI - Gold(I) complexes of tetrathiaheterohelicene phosphanes. AB - New tetrathia[7]helicene-based (7-TH-based) gold(I) complexes 6 and 7 have been readily prepared by reaction of the respective phosphine ligands 2 and 3 with Au(tht)Cl in a 1:1 and 1:2 molar ratio, respectively. These complexes have been fully characterized by analytical and spectroscopic techniques as well as quantum chemical calculations. The molecular structure of dinuclear complex 7 has been determined by single-crystal X-ray diffraction, showing a gold-gold interaction of 3.1825(3) A and a significant contraction of the 7-TH total dihedral angle. Au(I) complex 7 displays luminescence emission at room and low temperature in diluted solution and in the solid state. Quantum chemical calculations show that the luminescence emission at room temperature is primarily due to slightly perturbed fluorescence emission from purely pipi* excited states of the conjugated helicene scaffold. At 77 K phosphorescence emission is displayed as well. Preliminary studies on the use of 6 and 7 as catalysts in typical Au(I) catalyzed cycloisomerizations have demonstrated the reactivity of these systems in the intramolecular allene hydroarylations and the hydroxycarboxylation of allene-carboxylates. PMID- 23815096 TI - Mild and highly selective palladium-catalyzed monoarylation of ammonia enabled by the use of bulky biarylphosphine ligands and palladacycle precatalysts. AB - A method for the Pd-catalyzed arylation of ammonia with a wide range of aryl and heteroaryl halides, including challenging five-membered heterocyclic substrates, is described. Excellent selectivity for monoarylation of ammonia to primary arylamines was achieved under mild conditions or at rt by the use of bulky biarylphosphine ligands (L6, L7, and L4) as well as their corresponding aminobiphenyl palladacycle precatalysts (3a, 3b, and 3c). As this process requires neither the use of a glovebox nor high pressures of ammonia, it should be widely applicable. PMID- 23815097 TI - Highly sensitive SERS quantification of the oncogenic protein c-Jun in cellular extracts. AB - A surface-enhanced Raman scattering (SERS)-based sensor was developed for the detection of the oncoprotein c-Jun at nanomolar levels. c-Jun is a member of the bZIP (basic zipper) family of dimeric transcriptional activators, and its overexpression has been associated with carcinogenic mechanisms in several human cancers. For our sensing purpose, we exploited the ability of c-Jun to heterodimerize with its native protein partner, c-Fos, and therefore designed a c Fos peptide receptor chemically modified to incorporate a thiophenol (TP) group at the N-terminal site. The TP functionality anchors the c-Fos protein onto the metal substrate and works as an effective SERS probe to sense the structural rearrangements associated with the c-Fos/c-Jun heterodimerization. PMID- 23815099 TI - Magnetic separation of malaria-infected red blood cells in various developmental stages. AB - Malaria is a serious disease that threatens the public health, especially in developing countries. Various methods have been developed to separate malaria infected red blood cells (i-RBCs) from blood samples for clinical diagnosis and biological and epidemiological research. In this study, we propose a simple and label-free method for separating not only late-stage but also early-stage i-RBCs on the basis of their paramagnetic characteristics due to the malaria byproduct, hemozoin, by using a magnetic field gradient. A polydimethylsiloxane (PDMS) microfluidic channel was fabricated and integrated with a ferromagnetic wire fixed on a glass slide. To evaluate the performance of the microfluidic device containing the ferromagnetic wire, lateral displacement of NaNO2-treated RBCs, which also have paramagnetic characteristics, was observed at various flow rates. The results showed excellent agreement with theoretically predicted values. The same device was applied to separate i-RBCs. Late-stage i-RBCs (trophozoites and schizonts), which contain optically visible black dots, were separated with a recovery rate of approximately 98.3%. In addition, using an optimal flow rate, early-stage (ring-stage) i-RBCs, which had been difficult to separate because of their low paramagnetic characteristics, were successfully separated with a recovery rate of 73%. The present technique, using permanent magnets and ferromagnetic wire in a microchannel, can effectively separate i-RBCs in various developmental stages so that it could provide a potential tool for studying the invasion mechanism of the malarial parasite, as well as performing antimalarial drug assays. PMID- 23815098 TI - Biodegradable drug-eluting poly[lactic-co-glycol acid] nanofibers for the sustainable delivery of vancomycin to brain tissue: in vitro and in vivo studies. AB - Successful treatment of a brain infection requires aspiration of the pus or excision of the abscess, followed by long-term (usually 4-8 weeks) parenteral antibiotic treatment. Local antibiotic delivery using biodegradable drug impregnated carriers is effective in treating postoperative infections, thereby reducing the toxicity associated with parenteral antibiotic treatment and the expense involved with long-term hospitalization. We have developed vancomycin loaded, biodegradable poly[lactic-co-glycol acid] nanofibrous membranes for the sustainable delivery of vancomycin to the brain tissue of rats by using the electrospinning technique. A high-performance liquid chromatography assay was employed to characterize the in vitro and in vivo release behaviors of pharmaceuticals from the membranes. The experimental results suggested that the biodegradable nanofibers can release high concentrations of vancomycin for more than 8 weeks in the cerebral cavity of rats. Furthermore, the membranes can cover the wall of the cavity after the removal of abscess more completely and achieve better drug delivery without inducing adverse mass effects in the brain. Histological examination also showed no inflammation reaction of the brain tissues. By adopting the biodegradable, nanofibrous drug-eluting membranes, we will be able to achieve long-term deliveries of various antibiotics in the cerebral cavity to enhance the therapeutic efficacy of cerebral infections. PMID- 23815100 TI - 3-substituted indole inhibitors against Francisella tularensis FabI identified by structure-based virtual screening. AB - In this study, we describe novel inhibitors against Francisella tularensis SchuS4 FabI identified from structure-based in silico screening with integrated molecular dynamics simulations to account for induced fit of a flexible loop crucial for inhibitor binding. Two 3-substituted indoles, 54 and 57, preferentially bound the NAD(+) form of the enzyme and inhibited growth of F. tularensis SchuS4 at concentrations near that of their measured Ki. While 57 was species-specific, 54 showed a broader spectrum of growth inhibition against F. tularensis , Bacillus anthracis , and Staphylococcus aureus . Binding interaction analysis in conjunction with site-directed mutagenesis revealed key residues and elements that contribute to inhibitor binding and species specificity. Mutation of Arg-96, a poorly conserved residue opposite the loop, was unexpectedly found to enhance inhibitor binding in the R96G and R96M variants. This residue may affect the stability and closure of the flexible loop to enhance inhibitor (or substrate) binding. PMID- 23815101 TI - Understanding and addressing socio-cultural barriers to medical male circumcision in traditionally non-circumcising rural communities in sub-Saharan Africa. AB - Given recent clinical trials establishing the safety and efficacy of adult medical male circumcision (MMC) in Africa, attention has now shifted to barriers and facilitators to programmatic implementation in traditionally non-circumcising communities. In this study, we attempted to develop a fuller understanding of the role of cultural issues in the acceptance of adult circumcision. We conducted four focus-group discussions with 28 participants in Mutoko, Zimbabwe, and 33 participants in Vulindlela, KwaZulu-Natal, South Africa, as well as 19 key informant interviews in both settings. We found the concept of male circumcision to be an alien practice, particularly as expressed in the context of local languages. Cultural barriers included local concepts of ethnicity, social groups, masculinity and sexuality. On the other hand, we found that concerns about the impact of HIV on communities resulted in willingness to consider adult male circumcision as an option if it would result in lowering the local burden of the epidemic. Adult MMC-promotional messages that create a synergy between understandings of both traditional and medical circumcision will be more successful in these communities. PMID- 23815103 TI - Efficacy, safety, and optimal dose selection of beclomethasone dipropionate nasal aerosol for seasonal allergic rhinitis in adolescents and adults. AB - OBJECTIVE: Some patients with allergic rhinitis (AR) may prefer nonaqueous intranasal corticosteroid aerosols because of unwanted attributes of aqueous formulations. The mandatory removal of chlorofluorocarbon-propelled nonaqueous aerosols from the market limited available treatment options. To fulfill this unmet need, a nonaqueous, hydrofluoroalkane-propelled beclomethasone dipropionate (BDP) nasal aerosol was developed and approved for treatment of AR nasal symptoms. As part of the development program, this dose-ranging study evaluated three doses of BDP nasal aerosol to determine the optimally safe and effective dose for adolescent and adult patients (>=12 years old) with seasonal AR (SAR). METHODS: After a 7 to 21 day placebo run-in period, eligible patients with SAR were randomly assigned to once-daily BDP nasal aerosol 80 ug, 160 ug, 320 ug, or placebo. The primary endpoint was the change from baseline in average a.m. and p.m. patient-reported reflective total nasal symptom scores (rTNSS) over 2 weeks. Safety and tolerability were also assessed. A potential study limitation could be lack of objective assessment of AR symptoms. RESULTS: Significant improvements were seen in average a.m. and p.m. rTNSS (least squares [LS] mean treatment difference, -0.63; 95% CI: -1.13, -0.13; p = 0.013) as well as in average a.m. and p.m. instantaneous TNSS (iTNSS; LS mean treatment difference, -0.60; 95% CI: 1.09, -0.11; p = 0.016) with BDP nasal aerosol 320 ug/day compared with placebo. Although there were numerical improvements from baseline in patient-reported rTNSS and iTNSS with BDP nasal aerosol 80 ug and 160 ug, these doses did not achieve statistical significance compared with placebo. BDP nonaqueous nasal aerosol was well tolerated at all doses tested, with a safety profile comparable to that of placebo. CONCLUSIONS: These data indicate that 320 ug/day of BDP nasal aerosol is the optimally safe and effective dose for the treatment of SAR in adolescent and adult patients. Trial registration NCT: #NCT00854360. PMID- 23815102 TI - Protective role of IL-6 in vascular remodeling in Schistosoma pulmonary hypertension. AB - Schistosomiasis is one of the most common causes of pulmonary arterial hypertension worldwide, but the pathogenic mechanism by which the host inflammatory response contributes to vascular remodeling is unknown. We sought to identify signaling pathways that play protective or pathogenic roles in experimental Schistosoma-induced pulmonary vascular disease via whole-lung transcriptome analysis. Wild-type mice were experimentally exposed to Schistosoma mansoni ova by intraperitoneal sensitization followed by tail-vein augmentation, and the phenotype was assessed by right ventricular catheterization and tissue histology, as well as RNA and protein analysis. Whole-lung transcriptome analysis by microarray and RNA sequencing was performed, and RNA sequencing was analyzed according to two bioinformatics methods. Functional testing of the candidate IL-6 pathway was determined using IL-6 knockout mice and the signal transducers and activators of transcription protein-3 (STAT3) inhibitor S3I-201. Wild-type mice exposed to S. mansoni demonstrated increased right ventricular systolic pressure and thickness of the pulmonary vascular media. Whole-lung transcriptome analysis determined that the IL-6-STAT3-nuclear factor of activated T cells c2(NFATc2) pathway was up-regulated, as confirmed by PCR and the immunostaining of lung tissue from S. mansoni-exposed mice and patients who died of the disease. Mice lacking IL-6 or treated with S3I-201 developed pulmonary hypertension, associated with significant intima remodeling after exposure to S. mansoni. Whole-lung transcriptome analysis identified the up-regulation of the IL-6-STAT3-NFATc2 pathway, and IL-6 signaling was found to be protective against Schistosoma induced intimal remodeling. PMID- 23815104 TI - Predictors of medication adherence in patients with type 2 diabetes mellitus. AB - OBJECTIVE: Medical professionals are often challenged by lack of patient compliance with pharmaceutical treatments. Research has shown that patients with diabetes have one of the lowest medication adherence rates at 65% to 85%. Some causes have been identified in the literature, but the influence of type of medication is unknown. This study assessed the impact of a broad range of factors on medication adherence and persistence among adult patients with type 2 diabetes mellitus. METHODS: Patients were selected from the Truven Health MarketScan Research Databases of healthcare administrative claims (2009 through 2012), assigned to mutually exclusive cohorts based on initiation of saxagliptin (a dipeptidyl peptidase-4 [DPP-4] inhibitor), or a glucagon-like peptide 1 (GLP-1) receptor agonist (daily or twice daily formulation), sulfonylurea (SU), or thiazolidinedione (TZD), and screened for continuous enrollment 1 year before and after drug initiation. Adherence and persistence were measured using proportion of days covered and time to discontinuation, respectively. Multivariate models were used to examine the impact of study drug and demographic and clinical factors. RESULTS: Overall, 45.1% of patients were adherent with their study drug over the 1 year follow-up period. Adherence was higher among patients who were male, older, or residing in non-Southern states. Adherence was better with mail order use and lower levels of cost sharing. Patients taking a GLP-1 (OR = 0.40, 95% CI = 0.37, 0.42), SU (OR = 0.49, 95% CI = 0.46, 0.52), or TZD (OR = 0.54, 95% CI = 0.51, 0.57) were less likely to be adherent compared with those taking saxagliptin. Results were mixed regarding the impact of comorbidities and polypharmacy on medication adherence. Influencing factors may be the type of comorbidity, overall health level, number of drugs, and complexity of the drug regimen. KEY LIMITATIONS: Adherence was measured using data for prescriptions dispensed and it is not known whether patients actually took the medications, hence adherence may be overestimated. Whether patients who discontinued the study drugs switched to other diabetes medications or discontinued treatment completely was not measured. CONCLUSION: Identified risk factors can guide medical professionals in their attempts to increase the likelihood of patient adherence to drug treatment regimens. PMID- 23815105 TI - Could FEV1 decline have a role in daily clinical practice for asthma monitoring? AB - OBJECTIVE: The aim of this review was to understand whether FEV1 decline measured during the follow-up of asthmatic subjects (FEV1 variation between two different measurements at a distance of at least 5 years) may have a role in their management. METHODS: Articles, commentaries and reviews relating to the topic were searched in PubMed. RESULTS: Patients with an accelerated FEV1 decline (>30 ml/year) may be either steroid-resistant/difficult-to-treat asthmatics or not adequately treated because they are either under-perceivers or poorly adherent to their therapy. Sometimes they may be unable to use devices correctly. Untreated rhinitis and incorrect lifestyle (obesity status, a high-fat diet and lack of exercise) must be considered when facing a pulmonary function decline. Identifying asthmatics with an accelerated FEV1 decline, even with well controlled symptoms, may allow us to make possible treatment adjustments or to remove potentially harmful environmental exposure and suggest a correct lifestyle. Depending on FEV1 decline severity, we may detect different asthma phenotypes. One type is characterized by no/low lung function reduction. Among moderate/severe 'declining' subjects, there may be a group that might be responsive to treatment and a second one with a quicker loss in lung function that may be unresponsive to therapy. CONCLUSION: FEV1 decline calculation should be assessed early in clinical practice over the course of time in order to make all possible variations in treatment, environmental exposure and lifestyle more efficacious overall for declining subjects responsive to anti-inflammatory therapy. Further studies are necessary to validate this approach to asthma. PMID- 23815106 TI - Activation of 5-hydroxytryptamine1B/1D/1F receptors as a mechanism of action of antimigraine drugs. AB - INTRODUCTION: The introduction of the triptans (5-hydroxytryptamine (5-HT)1B/1D receptor agonists) was a great improvement in the acute treatment of migraine. However, shortcomings of the triptans have prompted research on novel serotonergic targets for the treatment of migraine. AREAS COVERED: In this review the different types of antimigraine drugs acting at 5-HT receptors, their discovery and development are discussed. The first specific antimigraine drugs were the ergot alkaloids, consisting of ergotamine, dihydroergotamine and methysergide, which are agonists at 5-HT receptors, but can also bind alpha adrenoceptors and dopamine receptors. In the 1990s, the triptans became available on the market. They are 5-HT1B/1D receptor agonists, showing fewer side effects due to their receptor specificity. In the last years, compounds that bind specifically to 5-HT1D, 5-HT1F and 5-HT7 receptors have been explored for their antimigraine potential. Furthermore, the serotonergic system seems to act in tight connection with the glutamatergic as well as the CGRP-ergic systems, which may open novel therapeutic avenues. EXPERT OPINION: Although the triptans are very effective in treating migraine attacks, their shortcomings have stimulated the search for novel drugs. Currently, the focus is on 5-HT1F receptor agonists, which seem devoid of vascular side effects. Moreover, novel compounds that affect multiple transmitter and/or neuropeptide systems that are involved in migraine could be of therapeutic relevance. PMID- 23815107 TI - Tracking change through treatment with the Inventory of Offender Risk, Needs, and Strengths. AB - Dynamic risk variables (or criminogenic needs; Andrews & Bonta, 2003) increase risk for criminal behavior and are conceptualized as changeable through intervention. Yet this assumption of changeability has been examined in only a few studies, and none of these studies have examined whether the measurement properties the risk assessments measure remain invariant over time--a necessary precursor to determining if actual change is occurring or if changes in measurement are producing differences. This study examines the dynamic needs index (DNI) and protective strengths index (PSI) of the inventory of offender risk, needs, and strengths (Miller, 2006b) pre- and post-treatment. Findings suggest the measurement properties of the DNI are acceptably invariant over time, although there is evidence that the intercept of the alcohol/drug Problems scale is higher after (opposed to before) treatment and the intercept of the Intra/Interpersonal Problems scale is higher before treatment. Subsequent latent difference score models suggest--as expected--that the dynamic needs latent variable decreased and the protective strengths latent variable increased through treatment. This study presents first evidence for invariance of measurement properties of a risk assessment measure at different points in treatment. PMID- 23815108 TI - Experimental manipulation of working memory model parameters: an exercise in construct validity. AB - As parametric cognitive models become more commonly used to measure individual differences, the construct validity of the interpretation of individual model parameters needs to be well established. The validity of the interpretation of 2 parameters of a formal model of the Continuous Recognition Memory Test (CRMT) was investigated in 2 experiments. The 1st study found that manipulating the percentage of trials on the CRMT for which degraded pseudowords were presented altered the model's stimulus encoding parameter but not the working memory displacement parameter. The 2nd experiment showed that manipulating the number of syllables forming a pseudoword altered the model's working memory displacement parameter for each syllable added to the pseudoword. Findings from both experiments supported the construct representation of the model parameters, supporting the construct validity of the model's use to interpret CRMT performance. Combining parametric models with the manipulation of factors that theory predicts are related to model parameters provides an approach to construct validation that bridges experimental and individual difference methods of studying human cognition. PMID- 23815109 TI - The Child PTSD Symptom Scale: an update and replication of its psychometric properties. AB - The psychometric properties of the child PTSD Symptom Scale (CPSS) were examined in 2 samples. Sample 1 (N = 185, ages 6-17 years) consisted of children recruited from hospitals after accidental injury, assault, and road traffic trauma, and assessed 6 months posttrauma. Sample 2 (N = 68, ages 6-17 years) comprised treatment-seeking children who had experienced diverse traumas. In both samples psychometric properties were generally good to very good (internal reliability for total CPSS scores = .83 and .90, respectively). The point-biserial correlation of the CPSS with posttraumatic stress disorder (PTSD) diagnosis derived from structured clinical interview was .51, and children diagnosed with PTSD reported significantly higher symptoms than non-PTSD children. The CPSS demonstrated applicability to be used as a diagnostic measure, demonstrating sensitivity of 84% and specificity of 72%. The performance of the CPSS Symptom Severity Scale to accurately identify PTSD at varying cutoffs is reported in both samples, with a score of 16 or above suggested as a revised cutoff. PMID- 23815110 TI - Psychophysiological assessment of PTSD: a potential research domain criteria construct. AB - Most research on posttraumatic stress disorder (PTSD) relies on clinician administered interview and self-report measures to establish the presence/absence and severity of the disorder. Accurate diagnosis of PTSD is made challenging by the presence of symptoms shared with other psychopathologies and the subjective nature of patients' descriptions of their symptoms. A physiological assessment capable of reliably "diagnosing" PTSD could provide adjunctive information that might mitigate these diagnostic limitations. In the present study, we examined the construct validity of a potential psychophysiological measure of PTSD, that is, psychophysiological reactivity to script-driven imagery (SDI-PR), as measured against the current diagnostic "gold-standard" for PTSD, the Clinician Administered PTSD Scale (CAPS). Convergent and predictive validity and stability were examined. Thirty-six individuals completed an SDI-PR procedure, the CAPS, and self-report measures of mental and physical health at their initial visit and approximately 6 months later. SDI-PR and the CAPS demonstrated excellent stability across measurement occasions. SDI-PR showed moderately strong convergent validity with the CAPS. After adjusting for self-reported depression, predictive validity for the CAPS, with regard to health sequelae, was reduced, whereas it remained mostly unchanged for SDI-PR. Findings support SDI-PR as a valid and stable measure of PTSD that captures a pathophysiologic process in individuals with PTSD. Results are discussed with regard to the research domain criteria framework. PMID- 23815112 TI - The impact of acquiescence on the evaluation of personality structure. AB - Acquiescence, or the tendency to respond to descriptions of conceptually distinct personality attributes with agreement/affirmation (acceptance acquiescence) or disagreement/opposition (counter-acquiescence), has been widely recognized as a source of bias that can substantially alter interitem correlations within scales. Acquiescence is also known to operate differently among some groups of persons; it is, for example, more pronounced among individuals with less formal education. Consequently, the biasing effects of acquiescence are of particular concern when the dimensionality underlying the item set of a measure is examined with representative samples comprised of persons with varying levels of educational attainment and evaluated with correlation-based statistical methods such as factor analysis. In the present study, we extended our earlier research by investigating the biasing effect of acquiescence on personality factor structures derived from the full-scale version of the Big Five Inventory (BFI) when administered to a large sample (N = 1,427) selected to be representative of Germany's adult population. Consistent with previous findings based on a short scale version of the BFI, factor analyses of the unadjusted BFI item set failed to replicate the expected Big Five-factor structure in the low/medium and high educational groups, with distortions in factor structure more pronounced in the former group. Once acquiescence was controlled in the item responses for both groups, however, the obtained factor structures were consistent with the Big Five framework. The implications of acquiescence on the evaluation of the factor structure of personality inventories and for the validity of personality assessments are discussed. PMID- 23815111 TI - Retrospective validation of WTAR and NART scores as estimators of prior cognitive ability using the Lothian Birth Cohort 1936. AB - In order to assess the degree of cognitive decline resulting from a pathological state, such as dementia, or from a normal aging process, it is necessary to know or to have a valid estimate of premorbid (or prior) cognitive ability. The National Adult Reading Test (NART; Nelson & Willison, 1991) and the Wechsler Test of Adult Reading (WTAR; Psychological Corporation, 2001) are 2 tests developed to estimate premorbid or prior ability. Due to the rarity of actual prior ability data, validation studies usually compare NART/WTAR performance with measures of current abilities in pathological and nonpathological groups. In this study, we validate the use of WTAR scores and extend the validation of the use of NART scores as estimates of prior ability, vis-a-vis the actual prior (childhood) cognitive ability. We do this in a large sample of healthy older people, the Lothian Birth Cohort 1936 (Deary, Gow, Pattie, & Starr, 2012; Deary et al., 2007). Both NART and WTAR scores were correlated with cognitive ability tested in childhood (r = .66-.68). Scores on both the NART and the WTAR had high stability over a period of 3 years in old age (r in excess of .90) and high interrater reliability. The NART accounted for more unique variance in childhood intelligence than did the WTAR. PMID- 23815113 TI - Invalid responding in questionnaire-based research: implications for the study of schizotypy. AB - Data collected through self-report questionnaires are particularly susceptible to inappropriate or random responding, and such invalid data increase noise and attenuate true statistical relationships. While many researchers studying schizotypy have employed infrequency measures to exclude participants, such measures are not universally employed. Moreover, some researchers have even outright questioned whether validity scales are warranted. Here, we show the effect of invalid responses on the relationship between schizotypy and hedonic reaction. For valid responders, negative schizotypal traits were inversely related to both anticipatory and consummatory pleasure (p < .01). Invalid responses were found for 23% of respondents, and within these subjects, no relationship was found between any of the measures. When the valid and invalid respondents were pooled, the relationship was dampened. Furthermore, linear multiple regression modeling showed that validity trended toward moderating the relationship between the variables of interest. These data highlight the importance of screening for, and excluding, invalid responses in schizotypy research. Our results also affirm that screening for random responding is effective and warranted. Implications for future studies employing questionnaire based methods are discussed. PMID- 23815114 TI - Personality assessment in a diverse urban sample. AB - In the present research, the authors examined the data quality and replicability of the revised NEO personality inventory (NEO-PI-R) factor structure in a sample that varied in ethnicity, socioeconomic status, and literacy. Participants (N = 546), drawn from the Healthy aging in neighborhoods of diversity across the life span study, were African American (58%) and white (42%) urban dwellers living above (49%) and below (51%) 125% of the federal poverty line. The NEO-PI-R, administered via telephone, was evaluated for data quality (percent valid, acquiescence, internal consistency), congruence with the normative factor structure, and readability. All indices of data quality and factor congruence were excellent in the full sample. Literacy was the most consistent predictor of data quality. A slightly worse structure was found for the Openness to Experience and Extraversion factors among lower socioeconomic status African American and white participants. The overall index of factor congruence, however, supports replication of the normative structure well beyond chance levels even among those with lower literacy. Despite the challenges of low literacy, the present findings indicate that personality traits can be assessed reliably in socioeconomically diverse populations that include those living in poverty. PMID- 23815115 TI - Is pedophilic sexual preference continuous? A taxometric analysis based on direct and indirect measures. AB - The present study addressed the question of whether deviant sexual preferences for children can be considered a taxon, utilizing data from a multimethod assessment battery. The test battery comprised direct self-report as well as indirect latency-based measures (Implicit Association Tests, viewing time) of deviant sexual preferences for children. In a mixed sample of adult men (N = 304, including sex offenders against children, sex offenders against adults, and controls who were either nonsexual offenders or nonoffenders), 27% of the offenders convicted for child sexual abuse or child pornography charges were identified as a homogeneous and distinct latent class. Additional taxometric analyses corroborated the notion of a pedophilic subgroup. Individuals in this pedophilic group showed elevated scores on measures of deviant sexual preference for children over adults. The offense histories of the individuals from the pedophilic cluster indicated an increased likelihood of pedophilic preference as assessed by a file-based summary index. We interpret the results as evidence for pedophilic sexual preference as a distinct and taxonic clinical construct. PMID- 23815116 TI - Development and validation of the Eating Pathology Symptoms Inventory (EPSI). AB - Many current measures of eating disorder (ED) symptoms have 1 or more serious limitations, such as inconsistent factor structures or poor discriminant validity. The goal of this study was to overcome these limitations through the development of a comprehensive multidimensional measure of eating pathology. An initial pool of 160 items was developed to assess 20 dimensions of eating pathology. The initial item pool was administered to a student sample (N = 433) and community sample (N = 407) to determine the preliminary structure of the measure using exploratory and confirmatory factor analyses. The revised measure was administered to independent samples of patients recruited from specialty ED treatment centers (N = 158), outpatient psychiatric clinics (N = 303), and students (N = 227). Analyses revealed an 8-factor structure characterized by Body Dissatisfaction, Binge Eating, Cognitive Restraint, Excessive Exercise, Restricting, Purging, Muscle Building, and Negative Attitudes Toward Obesity. Scale scores showed excellent convergent and discriminant validity; other analyses demonstrated that the majority of scales were invariant across sex and weight categories. Eating Pathology Symptoms Inventory scale scores had excellent internal consistency (median coefficient alphas ranged from .84-.89) and reliability over a 2- to 4-week period (mean retest r = .73). The current study represents one of the most comprehensive scale development projects ever conducted in the field of EDs and will enhance future basic and treatment research focused on EDs. PMID- 23815117 TI - Direct assessment of children's social-emotional comprehension. AB - Social-emotional comprehension includes the ability to encode, interpret, and reason about social-emotional information. The better developed children's social emotional comprehension, the more positive their social interactions and the better their peer relationships. Many clinical tools exist to assess children's social behavior. In contrast, fewer clinically interpretable tools are available to assess children's social-emotional comprehension. This study evaluated the psychometric properties of a group of direct assessments of social-emotional comprehension. Scores on these assessments reflected children's performance on challenging tasks that required them to demonstrate their social-emotional comprehension. In 2 independent samples, including a general education school sample (n = 174) and a clinic sample (n = 119), this study provided evidence that (a) individual assessments yield variably reliable scores, (b) composite scores are highly reliable, (c) direct assessments demonstrate a theoretically coherent factor structure and convergent and discriminant validity, and (d) composite scores yield expected age- and diagnostic-group differences. Implications for clinical practice, theory, and assessment development are discussed. PMID- 23815118 TI - Youth Offender Care Needs Assessment Tool (YO-CNAT): an actuarial risk assessment tool for predicting problematic child-rearing situations in juvenile offenders on the basis of police records. AB - In the juvenile justice system, much attention is paid to estimating the risk for recidivism among juvenile offenders. However, it is also important to estimate the risk for problematic child-rearing situations (care needs) in juvenile offenders, because these problems are not always related to recidivism. In the present study, an actuarial care needs assessment tool for juvenile offenders, the Youth Offender Care Needs Assessment Tool (YO-CNAT), was developed to predict the probability of (a) a future supervision order imposed by the child welfare agency, (b) a future entitlement to care indicated by the youth care agency, and (c) future incidents involving child abuse, domestic violence, and/or sexual norm trespassing behavior at the juvenile's address. The YO-CNAT has been developed for use by the police and is based solely on information available in police registration systems. It is designed to assist a police officer without clinical expertise in making a quick assessment of the risk for problematic child-rearing situations. The YO-CNAT was developed on a sample of 1,955 juvenile offenders and was validated on another sample of 2,045 juvenile offenders. The predictive validity (area under the receiver-operating-characteristic curve) scores ranged between .70 (for predicting future entitlement to care) and .75 (for predicting future worrisome incidents at the juvenile's address); therefore, the predictive accuracy of the test scores of the YO-CNAT was sufficient to justify its use as a screening instrument for the police in deciding to refer a juvenile offender to the youth care agency for further assessment into care needs. PMID- 23815119 TI - A test of two brief measures of grandiose narcissism: the narcissistic personality inventory-13 and the narcissistic personality inventory-16. AB - The most widely used measure of trait narcissism is the Narcissistic Personality Inventory (NPI), which can provide both total and subscale scores. However, with a length of 40 items, this measure may not be ideal in settings in which time or participant attention may limit the types of measures that can be administered. In response, Ames, Rose, and Anderson (2006) created the NPI-16, which provides a shorter, unidimensional measure of the construct. In the present research, we examine the reliability and validity of the NPI-16 in conjunction with a new short measure of narcissism, the NPI-13, which provides both a total score and 3 subscale scores (Leadership/Authority; Grandiose Exhibitionism; Entitlement/Exploitativeness). Across 2 studies, we demonstrate that both short measures manifest good convergent and discriminant validity and adequate overall reliability. The NPI-13 may be favored over the NPI-16 because it allows for the extraction of 3 subscales, consistent with the use of its parent measure. PMID- 23815120 TI - Psychometric properties of the Connor-Davidson Resilience Scale 10 among low income, African American men. AB - The Connor-Davidson Resilience Scale 10 (CD-RISC 10; Campbell-Sills & Stein, 2007) is a self-report measure of resilience that has been found to provide reliable and valid scores among U.S. and international samples, although its psychometric properties have not been validated among African Americans. This study used confirmatory factor analysis (CFA) and structural equation modeling to examine the psychometric properties of the CD-RISC 10 among a community sample of 127 low-income, African American men. Participants completed measures of resilience, spirituality, and psychological distress. CFA results supported the unidimensional factor structure of the CD-RISC 10. The CD-RISC 10 scores also evidenced construct validity by being related to theoretically relevant constructs (i.e., spirituality and psychological distress). Satisfactory internal consistency score reliability was demonstrated. These results support the validity of the CD-RISC 10 scores in a sample of low-income, African American men. PMID- 23815121 TI - The Basic Empathy Scale in adults (BES-A): factor structure of a revised form. AB - Initially thought of as a unitary ability, empathy has been more recently considered to consist of 2 components (i.e., an affective and a cognitive component). The Basic Empathy Scale (BES) is a tool that has been used to assess empathy in young people and adolescents on the basis of this dual-component conception (Jolliffe & Farrington, 2006). Recent studies of empathy have led to it being defined as underpinned by 3 components, namely, emotional contagion, emotional disconnection, and cognitive empathy. The aims of this study were (a) to validate the BES in Adults and (b) to compare the different conceptions of empathy. Three hundred seventy French adults took part in the study, and 160 of them filled out complementary scales measuring empathy, alexithymia, and emotional consciousness. The confirmatory factor analyses showed that the 3 factor model was the model that was best able to account for the data. Complementary tools confirmed the relationships previously observed between empathy as assessed with the BES and other scales assessing emotional processes. The results of this study make it clear that empathy can be seen as process dependent. This conception of empathy, which is based on 3 factors, is consistent with the current, more integrated view of empathy. The implications of this conception and the opportunity to use the 2 or 3 factors of the BES in adults are presented in the discussion. PMID- 23815123 TI - Linear combination test for gene set analysis of a continuous phenotype. AB - BACKGROUND: Gene set analysis (GSA) methods test the association of sets of genes with a phenotype in gene expression microarray studies. Many GSA methods have been proposed, especially methods for use with a binary phenotype. Equally, if not more importantly however, is the ability to test the enrichment of a gene signature or pathway against the continuous phenotypes which are routinely and commonly observed in, for example, clinicopathological measurements. It is not always easy or meaningful to dichotomize continuous phenotypes into two classes, and attempting to do this may lead to the inaccurate classification of samples, which would affect the downstream enrichment analysis. In the present study, we have build on recent efforts to incorporate correlation structure within gene sets and pathways into the GSA test statistic. To address the issue of continuous phenotypes directly without the need for artificial discrete classification and thus increase the power of the test while ensuring computational efficiency and rigor, new GSA methods that can incorporate a covariance matrix estimator for a continuous phenotype may present an effective approach. RESULTS: We have designed a new method by extending the GSA approach called Linear Combination Test (LCT) from a binary to a continuous phenotype. Simulation studies and a real microarray dataset were used to compare the proposed LCT for a continuous phenotype, a modification of LCT (referred to as LCT2), and two publicly available GSA methods for continuous phenotypes. CONCLUSIONS: We found that the LCT methods performed better than the other two GSA methods; however, this finding should be understood in the context of our specific simulation studies and the real microarray dataset that were used to compare the methods. Free R-codes to perform LCT for binary and continuous phenotypes are available at http://www.ualberta.ca/~yyasui/homepage.html. The R-code to perform LCT for a continuous phenotype is available as Additional file 1. PMID- 23815124 TI - Nitroglycerin 0.4% ointment vs placebo in the treatment of pain resulting from chronic anal fissure: a randomized, double-blind, placebo-controlled study. AB - BACKGROUND: Complications of chronic anal fissure (CAF) treatments are prompting interest in lower-risk therapies. This study was conducted to compare nitroglycerin (NTG) 0.4% ointment with placebo for pain associated with CAF. METHODS: In this randomized, double-blind, placebo-controlled trial, patients with one CAF and moderate-to-severe pain (>=50 mm on a 100 mm visual analog scale [VAS]) received 375 mg NTG 0.4% (1.5 mg active ingredient) or 375 mg placebo ointment applied anally every 12 hours for 21 days. The primary end point was change from baseline VAS score in 24-hour pain averaged over days 14-18. Review of data from patients who withdrew early was blinded to treatment. To control for the confounding effects of analgesics, all patients received 650 mg acetaminophen for headache prophylaxis before each application. RESULTS: A total of 247 patients were enrolled (NTG, n = 123; placebo, n = 124). The prespecified baseline observation carried forward (BOCF) analysis found no significant difference between groups; however, a last observation carried forward (LOCF) analysis showed a significant advantage for NTG. A post hoc analysis (LOCF/BOCF hybrid) demonstrated a significant adjusted mean difference of -7.0 mm in favor of NTG 0.4% (95% CI -13.6, -0.4; P = .038). Headache was the most common adverse event in the NTG (69.9%) and placebo (47.6%) groups. CONCLUSIONS: This was the first placebo-controlled study that also controlled for the confounding effects of analgesics used to treat NTG-induced headache. In patients with moderate-to severe CAF pain, NTG 0.4% ointment effectively reduced CAF pain compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00522041. PMID- 23815125 TI - epsilon-Decalactone: a thermoresilient and toughening comonomer to poly(L lactide). AB - The renewable monomer epsilon-decalactone is an excellent partner to L-lactide, where their copolymers overcome inherent drawbacks of polylactide, such as low thermal stability and brittleness. epsilon-Decalactone is a seven-membered lactone that was successfully polymerized with Sn(Oct)(2) and 1,5,7 triazabicyclo[4.4.0]dec-5-ene into both an amorphous homopolymer and copolymers with high molecular weight, low dispersity, and predicted macromolecular architecture. The thermoresilient nature of epsilon-decalactone is reflected in a high polymerization ceiling temperature and increased thermal stability for the prepared copolymers. The high ceiling temperature enables easy modulation of the polymerization rate via temperature while maintaining architectural control. The apparent rate constant was increased 15-fold when the temperature was increased from 110 to 150 degrees C. Copolymers of L-lactide and epsilon-decalactone, either with the latter as a central block in triblock polymers or with randomly positioned monomers, exhibited exceptionally tough material characteristics. The triblock copolymer had an elongation-at-break 250 times greater than that of pure poly(L-lactide). The toughness of the copolymers is attributed to the flexible nature of the polymer derived from the monomer epsilon-decalactone and to the segment immiscibility. These properties result in phase separation to soft and hard domains, which provides the basis for the elastomeric behavior. PMID- 23815126 TI - Protein localization prediction using random walks on graphs. AB - BACKGROUND: Understanding the localization of proteins in cells is vital to characterizing their functions and possible interactions. As a result, identifying the (sub)cellular compartment within which a protein is located becomes an important problem in protein classification. This classification issue thus involves predicting labels in a dataset with a limited number of labeled data points available. By utilizing a graph representation of protein data, random walk techniques have performed well in sequence classification and functional prediction; however, this method has not yet been applied to protein localization. Accordingly, we propose a novel classifier in the site prediction of proteins based on random walks on a graph. RESULTS: We propose a graph theory model for predicting protein localization using data generated in yeast and gram negative (Gneg) bacteria. We tested the performance of our classifier on the two datasets, optimizing the model training parameters by varying the laziness values and the number of steps taken during the random walk. Using 10-fold cross validation, we achieved an accuracy of above 61% for yeast data and about 93% for gram-negative bacteria. CONCLUSIONS: This study presents a new classifier derived from the random walk technique and applies this classifier to investigate the cellular localization of proteins. The prediction accuracy and additional validation demonstrate an improvement over previous methods, such as support vector machine (SVM)-based classifiers. PMID- 23815128 TI - Quadruply hydrogen bonding modules as highly selective nanoscale adhesive agents. AB - Covalently linking DNA base analogues DAN, DeUG, or UPy to glass slides led to functional surfaces that could be glued together using a functionalized polystyrene displaying the complementary recognition unit. Nonspecific adhesion was minimized with fluorinated alkane (Teflon-like or Scotchgard-like) surfaces. PMID- 23815129 TI - Fluorinated phosphorus-selenium heteroatom compounds: phenylphosphonofluorodiselenoic salts, adducts, and esters. AB - 2,4-Bis(phenyl)-1,3-diselenadiphosphetane-2,4-diselenide, [PhP(Se)(MU-Se)]2, Woollins' reagent (WR), reacts with dry KF or tetrabutylammonium fluoride (TBAF) at room temperature generating the corresponding potassium and tetrabutylammonium phenyldiselenofluorophosphinates 1 and 2 in almost quantitative yields. Treating 1 with equimolar amounts of tetraphenylphosphonium chloride or 1,3-dimesityl-1H imidazol-3-ium chloride in THF at room temperature afforded the corresponding organic adducts 3 and 4 in 90% and 87% yields. Reaction of 1 with mono- and dihalogenated alkanes gave a series of esters of phenylphosphonofluoridodiselenoates 5-8 and 9 in 79-93% yields. Two representative crystal structures are reported. PMID- 23815127 TI - Photoexpulsion of surface-grafted ruthenium complexes and subsequent release of cytotoxic cargos to cancer cells from mesoporous silica nanoparticles. AB - Ruthenium(II) polypyridyl complexes have emerged both as promising probes of DNA structure and as anticancer agents because of their unique photophysical and cytotoxic properties. A key consideration in the administration of those therapeutic agents is the optimization of their chemical reactivities to allow facile attack on the target sites, yet avoid unwanted side effects. Here, we present a drug delivery platform technology, obtained by grafting the surface of mesoporous silica nanoparticles (MSNPs) with ruthenium(II) dipyridophenazine (dppz) complexes. This hybrid nanomaterial displays enhanced luminescent properties relative to that of the ruthenium(II) dppz complex in a homogeneous phase. Since the coordination between the ruthenium(II) complex and a monodentate ligand linked covalently to the nanoparticles can be cleaved under irradiation with visible light, the ruthenium complex can be released from the surface of the nanoparticles by selective substitution of this ligand with a water molecule. Indeed, the modified MSNPs undergo rapid cellular uptake, and after activation with light, the release of an aqua ruthenium(II) complex is observed. We have delivered, in combination, the ruthenium(II) complex and paclitaxel, loaded in the mesoporous structure, to breast cancer cells. This hybrid material represents a promising candidate as one of the so-called theranostic agents that possess both diagnostic and therapeutic functions. PMID- 23815133 TI - Critical care nurses' perception of nursing error and its causes: a qualitative study. AB - Abstract Nurses' perceptions of nursing error could affect their professional practice. The aim of the study was to explore critical care nurses' perceptions of nursing error and its causes. This was a qualitative study in which 12 critical care nurses were recruited through purposive sampling. The data were collected via in-depth interviews and analyzed through qualitative content analysis method (Elo & Kyngas, 2008). Nursing error was deemed as an unavoidable issue which consisted of the lack of congruence with standards, doing extra nursing tasks and giving care against the agreed-upon routines. Five categories emerged as the causes of error: individual reasons, work pressure, caring blindly, the uniqueness of caring environment and the lack of coordination among health care team members. The perception of nursing error is sort of unique; hence, managers should provide support for critical care nurses and pave the way for the prevention of errors. PMID- 23815130 TI - Imaging diagnosis--Spontaneous subperiosteal vertebral hemorrhage in a greyhound. AB - A 4-year-old, spayed female greyhound dog was presented with an acute onset of paraplegia. There was no known history of trauma or coagulopathy. Spinal cord compression was identified on MRI. Intra-operative evaluation revealed the presence of a large subperiosteal hematoma and a smaller epidural hematoma. To the authors' knowledge, this is the first report of a spinal subperiosteal hematoma diagnosed antemortem through MRI, with surgical exploration and successful treatment in a dog. PMID- 23815135 TI - Piloting of an oral health education program and knowledge test for midwives. AB - Abstract Research shows limited emphasis being placed on oral health by midwives in Australia and the need for further education in this area. The study aim was to pilot a midwifery oral health education program and knowledge test and identify any flaws in its content and design. Twenty two midwives from an antenatal ward in South-western Sydney completed the program and 12 feedback forms/knowledge tests were returned. Data was analysed using descriptive statistics and content analysis. Feedback data showed all midwives appreciated that the program was available online and self-paced. Most found the program extremely informative and following completion were more confident in promoting maternal oral health. The mean correct responses in the knowledge test was 79 % (SD=12.3) which suggests most items were suitable for assessing knowledge improvement. However, in 3 items midwives had low correct responses. Various aspects that could be improved or clarified were identified and suggestions discussed. PMID- 23815140 TI - Hypoxia alters phosphorylation status of insulin-like growth factor (IGF)-binding protein-1 and attenuates biological activities of IGF-I in HepG2 cell cultures. AB - AIM: Insulin-like growth factor (IGF)-I is known to stimulate fetal growth. One of the IGF-binding proteins, IGFBP-1, suppresses IGF-I activity, and thereby inhibits fetal growth. Because hypoxic stress in the uterus is known to cause fetal growth restriction, we examined the effects of hypoxia on IGFBP-1 production and phosphorylation status. METHODS: Because liver is a main IGFBP-1 production site in the fetus, we used a hepatoma cell line, HepG2 cells, that secrete a large amount of IGFBP-1, express IGF-I receptors and model fetal liver metabolism in vitro. IGFBP-1 was analyzed by sodium dodecylsulfate polyacrylamide gel electrophoresis (PAGE) following immunoblotting, and IGFBP-1 phosphorylation status was analyzed by native PAGE following immunoblotting. RESULTS: Total concentrations of IGFBP-1 in media were higher and the highly phosphorylated isoforms were dominant in low oxygen conditions. Phosphorylation of IGF-I receptor by IGF-I was attenuated in low oxygen conditions. IGF-I-induced phosphorylation of insulin receptor substrate-1 (IRS-1) was attenuated in low oxygen conditions as well. However, attenuated phosphorylation of IGF-I receptor and IRS-1 were not observed in low oxygen conditions if the cells were stimulated with LR3IGF-I that has a similar binding affinity to IGF-I receptor but much less binding affinity to IGFBP-1 compared to those of native IGF-I. While IGF-I induced cell proliferation was also inhibited in low oxygen conditions, LR3IGF-I stimulated cell proliferation was not inhibited. These findings indicate that low oxygen conditions inhibit IGF-I action by increasing IGFBP-1, especially phosphorylated IGFBP-1, which inhibits IGF-I action. CONCLUSION: This study has indicated that hypoxia-induced IGFBP-1 production in the fetus may be a conserved physiological mechanism for restricting IGF-I-stimulated fetal growth. PMID- 23815141 TI - Nutritional essentiality of sulfur in health and disease. AB - Sulfur is the seventh most abundant element measurable in the human body and is supplied mainly by the intake of methionine (Met), an indispensable amino acid found in plant and animal proteins. Met controls the initiation of protein synthesis, governs major metabolic and catalytic activities, and may undergo reversible redox processes safeguarding protein integrity. Withdrawal of Met from customary diets causes the greatest downsizing of lean body mass following either unachieved replenishment (malnutrition) or excessive losses (inflammation). These physiopathologically unrelated morbidities nevertheless stimulate comparable remethylation reactions from homocysteine, indicating that Met homeostasis benefits from high metabolic priority. Inhibition of cystathionine-beta-synthase activity causes the upstream sequestration of homocysteine and the downstream drop in cysteine and glutathione. Consequently, the enzymatic production of hydrogen sulfide and the nonenzymatic reduction of elemental sulfur to hydrogen sulfide are impaired. Sulfur operates as cofactor of several enzymes critically involved in the regulation of oxidative processes. A combination of malnutrition and nutritional deprivation of sulfur maximizes the risk of cardiovascular disorders and stroke, constituting a novel clinical entity that threatens plant eating population groups. PMID- 23815142 TI - Diet beverages and the risk of obesity, diabetes, and cardiovascular disease: a review of the evidence. AB - "Diet beverage" is a common term used to describe beverages that are sweetened with non-nutritive or artificial sweeteners (ASBs). Marketing strategies often imply that consuming these beverages holds promise for weight control or weight loss. The objective of the present review is to provide a synthesis of the literature on the effects of ASBs on body weight, cardiovascular disease, and type 2 diabetes. Consumption of diet beverages is much lower than that of sugar sweetened beverages (SSBs), and people trying to lose weight report the highest levels of ASB consumption. To date, prospective observational studies have revealed mixed results, and it appears that reverse causality is a particular problem, since individuals who are at higher risk for weight gain may choose to consume ASBs in an attempt to control their weight or reduce disease risk. As for experimental studies, the evidence currently suggests that obesity risk may be lower when ASBs replace SSBs in the diet. Still, additional evidence from experimental studies is needed to more definitively determine the benefits and risks of frequent ASB consumption. PMID- 23815145 TI - Dietary fiber and the risk of precancerous lesions and cancer of the esophagus: a systematic review and meta-analysis. AB - Dietary fiber has several anticarcinogenic effects and is thought to be protective against esophageal cancer. The aim of this systematic review was to quantify the association between dietary fiber and the risk of esophageal cancer by investigating histological subtypes of esophageal cancer and the stage at which fiber may influence the carcinogenic pathway. Systematic search strategies were used to identify relevant studies, and adjusted odds ratios (ORs) were combined using random-effects meta-analyses to assess the risk of cancer when comparing extreme categories of fiber intake. Ten relevant case-control studies were identified within the timeframe searched. Pooled estimates from eight studies of esophageal adenocarcinoma revealed a significant inverse association with the highest fiber intakes (OR 0.66; 95% confidence interval [CI] 0.44-0.98). Two studies also identified protective effects of dietary fiber against Barrett's esophagus. Similar, though nonsignificant, associations were observed when results from five studies of fiber intake and risk of squamous cell carcinoma were combined (OR 0.61; 95%CI 0.31-1.20). Dietary fiber is associated with protective effects against esophageal carcinogenesis, most notably esophageal adenocarcinoma. Potential methods of action include modification of gastroesophageal reflux and/or weight control. PMID- 23815144 TI - Factors that determine energy compensation: a systematic review of preload studies. AB - Insufficient energy compensation after a preload (meal, snack, or beverage) has been associated with excess energy intake, but experimental studies have used heterogeneous methodologies, making energy compensation difficult to predict. The aim of this systematic review was to analyze the relative contributions of two key variables, preload physical form and intermeal interval (IMI), to differences in energy compensation. Forty-eight publications were included, from which percent energy compensation (%EC) data were extracted for 253 interventions (121 liquid, 69 semisolid, 20 solid, and 43 composite preloads). Energy compensation ranged from -370% (overconsumption, mostly of liquids) to 450% (overcompensation). A meta-regression analysis of studies reporting positive energy compensation showed that IMI (as the predominant factor) together with preload physical form and energy contributed significantly to %EC differences, accounting for 50% of the variance, independently from gender and BMI. Energy compensation was maximized when the preload was in semisolid/solid form and the IMI was 30-120 min. These results may assist in the interpretation of studies assessing the relative efficacy of interventions to enhance satiety, including functional foods and weight management products. PMID- 23815143 TI - The epigenome as a potential mediator of cancer and disease prevention in prenatal development. AB - Epigenetic events establish a particular gene expression signature for each cell type during differentiation and fertilization. Disruption of these epigenetic programs in response to environmental stimuli during prenatal exposure dysregulates the fetal epigenome, potentially impacting susceptibility to disease later in life (the fetal basis of adult disease). Maternal dietary modifications during gestation and lactation play a pivotal role in the period of fetal (re)programming. Recently, many studies have demonstrated the impact of maternal nutrition on the fetal epigenome. This review discusses the complex interplay among various environmental factors and epigenetic mechanisms that have been found to affect offspring in human and animal models. Further, it summarizes the impact of various dietary phytochemicals capable of modulating the epigenome with regard to diverse human cancers and childhood cancer, specifically those with potential environmental etiology through maternal consumption during pregnancy and lactation. Other dietary agents that are still untested as to their effectiveness in transplacental studies are also discussed. The recent developments discussed herein enhance current understanding of how chemopreventive agents act and their potential to impact the prenatal epigenome; they may also aid efforts to identify dietary interventions that can be beneficial in treating and preventing disease. PMID- 23815146 TI - Ethanol metabolism and its effects on the intestinal epithelial barrier. AB - Ethanol is widely consumed and is associated with an increasing global health burden. Several reviews have addressed the effects of ethanol and its oxidative metabolite, acetaldehyde, on the gastrointestinal (GI) tract, focusing on carcinogenic effects or alcoholic liver disease. However, both the oxidative and the nonoxidative metabolites of ethanol can affect the epithelial barrier of the small and large intestines, thereby contributing to GI and liver diseases. This review outlines the possible mechanisms of ethanol metabolism as well as the effects of ethanol and its metabolites on the intestinal barrier. Limited studies in humans and supporting in vitro data have indicated that ethanol as well as mainly acetaldehyde can increase small intestinal permeability. Limited evidence also points to increased colon permeability following exposure to ethanol or acetaldehyde. In vitro studies have provided several mechanisms for disruption of the epithelial barrier, including activation of different cell-signaling pathways, oxidative stress, and remodeling of the cytoskeleton. Modulation via intestinal microbiota, however, should also be considered. In conclusion, ethanol and its metabolites may act additively or even synergistically in vivo. Therefore, in vivo studies investigating the effects of ethanol and its byproducts on permeability of the small and large intestines are warranted. PMID- 23815147 TI - Pharmacodynamics of alfaxalone after single-dose intramuscular administration in red-eared sliders (Trachemys scripta elegans): a comparison of two different doses at two different ambient temperatures. AB - OBJECTIVE: This study compares the pharmacodynamics of two different doses of alfaxalone administered intramuscularly (IM) to red-eared sliders at two ambient temperatures. STUDY DESIGN: Prospective blinded crossover experimental study. ANIMALS: Nine adult female sliders (Trachemys scripta elegans). METHODS: Following a 2-week acclimation at 22-25 degrees C, nine sliders were randomly assigned to receive alfaxalone, 10 mg kg(-1) (W10), or 20 mg kg(-1) (W20) IM. Each turtle received each dose, with a minimum 7-day washout period. A blinded observer evaluated heart rate (HR), palpebral and corneal reflexes, muscle relaxation, handling, and response to toe pinch at the following points: pre injection, and 5, 12, 20, 30, 45, 60, and 120 minutes post-injection. Turtles then acclimated to 18-20 degrees C for 63 days, and the experiment was repeated in this lower-temperature environment, with treatment groups C10 (alfaxalone 10 mg kg(-1)) and C20 (alfaxalone 20 mg kg(-1)) subjected to the same crossover design. RESULTS: C10 and C20 groups had significantly lower intraanesthetic HR than W10 or W20, respectively. C10 and W20 were significantly more relaxed and easier to handle than W10. No significant differences were observed in palpebral reflex, nor responsiveness to the toe pinch stimulus. None of the turtles lost corneal reflex. W20 and C20 had prolonged recoveries, compared to low-dose groups within the same temperature environment. Recovery was also longer at C20 and C10 compared to W10. CONCLUSIONS: Turtles given 10 mg kg(-1) were more relaxed and easier to handle in cold than warm conditions. Warm turtles were more relaxed and easier to handle when given 20 mg kg(-1) than those given 10 mg kg(-1). Cold conditions correlated with lower HR and longer recovery time for each dose category. CLINICAL RELEVANCE: The turtles had dose-dependent and inconsistent responses to alfaxalone. Lower ambient temperature augmented the behavioral effects of this drug. PMID- 23815149 TI - Microparticles in health and disease. AB - Microparticles (MPs), small membrane-derived vesicles, are derived from many cell types and released into the circulation. Microparticles can express antigens, and contain cell surface proteins, cytoplasmic contents, and nuclear components from their cell of origin that determines their composition, characterization, and transfer of biologic information. Certain prompts for this release include shear stress, complement activation, proapoptotic stimulation, cellular damage, or agonist interaction with cell surface receptors. Release can be physiologic or pathologic and is associated with proinflammatory and procoagulant effects and has been implicated in thrombotic states. Microparticles also contribute to systemic inflammation and cardiovascular, hematologic, and oncologic disease states. The study of MPs in human medicine is rapidly advancing and extends into the physiology of health, the pathophysiology of disease, and the role of MPs in transfusion medicine. In veterinary medicine, published work on MPs has been limited to the area of inherited disorders, blood storage, and leukoreduction (LR). Microparticle research is still in its infancy, and this review should be seen as a snapshot of what is currently known. As research continues important limitations, including variations in preanalytic variables such as collection, storage, or centrifugation, and limitations of quantitation are coming to the forefront. Correlation of quantitation of MPs with assays of activity will hopefully shed light on the true nature of MPs in health and disease. This review will focus on the role of cellular exocytic vesiculation in health, disease, and transfusion medicine. PMID- 23815148 TI - Lymphotoxin alpha induces apoptosis, necroptosis and inflammatory signals with the same potency as tumour necrosis factor. AB - Both of the TNF superfamily ligands, TNF and LTalpha, can bind and signal through TNFR1 and TNFR2, yet mice mutant for each have different phenotypes. Part of this difference is because LTalpha but not TNF can activate Herpes Virus Entry Mediator and also heterotrimerise with LTbeta to activate LTbetaR, which is consistent with the similar phenotypes of the LTalpha and LTbetaR deficient mice. However, it has also been reported that the LTalpha3 homotrimer signals differently than TNF through TNFR1, and has unique roles in initiation and exacerbation of some inflammatory diseases. Our modeling of the TNF/TNFR1 interface compared to the LTalpha3/TNFR1 structure revealed some differences that could affect signalling by the two ligands. To determine whether there were any functional differences in the ability of TNF and LTalpha3 to induce TNFR1 dependent apoptosis or necroptosis, and if there were different requirements for cIAPs and Sharpin to transmit the TNFR1 signal, we compared the ability of cells to respond to TNF and LTalpha3. Contrary to our hypothesis, we were unable to discover differences in signalling by TNFR1 in response to TNF and LTalpha3. Our results imply that the reasons for the conservation of LTalpha are most likely due either to differential regulation, the ability to signal through Herpes Virus Entry Mediator or the ability of LTalpha to form heterotrimers with LTbeta. PMID- 23815150 TI - Human iPSC-derived neural crest stem cells promote tendon repair in a rat patellar tendon window defect model. AB - Induced pluripotent stem cells (iPSCs) hold great potential for cell therapy and tissue engineering. Neural crest stem cells (NCSCs) are multipotent that are capable of differentiating into mesenchymal lineages. In this study, we investigated whether iPSC-derived NCSCs (iPSC-NCSCs) have potential for tendon repair. Human iPSC-NCSCs were suspended in fibrin gel and transplanted into a rat patellar tendon window defect. At 4 weeks post-transplantation, macroscopical observation showed that the repair of iPSC-NCSC-treated tendons was superior to that of non-iPSC-NCSC-treated tendons. Histological and mechanical examinations revealed that iPSC-NCSCs treatment significantly enhanced tendon healing as indicated by the improvement in matrix synthesis and mechanical properties. Furthermore, transplanted iPSC-NCSCs produced fetal tendon-related matrix proteins, stem cell recruitment factors, and tenogenic differentiation factors, and accelerated the host endogenous repair process. This study demonstrates a potential strategy of employing iPSC-derived NCSCs for tendon tissue engineering. PMID- 23815151 TI - Rhinovirus-induced calcium flux triggers NLRP3 and NLRC5 activation in bronchial cells. AB - Human rhinoviruses have been linked with underlying lung disorders, such as asthma and chronic obstructive pulmonary disease, in children and adults. However, the mechanism of virus-induced airway inflammation is poorly understood. In this study, using virus deletion mutants and silencing for nucleotide-binding oligomerization domain-like receptors (NLRs), we show that the rhinovirus ion channel protein 2B triggers NLRP3 and NLRC5 inflammasome activation and IL-1beta secretion in bronchial cells. 2B protein targets the endoplasmic reticulum and Golgi and induces Ca(2+) reduction in these organelles, thereby disturbing the intracellular calcium homeostasis. NLRP3 and NLRC5 act in a cooperative manner during the inflammasome assembly by sensing intracellular Ca(2+) fluxes and trigger IL-1beta secretion. These results reveal for the first time that human rhinovirus infection in primary bronchial cells triggers inflammasome activation. PMID- 23815152 TI - Linear IgA bullous dermatosis: comparison between the drug-induced and spontaneous forms. AB - BACKGROUND: Linear IgA bullous dermatosis (LABD) is a rare autoimmune blistering skin disorder characterized by linear deposits of IgA along the dermoepidermal junction, visualized by direct immunofluorescence (DIF). It is usually spontaneous and drug induced. OBJECTIVES: To compare the clinical and histological forms of LABD. METHODS: This retrospective single-centre cohort study concerned 28 patients diagnosed with LABD between 1 January 1995 and 31 December 2010. Imputability, determined according to the French imputability method (modified Begaud score) and Naranjo score, enabled classification into drug-induced and spontaneous LABD groups. Clinical and histological features were compared by blinded analysis of images and histological patterns. RESULTS: Sixteen patients had spontaneous LABD and 12 had drug-induced LABD. Nikolsky sign and large erosions were significantly more frequent in drug-induced than spontaneous LABD (P = 0.003 and P = 0.03, respectively), with no between-group differences for erythematous plaques, target or target-like lesions, string of pearls, location, mucosal involvement or histological features. CONCLUSIONS: Drug induced LABD was more severe than the spontaneous form, with lesions mimicking toxic epidermal necrolysis. Because LABD may be polymorphic and sometimes life threatening, DIF assay is recommended for all patients with Nikolsky sign and large erosions. PMID- 23815153 TI - Fungal contamination and determination of fumonisins and aflatoxins in commercial feeds intended for ornamental birds in Rio de Janeiro, Brazil. AB - The purposes of this study were to determine the distribution of total mycobiota, to determine the occurrence of Aspergillus spp., Penicillium spp. and Fusarium spp. and to detect and quantify fumonisin B1 and aflatoxin B1 in birds' feedstuffs. Sixty samples from different commercial feeds were collected. Analysis of the total mycobiota was performed and total fungal counts were expressed as CFU g(-1). The isolation frequency (%) and relative density (%) of fungal genera and species were determined. Mycotoxins determination was carried out using commercial ELISA kits. The 48% of standard, 31% of premium and only 9% of super premium feed samples were found above of recommended limit (1 * 10(4) CFU g(-1)). Aspergillus (82%), Cladosporium (50%) and Penicillium (42%) were the most frequently isolated genera. Aspergillus niger aggregate (35%), Aspergillus fumigatus (28%) and Aspergillus flavus (18%) had the highest relative densities. Contamination with fumonisins was detected in 95% of total samples with levels from 0.92 to 6.68 MUg g(-1), and the aflatoxins contamination was found in 40% of total samples with levels between 1.2 and 9.02 MUg kg(-1). Feed samples contaminated with fumonisins and aflatoxins are potentially toxic to birds. PMID- 23815154 TI - Bioinformatics in Italy: BITS 2012, the ninth annual meeting of the Italian Society of Bioinformatics. AB - The BITS2012 meeting, held in Catania on May 2-4, 2012, brought together almost 100 Italian researchers working in the field of Bioinformatics, as well as students in the same or related disciplines. About 90 original research works were presented either as oral communication or as posters, representing a landscape of Italian current research in bioinformatics. This preface provides a brief overview of the meeting and introduces the manuscripts that were accepted for publication in this supplement, after a strict and careful peer-review by an International board of referees. PMID- 23815155 TI - Reversible near-infrared pH probes based on benzo[a]phenoxazine. AB - Several benzo[a]phenoxazine derivatives containing substituted N-aromatic groups are evaluated for their pH-dependent absorption and emission properties. Among the compounds exhibiting optical responses under near-neutral and subacid pH conditions, benzo[a]phenoxazine derivatives with an electron-withdrawing aromatic group attached to nitrogen of the imino group show potential application as near infrared pH sensors. Three water-soluble pH probes based on benzo[a]phenoxazine with different pyridinium structures are designed and synthesized. Their reversible pH-dependent emissions in buffer solution containing 0.1% dimethyl sulfoxide (DMSO) locate in 625-850 nm with the fluorescent enhancement of 8.2 40.1 times, and their calculated pKa values are 2.7, 5.8, and 7.1, respectively. A composite probe containing the three benzo[a]phenoxazines shows a linear pH emission relationship in the range of pH 1.9-8.0. Real-time detection of intracellular pH using an in vitro assay with HeLa cells is also reported. PMID- 23815156 TI - pH-sensitive docetaxel-loaded D-alpha-tocopheryl polyethylene glycol succinate poly(beta-amino ester) copolymer nanoparticles for overcoming multidrug resistance. AB - Multidrug resistance (MDR) is one of the major obstacles to successful chemotherapy. Overexpression of drug efflux transporters such as P-glycoprotein (P-gp) is an important factor responsible for MDR. Herein, a novel copolymer, D alpha-tocopheryl polyethylene glycol 1000-block-poly(beta-amino ester) (TPGS-b PBAE, TP), was synthesized for overcoming multidrug resistance by the synergistic effect of the pH-sensitive behavior of PBAE and P-gp inhibiting activity of TPGS. Docetaxel (DTX) was chosen as the model drug. The resulting DTX-loaded nanoparticles were stable at pH 7.4, while they dissociated in a weakly acidic environment (pH 5.5) and released the incorporated DTX quickly. The DTX-loaded TP nanoparticles increased the cell cytotoxicity against both drug-sensitive human ovarian A2780 and drug-resistant A2780/T cells. The IC(50) of DTX-loaded TP against A2780/T cells was 100-fold lower than that of commercial DTX. This was associated with enhanced DTX-induced apoptosis and cell arrest in the G2/M phase. Furthermore, P-gp inhibition assays, including enhancement of the fluorescence intensity of rhodamine 123 and reduction of the intracellular ATP levels, confirmed the P-gp inhibition nature of the TP copolymer. The use of the TP copolymer is a new approach to improve the therapeutic effect of anticancer drugs in MDR tumors. PMID- 23815157 TI - Psoriatic arthritis: current therapy and future directions. AB - INTRODUCTION: Psoriatic arthritis (PsA) once regarded as an auto-inflammatory arthritis that involves the skin is proving to be more complex with a different driver of disease process compared to rheumatoid arthritis. As growing differences emerge between PsA and rheumatoid arthritis so have the experiences and responses to therapeutics used in both disease processes. AREAS COVERED: This review highlights articles of interest in the past 10 years in the OVID and PubMed database and focuses on major concepts regarding current disease-modifying anti-rheumatic drugs in PsA as well as newer target agents. EXPERT OPINION: Presently, it is agreed upon that use of tumor necrosis factor inhibitors (TNFi) has greatly changed our ability to manage varying aspects of disease in PsA. However, there remain many unanswered questions in which research in PsA is mirroring RA work, these include: i) the need for outcome measures that are more specific to PsA, ii) the concept of early and treat to target, iii) the role of highly sensitive imaging, and iv) efficacy of combination therapy and further targets in those unable to tolerate or fail TNFi. PMID- 23815158 TI - Nonthyroidal illness: a risk factor for coronary calcification and arterial stiffness in patients undergoing peritoneal dialysis? AB - OBJECTIVES: Low triiodothyronine levels, as part of the nonthyroidal illness syndrome, are common in dialysis patients and have repeatedly been shown to be associated with increased (cardiovascular) mortality rates. We hypothesized that increased vascular calcification may mediate this relationship. METHODS: A total of 84 patients from the Stockholm region receiving maintenance peritoneal dialysis were included in the study. Serum concentrations of free triiodothyronine (fT3), thyroxine and thyroid-stimulating hormone were measured. Coronary artery calcium (CAC) scores were assessed by cardiac computed tomography scans. Surrogates of arterial stiffness included aortic diastolic and systolic blood pressures, pulse pressure, augmentation pressure and Buckberg's subendocardial viability ratio measured by pulse waveform analyses. Patients were subsequently followed, and events of death and censoring were recorded. Thyroid hormone concentrations were associated with CAC scores, measures of arterial stiffness and all-cause mortality. The associations between CAC scores and arterial stiffness surrogates and mortality were also determined to evaluate a possible causal pathway. RESULTS: Both CAC scores and arterial stiffness surrogates were substantially higher in individuals with low fT3 levels. These associations persisted in multivariate logistic and linear regression analyses. During a median (interquartile range) follow-up of 32 (22-42) months, 24 patients died. Both fT3 levels below the median value [HR crude 4.1, 95% confidence interval (CI) 1.4-12.6] and CAC scores above the median value (HR crude 5.8, 95% CI 1.7-20.1) were strongly associated with mortality. CONCLUSIONS: In patients undergoing peritoneal dialysis, fT3 levels were strongly associated with arterial stiffness, coronary artery calcification and mortality. We speculate that the association between nonthyroidal illness and mortality may be partly mediated by acceleration of vascular calcification. PMID- 23815159 TI - A class of sulfonamides with strong inhibitory action against the alpha-carbonic anhydrase from Trypanosoma cruzi. AB - Trypanosoma cruzi, the causative agent of Chagas disease, encodes for an alpha carbonic anhydrase (CA, EC 4.2.1.1) possessing high catalytic activity (TcCA) which was recently characterized (Pan et al. J. Med. Chem. 2013, 56, 1761-1771). A new class of sulfonamides possessing low nanomolar/subnanomolar TcCA inhibitory activity is described here. Aromatic/heterocyclic sulfonamides incorporating halogeno/methoxyphenacetamido tails inhibited TcCA with KIs in the range of 0.5 12.5 nM, being less effective against the human off-target isoforms hCA I and II. A homology model of TcCA helped us to rationalize the excellent inhibition profile of these compounds against the protozoan enzyme, a putative new antitrypanosoma drug target. These compounds were ineffective antitrypanosomal agents in vivo due to penetrability problems of these highly polar molecules that possess sulfonamide moieties. PMID- 23815161 TI - The effect of self-reported habitual sleep quality and sleep length on autobiographical memory. AB - A large number of studies have recently shown effects of sleep on memory consolidation. In this study the effects of the sleep quality and sleep length on the retention of autobiographical memories are examined, using an Internet-based diary technique (Kristo, Janssen, & Murre, 2009). Each of over 600 participants recorded one recent personal event and was contacted after a retention interval that ranged from 2 to 46 days. Recall of the content, time, and details of the event were scored and related to sleep quality and sleep length as measured with the Pittsburgh Sleep Quality Index. Hierarchical regression analyses indicated that poor sleep quality, but not short sleep length, was associated with significantly lower recall at the longer retention periods (30-46 days), but not at the shorter ones (2-15 days), although the difference in recall between good and poor sleepers was small. PMID- 23815160 TI - Mini-Mental State Examination in patients with hepatic encephalopathy and liver cirrhosis: a prospective, quantified electroencephalography study. AB - BACKGROUND: Mini-Mental State Examination (MMSE) is one of the most commonly used methods in the assessment of cognitive mental status. MMSE has been used in hepatology but its usefulness in the evaluation of hepatic encephalopathy (HE) has never been properly assessed. The aim of the study was to investigate the value of MMSE in detection of HE in patients with cirrhosis. METHODS: One hundred and one consecutive patients with liver cirrhosis underwent neurological examination, MMSE and electroencephalography (EEG). Spectral analysis of EEG was done with calculation of mean dominant frequency (MDF) and relative power of delta, theta, alpha and beta rhythms. Minimal HE was diagnosed in patients with normal neurological status and alterations in spectral EEG. Statistical analysis included Fisher's exact and Anova analysis. Categorical data were compared using Levene's test for equality of variances. Correlation-coefficient analysis was performed by the Pearson's r or Z-test, as needed. Tests performance was assessed by the calculating the area under the ROC curve (AUC) and evaluating its difference from reference area (AUC=0.5). A p value <0.05 was considered statistically significant. RESULTS: Overt HE was identified in 49 (48.5%) and minimal HE in 22 (21.8%) patients. Although there were significant correlations between both severity of liver disease (Child-Pugh classification), overt HE (West-Haven criteria) and various MMSE items, MDF showed no correlation with any of MMSE items as well as MMSE summary score. MMSE (score and items) did not discriminate patients without HE and minimal HE. The only significant differences between patients without HE and with overt HE were seen in respect of MMSE score (p<0.02), orientation to place (p<0.003), repetition (p<0.01) and complex commands-understanding (p<0.02). Test performance analysis has shown that MMSE has no value as a prediction method in determining minimal HE and in respect of overt HE has a sensitivity of 63% and specificity of 52% by a cut-off level at 27.5 points to diagnose overt HE. CONCLUSIONS: In conclusion, although MMSE score and single items are altered in patients with overt HE, MMSE has no value in the assessment of minimal HE. Because MMSE could be impaired in several cognitive dysfunctions, more specific test should be used for measuring HE. PMID- 23815162 TI - Scalable high-throughput identification of genetic targets by network filtering. AB - BACKGROUND: Discovering the molecular targets of compounds or the cause of physiological conditions, among the multitude of known genes, is one of the major challenges of bioinformatics. One of the most common approaches to this problem is finding sets of differentially expressed, and more recently differentially co expressed, genes. Other approaches require libraries of genetic mutants or require to perform a large number of assays. Another elegant approach is the filtering of mRNA expression profiles using reverse-engineered gene network models of the target cell. This approach has the advantage of not needing control samples, libraries or numerous assays. Nevertheless, the impementations of this strategy proposed so far are computationally demanding. Moreover the user has to arbitrarily choose a threshold on the number of potentially relevant genes from the algorithm output. RESULTS: Our solution, while performing comparably to state of the art algorithms in terms of discovered targets, is more efficient in terms of memory and time consumption. The proposed algorithm computes the likelihood associated to each gene and outputs to the user only the list of likely perturbed genes. CONCLUSIONS: The proposed algorithm is a valid alternative to existing algorithms and is particularly suited to contemporary gene expression microarrays, given the number of probe sets in each chip, also when executed on common desktop computers. PMID- 23815163 TI - Gold(III) complexes of pyridyl- and isoquinolylamido ligands: structural, spectroscopic, and biological studies of a new class of dual topoisomerase I and II inhibitors. AB - The structures, spectroscopy, and cytotoxicity of four novel nominally square planar gold(III) chelates 1-4 with the general formula cis-AuCl2(X), where the ligand X is an anionic bidentate pyridyl- or isoquinolylamido chelating agent, are described. The Au-N(amido), Au-N(pyridyl), and Au-N(isoquinolyl) distances are 2.002(9)-2.016(3), 2.01(1)-2.037(3), and 2.037(3) A, respectively. Density functional theory simulations afforded accurate gold(III) coordination geometries for 1-4 (bond distances and angles to within 5% of the X-ray values), while accurate transition energies were limited to those calculated in the UV spectral region. The complexes had variable stability in dimethyl sulfoxide: compound 3 (relatively rigid) was indefinitely stable, compounds 1 and 2 (conformationally flexible) slowly demetalated over 30 days, and 4 (extensively aromatic) formed an insoluble precipitate after 10 days (72 h in an aqueous buffer). The isoquinolylamido derivative 4 was sufficiently cytotoxic in the NCI-60 screen to undergo full five-dose testing. Notably low GI50 (1.8, 2.3, and 3.2 MUM) and IC50 (4.0, 9.8, and 15 MUM) values were recorded for the OVCAR-3, IGROV1, and SW-620 cell lines, respectively. Hierarchical cluster analysis employing the National Cancer Institute (NCI) data for known anticancer drugs and 4 revealed that compound 4 is mechanistically identical with the topoisomerase IIalpha (Top2) poison zorubicin and statistically similar to the topoisomerase IB (Top1) poisons camptothecin and 9-methoxycamptothecin. The Top2-catalyzed decatenation reaction of kinetoplast DNA was studied as a function of the concentration of 4: the compound acts as an interfacial poison of Top2 at low concentrations (<1 MUM) and a catalytic inhibitor of the enzyme above 5 MUM. Gel mobility shift assays (plasmid DNA substrate) showed that the catalytic inhibition of Top2 likely correlates with DNA binding by 4 at concentrations >5 MUM. Compound 4 is also a catalytic inhibitor of Top1 at higher concentrations, consistent with DNA binding by the complex. PMID- 23815165 TI - Synthesis of substituted picenes through Pd-catalyzed cross-coupling reaction/annulation sequences and their physicochemical properties. AB - A novel and versatile synthetic method for picene derivatives is developed using the Pd-catalyzed intramolecular double cyclization of the corresponding 2,3 bis[(1Z)-2-phenylethenyl]-1,4-dichlorobenzenes, which are readily prepared by Suzuki-Miyaura cross-coupling reactions of polyhalobenzenes with (Z) arylethenylboronates. The physical properties of the obtained picenes can be modified via introducing a variety of functional groups to the picene framework. All compounds are investigated by UV-vis and fluorescence spectroscopic measurements, CV, and DFT calculations as well as X-ray diffraction analysis. PMID- 23815166 TI - Bacterial culture of apheresis platelets: a mathematical model of the residual rate of contamination based on unconfirmed positive results. AB - BACKGROUND: Platelet septic reactions result from low concentrations of bacteria that escape detection by quality-control BacT/ALERTTM culture testing. We estimate the contamination rate with these bacteria at the time of testing using a mathematical model. METHODS: Culture results and reported septic reactions are described for platelets collected between January 2007 and December 2011. Initial positive results with negative confirmatory cultures were reclassified assuming some of the 'unconfirmed positive results' represent collections contaminated with low-concentration, dormant bacteria. A mathematical model based on the probability of the detection of bacteria describes the upper limit of the residual rate of contamination. RESULTS: The rate of confirmed or unconfirmed positive apheresis platelet donations was 188 per million (1:5317) and 110 per million (1:9124), respectively. The rate of post-transfusion sepsis and reported fatalities per distributed component was 1:106 931 and 1:1 015 843, respectively. A linear decrease in unconfirmed positive Bacillus spp. cultures most likely reflected diminishing environmental contamination over time. The remaining unconfirmed positive results identified similar bacteria species as those associated with septic reactions. Assuming that these represent contamination of the collection with low-concentration, dormant bacteria, the model identified a residual contamination of 3524-204 per million (1:284-1:4902) for collections contaminated with 1-20 bacteria, respectively. DISCUSSION: Greater than 99.5% of collections contain no viable, aerobic bacteria in solution at the time of early culture testing. For every confirmed positive contaminated collection detected, there are at most 19 collections with low concentrations of dormant bacteria that are not readily detected by early BacT/ALERTTM culture. PMID- 23815167 TI - An unusual complication of endotracheal intubation in a dog. PMID- 23815168 TI - Unusual clinical course of preeclampsia heralded by generalized edema. AB - Preeclampsia monitored by the amount of proteinuria usually does not show amelioration during pregnancy. A 37-year-old nulliparous woman was admitted to our hospital at gestational week (GW) 24(-1/7) due to rapid weight gain (6.2 kg/4 weeks) and oligohydramnios. Hypertension (151/91 mmHg) appeared at GW 25(-0/7) and proteinuria not detected at GW 24(-0/7) became significant (0.55 g/day) at GW 25(-2/7) . During the 2 successive weeks after administration of betamethasone at 12 mg twice and transabdominal amnioinfusion with 250 mL of Ringer's acetate solution at GW 25(-3/7) , generalized edema, proteinuria and thrombocytopenia markedly improved: bodyweight, 78.0 to 69.0 kg; proteinuria, from 7.1 to 1.3 g/day; and platelet count, from 111 to 230 * 10(9) /L. However, intrauterine infection accompanied by non-reassuring fetal status necessitated emergency cesarean section at GW 28(-3/7) . Extraordinary bodyweight gain can herald the occurrence of preeclampsia and this weight gain together with signs of preeclampsia can ameliorate even during pregnancy, although its mechanism is unclear. PMID- 23815169 TI - Distinct responses to mechanical grinding and hydrostatic pressure in luminescent chromism of tetrathiazolylthiophene. AB - Luminescent mechanochromism has been intensively studied in the past few years. However, the difference in the anisotropic grinding and the isotropic compression is not clearly distinguished in many cases, in spite of the importance of this discrimination for the application of such mechanochromic materials. We now report the distinct luminescent responses of a new organic fluorophore, tetrathiazolylthiophene, to these stresses. The multichromism is achieved over the entire visible region using the single fluorophore. The different mechanisms of a blue shift by grinding crystals and of a red shift under hydrostatic pressure are fully investigated, which includes a high-pressure single-crystal X ray diffraction analysis. The anisotropic and isotropic modes of mechanical loading suppress and enhance the excimer formation, respectively, in the 3D hydrogen-bond network. PMID- 23815170 TI - Epileptic seizures induced by cycloplegic eye drops. AB - OBJECTIVE: To assess the incidence of seizures induced by cycloplegic ophthalmic drops. MATERIALS AND METHODS: A survey among members of the American Association for Pediatric Ophthalmology and Strabismus yielded five patients who received cycloplegic eye drops between 1998 and 2010 and who consequently developed a seizure. RESULTS: The median age of the patients was 5 years (range 3 months to 12 years). Cyclopentolate hydrochloride 1% was the only causative agent. The seizure happened on average 12 min after the instillation of dilating eye drops. Three were generalized convulsions, and two patients had a focal seizure. Past medical history was unremarkable in four cases. In total, 16 previous cases of seizures induced by cycloplegic drugs were identified in reports published between 1890 and 2004, implicating atropine in nine reports, tropicamide and phenylephrine eye drops in one and cyclopentolate in six. DISCUSSION: A small amount of cyclopentolate drops could induce convulsions in young children after only minutes to less than an hour, while a larger dosage of atropine over the span of several hours could cause this rare and unpredictable complication. Predisposing factors were rare and those developing the seizures were healthy subjects. Generalized seizures were much more frequent than focal convulsions. CONCLUSIONS: Seizures after instillation of cycloplegic drops are extremely rare. PMID- 23815171 TI - Afrormosin, an Isoflavonoid from Amburana cearensis A. C. Smith, Modulates the Inflammatory Response of Stimulated Human Neutrophils. AB - Isoflavones are phytoestrogens known by their anti-inflammatory, antioxidant and immunomodulatory properties. Presently, there is no information on whether afrormosin, an isoflavone from Amburana cearensis A.C. Smith (Fabaceae), has some effect on the inflammatory response from stimulated human neutrophils. Thus, the aim of this study was to evaluate the anti-inflammatory and antioxidant potentials of afrormosin on human neutrophils. Neutrophils (2.5 * 10(6) cells/mL) were incubated with afrormosin (3.35-335.2 MUM) prepared from a product isolated from Amburana cearensis A.C. Smith with a 78.5% degree of purity and stimulated by the addition of cytochalasin B and N-formyl-methionyl-leucyl-phenylalanine (fMLP) or phorbol 12-myristate-13-acetate (PMA). Afrormosin inhibited the neutrophil degranulation induced by fMLP (10.47-335.2 MUM) or PMA (0.33-167.6 MUM), myeloperoxidase activity (3.3-335.2 MUM), TNF-alpha secretion (16.7-335.2 MUM) and the reactive oxygen species (ROS) generation (16.7-335.2 MUM). On the other hand, afrormosin did not show any effect either on elastase or as a free radical scavenger. These data suggest that afrormosin modulates intermediary steps of the neutrophil ROS generation process. In addition, the modulatory effect of afrormosin on human neutrophil degranulation seems to be directed towards PMA-induced activation, indicating a potent inhibition of the protein kinase C activity. This study provided evidence, for the first time, to support the anti-inflammatory and antioxidant activities of afrormosin, creating novel insights into the pharmacological actions of this natural isoflavone. PMID- 23815172 TI - "All roads lead to medication?" Qualitative responses from an Australian first person survey of antipsychotic discontinuation. AB - OBJECTIVE: The purpose of the survey was to better understand the experiences of people who attempt antipsychotic discontinuation. METHOD: A multiple-choice and short-answer survey was distributed in 2011-2012 to potential participants involved in participating organizations. Respondents were asked about past discontinuation events, including decision negotiation and withdrawal experience. This article thematically analyses their free-text responses. RESULTS: There were 98 valid surveys returned. Respondents highlighted the roles of the therapeutic alliance and health and illness explanatory models in understanding the context of discontinuation. Reported impacts of discontinuation were mixed and complex. Withdrawal syndromes were described by over half of the participants. Of the 98 respondents, 21 reported remaining antipsychotic-free at the time of survey completion. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Participant accounts highlight the importance of context and relationships in their thinking about antipsychotic discontinuation. Although results cannot necessarily be generalized, participant descriptions of withdrawal syndromes suggest there may be a need to improve education, monitoring, and support strategies for some people during discontinuation. Shifting toward a more collaborative, transparent, and service-user-driven approach to discontinuation may help to mitigate some of the negative discontinuation impacts identified. The polarized discontinuation outcomes described highlight the individuality of every participant's recovery journey and the need to avoid generalizing about the role of antipsychotics in care. PMID- 23815173 TI - Peer support, self-determination, and treatment engagement: a qualitative investigation. AB - OBJECTIVE: To address gaps in the literature concerning the relationships among participation in peer-led mental health programs, the development of self determination in service use, and medication use and engagement with medication prescribers and other traditional providers, we conducted focus groups with individuals involved in Wellness Recovery Action Plan (WRAP) programs. METHOD: We carried out five focus groups with 54 WRAP participants and/or facilitators, and analyzed transcripts using a grounded theory approach. RESULTS: Emergent themes revealed differences of opinion regarding the role and value of medication adherence, broad agreement on the benefits of WRAP in increasing self determination and self-awareness, and positive effects of participation on patient self-advocacy, medication-related decision-making and meaningful engagement with traditional providers. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Findings emphasize the importance of examining the influence of stand-alone peer led program involvement on relationships with traditional providers and decisions regarding medication use, as well as the heterogeneity of consumer treatment values, choices, and associated outcomes. PMID- 23815174 TI - Agenda setting in psychiatric consultations: an exploratory study. AB - OBJECTIVE: Patient- or consumer-centeredness has been recognized as a critical component of quality in primary health care, but is only beginning to be recognized and studied in mental health. Among the first opportunities to be consumer-centered is collaboratively producing an agenda of topics to be covered during a clinic visit. Early agenda setting sets the stage for what is to come and can affect the course, direction, and quality of care. The purpose of this work is to study agenda setting practices among 8 prescribers (5 psychiatrists and 3 nurse practitioners) at the beginning of their encounters with 124 consumers diagnosed with schizophrenia spectrum disorders (56%), bipolar disorder (23%), major depression (15%), and other disorders (6%). METHOD: We modified an extant agenda-setting rubric by adding behaviors identified by a multidisciplinary team who iteratively reviewed transcripts of the visit openings. Once overall consensus was achieved, two research assistants coded all of the transcripts. Twenty-five transcripts were scored by both raters to establish interrater reliability. RESULTS: We identified 10 essential elements of agenda setting. Almost 10% of visits had no agenda set, and only 1 of 3 encounters had partial or complete elicitation of a single concern. Few additional concerns (4%) were solicited, and no encounter contained more than 6 essential elements. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Collaborative agenda setting represents a unique opportunity to translate the concept of consumer-centeredness into mental health care. Initial results suggest the rating system is reliable, but the essential elements are not being used in practice. PMID- 23815175 TI - Causal attributions of job loss among people with psychiatric disabilities. AB - OBJECTIVE: Guided by Weiner's attribution theory (1985), the aim of this study is to describe the reasons given by people with psychiatric disabilities to explain job loss. METHODS: Using a sample of 126 people with psychiatric disabilities participating in a prospective study design, the authors evaluated the causal attributions pattern to explain job loss. During a 9-month follow-up phone interview, clients of supported employment programs were asked to explain the reasons why they had lost their jobs. The reasons provided were categorized according to type of job loss (voluntarily vs. involuntarily), locus of control (external vs. internal) and controllability (controllable vs. uncontrollable). RESULTS: The results show that 73% of participants had voluntarily ended their jobs. For the majority of participants, the reasons given to explain job loss were related to external and uncontrollable factors. Moreover, men used more external (34.1% vs. 23%) and uncontrollable (68.2% vs. 40%) reasons than women. Severity of symptoms and level of education also affected the attributional pattern. However, self-esteem, psychiatric diagnosis and work centrality did not correlate significantly to the attributional pattern. CONCLUSION AND IMPLICATIONS FOR PRACTICE: The results demonstrated that reasons given to explain job loss among people with psychiatric disabilities are mostly external. A more systematic evaluation of environmental factors should be put in place to favor longer job tenure for people with psychiatric disabilities. PMID- 23815176 TI - Consumer perspectives and mental health reform movements in the United States: 30 years of first-person accounts. AB - OBJECTIVE: The present qualitative study examined 69 published first-person accounts written by adults diagnosed with schizophrenia from 1979-2010 within the historical context of the four major mental health movements in the United States. METHODS: Content analysis techniques were used to identify major topics and overarching content categories in the first-person accounts written over the 30-year period. The frequency of topics in each content category was examined as a function of the decade and corresponding mental health movement in which accounts were published. RESULTS: Five overarching content categories emerged reflecting authors' conceptualizations of schizophrenia, their experiences with psychiatric hospitalization, medications, coping with social stigma, and achieving and maintaining valued social roles. Two summary categories emerged reflecting authors explicit views about what helped and what did not help in their experience of living with schizophrenia. With the exception of social stigma, frequency of topics within content categories did not change as a function of decade and corresponding mental health movement. CONCLUSION AND IMPLICATIONS FOR PRACTICE: Despite changes in mental health policies, treatment, and systems of care, the overall lack of significant differences in the content of first-person accounts across the 30-year period suggests an enduring nature to the experiences of individuals coping with schizophrenia. Implications of present findings for research and practice are discussed. PMID- 23815177 TI - High expression of midkine in the airways of patients with cystic fibrosis. AB - Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene result in impaired host defense during cystic fibrosis (CF), where Pseudomonas aeruginosa becomes a key pathogen. We investigated the expression pattern of the antibacterial growth factor midkine (MK) in CF and the possible interference with its activity by the altered airway microenvironment. High MK expression was found in CF lung tissue compared with control samples, involving epithelia of the large and small airways, alveoli, and cells of the submucosa (i.e., neutrophils and mast cells). In CF sputum, MK was present at 100-fold higher levels, but was also subject to increased degradation, compared with MK in sputum from healthy control subjects. MK exerted a bactericidal effect on P. aeruginosa, but increasing salt concentrations and low pH impaired this activity. Molecular modeling suggested that the effects of salt and pH were attributable to electrostatic screening and a charge-neutralization of the membrane, respectively. Both the neutrophil elastase and elastase of P. aeruginosa cleaved MK to smaller fragments, resulting in impaired bactericidal activity. Thus, MK is highly expressed in CF, but its bactericidal properties may be impaired by the altered microenvironment, as reflected by the in vitro conditions used in this study. PMID- 23815178 TI - Guanosine behind the scene. PMID- 23815179 TI - Characterizing the effects of heparin gel stiffness on function of primary hepatocytes. AB - In the liver, hepatocytes are exposed to a large array of stimuli that shape hepatic phenotype. This in vivo microenvironment is lost when hepatocytes are cultured in standard cell cultureware, making it challenging to maintain hepatocyte function in vitro. Our article focused on one of the least studied inducers of the hepatic phenotype-the mechanical properties of the underlying substrate. Gel layers comprised of thiolated heparin (Hep-SH) and diacrylated poly(ethylene glycol) (PEG-DA) were formed on glass substrates via a radical mediated thiol-ene coupling reaction. The substrate stiffness varied from 10 to 110 kPa by changing the concentration of the precursor solution. ELISA analysis revealed that after 5 days, hepatocytes cultured on a softer heparin gel were synthesizing five times higher levels of albumin compared to those on a stiffer heparin gel. Immunofluorescent staining for hepatic markers, albumin and E cadherin, confirmed that softer gels promoted better maintenance of the hepatic phenotype. Our findings point to the importance of substrate mechanical properties on hepatocyte function. PMID- 23815180 TI - Fashions change but tattoos are forever: time to regret. PMID- 23815181 TI - NGS-Trex: Next Generation Sequencing Transcriptome profile explorer. AB - BACKGROUND: Next-Generation Sequencing (NGS) technology has exceptionally increased the ability to sequence DNA in a massively parallel and cost-effective manner. Nevertheless, NGS data analysis requires bioinformatics skills and computational resources well beyond the possibilities of many "wet biology" laboratories. Moreover, most of projects only require few sequencing cycles and standard tools or workflows to carry out suitable analyses for the identification and annotation of genes, transcripts and splice variants found in the biological samples under investigation. These projects can take benefits from the availability of easy to use systems to automatically analyse sequences and to mine data without the preventive need of strong bioinformatics background and hardware infrastructure. RESULTS: To address this issue we developed an automatic system targeted to the analysis of NGS data obtained from large-scale transcriptome studies. This system, we named NGS-Trex (NGS Transcriptome profile explorer) is available through a simple web interface http://www.ngs-trex.org and allows the user to upload raw sequences and easily obtain an accurate characterization of the transcriptome profile after the setting of few parameters required to tune the analysis procedure. The system is also able to assess differential expression at both gene and transcript level (i.e. splicing isoforms) by comparing the expression profile of different samples.By using simple query forms the user can obtain list of genes, transcripts, splice sites ranked and filtered according to several criteria. Data can be viewed as tables, text files or through a simple genome browser which helps the visual inspection of the data. CONCLUSIONS: NGS-Trex is a simple tool for RNA-Seq data analysis mainly targeted to "wet biology" researchers with limited bioinformatics skills. It offers simple data mining tools to explore transcriptome profiles of samples investigated taking advantage of NGS technologies. PMID- 23815182 TI - Microfluidic droplet-based liquid-liquid extraction and on-chip IR spectroscopy detection of cocaine in human saliva. AB - We present a portable microsystem to quantitatively detect cocaine in human saliva. In this system, we combine a microfluidic-based multiphase liquid-liquid extraction method to transfer cocaine continuously from IR-light-absorbing saliva to an IR-transparent solvent (tetrachloroethylene) with waveguide IR spectroscopy (QC-laser, waveguide, detector) to detect the cocaine on-chip. For the fabrication of the low-cost polymer microfluidic chips a simple rapid prototyping technique based on Scotch-tape masters was further developed and applied. To perform the droplet-based liquid-liquid extraction, we designed and integrated a simple and robust droplet generation method based on the capillary focusing effect within the device. Compared to well-characterized and commonly used microfluidic H-filters, our system showed at least two times higher extraction efficiencies with potential for further improvements. The current liquid-liquid extraction method alone can efficiently extract cocaine and pre-concentrate the analytes in a new solvent. Our fully integrated optofluidic system successfully detected cocaine in real saliva samples spiked with the drug (500 MUg/mL) and allowed real time measurements, which makes this approach suitable for point-of care applications. PMID- 23815183 TI - Meta-analysis: rapid infliximab infusions are safe. AB - BACKGROUND: Infliximab is typically administered intravenously via 2- to 3-h duration infusions. Infusions are time-consuming and costly. Shorter duration infusions are administered at some centres. Limited safety data are available on shorter duration infusions. AIM: To determine risk of infusion reaction associated with standard 2- to 3-h infusions vs. rapid infusions in patients receiving infliximab therapy for inflammatory bowel disease (IBD), rheumatoid arthritis, spondylarthopathy and psoriatic disease. METHODS: MEDLINE, Embase, and Web of Science were searched. Inclusion required human subjects, documentation of number of standard and rapid infliximab infusions and number of incident infusion reactions. Studies of overlapping populations were excluded. Three reviewers independently extracted data. Study quality was assessed. Relative risk (RR) was pooled using random effects models. RESULTS: We identified 10 studies comprising 13 147 standard 2- to 3-h and 8497 <= 1-h infliximab infusions. Nine studies reported the risk of infusion reaction in standard vs. 1-h infusions, demonstrating decreased RR of infusion reaction with 1-h vs. standard infusions (0.9% vs. 2.2% of infusions; RR = 0.48, P = 0.009). Seven studies limited to IBD also demonstrated decreased risk of reaction (RR = 0.49, P = 0.002). Other comparisons demonstrated no difference in RR of reaction, including concomitant medication use (P = 0.30) or analysis limited to high and medium quality studies (P = 0.07). CONCLUSIONS: Rapid infliximab infusions of <=1-h duration are not associated with increased risk of infusion reaction when compared to standard 2- to 3-h infusions in selected patients who previously tolerated three to four standard infusions. One-hour infusions will conserve health care resources and may lead to improved adherence and quality of life in patients receiving infliximab. PMID- 23815184 TI - Homoeopathy and consumers' right to know. PMID- 23815185 TI - MACC1 - a novel target for solid cancers. AB - INTRODUCTION: The metastatic dissemination of primary tumors is directly linked to patient survival in many tumor entities. The previously undescribed gene metastasis-associated in colon cancer 1 (MACC1) was discovered by genome-wide analyses in colorectal cancer (CRC) tissues. MACC1 is a tumor stage-independent predictor for CRC metastasis linked to metastasis-free survival. AREAS COVERED: In this review, the discovery of MACC1 is briefly presented. In the following, the overwhelming confirmation of these data is provided supporting MACC1 as a new remarkable biomarker for disease prognosis and prediction of therapy response for CRC and also for a variety of additional forms of solid cancers. Lastly, the potential clinical utility of MACC1 as a target for prevention or restriction of tumor progression and metastasis is envisioned. EXPERT OPINION: MACC1 has been identified as a prognostic biomarker in a variety of solid cancers. MACC1 correlated with tumor formation and progression, development of metastases and patient survival representing a decisive driver for tumorigenesis and metastasis. MACC1 was also demonstrated to be of predictive value for therapy response. MACC1 is a promising therapeutic target for anti-tumor and anti-metastatic intervention strategies of solid cancers. Its clinical utility, however, must be demonstrated in clinical trials. PMID- 23815186 TI - 4-Amino-7-chloroquinolines: probing ligand efficiency provides botulinum neurotoxin serotype A light chain inhibitors with significant antiprotozoal activity. AB - Structurally simplified analogues of dual antimalarial and botulinum neurotoxin serotype A light chain (BoNT/A LC) inhibitor bis-aminoquinoline (1) were prepared. New compounds were designed to improve ligand efficiency while maintaining or exceeding the inhibitory potency of 1. Three of the new compounds are more active than 1 against both indications. Metabolically, the new inhibitors are relatively stable and nontoxic. 12, 14, and 15 are more potent BoNT/A LC inhibitors than 1. Additionally, 15 has excellent in vitro antimalarial efficacy, with IC90 values ranging from 4.45 to 12.11 nM against five Plasmodium falciparum (P.f.) strains: W2, D6, C235, C2A, and C2B. The results indicate that the same level of inhibitory efficacy provided by 1 can be retained/exceeded with less structural complexity. 12, 14, and 15 provide new platforms for the development of more potent dual BoNT/A LC and P.f. inhibitors adhering to generally accepted chemical properties associated with the druggability of synthetic molecules. PMID- 23815187 TI - Vitamin D status of older adults of diverse ancestry living in the Greater Toronto Area. AB - BACKGROUND: Physiological and lifestyle factors put older adults at an increased risk of vitamin D insufficiency and resulting negative health outcomes. Here we explore the vitamin D status in a sample of community dwelling older adults of diverse ancestry living in the Greater Toronto area (GTA). METHODS: Two hundred and twenty-four (224) adults over 60 years of age were recruited from the Square One Older Adult Centre, in Mississauga, Ontario. Circulating 25-hydroxyvitamin D (25(OH)D) concentrations were measured from dried blood spot cards. Dietary and supplemental intakes of vitamin D were assessed via questionnaires. Skin pigmentation was assessed quantitatively by measuring melanin levels using a reflectometer. RESULTS: The mean 25(OH)D concentration in the total sample was 82.4 nmol/L. There were no statistically significant differences in serum 25(OH)D concentrations, supplemental or dietary vitamin D intakes between the three major ancestral groups (East Asians, Europeans and South Asians). Females had significantly higher 25(OH)D concentrations than males (84.5 nmol/L vs. 72.2 nmol/L, p = 0.012). The proportion of participants with 25(OH)D concentrations below 50 nmol/L and 75 nmol/L were 12.1%, and 38.8%, respectively. The mean daily supplemental intake of vitamin D was 917 IU/day. Vitamin D intake from supplements was the major factor determining 25(OH)D concentrations (p < 0.001). CONCLUSIONS: Mean concentration of 25(OH)D in a sample of older adults of diverse ancestry living in the GTA exceeded 80 nmol/L, and there were no significant differences in 25(OH)D levels between ancestral groups. These results sharply contrast with our recent study focused on young adults of diverse ancestry living in the same geographic area, in which we found substantially lower 25(OH)D concentrations (mean 39.5 nmol/L), low supplemental vitamin D intake (114 IU/day), and significant differences in 25(OH)D levels between ancestral groups. High daily intake of supplemental vitamin D in this sample of older adults likely accounts for such disparate findings with respect to the young adult sample. PMID- 23815188 TI - Episodic but not semantic order memory difficulties in autism spectrum disorder: evidence from the Historical Figures Task. AB - Considerable evidence suggests that the episodic memory system operates abnormally in autism spectrum disorder (ASD) whereas the functions of the semantic memory system are relatively preserved. Here we show that the same dissociation also applies to the domain of order memory. We asked adult participants to order the names of famous historical figures either according to their chronological order in history (probing semantic memory) or according to a random sequence shown once on a screen (probing episodic memory). As predicted, adults with ASD performed less well than age- and IQ-matched comparison individuals only on the episodic task. This observation is of considerable importance in the context of developmental theory because semantic and episodic order memory abilities can be dissociated in typically developing infants before they reach the age at which the behavioural markers associated with ASD are first apparent. This raises the possibility that early emerging memory abnormalities play a role in shaping the developmental trajectory of the disorder. We discuss the broader implications of this possibility and highlight the urgent need for greater scrutiny of memory competences in ASD early in development. PMID- 23815190 TI - Supporting the wider use of laparoscopy in the treatment of ovarian masses. AB - Patients with ovarian masses which have a moderate risk of malignancy are frequently treated by open laparotomy, despite the Royal College of Obstetricians and Gynaecologists (RCOG) guidance indicating that laparoscopic oophorectomy may be performed in selected cases. The reluctance to perform laparoscopic surgery in these cases is normally due to the perception that survival is affected if the mass is subsequently diagnosed as being malignant, the risk of rupture impacting on FIGO stage and the need for additional staging surgery. However, there is no good evidence to support these views. Preoperative diagnosis of ovarian masses is limited and thus a significant number of patients are subjected to open surgery, where they may have benefitted from the advantages of laparoscopic surgery. We argue that in the absence of a definitive preoperative test, there are advantages to the laparoscopic approach in patients who have a moderate risk of malignancy and further high level evidence should be encouraged in this field. PMID- 23815191 TI - Interleukin-6 for the diagnosis of ovarian torsion: a systematic review and meta analysis. AB - Ovarian torsion may have significant fertility implications. Interleukin-6 is a pro-inflammatory cytokine, which may act as a helpful diagnostic test. Our objective was to investigate the accuracy of serum interleukin-6 in the diagnosis of ovarian torsion in women with ultrasonographic evidence of an ovarian cyst. An electronic search of published data, unpublished dissertations, theses and conference proceedings was performed. The systematic review involved observational studies. The studies had to provide data to construct 2 * 2 tables. A modified QUADAS tool was used to assess the quality of studies. Sensitivity, specificity, positive and negative predictive value, likelihood ratios and diagnostic odds ratios were calculated. Three studies were identified. Two were included in the meta-analysis. The prevalence of torsion was 30% (21/70). The pooled sensitivity was 85.1% and the pooled specificity was 84.1%. Although further cohort studies would be required, there may be a role for interleukin-6 in the diagnosis of ovarian torsion. PMID- 23815192 TI - Recruitment of pregnant women in research. AB - The aim was to identify factors that could influence recruitment in a prospective longitudinal study involving pregnant women. A total of 269 nulliparous women were enrolled for a prospective longitudinal study, to establish the prevalence of levator ani muscle defects during childbirth. The project was explained verbally and potential participants were given an information leaflet. When eligible and interested, they provided their contact details to enquire if they were willing to participate. Out of the 1,473 women approached, 269 (18.3%) agreed to participate and 1,043 (70.8%) declined; 420 women (40.3%) did not provide a reason for non-participation (see text for further details). Most often mentioned reasons were 'being too busy', 'other pregnancy problems', 'no additional (internal) examination', 'moving (abroad)' and 'husband'. Women from different ethnicities and age groups gave a wide variety of reasons for non participation. This information can now be used by researchers recruiting women for comparable studies, to enhance recruitment and participation of eligible patients. PMID- 23815193 TI - A comparison of fasting plasma glucose and glucose challenge test for screening of gestational diabetes mellitus. AB - Glucose challenge test (GCT) has been used as an effective screening test for gestational diabetes mellitus (GDM), though it has its own limitations. Hence, we assessed the effectiveness of fasting plasma glucose (FPG) as a simpler alternative procedure. A prospective study was done in 500 pregnant women with gestational age between 22 and 37 weeks. FPG, GCT and GTT were performed in all patients using the glucose oxidase/peroxidase method. The overall sensitivity and specificity of GCT were 75.0% and 92.0%, respectively and the corresponding values for FPG were 88.8% and 95.2%. The positive predictive value and negative predictive value were 42.2% and 97.9% for GCT and 59.2% and 99.1% for FPG, respectively. We conclude that FPG can be used as an effective screening tool for gestational diabetes mellitus. PMID- 23815194 TI - Anaemia in pregnancy: a public health problem in Enugu, southeast Nigeria. AB - The aim of the study was to determine the prevalence of anaemia in pregnancy at booking and to determine factors associated with its occurrence in order to proffer solutions. This was a 12-month cross-sectional study of pregnant women attending the antenatal clinic for the first time (booking visit) at ESUTTH, Enugu, Nigeria from 1 April 2009 to 31 March 2010. Sociodemographic characteristics of the mothers were extracted using an already prepared proforma. The blood haemoglobin concentration and HIV status of the women were determined and the results were analysed. The prevalence rate of anaemia in pregnancy was 64.1%. Based on severity, 94.6%, 4.3%, 1.1% of them had mild, moderate and severe anaemia. The mean age of the anaemic women was significantly lower than that of the non-anaemic women (p = 0.0001). Those that had no formal education and those that booked for antenatal care in the 3rd trimester had a significantly higher prevalence of anaemia. HIV-positive pregnant women had a significantly higher prevalence of anaemia than HIV-negative pregnant women (p = 0.0072, odds ratio 2.37). It was concluded that the prevalence of anaemia in pregnancy from the study is unacceptably high. To achieve Millennium Development Goals 4 and 5, efforts must be geared towards its prevention to ensure a healthy baby and mother. PMID- 23815195 TI - Pregnancy outcomes in severe hyperemesis gravidarum in a multi-ethnic population. AB - We evaluated pregnancy outcomes among women with hyperemesis gravidarum (HG) in a North London multi-ethnic population. A retrospective case-control study was performed on records of obstetric admissions during a 4-year period, at North Middlesex University Hospital in North London. A total of 208 women with HG were identified according to Fairweather's criteria occurring in the first 20 weeks of pregnancy, which is severe enough to require admission to hospital. The control study group consisted of 208 women without HG, matched for age, ethnicity and parity. Maternal characteristics as well as pregnancy outcomes were compared in the two groups. The incidence of a delivery of a small-for-gestational-age (SGA) neonate below the 10th per centile was significantly higher in the HG group compared with unaffected pregnancies (8.7% vs 16.8%, p = 0.01). Hyperemesis gravidarum in a multi-ethnic population in North London is associated with SGA neonates. PMID- 23815196 TI - Quality of obstetric and midwifery care for pregnant women who have undergone female genital mutilation. AB - Despite the availability of professional guidelines for the pregnancy management of women affected by female genital mutilation (FGM), this study demonstrated major deficits in identification, management and safeguarding. PMID- 23815197 TI - A critique of current practice of transvaginal pudendal nerve blocks: a prospective audit of understanding and clinical practice. AB - Pudendal nerve blocks are a pre-requisite to forceps delivery without regional anaesthesia. Their efficacy is dependent on introducing local anaesthetic in close proximity to the pudendal nerve and allowing sufficient time for its onset of action. An audit of 57 obstetricians evaluated their clinical technique against standards using both a questionnaire and adapted model pelvis. The majority of participants were unable to describe correctly the point of infiltration and were unaware of the lag time required to effect adequate analgesia. We identify a deficiency in training and describe a method by which training can be facilitated and assessed. PMID- 23815198 TI - International variation in caesarean section rates and maternal obesity. AB - This study examined variations in caesarean section (CS) rates associated with a woman's birthplace and differences in maternal adiposity. Women were enrolled in the 1st trimester. Maternal adiposity was assessed by body mass index (BMI) and bioelectrical impedance analysis (BIA). Irish women were compared with women born in the 14 countries who joined the European Union (EU) before 2004 (EU 14), and with those born in 12 countries who joined following enlargement (EU 12). Of the 2,811 women enrolled, 2,235 women were born in Ireland, 100 in EU 14 countries and 476 in EU 12 countries. Based on a BMI > 29.9 kg/m(2), maternal obesity was higher in Irish (19.8%; n = 443) and EU 14 women (19.0%; n = 19) compared with EU 12 women (9.5%; n = 45), p < 0.001. BIA of maternal body composition confirmed increased adiposity in both the Irish and EU 14 women. Variations in emergency CS rates in primigravidas based on the woman's birthplace were associated with maternal adiposity and induction of labour, both modifiable risk factors for CS. We recommend, therefore, that induction of labour in obese primigravidas should be undertaken only in carefully considered clinical circumstances. Our findings also suggest economic development in Europe may drive an increase in the CS rates mediated through increased levels of maternal obesity and, therefore, public health interventions should focus on optimising a woman's prepregnancy weight. PMID- 23815199 TI - Information shared with mothers prior to caesarean section: a national audit of compliance with recommended information. AB - We assessed how information on complications at caesarean section was shared with mothers undergoing this operation and determined whether this information was within the NICE and RCOG guidelines. A postal questionnaire survey, involving 170 consultant-led maternity units in England, was sent out. We analysed the methods of giving this information and compliance with National guidelines and explored the need to standardise this information nationally. A response rate of 84.11% was achieved (143/170). A total of 50/143 (34.97%) units share information using risk stickers, pre-typed or standard checklist forms, which aim to achieve consistency of information sharing. In contrast 92/143 (64.34%) units rely on information given from memory of doctors. Subgroup analysis of 23 hospitals revealed large heterogeneity in information provided to women before caesarean section. Our survey indicated a large variation in the information given to women prior to caesarean section and thus the need for standardised written information. PMID- 23815200 TI - Vaginal birth after caesarean section (VBAC) in women with spontaneous labour: predictors of success. AB - We evaluated the predictors of VBAC success in Jordanian women with a single previous low transverse caesarean section of a gestational age of at least 28 weeks, followed by a trial of spontaneous labour at two tertiary hospitals between January 2008 and February 2010. Among 207 women, 117 (57%) women achieved a successful VBAC. Multivariate analysis showed that a cervical dilatation of >= 7 cm at the time of previous caesarean section was an independent predictor of successful VBAC (with a success rate of 80%). Parity of >= 2 was significantly associated with increased odds of success (OR = 2.7, 95% CI: 1.2, 6.2). Compared with women who had no previous VBAC, those with previous VBAC had higher odds of success (OR = 3.8 (95% CI: 1.5, 9.5). We concluded that women with a previous caesarean section who achieved a cervical dilatation of >= 7 cm before caesarean, had a previous history of successful VBAC and had parity of >= 2, have the greatest likelihood of successful VBAC. PMID- 23815201 TI - Imiquimod therapy for extramammary Paget's disease of the vulva: a viable non surgical alternative. AB - Extramammary Paget's disease (EMPD) is a rare intraepidermal adenocarcinoma that can affect the vulval skin. Surgical excision is the gold-standard treatment, however, recurrence rates are high and extensive excisions can produce long lasting cosmetic and functional defects. We describe one of the largest case series to-date (n = 6) on the use of topical 5% imiquimod cream as a novel treatment option and discuss our experiences. With the addition of our six cases to the literature, there are now 29 documented cases of vulval EMPD treated with 5% imiquimod cream. Of these, 50% of primary disease cases and 73% of recurrent primary disease cases have achieved clinical resolution with 5% imiquimod therapy alone. These findings suggest that imiquimod provides a viable alternative to surgical excision for vulval EMPD. However, we acknowledge that this is a simple retrospective analysis and that treatment scheduling and follow-up needs investigation in a trial setting. PMID- 23815202 TI - Menstrual cycle disorders in female volleyball players. AB - The aim of this study was to examine the relation between increased physical activity and menstrual disorders in adolescent female volleyball players. The study was conducted on 210 Polish female volleyball players, aged 13-17 years, the authorship questionnaire was used. The results of the study showed that irregular menstruation occurred in 19% of girls, spotting between menstrual periods in 27% and heavy menstruation was reported in 33% of girls. Out of all volleyball female players participating in the study, 94 girls (45%) declared absence of menstrual periods after regular cycles. Statistical analysis showed that the more training hours per week, the bigger probability of the occurrence of irregular menstruation. It was concluded that the number of hours of volleyball training per week affects regularity of menstrual cycles in female volleyball players. The absence of menstruation might be caused by the duration of training per week or years of training. PMID- 23815203 TI - Does psychosocial stress influence menstrual abnormalities in medical students? AB - A cross-sectional study was conducted among 164 students in a medical school in Pondicherry, India, by administering a questionnaire consisting of anthropometric data, menstrual history and psychosocial stress. Psychosocial stress was assessed using Perceived Stress Scale (PSS10). We observed that out of the 164 students who answered the questionnaire, students who reported premenstrual symptoms, irregular cycles and dysmenorrhoea severe enough to take medication had significantly higher mean PSS scores (p = 0.000, 0.025, 0.035, respectively). High stress (fourth quartile PSS score) was significantly associated with occurrence of premenstrual symptoms and dysmenorrhoea severe enough to take medication. Stress in medical students is associated with severe dysmenorrhoea, irregular cycles and premenstrual syndrome. This implies that interventions to reduce the stress can improve the menstrual health of medical students, thereby reducing future health risks and improving the quality of life. PMID- 23815204 TI - The clinical characteristics of women with recurrent implantation failure. AB - Recurrent implantation failure (RIF) refers to failure to conceive after three or more in vitro fertilisation (IVF) or embryo transfer cycles. Implantation failure may be due to embryo or uterine factors. There are many controversies surrounding the investigation and management of this condition. The aim of our study was to describe the clinical characteristics and the outcome of investigations of a group of women with recurrent implantation failure. A total of 111 couples with RIF were managed in a dedicated clinic and investigated according to a clinic protocol. The frequency of abnormal investigations were as follows: high (>= 10 IU/l) FSH, 14/107(13%); high free androgen index 6/78(8%); abnormal hysteroscopic findings 7/45(16%); hydrosalpinges 8/33(24%); persistently elevated ACA or tested positive for lupus anticoagulant 19/108 (18%); abnormal karyotype analysis 3/101(3%); hyperprolactinaemia 1/79(1%); abnormal thyroid function 4/100(4%) and tested positive for thyroid peroxidase antibody 10/104(10%). Specific treatments according to the results of investigation produced a live birth rate of 29%. It was concluded that the findings should help practitioners to construct suitable investigation protocols for the initial management of this condition. PMID- 23815205 TI - Evaluation of a group programme of mindfulness-based cognitive therapy for women with fertility problems. AB - Mindfulness-based cognitive therapy (MBCT) has proved helpful for a number of health-related conditions but there is relatively little published literature about its use with fertility problems. The aim of this paper is to describe a pilot group programme adopted by a Clinical Health Psychology department, and to present findings from the routine outcomes data gathered by the service, evaluating its effectiveness. Data from nine women with fertility problems that took part in the programme were analysed. They completed measures of wellbeing and psychological distress before and after the treatment. The results showed clinically significant improvements in participants' wellbeing scores and psychological distress. It was a limitation of the study that the impact of concurrent treatments could not be assessed and so could also have contributed to this outcome in half of the cases. Nevertheless, these results suggest that MBCT may be a helpful treatment for women presenting with fertility-related distress. PMID- 23815206 TI - An evaluation of the effects of a service change from epidurals to rectus sheath catheters on postoperative pain. AB - Epidurals are frequently used as part of multi-modal perioperative analgesia. They are widely accepted as providing excellent pain relief but are associated with side-effects, have a significant failure rate and can limit a patient's mobility. We report on our use of rectus sheath catheters (RSCs), in conjunction with intravenous opiate via patient controlled analgesia (PCA), as a means of providing analgesia post-laparotomy for gynaecological oncological patients. Our experience is that this offers an alternative method of providing equivalent analgesia, avoiding the risks associated with epidural use and possibly has a role in reducing length of patient stay, although this requires further investigation. PMID- 23815207 TI - Supra-umbilical vertical midline abdominal incision in morbidly obese gynaecological oncology patients. AB - The prevalence of obesity is rapidly increasing globally. Female malignancies linked to obesity comprise approximately 51% of newly diagnosed cancers. Endometrial, breast, ovarian and cervical cancers have been associated with obesity. Obesity presents problems with laparotomy incision placement and closure. Access to the pelvis can be challenging and there is a higher incidence of intraoperative complications. We review the outcome of seven patients where a supra-umbilical midline vertical laparotomy incision has been used in an attempt to minimise the surgical morbidity. PMID- 23815208 TI - Expression of cyclin A, cyclin E and p27 in normal, hyperplastic and frankly malignant endometrial samples. AB - Cellular growth is under the control of certain molecules such as cyclins and cyclin dependent kinases. Dysregulation of these proteins disrupt cell cycle and may trigger malignant transformation. Cyclins and kinase inhibitors also play essential roles in endometrial cellular proliferation. But the exact roles of these mediators in the disease process is not clear. We evaluated expression of cyclin A, cyclin E and p27 in normal, hyperplastic and malignant endometrial samples assuming different expression patterns in physiological and pathological processes. A total of 75 patients with histopathological diagnosis of normal proliferative, hyperplastic or malignant endometrial samples were evaluated with different cellular proliferation markers, cyclin A, cyclin E and p27. For cyclin E, endometrial cancer samples had higher rate of immunoreactivity than normal proliferative and hyperplastic endometrial samples. Staining properties for cyclin A were comparable for three groups. However, p27 immunoreactivity decreased progressively as lesions progress from proliferative benign endometrium to frank carcinoma. Further large-scale studies with clinical follow-up will reveal the exact role of cyclins on endometrial carcinogenesis. PMID- 23815209 TI - Membrane expression of the death ligand trail receptors DR4 and DR5 in the normal endometrium, endometrial atypical hyperplasia and endometrioid endometrial cancer. AB - To assess membrane expression of DR4 and DR5 in the normal endometrium (NE), endometrial atypical hyperplasia (EAH) and endometrioid endometrial cancer (EEC), the study examined 101 patients: 20 NE, 14 EAH and 67 EEC. The expression of DR4 and DR5 was examined and presented as the total score (TS). DR4 expression was seen in 18 NE, 11 EAH and 10 EEC. DR5 expression was seen in 20 NE, 13 EAH and 21 EEC. A strong correlation between type of endometrial tissue and TS of both receptors was identified. In EEC TS of DR4 and DR5 was not related to grading, staging or survival. Malignant transformation in the endometrium is related to reduction of membrane DR4 and DR5 expression. The level of membrane staining of the receptors in EEC is not dependent on grading and staging, and is not sufficient to predict survival in EEC patients. PMID- 23815210 TI - Methylation of the HOXA10 homeobox gene promoter is associated with endometrial cancer: a pilot study. AB - Methylation in the promoter region represents an epigenetic mechanism that silences expression of various homeobox genes in cancers. We compare the methylation profile of HOXA10 promoter gene in 19 histologically proven endometrioid cancers and 27 normal endometrial tissues. Endometrial cancer tissue displays significantly higher methylation status in HOXA10 gene promoter than normal tissue, suggesting a possible role of epigenetic changes in HOXA10 gene regulation in tumorigenesis. Further studies in human tissue and cell lines are necessary to validate these preliminary results and to investigate HOXA10 expression according to methylation status in endometrial cancer. PMID- 23815211 TI - Bilateral luteomas of pregnancy. PMID- 23815212 TI - Giant retroperitoneal lipoma in a pregnant patient. PMID- 23815213 TI - Paroxysmal nocturnal haemoglobinuria, lupus and pregnancy. PMID- 23815214 TI - Extremely delayed delivery of second and third fetus in spontaneous triplet pregnancy. PMID- 23815215 TI - A case of spontaneous conceived twins in uterus didelphys, with induction and delayed delivery between twins. PMID- 23815216 TI - Dehydrated hereditary stomatocytosis and recurrent prenatal ascites. PMID- 23815217 TI - An unusual cause of postpartum collapse: undiagnosed myasthenia gravis. PMID- 23815218 TI - Fatal Clostridium septicum following medical termination of pregnancy. PMID- 23815219 TI - Longstanding Crohn's vulvitis successfully treated with combined anti-TNFalpha antibody and azathioprine. PMID- 23815220 TI - Cornual pregnancy treated with methotrexate. PMID- 23815221 TI - A devastating cause of amenorrhoea. PMID- 23815222 TI - Fatty necrosis of a mesenteric cyst in a woman initially diagnosed with a large ovarian cystic mass. PMID- 23815223 TI - Diffuse peritoneal leiomyomatosis. PMID- 23815224 TI - Unsuspected metastatic choriocarcinoma presenting as unexplained severe anaemia. PMID- 23815225 TI - Isomorphous substitution in a flexible metal-organic framework: mixed-metal, mixed-valent MIL-53 type materials. AB - Mixed-metal iron-vanadium analogues of the 1,4-benzenedicarboxylate (BDC) metal organic framework MIL-53 have been synthesized solvothermally in N,N' dimethylformamide (DMF) from metal chlorides using initial Fe:V ratios of 2:1 and 1:1. At 200 degrees C and short reaction time (1 h), materials (Fe,V)(II/III)BDC(DMF(1-x)F(x)) crystallize directly, whereas the use of longer reaction times (3 days) at 170 degrees C yields phases of composition [(Fe,V)(III)0.5(Fe,V)0.5(II)(BDC)(OH,F)](0.5-).0.5DMA(+) (DMA = dimethylammonium). The identity of the materials is confirmed using high resolution powder X-ray diffraction, with refined unit cell parameters compared to known pure iron analogues of the same phases. The oxidation states of iron and vanadium in all samples are verified using X-ray absorption near edge structure (XANES) spectroscopy at the metal K-edges. This shows that in the two sets of materials each of the vanadium and the iron centers are present in both +2 and +3 oxidation states. The local environment and oxidation state of iron is confirmed by (57)Fe Mossbauer spectrometry. Infrared and Raman spectroscopies as a function of temperature allowed the conditions for removal of extra-framework species to be identified, and the evolution of MU2-hydroxyls to be monitored. Thus calcination of the mixed-valent, mixed-metal phases [(Fe,V)(III)0.5(Fe,V)0.5(II)(BDC)(OH,F)](0.5-).0.5DMA(+) yields single-phase MIL 53-type materials, (Fe,V)(III)(BDC)(OH,F). The iron-rich, mixed-metal MIL-53 shows structural flexibility that is distinct from either the pure Fe material or the pure V material, with a thermally induced pore opening upon heating that is reversible upon cooling. In contrast, the material with a Fe:V content of 1:1 shows an irreversible expansion upon heating, akin to the pure vanadium analogue, suggesting the presence of some domains of vanadium-rich regions that can be permanently oxidized to V(IV). PMID- 23815226 TI - Recombinant activated factor VII in patients with acute liver failure with UNOS Status 1A: a single tertiary academic centre experience. AB - BACKGROUND AND OBJECTIVES: Recombinant activated factor VII (rFVIIa) is often used in off-label indications, including many situations in which the patients are at risk of thrombosis. In this study, we retrospectively reviewed the use of rFVIIa in patients with acute liver failure - UNOS Status 1A (ALF-1A) to determine its efficacy and safety profile. MATERIALS AND METHODS: Using the transplantation records, all adult patients with ALF-1A were identified from 6/2001 to 3/2009. From patients' medical charts, rFVIIa dose, blood component usage, short-term outcomes [length of intensive care unit (ICU) and hospital stay, ability to undergo orthotopic liver transplant (OLT) and in-hospital survival rate] and adverse events were examined. RESULTS: Forty-two patients with ALF-1A were identified. Fifteen patients received rFVIIa with doses ranging between 24.4 MUg/kg and 126.8 MUg/kg. Three patients received two doses of rFVIIa. The age, baseline activated partial thromboplastin time (aPTT) and platelet (PLT) count were not statistically different between the group receiving rFVIIa versus the group that did not. However, the prothrombin time (PT) was significantly higher in the rFVIIa group. Although the rFVIIa group stayed in the ICU longer and required significant more blood products during admission, there was no statistical difference between the two groups in terms of length of hospital stay, ability to undergo OLT and survival rate. There was no increase in complications, including thrombosis, after receiving rFVIIa. CONCLUSION: Recombinant activated factor VII (rFVIIa) appears to be safe in patients with ALF 1A, but to elucidate its full role, a randomized controlled trial would be ideal. PMID- 23815227 TI - Distinct position-specific sequence features of hexa-peptides that form amyloid fibrils: application to discriminate between amyloid fibril and amorphous beta aggregate forming peptide sequences. AB - BACKGROUND: Comparison of short peptides which form amyloid-fibrils with their homologues that may form amorphous beta-aggregates but not fibrils, can aid development of novel amyloid-containing nanomaterials with well defined morphologies and characteristics. The knowledge gained from the comparative analysis could also be applied towards identifying potential aggregation prone regions in proteins, which are important for biotechnology applications or have been implicated in neurodegenerative diseases. In this work we have systematically analyzed a set of 139 amyloid-fibril hexa-peptides along with a highly homologous set of 168 hexa-peptides that do not form amyloid fibrils for their position-wise as well as overall amino acid compositions and averages of 49 selected amino acid properties. RESULTS: Amyloid-fibril forming peptides show distinct preferences and avoidances for amino acid residues to occur at each of the six positions. As expected, the amyloid fibril peptides are also more hydrophobic than non-amyloid peptides. We have used the results of this analysis to develop statistical potential energy values for the 20 amino acid residues to occur at each of the six different positions in the hexa-peptides. The distribution of the potential energy values in 139 amyloid and 168 non-amyloid fibrils are distinct and the amyloid-fibril peptides tend to be more stable (lower total potential energy values) than non-amyloid peptides. The average frequency of occurrence of these peptides with lower than specific cutoff energies at different positions is 72% and 50%, respectively. The potential energy values were used to devise a statistical discriminator to distinguish between amyloid-fibril and non-amyloid peptides. Our method could identify the amyloid-fibril forming hexa-peptides to an accuracy of 89%. On the other hand, the accuracy of identifying non-amyloid peptides was only 54%. Further attempts were made to improve the prediction accuracy via machine learning. This resulted in an overall accuracy of 82.7% with the sensitivity and specificity of 81.3% and 83.9%, respectively, in 10-fold cross-validation method. CONCLUSIONS: Amyloid fibril forming hexa-peptides show position specific sequence features that are different from those which may form amorphous beta-aggregates. These positional preferences are found to be important features for discriminating amyloid-fibril forming peptides from their homologues that don't form amyloid-fibrils. PMID- 23815228 TI - Keloid-derived keratinocytes exhibit an abnormal gene expression profile consistent with a distinct causal role in keloid pathology. AB - Keloids are disfiguring scars that extend beyond the original wound borders and resist treatment. Keloids exhibit excessive extracellular matrix deposition, although the underlying mechanisms remain unclear. To better understand the molecular basis of keloid scarring, here we define the genomic profiles of keloid fibroblasts and keratinocytes. In both cell types, keloid-derived cells exhibit differential expression of genes encompassing a diverse set of functional categories. Strikingly, keloid keratinocytes exhibited decreased expression of a set of transcription factor, cell adhesion, and intermediate filament genes essential for normal epidermal morphology. Conversely, they exhibit elevated expression of genes associated with wound healing, cellular motility, and vascular development. A substantial number of genes involved in epithelial mesenchymal transition were also up-regulated in keloid keratinocytes, implicating this process in keloid pathology. Furthermore, keloid keratinocytes displayed significantly higher migration rates than normal keratinocytes in vitro and reduced expression of desmosomal proteins in vivo. Previous studies suggested that keratinocytes contribute to keloid scarring by regulating extracellular matrix production in fibroblasts. Our current results show fundamental abnormalities in keloid keratinocytes, suggesting they have a profoundly more direct role in keloid scarring than previously appreciated. Therefore, development of novel therapies should target both fibroblast and keratinocyte populations for increased efficacy. PMID- 23815229 TI - Resveratrol inhibits fibrogenesis and induces apoptosis in keloid fibroblasts. AB - Keloids are benign dermal fibrotic tumors arising during the wound healing process. The mechanisms of keloid formation and development still remain unknown, and no effective treatment is available. Resveratrol, a dietary compound, has anticancer properties and, from recent studies, it has been suggested that resveratrol may have an antifibrogenic effect on organs such as the liver and kidney. Based on this idea, we investigated its effect on the regulation of extracellular matrix expression, proliferation, and apoptosis of keloid fibroblasts. Type I collagen, alpha-smooth muscle actin, and heat shock protein 47 expression decreased in resveratrol-treated keloid fibroblasts in a dose dependent manner. In addition, resveratrol diminished transforming growth factor beta1 production by keloid fibroblasts. We also demonstrated that it suppressed their proliferation and induced apoptosis of the fibroblasts. Conversely, resveratrol did not decrease type I collagen, alpha-smooth muscle actin, and heat shock protein 47 mRNA expression in normal skin fibroblasts and barely suppressed cell proliferation. Our data indicate that resveratrol may have an antifibrogenic effect on keloid fibroblasts without any adversely effects on normal skin fibroblasts, suggesting the potential application of resveratrol for the treatment of keloids. PMID- 23815230 TI - Leucine-rich glioma inactivated 3 promotes HaCaT keratinocyte migration. AB - Our finding that human skin expresses leucine-rich glioma inactivated 3 (LGI3) raises the question of the function of this cytokine in keratinocytes. We have shown that LGI3 stimulates human HaCaT keratinocyte migration without affecting viability or proliferation. Western blot analysis showed that LGI3 induced focal adhesion kinase activation, Akt phosphorylation, and glycogen synthase kinase 3beta (GSK3beta) phosphorylation in these cells. Using the scratch wound assay and a modified Boyden chamber, we found that LY294002, a selective phosphatidylinositol 3-kinase inhibitor, and LiCl, a selective GSK3beta inhibitor, abolished LGI3-induced cell migration. We tested beta-catenin levels after LGI3 treatment because the Akt-GSK3beta pathway regulates beta-catenin accumulation, and beta-catenin promotes cell migration. LGI3 treatment increased beta-catenin protein and nuclear localization, whereas LY294002 prevented LGI3 induced focal adhesion kinase and Akt activation as well as beta-catenin accumulation. Overall, these data suggest that LGI3 stimulates HaCaT cell migration following beta-catenin accumulation through the Akt pathway. PMID- 23815231 TI - WEP: a high-performance analysis pipeline for whole-exome data. AB - BACKGROUND: The advent of massively parallel sequencing technologies (Next Generation Sequencing, NGS) profoundly modified the landscape of human genetics.In particular, Whole Exome Sequencing (WES) is the NGS branch that focuses on the exonic regions of the eukaryotic genomes; exomes are ideal to help us understanding high-penetrance allelic variation and its relationship to phenotype. A complete WES analysis involves several steps which need to be suitably designed and arranged into an efficient pipeline.Managing a NGS analysis pipeline and its huge amount of produced data requires non trivial IT skills and computational power. RESULTS: Our web resource WEP (Whole-Exome sequencing Pipeline web tool) performs a complete WES pipeline and provides easy access through interface to intermediate and final results. The WEP pipeline is composed of several steps:1) verification of input integrity and quality checks, read trimming and filtering; 2) gapped alignment; 3) BAM conversion, sorting and indexing; 4) duplicates removal; 5) alignment optimization around insertion/deletion (indel) positions; 6) recalibration of quality scores; 7) single nucleotide and deletion/insertion polymorphism (SNP and DIP) variant calling; 8) variant annotation; 9) result storage into custom databases to allow cross-linking and intersections, statistics and much more. In order to overcome the challenge of managing large amount of data and maximize the biological information extracted from them, our tool restricts the number of final results filtering data by customizable thresholds, facilitating the identification of functionally significant variants. Default threshold values are also provided at the analysis computation completion, tuned with the most common literature work published in recent years. CONCLUSIONS: Through our tool a user can perform the whole analysis without knowing the underlying hardware and software architecture, dealing with both paired and single end data. The interface provides an easy and intuitive access for data submission and a user-friendly web interface for annotated variant visualization.Non-IT mastered users can access through WEP to the most updated and tested WES algorithms, tuned to maximize the quality of called variants while minimizing artifacts and false positives.The web tool is available at the following web address: http://www.caspur.it/wep. PMID- 23815232 TI - The recovery of pelvic organ support during the first year postpartum. AB - OBJECTIVE: Compare changes in pelvic organ prolapse (POP) from 36-38 weeks of gestation to 1 year postpartum after unlaboured cesarean delivery(UCD)and trial of labour (TOL). DESIGN: Prospective observational cohort study. SETTING: Wenzhou Third People's Hospital, Wenzhou, Zhejiang, China. POPULATION: Nulliparous women undergoing UCD or TOL. METHODS: Pelvic organ prolapse was assessed at 36-38 weeks of gestation, then at 6 weeks, 6 months and 1 year postpartum, using the Pelvic Organ Prolapse Quantification (POPQ) system. MAIN OUTCOME MEASURES: Postpartum POP status in UCD and TOL determined by POPQ measurements over time. RESULTS: Points Aa (Ba) determined the final stage assignment in most cases. Stage II POP was present in 35% and 37% of women in UCD and TOL at 36-38 weeks of gestation. After delivery, the likelihood of stage II POP declined during the first year postpartum in the whole cohort. The TOL group was much less likely to recover from stage II POP compared with the UCD group (odds ratio 0.04, 95% confidence interval 0.01-0.18) after adjustment for POP status at 36-38 weeks of gestation, age, first-trimester body mass index, newborn birthweight, educational level, gravidity and smoking status. With the exception of age, education and gravidity, these covariates were also independent predictors of postpartum POP. CONCLUSION: Factors unique to labour and delivery lead to sustained pelvic floor relaxation postpartum. Pelvic organ prolapse at 36-38 weeks of gestation, and higher first trimester body mass index also appear to predict long-term POP. Further investigation into mechanisms leading to persistent or progressive POP after TOL are warranted. In addition, caution is needed in generalising the findings due to the single-centre design. PMID- 23815233 TI - Merely opting out of a public good is moralized: an error management approach to cooperation. AB - People regularly free ride on collective benefits, consuming them without contributing to their creation. In response, free riders are often moralized, becoming targets of negative moral judgments, anger, ostracism, or punishment. Moralization can change free riders' behavior (e.g., encouraging them to contribute or discouraging them from taking future benefits) or it can motivate others, including moralizers, to avoid or exclude free riders; these effects of moralization are critical to sustaining human cooperation. Based on theories of error management and fundamental social domains from evolutionary psychology, we propose that the decision to moralize is a cue-driven process. One cue investigated in past work is observing a person illicitly consume collective benefits. Here, we test whether the mind uses a 2nd cue: merely opting out of contributing. Use of this cue creates a phenomenon of preventive moralization: moralization of people who have not yet exploited collective benefits but who might-or might not--in the future. We tested for preventive moralization across 9 studies using implicit and explicit measures of moralization, a behavioral measure of costly punishment, mediation analyses of the underlying processes, and a nationally representative sample of almost 1,000 U.S. adults. Results revealed that merely opting out of contributing to the creation of exploitable collective benefits--despite not actually exploiting collective benefits-elicited moralization. Results further showed that preventive moralization is not due to the moralization of selfishness or deviance but instead follows from the uncertainty inherent in moralization decisions. These results imply that even people who will never exploit collective benefits can nonetheless be targets of moralization. We discuss implications for social and political dynamics. PMID- 23815234 TI - The meaning and role of ideology in system justification and resistance for high- and low-status people. AB - In this article we explore how beliefs about system ideals and the achievement of those ideals differentially predict system justification among low- and high status groups. Our goal was to reconcile how people can promote system ideals such as equal opportunities for all and at the same time recognize that group based disparities are, in part, due to these unfulfilled ideals. Three studies examined whether people perceived a discrepancy between a system's ideal goals and its achievement of those goals. Everyone endorsed these goal ideals more than they believed that the goals were being achieved; however, this discrepancy was larger for low-status people. The larger the perceived discrepancy, the more dissatisfied people were with the system and the more likely they were to support hierarchy-attenuating policies. Studies 2 and 3 also examined people's motivation for endorsing goal ideals. People of all statuses endorsed system ideals to promote an ideal system more than to legitimize the actual system (Study 2); however, high-status people were slightly more likely to endorse system ideals to legitimize the actual system than low-status people (Study 3). In summary, low status people were more likely than high-status people to recognize discrepancies between system goals and system outcomes, show dissatisfaction with the American system, and prefer policies that would attenuate extant hierarchies. PMID- 23815235 TI - Care managers' confidence in managing home-based end-of-life care: a cross sectional study. AB - BACKGROUND: There are increasing occasions for care managers (CMs) to manage end of-life (EOL) situations for older persons at home, in Japan. However, many CMs report anxiety, difficulties and low confidence in managing such care, although confidence is considered a significant determinant of professional performance. This study examined the confidence of CMs at managing home-based EOL situations and its factors. METHODS: Participants of this cross-sectional study were CMs from 1,200 homecare agencies in Japan, which were systematically sampled from a national database. Participants were asked about their overall confidence in managing home-based EOL situations, as well as their demographic, professional and agency characteristics. Multiple logistic regression analysis was conducted to examine the factors associated with CM confidence levels. RESULTS: Valid responses were obtained from 458 participants (response rate, 39.4%). Among the respondents, 81.0% (n = 371) were female; mean age 49.2 years old (standard deviation = 8.8). Their professional backgrounds included nurses (28.2%), care workers (49.8%), social workers (10.9%), and home attendants (6.1%). Approximately 70% of CMs expressed some level of confidence in managing home based EOL situations. Multiple logistic regression analysis showed that being confident was significantly associated with having a nursing license (OR: 2.71, 95% CI: 1.26-6.19) and having an additional work responsibility other than being a CM, such as working as a homecare nurse or a home attendant (OR: 2.78, 95% CI: 1.06-4.74). Higher confidence levels were more frequently reported among those who had multiple experiences with EOL situations, compared with those who had none, or only one experience: OR=2.60 (95% CI 1.26-5.50) for those with 2-3 cases; OR=7.12 (3.21-16.56) for those with 4-10 cases; OR = 33.67 (8.14-235.19) for those with 11 cases and over. CONCLUSIONS: These results suggest that CMs with direct, hands-on experience with EOL care, or who have managed multiple EOL cases, tended to be confident at managing home-based EOL situations. Given that the number of nurses working as CMs is decreasing, further research is needed to explore what support CMs need to increase their confidence, especially when the CMs do not have nursing licenses and/or experience with EOL situations. PMID- 23815236 TI - Characterization of a liver organoid tissue composed of hepatocytes and fibroblasts in dense collagen fibrils. AB - The adult liver is wrapped in a connective tissue sheet called the liver capsule, which consists of collagen fibrils and fibroblasts. In this study, we set out to construct a liver organoid tissue that would be comparable to the endogenous liver, using a bioreactor. In vitro liver organoid tissue was generated by combining collagen fibrils, fibroblasts, and primary murine hepatocytes or Hep G2 on a mesh of poly-lactic acid fabric using a bioreactor. Then, the suitability of this liver organoid tissue for transplantation was tested by implanting the constructs into partially hepatectomized BALB/cA-nu/nu mice. As determined by using scanning and transmission electron microscopes, the liver organoid tissues were composed of densely packed collagen fibrils with fibroblasts and aggregates of oval or spherical hepatocytes. Angiogenesis was induced after the transplantation, and blood vessels connected the liver organoid tissue with the surrounding tissue. Thus, a novel approach was applied to generate transplantable liver organoid tissue within a condensed collagen fibril matrix. These results suggested that a dense collagen network populated with fibroblasts can hold a layer of concentrated hepatocytes, providing a three-dimensional microenvrionment suitable for the reestablishment of cell-cell and cell-extracellular matrix (ECM) interactions, and resulting in the maintenance of their liver-specific functions. This liver organoid tissue may be useful for the study of intrahepatic functions of various cells, cytokines, and ECMs, and may fulfill the fundamental requirements of a donor tissue. PMID- 23815237 TI - Prenatal diagnosis of X-linked recessive Lenz microphthalmia syndrome. AB - Lenz microphthalmia syndrome comprises microphthalmia-anophthalmia with mental retardation, malformed ears and skeletal anomalies, and is inherited in an X linked recessive pattern. In 2004, it was reported that the missense mutation (BCL-6 co-repressor gene [BCOR] c.254C>T, p.P85L) in a single family with Lenz microphthalmia syndrome co-segregated with the disease phenotype. We report a case of prenatal diagnosis for X-linked recessive Lenz microphthalmia syndrome with the mutation. A 32-year-old gravida 5, para 2 Japanese woman was referred to Nagoya City University Hospital at 15 weeks of gestation. After genetic counseling and informed consent, amniocentesis was performed for fetal karyotyping, which was 46,XY. Using the extracted DNA from cultured amniotic cells, fetal search for BCOR c.254C>T mutation was undertaken. The couple requested medical termination of pregnancy, and the postabortion examination confirmed the diagnosis. This is the third report of a BCOR mutation, associated with X-linked syndromic microphthalmia, and most importantly, it is always the same mutation. The prenatal genetic diagnosis of the Lenz microphthalmia syndrome allowed time for parental counseling and delivery planning. PMID- 23815239 TI - The relationship between the FFM personality traits, state psychopathology, and sexual compulsivity in a sample of male college students. AB - INTRODUCTION: Several studies have advocated a relationship between psychopathological features and sexual compulsivity. Such relationship is often found among individuals seeking help for out of control sexual behavior, suggesting that the association between psychological adjustment and sexual compulsivity may have a significant clinical value. However, a more complete approach to the topic of sexual compulsivity would also include the analysis of nonclinical samples as healthy individuals may be at risk of developing some features of hypersexuality in the future. AIM: The aim of this study was to explore the relationship between stable traits of personality, state psychopathology, and sexual compulsivity in a sample of male college students. Furthermore, the potential mediating role of state psychopathology in the relationship between personality traits and sexual compulsivity was tested. MAIN OUTCOME MEASURES: Participants completed the following measures: the NEO Five Factor Inventory, the Brief Symptom Inventory, and the Compulsive Sexual Behavior Inventory-22. METHODS: The sample included 152 male college students recruited in a Portuguese university using nonrandom methods. The measures were completed individually and anonymously. RESULTS: Findings on state psychopathology suggested that psychoticism may be one of the key dimensions associated with sexual compulsivity in male students. The personality traits of Neuroticism and Agreeableness were also significant predictors of sexual compulsivity. Findings on the mediating effects suggested that state psychopathology mediated the relationship between Neuroticism and sexual compulsivity but not between Agreeableness and sexual compulsivity. CONCLUSIONS: A psychopathological path (encompassing Neuroticism and state psychopathology) and a behavioral path (encompassing Agreeableness features) may be involved in sexual compulsivity as reported by a nonclinical sample of male students. PMID- 23815240 TI - Quantifying cardiovascular disease risk factors in patients with psoriasis: a meta-analysis. AB - BACKGROUND: In a previous meta-analysis on categorical data we found an association between psoriasis and cardiovascular disease and associated risk factors. OBJECTIVES: To quantify the level of cardiovascular disease risk factors in order to provide additional data for the clinical management of the increased risk. METHODS: This was a meta-analysis of observational studies with continuous outcome using random-effects statistics. A systematic search of studies published before 25 October 2012 was conducted using the databases Medline, EMBASE, International Pharmaceutical Abstracts, PASCAL and BIOSIS. RESULTS: We included 59 studies with up to 18 666 cases and 50 724 controls. Psoriasis cases had a higher total cholesterol [weighted mean difference 8.83 mg dL(-1) , 95% confidence interval (CI) 2.94-14.72, P = 0.003 (= 0.23 mmol L(-1) )], higher low density lipoprotein cholesterol [9.90 mg dL(-1) , 95% CI 1.56-18.20, P = 0.020 (= 0.25 mmol L(-1) )], higher triglyceride [16.32 mg dL(-1) , 95% CI 12.02-20.63, P < 0.001 (= 0.18 mmol L(-1) )], a higher systolic blood pressure (4.77 mmHg, 95% CI 1.62-7.92, P = 0.003), a higher diastolic blood pressure (2.99 mmHg, 95% CI 0.60-5.38, P = 0.014), higher body mass idex (0.73 kg m(-2) , 95% CI 0.37-1.09, P < 0.001), higher waist circumference (3.61 cm, 95% CI 2.12-5.10, P < 0.001), higher fasting glucose [3.52 mg dL(-1) , 95% CI 0.64-6.41, P = 0.017 (= 0.20 mmol L(-1) )], higher nonfasting glucose [11.70 mg dL(-1) , 95% CI 11.24-12.15, P < 0.001 (= 0.65 mmol L(-1) )] and a higher HbA1c [1.09 mmol mol(-1) , 95% CI 0.87 1.31, P < 0.001 (= 2.2%)]. CONCLUSIONS: From a preventive medicine perspective, the weighted mean differences between cases and controls are significant, and therefore relevant to the clinical management of patients with psoriasis. PMID- 23815241 TI - Vitamin B12-induced acneiform eruption. AB - Drug-induced acne is a specific subset of acne that usually has some specific features, namely monomorphic pattern, unusual location of the lesions beyond the seborrheic areas, uncommon age of onset, a resistance to conventional acne treatment. Several drugs have been associated with the development of eruptions that may simulate acne vulgaris. However, so far, there are a few cases of vitamin B12-induced acne. We report a case of acneiform eruption induced by vitamin B12 injection in a 37-year-old female patient. PMID- 23815242 TI - Copolymer-incarcerated nickel nanoparticles with N-heterocyclic carbene precursors as active cross-linking agents for Corriu-Kumada-Tamao reaction. AB - We have developed heterogeneous polymer-incarcerated nickel nanoparticles (NPs), which catalyze cross-coupling reactions. The matrix structure of these catalysts incorporates both N-heterocyclic carbenes (NHCs) as ligands and Ni-NPs, thanks to a new design of cross-linking agents in polymer supports. These embedded NHCs were detected by field gradient swollen-resin magic angle spinning NMR analysis. They were successfully applied to Corriu-Kumada-Tamao reactions with a broad substrate scope including functional group tolerance, and the catalyst could be recovered and reused several times without loss of activity. PMID- 23815243 TI - Thromboelastographic evaluation of dogs with congenital portosystemic shunts. AB - BACKGROUND: On plasma-based assays, dogs with congenital portosystemic shunts (CPSS) have changes in serum concentrations of both pro- and anticoagulant proteins, but how these abnormalities affect whole blood coagulation assays (eg, thromboelastography) are unknown. OBJECTIVES: To conduct kaolin-activated thromboelastography (TEG) analysis in dogs with CPSS and to compare TEG coagulation status with clinical presentation, routine serum biochemistry, and plasma-based coagulation tests. ANIMALS: Twenty-one client-owned dogs with CPSS confirmed by ultrasound examination or nuclear scintigraphy. METHODS: In a prospective study, signalment, clinical presentation, TEG analysis, CBC, serum biochemistry, and hemostatic tests (platelet count, prothrombin time [PT], activated partial thromboplastin time [aPTT], quantitative fibrinogen, antithrombin [AT] activity, protein C [PC] activity, d-dimers, and factor VIII activity) were analyzed in dogs with CPSS. RESULTS: Dogs with CPSS had significantly shorter K values and increased angle, maximum amplitude (MA), and G values compared with the reference population. On plasma-based coagulation testing, dogs with CPSS had significantly prolonged PT, lower platelet counts, lower AT and PC activities, and increased d-dimers and factor VIII activity. Evaluation of G value defined 9/21 dogs with CPSS as hypercoagulable. These dogs were more likely to have hepatic encephalopathy (HE) than CPSS dogs that had normal coagulation. CONCLUSIONS AND CLINICAL IMPORTANCE: TEG analysis detected hemostatic abnormalities consistent with a hypercoagulable state in some dogs with CPSS. The presence of a hypercoagulable state was 40 times more likely in dogs with symptomatic HE. PMID- 23815244 TI - Synthesis and properties of 2'-O,4'-C-ethyleneoxy bridged 5-methyluridine. AB - 2'-O,4'-C-Ethyleneoxy bridged 5-methyluridine (EoNA-T), possessing a seven membered linkage and an anomeric 4'-carbon, was synthesized and introduced into oligonucleotides by using an automated DNA synthesizer. The EoNA-modified oligonucleotides significantly stabilized the duplexes with single-stranded RNA and triplexes with double-stranded DNA relative to the natural oligonucleotide and oligonucleotides modified by another seven-membered bridged 5-methyluridine, 2',4'-BNA(COC)-T. In addition, EoNA-T showed excellent nuclease resistance. PMID- 23815245 TI - Delayed diagnosis of cervical spondylotic myelopathy by primary care physicians. AB - OBJECT: A retrospective study analyzing medical files of patients who had undergone surgical management for cervical spondylotic myelopathy (CSM) at a single tertiary hospital was performed to determine the time needed by community care physicians to reach a diagnosis of CSM in patients presenting with typical myelopathic signs and symptoms, and to establish the reasons for the delayed diagnosis when present. Previous studies have documented that early diagnosis and surgical treatment of CSM may improve patients' neurological as well as general outcome. However, patients complaining of symptoms compatible with CSM may undergo lengthy medical investigations and treatments by community-based physicians before a correct diagnosis is made. The authors have found no published data on the process and time frame involved in attaining a diagnosis of CSM in the community setting. METHODS: The medical records of 42 patients were retrospectively reviewed for demographic data, symptoms, time to diagnosis, physician specialty, number of visits involved in the diagnostic process, and neurological status prior to surgery. RESULTS: The mean time delay from initiation of symptoms to diagnosis of CSM was 2.2 +/- 2.3 years. The majority of symptomatic patients (90.4%) initially presented to a family practitioner (69%) or an orthopedic surgeon (21.4%), with fewer patients (9.6%) referring to other disciplines (for example, the emergency department) for initial care. In contrast, the diagnosis of CSM was most often made by neurosurgeons (38.1%) and neurologists (28.6%), and less frequently by orthopedic surgeons (19%) or family physicians (4.8%). CONCLUSIONS: The diagnosis of CSM in the community is frequently delayed, leading to late referral for surgery. A higher index of suspicion for this debilitating entity is required from family practitioners and community-based orthopedic surgeons to prevent neurological sequelae. PMID- 23815246 TI - Epidemiology of cervical spondylotic myelopathy and its risk of causing spinal cord injury: a national cohort study. AB - OBJECT: This study aimed to determine the age- and sex-specific incidence of cervical spondylotic myelopathy (CSM) and its associated risk of causing subsequent spinal cord injury (SCI). METHODS: Using the National Health Insurance Research Database (NHIRD), a 12-year nationwide database in Taiwan, this retrospective cohort study analyzed the incidence of hospitalization caused by CSM. All patients diagnosed with and admitted for CSM were identified during the study period. The CSM patients were divided into 2 groups, a control group and an operated group. An incidence density method was used to estimate age- and sex specific incidence rates of CSM. The Kaplan-Meier method and Cox regression analyses were performed to compare the risk of SCI between the 2 groups. RESULTS: From 1998 to 2009, covering 349.5 million person-years, 14,140 patients were hospitalized for CSM. The overall incidence of CSM-related hospitalization was 4.04 per 100,000 person-years. Specifically, males and older persons had a higher incidence rate of CSM. During the follow-up of these patients for 13,461 person years, a total of 166 patients were diagnosed with SCI. The incidence of SCI was higher in the control group than the operated group (13.9 vs 9.4 per 1000 person years, respectively). During the follow-up, SCI was more likely to occur in CSM patients who were treated conservatively (crude HR 1.48, p = 0.023; adjusted HR 1.57, p = 0.011) than in those who underwent surgery for CSM. CONCLUSIONS: In a national cohort of eastern Asia, the incidence of CSM-caused hospitalization was 4.04 per 100,000 person-years, with higher incidences observed in older and male patients. Subsequent SCI was more likely to develop in patients who received nonoperative management than in those who underwent surgery. Therefore, patients with CSM managed without surgery should be cautioned about SCI. However, further investigations are still required to clarify the risks and complications associated with surgery for CSM. PMID- 23815247 TI - Clinical value of 2-deoxy-[18F]fluoro-D-glucose positron emission tomography in patients with cervical spondylotic myelopathy. AB - Cervical spondylotic myelopathy (CSM) is one of the most common spinal cord disorders in the elderly. It is usually diagnosed by MRI, but in a significant number of patients the clinical course of CSM does not correlate with the extent of the spinal cord compression. Recent studies have suggested that a distinct metabolic pattern of the cervical cord, as assessed by PET with 2-deoxy [(18)F]fluoro-D-glucose ((18)F-FDG) may predict a patient's clinical outcome after decompressive surgery for cervical spine stenosis. The authors provide an overview of the recent literature regarding the value of PET with (18)F-FDG of the cervical cord in patients with CSM, paying attention to prognostic aspects and the potential role of inflammatory processes in the acute phase of the disease. PMID- 23815248 TI - Synovial cysts of the cervicothoracic junction causing myelopathy: report of 3 cases and review of the literature. AB - Synovial cysts are uncommon pathological entities in patients with cervical degenerative spinal disease, and there are only a few reports in the literature. Treatment typically involves decompression; however, biomechanical data indicate that laminectomies in the cervical spine also result in cervical instability, specifically within the cervicothoracic junction, supporting the use of fusion as well. The authors describe the use of fusion with decompression in the treatment of 3 patients with cervicothoracic synovial cysts that presented in an acute fashion with associated myelopathy and neurological decline, and they review the diagnostic elements, histopathology, and treatment of these cysts. All 3 of the patients did well with decompression via a posterior approach with a single-level instrumented fusion from C-7 to T-1. Each patient regained complete neurological function and had no residual neurological deficits. These results are promising, although the sample size of 3 cases is too small to make any conclusive evaluations. Future studies incorporating Class I and Class II data are imperative to make firm conclusions regarding general management of this rare entity. PMID- 23815249 TI - A comparative effectiveness study of patient-rated and radiographic outcome after 2 types of decompression with fusion for spondylotic myelopathy: anterior cervical discectomy versus corpectomy. AB - OBJECT: Both anterior cervical discectomy with fusion (ACDF) and anterior cervical corpectomy with fusion (ACCF) are used to treat cervical spondylotic myelopathy; however, there is currently no evidence for the superiority of one over the other in terms of patient-rated outcomes. This comparative effectiveness study compared the patient-rated and radiographic outcomes of 2-level ACDF versus 1-level ACCF. METHODS: This single-center study was nested within the EuroSpine Spine Tango data acquisition system. Inclusion criteria were the following: consecutive patients presenting with signs of cervical spondylotic myelopathy who underwent 2-level ACDF or 1-level ACCF between 2004 and 2011. Before and 12 months after surgery, patients completed the multidimensional Core Outcome Measures Index (COMI) and also rated global treatment outcome and satisfaction with care on 5-point Likert scales. Cervical lordosis, segmental height, and fusion rate were assessed radiographically before and immediately after surgery and at the last follow-up (20.4 +/- 13.7 months, mean +/- SD). RESULTS: In total, 118 consecutive patients (80 in the ACDF group and 38 in the ACCF group) were included. Age, sex, comorbidity, baseline symptoms, baseline radiographic data, operation duration, and complication rates did not differ significantly between the 2 groups. Blood loss was significantly (p < 0.04) lower in the ACDF group. Postoperative mean segmental height was significantly (p = 0.0006) greater for ACDF (42.0 +/- 4.2 mm, mean +/- SD) than for ACCF (39.0 +/- 4.0 mm), and global average lordosis improved to a significantly (p = 0.003) greater extent in ACDF (by 1.6 degrees +/- 4.1 degrees ) than in ACCF (by -1.0 degrees +/- 4.0 degrees ). Fusion rates for ACDF were 97.5% and for ACCF were 94.7% (p = 0.59). The 12 month patient-rated outcomes did not differ significantly between ACDF and ACCF: 82.4% and 68.6% had a good global outcome (operation helped/helped a lot) (p = 0.10), 86.5% and 82.9% were satisfied/very satisfied with care (p = 0.62), and the reduction in the multidimensional COMI was 2.8 +/- 2.7 and 2.2 +/- 3 points (p = 0.30), respectively. The postoperative increase in lordosis angle showed low but significant correlations with the improvement in arm pain (r = 0.25, p = 0.014), highest pain (r = 0.25, p = 0.013), and function (r = 0.24, p = 0.016). CONCLUSIONS: Both ACDF and ACCF are safe and effective in the treatment of cervical spondylotic myelopathy, indicated by similarly good patient-rated outcomes 1 year after surgery. This precludes any conclusions regarding the superiority of one technique over the other, although it should be noted that ACDF resulted in less blood loss and greater improvements in cervical lordosis and segmental height than ACCF. Patients with improved lordosis angle had a better clinical outcome. PMID- 23815250 TI - Ventral fusion versus dorsal fusion: determining the optimal treatment for cervical spondylotic myelopathy. AB - Cervical spondylotic myelopathy (CSM) often can be surgically treated by either ventral or dorsal decompression and fusion. However, there is a lack of high level evidence on the relative advantages and disadvantages for these treatments of CSM. The authors' goal was to provide a comprehensive review of the relative benefits of ventral versus dorsal fusion in terms of quality of life (QOL) outcomes, complications, and costs. They reviewed 7 studies on CSM published between 2003 and 2013 and summarized the findings for each category. Both procedures have been shown to lead to statistically significant improvement in clinical outcomes for patients. Ventral fusion surgery has been shown to yield better QOL outcomes than dorsal fusion surgery. Complication rates for ventral fusion surgery range from 11% to 13.6%, whereas those for dorsal fusion surgery range from 16.4% to 19%. Larger randomized controlled trials are needed, with particular emphasis on QOL and minimum clinically important differences. PMID- 23815251 TI - Evidence-based management of central cord syndrome. AB - OBJECT: Evidence-based medicine is used to examine the current treatment options, timing of surgical intervention, and prognostic factors in the management of patients with traumatic central cord syndrome (TCCS). METHODS: A computerized literature search of the National Library of Medicine database, Cochrane database, and Google Scholar was performed for published material between January 1966 and February 2013 using key words and Medical Subject Headings. Abstracts were reviewed and selected, with the articles segregated into 3 main categories: surgical versus conservative management, timing of surgery, and prognostic factors. Evidentiary tables were then assembled, summarizing data and quality of evidence (Classes I-III) for papers included in this review. RESULTS: The authors compiled 3 evidentiary tables summarizing 16 studies, all of which were retrospective in design. Regarding surgical intervention versus conservative management, there was Class III evidence to support the superiority of surgery for patients presenting with TCCS. In regards to timing of surgery, most Class III evidence demonstrated no difference in early versus late surgical management. Most Class III studies agreed that older age, especially age greater than 60-70 years, correlated with worse outcomes. CONCLUSIONS: No Class I or Class II evidence was available to determine the efficacy of surgery, timing of surgical intervention, or prognostic factors in patients managed for TCCS. Hence, there is a need to perform well-controlled prospective studies and randomized controlled clinical trials to further investigate the optimal management (surgical vs conservative) and timing of surgical intervention in patients suffering from TCCS. PMID- 23815252 TI - Intraoperative neuromonitoring with MEPs and prediction of postoperative neurological deficits in patients undergoing surgery for cervical and cervicothoracic myelopathy. AB - OBJECT: The use of intraoperative neurophysiological monitoring (IONM) in surgical decompression surgery for myelopathy may assist the surgeon in taking corrective measures to reduce or prevent permanent neurological deficits. We evaluated the efficacy of IONM in cervical and cervicothoracic spondylotic myelopathy (CSM) cases. METHODS: The authors retrospectively reviewed 140 cases involving patients who underwent surgery for CSM utilizing IONM during 2011 at the University of California, San Francisco. Data on preoperative clinical variables, intraoperative changes in transcranial motor evoked potentials (MEPs), and postoperative new neurological deficits were collected. Associations between categorical variables were analyzed with the Fisher exact test. RESULTS: Of the 140 patients, 16 (11%) had significant intraoperative decreases in MEPs. In 8 of these cases, the MEP signal did not return to baseline values by the end of the operation. There were 8 (6%) postoperative deficits, of which 6 were C-5 palsies and 2 were paraparesis. Six of the patients with postoperative deficits had demonstrated persistent MEP signal change on IONM. There was a significant association between persistent MEP changes and postoperative deficits (p < 0.001). The sensitivity of intraoperative MEP monitoring was 75%, the specificity 98%, the positive predictive value 75%, and the negative predictive value 98%. Due to higher rates of false negatives, the sensitivity decreased to 60% in the subgroup of patients with vascular disease comorbidity. The sensitivity increased to 100% in elderly patients and in patients with preoperative motor deficits. The sensitivity and positive predictive value of deltoid and biceps MEP changes in predicting C-5 palsy were 67% and 67%, respectively. CONCLUSIONS: The authors found a correlation between decreased intraoperative MEPs and postoperative new neurological deficits in patients with CSM. Sensitivity varies based on patient comorbidities, age, and preoperative neurological function. Monitoring of MEPs is a useful adjunct for CSM cases, and the authors have developed a checklist to standardize their responses to intraoperative MEP changes. PMID- 23815253 TI - Microendoscopic decompression for cervical spondylotic myelopathy. AB - OBJECT: Cervical spondylotic myelopathy (CSM) is a common cervical degenerative disease that affects the elderly population. Spinal cord decompression is achieved through various anterior and posterior approaches including anterior cervical decompression and fusion, laminectomy, laminoplasty, and combined approaches. The authors describe another option, minimally invasive endoscopically assisted decompression of stenosis (MEDS), which obviates the need for muscle dissection and disruption of the posterior tension band, a cause of postlaminectomy kyphosis. METHODS: The authors conducted a retrospective study of 10 patients with CSM who underwent MEDS from January 2002 through July 2012. Data were collected on demographics, preoperative and postoperative Nurick scores, postoperative Odom scores, and preoperative and postoperative Cobb angles. RESULTS: The mean patient age (+/- SD) was 67 +/- 7.7 years; 8 patients were male. The average number of disc levels operated on was 2.2 (range 1-4). The mean Nurick score was 1.6 +/- 0.7 preoperatively and improved to 0.3 +/- 0.7 postoperatively (p < 0.0005). The postoperative Odom scores indicated excellent outcomes for 4 patients, good for 3, fair for 2, and poor for 1. The average preoperative focal Cobb angle at the disc levels operated on was -0.43o +/- 1.9o. The average Cobb angle at the last follow-up visit was 0.25 degrees +/- 1.6 degrees (p = 0.6). The average follow-up time was 18.9 +/- 32.1 months. There were no intraoperative or postoperative complications. CONCLUSIONS: For selected patients with CSM, whose pathologic changes are primarily posterior and who have acceptable preoperative lordosis, MEDS is an alternative to open laminectomy and laminoplasty. PMID- 23815254 TI - Is there a difference in range of motion, neck pain, and outcomes in patients with ossification of posterior longitudinal ligament versus those with cervical spondylosis, treated with plated laminoplasty? AB - OBJECT: There are little data on the effects of plated, or plate-only, open-door laminoplasty on cervical range of motion (ROM), neck pain, and clinical outcomes. The purpose of this study was to compare ROM after a plated laminoplasty in patients with ossification of posterior longitudinal ligament (OPLL) versus those with cervical spondylotic myelopathy (CSM) and to correlate ROM with postoperative neck pain and neurological outcomes. METHODS: The authors retrospectively compared patients with a diagnosis of cervical stenosis due to either OPLL or CSM who had been treated with plated laminoplasty in the period from 2007 to 2012 at the University of California, San Francisco. Clinical outcomes were measured using the modified Japanese Orthopaedic Association (mJOA) scale and neck visual analog scale (VAS). Radiographic outcomes included assessment of changes in the C2-7 Cobb angle at flexion and extension, ROM at C2 7, and ROM of proximal and distal segments adjacent to the plated lamina. RESULTS: Sixty patients (40 men and 20 women) with an average age of 63.1 +/- 10.9 years were included in the study. Forty-one patients had degenerative CSM and 19 patients had OPLL. The mean follow-up period was 20.9 +/- 13.1 months. The mean mJOA score significantly improved in both the CSM and the OPLL groups (12.8 to 14.5, p < 0.01; and 13.2 to 14.2, respectively; p = 0.04). In the CSM group, the mean VAS neck score significantly improved from 4.2 to 2.6 after surgery (p = 0.01), but this improvement did not reach the minimum clinically important difference (MCID). Neither was there significant improvement in the VAS neck score in the OPLL group (3.6 to 3.1, p = 0.17). In the CSM group, ROM at C2-7 significantly decreased from 32.7 degrees before surgery to 24.4 degrees after surgery (p < 0.01). In the OPLL group, ROM at C2-7 significantly decreased from 34.4 degrees to 20.8 degrees (p < 0.01). In the CSM group, the change in the VAS neck score significantly correlated with the change in the flexion angle (r = - 0.31) and the extension angle (r = - 0.37); however, it did not correlate with the change in ROM at C2-7 (r = - 0.1). In the OPLL group, the change in the VAS neck score did not correlate with the change in the flexion angle (r = 0.03), the extension angle (r = - 0.17), or the ROM at C2-7 (r = - 0.28). The OPLL group had a significantly greater loss of ROM after surgery than did the CSM group (p = 0.04). There was no significant correlation between the change in ROM and the mJOA score in either group. CONCLUSIONS: Plated laminoplasty in patients with either OPLL or CSM decreases cervical ROM, especially in the extension angle. Among patients who have undergone laminoplasty, those with OPLL lose more ROM than do those with CSM. No correlation was observed between neck pain and ROM in either group. Neither group had a change in neck pain that reached the MCID following laminoplasty. Both groups improved in neurological function and outcomes. PMID- 23815255 TI - Introduction: Cervical spondylotic myelopathy. PMID- 23815256 TI - Cardiac effects of echinocandin preparations - three case reports. AB - WHAT IS KNOWN AND OBJECTIVE: Echinocandins are antifungal agents, routinely used in invasive candida infections in critically ill patients. Their excellent anticandidal activity and their low frequency of reported adverse events and drug interactions make them first-line guideline treatments of candidiasis especially in intensive care units (ICU). We report on three ICU patients who developed cardiac insufficiency and hemodynamic instability during administration of loading doses of an echinocandin. CASE SUMMARY: Three ICU patients showed a substantial drop in their cardiac index or a deterioration of the mean arterial pressure following start of echinocandin administration. The patients were 75 years (female), 71 years (male) and 66 years (male) old. One patient received caspofungin, and two patients received anidulafungin as empirical antifungal treatment for severe sepsis. WHAT IS NEW AND CONCLUSION: Our cases suggest that the observed cardiac impairment could be associated with echinocandin administration. Therefore, we recommend close hemodynamic monitoring of critically ill patients receiving echinocandins. PMID- 23815260 TI - Pharbinilic acid, an allogibberic acid from morning glory (Pharbitis nil). AB - Pharbinilic acid (1), the first naturally occurring allogibberic acid, was isolated from ethanol extracts of morning glory (Pharbitis nil) seeds. Its absolute configuration was determined by NOESY NMR and ECD experiments. Compound 1 showed weak cytotoxicity against A549, SK-OV-3, SK-MEL-2, and HCT-15 cells and weakly inhibited nitric oxide production in lipopolysaccharide-activated BV-2 microglia cells. PMID- 23815257 TI - Neutrophil intercellular communication in acute lung injury. Emerging roles of microparticles and gap junctions. AB - A hallmark of acute inflammation involves the recruitment of polymorphonuclear leukocytes (neutrophils) to infected or injured tissues. The processes underlying this recruitment are complex, and include multiple mechanisms of intercellular communication between neutrophils and the inflamed tissue. In recent studies of the systemic and pulmonary vasculature, interest has increased in novel forms of intercellular communication, such as microparticle exchange and gap junctional intercellular communication. To understand the roles of these novel forms of communication in the onset, progression, and resolution of inflammatory lung injury (such as acute respiratory distress syndrome), we review the literature concerning the contributions of microparticle exchange and gap junctional intercellular communication to neutrophil-alveolar crosstalk during pulmonary inflammation. By focusing on these cell-cell communications, we aim to demonstrate significant gaps of knowledge and identify areas of considerable need for further investigations of the processes of acute lung inflammation. PMID- 23815261 TI - Predictive value of the surface-enhanced resonance Raman scattering-based MTT assay: a rapid and ultrasensitive method for cell viability in situ. AB - SERRS (surface-enhanced resonance Raman scattering) has been used to develop and optimize a novel and quantitative MTT assay for living cell viability. This highly sensitive method derives from two factors for formazan signal enhancing: the addition of Au nanoparticles and the resonance effect by 632.8 nm of excitation. The results show that the background elements, such as excessive MTT residues, serum, and the drug, did not interfere with the detection of formazan. Moreover, the detection limit of formazan is as low as 1 ng/mL. With the use of this method to quantify metabolically viable cells, dose-response curves of treated and untreated cells with the drug were constructed on the human lung cancer cell A549. The results also show that the Raman signal generated is dependent on the degree of activation of the cells. In comparison to the traditional method, the main advantages of this method are its rapidity (30 min), high-selectivity, high-precision, and cost-effectiveness (0.1 mg/mL MTT) without time-consuming steps and any modifying or labeling procedure. This work reports on an improved research tool that may help researchers apply this method for in situ cell assays. PMID- 23815262 TI - The Dimensions of Mastery Questionnaire in school-aged children with congenital hemiplegia: test-retest reproducibility and parent-child concordance. AB - AIM: To examine internal consistency, test-retest reproducibility, and parent child concordance of the Dimensions of Mastery Questionnaire 17.0 (DMQ) in school aged children with congenital hemiplegia. METHOD: Forty-two children (8.24 +/- 2.38 years, Manual Ability Classification System (MACS) I = 23, MACS II = 19) and their parents completed the DMQ, and a subset on two occasions 2-30 days apart (n = 27). Cronbach's alpha (alpha), intraclass correlation coefficients (ICCs), standard error of measurement (SEM), and 95% limits of agreement were calculated. RESULTS: Internal consistency for child self-report was variable (alpha = 0.57 0.90). Cronbach's alphas for parent proxy report were good (alpha = 0.69-0.86). Test-retest reproducibility for instrumental aspect (ICC = 0.86) and total motivation (ICC = 0.84) were excellent with subscales ranging from 0.70 to 0.91. The SEM for total motivation was 0.23 points. Parent-child concordance was poor across all scores (ICC = -0.04 to 0.42) with a large SEM (0.50-0.91). INTERPRETATION: The DMQ parent report has good test-retest reproducibility for subscales, instrumental, and total motivation scores in school-aged children with congenital hemiplegia. Parent-child concordance was low highlighting differences in individual and contextual perspectives. PMID- 23815265 TI - Are Neto1 and APP auxiliary subunits of NMDA receptors? PMID- 23815264 TI - Glucose-6-phosphate dehydrogenase deficiency in transfusion medicine: the unknown risks. AB - The hallmark of glucose-6-phosphate dehydrogenase (G6PD) deficiency is red blood cell (RBC) destruction in response to oxidative stress. Patients requiring RBC transfusions may simultaneously receive oxidative medications or have concurrent infections, both of which can induce haemolysis in G6PD-deficient RBCs. Although it is not routine practice to screen healthy blood donors for G6PD deficiency, case reports identified transfusion of G6PD-deficient RBCs as causing haemolysis and other adverse events. In addition, some patient populations may be more at risk for complications associated with transfusions of G6PD-deficient RBCs because they receive RBCs from donors who are more likely to have G6PD deficiency. This review discusses G6PD deficiency, its importance in transfusion medicine, changes in the RBC antioxidant system (of which G6PD is essential) during refrigerated storage and mechanisms of haemolysis. In addition, as yet unanswered questions that could be addressed by translational and clinical studies are identified and discussed. PMID- 23815267 TI - Precision oncology in breast cancer: better than ever, or less than before? PMID- 23815266 TI - Logic Learning Machine creates explicit and stable rules stratifying neuroblastoma patients. AB - BACKGROUND: Neuroblastoma is the most common pediatric solid tumor. About fifty percent of high risk patients die despite treatment making the exploration of new and more effective strategies for improving stratification mandatory. Hypoxia is a condition of low oxygen tension occurring in poorly vascularized areas of the tumor associated with poor prognosis. We had previously defined a robust gene expression signature measuring the hypoxic component of neuroblastoma tumors (NB hypo) which is a molecular risk factor. We wanted to develop a prognostic classifier of neuroblastoma patients' outcome blending existing knowledge on clinical and molecular risk factors with the prognostic NB-hypo signature. Furthermore, we were interested in classifiers outputting explicit rules that could be easily translated into the clinical setting. RESULTS: Shadow Clustering (SC) technique, which leads to final models called Logic Learning Machine (LLM), exhibits a good accuracy and promises to fulfill the aims of the work. We utilized this algorithm to classify NB-patients on the bases of the following risk factors: Age at diagnosis, INSS stage, MYCN amplification and NB-hypo. The algorithm generated explicit classification rules in good agreement with existing clinical knowledge. Through an iterative procedure we identified and removed from the dataset those examples which caused instability in the rules. This workflow generated a stable classifier very accurate in predicting good and poor outcome patients. The good performance of the classifier was validated in an independent dataset. NB-hypo was an important component of the rules with a strength similar to that of tumor staging. CONCLUSIONS: The novelty of our work is to identify stability, explicit rules and blending of molecular and clinical risk factors as the key features to generate classification rules for NB patients to be conveyed to the clinic and to be used to design new therapies. We derived, through LLM, a set of four stable rules identifying a new class of poor outcome patients that could benefit from new therapies potentially targeting tumor hypoxia or its consequences. PMID- 23815268 TI - Long-term impact of young age at diagnosis on treatment outcome and patterns of failure in patients with ductal carcinoma in situ treated with breast-conserving therapy. AB - We reviewed our institution's long-term experience treating patients diagnosed with ductal carcinoma in situ (DCIS) of the breast with breast-conserving therapy (BCT) to determine the impact of patient age on outcome over time. All DCIS cases receiving BCT between 1980 and 1993 were reviewed. Patient demographics (including age <45) and pathologic factors were analyzed for effect on outcomes including ipsilateral breast tumor recurrence (IBTR) and survival. BCT included limited surgery (excisional biopsy or lumpectomy) followed by radiotherapy to the whole breast (median whole-breast dose: 50 Gy, median tumor bed dose: 60.4 Gy). One hundred and forty-five cases were evaluated; the median follow-up was 19.3 years. Twenty-five patients developed an IBTR, for 5-, 10-, 15-, and 20-year actuarial rates of 9.9%, 12.2%, 13.7%, and 17.5%, respectively. The 10-year ipsilateral rate of recurrence was 23.3% (<45 years) versus 9.1% (>= 45 years) (p = 0.05). Younger patients more frequently developed invasive recurrences (20-year actuarial rates: 20.4% versus 12.8%, p = 0.22) and true recurrences/marginal misses of the index lesion (23.3% versus 9.7%, p = 0.04) with lower rates of contralateral breast cancer (0.0% and 0.0% versus 12.0% and 20.5%, p = < 0.01, at 10 and 20 years, respectively). Young women under the age of 45 diagnosed with DCIS have a greater risk of local recurrence with different patterns of failure following BCT, which is most notable within 10 years of diagnosis. PMID- 23815269 TI - Breast lymphoma presenting as gynecomastia in male patient. PMID- 23815270 TI - Functioning assessment vs. conventional medical assessment: a comparative study on health professionals' clinical decision-making and the fit with patient's own perspective of health. AB - AIMS AND OBJECTIVES: To compare a functioning assessment based on the International Classification of Functioning, Disability and Health (ICF) with a conventional medical assessment, in terms of their respective consequences for health professionals' clinical decision-making and the fit with patient's own perspective of health. BACKGROUND: In chronic diseases, pathogenic-oriented health care falls short in generating all the information required for determining healthcare provision to improve health. A broader, so-called salutogenic approach, by using the ICF, focusing on how to stay healthy, rather than on what causes diseases, seems more appropriate. DESIGN: A cross-sectional comparative study using data from a randomised controlled trial. METHODS: Data about patient problems and professional healthcare activities were collected from a total of 81 patients with severe multiple sclerosis who were randomly assigned to one of two groups: the ICF group, assessed with a functioning assessment (n = 43), and the medical group, assessed with a conventional medical assessment (n = 38). Data were analysed statistically using descriptive and inferential statistics. RESULTS: A functioning assessment resulted in the registration of significantly more patient problems in the health components 'participation' and 'environmental factors', as well as significantly more professional healthcare activities befitting these components. The ICF group had a significant positive correlation between registered problems by health professionals and patients' self-reported problems, whereas the medical group had several negative correlations. CONCLUSION: A functioning assessment resulted in a care plan that not only was broader and more complete but also reflected the patients' self reported problems more closely than a medical assessment, without a loss of focus on medical problems. RELEVANCE TO CLINICAL PRACTICE: This study has shown that some health problems remain unnoticed by a medical assessment alone, which is especially important for the chronically ill. A functioning assessment provides a strong foundation for identifying all relevant information related to health. PMID- 23815271 TI - Acceleration of sequence clustering using longest common subsequence filtering. AB - BACKGROUND: Huge numbers of genomes can now be sequenced rapidly with recent improvements in sequencing throughput. However, data analysis methods have not kept up, making it difficult to process the vast amounts of available sequence data. This increased processing time is especially critical in DNA sequence clustering because of the intrinsic difficulty in parallelization. Thus, there is a strong demand for a faster clustering algorithm. RESULTS: We developed a new fast DNA sequence clustering method called LCS-HIT, based on the popular CD-HIT program. The proposed method uses a novel filtering technique based on the longest common subsequence to identify similar sequence pairs. This filtering technique makes the LCS-HIT considerably faster than CD-HIT, without loss of sensitivity. For a dataset of two million DNA sequences, our method was approximately 7.1, 4.4, and 2.2 times faster than CD-HIT for 100, 150, and 400 bases, respectively. CONCLUSIONS: The LCS-HIT clustering program, using a novel filtering technique based on the longest common subsequence, is significantly faster than CD-HIT without compromising clustering accuracy. Moreover, the filtering technique itself is independent from the CD-HIT algorithm. Thus, this technique can be applied to similar clustering algorithms. PMID- 23815272 TI - Lipoic acid restores age-associated impairment of brain energy metabolism through the modulation of Akt/JNK signaling and PGC1alpha transcriptional pathway. AB - This study examines the progress of a hypometabolic state inherent in brain aging with an animal model consisting of Fischer 344 rats of young, middle, and old ages. Dynamic microPET scanning demonstrated a significant decline in brain glucose uptake at old ages, which was associated with a decrease in the expression of insulin-sensitive neuronal glucose transporters GLUT3/4 and of microvascular endothelium GLUT1. Brain aging was associated with an imbalance between the PI3K/Akt pathway of insulin signaling and c-Jun N-terminal kinase (JNK) signaling and a downregulation of the PGC1alpha-mediated transcriptional pathway of mitochondrial biogenesis that impinged on multiple aspects of energy homeostasis. R-(+)-lipoic acid treatment increased glucose uptake, restored the balance of Akt/JNK signaling, and enhanced mitochondrial bioenergetics and the PGC1alpha-driven mitochondrial biogenesis. It may be surmised that impairment of a mitochondria-cytosol-nucleus communication is underlying the progression of the age-related hypometabolic state in brain; the effects of lipoic acid are not organelle-limited, but reside on the functional and effective coordination of this communication that results in improved energy metabolism. PMID- 23815273 TI - Modeling the public health impact of malaria vaccines for developers and policymakers. AB - BACKGROUND: Efforts to develop malaria vaccines show promise. Mathematical model based estimates of the potential demand, public health impact, and cost and financing requirements can be used to inform investment and adoption decisions by vaccine developers and policymakers on the use of malaria vaccines as complements to existing interventions. However, the complexity of such models may make their outputs inaccessible to non-modeling specialists. This paper describes a Malaria Vaccine Model (MVM) developed to address the specific needs of developers and policymakers, who need to access sophisticated modeling results and to test various scenarios in a user-friendly interface. The model's functionality is demonstrated through a hypothetical vaccine. METHODS: The MVM has three modules: supply and demand forecast; public health impact; and implementation cost and financing requirements. These modules include pre-entered reference data and also allow for user-defined inputs. The model includes an integrated sensitivity analysis function. Model functionality was demonstrated by estimating the public health impact of a hypothetical pre-erythrocytic malaria vaccine with 85% efficacy against uncomplicated disease and a vaccine efficacy decay rate of four years, based on internationally-established targets. Demand for this hypothetical vaccine was estimated based on historical vaccine implementation rates for routine infant immunization in 40 African countries over a 10-year period. Assumed purchase price was $5 per dose and injection equipment and delivery costs were $0.40 per dose. RESULTS: The model projects the number of doses needed, uncomplicated and severe cases averted, deaths and disability-adjusted life years (DALYs) averted, and cost to avert each. In the demonstration scenario, based on a projected demand of 532 million doses, the MVM estimated that 150 million uncomplicated cases of malaria and 1.1 million deaths would be averted over 10 years. This is equivalent to 943 uncomplicated cases and 7 deaths averted per 1,000 vaccinees. In discounted 2011 US dollars, this represents $11 per uncomplicated case averted and $1,482 per death averted. If vaccine efficacy were reduced to 75%, the estimated uncomplicated cases and deaths averted over 10 years would decrease by 14% and 19%, respectively. CONCLUSIONS: The MVM can provide valuable information to assist decision-making by vaccine developers and policymakers, information which will be refined and strengthened as field studies progress allowing further validation of modeling assumptions. PMID- 23815274 TI - Can a smaller than expected crown-rump length reliably predict the occurrence of subsequent miscarriage in a viable first trimester pregnancy? AB - AIM: To elicit the diagnostic value of smaller than expected crown-rump length (CRL) to predict the occurrence of subsequent miscarriage in women with a viable first trimester pregnancy. METHODS: A cohort study was conducted in the fetal special care unit of a tertiary care maternity hospital. The recruited participants were young pregnant women at 6-13 weeks of gestation. Transvaginal ultrasonography was performed to determine pregnancy viability and measure the embryonic CRL. To compare the differences in CRL between those pregnancies that remained viable and those that subsequently miscarried, the deviation of observed and expected CRL was calculated and expressed in standard deviations (SD) as Z score. The primary outcome measure was the percentage of pregnancies with antecedent growth delay that miscarried by the end of the first trimester. RESULTS: Of the pregnancies that subsequently miscarried, 79.3% (42/53) had smaller than expected CRL, and in 56.6% (30/53) the CRL was 2 SD or less from that expected for gestational age (GA). The mean Z score for CRL was significantly lower in pregnancies that subsequently miscarried compared to pregnancies that remained viable (-2.9 +/- 2.6 vs -0.8 +/- 2.1, respectively, P < 0.001). A CRL of 2 SD or less from that expected for GA as a cut-off point had a sensitivity of 56.6, specificity of 81.9, positive predictive value of 36.6, negative predictive value of 91.1, likelihood ratio positive of 3.1 and likelihood ratio negative of 0.5 in predicting subsequent miscarriage. CONCLUSION: Viable first trimester pregnancies with small for GA CRL were associated with a higher probability of a subsequent miscarriage. PMID- 23815276 TI - Dermatology training in the U.K.: does it reflect the changing demographics of our population? PMID- 23815275 TI - Hybrid hydroxyapatite nanoparticle colloidal gels are injectable fillers for bone tissue engineering. AB - Injectable bone fillers have emerged as an alternative to the invasive surgery often required to treat bone defects. Current bone fillers may benefit from improvements in dynamic properties such as shear thinning during injection and recovery of material stiffness after placement. Negatively charged inorganic hydroxyapatite (HAp) nanoparticles (NPs) were assembled with positively charged organic poly(d,l-lactic-co-glycolic acid) (PLGA) NPs to create a cohesive colloidal gel. This material is held together by electrostatic forces that may be disrupted by shear to facilitate extrusion, molding, or injection. Scanning electron micrographs of the dried colloidal gels showed a well-organized, three dimensional porous structure. Rheology tests revealed that certain colloidal gels could recover after being sheared. Human umbilical cord mesenchymal stem cells were also highly viable when seeded on the colloidal gels. HAp/PLGA NP colloidal gels offer an attractive scheme for injectable filling and regeneration of bone tissue. PMID- 23815277 TI - Molecular characteristics of the MHC-DRA genes from yak (Bos grunniens) and Chinese yakow (Bos grunniens * Bos taurus). AB - Two full-length cDNAs (762 bp) of the DRA gene from yak and Chinese yakow were isolated and analysed to identify structural and functional variations. The sequences for DRA in yak (Bogr-DRA) and Chinese yakow (Bogr * BoLA-DRA) were essentially identical to those for cattle (99%) and buffalo (97%). Except for two substitutions in the amino acids comprising the domain for signal peptide (SP) in yak, the additional residues were highly conserved across the species investigated. Peptide-binding site (PBS) of Bogr-DRA and Bogr * BoLA-DRA was highly reserved in the alpha1 domain among all species investigated. The lack of mutation in Bogr-DRA is consistent with the conception that the gene is highly conserved among all mammalian species. The very high conservation of the DRA gene among ruminants, including yak, may be due to its recent evolutionary detachment. PMID- 23815278 TI - Human hamstring tenocytes survive when seeded into a decellularized porcine Achilles tendon extracellular matrix. AB - Tendon ruptures and defects remain major orthopaedic challenges. Tendon healing is a time-consuming process, which results in scar tissue with an altered biomechanical competence. Using a xenogeneic tendon extracellular matrix (ECM) as a natural scaffold, which can be reseeded with autologous human tenocytes, might be a promising approach to reconstruct damaged tendons. For this purpose, the porcine Achilles (AS) tendons serving as a scaffold were histologically characterized in comparison to human cell donor tendons. AS tendons were decellularized and then reseeded with primary human hamstring tenocytes using cell centrifuging, rotating culture and cell injection techniques. Vitality testing, histology and glycosaminoglycan/DNA quantifications were performed to document the success of tendon reseeding. Porcine AS tendons were characterized by a higher cell and sulfated glycosaminoglycan content than human cell donor tendons. Complete decellularization could be achieved, but led to a wash out of sulfated glycosaminoglycans. Nevertheless, porcine tendon could be recellularized with vital human tenocytes. The recellularization led to a slight increase in cell number compared to the native tendon and some glycosaminoglycan recovery. This study indicates that porcine tendon can be de- and recellularized using adult human tenocytes. Future work should optimize cell distribution within the recellularized tendon ECM and consider tendon- and donor species-dependent differences. PMID- 23815279 TI - Hexagonal graphene onion rings. AB - Precise spatial control of materials is the key capability of engineering their optical, electronic, and mechanical properties. However, growth of graphene on Cu was revealed to be seed-induced two-dimensional (2D) growth, limiting the synthesis of complex graphene spatial structures. In this research, we report the growth of onion ring like three-dimensional (3D) graphene structures, which are comprised of concentric one-dimensional hexagonal graphene ribbon rings grown under 2D single-crystal monolayer graphene domains. The ring formation arises from the hydrogenation-induced edge nucleation and 3D growth of a new graphene layer on the edge and under the previous one, as supported by first principles calculations. This work reveals a new graphene-nucleation mechanism and could also offer impetus for the design of new 3D spatial structures of graphene or other 2D layered materials. Additionally, in this research, two special features of this new 3D graphene structure were demonstrated, including nanoribbon fabrication and potential use in lithium storage upon scaling. PMID- 23815280 TI - Direct delivery of functional proteins and enzymes to the cytosol using nanoparticle-stabilized nanocapsules. AB - Intracellular protein delivery is an important tool for both therapeutic and fundamental applications. Effective protein delivery faces two major challenges: efficient cellular uptake and avoiding endosomal sequestration. We report here a general strategy for direct delivery of functional proteins to the cytosol using nanoparticle-stabilized capsules (NPSCs). These NPSCs are formed and stabilized through supramolecular interactions between the nanoparticle, the protein cargo, and the fatty acid capsule interior. The NPSCs are ~130 nm in diameter and feature low toxicity and excellent stability in serum. The effectiveness of these NPSCs as therapeutic protein carriers was demonstrated through the delivery of fully functional caspase-3 to HeLa cells with concomitant apoptosis. Analogous delivery of green fluorescent protein (GFP) confirmed cytosolic delivery as well as intracellular targeting of the delivered protein, demonstrating the utility of the system for both therapeutic and imaging applications. PMID- 23815281 TI - Impaired exercise capacity after lung transplantation is related to delayed recovery of muscle strength. AB - Lung transplant recipients report reduced exercise capacity despite satisfactory graft function. We analysed changes in lung function, six-min walk distance (6MWD), and quadriceps strength in the first 26-wk post-transplant and examined what factors predict 6MWD recovery. All lung transplant recipients at a single institution between June 2007 and January 2011 were considered for inclusion. Lung function, 6MWD, and quadriceps strength corrected for body weight (QS%) were recorded pre- and two-, six-, 13-, and 26-wk post-transplant. Fifty recipients, of mean (+/- SD) age 42 (+/- 13) yr, were studied. Mean FEV1 % and 6MWD improved from 26.4% to 88.9% and from 397 to 549 m at 26 wk, respectively (both p < 0.001). QS% declined in the first two wk but had improved to above pre-transplant levels by 26 wk (p = 0.027). On multivariate analysis (n = 35), lower pre transplant exercise capacity and greater recovery in muscle strength explained most of the improvement in exercise capacity. Delayed recovery of exercise capacity after lung transplantation is unrelated to delay in improvement in graft function, but occurs secondary to the slow recovery of muscle strength. Our findings show that additional controlled trials are needed to better understand the influence of exercise rehabilitation on improvement in exercise capacity post transplantation. PMID- 23815282 TI - Pd-catalyzed bis-cyclization/dimerization reactions of omega-aminovinyl halides. AB - Palladium is shown to catalyze the dimerization and cyclization of vinyl halides to generate pyrrolidine and piperidine dimers connected by a trans-ethylene bridge. The reaction tolerates a variety of N-alkyl substituents, including adamantyl. This remarkable dimerization reaction generates the skeleton of the alkaloid hyalbidone in a single step. A crossover experiment with a vinyl halide and a vinyl bromide is consistent with a Michael-type addition to a vinylpalladium cation to generate a Pd(0) alkylidene intermediate. PMID- 23815284 TI - Structure, kinetics, and thermodynamics of the aqueous uranyl(VI) cation. AB - In this work, molecular simulation techniques were employed to gain insight into the structural, kinetic, and thermodynamic properties of the uranyl(VI) cation (UO2(2+)) in aqueous solution. The simulations made use of an atomistic potential model (force field) derived in this work and based on the model of Guilbaud and Wipff [J. Mol. Struct. (THEOCHEM) 1996 , 366 , 55 - 63]. Reactive flux and thermodynamic integration calculations show that the derived potential model yields predictions for the water exchange rate and free energy of hydration, respectively, that are in agreement with experimental data. The water binding energies, hydration shell structure, and self-diffusion coefficient were also calculated and analyzed. Finally, a combination of metadynamics and transition path sampling simulations was employed to probe the mechanisms of water exchange reactions in the first hydration shell of the uranyl ion. These atomistic simulations indicate, based on two-dimensional free energy surfaces, that water exchanges follow an associative interchange mechanism. The nature and structure of the water exchange transition states were also determined. The improved potential model is expected to lead to more accurate predictions of uranyl adsorption energies at mineral surfaces using potential-based molecular dynamics simulations. PMID- 23815285 TI - Systematic review evaluating cardiovascular events of the 5-alpha reductase inhibitor - Dutasteride. AB - WHAT IS KNOWN AND OBJECTIVES: A recently published large, long-term randomized controlled trial (RCT) brought into question the safety of dutasteride after a significantly increased risk of 'cardiac failure' was noted in the dutasteride arm of the trial compared with placebo. Our objective was to perform a meta analysis to assess the risk of cardiovascular adverse events with the use of dutasteride for the prevention or treatment of prostatic disease. METHODS: We searched MEDLINE and EMBASE, unpublished articles identified through FDA/EMEA websites, study registers of pharmaceutical companies and reference lists of articles. Parallel-group, randomized controlled trials where men received dutasteride for the prevention of prostate cancer or treatment of prostatic hyperplasia against any comparator intervention were included. Heart failure was the primary outcome of interest but we also looked at myocardial infarction and stroke. Fixed-effect meta-analysis of pooled relative risk (RR) ratios of adverse effect outcomes was conducted. RESULTS AND DISCUSSION: In all, 12 RCTs were included in the meta-analysis after detailed screening of 564 citations. The total number of participants was 18,802, and study duration ranged from 6 to 208 weeks. Only two trials provided details on adequate allocation concealment, whereas all the trials stated they were double blind in nature. Dutasteride was not associated with a statistically significant increased risk of heart failure (RR 1.05; 95% confidence interval [CI], 0.71-1.57, I(2) = 20%), myocardial infarction (RR 1.00; 95% CI 0.77-1.30, I(2) = 0%) and stroke (RR, 1.20; 95% CI 0.88-1.64, I(2) = 0%) as compared to controls. WHAT IS NEW AND CONCLUSION: We did not find consistent evidence of a significant association between dutasteride therapy and the risk of cardiovascular adverse events. PMID- 23815286 TI - Development and characterization of LTA-appended chitosan nanoparticles for mucosal immunization against hepatitis B. AB - The present study was aimed at exploring the targeting potential of LTA-anchored chitosan nanoparticles (CH-NP) specifically to M cell following oral immunization. The lectinized CH-NP exhibited 7-29% coupling capacity depending upon the amount of glutaraldehyde added. Induction of the mucosal immunity was assessed by estimating secretory IgA level in the salivary, intestinal and vaginal secretions, and cytokine (IL-2 and IFN-gamma) levels in the spleen homogenates. The results demonstrated that LTA-anchored CH-NP elicited strong humoral and cellular responses and hence could be a competent carrier-adjuvant delivery system for oral mucosal immunization against Hepatitis B. PMID- 23815283 TI - Metabolic potential of the organic-solvent tolerant Pseudomonas putida DOT-T1E deduced from its annotated genome. AB - Pseudomonas putida DOT-T1E is an organic solvent tolerant strain capable of degrading aromatic hydrocarbons. Here we report the DOT-T1E genomic sequence (6,394,153 bp) and its metabolic atlas based on the classification of enzyme activities. The genome encodes for at least 1751 enzymatic reactions that account for the known pattern of C, N, P and S utilization by this strain. Based on the potential of this strain to thrive in the presence of organic solvents and the subclasses of enzymes encoded in the genome, its metabolic map can be drawn and a number of potential biotransformation reactions can be deduced. This information may prove useful for adapting desired reactions to create value-added products. This bioengineering potential may be realized via direct transformation of substrates, or may require genetic engineering to block an existing pathway, or to re-organize operons and genes, as well as possibly requiring the recruitment of enzymes from other sources to achieve the desired transformation. PMID- 23815287 TI - Occupational and socio-economic risk factors for giant cell arteritis: a nationwide study based on hospitalizations in Sweden. AB - OBJECTIVES: Socio-economic and occupational factors may contribute to risk of immune-mediated disorders. The importance of these factors in giant cell arteritis (GCA) is unknown. This is the first nationwide study with the aim of investigating possible associations between socio-economic status (SES)/occupation and hospitalization for GCA. METHOD: A nationwide database was constructed by linking Swedish census data to the Hospital Discharge Register to obtain data on all first hospitalizations with a main diagnosis of GCA in Swedish adults between 1970 and 2008. Standardized incidence ratios (SIRs) and 95% confidence intervals were calculated for different occupations. Three cohorts were defined based on 53 occupational titles recorded in Swedish census data in 1970, 1980, and 1990. RESULTS: In individuals aged over 50 years, 3293 males and 4726 females were hospitalized with GCA. Only minor or inconsistent associations were observed for education and SES and GCA. Some occupations were associated with increased risk of GCA. However, the risks were modest or not consistent between the three cohorts investigated. Only male fishermen, whalers, and sealers had an SIR of > 2 (2.14). However, the risk of GCA was only increased in one cohort. Both women (0.83) and men (0.83) born outside Sweden had a lower risk of GCA. The adjustment variables hypertension, diabetes, chronic obstructive pulmonary disease (COPD), and coronary heart disease (CHD) were associated with higher risk of GCA. CONCLUSIONS: Occupation and SES are not strong risk factors for GCA. However, GCA was associated with co-morbidities and country of birth, calling for further studies. PMID- 23815288 TI - Direct analysis of water content and movement in single dormant bacterial spores using confocal Raman microspectroscopy and Raman imaging. AB - Heavy water (D2O) has a distinct molecular vibration spectrum, and this has been used to analyze the water content, distribution, and movement in single dormant Bacillus cereus spores using confocal Raman microspectroscopy and Raman imaging. These methods have been used to measure the kinetics of D2O release from spores suspended in H2O, the spatial distribution of D2O in spores, and the kinetics of D2O release from spores during dehydration in air at room temperature. The results obtained were as follows. (1) The Raman spectrum of single D2O-loaded dormant spores suggests that D2O in spores is in a relatively weak hydrogen bonded mode, compared to the strong hydrogen-bonded mode in pure D2O. (2) The D2O content of individual spores in a population was somewhat heterogeneous. (3) The spatial distribution of D2O in single dormant spores is uneven, and is less dense in the central core region. Raman images of different molecular components indicate that the water distribution is somewhat different from those of proteins and Ca-dipicolinic acid. (4) Exchange of spore D2O with external H2O took place in less than 1 s. (5) However, release of spore D2O during air dehydration at room temperature was slow and heterogeneous and took 2-3 h for complete D2O release. PMID- 23815289 TI - Rab1a and Rab5a preferentially bind to binary lipid compositions with higher stored curvature elastic energy. AB - Rab proteins are a large family of GTP-binding proteins that regulate cellular membrane traffic and organelle identity. Rab proteins cycle between association with membranes and binding to RabGDI. Bound on membranes, each Rab has a very specific cellular location and it is this remarkable degree of specificity with which Rab GTPases recognize distinct subsets of intracellular membranes that forms the basis of their ability to act as key cellular regulators, determining the recruitment of downstream effectors to the correct membrane at the correct time. The molecular mechanisms controlling Rab localization remain poorly understood. Here, we present a fluorescence-based assay to investigate Rab GTPase membrane extraction and delivery by RabGDI. Using EGFP-Rab fusion proteins the amount of Rab:GDI complex obtained by GDI extraction of Rab proteins from HEK293 membranes could be determined, enabling control of complex concentration. Subsequent partitioning of the Rab GTPases into vesicles made up of artificial binary lipid mixtures showed for the first time, that the composition of the target membrane plays a key role in the localization of Rab proteins by sensing the stored curvature elastic energy in the membrane. PMID- 23815290 TI - On the anomalous magnetic behavior and the multiferroic properties in BiMn2O5. AB - Sealed-tube synthesis of BiMn2O5 materials and their physical properties have rationally been reinvestigated depending on the reactants. The aim of the study was to characterize its potential multiferroic properties and to investigate the anomalous magnetic properties in relation to the expected ferroelectric properties. Rietveld refinement of the room temperature X-ray diffraction data shows the stability of the crystallographic structure with a Mn(3+)/Mn(4+) ratio far from 1 because of bismuth and oxygen deficiencies despite the sealed-tube synthesis. Our detailed magnetic susceptibility and specific heat data analysis unambiguously support an intrinsic anomalous magnetic behavior in relation to the establishment of a magnetic short-range ordering far from the Neel temperature. Around room temperature, oxygen vacancies are responsible for supporting the dielectric loss peak measured, and, interestingly, the so-called T*, which was underlined in relation to an anomalous phonon shift (Garcia-Flores, A. F.; et al. Phys. Rev. B 2006, 73, 104411), is not a characteristic temperature in relation to the multiferroic properties because no ferroelectric transition was detected. PMID- 23815291 TI - Amyloid precursor proteins are constituents of the presynaptic active zone. AB - The amyloid precursor protein (APP) and its mammalian homologs, APLP1, APLP2, have been allocated to an organellar pool residing in the Golgi apparatus and in endosomal compartments, and in its mature form to a cell surface-localized pool. In the brain, all APPs are restricted to neurons; however, their precise localization at the plasma membrane remained enigmatic. Employing a variety of subcellular fractionation steps, we isolated two synaptic vesicle (SV) pools from rat and mouse brain, a pool consisting of synaptic vesicles only and a pool comprising SV docked to the presynaptic plasma membrane. Immunopurification of these two pools using a monoclonal antibody directed against the 12 membrane span synaptic vesicle protein2 (SV2) demonstrated unambiguously that APP, APLP1 and APLP2 are constituents of the active zone of murine brain but essentially absent from free synaptic vesicles. The specificity of immunodetection was confirmed by analyzing the respective knock-out animals. The fractionation experiments further revealed that APP is accumulated in the fraction containing docked synaptic vesicles. These data present novel insights into the subsynaptic localization of APPs and are a prerequisite for unraveling the physiological role of all mature APP proteins in synaptic physiology. PMID- 23815292 TI - A subgraph isomorphism algorithm and its application to biochemical data. AB - BACKGROUND: Graphs can represent biological networks at the molecular, protein, or species level. An important query is to find all matches of a pattern graph to a target graph. Accomplishing this is inherently difficult (NP-complete) and the efficiency of heuristic algorithms for the problem may depend upon the input graphs. The common aim of existing algorithms is to eliminate unsuccessful mappings as early as and as inexpensively as possible. RESULTS: We propose a new subgraph isomorphism algorithm which applies a search strategy to significantly reduce the search space without using any complex pruning rules or domain reduction procedures. We compare our method with the most recent and efficient subgraph isomorphism algorithms (VFlib, LAD, and our C++ implementation of FocusSearch which was originally distributed in Modula2) on synthetic, molecules, and interaction networks data. We show a significant reduction in the running time of our approach compared with these other excellent methods and show that our algorithm scales well as memory demands increase. CONCLUSIONS: Subgraph isomorphism algorithms are intensively used by biochemical tools. Our analysis gives a comprehensive comparison of different software approaches to subgraph isomorphism highlighting their weaknesses and strengths. This will help researchers make a rational choice among methods depending on their application. We also distribute an open-source package including our system and our own C++ implementation of FocusSearch together with all the used datasets (http://ferrolab.dmi.unict.it/ri.html). In future work, our findings may be extended to approximate subgraph isomorphism algorithms. PMID- 23815293 TI - Construction of planar and bulk integrated heterojunction polymer solar cells using cross-linkable D-A copolymer. AB - An integrated device architecture was constructed via vertical combination of planar and bulk heterojunctions by solution processing, where a cross-linked D-A copolymer (PBDTTT-Br25) was inserted between a PEDOT:PSS layer and the blended photoactive layer. PBDTTT-Br25 can readily undergo photo crosslinking to form an insoluble robust film via ultraviolet irradiation after solution-deposition, which enables the subsequent solution processing of a photoactive layer on the robust surface. The insertion of a pure PBDTTT-Br25 layer to build an integrated heterojunction could provide an additional donor/acceptor interface, which enables hole transport to the anode without interruption, thereby reducing the charge carrier recombination probability. The power conversion efficiency (PCE) of the polymer solar cell (PSC) with the integrated architecture reaches 5.24% under an AM1.5G illumination of 100 mW/cm(2), which is increased by 65%, in comparison with that of the reference single heterojunction device (3.17%), under the same experimental conditions. PMID- 23815294 TI - Sexual activity and adolescent health risk behaviours amongst high school students in three ethnic Chinese urban populations. AB - AIMS AND OBJECTIVES: To compare sexually active Chinese high school students in three major Asian cities with their non-sexually active counterparts in order to determine prevalence and associations with selected health outcomes. BACKGROUND: There have been limited studies to date on the association between sexual activity and substance use in Chinese high schools. While the role of the school nurse in the development of sexual health and harm reduction education in secondary schools has been well documented in international studies, this has received little attention in Asia. DESIGN: Cross-sectional survey. METHODS: This study was administered in 2003/2004 to 13,895 Grades 6 to 12 high school students in Hong Kong (3498), Macau (6286) and Taipei (4111). Descriptive analysis was conducted followed by univariate analysis comparing sexual behaviour with (1) substance use including alcohol, smoking, illicit drugs; (2) feeling depressed for greater than or equal to two weeks in last 12 months; contemplating suicide during the last 12 months; and (3) perception of poor health/academic performance. RESULTS: The students (8%) reported being sexually active had marked differences in selected health outcomes when compared with the nonsexually experienced students. More than 90% of the sexually active students had tried alcohol, with more than 50% being regular drinkers, more than 30% testifying to binge drinking and nearly 50% reported depression in the past 12 months. Substance use, poorer perception of health and academic performance were also significantly higher in the sexually experienced students relative to their nonexperienced counterparts. CONCLUSIONS: Sexually experienced Chinese high school students surveyed were at higher risk of substance abuse, poorer psychological health and academic performance. RELEVANCE TO CLINICAL PRACTICE: Community and public health nursing needs to address Asian adolescent sexual health education needs, in particular provide culturally targeted interventions for associated substance abuse and psychological health within the context of high school sex education. PMID- 23815295 TI - Liver diseases and aging: friends or foes? AB - The liver is the only internal human organ capable of natural regeneration of lost tissue, as little as 25% of a liver can regenerate into a whole liver. The process of aging predisposes to hepatic functional and structural impairment and metabolic risk. Therefore, understanding how aging could affect the molecular pathology of liver diseases is particularly important, and few studies to date have tackled this complex process. The most common liver disease, affecting one third of the overall population, is nonalcoholic fatty liver disease (NAFLD), characterized by an intrahepatic accumulation of lipids. NAFLD can evolve into nonalcoholic steatohepatitis (NASH) in the presence of oxidative stress and inflammation. NASH is a serious risk factor for disabling and deadly liver diseases such as cirrhosis and hepatocellular carcinoma (HCC). Old age seems to favor NAFLD, NASH, and ultimately HCC, in agreement with the inflamm-aging theory, according to which aging accrues inflammation. However, the incidence of HCC drops significantly in the very elderly (individuals aged more than 70) and the relationship between the progression of NAFLD/NASH/HCC and very old age is obscure. In this review, we discuss the literature and we argue that there might be an age window in which the liver becomes resistant to the development of injury; this needs to be studied to understand fully the interaction between age and liver diseases from a therapeutic perspective. PMID- 23815296 TI - Biomimicry of quorum sensing using bacterial lifecycle model. AB - BACKGROUND: Recent microbiologic studies have shown that quorum sensing mechanisms, which serve as one of the fundamental requirements for bacterial survival, exist widely in bacterial intra- and inter-species cell-cell communication. Many simulation models, inspired by the social behavior of natural organisms, are presented to provide new approaches for solving realistic optimization problems. Most of these simulation models follow population-based modelling approaches, where all the individuals are updated according to the same rules. Therefore, it is difficult to maintain the diversity of the population. RESULTS: In this paper, we present a computational model termed LCM-QS, which simulates the bacterial quorum-sensing (QS) mechanism using an individual-based modelling approach under the framework of Agent-Environment-Rule (AER) scheme, i.e. bacterial lifecycle model (LCM). LCM-QS model can be classified into three main sub-models: chemotaxis with QS sub-model, reproduction and elimination sub model and migration sub-model. The proposed model is used to not only imitate the bacterial evolution process at the single-cell level, but also concentrate on the study of bacterial macroscopic behaviour. Comparative experiments under four different scenarios have been conducted in an artificial 3-D environment with nutrients and noxious distribution. Detailed study on bacterial chemotatic processes with quorum sensing and without quorum sensing are compared. By using quorum sensing mechanisms, artificial bacteria working together can find the nutrient concentration (or global optimum) quickly in the artificial environment. CONCLUSIONS: Biomimicry of quorum sensing mechanisms using the lifecycle model allows the artificial bacteria endowed with the communication abilities, which are essential to obtain more valuable information to guide their search cooperatively towards the preferred nutrient concentrations. It can also provide an inspiration for designing new swarm intelligence optimization algorithms, which can be used for solving the real-world problems. PMID- 23815297 TI - Emerging trends in the epidemiology of melanoma. AB - Cutaneous melanoma (CM) is one of the most rapidly growing cancers worldwide, with a consistent increase in incidence among white populations over the past four decades. Despite the early detection of primarily thin melanomas and the improved survival rates observed in several countries, the rate of thick melanomas has remained constant or continues to increase, especially in the older age group. Current considerations in the epidemiology of melanoma focus on the observed survival benefit of females vs. males, the contributing role of indoor tanning in melanoma risk and the diverse effect of sun exposure in the development of different types of melanoma with respect to their clinical and mutational profile. Certain well-known risk factors, such as skin, hair and eye pigmentation and melanocytic naevi have been validated in large-scale association studies, while additional lifestyle factors and iatrogenic exposures, such as immunosuppressive agents and nonsteroidal anti-inflammatory drugs are being investigated. In addition, genome-wide association studies have revealed genetic loci that underlie the genetic susceptibility of melanoma, some of which are related to known risk factors. Recently, an interesting association of melanoma with Parkinson disease has been noted, with a higher than expected frequency of melanoma in patients with Parkinson disease and vice versa. This review article provides an update in the epidemiology of cutaneous melanoma and discusses recent developments in the field. PMID- 23815298 TI - The incidence and aetiology of hospitalised community-acquired pneumonia among Vietnamese adults: a prospective surveillance in Central Vietnam. AB - BACKGROUND: Lower respiratory tract infection (LRTI) including Community-acquired pneumonia (CAP) is a common infectious disease that is associated with significant morbidity and mortality. The patterns of aetiological pathogens differ by region and country. Special attention must be paid to CAP in Southeast Asia (SEA), a region facing rapid demographic transition. Estimates burden and aetiological patterns of CAP are essential for the clinical and public health management. The purposes of the study are to determine the incidence, aetiological pathogens, clinical pictures and risk factors of community-acquired pneumonia (CAP) in the Vietnamese adult population. METHODS: A prospective surveillance for hospitalised adult CAP was conducted in Khanh Hoa Province, Central Vietnam. All adults aged >=15 years with lower respiratory tract infections (LRTI) admitted to a provincial hospital from September 2009 to August 2010 were enrolled in the study. Patients were classified into CAP and non pneumonic LRTI (NPLRTI) according to the radiological findings. Bacterial pathogens were identified from sputum samples by the conventional culture and polymerase chain reaction (PCR) for Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis; 13 respiratory viruses were identified from nasopharyngeal specimens by PCR. RESULTS: Of all 367 LRTI episodes examined, 174 (47%) were CAP. Older age, the presence of underlying respiratory conditions, and higher index score of smoking were associated with CAP. The one-year estimated incidence of hospitalised adult CAP in our study population was 0.81 per 1,000 person years. The incidence increased considerably with age and was highest among the elderly. The case fatality proportion of hospitalised CAP patients was 9.8%. Among 286 sputum samples tested for bacterial PCR, 79 (28%) were positive for H. influenzae, and 65 (23%) were positive for S. pneumoniae. Among 357 samples tested for viral PCR, 73 (21%) were positive for respiratory viruses; influenza A (n = 32, 9%) was the most common. CONCLUSIONS: The current adult CAP incidence in Vietnam was relatively low; this result was mainly attributed to the young age of our study population. PMID- 23815299 TI - Effect of four different size reduction methods on the particle size, solubility enhancement and physical stability of nicergoline nanocrystals. AB - Nicergoline, a poorly soluble active pharmaceutical ingredient, possesses vaso active properties which causes peripheral and central vasodilatation. In this study, nanocrystals of nicergoline were prepared in an aqueous solution of polysorbate 80 (nanosuspension) by using four different laboratory scale size reduction techniques: high pressure homogenization (HPH), bead milling (BM) and combination techniques (high pressure homogenization followed by bead milling HPH + BM, and bead milling followed by high pressure homogenization BM + HPH). Nanocrystals were investigated regarding to their mean particles size, zeta potential and particle dissolution. A short term physical stability study on nanocrystals stored at three different temperatures (4, 20 and 40 degrees C) was performed to evaluate the tendency to change in particle size, aggregation and zeta potential. The size reduction technique and the process parameters like milling time, number of homogenization cycles and pressure greatly affected the size of nanocrystals. Among the techniques used, the combination techniques showed superior and consistent particle size reduction compared to the other two methods, HPH + BM and BM + HPH giving nanocrystals of a mean particle size of 260 and 353 nm, respectively. The particle dissolution was increased for any nanocrystals samples, but it was particularly increased by HPH and combination techniques. Independently to the production method, nicergoline nanocrystals showed slight increase in particle size over the time, but remained below 500 nm at 20 degrees C and refrigeration conditions. PMID- 23815300 TI - A novel automated alternating current biosusceptometry method to characterization of controlled-release magnetic floating tablets of metronidazole. AB - CONTEXT: Alternating Current Biosusceptometry is a magnetically method used to characterize drug delivery systems. This work presents a system composed by an automated ACB sensor to acquire magnetic images of floating tablets. OBJECTIVE: The purpose of this study was to use an automated Alternating Current Biosusceptometry (ACB) to characterize magnetic floating tablets for controlled drug delivery. MATERIALS AND METHODS: Floating tablets were prepared with hydroxypropyl methylcellulose (HPMC) as hydrophilic gel material, sodium bicarbonate as gas-generating agent and ferrite as magnetic marker. ACB was used to characterize the floating lag time and the tablet hydration rate, by quantification of the magnetic images to magnetic area. Besides the buoyancy, the floating tablets were evaluated for weight uniformity, hardness, swelling and in vitro drug release. RESULTS: The optimized tablets were prepared with equal amounts of HPMC and ferrite, and began to float within 4 min, maintaining the flotation during more than 24 h. The data of all physical parameters lied within the pharmacopeial limits. Drug release at 24 h was about 40%. CONCLUSIONS: The ACB results showed that this study provided a new approach for in vitro investigation of controlled-release dosage forms. Moreover, using automated ACB will also be possible to test these parameters in humans allowing to establish an in vitro.in vivo correlation (IVIVC). PMID- 23815301 TI - Real function of semiconducting polymer in GaAs/polymer planar heterojunction solar cells. AB - We systematically investigated GaAs/polymer hybrid solar cells in a simple planar junction, aiming to fundamentally understand the function of semiconducting polymers in GaAs/polymer-based heterojunction solar cells. A library of semiconducting polymers with different band gaps and energy levels were evaluated in GaAs/polymer planar heterojunctions. The optimized thickness of the active polymer layer was discovered to be ultrathin (~10 nm). Further, the open-circuit voltage (Voc) of such GaAs/polymer planar heterojunctions was fixed around 0.6 V, regardless of the HOMO energy level of the polymer employed. On the basis of this evidence and others, we conclude that n-type GaAs/polymer planar heterojunctions are not type II heterojunctions as originally assumed. Instead, n-type GaAs forms a Schottky barrier with its corresponding anode, while the semiconducting polymer of appropriate energy levels can function as hole transport layer and/or electron blocking layer. Additionally, we discover that both GaAs surface passivation and thermal annealing can improve the performance of GaAs/polymer hybrid solar cells. PMID- 23815302 TI - Induction therapy in adult intestinal transplantation: reduced incidence of rejection with "2-dose" alemtuzumab protocol. AB - The incidence of early rejection after intestinal transplantation correlates with heightened risk of graft loss and mortality. Many different induction or pre conditioning protocols have been reported in the last 10 yr to improve outcomes; however, sepsis remains prevalent and diminishes long-term results. We recently began a "2-dose" alemtuzumab trial protocol - 15 mg at day 0 and 15 mg repeated on day 7 - with the hope of reducing our infection rate. We compared three different protocols used at our institution (daclizumab, conventional "4-dose" alemtuzumab, and "2-dose" alemtuzumab). There was a significantly lower rate of early rejection with the "2-dose" alemtuzumab protocol in our study group of mainly (88%) intestinal grafts without accompanying liver engraftment with its protective immunologic effect. Sepsis remained low. Longer follow-up will be required to evaluate the effects of this new protocol on longer-term outcomes. PMID- 23815303 TI - A brief response to "Religious and secular death": a parting of the ways. PMID- 23815304 TI - Pilot of a novel intervention for postconcussive symptoms in active duty, veterans, and civilians. AB - PURPOSE/OBJECTIVE: The authors present a study aimed at pilot testing a novel delivery method, namely a computer intervention, for postconcussive symptom reduction in active duty, veteran, and civilian patients with acute and chronic complaints. Following a concussion/mild traumatic brain injury (MTBI), most individuals recover completely, but a significant proportion report postconcussive symptoms months to years following the injury. Psychoeducational intervention has shown to be effective in reducing postconcussive symptoms in studies done with acute civilian samples, but the efficacy of psychoeducational interventions with individuals who served in combat or have chronic complaints remains unclear. RESEARCH METHOD/DESIGN: Twenty-five active duty, veteran, and civilian participants took part in this study. At baseline, each participant completed a self-run psychoeducational computer-based treatment. Participants were reassessed 1-month postintervention via phone to evaluate postconconcussive symptom severity. RESULTS: Participants reported significantly fewer postconcussive symptoms at follow-up than baseline (d = .99). Intervention satisfaction was reported, with feedback related to ease of use and quality. CONCLUSIONS/IMPLICATIONS: Extending previous studies, current findings demonstrated that psychoeducational intervention following MTBI was associated with postconcussive symptom complaint reduction in both acute and chronic patients. These data also confirm the feasibility of using computerized psychoeducation and speak to the importance of providing education to both acute and chronic patients across settings. Feedback from participants was generally positive. Further investigation with a control group is warranted. PMID- 23815305 TI - Mild traumatic brain injury, meaning made of trauma, and posttraumatic stress: a preliminary test of a novel hypothesis. AB - OBJECTIVE: Research has demonstrated that a substantial number of veterans returning from Iraq and Afghanistan with mild traumatic brain injury (mTBI) also contend with symptoms of posttraumatic stress disorder (PTSD). One possible contributing factor for the development and/or exacerbation of PTSD symptoms among individuals with mTBI could involve challenges processing trauma and integrating their memories into existing global meaning systems. The goal of this study was to provide a preliminary examination of whether meaning made of trauma could account for the association between mTBI and PTSD (i.e., reexperiencing, avoidance, and hyperarousal symptoms). METHOD: The sample was comprised of 162 Iraq and/or Afghanistan veterans who presented for health care services at a Department of Veterans Affairs hospital. These veterans completed a two-level evaluation for mTBI as well as a self-report questionnaire assessing demographic and military background factors, meaning made of trauma, and PTSD symptomatology. RESULTS: Drawing on structural equation modeling, results indicated that probable mTBI was indirectly associated with the three domains of PTSD symptomatology via veterans' meaning made of trauma. CONCLUSIONS: Although the cross-sectional nature of this study limits the conclusions that can be drawn, these results offer support for difficulties with meaning-making as a contributing factor for risk of PTSD among veterans with mTBI. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 23815306 TI - Multicomponent synthesis of 1-aryl 1,2,4-triazoles. AB - A multicomponent (single reactor) process for the synthesis of 1-aryl 1,2,4 triazoles was explored and developed. This transformation prepared the 1,2,4 triazole directly from anilines, amino pyridines, and pyrimidines. The reaction scope was explored with 21 different substrates, and the position of the nitrogen atoms in the newly formed ring was established by (15)N labeling and NMR spectroscopy. PMID- 23815309 TI - Directed migration in neural tissue engineering. AB - Directed cell migration is particularly important in neural tissue engineering, where the goal is to direct neurons and support cells across injured nerve gaps. Investigation of the gradients present in the body during development provides an approach to guiding cells in peripheral and central nervous system tissue, but many different types of gradients and patterns can accomplish directed migration. The focus of this review is to describe current research paradigms in neural tissue gradients and review their effectiveness for directed migration. The review explores directed migration achieved through the use of chemical, adhesive, mechanical, topographical, and electrical types of gradients. Few studies investigate combined gradients, though it is known that a combination of therapies is necessary for reconnection of neuronal circuitry. To date, there has been no systematic review of gradient approaches to neural tissue engineering. By looking at effectiveness of various scaffold cue presentation and methods to combine these strategies, the potential for nerve repair is increased. PMID- 23815308 TI - Global competencies of regional stem cell research: bibliometrics for investigating and forecasting research trends. AB - We employed a bibliometric approach to examine regional stem cell research in the USA, the UK, Japan and China based on publications from 2007 to 2011 with a co citation clustering analysis to identify region-specific clusters of global competencies. We observed that there are clear differences in the number and interdisciplinary spread of competencies across regions: the USA retains the largest capacity and capability for pursuing medical and pharmaceutical applications; China has shown substantial growth through fusion approaches with chemistry and material sciences; Japan has been pursuing basic biology and is currently seeking further growth; and the UK has shown considerable growth and quality with a focus on medical research and the widest interdisciplinary spread. Furthermore, we discuss policy implications from these results in terms of industrial and clinical applications. These findings provide a rational way of evaluating research policies and forecasting research trends. PMID- 23815307 TI - Arrestin-dependent but G-protein coupled receptor kinase-independent uncoupling of D2-dopamine receptors. AB - We reconstituted D2 like dopamine receptor (D2R) and the delta opioid receptor (DOR) coupling to G-protein gated inwardly rectifying potassium channels (K(ir)3) and directly compared the effects of co-expression of G-protein coupled receptor kinase (GRK) and arrestin on agonist-dependent desensitization of the receptor response. We found, as described previously, that co-expression of a GRK and an arrestin synergistically increased the rate of agonist-dependent desensitization of DOR. In contrast, only arrestin expression was required to produce desensitization of D2R responses. Furthermore, arrestin-dependent GRK-independent desensitization of D2R-K(ir)3 coupling could be transferred to DOR by substituting the third cytoplasmic loop of DOR with that of D2R. The arrestin dependent GRK-independent desensitization of D2R desensitization was inhibited by staurosporine treatment, and blocked by alanine substitution of putative protein kinase C phosphorylation sites in the third cytoplasmic loop of D2R. Finally, the D2R construct in which putative protein kinase C phosphorylation sites were mutated did not undergo significant agonist-dependent desensitization even after GRK co-expression, suggesting that GRK phosphorylation of D2R does not play an important role in uncoupling of the receptor. PMID- 23815310 TI - Modeling the interaction of nanoparticles with mineral surfaces: adsorbed C60 on pyrophyllite. AB - We have applied DFT and molecular modeling to investigate the interaction between carbon-based nanoparticles (CNPs) and geosorbents using the adsorption of buckminsterfullerene (C60) on pyrophyllite and comparing it to the aggregation of C60 molecules. The approach is transferable and can be readily applied to more complex CNP-clay systems. We predict that C60 molecules adsorb preferably on the mineral surface and that the most stable adsorption site is the ditrigonal cavity of the surface. The free energy of adsorption on pyrophyllite was calculated to be more favorable than aggregation both in a vacuum (-0.47 vs -0.41 eV) and in water (-0.25 vs -0.19 eV). In aqueous environments, there are energy barriers as the C60 molecule approaches either a surface or another C60 molecule, and these occur upon disruption of the hydration layers that surround each component. There are also free energy minima that correspond to outer-sphere and more favorable inner-sphere complexes. We expect this adsorptive behavior to be a general feature of CNP-clay systems, and as clays are ubiquitous in the environment, it will offer an inexpensive remediative method to prevent the widespread impact of molecular C60 and CNPs. PMID- 23815311 TI - Commentary: Does the use of toluidine blue and hematoxylin and eosin improve tumor detection by Mohs surgery trainees? PMID- 23815312 TI - Commentary: Gene profiling analysis of the early effects of ablative fractional carbon dioxide laser treatment on human skin. PMID- 23815313 TI - Effect of subdermal 1,444-nm pulsed neodymium-doped yttrium aluminum garnet laser on the nasolabial folds and cheek laxity. AB - BACKGROUND: Wrinkle formation usually accompanies skin aging. In particular, accentuated nasolabial folds and loss of elasticity are early signs of skin aging. The use of 1,444-nm pulsed neodymium-doped yttrium aluminum garnet (Nd:YAG) lasers has increased in popularity. OBJECTIVE: To evaluate the safety and efficacy of a novel 1,444-nm pulsed Nd:YAG laser in the treatment of NLF and cheek laxity using subdermal laser therapy. METHODS: Ten Korean patients with moderate to severe NLF were enrolled. Each received a single treatment session with a 1,444-nm Nd:YAG laser. Two blinded physicians evaluated clinical improvement by rating comparative photographs on a 5-point scale. Efficacy was also assessed by measuring elasticity and roughness. Skin biopsies were performed on five volunteers before treatment and 3 months after treatment. RESULTS: The 1,444-nm Nd:YAG laser effectively promoted clinical improvement of NLF and cheek laxity (p < .05). Significant differences in elasticity and roughness were observed (p < .05). Epidermal proliferation was stimulated as demonstrated by increases in epidermal thickness and Ki-67 expression (p < .05). Quantitative image analyses of pre- and post-treatment biopsies revealed that collagen fibers increased from baseline (p > .05). Transforming growth factor beta and heat shock protein-70 messenger RNA levels quantified using real-time reverse transcriptase polymerase chain reaction increased significantly from baseline (p < .05). CONCLUSION: The 1,444-nm Nd:YAG laser is an effective treatment modality with minimal complications for the treatment of NLF and cheek laxity, but further research with a larger group of patients is needed to confirm these findings. PMID- 23815314 TI - Zeolitic imidazolate framework-based electrochemical biosensor for in vivo electrochemical measurements. AB - This study demonstrates the first exploitation of zeolitic imidazolate frameworks (ZIFs) as the matrix for constructing integrated dehydrogenase-based electrochemical biosensors for in vivo measurement of neurochemicals, such as glucose. In this study, we find that ZIFs are able to serve as a matrix for coimmobilizing electrocatalysts (i.e., methylene green, MG) and dehydrogenases (i.e., glucose dehydrogenase, GDH) onto the electrode surface and an integrated electrochemical biosensor is readily formed. We synthesize a series of ZIFs, including ZIF-7, ZIF-8, ZIF-67, ZIF-68, and ZIF-70 with different pore sizes, surface areas, and functional groups. The adsorption capabilities toward MG and GDH of these ZIFs are systematically studied with UV-vis spectroscopy, confocal laser scanning microscopy, and Fourier transfer-infrared spectroscopy. Among all the ZIFs demonstrated here, ZIF-70 shows excellent adsorption capacities toward both MG and GDH and is thus employed as the matrix for our glucose biosensor. To construct the biosensor, we first drop-coat a MG/ZIF-70 composite onto a glassy carbon electrode and then coat GDH onto the MG/ZIF-70 composite. In a continuous flow system, the as-prepared ZIF-based biosensor is very sensitive to glucose with a linear range of 0.1-2 mM. Moreover, the ZIF-based biosensor is more highly selective on glucose than on other endogenous electroactive species in the cerebral system. In the end, we demonstrate that our biosensor is capable of monitoring dialysate glucose collected from the brain of guinea pigs selectively and in a near real-time pattern. PMID- 23815315 TI - Experiences of living with dementia: qualitative content analysis of semi structured interviews. AB - AIMS AND OBJECTIVES: To describe people's experiences of living with dementia in Iran. BACKGROUND: A knowledge gap exists regarding the experiences of living with dementia in nonWestern contexts. This gap may be especially apparent within the Iranian context, where dementia research is relatively new. Deeper understanding about context-related experiences of dementia is a prerequisite for nurses' ability to provide adequate and meaningful care. DESIGN: Qualitative, cross sectional design. METHODS: Qualitative content analysis of semi-structured interviews with people living with dementia in urban Iran (six women and nine men; 60-87 years old). RESULTS: The participants experienced their condition as a state of forgetfulness that was accompanied by losses and dependency on others. They wanted to feel good about themselves and feel important, but they continually struggled with matters such as a loss of accountability, feelings of futility and the frustration of others. Economic dependency and a lack of economic resources were sources of feelings of futility. CONCLUSION: Experiences of living with dementia in Iran included a substantial struggle to stay connected to the social world and to deal with dramatic life changes, aspects of living with dementia that seem to be universal. However, the feelings of financial burden and the experience of being nagged for their shortfalls by family members have seldom been described in other studies and seem to represent a cultural aspect of their experience. RELEVANCE TO CLINICAL PRACTICE: The results of the study call for further nursing efforts in supporting people living with dementia in their struggle with their altered lives and in retaining their connections to everyday life. Furthermore, their family members might benefit from specific nursing interventions including information about dementia and advice on how to help the family members with dementia to interact with others while exercising their individual strengths. PMID- 23815316 TI - Genotypic prevalence of human papillomavirus infection during normal pregnancy: a cross-sectional study. AB - AIM: Genital human papillomavirus (HPV) infection is a necessary factor in most cases of cervical cancer, but malignant transformation requires the presence of additional cofactors such as pregnancy. Little is known about the effect of pregnancy on genital HPV carriage. We therefore analyzed the prevalence and genotypic patterns of genital HPV infections in normal pregnancies. METHODS: The prevalence of HPV infection was measured in 960 consecutive normal pregnant or post-partum women by HPV-DNA chip analysis of cervical swabs. Data were analyzed by trimester and adjusted for sociodemographic, reproductive and reported sexual history. RESULTS: The overall prevalence of HPV infection in the population was 24.3%. High-risk HPV genotypes were detected in 68.2% of infected subjects, including HPV 16 (18.7%), 39 (16.4%), 53 (10.1%), and 56 (9.4%). High-risk HPV genotypes were significantly more prevalent in the second trimester (23.8%) compared with the other periods (first trimester, 13.2%; third trimester, 17.4%; post-partum, 15.1%; P = 0.010). However, the high-risk HPV genotypes 16 or 18 were detected most frequently in the third trimester (7.2%) as compared to the other periods (first trimester, 2.9%; second trimester, 5.2%; post-partum, 2.1%; P = 0.03). After adjusting for confounding variables, overall HPV infection (odds ratio = 1.84, 95% confidence interval = 1.24-2.75) and high-risk HPV genotypes (odds ratio = 1.94, 95% confidence interval = 1.23-3.05) were significantly more common in the second trimester. CONCLUSION: The second trimester may be the most vulnerable period in high-risk HPV infections, which necessitates future investigations. PMID- 23815317 TI - Characterization of the mitochondrial genome of Rousettus leschenaulti. AB - We present a complete sequence of mitochondrial genome of echolocating megabat Rousettus leschenaulti (16,704 nt, GenBank record KC702803) and provide its annotation. We also show that phylogenetic analysis based on mitochondrial genomes of eighteen bat species, including R. leschenaulti, supports division of Chiroptera into Yinpterochiroptera and Yangochiroptera. PMID- 23815318 TI - Complete mitochondrial genome of the tiger shark Galeocerdo cuvier (Carcharhiniformes: Carcharhinidae). AB - The tiger shark Galeocerdo cuvier is the only member of the genus Galeocerdo. The complete mitochondrial genome of G. cuvier is presented for the first time in this study. The gene composition and arrangement in the mitogenome of G. cuvier is identical to most animal mitogenome. There are 22 bp short noncoding sequences and 44 bp overlaps in the mitogenome. The overall base composition is 31.8% A, 23.9% C, 13.0% G and 31.3% T. The dihydrouridine arm of tRNA-Ser2 was replaced by a simple loop and the other tRNAs could be folded into the typical cloverleaf structure. PMID- 23815319 TI - Complete mitochondrial genome of Abramis brama orientalis Berg (cypriniformes, Cyprinidae, Leuciscinae). AB - In this study, we cloned and sequenced the complete mitochondrial genome of Abramis brama orientalis Berg. The genome was 16,610 bp (LR) in length and consisted of 13 protein-coding genes, 22 tRNA genes, 2 ribosomal RNA genes and 2 main non-coding regions [the control region (CR) and the origin of the light strand replication], the gene composition and order of which was similar to those reported from other fish mitochondrial genomes. The overall base composition of the heavy strand was T 26.7%, C 26.5 %, A 30.0% and G 16.8%, with a slight A+T bias of 56.7%. This mitogenome sequence data would play an important role in population genetics and phylogenetic analysis of the Leuciscinae. PMID- 23815320 TI - Complete mitochondrial genome of Phoxinus tumensis (Cypriniformes: Cyprinidae). AB - Abstract The taxonomy and systematics of Phoxinus (Cypriniformes: Cyprinidae) is still not well-resolved. In this study, we determined the first complete mitochondrial genome (mitogenome) of Phoxinus tumensis. The mitogenome was 17,050 bp in length, including 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes and 1 control region. All genes were encoded on the heavy strain except for ND6 and eight tRNA genes. The overall base composition of the heavy strain was 27.9% for A, 25.5% for C, 28.4% for T and 18.2% for G. The control region was revealed to contain tandem repeats. The mitogenome data of P. tumensis should contribute to clarify the systematics of Phoxinus fishes. PMID- 23815321 TI - No association between mitochondrial tRNA(Val) T1658C mutation and chronic progressive external ophthalmoplegia (CPEO). AB - Mutations in mitochondrial tRNA genes are one of the most important causes of mitochondrial diseases. Recently, a novel mt-tRNA(Val) T1658C mutation has been reported to be associated with chronic progressive external ophthalmoplegia (CPEO). To test this association, we performed a phylogenetic analysis of T1658C mutation, moreover, we used the bioinformatic tool to predict the thermodynamic change of tRNA(Val) with and without this mutation. Surprisingly, T1658C mutation was not evolutionary conserved and had little effect on tRNA(Val) folding. These data indicated that T1658C mutation should still be categorized as a polymorphism. PMID- 23815322 TI - Complete mitochondrial genome of endangered Socorro Conure (Aratinga brevipes) - taxonomic position of the species and its relationship with Green Conure. AB - Socorro Conure (Aratinga brevipes.Aratinga holochlora brevipes) is a parrot endemic to the Island of Socorro. According to some taxonomists the species is considered a subspecies of Green Conure (Aratinga holochlora). Some other classifications treat brevipes as a separate species based on relatively minor morphological differences between both species/subspecies. However, taxonomic position of Aratinga brevipes was never determined by molecular research. We sequenced full mitochondrial genome of the species and constructed phylogenetic tree using sequences of mitochondrial ND2 gene from A. brevipes and some other representatives of Conures group. Our results showed, that despite Aratinga brevipes is closely related to Aratinga holochlora, this Conure should be treated as a separate species. PMID- 23815323 TI - The complete mitochondrial genome sequence of Xenocypris davidi (Bleeker). AB - Xenocypris davidi is a member of Cyprindae and widely distributed in China. To understand the systematic status of this species, we sequenced the whole mitochondrial genome of Xenocypris davidi. The complete mitochondrial genome is 16,630 bp in length including the typical structure of 22 tRNA, 2 rRNA, 13 protein-coding genes and the non-coding region. The major non-coding sequence which is the control region containing 6 CSBs (CSB-1, CSB-2, CSB-3, CSB-D, CSB-E and CSB-F). The second non-coding sequence is the origin of light-strand replication (OL). This region has the potential to fold in a step-loop secondary structure. The mitochondrial genomic sequence will help us to study the conservation genetic and evolution of Xenocypris. PMID- 23815324 TI - Mitochondrial genome of the Emberiza rutila (Emberizidae: Emberiza). AB - Emberiza rutila is a passerine bird of eastern Asia which belongs to the genus Emberiza in the bunting family Emberizidae. The complete mitochondrial genome of E. rutila was obtained for the first time in this study. The circular genome (16,803 bp in length) consists of 37 typical animal mitochondrial genes (13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes) and 1 control region. Overall base composition of the complete mitochondrial DNA was 30% A, 22.8% T, 32.8% C and 14.3% G. Except for 8 tRNA genes and ND6 gene, the relative position and orientation of all the genes were identical to those of most vertebrates. PMID- 23815325 TI - Complete mitochondrial genome of the natural triploid loach, Misgurnus anguillicaudatus (Teleostei: Cypriniformes: Cobitididae). AB - Abstract The complete mitochondrial genome of the natural triploid loach Misgurnus anguillicaudatus is a circular molecule of 16,646 bp in size, containing 13 protein-coding genes, 22 transfer RNA (tRNA) genes, 2 ribosomal RNA (rRNA) genes and 2 main noncoding regions (the control region and the origin of the light strand replication). Most of the genes are encoded on the heavy strand, except for ND6 and 8 tRNAs. The control region is 918 bp in length and located between the tRNA(Pro) and tRNA(Phe) genes, some typical conserved elements (TAS, CSB1-3 and CSB D-F) were found in this region. All these features reflect a typical vertebrate mitochondrial gene arrangement of the triploid M. anguillicaudatus. PMID- 23815326 TI - Structure comparison of control region in Stromateoidei and complete mitochondrial genome of the bluefin driftfish Psenes pellucidus (Perciformes, Nomeidae). AB - In the present study, the complete mitochondrial genome of the bluefin driftfish Psenes pellucidus was determined first. The genome was 16,572 bp in length and consisted of 13 protein-coding genes, 22 tRNA genes, 2 ribosomal RNA genes and 2 main non-coding regions. The mitochondrial genome of bluefin driftfish had common features about gene arrangement, base composition and tRNA structures compared with those of most of the bony fishes. In the control region, a termination associated sequence, the central conserved block (CSB-F, CSB-E and CSB-D) and the conserved sequence blocks (CSB-1, CSB-2 and CSB-3) were determined. Meanwhile, the conserved motif 5'-GCCGG-3' was identified in the origin of light strand replication of bluefin driftfish. This mitogenome sequence data would play key role in phylogenetic analysis of Stromateoidei. PMID- 23815327 TI - Complete mitochondrial genome of European pine marten, Martes martes. AB - Abstract We undertook the first sequencing of the entire mitogenome of Martes martes. The genome is 16,486 bp in length and contains 13 protein-coding genes, 22 tRNA genes, two rRNA genes and a control region. The total base composition of the mitogenome is 31.9% for A, 27. 6% for C, 25.8% for T and 14.7% for G. The genome organization, nucleotide composition and codon usage do not differ significantly from other martens. This mitogenome sequence data might be useful for phylogenetic and systematic analyses within the genus Martes. PMID- 23815328 TI - Mitochondrial genome of bamboo rat Rhizomys pruinosus. AB - Abstract Bamboo rats are a group of subterranean rodents some of which feed on the roots and shoots of bamboo and other plants. In this study, we sequence the mitochondrial genome of a hoary bamboo rat Rhizomys pruinosus from the south of China. The genome is 16,575 bp in length, and had a gene content of 13 protein coding, 22 tRNAs and 2 rRNAs. The overall base composition is 30.94% T, 24.83% C, 32.21% A and 12.02% G, with an A+T bias of 63.15%. The cytochrome genes were the most conservative genes compared with plateau zokor (Eospalax baileyi) and blind mole rats (Spalax carmeli) in the family Spalacidae. These mitochondrial data are potentially important for the study of molecular evolution, conservation genetics, agricultural technology and epidemiology. PMID- 23815329 TI - The complete mitochondrial genome sequence of pike perch (Sander canadensis). AB - Pike perch (Sander canadensis) is a member of the largest order of Osteichthyes, Perciformes, and is an important ecological and economic freshwater species, which distributes in Ili River and Ergis River of Xinjiang Province, China. In this study, we sequenced the whole mitochondrial genome of pike perch, and analyzed the similarity with its related species. The mitochondrial genome of S. canadensis is 16,542 bp in length with 55.05% AT content, contained 13 protein coding genes, 22 tRNA genes, 2 ribosomal genes and an 892 bp non-coding region. In control region, 6 CSBs (CSB-1, CSB-2, CSB-3, CSB-D, CSB-E and CSB-F), one potential TAS and one poly-T region were identified. Comparing all protein-coding genes and whole genome sequence with 4 species of Perciformes (three species of Percidae, Perca flavescens. Percina macrolepida. Etheostoma radiosum and one outgroup Oreochromis sp. red tilapia), ND3 gene has the highest mutation rate, and S. canadensis has higher similarity with Perca flavescens than others. The mitochondrial genomic sequence will help us to study the conservation genetic and evolution of Percidae. PMID- 23815330 TI - The complete mitochondrial genome of Micropercops swinhonis (Perciformes: Gobioidei: Odontobutidae). AB - For understanding the phylogenetic position of Micropercops swinhonis within the family Odontobutidae, the complete nucleotide sequence of M. swinhonis mitochondrial genome was firstly determined. The genome is 16,493 bp in length, and consists of 37 genes (13 protein-coding genes, 22 transfer RNA genes and 2 ribosomal RNA genes) and 2 main noncoding regions (the control region and the origin of the light strand replication). The gene composition and order of which were similar to most other vertebrates. Within the control region, typical conserved domains, such as the termination-associated sequence, central and conserved sequence blocks domains were identified. PMID- 23815331 TI - The complete mitochondrial genome of the fourfinger threadfin Eleutheronema tetradactylum (Perciforms: Polynemidae) and comparison of light strand replication origin within Percoidei. AB - The complete mitochondrial genome of Eleutheronema tetradactylum was determined, which was the first complete mitochondrial genome in Polynemidae family. The mitochondrial genome was 16,474 base pairs in length, encoding a standard set of 13 protein-coding genes, 2 ribosomal RNA genes, 22 tRNA genes and 2 main non coding regions (the control region and the origin of the light strand replication). The overall base composition of E. tetradactylum is A 27.2%, C 29.9%, G 17.0% and T 25.9%, with a slight A + T bias of 53.1%. The mitochondrial genome of E. tetradactylum had common features about gene arrangement and tRNA structures compared with those of other vertebrate fishes. Two non-coding regions were also determined within its mitogenome. These mitogenome sequence data would play an important role in population genetics and phylogenetic analysis of the Polynemidae. PMID- 23815332 TI - Complete mitochondrial genome of the rare hypogean gobiid, Luciogobius pallidus, from Korea. AB - The rare hypogean gobiid, Luciogobius pallidus, inhabits mainly in groundwater, spring, or upper rocky tidal regions in Korea and Japan. In this paper, the complete mitochondrial genome sequence of L. pallidus was firstly determined. The gene composition and order of L. pallidus were similar to most of the other fishes. The total length of the rare hypogean gobiid mitochondrial genome is 16,480 bp, including 13 protein-coding genes, 22 tRNA, 2 rRNA and 1 control region (CR). All genes were encoded on the heavy (H)-strand, with the exceptions of ND6 and eight tRNA genes, as found in other vertebrates. The CR (833 bp in length) is located between the tRNA-Pro and tRNA-Phe genes and contains three central conserved sequence blocks (CSB-D, CSB-E and CSB-F), three conserved sequence blocks (CSB-1, CBS-2 and CBS-3), and its 3' end embeds a poly-T nucleotide sequence. PMID- 23815333 TI - Complete mitochondrial genome of Lacerta agilis (Squamata, Lacertidae). AB - The complete mitochondrial genome sequence of Lacerta agilis was determined in the present paper. The genome was 17,090 bp in length and contained 13 protein coding genes, 2 rRNA genes, 22 tRNA genes and 1 control region (CR). The gene composition and order of which was similar to most other Squamate reptiles. The overall base composition of the genome in descending order was 31.29% A, 26. 39% C, 29.01% T and 13.29% G, with a slight AT bias of 60.30%. CR is located between the tRNA-Pro and tRNA-Phe genes and is 1688 bp in length, some tandem repeat sequences and conserved elements (CSB1-3) were found in the control region. PMID- 23815334 TI - Complete mitochondrial genome of the blue-spotted stingray Neotrygon kuhlii (Myliobatiformes: Dasyatidae). AB - The blue-spotted stingray Neotrygon kuhlii is a small stingray distributed in the Indian and West Pacific Ocean. It was considered a species complex by morphological and molecular evidences. In this study, we firstly presented the complete mitochondrial genome of N. kuhlii. It is 18,039 bp in length, including 13 protein-coding genes, two ribosomal RNA genes, 22 transfer RNA genes and 1 control region, with the typical gene order in the mitogenomes of vertebrates. The total base composition is 31.9% A, 26.4% C, 13.1% G and 28.6% T, with an A + T bias of 60.5%. Alignment results demonstrated that the mitochondrial sequences of N. kuhlii in this study were highly similar to the 12S, 16S, COI and Cyt b sequences of the specimens collected from the Chinese seas in other studies. PMID- 23815336 TI - Inductive foraging: improving the diagnostic yield of primary care consultations. AB - BACKGROUND: Physicians attempting to make a diagnosis arrive at specific hypotheses early in their encounter with patients. Further data are collected in the light of these early hypotheses. While this hypothetico-deductive model has been accepted as both a description of physicians' data gathering and a norm, little attention has been paid to the preceding stage of the consultation. HYPOTHESIS: It is suggested that 'inductive foraging' is a relevant and appropriate mode of data acquisition for the first part of the patient encounter. METHODS: Research evidence from cognitive psychology and medical reasoning research is discussed. RESULTS: With inductive foraging, 'pattern failure' rather than 'pattern recognition' is the mode of discovery. Largely, guidance should be left to the patient to lead the clinician into areas where departures from normality are to be found. This is in contrast to active and focused 'deductive inquiry,' which should be used only after most aetiologies, but a few have eliminated. IMPLICATION: Especially when the prevalence of serious disease is low, and a wide range of diagnoses must be evaluated, such as in General Practice, inductive foraging is a rational and efficient diagnostic strategy. Previously, too little attention has been paid to the initial stage of the consultation. Premature closure at this point may result in diagnostic error. PMID- 23815335 TI - Comparative genome analysis of Lactobacillus casei strains isolated from Actimel and Yakult products reveals marked similarities and points to a common origin. AB - The members of the Lactobacillus genus are widely used in the food and feed industry and show a remarkable ecological adaptability. Several Lactobacillus strains have been marketed as probiotics as they possess health-promoting properties for the host. In the present study, we used two complementary next generation sequencing technologies to deduce the genome sequences of two Lactobacillus casei strains LcA and LcY, which were isolated from the products Actimel and Yakult, commercialized as probiotics. The LcA and LcY draft genomes have, respectively, an estimated size of 3067 and 3082 Mb and a G+C content of 46.3%. Both strains are close to identical to each other and differ by no more than minor chromosomal re-arrangements, substitutions, insertions and deletions, as evident from the verified presence of one insertion-deletion (InDel) and only 29 single-nucleotide polymorphisms (SNPs). In terms of coding capacity, LcA and LcY are predicted to encode a comparable exoproteome, indicating that LcA and LcY are likely to establish similar interactions with human intestinal cells. Moreover, both L. casei LcA and LcY harboured a 59.6 kb plasmid that shared high similarities with plasmids found in other L. casei strains, such as W56 and BD II. Further analysis revealed that the L. casei plasmids constitute a good evolution marker within the L. casei species. The plasmids of the LcA and LcY strains are almost identical, as testified by the presence of only three verified SNPs, and share a 3.5 kb region encoding a remnant of a lactose PTS system that is absent from the plasmids of W56 and BD-II but conserved in another smaller L. casei plasmid (pLC2W). Our observations imply that the results obtained in animal and human experiments performed with the Actimel and Yakult strains can be compared with each other as these strains share a very recent common ancestor. PMID- 23815337 TI - Relative potencies of aroclor mixtures derived from avian in vitro bioassays: comparisons with calculated toxic equivalents. AB - The World Health Organization toxic equivalency factors (WHO-TEFs) for birds were developed to simplify risk assessments of environmental mixtures of dioxin-like compounds (DLCs). Under this framework, toxic equivalents (TEQs) are used to represent the toxic potency of DLC mixtures as an equivalent concentration of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Recently, a luciferase reporter gene (LRG) assay, measuring aryl hydrocarbon receptor 1 (AHR1)-mediated gene expression, accurately predicted the relative potency of individual polychlorinated biphenyl (PCB) congeners in different avian species. The study presented here used the LRG assay to predict the relative potency of Aroclors 1016, 1221, 1242, 1248, 1254, and 1260 on induction of LRG activity in cells transfected with chicken, ring necked pheasant, or Japanese quail AHR1 constructs. LRG assay results were compared to (1) results of ethoxyresorufin-O-deethylase (EROD) assays conducted in chicken hepatocytes and (2) calculated TEQs from the literature. The relative potencies of Aroclors were similar between the LRG and EROD assays, and bioassay derived TEQs for the chicken closely resembled calculated TEQs. However, LRG assay-derived TEQs for the Japanese quail construct were 1-2 orders of magnitude higher than calculated TEQs for Aroclors 1254 and 1016. These results suggest that the WHO-TEFs are not representative of relative PCB potency for all avian species. PMID- 23815339 TI - Molecular markers in melanoma. AB - The last few years have witnessed the dawn of the molecular era in melanoma treatment. With the advent of successful therapy targeting mutant BRAF, melanoma is leading the field of cancer research in the molecular approach to therapy of advanced disease. Attempting to keep pace with advances in therapy are advances in the molecular assessment of melanoma progression, facilitated by the availability of genome-wide approaches to interrogate the malignant phenotype. At the DNA level, this has included approaches such as comparative genomic hybridization. At the RNA level, this has consisted of gene expression profiling using various assay methodologies. In certain instances, markers identified using these platforms have been further examined and developed using fluorescence in situ hybridization and immunohistochemical analysis. In this article, we will review recent progress in the development of novel molecular markers for melanoma that are nearing clinical application. We will review developments in the molecular classification of melanoma, in the molecular diagnosis of melanoma, and in the molecular assessment of melanoma prognosis. PMID- 23815338 TI - Keratinocyte growth factor and glucocorticoid induction of human peroxiredoxin 6 gene expression occur by independent mechanisms that are synergistic. AB - AIMS: Peroxiredoxin 6 (Prdx6), a 1-cys Prdx has both peroxidase and phospholipase A2 activities, protecting against oxidative stress and regulating pulmonary surfactant phospholipid metabolism. This study determined the mechanism by which keratinocyte growth factor (KGF) and the glucocorticoid analogue, dexamethasone (Dex), induce increased Prdx6 expression. RESULTS: Transcriptional activation by KGF in both A549 lung adenocarcinoma cells and rat lung alveolar epithelial type II (ATII) cells utilizes an antioxidant response element (ARE), located between 357 and 349 nucleotides before the PRDX6 translational start, that is also necessary for upregulation of the human PRDX6 promoter in response to oxidative stress. Activation is mediated by binding of the transcription factor, Nrf2, to the ARE as shown by experiments using siRNA against Nrf2 and by transfecting ATII cells isolated from lungs of Nrf2 null mice. KGF triggers the migration of Nrf2 from cytoplasm to nucleus where it binds to the PRDX6 promoter as shown by chromatin immunoprecipitation assays. Activation of transcription by Dex occurs through a glucocorticoid response element located about 750 nucleotides upstream of the PRDX6 translational start. INNOVATION: This study demonstrates that KGF can activate an ARE in a promoter without reactive oxygen species involvement and that KGF and Dex can synergistically activate the PRDX6 promoter and protect cells from oxidative stress. CONCLUSION: These two different activators work through different DNA elements. Their combined effect on transcription of the reporter gene is synergistic; however, at the protein level, the combined effect is additive and protects cells from oxidative damage. PMID- 23815340 TI - A loss and confronting the future. PMID- 23815341 TI - Modulation of skeletal muscle performance and SERCA by exercise and adiponectin gene therapy in insulin-resistant rat. AB - This study addresses the potential application of adiponectin gene therapy and exercise in protection against skeletal muscle dysfunction in type 2 diabetes mellitus (T2DM) while focusing on the role of sarco and endoplasmic reticulum Ca(+2) ATPase (SERCA) and Glut4. 50 rats were divided into five groups: control, T2DM, T2DM treated with either adiponectin gene or exercise or a combination of both. Serum glucose, insulin, HOMA index, triglycerides, and cholesterol were measured. Weight gain%, muscle contractile parameters {(peak twitch tension (Pt), peak tetanic tension (PTT), half relaxation time (HRT)}, and gene expression of SERCA, Glut4, and adiponectin were assessed in gastrocnemius muscle. Diabetic rats treated with either adiponectin gene or exercise showed significant reduction in all serum parameters and wt gain%. There was significant elevation in Pt and PTT with shortening in HRT. Furthermore, a significant increase in SERCA, Glut4, and adiponectin gene expression was noticed in both groups. Combination therapy caused marked gene expression of SERCA, GLUT4, and greater improvement in muscle contractility than either of the monotherapies. Skeletal muscle dysfunction in T2DM is mediated via impaired SERCA and Glut 4. Combination therapy offered best protection against muscle dysfunction and provides a novel promising strategy for a complete cure of muscle dysfunction in T2DM. PMID- 23815342 TI - Predictors of mortality among TB-HIV Co-infected patients being treated for tuberculosis in Northwest Ethiopia: a retrospective cohort study. AB - BACKGROUND: Tuberculosis (TB) is the leading cause of mortality in high HIV prevalence populations. HIV is driving the TB epidemic in many countries, especially those in sub-Saharan Africa. The aim of this study was to assess predictors of mortality among TB-HIV co-infected patients being treated for TB in Northwest Ethiopia. METHODS: An institution-based retrospective cohort study was conducted between April, 2009 and January, 2012. Based on TB, antiretroviral therapy (ART), and pre-ART registration records, TB-HIV co-infected patients were categorized into "On ART" and "Non-ART" cohorts. A Chi-square test and a T-test were used to compare categorical and continuous variables between the two groups, respectively. A Kaplan-Meier test was used to estimate the probability of death after TB diagnosis. A log-rank test was used to compare overall mortality between the two groups. A Cox proportional hazard model was used to determine factors associated with death after TB diagnosis. RESULTS: A total of 422 TB-HIV co infected patients (i.e., 272 On ART and 150 Non-ART patients) were included for a median of 197 days. The inter-quartile range (IQR) for On ART patients was 140 to 221 days and the IQR for Non-ART patients was 65.5 to 209.5 days. In the Non-ART cohort, more TB-HIV co-infected patients died during TB treatment: 44 (29.3%) Non ART patients died, as compared to 49 (18%) On ART patients died. Independent predictors of mortality during TB treatment included: receiving ART (Adjusted Hazard Ratio (AHR) =0.35 [0.19-0.64]); not having initiated cotrimoxazole prophylactic therapy (CPT) (AHR = 3.03 [1.58-5.79]); being ambulatory (AHR = 2.10 [1.22-3.62]); CD4 counts category being 0-75 cells/micro liter, 75-150 cells/micro liter, or 150-250 cells/micro liter (AHR = 4.83 [1.98-11.77], 3.57 [1.48-8.61], and 3.07 [1.33-7.07], respectively); and treatment in a hospital (AHR = 2.64 [1.51-4.62]). CONCLUSIONS: Despite the availability of free ART from health institutions in Northwest Ethiopia, mortality was high among TB-HIV co infected patients, and strongly associated with the absence of ART during TB treatment. In addition cotrimoxazol prophylactic therapy remained important factor in reduction of mortality during TB treatment. The study also noted importance of early ART even at higher CD4 counts. PMID- 23815343 TI - Prediction of peptide drift time in ion mobility mass spectrometry from sequence based features. AB - BACKGROUND: Ion mobility-mass spectrometry (IMMS), an analytical technique which combines the features of ion mobility spectrometry (IMS) and mass spectrometry (MS), can rapidly separates ions on a millisecond time-scale. IMMS becomes a powerful tool to analyzing complex mixtures, especially for the analysis of peptides in proteomics. The high-throughput nature of this technique provides a challenge for the identification of peptides in complex biological samples. As an important parameter, peptide drift time can be used for enhancing downstream data analysis in IMMS-based proteomics. RESULTS: In this paper, a model is presented based on least square support vectors regression (LS-SVR) method to predict peptide ion drift time in IMMS from the sequence-based features of peptide. Four descriptors were extracted from peptide sequence to represent peptide ions by a 34-component vector. The parameters of LS-SVR were selected by a grid searching strategy, and a 10-fold cross-validation approach was employed for the model training and testing. Our proposed method was tested on three datasets with different charge states. The high prediction performance achieve demonstrate the effectiveness and efficiency of the prediction model. CONCLUSIONS: Our proposed LS-SVR model can predict peptide drift time from sequence information in relative high prediction accuracy by a test on a dataset of 595 peptides. This work can enhance the confidence of protein identification by combining with current protein searching techniques. PMID- 23815344 TI - The third paradigm in labour pain preparation and management: the childbearing woman's paradigm. AB - THE STUDY'S RATIONALE: Women's experiences regarding labour pain preparation and management have been largely neglected. AIMS AND OBJECTIVES: Explore women's experiences regarding labour pain preparation and management in normal childbirth. METHODOLOGICAL DESIGN AND JUSTIFICATION: The Vancouver School of doing phenomenology was the methodological approach of the study since it provides inside information about the lived experience. RESEARCH METHODS: Data were collected through in-depth interviews with 14 participants; seven primiparous and seven multiparous women. RESULTS: The women described a challenging journey of no return through labour pain, with different landmarks on the journey. They described how they prepared for the pain; the context of the pain experience; how they experienced and managed the pain with different strategies and how they saw the pain at the journey's end. The quality of the midwife's presence and professionalism was of great importance to them. The 'good midwives' they described created a special atmosphere which was warm and secure and was conducive to their managing the pain. The women also described how important it was for them to have a supportive partner, with whom they had a mutual understanding, in order to manage the pain. CONCLUSIONS: In this paper, we are presenting a study within the third paradigm in labour pain preparation and management: the childbearing woman's paradigm - the first and second being the midwifery and the medical paradigm, respectively. Midwives can play a major role in working with women in their preparation and management of labour pain. In the future, more research has to be done to illuminate this essential part of the childbearing woman's paradigm. PMID- 23815345 TI - The Caenorhabditis elegans LET-418/Mi2 plays a conserved role in lifespan regulation. AB - The evolutionarily conserved nucleosome-remodeling protein Mi2 is involved in transcriptional repression during development in various model systems, plays a role in embryonic patterning and germ line development, and participates in DNA repair and cell cycle progression. It is the catalytic subunit of the nucleosome remodeling and histone deacetylase (NuRD) complex, a key determinant of differentiation in mammalian embryonic stem cells. In addition, the Drosophila and C. elegans Mi2 homologs participate in another complex, the MEC complex, which also plays an important developmental role in these organisms. Here we show a new and unexpected feature of the C. elegans Mi2 homolog, LET-418/Mi2. Lack of LET-418/Mi2 results in longevity and enhanced stress resistance, a feature that we found to be conserved in Drosophila and in Arabidopsis. The fact that depletion of other components of the NuRD and the MEC complexes did not result in longevity suggests that LET-418 may regulate lifespan in a different molecular context. Genetic interaction studies suggest that let-418 could act in the germ cell-loss pathway, downstream of kri-1 and tcer-1. On the basis of our data and on previous findings showing a role for let-418 during development, we propose that LET-418/Mi2 could be part of a system that drives development and reproduction with concomitant life-reducing effects later in life. PMID- 23815346 TI - Lithographically patterned thin activated carbon films as a new technology platform for on-chip devices. AB - Continuous, smooth, visibly defect-free, lithographically patterned activated carbon films (ACFs) are prepared on the surface of silicon wafers. Depending on the synthesis conditions, porous ACFs can either remain attached to the initial substrate or be separated and transferred to another dense or porous substrate of interest. Tuning the activation conditions allows one to change the surface area and porosity of the produced carbon films. Here we utilize the developed thin ACF technology to produce prototypes of functional electrical double-layer capacitor devices. The synthesized thin carbon film electrodes demonstrated very high capacitance in excess of 510 F g(-1) (>390 F cm(-3)) at a slow cyclic voltammetry scan rate of 1 mV s(-1) and in excess of 325 F g(-1) (>250 F cm(-3)) in charge discharge tests at an ultrahigh current density of 45,000 mA g(-1). Good stability was demonstrated after 10,000 galvanostatic charge-discharge cycles. The high values of the specific and volumetric capacitances of the selected ACF electrodes as well as the capacity retention at high current densities demonstrated great potential of the proposed technology for the fabrication of various on-chip devices, such as micro-electrochemical capacitors. PMID- 23815349 TI - Pain during topical photodynamic therapy of actinic keratoses with 5 aminolevulinic acid and red light source: randomized controlled trial. AB - BACKGROUND: Pain is the major drawback of photodynamic therapy (PDT), an otherwise effective treatment for actinic keratoses (AKs). OBJECTIVE: To determine pain intensity and its dependence upon various factors during PDT with 5-aminolevulinic acid for face/scalp AKs. METHODS: A prospective, randomized, within-patient comparison study was performed. Thirty-eight patients with at least two clearly definable, mild or moderate AKs were randomized to receive either a red light dose of 70 or 100 J/cm(2) as a first or second split face/scalp treatment. They were blinded to the light dose administered. Pain during treatment was assessed using a visual analog scale (VAS). RESULTS: The mean intensity of pain during the first treatment session was 5.00 (+/- 1.78), while during the follow-up VAS score was 4.50 (+/- 1.51). Bigger AKs (> 130 mm(2) ) were more painful than the smaller ones (P = 0.003) and AKs on the face were twice more painful than the ones on the scalp (P = 0.002). Gender and patient age were poor pain predictors. Pain was independent of the patient's Fitzpatrick skin type, AK clinical grade, pretreatment fluorescence intensity, and the light dose during PDT. CONCLUSION: Pain during PDT is associated with AK location and size. Treatment of bigger lesions (> 130 mm(2) ) results in more pain than smaller ones and treatment of the face is more painful than the scalp area. PMID- 23815350 TI - Predicting the ultraviolet radiation protection by polyester-cotton blended woven fabrics using nonlinear regression and artificial neural network models. AB - INTRODUCTION: Ultraviolet protection factor (UPF) of fabric is mainly influenced by fabric cover which is dependent on the primary fabric construction parameters like yarn count and thread density. UPF can be modeled by using these primary fabric parameters as inputs by the help of nonlinear regression as well as artificial neural network (ANN). OBJECTIVES: The objective of this study is to develop prediction models for fabric UPF using nonlinear regression and ANN techniques and compare their relative efficacy. METHODS: Thirty-six woven fabric samples were produced by varying weft related parameters like proportion of polyester, weft count and pick density. Nonlinear regression and ANN models were developed from same experimental data sets. Prediction accuracy of both the models was evaluated and compared. Trend analysis was performed to check the generalization ability of the ANN model. RESULTS: UPF was well estimated from the three primary fabric parameters by both the nonlinear regression and ANN models. However, ANN model demonstrated better prediction accuracy than the nonlinear regression model. CONCLUSIONS: Fabric UPF can be predicted with high degree of accuracy using ANN and nonlinear regression models. These models can be used to estimate the UPF of woven fabrics without spectrophotometer based test. PMID- 23815351 TI - Good agreement between minimal erythema dose test reactions and objective measurements: an in vivo study of human skin. AB - BACKGROUND/PURPOSE: The erythema resulting from the minimal erythema dose (MED) test is subjectively assessed. The evaluator visually grades erythema on an ordinal scale. Both intra- and interobserver variation have been found for this erythema assessment. We wanted to examine if objective measurements could be used to confirm the subjective finding. METHODS: One hundred two ultraviolet radiation (UVR)-exposed skin sites on the backs of 17 healthy volunteers were assessed. Erythema was visually graded according to a 5-point scale [0, (+), 1+, 2+, 3+] and objectively measured by a skin reflectance meter. Skin water content was objectively measured by tissue dielectric constant measurements. RESULTS: The relationship between subjective assessments and objective measurements of erythema was found to be linear (R(2) = 0.482, P < 0.0001). A positive correlation was found between subjective assessments of erythema and objective measurements of water content (Spearman's Rho = 0.414, P < 0.0001). Water content in categories 2+ and 3+ of the subjective erythema assessments differed significantly from the lesser categories (P < 0.0001). A linear relationship was found between the objective measurements of erythema and water content (R(2) = 0.241, P < 0.0001). CONCLUSION: Objective measurements of skin erythema and water content after UV exposure were in good agreement with the subjective assessments of erythema, but showed considerable interpersonal variation. PMID- 23815352 TI - Photoprotective effects of inclusion complexes of fullerenes with polyvinylpyrrolidone. AB - BACKGROUND: The outermost surface of the body is covered by the stratum corneum, which is critical for proper skin barrier function. We investigated photoprotective effects of inclusion complexes of fullerenes with polyvinylpyrrolidone (PVP/fullerenes). METHODS: To examine the cytoprotective activity of PVP/fullerenes against ultraviolet B (UVB) irradiation, we placed a dish with or without PVP/fullerenes on top of dishes containing cultured keratinocytes with or without PVP/fullerenes. Next, we examined the effects of PVP/fullerenes on the ratio of cells with cornified envelopes and transglutaminase-1 expression by real-time polymerase chain reaction and immunohistochemistry. Finally, we examined the barrier recovery effect of PVP/fullerenes solution by measuring transepidermal water loss after tape stripping in humans. RESULTS: UVB irradiation at 40 mJ/cm(2) markedly induced inhibition of keratinocyte proliferation. The inhibition of keratinocyte proliferation was restored only when PVP/fullerenes were present before UVB irradiation in the lower dish with the cells. UVB irradiation decreased the ratio of cells with cornified envelopes and transglutaminase-1 expression; however, the application of PVP/fullerenes reversed this phenomenon. PVP/fullerenes solution significantly promoted the recovery of transepidermal water loss on the second and third days after tape stripping. CONCLUSION: PVP/fullerenes can be used in cosmetics, especially in those intended to protect photo damage and ameliorate skin barrier perturbations. PMID- 23815354 TI - Congenital plaque-like glomangioma treated successfully with dual wavelength pulsed-dye and neodymium:yttrium-aluminum-garnet laser. AB - Glomovenous malformations are disseminated variants of cutaneous glomus tumors. These malformations are subdivided into regional or localized, disseminated, and congenital plaque-like forms. The congenital plaque-like form is the rarest variant. Most treatment modalities have been disappointing in the treatment of large glomangiomas, leading to high recurrence rates. We report a case of a 34 year-old man with a congenital plaque-like glomangioma on his left arm and forearm treated successfully with sequential pulsed-dye neodymium yttrium aluminum garnet laser. PMID- 23815353 TI - Collagen hydrolysate intake improves the loss of epidermal barrier function and skin elasticity induced by UVB irradiation in hairless mice. AB - BACKGROUND: Ultraviolet B (UVB) irradiation induces serious damage to the skin. Collagen hydrolysate and collagen-derived peptides have effects on skin function in vivo and in vitro. However, few studies have investigated changes in the epidermal barrier or dermal elasticity caused by UVB. Here, we investigated the loss of epidermal barrier function and skin elasticity induced by UVB irradiation in hairless mice fed collagen hydrolysate. METHODS: Mice were orally administered collagen hydrolysate, in a single dose (20 mJ/cm(2) ) or repeated doses (10-30 mJ/cm(2) , 3 times/week for 6 weeks), and the dorsal skin was exposed to UVB. Skin measurements and histological and analytical studies were performed. RESULTS: In control mice, a single UVB irradiation induced epidermal barrier dysfunction including an increase in transepidermal water loss (TEWL), epidermal hyperplasia, and a decrease in stratum corneum water content. Administration of collagen hydrolysate significantly decreased TEWL and epidermal thickness and increased stratum corneum water content. Repeated UVB irradiation decreased skin elasticity and dermal hyaluronic acid (HA) content in control mice, whereas collagen hydrolysate significantly suppressed both the increase in TEWL and the decrease in stratum corneum water content and improved skin elasticity and dermal HA content. CONCLUSIONS: Collagen hydrolysate administration affects epidermal barrier function and dermal skin elasticity. PMID- 23815355 TI - A case of generalized lichen nitidus successfully treated with narrow-band ultraviolet B treatment. AB - Lichen nitidus (LN) is a rare skin disorder presenting with multiple, small and bright papules located on the chest, abdomen, penis glans and upper extremities. It usually presents with limited involvement; however, it can present as generalized involvement. There is no consensus on treatment. Corticosteroid, astemizole, phototherapy has been used; however, the results are controversial. A 15-year-old male with clinical and histopathological diagnosis of LN was treated with narrow-band ultraviolet B (NB-UVB). The lesions completely regressed with post-inflammatory hypopigmentation on the second month of the therapy (25 sessions). We believe that NB-UVB is an effective treatment on generalized LN. PMID- 23815356 TI - Second-degree burn within a tattoo after intense-pulsed-light epilation. AB - The use of high energy light sources [laser, intense pulsed light (IPL)] is booming in aesthetic surgery. A trend, especially concerning usage of photoepilation in cosmetic institutes, is detectable. Photoepilation works through selective photothermolysis, by heating the chromophore melanin within the hair follicles. We present a case impressionably demonstrating that high-energy light demands profound knowledge of its mechanism of action, and can cause severe harm in absence of basic knowledge. Photoepilation is a balancing act between maximal therapeutic effect and minimal side effect risk. Nevertheless, complications have to be clearly distinguished from professional errors. The latter are rising especially with IPL devices, mainly because its use depicts a legal grey area in most of the countries and is not bound to physicians' supervision. Due to its worse risk-benefit profile as compared with that of laser therapy, we advise against the use of IPL devices and claim for stricter regulation of its use, similar to laser devices. PMID- 23815357 TI - A sun holiday is a sunburn holiday. AB - Many people take holidays in sunny locations with the express aim of sunbathing. This may result in sunburn, which is a risk factor for skin cancer. We investigated 25 Danish sun seekers during a week's holiday in the Canary Islands. The percentage of body surface area with sunburn was determined by daily skin examinations by the same observer. Erythemally effective ultraviolet radiation (UVR) exposure was assessed with time-stamped personal dosimeters worn on the wrist. Volunteers reported their clothing cover and sunscreen use in diaries, and this information was used to determine body site-specific UVR doses after adjustment for sun protection factor. Remarkably, we found that all volunteers sunburned at some point. The risk of sunburn correlated significantly with the adjusted body site-specific UVR dose. Furthermore, there was also a significant relationship between the daily UVR dose and percentage of body surface area with sunburn. Our study shows that holiday UVR exposure results in a high risk of sunburn, which potentially increases the risk of skin cancer. Possible protection by melanogenesis is insufficient to protect against sunburn during a 1-week sun holiday. Finally, our data clearly support a substantial skin cancer risk from sun holidays. PMID- 23815358 TI - Metal nanoparticle-functionalized DNA tweezers: from mechanically programmed nanostructures to switchable fluorescence properties. AB - DNA tweezers are modified with two 10-nm sized Au NPs and one 5-nm sized Au NP. Upon treatment of the tweezers with fuel and antifuel nucleic acid strands, the switchable closure and opening of the tweezers proceed, leading to the control of programmed nanostructures of the tethered NPs. The tweezers are further modified with a single 10-nm sized nanoparticle, and a fluorophore unit (Cy3), positioned at different distinct sites of the tweezers. The reversible and cyclic fluorescence quenching or fluorescence enhancement phenomena, upon the dynamic opening/closure of the different tweezers, are demonstrated. PMID- 23815359 TI - Examples of sequence conservation analyses capture a subset of mouse long non coding RNAs sharing homology with fish conserved genomic elements. AB - BACKGROUND: Long non-coding RNAs (lncRNA) are a major class of non-coding RNAs. They are involved in diverse intra-cellular mechanisms like molecular scaffolding, splicing and DNA methylation. Through these mechanisms they are reported to play a role in cellular differentiation and development. They show an enriched expression in the brain where they are implicated in maintaining cellular identity, homeostasis, stress responses and plasticity. Low sequence conservation and lack of functional annotations make it difficult to identify homologs of mammalian lncRNAs in other vertebrates. A computational evaluation of the lncRNAs through systematic conservation analyses of both sequences as well as their genomic architecture is required. RESULTS: Our results show that a subset of mouse candidate lncRNAs could be distinguished from random sequences based on their alignment with zebrafish phastCons elements. Using ROC analyses we were able to define a measure to select significantly conserved lncRNAs. Indeed, starting from ~2,800 mouse lncRNAs we could predict that between 4 and 11% present conserved sequence fragments in fish genomes. Gene ontology (GO) enrichment analyses of protein coding genes, proximal to the region of conservation, in both organisms highlighted similar GO classes like regulation of transcription and central nervous system development. The proximal coding genes in both the species show enrichment of their expression in brain. In summary, we show that interesting genomic regions in zebrafish could be marked based on their sequence homology to a mouse lncRNA, overlap with ESTs and proximity to genes involved in nervous system development. CONCLUSIONS: Conservation at the sequence level can identify a subset of putative lncRNA orthologs. The similar protein coding neighborhood and transcriptional information about the conserved candidates provide support to the hypothesis that they share functional homology. The pipeline herein presented represents a proof of principle showing that a portion between 4 and 11% of lncRNAs retains region of conservation between mammals and fishes. We believe this study will result useful as a reference to analyze the conservation of lncRNAs in newly sequenced genomes and transcriptomes. PMID- 23815360 TI - An empirical evaluation of recovery transformation at a large community psychiatric rehabilitation organization. AB - In recent decades, the concept of "recovery" from Severe Mental Illness (SMI) has gained increased prominence among organizations providing behavioral health services. Many states and organizations are currently developing plans to transform their mental health systems in accordance with recovery-oriented care. Even though efforts to bring the principles of recovery to mental health agencies have been well documented in the United States and abroad, there is little empirical evidence to suggest that recovery-oriented services are advantageous. The purpose of this longitudinal study was to evaluate the effectiveness of a recovery-oriented transformation carried out by a large, private, not-for-profit psychiatric rehabilitation organization serving individuals with SMI. This transformation targeted the philosophy and specific procedures involved in the provision of care to residents within the organization. The outcome variables selected to evaluate the impact of the transformation were grouped into the following categories: (a) objective indicators of recovery, (b) self-report indicators of recovery, (c) indicators of staff competency, and (d) processes that promote recovery. Six-hundred and 27 residents and 490 staff participated in the evaluation. The findings suggest that recovery-oriented services had a positive impact on rates of overnight hospitalization, residents' ability to function in the community, some professional skills of employees, and working alliance between direct care providers and residents. This indicates that comprehensive and well-structured recovery-oriented care may offer a cost efficient and effective alternative to the deficit approach to mental health care. PMID- 23815361 TI - Two-Tiered Violence Risk Estimates: a validation study of an integrated-actuarial risk assessment instrument. AB - This study is an initial validation study of the Two-Tiered Violence Risk Estimates instrument (TTV), a violence risk appraisal instrument designed to support an integrated-actuarial approach to violence risk assessment. The TTV was scored retrospectively from file information on a sample of violent offenders. Construct validity was examined by comparing the TTV with instruments that have shown utility to predict violence that were prospectively scored: The Historical Clinical-Risk Management-20 (HCR-20) and Lifestyle Criminality Screening Form (LCSF). Predictive validity was examined through a long-term follow-up of 12.4 years with a sample of 78 incarcerated offenders. Results show the TTV to be highly correlated with the HCR-20 and LCSF. The base rate for violence over the follow-up period was 47.4%, and the TTV was equally predictive of violent recidivism relative to the HCR-20 and LCSF. Discussion centers on the advantages of an integrated-actuarial approach to the assessment of violence risk. PMID- 23815363 TI - Taming of a superbase for selective phenol desilylation and natural product isolation. AB - Hydroxyl moieties are highly prevalent in natural products. We previously reported a chemoselective strategy for enrichment of hydroxyl-functionalized molecules by formation of a silyl ether bond to a resin. To generate smaller pools of molecules for analysis, we developed cleavage conditions to promote stepwise release of phenolic silyl ethers followed by aliphatic silyl ethers with a "tamed" version of the superbase 1,1,3,3-tetramethylguanadine. We demonstrate this as a general strategy for selective deprotection of phenolic silyl ethers under neutral conditions at room temperature. PMID- 23815364 TI - Botulinum toxin injection for salivary gland enlargement evaluated using computed tomographic volumetry. PMID- 23815362 TI - Growth hormone releasing hormone (GHRH) signaling modulates intermittent hypoxia induced oxidative stress and cognitive deficits in mouse. AB - Intermittent hypoxia (IH) during sleep, such as occurs in obstructive sleep apnea (OSA), leads to degenerative changes in the hippocampus, and is associated with spatial learning deficits in adult mice. In both patients and murine models of OSA, the disease is associated with suppression of growth hormone (GH) secretion, which is actively involved in the growth, development, and function of the central nervous system (CNS). Recent work showed that exogenous GH therapy attenuated neurocognitive deficits elicited by IH during sleep in rats. Here, we show that administration of the Growth Hormone Releasing Hormone (GHRH) agonist JI-34 attenuates IH-induced neurocognitive deficits, anxiety, and depression in mice along with reduction in oxidative stress markers such as MDA and 8 hydroxydeoxyguanosine, and increases in hypoxia inducible factor-1alpha DNA binding and up-regulation of insulin growth factor-1 and erythropoietin expression. In contrast, treatment with a GHRH antagonist (MIA-602) during intermittent hypoxia did not affect any of the IH-induced deleterious effects in mice. Thus, exogenous GHRH administered as the formulation of a GHRH agonist may provide a viable therapeutic intervention to protect IH-vulnerable brain regions from OSA-associated neurocognitive dysfunction. Sleep apnea, characterized by chronic intermittent hypoxia (IH), is associated with substantial cognitive and behavioral deficits. Here, we show that administration of a GHRH agonist (JI-34) reduces oxidative stress, increases both HIF-1alpha nuclear binding and downstream expression of IGF1 and erythropoietin (EPO) in hippocampus and cortex, and markedly attenuates water maze performance deficits in mice exposed to intermittent hypoxia during sleep. PMID- 23815365 TI - Catalytic Friedel-Crafts reaction of aminocyclopropanes. AB - A Lewis acid catalyzed Friedel-Crafts reaction between donor-acceptor aminocyclopropanes and indoles and other electron-rich aromatic compounds is reported. Indole alkylation at the C3 position was generally obtained for a broad range of functional groups and substitution patterns. In the case of C3 substituted indoles, C2 alkylation was observed. The reaction gives a rapid access to gamma amino acid derivatives present in numerous bioactive molecules. PMID- 23815366 TI - Effects of nutritional parameters on nocturnal blood pressure in patients undergoing hemodialysis. AB - BACKGROUND: Malnutrition is a common problem in uremic patients. It is unclear whether there is an association between the degree of malnutrition and 24-h ambulatory blood pressure patterns in patients undergoing hemodialysis. In the present study, we observed the relationship between the degree of malnutrition and deterioration of the rhythm of diurnal blood pressure, which are both risk factors for cardiovascular morbidity-mortality and associated with hypervolemia. METHOD: We observed 148 patients undergoing hemodialysis in the Nephrology Department of Celal Bayar University Hospital. All cases were assessed for body weight alterations, dietary food intake, gastrointestinal symptoms, loss of subcutaneous fat and muscle tissue, presence and severity of comorbidities, functional capacity (subjective global assessment), and anthropometric indices. Ambulatory blood pressure measurements were performed for all cases on the day between the two hemodialysis sessions. RESULTS: We found that the circadian blood pressure rhythm deteriorated in patients with a high-malnutrition score, and that malnutrition was more common and severe in those subjects with the non-dipper and reverse-dipper blood pressure patterns. Malnutrition score was positively correlated with the nighttime systolic and nighttime mean blood pressures and mean 24-h arterial blood pressure (all p <= 0.01). We identified a positive correlation between malnutrition score and the reduction in serum albumin and anthropometric indices. CONCLUSION: This is the first study to demonstrate an association between malnutrition and deterioration in the circadian blood pressure rhythm in a hemodialysis population. Nutritional disturbance is associated with an increase in night-time blood pressure. Low serum albumin levels and hypervolemia may contribute this situation. PMID- 23815367 TI - Most and least helpful aspects of fall prevention education to prevent injurious falls: a qualitative study on nurses' perspectives. PMID- 23815368 TI - Hydrogen bond donors accelerate vibrational cooling of hot purine derivatives in heavy water. AB - Natural nucleobases and many of their derivatives have ultrashort excited state lifetimes that make them excellent model systems for studying intermolecular energy flow from a hot solute molecule to the solvent. UV-pump/broadband-mid-IR probe transient absorption spectra of canonical purine nucleobases and several xanthine derivatives were acquired in D2O and acetonitrile in the probe frequency range of 1500-1750 cm(-1). The spectra reveal that vibrationally hot ground state molecules created by ultrafast internal conversion return to thermal equilibrium in several picoseconds by dissipating their excess energy to solvent molecules. In acetonitrile solution, where hydrogen bonding is minimal, vibrational cooling (VC) occurs with the same time constant of 10 +/- 3 ps for paraxanthine, theophylline, and caffeine within experimental uncertainty. In D2O, VC by these molecules occurs more rapidly and at different rates that are correlated with the number of N-D bonds. Hypoxanthine has a VC time constant of 3 +/- 1 ps, while similar lifetimes of 2.3 +/- 0.8 ps and 3.1 +/- 0.3 ps are seen for 5'-adenosine monophosphate and 5'-guanosine monophosphate, respectively. All three molecules have at least two N-D bonds. Slightly slower VC time constants are measured for paraxanthine (4 +/- 1 ps) and theophylline (5.1 +/- 0.8 ps), dimethylated xanthines that have only one N-D bond. Caffeine, a trimethylated xanthine with no N-D bonds, has a VC time constant of 7.7 +/- 0.9 ps, the longest ever observed for any nucleobase in aqueous solution. Hydrogen bond donation by solute molecules is proposed to enable rapid energy disposal to water via direct coupling of high frequency solute-solvent modes. PMID- 23815369 TI - Retraction of Nanoporous PtCo surface alloy architecture with enhanced properties for methanol electrooxidation. PMID- 23815370 TI - Resonant microwave absorption in thermally deposited au nanoparticle films near percolation coverage. AB - We observe a resonant transition in the microwave absorption of thin thermally deposited Au nanoparticle films near the geometrical percolation transition pc where the films exhibit a 'fractal' heterogeneous geometry. Absorption of incident microwave radiation increases sharply near pc, consistent with effective medium theory predictions. Both the theory and our experiments indicate that the hierarchical structure of these films makes their absorption insensitive to the microwave radiation wavelength lambda, so that this singular absorption of microwave radiation is observed over a broad frequency range between 100 MHz and 20 GHz. The interaction of electromagnetic radiation with randomly distributed conductive scattering particles gives rise to localized resonant modes, and our measurements indicate that this adsorption process is significantly enhanced for microwaves in comparison to ordinary light. In particular, above the percolation transition a portion of the injected microwave power is stored within the film until dissipated. Finally, we find that the measured surface conductivity can be quantitatively described at all Au concentrations by generalized effective medium theory, where the fitted conductivity percolation exponents and pc itself are consistent with known two-dimensional estimates. Our results demonstrate that microwave measurements provide a powerful means of remotely measuring the electromagnetic properties of highly heterogeneous conducting films, enabling purposeful engineering of the electromagnetic properties of thin films in the microwave frequency range through fabrication of 'disordered' films of conducting particles such as metal nanoparticles or carbon nanotubes. PMID- 23815371 TI - Introduction of a sexual health practice nurse is associated with increased STI testing of men who have sex with men in primary care. AB - BACKGROUND: The study objective was to investigate the effect of the introduction of a sexual health practice nurse on HIV and STI testing in a general practice that specialized in gay men's health. METHODS: This observational study compared the proportion of gay and other men who have sex with men (MSM) tested for HIV, syphilis, chlamydia (urethral and anal) and gonorrhoea (anal), or all of the above (defined as a complete set of tests at a single visit), two years before and one year after the nurse was introduced (Clinic A). Clinic B, a general practice which also specialized in gay men's health, but with no sexual health nurse, was used as a control. RESULTS: In Clinic A, amongst HIV negative MSM the proportion of men who had a complete set of HIV and STI tests increased from 41% to 47% (p < 0.01) after the nurse was introduced. Amongst HIV positive MSM attending clinic A there was an increase in the proportion of men who had a complete set of tests after the nurse was introduced from 27% to 43% (p < 0.001). In Clinic B there was no significant increase in testing in the proportion of either HIV negative or HIV positive men who had a complete set of tests over the same time periods. CONCLUSIONS: The introduction of the sexual health practice nurse resulted in significant increases in episodes of complete STI testing among MSM. The effect was most pronounced among HIV positive MSM. PMID- 23815373 TI - Acute myeloid leukaemia with cup-like nuclei associated with t(9;22)(q34;q11.2). PMID- 23815374 TI - Visceral leishmaniasis with haemophagocytic lymphohistiocytosis: the importance of scrutinising your samples. PMID- 23815372 TI - Chronic glucolipotoxic conditions in pancreatic islets impair insulin secretion due to dysregulated calcium dynamics, glucose responsiveness and mitochondrial activity. AB - BACKGROUND: In the progression towards diabetes, glucolipotoxicity is one of the main causes of pancreatic beta cell pathology. The aim of this study was to examine the in vitro effects of chronic glucolipotoxic conditions on cellular responses in pancreatic islets, including glucose and fat metabolism, Calcium mobilization, insulin secretion and insulin content. RESULTS: Exposure of islets to chronic glucolipotoxic conditions decreased glucose stimulated insulin secretion in vitro. Reduced protein levels of Glut2/slc2a2, and decreased glucokinase and pyruvate carboxylase mRNA levels indicated a significant lowering in glucose sensing. Concomitantly, both fatty acid uptake and triglyceride accumulation increased significantly while fatty acid oxidation decreased. This general suppression in glucose metabolism correlated well with a decrease in mitochondrial number and activity, reduction in cellular ATP content and dampening of the TCA cycle. Further, we also observed a decrease in IP3 levels and lower Calcium mobilization in response to glucose. Importantly, chronic glucolipotoxic conditions in vitro decreased insulin gene expression, insulin content, insulin granule docking (to the plasma membrane) and insulin secretion. CONCLUSIONS: Our results present an integrated view of the effects of chronic glucolipotoxic conditions on known and novel signaling events, in vitro, that results in reduced glucose responsiveness and insulin secretion. PMID- 23815375 TI - Why some children hospitalized for pneumonia do not consult with a general practitioner before the day of hospitalization. AB - BACKGROUND: Early consultation in primary care may provide an opportunity for early intervention in children developing pneumonia, but little is known about why some children do not consult a general practitioner (GP) before hospitalization. OBJECTIVES: To identify differences between children who consulted a GP and children who did not consult a GP before the day of hospital presentation with pneumonia or empyema. METHODS: Carers of children aged six months to 16 years presenting to hospital with pneumonia or empyema completed a questionnaire, with a subset participating in an interview to identify physical, organizational and psychological barriers to consultation. Responses from those who had consulted a GP before the day of hospital presentation were compared with those who had not on a range of medical, social and environmental variables. RESULTS: Fifty seven (38%) of 151 participants had not consulted a GP before the day of hospital presentation. On multivariate analysis, illness duration >= 3 days (odds ratio [OR] 4.36, 95% confidence interval [CI]: 1.67-11.39), prior antibiotic use (OR: 10.35, 95% CI: 2.16-49.55) and home ownership (OR: 3.17, 95% CI: 1.07-9.37) were significantly associated with early GP consultation (P < 0.05). Interviews with 28 carers whose children had not seen a GP before the day of presentation revealed that most had not considered it and/or did not think their child's initial symptoms were serious or unusual; 11 (39.3%) had considered consulting a GP but reported barriers to access. CONCLUSION: Lack of early GP consultation was strongly associated with rapid evolution of pneumonia. PMID- 23815376 TI - Transforming growth factor Beta-releasing scaffolds for cartilage tissue engineering. AB - The maintenance of a critical threshold concentration of transforming growth factor beta (TGF-beta) for a given period of time is crucial for the onset and maintenance of chondrogenesis. Thus, the development of scaffolds that provide temporal and/or spatial control of TGF-beta bioavailability has appeal as a mechanism to induce the chondrogenesis of stem cells in vitro and in vivo for articular cartilage repair. In the past decade, many types of scaffolds have been designed to advance this goal: hydrogels based on polysaccharides, hyaluronic acid, and alginate; protein-based hydrogels such as fibrin, gelatin, and collagens; biopolymeric gels and synthetic polymers; and solid and hybrid composite (hydrogel/solid) scaffolds. In this study, we review the progress in developing strategies to deliver TGF-beta from scaffolds with the aim of enhancing chondrogenesis. In the future, such scaffolds could prove critical for tissue engineering cartilage, both in vitro and in vivo. PMID- 23815377 TI - An integrative review of the factors influencing new graduate nurse engagement in interprofessional collaboration. AB - AIM: To analyse critically the barriers and facilitators to new graduate nurse engagement in interprofessional collaboration. BACKGROUND: The acculturation of new graduate nurses must be considered in strategies that address the global nursing shortage. Interprofessional collaboration may support the transition and retention of new graduate nurses. DESIGN: Whittemore and Knafl's revised framework for integrative reviews guided the analysis. DATA SOURCES: A comprehensive multi-step search (published 2000-2012) of the North American interprofessional collaboration and new graduate literature indexed in the CINAHL, Proquest, Pubmed, PsychINFO and Cochrane databases was performed. A sample of 26 research and non-research reports met the inclusion criteria. REVIEW METHODS: All 26 articles were included in the review. A systematic and iterative approach was used to extract and reduce the data to draw conclusions. RESULTS: The analysis revealed several barriers and facilitators to new graduate engagement in interprofessional collaboration. These factors exist at the individual, team and organizational levels and are largely consistent with conceptual and empirical analyses of interprofessional collaboration conducted in other populations. However, knowledge and critical thinking emerged as factors not identified in previous analyses. CONCLUSION: Despite a weak-to-moderate literature sample, this review suggests implications for team and organizational development, education and research that may support new graduate nurse engagement in IPC. PMID- 23815378 TI - Poly(lactide-co-glycolide acid)/biphasic calcium phosphate composite coating on a porous scaffold to deliver simvastatin for bone tissue engineering. AB - In this study, simvastatin (SIM) drug incorporated poly(D,L-lactic-co-glycolide) (PLGA)/biphasic calcium phosphate (BCP) composite material (SPB) was coated on the BCP/ZrO2 (SPB-BCP/ZrO2) scaffold to enhance the mechanical and bioactive properties of the BCP/ZrO2 scaffold for bone engineering applications. The composite coating was prepared by combining different ratios of PLGA and BCP (1:2, 1:1, 2:1). After completion of the coating process, the compressive strength of the scaffolds was shown to increase with an increase in PLGA concentration from 8.5 +/- 0.52 MPa for the SPB1-BCP/ZrO2 (1:2) to 11 +/- 0.65 MPa for SPB3-BCP/ZrO2 (2:1) scaffolds when PLGA concentration was increased. Furthermore, the increase of PLGA in the coating composition corresponds to a decrease in porosity, degradation rate and weight loss of the scaffolds after 4 weeks. SIM release study demonstrated sustained release of the drug for the three kinds of scaffolds with improved biocompatibility. The increase of PLGA concentration also resulted in a lower release rate of SIM. Thus, the lower release rate of SIM brought upon by the increase of PLGA concentration further enhanced the performance of the scaffold in vitro making it a promising approach in the field of bone tissue regeneration. PMID- 23815379 TI - Potential role of oxidative exoenzymes of the extremophilic fungus Pestalotiopsis palmarum BM-04 in biotransformation of extra-heavy crude oil. AB - Large amount of drilling waste associated with the expansion of the Orinoco Oil Belt (OOB), the biggest proven reserve of extra-heavy crude oil (EHCO) worldwide, is usually impregnated with EHCO and highly salinized water-based drilling fluids. Oxidative exoenzymes (OE) of the lignin-degrading enzyme system (LDS) of fungi catalyse the oxidation of a wide range of toxic pollutants. However, very little evidences on fungal degradation or biotransformation of EHCO have been reported, which contain high amounts of asphaltenes and its biodegradation rate is very limited. The aims of this work were to study the ability of Pestalotiopsis palmarum BM-04 to synthesize OE, its potential to biotransform EHCO and to survive in extreme environmental conditions. Enzymatic studies of the LDS showed the ability of this fungus to overproduce high amounts of laccase (LACp) in presence of wheat bran or lignin peroxidase (LIPp) with EHCO as sole carbon and energy source (1300 U mgP(-1) in both cases). FT-IR spectroscopy with Attenuated Total Reflectance (ATR) analysis showed the enzymatic oxidation of carbon and sulfur atoms in both maltenes and asphaltenes fractions of biotreated EHCO catalysed by cell-free laccase-enriched OE using wheat bran as inducer. UV visible spectrophotometry analysis revealed the oxidation of the petroporphyrins in the asphaltenes fraction of biotreated EHCO. Tolerance assays showed the ability of this fungus to grow up to 50,000 p.p.m. of EHCO and 2000 mM of NaCl. These results suggest that P. palmarum BM-04 is a hopeful alternative to be used in remediation processes in extreme environmental conditions of salinity and EHCO contamination, such as the drilling waste from the OOB. PMID- 23815380 TI - Copper/zinc superoxide dismutase from the Cladoceran Daphnia magna: molecular cloning and expression in response to different acute environmental stressors. AB - The copper/zinc superoxide dismutase (Cu/Zn-SOD) is a representative antioxidant enzyme that is responsible for the conversion of superoxide to oxygen and hydrogen peroxide in aerobic organisms. Cu/Zn-SOD mRNAs have been cloned from many species and employed as useful biomarkers of oxidative stresses. In the present study, we cloned Cu/Zn-SOD cDNA from the cladoceran Daphnia magna, analyzed its catalytic properties, and investigated mRNA expression patterns after exposure to known oxidative stressors. The full-length Cu/Zn-SOD of the D. magna (Dm-Cu/Zn-SOD) sequence consisted of 703 bp nucleotides, encoding 178 amino acids, showing well-conserved domains that were required for metal binding and several common characteristics. The deduced amino acid sequence of Dm-Cu/Zn-SOD showed that it shared high identity with Daphnia pulex (88%), Alvinella pompejana (56%), and Cristaria plicata (56%). The phylogenetic analysis indicated that Dm Cu/Zn-SOD was highly homologous to D. pulex. The variation of Dm-Cu/Zn-SOD mRNA expression was quantified by real-time PCR, and the results indicated that the expression was up-regulated after 48-h exposure to copper, un-ionized ammonia, and low dissolved oxygen. This study shows that the Dm-Cu/Zn-SOD mRNA could be successfully employed as a biomarker of oxidative stress, which is a common mode of toxicity for many other aquatic hazardous materials. PMID- 23815381 TI - State of art fusion-finder algorithms are suitable to detect transcription induced chimeras in normal tissues? AB - BACKGROUND: RNA-seq has the potential to discover genes created by chromosomal rearrangements. Fusion genes, also known as "chimeras", are formed by the breakage and re-joining of two different chromosomes. It is known that chimeras have been implicated in the development of cancer. Few publications in the past showed the presence of fusion events also in normal tissue, but with very limited overlaps between their results. More recently, two fusion genes in normal tissues were detected using both RNA-seq and protein data.Due to heterogeneous results in identifying chimeras in normal tissue, we decided to evaluate the efficacy of state of the art fusion finders in detecting chimeras in RNA-seq data from normal tissues. RESULTS: We compared the performance of six fusion-finder tools: FusionHunter, FusionMap, FusionFinder, MapSplice, deFuse and TopHat-fusion. To evaluate the sensitivity we used a synthetic dataset of fusion-products, called positive dataset; in these experiments FusionMap, FusionFinder, MapSplice, and TopHat-fusion are able to detect more than 78% of fusion genes. All tools were error prone with high variability among the tools, identifying some fusion genes not present in the synthetic dataset. To better investigate the false discovery chimera detection rate, synthetic datasets free of fusion-products, called negative datasets, were used. The negative datasets have different read lengths and quality scores, which allow detecting dependency of the tools on both these features. FusionMap, FusionFinder, mapSplice, deFuse and TopHat-fusion were error prone. Only FusionHunter results were free of false positive. FusionMap gave the best compromise in terms of specificity in the negative dataset and of sensitivity in the positive dataset. CONCLUSIONS: We have observed a dependency of the tools on read length, quality score and on the number of reads supporting each chimera. Thus, it is important to carefully select the software on the basis of the structure of the RNA-seq data under analysis. Furthermore, the sensitivity of chimera detection tools does not seem to be sufficient to provide results consistent with those obtained in normal tissues on the basis of fusion events extracted from published data. PMID- 23815382 TI - Physical strain during activities of daily living of patients with coronary artery disease. AB - The purpose of this study was to determine the physical strain of activities of daily living (ADL) in patients with coronary artery disease (CAD) compared with healthy controls. Seventeen patients with CAD and 15 controls performed a graded exercise bicycle test and 5 ADL tasks: walking with/without load, vacuum cleaning, undressing, and walking stairs. Peak heart rate (HRpeak) and peak oxygen uptake (VO(2) peak) were determined during the bicycle test. Heart rate (HR) and oxygen uptake (VO(2)) were continuously measured during all ADL tasks. Physical strain during ADL tasks was calculated using HR and VO(2) response, expressed relative to individual HR and VO(2) reserves (%HRR, %VO(2) R, respectively). Perceived strain was measured using the Rating of Perceived Exertion (RPE) scale. HRpeak and VO(2) peak were lower (P<0.001) in patients. Patients performed the ADL tasks slower and with lower absolute VO(2), except for undressing. HR was only higher in patients during stair climbing. No differences in RPE scores were found between both groups, except for undressing. However, physical strain was significantly higher in patients (mean %VO(2) R ranged from 43% to 51%; mean %HRR ranged from 38% to 47%) compared with controls (mean %VO(2) R: 14% to 30%; mean %HRR: 14% to 29%) for all ADL tasks. In general, ADL tasks were performed slower and with higher physical strain in patients with CAD compared with controls. PMID- 23815383 TI - Plasma rich in growth factors had limited effect on early bone formation in extraction sockets: Response to "Anitua, E., Alkhraisat, M.H. & Orive, G. (2013) Letter to the Editor: Rigorous methodology is the school of coherent conclusions in science. European Journal of Oral Implantology 6: 9-11.". AB - AIM: To address the criticisms raised by Anitua et al. (European Journal of Oral Implantology, 6, 2013, 9-11) to the article "Plasma Rich in Growth Factors (PRGF) in Human Post-Extraction Sockets: an Histological and Histomorphometric Study.", recently published by Farina and colleagues (Clinical Oral Implants Research 2012; doi: 10.1111/clr.12033). METHODS: All the methodological aspects criticized in the letter by Anitua et al. were thoroughly reconsidered and discussed in a structured short communication. When indicated, pertinent, additional material was included to reinforce our considerations. RESULTS: As most clinical studies in implant dentistry, including previous studies evaluating the efficacy/effectiveness of PRGF, the study by Farina et al. has some limitations. However, it is currently the only published controlled trial using quantitative parameters related to PRGF-induced early bone formation. CONCLUSIONS: Despite all limitations, the results of the study by Farina et al., which were based on different quantitative parameters (micro-CT scan, immunohistochemical markers of wound healing and bone deposition), indicated a limited effect of PRGF on early bone formation in extraction sockets. PMID- 23815384 TI - Does constraining field of view prevent extraction of geometric cues for humans during virtual-environment reorientation? AB - Environment size has been shown to influence the reliance on local and global geometric cues during reorientation. Unless changes in environment size are produced by manipulating length and width proportionally, changes in environment size are confounded by the amount of the environment that is visible from a single vantage point. Yet, the influence of the amount of the environment that is visible from any single vantage point on the use of local and global geometric cues remains unknown. We manipulated the amount of an environment that was visually available to participants by manipulating field of view (FOV) in a virtual environment orientation task. Two groups of participants were trained in a trapezoid-shaped enclosure to find a location that was uniquely specified by both local and global geometric cues. One group (FOV 50 degrees ) had visually less of the environment available to them from any one perspective compared to another group (FOV 100 degrees ). Following training, we presented both groups with a control test along with three novel-shaped environments. Testing assessed the use of global geometry in isolation, in alignment with local geometry, or in conflict with local geometry. Results (confirmed by a follow-up experiment) indicated that constraining FOV prevented extraction of geometric properties and relationships of space and resulted in an inability to use either global or local geometric cues for reorientation. PMID- 23815385 TI - Impulsivity affects suboptimal gambling-like choice by pigeons. AB - Pigeons prefer a low-probability, high-payoff but suboptimal alternative over a reliable low-payoff optimal alternative (i.e., one that results in more food). This finding is analogous to suboptimal human monetary gambling because in both cases there appears to be an overemphasis of the occurrence of the winning event (a jackpot) and an underemphasis of losing events. In the present research we found that pigeons chose suboptimally to the degree that they were impulsive as indexed by the steeper slope of the hyperbolic delay-discounting function (i.e., the shorter the delay they would accept in a smaller-sooner/larger-later procedure). These correlational findings have implications for the mechanisms underlying suboptimal choice by humans (e.g., problem gamblers) and they suggest that high baseline levels of impulsivity can enhance acquisition of a gambling habit. PMID- 23815386 TI - Trial spacing during extinction: the role of context-US associations. AB - Studies of extinction in Pavlovian preparations can identify conditions that make extinction more enduring and increase the benefits of exposure-based behavior therapy. One such potential condition is the use of spaced extinction trials. Nevertheless, contradictory results of spacing extinction trials are found in the existing literature. Here we examine the strength of the association between the extinction context and the unconditioned stimulus as a variable that reconciles the seemingly contradictory prior reports. To assess the role of this variable, we evaluated the effects of extinction trial spacing as a function of the associative status of the extinction context in three lick suppression experiments with rats. In Experiment 1, the associative status of the extinction context was manipulated by giving extinction treatment in either the same context as acquisition or a different context. In Experiment 2, the associative status of the extinction context was initially high as a result of the acquisition context being used for extinction and then it was manipulated through postacquisition context exposure. In Experiment 3, extinction was administered in a context different from that of acquisition and the associative status of the extinction context was manipulated by delivering unsignaled footshock (i.e., the unconditioned stimuli) in the extinction context between acquisition and extinction. In all three experiments, consistently less conditioned suppression was observed with spaced extinction trials relative to massed extinction trials when the associative value of the extinction context was relatively low. In contrast, massed extinction trials produced less conditioned suppression when the associative status of the extinction context was high. Thus, stimulus control after extinction is influenced by an interaction between the intertrial interval during extinction and the associative status of the extinction context. PMID- 23815387 TI - Associative models of instrumental learning: a response to Dupuis and Dawson. AB - Miller and Shettleworth (2007) used an associative model of instrumental choice to explain a confusing pattern of results in the geometry learning literature. Dupuis and Dawson (in press) identified a structural flaw in the Miller Shettleworth (MS) model and suggested replacing it with an operant perceptron model which can correctly reproduce some experimental results that the MS model does not. Here we demonstrate that the error in the MS model can be easily corrected without altering any of the model's predictions by making it stochastic rather than deterministic. In addition, we show that the raw outputs of the perceptron model cannot be interpreted as discriminative choices in an instrumental task without first being normalized. We show that this additional step renders the results of the perceptron model identical to those of the MS model in exactly those cases in which it has been claimed to correctly predict results that the latter cannot. PMID- 23815388 TI - Proximity injection of plasticizing molecules to self-assembling polymers for large-area, ultrafast nanopatterning in the sub-10-nm regime. AB - While the uses of block copolymers (BCPs) with a high Flory-Huggins interaction parameter (chi) are advantageous for the improvement of resolution and line edge fluctuations of self-assembled nanoscale patterns, their slow chain diffusion results in a prolonged assembly time. Although solvent vapor annealing has shown great effectiveness in promoting the self-assembly of such BCPs, a practical methodology to achieve a uniform swelling level in wafer-scale BCP thin films has not been reported. Here, we show that a solvent-swollen polymer gel pad can be used as a highly controllable vapor source for the rapid, large-area (>200 mm in diameter) formation of sub-10-nm patterns from a high-chi BCP. The proximal injection of solvent vapors to BCP films and the systematic control of the swelling levels and temperatures can significantly boost the self-assembly kinetics, realizing the formation of well-aligned sub-10-nm half-pitch patterns within 1 min of self-assembly. Moreover, we show that the gel pad can be used for the shear-induced alignment of BCP microdomains in an extremely short time of ~5 s as well as for the generation of three-dimensional crossed-wire nanostructures with controlled alignment angles. PMID- 23815389 TI - Low-loss, extreme subdiffraction photon confinement via silicon carbide localized surface phonon polariton resonators. AB - Plasmonics provides great promise for nanophotonic applications. However, the high optical losses inherent in metal-based plasmonic systems have limited progress. Thus, it is critical to identify alternative low-loss materials. One alternative is polar dielectrics that support surface phonon polariton (SPhP) modes, where the confinement of infrared light is aided by optical phonons. Using fabricated 6H-silicon carbide nanopillar antenna arrays, we report on the observation of subdiffraction, localized SPhP resonances. They exhibit a dipolar resonance transverse to the nanopillar axis and a monopolar resonance associated with the longitudinal axis dependent upon the SiC substrate. Both exhibit exceptionally narrow linewidths (7-24 cm(-1)), with quality factors of 40-135, which exceed the theoretical limit of plasmonic systems, with extreme subwavelength confinement of (lambda(res)3/V(eff))1/3 = 50-200. Under certain conditions, the modes are Raman-active, enabling their study in the visible spectral range. These observations promise to reinvigorate research in SPhP phenomena and their use for nanophotonic applications. PMID- 23815390 TI - Deep brain stimulation of the internal globus pallidus for generalized dystonia associated with spinocerebellar ataxia type 1: a case report. PMID- 23815391 TI - Hyperfine interactions and electric dipole moments in the [16.0]1.5(v = 6), [16.0]3.5(v = 7), and X2Delta(5/2) states of iridium monosilicide, IrSi. AB - The (6,0)[16.0]1.5-X(2)Delta(5/2) and (7,0)[16.0]3.5-X(2)Delta(5/2) bands of IrSi have been recorded using high-resolution laser-induced fluorescence spectroscopy. The field-free spectra of the (191)IrSi and (193)IrSi isotopologues were modeled to generate a set of fine, magnetic hyperfine, and nuclear quadrupole hyperfine parameters for the X(2)Delta(5/2)(v = 0), [16.0]1.5(v = 6), and [16.0]3.5 (v = 7) states. The observed optical Stark shifts for the (193)IrSi and (191)IrSi isotopologues were analyzed to produce the permanent electric dipole moments, MU(el), of -0.414(6) D and 0.782(6) D for the X(2)Delta(5/2) and [16.0]1.5 (v = 6) states, respectively. Properties of the X(2)Delta(5/2) state computed using relativistic coupled-cluster methods clearly indicate that electron correlation plays an essential role. Specifically, inclusion of correlation changes the sign of the dipole moment and is essential for achieving good accuracy for the nuclear quadrupole coupling parameter eQq0. PMID- 23815392 TI - Achieving success in intervention studies: an analysis of variable staff engagement across three midwifery settings. AB - AIMS AND OBJECTIVES: To critically analyse the success of staff's behaviour changes in the practice setting. Facilitators were employed to initiate and facilitate a four-step process (optimism, overcoming obstacles, oversight and reinforcing outcomes) that fostered development of behaviours consistent with learning in everyday practice. BACKGROUND: Many studies seek to engage staff in workplace behaviour improvement. The success of such studies is highly variable. Little is known about the work of the facilitator in ensuring success. Understanding the contextual factors that contribute to effective facilitation of workplace improvement is essential to ensure best use of resources. DESIGN: Mixed methods METHODS: Facilitators employed a four-step process - optimism, overcoming obstacles, oversight and reinforcing outcomes - to stage behaviour change implementation. The analysis of staff engagement in behaviour changes was assessed through weekly observation of workplaces, informal discussions with staff and facilitator diaries. The impact of behaviour change was informed through pre- and postsurveys on staff's perception across three midwifery sites. Surveys measured (1) midwives' perception of support for their role in facilitating learning (Support Instrument for Nurses Facilitating the Learning of Others) and (2) development of a learning culture in midwifery practice settings (Clinical Learning Organisational Culture Survey). Midwives across three sites completed the presurvey (n = 216) and postsurvey (n = 90). RESULTS: Impact varied according to the degree that facilitators were able to progress teams through four stages necessary for change (OOORO). Statistically significant results were apparent in two subscales important for supporting staff, namely teamwork and acknowledgement; in the two areas, facilitators worked through 'obstacles' and coached staff in performing the desired behaviours and rewarded them for their success. Elements of the learning culture also statistically improved in one site. CONCLUSIONS: Findings suggest behaviour change success is dependent on facilitators to systematically engage staff through all four stages of implementation. RELEVANCE TO CLINICAL PRACTICE: It is important that investment is made to commitment and resources to all four stages before embarking on change processes. PMID- 23815393 TI - Neurofibromas of the bladder in a child with neurofibromatosis type 1 causing chronic renal disease. AB - Neurofibromatosis type 1 (NF1) is an autosomal-dominant inherited disorder and its prominent feature is the neurofibroma and renal involvement includes renal artery stenosis and renal artery aneurysms causing renovascular hypertension. The genitourinary tract may be rarely involved, leading to urinary symptoms of obstruction and hydronephrosis. Herein, we report a 12-year-old boy with chronic renal failure associated with neurofibromas of the bladder, which leads to urinary obstruction. PMID- 23815395 TI - The DSM-5 dimensional trait model and five-factor models of general personality. AB - The current study tests empirically the relationship of the dimensional trait model proposed for the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) with five-factor models of general personality. The DSM 5 maladaptive trait dimensional model proposal included 25 traits organized within five broad domains (i.e., negative affectivity, detachment, antagonism, disinhibition, and psychoticism). Consistent with the authors of the proposal, it was predicted that negative affectivity would align with five-factor model (FFM) neuroticism, detachment with FFM introversion, antagonism with FFM antagonism, disinhibition with low FFM conscientiousness and, contrary to the proposal; psychoticism would align with FFM openness. Three measures of alternative five factor models of general personality were administered to 445 undergraduates along with the Personality Inventory for DSM-5. The results provided support for the hypothesis that all five domains of the DSM-5 dimensional trait model are maladaptive variants of general personality structure, including the domain of psychoticism. PMID- 23815396 TI - Distinguishing healthy adults from people with social anxiety disorder: evidence for the value of experiential avoidance and positive emotions in everyday social interactions. AB - Despite the increased attention that researchers have paid to social anxiety disorder (SAD), compared with other anxiety and mood disorders, relatively little is known about the emotional and social factors that distinguish individuals who meet diagnostic criteria from those who do not. In this study, participants with and without a diagnosis of SAD (generalized subtype) described their daily face to-face social interactions for 2 weeks using handheld computers. We hypothesized that, compared with healthy controls, individuals diagnosed with SAD would experience fewer positive emotions, rely more on experiential avoidance (of anxiety), and have greater self-control depletion (feeling mentally and physically exhausted after socializing), after accounting for social anxiety, negative emotions, and feelings of belonging during social interactions. We found that compared with healthy controls, individuals with SAD experienced weaker positive emotions and greater experiential avoidance, but there were no differences in self-control depletion between groups. Moreover, the differences we found could not be attributed to comorbid anxiety or depressive disorders. Our results suggest that negative emotions alone do not fully distinguish normal from pathological social anxiety, and that assessing social anxiety disorder should include impairments in positive emotional experiences and dysfunctional emotion regulation (in the form of experiential avoidance) in social situations. PMID- 23815397 TI - Mitochondrial dynamics modulate the expression of pro-inflammatory mediators in microglial cells. AB - Over-activation of microglia cells in the brain contributes to neurodegenerative processes promoted by the production of various neurotoxic factors including pro inflammatory cytokines and nitric oxide. Recently, accumulating evidence has suggested that mitochondrial dynamics are an important constituent of cellular quality control and function. However, the role of mitochondrial dynamics in microglial activation is still largely unknown. In this study, we determined whether mitochondrial dynamics are associated with the production of pro inflammatory mediators in lipopolysaccharide (LPS)-stimulated immortalization of murine microglial cells (BV-2) by a v-raf/v-myc carrying retrovirus (J2). Excessive mitochondrial fission was observed in lentivirus-transfected BV-2 cells stably expressing DsRed2-mito following LPS stimulation. Furthermore, mitochondrial localization of dynamin-related protein 1 (Drp1) (a key regulator of mitochondrial fission) was increased and accompanied by de-phosphorylation of Ser637 in Drp1. Interestingly, inhibition of LPS-induced mitochondrial fission and reactive oxygen species (ROS) generation by Mdivi-1 and Drp1 knock-down attenuated the production of pro-inflammatory mediators via reduced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and mitogen activated protein kinase (MAPK) signaling. Our results demonstrated for the first time that mitochondrial fission regulates mitochondrial ROS production in activated microglial cells and influences the expression of pro-inflammatory mediators through the activation of NF-kappaB and MAPK. We therefore suggest that mitochondrial dynamics may be essential for understanding pro-inflammatory mediator expression in activated microglial cells. This could represent a new therapeutic approach for preventing neurodegenerative diseases. PMID- 23815398 TI - Bone marrow-derived cell concentrates have limited effects on osteochondral reconstructions in the mini pig. AB - This study investigates the effects of seeding a chondrogenic and osteogenic scaffold with a bone marrow-derived cell concentrate (BMCC) and reports the histological and mechanical properties 3 months after implantation in the miniature pig. Twenty defects (7*10 mm) were created in the femoral condyles of 10 miniature pigs. The defects were left empty (E), filled with the grafted cylinder upside down (U) or with a combined scaffold (S) containing a spongious bone cylinder (Tutobone(r)) covered with a collagen membrane (Chondrogide(r)). In a fourth group, the same scaffolds were implanted but seeded with a stem cell concentrate (S+ BMCC). The animals were stained with calcein green after 2 weeks and xylenol orange after 4 weeks. After 3 months, the animals were sacrificed, and a mechanical analysis (Young's modulus), macroscopic, and histologic (ICRS Score) examination of the specimens was conducted. Young's modulus in the periphery was significantly lower for group E (67.5+/-15.3 kPa) compared with untreated controls (171.7+/-21.6 kPa, p<0.04). Bone defects were smaller in group S (10%+/-8%) compared with E (27%+/-7%; p<0.05). There was a trend toward smaller bony defects on comparing groups E and S+ BMCC (11%+/-8%; p=0.07). More red fluorescence was detected in group S+ BMCC (2.3%+/-1.1%) compared with groups E (0.4%+/-0.2%) and U (0.5%+/-0.2%, p<0.03). ICRS scores were higher for groups S (25.3+/-3.8) and S+ BMCC (26.2+/-5.2, p<0.01). In this animal model of osteochondral defects, stem cell concentrates enhance new bone apposition but fail to improve mechanical properties or histological appearance of cartilage regenerates in critical-sized defects. PMID- 23815399 TI - Surface charge-switchable polymeric magnetic nanoparticles for the controlled release of anticancer drug. AB - We develop paclitaxel (PTX) and magnetic nanoparticles (MNPs) coencapsulated, surface charge-switchable, thermosensitive poly(d,l-lactic-co-glycolic acid)-l lysine-d-galactose (PTX-MNP-PLGA-Lys-Gal) NPs for the controlled release of the anticancer drug. The novel dual signal-responsive nanovehicle is formulated to shield off target at pH 7.4 but bind avidly to tumor cells in acidity, alleviating toxicity and side effects of the drug to normal tissues. The mechanism involves pH-sensitive NPs surface charge switching by the deblocking process of galactose molecules followed by protonation of epsilon-NH2 in lysine residue at acidic pH. Magnetic hyperthermia under near infrared (NIR) irradiation induced the contraction of PTX-MNP-PLGA-Lys-Gal NPs and, in turn, triggered burst release of PTX. Transmission electron microscopy (TEM), fluorescence microscope analyses, Fourier transform infrared (FTIR), X-ray diffraction (XRD), vibrating sample magnetometer (VSM), dynamic light scattering (DLS), and xi-potential analyses were performed to characterize physicochemical properties of the as prepared NPs. The size range of the globule PTX-MNP-PLGA-Lys-Gal NPs after being prescreened was from 130 to 150 nm under simulated physiological medium. The high encapsulation efficiencies of MNPs and PTX were obtained, reaching 85 and 78 wt % for PTX-MNP-PLGA-Lys-Gal NPs, respectively. The tumor inhibitory rate of 78.8% reflected that the resulting NPs could be promising to treat cancer by specific binding and targeting release drug to tumor. PMID- 23815400 TI - Biochemical studies of the multicopper oxidase (small laccase) from Streptomyces coelicolor using bioactive phytochemicals and site-directed mutagenesis. AB - Multicopper oxidases can act on a broad spectrum of phenolic and non-phenolic compounds. These enzymes include laccases, which are widely distributed in plants and fungi, and were more recently identified in bacteria. Here, we present the results of biochemical and mutational studies of small laccase (SLAC), a multicopper oxidase from Streptomyces coelicolor (SCO6712). In addition to typical laccase substrates, SLAC was tested using phenolic compounds that exhibit antioxidant activity. SLAC showed oxidase activity against 12 of 23 substrates tested, including caffeic acid, ferulic acid, resveratrol, quercetin, morin, kaempferol and myricetin. The kinetic parameters of SLAC were determined for 2,2' azino-bis(3-ethylbenzthiazoline-6-sulphonic acid), 2,6-dimethoxyphenol, quercetin, morin and myricetin, and maximum reaction rates were observed with myricetin, where kcat and Km values at 60 degrees C were 8.1 (+/- 0.8) s-1 and 0.9 (+/- 0.3) mM respectively. SLAC had a broad pH optimum for activity (between pH 4 and 8) and temperature optimum at 60-70 degrees C. It demonstrated remarkable thermostability with a half-life of over 10 h at 80 degrees C and over 7 h at 90 degrees C. Site-directed mutagenesis revealed 17 amino acid residues important for SLAC activity including the 10 His residues involved in copper coordination. Most notably, the Y229A and Y230A mutant proteins showed over 10 fold increase in activity compared with the wild-type SLAC, which was correlated to higher copper incorporation, while kinetic analyses with S929A predicts localization of this residue near the meta-position of aromatic substrates. PMID- 23815401 TI - The role of planning skills in the income-achievement gap. AB - The pervasive income-achievement gap has been attributed in part to deficiencies in executive functioning (EF). The development of EF is related to children's planning ability, an aspect of development that has received little attention. Longitudinal data from the National Institute of Child Health and Human Development study of early child care show that early childhood poverty (1 and 24 months) is significantly related to fifth grade, math, and reading achievement (n = 1,009). The ability to plan in Grade 3, indexed by the Tower of Hanoi task, mediates the income-achievement gap in math and to a lesser extent in reading. IQ was incorporated as a statistical control throughout. PMID- 23815402 TI - Assessment of predictive molecular variables in feline oral squamous cell carcinoma treated with stereotactic radiation therapy. AB - This study evaluated molecular characteristics that are potentially prognostic in cats with oral squamous cell carcinoma (SCC) that underwent stereotactic radiation therapy (SRT). Survival time (ST) and progression-free interval (PFI) were correlated with mitotic index, histopathological grades, Ki67 and epidermal growth factor receptor expressions, tumour microvascular density (MVD), and tumour oxygen tension (pO(2)). Median ST and PFI were 106 and 87 days, respectively (n = 20). Overall response rate was 38.5% with rapid improvement of clinical symptoms in many cases. Patients with higher MVD or more keratinized SCC had significantly shorter ST or PFI than patients with lower MVD or less keratinized SCC (P = 0.041 and 0.049, respectively). Females had significantly longer PFI and ST than males (P <= 0.016). Acute toxicities were minimal. However, treatment-related complications such as fractured mandible impacted quality of life. In conclusion, SRT alone should be considered as a palliative treatment. MVD and degree of keratinization may be useful prognostic markers. PMID- 23815404 TI - Sensing dissolved methane in aquatic environments: an experiment in the central baltic sea using surface plasmon resonance. AB - A new sensor for in situ, real time methane (CH4) measurements in aqueous environments is based on the refractive index (RI) modulation of a sensitive film composed of a polydimethylsiloxane (PDMS) layer incorporating molecules of cryptophane-A. The RI varies according to the amount of CH4 bound to the cryptophane-A in the film and is determined using surface plasmon resonance (SPR). Tests of the sensor in the summer of 2012 reveal the expansive range of conditions of the Central Baltic Sea with CH4 concentrations varying from 5 nM up to a few hundred nanomolar. The sensor showed detection limits down to 3 nM, sensitivity of 6 to 7 * 10(-6) RIU/nM, and response times of 1 to 2 min. Best responses were obtained for concentrations up to 200 nM. Side effects (temperature, cross-sensitivity) are reviewed for future improvements to the sensor design. CH4 values are highest in the Landsort Deep up to 1.2 MUM at 400 m depth and lowest in the Gotland Deep with 900 nM at 220 m depth. However, variable values in the upper layers indicate higher mixing rates due to currents and wind driven forces in the Gotland Basin compared with almost constant CH4 values in the Landsort Deep. PMID- 23815403 TI - Phylogenetic signal in the acoustic parameters of the advertisement calls of four clades of anurans. AB - BACKGROUND: Anuran vocalizations, especially their advertisement calls, are largely species-specific and can be used to identify taxonomic affiliations. Because anurans are not vocal learners, their vocalizations are generally assumed to have a strong genetic component. This suggests that the degree of similarity between advertisement calls may be related to large-scale phylogenetic relationships. To test this hypothesis, advertisement calls from 90 species belonging to four large clades (Bufo, Hylinae, Leptodactylus, and Rana) were analyzed. Phylogenetic distances were estimated based on the DNA sequences of the 12S mitochondrial ribosomal RNA gene, and, for a subset of 49 species, on the rhodopsin gene. Mean values for five acoustic parameters (coefficient of variation of root-mean-square amplitude, dominant frequency, spectral flux, spectral irregularity, and spectral flatness) were computed for each species. We then tested for phylogenetic signal on the body-size-corrected residuals of these five parameters, using three statistical tests (Moran's I, Mantel, and Blomberg's K) and three models of genetic distance (pairwise distances, Abouheif's proximities, and the variance-covariance matrix derived from the phylogenetic tree). RESULTS: A significant phylogenetic signal was detected for most acoustic parameters on the 12S dataset, across statistical tests and genetic distance models, both for the entire sample of 90 species and within clades in several cases. A further analysis on a subset of 49 species using genetic distances derived from rhodopsin and from 12S broadly confirmed the results obtained on the larger sample, indicating that the phylogenetic signals observed in these acoustic parameters can be detected using a variety of genetic distance models derived either from a variable mitochondrial sequence or from a conserved nuclear gene. CONCLUSIONS: We found a robust relationship, in a large number of species, between anuran phylogenetic relatedness and acoustic similarity in the advertisement calls in a taxon with no evidence for vocal learning, even after correcting for the effect of body size. This finding, covering a broad sample of species whose vocalizations are fairly diverse, indicates that the intense selection on certain call characteristics observed in many anurans does not eliminate all acoustic indicators of relatedness. Our approach could potentially be applied to other vocal taxa. PMID- 23815405 TI - A unique strain of community-acquired Clostridium difficile in severe complicated infection and death of a young adult. AB - BACKGROUND: Clostridium difficile is the major cause of nosocomial antibiotic associated diarrhoea with the potential risk of progressing to severe clinical outcomes including death. It is not unusual for Clostridium difficile infection to progress to complications of toxic megacolon, bowel perforation and even Gram negative sepsis following pathological changes in the intestinal mucosa. These complications are however less commonly seen in community-acquired Clostridium difficile infection than in hospital-acquired Clostridium difficile infection. To the best of our knowledge, this was the first case of community-acquired Clostridium difficile infection of its type seen in Jamaica. CASE PRESENTATION: We report a case of a 22-year-old female university student who was admitted to the University Hospital of the West Indies, Jamaica with a presumptive diagnosis of pseudomembranous colitis PMC. She presented with a 5-day history of diarrhoea following clindamycin treatment for coverage of a tooth extraction due to a dental abscess. Her clinical condition deteriorated and progressed from diarrhoea to toxic megacolon, bowel perforation and Gram-negative sepsis. Clostridium difficile NAP12/ribotype 087 was isolated from her stool while blood cultures grew Klebsiella pneumoniae. Despite initial treatment intervention with empiric therapy of metronidazole and antibiotic clearance of Klebsiella pneumoniae from the blood, the patient died within 10 days of hospital admission. CONCLUSIONS: We believe that clindamycin used for coverage of a dental abscess was an independent risk factor that initiated the disruption of the bowel micro-flora, resulting in overgrowth of Clostridium difficile NAP12/ribotype 087. This uncommon strain, which is the same ribotype (087) as ATCC 43255, was apparently responsible for the increased severity of the infection and death following toxic megacolon, bowel perforation and pseudomembranous colitis involving the entire large bowel. K. pneumoniae sepsis, resolved by antibiotic therapy was secondary to Clostridium difficile infection. The case registers community-acquired Clostridium difficile infection as producing serious complications similar to hospital-acquired Clostridium difficile infection and should be treated with the requisite importance. PMID- 23815407 TI - Solid lipid nanoparticles carrying chemotherapeutic drug across the blood-brain barrier through insulin receptor-mediated pathway. AB - Carmustine (BCNU)-loaded solid lipid nanoparticles (SLNs) were grafted with 83-14 monoclonal antibody (MAb) (83-14 MAb/BCNU-SLNs) and applied to the brain targeting delivery. Human brain-microvascular endothelial cells (HBMECs) incubated with 83-14 MAb/BCNU-SLNs were stained to demonstrate the interaction between the nanocarriers and expressed insulin receptors (IRs). The results revealed that the particle size of 83-14 MAb/BCNU-SLNs decreased with an increasing weight percentage of Dynasan 114 (DYN). Storage at 4 degrees C for 6 weeks slightly deformed the colloidal morphology. In addition, poloxamer 407 on 83-14 MAb/BCNU-SLNs induced cytotoxicity to RAW264.7 cells and inhibited phagocytosis by RAW264.7 cells. An increase in the weight percentage of DYN from 0% to 67% slightly reduced the viability of RAW264.7 cells and promoted phagocytosis. Moreover, the transport ability of 83-14 MAb/BCNU-SLNs across the blood-brain barrier (BBB) in vitro enhanced with an increasing weight percentage of Tween 80. 83-14 MAb on MAb/BCNU-SLNs stimulated endocytosis by HBMECs via IRs and enhanced the permeability of BCNU across the BBB. 83-14 MAb/BCNU-SLNs can be a promising antitumor drug delivery system for transporting BCNU to the brain. PMID- 23815408 TI - Two new steroidal glycosides isolated from the aerial part of Solanum torvum Swartz. AB - One novel C-22 steroidal lactone saponin, namely solanolactoside C (1), and one new spirostanol glycoside, namely torvoside Q (2), were isolated from the ethanolic extract of aerial parts of Solanum torvum Swartz. The structures of 1 and 2 were determined by extensive NMR experiments including (1)H NMR, (13)C NMR, DEPT, (1)H-(1)H COSY, HSQC, HMBC and ROESY and HRESIMS to be solanolide 6-O-beta d-quinovopyranoside and neochlorogenin 6-O-[beta-d-xylopyranosyl-(1 -> 3)-beta-d glucopyranoside], respectively. PMID- 23815409 TI - The UK Francis Report: the key messages for nursing. PMID- 23815410 TI - Large-scale synthesis of transition-metal-doped TiO2 nanowires with controllable overpotential. AB - Practical implementation of one-dimensional semiconductors into devices capable of exploiting their novel properties is often hindered by low product yields, poor material quality, high production cost, or overall lack of synthetic control. Here, we show that a molten-salt flux scheme can be used to synthesize large quantities of high-quality, single-crystalline TiO2 nanowires with controllable dimensions. Furthermore, in situ dopant incorporation of various transition metals allows for the tuning of optical, electrical, and catalytic properties. With this combination of control, robustness, and scalability, the molten-salt flux scheme can provide high-quality TiO2 nanowires to satisfy a broad range of application needs from photovoltaics to photocatalysis. PMID- 23815411 TI - Analysis and consensus of currently available intrinsic protein disorder annotation sources in the MobiDB database. AB - BACKGROUND: Intrinsic protein disorder is becoming an increasingly important topic in protein science. During the last few years, intrinsically disordered proteins (IDPs) have been shown to play a role in many important biological processes, e.g. protein signalling and regulation. This has sparked a need to better understand and characterize different types of IDPs, their functions and roles. Our recently published database, MobiDB, provides a centralized resource for accessing and analysing intrinsic protein disorder annotations. RESULTS: Here, we present a thorough description and analysis of the data made available by MobiDB, providing descriptive statistics on the various available annotation sources. Version 1.2.1 of the database contains annotations for ca. 4,500,000 UniProt sequences, covering all eukaryotic proteomes. In addition, we describe a novel consensus annotation calculation and its related weighting scheme. The comparison between disorder information sources highlights how the MobiDB consensus captures the main features of intrinsic disorder and correlates well with manually curated datasets. Finally, we demonstrate the annotation of 13 eukaryotic model organisms through MobiDB's datasets, and of an example protein through the interactive user interface. CONCLUSIONS: MobiDB is a central resource for intrinsic disorder research, containing both experimental data and predictions. In the future it will be expanded to include additional information for all known proteins. PMID- 23815412 TI - Covalent immobilization of lysozyme on ethylene vinyl alcohol films for nonmigrating antimicrobial packaging applications. AB - The objective of this study was to develop a new antimicrobial film, in which lysozyme was covalently attached onto two different ethylene vinyl alcohol copolymers (EVOH 29 and EVOH 44). The EVOH surface was modified with UV irradiation treatment to generate carboxylic acid groups, and lysozyme was covalently attached to the functionalized polymer surface. Surface characterization of control and modified films was performed using attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) and dye assay. The value of protein loading after attachment on the surface was 8.49 MUg protein/cm(2) and 5.74 MUg protein/cm(2) for EVOH 29 and EVOH 44, respectively, after 10 min UV irradiation and bioconjugation. The efficacy of the EVOH-lysozyme films was assessed using Micrococcus lysodeikticus. The antimicrobial activity of the films was tested against Listeria monocytogenes and was similar to an equivalent amount of free enzyme. The reduction was 1.08 log for EVOH 29 lysozyme, 0.95 log for EVOH 44-lysozyme, and 1.34 log for free lysozyme. This work confirmed the successful use of lysozyme immobilization on the EVOH surface for antimicrobial packaging. PMID- 23815413 TI - Adherence of backcountry winter recreationists to avalanche prevention and safety practices in northern Italy. AB - Backcountry recreationists account for a high percentage of avalanche fatalities, but the total number of recreationists and relative percentage of different recreation types are unknown. The aim of this study was to collect the first comprehensive survey of backcountry skiers and snowshoers in a region in the European Alps to quantify adherence to basic prevention and safety practices. Over a 1-week period in February 2011 in South Tyrol, Italy, 5576 individuals (77.7% skiers, 22.3% snowshoers) in 1927 groups were surveyed. Significantly more skiers than snowshoers could report the avalanche danger level (52.5% vs 28.0% of groups) and carried standard rescue equipment (transceiver, probe, and shovel) (80.6% vs 13.7% of individuals). Complete adherence to minimum advisable practices (i.e., an individual being in a group with one member correctly informed about the danger level and carrying personal standard rescue equipment) was 41.5%, but was significantly higher in skiers (51.1% vs 8.7% snowshoers) and in individuals who were younger, reported more tours per season, traveled in larger groups, and started earlier. A transnational survey over a complete winter season would be required to obtain total participation prevalence, detect regional differences, and assess the influence of prevention and safety practices on relative reduction in mortality. PMID- 23815414 TI - Au nanotip as luminescent near-field probe. AB - We introduce a new optical near-field mapping method, namely utilizing the plasmon-mediated luminescence from the apex of a sharp gold nanotip. The tip acts as a quasi-point light source which does not suffer from bleaching and gives a spatial resolution of <=25 nm. We demonstrate our method by imaging the near field of azimuthally and radially polarized plasmonic modes of nonluminescent aluminum oligomers. PMID- 23815415 TI - Flexibility and torsional behaviour of rotary nickel-titanium PathFile, RaCe ISO 10, Scout RaCe and stainless steel K-File hand instruments. AB - AIM: To assess and compare the flexibility and torsional resistance of PathFile, RaCe ISO 10 and Scout RaCe instruments in relation to stainless steel K-File hand instruments. METHODOLOGY: Rotary PathFile (sizes 13, 16 and 19; .02 taper), Race ISO 10 (size 10; 0.02, 0.04 and 0.06 tapers), Scout RaCe (sizes 10, 15 and 20; 0.02 taper) and hand K-File (sizes 10, 15 and 20; 0.02 taper) instruments were evaluated. Alloy chemical composition, phases present and transformation temperatures were determined for the NiTi instruments. For all instruments, diameters at each millimetre from the tip as well as cross-sectional areas at 3 mm from the tip were measured based on ANSI/ADA Specification No. 101 using image analysis software. Resistance to bending and torsional resistance were determined according to specification ISO 3630-1. Vickers microhardness measurements were also taken in all instruments to assess their strength. Data were analysed using analysis of variance (alpha = 0.05). RESULTS: The alloys used in the manufacture of the three types of NiTi instruments had approximately the same chemical composition, but the PathFile instruments had a higher Af transformation temperature and contained a small amount of B19' martensite. All instruments had diameter values within the standard tolerance. The bending and torsional resistance values were significantly increased relative to the instrument diameter and cross-sectional area. CONCLUSIONS: PathFile instruments were the most flexible and the least torque resistant, whilst the stainless steel instruments were the least flexible although they were more torque resistant than the NiTi instruments. PMID- 23815416 TI - Surgical paddle-lead placement for screening trials of spinal cord stimulation. AB - OBJECTIVES: Spinal cord stimulation (SCS) has become an evidence-based treatment for a variety of chronic pain disorders. A key step in appropriate patient selection and long-term outcome predictability is a percutaneous screening trial of stimulation. Occasionally, a trial cannot be adequately completed with a percutaneous electrode. Rather than depriving this therapy from these patients, the authors have developed a program providing surgically implanted paddle-lead screening trials of SCS. METHODS: Data from 22 patients undergoing paddle-lead screening trials of SCS from October 2009 to August 2012 were retrospectively reviewed. The surgical paddle leads were positioned with thoracic or cervical laminotomies under local anesthetic and conscious sedation, allowing awakened patients to confirm optimal lead placement. Externalized lead extensions were connected to an external pulse generator for a five-day screening trial. Pain reduction of at least 50% was required for patients to have the previously implanted paddle lead connected to an internalized pulse generator; otherwise, the trial surgical paddle leads were removed. RESULTS: Twenty-two patients received five-day paddle-lead stimulation screening trials for various chronic neuropathic pain conditions. All paddle screening trials were well tolerated and completed as outpatient procedures. Sixteen patients received fully implanted systems. At an average follow-up of 23 months, all implanted patients continue to have satisfactory pain control. There were no infections, lead migrations, or revisions. CONCLUSIONS: Surgically implanted paddle-lead screening trials of SCS can be used safely and effectively in those patients in which an adequate percutaneous-electrode trial cannot be completed. Results are similar to those seen with standard percutaneous screening trials. A systematic approach to surgical-paddle screening trials of SCS has not been previously reported. PMID- 23815406 TI - Brain iron homeostasis: from molecular mechanisms to clinical significance and therapeutic opportunities. AB - Iron has emerged as a significant cause of neurotoxicity in several neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), sporadic Creutzfeldt-Jakob disease (sCJD), and others. In some cases, the underlying cause of iron mis-metabolism is known, while in others, our understanding is, at best, incomplete. Recent evidence implicating key proteins involved in the pathogenesis of AD, PD, and sCJD in cellular iron metabolism suggests that imbalance of brain iron homeostasis associated with these disorders is a direct consequence of disease pathogenesis. A complete understanding of the molecular events leading to this phenotype is lacking partly because of the complex regulation of iron homeostasis within the brain. Since systemic organs and the brain share several iron regulatory mechanisms and iron-modulating proteins, dysfunction of a specific pathway or selective absence of iron modulating protein(s) in systemic organs has provided important insights into the maintenance of iron homeostasis within the brain. Here, we review recent information on the regulation of iron uptake and utilization in systemic organs and within the complex environment of the brain, with particular emphasis on the underlying mechanisms leading to brain iron mis-metabolism in specific neurodegenerative conditions. Mouse models that have been instrumental in understanding systemic and brain disorders associated with iron mis-metabolism are also described, followed by current therapeutic strategies which are aimed at restoring brain iron homeostasis in different neurodegenerative conditions. We conclude by highlighting important gaps in our understanding of brain iron metabolism and mis-metabolism, particularly in the context of neurodegenerative disorders. PMID- 23815417 TI - Efficacy of mizoribine followed by low-dose prednisone in patients with idiopathic membranous nephropathy and nephrotic-range proteinuria. AB - BACKGROUND: Idiopathic membranous nephropathy (IMN) patients with persistent high grade proteinuria are at the highest risk for developing end-stage renal failure. We previously reported the effects of treatment with mizoribine followed by low dose prednisone treatment in 4 IMN patients. The purpose of the present study was to further assess the effects of this combined treatment in a larger study group. METHOD: Thirteen patients with IMN and nephrotic-range proteinuria received combined treatment. Mizoribine was initiated at a dose of 150 mg/day, and 2-3 months later, 20 mg/day prednisone was added to the mizoribine regimen. The dosage of prednisone and/or mizoribine was tapered according to the urinary protein-to-creatinine ratio (P/C). We evaluated patient responses for up to 12 months after the initiation of combination therapy. RESULTS: Before treatment, patient urinary P/C ranged from 3.7 to 15.9 g/g. Although these values did not decrease during mizoribine monotherapy, all patients showed dramatic P/C decreases over the course of combination therapy. At 3, 6, and 12 months after combination therapy, 15%, 31%, and 62% of patients attained complete remission, respectively, and all patients were in partial or complete remission 6 months after combination therapy. No notable side effects were observed. CONCLUSION: The addition of prednisone after mizoribine monotherapy can be beneficial for all IMN patients with nephrotic-range proteinuria syndrome. The risks associated with immunotherapy can be decreased by initially prescribing mizoribine alone, which might act as a base for establishing therapy, followed by low-dose prednisone treatment. PMID- 23815418 TI - The reliability and validity of the Chinese version of the Short-form Chronic Disease Self-Efficacy Scales for older adults. AB - AIMS AND OBJECTIVES: To examine the reliability and validity of the Chinese version of the Short-form Chronic Disease Self Efficacy Scales. BACKGROUND: The prevalence of chronic disease is accelerating globally, advancing across every region and pervading all socioeconomic classes. Among the interventions, self management programmes focusing on increasing self-efficacy have demonstrated significant patient outcomes, including the improvement of quality of life and functional status. The Chronic Disease Self-Efficacy Scales (CDSES) system developed by Lorig in 1996 has been widely used by healthcare professionals from different disciplines to measure self-efficacy for chronic disease patients due to their tested psychometric properties. The Short-form of the scales system is used today, as it takes substantially less time to administer. DESIGN: This study used psychometric testing to establish the validity and reliability of the Short form Chronic Disease Self-Efficacy Scales (CDSES). METHODS: A convenience sample of 163 older patients with chronic diseases were recruited. The Chinese version of the CDSES, short-form CDSES, SF-36 and self-rated health were used to test for construct validity, concurrent validity, convergent validity and internal consistency. RESULTS: Short-form CDSES had a single-factor structure with high internal consistency (0.96) and demonstrated no floor or ceiling effects. High intraclass correlation, 0.98, was demonstrated in test-retest. Correlations with the domain scores of the CDSES were found to be r = 0.97 and 0.98. The scale also demonstrated significant moderate correlations with SF-36 and self-rated health. CONCLUSION: The Chinese version of the Short-form CDSES has shown statistically acceptable levels of reliability and validity for assessing self-efficacy in older patients with chronic diseases. RELEVANCE TO CLINICAL PRACTICE: The scale is particularly valuable for use among older patients with chronic illness. The questionnaire can be used to assess nursing interventions focusing on increasing patients' self-efficacy or routine patient screening in carrying out daily activities. PMID- 23815419 TI - Sulfur-containing flavors: gas phase structures of dihydro-2-methyl-3 thiophenone. AB - Dihydro-2-methyl-3-thiophenone was investigated using a combination of quantum chemical calculations and molecular beam Fourier transform microwave spectroscopy. The substance is present in coffee, roasted peanuts, and whiskey. The microwave spectrum was recorded under molecular beam conditions in the frequency range from 9 to 14 GHz. We report on the two main conformers of dihydro 2-methyl-3-thiophenone, for which highly accurate rotational constants and centrifugal distortion constants were obtained. No splittings due to internal rotation of the methyl group could be observed in the microwave spectrum. This is in agreement with the theoretical predictions of the barrier heights, which have been determined to be more than 1000 cm(-1) at the MP2/6-311++G(d,p) level of theory. In addition to the most abundant (32)S-isotopologue of the main conformer, also the (34)S-isotopologue was assigned, which occurs with a natural abundance of about 4%. Using the experimental rotational constants, different quantum chemical calculations were validated for the two observed conformers. To complete the theoretical investigation of dihydro-2-methyl-3-thiophenone, different transition states were optimized to understand the intramolecular conversion between the two conformers at the MP2/6-311++G(d,p) level. The transition states were optimized using the Berny algorithm. PMID- 23815420 TI - Substance use among women veterans: epidemiology to evidence-based treatment. AB - An increasing percentage of women are U.S. Military Veterans. We review the substance misuse rates and comorbidities and the risk factors for and consequences of substance use among women Veterans. Women Veterans may have higher rates of substance misuse and comorbid psychiatric and medical disorders than male Veterans and women who are not Veterans. Studies support the AUDIT-C as a scaled marker of alcohol-related risk among female Veterans, but validated drug screening instruments are needed. We discuss evidence-based approaches in terms of treating women Veterans' substance misuse in primary and specialty care settings, along with knowledge gaps and potential research priorities to improve care in this special population. PMID- 23815421 TI - Gender differences in heroin users receiving methadone maintenance therapy in Taiwan. AB - This study examined gender differences in heroin users who first received MMT. Compared with men, female heroin users were younger and more likely to be unemployed, to have family members using illicit substances, to initiate heroin use at a younger age, to begin MMT earlier after starting heroin use, to have methamphetamine use, to initiate methamphetamine use at a younger age, and to report a child-raising burden and a prior history of traumatic experiences. Men were more likely to have use of betel quid, and to initiate alcohol, nicotine and betel quid use at a younger age than women. PMID- 23815422 TI - The association between phencyclidine use and partner violence: an initial examination. AB - The association between phencyclidine (PCP) use and violent behavior is unclear. The current investigation evaluated the association between PCP addiction and intimate partner violence, a specific violent behavior, using the substance abuse evaluations of 109 PCP, 81 cannabis, and 97 polysubstance (alcohol and cannabis) abusing offenders. Relative to both comparison groups, PCP users were more likely to receive inpatient referrals, have a significant legal history, and have perpetrated past-year general and intimate partner violence. Data suggest that PCP use may be associated with greater violence perpetration than cannabis use alone or in conjunction with problematic alcohol use. PMID- 23815423 TI - "Dangerous relationships": asthma and substance abuse. AB - Commonly abused drug are cocaine, marijuana, cigarettes, heroin, and alcohol. The review emphasizes the importance for clinicians to be alert to the possibility of this substance as a precipitating factor for acute asthma. Substance use disorders to characterize illnesses associated with drug use. The use of drugs of abuse increases risk of developing more severe symptoms, higher frequency of exacerbations and having and significant effect on care resources due to clinicians visits and frequent hospital admissions. Abused drug has been shown to accelerate the decline in lung function and to increase numbers of life threatening asthma attacks, and greater asthma mortality. PMID- 23815424 TI - Comorbid posttraumatic stress disorder and opiate addiction: a literature review. AB - Treatment of comorbid posttraumatic stress disorder (PTSD) and opioid dependence has been a challenge for many clinicians. There are limited evidence-based guidelines for treatment of this comorbidity. Symptoms of PTSD and opiate dependence may converge, and it is sometimes difficult to differentiate between both conditions. For example, opioid withdrawal symptoms may mimic the hypervigilance and exacerbated startle response of patients with PTSD. A common neurobiologic circuit is suggested for the pathophysiologic mechanism of this comorbidity. There is evidence that opioid substitution therapy may improve treatment outcomes for opioid addiction in patients with comorbid PTSD and opioid dependence. Evidence-based psychotherapeutic intervention is recommended for this population to improve the psychological outcome as well. Combining opioid substitution therapy with evidence-based cognitive behavioral therapy designed for individuals with comorbid PTSD and substance abuse (e.g., Seeking Safety) may improve treatment outcomes in this population. More research is needed to understand the underlying mechanisms for this comorbidity and to improve treatment response. PMID- 23815425 TI - The association between self-reported mental health status and alcohol and drug abstinence 5 years post-assessment for an addiction disorder in U.S. and Swedish samples. AB - This study compared whether self-reported mental health status was associated with likelihood of being abstinent from alcohol and drugs five years after baseline assessment for an addiction disorder in two representative samples; one from Sweden (n = 469) and one from the US (n = 667). Self-reported mental health status was measured through the ASI score of mental health symptoms and history of inpatient and/or outpatient treatment. Through logistic regression modeling the study controlled for demographic characteristics including age, gender, employment status and social network connection with individuals who do not use alcohol/drugs. For both the US and Swedish samples employment status and having a social network that does not use alcohol and drugs were associated with being likely to be abstinent from alcohol and drugs five years after initial assessment. For the US sample only, individuals who reported symptoms of anxiety were 50% more likely not to be abstinent from alcohol and drugs at follow-up. For the Swedish sample, current mental health status was not significantly associated with abstinence. However, reporting a lifetime history of inpatient psychiatric treatment at the baseline assessment was significantly associated with not being abstinent at 5 years post assessment; those with a lifetime history of inpatient mental health treatment were 47% less likely to report abstinence. While specific variables differ across Sweden and the US, psychiatric comorbid status, employment and social network are each associated with drug and alcohol abstinence cross-nationally. PMID- 23815426 TI - Clinical and reliable change in an Australian residential substance use program using the Addiction Severity Index. AB - Although the Addiction Severity Index (ASI) is one of the most frequently used measures in alcohol and other drug research, it has rarely been used to assess clinical and reliable change. This study assessed clients' clinical and reliable change at The Salvation Army residential substance abuse treatment centers in Australia. A total of 296 clients completed ASI interviews on admission to treatment and 3 months after discharge from treatment. Clients demonstrated significant improvement on all seven ASI composites. The range of reliable change for each ASI composite varied from 30% to 70%. More than two-thirds of clients experienced clinically significant improvement for alcohol and drug problems. Psychiatric distress was clinically reduced in 44% of clients. This research indicates that residential substance abuse treatment can make important differences in client's lives at a clinical and functional level. However, the research highlights the challenge of effectively targeting psychiatric comorbidity within alcohol and other drug abuse populations. PMID- 23815429 TI - The "citizens petition" to the FDA: a call to arms or a cause for reflection? PMID- 23815428 TI - Inhalants as intermediate drugs between legal and illegal drugs among middle and high school students. AB - The aims of this study are to: (1) describe the prevalence and sociodemographic characteristics of inhalant use among middle and high school students in Brazil, and (2) test the hypothesis of inhalants being intermediate drugs between legal and illegal drug use. A representative sample of 5226 students from private schools in Sao Paulo, Brazil, was selected to answer a self-report questionnaire. Weighted data was analyzed through Cox proportional hazards models. In the overall sample, inhalants seems to be an intermediate drug, since prior inhalant initiation was associated with first marijuana use, adjusted for previous alcohol and tobacco initiation. PMID- 23815427 TI - Relationship of age to impulsivity and decision making: a baseline secondary analysis of a behavioral treatment study in stimulant use disorders. AB - Because stimulant use disorders remain prevalent across the lifespan, cognition is an important area of clinical care and research focus among aging adults with stimulant use disorders. This secondary analysis of a National Institute on Drug Abuse Clinical Trials Network study suggests that decision making, verbal learning/memory, executive function, and set shifting are important cognitive domains to screen clinically and treat in aging adults with stimulant use disorders. Some suggestions are made on how clinical treatment providers can practically use these results. An important direction for future research is the development of cognitively remediating treatments for impaired cognitive domains in aging adults with stimulant use disorders. PMID- 23815430 TI - Accumulated phosphatidylcholine (16:0/16:1) in human colorectal cancer; possible involvement of LPCAT4. AB - The identification of cancer biomarkers is critical for target-linked cancer therapy. The overall level of phosphatidylcholine (PC) is elevated in colorectal cancer (CRC). To investigate which species of PC is overexpressed in colorectal cancer, an imaging mass spectrometry was performed using a panel of non neoplastic mucosal and CRC tissues. In the present study, we identified a novel biomarker, PC(16:0/16:1), in CRC using imaging mass spectrometry. Specifically, elevated levels of PC(16:0/16:1) expression were observed in the more advanced stage of CRC. Our data further showed that PC(16:0/16:1) was specifically localized in the cancer region when examined using imaging mass spectrometry. Notably, because the ratio of PC(16:0/16:1) to lyso-PC(16:0) was higher in CRC, we postulated that lyso-PC acyltransferase (LPCAT) activity is elevated in CRC. In an in vitro analysis, we showed that LPCAT4 is involved in the deregulation of PC(16:0/16:1) in CRC. In an immunohistochemical analysis, LPCAT4 was shown to be overexpressed in CRC. These data indicate the potential usefulness of PC(16:0/16:1) for the clinical diagnosis of CRC and implicate LPCAT4 in the elevated expression of PC(16:0/16:1) in CRC. PMID- 23815431 TI - Characterization and application of a flow system for in vitro multispecies oral biofilm formation. AB - BACKGROUND AND OBJECTIVE: Bacteria in the oral cavity grow in the form of biofilms; these structures are subject to constant saliva or gingival crevicular fluid flow conditions. The aims of this study were: (i) to develop and to characterize an in-vitro biofilm model with oral bacteria growing under flow and shear conditions; and (ii) to demonstrate the usefulness of the model for evaluating the activity of three antiplaque agents. MATERIAL AND METHODS: We used a bioreactor to grow the oral bacteria Streptococcus oralis, Actinomyces naeslundii, Veillonella parvula, Fusobacterium nucleatum, Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis under planktonic conditions. Biofilms were established using a modified Robbins device on hydroxyapatite (HAP) discs. Three- to 7-d-old biofilms were analysed using culture methods, scanning electron microscopy, Live/Dead staining and fluorescence in-situ hybridization (confocal laser scanning microscopy). Finally, we assessed the antimicrobial activity of three mouthrinses [0.12% chlorhexidine (CHX), 0.12% chlorhexidine and sodium fluoride (CHX+NaF) and 0.12% chlorhexidine and 0.05% cetylpyridinium chloride (CHX+CPC)] using a planktonic test (short interval-killing test) and in our 4-d biofilm model. RESULTS: The viable cell counts showed that each species was consistently found in the biofilms throughout the study. The architecture and cell distribution were similar to those described for biofilms in situ, with the exception of a thin layer of living cells that was found close to the HAP. The effectiveness test of the mouthwashes demonstrated that cells in biofilms showed more tolerance compared with planktonic cells. Moreover, it was observed that in 4-d biofilm formed in vitro, CHX+CPC caused significantly higher mortality compared with CHX (p = 0.003) and CHX+NaF (p < 0.001). CONCLUSION: Our results suggest that we have a highly reproducible system for multispecies oral biofilm formation and that it is a useful tool for assessing antibacterial molecules before their clinical evaluation. It also has great potential to be used in basic research on supragingival and subgingival biofilms. PMID- 23815432 TI - Influence of hydrogen annealing on the photocatalytic activity of diamond supported gold catalysts. AB - Fenton-treated diamond nanoparticles have been submitted to hydrogen reduction at 500 degrees C with the purpose of modifying the nature of the functional groups present on the diamond surface. The nature of the functional groups on the diamond samples was characterized by a combination of spectroscopic and analytical techniques. In particular, Fourier-transformed infrared spectroscopy, temperature-programmed desorption, and X-ray photoelectron spectroscopy (XPS) show the decrease in the population of carboxylic acids, esters, and anhydrides after hydrogen treatment. XPS also shows a decrease on the oxygen content after the hydrogen treatment of the diamond nanoparticles and lower electronegativity of the carbons as assessed by the lower binding energy values. Although Fenton treated diamond colloids in water changes the zeta potential from positive to negative values as a function of the pH, hydrogen annealing and the disappearance of the carboxyl groups determines that the zeta potential of the resulting sample remains positive in the complete pH range. Deposition of gold nanoparticles was carried out by the polyol method consisting on the reduction of HAuCl4 by hot ethylene glycol in the presence of the support. TEM analysis shows a variation of the average gold nanoparticle size that decreases after hydrogen reduction of carboxylic groups and becomes smaller for low gold loadings. The catalytic activity of the diamond supported gold nanoparticles as a function of the surface annealing treatment and gold loading was evaluated for the natural sunlight assisted peroxidation of phenol by H2O2. It was observed that the most efficient sample was the one having lower gold nanoparticle size that was obtained for diamond samples reduced by hydrogen at 500 degrees C after the Fenton treatment and having low gold loading (0.05 wt %). Turnover frequencies above 2400 and 940 h(-1) were obtained for phenol degradation and H2O2 decomposition, respectively. PMID- 23815433 TI - Activated gammadelta T cells inhibit osteoclast differentiation and resorptive activity in vitro. AB - Extensive evidence suggests that the immune system exerts powerful effects on bone cells, particularly in chronic disease pathologies such as rheumatoid arthritis (RA). The chronic inflammatory state in RA, particularly the excessive production of T cell-derived proinflammatory cytokines such as tumour necrosis factor (TNF)-alpha and interleukin (IL)-17, triggers bone erosions through the increased stimulation of osteoclast formation and activity. While evidence supports a role for IL-17 and TNF-alpha secreted by conventional CD4+ T cells in RA, recent evidence in animal models of RA have implicated gammadelta T cells as a major producer of pathogenic IL-17. However, the capacity of gammadelta T cells to influence osteoclast formation and activity in humans has not yet been investigated widely. To address this issue we investigated the effects of gammadelta T cells on osteoclast differentiation and resorptive activity. We have demonstrated that anti-CD3/CD28-stimulated gammadelta T cells or CD4+ T cells inhibit human osteoclast formation and resorptive activity in vitro. Furthermore, we assessed cytokine production by CD3/CD28-stimulated gammadelta T cells and observed a lack of IL-17 production, with activated gammadelta T cells producing abundant interferon (IFN)-gamma. The neutralization of IFN-gamma markedly restored the formation of osteoclasts from precursor cells and the resorptive activity of mature osteoclasts, suggesting that IFN-gamma is the major factor responsible for the inhibitory role of activated gammadelta T cells on osteoclastogenesis and resorptive activity of mature osteoclasts. Our work therefore provides new insights on the interactions between gammadelta T cells and osteoclasts in humans. PMID- 23815434 TI - Immediate placement of implants into infected sites: a systematic review. AB - BACKGROUND: Traditionally, before placing dental implants, the compromised teeth are removed and the extraction sockets are left to heal for several months. To preserve the alveolar bone level from the collapse caused by healing and to reduce treatment time in situations in which tooth extraction precedes implant placement, some clinicians began to install the implant immediately into the postextraction socket without waiting for the site to heal. PURPOSE: The purpose of this study was to review the literature regarding treatment outcomes of immediate implant placement into sites exhibiting pathology after clinical procedures to perform the decontamination of the implant's site. The following questions were raised: Does the presence of periodontal or endodontic infection affect immediate implant placement success? What is suggested to address the infection in the socket prior to immediate placement? MATERIALS AND METHODS: An electronic search in PubMed (U.S. National Library of Medicine, Bethesda, MD, USA) was undertaken in March 2013. The titles and abstracts from these results were read to identify studies within the selection criteria. Eligibility criteria included both animal and human studies, and excluded any review and case reports articles. The publication's intervention had to have been implant placement into a site classified as having an infection (periapical, endodontic, perioendodontic, and periodontal). RESULTS: The search strategy initially yielded 706 references. Thirty-two studies were identified within the selection criteria, from which nine were case reports and review articles and were excluded. Additional hand-searching of the reference lists of selected studies yielded five additional papers. CONCLUSIONS: The high survival rate obtained in several studies supports the hypothesis that implants may be successfully osseointegrated when placed immediately after extraction of teeth presenting endodontic and periodontal lesions, provided that appropriate clinical procedures are performed before the implant surgical procedure such as meticulous cleaning, socket curettage/debridement, and chlorhexidine 0.12% rinse. However, more randomized controlled clinical trials with a longer follow-up are required to confirm this procedure as a safe treatment. Moreover, the outcome measures were not related to the type of infection; the classification of infection was often vague and varied among the studies. The benefits of antibiotic solution irrigation and systemic antibiotic administration in such conditions are not yet proved and remain unclear. PMID- 23815435 TI - Does identification to species level provide sufficient evidence to confirm catheter-related fungemia caused by Candida albicans? AB - We retrospectively studied 22 patients with catheter-related candidemia caused by Candida albicans. Strains isolated simultaneously from blood and catheter tips were genotyped using six microsatellite markers. Matches between genotypes of isolates recovered from both sample sources were found in 20/22 (91%) patients. Consequently, identification of the same species from both the catheter tip and blood could be used to confirm catheter-related candidemia. PMID- 23815436 TI - A model for treating avian aspergillosis: serum and lung tissue kinetics for Japanese quail (Coturnix japonica) following single and multiple aerosol exposures of a nanoparticulate itraconazole suspension. AB - Aspergillosis is frequently reported in parrots, falcons and other birds held in captivity. Inhalation is the main route of infection for Aspergillus fumigatus, resulting in both acute and chronic disease conditions. Itraconazole (ITRA) is an antifungal commonly used in birds, but administration requires repeated oral dosing and the safety margin is narrow. We describe lung tissue and serum pharmacokinetics of a nanoparticulate ITRA suspension administered to Japanese quail by aerosol exposure. Aerosolized ITRA (1 and 10% suspension) administered over 30 min did not induce adverse clinical reactions in quail upon single or 5 day repeated doses. High lung concentrations, well above the inhibitory levels for A. fumigatus, of 4.14 +/- 0.19 MUg/g and 27.5 +/- 4.58 MUg/g (mean +/- SEM, n = 3), were achieved following single-dose inhalation of 1% and 10% suspension, respectively. Upon multiple dose administration of 10% suspension, mean lung concentrations reached 104.9 +/- 10.1 MUg/g. Drug clearance from the lungs was slow with terminal half-lives of 19.7 h and 35.8 h following inhalation of 1% and 10% suspension, respectively. Data suggest that lung clearance is solubility driven. Lung concentrations of hydroxy-itraconazole reached 1-2% of the ITRA lung tissue concentration indicating metabolism in lung tissue. Steady, but low, serum concentrations of ITRA could be measured after multiple dose administration, reaching less than 0.1% of the lung tissue concentration. This formulation may represent a novel, easy to administer treatment modality for fungal lung infection, preventing high systemic exposure. It may also be useful as metaphylaxis to prevent the outbreak of aspergillosis in colonized animals. PMID- 23815437 TI - Candida krusei colonization in patients with gastrointestinal diseases. AB - A total of 135 stomach samples from patients with gastrointestinal diseases and normal controls were examined for Helicobacter pylori infection and Candida colonization. Candida krusei was found in specimens from 20% bleeding, 52% ulcer, and 100% gastritis patients, whereas H. pylori infection rates were 82%, 35% and 30%, respectively, for the same groups of patients. C. krusei was not detected in stomach samples from normal controls. PMID- 23815438 TI - Splice variants and promoter methylation status of the Bovine Vasa Homology (Bvh) gene may be involved in bull spermatogenesis. AB - BACKGROUND: Vasa is a member of the DEAD-box protein family that plays an indispensable role in mammalian spermatogenesis, particularly during meiosis. Bovine vasa homology (Bvh) of Bos taurus has been reported, however, its function in bovine testicular tissue remains obscure. This study aimed to reveal the functions of Bvh and to determine whether Bvh is a candidate gene in the regulation of spermatogenesis in bovine, and to illustrate whether its transcription is regulated by alternative splicing and DNA methylation. RESULTS: Here we report the molecular characterization, alternative splicing pattern, expression and promoter methylation status of Bvh. The full-length coding region of Bvh was 2190 bp, which encodes a 729 amino acid (aa) protein containing nine consensus regions of the DEAD box protein family. Bvh is expressed only in the ovary and testis of adult cattle. Two splice variants were identified and termed Bvh-V4 (2112 bp and 703 aa) and Bvh-V45 (2040 bp and 679 aa). In male cattle, full-length Bvh (Bvh-FL), Bvh-V4 and Bvh-V45 are exclusively expressed in the testes in the ratio of 2.2:1.6:1, respectively. Real-time PCR revealed significantly reduced mRNA expression of Bvh-FL, Bvh-V4 and Bvh-V45 in testes of cattle-yak hybrids, with meiotic arrest compared with cattle and yaks with normal spermatogenesis (P < 0.01). The promoter methylation level of Bvh in the testes of cattle-yak hybrids was significantly greater than in cattle and yaks (P < 0.01). CONCLUSION: In the present study, Bvh was isolated and characterized. These data suggest that Bvh functions in bovine spermatogenesis, and that transcription of the gene in testes were regulated by alternative splice and promoter methylation. PMID- 23815439 TI - Carbon monoxide signaling in human red blood cells: evidence for pentose phosphate pathway activation and protein deglutathionylation. AB - AIMS: The biochemistry underlying the physiological, adaptive, and toxic effects of carbon monoxide (CO) is linked to its affinity for reduced transition metals. We investigated CO signaling in the vasculature, where hemoglobin (Hb), the CO most important metal-containing carrier is highly concentrated inside red blood cells (RBCs). RESULTS: By combining NMR, MS, and spectrophotometric techniques, we found that CO treatment of whole blood increases the concentration of reduced glutathione (GSH) in RBC cytosol, which is linked to a significant Hb deglutathionylation. In addition, this process (i) does not activate glycolytic metabolism, (ii) boosts the pentose phosphate pathway (PPP), (iii) increases glutathione reductase activity, and (iv) decreases oxidized glutathione concentration. Moreover, GSH concentration was partially decreased in the presence of 2-deoxyglucose and the PPP antagonist dehydroepiandrosterone. Our MS results show for the first time that, besides Cys93, Hb glutathionylation occurs also at Cys112 of the beta-chain, providing a new potential GSH source hitherto unknown. INNOVATION: This work provides new insights on the signaling and antioxidant-boosting properties of CO in human blood, identifying Hb as a major source of GSH release and the PPP as a metabolic mechanism supporting Hb deglutathionylation. CONCLUSIONS: CO-dependent GSH increase is a new RBC process linking a redox-inactive molecule, CO, to GSH redox signaling. This mechanism may be involved in the adaptive responses aimed to counteract stress conditions in mammalian tissues. PMID- 23815440 TI - Use of impact fees to incentivize low-impact development and promote compact growth. AB - Low-impact development (LID) is an innovative stormwater management strategy that restores the predevelopment hydrology to prevent increased stormwater runoff from land development. Integrating LID into residential subdivisions and increasing population density by building more compact living spaces (e.g., apartment homes) can result in a more sustainable city by reducing stormwater runoff, saving infrastructural cost, increasing the number of affordable homes, and supporting public transportation. We develop an agent-based model (ABM) that describes the interactions between several decision-makers (i.e., local government, a developer, and homebuyers) and fiscal drivers (e.g., property taxes, impact fees). The model simulates the development of nine square miles of greenfield land. A more sustainable development (MSD) scenario introduces an impact fee that developers must pay if they choose not to use LID to build houses or apartment homes. Model simulations show homeowners selecting apartment homes 60% or 35% of the time after 30 years of development in MSD or business as usual (BAU) scenarios, respectively. The increased adoption of apartment homes results from the lower cost of using LID and improved quality of life for apartment homes relative to single-family homes. The MSD scenario generates more tax revenue and water savings than does BAU. A time-dependent global sensitivity analysis quantifies the importance of socioeconomic variables on the adoption rate of apartment homes. The top influential factors are the annual pay rates (or capital recovery factor) for single-family houses and apartment homes. The ABM can be used by city managers and policymakers for scenario exploration in accordance with local conditions to evaluate the effectiveness of impact fees and other policies in promoting LID and compact growth. PMID- 23815441 TI - Natural ventilation reduces high TB transmission risk in traditional homes in rural KwaZulu-Natal, South Africa. AB - BACKGROUND: Transmission of drug susceptible and drug resistant TB occurs in health care facilities, and community and households settings, particularly in highly prevalent TB and HIV areas. There is a paucity of data regarding factors that may affect TB transmission risk in household settings. We evaluated air exchange and the impact of natural ventilation on estimated TB transmission risk in traditional Zulu homes in rural South Africa. METHODS: We utilized a carbon dioxide decay technique to measure ventilation in air changes per hour (ACH). We evaluated predominant home types to determine factors affecting ACH and used the Wells-Riley equation to estimate TB transmission risk. RESULTS: Two hundred eighteen ventilation measurements were taken in 24 traditional homes. All had low ventilation at baseline when windows were closed (mean ACH = 3, SD = 3.0), with estimated TB transmission risk of 55.4% over a ten hour period of exposure to an infectious TB patient. There was significant improvement with opening windows and door, reaching a mean ACH of 20 (SD = 13.1, p < 0.0001) resulting in significant decrease in estimated TB transmission risk to 9.6% (p < 0.0001). Multivariate analysis identified factors predicting ACH, including ventilation conditions (windows/doors open) and window to volume ratio. Expanding ventilation increased the odds of achieving >=12 ACH by 60-fold. CONCLUSIONS: There is high estimated risk of TB transmission in traditional homes of infectious TB patients in rural South Africa. Improving natural ventilation may decrease household TB transmission risk and, combined with other strategies, may enhance TB control efforts. PMID- 23815442 TI - New cycloartane triterpene glycosides from Beesia calthaefolia. AB - Two new cycloartane triterpene glycosides (compounds 1 and 4) were isolated from the whole plants of Beesia calthaefolia with two known glycosides (compounds 2 and 3). Compounds 1 and 4 were assigned as (20S(*),24R(*))-16beta-acetoxy-20, 24 epoxy-9, 19-cyclolanostane-3beta,12beta,15alpha,18,25-pentaol-3-O-beta-d xylopyranoside and (20S(*),24 R(*))-16beta-acetoxy-20,24-epoxy-9,19 cyclolanostane-3beta,15alpha,18,25-tetraol-3-O-beta-d-xylopyranoside, respectively. Their structures were elucidated on the basis of extensive spectroscopic data analyses and comparison with spectroscopic data reported. Compounds 1 and 4 showed potential inhibition activity for the proliferation of splenocytes. PMID- 23815443 TI - Targeted delivery of Epirubicin to cancer cells by PEGylated A10 aptamer. AB - Clinical administrations of anthracyclines are limited by cardiotoxicity and myelosuppression. Targeted delivery of anticancer agents is especially important in reducing their side effects. In this work, A10 (Apt), an aptamer for prostate specific membrane anytigen (PSMA), was applied for targeted delivery of Epirubicin (Epi) to LNCaP cells (PSMA(+)). Flow cytometry analysis showed that PEG-Apt-Epi complex was internalized effectively to LNCaP cells (PSMA(+)), but not to PC3 cells (PSMA(-)). This fact was confirmed by less cytotoxicity of PEG Apt-Epi complex in PC3 cells in comparison with Epi alone. No significant change in viability between Epi- and complex-treated LNCaP cells was observed. In conclusion, PEG-Apt-Epi complex is an efficient and simple system for specific delivery of drug to PSMA-expressing cell lines. PMID- 23815444 TI - Alignment-free analysis of barcode sequences by means of compression-based methods. AB - BACKGROUND: The key idea of DNA barcode initiative is to identify, for each group of species belonging to different kingdoms of life, a short DNA sequence that can act as a true taxon barcode. DNA barcode represents a valuable type of information that can be integrated with ecological, genetic, and morphological data in order to obtain a more consistent taxonomy. Recent studies have shown that, for the animal kingdom, the mitochondrial gene cytochrome c oxidase I (COI), about 650 bp long, can be used as a barcode sequence for identification and taxonomic purposes of animals. In the present work we aims at introducing the use of an alignment-free approach in order to make taxonomic analysis of barcode sequences. Our approach is based on the use of two compression-based versions of non-computable Universal Similarity Metric (USM) class of distances. Our purpose is to justify the employ of USM also for the analysis of short DNA barcode sequences, showing how USM is able to correctly extract taxonomic information among those kind of sequences. RESULTS: We downloaded from Barcode of Life Data System (BOLD) database 30 datasets of barcode sequences belonging to different animal species. We built phylogenetic trees of every dataset, according to compression-based and classic evolutionary methods, and compared them in terms of topology preservation. In the experimental tests, we obtained scores with a percentage of similarity between evolutionary and compression-based trees between 80% and 100% for the most of datasets (94%). Moreover we carried out experimental tests using simulated barcode datasets composed of 100, 150, 200 and 500 sequences, each simulation replicated 25-fold. In this case, mean similarity scores between evolutionary and compression-based trees span between 83% and 99% for all simulated datasets. CONCLUSIONS: In the present work we aims at introducing the use of an alignment-free approach in order to make taxonomic analysis of barcode sequences. Our approach is based on the use of two compression-based versions of non-computable Universal Similarity Metric (USM) class of distances. This way we demonstrate the reliability of compression-based methods even for the analysis of short barcode sequences. Compression-based methods, with their strong theoretical assumptions, may then represent a valid alignment-free and parameter-free approach for barcode studies. PMID- 23815445 TI - Chiral structure of thiolate-protected 28-gold-atom nanocluster determined by X ray crystallography. AB - We report the crystal structure of a new nanocluster formulated as Au28(TBBT)20, where TBBT = 4-tert-butylbenzenethiolate. It exhibits a rod-like Au20 kernel consisting of two interpenetrating cuboctahedra. The kernel is protected by four dimeric "staples" (-SR-Au-SR-Au-SR-) and eight bridging thiolates (-SR-). The unit cell of Au28(TBBT)20 single crystals contains a pair of enantiomers. The origin of chirality is primarily rooted in the rotating arrangement of the four dimeric staples as well as the arrangement of the bridging thiolates (quasi-D2 symmetry). The enantiomers were separated by chiral HPLC and characterized by circular dichroism spectroscopy. PMID- 23815446 TI - Automatic detection of basal cell carcinoma using telangiectasia analysis in dermoscopy skin lesion images. AB - BACKGROUND: Telangiectasia, dilated blood vessels near the surface of the skin of small, varying diameter, are critical dermoscopy structures used in the detection of basal cell carcinoma (BCC). Distinguishing these vessels from other telangiectasia, that are commonly found in sun-damaged skin, is challenging. METHODS: Image analysis techniques are investigated to find vessels structures in BCC automatically. The primary screen for vessels uses an optimized local color drop technique. A noise filter is developed to eliminate false-positive structures, primarily bubbles, hair, and blotch and ulcer edges. From the telangiectasia mask containing candidate vessel-like structures, shape, size and normalized count features are computed to facilitate the discrimination of benign skin lesions from BCCs with telangiectasia. RESULTS: Experimental results yielded a diagnostic accuracy as high as 96.7% using a neural network classifier for a data set of 59 BCCs and 152 benign lesions for skin lesion discrimination based on features computed from the telangiectasia masks. CONCLUSION: In current clinical practice, it is possible to find smaller BCCs by dermoscopy than by clinical inspection. Although almost all of these small BCCs have telangiectasia, they can be short and thin. Normalization of lengths and areas helps to detect these smaller BCCs. PMID- 23815450 TI - Neuroimaging in clinical studies of craving: importance of reward and control networks. AB - Research on neurobiological mechanisms, especially the function of networks that underlie reward and cognitive control, may offer an opportunity to explore how existing treatments work and provide means for developing new treatments for substance use disorders. In this respect, the special issue of Psychology of Addictive Behaviors highlights efforts to integrate translational neuroimaging with clinical research by actively linking neuroimaging measures with psychosocial treatment mechanisms. Based on several of the articles in this special issue, mindfulness-based approaches appear poised to make rapid progress in terms of integrating neuroimaging with research on mechanisms that mediate treatment success. This commentary briefly discusses research on incentive salience and cognitive control networks in the context of addiction, followed by a discussion of specific studies within this special issue that address the integration of neuroimaging assessments in the context of mindfulness approaches. Future work may be able to leverage measures of changes in networks and regions that underlie reward processing and cognitive control to better understand how treatments work, especially for mindfulness-based approaches. PMID- 23815447 TI - Neuroimaging mechanisms of change in psychotherapy for addictive behaviors: emerging translational approaches that bridge biology and behavior. AB - Research on mechanisms of behavior change provides an innovative method to improve treatment for addictive behaviors. An important extension of mechanisms of change research involves the use of translational approaches, which examine how basic biological (i.e., brain-based mechanisms) and behavioral factors interact in initiating and sustaining positive behavior change as a result of psychotherapy. Articles in this special issue include integrative conceptual reviews and innovative empirical research on brain-based mechanisms that may underlie risk for addictive behaviors and response to psychotherapy from adolescence through adulthood. Review articles discuss hypothesized mechanisms of change for cognitive and behavioral therapies, mindfulness-based interventions, and neuroeconomic approaches. Empirical articles cover a range of addictive behaviors, including use of alcohol, cigarettes, marijuana, cocaine, and pathological gambling and represent a variety of imaging approaches including fMRI, magneto-encephalography, real-time fMRI, and diffusion tensor imaging. Additionally, a few empirical studies directly examine brain-based mechanisms of change, whereas others examine brain-based indicators as predictors of treatment outcome. Finally, two commentaries discuss craving as a core feature of addiction, and the importance of a developmental approach to examining mechanisms of change. Ultimately, translational research on mechanisms of behavior change holds promise for increasing understanding of how psychotherapy may modify brain structure and functioning and facilitate the initiation and maintenance of positive treatment outcomes for addictive behaviors. PMID- 23815451 TI - Integrating translational neuroscience to improve drug abuse treatment for adolescents. AB - Adolescence is an exciting and challenging period of maturation, rapid brain development, and developmental changes in neurobiological, neurocognitive, and neurobehavioral processes. Although behavioral therapies available for adolescent substance abuse have increased, effectiveness research in this area lags considerably behind that of clinical research on treatment for drug-abusing adults. Behavioral treatment approaches show significant promise for treating drug-abusing adolescents, but many have not incorporated innovations in neuroscience on brain development, cognitive processes, and neuroimaging. Linking developmental neuroscience with behavioral treatments can create novel drug abuse interventions and increase the effectiveness of existing interventions for substance-abusing adolescents. Contemporary research on brain development, cognition, and neuroscience is ripe for translation to inform developmentally sensitive drug abuse treatments for adolescents. Neuroscientists and interventionists are challenged to build mutual collaborations for integration of neuroscience and drug abuse treatment for adolescents. PMID- 23815452 TI - Personal awareness and behavioural choices on having a stoma: a qualitative metasynthesis. AB - AIMS AND OBJECTIVES: To answer how personal awareness and behavioural choices on having a stoma have been described and interpreted in previous qualitative studies. BACKGROUND: Over the past two decades, there has been an accumulation of the qualitative studies concerning the experiences of individuals living with a stoma. Synthesising the findings of these studies would be able to improve the understanding among health providers. DESIGN: Qualitative metasynthesis. METHODS: The literature was obtained through searching CINAHL and PubMed databases for papers published in English, and China National Knowledge Infrastructure database for papers published in Chinese from 1990-March 2012. Sixteen articles were selected using the predefined criteria. RESULTS: Three themes about personal awareness and behavioural choices on having a stoma were identified: altered self, restricted life and overcoming restrictions. The results showed the impacts of having a stoma through the analysis on connections between personal awareness and behavioural choices. CONCLUSIONS: Having a stoma means that the individuals have to learn to be aware of and accustomed to changes and restrictions in their everyday lives. The individuals take behavioural efforts to overcome these restrictions involving: deciding on whether to reveal or conceal their stomas to others based on the possibility of being accepted or rejected, using internal resources, seeking and receiving external supports. RELEVANCE TO CLINICAL PRACTICE: The description and interpretation on personal awareness and behavioural choices associated with having a stoma is useful for nurses in providing practical, informational and emotional supports to help the individuals successfully adapt to their lives with a stoma. PMID- 23815453 TI - Diagnostic accuracy of arterial line blood gas measurements as an estimate of arteriovenous fistula recirculation. AB - AIM: We studied the diagnostic accuracy of blood gas determination as a novel method for the estimation of arteriovenous fistula (AVF) recirculation (RC). METHODS: In 25 patients on chronic haemodialysis, with failure of a previously well functioning native AVF (mean two-needle urea-based RC: 41 +/- 10%), arterial line (AL) as well as a peripheral vein (PV) blood samples drawn by the end of a 4 h haemodialysis session, before and after the surgical repair of their AVF. RESULTS: Compared to PV samples, patients with RC had significantly higher AL blood pCO2 and pO2 values (P < 0.001) and lower AL blood pH and K(+) values (P < 0.001), findings that were reversed after the surgical restoration of adequate AVF function. On regression analysis, urea RC values were correlated positively with AL pCO2 values (r = 0.683, P < 0.001) and negatively with AL pH values (r = 0.896, P < 0.001). AL pCO2 > 40 mmHg was shown to have the best sensitivity and AL pH < 7.25 the best specificity. RC index, that is, the AL pCO2 /pH ratio, was found to have superior test characteristics compared to pH and pCO2 (sensitivity 95% and specificity 88% for values >5.5) making it a powerful diagnostic as well as screening tool. CONCLUSION: We propose the regular AL blood gas measurement as a novel method of AVF function surveillance and RC diagnosis. AL blood pH < 7.25, pCO2 > 40 mmHg and RC index > 5.5, escorted by rather high pO2 and low K(+) by the end of dialysis session, but probably earlier as well, signify an important RC (>20%) and warrant further investigation of AVF patency. PMID- 23815455 TI - Power changes how the brain responds to others. AB - Power dynamics are a ubiquitous feature of human social life, yet little is known about how power is implemented in the brain. Motor resonance is the activation of similar brain networks when acting and when watching someone else act, and is thought to be implemented, in part, by the human mirror system. We investigated the effects of power on motor resonance during an action observation task. Separate groups of participants underwent a high-, neutral, or low-power induction priming procedure, prior to observing the actions of another person. During observation, motor resonance was determined with transcranial magnetic stimulation (TMS) via measures of motor cortical output. High-power participants demonstrated lower levels of resonance than low-power participants, suggesting reduced mirroring of other people in those with power. These differences suggest that decreased motor resonance to others' actions might be one of the neural mechanisms underlying power-induced asymmetries in processing our social interaction partners. PMID- 23815454 TI - Second-generation dopamine agonists and recollection impairments in Parkinson's disease. AB - A selective deficit in the recollection of episodic details is frequently reported in Parkinson's disease (PD). Previous explanations implicate dopamine dysregulation in prefrontal structures on which strategic memory processes rely. However, neuroimaging advancements suggest dopaminergic dysregulation of hippocampally dependent memory processes. Accordingly, dopamine agonists, which target D3 receptors in the hippocampus, may impair hippocampal functioning, causing a more pronounced recollection decline. Recognition memory (RM), familiarity, and recollection were examined in 21 patients with mild-to-moderate PD (Hoehn and Yahr mean: 2.67). Patients were subdivided into two subgroups according to dopamine agonist (pramipexole [PPX] or ropinirole [RPR]), and completed matched versions of an RM test in a medicated and unmedicated condition (termed ON and OFF, respectively). Ten demographically matched healthy volunteers (HVs) also completed both RM tasks in two separate sessions. The PD group (PPX and RPR subgroups combined) showed impairments in RM and recollection, but spared familiarity. When subdivided by dopamine agonist, the PPX subgroup's ON medication recollection performance was significantly lower than that of both the HVs and RPR subgroup. There was no evidence of decline in OFF-medication recollection or familiarity in either the PPX or RPR subgroups. Recollection in both PD subgroups correlated positively with a composite measure of recall, but not prefrontally dependent measures of cognitive control. These findings suggest that mild-to-moderate PD patients may show relatively preserved recollection and familiarity, but that recollection is selectively disrupted by PPX, but not RPR and that this effect may depend on disrupted hippocampal function rather than impaired pre-frontally dependent executive functions. PMID- 23815456 TI - How decision reversibility affects motivation. AB - The present research examined how decision reversibility can affect motivation. On the basis of extant findings, it was suggested that 1 way it could affect motivation would be to strengthen different regulatory foci, with reversible decision making, compared to irreversible decision making, strengthening prevention-related motivation relatively more than promotion-related motivation. If so, then decision reversibility should have effects associated with the relative differences between prevention and promotion motivation. In 5 studies, we manipulated the reversibility of a decision and used different indicators of regulatory focus motivation to test these predictions. Specifically, Study 1 tested for differences in participants' preference for approach versus avoidance strategies toward a desired end state. In Study 2, we used speed and accuracy performance as indicators of participants' regulatory motivation, and in Study 3, we measured global versus local reaction time performance. In Study 4, we approached the research question in a different way, making use of the value-from fit hypothesis (Higgins, 2000, 2002). We tested whether a fit between chronic regulatory focus and focus induced by the reversibility of the decision increased participants' subjective positive feelings about the decision outcome. Finally, in Study 5, we tested whether regulatory motivation, induced by decision reversibility, also influenced participants' preference in specific product features. The results generally support our hypothesis showing that, compared to irreversible decisions, reversible decisions strengthen a prevention focus more than a promotion focus. Implications for research on decision making are discussed. PMID- 23815457 TI - The benefit of generating errors during learning. AB - Testing has been found to be a powerful learning tool, but educators might be reluctant to make full use of its benefits for fear that any errors made would be harmful to learning. We asked whether testing could be beneficial to memory even during novel learning, when nearly all responses were errors, and where errors were unlikely to be related to either cues or targets. In 4 experiments, participants learned definitions for unfamiliar English words, or translations for foreign vocabulary, by generating a response and being given corrective feedback, by reading the word and its definition or translation, or by selecting from a choice of definitions or translations followed by feedback. In a final test of all words, generating errors followed by feedback led to significantly better memory for the correct definition or translation than either reading or making incorrect choices, suggesting that the benefits of generation are not restricted to correctly generated items. Even when information to be learned is novel, errorful generation may play a powerful role in potentiating encoding of corrective feedback. Experiments 2A, 2B, and 3 revealed, via metacognitive judgments of learning, that participants are strikingly unaware of this benefit, judging errorful generation to be a less effective encoding method than reading or incorrect choosing, when in fact it was better. Predictions reflected participants' subjective experience during learning. If subjective difficulty leads to more effort at encoding, this could at least partly explain the errorful generation advantage. PMID- 23815458 TI - Hippocampal immediate poststimulus activity in the encoding of consecutive naturalistic episodes. AB - In the encoding of narrative episodes, the hippocampus exhibits memory-predictive activity time-locked to stimulus offset. In real life, however, events usually occur in succession, raising the question of how the immediate offline processing of one event is affected by presentation of another. To address this issue, participants were presented with brief narrative movie clips in a functional magnetic resonance imaging scanner. Each clip was immediately followed by an additional, unrelated, clip; by a visually scrambled clip with background auditory noises; or by a fixation cross. Memory for the gist of the clips was tested outside the scanner in a cued-recall test 20 min after termination of the study session. The hippocampus responded at the offset of each clip, even when a second clip was presented in immediate succession, suggesting that the hippocampus processes each brief clip as a discrete event. Presentation of a second narrative clip, and to a lesser degree of a scrambled clip, retroactively interfered with memory for the first clip. In parallel, the offline response of the posterior hippocampus to the first movie was reduced. In the anterior hippocampus, presentation of a second clip did not reduce the overall offline response but significantly reduced the difference in activity between remembered and forgotten clips. These findings are in line with the proposition that immediate offline hippocampal activity reflects registration of episodes to memory and suggest a potential brain correlate of retroactive interference. PMID- 23815459 TI - Significant reduction of Tacrolimus trough level after conversion from twice daily Prograf to once daily Advagraf in Chinese renal transplant recipients with or without concomitant diltiazem treatment. AB - A dose ratio of 1:1 was recommended for the conversion from Standard-release Tacrolimus (Prograf) to Prolonged-release Tacrolimus (Advagraf). We investigated the trough tacrolimus blood level in Chinese kidney transplant recipients after conversion, including subjects receiving concomitant treatment with diltiazem. Eighteen stable renal allograft recipients were followed prospectively for 12 weeks after conversion from Prograf to Advagraf at the same daily dose. Tacrolimus blood trough level decreased significantly within 8 weeks after conversion (p < 0.01). Twelve patients required escalation of the Advagraf dose by 1.10 +/- 0.36 mg. For the whole group the daily tacrolimus dose was increased from 0.057 +/- 0.032 mg/kg to 0.068 +/- 0.033 mg/kg (p < 0.0001). At week 12 the daily dose of Advagraf was 127 +/- 32% of the original daily dose of Prograf. In the subgroup of patients receiving diltiazem, their tacrolimus trough level decreased significantly after conversion (p = 0.001), and the daily tacrolimus dose was increased from 0.060 +/- 0.036 mg/kg to 0.073 +/- 0.036 mg/kg (p < 0.0001). At week 12, their daily dose of Advagraf was 131 +/- 34% of the original daily dose before conversion. To conclude, conversion from Prograf to Advagraf in renal allograft recipients with or without diltiazem co-treatment necessitated an increase in the daily dose by approximately 30% to maintain the target blood trough level unchanged. PMID- 23815460 TI - Involvement of SDF-1 and monocyte chemoattractant protein-1 in hydrogen peroxide induced extracellular matrix degradation in human dental pulp cells. AB - AIM: To determine whether chemokines such as SDF-1 and monocyte chemoattractant protein-1 (MCP-1) are responsible for hydrogen peroxide (H2 O2 )-induced extracellular matrix (ECM) degradation and to identify the underlying mechanism in human dental pulp cells (HDPCs). METHOD: Human dental pulp cells were exposed to 0.4 mmol H2 O2 for 48 h. mRNA expression and protein expression were examined by RT-PCR and Western blot analysis, respectively. The mRNA expression of chemokine (SDF-1 and MCP-1), their receptors (CXCR4 and CXCR2) and extracellular matrix proteins was evaluated by reverse transcriptase-polymerase chain reaction. The production of SDF-1, MCP-1, CXCR4 and CCR2 in the culture medium was determined by enzyme-linked immunosorbent assay. Signal transduction pathway was examined by Western blotting. RESULTS: Hydrogen peroxide provoked the activation of MCP-1 and SDF-1 mRNA and their respective receptors, CXCR4 and CXCR2. H2 O2 treatment concomitantly downregulated the expression of ECM molecules, such as type I collagen, elastin and fibronectin, and upregulated the mRNA expression of matrix metalloproteinase-1 (MMP-1), MMP-2, MMP-8 and MMP-9. Hydrogen peroxide induced ECM degradation and MMP upregulation were blocked by neutralizing antibodies and siRNAs directed against SDF-1 and MCP-1. Inhibition of SDF-1 and MCP-1 blocked the H2 O2 -induced activation of Akt, p38, ERK and NF-kB. CONCLUSION: Inhibition of SDF and MCP-1 is a potent component of reducing release reactive oxygen species-induced ECM degradation in HDPCs and may play an important role in pulpal and periapical inflammation. PMID- 23815461 TI - Interactions between sleep disorders and oral diseases. AB - Dental sleep medicine is a rapidly growing field that is in close and direct interaction with sleep medicine and comprises many aspects of human health. As a result, dentists who encounter sleep health and sleep disorders may work with clinicians from many other disciplines and specialties. The main sleep and oral health issues that are covered in this review are obstructive sleep apnea, chronic mouth breathing, sleep-related gastroesophageal reflux, and sleep bruxism. In addition, edentulism and its impact on sleep disorders are discussed. Improving sleep quality and sleep characteristics, oral health, and oral function involves both pathophysiology and disease management. The multiple interactions between oral health and sleep underscore the need for an interdisciplinary clinical team to manage oral health-related sleep disorders that are commonly seen in dental practice. PMID- 23815462 TI - Nanoscale fluorescence lifetime imaging of an optical antenna with a single diamond NV center. AB - Solid-state quantum emitters, such as artificially engineered quantum dots or naturally occurring defects in solids, are being investigated for applications ranging from quantum information science and optoelectronics to biomedical imaging. Recently, these same systems have also been studied from the perspective of nanoscale metrology. In this letter, we study the near-field optical properties of a diamond nanocrystal hosting a single nitrogen vacancy center. We find that the nitrogen vacancy center is a sensitive probe of the surrounding electromagnetic mode structure. We exploit this sensitivity to demonstrate nanoscale fluorescence lifetime imaging microscopy (FLIM) with a single nitrogen vacancy center by imaging the local density of states of an optical antenna. PMID- 23815463 TI - Alternative approach to calculate two-center overlap matrix through deformed exponential function. AB - In this work, we propose an alternative approach to evaluate two-center overlap integrals. It is computationally more efficient than the standard procedure and is based on the deformed exponential function. In the new procedure, the CPU time to calculate each element of the overlap matrix (SMU,nu) is constant and independent of the number of Gaussian primitives (NG), whereas in the usual procedure this time increases, formally, with NG2. To evaluate the accuracy of the proposed methodology, we computed different molecular properties such as dipole moments, hardness values, atomic charges, multicenter bond indices, group indices, and some thermodynamic properties. In this work, all calculations were performed using a minimal STO-6G basis set and WTBS and the double-zeta Pople split-valence 6-31G basis set on the Hartree-Fock (HF) and post-HF approximations. The integrals were parametrized for the atoms of the first two rows of the periodic table. All calculations were performed in the general ab initio quantum chemistry package GAMESS, where the integrals were implemented. PMID- 23815464 TI - Multifunctional free-standing membrane from the self-assembly of ultralong MnO2 nanowires. AB - In this work, we report the preparation of a free-standing membrane with strong mechanical stability and flexibility through a facile vacuum filtration approach. A field-emission scanning electron microscopy image demonstrates that the membrane composed of MnO2 nanowires is 50 nm in width and up to 100 MUm long and the nanowires are assembled in parallel into bundles. A possible formation mechanism for the ultralong nanowires and the free-standing membrane has been proposed. Meanwhile, the properties of the membrane could be controlled by incorporating different materials to achieve composite membranes. In order to demonstrate the broad applicability of the MnO2 membrane, we fabricate a variety of composite membranes exhibiting various novel properties including magnetism and reversibly switchable wettability between hydrophilicity and hydrophobicity through various material modification, including CoFe2O4 nanoparticles and organic triethoxy(octyl)silane. Furthermore, the free-standing membrane could also simultaneously be functionalized with two materials, which reveal multiple properties. The synthesis method of a free-standing MnO2 membrane is simple and environmentally friendly, and it is easily scalable for industry. These composite membranes constitute a significant contribution to advanced technology. PMID- 23815465 TI - Single-walled carbon nanotube transport in representative municipal solid waste landfill conditions. AB - Single-walled carbon nanotubes (SWNTs) are being used in many consumer products and devices. It is likely that as some of these products reach the end of their useful life, they will be discarded in municipal solid waste landfills. However, there has been little work evaluating the fate of nanomaterials in solid waste environments. The purpose of this study is to systematically evaluate the influence of organic matter type and concentration in landfill-relevant conditions on SWNT transport through a packed-bed of mixed municipal solid waste collectors. The influence of individual waste materials on SWNT deposition is also evaluated. Transport experiments were conducted through saturated waste containing columns over a range of simulated leachate conditions representing both mature and young leachates. Results indicate that SWNT transport may be significant in mature waste environments, with mobility decreasing with decreasing humic acid concentration. SWNT mobility in the presence of acetic acid was inhibited, suggesting their mobility in young waste environments may be small. SWNTs also exhibited collector media-dependent transport, with greatest transport in glass and least in paper. These results represent the first study evaluating how leachate age and changes in waste composition influence potential SWNT mobility in landfills. PMID- 23815466 TI - Redox pioneer: Professor Stuart A. Lipton. AB - [Figure: see text] Stuart A. Lipton, M.D., Ph.D. is recognized here as a Redox Pioneer because of his publication of four articles that have been cited more than 1000 times, and 96 reports which have been cited more than 100 times. In the redox field, Dr. Lipton is best known for his work on the regulation by S nitrosylation of the NMDA-subtype of neuronal glutamate receptor, which provided early evidence for in situ regulation of protein activity by S-nitrosylation and a prototypic model of allosteric control by this post-translational modification. Over the past several years, Lipton's group has pioneered the discovery of aberrant protein nitrosylation that may contribute to a number of neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (Lou Gehrig's disease). In particular, the phenotypic effects of rare genetic mutations may be understood to be enhanced or mimicked by nitrosative (and oxidative) modifications of cysteines and thereby help explain common sporadic forms of disease. Thus, Lipton has contributed in a major way to the understanding that nitrosative stress may result from modifications of specific proteins and may operate in conjunction with genetic mutation to create disease phenotype. Lipton (collaborating with Jonathan S. Stamler) has also employed the concept of targeted S-nitrosylation to produce novel neuroprotective drugs that act at allosteric sites in the NMDA receptor. Lipton has won a number of awards, including the Ernst Jung Prize in Medicine, and is an elected fellow of the AAAS. Antioxid. Redox Signal. 19, 757 764. PMID- 23815467 TI - Immunoglobulin G anti-endothelial cell antibodies: inducers of endothelial cell apoptosis in pulmonary arterial hypertension? AB - Endothelial cell (EC) apoptosis seems to play an important role in the pathophysiology of pulmonary arterial hypertension (PAH). We aimed to test the hypothesis that circulating anti-endothelial cell antibodies (AECA) of PAH patients induce EC apoptosis. Immunoglobulin (Ig)G was purified from sera of PAH patients (n = 26), patients with systemic lupus erythematosus (SLE) nephritis without PAH (n = 16), patients with systemic sclerosis (SSc) without PAH (n = 58) and healthy controls (n = 14). Human umbilical vein endothelial cells (HUVECs) were incubated with patient or healthy control IgG for 24 h. Thereafter, apoptosis was quantified by annexin A5 binding and hypoploid cell enumeration by flow cytometry. Furthermore, real-time cell electronic sensing (RT-CESTM) technology was used to monitor the effects of purified IgG from patient and healthy control IgG on HUVECs. As demonstrated previously, IgG of AECA-positive SLE nephritis patients (n = 7) induced a higher percentage of apoptosis of HUVECs compared to IgG of AECA-negative SLE nephritis patients and healthy controls. Furthermore, IgG of AECA-positive SLE nephritis patients induced a marked decrease in cell index as assessed by RT-CESTM technology. IgG of AECA-positive PAH patients (n = 12) and SSc patients (n = 13) did not alter the percentage of HUVEC apoptosis or cell index compared to IgG of AECA-negative PAH and SSc patients and healthy controls. AECA-positive PAH patients, in contrast to SLE nephritis patients, do not have circulating IgG AECA that enhances apoptosis of HUVECs in vitro. Further studies should focus on other mechanisms by which AECA may enhance EC apoptosis in PAH, such as antibody-dependent cell-mediated cytotoxicity. PMID- 23815469 TI - Clinical applications of cell-based approaches in alveolar bone augmentation: a systematic review. AB - BACKGROUND: Cell-based approaches, utilizing adult mesenchymal stem cells (MSCs), are reported to overcome the limitations of conventional bone augmentation procedures. PURPOSE: The study aims to systematically review the available evidence on the characteristics and clinical effectiveness of cell-based ridge augmentation, socket preservation, and sinus-floor augmentation, compared to current evidence-based methods in human adult patients. MATERIALS AND METHODS: MEDLINE, EMBASE, and CENTRAL databases were searched for related literature. Both observational and experimental studies reporting outcomes of "tissue engineered" or "cell-based" augmentation in >=5 adult patients alone, or in comparison with non-cell-based (conventional) augmentation methods, were eligible for inclusion. Primary outcome was histomorphometric analysis of new bone formation. Effectiveness of cell-based augmentation was evaluated based on outcomes of controlled studies. RESULTS: Twenty-seven eligible studies were identified. Of these, 15 included a control group (8 randomized controlled trials [RCTs]), and were judged to be at a moderate-to-high risk of bias. Most studies reported the combined use of cultured autologous MSCs with an osteoconductive bone substitute (BS) scaffold. Iliac bone marrow and mandibular periosteum were frequently reported sources of MSCs. In vitro culture of MSCs took between 12 days and 1.5 months. A range of autogenous, allogeneic, xenogeneic, and alloplastic scaffolds was identified. Bovine bone mineral scaffold was frequently reported with favorable outcomes, while polylactic-polyglycolic acid copolymer (PLGA) scaffold resulted in graft failure in three studies. The combination of MSCs and BS resulted in outcomes similar to autogenous bone (AB) and BS. Three RCTs and one controlled trial reported significantly greater bone formation in cell-based than conventionally grafted sites after 3 to 8 months. CONCLUSIONS: Based on limited controlled evidence at a moderate-to-high risk of bias, cell-based approaches are comparable, if not superior, to current evidence-based bone grafting methods, with a significant advantage of avoiding AB harvesting. Future clinical trials should additionally evaluate patient-based outcomes and the time-/cost effectiveness of these approaches. PMID- 23815468 TI - Genomic distribution of SINEs in Entamoeba histolytica strains: implication for genotyping. AB - BACKGROUND: The major clinical manifestations of Entamoeba histolytica infection include amebic colitis and liver abscess. However the majority of infections remain asymptomatic. Earlier reports have shown that some E. histolytica isolates are more virulent than others, suggesting that virulence may be linked to genotype. Here we have looked at the genomic distribution of the retrotransposable short interspersed nuclear elements EhSINE1 and EhSINE2. Due to their mobile nature, some EhSINE copies may occupy different genomic locations among isolates of E. histolytica possibly affecting adjacent gene expression; this variability in location can be exploited to differentiate strains. RESULTS: We have looked for EhSINE1- and EhSINE2-occupied loci in the genome sequence of Entamoeba histolytica HM-1:IMSS and searched for homologous loci in other strains to determine the insertion status of these elements. A total of 393 EhSINE1 and 119 EhSINE2 loci were analyzed in the available sequenced strains (Rahman, DS4 868, HM1:CA, KU48, KU50, KU27 and MS96-3382. Seventeen loci (13 EhSINE1 and 4 EhSINE2) were identified where a EhSINE1/EhSINE2 sequence was missing from the corresponding locus of other strains. Most of these loci were unoccupied in more than one strain. Some of the loci were analyzed experimentally for SINE occupancy using DNA from strain Rahman. These data helped to correctly assemble the nucleotide sequence at three loci in Rahman. SINE occupancy was also checked at these three loci in 7 other axenically cultivated E. histolytica strains and 16 clinical isolates. Each locus gave a single, specific amplicon with the primer sets used, making this a suitable method for strain typing. Based on presence/absence of SINE and amplification with locus-specific primers, the 23 strains could be divided into eleven genotypes. The results obtained by our method correlated with the data from other typing methods. We also report a bioinformatic analysis of EhSINE2 copies. CONCLUSIONS: Our results reveal several loci with extensive polymorphism of SINE occupancy among different strains of E. histolytica and prove the principle that the genomic distribution of SINEs is a valid method for typing of E. histolytica strains. PMID- 23815470 TI - Induction and suppression of PEN3 focal accumulation during Pseudomonas syringae pv. tomato DC3000 infection of Arabidopsis. AB - The pleiotropic drug resistance (PDR) proteins belong to the super-family of ATP binding cassette (ABC) transporters. AtPDR8, also called PEN3, is required for penetration resistance of Arabidopsis to nonadapted powdery mildew fungi. During fungal infection, plasma-membrane-localized PEN3 is concentrated at fungal entry sites, as part of the plant's focal immune response. Here, we show that the pen3 mutant is compromised in resistance to the bacterial pathogen Pseudomonas syringae pv. tomato DC3000. P. syringae pv. tomato DC3000 infection or treatment with a flagellin-derived peptide, flg22, induced strong focal accumulation of PEN3-green fluorescent protein. Interestingly, after an initial induction of PEN3 accumulation, P. syringae pv. tomato DC3000 but not the type-III-secretion deficient mutant hrcC could suppress PEN3 accumulation. Moreover, transgenic overexpression of the P. syringae pv. tomato DC3000 effector AvrPto was sufficient to suppress PEN3 focal accumulation in response to flg22. Analyses of P. syringae pv. tomato DC3000 effector deletion mutants showed that individual effectors, including AvrPto, appear to be insufficient to suppress PEN3 accumulation when delivered by bacteria, suggesting a requirement for a combined action of multiple effectors. Collectively, our results indicate that PEN3 plays a positive role in plant resistance to a bacterial pathogen and show that focal accumulation of PEN3 protein may be a useful cellular response marker for the Arabidopsis-P. syringae interaction. PMID- 23815471 TI - In vitro and in vivo characterization of porcine acellular dermal matrix for gingival augmentation procedures. AB - BACKGROUND AND OBJECTIVE: Recently, porcine acellular dermal matrix (PADM) has been proposed as a possible alternative to autogenous grafts in periodontal plastic surgery. The aim of the present study was to investigate the in vitro responses of four different oral cell lines cultured on a novel PADM. Furthermore, tissue reaction to PADM was evaluated histologically after subcutaneous implantation in mice. MATERIAL AND METHODS: Human gingival fibroblasts (HGF), human osteoblast-like cells, human umbilical vein endothelial cells and human oral keratinocytes (HOK) were cultured and transferred on to the PADM. A tissue culture polystyrene surface served as the control. The viability of all tested cell lines on PADM was measured by using the 3-(4,5-dimethylthiazol 2-yl)-2,5-diphenyl tetrazolium bromide colorimetric assay and PrestoBlue((r)) reagent. The ToxiLight((r)) assay was performed to analyze the effect of PADM on adenylate kinase release. PADM was implanted into nude mice subcutaneously and subjected to histological analysis after 21 d. RESULTS: Using 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide colorimetric assays, all tested cell lines cultured on PADM demonstrated a significant increase of viability compared to the control group (each p < 0.001) with the exception of HGF and HOK after 3 d (each p > 0.05). According to the PrestoBlue((r)) analysis, all cell lines demonstrated a significant increase of viability compared to the control group at the particular points of measurement after 18 h (HGF p < 0.01; human osteoblast-like cells, human umbilical vein endothelial cells, HOK each p < 0.001). No significant cytotoxic effects of PADM on the tested cell lines could be observed, as assessed by changes in adenylate kinase release. Subcutaneous implantation of PADM into nude mice demonstrated good integration with surrounding tissues and significant revascularization of its collagen structure. CONCLUSION: Overall, the results suggest that PADM is a promising substitute for autogenous soft tissue grafts in periodontal surgery. PMID- 23815473 TI - A new antibacterial lipopeptide found by UPLC-MS from an actinomycete Streptomyces sp. HCCB10043. AB - It is an attractive and interesting thing for us to mine the diversity of microbial metabolites by means of ultra performance liquid chromatography tandem quadrupole and time of flight high-resolution mass spectrometry. Through this method, two trace compounds, a new lipopeptide, named arylomycin A6 (1), and a known lipopeptide (arylomycin A5, 2) were found and isolated from an actinomycete Streptomyces parvus HCCB10043. The structure of the new lipopeptide was elucidated by a combination of 1D, 2D NMR (correlation spectroscopy, heteronuclear multiple quantum correlation and heteronuclear multiple bond coherence) techniques, high-resolution electrospray ionization mass spectrometry and MS/MS spectrometry and fatty acid analyses. Arylomycin A6 exhibited antibacterial activity against Staphylococcus epidermidis HCCB20256 with the minimum inhibitory concentration of 1 MUg/mL. Till now, arylomycins are the third series of active secondary metabolites we found in S. parvus HCCB10043. The results strongly support and encourage the studies for mining trace natural active products from microorganisms like Streptomyces. PMID- 23815472 TI - Impact of a tenofovir disoproxil fumarate plus ritonavir-boosted protease inhibitor-based regimen on renal function in HIV-infected individuals: a prospective, multicenter study. AB - BACKGROUND: The aim of this study was to investigate the impact of a tenofovir disoproxil fumarate (TDF) plus ritonavir-boosted protease inhibitor (PI/r) regimen on renal function in Chinese HIV-infected patients. METHODS: Seventy-five HIV-1 infected patients failing first-line antiretroviral therapy (ART) comprised the TDF+PI/r group. Seventy-five HIV-1 infected patients matched for gender, age, and renal function made up the control. All subjects completed follow-up visits over 48 weeks. CD4 cell count, plasma HIV-1 viral load, and urine protein level were assessed at the trial start (baseline, week 0) and at week 48. The serum creatinine and estimated glomerular filtration rate (eGFR) were monitored at each follow-up point. Change in eGFR from baseline to week 48 was also compared. RESULTS: Compared to control, the TDF+PI/r group exhibited higher levels of serum creatinine (79 vs. 69.7 MUmol/L, P<0.001) and a lower rate of eGFR (93.0 vs. 101.6 ml/min/1.73 m2, P=0.009) at the end of week 48. Patients treated with TDF+PI/r showed greater decline in eGFR than control (-8.8 vs. 6.4 ml/min/1.73 m2, P<0.001). Compared to baseline renal function of the control group, the TDF+PI/r group exhibited a greater median decline in eGFR at the end of week 48 (P<0.001). CONCLUSIONS: We found that a TDF+PI/r based ART regimen resulted in greater renal function decline over 48 weeks. Therefore, renal function should be monitored especially when TDF is used in combination with PI/r. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00872417. PMID- 23815474 TI - VIRGO: visualization of A-to-I RNA editing sites in genomic sequences. AB - BACKGROUND: RNA Editing is a type of post-transcriptional modification that takes place in the eukaryotes. It alters the sequence of primary RNA transcripts by deleting, inserting or modifying residues. Several forms of RNA editing have been discovered including A-to-I, C-to-U, U-to-C and G-to-A. In recent years, the application of global approaches to the study of A-to-I editing, including high throughput sequencing, has led to important advances. However, in spite of enormous efforts, the real biological mechanism underlying this phenomenon remains unknown. DESCRIPTION: In this work, we present VIRGO (http://atlas.dmi.unict.it/virgo/), a web-based tool that maps Ato-G mismatches between genomic and EST sequences as candidate A-to-I editing sites. VIRGO is built on top of a knowledge-base integrating information of genes from UCSC, EST of NCBI, SNPs, DARNED, and Next Generations Sequencing data. The tool is equipped with a user-friendly interface allowing users to analyze genomic sequences in order to identify candidate A-to-I editing sites. CONCLUSIONS: VIRGO is a powerful tool allowing a systematic identification of putative A-to-I editing sites in genomic sequences. The integration of NGS data allows the computation of p-values and adjusted p-values to measure the mapped editing sites confidence. The whole knowledge base is available for download and will be continuously updated as new NGS data becomes available. PMID- 23815475 TI - Amino acid sequence variations of signaling lymphocyte activation molecule and mortality caused by morbillivirus infection in cetaceans. AB - Morbillivirus infection is a severe threat to marine mammals. Mass die-offs caused by this infection have repeatedly occurred in bottlenose dolphins (Turiops truncatus) and striped dolphins (Stenella coeruleoalba), both of which belong to the family Delphinidae, but not in other cetaceans. However, it is unknown whether sensitivity to the virus varies among cetacean species. The signaling lymphocyte activation molecule (SLAM) is a receptor on host cells that allows morbillivirus invasion and propagation. Its immunoguloblin variable domain-like (V) region provides an interface for the virus hemagglutinin (H) protein. In this study, variations in the amino acid residues of the V region of 26 cetacean species, covering almost all cetacean genera, were examined. Three-dimensional (3D) models of them were generated in a homology model using the crystal structure of the marmoset SLAM and measles virus H protein complex as a template. The 3D models showed 32 amino acid residues on the interface that possibly bind the morbillivirus. Among the cetacean species studied, variations were found at six of the residues. Bottlenose and striped dolphins have substitutions at five positions (E68G, I74V, R90H, V126I, and Q130H) compared with those of baleen whales. Three residues (at positions 68, 90 and 130) were found to alternate electric charges, possibly causing changes in affinity for the virus. This study shows a new approach based on receptor structure for assessing potential vulnerability to viral infection. This method may be useful for assessing the risk of morbillivirus infection in wildlife. PMID- 23815476 TI - Optimizing EEMCO guidance for the assessment of dry skin (xerosis) for pharmacies. AB - PURPOSE: People with dry skin (xerosis) are common in community pharmacies, but there is no consistent guidance for community pharmacists to evaluate and alleviate dry skin. Through evaluating any difference of the clinical scoring systems of EEMCO guidance between a dermatologist and pharmacists and the efficacy of moisturizers for the treatment of dry skin recommended by community pharmacists, we aim to validate a dry skin guidance through the help of community pharmacists. These results provide insight into how community pharmacists can help patients with dry skin. METHODS: The clinical scoring systems of EEMCO guidance used in this study comprised analog scales, the overall dry skin score (ODS), and the specific symptom sum score (SRRC) system. All pictures of the dry skin scored by pharmacists were visually evaluated by a dermatologist. The efficacy of the moisturizers was determined by the difference of the scales on day 0 and on day 28. RESULTS: In this study, 387 patients with dry skin from 157 community pharmacies were evaluated by pharmacists. Visual scale with divisions, ODS and SRRC that were evaluated by pharmacists on day 0 and day 28 were moderately reliable by a dermatologist. All parameters of dry skin were significantly improved by the moisturizers which were recommended by community pharmacists on day 28. CONCLUSION: Visual scale, ODS and SRRC can be generally measured to evaluate dry skin in community pharmacies with moderate degree of reliability. This finding has possible applications for investigating the assessment of the community pharmacists on clinical scoring system of dry skin and moisturizers. PMID- 23815477 TI - Autoimmune hepatitis in southern Israel: a 15-year multicenter study. AB - OBJECTIVE: In this study we aimed to assess the incidence, prevalence and clinical outcomes of patients with autoimmune hepatitis (AIH) in southern Israel. METHODS: Case-finding methods and population-based administrative data were used to evaluate the epidemiology and prognostic factors of AIH from 1995 to 2010. RESULTS: During the study period, the average annual prevalence and incidence of AIH in southern Israel were 11.0/100000 and 0.67/100000, respectively. We identified 100 AIH cases with a mean age of 47.9 years, including 95 women and five men. Type 1 AIH was found in 77 cases, and liver fibrosis and cirrhosis were found in 73.4% and 22.3% of all patients who underwent liver biopsy. In all, 98 patients were treated with a combination of steroids and azathioprine or steroids alone (prednisone and azathioprine in 71, budesonide and azathioprine in 11, prednisone or budesonide alone in six and ten, respectively). Complete remission was recorded in 56 patients, whereas partial response or failure of treatment was noted in 42 patients. In multivariate analysis the independent predictors of remission were the degree of liver fibrosis (mild vs bridging fibrosis (F3) and cirrhosis [F4]) (P=0.003) and level of albumin (P=0.031). The estimated 1-year and 10-year survival for AIH were 96.5% and 89.7%, respectively. CONCLUSIONS: The prevalence of AIH in Israel is quite similar to that of other European Caucasian populations, with a relatively long-term good prognosis, despite a low rate of response to immunosuppressive therapy. PMID- 23815478 TI - Perceptual learning of speech under optimal and adverse conditions. AB - Humans have a remarkable ability to understand spoken language despite the large amount of variability in speech. Previous research has shown that listeners can use lexical information to guide their interpretation of atypical sounds in speech (Norris, McQueen, & Cutler, 2003). This kind of lexically induced perceptual learning enables people to adjust to the variations in utterances due to talker-specific characteristics, such as individual identity and dialect. The current study investigated perceptual learning in two optimal conditions: conversational speech (Experiment 1) versus clear speech (Experiment 2), and three adverse conditions: noise (Experiment 3a) versus two cognitive loads (Experiments 4a and 4b). Perceptual learning occurred in the two optimal conditions and in the two cognitive load conditions, but not in the noise condition. Furthermore, perceptual learning occurred only in the first of two sessions for each participant, and only for atypical /s/ sounds and not for atypical /f/ sounds. This pattern of learning and nonlearning reflects a balance between flexibility and stability that the speech system must have to deal with speech variability in the diverse conditions that speech is encountered. PMID- 23815479 TI - Tracking by location and features: object correspondence across spatiotemporal discontinuities during multiple object tracking. AB - We examined whether surface feature information is utilized to track the locations of multiple objects. In particular, we tested whether surface features and spatiotemporal information are weighted according to their availability and reliability. Accordingly, we hypothesized that surface features should affect location tracking across spatiotemporal discontinuities. Three kinds of spatiotemporal discontinuities were implemented across five experiments: abrupt scene rotations, abrupt zooms, and a reduced presentation frame rate. Objects were briefly colored across the spatiotemporal discontinuity. Distinct coloring that matched spatiotemporal information across the discontinuity improved tracking performance as compared with homogeneous coloring. Swapping distinct colors across the discontinuity impaired performance. Correspondence by color was further demonstrated by more mis-selected distractors appearing in a former target color than distractors appearing in a former distractor color in the swap condition. This was true even when color never supported tracking and when participants were instructed to ignore color. Furthermore, effects of object color on tracking occurred with unreliable spatiotemporal information but not with reliable spatiotemporal information. Our results demonstrate that surface feature information can be utilized to track the locations of multiple objects. This is in contrast to theories stating that objects are tracked based on spatiotemporal information only. We introduce a flexible-weighting tracking account stating that spatiotemporal information and surface features are both utilized by the location tracking mechanism. The two sources of information are weighted according to their availability and reliability. Surface feature effects on tracking are particularly likely when distinct surface feature information is available and spatiotemporal information is unreliable. PMID- 23815480 TI - Revisiting the innate preference for consonance. AB - The origin of the Western preference for consonance remains unresolved, with some suggesting that the preference is innate. In Experiments 1 and 2 of the present study, 6-month-old infants heard six different consonant/dissonant pairs of stimuli, including those tested in previous research. In contrast to the findings of others, infants in the present study failed to listen longer to consonant stimuli. After 3 minutes of exposure to consonant or dissonant stimuli in Experiment 3, 6-month-old infants listened longer to the familiar stimulus, whether consonant or dissonant. Our findings are inconsistent with innate preferences for consonant stimuli. Instead, the effect of short-term exposure is consistent with the view that familiarity underlies the origin of the Western preference for consonant intervals. PMID- 23815481 TI - Discussing sexual and relationship health with young people in a children's hospital: evaluation of a computer-based resource. AB - AIMS AND OBJECTIVES: To investigate health professionals' evaluation of a computer-based resource designed to improve discussions about sexual and relationship health with young people. BACKGROUND: Evidence suggests that some health professionals can experience discomfort discussing sexual health and relationship issues with young people. Professionals within hospital settings should have the knowledge, competencies and skills to be able to ask young people sexual health questions and provide accurate sexual health education. Despite some educational material being available for community and adult services, there are no resources available, which are directly relevant to holding opportunistic discussions with young people within an acute children's hospital. DESIGN: A descriptive survey design. METHODS: One hundred and fourteen health professionals from a children's hospital in the UK were involved in evaluating a computer-based resource. All completed an online questionnaire survey comprising of closed and open questions. RESULTS: The health professionals reported that the computer based resource had a positive influence on their knowledge and clinical practice. The videos as well as the concise nature of the resource were evaluated highly. Learning was facilitated by professionals being able to control their learning through rerunning and accessing the resource on numerous occasions. CONCLUSIONS: An engaging, accessible computer-based resource has the capability to positively impact on health professionals' knowledge of, and skills in, starting and holding sexual health conversations with young people accessing a children's hospital. RELEVANCE TO CLINICAL PRACTICE: Health professionals working with children and young people value accessible, relevant and short computer-based training. This can facilitate knowledge and skill acquisition despite variation in working patterns. Improving the knowledge and skills of professionals working with young people to facilitate appropriate yet opportunistic sexual health discussions is important within the public health agenda. PMID- 23815482 TI - A 5-year retrospective study on Replace Select Tapered dental implants. AB - BACKGROUND: Long-term data regarding survival and crestal bone loss for Replace Select Tapered implants (Nobel Biocare AB, Gothenburg, Sweden) are lacking. PURPOSE: The study aims to present the 5-year outcomes from a retrospective analysis of Replace Select Tapered implants placed and restored in consecutive patients. MATERIALS AND METHODS: A total of 88 consecutive patients (32 male, 56 female, mean age 65 +/- 12 years) treated by one clinician (PP) were clinically and radiographically evaluated during at least 5 years of function. A total of 271 dental implants (Replace Select Tapered, Nobel Biocare AB) with an oxidized surface (TiUnite, Nobel Biocare AB) had been placed in both jaws (228 in the maxilla, 43 in the mandible). The majority of implants were placed in healed sites (n = 244), while 27 implants were immediately placed in extraction sockets. The majority of implants (n = 262) healed for 3 to 4 months prior to loading, and nine implants were immediately loaded. A total of 121 implant-supported restorations were delivered; 42 single tooth replacements, 61 fixed partial bridges, 14 fixed full bridges, and 4 fixed partial implant-tooth connected bridges. The marginal bone level was measured in intraoral radiographs taken after surgery (baseline), and after 1, 2, 3, 4, and 5 years. RESULTS: Fifty-one patients with 160 implants were followed throughout the study. One implant failed at healing abutment connection 4 months after insertion, resulting in a cumulative survival rate of 99.6%. The average crestal bone loss was 0.9 +/- 1.6 mm after 1 year and 0.1 mm +/- 2.4 after 5 years. There were 14.8% of measured implants that showed more than 2 mm and 5.2% more than 3 mm bone loss after 5 years, with no progression since the 1-year examination. One patient (2.0%) treated with six implants presented with significant crestal bone loss and recurrent peri-implant purulent infections at all implants. CONCLUSION: The present retrospective 5-year study showed high survival rate and steady crestal bone levels for Replace Select Tapered dental implants. PMID- 23815484 TI - Atrial electromechanical delay measured by tissue Doppler imaging in patients with secundum atrial septal defects. PMID- 23815483 TI - Genome-wide identification and expression analysis of calcium-dependent protein kinase in maize. AB - BACKGROUND: Calcium-dependent protein kinases (CDPKs) have been shown to play important roles in various physiological processes, including plant growth and development, abiotic and biotic stress responses and plant hormone signaling in plants. RESULTS: In this study, we performed a bioinformatics analysis of the entire maize genome and identified 40 CDPK genes. Phylogenetic analysis indicated that 40 ZmCPKs can be divided into four groups. Most maize CDPK genes exhibited different expression levels in different tissues and developmental stages. Twelve CDPK genes were selected to respond to various stimuli, including salt, drought and cold, as well as ABA and H2O2. Expression analyses suggested that maize CDPK genes are important components of maize development and multiple transduction pathways. CONCLUSION: Here, we present a genome-wide analysis of the CDPK gene family in maize for the first time, and this genomic analysis of maize CDPK genes provides the first step towards a functional study of this gene family in maize. PMID- 23815486 TI - Pulmonary arterial hypertension versus pulmonary venous hypertension: how much information can contrast Doppler echocardiography provide? PMID- 23815487 TI - Reply: To PMID 23227919. PMID- 23815488 TI - Dobutamine stress echocardiography and Takotsubo syndrome: could milder forms of this pathology confound the diagnostic value of the test? PMID- 23815489 TI - Reply: To PMID 23305309. PMID- 23815490 TI - Epicardial fat thickness should be evaluated with other inflammatory markers and cardiovascular risk factors. PMID- 23815491 TI - Reply: To PMID 23305488. PMID- 23815495 TI - Pitfalls in the measurement of skin autofluorescence to determine tissue advanced glycosylation content in haemodialysis patients. AB - AIM: Skin autofluoresence has been advocated as a quick non-invasive method of measuring tissue advanced glycosylation end products (AGE), which have been reported to correlate with cardiovascular risk in the dialysis patient. Most studies have been performed in patients from a single racial group, and we wanted to look at the reliability of skin autofluoresence measurements in a multiracial dialysis population and whether results were affected by haemodialysis. METHODS: We measured skin autofluoresence three times in both forearms of 139 haemodialysis patients pre-dialysis and 36 post-dialysis. RESULTS: One hundred and thirty-nine patients, 62.2% male, 35.3% diabetic, 59% Caucasoid, mean age 65.5 +/- 15.2 years were studied. Reproducibility of measurements between the 1st and 2nd measurements was very good (r(2 ) = 0.94, P < 0.001, Bland Altman bias 0.05, confidence limits -0.02 to 0.04). However, skin autoflourescence measurements were not possible in one forearm in 8.5% Caucasoids, 25% Far Asian, 28% South Asians and 75% African or Afro Caribbean (P < 0.001). Mean skin autofluorescence in the right forearm was 3.3 +/- 0.74 arbitrary units (AU) and left forearm 3.18 +/- 0.82 AU pre-dialysis, and post-dialysis there was a fall in those patients dialysing with a left sided arteriovenous fistula (left forearm pre 3.85 +/- 0.72 vs post 3.36 +/- 0.55 AU, P = 0.012). CONCLUSION: Although skin autofluorescence is a relatively quick non-invasive method of measuring tissue AGE and measurements were reproducible, it was often not possible to obtain measurements in patients with highly pigmented skin. To exclude potential effects of arteriovenous fistulae we would suggest that measurements are made in the non fistula forearm pre-dialysis. PMID- 23815497 TI - Modeling cascading diffusion of new energy technologies: case study of residential solid oxide fuel cells in the US and internationally. AB - Subsidy programs for new energy technologies are motivated by the experience curve: increased adoption of a technology leads to learning and economies of scale that lower costs. Geographic differences in fuel prices and climate lead to large variability in the economic performance of energy technologies. The notion of cascading diffusion is that regions with favorable economic conditions serve as the basis to build scale and reduce costs so that the technology becomes attractive in new regions. We develop a model of cascading diffusion and implement via a case study of residential solid oxide fuel cells (SOFCs) for combined heating and power. We consider diffusion paths within the U.S. and internationally. We construct market willingness-to-pay curves and estimate future manufacturing costs via an experience curve. Combining market and cost results, we find that for rapid cost reductions (learning rate = 25%), a modest public subsidy can make SOFC investment profitable for 20-160 million households. If cost reductions are slow however (learning rate = 15%), residential SOFCs may not become economically competitive. Due to higher energy prices in some countries, international diffusion is more favorable than domestic, mitigating much of the uncertainty in the learning rate. PMID- 23815496 TI - Cross-reactivities between human IgMs and the four serotypes of dengue virus as probed with artificial homodimers of domain-III from the envelope proteins. AB - BACKGROUND: Dengue fever is the most important vector-borne viral disease. Four serotypes of dengue virus, DENV1 to DENV4, coexist. Infection by one serotype elicits long-lasting immunity to that serotype but not the other three. Subsequent infection by a different serotype is a risk factor for severe dengue. Domain III (ED3) of the viral envelope protein interacts with cell receptors and contains epitopes recognized by neutralizing antibodies. We determined the serotype specificity and cross-reactivity of human IgMs directed against ED3 by using a well-characterized collection of 90 DENV-infected and 89 DENV-uninfected human serums. METHODS: The recognitions between the four serotypes of ED3 and the serums were assayed with an IgM antibody-capture ELISA (MAC-ELISA) and artificial homodimeric antigens. The results were analyzed with Receiving Operator Characteristic (ROC) curves. RESULTS: The DENV-infected serums contained IgMs that reacted with one or several ED3 serotypes. The discrimination by ED3 between serums infected by the homotypic DENV and uninfected serums varied with the serotype in the decreasing order DENV1 > DENV2 > DENV3 > DENV4. The ED3 domain of DENV1 gave the highest discrimination between DENV-infected and DENV-uninfected serums, whatever the infecting serotype, and thus behaved like a universal ED3 domain for the detection of IgMs against DENV. Some ED3 serotypes discriminated between IgMs directed against the homotypic and heterotypic DENVs. The patterns of cross-reactivities and discriminations varied with the serotype. CONCLUSIONS: The results should help better understand the IgM immune response and protection against DENV since ED3 is widely used as an antigen in diagnostic assays and an immunogen in vaccine candidates. PMID- 23815498 TI - Green synthetic, multifunctional hybrid micelles with shell embedded magnetic nanoparticles for theranostic applications. AB - The objective of this study is to design and develop a green-synthetic, multifunctional hybrid micelles with shell embedded magnetic nanoparticles for theranostic applications. The hybrid micelles were engineered based on complex micelles self-assembled from amphiphilic block copolymers Pluronic F127 and peptide-amphiphile (PA) pal-AAAAHHHD. The reason to choose PA is due to its amphiphilic character and the coordination capability for Fe(3+) and Fe(2+). The PA incorporation allows the in situ growth of the magnetic iron oxide nanoparticles onto the complex micelles, to yield the nanostructures with shell embedded magnetic nanoparticles at an ambient condition without any organic solvents. The anticancer drug doxorubicin (DOX) can be efficiently loaded into the hybrid micelles. Interestingly, the magnetic nanoparticles anchored on the shell were found to significantly retard the DOX release behavior of the drug loaded hybrid micelles. It was proposed that a cross-linking effect of the shell by magnetic nanoparticles is a key to underlie the above intriguing phenomenon, which could enhance the stability and control the drug diffusion of the hybrid micelles. Importantly, in vitro and in vivo magnetic resonance imaging (MRI) revealed the potential of these hybrid micelles to be served as a T2-weighted MR imaging contrast enhancer for clinical diagnosis. PMID- 23815499 TI - 3D hollow nanostructures as building blocks for multifunctional plasmonics. AB - We present an advanced and robust technology to realize 3D hollow plasmonic nanostructures which are tunable in size, shape, and layout. The presented architectures offer new and unconventional properties such as the realization of 3D plasmonic hollow nanocavities with high electric field confinement and enhancement, finely structured extinction profiles, and broad band optical absorption. The 3D nature of the devices can overcome intrinsic difficulties related to conventional architectures in a wide range of multidisciplinary applications. PMID- 23815500 TI - Oxidized fatty acids: A potential pathogenic link between fatty liver and type 2 diabetes in obese adolescents? AB - In this study, we sought to investigate the putative association of the oxidized metabolites derived from linoleic acid (OXFAs) with pediatric nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). We studied 80 obese adolescents (age 13.3 +/- 3.31 years; body mass index 33.0 +/- 6.79 kg/m(2)), who underwent an oral glucose tolerance test, a magnetic resonance imaging (MRI) to measure the hepatic fat content, and the measurement of OXFAs and caspase-cleaved Citokeratin18 fragment (CK-18), a robust biomarker of liver injury. In this study, we show that only in subjects with hepatic steatosis, the OXFAs are associated with the CK-18 and that this association is modulated by the PNPLA3 rs738409 variant. We also show that most of the OXFAs are associated with a lower insulin secretion and that adolescents with T2D have higher levels of OXFAs than subjects with impaired or normal glucose tolerance. These observations lead to the hypothesis that the OXFAs may be the pathogenic link between liver injury and T2D and that the novel therapeutic opportunities targeting the OXFAs are possible in adolescents with early-onset NAFLD and T2D. PMID- 23815501 TI - Detection and measurement of artificial periapical lesions by cone-beam computed tomography. AB - AIM: To test the ability of periapical radiography (PA) and cone-beam computed tomography (CBCT) to determine the presence/absence of periapical lesions and examine the reliability of volumetric measurements of periapical lesions on CBCT scans. METHODOLOGY: After tooth extractions in human mandibles, bone defects were cut at the base of extraction sockets to mimic periapical bone lesions. The teeth were then returned into the extraction sockets. Sixty-three roots of anterior teeth, premolars and molars with artificial periapical lesions and 37 roots without lesions were examined with PA and CBCT. Presence/absence of periapical lesion was noted. The CBCT-based volume of each lesion (Vct) was measured using Amira software 5.4 (Visage Imaging GmbH, Berlin, Germany). A replica of each lesion was created using silicone impression material, and the volume of the replica was measured using a water displacement method, representing the physical volume of the lesion (Vp). Regression analysis was used to test the correlation between the Vp and Vct values. RESULTS: The positive and negative predictive values and accuracy for CBCT in diagnosing periapical lesions were all 1, compared with 1, 0.64 and 0.79 for PA diagnosis. Twenty-one (33%) lesions were undetected by PA. The Vp (21.5 +/- 11.0 mm(3) ) and Vct (21.4 +/- 11.5 mm(3) ) values of 63 lesions were highly correlated (R(2) = 96.9%, P < 0.001). CONCLUSION: Cone-beam computed tomography is more accurate than PA in diagnosing periapical lesions associated with mandibular teeth. The volumes of artificial mandibular periapical lesions were accurately measured with CBCT data. PMID- 23815502 TI - A modified rat model of exercise-induced renal injury and the protective effects of losartan and yishen huanji decoction. AB - We modified a rat model of exercise-induced renal injury by forcing 4-week-old male Sprague-Dawley (SD) rats (the MOD group) running on a treadmill for 8 weeks under conditions of high temperature, high humidity, bearing weight with some additional stimulations. Compared with the control (CON) group, the traditional running group (TRA), the losartan potassium intervention running group (LOS) and the traditional Chinese medicine "Yishen Huanji Decoction" intervention running group (CHI), the urinary, biochemistry indicators, the concentrations of angiotensin II (Ang II) were significantly higher in the MOD group than in the TRA group. After 3--4 weeks and 8-week training program, the 24-h urine protein and NAG levels in the LOS group and CHI group were lower than in the MOD group respectively. The BUN and SCr levels in the CHI group were lower than in the MOD group and higher than in the LOS group. AngII concentrations in the LOS group were higher than the MOD group. The modified rat renal injury model induced greater lesions than the traditional model. High temperatures, humidity and weight bearing were critical factors to induce Ang II activation, which can aggravate renal injury. Losartan potassium and the "Yishen Huanji Decoction" can protect against renal injury. PMID- 23815503 TI - GAM-NGS: genomic assemblies merger for next generation sequencing. AB - BACKGROUND: In recent years more than 20 assemblers have been proposed to tackle the hard task of assembling NGS data. A common heuristic when assembling a genome is to use several assemblers and then select the best assembly according to some criteria. However, recent results clearly show that some assemblers lead to better statistics than others on specific regions but are outperformed on other regions or on different evaluation measures. To limit these problems we developed GAM-NGS (Genomic Assemblies Merger for Next Generation Sequencing), whose primary goal is to merge two or more assemblies in order to enhance contiguity and correctness of both. GAM-NGS does not rely on global alignment: regions of the two assemblies representing the same genomic locus (called blocks) are identified through reads' alignments and stored in a weighted graph. The merging phase is carried out with the help of this weighted graph that allows an optimal resolution of local problematic regions. RESULTS: GAM-NGS has been tested on six different datasets and compared to other assembly reconciliation tools. The availability of a reference sequence for three of them allowed us to show how GAM NGS is a tool able to output an improved reliable set of sequences. GAM-NGS is also a very efficient tool able to merge assemblies using substantially less computational resources than comparable tools. In order to achieve such goals, GAM-NGS avoids global alignment between contigs, making its strategy unique among other assembly reconciliation tools. CONCLUSIONS: The difficulty to obtain correct and reliable assemblies using a single assembler is forcing the introduction of new algorithms able to enhance de novo assemblies. GAM-NGS is a tool able to merge two or more assemblies in order to improve contiguity and correctness. It can be used on all NGS-based assembly projects and it shows its full potential with multi-library Illumina-based projects. With more than 20 available assemblers it is hard to select the best tool. In this context we propose a tool that improves assemblies (and, as a by-product, perhaps even assemblers) by merging them and selecting the generating that is most likely to be correct. PMID- 23815504 TI - Links between Schwann cells and melanocytes in development and disease. AB - Melanocytes are pigment-producing cells that reside in the skin, eyes, ears, heart, and central nervous system meninges of mammals. Schwann cells are glial cells, which closely associate with peripheral nerves, myelinating, and sheathing them. Melanocytes and Schwann cells both arise from the neural crest during development, and some melanocytes arise directly from Schwann cell precursors lining developing spinal nerves. In this review, we explore the connections between melanocytes and Schwann cells in development and transformation. PMID- 23815505 TI - Chemometric classification of apple juices according to variety and geographical origin based on polyphenolic profiles. AB - To characterize and classify apple juices according to apple variety and geographical origin on the basis of their polyphenol composition, the polyphenolic profiles of 58 apple juice samples belonging to 5 apple varieties and from 6 regions in Shaanxi province of China were assessed. Fifty-one of the samples were from protected designation of origin (PDO) districts. Polyphenols were determined by high-performance liquid chromatography coupled to photodiode array detection (HPLC-PDA) and to a Q Exactive quadrupole-Orbitrap mass spectrometer. Chemometric techniques including principal component analysis (PCA) and stepwise linear discriminant analysis (SLDA) were carried out on polyphenolic profiles of the samples to develop discrimination models. SLDA achieved satisfactory discriminations of apple juices according to variety and geographical origin, providing respectively 98.3 and 91.2% success rate in terms of prediction ability. This result demonstrated that polyphenols could served as characteristic indices to verify the variety and geographical origin of apple juices. PMID- 23815506 TI - Quadrivalent meningococcal serogroups A, C, W, and Y tetanus toxoid conjugate vaccine (MenACWY-TT): a review. AB - INTRODUCTION: Meningococcal disease poses serious health risks globally. The six Neisseria meningitidis serogroups responsible for most of the disease burden are A, B, C, W, X and Y. The case fatality rate remains high worldwide and prevention by vaccination remains the best strategy. Because polysaccharide vaccines are poorly immunogenic in young children, conjugated vaccines were developed to overcome this drawback. The quadrivalent meningococcal conjugate vaccine (MenACWY TT), comprising the serogroups A, C, W and Y conjugated to tetanus toxoid carrier protein (marketed under the trade name Nimenrix TM), is the first quadrivalent vaccine to be approved in Europe as a single dose for ages 12 months and in Canada for ages 12 months to 55 years. AREAS COVERED: This review addresses the limitations posed by polysaccharide vaccines, compares them with the MenACWY-TT conjugated alternative, and focuses on the clinical studies that investigate the immunogenicity and reactogenicity of MenACWY-TT in various age groups and its co administration with other vaccines compatible with each age group. EXPERT OPINION: Evidence suggests that MenACWY-TT has a good immunogenicity profile across a broad age range including toddlers, children, adolescents, and adults. It also has an acceptable safety profile and is well tolerated when administered with other vaccines. PMID- 23815508 TI - Using smartphone cameras to photograph microscopic dermatologic images. PMID- 23815507 TI - Enhanced and persistent levels of interleukin (IL)-17+ CD4+ T cells and serum IL 17 in patients with early inflammatory arthritis. AB - Prognosis of patients with early inflammatory arthritis (EIA) is highly variable. The aim of this study was to compare, longitudinally and cross-sectionally, the levels of cytokine-expressing cells in peripheral blood (PB) from patients with EIA to those in established rheumatoid arthritis (RA) and healthy controls (HC). PB mononuclear cells from HC (n = 30), patients with EIA (n = 20) or RA (n = 38) were stimulated with phorbol myristate acetate (PMA)/ionomycin for 3 h, and stained for cell markers and cytokines. Serum cytokines and chemokines were measured by Luminex. Patients with EIA were reassessed at 6 and 12 months. The percentage of interleukin (IL)-17+ interferon (IFN)-gamma- CD4+ T cells [T helper type 17 (Th17)] was increased in RA and EIA versus HC. Serum IL-1beta, IL-2, IL-4 IL-17 and macrophage inflammatory protein (MIP)-1alpha were increased in RA and EIA versus HC. IL-1Ra, IL-15 and IFN-alpha were increased in EIA versus HC. IL-6 and tumour necrosis factor (TNF)-alpha was increased in RA but not EIA versus HC. Disease activity scores in EIA patients improved over 12 months' treatment. Th17 percentage at baseline was correlated with both rheumatoid factor (RF) titre and functional deficit at 12 months. Baseline levels of serum granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6 and IL-8 were correlated with Larsen score at 12 months. There were no significant changes in cytokine-expressing CD4+ T cells over time, although the percentage of IL-6+monocytes increased. IL-17+ CD4+ T cells and serum IL-17 levels are increased in EIA. IL-6-expressing monocytes increase during the first year of disease, irrespective of disease modifying anti-rheumatic drug (DMARD) therapy. We observed incomplete clinical responses, suggesting EIA patients need more intensive early therapy. PMID- 23815509 TI - Bone mineral changes during pregnancy and lactation. AB - OBJECTIVE: Significant calcium transfer from the mother to the fetus and infant occurs during pregnancy and lactation, theoretically placing the mother at an increased risk for osteoporosis. The relationship between pregnancy, breast feeding and low bone mass is controversial. In this study we aimed to elucidate the relationship between pregnancy, breast-feeding and bone mass in third trimester pregnants, at least 3 months lactating mothers, and healthy young nulliporous women by using quantitative ultrasonometry. METHOD: The study included 120 women divided in three groups: third trimester pregnants, at least 3 months lactating mothers and healthy young nulliporous women. Demographics, total lactation time, number of pregnancies, births and miscarriages-abortions were recorded. Study groups underwent quantitative ultrasonometry measurement at midtibial shaft. Values of the ultrasonometry variables were calculated and compared for groups. RESULTS: There were no significant differences among the groups with respect to parameters of age, age at menarche, smoking, alcohol intake and physical exercise in all of the three groups (p > 0.05). No differences were found among the three groups in analyzed variables, when comparing SOS, T- and Z-scores mid-tibial shaft quantitative ultrasonometry. CONCLUSION: No statistically significant associations were found between ultrasonometry variables and pregnancy, breast-feeding or nulliparity. PMID- 23815510 TI - Determination of vaccination status of pregnant women during pregnancy and the affecting factors. AB - AIMS AND OBJECTIVES: To determine the vaccination status of pregnant women during pregnancy and factors affecting their vaccination. BACKGROUND: Immunisation provided through vaccination is one of the most effective ways to reduce or prevent the risks of disease, disability and death. Maternal and newborn health may be protected and morbidity may be decreased through vaccinating pregnant women when necessary. DESIGN: This was a descriptive and cross-sectional survey. METHODS: This study was conducted in a university hospital in Ankara, Turkey, between 01 March and 31 May 2010. The study was carried out with 198 healthy pregnant women who had completed the 26th week of gestation. Data were collected using the data collection form composed of questions enquiring about the demographic and obstetric features of pregnant women and whether or not they knew that vaccinations could be given during pregnancy, and which vaccines could be used during pregnancy, which vaccine/vaccines they had previously received and the reasons for having been vaccinated or not. RESULTS: Approximately half of the participants had received at least one of the vaccines that may be used in pregnancy (52.0%). The pregnant women received vaccinations for tetanus (47.0%), H1N1 (9.1%), seasonal influenza (3.0%) and hepatitis B (0.5%), respectively. The pregnant women who had been educated about vaccinations had been vaccinated at a statistically significantly higher rate compared with those who had not. CONCLUSION: This study revealed that pregnant women's knowledge about the required vaccines during pregnancy affected their behaviour towards vaccination. Acquiring knowledge about vaccines that may be used during pregnancy from health personnel is effective to increase vaccination. This result may be interpreted as 'acquired information affects behaviour towards vaccination'. RELEVANCE TO CLINICAL PRACTICE: Providing information about immunisation to pregnant women at the antenatal clinic is important in terms of maternal and newborn health. Nurses and midwives working in the antenatal field should be sufficiently educated about immunisation. PMID- 23815511 TI - Prevalence of Type 2 diabetes and pre-diabetes among overweight or obese children in Tianjin, China. AB - AIMS: To determine the prevalence of Type 2 diabetes and pre-diabetes and their risk factors among overweight or obese school children aged 7-18 years in Tianjin, China. METHODS: A cross-sectional survey in a representative sample of overweight/obese children or adolescents in Tianjin was conducted from May to August 2010 using a stratified cluster sampling method. A two-step screening, which was conducted to identify Type 2 diabetes and pre-diabetes in these children, consisted of a fasting capillary glucose test and a standard 2-h oral glucose tolerance test. Subjects who had fasting capillary glucose >= 5.6 mmol/l were invited for an oral glucose tolerance test. The study used Chinese criteria for classification of obesity/overweight and World Health Organization criteria for diabetes/pre-diabetes. RESULTS: A total of 3173 children participated in the survey, with a response rate of 99.0%. Of the children, 13.0% (n = 413) were overweight and 15.4% (n = 490) were obese. Among these 903 children, 727 (80.5%) agreed to and underwent the diabetes screening and two (0.28%) were diagnosed as having Type 2 diabetes, six (0.83%) to have impaired fasting glucose, 16 (2.20%) to have impaired glucose tolerance and two (0.28%) to have both. The prevalence of Type 2 diabetes and pre-diabetes was 0.28% (95% CI 0.08-1.00%) and 3.30% (95% CI 2.23-4.87%), respectively. Abdominal obesity and motorized commuting were associated with Type 2 diabetes or pre-diabetes among overweight or obese boys, while high birthweight was associated with Type 2 diabetes or pre-diabetes among girls. CONCLUSIONS: Type 2 diabetes among school-aged children was still low in Tianjin, China. However, Type 2 diabetes-related factors were very common, especially overweight and obesity. PMID- 23815512 TI - Exogenous social identity cues differentially affect the dynamic tracking of individual target faces. AB - We report on an experiment to investigate the top-down effect of exogenous social identity cues on a multiple-identity tracking task, a paradigm well suited to investigate the processes of binding identity to spatial locations. Here we simulated an eyewitness event in which dynamic targets, all to be tracked with equal effort, were identified from among a "crowd" of 8 faces, as an assailant, bystander, policeman, and victim. Even in such a simplistic paradigm, where no actual assault was witnessed and no consequences were associated with the task, results demonstrated a significant attentional bias, namely that participants were significantly better at tracking the assailant, bystander, and policeman than they were the victim. We found no difference in accurate recall based on the use of text or face cues and no systematic pattern of response errors. PMID- 23815513 TI - Covert retrieval practice benefits retention as much as overt retrieval practice. AB - Many experiments provide evidence that practicing retrieval benefits retention relative to conditions of no retrieval practice. Nearly all prior research has employed retrieval practice requiring overt responses, but a few experiments have shown that covert retrieval also produces retention advantages relative to control conditions. However, direct comparisons between overt and covert retrieval are scarce: Does covert retrieval-thinking of but not producing responses-on a first test produce the same benefit as overt retrieval on a criterial test given later? We report 4 experiments that address this issue by comparing retention on a second test following overt or covert retrieval on a first test. In Experiment 1 we used a procedure designed to ensure that subjects would retrieve on covert as well as overt test trials and found equivalent testing effects in the 2 cases. In Experiment 2 we replicated these effects using a procedure that more closely mirrored natural retrieval processes. In Experiment 3 we showed that overt and covert retrieval produced equivalent testing effects after a 2-day delay. Finally, in Experiment 4 we showed that covert retrieval benefits retention more than restudying. We conclude that covert retrieval practice is as effective as overt retrieval practice, a conclusion that contravenes hypotheses in the literature proposing that overt responding is better. This outcome has an important educational implication: Students can learn as much from covert self-testing as they would from overt responding. PMID- 23815515 TI - Prevention, detection and management of early chronic kidney disease: a systematic review of clinical practice guidelines. AB - AIM: In response to the increase in Chronic Kidney Disease (CKD) worldwide, several professional organizations have developed clinical practice guidelines to manage and prevent its progression. This study aims to compare the scope, content and consistency of published guidelines on CKD stages I-III. METHODS: Electronic databases of the medical literature, guideline organizations, and the websites of nephrology societies were searched to November 2011. The Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument and textual synthesis was used to appraise and compare recommendations. RESULTS: One consensus statement and 15 guidelines were identified and included. Methodological rigour across guidelines was variable, with average domain scores ranging from 24% to 95%. For detection of CKD, all guidelines recommended estimated glomerular filtration rate measurement, some also recommended serum creatinine and dipstick urinalysis. The recommended protein and albumin creatinine ratios and proteinuria definition thresholds varied (>150-300 mg/day to >500 mg/day). Blood pressure targets ranged (<125/75 to <140/90 mmHg). Angiotensin converting enzyme inhibitor and angiotensin receptor blockers were recommended for hypertension, as combined or as monotherapy. Protein intake recommendations varied (no restriction or 0.75 g/kg per day-1.0 g/kg per day). Salt intake of 6 g/day was recommended by most. Psychosocial support and education were recommended by few but specific strategies were absent. CONCLUSION: CKD guidelines were consistent in scope but were variable with respect to their recommendations, coverage and methodological quality. To promote effective primary and secondary prevention of CKD, regularly updated guidelines that are based on the best available evidence and augmented with healthcare context-specific strategies for implementation are warranted. PMID- 23815514 TI - De novo transcriptome sequencing of axolotl blastema for identification of differentially expressed genes during limb regeneration. AB - BACKGROUND: Salamanders are unique among vertebrates in their ability to completely regenerate amputated limbs through the mediation of blastema cells located at the stump ends. This regeneration is nerve-dependent because blastema formation and regeneration does not occur after limb denervation. To obtain the genomic information of blastema tissues, de novo transcriptomes from both blastema tissues and denervated stump ends of Ambystoma mexicanum (axolotls) 14 days post-amputation were sequenced and compared using Solexa DNA sequencing. RESULTS: The sequencing done for this study produced 40,688,892 reads that were assembled into 307,345 transcribed sequences. The N50 of transcribed sequence length was 562 bases. A similarity search with known proteins identified 39,200 different genes to be expressed during limb regeneration with a cut-off E-value exceeding 10-5. We annotated assembled sequences by using gene descriptions, gene ontology, and clusters of orthologous group terms. Targeted searches using these annotations showed that the majority of the genes were in the categories of essential metabolic pathways, transcription factors and conserved signaling pathways, and novel candidate genes for regenerative processes. We discovered and confirmed numerous sequences of the candidate genes by using quantitative polymerase chain reaction and in situ hybridization. CONCLUSION: The results of this study demonstrate that de novo transcriptome sequencing allows gene expression analysis in a species lacking genome information and provides the most comprehensive mRNA sequence resources for axolotls. The characterization of the axolotl transcriptome can help elucidate the molecular mechanisms underlying blastema formation during limb regeneration. PMID- 23815516 TI - Psychometric properties of the gaze anxiety rating scale: convergent, discriminant, and factorial validity. AB - Fear and avoidance of gaze are two features thought to be associated with problematic social anxiety. Avoidance of eye contact has been linked with such undesirable traits as deceptiveness, insincerity, and lower self-esteem. The Gaze Anxiety Rating Scale (GARS) is a self-report measure designed to assess gaze anxiety and avoidance, but its psychometric properties have only been assessed in one preliminary study. We further investigated psychometric properties of the GARS by assessing convergent and factorial validity. We obtained a two-factor solution: gaze anxiety and avoidance across situations (1) in general (GARS General) and (2) related to dominance communication (GARS-Dominance). The GARS General factor related more strongly to social anxiety than the GARS-Dominance, and convergent validity of the factors was supported by expected relationships with personality and social anxiety variables. Our results indicate that the GARS subscales are psychometrically valid measures of gaze aversion, supporting their use in future study of the relationship between social anxiety and eye contact behavior. PMID- 23815517 TI - Treatment of vitiligo with a chimeric monoclonal antibody to CD20: a pilot study. AB - Five patients with active disseminated vitiligo were given 1g of a chimeric (murine/human) monoclonal antibody to CD20 in a single intravenous infusion and followed-up for 6 months. Three of the patients showed an overt clinical and histological improvement of the disease, one presented slight improvement and the remaining patient showed no changes. Improvement was neither associated with changes in laboratory parameters nor to a specific human leucocyte antigen D related (HLA-DR) phenotype. We believe that these preliminary results are encouraging, and further clinical trials should be undertaken. An important aim should be the finding of a marker with a good response to this therapeutic approach. PMID- 23815518 TI - A combined natural supplement lowers LDL cholesterol in subjects with moderate untreated hypercholesterolemia: a randomized placebo-controlled trial. AB - OBJECTIVE: To investigate the effect of a natural cholesterol-lowering supplement (NCLS) containing red yeast rice, policosanols and artichoke leaf extracts on blood lipid concentrations as well as on safety parameters when given over 16 weeks in 100 volunteers with untreated moderate hypercholesterolemia, in a randomized, double-blind, placebo-controlled trial. RESULTS: Reduction of primary outcome low-density lipoprotein cholesterol [-0.22 g/L (95% confidence interval, CI: -0.31 to -0.12) corresponding to -14.3% from baseline (95% CI: -21.5 to -7.2) compared to placebo], as well as total cholesterol, apolipoprotein B100 and apolipoprotein B100/apolipoprotein A-I ratio, were observed after 16 weeks of supplementation with NCLS. These effects were already observed at Week 4 and 10 of supplementation. No significant changes were observed in high-density lipoprotein, triacylglycerol, creatine kinase, lactate dehydrogenase and coenzyme Q10 levels, as well as in markers of liver and renal function. CONCLUSIONS: The NCLS was effective in reducing low-density lipoprotein cholesterol and apolipoprotein B100 in subjects with moderate hypercholesterolemia, without modifying safety parameters. PMID- 23815519 TI - Bevacizumab in the treatment of hereditary hemorrhagic telangiectasia. AB - INTRODUCTION: Hereditary hemorrhagic telangiectasia (HHT) is a rare multisystem vascular disorder characterized by epistaxis, mucocutaneous telangiectases and visceral arteriovenous malformations predisposing to shunting and hemorrhage. Angiogenesis has been implicated in the pathogenesis of HHT and therefore angiogenesis inhibitors appear to be the most promising agents. A literature search was performed to identify all articles reporting bevacizumab , a recombinant humanized monoclonal antibody that inhibits vascular endothelial growth factor (VEGF). We focused on the HHT pathogenesis, mechanism of action of the drug, its impact on the HHT symptoms and safety profile. AREAS COVERED: Systemic intravenous administration of bevacizumab improves the frequency and intensity of epistaxis, gastrointestinal (GI) bleeding episodes and liver arteriovenous malformations consequences. The safety profile of the systematic administration of the drug appears to be excellent with hypertension as the unique adverse effect reported so far. Its intranasal administration significantly decreases frequency and severity of nosebleeds and blood transfusion requirements. EXPERT OPINION: In the absence of randomized controlled trials in HHT, criteria of selecting patients and formal recommendations for treatment are lacking. For life-threatening epistaxis requiring blood transfusion, topical treatment with bevacizumab may be beneficial. Systemic treatment with bevacizumab is promising in symptomatic patients with organ involvement and life-threatening conditions. PMID- 23815520 TI - Flavor binding: Its nature and cause. AB - The brain binds inputs from multiple senses to enhance our ability to identify key events in the environment. Understanding this process is based mainly on data from the major senses (vision and audition), yet compelling examples of binding occur in other domains. When we eat, in fact taste, smell, and touch combine to form flavor. This process can be so complete that most people fail to recognize that smell contributes to flavor. The flavor percept has other features: (a) it feels located in the mouth, even though smell is detected in the nose and taste on the tongue, and (b) it feels continuous, yet smell is delivered in pulses to the nose during eating. Furthermore, tastes can modify smell perception and vice versa. Current explanations of these binding-related phenomena are explored. Preattentive processing provides a well-supported account of taste-to-tongue binding. Learning between taste and smell can explain perceptual interactions between these senses and perhaps localization of smell to the mouth. Attentional processes may also be important, especially given their role in binding the major senses. Two are specifically examined. One claims that the failure to recognize smell's role in flavor stems from the role of involuntary attention's "defaulting" to the mouth and taste (i.e., binding by ignoring). Another claims that taste and smell form a common attentional channel in the mouth, in effect becoming one sense. Except for preattentive processing, the mechanisms involved in flavor binding differ markedly from those proposed for the major senses. This distinction may result from functional differences, with flavor supporting future food choice but not current identification. PMID- 23815521 TI - Nucleotide-assisted [Fe4S4] redox state interconversions of the Azotobacter vinelandii Fe protein and their relevance to nitrogenase catalysis. AB - The [Fe4S4] cluster of the nitrogenase Fe protein from Azotobacter vinelandii can exist in three redox states: oxidized [Fe4S4](2+), dithionite reduced [Fe4S4](1+), and two forms of the all ferrous [Fe4S4](0), S = 4 and 0. Operation of the [Fe4S4](2+)/ [Fe4S4](1+) redox couple transfers one electron to the MoFe protein during catalysis with hydrolysis of two MgATPs. In contrast, the [Fe4S4](2+)/[Fe4S4](0) couple transfers two electrons per binding event, accompanied by hydrolysis of only two MgATPs. Both reactions occur at nearly identical rates even though the number of electrons transferred differs by a factor of 2. MgATP and MgADP facilitate interconversion of the three redox states: 2[Fe4S4](1+) + 4 MgATP = [Fe4S4](2+)(MgATP)2 + [Fe4S4](0)(MgATP)2, as demonstrated by the MgATP reaction. This reaction was investigated as a possible precursor reaction to provide two electrons in the form of [Fe4S4](0)(MgATP)2 for delivery to the MoFe protein to then conduct a two-electron substrate reduction. However, experiments showed that this disproportionation reaction, which readily occurs, was not viable during nitrogenase catalysis utilizing the [Fe4S4](1+) cluster state. The known cooperative behavior of the Fe protein in the [Fe4S4](1+) state taken together with a measured turnover potential of -460 mV with an n = 2 value, suggest a gating process on the MoFe protein involving a two electron step. PMID- 23815522 TI - Quasi-cellular systems: stochastic simulation analysis at nanoscale range. AB - BACKGROUND: The wet-lab synthesis of the simplest forms of life (minimal cells) is a challenging aspect in modern synthetic biology. Quasi-cellular systems able to produce proteins directly from DNA can be obtained by encapsulating the cell free transcription/translation system PURESYSTEM(PS) in liposomes. It is possible to detect the intra-vesicle protein production using DNA encoding for GFP and monitoring the fluorescence emission over time. The entrapment of solutes in small-volume liposomes is a fundamental open problem. Stochastic simulation is a valuable tool in the study of biochemical reaction at nanoscale range. QDC (Quick Direct-Method Controlled), a stochastic simulation software based on the well known Gillespie's SSA algorithm, was used. A suitable model formally describing the PS reactions network was developed, to predict, from inner species concentrations (very difficult to measure in small-volumes), the resulting fluorescence signal (experimentally observable). RESULTS: Thanks to suitable features specific of QDC, we successfully formalized the dynamical coupling between the transcription and translation processes that occurs in the real PS, thus bypassing the concurrent-only environment of Gillespie's algorithm. Simulations were firstly performed for large liposomes (2.67um of diameter) entrapping the PS to synthetize GFP. By varying the initial concentrations of the three main classes of molecules involved in the PS (DNA, enzymes, consumables), we were able to stochastically simulate the time-course of GFP-production. The sigmoid fit of the GFP-production curves allowed us to extract three quantitative parameters which are significantly dependent on the various initial states. Then we extended this study for small-volume liposomes (575 nm of diameter), where it is more complex to infer the intra-vesicle composition, due to the expected anomalous entrapment phenomena. We identified almost two extreme states that are forecasted to give rise to significantly different experimental observables. CONCLUSIONS: The present work is the first one describing in the detail the stochastic behavior of the PS. Thanks to our results, an experimental approach is now possible, aimed at recording the GFP production kinetics in very small micro emulsion droplets or liposomes, and inferring, by using the simulation as a reverse-engineering procedure, the internal solutes distribution, and shed light on the still unknown forces driving the entrapment phenomenon. PMID- 23815524 TI - The effects of the timing of spinal surgery after traumatic spinal cord injury: a systematic review and meta-analysis. AB - Abstract The debate over the effects of the timing of surgical spinal decompression after traumatic spinal cord injury (tSCI) has remained unresolved for over a century. The aim of the current study was to perform a systematic review and quality-adjusted meta-analysis of studies evaluating the effects of the timing of spinal surgery after tSCI. Studies were searched for through the MEDLINE((r)) database (1966 to August 2012) and a 15-item, tailored scoring system was used for assessing the included studies' susceptibility to bias. Random effects and quality effects meta-analyses were performed. Models were tested for robustness using one way and criterion-based sensitivity analysis and funnel plots. Results are presented as weighted mean differences (WMDs) and odds ratios (ORs) with 95% confidence intervals (CIs). A total of 18 studies were analyzed. Heterogeneity was evident among the studies included. Quality effects models showed that - when compared with "late" surgery - "early" spinal surgery was significantly associated with a higher total motor score improvement (WMD: 5.94 points, 95% CI:0.74,11.15) in seven studies, neurological improvement rate (OR: 2.23, 95% CI:1.35,3.67) in six studies, and shorter length of hospital stay (WMD: -9.98 days, 95% CI:-13.10,-6.85) in six studies. However, one way and criterion-based sensitivity analyses demonstrated a profound lack of robustness among pooled estimates. Funnel plots showed significant proof of publication bias. In conclusion, despite the fact that "early" spinal surgery was significantly associated with improved neurological and length of stay outcomes, the evidence supporting "early" spinal surgery after tSCI lacks robustness as a result of different sources of heterogeneity within and between original studies. Where the conduct of a surgical, randomized controlled trial seems to be an unfeasible undertaking in acute tSCI, methodological safeguards require the utmost attention in future cohort studies. (Prospero registration number: PROSPERO CRD42012003182. See also http://www.crd.york.ac.uk/NIHR_PROSPERO/ ). PMID- 23815525 TI - Stable isotopes of nitrate reflect natural attenuation of propellant residues on military training ranges. AB - Nitroglycerin (NG) and nitrocellulose (NC) are constituents of double-base propellants used notably for firing antitank ammunitions. Nitroglycerin was detected in soil and water samples from the unsaturated zone (pore water) at an active antitank firing position, where the presence of high nitrate (NO3(-)) concentrations suggests that natural attenuation of NG is occurring. However, concentrations alone cannot assess if NG is the source of NO3(-), nor can they determine which degradation processes are involved. To address this issue, isotopic ratios (delta(15)N, delta(18)O) were measured for NO3(-) produced from NG and NC through various controlled degradation processes and compared with ratios measured in field pore water samples. Results indicate that propellant combustion and degradation mediated by soil organic carbon produced the observed NO3(-) in pore water at this site. Moreover, isotopic results are presented for NO3(-) produced through photolysis of propellant constituents, which could be a dominant process at other sites. The isotopic data presented here constitute novel information regarding a source of NO3(-) that was practically not documented before and a basis to study the contamination by energetic materials in different contexts. PMID- 23815523 TI - Varicella routine vaccination and the effects on varicella epidemiology - results from the Bavarian Varicella Surveillance Project (BaVariPro), 2006-2011. AB - BACKGROUND: In 2004, routine varicella vaccination was recommended in Germany for children 11-14 months of age with one dose, and since 2009, with a second dose at 15-23 months of age. The effects on varicella epidemiology were investigated. METHODS: Data on varicella vaccinations, cases and complications were collected from annual parent surveys (2006-2011), monthly paediatric practice surveillance (Oct 2006 - Sep 2011; five varicella seasons) and paediatric hospital databases (2005-2009) in the area of Munich (about 238,000 paediatric inhabitants); annual incidences of cases and hospitalisations were estimated. RESULTS: Varicella vaccination coverage (1st dose) in children 18-36 months of age increased in two steps (38%, 51%, 53%, 53%, 66% and 68%); second-dose coverage reached 59% in the 2011 survey. A monthly mean of 82 (62%) practices participated; they applied a total of 50,059 first-dose and 40,541 second-dose varicella vaccinations, with preferential use of combined MMR-varicella vaccine after recommendation of two doses, and reported a total of 16,054 varicella cases <17 years of age. The mean number of cases decreased by 67% in two steps, from 6.6 (95%CI 6.1-7.0) per 1,000 patient contacts in season 2006/07 to 4.2 (95%CI 3.9-4.6) in 2007/08 and 4.0 (95%CI 3.6-4.3) in 2008/09, and further to 2.3 (95%CI 2.0-2.6) in 2009/10 and 2.2 (95%CI 1.9-2.5) in 2010/11. The decrease occurred in all paediatric age groups, indicating herd protection effects. Incidence of varicella was estimated as 78/1,000 children <17 years of age in 2006/07, and 19/1,000 in 2010/11. Vaccinated cases increased from 0.3 (95%0.2-0.3) per 1,000 patient contacts in 2006/07 to 0.4 (95%CI 0.3-0.5) until 2008/09 and decreased to 0.2 (95%CI 0.2-0.3) until 2010/11. The practices treated a total of 134 complicated cases, mainly with skin complications. The paediatric hospitals recorded a total of 178 varicella patients, including 40 (22.5%) with neurological complications and one (0.6%) fatality due to varicella pneumonia. Incidence of hospitalisations decreased from 7.6 per 100,000 children <17 years of age in 2005 to 4.3 in 2009, and from 21.0 to 4.7 in children <5 years of age. CONCLUSIONS: Overall, the results show increasing acceptance and a strong impact of the varicella vaccination program, even with still suboptimal vaccination coverage. PMID- 23815526 TI - Brain activity during bladder filling and pelvic floor muscle contractions: a study using functional magnetic resonance imaging and synchronous urodynamics. AB - OBJECTIVES: To map the brain activity during bladder filling by functional magnetic resonance imaging using a refined scanning protocol including synchronous urodynamics and pelvic floor muscle contractions. METHODS: A total of 23 healthy female volunteers (age 20-68 years) were enrolled. Participants were asked to contract their pelvic floor muscles. This was followed by a urodynamic examination consisting of repeated filling cycles. Brain activity was measured by functional magnetic resonance imaging using a 3T magnetic resonance system. Measurements of brain activity consisted of 120 functional scans during pelvic floor contractions and 210 scans during bladder filling. Each functional magnetic resonance imaging scan covered the brain with 35 slices. Statistical analyses used the general linear model and independent component analysis. Areas of activation were visualized using group statistics. RESULTS: The following main clusters of activation were observed during pelvic floor muscle contractions: medial surface of the frontal lobe (primary motor area), bilaterally; supplementary motor area, bilaterally; and left gyrus precentralis. During bladder filling, activation was detected in the inferior frontal lobe bordering the frontal cingulum, left gyrus parietalis superior, left central area, right insula, brainstem and thalamus with subcortical gray matter nuclei. CONCLUSIONS: Our work extends an existing functional magnetic resonance imaging protocol for researching the neural control of the lower urinary tract. The present results are consistent with the available literature and agree with the present hypothetical functional model of lower urinary tract neural control. PMID- 23815528 TI - Ultrathin porous NiCo2O4 nanosheet arrays on flexible carbon fabric for high performance supercapacitors. AB - NiCo2O4 with higher specific capacitance is an excellent pseudocapacitive material. However, the bulk NiCo2O4 material prevents the achievement of high energy desity and great rate performance due to the limited electroactive surface area. In this work, NiCo2O4 nanosheet arrays were deposited on flexible carbon fabric (CF) as a high-performance electrode for supercapacitors. The NiCo2O4 arrays were constructed by interconnected ultrathin nanosheets (10 nm) with many interparticle pores. The porous feature of NiCo2O4 nanosheets increases the amount of electroactive sites and facilitates the electrolyte penetration. Hence, the NiCo2O4/CF composites exhibited a high specific capacitance of 2658 F g(-1) (2 A g(-1)), good rate performance, and superior cycling life, suggesting the NiCo2O4/CF is a promising electrode material for flexible electrochemical capacitors. PMID- 23815529 TI - Is it variants in the apolipoprotein l1 gene, or blood pressure control, that predicts progression of nondiabetic hypertensive nephropathy in African Americans? PMID- 23815530 TI - Patient and physician adherence in hypertension management. PMID- 23815527 TI - Mechanosignaling in bone health, trauma and inflammation. AB - SIGNIFICANCE: Mechanosignaling is vital for maintaining the structural integrity of bone under physiologic conditions. These signals activate and suppress multiple signaling cascades regulating bone formation and resorption. Understanding these pathways is of prime importance to exploit their therapeutic potential in disorders associated with bone loss due to disuse, trauma, or disruption of homeostatic mechanisms. RECENT ADVANCES: In the case of cells of the bone, an impressive amount of data has been generated that provides evidence of a complex mechanism by which mechanical signals can maintain or disrupt cellular homeostasis by driving transcriptional regulation of growth factors, matrix proteins and inflammatory mediators in health and inflammation. Mechanical signals act on cells in a magnitude dependent manner to induce bone deposition or resorption. During health, physiological levels of these signals are essential for maintaining bone strength and architecture, whereas during inflammation, similar signals can curb inflammation by suppressing the nuclear factor kappa B (NF-kappaB) signaling cascade, while upregulating matrix synthesis via mothers against decapentaplegic homolog and/or Wnt signaling cascades. Contrarily, excessive mechanical forces can induce inflammation via activation of the NF kappaB signaling cascade. CRITICAL ISSUES: Given the osteogenic potential of mechanical signals, it is imperative to exploit their therapeutic efficacy for the treatment of bone disorders. Here we review select signaling pathways and mediators stimulated by mechanical signals to modulate the strength and integrity of the bone. FUTURE DIRECTIONS: Understanding the mechanisms of mechanotransduction and its effects on bone lay the groundwork for development of nonpharmacologic mechanostimulatory approaches for osteodegenerative diseases and optimal bone health. PMID- 23815531 TI - Weight and blood pressure changes in high vascular risk patients. PMID- 23815532 TI - A two-for-one bargain: using cilnidipine to treat hypertension and its comorbidities. PMID- 23815534 TI - Effect of a novel calcium channel blocker on abnormal nocturnal blood pressure in hypertensive patients. AB - The authors examined the effect of cilnidipine, a unique L/N-type calcium channel blocker, on abnormal nocturnal blood pressure (BP) dipping in Japanese hypertensive patients in the real world. The Ambulatory Blood Pressure Control and Home Blood Pressure (Morning and Evening) Lowering by N-Channel Blocker Cilnidipine (ACHIEVE-ONE), a large-scale clinical study, was designed to evaluate the effects of cilnidipine in daily medical practice. Among the study, 24-hour ambulatory BP data were obtained from 615 patients and classified according to their nocturnal dipping status as extreme dippers, dippers, nondippers, or risers. A 12-week treatment with cilnidipine significantly reduced 24-hour BP in all groups (P<.001). Changes in nocturnal systolic BP (SBP) from baseline were 17.9 mm Hg from 154.6 mm Hg in risers and -11.9 mm Hg from 142.1 mm Hg, -6.6 mm Hg from 128.5 mm Hg, and 0.1 mm Hg from 115.8 mm Hg in nondippers, dippers, and extreme dippers, respectively. Changes from baseline in nocturnal SBP reduction rate were 8.2% in risers (P<.001) but -7.0% in extreme dippers (P<.001), while no change was observed in the nighttime SBP reduction rate for the total patients ( 0.2%+/-9.6%, P=.617). Cilnidipine partially, but significantly, restored abnormal nocturnal dipping status toward a normal dipping pattern in hypertensive patients. PMID- 23815533 TI - Impact of 5-year weight change on blood pressure: results from the Weight Loss Maintenance trial. AB - In this secondary analysis of the Weight Loss Maintenance trial, the authors assessed the relationship between blood pressure (BP) change and weight change in overweight and obese adults with hypertension and/or dyslipidemia who were randomized to 1 of 3 weight loss maintenance strategies for 5 years. The participants were grouped (N=741) based on weight change from randomization to 60 months as: (1) weight loss, (2) weight stable, or (3) weight gain. A significant positive correlation between weight change and systolic BP (SBP) change at 12, 30, and 60 months and between weight change and diastolic BP (DBP) change at 30 months was observed. From randomization to 60 months, mean SBP increased to a similar degree for the weight gain group (4.2+/-standard error=0.6 mm Hg; P<.001) and weight stable group (4.6+/-1.1 mm Hg; P<.001), but SBP did not rise in the weight loss group (1.0+/-1.7 mm Hg, P=.53). DBP was unchanged for all groups at 60 months. Although aging may have contributed to rise in BP at 60 months, it does not appear to fully account for observed BP changes. These results suggest that continued modest weight loss may be sufficient for long-term BP lowering. PMID- 23815535 TI - Effects of nebivolol on aortic compliance in patients with diabetes and maximal renin angiotensin system blockade: the EFFORT study. AB - The beneficial effects of nebivolol on arterial stiffness and endothelial dysfunction are well documented in untreated hypertensive patients and differ from nonvasodilatory beta-blockers. This study tests the hypothesis that the addition of nebivolol in predominantly African American patients with type 2 diabetes already receiving maximally tolerated doses of renin-angiotensin system (RAS) blockers will further improve large artery compliance. Patients with type 2 diabetes and hypertension on maximal RAS blockade (n=70) were randomized to nebivolol or metoprolol succinate daily. Doses were titrated until systolic blood pressure (SBP) was <130 mm Hg. Radial artery applanation tonometry and pulse wave velocity (PWV) analysis were used to derive central aortic pressures and hemodynamic indices at repeated visits at intervals during a 6-month period. Both metoprolol succinate and nebivolol groups demonstrated reductions in brachial SBP (-8.2+/-4.3 mm Hg [P=.01] and -7.8+/-3.7 [P=.002], respectively) and aortic DBP ( 2.4+/-1.8 [P=.039] and -4.0+/-2.9 mm Hg [P=.013], respectively). Aortic SBP decreased in the nebivolol group only (125.3+/-8 to 121.6+/-8.2, P=.025). There were no between group differences in aortic SBP, DBP, augmentation index, or PWV reduction. A significant increase in hemoglobin A1c was observed only in the metoprolol group. In patients with well-controlled type 2 diabetes and hypertension treated with maximally tolerated RAS blockade, nebivolol does not offer significant reductions in aortic BP over metoprolol succinate but maintains a stable metabolic profile. PMID- 23815536 TI - Catheterization during adrenal vein sampling for primary aldosteronism: failure to use (1-24) ACTH may increase apparent failure rate. AB - "Successful" adrenal vein catheterization in primary aldosteronism (PA) is often defined by a ratio of >3:1 of cortisol in the adrenal vein vs the inferior vena cava. Non-use of corticotropin (ACTH) during sampling may increase the apparent failure rate of adrenal vein catheterization due to lower cortisol levels. A retrospective study was performed on all patients with confirmed unilateral PA between June 2005 and August 2011. Adrenal vein sampling (AVS) included simultaneous bilateral baseline samples with repeat sampling 15 minutes after intravenous infusion of 250 MUg of Cortrosyn (ACTH-S). Successful catheter placement was judged as adrenal cortisol:IVC cortisol of >3:1, applied to both baseline and ACTH-S samples and lateralization of aldosteronism was judged as normalized aldosterone/cortisol (A/C) ratio >3 times the contralateral A/C ratio. In ACTH-S samples, 94% of right-sided catheterizations were biochemically successful with 100% success on the left. Among baseline samples, only 47% of right- and 44% of left-sided samples met the 3:1 cortisol criteria. However, 95% of apparent "failed" baseline cortisol sets still showed lateralization of A/C ratios that matched the ultimate pathology. Non-ACTH-stimulated samples may be incorrectly judged as failed catheter placement when a 3:1 ratio is used. ACTH stimulated sampling is the preferred means to confirm catheterization during AVS. PMID- 23815537 TI - Salt loading and potassium supplementation: effects on ambulatory arterial stiffness index and endothelin-1 levels in normotensive and mild hypertensive patients. AB - The authors investigated effects of excessive salt intake and potassium supplementation on ambulatory arterial stiffness index (AASI) and endothelin-1 (ET-1) in salt-sensitive and non-salt-sensitive individuals. AASI and symmetric AASI (s-AASI) were used as indicators of arterial stiffness. Plasma ET-1 levels were used as an index of endothelial function. Chronic salt-loading and potassium supplementation were studied in 155 normotensive to mild hypertensive patients from rural northern China. After 3 days of baseline investigation, participants were maintained sequentially for 7 days each on diets of low salt (51.3 mmol/d), high salt (307.7 mmol/d), and high salt+potassium (60 mmol/d). Ambulatory 24-hour blood pressure (BP) and plasma ET-1 were measured at baseline and on the last 2 days of each intervention. High-salt intervention significantly increased BP, AASI, s-AASI (all P<.001); potassium supplementation reversed increased plasma ET 1 levels. High-salt-induced changes in BP, s-AASI, and plasma ET-1 were greater in salt-sensitive individuals. Potassium supplementation decreased systolic BP and ET-1 to a significantly greater extent in salt-sensitive vs non-salt sensitive individuals (P<.001). Significant correlations were identified between s-AASI and ET-1 change ratios in response to both high-salt intervention and potassium supplementation (P<.001). Reducing dietary salt and increasing daily potassium improves arterial compliance and ameliorates endothelial dysfunction. PMID- 23815538 TI - A hypertensive response to exercise is prominent in patients with obstructive sleep apnea and hypertension: a controlled study. AB - Blood pressure (BP) behavior during exercise is not clear in hypertensive patients with obstructive sleep apnea (OSA). The authors studied 57 men with newly diagnosed essential hypertension and untreated OSA (apnea-hypopnea index [AHI] >=5) but without daytime sleepiness (Epworth Sleepiness Scale score <=10), and an equal number of hypertensive controls without OSA matched for age, body mass index, and office systolic BP. All patients underwent ambulatory BP measurements, transthoracic echocardiography, and exercise treadmill testing according to the Bruce protocol. A hypertensive response to exercise (HRE) was defined as peak systolic BP >=210 mm Hg. Patients with OSA and control patients had similar ambulatory and resting BP, ejection fraction, and left ventricular mass. Peak systolic BP was significantly higher in patients with OSA (197.6+/ 25.6 mm Hg vs 187.8+/-23.6 mm Hg; P=.03), while peak diastolic BP and heart rate did not differ between groups. Furthermore, an HRE was more prevalent in patients with OSA (44% vs 19%; P=.009). Multiple logistic regression revealed that an HRE is independently predicted by both the logAHI and minimum oxygen saturation during sleep (odds ratio, 3.94; confidence interval, 1.69-9.18; P=.001 and odds ratio, 0.94; confidence interval, 0.89-0.99; P=.02, respectively). Exaggerated BP response is more prevalent in nonsleepy hypertensives with OSA compared with their nonapneic counterparts. This finding may have distinct diagnostic and prognostic implications. PMID- 23815539 TI - An update on the cardiovascular pleiotropic effects of milk and milk products. AB - Hypertension is a major risk factor in addition to atherosclerosis and type 2 diabetes mellitus for the development of coronary heart disease and strokes. Several prospective clinical studies have demonstrated a possible protective effect of milk and dairy product consumption on these conditions. The putative effects of milk and dairy products are possibly mediated through their mineral content of calcium, magnesium, potassium, and vitamin D. These dairy substances exercise their blood pressure-lowering effect either directly on the arterial wall by these minerals or indirectly through blockade of the angiotensin converting enzyme (ACE) by the amino acids contained in the casein and whey of milk. The blockade of ACE results in the inhibition of production of angiotensin II, a potent vasoconstrictive peptide, and the prevention of degradation of bradykinin, a potent vasodilating peptide. For this concise review, a Medline search of the English language literature was conducted from 2006 to September 2012 and 16 pertinent papers were selected. The potential beneficial pleiotropic effects from these studies together with collateral literature will be discussed in this review. PMID- 23815540 TI - "Get thee up, eat and drink: for there is a sound of abundance of rain" [1 Kings 18:41 King James Version]. PMID- 23815541 TI - Systemic therapies for malignant pheochromocytoma and paraganglioma can exacerbate hypertension. PMID- 23815542 TI - Vascular endothelial growth factor: a novel potential therapeutic target for hypertension. PMID- 23815543 TI - Reply to vascular endothelial growth factor: a novel potential therapeutic target for hypertension. PMID- 23815545 TI - Redox multiphoton polymerization for 3D nanofabrication. AB - We report for the first time on the redox multiphoton polymerization of an organic-inorganic composite material, in which one of the components, a vanadium metallo-organic complex, initiates the polymerization. The composite employs multiphoton absorption to self-generate radicals by photoinduced reduction of the metal species from vanadium (V) to vanadium (IV). We exploit this material for the fabrication of fully 3D structures by multiphoton polymerization with 200 nm resolution, employing a femtosecond laser operating at 800 nm, in the absence of a photoinitiator. Nonlinear absorption measurements indicate that the use of an 800 nm laser initiates the photopolymerization due to three-photon absorption of the vanadium alkoxide. The laser power required to induce this three-photon polymerization is comparable to what is required for inducing two-photon polymerization in materials using standard two-photon absorbers, most likely due to the high content of vanadium in the final composite (up to 50% mole). PMID- 23815546 TI - Becoming a father is an emotional roller coaster - an analysis of first-time fathers' blogs. AB - AIMS AND OBJECTIVES: To identify and describe the process of fatherhood during the partner's pregnancy among expectant, first-time fathers. BACKGROUND: Pregnancy seems to be a demanding period for expectant fathers, and this period is a part of their transition to fatherhood. Blogs can be seen as personal diaries and offer an alternative method of collecting data as they are an arena for sharing experiences and narratives. DESIGN: An explorative qualitative design. METHODS: Blogs from the Internet by eleven first-time fathers living in Sweden were included in the study. Qualitative content analysis was used for the analysis of the blogs. RESULTS: A theme emerged expressing the latent content of the text: 'Becoming a father for the first time is an emotional roller coaster where the role of the expectant father is not obvious' and five different categories describing the manifest content: the pregnancy, a new life, to make the child real, preparations for the delivery and the arrival of the child, and a new role in life. CONCLUSIONS: The metaphor 'roller coaster' indicates the tension between different feelings about the men's future as fathers. They are searching for answers on how to be a good father. They feel excluded when they visit antenatal care centres and have difficulties finding out how to support their partner. This is an existential period when they understand themselves as adults and also miss relatives who have died. During pregnancy, the men start to communicate with their child, and this interaction gives a sense of reality and creates hope and joy about being a father. RELEVANCE TO CLINICAL PRACTICE: Staff involved in antenatal care can use the knowledge from this study when meeting with expectant fathers. Perspectives expressed in blogs may enhance the professionals' understanding that the transition process of fatherhood is complex. PMID- 23815547 TI - The cost-effectiveness of the Dose Adjustment for Normal Eating (DAFNE) structured education programme: an update using the Sheffield Type 1 Diabetes Policy Model. AB - AIMS: To estimate the cost-effectiveness of training in flexible intensive insulin therapy [as provided in the Dose Adjustment for Normal Eating (DAFNE) structured education programme] compared with no training for adults with Type 1 diabetes mellitus in the UK using the Sheffield Type 1 Diabetes Policy Model. METHODS: The Sheffield Type 1 Diabetes Policy Model was used to simulate the development of long-term microvascular and macrovascular diabetes-related complications and the occurrence of diabetes-related adverse events in 5000 adults with Type 1 diabetes. Total costs and quality-adjusted life years were estimated from a National Health Service perspective over a lifetime horizon, discounted at a rate of 3.5%. The treatment effectiveness of DAFNE was modelled as a reduction in HbA1c that affected the risk of developing long-term diabetes related complications. Probabilistic and structural sensitivity analyses were conducted. RESULTS: DAFNE resulted in greater life expectancy and reduced incidence of some diabetes-related complications compared with no DAFNE. DAFNE was found to generate an average of 0.0294 additional quality-adjusted life years for an additional cost of L426 per patient, leading to an incremental cost effectiveness ratio of L14 400 compared with no DAFNE. There was a 54% probability that DAFNE would be cost-effective at a willingness-to-pay threshold of L20 000 per quality-adjusted life year. CONCLUSIONS: The results of this study suggest that DAFNE is a cost-effective structured education programme for people with Type 1 diabetes and support its provision by the National Health Service in the UK. PMID- 23815548 TI - Synthesis and characterization of a glycerol salicylate resin for bioactive root canal sealers. AB - AIM: To develop and characterize a salicylate resin with potential use in bioactive endodontic sealers. METHODOLOGY: Methyl salicylate, glycerol and titanium isopropoxide were added in a closed system for the transesterification reaction. The resin obtained was characterized by proton nuclear magnetic resonance spectroscopy (1H NMR) and size exclusion chromatography (SEC). To verify the applicability of the resin to the development of endodontic sealers, experimental cements were prepared by mixing glycerol salicylate resin, calcium hydroxide and methyl salicylate in the ratios of 2 : 1 : 1, 1 : 2 : 1, 1 : 1 : 2, 1 : 1 : 1, 4 : 1 : 1, 1 : 4 : 1 and 1 : 1 : 4. Setting times were measured according to ISO 6876. Features of the hardening reaction were described by micro RAMAN spectroscopy. RESULTS: The transesterification reaction had a 72% efficiency. The (1) H NMR analysis revealed the presence of the expected functional groups (hydroxyls and aromatic rings), and the SEC confirmed the molar mass of the resin produced. The setting times of experimental sealers ranged from 70 min (ratio 1 : 1 : 1) to 490 min (ratio 1 : 1 : 4). The conversion of the salicylic groups (1 613 cm(-1) ) to salicylate salt (1 543 cm(-1) ) and the reduction in calcium hydroxide peaks (1084 and 682 cm(-1) ) were confirmed by micro-RAMAN spectroscopy, which showed the calcium chelation by the resin. CONCLUSION: The new glycerol salicylate resin was successfully synthesized and revealed a potential application in the development of endodontic sealers. PMID- 23815549 TI - Prediction of the origin of French Legionella pneumophila strains using a mixed genome microarray. AB - BACKGROUND: Legionella is a water and soil bacterium that can infect humans, causing a pneumonia known as Legionnaires' disease. The pneumonia is almost exclusively caused by the species L. pneumophila, of which serogroup 1 is responsible for 90% of patients. Within serogroup 1, large differences in prevalence in clinical isolates have been described. A recent study, using a Dutch Legionella strain collection, identified five virulence associated markers. In our study, we verify whether these five Dutch markers can predict the patient or environmental origin of a French Legionella strain collection. In addition, we identify new potential virulence markers and verify whether these can predict better. A total of 219 French patient isolates and environmental strains were compared using a mixed-genome micro-array. The micro-array data were analysed to identify predictive markers, using a Random Forest algorithm combined with a logistic regression model. The sequences of the identified markers were compared with eleven known Legionella genomes, using BlastN and BlastX; the functionality for each of the predictive markers was checked in the literature. RESULTS: The five Dutch markers insufficiently predicted the patient or environmental origin of the French Legionella strains. Subsequent analyses identified four predictive markers for the French collection that were used for the logistic regression model. This model showed a negative predictive value of 91%. Three of the French markers differed from the Dutch markers, one showed considerable overlap and was found in one of the Legionella genomes (Lorraine strain). This marker encodes for a structural toxin protein RtxA, described for L. pneumophila as a factor involved in virulence and entry in both human cells and amoebae. CONCLUSIONS: The combination of a mixed-genome micro-array and statistical analysis using a Random Forest algorithm has identified virulence markers in a consistent way. The Lorraine strain and related Dutch and French Legionella strains contain a marker that encodes a RtxA protein which probably is involved in the increased prevalence in clinical isolates. The current set of predictive markers is insufficient to justify its use as a reliable test in the public health field in France. Our results suggest that genetic differences in Legionella strains exist between geographically distinct entities. It may be necessary to develop region specific mixed-genome microarrays that are constantly adapted and updated. PMID- 23815550 TI - Prospective evaluation of the Amplicor HPV test for predicting progression of cervical intraepithelial neoplasia 2. AB - AIM: The aim of this study was to evaluate the clinical performance of the Amplicor HPV test, which detects 13 high-risk human papillomaviruses (HR-HPV), and to determine the association between consistent HR-HPV infection and progression of cervical intraepithelial neoplasia (CIN) 2 to CIN3. MATERIAL AND METHODS: This multi-institutional prospective study enrolled 122 women diagnosed with CIN2 by central pathological review. Subjects were tested at study entry and every 6 months over a 24-month period by cytology, Amplicor HPV test and colposcopy. Central pathological review was performed at the end of the study or if CIN progression was suspected. RESULTS: Ninety-three of the 122 participants completed all tests in the study and were included in the analysis. HR-HPV was detected in 87/93 (93.5%) participants at study entry. Twenty-four of the 87 HR HPV-positive participants progressed to >=CIN3, compared with none of the six participants who were HR-HPV-negative at study entry. The positive predictive value, negative predictive value, sensitivity and specificity of the Amplicor HPV test at study entry for predicting >=CIN3 progression were 27.6%, 100%, 100% and 8.7%, respectively. Sixty-two participants were HR-HPV-positive from study entry through to study completion, 24 of whom progressed to >=CIN3. None of 31 participants without continuous HR-HPV detection progressed to >=CIN3. For continuous HR-HPV detection, the positive predictive value, negative predictive value, sensitivity and specificity of the Amplicor HPV test were 38.7%, 100%, 100% and 44.9%, respectively. CONCLUSIONS: All participants who progressed to >=CIN3 were continuously HR-HPV-positive. The Amplicor HPV test thus demonstrated a good performance for predicting CIN3 progression. PMID- 23815551 TI - Coffin-Siris syndrome is a SWI/SNF complex disorder. AB - Coffin-Siris syndrome (CSS) is a congenital disorder characterized by intellectual disability, growth deficiency, microcephaly, coarse facial features, and hypoplastic or absent fifth fingernails and/or toenails. We previously reported that five genes are mutated in CSS, all of which encode subunits of the switch/sucrose non-fermenting (SWI/SNF) ATP-dependent chromatin-remodeling complex: SMARCB1, SMARCA4, SMARCE1, ARID1A, and ARID1B. In this study, we examined 49 newly recruited CSS-suspected patients, and re-examined three patients who did not show any mutations (using high-resolution melting analysis) in the previous study, by whole-exome sequencing or targeted resequencing. We found that SMARCB1, SMARCA4, or ARID1B were mutated in 20 patients. By examining available parental samples, we ascertained that 17 occurred de novo. All mutations in SMARCB1 and SMARCA4 were non-truncating (missense or in-frame deletion) whereas those in ARID1B were all truncating (nonsense or frameshift deletion/insertion) in this study as in our previous study. Our data further support that CSS is a SWI/SNF complex disorder. PMID- 23815552 TI - A randomised cross-over trial investigating the ease of use and preference of two dry powder inhalers in patients with asthma or chronic obstructive pulmonary disease. AB - OBJECTIVES: The objective of this randomised, cross-over study was to compare a new single-dose dry powder inhaler (Elpenhaler (EH)), with a widely used, multi dose dry powder inhaler (Diskus (DK)) on critical errors, patient preference, and satisfaction with the inhalers. METHODS: First, patients read the instructions of one device, followed by a first inhalation attempt. Inhalation errors were assessed and if mistakes were made, correct inhaler use was demonstrated. Then patients had to demonstrate again and mistakes were registered. This was repeated up to four times. After completing the first device, the same procedure was started with the second inhaler. Primary outcome was the percentage of patients making at least one critical error after reading the insert. Secondary outcomes were inhaler preference and satisfaction with the inhalers. RESULTS: After reading the insert, 19 of 113 patients (17%) made at least one critical error with DK and 40 (35%) with EH (p = 0.001); 73% preferred the DK and 27% the EH (p < 0.001). The mean overall satisfaction score (1 = very satisfied; 5 = very dissatisfied) for DK was 1.59 and for EH 2.48 (p < 0.001). CONCLUSION: With DK fewer errors were made, more patients preferred DK over EH and patients were more satisfied with DK. This may enable DK to improve treatment outcomes more than EH. PMID- 23815554 TI - New isotonic drinks with antioxidant and biological capacities from berries (maqui, acai and blackthorn) and lemon juice. AB - The aim of the study was to design new isotonic drinks with lemon juice and berries: maqui [Aristotelia chilensis (Molina) Stuntz], acai (Euterpe oleracea Mart.) and blackthorn (Prunus spinosa L.), following on from previous research. Quality parameters - including colour (CIELab parameters), minerals, phytochemical identification and quantification by high-performance liquid chromatography with diode array detector, total phenolic content by the Folin Ciocalteu reagent, the antioxidant capacity (ABTS(+), DPPH* and [Formula: see text] assays) and biological activities (in vitro alpha-glucosidase and lipase inhibitory effects) - were tested in the samples and compared to commercially available isotonic drinks. The new isotonic blends with lemon and anthocyanins rich berries showed an attractive colour, especially in maqui samples, which is essential for consumer acceptance. Significantly higher antioxidant and biological effects were determined in the new blends, in comparison with the commercial isotonic beverages. PMID- 23815553 TI - A novel biclustering algorithm for the discovery of meaningful biological correlations between microRNAs and their target genes. AB - BACKGROUND: microRNAs (miRNAs) are a class of small non-coding RNAs which have been recognized as ubiquitous post-transcriptional regulators. The analysis of interactions between different miRNAs and their target genes is necessary for the understanding of miRNAs' role in the control of cell life and death. In this paper we propose a novel data mining algorithm, called HOCCLUS2, specifically designed to bicluster miRNAs and target messenger RNAs (mRNAs) on the basis of their experimentally-verified and/or predicted interactions. Indeed, existing biclustering approaches, typically used to analyze gene expression data, fail when applied to miRNA:mRNA interactions since they usually do not extract possibly overlapping biclusters (miRNAs and their target genes may have multiple roles), extract a huge amount of biclusters (difficult to browse and rank on the basis of their importance) and work on similarities of feature values (do not limit the analysis to reliable interactions). RESULTS: To overcome these limitations, HOCCLUS2 i) extracts possibly overlapping biclusters, to catch multiple roles of both miRNAs and their target genes; ii) extracts hierarchically organized biclusters, to facilitate bicluster browsing and to distinguish between universe and pathway-specific miRNAs; iii) extracts highly cohesive biclusters, to consider only reliable interactions; iv) ranks biclusters according to the functional similarities, computed on the basis of Gene Ontology, to facilitate bicluster analysis. CONCLUSIONS: Our results show that HOCCLUS2 is a valid tool to support biologists in the identification of context-specific miRNAs regulatory modules and in the detection of possibly unknown miRNAs target genes. Indeed, results prove that HOCCLUS2 is able to extract cohesiveness-preserving biclusters, when compared with competitive approaches, and statistically confirm (at a confidence level of 99%) that mRNAs which belong to the same biclusters are, on average, more functionally similar than mRNAs which belong to different biclusters. Finally, the hierarchy of biclusters provides useful insights to understand the intrinsic hierarchical organization of miRNAs and their potential multiple interactions on target genes. PMID- 23815555 TI - Preliminary studies of bio-oil from fast pyrolysis of coconut fibers. AB - This work studied fast pyrolysis as a way to use the residual fiber obtained from the shells of coconut ( Cocos nucifera L. var. Dwarf, from Aracaju, northeastern Brazil). The bio-oil produced by fast pyrolysis and the aqueous phase (formed during the pyrolysis) were characterized by GC/qMS and GC*GC/TOF-MS. Many oxygenated compounds such as phenols, aldehydes, and ketones were identified in the extracts obtained in both phases, with a high predominance of phenolic compounds, mainly alkylphenols. Eighty-one compounds were identified in the bio oil and 42 in the aqueous phase using GC/qMS, and 95 and 68 in the same samples were identified by GC*GC/TOF-MS. The better performance of GC*GC/TOF-MS was due to the possibility of resolving some coeluted peaks in the one-dimension gas chromatography. Semiquantitative analysis of the samples verified that 59% of the area on the chromatogram of bio-oil is composed by phenols and 12% by aldehydes, mainly furfural. Using the same criterion, 77% of the organic compounds in the aqueous phase are phenols. Therefore, this preliminary assessment indicates that coconut fibers have the potential to be a cost-effective and promising alternative to obtain new products and minimize environmental impact. PMID- 23815556 TI - Lipomatous metaplasia identified in rabbits with reperfused myocardial infarction by 3.0 T magnetic resonance imaging and histopathology. AB - BACKGROUND: Cardiac lipomatous metaplasia (LM) occurs in patients with chronic ischemic heart disease and heart failure with unclear mechanisms. We studied coronary occlusion/reperfusion-induced myocardial infarction (MI) in rabbits during a 9-months follow-up using 3.0 T magnetic resonance scanner, and confirmed the presence of MI in acute phase and LM in chronic phase using histopathology. METHODS: MI was surgically induced in 10 rabbits by 90-min coronary artery occlusion and reperfusion. Forty-eight hours later, multiparametric cardiac magnetic resonance imaging (cMRI) was performed at a 3.0 T clinical scanner for MI diagnosis and cardiac function analysis. Afterwards, seven rabbits were scarified for histochemical staining with triphenyltetrazolium chloride (TTC), and hematoxylin-eosin (HE), and 3 were scanned with cMRI at 2 days, 2 weeks, 2 months and 9 months for longitudinal observations of morphological and functional changes, and the fate of the animals. Post-mortem TTC, HE and Masson's trichrome (MTC) were studied for chronic stage of MI. RESULTS: The size of acute MI correlated well between cMRI and TTC staining (r(2)=0.83). Global cardiac morphology-function analysis showed significant correlation between increasing acute MI size and decreasing ejection fraction (p<0.001). During 9 months, cMRI documented evolving morphological and functional changes from acute MI to chronic scar transformation and fat deposition with a definite diagnosis of LM established by histopathology. CONCLUSIONS: Acute MI and chronic LM were induced in rabbits and monitored with 3.0 T MRI. Studies on this platform may help investigate the mechanisms and therapeutic interventions for LM. PMID- 23815557 TI - FoxO3a contributes to the reprogramming process and the differentiation of induced pluripotent stem cells. AB - Induced pluripotent stem (iPS) cells, which are morphologically and functionally similar with embryonic stem (ES) cells, have been successfully generated from somatic cells through defined reprogramming transcription factors. Forkhead class O3a (FoxO3a) has been recently reported to play an important role in the homeostasis and maintenance of certain types of stem cells; however, the role of FoxO3a in the reprogramming process and differentiation of iPS cells remains unclear. In this study, we investigate the function of FoxO3a during the reprogramming process and characterize the properties of iPS cells from FoxO3a wild type and -null mouse embryonic fibroblasts (MEFs). Our results show that the FoxO3a-null iPS cells are similar to the wild-type iPS cells in the levels of ES cell markers, alkaline phosphatase activity, and formation of teratoma in vivo. The reprogramming process is delayed in the FoxO3a-null MEFs compared to the wild type MEFs; whereas the overexpression of FoxO3a partially recovers the impaired reprogramming efficiency in the null group. More importantly, FoxO3a deficiency impairs the neuronal lineage differentiation potential of iPS cells in vitro. These results suggest that FoxO3a affects the reprogramming kinetics and the neuronal lineage differentiation potential of the resulting iPS cells. Therefore, this study demonstrates a novel function of FoxO3a in cell reprogramming, which will help the development of alternative strategies for generating iPS cells. PMID- 23815558 TI - Perceptions of ageing as an older gay man: a qualitative study. AB - AIMS AND OBJECTIVES: To explore the ageing experiences of gay men in New Zealand over the age of 65 years. BACKGROUND: An increased acceptance by many people in Western societies towards men who are same-sex attracted is likely to result in a corresponding increase in the number of visible older gay men being the recipients of nursing care. Previous research has shown that nursing has some way to go towards providing a service that is culturally safe and appropriate. DESIGN: A critical gerontological approach was employed to explore the ageing experiences of gay men in New Zealand over the age of 65 years. This methodology ensured the voices of older gay men were foregrounded in the research. METHODS: Semi-structured digitally recorded individual interviews with 12 gay men aged between 65-81 years who lived in the community were undertaken. Data were analysed using thematic analysis to identify the repeated patterns across the men's talk. RESULTS: Three main themes relating to the ageing experiences of these men were identified: 'homophobia', 'being with someone' and 'future care'. CONCLUSIONS: Resilience was a significant factor in how well older gay men aged even in an environment where homophobia and heterosexism were common. Having a strong social support network was an important factor that contributed to supporting the ageing process. These gay men were wary about having to go into residential care, preferring to age in their own homes. RELEVANCE TO CLINICAL PRACTICE: Nurses and other healthcare professionals need to ensure healthcare services meet the needs of older gay men. Any interaction with older gay men should occur in a way that is open and respectful. The usage of best practice guidelines will assist organisations to deliver culturally safe and appropriate care to this group. PMID- 23815559 TI - Comparative development of knowledge-based bioeconomy in the European Union and Turkey. AB - Biotechnology, defined as the technological application that uses biological systems and living organisms, or their derivatives, to create or modify diverse products or processes, is widely used for healthcare, agricultural and environmental applications. The continuity in industrial applications of biotechnology enables the rise and development of the bioeconomy concept. Bioeconomy, including all applications of biotechnology, is defined as translation of knowledge received from life sciences into new, sustainable, environment friendly and competitive products. With the advanced research and eco efficient processes in the scope of bioeconomy, more healthy and sustainable life is promised. Knowledge-based bioeconomy with its economic, social and environmental potential has already been brought to the research agendas of European Union (EU) countries. The aim of this study is to summarize the development of knowledge-based bioeconomy in EU countries and to evaluate Turkey's current situation compared to them. EU-funded biotechnology research projects under FP6 and FP7 and nationally-funded biotechnology projects under The Scientific and Technological Research Council of Turkey (TUBITAK) Academic Research Funding Program Directorate (ARDEB) and Technology and Innovation Funding Programs Directorate (TEYDEB) were examined. In the context of this study, the main research areas and subfields which have been funded, the budget spent and the number of projects funded since 2003 both nationally and EU-wide and the gaps and overlapping topics were analyzed. In consideration of the results, detailed suggestions for Turkey have been proposed. The research results are expected to be used as a roadmap for coordinating the stakeholders of bioeconomy and integrating Turkish Research Areas into European Research Areas. PMID- 23815560 TI - Directed evolution of polymerases to accept nucleotides with nonstandard hydrogen bond patterns. AB - Artificial genetic systems have been developed by synthetic biologists over the past two decades to include additional nucleotides that form additional nucleobase pairs independent of the standard T:A and C:G pairs. Their use in various tools to detect and analyze DNA and RNA requires polymerases that synthesize duplex DNA containing unnatural base pairs. This is especially true for nested polymerase chain reaction (PCR), which has been shown to dramatically lower noise in multiplexed nested PCR if nonstandard nucleotides are used in their external primers. We report here the results of a directed evolution experiment seeking variants of Taq DNA polymerase that can support the nested PCR amplification with external primers containing two particular nonstandard nucleotides, 2-amino-8-(1'-beta-d-2'-deoxyribofuranosyl)imidazo[1,2-a]-1,3,5 triazin-4(8H)-one (trivially called P) that pairs with 6-amino-5-nitro-3-(1'-beta d-2'-deoxyribofuranosyl)-2(1H)-pyridone (trivially called Z). Variants emerging from the directed evolution experiments were shown to pause less when challenged in vitro to incorporate dZTP opposite P in a template. Interestingly, several sites involved in the adaptation of Taq polymerases in the laboratory were also found to have displayed "heterotachy" (different rates of change) in their natural history, suggesting that these sites were involved in an adaptive change in natural polymerase evolution. Also remarkably, the polymerases evolved to be less able to incorporate dPTP opposite Z in the template, something that was not selected. In addition to being useful in certain assay architectures, this result underscores the general rule in directed evolution that "you get what you select for". PMID- 23815561 TI - Editorial comment to Brain activity during bladder filling and pelvic floor muscle contractions: a study using functional magnetic resonance imaging and synchronous urodynamics. PMID- 23815562 TI - Evaluation of safety and efficacy of a fixed olmesartan/amlodipine combination therapy compared to single monotherapies. AB - BACKGROUND: Hypertension is known to be one of the main risk factors for cardiovascular disease. OBJECTIVES: To evaluate the safety and efficacy of a fixed olmesartan/amlodipine (Olme/Amlo) combination in improving blood pressure control, lipid profile, insulin sensitivity and some inflammatory and insulin resistance markers. Two hundred and seventy-six hypertensive patients were randomly assigned to olmesartan 20 mg, amlodipine 10 mg or a single pill containing an Olme/Amlo combination 20/5 mg for 12 months. We evaluated after 6 and 12 months: body weight, body mass index (BMI), systolic and diastolic blood pressure (SBP and DBP, respectively), fasting plasma glucose (FPG), fasting plasma insulin (FPI), lipid profile, vaspin, visfatin, interleukins 8 and 10 (IL 8 and IL-10, respectively). Patients also underwent an euglycemic, hyperinsulinemic clamp. RESULTS: Olme/Amlo combination was more effective in decreasing SBP, and DPB compared to single monotherapies after 12 months. Olme/Amlo combination, but not amlodipine, decreased FPG after 12 months. FPI and HOMA index were decreased, and M value increased by Olme/Amlo combination compared to olmesartan monotherapy, and to amlodipine monotherapy. Olme/Amlo significantly decreased IL-8 and IL-10 better than each monotherapy. CONCLUSIONS: Olme/Amlo single pill combination can be a safe and effective option to reduce blood pressure, improve insulin sensitivity and decrease inflammatory markers. PMID- 23815564 TI - An experimental protocol for structural characterization of Fe in dilute natural waters. AB - The properties of iron (Fe) complexes and compounds in the environment influence several central processes, e.g., iron uptake, adsorption/desorption of contaminants and nutrients, and redox transformations, as well as the fate of of natural organic matter (NOM). It is thus important to characterize Fe species in environmental samples. Synchrotron-based extended X-ray absorption fine structure (EXAFS) spectroscopy has been used in several studies on soils and sediments, but literature is scarce on investigations of natural waters because of low Fe concentrations. In this study we have described a gentle and noninvasive preconcentration method, based on electrostatic adsorption onto ion-exchange resins, suitable for EXAFS analysis of Fe species in dilute stream water samples. The EXAFS results of metal-organic model complexes showed that no significant local structural distortions were induced by the method. We also demonstrated the feasibility for an 8 MUM Fe stream water sample. The Fe heterogeneity in this stream water was investigated via a gradient series at 28%, 42%, 77%, 84%, and 100% adsorption of total iron. The EXAFS results showed that Fe(III) in this stream water was divided into Fe(III)-NOM complexes and Fe(III) (oxyhydr)oxides associated with NOM, and that each class consisted of several subspecies. PMID- 23815563 TI - Transforming research and clinical knowledge in traumatic brain injury pilot: multicenter implementation of the common data elements for traumatic brain injury. AB - Traumatic brain injury (TBI) is among the leading causes of death and disability worldwide, with enormous negative social and economic impacts. The heterogeneity of TBI combined with the lack of precise outcome measures have been central to the discouraging results from clinical trials. Current approaches to the characterization of disease severity and outcome have not changed in more than three decades. This prospective multicenter observational pilot study aimed to validate the feasibility of implementing the TBI Common Data Elements (TBI-CDEs). A total of 650 subjects who underwent computed tomography (CT) scans in the emergency department within 24 h of injury were enrolled at three level I trauma centers and one rehabilitation center. The TBI-CDE components collected included: 1) demographic, social and clinical data; 2) biospecimens from blood drawn for genetic and proteomic biomarker analyses; 3) neuroimaging studies at 2 weeks using 3T magnetic resonance imaging (MRI); and 4) outcome assessments at 3 and 6 months. We describe how the infrastructure was established for building data repositories for clinical data, plasma biomarkers, genetics, neuroimaging, and multidimensional outcome measures to create a high quality and accessible information commons for TBI research. Risk factors for poor follow-up, TBI-CDE limitations, and implementation strategies are described. Having demonstrated the feasibility of implementing the TBI-CDEs through successful recruitment and multidimensional data collection, we aim to expand to additional study sites. Furthermore, interested researchers will be provided early access to the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) data set for collaborative opportunities to more precisely characterize TBI and improve the design of future clinical treatment trials. (ClinicalTrials.gov Identifier NCT01565551.). PMID- 23815565 TI - Biogenic amines as freshness index of meat wrapped in a new active packaging system formulated with essential oils of Rosmarinus officinalis. AB - Biogenic amines (BAs) are considered as an important indicator of freshness and quality of food. In this work, a new active packaging (AP) system for meat that, incorporating essential oil of Rosmarinus officinalis at 4% (w/w), inhibits the increase of BAs and the bacteria involved into their production was developed. BAs were analyzed by a SPE-HPLC-DAD method during the storage time of meat (0-7 d, 4 degrees C). Results showed that, in each monitored day, Biogenic Amine Index (BAI) expressed in mg kg(-1) is lower in meat wrapped in AP with respect to that packed in polycoupled packaging (PP) (from 19% to 62%). A strong correlation was found between the inhibition of increase of putrescine, cadaverine, histamine and their bacteria producers such as Enterobacteriaceae, Pseudomonas spp. and Brocothrix thermospacta. By exploiting antimicrobial and antioxidant action of essential oil of R. officinalis, the new APs contribute to increase the shelf life of fresh meat and to preserve its important nutrients. PMID- 23815566 TI - Cis-2-dodecenoic acid quorum sensing system modulates N-acyl homoserine lactone production through RpfR and cyclic di-GMP turnover in Burkholderia cenocepacia. AB - BACKGROUND: Burkholderia cenocepacia employs both N-Acyl homoserine lactone (AHL) and cis-2-dodecenoic acid (BDSF) quorum sensing (QS) systems in regulation of bacterial virulence. It was shown recently that disruption of BDSF synthase RpfFBc caused a reduction of AHL signal production in B. cenocepacia. However, how BDSF system influences AHL system is still not clear. RESULTS: We show here that BDSF system controls AHL system through a novel signaling mechanism. Null mutation of either the BDSF synthase, RpfFBc, or the BDSF receptor, RpfR, caused a substantial down-regulation of AHL signal production in B. cenocepacia strain H111. Genetic and biochemical analyses showed that BDSF system controls AHL signal production through the transcriptional regulation of the AHL synthase gene cepI by modulating the intracellular level of second messenger cyclic di-GMP (c di-GMP). Furthermore, we show that BDSF and AHL systems have a cumulative role in the regulation of various biological functions, including swarming motility, biofilm formation and virulence factor production, and exogenous addition of either BDSF or AHL signal molecules could only partially rescue the changed phenotypes of the double deletion mutant defective in BDSF and AHL signal production. CONCLUSIONS: These results, together with our previous findings, thus depict a molecular mechanism with which BDSF regulates AHL signal production and bacterial virulence through modulating the phosphodiesterase activity of its receptor RpfR to influence the intracellular level of c-di-GMP. PMID- 23815567 TI - Insulin oedema and treatment-induced neuropathy occurring in a 20-year-old patient with Type 1 diabetes commenced on an insulin pump. AB - BACKGROUND: Oedema may occur following initiation or intensification of insulin therapy in patients with Type 1 and Type 2 diabetes. Mild oedema is thought to be not uncommon, but under-reported, whilst generalized oedema with involvement of serous cavities has rarely been described. Multiple pathogenic mechanisms have been proposed, including insulin-induced sodium and water retention. Patients at greater risk for insulin oedema include those with poor glycaemic control. Dramatic improvement in glycaemic control is also associated with sensory and autonomic neuropathy. CASE REPORT: We describe a case of generalized oedema occurring in a 20-year-old, low body weight patient with Type 1 diabetes with poor glycaemic control 3 days following commencement of an insulin pump; blood sugars had dramatically improved with this treatment. Alternative causes for oedema were excluded. Oedema slowly improved with insulin dose reduction with higher blood sugar targets plus frusemide treatment. Subsequent to oedema resolution, the patient unfortunately developed generalized neuropathic pain, thought to be another manifestation of rapid improvement in glycaemic control. CONCLUSION: Caution should be taken when a patient with diabetes that is poorly controlled has an escalation in therapy that may dramatically improve their blood sugar levels; this includes the initiation of an insulin pump. Clinicians and patients should be aware of the potential risk of insulin oedema, treatment induced neuropathy and worsening of diabetic retinopathy in the setting of rapid improvement in glycaemic control. PMID- 23815568 TI - The omics in migraine. AB - The term omics consist of three main areas of molecular biology, such as genomics, proteomics and metabolomics. The omics synergism recognise migraine as an ideal study model, due to its multifactorial nature. In this review, the plainly research data featuring in this complex network are reported and analyzed, as single or multiple factor in pathophysiology of migraine. The future of migraine biomolecular research shall be focused on networking among these different and hierarchical disciplines. We have to look for its Ariadne's tread, in order to see the whole painting of migraine molecular biology. PMID- 23815569 TI - Post-partum urinary retention in a teaching hospital in southwestern Nigeria. AB - AIM: This study was undertaken to determine the prevalence of post-partum urinary retention after vaginal delivery and to examine the associated risk factors. MATERIAL AND METHODS: This was a prospective observational study carried out over a 2-month period at the major university teaching hospital in southwestern Nigeria. RESULTS: Prevalence of post-partum urinary retention was 29.4%. The majority (93.3%) of women had covert urinary retention while 6.7% had overt urinary retention. From the bivariate analysis, episiotomy, reduced voiding desire and primiparity were risk factors for post-partum urinary retention (66.6% vs 30.6%; P = 0.017; 47.75% vs 13.9%; P = 0.037; and 60.0% vs 30.6%; P = 0.05; respectively). CONCLUSION: Post-partum urinary retention, particularly covert retention, is a common complication of labor and delivery in our clinical practice but is rarely reported in the published work, especially from this part of the world. No factor has been found to be independently associated with its occurrence, hence there is need for vigilance in the immediate post-partum period as most cases of urinary retention would have been avoided if women were encouraged to void early following delivery. PMID- 23815570 TI - Introduction of new Editors-in-Chief, Epilepsia. PMID- 23815571 TI - Increased resting functional connectivity in spike-wave epilepsy in WAG/Rij rats. AB - PURPOSE: Functional magnetic resonance imaging (fMRI)-based resting functional connectivity is well suited for measuring slow correlated activity throughout brain networks. Epilepsy involves chronic changes in normal brain networks, and recent work demonstrated enhanced resting fMRI connectivity between the hemispheres in childhood absence epilepsy. An animal model of this phenomenon would be valuable for investigating fundamental mechanisms and testing therapeutic interventions. METHODS: We used fMRI-based resting functional connectivity for studying brain networks involved in absence epilepsy. Wistar Albino Glaxo rats from Rijswijk (WAG/Rij) exhibit spontaneous episodes of staring and unresponsiveness accompanied by spike-wave discharges (SWDs) resembling human absence seizures in behavior and electroencephalography (EEG). Simultaneous EEG fMRI data in epileptic WAG/Rij rats in comparison to nonepileptic Wistar controls were acquired at 9.4 T. Regions showing cortical fMRI increases during SWDs were used to define reference regions for connectivity analysis to investigate whether chronic seizure activity is associated with changes in network resting functional connectivity. KEY FINDINGS: We observed high degrees of cortical-cortical correlations in all WAG/Rij rats at rest (when no SWDs were present), but not in nonepileptic controls. Strongest connectivity was seen between regions most intensely involved in seizures, mainly in the bilateral somatosensory and adjacent cortices. Group statistics revealed that resting interhemispheric cortical-cortical correlations were significantly higher in WAG/Rij rats compared to nonepileptic controls. SIGNIFICANCE: These findings suggest that activity dependent plasticity may lead to long-term changes in epileptic networks even at rest. The results show a marked difference between the epileptic and nonepileptic animals in cortical-cortical connectivity, indicating that this may be a useful interictal biomarker associated with the epileptic state. PMID- 23815573 TI - Epilepsy in Mowat-Wilson syndrome: is it a matter of GABA? PMID- 23815572 TI - Decreased A-currents in hippocampal dentate granule cells after seizure-inducing hypoxia in the immature rat. AB - PURPOSE: Cerebral hypoxia is a major cause of neonatal seizures, and can lead to epilepsy. Pathologic anatomic and physiologic changes in the dentate gyrus have been associated with epileptogenesis in many experimental models, as this region is widely believed to gate the propagation of limbic seizures. However, the consequences of hypoxia-induced seizures for the immature dentate gyrus have not been extensively examined. METHODS: Seizures were induced by global hypoxia (5-7% O2 for 15 min) in rat pups on postnatal day 10. Whole-cell voltage-clamp recordings were used to examine A-type potassium currents (IA ) in dentate granule cells in hippocampal slices obtained 1-17 days after hypoxia treatment. KEY FINDINGS: Seizure-inducing hypoxia resulted in decreased maximum IA amplitude in dentate granule cells recorded within the first week but not at later times after hypoxia treatment. The decreased IA amplitude was not associated with changes in the voltage-dependence of activation or inactivation removal, or in sensitivity to inhibition by 4-aminopyridine (4-AP). However, consistent with the role of IA in shaping firing patterns, we observed in the hypoxia group a significantly decreased latency to first spike with depolarizing current injection from hyperpolarized potentials. These differences were not associated with changes in resting membrane potential or input resistance, and were eliminated by application of 10 m 4-AP. SIGNIFICANCE: Given the role of IA to slow action potential firing, decreased IA could contribute to long-term hippocampal pathology after neonatal seizure-inducing hypoxia by increasing dentate granule cell excitability during a critical window of activity-dependent hippocampal maturation. PMID- 23815574 TI - Single-molecule study on polymer diffusion in a melt state: effect of chain topology. AB - We report a new methodology for studying diffusion of individual polymer chains in a melt state, with special emphasis on the effect of chain topology. A perylene diimide fluorophore was incorporated into the linear and cyclic poly(THF)s, and real-time diffusion behavior of individual chains in a melt of linear poly(THF) was measured by means of a single-molecule fluorescence imaging technique. The combination of mean squared displacement (MSD) and cumulative distribution function (CDF) analysis demonstrated the broad distribution of diffusion coefficient of both the linear and cyclic polymer chains in the melt state. This indicates the presence of spatiotemporal heterogeneity of the polymer diffusion which occurs at much larger time and length scales than those expected from the current polymer physics theory. We further demonstrated that the cyclic chains showed marginally slower diffusion in comparison with the linear counterparts, to suggest the effective suppression of the translocation through the threading-entanglement with the linear matrix chains. This coincides with the higher activation energy for the diffusion of the cyclic chains than of the linear chains. These results suggest that the single-molecule imaging technique provides a powerful tool to analyze complicated polymer dynamics and contributes to the molecular level understanding of the chain interaction. PMID- 23815576 TI - Living with hypertrophic cardiomyopathy. AB - PURPOSE: The purpose of this study is to provide an insider's account of what it is like to live with hypertrophic cardiomyopathy (HCM), a genetic cardiovascular illness that carries the risk for sudden cardiac death. This study aims to reveal how HCM impacts the family and guides the decision whether or not to pursue genetic testing, how the physical limitations associated with HCM alter being-in the-world, and how HCM alters social relationships. DESIGN: Fifteen adults with HCM were recruited for a longitudinal, phenomenological, qualitative study through purposive sampling and word of mouth. A total of 45 interviews were conducted by the researcher at a time and place designated by the participant between August 2011 and January 2012. The first interview with each participant was conducted in person. While efforts were made to conduct all interviews in person, a total of three interviews were conducted by telephone as requested by three participants due to scheduling conflicts. METHODS: Through methods of interpretive phenomenology, three audio-recorded, semistructured interviews occurred over the course of 3 months. Detailed narratives were solicited and transcribed verbatim. Methodological and analytical documentation was supported with the identification of key phrases, similar experiences, themes, and documentation of the rationale for decisions throughout the research process. CONCLUSIONS: Participation in genetic testing carries a multitude of personal, familial, financial, and emotional implications. The results of a genetic test elicited an emotional response regardless of whether the results were negative, positive, or inconclusive. Living with a potentially life-threatening illness altered identity, disrupted social relationships, and generated chronic fear and uncertainty. A new normal was re-ordered or transformed by the demands and limitations posed by HCM, and by the person's concerns, priorities, and the meaning of the illness. CLINICAL RELEVANCE: Results from this study underscore the need for healthcare professionals to learn more about HCM and to conduct screenings that will facilitate a prompt and accurate diagnosis. In doing so, the risk for sudden cardiac death may be averted. There is a need to educate and to advocate for genetic testing of HCM. It is necessary for healthcare providers to move beyond their biomedical understanding of genetic illness and to address the lived experience of the illness, how the illness impacts the family, and the multifaceted concerns of people who have a genetic illness as well as the concerns of their family members. PMID- 23815575 TI - Differential regulatory T cell activity in HIV type 1-exposed seronegative individuals. AB - The potential role of conventional and regulatory T cells (Tregs) in protection from HIV-1 infection remains unclear. To address this question, we analyzed samples from 129 HIV-1-exposed seronegative individuals (HESN) from an HIV-1 serodiscordant couples cohort. To assess the presence of HIV-specific T cell responses and Treg function, we measured the proliferation of T cells in response to HIV-1 peptide pools in peripheral blood mononuclear cells (PBMCs) and PBMCs depleted of Tregs. We identified HIV-specific CD4(+) and CD8(+) T cell responses and, surprisingly, the overall CD4(+) and CD8(+) T cell response rate was not increased when Tregs were removed from cell preparations. Of the 20 individuals that had HIV-1-specific CD4(+) T cell responses, only eight had Tregs that could suppress this proliferation. When compared with individuals whose Tregs could suppress HIV-1-specific CD4(+) T cell proliferation, individuals with Tregs unable to suppress showed a trend toward increased T cell activation and Treg frequency and a significant increase in HIV-1-specific production of microphage inflammatory protein-1beta (MIP-1beta) by CD4(+) T cells, autocrine production of which has been shown to be protective in terms of HIV-1 infection of CD4(+) T cells. PMID- 23815577 TI - In silico study of structural and geometrical requirements of natural sesquiterpene lactones with trypanocidal activity. AB - Chagas' disease, caused by the intracellular protozoan Trypanosoma cruzi, is one of the most serious health problems throughout South America. Despite the progress that has been made in the study of its biochemistry and physiology, more efficient chemotherapies to control this parasitic infection are still lacking. In this paper we report the trypanocidal and cytotoxic activities of a series of sesquiterpene lactones, isolated from Asteraceae medicinal plants. The significant trypanocidal activity and high selectivity indexes found for many of the compounds evaluated, prompted us to undertake a quantitative structure activity relationship study. A model using 3D molecular descriptors allowed us to set up a high correlation of the observed activity and the atomic spatial arrangement of these sesquiterpene lactones closely related to steric parameters. PMID- 23815578 TI - Activin Receptor-like kinase 1: a novel anti-angiogenesis target from TGF-beta family. AB - Anti-angiogenic therapy represents a very promising approach in cancer treatment, as most tumors needs to be supplied by a functional vascular network in order to grow beyond the local boundaries and metastatize. The accessibility of vessels to drug delivery and the broad spectrum of cancers treatable with the same compound have arisen interest in research of suitable molecules, with several, especially targeting the VEGF pathway, entered in clinical trials and approved by the Food and Drug Administration. Despite good results, the major hurdle resides in the limited duration of an effective clinical response before tumors start to grow again. Thus, researchers are looking for different alternative targets for a combined and parallel multi-targeting of angiogenic signaling circuits. Activin Receptor-like kinase 1 (ALK1) is a TGF-beta type I receptor with high affinity for the BMP9 member of Bone Morphogenic Proteins superfamily: it is expressed mainly, even if not exclusively, on endothelial cells and seems to be involved in the regulatory phase of angiogenesis. Despite a non-completely elucidated mechanism, the targeting of this pathway, both by a soluble ALK1-Fc receptor developed by Acceleron Pharma and by a fully human monoclonal antibody developed by Pfizer, has achieved encouraging results. After having briefly summarized the state of the art of anti-angiogenic therapy, we will first review existing evidence about the molecular mechanisms of ALK1 signaling and we will then analyse in detail the pre-clinical and clinical data available about these two drugs. PMID- 23815579 TI - Investigational selective melatoninergic ligands for receptor subtype MT2. AB - Melatonin, an endogenous ligand for melatonin receptor, plays an important role in modulating various physiological activities through acting on different subtypes MT1, MT2 or the binding site MT3. The distinct roles of the receptor subtypes provide great potential for receptor-specific pharmacological agents. Melatonin has no subtypeselectivity, so it is very important to develop different subtype-selective ligand for receptor subtype research and drug development. In order to provide guidance for developing high selective ligand, this paper focused on the MT2-selective ligands, which developed well in the past years. The MT2-selective ligands, mainly focusing on binding data on MT1 and MT2 receptor, are reviewed in detail according to their structural classes, and the relative pharmacophore, receptor binding models and the relationship between the structure of ligand and the affinity along with selectivity for receptor subtype were discussed, which may facilitate the exploration of more potent and effective MT2 selective ligands. PMID- 23815580 TI - Novel Research Strategies of Benzimidazole Derivatives: A Review. AB - Benzimidazole plays an important role in the medicinal chemistry and drug discovery with many pharmacological activities which have made an indispensable anchor for discovery of novel therapeutic agents. Substitution of benzimidazole nucleus is an important synthetic strategy in the drug discovery process. Therapeutic properties of the benzimidazole related drugs have encouraged the medicinal chemists to synthesize novel therapeutic agents. Therefore, it is required to couple the latest information with the earliest information to understand the current status of benzimidazole nucleus in drug discovery. In the present review, benzimidazole derivatives with different pharmacological activities are described on the basis of substitution pattern around the nucleus with an aim to help medicinal chemists for the development of SAR on benzimidazoles for each activity. This article aims to review the work reported, chemistry and pharmacological activities of benzimidazole derivatives during past years. PMID- 23815581 TI - Dendrimer a new dimension in targeting biofilms. AB - Biofilms prevail in natural and man-made environment on all surfaces. They play a beneficial role in water treatment, waste management and are important reservoirs of pathogens involved in fouling of medical and industrial equipments. Biofilms are resistant to antimicrobial agents and there is a lack of understanding in combating these communities. With the advent of dendrimer this scenario has shown promising change. Dendrimers are complex 3D structure molecules that provide well defined functionality with potential application. Although the studies regarding dendrimer technology are in infancy it serves as an attractive feature for drug encapsulation, binding and delivery to the target site. The synthesis of dendrimers is cumbersome and suffers from certain shortcomings such as extensive purification, lower yield and steric hindrance. However, these drawbacks are overcome by engineering alteration in the dendritic structure. In this review we focus on the biological application of dendrimer derived from peptide, carbohydrate, quaternary ammonia and metal ion in inhibiting biofilm formation and antimicrobial activities. PMID- 23815582 TI - Evaluation of in vivo anti-inflammatory and analgesic activities of novel derivatives of Ugi-4CR. AB - In the present research, anti-inflammatory and analgesic activities of the synthesized agents derived from Ugi four-component reaction (Ugi-4CR) have been described. The synthesis was initiated by the imine formation under microwave irradiation. Ugi-4CR adducts has been achieved by the condensation of imine with aromatic aldehyde, 4- aminoantipyrine and ethylisocyanoacetate. The reaction was carried out at room temperature in presence of Fluorite as a catalyst. The novel Ugi derivatives were characterized on the basis of IR, 1H NMR, 13C NMR, Mass and Elemental analysis. All the synthesized agents were screened for their potential anti-inflammatory and analgesic activities using healthy wistar albino rats. Anti inflammatory and analgesic activities were evaluated by Mercury displacement and Hot plate method using Diclofenac and Morphine Sulfate as standard reference drugs respectively. The screening data shows that synthesized compounds are potent agents to act as analgesic and anti-inflammatory drugs. PMID- 23815583 TI - Imidazoles as potential antifungal agents: a review. AB - Imidazoles are one of the most promising and vigorously pursued areas of contemporary antifungal chemotherapy depicting broad spectrum and potent activity. They have relatively simple molecular nucleus, which is amenable to many structural modifications. These agents have several favorable properties such as excellent bioavailability, good tissue penetrability and permeability and a relatively low incidence of adverse and toxic effects. They have been found effective in the treatment of various infectious diseases. This paper is an attempt to review the therapeutic potential of imidazoles as antifungal with an updated account on their development. PMID- 23815584 TI - An update on saccharide arrays. AB - Saccharide arrays are powerful tools to investigate the saccharide-mediated recognition events in highthroughput mode. Many methods have been used to immobilize the saccharides on support surface in the array format. The array based technologies were widely utilized to analyze the characters of saccharide binding lectins and antibodies, quantitatively determine saccharide-protein interactions, detect cells and pathogens, identify disease-related antisaccharide antibodies for diagnosis, and fast assess substrate specificities of glycosyltransferases. This review has mainly summarized the fabrication methods of saccharide arrays and their applications in recent years. PMID- 23815585 TI - 1,3,4-oxadiazole derivatives as potential biological agents. AB - The synthesis of novel compound libraries along with screening is a rapid and effective approach for the discovery of potential chemical agents, and it becomes an important method in pharmaceutical chemistry research. 1,3,4- oxadiazole derivatives as the typical heterocyclic compounds, exhibit a broad spectrum of biological activities and vital leading compounds for the development of chemical drugs. Herein, we focus on the synthesis and screening of novel 1,3,4-oxadiazoles derivatives with antimicrobial, antitumor or antiviral activities during the past decade. In this review, we discussed the synthetic development of 1,3,4 oxadiazoles derivatives, and also the relevant bioactivity and their prospects as the potential chemical drugs. PMID- 23815586 TI - Tetrapod nanocrystals as fluorescent stress probes of electrospun nanocomposites. AB - A nanoscale, visible-light, self-sensing stress probe would be highly desirable in a variety of biological, imaging, and materials engineering applications, especially a device that does not alter the mechanical properties of the material it seeks to probe. Here we present the CdSe-CdS tetrapod quantum dot, incorporated into polymer matrices via electrospinning, as an in situ luminescent stress probe for the mechanical properties of polymer fibers. The mechanooptical sensing performance is enhanced with increasing nanocrystal concentration while causing minimal change in the mechanical properties even up to 20 wt % incorporation. The tetrapod nanoprobe is elastic and recoverable and undergoes no permanent change in sensing ability even upon many cycles of loading to failure. Direct comparisons to side-by-side traditional mechanical tests further validate the tetrapod as a luminescent stress probe. The tetrapod fluorescence stress strain curve shape matches well with uniaxial stress-strain curves measured mechanically at all filler concentrations reported. PMID- 23815587 TI - Complexation-tailored morphology of asymmetric block copolymer membranes. AB - Hydrogen-bond formation between polystyrene-b-poly (4-vinylpyridine) (PS-b-P4VP) block copolymer (BCP) and -OH/-COOH functionalized organic molecules was used to tune morphology of asymmetric nanoporous membranes prepared by simultaneous self assembly and nonsolvent induced phase separation. The morphologies were characterized by field emmision scanning electron microscopy (FESEM) and atomic force microscopy (AFM). Hydrogen bonds were confirmed by infrared (IR), and the results were correlated to rheology characterization. The OH-functionalized organic molecules direct the morphology into hexagonal order. COOH-functionalized molecules led to both lamellar and hexagonal structures. Micelle formation in solutions and their sizes were determined using dynamic light scattering (DLS) measurements and water fluxes of 600-3200 L/m(2).h.bar were obtained. The pore size of the plain BCP membrane was smaller than with additives. The following series of additives led to pores with hexagonal order with increasing pore size: terephthalic acid (COOH-bifunctionalized) < rutin (OH-multifunctionalized) < 9 anthracenemethanol (OH-monofunctionalized) < 3,5-dihydroxybenzyl alcohol (OH trifunctionalized). PMID- 23815588 TI - Colloidal polarization of yolk/shell particles by reconfiguration of inner cores responsive to an external magnetic field. AB - Yolk/shell particles, which were hollow silica particles containing a movable magnetic silica core (MSC), were prepared by removing a middle polystyrene layer from multilayered particles of MSC/polystyrene/silica shell with heat treatment followed by a slight etching with a basic solution. An ac electric field was applied to the suspension of the yolk/shell particles to form pearl chains (1D structure) of yolk/shell particles. Observation with an optical microscope showed that the MSCs in the silica compartment of the pearl chains had a zigzag structure under the electric field. An external magnetic field applied to the suspension could form a novel structure of doublet MSC in the shell compartment of the quasi-pearl chain structure. Application of a magnetic field was also performed for 2D hexagonally close-packed assemblies of the yolk/shell particles, which could two-dimensionally form a doublet structure of MSCs as if they were polarized in the compartment. Switching on/off the magnetic field successfully controlled the positional ordering of cores in the consolidated silica shell. PMID- 23815589 TI - Identification and analysis of conserved pockets on protein surfaces. AB - BACKGROUND: The interaction between proteins and ligands occurs at pockets that are often lined by conserved amino acids. These pockets can represent the targets for low molecular weight drugs. In order to make the research for new medicines as productive as possible, it is necessary to exploit "in silico" techniques, high throughput and fragment-based screenings that require the identification of druggable pockets on the surface of proteins, which may or may not correspond to active sites. RESULTS: We developed a tool to evaluate the conservation of each pocket detected on the protein surface by CastP. This tool was named DrosteP because it recursively searches for optimal input sequences to be used to calculate conservation. DrosteP uses a descriptor of statistical significance, Poisson p-value, as a target to optimize the choice of input sequences. To benchmark DrosteP we used monomeric or homodimer human proteins with known 3D structure whose active site had been annotated in UniProt. DrosteP is able to detect the active site with high accuracy because in 81% of the cases it coincides with the most conserved pocket. Comparing DrosteP with analogous programs is difficult because the outputs are different. Nonetheless we could assess the efficacy of the recursive algorithm in the identification of active site pockets by calculating conservation with the same input sequences used by other programs.We analyzed the amino-acid composition of conserved pockets identified by DrosteP and we found that it differs significantly from the amino acid composition of non conserved pockets. CONCLUSIONS: Several methods for predicting ligand binding sites on protein surfaces, that combine 3D-structure and evolutionary sequence conservation, have been proposed. Any method relying on conservation mainly depends on the choice of the input sequences. DrosteP chooses how deeply distant homologs must be collected to evaluate conservation and thus optimizes the identification of active site pockets. Moreover it recognizes conserved pockets other than those coinciding with the sites annotated in UniProt that might represent useful druggable sites. The distinctive amino-acid composition of conserved pockets provides useful hints on the fundamental principles underlying protein-ligand interaction. AVAILABILITY: http://www.icb.cnr.it/project/drosteppy/ PMID- 23815590 TI - Living with 'Hwa-byung': the psycho-social impact of elder mistreatment on the health and well-being of older people. AB - OBJECTIVES: Elder abuse and neglect is an increasing concern that adversely affects the health and well-being of older people in most societies. The purpose of this paper is to describe the psycho-social impact of elder mistreatment on the health and well-being of older Korean people living in New Zealand. METHOD: Data were collected from in-depth interviews. The lived experiences of elder abuse and neglect were studied with 10 older people who were, or who had been, mistreated in their family context. To analyse the data collected, a combined analysis approach was employed using traditional code-based techniques and a concept-mapping method. RESULTS: The findings of the study show that the effects of elder mistreatment were complex and multidimensional. The older persons who were mistreated in family settings experienced a range of emotional, psychological distress and physical symptoms. Many of them identified 'Hwa-byung' (literally anger disease) as a health issue associated with suppressed emotions of anger, demoralisation, heat sensation and other somatised symptoms. CONCLUSION: Elder abuse and neglect is a traumatic life event that has considerable psycho-social impacts on older people experiencing the problem. It is important to recognise the power of multidimensional challenges caused by elder mistreatment in health and well-being. PMID- 23815591 TI - Transmembrane domain V plays a stabilizing role in the function of human bile acid transporter SLC10A2. AB - The human apical sodium-dependent bile acid transporter (hASBT, SLC10A2), primarily expressed in the ileum, is involved in both the recycling of bile acids and cholesterol homeostasis. In this study, the structure-function relationship of transmembrane domain 5 (TM5) residues involved in transport is elucidated. Cysteine scanning mutagenesis of each consecutive residue on TM5 resulted in 96% of mutants having a significantly decreased transport activity, although each was expressed at the cell surface. Specifically, G197 and I208 were no longer functional, and G201 and G212 functioned at a level of <10% upon cysteine mutation. Interestingly, each of these exists along one face of the helix. Studies suggest that neither G201 nor G212 is on the substrate pathway. Conservative alanine mutations of the four residues displayed a higher activity in all but G197A, indicating its functional importance. G197 and G201 form a GxxxG motif, which has been found to be important in helix-helix interactions. According to our model, G197 and G201 face transmembrane domain 4 (TM4) residues G179 and P175, respectively. Similarly, G212 faces G237, which forms part of a GxxxG domain in transmembrane domain 6 (TM6). It is possible that these GxxxG domains and their interacting partners are responsible for maintaining the structure of the helices and their interactions with one another. I205 and I208 are both in positions to anchor the GxxxG domains and direct the change in interaction of TM5 from TM4 to TM6. Combined, the results suggest that residues along TM5 are critical for ASBT function but are not directly involved in substrate translocation. PMID- 23815593 TI - Learning of geometry and features in bumblebees (Bombus terrestris). AB - Bumblebees (Bombus terrestris) were trained to find one of the four exit holes located in the corners of an enclosed environment with a distinctive geometry (a rectangular cage). Panels located at the corners provided nongeometric, featural cues. Between trials bumblebees were passively disoriented to disable dead reckoning. When tested after removal of the panels, bumblebees reoriented using the residual information provided by the geometry of the cage. When tested after removal of only the two panels located in the two geometrically correct corners (the one with the exit and the diagonally opposite one), bumblebees were not able to use features in corners distant to the goal to reorient themselves. Finally, when geometric and featural cues provided contradictory information, bumblebees showed more reliance on featural cues. A similar outcome was observed when the conflict between geometrical and featural information was determined by first training bumblebees in a rectangular cage with a single wall of a different color used as a feature, and then testing animals with the feature displaced along a different wall. When the feature was close to the goal during training, bumblebees chose the corners with the feature at test, when the feature was far from goal during training, bumblebees chose the corners with the correct geometry at test. These results are similar to those revealed by similar transformational tests carried out in vertebrates relying mainly on vision for spatial orientation, that is, birds and monkeys. PMID- 23815592 TI - How domestication modulates play behavior: a comparative analysis between wild rats and a laboratory strain of Rattus norvegicus. AB - Laboratory rats have been widely used to study the development and neural underpinnings of play behavior. However, it is not known whether domestic rats play in the same way and at the same frequency as their wild counterparts. In this study, the play of juvenile rats from a colony of wild rats maintained in captivity was compared to that of a strain of domesticated rats (e.g., Long Evans hooded). Three predictions were tested. First, it was predicted that wild rats would incorporate more agonistic behavior in their play. This was not found, as in all cases, both the wild and the laboratory rats attacked and defended the nape during play, a nonagonistic body target. Second, because play is typically more frequent in domesticated animals than their wild progenitors, it was predicted that the wild rats should play less than the laboratory rats. This was found to be the case. Third, because wild animals tend to be less tolerant of proximity by conspecifics and tend to be more agile in their movements, it was predicted that there would be less contact between wild pair mates. This was found to be the case; data show that the play of laboratory rats involves the same target (i.e., the nape of the neck) and tactics of defense as those used by wild rats. However, the laboratory rats initiated playful attacks more frequently, and were more likely to use tactics that promoted bodily contact. These similarities and differences need to be considered when using laboratory animals as models for play in general. PMID- 23815594 TI - Cytokine gene polymorphisms and serum cytokine levels in patients with idiopathic pulmonary fibrosis. AB - BACKGROUND: Studies have demonstrated associations between cytokine gene polymorphisms and the risk of idiopathic pulmonary fibrosis (IPF). We therefore examined polymorphisms in the genes encoding interleukin (IL)-6, IL-10, interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and transforming growth factor-beta 1 (TGF-beta1), and compared the serum levels of these cytokines in IPF patients and healthy controls. Furthermore, we examined the association of the studied genotypes and serum cytokine levels with physiological parameters and the extent of parenchymal involvement determined by high-resolution computed tomography (HRCT). METHODS: Sixty patients with IPF and 150 healthy controls were included. Cytokine genotyping was performed using the polymerase chain reaction sequence specific primer (PCR-SSP) method. In a subset of patients and controls, serum cytokine levels were determined by enzyme-linked immunosorbent assay. RESULTS: There was no difference between IPF patients and controls in the genotype and allele distributions of polymorphisms in TNF-alpha, IFN-gamma, IL-6, IL-10, and TGF-beta1 (all p > 0.05). The TNF-alpha (-308) GG, IL 6 (-174) GG and CG, and IL-10 (-1082, -819, -592) ACC ATA genotypes were significantly associated with HRCT scores (all p < 0.05). IL-10 (-1082, -819, 592) ACC haplotype was associated with the diffusion capacity of the lung for carbon monoxide, and ATA haplotype was associated with the partial pressure of oxygen (PaO2) (all p < 0.05). The TGF-beta1 (codons 10 and 25) TC GG, TC GC, CC GG and CC GC genotypes were significantly associated with the PaO2 and HRCT scores (p < 0.05). The TGF-beta1 (codons 10 and 25) CC GG genotype (5 patients) was significantly associated with higher PaO2 value and less parenchymal involvement (i.e., a lower total extent score) compared to the other TGF-beta1 genotypes (81.5 +/- 11.8 mm Hg vs. 67.4 +/- 11.1 mm Hg, p = 0.009 and 5.60 +/- 1.3 vs. 8.51 +/- 2.9, p = 0.037, respectively). Significant differences were noted between patients (n = 38) and controls (n = 36) in the serum levels of IL-6 and IL-10 (both, p < 0.0001), but not in the levels of TNF-alpha and TGF-beta1 (both, p > 0.05). CONCLUSION: The studied genotypes and alleles do not predispose to the development of IPF but appear to play an important role in disease severity. Our results suggest that the TGF-beta1 (codons 10 and 25) CC GG genotype could be a useful genetic marker for identifying a subset of IPF patients with a favorable prognosis; however, validation in a larger sample is required. PMID- 23815595 TI - In vivo identity of tendon stem cells and the roles of stem cells in tendon healing. AB - We investigated the spatial distribution of stem cells in tendons and the roles of stem cells in early tendon repair. The relationship between tendon-derived stem cells (TDSCs) isolated in vitro and tendon stem cells in vivo was also explored. Iododeoxyuridine (IdU) label-retaining method was used for labeling stem cells in rat patellar tendons with and without injury. Co-localization of label-retaining cells (LRCs) with different markers was done by immunofluorescent staining. TDSCs were isolated from patellar tendon mid-substance after IdU pulsing, and the expression of different markers in fresh and expanded cells was done by immunofluorescent staining. More LRCs were found at the peritenon and tendon-bone junction compared with the mid-substance. Some LRCs at the peritenon were located at the perivascular niche. The LRC number and the expression of proliferative, tendon-related, pluripotency, and pericyte-related markers in LRCs in the window wound increased. Most of the freshly isolated TDSCs expressed IdU, and some TDSCs expressed pericyte-related markers, which were lost during expansion. Both freshly isolated and subcultured TDSCs expressed pluripotency markers, which were absent in LRCs in intact tendons. In conclusion, we identified LRCs at the peritenon, mid-substance, and tendon-bone junction. There were both vascular and non-vascular sources of LRCs at the peritenon, while the source of LRCs at the mid-substance was non-vascular. LRCs participated in tendon repair via migration, proliferation, activation for tenogenesis, and increased pluripotency. Some LRCs in the window wound were pericyte like. Most of the mid substance TDSCs were LRCs. The pluripotency markers and pericyte-related marker in LRCs might be important for function after injury. PMID- 23815596 TI - Vitamin D supplementation and risk of respiratory tract infections: a meta analysis of randomized controlled trials. AB - BACKGROUND: It is well-documented that serum levels of 25-hydroxyvitamin D (25 OHD) are inversely associated with the risk of respiratory tract infections (RTIs). However, whether or not vitamin D supplementation prevents RTIs remains inconclusive. The aim of this study was to evaluate the role of vitamin D supplementation in preventing RTIs in healthy populations by performing a meta analysis of randomized controlled trials (RCTs). METHODS: RCTs regarding the association between vitamin D supplementation and the risk of RTIs were identified by searching PubMed, Embase, and Cochrane databases through January 2013. Reference lists of retrieved articles were also reviewed. Either a fixed effects or, in the presence of heterogeneity, a random-effects model was used to calculate the pooled preventive effects. RESULTS: Seven RCTs involving 4827 participants were included in this meta-analysis. The pooled relative risk (RR) for subjects administered with vitamin D compared with control groups was 0.98 (95% confidence interval 0.93-1.03, p = 0.45). Meta-regression analyses showed almost no impact on the RR of age, vitamin D dosing regimen, and length of follow up. Omission of any single trial had little impact on the pooled risk estimates. No evidence of publication bias was observed. CONCLUSIONS: Our findings do not support the routine use of vitamin D supplementation for RTI prevention in healthy populations. Larger studies are needed to investigate the effects of vitamin D supplementation on RTI prevention in various populations and to further clarify the influences of age, vitamin D dosing regimen, baseline levels of vitamin D, and study length. PMID- 23815597 TI - Innate type 2 immunity is associated with eosinophilic pleural effusion in primary spontaneous pneumothorax. AB - RATIONALE: Eosinophilic pleural effusion (EPE) is characterized by greater than 10% eosinophilia and is frequently associated with air and/or blood in the pleural cavity. Primary spontaneous pneumothorax (PSP), defined as the spontaneous presence of air in the pleural space, is one of the most common causes of EPE. Recent studies have shown that type 2 immune responses play important roles in eosinophilic airway inflammation resulting in pleural pathology. OBJECTIVES: To determine the predominant immune responses associated with PSP in humans, and to examine whether IL-33, thymic stromal lymphopoietin (TSLP), or type 2 innate lymphoid cell (ILC2)-mediated immune responses are associated factors. METHODS: Eosinophil-associated cytokines were measured in the pleural fluid of patients with PSP and control subjects. Th2 cell and ILC2 responses in the pleural cavity and peripheral blood were also evaluated by in vitro restimulation and intracellular cytokine staining of T cells and ILC2s in patients with PSP (n = 62) and control subjects (n = 33). IL-33-mediated IL-5 production by ILC2s was also evaluated. MEASUREMENTS AND MAIN RESULTS: Significantly higher concentrations of IL-5 and eotaxin-3 were detected in the pleural fluid of patients with PSP, in addition to significantly higher concentrations of IL-33 and TSLP. Although IL-5 production was induced by IL-33 treatment of ILC2s, other Th2 cell-mediated immune responses were not detected. CONCLUSIONS: Our results indicate that innate immune responses characterized by the production of IL-33, TSLP, and IL-5 are associated with the development of EPE in PSP by an ILC2-dependent and Th2-independent mechanism. PMID- 23815598 TI - Toxicity of oxidatively degraded quantum dots to developing zebrafish (Danio rerio). AB - Once released into the environment, engineered nanoparticles (eNPs) are subjected to processes that may alter their physical or chemical properties, potentially altering their toxicity vis-a-vis the as-synthesized materials. We examined the toxicity to zebrafish ( Danio rerio ) embryos of CdSecore/ZnSshell quantum dots (QDs) before and after exposure to an in vitro chemical model designed to simulate oxidative weathering in soil environments based on a reductant-driven Fenton's reaction. Exposure to these oxidative conditions resulted in severe degradation of the QDs: the Zn shell eroded, Cd(2+) and selenium were released, and amorphous Se-containing aggregates were formed. Products of QD weathering exhibited higher potency than did as-synthesized QDs. Morphological endpoints of toxicity included pericardial, ocular and yolk sac edema, nondepleted yolk, spinal curvature, tail malformations, and craniofacial malformations. To better understand the selenium-like toxicity observed in QD exposures, we examined the toxicity of selenite, selenate, and amorphous selenium nanoparticles (SeNPs). Selenite exposures resulted in high mortality to embryos/larvae while selenate and SeNPs were nontoxic. Co-exposures to SeNPs + CdCl2 resulted in dramatic increase in mortality and recapitulated the morphological endpoints of toxicity observed with exposure to products of QD weathering. Cadmium body burden was increased in larvae exposed to weathered QDs or SeNP + CdCl2 suggesting the increased potency of products of QD weathering was due to selenium modulation of cadmium toxicity. Our findings highlight the need to examine the toxicity of eNPs after they have undergone environmental weathering processes. PMID- 23815599 TI - An adenine insertion in exon 6 of human GP6 generates a truncated protein associated with a bleeding disorder in four Chilean families. AB - BACKGROUND: Glycoprotein VI (GPVI), 60-65 kDa, is a major collagen receptor on platelet membranes involved in adhesive and signaling responses. Mice lacking GPVI have impaired platelet response to collagen and defective primary adhesion and subsequent thrombus formation. Complete or partial deficiency of GPVI in humans is a rare condition presenting as a mild bleeding disorder. The defect in most of the reported patients is acquired and associated with other diseases. To date, only two patients have been characterized at the molecular level who carry different compound heterozygous mutations in the GP6 gene. OBJECTIVE: To report four unrelated patients from non-consanguineous families who presented with mucocutaneous bleeding. They had absent platelet aggregation and (14) C-5-HT secretion with collagen, convulxin and collagen-related peptide. RESULTS: Flow cytometry and immunofluorescence-confocal microscopy showed an absence of GPVI in non-permeabilized platelets. All the patients had an adenine insertion in exon 6 (c.711_712insA), changing the reading frame and generating a premature 'stop codon' in site 242 of the protein. The mutation predicts the synthesis of the truncated protein before the trans-membrane domain, corresponding to a band of ~49 kDa observed in western blots and in permeabilized platelets by immunofluorescence. Platelet mRNA from all the patients was sequenced and contained the corresponding adenine insertion. Heterozygous relatives had no pathological bleeding, normal response to collagen and convulxin and intermediate membrane expression of GPVI. CONCLUSIONS: The identification of four unrelated homozygous patients with an identical defect suggests that inherited GPVI deficiency is more frequent than previously suspected, at least in Chile. PMID- 23815600 TI - Sesquiterpenoids with new carbon skeletons from the resin of Toxicodendron vernicifluum as new types of extracellular matrix inhibitors. AB - Toxicodenanes A-C (1-3), representing sesquiterpenoids with three new carbon skeletons, were isolated from the dried resin of Toxicodendron vernicifluum. Their structures were identified by spectroscopic data and X-ray diffraction crystallography. Their plausible biosynthetic route was proposed via the isolated intermediate (4). Compounds 2 and 3 could significantly inhibit overproduction of fibronectin, collagen IV, and IL-6 in high-glucose-induced mesangial cells in a dose- and time-dependent manner, showing their potential in diabetic nephropathy. PMID- 23815601 TI - Children often present with infantile spasms after herpetic encephalitis. AB - PURPOSE: To determine what epilepsy types occur after herpetic encephalitis and what are the determinant factors for subsequent infantile spasms. METHODS: We analyzed retrospectively the clinical history of 22 patients, referred to Necker and Saint Vincent de Paul Hospitals (Paris) through the French pediatric epilepsy network from March 1986 to April 2010 and who developed epilepsy some months after herpetic encephalitis. We focused on seizure semiology with video electroencephalography (EEG) recording, and on neuroradiology and epilepsy follow up. KEY FINDINGS: Fourteen patients developed pharmacoresistant spasms, and eight developed focal epilepsy, but none had both. The patients who developed spasms were more frequently younger than 30 months at age of onset of epilepsy and had herpetic encephalitis earlier (mean 10.6 months of age) than those who developed focal epilepsy (mean 59.7 and 39.6 months, respectively). Epilepsy follow-up was similar in both groups (8.5 and 11 years, respectively). We found 26 affected cerebral areas; none alone was related to the development of epileptic spasms. SIGNIFICANCE: Risk factors to develop epileptic spasms were to have had herpetic encephalitis early (mean 10 months); to be significantly younger at onset of epilepsy (mean 22.1 months); and to have cerebral lesions involving the insula, the hippocampus, and the temporal pole. PMID- 23815603 TI - Chemical suppression of an oncogenic splicing variant of AIMP2 induces tumour regression. AB - AIMP2 (aminoacyl-tRNA synthetase-interacting multifunctional protein 2) is a potent tumour suppressor that induces apoptosis in response to various oncogenic signals. AIMP2-DX2, an exon2-deleted splicing variant of AIMP2, is up-regulated in lung cancer and competitively suppresses the pro-apoptotic activity of AIMP2, resulting in tumorigenesis. In the present study we report that BC-DXI01, a synthetic compound, specifically reduces the cellular levels of AIMP2-DX2 through selective degradation of the AIMP2-DX2 mRNA transcript. We found that BC-DXI01 mediated cell death positively correlates with AIMP2-DX2 expression in the lung cancer cell lines tested. Administration of BC-DXI01 in a AIMP2-DX2-driven tumour xenograft mice model led to reduced tumour sizes and volumes of up to 60% in comparison with vehicle-treated mice group, consistent with decreases in AIMP2 DX2 transcript and protein levels. Taken together, our findings suggest that tumorigenic activity of AIMP2-DX2 can be controlled by the small chemical BC DXI01, which can selectively suppress the AIMP2-DX2 mRNA transcript. PMID- 23815602 TI - Identification of species belonging to the Bifidobacterium genus by PCR-RFLP analysis of a hsp60 gene fragment. AB - BACKGROUND: Bifidobacterium represents one of the largest genus within the Actinobacteria, and includes at present 32 species. These species share a high sequence homology of 16S rDNA and several molecular techniques already applied to discriminate among them give ambiguous results. RESULTS: This work illustrates a simple and cheap molecular tool for the identification of Bifidobacterium species. The hsp60 universal primers were used in a simple PCR procedure for the direct amplification of 590 bp of the hsp60 sequence. The in silico restriction analysis of bifidobacterial hsp60 partial sequences allowed the identification of a single endonuclease (HaeIII) able to provide different PCR-restriction fragment length polymorphism (RFLP) patterns in the Bifidobacterium spp. type strains evaluated. The electrophoretic analyses allowed to confirm the different RFLP patterns. CONCLUSIONS: The developed PCR-RFLP technique resulted in efficient discrimination of the tested species and subspecies and allowed the construction of a dichotomous key in order to differentiate the most widely distributed Bifidobacterium species as well as the subspecies belonging to B. pseudolongum and B. animalis. PMID- 23815604 TI - Surface and size effects on cell interaction of gold nanoparticles with both phagocytic and nonphagocytic cells. AB - With the development of nanotechnology and its application in biomedicine, studies on the interaction between nanoparticles and cells have become increasingly important. To understand the surface and size effects on cell interaction of nanoparticles, the cellular uptake behaviors of two series of gold nanoparticles (AuNPs) with both positively and negatively charged surfaces and sizes range from ~16 to ~58 nm were investigated in both phagocytic RAW 264.7 and nonphagocytic HepG2 cells. The internalization of AuNPs was quantified by ICP-MS, and the intracellular fate of NPs was evaluated by TEM analysis. The results showed that the AuNPs with positive surface charge have much higher cell internalization ability than those with negative surface charge in nonphagocytic HepG2 cells. However, the uptake extent of negatively charged AuNPs was similar with that of the positively charged AuNPs when in phagocytic RAW 264.7 cells. Among the tested size range, negatively charged AuNPs with a diameter of ~40 nm had the highest uptake in both cells, while the positively charged AuNPs did not show a certain tendency. Intracellular TEM analysis demonstrated the different fate of AuNPs in different cells, where both the positively and negatively charged AuNPs were mainly trapped in the lysosomes in HepG2 cells, but many of them were localized in phagosomes when in RAW 264.7 cells. Cytotoxicity of these AuNPs was tested by both MTT and LDH assays, which suggested NP's toxicity is closely related to the tested cell types besides the surface and size of NPs. It demonstrates that cell interaction between nanoparticles and cells is not only affected by surface and size factors but also strongly depends on cell types. PMID- 23815605 TI - Investigational drugs for pruritus. AB - INTRODUCTION: Chronic pruritus (CP), defined as itch lasting for > 6 weeks, is a burdensome symptom of several different diseases, dermatological and systemic, with a high negative impact on the quality of life of patients. Given the manifold aetiologies of CP, therapy is often difficult. In recent years, however, novel substances have been developed for treatment of certain CP entities and identified targets. AREAS COVERED: In this review, the authors present a survey of targets currently believed to be promising (H4R, IL-31, MOR, KOR, GRPR, NGF, NK-1R, TRP channels) and related investigational drugs that are in the preclinical or clinical stage of development. Some substances have already undergone clinical testing, but only one of them (nalfurafine) has been licensed so far. Many of them are most likely to exert their effects on the skin and interfere there with the cutaneous neurobiology of CP. EXPERT OPINION: Currently, the most promising candidates for new therapeutic agents in CP are neurokinin-1 receptor antagonists and substances targeting the kappa- or mu-opioid receptor, or both. They have the potential to target the neuronal pathway of CP and are thus of interest for several CP entities. The goal for the coming years is to validate these concepts and move forward in developing new drugs for the therapy of CP. PMID- 23815606 TI - Differences in post-mortem findings after stillbirth in women with and without diabetes. AB - AIMS: The reason for the fivefold increased risk of stillbirth in women with diabetes is not known. Further understanding of the underlying mechanisms may facilitate identification of pregnancies at increased risk. We have compared post mortem reports in matched pairs of stillbirths in women with and without diabetes. METHODS: Post-mortem reports were provided by the Centre for Maternal and Child Enquiries. Stillbirths as a result of lethal congenital and genetic abnormalities were excluded. Whole body, placenta and organ weights and histo pathological findings in cases and controls were compared and also related to published reference values. RESULTS: We analysed post-mortem reports on 23 matched pairs of stillbirths from 2009 to 2010. Mean placental weight in women with diabetes was 75 g less than in control subjects (95% CI -143 to -7 g; P = 0.032). In maternal diabetes, the thymus was often small and showed a 'starry sky' pattern on histology in 11 of 20 cases compared with four of 22 controls (P = 0.03). This histological finding was associated with a particularly low mean placental weight z-score -2.1 (1.1) standard deviations below a reference population corrected for gestational age. CONCLUSIONS: In over half of the stillbirths occurring in women with diabetes, there was a 'starry sky' appearance in the fetal thymus on histology, this being associated with a small placenta. These findings are consistent with a critical subacute metabolic disturbance being a prominent cause of the increased risk of stillbirth in pregnancies complicated by maternal diabetes. PMID- 23815607 TI - Answer to comment on "sleep quality, arousal and pain thresholds in migraineurs: a blinded controlled polysomnographic study". AB - We discuss the comments on our article "Sleep quality, arousal and pain thresholds in migraineurs. A blinded controlled polysomnographic study" published in JHP 2013 Feb 14;14(1):12. We hypothesize that migraineurs need more sleep than healthy controls and more sleep than they manage to achieve. Some migraineurs probably have a decreased ability to process incoming stimuli. Increased spontaneous pain may follow either sleep restriction or sleep disturbance. A comparison of migraineurs with attack onset related to sleep, migraineurs with attack onset not related to sleep and controls will be reported in another paper. PMID- 23815608 TI - Changes of maternal dietary intake, bodyweight and fetal growth throughout pregnancy in pregnant Japanese women. AB - AIM: The associations among changes in dietary intake, maternal bodyweight, and fetal growth during the course of pregnancy were investigated in a prospective cohort study carried out on 135 Japanese women. MATERIAL AND METHODS: Dietary intake was analyzed using digital photos of meals taken over 3 consecutive days, in the first, second and third trimester, and was compared with maternal bodyweight, estimated fetal bodyweight by ultrasound examination, and birthweight. RESULTS: Surprisingly, the mean total calorie intake remained below 1600 kcal/day during pregnancy, much lower than the value recommended in the 2010 edition of 'Dietary Reference Intakes for Japanese'. Dietary intake was similar throughout despite the recommendation of extra intake in late pregnancy. Maternal dietary intake did not correlate with fetal growth, although maternal bodyweight in the second trimester positively correlated with estimated fetal bodyweight in the third trimester. Maternal bodyweight before pregnancy positively correlated with birthweight. CONCLUSIONS: Maternal bodyweight as well as eating habits established before pregnancy may have a considerable effect on fetal growth. There is an urgent need to improve the diet of Japanese women of child-bearing age, especially during pregnancy. PMID- 23815609 TI - Magnetic alignment of hexagonal boron nitride platelets in polymer matrix: toward high performance anisotropic polymer composites for electronic encapsulation. AB - We report magnetic alignment of hexagonal boron nitride (hBN) platelets and the outstanding material properties of its polymer composite. The magnetically responsive hBN is produced by surface modification of iron oxide, and their orientations can be controlled by applying an external magnetic field during polymer curing. Owing to the anisotropic properties of hBN, the epoxy composite with aligned hBN platelets shows interesting properties along the alignment direction, including significantly reduced coefficient of thermal expansion, reaching ~28.7 ppm/ degrees C, and enhanced thermal conductivity, 104% higher than that of unaligned counterpart, both of which are observed at a low filler loading of 20 wt %. Our modeling suggests the filler alignment is the major reason for these intriguing material properties. Finite element analysis reveals promising applications for the magnetically aligned hBN-based composites in modern microelectronic packaging. PMID- 23815610 TI - Inkjet nanoinjection for high-thoughput chemiluminescence immunoassay on multicapillary glass plate. AB - We report a novel chemiluminescence diagnosis system for high-throughput human IgA detection by inkjet nanoinjection on a multicapillary glass plate. As proof of-concept, microhole-based polydimethylsiloxane (PDMS) sheets were aligned on a multicapillary glass plate to form a microwell array as microreactors for enzyme linked immunosorbent assay (ELISA). The multicapillary glass plate was utilized as a switch that controlled the holding/passing of the solution. Further, anti IgA-labeled polystyrene (PS) microbeads was assembled into the microwell array, and an inkjet nanoinjection was specially used to distribute the sample and reagent solution for chemiluminescence ELISA, enabling high-throughput detection of human IgA. As a result, the performance of human IgA tests revealed a wider range for the calibration curve and a lower limit of detection (LOD) of 0.1 ng mL(-1) than the ELISA by a standard 96-well plate. The analysis time and reagent consumption were significantly decreased. The IgA concentrations in saliva samples were determined after 10000-fold dilution by the developed ELISA system showing comparable results by conventional immune assay with 96-wells. Thus, we believe that the inkjet nanoinjection for high-throughput chemiluminescence immunoassay on a multicapillary glass plate will be promising in disease diagnosis. PMID- 23815611 TI - Integrating peptides' sequence and energy of contact residues information improves prediction of peptide and HLA-I binding with unknown alleles. AB - BACKGROUND: The HLA (human leukocyte antigen) class I is a kind of molecule encoded by a large family of genes and is characteristic of high polymorphism. Now the number of the registered HLA-I molecules has exceeded 3000. Slight differences in the amino acid sequences of HLAs would make them bind to different sets of peptides. In the past decades, although many methods have been proposed to predict the binding between peptides and HLA-I molecules and achieved good performance, most experimental data used by them is limited to the HLAs with a small number of alleles. Thus they are inclined to obtain high prediction accuracy only for data with similar alleles. Because the peptides and HLAs together determine the binding, it's necessary to consider their contribution meanwhile. RESULTS: By taking into account the features of the peptides sequence and the energy of contact residues, in this paper a method based on the artificial neural network is proposed to predict the binding of peptides and HLA I even when the HLAs' potential alleles are unknown. Two experiments in the allele-specific and super-type cases are performed respectively to validate our method. In the first case, we collect 14 HLA-A and 14 HLA-B molecules on Bjoern Peters dataset, and compare our method with the ARB, SMM, NetMHC and other 16 online methods. Our method gets the best average AUC (Area under the ROC) value as 0.909. In the second one, we use leave one out cross validation on MHC-peptide binding data that has different alleles but shares the common super-type. Compared to gold standard methods like NetMHC and NetMHCpan, our method again achieves the best average AUC value as 0.847. CONCLUSIONS: Our method achieves satisfactory results. Whenever it's tested on the HLA-I with single definite gene or with super-type gene locus, it gets better classification accuracy. Especially, when the training set is small, our method still works better than the other methods in the comparison. Therefore, we could make a conclusion that by combining the peptides' information, HLAs amino acid residues' interaction information and contact energy, our method really could improve prediction of the peptide HLA-I binding even when there aren't the prior experimental dataset for HLAs with various alleles. PMID- 23815612 TI - Slug promoted vasculogenic mimicry in hepatocellular carcinoma. AB - Vasculogenic mimicry (VM) refers to the unique capability of aggressive tumour cells to mimic the pattern of embryonic vasculogenic networks. Epithelial mesenchymal transition (EMT) regulator slug have been implicated in the tumour invasion and metastasis of human hepatocellular carcinoma (HCC). However, the relationship between slug and VM formation is not clear. In the study, we demonstrated that slug expression was associated with EMT and cancer stem cell (CSCs) phenotype in HCC patients. Importantly, slug showed statistically correlation with VM formation. We consistently demonstrated that an overexpression of slug in HCC cells significantly increased CSCs subpopulation that was obvious by the increased clone forming efficiency in soft agar and by flowcytometry analysis. Meantime, the VM formation and VM mediator overexpression were also induced by slug induction. Finally, slug overexpression lead to the maintenance of CSCs phenotype and VM formation was demonstrated in vivo. Therefore, the results of this study indicate that slug induced the increase and maintenance of CSCs subpopulation and contributed to VM formation eventually. The related molecular pathways may be used as novel therapeutic targets for the inhibition of HCC angiogenesis and metastasis. PMID- 23815614 TI - Indirect measures as a signal for evaluative change. AB - Implicit and explicit attitudes can be changed by using evaluative learning procedures. In this contribution we investigated an asymmetric effect of order of administration of indirect and direct measures on the detection of evaluative change: A change in explicit attitudes is more likely detected if they are measured after implicit attitudes, whereas these latter change regardless of the order. This effect was demonstrated in two studies (n=270; n=138) using the self referencing task whereas it was not found in a third study (n=151) that used a supraliminal sequential evaluative conditioning paradigm. In all studies evaluative change was present only for contingency aware participants. We discuss a potential explanation underlying the order of measure effect entailing that, in some circumstances, an indirect measure is not only a measure but also a signal that can be detected through self-perception processes and further elaborated at the propositional level. PMID- 23815613 TI - Glucosamine-induced reduction of integrin beta4 and plectin complex stimulates migration and proliferation in mouse embryonic stem cells. AB - We investigated the role of glucosamine (GlcN) on the integrin beta4/plectin complex and its role in the regulation of mouse embryonic stem cell (mESC) migration and proliferation. GlcN significantly decreased integrin beta4 mRNA/protein expression, whereas plectin protein expression did not change. Also, decrease of integrin beta4 expression caused reduction of integrin beta4/plectin complex formation, and then increased cell migration. GlcN increased intracellular calcium influx and protein kinase C (PKC) phosphorylation followed by integrin beta4 serine phosphorylation and reduction of the integrin beta4/plectin complex. GlcN entered into the cell through glucose transporter 1 and then increased O-GlcNAc transferase (OGT) and the level of glycosylation (CTD110.6). Inhibition of OGT (OGT inhibitor; ST045849) increased integrin beta4/plectin complex opposite with decreased cell migration. Moreover, GlcN increased O-GlcNAc-specificity protein 1 (Sp1) and nuclear translocated p-Sp1 stimulated calmodulin (CaM) expression, which combined with plectin. In addition, GlcN increased Akt glycosylation and glycogen synthase kinase-3beta (GSK-3beta) phosphorylation, and then Snail1 glycosylation. Snail small interfering ribonucleic acid (siRNA) reversed the reduction of integrin beta4/plectin complex and dissociation of cell junctions (tight and adherent junction). GlcN increased cell migration, cell cycle regulatory proteins [cyclinD1, cyclin-dependent kinase 4 (CDK4), cyclinE, and CDK2], and the percentage of S phase cells, which were inhibited by a PKC inhibitor, CaM siRNA, or Snail1 siRNA. Additionally, GlcN maintained the undifferentiation status of ESCs. In conclusion, GlcN contributed to migration and proliferation of mESCs through integrin beta4/plectin complex reduction via Ca2+/PKC, as well as the Sp1/CaM and Akt/GSK-3beta/Snail1 signaling pathway. PMID- 23815615 TI - A tribute to Rene P. Schwarzenbach. PMID- 23815616 TI - Interdisciplinary research to address societal issues. PMID- 23815617 TI - Teaching how pollutants behave. PMID- 23815618 TI - Biotransformation of the UV-filter sulisobenzone: challenges for the identification of transformation products. AB - The UV-filter substance Sulisobenzone (BP-4) is widely employed in sunscreens and other personal care products. In the current study, its behavior during biological wastewater treatment was investigated. In contact with activated sludge BP-4 was degraded in aerobic batch experiments forming at least nine transformation products (TPs). The mass balance in the batch experiments was closed, as measurements with LC-UV underlined that the quantity of the TPs was comparable to the BP-4 quantity transformed. The chemical structures of the nine TPs could be proposed based on accurate mass measurements by high resolution mass spectrometry (LTQ-Orbitrap-MS), several fragmentation experiments up to MS(6) and synthesis of one TP. NMR analyses of the main TP confirmed its proposed chemical structure. At the beginning of the biotransformation of BP-4, a benzhydrol analogue was formed due to the reduction of the keto moiety. Further reactions (e.g., oxidation, demethylation, decarboxylation) led to the formation of extremely polar TPs. A biodegradation pathway was proposed based on the TP structures identified and the sequence of the TP formation. The isolated TPs exhibited higher toxic effects on Vibrio fischeri than BP-4. The results contribute to a better general understanding and prediction of the biotransformation of aromatic sulfonic acids in WWTPs. PMID- 23815619 TI - Evaluation of the adjuvant effect of Salmonella-based Escherichia coli heat labile toxin B subunits on the efficacy of a live Salmonella-delivered avian pathogenic Escherichia coli vaccine. AB - The present study evaluated the adjuvant effect of live attenuated salmonella organisms expressing the heat-labile toxin of Escherichia coli B subunit (LTB) on the efficacy of an avian pathogenic Escherichia coli (APEC) vaccine. The Asd(+) (aspartate semialdehyde dehydrogenase) plasmid pMMP906 containing the LTB gene was introduced into a Salmonella enterica Typhimurium strain lacking the lon, cpxR and asd genes to generate the adjuvant strain. Live recombinant Salmonella delivered APEC vaccine candidates were used for this study. The birds were divided into three groups: group A, non-vaccinated controls; group B, immunized with vaccine candidates only; and group C, immunized with vaccine candidates and the LTB strain. The immune responses were measured and the birds were challenged at 21 days of age with a virulent APEC strain. Group C showed a significant increase in plasma IgG and intestinal IgA levels and a significantly higher lymphocyte proliferation response compared with the other groups. Upon challenge with the virulent APEC strain, group C showed effective protection whereas group B did not. We also attempted to optimize the effective dose of the adjuvant. The birds were immunized with the vaccine candidates together with 1*107 or 1*108 colony-forming units of the LTB strain and were subsequently challenged at 3 weeks of age. The 1*107 colony-forming units of the LTB strain showed a greater adjuvant effect with increased levels of serum IgG, intestinal IgA and a potent lymphocyte proliferation response, and yielded higher protection against challenge. Overall, the LTB strain increased the efficacy of the Salmonella delivered APEC vaccine, indicating that vaccination for APEC along with the LTB strain appears to increase the efficacy for protection against colibacillosis in broiler chickens. PMID- 23815620 TI - Prediction of protein-protein interactions from amino acid sequences with ensemble extreme learning machines and principal component analysis. AB - BACKGROUND: Protein-protein interactions (PPIs) play crucial roles in the execution of various cellular processes and form the basis of biological mechanisms. Although large amount of PPIs data for different species has been generated by high-throughput experimental techniques, current PPI pairs obtained with experimental methods cover only a fraction of the complete PPI networks, and further, the experimental methods for identifying PPIs are both time-consuming and expensive. Hence, it is urgent and challenging to develop automated computational methods to efficiently and accurately predict PPIs. RESULTS: We present here a novel hierarchical PCA-EELM (principal component analysis-ensemble extreme learning machine) model to predict protein-protein interactions only using the information of protein sequences. In the proposed method, 11188 protein pairs retrieved from the DIP database were encoded into feature vectors by using four kinds of protein sequences information. Focusing on dimension reduction, an effective feature extraction method PCA was then employed to construct the most discriminative new feature set. Finally, multiple extreme learning machines were trained and then aggregated into a consensus classifier by majority voting. The ensembling of extreme learning machine removes the dependence of results on initial random weights and improves the prediction performance. CONCLUSIONS: When performed on the PPI data of Saccharomyces cerevisiae, the proposed method achieved 87.00% prediction accuracy with 86.15% sensitivity at the precision of 87.59%. Extensive experiments are performed to compare our method with state-of the-art techniques Support Vector Machine (SVM). Experimental results demonstrate that proposed PCA-EELM outperforms the SVM method by 5-fold cross-validation. Besides, PCA-EELM performs faster than PCA-SVM based method. Consequently, the proposed approach can be considered as a new promising and powerful tools for predicting PPI with excellent performance and less time. PMID- 23815621 TI - Electrochemical tattoo biosensors for real-time noninvasive lactate monitoring in human perspiration. AB - The present work describes the first example of real-time noninvasive lactate sensing in human perspiration during exercise events using a flexible printed temporary-transfer tattoo electrochemical biosensor that conforms to the wearer's skin. The new skin-worn enzymatic biosensor exhibits chemical selectivity toward lactate with linearity up to 20 mM and demonstrates resiliency against continuous mechanical deformation expected from epidermal wear. The device was applied successfully to human subjects for real-time continuous monitoring of sweat lactate dynamics during prolonged cycling exercise. The resulting temporal lactate profiles reflect changes in the production of sweat lactate upon varying the exercise intensity. Such skin-worn metabolite biosensors could lead to useful insights into physical performance and overall physiological status, hence offering considerable promise for diverse sport, military, and biomedical applications. PMID- 23815622 TI - Pregabalin is increasingly prescribed for neuropathic pain, generalised anxiety disorder and epilepsy but many patients discontinue treatment. AB - AIM: To assess prescribing patterns, sociodemographic characteristics and previous disease history in patients receiving pregabalin. METHODS: An observational study using register data on dispensed drugs and recorded diagnoses for all patients in Stockholm, Sweden, who filled at least one prescription of pregabalin between July 2005 and December 2009. Analyses focused on prevalence, incidence, diagnosis patterns, prior dispensing of other analgesics/psychotropics and persistence to treatment over time. RESULT: A total of 18,626 patients (mean age 55 years, 63% women) were initiated on treatment between July 2006 and December 2009. Approved indications were recorded in hospital and/or primary care within 1 year prior to the first dispensing for 40% of the patients (epilepsy 1.3%, neuropathic pain 35.5% and generalised anxiety disorder (GAD) 3.6%). Antidepressants were used by 55%, opioids by 49% and sedatives by 48% prior to initiation of pregabalin. One-third (34%) only purchased one prescription and the proportion purchasing pregabalin 1 year after initiation was 42.1% for epilepsy, 36.3% for GAD, 21.5% for neuropathic pain and 25.6% for those without any of the included diagnoses. CONCLUSION: Pregabalin was mainly used as a second-line drug for the treatment of GAD or neuropathic pain and to a lesser extent as add-on therapy in epilepsy. However, a large proportion of all patients only purchased one prescription and the persistence declined rapidly over time. The issue of potential off-label prescribing or poor registration of diagnoses should also be noted as a high proportion had been prescribed the drug without a record of any of the approved indications. PMID- 23815623 TI - Migraine and periodic limb movement disorders in sleep in children: a preliminary case-control study. AB - BACKGROUND: The relationships between sleep and headaches are complex and manifold. About the variety of phenomena that can disrupt the sleep macrostructure and can impact its restorative function, the periodic limb movements disorder (PLMd) can be considered as the most powerful.No studies are known about the role of PLMd in the pathophysiology of migraine in children.Aim of study is to assess the prevalence of PLMd and migraine and their relationship with disability and pain intensity in a pediatric sample, referred for migraine without aura by pediatricians. METHODS: After a preliminary sleep habits screening with the Sleep Disturbances Scale for Children, 34 migraine subjects affected by migraine without aura (20 M, 14 F) (mean age 9.08; SD +/- 2.28) and 51 volunteers healthy children (28 M, 23 F) (mean age 9.37; SD +/- 1.81) accepted to underwent overnight PSG recordings in the Sleep Laboratory of the Clinic of Child and Adolescent Neuropsychiatry, in order to define the macrostructural sleep characteristics and the prevalence of PLMd. Subsequently, the migraineurs sample was studied in order to define the relationship between disability, pain intensity, therapeutical responsiveness and the presence of PLMd. RESULTS: In the migraineurs children group, the individuals with PLM pathological index (PLMI >= 5) represent the 26.47% of sample and present higher frequency (p < 0.001), intensity (p < 0.001), duration (p = 0.006) and life impairment as scored in the PedMIDAS (p < 0.001) of headache and lower efficacy of prophylactic (p = 0.001) and acute (p = 0.006) pharmacological treatment than MoA children without PLM pathological index. CONCLUSIONS: This preliminary study indicates the potential value of the determination of the PLMd signs, and the importance of the PSG evaluation in children affected by migraine, particularly when the clinical and pharmacological management tend to fail in the attacks control. PMID- 23815624 TI - Self-cleaning organic/inorganic photo-sensors. AB - We present the fabrication of a multifunctional, hybrid organic-inorganic micropatterned device, which is capable to act as a stable photosensor and, at the same time, displaying inherent superhydrophobic self-cleaning wetting characteristics. In this framework several arrays of epoxy photoresist square micropillars have been fabricated on n-doped crystalline silicon substrates and subsequently coated with a poly(3-hexylthiophene-2,5-diyl) (P3HT) layer, giving rise to an array of organic/inorganic p-n junctions. Their photoconductivity has been measured under a solar light simulator at different illumination intensities. The current-voltage (I-V) curves show high rectifying characteristics, which are found to be directly correlated with the illumination intensity. The photoresponse occurs in extremely short times (within few tens of milliseconds range). The influence of the interpillar distance on the I-V characteristics of the sensors is also discussed. Moreover, the static and dynamic wetting properties of these organic/inorganic photosensors can be easily tuned by changing the pattern geometry. Measured static water contact angles range from 125 degrees to 164 degrees , as the distance between the pillars is increased from 14 to 120 MUm while the contact angle hysteresis decreases from 36 degrees down to 2 degrees . PMID- 23815626 TI - Melatonin ameliorates angiotensin II-induced vascular endothelial damage via its antioxidative properties. AB - Melatonin is well known to have a beneficial effect on the cardiovascular system, but it remains to be elucidated whether melatonin has a therapeutic effect on the vascular damage induced by the potential vasoactive substance angiotensin II (Ang II). In this study, the effects of melatonin on Ang II-induced vascular endothelial damage were investigated. In cultured vascular endothelial cells, Ang II stimulation increased ROS generation and inhibited eNOS phosphorylation (Ser1177), both of which were clearly restored by pretreatment with melatonin. The translocation of p47(phox) subunit of NADPH oxidase from the cytosol to plasma membrane was promoted in Ang II-treated vascular endothelial cells, which was canceled by melatonin pretreatment. In Ang II-infused rats, increased ROS generation in the aortic wall and impaired endothelial function of the aortic ring were observed, which were rescued by coadministration of melatonin. In vasculature, melatonin receptor agonist ramelteon had the antioxidative effect in the same manner as melatonin by itself. These findings suggest that melatonin directly ameliorates Ang II-induced vascular endothelial damage partly via its antioxidative properties, providing with us the potential rationale for clinical application of melatonin to the prevention from cardiovascular diseases. PMID- 23815627 TI - Relationship self-efficacy protects against mental health problems among women in bidirectionally aggressive intimate relationships with men. AB - Research examining predictors or correlates of mental health problems among women who experience or use aggression in intimate relationships typically assesses factors that confer risk. Such research has primarily examined intimate partner violence (IPV) victimization or aggression frequency or severity as central risk factors for mental health problems. In the general population, one factor demonstrating a protective effect on mental health problems is self-efficacy. Research on self-efficacy among women who experience or use aggression in intimate relationships is nearly absent. The purpose of this study was to determine if self-efficacy specific to a woman's ability to manage various relationship problems (i.e., relationship self-efficacy [RSE]) played a protective role against the severity of posttraumatic stress, depression, and anxiety symptoms among 354 community-residing women who were victimized and used aggression (bidirectional IPV). Regression analyses found that RSE uniquely predicted each mental health outcome above and beyond what was accounted for by the frequency of physical, sexual, and psychological victimization and aggression. Further, RSE fully mediated the relationships between psychological victimization and each mental health outcome. If replicated, and in circumstances where it is determined safe to do so, findings suggest RSE as a promising avenue for future research to improve the health and well-being of women in bidirectionally aggressive relationships. PMID- 23815625 TI - Caspase-2 is essential for c-Jun transcriptional activation and Bim induction in neuron death. AB - Neuronal apoptotic death generally requires de novo transcription, and activation of the transcription factor c-Jun has been shown to be necessary in multiple neuronal death paradigms. Caspase-2 has been implicated in death of neuronal and non-neuronal cells, but its relationship to transcriptional activation has not been clearly elucidated. In the present study, using two different neuronal apoptotic paradigms, beta-amyloid treatment and NGF (nerve growth factor) withdrawal, we examined the hierarchical role of caspase-2 activation in the transcriptional control of neuron death. Both paradigms induce rapid activation of caspase-2 as well as activation of the transcription factor c-Jun and subsequent induction of the pro-apoptotic BH3 (Bcl-homology domain 3)-only protein Bim (Bcl-2-interacting mediator of cell death). Caspase-2 activation is dependent on the adaptor protein RAIDD {RIP (receptor-interacting protein) associated ICH-1 [ICE (interleukin-1beta-converting enzyme)/CED-3 (cell-death determining 3) homologue 1] protein with a death domain}, and both caspase-2 and RAIDD are required for c-Jun activation and Bim induction. The present study thus shows that rapid caspase-2 activation is essential for c-Jun activation and Bim induction in neurons subjected to apoptotic stimuli. This places caspase-2 at an apical position in the apoptotic cascade and demonstrates for the first time that caspase-2 can regulate transcription. PMID- 23815628 TI - Navigating the borderlands: the roles of minority stressors, bicultural self efficacy, and cognitive flexibility in the mental health of bisexual individuals. AB - The present study examined the relations of minority stressors (i.e., experiences of prejudice, expectations of stigma, internalized biphobia, outness/concealment of bisexuality) as well as posited mental health promoters (i.e., bicultural self efficacy, cognitive flexibility) with psychological distress and well-being in a sample of 411 bisexual people. Most of the minority stress variables were related positively with psychological distress and negatively with well-being, whereas the mental health-promoting variables were related negatively with psychological distress and positively with well-being. Results also indicated that expectations of stigma mediated the associations of antibisexual prejudice with greater distress and lower well-being, internalized biphobia was related directly with greater distress and lower well-being, and outness was linked with some costs and benefits. Moderated mediation analyses offered some evidence consistent with cognitive flexibility (but not bicultural self-efficacy) as a moderator. Specifically, within the mediation models, cognitive flexibility moderated the unique direct relation of antibisexual prejudice with psychological well-being, the relation of antibisexual prejudice with expectations of stigma, and the indirect relations of antibisexual prejudice with distress and well-being through the mediating role of expectations of stigma. These moderations were consistent with the expected buffering role of cognitive flexibility, but they also revealed that some of this buffering effect is exhausted in the context of high prejudice. Limitations of the study as well as implications for future research and practice with bisexual populations are discussed. PMID- 23815629 TI - Disentangling self-stigma: are mental illness and help-seeking self-stigmas different? AB - Two established but disparate lines of research exist: studies examining the self stigma associated with mental illness and studies examining the self-stigma associated with seeking psychological help. Whereas some researchers have implicitly treated these 2 constructs as synonymous, others have made the argument that they are theoretically and empirically distinct. To help clarify this debate, we examined in the present investigation the overlap and uniqueness of the self-stigmas associated with mental illness and with seeking psychological help. Data were collected from a sample of college undergraduates experiencing clinical levels of psychological distress (N = 217) and a second sample of community members with a self-reported history of mental illness (N = 324). Confirmatory factor analyses provide strong evidence for the factorial independence of the 2 types of self-stigma. Additionally, results of regression analyses in both samples suggest that the 2 self-stigmas uniquely predict variations in stigma-related constructs (i.e., shame, self-blame, and social inadequacy) and attitudes and intentions to seek help. Implications for researchers and clinicians interested in understanding stigma and enhancing mental health service utilization are discussed. PMID- 23815630 TI - Substance use disorders and racial/ethnic minorities matter: a meta-analytic examination of the relation between alliance and outcome. AB - The purpose of this meta analysis was to examine the moderating impact of substance use disorder as inclusion/exclusion criterion as well as the percentage of racial/ethnic minorities on the strength of the alliance-outcome relationship in psychotherapy. It was hypothesized that the presence of a Diagnostic and Statistical Manual of Mental Disorders (DSM) Axis I substance use disorder as a criterion and the presence of racial/ethnic minorities as a sociocultural indicator are moderately correlated client factors reducing the relationship between alliance and outcome. A random effects restricted maximum-likelihood estimator was used for omnibus and moderator models (k = 94). The presence of (a) substance use disorder and (b) racial/ethnic minorities (overall and specific to African Americans) partially moderated the alliance-outcome correlation. The percentage of substance use disorders and racial/ethnic minority status was unexpectedly highly correlated in the present treatment research samples. Sociocultural contextual variables should be considered along with a DSM Axis I diagnosis of substance use disorders in analyzing and interpreting therapy process variables such as the alliance. PMID- 23815631 TI - Social cognitive model of career self-management: toward a unifying view of adaptive career behavior across the life span. AB - Social cognitive career theory (SCCT) currently consists of 4 overlapping, segmental models aimed at understanding educational and occupational interest development, choice-making, performance and persistence, and satisfaction/well being. To this point, the theory has emphasized content aspects of career behavior, for instance, prediction of the types of activities, school subjects, or career fields that form the basis for people's educational/vocational interests and choice paths. However, SCCT may also lend itself to study of many process aspects of career behavior, including such issues as how people manage normative tasks and cope with the myriad challenges involved in career preparation, entry, adjustment, and change, regardless of the specific educational and occupational fields they inhabit. Such a process focus can augment and considerably expand the range of the dependent variables for which SCCT was initially designed. Building on SCCT's existing models, we present a social cognitive model of career self-management and offer examples of the adaptive, process behaviors to which it can be applied (e.g., career decision making/exploration, job searching, career advancement, negotiation of work transitions and multiple roles). PMID- 23815632 TI - Testing the tenets of minority stress theory in workplace contexts. AB - The links of minority stressors (workplace discrimination, expectations of stigma, internalized heterosexism, and identity management strategies) with psychological distress and job satisfaction were examined in a sample of 326 sexual minority employees. Drawing from minority stress theory and the literature on the vocational experiences of sexual minority people, patterns of mediation and moderation were tested. Minority stressors were associated with greater distress and lower job satisfaction. A mediation model was supported in which the links of discrimination and internalized heterosexism with psychological distress were mediated by a concealment-focused identity management strategy (i.e., avoiding), and the links of discrimination, expectations of stigma, and internalized heterosexism with job satisfaction were mediated by a disclosure focused identity management strategy (i.e., integrating). Tests of moderation indicated that for sexual minority women (but not men), the positive association of discrimination with distress was stronger at higher levels of internalized heterosexism than at lower levels. In addition, lower levels of internalized heterosexism and concealment strategies (i.e., counterfeiting and avoiding) and higher levels of a disclosure strategy (i.e., integrating) were associated with higher job satisfaction in the context of low discrimination, but this buffering effect disappeared as level of discrimination increased. The implications of these findings for minority stress research are discussed, and clinical recommendations are made. PMID- 23815633 TI - Dose-effect relationship in routine outpatient psychotherapy: does treatment duration matter? AB - OBJECTIVE: There is an ongoing debate concerning how outcome variables change during the course of psychotherapy. We compared the dose-effect model, which posits diminishing effects of additional sessions in later treatment phases, against a model that assumes a linear and steady treatment progress through termination. METHOD: Session-by-session outcome data of 6,375 outpatients were analyzed, and participants were categorized according to treatment length. Linear and log-linear (i.e., negatively accelerating) latent growth curve models (LGCMs) were estimated and compared for different treatment length categories. RESULTS: When comparing the fit of the various models, the log-linear LGCMs assuming negatively accelerating treatment progress consistently outperformed the linear models irrespective of treatment duration. The rate of change was found to be inversely related to the length of treatment. CONCLUSION: As proposed by the dose effect model, the expected course of improvement in psychotherapy appears to follow a negatively accelerated pattern of change, irrespective of the duration of the treatment. However, our results also suggest that the rate of change is not constant across various treatment lengths. As proposed by the "good enough level" model, longer treatments are associated with less rapid rates of change. PMID- 23815635 TI - Small bite-angle P-OP ligands for asymmetric hydroformylation and hydrogenation. AB - A series of small bite-angle phosphine-phosphite (P-OP) ligands have been synthesized by a two-step method. The key intermediate was prepared by an unprecedented asymmetric carbonyl reduction of a phosphamide using the CBS (Corey Bakshi-Shibata) catalyst. The topology of these ligands (a configurationally stable stereogenic carbon with two heteroatom substituents) and their small bite angle (created by the close proximity of the two ligating groups to the metal center) together provide a rigid asymmetric environment around this center, enabling high stereoselectivity in hydroformylations and hydrogenations of standard substrates. PMID- 23815634 TI - Induction of cortical plasticity and improved motor performance following unilateral and bilateral transcranial direct current stimulation of the primary motor cortex. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) is a non-invasive technique that modulates the excitability of neurons within the primary motor cortex (M1). Research shows that anodal-tDCS applied over the non-dominant M1 (i.e. unilateral stimulation) improves motor function of the non-dominant hand. Similarly, previous studies also show that applying cathodal tDCS over the dominant M1 improves motor function of the non-dominant hand, presumably by reducing interhemispheric inhibition. In the present study, one condition involved anodal-tDCS over the non-dominant M1 (unilateral stimulation) whilst a second condition involved applying cathodal-tDCS over the dominant M1 and anodal tDCS over non-dominant M1 (bilateral stimulation) to determine if unilateral or bilateral stimulation differentially modulates motor function of the non-dominant hand. Using a randomized, cross-over design, 11 right-handed participants underwent three stimulation conditions: 1) unilateral stimulation, that involved anodal-tDCS applied over the non-dominant M1, 2) bilateral stimulation, whereby anodal-tDCS was applied over the non-dominant M1, and cathodal-tDCS over the dominant M1, and 3) sham stimulation. Transcranial magnetic stimulation (TMS) was performed before, immediately after, 30 and 60 minutes after stimulation to elucidate the neural mechanisms underlying any potential after-effects on motor performance. Motor function was evaluated by the Purdue pegboard test. RESULTS: There were significant improvements in motor function following unilateral and bilateral stimulation when compared to sham stimulation at all-time points (all P < 0.05); however there was no difference across time points between unilateral and bilateral stimulation. There was also a similar significant increase in corticomotor excitability with both unilateral and bilateral stimulation immediately post, 30 minutes and 60 minutes compared to sham stimulation (all P < 0.05). Unilateral and bilateral stimulation reduced short-interval intracortical inhibition (SICI) immediately post and at 30 minutes (all P < 0.05), but returned to baseline in both conditions at 60 minutes. There was no difference between unilateral and bilateral stimulation for SICI (P > 0.05). Furthermore, changes in corticomotor plasticity were not related to changes in motor performance. CONCLUSION: These results indicate that tDCS induced behavioural changes in the non-dominant hand as a consequence of mechanisms associated with use-dependant cortical plasticity that is independent of the electrode arrangement. PMID- 23815636 TI - The psychometric properties of the Chinese version of the Conditions of Work Effectiveness Questionnaire-II. AB - AIMS: The present study was conducted to evaluate the psychometric properties of a newly adapted Chinese version of an instrument designed to measure structural empowerment among staff nurses. BACKGROUND: Structural empowerment has been shown to be important to nurses in Western cultures, but its importance in China is unknown. METHODS: A convenience sample of 650 staff nurses was selected from six hospitals in Harbin, China. After linguistic adaptation using the forward backward translation method, the 19-item Conditions of Work Effectiveness Questionnaire-II (CWEQ-II-CV) was answered by participants. Content validity, Cronbach's alpha, item-to-total correlation and exploratory factor analysis were used to assess the reliability and validity of the translated instrument. RESULTS: In the factor analysis, a six-factor solution was found to be reasonable with the sub-dimensions of structural empowerment that included support (three items), resources (three items), information (three items), opportunity (three items), formal power (three items) and informal power (four items). Cronbach's alpha coefficient for the total instrument was 0.92 and ranged from 0.68 to 0.86 in the six subscales. The item-to-total correlation coefficients ranged from 0.48 to 0.80. The findings also gave support for content validity. CONCLUSIONS: Evidence was found to support the reliability and validity of the CWEQ-II-CV scale that measures the quality of the work environment for nurses from a structural empowerment perspective. IMPLICATIONS FOR NURSING MANAGEMENT: The translated version of CWEQ-II-CV can provide an effective evaluation tool for structural empowerment in the Chinese nursing workplace. PMID- 23815637 TI - Radioactive cesium (134Cs and 137Cs) content in human placenta after the Fukushima nuclear power plant accident. AB - AIM: The degree of contamination with radioactive cesium (134Cs and 137Cs) in the human placenta after the accident at Fukushima nuclear power plant (FNP), which occurred on 11 March 2011, has not been assessed. MATERIAL AND METHODS: 134Cs and 137Cs contents were determined in 10 placentas from 10 women who gave birth to term singleton infants during the period between October 2011 and August 2012 using high-purity germanium detectors for gamma ray spectrometry. Five women resided within 50 km of FNP (neighbor group) and gave birth by the end of February 2012, while the other five women resided within 210-290 km of FNP (distant group) and gave birth in July and August 2012. RESULTS: All except one of the 10 placentas contained detectable levels of 134Cs and 137Cs, ranging 0.042 0.742 Bq/kg for 134Cs and 0.078-0.922 Bq/kg for 137Cs. One placenta from a woman living in Tokyo contained 0.109 Bq/kg 137Cs and no detectable level of 134Cs (<0.054 Bq/kg). 137Cs content was more than 0.2 Bq/kg in four and one placentas in the neighbor and distant groups, respectively. CONCLUSION: Degree of contamination of the placenta with radioactive Cs was lower even in women who resided within 50 km of FNP compared to Japanese and Canadian placentas in the mid-1960s after repeated nuclear tests and in northern Italian placentas from 1986-1987 after the Chernobyl power plant accident. PMID- 23815638 TI - Microbial source tracking markers for detection of fecal contamination in environmental waters: relationships between pathogens and human health outcomes. AB - Microbial source tracking (MST) describes a suite of methods and an investigative strategy for determination of fecal pollution sources in environmental waters that rely on the association of certain fecal microorganisms with a particular host. MST is used to assess recreational water quality and associated human health risk, and total maximum daily load allocations. Many methods rely on signature molecules (markers) such as DNA sequences of host-associated microorganisms. Human sewage pollution is among the greatest concerns for human health due to (1) the known risk of exposure to human waste and (2) the public and regulatory will to reduce sewage pollution; however, methods to identify animal sources are receiving increasing attention as our understanding of zoonotic disease potential improves. Here, we review the performance of MST methods in initial reports and field studies, with particular emphasis on quantitative PCR (qPCR). Relationships among human-associated MST markers, fecal indicator bacteria, pathogens, and human health outcomes are presented along with recommendations for future research. An integrated understanding of the advantages and drawbacks of the many MST methods targeting human sources advanced over the past several decades will benefit managers, regulators, researchers, and other users of this rapidly growing area of environmental microbiology. PMID- 23815640 TI - Surface stability of Pt3Ni nanoparticulate alloy electrocatalysts in hydrogen adsorption. AB - Nanoparticles of Pt/Ni alloys represent state of the art electrocatalysts for fuel cell reactions. Density functional theory (DFT) based calculations along with in situ X-ray absorption spectroscopy (XAS) data show that the surface structure of Pt3Ni nanoparticulate alloys is potential-dependent during electrocatalytic reactions. Pt3Ni based electrocatalysts demonstrate preferential confinement of Ni to the subsurface when the electrode is polarized in the double layer region where the surface is free of specifically adsorbed species. Hydrogen adsorption triggers nickel segregation to the surface. This process is facilitated by a high local surface coverage of adsorbed hydrogen in the vicinity of the surface confined Ni due to an uneven distribution of the adsorbate(s) on the catalyst's surface. The adsorption triggered surface segregation shows a non monotonous dependence on the electrode potential and can be identified as a breathing of the catalyst as was proposed previously. The observed breathing behavior is relatively fast and proceeds on a time scale of 100-1000 s. PMID- 23815641 TI - Nonclassical oxygen atom transfer as a synthetic strategy: preparation of an oxorhenium(V) complex of the bis(3,5-di-tert-butyl-2-phenoxo)amide ligand. AB - Oxo(triphenylphosphine)[bis(3,5-di-tert-butyl-2-phenoxo)amido]rhenium(V) [(ONO(Cat))ReO(PPh3)] is prepared by the reaction of iododioxobis(triphenylphosphine)rhenium(V) [ReO2(PPh3)2I] with lead bis(3,5-di tert-butyl-1,2-quinone-1-(2-oxy-3,5-di-tert-butylphenyl)imine) [Pb(ONO(Q))2]. In this reaction, the ONO ligand undergoes a two-electron reduction, with concomitant oxidation of PPh3 to OPPh3 and transformation of the dioxorhenium(V) fragment into a monooxorhenium(V) fragment, constituting a net nonclassical oxygen atom transfer. (ONO(Cat))ReO(PPh3) adopts a square pyramidal geometry with an apical oxo group [d(ReO) = 1.6873(14) A] and a highly folded ONO ligand [O-Re O = 129.55(6) degrees ]. The fully reduced, trianionic oxidation state of the ONO ligand is confirmed by spectroscopic and metrical data. PMID- 23815639 TI - The Ktr potassium transport system in Staphylococcus aureus and its role in cell physiology, antimicrobial resistance and pathogenesis. AB - Potassium (K(+) ) plays a vital role in bacterial physiology, including regulation of cytoplasmic pH, turgor pressure and transmembrane electrical potential. Here, we examine the Staphylococcus aureus Ktr system uniquely comprised of two ion-conducting proteins (KtrB and KtrD) and only one regulator (KtrA). Growth of Ktr system mutants was severely inhibited under K(+) limitation, yet detectable after an extended lag phase, indicating the presence of a secondary K(+) transporter. Disruption of both ktrA and the Kdp-ATPase system, important for K(+) uptake in other organisms, eliminated regrowth in 0.1 mM K(+) , demonstrating a compensatory role for Kdp to the Ktr system. Consistent with K(+) transport mutations, S. aureus devoid of the Ktr system became sensitive to hyperosmotic conditions, exhibited a hyperpolarized plasma membrane, and increased susceptibility to aminoglycoside antibiotics and cationic antimicrobials. In contrast to other organisms, the S. aureus Ktr system was shown to be important for low-K(+) growth under alkaline conditions, but played only a minor role in neutral and acidic conditions. In a mouse competitive index model of bacteraemia, the ktrA mutant was significantly outcompeted by the parental strain. Combined, these results demonstrate a primary mechanism of K(+) uptake in S. aureus and a role for this system in pathogenesis. PMID- 23815642 TI - New model systems for experimental evolution. AB - Microbial experimental evolution uses a few well-characterized model systems to answer fundamental questions about how evolution works. This special section highlights novel model systems for experimental evolution, with a focus on marine model systems that can be used to understand evolutionary responses to global change in the oceans. PMID- 23815643 TI - Experimental evolution meets marine phytoplankton. AB - Our perspective highlights potentially important links between disparate fields biological oceanography, climate change research, and experimental evolutionary biology. We focus on one important functional group-photoautotrophic microbes (phytoplankton), which are responsible for ~50% of global primary productivity. Global climate change currently results in the simultaneous change of several conditions such as warming, acidification, and nutrient supply. It thus has the potential to dramatically change phytoplankton physiology, community composition, and may result in adaptive evolution. Although their large population sizes, standing genetic variation, and rapid turnover time should promote swift evolutionary change, oceanographers have focussed on describing patterns of present day physiological differentiation rather than measure potential adaptation in evolution experiments, the only direct way to address whether and at which rate phytoplankton species will adapt to environmental change. Important open questions are (1) is adaptation limited by existing genetic variation or fundamental constraints? (2) Will complex ecological settings such as gradual versus abrupt environmental change influence adaptation processes? (3) How will increasing environmental variability affect the evolution of phenotypic plasticity patterns? Because marine phytoplankton species display rapid acclimation capacity (phenotypic buffering), a systematic study of reaction norms renders them particularly interesting to the evolutionary biology research community. PMID- 23815644 TI - Temporal dynamics of outcrossing and host mortality rates in host-pathogen experimental coevolution. AB - Cross-fertilization is predicted to facilitate the short-term response and the long-term persistence of host populations engaged in antagonistic coevolutionary interactions. Consistent with this idea, our previous work has shown that coevolving bacterial pathogens (Serratia marcescens) can drive obligately selfing hosts (Caenorhabditis elegans) to extinction, whereas the obligately outcrossing and partially outcrossing populations persisted. We focused the present study on the partially outcrossing (mixed mating) and obligately outcrossing hosts, and analyzed the changes in the host resistance/avoidance (and pathogen infectivity) over time. We found that host mortality rates increased in the mixed mating populations over the first 10 generations of coevolution when outcrossing rates were initially low. However, mortality rates decreased after elevated outcrossing rates evolved during the experiment. In contrast, host mortality rates decreased in the obligately outcrossing populations during the first 10 generations of coevolution, and remained low throughout the experiment. Therefore, predominant selfing reduced the ability of the hosts to respond to coevolving pathogens compared to outcrossing hosts. Thus, we found that host-pathogen coevolution can generate rapid evolutionary change, and that host mating system can influence the outcome of coevolution at a fine temporal scale. PMID- 23815645 TI - Evolutionary responses of a coccolithophorid Gephyrocapsa oceanica to ocean acidification. AB - The ongoing ocean acidification associated with a changing carbonate system may impose profound effects on marine planktonic calcifiers. Here, we show that a coccolithophore, Gephyrocapsa oceanica, evolved in response to an elevated CO2 concentration of 1000 MUatm (pH reduced to 7.8) in a long-term (~670 generations) selection experiment. The high CO2 -selected cells showed increases in photosynthetic carbon fixation, growth rate, cellular particulate organic carbon (POC) or nitrogen (PON) production, and a decrease in C:N elemental ratio, indicating a greater upregulation of PON than of POC production under the ocean acidification condition. Cells from the low CO2 selection process shifted to high CO2 exposure showed an enhanced cellular POC and PON production rates. Our data suggest that the coccolithophorid could adapt to ocean acidification with enhanced assimilations of carbon and nitrogen but decreased C:N ratios. PMID- 23815646 TI - Short- versus long-term responses to changing CO2 in a coastal dinoflagellate bloom: implications for interspecific competitive interactions and community structure. AB - Increasing pCO2 (partial pressure of CO2 ) in an "acidified" ocean will affect phytoplankton community structure, but manipulation experiments with assemblages briefly acclimated to simulated future conditions may not accurately predict the long-term evolutionary shifts that could affect inter-specific competitive success. We assessed community structure changes in a natural mixed dinoflagellate bloom incubated at three pCO2 levels (230, 433, and 765 ppm) in a short-term experiment (2 weeks). The four dominant species were then isolated from each treatment into clonal cultures, and maintained at all three pCO2 levels for approximately 1 year. Periodically (4, 8, and 12 months), these pCO2 conditioned clones were recombined into artificial communities, and allowed to compete at their conditioning pCO2 level or at higher and lower levels. The dominant species in these artificial communities of CO2 -conditioned clones differed from those in the original short-term experiment, but individual species relative abundance trends across pCO2 treatments were often similar. Specific growth rates showed no strong evidence for fitness increases attributable to conditioning pCO2 level. Although pCO2 significantly structured our experimental communities, conditioning time and biotic interactions like mixotrophy also had major roles in determining competitive outcomes. New methods of carrying out extended mixed species experiments are needed to accurately predict future long term phytoplankton community responses to changing pCO2 . PMID- 23815647 TI - Functional genetic divergence in high CO2 adapted Emiliania huxleyi populations. AB - Predicting the impacts of environmental change on marine organisms, food webs, and biogeochemical cycles presently relies almost exclusively on short-term physiological studies, while the possibility of adaptive evolution is often ignored. Here, we assess adaptive evolution in the coccolithophore Emiliania huxleyi, a well-established model species in biological oceanography, in response to ocean acidification. We previously demonstrated that this globally important marine phytoplankton species adapts within 500 generations to elevated CO2 . After 750 and 1000 generations, no further fitness increase occurred, and we observed phenotypic convergence between replicate populations. We then exposed adapted populations to two novel environments to investigate whether or not the underlying basis for high CO2 -adaptation involves functional genetic divergence, assuming that different novel mutations become apparent via divergent pleiotropic effects. The novel environment "high light" did not reveal such genetic divergence whereas growth in a low-salinity environment revealed strong pleiotropic effects in high CO2 adapted populations, indicating divergent genetic bases for adaptation to high CO2 . This suggests that pleiotropy plays an important role in adaptation of natural E. huxleyi populations to ocean acidification. Our study highlights the potential mutual benefits for oceanography and evolutionary biology of using ecologically important marine phytoplankton for microbial evolution experiments. PMID- 23815648 TI - Differences in the regulation of growth and biomineralization genes revealed through long-term common-garden acclimation and experimental genomics in the purple sea urchin. AB - Across heterogeneous landscapes, populations may have adaptive differences in gene regulation that adjust their physiologies to match local environments. Such differences could have origins in acclimation or in genetically fixed variation between habitats. Here we use common-garden experiments to evaluate differences in gene expression between populations of the purple sea urchin, Strongylocentrotus purpuratus, spanning 1700 km and average temperature differences of 5 degrees C to 8 degrees C. Across expression profiles from 18,883 genes after 3 years of common conditions, we find highly correlated expression patterns (Pearson's r = 0.992) among most genes. However, 66 genes were differentially expressed, including many ribosomal protein and biomineralization genes, which had higher expression in urchins originally from the southern population. Gene function analyses revealed slight but pervasive expression differences in genes related to ribosomal function, metabolism, transport, "bone" development, and response to stimuli. In accord with gene expression patterns, a post-hoc spine regrowth experiment revealed that urchins of southern origin regrew spines at a faster rate than northern urchins. These results suggest that there may be genetically controlled, potentially adaptive differences in gene regulation across habitats and that gene expression differences may be under strong enough selection to overcome high, dispersal-mediated gene flow in this marine species. PMID- 23815649 TI - Evolutionarily stable sex ratios and mutation load. AB - Frequency-dependent selection should drive dioecious populations toward a 1:1 sex ratio, but biased sex ratios are widespread, especially among plants with sex chromosomes. Here, we develop population genetic models to investigate the relationships between evolutionarily stable sex ratios, haploid selection, and deleterious mutation load. We confirm that when haploid selection acts only on the relative fitness of X- and Y-bearing pollen and the sex ratio is controlled by the maternal genotype, seed sex ratios evolve toward 1:1. When we also consider haploid selection acting on deleterious mutations, however, we find that biased sex ratios can be stably maintained, reflecting a balance between the advantages of purging deleterious mutations via haploid selection, and the disadvantages of haploid selection on the sex ratio. Our results provide a plausible evolutionary explanation for biased sex ratios in dioecious plants, given the extensive gene expression that occurs across plant genomes at the haploid stage. PMID- 23815650 TI - Homage to Bateman: sex roles predict sex differences in sexual selection. AB - Classic sex role theory predicts that sexual selection should be stronger in males in taxa showing conventional sex roles and stronger in females in role reversed mating systems. To test this very central prediction and to assess the utility of different measures of sexual selection, we estimated sexual selection in both sexes in four seed beetle species with divergent sex roles using a novel experimental design. We found that sexual selection was sizeable in females and the strength of sexual selection was similar in females and males in role reversed species. Sexual selection was overall significantly stronger in males than in females and residual selection formed a substantial component of net selection in both sexes. Furthermore, sexual selection in females was stronger in role-reversed species compared to species with conventional sex roles. Variance based measures of sexual selection (the Bateman gradient and selection opportunities) were better predictors of sexual dimorphism in reproductive behavior and morphology across species compared to trait-based measures (selection differentials). Our results highlight the importance of using assays that incorporate components of fitness manifested after mating. We suggest that the Bateman gradient is generally the most informative measure of the strength of sexual selection in comparisons across sexes and/or species. PMID- 23815651 TI - Operational sex ratio but not density affects sexual selection in a fish. AB - The operational sex ratio (OSR) and density are considered important factors affecting the strength of sexual selection. Although there is increasing evidence that OSR and density affect the potential for sexual selection, few studies have addressed whether this is realized in phenotypic selection and how the two factors interact. We manipulated OSR (three levels) and male density (two levels) in 36 experimental breeding populations of Gobiusculus flavescens-a fish with paternal care. We measured mating competition behavior, the opportunity for selection (I), and selection on four morphological traits in males. We found sexual selection on two male traits, with the strongest selection being 20% of I. As predicted from OSR theory, increasing female scarcity caused males to become more competitive, concomitant with an increase in I and selection on morphological traits. Model simulations of I based on random mating (Imin ) and maximum mate monopolization (Imax ) demonstrated that the potential for sexual selection was close to its theoretical maximum across the range of OSRs. However, male density and its interaction with the OSR did not affect sexual selection. We argue that a multifaceted approach, combining mating behavior and selection analyses, can help us to understand how ecological factors affect sexual selection. PMID- 23815652 TI - Transcriptome-wide expression variation associated with environmental plasticity and mating success in cactophilic Drosophila mojavensis. AB - Ecological speciation occurs with the adaptation of populations to different environments and concurrent evolution of reproductive isolation. Phenotypic plasticity might influence both ecological adaptation and reproductive traits. We examined environment-specific gene expression and male mating success in cactophilic Drosophila mojavensis using transcriptome sequencing. This species exhibits cactus-dependent mating success across different species of host plants, with genotype-by-environment interactions for numerous traits. We cultured flies from egg to eclosion on two natural cactus hosts and surveyed gene expression in adult males that were either successful or unsuccessful in achieving copulation in courtship trials. We identified gene expression differences that included functions involved with metabolism, most likely related to chemical differences between host cactus species. Several epigenetic-related functions were identified that might play a role in modulating gene expression in adults due to host cactus effects on larvae, and mating success. Cactus-dependent mating success involved expression differences of genes implicated in translation, transcription, and nervous system development. This suggests a role of neurological function genes in the mating success of D. mojavensis males. Together, these results suggest that the influence of environmental variation on mating success via regulation of gene expression might be an important aspect of ecological speciation. PMID- 23815653 TI - The effect of maternal age and reproductive history on offspring survival and lifetime reproduction in preindustrial humans. AB - Senescence is one of the least understood aspects of organism life history. In part, this stems from the relatively late advent of complete individual-level datasets and appropriate statistical tools. In addition, selection against senescence should depend on the contribution to population growth arising from physiological investment in offspring at given ages, but offspring are rarely tracked over their entire lives. Here, we use a multigenerational dataset of preindustrial (1732-1860) Finns to describe the association of maternal age at offspring birth with offspring survival and lifetime reproduction. We then conduct longitudinal analyses to understand the drivers of this association. At the population level, offspring lifetime reproductive success (LRS) declined by 22% and individual lambda, which falls with delays to reproduction, declined by 45% as maternal age at offspring birth increased from 16 to 50 years. These results were mediated by within-mother declines in offspring survival and lifetime reproduction. We also found evidence for modifying effects of offspring sex and maternal socioeconomic status. We suggest that our results emerge from the interaction of physiological with social drivers of offspring LRS, which further weakens selection on late-age reproduction and potentially molds the rate of senescence in humans. PMID- 23815654 TI - Skull shape evolution in durophagous carnivorans. AB - In this article, we investigate convergent evolution toward durophagy in carnivoran skull shape using geometric morphometrics in a sample of living and extinct species. Principal components analysis indicate that, in spite of the different dietary resources consumed by durophages-that is, bone-crackers and bamboo-feeders-both groups of carnivorans share portions of skull phenotypic spaces. We identify by discriminant analyses a shared set of adaptations toward durophagy in the skull of carnivores. However, ancestral states indicate that although durophages reached similar phenotypes, the evolutionary pathways that they followed are different depending upon the family to which they belong. Furthermore, while the carnivoran cranium more closely reflects the nature of the resources consumed-that is, soft or hard and tough items-the mandible shows particular feeding adaptations-that is, bamboo or bone. This finding supports the interpretation that the mandible has more evolutionary plasticity than the cranium, which is more limited to evolve toward a particular feeding adaptation. However, we find that the shapes of the cranium and the mandible are highly integrated for the whole order Carnivora. Published studies of teratological cats and dogs indicate that the role of internal constraints in shaping this pattern of integration is absent or weak and malleable by selection. PMID- 23815655 TI - Patterns of ossification in southern versus northern placental mammals. AB - Consensus on placental mammal phylogeny is fairly recent compared to that for vertebrates as a whole. A stable phylogenetic hypothesis enables investigation into the possibility that placental clades differ from one another in terms of their development. Here, we focus on the sequence of skeletal ossification as a possible source of developmental distinctiveness in "northern" (Laurasiatheria and Euarchontoglires) versus "southern" (Afrotheria and Xenarthra) placental clades. We contribute data on cranial and postcranial ossification events during growth in Afrotheria, including elephants, hyraxes, golden moles, tenrecs, sengis, and aardvarks. We use three different techniques to quantify sequence heterochrony: continuous method, sequence-ANOVA (analysis of variance) and event paring/Parsimov. We show that afrotherians significantly differ from other placentals by an early ossification of the orbitosphenoid and caudal vertebrae. Our analysis also suggests that both southern placental groups show a greater degree of developmental variability; however, they rarely seem to vary in the same direction, especially regarding the shifts that differ statistically. The latter observation is inconsistent with the Atlantogenata hypothesis in which afrotherians are considered as the sister clade of xenarthrans. Interestingly, ancestral nodes for Laurasiatheria and Euarchontoglires show very similar trends and our results suggest that developmental homogeneity in some ossification sequences may be restricted to northern placental mammals (Boreoeutheria). PMID- 23815656 TI - Single-gene speciation with pleiotropy: effects of allele dominance, population size, and delayed inheritance. AB - Single-gene speciation is considered to be unlikely, but an excellent example is found in land snails, in which a gene for left-right reversal has given rise to new species multiple times. This reversal might be facilitated by their small population sizes and maternal effect (i.e., "delayed inheritance," in which an individual's phenotype is determined by the genotype of its mother). Recent evidence suggests that a pleiotropic effect of the speciation gene on antipredator survival may also promote speciation. Here we theoretically demonstrate that, without a pleiotropic effect, in small populations the fixation probability of a recessive mutant is higher than a dominant mutant, but they are identical for large populations and sufficiently weak selection. With a pleiotropic effect that increases mutant viability, a dominant mutant has a higher fixation probability if the strength of viability selection is sufficiently greater than that of reproductive incompatibility, whereas a recessive mutant has a higher fixation probability otherwise. Delayed inheritance increases the fixation probability of a mutant if viability selection is sufficiently weaker than reproductive incompatibility. Our results clarify the conflicting effects of viability selection and positive frequency-dependent selection due to reproductive incompatibility and provide a new perspective to single-gene speciation theory. PMID- 23815657 TI - Phylogeographic structure and outbreeding depression reveal early stages of reproductive isolation in the neotropical orchid Epidendrum denticulatum. AB - Phylogeographic studies provide an important framework for investigating the mechanisms operating during the earliest stages of speciation, as reproductive barriers can be examined among divergent lineages in a geographic context. We investigated the evolution of early stages of intrinsic postmating isolation among different populations and lineages of Epidendrum denticulatum, a Neotropical orchid distributed across different biomes in South America. We estimated genetic diversity and structure for both nuclear and plastid markers, using a haplotype network, differentiation tests, Bayesian assignment analysis, and divergence time estimates of the main lineages. Reproductive barriers among divergent lineages were examined by analyzing seed viability following reciprocal crossing experiments. Strong plastid phylogeographic structure was found, indicating that E. denticulatum was restricted to multiple refuges during South American forest expansion events. In contrast, significant phylogeographic structure was not found for nuclear markers, suggesting higher gene flow by pollen than by seeds. Large asymmetries in seed set were observed among different plastid genetic groups, suggesting the presence of polymorphic genic incompatibilities associated with cytonuclear interactions. Our results confirm the importance of phylogeographic studies associated with reproductive isolation experiments and suggest an important role for outbreeding depression during the early stages of lineage diversification. PMID- 23815658 TI - Do freshwater fishes diversify faster than marine fishes? A test using state dependent diversification analyses and molecular phylogenetics of new world silversides (atherinopsidae). AB - Freshwater habitats make up only ~0.01% of available aquatic habitat and yet harbor 40% of all fish species, whereas marine habitats comprise >99% of available aquatic habitat and have only 60% of fish species. One possible explanation for this pattern is that diversification rates are higher in freshwater habitats than in marine habitats. We investigated diversification in marine and freshwater lineages in the New World silverside fish clade Menidiinae (Teleostei, Atherinopsidae). Using a time-calibrated phylogeny and a state dependent speciation-extinction framework, we determined the frequency and timing of habitat transitions in Menidiinae and tested for differences in diversification parameters between marine and freshwater lineages. We found that Menidiinae is an ancestrally marine lineage that independently colonized freshwater habitats four times followed by three reversals to the marine environment. Our state-dependent diversification analyses showed that freshwater lineages have higher speciation and extinction rates than marine lineages. Net diversification rates were higher (but not significant) in freshwater than marine environments. The marine lineage-through time (LTT) plot shows constant accumulation, suggesting that ecological limits to clade growth have not slowed diversification in marine lineages. Freshwater lineages exhibited an upturn near the recent in their LTT plot, which is consistent with our estimates of high background extinction rates. All sequence data are currently being archived on Genbank and phylogenetic trees archived on Treebase. PMID- 23815659 TI - Geographic and taxonomic disparities in species diversity: dispersal and diversification rates across Wallace's line. AB - Broad-scale patterns of species diversity have received much attention in the literature, yet the mechanisms behind their formation may not explain species richness disparities across small spatial scales. Few taxa display high species diversity on either side of Wallace's Line and our understanding of the processes causing this biogeographical pattern remains limited, particularly in plant lineages. To understand the evolution of this biogeographical pattern, a time calibrated molecular phylogeny of Livistoninae palms (Arecaceae) was used to infer the colonization history of the Sahul tectonic plate region and to test for disparities in diversification rates across taxa and across each side of Wallace's Line. Our analyses allowed us to examine how timing, migration history, and shifts in diversification rates have contributed to shape the biogeographical pattern observed in Livistoninae. We inferred that each of the three genera found in Sahul crossed Wallace's Line only once and relatively recently. In addition, at least two of the three dispersing genera underwent an elevation in their diversification rate leading to high species richness on each side of Wallacea. The correspondence of our results with Southeast Asian geologic and climatic history show how palms emerge as excellent models for understanding the historical formation of fine-scale biogeographic patterns in a phylogenetic framework. PMID- 23815660 TI - Deconstructing heterostyly: the evolutionary role of incompatibility system, pollinators, and floral architecture. AB - Darwin's early work on heterostyly and related style polymorphisms (the presence of two or three style morphs within a population) generated much interest to understand how precise interactions between ecological and genetic mechanisms influence the evolution of floral diversity. Here we tested three key hypotheses proposed to explain the evolution of heterostyly: (i) the presence of self incompatibility; (ii) the role of pollinators in promoting dissasortative mating; and (iii) floral architecture, which restricts pollinators' movements and ensures more exact pollen deposition on their bodies. We combined data from experiments, field observations, and published studies to test whether evolution of style polymorphism in Narcissus is driven by the incompatibility system, pollinator guilds, or floral architecture, within a phylogenetic framework. Neither differences in pollinator environment nor the presence of genetic self incompatibility were correlated with presence of style polymorphism. However, our results indicate that the evolution of style polymorphism was driven by the presence of a narrow and long floral tube. PMID- 23815661 TI - Components of reproductive isolation between Orchis mascula and Orchis pauciflora. AB - Studies of the strength and nature of reproductive isolation (RI) between species can greatly contribute to our understanding of speciation. Although the role of RI in speciation is well recognized, there is a dearth of information on the contributions of different barriers between related plant species. Here, we estimated multiple components of RI between two Mediterranean orchid sister species (Orchis mascula and Orchis pauciflora), disentangling the strength and absolute contributions of seven different isolating mechanisms. Our survey includes one prepollination, two postpollination prezygotic (pollen-stigma incompatibility, conspecific pollen precedence), two intrinsic postzygotic (embryo mortality and hybrid sterility) and two extrinsic postzygotic (hybrid habitat differentiation and hybrid pollination) isolating mechanisms. We found strong RI between the investigated species, although none of the barriers were able to completely impede gene flow. Five isolating mechanisms contributed positively to the maintenance of species boundaries. Contrary to most surveys of isolating mechanisms, our data speak against a clear predominance of prepollination or of prezygotic barriers but confirm the emerging pattern of multiple barriers contributing to the maintenance of species integrity. These findings suggest an allopatric condition during early phases of species divergence. We discuss our data in the wider context of previous studies carried out in this orchid group by using a comparative approach. PMID- 23815662 TI - Unification of regression-based methods for the analysis of natural selection. AB - Regression analyses are central to characterization of the form and strength of natural selection in nature. Two common analyses that are currently used to characterize selection are (1) least squares-based approximation of the individual relative fitness surface for the purpose of obtaining quantitatively useful selection gradients, and (2) spline-based estimation of (absolute) fitness functions to obtain flexible inference of the shape of functions by which fitness and phenotype are related. These two sets of methodologies are often implemented in parallel to provide complementary inferences of the form of natural selection. We unify these two analyses, providing a method whereby selection gradients can be obtained for a given observed distribution of phenotype and characterization of a function relating phenotype to fitness. The method allows quantitatively useful selection gradients to be obtained from analyses of selection that adequately model nonnormal distributions of fitness, and provides unification of the two previously separate regression-based fitness analyses. We demonstrate the method by calculating directional and quadratic selection gradients associated with a smooth regression-based generalized additive model of the relationship between neonatal survival and the phenotypic traits of gestation length and birth mass in humans. PMID- 23815663 TI - Asynchronous evolution of physiology and morphology in Anolis lizards. AB - Species-rich adaptive radiations typically diversify along several distinct ecological axes, each characterized by morphological, physiological, and behavioral adaptations. We test here whether different types of adaptive traits share similar patterns of evolution within a radiation by investigating patterns of evolution of morphological traits associated with microhabitat specialization and of physiological traits associated with thermal biology in Anolis lizards. Previous studies of anoles suggest that close relatives share the same "structural niche" (i.e., use the same types of perches) and are similar in body size and shape, but live in different "climatic niches" (i.e., use habitats with different insolation and temperature profiles). Because morphology is closely tied to structural niche and field active body temperatures are tied to climatic niches in Anolis, we expected phylogenetic analyses to show that morphology is more evolutionarily conservative than thermal physiology. In support of this hypothesis, we find (1) that thermal biology exhibits more divergence among recently diverged Anolis taxa than does morphology; and (2) diversification of thermal biology among all species often follows diversification in morphology. These conclusions are remarkably consistent with predictions made by anole biologists in the 1960s and 1970s. PMID- 23815664 TI - Strong assortative mating by diet, color, size, and morphology but limited progress toward sympatric speciation in a classic example: Cameroon crater lake cichlids. AB - Models predict that sympatric speciation depends on restrictive parameter ranges, such as sufficiently strong disruptive selection and assortative mating, but compelling examples in nature have rarely been used to test these predictions. I measured the strength of assortative mating within a species complex of Tilapia in Lake Ejagham, Cameroon, a celebrated example of incipient sympatric adaptive radiation. This species complex is in the earliest stages of speciation: morphological and ecological divergence are incomplete, species differ primarily in breeding coloration, and introgression is common. I captured 27 mated pairs in situ and measured the diet, color, size, and morphology of each individual. I found strong assortative mating by color, size, head depth, and dietary source of benthic or pelagic prey along two independent dimensions of assortment. Thus, Ejagham Tilapia showed strong assortative mating most conducive to sympatric speciation. Nonetheless, in contrast to a morphologically bimodal Sarotherodon cichlid species pair in the lake, Ejagham Tilapia show more limited progress toward speciation, likely due to insufficient strength of disruptive selection on morphology estimated in a previous study (gamma = 0.16). This supports the predicted dependence of sympatric speciation on strong assortment and strong disruptive selection by examining a potentially stalled example in nature. PMID- 23815665 TI - Genetic and developmental basis of F2 hybrid breakdown in Nasonia parasitoid wasps. AB - Speciation is responsible for the vast diversity of life, and hybrid inviability, by reducing gene flow between populations, is a major contributor to this process. In the parasitoid wasp genus Nasonia, F2 hybrid males of Nasonia vitripennis and Nasonia giraulti experience an increased larval mortality rate relative to the parental species. Previous studies indicated that this increase of mortality is a consequence of incompatibilities between multiple nuclear loci and cytoplasmic factors of the parental species, but could only explain ~40% of the mortality rate in hybrids with N. giraulti cytoplasm. Here we report a locus on chromosome 5 that can explain the remaining mortality in this cross. We show that hybrid larvae that carry the incompatible allele on chromosome 5 halt growth early in their development and that ~98% die before they reach adulthood. On the basis of these new findings, we identified a nuclear-encoded OXPHOS gene as a strong candidate for being causally involved in the observed hybrid breakdown, suggesting that the incompatible mitochondrial locus is one of the six mitochondrial-encoded NADH genes. By identifying both genetic and physiological mechanisms that reduce gene flow between species, our results provide valuable and novel insights into the evolutionary dynamics of speciation. PMID- 23815666 TI - Sperm competitive ability evolves in response to experimental alteration of operational sex ratio. AB - In naturally polygamous organisms such as Drosophila, sperm competitive ability is one of the most important components of male fitness and is expected to evolve in response to varying degrees of male-male competition. Several studies have documented the existence of ample genetic variation in sperm competitive ability of males. However, many experimental evolution studies have found sperm competitive ability to be unresponsive to selection. Even direct selection for increased sperm competitive ability has failed to yield any measurable changes. Here we report the evolution of sperm competitive ability (sperm defense-P1, offense-P2) in a set of replicate populations of Drosophila melanogaster subjected to altered levels of male-male competition (generated by varying the operational sex ratio) for 55-60 generations. Males from populations with female biased operational sex ratio evolved reduced P1 and P2, without any measurable change in the male reproductive behavior. Males in the male-biased regime evolved increased P1, but there was no significant change in P2. Increase in P1 was associated with an increase in copulation duration, possibly indicating greater ejaculate investment by these males. This study is one of the few to provide empirical evidence for the evolution of sperm competitive ability of males under different levels of male-male competition. PMID- 23815667 TI - Comment on Marden (2013): "reanalysis and experimental evidence indicate that the earliest trace fossil of a winged insect was a surface skimming neopteran". AB - Marden's (2013) reanalysis of Knecht et al. (2011) suggesting that specimen SEMC F97 is the result of the skimming behavior of a neopteran insect and, more importantly, fossil evidence of "... surface skimming as a precursor to the evolution of flight in insects" (Marden 2013) is found to be deficient on three fronts: (1) the principal specimen was never viewed firsthand which led to significant morphological misinterpretations; (2) poorly designed and executed neoichnological experiments led to incredulous results; and (3) the assumption that this specimen is fossil evidence supporting the surface skimming hypothesis of the origin of insect flight despite the fact that since its induction into the literature that hypothesis has been refuted based on significant paleontological, phylogenetic, genetic, and developmental evidence. PMID- 23815668 TI - Reply to "comment on Marden (2013) regarding the interpretation of the earliest trace fossil of a winged insect". AB - Benner, Knecht, and Engel have replied to my critique of their interpretation of a Carboniferous trace fossil produced by an insect at the edge of water. Here I respond by pointing out that their reiterated scenario still requires mutually exclusive paths of motion and I show that their assertions of methodological shortcomings are tangential and lack merit. Overall, this discussion provides an opportunity to examine in greater detail competing hypothesis about behaviors and taxonomic identity of the trace maker, and relevance thereof to competing theories regarding early events in the evolution of pterygote insects. PMID- 23815669 TI - Lung clearance index and high-resolution computed tomography scores in primary ciliary dyskinesia. AB - RATIONALE: Lung clearance index (LCI) is a more sensitive measure of lung function than spirometry in cystic fibrosis (CF) and correlates well with abnormalities in high-resolution computed tomography (HRCT) scanning. We hypothesized LCI would be equally sensitive to lung disease in primary ciliary dyskinesia (PCD). OBJECTIVES: To test the relationships between LCI, spirometry, and HRCT in PCD and to compare them to the established relationships in CF. METHODS: Cross-sectional study of 127 patients with CF and 33 patients with PCD, all of whom had spirometry and LCI, of which a subset of 21 of each had HRCT performed. HRCT was scored for individual features and these features compared with physiological parameters. MEASUREMENTS AND MAIN RESULTS: Unlike in CF, and contrary to our hypothesis, there was no correlation between spirometry and LCI in PCD and no correlation between HRCT features and LCI or spirometry in PCD. CONCLUSIONS: We show for the first time that HRCT, spirometry, and LCI have different relationships in different airway diseases and that LCI does not appear to be a sensitive test of airway disease in advanced PCD. We hypothesize that this results from dissimilarities between the components of large and small airway disease in CF and PCD. These differences may in part lead to the different prognosis in these two neutrophilic airway diseases. PMID- 23815670 TI - The dimerization domain in outer segment guanylate cyclase is a Ca2+-sensitive control switch module. AB - Membrane-bound guanylate cyclases harbor a region called the dimerization or linker domain, which aids the enzymes in adopting an optimal monomer-monomer arrangement for catalysis. One subgroup of these guanylate cyclases is expressed in rod and cone cells of vertebrate retina, and mutations in the dimerization domain of rod outer segment guanylate cyclase 1 (ROS-GC1, encoded by the GUCY2D gene) correlate with retinal cone-rod dystrophies. We investigate how a Q847L/K848Q double mutation, which was found in patients suffering from cone-rod dystrophy, and the Q847L and K848Q single-point mutations affect the regulatory mechanism of ROS-GC1. Both the wild type and mutants of heterologously expressed ROS-GC1 were present in membranes. However, the mutations affected the catalytic properties of ROS-GC1 in different manners. All mutants had higher basal guanylate cyclase activities but lower levels of activation by Ca2+-sensing guanylate cyclase-activating proteins (GCAPs). Further, incubation with wild-type GCAP1 and GCAP2 revealed for all ROS-GC1 mutants a shift in Ca2+ sensitivity, but activation of the K848Q mutant by GCAPs was severely impaired. Apparent affinities for GCAP1 and GCAP2 were different for the double mutant and the wild type. Circular dichroism spectra of the dimerization domain showed that the wild type and mutants adopt a prevalently alpha-helical structure, but mutants exhibited lower thermal stability. Our results indicate that the dimerization domain serves as a Ca2+-sensitive control module. Although it is per se not a Ca2+-sensing unit, it seems to integrate and process information regarding Ca2+ sensing by sensor proteins and regulator effector affinity. PMID- 23815671 TI - Interactive effect of STAT6 and IL13 gene polymorphisms on eczema status: results from a longitudinal and a cross-sectional study. AB - BACKGROUND: Eczema is a prevalent skin disease that is mainly characterized by systemic deviation of immune response and defective epidermal barrier. Th2 cytokines, such as IL-13 and transcription factor STAT6 are key elements in the inflammatory response that characterize allergic disorders, including eczema. Previous genetic association studies showed inconsistent results for the association of single nucleotide polymorphisms (SNPs) with eczema. Our aim was to investigate whether SNPs in IL13 and STAT6 genes, which share a biological pathway, have an interactive effect on eczema risk. METHODS: Data from two independent population-based studies were analyzed, namely the Isle of Wight birth cohort study (IOW; n = 1,456) and for the purpose of replication the Swansea PAPA (Poblogaeth Asthma Prifysgol Abertawe; n = 1,445) cross-sectional study. Log-binomial regressions were applied to (i) account for the interaction between IL13 (rs20541) and STAT6 (rs1059513) polymorphisms and (ii) estimate the combined effect, in terms of risk ratios (RRs), of both risk factors on the risk of eczema. RESULTS: Under a dominant genetic model, the interaction term [IL13 (rs20541) * STAT6 (rs1059513)] was statistically significant in both studies (IOW: adjusted P(interaction) = 0.046; PAPA: P(interaction) = 0.037). The assessment of the combined effect associated with having risk genotypes in both SNPs yielded a 1.52-fold increased risk of eczema in the IOW study (95% confidence interval (CI): 1.05 - 2.20; P = 0.028) and a 2.01-fold higher risk of eczema (95% CI: 1.29 - 3.12; P = 0.002) in the PAPA study population. CONCLUSIONS: Our study adds to the current knowledge of genetic susceptibility by demonstrating for the first time an interactive effect between SNPs in IL13 (rs20541) and STAT6 (rs1059513) on the occurrence of eczema in two independent samples. Findings of this report further support the emerging evidence that points toward the existence of genetic effects that occur via complex networks involving gene-gene interactions (epistasis). PMID- 23815672 TI - Therapies currently in Phase II trials for malignant pleural mesothelioma. AB - INTRODUCTION: Malignant pleural mesothelioma (MPM) is an aggressive cancer associated with asbestos exposure, whose incidence will peak within the next years. Despite an overall low response rate, the current first-line therapy is represented by combined chemotherapy with cisplatin and antifolate. Moreover, there are no currently approved regimens for relapsed or refractory MPM. Therefore, it is clear how both preclinical and clinical researches aimed at identifying new therapeutic targets and testing them in early clinical settings are badly needed. AREAS COVERED: The aim of this review is to summarize and critically comment the ongoing Phase II trials for MPM. EXPERT OPINION: Over the past few years, there has been a significant endeavor of addressing the clinical research for MPM beyond the very modest results of chemotherapy. Nonetheless, our understanding is that the treatment of MPM should not be merely 'copied' from that of other much better studied tumors. In the light of recent results, studies toward the metabolic characteristics of this tumor are being progressively addressed. These evidences are disclosing a rather unusual model of malignancy, very likely to be more sensitive to novel 'MPM cells- and microenvironment tailored' therapy addressing these characteristics rather than the sole cancer proliferation. PMID- 23815673 TI - Foetal defence against cancer: a hypothesis. PMID- 23815674 TI - Antimicrobial resistance of Salmonella enterica serovar Heidelberg isolated from poultry in Alberta. AB - Salmonella enterica serovar Heidelberg is one of the top three serovars implicated in human infections in Canada. In 2003, the Canadian Integrated Program for Antimicrobial Resistance Surveillance reported antimicrobial resistance (AMR) in S. Heidelberg in Canada. The study objective was to investigate the AMR of S. Heidelberg isolated from poultry in Alberta. We examined 951 S. Heidelberg poultry isolates obtained during 1996 to 2010 and tested against 18 antibiotics using the Sensititre AVIAN1F system. Temporal resistance patterns were analysed using single-level logistic regression models. Continuous variables were included in the multivariable models. Multivariable models were built and variables and interactions were included in these final models. Data were analysed using Stata 11 Intercooled. Ceftiofur resistance ranged annually from 0 to 10.5% and gentamicin resistance ranged annually from 0 to 33.3%; no isolates were enrofloxacin resistant. Resistance to amoxicillin (annual range 0 to 42.6%) varied significantly by time and interaction with commodity type. Meat turkey S. Heidelberg isolates had higher ceftiofur resistance compared with chickens: layers plus layer breeders (odds ratio = 22.6, P < 0.01) and broiler breeders (odds ratio = 9.1, P < 0.01). Gentamicin resistance decreased significantly over the study period (odds ratio = 0.72 per year, P < 0.01). Tetracycline (TET) resistance changed significantly over time (annual range 0 to 39.6%), interacting with poultry commodity type. Meat turkey isolate TET resistance, higher overall than that of chicken, increased throughout the study. All turkey breeder isolates were resistant to TET. In conclusion, this study provides AMR data for S. Heidelberg isolates from the Alberta poultry industry and demonstrated significant trends in resistance, both temporal and between poultry commodities. PMID- 23815675 TI - Effect of isomeric structures of branched cyclic hydrocarbons on densities and equation of state predictions at elevated temperatures and pressures. AB - The cis and trans conformation of a branched cyclic hydrocarbon affects the packing and, hence, the density, exhibited by that compound. Reported here are density data for branched cyclohexane (C6) compounds including methylcyclohexane, ethylcyclohexane (ethylcC6), cis-1,2-dimethylcyclohexane (cis-1,2), cis-1,4 dimethylcyclohexane (cis-1,4), and trans-1,4-dimethylcyclohexane (trans-1,4) determined at temperatures up to 525 K and pressures up to 275 MPa. Of the four branched C6 isomers, cis-1,2 exhibits the largest densities and the smallest densities are exhibited by trans-1,4. The densities are modeled with the Peng Robinson (PR) equation of state (EoS), the high-temperature, high-pressure, volume-translated (HTHP VT) PREoS, and the perturbed chain, statistical associating fluid theory (PC-SAFT) EoS. Model calculations highlight the capability of these equations to account for the different densities observed for the four isomers investigated in this study. The HTHP VT-PREoS provides modest improvements over the PREoS, but neither cubic EoS is capable of accounting for the effect of isomer structural differences on the observed densities. The PC SAFT EoS, with pure component parameters from the literature or from a group contribution method, provides improved density predictions relative to those obtained with the PREoS or HTHP VT-PREoS. However, the PC-SAFT EoS, with either set of parameters, also cannot fully account for the effect of the C6 isomer structure on the resultant density. PMID- 23815676 TI - Monocytopenia as a diagnostic clue to pediatric B-lymphoblastic leukemia with rare circulating blasts. AB - Abstract Background: B-lymphoblastic leukemia/lymphoma (B-LL) is the most common childhood cancer. Occasionally, circulating blasts in the peripheral blood are rare ({less than or equal to}1%) and may be missed, even when flow cytometric immunophenotyping is performed, leading to a false negative report. Methods: The records from all patients with a new diagnosis of B-LL at our institution were reviewed from Jan 2009-Dec 2011. Of 130 cases with peripheral blood flow cytometry, 15 had a blast count of {less than or equal to}1%, with 14 having electronic files for gating monocytes. The percentage of monocytes by flow cytometry and absolute monocyte counts (AMCs) were compared with peripheral blood samples that were negative by flow cytometry, sent due to at least one lineage cytopenia (n=39). Results: The monocytes from the patients with leukemia averaged 0.8%, and were statistically lower than the negative controls, which averaged 7.1% (p<0.001). 11 of the 14 (79%) patients with leukemia had monocytes <1%, compared to only 3 (8%) of the negative controls. The AMCs were also significantly lower (p<0.001), with 93% of the leukemia group having an AMC of <100 cells/uL, compared to only 28% of the negative controls. Conclusions: In patients presenting with cytopenias, assessment of percentage monocytes may be an important diagnostic clue in determining the presence of occult leukemia. If flow cytometry is performed, acquisition of more than the standard 10,000 events is necessary to adequately assess for leukemia. If monocytes are <1% by flow cytometry in the setting of cytopenias, bone marrow examination is recommended, even with negative peripheral blood flow cytometry. PMID- 23815677 TI - Diagnostic prediction of complex diseases using phase-only correlation based on virtual sample template. AB - MOTIVATION: Complex diseases induce perturbations to interaction and regulation networks in living systems, resulting in dynamic equilibrium states that differ for different diseases and also normal states. Thus identifying gene expression patterns corresponding to different equilibrium states is of great benefit to the diagnosis and treatment of complex diseases. However, it remains a major challenge to deal with the high dimensionality and small size of available complex disease gene expression datasets currently used for discovering gene expression patterns. RESULTS: Here we present a phase-only correlation (POC) based classification method for recognizing the type of complex diseases. First, a virtual sample template is constructed for each subclass by averaging all samples of each subclass in a training dataset. Then the label of a test sample is determined by measuring the similarity between the test sample and each template. This novel method can detect the similarity of overall patterns emerged from the differentially expressed genes or proteins while ignoring small mismatches. CONCLUSIONS: The experimental results obtained on seven publicly available complex disease datasets including microarray and protein array data demonstrate that the proposed POC-based disease classification method is effective and robust for diagnosing complex diseases with regard to the number of initially selected features, and its recognition accuracy is better than or comparable to other state-of-the-art machine learning methods. In addition, the proposed method does not require parameter tuning and data scaling, which can effectively reduce the occurrence of over-fitting and bias. PMID- 23815678 TI - Isolation and in vitro culture of rare cancer stem cells from patient-derived xenografts of pancreatic ductal adenocarcinoma. AB - Described is the construction of a large array of releasable microstructures (micropallets) along with screening and isolation protocols for sorting rare, approximately 1 in 10,000, cancer stem cells (CSCs) from a heterogeneous cell population. A 10.1 * 7.1 cm array of micropallets (50 * 50 * 75 MUm structures and 25 MUm micropallet gap) was fabricated on a large glass substrate, providing an array of approximately 1.3 million releasable microstructures. Image analysis algorithms were developed to permit array screening for identification of fluorescently labeled cells in less than 15 min using an epifluorescent wide field microscope with a computer controlled translational stage. Device operation was tested by culturing HeLa cells transfected with green fluorescent protein (GFP) admixed with wild-type HeLa cells at ratios of 1:10(4) to 1:10(6) on the array followed by screening to identify flourescent cells. Micropallets containing cells of interest were then selectively released by a focused laser pulse and collected on a numbered poly(dimethylsiloxane) (PDMS) substrate with high viability. A direct comparison of this technology with fluorescence activated cell sorting (FACS) demonstrated that micropallet arrays offered enhanced post sorting purity (100%), yield (100%), and viability (94-100%) for rare cell isolation. As a demonstration of the technology's value, pancreatic tumor cells from Panc-1 cell lines and patient-derived xenografts were screened for the presence of CD24, CD44, and CD326: surface markers of pancreatic CSCs. Following cell isolation and culture, 63 +/- 23% of the isolated Panc-1 cells and 35% of sorted human xenograft cells formed tumor spheroids retaining high expression levels of CD24, CD44, and CD326. The ability to isolate rare cells from relatively small sample sizes will facilitate our understanding of cell biology and the development of new therapeutic strategies. PMID- 23815679 TI - Conformational stability and activity analysis of two hydroxymethylbilane synthase mutants, K132N and V215E, with different phenotypic association with acute intermittent porphyria. AB - The autosomal dominantly inherited disease AIP (acute intermittent porphyria) is caused by mutations in HMBS [hydroxymethylbilane synthase; also known as PBG (porphobilinogen) deaminase], the third enzyme in the haem biosynthesis pathway. Enzyme-intermediates with increasing number of PBG molecules are formed during the catalysis of HMBS. In this work, we studied the two uncharacterized mutants K132N and V215E comparative with wt (wild-type) HMBS and to the previously reported AIP-associated mutants R116W, R167W and R173W. These mainly present defects in conformational stability (R116W), enzyme kinetics (R167W) or both (R173W). A combination of native PAGE, CD, DSF (differential scanning fluorimetry) and ion-exchange chromatography was used to study conformational stability and activity of the recombinant enzymes. We also investigated the distribution of intermediates corresponding to specific elongation stages. It is well known that the thermostability of HMBS increases when the DPM (dipyrromethane) cofactor binds to the apoenzyme and the holoenzyme is formed. Interestingly, a decrease in thermal stability was measured concomitant to elongation of the pyrrole chain, indicating a loosening of the structure prior to product release. No conformational or kinetic defect was observed for the K132N mutant, whereas V215E presented lower conformational stability and probably a perturbed elongation process. This is in accordance with the high association of V215E with AIP. Our results contribute to interpret the molecular mechanisms for dysfunction of HMBS mutants and to establish genotype-phenotype relations for AIP. PMID- 23815680 TI - Introgression and isolation contributed to the development of Hungarian Mangalica pigs from a particular European ancient bloodline. AB - BACKGROUND: Mangalica breeds are indigenous to Hungary and their breeding history dates back to about 200-250 years ago. They are fat-type pigs and have a rare curly hair phenotype. The aim of our study was to establish the relationships between these unique breeds and other European breeds. RESULTS: Based on a core sequence of 382 bp present in 2713 mitochondrial D-loop sequences from pigs belonging to 38 local breeds from nine countries, five cosmopolitan breeds and wild boars from 14 countries, we identified 164 haplotypes. More than half of the 2713 sequences belonged to either four haplotypes characteristic of continental European breeds or two haplotypes characteristic of British/cosmopolitan breeds; each haplotype is present in more than 100 individuals. Most Mangalica individuals belonged either to one of these common continental European haplotypes or to two Mangalica-specific haplotypes that were absent in all other breeds. In addition, we identified the ancestral mitochondrial D-loop signature present in these 2713 sequences and found that ~ 80% carried the European ancient signatures, ANC-Aside and ANC-Cside or their closely related signatures, while most of the remaining sequences carried a modern Asian signature, ANC-Easia. Mangalica individuals carried the ANC-Aside signature, but not the ANC-Cside or ANC-Easia signatures. CONCLUSIONS: In all the Mangalica individuals, a unique ancient European signature was found in the mitochondrial DNA D-loop region, but they belonged almost exclusively to either certain very abundant European or two Mangalica-specific D-loop haplotypes. This indicates that the present-day Mangalica population in Hungary evolved either by introgression of other European breeds and wild boars or via total isolation after the divergence of European ancient porcine bloodlines. PMID- 23815681 TI - Mesocortical dopamine system modulates mechanical nociceptive responses recorded in the rat prefrontal cortex. AB - BACKGROUND: Psychological conditions affect pain responses in the human anterior cingulate cortex (ACC) according to brain imaging analysis. The rodent prefrontal cortex (PFC) including cingulate areas is also related to the affective dimension of pain. We previously reported PFC nociceptive responses inhibited by inputs from the amygdala, such as with dopamine (DA) D2 receptor (D2R) blockers, to show decreased effect on amygdala projections. In this study, we examined whether direct projections from the ventral tegmental area (VTA) to the PFC affect nociceptive responses in the PFC. RESULTS: High frequency stimulation (HFS, 50 Hz, 30 s) delivered to the VTA produced long-lasting suppression (LLS) of nociceptive responses in the rat PFC including cingulate and prelimbic areas. Nociceptive responses evoked by mechanical pressure stimulation (2 s duration at 500 g constant force) applied to the tails of urethane-anesthetized rats were recorded using extracellular unit recording methods in the PFC. HFS delivered to the VTA, which has been reported to increase DA concentrations in the PFC, significantly suppressed nociceptive responses. The LLS of nociceptive responses persisted for about 30 minutes and recovered to the control level within 60 min after HFS. We also demonstrated local microinjection of a selective D2 agonist of DA receptors to induce LLS of mechanical nociceptive responses, while a D2 but not a D1 antagonist impaired the LLS evoked by HFS. In contrast, DA depletion by a 6-hydroxydopamine injection or a low concentration of DA induced by a kappa opiate receptor agonist injected into the VTA had minimal effect on nociceptive responses in the PFC. CONCLUSION: HFS delivered to VTA inhibited nociceptive responses for a long period in PFC. DA D2R activation mediated by local D2 agonist injection also induced LLS of mechanical nociceptive responses. The mesocortical DA system may modify PFC nociceptive responses via D2 activity. PMID- 23815682 TI - Asthma in USA: its impact on health-related quality of life. AB - OBJECTIVES: Given the growing prevalence of asthma in USA, it is important to understand its national burden from the patient's perspective. The objective of this research is to examine the national burden of asthma and poor asthma control on health function, health perception and preference-based health-related quality of life (HRQL). METHODS: The Medical Expenditure Panel Survey (MEPS), a nationally representative survey, was used to estimate the impact of asthma and indicators of poor asthma control on health function, self-rated health perception and preference-based HRQL using multivariate regression methods controlling for socioeconomic, clinical and demographic characteristics. Two HRQL instruments were used: SF-12v2 Physical Component Scale (PCS-12) and Mental Component Scale (MCS-12); EQ-5D-3L index and visual analogue scale (VAS). Two multivariate regression methods were used, Censored Least Absolute Deviation [EQ 5D-3L and VAS (due to censoring)] and Ordinary Least Squares (OLS) (PCS-12 and MCS-12). RESULTS: After controlling for covariates, asthma resulted in a statistically significant reduction in preference-based HRQL, health perception and physical and mental function (EQ-5D -0.023; VAS -2.21; PCS-12 -2.36; MCS-12 0.96). Likewise, experiencing an exacerbation in the previous year and using more than three canisters of quick-relief medication in the previous 3 months were both associated with a statistically significant and clinically meaningful reduction in all four measures. CONCLUSIONS: Asthma itself and especially indicators of poor asthma control were associated with a deleterious effect on health function, preference-based HRQL and self-perceived health status. Given the prevalence of asthma, poorly controlled asthma constitutes a significant national burden in USA. PMID- 23815683 TI - Drug resistance in vectorborne parasites: multiple actors and scenarios for an evolutionary arms race. AB - Drug-resistant pathogens emerge faster than new drugs come out of drug discovery pipelines. Current and future drug options should therefore be better protected, requiring a clear understanding of the factors that contribute to the natural history of drug resistance. Although many of these factors are relatively well understood for most bacteria, this proves to be more complex for vectorborne parasites. In this review, we discuss considering three key models (Plasmodium, Leishmania and Schistosoma) how drug resistance can emerge, spread and persist. We demonstrate a multiplicity of scenarios, clearly resulting from the biological diversity of the different organisms, but also from the different modes of action of the drugs used, the specific within- and between-host ecology of the parasites, and environmental factors that may have direct or indirect effects. We conclude that integrated control of drug-resistant vectorborne parasites is not dependent upon chemotherapy only, but also requires a better insight into the ecology of these parasites and how their transmission can be impaired. PMID- 23815684 TI - Anthrone and related hydroxyarenes: tautomerization and hydrogen bonding. AB - The keto-enolization of hydroxyl-substituted naphthols and 9-anthrols has been investigated by means of CBS-QB3 calculations. An excellent agreement between experiment and theory is found for the energetics for the anthrone (5) ? anthrol (6) equilibrium, with an enthalpy of tautomerization, Delta(t)H, of 3.8 kcal mol( 1). In contrast, 1-naphthol is the preferred tautomer with a Delta(t)H = -9.0 kcal mol(-1). Substitution of the hydrogens at the adjacent carbons by hydroxyl groups leads to the formation of strong intramolecular hydrogen bonds within a six-membered ring in the enones and the enols. Due to the difference in the intramolecular hydrogen bond enthalpy, Delta(HB)H(intra), the equilibrium shifts further to the enone. Thus, for 1,8-dihydroxy-anthrone (anthralin, dithranol) Delta(t)H increases to 12.7 kcal mol(-1) with an enol/enone ratio of 10(-10). The solvent effect on the 5 ? 6 equilibrium has been quantified by considering the formation of intermolecular hydrogen bond(s), leading to an acidity parameter alpha2(H) for anthrol of 0.42. It is shown that the hydrogen bond donating ability of bulk methanol is greatly attenuated through the formation of cyclic oligomers. The benzylic and phenolic bond dissociation enthalpies for anthrone up to anthralin suggest some antioxidant potency but the precise (radical) mechanism of action remains uncertain. PMID- 23815685 TI - Synthesis of D-mannose capped silicon nanoparticles and their interactions with MCF-7 human breast cancerous cells. AB - Silicon nanoparticles (SiNPs) hold prominent interest in various aspects of biomedical applications. For this purpose, surface functionalization of the NPs is essential to stabilize them, target them to specific disease area, and allow them to selectively bind to the cells or the bio-molecules present on the surface of the cells. However, no such functionalization has been explored with Si nanoparticles. Carbohydrates play a critical role in cell recognition. Here, we report the first synthesis of silicon nanoparticles functionalized with carbohydrates. In this study, stable and brightly luminescent d-Mannose (Man) capped SiNPs have been synthesized from amine terminated SiNPs and d mannopyranoside acid. The surface functionalization is confirmed by Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance spectroscopy (NMR), and energy dispersive X-ray spectroscopy (EDX) studies. The mean diameter of the crystal core is 5.5 nm, as measured by transmission electron microscopy (TEM), while the hydrodynamic diameter obtained by dynamic light scattering (DLS) is 16 nm. The quantum yield (QY) of photoluminescence emission is found to be 11.5%, and the nanoparticles exhibit an exceptional stability over two weeks. The Man-capped SiNPs may prove to be valuable tools for further investigating glycobiological, biomedical, and material science fields. Experiments are carried out using Concanavalin A (ConA) as a target protein in order to prove the hypothesis. When Man functionalized SiNPs are treated with ConA, cross-linked aggregates are formed, as shown in TEM images as well as monitored by photoluminescence spectroscopy (PL). Man functionalized SiNPs can target cancerous cells. Visualization imaging of SiNPs in MCF-7 human breast cancer cells shows the fluorescence is distributed throughout the cytoplasm of these cells. PMID- 23815686 TI - Electrocapillary instability of magnetic fluid peak. AB - This Article presents an experimental study of the capillary electrostatic instability occurring under the effect of a constant electric field on a magnetic fluid individual peak. The peaks under study occur at disintegration of a magnetic fluid layer applied on a flat electrode surface under the effect of a perpendicular magnetic field. The electrocapillary instability shows itself as an emission of charged drops jets from the peak point in direction of the opposing electrode. The charged drops emission repeats periodically and results in the peak shape pulsations. It is shown that a magnetic field affects the electrocapillary instability occurrence regularities and can stimulate its development. The critical electric and magnetic field strengths at which the instability occurs have been measured; their dependence on the peak size is shown. The hysteresis in the system has been studied; it consists in that the charged drops emission stops at a lesser electric (or magnetic) field strength than that of the initial occurrence. The peak pulsations frequency depending on the magnetic and electric field strengths and on the peak size has been measured. PMID- 23815687 TI - Assisted conception, maternal age and breastfeeding: an Australian cohort study. AB - AIM: To establish the relationships between age, mode of conception and breastfeeding. METHOD: Consecutive cohorts of nulliparous women >25 weeks pregnant who had conceived through ART (ARTC) or spontaneously (SC) in three age groups <=30, 31-36 and >=37 years were recruited. Data were obtained via telephone interviews and postal questionnaires in late pregnancy and 4 months postpartum. Sociodemographic characteristics, reproductive health, birth and breastfeeding experiences were assessed by study-specific questions. Self-rated general health and symptoms of depression and anxiety were assessed with standardized psychometric instruments. Main outcomes were exclusive breastfeeding at discharge from maternity hospital and 4 months postpartum. RESULTS: Of 1179 eligible women, 791 (67%) participated; 549 (93%) had singleton infants, provided complete data and were included in analyses. Overall, 37.2% of participants aged <=30, 33% aged 31-36 and 55.1% aged >=37 years experienced Caesarean births. Regardless of age, compared with the SC group, ARTC women had twice the rate of Caesareans prior to labour. Controlling for other factors, exclusive breastfeeding rates at hospital discharge and 4 months postpartum were lowest amongst ARTC women who experienced Caesarean prior to labour (p < .001). CONCLUSION: Independent of age, assisted conception increases the risk conferred by Caesarean birth to breastfeeding initiation and maintenance. PMID- 23815689 TI - Knowledge and attitude of dental faculty members towards evidence-based dentistry in Iran. AB - INTRODUCTION: Educating dental practitioners is a major component in obtaining evidence-based approach to oral health care, but there is no evidence about knowledge and attitude of dental faculty members towards evidence-based dentistry (EBD) in Iran. MATERIALS AND METHODS: A cross-sectional study was conducted using self-administered questionnaires on dental school faculties in Iran to assess their knowledge and attitude towards basic principles and methods of EBD. A total of eight dental schools were randomly selected of 17 public and two existing private schools. Validated questionnaire with an appropriate reliability (Cronbach's alpha 0.67 - 0.87) was conducted on (n = 505) available dental instructors. The covered dimensions were perceived knowledge on critical appraisal, actual knowledge of EBD concepts, evidence-accessing methods and attitudes about EBD. Correlations were assessed between background characteristics and four main parts of the questionnaire, and multiple linear regression analysis was also used. RESULTS: A total of 377 of 505 dental instructors returned completed questionnaires (response rate 74.65%). The mean perceived knowledge score was 15.32 +/- 4.69 on a range of 6-36, and mean actual knowledge was 7.98 +/- 2.0 on a range of 0-11 for all respondents with an overall positive attitude towards EBD. CONCLUSIONS: This study suggests that the level of actual knowledge of dental faculties about basic principles of EBD was moderate in Iran. However, faculties' overall interest and positive attitude towards learning EBD is encouraging. Therefore, it is highly recommended that degree/certificate continuing educational programmes be planned by the organising committees. PMID- 23815688 TI - Decreased coenzyme A levels in ridA mutant strains of Salmonella enterica result from inactivated serine hydroxymethyltransferase. AB - The RidA/Yer057/UK114 family of proteins is well represented across the domains of life and recent work has defined both an in vitro activity and an in vivo role for RidA. RidA proteins have enamine deaminase activity, and in their absence the reactive 2-aminoacrylate (2-AA) accumulates and inactivates at least some pyridoxal 5'-phosphate (PLP)-containing enzymes in Salmonella enterica. The conservation of RidA suggested that 2-AA was a ubiquitous cellular stressor that was generated in central metabolism. Phenotypically, strains of S. enterica that lack RidA accumulated significantly more pyruvate in the growth medium than wild type strains. Here we dissected this ridA mutant phenotype and showed it was an indirect consequence of damage to serine hydroxymethyltransferase (GlyA; E.C. 2.1.2.1). The results here identified a fourth PLP enzyme as a target of enamine stress in Salmonella. PMID- 23815690 TI - Testing manual dexterity using a virtual reality simulator: reliability and validity. AB - Virtual reality dental training simulators, unlike traditional human-based assessment, have the potential to enable consistent and reliable assessment. The purpose of this study was to determine whether a haptic simulator (IDEA Dental((r)) ) could provide a reliable and valid assessment of manual dexterity. A total of 106 participants were divided into three groups differing in dental manual dexterity experience: (i) 63 dental students, (ii) 28 dentists, (iii) 14 non-dentists. The groups, which were expected to display various performance levels, were required to perform virtual drilling tasks in different geometric shapes. The following task parameters were registered: (i) Time to completion (ii) accuracy (iii) number of trials to successful completion and (iv) score provided by the simulator. The reliability of the tasks was calculated for each parameter. The simulator and its scoring algorithm showed high reliability in all the parameters measured. The simulator was able to differentiate between non professionals and dental students or non-professionals and dentists. Our study suggests that for improved construct validity, shorter working times and more difficult tasks should be introduced. The device should also be designed to provide greater sensitivity in measuring the accuracy of the task. PMID- 23815691 TI - Using e-learning to train dentists in the development of standardised oral health promotion interventions for persons with disability. AB - BACKGROUND: This study aims to evaluate whether an e-learning curriculum was sufficient to impart the necessary knowledge to dentists to allow them to implement an oral health promotion intervention in an institution for persons with disability. MATERIALS AND METHODS: Participants were asked to complete a 10 module online training course and to implement a standardised intervention in an institution. The outcome measures were as follows: online tracking of progress; multiple choice questionnaires completed at the end of most modules; self efficacy questionnaire completed before and after online training; completion of training and calibration in the use of a standardised risk assessment form; initiation and full completion of an oral health promotion intervention in an institution; satisfaction of participants with the online training experience; and evaluation of the impact of the intervention by the institution staff. RESULTS: The study sample included 26 dentists. The 10 modules were passed by 24 dentists, and the mean value of the highest overall score recorded in the multiple questionnaires was 88.4% (+/- 4.0). Twenty participants completed the self-efficacy questionnaire before and after training; the mean values of scores after training were statistically different and higher than those at baseline. Questionnaire regarding satisfaction with the online training experience was completed by 22 participants; all of them stated that they were satisfied with the online training experience. CONCLUSIONS: The results indicate that the online training course helped participants to increase self-efficacy and to provide interventions in institutions. This study could have implications for both undergraduate and postgraduate dental education in France. PMID- 23815692 TI - Do educational methods affect students' ability to remove artificial carious dentine? A randomised controlled trial. AB - This trial aimed to evaluate the influence of two educational methods on students' ability to remove artificial carious dentine. Traditional lecture and lecture plus a live demonstration of artificial carious tissue removal were compared in a blind two-parallel-group design. Twenty-six students were randomly divided into two groups, and their skills were evaluated according to the following criteria: time spent on the dentine excavation procedure (in min), students' perceived confidence in conducting the procedure (graded assessed on a scale from 0 to 10), and the outcome of artificial carious tissue removal, evaluated by measuring the residual dyed artificial carious dentine layer (in MUm). Statistical analyses were carried out using a t-test to compare the students' confidence and time spent on the procedure, and a two-way ANOVA was used to compare residual artificial decayed dentine with educational methods and tooth region (incisal, medium, and cervical thirds) as factors. There were no differences between the methods regarding excavation time (P = 0.898) and students' confidence (P = 0.382). The residual artificial carious dentine results showed that the educational method (P < 0.001) and cavity region (P < 0.001) were statistically significant, as was their interaction (P = 0.040). The lecture plus live demonstration group presented the best results for artificial caries removal. Although there were no differences between the two groups for the cervical region, the best results for the lecture plus live demonstration group was in the other two-thirds of the tooth. PMID- 23815694 TI - Transition to university: the role played by emotion. AB - Students experience transition to university as challenging. Recent studies implicate emotion in university success. This article reports on a pilot study to examine the extent to which school to university transition is experienced as emotional. Understanding the role of emotion in this transition can inform mechanisms for student support. This qualitative study used focus group interviews to elicit insider accounts of transition. The pilot cohort consisted of a tutorial group of twenty-eight students from within the class of one hundred and eight-first-year students at one Faculty of Dentistry in South Africa. Three focus group interviews were conducted. Issues identified in the literature as significant were used to analyse the data. Eleven descriptive tags related to transition and associated with emotion were identified from the data. These were clustered into four themes - 'academic challenges', 'friends and family', 'outside constraints' and 'identity'. Findings suggest that emotions are a natural part of the experience of transition. Drawing on insights of students' emotional needs, it is suggested that students in transition need a roadmap and a guide. A framework, to be used as a roadmap, is suggested. Peer mentoring is discussed as a mechanism for mediating the framework and thus for supporting students in the transition. PMID- 23815693 TI - Analysis of the 'Educational Climate' in Spanish Public Schools of Dentistry using the Dundee Ready Education Environment Measure: a multicenter study. AB - AIM: To analyse the 'Educational Climate' (EC) of dental students in Spain. METHODS: The study group consisted of 1391 students from nine Spanish Public Schools of Dentistry, who responded to the questionnaire based on 'Dundee Ready Education Environment Measure' (DREEM). This questionnaire has 50 items that are grouped into five domains: Learning, Teachers, Academic, Atmosphere and Social. RESULTS: The global score on the EC was 123.1 (interpretation: 'EC more positive than negative'). The scores obtained in the different domains were: 28.0 in Learning (interpretation: 'a generally positive perception of learning'), 26.8 in Teachers (interpretation: 'teachers are going in the right direction'), 20.8 in Academic (interpretation: 'feeling more on the positive side'), 29.7 in Atmosphere (interpretation: 'a generally positive atmosphere') and 17.7 in Social (interpretation: 'social perception acceptable'). In seven items (14%), an average of <2 was detected, showing that there are some educational problem areas. Regarding the EC in the different Schools of Dentistry, an average of >100 was achieved in all of them, although there were two centres that showed significantly higher values of EC. CONCLUSIONS: Spanish dental students felt that their EC was more positive than negative and considered that the different domains were positive and acceptable. However, they pointed out the existence of several educational problem areas associated with the development of a traditional curriculum. Accordingly, and in parallel with the implementation of an innovative curriculum in all Spanish Dental Schools in the coming years, immediate educational goals must address the problem areas identified, thereby further promoting a more positive perception of EC. PMID- 23815695 TI - Acceptability of a reflective e-portfolio instituted in an orthodontic specialist programme: a pilot study. AB - AIM: The purpose of the study was to highlight students' and mentors' acceptability of a reflective e-portfolio instituted in a postgraduate orthodontic programme in the UK. METHODS: A reflective e-portfolio was developed on the basis of principles provided by a literature search and was piloted for 2 months with six students and seven mentors. At the end of the experience, mentors' and students' acceptability of the e-portfolio with a reflective component was studied using questionnaires. The data were analysed using basic quantitative and qualitative methods. RESULTS: Students' response highlighted acceptability issues related to each aspect of the e-portfolio derived from the literature: relevance of the e-portfolio reflective part; time required for the process; support and mentoring; the implementation method; and the electronic medium. Mentors showed a more positive attitude towards the e-portfolio, expressing only some concerns about the time involved in using it. Furthermore, the analysis of the data highlighted some other acceptability matters: the specificity of the e-portfolio, the communication amongst students and the relationship between students and mentors. CONCLUSIONS: The future successful implementation of the reflective e-portfolio will depend on the productive management of the acceptability issues identified by students and mentors, in particular:(i)the specificity of the e-portfolio that would avoid its overlapping with other part of the programme;(ii)the increasing communication amongst students to improve their knowledge of the reflective writing process; and (iii)the development of a relationship between students and mentors helping to create the appropriate environment for reflection. PMID- 23815696 TI - Role of 'student-to-student local analgesia administration' on undergraduate students' opinions regarding 'pain-free local analgesia technique' in children. AB - AIM: To examine the role of 'student-to-student local analgesia administration' on undergraduate dental students' opinions regarding pain-free local analgesia techniques in children. METHODS: Grade 3 (n:29), Grade 4 (n:59) and Grade 5 students (n:28) of Yeditepe University, School of Dentistry, Istanbul, Turkey participated in the study. Informed consent and ethical approval were obtained. Students' opinions were evaluated by means of a short survey administered before and after educational activities. Activities were provided in a didactic manner (theoretical, practical and clinical stages) and lasted for 6 months. Theoretical lectures on 'pain-free local analgesia techniques in children' were given to all classes. In the practical stage, 3rd and 4th grade students were paired and performed infiltration analgesia on each other according to the lectured technique. In the final clinical stage, 4th and 5th grade students were supervised, whilst administering the technique on children during their clinical training. RESULTS: Before the activities, only 40% of students believed in the possibility of pain-free local analgesia in children, whereas after the educational activities, the percentage had risen to 68% (P = 0.0001). A significant difference was observed between the opinions of 4th grade students who attended the practical stage and 5th grade students who did not. CONCLUSION: The role of 'student-to-student local analgesia administration' was found to be significant in changing undergraduate students' opinions about pain-free dental injections in children. PMID- 23815697 TI - Microwave endometrial ablation for endometrial protection in women with breast cancer on adjuvant tamoxifen. AB - AIM: The purpose of the current study was to determine the effectiveness of microwave endometrial ablation (MEA) in inhibiting the proliferative response of the endometrium in women with breast cancer who are treated with tamoxifen. MATERIAL AND METHODS: In the before-after study, we treated 31 postmenopausal patients who had received adjuvant tamoxifen for 1 year or more with MEA, the endometrial changes were compared before and after MEA. RESULTS: After MEA, the thickness of the uterine lining was decreased significantly. No patient had recurrent endometrial polyps or abnormal vaginal bleeding during the follow-up period. CONCLUSION: MEA had a protective action against the uterine effects of tamoxifen for postmenopausal patients. MEA is a safe and effective minimally invasive treatment method for breast cancer patients treated with tamoxifen. PMID- 23815698 TI - Application of gas chromatography-mass spectrometry/combustion/isotope ratio mass spectrometry (GC-MS/C/IRMS) to detect the abuse of 17beta-estradiol in cattle. AB - Although the ability to differentiate between endogenous steroids and synthetic homologues on the basis of their (13)C/(12)C isotopic ratio has been known for over a decade, this technique has been scarcely implemented for food safety purposes. In this study, a method was developed using gas chromatography-mass spectrometry/combustion/isotope ratio mass spectrometry (GC-MS/C/IRMS) to demonstrate the abuse of 17beta-estradiol in cattle, by comparison of the (13)C/(12)C ratios of the main metabolite 17alpha-estradiol and an endogenous reference compound (ERC), 5-androstene-3beta,17alpha-diol, in bovine urine. The intermediate precisions were determined as 0.46 and 0.260/00 for 5-androstene 3beta,17alpha-diol and 17alpha-estradiol, respectively. This is, to the authors' knowledge, the first reported use of GC-MS/C/IRMS for the analysis of steroid compounds for food safety issues. PMID- 23815699 TI - The flexibility of 12-month-olds' preferences for phonologically appropriate object labels. AB - We explored 12-month-olds' flexibility in accepting phonotactically illegal or ill-formed word forms in a modified associative-learning task. Sixty-four English learning infants were presented with a training phase that either clarified the purpose of a sound-object association task or left the task ambiguous. Infants were then habituated to sets of Czech words with onsets that are illegal in English (e.g., ptak), consonantal sounds (e.g., /l/), or novel functionlike words (e.g., iv). When infants were provided with a training phase that highlighted the purpose of the task, they associated the phonotactically illegal Czech words, but not the consonantal sounds or novel functionlike words, with objects. Thus, English-learning 12-month-old infants' flexibility in associating various sound forms with novel objects is limited to labels that share the structural shape of well-formed nounlike words. PMID- 23815700 TI - Reciprocating risks of peer problems and aggression for children's internalizing problems. AB - Three complementary models of how peer relationship problems (exclusion and victimization) and aggressive behaviors relate to prospective levels of internalizing problems are examined. The additive risks model proposes that peer problems and aggression cumulatively increase risks for internalizing problems. The reciprocal risks model hypothesizes that peer problems and aggression transact over time and mediate the effects of each other on prospective internalizing problems. Last, the internalizing risks model proposes that, in addition to aggressive behaviors, prior internalizing problems also provoke peer problems that, in turn, further elevate risks for prospective internalizing problems. Data came from a sample of 453 low-income, ethnically diverse children in kindergarten to Grade 3 who were assessed 3 times over 1 school term (in January, March and June). Findings supported the internalizing risks model. Four key pathways were found to increase risks for internalizing problems by the end of the school year; 2 of these routes were rooted in aggressive behaviors, and 3 paths operated indirectly via levels of peer problems in the spring. Children who were initially aggressive became excluded by peers by the spring, whereas children who initially showed more symptoms of depression and anxiety became victimized by peers by the spring. In turn, both peer exclusion and victimization increased prospective levels of internalizing problems by the end of the school year. PMID- 23815701 TI - Mental spatial transformations of objects and bodies: different developmental trajectories in children from 7 to 11 years of age. AB - Despite the large body of knowledge on adults suggesting that 2 basic types of mental spatial transformation--namely, object-based and egocentric perspective transformations--are dissociable and specialized for different situations, there is much less research investigating the developmental aspects of such spatial transformation systems. Here, an "own body transformation" paradigm and a letter transformation task were employed in a group of children ranging from 7 to 11 years of age to respectively investigate the development of egocentric perspective transformations and object-related transformations. A group of 30 young adults was also administered the 2 experimental tasks. Moreover, the Temperament and Character Inventory (Cloninger, Przybeck, Svrakic, & Wetzel, 1994) was also administered to children and adults with the goal of testing for possible influences of personality traits on imagined perspective transformation abilities. We found that egocentric perspective transformations develop later than object-based transformations--namely, from 8 rather than 7 years of age. We also found that high scores on temperament and character scales reflecting the acceptance of others (i.e., cooperativeness) were positively related to the ability to engage in imagined perspective transformations, especially when such ability first appears (i.e., at 8 years of age). These findings were held to support the view that the 2 mental spatial transformation systems are separated in that they follow 2 different developmental trajectories and are differentially influenced by personality traits in children. PMID- 23815703 TI - Children's preference for social stories. AB - Many scholars have proposed theories to explain the appeal of fictional stories, but relatively little research has examined this issue from a developmental perspective. Here, we investigate the role that social and mental content play in attracting children to stories. In Experiment 1, 4- to 8-year-old children preferred stories that contained people over those that focused on objects. In Experiment 2, children preferred stories with mental content over stories that were described purely in terms of action, while in Experiment 3, children preferred stories with more characters to those with fewer but did not prefer stories that contained mental states embedded in other mental states. No age effects were found. These results are discussed in terms of theories of fiction, and directions are suggested for future research. PMID- 23815702 TI - Essentialist thinking predicts decrements in children's memory for racially ambiguous faces. AB - Past research shows that adults often display poor memory for racially ambiguous and racial outgroup faces, with both face types remembered worse than own-race faces. In the present study, the authors examined whether children also show this pattern of results. They also examined whether emerging essentialist thinking about race predicts children's memory for faces. Seventy-four White children (ages 4-9 years) completed a face-memory task comprising White, Black, and racially ambiguous Black-White faces. Essentialist thinking about race was also assessed (i.e., thinking of race as immutable and biologically based). White children who used essentialist thinking showed the same bias as White adults: They remembered White faces significantly better than they remembered ambiguous and Black faces. However, children who did not use essentialist thinking remembered both White and racially ambiguous faces significantly better than they remembered Black faces. This finding suggests a specific shift in racial thinking wherein the boundaries between racial groups become more discrete, highlighting the importance of how race is conceptualized in judgments of racially ambiguous individuals. PMID- 23815704 TI - Daily stress and emotional well-being among Asian American adolescents: same-day, lagged, and chronic associations. AB - Daily-diary data from 180 Asian American 9th-10th graders (58% female, 75% second generation; M age = 14.97 years) were used to investigate how family, school, and peer stress are each associated with same-day and next-day (lagged) well-being, and vice versa. Hierarchical linear modeling provided support for reciprocal links when considering same-day reports. More daily stress was associated with lower same-day happiness and higher distress and anxiety. At the same time, well being was associated with same-day stress, although the specific patterns were not as consistent and varied somewhat by stress domain. With a 1-day lag between daily experiences, stress was not associated with next-day well-being, but daily distress was associated with more next-day family stress. Females and first generation adolescents were particularly vulnerable to daily stress and well being processes. Sustained effects were also found in that chronic experiences of school stress over the 14-day period were associated with higher reports of depression and anxiety. PMID- 23815706 TI - An amphiphilic pillar[5]arene as efficient and substrate-selective phase-transfer catalyst. AB - An amphiphilic macrocyclic compound consisting of 10 tetra-alkyl phosphonium bromide groups and a pillar[5]arene core was prepared. This compound was soluble in both aqueous and organic media and acted as a highly efficient and substrate selective phase-transfer catalyst. In particular, oxidation of the linear alkene1 hexene to 1-pentanal by KMnO4 was >99%, whereas that of the branched alkene 4 methyl-1-hexene was only 31%, under ideal conditions. PMID- 23815705 TI - Associations among negative parenting, attention bias to anger, and social anxiety among youth. AB - Theories of affective learning suggest that early experiences contribute to emotional disorders by influencing the development of processing biases for negative emotional stimuli. Although studies have shown that physically abused children preferentially attend to angry faces, it is unclear whether youth exposed to more typical aspects of negative parenting exhibit the same type of bias. The current studies extend previous research by linking observed negative parenting styles (e.g., authoritarian) and behaviors (e.g., criticism and negative affect) to attention bias for angry faces in both a psychiatrically enriched (ages 11-17 years; N = 60) and a general community (ages 9-15 years; N = 75) sample of youth. In addition, the association between observed negative parenting (e.g., authoritarian style and negative affect) and youth social anxiety was mediated by attention bias for angry faces in the general community sample. Overall, findings provide preliminary support for theories of affective learning and risk for psychopathology among youth. PMID- 23815707 TI - Quaternary germanides RE4Mn2InGe4 (RE = La-Nd, Sm, Gd-Tm, Lu). AB - The quaternary germanides RE4Mn2InGe4 (RE = La-Nd, Sm, Gd-Tm, Lu) have been prepared by arc-melting reactions of the elements and annealing at 800 degrees C and represent the second example of the RE4M2InGe4 series previously known only for M = Ni. Single-crystal X-ray diffraction studies conducted on the earlier RE members of RE4Mn2InGe4 confirmed that they adopt the monoclinic Ho4Ni2InGe4-type structure [space group C2/m, a = 16.646(2)-15.9808(9) A, b = 4.4190(6)-4.2363(2) A, c = 7.4834(10)-7.1590(4) A, beta = 106.893(2)-106.304(1) degrees in the progression of RE from La to Gd]. The covalent framework contains Mn-centered tetrahedra and Ge2 dimers that build up [Mn2Ge4] layers, which are held weakly together by four-coordinate In atoms and outline tunnels filled by the RE atoms. This bonding picture is supported by band-structure calculations. An alternative description based on Ge-centered trigonal prisms reveals that RE4Mn2InGe4 is closely related to RE2InGe2. The electrical resistivity behavior of Pr4Mn2InGe4 is similar to that of Pr2InGe2. PMID- 23815708 TI - Anthropogenic impacts on a bedrock aquifer at the village scale. AB - This study focuses on assessing groundwater potability in a highly complex and heterogeneous fractured bedrock aquifer having variable overburden cover. Eight monitoring wells were installed in a privately serviced lakeside village, and groundwater was routinely sampled over a 2-year timeframe for concentration analysis of nitrate, fecal indicator bacteria, stable isotopes, and a total of 41 pharmaceutical compounds. While pollutant concentrations remained low throughout the study, the presence of fecal indicator bacteria and pharmaceuticals was noted at least once (but not always consistently) in most sampling intervals. An interpretation based on the integration of chemical, bacterial, and site characterization datasets suggests that: (1) the fracture network is complex and heterogeneous with limited vertical connectivity; (2) existing pathways are sufficient for the quick and widespread migration of surface contaminants to depth; (3) anthropogenic contaminants from both septic systems and agriculture are likely sourced in the surrounding uplands where overburden is thin; and (4) fecal contamination, as observed over the long term, is ubiquitous at the village scale. Groundwater quality is continually changing in this hydrogeologic environment and the determination of potability on the larger scale is not likely to be adequately captured with infrequent domestic well sampling (i.e., voluntary annual sampling by homeowners). PMID- 23815709 TI - Compound heterozygosity of predicted loss-of-function DES variants in a family with recessive desminopathy. AB - BACKGROUND: Variants in the desmin gene (DES) are associated with desminopathy; a myofibrillar myopathy mainly characterized by muscle weakness, conduction block, and dilated cardiomyopathy. To date, only ~50 disease-associated variants have been described, and the majority of these lead to dominant-negative effects. However, the complete genotypic spectrum of desminopathy is not well established. CASE PRESENTATION: Next-generation sequencing was performed on 51 cardiac disease genes in a proband with profound skeletal myopathy, dilated cardiomyopathy, and respiratory dysfunction. Our analyses revealed compound heterozygous DES variants, both of which are predicted to lead to a loss-of-function. Consistent with recessive inheritance, each variant was identified in an unaffected parent. CONCLUSIONS: This case report serves to broaden the variant spectrum of desminopathies and provides insight into the molecular mechanisms of desminopathy, supporting distinct dominant-negative and loss-of-function etiologies. PMID- 23815710 TI - Targeting tyrosine-kinases in ovarian cancer. AB - INTRODUCTION: Epithelial ovarian cancer (EOC) is the leading cause of gynaecologic cancer death. Although in some cases initial treatment is effective, most of the women diagnosed with EOC will probably need medical treatment for their disease. There is a critical need to develop effective new strategies for the management of patients with advanced or recurrent EOC, and targeted therapy with tyrosine kinase inhibitors (TKIs) has continued to be an area of active research and development in this setting. AREAS COVERED: This review summarises the available evidence on the use of TKIs in the clinical management of women with EOC. This article consists of material obtained via Medline, PubMed and EMBASE literature searches up to March 2013. EXPERT OPINION: Several Phase I/II and III trials evaluated TKIs in EOC; however, it is difficult to draw conclusions on the efficacy of TKI regimens in these patients. TKIs seem to be better tolerated than conventional chemotherapy with a different toxicity profile. A better understanding of the signalling pathways, the toxicity profiles, the potential pharmacokinetic interactions as well as the identification of predictive biomarkers are needed to better identify a targeted patient population before these agents become part of routine treatment. PMID- 23815711 TI - Locating tandem repeats in weighted sequences in proteins. AB - A weighted biological sequence is a string in which a set of characters may appear at each position with respective probabilities of occurrence. We attempt to locate all the tandem repeats in a weighted sequence. A repeated substring is called a tandem repeat if each occurrence of the substring is directly adjacent to each other. By introducing the idea of equivalence classes in weighted sequences, we identify the tandem repeats of every possible length using an iterative partitioning technique. We also present the algorithm for recording the tandem repeats, and prove that the problem can be solved in O(n2) time. PMID- 23815712 TI - Deadly H7N9 influenza virus: a pandemic in the making or a warning lesson? PMID- 23815713 TI - Additional insights into epithelial secreted phospholipase A2 group X in asthma. PMID- 23815714 TI - Evolution of the GOLD documents for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Controversies and questions. PMID- 23815715 TI - Chronic obstructive pulmonary disease: a disease of the endothelium? PMID- 23815716 TI - Early recognition and treatment of severe sepsis. PMID- 23815717 TI - Asbestos and lung cancer: what we know. PMID- 23815718 TI - Rationalizing use of fluoroquinolones and pyrazinamide in the battle against multidrug-resistant tuberculosis. PMID- 23815719 TI - Update in environmental and occupational medicine 2012. PMID- 23815720 TI - Update in pulmonary vascular diseases 2012. PMID- 23815721 TI - Update in chronic obstructive pulmonary disease 2012. PMID- 23815722 TI - An official American Thoracic Society/International Society for Heart and Lung Transplantation/Society of Critical Care Medicine/Association of Organ and Procurement Organizations/United Network of Organ Sharing Statement: ethical and policy considerations in organ donation after circulatory determination of death. AB - RATIONALE: Donation after circulatory determination of death (DCDD) has the potential to increase the number of organs available for transplantation. Because consent and management of potential donors must occur before death, DCDD raises unique ethical and policy issues. OBJECTIVES: To develop an ethics and health policy statement on adult and pediatric DCDD relevant to critical care and transplantation stakeholders. METHODS: A multidisciplinary panel of stakeholders was convened to develop an ethics and health policy statement. The panel consisted of representatives from the American Thoracic Society, Society of Critical Care Medicine, International Society for Heart and Lung Transplantation, Association of Organ Procurement Organizations, and the United Network of Organ Sharing. The panel reviewed the literature, discussed important ethics and health policy considerations, and developed a guiding framework for decision making by stakeholders. RESULTS: A framework to guide ethics and health policy statement was established, which addressed the consent process, pre- and post mortem interventions, the determination of death, provisions of end-of-life care, and pediatric DCDD. CONCLUSIONS: The information presented in this Statement is based on the current evidence, experience, and clinical rationale. New clinical research and the development and dissemination of new technologies will eventually necessitate an update of this Statement. PMID- 23815723 TI - An atoll variant that mocks. PMID- 23815724 TI - Reply: from idiopathic pulmonary fibrosis to cystic fibrosis: got lactate? PMID- 23815725 TI - Lactate levels in airways of patients with cystic fibrosis and idiopathic pulmonary fibrosis. PMID- 23815726 TI - Performing bronchoalveolar lavage as per the American Thoracic Society guidelines 2012: an analysis of 100 consecutive cases. PMID- 23815727 TI - Reply: performing bronchoalveolar lavage as per the ATS guidelines 2012. PMID- 23815728 TI - Family outbreak of severe pneumonia induced by H7N9 infection. PMID- 23815729 TI - Sharing insights and H7N9 patient clinical data. PMID- 23815730 TI - Effects of decontamination of the digestive tract and oropharynx in intensive care unit patients on 1-year survival. PMID- 23815731 TI - An inactivating caspase-11 passenger mutation muddles sepsis research. PMID- 23815732 TI - Recurrent spontaneous pneumothoraces. PMID- 23815733 TI - Abstracts of the 38th FEBS (Federation of European Biochemical Societies) Congress. Saint Petersburg, Russia. July 6-11, 2013. PMID- 23815734 TI - Novel LDLR variants in patients with familial hypercholesterolemia: in silico analysis as a tool to predict pathogenic variants in children and their families. AB - Familial hypercholesterolemia (FH) is an autosomal dominant disease with a frequency of 1:500 in its heterozygous form. To date, mutations in the low density lipoprotein receptor gene (LDLR) are the only identified causes of FH in the Greek population, causing high levels of low-density lipoprotein (LDL) and total cholesterol and premature atherosclerosis. The Greek FH population is genetically homogeneous, but most previous studies screened for the most common mutations only. The study aimed to characterize and assess novel LDLR variants. LDLR was examined by whole-gene DNA sequencing in 561 FH patients from 262 families of Greek origin. Novel LDLR variants were analyzed in silico using various software predicting pathogenicity and changes in protein stability. Twelve novel LDLR variants were identified, six of which are putative disease causing variants: c.977C>G in exon 7, c.1124A>C in exon 8, c.1381G>T in exon 10, c.628_643dup{636del}, c.661-673dup in exon 4, and 13 c.1987+1_+33del in intron 13. All six putative variants were confirmed in the hypercholesterolemic members of the family. The results show that in silico analysis is a valuable tool to predict potential pathogenicity of novel variants, especially for populations that have not been extensively studied. The identification of novel pathogenic variants will facilitate the molecular diagnosis of FH from early childhood. PMID- 23815735 TI - Electrolysed reduced water decreases reactive oxygen species-induced oxidative damage to skeletal muscle and improves performance in broiler chickens exposed to medium-term chronic heat stress. AB - 1. The present study was designed to achieve a reduction of reactive oxygen species (ROS)-induced oxidative damage to skeletal muscle and to improve the performance of broiler chickens exposed to chronic heat stress. 2. Chickens were given a control diet with normal drinking water, or diets supplemented with cashew nut shell liquid (CNSL) or grape seed extract (GSE), or a control diet with electrolysed reduced water (ERW) for 19 d after hatch. Thereafter, chickens were exposed to a temperature of either 34 degrees C continuously for a period of 5 d, or maintained at 24 degrees C, on the same diets. 3. The control broilers exposed to 34 degrees C showed decreased weight gain and feed consumption and slightly increased ROS production and malondialdehyde (MDA) concentrations in skeletal muscle. The chickens exposed to 34 degrees C and supplemented with ERW showed significantly improved growth performance and lower ROS production and MDA contents in tissues than control broilers exposed to 34 degrees C. Following heat exposure, CNSL chickens performed better with respect to weight gain and feed consumption, but still showed elevated ROS production and skeletal muscle oxidative damage. GSE chickens did not exhibit improved performance or reduced skeletal muscle oxidative damage. 4. In conclusion, this study suggests that ERW could partially inhibit ROS-induced oxidative damage to skeletal muscle and improve growth performance in broiler chickens under medium-term chronic heat treatment. PMID- 23815737 TI - Metabolism of dimethylsulphoniopropionate by Ruegeria pomeroyi DSS-3. AB - Ruegeria pomeroyi DSS-3 possesses two general pathways for metabolism of dimethylsulphoniopropionate (DMSP), an osmolyte of algae and abundant carbon source for marine bacteria. In the DMSP cleavage pathway, acrylate is transformed into acryloyl-CoA by propionate-CoA ligase (SPO2934) and other unidentified acyl CoA ligases. Acryloyl-CoA is then reduced to propionyl-CoA by AcuI or SPO1914. Acryloyl-CoA is also rapidly hydrated to 3-hydroxypropionyl-CoA by acryloyl-CoA hydratase (SPO0147). A SPO1914 mutant was unable to grow on acrylate as the sole carbon source, supporting its role in this pathway. Similarly, growth on methylmercaptopropionate, the first intermediate of the DMSP demethylation pathway, was severely inhibited by a mutation in the gene encoding crotonyl-CoA carboxylase/reductase, demonstrating that acetate produced by this pathway was metabolized by the ethylmalonyl-CoA pathway. Amino acids and nucleosides from cells grown on (13) C-enriched DMSP possessed labelling patterns that were consistent with carbon from DMSP being metabolized by both the ethylmalonyl-CoA and acrylate pathways as well as a role for pyruvate dehydrogenase. This latter conclusion was supported by the phenotype of a pdh mutant, which grew poorly on electron-rich substrates. Additionally, label from [(13) C-methyl] DMSP only appeared in carbons derived from methyl-tetrahydrofolate, and there was no evidence for a serine cycle of C-1 assimilation. PMID- 23815736 TI - Defense-related transcription factors WRKY70 and WRKY54 modulate osmotic stress tolerance by regulating stomatal aperture in Arabidopsis. AB - WRKY transcription factors (TFs) have been mainly associated with plant defense, but recent studies have suggested additional roles in the regulation of other physiological processes. Here, we explored the possible contribution of two related group III WRKY TFs, WRKY70 and WRKY54, to osmotic stress tolerance. These TFs are positive regulators of plant defense, and co-operate as negative regulators of salicylic acid (SA) biosynthesis and senescence. We employed single and double mutants of wrky54 and wrky70, as well as a WRKY70 overexpressor line, to explore the role of these TFs in osmotic stress (polyethylene glycol) responses. Their effect on gene expression was characterized by microarrays and verified by quantitative PCR. Stomatal phenotypes were assessed by water retention and stomatal conductance measurements. The wrky54wrky70 double mutants exhibited clearly enhanced tolerance to osmotic stress. However, gene expression analysis showed reduced induction of osmotic stress-responsive genes in addition to reduced accumulation of the osmoprotectant proline. By contrast, the enhanced tolerance was correlated with improved water retention and enhanced stomatal closure. These findings demonstrate that WRKY70 and WRKY54 co-operate as negative regulators of stomatal closure and, consequently, osmotic stress tolerance in Arabidopsis, suggesting that they have an important role, not only in plant defense, but also in abiotic stress signaling. PMID- 23815738 TI - Cell nucleus targeting for living cell extraction of nucleic acid associated proteins with intracellular nanoprobes of magnetic carbon nanotubes. AB - Since nanoparticles could be ingested by cells naturally and target at a specific cellular location as designed, the extraction of intracellular proteins from living cells for large-scale analysis by nanoprobes seems to be ideally possible. Nucleic acid associated proteins (NAaP) take the crucial position during biological processes in maintaining and regulating gene structure and gene related behaviors, yet there are still challenges during the global investigation of intracellular NAaP, especially from living cells. In this work, a strategy to extract intracellular proteins from living cells with the magnetic carbon nanotube (oMWCNT@Fe3O4) as an intracellular probe is developed, to achieve the high throughput analysis of NAaP from living human hepatoma BEL-7402 cells with a mass spectrometry-based proteomic approach. Due to the specific intracellular localization of the magnetic carbon nanotubes around nuclei and its strong interaction with nucleic acids, the highly efficient extraction was realized for cellular NAaP from living cells, with the capability of identifying 2383 intracellular NAaP from only ca. 10,000 living cells. This method exhibited potential applications in dynamic and in situ analysis of intracellular proteins. PMID- 23815740 TI - Oxidant-free Rh(III)-catalyzed direct C-H olefination of arenes with allyl acetates. AB - Rh(III)-catalyzed direct olefination of arenes with allyl acetate via C-H bond activation is described using N,N-disubstituted aminocarbonyl as the directing group. The catalyst undergoes a redox neutral process, and high to excellent yields of trans-products are obtained. This protocol exhibits a wide spectrum of functionality compatibility because of the simple reaction conditions employed and provides a highly effective synthetic method in the realm of C-H olefination. PMID- 23815739 TI - The efficacy of SMART Arm training early after stroke for stroke survivors with severe upper limb disability: a protocol for a randomised controlled trial. AB - BACKGROUND: Recovery of upper limb function after stroke is poor. The acute to subacute phase after stroke is the optimal time window to promote the recovery of upper limb function. The dose and content of training provided conventionally during this phase is however, unlikely to be adequate to drive functional recovery, especially in the presence of severe motor disability. The current study concerns an approach to address this shortcoming, through evaluation of the SMART Arm, a non-robotic device that enables intensive and repetitive practice of reaching by stroke survivors with severe upper limb disability, with the aim of improving upper limb function. The outcomes of SMART Arm training with or without outcome-triggered electrical stimulation (OT-stim) to augment movement and usual therapy will be compared to usual therapy alone. METHODS/DESIGN: A prospective, assessor-blinded parallel, three-group randomised controlled trial is being conducted. Seventy-five participants with a first-ever unilateral stroke less than 4 months previously, who present with severe arm disability (three or fewer out of a possible six points on the Motor Assessment Scale [MAS] Item 6), will be recruited from inpatient rehabilitation facilities. Participants will be randomly allocated to one of three dose-matched groups: SMART Arm training with OT-stim and usual therapy; SMART Arm training without OT-stim and usual therapy; or usual therapy alone. All participants will receive 20 hours of upper limb training over four weeks. Blinded assessors will conduct four assessments: pre intervention (0 weeks), post intervention (4-weeks), 26 weeks and 52 weeks follow-up. The primary outcome measure is MAS item 6. All analyses will be based on an intention-to treat principle. DISCUSSION: By enabling intensive and repetitive practice of a functional upper limb task during inpatient rehabilitation, SMART Arm training with or without OT-stim in combination with usual therapy, has the potential to improve recovery of upper limb function in those with severe motor disability. The immediate and long-term effects of SMART Arm training on upper limb impairment, activity and participation will be explored, in addition to the benefit of training with or without OT-stim to augment movement when compared to usual therapy alone. TRIAL REGISTRATION: ACTRN12608000457347. PMID- 23815741 TI - Impact of cilia ultrastructural examination on the diagnosis of primary ciliary dyskinesia. AB - Ultrastructural examination of cilia is the "gold standard" for diagnosing primary ciliary dyskinesia. There is little evidence suggesting the most effective method of procuring a ciliary biopsy and scant benchmark data on rates of conclusive biopsies or on the diagnostic impact of such biopsies. To critically assess rates of inconclusive, positive, and negative ciliary biopsies and to identify clinical factors associated with conclusive results, we reviewed ciliary biopsies submitted for electron microscopy from 2006 to 2011, noting whether specimens were adequate for analysis and whether the ciliary structure was normal. The biopsy site, method used, procedurist's specialty, and clinical diagnoses were determined. Biopsy findings were categorized by diagnostic impact. Over 5 years, 187 patients had 211 biopsies. Conclusive results were obtained on 133/211 biopsies (63%); the remainder were insufficient. The rate of inconclusive biopsies did not vary significantly (P > 0.05; Fisher's exact) among sampling methods. Abnormal results were identified in 8/133 (6.0%) of the adequate specimens. Forceps compared to brush biopsies (abnormal in 4/12 versus 4/121 of the adequate specimens, P = 0.002), along with multiple biopsy samples (taken on same or different days) compared with a single biopsy sample (abnormal in 3/12 versus 1/110 of the adequate specimens, P = 0.01), were more likely to yield an abnormal result. Only 63% of pediatric ciliary biopsies provide adequate morphology for analysis, the large majority of these samples showing normal ciliary anatomy. The method of obtaining biopsies did not significantly affect result conclusiveness. Understanding the diagnostic impact of ultrastructural analysis is important as new diagnostic algorithms are developed for primary ciliary dyskinesia. PMID- 23815742 TI - T/L-type calcium channel blocker reduces the composite ranking of relative risk according to new KDIGO guidelines in patients with chronic kidney disease. AB - BACKGROUND: Recently, the Kidney Disease: Improving Global Outcomes (KDIGO) group recommended that patients with chronic kidney disease (CKD) be assigned according to stage and composite relative risk on the basis of glomerular filtration rate (GFR) and albuminuria criteria. The aim of this post-hoc analysis was to investigate the effects of add-on therapy with calcium channel blockers (CCBs) on changes in the composite ranking of relative risk according to KDIGO guidelines. Benidipine, an L- and T-type CCB, and amlodipine, an L-type CCB to angiotensin II receptor blocker (ARB), were examined. METHODS: Patients with blood pressure (BP) > 130/80 mmHg, an estimated GFR (eGFR) of 30-90 mL/min/1.73 m2, and albuminuria > 30 mg/gCr, despite treatment with the maximum recommended dose of ARB, were randomly assigned to two groups. Each group received one of two treatments: 2 mg benidipine daily, increased to 8 mg daily (n = 52), or 2.5 mg amlodipine daily, increased to 10 mg daily (n = 52). RESULTS: After 6 months of treatment, a significant and comparable reduction in systolic and diastolic BP was observed in both groups. The eGFR was significantly decreased in the amlodipine group, but there was no significant change in the benidipine group. The decrease in albuminuria in the benidipine group was significantly lower than in the amlodipine group. The composite ranking of relative risk according to the new KDIGO guidelines was significantly improved in the benidipine group; however, no significant change was noted in the amlodipine group. Moreover, significantly fewer cases in the benidipine group than the amlodipine group showed a reduced risk category score. CONCLUSION: The present post-hoc analysis showed that compared to amlodipine benidipine results in a greater reduction in albuminuria accompanied by an improved composite ranking of relative risk according to the KDIGO CKD severity classification. TRIAL REGISTRATION: TRIAL REGISTRATION NUMBER: UMIN000002644. PMID- 23815743 TI - Can pathoanatomical pathways of degeneration in lumbar motion segments be identified by clustering MRI findings. AB - BACKGROUND: Magnetic Resonance Imaging (MRI) is the gold standard for detailed visualisation of spinal pathological and degenerative processes, but the prevailing view is that such imaging findings have little or no clinical relevance for low back pain. This is because these findings appear to have little association with treatment effects in clinical populations, and mostly a weak association with the presence of pain in the general population. METHODS: This study is a secondary analysis of data from 631 patients, from an outpatient spine clinic, who had been screened for inclusion in a randomised controlled trial. The available data created a total sample pool of 3,155 vertebral motion segments. The mean age of the cohort was 42 years (SD 10.8, range 18-73) and 54% were women. RESULTS: Twelve clusters of MRI findings were identified, described and grouped into five different hypothetical pathways of degeneration that appear to have face validity. CONCLUSIONS: This study has shown that Latent Class Analysis can be used to identify clusters of MRI findings from people with LBP and that those clusters can be grouped into degenerative pathways that are biologically plausible. If these clusters of MRI findings are reproducible in other datasets of similar patients, they may form a stable platform to investigate the relationship between degenerative pathways and clinically important characteristics such as pain and activity limitation. PMID- 23815744 TI - Effect of ventilation technique and airway diameter on bronchial lumen to pulmonary artery diameter ratios in clinically normal beagle dogs. AB - In dogs, a mean broncho-arterial ratio of 1.45 +/- 0.21 has been previously defined as normal. These values were obtained in dogs under general inhalational anesthesia using a single breath-hold technique. The purpose of the study was to determine whether ventilation technique and bronchial diameter have an effect on broncho-arterial ratios. Four healthy Beagle dogs were scanned twice, each time with positive-pressure inspiration and end expiration. For each ventilation technique, broncho-arterial ratios were grouped into those obtained from small or large bronchi using the median diameter of the bronchi as the cutoff value. Mean broncho-arterial ratios obtained using positive-pressure inspiration (1.24 +/- 0.23) were statistically greater than those obtained at end expiration (1.11 +/- 0.20) P = 0.005. There was a strong positive correlation between bronchial diameter and broncho-arterial ratios for both ventilation techniques (positive pressure inspiration rs = .786, P < 0.0005 and end expiration rs = .709, P < 0.0005). Mean broncho-arterial ratio for the large bronchi obtained applying positive-pressure inspiration was 1.39 cm +/- 0.20 and during end expiration was 1.22 cm +/- 0.20. Mean broncho-arterial ratio for the small bronchi obtained during positive-pressure inspiration was 1.08 cm +/- 0.13 and during end expiration was 1.01 cm +/- 0.13. There was a statistically significant difference between these groups (F = 248.60, P = 0.005). Findings indicated that reference values obtained using positive-pressure inspiration or from the larger bronchi may not be applicable to dogs scanned during end expiration or to the smaller bronchi. PMID- 23815745 TI - Soil microbial effects on the stereoselective mineralization, extractable residue, bound residue, and metabolism of a novel chiral cis neonicotinoid, paichongding. AB - Fate characteristics of the four stereoisomers of paichongding [IPP, 1-((6 chloropyridin-3-yl)methyl)-7-methyl-8-nitro-5-propoxy-1,2,3,5,6,7 hexahydroimidazo[1,2-a]pyridine] in aerobic sterilized and nonsterilized fluvio marine yellow loamy soil were investigated using a (14)C tracer technique combined with HPLC and LC-MS/MS. Results showed that the mineralization and bound residue (nonsterile/sterilized soil, % of applied amount) of four stereoisomers of IPP were 1.76-6.10/0.33-0.82 and 12.01-31.20/6.58-20.81 at 100 days after treatment. Seven and five incomplete intermediates of IPP were detected in nonsterilized and sterilized soil, respectively, and a possible degradation pathway was proposed. Degradation mainly occurred on the tetrahydropyridine ring, including oxidation and elimination of the methyl, propyl, and nitro groups. All of these results suggest that soil microbial activity greatly contributes to the epimeride-selective mineralization, formation of bound residue, and degradation of IPP in loamy soil. The identified transformation intermediates could be used for further study on their toxicity to target and nontarget species. PMID- 23815746 TI - Paediatric and adolescent traumatic gastrointestinal injuries: results of a European multicentre analysis. AB - AIM: Paediatric gastrointestinal injuries (GIIs) are rare, and the aim of this multicentre study was to evaluate their outcomes in a large cohort. METHODS: Hospital databases of 10 European paediatric surgical centres were reviewed for paediatric traumatic GIIs managed between 2000-2010. RESULTS: Ninety-seven patients with a median age of 9 years (0-17 years) were identified, with 72 blunt and 25 penetrating GIIs. Initial diagnostics in 90 patients led to correct diagnosis in 71%. Diagnostics were delayed in 26 patients (median 24 h). Eighty two patients required surgery (67 laparotomy, 12 laparoscopy and three other approaches). There was a 50% conversion in the laparoscopic group. Median hospital stay was 10 days (range 1-137 days), with longer duration influenced by associated injuries (n = 41). Diagnosis <24 h was associated with significantly shorter hospital stay compared to more than 24 h (p = 0.011). In one-third of patients, morbidities were not related to a diagnostic delay or type of injury. There were five lethal outcomes, four due to associated injuries. CONCLUSION: Initial diagnostics in traumatic paediatric GIIs provide false negatives in one third of patients. Diagnostic delay <24 h is associated with a significantly shorter hospital stay. Although laparoscopy is associated with a conversion rate of 50%, it can be used for diagnosis in suspected cases to avoid nontherapeutic laparotomy. PMID- 23815747 TI - Transversus abdominis plane block provides postoperative analgesic effects after cesarean section: additional analgesia to epidural morphine alone. AB - AIM: The aim of our study was: (i) to investigate whether transversus abdominis plane (TAP) block confers additional analgesic effects to epidural morphine alone; and (ii) to determine plasma levels of local anesthetics after TAP block in post-cesarean women. MATERIAL AND METHODS: The subjects were parturients undergoing cesarean section under combined spinal-epidural anesthesia. Morphine (2 mg) was administered to the epidural space close to the end of surgery. Women who desired TAP block were allocated to the TAP group. Women who did not undergo TAP block were allocated to the control group. In the TAP group, 20 mL of either 0.375% ropivacaine or 0.3% levobupivacaine was infused to both sides of the transversus abdominis plane after surgery. All patients were placed on a patient controlled i.v. analgesia regimen with morphine after surgery. Time to the first morphine request and amount of morphine consumption within 24 h after surgery were compared in patients with and without TAP block. Plasma concentrations of local anesthetics were determined at 15, 30 and 60 min after TAP block. RESULTS: Forty and 54 patients were allocated to the control and TAP group, respectively. The median time to the first morphine request was longer (555 vs 215 min), and the median cumulative morphine consumption within 24 h was lower (5.3 vs 7.7 mg) in the TAP group than in the control group. The maximum median concentrations of ropivacaine and bupivacaine after TAP block were 784 and 553 ng/mL, respectively. CONCLUSION: TAP block had additional analgesic effects to epidural morphine alone. PMID- 23815748 TI - Lactobacillus plantarum 29 inhibits Penicillium spp. involved in the spoilage of black truffles (Tuber aestivum). AB - The effect of an antifungal culture of Lactobacillus plantarum to be used in the storage at refrigeration temperature of fresh black truffles was examined. The strain was selected among 29 lactobacilli isolated from foods and evaluated for their viability and acidification activity at 4 degrees C, as well as for their inhibitory activity against 11 Penicillium strains isolated from truffles stored at refrigeration temperature. Lb. plantarum 29 showed the ability to hold not only the growth of Penicillium isolated from truffles, but also that of P. digitatum DSM 2750, a green mold involved in the spoilage of truffles. The antifungal activity was observed in vitro and in situ, and the sensory characteristics of truffles were preserved during the cold storage. PMID- 23815751 TI - Vertical photoionization of liquid-to-supercritical ammonia: thermal effects on the valence-to-conduction band gap. AB - We recently reported first femtosecond pump-probe experiments on the geminate recombination dynamics of solvated electrons in fluid ammonia (Urbanek et al., J. Phys. Chem. B 2012, 116, 2223-2233). The electrons were generated through a vertical two-photon ionization at a total energy of 9.3 eV. Here, we present a full Monte Carlo analysis of the time-resolved data to determine the solvated electron's thermalization distance from the ionization hole, NH(3)(+). The simulations are compared with the experiment over wide thermodynamic conditions to obtain insight into the dependence of the vertical ionization mechanism on the electronic properties of the solvent network. The simulations reveal that the average thermalization distance, , decreases strongly with both increasing temperature, T, and decreasing density, rho, from 3.2 nm in the cryogenic fluid down to roughly 0.5 nm in the dilute supercritical phase with almost gas-like densities. We combine our results with the current understanding of the T,rho dependence of the electronic structure of the liquid phase and discuss in detail the role of thermally induced energy level shifts for the valence-to-conduction band gap. The observed changes of the thermalization distance can be well attributed to a gradual decrease of the excess energy initially imparted on the ejected electron as gas-like conditions are progressively approached. PMID- 23815750 TI - The Arabidopsis LRR-RLK, PXC1, is a regulator of secondary wall formation correlated with the TDIF-PXY/TDR-WOX4 signaling pathway. AB - BACKGROUND: Although a number of leucine-rich repeat receptor-like kinase encoding genes (LRR-RLKs) have been identified in plants, a functional role has been determined for only a few. Recent studies have demonstrated that an LRR-RLK, PXY/TDR, is important for the process of secondary vascular development. Other studies have indicated that PXY/TDR is unlikely to be the sole LRR-RLK involved in this complex process. RESULTS: In this study, in silico analyses led to the identification of three Arabidopsis LRR-RLK genes (PXY-correlated; PXC1, 2, 3) with transcript accumulation profiles that correlated strongly with several key regulators of vascular development, including PXY/TDR, HB-8, REV, and CLE41. Expression profiling using qPCR and promoter:reporter lines indicated that all three PXC genes are associated with the vasculature. One in particular, PXC1 (At2g36570), had a strong correlation with PXY/TDR. Shifting pxc1 mutants from long-days to short-days showed that loss of the gene led to a dramatic reduction in secondary wall formation in xylem fibers. Transcript analysis of mutants for a variety of secondary cell wall-associated genes, including PXY/TDR indicated that the pathways mediated by PXC1 connect with those mediated by the TDIF-PXY/TDR WOX4 system. CONCLUSIONS: The data indicate that the LRR-RLK, PXC1 is involved in secondary cell wall formation in xylem fibers. Whereas further study is needed to identify the ligands and mode of action of the PXC1 protein, it is clear from this work that similarly to the shoot apical meristem (SAM), secondary vascular development requires contributions from a number of LRR-RLKs. PMID- 23815749 TI - Adaptive laboratory evolution -- principles and applications for biotechnology. AB - Adaptive laboratory evolution is a frequent method in biological studies to gain insights into the basic mechanisms of molecular evolution and adaptive changes that accumulate in microbial populations during long term selection under specified growth conditions. Although regularly performed for more than 25 years, the advent of transcript and cheap next-generation sequencing technologies has resulted in many recent studies, which successfully applied this technique in order to engineer microbial cells for biotechnological applications. Adaptive laboratory evolution has some major benefits as compared with classical genetic engineering but also some inherent limitations. However, recent studies show how some of the limitations may be overcome in order to successfully incorporate adaptive laboratory evolution in microbial cell factory design. Over the last two decades important insights into nutrient and stress metabolism of relevant model species were acquired, whereas some other aspects such as niche-specific differences of non-conventional cell factories are not completely understood. Altogether the current status and its future perspectives highlight the importance and potential of adaptive laboratory evolution as approach in biotechnological engineering. PMID- 23815752 TI - Nanostructured composite layers of mussel adhesive protein and ceria nanoparticles. AB - Mussel adhesive proteins are known for their high affinity to a range of different surfaces, and they therefore appear as ideal candidates for producing thin inorganic-organic composite films with high robustness. In this work we explore the possibility of making cohesive films utilizing layer-by-layer deposition of the highly positively charged mussel adhesive protein, Mefp-1, and negatively charged ceria nanoparticles. This particular material combination was chosen due to recent findings that such films provide good corrosion protection. Quartz crystal microbalance with dissipation monitoring (QCM-D) was used for following the film formation process in situ on silica surfaces. A close to linear growth of the film with number of deposited layers was found for up to 18 deposition steps, the highest number of depositions investigated in this work. The Mefp-1 concentration during film deposition affected the film properties, where a higher protein concentration resulted in a stiffer film. It was also found that the added mass could be amplified by using a Mefp-1 solution containing small aggregates. The surface nanomechanical properties of dried multilayer films were investigated using peak force QNM (quantitative nanomechanical mapping) in air. Homogeneous surface coverage was found under all conditions explored, and the Young's modulus of the outer region of the coating increased when a higher Mefp-1 concentration was used during film deposition. The nature of the outermost surface layer was found to significantly affect the surface nanomechanical properties. The abrasion resistance of the coating was measured by using controlled-force contact mode AFM. PMID- 23815753 TI - The effect of dietary supplementation with phytase transgenic maize and different concentrations of non-phytate phosphorus on the performance of laying hens. AB - 1. The objective of this study was to evaluate the effects of dietary supplementation with phytase transgenic corn (maize) (PTC) which has a phytase activity of 21 000 units (U) phytase per kg of maize on productive performance, egg quality, tibia bone quality and phosphorus (P) excretion in laying hens. 2. In the experiment, 1800 44-week-old Hy-line brown laying hens were divided into 5 groups with 6 replicates per group and 60 hens per replicate. The experiment lasted for 12 weeks. The layers in the control group (control) were given a basal diet with 0.36% non-phytate P (NPP), while the treatment groups received diets containing 360 U of exogenous phytase/kg with 0.26% NPP (EP) or 360 phytase U of PTC/kg diet with 0.26% (PTC1), 0.21% (PTC2) or 0.16% (PTC3) NPP. 3. The results showed that there was no significant difference in egg production, average daily feed intake, feed efficiency, rate of broken or soft-shell egg production or egg mass among the treatments. There was no significant difference in eggshell thickness or eggshell strength. On the other hand, no differences in any of the bone variables were found between treatments. The faecal P percentage content in EP, PTC1, PTC2 and PTC3 groups was significantly lower than the control group. 4. In summary, the PTC could be used in the feed of laying hens instead of EP to reduce P excretion without effecting production and bone mineralisation. PMID- 23815754 TI - Patient-reported outcomes in meta-analyses--Part 1: assessing risk of bias and combining outcomes. AB - Systematic reviews and meta-analyses of randomized trials that include patient reported outcomes (PROs) often provide crucial information for patients and clinicians facing challenging health care decisions. Based on emerging methods, guidance on combining PROs in meta-analysis is likely to enhance their usefulness.The objectives of this paper are: i) to describe PROs and why they are important for health care decision-making, ii) illustrate the key risk of bias issues that systematic reviewers should consider and, iii) address outcome characteristics of PROs and provide guidance for combining outcomes.We suggest a step-by-step approach to addressing issues of PROs in meta-analyses. Systematic reviewers should begin by asking themselves if trials have addressed all the important effects of treatment on patients' quality of life. If the trials have addressed PROs, have investigators chosen the appropriate instruments? In particular, does evidence suggest the PROs used are valid and responsive, and is the review free of outcome reporting bias? Systematic reviewers must then decide how to categorize PROs and when to pool results. PMID- 23815755 TI - Replication arrest is a major threat to growth at low temperature in Antarctic Pseudomonas syringae Lz4W. AB - Chromosomal damage was detected previously in the recBCD mutants of the Antarctic bacterium Pseudomonas syringae Lz4W, which accumulated linear chromosomal DNA leading to cell death and growth inhibition at 4 degrees C. RecBCD protein generally repairs DNA double-strand breaks by RecA-dependent homologous recombination pathway. Here we show that DeltarecA mutant of P. syringae is not cold-sensitive. Significantly, inactivation of additional DNA repair genes ruvAB rescued the cold-sensitive phenotype of DeltarecBCD mutant. The DeltarecA and DeltaruvAB mutants were UV-sensitive as expected. We propose that, at low temperature DNA replication encounters barriers leading to frequent replication fork (RF) arrest and fork reversal. RuvAB binds to the reversed RFs (RRFs) having Holliday junction-like structures and resolves them upon association with RuvC nuclease to cause linearization of the chromosome, a threat to cell survival. RecBCD prevents this by degrading the RRFs, and facilitates replication re initiation. This model is consistent with our observation that low temperature induced DNA lesions do not evoke SOS response in P. syringae. Additional studies show that two other repair genes, radA (encoding a RecA paralogue) and recF are not involved in providing cold resistance to the Antarctic bacterium. PMID- 23815756 TI - Placental release or disposal? Experiences of perinatal pathologists. AB - Placentas have been often considered medical waste in hospitals. This view is particularly held by the patients themselves, who may not understand the importance of placental examination. Hospitals have been receiving requests for placental release to patients and need to be prepared to handle these requests. Therefore, a survey was conducted to explore the experiences and practices of perinatal pathologists with respect to placental release. Utilizing SurveyMonkey, we emailed a survey to 192 practicing perinatal pathologists in the United States and Canada. Questions were asked about policies in force at their particular institution, conditions of release, and the purpose of release, ie, what the disposition of the placenta was after release to the family. Thirty-six responses were received; 22 (61.1%) of respondents did allow release of placentas, and those who did not release usually reported that they had not received requests for release. In most cases, specific policies were in place, with multiple departments within the hospital having input on the creation of the policy. Parental signature was required in most cases. The most common reason for patient request was to bury the placenta, although some placental release was for consumption and/or encapsulation. Although there are no specific religious requirements for use or burial of the placenta after delivery, there are many cultural reasons for requests. Hospitals and specific providers need to be aware of this interest and have a specific policy in place so that they are prepared when a request is received. PMID- 23815757 TI - Simultaneous detection of monoamine and purine molecules using high-performance liquid chromatography with a boron-doped diamond electrode. AB - A recently available boron-doped diamond (BDD) working electrode has been developed for use with high-performance liquid chromatography (HPLC) to aid in the detection of molecules with high redox potentials. In this work, we developed a method using a commercially available BDD working electrode for detecting neurotransmitters from two different families with large oxidation potential differences, namely, dopamine (DA) and adenosine (Ado). Hydrodynamic voltammograms were constructed for DA and Ado, and the optimal potentials for the detection of DA and Ado were determined to be +740 and +1200 mV versus a palladium reference electrode, respectively. A working potential of +840 mV was chosen, and the detection range achieved with the BDD electrode for DA and Ado was from low nanomolar to high millimolar levels. To determine the practical function of the BDD electrode, tissue content was analyzed for seven monoamine and two purine molecules, which were resolved in a single run in less than 28 min. Our results demonstrate that the BDD electrode is sensitive and robust enough to detect monoamine and purine molecules from frontal cortex and striatal mouse samples. Using a BDD electrode opens the possibility of exploring multiple classes of neurotransmitters in a single run using electrochemical detection to probe their interactions. PMID- 23815758 TI - National survey of molecular bacterial diversity of New Zealand groundwater: relationships between biodiversity, groundwater chemistry and aquifer characteristics. AB - Groundwater is a vital component of rural and urban water supplies in New Zealand. Although extensive monitoring of chemical and physical properties is conducted due to the high demand for this valuable resource, current information on its bacterial content is limited. However, bacteria provide an immense contribution to drive the biogeochemical processes in the groundwater ecosystem as in any other ecosystem. Therefore, a proper understanding of bacterial diversity is crucial to assess the effectiveness of groundwater management policies. In this study, we investigated the bacterial community structure in NZ groundwater at a national scale using the terminal restriction fragment length polymorphism (T-RFLP) molecular profiling tool and determined the relationships between bacterial diversity and groundwater chemistry, geological parameters and human impact. Considerable bacterial diversity was present and the community structures were strongly related to groundwater chemistry, and in particular to redox potential and human impact, reflecting their potential influence on determination of bacterial diversity. Further, the mean residence time of groundwater also showed relationships with bacterial community structure. These novel findings pertaining to community composition and its relationships with environmental parameters will provide a strong foundation for qualitative exploration of the bacterial diversity in NZ groundwater in relation to sustainable management of this valuable resource. PMID- 23815759 TI - Downregulated adaptor protein p66(Shc) mitigates autophagy process by low nutrient and enhances apoptotic resistance in human lung adenocarcinoma A549 cells. AB - Macroautophagy or autophagy is a lysosome-dependent process in which enzymatic degradation and recycling of cytosolic components occur in stressful contexts. The mechanisms underlying the signaling from starvation to the regulation of autophagy are not fully understood. We previously showed that the Src family member p66(Shc) (focal adhesion-associated 66 kDa isoform of the Src homology and collagen) promotes anoikis and suppresses tumor metastasis via k-Ras-dependent control of proliferation and survival. However, the role of p66(Shc) in low nutrient-induced autophagy-related pathways remains elusive. In this work, human lung adenocarcinoma A549 cells were used to further investigate the biological effects of p66(Shc) on autophagy and apoptotic resistance. Here, we show that deficiency of p66(Shc) mitigates the low-nutrient-induced autophagy process in the levels of microtubule-associated protein 1A light chain protein 3B (LC3B) conversion, in the number of autophagic vacuoles and in p62/sequestosome 1 protein degradation. However, autophagy-related protein Beclin 1 was not significantly changed during low-nutrient treatment. Furthermore, we found that prolonged phosphorylation of extracellular signaling-regulated kinase (Erk)1/2, but not phosphorylation of Akt is significantly sustained when p66(Shc) expression is inhibited by shRNA. In addition, cleavage of caspase 7 and poly(ADP ribose) polymerase, but not caspase 6 and 9 are retarded with this effect compared to the shRNA control cells. Together, these findings suggest the possibility that p66(Shc) plays a pivotal role in coordinately regulating autophagy process and apoptotic resistance in A549 cells under nutrient-limited conditions. PMID- 23815760 TI - NF-kappaB inhibitory activity of sucrose fatty acid esters and related constituents from Astragalus membranaceus. AB - Twelve compounds, including six sucrose fatty acid esters (1-6), four galactosyl acylglycerols (7-10), and two sphingolipids (11 and 12), were isolated from the roots of Astragalus membranaceus . Their structures were identified on the basis of spectroscopic analysis. Among the isolated sucrose fatty acid esters, 6'-O linoleyl sucrose (1) was identified as a new compound, and 6'-O-palmitoyl sucrose (2) and 6-O-palmitoyl sucrose (3) were isolated from nature for the first time. This is the first report on sucrose fatty acid ester components from A. membranaceus. The nuclear factor-kappaB (NF-kappaB) inhibitory activity of isolated compounds was measured in HepG2 cells stimulated with TNF-alpha using a luciferase reporter system. Among them, compounds 1-6 exhibited significant inhibition of NF-kappaB activation in a dose-dependent manner, with IC50 values ranging from 4.4 to 24.7 MUM. Compounds 1-6 also exhibited inhibition of TNF alpha-induced expression of iNOS and ICAM-1 mRNA and dose-dependent inhibition of iNOS promoter activity, with IC50 values ranging from 3.3 to 5.0 MUM. These data demonstrate the potential of sucrose fatty acid esters from A. membranaceus to prevent and treat inflammatory diseases. PMID- 23815761 TI - Molecular dynamics simulation of neuropeptide B and neuropeptide W in the dipalmitoylphosphatidylcholine membrane bilayer. AB - GPR7 and GPR8 are recently deorphanized G-protein-coupled receptors that are implicated in the regulation of neuroendocrine function, feeding behavior, and energy homeostasis. Neuropeptide B (NPB) and neuropeptide W (NPW) are two membrane-bound hypothalamic peptides, which specifically antagonize GPR7 and GPR8. Despite years of research, an accurate estimation of structure and molecular recognition of these neuropeptide systems still remains elusive. Herein, we investigated the structure, orientation, and interaction of NPB and NPW in a dipalmitoylphosphatidylcholine bilayer using long-range molecular dynamics (MD) simulation. During 30-ns simulation, membrane-embedded helical axes of NPB and NPW tilted 30 and 15 degrees , respectively, from the membrane normal in order to overcome possible hydrophobic mismatch with the lipid bilayer. The calculation of various structural parameters indicated that NPW is more rigid and compact as compared to NPB. Qualitatively, the peptides exhibited flexible N terminal (residues 1-12) and rigid C-terminal alpha-helical parts (residues 13 21), confirming previous NMR data. A strong electrostatic attraction between C termini and headgroup atoms caused translocation of the peptides towards lower leaflet of the bilayer. The stabilizing hydrogen bonds (H-bonds) between phosphate groups and Trp1, Lys3, and Arg15 of the peptides played important roles for membrane anchoring. MD simulations of Alanine (Ala) mutants revealed that WYK >Ala variant of NPB/NPW lacked crucial H-bond interactions with phospholipid headgroups and also caused severe misfolding in NPB. Altogether, the knowledge of preferred structural fold and interaction of neuropeptides within the membrane bilayer will be useful to develop synthetic agonist or antagonist peptides for GPR7 and GPR8. PMID- 23815762 TI - Must we press on until a young mother dies? Remifentanil patient controlled analgesia in labour may not be suited as a "poor man's epidural". AB - BACKGROUND: The epidural route is still considered the gold standard for labour analgesia, although it is not without serious consequences when incorrect placement goes unrecognized, e.g. in case of intravascular, intrathecal and subdural placements. Until now there has not been a viable alternative to epidural analgesia especially in view of the neonatal outcome and the need for respiratory support when long-acting opioids are used via the parenteral route. Pethidine and meptazinol are far from ideal having been described as providing rather sedation than analgesia, affecting the cardiotocograph (CTG), causing fetal acidosis and having active metabolites with prolonged half-lives especially in the neonate. Despite these obvious shortcomings, intramuscular and intravenously administered pethidine and comparable substances are still frequently used in delivery units. Since the end of the 90 ths remifentanil administered in a patient-controlled mode (PCA) had been reported as a useful alternative for labour analgesia in those women who either don't want, can't have or don't need epidural analgesia. DISCUSSION: In view of the need for conversion to central neuraxial blocks and the analgesic effect remifentanil has been demonstrated to be superior to pethidine. Despite being less effective in terms of the resulting pain scores, clinical studies suggest that the satisfaction with analgesia may be comparable to that obtained with epidural analgesia. Owing to this fact, remifentanil has gained a place in modern labour analgesia in many institutions. However, the fact that remifentanil may cause harm should not be forgotten when the use of this potent mu-agonist is considered for the use in labouring women. In the setting of one-to-one midwifery care, appropriate monitoring and providing that enough experience exists with this potent opioid and the treatment of potential complications, remifentanil PCA is a useful option in addition to epidural analgesia and other central neuraxial blocks. Already described serious consequences should remind us not refer to remifentanil PCA as a "poor man's epidural" and to safely administer remifentanil with an appropriate indication. SUMMARY: Therefore, the authors conclude that economic considerations and potential cost-savings in conjunction with remifentanil PCA may not be appropriate main endpoints when studying this valuable method for labour analgesia. PMID- 23815763 TI - Examination of the association between lifestyle behavior changes and weight outcomes in preschoolers receiving treatment for obesity. AB - OBJECTIVE: Preschoolers (ages 2-5 years) have been significantly underrepresented in the obesity treatment outcome literature, despite estimates that 12.1% are already obese. As such, little is known about the most important intervention targets for weight management within this age group. The aims of this study were (a) to examine lifestyle behavior changes for 30 obese preschoolers participating in a weight-control intervention and (b) to explore which lifestyle behavior changes predicted changes in body mass index (BMI) z score. METHOD: Preschooler height, weight, diet (three 24-hr recalls), physical activity (accelerometry), and television use (parent report) were measured at baseline and posttreatment (6 months). A linear regression was conducted to examine pre- to posttreatment changes in diet (i.e., intake of calories, sugar-sweetened beverages, fruits and vegetables, and sweet and salty snacks) and activity (i.e., moderate-to-vigorous activity and television use) behaviors on changes in BMI z score. RESULTS: Despite significant reductions in sugar-sweetened beverage intake and television use, and increases in fruit and vegetable intake, only reductions in absolute caloric intake significantly predicted reductions in BMI z score. CONCLUSION: Our findings suggest that attaining healthy caloric goals may be the most important component of weight-control interventions for preschoolers. Future research using innovative methodologies, such as the Multiphase Optimization Strategy, may be helpful to prospectively identifying the lifestyle behavior changes that are most effective in helping families to achieve healthy weight outcomes for preschoolers and thereby improve intervention efficiency and decrease treatment burden for families. PMID- 23815765 TI - Effective behavior change techniques in asthma self-care interventions: systematic review and meta-regression. AB - OBJECTIVES: The purpose of this study is to update previous systematic reviews of interventions targeting asthma self-care in adults with asthma, and to use meta regression to examine the association between the use of specific behavior change techniques and intervention effectiveness. METHODS: Electronic bibliographies were searched systematically to identify randomized controlled trials of interventions targeting asthma self-care. Intervention content was coded using a published taxonomy of behavior change techniques. For trials with a low-to moderate risk of bias, study outcomes were pooled using random effects meta analysis. Associations between intervention content and effect size were explored using meta-regression. RESULTS: Meta-analysis of 38 trials (7883 patients) showed that interventions targeting asthma self-care reduced symptoms (standardized mean difference [SMD] = -0.38 [-0.52, -0.24]) and unscheduled health care use (odds ratio [OR] = 0.71 [0.56 to 0.90]) and increased adherence to preventive medication (OR = 2.55 [2.11 to 3.10]). meta-regression analyses found that "active involvement of participants" was associated with a reduction in unscheduled health care use (OR = 0.50 vs. 0.79). Inclusion of "stress management" techniques was associated with an increase in asthma symptoms (SMD = 0.01 vs. -0.44). Existing recommendations about the "optimal" content of asthma self-care interventions were tested but were not supported by the data. CONCLUSIONS: Interventions targeting asthma self-care are effective. Active involvement of participants is associated with increased intervention effectiveness, but the use of stress management techniques may be counterproductive. Taxonomy-based systematic reviews using meta-regression have potential for identifying techniques associated with increased effectiveness in behavioral interventions. PMID- 23815764 TI - History of weight control attempts among adolescent girls with loss of control eating. AB - OBJECTIVE: Loss of control (LOC) eating and a weight control attempt (WCA) history during adolescence are important behavioral risk factors for eating disorders and obesity. The current study investigated the significance of the presence of a WCA history among adolescent girls with LOC eating. METHOD: Participants were 114 obesity-prevention-seeking 12-17-year-old (M = 14.5, SD = 1.7 years) girls who were between the 75th and 97th body mass index (BMI) percentile (BMI-z: M = 1.5, SD = 0.3) and reported LOC eating episodes during the previous month (M = 4.0, SD = 4.9 episodes; Median = 2.0). Measures included the Eating Disorder Examination to assess LOC eating, eating pathology, and WCA history, and self-report questionnaires for symptoms of general psychopathology. Eating behavior was observed during a laboratory meal designed to capture a LOC eating episode. RESULTS: 67.5% reported a WCA history. As compared to girls without a WCA history (no-WCA), those with a WCA history (WCA) had greater disordered eating attitudes and depressive symptoms (ps < .04). There were no significant group differences in BMI-z or LOC eating frequency (ps > .10). During the laboratory meal, WCA consumed less energy from snack-type foods than no-WCA (M = 245.0, SD = 156.1 vs. M = 341.6, SD = 192.3 kcal; p = .01). CONCLUSIONS: Reported WCAs are highly prevalent and are associated with greater psychopathology symptoms among adolescent girls with LOC eating. Prospective data are needed to determine whether these overlapping risk behaviors confer differential vulnerability for developing eating disorders and obesity. PMID- 23815766 TI - Knowledge is insufficient for self-care among heart failure patients with psychological distress. AB - OBJECTIVE: We conducted a study to identify barriers to, and factors promoting, self-care among heart failure (HF) patients with higher or lower levels of knowledge. METHOD: Baseline data from 612 patients with HF enrolled in the REMOTE HF trial were analyzed. Using median splits on the HF Knowledge Scale and the European HF Self-Care Behavior Scale, patients were divided into four groups: (a) low knowledge and good self-care, (b) low knowledge and poor self-care, (c) high knowledge and good self-care, and (d) high knowledge and poor self-care. Characteristics of the groups were compared using ANOVA, Kruskal-Wallis tests, and chi-square tests, followed by pairwise tests with Bonferroni correction. Variables significant in the univariate analyses were evaluated as predictors of self-care using hierarchical multiple linear regression. The potential moderating effect of knowledge was tested with interaction terms. RESULTS: The four groups did not differ in sociodemographics or health literacy scores, but differed in New York Heart Association (NYHA) class, comorbidities, and scores on depression, anxiety, and perceived control. In post hoc pairwise tests, patients with high knowledge and poor self-care tended to have worse NYHA class, greater depression and anxiety, and lower levels of perceived control than others. In the multivariate analysis, knowledge, depressive symptoms, and perceived control were significant predictors of self-care, as was the interaction between knowledge and anxiety. CONCLUSIONS: Screening and treatment of depression and anxiety is important in improving self-care among HF patients. HF management programs need to include strategies for increasing patients' perceived control over their heart disease. PMID- 23815768 TI - Surgical approach to a vulval-pubic cartilaginous cyst: A case report and review of published work. AB - Cartilaginous cyst of symphysis pubis is rare and to our knowledge 12 cases have been reported in the published work. Although cartilaginous cysts of the vulva and pubis are likely to present to a gynecologist as a vulval-pubic mass, their diagnosis and management warrants a multidisciplinary team approach because of their rarity and anatomical location. Non-invasive diagnosis includes magnetic resonance imaging and ultrasound scan, while the invasive preoperative biopsy is reserved for cases with a high index of suspicion of malignancy. The surgical approach for the management of vulval-pubic cartilaginous cyst is not well established. The current case demonstrates a joint surgical approach involving a gynecologist and orthopedic surgeon in management of a degenerative cartilaginous cyst. As this condition is benign, every effort should be made to preserve the stability of the pubic symphysis. Symphyseal dysfunction from surgery remains a potential complication for which treatment is not straightforward. PMID- 23815767 TI - Divergent associations of adaptive and maladaptive emotion regulation strategies with inflammation. AB - OBJECTIVE: Recent work suggests effective emotion regulation may protect against risk of developing coronary heart disease (CHD), but the mechanisms remain unknown. Strategies for regulating emotions vary in how effectively they mitigate potentially toxic effects of stressful life experiences, and therefore may be differentially associated with CHD risk. In this study, we examined the emotion regulation strategies of reappraisal and suppression in relation to inflammation, a biological state associated with both stress and CHD. We hypothesized that suppression would be associated with elevated inflammation and reappraisal would be associated with lower levels of inflammation. METHODS: We studied adult offspring (n = 379; mean age = 42.2 years) of Collaborative Perinatal Project participants, a national cohort of pregnant women enrolled in 1959-1966. Validated measures of two emotion regulation strategies were examined: reappraisal and suppression. Inflammation was measured as plasma C-reactive protein (CRP) levels. We fit multiple linear regression models predicting CRP while controlling for demographic, socioeconomic, and health factors, including depressive symptoms, measured across the life course. RESULTS: A 1 standard deviation increase in reappraisal was associated with significantly lower CRP (b = -0.18, SE = 0.06, p < .01) controlling for demographics. This relation was somewhat attenuated in life course models, with adulthood body mass index partially explaining the association. A 1 standard deviation increase in suppression was associated with significantly higher CRP (b = 0.21, SE = 0.05, p < .001), and this association was not substantively attenuated with further covariate adjustment. CONCLUSION: Adaptive emotion regulation was associated with lower levels of inflammation and maladaptive emotion regulation was associated with higher levels of inflammation. If these associations are confirmed by prospective and experimental studies, such evidence may provide insight into novel targets for interventions to promote health and reduce cardiovascular risk. PMID- 23815769 TI - Contrasting modes of inorganic carbon acquisition amongst Symbiodinium (Dinophyceae) phylotypes. AB - Growing concerns over ocean acidification have highlighted the need to critically understand inorganic carbon acquisition and utilization in marine microalgae. Here, we contrast these characteristics for the first time between two genetically distinct dinoflagellate species of the genus Symbiodinium (phylotypes A13 and A20) that live in symbiosis with reef-forming corals. Both phylotypes were grown in continuous cultures under identical environmental conditions. Rubisco was measured using quantitative Western blots, and radioisotopic (14) C uptake was used to characterize light- and total carbon dioxide (TCO2 )-dependent carbon fixation, as well as inorganic carbon species preference and external carbonic anhydrase activity. A13 and A20 exhibited similar rates of carbon fixation despite cellular concentrations of Rubisco being approximately four-fold greater in A13. The uptake of CO2 over HCO3 - was found to support the majority of carbon fixation in both phylotypes. However, A20 was also able to indirectly utilize HCO3 - by first converting it to CO2 via external carbonic anhydrase. These results show that adaptive differences in inorganic carbon acquisition have evolved within the Symbiodinium genus, which thus carries fundamental implications as to how this functionally key genus will respond to ocean acidification, but could also represent a key trait factor that influences their productivity when in hospite of their coral hosts. PMID- 23815770 TI - Imaging diagnosis--Spinal epidural hemangiosarcoma in a dog. AB - An 8-year-old, male Boxer was examined for an acute onset of ambulatory paraparesis. Neurologic examination was consistent with a T3-L3 myelopathy. Myelography revealed an extradural spinal cord compression in the region of the T10-T13 vertebrae. On magnetic resonance (MR) imaging, a well-defined epidural mass lesion was detected. The mass was mildly hyperintense on T1-weighted, hyperintense on T2-weighted and STIR images compared to normal spinal cord and enhanced strongly and homogenously. Postmortem examination confirmed a primary epidural hemangiosarcoma. Findings indicated that the MRI characteristics of spinal epidural hemangiosarcoma may mimic other lesions including meningioma and epidural hemorrhages/hematomas of non-neoplastic etiology. PMID- 23815771 TI - Se-(9-Fluorenylmethyl) selenoesters; preparation, reactivity, and use as convenient synthons for selenoacids. AB - Se-(9-Fluorenylmethyl) selenoesters are readily prepared, stable precursors to selenocarboxylates, which they liberate on treatment with DBU. Fm selenoesters are compatible with the use of TFA for the removal of Boc groups and with simple peptide bond forming reactions. Amino acid derived selenocarboxylates condense directly with amines to give amides, react smoothly with isocyanates and isothiocyanates to give amides, and couple with electron-deficient azides also to give amides. PMID- 23815772 TI - Single-atom catalysts: a new frontier in heterogeneous catalysis. AB - Supported metal nanostructures are the most widely used type of heterogeneous catalyst in industrial processes. The size of metal particles is a key factor in determining the performance of such catalysts. In particular, because low coordinated metal atoms often function as the catalytically active sites, the specific activity per metal atom usually increases with decreasing size of the metal particles. However, the surface free energy of metals increases significantly with decreasing particle size, promoting aggregation of small clusters. Using an appropriate support material that strongly interacts with the metal species prevents this aggregation, creating stable, finely dispersed metal clusters with a high catalytic activity, an approach industry has used for a long time. Nevertheless, practical supported metal catalysts are inhomogeneous and usually consist of a mixture of sizes from nanoparticles to subnanometer clusters. Such heterogeneity not only reduces the metal atom efficiency but also frequently leads to undesired side reactions. It also makes it extremely difficult, if not impossible, to uniquely identify and control the active sites of interest. The ultimate small-size limit for metal particles is the single-atom catalyst (SAC), which contains isolated metal atoms singly dispersed on supports. SACs maximize the efficiency of metal atom use, which is particularly important for supported noble metal catalysts. Moreover, with well-defined and uniform single-atom dispersion, SACs offer great potential for achieving high activity and selectivity. In this Account, we highlight recent advances in preparation, characterization, and catalytic performance of SACs, with a focus on single atoms anchored to metal oxides, metal surfaces, and graphene. We discuss experimental and theoretical studies for a variety of reactions, including oxidation, water gas shift, and hydrogenation. We describe advances in understanding the spatial arrangements and electronic properties of single atoms, as well as their interactions with the support. Single metal atoms on support surfaces provide a unique opportunity to tune active sites and optimize the activity, selectivity, and stability of heterogeneous catalysts, offering the potential for applications in a variety of industrial chemical reactions. PMID- 23815773 TI - Environmental health outcomes and exposure risks among at-risk communities living in the Upper Olifants River Catchment, South Africa. AB - Potential exposure to water and air pollution and associated health impacts of three low-income communities in the Upper Olifants River Catchment, South Africa, was investigated through a cross-sectional epidemiological study comprising a household survey. Water samples were collected and analysed for microbial indicators and pathogens. Ambient air-monitoring included some of the criteria pollutants, as well as mercury and manganese. Associations between environmental exposure and health outcomes were analysed by means of logistic regression. Despite poor water and air quality episodes, the communities' self-perceived health was good with relatively low prevalence of reported health outcomes. Hygiene practices with respect to water collection and storage were often poor, and most likely contributed to the regularly contaminated water storage containers. Community proximity to the polluted stream was associated with increased prevalence in adverse health outcomes. This paper reports on preliminary results and additional multivariate analyses are necessary to further understand study results. PMID- 23815774 TI - Foxc2 regulates osteogenesis and angiogenesis of bone marrow mesenchymal stem cells. AB - BACKGROUND: The Forkhead/Fox transcription factor Foxc2 is a critical regulator of osteogenesis and angiogenesis of cells. Bone marrow mesenchymal stem cells (BMSCs) have the capacity to differentiate into osteoblasts, chondrocytes, adipocytes, myocytes and fibroblasts. The present study investigates the role of Foxc2 overexpression in osteogenesis and angiogenesis of BMSCs in vitro. METHODS: BMSCs were isolated from SD rat femurs and tibias, and characterized by cell surface antigen identification and osteoblasts and adipocytes differentiation. The cells were transfected with lentiviral Foxc2 (Lv-Foxc2) or green fluorescent protein (Lv-GFP). Seventy hours later, Foxc2 expression was observed using real time-PCR and Western blot. The transfected cells were stained with Alizarin red S or alkaline phosphatase (ALP) after osteogenic induction. Meanwhile, the expression levels of osteocalcin (OCN), Runt-related transcription factor 2 (Runx2), vascular endothelial growth factor (VEGF) and platelet-derived growth factor-beta (PDGF-beta) were measured by real time-PCR, Western blot and immunostaining. RESULTS: Results of cell characterization showed that the cells were positive to CD44 (99.56%) and negative to CD34 (0.44%), and could differentiate into osteoblasts and adipocytes. Foxc2 overexpression not only increased the numbers of mineralized nodes and ALP activity, but also enhanced the expressions of Runx2, OCN, VEGF and PDGF-beta in transfected BMSCs after osteogenic induction. The effects of Foxc2 on osteogenesis and angiogenesis were significantly different between Lv-Foxc2 transfected BMSCs and Lv-GFP transfected BMSCs (P<0.05). In addition, the MAPK-specific inhibitors, PD98059 and LY294002, blocked the Foxc2-induced regulation of BMSC differentiation. CONCLUSIONS: Foxc2 gene is successfully transfected into BMSCs with stable and high expression. The overexpression of Foxc2 acts on BMSCs to stimulate osteogenesis and angiogenesis. The effect of Foxc2 on angiogenesis of the cells is mediated via activating PI3K and ERK. PMID- 23815775 TI - Identification of human immunodeficiency virus type 1 (HIV-1) gp120-binding sites on scavenger receptor cysteine rich 1 (SRCR1) domain of gp340. AB - BACKGROUND: gp340, a member of scavenger receptor cysteine rich family encoded by Deleted in Malignant Brain Tumors 1 (DMBT1), is an important component in innate immune defense. The first scavenger receptor cysteine rich domain (SRCR1) of gp340 has been shown to inhibit HIV-1 infection through binding to the N-terminal flank of the V3 loop of HIV-1 gp120. RESULTS: Through homology modeling and docking analysis of SRCR1 to a gp120-CD4-X5 antibody complex, we identified three loop regions containing polar or acidic residues that directly interacted with gp120. To confirm the docking prediction, a series of over-lapping peptides covering the SRCR1 sequence were synthesized and analyzed by gp120-peptide binding assay. Five peptides coincide with three loop regions showed the relative high binding index. An alanine substitution scan revealed that Asp34, Asp35, Asn96 and Glu101 in two peptides with the highest binding index are the critical residues in SRCR1 interaction with gp120. CONCLUSION: We pinpointed the vital gp120-binding regions in SRCR1 and narrowed down the amino acids which play critical roles in contacting with gp120. PMID- 23815776 TI - Absence of anti-hepatitis B virus (HBV) core in HIV/HBV coinfection with advanced immunosuppression. PMID- 23815777 TI - Validity and responsiveness of EuroQol-5 dimension (EQ-5D) versus Short Form-6 dimension (SF-6D) questionnaire in chronic pain. AB - BACKGROUND: Assessments of health-related quality of life and particularly utility values are important components of health economic analyses. Several instruments have been developed to measure utilities. However no consensus has emerged regarding the most appropriate instrument within a therapeutic area such as chronic pain. The study compared two instruments - EQ-5D and SF-6D - for their performance and validity in patients with chronic pain. METHODS: Pooled data from three randomised, controlled clinical trials with two active treatment groups were used. The included patients suffered from osteoarthritis knee pain or low back pain. Differences between the utility measures were compared in terms of mean values at baseline and endpoint, Bland-Altman analysis, correlation between the dimensions, construct validity, and responsiveness. RESULTS: The analysis included 1977 patients, most with severe pain on the Numeric Rating Scale. The EQ 5D showed a greater mean change from baseline to endpoint compared with the SF-6D (0.43 to 0.58 versus 0.59 to 0.64). Bland-Altman analysis suggested the difference between two measures depended on the health status of a patient. Spearmans rank correlation showed moderate correlation between EQ-5D and SF-6D dimensions. Construct validity showed both instruments could differentiate between patient subgroups with different severities of adverse events and analgesic efficacies but larger differences were detected with the EQ-5D. Similarly, when anchoring the measures to a disease-specific questionnaire - Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) - both questionnaires could differentiate between WOMAC severity levels but the EQ-5D showed greater differences. Responsiveness was also higher with the EQ-5D and for the subgroups in which improvements in health status were expected or when WOMAC severity level was reduced the improvements with EQ-5D were higher than with SF 6D. CONCLUSIONS: This analysis showed that the mean EQ-5D scores were lower than mean SF-6D scores in patients with chronic pain. EQ-5D seemed to have higher construct validity and responsiveness in these patients. PMID- 23815778 TI - Synthesis of 2,4,5-trisubstituted thiazoles via Lawesson's reagent-mediated chemoselective thionation-cyclization of functionalized enamides. AB - An efficient route to 2-phenyl/(2-thienyl)-5-(het)aryl/(methylthio)-4 functionalized thiazoles via one-step chemoselective thionation-cyclization of highly functionalized enamides mediated by Lawesson's reagent is reported. These enamide precursors are obtained by nucleophilic ring-opening of 2-phenyl/(2 thienyl)-4-[bis(methylthio)/(methylthio)(het)arylmethylene]-5-oxazolones with alkoxides and a variety of primary aromatic/aliphatic amines or amino acid esters, leading to the introduction of an ester, an N-substituted carboxamide, or a peptide functionality in the 4-position of the product thiazoles. PMID- 23815779 TI - An unusual presentation of a urethral diverticulum as a vaginal wall mass: a case report. AB - INTRODUCTION: The diagnosis of urethral diverticulum can be challenging given the vague or absent presenting symptoms. In addition, vaginal cancer can present with elusive symptoms--some parallel to urethral diverticula. A case of a bleeding ulcerated mass anticipated to be a vaginal cancer was instead identified as a benign urethral diverticulum. To the best of our knowledge, this is the first case report of a benign urethral diverticulum presenting as a bleeding, necrotic ulcerated mass. CASE PRESENTATION: A 52 year-old multiparous African-American woman presented with a 2-day history of heavy vaginal bleeding passing large clots and suprapubic pain. A pelvic examination revealed blood clots in the vagina along with a friable, fibrous ulcerated lesion on the anterior suburethral vagina, just left of the midline measuring 4 * 2cm. Initially, this mass was considered to be a vaginal cancer. Intraoperative diagnosis of a benign urethral diverticulum was made. CONCLUSIONS: The diagnosis of urethral diverticula based on the vast array of presenting symptoms, is difficult. This original case report may benefit both gynecologic oncologists and female pelvic surgeons and reconstructive surgeons to keep urethral diverticulum in the differential diagnosis when faced with a bleeding midline anterior vaginal mass. This unusual presentation of a urethral diverticulum demonstrates how similarly it may present to a vaginal cancerous mass. PMID- 23815781 TI - Influence of the water content on the structure and physicochemical properties of an ionic liquid and its Li+ mixture. AB - The effect of water on the hydrophobic ionic liquid (IL) 1-n-butyl-2,3 dimethylimidazolium bis(trifluoromethanesulfonylimide) and its Li(+) mixture was evaluated. The electrochemical stability, density, viscosity, and ionic conductivity were measured for both systems in different concentrations of water. The presence of Li(+) causes a large increase in the water absorption ability of the IL. The experimental results suggest a break of the interactions between Li(+) and Tf2N(-) anions in the strong aggregates formed in dried Li(+) mixtures, modifying the size and physicochemical nature of these aggregates. It is also observed that the size of the ions aggregates with formal charge increases at high temperature and decreases the mobility of the charge carrier, explaining the break in the Walden rules at high temperature. Raman spectroscopy and molecular dynamic simulations show the structural change of these systems. In neat ILs, the water molecules interact mainly among each other, while in the Li(+) mixtures, water interacts preferentially with the metallic cation, causing an important change in the aggregates present in this system. PMID- 23815780 TI - Frizzled-8 receptor is activated by the Wnt-2 ligand in non-small cell lung cancer. AB - BACKGROUND: Wnt-2 plays an oncogenic role in cancer, but which Frizzled receptor(s) mediates the Wnt-2 signaling pathway in lung cancer remains unclear. We sought to (1) identify and evaluate the activation of Wnt-2 signaling through Frizzled-8 in non-small cell lung cancer, and (2) test whether a novel expression construct dominant negative Wnt-2 (dnhWnt-2) reduces tumor growth in a colony formation assay and in a xenograft mouse model. METHODS: Semi-quantitative RT-PCR was used to identify the expression of Wnt-2 and Frizzled-8 in 50 lung cancer tissues from patients. The TCF reporter assay (TOP/FOP) was used to detect the activation of the Wnt canonical pathway in vitro. A novel dnhWnt-2 construct was designed and used to inhibit activation of Wnt-2 signaling through Frizzled-8 in 293T, 293, A549 and A427 cells and in a xenograft mouse model. Statistical comparisons were made using Student's t-test. RESULTS: Among the 50 lung cancer samples, we identified a 91% correlation between the transcriptional increase of Wnt-2 and Frizzled-8 (p<0.05). The Wnt canonical pathway was activated when both Wnt-2 and Frizzled-8 were co-expressed in 293T, 293, A549 and A427 cells. The dnhWnt-2 construct we used inhibited the activation of Wnt-2 signaling in 293T, 293, A549 and A427 cells, and reduced the colony formation of NSCLC cells when beta-catenin was present (p<0.05). Inhibition of Wnt-2 activation by the dnhWnt-2 construct further reduced the size and mass of tumors in the xenograft mouse model (p<0.05). The inhibition also decreased the expression of target genes of Wnt signaling in these tumors. CONCLUSIONS: We demonstrated an activation of Wnt 2 signaling via the Frizzled-8 receptor in NSCLC cells. A novel dnhWnt-2 construct significantly inhibits Wnt-2 signaling, reduces colony formation of NSCLC cells in vitro and tumor growth in a xenograft mouse model. The dnhWnt-2 construct may provide a new therapeutic avenue for targeting the Wnt pathway in lung cancer. PMID- 23815782 TI - Outbreak of multidrug-resistant Klebsiella pneumoniae carrying qnrB1 and blaCTX M15 in a French intensive care unit. AB - BACKGROUND: The prevalence of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae is increasing globally and is a major clinical concern. Between June 2008 and September 2009, 4% of patients in an intensive care unit (ICU) were found to be colonized or infected by strains of Klebsiella pneumoniae multiresistant to ceftazidime, ciprofloxacin, and tobramycin; an investigation was initiated and isolates were characterized by molecular typing and resistance patterns. METHODS: Antibiotic susceptibilities were determined by Vitek2(r), Etest(r), and agar dilution. Gene encoding beta-lactamases and plasmid-mediated quinolone resistance PMQR determinants (qnr, aac(6')-Ib) were characterized by PCR, sequencing, and transfer assays. DiversiLab(r) fingerprints were used to study the relatedness of isolates. RESULTS: Fourteen isolates co-expressing blaCTX-M15, qnrB1, and aac(6')-Ib-cr were identified. Genotypic analysis of these isolates identified 12 clonally related strains recovered from 10 patients. The increased prevalence of blaCTX-M15-qnrB1-aac(6')-Ib-cr-producing K. pneumoniae coincided with the presence in the ICU of a patient originally from Nigeria. This patient was infected by a strain not clonally related to the others but harbouring qnrB1 and aac(6')-Ib-cr genes, a finding not hitherto observed in France. We suspected transmission of resistance plasmids followed by rapid dissemination of the multiresistant K. pneumoniae clone by cross-transmission. CONCLUSION: This study highlights the importance of microbiological screening for multidrug-resistant strains in ICUs, particularly among patients from regions in which multidrug-resistant bacteria are known to exist. PMID- 23815783 TI - Differential roles of the prefrontal cortical subregions and basolateral amygdala in compulsive cocaine seeking and relapse after voluntary abstinence in rats. AB - Compulsive drug use and a persistent vulnerability to relapse are key features of addiction. Imaging studies have suggested that these features may result from deficits in prefrontal cortical structure and function, and thereby impaired top down inhibitory control over limbic-striatal mechanisms of drug-seeking behaviour. We tested the hypothesis that selective damage to distinct subregions of the prefrontal cortex, or to the amygdala, after a short history of cocaine taking would: (i) result in compulsive cocaine seeking at a time when it would not usually be displayed; or (ii) facilitate relapse to drug seeking after abstinence. Rats with selective, bilateral excitotoxic lesions of the basolateral amygdala or anterior cingulate, prelimbic, infralimbic, orbitofrontal or anterior insular cortices were trained to self-administer cocaine under a seeking-taking chained schedule. Intermittent mild footshock punishment of the cocaine-seeking response was then introduced. No prefrontal cortical lesion affected the ability of rats to withhold their seeking responses. However, rats with lesions to the basolateral amygdala increased their cocaine-seeking responses under punishment and were impaired in their acquisition of conditioned fear. Following a 7-day abstinence period, rats were re-exposed to the drug-seeking environment for assessment of relapse in the absence of punishment or cocaine. Rats with prelimbic cortex lesions showed decreased seeking responses during relapse, whereas those with anterior insular cortex lesions showed an increase. Combined, these results show that acute impairment of prefrontal cortical function does not result in compulsive cocaine seeking after a short history of self-administering cocaine, but further implicates subregions of the prefrontal cortex in relapse. PMID- 23815784 TI - Music therapy for early cognitive rehabilitation post-childhood TBI: an intrinsic mixed methods case study. AB - OBJECTIVE: The primary aim of this case study was to explore the behavioural changes of a paediatric patient in post-traumatic amnesia (PTA) during a music therapy session. A secondary objective was to measure the effect of the music therapy intervention on agitation. METHOD: Video data from pre, during and post music therapy sessions were collected and analysed using video micro-analysis and the Agitated Behaviour Scale. RESULTS: The participant displayed four discrete categories of behaviours: Neutral, Acceptance, Recruitment and Rejection. Further analysis revealed brief but consistent and repeated periods of awareness and responsiveness to the live singing of familiar songs, which were classified as Islands of Awareness. Song offered an Environment of Potential to maximise these periods of emerging consciousness. The quantitative data analysis yielded inconclusive results in determining if music therapy was effective in reducing agitation during and immediately post the music therapy sessions. CONCLUSION: The process of micro-analysis illuminated four discrete participant behaviours not apparent in the immediate clinical setting. The results of this case suggest that the use of familiar song as a music therapy intervention may harness early patient responsiveness to foster cognitive rehabilitation in the early acute phase post-TBI. PMID- 23815785 TI - Australian optometric research and the H Barry Collin Research Medal. PMID- 23815786 TI - Professor Donald E Mitchell the H Barry Collin Research Medallist 2012 Foundation Director of the National Vision Research Institute of Australia. PMID- 23815788 TI - Simple and direct sp3 C-H bond arylation of tetrahydroisoquinolines and isochromans via 2,3-dichloro-5,6-dicyano-1,4-benzoquinone oxidation under mild conditions. AB - The 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)-mediated sp(3) C-H bond arylation of tetrahydroisoquinolines and isochromans is described. The corresponding products were facilely synthesized via a simple nucleophilic addition reaction between readily available aryl Grignard reagents and iminium (or oxonium) cations generated in situ by DDQ oxidation of tetrahydroisoquinolines (or isochromans) under mild conditions. PMID- 23815789 TI - A genome-wide screen for ethylene-induced ethylene response factors (ERFs) in hybrid aspen stem identifies ERF genes that modify stem growth and wood properties. AB - Ethylene Response Factors (ERFs) are a large family of transcription factors that mediate responses to ethylene. Ethylene affects many aspects of wood development and is involved in tension wood formation. Thus ERFs could be key players connecting ethylene action to wood development. We identified 170 gene models encoding ERFs in the Populus trichocarpa genome. The transcriptional responses of ERF genes to ethylene treatments were determined in stem tissues of hybrid aspen (Populus tremula * tremuloides) by qPCR. Selected ethylene-responsive ERFs were overexpressed in wood-forming tissues and characterized for growth and wood chemotypes by FT-IR. Fifty ERFs in Populus showed more than five-fold increased transcript accumulation in response to ethylene treatments. Twenty-six ERFs were selected for further analyses. A majority of these were induced during tension wood formation. Overexpression of ERFs 18, 21, 30, 85 and 139 in wood-forming tissues of hybrid aspen modified the wood chemotype. Moreover, overexpression of ERF139 caused a dwarf-phenotype with altered wood development, and overexpression of ERF18, 34 and 35 slightly increased stem diameter. We identified ethylene induced ERFs that respond to tension wood formation, and modify wood formation when overexpressed. This provides support for their role in ethylene-mediated regulation of wood development. PMID- 23815791 TI - Purification and characterization of Bacillus thuringiensis vegetative insecticidal toxin protein(s). AB - Bacillus thuringiensis subsp. aegypti C18 is an Egyptian isolate, obtained from dead pink bollworm larvae. Insecticidal active proteins against different insect were purified from BtaC18 strain during vegetative states. Both the bacterial pellet and cell-free supernatant obtained during vegetative growth had insecticidal activity against black cutworm (BCW). Bioassays revealed that the pellet after 48 h of growth is more potent and toxic against BCW. The toxin in the pellet was active at very high temperatures but lost toxicity after boiling or autoclaving. Proteins extracted from the BtaC18 pellet were further purified by ammonium sulfate precipitation, and the 40% fraction was then subjected to fast protein liquid chromatography (FPLC). Seven major protein peaks were detected after FPLC (Pi- a, b, c, d, e, f and g). Pic protein fraction was active against BCW with an estimated LC50 = 26 ng cm(-2) , Pid protein killed 50% of European corn borer (ECB) at 46 ng cm(-2) , and Pif showed insecticidal activity against western corn root worm (WCRW) with estimated LC50 was 94 ng cm(-2) . Based on the significant and high toxicity of Pic against BCW and Pif against WCRW, the 88- and 44-kDa proteins were further characterized by N-terminal amino acid sequencing. SIGNIFICANCE AND IMPACT OF THE STUDY: Insecticidal activity of Bacillus thuringiensis subsp. aegypti was determined, and its vegetative insecticidal protein was subjected to FPLC for protein purification. This work contributes to improve understanding the different toxins secreted during vegetative growth of Bt. Moreover, the N-terminal amino acid sequences of 88-kDa protein was only 92% identical to that of vip3A, and for 44 kDa was 92% identical with Cry35a, suggesting that we might have identified a new genes. Finally, we have proven these proteins to be novel insecticidal agents that may complement the use of known insecticidal proteins derived from Bacillus. PMID- 23815790 TI - Nuclear entrapment and extracellular depletion of PCOLCE is associated with muscle degeneration in oculopharyngeal muscular dystrophy. AB - BACKGROUND: Muscle fibrosis characterizes degenerated muscles in muscular dystrophies and in late onset myopathies. Fibrotic muscles often exhibit thickening of the extracellular matrix (ECM). The molecular regulation of this process is not fully understood. In oculopharyngeal muscular dystrophy (OPMD), an expansion of an alanine tract at the N-terminus of poly(A)-binding protein nuclear 1 (PABPN1) causes muscle symptoms. OPMD patient muscle degeneration initiates after midlife, while at an earlier age carriers of alanine expansion mutant PABPN1 (expPABPN1) are clinically pre-symptomatic. OPMD is characterized by fibrosis in skeletal muscles but the causative molecular mechanisms are not fully understood. METHODS: We studied the molecular processes that are involved in OPMD pathology using cross-species mRNA expression profiles in muscles from patients and model systems. We identified significant dysregulation of the ECM functional group, among which the procollagen C-endopeptidase enhancer 1 gene (PCOLCE) was consistently down-regulated across species. We investigated PCOLCE subcellular localization in OPMD muscle samples and OPMD model systems to investigate any functional relevance of PCOLCE down-regulation in this disease. RESULTS: We found that muscle degeneration in OPMD is associated with PCOLCE down regulation. In addition to its known presence at the ECM, we also found PCOLCE within the nucleus of muscle cells. PCOLCE sub-cellular localization changes during myoblast cell fusion and is disrupted in cells expressing mutant expPABPN1. Our results show that PCOLCE binds to soluble PABPN1 and co-localizes with aggregated PABPN1 with a preference for the mutant protein. In muscle biopsies from OPMD patients we find that extracellular PCOLCE is depleted with its concomitant enrichment within the nuclear compartment. CONCLUSIONS: PCOLCE regulates collagen processing at the ECM. Depletion of extracellular PCOLCE is associated with the expression of expPABPN1 in OPMD patient muscles. PCOLCE is also localized within the nucleus where it binds to PABPN1, suggesting that PCOLCE shuttles between the ECM and the nucleus. PCOLCE preferentially binds to expPABPN1. Nuclear-localized PCOLCE is enriched in muscle cells expressing expPABPN1. We suggest that nuclear entrapment of PCOLCE and its extracellular depletion represents a novel molecular mechanism in late-onset muscle fibrosis. PMID- 23815793 TI - Binder-block copolymer micelle interactions in bactericidal filter paper. AB - We previously produced a bactericidal filter paper loaded with PAA47-b-PS214 block copolymer micelles containing the biocide triclosan (TCN), using cationic polyacryamide (cPAM) as a binder. However, we encountered a very slow filtration, resulting in long bacteria deactivation times. Slow drainage occurred only when the filter paper was left to dry. It appears that the filter paper with cPAM and micelles develops hydrophobic properties responsible for this very slow filtration. Three approaches were taken to accelerate the very slow drainage all based on modification of binder-micelle interactions: (i) keeping the micelles wet, (ii) modification of the corona, and (iii) replacing cPAM with smaller and more highly charged cationic poly(isopropanol dimethylammonium) chloride (PIDMAC). In all cases, the drainage time of bactericidal filter paper became close to that of untreated filter paper, without decreasing its efficiency. Moreover, replacing cPAM with PIDMAC led to a much more efficient bactericidal filter paper that reduced bacteria viability by more than 6 orders of magnitude. In addition to resolving the hydrophobic drainage hurdle, the three solutions also offer a better understanding of the interaction between cPAM and micelles in the filter paper. PMID- 23815792 TI - Disruption of rimP-SC, encoding a ribosome assembly cofactor, markedly enhances the production of several antibiotics in Streptomyces coelicolor. AB - BACKGROUND: Ribosome assembly cofactor RimP is one of the auxiliary proteins required for maturation of the 30S subunit in Escherichia coli. Although RimP in protein synthesis is important, its role in secondary metabolites biosynthesis has not been reported so far. Considering the close relationship between protein synthesis and the production of secondary metabolites, the function of ribosome assembly cofactor RimP on antibiotics production was studied in Streptomyces coelicolor and Streptomyces venezuelae. RESULTS: In this study, the rimP homologue rimP-SC was identified and cloned from Streptomyces coelicolor. Disruption of rimP-SC led to enhanced production of actinorhodin and calcium dependent antibiotics by promoting the transcription of actII-ORF4 and cdaR. Further experiments demonstrated that MetK was one of the reasons for the increment of antibiotics production. In addition, rimP-SC disruption mutant could be used as a host to produce more peptidyl nucleoside antibiotics (polyoxin or nikkomycin) than the wild-type strain. Likewise, disruption of rimP-SV of Streptomyces venezuelae also significantly stimulated jadomycin production, suggesting that enhanced antibiotics production might be widespread in many other Streptomyces species. CONCLUSION: These results established an important relationship between ribosome assembly cofactor and secondary metabolites biosynthesis and provided an approach for yield improvement of secondary metabolites in Streptomyces. PMID- 23815794 TI - Soil water stress affects both cuticular wax content and cuticle-related gene expression in young saplings of maritime pine (Pinus pinaster Ait). AB - BACKGROUND: The cuticle is a hydrophobic barrier located at the aerial surface of all terrestrial plants. Recent studies performed on model plants, such as Arabidopsis thaliana, have suggested that the cuticle may be involved in drought stress adaptation, preventing non-stomatal water loss. Although forest trees will face more intense drought stresses (in duration and intensity) with global warming, very few studies on the role of the cuticle in drought stress adaptation in these long-lived organisms have been so far reported. RESULTS: This aspect was investigated in a conifer, maritime pine (Pinus pinaster Ait.), in a factorial design with two genetic units (two half-sib families with different growth rates) and two treatments (irrigated vs non-irrigated), in field conditions. Saplings were grown in an open-sided greenhouse and half were irrigated three times per week for two growing seasons. Needles were sampled three times per year for cuticular wax (composition and content) and transcriptome (of 11 genes involved in cuticle biosynthesis) analysis. Non-irrigated saplings (i) had a higher cuticular wax content than irrigated saplings and (ii) overexpressed most of the genes studied. Both these trends were more marked in the faster growing family. CONCLUSIONS: The higher cuticular wax content observed in the non-irrigated treatment associated with strong modifications in products from the decarbonylation pathway suggest that cuticular wax may be involved in drought stress adaptation in maritime pine. This study provides also a set of promising candidate genes for future forward genetic studies in conifers. PMID- 23815795 TI - Insight into the binding modes and inhibition mechanisms of adamantyl-based 1,3 disubstituted urea inhibitors in the active site of the human soluble epoxide hydrolase. AB - Soluble epoxide hydrolase (sEH) is a promising new target for treating hypertension and inflammation. Considerable efforts have been devoted to develop novel inhibitors. In this study, the binding modes and interaction mechanisms of a series of adamantyl-based 1,3-disubstituted urea inhibitors were investigated by molecular docking, molecular dynamics simulations, binding free energy calculations, and binding energy decomposition analysis. Based on binding affinity, the most favorable binding mode was determined for each inhibitor. The calculation results indicate that the total binding free energy (DeltaGTOT, the sum of enthalpy DeltaGMM-GB/SA, and entropy -TDeltaS) presents a good correlation with the experimental inhibitory activity (IC50, r(2) = .99). The van der Waals energy contributes most to the total binding free energy (DeltaGTOT). A detailed discussion on the interactions between inhibitors and those residues located in the active pocket is made based on hydrogen bond and binding modes analysis. According to binding energy decomposition, the residues Asp333 and Trp334 contribute the most to binding free energy in all systems. Furthermore, Hip523 plays a major role in determining this class of inhibitor-binding orientations. Combined with the results of hydrogen bond analysis and binding free energy, we believe that the conserved hydrogen bonds play a role only in anchoring the inhibitors to the exact site for binding and the number of hydrogen bonds may not directly relate to the binding free energy. The results we obtained will provide valuable information for the design of high potency sEH inhibitors. PMID- 23815796 TI - Systematic comparison of hedonic ranking and rating methods demonstrates few practical differences. AB - Hedonic ranking is one of the commonly used methods to evaluate consumer preferences. Some authors suggest that it is the best methodology for discriminating among products, while others recommend hedonic rating. These mixed findings suggest the statistical outcome(s) are dependent on the experimental conditions or a user's expectation of "what is" and "what is not" desirable for evaluating consumer preferences. Therefore, sensory and industry professionals may be uncertain or confused regarding the appropriate application of hedonic tests. This paper would like to put this controversy to rest, by evaluating 3 data sets (3 yogurts, 79 consumers; 6 yogurts, 109 consumers; 4 apple cultivars, 70 consumers) collected using the same consumers and by calculating nontied ranks from hedonic scores. Consumer responses were evaluated by comparing bivariate associations between the methods (nontied ranks, tied ranks, hedonic rating scores) using trellis displays, determining the number of consumers with discrepancies in their responses between the methods, and comparing mean values using conventional statistical analyses. Spearman's rank correlations (0.33-0.84) revealed significant differences between the methods for all products, whether or not means separation tests differentiated the products. The work illustrated the inherent biases associated with hedonic ranking and recommended alternate hedonic methodologies. PMID- 23815797 TI - The current practice trends in pediatric bone-anchored hearing aids in Canada: a national clinical and surgical practice survey. AB - BACKGROUND: Since the introduction of bone-anchored hearing aids (BAHAs) in the 1980s, the practices of surgeons who implant these hearing aids have become varied; different indications and surgical techniques are utilized depending on the surgeon and institution. The objective of the current study is to describe the clinical and surgical practices of otolaryngologists in Canada who perform pediatric BAHA operations. METHODS: A detailed practice questionnaire was devised and sent to all members of the Canadian Society of Otolaryngology-Head and Neck Surgery. Those who performed pediatric BAHA surgeries were asked to participate. RESULTS: Twelve responses were received (response rate of 80%). All of the respondents identified congenital aural atresia to be an indication for pediatric BAHAs. Other indications were chronic otitis externa or media with hearing loss (92%), allergic reactions to conventional hearing aids (75%), congenital fixation or anomaly of ossicular chain (67%), and unilateral deafness (25%). Minor complications, such as skin reactions, were reported in 25% of cases, while major complications were very rare. There was great variability with regards to surgical techinque and post-operative management. The extent of financial support for the BAHA hardware and device also varied between provinces, and even within the same province. CONCLUSION: There is a lack of general consensus regarding pediatric BAHA surgeries in Canada. With such a small community of otolaryngologists performing this procedure, we are hopeful that this survey can serve as an impetus for a national collaboration to establish a set of general management principles and inspire multi-site research ventures. PMID- 23815798 TI - Prothrombin complex concentrate in the reduction of blood loss during orthotopic liver transplantation: PROTON-trial. AB - BACKGROUND: In patients with cirrhosis, the synthesis of coagulation factors can fall short, reflected by a prolonged prothrombin time. Although anticoagulants factors are decreased as well, blood loss during orthotopic liver transplantation can still be excessive. Blood loss during orthotopic liver transplantation is currently managed by transfusion of red blood cell concentrates, platelet concentrates, fresh frozen plasma, and fibrinogen concentrate. Transfusion of these products may paradoxically result in an increased bleeding tendency due to aggravated portal hypertension. The hemostatic effect of these products may therefore be overshadowed by bleeding complications due to volume overload.In contrast to these transfusion products, prothrombin complex concentrate is a low volume highly purified concentrate, containing the four vitamin K dependent coagulation factors. Previous studies have suggested that administration of prothrombin complex concentrate is an effective method to normalize a prolonged prothrombin time in patients with liver cirrhosis. We aim to investigate whether the pre-operative administration of prothrombin complex concentrate in patients undergoing liver transplantation for end-stage liver cirrhosis, is a safe and effective method to reduce perioperative blood loss and transfusion requirements. METHODS/DESIGN: This is a double blind, multicenter, placebo-controlled randomized trial.Cirrhotic patients with a prolonged INR (>=1.5) undergoing liver transplantation will be randomized between placebo or prothrombin complex concentrate administration prior to surgery. Demographic, surgical and transfusion data will be recorded. The primary outcome of this study is RBC transfusion requirements. DISCUSSION: Patients with advanced cirrhosis have reduced plasma levels of both pro- and anticoagulant coagulation proteins. Prothrombin complex concentrate is a low-volume plasma product that contains both procoagulant and anticoagulant proteins and transfusion will not affect the volume status prior to the surgical procedure. We hypothesize that administration of prothrombin complex concentrate will result in a reduction of perioperative blood loss and transfusion requirements. Theoretically, the administration of prothrombin complex concentrate may be associated with a higher risk of thromboembolic complications. Therefore, thromboembolic complications are an important secondary endpoint and the occurrence of this type of complication will be closely monitored during the study. TRIAL REGISTRATION: The trial is registered at http://www.trialregister.nl with number NTR3174. This registry is accepted by the ICMJE. PMID- 23815799 TI - Fructose in perspective. AB - Whether dietary fructose (as sucrose or high fructose corn syrup) has unique effects separate from its role as carbohydrate, or, in fact, whether it can be considered inherently harmful, even a toxin, has assumed prominence in nutrition. Much of the popular and scientific media have already decided against fructose and calls for regulation and taxation come from many quarters. There are conflicting data, however. Outcomes attributed to fructose - obesity, high triglycerides and other features of metabolic syndrome - are not found in every experimental test and may be more reliably caused by increased total carbohydrate. In this review, we try to put fructose in perspective by looking at the basic metabolic reactions. We conclude that fructose is best understood as part of carbohydrate metabolism. The pathways of fructose and glucose metabolism converge at the level of the triose-phosphates and, therefore, any downstream effects also occur with glucose. In addition, a substantial part of ingested fructose is turned to glucose. Regulation of fructose metabolism per se, is at the level of substrate control - the lower Km of fructokinase compared to glucokinase will affect the population of triose-phosphates. Generally deleterious effects of administering fructose alone suggest that fructose metabolism is normally controlled in part by glucose. Because the mechanisms of fructose effects are largely those of a carbohydrate, one has to ask what the proper control should be for experiments that compare fructose to glucose. In fact, there is a large literature showing benefits in replacing total carbohydrate with other nutrients, usually fat, and such experiments sensibly constitute the proper control for comparisons of the two sugars. In terms of public health, a rush to judgement analogous to the fat-cholesterol-heart story, is likely to have unpredictable outcome and unintended consequences. Popular opinion cannot be ignored in this problem and comparing fructose to ethanol, for example, is without biochemical correlates. Also, nothing in the biochemistry suggests that sugar is a toxin. Dietary carbohydrate restriction remains the best strategy for obesity, diabetes and metabolic syndrome. The specific contribution of the removal of fructose or sucrose to this effect remains unknown. PMID- 23815800 TI - Mitofusion-2-mediated alleviation of insulin resistance in rats through reduction in lipid intermediate accumulation in skeletal muscle. AB - BACKGROUND: Increased lipid accumulation and mitochondrial dysfunction within skeletal muscle have been shown to be strongly associated with insulin resistance. However, the role of mitofusion-2 (MFN2), a key factor in mitochondrial function and energy metabolism, in skeletal muscle lipid intermediate accumulation remains to be elucidated. RESULTS: A high-fat diet resulted in insulin resistance as well as accumulation of cytosolic lipid intermediates and down-regulation of MFN2 and CPT1 in skeletal muscle in rats, while MFN2 overexpression improved insulin sensitivity and reduced lipid intermediates in muscle, possibly by upregulation of CPT1 expression. CONCLUSIONS: MFN2 overexpression can rescue insulin resistance, possibly by upregulating CPT1 expression leading to reduction in the accumulation of lipid intermediates in skeletal muscle. These observations contribute to the investigations of new diabetes therapies. PMID- 23815801 TI - Air quality at outdoor community events: findings from fine particulate (PM2.5) sampling at festivals in Edmonton, Alberta. AB - Exposure to fine particulate matter (PM2.5) is associated with a broad range of health risks. This study assessed the impacts of cooking smoke and environmental tobacco smoke on air quality at outdoor community events in Edmonton, Alberta (Canada). Data were collected at three festivals in July-August 2011 using a portable real-time airborne particle monitor. The pooled mean PM2.5 level was 12.41 MUg/m(3). Peak readings varied from 52 to 1877 MUg/m(3). Mean PM2.5 near food stalls was 35.42 MUg/m(3), which exceeds the WHO limit for 24 h exposure. Mean PM2.5 levels with smokers present were 16.39 MUg/m(3) (all points) and 9.64 MUg/m(3) (excluding points near food stalls). Although some smokers withdrew from common spaces, on average 20 smokers/hour were observed within 3 m. Extending smoking bans would improve air quality and address related concerns. However, food preparation is a more pressing area for policy action to reduce PM2.5 exposure at these community events. PMID- 23815802 TI - Robot-assisted laparoscopic vs open radical cystectomy: comparison of complications and perioperative oncological outcomes in 200 patients. AB - OBJECTIVE: To compare perioperative morbidity and oncological outcomes of robot assisted laparoscopic radical cystectomy (RARC) to open RC (ORC) at a single institution. PATIENTS AND METHODS: A retrospective analysis was performed on a consecutive series of patients undergoing RC (100 RARC and 100 ORC) at Wake Forest University with curative intent from 2006 until 2010. Complication data using the Clavien system were collected for 90 days postoperatively. Complications and other perioperative outcomes were compared between patient groups. RESULTS: Patients in both groups had comparable preoperative characteristics. The overall and major complication (Clavien >= 3) rates were lower for RARC patients at 35 vs 57% (P = 0.001) and 10 vs 22% (P = 0.019), respectively. There were no significant differences between groups for pathological outcomes, including stage, number of nodes harvested or positive margin rates. CONCLUSION: Our data suggest that patients undergoing RARC have perioperative oncological outcomes comparable with ORC, with fewer overall or major complications. Definitive claims about comparative outcomes with RARC require results from larger, randomised controlled trials. PMID- 23815803 TI - Long-term disease-free survival in a patient with cerebral recurrence from adenocarcinoma of the fallopian tube. AB - Cerebral recurrence from Mullerian cancer is a rare event and prognosis of patients with such a condition is poor. We report a case of cerebral recurrence from International Federation of Gynecology and Obstetrics classification stage IV tubal cancer presenting with inguinal lymphadenopathy. The patient achieved more than 7 years' disease-free survival after irradiation to the brain despite the inauspicious event. The present case had a rare clinical course in terms of primary site, primary symptom, failure site, and clinical outcome. Patients with brain metastasis from Mullerian cancer have a chance for long-term survival under specified circumstances, such as solitary metastasis, no extracranial metastasis, no recurrence preceding brain metastasis and small tumor size. PMID- 23815804 TI - How caregivers view patient comfort and what they do to improve it: a French survey. AB - BACKGROUND: Intensive care unit (ICU) patients are exposed to many sources of discomfort. Most of these are related to the patient's condition, but ICU design or how care is organized also can contribute. The present survey was designed to describe the opinions of ICU caregivers on sources of patient discomfort and to determine how they were dealt with in practice. The architectural and organizational characteristics of ICUs also were analyzed in relation to patient comfort. METHODS: An online, closed-ended questionnaire was developed. ICU caregivers registered at the French society of intensive care were invited to complete this questionnaire. RESULTS: A total of 915 staff members (55% nurses) from 264 adult and 28 pediatric ICUs completed the questionnaire. Analysis of the answers reveals that: 68% of ICUs had only single-occupancy rooms, and 66% had natural light in each room; ICU patients had access to television in 59% of ICUs; a clock was present in each room in 68% of ICUs. Visiting times were <4 h in 49% of adult ICUs, whereas 64% of respondents considered a 24-h policy to be very useful or essential to patients' well-being. A nurse-driven analgesia protocol was available in 42% of units. For caregivers, the main sources of patient discomfort were anxiety, feelings of restraint, noise, and sleep disturbances. Paramedics generally considered discomfort related to thirst, lack of privacy, and the lack of space and time references, whereas almost 50% of doctors ignored these sources of discomfort. Half of caregivers indicated they assessed sleep quality. A minority of caregivers declared regular use of noise-reduction strategies. Twenty percent of respondents admitted to having non-work-related conversations during patient care, and only 40% indicated that care often was or always was provided without closing doors. Family participation in care was planned in very few adult ICUs. CONCLUSIONS: Results of this survey showed that ICUs are poorly equipped to ensure patient privacy and rest. Access by loved ones and their participation in care also is limited. The data also highlighted that some sources of discomfort are less often taken into account by caregivers, despite being considered to contribute significantly. PMID- 23815805 TI - Enrichment of soybean meal with microelements during the process of biosorption in a fixed-bed column. AB - The aim of the present investigation was to enrich the mineral content of soybean meal with essential chromium and copper metal ions by a biosorption technique in a fixed-bed column. The values of column parameters were determined at various process conditions: pH, temperature, flow rate, and concentration of the feed solution; mass and size of the particles of the bed to determine the breakthrough curves. Biosorption efficiency at optimal conditions (pH 5.0, temperature = 20 degrees C, Cr(3+) concentration = 200 mg/L, flow rate = 10 mL/min, and sorbent mass = 40 g) was 71.4%. Maximum uptake for Cr(III) and Cu(II) obtained in column was around 15.3 and 12.3 mg/g, respectively. The model constants obtained in this study can be used for design pilot plant systems. Soybean enriched with microelements by biosorption can be considered as biological carrier of microelements and therefore used as the component of livestock feed. PMID- 23815806 TI - Bacterial bioaugmentation for improving methane and hydrogen production from microalgae. AB - BACKGROUND: The recalcitrant cell walls of microalgae may limit their digestibility for bioenergy production. Considering that cellulose contributes to the cell wall recalcitrance of the microalgae Chlorella vulgaris, this study investigated bioaugmentation with a cellulolytic and hydrogenogenic bacterium, Clostridium thermocellum, at different inoculum ratios as a possible method to improve CH4 and H2 production of microalgae. RESULTS: Methane production was found to increase by 17?~?24% with the addition of C. thermocellum, as a result of enhanced cell disruption and excess hydrogen production. Furthermore, addition of C. thermocellum enhanced the bacterial diversity and quantities, leading to higher fermentation efficiency. A two-step process of addition of C. thermocellum first and methanogenic sludge subsequently could recover both hydrogen and methane, with a 9.4% increase in bioenergy yield, when compared with the one-step process of simultaneous addition of C. thermocellum and methanogenic sludge. The fluorescence peaks of excitation-emission matrix spectra associated with chlorophyll can serve as biomarkers for algal cell degradation. CONCLUSIONS: Bioaugmentation with C. thermocellum improved the degradation of C. vulgaris biomass, producing higher levels of methane and hydrogen. The two-step process, with methanogenic inoculum added after the hydrogen production reached saturation, was found to be an energy-efficiency method for hydrogen and methane production. PMID- 23815807 TI - Sperm-associated antigen 11A is expressed exclusively in the principal cells of the mouse caput epididymis in an androgen-dependent manner. AB - BACKGROUND: Epididymal sperm maturation occurs via interactions between sperm and proteins secreted by the epididymal epithelium. Although this is an important process, the genes that encode the involved proteins remain largely uncharacterized. Previous studies have demonstrated that the genes involved in sperm maturation are regulated by androgen. Spag11a is an epididymal gene that is influenced by androgen. However, little is known about the putative role of this gene in the sperm maturation process. The objective of this study was to characterize Spag11a in the mouse epididymis. METHODS: In silico analyses were performed to predict signal peptides and functional domains. Spag11a expression was measured by quantitative real-time RT-PCR. Western blots and immunocytochemistry were performed to determine protein expression. RESULTS: SPAG11A is a member of the beta defensin protein family and constitutes a secretory protein. Spag11a was expressed exclusively in the epididymis. Moreover, it exhibited region-specific expression in the caput, which is typical for genes that are involved in creating a suitable microenvironment for sperm maturation. Mouse Spag11a was regulated by androgen. A significant decrease of Spag11a expression was observed at third day following a gonadectomy (P < 0.001). Interestingly, testosterone replacement therapy was able to maintain the expression almost at the normal level, indicating a dependency on androgen. Besides androgen, testicular factors influenced Spag11a expression in a different way. This was revealed by efferent duct ligation in which Spag11a was transiently up-regulated at the third day following the ligation before returning to the normal level at day 5. Spag11a regional expression was also observed at protein level detected by western immunoblotting which revealed a clear band in the caput but not in other regions. The prediction that SPAG11A is a secretory protein was confirmed by immunocytochemical analyses indicating cell-specific expression mainly in the caput principal cells and detection of the protein in epididymal luminal fluid and spermatozoa. CONCLUSIONS: Based on the characteristics of Spag11a, it is likely that this gene has a specific role in epididymal sperm maturation. Further studies using functional assays are necessary to confirm this finding. PMID- 23815808 TI - Sox2 suppresses the invasiveness of breast cancer cells via a mechanism that is dependent on Twist1 and the status of Sox2 transcription activity. AB - BACKGROUND: Sox2, an embryonic stem cell marker, is aberrantly expressed in a subset of breast cancer (BC). While the aberrant expression of Sox2 has been shown to significantly correlate with a number of clinicopathologic parameters in BC, its biological significance in BC is incompletely understood. METHODS: In vitro invasion assay was used to evaluate whether the expression of Sox2 is linked to the invasiveness of MCF7 and ZR751 cells. Quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and/or Western blots were used to assess if Sox2 modulates the expression of factors known to regulate epithelial mesenchymal transition (EMT), such as Twist1. Chromatin immunoprecipitation (ChIP) was used to assess the binding of Sox2 to the promoter region of Twist1. RESULTS: We found that siRNA knockdown of Sox2 expression significantly increased the invasiveness of MCF7 and ZR751 cells. However, when MCF7 cells were separated into two distinct subsets based on their differential responsiveness to the Sox2 reporter, the Sox2-mediated effects on invasiveness was observed only in 'reporter un-responsive' cells (RU cells) but not 'reporter responsive' cells (RR cells). Correlating with these findings, siRNA knockdown of Sox2 in RU cells, but not RR cells, dramatically increased the expression of Twist1. Accordingly, using ChIP, we found evidence that Sox2 binds to the promoter region of Twist1 in RU cells only. Lastly, siRNA knockdown of Twist1 largely abrogated the regulatory effect of Sox2 on the invasiveness in RU cells, suggesting that the observed Sox2-mediated effects are Twist1-dependent. CONCLUSION: Sox2 regulates the invasiveness of BC cells via a mechanism that is dependent on Twist1 and the transcriptional status of Sox2. Our results have further highlighted a new level of biological complexity and heterogeneity of BC cells that may carry significant clinical implications. PMID- 23815809 TI - Kinetic modeling of the X-ray-induced damage to a metalloprotein. AB - It is well-known that biological samples undergo X-ray-induced degradation. One of the fastest occurring X-ray-induced processes involves redox modifications (reduction or oxidation) of redox-active cofactors in proteins. Here we analyze room-temperature data on the photoreduction of Mn ions in the oxygen-evolving complex (OEC) of photosystem II, one of the most radiation damage-sensitive proteins and a key constituent of natural photosynthesis in plants, green algae, and cyanobacteria. Time-resolved X-ray emission spectroscopy with wavelength dispersive detection was used to collect data on the progression of X-ray-induced damage. A kinetic model was developed to fit experimental results, and the rate constant for the reduction of OEC Mn(III) and Mn(IV) ions by solvated electrons was determined. From this model, the possible kinetics of X-ray-induced damage at a variety of experimental conditions, such as different rates of dose deposition as well as different excitation wavelengths, can be inferred. We observed a trend of increasing dosage threshold prior to the onset of X-ray-induced damage with increasing rates of dose deposition. This trend suggests that experimentation with higher rates of dose deposition is beneficial for measurements of biological samples sensitive to radiation damage, particularly at pink beam and X-ray free electron laser sources. PMID- 23815810 TI - Brain anatomy of autism spectrum disorders II. Focus on amygdala. AB - This brief review encompasses the key findings of structural Magnetic Resonance Imaging (sMRI) research on amygdala volume in autism spectrum disorders (ASD). We also highlight the possible correlation between the autistic behavioural phenotype and amygdala alteration. PMID- 23815811 TI - Epidemiology of subpatent Plasmodium falciparum infection: implications for detection of hotspots with imperfect diagnostics. AB - BACKGROUND: At the local level, malaria transmission clusters in hotspots, which may be a group of households that experience higher than average exposure to infectious mosquitoes. Active case detection often relying on rapid diagnostic tests for mass screen and treat campaigns has been proposed as a method to detect and treat individuals in hotspots. Data from a cross-sectional survey conducted in north-western Tanzania were used to examine the spatial distribution of Plasmodium falciparum and the relationship between household exposure and parasite density. METHODS: Dried blood spots were collected from consenting individuals from four villages during a survey conducted in 2010. These were analysed by PCR for the presence of P. falciparum, with the parasite density of positive samples being estimated by quantitative PCR. Household exposure was estimated using the distance-weighted PCR prevalence of infection. Parasite density simulations were used to estimate the proportion of infections that would be treated using a screen and treat approach with rapid diagnostic tests (RDT) compared to targeted mass drug administration (tMDA) and Mass Drug Administration (MDA). RESULTS: Polymerase chain reaction PCR analysis revealed that of the 3,057 blood samples analysed, 1,078 were positive. Mean distance-weighted PCR prevalence per household was 34.5%. Parasite density was negatively associated with transmission intensity with the odds of an infection being subpatent increasing with household exposure (OR 1.09 per 1% increase in exposure). Parasite density was also related to age, being highest in children five to ten years old and lowest in those > 40 years. Simulations of different tMDA strategies showed that treating all individuals in households where RDT prevalence was above 20% increased the number of infections that would have been treated from 43 to 55%. However, even with this strategy, 45% of infections remained untreated. CONCLUSION: The negative relationship between household exposure and parasite density suggests that DNA-based detection of parasites is needed to provide adequate sensitivity in hotspots. Targeting MDA only to households with RDT-positive individuals may allow a larger fraction of infections to be treated. These results suggest that community-wide MDA, instead of screen and treat strategies, may be needed to successfully treat the asymptomatic, subpatent parasite reservoir and reduce transmission in similar settings. PMID- 23815812 TI - Regio-selectively reduced streptogramin A analogue, 5,6-dihydrovirginiamycin M1 exhibits improved potency against MRSA. AB - A newly reduced macrocyclic lactone antibiotic streptogramin A, 5,6 dihydrovirginiamycin M1 was created by feeding virginiamycin M1 into a culture of recombinant Streptomyces venezuelae. Its chemical structure was spectroscopically elucidated, and this streptogramin A analogue showed twofold higher antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA) compared with its parent molecule virginiamycin M1. Docking studies using the model of streptogramin A acetyltransferase (VatA) suggested that the newly generated analogue binds tighter with overall lower free energy compared with the parent molecule virginiamycin M1. This hypothesis was validated experimentally through the improvement of efficacy of the new analogue against MRSA strains. The biotransformation approach presented herein could have a broad application in the production of reduced macrocyclic molecules. PMID- 23815813 TI - Engineered silica nanoparticles act as adjuvants to enhance allergic airway disease in mice. AB - BACKGROUND: With the increase in production and use of engineered nanoparticles (NP; <= 100 nm), safety concerns have risen about the potential health effects of occupational or environmental NP exposure. Results of animal toxicology studies suggest that inhalation of NP may cause pulmonary injury with subsequent acute or chronic inflammation. People with chronic respiratory diseases like asthma or allergic rhinitis may be even more susceptible to toxic effects of inhaled NP. Few studies, however, have investigated adverse effects of inhaled NP that may enhance the development of allergic airway disease. METHODS: We investigated the potential of polyethylene glycol coated amorphous silica NP (SNP; 90 nm diameter) to promote allergic airway disease when co-exposed during sensitization with an allergen. BALB/c mice were sensitized by intranasal instillation with 0.02% ovalbumin (OVA; allergen) or saline (control), and co-exposed to 0, 10, 100, or 400 MUg of SNP. OVA-sensitized mice were then challenged intranasally with 0.5% OVA 14 and 15 days after sensitization, and all animals were sacrificed a day after the last OVA challenge. Blood and bronchoalveolar lavage fluid (BALF) were collected, and pulmonary tissue was processed for histopathology and biochemical and molecular analyses. RESULTS: Co-exposure to SNP during OVA sensitization caused a dose-dependent enhancement of allergic airway disease upon challenge with OVA alone. This adjuvant-like effect was manifested by significantly greater OVA-specific serum IgE, airway eosinophil infiltration, mucous cell metaplasia, and Th2 and Th17 cytokine gene and protein expression, as compared to mice that were sensitized to OVA without SNP. In saline controls, SNP exposure did cause a moderate increase in airway neutrophils at the highest doses. CONCLUSIONS: These results suggest that airway exposure to engineered SNP could enhance allergen sensitization and foster greater manifestation of allergic airway disease upon secondary allergen exposures. Whereas SNP caused innate immune responses at high doses in non-allergic mice, the adjuvant effects of SNP were found at lower doses in allergic mice and were Th2/Th17 related. In conclusion, these findings in mice suggest that individuals exposed to SNP might be more prone to manifest allergic airway disease, due to adjuvant-like properties of SNP. PMID- 23815814 TI - CD133: a stem cell biomarker and beyond. AB - Cancer stem cells (CSCs) or tumor initiating cells (TICs) contribute to tumorigenesis, metastasis, recurrence and chemoresistance. CD133, a pentaspan membrane glycoprotein, has been used as a stem cell biomarker for isolation of stem-like cells from a variety of normal and pathological tissues as well as cell lines since its discovery in 1999. Recent studies are focusing on the functionality of CD133. In this review, we summarize new insights into CD133 regulation and the involvement of CD133 in cell self-renewal, tumorigenesis, metastasis, resistance, metabolism, differentiation, autophagy, apoptosis, and regeneration. PMID- 23815815 TI - The cAMP effector EPAC activates Elk1 transcription factor in prostate smooth muscle, and is a minor regulator of alpha1-adrenergic contraction. AB - BACKGROUND: Prostate smooth muscle tone is regulated by alpha1-adrenoceptor induced contraction and cAMP-mediated relaxation. EPAC is an effector of cAMP, being involved in smooth muscle relaxation and cell cycle control outside the lower urinary tract. Here, we investigated the expression and function of EPAC in human prostate tissues from patients undergoing radical prostatectomy. RESULTS: mRNA and protein expression of EPAC was detected in all prostate tissues by RT PCR and Western blot analysis. Immunoreactivity was observed in stromal cells, and colocalized with immunofluorescence for alpha-smooth muscle actin and calponin. Under normal conditions, noradrenaline- or phenylephrine-induced contraction of prostate strips in the organ bath was not affected by the EPAC activator pCPT (SP-8-pCPT-2'-O-Me-cAMPS.NA) (30 MUM). However, when the cyclooxygenase inhibitor indomethacin (50 MUM) was added, EPAC activators pCPT and OME (8-CPT-2'-O-Me-cAMP.Na) (30 MUM) significantly reduced contractions by low concentrations of phenylephrine. These effects were not observed on noradrenaline-induced contraction. OME and pCPT caused phosphorylation of the transcription factor Elk1 in prostate tissues. Elk1 activation was confirmed by EMSA (electrophoretic mobility shift assay), where OME and pCPT incresed Elk1 binding to a specific DNA probe. CONCLUSIONS: EPAC activation may reduce alpha1 adrenergic prostate contraction in the human prostate, although this effect is masked by cyclooxygenases and beta-adrenoceptors. A main EPAC function in the human prostate may be the regulation of the transcription factor Elk1. PMID- 23815816 TI - Seeking allergy when it hides: which are the best fitting tests? AB - In the common practice of respiratory allergy, the confirmation by IgE tests of the relationship between the occurrence and duration of symptoms and the exposure to specific inhalant allergens allows an aetiological diagnosis. However, to see patients with suggestive history but negative IgE tests is not rare, and this generally leads to a diagnosis of nonallergic rhinitis or asthma. In many cases, such diagnosis is wrong, because the patient may be revealed as allergic by using additional testing. This is true for local allergic rhinitis, characterized by an exclusive IgE production in the nasal mucosa, that may be correctly diagnosed by performing a nasal IgE measurement or a nasal provocation test with the suspected allergen (s). Another misleading issue is the role of T cell-mediated, delayed hypersensitivity in the pathophysiology of rhinitis and asthma. Recent studies showed that in patients with rhinitis or asthma and negative IgE tests, especially when there is a positive history for current or past atopic dermatitis, the clinical symptoms are actually driven by such mechanism, that may be detected by performing an atopy patch test (APT). The allergen source most frequently responsible for this kind of allergy is the house dust mite, but other allergens may also be involved. Thus, before delivering a diagnosis of nonallergic rhinitis or asthma in patients with negative result to common allergy testing, further tests are needed. To miss the diagnosis of allergy has obvious consequences in terms of management, including allergen avoidance, patient's education, and specific immunotherapy. PMID- 23815818 TI - Effect of apolipoprotein E genotypes on the efficacy of ezetimibe monotherapy in patients with statin induced adverse effects. AB - OBJECTIVE: The aim of this study was to clarify the effect of Apolipoprotein E (ApoE) polymorphism on the efficacy of cholesterol absorption inhibitor ezetimibe monotherapy on lipid parameters. METHODS: 63 hyperlipidemic patients with statin induced adverse effects were involved in the study. We examined the effect of 10 mg/day ezetimibe treatment on lipid levels after 3, 6 and 12 months of treatment in patients on a diet of only different ApoE genotypes. RESULTS: Three months of ezetimibe treatment significantly decreased the total cholesterol (TC) (-10.1%), low-density lipoprotein (LDL-C) (-12.0%) (p < 0.001) and triglyceride (Tg) (-8%) levels (p < 0.05). After 6 and 12 months of treatment reduction in TC, LDL-C and Tg levels were even more pronounced. The genotype distribution of the patients were 2/2: 4.8%, 2/3: 7.9%, 3/3: 68.3%, 3/4: 19.0%. There were no patients with 2/4 and 4/4 genotypes. In patients with 2/3, 3/3 or 3/4 genotype, the ezetimibe treatment tended to be more effective on TC and LDL-C levels than in the 2/2 group, and the efficacy of ezetimibe on Tg levels were slightly better in 2/2 carriers compared to other patients. CONCLUSIONS: The ApoE genotype does not predict the efficacy of ezetimibe treatment on serum lipid parameters. PMID- 23815817 TI - Recent development and biomedical applications of probabilistic Boolean networks. AB - Probabilistic Boolean network (PBN) modelling is a semi-quantitative approach widely used for the study of the topology and dynamic aspects of biological systems. The combined use of rule-based representation and probability makes PBN appealing for large-scale modelling of biological networks where degrees of uncertainty need to be considered.A considerable expansion of our knowledge in the field of theoretical research on PBN can be observed over the past few years, with a focus on network inference, network intervention and control. With respect to areas of applications, PBN is mainly used for the study of gene regulatory networks though with an increasing emergence in signal transduction, metabolic, and also physiological networks. At the same time, a number of computational tools, facilitating the modelling and analysis of PBNs, are continuously developed.A concise yet comprehensive review of the state-of-the-art on PBN modelling is offered in this article, including a comparative discussion on PBN versus similar models with respect to concepts and biomedical applications. Due to their many advantages, we consider PBN to stand as a suitable modelling framework for the description and analysis of complex biological systems, ranging from molecular to physiological levels. PMID- 23815819 TI - Chromosomal imbalance letter: Phenotypic consequences of combined deletion 8pter and duplication 15qter. AB - Exact breakpoint determination by oligonucleotide array-CGH has improved the analysis of genotype-phenotype correlations in cases with chromosome aberrations allowing a more accurate definition of relevant genes, particularly their isolated or combined impact on the phenotype in an unbalanced state. Chromosomal imbalances have been identified as one of the major causes of mental retardation and/or malformation syndromes and they are observed in ~2-5% of the cases. Here we report a female child born to non-consanguineous parents and having multiple congenital anomalies such as atrial septal defect and multiple ventricular septal defects, convergent strabismus, micropthalmia, seizures and mental retardation, with her head circumference and stature normal for her age. Cytogenetic study suggested 46,XX,add(8)(p23). Further analysis by array-CGH using 44K oligonucleotide probe confirmed deletion on 8p23.3p23.1 of 7.1 Mb and duplication involving 15q23q26.3 of 30 Mb size leading to 46,XX,der(8)t(8;15)(p23.3;q23)pat.arr 8p23.3p23.1(191,530 7,303,237)x1,15q23q26.3(72,338,961-102,35,195)x3. The unique phenotypic presentation in our case may have resulted from either loss or gain of a series of contiguous genes which may have resulted in a direct phenotypic effect and/or caused a genetic regulatory disturbance. Double segmental aberrations may have conferred phenotypic variability, as in our case, making it difficult to predict the characteristics that evolved as a result of the global gene imbalance, caused by the concomitant deletion and duplication. PMID- 23815820 TI - Is on-admission capillary blood beta-hydroxybutyrate concentration associated with the acute stroke severity and short-term functional outcome? AB - OBJECTIVES: In conditions with reduced glucose levels/inability of glucose utilization, ketone bodies, especially beta-hydroxybutyrate (BHB), become a major energy source in the brain. In animal models, BHB infusion shows acute beneficial effects on the hypoxic brain. The present prospective observational study is the first to assess the relationship between on-admission capillary blood BHB levels and acute stroke severity/short-term functional outcomes. METHODS: A total of 51 consecutive first-ever stroke patients (46 ischemic stroke) admitted within 24 hours since the symptom onset and <= 44 hours since the last meal were evaluated for stroke severity (National institutes of health stroke scale, NIHSS) and for disability (modified Rankin scale, mRS) 3 months post-stroke. RESULTS: On admission BHB values ranged between 0 and 1.6 mmol/l, with 43 (84.3%) values <= 0.4 mmol/l (normal). Higher BHB values were independently associated with longer fasting and hyperglycemia, whereas lower values were associated with dyslipidemia and diabetes. No association between on-admission BHB levels and NIHSS scores at presentation or day 5 was observed. The BHB levels considered either as continuous or as binary (> 0.4 vs <= 0.4 mmol/l) variables were independently (adjustment for age, NIHSS score at presentation, fasting period, stroke type, hyperglycemia, diabetes, and dyslipidemia) associated with lower odds of mRS 0-2 (non-to-mild disability) 3 months post-stroke: OR = 0.09 (95% CI 0.00-0.97, P = 0.047) and OR = 0.07 (95% CI 0.00-0.78, P = 0.028), respectively. DISCUSSION: This preliminary study suggests that higher on-admission BHB values are associated with poorer stroke outcomes and emphasizes the need for further investigations. PMID- 23815822 TI - Intensity-modulated radiotherapy with simultaneous modulated accelerated boost technique and chemotherapy in patients with nasopharyngeal carcinoma. AB - BACKGROUND: To present our experience of intensity-modulated radiotherapy (IMRT) with simultaneous modulated accelerated radiotherapy (SMART) boost technique in patients with nasopharyngeal carcinoma (NPC). METHODS: Sixty eight patients of NPC were treated between April 2006 and December 2011 including 45 males and 23 females with mean age of 46 (range 15-78). Stage distribution was; stage I 3, stage II 7, stage III 26 and stage IV 32. Among 45 (66.2%) evaluated patients for presence of Epstein-Barr virus (EBV), 40 (88.8%) were positive for EBV. Median radiation doses delivered to gross tumor volume (GTV) and positive neck nodes were 66-70 Gy, 63 Gy to clinical target volume (CTV) and 50.4 Gy to clinically negative neck. In addition 56 (82.4%) patients with bulky tumors (T4/N2+) received neoadjuvant chemotherapy 2-3 cycles (Cisplatin/Docetaxel or Cisplatin/Epirubicin or Cisplatin/5 Flourouracil). Concurrent chemotherapy with radiation was weekly Cisplatin 40 mg/m2 (40 patients) or Cisplatin 100 mg/m2 (28 patients). RESULTS: With a median follow up of 20 months (range 3-43), one patient developed local recurrence, two experienced regional recurrences and distant failure was seen in 3 patients. Estimated 3 year disease free survival (DFS) was 94%. Three year DFS for patients with EBV was 100% as compared to 60% without EBV (p = 0.0009). Three year DFS for patients with undifferentiated histology was 98% as compared to 82% with other histologies (p = 0.02). Acute grade 3 toxicity was seen as 21 (30.9%) having G-III mucositis and 6 (8.8%) with G-III skin reactions. Late toxicity was minimal and loss of taste was seen in 3 patients (7.5%) at time of analysis. CONCLUSIONS: IMRT with SMART in combination with chemotherapy is feasible and effective in terms of both the clinical response and safety profile. EBV, histopathology and nodal involvement were found important prognostic factors for locoregional recurrence. PMID- 23815823 TI - [Giant liver abscess. Primary surgical treatment]. PMID- 23815821 TI - Diffusion of small molecules into medaka embryos improved by electroporation. AB - BACKGROUND: Diffusion of small molecules into fish embryos is essential for many experimental procedures in developmental biology and toxicology. Since we observed a weak uptake of lithium into medaka eggs we started a detailed analysis of its diffusion properties using small fluorescent molecules. RESULTS: Contrary to our expectations, not the rigid outer chorion but instead membrane systems surrounding the embryo/yolk turned out to be the limiting factor for diffusion into medaka eggs. The consequence is a bi-phasic uptake of small molecules first reaching the pervitelline space with a diffusion half-time in the range of a few minutes. This is followed by a slow second phase (half-time in the range of several hours) during which accumulation in the embryo/yolk takes place. Treatment with detergents improved the uptake, but strongly affected the internal distribution of the molecules. Testing electroporation we could establish conditions to overcome the diffusion barrier. Applying this method to lithium chloride we observed anterior truncations in medaka embryos in agreement with its proposed activation of Wnt signalling. CONCLUSIONS: The diffusion of small molecules into medaka embryos is slow, caused by membrane systems underneath the chorion. These results have important implications for pharmacologic/toxicologic techniques like the fish embryo test, which therefore require extended incubation times in order to reach sufficient concentrations in the embryos. PMID- 23815825 TI - Antigenicity in sheep of synthetic peptides derived from stress-regulated Mycobacterium avium subsp. paratuberculosis proteins and comparison with recombinant protein and complex native antigens. AB - Serum antibody enzyme-linked immunosorbent assay is the most commonly used test for diagnosis of Mycobacterium avium subsp. paratuberculosis infection in ruminants. However, the assay requires serum preabsorption with Mycobacterium phlei proteins to reduce cross reactions potentially contributed by the exposure of livestock to environmental mycobacteria. To trial the discovery of novel antigens which do not require serum absorption, synthetic MAP-specific peptides were selected based on in silico research to identify putative B cell epitopes. Four peptides from previously identified stress-regulated proteins were synthesized and evaluated using enzyme linked immunosorbent assay to detect Mycobacterium avium subsp. paratuberculosis specific antibodies in sheep. Two peptides were from hypothetical MAP proteins (MAP3567 and MAP1168c) and two were from proteins with known function (MAP2698c, an acyl-acyl carrier protein desaturase-DesA2 and MAP2487c a carbonic anhydrase). The ability of each peptide to discriminate between unexposed and MAP exposed (infected and vaccinated) animals was similar to that of the parent recombinant MAP antigen, with area under receiver operating curve values of 0.86-0.93. Assays run with a combination of two peptides showed slightly higher reactivity than those of individual peptides. Peptides evaluated in this study had diagnostic potential similar to corresponding recombinant proteins but not superior to a complex native MAP antigen or a commercial assay. Further study is required to investigate other peptides for their diagnostic potential, and this may be simpler and cheaper than subunit protein-based research. PMID- 23815824 TI - Experimental model of equine alveolar macrophage stimulation with TLR ligands. AB - Pulmonary diseases are common in horses and have a major economic impact on the equine industry. Some of them could be associated with an inadequate immune response in the lung, but methods to evaluate this response in horses are lacking. The aim of this study was to develop and validate an experimental model that could be applied in several physiological and pathological conditions to assess the innate immune response of equine pulmonary cells. Equine alveolar macrophages (AMs) obtained from bronchoalveolar lavages were isolated from other cells by adhesion. TLR2, 3, and 4 expression in AMs was studied and their responses to commercial ligands (respectively FSL-1, Poly(I:C), and LPS) were evaluated after determination of the appropriate dose and time of incubation. TLR responses were assessed by measuring cytokine production using (1) gene expression of TNFalpha, IFNbeta, Il-1beta, and IFNalpha by qPCR (indirect method); and (2) cytokine production for TNFalpha and IFNbeta by ELISA (direct method). TLR 2, 3, and 4 were expressed by AMs. TLR 2 stimulation with 10 ng/mL of FSL-1 during 3h significantly increased IL-1beta and TNFalpha gene expression. TLR 3 stimulation with 1000 ng/mL of Poly(I:C) during 1h increased IFNbeta, IFNalpha, Il-1beta and TNFalpha expression. TLR 4 stimulation with 100 ng/mL of LPS during 3h increased TNFalpha, IFNbeta, and Il-1beta expression. Results obtained by ELISA quantification of TNFalpha and IFNbeta produced by AMs following stimulation during 6h were similar: FSL-1 increased TNFalpha production but not IFNbeta, Poly(I:C) and LPS increased production of IFNbeta and TNFalpha. In conclusion, pulmonary innate immunity of horses can be assessed ex vivo by measuring cytokine production following stimulation of AMs with TLR agonists. This experimental model could be applied under several conditions especially to improve the understanding of equine respiratory disease pathogenesis, and to suggest novel therapeutic opportunities. PMID- 23815826 TI - Seroepidemiological and parasitological evaluation of the heterogeneity of malaria infection in the Gambia. AB - BACKGROUND: As countries make progress in malaria control, transmission may be reduced to such an extent that few cases occur, and identification of the remaining foci of transmission may require a combination of surveillance tools. The study explored the usefulness of parasite prevalence, seroprevalence and model-estimated seroconversion rates for detecting local differences in malaria transmission in a West African country. METHODS: Age-stratified cross-sectional surveys were conducted during the wet season in 2008 and the following dry season in 2009 in The Gambia. In each season, 20 village communities were sampled from six diverse areas throughout the country. A total of 7,586 participants were surveyed, 51% (3,870) during the wet season. Parasites were detected by thick film slide microscopy, and anti-MSP1-19 antibodies were detected by ELISA using eluted dried blood from filter papers. RESULTS: Overall parasite prevalence was 12.4% in the wet season and 2.2% in the dry season, with village-specific parasite prevalence ranging from 1.4 to 45.9% in the wet season and from 0.0 to 13.2% in the dry season. Prevalence was highest in the eastern part of the country. Serological indices also varied between villages, indicating local heterogeneity in transmission, and there was a high correlation between wet and dry season estimates across the villages. The overall prevalence of anti-MSP119 antibodies was similar in the wet (19.5%) and in the dry (19.6%) seasons. CONCLUSION: The study illustrates the utility of measuring both parasite prevalence and serological indices for monitoring local variation in malaria transmission, which are more informative than single measures as control intensifies and malaria declines. Measurements of seropositivity have the logistical advantage of being relative stable seasonally so that sampling at any time of year may be conducted. PMID- 23815827 TI - Mojokerto revisited: evidence for an intermediate pattern of brain growth in Homo erectus. AB - Brain development in Homo erectus is a subject of great interest, and the infant calvaria from Mojokerto, Indonesia, has featured prominently in these debates. Some researchers have suggested that the pattern of brain development in H. erectus resembled that of non-human apes, while others argue for a more human like growth pattern. In this study, we retested hypotheses regarding brain ontogeny in H. erectus using new methods (resampling), and data from additional H. erectus crania. Our results reveal that humans achieve 62% (+/-10%) and chimpanzees 80% (+/-9%) of their adult endocranial volume by 0.5-1.5 years of age. Using brain mass data, humans achieve on average 65% and chimpanzees 81% of adult size by 0.5-1.5 years. When compared with adult H. erectus crania (n = 9) from Indonesian sites greater than 1.2 million years old, Mojokerto had reached ~70% of its adult cranial capacity. Mojokerto thus falls almost directly between the average growth in humans and chimpanzees, and well within the range of both. We therefore suggest that brain development in H. erectus cannot be dichotomized as either ape-like or human-like; it was H. erectus-like. These data indicate that H. erectus may have had a unique developmental pattern that should be considered as an important step along the continuum of brain ontogeny between apes and humans. PMID- 23815828 TI - [New paths for anatomy]. PMID- 23815829 TI - World Health Organization. PMID- 23815830 TI - Improvement of the embalming perfusion method: the innovation and the results by light and scanning electron microscopy. AB - Embalming is a chemical process that aims the preservation and sanitization of the human body indefinitely. The technique of embalming is an important tool in teaching and research in anatomy enabling the preservation of cadaveric material in good conditions (lessening any significant structural changes and maintaining the natural appearance). This article presents the results of embalmed cadavers in the course of arterial perfusion, through the use of a perfusion machine, particularly designed to this objective, and which allows the control of the embalming fluid injection process. The influence of this technique and the optimization of its parameters on the final quality of embalming were evaluated by sequential histological analysis of the cadaveric tissues using an original method of classification of samples collected from 17 deceased corpses of the Corpses Donation Office of the Department of Anatomy of Faculdade de Ciencias Medicas from Universidade Nova de Lisboa, subject to the embalming technique developed in the Department. We concluded that, with this method, there is a decrease of the decomposition process at the time of embalming, which is effective at long term (over a year), requiring merely the maintenance of the body at low temperatures (4 degrees C) and it is possible to observe that the tissue best preserved over time is muscle, showing a conservation considered optimal. PMID- 23815831 TI - [Identification and preservation of parathyroid glands in cadaver parts]. AB - INTRODUCTION: It is essential to know the thyroid gland morphology and its anatomical relations in the anterior compartment of the neck in order to minimize the rate of thyroid surgery morbidity, especially the lesion of parathyroid glands and laryngeal nerves. The aim of this study was the identification of parathyroid glands in cadaver parts and their histological confirmation. MATERIAL AND METHODS: Twenty cadaver parts were used to simulate thyroidectomies. During dissection, the thyroid glands and eventual parathyroid glands were isolated and then submitted to histological study. DISCUSSION: Twenty cadaver parts (anterior cervical organs) were used for macroscopic dissection during which 48 fragments that corresponded to eventual parathyroid glands were isolated, 35 of which were effectively confirmed through histological observation to be parathyroid glands. The 20 cadaver parts were then divided into three groups according to the number of histologically confirmed parathyroid glands. In the first group, composed of 11 cases, all eventual parathyroid glands were confirmed. In the second group, composed of six cases, only some glands were confirmed. In the third group, composed of three cases, none of the possible glands were confirmed. In seven of the 20 isolated thyroid glands, eight parathyroid glands were identified during histological study: four subcapsular, three extra-capsular, one intra-thyroidal. There was no statistical relation in the dimensions of the parathyroid glands. CONCLUSIONS: The knowledge of the anatomy of the central visceral compartment of the neck and its most frequent variations reduces but doesn't eliminate thyroid surgery morbidity, especially parathyroid iatrogenic excision, difficulty which has been demonstrated during the dissection of cadaver parts. PMID- 23815832 TI - [Localization and distribution of human olfactory mucosa in the nasal cavities]. AB - INTRODUCTION: The exact distribution of the human olfactory mucosa can only be determined in studies that evaluate the entire olfactory region. The purpose of this study is to determine the distribution of human olfactory mucosa in the nasal cavities, by performing the histological analysis, by light microscopy, of anatomical specimens of the olfactory region obtained from cadavers. MATERIAL AND METHODS: The specimens were taken during the autopsy of fresh cadavers. In each of the specimens, the distance between the cribiform plate and the lower limit of the olfactory region was determined in three different locations of the septal and lateral walls. RESULTS: Of the 230 anatomical specimens available, 217 were excluded for medical or technical reasons. Morphometric studies were performed on 13 specimens (total 156 measurements). The lower limit of the olfactory mucosa in the nasal septum was 15.9 +/- 3.2 mm, 15.3 mm +/- 3 and 16 +/- 2.8 mm in the anterior, middle and posterior olfactory regions. The lower limit of the olfactory mucosa in the turbinate wall was 15.3 +/- 2.4 mm, 14.8 +/- 2.3 mm and 12.3 +/- 1.9 mm in the equivalent regions. The minimum value observed was 12 mm. CONCLUSIONS: The olfactory mucosa extends through the upper and middle turbinates and the confronting nasal septum in a minimum distance of 12 mm and that may exceed 16 mm. Knowing the exact distribution of the olfactory mucosa can guide the collection of this tissues in humans, for diagnostic or therapeutic purposes. PMID- 23815833 TI - Sciatic nerve high division: two different anatomical variants. AB - INTRODUCTION: Sciatic nerve variations are relatively common. These variations are often very significant in several fields of Medicine. The purpose of this paper is to present two such variants and discuss their clinical implications. MATERIAL AND METHODS: Three Caucasian cadavers with no prior history of lower limb trauma or surgery were dissected and found to present anatomical variants of the sciatic nerve. RESULTS: In all cases the sciatic nerve divided above the popliteal fossa. In two cases (cadavers 1 and 2) it divided on both sides in the inferior portion of the gluteal region in its two terminal branches: the common fibular and the tibial nerves. In another case (cadaver 3) the sciatic nerve was found to divide inside the pelvis just before coursing the greater sciatic notch. The common fibular nerve exited the pelvis above the pyriformis muscle and then passed along its posterior aspect, while the tibial nerve coursed deep to the pyriformis muscle. DISCUSSION: According to the literature, the anatomical variant described in cadaver 3 is considered relatively rare. This variant can predispose to nerve entrapment and thus to the pyriformis syndrome, sciatica and coccygodynia. The high division of the sciatic nerve, as presented in cadavers 1 and 2, can make popliteal nerve blocks partially ineffective. CONCLUSION: The anatomical variants associated with a high division of the sciatic nerve, must always be born in mind, as they are relatively prevalent, and have important clinical implications, namely in Anesthesiology, Neurology, Sports Medicine and Surgery. PMID- 23815834 TI - [Clinical anatomy: anthropometry for nutritional assessment of 367 adults who underwent endoscopic gastrostomy]. AB - INTRODUCTION: Patients suffering from long standing dysphagia need tube feeding through gastrostomy. Nutritional assessment of these patients is challenging and must be supported on objective data, including anthropometric evaluation. AIM: The aim of this study was the evaluation of the usefulness of anthropometry for identifying and grading malnutrition, as part of the initial assessment of patients that underwent endoscopic gastrostomy. MATERIAL AND METHODS: From the files of consecutive adults underwent gastrostomy we selected patients with anthropometric data obtained before the procedure: Body Mass Index, Mid Upper Arm Circumference, Triceps Skinfold Thickness and Mid Arm Muscle Circumference. Nutritional status was classified according with World Health Organization criteria for Body Mass Index, and for Mid Upper Arm Circumference, Triceps Skinfold Thickness and Mid Arm Muscle Circumference using comparison with Frisancho reference-tables. RESULTS: Were selected 367 patients (median of ages: 74.1 years): neurological disease: 172; head and neck cancer: 176; other diseases: 19. Body Mass Index identified 136 underweight and 231 eutrophic or overweight patients. Mid Upper Arm Circumference identified 310 malnourished and 57 eutrophic or overweight patients. Triceps Skinfold Thickness identified 301 malnourished and 66 eutrophic or overweight patients. Mid Arm Muscle Circumference identified 269 malnourished, 97 eutrophic and one with MAMC above normal. DISCUSSION AND CONCLUSIONS: Anthropometry identified the malnourished endoscopic gastrostomy-patients, contributed for malnutrition grading and demonstrated the impact on muscle and fat reserves. Mid Upper Arm Circumference, Triceps Skinfold Thickness and Mid Arm Muscle Circumference identified malnutrition in nearly 80% of the patients, most clearly with fat tissue wasting than muscle. Easily accessible e inexpensive, anthropometry allowed personalized nutritional therapy. Anthropometry must be recognized as a fundamental tool for enteral feeding teams. PMID- 23815835 TI - Radiologic anatomy of arteriogenic erectile dysfunction: a systematized approach. AB - INTRODUCTION: Erectile Dysfunction is a highly prevalent disease and there is growing interest in its endovascular treatment. Due to the complexity of the male pelvic arterial system, thorough anatomical knowledge is paramount. We evaluated the applicability of the Yamaki classification with Computerized Tomography Angiography and Digital Subtraction Angiography in the evaluation of patients with arteriogenic Erectile Dysfunction, illustrating the arterial lesions that can cause Erectile Dysfunction. METHODS: Single-center retrospective analysis of the Computerized Tomography Angiography and Digital Subtraction Angiography imaging findings in 21 male patients with suspected arteriogenic Erectile Dysfunction that underwent selective pelvic arterial embolization. Assessment of erectile function was achieved using the IIEF-5. The branching patterns of the Internal Iliac Artery were classified according to the Yamaki classification. The diagnosis of arteriogenic Erectile Dysfunction was based on the presence of atherosclerotic lesions (stenoses and/or occlusions) of the Internal Iliac Artery or the Internal Pudendal Arteries. RESULTS: The mean patient age was 67.2 years; with a mean IIEF of 10.6 points. Computerized Tomography Angiography and Digital Subtraction Angiography findings allowed classification of all the 42 pelvic sides according to the Yamaki classification. Twenty-four pelvic sides were classified as Group A (57%), 9 as Group B (21.5%) and 9 as Group C (21.5%). The Digital Subtraction Angiography detected 19 abnormal Internal Pudendal Arteries (with atherosclerotic lesions) (45%). The Computerized Tomography Angiography detected 24 abnormal Internal Pudendal Arteries (57%). CONCLUSION: Computerized Tomography Angiography and Digital Subtraction Angiography findings of arteriogenic Erectile Dysfunction include stenotic and occlusive lesions of the Internal Iliac Artery and Internal Pudendal Artery. The Yamaki classification is radiologically reproducible and allows easy recognition of the Internal Pudendal Artery in patients with arteriogenic Erectile Dysfunction. PMID- 23815836 TI - [Vertebral metrics: application of a new mechanical instrument to evaluate the spinal column]. AB - OBJECTIVE: To present the results of the first application of the new technology Vertebral Metrics - the analysis of the 3D position of the vertex of each spinous process in pregnant women. MATERIAL AND METHODS: The Vertebral Metrics was applied to women without associated pathology in four stages of pregnancy (12, 20, 32, 37 weeks gestation). We applied univariate linear models. RESULTS: We found that the differences that occur during pregnancy are more significant at the position y (anteroposterior). It was found also that there is a positive correlation between the biomechanical position of the vertex of each of the vertebrae with the homologous position of rest. DISCUSSION/CONCLUSION: Through Vertebral Metrics innovative results could be obtained in analyzing biomechanics of the spine. A device that has different applications can be easily adopted in areas such as orthopedics, neurosurgery, pediatrics and rehabilitation. It should also be noted that this instrument is not exhausted in the sample of this research because it can be further applied to the general population. PMID- 23815837 TI - Osteotomy at low-speed drilling without irrigation versus high-speed drilling with irrigation: an experimental study. AB - INTRODUCTION: Excessively traumatic surgery can adversely affect the maturation of bone tissue and consequently diminish the predictability of osseointegration so the mechanical and thermal damage should be minimized during surgical procedure. The purpose of this study is to evaluate immediate histological alterations in rabbit tibias, produced by low speed drilling (50 rpm) without irrigation and conventional drilling (800 rpm) under profuse irrigation. MATERIAL AND METHODS: Thirty-six implant osteotomies were created in the tibias of 6 White female rabbits. Drilling began with a 1.5 mm round bur, followed by 2.0 mm, 2.5 mm and 3.5 mm helical drills. The posterior tibial cortex was evaluated as the positive control, and it was preserved during the surgical procedure. The receptor beds were collected for histological analysis. RESULTS: All defects showed regular edges. Hematoxylin eosin (HE) sections showed that both techniques preserved the bone structure and the presence of living cells. No histological differences between the two surgical drilling techniques were found. CONCLUSIONS: Based on our results, we can conclude that the effects of implant site preparation on bone by low speed drilling (50 rpm) without irrigation and conventional drilling (800 rpm) under abundant irrigation are similar. Both surgical drilling techniques preserve bone-cell viability and the clinician can decide which drilling technique to use, based on other criteria. PMID- 23815838 TI - Effects of large pressure amplitude low frequency noise in the parotid gland perivasculo-ductal connective tissue. AB - INTRODUCTION: In tissues and organs exposed to large pressure amplitude low frequency noise fibrosis occurs in the absence of inflammatory signs, which is thought to be a protective response. In the parotid gland the perivasculo-ductal connective tissue surrounds arteries, veins and the ductal tree. Perivasculo ductal connective tissue is believed to function as a mechanical stabilizer of the glandular tissue. MATERIAL AND METHODS: In order to quantify the proliferation of perivasculo-ductal connective tissue in large pressure amplitude low frequency noise-exposed rats we used sixty Wistar rats which were equally divided into 6 groups. One group kept in silence, and the remaining five exposed to continuous large pressure amplitude low frequency noise: g1-168h (1 week); g2 504h (3 weeks); g3-840h (5 weeks); g4-1512h (9 weeks); and g5-2184h (13 weeks). After exposure, parotid glands were removed and the perivasculo-ductal connective tissue area was measured in all groups. We applied ANOVA statistical analysis, using SPSS 13.0. RESULTS: The global trend is an increase in the average perivasculo-ductal connective tissue areas, that develops linearly and significantly with large pressure amplitude low frequency noise exposure time (p < 0.001). DISCUSSION: It has been suggested that the biological response to large pressure amplitude low frequency noise exposure is associated with the need to maintain structural integrity. The structural reinforcement would be achieved by increased perivasculo-ductal connective tissue. CONCLUSIONS: Hence, these results show that in response to large pressure amplitude low frequency noise exposure, rat parotid glands increase their perivasculo-ductal connective tissue. PMID- 23815839 TI - Brachial plexus morphology and vascular supply in the wistar rat. AB - INTRODUCTION: The rat is probably the animal species most widely used in experimental studies on nerve repair. The aim of this work was to contribute to a better understanding of the morphology and blood supply of the rat brachial plexus. MATERIAL AND METHODS: Thirty adult rats were studied regarding brachial plexus morphology and blood supply. Intravascular injection and dissection under an operating microscope, as well as light microscopy and scanning electron microscopy techniques were used to define the microanatomy of the rat brachial plexus and its vessels. RESULTS: The rat brachial plexus was slightly different from the human brachial plexus. The arterial and venous supply to the brachial plexus plexus was derived directly or indirectly from neighboring vessels. These vessels formed dense and interconnected plexuses in the epineurium, perineurium, and endoneurium. Several brachial plexus components were accompanied for a relatively long portion of their length by large and constant blood vessels that supplied their epineural plexus, making it possible to raise these nerves as flaps. DISCUSSION: The blood supply to the rat brachial plexus is not very different from that reported in humans, making the rat a useful animal model for the experimental study of peripheral nerve pathophysiology and treatment. CONCLUSION: Our results support the homology between the rat and the human brachial plexus in terms of morphology and blood supply. This work suggests that several components of the rat brachial plexus can be used as nerve flaps, including predominantly motor, sensory or mixed nerve fibers. This information may facilitate new experimental procedures in this animal model. PMID- 23815840 TI - [Teaching human anatomy to the graduation course in Health Sciences of the Lisbon University: five years of a new educational experience]. AB - INTRODUCTION/OBJECTIVES: The authors make the balance of the first five years of teaching Anatomy to the Licensure in Health Sciences, of Lisbon University. MATERIALS AND METHODS: Were studied 408 students, enrolled in the Curricular Unit of Anatomy (mandatory subject of the 1st semester) and 29 in the Curricular Unit of Neuroanatomy (optional subject of the 6th semester). It was performed the statistical analysis by Anova and t Student test. RESULTS AND DISCUSSION: There was an annual growing influx of students enrolled in Curricular Unit of Anatomy, a stable number in Neuroanatomy and clear predominance of female students; ratio teacher / student variable between 1/9 and 1/17 in Anatomy and 1/8 in Neuroanatomy; high number of initial dropouts (15.69%) in Anatomy; approval levels of 95.93% in Anatomy and Neuroanatomy 100%; trend of improvement in the last two years, with statistical significance in the Curricular Unit of Anatomy (p = 0.0001) and equal academic performance of students of both genders; satisfaction scores of students of Anatomy, Good = 71% and Very Good = 8%; in Neuroanatomy, unanimous classification by students = Very Good. CONCLUSIONS: It was a very positive learning experience. The authors propose: the study of the causes and prevention of early dropout of incoming students, improving the ratio teacher / student, possible extension to a 2nd semester of the Curricular Unit of Anatomy and improving facilities that are already underway and includes the refurbishment and modernization of the anatomical theater of the Institute of Anatomy, Faculty of Medicine, University of Lisbon. PMID- 23815841 TI - [Physical activity and respiratory function: corporal composition and spirometric values analysis]. AB - OBJECTIVE: The main aim of this research project was to measure the effects of physical activity on corporal composition (BMI and waist circumference) on spirometric values and relate these indicators to the respiratory/ventilator function. MATERIAL AND METHODS: The sample consisted of 86 individuals, higher education students, with an average age of 21.3 +/- 2.4 years, who were divided into two groups: the control group consisted of 28 sedentary subjects (20.9 +/- 1.3 years), and the experimental group consisting of 58 subjects (21.5 +/- 2.8 years) who undertook supervised exercise. To characterize the sample of the type of physical activity, we used an adaptation of the questionnaire Telama et al.19 We assessed the value of spirometry (PEF, FVC and FEV1) with a Microquark Cosmed spirometer and the BMI and waist circumference. The figures obtained were processed with the S.P.S.S. 19.0, the t-test, the Levene test, the Mann-Whitney test and the Spearman correlation test, adopting a significance level of 5%. RESULTS: The experimental group achieved significantly better BMI and waist circumference results (p = 0.05) and in all of the values assessed by spirometry (PEF, FVC and FEV1) compared to the control group. We also found that there is a tendency for a negative correlation between the values of body composition and spirometric values, only observable in some variables (PEF, FEV1), i.e., the higher the values of body composition, the lower the spirometric values. CONCLUSION: The students that performed supervised exercise had higher levels of body composition and lung function. Poor BMI and waist circumference values may lead to respiratory dysfunction in terms of ventilation and the respective lung volumes, limiting the practice of physical activity and increasing the probability of respiratory pathologies. PMID- 23815842 TI - [Patients' access to their medical records]. AB - Until recently, the medical record was seen exclusively as being the property of health institutions and doctors. Its great technical and scientific components, as well as the personal characteristics attributed by each doctor, have been the reasons appointed for that control. However, nowadays throughout the world that paradigm has been changing. In Portugal, since 2007 patients are allowed full and direct access to their medical records. Nevertheless, the Deontological Code of the Portuguese Medical Association (2009) explicitly states that patients' access to their medical records should have a doctor as intermediary and that the records are each physician's intellectual property. Furthermore, several doctors and health institutions, receiving requests from patients to access their medical records, end up requesting the legal opinion of the Commission for access to administrative documents. Each and every time, that opinion goes in line with the notion of full and direct patient access. Sharing medical records with patients seems crucial and inevitable in the current patient-centred care model, having the potential to improve patient empowerment, health literacy, autonomy, self efficacy and satisfaction with care. With the recent technological developments and the fast dissemination of Personal Health Records, it is foreseeable that a growing number of patients will want to access their medical records. Therefore, promoting awareness on this topic is essential, in order to allow an informed debate between all the stakeholders. PMID- 23815843 TI - [Giant cysts of seminal vesicles]. AB - We report a clinical case of a 60 year-old man, asymptomatic to whom was incidentally found two retrovesical cysts. Physical examination revealed hypogastric, elastic and painless masses; digital rectal examination documented a normal prostate gland. Computerized tomography confirmed the presence of two giant seminal vesicle cysts. PMID- 23815844 TI - [AICA anatomic variation as a factor of worse prognosis for the surgical treatment of hemi-facial spasm]. AB - Hemifacial spasm is a neurovascular compression syndrome. These consist in a contacting vessel (most often an artery) to a cranial nerve in cerebelar-pontine angle. The most common is trigeminal neuralgia caused by contact between the superior cerebellar artery and the trigeminal nerve, and less commonly hemifacial spasm, vertiginous syndrome by contact of the antero inferior cerebelar artery with the eighth cranial nerve, glossopharyngeal neuralgia by contact of the postero inferior cerebelar artery and the IX cranial nerve, etc. These syndromes typically occur after the fifth decade of life, when the arterial tortuosity increases due to the arteriosclerosis process. They are however associated anatomical variations of the origin and course of the arteries, which facilitate contact with the nerves of the cerebellar-pontine angle. In hemifacial spasm, the vessel most often related is antero inferior cerebelar and the authors describe a case of a rare anatomical variant in the course of the artery that motivated the development of the disease, which was identified intraoperatively on a surgical approach to the cerebellar-pontine for vascular microdescompression. PMID- 23815845 TI - [The anatomical variations of the extensor muscles of the hand fingers]. AB - INTRODUCTION: The extensor tendons of fingers are subject of many variations, some of them quite frequent. MATERIAL AND METHODS: The dissection of the posterior region of forearm and hand was carried out, and the anatomical variations were documented. RESULTS: In Case 1 the extensor digitorum divided into 5 tendons: one for the index finger, one for the middle finger, two for the ring finger and one for the little finger; the extensor indicis proprius divided into two tendons: one for the index and one for the middle finger. In Case 2 the extensor digitorum divided into 4 tendons: one tendon joined the extensor pollicis longus, one tendon for the index, one for the middle finger and one for the ring finger with one slip to the little finger; the extensor indicis proprius divided into two tendons, one for the index and one for the middle finger; the extensor digiti minimi divided into two slips for the little finger. DISCUSSION/CONCLUSIONS: The existence of a double tendon from extensor digitorum for the ring finger is described in several studies. The tendinous slip from extensor digitorum to extensor pollicis longus is not a frequent finding. The double tendon from extensor digiti minimi may occur in 60 to 90% of cases. The knowledge of the most common variations of the tendons of extensor muscles is very important in surgical practice. PMID- 23815846 TI - An unusual variety of the extensor digiti muscles: report with notes on repetition strain injuries. AB - In over 500 human cadaveric dissections of arms and forearms, performed to the present date, we find frequent anatomical variations, corresponding to classic descriptions. Last year, we found a singular anatomic variation of the extensor muscles of the forearm, which seems previously undescribed. It is our strong belief that gross anatomy studies, and gross dissection should be updated and reintroduced in modern anatomical studies, for teaching, research, or surgical training purposes. We detected a peculiar anatomical variant of the Superficial Extensor Digiti Muscles in the forearm of a human 73 year old male Caucasian cadaver. We clearly identified a thick bundle of muscular fibres, connecting the main muscular shafts of the Extensor Digiti Minimi, and the Extensor Digitorum Communis Muscles, in a perfectly defined muscular expansion, bridging obliquely downwards and outwards, between the two main muscular shafts. In our series, this is the first occurrence of such anatomical disposition. Anatomical variations of the extensor tendons to the fingers are frequently detected in the wrist, hand and fingers compartments. The careful analysis of the variants of muscular shafts in the forearm compartment, as commonly reported in the earliest anatomical descriptions will bring renewed light to the functional assessment of the extensor mechanism of the human fingers. In this sense, we reviewed the oldest anatomical descriptions, from the 16th century to the present date. PMID- 23815847 TI - [Rare anatomical variation of absence of the sciatic nerve: completely substituted by the tibial and common fibular nerve]. AB - INTRODUCTION: There are several reports of sciatic nerve anatomical variations. Some are associated with clinical entities, such as piriformis syndrome. We aim to report a rare anatomical variation of this nerve. CASES REPORT: Two leucodermic, 74 and 78-year-old male subjects, deceased of natural causes, without lower limb relevant medical history. In both subjects, the right sciatic nerve was absent, with an independent origin and course of the tibial and common fibular nerves. The contralateral sciatic nerve had the common anatomical presentation. DISCUSSION: After the analysis of the available data indexed in Medline, we conclude that we are reporting two cases of a rare anatomical variation (the absence of sciatic nerve, with an independent origin and course of the tibial and common fibular nerve). This anatomical variation may have clinical importance, as it may be, for example, a risk factor to unsuccessful sciatic nerve popliteal blocks and to the pyriformis syndrome. PMID- 23815848 TI - [Norwegian scabies]. PMID- 23815849 TI - Plombage therapy. PMID- 23815850 TI - [The relic in the Panels of Sao Vicente de Fora]. AB - The Panels of Sao Vicente de Fora, a polyptych dated from 1470 to 1480, are a work composed of 6 panels, authored by Nuno Goncalves, a painter of King Afonso V. This work reveals one of the most remarkable collective portraits of European painting, making this polyptych an inexhaustible source of readings and interpretations, fueling a secular controversy. The present work aims analyzing precise an iconographic anatomical image repainted in the 6th panel, or the panel of the Relic. This consists of a central image within a structure shown by a red figure with special reverence. The investigation conducted and justification was based on direct observation and comparative analysis of iconographic data collected in the Museum of Antique Art. The bone pieces were selected at the Museum of Anatomy, Department of Anatomy, Faculty of Medical Sciences, New University of Lisbon, and the comparative analyses performed by two observers, with further analysis of the images obtained in the National Museum of Ancient Art using specific software. After watching these, it was concluded that this representation of a relic in the Panels of Sao Vicente is an iconic representation of an Occipital bone, fractured at its lower edge, being evident, almost complete, its vertical portion or scale. PMID- 23815851 TI - MicroRNAs networks in thyroid cancers: focus on miRNAs related to the fascin. AB - miRNAs are non coding ribonucleic acids which are protected with respect to evolution, and have a length of 18-25 nucleotides. microRNAs control the gene expression after transcription, through mRNA destruction or translation processing, and therefore participate in arrangement of the physiologic and pathologic cellular processes; They also may act as oncogene or tumor suppressors. Altered expression of a number of microRNAs is reported in process of progression and metastasis of thyroid cancers. Therefore, identification of these microRNAs may shed a light to oncogenesis pathway of thyroid cancers and their metastasis. In addition, microRNAs might apply as potential biological markers in diagnosis and treatment of thyroid cancers. The changes made in miRNAs profile of thyroid cancers are reviewed in this paper. PMID- 23815852 TI - Modified Gadonanotubes as a promising novel MRI contrasting agent. AB - BACKGROUND AND PURPOSE OF THE STUDY: Carbon nanotubes (CNTs) are emerging drug and imaging carrier systems which show significant versatility. One of the extraordinary characteristics of CNTs as Magnetic Resonance Imaging (MRI) contrasting agent is the extremely large proton relaxivities when loaded with gadolinium ion (Gdn3+) clusters. METHODS: In this study equated Gdn3+ clusters were loaded in the sidewall defects of oxidized multiwalled (MW) CNTs. The amount of loaded gadolinium ion into the MWCNTs was quantified by inductively coupled plasma (ICP) method. To improve water solubility and biocompatibility of the system, the complexes were functionalized using diamine-terminated oligomeric poly (ethylene glycol) via a thermal reaction method. RESULTS: Gdn3+ loaded PEGylated oxidized CNTs (Gdn3+@CNTs-PEG) is freely soluble in water and stable in phosphate buffer saline having particle size of about 200 nm. Transmission electron microscopy (TEM) images clearly showed formation of PEGylated CNTs. MRI analysis showed that the prepared solution represents 10% more signal intensity even in half concentration of Gd3+ in comparison with commerciality available contrasting agent Magnevist(r). In addition hydrophilic layer of PEG at the surface of CNTs could prepare stealth nanoparticles to escape RES. CONCLUSION: It was shown that Gdn3+@CNTs-PEG was capable to accumulate in tumors through enhanced permeability and retention effect. Moreover this system has a potential for early detection of diseases or tumors at the initial stages. PMID- 23815853 TI - Prevalence and factors associated with neck, shoulder and low back pains among medical students in a Malaysian Medical College. AB - BACKGROUND: The main purpose of the study was to assess the prevalence, body distributions and factors associated with musculoskeletal pain (MSP) among medical students in a private Malaysian medical college. METHOD: This cross sectional study was conducted among 232 medical students in a private medical college using an online questionnaire. The questionnaire was a modified Standardized Nordic Questionnaire focused on neck, shoulder and low back pain in the past week and the past year. RESULTS: Two hundred and thirty two medical students responded to the questionnaire out of 642. Mean age was 20.7 +/- 2.1 years. The majority were female (62.9%), Malay (80.6%) and in the preclinical years (72%). One hundred and six (45.7%) of all students had at least one site of MSP in the past week and 151 (65.1%) had at least one site of MSP in the past year. MSP in the past week was associated significantly with the academic year, (OR 2.0, 95% CI 1.15-3.67, P = 0.015), history of trauma (OR 2.6, 95% CI 1.2-5.3, P = 0.011), family history of MSP (OR 2.1, 95% CI 1.1-3.9, P = 0.023) and Body Mass Index (BMI) (P = 0.028). MSP in the past year was significantly associated with computer use (P = 0.027), daily hours of computer use (median +/- IQR (5.0 +/-3.0), history of trauma (OR 7.5, 95% CI 2.24-2.56, P < 0.01) and family history of MSP (OR 2.5, 95% CI 1.31-4.90, P = 0.006). On multivariate analysis, factors associated with MSP during the past week were a family history of MSP (p = 0.029) and BMI (p = 0.03). Factors associated with MSP during the past year were being in clinical years (p = 0.002, computer use (p = 0.038), and a history of trauma (p = 0.030). CONCLUSION: MSP among medical students was relatively high, thus, further clinical assessment is needed in depth study of ergonomics. The study results indicate that medical school authorities should take measures to prevent MSP due to factors related to medical school. Students should make aware of importance of weight reduction to reduce MSP. PMID- 23815854 TI - Analgesic effect of a mixed T-type channel inhibitor/CB2 receptor agonist. AB - BACKGROUND: Cannabinoid receptors and T-type calcium channels are potential targets for treating pain. Here we report on the design, synthesis and analgesic properties of a new mixed cannabinoid/T-type channel ligand, NMP-181. RESULTS: NMP-181 action on CB1 and CB2 receptors was characterized in radioligand binding and in vitro GTPgamma[35S] functional assays, and block of transiently expressed human Cav3.2 T-type channels by NMP-181 was analyzed by patch clamp. The analgesic effects and in vivo mechanism of action of NMP-181 delivered spinally or systemically were analyzed in formalin and CFA mouse models of pain. NMP-181 inhibited peak CaV3.2 currents with IC50 values in the low micromolar range and acted as a CB2 agonist. Inactivated state dependence further augmented the inhibitory action of NMP-181. NMP-181 produced a dose-dependent antinociceptive effect when administered either spinally or systemically in both phases of the formalin test. Both i.t. and i.p. treatment of mice with NMP-181 reversed the mechanical hyperalgesia induced by CFA injection. NMP-181 showed no antinocieptive effect in CaV3.2 null mice. The antinociceptive effect of intrathecally delivered NMP-181 in the formalin test was reversed by i.t. treatment of mice with AM-630 (CB2 antagonist). In contrast, the NMP-181-induced antinociception was not affected by treatment of mice with AM-281 (CB1 antagonist). CONCLUSIONS: Our work shows that both T-type channels as well as CB2 receptors play a role in the antinociceptive action of NMP-181, and also provides a novel avenue for suppressing chronic pain through novel mixed T type/cannabinoid receptor ligands. PMID- 23815855 TI - Perceived benefits and barriers to exercise for recently treated patients with multiple myeloma: a qualitative study. AB - BACKGROUND: Understanding the physical activity experiences of patients with multiple myeloma (MM) is essential to inform the development of evidence-based interventions and to quantify the benefits of physical activity. The aim of this study was to gain an in-depth understanding of the physical activity experiences and perceived benefits and barriers to physical activity for patients with MM. METHODS: This was a qualitative study that used a grounded theory approach. Semi structured interviews were conducted in Victoria, Australia by telephone from December 2011-February 2012 with patients who had been treated for MM within the preceding 2-12 months. Interviews were transcribed and analysed using the constant comparison coding method to reduce the data to themes. Gender differences and differences between treatment groups were explored. RESULTS: Twenty-four interviews were completed. The sample comprised 13 females (54%), with a mean age of 62 years (SD = 8.8). Sixteen (67%) participants had received an autologous stem cell transplant (ASCT). All participants currently engaged in a range of light to moderate intensity physical activity; walking and gardening were the most common activities. Recovery from the symptoms of MM and side effects of therapy, psychological benefits, social factors and enjoyment were important benefits of physical activity. Barriers to physical activity predominately related to the symptoms of MM and side effects of therapy, including pain, fatigue, and fear of infection. Low self- motivation was also a barrier. Women participated in a more diverse range of physical activities than men and there were gender differences in preferred type of physical activity. Women were more likely to report psychological and social benefits; whereas men reported physical activity as a way to keep busy and self-motivation was a barrier. Patients treated with an ASCT more often reported affective benefits of participation in physical activity and fatigue as a barrier. Patients treated with other therapies (e.g., chemotherapy, radiotherapy) were more likely to report pain as a barrier. CONCLUSIONS: Patients with MM experience debilitating effects of their condition and therapy, which influences their level and intensity of physical activity participation. Physical activity programs should be individualised; take into consideration gender differences and the impact of different types of therapy on physical activity; and focus on meeting the psychological, coping and recovery needs of patients. PMID- 23815856 TI - Probing the stability of the "naked" mucin-like domain of human alpha dystroglycan. AB - BACKGROUND: alpha-Dystroglycan (alpha-DG) is heavily glycosylated within its central mucin-like domain. The glycosylation shell of alpha-dystroglycan is known to largely influence its functional properties toward extracellular ligands. The structural features of this alpha-dystroglycan domain have been poorly studied so far. For the first time, we have attempted a recombinant expression approach in E. coli cells, in order to analyze by biochemical and biophysical techniques this important domain of the alpha-dystroglycan core protein. RESULTS: We expressed the recombinant mucin-like domain of human alpha-dystroglycan in E. coli cells, and purified it as a soluble peptide of 174 aa. A cleavage event, that progressively emerges under repeated cycles of freeze/thaw, occurs at the carboxy side of Arg461, liberating a 151 aa fragment as revealed by mass spectrometry analysis. The mucin-like peptide lacks any particular fold, as confirmed by its hydrodynamic properties and its fluorescence behavior under guanidine hydrochloride denaturation. Dynamic light scattering has been used to demonstrate that this mucin-like peptide is arranged in a conformation that is prone to aggregation at room temperature, with a melting temperature of ~40 degrees C, which indicates a pronounced instability. Such a conclusion has been corroborated by trypsin limited proteolysis, upon which the protein has been fully degraded in less than 60 min. CONCLUSIONS: Our analysis indirectly confirms the idea that the mucin-like domain of alpha-dystroglycan needs to be extensively glycosylated in order to reach a stable conformation. The absence/reduction of glycosylation by itself may greatly reduce the stability of the dystroglycan complex. Although an altered pattern of alpha-dystroglycan O-mannosylation, that is not significantly changing its overall glycosylation fraction, represents the primary molecular clue behind currently known dystroglycanopathies, it cannot be ruled out that still unidentified forms of alphaDG-related dystrophy might originate by a more substantial reduction of alpha-dystroglycan glycosylation and by its consequent destabilization. PMID- 23815857 TI - Crystal structure of the C-terminal globular domain of the third paralog of the Archaeoglobus fulgidus oligosaccharyltransferases. AB - BACKGROUND: Protein N-glycosylation occurs in the three domains of life. Oligosaccharyltransferase (OST) transfers an oligosaccharide chain to the asparagine residue in the N-glycosylation sequons. The catalytic subunits of the OST enzyme are STT3 in eukaryotes, AglB in archaea and PglB in eubacteria. The genome of a hyperthermophilic archaeon, Archaeoglobus fulgidus, encodes three paralogous AglB proteins. We previously solved the crystal structures of the C terminal globular domains of two paralogs, AglB-Short 1 and AglB-Short 2. RESULTS: We determined the crystal structure of the C-terminal globular domain of the third AglB paralog, AglB-Long, at 1.9 A resolutions. The crystallization of the fusion protein with maltose binding protein (MBP) afforded high quality protein crystals. Two MBP-AglB-L molecules formed a swapped dimer in the crystal. Since the fusion protein behaved as a monomer upon gel filtration, we reconstituted the monomer structure from the swapped dimer by exchanging the swapped segments. The C-terminal domain of A. fulgidus AglB-L includes a structural unit common to AglB-S1 and AglB-S2. This structural unit contains the evolutionally conserved WWDYG and DK motifs. The present structure revealed that A. fulgidus AglB-L contained a variant type of the DK motif with a short insertion, and confirmed that the second signature residue, Lys, of the DK motif participates in the formation of a pocket that binds to the serine and threonine residues at the +2 position of the N-glycosylation sequon. CONCLUSIONS: The structure of A. fulgidus AglB-L, together with the two previously solved structures of AglB-S1 and AglB-S2, provides a complete overview of the three AglB paralogs encoded in the A. fulgidus genome. All three AglBs contain a variant type of the DK motif. This finding supports a previously proposed rule: The STT3/AglB/PglB paralogs in one organism always contain the same type of Ser/Thr binding pocket. The present structure will be useful as a search model for molecular replacement in the structural determination of the full-length A. fulgidus AglB-L. PMID- 23815858 TI - An international database of radionuclide concentration ratios for wildlife: development and uses. AB - A key element of most systems for assessing the impact of radionuclides on the environment is a means to estimate the transfer of radionuclides to organisms. To facilitate this, an international wildlife transfer database has been developed to provide an online, searchable compilation of transfer parameters in the form of equilibrium-based whole-organism to media concentration ratios. This paper describes the derivation of the wildlife transfer database, the key data sources it contains and highlights the applications for the data. PMID- 23815859 TI - Neuroprotective effects of the SCR1-3 functional domain of CR1 on acute cerebral ischemia and reperfusion injury in rats. AB - OBJECTIVE: Complement receptor type 1 (CR1), one of the most potent inhibitors in complement activation, shows a protective effect on cerebral ischemia/reperfusion (CI/R) injury due to its ability to bind C3b and C4b and to inactivate C3/C5 convertases. So far, no study assessed the effect of the first three short consensus repeats (SCR1-3) with low molecular weight, one of the most active functional domains of CR1, binding C4b with a powerful decay-acceleration effect on classical and alternative C3/C5 convertases pathways. Therefore, we aim to assess this effect on CI/R injury in the present study. METHODS: Seventy-five adult male Sprague-Dawley rats were randomly divided into three groups: sham operation group (n = 15), CI/R group (n = 30), and CI/R group treated with CR1 SCR1-3 protein (n = 30). After middle cerebral artery occlusion (MCAO) for 1 hour and reperfusion for 24 hours, neurological motor deficits, cerebral infarct size, and biochemical parameters including myeloperoxidase (MPO), malondialdehyde (MDA), and superoxide dismutase (SOD) were assessed. Meanwhile, tissues in cerebral cortex were collected and processed for western blotting, immunohistochemistry, and HE staining. RESULTS: CR1-SCR1-3 could improve neurological functions in brain with a 26.8% decrease in neurological motor deficit score and could lead to a 63.8% reduction in cerebral infarct size. Besides, pretreatment using CR1-SCR1-3 could prevent neutrophil infiltration and alleviate inflammation severity and subsequent tissue damage. Decreased C4b expression and action, as well as improved morphological changes, were also observed in cerebral tissues of CI/R+CR1-SCR1-3 rats. CONCLUSION: CR1-SCR1-3 protein could possess a neuroprotective effect on acute CI/R injury. PMID- 23815860 TI - Identifying state-level policy and provision domains for physical education and physical activity in high school. AB - BACKGROUND: It is important to quickly and efficiently identify policies that are effective at changing behavior; therefore, we must be able to quantify and evaluate the effect of those policies and of changes to those policies. The purpose of this study was to develop state-level physical education (PE) and physical activity (PA) policy domain scores at the high-school level. Policy domain scores were developed with a focus on measuring policy change. METHODS: Exploratory factor analysis was used to group items from the state-level School Health Policies and Programs Study (SHPPS) into policy domains. Items that related to PA or PE at the High School level were identified from the 7 SHPPS health program surveys. Data from 2000 and 2006 were used in the factor analysis. RESULTS: From the 98 items identified, 17 policy domains were extracted. Average policy domain change scores were positive for 12 policy domains, with the largest increases for "Discouraging PA as Punishment", "Collaboration", and "Staff Development Opportunities". On average, states increased scores in 4.94 +/- 2.76 policy domains, decreased in 3.53 +/- 2.03, and had no change in 7.69 +/- 2.09 policy domains. Significant correlations were found between several policy domain scores. CONCLUSIONS: Quantifying policy change and its impact is integral to the policy making and revision process. Our results build on previous research offering a way to examine changes in state-level policies related to PE and PA of high-school students and the faculty and staff who serve them. This work provides methods for combining state-level policies relevant to PE or PA in youth for studies of their impact. PMID- 23815861 TI - Critical issue in the cardiovascular field: Hospitalization for heart failure. PMID- 23815862 TI - Changes in the burden of malaria following scale up of malaria control interventions in Mutasa District, Zimbabwe. AB - BACKGROUND: To better understand trends in the burden of malaria and their temporal relationship to control activities, a survey was conducted to assess reported cases of malaria and malaria control activities in Mutasa District, Zimbabwe. METHODS: Data on reported malaria cases were abstracted from available records at all three district hospitals, three rural hospitals and 25 rural health clinics in Mutasa District from 2003 to 2011. RESULTS: Malaria control interventions were scaled up through the support of the Roll Back Malaria Partnership, the Global Fund to Fight AIDS, Tuberculosis and Malaria, and The President's Malaria Initiative. The recommended first-line treatment regimen changed from chloroquine or a combination of chloroquine plus sulphadoxine/pyrimethamine to artemisinin-based combination therapy, the latter adopted by 70%, 95% and 100% of health clinics by 2008, 2009 and 2010, respectively. Diagnostic capacity improved, with rapid diagnostic tests (RDTs) available in all health clinics by 2008. Vector control consisted of indoor residual spraying and distribution of long-lasting insecticidal nets. The number of reported malaria cases initially increased from levels in 2003 to a peak in 2008 but then declined 39% from 2008 to 2010. The proportion of suspected cases of malaria in older children and adults remained high, ranging from 75% to 80%. From 2008 to 2010, the number of RDT positive cases of malaria decreased 35% but the decrease was greater for children younger than five years of age (60%) compared to older children and adults (26%). CONCLUSIONS: The burden of malaria in Mutasa District decreased following the scale up of malaria control interventions. However, the persistent high number of cases in older children and adults highlights the need for strategies to identify locally effective control measures that target all age groups. PMID- 23815864 TI - Metabolic profile of serum and follicular fluid from postpartum dairy cows during summer and winter. AB - This study was designed to monitor the biochemical profiles of serum and follicular fluid (FF) of postpartum dairy cows during the summer (n=30) and winter (n=30). Blood and FF (follicles >= 9 mm) were obtained from Girolando cows at 30, 45, 60, 75 and 90 days postpartum. The samples were collected and analysed to determine glucose, total cholesterol (TC), triglyceride (TG), urea, sodium (Na), potassium (K) and calcium (Ca) levels. Throughout the study, the following clinical variables were measured: rectal temperature (RT), respiratory rate (RR) and body condition score (BCS). In addition, the temperature humidity index (THI) was calculated for each season. During the summer season, THI was higher, BCS decreased, there was an increase in RT, and glucose, urea, Na and K serum levels were decreased (P<0.05). The levels of TC, TG, urea, K and Ca in follicular fluid increased (P<0.05). Positive correlations (P<0.05) were observed between the serum and FF levels for glucose (r=0.29), TC (r=0.24) and Ca (r=0.30). Therefore, the biochemical profile of serum and FF of dairy cows under summer heat-stress conditions demonstrates marked changes that may impair fertility during lactation. PMID- 23815863 TI - Essential genes in thyroid cancers: focus on fascin. AB - Although thyroid cancers are not among common malignancies, they rank as the first prevalent endocrine cancers in human. According to the results of published studies it has been shown the gradual progress from normal to the neoplastic cell in the process of tumor formation is the result of sequential genetic events. Among them we may point the mutations and rearrangements occurred in a group of proto-oncogenes, transcription factors and metastasis elements such as P53, RAS,RET,BRAF, PPARgamma and Fascin. In the present article,we reviewed the most important essential genes in thyroid cancers, the role of epithelial mesenchymal transition and Fascin has been highlighted in this paper. PMID- 23815865 TI - Infectious conjunctivitis caused by Pseudomonas aeruginosa isolated from a bathroom. AB - BACKGROUND: The elucidation of the routes of transmission of a pathogen is crucial for the prevention of infectious diseases caused by bacteria that are not a resident in human tissue. The purpose of this report is to describe a case of suture-related conjunctivitis caused by Pseudomonas aeruginosa for which we identified the transmission route using pulsed-field gel electrophoresis (PFGE). CASE PRESENTATION: A 38-year-old man, who had undergone surgery for glaucoma 2 years ago previously, presented with redness, discomfort, and mucopurulent discharge in the right eye. A 9-0 silk suture had been left on the conjunctiva. A strain of P. aeruginosa was isolated from a culture obtained from the suture, and the patient was therefore diagnosed with suture-related conjunctivitis caused by P. aeruginosa. The conjunctivitis was cured by the application of an antimicrobial ophthalmic solution and removal of the suture. We used PFGE to survey of the indoor and outdoor environments around the patient's house and office in order to elucidate the route of transmission of the infection. Three strains of P. aeruginosa were isolated from the patient's indoor environment, and the isolate obtained from the patient's bathroom was identical to that from the suture. CONCLUSION: The case highlights the fact that an indoor environmental strain of P. aeruginosa can cause ocular infections. PMID- 23815866 TI - Individual differences in non-symbolic numerical abilities predict mathematical achievements but contradict ATOM. AB - BACKGROUND: A significant debate surrounds the nature of the cognitive mechanisms involved in non-symbolic number estimation. Several studies have suggested the existence of the same cognitive system for estimation of time, space, and number, called "a theory of magnitude" (ATOM). In addition, researchers have proposed the theory that non-symbolic number abilities might support our mathematical skills. Despite the large number of studies carried out, no firm conclusions can be drawn on either topic. METHODS: In the present study, we correlated the performance of adults on non-symbolic magnitude estimations and symbolic numerical tasks. Non symbolic magnitude abilities were assessed by asking participants to estimate which auditory tone lasted longer (time), which line was longer (space), and which group of dots was more numerous (number). To assess symbolic numerical abilities, participants were required to perform mental calculations and mathematical reasoning. RESULTS: We found a positive correlation between non symbolic and symbolic numerical abilities. On the other hand, no correlation was found among non-symbolic estimations of time, space, and number. CONCLUSIONS: Our study supports the idea that mathematical abilities rely on rudimentary numerical skills that predate verbal language. By contrast, the lack of correlation among non-symbolic estimations of time, space, and number is incompatible with the idea that these magnitudes are entirely processed by the same cognitive system. PMID- 23815867 TI - Non-synonymous single-nucleotide variations of the human oxytocin receptor gene and autism spectrum disorders: a case-control study in a Japanese population and functional analysis. AB - BACKGROUND: The human oxytocin receptor (hOXTR) is implicated in the etiology of autism spectrum disorders (ASDs) and is a potential target for therapeutic intervention. Several studies have reported single-nucleotide polymorphisms (SNPs) of the OXTR gene associated with ASDs. These SNPs, however, reside outside the protein-coding region. Not much is known about genetic variations that cause amino acid substitutions that alter receptor functions. METHODS: Variations in the OXTR gene were analyzed in 132 ASD patients at Kanazawa University Hospital in Japan and 248 unrelated healthy Japanese volunteers by re-sequencing and real time polymerase chain reaction-based genotyping. Functional changes in variant OXTRs were assessed by radioligand binding assay and measurements of intracellular free calcium concentrations ([Ca2+]i) and inositol 1,4,5 trisphosphate (IP3) levels. RESULTS: Six subjects (4.5%) in the ASD group and two in the control group (0.8%) were identified as heterozygotes carrying the R376G variation (rs35062132; c.1126C>G); one individual from the ASD group (0.8%) and three members of the control group (1.2%) were found to be carrying R376C (c.1126C>T). The C/G genotype significantly correlated with an increased risk of ASDs (odds ratio (OR) = 5.83; 95% confidence interval (CI) = 1.16 to 29.33; P = 0.024, Fisher's exact test). Consistently, the G allele showed a correlation with an increased likelihood of ASDs (OR = 5.73; 95% CI = 1.15 to 28.61; P = 0.024, Fisher's exact test). The frequencies of the C/T genotype and the T allele in the ASD and control groups did not differ significantly. We also examined changes in agonist-induced cellular responses mediated by the variant receptors hOXTR-376G and hOXTR-376C. OXT-induced receptor internalization and recycling were faster in hOXTR-376G-expressing HEK-293 cells than in cells expressing hOXTR-376R or hOXTR 376C. In addition, the elevation in [Ca2+]i and IP3 formation decreased in the cells expressing hOXTR-376G and hOXTR-376C tagged with enhanced green fluorescent protein (EGFP), in comparison with the cells expressing the common-type hOXTR 376R tagged with EGFP. CONCLUSIONS: These results suggest that the rare genetic variation rs35062132 might contribute to the pathogenesis of ASDs, and could provide a molecular basis of individual differences in OXTR-mediated modulation of social behavior. PMID- 23815868 TI - Anti-angiogenic effect of the total flavonoids in Scutellaria barbata D. Don. AB - BACKGROUND: Angiogenesis is closely related to the growth, invasion and metastasis of tumors, also considered as the key target of anticancer therapy. Scutellaria barbata D. Don (S. barbata), a traditional Chinese medicine, is being used to treat various diseases, including cancer. However, the antitumor molecular mechanism of S. barbata was still unclear. This study aimed to investigate the inhibitory effects of the total flavones in S. barbata (TF-SB) on angiogenesis. METHODS: Human umbilical vein endothelial cells (HUVECs) were treated with various concentrations of TF-SB. Cell viability was examined using the MTT assay. The scratch assay was used to detect the migration of HUVECs after treatment with TF-SB. The ability of HUVECs to form network structures in vitro was demonstrated using the tube formation assay. The chick embryo chorioallantoic membrane assay was performed to detect the in vivo anti-angiogenic effect. The expression of VEGF was measured by the enzyme-linked immunosorbent. RESULTS: Results showed that TF-SB inhibited the proliferation and migration of HUVECs in a dose- dependent manner. Simultaneously, TF-SB significantly suppressed HUVEC angiogenesis in vitro and in vivo. Furthermore, VEGF was downregulated in both HUVECs and MHCC97-H cells after TF-SB treatment. CONCLUSION: TF-SB could suppress the process of angiogenesis in vitro and in vivo. TF-SB potentially suppresses angiogenesis in HUVECs by regulating VEGF. These findings suggested that TF-SB may serve as a potent anti-angiogenic agent. PMID- 23815869 TI - Anti-lymphangiogenic properties of mTOR inhibitors in head and neck squamous cell carcinoma experimental models. AB - BACKGROUND: Tumor dissemination to cervical lymph nodes via lymphatics represents the first step in the metastasis of head and neck squamous cell carcinoma (HNSCC) and is the most significant predictor of tumor recurrence decreasing survival by 50%. The lymphatic suppressing properties of mTOR inhibitors are not yet well understood. METHODS: Lymphatic inhibiting effects of rapamycin were evaluated in vitro using two lymphatic endothelial cell (LEC) lines. An orthotopic mouse model of HNSCC (OSC-19 cells) was used to evaluate anti-lymphangiogenic effects of rapamycin in vivo. The incidence of cervical lymph node metastases, numbers of tumor-free lymphatic vessels and those invaded by tumor cells in mouse lingual tissue, and expression of pro-lymphangiogenic markers were assessed. RESULTS: Rapamycin significantly decreased lymphatic vascular density (p = 0.027), reduced the fraction of lymphatic vessels invaded by tumor cells in tongue tissue (p = 0.013) and decreased metastasis-positive lymph nodes (p = 0.04). Rapamycin also significantly attenuated the extent of metastatic tumor cell spread within lymph nodes (p < 0.0001). We found that rapamycin significantly reduced LEC proliferation and was correlated with decreased VEGFR-3 expression in both LEC, and in some HNSCC cell lines. CONCLUSIONS: The results of this study demonstrate anti-lymphangiogenic properties of mTOR inhibitors in HNSCC. mTOR inhibitors suppress autocrine and paracrine growth stimulation of tumor and lymphatic endothelial cells by impairing VEGF-C/VEGFR-3 axis and release of soluble VEGFR 2. In a murine HNSCC orthotopic model rapamycin significantly suppressed lymphovascular invasion, decreased cervical lymph node metastasis and delayed the spread of metastatic tumor cells within the lymph nodes. PMID- 23815870 TI - Vitamin D deficiency and its supplementation in patients with amyotrophic lateral sclerosis. AB - We studied 25-hydroxyvitamin D (vitamin D) levels in patients with amyotrophic lateral sclerosis (ALS) and the effect of vitamin D supplementation. Vitamin D levels were checked in 37 consecutive patients with ALS. Demographic data, vitamin D supplementation, change in Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score, and side effects from vitamin D were noted over a 9 month follow-up period. ALSFRS-R scores were compared between patients who took vitamin D and those who did not. The median age was 55 years and median time since symptom onset was 61 months. The mean vitamin D level was 22.3 ng/mL (normal range, 30-80 ng/mL). Eighty-one percent of patients had a vitamin D level lower than 30 ng/mL and 43% had a vitamin D level lower than 20 ng/mL. Twenty patients took 2000 international units of vitamin D daily. After adjustment for age and baseline vitamin D levels in a linear regression model, the ALSFRS-R score decline was smaller in patients taking vitamin D at 9 months (p=0.02) but was not significantly different at 3 or 6 months. Median vitamin D levels rose from 18.5 to 31.0 ng/mL at 6 months in the group taking vitamin D. No side effects secondary to vitamin D supplementation were reported. Vitamin D supplementation at 2000 international units daily was safe over a period of 9 months and may have a beneficial effect on ALSFRS-R scores. Further studies are warranted to determine whether there is a benefit in vitamin D supplementation for all ALS patients. PMID- 23815871 TI - Epidemiology of complementary and alternative medicine use in patients with Parkinson's disease. AB - Parkinson's disease (PD) is a common and debilitating neurodegenerative disorder without a known neuroprotective cure. Currently, an increasing number of patients with PD resort to complementary and alternative medicine (CAM). This study aimed to determine the epidemiology of CAM use for PD worldwide. Methodological issues included the definition of CAM, running a search strategy using five databases, and citation tracking. Six studies estimated the prevalence of CAM use for PD to be between 25.7% and 76%. The response rates in these surveys varied from 81% to 100%. Frequently utilized forms of therapy were acupuncture, massage, herbs, and vitamins/health supplements, and these therapies were mainly used to improve the associated motor symptoms of PD. However, only 11% to 20% of these patients were referred to use CAM by a healthcare professional. Of the sociodemographic and disease-specific factors, CAM use was correlated with female sex, age, age at onset of PD, longer duration of PD, degree of education, higher income, rural location, comorbidity for indications, levodopa load, and severe motor symptoms. These results suggested that CAM use is widespread among patients with PD worldwide, but the largely unexamined use of CAM requires more attention. Moreover, there is a lack of communication between physicians and patients, increasing the risks associated with CAM use and the potential for adverse events. PMID- 23815872 TI - Correlates of walking and cycling for transport and recreation: factor structure, reliability and behavioural associations of the perceptions of the environment in the neighbourhood scale (PENS). AB - BACKGROUND: Emerging evidence suggests that walking and cycling for different purposes such as transport or recreation may be associated with different attributes of the physical environment. Few studies to date have examined these behaviour-specific associations, particularly in the UK. This paper reports on the development, factor structure and test-retest reliability of a new scale assessing perceptions of the environment in the neighbourhood (PENS) and the associations between perceptions of the environment and walking and cycling for transport and recreation. METHODS: A new 13-item scale was developed for assessing adults' perceptions of the environment in the neighbourhood (PENS). Three sets of analyses were conducted using data from two sources. Exploratory and confirmatory factor analyses were used to identify a set of summary environmental variables using data from the iConnect baseline survey (n = 3494); test-retest reliability of the individual and summary environmental items was established using data collected in a separate reliability study (n = 166); and multivariable logistic regression was used to determine the associations of the environmental variables with walking for transport, walking for recreation, cycling for transport and cycling for recreation, using iConnect baseline survey data (n = 2937). RESULTS: Four summary environmental variables (traffic safety, supportive infrastructure, availability of local amenities and social order), one individual environmental item (street connectivity) and a variable encapsulating general environment quality were identified for use in further analyses. Intraclass correlations of these environmental variables ranged from 0.44 to 0.77 and were comparable to those seen in other similar scales. After adjustment for demographic and other environmental factors, walking for transport was associated with supportive infrastructure, availability of local amenities and general environment quality; walking for recreation was associated with supportive infrastructure; and cycling for transport was associated only with street connectivity. There was limited evidence of any associations between environmental attributes and cycling for recreation. CONCLUSION: PENS is acceptable as a short instrument for assessing perceptions of the urban environment. Previous findings that different attributes of the environment may be associated with different behaviours are confirmed. Policy action to create supportive environments may require a combination of environmental improvements to promote walking and cycling for different purposes. PMID- 23815873 TI - Time spent on health related activity by older Australians with diabetes. AB - AIMS: There is little information available about what people do to look after their health, or how long people spend on health activities. This study identifies key health related activities and time taken as part of self management by people with diabetes. Management planning often lacks information that this study provides that would help clinicians and patients to create manageable and do-able plans that patients can follow. METHODS: Data were collected in 2010 using a national survey of people aged 50 years the National Diabetes Services Scheme. Respondents provided recall data on time used for personal health care, non-clinical health activity; and health service interactions. Data were analysed using Stata 12 and SPSS 19. RESULTS: While most people with diabetes spend on average less than 30 minutes a day on health related activities (excluding exercise), the highest decile of respondents averaged over 100 minutes. Time spent increased with the number of co-existent conditions. Taking medication and sitting in waiting rooms were the most frequently reported activities. The greatest amount of time was spent on daily personal health care activities. CONCLUSION: The time demands of diabetes for older people can be substantial. Better patient engagement in self management might result from a better match in care planning between the illness demands and the patient time availability, with potential to reduce admissions for hospital care. PMID- 23815875 TI - Anthropometric characteristics of four Polish children with mucopolysaccharidosis. AB - BACKGROUND: Mucopolysaccharidosis relates to a group of seven prevalent types of disorders that are categorized on the basis of specific enzyme deficiency or the major symptoms, or both. A typical clinical presentation includes such symptoms and characteristics as short stature, facial dysmorphism, skeletal deformities, pulmonary dysfunction, joint stiffness and contractures, myocardial hypertrophy, neurological symptoms, and mental retardation. CASE PRESENTATION: The purpose of this study was to perform a detailed anthropometric assessment in four cases of children with mucopolysaccharidosis (MPS) I and II types aged from 4 to 13 years from the Podkarpacie Province (south-eastern Poland). Anthropometric assessment included several parameters and indices related to body structure. All examined patients are characterized by severely disordered physical growth in comparison with the Polish norms presented in the reference charts. CONCLUSIONS: Examined children with MPS are characterized by especially low values relating to longitudinal and transversal parameters of body build. Anthropometric data could be used in early diagnosis of MPS and assessment of results of its treatment. PMID- 23815874 TI - Consumption habits of pregnant women and implications for developmental biology: a survey of predominantly Hispanic women in California. AB - BACKGROUND: Healthy post-pregnancy outcomes are contingent upon an informed regimen of prenatal care encouraging healthy maternal consumption habits. In this article, we describe aspects of maternal intake of food, drink, and medication in a population of predominantly Hispanic women in Southern California. Potential implications for unhealthy prenatal dietary choices are discussed. METHODS: The Food, Beverage, and Medication Intake Questionnaire (FBMIQ) measures common practices of maternal consumption during pregnancy. The FBMIQ was administered to English and Spanish speaking pregnant and recently pregnant (36 weeks pregnant - 8 weeks post-partum) women over the age of 18 who were receiving care from a private medical group in Downey CA. RESULTS: A total of 200 women completed the FBMIQ. Consumption habits of healthy foods and beverages, unhealthy foods, unhealthy beverages, and medication are characterized in this article. Data indicate widespread consumption of fresh fruit, meats, milk and juice and indicate most women used prenatal vitamin supplements. Studies in developmental neuroscience have shown that certain substances may cause teratogenic effects on the fetus when ingested by the mother during pregnancy. Those potentially harmful substances included in our study were Bisphenol-A (BPA), methylmercury, caffeine, alcohol and certain medications. Our results show that a proportion of the women surveyed in our study consumed BPA, methylmercury, caffeine, alcohol, and certain medications at varied levels during pregnancy. This represents an interesting finding and suggests a disconnect between scientific data and general recommendations provided to pregnant mothers by obstetricians. CONCLUSIONS: The results of our study demonstrate that a proportion of pregnant women consume substances that are potentially teratogenic and may impact the health and well being of the offspring. It is important to appraise healthy and unhealthy consumption habits in order to encourage healthy practices and alleviate future effects of preventable, toxin-induced developmental issues. Prenatal advising should discourage the consumption of dangerous foods, beverages, and medications that women commonly report eating during pregnancy. PMID- 23815876 TI - Increased gene expression of FOXP1 in patients with autism spectrum disorders. AB - BACKGROUND: Comparative gene expression profiling analysis is useful in discovering differentially expressed genes associated with various diseases, including mental disorders. Autism spectrum disorders (ASD) are a group of complex childhood-onset neurodevelopmental and genetic disorders characterized by deficits in language development and verbal communication, impaired reciprocal social interaction, and the presence of repetitive behaviors or restricted interests. The study aimed to identify novel genes associated with the pathogenesis of ASD. METHODS: We conducted comparative total gene expression profiling analysis of lymphoblastoid cell lines (LCL) between 16 male patients with ASD and 16 male control subjects to screen differentially expressed genes associated with ASD. We verified one of the differentially expressed genes, FOXP1, using real-time quantitative PCR (RT-qPCR) in a sample of 83 male patients and 83 male controls that included the initial 16 male patients and male controls, respectively. RESULTS: A total of 252 differentially expressed probe sets representing 202 genes were detected between the two groups, including 89 up and 113 downregulated genes in the ASD group. RT-qPCR verified significant elevation of the FOXP1 gene transcript of LCL in a sample of 83 male patients (10.46 +/- 11.34) compared with 83 male controls (5.17 +/- 8.20, P = 0.001). CONCLUSIONS: Comparative gene expression profiling analysis of LCL is useful in discovering novel genetic markers associated with ASD. Elevated gene expression of FOXP1 might contribute to the pathogenesis of ASD. CLINICAL TRIAL REGISTRATION: Identifier: NCT00494754. PMID- 23815877 TI - Comparative effects of adding beta-mercaptoethanol or L-ascorbic acid to culture or vitrification-warming media on IVF porcine embryos. AB - The aims of the present study were to; (1) determine the effects of supplementation with two antioxidants during in vitro culture (IVC) on embryo development and quality; and (2) test the effects of adding the antioxidants to vitrification-warming media on the cryotolerance of in vitro-produced (IVP) porcine blastocysts. In Experiment 1, presumptive zygotes were cultured without antioxidants, with 50 uM beta-mercaptoethanol (beta-ME) or with 100 uM L-ascorbic acid (AC). After culture, blastocyst yield, quality and cryotolerance were evaluated in each treatment group. In Experiment 2, survival rates (3 and 24 h), total cell number, apoptosis index and the formation of reactive oxygen species (ROS) in blastocysts vitrified-warmed with 100 uM AC or 50 uM beta-ME or without antioxidants added to the vitrification medium were compared. Antioxidant addition during IVC had no effect on embryo development, total cell number or the apoptosis index, and culturing embryos in the presence of beta-ME had no effects on cryotolerance. In contrast, ROS levels and survival rates after vitrification warming were significantly improved in embryos cultured with AC. Furthermore, addition of AC into vitrification-warming media enhanced embryo survival and embryo quality after warming. In conclusion, our results suggest that supplementing culture or vitrification media with 100 uM AC improves the quality and cryosurvival of IVP porcine blastocysts. PMID- 23815878 TI - Lessons learnt during a complex, multicentre cluster randomised controlled trial: the ProAct65+ trial. AB - BACKGROUND: Failure to recruit to target or schedule is common in randomized controlled trials (RCTs). Innovative interventions are not always fully developed before being tested, and maintenance of fidelity to the intervention during trials can be problematic. Missing data can compromise analyses, and inaccurate capture of risks to participants can influence reporting of intervention harms and benefits.In this paper we describe how challenges of recruitment and retention of participants, standardisation and quality control of interventions and capture of adverse events were overcome in the ProAct65+ cluster RCT. This trial compared class-based and home-based exercise with usual care in people aged 65 years and over, recruited through general practice. The home-based exercise participants were supported by Peer Mentors. RESULTS: (1) Organisational factors, including room availability in general practices, slowed participant recruitment so the recruitment period was extended and the number invited to participate increased. (2) Telephone pre-screening was introduced to exclude potential participants who were already very active and those who were frequent fallers. (3) Recruitment of volunteer peer mentors was difficult and time consuming and their acceptable case load less than expected. Lowering the age limit for peer mentors and reducing their contact schedule with participants did not improve recruitment. (4) Fidelity to the group intervention was optimised by introducing quality assurance observation of classes by experienced exercise instructors. (5) Diaries were used to capture data on falls, service use and other exercise related costs, but completion was variable so their frequency was reduced. (6) Classification of adverse events differed between research sites so all events were assessed by both sites and discrepancies discussed. CONCLUSIONS: Recruitment rates for trials in general practice may be limited by organisational factors and longer recruitment periods should be allowed for. Exercise studies may be attractive to those who least need them; additional screening measures can be employed to avoid assessment of ineligible participants. Enrolment of peer mentors for intervention support is challenging and needs to be separately tested for feasibility. Standardisation of exercise interventions is problematic when exercise programmes are tailored to participants' capabilities; quality assurance observations may assure fidelity of the intervention. Data collection by diaries can be burdensome to participants, resulting in variable and incomplete data capture; compromises in completion frequency may reduce missing data. Risk assessments are essential in exercise promotion studies, but categorisation of risks can vary between assessors; methods for their standardisation can be developed. TRIAL REGISTRATION: ISRCTN43453770. PMID- 23815879 TI - Antimicrobial activity and rutin identification of honey produced by the stingless bee Melipona compressipes manaosensis and commercial honey. AB - BACKGROUND: Honey has been identified as a potential alternative to the widespread use of antibiotics, which are of significant concern considering the emergence of resistant bacteria. In this context, this study aimed to evaluate the antimicrobial activity of honey samples produced by a stingless bee species and by Apis sp. against pathogenic bacteria, as well as to identify the presence of phenolic compounds. METHODS: Honey samples from the stingless bee M. compressipes manaosensis were collected twice, during the dry and rainy seasons. Three commercial honey samples from Apis sp. were also included in this study. Two different assays were performed to evaluate the antibacterial potential of the honey samples: agar-well diffusion and broth macrodilution. Liquid-liquid extraction was used to assess phenolic compounds from honey. HPLC analysis was performed in order to identify rutin and apigenin on honey samples. Chromatograms were recorded at 340 and 290 nm. RESULTS: Two honey samples were identified as having the highest antimicrobial activity using the agar diffusion method. Honey produced by Melipona compressipes manaosensis inhibited the growth of Staphylococcus aureus, Escherichia coli (0157: H7), Proteus vulgaris, Shigella sonnei and Klebsiella sp. A sample of honey produced by Apis sp. also inhibited the growth of Salmonella paratyphi. The macrodilution technique presented greater sensitivity for the antibacterial testing, since all honey samples showed activity. Flavonoid rutin was identified in the honey sample produced by the stingless bee. CONCLUSIONS: Honey samples tested in this work showed antibacterial activity against Gram-positive and Gram-negative bacteria. The results reported herein highlight the potential of using honey to control bacterial growth. PMID- 23815881 TI - New biogeographical and morphological information on Physaloptera ngoci Le-Van Hoa, 1961 (Nematoda: Physalopteridae) in South-east Asian rodents. AB - During a study of the helminth fauna of 1,643 rodents trapped along the Mekong River (Thailand, Lao People's Democratic Republic and Cambodia) in 2008-2011, the spirurid nematode Physaloptera ngoci Le-Van-Hoa, 1961 was recovered with an overall prevalence of 2.8%. Based on the original description, it was identified in nine of 23 different Murinae host species and is here reported for the first time from these three countries. A scanning electron microscopy study provides additional morphological data. PMID- 23815880 TI - A multi-site feasibility study for personalized medicine in canines with osteosarcoma. AB - BACKGROUND: A successful therapeutic strategy, specifically tailored to the molecular constitution of an individual and their disease, is an ambitious objective of modern medicine. In this report, we highlight a feasibility study in canine osteosarcoma focused on refining the infrastructure and processes required for prospective clinical trials using a series of gene expression-based Personalized Medicine (PMed) algorithms to predict suitable therapies within 5 days of sample receipt. METHODS: Tumor tissue samples were collected immediately following limb amputation and shipped overnight from veterinary practices. Upon receipt (day 1), RNA was extracted from snap-frozen tissue, with an adjacent H&E section for pathological diagnosis. Samples passing RNA and pathology QC were shipped to a CLIA-certified laboratory for genomic profiling. After mapping of canine probe sets to human genes and normalization against a (normal) reference set, gene level Z-scores were submitted to the PMed algorithms. The resulting PMed report was immediately forwarded to the veterinarians. Upon receipt and review of the PMed report, feedback from the practicing veterinarians was captured. RESULTS: 20 subjects were enrolled over a 5 month period. Tissue from 13 subjects passed both histological and RNA QC and were submitted for genomic analysis and subsequent PMed analysis and report generation. 11 of the 13 samples for which PMed reports were produced were communicated to the veterinarian within the target 5 business days. Of the 7 samples that failed QC, 4 were due to poor RNA quality, whereas 2 were failed following pathological review. Comments from the practicing veterinarians were generally positive and constructive, highlighting a number of areas for improvement, including enhanced education regarding PMed report interpretation, drug availability, affordable pricing and suitable canine dosing. CONCLUSIONS: This feasibility trial demonstrated that with the appropriate infrastructure and processes it is possible to perform an in depth molecular analysis of a patient's tumor in support of real time therapeutic decision making within 5 days of sample receipt. A number of areas for improvement have been identified that should reduce the level of sample attrition and support clinical decision making. PMID- 23815882 TI - Overexpression of peptide deformylase in breast, colon, and lung cancers. AB - BACKGROUND: Human mitochondrial peptide deformylase (PDF) has been proposed as a novel cancer therapeutic target. However, very little is known about its expression and regulation in human tissues. The purpose of this study was to characterize the expression pattern of PDF in cancerous tissues and to identify mechanisms that regulate its expression. METHODS: The mRNA expression levels of PDF and methionine aminopeptidase 1D (MAP1D), an enzyme involved in a related pathway with PDF, were determined using tissue panels containing cDNA from patients with various types of cancer (breast, colon, kidney, liver, lung, ovarian, prostate, or thyroid) and human cell lines. Protein levels of PDF were also determined in 2 colon cancer patients via western blotting. Colon cancer cells were treated with inhibitors of ERK, Akt, and mTOR signaling pathways and the resulting effects on PDF and MAP1D mRNA levels were determined by qPCR for colon and lung cancer cell lines. Finally, the effects of a PDF inhibitor, actinonin, on the proliferation of breast, colon, and prostate cell lines were determined using the CyQUANT assay. RESULTS: PDF and MAP1D mRNA levels were elevated in cancer cell lines compared to non-cancer lines. PDF mRNA levels were significantly increased in breast, colon, and lung cancer samples while MAP1D mRNA levels were increased in just colon cancers. The expression of PDF and MAP1D varied with stage in these cancers. Further, PDF protein expression was elevated in colon cancer tissue samples. Inhibition of the MEK/ERK, but not PI3K or mTOR, pathway reduced the expression of PDF and MAP1D in both colon and lung cancer cell lines. Further, inhibition of PDF with actinonin resulted in greater reduction of breast, colon, and prostate cancer cell proliferation than non cancer cell lines. CONCLUSIONS: This is the first report showing that PDF is over expressed in breast, colon, and lung cancers, and the first evidence that the MEK/ERK pathway plays a role in regulating the expression of PDF and MAP1D. The over-expression of PDF in several cancers and the inhibition of cancer cell growth by a PDF inhibitor suggest this enzyme may act as an oncogene to promote cancer cell proliferation. PMID- 23815883 TI - Velopharyngeal insufficiency, submucous cleft palate and a phonological disorder as the associated clinical features which led to the diagnosis of Jacobsen syndrome. Case report and review of the literature. AB - Jacobsen syndrome is an uncommon but well-known contiguous gene syndrome caused by partial deletion involving the long arm of chromosome 11. Most common features include: psychomotor impairment, facial dysmorphism, and thrombocytopenia. Cleft palate has been rarely reported. A case of Jacobsen syndrome confirmed by cytogenomic analysis is presented with review of the literature. Main clinical features were phonological disorder, submucous cleft palate (SMCP) and velopharyngeal insufficiency (VPI). VPI was corrected surgically according to findings of videonasopharyngoscopy and videofluoroscopy. It is concluded that clinicians should consider that VPI associated with SMCP may be the main manifestations of a chromosomal syndrome. PMID- 23815884 TI - Newborn genetic screening for high risk deafness-associated mutations with a new Tetra-primer ARMS PCR kit. AB - OBJECTIVE: Previous epidemiological studies indicate that GJB2, SLC26A4 or mtDNA 12S rRNA mutations were chiefly responsible for the hearing loss in children. A cost-effective method for screening deafness-associated mutations at early age is needed. This study aimed to develop a simple kit for screening of high risk deafness-associated mutations in newborns using tetra-primer amplification refractory mutation system PCR. METHODS: The screening kit was designed to detect high risk deafness-associated mutations (GJB2 c.235delC, SLC26A4 c.919-2A>G, mtDNA 12S rRNA mt.1555A>G and mt.1494C>T). The kit was able to amplify both wild type and mutant alleles with a control fragment. The proposed method was conducted to genotype the above four deafness gene mutations in four PCR reactions. Each mutation was genotyped by a set of four primers, two allele specific inner primers, and two common outer primers. A mismatch at the penultimate or antepenult nucleotide of the 3' terminus was introduced in order to maximize specificity. The 16 primers were used for the amplification of genomic DNA as a template. Amplified fragments were separated by electrophoresis. We designed and validated the kit with wild and mutant type DNA samples that had been previously been confirmed by Sanger sequencing. Then 1181 newborns were enrolled, and those samples with mutations were further validated with sequencing too. RESULTS: Among 1181 newborns, 29 individuals had one or two mutant alleles, with the carrier rate being 2.46% (29/1181). For GJB2 c.235delC mutation, one case was homozygote and 12 cases were heterozygote carriers. For SLC26A4 c.919 2A>G mutation, 12 cases were heterozygotes carriers, and no homozygotes were found; for mtDNA 12S rRNA mt.1555A>G mutation, one case was identified; three cases of mtDNA 12S rRNA mt.1494C>T mutation were detected. All mutations were detected with high specificity. Mutation samples were confirmed via Sanger sequencing. No false positive was found. CONCLUSION: A user-friendly screening kit for deafness-associated mutations was successfully developed. It provided rapid, reproducible, and cost-effective detection of deafness gene mutation without special equipment. The kit allowed the detection of the four high risk deafness-associated mutations with only 4 single tube PCR reactions. In the future, the kit could be applied to large population-based epidemiological studies for newborn hearing defects screening. PMID- 23815885 TI - Are all skilled birth attendants created equal? A cluster randomised controlled study of non-physician based obstetric care in primary health care clinics in Mexico. AB - BACKGROUND: the great majority of births in Mexico are attended by physicians. Non-physician health professionals have never been evaluated or compared to the medical model of obstetric care. This study evaluates the relative strengths of adding an obstetric nurse or professional midwife to the physician based team in rural clinics. METHODS: we undertook a cluster-randomised trial in 27 clinics in 2 states with high maternal mortality. Twelve non-physician providers (obstetric nurses (4) and professional midwives (8)) were randomly assigned to clinics; 15 clinics served as control sites. Over an 18-month period in 2009-2010, we evaluated quality of care through chart review and monthly interviews with providers about last three deliveries performed. We analysed practices by creating indices using WHO care guidelines for normal labour and childbirth. Volume of care was assessed using administrative reporting forms. FINDINGS: two thousand two hundred fifty-four pregnancies were followed, and a total of 461 deliveries occurred in study sites. Intervention clinics were more likely to score highly on the index for favourable practices on admission (OR=3.6, 95% CI 2.3-5.8), and during labour, childbirth, and immediately post partum (OR=8.6, 95% CI 2.9-25.6) and less likely to use excessively used or harmful practices during labour, childbirth and immediately post partum (OR=0.2, 95% CI 0.1-0.4). There was a significant increase in volume of care in intervention clinics for antenatal visits (incidence rate ratio (IRR) 1.3, 95% CI 1.2-1.4), deliveries (IRR=2.5, 95% CI 1.7-3.7) and for postpartum visits (IRR=1.4, 95% CI 1.1-1.7). INTERPRETATION: the addition of non-physician skilled birth attendants to rural clinics in Mexico where they independently provided basic obstetric services led to improved care and higher coverage than clinics without. The potential value of including a professional midwife or obstetric nurse in all rural clinics providing obstetric care should be considered. FUNDING: Mexican National Institute for Women, Mexican National Center for Gender Equity and Reproductive Health, MacArthur Foundation, Bill and Melinda Gates Foundation. PMID- 23815886 TI - Perceptions of the social determinants of health by two groups more and less affiliated with public health in Canada. AB - BACKGROUND: Despite strong academic recognition of the SDOH both in Canada and internationally, acknowledgement and uptake of the SDOH in health policy and public consciousness have remained weak. This paper aims to discern reasons for limited action on the SDOH by examining the perceptions of the SDOH held by two groups more and less affiliated with public health in Canada.We conducted formal consultation with group members on their interpretation of the SDOH and their thoughts on the nature and basis of differences between those more and less aligned with the SDOH as a basis for action. Thematic analysis was used to evaluate the views of the two groups. FINDINGS: Group 1 (community/public health workers) felt overwhelmed when confronted with questions regarding action on the SDOH within the context of their professional lives. They suggested an expanded list of health determinants that included factors such as voluntarism and happiness, transcending traditional notions of "root causes." Furthermore, they did not articulate value-based reasons why others would oppose the SDOH; rather, in line with their professional roles, they adopted a value-neutral and pragmatic approach to working to improve health. Group 2 (child and youth advocacy organization members) seemed rooted in the 1986 Ottawa Charter for Health Promotion framework, with their recommendations aligned with strategies such as building healthy public policy and reorienting health services. Neither group made reference to issues of social justice or inequity when they made suggestions for improving health. CONCLUSIONS: We found that two groups with different affiliations to formal public health could discuss the SDOH without acknowledging the inequitable distribution of power and resources that lies at its root. We also found that those working in public health had difficulty moving beyond individual actions that they or their clients could take to improve health. For a group more focused on advocacy than direct service provision, the Ottawa Charter framework seemed more easily suited to their recommendations for action than suggesting actions that would address the SDOH. Our findings indicate that there remains work to be done in terms of translating the SDOH concept into action in Canada. PMID- 23815888 TI - Inference of human continental origin and admixture proportions using a highly discriminative ancestry informative 41-SNP panel. AB - BACKGROUND: Accurate determination of genetic ancestry is of high interest for many areas such as biomedical research, personal genomics and forensics. It remains an important topic in genetic association studies, as it has been shown that population stratification, if not appropriately considered, can lead to false-positive and -negative results. While large association studies typically extract ancestry information from available genome-wide SNP genotypes, many important clinical data sets on rare phenotypes and historical collections assembled before the GWAS area are in need of a feasible method (i.e., ease of genotyping, small number of markers) to infer the geographic origin and potential admixture of the study subjects. Here we report on the development, application and limitations of a small, multiplexable ancestry informative marker (AIM) panel of SNPs (or AISNP) developed specifically for this purpose. RESULTS: Based on worldwide populations from the HGDP, a 41-AIM AISNP panel for multiplex application with the ABI SNPlex and a subset with 31 AIMs for the Sequenome iPLEX system were selected and found to be highly informative for inferring ancestry among the seven continental regions Africa, the Middle East, Europe, Central/South Asia, East Asia, the Americas and Oceania. The panel was found to be least informative for Eurasian populations, and additional AIMs for a higher resolution are suggested. A large reference set including over 4,000 subjects collected from 120 global populations was assembled to facilitate accurate ancestry determination. We show practical applications of this AIM panel, discuss its limitations for admixed individuals and suggest ways to incorporate ancestry information into genetic association studies. CONCLUSION: We demonstrated the utility of a small AISNP panel specifically developed to discern global ancestry. We believe that it will find wide application because of its feasibility and potential for a wide range of applications. PMID- 23815887 TI - Childhood sexual abuse increases risk of auditory hallucinations in psychotic disorders. AB - BACKGROUND/AIMS: Previous studies point to an association between childhood sexual abuse (CSA) and auditory hallucinations (AH). However, methodological issues limit the strength of these results. Here we compared childhood abuse between psychotic disorder patients and healthy control subjects using a reliable measure of abuse, and assessed the relationship between CSA and AH. METHODS: 114 psychotic disorder patients and 81 healthy control subjects were administered the Structured Clinical Interview of the DSM-IV (SCID) and the Childhood Trauma Questionnaire (CTQ). We compared the severity of abuse between groups, and tested the relationship between different types of childhood abuse and specific psychotic symptoms. RESULTS: Psychotic patients reported more childhood abuse than controls (p<.001). Psychotic patients with a history of AH reported significantly more sexual, emotional, and physical abuse than patients without a history of AH (p<.05). Emotional and physical abuse, in the absence of sexual abuse, did not lead to a higher rate of AH. Finally, reports of childhood abuse did not increase the risk of any form of hallucination other than AH or of any form of delusion. CONCLUSIONS: These results suggest that childhood abuse, especially childhood sexual abuse, shapes the phenotype of psychotic disorders by conferring a specific risk for AH. PMID- 23815889 TI - Derivatives of valproic acid are active against pentetrazol-induced seizures in immature rats. AB - Propylisopropyl acetamide (PID) and valnoctamide (VCD) are two CNS-active constitutional isomers of valproic acid (VPA) corresponding amide (and prodrug) valpromide. VPA is a major antiepileptic drug (AED) used also in children. Consequently, the purpose of the current study was to see if PID, VCD and two of VCD stereoisomers are active also in juvenile anticonvulsant animal seizure models. Rat pups 7, 12, 18 and 25 days old were pretreated with PID, VCD or the VCD stereoisomers (2S,3S)-VCD, and (2R,3S)-VCD and 30 min later pentetrazol (100mg/kg s.c.) was administered. The incidence of seizures, their expression pattern and their latencies were registered and the severity was expressed by means of a five-point scale. All four tested compounds exhibited anticonvulsant activity against generalized tonic-clonic seizures. Lower doses suppressed specifically the tonic phase in 7-, 12- and 18-day-old rats, while higher doses abolished both phases of generalized seizures. This effect was most pronounced in 12-day-old rats. Twenty-five-day-old rats exhibited suppression of the entire pattern of generalized seizures. There were no significant differences among the drugs used. The CNS-active amide derivatives of VPA, VCD (racemate or individual stereoisomers) and PID exhibit potent anticonvulsant activity against generalized convulsive seizures in developing rats. The majority of these developmental effects are quantitative; while a specific selective action on the tonic phase of generalized seizures is the main qualitative change found in our study. PMID- 23815890 TI - A simple strategy for heritable chromosomal deletions in zebrafish via the combinatorial action of targeting nucleases. AB - Precise and effective genome-editing tools are essential for functional genomics and gene therapy. Targeting nucleases have been successfully used to edit genomes. However, whole-locus or element-specific deletions abolishing transcript expression have not previously been reported. Here, we show heritable targeting of locus-specific deletions in the zebrafish nodal-related genes squint (sqt) and cyclops (cyc). Our strategy of heritable chromosomal editing can be used for disease modeling, analyzing gene clusters, regulatory regions, and determining the functions of non-coding RNAs in genomes. PMID- 23815891 TI - Improving stroke prevention in patients with atrial fibrillation. AB - BACKGROUND: Patients with atrial fibrillation (AF) are at increased risk for stroke. Antithrombotic treatment reduces this risk. Antithrombotic treatment consists of either administration of oral anticoagulants (OAC) or the provision of an antiplatelet drug. International guidelines provide advice on the preferred treatment, thereby balancing the risks and benefits of OAC. However, adherence to these guidelines is reported to be as low as 50%. There is paucity in research on why adherence rates are low. Recent studies have shown decision support systems can improve guideline adherence. We investigate the use of a clinical decision support system to improve guideline adherence among general practitioners (GPs) treating patients with AF and study reasons for guideline non-adherence. METHODS/DESIGN: The study is a randomized controlled trial, which is performed among Dutch general practitioners. Initially, GPs in the vicinity of the Academic Medical Center (AMC) in Amsterdam will be included, after which other practices will be recruited. We have developed a novel decision support system that displays a list with pending messages for the on-screen medical record in real time. Messages are generated on a server that evaluates a decision rule based on the atrial fibrillation guideline of the Dutch College of General Practitioners. By interacting with the list, messages can be opened for a description and explanation, or be ignored. GPs are allocated into three groups: 1) control group; 2) intervention group A, in which messages can be ignored without justification; and 3) intervention group B, in which messages can only be ignored with justification.Our main outcome measure is the between-group difference in the proportion of patients receiving antithrombotic prescriptions in adherence to the Dutch GP guideline for atrial fibrillation. Secondary outcomes are reasons GPs state for deviating from the guideline and the effect on guideline adherence of requiring justification when ignoring a message. DISCUSSION: This paper describes the protocol for a cluster randomized trial to study the effects of a clinical decision support system in patients with atrial fibrillation. The system is characterized by a non-interruptive presentation and real-time messages that are updated after each relevant action the GP performs. TRIAL REGISTRATION: This trial is registered with the Dutch Trial Register under registration number 3570. PMID- 23815892 TI - The protective effect of geniposide on human neuroblastoma cells in the presence of formaldehyde. AB - BACKGROUND: Formaldehyde can induce misfolding and aggregation of Tau protein and beta amyloid protein, which are characteristic pathological features of Alzheimer's disease (AD). An increase in endogenous formaldehyde concentration in the brain is closely related to dementia in aging people. Therefore, the discovery of effective drugs to counteract the adverse impact of formaldehyde on neuronal cells is beneficial for the development of appropriate treatments for age-associated cognitive decline. METHODS: In this study, we assessed the neuroprotective properties of TongLuoJiuNao (TLJN), a traditional Chinese medicine preparation, against formaldehyde stress in human neuroblastoma cells (SH-SY5Y cell line). The effect of TLJN and its main ingredients (geniposide and ginsenoside Rg1) on cell viability, apoptosis, intracellular antioxidant activity and the expression of apoptotic-related genes in the presence of formaldehyde were monitored. RESULTS: Cell counting studies showed that in the presence of TLJN, the viability of formaldehyde-treated SH-SY5Y cells significantly recovered. Laser scanning confocal microscopy revealed that the morphology of formaldehyde-injured cells was rescued by TLJN and geniposide, an effective ingredient of TLJN. Moreover, the inhibitory effect of geniposide on formaldehyde induced apoptosis was dose-dependent. The activity of intracellular antioxidants (superoxide dismutase and glutathione peroxidase) increased, as did mRNA and protein levels of the antiapoptotic gene Bcl-2 after the addition of geniposide. In contrast, the expression of the apoptotic-related gene - P53, apoptotic executer - caspase 3 and apoptotic initiator - caspase 9 were downregulated after geniposide treatment. CONCLUSIONS: Our results indicate that geniposide can protect SH-SY5Y cells against formaldehyde stress through modulating the expression of Bcl-2, P53, caspase 3 and caspase 9, and by increasing the activity of intracellular superoxide dismutase and glutathione peroxidase. PMID- 23815893 TI - Topical tranexamic acid in total knee replacement: a systematic review and meta analysis. AB - BACKGROUND: To examine the safety and efficacy of topical use of tranexamic acid (TA) in total knee arthroplasty (TKA). METHODS: An electronic literature search of PubMed Medline; Ovid Medline; Embase; and the Cochrane Library was performed, identifying studies published in any language from 1966 to February 2013. The studies enrolled adults undergoing a primary TKA, where topical TA was used. Inverse variance statistical method and either a fixed or random effect model, depending on the absence or presence of statistical heterogeneity were used; subgroup analysis was performed when possible. RESULTS: We identified a total of seven eligible reports for analysis. Our meta-analysis indicated that when compared with the control group, topical application of TA limited significantly postoperative drain output (mean difference: -268.36ml), total blood loss (mean difference=-220.08ml), Hb drop (mean difference=-0.94g/dL) and lowered the risk of transfusion requirements (risk ratio=0.47, 95CI=0.26-0.84), without increased risk of thromboembolic events. Sub-group analysis indicated that a higher dose of topical TA (>2g) significantly reduced transfusion requirements. CONCLUSIONS: Although the present meta-analysis proved a statistically significant reduction of postoperative blood loss and transfusion requirements with topical use of TA in TKA, the clinical importance of the respective estimates of effect size should be interpreted with caution. LEVEL OF EVIDENCE: I, II. PMID- 23815894 TI - [Expression and clinical significance of IKZF1 gene IK6 isoform in adult acute lymphoblastic leukemia]. AB - This study was aimed to detect the expression of IKZF1 gene isoforms in bone marrow cells of patients with adult acute lymphoblastic leukemia and to investigate the clinical characteristics and prognosis of patients with IK6 isoform. The expression of IKZF1 gene isoforms were measured by nested RT-PCR in 79 newly diagnosed ALL patients. The clinical characteristics of IK6 positive patients and overall survival, disease-free survival of the IK6 positive group and IK6 negative group were compared. The results showed that IK1 and IK2/3 were the functional isoform while the IK4, IK6, IK8 and IK9 were the dominant negative isoform in adult ALL. The dominant negative isoform IK6 accounted for 34.4% in B ALL patients and accounted for 22.2% in T-ALL patients. The BCR/ABL1 positive rate and the percentage of high risk patients in IK6 positive group was higher than that of IK6 negtive group in B-ALL patients (P = 0.027, P = 0.048). The expression of IK6 isoform did not correlate with sex, age and WBC count of B-ALL and T-ALL patients. The overall survival and disease-free survival of IK6 positive group were both lower than that of IK6 negtive group in Ph negative B ALL patients (P = 0.009, P = 0.002). It is concluded that IK6 is a main isoform of the expression of IKZF1 gene in adult ALL patients, and can be used as a prognostic factor for guiding treatment in Ph negative B-ALL patients. PMID- 23815895 TI - [Dual over-expression of P2X7 receptor and intracellular domain of Notch1 in leukemia cells]. AB - This study aimed to construct the dual expression vectors of wide type or N187D mutant P2X7 receptor and intracellular domain of Notch1 (ICN1) linked by 2A peptide to coexpress them in leukemia cells so as to lay a foundation for further investigating the role of P2X7 in development of leukemia. Overlap PCR was used to construct the dual expression vectors encoding wide type or N187D mutant type P2X7 receptor and ICN1 linked by the self-cleaving 2A sequence. The results showed that stable expressing cell lines were obtained by retroviral infection followed by cell sorting after DNA sequence analysis. RT-PCR, Western blot, intracellular free calcium concentration analysis were used to verify the functionally successful construction of K562 cell line expressing P2X7 receptor alone or with ICN1. DNA sequence analysis revealed that all construction were right. The infection efficiency of packaged constructed virus ranged from 40% to 70% for K562 cells. Stable infected cell line was obtained by cell sorting. RT PCR analysis revealed that P2X7 receptor and/or ICN1 could be detected at high level in their stable infected cell lines, respectively. Western blot analysis also showed that P2X7 receptor was highly expressed in cell line infected by virus with P2X7 receptor. Sustained increase in intracellular free calcium concentration ([Ca(2+)]i) could be observed in K562 cells overexpressing either type of P2X7 receptor upon stimulation with BzATP. It is concluded that the wide type or N187D mutant P2X7 receptor and ICN1 are simultaneously and functionally over-express in leukemia cells, which lay a foundation for further studying the role of P2X7 receptor in the development of leukemia. PMID- 23815896 TI - [Effects of transcription factor GATA-2 on transcriptive regulation of iASPP gene]. AB - iASPP can prompt the cell proliferation and inhibit the apoptosis of many cells. There are putative binding sites of transcription factor GATA-2 upstream of iASPP transcription start site. GATA-2 plays an important role in the proliferation and differentiation of hematopoietic stem cells (HSC) and progenitors. This study was aimed to explore the role of GATA-2 protein in iASPP gene transcription. Firstly, the expression of iASPP and GATA-2 protein in some leukemia cell lines was detected by Western blot. Second, The expressive vector of pCMV5-GATA2 and the luciferase reporter vectors containing possible binding sites of GATA-2 were constructed and co-transfected into HEK293 and CV-1 cells. Then the luciferase activity was assayed by luminometer. Also, ChIP assays were performed to further confirm the specific binding of GATA-2 to iASPP promoter. The results showed that GATA-2 was overexpressed in most cell lines with high level of iASPP. GATA-2 exhibited a significant effect on luciferase activity of reporter gene iASPP and in a dose-dependant manner. The relative luciferase activity was up-regulated to about two-fold of the empty vector control when the transfection dose of pCMV5 GATA2 plasmid was increased to 100 ng. While the effect was more significant in CV-1 cells and showed a 6.7-fold increase. The ChIP assay demonstrated the in vivo specific binding of GATA-2 to iASPP. The binding sites of GATA2 were located between nt -361 ~ -334 in upstream of iASPP gene transcription start site. It is concluded that transcription factor GATA-2 can bind with the cis-regulatory region of the iASPP promoter and up-regulate iASPP expression. PMID- 23815897 TI - [Expression of microRNA-223 in lymphocytic leukemia cells and its action mechanism]. AB - This study was aimed to investigate the expression level and mechanism of microRNA-223 and LMO2 in acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL) cells and the mechanism. MicroRNA-223 mimics was transfected to increase the expression of MicroRNA-223 in the lymphocytes sorted by ficoll separation from the bone marrow mononuclear cells (BMMNC) of ALL and CLL patients. MicroRNA-223 inhibitor was transfected to decrease the expression of the MicroRNA-223 in the lymphocytes of normal controls. Then the expression of the MicroRNA-223 and LMO2 in transfected lymphocytes before and after cultivating for 72 hours were detected by RT-PCR, the apoptosis and cell cycle of these cells were measured by flow cytometery. The results indicated that before the transfection, the expression of MicroRNA-223 in ALL and CLL cells was (433.11 +/- 144.88), which was significantly lower than that in the normal lymphocyte (949.59 +/- 267.39); the expression of LMO2 was (807.10 +/- 238.41), which was significantly higher than that in the normal lymphocytes (455.32 +/- 176.83) (P < 0.05); after the transfection, the expression of MicroRNA-223 was (571.86 +/- 142.00) in ALL and CLL cells, which was significantly higher than that before transfection (P < 0.05), but the expression of LMO2 was significantly lower than that before transfection (651.97 +/- 230.12) (P < 0.05); in the normal control the expression of MicroRNA-223 obviously decreased (646.32 +/- 172.93) (P < 0.05), the expression of LMO2 was significantly increased (541.27 +/- 158.86.2) (P < 0.05). After transfection, the cell cycle G1/G2 phase and apoptosis changed in ALL and CLL cells. Before transfection the cell ratio in cell cycle G1/G2 phase was (94.75 +/- 3.15)%, the cell ratio in S phase was (5.14 +/- 3.12)%; after transfection the cell ratio in cell cycle G1/G2 phase was (97.03 +/- 2.08)% and obviously increased (P < 0.05), the cell ratio in S phase was (2.97 +/- 2.08)% and significantly decreased (P < 0.05). Before transfection the apoptosis rate was (54.47 +/- 8.72)%, and obviously was higher than that after transfection (60.48 +/- 8.81)%. And in the normal control, the cell ratio in G1/G2 phase was significantly higher than that after transfection [(96.73 +/- 2.26)%, (94.55 +/- 2.77)%, P < 0.05)], and the cell ratio in S phase was significantly increased [(3.25 +/- 2.26)%, (5.45 +/- 2.77)% (P < 0.05)]. The apoptotic rate in the ALL and CLL patients was significantly higher than that after the transfection [(54.47 +/- 8.72)% vs (60.48 +/- 8.81)%, respectively (P < 0.05)]. The apoptotic rate in the normal control was significantly lower than that after the transfection [(59.02 +/- 10.20)%, (51.96 +/- 10.20)%, respectively (P < 0.05)]. It is concluded that the expression of MicroRNA-223 decreases, and the expression of LMO2 increases in lymphocytic leukemia cells which leads to the lymphocytes over-proliferation and abnormal apoptosis, thus may be one of pathogenesis in lymphocytic leukemia. PMID- 23815898 TI - [Analysis of bone marrow and peripheral blood cytologic features in hyperleukocytic acute leukemia]. AB - This study was purpose to investigate the cytologic features of bone marrow (BM) and peripheral blood (PB) in hyperleukocytic acute leukemia (HAL) and their clinical significance in accordance with high leukocyte count as poor prognostic factor for acute leukemia. The smears of BM and PB were collected from 68 out patients and inpatients including 28 cases of HLA and 40 cases of non HAL (NHAL) in our hospital since 2009. The proliferation degree, morphology and abnormal appearance in each cell lineage were observed with HE, POX, PAS, NSE+ NaF staining for BM mears and HE staining for PB smears by means of optical microscope. The final diagnosis was made by cellular chemical staining results, then the counting and classification were performed in 200 nucleated cells to calculate the percentage of each cell lineage, the myeloid/erythroid ratio and so on. The BP smears were observed with the same methods, the counting and classification of 100 nucleated cells were performed to calculate a variety of nucleated cell percentage. The resulted data were analyzed by the SPSS 12.0 statistical software, the difference of proliferation degree and ratio of each cell lineage in BM smears were compared, the relationship of morphological features of PB smears with BM smears was analyzed. The results showed that obvious or extreme active proliferation of nucleated cells was observed in HAL and NHAL groups, but the myeloproliferation in HAL group was more active than that in NHAL group (P < 0.05). The erythrocyte and megakaryocyte lineages were suppressed in both groups, while the HAL group showed a lower proportion of erythrocyte and megakaryocyte lineages in BM as compared with NHAL group (P < 0.05). The hemoglobin and platelet levels in PB of HAL group were obviously lower than those in PB of NHAL group (P < 0.05). The leukemia cells could be seen in PB smears of NHAL, but the proportion of leukemia cells in NHAL group was smaller than that in HAL group (P < 0.05). The leukocyte count in PB of HAL group strongly positively correlated with the proliferation degree of leukemia cells in BM of HAL group (r = 0.422). It is concluded that the significant difference of proliferation degree, cell levels and blast ratio in BM and PB exists in HAL and NHAL groups, moreover the leukemia cells ratio, leukocyte, hemoglobin and platelet levels in PB of HAL all show characteristic changes. Therefore the contrast analysis of characteristic changes from laboratorial detection contributes to grasp the regular pattern of HAL, meanwhile has an important value for guiding correct diagnosis of acute leukemia and choosing suitable treatment options. PMID- 23815899 TI - [Construction of shRNA expression vector targeting AATF and establishment of stably transfected U937 cells]. AB - This study was aimed to construct the targeting AATF shRNA eukaryotic expression vector and establish the stably transfected U937 cell lines. The sequence of AATF mRNA was obtained from GenBank. After excluding homology, three plasmid expression vectors coding shRNA targeting 228 ~ 249, 303 ~ 324 and 443 ~ 464 of AATF gene sequence were synthesized. Two terminals of shRNA carried BamHI and HindIII restriction sites. The selected nucleotides were cloned into the plasmid pSilencer 3.1-H1 neo respectively, and the resultant recombinant plasmids were named as pSA-1, pSA-2, pSA-3. The sequences of the recombinant plasmids were identified by DNA sequencing. The recombinant plasmids were transfected into the cell line U937 by electroporation with Neon(TM) Transfection System. The transfected cells were persistently screened under G418 (500 mg/L), and isolated with a limited dilution for 8 weeks. The inhibition of AATF mRNA and protein expression was respectively detected by RT-PCR and Western blot. The results indicated that RNAi eukaryotic expression vectors targeting AATF had correct reading frame and nucleotide sequence. Real-time PCR revealed that AATF shRNA effectively silenced mRNA expression of AATF. Western blot analysis found that AATF shRNA obviously suppressed protein expression of AATF (P < 0.05). It is concluded that the shRNA eukaryotic expression vector has been successfully constructed which can inhibit the expression of AATF, and the establishment of stably transfected U937 cell lines provide a original route for exploring the mechanism of AATF in human Leukemia further. PMID- 23815900 TI - [Correlation of NPM1, FLT3-ITD mutations with leukocyte count and myeloblasts percentage in AML patients with normal karyotype]. AB - This study was aimed to investigate the correlation of NPM1 and FLT3-ITD mutations with leukocyte count in peripheral blood and bone marrow blasts in patients with acute myeloid leukemia (AML). Fifty-one acute myeloid leukemia patients with normal karyotype from January 2009 to December 2011 were enrolled in this study. The clinical data of 51 cases were analyzed retrospectively. Out of 52 cases 22 were male, and 29 were female. The median age was 47 years old (ranged from 14 to 83 years old). The de novo patients were examined by bone marrow cytomorphology and blood routine analysis. Polymerase chain reaction was used to analyze the NPM1 and FLT3-ITD mutations. The results showed that the patients with NPM1 mutations had higher leukocyte count compared with those without mutations (30.7*10(9)/L vs 8.6*10(9)/L, P = 0.002). FLT3-ITD mutation was related to higher leukocyte count (42.38*10(9)/L vs 11.45*10(9)/L without mutation, P = 0.033) and blasts (74.0% vs 60.25% without mutation, P = 0.036). The leukocyte count and percentage of bone marrow blasts were lowest in the patients with neither mutations, and gradually increasing in the NPM1(-) mutation, FLT3-ITD(-) mutation, and NPM1(+) mutation, FLT3-ITDI(+) mutation, and NPM1(+)/FLT3-ITD(+) mutation groups (P < 0.05). The patients tended to have NPM1 (P = 0.002) and FLT3-ITD (P = 0.033) mutations when their leukocyte counts were more than 12.55*10(9)/L and 37.85*10(9)/L, respectively. Those with bone marrow blast more than 72.25% showed higher rate of FLT3-ITD mutation (P = 0.008). Patients with NPM1 mutations had higher complete remission rate than those without NPM1 mutation (78.13% vs 40.0%, chi(2) = 4.651, P = 0.031) after remission induction therapy. It is concluded that both NPM1 and FLT3-ITD mutations are linked to higher leukocyte count and blast percentage, suggesting that both mutations may be associated with increased proliferation of leukemia cells, and may have a synergistic function in stimulating proliferation. PMID- 23815901 TI - [Transfection of HL-60 cells by Venus lentiviral vector]. AB - In order to study the potential of Venus, lentiviral vector, applied to acute myeloid leukemia, the recombinant vector Venus-C3aR was transfected into 293T packing cells by DNA-calcium phosphate coprecipitation. All virus stocks were collected and transfected into HL-60, the GFP expression in HL-60 cells was measured by flow cytometry. The expression level of C3aR1 in transfected HL-60 cells was identified by RT-PCR and flow cytometry. The lentiviral toxicity on HL 60 was measured by using CCK-8 method and the ability of cell differentiation was observed. The results indicated that the transfection efficacy of lentiviral vector on HL-60 cells was more than 95%, which meets the needs for further study. C3aR1 expression on HL-60 cells increased after being transfected with recombinant lentiviral vector. Before and after transfection, the proliferation and differentiation of cells were not changed much. It is concluded that the lentiviral vector showed a high efficacy to transfect AML cells and can be integrated in genome of HL-60 cells to realize the stable expression of interest gene. Meanwhile, lentiviral vector can not affect HL-60 cell ability to proliferate and differentiate. PMID- 23815902 TI - [Efficacy of dasatinib in treatment of imatinib-resistant BCR/ABL positive leukemia]. AB - This study was aimed to evaluate the efficacy and safety of dasatinib in BCR/ABL positive leukemia patients with primary or secondary resistance to imatinib. 27 patients with primary or secondary imatinib-resistant chronic myelogenous leukemia (CML) or Philadelphia chromosome positive acute lymphocytic leukemia (Ph(+) ALL) received 100 - 140 mg/d dasatinib orally. Their overall survival and tolerance were evaluated. The results showed that the median duration of dasatinib therapy was 8 (1-66) months in the 27 imatinib-resistant BCR/ABL positive leukemia cases, with a median follow-up of 54 (3-75) months. After the dasatinib treatment, 88.8% of all the 27 cases achieved complete hematologic response (CHR), 29.6% of them achieved major cytogenetic response (mCyR), 37% of all achieved complete cytogenetic response (CCyR) and 18.5% cases achieved major molecular response (MMR). Patients who received dasatinib in progress of disease (CML-AP, CML-BC and bone marrow relapse Ph(+) ALL) had a lower CCyR rate than those in stable disease (CML-CP and bone marrow remission Ph(+) ALL) (P = 0.0377), and 3 - 4 grade adverse events occurred more frequently in progress of disease than that in stable disease. Overall survival of the patients who achieved CCyR after dasatinib therapy was statistically longer than those who did not achieve CCyR (63 m vs 9 m, P = 0.0126). The most common grade 3 - 4 adverse events during dasatinib therapy including hematology events such as thrombocytopenia (51.8%), neutropenia (48.1%), anemia (33.3%), and non hematologic events such as pleural effusion (18.5%), pulmonary infection (18.5%), pericardial effusion (11.1%). The 3-4 grade adverse events occurred within 12 months from dasatinib therapy, and were mainly observed in patients with progress of disease. It is concluded that dasatinib is an effective drug in imatinib resistant BCR/ABL positive leukemia patients, the better curative effect and better tolerance has been observed in patients who received dasatinib in stable disease. PMID- 23815903 TI - [Influence of TIEG1 on apoptosis of HL-60 cells and expression of Bcl-2/Bax]. AB - This study was aimed to investigate the influence of TIEG1 on apoptosis of HL-60 cells and the expression of Bcl-2/Bax. Different concentration of TIEG1 were used to treat HL-60 cells, the cell growth inhibition rate was detected by MTT method. After treating HL-60 cells with 12.03 ng/ml TIEG1, cell apoptosis was detected with flow cytometry. Bcl-2 and Bax was detected with RT-PCR. The results showed that TIEG1 had inhibitory effect on HL-60 cell proliferation, and in time-and dose-dependent manners. The more obvious inhibitory effect was observed in HL-60 cells treated with TIEG1 of 12.03 ng/ml. During the course of cell apoptosis, Bax expression increased, but Bcl-2 expression decreased (P < 0.05). It is concluded that TIEG1 inhibits HL-60 cell proliferation and induces apoptosis in time and dose-dependent manners. During the course of HL-60 cells apoptosis induced by TIEG1, Bcl-2/Bax are associated with HL-60 cell apoptosis induced by TIEG1. PMID- 23815904 TI - [Mitochondrial mechanisms of apoptosis of human leukemia K562 cells induced by AVVC-1]. AB - This study was purpose to investigate apoptosis pathway of leukemia K562 cells induced by anticoagulant fraction from Agkistrodon acutus venom (AVVC-1). The mitochondrial transmembrane potential (DeltaPsim) of leukemia K562 cells was detected by flow cytometry with JC-1 single staining. The expression of cytochrome C in the mitochondrial of leukemia K562 cells was analyzed by Western blot after AVVC-1 treatment. The distribution of cytochrome C in leukemia K562 cells was measured by immuno-fluorescence test. The results showed that the potential of mitochondrial membrane decreased after treatment with different concentrations of AVVC-1 (12.5, 25, 50, 100 ug/ml) for 6 h (P < 0.01). The expression level of cytochrome C protein in mitochondria obviously declined after treatment with 30 ug/ml AVVC-1 for 48 h, and the fluorescent intensity of cytochrome C in cytosol was enhanced at the same time. It is concluded that AVVC 1-induced K562 cell apoptosis is related with mitochondrial damage, and cytochrome C may be a useful agent for investigating human leukemia therapy by using AVVC-1. PMID- 23815905 TI - [Clinical characteristics of CD56(+) patients with acute monocytic leukemia and their prognostic significance]. AB - This study was aimed to investigate the clinical features of CD56(+) patients with acute monocytic leukemia (AML-M5) and their prognostic significance. The data of 76 newly-diagnosed patients from our hospital were analyzed retrospectively. Patients were divided into two groups: CD56(+) group (21 patients) and CD56(-) group (55 patients). The clinical features, CR rate, relapse rate, the duration of CR, and survival time of patients between the two groups were compared. The results indicated that the CD56(+) antigen was observed in 21 patients (27.6%), their median age was 51.5 years and with a range 16 - 70 years. Of the 21 CD56(+) patients, the high WBC count was found in 57.1% CD56(+) patients (12/21), but it only in 15% CD56(-) patients (P < 0.05). The extramedullary infiltration was seen in 13 CD56(+) patients, and accounted for 62% (13/21), meanwhile this infiltration was found in 18 CD56(-) patients (18/55) and accounted for 33% (P < 0.05). All cases immunophenotypically highly expressed CD13, CD33, CD64, CD11b, cMPO, CD38, in which only the expression frequency of CD11b was positively related with CD56 (r = 0.59, P < 0.05). The CR rate in CD56(+) group accounted for 60.0%, and had no significant difference in comparison with that in CD56(-) group. In CD56(+) group the relapse rate was 75% (P = 0.042), the mean duration of CR was 5.5 months (95%CI, 3.1 - 8.6, P = 0.002), the median overall survival time was 10.1 months (95%CI, 2.3 - 16.3, P = 0.001). and all these had statistical significance as compared with that in CD56( ) group. It is concluded that CD56(+) AML-M5 patients always complicate with high WBC count and extramedullary infiltration, their CR rate and duration of CR are lower and shorter respectively, their relapse rate and prognosis are high and poor respectively. PMID- 23815906 TI - [Detection of NPM1, FLT3 and C-KIT mutations in acute myeloid leukemia and their prognostic analysis]. AB - This study was aimed to evaluate the frequencies and prognostic significance of the nucleophosmin 1 (NPM1) mutation, the fms-like tyrosine kinase 3 (FLT3) mutation and c-KIT mutation in acute myeloid leukemia (AML) and to explore their relevance to clinical characteristics, cytogenetics and survival. Genomic DNA from 78 newly diagnosed AML from August 2010 to October 2012 was screened by PCR and sequencing or capillary electrophoresis (CE) for NPM1, FLT3 and c-KIT mutations. The results showed that the incidence of NPM1 mutation was 14.1% in AML patients and 26.7% in normal karyotype AML patients. NPM1 mutant cases were significantly associated with old age (P < 0.05), high peripheral white cell count and platelet counts (P < 0.05) and low expression of CD34 (P < 0.05), but no statistic difference was found in sex, percentage of bone marrow blasts, Hb, expression of CD117 and HLA-DR, complete remission rate, overall survival and relapse rate (P > 0.05). The prevalences of FLT3-ITD and FLT3-TKD mutations were 11.5% (9/78) and 3.8% (3/78) respectively, and no one patient has both of the two mutations. Patients with FLT3-ITD mutation had higher white blood cell counts and percentage of in bone marrow blasts (P < 0.05), and lower overall survival (P < 0.05), more relative to normal karyotype (P < 0.05), while no statistic difference was found in sex, age, platelet count, Hb level, complete remission rate and relapse rate (P > 0.05). No statistic analysis was performed due to the cases of less FLT3-TKD mutation. C-KIT mutation accounts for 7.7% (6/78). Patients with C-KIT mutation had a higher percentage in abnormal karyotype (P < 0.05), and higher relapse rate (P < 0.05), and lower overall survival, whereas no statistic difference was found in sex, age, percentage of bone marrow blasts, peripheral blood cell count, complete remission rate (P > 0.05). It is concluded that the detection of NPM1, FLT3 and C-KIT mutations may contribute to guiding treatment and evaluating prognosis of patients with AML. PMID- 23815907 TI - [Mutation of isocitrate dehydrogenase 2 (IDH2) gene in Chinese AML patients and its clinical significance]. AB - This study was purpose to analyze the frequency and of isocitrate dehydrogenase 2 (IDH2) gene mutation in acute myeloid leukemia (AML) and its clinic significance. The multiplex polymerase chain reaction (PCR) and sequencing were performed to screen 192 AML patients for exon 4 of the IDH2 gene. FLT3, NPM1, CEBPA, c-kit and WT1 mutations were also included in analysis. The results showed that IDH2 mutation was found in 14 (7.29%) of 192 patients. There were 9 AML patients with R140Q mutation, 1 patient with R140W mutation, and 1 patient with R172K mutation. IDH2 aberrations significantly more were detected in French-American-British (FAB) M5 (P < 0.005) than other types. There was no statistical difference in age, sex, WBC, platelet count, bone marrow blasts count, hemoglobin as compared with IDH2 wild-type. For immunotype analysis, IDH2 mutation patients were more likely to express CD34 and CD13, less CD36. IDH2 mutation combined with FLT3/ITD mutation was found in 7 cases, with CEBPA mutation in 4 cases, with NPM1 mutation in 4 cases, with Dnmt3a mutation in 5 cases, neither with c-kit, IDH1 or WT1 mutation for no one, which revealed a significant interaction between IDH2 mutation and the FLT3/ITD positive genotype, Dnmt3a mutated, and IDH1 wild-type. IDH2 mutation was detected in 5 (8.47%) of 59 CN-AML. There was no significant difference of IDH2 mutation incidence between the normal and abnormal karyotype. The CR rate was higher in IDH2 R140 mutated patients than wild-type ones, but there was no significant in the two group. It is concluded that the rate of IDH2 mutation is 7.29% in Chinese AML patients and 7.81% in CN-AML. IDH2 mutation is significantly associated with AML-M5, FLT3/ITD, Dnmt3a, IDH1 wild-type and fusion gene wild-type, but not with age, leucocyte and platelet counts in peripheral blood, karyotype, NPM1, CEBPA, c-kit or WT1 mutation. And IDH2 R140 mutation has no impact on CR rate. PMID- 23815908 TI - [Demethylation effect of inhibitor As2O3 on expression of SHP-1 and C-kit genes in leukemia HL-60 cells]. AB - This study was aimed to investigate the expression level of SHP-1 and C-kit genes in acute leukemia HL-60 cells and effect of inhibitor As2O3 demethylation on SHP 1 and C-kit genes expression. RT-PCR was used to detect the expression level of SHP-1 and C-kit mRNA in drug-treated cell group and control group. The methylation specific PCR (MSP) was applied to measure the methylation status of SHP-1 gene in HL-60 cells. The results showed that after being treated with As2O3 the recovery of SHP-1 gene expression was observed in HL-60 cells in which SHP-1 mRNA originally did not expressed, meanwhile the expression level of C-kit mRNA in HL-60 cells with high expression decreased. When HL-60 cells were treated with As2O3 of 1.0, 2.5, 5.0 umol/L, the demethylation effects was enhanced, the expression of SHP-1 mRNA displayed an ascending tendency, and expression of C-kit mRNA showed an descending tendency in dose-dependent manner (P < 0.05). It is concluded that the absence of SHP-1 mRNA expression in HL-60 cells and recovery of expression after treatment with As2O3 suggest the hypermethylation of SHP-1 gene related with pathogenesis of leukemia, and the abnormal increase of C-kit mRNA expression maybe exist in formation of leukemia. The effect of As2O3 on expression of SHP-1 and C-kit shows dose-dependency, the higher the As2O3 concentration, the higher the SHP-1 expression and the lower the C-kit expression, moreover, the effect of As2O3 shows time-dependency in specific concentration. The SHP-1 mRNA expression negatively relates with C-kit mRNA expression, suggesting that the decrease or absence of SHP-1 expression in leukemia cells weakens the negative regulation on C-kit signaling pathway, thus plays a role in the formation of leukemia. PMID- 23815909 TI - [Autologous hematopoietic stem cell transplantation for patients with diffuse large B-cell lymphoma: a retrospective study]. AB - The purpose of this study was to investigate the efficacy of autologous hematopoietic stem cell transplantation (auto-HSCT) for patients with diffuse large B-cell lymphoma (DLBCL), and analyse the factors influencing prognosis. The clinical data of 67 patients with DLBCL received auto-HSCT from 1996 to 2011 and cumulative overall survival (OS), progression-free survival (PFS), transplant related mortality (TRM), and relapse rate were retrospectively analyzed. The results showed that the median follow-up time was 40 months after transplantation. Three-year cumulative OS and PFS were 70.6% and 66.4% respectively, 5-year cumulative OS and PFS were 70.6% and 63.8% respectively, and TRM was 7.2%. One-year and three-year cumulative relapse rate were 16.5% and 23.7% respectively. Univariate analysis revealed that the age and pre-transplant disease status were significantly associated with poor prognosis (P < 0.05). It is concluded that auto-HSCT is a safe and effective therapeutic option for patients with DLBCL, especially for the young patients or patients with better remission. PMID- 23815910 TI - [Influence of transplantation and some clinical factors on prognosis of patients with diffuse large B-cell lymphoma]. AB - This study was aimed to analyze the survival status of patients with diffuse large B-cell lymphoma (DLBCL) and to investigate the influence of autologous hematopoietic stem cell transplantation (auto-HSCT), different pathological types, International Prognosis Idex (IPI) on prognosis. One hundred and sixteen cases of DLBCL were analyzed retrospectively. The treatment efficacy of R-CHOP alone and R-CHOP combined with auto-HSCT as well as the influence of different immunopathologic types, IPI, hypersensitive C-reactive protein (HSCRP), alpha hydroxybutyric acid deaminase (HBDH) on the prognosis of DLBCL patients including overall survival (OS) rate, progression-free survival (PFS) rate were analyzed. The results indicated that the 5-year OS for all patients was 72.4%. in which 30 patients with Ann Arbor staging III-IV received auto-HSCT plus R-CHOP. The prognosis of the 30 patients was better than that of 86 cases received R-CHOP chemotherapy alone (5-year OS was 82.5% vs 69.0%, 5-year PFS was 77.1% vs 68.3%) (P < 0.05). The prognosis of patients in germinal center B-cell-like group (GCB group) was better than that of patients in activated B-cell-like group (ABC group). Some clinical features were associated with poor prognosis including OS and PFS, such as age, B symptoms, IPI scores, the level of LDH, HSCRP and HBDH (P < 0.05) in which the level of LDH, age >= 60 years and B symptoms were independent prognostic factors in DLBCL patients (P < 0.05). It is concluded that auto-HSCT combined with R-CHOP can improve the long-term survival of DLBCL patients. The prognosis of patients in GCB group is better than that of patients in the ABC group. The clinical features such as age, B symptoms, IPI scores and LDH are associated with prognosis. PMID- 23815911 TI - [Effect of BCL11A gene on transcription of gamma-globin gene]. AB - This study was aimed to explore the effect of BCL11A gene on transcription of gamma-globin gene in K562 cells. B-cell lymphoma/leukemia 11A (BCL11A) gene was silenced by small interfering RNA (siRNA) expression vectors in K562 cells (human erythroblastic leukemia cell line). Gamma-globin mRNA level in K562 cells was determined by RT-PCR. Association between the BCL11A gene and gamma-globin gene transcription was explored by comparison of mRNA levels. The results indicated that the silence rate of the BCL11A gene in K562 cells by 4 siRNA expression vectors was 49.7%, 55.4%, 78.2%, and 84.1%, respectively. The siRNA expression vector with 84.1% silence rate was transfected into K562 cells, transcription level of gamma-globin mRNA in K562 cells transfected with siRNA expression vector increased 2.4 times as compared with control K562 cells. It is concluded that level of gamma-globin mRNA increases when the BCL11A gene is silenced. It indicates that the BCL11A gene may be a negative regulator for gamma-globin gene expression. PMID- 23815912 TI - [Autoimmune hemolytic anemia associated with B-cell chronic lymphoproliferative disorders]. AB - This study was purpose to investigate the clinical characteristics of B-cell chronic lymphoproliferative disorders (B-CLPD) complicated by autoimmune hemolytic anemia (AIHA) so as to improve the understanding of this disease. The clinical characteristics, laboratory data, therapy and outcome of 14 patients suffering from B-CLPD complicated by AIHA were retrospectively analyzed in Wuxi People Hospital and the First Affiliated Hospital of Nanjing Medical University from 2000 to 2012. The results showed that 9 cases of the 14 patients were patients with chronic lymphocytic leukemia (CLL), 5 cases were patients with lymphoma, at time of hemolysis the median level of hemoglobin was 61 (33 - 84)g/L, the median ratio of reticulocytes was 12.0 (3.1 - 35.0)%, the positive rate of Coombs test was 100%. 1 case received corticosteroid alone, 5 cases were treated with chemotherapy combined with corticosteroid, 8 cases were treated with immunochemotherapy rituximab combined with corticosteroid. Overall response rate was 100%, in which CR was 78.6% (11/14), PR was 21.4% (3/14). The follow-up for these patients were performed to now, 35.7% (5/14) patients relapsed with hemolysis again, but they showed therapeutic response to treatment with above mentioned therapy. From patients treated with rituximab alone, only 1 patient relapsed. Among 14 patients, 6 cases died, 1 case was lost, the other cases are still alive. It is concluded that the AIHA is the commonest complication of B CLPD, it can be observed at different stages of B-CLPD, the treatment with corticosteroids can give well therapeutic effect for these patients, but the long time CR is lower, the rituximab has been confirmed to be effective for B-CLPD complicated by AIHA. PMID- 23815913 TI - [Relation of B7-H3 molecule expression in multiple myeloma with poor prognosis and bone destruction]. AB - This study was purpose to investigate the B7-H3 expression in multiple myeloma cell lines and CD138 cells of patients with multiple myeloma, and explore its clinical significance. Three myeloma cell lines (RPMI8226, U266 and H929) were used. Forty-five patients with multiple myeloma were enrolled in the study. The expression of B7-H3 was detected by flow cytometry and RT-PCR. The relationship between B7-H3 and clinical prognostic factor was analyzed. The results showed that (1)In myeloma cell lines, high expression of B7-H3 was seen in RPMI8226 (92.30 +/- 1.1)% and U266 (79.03 +/- 1.2)% but not in H929 cell line (4.26 +/- 0.2)%. (2) Exogenous IL-6 had no effect on upregulation of B7-H3 in myeloma cell lines. (3) In multiple myeloma patients, the proportions of B7-H3 positive cells in newly diagnosed, remission and relapsed patients were (48.58 +/- 33.593)%, (22.16 +/- 18.853)%, and (57.65 +/- 28.296)%, respectively. The difference between the newly diagnosed and remission patients, and remission and relapsed patients was significant (P = 0.023, P = 0.004). (4)High B7-H3 expression was correlated with high numbers of bone destruction and high levels of serum calcium (P = 0.027, P = 0.046, respectively). It is concluded that the relation of B7-H3 molecule expression with prognosis of multiple myeloma may be negative, but with degree of bone destruction is positive, thus the high expression of B7-H3 may correlated with disease progression and bone destruction of patients with multiple myeloma. PMID- 23815914 TI - [Mechanisms of ROS in U266 cell death induced by FTY720]. AB - This study was purpose to investigate the role of reactive oxygen species (ROS) in apoptosis and autophagy induced by FTY720 in multiple myeloma cell line U266. U266 cells were treated by different concentrations of FTY720 for 24 h, the apoptotic rates were detected by flow cytometry, and the expression of LC3B was detected by Western blot. The results indicated that apoptosis and autophagy were induced by FTY720 in U266 cells. Autophagy induced by FTY720 could lead to cell death. Bafilomycin A1, the inhibitor of autophagy, could enhance the cell viability in U266 cells treated with FTY720. NAC or Tiron, ROS scavenger, could decrease the FTY720 induced apoptosis and the expression of LC3B-II was reduced in combination of FTY720 with NAC or Tiron as compared with treatment with FTY720 only. It is concluded that FTY720 can induce U266 cell apoptosis and autophagy. ROS is the mediator that regulates both the apoptosis and autophagy in multiple myeloma cells. PMID- 23815915 TI - [Therapeutic efficacy analysis of VD regimen and VAD regimen for multiple myeloma]. AB - This study was purpose to explore the therapeutic efficacy and safety of VD regimen and VAD regimen for patients with multiple myeloma. The clinical data of 59 patients with multiple myeloma in our hospital from June 2008 to June 2011 were analyzed retrospectively. The 59 patients with multiple myeloma were divided randomly into VD and VAD groups. The patients in VD group were treated with bortezomib combined dexamethasone. The patients in VAD group were treated with vincristine, doxorubicin and dexamethasone. The efficacy, median survival time, 1 and 2-year survival rate, and toxicity were estimated for the patients in VD group and VAD group. The results showed that the efficacy in the VD group and VAD group was 83.78% and 59.09% respectively. The efficacy in the VD group was significantly higher than that in the VAD group (P < 0.05). The median survival time and 1-and 2-year survival rate in VD group were significantly higher than that in VAD group (P < 0.05). The side effects in VD group mainly were haematologic toxicity, gastrointestinal disorder and peripheral neuropathy. The adverse events were mild and tolerable. The main side effects in the VAD group were haematologic toxicity, infection and hair loss. Most of the infectious in VAD group were at Grade III-IV. It is concluded that VD regimen is an effective and safe therapy regimen for multiple myeloma, and it seems significantly superior to VAD regimen and its side effect can be tolerable for the patients. PMID- 23815916 TI - [Study of the clonal origin and development of MDS by FISH analysis of dysplasia cells in bone marrow of patients with MDS]. AB - This study was purpose to explore whether the dysplasia of myelodysplastic syndromes (MDS) is unspecific feature or results of the abnormal clone, and to provide the evaluation of abnormal clone changes in bone marrow cells of MDS patients. The dysplasia cells in bone marrow smears was analyzed by morphologic observation, the clonal origin and development in 16 cases of MDS with abnormality of chromosome karyotypes were investigated by FISH combined with morphologic observation. The results found that both the dysplastic and nondysplastic bone cells displayed abnormal clones in the erythroid and granulocytic cells. The dysplastic bone marrow cells displayed more abnormal clones than the nondysplastic bone marrow cells in most of the patients, and the abnormal clones displayed more dysplastic cells than the normal clones. Most of the dysplastic and nondysplastic megakaryocytes were derived from abnormal clones. The abnormal clone showed a decreasing trend from the primitive stage to the terminal stage of cell differentiation. It is concluded that there is a correlation between the dysplastic cells and the abnormal clones in MDS, but the dysplasia of bone marrow cells is not a specific feature. The abnormal clones can differentiate into mature granulocytes and erythrocytes, and can be in coexistence with cells originated from the normal clones. PMID- 23815917 TI - [Diagnostic value of dysplasia characteristics in typing of myelodysplastic syndrome]. AB - This study was purpose to investigate the diagnostic value of hematopoietic cell dysplasia in myelodysplastic syndrome (MDS). Sixty-four cases of WHO-MDS were detected by cytomorphology, cytohistochemical staining and bone marrow biopsy. The characteristics of hematopoietic cell dysplasia were analyzed, and its sensitivity and specificity were evaluated for WHO-MDS diagnosis. The results showed that though myeloblast, megakaryocytes presented in peripheral blood and granular Auer body, abnormal granular pseudo Pelger-Huer, vacuole of erythroid, micro-megakaryocytes appeared in bone marrow for diagnosis sensitivity were not very high, and respectively were 34.4%, 3.1%, 3.1%, 75.0%, 6.3%, 42.4%, the specificity of these characteristics was 100%. Moreover, erythroid odd nucleus, nuclear deformity, fragmentation, nuclear budding, ring sideroblasts, single and more round nuclear megakaryocyte had better reference value for WHO-MDS diagnosis. By bone marrow biopsy, the dysplasia and abnormal localization of immature precursor (ALIP) also were found in patients with WHO-MDS. More than half patients with WHO-MDS had mild to moderate increase in reticulin fibres. It is concluded that the cytomorphology assay is the base and key for the diagnosis of WHO-MDS. Diagnostic accuracy can be improved by combinative use of a variety of detection methods. PMID- 23815918 TI - [Clinical efficacy of decitabine plus improved CAG chemotherapy and haplo identical donor peripheral lymphocyte infusion regimen on elderly patients with high risk myelodysplastic syndrome and acute myeloid leukemia]. AB - This study was aimed to observe the clinical efficacy and adverse effects of decitabine plus improved CAG chemotherapy and haploid-identical donor peripheral lymphocyte infusion regimen on elderly patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Five elderly patients with MDS and AML were treated with decitabine plus improved CAG chemotherapy and donor peripheral lymphocyte infusion regimen. Examinations on liver and renal function, electrocardiogram and bone marrow analysis were performed before and after treatment, and adverse effects were observed. The results indicated that after a course of treatment by decitabine plus improved CAG chemotherapy and haplo identical donor peripheral lymphocyte infusion regimen, the total effective rate was 100%, and 4 patients (80%) achieved complete remission, 1 patient achieved partial remission. The dominant clinical adverse effect was bone marrow depression, the median time of neutrophil>0.5*10(9)/L and platelet>20*10(9)/L was 15 d and 16 d respectively for patients without previous MDS. It is concluded that decitabine plus improved CAG chemotherapy and haploid-identical donor peripheral lymphocyte infusion regimen may be effective with less adverse effects for elderly primary AML and high risk MDS patients, it is a promising therapeutic methods and worthy to deeply study. PMID- 23815919 TI - [Transgenic mouse models of the truncated platelet integrin beta3 cytoplasmic tail established by stem cell transplantation]. AB - This study was purpose to establish the transgenic mouse models of the truncated platelet integrin beta3 by retrovirus-infected hematopoietic stem cells (HSCs) transplantation and to provide the basis for further study of the role of integrin beta3 cytoplasmic domain in platelet bi-directional signaling pathways. Wild-type beta3, beta3-Delta759 (R(760) GT(762) truncated beta3) and beta3 Delta754 (T(755) NITYRGT(762) truncated beta3) cDNAs were subcloned into MSCV MigR1 retroviral vector bearing a GFP gene and packaged into infective retrovirus with BOSC23 cell strain. The bone marrow HSCs of the beta3 deficient mice were infected by the retroviruses, and transplanted into lethally-irradiated wild type C57BL/6 mice. GFP positive rate and surface beta3 expression of the recipients' platelets at 6 to 8 weeks after transplantation were detected by flow cytometry to evaluate the transgenic efficiency. The results showed that four kinds of transgenic mouse models including vector, wild-type beta3, beta3-Delta759 and beta3-Delta754 were established successfully. GFP positive rates of transgenic mouse platelets ranged from 18% to 66% and the beta3 expression of transgenic mouse reached heterozygote (beta3(+/-) level of mouse). It is concluded that establishment of transgenic mouse models mediated by retrovirus-infected HSCs transplantation is a feasible, fast, and high throughput transgenic approach and laid a solid foundation for further research on the role of integrin beta3 cytoplasmic domain for bi-directional signaling of platelets in vivo, and for the gene therapy of platelet disorders. PMID- 23815920 TI - [Evaluation of a new method and instrument for detection platelet aggregation function and its clinical application]. AB - This study was purpose to evaluate a new method and instrument for detecting platelet aggregation function, establish the reference intervals for PL-11 platelet analyzer, and evaluate its clinical application. The evaluation was based on the guidelines of Clinical and Laboratory Standards Institute (CLSI or NCCLS) and Clinical Laboratory Improvement Amendment 88. Intravenous blood samples anticoagulated with sodium citrate were detected by PL-11 platelet analyzer. The reference intervals were defined after statistic analysis. The clinical diagnostic significance of the PL-11 platelet analyzer was evaluated by testing the change rate of platelet maximum aggregation rate (MAR) of acute cerebral infarction (ACI) patients in the department of Neurology who took clopidogrel 7 d before and after. The result showed that all the parameters meet the standard of CLIA'88. The platelet MAR of 247 healthy volunteers which was induced by PLR-06, PLR-07, PLR-09 and PLR-10, was detected by the PL-11 platelet analyzer, respectively. The MAR is 58.8 +/- 10.1 (%), 61.2 +/- 11.8 (%), 51 +/- 10.2 (%), 53.1 +/- 9.2 (%), respectively. The MAR of ACI patients is significantly lower than that after taking clopidogrel. It is concluded that the PL-11 platelet analyzer is an ideal platelet function detector for early warning and diagnosis of thromboembolic disease, which is worthy to be extended and applied. PMID- 23815921 TI - [Tissue factor expression of platelets and leukocytes in patients with acute coronary syndromes]. AB - The aim of this study was to investigate the tissue factor (TF) expression of platelets and leukocytes in patients with acute coronary syndrome (ACS), patients with stable angina (SA) and healthy subjects (as controls). 26 patients with ACS, 29 patients with SA, and 25 controls were enrolled in this study. The peripheral blood samples of above-mentioned subjects were collected and isolated to obtain the monocytes and platelet-rich plasma, the TF-mRNA expression of monocytes, and platelets among 3 groups was detected by RT-PCR, the TF expression ratio of platelets, platelet-leukocyte aggregates (PLA) and platelet-monocyte aggregates (PMP) was detected by flow cytometry among 3 groups. The results showed that the TF mRNA expression level of platelets in ACS group were significantly higher (3.11 +/- 0.51 relative expression) as compared with SA and control groups (1.88 +/- 0.78 and 0.7 +/- 0.1, respectively) (P = 0.03). Expression of TF mRNA of monocytes was higher in ACS group (P = 0.05 versus controls) too. ACS group had a significantly higher amount of TF-positive platelets (8.8 +/- 2.6) than SA (2.6 +/- 0.5, P = 0.02) or control groups (2.5 +/- 0.4, P = 0.02). A significantly greater number of TF positive platelet-leukocyte aggregates and platelet-monocyte aggregates were also found by flow cytometry in blood of ACS patients than in either SA patients or controls. It is concluded that the high TF expression of platelets and leukocytes in ACS patients strengthens the platelet activation, blood coagulation, and thrombus formation and may further contribute to the hypercoagulability associated with the disease. The present study further extends the proinflammatory/prothrombotic phenotype of ACS patients showing that new players on the scene. PMID- 23815922 TI - [Expression and significance of vitamin D and its receptor mRNA in the peripheral blood of initial immune thrombocytopenic patients]. AB - To investigate the effect of vitamin D in pathogenesis and clinical treatment of patients with immune thrombocytopenic (ITP), ELISA was used to detect the level of 25-hydroxylate vitamin D3[25(OH)D3] and 1,25-dihydroxyvitamin D3[1,25(OH)2D3] in peripheral blood from 45 ITP patients and 30 normal controls. Vitamin D receptor (VDR) mRNA expression was detected by RT-PCR. The results showed that the levels of 25(OH)D3 (10.6 +/- 7.7 ng/ml) and 1,25(OH)2D3 (69.9 +/- 29.0 pg/ml) in peripheral blood of the initial ITP patients were lower than those in peripheral blood of normal controls (13.7 +/- 9.1 ng/ml, 87.3 +/- 19.9 pg/ml) (P < 0.05). The expression of VDR gene obviously increased in peripheral blood of initial ITP patients (1.588 +/- 0.127), as compared with that in peripheral blood of normal controls (1.055 +/- 0.734) (P < 0.05). It is concluded that vitamin D level and its receptor expression may play an important role in ITP, and vitamin D and its similarities may be a new agent to treat patients with ITP. PMID- 23815923 TI - [Relationship between HLA-A, B alleles and red blood cell parameters of patients with --(SEA/alphaalpha) subtype of alpha(0)-thalassemia of Han ethnic population of Wuzhou city]. AB - This study was purposed to investigate the relationship between HLA-A, B allele polymorphisms and red blood cell parameters of patients with --(SEA/alphaalpha) subtype of alpha(0)-thalassemia in Han ethnic population of Wuzhou city. The HLA genetic polymorphisms were determined by polymerase chain reaction-sequence-based typing (PCR-SBT) in 57 patients with --(SEA/alphaalpha) subtype of alpha(0) thalassemia of Han ethnic population in Wuzhou city, Guangxi province, China. Mean corpuscular volume (MCV), hemoglobin (Hb), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) were detected by automatic blood analyzer system. HbA2 were detected by electrophoretic method. The statistical analysis was performed by ordinal polytomous logistic regression. The results showed that Hb and HbA2 levels were significantly lower in patients positive for HLA-A*33:03, B*15:01 or B*55:02, and were significantly higher in patients positive for B*15:02 (P < 0.05). It is concluded that several HLA alleles may be associated with Hb level of --(SEA/alphaalpha) subtype of alpha(0) thalassemia of Han ethnic population in Wuzhou city. This result has the value for understanding phenotype-genotype relationships in thalassemia. PMID- 23815924 TI - [Type III familial hemophagocytic lymphohistiocytosis susceptibility gene UNC13D involves in homologous recombination repair]. AB - This study was aimed to explore the pathogenesis of type III familial hemophagocytic lymphohistiocytosis (FHL3) via susceptibility gene UNC13D involving in homologous recombination repair (HRR) of DNA double-strand break (DSB). By means of DNA homologous recombination repair, the change of homologous recombination repair rate of normal control cells and DR-U2OS cells after down regulation of UNC13D was detected; the UNC13D gene related function was explored. The results showed that DR-U2OS cells displayed a significant reduction in homologous recombination repair of DNA DSB after siRNA knockdown of UNC13D, compared to its normal control cell counterparts (P < 0.05), suggesting that UNC13D was involved in DNA double-stranded breakage repair. It is concluded that UNC13D gene mutation may be involved in the pathogenesis of FHL3 via its dual effects of both the cytotoxic granule exocytosis and decrease of homologous recombination repair rate after the DNA double-strand break, therefore, providing a new theoretical basis to reveal the pathogenesis of FHL3. PMID- 23815925 TI - [Efficacy analysis of unrelated donor hematopoietic stem cell transplantation for treatment of high risk acute myeloid leukemia]. AB - This study was purposed to investigate the therapeutic efficacy of unrelated donor hematopoietic stem cell transplantation (URD-HSCT) for patients with high risk and refractory acute myeloid leukemia (AML). Twenty-two patients with high risk and refractory AML receive URD-HSCT were enrolled in this study. All the patients received myeloablative preconditioning regimen consisting of busulfan/cyclophosphamide (for 20 cases) or total body irradiation/cyclophosphamide (for 2 cases) before URD-HSCT. The cyclosporin A (CsA)/MTX/MMF/ATG were used to prevent the acute graft versus host disease (aGVHD). The results showed that 21 out of 22 patients acquired engraftment with implantation rate 95.5%. The median time of ANC >= 0.5*10(9)/L was 12 (10-19) days, and that of Plt >= 20*10(9)/L was 14 (5 - 22) days. The median follow-up time post transplantation was 18 (3 to 135.5) months. The 2-year overall survival (OS) and leukemia-free survival (LFS) were (53.9 +/- 12.2) % and (49.1 +/- 10.7)% respectively. Eight cases developed aGVHD. The cumulative incidence of aGVHD was (39.1 +/- 10.6) %. Six patients developed I-II grade of aGVHD and two patients developed III-IV grade of aGVHD. The chronic graft versus host disease (cGVHD) was occurred in 6 patients (4 patients limited, 2 patients extensive) of the 19 evaluable patients. The cumulative incidence was (28.8 +/- 9.6)%. Seven cases relapsed, and the cumulative response rate of 2 years was (35.8 +/- 11) %. One of 9 patients died from sepsis before hematopoietic reconstruction, one died from lung infection, Six died from relapse and one relapsed patient died from IV grade of aGVHD post chemotherapy and donor lymphocyte infusion (DLI). The univariate analysis revealed that relapse was the major factor for the OS, and the sex, age, preconditioning regimen, aGVHD and infection didn't significantly influence the efficacy of URD-HSCT. The survival of patients with cGVHD was superior to those who didn't have cGVHD (83.3% vs 37%, P = 0.152). It is concluded that URD-HSCT is a safe and effective therapy for high-risk AML patients without related donor. Notably, patients with cGVHD had a better survival. Relapse is an unfavourable factor for the efficacy of URD-HSCT and adoptive immunotherapy such as DLI can prevent it and improve the prognosis to achieve the long-time survival. PMID- 23815926 TI - [Analysis of T lymphocyte absolute number and function in the early phase after haploidentical hematopoietic stem cell transplantation]. AB - This study was purposed to investigate the immune reconstitution of T-cells in patients who received haploidentical hematopoietic stem cell transplantation (hiHSCT). The peripheral blood was harvested from 22 patients before transplantation and at month 1, 3, 6 after hiHSCT. The proportions of T lymphocyte subtypes including CD3(+), CD4(+), CD8(+), CD45RO(+), and CD45RA(+)CD62L(+) were analyzed by flow cytometry, followed by the calculation of T cell numbers according to the amounts of peripheral blood leukocytes. Adenosine triphosphate (ATP) value in CD4(+) T cells was measured by ImmuKnow method to evaluate the function of lymphocytes. The results showed that the CD3(+) cell absolute value before transplantation was 833.75 +/- 359.84/ul, but those values at month 1, 3, 6 after transplantation were 318.87 +/- 266.71/ul, 1006.76 +/- 512.32/ul and 1296.38 +/- 958.77/ul respectively. The CD4(+) cell absolute value before transplantation was 336.99 +/- 211.11/ul, but such values at month 1, 3, 6 after transplantation were 45.89 +/- 44.21/ul, 142.97 +/- 114.85/ul, and 181.78 +/- 120.61/ul respectively. The CD8(+) cell absolute value before transplantation was 430.21 +/- 159.48/ul, but those values at month 1, 3, 6 after transplantation were 230.44 +/- 195.89/ul, 621.64 +/- 318.83/ul, and 823.07 +/- 633.55/ul respectively. The CD4(+)CD45RO(+) memory T cell absolute value before transplantation was 227.44 +/- 73.34/ul, but such values at month 1, 3, 6 after transplantation were 43.47 +/- 43.40/ul, 138.69 +/- 110.17/ul, 147.73 +/- 82.94/ul respectively. The CD8(+)CD45RO(+) memory T cell absolute value before transplantation was 212.70 +/- 98.48/ul, but such values at month 1, 3, 6 after transplantation were 184.76 +/- 168.65/ul, 445.90 +/- 252.50/ul, 519.80 +/- 475.53/ul respectively. CD4(+)CD45RA(+)CD62L(+) naive T cell number before transplantation was 68.94 +/- 59.74/ul, but such cell numbers at month 1, 3, 6 after transplantation decreased to 2.44 +/- 2.93/ul, 3.14 +/- 3.48/ul, 23.22 +/- 38.38/ul respectively. The CD8(+)CD45RA(+)CD62L(+) naive T cell absolute value before transplantation was 124.82 +/- 60.95/ul, but those values at month 1, 3, 6 decreased to 19.37 +/- 17.71/ul, 76.63 +/- 50.85/ul, and 114.49 +/- 174.29/ul respectively. The ATP value in CD4(+) T cells decreased to 210.19 +/- 119.37 ng/ml at month 1 after transplantation and increased to 280.62 +/- 110.03 ng/ml at month 3, and 357.28 +/- 76.18 ng/ml at month 6 after transplantation. It is concluded that CD8(+) memory T cell reconstruction contributes critically to T cell recovery early after hiHSCT, while the thymic output function remains low. However, T cell function recovers to normal range at month 3 after transplantation. PMID- 23815927 TI - [HLA antigen compatibility between patients with hematologic diseases and their parents]. AB - This study was aimed to investigate and analyze the HLA antigen compatibility between patients with hematologic diseases and their parents so as to provide basis for selecting the suitable donors in haploidentical hematopoietic stem cell transplantation. The HLA low resolution for 174 families was typed and analyzed by using PCR-SSP. The results showed that 52.30% of patients with hematologic diseases possessed father and/or mother with HLA matching over haploidentity, 10.92% patients were over 8/10 matched with their father and/or mother. 11.49% were over semi-matched with both their father and mother. The rate of 6/10 matched pairs (28.16%), 7/10 matched pairs (16.1%) and 8/10 matched pairs (8.62%) were all beyond 5%; 9/10 (2.3%) and 10/10 matched pairs (1.15%) were all below 5%. It is concluded that with the matching degree increasing between two generations, HLA matching rate is decreasing. Over 50% and 10% patients were over HLA semi-matched and 8/10 matched with their father and/or mother, respectively. This high matching rate offered a big chance for success of haploidentical HSCT. Patients are more likely over semi-matched with their father and/or mother when they have high frequency and strong linkage HLA disequilibrium. High frequency and strong linkage disequilibrium in populations are main reason, and population concentrating and isolated living may be another reason for this phenomenon. PMID- 23815928 TI - [Treatment of leukemia with immunized donor cell infusion after nonmyeloablative haploidentical bone marrow transplantation]. AB - This study was purposed to investigate the therapeutic effects of early transfusion of immunized donor lymphocytes after haploidentical transplantation by means of mouse model of nonmyeloablative haploidentical bone marrow transplantation. CB6F1 female mouse was served as recipient and C57BL/6 male mouse was served as donor. Each CB6F1 female mouse was subjected to intravenous transfusion with 1*10(6) erythroleukemia (EL9611) cells at day 4 before transplantation, followed with intraperitoneal injection of Ara-C (0.015 g) respectively at day 2 and day 1, then conditioned for BMT with TBI (450 cGy) at day 1 before transplantation. After conditioning (day 0), each of recipients was transplanted with 6*10(7) mixture of bone marrow and spleen cells from the C57BL/6 mice, and was infused with 6 * 10(7) immunized donor lymphocytes at day 15 after transplantation. All treated animals were evaluated for survival, development of leukemia and aGVHD. The donor CD3(+) cell chimerism and sex determining region Y gene (SRY)in recipients were monitored periodically after transplantation. The results showed tht all mice with only inoculation of 10(6) EL9611 cells survived for 15 +/- 1 days (n = 4); all mice of other groups obtained the varying degrees of implantation. SRY could be detected at day 30 and 60 after transplantation. The chimerism of donor CD3(+) cells in mixed bone marrow transplantation (MT) group at day 14, 30 and 60 respectively reached 17.95% +/- 12.03%, 37.34% +/- 2.78% and 47.06% +/- 6.1%. In donor lymphocyte infusion (DLI) group it reached 69.78% +/- 12.62%, 75% +/- 15.97%, 83.41% +/- 16.07% at day 30, 45 and 60 after transplantation. The mice of MT and DLI group survived for 66.66 +/- 1.47 days and 78.2 +/- 7.82 days. It is concluded that the high tumor burden before transplantation can affect donor cell engraftment and prognosis.Early post-transplanted infusion of immunized lymphocytes from donor can help to improve the therapeutic efficacy and survival. PMID- 23815929 TI - [Curative effect of human umbilical cord mesenchymal stem cells for treatment of acute graft-versus-host disease of children after allo-HSCT]. AB - This study was aimed to investigate the curative effect and safety of human umbilical cord mesenchymal stem cells (hUCMSC) to treat acute graft-versus-host disease (aGVHD) of children after hematopoietic stem cell transplantation (HSCT). HUCMSC were isolated and cultured by collagenase digestion and passage culture. The 3rd to the 5th passage of hUCMSC were used for clinical treatment. Five cases of children acute leukemia achieved complete remission after chemotherapy. Two cases received HLA 3/6 loci matched haploidentical bone marrow HSCT. One case received HLA-matched sibling bone marrow and peripheral blood HSCT. One case received unrelated HLA 4/6 loci matched umbilical cord blood HSCT. One case received unrelated HLA 5/6 loci matched umbilical cord blood HSCT. The children received immunosuppressive therapy after III-IV aGVHD occurring. They received 0.5*10(6)/kg hUCMSC infusion when conventional therapy was ineffective. The results showed that 5 cases of children acute leukemia achieved hematopoietic reconstitution and developed the III-IV grade aGVHD. The five cases of children were infused with hUCMSC. The rash subsided, the liver function was normalized and the gastrointestinal symptoms were improved. The infusion-related adverse reaction did not happen. At present, the 5 children are in remission. It is concluded that allogeneic HSCT is an effective therapeutic method for children with acute leukemia. HUCMSC infusion can be safely and effectively used for the treatment of refractory aGVHD. PMID- 23815930 TI - [Different changes of serum cytokines following HLA-identical and HLA haploidentical non-myeloablative allogeneic hematopoietic stem cell transplantation]. AB - This study was aimed to investigate the expression difference of serum cytokines in 20 patients receiving HLA-identical nonmyeloablative allogeneic hematopoietic stem cell transplantation (iNAHSCT) and HLA-haploidentical nonmyeloablative allogeneic hematopoietic stem cell transplantation (hiNAHSCT). IL-2, IL-4, IL-6, IL-10, TNF-alpha, gamma-IFN and IL-17 were detected by flow cytometric bead array before and on week 1, 2, 4 after transplantation respectively. The results showed that the IL-2 level was found to be up-regulated at week 1 and 2 after transplantation in iNAHSCT group and in hiNAHSCT group respectively, but there was no difference between these two groups (P > 0.05). The gamma-IFN levels was up-regulated at week 4 after transplantation in above-mentioned two groups, but no difference was found between these two groups. The IL-4 level increased at week 2 and 1 after transplantation in iNAHSCT and hiNAHCT groups respectively, but the IL-4 level in iNAHSCT group was higher than that in hiNAHSCT group. The IL-6 level rose at week 1 and 2 after transplant in above mentioned groups respectively, and reached to peak level at week 4 after transplantation, but IL-6 level in hiNAHSCT was higher than that in iNAHSCT group (P < 0.02). The IL-10 level was up-regulated at week 1 and 2 in iNAHSCT and hiNAHSCT groups respectively, but the IL-10 level in iNAHSC was higher than that in hiNAHSCT group. The TNF-alpha level was up-regulated at week 1 in hiNAHSCT group, but at week 2 in iNAHSCT group after transplantation. The TNF-alpha level in hiNHASCT group was higher than that in iNAHSCT group (P < 0.01). The IL-17 level was up regulated at week 1 and week 4 after transplantation in hiNAHSCT and iNAHSCT groups respectively, the IL-17 level in hiNAHSCT group was high as compared with that in iNAHSCT group. It is concluded that the serum cytokine levels are obviously up-regulated in iNAHSCT and hiNHASCT groups, and reach to peak level at week 4 after transplantation. The IL-6, TNF-alpha and IL-17 level up-regulated significantly in hiNAHSCT group, but the IL-4 and IL-10 level up-regulated significantly in iNAHSCT. PMID- 23815931 TI - [Efficient reprogramming of human cord blood CD34(+) cells for formation of induced pluripotent stem cells with non-integrating plasmid system]. AB - This study was to establish the episomal vector reprogramming method to reprogram iPSC from human cord blood (CB) CD34(+) cells. The non-integrating plasmids of pEB-C5 and pEB-Tg were transfected into short-term cultured CB CD34(+) cells by using the nucleofector, so as to demonstrate efficient reprogramming of CB CD34(+) cells. Within 14 days of one-time transfection by two plasmids together, up to 200 iPSC-like colonies per 2 million transfected CB CD34(+) cells were generated. The results showed that the pluripotency of iPSC-derived CB CD34(+) cells was similar to that of hESC and the karyotypes of iPSC were normal. In addition, no vector integration was found in iPSC of 9th and 10th passages. Furthermore, hiPSC formed teratoma with three embryonic germ layers. It is concluded that the integration-free method to generate human iPSC from CB CD34(+) cells is reliable and can provide new ways for both research and future clinical applications. PMID- 23815932 TI - [Knockdown of Larp4b in Lin(-) cells does not affect the colony forming ability of mouse hematopoietic cells]. AB - Larp4b is a member of the LARP family, which can interact with RNA and generally stimulate the translation of mRNA. Abnormal expression of Larp4b can be found in leukemia patients in our previous study. This study was purposed to detect the relative expression of Larp4b mRNA in different subpopulations of mouse hematopoietic cells, to construct lentivirus vector containing shLarp4b targeting mouse gene Larp4b and to explore its effects on mouse Lin(-) cells infected with shLarp4b by lentivirus. SF-LV-shLarP4b-EGFP and control vectors were constructed and two-plasmid lentivirus packing system was used to transfect 293T cells. After 48 h and 72 h, lentivirus SF-LV-shLarp4b-EGFP was harvested and was used to infect Lin(-) cells. After 48 h, EGFP(+) cells was sorted by flow cytometry (FCM). Meanwhile, semi-quantitative real time-PCR, AnnexinV-PE/7-AAD staining, PI staining and colony forming cell assay (CFC) were performed to determine the expression of Larp4b and its effect on the proliferation of hematopoietic progenitor cells. The results showed that Larp4b was highly expressed in myeloid cells. SF-LV-shLarp4b-EGFP was successfully constructed according to the restriction endonuclease digestion assay. RT-PCR confirmed that Larp4b was efficiently knockdown in mouse Lin(-) cells. The low expression of Larp4b did not affect the colony forming number, the apoptosis and cell cycle of Lin(-) cells. It is concluded that knockdown of Larp4b in mouse Lin(-) cells do not contribute to the colony forming ability and the growth of Lin(-) cells in vitro. This useful knockdown system will be used to study in vivo Larp4b in future. PMID- 23815933 TI - [Effect of SNS-032 on biological activity of hematopoietic stem cells in mice]. AB - This study was aimed to investigate the effect of SNS-032 (C17 H24 N4O2S2) on cell cycle, apoptosis, differentiation and self-renewal of hematopoietic stem cells (HSC) in mice. The self-renewal capability of bone marrow cells was measured by cobblestone forming cell test. The expressions of self-renewal regulation genes, cell cycle-related genes, apoptosis-related genes were measured by real-time PCR. The cell cycle status and apoptosis of HSC and HPC were detected by flow cytometry. The results showed that there was no significant difference of the frequency of HSC between SNS-032 and control group. The expressions of CDK1, CDK2, CDK7 and p27 decreased in HSC (P < 0.05) while the expressions of CDK4, CDK6, p21, p18, p19, Bcl-2, Bax, Puma, p53, Bim1, Sall4 and Notch1 showed no difference between SNS-032 group and control group (P > 0.05). The fraction of viable HSC in each phase of cell cycle remained unchanged after the treatment of SNS-032 (P > 0.05). Furthermore, there was no statistical difference in the apoptotic fractions between control and drug-treated groups (P > 0.05). It is concluded that SNS-032 induce apoptosis of cancer cells. Interestingly, SNS-032 has no significant inhibitory effect on self-renewal and differentiation of normal HSC, as well as no obvious effect inducing apoptosis of normal HSC and HPC. PMID- 23815934 TI - [Mesenchymal stem cells and endothelial progenitor cells obtained from rabbit bone marrow with differential adhesion methods and their biological characteristics]. AB - This study was aimed to evaluate an effective and stable method for obtaining mesenchymal stem cells (MSC) and endothelial progenitor cells (EPC) from the rabbit bone marrow and to investigate the biological characteristics of MSC and EPC. Mononuclear cells were obtained from rabbit bone marrow using density gradient method, and were differentially adhered to the cell culture plate enclosed with fibronectin. Then, MSC and EPC were amplified with EGB-2MV medium. Trypan blue method was used to test the passage survival rate. Growth curve, MTT and DNA cycle were used to evaluate the proliferation ability of MSC and EPC. MSC were identified with induced differentiation into the osteoblasts and adipocytes, and their immune phenotype was detected by flow cytometry (FCM). EPC were characterized by the special digestion of Dil-ac-LDL, FITC-UEA-I, and the conjunction with CD133, VEGFR2/KDR and CD34, their purity was also calculated. The results indicated that the colony was obviously formed when the mononuclear cells were cultured for 24 hours and, 80% of the cells became long spindle and integrated at d 8. Cells, which were adhered for twice, were cultured with EGM 2MV medium, began to extend at d 3, and became strip-shaped and integrated for about 80% at d 8. Passage survival rates were more than 90% for both cells, and after passage 2 the growth curve was like "S". Optical density was changed obviously when the cells were cultured for 3 - 5 d, but there were no significant difference of cell cycles between MSC and EPC, which G0-G1 was (93.32 +/- 1.65)% and (93.05 +/- 1.95)% respectively. Positive rates were (99.7 +/- 1.12)%, (99.1 +/- 2.33)%, (4.8 +/- 0.38)%, (6.8 +/- 0.49)% and (0.4 +/- 0.08)% for CD90, CD44, CD14, CD45 and CD79a respectively. MSC were identified by induced differentiation into osteoblasts and adipocytes. Positive rates of the EPC, which were adhered for twice and passaged 2, were (82.1 +/- 3.4)% for fluorescent staining of Dil-ac LDL and FITC-UEA-I, and (74.2 +/- 3.2)%, (64.7 +/- 4.3)% and (43.5 +/- 1.5)% for CD133, VEGFR2/KDR and CD34 respectively. It is concluded that high-purity MSC can be obtained with density gradient and differential adhesion method, and high proliferation EPC can be cultured with EGM-2MV medium in cell plates enclosed with fibronectin, so they may become the optimal seed cells for tissue engineering study. PMID- 23815935 TI - [Isolation and biological characteristics of mesenchymal stem cells derived from human placenta decidua basalis]. AB - Comparing to bone marrow mesenchymal stem cells (MSCs), placenta-derived MSCs have the advantages of adequate sources, low immunogenicity, little risk of viral contamination, and no ethical controversy, and thus possess a better prospect for clinical application. Placental tissue not only includes chorionic and amniotic, but also contains decidua basalis which locate in the maternal placenta surface. The biological characteristics of MSCs isolated from decidua basalis have not been well studied. This study was aimed to investigate the biologic characteristics of placenta decidua basalis-derived MSC from placenta decidua basalis (DB) by enzymatic digestion. Short tandem repeats (STR) test was used to identify the cells derived from the maternal placenta surface. Growth rate of decidua basalis mesenchymal stem cells (DB-MSC) was measured by MTT. Cell cycle and cell phenotype were detected by flow cytometry. Inducing differentiation was used to evaluate multipotency of DB-MSC. For testing the immunosuppression of DB MSC, they were co-cultured with peripheral blood mononuclear cells (PBMNC) stimulated by phytohemagglutinin (PHA) and then IFN-gamma in the co-cultured media was quantified by ELISA. The results showed that the cells were derived from the maternal placenta by STR analysis. DB-MSC showed typical fibroblast morphology in the culture and were positive for the MSC surface markers: CD90, CD73, CD105, CD44 and negative for CD45, CD11b, and CD34. DB-MSC underwent osteogenic, adipogenic and chondrogenic differentiation in inducing medium. DB MSC could inhibit the secretion of IFN-gamma by PBMNC. It is concluded that the cells are isolated from placenta decidua basalis and possess the basic characteristics of MSC. DB-MSC can be an important maternal autologous MSC and may be a safe and effective treatment for immune system diseases, which makes the DB-MSC as an important source of autologous MSC from mother. DB-MSC can be safely for the treatment of the mother's immune system diseases. PMID- 23815936 TI - [Human umbilical cord mesenchymal stem cells reduce the sensitivity of HL-60 cells to cytarabine]. AB - This study was purposed to investigate the impact of human umbilical cord-derived mesenchymal stem cells (hUC-MSC) on the sensitivity of HL-60 cells to therapeutic drugs so as to provide more information for exploring the regulatory effect of hUC-MSC on leukemia cells. Transwell and direct co-culture systems of HL-60 and hUC-MSC were established. The apoptosis and cell cycle of HL-60 cells were detected by flow cytometry. RT-PCR and Western blot were used to detect the mRNA and protein levels of Caspase 3, respectively. The results showed that the apoptosis of HL-60 induced by cytarabine (Ara-C) decreased significantly after direct co-cultured with hUC-MSC cycle mRNA (P < 0.05). The similar phenomenon was observed in transwell co-culture system. Cell cycle of HL-60 cells were arrested at G0/G1 phase and did not enter into S phase (P < 0.05) and the expression of Caspase-3 mRNA and protein in HL-60 cells were reduced (P < 0.05). It is concluded that hUC-MSC protected HL-60 from Arc-C induced apoptosis through regulating the cell cycle and down-regulating expression of Caspase 3 in HL-60 cells. In addition, this effect is caused by the soluble factors from hUC-MSC. PMID- 23815937 TI - [Therapeutic effect of human bone marrow mesenchymal stem cell lysates on rat arthritis induced by collagen]. AB - Our previous work has shown that mesenchymal stem cells (MSC) have little therapeutic effect on rat arthritis induced by collagen. This study was aimed to further investigate whether the MSC lysates exhibit beneficial effects on rheumatoid arthritis. Aliquots of cell lysates from 1*10(7) human bone marrow MSC were intraperitoneally injected into collagen-induced arthritis (CIA) Wistar rats weekly for 4 consecutive weeks. Methotrexate at a dose of 1 mg/kg or normal saline was served as positive and negative controls respectively. On week 4 the symptom scores were recorded and the hind joints of the rats were pathologically examined and X-ray examination was performed. The results showed that on week 4, the symptom scores of the rats that received MSC lysates (6.87 +/- 0.83) and MTX (6.44 +/- 1.13) were significantly lower than that of control rats (7.33 +/- 0.77, P < 0.01). Meanwhile, pathological examination on the involved ankle showed that the synovitis and arthritis scores of MSC lysates and control groups were 2.28 +/- 0.48 and 2.28 +/- 0.55 respectively, significantly higher than that of MTX treatment rats (0.71 +/- 0.48, P < 0.05). However, X-ray examination on the ankle joints showed that the injury score of control rats was 4 +/- 0.57, greatly higher than those from MSC lysates (2.71 +/- 0.75) and MTX treatment groups (2.57 +/- 0.78, P < 0.05 for both groups). It is concluded that MSC lysate infusion has beneficial effects on CIA rat, but the effectiveness seems inferior to MTX. PMID- 23815938 TI - [Mechanism of MBL inhibiting the LPS-induced DC maturation]. AB - The study was aimed to investigate the mechanism of mannan-binding lectin (MBL) on bacterial lipopolysaccharide (LPS)-induced human peripheral blood monocyte derived dendritic cell (DC) maturation. The monocytes were prepared from the peripheral blood of healthy adult volunteers. The immature dendritic cells (imDC) were induced by 5-day-culture in medium supplemented with rhGM-CSF and rhIL-4. FACS was used to investigate the interaction of MBL with imDC and the impact of MBL on LPS binding to imDC. ELISA and Western blot was used to analyze the interaction of MBL with soluble TLR4 ectodomain protein (sTLR4); Western blot was used to detect LPS-induced NF-kappaB translocation in imDC. The results showed that MBL could directly bind to imDC in the presence of calcium. sTLR4 protein or LPS could competitively inhibit the binding of MBL to imDC. ELISA and Western blot showed that MBL could evidently bind to sTLR4 protein in a concentration dependent manner. FACS showed that MBL could competitively inhibit the binding of LPS to imDC by binding to imDC directly. Western blot showed that MBL decreased LPS-induced NF-kappaB translocation in imDC. It is concluded that MBL may competitively inhibit the binding of LPS to imDC by binding to TLR4 expressed on imDC, resulted in inhibition of LPS-induced DC maturation, suggesting that MBL can regulate DC maturation through ligand-binding. This study provides the good foundation to clarify the mechanism of MBL inhibiting the LPS-induced DC maturation. PMID- 23815939 TI - [Effects of different lyophilizing protectants on lyophilized trehalose-loading red blood cells]. AB - This study was purposed to evaluate the effect of different lyophilizing protectants including human albumin, glucan, polyvinyl pyrrolidone and glycerine on lyophilized trehalose-loading red blood cells (RBC), then to screen the optimal lyophilizing protectant. The RBC were incubated in 800 mmol/L concentration of trehalose solution at 37 degrees C for 7 hours, and washed 3 times with PBS solution to obtain the trehalose-loading RBC. The trehalose loading RBC in control group were directly lyophilized without lyophilizing protectants, the trehalose-loading RBC in the experimental group were mixed with Lyophilizing protectants. The samples of 2 groups were kept at room temperature for 30 minutes, pre-frozen at -80 degrees C for 24 hours, then lyophilized in freeze-dryer for 24 hours. Finally the samples were quickly rehydrated by 6% HES at 37 degrees C. The recovery rate and hemolysis rate of hemoglobin were detected by using cyanohemoglobin detection kit. The water content of unhydrated samples were detected at the same time. The results showed that when the moisture content of sample was 3% - 5%, the recovery rate of hemoglobin in control group was 33.57 +/- 2.89%, and that in experimental group was 51.15 +/- 1.98%, there was statistically significant difference between the control and experimental group (P < 0.05). When the different concentration of dextran solution was chosen as protectants, the recovery rate of hemoglobin of lyophilized RBC was obviously lower. The higher concentration of dextran, the better the recovery rate. The recovery rate of hemoglobin was 22.15 +/- 4.12% when the concentration of dextran was 36%, there were statistically significant difference between the two groups (P < 0.05). When the different concentration of polyvinyl pyrrolidone (PVP) solutions was chosen as protectants, especially the concentration below 40%, the recovery rate of hemoglobin of lyophilized RBC was significantly belower than the control group, there was statistically significant difference between the two groups (P < 0.05). When 10% glycerol was used as protectants, the recovery rate of hemoglobin was 3.93 +/- 1.80%. There was also statistically significant difference between the two groups (P < 0.05). It is concluded that human serum albumin shows an important protective effect on the lyophilization of the trehalose-loading red blood cells. The dextran and PVP at the concentration lower than 40% can decrease the protective effect of trehalose in cells. Glycerol can not be chosen as protectant for lyophilized trehalose-loading red blood cells. PMID- 23815940 TI - [Identification and genotyping of difficult blood groups in the patients with phymatosis]. AB - In part of the patients with blood disease or malignant tumors, especially those with leukemia and multiple myeloma, the disease state and unsuitable treatment often resulted in the inconsistence between positive and negative ABO blood group, displaying attenuation of the antigen or antibody of ABO blood group. This study was purposed to analyze the course of inconsistence between positive and negative ABO blood group and to perform the correct typing of erythrocytes and genes. The serology, absorption and elution test were used to examine the 12 tumor patient of the inconsistence between positive and negative typing. The 6th, 7th exon and 5-7th introns were amplified by PCR for questionable samples, and the gene sequencing of exon was performed. The results showed that 9 specimens were determined as 6 of A group, 2 of O group, 1 of B group, 3 cases were identified as O46, B108, and A102 group, respectively, by the serology, absorption and elution typing. The genotype of 2 cases among them was not identified because of the erroneous PCR amplified result or the contradicted sequencing results, failing to determine the ABO genotype. It is concluded that the serological method for blood grouping, genotyping, absorption and elution method can be used for the blood samples unable to typing because of the inconsistence between positive and negative typing of ABO group, therefore, guaranteeing the safety and effectiveness. PMID- 23815941 TI - [Research advances in value of flow cytometric immunophenotyping in diagnosis and prognostic evaluation of myelodysplastic syndrome]. AB - Myelodysplastic syndromes (MDS) are myeloid neoplasms characterized by dysplasia in one or more linages of cells and increased risk of development of acute myeloid leukemia (AML). Along with the deeply understanding of myelodysplastic syndrome, the diagnosis standards of this disease experienced a leap in essence: from a single standard of morphological test in FAB to multiple detecting means in WHO standard of 2008, flow cytometry has been proposed as an adjunctive diagnostic test in the 2007 Vienna standards and the 2008 WHO standards. Recently, A heterogeneous spectrum of immunophenotypic abnormalities have been reported in MDS, and some of which are of great significance to the diagnosis, classification, prognosis assessment, and treatment of the disease. In the year of 2003, a flow cytometric scoring system (FCSS) was built to evaluate the prognosis of MDS patients, which was able to qualify the phenotypic aberrancies in the myelomonocytic, erythroid, and megakaryocytic lineage. It filled the gap of the international prognostic scoring system (IPSS) and the WHO classification based prognostic scoring system (WPSS), and was of great value to the clinical diagnosis and treatment of MDS. In this article, the value of MDS immunophenotyping in diagnosis and prognosis evaluation of MDS is reviewed in term of MDS immunophenotypic abnormalities and flow cytometric scoring system. PMID- 23815942 TI - [Progress of studies on genetics of childhood acute leukemia]. AB - This study on determination of leukemia-specific chromosomal abnormalities and their relationship with prognosis of childhood acute leukemia (AL) had an important significance for childhood acute leukemia. In recent years, the efficacy of treatment of childhood AL has been greatly improved, but relapse is still a main factor affecting prognosis. Treatment based on the risk stratification by cytogenetic abnormalities can improve the prognosis and survival rate. In the past 3 decades, the genetic techniques have developed rapidly and many new genetic abnormalities have been found. This review highlights the main chromosomal and genomic abnormalities of 3 common childhood AL, including B-cell precursor acute lymphoblastic leukemia (BCP-ALL), T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). PMID- 23815943 TI - [Progress of study on PML in cancer stem cell of hematologic malignancies]. AB - The promyelocytic leukemia protein (PML), encoded by PML gene, plays a tumor suppressor in acute promyelocytic leukemia and other hematologic malignancies. Recent evidence indicates that PML involves in regulating multiple cell biological function, regulates self-renewal and maintains stable function in stem cell/cancer stem cell of multiple tissues, leading to drug resistance of cancer. This review summarizes the latest research advances about the relationship and therapeutic options between PML and cancer stem cell of hematologic neoplasms, aiming to propose a new avenue for blood cancer treatment. PMID- 23815944 TI - [Research advance in von Willebrand factor]. AB - von Willebrand factor (vWF) is a multimeric glycoprotein exclusively synthesized in endothelial cells and megakaryocytes. It plays important roles in the primary and secondary haemostasis. Deficiency or dysfunction of vWF may cause von Willebrand disease (vWD), and overexpression of vWF may cause thrombosis. Making an intensive study on vWF will help us to understand the pathophysiology, diagnosis and treatment of vWF-related diseases, such as vWD, TTP, venous thrombosis, stroke, and so on. In this article, the regulation of vWF activity and its relation with diseases mentioned above are reviewed. PMID- 23815945 TI - Influence of miRNA-155 on lymphoma. AB - Lymphomas are the most common ones of hematologic tumors. In China, Hodgkin's lymphoma accounts for 9% - 10% of lymphomas, which has a good response to chemotherapy, while non-Hodgkin's lymphoma accounts for nearly 90% of lymphomas, and the incidence of which tends to rise in recent years. At present, it was realized that miRNA and lymphomas are closely related to each other. More attention has been paid to the effects of miRNA on the pathophysiological process of lymphoma. This review is focused on miRNA-155, one of the miRNA family members, and its action mechanism in diffuse large B-cell lymphoma, Burkitt lymphoma and Hodgkin's lymphoma, expecting to shed light on the future therapy. PMID- 23815946 TI - [Relationship between microRNA-155 and hematological malignancies]. AB - MicroRNA (miRNA) are small non-coding RNA that act at the post-transcriptional level, regulating protein expression by repressing translation mRNA target. They can be detected in plants, animal species and viruses, and are involved in numerous cellular processes. MicroRNA-155 (miR-155) which is a kind of microRNAs expressed in hematopoietic cells. Recent data indicate that MiR-155 plays a key role in the pathogenesis of hematological malignancies through regulating cell signal transduction pathways of cell proliferation, differentiation and apoptosis, acting predominantly as an oncomir. MiR-155 may be an important indicator to assess the diagnosis, treatment and prognosis of patients with hematological malignancies, including malignant lymphoma, acute myeloid leukemia, and myelodysplastic syndrome. It could be suggested that drugs such as antisense oligonucleotides able to down-regulate miR-155 expression would provide a novel, and possibly specific way to control the growth of a range of haematopoietic malignancies in conjunction with classical cytotoxic therapy. The purpose of this review is to summarize current findings on the role of miR-155 in hematopoietic malignancies and, moreover, to highlight their role as potential therapeutic tools. PMID- 23815947 TI - Fat utilization and arterial hypertension in overweight/obese subjects. AB - BACKGROUND: The Respiratory Quotient is a parameter reflecting the utilization of the nutrients by a subject. It is associated with an high rate of subsequent weight gain and with the atherosclerosis. Subjects tending to burn less fat have an increased Respiratory Quotient. Aim of this study was to investigate on the relationship between the Respiratory Quotient and the cardiovascular risk factors. METHODS: In this cross-sectional study we enrolled 223 individuals of both sexes aged 45-75 ys that were weight stable, receiving a balanced diet, and not affected by debilitating disease or cardiovascular disease. The Respiratory Quotient was measured by Indirect Calorimetry. The measurement of the Blood Pressure was obtained by a mercury sphygmomanometer. RESULTS: We enrolled 133 female and 90 male. Systolic blood pressure only was positively correlated to the Respiratory Quotient in univariate and multivariate regression analysis (p=0,017). The prevalence of hypertension was significatively different between the quartiles of the Respiratory Quotient, with the highest prevalence in the IV quartile (p=0,024). CONCLUSION: High value of the Respiratory Quotient, an index of nutrients utilization, is associated to an high prevalence of Hypertension. It is possible that in the subjects with high Respiratory Quotient and high body mass index, the activation of the renin angiotensin system, in concert to the reduction of the utilization of the endogenous fat stores, could increase the risk of hypertension. PMID- 23815948 TI - Development and validation of anthropometric equations to estimate appendicular muscle mass in elderly women. AB - OBJECTIVE: This study aimed to examine the cross validity of two anthropometric equations commonly used and propose simple anthropometric equations to estimate appendicular muscle mass (AMM) in elderly women. METHODS: Among 234 physically active and functionally independent elderly women, 101 (60 to 89 years) were selected through simple drawing to compose the study sample. The paired t test and the Pearson correlation coefficient were used to perform cross-validation and concordance was verified by intraclass correction coefficient (ICC) and by the Bland and Altman technique. To propose predictive models, multiple linear regression analysis, anthropometric measures of body mass (BM), height, girth, skinfolds, body mass index (BMI) were used, and muscle perimeters were included in the analysis as independent variables. Dual-Energy X-ray Absorptiometry (AMMDXA) was used as criterion measurement. The sample power calculations were carried out by Post Hoc Compute Achieved Power. Sample power values from 0.88 to 0.91 were observed. RESULTS: When compared, the two equations tested differed significantly from the AMMDXA (p <0.001 and p = 0.001). Ten population / specific anthropometric equations were developed to estimate AMM, among them, three equations achieved all validation criteria used: AMM (E2) = 4.150 +0.251 [bodymass (BM)] - 0.411 [bodymass index (BMI)] + 0.011 [Right forearm perimeter (PANTd) 2]; AMM (E3) = 4.087 + 0.255 (BM) - 0.371 (BMI) + 0.011 (PANTd) 2 - 0.035 [thigh skinfold (DCCO)]; MMA (E6) = 2.855 + 0.298 (BM) + 0.019 (Age) - 0,082 [hip circumference (PQUAD)] + 0.400 (PANTd) - 0.332 (BMI). The equations estimated the criterion method (p = 0.056 p = 0.158), and explained from 0.69% to 0.74% of variations observed in AMMDXA with low standard errors of the estimate (1.36 to 1.55 kg) and high concordance (ICC between 0,90 and 0.91 and concordance limits from -2,93 to 2,33 kg). CONCLUSION: The equations tested were not valid for use in physically active and functionally independent elderly women. The simple anthropometric equations developed in this study showed good practical applicability and high validity to estimate AMM in elderly women. PMID- 23815949 TI - Chemokine (C-X-C) ligand 1 (CXCL1) protein expression is increased in aggressive bladder cancers. AB - BACKGROUND: Chemokines, including chemokine (C-X-C motif) ligand 1 (CXCL1), may regulate tumor epithelial-stromal interactions that facilitate tumor growth and invasion. Studies have linked CXCL1 expression to gastric, colon and skin cancers, but limited studies to date have described CXCL1 protein expression in human bladder cancer (BCa). METHODS: CXCL1 protein expression was examined in 152 bladder tissue specimens (142 BCa) by immunohistochemical staining. The expression of CXCL1 was scored by assigning a combined score based on the proportion of cells staining and intensity of staining. CXCL1 expression patterns were correlated with clinicopathological features and follow-up data. RESULTS: CXCL1 protein expression was present in cancerous tissues, but was entirely absent in benign tissue. CXCL1 combined immunostaining score was significantly higher in high-grade tumors relative to low-grade tumors (p = 0.012). Similarly, CXCL1 combined immunostaining score was higher in high stage tumors (T2-T4) than in low stage tumors (Ta-T1) (p < 0.0001). An increase in the combined immunostaining score of CXCL1 was also associated with reduced disease-specific survival. CONCLUSION: To date, this is the largest study describing increased CXCL1 protein expression in more aggressive phenotypes in human BCa. Further studies are warranted to define the role CXCL1 plays in bladder carcinogenesis and progression. PMID- 23815951 TI - How to review a manuscript. PMID- 23815950 TI - Hemophilia A in the third millennium. AB - Hemophilia A is an X-linked hereditary bleeding disorder due to the deficiency of coagulation factor VIII (FVIII). According to the degree of FVIII deficiency, mild, moderate or severe forms are recognized. Although patients with mild hemophilia A usually bleed excessively only after trauma or surgery, those with severe hemophilia experience frequent episodes of spontaneous or excessive bleeding after minor trauma, particularly into joints and muscles. The modern management of hemophilia began in the 1970s and is actually based upon several plasma-derived or recombinant FVIII products. In addition, the synthetic drug desmopressin can be used to prevent or treat bleeding episodes in patients with mild hemophilia A. Long-term and continuous substitution therapy (prophylaxis), the recommended treatment in severe hemophilia, prevents bleeding and the resultant joint damage. In the last twenty years the high standard of hemophilia care has greatly improved the quality of life of patients and their life expectancy has reached that of the non-hemophilic male population, at least in high-income countries. The most serious and challenging complication of treatment of hemophilia A is the development of inhibitors, which renders FVIII concentrate infusion ineffective and exposes patients to an increased risk of morbidity and mortality. In this narrative review, the actual knowledge on the clinical features and management of patients with hemophilia A is summarized. PMID- 23815953 TI - An unusual presentation of tinea cruris with bullous lesions. PMID- 23815954 TI - Familial pityriasis rubra pilaris: case report and review. AB - BACKGROUND: Pityriasis rubra pilaris (PRP) is a rare dermatosis of unknown etiology. Most cases of PRP are sporadic; however, rare cases of familial PRP have been reported. OBJECTIVES: To present a case of PRP inherited in an autosomal dominant (AD) fashion and to evaluate the current literature on familial PRP and formulate a comprehensive, up-to-date summary of this rare condition. METHODS: PubMed was used to conduct a search for articles pertaining to familial PRP published through May 2011. RESULTS: The first documented case was published in 1910, and 36 subsequent familial cases of PRP have been reported. Familial PRP typically presents very early in childhood, has a gradual onset, and persists throughout life. Given the rarity of this subtype, determining the best therapy has been a challenge. In the pediatric population, a conservative treatment approach, including topical therapy, is frequently used, whereas systemic treatments are reserved for patients with a severe disease that is refractory to therapy. CONCLUSION: Rare cases of PRP inherited in an AD fashion have been described and tend to have a chronic clinical course and are treatment refractory. Therefore, the awareness of familial PRP is important for early and accurate diagnosis and administration of appropriate therapy. PMID- 23815955 TI - Therapy of ulcerated hemangiomas. AB - BACKGROUND: Cutaneous ulceration is the most common complication of infantile hemangiomas (IHs) seen in a pediatric dermatology practice. OBJECTIVE: The most effective treatments in our experience are compared to those in the current literature. METHODS: The study was a retrospective chart review of therapy of 169 ulcerated IHs at a tertiary care pediatric hospital and a literature review. RESULTS: Combination therapy was the rule. Local wound care was required in all, pain management in 72%, pulsed dye laser in 42%, infection control in 38%, diminution of the hemangioma through systemic therapy in 36%, and suppression of bleeding in 2%. LIMITATIONS: A retrospective review compared to a case-control study has inherent bias. In addition, our cases were all at a tertiary referral center. CONCLUSION: All ulcerated IHs benefit from local barrier creams or dressings. Pulsed dye laser, antibiotics, topical morphine 0.1% in hydrogel, topical becaplermin, and, most importantly, systemic therapy (especially propranolol) to reduce the hemangioma may be useful. PMID- 23815957 TI - Friction-induced pagetoid dyskeratosis. AB - BACKGROUND: Pagetoid dyskeratosis (PD) is characterized by pale cells within the epidermis resembling those of Paget disease. These cells have been seen as an incidental finding in a variety of benign papules most commonly located in intertriginous areas. The lesion is considered a reactive process in which a small proportion of the normal population of keratinocytes is altered. Among the triggers for this lesion, friction has been suggested; however, a direct cause and-effect relationship has not yet been reported. RESULTS: We confirmed the relationship between PD and friction in a biopsy taken from a 19-year-old woman who presented with clinical features indicating exogenously induced bullae and erosions and consented to a biopsy of a lesion immediately after its induction, demonstrating combined features of PD and friction bulla. PMID- 23815956 TI - Sanitization of contaminated footwear from onychomycosis patients using ozone gas: a novel adjunct therapy for treating onychomycosis and tinea pedis? AB - BACKGROUND: Ozone gas possesses antimicrobial properties against bacteria, viruses, and yeasts. Previously, we demonstrated the efficacy of ozone in killing ATCC strains of the dermatophyte fungi Trichophyton rubrum and Trichophyton mentagrophytes. OBJECTIVE: To test the efficacy of ozone gas in sanitizing onychomycosis patient footwear contaminated with fungal material as a means of minimizing the risk of reinfection. METHODS: Swabs of footwear from onychomycosis patients were cultured prior to and after ozone exposure to test the ability of ozone to sanitize these items. RESULTS: We identified contamination of footwear from most onychomycosis patients, a potential source of reinfection in these individuals. Furthermore, ozone gas was effective in sanitizing contaminated footwear. CONCLUSION: Ozone gas is effective in sanitizing footwear and represents a novel adjunct therapy to be used in conjunction with antifungal medications and/or devices to better treat onychomycosis and tinea pedis patients in both the short and the long term. PMID- 23815958 TI - Effect of age at onset on disease characteristics in vitiligo. AB - BACKGROUND: Vitiligo is a multifactorial disease in which genetic, immunologic, and environmental factors play an important part. Late-onset vitiligo is a poorly defined entity. MATERIALS AND METHODS: Case records of patients who attended the pigmentary clinic at our institute from January 2001 to December 2010 were reviewed. Patients with a diagnosis of vitiligo were analyzed with respect to their demographic characteristics with special reference to their age at onset. RESULTS: Patients with disease onset after 30 years had a significantly higher association with precipitating factors such as trauma, stress, and drugs in comparison with early-onset vitiligo (p < .004). However, the difference did not reach statistical significance when these factors were analyzed individually. There was a significantly higher association with other nonautoimmune diseases (p = .05), a higher incidence of positive family history (p < .0001), and a higher association with leukotrichia (p < .002) in late-onset disease. Early-onset nonsegmental vitiligo was associated with a higher incidence of photosensitivity and pruritus compared to early-onset segmental vitiligo. CONCLUSION: Late-onset vitiligo has certain distinguishing features compared to early-onset vitiligo. PMID- 23815959 TI - Low-dose oral mini-pulse dexamethasone therapy in progressive unstable vitiligo. AB - BACKGROUND: The course of vitiligo is unpredictable. If the disease is spreading rapidly, the progression can be controlled with the use of systemic steroids daily or in pulsed form. The present study was planned to assess the efficacy of low-dose dexamethasone oral mini-pulse therapy in progressive unstable vitiligo. MATERIALS AND METHODS: In this retrospective study, the case records of patients with vitiligo during the period from January 2006 to December 2010 were studied. Patients who had progressive unstable disease were included. These patients were administered oral dexamethasone 2.5 mg per day on 2 consecutive days after breakfast in a week. The patients were asked to come for regular follow-up to assess the arrest of disease activity, relapse of disease activity, and adverse effects. RESULTS: A total of 444 patients were analyzed. In 408 (91.8%) patients, arrest of disease activity was achieved at a mean duration of 13.2 +/- 3.1 weeks. In addition, some repigmentation of the lesions was seen in all patients after a mean of 16.1 +/- 5.9 weeks. During the follow-up, 50 of 408 (12.25%) patients experienced one or two episodes of relapse in disease activity, which were treated with reinstitution of low-dose dexamethasone oral mini-pulse therapy. The mean disease-free survival (DFS) until the first relapse was 55.7 +/- 26.7 weeks, and the mean DFS until the second relapse was 43.8 +/- 7.2 weeks. Adverse reactions such as weight gain, lethargy, and acneiform eruptions were observed in 41 (9.2%) patients. CONCLUSION: Low-dose oral mini-pulse dexamethasone therapy is a good option for arresting progressive unstable vitiligo with minimal adverse effects. PMID- 23815960 TI - Skin manifestations of outpatient adverse drug events in the United States: a national analysis. AB - BACKGROUND: Cutaneous reactions to drugs are among the most common clinical manifestations of adverse drug events (ADEs); however, data on outpatient cutaneous adverse drug events (CADEs) are limited. PURPOSE: To provide national estimates of outpatient CADEs and determine their most frequent causes. METHODS: Outpatient CADEs recorded in the National Ambulatory Medical Care Survey (NAMCS) and the National Hospital Ambulatory Medical Care Survey (NHAMCS) between 1995 and 2005 were analyzed. The national incidence of outpatient CADEs in those seeking medical attention in the United States was estimated, and the common medication classes implicated with CADEs were identified. RESULTS: There were a mean annual total of 635,982 CADE-related visits, resulting in an annual incidence of 2.26 CADEs per 1,000 persons. Patients took an average of 2.2 medications in addition to the one causing the CADE. The incidence of CADEs increased with age, with a peak in the age group from 70 to 79 years. The medications most frequently causing a CADE were antimicrobial agents. Dermatitis and urticaria were the two main types of skin reactions reported. CONCLUSIONS: CADEs occur less frequently in outpatients than in inpatients and result in few hospital admissions. Physicians must be particularly cognizant of the occurrence of CADEs when prescribing antimicrobial agents. PMID- 23815961 TI - The care triangle: determining the gaps in the management of atopic dermatitis. AB - BACKGROUND: Atopic dermatitis (AD) is a chronic, relapsing, intensely pruritic dermatosis that usually affects infants, children, and young adults. The treatment of AD entails an individualized regimen that depends on the age of the patient, the stage and variety of lesions present, the sites and extent of involvement, the presence of infection, and the previous response to treatment. OBJECTIVES: To identify the evidence surrounding potential strategies for closing these gaps-ultimately improving the quality of care, the care process itself, and patient outcomes-and to encourage discussions that help develop tools to bridge the gap between suggested therapy and what is done by the patient. METHODS: Review of the literature including searches on PubMed Central and Medline and in seminal dermatology texts. RESULTS: There are several disconnections between the evidence-based guidelines in the management of AD, what the individual dermatologist recommends, and what the patient does. CONCLUSION: Applying the concept of the care triangle requires a balance of evidence-based medicine, the physician's experiences and the patient's needs and expectations in the decisions surrounding appropriate management of the disease. PMID- 23815962 TI - Doxycycline-induced cutaneous inflammation with systemic symptoms in a patient with acne vulgaris. AB - BACKGROUND: Doxycycline is a commonly prescribed antibiotic for the treatment of acne vulgaris. Often preferred to other tetracyclines due to a safer and milder side-effect profile, doxycycline is more frequently prescribed as a treatment of this common condition. OBJECTIVE: To present a case report of a young patient who developed skin eruptions over the extremities; myalgias; fatigue; swelling involving the face, hands, and feet; headache; and mood changes after 2 years of using doxycycline. She promptly developed similar symptoms after a rechallenge with doxycycline 1 year later. RESULTS/CONCLUSION: This important finding will make practitioners more vigilant to the side effects of this medication despite its current safety profile and regardless of the time that a patient is using it. PMID- 23815963 TI - Vulvar sarcoidosis: case report and review of the literature. AB - BACKGROUND: Sarcoidosis is a multisystemic disorder of unknown etiology that can affect multiple organs, including the lungs, skin, and eyes. Vulvar sarcoidosis has anecdotally been reported. OBJECTIVE: The aim of this article is to describe a case of vulvar sarcoidosis and review the few cases that have been reported. METHODS: We report the case of a 39-year-old woman who presented to the dermatologist with a 2-year history of vulvar pruritus. RESULTS: Examination revealed infiltrated plaques on the vulva and perianal region. The biopsy demonstrated well-defined, non-necrotizing granulomas in the dermis. Further investigation revealed hilar adenopathy consistent with sarcoidosis. The patient responded well to topical corticosteroids. CONCLUSION: In the presence of granulomatous lesions of the genital region, infectious causes, foreign body reaction, Crohn disease, and sarcoidosis should be part of the differential diagnosis. PMID- 23815964 TI - Sexual and reproductive health workforce project: overview and recommendations from the SRH Workforce Summit, January 2013. PMID- 23815965 TI - Abortion politics and the production of knowledge. AB - It is common to think of scientific research and the knowledge it generates as neutral and value free. Indeed, the scientific method is designed to produce "objective" data. However, there are always values built into science, as historians of science and technology have shown over and over. The relevant question is not how to rid science of values but, instead, to ask which values and whose values belong? Currently, antiabortion values consistently determine US research policy. Abortion research is declared illegitimate in covert and overt ways, at the level of individual researchers and research policy broadly. Most importantly, federal policy impedes conduct of both basic and clinical research in abortion. However, it is not just research in abortion that is deemed "illegitimate;" research in infertility and in vitro fertilization is as well. Federal funding of any reproductive health research agenda that would pose more than minimal risk to a fetus or embryo is banned. This leaves unanswered scientific questions about abortion, infertility, miscarriage and contraception among other areas. Since moral ground is occupied not just by abortion opponents but also by people who support abortion rights, there is at the very least a competing moral claim to consider changing federal research funding policy. Women and families deserve access to knowledge across the spectrum of reproductive health issues, whether they seek to end or start a pregnancy. Thus, research funding is an issue of reproductive justice. PMID- 23815966 TI - Genetic diversity among Trypanosoma (Duttonella) vivax strains from Zambia and Ghana, based on cathepsin L-like gene. AB - Understanding the evolutionary relationships of Trypanosoma (Duttonella) vivax genotypes between West Africa and Southern Africa can provide information on the epidemiology and control of trypanosomosis. Cattle blood samples from Zambia and Ghana were screened for T. vivax infection using specie-specific PCR and sequencing analysis. Substantial polymorphism was obtained from phylogenetic analysis of sequences of cathepsin L-like catalytic domains. T. vivax from Ghana clustered together with West African and South American sequences, while T. vivax from Zambia formed one distinct clade and clustered with East African and Southern African sequences. This study suggests existence of distinct genetic diversity between T. vivax genotypes from West Africa and Zambia as per their geographical origins. PMID- 23815967 TI - Cold shock CspA and CspB protein production during periodic temperature cycling in Escherichia coli. AB - BACKGROUND: Temperature is an important environmental factor which can dramatically affect biochemical processes in bacteria. Temperatures above optimal cause heat shock, while low temperatures induce cold shock. Since the physiological response of the bacterium Escherichia coli to slow temperature fluctuation is not well known, we investigated the effect of periodic temperature cycling between 37 degrees and 8 degrees C with a period of 2 h on proteome profile, cold shock CspA and CspB protein and gene production. RESULTS: Several proteins (i.e. succinyl-CoA synthetase subunit alpha, periplasmic oligopeptide binding protein, maltose-binding periplasmic protein, outer membrane porin protein, flavodoxin-1, phosphoserine aminotransferase) were up or down regulated during temperature cycling, in addition to CspA and CspB production. The results indicate that transcription of cspA and cspB increased during each temperature downshift and consistently decreased after each temperature upshift. In sharp contrast CspA-FLAG and CspB-FLAG protein concentrations in the cell increased during the first temperature down-shift and remained unresponsive to further temperature fluctuations. The proteins CspA-FLAG and CspB-FLAG were not significantly degraded during the temperature cycling. CONCLUSION: The study demonstrated that slow periodic temperature cycling affected protein production compared to cells constantly incubated at 37 degrees C or during classical cold shock. Bacterial cspA and cspB mRNA transcript levels fluctuated in synchrony with the temperature fluctuations. There was no corresponding pattern of CspA and CspB protein production during temperature cycling. PMID- 23815968 TI - Natural evolution from idiopathic photosensitive occipital lobe epilepsy to idiopathic generalized epilepsy in an untreated young patient. AB - Idiopathic photosensitive occipital lobe epilepsy (IPOE) is an idiopathic localization-related epilepsy characterized by age-related onset, specific mode of precipitation, occipital photic-induced seizures--frequently consisting of visual symptoms--and good prognosis. This uncommon epilepsy, which usually starts in childhood or adolescence, has rarely been observed in families in which idiopathic generalized epilepsy also affects other members. We describe a nuclear family in which the proband showed electro-clinical features of idiopathic photosensitive occipital lobe epilepsy in childhood, which subsequently evolved into absences and a single generalized tonico-clonic seizure in early adolescence. His mother had features suggestive of juvenile myoclonic epilepsy. This case illustrates a continuum between focal and generalized entities in the spectrum of the so-called idiopathic (genetically determined) epileptic syndromes. PMID- 23815969 TI - Twelve-year-old girl with intracranial epidural abscess and sphenoiditis. AB - We report the case of a 12-year-old girl with an intracranial epidural abscess and sphenoiditis. Although she had no history of sinusitis, she developed acute severe headache, fever, and vomiting. Emergent CT and MRI showed a spherical space-occupying lesion of diameter 3 cm in the right cranial fossa with rim enhancement. The lesion was thought to be an epidural abscess adjacent to the right sphenoiditis. On the basis of the MRI findings, we performed emergent surgery to drain the abscess and sinusitis because of severe and rapidly worsening headaches. The patient showed great improvement the day after the operation. Intravenous antibiotics were administered for 8 days. She has completely recovered, with neither sequelae nor recurrence at 7 months after the operation. We believe that this report will be a useful reference for cases of acute onset headache and may be helpful in diagnosis and treatment decisions for severe sinusitis-related intracranial abscess in childhood. PMID- 23815970 TI - Stroke severity and outcomes for octogenarians receiving statins. AB - Pre-exposure to 3-hydroxy-3-methylgutaryl-coenzyne A reductase inhibitors (statins) appears to improve outcomes in patients with acute ischemic stroke (AIS). Whether this extends to patients over 80 is not known. Patients >=80 years of age with AIS were retrospectively reviewed from the stroke registry of a tertiary stroke center. Pre-admission statin use, demographics, vascular risk factors, and comorbid conditions were assessed. Primary outcomes were admission National Institutes of Health Stroke Scale (NIHSS) scores and in-hospital mortality/discharge to hospice, and secondary outcomes included subsequent intracerebral hemorrhage (ICH) and modified Barthel index (mBI) at 3 months. Multivariable logistic regression was used to evaluate the association between pre-admission statin use and outcomes among elderly patients. Among 804 patients >=80, those taking statins prior to AIS admission were overall younger, were more likely to have hypertension, coronary artery disease, diabetes, hyperlipidemia, and were more likely to be on an antiplatelet, but less likely to receive treatment with IV tissue plasminogen activator (tPA). Patients on statin had lower stroke severity (NIHSS>16: 21.9% vs. 27.6%) and in-hospital mortality/discharge to hospice (22.8% vs. 27.6%), but neither was significant. There was no difference in ICH (1.2% vs. 1.9%), and patients on statins had a non significant trend toward less disability on mBI (27.5% vs. 35.7%). Pre-admission statin use did not show a statistical difference in either outcome, but it did show a trend toward lower stroke severity and improved short-term outcomes. In addition, our study suggests that statins may be safe in elderly stroke patients and may not increase the risk of ICH. PMID- 23815971 TI - Redevelopment of tertiary psychiatric services in British Columbia: a prospective study of clinical, social, and residential outcomes of former long-stay inpatients. AB - OBJECTIVE: The objective of this study is to assess the clinical and social outcomes for a cohort of patients who were part of the redevelopment of psychiatric services in British Columbia. METHOD: This study used a naturalistic, quasi-experimental design, to examine the outcomes of a cohort of 189 long-stay patients at Riverview Hospital (RVH), some of whom moved into Tertiary Psychiatric Residential Facilities (TPRFs), some into the community in less structured facilities, and some remained at RVH. Data was collected from clinical files at RVH and at each participating site, semi-structured interviews and self report measures were completed with patients. In addition, semi-structured interviews were also conducted with staff members. RESULTS: There was very minimal evidence of transinstitutionalization to prisons or homelessness; one participant resided in a correctional facility, one resided in a forensic facility, and one participant spent some time homeless. In addition, the majority of participants remained in residences that provided 24h care. Eighty percent of our population was diagnosed with a schizophrenia spectrum disorder. Psychiatric symptoms remained fairly stable; some embarrassing social behaviors increased; however, aggressive behaviors showed no increase; neuropsychological deficits did not deteriorate, there were even some improvements. Participants demonstrated increases in several independent living skills including: money management, food preparation and storage, job skills, and transportation skills. In addition, participants experienced a significant increase in their perceived quality of life. CONCLUSIONS: This study builds on existing research demonstrating that well planned and appropriately resourced hospital closures can lead to positive psycho social outcomes for participants and can successfully avoid negative outcomes such as transinstitutionalization to the judiciary system and homelessness. PMID- 23815972 TI - Neuropsychological, clinical and cognitive insight predictors of outcome in a first episode psychosis study. AB - The outcome of first episode psychosis (FEP) is highly variable and difficult to predict. We studied prospectively the impact of poor insight and neuropsychological deficits on outcomes in a longitudinal cohort of 127 FEP patients. Participants were assessed on 5 domains of cognitive function and 2 domains of insight (clinical and cognitive). At 12 months, patients were assessed again for symptom severity and psychosocial function. Regression analyses revealed that cognitive insight (a measure of self-reflectiveness and self certainty) was the best baseline predictor of overall psychopathology at 12 months whereas executive function performance at admission to the study indicated later severity of negative symptoms. Other neuropsychological and insight measures were poor predictors of psychosocial function at 1 year. The results suggest that specific neuropsychological and insight factors have separate predictive capacities indicating that they are distinct psychological processes in psychosis. Cognitive insight proved to be a useful prognostic indicator, and should be considered for future studies and as a potential focus for treatment. PMID- 23815973 TI - Meta-analysis supports association of a non-synonymous SNP in ZNF804A with schizophrenia. PMID- 23815974 TI - Histone methylation at H3K9: evidence for a restrictive epigenome in schizophrenia. AB - OBJECTIVE: Epigenetic changes are stable and long-lasting chromatin modifications that regulate genomewide and local gene activity. The addition of two methyl groups to the 9th lysine of histone 3 (H3K9me2) by histone methyltransferases (HMT) leads to a restrictive chromatin state, and thus reduced levels of gene transcription. Given the numerous reports of transcriptional down-regulation of candidate genes in schizophrenia, we tested the hypothesis that this illness can be characterized by a restrictive epigenome. METHODS: We obtained parietal cortical samples from the Stanley Foundation Neuropathology Consortium and lymphocyte samples from the University of Illinois at Chicago (UIC). In both tissues we measured mRNA expression of HMTs GLP, SETDB1 and G9a via real-time RT PCR and H3K9me2 levels via western blot. Clinical rating scales were obtained from the UIC cohort. RESULTS: A diagnosis of schizophrenia is a significant predictor for increased GLP, SETDB1 mRNA expression and H3K9me2 levels in both postmortem brain and lymphocyte samples. G9a mRNA is significantly increased in the UIC lymphocyte samples as well. Increased HMT mRNA expression is associated with worsening of specific symptoms, longer durations of illness and a family history of schizophrenia. CONCLUSIONS: These data support the hypothesis of a restrictive epigenome in schizophrenia, and may associate with symptoms that are notoriously treatment resistant. The histone methyltransferases measured here are potential future therapeutic targets for small molecule pharmacology, and better patient prognosis. PMID- 23815975 TI - Negative symptoms in schizophrenia--the remarkable impact of inclusion definitions in clinical trials and their consequences. AB - BACKGROUND: Negative symptoms are an important target for intervention in schizophrenia. There is lack of clarity in defining appropriate patients for negative symptom trials. While regulators, drug developers and academics have expressed positions in this regard, the implications of these definitions are not yet tested in large-scale trials and there is no consensus. OBJECTIVES: We examined the extent to which various operational criteria for inclusion in negative symptoms in schizophrenia clinical trials can impact patient selection and examined the effectiveness of second generation antipsychotics (SGAs) in patients with various degrees of negative symptoms. METHOD: Using anonymized patient data from AstraZeneca, Janssen Pharmaceuticals, Eli Lilly, Lundbeck, and Pfizer from 20 placebo-controlled trials of SGAs in schizophrenia from the NewMeds repository, we applied different criteria for negative symptoms: prominent, predominant, and EMA criteria, which require predominant and core negative symptoms to be present and examined the impact of these on inclusion and outcome. RESULTS: Operational criteria for negative symptoms in trials vary greatly in their inclusion of patients from "typical" trial samples. Of the patients in our studies, 8.1% and 62.3% met criteria for prominent negative symptoms, 10.2% to 50.2% met criteria for predominant negative symptoms and 7.6% to 40.0% met EMA criteria at baseline. After 6weeks of active treatment, 8% and 33.1% of patients met criteria for prominent residual negative symptoms and 14.9% to 65% met criteria for prominent and 12.2% to 45.5% met EMA criteria. Patients with predominant or prominent negative symptoms showed marked improvement on second generation antipsychotics. CONCLUSIONS: Applying various operational criteria for selecting patients for negative symptoms trials provides a great variability in percentage of suitable patients calling into question the extent to which some definitions may be overly narrow. PMID- 23815976 TI - Total laparoscopic Roux-en-Y cholangiojejunostomy for the treatment of biliary disease. AB - BACKGROUND AND OBJECTIVES: Roux-en-Y cholangiojejunostomy (RCJS) has been widely used in biliary bypass surgeries, but in most reported literature, an assisted miniincision was needed, and studies reporting total laparoscopic Roux-en-Y cholangiojejunostomy (TLRCJS) are rare. The goal of this study was to investigate how to treat hepatic portal bile duct diseases and perform jejunojejunostomy and cholangiojejunostomy totally laparoscopically. We evaluated the feasibility of TLRCJS in treating biliary tract diseases. METHODS: TLRCJS were performed in 103 patients from January 2000 to August 2011. There were 28 cases of recurrent choledocholithiasis combined with stricture of the common bile duct (CBD) after several stone extractions, 3 patients with iatrogenic bile duct injury, 24 patients with choledochal cyst, 36 patients with hepatic portal cholangiocarcinoma, and 12 patients with cancer of the pancreatic head and periampullary cancer. All surgeries were performed through 5 trocars. First, laparoscopic surgery on the CBD was performed according to the original disease. The CBD was opened and stones were extracted in choledocholithiasis patients. In iatrogenic injury patients, strictured CBD was resected and repaired. Dilated CBD or choledochal cyst with tumor was transected. In patients with malignant jaundice, the CBD was opened longitudinally. At the same time, the bile duct was prepared for cholangiojejunostomy. Second, the positions of the laparoscope and surgeons were altered. The jejunal mesentery and jejunum were transected, and side-to-side jejunojejunostomy (JJS) was performed. The laparoscope and surgeon positions were exchanged again; the Rouxen-Y biliary limb was lifted close to the residual bile duct; and side-to-side or end-to-side choledochojejunostomy (CJS) was performed. Finally, an abdominal drainage tube was placed. RESULTS: All the surgeries were performed successfully. The diameter of the residual bile duct ranged from 0.4 to 3.2 cm (average, 0.9 cm). Three patients had postoperative bile leakage and were treated from 1 week to approximately 1 month with abdominal drainage. Postoperative intraperitoneal hemorrhage and stress ulcer of the stomach occurred in 2 patients with biliary tract injury combined with obstructive jaundice. One with intraperitoneal hemorrhage was cured by another laparoscopic surgery. The other patient was cured after 2 days of abdominal drainage, antacids, and hemostatic drug therapy. The follow-up duration of 95 patients was 4 to 93 months (average, 48.3 months). The follow-up rate was 92.2% (95/103). Patients with cancer died of metastasis or cachexia during 14-month follow-up with no postoperative complication. Reflux cholangitis occurred in 3 patients 2, 3, and 5 years after the operation, respectively. No anastomotic stricture or other complication was found in other patients during the follow-up. CONCLUSIONS: TLRCJS is the best and first choice for patients with biliary tract diseases that need biliary-jejunal anastomosis. But it is essential that the surgeon has proficiency in laparoscopic surgeries. PMID- 23815978 TI - Can control of soil erosion mitigate water pollution by sediments? AB - The detrimental impact of sediment and associated pollutants on water quality is widely acknowledged, with many watercourses in the UK failing to meet the standard of 'good ecological status'. Catchment sediment budgets show that hill slope erosion processes can be significant sources of waterborne sediment, with rates of erosion likely to increase given predicted future weather patterns. However, linking on-site erosion rates with off-site impacts is complicated because of the limited data on soil erosion rates in the UK and the dynamic nature of the source-pathway-receptor continuum over space and time. Even so, soil erosion control measures are designed to reduce sediment production (source) and mobilisation/transport (pathway) on hill slopes, with consequent mitigation of pollution incidents in watercourses (receptors). The purpose of this paper is to review the scientific evidence of the effectiveness of erosion control measures used in the UK to reduce sediment loads of hill slope origin in watercourses. Although over 73 soil erosion mitigation measures have been identified from the literature, empirical data on erosion control effectiveness are limited. Baseline comparisons for the 18 measures where data do exist reveal erosion control effectiveness is highly variable over time and between study locations. Given the limitations of the evidence base in terms of geographical coverage and duration of monitoring, performance of the different measures cannot be extrapolated to other areas. This uncertainty in effectiveness has implications for implementing erosion/sediment risk reduction policies, where quantified targets are stipulated, as is the case in the EU Freshwater Fish and draft Soil Framework Directives. Also, demonstrating technical effectiveness of erosion control measures alone will not encourage uptake by land managers: quantifying the costs and benefits of adopting erosion mitigation is equally important, but these are uncertain and difficult to express in monetary terms. PMID- 23815977 TI - Distinct roles for Ste20-like kinase SLK in muscle function and regeneration. AB - BACKGROUND: Cell growth and terminal differentiation are controlled by complex signaling systems that regulate the tissue-specific expression of genes controlling cell fate and morphogenesis. We have previously reported that the Ste20-like kinase SLK is expressed in muscle tissue and is required for cell motility. However, the specific function of SLK in muscle tissue is still poorly understood. METHODS: To gain further insights into the role of SLK in differentiated muscles, we expressed a kinase-inactive SLK from the human skeletal muscle actin promoter. Transgenic muscles were surveyed for potential defects. Standard histological procedures and cardiotoxin-induced regeneration assays we used to investigate the role of SLK in myogenesis and muscle repair. RESULTS: High levels of kinase-inactive SLK in muscle tissue produced an overall decrease in SLK activity in muscle tissue, resulting in altered muscle organization, reduced litter sizes, and reduced breeding capacity. The transgenic mice did not show any differences in fiber-type distribution but displayed enhanced regeneration capacity in vivo and more robust differentiation in vitro. CONCLUSIONS: Our results show that SLK activity is required for optimal muscle development in the embryo and muscle physiology in the adult. However, reduced kinase activity during muscle repair enhances regeneration and differentiation. Together, these results suggest complex and distinct roles for SLK in muscle development and function. PMID- 23815979 TI - Precision of posttraumatic primary orbital reconstruction using individually bent titanium mesh with and without navigation: a retrospective study. AB - BACKGROUND: The aim of orbital wall reconstruction is to reestablish anatomically exact orbital volumes to avoid long-term complications. Navigation could facilitate complex reconstructions. METHODS: Quality of the orbital reconstruction (n=94) was measured based on (A) volume changes and (B) on 3D shape deviations compared to the unaffected side. Volume analysis included segmentation of the orbital cavity in the pre- and post-operative 3D data set (VoXim(r), IVS Solutions, Germany), and shape analysis was performed by vector based 3D tools (Comparison(r), 3Dshape, Germany). RESULTS: Orbital volume of the unaffected side ranged from 26.6 ml+/-2.8 ml in male and 25.2 ml+/-2.6 ml in female (CT). Significant orbital enlargement was found in orbital fractures with involvement of the posterior third of the orbital floor and in comminuted fracture pattern. Reconstructed orbital volume ranged from 26.9+/-2.7 ml in male and 24.26+/-2.5 ml in female (CBCT). 3D Analysis of the color mapping showed minor deviations compared to the mirrored unaffected side. CONCLUSION: Measurements demonstrate that even in comminuted orbital fractures true-to original reconstruction is feasible. PMID- 23815980 TI - Transcriptome analysis of human tissues and cell lines reveals one dominant transcript per gene. AB - BACKGROUND: RNA sequencing has opened new avenues for the study of transcriptome composition. Significant evidence has accumulated showing that the human transcriptome contains in excess of a hundred thousand different transcripts. However, it is still not clear to what extent this diversity prevails when considering the relative abundances of different transcripts from the same gene. RESULTS: Here we show that, in a given condition, most protein coding genes have one major transcript expressed at significantly higher level than others, that in human tissues the major transcripts contribute almost 85 percent to the total mRNA from protein coding loci, and that often the same major transcript is expressed in many tissues. We detect a high degree of overlap between the set of major transcripts and a recently published set of alternatively spliced transcripts that are predicted to be translated utilizing proteomic data. Thus, we hypothesize that although some minor transcripts may play a functional role, the major ones are likely to be the main contributors to the proteome. However, we still detect a non-negligible fraction of protein coding genes for which the major transcript does not code a protein. CONCLUSIONS: Overall, our findings suggest that the transcriptome from protein coding loci is dominated by one transcript per gene and that not all the transcripts that contribute to transcriptome diversity are equally likely to contribute to protein diversity. This observation can help to prioritize candidate targets in proteomics research and to predict the functional impact of the detected changes in variation studies. PMID- 23815982 TI - Combating enteropathogenic Escherichia coli (EPEC) infections: the way forward. AB - Enteropathogenic Escherichia coli (EPEC) strains continue to cause severe and sometimes fatal infantile diarrhea, particularly in Africa. Increased efforts at diagnosis, defining the clinical spectrum of disease, understanding pathogenic mechanisms, and delineating immune responses are desperately needed to develop new strategies to combat EPEC. PMID- 23815981 TI - Immunotherapy with FBTA05 (Bi20), a trifunctional bispecific anti-CD3 x anti-CD20 antibody and donor lymphocyte infusion (DLI) in relapsed or refractory B-cell lymphoma after allogeneic stem cell transplantation: study protocol of an investigator-driven, open-label, non-randomized, uncontrolled, dose-escalating Phase I/II-trial. AB - BACKGROUND: Patients with B cell malignancies refractory to allogeneic stem cell transplantation (SCT) can be treated by subsequent immunotherapy with donor lymphocyte infusions (DLI). But unlike myeloid leukemia, B cell leukemia and lymphoma are less sensitive to allogeneic adoptive immunotherapy. Moreover, the beneficial graft-versus-lymphoma (GVL) effect may be associated with moderate to severe graft-versus-host disease (GVHD). Thus, novel therapeutic approaches augmenting the anti-tumor efficacy of DLI and dissociating the GVL effect from GVHD are needed. The anti-CD20 x anti-CD3 trifunctional bispecific antibody (trAb) FBTA05 may improve the targeting of tumor cells by redirecting immune allogeneic effector cells while reducing the risk of undesirable reactivity against normal host cells. Hence, FBTA05 may maximize GVL effects by simultaneously decreasing the incidence and severity of GVHD. METHODS/DESIGN: Based on this underlying treatment concept and on promising data taken from preclinical results and a small pilot study, an open-label, non-randomized, uncontrolled, dose-escalating phase I/II-study is conducted to evaluate safety and preliminary efficacy of the investigational antibody FBTA05 in combination with DLI for patients suffering from rituximab- and/or alemtuzumab-refractory, CD20-positive low- or high-grade lymphoma after allogeneic SCT. During the first trial phase with emphasis on dose escalation a maximum of 24 patients distributed into 4 cohorts will be enrolled. For the evaluation of preliminary efficacy data a maximum of 12 patients (6 patients with low-grade lymphoma and/or Chronic Lymphocytic Leukemia (CLL) / 6 patients with high-grade or aggressive lymphoma) will attend the second phase of this clinical trial. DISCUSSION: Promising data (e.g. induction of cellular immunity; GVL predominance over GVHD; achievement of partial or complete responses; prolongation of time-to-progression) obtained from this phase I/II trial would represent the first milestone in the clinical evaluation of a novel immunotherapeutic concept for treatment-resistant low- and high-grade lymphoma and NHL patients in relapse. TRIAL REGISTRATION: NCT01138579. PMID- 23815983 TI - Prevalence of herbal and dietary supplement usage in Thai outpatients with chronic kidney disease: a cross-sectional survey. AB - BACKGROUND: There are few studies of the prevalence and patterns of herbal and dietary supplement (HDS) use in patients with chronic kidney disease (CKD), although many researchers and health professionals worldwide have raised concern about the potential effects of HDS on patients with renal insufficiency. A survey was conducted to determine: the prevalence and patterns of HDS use in Thai patients with CKD; the demographic factors related to HDS use; the reasons why Thai patients with CKD use HDS; respondent experiences of benefits and adverse effects from HDS; and the association between conventional medication adherence and HDS use. METHODS: This cross-sectional survey recruited patients with CKD attending two teaching hospitals in Thailand. Data were collected via an interview using a semi-structured interview schedule regarding demographics, HDS usage, reasons for HDS use, and respondent experiences of effects from HDS. Conventional medication adherence was measured using the Thai version of 8-Item Morisky Medication Adherence Scale. Descriptive statistics were used to analyse the prevalence and the patterns of HDS use. Chi-square tests and multiple logistic regression were used to determine any associations between HDS use, demographics and conventional medication adherence. RESULTS: Four hundred and twenty-one eligible patients were recruited. The prevalence of HDS use in the previous 12 months was 45%. There were no demographic differences between HDS users and non-users, except former drinkers were less likely to use HDS, compared with non-drinkers (OR 0.43, 95% CI 0.25-0.75). Those with a medium level of adherence to conventional medication were less likely to use HDS compared with those with a low level of adherence (OR 0.53, 95% CI 0.32-0.87). Maintaining well being was most common purpose for using HDS (36%). Nearly 18% used HDS, such as holy mushroom, river spiderwort and boesenbergia, to treat kidney disease. The top three most often reported reasons why respondents used HDS were family and friend's recommendation, followed by expecting to gain benefit from HDS and wanting to try them. Perceived beneficial effects on renal function from HDS were reported by around 10% of HDS users. Among HDS users, seven patients perceived worsening CKD from HDS, such as river spiderwort, kariyat and wheatgrass. Additionally, 72% of respondents did not inform their doctor about their HDS use mainly because their doctor did not ask (46%) or would disapprove of their HDS use (15%). CONCLUSIONS: Around half of the Thai patients with CKD used HDS. Health professionals should be aware of HDS use amongst such patients and enquire about HDS use as a part of standard practice in order to prevent any detrimental effects on kidney function. PMID- 23815984 TI - Mobile sailing robot for automatic estimation of fish density and monitoring water quality. AB - INTRODUCTION: The paper presents the methodology and the algorithm developed to analyze sonar images focused on fish detection in small water bodies and measurement of their parameters: volume, depth and the GPS location. The final results are stored in a table and can be exported to any numerical environment for further analysis. MATERIAL AND METHOD: The measurement method for estimating the number of fish using the automatic robot is based on a sequential calculation of the number of occurrences of fish on the set trajectory. The data analysis from the sonar concerned automatic recognition of fish using the methods of image analysis and processing. RESULTS: Image analysis algorithm, a mobile robot together with its control in the 2.4 GHz band and full cryptographic communication with the data archiving station was developed as part of this study. For the three model fish ponds where verification of fish catches was carried out (548, 171 and 226 individuals), the measurement error for the described method was not exceeded 8%. SUMMARY: Created robot together with the developed software has features for remote work also in the variety of harsh weather and environmental conditions, is fully automated and can be remotely controlled using Internet. Designed system enables fish spatial location (GPS coordinates and the depth). The purpose of the robot is a non-invasive measurement of the number of fish in water reservoirs and a measurement of the quality of drinking water consumed by humans, especially in situations where local sources of pollution could have a significant impact on the quality of water collected for water treatment for people and when getting to these places is difficult. The systematically used robot equipped with the appropriate sensors, can be part of early warning system against the pollution of water used by humans (drinking water, natural swimming pools) which can be dangerous for their health. PMID- 23815985 TI - Spatial and temporal variations relevant to tsetse control in the Bipindi focus of southern Cameroon. AB - BACKGROUND: Human African Trypanosomiasis (HAT) remains a public health problem in many poor countries. Due to lack of financial resources in these countries, cost-effective strategies are needed for efficient control of this scourge, especially the tsetse vector. It was shown that perennial water sources maintain a favourable biotope for tsetse flies and thus the transmission dynamics of sleeping sickness. The present paper aimed at assessing the transmission dynamics of HAT in a forest environment where the hydrographic network is important. METHODS: Two entomological surveys were carried out in July 2009 and March 2010 in the Bipindi sleeping sickness focus of the South Region of Cameroon. Entomological and parasitological data were collected during both trapping periods (including the climate variations throughout a year) and compared to each other. The level of risk for transmission of the disease during each trapping period was also evaluated at the trap level and materialised on the map of the Bipindi focus. RESULTS: Glossina palpalis palpalis was the most prevalent tsetse fly species captured in this focus. The overall densities of tsetse flies as well as the risk for transmission of HAT in the Bipindi focus were significantly higher in July than in March. At the trap level, we observed that these parameters were almost constant, whatever the trapping period, when the biotope included perennial water sources. CONCLUSIONS: This study shows that the spatial distribution of traps, as well as the temporal climatic variations might influence entomological and parasitological parameters of HAT and that the presence of perennial water sources in biotopes would favour the development of tsetse flies and thus the transmission of sleeping sickness. These factors should, therefore, be taken into account in order to provide more efficient vector control. PMID- 23815986 TI - RBC transfusions among hemodialysis patients (1999-2010): influence of hemoglobin concentrations below 10 g/dL. AB - BACKGROUND: Changes in anemia management over the past decade have produced downward shifts in hemoglobin concentrations. We aimed to examine the effect on use of red blood cell (RBC) transfusions. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: We identified point prevalent Medicare hemodialysis patients as of January 1 of each year (1999-2010) and categorized them based on 3-month (April to June) mean hemoglobin levels (<10 or >=10 g/dL) in each year. PREDICTORS: Hemoglobin patterns over time and clinical profiles based on achieved hemoglobin concentrations. OUTCOMES: RBC transfusion use. MEASUREMENTS: We used negative binomial modeling to examine the effect of hemoglobin level <10 g/dL on transfusion use, adjusting for case-mix differences. RESULTS: Proportions of patients with mean hemoglobin levels <10 g/dL decreased from 10% (1999) to ~4% (2005), but began increasing after 2006 and reached 6% by 2010. Accounting for case-mix differences, transfusion rates remained relatively constant at approximately 7.9 per 100 person-months for patients with hemoglobin levels <10 g/dL and 2 per 100 person-months for patients with hemoglobin levels >=10 g/dL. Patients with average hemoglobin levels <10 g/dL were more likely to receive transfusions (risk ratio, 2.2; 95% CI, 2.1-2.2) even after adjustment; the risk ratio doubled if hemoglobin levels remained <10 g/dL for 6 months (4.4; 95% CI, 3.7-5.2). LIMITATIONS: Limited in generalizability to patients with Medicare as primary payer; residual confounding from factors such as frailty and chronic inflammation cannot be excluded; categorizing patients based on an average of 3 outpatient hemoglobin measurements may introduce some misclassification. CONCLUSIONS: Risk of transfusion increases substantially with hemoglobin concentrations <10 g/dL; risk appears to be independent of other clinical factors. If anemia management patterns shift toward lower hemoglobin concentrations, RBC transfusion use likely will increase in dialysis patients. PMID- 23815987 TI - Curcumin analogue T83 exhibits potent antitumor activity and induces radiosensitivity through inactivation of Jab1 in nasopharyngeal carcinoma. AB - BACKGROUND: Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated malignancy that is most common in East Asia, Africa, and Alaska. Radiotherapy is the main treatment option; unfortunately, disease response to concurrent radiotherapy and chemotherapy varies among patients with NPC, and in many cases, NPC becomes resistant to radiotherapy. Our previous studies indicated that Jab1/CSN5 was overexpressed and plays a role in the pathogenesis and radiotherapy resistance in NPC. Therefore, it is important to seek for innovative therapeutics targeting Jab1/CSN5 for NPC. In this study, we explored the antitumor effect of a curcumin analogue T83 in NPC, and found T83 exhibits antitumor activity and induces radiosensitivity through inactivation of Jab1 in NPC. METHODS: NPC cell viability and proliferation were detected by the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) and colony formation assays. Cell cycle distribution was detected with use of flow cytometry. Apoptosis was examined by using the Annexin V/propidium iodide staining assay and cleavage poly(ADP-ribose polymerase (PARP) and cleavage caspase-3 expression. Jab1 expression was examined by Western blotting. RESULTS: A growth inhibitory effect was observed with T83 treatment in a dose- and time-dependent manner. T83 significantly induced G2/M arrest and apoptosis in NPC. In addition, T83 inhibited Jab1 expression and sensitized NPC cells to radiotherapy. CONCLUSION: Our data indicate that T83 exhibits potent inhibitory activity in NPC cells and induces radiotherapy sensitivity. Thus, T83 has translational potential as a chemopreventive or therapeutic agent for NPC. PMID- 23815989 TI - A failure in endothelin-1 production from vitiligo keratinocytes in response to ultraviolet B irradiation. PMID- 23815988 TI - Inhibition of extracellular signal-regulated kinase 1/2 signaling has beneficial effects on skeletal muscle in a mouse model of Emery-Dreifuss muscular dystrophy caused by lamin A/C gene mutation. AB - BACKGROUND: Autosomal Emery-Dreifuss muscular dystrophy is caused by mutations in the lamin A/C gene (LMNA) encoding A-type nuclear lamins, intermediate filament proteins of the nuclear envelope. Classically, the disease manifests as scapulo humeroperoneal muscle wasting and weakness, early joint contractures and dilated cardiomyopathy with conduction block; however, move variable skeletal muscle involvement can be present. Previously, we demonstrated increased activity of extracellular signal-regulated kinase (ERK) 1/2 in hearts of LmnaH222P/H222P mice, a model of autosomal Emery-Dreifuss muscular dystrophy, and that blocking its activation improved cardiac function. We therefore examined the role of ERK1/2 activity in skeletal muscle pathology. METHODS: Sections of skeletal muscle from LmnaH222P/H222P mice were stained with hematoxylin and eosin and histological analysis performed using light microscopy. ERK1/2 activity was assessed in mouse tissue and cultured cells by immunoblotting and real-time polymerase chain reaction to measure expression of downstream target genes. LmnaH222P/H222P mice were treated with selumetinib, which blocks mitogen activated protein kinase/extracellular signal-regulated kinase kinase 1/2 that activates ERK1/2, from 16 to 20 weeks of age to assess the effects of treatment on muscle histology, ERK1/2 activity and limb grip strength. RESULTS: We detected enhanced activation of ERK1/2 in skeletal muscle of LmnaH222P/H222P mice. Treatment with selumetinib ameliorated skeletal muscle histopathology and reduced serum creatine phosphokinase and aspartate aminotransferase activities. Selumetinib treatment also improved muscle function as assessed by in vivo grip strength testing. CONCLUSIONS: Our results show that ERK1/2 plays a role in the development of skeletal muscle pathology in LmnaH222/H222P mice. They further provide the first evidence that a small molecule drug may be beneficial for skeletal muscle in autosomal Emery-Dreifuss muscular dystrophy. PMID- 23815990 TI - Small bowel diverticulitis masquerading as Crohn's disease. PMID- 23815991 TI - Adult soft tissue Ewing's sarcoma/primitive neuroectodermal tumor. PMID- 23815992 TI - Minimally invasive surgical management of acute cholecystitis during pregnancy: what are the recommendations? PMID- 23815993 TI - Migrated biliary stent complicated by small bowel obstruction. PMID- 23815994 TI - Primary adenosquamous carcinoma of the rectum. PMID- 23815995 TI - Malignant blue nevus: clinicopathologically similar to melanoma. AB - Malignant blue nevus (MBN) is a rare melanocytic lesion and controversy exists whether it is a melanoma or a unique entity. We sought to establish clinical behavior using a large national registry. All patients with MBN and melanoma from 1973 to 2008 were identified in the Surveillance Epidemiology and End Results tumor registry. We performed comparative and survival analysis among the two tumor types. A total of 228,038 patients were identified (227,986 with melanoma and 52 with MBN). The mean age was 57.7 years. Both lesions had similar age of presentation (55.8 vs 55.7 years, P = 0.527), sex (male 50 vs 55%, P = 0.44), and nodal positivity rate (9.6 vs 5.4%, P = 0.22). MBNs were more likely to be nonwhite (11.8 vs 1.6%, P < 0.0001) and present with metastatic disease (15.2 vs 4%, P = 0.0028). MBN and melanoma had a similar survival (264 vs 240 months, P = 0.78) and remained similar when stratified by race (264 vs 242 months, P = 0.99) and stage (264 vs 256 months, P = 0.83). This is the largest study to date demonstrating similar clinical behavior and survival between patients with MBN and those with melanoma. We believe MBN is a variant of melanoma and suggest using a similar treatment algorithm as that of melanoma. PMID- 23815996 TI - Gastrointestinal stromal tumors: a single institution experience of 176 surgical patients. AB - Large single-institution series of patients undergoing resection for gastrointestinal stromal tumors (GIST) are lacking. Clinicopathologic characteristics and postoperative outcomes were retrospectively collected and analyzed from patients undergoing resection for GIST from 2002 to 2011. One hundred seventy-six patients were identified; 156 underwent resection of primary nonmetastatic disease. KIT mutations were identified in 131 patients (84.0%). Of the 156 patients with primary disease, the most common site was the stomach (75.6%). Tumors were categorized as very low (24.4%), low (35.9%), intermediate (12.2%), high (24.4%), or unknown (3.2%) risk. Symptomatic patients more often had high risk (35.6 vs 9.8%; P < 0.0001) and larger tumors (7.3 vs 3.0 cm; P < 0.0001). Forty-seven patients (30.1%) underwent laparoscopic resection (LR). Compared with open surgery, LR was performed for smaller tumors (3.8 vs 6.2 cm; P = 0.002). Positive margin rates were similar (4.3% LR vs 10.2% open; P = 0.346). Median follow-up for the 156 patients with primary tumors was 32.9 months; mean overall survival was 120.9 months (median not reached). Of the 20 patients with metastatic GIST (excluded from above analysis), five patients (25.0%) died of disease with a median follow-up of 15.9 months. Most patients with resectable primary GIST have a favorable prognosis. The presence of symptoms directly related to GIST may be associated with a poor prognosis and is likely related to increased tumor size. Laparoscopic resection is well tolerated and does not appear to compromise outcomes in well-selected patients. Highly selected patients with metastatic disease may benefit from resection. PMID- 23815997 TI - The green operating room: simple changes to reduce cost and our carbon footprint. AB - Generating over four billion pounds of waste each year, the healthcare system in the United States is the second largest contributor of trash with one-third produced by operating rooms. Our objective is to assess improvement in waste reduction and recycling after implementation of a Green Operating Room Committee (GORC) at our institution. A surgeon and nurse-initiated GORC was formed with members from corporate leadership, nursing, anesthesia, and OR staff. Initiatives for recycling opportunities, reduction of energy and water use as well as solid waste were implemented and the results were recorded. Since formation of GORC in 2008, our OR has diverted 6.5 tons of medical waste. An effort to recycle all single-use devices was implemented with annual solid waste reduction of approximately 12,860 lbs. Disposable OR foam padding was replaced with reusable gel pads at greater than $50,000 per year savings. Over 500 lbs of previously discarded batteries were salvaged from the OR and donated to charity or redistributed in the hospital ($9,000 annual savings). A "Power Down" initiative to turn off all anesthesia and OR lights and equipment not in use resulted in saving $33,000 and 234.3 metric tons of CO2 emissions reduced per year. Converting from soap to alcohol-based waterless scrub demonstrated a potential saving of 2.7 million liters of water annually. Formation of an OR committee dedicated to ecological initiatives can provide a significant opportunity to improve health care's impact on the environment and save money. PMID- 23815998 TI - Impact of magnetic resonance imaging in management of pediatric Crohn's disease. AB - Crohn's disease (CD) is a chronic illness and radiographic evaluation is frequently used. Consequently, pediatric patients with CD who are diagnosed in childhood are at risk for high levels of radiation exposure during their lifetimes. We sought to evaluate the impact of magnetic resonance enterography (MRE) in management of pediatric patients with known or suspected Crohn's disease. A retrospective review of patients with known or suspected CD who underwent MRE for new onset of symptoms was conducted. All demographic data, clinical history, and results of all radiographic, endoscopic, and pathology studies were recorded. Twenty-eight patients with known or suspected CD underwent 31 MRE examinations. MRE showed active disease in 16 (52%), fistula or abscess in seven (22%), and no evidence of active disease in eight (26%). Sixty-five per cent of patients underwent MRE with no other radiation-based imaging used. Surgical intervention was deemed necessary after the MRE in 16 per cent. In all cases, surgical findings were consistent with MRE results. Nearly 60 per cent of patients with CD are managed based on the findings of MRE without additional radiographic evaluation. Based on the results of this retrospective study, we propose a clinical pathway for use of MRE in patients with known or suspected CD with new onset of symptoms. PMID- 23815999 TI - Increase in postoperative insulin requirements does not lead to decreased quality of life after total pancreatectomy with islet cell autotransplantation for chronic pancreatitis. AB - Previous studies have shown that total pancreatectomy with islet cell autotransplantation improves quality of life in chronic pancreatitis. A significant number of these patients develop postoperative hyperglycemia and daily insulin requirements or increase in daily insulin requirements. Our study investigates whether increased insulin requirements postoperatively have a negative impact on quality of life. A prospectively collected database of 74 patients undergoing extensive pancreatectomy with islet autotransplantation for pancreatitis was reviewed. Data pertaining to daily requirements and quality of life (QOL), as measured by the SF-12 questionnaire, in the preoperative and postoperative period were reviewed. Approval from the Institutional Review Board for the evaluation of human subjects was obtained. Seventy-four patients underwent extensive pancreatectomy with islet autotransplantation for pancreatitis. The majority of these patients required new daily insulin or an increase in daily insulin requirements postoperatively. Mean preoperative HA1c in this group was 5.6 with an increase to 7.3 at 6 months postoperatively (P < 0.001), a mean of 8.1 at 12 months, and 8.9 at 2 years. Mean preoperative daily insulin requirements for this group were five units/day with average increase to 19 units/day at 6 months, 21 units/day at 12 months, and 26 units/day at 2 years. Preoperative QOL scores were a mean of 26 for the physical component and 36 for the mental health component. Postoperatively, physical component scores averaged 33 at 6 months (p < 0.001), 36 at 12 months, and 36 at 2 years; the mental health component scores averaged 42 at 6 months (p = 0.007), 41 at 12 months, and 41 at 2 years. There is no correlation between physical component score or mental component score QOL scores and daily insulin requirements (r = -0.016 and r = 0.039, respectively). Total pancreatectomy with islet cell autotransplantation is an effective surgery for end-stage chronic pancreatitis. Quality of life significantly improves in physical and mental health components regardless of a postoperative increase in daily insulin requirements. PMID- 23816000 TI - Surgeon-performed ultrasound for primary hyperparathyroidism. AB - The role of preoperative parathyroid imaging continues to evolve. This study evaluated whether surgeon-performed ultrasound (U/S) obviates the need for other imaging studies and leads to a focused exploration with a high degree of surgical success. From July 2010 to February 2012, 200 patients presenting with nonfamilial primary hyperparathyroidism underwent neck U/S in the surgeon's office. The U/S interpretation was classified as Class 1 if an adenoma was identified with high confidence, Class 2 if a possible but not definite enlarged gland was imaged, and Class 0 (zero) if no adenoma was identified. The findings were correlated with subsequent intraoperative findings. There were 144 Class 1 U/Ss (72%); of 132 patients coming to surgery, 96.2 per cent had surgical findings concordant with preoperative U/S and all had apparent surgical cure. Twenty-nine patients (14.5%) had Class 2 U/S; the 31 per cent confirmed false positives in this group were usually colloid nodules. Fourteen of 27 with Class 0 U/S underwent surgery after being offered dynamically enhanced computed tomography scan. All 200 patients were apparent surgical cures. Surgeon-performed U/S is expedient, convenient, inexpensive, and accurate. A clearly identified adenoma can safely lead to a focused limited exploration and avoid additional imaging 93 per cent of the time. PMID- 23816001 TI - Abdominal versus perineal approach for treatment of rectal prolapse: comparable safety in a propensity-matched cohort. AB - Abdominal operations for rectal prolapse are associated with lower recurrence rates than perineal procedures but presumed higher morbidity. Therefore, perineal procedures are recommended for patients deemed unfit for abdominal repair. Consequently, bias confounds retrospective comparisons of the two approaches. To clarify the impact of operative approach on outcomes, we analyzed abdominal and perineal procedures in a propensity score-matched analysis. We selected patients undergoing surgery for rectal prolapse from the American College of Surgeons National Surgical Quality Improvement Program data set from 2005 to 2010. We grouped procedures as abdominal or perineal. We identified preoperative variables predictive of complications and regressed against operative approach. The resulting propensity score was used to select a matched cohort with similar clinical risk. We identified 2188 patients (848 abdominal [38.8%]; 1340 perineal [61.2%]). Patients undergoing the perineal approach had higher rates of most risk variables. Propensity matching resulted in 563 matched pairs (1126 patients) with similar clinical risk. In this matched cohort, no significant difference was found in the rate of any complication between the operative approaches; mortality was 0.9 per cent in each group (P = 1.0). Relative risk for major morbidity after abdominal approach was 1.39 (95% confidence interval, 0.92 to 2.10; P = 0.15). Although many patients with rectal prolapse are high risk for abdominal surgery, our study indicates that many patients treated by perineal repair could be safely treated with a more durable operation. PMID- 23816002 TI - The regionalization of ventral hernia repair: occurrence and outcomes over a decade. AB - Ventral hernia repairs (VHRs) have always been considered standard general surgery cases. Recently, there has been a call for "Centers of Excellence." We sought to investigate outcomes and trends between high- and low-volume centers. The Nationwide Inpatient Sample (NIS) data were analyzed from 1998-1999 (T1) and 2008-2009 (T2) for all VHRs. Hospitals were stratified into high-, medium-, and low-volume centers (HVC/MVC/LVC). Demographics, comorbidities, and outcomes were compared. Surgical cases totaled 22,771 in T1 and 37,044 in T2. In T1, 34.3 per cent were performed in HVC versus 64.2 per cent in T2 (P < 0.0001). LVC cases decreased between eras: 32.6 versus 16.1 per cent (P < 0.0001). Comorbidities and emergent admissions increased with time (P < 0.0001). Mortality was similar in both eras and between volume centers. Length of stay was less in LVC in T2 only (4.2 vs 4.8 days, P < 0.0001). Total charges were higher in HVCs in both eras (P < 0.0001). These remained significant in T2 in multivariate regression (MVR). Hospital volume was not associated with most complications or death in either era with MVR. Charlson comorbidity score, age, and emergent admission were predictors of complications and death. Regionalization has occurred for VHRs. However, most complication and mortality rates are unrelated to volume and are linked to comorbidities, age, and emergencies. PMID- 23816003 TI - Associated injuries in traumatic sternal fractures: a review of the National Trauma Data Bank. AB - Sternal fractures occur infrequently with blunt force trauma. The demographics and epidemiology of associated injuries have not been well characterized from a national trauma database. The National Trauma Data Bank was queried for patients with closed sternal fractures. The demographics were analyzed by age, gender, mechanism and indicators of anatomic and physiologic injuries. Types of commonly associated injuries were also determined. A total of 23,985 records were analyzed. Males accounted for 68.3 per cent and whites 70.9 per cent. Motor vehicle crash was the leading mechanism. More than 56 per cent had severe injuries based on Injury Severity Score (greater than 15) and 17 per cent with Glasgow Coma Score 8 or less. Crude mortality was 7.9 per cent. The majority (57.8%) and approximately one-third (33.7%) of the patients had rib fractures and lung contusions, respectively, 22.0 per cent with closed pneumothorax, 21.6 per cent had a closed thoracic vertebra fracture, 16.9 per cent with lumbar spine fracture, 3.9 per cent with concussion, and blunt cardiac injury in 3.6 per cent. Sternal fractures are usually associated with severe blunt trauma. Lung contusion remains the leading associated injury followed by vertebral spine fractures. Cardiac injuries are less frequent and vascular injuries less so. Mechanism of injury and presence of sternal fractures should alert providers to these potential associated injuries. PMID- 23816004 TI - Using a relational database to improve mortality and length of stay for a department of surgery: a comparative review of 5200 patients. AB - The emphasis on high-quality care has spawned the development of quality programs, most of which focus on broad outcome measures across a diverse group of providers. Our aim was to investigate the clinical outcomes for a department of surgery with multiple service lines of patient care using a relational database. Mortality, length of stay (LOS), patient safety indicators (PSIs), and hospital acquired conditions were examined for each service line. Expected values for mortality and LOS were derived from University HealthSystem Consortium regression models, whereas expected values for PSIs were derived from Agency for Healthcare Research and Quality regression models. Overall, 5200 patients were evaluated from the months of January through May of both 2011 (n = 2550) and 2012 (n = 2650). The overall observed-to-expected (O/E) ratio of mortality improved from 1.03 to 0.92. The overall O/E ratio for LOS improved from 0.92 to 0.89. PSIs that predicted mortality included postoperative sepsis (O/E:1.89), postoperative respiratory failure (O/E:1.83), postoperative metabolic derangement (O/E:1.81), and postoperative deep vein thrombosis or pulmonary embolus (O/E:1.8). Mortality and LOS can be improved by using a relational database with outcomes reported to specific service lines. Service line quality can be influenced by distribution of frequent reports, group meetings, and service line-directed interventions. PMID- 23816005 TI - SESC Practice Committee survey: surgical practice in the duty-hour restriction era. AB - Debate continues as to the relevance of Accreditation Council for Graduate Medical Education (ACGME) duty-hour restrictions in actual practice and the adequacy of resident training in surgery. A survey of the membership of the Southeastern Surgical Congress using an Internet-based questionnaire was conducted: adherence to duty-hour restrictions, evidence of sleepiness and fatigue, opinions regarding the training, and clinical performance of surgeons who had trained after the institution of duty-hour restrictions in 2003 (termed "recently trained surgeons"). One hundred seventy-seven members respondents out of 1008 (18%). Most (101 of 170 [59%]) worked more than 80 hours in a week and half (86 of 174 [49%]) more than 24 hours consecutively once or more a month. Falling asleep inappropriately was reported by 6 to 12 per cent. Forty per cent (71 of 176) thought that graduates of residencies today are prepared for clinical practice. Those who had hired a recently trained surgeon believed the latter was sufficiently trained (61 of 123 [50%]) more often than those who had not hired one (10 of 51 [20%]; P = 0.006). Those with a new colleague gave first assistant help in 75 per cent (91 of 121) during the first year. Surgeons in practice regularly violate ACGME duty-hour restrictions. Many surgeons have doubts whether new graduates of residency training programs have adequate training to practice surgery. Those who have hired a new surgeon trained under duty-hour restrictions are more likely to be satisfied with the latter's training. Most new trainees receive direct assistance from their practice partners, continuing their training beyond residency. PMID- 23816006 TI - Evaluation of alpha-fetoprotein staging system for hepatocellular carcinoma in noncirrhotic patients. AB - The Barcelona Clinic Liver Cancer (BCLC) staging classification is commonly used for staging hepatocellular carcinoma (HCC). This system assumes the coexistence of cirrhosis; however, a significant proportion of patients with HCC present without cirrhosis. Recently, an alternative system was proposed that stratifies patients according to alpha-fetoprotein (AFP) level. The aim of this study was to apply the AFP staging system to noncirrhotic patients with HCC and evaluate its ability to predict overall survival (OS). A prospective hepatopancreatobiliary database was reviewed for all patients with a diagnosis of HCC. Patients were staged based on BCLC classification as well as by AFP stage according to four levels: less than 10 ng/mL, 10 to 150 ng/mL, 150 to 500 ng/mL, and greater than 500 ng/mL. Cirrhotic patients were compared with noncirrhotic patients in terms of patient demographics and HCC stage. Kaplan-Meier (KM) analysis of OS was performed for noncirrhotic patients according to BCLC and AFP staging systems. Cirrhotic and noncirrhotic patients differed significantly in terms of median age at presentation (64 vs 70 years, P < 0.001) and gender (76 vs 65% male, P = 0.006). BCLS staging classification did not distinguish between cirrhotics and noncirrhotics (P = 0.733), whereas AFP staging demonstrated a significant difference between the two groups (P < 0.0001). KM analysis of OS for noncirrhotic patients with HCC was significant for both the BCLC and the AFP staging systems (P = 0.003 vs P < 0.0001, respectively). Patients presenting with HCC in the absence of cirrhosis appear to have different characteristics than patients with cirrhosis. Staging according to AFP level is an appropriate predictor of prognosis in noncirrhotic patients with HCC. PMID- 23816007 TI - Treatment of refractory perianal fistulas with ligation of the intersphincteric fistula tract: preliminary results. AB - Several surgical options exist for management of fistula in ano. The goal of treatment is to achieve closure of the fistula while maintaining continence. Sphincter-sparing operations to close perianal fistulas include advancement flap, anal fistula plug, fibrin glue, and fistulectomy. Variable success rates from 30 to 80 per cent have been reported. Ligation of intersphincteric fistula tract (LIFT), first described in 2007, has a reported success rate from 40 to 94 per cent. The objective of this study was to study our results of the LIFT procedure for refractory perianal fistulas. We conducted a retrospective 18-month review of consecutive patients with refractory perianal disease treated with the LIFT procedure at an academic, tertiary, colorectal practice. All patients undergoing a LIFT procedure for anal fistula from August 2010 to August 2012 were included in the study. The primary end points were success rates at 1 month and 3 months. Secondary end points were postoperative complications and maintenance of continence. Twenty patients underwent LIFT procedures of whom nine had previously failed treatments. Mean age was 45 years and included 12 male and eight female patients. Success rate at 1 month was 70 per cent (14 patients) and at 3 months was 80 per cent (16 patients). Success rates for patients with previously failed attempts were 67 per cent at 1 month and 89 per cent at 3 months. Continence was maintained in 100 per cent of patients. Our data support the use of the LIFT procedure for refractory perirectal fistulas. PMID- 23816008 TI - Water as a contrast medium: a re-evaluation using the multidetector-row computed tomography. AB - Water as an intraluminal negative contrast medium produces improved image quality with reduced artefact. However, rapid absorption of oral water in the bowel relative to speed and timing of image capturing has limited its clinical application. These findings predate advances in multidetector-row computed tomography (CT). To re-evaluate differences in image quality, we studied image clarity and luminal distention between the same group of patients who received both a pancreas protocol CT (PPCT) that uses oral water and a conventional positive oral contrast scan. We reviewed 66 patients who had previously undergone both a PPCT and an oral contrast abdominal CT. CT images were independently reviewed by two board-certified radiologists who scored degree of hollow viscus distention and visualization of mural detail using a Likert 5-point scale. Results were evaluated by using the Wilcoxon-signed rank test. Student's t test was applied to evaluate the differences in radiation dosage and Spearman's correlational test was used to evaluate interrater correlation between the radiologists. In comparing the mean radiation dosage, there was no statistical difference between the two protocols, and there was good interrater association with ratios of 0.595 and 0.51 achieved for the PPCT and conventional oral scan, respectively. The Wilcoxon signed-rank test showed statistical differences in the stomach (P < 0.001) for both clarity (P < 0.001) and distention (P < 0.001), the duodenum for both clarity (P < 0.001) and distention (P = 0.02), and the ileum for distention (P = 0.02) with the PPCT having a better median score for organ clarity in the stomach and duodenum and better luminal distention in the stomach, equal distention in the duodenum, and slightly worse distention in the ileum. For the remainder of the bowel and organs evaluated, there was no statistically significant difference in the ratings between the two protocols. Using present CT scan technology, water can be an effective contrast medium causing better or equal distention in the bowel and better or equal clarity than routine barium contrast. This calls for a need to reconsider the use of water as a contrast medium in clinical practice. PMID- 23816009 TI - Hirschsprung's disease in the preterm infant: implications for diagnosis and outcome. AB - Hirschsprung's disease (HD), congenital absence of ganglion cells, is considered uncommon in preterm infants. The aim was to describe the frequency, presentation, and surgical outcomes of preterm infants with HD. A retrospective cohort study was conducted of all patients diagnosed with HD from 2002 to 2012 at a single children's hospital. Clinical presentation and surgical outcomes were obtained for term (37 weeks of gestation or greater) and preterm infants. One hundred twenty-nine subjects with HD were identified, 24 (19%) preterm and 105 (81%) term. Preterm infants were more likely to be diagnosed after 30 days of life (66.7 vs 37.1%, P < 0.01; median age 2.9 vs 0.3 months, P < 0.05) and to have associated major congenital anomalies (45.8 vs 20.0%, P < 0.01). Fewer preterm infants had primary pull-through operations (45.8 vs 76.2%, P < 0.005). Preterm infants were more likely to have an episode of Hirschsprung's-associated enterocolitis (45.8 vs 24.0%, P < 0.05) but were not more likely to die from any cause (8.3 vs 5.8%, P = 0.64). HD may be more common in preterm infants than previously recognized, and increased comorbidities in these patients may lead to delayed diagnosis and increased morbidity. HD should be considered in the preterm infant presenting with a bowel obstruction, especially when accompanied by associated anomalies. PMID- 23816010 TI - Laparoscopic sleeve gastrectomy with comparable weight loss in all obese groups: a VA hospital experience. AB - Laparoscopic sleeve gastrectomy (LSG) is gaining popularity as a standalone procedure for the surgical treatment of obesity in the superobese because of higher failure with Roux-en-Y gastric bypass. We report a single-institution experience with LSG as the procedure of choice in all obese groups and comparing weight loss in the nonsuperobese and superobese patients. LSGs performed between February 2009 and June 2011 were reviewed. Body mass index (BMI), percentage excess weight loss (%EWL), and percentage excess BMI loss were analyzed for two groups of nonsuperobese (Group I) and superobese (Group II) at 3, 6, and 12 months postoperative visits. Two-sample t tests were used to compare groups. At each postoperative visit, reductions in BMI and amount of weight loss were higher in Group II but %EWL was statistically similar in both groups. The %EWL was 29.5 versus 29.9 per cent at 3 months (P = 0.9246), 51.7 versus 47.5 per cent at 6 months (P = 0.9800), and 52.8 versus 52.6 per cent at 12 months (P = 0.9755). Both groups demonstrated satisfactory resolution of most preoperative comorbidities. Success rate of weight loss after LSG as a standalone procedure is comparable in the superobese and nonsuperobese patients. PMID- 23816011 TI - Pulmonary hypertension is not an independent risk factor for morbidity and mortality in the trauma population. PMID- 23816012 TI - Success of reminder systems in reducing catheter-associated urinary tract infections. PMID- 23816014 TI - Does fitness completely explain the obesity paradox? PMID- 23816015 TI - Rationale and design of the Primary pREvention strategies at the community level to Promote Adherence of treatments to pREvent cardiovascular diseases trial number (CTRI/2012/09/002981). AB - INTRODUCTION: Cardiovascular diseases (CVDs) are a leading cause of morbidity and mortality in low-income countries including India. There is a need for effective, low-cost methods to prevent CVDs in rural India. One strategy is to identify and implement interventions at high-risk individuals using community health workers (CHWs). There is a paucity of CHW-based CVD intervention trials from low-income countries. METHODS: We designed a multicenter, household-level, cluster randomized trial with 1:1 allocation to intervention and control arms. The CHWs undertook a door-to-door survey and screened 5,699 households in 28 villages from 3 rural regions in India to identify at-risk households. The households were defined as those with >=1 individual aged >=35 years and at moderate or high risk for CVD based on the non-laboratory-based National Health and Nutrition Examination Survey score. All at-risk individuals were invited to attend a physician-led village clinic that provided a CVD risk reduction prescription and education about target risk factor levels for CVD control. All households in which at least 1 member at moderate to high risk for CVD had received a risk reduction prescription were eligible for randomization. Households randomized to the CHW-based intervention will receive 1 household visit by a CHW every 2 months, for 12 months. During these visits, CHWs will measure blood pressure, ascertain and reinforce adherence to prescribed therapies, and modify therapy to meet targets. Households randomized to the control arm do not receive CHW visits. At 12 months after randomization, we will evaluate 2 primary outcomes of systolic blood pressure and adherence to antihypertensive drugs and secondary outcomes of INTERHEART risk score, body mass index, and waist-to-hip ratios. At 18 to 24 months after randomization and 6 to 12 months after the last intervention, we will record these outcomes to evaluate sustainability of intervention. RESULTS: Community health workers screened a total of 5,033 households that included 9,248 individuals and identified 2,571 households with 3,784 at-risk individuals. We randomized 2,438 households (1,219 to intervention and 1,219 to control groups). CONCLUSION: Our large trial of CHWs in rural India will provide important information regarding a promising approach to primary prevention of CVDs. PMID- 23816016 TI - Rationale and design of the COlchicine for Prevention of the Post-pericardiotomy Syndrome and Post-operative Atrial Fibrillation (COPPS-2 trial): a randomized, placebo-controlled, multicenter study on the use of colchicine for the primary prevention of the postpericardiotomy syndrome, postoperative effusions, and postoperative atrial fibrillation. AB - BACKGROUND: The efficacy and safety of colchicine for the primary prevention of the postpericardiotomy syndrome (PPS), postoperative effusions, and postoperative atrial fibrillation (POAF) remain uncertain. Although preliminary data from a single trial of colchicine given for 1 month postoperatively (COPPS trial) were promising, the results have not been confirmed in a large, multicenter trial. Moreover, in the COPPS trial, colchicine was given 3 days postoperatively. METHODS: The COPPS-2 study is a multicenter, double-blind, placebo-controlled randomized trial. Forty-eight to 72 hours before planned cardiac surgery, 360 patients, 180 in each treatment arm, will be randomized to receive placebo or colchicine without a loading dose (0.5 mg twice a day for 1 month in patients weighing >=70 kg and 0.5 mg once for patients weighing <70 kg or intolerant to the highest dose). The primary efficacy end point is the incidence of PPS, postoperative effusions, and POAF at 3 months after surgery. Secondary end points are the incidence of cardiac tamponade or need for pericardiocentesis or thoracentesis, PPS recurrence, disease-related admissions, stroke, and overall mortality. CONCLUSIONS: The COPPS-2 trial will evaluate the use of colchicine for the primary prevention of PPS, postoperative effusions, and POAF, potentially providing stronger evidence to support the use of preoperative colchicine without a loading dose to prevent several postoperative complications. ClinicalTrials.gov Identifier: NCT01552187. PMID- 23816017 TI - Effect of atrioventricular and ventriculoventricular delay optimization on clinical and echocardiographic outcomes of patients treated with cardiac resynchronization therapy: a meta-analysis. AB - BACKGROUND: Optimization of atrioventricular (AV) and ventriculoventricular (VV) delays of cardiac resynchronization therapy (CRT) devices maximizes left ventricular filling and stroke volume. However, the incremental value of these optimizations over empiric device programming remains unclear. The objective of this analysis was to perform a systematic review and meta-analysis of the effects of AV and VV delay optimization on clinical and echocardiographic end points of patients with heart failure treated with CRT. METHODS: A standardized search strategy was performed and identified 12 trials comparing AV and/or VV delay optimization and conventional CRT device programming and their effects on various clinical and echocardiographic outcomes. Pooled odds ratios were analyzed using random-effect meta-analysis with Mantel-Haenszel method. RESULTS: Combined data from a total of 4,356 patients with heart failure treated with CRT showed no differences in clinical or echocardiographic outcomes between patients who underwent AV and/or VV delay optimization and patients who underwent empiric device programming (Mantel-Haenszel odds ratio 0.86 [95% CI 0.68-1.09], P value for overall effect = .21 by intention-to-treat analysis). CONCLUSION: The current literature suggests that routine AV and/or VV delay optimization has a neutral effect on clinical and echocardiographic outcomes based on pooled data from randomized and nonrandomized studies. Standardization of patient selection and optimization timing and method may help to further define the role of CRT device optimization. PMID- 23816018 TI - Comparison of the performances of cardiac troponins, including sensitive assays, and copeptin in the diagnostic of acute myocardial infarction and long-term prognosis between women and men. AB - BACKGROUND: Concerns have been raised about possible gender disparities in cardiac investigations and/or outcome. This study sought to examine and compare the diagnostic and prognostic performance of selected cardiac biomarkers in women versus men. METHODS: In a prospective, multicenter cohort of patients with acute chest pain cardiac troponin T (cTnT) (fourth-generation Roche assay), high sensitivity cTnT (hs-cTnT), and copeptin were measured at presentation. RESULTS: Of 1,247 patients, 420 were women and 827 were men. Although the rate of acute myocardial infarction was similar in women (14.5%) and men (16.6%, P = .351), women more frequently had cardiac but noncoronary causes of chest pain (17.4% vs 10.8%, P = .001) and less frequently had unstable angina (8.8% vs 16.6%, P = .002) than men. Diagnostic accuracy as quantified by the area under the receiver operating characteristic curve (AUC) for acute myocardial infarction in women was 0.90 (95% CI 0.84-0.95) for cTnT, which was lower than the AUC for hs-cTnT alone (0.94, 95% CI [0.91-0.98]), the combination of cTnT with copeptin (0.96, 95% CI [0.94-0.98]) or the combination of hs-cTnT with copeptin (0.96, 95% CI [0.93 0.98]) (P = .008, P = .006, and P = .002, respectively). Prognostic accuracy as quantified by the AUCs for 1-year mortality was 0.69 (0.56-0.83), 0.86 (0.79 0.93), 0.87 (0.81-0.94), and 0.87 (0.80-0.94), respectively. No relevant gender differences in AUCs were observed. CONCLUSION: The diagnostic and prognostic performance of cTnT, hs-cTnT, and copeptin is as good in women as in men. High sensitivity cTnT and the combination of cTnT and copeptin outperform cTnT alone, both in women and men. PMID- 23816019 TI - Sex differences in clinical outcomes in patients with stable angina and no obstructive coronary artery disease. AB - BACKGROUND: We comparatively evaluated clinical outcomes in men and women presenting with stable angina with no coronary artery disease (CAD), nonobstructive CAD, and obstructive CAD on coronary angiography. METHODS: We studied all patients >=20 years with stable angina, undergoing coronary angiography in British Columbia, Canada, from July 1999 to December 2002 (n = 13,695) with maximum follow-up to 3 years. No CAD, nonobstructive CAD, and obstructive CAD were defined as 0%, 1% to 49%, and >=50% luminal narrowing in any epicardial coronary artery, respectively. Freedom from major adverse cardiac events (MACEs), which included the combined end points of all-cause mortality, nonfatal acute myocardial infarction, nonfatal stroke, and heart failure admissions, was estimated using the Kaplan-Meier method. Hazard ratios (HRs) and 95% CIs for MACE were estimated up to 3 years postcatheterization and compared between sex and CAD groups. RESULTS: Within the first year, women with nonobstructive CAD had a higher risk of MACE than men with nonobstructive CAD (adjusted HR 2.43, 95% CI 1.08-5.49). Furthermore, women with nonobstructive CAD had a 2.55-fold higher risk of MACE than women with no CAD (95% CI 1.33-4.88). In contrast, men with nonobstructive CAD had a similar risk as men with no CAD (adjusted HR 0.61, 95% CI 0.26-1.45). The differences in MACE according to extent of CAD were not evident in the longer term. CONCLUSIONS: Women with stable angina and nonobstructive CAD are 3 times more likely to experience a cardiac event within the first year of cardiac catheterization than men. A prospective trial to examine the impact of medical therapy on MACE in patients with nonobstructive CAD is warranted. PMID- 23816020 TI - Gender differences in cardiovascular mortality by C-reactive protein level in the United States: evidence from the National Health and Nutrition Examination Survey III. AB - BACKGROUND: The association between C-reactive protein (CRP) and cardiovascular (CV) mortality by gender has not been previously described using a data set that is representative of the US population. METHODS: We used Cox proportional hazards models to explore gender differences in CRP-associated mortality via the National Health and Nutrition Examination Survey III 1988-1994 linked to the National Death Index with mortality follow-up through 2006. We examined CV mortality as well as all-cause mortality hazards. RESULTS: The final sample size included a total of 13,878 individuals (7,364 women and 6,514 men) with a median follow up of 18.2 years. All models controlled for race, age, smoking, high-density lipoprotein, hypertension, diabetes mellitus, waist circumference, and total cholesterol. Men with a CRP >3.0 mg/L relative to those with a CRP <=3.0 mg/L had elevated CV mortality hazards (hazard ratio [HR] 1.79, 95% CI 1.23-2.60) and all cause mortality hazards (HR 1.57, 95% CI 1.29-1.90). In women, elevated CRP was not significantly associated with either increased CV (HR 1.20, 95% CI 0.90-1.59) or all-cause mortality hazards (HR 1.09, CI 0.93-1.29). CONCLUSION: National guidelines from various agencies that make recommendations on the diagnostic and prognostic use of CRP have treated men and women equally. We find that there may be reason to tailor recommendations based upon one's gender. PMID- 23816021 TI - Reporting and representation of ethnic minorities in cardiovascular trials: a systematic review. AB - BACKGROUND: Ethnic minority groups in the United States are at increased risk of developing cardiovascular diseases, experiencing adverse outcomes, and receiving suboptimal treatment. Such discrepancies may be related to a difference in race specific outcomes in the management of cardiovascular diseases. However, little is known about the reporting and representation of ethnic minorities in major cardiovascular trials. METHODS: A systematic review of major cardiovascular randomized controlled trials published in The Journal of the American Medical Association, The Lancet, and The New England Journal of Medicine between 1997 and 2010 was performed. We determined the reporting rate of the following ethnic minority groups in studies that enrolled American patients: whites, African Americans, Asians, and Hispanics. RESULTS: A total of 250 randomized controlled trials that enrolled 1,103,694 patients were included in the systematic review. Among them, 56% (n = 140) of the trials reported information on race. No significant temporal changes in racial reporting were observed during the study period (P = .21). The median enrollment rate in trials for whites, African Americans, Hispanics, and Asians was 86%, 7%, 6%, and 4%, respectively. When compared with the population prevalence of disease burden, we found that whites were overrepresented (88% vs 78%, P < .001), whereas African Americans were underrepresented (3% vs 11%, P < .001), in trials of coronary artery disease. CONCLUSIONS: Despite significant changes in the ethnic composition of the United States, we found that only about half of all major cardiovascular trials reported any racial information. Underrepresentation of ethnic minority groups in cardiovascular trials was observed. PMID- 23816022 TI - Canada Acute Coronary Syndrome Risk Score: a new risk score for early prognostication in acute coronary syndromes. AB - BACKGROUND: Despite the availability of several acute coronary syndrome (ACS) prognostic risk scores, there is no appropriate score for early-risk stratification at the time of the first medical contact with patients with ACS. The primary objective of this study is to develop a simple risk score that can be used for early-risk stratification of patients with ACS. METHODS: We derived the risk score from the Acute Myocardial Infarction in Quebec and Canada ACS-1 registries and validated the risk score in 4 other large data sets of patients with ACS (Canada ACS-2 registry, Canada-GRACE, EFFECT-1, and the FAST-MI registries). The final risk score is named the Canada Acute Coronary Syndrome Risk Score (C-ACS) and ranged from 0 to 4, with 1 point assigned for the presence of each of these variables: age >=75 years, Killip >1, systolic blood pressure <100 mm Hg, and heart rate >100 beats/min. The primary end points were short-term (inhospital or 30-day) and long-term (1- or 5-year) all-cause mortality. RESULTS: The C-ACS has good predictive values for short- and long-term mortality of patients with ST-segment elevation myocardial infarction and non-ST-segment elevation ACS. The negative predictive value of a C-ACS score >=1 is excellent at >=98% (95% CI 0.97-0.99) for short-term mortality and >=93% (95% CI 0.91-0.96) for long-term mortality. In other words, a C-ACS score of 0 can potentially identify correctly >=97% short-term survivors and >=91% long-term survivors. CONCLUSION: The C-ACS risk score permits rapid stratification of patients with ACS. Because this risk score is simple and easy to memorize and calculate, it can be rapidly applied by health care professionals without advanced medical training. PMID- 23816023 TI - Infarct size and mortality in patients with proximal versus mid left anterior descending artery occlusion: the Intracoronary Abciximab and Aspiration Thrombectomy in Patients With Large Anterior Myocardial Infarction (INFUSE-AMI) trial. AB - OBJECTIVE: This study aimed to compare infarct size and clinical outcomes in patients with proximal versus mid left anterior descending (mLAD) infarction. BACKGROUND: The extent of myocardium at risk is an important prognostic determinate in patients with ST-segment elevation myocardial infarction. METHODS: The INFUSE-AMI trial randomized patients with anterior ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention with bivalirudin anticoagulation to intracoronary (IC) bolus abciximab versus no abciximab and to thrombus aspiration versus no aspiration. The primary end point was magnetic resonance imaging infarct size (% of left ventricular mass) at 30 days. Lesion location was independently assessed and was defined as proximal (pLAD) if present before or at first significant septal perforator branch, or mLAD if beyond. RESULTS: Among 452 patients, 292 (64.7%) had pLAD and 159 (35.3%) had mLAD occlusions. Patients with pLAD infarcts were significantly more likely to have Killip class >1 heart failure and ejection fraction <40% and to present earlier to the hospital. Proximal LAD infarcts had significantly lower rates of final Thrombolysis In Myocardial Infarction flow 3 and procedural success but similar rates of myocardial blush grade 2/3 and ST-segment resolution compared with mLAD infarcts. Infarct size at 30 days was significantly greater in the pLAD group (19.3% [9.2-25.9] vs 14.3% [6.2-18.9], P < .0001). Mortality at 30 days was also higher in the pLAD group (4.2% vs 0.6%, P = .04). The effect of IC abciximab on reducing infarct size was comparable in both groups. CONCLUSION: ST-segment elevation myocardial infarction caused by pLAD compared with mLAD occlusion results in larger infarcts and greater mortality even with contemporary reperfusion therapy. PMID- 23816024 TI - Sleeping altitude and sudden cardiac death. AB - BACKGROUND: Mountain activities characterized by strenuous exercise in a hypoxic setting place unique demands on the body. The mortality rate associated with mountain activities is high, with sudden cardiac death (SCD) representing the most frequent of all nontraumatic deaths. We evaluated the possible effect of acclimatization in reduction of SCD during high-altitude sojourns. METHODS: This was a retrospective cohort study involving all deaths (N = 559) that occurred during mountain activities in Austria from 1985 through 1993. Baseline patient demographics, cardiovascular comorbidities, smoking history, family history of SCD, sleeping altitude, annual mountaineering frequency, and physical activity on the day of SCD were included in a questionnaire previously used in a pilot study. RESULTS: Data from 301 of 599 individuals without prespecified exclusions were available for analysis (79% of eligible cohort). Sudden cardiac deaths happened mostly around noon (29%), and mean altitude at which SCDs occurred was 1,710 +/- 501 m. When sleeping altitude was divided into quartiles (<700 m, 700-999 m, 1,000-1,299 m, and >1,299 m), the odds ratio for SCD on the first day at altitude when sleeping below 700 m was 5.7 (95% CI 2.8-11.6) as compared with sleeping above 1,299 m. CONCLUSION: For males >34 years, those with history of coronary artery disease and/or prior infarction, and those unaccustomed to physical activity at altitude, sleeping at moderate altitude before exercising at altitude may reduce the risk of SCD. PMID- 23816025 TI - Heart failure performance measures: eligibility and implementation in the community. AB - BACKGROUND: The goal of heart failure (HF) performance measures is to improve quality of care by assessing the implementation of guidelines in eligible patients. Little is known about the proportion of eligible patients and how performance measures are implemented in the community. METHODS: We determined the eligibility for and adherence to performance measures and beta-blocker therapy in a community-based cohort of hospitalized HF patients from January 2005 to June 2011. RESULTS: All of the 465 HF inpatients (median age 76 years, 48% men) included in the study received an ejection fraction assessment. Only 164 had an ejection fraction <40% thus were candidates for beta-blocker and angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blocker (ARB) therapy. Considering absolute contraindications, 99 patients were eligible to receive ACE inhibitors/ARB, and 162 to receive beta-blockers. Among these, 85% received ACE inhibitors/ARBs and 91% received beta-blockers. Among the 261 individuals with atrial fibrillation, 89 were eligible for warfarin and 54% received it. Of 52 current smokers, 69% received cessation counseling during hospitalization. CONCLUSION: In the community, among eligible hospitalized HF patients, the implementation of performance measures can be improved. However, as most patients are not candidates for current performance measures, other approaches are needed to improve care and outcomes. PMID- 23816026 TI - Tissue coverage and neointimal hyperplasia in overlap versus nonoverlap segments of drug-eluting stents 9 to 13 months after implantation: in vivo assessment with optical coherence tomography. AB - BACKGROUND: Histologic experimental studies have reported incomplete neointimal healing in overlapping with respect to nonoverlapping segments in drug-eluting stents (DESs), but these observations have not been confirmed in human coronary arteries hitherto. On the contrary, angiographic and optical coherence tomography studies suggest that DES overlap elicits rather an exaggerated than an incomplete neointimal reaction. METHODS: Optical coherence tomography studies from 2 randomized trials including sirolimus-eluting, biolimus-eluting, everolimus eluting, and zotarolimus-eluting stents were analyzed at 9- to 13-month follow up. Coverage in overlapping segments was compared versus the corresponding nonoverlapping segments of the same stents, using statistical pooled analysis. RESULTS: Forty-two overlaps were found in 31 patients: 11 in sirolimus-eluting stents, 3 in biolimus-eluting stents, 17 in everolimus-eluting stents, and 11 in zotarolimus-eluting stents. The risk ratio of incomplete coverage was 2.35 (95% CI 1.86-2.98) in overlapping versus nonoverlapping segments. Thickness of coverage in overlaps was only 85% (95% CI 81%-90%) of the thickness in nonoverlaps. Significant heterogeneity of the effect was observed, especially pronounced in the comparison of thickness of coverage (I(2) = 90.31). CONCLUSIONS: The effect of overlapping DES on neointimal inhibition is markedly heterogeneous: on average, DES overlap is associated with more incomplete and thinner coverage, but in some cases, the overlap elicits an exaggerated neointimal reaction, thicker than in the corresponding nonoverlapping segments. These results might help to understand why overlapping DES is associated with worse clinical outcomes, both in terms of thrombotic phenomena and in terms of restenosis and revascularization. PMID- 23816027 TI - Relation between the vasodilator-stimulated phosphoprotein phosphorylation assay and light transmittance aggregometry in East Asian patients after high-dose clopidogrel loading. AB - OBJECTIVES: We analyzed the relation between platelet aggregation measured by light transmittance aggregometry (LTA) and platelet reactivity index (PRI) measured by vasodilator-stimulated phosphoprotein phosphorylation (VASP-P) assay. BACKGROUND: It has been suggested that LTA and VASP-P assay correlate differently according to the level of P2Y12 receptor blockade by thienopyridines. METHODS: We simultaneously measured platelet function by LTA and VASP-P assay in 466 East Asians undergoing elective percutaneous coronary intervention after a 600-mg clopidogrel loading. High on-clopidogrel platelet reactivity (HPR) was defined by published consensus criteria. RESULTS: The degree of correlation between LTA and the VASP-P assay was different according to PRI levels. The correlation was lower in patients with poor responsiveness (PRI >60%) (n = 216) (0.035 <= r(2) <= 0.047), which was greater in responsive patients (PRI <=60%) (n = 250) (0.315 <= r(2) <= 0.526). Despite a 600-mg loading, East Asians had a high prevalence of HPR (40.1%-63.5%), and the prevalence of HPR also differed between LTA and VASP-P assay. A PRI cutoff of >58% (area under curve, 0.829; 95% confidence intervals, 0.792-0.862; P < .001) corresponded to the published HPR cutoff by 5-MUM adenosine diphosphate-induced maximal platelet aggregation >46%. CONCLUSIONS: This is the largest study correlating platelet reactivity measured by LTA and VASP-P assay in a percutaneous coronary intervention-treated cohort. The correlation is dependent on the level of responsiveness. Future investigations are needed to better define the optimal cutoffs of HPR measured by LTA and VASP-P assay for personalized antiplatelet therapy. PMID- 23816028 TI - Red cell distribution width as a bleeding predictor after percutaneous coronary intervention. AB - BACKGROUND: Red cell distribution width (RDW), a measure of variability in the size of circulating erythrocytes, is an independent predictor of mortality in cardiovascular disease and in patients undergoing percutaneous coronary intervention (PCI). We set out to determine if RDW is a prognostic marker of major bleeding post-PCI. METHODS: The study population included 6,689 patients who were subjected to PCI. The RDW was derived from a complete blood count drawn before PCI. Major inhospital bleeding was defined as a hematocrit decrease >=12%, hemoglobin drop of >=4, transfusion of >=2 units of packed red blood cells, retroperitoneal, or gastrointestinal or intracranial bleeding. Multivariable logistic analysis of major inhospital bleeding was performed using a logistic regression model that comprised the National Cardiovascular Data Registry (NCDR) risk score model as a single variable. RESULTS: Major bleeding (P < .001), vascular complications (P = .005), and transfusions (P < .001) were significantly higher in patients with higher baseline RDW values. After adjustment for known bleeding correlates, RDW was a significant predictor for major bleeding (odds ratio 1.12, 95% CI 1.06-1.19, P < .001). Although the c statistic of the NCDR risk prediction model changed from 0.730 to 0.737 (P = .032), the net reclassification improvement increased significantly after the addition of RDW as a continuous variable (17.3% CI 6.7%-28%, P = .002). CONCLUSIONS: Red cell distribution width, an easily obtainable marker, has an independent, linear relationship with major bleeding post-PCI and incrementally improves the well validated NCDR risk prediction model. These data suggest that further investigation is necessary to determine the relationship of RDW and post-PCI bleeding. PMID- 23816029 TI - Long-term clinical outcome after fractional flow reserve- versus angio-guided percutaneous coronary intervention in patients with intermediate stenosis of coronary artery bypass grafts. AB - BACKGROUND: Fractional flow reserve (FFR)-guided percutaneous revascularization (percutaneous coronary intervention [PCI]) of intermediate stenosis in native coronary artery is safe and associated with better clinical outcomes as compared with an angiography-guided PCI. It is unknown whether this applies to coronary artery bypass grafts (CABGs). METHODS: We included 223 patients with CABG and with stable or unstable angina and an intermediate stenosis involving an arterial or a venous graft. Patients were divided into 2 groups: FFR guided (n = 65, PCI performed in case of FFR <=0.80) and angio guided (n = 158, PCI performed based on angiographic evaluation). Primary end point was major adverse cardiac and cerebrovascular event, defined as death, myocardial infarction, target vessel failure, and cerebrovascular accident (CVA). RESULTS: The 2 groups were similar in terms of demographic and clinical characteristics. Percutaneous coronary intervention was performed in 23 patients (35%) of the FFR-guided group and 90 patients (57%) of the angio-guided group (P < .01). In the FFR-guided group, PCI was more often performed in arterial grafts as compared with the angio-guided group (16 [70%] vs 12 [13%], respectively; P < .01). Follow-up was obtained in 96% of patients at a median of 3.8 years (1.6-4.0 years). At multivariate analysis, major adverse cardiac and cerebrovascular event rate was significantly lower in the FFR-guided group as compared with the angio-guided group (18 [28%] vs 77 [51%], hazard ratio 0.33 [0.11-0.96], P = .043]. Procedure costs were overall reduced in the FFR-guided group (?2240 +/- ?652 vs ?2416 +/- ?522, P = .03). CONCLUSIONS: An FFR-guided PCI of intermediate stenosis in bypass grafts is safe and results in better clinical outcomes as compared with an angio-guided PCI. This clinical benefit is achieved with a significant overall reduction in procedural costs. PMID- 23816031 TI - The interaction of exercise ability and body mass index upon long-term outcomes among patients undergoing stress-rest perfusion single-photon emission computed tomography imaging. AB - BACKGROUND: The obesity paradox has been reported in several populations of patients with cardiovascular disease. Recent data have shown that physical fitness may attenuate the obesity paradox. Patients who undergo pharmacologic stress testing are known to have a higher risk of mortality than those who can exercise. The purpose of this study is to determine the interaction of obesity and exercise ability on survival among patients with a normal stress-rest single photon emission computed tomography (SPECT). METHODS: A total of 5,203 (60 +/- 13 years, male 37%) patients without a history of heart disease and a normal stress rest SPECT between the years 1995 and 2010 were included in this analysis. Body mass index categories were defined according to the World Health Organization classification: normal weight, 18.5 to 24.9 kg/m(2); overweight, 25 to 29.9 kg/m(2); and obese, >=30 kg/m(2). Patients were divided into 3 groups based on their ability to exercise: those who reached >=6 METs on exercise, those who attained a level of <6 METs, and those who required pharmacologic stress. Patients in each of these fitness groups were further divided into 3 subgroups based on their body mass index. RESULTS: There were 939 (18%) deaths during a mean follow-up of 8.1 +/- 4.1 years, for an overall event rate of 2.3%/y. Both exercise to >=6 METs and being obese were associated with lower mortality. Adjusted multivariate analysis using the obese high-fit patients as the reference showed a wide heterogeneity in annualized mortality rates according to exercise and weight status, with annualized event rates which varied from 0.6%/y in the obese subjects who were physically fit to 5.3%/y among healthy subjects who underwent pharmacologic stress testing (P < .001). CONCLUSIONS: Stress mode and body weight impacted long-term survival in patients with a normal stress SPECT. The benefit of being physically fit was evident in all weight groups, as was the adverse effect of being unable to exercise. However, with regard to body weight, there was a paradoxical survival advantage for those patients who were overweight and obese, regardless of their exercise ability. PMID- 23816030 TI - Everolimus-eluting stent versus bare metal stent in proximal left anterior descending ST-elevation myocardial infarction: insights from the EXAMINATION trial. AB - BACKGROUND: ST-elevation myocardial infarctions (STEMI) caused by proximal left anterior descending (LAD) lesions have more myocardium at risk and worse outcomes than those located in other segments. The aim is to compare outcomes of patients with STEMI and proximal-LAD lesions treated with bare-metal stents (BMS) versus everolimus-eluting stents (EES). METHODS: The EXAMINATION trial randomized 1498 STEMI patients to BMS versus EES. The primary end point was the patient-oriented combined of all-cause death, any-recurrent myocardial infarction (MI) and any revascularization. The secondary end point included the device-oriented combined of cardiac death, target-vessel MI and target-lesion revascularization (TLR). RESULTS: STEMI with a proximal-LAD occlusion was observed in 290 patients (BMS = 132 and EES = 158). Both groups were similar except for diabetes (12.9% vs 24.1%; P = .016). At 1 year, the primary end point was observed in 18.9% and 9.5% of patients treated with BMS and EES, respectively (P = .023). The secondary end point was observed in 11.4% and 5.1%, respectively (P = .053). There were no differences in cardiac death (4.5% vs 3.8%; P = .750) and MI (1.5% vs 0%; P = .121). BMS had higher rate of TLR compared to EES (6.8% vs 1.3%; P = .014). Patients with proximal-LAD STEMI had higher mortality than patients with non proximal-LAD STEMI (5.5% vs 2.9%; P = .027). Proximal-LAD lesions treated with BMS tended to increase the risk of the primary end point compared with other segments (18.9% vs 13.0%; P = .079). However, EES implanted in proximal-LAD had similar outcomes compared with other locations (9.5% vs 12.0%; P = .430). Adjusting for confounders, the interaction between BMS and proximal-LAD location was associated with the primary end point. CONCLUSION: Patients with STEMI and proximal-LAD lesions treated with EES have better outcomes compared with BMS at 1 year. Although further investigations are required, it seems reasonable to consider EES for proximal-LAD STEMI-lesions. PMID- 23816032 TI - Adverse outcomes among women presenting with signs and symptoms of ischemia and no obstructive coronary artery disease: findings from the National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation (WISE) angiographic core laboratory. AB - BACKGROUND: Women presenting with signs and symptoms of myocardial ischemia frequently have no or nonobstructive coronary artery disease (CAD). OBJECTIVE: This study aimed to investigate the associations between angiographic measures and longer-term clinical outcomes among women with signs and symptoms of ischemia referred for coronary angiography. METHODS: A prospective cohort analysis of women referred for coronary angiography and enrolled in the National Heart, Lung, and Blood Institute-sponsored WISE was performed. An angiographic severity score was prospectively developed, assigning points for any stenosis weighted by stenosis severity, location, and collaterals and was then tested for prediction for adverse outcome in 917 women, over a median of 9.3 years. SETTING: The study was conducted in referral centers. PATIENTS: Women with signs and/or symptoms of myocardial ischemia referred for coronary angiography were consecutively consented and enrolled in a prospective study. MAIN OUTCOME MEASURES: Main outcomes included first occurrence of cardiovascular death or nonfatal myocardial infarction. Hospitalization for angina was a secondary outcome. RESULTS: Cardiovascular death or myocardial infarction at 10 years occurred in 6.7%, 12.8%, and 25.9% of women with no, nonobstructive, and obstructive CAD (P < .0001), respectively. Cumulative 10-year cardiovascular death or myocardial infarction rates showed progressive, near-linear increases for each WISE CAD severity score range of 5, 5.1 to 10, 10.1 to 20, 20.1 to 50, and >50. The optimal threshold in the WISE severity score classifications for predicting cardiovascular mortality was >10 (eg, 5.0-10 vs 10.1-89), with both a sensitivity and specificity of 0.64 and an area under the curve of 0.64 (P = .02, 95% CI 0.59 0.68). CONCLUSIONS: Among women with signs and symptoms of ischemia, nonobstructive CAD is common and associated with adverse outcomes over the longer term. The new WISE angiographic score appears to be useful for risk prediction in this population. PMID- 23816033 TI - Renal dysfunction and long-term risk of heart failure after coronary artery bypass grafting. AB - BACKGROUND: Renal dysfunction is associated with increased long-term mortality and incidence of myocardial infarction after coronary artery bypass grafting (CABG). The aim was to investigate the relationship between renal dysfunction and long-term risk of heart failure after CABG. METHODS: All 29,602 patients who underwent primary isolated CABG from 2000 through 2008 in Sweden, with no myocardial infarction within 14 days before surgery, no prior hospitalization for heart failure, and alive 30 days postoperatively, were included from the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies registry. Glomerular filtration rates (eGFR) were estimated using the Modification of Diet in Renal Disease equation. Hazard ratios with 95% CIs were calculated for first hospitalization for heart failure. RESULTS: Mean age in the study population was 67 years, and 20% had eGFR <60 mL/min per 1.73 m(2). During a mean follow-up of 4.5 years, there were 1,690 (5.7%) cases of heart failure. Adjusted hazard ratios with 95% CI for heart failure in patients with eGFR 45 to 60, 30 to 45, and 15 to 30 mL/min per 1.73 m(2) were 1.53 (1.36-1.72), 2.08 (1.76-2.45), and 2.14 (1.52 3.01), respectively, compared with patients with eGFR >60 mL/min per 1.73 m(2). CONCLUSIONS: Renal dysfunction is a long-term predictor of new-onset heart failure after primary isolated CABG. PMID- 23816034 TI - Cardiovascular risk factor burden, treatment, and control among adults with chronic kidney disease in the United States. AB - BACKGROUND: Cardiovascular disease is a major concern in persons with chronic kidney disease (CKD). We assessed the current burden of cardiovascular risk factors and differences in risk factor treatment and control in the general US adult population by CKD status. METHODS: A cross-sectional study of 10,741 adults aged 20+ years from the 2007-2010 National Health and Nutrition Examination Survey was performed. Persons were categorized into 3 groups: CKD stages 3 to 5 (estimated glomerular filtration rate <60 mL/min/1.73 m(2)), CKD stages 1 and 2 (urinary albumin-to-creatinine ratio >=30 mg/g and estimated glomerular filtration rate >=60 mL/min/1.73 m(2)), and no CKD. RESULTS: The majority of adults with CKD stages 3 to 5 (79.8%) and stages 1 and 2 (59.1%) had >=2 cardiovascular risk factors, substantially higher than adults without CKD (32.7%, P < .001). Diabetes was the most strongly associated risk factor and was highly specific for CKD stages 1 and 2 (prevalence ratio 2.53, 95% CI 2.21-2.89) and, to a lesser extent, CKD stages 3 to 5 (prevalence ratio 1.59, 95% CI 1.38-1.84). Most adults with diagnosed risk factors reported medication use for risk factor control, and pharmacologic treatment was more common among those with than without CKD. However, poor risk factor control was also common among persons treated for risk factors with CKD compared with those without CKD. CONCLUSIONS: There continues to be a substantial cardiovascular risk factor burden among adults with CKD stages 3 to 5 and, to a lesser extent, adults with CKD stages 1 and 2 when compared with adults without CKD. Overall, optimal risk factor control is low in adults with CKD, highlighting the need for aggressive cardiovascular risk reduction in adults with CKD. PMID- 23816035 TI - Educational videos to reduce racial disparities in ICD therapy via innovative designs (VIVID): a randomized clinical trial. AB - BACKGROUND: Black individuals eligible for an implantable cardioverter/defibrillator (ICD) are considerably less likely than white individuals to receive one. This disparity may, in part, be explained by racial differences in patient preferences. We hypothesized that a targeted patient centered educational video could improve knowledge of sudden cardiac arrest (SCA) and ICDs and reduce racial differences in ICD preferences. We conducted a pilot study to assess the feasibility of testing this hypothesis in a randomized trial. METHODS: We created a video that included animation, physician commentary, and patient testimonials on SCA and ICDs. The primary outcome was the decision to have an ICD implanted as a function of race and intervention. Between January 1, 2011, and December 31, 2011, 59 patients (37 white and 22 black) were randomized to the video or health care provider counseling/usual care. RESULTS: Relative to white patients, black patients were younger (median age, 55 vs 68 years) and more likely to have attended college or technical school. Baseline SCA and ICD knowledge was similar and improved significantly in both racial groups after the intervention. Black patients viewing the video were as likely as white patients to want an ICD (60.0% vs 79.2%, P = .20); and among those in the usual care arm, black patients were less likely than white patients to want an ICD (42.9% vs 84.6% P = .05). CONCLUSION: Among individuals eligible for an ICD, a video decision aid increased patient knowledge and reduced racial differences in patient preference for an ICD. PMID- 23816036 TI - Consideration of patient age and life expectancy in implantable cardioverter defibrillator referral. AB - BACKGROUND: Primary prevention implantable cardioverter-defibrillator (ICD) guidelines recommend device consideration for at-risk patients with a life expectancy of greater than 1 year regardless of age. We sought to assess the influence of patient age and prognosis on ICD referral. METHODS: A survey was mailed to a random, national sample of 3,000 physicians in the specialties of cardiology, family medicine, and internal medicine. Participants were asked focused questions regarding patient age, life expectancy, and ICD referral. RESULTS: The overall response rate was 64%. More than one quarter of physicians (n = 386 [27%], 95% CI 25%-30%) withhold primary prevention ICD referral solely because of patient age. Life expectancy is not considered by 23% (n = 324, 95% CI 20%-25%) of physicians before referral, whereas 13% (n = 144, 95% CI 11%-15%) refer patients with a prognosis of less than 1 year. Providers who refer patients for ICD implantation with a life expectancy of less than 1 year are less likely to be cardiologists (odds ratio [OR] 0.50, 95% CI 0.32-0.79, P = .003), are less often affiliated with a teaching hospital (OR 0.62, 95% CI 0.41-0.94, P = .025), and have a greater number of years in practice (OR 1.25 for each 10 years in practice, 95% CI 1.03-1.51, P = .026). Only a minority (n = 315 [22%], 95% CI 20% 24%) of physicians use a life expectancy threshold of 1 year to guide ICD referral. CONCLUSION: Physicians frequently withhold ICD referral because of patient age. The referral of patients with a prognosis of less than 1 year or without consideration of life expectancy is common. PMID- 23816037 TI - Reciprocal relations between physical disability, subjective health, and atrial fibrillation: the Framingham Heart Study. AB - BACKGROUND: Atrial fibrillation (AF)-related symptoms and physical performance are relied upon to guide therapeutic management of patients with AF. We sought to understand whether AF predisposes to or is a result of physical disability and poor subjective health in the community. METHODS: We studied relations between physical disability (Rosow-Breslau Functional Health Scale), subjective health (self-report) and incident AF, and the converse, in the Framingham Heart Study. RESULTS: In 3,609 participants (age 73 +/- 8 years, 59% women), a subset of 861 participants (24%) had prevalent physical disability at baseline. During 5.8 +/- 1.8 years of follow-up, 555 participants (10-year age- and sex-adjusted incidence rate 13%) developed incident AF. Prevalent physical disability was related to incident AF (multivariable-adjusted hazard ratio 1.25, 95% CI 1.02-1.54, P = .03). In 3,525 participants, prevalent poor subjective health (n = 333) also was related to incident AF (n = 552, multivariable-adjusted hazard ratio 1.31, 95% CI 1.00-1.70, P = .048). Conversely, in 2,080 participants (age 69 +/- 6 years, 55% women), interim AF (n = 106) was associated with newly reported physical disability (n = 573) at a follow-up examination (multivariable-adjusted odds ratio 1.58, 95% CI 1.08-2.31, P = .01). In 1,954 participants, interim AF (n = 96) likewise was related to newly reported poor subjective health (n = 224, multivariable-adjusted odds ratio 1.83, 95% CI 1.10-3.02, P = .02). CONCLUSIONS: Physical disability and poor subjective health were related to incident AF in a community-based cohort. Conversely, interim AF was related to newly reported physical disability and poor subjective health. Because AF guidelines incorporate symptoms, it is essential to clarify the temporality and mechanisms linking physical disability, subjective health, and AF. PMID- 23816038 TI - The Cholesterol, Hypertension, And Glucose Education (CHANGE) study: results from a randomized controlled trial in African Americans with diabetes. AB - BACKGROUND: Cardiovascular disease (CVD) and diabetes account for one-third of the mortality difference between African American and white patients. We evaluated the effect of a CVD risk reduction intervention in African Americans with diabetes. METHODS: We randomized 359 African Americans with type 2 diabetes to receive usual care or a nurse telephone intervention. The 12-month intervention provided monthly self-management support and quarterly medication management facilitation. Coprimary outcomes were changes in systolic blood pressure (SBP), hemoglobin A1c (HbA1c), and low-density lipoprotein cholesterol (LDL-C) over 12 months. We estimated between-intervention group differences over time using linear mixed-effects models. The secondary outcome was self-reported medication adherence. RESULTS: The sample was 72% female; 49% had low health literacy, and 37% had annual income <$10,000. Model-based estimates for mean baseline SBP, HbA1c, and LDL-C were 136.8 mm Hg (95% CI 135.0-138.6), 8.0% (95% CI 7.8-8.2), and 99.1 mg/dL (95% CI 94.7-103.5), respectively. Intervention patients received 9.9 (SD 3.0) intervention calls on average. Primary providers replied to 76% of nurse medication management facilitation contacts, 18% of these resulted in medication changes. There were no between-group differences over time for SBP (P = .11), HbA1c (P = .66), or LDL-C (P = .79). Intervention patients were more likely than those receiving usual care to report improved medication adherence (odds ratio 4.4, 95% CI 1.8-10.6, P = .0008), but adherent patients did not exhibit relative improvement in primary outcomes. CONCLUSIONS: This intervention improved self-reported medication adherence but not CVD risk factor control among African Americans with diabetes. Further research is needed to determine how to maximally impact CVD risk factors in African American patients. PMID- 23816039 TI - Phytosterols, red yeast rice, and lifestyle changes instead of statins: a randomized, double-blinded, placebo-controlled trial. AB - BACKGROUND: Many patients who refuse or cannot tolerate statin drugs choose alternative therapies for lipid lowering. OBJECTIVES: This study aimed to determine the lipid-lowering effects of phytosterol tablets and lifestyle change (LC) on top of red yeast rice (RYR) therapy in patients with a history of statin refusal or statin-associated myalgias. DESIGN: A total of 187 participants (mean low-density lipoprotein cholesterol [LDL-C], 154 mg/dL) took RYR 1800 mg twice daily and were randomized to phytosterol tablets 900 mg twice daily or placebo. Participants were also randomized to a 12-week LC program or usual care (UC). Primary end point was change in LDL-C at 12, 24, and 52 weeks. Secondary end points were effect on other lipoproteins, high-sensitivity C-reactive protein, weight, and development of myalgia. RESULTS: Phytosterols did not significantly improve LDL-C at weeks 12 (P = .54), 24 (P = .67), or 52 (P = .76) compared with placebo. Compared with the UC group, the LC group had greater reductions in LDL-C at weeks 12 (-51 vs -42 mg/dL, P = .006) and 24 (-48 vs -40 mg/dL, P = .034) and was 2.3 times more likely to achieve an LDL-C <100 mg/dL (P = .004). The LC group lost more weight for 1 year (-2.3 vs -0.3 kg, P < .001). All participants took RYR and had significant decreases in LDL-C, total cholesterol, triglycerides, high-sensitivity C-reactive protein, and an increase in high-density lipoprotein cholesterol for 1 year when compared with baseline (P < .001). Four participants stopped supplements because of myalgia. CONCLUSIONS: The addition of phytosterol tablets to RYR did not result in further lowering of LDL-C levels. Participants in an LC program lost significantly more weight and were more likely to achieve an LDL-C <100 mg/dL compared with UC. PMID- 23816040 TI - 5-Nitro-2-furfuriliden derivatives as potential anti-Trypanosoma cruzi agents: design, synthesis, bioactivity evaluation, cytotoxicity and exploratory data analysis. AB - The anti-Trypanosoma cruzi activity of 5-nitro-2-furfuriliden derivatives as well as the cytotoxicity of these compounds on J774 macrophages cell line and FN1 human fibroblast cells were investigated in this study. The most active compounds of series I and II were 4-butyl-[N'-(5-nitrofuran-2-yl) methylene] benzidrazide (3g; IC50=1.05MUM+/-0.07) and 3-acetyl-5-(4-butylphenyl)-2-(5-nitrofuran-2-yl) 2,3-dihydro,1,3,4-oxadiazole (4g; IC50=8.27MUM+/-0.42), respectively. Also, compound 3g was more active than the standard drugs, benznidazole (IC50=22.69MUM+/-1.96) and nifurtimox (IC50=3.78MUM+/-0.10). Regarding the cytotoxicity assay, the 3g compound presented IC50 value of 28.05MUM (SI=26.71) against J774 cells. For the FN1 fibroblast assay, 3g showed IC50 value of 98MUM (SI=93.33). On the other hand, compound 4g presented a cytotoxicity value on J774 cells higher than 400MUM (SI >48), and for the FN1 cells its IC50 value was 186MUM (SI=22.49). Moreover, an exploratory data analysis, which comprises hierarchical cluster (HCA) and principal component analysis (PCA), was carried out and the findings were complementary. The molecular properties that most influenced the compounds' grouping were ClogP and total dipole moment, pointing out the need of a lipophilic/hydrophilic balance in the designing of novel potential anti-T. cruzi molecules. PMID- 23816041 TI - Synthesis of 4-methylumbelliferyl alpha-d-mannopyranosyl-(1->6)-beta-d mannopyranoside and development of a coupled fluorescent assay for GH125 exo alpha-1,6-mannosidases. AB - Certain bacterial pathogens possess a repertoire of carbohydrate processing enzymes that process host N-linked glycans and many of these enzymes are required for full virulence of harmful human pathogens such as Clostridium perfringens and Streptococcus pneumoniae. One bacterial carbohydrate processing enzyme that has been studied is the pneumococcal virulence factor SpGH125 from S. pneumoniae and its homologue, CpGH125, from C. perfringens. These exo-alpha-1,6-mannosidases from glycoside hydrolase family 125 show poor activity toward aryl alpha mannopyranosides. To circumvent this problem, we describe a convenient synthesis of the fluorogenic disaccharide substrate 4-methylumbelliferone alpha-d mannopyranosyl-(1->6)-beta-d-mannopyranoside. We show this substrate can be used in a coupled fluorescent assay by using beta-mannosidases from either Cellulomonas fimi or Helix pomatia as the coupling enzyme. We find that this disaccharide substrate is processed much more efficiently than aryl alpha mannopyranosides by CpGH125, most likely because inclusion of the second mannose residue makes this substrate more like the natural host glycan substrates of this enzyme, which enables it to bind better. Using this sensitive coupled assay, the detailed characterization of these metal-independent exo-alpha-mannosidases GH125 enzymes should be possible, as should screening chemical libraries for inhibitors of these virulence factors. PMID- 23816042 TI - Synthetic studies of centromere-associated protein-E (CENP-E) inhibitors: 1.Exploration of fused bicyclic core scaffolds using electrostatic potential map. AB - Centromere-associated protein-E (CENP-E), a mitotic kinesin that plays an important role in mitotic progression, is an attractive target for cancer therapeutic drugs. For the purpose of developing novel CENP-E inhibitors as cancer therapeutics, we investigated a fused bicyclic compound identified by high throughput screening, 4-oxo-4,5-dihydrothieno[3,4-c]pyridine-6-carboxamide 1a. Based on this scaffold, we designed inhibitors for efficient binding at the L5 site in CENP-E utilizing homology modeling as well as electrostatic potential map (EPM) analysis to enhance CENP-E inhibitory activity. This resulted in a new lead, 5-bromoimidazo[1,2-a]pyridine 7, which showed potent CENP-E enzyme inhibition (IC50: 50nM) and cellular activity with accumulation of phosphorylated histone H3 in HeLa cells. Our homology model and EPM analysis proved to be useful tools for the rational design of CENP-E inhibitors. PMID- 23816043 TI - Antiproliferative activity on human prostate carcinoma cell lines of new peptidomimetics containing the spiroazepinoindolinone scaffold. AB - Peptidomimetics containing the spiroazepinoindolinone scaffold were designed and synthesized in order to ascertain their antiproliferative activity on the DU-145 human prostatic carcinoma cell line. Ethyl 2'-oxa-1,2,3,5,6,7-hexahydrospiro[4H azepine-4,3'-3H-indole]-1'-carboxylate scaffold was functionalized at nitrogen azepino ring with Aib-(l/d)Trp-OH dipeptides. Combining the different stereochemistries of the scaffold and the tryptophan, diastereoisomeric peptidomimetics were prepared and tested. Their biological activity was evaluated by proliferation studies proving that the isomer containing S spiroazepino indolinone scaffold and l tryptophan is the most active compound. Docking studies confirmed that the active peptidomimetic could bind the GHSR-1a receptor with docking scores comparable with those of well-known agonists even though with a somewhat different binding mode. PMID- 23816044 TI - Autotaxin inhibition: development and application of computational tools to identify site-selective lead compounds. AB - Autotaxin (ATX) catalyzes the conversion of lysophosphatidyl choline (LPC) to lysophosphatidic acid (LPA). Both ATX and LPA have been linked to pathophysiologies ranging from cancer to neuropathic pain. Inhibition of LPA production by ATX is therefore of therapeutic interest. Here we report the application of previously-developed, subsite-targeted pharmacophore models in a screening workflow that involves either docking or binary QSAR as secondary filters to identify ATX inhibitors from previously unreported structural types, four of which have sub-micromolar inhibition constants. Cell-based assays demonstrate that ATX inhibition and cytotoxicity structure-activity-relationships (SAR) exhibit selectivity cliffs, characterized by structurally similar compounds exhibiting similar biological activities with respect to ATX inhibition but very different biological activities with respect to cytotoxicity. Thus, general cytotoxicity should not be used as an early filter to eliminate candidate ATX inhibitor scaffolds from further SAR studies. Assays using two substrates of vastly different sizes demonstrate that the tools developed to identify compounds binding outside the central core of the active site did identify compounds acting at an allosteric site. In contrast, tools developed to identify active-site directed compounds did not identify active-site directed compounds. The stronger volume overlap imposed when selecting screening candidates expected to bind outside the active site is likely responsible for the stronger match between intended and actual target site. PMID- 23816045 TI - Fluorescent probes for investigation of isoprenoid configuration and size discrimination by bactoprenol-utilizing enzymes. AB - Undecaprenyl Pyrophosphate Synthase (UPPS) is an enzyme critical to the production of complex polysaccharides in bacteria, as it produces the crucial bactoprenol scaffold on which these materials are assembled. Methods to characterize the systems associated with polysaccharide production are non trivial, in part due to the lack of chemical tools to investigate their assembly. In this report, we develop a new fluorescent tool using UPPS to incorporate a powerful fluorescent anthranilamide moiety into bactoprenol. The activity of this analogue in polysaccharide biosynthesis is then tested with the initiating hexose 1-phosphate transferases involved in Capsular Polysaccharide A biosynthesis in the symbiont Bacteroides fragilis and the asparagine-linked glycosylation system of the pathogenic Campylobacter jejuni. In addition, it is shown that the UPPS used to make this probe is not specific for E-configured isoprenoid substrates and that elongation by UPPS is required for activity with the downstream enzymes. PMID- 23816046 TI - Synthesis and in vivo evaluation of [(18)F]2-(4-(4-(2-(2 fluoroethoxy)phenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H) dione ([(18)F]FECUMI-101) as an imaging probe for 5-HT1A receptor agonist in nonhuman primates. AB - The 5-HT1AR partial agonist PET radiotracer, [(11)C]CUMI-101, has advantages over an antagonist radiotracer as it binds preferentially to the high affinity state of the receptor and thereby provides more functionally meaningful information. The major drawback of C-11 tracers is the lack of cyclotron facility in many health care centers thereby limiting widespread clinical or research use. We identified the fluoroethyl derivative, 2-(4-(4-(2-(2 fluoroethoxy)phenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)dione (FECUMI-101) (Ki=0.1nM; Emax=77%; EC50=0.65nM) as a partial agonist 5-HT1AR ligand of the parent ligand CUMI-101. FECUMI-101 is radiolabeled with F-18 by O fluoroethylation of the corresponding desmethyl analogue (1) with [(18)F]fluoroethyltosylate in DMSO in the presence of 1.6equiv of K2CO3 in 45+/ 5% yield (EOS). PET shows [(18)F]FECUMI-101 binds specifically to 5-HT1AR enriched brain regions of baboon. The specificity of [(18)F]FECUMI-101 binding to 5-HT1AR was confirmed by challenge studies with the known 5-HT1AR ligand WAY100635. These findings indicate that [(18)F]FECUMI-101 can be a viable agonist ligand for the in vivo quantification of high affinity 5-HT1AR with PET. PMID- 23816047 TI - [Chromametry, a promising technique for the quantification of skin changes in chronic venous disorders]. AB - OBJECTIVE: The development and validation of new clinimetric tools is essential for the progress of clinical research in the field of chronic venous insufficiency. Chromametry is a simple, quick and non-invasive technique that measures the color of the skin. The aim of this study was to evaluate the ability of this technique to quantify skin pigmentation as a marker of severity of chronic venous disease and to assess the variability of measurements obtained in this condition. METHODS: Chomametry was performed on three different sites on each lower limb in 42 patients undergoing a spa treatment in La Lechere (Savoie) for chronic venous disorders (CVD). Four series of measurements were taken by two investigators for each patient, at two sessions two to four days apart. RESULTS: The chromameter readily measured the pigmentation index (PI). The PI increased with higher clinical class (CEAP classification) for measurements made at the malleolar level (r=0.48; P<0.001) and the supra-malleolar area (r=0.55; P<0.001), but not at the level of the anterior tibial tuberosity (r=-0.09; P=0.45). The repeatability and the intra- and inter-observer reproducibility of this PI index were 15%, 18% and 21% respectively of the mean of the observed difference at the malleolar level. The chromameter also provided an erythema index, which appears to be less relevant and more variable than the PI, but which might add potentially useful information regarding the characterization of skin inflammation related to the venous disease. CONCLUSION: This study shows that chromametry can be used in clinical research studies to quantify skin changes associated with CVD. Whether it can also be useful for early detection and follow up of patients with venous trophic changes remains to be investigated. PMID- 23816048 TI - Malignant lymphoma in primary Sjogren's syndrome: an update on the pathogenesis and treatment. AB - OBJECTIVES: Sjogren's syndrome (SS), a chronic autoimmune disorder, particularly compromises the function of exocrine glands. Its association with lymphoma is well documented. Our aim was to systematically review the molecular, clinical, histopathologic, and therapeutic aspects of these SS-related malignant lymphoproliferations. METHODS: The literature was searched for original articles published between 1968 and 2012 focusing on the risk factors for lymphoma development in Sjogren's syndrome using MEDLINE and PubMed. The search terms we used were "Sjogren's syndrome," "lymphoma," and "risk factors." All papers identified were English-language, full-text papers. RESULTS: A low-grade marginal zone lymphoma related to mucosa-associated lymphoid tissue is the commonest lymphoid neoplasia in SS. The majority of SS-associated lymphomas are characterized by localized stage, indolent clinical course, and recurrence in other extranodal sites. Although the transition from a chronic inflammatory condition to malignant lymphoma is a multistep process that is yet poorly understood, there is increasing evidence that chronic antigenic stimulation by an exoantigen or autoantigens plays an essential role in the development of SS associated lymphoproliferation. CONCLUSIONS: This review discusses the pathogenetic aspects of lymphomagenesis in SS. Recent advances in the treatment of lymphoma in SS are also stated. PMID- 23816049 TI - Oral supplementation with areca-derived polyphenols attenuates food allergic responses in ovalbumin-sensitized mice. AB - BACKGROUND: Arecae semen, the dried slice of areca nuts, is a traditional Chinese medicine used to treat intestinal parasitosis, rectal tenesmus and diarrhea. Areca nuts contain a rich amount of polyphenols that have been shown to modulate the functionality of mast cells and T cells. The objective of this study is to investigate the effect of polyphenol-enriched areca nut extracts (PANE) against food allergy, a T cell-mediated immune disorder. METHODS: BALB/c mice were left untreated or administered with PANE (0.05% and 0.1%) via drinking water throughout the entire experiment. The mice were sensitized with ovalbumin (OVA) twice by intraperitoneal injection, and then repeatedly challenged with OVA by gavage to induce food allergic responses. RESULTS: PANE administration attenuated OVA-induced allergic responses, including the occurrence of diarrhea and the infiltration and degranulation of mast cells in the duodenum. The serum level of OVA-specific IgE and the expression of interleukin-4 in the duodenum were suppressed by PANE treatment. In addition, PANE administration induced Gr-1+, IL 10+ and Gr-1+IL-10+ cells in the duodenum. CONCLUSION: These results demonstrate that oral intake of areca-derived polyphenols attenuates food allergic responses accompanied with a decreased Th2 immunity and an enhanced induction of functional myeloid-derived suppressor cells. PMID- 23816050 TI - A novel approach to fabricate silk nanofibers containing hydroxyapatite nanoparticles using a three-way stopcock connector. AB - Electrospinning technique is commonly used to produce micro- and/or nanofibers, which utilizes electrical forces to produce polymeric fibers with diameters ranging from several micrometers down to few nanometers. Desirably, electrospun materials provide highly porous structure and appropriate pore size for initial cell attachment and proliferation and thereby enable the exchange of nutrients. Composite nanofibers consisting of silk and hydroxyapatite nanoparticles (HAp) (NPs) had been considered as an excellent choice due to their efficient biocompatibility and bone-mimicking properties. To prepare these nanofiber composites, it requires the use of acidic solutions which have serious consequences on the nature of both silk and HAp NPs. It is ideal to create these nanofibers using aqueous solutions in which the physicochemical nature of both materials can be retained. However, to create those nanofibers is often difficult to obtain because of the fact that aqueous solutions of silk and HAp NPs can precipitate before they can be ejected into fibers during the electrospinning process. In this work, we had successfully used a three-way stopcock connector to mix the two different solutions, and very shortly, this solution is ejected out to form nanofibers due to electric fields. Different blend ratios consisting HAp NPs had been electrospun into nanofibers. The physicochemical aspects of fabricated nanofiber had been characterized by different state of techniques like that of FE-SEM, EDS, TEM, TEM-EDS, TGA, FT-IR, and XRD. These characterization techniques revealed that HAp NPs can be easily introduced in silk nanofibers using a stopcock connector, and this method favorably preserves the intact nature of silk fibroin and HAp NPs. Moreover, nanofibers obtained by this strategy were tested for cell toxicity and cell attachment studies using NIH 3 T3 fibroblasts which indicated non-toxic behavior and good attachment of cells upon incubation in the presence of nanofibers. PMID- 23816051 TI - HES1, a target of Notch signaling, is elevated in canine osteosarcoma, but reduced in the most aggressive tumors. AB - BACKGROUND: Hairy and enhancer of split 1 (HES1), a basic helix-loop-helix transcriptional repressor, is a downstream target of Notch signaling. Notch signaling and HES1 expression have been linked to growth and survival in a variety of human cancer types and have been associated with increased metastasis and invasiveness in human osteosarcoma cell lines. Osteosarcoma (OSA) is an aggressive cancer demonstrating both high metastatic rate and chemotherapeutic resistance. The current study examined expression of Notch signaling mediators in primary canine OSA tumors and canine and human osteosarcoma cell lines to assess their role in OSA development and progression. RESULTS: Reverse transcriptase - quantitative PCR (RT-qPCR) was utilized to quantify HES1, HEY1, NOTCH1 and NOTCH2 gene expression in matched tumor and normal metaphyseal bone samples taken from dogs treated for appendicular OSA at the Colorado State University Veterinary Teaching Hospital. Gene expression was also assessed in tumors from dogs with a disease free interval (DFI) of <100 days compared to those with a DFI > 300 days following treatment with surgical amputation followed by standard chemotherapy. Immunohistochemistry was performed to confirm expression of HES1. Data from RT qPCR and immunohistochemical (IHC) experiments were analyzed using REST2009 software and survival analysis based on IHC expression employed the Kaplan-Meier method and log rank analysis. Unbiased clustered images were generated from gene array analysis data for Notch/HES1 associated genes. Gene array analysis of Notch/HES1 associated genes suggested alterations in the Notch signaling pathway may contribute to the development of canine OSA. HES1 mRNA expression was elevated in tumor samples relative to normal bone, but decreased in tumor samples from dogs with a DFI < 100 days relative to those with a DFI > 300 days. NOTCH2 and HEY1 mRNA expression was also elevated in tumors relative to normal bone, but was not differentially expressed between the DFI tumor groups. Survival analysis confirmed an association between decreased HES1 immunosignal and shorter DFI. CONCLUSIONS: Our findings suggest that activation of Notch signaling occurs and may contribute to the development of canine OSA. However, association of low HES1 expression and shorter DFI suggests that mechanisms that do not alter HES1 expression may drive the most aggressive tumors. PMID- 23816052 TI - Patterns and correlates of self-reported racial discrimination among Australian Aboriginal and Torres Strait Islander adults, 2008-09: analysis of national survey data. AB - BACKGROUND: There is now considerable evidence that racism is a pernicious and enduring social problem with a wide range of detrimental outcomes for individuals, communities and societies. Although indigenous people worldwide are subjected to high levels of racism, there is a paucity of population-based, quantitative data about the factors associated with their reporting of racial discrimination, about the settings in which such discrimination takes place, and about the frequency with which it is experienced. Such information is essential in efforts to reduce both exposure to racism among indigenous people and the harms associated with such exposure. METHODS: Weighted data on self-reported racial discrimination from over 7,000 Indigenous Australian adults participating in the 2008-09 National Aboriginal and Torres Strait Islander Survey, a nationally representative survey conducted by the Australian Bureau of Statistics, were analysed by socioeconomic, demographic and cultural factors. RESULTS: More than one in four respondents (27%) reported experiencing racial discrimination in the past year. Racial discrimination was most commonly reported in public (41% of those reporting any racial discrimination), legal (40%) and work (30%) settings. Among those reporting any racial discrimination, about 40% experienced this discrimination most or all of the time (as opposed to a little or some of the time) in at least one setting. Reporting of racial discrimination peaked in the 35-44 year age group and then declined. Higher reporting of racial discrimination was associated with removal from family, low trust, unemployment, having a university degree, and indicators of cultural identity and participation. Lower reporting of racial discrimination was associated with home ownership, remote residence and having relatively few Indigenous friends. CONCLUSIONS: These data indicate that racial discrimination is commonly experienced across a wide variety of settings, with public, legal and work settings identified as particularly salient. The observed relationships, while not necessarily causal, help to build a detailed picture of self-reported racial discrimination experienced by Indigenous people in contemporary Australia, providing important evidence to inform anti-racism policy. PMID- 23816053 TI - [Surgical treatment of acral melanoma: a report of eight cases]. AB - Acral melanoma represents 3 to 15% of all cutaneous melanoma. In Morocco, this location is predominant. Through our study, we intend to analyze the therapeutic aspects of acral melanoma, while focusing on the epidemiological, clinical, pathological and prognostic profile of acral melanoma cases listed in osteoarticular surgery department of the CHU Hassan II of Fez in the period from January 2009 to December 2012. The mean age of the patients was 63 years, with slight predominance of women. The most commonly involved location was plantar region (including the heel) and pigmented color was the most common. The concept of micro trauma was found in almost half of our patients. Plantar localization was the most commun lesion. Inguinal lymph nodes attended three patients and one patient had deep lymph nodes. Only one of them had a lymphadenectomy. Nodular melanoma os the most found histological type in our study with a Breslow thickness of 8.5mm on average, and Clark level IV is found in the majority of cases. Excision of the tumour was performed in all patients. It was estimated wide in all cases. Five patients received reparative surgery consisting of flap coverage. This study has proved a high incidence of poor prognostic factors clinically and histologically. PMID- 23816054 TI - ["The ambulatory surgery of breast reduction: The adaptation to a North-American practice"]. AB - OBJECTIVE: After the recent publication of the prospective study of feasibility of mammary reduction in ambulatory setting by Guilbert et al., we would like to present our North-American experience and share some data from the last year. METHODS: We obtained four data from our medical archives: the total number of reduction mammaplasties done during the last year, the number of cases done in ambulatory setting, the number of cases done with hospitalization, and the number of conversions (ambulatory cases transformed into hospitalizations lasting more than 24 hours) RESULTS: Two hundred and eighteen bilateral mammary reductions were completed between March 2011 and April 2012. Of these 218 cases, 97% were planned for a surgery in ambulatory setting whereas only six were planned with hospitalization. Moreover, only seven of the 212 cases in ambulatory setting required a conversion to a brief hospitalization. CONCLUSION: Cost-effectiveness, low rate of complication, and high satisfaction rate are all advantages of surgery in ambulatory setting. Our 10-year experience with this mode of care confirms these benefits. PMID- 23816055 TI - Epidemiological profile of Clonorchis sinensis infection in one community, Guangdong, People's Republic of China. AB - BACKGROUND: Clonorchiasis caused by ingesting improperly prepared fish ranks among the most important but still neglected food-borne parasitic diseases, especially in the People's Republic of China (P.R. China). To promote the implementation of interventions efficiently, the demonstration of an epidemiological profile of Clonorchis sinensis infection is essential in hyper epidemic areas. METHODS: In one community with higher levels of economic development in Guangdong province, P.R. China, villagers were motivated to provide stool samples for examining helminth eggs. Then, those infected with C. sinensis completed the structured questionnaire including demographical characteristics, knowledge and behavior. RESULTS: A total of 293 villagers infected with C. sinensis participated in questionnaire investigation. Among them, 94.54% were adult and 93.17% were indigenous. The geometric mean of C. sinensis eggs per gram of feces in the children, adult females and adult males was 58, 291 and 443, respectively. The divergence between knowledge and behavior in the adults, especially the adult males, was shown. Out of 228 persons eating raw fish, 160 did it more frequently at restaurants, the proportion of which varied in different populations, showing 25.00%, 54.88% and 80.28% in the children, adult females and adult males, respectively. CONCLUSIONS: Different interventions need to be adopted in different populations. Chemotherapy should be prioritized in the adults, especially the adult males. In addition, health education targeting the children, is essential and may play a crucial role in controlling clonorchiasis in the long term. In order to successfully control clonorchiasis, intervention in the restaurant should not be overlooked in some endemic areas. PMID- 23816057 TI - [Children's oppositional behaviour, practice of parental authority and temporal anomie]. AB - OBJECTIVES: This article examines the relationship between children's oppositional behaviour and the exercise of parental authority. It seeks to explore the value of a heuristic approach to psychic temporality in exercising parental authority. The study aims to better understand the role of psychic temporality in operations producing symbolic law. It goes on to describe a disorder of temporality, known as temporal anomie, which may be involved in a child's oppositional disorders. STUDY: Psychiatric or psychological consultations motivated by oppositional disorders in children have increased steadily in the past fifteen years in France. The primary reason for consultation is in the form of difficulties for children in accepting the social rules or constraints, but also the difficulties of parenting while coping with the opposition of their children. This increase is made in connection with the works analysing the social and psychological effects imposed by modernity and its acceleration. Correspondingly, we find that some parents do not prioritize their educational requirements, do not know when or how to frustrate their child, or even if it is legitimate to expect from him/her a certain type of behaviour. They seem more preoccupied with the fear of not being loved by their child more than their duty to educate. A general trend suggests an alteration of psychological time, characterized by: a) a disinvestment of links between present and past for the enjoyment of the moment and its extension in the immediate future ; b) a difficulty in supporting educational responses causing frustration for the child ; c) a lack of continuity and constancy in educational requirements. The author proposes to define temporal anomie as the psychical time that weakens the consistency of educational responses. A link between psychological temporality and the symbolic law is discussed. Specifically, the study notes that: in intersubjective relations, mastery of psychological time by parents is an integrating factor of the law for the child. In this sense, temporal anomie can affect the child's development of superego. Anomie time is the result of a weakening of the transitional temporality. Transitional temporality provides legitimacy for educational interventions. This allows parents to support conflicts and opposition of the child. To this end, transitional temporality promotes links between past, present and future, between tradition and innovation. CONCLUSION: Psychic temporality offers a new perspective, particularly heuristic because it is undoubtedly an essential dimension involved in the process of subjectivation and socialization. The concept of anomie time enables one to better understand the fragility of parenthood frequently encountered in child psychiatric consultations and allows one to link this to the evolution of society. PMID- 23816056 TI - Defect in recruiting effector memory CD8+ T-cells in malignant pleural effusions compared to normal pleural fluid. AB - BACKGROUND: Malignant pleural effusions (MPE) are a common and fatal complication in cancers including lung or breast cancers, or malignant pleural mesothelioma (MPM). MPE animal models and immunotherapy trials in MPM patients previously suggested defects of the cellular immunity in MPE. However only few observational studies of the immune response were done in MPM patients, using questionable control groups (transudate...). METHODS: We compared T cell populations evaluated by flow cytometry from blood and pleural effusion of untreated patients with MPM (n = 58), pleural metastasis of adenocarcinoma (n = 30) or with benign pleural lesions associated with asbestos exposure (n = 23). Blood and pleural fluid were also obtained from healthy subjects, providing normal values for T cell populations. RESULTS: Blood CD4+ or CD8+ T cells percentages were similar in all groups of patients or healthy subjects. Whereas pleural fluid from healthy controls contained mainly CD8+ T cells, benign or malignant pleural effusions included mainly CD4+ T cells. Effector memory T cells were the main T cell subpopulation in pleural fluid from healthy subjects. In contrast, there was a striking and selective recruitment of central memory CD4+ T cells in MPE, but not of effector cells CD8+ T cells or NK cells in the pleural fluid as one would expect in order to obtain an efficient immune response. CONCLUSIONS: Comparing for the first time MPE to pleural fluid from healthy subjects, we found a local defect in recruiting effector CD8+ T cells, which may be involved in the escape of tumor cells from immune response. Further studies are needed to characterize which subtypes of effector CD8+ T cells are involved, opening prospects for cell therapy in MPE and MPM. PMID- 23816058 TI - [Prevalence of type 2 diabetes and factors associated in depression]. AB - OBJECTIVES: The aim of our study was to estimate the prevalence of type 2 diabetes in patients with depression and to describe its associated factors. METHODS: A cross-sectional descriptive study was conducted over a period of three months (from May to August 2012) in a hospital in Tlemcen, Algeria. The sample study had included 73 consecutive depressed patients who had attended the unit for assessment, education or treatment of depression or its complications. Data collection was conducted using a questionnaire. Blood sampling was performed in all patients to measure glycemic levels. Data analysis was performed using the spss version 10 software. P-value was considered significant when <= 0.05. RESULTS: Means age was 53 +/- 15 years. Sex-ratio female/male was 1.35. The prevalence of type 2 diabetes was 69.9% with 95% CI [57.9; 79.8]. Heredity and collective lifestyle were significantly associated with diabetes (P<0.0001). We have not found an association of diabetes with the factors studied: gender, presence of remaining associated diseases, smoking, and treatment regime. CONCLUSION: In the absence of national epidemiological data, the results of our study provide the frequency of type 2 diabetes during depression. This requires planning strategies for diagnosis and appropriate care for this population. PMID- 23816059 TI - [Psychotic disorder induced by Fahr's syndrome: a case report]. AB - Fahr's syndrome is a rare disorder characterized by abnormal deposits of calcium in areas of the brain that control movement, including the basal ganglia and the cerebral cortex associated with many neurological and psychiatric abnormalities such as a rigid hypokinetic syndrome, mood disorders and cognitive impairment. Fahr's syndrome is secondary to some disorders, such as hypoparathyroidism. CASE REPORT: We report the case of a 56 year-old man, with a history of cataract, who was admitted to our psychiatric hospital for the first time in his life because of psychotic symptoms associated with irritability and aggressiveness. Since the age of 38 the patient had become nervous, 10 years later he developed tonic clonic seizures. Two months ago, he began expressing delusions of persecution against his wife and sons and making fugues. According to his family during this period, he was agitated, aggressive, and suffered from insomnia and anorexia. The general and psychiatric examination showed an upright and bronzed patient with neglected hygiene. He was indifferent to his environment and expressed poor mimics and gestures. He was anxious, suspicious and not very talkative. He was conscious but his attention was slightly decreased. Moreover, he was not aware of his problems. The neurological examination showed extrapyramidal syndrome with postural tremor and cerebellar ataxia. A cranial computed tomography brain scan found bilateral, symmetric basal ganglia calcifications, in favour of Fahr's syndrome. Phosphocalcic investigations revealed low concentration of serum calcium at 1.01mmol/L (normal 2.15 to 2.57mmol/L) and hyperphosphoremia at 2.69mmol/L (normal 0.81 to 1.55mmol/L). He also had low concentrations of 25-OH vitamin as well as decreased urinary levels of phosphate and calcium. The blood level of parathyroid hormone was 0ng/L. The diagnosis of Fahr's syndrome, revealing a hypoparathyroidism was posed. He was supplemented with calcium and alpha cholecalciferol and treated with clozapine (100mg per day). After four weeks, psychotic symptoms responded well to this treatment without expressing any side effects, notably seizures. DISCUSSION: Psychotic symptoms seen in Fahr's disease include auditory and visual hallucinations, complex perceptual distortions, delusions, and fugue state. Some of them were manifest in this patient. It is likely that the psychosis in both Fahr's disease and schizophrenia share a similar pathology. Positive psychotic symptoms, hallucinations, and paranoia are not necessarily generated by the classical hypothesis of dopamine mediated attachment of salience to internally generated stimuli. Still, there is some evidence that disruption of the cortex involved in the pathophysiology of schizophrenia is also seen in Fahr's disease, particularly in areas of the limbic system. CONCLUSION: Psychiatrists should consider Fahr's syndrome as a differential diagnosis in the evaluation of psychosis associated with seizures. This case, along with others in the literature, further emphasizes the importance of the role of neuro-imaging and the search for disrupted phosphocalcic metabolism in patients with atypical psychotic symptoms. Moreover, further research should focus on pharmacologic interventions. The efficacy and risks of neuropharmacologic and psychopharmacologic interventions in Fahr's syndrome, and correlates of good and poor outcome with these interventions remain to be defined. PMID- 23816060 TI - [Cellular and molecular effects of the antidepressant hyperforin on brain cells: Review of the literature]. AB - INTRODUCTION: Hypericum perforatum is, with Ginkgo biloba, one of the most frequently prescribed medicinal plants in the world. Its popular name, St. John's wort (SJW), is due to the fact that its flowers, yellow, are gathered around the feast of St. John the Baptist (24th June) whereas "wort" is an old English word for plant. Of interest, SJW possesses antidepressant actions and is currently used to alleviate symptoms of mild to moderate depression. Nearly two dozens of bioactive compounds have been isolated from SJW. Hypericin, originally described as a monoamine oxidase inhibitor type A, was thought to be responsible for the antidepressant properties of SJW extracts. However, subsequent studies could not confirm this observation and hyperforin, a phloroglucinol derivative, was shown to display antidepressive properties. Indeed, the efficiency of the extracts of SJW has been reported to be dependent on the concentration of hyperforin. However, its effects on brain cells and on the mechanisms underlying its putative clinical antidepressant effect remain poorly characterized. OBJECTIVE: The aim of this review article is to propose an overview of the recent scientific publications that have provided new and relevant insights into the neurobiological actions of hyperforin. RESULTS: Hyperforin has been described as an inhibitor of the reuptake of many neurotransmitters such as dopamine, norepinephrine, serotonin or glutamate. It is thus a potent modulator of synaptic transmission. In addition, it blocks the activity of many receptors such as gamma aminobutyric acid (GABA) and N-Methyl-D-aspartate (NMDA) receptors. More recently, hyperforin has been shown to activate TRPC6, a Ca(2+)-conducting channel of the plasma membrane, which is the only channel opened by this molecule. Interestingly, the other transient receptor potential channels of C type (TRPC) isoforms (TRPC1, TRPC3, TRPC4, TRPC5 and TRPC7) are insensitive to hyperforin. Due to this specific property, it is now used as a convenient pharmacological tool to investigate the functions of endogenous TRPC6 channels in various cell types. Chronically applied to neuronal cell line PC12, hyperforin promotes the extension of neurites via a mechanism implying TRPC6 channels. It is also known to trigger an intracellular signalling pathway that involves the cAMP dependent protein kinase A and the transcription factor cyclic adenosine monophosphate response element binding protein (CREB). This leads to an up regulation of the expression of the brain-derived neurotrophic factor (BDNF) receptor neurotrophic tyrosine kinase (TrkB) and TRPC6. This hyperforin-dependent cascade is controlled by Ca(2+) ions and occurs specifically in the cortex but not in the hippocampus. One key aspect of the cellular responses induced by hyperforin is its impact on the homeostasis of several cations (Na(+), Ca(2+), Zn(2+) and H(+)). In vitro experiments demonstrated that hyperforin, which changes the fluidity of membranes, elevates the intracellular concentration of these elements by promoting their influx and/or their release from internal compartments. CONCLUSION: The phloroglucinol derivative hyperforin is an important bioactive molecule of Hypericum perforatum exhibiting antidepressive properties. Although it inhibits the reuptake of many neurotransmitters, hyperforin is in fact a multi-target drug influencing the cellular homeostatic mechanisms of Ca(2+), Zn(2+), H(+) and Na(+) due to its effects on their influx and/or release from internal stores. In addition, hyperforin is a potent modulator of mitochondrial functions. In spite of recent progress in the characterization of the cellular hyperforin responses, it remains unclear what pharmacological aspects of hyperforin functions are relevant in vivo. PMID- 23816061 TI - The role of 5-HT in response inhibition and re-engagement. AB - In animal and human research, the neurotransmitter serotonin (5-HT) has been implicated in inhibitory control. Using functional magnetic resonance imaging (fMRI), the present study investigated the acute effects of pharmacological modulation of the serotonergic system on brain activation during response inhibition and re-engagement in healthy human volunteers. In a randomized double blind placebo-controlled cross-over design 14 men received either a single oral dose of the selective serotonin reuptake inhibitor (SSRI) escitalopram (10mg) or a placebo. At the time of the expected plasma peak concentration, participants performed a stop-change task during fMRI. Escitalopram did not affect behavioural performance, since the main effect did not reveal significant differences between reaction times of go-, stop- or change-trials. During successful response inhibition, escitalopram, however, was associated with enhanced brain activation in right prefrontal cortex, right supplementary/pre-motor and bilateral cingulate cortex, and subcortical regions. During inhibition failures, escitalopram also modulated a broad network of brain regions, including anterior cingulate, right parietal cortex, right orbitofrontal cortex, and areas in right temporal cortex and subcortical regions. During response re-engagement escitalopram increased brain activation in right inferior frontal gyrus and precuneus as well as in left middle temporal gyrus. The results implicate the involvement of 5-HT in neural regulation of response inhibition and re-engagement. This study also provides evidence that 5-HT affects both action restraint and action cancellation through modulation of activation of brain areas. The results support the view for a fronto-striatal circuitry for response inhibition in conjunction with serotonin. PMID- 23816063 TI - Health-related quality of life, assessed with a disease-specific questionnaire, in Swedish adults suffering from well-diagnosed food allergy to staple foods. AB - BACKGROUND: Our aim was to investigate the factors that affect health related quality of life (HRQL) in adult Swedish food allergic patients objectively diagnosed with allergy to at least one of the staple foods cow's milk, hen's egg or wheat. The number of foods involved, the type and severity of symptoms, as well as concomitant allergic disorders were assessed. METHODS: The disease specific food allergy quality of life questionnaire (FAQLQ-AF), developed within EuroPrevall, was utilized. The questionnaire had four domains: Allergen Avoidance and Dietary Restrictions (AADR), Emotional Impact (EI), Risk of Accidental Exposure (RAE) and Food Allergy related Health (FAH). Comparisons were made with the outcome of the generic questionnaire EuroQol Health Questionnaire, 5 Dimensions (EQ-5D). The patients were recruited at an outpatient allergy clinic, based on a convincing history of food allergy supplemented by analysis of specific IgE to the foods in question. Seventy-nine patients participated (28 males, 51 females, mean-age 41 years). RESULTS: The domain with the most negative impact on HRQL was AADR, assessing the patients' experience of dietary restrictions. The domain with the least negative impact on HRQL was FAH, relating to health concerns due to the food allergy. One third of the patients had four concomitant allergic disorders, which had a negative impact on HRQL. Furthermore, asthma in combination with food allergy had a strong impact. Anaphylaxis, and particularly prescription of an epinephrine auto-injector, was associated with low HRQL. These effects were not seen using EQ-5D. Analyses of the symptoms revealed that oral allergy syndrome and cardiovascular symptoms had the greatest impact on HRQL. In contrast, no significant effect on HRQL was seen by the number of food allergies. CONCLUSIONS: The FAQLQ-AF is a valid instrument, and more accurate among patients with allergy to staple foods in comparison to the commonly used generic EQ-5D. It adds important information on HRQL in food allergic adults. We found that the restrictions imposed on the patients due to the diet had the largest negative impact on HRQL. Both severity of the food allergy and the presence of concomitant allergic disorders had a profound impact on HRQL. PMID- 23816064 TI - Role of protein farnesylation events in the ABA-mediated regulation of the Pinoresinol-Lariciresinol Reductase 1 (LuPLR1) gene expression and lignan biosynthesis in flax (Linum usitatissimum L.). AB - A Linum usitatissimum LuERA1 gene encoding a putative ortholog of the ERA1 (Enhanced Response to ABA 1) gene of Arabidopsis thaliana (encoding the beta subunit of a farnesyltransferase) was analyzed in silico and for its expression in flax. The gene and the protein sequences are highly similar to other sequences already characterized in plants and all the features of a farnesyltransferase were detected. Molecular modeling of LuERA1 protein confirmed its farnesyltransferase nature. LuERA1 is expressed in the vegetative organs and also in the outer seedcoat of the flaxseed, where it could modulate the previously observed regulation operated by ABA on lignan synthesis. This effect could be mediated by the regulation of the transcription of a key gene for lignan synthesis in flax, the LuPLR1 gene, encoding a pinoresinol lariciresinol reductase. The positive effect of manumycin A, a specific inhibitor of farnesyltransferase, on lignan biosynthesis in flax cell suspension systems supports the hypothesis of the involvement of such an enzyme in the negative regulation of ABA action. In Arabidopsis, ERA1 is able to negatively regulate the ABA effects and the mutant era1 has an enhanced sensitivity to ABA. When expressed in an Arabidopsis cell suspension (heterologous system) LuERA1 is able to reverse the effect of the era1 mutation. RNAi experiments in flax targeting the farnesyltransferase beta-subunit encoded by the LuERA1 gene led to an increase LuPLR1 expression level associated with an increased content of lignan in transgenic calli. Altogether these results strongly suggest a role of the product of this LuERA1 gene in the ABA-mediated upregulation of lignan biosynthesis in flax cells through the activation of LuPLR1 promoter. This ABA signaling pathway involving ERA1 probably acts through the ABRE box found in the promoter sequence of LuPLR1, a key gene for lignan synthesis in flax, as demonstrated by LuPLR1 gene promoter-reporter experiments in flax cells using wild type and mutated promoter sequences. PMID- 23816065 TI - [Increase of repeat abortion in France: from contraceptive issues to postponement of childbearing age]. AB - BACKGROUND: The number of women resorting to abortion several times has increase continuously in France since 1975, similar to the situation in many countries where contraception is widely available and used. The analysis of time trends in so-called "repeat" abortion across social, demographic and contraceptive characteristics can be helpful in capturing the social meaning of this practice and informing policies for sexual and reproductive health. METHODS: The present analysis was based on statistical reports of abortions performed in France from 1990 to 2007 and on data from the National Survey of Abortion Patients, a representative sample of 7067 women undergoing an abortion in France. Chi(2) and logistic regression models were used for the statistical analysis. RESULTS: Increase in "repeated" abortion was seen across all groups of the population but was greater in women under 30, women who live alone and students. Women presenting for a second abortion were more likely to report the pregnancy followed a contraceptive failure than women presenting for an abortion for the first time. CONCLUSION: The trend for an increasing use of multiple abortions over time occurs primarily because of longer time between first intercourse and first child. Having several abortions is an expression of the difficulties women have in managing daily contraceptive use in the context of more diversified emotional and sexual trajectories. PMID- 23816066 TI - [Homicide, schizophrenia and substance abuse: a complex interaction]. AB - BACKGROUND AND AIM: The prevalence of homicide perpetrators with a diagnosis of schizophrenia is 6% in Western countries populations. The relationship between schizophrenia and homicide is complex and cannot be reduced to a simple causal link. The aim of this systematic review was to clarify the role of substance abuse in the commission of murder in people suffering from schizophrenia. METHODS: A systematic English-French Medline and EMBASE literature search of cohort studies, case-control studies and transversal studies published between January 2001 and December 2011 was performed, combining the MeSH terms "schizophrenia", "psychotic disorders", "homicide", "violence", "substance use disorder", and the TIAB term "alcohol". Abstract selection was based on the STROBE and PRISMA checklist for observational studies and systematic and meta analysis studies, respectively. RESULTS: Of the 471 selected studies, eight prospective studies and six systematic reviews and meta-analysis studies met the selection criteria and were included in the final analysis. Homicide committed by a schizophrenic person is associated with socio-demographic (young age, male gender, low socioeconomic status), historical (history of violence against others), contextual (a stressful event in the year prior to the homicide), and clinical risk factors (severe psychotic symptoms, long duration of untreated psychosis, poor adherence to medication). In comparison to the general population, the risk of homicide is increased 8-fold in schizophrenics with a substance abuse disorder (mainly alcohol abuse) and 2-fold in schizophrenics without any comorbidities. A co-diagnosis of substance abuse allows us to divide the violent schizophrenics into "early-starters" and "late-starters" according to the age of onset of their antisocial and violent behavior. The violence of the "early-starters" is unplanned, usually affects an acquaintance and is not necessarily associated with the schizophrenic symptoms. Substance abuse is frequent and plays an important role in the homicide commission. In addition, the risk of reoffending is high. In the "late-starters", the violence is linked to the psychotic symptoms and is directed to a member of the family. The reoffence risk is low and it depends on the pursuit of care or not. CONCLUSION: Defining subgroups of violent schizophrenic patients would avoid stigmatization and would help to prevent the risk of homicide by offering a multidisciplinary care which would take into account any substance abuse. PMID- 23816067 TI - Who do you say you are? PMID- 23816068 TI - Surgical tourism: the role of cardiothoracic surgery societies in evaluating international surgery centers. PMID- 23816069 TI - Invited commentary. PMID- 23816070 TI - Invited commentary. PMID- 23816071 TI - Invited commentary. PMID- 23816073 TI - Invited commentary. PMID- 23816072 TI - Mammalian cardiac regeneration after fetal myocardial infarction requires cardiac progenitor cell recruitment. AB - BACKGROUND: In contrast to the adult, fetal sheep consistently regenerate functional myocardium after myocardial infarction. We hypothesize that this regeneration is due to the recruitment of cardiac progenitor cells to the infarct by stromal-derived factor-1alpha (SDF-1alpha) and that its competitive inhibition will block the regenerative fetal response. METHODS: A 20% apical infarct was created in adult and fetal sheep by selective permanent coronary artery ligation. Lentiviral overexpression of mutant SDF-1alpha competitively inhibited SDF-1alpha in fetal infarcts. Echocardiography was performed to assess left ventricular function and infarct size. Cardiac progenitor cell recruitment and proliferation was assessed in fetal infarcts at 1 month by immunohistochemistry for nkx2.5 and 5-bromo-2-deoxyuridine. RESULTS: Competitive inhibition of SDF-1alpha converted the regenerative fetal response into a reparative response, similar to the adult. SDF-inhibited fetal infarcts demonstrated significant infarct expansion by echocardiography (p < 0.001) and a significant decrease in the number of nkx2.5+ cells repopulating the infarct (p < 0.001). CONCLUSIONS: The fetal regenerative response to myocardial infarction requires the recruitment of cardiac progenitor cells and is dependent on SDF1alpha. This novel model of mammalian cardiac regeneration after myocardial infarction provides a powerful tool to better understand cardiac progenitor cell biology and to develop strategies to cardiac regeneration in the adult. PMID- 23816074 TI - Invited commentary. PMID- 23816075 TI - Invited commentary. PMID- 23816076 TI - Invited commentary. PMID- 23816078 TI - Multiple ventricular septal rupture after blunt trauma. AB - Ventricular septal rupture occurring as a result of blunt trauma is a very rare clinical condition. Compression of the heart between the sternum and the vertebral column during late diastole or isovolumetric contraction resulting in sudden increase in the intracardiac pressure is a prerequisite for its occurrence. Sudden relief of the inner pressure becomes impossible when the heart is full, thereby resulting in myocardial contusion and rupture. We report a case of a young schoolboy who presented to us with this serious disease and was successfully treated with surgical closure of the defect with a polytetrafluoroethylene patch. PMID- 23816077 TI - Video-assisted pericardioscopic surgery for epimyocardial lead implantation. AB - PURPOSE: Video-assisted pericardioscopic surgery (VAPS) for epimyocardial lead implantation has demonstrated positive acute results concerning the safety and degree of freedom inside the pericardium. We evaluated the employment of a newly developed trocar for pericardioscopy with regard to long-term effects and feasibility of reoperation. DESCRIPTION: Eight adult sheep were divided into three groups. In two animals, VAPS was used exclusively. All other animals received four small-caliber epicardial leads through VAPS. After 6 and 12 months (n = 3 each), reoperation was conducted for reevaluation of entry site, intrapericardial adhesions, lead position, and morphology of the implantation site. EVALUATION: Reentry close to the previous entry site proves unproblematic. Adhesions were mild to moderate in the immediate area of the implanted leads. Throughout the follow-up, pacing parameters were satisfactory. Lead dislodgement occurred in 1 of 24 leads. The deployment of small-caliber flexible endoscopes through the new trocar provided sufficient navigation, stability, and maneuverability. CONCLUSIONS: Reoperation from the same subxiphoid approach proved feasible. Lead removal and reimplantation were feasible at both 6 months and 12 months after initial implantation. The intrapericardial adhesions caused by VAPS alone are mild. PMID- 23816079 TI - Chronic dissection and aneurysmal dilatation of a BioValsalva conduit. AB - The BioValsalva (Vascutek Terumo, Renfrewshire, Scotland, UK) conduit is the first commercially available prefabricated bioprosthetic aortic valved conduit. We present a case of chronic dissection of a BioValsalva valved conduit presenting as a 7.5-cm aortic root aneurysm 1 year after a Bentall operation. Intraoperatively, the conduit was found to have dissected from the annulus upward, and the coronary buttons were avulsed from the inner layers while remaining attached to the outer layer. Both the outer layer and the coronary buttons were grossly dilatated. PMID- 23816080 TI - Diaphragmatic and intercostal muscle tear after an episode of violent sneezing: spontaneous diaphragmatic injury. AB - Spontaneous diaphragmatic injuries are rare, accounting for approximately 1% of all diaphragmatic injuries. We report a case of a 69-year-old male with a concurrent lower respiratory tract infection who sustained diaphragmatic and intercostal muscle injuries after an episode of violent sneezing. To our knowledge, this is the first reported case of spontaneous diaphragmatic injury after sneezing. PMID- 23816081 TI - Mycotic aneurysm of the aortic arch presenting with left vocal cord palsy. AB - We report a case of a 71-year-old man with a mycotic aneurysm of the aortic arch who presented with progressive hoarseness. Three weeks prior to this event the patient was admitted to an outside hospital in septic condition and was diagnosed with a mycotic abdominal aortic aneurysm. Resection of the infected abdominal aortic aneurysm with right axillofemoral and femoral-femoral bypass grafts was performed and the patient was discharged home on intravenous antibiotics. At our institution, the aortic arch aneurysm was treated with extensive debridement and replaced with a Dacron prosthesis under circulatory arrest with antegrade cerebral perfusion through the axillofemoral bypass. PMID- 23816082 TI - Modified intraatrial translocation for prosthetic mitral valve endocarditis. AB - Despite prompt diagnosis and aggressive surgical treatment of prosthetic mitral valve endocarditis (PVE), morbidity and mortality remain high. Surgical strategies have mostly been limited to debridement and anatomic valve reinstallation. Alternative surgical techniques have been attempted sporadically against this mortal disease, either with protection by antibiotic sewing rings or by anatomic evacuation of infectious foci. These methods have not been performed concurrently, however, and their joint deployment might improve surgical outcome. We describe a surgical procedure of modified intraatrial translocation combined with sewing ring shielding, aimed at preventing the recurrence of severe methicillin-resistant staphylococci PVE in the mitral position. PMID- 23816083 TI - Left anomalous brachiocephalic vein in a patient with right lung cancer. AB - The left anomalous brachiocephalic vein is a rare anomaly without congenital heart disease. It is important to recognize this anomalous vein especially in patients with lung cancer because misinterpretation as a superior mediastinal lymph node enlargement may cause serious complications. We report a case of a 62 year-old lung cancer patient with left anomalous brachiocephalic vein, who underwent surgical treatment safely under video-assisted thoracoscopic surgery after confirmation of this anomaly on contrast-enhanced computed tomographic scan. PMID- 23816084 TI - Tricuspid valve implantation after Bjork procedure to establish biventricular physiology. AB - A 29-year-old male, who had undergone a Bjork procedure for tricuspid atresia with a ventricular septal defect, had redo surgery for relief of stenosis and systolic regurgitation of the right atrioventricular pathway. After revision using a valved bioprosthesis, effective biventricular physiology was established and the patient's functional status improved. PMID- 23816085 TI - Redo aortic valve replacement in a patient with immunoglobulin A deficiency and hemophilia A. AB - Immunoglobulin A (IgA) deficiency may result in the development of anti-IgA antibodies. Such antibodies may result in anaphylaxis when patients receive standard blood products. Hemophilia A is a deficiency of clotting factor VIII that results in a significant coagulopathy and bleeding in the perioperative period unless precautions are taken. We present a case of successful management of combined hemophilia A and IgA deficiency in a patient undergoing repeated sternotomy for aortic valve replacement. PMID- 23816086 TI - Falsely elevated valve gradients by echocardiography in the 3f aortic bioprosthesis. AB - The 3f Aortic Bioprosthesis (Medtronic, Inc, Minneapolis, MN) is a stentless aortic valve with a novel design that resembles a "tube within a tube." Although it has the potential for improved durability and hemodynamic performance, long term data on this valve remain elusive. We present here 3 patients in whom postoperative echocardiography revealed significantly elevated transvalvular gradients of the 3f valve while transcatheter gradients proved to be negligible. By virtue of the unique design of the 3f bioprosthesis, great caution should be taken when interpreting echocardiographically derived gradients. PMID- 23816088 TI - Solitary fibrous tumor causing cardiac tamponade. AB - Solitary fibrous tumor of the pleura is a rare primary tumor arising from mesenchymal cells in the areolar tissue subjacent to the mesothelial-lined pleura. Most solitary fibrous tumor of the pleura arises from the visceral or the parietal pleura, and asymptomatically occupies the hemithoracic cavity. We report a rare case of solitary fibrous tumor of the pleura causing cardiac tamponade. A 30-year-old woman presented with pericardial tumor. The surgical resection of the tumor was complete. We describe the details of this case and a brief review of the literature about solitary fibrous tumor. PMID- 23816087 TI - Potts shunt and atrial septostomy in pulmonary hypertension caused by left ventricular disease. AB - We report a 20-year-old patient with Shone's complex and severe diastolic dysfunction of his small left ventricle (LV) in whom severe pulmonary hypertension and biventricular failure developed while he was awaiting combined heart-lung transplantation. We performed a percutaneous balloon atrial septostomy and a modified Potts shunt (13-mm graft from left pulmonary artery to descending aorta), with the aim of decompressing the hypertensive right ventricle (RV) by reducing left ventricular preload and left atrial hypertension. The procedures were uneventful. The patient's condition improved rapidly and biventricular function was restored. In contrast to a Potts shunt in other conditions, patients with pulmonary hypertension caused by left ventricular disease may benefit from an additional atrial left-to-right shunt. PMID- 23816089 TI - Aspergillus endocarditis in lung transplant recipient: successful surgical treatment. AB - Solid organ transplantation can be followed by Aspergillus infection, implying high mortality rates. The highest infection rates are registered among lung transplant recipients. We present a recent case of an Aspergillus endocarditis in a young lung transplant recipient. PMID- 23816090 TI - Bilateral pulmonary metastasectomy through right thoracotomy. AB - Bilateral thoracotomies spaced at least 4 weeks apart are often required for the resection of bilateral pulmonary metastases. The anatomic distribution of the metastatic disease may rarely permit excision of bilateral pulmonary deposits through one thoracotomy incision. We demonstrate a successful bilateral pulmonary metastasectomy in the right upper lobe, right middle lobe, and left upper lobe through a right thoracotomy in a 40-year-old man with a past history of rectal adenocarcinoma and of left open pulmonary metastasectomy 1 year previously. The left upper lobe was approached by opening the pleura anterior to the ascending aorta. PMID- 23816091 TI - Intrathoracic migration of a silicone breast implant after video-assisted thoracoscopic surgery. PMID- 23816092 TI - Asymptomatic right ventricular cavernous hemangioma. PMID- 23816093 TI - Cardiac lymphangioma in the right atrium. PMID- 23816094 TI - Isolated three coronary arteries and malformation of left anterior descending. PMID- 23816095 TI - An effective modification to simplify the right atrial lesion set of the Cox cryomaze. AB - Reluctance to perform biatrial Cox-cryomaze is primarily to avoid the vexation of creating a right-atrial-lesion (RAL) set of Cox-Maze-III. An alternative pattern of RAL set includes (i) a horizontal atriotomy, continued medially as a linear cryolesion across the posterior tricuspid annulus, (ii) a cavocaval lesion, and (iii) a lateral cryolesion from the midportion of the atriotomy to the tip of the right atrial appendage (RAA). This latter lesion is a substitute for a cryolesion that, in past, was directed medially by a stab wound in the tip of the RAA to the anterior tricuspid annulus. Use of the simplified RAL set, therefore, allows for more deftly achieving a complete biatrial Cox-cryomaze. PMID- 23816096 TI - Right ventricular outflow tract cannulation for right ventricular assist device implantation. AB - A need persists for implantable devices that provide support for the failing right ventricle. The anatomy of the right ventricle presents unique challenges at the time of right ventricular assist device implant. We describe a technique for right ventricular outflow tract cannulation that minimizes the risk of right ventricular assist device inflow cannula obstruction and right ventricular compression. PMID- 23816097 TI - Cryotechnology for staged removal of self-expandable metallic airway stents. AB - Self-expandable covered metallic airway stents (SEMAS) deployed for relieving inoperable central airway obstruction frequently develop complications that require removal of the device. Current techniques for SEMAS removal also involve serious complications. We are reporting a novel two-staged endoscopic approach using cryotechnology for removal of SEMAS obstructed by exuberant granulation tissue in two patients. During the first stage, the obstructing intraluminal granulation tissue was removed with cryodebridement and residual extraluminal deposits were lysed with cryotherapy. During the second stage, performed two days later, the SEMAS was liberated by mechanical means and removed in one piece. The staged approach with cryotechnology was successful and without complications. PMID- 23816098 TI - Clinical statement on the role of the surgeon and surgical issues relating to computed tomography screening programs for lung cancer. PMID- 23816099 TI - Preoperative use of steroids in pediatric cardiac surgery: new directions for future research? PMID- 23816100 TI - Reply: To PMID 22289904. PMID- 23816101 TI - Comparing outcomes in ECMO between roller and centrifugal pumps in the face of evolving technology. PMID- 23816102 TI - Reply: To PMID 22921236. PMID- 23816103 TI - Ultrasonography-guided transbronchial needle aspiration and microRNA: return to the past? PMID- 23816104 TI - Reply: To PMID 22186468. PMID- 23816105 TI - The One and Only: II. PMID- 23816106 TI - miR-296 and Modulation of tumor growth in systemic malignancies. PMID- 23816107 TI - Reply: To PMID 23176919. PMID- 23816108 TI - Aberrant right subclavian artery and axillary artery cannulation in type a aortic dissection repair. AB - Currently, right axillary artery cannulation and unilateral antegrade cerebral perfusion through the same cannula are preferred choices for acute type A aortic dissection repair. However, the existence of an aberrant right subclavian artery can jeopardize cerebral perfusion through the right axillary artery cannula. In this study, we intended to explain the repair of acute type A aortic dissection using right axillary artery cannulation in a patient with aberrant right subclavian artery. PMID- 23816109 TI - Left ventricular metastasis from ocular melanoma: a new, rare, and unusual pathway? AB - Melanoma is a neoplasm known for its propensity for cardiac involvement. When there exists an isolated metastasis to the heart, the melanoma tends to involve the right heart. Rarely does melanoma metastasize to the left ventricle. We report the first case of choroidal melanoma that had indeed metastasized to the left ventricle and was associated with a patent foramen ovale, which may explain its initially surprising location on this side of the heart. PMID- 23816110 TI - Esophageal cancer with esophageal duplication cyst. AB - Esophageal duplication cysts are benign, asymptomatic anomalies of foregut formation. We report a case of esophageal duplication cyst with esophageal squamous cancer. An upper endoscopy visualized with esophageal scan disclosed a stenotic lesion in the lower esophagus. Computed tomography images revealed a cystic mass in the inferior mediastinum, which was on the right wall of the esophagus. The postoperative pathology report confirmed the diagnosis of esophageal squamous cancer (ulcer type) and esophageal duplication cyst with calcification. PMID- 23816111 TI - Reconstruction of pulmonary artery with donor aorta and autopericardium in lung transplantation. AB - A 44-year-old man with Eisenmenger's syndrome due to ventricular septal defect (VSD) was listed for lung transplantation. The patient's condition was complicated by a giant pulmonary artery (PA) aneurysm. Concurrent VSD closure and total reconstruction of the recipient PA with the donor aorta were planned. When the patient underwent bilateral lung transplantation, the aortic graft obtained turned out to be too short to complete the reconstruction. A PA graft made of the recipient's pericardium was successfully interposed between the donor's PA and the donor's aortic graft. PMID- 23816112 TI - Anomalous origin of the left coronary artery from the right pulmonary artery: an extremely rare cardiac malformation. PMID- 23816113 TI - Valve-sparing aortic root replacement for rapidly growing multiple sinus of Valsalva pseudoaneurysms in a case of Behcet's-like aortitis. PMID- 23816114 TI - Guidelines for sizing pericardium for aortic valve leaflet grafts. AB - Surgical repair of the aortic valve with the use of leaflet grafts made from pericardium has been shown to be a viable option, particularly in children, in whom valve replacement has strong disadvantages. We present guidelines for sizing treated autologous pericardium to fabricate a leaflet graft for single-leaflet replacement. Both our clinical experience and experimental evidence indicate that effective repairs are best achieved by use of a semicircular graft with a diameter 10% to 15% greater than the sinotubular junction diameter in diastole. We also provide a simple formula to allow adjustment of these guidelines to account for variations in valve geometry and tissue properties. PMID- 23816115 TI - Pulmonary artery perforation by plug anchoring system after percutaneous closure of left appendage. AB - Patients receiving oral anticoagulant therapy for atrial fibrillation who are at high risk of bleeding are increasingly referred for percutaneous left atrial appendage exclusion. Although effective, this procedure is not free from risk. We report a case of pericardial tamponade due to pulmonary artery tear caused by a trespassing anchoring hook of an AGA plug. Intraoperatively, no actual bleeding was found from the left appendage, a proof of its complete occlusion by the device. The patient underwent successful surgical repair and radio-frequency ablation of atrial fibrillation was performed by pulmonary veins encircling. PMID- 23816116 TI - Intraaortic migration of an epicardial pacing wire: percutaneous extraction. AB - Infrequent but serious complications have been described in association with temporary epicardial pacing wires. We describe the case of an intraaortic migration of an infected retained atrial temporary epicardial pacing wire and the transfemoral percutaneous interventional approach for its extraction. PMID- 23816117 TI - Tuberculosis bronchopleural fistula treated with atrial septal defect occluder. AB - Bronchopleural fistula (BPF) is an uncommon and potentially fatal complication of lobectomy or pneumonectomy, particularly in tuberculosis patients. It is associated with high mortality and its treatment remains a challenge. The development of plugging technology has led to the emergence of less invasive endobronchial methods for treating BPF. We describe the successful treatment of a multidrug-resistant tuberculosis patient with BPF using an occlusion device originally designed for transcatheter closure of an atrial septal defect. Follow up over 10 months revealed maintenance of the repair without any recurrence. This novel technique can be effective for treating a tuberculosis patient with postoperative BPF. PMID- 23816120 TI - Derivative spectrophotometry for the determination of faropenem in the presence of degradation products: an application for kinetic studies. AB - A simple and selective derivative spectrophotometric method was developed for the quantitative determination of faropenem in pure form and in pharmaceutical dosage. The method is based on the zero-crossing effect of first-derivative spectrophotometry (lambda = 324 nm), which eliminates the overlapping effect caused by the excipients present in the pharmaceutical preparation, as well as degradation products, formed during hydrolysis, oxidation, photolysis, and thermolysis. The method was linear in the concentration range 2.5-300 MUg/mL (r = 0.9989) at lambda = 341 nm; the limits of detection and quantitation were 0.16 and 0.46 MUg/mL, respectively. The method had good precision (relative standard deviation from 0.68 to 2.13%). Recovery of faropenem ranged from 97.9 to 101.3%. The first-order rate constants of the degradation of faropenem in pure form and in pharmaceutical dosage were determined by using first-derivative spectrophotometry. A statistical comparison of the validation results and the observed rate constants for faropenem degradation with these obtained with the high-performance liquid chromatography method demonstrated that both were compatible. PMID- 23816121 TI - Solid phase-enhanced photothermal lensing with mesoporous polymethacrylate matrices for optical-sensing chemical analysis. AB - Procedures for the photothermal lens determination of metals and organic compounds, on the basis of solid-phase mesoporous optical-sensing materials (polymethacrylate [PMA]) matrices with immobilized reagents, were developed. These procedures combine (i) selective and efficient preconcentration of trace substances to be analyzed in specially designed and synthesized transparent mesoporous PMA plates; (ii) sensitive determination with the reliable and traceable photometric reactions previously developed for classical spectrophotometry; and (iii) the sensitivity enhancement of photothermal lens detection in polymers, which provides at least a ten-fold increase in sensitivity compared with solutions due to polymer thermo-optical properties (solid phase enhanced thermal lensing). It is shown that the overall sensitivity of photothermal lens measurements in PMA matrices is two orders higher than photometric absorbance measurements for the same excitation source power, which is in good agreement with the expected theoretical sensitivity. Changes in the preparation of transparent PMA plates and analytical procedures for photothermal measurements compared with spectrophotometry are discussed. PMA matrices modified with various analytical reagents were applied to trace determination of Hg(II), Fe(II), Ag(I), Cu(II), and ascorbic acid, with subnanomolar to nanomolar limits of detection. PMID- 23816122 TI - Weighted fusion of multiple models for wavelength selection. AB - A new method based on the weighted fusion of multiple models is presented for wavelength selection in multivariate calibration of spectral data. It fuses the regression coefficients of multiple models with weights based on minimum mean square error to improve the accuracy and stability of the wavelength selection. To validate the performance of the proposed method, it was applied to the partial least squares (PLS) modeling of three near-infrared spectral datasets and compared with full-spectrum PLS, genetic algorithm-based PLS, and uninformative variable elimination-based PLS methods. Results show that the proposed method can effectively select the informative wavelength and enhance the prediction ability of the PLS model. On account of its simpler algorithm and higher efficiency, it can be widely used in practical applications. PMID- 23816123 TI - Two-dimensional heterospectral correlation analysis of water and liquid oleic acid using an online near-infrared/mid-infrared dual-region spectrometer. AB - Two-dimensional (2D) near-infrared (NIR) and mid-infrared (mid-IR) heterospectral correlation analyses were used to characterize temperature-dependent spectral variations of water and liquid oleic acid (OA), utilizing a dataset obtained with an online NIR/mid-IR dual-region spectrometer. The spectrometer facilitated sequential acquisition of both NIR (10 000-4000 cm(-1)) and mid-IR (5000-1200 cm( 1)) spectra, which compose the spectral dataset required for 2D NIR/mid-IR heterospectral correlation analysis. Both NIR and mid-IR spectra were obtained under the same conditions by using the same sample compartment, more quickly and easily than is possible when using existing spectrometers. Successful 2D NIR/mid IR correlation analysis was performed with the data collected with this instrument to characterize the temperature dependence of the molecular structures of water and pure liquid OA. Temperature-induced NIR/mid-IR spectral changes for water and OA were analyzed in detail, and band assignments in the NIR and mid-IR regions were elucidated by 2D NIR/mid-IR heterospectral correlation analysis. The results of this study indicate that liquid water consists of two major species, strongly hydrogen-bonded species and weakly hydrogen-bonded species, as well as one minor species. Additionally, OA was found to form an intermolecularly hydrogen-bonded species in which a single hydrogen bond of the dimer was broken; a mid-IR band at 1724 cm(-1) was assigned to this species. Moreover, 2D NIR/mid IR heterospectral correlation analysis revealed that NIR bands at 4690 and 4644 cm(-1) also arose from intermolecularly hydrogen-bonded species. These results demonstrate that 2D NIR/mid-IR heterospectral correlation analysis is useful not only for NIR band assignments, but also for molecular structure studies. The spectrometer we developed makes this analysis even more accessible. PMID- 23816124 TI - Comparison method for uranium determination in ore sample by inductively coupled plasma optical emission spectrometry (ICP-OES). AB - A comparison method for the determination (without sample pre-concentration) of uranium in ore by inductively coupled plasma optical emission spectrometry (ICP OES) has been performed. The experiments were conducted using three procedures: matrix matching, plasma optimization, and internal standardization for three emission lines of uranium. Three wavelengths of Sm were tested as internal standard for the internal standardization method. The robust conditions were evaluated using applied radiofrequency power, nebulizer argon gas flow rate, and sample uptake flow rate by considering the intensity ratio of the Mg(II) 280.270 nm and Mg(I) 285.213 nm lines. Analytical characterization of method was assessed by limit of detection and relative standard deviation values. The certificated reference soil sample IAEA S-8 was analyzed, and the uranium determination at 367.007 nm with internal standardization using Sm at 359.260 nm has been shown to improve accuracy compared with other methods. The developed method was used for real uranium ore sample analysis. PMID- 23816125 TI - Multispectral image analysis for robust prediction of astaxanthin coating. AB - The aim of this study was to investigate the possibility of predicting the type and concentration level of astaxanthin coating of aquaculture feed pellets using multispectral image analysis. We used both natural and synthetic astaxanthin, and we used several different concentration levels of synthetic astaxanthin in combination with four different recipes of feed pellets. We used a VideometerLab with 20 spectral bands in the range of 385-1050 nm. We used linear discriminant analysis and sparse linear discriminant analysis for classification and variable selection. We used partial least squares regression (PLSR) for prediction of the concentration level. The results show that it is possible to predict the level of synthetic astaxanthin coating using PLSR on either the same recipe, or when calibrating on all recipes. The concentration prediction is adequate for screening for all recipes. Moreover, it shows that it is possible to predict the type of astaxanthin used in the coating using only ten spectral bands. Finally, the most selected spectral bands for astaxanthin prediction are in the visible range of the spectrum. PMID- 23816126 TI - Flow-injection post-chemiluminescence method for the determination of palmatine. AB - A post-chemiluminescence (PCL) phenomenon was observed when palmatine was injected in a mixture of N-bromosuccinimide (NBS) and alkaline dichlorofluorescein (DCF) after the chemiluminescence (CL) reaction of NBS alkaline DCF had finished. Based on the PCL reaction, a rapid and sensitive method for the determination of palmatine was established. Under optimum conditions, the CL intensity was linear, with the concentration of palmatine in the range of 5.0 * 10(-9) to 1.0 * 10(-6) M. The detection limit was 6.0 * 10( 10) M for palmatine. The relative standard deviation for 11 parallel measurements of 1.0 * 10(-7) M palmatine was 1.5%. This method was applied to the determination of palmatine in pharmaceutical samples and biological fluids, with satisfactory results. The possible reaction mechanism is discussed briefly. PMID- 23816127 TI - Investigating the binding of acridine, acridine orange, and acridine yellow G to humic acid through fluorescence quenching. AB - A fluorescence quenching method was used to determine the equilibrium binding constants for the association of acridine, acridine orange, and acridine yellow G to humic acid. The fluorescence of each polycyclic aromatic nitrogen heterocycle (PANH) was monitored as aliquots of humic acid were added, and a Stern-Volmer plot was produced in which the slope is the equilibrium constant of the binding reaction. The quenching experiments were performed at temperatures of 30, 35, 40, and 45 degrees C. A van't Hoff plot generated from the equilibrium binding constants as a function of temperature for a given PANH resulted in a linear plot. Calculation of the DeltaHbinding, DeltaGbinding, and DeltaSbinding for each PANH leads to the conclusion that the equilibrium binding constant, and DeltaGbinding, may be predictors of bioavailability. The other thermodynamic quantities, DeltaHbinding and DeltaSbinding, are helpful in understanding the relative binding of the compounds. For example, acridine yellow G appears to be the least bioavailable of the three PANHs studied because of its strong DeltaHbinding = -29.8 kJ/mol, which leads to DeltaGbinding = -0.71 kJ/mol. While acridine orange and acridine have similar DeltaHbinding values, acridine orange is more likely to bind to humic acid because the DeltaSbinding for the process is less negative. Thermodynamic values and equilibrium binding constants for all three compounds are reported. PMID- 23816128 TI - Quantitative determination of citric acid in seminal plasma by using Raman spectroscopy. AB - In this study, Raman spectroscopy was first used to study the linear relationship between Raman spectral intensities and citric acid concentrations in aqueous solution. By using the specific Raman band of 942 cm(-1), concentrations of citric acid ranging from 2 to 20 mg/mL were observed linearly (R(2) = 0.993), and the limit of detection was 1.0 mg/mL. Then, citric acid detection in clinical seminal plasma ultrafiltrate samples was performed, and the intensity of the Raman-specific peak demonstrates a good linear correlation (R(2) = 0.946) with citric acid concentrations determined by the enzymatic method. Our results showed that Raman spectroscopy has the potential of being applied to detect concentrations of citric acid in seminal plasma in clinic. PMID- 23816129 TI - Silver nanoaggregates on chitosan functionalized graphene oxide for high performance surface-enhanced Raman scattering. AB - Herein we describe a self-assembly synthesis of graphene oxide/Ag nanoparticles nano-composites (GO/CS/AgNPs) by non-covalent attachment of AgNPs to chitosan (CS) functionalized graphene oxide (GO) sheets. The negatively charged AgNPs are prone to form aggregates on GO/CS via electrostatic interaction, which is extremely beneficial to the surface-enhanced Raman scattering (SERS) detection of aromatic molecules. Taking advantage of the enrichment of target molecules on GO, the obtained hybrids exhibit strong SERS activity to aromatic molecules (trypan blue and methylene blue). Furthermore, SERS signals of a negatively charged molecule (trypan blue) are stronger than signals of a positively charged molecule (methylene blue) due to the different adsorption capacity of GO/CS/AgNPs for the two opposite charged molecules through electrostatic interaction. Moreover, GO/CS/AgNPs remarkably enhance the main peaks of l-phenylalanine, in comparison with the silver nanoparticles, showing great potential for biomedical applications. PMID- 23816130 TI - Practical considerations for the field application of miniaturized portable Raman instrumentation for the identification of minerals. AB - The nondestructive identification of both inorganic and organic compounds without the need for chemical or mechanical sample preparation is an advantage of the Raman spectroscopic analytical technique when applied in situ using miniaturized equipment for the geosciences. This is critically assessed here for several real life geoscientific scenarios in which several groups of minerals were analyzed with emphasis on evaporites, carbonates, and selected types of dark minerals and weak Raman scatterers. The role of individual analytical instrumental parameters such as focal plane precision, exposure time, and ambient light conditions that can affect the acquisition and interpretation of spectroscopic data from these specimens in field conditions was also evaluated. PMID- 23816131 TI - Automated analysis of carbon in powdered geological and environmental samples by Raman spectroscopy. AB - Raman spectroscopy can be used to assess the structure of naturally occurring carbonaceous materials (CM), which exist in a wide range of crystal structures. The sources of these geological and environmental materials include rocks, soils, river sediments, and marine sediment cores, all of which can contain carbonaceous material ranging from highly crystalline graphite to amorphous-like organic compounds. In order to fully characterize a geological sample and its intrinsic heterogeneity, several spectra must be collected and analyzed in a precise and repeatable manner. Here, we describe a suitable processing and analysis technique. We show that short-period ball-mill grinding does not introduce structural changes to semi-graphitized material and allows for easy collection of Raman spectra from the resulting powder. Two automated peak-fitting procedures are defined that allow for rapid processing of large datasets. For very disordered CM, Lorentzian profiles are fitted to five characteristic peaks, for highly graphitized material, three Voigt profiles are fitted. Peak area ratios and peak width measurements are used to classify each spectrum and allow easy comparison between samples. By applying this technique to samples collected in Taiwan after Typhoon Morakot, sources of carbon to offshore sediments have been identified. Carbon eroded from different areas of Taiwan can be seen mixed and deposited in the offshore flood sediments, and both graphite and amorphous-like carbon have been recycled from terrestrial to marine deposits. The practicality of this application illustrates the potential for this technique to be deployed to sediment-sourcing problems in a wide range of geological settings. PMID- 23816132 TI - Assessing variability of in vivo tissue Raman spectra. AB - Raman spectroscopy (RS) has received increasing attention as a potential tool for clinical diagnostics. However, the unknown comparability of multiple tissue RS systems remains a major issue for technique standardization and future multisystem trials. In this study, we evaluated potential factors affecting data collection and interpretation, utilizing the skin as an example tissue. The effects of contact pressure and probe angle were characterized as potential user induced variability sources. Similarly, instrumentation-induced variability sources of system stability and system-dependent response were also analyzed on skin and a nonvolatile biological tissue analog. Physiologically induced variations were studied on multiple tissue locations and patients. The effect of variability sources on spectral line shape and dispersion was analyzed with analysis-of-variance methods, and a new metric for comparing spectral dispersion was defined. In this study, in vivo measurements were made on multiple sites of skin from five healthy volunteers, with four stand-alone fiber optic probe-based tissue RS systems. System stability and controlled user-induced variables had no effects on obtained spectra. By contrast, instrumentation and anatomical location of measurement were significant sources of variability. These findings establish the comparability of tissue Raman spectra obtained by unique systems. Furthermore, we suggest steps for further procedural and instrumentation standardization prior to broad clinical applications of the technique. PMID- 23816133 TI - Surface-enhanced Raman spectroscopy detection of ionic solutes by surfactant mediated adsorption to a hydrophobic surface. AB - Chemical modification of the surfaces of surface-enhanced Raman spectroscopy (SERS)-active metals with thin molecular layers expands the variety of molecular species that can be attracted to the SERS surface from solution. This approach can provide selective detection of new classes of molecules that would not otherwise be detectable through direct interaction with a SERS-active metal. For example, polycyclic aromatic compounds can be attracted from aqueous solution to gold or silver SERS substrates that are modified with alkylsilanes or alkanethiols. While n-alkane monolayers attract hydrophobic solutes to a SERS active surface, they are not well suited to adsorbing more water-soluble, ionized species from solution. In this work, we address SERS detection of ionic solutes by applying the principles of ion-interaction chromatography, where a charged surfactant is added to solution and adsorbs to an n-alkane-modified, SERS-active surface. The adsorbed charged surfactant serves to attract an ionic solute of opposite charge to the surface, where it can be detected. This concept was tested with a model anionic solute, 3-nitrobenzenesulfonate (NBS(-)), with a cationic surfactant, cetylpyridinium (CP(+)), that adsorbs to a 1-dodecanethiol (C12) modified silver surface. The interfacial populations of both the surfactant and anionic solute can be determined simultaneously from SERS spectra. The adsorption equilibrium of CP(+) to the C12 surface was fit to a Langmuir model, and the effect of supporting electrolyte on its adsorption equilibria was also investigated by SERS. The retention of NBS(-) at the C12 surface depends on the concentration of CP(+). The binding of NBS(-) to adsorbed CP(+) is described by an ion-interaction model that includes competition for the NBS(-) population due to association with surfactant ions in solution. While the strength of this binding interaction is not as great as the hydrophobic interactions that drive aromatic hydrocarbons to hydrophobic SERS surfaces, SERS detection of analyte ions by this approach could be accomplished at concentrations two orders of magnitude lower compared with Raman detection in free solution. PMID- 23816134 TI - Determination of the internal pressure of fluid inclusions by using Raman spectroscopy. AB - In situ Raman spectroscopic measurements of H2O-NaCl systems with three different salinities (0, 5.0, and 10.0 wt% NaCl) in the region of O-H stretching vibration were obtained at pressures up to 1800 MPa and temperatures from 298 to 453 K, with a hydrothermal diamond-anvil cell. The peak position was determined by fitting the obtained O-H stretching band with one Gaussian component. At a given temperature, the shift of the band decreased systematically with increasing pressure, and the data show a good linear relationship. For systems of different salinity, the slopes of the isotherms seem to be independent of temperature under the conditions investigated. With increasing salinity, the slope of the isotherm gradually increases. The relationships measured for the shift of the O-H stretching band with temperature, salinity, and pressure can be used to determine the internal pressure and isochore of fluid inclusions as well as the formation temperature and pressure of host minerals. PMID- 23816135 TI - Simvastatin increases ADAMTS13 expression in podocytes. AB - INTRODUCTION: ADAMTS13 is a specific von Willebrand factor-cleaving protease. Severe deficiency of ADAMTS13 is the main cause of thrombotic thrombocytopenic purpura. ADAMTS13 is mainly synthesized and released from hepatic stellate cells and endothelial cells, but is also expressed in other cells, including kidney podocytes. Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has a beneficial effect on atherosclerosis and also has anti inflammatory and antithrombotic properties. A recent study indicates that ADAMTS13 reduces inflammatory plaque formation during early atherosclerosis in mice. In our study, we investigated the effects of simvastatin on inflammatory cytokines-induced ADAMTS13 expression in podocytes. MATERIALS AND METHODS: A conditionally immortalized mouse podocyte cell line was utilized to study the expression of ADAMTS13 in podocytes. The influence of TNF-alpha, IL-4, IL-6 and simvastatin on ADAMTS13 was investigated. ADAMTS13 mRNA levels in podocytes were measured by using real-time PCR and protein levels were detected by Western blotting. RESULTS: Simvastatin significantly up-regulated the expression levels of ADAMTS13 mRNA and protein in podocytes. IL-6 decreased ADAMTS13 expression, and TNF-alpha had no significant effects on ADAMTS13 expression in podocytes. IL 4 reduced ADAMTS13 mRNA expression but not its protein level. Simvastatin was able also reversed the inhibitory effect of IL-6. CONCLUSIONS: We demonstrate that simvastatin increases the expression of ADAMTS13 in a dose-dependent manner in podocytes, which likely contributes to the antithrombotic property of statin. Different inflammatory cytokines have different effects on the levels of ADAMTS13 mRNA expression and protein within podocytes. PMID- 23816136 TI - miR-381, a novel intrinsic WEE1 inhibitor, sensitizes renal cancer cells to 5-FU by up-regulation of Cdc2 activities in 786-O. AB - BACKGROUND: Few researches on increase of chemotherapy sensitivity by microRNA (miRNA) were reported. We aim to investigate exact role of miR-381 in chemotherapy sensitivity of 5-fluorouracil (5-FU) in renal cancer cells. METHODS: We investigated the cell survival, cell-cycle and apoptosis of 786-O and HK-2 cells treated with miR-381 and 5-FU. IC50 of 5-FU was calculated. To study apoptosis and G2/M arrest, we determined pHH3, mitotic index and caspase-3/7 activity. RESULTS: We showed that miR-381 combined with 5-FU inhibited proliferation and potentiated the anti-tumour efficacies of 5-FU at tolerated concentration in vitro. miR-381 combined with 5-FU led to Cdc2 activation, mitotic catastrophe, and cell apoptosis through inhibitory WEE1. WEE1 was also validated as the direct target of miR-381. IC50 of 5-FU decreased significantly in the presence of miR-381. CONCLUSION: miR-381 increases sensitivity of 786-O cells to 5-FU by inhibitory WEE1 and increase of Cdc2 activity. PMID- 23816137 TI - Dependencies of microstructure and stress on the thickness of GdBa2Cu3O7 - delta thin films fabricated by RF sputtering. AB - GdBa2Cu3O7 - delta (GdBCO) films with different thicknesses from 200 to 2,100 nm are deposited on CeO2/yttria-stabilized zirconia (YSZ)/CeO2-buffered Ni-W substrates by radio-frequency magnetron sputtering. Both the X-ray diffraction and scanning electron microscopy analyses reveal that the a-axis grains appear at the upper layers of the films when the thickness reaches to 1,030 nm. The X-ray photoelectron spectroscopy measurement implies that the oxygen content is insufficient in upper layers beyond 1,030 nm for a thicker film. The Williamson Hall method is used to observe the variation of film stress with increasing thickness of our films. It is found that the highest residual stresses exist in the thinnest film, while the lowest residual stresses exist in the 1,030-nm-thick film. With further increasing film thickness, the film residual stresses increase again. However, the critical current (Ic) of the GdBCO film first shows a nearly linear increase and then shows a more slowly enhancing to a final stagnation as film thickness increases from 200 to 1,030 nm and then to 2,100 nm. It is concluded that the roughness and stress are not the main reasons which cause the slow or no increase in Ic. Also, the thickness dependency of GdBa2Cu3O7 - delta films on the Ic is attributed to three main factors: a-axis grains, gaps between a-axis grains, and oxygen deficiency for the upper layers of a thick film. PMID- 23816139 TI - Evaluation of CP Chromo Select Agar for the enumeration of Clostridium perfringens from water. AB - The European Directive on drinking water quality has included mCP agar as the reference method for recovering Clostridium perfringens from drinking waters. In the present study, three media (mCP, TSCF and CP Chromo Select Agar) were evaluated for recovery of C. perfringens in different surface water samples. Out of 139 water samples, using a membrane filtration technique, 131 samples (94.2%) were found to be presumptively positive for C. perfringens in at least one of the culture media. Green colored colonies on CP Chromo Select Agar (CCP agar) were counted as presumptive C. perfringens isolates. Out of 483 green colonies on CCP agar, 96.3% (465 strains, indole negative) were identified as C. perfringens, and 15 strains (3.1%) were indole positive and were identified as Clostridium sordellii, Clostridium bifermentans or Clostridium tetani. Only 3 strains (0.6%) gave false positive results and were identified as Clostridium fallax, Clostridium botulinum, and Clostridium tertium. Variance analysis of the data obtained shows statistically no significant differences in the counts obtained between media employed in this work. The mCP method is very onerous for routine screening and bacterial colonies could not be used for further biochemical testing. The colonies on CCP and TSCF were easy to count and subculture for confirmation tests. TSCF detects sulfite-reducing clostridia, including species other than C. perfringens, and in some cases excessive blackening of the agar frustrated counting of the colonies. If the contamination was too high, TSCF did not consistently produce black colonies and as a consequence, the colonies were white and gave false negative results. On the other hand, the identification of typical and atypical colonies isolated from all media demonstrated that CCP agar was the most useful medium for C. perfringens recovery in water samples. PMID- 23816138 TI - The evidence for the effectiveness of safety alerts in electronic patient medication record systems at the point of pharmacy order entry: a systematic review. AB - BACKGROUND: Electronic Patient Medication Record (ePMR) systems have important safety features embedded to alert users about potential clinical hazards and errors. To date, there is no synthesis of evidence about the effectiveness of these safety features and alerts at the point of pharmacy order entry. This review aims to systematically explore the literature and synthesise published evidence about the effectiveness of safety features and alerts in ePMR systems at the point of pharmacy order entry, in primary and secondary care. METHODS: We searched MEDLINE, EMBASE, Inspec, International Pharmaceutical Abstracts, PsycINFO, CINHAL (earliest entry to March 2012) and reference lists of articles. Two reviewers examined the titles and abstracts, and used a hierarchical template to identify comparative design studies evaluating the effectiveness of safety features and alerts at the point of pharmacy order entry. The two reviewers independently assessed the quality of the included studies using Cochrane Collaboration's risk of bias tool. RESULTS: Three randomised trials and two before-after studies met our criteria. Four studies involved integrated care facilities and one was hospital-based. The studies were all from the United States (US). The five studies demonstrated statistically significant reduction in medication errors in patients with renal insufficiency, pregnant women dispensed US Food Drug and Administration (FDA) risk category D (evidence of fetal risk but therapeutic benefits can outweigh the risk) or X (evidence suggests that risk to the fetus outweighs therapeutic benefits) medication, first dispensing of inappropriate medications in patients aged 65 and above, co-dispensing of interacting drugs, and adverse drug events related to hyperkalaemia. CONCLUSIONS: This systematic review shows that the safety features of ePMR systems are effective in alerting users about potential clinical hazards and errors during pharmacy order entry. There are however, problems such as false alerts and inconsistencies in alert management. More studies are needed from other countries and pharmacy practice settings to assess the effectiveness of electronic safety features and alerts in preventing error and reducing harm to patients. PMID- 23816140 TI - Mutually dependent degradation of Ama1p and Cdc20p terminates APC/C ubiquitin ligase activity at the completion of meiotic development in yeast. AB - BACKGROUND: The execution of meiotic nuclear divisions in S. cerevisiae is regulated by protein degradation mediated by the anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase. The correct timing of APC/C activity is essential for normal chromosome segregation. During meiosis, the APC/C is activated by the association of either Cdc20p or the meiosis-specific factor Ama1p. Both Ama1p and Cdc20p are targeted for degradation as cells exit meiosis II with Cdc20p being destroyed by APC/CAma1. In this study we investigated how Ama1p is down regulated at the completion of meiosis. FINDINGS: Here we show that Ama1p is a substrate of APC/CCdc20 but not APC/CCdh1 in meiotic cells. Cdc20p binds Ama1p in vivo and APC/CCdc20 ubiquitylates Ama1p in vitro. Ama1p ubiquitylation requires one of two degradation motifs, a D-box and a "KEN-box" like motif called GxEN. Finally, Ama1p degradation does not require its association with the APC/C via its conserved APC/C binding motifs (C-box and IR) and occurs simultaneously with APC/CAma1-mediated Cdc20p degradation. CONCLUSIONS: Unlike the cyclical nature of mitotic cell division, meiosis is a linear pathway leading to the production of quiescent spores. This raises the question of how the APC/C is reset prior to spore germination. This and a previous study revealed that Cdc20p and Ama1p direct each others degradation via APC/C-dependent degradation. These findings suggest a model that the APC/C is inactivated by mutual degradation of the activators. In addition, these results support a model in which Ama1p and Cdc20p relocate to the substrate address within the APC/C cavity prior to degradation. PMID- 23816141 TI - A cross-sectional study of the impact of blood selenium on blood and urinary arsenic concentrations in Bangladesh. AB - BACKGROUND: Arsenic can naturally occur in the groundwater without an anthropogenic source of contamination. In Bangladesh over 50 million people are exposed to naturally occurring arsenic concentrations exceeding the World Health Organization's guideline of 10 MUg/L. Selenium and arsenic have been shown to facilitate the excretion of each other in bile. Recent evidence suggests that selenium may play a role in arsenic elimination by forming a selenium-arsenic conjugate in the liver before excretion into the bile. METHODS: A cross-sectional study of 1601 adults and 287 children was conducted to assess the relationship between blood selenium and urinary and blood arsenic in a study population residing in a moderately arsenic-contaminated rural area in Bangladesh. RESULTS: The results of this study indicate a statistically significant inverse relationship between blood selenium and urinary arsenic concentrations in both adult and pediatric populations in rural Bangladesh after adjustment for age, sex, Body Mass Index, plasma folate and B12 (in children), and ever smoking and current betel nut use (in adults). In addition, there appears to be a statistically significant inverse relationship between blood selenium and blood arsenic in children. CONCLUSIONS: Our results suggest that selenium is inversely associated with biomarkers of arsenic burden in both adults and children. These findings support the hypothesis that Se facilitates the biliary elimination of As, possibly via the putative formation of a Se-As conjugate using a glutathione complex. However, laboratory based studies are needed to provide further evidence to elucidate the presence of Se-As conjugate and its role in arsenic elimination in humans. PMID- 23816142 TI - Does high biodiversity reduce the risk of Lyme disease invasion? AB - BACKGROUND: It has been suggested that increasing biodiversity, specifically host diversity, reduces pathogen and parasite transmission amongst wildlife (causing a "dilution effect"), whereby transmission amongst efficient reservoir hosts, (e.g. Peromyscus spp. mice for the agent of Lyme disease Borrelia burgdorferi) is reduced by the presence of other less efficient host species. If so, then increasing biodiversity should inhibit pathogen and parasite invasion. METHODS: We investigated this hypothesis by studying invasion of B. burgdorferi and its tick vector Ixodes scapularis in 71 field sites in southeastern Canada. Indices of trapped rodent host diversity, and of biodiversity of the wider community, were investigated as variables explaining the numbers of I. scapularis collected and B. burgdorferi infection in these ticks. A wide range of alternative environmental explanatory variables were also considered. RESULTS: The observation of low I. scapularis abundance and low B. burgdorferi infection prevalence in sites where I. scapularis were detected was consistent with early stage invasion of the vector. There were significant associations between the abundance of ticks and season, year of study and ambient temperature. Abundance of host-seeking larvae was significantly associated with deer density, and abundance of host-seeking larvae and nymphs were positively associated with litter layer depth. Larval host infestations were lower where the relative proportion of non-Peromyscus spp. was high. Infestations of hosts with nymphs were lower when host species richness was higher, but overall nymphal abundance increased with species richness because Peromyscus spp. mouse abundance and host species richness were positively correlated. Nymphal infestations of hosts were lower where tree species richness was higher. B. burgdorferi infection prevalence in ticks varied significantly with an index of rates of migratory bird-borne vector and pathogen invasion. CONCLUSIONS: I. scapularis abundance and B. burgdorferi prevalence varied with explanatory variables in patterns consistent with the known biology of these species in general, and in the study region in particular. The evidence for a negative effect of host biodiversity on I. scapularis invasion was mixed. However, some evidence suggests that community biodiversity beyond just host diversity may have direct or indirect inhibitory effects on parasite invasion that warrant further study. PMID- 23816144 TI - Change in condylar position in posterior bending osteotomy minimizing condylar torque in BSSRO for facial asymmetry. AB - During the correction of an asymmetric mandible with sagittal split ramus osteotomy (SSRO), bony interference between the proximal and distal segments inevitably occurs. This results in positional change of the condyle. In order to avoid this, a posterior bending osteotomy (PBO) has been introduced. This is an additional vertical osteotomy posterior to the second molar after SSRO. To investigate the change in condylar position after SSRO with PBO, 22 patients with facial asymmetry were enrolled and divided into two groups based on the surgical method used to remove the bony interference after SSRO: PBO (n = 13) and the grinding method (n = 9). Each group was subdivided into large and small bony interference groups by estimating the volume of bony interference with simulation surgery. Condylar displacement was evaluated by three-dimensional superimposition and the amount of condylar displacement was calculated. The positional changes of the condyles were variable in each patient. When comparing patients with large bony interference in the PBO and grinding groups, the condyles were significantly inwardly rotated in the grinding group (p < 0.05). The grinding method can be used to remove small bony interferences with tolerable condylar torque. However, PBO would be beneficial in correcting large bony interferences while minimizing condylar torque. PMID- 23816147 TI - [A case of neuroborelliosis complicated by acute adrenal insufficiency]. PMID- 23816148 TI - Variants at the 9p21 locus and melanoma risk. AB - BACKGROUND: The influence of variants at the 9p21 locus on melanoma risk has been reported through investigation of CDKN2A variants through candidate gene approach as well as by genome wide association studies (GWAS). METHODS: In the present study we genotyped, 25 SNPs that tag 273 variants on chromosome 9p21 in 837 melanoma cases and 1154 controls from Spain. Ten SNPs were selected based on previous associations, reported in GWAS, with either melanocytic nevi or melanoma risk or both. The other 15 SNPs were selected to fine map the CDKN2A gene region. RESULTS: All the 10 variants selected from the GWAS showed statistically significant association with melanoma risk. Statistically significant association with melanoma risk was also observed for the carriers of the variant T-allele of rs3088440 (540 C>T) at the 3' UTR of CDKN2A gene with an OR 1.52 (95% CI 1.14 2.04). Interaction analysis between risk associated polymorphisms and previously genotyped MC1R variants, in the present study, did not show any statistically significant association. Statistical significant association was observed for the interaction between phototypes and the rs10811629 (located in intron 5 of MTAP). The strongest association was observed between the homozygous carrier of the A allele and phototype II with an OR of 15.93 (95% CI 5.34-47.54). CONCLUSIONS: Our data confirmed the association of different variants at chromosome 9p21 with melanoma risk and we also found an association of a variant with skin phototypes. PMID- 23816150 TI - Pap, mammography, and clinical breast examination screening among women with disabilities: a systematic review. AB - BACKGROUND: Research has found some disparities between U.S. women with and without disabilities in receiving clinical preventive services. Substantial differences may also exist within the population of women with disabilities. The current study examined published research on Pap smears, mammography, and clinical breast examinations across disability severity levels among women with disabilities. METHODS: Informed by an expert panel, we followed guidelines for systematic literature reviews and searched MEDLINE, PsycINFO, and Cinahl databases. We also reviewed in-depth four disability- or preventive service relevant journals. Two reviewers independently extracted data from all selected articles. FINDINGS: Five of 74 reviewed publications of met all our inclusion criteria and all five reported data on Pap smears, mammography, and clinical breast examination. Articles classified disability severity groups by functional and/or activity levels. Associations between disability severity and Pap smear use were inconsistent across the publications. Mammography screening fell as disability level increased according to three of the five studies. Results demonstrated modestly lower screening, but also were inconsistent for clinical breast examinations across studies. CONCLUSION: Evidence is inconsistent concerning disparities in these important cancer screening services with increasing disability levels. Published studies used differing methods and definitions, adding to concerns about the evidence for screening disparities rising along with increasing disability. More focused research is required to determine whether significant disparities exist in cancer screening among women with differing disability levels. This information is essential for national and local public health and health care organizations to target interventions to improve care for women with disabilities. PMID- 23816146 TI - Encephalitis due to Mycobacterium tuberculosis in France. AB - PURPOSE: Two hundred and fifty-three patients were included in a study on the etiology of encephalitis, carried out in France in 2007. Tuberculosis was the second most frequently identified cause, after HSV and with the same number of cases as VZV. The authors report the specific features of patients presenting with tuberculosis encephalitis (TE). METHODS: TE patients were defined as patients presenting with encephalitis, with positive culture or PCR for Mycobacterium tuberculosis, or the association of clinical, biological, imaging, and epidemiological evidence (possible cases). Clinical, microbiological, and brain imaging data was analyzed and compared to that of other included patients. RESULTS: Twenty cases of TE were identified. The M/F sex-ratio was 1.5, the mean age 53 years. Four (20%) patients had a history of tuberculosis before the encephalitis. The median delay between the onset of general and neurological symptoms was significantly longer for tuberculosis cases than for others (10 days vs. 2; P<10(-10)). The median CSF protein level was significantly higher for tuberculosis cases (2.1 g/L vs. 0.8 g/L, P=0.002). CT scan and MRI were normal on admission for eight patients out of 17. Fourteen isolated strains of M. tuberculosis were susceptible to first-line anti-tuberculosis drugs and one was rifampicin-resistant. Six (33%) patients died during hospitalization and two were lost to follow-up. Ten out of 12 (78.6%) had persisting neurological symptoms on discharge. DISCUSSION: Despite non-multiresistant MT strains, the case fatality rate among TE patients was high in our series. Early brain imaging is poor contributive for the diagnosis of TE. PMID- 23816151 TI - Combat deployment is associated with sexual harassment or sexual assault in a large, female military cohort. AB - BACKGROUND: Previous studies have examined the prevalence, risk factors, and health correlates of sexual stressors in the military, but have been limited to specific subpopulations. Furthermore, little is known about sexual stressors' occurrence and their correlates in relation to female troops deployed to the current operations in Iraq and Afghanistan. METHODS: Using longitudinal data from Millennium Cohort participants, the associations of recent deployment as well as other individual and environmental factors with sexual harassment and sexual assault were assessed among U.S. female military personnel. Multivariable analyses were used to investigate the associations. FINDINGS: Of 13,262 eligible participants, 1,362 (10.3%) reported at least one sexual stressor at follow-up. Women who deployed and reported combat experiences were significantly more likely to report sexual harassment (odds ratio [OR], 2.20; 95% confidence interval [CI], 1.84-2.64) or both sexual harassment and sexual assault (OR, 2.47; 95% CI, 1.61 3.78) compared with nondeployers. In addition, significant risk factors for sexual stressors included younger age, recent separation or divorce, service in the Marine Corps, positive screen for a baseline mental health condition, moderate/severe life stress, and prior sexual stressor experiences. CONCLUSIONS: Although deployment itself was not associated with sexual stressors, women who both deployed and reported combat were at a significantly increased odds for sexual stressors than other female service members who did not deploy. Understanding the factors associated with sexual stressors can inform future policy and prevention efforts to eliminate sexual stressors. PMID- 23816152 TI - Caregiving experiences and health conditions of women veteran and non-veteran caregivers. AB - BACKGROUND: Unique experiences, for example, trauma, of women veteran caregivers may create differences in the caregiving experience and may be associated with health concerns. We examined caregiving factors and health concerns in women veteran caregivers compared to non-veteran women (civilian) caregivers, and identified variables associated with being a woman veteran caregiver. METHODS: We conducted secondary data analyses using data from a multistate survey to examine sociodemographics, the caregiver experience (relationship to recipient, duration as caregiver, hours of care provided, area help is needed, and greatest difficulty faced as a caregiver); emotional support; life satisfaction; lifestyle behaviors; general, physical, and mental health; and chronic conditions in women informal caregivers. FINDINGS: Of women caregivers, more veteran caregivers provided activities of daily living (ADL) help (33%) than non-veteran caregivers (21%; p = .02). There were no differences in years as a caregiver, hours of care provided, or the relationship to the recipient. Poor sleep and poor mental health were experienced by more women veteran caregivers (vs. non-veteran), but physical health, general health, and chronic condition prevalence did not differ. Women veteran caregivers had twofold greater odds of being Black, never married, college educated, and providing ADL assistance. Odds of obesity were lower for women veteran caregivers relative to other women caregivers. CONCLUSIONS: Women veteran caregivers experience health concerns, including sleeplessness, poor mental health, and some chronic conditions. Our cohort were young women, yet had concerns that may be exacerbated by being a veteran and assuming a caregiver role. Comprehensive services to support their needs as veteran patients and as caregivers are needed. PMID- 23816153 TI - Association of prenatal physical activity and gestational weight gain: results from the first baby study. AB - BACKGROUND: In response to increasing rates of excessive gestational weight gain (GWG) and evidence of postpartum weight retention and long-term overweight and obesity, the Institute of Medicine (IOM) revised their guidelines for GWG in 2009. Prenatal physical activity is recommended, although its role in preventing excessive GWG is unclear. We sought to understand the association between prenatal physical activity and GWG in a longitudinal cohort. METHODS: During a baseline survey at 34 weeks, women (n = 3,006) reported their height, prepregnancy weight, and physical activity during pregnancy. GWG was self reported at 1-month postpartum. Multivariable logistic regression adjusting for age, race/ethnicity, education, poverty status, marital status, gestational age at the time of delivery, and smoking was used to model the association between adequate physical activity during pregnancy and exceeding the IOM recommendations for GWG. FINDINGS: Overweight women were most likely to exceed the IOM recommendations for GWG (78.7%), followed by obese women and normal weight women (65.0% and 42.4%, respectively). The majority of women participated in some physical activity during pregnancy, with 41.2% engaging in 60 to 149 minutes and 32.1% engaging in at least 150 minutes of physical activity per week. In adjusted analysis, meeting the physical activity guidelines was associated with a 29% (confidence interval, 0.57-0.88) lower odds of exceeding the IOM recommendations for GWG compared with inactive women. CONCLUSIONS: Findings of high rates of excessive GWG, especially among women with overweight and obesity, are concerning given the associated health burdens. The association of guideline-concordant physical activity with appropriate GWG suggests this is an important target for future interventions. PMID- 23816154 TI - Connecting knowledge about abortion and sexual and reproductive health to belief about abortion restrictions: findings from an online survey. AB - BACKGROUND: The objective of this research was to examine individuals' knowledge about abortion in the context of their knowledge about other sexual and reproductive health (SRH) issues, including contraception, abortion, pregnancy, and birth. METHODS: During August 2012, we administered an online questionnaire to a randomly selected sample of 639 men and women of reproductive age (18-44 years) in the United States. FINDINGS: Respondents reported the highest levels of perceived knowledge about SRH in general (81%), followed by pregnancy and birth (53%), contraception (48%), and abortion (35%); knowledge of specific items within each of these areas paralleled this pattern. Respondents who believe that abortion should be allowed in at least some circumstances were more likely to be correct regarding the safety and consequences of contraception and abortion. Characteristics associated with higher levels of knowledge regarding abortion related issues included having higher levels of knowledge about non-abortion related SRH issues and having less restrictive abortion beliefs. CONCLUSIONS: Women and men are not well-informed about the relative safety and consequences of SRH-related experiences. Many overestimate their knowledge, and personal beliefs about abortion restrictions may influence their knowledge about the safety and consequences of abortion and contraception. Providers of SRH services should provide comprehensive evidence-based information about the risks and consequences of SRH matters during consultations, particularly in the case of abortion providers serving women who hold more restrictive abortion beliefs. PMID- 23816155 TI - Predictors of abortion counseling receipt and helpfulness in the United States. AB - BACKGROUND: Little is known about women's expectations, needs, and experiences with abortion counseling and the factors that influence their experiences. METHODS: This study sought to investigate individual- and facility-level factors that influenced women's reports of receiving abortion counseling and the helpfulness of counseling. Data were drawn from quantitative interviews with 718 patients recruited from 30 abortion facilities, and 27 interviews with facility informants in the United States. FINDINGS: Sixty-eight percent of participants reported receiving counseling; reports varied by facility. Almost all participants who reported receiving counseling described counseling as helpful: 40% extremely, 28% quite, 17% moderately, 10% a little, and 4% not at all. Nearly all (99%) reported that their counselor communicated support for whatever decision they made. No individual-level factors predicted counseling receipt or helpfulness. Facility informant reports that it is their role to counsel patients about emotional issues was positively associated with women's reports of counseling receipt (p < .001). Women at facilities subject to laws requiring provision of specific information and/or state-approved, written materials had lesser odds of finding counseling helpful, compared with women at facilities not subject to such laws (p < .01). CONCLUSIONS: Legal mandates that regulate abortion counseling do not seem to be helpful to women. More research is needed to understand the effects of abortion counseling and whether policies regulating counseling have a deleterious effect on women. PMID- 23816156 TI - Knowledge and attitudes about long-acting reversible contraception among Latina women who desire sterilization. AB - BACKGROUND: There is growing interest in increasing the use of long-acting reversible contraception (LARC), and suggestions that such methods may serve as an alternative to sterilization. However, there is little information about whether women who do not want more children would be interested in using LARC. METHODS: We conducted semistructured interviews with 120 parous Latina women in El Paso, Texas, who wanted a sterilization but had not obtained one. We assessed women's awareness of and interest in using the copper intrauterine device (IUD), levonorgestrel intrauterine system (LNG-IUS), and etonogestrel implant. FINDINGS: Overall, 51%, 23%, and 47% of women reported they had heard of the copper IUD, LNG-IUS, and implant, respectively. More women stated they would use the copper IUD (24%) than the LNG-IUS (14%) or implant (9%). Among women interested in LARC, the most common reasons were that, relative to their current method, LARC methods were more convenient, effective, and provided longer-term protection against pregnancy. Those who had reservations about LARC were primarily concerned with menstrual changes. Women also had concerns about side effects and the methods' effectiveness in preventing pregnancy, preferring to use a familiar method. CONCLUSIONS: Although these findings indicate many Latina women in this setting do not consider LARC an alternative to sterilization, they point to an existing demand among some who wish to end childbearing. Efforts are needed to improve women's knowledge and access to a range of methods so they can achieve their childbearing goals. PMID- 23816157 TI - Cost-savings from the provision of specific contraceptive methods in 2009. AB - BACKGROUND: Previous studies have shown that contraceptive provision generates significant public sector cost-savings by preventing health care and social service expenditures on unintended pregnancies. Over the past decade, women's contraceptive options have expanded considerably, calling for the need to better understand the relative cost-benefit of new contraceptive methods. METHODS: We estimated the number of pregnancies averted by each specific contraceptive method by subtracting the total number of pregnancies expected under Family PACT from the total number of pregnancies that would be expected if the program were not available. The cost of providing each method was compared with the savings in reduced public expenditures from averted pregnancies. A resultant cost-benefit ratio was calculated for 11 specific contraceptive methods provided to women under Family PACT. RESULTS: Every contraceptive method studied saved more in public expenditures for unintended pregnancy than it costs to provide. Over half (51%) of the pregnancies averted in 2009 were attributable to the most commonly used method, oral contraceptives. Injectable methods accounted for 13% of averted pregnancies, followed by intrauterine contraceptives (12%), and barrier methods (9%). Intrauterine contraception and contraceptive implants had the highest cost savings with approximately $5.00 of savings for every dollar spent for users of these methods. CONCLUSIONS: Because no single method is recommended clinically for every woman, it is medically and fiscally advisable to offer women all contraceptive methods to enable them to choose methods that best meet their needs, increasing the likelihood of compliance with the method chosen and prevention of unintended pregnancies. PMID- 23816158 TI - Carbonic anhydrase IX: a promising diagnostic and prognostic biomarker in breast carcinoma. AB - We examined the expression of carbonic anhydrase IX (CA IX) by immunohistochemical staining using monoclonal antibody M75 (Institute of Virology, Slovak Academy of Sciences, Bratislava) in a group of 38 fibroadenomas and 55 carcinomas of the breast. In each case, the intensity of staining, percentage of labeled cells and subcellular localization of CA IX were assessed. CA IX was detected in 11/38 fibroadenomas (28.9%). Weak cytoplasmic positivity was dominant in these positive cases. Immunohistochemical analysis of 55 carcinomas showed CA IX expression in 34 cases (61.8%). Membrane staining alone was observed in 27/55 carcinomas (49.1%), while cytoplasmic positivity was found in 4/55 cases (7.3%). Combined membrane and cytoplasmic immunostaining of CA IX was detected in 3/55 carcinomas (5.4%). The intensity of immunoreactivity varied from weak to strong. Under 50% of reactive cells were found in 9/38 fibroadenomas (23.6%) and in 29/55 carcinomas (52.7%). More than 50% of reactive cells were found in 2/38 fibroadenomas (5.3%) and in 5/55 carcinomas (9.1%). Statistical analysis confirmed significant differences in the subcellular localization, intensity of immunoreactivity and percentage of labeled cells in fibroadenomas and carcinomas (p<0.05). Our results confirmed the hypothesis that expression of CA IX may represent a valuable tumor biomarker as well as a promising diagnostic and prognostic parameter in breast cancer. PMID- 23816159 TI - Wavelet analysis of circadian and ultradian behavioral rhythms. AB - : We review time-frequency methods that can be useful in quantifying circadian and ultradian patterns in behavioral records. These records typically exhibit details that may not be captured through commonly used measures such as activity onset and so may require alternative approaches. For instance, activity may involve multiple bouts that vary in duration and magnitude within a day, or may exhibit day-to-day changes in period and in ultradian activity patterns. The discrete Fourier transform and other types of periodograms can estimate the period of a circadian rhythm, but we show that they can fail to correctly assess ultradian periods. In addition, such methods cannot detect changes in the period over time. Time-frequency methods that can localize frequency estimates in time are more appropriate for analysis of ultradian periods and of fluctuations in the period. The continuous wavelet transform offers a method for determining instantaneous frequency with good resolution in both time and frequency, capable of detecting changes in circadian period over the course of several days and in ultradian period within a given day. The discrete wavelet transform decomposes a time series into components associated with distinct frequency bands, thereby facilitating the removal of noise and trend or the isolation of a particular frequency band of interest. To demonstrate the wavelet-based analysis, we apply the transforms to a numerically-generated example and also to a variety of hamster behavioral records. When used appropriately, wavelet transforms can reveal patterns that are not easily extracted using other methods of analysis in common use, but they must be applied and interpreted with care. PMID- 23816160 TI - Breast size, thoracic kyphosis & thoracic spine pain - association & relevance of bra fitting in post-menopausal women: a correlational study. AB - BACKGROUND: Menopause would seem to exist as a period of accelerated changes for women and their upper torso mechanics. Whether these anthropometric changes reflect changes in pain states remains unclear. Plausible mechanisms of pain exist for the independent and combined effect of increasing breast size and thoracic kyphosis. Bra fit has the potential to change when the anthropometric measures (chest circumference and bust circumference) used to determine bra size change, such as postmenopausally.Identifying an association between breast size, thoracic kyphosis and thoracic spine pain in postmenopausal women and identifying the relevance of bra fit to this association may be of importance to the future management and education of post-menopausal women presenting clinically with thoracic spine pain. METHODS: A cross-sectional study design. Fifty-one postmenopausal bra-wearing women were recruited. Measures included breast size (Triumph International), thoracic kyphosis (flexible curve), bra fitted (Y/N) and pain (Short Form McGill Pain Questionnaire) and tenderness on palpation (posteroanterior pressure testing). These measures were collected in one session at a physiotherapy clinic. RESULTS: The majority of the women in this study were overweight or obese and wearing an incorrect sized bra. Pain was significantly related to breast size, body weight and BMI at mid thoracic levels (T7-8). In contrast self-reported thoracic pain was not correlated with age or index of kyphosis (thoracic kyphosis). Women with thoracic pain were no more likely to have their bra professionally fitted whereas women with a higher BMI and larger breasts were more likely to have their bra professionally fitted. CONCLUSION: The findings of this study show that larger breasts and increased BMI are associated with thoracic pain in postmenopausal women. This is unrelated to thoracic kyphosis. Increasing breast size and how a bra is worn may have biomechanical implications for the loaded thoracic spine and surrounding musculature. Post menopause women present with a spectrum of anthropometrical changes that have the potential to contribute to altered biomechanics and affect pain states in the thoracic spine. PMID- 23816161 TI - Development of ClickClinica: a novel smartphone application to generate real-time global disease surveillance and clinical practice data. AB - BACKGROUND: Identification and tracking of important communicable diseases is pivotal to our understanding of the geographical distribution of disease, the emergence and spread of novel and resistant infections, and are of particular importance for public health policy planning. Moreover, understanding of current clinical practice norms is essential to audit clinical care, identify areas of concern, and develop interventions to improve care quality.However, there are several barriers to obtaining these research data. For example current disease surveillance mechanisms make it difficult for the busy doctor to know which diseases to notify, to whom and how, and are also time consuming. Consequently, many cases go un-notified. In addition assessments of current clinical practice are typically limited to small retrospective audits in individual hospitals.Therefore, we developed a free smartphone application to try to increase the identification of major infectious diseases and other acute medical presentations and improve our understanding of clinical practice. DESCRIPTION: Within the first month there were over 1000 downloads and over 600 specific disease notifications, coming from a broad range of specialities, grades and from all across the globe, including some resource poor settings.Notifications have already provided important information, such as new cases of TB meningitis, resistant HIV and rabies, and important clinical information, such as where patient with myocardial infarctions are and are not receiving potentially life saving therapy.The database generated can also answer new, dynamic and targeted questions. When a new guideline is released, for example for a new pandemic infection, we can track, in real-time, the global usage of the guideline and whether the recommendations are being followed. In addition this allows identification of where cases with key markers of severe disease are occurring. This is a potential resource for guideline-producing bodies, clinical governance and public health institutions and also for patient recruitment into ongoing studies. CONCLUSIONS: Further parallel studies are needed to assess the clinical and epidemiological utility of novel disease surveillance applications, such as this, with direct comparisons made to data collected through routine surveillance routes.Nevertheless, current disease surveillance mechanisms do not always comprehensively and accurately reflect disease distribution for many conditions. Smartphone applications, such as ClickClinica, are a novel approach with the potential to generate real-time disease surveillance data that may augment current methods. PMID- 23816162 TI - Factors associated with disordered gambling in Finland. AB - BACKGROUND: The purpose of this study was to compare the socio-demographic characteristics of non-problem gamblers, problem gamblers and pathological gamblers, to investigate the association between gambling related factors and perceived health and well-being among the three subgroups of gamblers, and to analyse simultaneously socio-demographic characteristics, gambling related factors and perceived health and well-being and the severity of disordered gambling (problem gamblers and pathological gamblers). METHODS: The data were collected through a nationwide telephone survey in 2011. Participants were selected through a random population sample of 15-74-year-old Finns. From that sample, persons with any past-year gambling involvement (N = 3451) were selected for a subsample for the descriptive and inferential analysis in the present paper. Gambling was assessed using the South Oaks Gambling Screen. Statistical significance was determined by chi-squared tests. The odds ratio and effect size were computed by using multivariate-adjusted multinomial logistic regression analysis. RESULTS: The most significant socio-demographic characteristics (male gender, young age, education <= 12 years), gambling related factors (slot machine gambling, internet gambling) and perceived health and well-being (feeling lonely, smoking daily, risky alcohol consumption, mental health problems) explained 22.9 per cent of the variation in the severity of disordered gambling. CONCLUSION: Male gender and loneliness were found to be associated with problem gambling in particular, along with smoking and risky alcohol consumption. Mental health problems and risky alcohol consumption were associated with pathological gambling. These identified associations between disordered gambling, mental health problems and risky alcohol consumption should be taken into consideration when implementing screenings of disordered gambling. PMID- 23816163 TI - How lenalidomide is changing the treatment of patients with multiple myeloma. AB - Lenalidomide is a distinct second-generation immunomodulatory drug with multiple anticancer and immunomodulatory effects against hematologic malignancies, in particular multiple myeloma (MM). Dexamethasone synergistically enhances the anticancer effects of lenalidomide, and the combination of lenalidomide and dexamethasone (Len/Dex) is approved for the treatment of patients with relapsed and/or refractory MM. Results from pivotal phase III trials in this setting have demonstrated that Len/Dex extends overall survival compared with dexamethasone alone. Optimal clinical benefits are seen when Len/Dex is initiated at first relapse and continued, beyond best treatment response, until disease progression. Lenalidomide based regimens are also effective as induction therapy in patients with newly diagnosed MM. Importantly, lenalidomide has a predictable and manageable tolerability profile, with minimal neurotoxicity, allowing long-term administration. As the paradigm of myeloma disease continues to change, future studies will determine the efficacy of lenalidomide in novel combinations with potentially complimentary agents. PMID- 23816164 TI - Update on ultrasound elastography: miscellanea. Prostate, testicle, musculo skeletal. AB - Nowadays ultrasound elastosonography is an established technique, although with limited clinical application, used to assess tissue stiffness, which is a parameter that in most cases is associated with malignancy. However, although a consistent number of articles have been published about several applications of elastosonography, its use in certain human body districts is still not well defined. In this paper we write on the use of elastosonography in prostate, testicle and musculo-skeletal apparatus. We report and compare the work of several authors, different type of elastosonography (shear wave, strain elastography, etc.) and instrumental data obtained in the study of both benign and malignant lesions. PMID- 23816165 TI - Reliability and validity of the Sheehan Disability Scale modified for pathological gambling. AB - BACKGROUND: An interview format version of the Sheehan Disability Scale (SDS) modified to assess gambling treatment outcomes was assessed for reliability and validity. The SDS assesses impairment in work, family and social functioning related to mental disorders. METHODS: A pilot study (N = 21) determined the preferred wording for oral administration. Participants with pathological gambling in a relapse prevention clinical trial completed the scale and other validation measures at baseline, six and twelve month follow-ups (N = 169). RESULTS: Confirmatory factor analysis supported a one factor solution and the scale had good internal reliability for a three item scale. The SDS was sensitive to change and correlations with recent gambling behaviour and severity were moderate as expected. Similarly, correlations with self-efficacy, perceived control over gambling, and craving were moderate, but they were lower for less directly related constructs such as depression and perceived family and friend support. CONCLUSIONS: The SDS is a brief, psychometrically sound, outcome measure of impairment associated with gambling disorders that can be administered by telephone. PMID- 23816167 TI - Physician-based emergency medical service deployment characteristics in severe traumatic brain injury: a Dutch multicenter study. AB - INTRODUCTION: Prehospital guidelines advise advanced life support in all patients with severe traumatic brain injury (TBI). In the Netherlands, it is recommended that prehospital advanced life support is particularly provided by a physician based helicopter emergency medical service (P-HEMS) in addition to paramedic care (EMS). Previous studies have however shown that a substantial part of severe TBI patients is exclusively treated by an EMS team. In order to better understand this phenomenon, we evaluated P-HEMS deployment characteristics in severe TBI in a multicenter setting. METHODS: The database included patient demographics, prehospital and injury severity parameters and determinants of EMS or EMS/P-HEMS dispatch in 334 patients with severe TBI admitted to level 1 trauma centres in the Netherlands. RESULTS: P-HEMS was deployed in 62% of patients with severe TBI. Patients treated by the P-HEMS had a higher injury severity score (29 (20-38)) vs. (25 (16-30); P<0.001), more frequently required blood product transfusions (41% vs. 29%; P=0.03) and recurrently suffered from TBI with extracranial injuries (33% vs. 6%; P<0.001) than patients solely treated by an EMS. The prehospital endotracheal intubation rate was higher in the P-HEMS group in isolated TBI (93% vs. 19%; P<0.001) or TBI with extracranial injuries (96% vs. 43%; P<0.001) compared to the EMS group. In the EMS group, more patients were secondary referred to a level 1 trauma centre (32% vs. 4%; P<0.001 vs. P-HEMS). Despite higher injury severity levels in P-HEMS patients, 6-month mortality rates were similar among groups, irrespective of the presence of extracranial injuries in addition to TBI. Deployment of P-HEMS estimated 52% and 72% (P<0.001) in urban and rural regions, respectively, with comparable endotracheal intubation rates among regions. CONCLUSIONS: This study shows that a physician-based HEMS was more frequently deployed in patients with severe TBI in the presence of extracranial injuries, and in rural trauma regions. Treatment of severe TBI patients by a paramedic EMS only was associated with a higher incidence of secondary referrals to a level I trauma centre. Our data support adjustment of local prehospital guidelines for patients with severe TBI to the geographical context. PMID- 23816168 TI - Thromboprophylaxis in patients with pelvic and acetabular fractures: A short review and recommendations. AB - The management of thromboprophylaxis in patients with pelvic and acetabular fractures remains a highly controversial topic within the trauma community. Despite anticoagulation, venous thromboembolism (VTE) remains the most common cause of surgical morbidity and mortality in this high-risk patient group. Although various thromboprophylactic regimes are employed, evidence relating to the most effective method remains unclear. Controversies surrounding screening, the use of prophylactic inferior vena cava filters (IVCF) and chemothromboprophylaxis in polytraumatised patients, particularly those with pelvic and acetabular fractures, form the basis of considerable debate. With the absence of a well-designed clinical trial and the presence of ongoing controversies within the literature, this review will explore current treatment options available to trauma surgeons and highlight differing scientific opinions, providing an update on the role of screening and current available preventative measures. We cover existing as well as recent advances in chemical thromboprophylactic agents and discuss external mechanical compression devices, the usefulness of serial duplex ultrasonography and the role of extended chemothromboprophylaxis on discharge. The evidence behind prophylactic IVCF is also considered, along with reported complication profiles. We conclude with a proposed protocol for use in major trauma centres, which can form the basis of local policy for the prevention of VTE in trauma patients with pelvic and acetabular fractures. PMID- 23816169 TI - Standalone functional CAD system for multi-object case analysis in hepatic disorders. AB - A new algorithm able to automatically diagnose the presence of the hemangioma areas in the hepatic ultrasonographic image is proposed. The algorithm uses a new multi-object approach which decomposes the image into three biological regions: a normal hepatic area, a hemangioma area and other areas. The de-noising process is efficiently accomplished for both Gaussian and Rayleigh noise distributions. Furthermore, a segmentation technique, based on gray level intensity analysis and the Moore-Neighbor contour tracing algorithm for a robust differentiation of the hemangioma area are employed. This new proposed technique is almost fully automatic, fast, and simple and its results are satisfactory. PMID- 23816170 TI - Using experts feedback in clinical case resolution and arbitration as accuracy diagnosis methodology. AB - This paper proposes a new methodology for assessing the efficiency of medical diagnostic systems and clinical decision support systems by using the feedback/opinions of medical experts. The methodology behind this work is based on a comparison between the expert feedback that has helped solve different clinical cases and the expert system that has evaluated these same cases. Once the results are returned, an arbitration process is carried out in order to ensure the correctness of the results provided by both methods. Once this process has been completed, the results are analyzed using Precision, Recall, Accuracy, Specificity and Matthews Correlation Coefficient (MCC) (PRAS-M) metrics. When the methodology is applied, the results obtained from a real diagnostic system allow researchers to establish the accuracy of the system based on objective facts. The methodology returns enough information to analyze the system's behavior for each disease in the knowledge base or across the entire knowledge base. It also returns data on the efficiency of the different assessors involved in the evaluation process, analyzing their behavior in the diagnostic process. The proposed work facilitates the evaluation of medical diagnostic systems, having a reliable process based on objective facts. The methodology presented in this research makes it possible to identify the main characteristics that define a medical diagnostic system and their values, allowing for system improvement. A good example of the results provided by the application of the methodology is shown in this paper. A diagnosis system was evaluated by means of this methodology, yielding positive results (statistically significant) when comparing the system with the assessors that participated in the evaluation process of the system through metrics such as recall (+27.54%) and MCC (+32.19%). These results demonstrate the real applicability of the methodology used. PMID- 23816172 TI - An efficient and secure medical image protection scheme based on chaotic maps. AB - Recently, the increasing demand for telemedicine services has raised interest in the use of medical image protection technology. Conventional block ciphers are poorly suited to image protection due to the size of image data and increasing demand for real-time teleradiology and other online telehealth applications. To meet this challenge, this paper presents a novel chaos-based medical image encryption scheme. To address the efficiency problem encountered by many existing permutation-substitution type image ciphers, the proposed scheme introduces a substitution mechanism in the permutation process through a bit-level shuffling algorithm. As the pixel value mixing effect is contributed by both the improved permutation process and the original substitution process, the same level of security can be achieved in a fewer number of overall rounds. The results indicate that the proposed approach provides an efficient method for real-time secure medical image transmission over public networks. PMID- 23816171 TI - Detection of masses based on asymmetric regions of digital bilateral mammograms using spatial description with variogram and cross-variogram functions. AB - A mammogram is an examination of the breast intended to prevent and diagnose breast cancer. In this work we propose a methodology for detecting masses by determining certain asymmetric regions between pairs of mammograms of the left and the right breast. The asymmetric regions are detected by means of structural variations between corresponding regions, defined by a spatial descriptor called cross-variogram function. After determining the asymmetric regions of a pair of images, the variogram function is applied to each asymmetric region separately, for classification as either mass or non-mass. The first stage of the methodology consists in preprocessing the images to make them adequate for registration. The following step performs the bilateral registration of pairs of left and right breasts. Pairs of corresponding regions are listed and their variations are measured by means of the cross-variogram spatial descriptor. Next, a model is created to train a Support Vector Machine (SVM) using the values of the cross variogram function of each pair of windows as features. The pairs of breasts containing lesions are classified as asymmetric regions; the remaining ones are classified as symmetric regions. From the asymmetric regions, features are extracted from the variogram function to be used as tissue texture descriptors. The regions containing masses are classified as mass regions, and the other ones as non-mass regions. Stepwise linear discriminant analysis is used to select the most statistically significant features. Tests are performed with new cases for the final classification as either mass or non-mass by the trained SVM. The best results presented in the final classification were 96.38% of accuracy, 100% of sensitivity and 95.34% of specificity. The worst case presented 70.21% of accuracy, 100% of sensitivity and 67.56% of specificity. The average values for all tests were 90.26% of accuracy, 100% of sensitivity and 85.37% of specificity. PMID- 23816173 TI - GPU-based acceleration of an RNA tertiary structure prediction algorithm. AB - Experimental techniques such as X-ray crystallography and nuclear magnetic resonance have been useful for the accurate determination of RNA tertiary structures. However, high-throughput structure determination using such methods often becomes difficult, due to the need for a large quantity of pure samples. Computational techniques for the prediction of RNA tertiary structures are thus becoming increasingly popular. Most of the existing prediction algorithms are computationally intensive, and there is a clear need for acceleration. In this paper, we propose a parallelization methodology for the fragment assembly of RNA (FARNA) algorithm, one of the most effective methods for computational prediction of RNA tertiary structure. The proposed parallelization scheme exploits multi core CPUs and GPUs in harmony to maximize their utilization. We tested our approach with a number of RNA sequences and confirmed that it allows the time required for structure prediction to be significantly reduced. With respect to the baseline architecture equipped with a single CPU core, we achieved a speedup of up to approximately 24*(roughly 4* by multi-core CPUs and 20* by GPUs). Compared with a quad-core CPU setup, the proposed approach delivers an additional 12* speedup by utilizing GPU devices. Given that most PCs these days have a multi core CPU and a GPU card, our methodology will be very helpful for accelerating algorithms in a cost-effective manner. PMID- 23816174 TI - ExonSuite: algorithmically optimizing alternative gene splicing for the PUF proteins. AB - The stability of mRNA and its translation is a vital process necessary for proper protein production. The specificity of the regulation is controlled by specific RNA motifs and regulatory proteins. Pumilio/fem-3 mRNA-binding factor (PUF) proteins are usually used in regulating mRNA stability as well as translation. Here, we optimized a PUF protein target finder program to understand the natural diversity of RNA recognition by this family of proteins. ExonSuite is available to compile and run at https://github.com/dilanustek/ExonSuite. PMID- 23816175 TI - Wall shear stress variations and unsteadiness of pulsatile blood-like flows in 90 degree bifurcations. AB - Complex and slow interaction of different mechanical and biochemical processes in hemodynamics is believed to govern atherogenesis. Over the last decades studies have shown that fluid mechanical factors such as the Wall Shear Stress (WSS) and WSS gradients can play an important role in the pathological changes of the endothelium. This study provides further indications that the effects of fluid mechanical aspects are correlated with the diseased regions of the larger arteries. Unsteady high temporal WSS gradients (TWSSG), a function of the shear thinning property of the non-Newtonian viscosity, move with the separation bubble. Red Blood Cell (RBC) dilution due to the secondary flows determines the magnitudes of the WSS and TWSSG. The results indicate that the focal nature of the TWSSG may have implications on the response of the endothelium. PMID- 23816176 TI - Identification of BACE1 inhibitors from Panax ginseng saponins-An Insilco approach. AB - BACE1, a beta secretase candidate enzyme, initiates the Alzheimer's disease (AD) pathogenesis via amyloid beta (Abeta) peptide production serving as a potential therapeutic target. Previous experimental evidence suggested that ginsenosides, a key component of Panax ginseng, are effective against AD. In this study, we implemented a molecular modeling method to reveal the inhibitory action of ginsenosides on BACE1 activity. We selected 12 ginsenosides and performed molecular docking studies to evaluate its interaction with the BACE1 active site, which is essential for inhibition. Further ADMET filtration was applied to find drug-like molecules with a specific ability to cross blood brain barrier (BBB), and to determine toxicity. The BACE1-ginsenosides complex was further subjected to a molecular dynamics simulation to study the stability of the complex and its hydrogen bond interactions. In summary, our findings show ginsenosides CK, F1, Rh1 and Rh2 are potential BACE1 inhibitors from Panax ginseng. PMID- 23816177 TI - The effect of ambient air temperature and precipitation on monthly counts of salmonellosis in four regions of Kazakhstan, Central Asia, in 2000-2010. AB - We studied associations between monthly counts of laboratory-confirmed cases of salmonellosis, ambient air temperature and precipitation in four settings in Kazakhstan. We observed a linear association between the number of cases of salmonellosis and mean monthly temperature during the same months only in Astana: an increase of 1 degrees C was associated with a 5.5% [95% confidence interval (CI) 2.2-8.8] increase in the number of cases. A similar association, although not reaching the level of significance was observed in the Southern Kazakhstan region (3.5%, 95% CI -2.1 to 9.1). Positive association with precipitation with lag 2 was found in Astana: an increase of 1 mm was associated with a 0.5% (95% CI 0.1-1.0) increase in the number of cases. A similar association, but with lag 0 was observed in Southern Kazakhstan region (0.6%, 95% CI 0.1-1.1). The results may have implications for the future patterns of salmonellosis in Kazakhstan with regard to climate change. PMID- 23816178 TI - A prospective phase II study of L-asparaginase- CHOP plus radiation in newly diagnosed extranodal NK/T-cell lymphoma, nasal type. AB - PURPOSE: To explore the efficacy and safety of L-asparaginase in newly-diagnosed extranodal nature killer (NK)/T -cell lymphoma (ENKTL), we conducted a prospective phase II study of L-asparaginase, cyclophosphamide, vincristine, doxorubicin and dexamethasone (CHOP-L) regimen in combination with radiotherapy. PATIENTS AND METHODS: Patients with newly diagnosed ENKTL and an ECOG performance status of 0 to 2 were eligible for enrollment. Treatment included 6-8 cycles of CHOP-L (cyclophosphamide, 750 mg/m(2) day 1; vincristine, 1.4 mg/m(2) day 1 (maximal dose 2 mg), doxorubicin 50 mg/m(2) day 1; dexamethasone 10 mg days 1-8; L-asparaginase 6000 u/m(2) days 2-8). Radiotherapy was scheduled after 4-6 cycles of CHOP-L regimen, depending on stage and primary anatomic site. The primary endpoint was complete response (CR) rate. RESULTS: A total of 38 eligible patients were enrolled. The median age was 40.5 years (range, 15 to 71 years). Their clinical characteristics were male to female ratio, 24:14; Ann Arbor stage I, 20; II, 11; III, 3; IV, 4. CR and overall response rates were 81.6% (95% CI, 69.3% to 93.9%) and 84.2%, respectively. With a median follow-up of 25 months, the 2-year overall survival, progression-free survival and disease-free survival rates were 80.1% (95%CI, 73.3% to 86.9%), 81% (95%CI, 74.5% to 87.5%) and 93.6% (95%CI, 89.3% to 97.9%), respectively. The major adverse events were myelosuppression, liver dysfunction, and digestive tract toxicities. Grade 3 to 4 leukopenia and neutropenia were 76.3% and 84.2%, respectively. No treatment related death was observed. CONCLUSION: CHOP-L chemotherapy in combination with radiotherapy is a safe and highly effective treatment for newly diagnosed ENKTL. PMID- 23816179 TI - Primary CD8+ T cells from elite suppressors effectively eliminate non productively HIV-1 infected resting and activated CD4+ T cells. AB - BACKGROUND: Elite controllers or suppressors have the remarkable capacity to maintain HIV-1 plasma RNA levels below the limit of detection of clinical assays (<50 copies/mL) without therapy and have a lower frequency of latently infected cells compared to chronic progressors. While it is unclear how this reduced seeding of the reservoir is achieved, it is possible that effective CTL responses play an in important role in limiting the size of the latent reservoir. RESULTS: Herein, we demonstrate that primary CD8+ T cells from HLA-B*57/5801 elite suppressors were able to efficiently eliminate resting and activated primary CD4+ T cells shortly after viral entry and prior to productive infection. CD8+ T cells from elite suppressors were significantly more effective at eliminating these cells than CD8+ T cells from chronic progressors. CONCLUSIONS: Nonproductively infected CD4+ T cells may represent a subpopulation of cells that are precursors to latently infected cells; therefore, the effective elimination of these cells may partially explain why elite suppressors have a much lower frequency of latently infected cells compared to chronic progressors. Thus, a vaccine strategy that elicits early and potent CD8+ T cell responses may have the capacity to limit the seeding of the latent reservoir in HIV-1 infection. PMID- 23816180 TI - Dispelling urban myths about default uncertainty factors in chemical risk assessment--sufficient protection against mixture effects? AB - Assessing the detrimental health effects of chemicals requires the extrapolation of experimental data in animals to human populations. This is achieved by applying a default uncertainty factor of 100 to doses not found to be associated with observable effects in laboratory animals. It is commonly assumed that the toxicokinetic and toxicodynamic sub-components of this default uncertainty factor represent worst-case scenarios and that the multiplication of those components yields conservative estimates of safe levels for humans. It is sometimes claimed that this conservatism also offers adequate protection from mixture effects. By analysing the evolution of uncertainty factors from a historical perspective, we expose that the default factor and its sub-components are intended to represent adequate rather than worst-case scenarios. The intention of using assessment factors for mixture effects was abandoned thirty years ago. It is also often ignored that the conservatism (or otherwise) of uncertainty factors can only be considered in relation to a defined level of protection. A protection equivalent to an effect magnitude of 0.001-0.0001% over background incidence is generally considered acceptable. However, it is impossible to say whether this level of protection is in fact realised with the tolerable doses that are derived by employing uncertainty factors. Accordingly, it is difficult to assess whether uncertainty factors overestimate or underestimate the sensitivity differences in human populations. It is also often not appreciated that the outcome of probabilistic approaches to the multiplication of sub-factors is dependent on the choice of probability distributions. Therefore, the idea that default uncertainty factors are overly conservative worst-case scenarios which can account both for the lack of statistical power in animal experiments and protect against potential mixture effects is ill-founded. We contend that precautionary regulation should provide an incentive to generate better data and recommend adopting a pragmatic, but scientifically better founded approach to mixture risk assessment. PMID- 23816181 TI - Inequities in access to healthcare: analysis of national survey data across six Asia-Pacific countries. AB - BACKGROUND: Evidence suggests that there is a link between inequitable access to healthcare and inequitable distribution of illness. A recent World Health Organization report stated that there is a need for research and policy to address the critical role of health services in reducing inequities and preventing future inequities. The aim of this manuscript is to highlight disparities and differences in terms of the factors that distinguish between poor and good access to healthcare across six Asia-Pacific countries: Australia, Hong Kong, Japan, South Korea, Taiwan, and Thailand. METHODS: A population survey was undertaken in each country. This paper is a secondary analysis of these existing data. Data were collected in each country between 2009 and 2010. Four variables related to difficulties in access to healthcare (distance, appointment, waiting time, and cost) were analysed using binomial logistic regression to identify socio- and demographic predictors of inequity. RESULTS: Consistent across the findings, poor health and low income were identified as difficulties in access. Country specific indicators were also identified. For Thailand, the poorest level of access appears to be for respondents who work within the household whereas in Taiwan, part-time work is associated with difficulties in access. Within Hong Kong, results suggest that older (above 60) and retired individuals have the poorest access and within Australia, females and married individuals are the worst off. CONCLUSION: Recognition of these inequities, from a policy perspective, is essential for health sector policy decision-making. Despite the differences in political and economic climate in the countries under analysis, our findings highlight patterns of inequity which require policy responses. Our data should be used as a means of deciding the most appropriate policy response for each country which includes, rather than excludes, socially marginalised population groups. These findings should be of interest to those involved in health policy, but also in policy more generally because as we have identified, access to health care is influenced by determinants outside of the health system. PMID- 23816182 TI - Response to the letter by Dr Somsak Tiamkao. PMID- 23816183 TI - Group size limitations and causes of strokes in the young. PMID- 23816184 TI - More studies required to understand mortality rates of dialysis-dependent patients after acute thrombolysis for stroke. PMID- 23816185 TI - Response to the letter by Tariq. PMID- 23816186 TI - Brain pericytes increase the lipopolysaccharide-enhanced transcytosis of HIV-1 free virus across the in vitro blood-brain barrier: evidence for cytokine mediated pericyte-endothelial cell crosstalk. AB - BACKGROUND: Human immunodeficiency virus-1 (HIV-1) enters the brain by crossing the blood-brain barrier (BBB) as both free virus and within infected immune cells. Previous work showed that activation of the innate immune system with lipopolysaccharide (LPS) enhances free virus transport both in vivo and across monolayer monocultures of brain microvascular endothelial cells (BMECs) in vitro. METHODS: Here, we used monocultures and co-cultures of brain pericytes and brain endothelial cells to examine the crosstalk between these cell types in mediating the LPS-enhanced permeation of radioactively-labeled HIV-1 (I-HIV) across BMEC monolayers. RESULTS: We found that brain pericytes when co-cultured with BMEC monolayers magnified the LPS-enhanced transport of I-HIV without altering transendothelial electrical resistance, indicating that pericytes affected the transcytotic component of HIV-1 permeation. As LPS crosses the BBB poorly if at all, and since pericytes are on the abluminal side of the BBB, we postulated that luminal LPS acts indirectly on pericytes through abluminal secretions from BMECs. Consistent with this, we found that the pattern of secretion of cytokines by pericytes directly exposed to LPS was different than when the pericytes were exposed to the abluminal fluid from LPS-treated BMEC monolayers. CONCLUSION: These results are evidence for a cellular crosstalk in which LPS acts at the luminal surface of the brain endothelial cell, inducing abluminal secretions that stimulate pericytes to release substances that enhance the permeability of the BMEC monolayer to HIV. PMID- 23816187 TI - Effects of sodium hyaluronate and methylprednisolone alone or in combination in preventing epidural fibrosis. AB - OBJECTIVE: Epidural fibrosis and leptomeningeal adhesion formation are common causes of failed back surgery syndrome (FBSS). We employed a rat model of lumbar laminectomy to evaluate the histopathological effects of sodium hyaluronate (HA) and methylprednisolone (MP) alone or in combination on post-laminectomy epidural fibrosis. METHODS: Thirty-two male Sprague-Dawley rats were divided into four groups. All rats underwent three-level lumbar laminectomy. In the treatment groups, HA solution, MP, or a combination of both was applied locally to the epidural spaces of the laminectomy fields. No neurological deficits or pathological wound site changes were observed in any of the groups. At the end of the sixth week, all rats were sacrificed, and the laminectomy vertebral column areas were removed en-bloc. Specimens were evaluated by an expert neuropathologist according to histopathological criteria. RESULTS: The results of the three treatment groups were separately compared with the control group to assess epidural fibrosis. Minimal reduction in the rate of epidural fibrosis was observed in the groups treated with HA or MP compared with the control group. However, no significant difference in epidural fibrosis was noted between the combined treatment group and the control group. CONCLUSIONS: Our study showed that MP and HA, given separately, significantly reduce post-laminectomy epidural fibrosis; however, the combination of these drugs is not effective. Further investigation is needed to address the causative drug interactions. PMID- 23816189 TI - Regional cerebral volumes in veterans with current versus remitted posttraumatic stress disorder. AB - We previously reported that hippocampal volume was associated with current, but not lifetime posttraumatic stress disorder (PTSD) symptom severity. In the present study, we test the hypothesis that like the hippocampus, the volumes of other brain regions previously implicated in PTSD, are also negatively related to current, but not lifetime PTSD symptom severity. One hundred ninety-one veterans underwent structural magnetic resonance imaging (MRI) on a 4T scanner. Seventy five veterans were trauma unexposed, 43 were trauma exposed without PTSD, 39 were trauma exposed with current PTSD, and 34 were trauma exposed veterans with remitted PTSD. Hippocampal, amygdala, rostral and caudal anterior cingulate, insula, and corpus callosum volumes, quantified with Freesurfer version 4.5, were analyzed by group using multivariate analysis of covariance. Veterans with PTSD had smaller hippocampal, caudal anterior cingulate, insula, and corpus callosum volumes than the unexposed controls (p<=0.009); smaller hippocampal, caudal anterior cingulate, insula (p<=0.009) and marginally smaller corpus callosum (p=0.06) than veterans with remitted PTSD; and smaller hippocampal and caudal anterior cingulate volumes than veterans without PTSD (p<=0.04). In contrast, there was no significant volume differences between veterans with remitted PTSD compared to those without PTSD or unexposed controls. The finding that current but not lifetime PTSD accounts for the volumes of multiple brain regions suggests that either smaller brain volume is a vulnerability factor that impedes recovery from PTSD or that recovery from PTSD is accompanied by a wide-spread restoration of brain tissue. PMID- 23816188 TI - Knowledge brokering between researchers and policymakers in Fiji to develop policies to reduce obesity: a process evaluation. AB - BACKGROUND: The importance of using research evidence in decisionmaking at the policy level has been increasingly recognized. However, knowledge brokering to engage researchers and policymakers in government and non-government organizations is challenging. This paper describes and evaluates the knowledge exchange processes employed by the Translational Research on Obesity Prevention in Communities (TROPIC) project that was conducted from July 2009 to April 2012 in Fiji. TROPIC aimed to enhance: the evidence-informed decisionmaking skills of policy developers; and awareness and utilization of local and other obesity related evidence to develop policies that could potentially improve the nation's food and physical activity environments. The specific research question was: Can a knowledge brokering approach advance evidence-informed policy development to improve eating and physical activity environments in Fiji. METHODS: The intervention comprised: recruiting organizations and individuals; mapping policy environments; analyzing organizational capacity and support for evidence-informed policymaking (EIPM); developing EIPM skills; and facilitating development of evidence-informed policy briefs. Flexible timetabling of activities was essential to accommodate multiple competing priorities at both individual and organizational levels. Process diaries captured the duration, frequency and type of each interaction and/or activity between the knowledge brokering team and participants or their organizations. RESULTS: Partnerships were formalized with high-level officers in each of the six participating organization. Participants (n = 49) developed EIPM skills (acquire, assess, adapt and apply evidence) through a series of four workshops and applied this knowledge to formulate briefs with ongoing one-to-one support from TROPIC team members. A total of 55% of participants completed the 12 to18 month intervention, and 63% produced one or more briefs (total = 20) that were presented to higher-level officers within their organizations. The knowledge brokering team spent an average of 30 hours per participant during the entire TROPIC process. CONCLUSIONS: Active engagement of participating organizations from the outset resulted in strong individual and organizational commitment to the project. The TROPIC initiative provided a win win situation, with participants expanding skills in EIPM and policy development, organizations increasing EIPM capacity, and researchers providing data to inform policy. PMID- 23816190 TI - Cavum septum pellucidum in pediatric traumatic brain injury. AB - The cavum septum pellucidum (CSP) is a fluid-filled cavity in the thin midline structure of the septum pellucidum. The CSP has been linked to several neurodevelopmental disorders, but it also occurs as a result of head injury. The aims were to assess the presence and characterization of the CSP in youth with traumatic brain injury (TBI), to assess whether injury severity or IQ measures were related to CSP size, and to examine brain morphometry changes associated with the CSP size. Ninety-eight survivors of TBI and 34 control children underwent magnetic resonance imaging (MRI). Numerous methods were used to define the presence and characterization of the CSP including length, classification of abnormally large CSP, rating of the CSP, and volume. There was no difference in presence of CSP between TBI patients and controls; however, there was larger and more severely graded CSP in the patient group. Size of the CSP correlated positively with injury severity, and regions that correlated most significantly with CSP size were the right entorhinal cortex and bilateral hippocampus. Characterizing the CSP and related brain changes may provide important information concerning disturbances seen after a TBI. PMID- 23816191 TI - Closing the loop: best practices for cross-setting communication at ED discharge. AB - PURPOSE: This study aimed to develop emergency department best practice guidelines for improved communication during patient care transitions. BASIC PROCEDURES: To our knowledge, there are no specific guidelines for communication at the point of transition from the emergency department to the community. In Rhode Island, we used a multistage collaborative quality improvement process to define best practices for emergency department care transitions. We reviewed the medical literature, consensus statements, and materials from national campaigns; gathered preferences from emergency medicine and primary care clinicians; and created guidelines that we vetted with emergency medicine clinicians and other key stakeholders. MAIN FINDINGS: Because we did not find any guidelines that globally addressed care transitions from the emergency department, we drew from studies on patient discharge instructions and extrapolated from the evidence base available for other, related settings. Our key outcome is a set of care transition best practices for emergency departments, which can be implemented to establish measurable, communitywide expectations for cross-setting clinician-to clinician communication. They include obtaining information about patients' outpatient clinicians, sending summary clinical information to downstream clinicians, performing modified medication reconciliation, and providing patients with effective education and written discharge instructions. PRINCIPAL CONCLUSIONS: The best practices provide feasible standards for evaluating and improving how patients transition out of the emergency department and can provide a framework for emergency department leaders expanding their collaboration with community partners, particularly in the context of emerging payment models. They also catalyze introspection and debate about how to improve communication and accountability across the care continuum. PMID- 23816192 TI - Manual corrected QT and Tpeak-Tend calculations may assist emergency physicians risk stratify patients for arrhythmia. PMID- 23816193 TI - Cerebellitis developing after tricyclic antidepressant poisoning. AB - Acute cerebellitis is a rare inflammatory disease involving the cerebellum and is characterized by acute compromise of cerebellar functions. It most frequently originates from infectious causes, although cases of cerebellitis associated with other causes have also been reported. This report discusses a case of cerebellitis developing in a 4-year-old girl who had to be intubated after accidental ingestion of tricyclic antidepressant. There are no previous reports of cerebellitis after tricyclic antidepressant. This case shows that cerebellitis can develop in patients with poisoning of this kind. PMID- 23816194 TI - Epinephrine-induced myocardial infarction in severe anaphylaxis: is beta-blocker a bad actor or bystander? PMID- 23816195 TI - Simultaneous thrombosis of 2 vascular territories: is thrombolytic therapy a better option? PMID- 23816196 TI - Early rule out of acute myocardial infarction in ED patients: value of combined high-sensitivity cardiac troponin T and ultrasensitive copeptin assays at admission. AB - OBJECTIVE: We sought to evaluate the added value of ultrasensitive copeptin (us copeptin) for early rule out of acute myocardial infarction in a prospective cohort of emergency department (ED) patients with acute chest pain. METHODS: This was a prospective study including consecutive patients with acute chest pain presenting to the ED within 12 hours of symptom onset. High-sensitivity cardiac troponin T (hs-cTnT, Roche Diagnostics, Meylan, France) and us-copeptin (ThermoFisher Scientific, Clichy, France) were blindly assayed from venous blood samples obtained at admission. Diagnosis was made by 2 ED physicians using all available data and serial cardiac troponin I as the biochemical standard. Diagnostic performances of us-copeptin combined with hs-cTnT were assessed using logistic regression. Analysis was conducted in all patients and in patients without ST-elevation myocardial infarction. RESULTS: A total of 194 patients were included (age, 61 [48-75] years; male sex, 63%). Acute myocardial infarction occurred in 52 (27%) patients, including non-ST-elevation myocardial infarction (NSTEMI) in 25 (13%). Patients with acute myocardial infarction had higher levels of hs-cTnT (50 [95% confidence interval, 19-173] ng/L) and us-copeptin (30 [13 113] pmol/L) at admission compared with those without (P < .05). Combination of markers significantly improved receiver operating characteristic area under the curve (from 0.89 [0.85-0.92] for hs-cTnT alone to 0.93 [0.89-0.97], P = .018). Sensitivity and negative predictive value were increased, particularly for NSTEMI diagnosis (sensitivity, 76% [54.9-90.6] to 96% [79.6-99.9]; negative predictive value, 95% [90.4-98.3] to 98.9% [94.2 to 100]). CONCLUSION: Assessment of us copeptin combined with hs-cTnT on ED admission could allow safe and early rule out of NSTEMI for patients with negative results on both markers and help identify patients who may be suitable for discharge. PMID- 23816198 TI - Optimization of liquid chromatography-multiple reaction monitoring cubed mass spectrometry assay for protein quantification: application to aquaporin-2 water channel in human urine. AB - Aquaporin-2 (AQP2) is a water channel protein located in the kidney collecting ducts that has been studied as a potential biomarker of a wide variety of water handling disorders and that could also be used to monitor lesions in the collecting ducts. Enzyme-linked immunosorbent assay (ELISA), the most commonly used approach for protein assay in biofluids, has a limited potential for biomarker verification due to the restricted possibility to perform multiplex assays, the cost and complexity of assay development for new candidates. Liquid chromatography tandem mass spectrometry (LC-MS/MS), in multiple reaction monitoring (MRM) mode, has been demonstrated as a powerful alternative technique, and applied to multiple protein quantification. An even more specific method, termed MRM cubed (MRM(3)), has recently been developed. This paper focuses on the development of an AQP2 assay in urine by LC-MS/MS, based on the MRM(3) strategy, and the influence of key MRM(3) parameters that enable to increase the method sensitivity by a factor of 10. Linearity is observed within the concentration range 0.5-50ng/mL, intra and inter assay precision ranged from 9 to 35% at the lower limit of quantification (LLOQ), and accuracy from 94 to 114%. This assay could therefore be used in the near future to evaluate human urinary AQP2 as a potential biomarker of kidney collecting duct injury. PMID- 23816200 TI - "Shunt index" can be used to predict clinically significant patent ductus arteriosus in premature neonates in early post-natal life. AB - BACKGROUND: This study aimed to examine the differences between arterial and inferior caval vein oxygen saturation, fractional oxygen extraction, and the shunt index, which were calculated in the diagnosis of patent ductus arteriosus. METHODS: Twenty-seven preterm infants were included in this study and were divided into two groups according to patent ductus arteriosus. Among them, 11 (41%) infants had haemodynamically significant patent ductus arteriosus and 16 (59%) did not have significant patent ductus arteriosus. Synchronous arterial and venous blood gases were measured during the first post-natal hours after the insertion of umbilical catheters. The differences between arterial and inferior caval vein oxygen saturation, inferior body fractional oxygen extraction, and the shunt index were calculated. Echocardiography was performed before the 72nd hour of life in a selected group of patients who had haemodynamically significant patent ductus arteriosus. Ibuprofen treatment was administered to patients with patent ductus arteriosus. Echocardiography was performed on the 72nd hour of life in preterm infants without any clinical suspicion of patent ductus arteriosus. RESULTS: The early measured differences between arterial and inferior caval vein oxygen saturation and inferior body fractional oxygen extraction were found to be lower and the shunt index was found to be higher in the haemodynamically significant patent ductus arteriosus group than in the group without haemodynamically significant patent ductus arteriosus. CONCLUSION: We found that the shunt index, calculated in the first hours of life as >=63%, predicted haemodynamically significant patent ductus arteriosus with a sensitivity of 78% and specificity of 82% in preterm newborns. PMID- 23816199 TI - A multicenter randomized controlled trial of aftercare services for severe mental illness: study protocol. AB - BACKGROUND: Severe mental illness is responsible for a significant proportion of burden of diseases in Iranian population. People with severe mental illnesses are more likely to have high rates of non-attendance at follow-up visits, and lack of an active follow-up system, particularly in the country's urban areas that has resulted in the revolving door phenomenon of rehospitalizations. Therefore, there is an increasing need for implementation of effective and cost-effective aftercare services. METHOD/DESIGN: This is a randomized control trial with the primary hypothesis that aftercare services delivered to patients with severe mental illnesses in outpatient department and patient's home by a community care team would be more effective when compared to treatment as usual (TAU) in reducing length of hospital stay and any psychiatric hospitalization. Patients were recruited from three psychiatric hospitals in Iran. After obtaining informed written consent, they were randomly allocated into aftercare intervention and control (TAU) groups. Aftercare services included treatment follow-up (through either home care or telephone follow-up prompts for outpatient attendance), family psychoeducation, and patient social skills training that were provided by community mental health teams. Patients were followed for 12 months after discharge. The primary outcome measures were length of hospital stay and any hospitalization in the 12 month follow-up. Secondary outcome measures included patients' clinical global impression, global functioning, quality of life, and patient's satisfaction. The trial also allowed an assessment of direct cost effectiveness of the aftercare services. DISCUSSION: This paper presents a protocol for an RCT of aftercare services delivered to patients with severe mental illnesses within patients' home or outpatient department. The findings of this study can influence policy and program planning for people with severe mental illnesses in Iran. TRIAL REGISTRATION: IRCT201009052557N2. PMID- 23816201 TI - Effects of geodemographic profiles on healthcare service utilization: a case study on cardiac care in Ontario, Canada. AB - BACKGROUND: Although literature has associated geodemographic factors with healthcare service utilization, little is known about how these factors - such as population size, age profile, service accessibility, and educational profile - interact to influence service utilization. This study fills this gap in the literature by examining both the direct and the moderating effects of geodemographic profiles on the utilization of cardiac surgery services. METHODS: We aggregated secondary data obtained from Statistics Canada and Cardiac Care Network of Ontario to derive the geodemographic profiles of Ontario and the corresponding cardiac surgery service utilization in the years between 2004 and 2007. We conducted a two-step test using Partial Least Squares-based structural equation modeling to investigate the relationships between geodemographic profiles and healthcare service utilization. RESULTS: Population size and age profile have direct positive effects on service utilization (beta = 0.737, p < 0.01; beta = 0.284, p < 0.01, respectively), whereas service accessibility is negatively associated with service utilization (beta = -0.210, p < 0.01). Service accessibility decreases the effect of population size on service utilization (beta = -0.606, p < 0.01), and educational profile weakens the effects of population size and age profile on service utilization (beta = -0.595, p < 0.01; beta = -0.286, p < 0.01, respectively). CONCLUSIONS: In this study, we found that (1) service accessibility has a moderating effect on the relationship between population size and service utilization, and (2) educational profile has moderating effects on both the relationship between population size and service utilization, and the relationship between age profile and service utilization. Our findings suggest that reducing regional disparities in healthcare service utilization should take into account the interaction of geodemographic factors such as service accessibility and education. In addition, the allocation of resources for a particular healthcare service in one area should consider the geographic distribution of the same services in neighboring areas, as patients may be willing to utilize these services in areas not far from where they reside. PMID- 23816204 TI - Value lay findings and early warnings. PMID- 23816202 TI - Effect of lingual plates on generating intra-oral pressure during swallowing: an experimental study in healthy subjects. AB - BACKGROUND: Although palatal augmentation prostheses (PAPs) can improve dysphagia, their application is compromised in the absence of maxillary abutment teeth. Experimental lingual plates (ELPs) used for raising the tongue may be employed as alternative to PAPs. METHODS: Influence of different ELP designs, plateau (P-type) and drop-shaped (D-type), on the intra-oral pressure during swallowing were tested. Eleven healthy dentate volunteers, with a mean age of 35.5+/-10.5 years, participated in this study. Tongue pressure on the hard palate was measured using an ultra-thin sensor sheet with five measuring points, whilst performing dry, 5-ml and 15-ml water swallows, with and without the ELPs in situ. Additional pressure sensors were installed in the lingual aspects of the ELPs, and on the vestibular aspect of the lower molars for measuring sublingual and oral vestibule pressures, respectively. Each measurement was recorded thrice. A repeated measures ANOVA was employed to verify differences in duration, maximal magnitude and integrated value for the different experimental situations. Tukey's post hoc test was performed for comparison testing. Statistical significance was set at p<0.05. RESULTS: The sequence of tongue-palate contact on the median line of the hard palate without ELPs was maintained, except for the 15 ml P-type swallow. Tongue pressure started earlier with the D-type but reached its peak nearly at the same time as without ELPs. The peak magnitude and cumulative tongue pressure against the hard palate decreased by wearing ELPs (p<0.05), but was inconsistent between the two types of ELPs and for the different swallowing volumes. Both, maximum and cumulative vestibular pressures were mostly similar or larger with P-type than that with D-type. CONCLUSION: D-type and P-type ELPs seem to have the inverse effect of PAPs on the palatal tongue pressure during swallowing. These first counterintuitive findings do not yet justify rejecting the basic rationale of using ELPs for the treatment of dysphagia; hence a rather biologically designed piezographic lingual plate may be more appropriate. PMID- 23816203 TI - Dioxin-like compounds and bone quality in Cree women of Eastern James Bay (Canada): a cross-sectional study. AB - BACKGROUND: Aboriginal populations living in Canada's northern regions are exposed to a number of persistent organic pollutants through their traditional diet which includes substantial amounts of predator fish species. Exposure to dioxin-like compounds (DLCs) can cause a variety of toxic effects including adverse effects on bone tissue. This descriptive cross-sectional study was conducted to investigate the relationship between plasma concentrations of DLCs and bone quality parameters in Cree women of Eastern James Bay (Canada). METHODS: Two hundred and forty-nine Cree women from seven communities in Eastern James Bay (Canada), aged 35 to 74 years old, participated in the study. In order to determine the total DLC concentration in plasma samples of participants, we measured the aryl hydrocarbon receptor-mediated transcriptional activity elicited by plasma sample extracts using a luciferase reporter gene assay. Plasma concentrations of mono-ortho-substituted dioxin-like polychlorinated biphenyls (DL-PCBs) 105, 118 and 156 were measured by gas chromatography-mass spectrometry. Bone quality parameters (speed of sound, m/s; broadband ultrasound attenuation, dB/MHz; stiffness index, %) were assessed by quantitative ultrasound at the right calcaneus with the Achilles InSight system. Several factors known to be associated with osteoporosis were documented by questionnaire. Multiple linear regression models were constructed for the three ultrasound parameters. RESULTS: DL-PCBs 105 and 118 concentrations, but not the global DLC concentration, were inversely associated with the stiffness index, even after adjusting for several confounding factors. The stiffness index (log) decreased by -0.22% (p=0.0414) and -0.04% (p=0.0483) with an increase of one MUg/L in plasma concentrations of DL PCB 105 and DL-PCB 118, respectively. Other factors, including age, height, smoking status, menopausal status and the percentage of omega-6 polyunsaturated fatty acids (PUFAs) in erythrocyte membranes were negatively associated with one of the ultrasound parameters, while the percentage of omega-3 PUFAs in these membranes and levels of physical activity and education were positively associated with them. CONCLUSIONS: Our results show that an increase in plasma concentrations of DL-PCBs 105 and 118 was negatively associated with stiffness index, a measure of bone quality/strength, in women of this population. In addition to environmental contaminants, future studies should also consider PUFA intake as a factor influencing bone quality. PMID- 23816205 TI - Arteriogenic therapy based on simultaneous delivery of VEGF-A and FGF4 genes improves the recovery from acute limb ischemia. AB - BACKGROUND: Gene therapy stimulating the growth of blood vessels is considered for the treatment of peripheral and myocardial ischemia. Here we aimed to achieve angiogenic synergism between vascular endothelial growth factor-A (VEGF-A, VEGF) and fibroblast growth factor 4 (FGF4) in murine normoperfused and ischemic limb muscles. METHODS: Adeno-associated viral vectors (AAVs) carrying beta galactosidase gene (AAV-LacZ), VEGF-A (AAV-VEGF-A) or two angiogenic genes (AAV FGF4-IRES-VEGF-A) were injected into the normo-perfused adductor muscles of C57Bl/6 mice. Moreover, in a different experiment, mice were subjected to unilateral hindlimb ischemia by femoral artery ligation followed by intramuscular injections of AAV-LacZ, AAV-VEGF-A or AAV-FGF4-IRES-VEGF-A below the site of ligation. Post-ischemic blood flow recovery was assessed sequentially by color laser Doppler. Mice were monitored for 28 days. RESULTS: VEGF-A delivered alone (AAV-VEGF-A) or in combination with FGF4 (AAV-FGF4-IRES-VEGF-A) increased the number of capillaries in normo-perfused hindlimbs when compared to AAV-LacZ. Simultaneous overexpression of both agents (VEGF-A and FGF4) stimulated the capillary wall remodeling in the non-ischemic model. Moreover, AAV-FGF4-IRES-VEGF A faster restored the post-ischemic foot blood flow and decreased the incidence of toe necrosis in comparison to AAV-LacZ. CONCLUSIONS: Synergy between VEGF-A and FGF4 to produce stable and functional blood vessels may be considered a promising option in cardiovascular gene therapy. PMID- 23816206 TI - Letter to the editors. The Airtraq optical. PMID- 23816207 TI - Letter to the editors. Helicopter emergency. PMID- 23816209 TI - Part 21: categoric analysis: Pearson chi-square test. PMID- 23816210 TI - Hypokalemic periodic paralysis: two cases of profound weakness. PMID- 23816211 TI - Do you still "like" facebook? PMID- 23816212 TI - Volume resuscitation issues. PMID- 23816213 TI - Commercial aircraft repatriation of patients with pneumothorax. AB - The transfer of patients with a pneumothorax via a commercial airline involves many medical, aeronautic, and regulatory considerations. In an attempt to further investigate these issues, we reviewed the medical records of 32 patient cases with a pneumothorax who were repatriated on commercial aircrafts. Sixteen patients were transferred with the thoracostomy tube in place and were escorted by medical personnel at an average of 5 days (interquartile range [IQR], 4-7 days) from diagnosis. Five patients without initial intercostal drainage (who either showed very limited air collection or underwent immediate surgical treatment) were all escorted by a physician at an average of 24 days (IQR, 18-25 days) of diagnosis. Eleven patients were transferred without medical escort aboard a commercial flight after removal of the chest tube at an average of 15 days (IQR, 9-17 days) of the diagnosis. This case review suggests that physicians recommend and follow markedly different management plans for the patient with a pneumothorax who is being transferred nonurgently by a commercial airliner. This differing practice management also is noted in the various existing specialty and industry guidelines, which are not evidence based; our review shows that poor agreement exists not only in these various guidelines but also among medical practitioners. PMID- 23816214 TI - Long-acting neuromuscular blocker use during prehospital transport of trauma patients. AB - INTRODUCTION: The purpose of this study was to determine the rate of long-acting neuromuscular blocker (LA-NMB) use and evaluate the concurrent use of sedatives during prehospital care. SETTING: Prehospital patients who were brought to a single emergency department in the United States. METHODS: This was a retrospective cohort study of trauma patients who were intubated in the prehospital setting. The primary outcome measure was to determine the rate of LA NMB use. The use of postintubation sedatives and the time to the administration of sedative agents was compared between patients who received an LA-NMB and those who did not. RESULTS: A total of 51 patients were included in the final analyses. Overall, 82% (n = 42) of patients received an LA-NMB during transport. There was no difference in the rate of postintubation sedative use during transport between the LA-NMB and no LA-NMB groups (79% vs. 67%, respectively, P = .42). The LA-NMB group received sedatives less promptly after intubation compared with those who did not receive LA-NMBs (16 vs. 7 minutes, respectively; P = .04). CONCLUSION: The use of LA-NMB is common during the prehospital transport of trauma patients. Some of these patients may not be given sedatives or may have delays in receiving sedatives after intubation. PMID- 23816215 TI - Perceived patient safety culture in a critical care transport program. AB - BACKGROUND: The purpose of this study was to examine the association among selected safety culture dimensions and safety outcomes in the context of a critical care transport (CCT) program. METHODS: A descriptive cross-sectional correlational design used the Agency for Healthcare Research and Quality Hospital Survey on Patient Safety Culture to validate perceived safety culture among personnel (n = 76) in a large Midwestern CCT program. RESULTS: Findings revealed significant associations between 1) teamwork and frequency of error reporting (r = .428, P < .001), overall perception of safety (r = .745, P < .001), and perceived patient safety grade (r = -.681, P < .001); 2) between perception of manager actions promoting safety and frequency of error reporting (r = .521, P < .001), overall perception of safety (r = .779, P < .001), and perceived patient safety grade (r = -.756, P < .001); and 3) between communication openness and frequency of error reporting (r = .575, P < .001), overall perception of safety (r = .588, P < .001), and perceived patient safety grade (r = -.627, P < .001). CONCLUSION: The study supports other literature showing significant associations among safety culture dimensions and safety outcomes and provides a framework for future research on safety culture in CCT programs. PMID- 23816216 TI - Should air medical patients be transferred on helipad or trauma bay? AB - OBJECTIVE: Helicopter emergency medical services (HEMS) are widely used in regional trauma care and present unique challenges in the patient handoff process. In particular, the practice of patient handoff on the landing zone versus the trauma bay does not exist in ground emergency medical services. We hypothesized that patients handed off on the landing zone versus the trauma bay would have different patient characteristics and outcomes. METHODS: A retrospective review identified 305 HEMS trauma patients received at our level 1 trauma center over a 3-year period. Patients were sorted on the basis of the handoff location, (landing zone vs. trauma bay) and assessed for predictors of injury severity including the Revised Trauma Score, the Injury Severity Score, the Trauma and Injury Severity Score, and other outcomes, primarily mortality. RESULTS: Of the 305 patients, 235 (77%) were handed off in the bay, and 70 (23%) were not. Regarding the characteristics of patients who were handed off in the bay, they were more likely to have hypotension (100% vs. 73%), have a lower O(2) saturation level (97.9 vs. 99.4), and a lower Glasgow Coma Scale at the scene (10.9 vs. 13.9.). When controlling for injury severity, the odds of survival for patients who were handed off in the bay were 11.06 times the odds for patients who were not handed off in the bay. CONCLUSION: In this limited study, we found that HEMS did identify the sickest patients and brought them to the trauma bay. Despite their greater injury severity, the patients handed off in the bay fared better than those handed off on the landing zone. PMID- 23816217 TI - Ambiguity. PMID- 23816219 TI - Early stage follicular lymphoma: what is the clinical impact of the first-line treatment strategy? AB - BACKGROUND: Less than 20% of patients with follicular lymphoma (FL) present with Ann Arbor Stage I or II disease at diagnosis. Numerous therapeutic options exist, however radiation therapy is considered the standard of care for early-stage disease based on single-institution or retrospective series. Our aim was to revisit the outcome of patients with localized FL in the rituximab era. PATIENTS AND METHODS: We analyzed the characteristics and outcomes of 145 early-stage FL patients, who were retrospectively divided into six groups according to their initial treatment: watchful waiting (WW), chemotherapy alone (CT), radiotherapy alone (RT), combined radiotherapy and chemotherapy (RT-CT), rituximab alone (Ri), and immunochemotherapy (Ri-CT). RESULTS: Of the 145 patients, 84 (57.9%) had stage I disease and 61 (42.1%) stage II. The complete response (CR) rate varied from 57% for the Ri group to 95% for the RT-CT group. Overall survival (OS) at 7.5 y of patients treated after 2000 was better than that of those treated prior to 2000. OS did not significantly differ from one treatment to another. In contrast, a significant difference was found for progression-free survival (PFS) at 7.5 y, which favored Ri-CT (60%) therapy versus the others (p=0.00135). CONCLUSION: Delayed therapy initiation was associated with a similar OS than that observed in patients receiving immediate intervention. The "watchful waiting" strategy may thus be proposed as first-line therapy, similar to stage III and IV FL patients with a low tumor burden. However, when treatment is required, immunochemotherapy appears to be the best option. PMID- 23816220 TI - A novel glucose biosensor platform based on Ag@AuNPs modified graphene oxide nanocomposite and SERS application. AB - This study represents a novel template demonstration of a glucose biosensor based on mercaptophenyl boronic acid (MBA) terminated Ag@AuNPs/graphene oxide (Ag@AuNPs GO) nanomaterials. The nanocomposites were characterized by transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), and X-ray diffraction (XRD) method. The TEM image shows that Ag@AuNPs in the nanocomposite is in the range of diameters of 10-20 nm. The nanocomposite was used for the determination of glucose through the complexation between boronic acid and diol groups of glucose. Thus, a novel glucose biosensor was further fabricated by immobilizing glucose oxidase (GOD) into MBA terminated Ag@AuNPs-GO nanocomposite film (MBA Ag@AuNPs-GO). The linearity range of glucose was obtained as 2-6mM with detection limit of 0.33 mM. The developed biosensor was also applied successfully for the determination of glucose in blood samples. The concentration value of glucose in blood samples was calculated to be 1.97+/-0.002 mM from measurements repeated for six times. PMID- 23816221 TI - Biomimetic photonic materials with tunable structural colors. AB - Nature is a huge gallery of art involving nearly perfect structures and forms over the millions of years developing. Inspiration from natural structures exhibiting structural colors is first discussed. We give some examples of natural one-, two-, and three-dimensional photonic structures. This review article presents a brief summary of recent progress on bio-inspired photonic materials with variable structural colors, including the different facile and efficient routes to construct the nano-architectures, and the development of the artificial variable structural color photonic materials. Besides the superior optical properties, the excellent functions such as robust mechanical strength, good wettability are also mentioned, as well as the technical importance in various applications. This review will provide significant insight into the fabrication, design and application of the structural color materials. PMID- 23816222 TI - Pregnancy and blue rubber bleb nevus syndrome. PMID- 23816223 TI - Conformance to schizophrenia treatment guidelines in North West-Bank, Palestine: focus on antipsychotic dosing and polytherapy. AB - BACKGROUND: Analysis of the prescribing patterns of antipsychotic drugs can improve therapeutic outcomes. The purpose of this study was to evaluate the prescribing pattern of antipsychotics and its conformance to international treatment guidelines. METHODS: A cross sectional study at primary psychiatric centers was carried out. Patients' medical files were used to obtain demographic, medication and clinical information. International guidelines for schizophrenia were used to create conformance indicators. All statistical analyses were conducted using Statistical Package for Social Sciences. RESULTS: 250 patients were included in this study. A total of 406 antipsychotic agents were used; 348 (85.7%) were first generation antipsychotics (FGA). The prevalence of antipsychotic combination was 50.4% (n=126). There was no significant difference in positive (p=0.3), negative (p=0.06) and psychopathology (p=0.5) scores of schizophrenia symptoms among patients on monotherapy versus those on antipsychotic combination. Furthermore, no significant difference was observed in the annual cost of antipsychotic monotherapy versus combination therapy. One hundred and five patients (42%) were using optimum dose of (300 - 600 mg CPZeq) while the remaining were using sub or supra therapeutic doses. Analysis showed that use of depot, use of anticholinergic agents and increasing amount of total CPZeq were significant factors associated with antipsychotic combination. CONCLUSIONS: This study indicated that antipsychotic prescribing was not in conformance with international guidelines with respect to maintenance dose and combination therapy. Type of antipsychotic treatment regimen, combination versus monotherapy, was not associated with better clinical or economic outcome. PMID- 23816224 TI - The destiny of an ace: Algimantas Otanas Narakas (1927-1993). PMID- 23816225 TI - Enactment and evolution of the vision of the future of the Journal of School Psychology. PMID- 23816226 TI - Scientific research in school psychology: Leading researchers weigh in on its past, present, and future. AB - A survey of established researchers in school psychology was conducted to reflect on the state of the science of school psychology research. A total of 54 members of the Society for the Study of School Psychology shared their perceptions of (a) the most significant findings of the past 25years that have influenced research and practice in school psychology, (b) current, exciting research topics, and (c) topics that are likely to guide the future of research in school psychology. Qualitative analyses revealed 6 major categories and 17 minor categories within the major categories. Four major categories were present across each of the three time periods: (a) Data-Informed Practices and their Implementation, (b) Theory Development, (c) Changing Role and Function, and (d) Biological Bases of Behavior. Additional major categories included Advances in Research Methodology and Psychometrics (found across past and present time periods) and There is Not One Single Most Important Idea (found during only the past time period). Quotations are provided to illustrate these categories and share the respondents' ideas in their own words. PMID- 23816227 TI - Grade retention: historical perspectives and new research. PMID- 23816228 TI - First-grade retention in the Flemish educational context: Effects on children's academic growth, psychosocial growth, and school career throughout primary education. AB - This study examined the effects of first-grade retention on children's academic growth, psychosocial growth, and future school career by following a cohort of first graders until the start of secondary school. The study took place in the Flemish educational context where primary school students are taught in uniform curricular year groups; the same curricular goals are set for all students, irrespective of ability; and grade retention is used as the main way to cater for students not reaching these goals. Propensity score stratification was used to deal with selection bias. Three-level curvilinear growth curve models, encompassing both grade and age comparisons, were used to model children's growth in math skills, reading fluency skills, and psychosocial skills. Two-level logistic regression models were used to model children's likelihood of repeating any grade between Grades 2 and 6, transitioning to a special education primary school, moving to another primary school, and transitioning to the A (versus B) track in secondary education. Overall, results showed that first-grade retention was less helpful for struggling students than generally thought by parents and educators. Limitations of the study and further research suggestions are provided, and practical implications are discussed. PMID- 23816229 TI - Effect of retention in elementary grades on transition to middle school. AB - The authors investigated the effects of retention in grades 1 to 5 on students' reading and math achievement, teacher-rated engagement, and student-reported school belonging in middle school. From a multiethnic sample (N=784) of children who scored below the median on a test of literacy in grade 1, an average of 75 students subsequently retained in grades 1 to 5 were matched with an average of 299 continuously promoted students on the basis of propensity to be retained in the elementary grades. A total of 20 imputed datasets were analyzed, all of which showed good balance across the 67 baseline covariates used to calculate propensity scores. The hypothesis that retained students, who are "old for grade" when they make the transition to middle school, would have a more difficult transition to middle school than promoted peers was tested with 3-level, piecewise growth modeling. Piece 1 included assessments prior to the transition to middle school, and piece 2 included assessments after the transition. Retained and continuously promoted students did not differ on any of the outcome measures during the year prior to transition, nor did they differ in their post-transition trajectories. Discrepancies between these results and results of prior research are discussed in terms of demographic and generational differences as well as differences in methodological rigor. PMID- 23816230 TI - Direct behavior rating as a school-based behavior screener for elementary and middle grades. AB - The purpose of this study was to investigate how Direct Behavior Rating Single Item Scales (DBR-SIS) involving targets of academically engaged, disruptive, and respectful behaviors function in school-based screening assessment. Participants included 831 students in kindergarten through eighth grades who attended schools in the northeastern United States. Teachers provided behavior ratings for a sample of students in their classrooms on the DBR-SIS, the Behavioral and Emotional Screening System (Kamphaus & Reynolds, 2007), and the Student Risk Screening Scale (Drummond, 1994). Given variations in rating procedures to accommodate scheduling differences across grades, analysis was conducted separately for elementary school and middle school grade levels. Results suggested that the recommended cut scores, the combination of behavior targets, and the resulting conditional probability indices varied depending on grade level grouping (lower elementary, upper elementary, middle). For example, for the lower elementary grade level grouping, a combination of disruptive behavior (cut score=2) and academically engaged behavior (cut score=8) was considered to offer the best balance among indices of diagnostic accuracy, whereas a cut score of 1 for disruptive behavior and 8 for academically engaged behavior were recommended for the upper elementary school grade level grouping and cut scores of 1 and 9, respectively, were suggested for middle school grade level grouping. Generally, DBR-SIS cut scores considered optimal for screening using single or combined targets including academically engaged behavior and disruptive behavior by offering a reasonable balance of indices for sensitivity (.51-.90), specificity (.47-.83), negative predictive power (.94-.98), and positive predictive power (.14-.41). The single target of respectful behavior performed poorly across all grade level groups, and performance of DBR-SIS targets was relatively better in the elementary school than middle school grade level groups. Overall, results supported that disruptive behavior is highly important in evaluating risk status in lower grade levels and that academically engaged behavior becomes more pertinent as students reach higher grade levels. Limitations, future directions, and implications are discussed. PMID- 23816231 TI - Vocabulary learning in Head Start: Nature and extent of classroom instruction and its contributions to children's learning. AB - In the current study, we employed the 2006 cohort of the large-scale, nationally representative, Head Start Family and Child Experiences (FACES) dataset to construct a snapshot of vocabulary instruction and learning in high-poverty preschools. Specifically, we examined Head Start teachers' reports of the frequency of vocabulary instruction in their classrooms as well as the overall quality of their classroom instruction. We also explored the teacher- and center level factors that predicted these dual aspects of instruction, and the role of that instruction in children's vocabulary development over the preschool year. Participants included 293 teachers in 116 Head Start centers, as well as 2501 children in their classrooms. Results showed that, whereas there was notable variation, most teachers reported providing a variety of vocabulary-focused instructional activities nearly every day. The quality of their classroom instruction was generally modest. Classroom instructional quality was predictive of children's vocabulary learning, with stronger relations apparent for children with lower initial skills and for classrooms with higher quality instruction. The frequency of instruction in vocabulary was not related to children's word learning. Results provide new descriptive data about the state of vocabulary instruction in Head Start preschools and highlight both areas of success and opportunities for additional support. PMID- 23816232 TI - Middle school students' willingness to engage in activities with peers with ADHD symptoms: a multiple indicators multiple causes (MIMIC) model. AB - Researchers examining peers' behavioral intentions toward students diagnosed with ADHD have frequently used vignettes and asked students to indicate their willingness to engage with an individual described either with or without symptoms of ADHD. The Shared Activities Questionnaire (SAQ-B) is one instrument that has been used to measure students' intentions to engage with students represented in these vignettes. Confirmatory factor analysis results from 183 middle school students supported the three-factor model underlying the SAQ-B, although there were some areas of model misfit. To examine the effects of experimentally manipulating two vignette conditions (describing a peer displaying ADHD symptoms or a peer without these symptoms) on students' responses to items on the SAQ-B, a multiple indicators, multiple causes (MIMIC) analysis was used. Results of the MIMIC analyses identified 4 of the 24 SAQ-B items that exhibited statistically significant uniform differential item functioning between the experimental vignette conditions. Comparisons of the latent variable means between experimental conditions indicated that participants expressed greater willingness to engage with a peer without ADHD symptoms than with one with symptoms on academic activities; no differences were found on the latent variable means for social and recreational activities. Familiarity with ADHD did not have a significant relation to participants' willingness to engage in any of the three types of activities. Implications for practice and research are discussed. PMID- 23816233 TI - Student-, classroom-, and school-level risk factors for victimization. AB - The purpose of this study was to simultaneously investigate student-, classroom-, and school-level risk factors for victimization. Both peer nominations and students' self-reports of victimization were utilized. The sample consisted of 6731 Finnish elementary school students (3386 girls and 3345 boys) nested in 358 classrooms in 74 schools. The participants were from Grades 3, 4, and 5 (mean age 11years). The results of multilevel analyses indicated that there was considerable variability in, and distinctive risk factors associated with, both peer- and self-reported victimization at all the three levels investigated. Social anxiety and peer rejection synergistically predicted victimization at the student level. At the classroom level, negative social outcome expectations of defending the victim were associated with an increased risk of a student being bullied. Victimization was also common in classrooms and schools where students perceived their teachers to have less disapproving attitudes toward bullying. Furthermore, the effects of the student-level predictors were found to vary across classrooms, and classroom size moderated the effects of social anxiety and peer rejection on victimization. By identifying the risk factors at the multiple levels, and looking into cross-level interactions among these factors, research can help to target interventions at the key ecological factors contributing to victimization, making it possible to maximize the effectiveness of interventions. PMID- 23816234 TI - Brain microglia were activated in sporadic CJD but almost unchanged in fatal familial insomnia and G114V genetic CJD. AB - BACKGROUND: Microglial activations have been described in different subtypes of human prion diseases such as sporadic Creutzfeldt-Jakob disease (CJD), variant CJD, Kuru and Gerstmann-Straussler-Scheinker disease (GSS). However, the situation of microglia in other genetic prion diseases such as fatal familial insomnia (FFI) and familial CJD remains less understood. The brain microglia was evaluated comparatively between the FFI, G114V and sCJD cases in the study. METHODS: Specific Western blots, immunohistochemical and immunofluorescent assays were used to detect the changes of microglia and ELISA tests were used for levels of inflammatory cytokines. RESULTS: Western blots, immunohistochemical and immunofluorescent assays illustrated almost unchanged microglia in the temporal lobes of FFI and G114V gCJD, but obviously increased in those of sCJD. The Iba1 levels maintained comparable in six different brain regions of FFI and G114V cases, including thalamus, cingulate gyrus, frontal cortex, parietal cortex, occipital cortex and temporal cortex. ELISA tests for inflammatory cytokines revealed significantly up-regulated IL-1beta, IL-6 and TNF-alpha in the brain homogenates from sCJD, but not in those from FFI and G114V gCJD. CONCLUSION: Data here demonstrates silent brain microglia in FFI and G114V gCJD but obviously increased in sCJD, which reflects various pathogenesis of different human prion diseases subtypes. PMID- 23816235 TI - Therapeutic benefit of a combined strategy using erythropoietin and endothelial progenitor cells after transient focal cerebral ischemia in rats. AB - OBJECTIVE: Many studies have demonstrated beneficial effects of either erythropoietin (EPO) or endothelial progenitor cell (EPC) treatment in cerebral ischemia. To improve post-ischemic tissue repair, we investigated the effect of systemic administration of endothelial colony-forming cells (ECFCs), considered as relevant endothelial progenitors due to their specific vasculogenic activity, in the presence or absence of EPO, on functional recovery, apoptosis, angiogenesis, and neurogenesis in a transient focal cerebral ischemia model in the adult rat. DESIGN: Experimental study. INTERVENTION: The rats were divided into four groups 24 hours after ischemia,, namely control, ECFCs, EPO, and ECFCs+EPO, and received a single intravenous injection of ECFCs (5 * 10(6) cells) and/or intraperitoneal administration of EPO (2500 UI/kg per day for 3 days). MEASUREMENT: Infarct volume, functional recovery, apoptosis, angiogenesis, and neurogenesis were assessed at different time points after ischemia. MAIN RESULTS: The combination of EPO and ECFCs was the only treatment that completely restored neurological function. The ECFCs+EPO treatment was also the most effective to decrease apoptosis and to increase angiogenesis and neurogenesis in the ischemic hemisphere compared to controls and to groups receiving ECFCs or EPO alone. CONCLUSION: These results suggest that EPO could act in a synergistic way with ECFCs to potentiate their therapeutic benefits. PMID- 23816237 TI - Social inequalities in patient experiences with general practice and in access to specialists: the population-based HUNT Study. AB - BACKGROUND: In countries with gatekeeping and equitable access to general practitioners (GPs), social inequalities in GP-patient interaction could be an important mechanism by which inequalities in access to medical specialists arise. The aim of this study was to investigate whether socioeconomic inequalities in experiences with general practice are associated with socioeconomic inequalities in access to specialist services. METHODS: The study included 6,067 participants in the third survey of the Nord-Trondelag Health Study (HUNT3, 2006-08) who were asked to evaluate their experiences with primary care and their regular general practitioner in Norway. Self-reported data on health status and number of visits to GP and specialist services in the last 12 months were included in the study. Socioeconomic status was measured by education and household income and rescaled to relative index of inequality (RII). Relative risks were calculated using Poisson regression. RESULTS: We found that a majority of patients reported positive experiences with general practice. Low socioeconomic status (SES) and male gender were associated with negative experiences. Patient experiences both directly and indirectly related to referrals were associated with the probability and quantity of specialist utilization: perception of low subjective influence on decisions about choice of medical care was associated with lower probability and quantity of specialist utilization, whereas desire to change the regular GP or to use GPs other than the regular GP and critical evaluations of the GP were associated with higher specialist consultation frequency. However, the level of education-related inequity in access to specialists was not sensitive to adjustment by survey responses. CONCLUSION: Patient experiences with general practice were associated with the patients' level of utilization of specialist services. There are socioeconomic inequalities in patient experiences with general practice, however the aspects measured in this study do not explain the observed socioeconomic inequity in access to specialists. PMID- 23816238 TI - Creating 'obesogenic realities'; do our methodological choices make a difference when measuring the food environment? AB - BACKGROUND: The use of Geographical Information Systems (GIS) to objectively measure 'obesogenic' food environment (foodscape) exposure has become common place. This increase in usage has coincided with the development of a methodologically heterogeneous evidence-base, with subsequent perceived difficulties for inter-study comparability. However, when used together in previous work, different types of food environment metric have often demonstrated some degree of covariance. Differences and similarities between density and proximity metrics, and within methodologically different conceptions of density and proximity metrics need to be better understood. METHODS: Frequently used measures of food access were calculated for North East England, UK. Using food outlet data from local councils, densities of food outlets per 1000 population and per km2 were calculated for small administrative areas. Densities (counts) were also calculated based on population-weighted centroids of administrative areas buffered at 400/800/1000 m street network and Euclidean distances. Proximity (street network and Euclidean distances) from these centroids to the nearest food outlet were also calculated. Metrics were compared using Spearman's rank correlations. RESULTS: Measures of foodscape density and proximity were highly correlated. Densities per km2 and per 1000 population were highly correlated (r(s) = 0.831). Euclidean and street network based measures of proximity (r(s) = 0.865) and density (r(s) = 0.667-0.764, depending on neighbourhood size) were also highly correlated. Density metrics based on administrative areas and buffered centroids of administrative areas were less strongly correlated (r(s) = 0.299-0.658). CONCLUSIONS: Density and proximity metrics were largely comparable, with some exceptions. Whilst results suggested a substantial degree of comparability across existing studies, future comparability could be ensured by moving towards a more standardised set of environmental metrics, where appropriate, lessening the potential pitfalls of methodological variation between studies. The researchers' role in creating their own obesogenic 'reality' should be better understood and acknowledged. PMID- 23816239 TI - Transperitoneal administration of dissolved hydrogen for peritoneal dialysis patients: a novel approach to suppress oxidative stress in the peritoneal cavity. AB - BACKGROUND: Oxidative stress (OS) related to glucose degradation products such as methylglyoxal is reportedly associated with peritoneal deterioration in patients treated with peritoneal dialysis (PD). However, the use of general antioxidant agents is limited due to their harmful effects. This study aimed to clarify the influence of the novel antioxidant molecular hydrogen (H2) on peritoneal OS using albumin redox state as a marker. METHODS: Effluent and blood samples of 6 regular PD patients were obtained during the peritoneal equilibrium test using standard dialysate and hydrogen-enriched dialysate. The redox state of albumin in effluent and blood was determined using high-performance liquid chromatography. RESULTS: Mean proportion of reduced albumin (f(HMA)) in effluent was significantly higher in H2-enriched dialysate (62.31 +/- 11.10%) than in standard dialysate (54.70 +/- 13.08%). Likewise, serum f(HMA) after administration of hydrogen-enriched dialysate (65.75 +/- 7.52%) was significantly higher than that after standard dialysate (62.44 +/- 7.66%). CONCLUSIONS: Trans-peritoneal administration of H2 reduces peritoneal and systemic OS. PMID- 23816240 TI - Prefrontal cortex activity during response selection predicts processing speed impairment in schizophrenia. AB - Processing speed is the most impaired neuropsychological domain in schizophrenia and a robust predictor of functional outcome. Determining the specific cognitive operations underlying processing speed dysfunction and identifying their neural correlates may assist in developing pro-cognitive interventions. Response selection, the process of mapping stimuli onto motor responses, correlates with neuropsychological tests of processing speed and may contribute to processing speed impairment in schizophrenia. This study investigated the relationship between behavioral and neural measures of response selection, and a neuropsychological index of processing speed in schizophrenia. Twenty-six patients with schizophrenia and 21 healthy subjects underwent functional magnetic resonance imaging scanning during performance of two- and four-choice reaction time (RT) tasks and completed the Wechsler Adult Intelligence Scale-III (WAIS) Processing Speed Index (PSI). Response selection, defined as RT slowing between two- and four-choice RT, was impaired in schizophrenia and correlated with psychometric processing speed. Greater activation of the dorsolateral prefrontal cortex (PFC) was observed in schizophrenia and correlated with poorer WAIS PSI scores. Deficient response selection and abnormal recruitment of the dorsolateral PFC during response selection contribute to processing speed impairment in schizophrenia. Interventions that improve response selection and normalize dorsolateral PFC function may improve processing speed in schizophrenia. PMID- 23816241 TI - Constitutional trisomy 8 mosaicism as a model for epigenetic studies of aneuploidy. AB - BACKGROUND: To investigate epigenetic patterns associated with aneuploidy we used constitutional trisomy 8 mosaicism (CT8M) as a model, enabling analyses of single cell clones, harboring either trisomy or disomy 8, from the same patient; this circumvents any bias introduced by using cells from unrelated, healthy individuals as controls. We profiled gene and miRNA expression as well as genome wide and promoter specific DNA methylation and hydroxymethylation patterns in trisomic and disomic fibroblasts, using microarrays and methylated DNA immunoprecipitation. RESULTS: Trisomy 8-positive fibroblasts displayed a characteristic expression and methylation phenotype distinct from disomic fibroblasts, with the majority (65%) of chromosome 8 genes in the trisomic cells being overexpressed. However, 69% of all deregulated genes and non-coding RNAs were not located on this chromosome. Pathway analysis of the deregulated genes revealed that cancer, genetic disorder, and hematopoiesis were top ranked. The trisomy 8-positive cells displayed depletion of 5-hydroxymethylcytosine and global hypomethylation of gene-poor regions on chromosome 8, thus partly mimicking the inactivated X chromosome in females. CONCLUSIONS: Trisomy 8 affects genes situated also on other chromosomes which, in cooperation with the observed chromosome 8 gene dosage effect, has an impact on the clinical features of CT8M, as demonstrated by the pathway analysis revealing key features that might explain the increased incidence of hematologic malignancies in CT8M patients. Furthermore, we hypothesize that the general depletion of hydroxymethylation and global hypomethylation of chromosome 8 may be unrelated to gene expression regulation, instead being associated with a general mechanism of chromatin processing and compartmentalization of additional chromosomes. PMID- 23816242 TI - Effects of adrenomedullin and vascular endothelial growth factor on ischemia/reperfusion injury in skeletal muscle in rats. AB - BACKGROUND: In this study we investigated the effects of adrenomedullin (AM) and vascular endothelial growth factor (VEGF) on skeletal muscle ischemia/reperfusion (I/R) injury in a rat model. MATERIALS AND METHODS: Thirty-six Wistar rats were randomized into six groups (n = 6). Laparotomy was performed in all groups under general anesthesia. Nothing else was done in Group S (Sham). The Group I/R underwent I/R performed by clamping and declamping of the infrarenal abdominal aorta for 120 min, respectively. Group VEGF and Group AM received intravenous infusion of VEGF (0.8 MUg/kg) or AM (12 MUg/kg) respectively, without I/R. Group I/R + VEGF and Group I/R + AM received intravenous infusion of VEGF (0.8 MUg/kg) or AM (12 MUg/kg) immediately after 2 h period of ischemia, respectively. At the end of reperfusion period, skeletal muscle samples of lower extremity were taken from all groups for biochemical and histopathologic examinations. RESULTS: Tissue levels of malondialdehyde (MDA), superoxide dismutase (SOD), nitric oxide (NO), and hypoxia inducible factor 1 alpha (HIF 1alpha) were found to be significantly higher in Group I/R than the levels in Group S (P < 0.05). Tissue levels of MDA, SOD, NO, and HIF 1alpha were significantly lower in Group I/R + AM compared with the levels in Group I/R (P < 0.05). In Group I/R + VEGF, tissue levels of MDA and NO were significantly lower than the levels in Group I/R (P < 0.05). No statistically significant difference was found in the tissue levels of catalase among the groups. Histologic examination revealed a larger central muscular necrosis than the peripheral necrosis, red blood cells in the lumens of capillary vessels, and a stronger atrophy and elliptical or round shape in muscle fibers in Group I/R. Terminal deoxynucleotidyl transferase mediated dUPT nick end labeling (TUNEL)-positive cell count was significantly lower in groups I/R + AM and I/R + VEGF than Group I/R (P < 0.0001, P < 0.0001, respectively). CONCLUSIONS: These results indicate that AM and VEGF have protective effects on I/R injury in skeletal muscle in a rat model. PMID- 23816243 TI - Increased risk of pneumonia among ventilated patients with traumatic brain injury: every day counts! AB - BACKGROUND: Patients with traumatic brain injury (TBI) frequently require mechanical ventilation (MV). The objective of this study was to examine the association between time spent on MV and the development of pneumonia among patients with TBI. MATERIALS AND METHODS: Patients older than 18 y with head abbreviated injury scale (AIS) scores coded 1-6 requiring MV in the National Trauma Data Bank 2007-2010 data set were included. The study was limited to hospitals reporting pneumonia cases. AIS scores were calculated using ICDMAP-90 software. Patients with injuries in any other region with AIS score >3, significant burns, or a hospital length of stay >30 d were excluded. A generalized linear model was used to determine the approximate relative risk of developing all-cause pneumonia (aspiration pneumonia, ventilator-associated pneumonia [VAP], and infectious pneumonia identified by the International Classification of Disease, Ninth Revision, diagnosis code) for each day of MV, controlling for age, gender, Glasgow coma scale motor score, comorbidity (Charlson comorbidity index) score, insurance status, and injury type and severity. RESULTS: Among the 24,525 patients with TBI who required MV included in this study, 1593 (6.5%) developed all-cause pneumonia. After controlling for demographic and injury factors, each additional day on the ventilator was associated with a 7% increase in the risk of pneumonia (risk ratio 1.07, 95% confidence interval 1.07-1.08). CONCLUSIONS: Patients who have sustained TBIs and require MV are at higher risk for VAP than individuals extubated earlier; therefore, shortening MV exposure will likely reduce the risk of VAP. As patients with TBI frequently require MV because of neurologic impairment, it is key to develop aggressive strategies to expedite ventilator independence. PMID- 23816244 TI - Selective lateral compartment neck dissection for thyroid cancer. AB - BACKGROUND: Compartment-oriented lymph node dissection in patients with thyroid cancer and macroscopic lymph node metastases reduces recurrence and improves survival. However, the extent of lymph node dissection remains controversial. The purpose of this study was to examine the results of selective lateral compartment neck dissection (LCND) for thyroid cancer. METHODS: We completed a retrospective review of patients with thyroid cancer who underwent selective LCND from 1992 2012 to determine the extent of lymph node resection, morbidity, recurrence, subsequent operations, mortality, and duration of follow-up. RESULTS: A total of 45 LCNDs (five bilateral) were performed in 40 patients, 35 with differentiated thyroid cancer (DTC) and five with medullary carcinoma. Nineteen LCNDs (42%) were completed at the time of thyroidectomy. Levels IIA, III, IV, and VB were included in 43 LCNDs (96%) and levels IIA, III, and IV in two LCNDs (4%). Morbidity included neck or ear numbness in 19 patients (48%), neuropathic symptoms in 14 (35%), Horner syndrome in two (5%), marginal mandibular nerve paresis in two (5%), and wound infection in one (3%). Recurrence rate was 25% (10 patients) and one or more reoperations were performed in seven patients (18%) with a mean follow-up of 58 +/- 60 mo (range, 1-244 mo). There were 3 ipsilateral recurrences (8%) after 40 LCNDs for DTC. Four patients died from systemic disease: three with medullary carcinoma and one with PTC. CONCLUSIONS: Selective LCND is an effective therapeutic strategy for macroscopic lymph node metastases, with an 8% recurrence rate in the ipsilateral neck in patients with DTC. Neuropathic symptoms, however, remain an important source of morbidity. PMID- 23816245 TI - Leflunomide suppresses growth in human medullary thyroid cancer cells. AB - BACKGROUND: Medullary thyroid cancer (MTC) is a neuroendocrine tumor that arises from the calcitonin-secreting parafollicular cells of the thyroid gland. Leflunomide (LFN) is a disease-modifying antirheumatic drug approved for the treatment of rheumatoid arthritis, and its active metabolite teriflunomide has been identified as a potential anticancer drug. In this study we investigated the ability of LFN to similarly act as an anticancer drug by examining the effects of LFN treatment on MTC cells. METHODS: Human MTC-TT cells were treated with LFN (25 150 MUmol/L) and Western blotting was performed to measure levels of neuroendocrine markers. MTT assays were used to assess the effect of LFN treatment on cellular proliferation. RESULTS: LFN treatment downregulated neuroendocrine markers ASCL1 and chromogranin A. Importantly, LFN significantly inhibited the growth of MTC cells in a dose-dependent manner. CONCLUSIONS: Treatment with LFN decreased neuroendocrine tumor marker expression and reduced the cell proliferation in MTC cells. As the safety of LFN in human beings is well established, a clinical trial using this drug to treat patients with advanced MTC may be warranted. PMID- 23816246 TI - Angelicin regulates LPS-induced inflammation via inhibiting MAPK/NF-kappaB pathways. AB - BACKGROUND: Angelicin is a furocoumarin found in Psoralea corylifolia L. fruit. The purpose of this study was to investigate the protective ability of angelicin against inflammation in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells and LPS-induced in vivo acute lung injury model. MATERIALS AND METHODS: The concentrations of tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-6 in the culture supernatants of RAW 264.7 cells were determined 24 h after LPS administration. ALI was induced by intratracheal instillation of LPS. Six hours after LPS inhalation, bronchoalveolar lavage fluid and lung tissue samples were obtained for enzyme-linked immunosorbent assay, histologic, and Western blotting analyses. RESULTS: The results showed that pretreatment with angelicin markedly downregulated TNF-alpha and IL-6 levels in vitro and in vivo, and significantly decreased the amount of inflammatory cells, lung wet-to-dry weight ratio, and myeloperoxidase activity in LPS-induced ALI mice. Furthermore, Western blotting analysis results demonstrated that angelicin blocked the phosphorylation of IkappaBalpha, NF-kappaBp65, p38 MAPK, and JNK in LPS-induced ALI. CONCLUSIONS: These results suggest that angelicin was potentially advantageous to prevent inflammatory diseases by inhibiting NF-kappaB and MAPK pathways. Our data indicated that angelicin might be a potential new agent for prevention of inflammatory reactions and diseases in the clinic. PMID- 23816247 TI - Initial assessment on the impact of crystalloids versus colloids during damage control resuscitation. AB - BACKGROUND: High ratios of fresh frozen plasma:packed red blood cells in damage control resuscitation (DCR) are associated with increased survival. The impact of volume and type of resuscitative fluid used during high ratio transfusion has not been analyzed. We hypothesize a difference in outcomes based on the type and quantity of resuscitative fluid used in patients that received high ratio DCR. METHODS: A matched case control study of patients who received transfusions of >= four units of PRBC during damage control surgery over 4 1/2 y, was conducted at a Level I Trauma Center. All patients received a high ratio DCR, >1:2 of fresh frozen plasma:packed red blood cells. Demographics and outcomes of the type and quantity of resuscitative fluids used in combination with high ratio DCR were compared and analyzed. A Kaplan-Meier survival analysis was computed among four groups: colloid (median quantity = 1.0 L), <3 L crystalloid, 3-6 L crystalloid, and >6 L crystalloid. RESULTS: There were 56 patients included in the analysis (28 in the crystalloid group and 28 in the colloid group). Demographics were statistically similar. Intraoperative median units of PRBC: crystalloid versus colloid groups was 13 (IQR 8-21) versus 16 (IQR 12-19), P = 0.135; median units of FFP: 12 (IQR 7-18) versus 12 (IQR 10-18), P = 0.440. OR for 10-d mortality in the crystalloid group was 8.41 [95% CI 1.65-42.76 (P = 0.01)]. Kaplan-Meier survival analysis demonstrated lowest mortality in the colloid group and higher mortality with increasing amounts of crystalloid (P = 0.029). CONCLUSIONS: During high ratio DCR, resuscitation with higher volumes of crystalloids was associated with an overall decreased survival, whereas low volumes of colloid use were associated with increased survival. In order to improve outcomes without diluting the survival benefit of hemostatic resuscitation, guidelines should focus on effective low volume resuscitation when high ratio DCR is used. A multi institutional analysis is needed in order to validate these results. PMID- 23816248 TI - Temperature and pressure dependence of azurin stability as monitored by tryptophan fluorescence and phosphorescence. The case of F29A mutant. AB - The effects of a single-point, F29A, cavity-forming mutation on the unfolding thermodynamic parameters of azurin from Pseudomonas aeruginosa and on the internal dynamics of the protein fold under pressure were probed by the fluorescence and phosphorescence emission of Trp48, deeply buried in the compact hydrophobic core of the macromolecule. Pressure-induced unfolding, monitored by the shift in the fluorescence spectrum, led to a volume change of 70-90mlmol(-1). The difference in the unfolding volume between F29A and wild type azurin was smaller than the volume of the space theoretically created in the mutant, indicating that the cavity is, at least partially, filled with water molecules. The complex temperature dependence of the unfolding volume, for temperatures up to 20 degrees C, suggests the formation of an expanded form of the protein and highlights how the packing efficiency of azurin appears to contribute to the magnitude of internal void volume at any given temperature. Changes in flexibility of the protein matrix around the chromophore were monitored by the intrinsic phosphorescence lifetime. At 40 degrees C the application of pressure in the predenaturation range initially decreases the internal flexibility of azurin, the trend eventually reverting on approaching unfolding. The main difference between wild type and the cavity mutant is the inversion point which happens at 300MPa for wild type and at 150MPa for F29A. This suggests that, for the cavity mutant, pressure-induced internal hydration is more dominant than any compaction of the globular fold at relatively low pressures. PMID- 23816249 TI - Does hyperbaric oxygen therapy have the potential to improve salivary gland function in irradiated head and neck cancer patients? AB - Following radiotherapy, many patients with osteoradionecrosis suffer from xerostomia, thereby decreasing their quality of life. Patients can develop problems with speech, eating, increased dental caries, dysphagia, fractured dentition, chronic refractory osteomyelitis and osteoradionecrosis. Symptoms associated with salivary gland dysfunction can be severe enough that patients terminate the course of their radiotherapy prematurely due to the decrease in their quality of life. Currently, the only treatments available to patients are palliative. A definitive treatment has yet to be discovered. Head and neck cancers, which comprise 5% of overall cancer treatments, rank 8th most expensive to treat in the United States today. Hyperbaric oxygen is being considered for the therapy of radiated salivary glands because it has been shown to stimulate capillary angiogenesis and fibroplasia in radiation treated tissues. It has been hypothesized that salivary acinar cells undergo apoptosis following radiation therapy. The purpose of this paper is to discuss the mechanisms of salivary gland injury and evaluate whether hyperbaric oxygen therapy improves salivary gland function in patients who develop xerostomia and osteoradionecrosis following head and neck radiation. PMID- 23816251 TI - Effective management of medical information through ROI-lossless fragile image watermarking technique. AB - In this article, we have proposed a blind, fragile and Region of Interest (ROI) lossless medical image watermarking (MIW) technique, providing an all-in-one solution tool to various medical data distribution and management issues like security, content authentication, safe archiving, controlled access retrieval, and captioning. The proposed scheme combines lossless data compression and encryption technique to embed electronic health record (EHR)/DICOM metadata, image hash, indexing keyword, doctor identification code and tamper localization information in the medical images. Extensive experiments (both subjective and objective) were carried out to evaluate performance of the proposed MIW technique. The findings offer suggestive evidence that the proposed MIW scheme is an effective all-in-one solution tool to various issues of medical information management domain. Moreover, given its relative simplicity, the proposed scheme can be applied to the medical images to serve in many medical applications concerned with privacy protection, safety, and management. PMID- 23816250 TI - A novel A781V mutation in the CSF1R gene causes hereditary diffuse leucoencephalopathy with axonal spheroids. AB - We report a family with a novel CSF1R mutation causing hereditary diffuse leucoencephalopathy with axonal spheroids. Family members presented with neuropsychiatric and behavioural symptoms, with subsequent development of motor symptoms and gait disturbance. MRI brain showed extensive white matter change with a frontal predominance and associated atrophy in two members of the family. Genetic testing revealed a novel mutation c.2342C>T (p.A781V) in the CSF1R gene in two brothers of the family. This report highlights the difficulties in diagnosing HDLS and discusses the indications for testing for mutations in the CSF1R gene. PMID- 23816252 TI - Use of shape-from-shading to estimate three-dimensional architecture in the small intestinal lumen of celiac and control patients. AB - BACKGROUND: As measured from videocapsule endoscopy images, the small intestinal mucosa of untreated celiac patients has significantly greater and more varied texture compared to normal patients. Three-dimensional modeling using shape-from shading principles may further increase classification accuracy. METHODS: A sequence of 200 consecutive videocapsule images acquired at a 2s(-1) frame rate and 576*576 pixel dimension, were obtained at four locations in the small intestinal lumen of ten patients with biopsy-proven celiac disease and ten control patients. Each two-dimensional image was converted to a three-dimensional architectural approximation by considering the 256 grayscale level to be linearly representative of image depth. From the resulting three-dimensional architecture, distinct luminal protrusions, representative of the macro-architecture, were automatically identified by computer algorithm. The range and number of protrusions per image, and their width and height, were determined for celiacs versus controls and tabulated as mean+/-SD. RESULTS: The mean number of villous protrusions per image was 402.2+/-15.0 in celiacs versus 420.8+/-24.0 in controls (p<0.001). The average protrusion width was 14.7 pixels in celiacs versus 13.9 pixels in controls (p=0.01). The mean protrusion height was 3.10+/-2.34 grayscale levels for celiacs versus 2.70+/-0.43 grayscale levels for controls (p<0.001). Thus celiac patients had significantly fewer protrusions on the luminal surface of the small intestine as compared with controls, and these protrusions had greater dimensions, suggesting they are indicative of a mosaic (cobblestone) macro-architectural pattern which is common in celiacs. CONCLUSIONS: Shape-from shading modeling is useful to explore luminal macro-architecture and to detect significant differences in luminal morphology in celiac versus normal patients, which can increase the usefulness of videocapsule studies. PMID- 23816253 TI - Trends in HIV counseling and testing uptake among married individuals in Rakai, Uganda. AB - BACKGROUND: Despite efforts to promote HIV counseling and testing (HCT) among couples, few couples know their own or their partners' HIV status. We assessed trends in HCT uptake among married individuals in Rakai district, southwestern Uganda. METHODS: We analysed data for 11,268 married individuals aged 15-49 years who were enrolled into the Rakai Community Cohort Study (RCCS) between 2003 and 2009. Married individuals were interviewed separately but were retrospectively linked to their partners at analysis. All participants had serologic samples obtained for HIV testing, and had the option of receiving HCT together (couples' HCT) or separately (individual HCT). Individuals were categorized as concordant HIV-positive if both partners had HIV; concordant HIV-negative if both did not have HIV; or HIV-discordant if only one of the partners had HIV. We used chi2 tests to assess linear trends in individual and couples' HCT uptake in the entire sample and conducted multinomial logistic regression on a sub-sample of 10,712 individuals to assess relative risk ratios (RRR) and 95% Confidence Intervals (95% CI) associated with individual and couples' HCT uptake. Analysis was done using STATA version 11.0. RESULTS: Uptake of couples' HCT was 27.2% in 2003/04, 25.1% in 2005/06, 28.5% in 2006/08 and 27.8% in 2008/09 (chi2 for trend = 2.38; P = 0.12). Uptake of individual HCT was 57.9% in 2003/04, 60.2% in 2005/06, 54.0% in 2006/08 and 54.4% in 2008/09 (chi2 for trend = 8.72; P = 0.003). The proportion of couples who had never tested increased from 14.9% in 2003/04 to 17.8% in 2008/09 (chi2 for trend = 18.16; P < 0.0001). Uptake of couples' HCT was significantly associated with prior HCT (Adjusted [Adj.] RRR = 6.80; 95% CI: 5.44, 8.51) and being 25-34 years of age (Adj. RRR = 1.81; 95% CI: 1.32, 2.50). Uptake of individual HCT was significantly associated with prior HCT (Adj. RRR = 6.26; 95% CI: 4.24, 9.24) and the female partner being HIV-positive (Adj. RRR = 2.46; 95% CI: 1.26, 4.80). CONCLUSION: Uptake of couples' HCT remained consistently low (below 30%) over the years, while uptake of individual HCT declined over time. These findings call for innovative strategies to increase demand for couples' HCT, particularly among younger couples and those with no prior HCT. PMID- 23816255 TI - The antennal lobe of Libellula depressa (Odonata, Libellulidae). AB - Here we describe the antennal lobe of Libellula depressa (Odonata, Libellulidae), identified on the basis of the projections of the afferent sensory neurons stemming from the antennal flagellum sensilla. Immunohistochemical neuropil staining as well as antennal backfills revealed sensory neuron terminal arborizations covering a large portion of the antennal lobe. No clear glomerular structure was identified, thus suggesting an aglomerular antennal lobe condition as previously reported in Palaeoptera. The terminal arbors of backfilled sensory neurons do, however, form spherical knots, probably representing the connections between the few afferent neurons and the antennal lobe interneurons. The reconstruction revealed that the proximal part of the antennal nerve is divided into two branches that innervate two spatially separated areas of the antennal lobe, an anterioventral lobe and a larger posteriodorsal lobe. Our data are consistent with the hypothesis that one tract of the antennal nerve of L. depressa contains olfactory sensory neurons projecting into one of the sublobes, while the other tract contains thermo-hygroreceptive neurons projecting into the other sublobe. PMID- 23816254 TI - A gene expression profile indicative of early stage HER2 targeted therapy response. AB - BACKGROUND: Efficacious application of HER2-targetting agents requires the identification of novel predictive biomarkers. Lapatinib, afatinib and neratinib are tyrosine kinase inhibitors (TKIs) of HER2 and EGFR growth factor receptors. A panel of breast cancer cell lines was treated with these agents, trastuzumab, gefitinib and cytotoxic therapies and the expression pattern of a specific panel of genes using RT-PCR was investigated as a potential marker of early drug response to HER2-targeting therapies. RESULTS: Treatment of HER2 TKI-sensitive SKBR3 and BT474 cell lines with lapatinib, afatinib and neratinib induced an increase in the expression of RB1CC1, ERBB3, FOXO3a and NR3C1. The response directly correlated with the degree of sensitivity. This expression pattern switched from up-regulated to down-regulated in the HER2 expressing, HER2-TKI insensitive cell line MDAMB453. Expression of the CCND1 gene demonstrated an inversely proportional response to drug exposure. A similar expression pattern was observed following the treatment with both neratinib and afatinib. These patterns were retained following exposure to traztuzumab and lapatinib plus capecitabine. In contrast, gefitinib, dasatinib and epirubicin treatment resulted in a completely different expression pattern change. CONCLUSIONS: In these HER2 expressing cell line models, lapatinib, neratinib, afatinib and trastuzumab treatment generated a characteristic and specific gene expression response, proportionate to the sensitivity of the cell lines to the HER2 inhibitor.Characterisation of the induced changes in expression levels of these genes may therefore give a valuable, very early predictor of the likely extent and specificity of tumour HER2 inhibitor response in patients, potentially guiding more specific use of these agents. PMID- 23816256 TI - Comparative full length genome sequence analysis of Usutu virus isolates from Africa. AB - BACKGROUND: Usutu virus (USUV), a flavivirus belonging to the Japanese encephalitis serocomplex, was identified in South Africa in 1959 and reported for the first time in Europe in 2001. To date, full length genome sequences have been available only for the reference strain from South Africa and a single isolate from each of Austria, Hungary, and Italy. METHODS: We sequenced four USUV isolates from Senegal and the Central African Republic (CAR) between 1974 and 2007 and compared the sequence data to USUV strains from Austria, Hungary, Italy, and South Africa using a Bayesian Markov chain Monte Carlo method. We further clarified the taxonomic status of a USUV strain isolated in CAR in 1969 and proposed earlier as a subtype of USUV due to an asymetric serological cross reactivity with USUV reference strain. RESULTS: A comparison of the four newly obtained USUV sequences with those from SouthAfrica_1959, Vienna_2001, Budapest_2005, and Italy_2009 revealed that they are all 96-99% and 99% similar at the nucleotide and amino acid levels, respectively. The phylogenetic relationships between these sequences indicated that a strain isolated in Senegal in 1993 is most closely related to the USUV strains detected in Europe. Analysis of a strain isolated from a human in CAR in 1981 (CAR_1981) revealed the presence of specific amino acid substitutions and a deletion in the 3' noncoding region. This is the first fully sequenced human USUV isolate.The putative USUV subtype, CAR_1969, was 81% and 94% identical at the nucleotide and amino acid levels, respectively, compared to the other USUV strains. Our phylogenetic analyses support the serological identification of CAR_1969 as a subtype of USUV. CONCLUSIONS: In this study, we investigate the genetic diversity of USUV in Africa and the phylogenetic relationship of isolates from Africa and Europe for the first time. The results suggest a low genetic diversity within USUV, the existence of a distinct USUV subtype strain, and support the hypothesis that USUV was introduced to Europe from Africa. Further sequencing and analysis of USUV isolates from other African countries would contribute to a better understanding of its genetic diversity and geographic distribution. PMID- 23816258 TI - Quantification of cavitation and gapping of lumbar zygapophyseal joints during spinal manipulative therapy. PMID- 23816259 TI - Accelerators/decelerators of achieving universal access to sexual and reproductive health services: a case study of Iranian health system. AB - BACKGROUND: At the 1994 International Conference on Population and Development (ICPD), held in Cairo, the global community agreed to the goal of achieving universal access to sexual and reproductive health (SRH) and rights by 2015. This research explores the accelerators and decelerators of achieving universal access to the sexual and reproductive health targets and accordingly makes some suggestions. METHOD: We have critically reviewed the latest national reports and extracted the background data on each SRH indicator. The key stakeholders, both national and international, were visited and interviewed at two sites. A total of 55 in-depth interviews were conducted with religious leaders, policy-makers, senior managers, senior academics, and health care managers. Six focus-group discussions were also held among health care providers. The study was qualitative in nature. RESULTS: Obstacles on the road to achieving universal access to SRH can be viewed from two perspectives. One gap exists between current achievements and the targets. The other gap arises due to age, marital status, and residency status. The most recently observed trends in the indicators of the universal access to SRH shows that the achievements in the "unmet need for family planning" have been poor. Unmet need for family planning could directly be translated to unwanted pregnancies and unwanted childbirths; the former calls for sexual education to underserved people, including adolescents; and the latter calls for access to safe abortion. Local religious leaders have not actively attended international goal-setting programs. Therefore, they usually do not presume a positive attitude towards these goals. Such negative attitudes seem to be the most important factors hindering the progress towards universal access to SRH. Lack of international donors to fund for SRH programs is also another barrier. In national levels both state and the society are interactively playing their roles. We have used a cascade model for presenting the barriers at the state levels from the strategic planning to implementation. Social factors are to be considered as a background for other factors at all stages. CONCLUSION: Accelerating universal access to SRH requires adequate funding, firm political commitment, creative programming, and the involvement of diverse actors, including faith-based, civil society, and private sector partners. PMID- 23816260 TI - Management of war-related vascular injuries: experience from the second gulf war. AB - AIM: To study the biomechanism, pattern of injury, management, and outcome of major vascular injuries treated at Mubarak Al-Kabeer Teaching Hospital, Kuwait during the Second Gulf War. METHODS: This is a descriptive retrospective study. War-related injured patients who had major vascular injuries and were treated at Mubarak Al-Kabeer Teaching Hospital from August 1990 to September 1991 were studied. Studied variables included age, gender, anatomical site of vascular injury, mechanism of injury, associated injuries, type of vascular repair, and clinical outcome. RESULTS: 36 patients having a mean (SD) age of 29.8 (10.2) years were studied. 32 (89%) were males and 21 (58%) were civilians. Majority of injuries were caused by bullets (47.2%) and blast injuries (47.2%). Eight patients (22%) presented with shock.There were 31 arterial injuries, common and superficial femoral artery injuries were most common (10/31). Arterial repair included interposition saphenous vein graft in seven patients, thrombectomy with end-to-end / lateral repair in twelve patients, vein patch in two patients, and arterial ligation in four patients. Six patients had arterial ligation as part of primary amputation. 3/21 (14.3%) patients had secondary amputation after attempted arterial vascular repair of an extremity. There were a total of 17 venous injuries, 13 managed by lateral suture repair and 4 by ligation. The median (range) hospital stay was 8 (1-76) days. 5 patients died (14%). CONCLUSIONS: Major vascular injuries occurred in 10% of hospitalized war-related injured patients. Our secondary amputation rate of extremities was 14%. The presence of a vascular surgeon within a military surgical team is highly recommended. Basic principles and techniques of vascular repair remain an essential part of training general surgeons because it may be needed in unexpected wars. PMID- 23816261 TI - Development and validation of a sensitive enzyme immunoassay (EIA) for blood plasma cortisol in female cattle, buffaloes, and goats. AB - A highly sensitive enzyme immunoassay (EIA) that used the second antibody coating technique and the cortisol-horseradish peroxidase conjugate as a label for determination of free and total cortisol in blood plasma of dairy animals (cows, buffaloes, and goats) was developed. For biological validation of the EIA, blood samples were collected from the animals at 48 and 24 h before and 0, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, and 132 h after dexamethasone administration. The EIA was performed directly with 20 MUL of fresh plasma (for free cortisol) and also with 20 MUL of heat-treated plasma (for total cortisol) after 1:5 dilutions with PBS. Cortisol standards ranging from 0.39 to 200 pg/well/20 MUL were used, and the sensitivity of the EIA procedure was found to be 0.39 pg/well/20 MUL, which corresponded to 0.02 ng/mL. In comparison with RIA the EIA was at least 4 times more sensitive and required 5 times less cortisol antiserum. In female cattle, buffaloes, and goats, the total, free, and bound plasma cortisol before dexamethasone administration was significantly (P < 0.05) higher than the total, free, and bound cortisol after dexamethasone administration. It can be concluded from these studies that the direct, sensitive EIA validated for estimating the free and total cortisol concentrations was sufficiently reliable and quick for studying the dynamics of cortisol distribution in blood plasma of dairy animals. PMID- 23816262 TI - Perceived discrimination from management and musculoskeletal symptoms among New York City restaurant workers. AB - BACKGROUND: Compared with other restaurant hazards, organizational stressors are an understudied topic. Among organizational stressors, discrimination from management (DFM) appears widespread. OBJECTIVE: Objectives were to assess the prevalence and links between musculoskeletal symptoms (MSSs) in three anatomical regions and five sources of DFM. METHODS: A cross-sectional, interviewer administered survey among restaurant workers was used. Participants were randomly selected by type and geographic distribution. RESULTS: Eighty-four percent of workers reported having MSSs in at least one anatomical region. The prevalence of severe MSSs was 24.9%. The strongest association between DFM and frequency of MSSs was "upper extremities." The strongest association between DFM and severity of MSSs was "any anatomical location." Thirty-four percent of restaurant workers reported DFM; age was the most prevalent source of DFM. CONCLUSIONS: In general, associations between DFM and MSSs were stronger by frequency than severity. The largest number of significant associations by sources of DFM was language and age. PMID- 23816263 TI - How inhibition relates to impulsivity after moderate to severe traumatic brain injury. AB - Impulsive behaviors and poor inhibition performances are frequently described in patients with traumatic brain injury(TBI). However, few studies have examined impulsivity and associated inhibition impairments in these patients.Twenty-eight patients with moderate to severe TBI and 27 matched controls performed a stop signal task designed to assess prepotent response inhibition (the ability to inhibit a dominant or automatic motor response) in a neutral or emotional context and a recent negative task to assess resistance to proactive interference (the ability to resist the intrusion into memory of information that was previously relevant but has since become irrelevant). Informants of each patient completed a short questionnaire designed to assess impulsivity. Patients showed a significant increase in current urgency,lack of premeditation, and lack of perseverance when retrospectively compared with the preinjury condition. Group comparisons revealed poorer prepotent response inhibition and resistance to proactive interference performances inpatients with TBI. Finally, correlation analyses revealed a significant positive correlation between urgency (the tendency to act rashly when distressed) and prepotent response inhibition in patients with TBI. This study sheds new light on the construct of impulsivity after a TBI, its related cognitive mechanisms, and its potential role in problematic behaviors described after a TBI. PMID- 23816264 TI - Trunk muscle activation during golf swing: Baseline and threshold. AB - There is a lack of studies regarding EMG temporal analysis during dynamic and complex motor tasks, such as golf swing. The aim of this study is to analyze the EMG onset during the golf swing, by comparing two different threshold methods. Method A threshold was determined using the baseline activity recorded between two maximum voluntary contraction (MVC). Method B threshold was calculated using the mean EMG activity for 1000ms before the 500ms prior to the start of the Backswing. Two different clubs were also studied. Three-way repeated measures ANOVA was used to compare methods, muscles and clubs. Two-way mixed Intraclass Correlation Coefficient (ICC) with absolute agreement was used to determine the methods reliability. Club type usage showed no influence in onset detection. Rectus abdominis (RA) showed the higher agreement between methods. Erector spinae (ES), on the other hand, showed a very low agreement, that might be related to postural activity before the swing. External oblique (EO) is the first being activated, at 1295ms prior impact. There is a similar activation time between right and left muscles sides, although the right EO showed better agreement between methods than left side. Therefore, the algorithms usage is task- and muscle-dependent. PMID- 23816265 TI - Occult leydig cell tumour and androgen-receptor positive breast cancer in a woman with severe hyperandrogenism. AB - Leydig cell tumours represent more than 75% of all testosterone-secreting ovarian masses. These benign tumours are frequently occult or very small, but cause dramatic virilization. Chronic hyperandrogenism can also induce systemic complications, which increase morbidity and mortality risk. One of the most obvious effects of increased testosterone levels is polycythemia, a complication which induces dermatologic, osteoarticular and gastrointestinal manifestations and is associated with increased thrombotic risk. However, scientific literature reports few data concerning etiopathogenesis and management of polycythemia in patients with Leydig cell tumours. Moreover, no data are available about the effect of androgen excess on other concomitant tumours expressing androgen receptors. In this paper we report for the first time the case of a woman, with previous infertility, dramatic virilisation and chronic erythrocytosis, who was affected by an occult Leydig cell tumour and an androgen receptor positive breast cancer. This association gives us the opportunity to discuss the role of the steroid receptor expression of breast cancer in the presence of circulating androgen excess. Moreover, we demonstrate for the first time that treatment with flutamide (anti-androgen drug) is able to normalize blood cell count and haematocrit, before of achieving the definitive cure of hyperandrogenism by oophorectomy. PMID- 23816266 TI - Study protocol: a systematic review of pediatric shared decision making. AB - BACKGROUND: Shared decision making in pediatrics is unique because it often involves active participation of both the child or adolescent patient and his or her caregiver(s) in the decision making process with the clinician or care team, and the extent to which the patient is involved is commensurate with their developmental level. However, little is known about the nature of pediatric specific shared decision making interventions and their impact. METHODS/DESIGN: We will perform a systematic review with the objective of summarizing the nature of shared decision making practices, tools, techniques and technologies in the pediatric setting as well as their effects. A literature search will include Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Library, Web of Science, Scopus and Ovid PsycInfo databases in addition to consultation of a group of shared decision making experts to identify unpublished or in-progress works. We will include original research studies involving patients <18 years, their caregivers, or both, and summarize methods and approaches designed to engage participants in the health care decision making process with clinicians. Perinatal and research participation decisions will be excluded. Descriptions of participants involved, interventions used and the measured outcomes will be reported. Quality assessment will be performed according to the design of each study, where possible. DISCUSSION: We anticipate that the paucity of published quantitative data and the heterogeneous nature of the reported results will preclude quantitative analysis. In this event, a meta-narrative approach will be undertaken. TRIAL REGISTRATION: PROSPERO registration number: CRD42013004761. PMID- 23816267 TI - Complexity and simplicity in the evolution of decision-making biases. PMID- 23816268 TI - Tumor growth dynamics: insights into evolutionary processes. AB - Identifying the types of event that drive tumor evolution and progression is crucial for understanding cancer. We suggest that the analysis of tumor growth dynamics can provide a window into tumor biology and evolution by connecting them with the types of genetic change that have occurred. Although fundamentally important, the documentation of tumor growth kinetics is more sparse in the literature than is the molecular analysis of cells. Here, we provide a historical summary of tumor growth patterns and argue that they can be classified into five basic categories. We then illustrate how those categories can provide insights into events that drive tumor progression, by discussing a particular evolutionary model as an example and encouraging such analysis in a more general setting. PMID- 23816269 TI - Quality of life and long-term outcomes of octo- and nonagenarians following acute care surgery: a cross sectional study. AB - BACKGROUND: While advanced age is often associated with poorer surgical outcomes, long-term age-related health status following acute care surgery is unknown. The objective of our study was to assess post-operative cognitive impairment, functional status, and quality of life in elderly patients who underwent emergency surgery. METHODS: We identified 159 octo- and nonagenarians who underwent emergency surgery between 2008 and 2010 at a single tertiary hospital. Patients were grouped into three cohorts: 1, 2, and 3 years post-operative. We conducted a survey in 2011, with octo- and nonagenarians regarding the impact of emergency surgical procedures. Consenting participants responded to four survey questionnaires: (1) Abbreviated Mental Test Score-4, (2) Barthel Index, (3) Vulnerable Elders Survey, and (4) EuroQol-5 Dimensional Scale. RESULTS: Of the 159 octo- and nonagenarians, 88 (55.3%) patients were alive at the time of survey conduction, and 55 (62.5%) of the surviving patients consented to participate. At 1, 2, and 3 years post-surgery, mortality rates were 38.5%, 44.7%, and 50.0%, respectively. More patients had cognitive impairments at 3 years (33.3%) than at 1 (9.5%) and 2 years (9.1%) post-operatively. No statistical difference in the ability to carry out activities of daily living or functional decline with increasing time post-operatively. However, patients perceived a significant health decline with the greater time that passed following surgery. CONCLUSIONS: Our study showed that half of the patients over the age of 80 are surviving up to 3 years post-operatively. While post-operative functional status appears to be stable across the 3 cohorts of patients, perceived health status declines over time. Understanding the long-term post-operative impact on cognitive impairment, functional status, and quality of life in elderly patients who undergo acute care surgery allows health care professionals to predict their patients' likely post operative needs. PMID- 23816270 TI - Evaluating national practice of preoperative radiotherapy for rectal cancer based on clinical auditing. AB - OBJECTIVES: Internationally, the use of preoperative radiotherapy (RT) for rectal cancer varies largely, related to different decision-making based on the harm benefit ratio. In the Dutch guideline, RT is indicated in all cT2-4 tumours. We aimed to evaluate the use of RT in the Netherlands and to discuss Dutch practice in the context of current literature. METHODS: Data of the Dutch Surgical Colorectal Audit (DSCA) were used and 6784 patients surgically treated for primary rectal cancer in 2009-2011 were included. The application and type of RT were described according to age, comorbidity, tumour localization and tumour stage at population level with analysis of hospital variation for specific subsets. RESULTS: In total, 85% of patients who underwent resection for rectal cancer received RT. Comorbidity (Charlson Comorbidity Index 2+) and older age (>=70 years) were associated with a slight decrease in application of RT (75 and 80% respectively). In stage I tumours, 77% of patients received RT, but large hospital variation existed (0-100%). The proportion chemoradiotherapy of the whole group of RT increased with increasing N-stage, increasing T-stage, decreasing distance from the anus, younger age and less comorbidity with hospital variation from 0 to 73%. CONCLUSION: From a European perspective, a high percentage of rectal cancer patients are treated with RT in the Netherlands. Considerable hospital variation was observed for RT in stage I and the proportion of chemoradiotherapy among all RT schemes. Data from clinical auditing enable evaluation of national practice and current standards from both a scientific and international perspective. PMID- 23816271 TI - Dynamic interplay between CXCL levels in chronic hepatitis C patients treated by interferon. AB - BACKGROUND: Combined pegylated interferon-alpha and ribavirin therapy has sustained virological response (SVR) rates of 54% to 61%. Pretreatment predictors of SVR to interferon therapy have not been fully investigated yet. The current study assesses a group of chemokines that may predict treatment response in Egyptian patients with chronic HCV infection. PATIENTS AND METHODS: CXCL5, CXCL9, CXCL11, CXCL12, CXCL 13, CXCL 16 chemokines and E-Cadherin were assayed in 57 chronic HCV patients' sera using quantitative ELISA plate method. All studied patients were scheduled for combined pegylated interferon alpha and ribavirin therapy (32 patients received pegylated interferon alpha 2b, and 25 patients received pegylated interferon alpha 2a). Quantitative hepatitis C virus RNA was done by real time RT-PCR and HCV genotyping by INNOLIPAII. RESULTS: There was no significant difference (p > 0.05) in baseline HCV RNA levels between responders and non-responders to interferon. A statistically significant difference in CXCL13 (p = 0.017) and E-Cadherin levels (P = 0.041) was reported between responders and nonresponders at week 12. Significant correlations were found between changes in the CXCL13 levels and CXCL9, CXCL16, E-cadherin levels as well as between changes in E-cadherin levels and both CXCL16 and ALT levels that were maintained during follow up. Also, significant changes have been found in the serum levels of CXCL5, CXCL13, and CXCL16 with time (before pegylated interferon alpha 2 a and alpha 2 b therapy, and at weeks 12 and 24) with no significant difference in relation to interferon type and response to treatment. CONCLUSION: Serum levels of CXCL13 and E-Cadherin could be used as surrogate markers to predict response of combined PEG IFN-alpha/RBV therapy, especially at week 12. However, an extended study including larger number of patients is needed for validation of these findings. CLINICAL TRIAL NO: NCT01758939. PMID- 23816273 TI - Reply from authors re: Michael Baum. Screening for prostate cancer: can we learn from the mistakes of the breast screening experience? Eur Urol 2013;64:540-1: screening for prostate cancer: we have learned and are still learning. PMID- 23816274 TI - Reply from authors re: Apostolos Apostolidis. Male lower urinary tract symptoms: a riddle waiting to be solved. Eur Urol 2013;64:408-10: a rationale for combination antimuscarinic-alpha-blocker therapy for male lower urinary tract symptoms. PMID- 23816275 TI - GEMSP exerts a myelin-protecting role in the rat optic nerve. AB - OBJECTIVES: Chronic experimental autoimmune encephalomyelitis (EAE) was induced in rats to evaluate the potential protective effect of GEMSP, a mixture made up of fatty acids (FA), vitamins, and amino acids or their derivatives, linked to Poly-L-Lysine, on the myelin sheath of the optic nerve. METHODS: To evaluate the effects of GEMSP on the optic nerve, animals were divided into three experimental groups: (1) EAE rats treated with GEMSP; (2) EAE rats treated with 0.9% NaCl; and (3) control, non-EAE rats. Using electron microscopy, we investigated the possibility that this new drug candidate has a myelin-protective role. RESULTS: A marginally significant reduction in the thickness of the myelin around optic nerve medium-size axons (diameter between 0.8-1.3 MUm) was found in EAE rats. Treatment of EAE rats with GEMSP ameliorated myelin damage. Significantly increased myelin thickness was found when animals in groups 2 and 3 were compared. However, the number of myelinated axons studied was not altered in groups 1 or 2 when compared to controls. DISCUSSION: Our results suggest that in a model of demyelination, GEMSP protects and enhances the formation of the myelin sheath of the optic nerve and therefore could be a potential drug candidate to reduce optic nerve pathogenesis in multiple sclerosis (MS). PMID- 23816276 TI - Accurate evaluation and monitoring of renal function will be crucial. PMID- 23816277 TI - Prevalence and clinical characteristics of the DSM IV major depression among general internal medicine patients. AB - OBJECTIVE: The aim of this study was to investigate the prevalence and clinical characteristics of the DSM IV major depressive disorder (MDD) among patients admitted to the General Internal Medicine Service of the Geneva University Hospital. METHOD: 557 patients admitted to the IM of the Geneva University Hospital aged 18 to 70 were investigated. Each subject was assessed by a clinical psychologist using the SCID (Structured Clinical Interview Depression for DSM-IV) questionnaire. RESULTS: 69 patients (12.4%) met diagnostic criteria for MDD (men: 8.8%, women: 16.9%, p=.004). Among subjects with major depression, depressed mood (97%), fatigue (91%), and diminished interest and pleasure (81%) were the most prevalent symptoms. Recurrent thoughts of death were present in 48% of depressed patients. CONCLUSIONS: This study raises further evidence that an elevated proportion of patients admitted to an acute care general internal medicine facility meet DSM IV criteria for MDD with nearly half of depressed patients suffering from recurrent thoughts of death. It emphasizes the necessity of a targeted, continuous, and active support given by the psychiatry liaison service in the internal medicine setting. PMID- 23816278 TI - Facility-level intervention to improve attendance and adherence among patients on anti-retroviral treatment in Kenya--a quasi-experimental study using time series analysis. AB - BACKGROUND: Achieving high rates of adherence to antiretroviral therapy (ART) in resource-poor settings comprises serious, but different, challenges in both the first months of treatment and during the life-long maintenance phase. We measured the impact of a health system-oriented, facility-based intervention to improve clinic attendance and patient adherence. METHODS: This was a quasi-experimental, longitudinal, controlled intervention study using interrupted time series analysis. The intervention consisted of (1) using a clinic appointment diary to track patient attendance and monitor monthly performance; (2) changing the mode of asking for self-reported adherence; (3) training staff on adherence concepts, intervention methods, and use of monitoring data; (4) conducting visits to support facility teams with the implementation.We conducted the study in 12 rural district hospitals (6 intervention, 6 control) in Kenya and randomly selected 1894 adult patients over 18 years of age in two cohorts: experienced patients on treatment for at least one year, and newly treated patients initiating ART during the study. Outcome measures were: attending the clinic on or before the date of a scheduled appointment, attending within 3 days of a scheduled appointment, reporting perfect adherence, and experiencing a gap in medication supply of more than 14 days. RESULTS: Among experienced patients, the percentage attending the clinic on or before a scheduled appointment increased in both level (average total increase immediately after intervention) (+5.7%; 95% CI=2.1, 9.3) and trend (increase per month) (+1.0% per month; 95% CI=0.6, 1.5) following the intervention, as did the level and trend of those keeping appointments within three days (+4.2%; 95% CI=1.6, 6.7; and +0.8% per month; 95% CI=0.6, 1.1, respectively). The relative difference between the intervention and control groups based on the monthly difference in visit rates increased significantly in both level (+6.5; 95% CI=1.4, 11.6) and trend (1.0% per month; 95% CI=0.2, 1.8) following the intervention for experienced patients attending the clinic within 3 days of their scheduled appointments.The decrease in the percentage of experienced patients with a medication gap greater than 14 days approached statistical significance (-11.3%; 95% CI=-22.7, 0.1), and the change seemed to persist over 11 months after the intervention. All facility staff used appointment-keeping data to calculate adherence and discussed outcomes regularly. CONCLUSION: The appointment-tracking system and monthly performance monitoring was strengthened, and patient attendance was improved. Scale-up to national level may be considered. PMID- 23816279 TI - Interventions to reduce dependency in personal activities of daily living in community-dwelling adults who use homecare services: protocol for a systematic review. AB - BACKGROUND: There is a growing demand for services whereby individuals receive assistance from care workers for personal care within the home. This has led to the development of re-ablement or restorative homecare services that provide time limited input aimed at reducing dependency in personal activities of daily living, and preventing or delaying the need for further homecare support. However, little is currently known about how such interventions are configured, or how they may affect individuals' ability to carry out personal care independently. METHODS/DESIGN: We will seek to identify studies that compare an intervention designed to reduce dependency in personal activities of daily living with routine input or usual care as the control. We will include randomised controlled trials, nonrandomised controlled trials, and controlled before and after studies. We will also include interrupted time series studies. We shall search electronic databases in addition to searching for ongoing and unpublished studies, and where appropriate will contact key authors. Two reviewers will independently screen articles for inclusion; will assess risk of bias using quality assessment tools; and will carry out data extraction using pre-prepared forms. Any disagreements, at any stage, will be resolved by discussion and the involvement of a third reviewer if needed. We will produce a narrative summary of the results. A meta-analysis will be conducted if sufficient data are available of appropriate quality and comparability. DISCUSSION: The findings from this review will inform future practice within homecare re-ablement services; will inform policy decisions about the structure, organisation and content of such services; and will identify areas where further research is warranted. TRIAL REGISTRATION: This review protocol has been registered on the PROSPERO database (CRD42013004163). PMID- 23816280 TI - Length of initial prescription at hospital discharge and long-term medication adherence for elderly patients with coronary artery disease: a population-level study. AB - BACKGROUND: Patient adherence to cardiac secondary prevention medications declines over time. We examined whether the length of the initial prescription at hospital discharge after coronary angiography would be associated with long-term adherence. METHODS: We conducted a population-level cohort study to examine adherence to cardiac medications for 18 months after coronary angiography in elderly patients with coronary artery disease (CAD). We identified patients with clinical indications for angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACE-I/ARB), beta-blockers (BB), and/or statins. In each medication class cohort, we defined high adherence as proportion of days covered (PDC) > 80%. The length of the initial prescription was defined as 0-30 days, 31 60 days, and more than 60 days. We controlled for patient sociodemographic factors, previous adherence, and comorbidities. RESULTS: The ACE-I/ARB cohort included 13,305 patients, the BB cohort included 5,792 patients, and the statin cohort included 16,134 patients. Using < 30 days as the reference, initial prescriptions covering at least 60 days were more likely to result in high long term adherence for ACE-I/ARB (adjusted odds ratio [aOR], 4.1; 95% confidence interval [CI], 3.6-4.7); BB (aOR, 2.4; 95% CI, 1.9-3.1), and statins (aOR, 3.0; 95% CI, 2.6-3.4). More than 80% of patients had outpatient follow-up with a primary care provider within 30 days, and this did not vary based on length of initial prescription. CONCLUSIONS: Giving patients longer prescriptions for cardiac secondary prevention medications at hospital discharge seems to increase the likelihood of high long-term adherence in elderly patients. PMID- 23816281 TI - Factors affecting the infant antibody response to measles immunisation in Entebbe Uganda. AB - BACKGROUND: Vaccine failure is an important concern in the tropics with many contributing elements. Among them, it has been suggested that exposure to natural infections might contribute to vaccine failure and recurrent disease outbreaks. We tested this hypothesis by examining the influence of co-infections on maternal and infant measles-specific IgG levels. METHODS: We conducted an observational analysis using samples and data that had been collected during a larger randomised controlled trial, the Entebbe Mother and Baby Study (ISRCTN32849447). For the present study, 711 pregnant women and their offspring were considered. Helminth infections including hookworm, Schistosoma mansoni and Mansonella perstans, along with HIV, malaria, and other potential confounding factors were determined in mothers during pregnancy and in their infants at age one year. Infants received their measles immunisation at age nine months. Levels of total IgG against measles were measured in mothers during pregnancy and at delivery, as well as in cord blood and from infants at age one year. RESULTS: Among the 711 pregnant women studied, 66% had at least one helminth infection at enrolment, 41% had hookworm, 20% M. perstans and 19% S. mansoni. Asymptomatic malaria and HIV prevalence was 8% and 10% respectively. At enrolment, 96% of the women had measles-specific IgG levels considered protective (median 4274 mIU/ml (IQR 1784, 7767)). IgG levels in cord blood were positively correlated to maternal measles specific IgG levels at delivery (r = 0.81, p < 0.0001). Among the infants at one year of age, median measles-specific IgG levels were markedly lower than in maternal and cord blood (median 370 mIU/ml (IQR 198, 656) p < 0.0001). In addition, only 75% of the infants had measles-specific IgG levels considered to be protective. In a multivariate regression analysis, factors associated with reduced measles-specific antibody levels in infancy were maternal malaria infection, infant malaria parasitaemia, infant HIV and infant wasting. There was no association with maternal helminth infection. CONCLUSION: Malaria and HIV infection in mothers during pregnancy, and in their infants, along with infant malnutrition, may result in reduction of the antibody response to measles immunisation in infancy. This re-emphasises the importance of malaria and HIV control, and support for infant nutrition, as these interventions may have benefits for vaccine efficacy in tropical settings. PMID- 23816283 TI - Diet-related practices and BMI are associated with diet quality in older adults. AB - OBJECTIVE: To assess the association of diet-related practices and BMI with diet quality in rural adults aged >=74 years. DESIGN: Cross-sectional. Dietary quality was assessed by the twenty-five-item Dietary Screening Tool (DST). Diet-related practices were self-reported. Multivariate linear regression models were used to analyse associations of DST scores with BMI and diet-related practices after controlling for gender, age, education, smoking and self- v. proxy reporting. SETTING: Geisinger Rural Aging Study (GRAS) in Pennsylvania, USA. SUBJECTS: A total of 4009 (1722 males, 2287 females; mean age 81.5 years) participants aged >=74 years. RESULTS: Individuals with BMI < 18.5 kg/m2 had a significantly lower DST score (mean 55.8, 95 % CI 52.9, 58.7) than those individuals with BMI = 18.5 24.9 kg/m2 (mean 60.7, 95 % CI 60.1, 61.5; P = 0.001). Older adults with higher, more favourable DST scores were significantly more likely to be food sufficient, report eating breakfast, have no chewing difficulties and report no decline in intake in the previous 6 months. CONCLUSIONS: The DST may identify potential targets for improving diet quality in older adults including promotion of healthy BMI, breakfast consumption, improving dentition and identifying strategies to decrease concern about food sufficiency. PMID- 23816284 TI - Can Coxiella burnetii be transmitted by embryo transfer in goats? AB - The detection of significant bacterial loads of Coxiella burnetii in flushing media and tissue samples from the genital tracts of nonpregnant goats represents a risk factor for in utero infection and transmission during embryo transfer. The aim of this study was to investigate (1) whether cells of early goat embryos isolated from in vivo-fertilized goats interact with C. burnetii in vitro, (2) whether the embryonic zona pellucida (ZP) protects early embryo cells from infection, and (3) the efficacy of the International Embryo Transfer Society (IETS) washing protocol for bovine embryos. The study was performed in triple replicate: 12 donor goats, certified negative by ELISA and polymerase chain reaction, were synchronized, superovulated, and subsequently inseminated by Q fever-negative males. Sixty-eight embryos were collected 4 days later by laparotomy. Two-thirds of the resulting ZP-intact and ZP-free 8- to 16-cell embryos (9-9, 11-11, and 4-4 in replicates 1, 2, and 3, respectively) were placed in 1 mL minimum essential medium containing 10(9)C. burnetii CBC1 (IASP, INRA Tours). After overnight incubation at 37 degrees C and 5% CO2, the embryos were washed according to the IETS procedure. In parallel, the remaining third ZP intact and ZP-free uninfected embryos (3-3, 5-5, and 2-2 in replicates 1, 2, and 3, respectively) were subjected to the same procedures, but without C. burnetii, thus serving as controls. The 10 washing fluids for all batches of each replicate were collected and centrifuged for 1 hour at 13,000 * g. The washed embryos and pellets were tested by polymerase chain reaction. Coxiella burnetii DNA was found in all batches of ZP-intact and ZP-free infected embryos after 10 successive washes. It was also detected in the first five washing fluids for ZP-intact embryos and in the first eight washing fluids for ZP-free embryos. None of the control batches (embryos and washing fluids) were found to contain bacterial DNA. These results clearly indicate that caprine early embryonic cells are susceptible to infection by C. burnetii. The bacterium shows a strong tendency to adhere to the ZP after in vitro infection, and the washing procedure recommended by the IETS for bovine embryos failed to remove it. The persistence of these bacteria makes the embryo a potential means of transmission to recipient goats. Further studies are needed to investigate whether the enzymatic treatment of caprine embryos infected by C. burnetii would eliminate the bacteria from the ZP. PMID- 23816285 TI - Serial ovarian ultrasonography in wild-caught wood bison (Bison bison athabascae). AB - The objectives of this study were to determine the feasibility of daily examination of wild-caught wood bison and to characterize the ovarian function using serial transrectal ultrasonography and blood hormone analysis. Ten 2-year old wood bison heifers obtained from Elk Island National Park were placed in a corral adjacent to a handling system designed for restraining bison. The handling system was left open to the corral allowing the bison to explore it freely for 2 months. Active acclimation followed for a 2-week period, during which the bison were herded daily through the handling system and rewarded with whole oats. Finally, the bison were restrained in the handling system and rewarded with whole oats upon release. Once conditioned, daily transrectal examination of the ovaries was completed in 100% of attempts for 30 days (January-February) using a B-mode scanner with a 5 to 10-MHz linear array. Follicle size and numbers were recorded, and individual follicles were identified serially. Blood samples were collected daily and the serum was analyzed for FSH concentrations. Nonrandom changes were detected in the number of follicles >= 4 mm in diameter per day (P < 0.05). Each peak in follicle numbers was associated with the development of a single dominant follicle. The interval between the emergence of successive dominant follicles was 6.8 +/- 0.6 days (mean +/- SEM). The maximum diameter of the dominant follicle was 9.9 +/- 0.4 mm. In conclusion, wild-caught wood bison were amenable to daily examination and blood sampling, and ovarian dynamics were characterized by wave like development of anovulatory antral follicles. The demonstrated success of this approach to the study of ovarian function will be useful for characterizing the annual reproductive pattern in wood bison, which is necessary for the development of bison-specific protocols for controlling ovarian function for species conservation. PMID- 23816286 TI - The use of HE4, CA125 and CA72-4 biomarkers for differential diagnosis between ovarian endometrioma and epithelial ovarian cancer. AB - BACKGROUND: Endometriosis is frequently associated with high levels of CA125. This marker is therefore not useful for discriminating ovarian endometrioma from ovarian malignancy. The aim of this study was to establish a panel of complementary biomarkers that could be helpful in the differential diagnosis between ovarian endometriosis or other ovarian benign masses and ovarian cancer. METHODS: Blood samples from 50 healthy women, 17 patients with benign ovarian tumors, 57 patients with ovarian endometrioma and 39 patients with ovarian cancer were analyzed and serum values were measured for the following biomarkers: CA125, HE4 and CA72-4. RESULTS: Serum CA125 concentration was elevated in both patients with ovarian endometriosis and ovarian cancer but not in patients with other benign ovarian masses. HE4 was never increased in patients with endometriosis or benign masses whereas it was significantly higher in all patients with ovarian cancer (p < 0.05). A marked difference in CA72-4 values was observed between women with ovarian cancer (67%) and those with endometriosis (p < 0.05). CONCLUSIONS: The results of the study suggest that HE4 and CA72-4 determination is the best approach to confirm the benign nature of ovarian endometrioma in women with high CA125 levels. PMID- 23816288 TI - It doesn't stop at cure: monitoring childhood cancer survivors. PMID- 23816289 TI - Has targeted therapy for melanoma made chemotherapy obsolete? PMID- 23816290 TI - Workplace cancer screening. PMID- 23816291 TI - Recognition of surgical need as part of cancer control in Africa. PMID- 23816292 TI - Digital cancer pathology in Africa. PMID- 23816293 TI - Cancer in Botswana: resources and opportunities. PMID- 23816294 TI - Challenges imposed by the complexity of cancer genome. PMID- 23816295 TI - Integrated 2D and 3D mammography. PMID- 23816296 TI - Novel targets in HPV-negative head and neck cancer: overcoming resistance to EGFR inhibition. AB - Cancers of the head and neck that arise from habitual exposure to carcinogens have lower cure rates than those that arise from infection with human papillomavirus (HPV), and intensification of cytotoxic chemotherapy and radiation has not improved outcomes. HPV-negative head and neck cancers abundantly express EGFR, and the monoclonal antibody cetuximab, directed against EGFR, is the only targeted therapy that has improved disease survival so far. However, response rates to single-agent cetuximab are lower than 15%, and cetuximab given with chemotherapy or radiation leads to only a modest effect on survival. Thus, investigating the mechanisms of resistance to EGFR inhibition in HPV-negative head and neck cancer might help identify novel and active therapies. In this Review, we focus on therapies in development that target redundant receptor tyrosine kinases (eg, HER2 and MET), reduce or abrogate nuclear functions of EGFR, affect cellular trafficking by inhibition of histone deacetylase, or treatments that might address resistance that arises in the EGFR signalling stream (eg, aurora-kinase inhibitors and STAT decoys). PMID- 23816297 TI - Vertebral compression fracture after stereotactic body radiotherapy for spinal metastases. AB - The use of stereotactic body radiotherapy for metastatic spinal tumours is increasing. Serious adverse events for this treatment include vertebral compression fracture (VCF) and radiation myelopathy. Although VCF is a fairly low risk adverse event (approximately 5% risk) after conventional radiotherapy, crude risk estimates for VCF after spinal SBRT range from 11% to 39%. In this Review, we summarise the evidence and predictive factors for VCF induced by spinal SBRT, review the pathophysiology of VCF in the metastatic spine, and discuss strategies used to prevent and manage this potentially disabling complication. PMID- 23816298 TI - Subsequent neoplasms of the CNS among survivors of childhood cancer: a systematic review. AB - Childhood cancer survivors are at risk for development of subsequent neoplasms of the CNS. Better understanding of the rates, risk factors, and outcomes of subsequent neoplasms of the CNS among survivors of childhood cancer could lead to more informed screening guidelines. Two investigators independently did a systematic search of Medline and Embase (from January, 1966, through March, 2012) for studies examining subsequent neoplasms of the CNS among survivors of childhood cancer. Articles were selected to answer three questions: what is the risk of CNS tumours after radiation to the cranium for a paediatric cancer, compared with the risk in the general population; what are the outcomes in children with subsequent neoplasms of the CNS who received CNS-directed radiation for a paediatric cancer; and, are outcomes of subsequent neoplasms different from primary neoplasms of the same histology? Our search identified 72 reports, of which 18 were included in this Review. These studies reported that childhood cancer survivors have an 8.1-52.3-times higher incidence of subsequent CNS neoplasms compared with the general population. Nearly all cancer survivors who developed a CNS neoplasm had been exposed to cranial radiation, and some studies showed a correlation between radiation dose and risk of subsequent CNS tumours. 5 year survival ranged from 0-19.5% for subsequent high-grade gliomas and 57.3-100% for meningiomas, which are similar rates to those observed in patients with primary gliomas or meningiomas. The quality of evidence was limited by variation in study design, heterogeneity of details regarding treatment and outcomes, limited follow-up, and small sample sizes. We conclude that survivors of childhood cancer who received cranial radiation therapy have an increased risk for subsequent CNS neoplasms. The current literature is insufficient to comment about the potential harms and benefits of routine screening for subsequent CNS neoplasms. PMID- 23816299 TI - Extracranial rhabdoid tumours: what we have learned so far and future directions. AB - Extracranial rhabdoid tumours are rare, and often occur in infants. Although the kidney is the most common site, they can occur anywhere in the body. Most contain a biallelic inactivating mutation in SMARCB1, which is part of the chromatin remodelling complex SWI/SNF, and functions as a classic tumour suppressor gene. Despite multimodal therapy, outcome in rhabdoid tumours remains poor with only 31% of patients surviving to 1 year. The young age of patients limits use of radiotherapy, which, along with age, is an important prognostic factor. Because the tumours are rare, no standard therapeutic pathway exists, and no randomised trials have examined the role of new therapeutic approaches. Improved understanding of the biology and role of SMARCB1 has enabled identification of new targets for small molecule inhibitors to combine with chemotherapy backbones that we might establish from the current EpSSG and COG studies. PMID- 23816300 TI - IL-10 production from dendritic cells is associated with DC SIGN in human leprosy. AB - The defective antigen presenting ability of antigen presenting cells (APCs) modulates host cytokines and co-stimulatory signals that may lead to severity of leprosy. In the present study, we sought to evaluate the phenotypic features of APCs along with whether DC SIGN (DC-specific intercellular adhesion molecule grabbing nonintegrin) influences IL-10 production while moving from tuberculoid (BT/TT) to lepromatous (BL/LL) pole in leprosy pathogenesis. The study revealed an increased expression of DC SIGN on CD11c+ cells from BL/LL patients and an impaired form of CD83 (~50 kDa). However, the cells after treatment with GM CSF+IL-4+ManLAM showed an increased expression of similar form of CD83 on DCs. Upon treatment with ManLAM, DCs were found to show increased nuclear presence of NF-kappaB, thus leading to higher IL-10 production. High IL-10 production from ManLAM treated PBMCs further suggested the role of DC SIGN in subverting the DCs function towards BL/LL pole of leprosy. Anti-DC SIGN treatment resulting in restricted nuclear ingression of NF-kappaB as well as its acetylation along with enhanced T cell proliferation validated our findings. In conclusion, Mycobacterium leprae component triggers DC SIGN on DCs to induce production of IL 10 by modulating intracellular signalling pathway at the level of transcription factor NF-kappaB towards BL/LL pole of disease. PMID- 23816301 TI - Enhancement of humoral and cellular immune responses by monophosphoryl lipid A (MPLA) as an adjuvant to the rabies vaccine in BALB/c mice. AB - The development of effective vaccines against the rabies virus could prevent infection with this fatal virus. However, the current rabies vaccine fails to provide a full range of protection because of its limited ability to elicit a cellular immune response and the requirement for repeat vaccination. Monophosphoryl lipid A (MPLA) is well known as a potent adjuvant to enhance immune responses against virus infection. Here we investigated the efficacy of MPLA as an adjuvant to improve the humoral and cellular immune responses to the rabies vaccine in BALB/c mice. Supplementation of the rabies vaccine with MPLA significantly accelerated the production of specific antibodies by 10 days compared to the original vaccines. Furthermore, MPLA promoted the induction of stronger cellular immune responses by the rabies vaccine, including the production of IL-4, IFN-gamma and the activation of CD4+/CD8+ T cells, than those elicited without MPLA. Collectively, our findings indicated that MPLA enhances humoral and cellular immunity and is a promising adjuvant for the development of more effective rabies vaccines. PMID- 23816302 TI - Adipose tissue inflammation: feeding the development of type 2 diabetes mellitus. AB - The global increase in obesity-induced type 2 diabetes (T2DM) represents a burden for healthcare systems worldwide. Of particular concern is the increased morbidity associated with T2DM, in particular cardiovascular disease (CVD), leading to premature death. Obesity initially leads to the development of insulin resistance in adipose and other tissues. Insulin resistance is initially compensated by increased insulin secretion but ultimately insufficient insulin is produced and this leads to the development of T2DM. Understanding the causal mechanisms underpinning the development of obesity-induced insulin resistance may be beneficial in improving quality of life and life expectancy, with the potential for a major global impact on healthcare systems. There is abundant evidence from animal, human studies and in vitro studies to support functional roles for a number of inflammatory factors in obesity-induced insulin resistance. In this review we provide an overview of the evidence supporting a fundamental role for the fluid phase (in particular the complement system) and the cellular components of the innate immune system in the pathogenesis of obesity-induced insulin resistance and ultimately development of T2DM. PMID- 23816304 TI - The identification and characteristics of IL-22-producing T cells in acute graft versus-host disease following allogeneic bone marrow transplantation. AB - Graft-versus-host disease (GVHD) remains the major obstacle for allogeneic bone marrow transplantation, in which many proinflammatory cytokines secreted by alloreactive donor T cells are involved. Role of IL-22 as a member of IL-10 family in GVHD is still disputed and the properties of IL-22-producing cells are unclear. We demonstrated here that CD4+ T cells but not CD8+ T cells involved in GVHD were the main cellular source of donor-derived IL-22. Th1 and Th17 cells were detected not only express classical cytokine IFN-gamma or IL-17, but also contributed to IL-22 secretion in GVHD. Th22 cells characterized by the independent secretion of IL-22 were identified and occupied almost half percentage of IL-22-producing CD4+ T cells. The frequency of IL-22-producing CD4+ T cells showed dynamic changes with the development of GVHD. Finally, we observed that IL-22-producing CD4+ T cells in GVHD mouse carried CD62L-CD44(high/low) surface markers. In conclusion, we illuminate the characteristics of donor derived IL-22-producing CD4+ T cells, which may have potent implication for further study of pathogenesis of GVHD. PMID- 23816303 TI - Retinoic acid and alpha-galactosylceramide regulate the expression of costimulatory receptors and transcription factors responsible for B cell activation and differentiation. AB - Mature naive B cells possess a number of BCR coreceptors and other antigen receptors, including the MHC class I-like molecule CD1d, but little is known of the response of B cells to stimulation by the CD1d ligand, alpha galactosylceramide (alphaGalCer). Previously, we showed that all-trans-retinoic acid (RA) increases the expression of CD1d and the magnitude of CD1d-mediated antibody production in vivo. Potential mechanisms could include changes in the expression of costimulatory molecules and transcription factors that regulate plasma cell formation. In the present study, we have used isolated purified B cells and in vivo studies to demonstrate that alphaGalCer and RA initiate a regulated expression of several genes essential for B cell activation and differentiation, such as Pax-5, Blimp-1, IRF-4 and activation-induced cytidine deaminase (Aid). Moreover, whereas alphaGalCer mainly increased the expression of Pax-5, CD40 and CD86 that are critical for B cell activation, RA predominantly increased CD138+ and Fas+-PNA+ B cells, which represent more advanced B cell differentiation. It is also noteworthy that alphaGalCer enriched a CD19hi subset of B cells, which represent B cells with more differentiated phenotype and higher potential for antibody production. In vivo, treatment with alphaGalCer enriched the CD19hi population, which, after sorting, produced more anti-TT IgG by ELISPOT assay. Together, our data demonstrate that RA and alphaGalCer can regulate B cell activation and differentiation at multiple levels in a complementary manner, facilitating the progress of B cells towards antibody secreting cells. PMID- 23816305 TI - Dredging displaces bottlenose dolphins from an urbanised foraging patch. AB - The exponential growth of the human population and its increasing industrial development often involve large scale modifications of the environment. In the marine context, coastal urbanisation and harbour expansion to accommodate the rising levels of shipping and offshore energy exploitation require dredging to modify the shoreline and sea floor. While the consequences of dredging on invertebrates and fish are relatively well documented, no study has robustly tested the effects on large marine vertebrates. We monitored the attendance of common bottlenose dolphins (Tursiops truncatus) to a recently established urbanised foraging patch, Aberdeen harbour (Scotland), and modelled the effect of dredging operations on site usage. We found that higher intensities of dredging caused the dolphins to spend less time in the harbour, despite high baseline levels of disturbance and the importance of the area as a foraging patch. PMID- 23816306 TI - Link between sewage-derived nitrogen pollution and coral disease severity in Guam. AB - The goals of this study were to evaluate the contribution of sewage-derived N to reef flat communities in Guam and to assess the impact of N inputs on coral disease. We used stable isotope analysis of macroalgae and a soft coral, sampled bimonthly, as a proxy for N dynamics, and surveyed Porites spp., a dominant coral taxon on Guam's reefs, for white syndrome disease severity. Results showed a strong influence of sewage-derived N in nearshore waters, with delta(15)N values varying as a function of species sampled, site, and sampling date. Increases in sewage-derived N correlated significantly with increases in the severity of disease among Porites spp., with delta(15)N values accounting for more than 48% of the variation in changes in disease severity. The anticipated military realignment and related population increase in Guam are expected to lead to increased white syndrome infections and other coral diseases. PMID- 23816307 TI - Climate change impacts on coral reefs: synergies with local effects, possibilities for acclimation, and management implications. AB - Most reviews concerning the impact of climate change on coral reefs discuss independent effects of warming or ocean acidification. However, the interactions between these, and between these and direct local stressors are less well addressed. This review underlines that coral bleaching, acidification, and diseases are expected to interact synergistically, and will negatively influence survival, growth, reproduction, larval development, settlement, and post settlement development of corals. Interactions with local stress factors such as pollution, sedimentation, and overfishing are further expected to compound effects of climate change. Reduced coral cover and species composition following coral bleaching events affect coral reef fish community structure, with variable outcomes depending on their habitat dependence and trophic specialisation. Ocean acidification itself impacts fish mainly indirectly through disruption of predation- and habitat-associated behavior changes. Zooxanthellate octocorals on reefs are often overlooked but are substantial occupiers of space; these also are highly susceptible to bleaching but because they tend to be more heterotrophic, climate change impacts mainly manifest in terms of changes in species composition and population structure. Non-calcifying macroalgae are expected to respond positively to ocean acidification and promote microbe-induced coral mortality via the release of dissolved compounds, thus intensifying phase-shifts from coral to macroalgal domination. Adaptation of corals to these consequences of CO2 rise through increased tolerance of corals and successful mutualistic associations between corals and zooxanthellae is likely to be insufficient to match the rate and frequency of the projected changes. Impacts are interactive and magnified, and because there is a limited capacity for corals to adapt to climate change, global targets of carbon emission reductions are insufficient for coral reefs, so lower targets should be pursued. Alleviation of most local stress factors such as nutrient discharges, sedimentation, and overfishing is also imperative if sufficient overall resilience of reefs to climate change is to be achieved. PMID- 23816308 TI - Disinfection by-products and ecotoxicity of ballast water after oxidative treatment--results and experiences from seven years of full-scale testing of ballast water management systems. AB - Since 2005, five different ballast water management systems (BWMSs) based on chlorination treatment have been tested by Norwegian Institute for Water Research (NIVA) according to guidelines from the International Maritime Organization (IMO). 25% and >50% of all the tested discharge samples exhibited acute and chronic toxic effects on algae, respectively. In most cases this toxicity was plausibly caused by a high free residual oxidant (FRO) level (>0.08 mg Cl/l). Of the 22 disinfection by-products (DBPs) that were identified in treated water at discharge, four compounds were at times found at concentrations that may pose a risk to the local aquatic environment. However, there seemed to be no clear indication that the measured DBP concentrations contributed to the observed algal toxicity. The addition of methylcellulose instead of lignin in the test water to comply with IMO requirements seemed to limit the formation of DBP. PMID- 23816309 TI - Risk factors for the development of reexpansion pulmonary edema in patients with spontaneous pneumothorax. AB - BACKGROUND: Reexpansion pulmonary edema (REPE) is known as a rare and fatal complication after tube thoracostomy. OBJECTIVES: We investigated the risk factors for the development of REPE in patients with spontaneous pneumothorax. METHODS: We selected patients who were diagnosed with spontaneous pneumothorax and were initially treated with tube thoracostomy between August 1, 2003 and December 31, 2011. The patients' electronic medical records, including operative notes and chest x-ray and computed tomography scans, were reviewed. RESULTS: REPE developed in 49 of the 306 patients (16.0%). REPE was more common in patients with diabetes (14.3% vs 3.9%, P=0.004) or tension pneumothorax (46.8% vs 16.2%, P=0.000). The pneumothorax was larger in patients with REPE than without REPE (57.0+/-16.0% vs 34.2+/-17.6%, P=0.000), and the incidence of REPE increased with the size of pneumothorax. On multivariate analysis, diabetes mellitus [(odds ratio (OR)=9.93, P=0.003), and the size of pneumothorax (OR=1.07, P=0.000) were independent risk factors of REPE. CONCLUSIONS: The presence of diabetes increases the risk of REPE development in patients with spontaneous pneumothorax. The risk of REPE also increases significantly with the size of pneumothorax. PMID- 23816310 TI - Characterization of Farmington virus, a novel virus from birds that is distantly related to members of the family Rhabdoviridae. AB - BACKGROUND: Farmington virus (FARV) is a rhabdovirus that was isolated from a wild bird during an outbreak of epizootic eastern equine encephalitis on a pheasant farm in Connecticut, USA. FINDINGS: Analysis of the nearly complete genome sequence of the prototype CT AN 114 strain indicates that it encodes the five canonical rhabdovirus structural proteins (N, P, M, G and L) with alternative ORFs (> 180 nt) in the N and G genes. Phenotypic and genetic characterization of FARV has confirmed that it is a novel rhabdovirus and probably represents a new species within the family Rhabdoviridae. CONCLUSIONS: In sum, our analysis indicates that FARV represents a new species within the family Rhabdoviridae. PMID- 23816311 TI - Cost effectiveness of recycling: a systems model. AB - Financial analytical models of waste management systems have often found that recycling costs exceed direct benefits, and in order to economically justify recycling activities, externalities such as household expenses or environmental impacts must be invoked. Certain more empirically based studies have also found that recycling is more expensive than disposal. Other work, both through models and surveys, have found differently. Here we present an empirical systems model, largely drawn from a suburban Long Island municipality. The model accounts for changes in distribution of effort as recycling tonnages displace disposal tonnages, and the seven different cases examined all show that curbside collection programs that manage up to between 31% and 37% of the waste stream should result in overall system savings. These savings accrue partially because of assumed cost differences in tip fees for recyclables and disposed wastes, and also because recycling can result in a more efficient, cost-effective collection program. These results imply that increases in recycling are justifiable due to cost-savings alone, not on more difficult to measure factors that may not impact program budgets. PMID- 23816312 TI - Experimental study of the bio-oil production from sewage sludge by supercritical conversion process. AB - Environment-friendly treatment of sewage sludge has become tremendously important. Conversion of sewage sludge into energy products by environment friendly conversion process, with its energy recovery and environmental benefits, is being paid significant attention. Direct liquefaction of sewage sludge into bio-oils with supercritical water (SCW) was therefore put forward in this study, as de-water usually requiring intensive energy input is not necessary in this direct liquefaction. Supercritical water may act as a strong solvent and also a reactant, as well as catalyst promoting reaction process. Experiments were carried out in a self designed high-pressure reaction system with varying operating conditions. Through orthogonal experiments, it was found that temperature and residence time dominated on bio-oil yield compared with other operating parameters. Temperature from 350 to 500 degrees C and reaction residence time of 0, 30, 60min were accordingly investigated in details, respectively. Under supercritical conversion, the maximum bio-oil yield could achieve 39.73%, which was performed at 375 degrees C and 0min reaction residence time. Meanwhile, function of supercritical water was concluded. Fuel property analysis showed the potential of bio-oil application as crude fuel. PMID- 23816313 TI - Effects of health insurance on non-working married women's medical care use and bed days at home. AB - BACKGROUND: This study examines whether bed days are alternative methods to medical care use for treating a particular illness. If bed days at home are considered as an alternative to medical treatment, then medical care use and bed days at home should be influenced by an individual's health insurance status. METHOD: This study uses data from the 2003 Medical Expenditure Panel Survey (MEPS) on medical care use and bed days at home for each contracted illness of non-working married women. RESULTS: The results suggest that the health insurance status of non-working married women has considerable influence on their choice between medical care use and bed days at home. In addition, those with health insurance are more likely to use medical care and less likely to use bed days at home, but they tend to avoid the simultaneous use of medical care and bed days at home. CONCLUSIONS: In contrast to previous studies' findings indicating that absences from work and medical care use among working males may be complements, this study's results for non-working married women without health insurance suggest that they use rest and medical treatment as substitutes, not complements. PMID- 23816314 TI - [Non-obstructive coronary artery disease documented by cardiac computed tomography: Discrepancy between atherosclerotic burden and cardiovascular risk]. AB - Cardiac computed tomography (CT) documents the presence of coronary artery disease, regardless of the degree of stenosis. The prognostic value of non obstructive coronary artery disease documented by cardiac CT has recently been validated. However, there are still no clear guidelines on the management of such patients, particularly concerning initiation of more aggressive pharmacological measures for primary prevention. The approach to these patients remains controversial, especially in cases in which there is a discrepancy between cardiovascular risk and the atherosclerotic burden as documented by cardiac CT. The authors describe the case of a patient with a discrepancy between the extent of documented coronary atherosclerosis and that estimated according to pretest probability and cardiovascular risk scores. As this individual had more severe coronary atherosclerosis than expected (calcium score above the 90th percentile and non-obstructive coronary artery disease on cardiac CT) but was a competitive athlete and otherwise asymptomatic and without risk factors or cardiovascular history, with a very low estimated cardiovascular risk, it was difficult to decide on the risks and benefits of pharmacological primary prevention. PMID- 23816315 TI - A commentary on the XIII(th) International Rotifer Symposium (Shillong, 2012). AB - Rotifers have attracted the attention of biologists for well over 200 years. Interest in these exquisite animals rests in their diverse morphology, short generation time resulting in high growth rates, ability to withstand desiccation, and wide distribution, coupled with evidence of cryptic speciation. Moreover, three modes of reproduction are present in the phylum: obligatory sexuality, cyclical parthenogenesis, and obligatory ameiotic parthenogenesis. Thus, this phylum offers a rich field of study. Recognizing the need to share advances in knowledge, a triennial meeting, the International Rotifer Symposium (IRS), was begun in 1976. The most recent symposium (13(th) IRS) was held at Shillong (India) from 18-24, November 2012. In this commentary we considered the development of rotifer research as viewed through the lens of more than 35 years of IRS. Initially papers presented at the IRS focused on ecology, morphology, and pure taxonomic problems, with little applied work being reported. However, after more than three decades, the emphasis has swung to a balance of both basic (e.g., aging, ecology, genetics, and taxonomy) and applied (aquaculture and ecotoxicology) research. PMID- 23816316 TI - Walk Well: a randomised controlled trial of a walking intervention for adults with intellectual disabilities: study protocol. AB - BACKGROUND: Walking interventions have been shown to have a positive impact on physical activity (PA) levels, health and wellbeing for adult and older adult populations. There has been very little work carried out to explore the effectiveness of walking interventions for adults with intellectual disabilities. This paper will provide details of the Walk Well intervention, designed for adults with intellectual disabilities, and a randomised controlled trial (RCT) to test its effectiveness. METHODS/DESIGN: This study will adopt a RCT design, with participants allocated to the walking intervention group or a waiting list control group. The intervention consists of three PA consultations (baseline, six weeks and 12 weeks) and an individualised 12 week walking programme.A range of measures will be completed by participants at baseline, post intervention (three months from baseline) and at follow up (three months post intervention and six months from baseline). All outcome measures will be collected by a researcher who will be blinded to the study groups. The primary outcome will be steps walked per day, measured using accelerometers. Secondary outcome measures will include time spent in PA per day (across various intensity levels), time spent in sedentary behaviour per day, quality of life, self-efficacy and anthropometric measures to monitor weight change. DISCUSSION: Since there are currently no published RCTs of walking interventions for adults with intellectual disabilities, this RCT will examine if a walking intervention can successfully increase PA, health and wellbeing of adults with intellectual disabilities. TRIAL REGISTRATION ISRCTN: ISRCTN50494254. PMID- 23816317 TI - Clinical significance and diagnostic usefulness of serologic markers for improvement of outcome of tonsillectomy in adults with chronic tonsillitis. AB - BACKGROUND: The aim of the present study was to explore serological biomarkers which predict the outcome of tonsillectomy for chronic tonsillitis. METHODS: A case study in a University ENT department of 24 adult patients with chronic tonsillitis (CHT) in comparison to 24 patients with acute peritonsillar abscess (PTA) was performed. Blood samples for clinical routine hematological and serological parameters were assessed prior to surgery (T-1) and five days (T5) after tonsillectomy. Outcome 6 months later (T180) was documented using the Glasgow Benefit Inventory (GBI) and the Specific Benefits from Tonsillectomy Inventory (SBTI). Correlation analyses between CHT and PTA group as well as between the different time points within each group concerning the serological parameters and the outcome parameters were performed. RESULTS: At T-1, patients in the CHT group presented with significantly higher lymphocytes counts (relative and absolute), basophils (relative and absolute) and eosinophils but less white cells, monocytes, neutrophils (absolute and relative), alpha-1, alpha-2, beta globulins, immunoglobulin and lower C-reactive protein and procalcitonin values than patients in the PTA group (all p < 0.05, respectively). Within each group, different significant changes of the serum parameters (often in opposite direction) were observed between T-1 and T5. SBTI scores at T-1 were significantly lower in the CHT group. In contrast, most GBI scores at T180 were significantly higher in the CHT group. Between T-1 and T180 the SBTI scores improved in three quarters of the CHT patients but only in three fifths of the PTA patients. Higher eosinophil counts and immunoglobulin E levels at T-1 predicted higher GBI scores at T180 in the CHT group. CONCLUSIONS: This pilot study showed a specific serological pattern for patients with chronic tonsillitis with a specific pattern of changes after tonsillectomy. But there is no established role for biomarkers currently used in clinical practice to predict the outcome of tonsillectomy for chronic tonsillitis. PMID- 23816318 TI - Prevalence and correlates of violence exposure among HIV-infected adolescents. AB - Violence exposure among HIV-infected adolescents was estimated using Poisson regression and adjusted event rate ratios (ERR). Of 166 urban adolescents (99 perinatally infected youth [PIY]; 67 behaviorally infected youth [BIY]) 52.5% (n = 85) experienced violence; 79% (n = 131) witnessed violence. Sexual violence was experienced by 18% (6 PIY, 24 BIY) before age 13 years and by 15% (6 PIY, 19 BIY) during adolescence. BIY were significantly more likely than PIY to have experienced and witnessed violence. Controlling for transmission, ever-bartered sex (ERR = 1.92, CI [1.31 to 2.81], p = .009) and family disruptions (ERR = 1.19, CI [1.03 to 1.39], p = .022) were associated with violence victimization. Family disruptions (ERR = 1.17, CI [1.05 to 1.30], p = .004), female gender (ERR = 1.32, CI [1.05 to 1.66], p = .017), and heterosexual orientation (ERR = 1.48, CI = [1.11 to 1.97], p = .006) were associated with witnessing violence. PMID- 23816319 TI - Evaluation of analgesic, antioxidant, cytotoxic and metabolic effects of pregabalin for the use in neuropathic pain. AB - OBJECTIVE: The aim of this research was to evaluate analgesic, antioxidant, metabolic, and cytotoxic effects of pregabalin (PGB), which is widely applied for the treatment of neuropathic pain syndromes in diabetic patients. METHODS: We used the streptozotocin (STZ) model of painful diabetic neuropathy (PDN) in mice and we measured the effect of intraperitoneally administered PGB on tactile and thermal nociceptive thresholds in the von Frey and hot plate assays, respectively. The influence of PGB on the motor coordination of diabetic animals was investigated in the rotarod test. In vitro in HepG2 and 3T3-L1 cell lines cytotoxicity of PGB, its influence on glucose utilization, and lipid accumulation were assessed. The antioxidant capacity of PGB was evaluated spectrophotometrically using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical method. RESULTS: Pregabalin was a very efficacious antiallodynic and analgesic drug capable of increasing the pain thresholds for tactile allodynia and thermal hyperalgesia in diabetic mice. In the von Frey test at a dose of 30 mg/kg it elevated the pain threshold for 168% versus diabetic control and in the hot plate test this dose prolonged the latency time to pain reaction for 130% versus control value of diabetic mice. No motor deficits were observed in PGB-treated diabetic animals. In vitro PGB did not influence glucose utilization or lipid accumulation. No antioxidant or cytotoxic effects of PGB were observed at concentrations 1-100 MUM. DISCUSSION AND CONCLUSION: Our experiments demonstrated significant antiallodynic and analgesic properties of PGB in mice. In vitro studies showed that this drug is metabolically neutral. It did not cause motor coordination impairments in diabetic animals either. These effects might be of great importance for diabetic patients. PMID- 23816320 TI - Malaria, clinical features and acute crisis in children suffering from sickle cell disease in resource-limited settings: a retrospective description of 90 cases. AB - BACKGROUND: The prevalence of sickle cell disease (SCD) is extremely high in the Democratic Republic of Congo (DRC). Despite the high prevalence of this disease in our midst, there has been no report on the clinical features in the sickle cell pediatric population suffering from malaria in our midst. METHODS: A retrospective survey of records from the Department of Paediatrics of the University Hospital of Kinshasa, Kinshasa, Democratic Republic of Congo, was done for the period 1998-2008. For the 10 years studied, 108 children with SCD were reviewed and the data of those who developed malaria during admission were retrieved and analyzed. RESULTS: Of the 90 homozygous sickle cell children with malaria, fever, pallor, and jaundice were the commonly-found symptoms. Lethargy, severe anemia, respiratory distress, splenomegaly, hepatomegaly,digestive disorders, and prostration were common in children under 5 years, with significant difference (P, 0.05) to the older children. Transfusion because of to severe anemia was found necessary in 54.4% of cases. No case of cerebral malaria was found. Blackwater fever was a rare event. Hand-foot syndrome was present in 12.8% of patients, exclusively in those less than 5 years old. Pain crisis was associated in 46 cases (51.1%). Pain crisis was particularly present in SCD children less than 5 years of age (74.5% vs 25.6%, P , 0.001). No death was observed in this series. CONCLUSION: We conclude that the acute crisis related to SCD is more common in children less than 5 years of age. High risk of a requirement for blood transfusion was found in young children. Anti-malarial prophylaxis is advocated in Kinshasa. PMID- 23816321 TI - Home fortification with calcium reduces Hb response to iron among anaemic Bangladeshi infants consuming a new multi-micronutrient powder formulation. AB - OBJECTIVE: To investigate whether the recommended dietary intake of Ca in anaemic infants compromises the expected Hb response, via home fortification with a new Ca- and Fe-containing SprinklesTM micronutrient powder (MNP). DESIGN: A double blind, randomized controlled, 2-month trial was conducted in Bangladesh. Infants were randomized to one of two MNP intervention groups containing Fe and other micronutrients, with or without Ca. Hb, anthropometrics and dietary intake were measured pre- and post-intervention while family demographics were collected at baseline. SETTING: Twenty-six rural villages in the Kaliganj sub-district of Gazipur, Bangladesh. SUBJECTS: One hundred infants aged 6-11 months. RESULTS: A significant increase in Hb (MNP, 13.3 (sd 12.6) g/l v. Ca-MNP, 7.6 (sd 11.6) g/l; P < 0.0001) was noted in infants from both groups. However, infants receiving MNP without Ca had a significantly higher end-point Hb concentration (P = 0.024) and rate of anaemia recovery (P = 0.008). Infants receiving MNP with Ca were more likely to remain anaemic (OR 3.2; 95 % CI 1.4, 7.5). Groups did not differ in dietary intake or demographic and anthropometric indicators. CONCLUSIONS: Although both groups showed significant improvement in Hb status, the nutrient nutrient interaction between Fe and Ca may have diminished the Hb response in infants receiving the Ca-containing MNP. PMID- 23816322 TI - Low pressure hydrocephalus acutely following sepsis and cardiovascular collapse. PMID- 23816323 TI - Progressive visual field defect caused by an unruptured middle cerebral artery aneurysm. PMID- 23816324 TI - Blood culture accuracy: discards from central venous catheters in pediatric oncology patients in the emergency department. AB - INTRODUCTION: Lack of specific guidelines regarding collection of blood for culture from central venous catheters (CVCs) has led to inconsistencies in policies among hospitals. Currently, no specific professional or regulatory recommendations exist in relation to using, reinfusing, or discarding blood drawn from CVCs before drawing blood for a culture. Repeated wasting of blood may harm immunocompromised pediatric oncology patients. The purpose of this comparative study was to determine whether differences exist between blood cultures obtained from the first 5 mL of blood drawn from a CVC line when compared with the second 5 mL drawn. METHODS: During 2009-2011, 62 pediatric oncology patients with CVCs and orders for blood cultures to determine potential sepsis were enrolled during ED visits. Trained study nurses aseptically drew blood and injected the normally discarded first 5 mL and the second specimen (usual care) into separate culture bottles. Specimens were processed in the microbiology laboratory per hospital policy. RESULTS: Positive cultures were evaluated to assess agreement between specimen results and to determine that the identified pathogen was not a contaminant. Out of 186 blood culture pairs, 4.8% demonstrated positive results. In all positive-positive matches, the normal discard specimen contained the same organism as the usual care specimen. In 4 matches, the normally discarded specimen demonstrated notably earlier time to positivity (4 to 31 hours) compared with the usual care specimen, which resulted in earlier initiation of definitive antibiotics. DISCUSSION: These findings support the accuracy of the specimen that is normally discarded and suggest the need to reconsider its use for blood culture testing. PMID- 23816325 TI - Real-time audiovisual feedback system in a physician-staffed helicopter emergency medical service in Finland: the quality results and barriers to implementation. AB - OBJECTIVES: To evaluate the quality of cardiopulmonary resuscitation (CPR) in a physician staffed helicopter emergency medical service (HEMS) using a monitor defibrillator with a quality analysis feature. As a post hoc analysis, the potential barriers to implementation were surveyed. METHODS: The quality of CPR performed by the HEMS from November 2008 to April 2010 was analysed. To evaluate the implementation rate of quality analysis, the HEMS database was screened for all cardiac arrest missions during the study period. As a consequence of the observed low implementation rate, a survey was sent to physicians working in the HEMS to evaluate the possible reasons for not utilizing the automated quality analysis feature. RESULTS: During the study period, the quality analysis was used for 52 out of 187 patients (28%). In these cases the mean compression depth was < 40 mm in 46% and < 50 mm in 96% of the 1-min analysis intervals, but otherwise CPR quality corresponded with the 2005 resuscitation guidelines. In particular, the no-flow fraction was remarkably low 0.10 (0.07, 0.16). The most common reasons for not using quality-controlled CPR were that the device itself was not taken to the scene, or not applied to the patient, because another EMS unit was already treating the patient with another defibrillator. CONCLUSIONS: When quality-controlled CPR technology was used, the indicators of good quality CPR as described in the 2005 resuscitation guidelines were mostly achieved albeit with sufficient compression depth. The use of the well-described technology in improving patient care was low. Wider implementation of the automated quality control and feedback feature in defibrillators could further improve the quality of CPR on the field. TRIAL REGISTRATION: ClinicalTrials.gov (NCT00951704). PMID- 23816326 TI - Circulating miRNAs reflect early myocardial injury and recovery after heart transplantation. AB - BACKGROUND: MicroRNAs (miRNAs) are short, single-stranded and non-coding RNAs, freely circulating in human plasma and correlating with vary pathologies. In this study, we monitored early myocardial injury and recovery after heart transplantation by detecting levels of circulating muscle-specific miR-133a, miR 133b and miR-208a. METHODS: 7 consecutive patients underwent heart transplantation in Fuwai hospital and 14 healthy controls were included in our study. Peripheral vein blood was drawn from patients on the day just after transplantation (day 0), the 1st, 2nd, 3rd, 7th and 14th day after transplantation respectively. Serum from peripheral blood was obtained for cardiac troponin I (cTnI) measurement. Plasma was centrifuged from peripheral blood for measuring miR-133a, miR-133b and miR-208a by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The plasma concentration of miRNAs were calculated by absolute quantification method. The sensitivity and specificity of circulating miRNAs were revealed by receiver operating characteristic curve (ROC) analysis. Correlations between miRNAs and cTnI / perioperative parameters were analyzed. RESULTS: Similar to cTnI, miR-133a, miR 133b and miR-208a all showed dynamic changes from high to low levels early after operation. The Sensitivity and specificity of miRNAs were: miR-133a (85.7%,100%), miR-208a (100%,100%), and miR-133b (90%,100%). Correlations between miRNAs and cTnI were statistically significant (p < 0.05), especially for miR-133b (R2 = 0.813, p < 0.001). MiR-133b from Day 0-Day 2 (r > 0.98, p < 0.01), and cTnI from Day 1- Day 3 (r > 0.86, p < 0.05) had strong correlations with bypass time, particularly parallel bypass time. Obviously, miR-133b had a better correlation than cTnI. Circulating miR-133b correlated well with parameters of heart function such as central venous pressure (CVP), pulmonary capillary wedge pressure (PCWP), cardiac output (CO) and inotrope support, while cTnI only correlated with 3 of the 4 parameters mentioned above. MiR-133b also had strong correlations with ventilation time (r > 0.99, p < 0.001) and length of ICU stay (r > 0.92, p < 0.05), both of which reflected the recovery after operation. The correlation coefficients of miR-133b were also higher than that of cTnI. CONCLUSIONS: The dynamic change in circulating muscle-specific miRNAs, especially miR-133b can reflect early myocardial injury after heart transplantation. And miR-133b may have advantages over cTnI in forecasting graft dysfunction and recovery of patients after operation. PMID- 23816327 TI - The Stay-Green Rice like (SGRL) gene regulates chlorophyll degradation in rice. AB - The Stay-Green Rice (SGR) protein is encoded by the SGR gene and has been shown to affect chlorophyll (Chl) degradation during natural and dark-induced leaf senescence. An SGR homologue, SGR-like (SGRL), has been detected in many plant species. We show that SGRL is primarily expressed in green tissues, and is significantly downregulated in rice leaves undergoing natural and dark-induced senescence. As the light intensity increases during the natural photoperiod, the intensity of SGRL expression declines while that of SGR expression increases. Overexpression of SGRL reduces the levels of Chl and Chl-binding proteins in leaves, and accelerates their degradation in dark-induced senescence leaves in rice. Our results suggest that the SGRL protein is also involved in Chl degradation. The relationship between SGRL and SGR and their effects on the degradation of the light-harvesting Chl a/b-binding protein are also discussed. PMID- 23816329 TI - Multiple rewards from a treasure trove of novel glycoside hydrolase and polysaccharide lyase structures: new folds, mechanistic details, and evolutionary relationships. AB - Recent progress in three-dimensional structure analyses of glycoside hydrolases (GHs) and polysaccharide lyases (PLs), the historically relevant enzyme classes involved in the cleavage of glycosidic bonds of carbohydrates and glycoconjugates, is reviewed. To date, about 80% and 95% of the GH and PL families, respectively, have a representative crystal structure. New structures have been determined for enzymes acting on plant cell wall polysaccharides, sphingolipids, blood group antigens, milk oligosaccharides, N-glycans, oral biofilms and dietary seaweeds. Some GH enzymes have very unique catalytic residues such as the Asp-His dyad. New methods such as high-speed atomic force microscopy and computational simulation have opened up a path to investigate both the dynamics and the detailed molecular interactions displayed by these enzymes. PMID- 23816330 TI - Extended pancreas donor program - the EXPAND study rationale and study protocol. AB - BACKGROUND: Simultaneous pancreas kidney transplantation (SPK), pancreas transplantation alone (PTA) or pancreas transplantation after kidney (PAK) are the only curative treatment options for patients with type 1 (juvenile) diabetes mellitus with or without impaired renal function. Unfortunately, transplant waiting lists for this indication are increasing because the current organ acceptability criteria are restrictive; morbidity and mortality significantly increase with time on the waitlist. Currently, only pancreas organs from donors younger than 50 years of age and with a body mass index (BMI) less than 30 are allocated for transplantation in the Eurotransplant (ET) area. To address this issue we designed a study to increase the available donor pool for these patients. METHODS/DESIGN: This study is a prospective, multicenter (20 German centers), single blinded, non-randomized, two armed trial comparing outcome after SPK, PTA or PAK between organs with the currently allowed donor criteria versus selected organs from donors with extended criteria. Extended donor criteria are defined as organs procured from donors with a BMI of 30 to 34 or a donor age between 50 and 60 years. Immunosuppression is generally standardized using induction therapy with Myfortic, tacrolimus and low dose steroids. In principle, all patients on the waitlist for primary SPK, PTA or PAK are eligible for the clinical trial when they consent to possibly receiving an extended donor criteria organ. Patients receiving an organ meeting the current standard criteria for pancreas allocation (control arm) are compared to those receiving extended criteria organ (study arm); patients are blinded for a follow-up period of one year. The combined primary endpoint is survival of the pancreas allograft and pancreas allograft function after three months, as an early relevant outcome parameter for pancreas transplantation. DISCUSSION: The EXPAND Study has been initiated to investigate the hypothesis that locally allocated extended criteria organs can be transplanted with similar results compared to the currently allowed standard ET organ allocation. If our study shows a favorable comparison to standard organ allocation criteria, the morbidity and mortality for patients waiting for transplantation could be reduced in the future. TRIAL REGISTRATION: Trial registered at: NCT01384006. PMID- 23816331 TI - A prospective cohort study of disability pension due to mental diagnoses: the importance of health factors and behaviors. AB - BACKGROUND: Previous studies have found associations between various health factors and behaviors and mental disorders. However, knowledge of such associations with disability pension (DP) due to mental diagnoses is scarce. Moreover, the influence of familial factors (genetics and family background) on the associations are mainly unknown. The aim of the study was to investigate associations between health factors and behaviors and future DP due to mental diagnoses in a twin cohort, accounting for familial confounding. METHODS: A prospective cohort study of Swedish twins (N=28 613), including survey data and national register data on DP and other background factors was conducted. Cox proportional hazards regression models were used to calculate hazard ratios (HR) with 95% confidence intervals (CI) for the whole twin cohort, and for discordant twin pairs. RESULTS: During follow-up 1998-2008 (median 10 years), 2.2% of the cohort was granted a DP with a mental diagnosis. In the fully adjusted analyses of the whole cohort, the associations of poor or moderate self-rated health (SRH), under- or overweight, former or current tobacco use, or being an abstainer from alcohol were significantly associated with risk of DP due to mental diagnoses. Analyses of discordant twin pairs confirmed all these associations, except for current tobacco use, being independent from familial confounding. Exclusion of individuals with current or previous depression or anxiety at baseline did not influence the associations found. CONCLUSIONS: Poor or moderate SRH, under- or overweight, former tobacco use or being an abstainer from alcohol seem to be strong direct predictors of DP due to mental diagnoses, independently of several confounders of this study, including familial factors. PMID- 23816332 TI - Shifts from native to non-indigenous mussels: enhanced habitat complexity and its effects on faunal assemblages. AB - Ecosystem engineers such as mussels may affect strongly both the structure of benthic assemblages and the ecosystem functioning. The black-pygmy mussel Limnoperna securis is an invasive species that is spreading along the Galician coast (NW Spain). Its current distribution overlaps with the distribution of the commercial native mussel species Mytilus galloprovincialis, but only in the inner part of two southern Galician rias. Here, we analysed the assemblages associated with clumps of the two mussel species and evaluated if the invasive species increased complexity of habitat. To measure complexity of clumps we used a new method modified from the "chain and tape" method. Results showed that the identity of the mussel influenced macrofaunal assemblages, but not meiofauna. L. securis increased the complexity of clumps, and such complexity explained a high percentage of variability of macrofauna. The shift in dominance from M. galloprovincialis to L. securis may alter habitat structure and complexity, affecting the macrofaunal assemblages with unpredictable consequences on trophic web relations. PMID- 23816333 TI - A wild-type Botrytis cinerea strain co-infected by double-stranded RNA mycoviruses presents hypovirulence-associated traits. AB - BACKGROUND: Botrytis cinerea CCg378 is a wild-type strain infected with two types of double-stranded RNA (dsRNA) mycoviruses and which presents hypovirulence associated traits. The objectives of the present study were to characterize the mycoviruses and investigate their relationship with the low virulence degree of the fungal host. RESULTS: B. cinerea CCg378 contains five dsRNA molecules that are associated with two different types of isometric viral particles of 32 and 23 nm in diameter, formed by structural polypeptides of 70-kDa and 48-kDa, respectively. The transfection of spheroplasts of a virus-free strain, B. cinerea CKg54, with viral particles purified from the CCg378 strain revealed that the 2.2 kbp dsRNAs have no dependency on the smaller molecules for its stable maintenance in the fungal cytoplasm, because a fungal clone that only contains the 2.2-kbp dsRNAs associated with the 32-nm particles was obtained, which we named B. cinerea CKg54vi378. One of the 2.2 kbpdsRNA segments (2219 bp) was sequenced and corresponds to the gene encoding the capsid protein of B. cinerea CCg378 virus 1 (Bc378V1), a putative new member of the Partitiviridae family. Furthermore, physiological parameters related to the degree of virulence of the fungus, such as the sporulation rate and laccase activity, were lower in B. cinerea CCg378 and B. cinerea CKg54vi378 than in B. cinerea CKg54. Additionally, bioassays performed on grapevine leaves showed that the CCg378 and CKg54vi378 strains presented a lower degree of invasiveness on the plant tissue than the CKg54 strain. CONCLUSIONS: The results show that B. cinerea CCg378 is coinfected by two mycoviruses and that the 2.2-kbp dsRNAs correspond to the 32-nm mycovirus genome, which would be a new member of the Partitiviridae family as it has the typical pattern of partitiviruses. On the other hand, the results suggest that the hypovirulence of B. cinerea CCg378 could be conferred by both mycoviruses, since the fungal clone B. cinerea CKg54vi378 presents an intermediate virulence between the CKg54 and CCg378 strains. Therefore, the putative partitivirus would be partially contributing to the hypovirulence phenotype of the CCg378 strain. PMID- 23816334 TI - The origin of long-period lattice spacings observed in iron-carbide nanowires encapsulated by multiwall carbon nanotubes. AB - Structures comprising single-crystal, iron-carbon-based nanowires encapsulated by multiwall carbon nanotubes self-organize on inert substrates exposed to the products of ferrocene pyrolysis at high temperature. The most commonly observed encapsulated phases are Fe3C, alpha-Fe, and gamma-Fe. The observation of anomalously long-period lattice spacings in these nanowires has caused confusion since reflections from lattice spacings of >= 0.4 nm are kinematically forbidden for Fe3C, most of the rarely observed, less stable carbides, alpha-Fe, and g-Fe. Through high-resolution electron microscopy, selective area electron diffraction, and electron energy loss spectroscopy we demonstrate that the observed long period lattice spacings of 0.49, 0.66, and 0.44 nm correspond to reflections from the (100), (010), and (001) planes of orthorhombic Fe3C (space group Pnma). Observation of these forbidden reflections results from dynamic scattering of the incident beam as first observed in bulk Fe3C crystals.With small amounts of beam tilt these reflections can have significant intensities for crystals containing glide planes such as Fe3C with space groups Pnma or Pbmn. PMID- 23816335 TI - Comparative secretome analysis of four isogenic Bacillus clausii probiotic strains. AB - BACKGROUND: The spore-bearing alkaliphilic Bacillus species constitute a large, heterogeneous group of microorganisms, important for their ability to produce enzymes, antibodies and metabolites of potential medical use. Some Bacillus species are currently being used for manufacturing probiotic products consisting of bacterial spores, exhibiting specific features (colonization, immune stimulation and antimicrobial activity) that can account for their claimed probiotic properties. In the present work a comparative proteomic study was performed aimed at characterizing the secretome of four closely related isogenic O/C, SIN, N/R and T B. clausii strains, already marketed in a pharmaceutical mixture as probiotics. RESULTS: Proteomic analyses revealed a high degree of concordance among the four secretomes, although some proteins exhibited considerable variations in their expression level in the four strains. Among these, some proteins with documented activity in the interaction with host cells were identified, such as the glycolytic enzyme enolase, with a putative plasminogen-binding activity, GroEL, a molecular chaperone shown to be able to bind to mucin, and flagellin protein, a structural flagella protein and a putative immunomodulation agent. CONCLUSION: This study shows, for the first time, differences in the secretome of the OC, SIN, NR and T B. clausii strains. These differences indicate that specific secretome features characterize each of the four strains despite their genotypic similarity. This could confer to the B. clausii strains specific probiotic functions associated with the differentially expressed proteins and indicate that they can cooperate as probiotics as the secretome components of each strain could contribute to the overall activity of a mixed probiotic preparation. PMID- 23816336 TI - A rare case of Endometriosis in vaginal hysterectomy scar. AB - Presented hereunder is probably the first reported case of endometriosis at the vaginal apex following vaginal hysterectomy. No other similar case could be traced in the review of the literature. PMID- 23816337 TI - Determination of the detectable concentration of manganese used in neuronal MEMRI and its effect on cortical neurons in vitro. AB - OBJECTIVE: Manganese (Mn(2+))-enhanced magnetic resonance imaging (MEMRI) has received increasing attention because of its functional and anatomic value in brain studies. However, the contrast agent, Mn(2+), will lead to neurotoxicity at high concentrations, which limits its use in biomedical research. This study was designed to determine whether Mn(2+) can significantly enhance the signal intensity (SI) of primary cultured cortical neurons at non-toxic levels. METHOD: Neurons were incubated with different concentrations of Mn(2+) (control and 0.01, 0.05, 0.10, and 0.20 mM), then a cellular MRI was performed in vitro and the intracellular Mn(2+) concentrations were analyzed by ICP-MS. At the same time, the cell viability, LDH release assay, intracellular ROS level, and apoptosis were measured 24 h after treatment. RESULTS: (1) After the neurons were treated with Mn(2+) at a low concentration (0.01 mM), there was no impact on cell viability and cytotoxicity, and no significant signal was enhanced on MEMRI. (2) When the neurons were exposed to higher concentrations of Mn(2+) (0.05, 0.1, and 0.2 mM), a significant increase in signal quality was achieved, but cell viability was significantly reduced and the intracellular ROS formation and percentage of TUNEL-positive cells were increased significantly. CONCLUSION: At Mn(2+) concentrations > 0.05 mM, significant enhancement of MEMRI SI occurred, but with overt cytotoxicity. PMID- 23816338 TI - Factors predicting hospital length-of-stay after radical prostatectomy: a population-based study. AB - BACKGROUND: Radical prostatectomy (RP) is a leading treatment option for localised prostate cancer. Although hospital in-patient stays accounts for much of the costs of treatment, little is known about population-level trends in length-of-stay (LOS). We investigated factors predicting hospital LOS and readmissions in men who had RP following prostate cancer. METHODS: Incident prostate cancers (ICD-O3: C61), diagnosed January 2002-December 2008 in men < 70 years, were identified from the Irish Cancer Registry, and linked to public hospital episodes. For those who had RP (ICD-9 CM procedure codes 60.3, 60.4, 60.5, 60.62) the associated hospital episode was identified. LOS was calculated as the number of days from date of admission to date of discharge. Patient-, tumour-, and health service-related factors predicting longer LOS (upper quartile, >9 days) were investigated using logistic regression. Patterns in day case and in-patient readmissions within 28 days of discharge following RP were explored. RESULTS: Over the study period 9096 prostate cancers were diagnosed in men under 70, 26.5% of whom had RP by end of follow-up 31/12/2009. Two of eight public hospitals and eight of forty surgeons carried out 50% of all public service RPs. Median LOS was 8 days (10th-90th percentile = 6-13 days) and fell significantly over time (2002, 9 days; 2008, 7 days; p < 0.001). In adjusted analyses men who were not married (OR = 1.71, 95% CI 1.25-2.34), had co morbidities (OR = 1.64, 95% CI 1.25-2.16) or stage III-IV cancer (OR = 2.19, 95% CI 1.44-3.34) were significantly more likely to have prolonged LOS. Those treated in higher volume hospitals (annual median >49 RPs) or by higher volume surgeons (annual median >17 RPs) were significantly less likely to have prolonged LOS (OR = 0.34, 95% CI 0.26-0.45; OR = 0.55, 95% CI 0.42-0.71 respectively). CONCLUSION: Median LOS after RP decreased between 2002 and 2008 in Ireland but it remains higher than in both England and the US. Although volumes of RPs conducted in Ireland are low, there is considerable variation between hospitals and surgeons. Hospital and surgeon volume were strong predictors of shorter LOS, after adjusting for other variables. These factors point to a need for a comprehensive review of prostate cancer service provision. PMID- 23816339 TI - An unusual complication of weightlifting: a case report. AB - Acute exertional compartment syndrome is an uncommon illness that occurs after a period of strenuous exercise. We present a case of acute exertional compartment syndrome of the bilateral supraspinatus muscles after weight lifting. The diagnosis was made in the emergency department and the patient subsequently underwent successful decompressive fasciotomies of both compartments. We highlight the unusual presentation of this case and the approach to make the diagnosis. PMID- 23816340 TI - Effects of salubrinal on development of osteoclasts and osteoblasts from bone marrow-derived cells. AB - BACKGROUND: Osteoporosis is a skeletal disease leading to an increased risk of bone fracture. Using a mouse osteoporosis model induced by administration of a receptor activator of nuclear factor kappa-B ligand (RANKL), salubrinal was recently reported as a potential therapeutic agent. To evaluate the role of salubrinal in cellular fates as well as migratory and adhesive functions of osteoclast/osteoblast precursors, we examined the development of primary bone marrow-derived cells in the presence and absence of salubrinal. We addressed a question: are salubrinal's actions more potent to the cells isolated from the osteoporotic mice than those isolated from the control mice? METHODS: Using the RANKL-injected and control mice, bone marrow-derived cells were harvested. Osteoclastogenesis was induced by macrophage-colony stimulating factor and RANKL, while osteoblastogenesis was driven by dexamethasone, ascorbic acid, and beta glycerophosphate. RESULTS: The results revealed that salubrinal suppressed the numbers of colony forming-unit (CFU)-granulocyte/macrophages and CFU-macrophages, as well as formation of mature osteoclasts in a dosage-dependent manner. Salubrinal also suppressed migration and adhesion of pre-osteoclasts and increased the number of CFU-osteoblasts. Salubrinal was more effective in exerting its effects in the cells isolated from the RANKL-injected mice than the control. Consistent with cellular fates and functions, salubrinal reduced the expression of nuclear factor of activated T cells c1 (NFATc1) as well as tartrate resistant acid phosphatase. CONCLUSIONS: The results support the notion that salubrinal exhibits significant inhibition of osteoclastogenesis as well as stimulation of osteoblastogenesis in bone marrow-derived cells, and its efficacy is enhanced in the cells harvested from the osteoporotic bone samples. PMID- 23816341 TI - Pleiotropic effects of rosuvastatin on the glucose metabolism and the subcutaneous and visceral adipose tissue behavior in C57Bl/6 mice. AB - The aim of this study was to evaluate whether rosuvastatin (HMG-CoA reductase inhibitor) modulates the carbohydrate and lipid metabolism, the development of non-alcoholic fatty liver disease (NAFLD), and the increase in body mass in a model of diet-induced obesity. Male C57Bl/6 mice (3-months-old) were fed a high fat diet (HF, 60% lipids) or the standard chow (SC, 10% lipids) for 15 weeks. The animals were then treated with 10 mg/kg/day (HF-R10 group), 20 mg/kg/day (HF R20), or 40 mg/kg/day (HF-R40) of rosuvastatin for five weeks. The HF diet led to glucose intolerance, insulin resistance, weight gain, increased visceral adiposity with adipocyte hypertrophy, and hepatic steatosis (micro and macrovesicular). The rosuvastatin treatment decreased the adiposity and the adipocyte size in the HF-R10 and HF-R20 groups. In addition, rosuvastatin changed the pattern of fat distribution in the HF-R40 group because more fat was stored subcutaneously than in visceral depots. This redistribution improved the fasting glucose and the glucose intolerance. Rosuvastatin also improved the liver morphology and ultrastructure in a dose-dependent manner. In conclusion, rosuvastatin exerts pleiotropic effects through a dose-dependent improvement of glucose intolerance, insulin sensitivity and NAFLD and changes the fat distribution from visceral to subcutaneous fat depots in a mouse model of diet induced obesity. PMID- 23816342 TI - Early myoclonic epilepsy, hypertrophic cardiomyopathy and subsequently a nephrotic syndrome in a patient with CoQ10 deficiency caused by mutations in para hydroxybenzoate-polyprenyl transferase (COQ2). AB - BACKGROUND: Primary coenzyme Q10 (CoQ10) deficiencies are heterogeneous autosomal recessive disorders. CoQ2 mutations have been identified only rarely in patients. All affected individuals presented with nephrotic syndrome in the first year of life. METHODS: An infant is studied with myoclonic seizures and hypertrophic cardiomyopathy in the first months of life and developed a nephrotic syndrome in a later stage. RESULTS: At three weeks of age, the index patient developed myoclonic seizures. In addition, he had hypertrophic cardiomyopathy and increased CSF lactate. A skeletal muscle biopsy performed at two months of age disclosed normal activities of the oxidative phosphorylation complexes. The child was supplemented with CoQ10 (5 mg/kg/day). At the age of four months, brain MR images showed bilateral increased signal intensities in putamen and cerebral cortex. After that age, he developed massive proteinuria. The daily dose of CoQ10 was increased to 30 mg/kg. Renal biopsy showed focal segmental glomerulosclerosis. Biochemical analyses of a kidney biopsy sample revealed a severely decreased activity of succinate cytochrome c reductase [complex II + III] suggesting ubiquinone depletion. Incorporation of labelled precursors necessary for CoQ10 synthesis was significantly decreased in cultured skin fibroblasts. His condition deteriorated and he died at the age of five months. A novel homozygous mutation c.326G > A (p.Ser109Asn) was found in COQ2. CONCLUSIONS: In contrast to previously reported patients with CoQ2 the proband presented with early myoclonic epilepsy, hypertrophic cardiomyopathy and only in a later stage developed a nephrotic syndrome. The phenotype of this patient enlarges the phenotypical spectrum of the multisystem infantile variant. PMID- 23816343 TI - Vascular leak ensues a vigorous proinflammatory cytokine response to Tacaribe arenavirus infection in AG129 mice. AB - BACKGROUND: Tacaribe virus (TCRV) is a less biohazardous relative of the highly pathogenic clade B New World arenaviruses that cause viral hemorrhagic fever syndromes and require handling in maximum containment facilities not readily available to most researchers. AG129 type I and II interferon receptor knockout mice have been shown to be susceptible to TCRV infection, but the pathogenic mechanisms contributing to the lethal disease are unclear. METHODS: To gain insights into the pathogenesis of TCRV infection in AG129 mice, we assessed hematologic and cytokine responses during the course of infection, as well as changes in the permeability of the vascular endothelium. We also treated TCRV challenged mice with MY-24, a compound that prevents mortality without affecting viral loads during the acute infection, and measured serum and tissue viral titers out to 40 days post-infection to determine whether the virus is ultimately cleared in recovering mice. RESULTS: We found that the development of viremia and splenomegaly precedes an elevation in white blood cells and the detection of high levels of proinflammatory mediators known to destabilize the endothelial barrier, which likely contributes to the increased vascular permeability and weight loss that was observed several days prior to when the mice generally succumb to TCRV challenge. In surviving mice treated with MY-24, viremia and liver virus titers were not cleared until 2-3 weeks post-infection, after which the mice began to recover lost weight. Remarkably, substantial viral loads were still present in the lung, spleen, brain and kidney tissues at the conclusion of the study. CONCLUSIONS: Our findings suggest that vascular leak may be a contributing factor in the demise of TCRV-infected mice, as histopathologic findings are generally mild to moderate in nature, and as evidenced with MY-24 treatment, animals can survive in the face of high viral loads. PMID- 23816344 TI - The impact of upfront versus sequential use of bortezomib among patients with newly diagnosed multiple myeloma (MM): a joint analysis of the Singapore MM Study Group and the Korean MM Working Party for the Asian myeloma network. AB - From the comprehensive MM registries of the Singapore (SG) and South Korea (SK) MM study groups, we study the survival data of 432 unselected and previously untreated MM patients diagnosed from 2006 to 2009. Although novel agents were introduced to both countries which have compatible healthcare standards at the same time, MM patients with high-risk features in SG could receive frontline bortezomib while bortezomib could only be approved for salvage setting in SK. After a median follow-up of 19 months, despite 26% of patients in SG versus none in SK having received frontline bortezomib, the overall bortezomib-exposure rate was higher in SK (60% versus 47%, p<0.001). Significantly more patients had no response to induction in SK. Although the median overall survival (OS) of patients in SG and SK was not significantly different (not reached versus 4.83 years respectively, p=0.2), corresponding 2-year OS for high-risk ISS patients treated in SG and SK was 81% and 67% respectively (p=0.01). On multivariate analysis stratified by country, the attainment of >= VGPR was the only significant prognostic factor in SG while the presence of high-risk ISS has significant early prognostic impact in SK. Frontline use of bortezomib compared to its sequential may avert early mortality especially among patients with high risk MM. PMID- 23816345 TI - Clathrin heavy chain 1 is required for spindle assembly and chromosome congression in mouse oocytes. AB - Clathrin heavy chain 1 (CLTC) has been considered a "moonlighting protein" which acts in membrane trafficking during interphase and in stabilizing spindle fibers during mitosis. However, its roles in meiosis, especially in mammalian oocyte maturation, remain unclear. This study investigated CLTC expression and function in spindle formation and chromosome congression during mouse oocyte meiotic maturation. Our results showed that the expression level of CLTC increased after germinal vesicle breakdown (GVBD) and peaked in the M phase. Immunostaining results showed CLTC distribution throughout the cytoplasm in a cell cycle dependent manner. Appearance and disappearance of CLTC along with beta-tubulin (TUBB) could be observed during spindle dynamic changes. To explore the relationship between CLTC and microtubule dynamics, oocytes at metaphase were treated with taxol or nocodazole. CLTC colocalized with TUBB at the enlarged spindle and with cytoplasmic asters after taxol treatment; it disassembled and distributed into the cytoplasm along with TUBB after nocodazole treatment. Disruption of CLTC function using stealth siRNA caused a decreased first polar body extrusion rate and extensive spindle formation and chromosome congression defects. Taken together, these results show that CLTC plays an important role in spindle assembly and chromosome congression through a microtubule correlation mechanism during mouse oocyte maturation. PMID- 23816346 TI - Epidemiology of Clostridium difficile infection in Asia. AB - While Clostridium difficile infection (CDI) has come to prominence as major epidemics have occurred in North America and Europe over the recent decade, awareness and surveillance of CDI in Asia have remained poor. Limited studies performed throughout Asia indicate that CDI is also a significant nosocomial pathogen in this region, but the true prevalence of CDI remains unknown. A lack of regulated antibiotic use in many Asian countries suggests that the prevalence of CDI may be comparatively high. Molecular studies indicate that ribotypes 027 and 078, which have caused significant outbreaks in other regions of the world, are rare in Asia. However, variant toxin A-negative/toxin B-positive strains of ribotype 017 have caused epidemics across several Asian countries. Ribotype smz/018 has caused widespread disease across Japan over the last decade and more recently emerged in Korea. This review summarises current knowledge on CDI in Asian countries. PMID- 23816347 TI - Proteomic analyses of age related changes in A.BY/SnJ mouse hearts. AB - BACKGROUND: A.BY/SnJ mice are used to study pathological alterations in the heart due to enteroviral infections. Since age is a well-known factor influencing the susceptibility of mice to infection, response to stress and manifestation of cardiovascular diseases, the myocardial proteome of A.BY/SnJ mice aged 1 and 4 months was comparatively studied using two dimensional-differential in-gel electrophoresis (2D-DIGE) and liquid chromatography tandem mass spectrometry (LC MS/MS). RESULTS: Complementary analyses by 2D-DIGE and gel-free LC-MS/MS revealed 96 distinct proteins displaying age associated alterations in their levels. Proteins related to protein transport, and transport chain, lipid metabolism and fatty acid transport showed significant changes in 4 months old mouse hearts compared to juvenile hearts. Proteins involved in lipid metabolism and transport were identified at significantly higher levels in older mice and dysregulation of proteins of the respiratory transport chain were observed. CONCLUSION: The current proteomics study discloses age dependent changes occurring in the hearts already in young mice of the strain A.BY/SnJ. Besides alterations in protein transport, we provide evidence that a decrease of ATP synthase in murine hearts starts already in the first months of life, leading to well-known low expression levels manifested in old mice thereby raising the possibility of reduced energy supply. In the first few months of murine life this seems to be compensated by an increased lipid metabolism. The functional alterations described should be considered during experimental setups in disease related studies. PMID- 23816348 TI - Aggressive mature natural killer cell neoplasms: from epidemiology to diagnosis. AB - Mature natural killer (NK) cell neoplasms are classified by the World Health Organization into NK/T cell lymphoma, nasal type (NKTCL), aggressive NK-cell leukemia (ANKCL) and chronic lymphoproliferative disorders of NK-cells, the latter being considered provisionally. NKTCL and ANKCL are rare diseases, with higher prevalence in Asia, Central and South America. Most NKTCL present extranodal, as a destructive tumor affecting the nose and upper aerodigestive tract (nasal NKTCL) or any organ or tissue (extranasal NKTCL) whereas ANKCL manifests as a systemic disease with multiorgan involvement and naturally evolutes to death in a few weeks. The histopathological hallmark of these aggressive NK-cell tumors is a polymorphic neoplastic infiltrate with angiocentricity, angiodestruction and tissue necrosis. The tumor cells have cytoplasmatic azurophilic granules and usually show a CD45(+bright), CD2(+), sCD3(-), cytCD3epsilon(+), CD56(+bright), CD16(-/+), cytotoxic granules molecules(+) phenotype. T-cell receptor genes are in germ-line configuration. Epstein-Barr virus (EBV) -encoded membrane proteins and early region EBV RNA are usually detected on lymphoma cells, with a pattern suggestive of a latent viral infection type II. Complex chromosomal abnormalities are frequent and loss of chromosomes 6q, 11q, 13q, and 17p are recurrent aberrations. The rarity of the NK cell tumors limits our ability to standardize the procedures for the diagnosis and clinical management and efforts should be made to encourage multi institutional registries. PMID- 23816349 TI - Assessing therapist reservations about exposure therapy for anxiety disorders: the Therapist Beliefs about Exposure Scale. AB - Exposure therapy is underutilized in the treatment of pathological anxiety and is often delivered in a suboptimal manner. Negative beliefs about exposure appear common among therapists and may pose a barrier to its dissemination. To permit reliable and valid assessment of such beliefs, we constructed the 21-item Therapist Beliefs about Exposure Scale (TBES) and examined its reliability and validity in three samples of practicing clinicians. The TBES demonstrated a clear single-factor structure, excellent internal consistency (alphas=.90-.96), and exceptionally high six-month test-retest reliability (r=.89). Negative beliefs about exposure therapy were associated with therapist demographic characteristics, negative reactions to a series of exposure therapy case vignettes, and the cautious delivery of exposure therapy in the treatment of a hypothetical client with obsessive-compulsive disorder. Lastly, TBES scores decreased markedly following a didactic workshop on exposure therapy. The present findings support the reliability and validity of the TBES. PMID- 23816351 TI - Identification of the thiamin salvage enzyme thiazole kinase in Arabidopsis and maize. AB - The breakdown of thiamin (vitamin B1) and its phosphates releases a thiazole moiety, 4-methyl-5-(2-hydroxyethyl)thiazole (THZ), that microorganisms and plants are able to salvage for re-use in thiamin synthesis. The salvage process starts with the ATP-dependent phosphorylation of THZ, which in bacteria is mediated by ThiM. The Arabidopsis and maize genomes encode homologs of ThiM (At3g24030 and GRMZM2G094558, respectively). Plasmid-driven expression of either plant homolog restored the ability of THZ to rescue Escherichia coli thiM deletant strains, showing that the plant proteins have ThiM activity in vivo. Enzymatic assays with purified recombinant proteins confirmed the presence of THZ kinase activity. Furthermore, ablating the Arabidopsis At3g24030 gene in a thiazole synthesis mutant severely impaired rescue by THZ. Collectively, these results show that ThiM homologs are the main source of THZ kinase activity in plants and are consequently crucial for thiamin salvage. PMID- 23816352 TI - The diagnostic accuracy of TCD for intracranial arterial stenosis/occlusion in patients with acute ischemic stroke: the importance of time interval between detection of TCD and CTA. AB - OBJECTIVE: To evaluate prospectively the diagnostic accuracy of transcranial doppler (TCD) as an additional screening tool for intracranial arterial steno occlusive disease against computed tomography angiography (CTA) in patients with acute ischemic stroke (AIS) if both are performed in a short time interval. METHODS: Between July 2011 and May 2012, 128 patients who were hospitalized within 24 hours of symptom onset and fulfilled the criteria for the clinical diagnosis of AIS were enrolled. Bedside detection of TCD was accomplished immediately after admission. High-resolution brain CTA was performed within 3 hours after the completion of TCD and the images were interpreted by a neuroradiologist blinded to TCD findings. The accuracy parameters of TCD against CTA were calculated after computation of true-positive, false-positive, true negative, and false-negative values. RESULTS: Among the 128 patients, there were 68 males and 60 females, aged 61.4 +/- 17.5 years. The mean time interval between the detection of TCD and CTA was 89.7 (77.8) minutes. In 65% of patients, both examinations were performed with less than a half-hour interval between them. The diagnostic accuracy of TCD for different arteries showed slight distinction. Transcranial doppler demonstrated the most accurate diagnosis for middle cerebral artery (MCA), where TCD showed 35 true-positive, 0 false-negative, 1 false positive, and 92 true-negative studies compared with CTA. Furthermore, elevated MCA velocities on TCD correlated well with the severity of intracranial stenosis detected on CTA. Vertebral artery (VA) is one of the arteries with the lowest sensitivity for TCD diagnosis (sensitivity 63.4%, specificity 96.5%, positive predictive value (PPV) 89.6%, negative predictive value (NPV) 84.8%, and accuracy 85.9%). In 20 cases (15.6%), TCD showed findings complementary to CTA (real-time embolization, collateral flow patterns, and steal phenomenon). CONCLUSIONS: Transcranial doppler shows high diagnostic accuracy against CTA if both are performed in a short time interval in evaluating intracranial arterial stenosis/occlusion in patients with AIS, especially for MCA obstruction. Transcranial doppler can also provide additional real-time dynamic findings complementary to the information provided by CTA. This can result in changes in the management in some of these patients. PMID- 23816353 TI - A needs-based method for estimating the behavioral health staff needs of community health centers. AB - BACKGROUND: Federally Qualified Health Centers are expanding to increase access for millions of more Americans with a goal of doubling capacity to serve 40 million people. Health centers provide a lot of behavioral health services but many have difficulty accessing mental health and substance use professionals for their patients. To meet the needs of the underserved and newly insured it is important to better estimate how many behavioral health professionals are needed. METHODS: Using health center staffing data and behavioral health service patterns from the 2010 Uniform Data System and the 2010 National Survey on Drug Use and Health, we estimated the number of patients likely to need behavioral health care by insurance type, the number of visits likely needed by health center patients annually, and the number of full time equivalent providers needed to serve them. RESULTS: More than 2.5 million patients, 12 or older, with mild or moderate mental illness, and more than 357,000 with substance abuse disorders, may have gone without needed behavioral health services in 2010. This level of need would have required more than 11,600 full time providers. This translates to approximately 0.9 licensed mental health provider FTE, 0.1 FTE psychiatrist, 0.4 FTE other mental health staff, and 0.3 FTE substance abuse provider per 2,500 patients. These estimates suggest that 90% of current centers could not access mental health services or provide substance abuse services to fully meet patients' needs in 2010. If needs are similar after health center expansion, more than 27,000 full time behavioral health providers will be needed to serve 40 million medical patients, and grantees will need to increase behavioral health staff more than four-fold. CONCLUSIONS: More behavioral health is seen in primary care than in any other setting, and health center clients have greater behavioral health needs than typical primary care patients. Most health centers needed additional behavioral health services in 2010, and this need will be magnified to serve 40 million patients. Further testing of these workforce models are needed, but the degree of current underservice suggests that we cannot wait to move on closing the gap. PMID- 23816354 TI - Effect of vacuum spine board immobilization on incidence of pressure ulcers during evacuation of military casualties from theater. AB - BACKGROUND CONTEXT: In the summer of 2009, the vacuum spine board (VSB) was designated by the US Air Force as the preferred method of external spinal immobilization during aeromedical transport of patients with suspected unstable thoracolumbar spine fractures. One purported advantage of the VSB is that, by distributing weight over a larger surface area, it decreases the risk of skin pressure ulceration. PURPOSE: To examine whether the rate of pressure ulcers has changed since the introduction of the VSB. STUDY DESIGN: Retrospective cohorts. PATIENT SAMPLE: Injured US service members undergoing spinal immobilization during evacuation from the Iraq and Afghanistan theaters to Landstuhl, Germany. OUTCOME MEASURES: Presence and stage of pressure ulceration, and deterioration in neurologic status. METHODS: Records of the initial 60 patients medically evacuated on the VSB to Landstuhl Regional Medical Center were retrospectively analyzed for patient demographics, injury characteristics, and incidence of pressure injury. The incidence of pressure ulcers after the use of VSB was compared with that in a historical control consisting of 30 patients with unstable spinal injuries evacuated before the introduction of the VSB. No sources of external funding were used for this investigation. RESULTS: The combined cohort had a mean age of 28.8 years and mean Injury Severity Score (ISS) of 20.63 and comprised 96% men. Most injury mechanisms were blunt (58%). The rate of neurological injury was 19%. There were no cases of progressive neurological deficit or deformity in either cohort. In the VSB group, using a broad definition of pressure ulcer, incidence was 13 of 60 patients (22%). Using a strict definition, incidence was eight of 60 (13%): five Stage I and three Stage II. In the non-VSB group, incidence of pressure ulcers was three of 30 (10%), using either definition, all Stage II. Difference in incidence between the groups was not statistically significant. Intubated patients had a significantly higher incidence of pressure ulcers. CONCLUSION: Both the VSB and historic means (non VSB) of spinal immobilization appear to be safe and produce only transient morbidity despite an average of 9 to 10 hours of transport. Intubated status was identified as the most important risk factor for the development of a pressure ulcer. PMID- 23816355 TI - Development and validation of a predictive model of acute glucose response to exercise in individuals with type 2 diabetes. AB - BACKGROUND: Our purpose was to develop and test a predictive model of the acute glucose response to exercise in individuals with type 2 diabetes. DESIGN AND METHODS: Data from three previous exercise studies (56 subjects, 488 exercise sessions) were combined and used as a development dataset. A mixed-effects Least Absolute Shrinkage Selection Operator (LASSO) was used to select predictors among 12 potential predictors. Tests of the relative importance of each predictor were conducted using the Lindemann Merenda and Gold (LMG) algorithm. Model structure was tested using likelihood ratio tests. Model accuracy in the development dataset was assessed by leave-one-out cross-validation.Prospectively captured data (47 individuals, 436 sessions) was used as a test dataset. Model accuracy was calculated as the percentage of predictions within measurement error. Overall model utility was assessed as the number of subjects with <=1 model error after the third exercise session. Model accuracy across individuals was assessed graphically. In a post-hoc analysis, a mixed-effects logistic regression tested the association of individuals' attributes with model error. RESULTS: Minutes since eating, a non-linear transformation of minutes since eating, post-prandial state, hemoglobin A1c, sulfonylurea status, age, and exercise session number were identified as novel predictors. Minutes since eating, its transformations, and hemoglobin A1c combined to account for 19.6% of the variance in glucose response. Sulfonylurea status, age, and exercise session each accounted for <1.0% of the variance. In the development dataset, a model with random slopes for pre-exercise glucose improved fit over a model with random intercepts only (likelihood ratio 34.5, p < 0.001). Cross-validated model accuracy was 83.3%.In the test dataset, overall accuracy was 80.2%. The model was more accurate in pre-prandial than postprandial exercise (83.6% vs. 74.5% accuracy respectively). 31/47 subjects had <=1 model error after the third exercise session. Model error varied across individuals and was weakly associated with within-subject variability in pre exercise glucose (Odds ratio 1.49, 95% Confidence interval 1.23-1.75). CONCLUSIONS: The preliminary development and test of a predictive model of acute glucose response to exercise is presented. Further work to improve this model is discussed. PMID- 23816356 TI - iPads, droids, and bugs: Infection prevention for mobile handheld devices at the point of care. AB - Health care providers are increasingly using wireless media tablets, such as the Apple iPad, especially in the hospital setting. In the absence of specific tablet disinfection guidelines the authors applied what is known about the contamination of other nonmedical mobile communication devices to create a "common sense" bundle to guide wireless media tablet infection prevention practices. PMID- 23816357 TI - Moving forward with hospital cleaning. PMID- 23816358 TI - Biodiesel from Forsythia suspense [(Thunb.) Vahl (Oleaceae)] seed oil. AB - In the present work, Forsythia suspense seed oil (FSSO) was investigated for the first time as an alternative non-conventional feedstock for the preparation of biodiesel. The FSSO yield is 30.08+/-2.35% (dry weight of F. suspense seed basis), and the oil has low acid value (1.07 mg KOH/g). The fatty acid composition of FSSO exhibits the predominance of linoleic acid (72.89%) along with oleic acid (18.68%) and palmitic acid (5.65%), which is quite similar to that of sunflower oil. Moreover, microwave-assisted transesterification process of FSSO with methanol in the presence of potassium hydroxide catalyst was optimized and an optimal biodiesel yield (90.74+/-2.02%) was obtained. Furthermore, the fuel properties of the biodiesel product were evaluated as against ASTM D-6751 biodiesel standards and an acceptable agreement was observed except the cetane number. Overall, this study revealed the possibility of FSSO as a potential resource of biodiesel feedstock. PMID- 23816359 TI - Biowaste: a Lactobacillus habitat and lactic acid fermentation substrate. AB - Composite organic waste was assessed for its physical, chemical and microbial suitability to serve as a substrate for the fermentative production of lactic acid. The biowaste studied was highly acidic (pH 4.3) and had high organic carbon content (45%). A clone library identified 90% of the bacterial community were lactic acid bacteria, mainly represented by Lactobacilli (70%). Cultivation using semiselective media identified Lactobacillus plantarum, Lactobacillus brevis and their closest relatives as the dominating taxa. PCR-DGGE using general bacterial and lactic acid bacterial specific primers resulted in little heterogeneity of microbial community. These data indicate that biowaste is a preferred habitat of lactic acid bacteria, suggesting that the unsterilized biowaste and its natural flora could be used in a fermentation process for lactic acid production. Such kind of biowaste application could be an alternative for current substrates and provide a modern, efficient and environmental friendly waste treatment technology. PMID- 23816360 TI - Reply: To PMID 22196455. PMID- 23816361 TI - Combined toxicity of pesticide mixtures on green algae and photobacteria. AB - Different organisms have diverse responses to the same chemicals or mixtures. In this paper, we selected the green algae Chlorella pyrenoidosa (C. pyrenoidosa) and photobacteria Vibrio qinghaiensis sp.-Q67 (V. qinghaiensis) as target organisms and determined the toxicities of six pesticides, including three herbicides (simetryn, bromacil and hexazinone), two fungicides (dodine and metalaxyl) and one insecticide (propoxur), and their mixtures by using the microplate toxicity analysis. The toxicities of three herbicides to C. pyrenoidosa are much higher than those to V. qinghaiensis, and the toxicities of metalaxyl and propoxur to V. qinghaiensis are higher than those to C. pyrenoidosa, while the toxicity of dodine to C. pyrenoidosa is similar to those to V. qinghaiensis. Using the concentration addition as an additive reference model, the binary pesticide mixtures exhibited different toxicity interactions, i.e., displayed antagonism to C. pyrenoidosa but synergism to V. qinghaiensis. However, the toxicities of the multi-component mixtures of more than two components are additive and can be predicted by the concentration addition model. PMID- 23816362 TI - Histopathological effects of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) in the gills, intestine and liver of turbot (Psetta maxima). AB - Polybrominated diphenyl ethers (PBDEs) have become ubiquitous environmental pollutants because of their widespread use as flame retardants in various consumer products (plastics, textiles, electronic appliances and building materials) and their long half-life. BDE-47 (2,2',4,4'-tetrabromodiphenyl ether) is the major PBDE congener detected in the environment and in animal tissues. In the present study, the histopathological effects are examined of BDE-47 on the gills, intestine and liver tissues of juvenile turbot (Psetta maxima).The specimens were exposed to two concentrations of BDE-47 (0.03 and 0.3 ug/L) for a period of 15 days. The histological changes were detected microscopically and evaluated with quantitative or semi-quantitative analyses. At the doses of BDE-47 assayed, the most common gill injuries were lamellar fusion, blood congestion and hyperplasia and hypertrophy of the epithelial and mucous cells. In the intestine of fish exposed to BDE-47, the alterations detected were hyperplasia and hypertrophy of mucous cells. Hepatic lesions in the liver of fish exposed to BDE 47 were characterized by circulatory disturbances, irregular morphology of hepatocytes, cellular and nuclear hypertrophy, and nuclear vacuolation and pyknosis. As BDE-47 is present in food and other material related to aquaculture systems, our results indicate that exposure to this pollutant could have serious consequences on health in turbot and other cultured fish. PMID- 23816363 TI - Fast determination of fish mineral profile. Application to Vietnamese panga fish. AB - A methodology, based on inductively coupled plasma optical emission spectrometry after microwave-assisted digestion with HNO3/H2O2, was developed to determine the mineral profile of panga fish samples imported from Vietnam. A total of 42 essential and toxic elements were studied in seven samples taken from the local market. Preliminary studies were focused on selecting the best wavelength and the required dilution of samples in order to provide the highest sensitivity to maximize the number of analytes to be determined without spectral or matrix interferences. Adequate accuracy was assured by the analysis of certified reference material TORT-2. Mercury was also determined by a direct method based on atomic absorption spectrometry. Results obtained indicated a low mineral profile, fourteen elements were found at quantitatively levels, Na (6000 ug g( 1)) K (1800 ug g(-1)) Mg (173 ug g(-1)), Ca (80 ug g(-1)), Zn (2.44 ug g(-1)), Fe (1.6 ug g(-1)), Al (1.1 ug g(-1)), Sr (0.4 ug g(-1)) and B, Ba, Hg, Mn, V (under 0.1 ug g(-1)). Additionally data were compared with those previously reported in literature and an estimation of daily intake was calculated and compared with recommended or tolerable guidelines values. Levels of As, Cd, Pb and Hg were far below the established values by the European Community. PMID- 23816364 TI - Induction of autophagy by cystatin C: a potential mechanism for prevention of cerebral vasospasm after experimental subarachnoid hemorrhage. AB - BACKGROUND: Studies have demonstrated that autophagy pathways are activated in the brain after experimental subarachnoid hemorrhage (SAH) and this may play a protective role in early brain injury. However, the contribution of autophagy in the pathogenesis of cerebral vasospasm (CVS) following SAH, and whether up regulated autophagy may contribute to aggravate or release CVS, remain unknown. Cystatin C (CysC) is a cysteine protease inhibitor that induces autophagy under conditions of neuronal challenge. This study investigated the expression of autophagy proteins in the walls of basilar arteries (BA), and the effects of CysC on CVS and autophagy pathways following experimental SAH in rats. METHODS: All SAH animals were subjected to injection of 0.3 mL fresh arterial, non-heparinized blood into the cisterna magna. Fifty rats were assigned randomly to five groups: control group (n = 10), SAH group (n = 10), SAH + vehicle group (n = 10), SAH + low dose of CysC group (n = 10), and SAH + high dose of CysC group (n = 10). We measured proteins by western blot analysis, CVS by H&E staining method, morphological changes by electron microscopy, and recorded neuro-behavior scores. RESULTS: Microtubule-associated protein light chain-3, an autophagosome biomarker, and beclin-1, a Bcl-2-interacting protein required for autophagy, were significantly increased in the BA wall 48 h after SAH. In the CysC-handled group, the degree of CVS, measured as the inner BA perimeter and BA wall thickness, was significantly ameliorated in comparison with vehicle-treated SAH rats. This effect paralleled the intensity of autophagy in the BA wall induced by CysC. CONCLUSIONS: These results suggest that the autophagy pathway is activated in the BA wall after SAH and CysC-induced autophagy may play a beneficial role in preventing SAH-induced CVS. PMID- 23816365 TI - Heritability and repeatability of milk coagulation properties predicted by mid infrared spectroscopy during routine data recording, and their relationships with milk yield and quality traits. AB - The aim of this study was to estimate (co)variance components for milk coagulation properties (MCP) predicted by mid-infrared spectroscopy (MIRS) during routine milk recording, and to assess their relationships with yield and quality traits. A total of 63 470 milk samples from Holstein-Friesian cows were analyzed for MCP, pH and quality characteristics using MIRS. Casein to protein and protein to fat ratios were calculated from information obtained by MIRS. Records were collected across 1 year on 16 089 cows in 345 herds. The model used for genetic analysis included fixed effects of parity and stage of lactation, and random effects of herd-test-day, cow permanent environmental, animal additive genetic and residual. (Co)variance components were assessed in a Bayesian framework using the Gibbs Sampler. Estimates of heritabilities were consistent with those reported in the literature, being moderate for MCP (0.210 and 0.238 for rennet coagulation time (RCT) and curd firmness (a30), respectively), milk contents (0.213 to 0.333) and pH (0.262), and low for somatic cell score (0.093) and yield traits (0.098 to 0.130). Repeatabilities were 0.391 and 0.434 for RCT and a30, respectively, and genetic correlations were generally low, with estimates greater than 0.30 (in absolute value) only for a30 with fat, protein and casein contents. Overall, results suggest that genetic evaluation for MCP predicted by MIRS is feasible at population level, and several repeated measures per cow during a lactation are required to estimate reliable breeding values for coagulation traits. PMID- 23816367 TI - [Clinic recommendations according to the Grading of Recommendations, Assessment, Development and Evaluation system]. PMID- 23816366 TI - Motives, beliefs and attitudes towards waterpipe tobacco smoking: a systematic review. AB - BACKGROUND: In spite of the negative health effects of waterpipe tobacco smoking, its use is becoming more common. The objective of this study is to systematically review the medical literature for motives, beliefs and attitudes towards waterpipe tobacco smoking. METHODS: We electronically searched MEDLINE, EMBASE, and the ISI the Web of Science in January 2012. We included both quantitative and qualitative studies. We selected studies and abstracted data using standard systematic review methodology. We synthesized data qualitatively. RESULTS: We included 58 papers reporting on 56 studies. The main motives for waterpipe tobacco smoking were socializing, relaxation, pleasure and entertainment. Peer pressure, fashion, and curiosity were additional motives for university and school students while expression of cultural identity was an additional motive for people in the Middle East and for people of Middle Eastern descent in Western countries. Awareness of the potential health hazards of waterpipe smoking was common across settings. Most but not all studies found that the majority of people perceived waterpipe smoking as less harmful than cigarette smoking. Waterpipe smoking was generally socially acceptable and more acceptable than cigarette smoking in general. In Middle Eastern societies, it was particularly more acceptable for women's use compared to cigarette use. A majority perceived waterpipe smoking as less addictive than cigarette smoking. While users were confident in their ability to quit waterpipe smoking at any time, willingness to quit varied across settings. CONCLUSIONS: Socializing, relaxation, pleasure and entertainment were the main motives for waterpipe use. While waterpipe users were aware of the health hazards of waterpipe smoking, they perceived it as less harmful, less addictive and more socially acceptable than cigarette smoking and were confident about their ability to quit. PMID- 23816368 TI - The curry spice curcumin attenuates beta-amyloid-induced toxicity through beta catenin and PI3K signaling in rat organotypic hippocampal slice culture. AB - OBJECTIVE: Accumulating evidence indicates that curcumin potently protects against beta-amyloid (Abeta) due to its oxygen free radicals scavenging and anti inflammatory properties. However, cellular mechanisms that may underlie the neuroprotective effect of curcumin in Abeta-induced toxicity are not fully understood yet. The present study was undertaken to investigate the mechanisms involved in neuroprotective effects of curcumin, particularly involving Wnt/beta catenin and PI3K pathways. METHODS: Organotypic hippocampal slice cultures were treated with curcumin and exposed to Abeta1-42 for 48 hours. Synaptic dysfunction, cell death, ROS formation, neuroinflammation and beta-catenin, Akt, and GSK-3beta phosphorylation were measured to determine the effects of curcumin against Abeta toxicity. RESULTS: Curcumin significantly attenuated Abeta-induced cell death, loss of synaptophysin, and ROS generation. Furthermore, curcumin was able to decrease IL-6 release and increase IL-10 release, and prevented glial activation. The phosphorylation of beta-catenin was avoided and the levels of free beta-catenin were increased by curcumin to promote cell survival upon treatment with Abeta. Curcumin, in the presence of Abeta, activated Akt which in turn phosphorylates GSK-3beta, and resulted in the inhibition of GSK-3beta. The presence of LY294002, an inhibitor of PI3K pathway, blocked the pro-survival effect of curcumin. DISCUSSION: These results reinforce the neuroprotective effects of curcumin on Abeta toxicity and add some evidence that its mechanism may involve beta-catenin and PI3K signaling pathway in organotypic hippocampal slice culture. PMID- 23816370 TI - Clothing insulation and temperature, layer and mass of clothing under comfortable environmental conditions. AB - This study was designed to investigate the relationship between the microclimate temperature and clothing insulation (Icl) under comfortable environmental conditions. In total, 20 subjects (13 women, 7 men) took part in this study. Four environmental temperatures were chosen: 14 degrees C (to represent March/April), 25 degrees C (May/June), 29 degrees C (July/August), and 23 degrees C (September/October). Wind speed (0.14ms-1) and humidity (45%) were held constant. Clothing microclimate temperatures were measured at the chest (Tchest) and on the interscapular region (Tscapular). Clothing temperature of the innermost layer (Tinnermost) was measured on this layer 30 mm above the centre of the left breast. Subjects were free to choose the clothing that offered them thermal comfort under each environmental condition. We found the following results. 1) All clothing factors except the number of lower clothing layers (Llower), showed differences between the different environmental conditions (P<0.05). The ranges of Tchest were 31.6 to 33.5 degrees C and 32.2 to 33.4 degrees C in Tscapular. The range of Tinnermost was 28.6 to 32.0 degrees C. The range of the upper clothing layers (Lupper) and total clothing mass (Mtotal) was 1.1 to 3.2 layers and 473 to 1659 g respectively. The range of Icl was 0.78 to 2.10 clo. 2) Post hoc analyses showed that analysis of Tinnermost produced the same results as for that of Icl. Likewise, the analysis of Lupper produced the same result as the analysis of the number of total layers (Ltotal) within an outfit. 3) Air temperature (ta) had positive relationships with Tchest and Tscapular and with Tinnermost but had inverse correlations with Icl, Mtotal, Lupper and Ltotal. Tchest, Tscapular, and Tinnermost increased as ta rose. 4) Icl had inverse relationships with Tchest and Tinnermost, but positive relationships with Mtotal, Lupper and Ltotal. Icl could be estimated by Mtotal, Lupper, and Tscapular using a multivariate linear regression model. 5) Lupper had positive relationships with Icl and Mtotal, but Llower did not. Subjects hardly changed Llower under environmental comfort conditions between March and October. This indicates that each of the Tchest, Mtotal, and Lupper was a factor in predicting Icl. Tinnermost might also be a more influential factor than the clothing microclimate temperature. PMID- 23816371 TI - Identification of N-substituted 8-azatetrahydroquinolone derivatives as selective and orally active M(1) and M(4) muscarinic acetylcholine receptors agonists. AB - We designed and synthesized N-substituted 8-azatetrahydroquinolone derivatives as selective M1 and M4 muscarinic acetylcholine receptors agonists. Optimization of selected derivatives led to the discovery of compound 7 as a highly potent M1 and M4 agonist with weak hERG inhibition. Oral administration of compound 7 improved psychosis-like behavior in rats. PMID- 23816372 TI - Non hemolytic short peptidomimetics as a new class of potent and broad-spectrum antimicrobial agents. AB - Since the bacterial resistance to antibiotics is increasing rapidly, numerous studies have contributed to the design and synthesis of potent synthetic mimics of antimicrobial peptides (AMPs). In an attempt to find the pharmacophore of short antimicrobial peptidomimetics through systematic tuning of hydrophobic and hydrophilic patterns, we have identified a set of short histidine-derived antimicrobial peptides (SAMPs) with potent and broad-spectrum activity. A combination of high antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA), without hemolytic activity and proteolytic stability makes these molecules promising candidates for novel antimicrobial therapeutics. PMID- 23816373 TI - Effect of the orthoquinone moiety in 9,10-phenanthrenequinone on its ability to induce apoptosis in HCT-116 and HL-60 cells. AB - 9,10-Phenanthrenequinone (9,10-PQ) is one of the most abundant quinones among diesel exhaust particulates. Recent data have suggested that quinones induce apoptosis in immune, epithelial and tumor cells, leading to respirator illness; however, the mechanisms by which quinones induce apoptosis and the structure required for this remain unknown. We studied the antitumor activity of 9,10-PQ analogs against two human tumor cell lines, HCT-116 colon tumor cells and HL-60 promyelocytic leukemia cells. The loss of the cis-orthoquinone unit in 9,10-PQ abrogated its ability to induce apoptosis in the two tumor cell lines, and the LC50 values of these analogs were indicated over 10 MUM. An analog of 9,10-PQ in which the biaryl unit had been deleted displayed a reduced ability to induce tumor cell apoptosis, while the analogs 1,10-phenanthroline-5,6-dione (9) and pyrene-4,5-dione (10), which also had modified biaryl units, exhibited increased tumor cell apoptotic activity. The cis-orthoquinone unit in 9,10-PQ was identified as essential for its ability to induce apoptosis in tumor cells, and its biaryl unit is also considered to influence orthoquinone-mediated apoptotic activity. PMID- 23816374 TI - Decreased and increased cerebral regional homogeneity in early Parkinson's disease. AB - Regional homogeneity (ReHo), a processed data from resting-state functional magnetic resonance imaging, provides information about spontaneous brain activity in focal areas. Altered ReHo in brain regions has been reported in Parkinson's disease (PD). We compared ReHo of 22 patients with PD in their off-medication state to 25 healthy controls. We observed decreased ReHo in the right primary sensory cortex, the right primary motor cortex and the right middle frontal gyrus in PD patients. Conversely, ReHo was increased in the left inferior parietal lobule, the angular gyrus, the supramarginal gyrus, the middle occipital gyrus and the parahippocampal gyrus. In the right primary sensory cortex, ReHo showed a positive association with disease duration which proposed the low level of ReHo in the early phase of PD. ReHo was decreased in the seven de novo PD patients with disease duration less than 1 year as compared to the control which corresponded to the prediction. In both the off-medication and de novo PD patients, ReHo decreased in the right primary sensory cortex and increased in the angular gyrus as compared to the control. Potential regression of ReHo extrapolated backwards to PD-onset may provide a clue for 'premotor diagnosis'. PMID- 23816375 TI - Role of angiotensin II type 1 receptors in the subfornical organ in the pressor responses to central sodium in rats. AB - Central infusion of Na(+)-rich artificial cerebro-spinal fluid (aCSF) activates the brain renin-angiotensin system and causes sympatho-excitatory and pressor responses. We evaluated the role of the subfornical organ (SFO) and angiotensin II type 1 (AT1) receptors in the SFO in mediating the central Na(+)-induced pressor response. In conscious Wistar rats, intra SFO infusions of Na(+)-rich aCSF containing 0.45 and 0.6M Na(+) at 10 nl/min or injection of angiotensin II (Ang II) at 80 ng increased blood pressure (BP) by 15-22 mmHg, whereas mannitol with the same osmolarity as the Na(+)-rich aCSF had no effects. Intra SFO infusion of the AT1 receptor blocker candesartan abolished the pressor response induced by intra SFO administration of Na(+)-rich aCSF or Ang II. Intra cerebro ventricular (icv) infusion of Na(+)-rich aCSF (0.3M Na(+)) at 3.8 MUl/min for 10 min increased BP by 15-20 mmHg. Electrolytic lesion of the SFO attenuated these BP increases by 50-70%. Intra SFO infusion of candesartan also prevented 50% of these pressor responses. These data suggest that SFO neurons are indeed sensitive to Na(+), the SFO is a major - but not only - site in the brain to sense an increase in CSF [Na(+)], and activation of AT1 receptors in the SFO mediates the SFO component of the Na(+)-induced pressor response. PMID- 23816376 TI - Validity and reliability of the modified John Hopkins Fall Risk Assessment Tool for elderly patients in home health care. AB - This prospective cohort study was conducted to evaluate the validity and reliability of the modified Johns Hopkins Fall Risk Assessment Tool (mJH-FRAT) among elderly patients receiving home health care visits. Out of 107 patients, 33 (30.8%) had one or more falls and seven (6.5%) experienced falls with injury. Receiver Operating Characteristics of the tool in predicting falls showed an Area Under Curve (AUC) of 0.66 (p = 0.011) with sensitivity and specificity of 72.5% and 52.2% at the cutoff score of 14. For predicting falls with injury, the AUC was 0.82 (p = 0.016) with sensitivity and specificity of 100% and 65.9% at the cutoff score of 17. Inter-rater reliability of the tool was 85.7% agreement with Cohen's kappa of 0.714 (p < 0.001). The mJH-FRAT is a simple and easy-to-use multi-factor fall risk assessment tool with promising sensitivity, specificity and inter-rater reliability for prospectively identifying patients at risk of falls with injury among community-dwelling elderly populations. PMID- 23816377 TI - Risk of suicide is insufficient warrant for coercive treatment for mental illness. AB - Mental health laws in many jurisdictions currently permit coercive treatment for persons with mental illness who are thought to be at risk of harm to themselves or others. These laws are often used to provide involuntary treatment to persons who are thought to be at risk of suicide. In this article we argue that legislated coercive psychiatric treatment should not be triggered by an assessment of the likelihood of harm, including a likelihood of suicide, but should be available only where a person is found to lack capacity to make their own decisions about their own health risks, after appropriate support has been given. We suggest that current opposition to this approach may find its origin in factors including uncertainties about the idea of vulnerability and its relationship to capacity as well as tendency to minimise the real costs of psychiatric treatment and coercion against the aim of suicide prevention. Given the limits of suicide risk assessment, we argue that a public policy that allows involuntary preventative detention of competent persons thought to be at risk of suicide, places too great a burden on all persons living with mental illness to be justified. We suggest that we are better placed to serve the interests and respect the human rights of people with mental illness if we respect and support the right of persons to make decisions, rather than focussing on perceived vulnerabilities and calculations of suicide risk. PMID- 23816378 TI - Physician-assisted dying and psychiatry: recent developments in The Netherlands. AB - The Netherlands was one of the first countries in the world to establish a legal framework for physician-assisted dying (PAD). In this article, we provide an overview of the public, political, legal, and medical debates on physician assisted dying in The Netherlands, focusing on the role of psychiatry and mental illness. The number of individuals with chronic mental illness requesting PAD has been relatively small (although the number can be expected to increase because of the activities of various civic organizations advocating the right to die) and Dutch psychiatrists have been extremely reluctant to respond to such requests. Nevertheless, mental conditions have been central to the public debate on PAD by helping to define the nature and limits of current legislation and professional practice. Although a few Dutch psychiatrists have campaigned to increase the involvement of psychiatrists and many support PAD in principle, the majority has been hesitant to engage in PAD despite increasing public pressure. PMID- 23816379 TI - Rational suicide, assisted suicide, and indirect legal paternalism. AB - This article argues in favour of three related claims: First, suicide is not an immoral act. If people autonomously choose to kill themselves, this ought to be respected. Second, we can deem the desire to die comprehensible, and even rational, when the person contemplating suicide does not see a meaning in her life. This assessment is not based on a metaphysically dubious comparison between the actual life of a person and the supposed state of being dead. Third, from the first two theses it does not automatically follow that we should allow other people to help someone who autonomously and rationally chooses to die to pursue this plan. To argue against indirect legal paternalism, the practice of legally preventing someone else to assist a person to perform a suicide or to be killed on request, needs additional reasons. It is argued that assisted suicide and voluntary active euthanasia can indeed be justified by establishing a claim of persons who want to die but are not able to kill themselves. This mainly means that being really free to die should be interpreted as involving the means to fulfil one's desire to die. PMID- 23816380 TI - "A Kantian care ethics suicide duty". AB - Standard arguments for a duty to die or to commit suicide generally rely upon contractarian or other form of justice or the Principle of Beneficence. Even though some of these arguments might appear deontological, there is an explicit or implicit consequentialist common thread in all of them in which utility of some sort is maximized only through the taking of one's own life. Hence, most arguments for a suicide duty are consequentialist in nature. There are a number of relatively unexplored deontological arguments that make plausible cases for the mandatory taking of one's own life. For example, although Kant is widely thought to prohibit all suicides, a careful reading of his work can show a plausible case based on the Categorical Imperative. If it is necessary to preserve the individual's moral life, then everyone could will the generalized maxim governing the situation as a law of nature. Unfortunately, Kant's argument is weakened by his poor understanding of moral psychology. To strengthen Kant's case, care-relationship ethics can be combined with the argument to produce a plausible case that people are obligated to kill themselves if a number of criteria are satisfied. PMID- 23816381 TI - Complex reconstruction of desmoid tumor resections does not increase desmoid tumor recurrence. AB - BACKGROUND: The propensity of desmoid tumors to develop in scars has led some surgeons to limit the complexity of desmoid defect reconstruction as a strategy for avoiding desmoid recurrence. We hypothesized that desmoid recurrence rates are similar despite the magnitude of reconstruction. STUDY DESIGN: We retrospectively compared recurrence rates between patients who underwent reconstruction and patients who underwent primary closure without reconstruction after desmoid tumor resection in consecutive patients for 15 years. Univariate and multivariate regression analyzed associations between patient, tumor, and treatment characteristics and outcomes. RESULTS: We included 164 consecutive patients (80 [49%] reconstructions vs 84 [51%] primary closures). Mean follow-up duration was 7.1 +/- 4.5 years. Patients who underwent reconstruction had more desmoids in an area of earlier trauma or surgery (p < 0.001), greater defect volume (p < 0.01), longer operative time (p < 0.001) and hospital stay (p < 0.001), and more postoperative complications (p = 0.015) compared with the primary closure group. Despite these differences, desmoid recurrence rates were similar for the reconstruction and primary closure groups (30% and 29%, respectively; p = 0.7), as was mean time to tumor recurrence, and no tumors recurred within flap donor sites. Multivariate regression analysis demonstrated the 45F mutation to be the only independent predictor of recurrence (hazard ratio = 1.87; p = 0.04). CONCLUSIONS: Rates of desmoid recurrence in resection defects are similar for primary closures and complex reconstructions. Therefore, surgeons should not limit the magnitude of reconstructions in an attempt to avoid tumor recurrence. However, given the propensity of desmoids to recur, reconstructions should allow for the possibility of future resections and reconstructions, particularly in tumors with 45F gene mutations. PMID- 23816382 TI - Mesocaval shunting: a novel technique to facilitate venous resection and reconstruction and enhance exposure of the superior mesenteric and celiac arteries during pancreaticoduodenectomy. PMID- 23816383 TI - Surgeon-specific performance reports in general surgery: an observational study of initial implementation and adoption. AB - BACKGROUND: As national quality initiatives are increasing requirements for individual physician data, our department of surgery initiated a surgeon-specific reporting (SSR) program to assess the value of personal knowledge on individual performance quality. We sought to evaluate the use of SSR as a tool to enable surgeons to assess and improve their clinical performance, and to identify barriers to use of their reports. STUDY DESIGN: Qualitative research design involving semistructured interviews of surgeons who received performance reports derived from National Surgical Quality Improvement Program (NSQIP), Surgical Care Improvement Project (SCIP), and the Centers for Medicare and Medicaid Services (CMS) core measures and hospital administrative data. Transcripts were analyzed by the constant comparative method. RESULTS: Twenty-four of 39 surgeons (61.5%) who received their SSRs agreed to be interviewed and 23 were interviewed. About half (11 of 23) demonstrated comprehension of the data validity, accuracy, or complexity. Of these, 6 took steps to validate data or improve performance. Most respondents believed SSR would lead to performance improvement through knowledge of personal outcomes and peer comparison; however, they perceived SSR had limitations, such as small sample size and potential coding errors, and could lead to unintended consequences, such as inaccurate interpretation by others and surgeons' aversion to selecting high-risk patients. Respondents also suggested logistical improvements to reporting methods, such as report format and definitions of metrics. CONCLUSIONS: Surgeon-specific reporting has the potential to empower surgeons to improve their practice; however, more surgeons need efficient guidelines to understand the metrics. Our findings can be used to guide development of more SSR programs. Whether SSR programs lead to improvements in surgical outcomes is a matter for future research. PMID- 23816384 TI - Tissue engineering of skin. PMID- 23816385 TI - Role of tissue-engineered artificial tendon in healing of a large Achilles tendon defect model in rabbits. AB - BACKGROUND: Treatment of large Achilles tendon defects is technically demanding. Tissue engineering is an option. We constructed a collagen-based artificial tendon, covered it with a polydioxanon (PDS) sheath, and studied the role of this bioimplant on experimental tendon healing in vivo. STUDY DESIGN: A 2-cm tendon gap was created in the left Achilles tendon of rabbits (n = 120). The animals were randomly divided into 3 groups: control (no implant), treated with tridimensional-collagen, and treated with tridimensional-collagen-bidimensional PDS implants. Each group was divided into 2 subgroups of 60 and 120 days postinjury (DPI). Another 50 pilot animals were used to study the host-implant interaction. Physical activity of the animals was scored and ultrasonographic and bioelectrical characteristics of the injured tendons were investigated weekly. After euthanasia, macro, micro, and nano morphologies and biophysical and biomechanical characteristics of the healing tendons were studied. RESULTS: Treatment improved function of the animals, time dependently. At 60 and 120 DPI, the treated tendons showed significantly higher maximum load, yield, stiffness, stress, and modulus of elasticity compared with controls. The collagen implant induced inflammation and absorbed the migrating fibroblasts in the defect area. By its unique architecture, it aligned the fibroblasts and guided their proliferation and collagen deposition along the stress line of the tendon and resulted in improved collagen density, micro-amp, micro-ohm, water uptake, and delivery of the regenerated tissue. The PDS-sheath covering amplified these characteristics. The implants were gradually absorbed and replaced by a new tendon. Minimum amounts of peritendinous adhesion, muscle atrophy, and fibrosis were observed in the treated groups. Some remnants of the implants were preserved and accepted as a part of the new tendon. CONCLUSIONS: The implants were cytocompatible, biocompatible, biodegradable, and effective in tendon healing and regeneration. This implant may be a valuable option in clinical practice. PMID- 23816386 TI - Risk-scoring model for prediction of non-home discharge in epithelial ovarian cancer patients. AB - BACKGROUND: Identification of preoperative factors predictive of non-home discharge after surgery for epithelial ovarian cancer (EOC) may aid counseling and optimize discharge planning. We aimed to determine the association between preoperative risk factors and non-home discharge. STUDY DESIGN: Patients who underwent primary surgery for EOC at Mayo Clinic between January 2, 2003 and December 29, 2008 were included. Demographic, preoperative, and intraoperative factors were retrospectively abstracted. Logistic regression models were fit to identify preoperative factors associated with non-home discharge. Multivariable models were developed using stepwise and backward variable selection. A risk scoring system was developed for use in preoperative counseling. RESULTS: Within our cohort of 587 EOC patients, 12.8% were not discharged home (61 went to a skilled nursing facility, 1 to a rehabilitation facility, 1 to hospice, and there were 12 in-hospital deaths). Median length of stay was 7 days (interquartile range [IQR] 5, 10 days) for patients dismissed home compared with 11 days (IQR 7, 17 days) for those with non-home dismissals (p < 0.001). In multivariable analyses, patients with advanced age (odds ratio [OR] 3.75 95% CI [2.57, 5.48], p < 0.001), worse Eastern Cooperative Oncology Group (ECOG) performance status (OR 0.92 [95% CI 0.43, 1.97] for ECOG performance status 1 vs 0 and OR 5.40 (95% CI 2.42, 12.03) for score of 2+ vs 0; p < 0.001), greater American Society of Anesthesiologists (ASA) score (OR 2.03 [95% CI 1.02, 4.04] for score >=3 vs < 3, p = 0.04), and higher CA-125 (OR 1.28 [95% CI 1.12, 1.46], p < 0.001) were less likely to be discharged home. The unbiased estimate of the c-index was excellent at 0.88, and the model had excellent calibration. CONCLUSIONS: Identification of preoperative factors associated with non-home discharge can assist patient counseling and postoperative disposition planning. PMID- 23816387 TI - Prospective study of natural history of deep vein thrombosis: early predictors of poor late outcomes. AB - BACKGROUND: A proportion of patients with deep vein thrombosis (DVT) will develop postthrombotic syndrome (PTS). Currently, the only clearly identified risk factors for developing PTS are recurrent ipsilateral DVT and extensive proximal disease. The aim of the study was to assess the natural history of DVT and identify early predictors of poor clinical outcome at 5 years. METHODS: Patients with suspected acute DVT in the lower limb were assessed prospectively. All patients with a confirmed DVT were asked to participate in this study. Within 7 10 days after diagnosis of DVT, patients underwent a further review, involving clinical, ultrasound, and air plethysmography assessment of both lower limbs. Patients were reassessed at regular intervals for 5 years. RESULTS: One hundred twenty-two limbs in 114 patients were included in this study. Thrombus regression occurred in two phases, with a rapid regression between 10 days and 3 months, and a more gradual regression thereafter. Reflux developed as thrombus regression occurred. Segmental reflux progressed to axial deep reflux and continued to deteriorate in a significant proportion of patients with iliofemoral-popliteal calf DVT throughout the 5-year study period. Similarly, venous filling index became progressively more abnormal, in this group, over the course of the study. Four risk factors for PTS were identified as best predictors: extensive clot load on presentation; <50% clot regression at 6 months; venous filling index >2.5 mL/sec; and abnormal outflow rate (<0.6). Patients with three or more of these risk factors had a significant risk of developing PTS with sensitivity 100%, specificity 83%, and positive predictive value 67%. Patients scoring 2 or less did not have PTS at 5 years with a negative predictive value of 100%. CONCLUSIONS: This is the first study to show that venous assessment at 6 months post-DVT can predict PTS at 5 years. Those who will not develop PTS can be reassured of this at 6 months. PMID- 23816388 TI - Midterm follow-up of quality of life following peripheral bypass surgery. AB - BACKGROUND: Peripheral bypass surgery is an important treatment option for patients with peripheral arterial disease. Short-term results of quality of life (QoL) after peripheral bypass surgery showed an increase in QoL at 3 months. Little is known about QoL at more than 2 years of follow-up. This study was performed to analyze QoL at midterm follow-up, and overall survival after peripheral bypass surgery. METHODS: This study was part of a randomized control trial in which intermittent pneumatic compression was compared with compression stockings in the treatment of edema after bypass surgery. Patients completed a QoL questionnaire before surgery, 14 days and 3 months postoperatively, and at least 2 years after the original operation. A survival analysis was performed to calculate survival for patients who received both autologous and polytetrafluoroethylene (PTFE) bypass grafts. RESULTS: The original study consisted of 93 patients, and QoL midterm follow-up was achieved for 42. QoL scores at midterm follow-up were comparable to the preoperative baseline scores for both the autologous and the PTFE groups. Three-year survival rates were 75% and 54%, respectively. CONCLUSION: Although peripheral bypass surgery significantly increased QoL 3 months after surgery, midterm follow-up showed a return to baseline scores. No significant difference was found in survival between patients in the autologous and PTFE groups. PMID- 23816390 TI - Latent papillomavirus infections and their regulation. AB - Model systems show that papillomavirus DNA can persist after lesion-regression, and be maintained in a subset of epithelial basal cells. These are very likely long-lived 'stem-cells' or 'stem-like cells', with latency arising via at least two distinct mechanisms. The first involves low-titre virus infection and the retention of viral DNA at levels that are too low to allow life-cycle completion. The second involves lesion-formation, and clearance by the adaptive immune system, followed by persistence with low-level viral gene expression, and possible reactivation upon immune depletion. Mechanical irritation, inflammation and other extracellular influences affect viral copy number in the latently infected cell, and may predispose to lesion-reappearance. Reactivation may account for the recurrence of 'apparently cleared' cervical lesions caused by high-risk types, the appearance of Beta HPV-lesions following immunosuppression, and the development of recurrent respiratory papillomatosis in afflicted children. PMID- 23816389 TI - Functional genomics approaches to understand cytomegalovirus replication, latency and pathogenesis. AB - Cytomegalovirus (CMV) is a species-specific herpesvirus that is ubiquitous in the population and has the potential to cause significant disease in immunocompromised individuals as well as in congenitally infected infants. CMV establishes latency in cells of the myeloid lineage following primary infection. High-throughput functional genomics approaches have provided insight into the mechanisms of CMV replication, but although CMV latency cell models have been useful in elucidating the mechanisms of viral latency and reactivation, omics approaches have proven challenging in these cell systems. This review will summarize the current state of knowledge concerning the use of functional genomics technologies to understand mechanisms of CMV replication, latency and pathogenesis. PMID- 23816391 TI - Polydnavirus-wasp associations: evolution, genome organization, and function. AB - Viruses replicate to produce virions that transfer the viral genome among hosts, while endogenous viral elements (EVEs) are DNA sequences derived from viruses that integrate into the germline of multicellular organisms and are thereafter inherited like host alleles. Viruses in the family Polydnaviridae are specifically associated with insects called parasitoid wasps and exhibit many traits associated with other viruses. Polydnavirus genomes also persist as EVEs. In this short review we discuss polydnavirus evolution, compare polydnaviruses to other known EVEs of ancient origin, and examine some of the functional similarities polydnaviruses share with phage-like gene transfer agents (GTAs) from prokaryotes. PMID- 23816392 TI - Low pathogenic avian influenza A(H7N9) virus causes high mortality in ferrets upon intratracheal challenge: a model to study intervention strategies. AB - Infections with low pathogenic avian influenza (LPAI) A(H7N9) viruses have caused more than 100 hospitalized human cases of severe influenza in China since February 2013 with a case fatality rate exceeding 25%. Most of these human infections presented with severe viral pneumonia, while limited information is available currently on the occurrence of mild and subclinical cases. In the present study, a ferret model for this virus infection in humans is presented to evaluate the pathogenesis of the infection in a mammalian host, as ferrets have been shown to mimic the pathogenesis of human infection with influenza viruses most closely. Ferrets were inoculated intratracheally with increasing doses (>10 e5 TCID50) of H7N9 influenza virus A/Anhui/1/2013 and were monitored for clinical and virological parameters up to four days post infection. Virus replication was detected in the upper and lower respiratory tracts while animals developed fatal viral pneumonia. This study illustrates the high pathogenicity of LPAI-H7N9 virus for mammals. Furthermore, the intratracheal inoculation route in ferrets proofs to offer a solid model for LPAI-H7N9 virus induced pneumonia in humans. This model will facilitate the development and assessment of clinical intervention strategies for LPAI-H7N9 virus infection in humans, such as preventive vaccination and the use of antivirals. PMID- 23816393 TI - Safety of ultrasound contrast agents in patients with known or suspected cardiac shunts. AB - Contrast-enhanced ultrasound imaging is a radiation-free diagnostic tool that uses biocompatible ultrasound contrast agents (UCAs) to improve image clarity. UCAs, which do not contain dye, often salvage "technically difficult" ultrasound scans, increasing the accuracy and reliability of a front-line ultrasound diagnosis, reducing unnecessary downstream testing, lowering overall health care costs, changing therapy, and improving patient care. Two UCAs currently are approved and regulated by the US Food and Drug Administration. They have favorable safety profiles and risk/benefit ratios in adult and pediatric populations, including compromised patients with severe cardiovascular diseases. Nevertheless, these UCAs are contraindicated in patients with known or suspected right-to-left, bidirectional, or transient right-to-left cardiac shunts. These patients, who constitute 10% to 35% of the general population, typically receive no UCAs when they undergo echocardiography. If their echocardiographic images are suboptimal, they may receive inappropriate diagnosis and treatment, or they may be referred for additional diagnostic testing, including radiation-based procedures that increase their lifetime risk for cancer or procedures that use contrast agents containing dye, which may increase the risk for kidney damage. An exhaustive review of current peer-reviewed research demonstrated no scientific basis for the UCA contraindication in patients with known or suspected cardiac shunts. Initial safety concerns were based on limited rodent data and speculation related to macroaggregated albumin microspheres, a radioactive nuclear imaging agent with different physical and chemical properties and no relation to UCAs. Radioactive macroaggregated albumin is not contraindicated in adult or pediatric patients with cardiac shunts and is routinely used in these populations. In conclusion, the International Contrast Ultrasound Society Board recommends removal of the contraindication to further the public interest in safe, reliable, radiation-free diagnostic imaging options for patients with known or suspected cardiac shunts and to reduce their need for unnecessary downstream testing. PMID- 23816394 TI - Energy balance of individual cows can be estimated in real-time on farm using frequent liveweight measures even in the absence of body condition score. AB - Existing methods for estimating individual dairy cow energy balance typically either need information on feed intake, that is, the traditional input-output method, or frequent measurements of BW and body condition score (BCS), that is, the body reserve changes method (EB(body)). The EB(body) method holds the advantage of not requiring measurements of feed intake, which are difficult to obtain in practice. The present study aimed first to investigate whether the EB(body) method can be simplified by basing EB(body) on BW measurements alone, that is, removing the need for BCS measurements, and second to adapt the EB(body) method for real-time use, thus turning it into a true on-farm tool. Data came from 77 cows (primiparous or multiparous, Danish Holstein, Red or Jersey) that took part in an experiment subjecting them to a planned change in concentrate intake during milking. BW was measured automatically during each milking and real time smoothed using asymmetric double-exponential weighting and corrected for the weight of milk produced, gutfill and the growing conceptus. BCS assessed visually with 2-week intervals was also smoothed. EB(body) was calculated from BW changes only, and in conjunction with BCS changes. A comparison of the increase in empty body weight (EBW) estimated from EB(body) with EBW measured over the first 240 days in milk (DIM) for the mature cows showed that EB(body) was robust to changes in the BCS coefficients, allowing functions for standard body protein change relative to DIM to be developed for breeds and parities. These standard body protein change functions allow EB(body) to be estimated from frequent BW measurements alone, that is, in the absence of BCS measurements. Differences in EB(body) levels before and after changes in concentrate intake were calculated to test the real-time functionality of the EB(body) method. Results showed that significant EB(body) increases could be detected 10 days after a 0.2 kg/day increase in concentrate intake. In conclusion, a real-time method for deriving EB(body) from frequent BW measures either alone or in conjunction with BCS measures has been developed. This extends the applicability of the EB(body) method, because real-time measures can be used for decision support and early intervention. PMID- 23816395 TI - A brief 5-item version of the Neck Disability Index shows good psychometric properties. AB - BACKGROUND: The purpose of this secondary analysis of clinical databases of people with neck pain was to use a mixed unique conceptual and statistical approach to develop a brief version of the Neck Disability Index (NDI). METHODS: An a priori framework of neck-related function based on the International Classification of Functioning, Disability and Health was used to identify items from the original 10-item NDI that do not conceptually fit. Remaining items were subject to Rasch analysis to identify items that did not statistically fit with axioms of quantitative measurement. Finally, approaches drawn from classical test theory were used to compare stability, responsiveness and concurrent validity of the original NDI, the new brief NDI and the linearly-transformed brief NDI. RESULTS: Conceptual analysis identified 3 items that did not fit with the construct of self-reported ability to perform activity: pain intensity, headache, and sleeping. These items were removed, and responses to the remaining 7 items drawn from an assembled database of 316 physiotherapy patients with neck pain were subject to Rasch analysis. Two items were removed due to either considerable differential item functioning (reading) or statistical redundancy (lifting). The remaining items were considered the NDI-5. Test-retest reliability, responsiveness, sensitivity to change, and concurrent validity were all comparable across the original NDI, NDI-5 and linearly-transformed NDI-5. Sensitivity to change over a 1-month period of physiotherapy was the notable exception, where the linearly-transformed NDI-5 showed superiority over the other two forms. CONCLUSIONS: A shortened version of the NDI, the NDI-5, has been constructed that is conceptually and statistically sound. Implications for research and clinical practice are discussed. Comparison with the NDI-8 is provided that suggests overall similar function across the forms, although the latter may be more sensitive to change. PMID- 23816396 TI - Impact of targeting insulin-like growth factor signaling in head and neck cancers. AB - The IGF system has been shown to have either negative or negligible impact on clinical outcomes of tumor development depending on specific tumor sites or stages. This review focuses on the clinical impact of IGF signaling in head and neck cancer, the effects of IGF targeted therapies, and the multi-dimensional role of IRS 1/2 signaling as a potential mechanism in resistance to targeted therapies. Similar to other tumor sites, both negative and positive correlations between levels of IGF-1/IGF-1-R and clinical outcomes in head and neck cancer have been reported. In addition, utilization of IGF targeted therapies has not demonstrated significant clinical benefit; therefore the prognostic impact of the IGF system on head and neck cancer remains uncertain. PMID- 23816397 TI - The prevalence of human papillomavirus and its impact on cervical dysplasia in Northern Canada. AB - INTRODUCTION: Certain types of the Human Papillomavirus (HPV) are sexually transmitted and highly associated with development of cervical dysplasia and cervical cancer but the distribution of HPV infection in the North, particularly amongst First Nations, Metis, and Inuit peoples, is little known. The purposes of the study are to identify the prevalence of type-specific HPV infections and the association of different HPV types with cervical dysplasia among women in Northern Canada. METHODS: This was a cross-sectional study with attendants of the routine or scheduled Pap testing program in the Northwest Territories (NWT), Nunavut, Labrador and Yukon, Canada. Approximately half of each sample was used for Pap test and the remaining was used for HPV genotyping using a Luminex-based method. Pap test results, HPV types, and demographic information were linked for analyses. RESULTS: Results from 14,598 specimens showed that HPV infection was approximately 50% higher among the Aboriginal than the non-Aboriginal population (27.6% vs. 18.5%). Although the most common HPV type detected was HPV 16 across region, the prevalence of other high risk HPV types was different. The age specific HPV prevalence among Aboriginal showed a 'U' shape which contrasted to non-Aboriginal. The association of HPV infection with cervical dysplasia was similar in both Aboriginal and non-Aboriginal populations. CONCLUSIONS: The HPV prevalence was higher in Northern Canada than in other Areas in Canada. The prevalence showed a higher rate of other high risk HPV infections but no difference of HPV 16/18 infections among Aboriginal in comparison with non Aboriginal women. This study provides baseline information on HPV prevalence that may assist in surveillance and evaluation systems to track and assess HPV vaccine programs. PMID- 23816398 TI - Electrical injury in construction workers: a special focus on injury with electrical power. AB - BACKGROUND: Electrical injury in construction workers due to contact with overhead power lines accounts for an important cause of admission at the emergency department. Due to lack of specific treatment options for this type of injury, prevention remains the mainstay of management. AIMS: Our study aimed to demonstrate the characteristics of electrical injury in construction workers among one of the largest Iranian population at a burn care hospital. METHODS: Through a retrospective review of hospital data base, patients with electrical injuries admitted to Motahari hospital in Tehran, Iran between March 2011 and June 2012 were included for analysis. Patients were divided into construction workers and other patients. Primary characteristics and final outcomes were then compared between the 2 study groups. RESULTS: Of 202 patients included in this study, 105 patients (52%) were construction workers and 97 patients (48%) constituted the remainder. There was significant difference between the 2 groups in terms of mean age, gender, and average burn size. In contrast, mean duration of hospitalization and mortality rate did not differ significantly between the 2 study groups (p>0.05). Contacts with over head power-lines accounted for the most common mechanism of injury. There was significant difference between the 2 groups in terms of place of injury and electrical current power. However, total cost of treatment did not differ significantly between the 2 groups (p>0.05). Frequency of severe complications was higher in construction workers and this group underwent more invasive procedures such as limb amputation and fasciotomy. CONCLUSION: The most common mechanism of electrical injuries in construction workers is due to contact with over head high voltage power-lines at workplace. This type of electrical injury is associated with higher use of fasciotomy, flap and limb amputation. PMID- 23816399 TI - 3D reconstruction of 2D fluorescence histology images and registration with in vivo MR images: application in a rodent stroke model. AB - To validate and add value to non-invasive imaging techniques, the corresponding histology is required to establish biological correlates. We present an efficient, semi-automated image-processing pipeline that uses immunohistochemically stained sections to reconstruct a 3D brain volume from 2D histological images before registering these with the corresponding 3D in vivo magnetic resonance images (MRI). A multistep registration procedure that first aligns the "global" volume by using the centre of mass and then applies a rigid and affine alignment based on signal intensities is described. This technique was applied to a training set of three rat brain volumes before being validated on three normal brains. Application of the approach to register "abnormal" images from a rat model of stroke allowed the neurobiological correlates of the variations in the hyper-intense MRI signal intensity caused by infarction to be investigated. For evaluation, the corresponding anatomical landmarks in MR and histology were defined to measure the registration accuracy. A registration error of 0.249 mm (approximately one in-plane voxel dimension) was evident in healthy rat brains and of 0.323 mm in a rodent model of stroke. The proposed reconstruction and registration pipeline allowed for the precise analysis of non invasive MRI and corresponding microstructural histological features in 3D. We were thus able to interrogate histology to deduce the cause of MRI signal variations in the lesion cavity and the peri-infarct area. PMID- 23816401 TI - Laser-based linear and nonlinear guided elastic waves at surfaces (2D) and wedges (1D). AB - The characteristic features and applications of linear and nonlinear guided elastic waves propagating along surfaces (2D) and wedges (1D) are discussed. Laser-based excitation, detection, or contact-free analysis of these guided waves with pump-probe methods are reviewed. Determination of material parameters by broadband surface acoustic waves (SAWs) and other applications in nondestructive evaluation (NDE) are considered. The realization of nonlinear SAWs in the form of solitary waves and as shock waves, used for the determination of the fracture strength, is described. The unique properties of dispersion-free wedge waves (WWs) propagating along homogeneous wedges and of dispersive wedge waves observed in the presence of wedge modifications such as tip truncation or coatings are outlined. Theoretical and experimental results on nonlinear wedge waves in isotropic and anisotropic solids are presented. PMID- 23816402 TI - Historical perspective on effects and treatment of sulfur mustard injuries. AB - Sulfur mustard (2,2'-dichlorodiethyl sulfide; SM) is a potent vesicating chemical warfare agent that poses a continuing threat to both military and civilian populations. Significant SM injuries can take several months to heal, necessitate lengthy hospitalizations, and result in long-term complications affecting the skin, eyes, and lungs. This report summarizes initial and ongoing (chronic) clinical findings from SM casualties from the Iran-Iraq War (1980-1988), with an emphasis on cutaneous injury. In addition, we describe the cutaneous manifestations and treatment of several men recently and accidentally exposed to SM in the United States. Common, chronic cutaneous problems being reported in the Iranian casualties include pruritis (the primary complaint), burning, pain, redness, desquamation, hyperpigmentation, hypopigmentation, erythematous papular rash, xerosis, multiple cherry angiomas, atrophy, dermal scarring, hypertrophy, and sensitivity to mechanical injury with recurrent blistering and ulceration. Chronic ocular problems include keratitis, photophobia, persistent tearing, sensation of foreign body, corneal thinning and ulceration, vasculitis of the cornea and conjunctiva, and limbal stem cell deficiency. Chronic pulmonary problems include decreases in lung function, bronchitis with hyper-reactive airways, bronchiolitis, bronchiectasis, stenosis of the trachea and other large airways, emphysema, pulmonary fibrosis, decreased total lung capacity, and increased incidences of lung cancer, pulmonary infections, and tuberculosis. There are currently no standardized or optimized methods of casualty management; current treatment strategy consists of symptomatic management and is designed to relieve symptoms, prevent infections, and promote healing. New strategies are needed to provide for optimal and rapid healing, with the goals of (a) returning damaged tissue to optimal appearance and normal function in the shortest period of time, and (b) ameliorating chronic effects. Further experimental research and clinical trials will be needed to prevent or mitigate the acute clinical effects of SM exposure and to reduce or eliminate the long-term manifestations. PMID- 23816403 TI - Reducing risk for ventilator associated pneumonia through nursing sensitive interventions. AB - The purpose of this paper is to describe an improvement initiative designed to implement nurse sensitive interventions known to reduce patients' risk for ventilator associated pneumonia (VAP), in cardiothoracic intensive care patients. This initiative is a part of one Australian critical care unit's efforts to identify and measure compliance with key nursing interventions known to improve cardiac surgical patients' outcomes. The premise behind the initiative is that improved nursing process and surveillance systems allow emerging trends to catalyse action and motivate nurses to reduce patients' risk for infection acquisition. At five and nine months following implementation of the initiative a>70% compliance rate in 11 out of the 15 nurse sensitive interventions known to reduce patients' risks for VAP and a drop in VAP incidence from 13.4% to 7.69% from per 1000 ventilator days was accomplished. PMID- 23816404 TI - Properdin in complement activation and tissue injury. AB - The plasma protein properdin is the only known positive regulator of complement activation. Although regarded as an initiator of the alternative pathway of complement activation at the time of its discovery more than a half century ago, the role and mechanism of action of properdin in the complement cascade has undergone significant conceptual evolution since then. Despite the long history of research on properdin, however, new insight and unexpected findings on the role of properdin in complement activation, pathogen infection and host tissue injury are still being revealed by ongoing investigations. In this article, we provide a brief review on recent studies that shed new light on properdin biology, focusing on the following three topics: (1) its role as a pattern recognition molecule to direct and trigger complement activation, (2) its context dependent requirement in complement activation on foreign and host cell surfaces, and (3) its involvement in alternative pathway complement-mediated immune disorders and considerations of properdin as a potential therapeutic target in human diseases. PMID- 23816405 TI - A novel deletion mutation in the proton-coupled folate transporter (PCFT; SLC46A1) in a Nicaraguan child with hereditary folate malabsorption. AB - Hereditary folate malabsorption (OMIM 229050) is a rare autosomal recessive disorder caused by loss-of-function mutations in the proton-coupled folate transporter gene (pcft/SLC46A1) resulting in impaired folate transport across the intestine and into the central nervous system. We report a novel, homozygous, deletion mutation in a child of Nicaraguan descent in exon 2 (c.558-588 del, ss778190447) at amino acid position I188 resulting in a frameshift with a premature stop. PMID- 23816406 TI - Megalobrama amblycephala cardiac troponin T variants: molecular cloning, expression and response to nitrite. AB - Cardiac troponin T (TNNT2), as a member of troponin superfamily, plays important roles during early cardiogenesis, and contraction and relaxation of myocardial cells. In this study, two alternatively spliced variants of Megalobrama amblycephala TNNT2 were identified showing a difference of 19 amino acids in the N-terminal hypervariable region. The longer cDNA (TNNT2-1) was 1,118 bp, encoding 284 amino acid residues, contained conserved central tropomyosin-binding region, cardiac specific signal and C-terminal segments except the N-terminal hypervariable region. The TNNT2 transcripts first appeared at 16 hours post fertilization (hpf) peaking at 28 hpf (onset of heartbeat). In addition, strong expression of TNNT2 was found in the cardiac muscle. After nitrite exposure, the increased TNNT2 expression levels in the heart indicated that nitrite might induce cardiac injury. Results of semi-quantitative RT-PCR indicated that the two alternatively spliced variants existed in early development stages since their first appearance at 16 hpf and heart, spleen, headkiney of M. amblycephala. The shorter transcript (TNNT2-2) was proved to be dominant in the embryos and heart of M. amblycephala, furthermore, the increase of TNNT2 expression level in the heart after nitrite exposure was mainly caused by TNNT2-2. PMID- 23816408 TI - Detection of a large duplication mutation in the myosin-binding protein C3 gene in a case of hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is a cardiovascular disease with autosomal dominant inheritance caused by mutations in genes coding for sarcomeric and/or regulatory proteins expressed in cardiomyocytes. In a small cohort of HCM patients (n=8), we searched for mutations in the two most common genes responsible for HCM and found four missense mutations in the MYH7 gene encoding cardiac beta-myosin heavy chain (R204H, M493V, R719W, and R870H) and three mutations in the myosin-binding protein C3 gene (MYBPC3) including one missense (A848V) and two frameshift mutations (c.3713delTG and c.702ins26bp). The c.702ins26bp insertion resulted from the duplication of a 26-bp fragment in a 54 year-old female HCM patient presenting with clinical signs of heart failure due to diastolic dysfunction. Although such large duplications (>10 bp) in the MYBPC3 gene are very rare and have been identified only in 4 families reported so far, the identical duplication mutation was found earlier in a Dutch patient, demonstrating that it may constitute a hitherto unknown founder mutation in central European populations. This observation underscores the significance of insertions into the coding sequence of the MYBPC3 gene for the development and pathogenesis of HCM. PMID- 23816407 TI - The association of MDR1 C3435T and G2677T/A polymorphisms with plasma platelet activating factor levels and coronary artery disease risk in Turkish population. AB - Increased levels of peripheral proinflammatory mediators can contribute to the development of coronary artery disease (CAD). Platelet activating factor (PAF) is an important proinflammatory mediator and plasma levels of PAF correlate with transmembrane transporter multidrug resistant 1 P-glycoprotein (MDR1 Pgp) expression and activity. MDR1 polymorphisms can affect the expression and activity of Pgp and plasma PAF levels. Therefore, we investigated the possible relationship between MDR1 C3435T and G2677T/A polymorphisms and plasma PAF levels and the risk of CAD. The study population consisted of 198 patients angiographically documented CAD, including 113 cases with at least 1 coronary artery with >=50% luminal diameter stenosis and 85 control subjects with strictly normal coronary angiograms. Genotypes of the MDR1 C3435T and G2677T/A polymorphisms were determined by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP). Plasma PAF levels were detected by enzyme-linked immunosorbent assay (ELISA). There were no significant differences among plasma PAF levels in regard to MDR1 C3435T and G2677T polymorphisms in CAD patients and controls. No statistically significant difference was found for the genotypic and allelic distributions of the polymorphisms in the MDR1 gene between the patients and the control subjects. Furthermore, analysis of MDR1 haplotypes did not show any associations with increased plasma PAF levels and risk of CAD. Our results suggest that plasma PAF levels are not associated with MDR1 gene polymorphisms. There is no association between MDR1 C3435T and G2677T/A polymorphisms and the risk of CAD in Turkish patients. PMID- 23816409 TI - BIMLR: a method for constructing rooted phylogenetic networks from rooted phylogenetic trees. AB - Rooted phylogenetic trees constructed from different datasets (e.g. from different genes) are often conflicting with one another, i.e. they cannot be integrated into a single phylogenetic tree. Phylogenetic networks have become an important tool in molecular evolution, and rooted phylogenetic networks are able to represent conflicting rooted phylogenetic trees. Hence, the development of appropriate methods to compute rooted phylogenetic networks from rooted phylogenetic trees has attracted considerable research interest of late. The CASS algorithm proposed by van Iersel et al. is able to construct much simpler networks than other available methods, but it is extremely slow, and the networks it constructs are dependent on the order of the input data. Here, we introduce an improved CASS algorithm, BIMLR. We show that BIMLR is faster than CASS and less dependent on the input data order. Moreover, BIMLR is able to construct much simpler networks than almost all other methods. BIMLR is available at http://nclab.hit.edu.cn/wangjuan/BIMLR/. PMID- 23816411 TI - Group G streptococcal endocarditis-associated hemophagocytic syndrome. AB - We report the case of a 28-year-old previously healthy male who presented with a 1-week history of fever, headache, vomiting, and jaundice. Blood cultures were positive for group G streptococci and transesophageal echocardiography demonstrated vegetations on the aortic valve, leading to a definitive diagnosis of infective endocarditis. The combination of fever, splenomegaly, anemia, thrombocytopenia, hypertriglyceridemia, elevated ferritin level, low natural killer (NK) cell activity, and hemophagocytosis in bone marrow aspirate confirmed the diagnosis of hemophagocytic syndrome (hemophagocytic lymphohistiocytosis). Antibiotic treatment and intravenous immunoglobulins were administered and the patient made a full recovery. PMID- 23816412 TI - Recommended precaution procedures protect healthcare workers from Crimean-Congo hemorrhagic fever virus. AB - OBJECTIVES: The Crimean-Congo hemorrhagic fever (CCHF) virus can spread from person to person and may cause nosocomial outbreaks among healthcare workers (HCWs). The US Centers for Disease Control and Prevention have recommended the use of personal protective equipment (PPE). We investigated the compliance of HCWs with PPE usage during the follow-up of patients, and also the number of risky contacts that occurred between patients and HCWs. We also aimed to determine the seroprevalence of CCHF virus in HCWs. METHODS: This study was conducted at Cumhuriyet University Education and Research Hospital, a medical center located in a highly endemic area for CCHF where a total of 1284 confirmed CCHF patients were followed-up between 2002 and 2012. All HCWs who were at risk of CCHF virus contact and infection were included in the study. The compliance of the HCWs with PPE usage and the number of contacts that had occurred were recorded. HCW serum samples were analyzed for CCHF virus IgM and IgG by ELISA. RESULTS: The total rates of PPE usage were 93.7% for gowns, 77.4% for gloves, and 38.9% for masks; the highest compliance was detected in the infectious diseases ward: 100%, 88.6%, and 82.9%, respectively. A total of four HCWs had a history of high-risk contact with contaminated material (two percutaneous exposure and two mucosal contacts), but the number of low-risk contacts was quite high. The total seroprevalence rate was only 0.53%. CONCLUSIONS: Although the HCWs at our medical center have dealt with an extremely high number of CCHF patients during the last decade, the total seropositivity for CCHFV IgG was only 0.53%. This low rate may be a result of high compliance with PPE usage and also regular education programs. PMID- 23816410 TI - Impact of tuberculosis treatment on CD4 cell count, HIV RNA, and p24 antigen in patients with HIV and tuberculosis. AB - OBJECTIVES: To describe HIV RNA levels during tuberculosis (TB) infection in patients co-infected with TB and HIV. Moreover, to examine the p24 antigen profile during TB treatment. METHODS: We examined the changes in CD4 cell count, HIV RNA, and p24 levels during anti-tuberculous therapy in a group of TB/HIV-1 co infected and HIV-untreated patients from Guinea-Bissau. RESULTS: A total of 365 TB patients were enrolled, of whom 76 were co-infected with HIV-1 and 19 were dually infected with HIV-1 + HIV-2. No significant changes in CD4, HIV RNA, or p24 levels were found during 8 months of TB treatment. HIV RNA levels correlated well with p24 (Spearman's R(2)=0.52, p<0.00001) and both markers were strong predictors of mortality. Initial HIV RNA levels correlated with a clinical TB severity index--the TBscore (Spearman's R(2)=0.23, p=0.02)--and the TBscore decreased dramatically during TB treatment although HIV RNA levels remained unchanged. CONCLUSION: We found no significant changes in CD4, HIV RNA, or p24 antigen levels during 8 months of TB treatment among TB/HIV co-infected individuals, who did not receive antiretroviral treatment. The markers were unaffected by a strong improvement in TBscore and all three markers showed predictive capacity for mortality risk. PMID- 23816413 TI - Predictors of reintervention after repair of interrupted aortic arch with ventricular septal defect. AB - BACKGROUND: Left ventricular outflow tract obstruction after neonatal repair of interrupted aortic arch with ventricular septal defect may warrant reintervention. We sought to identify clinical and preoperative echocardiographic predictors of reintervention for postoperative left ventricular outflow tract obstruction. METHODS: Retrospective data were collected on neonates with interrupted aortic arch with ventricular septal defect who underwent single-stage repair from 1995 to 2009. Univariate and multivariate analyses were performed to identify predictors of reintervention. RESULTS: Seventy patients underwent repair, with 16 patients requiring reintervention: 8 underwent surgical reintervention, 5 underwent percutaneous reintervention, and 3 underwent both. The median time to reintervention was 1.2 years (range, 0.2 to 7.7). All surgical reoperations involved subaortic resection, and all percutaneous reinterventions included balloon aortic valve dilation. Several preoperative echocardiographic measurements were significant by univariate analysis; however, smaller preoperative aortic root size was an independent predictor (p = 0.02) by multivariate analysis. Patients with an aortic root size less than 6.5 mm were at greater risk for reintervention compared with patients with a root size greater than 6.5 mm (reintervention rate 44% and 12%, respectively; p < 0.001). Postoperative left ventricular outflow tract gradient by echocardiogram before discharge was significantly higher in the reintervention group. CONCLUSIONS: Preoperative aortic root size predicts reintervention for postoperative left ventricular outflow tract obstruction after single-stage repair of interrupted aortic arch with ventricular septal defect. Patients with elevated left ventricular outflow tract gradients at discharge are at higher risk of having progressive obstruction and require closer follow-up to ensure early identification and management. PMID- 23816414 TI - Prevalence and outcomes of anatomic lung resection for hemoptysis: an analysis of the nationwide inpatient sample database. AB - BACKGROUND: Pulmonary resection for hemoptysis carries an increased risk of death. However, the extent and predictors of risk are poorly characterized and based on institutional case series. We analyzed the Nationwide Inpatient Sample (NIS) database to determine the outcome of patients undergoing anatomic pulmonary resection who were admitted with a diagnosis of hemoptysis. METHODS: We queried the NIS for hospitalized patients who were admitted emergently or urgently with hemoptysis as the principal diagnosis or as a secondary or tertiary diagnosis. We examined the outcomes of those patients who underwent lobectomy or pneumonectomy. Logistic regression analysis was used to determine clinical characteristics that were independent risk factors for death. RESULTS: During a 10-year period, 457,523 admissions for the diagnosis of hemoptysis were identified, and 2,671 patients (0.58%) underwent resection, comprising lobectomy in 2,205 and pneumonectomy in 466. The median age was 58 years, and 1,682 (63%) were men. Compared with those patients resected without a diagnosis of hemoptysis, those admitted with a hemoptysis diagnosis had a higher mortality rate after pneumonectomy (15.2% vs 9.7 %, p = 0.320) and lobectomy (6.6% vs 3.0%, p = 0.006). Advanced age, associated bacterial infections, the presence of a lung abscess/necrosis, extent of resection, and associated diagnoses of sarcoidosis and renal failure were multivariable independent risk factors for death. CONCLUSIONS: Analysis of this national database with its inherent limitations demonstrates that major lung resection can be performed in the setting of hemoptysis with reasonable mortality rate. Advanced age, extent of resection, systemic illnesses such as renal failure, sarcoidosis, and the presence of a lung abscess are independent predictors of death. PMID- 23816415 TI - Issues in quality measurement: target population, risk adjustment, and ratings. AB - This review investigates three fundamental issues in health care performance measurement: selection of a homogeneous target population, risk adjustment, and assignment of quality rating categories. Many but not all organizations involved in quality measurement have adopted similar approaches to these important methodological issues. To illustrate the practical implications of different profiling strategies, we use The Society of Thoracic Surgeons' data to compare profiling results derived using prevailing analytical methodologies with those obtained from alternative approaches, exemplified by those of a well-known health care performance rating organization. We demonstrate the differences in provider classification that may result from these methodologic decisions. PMID- 23816416 TI - Hospital variation in postoperative infection and outcome after congenital heart surgery. AB - BACKGROUND: Several initiatives aim to reduce postoperative infection across a variety of surgical patients as a means to improve overall quality of care and reduce variation across centers. However, the association of infection rates with hospital-level outcomes and resource utilization has not been well described. We evaluated this association across a multicenter cohort undergoing congenital heart surgery. METHODS: The Society of Thoracic Surgeons Congenital Heart Surgery Database was linked to resource utilization data from the Pediatric Health Information Systems Database for hospitals participating in both (2006 to 2010). Hospital-level infection rates (sepsis, wound infection, mediastinitis, endocarditis, pneumonia) adjusted for patient risk factors and case mix were calculated using Bayesian methodology, and association with hospital mortality rates, postoperative length of stay (LOS), and total costs evaluated. RESULTS: The cohort included 32,856 patients (28 centers); 3.7% had a postoperative infection. Across hospitals, the adjusted infection rate varied from 0.9% to 9.8%. Hospitals with the highest infection rates had longer (LOS) (13.2 vs 11.7 days, p < 0.001) and increased hospital costs ($71,100 vs $65,100, p < 0.001), but similar mortality rates (odds ratio 0.99, 95% confidence interval 0.80 to 1.21, p = 0.9). The proportion of variation in costs and LOS explained by infection was 15% and 6%, respectively. CONCLUSIONS: Infection after congenital heart surgery contributes to prolonged LOS and increased costs on a hospital level. However, given that infection rates alone explained relatively little of the variation in these outcomes across hospitals, further study is needed to identify additional factors that may be targeted in initiatives to reduce variation and improve outcomes across centers. PMID- 23816417 TI - A meta-analysis of transcatheter aortic valve implantation versus surgical aortic valve replacement. AB - BACKGROUND: Our preliminary meta-analysis suggests that transcatheter aortic valve implantation (TAVI) may not reduce the 30-day mortality rate over surgical aortic valve replacement (AVR) in high-risk patients with severe aortic stenosis (AS). We performed an updated formal meta-analysis of TAVI vs AVR for reduction not only of early but also of late all-cause mortality in AS. METHODS: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched through October 2012. Eligible studies were randomized controlled trials or adjusted observational comparative studies of TAVI vs AVR enrolling individuals with AS and reporting early (30-day or in-hospital) or late all-cause mortality, or both, as an outcome. Odds ratios or hazard ratios with 95% confidence intervals (adjusted odds ratios or hazard ratios in case of observational studies) were abstracted from each study. RESULTS: We identified two randomized trials and 15 adjusted observational studies enrolling 4,873 patients with severe AS. Pooled analysis suggested no significant difference in early (odds ratio, 0.92; 95% confidence interval, 0.70 to 1.19) and midterm (3-month to 3-year) total mortality (hazard ratio, 0.99; 95% confidence interval, 0.83 to 1.17) among patients assigned to TAVI vs AVR. Exclusion of any single study from the analysis did not substantively alter the overall result of our analysis. No evidence of significant publication bias was found. CONCLUSIONS: Our meta-analysis of data of approximately 5,000 patients from 17 studies showed that TAVI is likely ineffective in reducing early and midterm all-cause mortality vs AVR in high-risk patients with AS. PMID- 23816418 TI - Remote ischemic preconditioning for coronary artery bypass graft operations. AB - Ischemia-reperfusion injury occurs during coronary artery bypass graft operations. Strategies are needed to lower the extent of damage. Attempts to find these strategies have been occurring for more than 40 years, with remote ischemic preconditioning being one method. This review provides a look at potential mechanisms involved in remote ischemic preconditioning, experimental evidence supporting it, clinical studies that support and negate it, and potential reasons for differences between clinical studies. With remote ischemic preconditioning having the potential to better clinical outcomes in patients undergoing coronary artery bypass graft operations, a large clinical trial needs to be undertaken to better assess its practical clinical application. PMID- 23816419 TI - Risks associated with the transfusion of various blood products in aortic valve replacement. AB - BACKGROUND: Patients undergoing cardiac operations often require transfusions of red blood cells, plasma, and platelets. From a statistical point of view, there is a significant collinearity between the components, but they differ in indications for use and composition. This study explores the relationship between the transfusion of different blood components and long-term mortality in patients undergoing aortic valve replacement alone or combined with revascularization. METHODS: A retrospective single-center study was performed including 1,311 patients undergoing aortic valve replacement. Patients who received more than 7 units of red blood cells, those who died early (7 days), and emergency cases were excluded. Patients were monitored for up to 9.5 years. A broad selection of potential risk factors were analyzed using Cox proportional hazards regression, where transfusion of red blood cells, plasma, and platelets were forced to remain in the model. RESULTS: The transfusion of red blood cells was not associated with decreased long-term survival (hazard ratio [HR], 1.01; p = 0.520) nor was the transfusion of platelets (HR, 0.946; p = 0.124); however, the transfusion of plasma was (HR, 1.041; p < 0.001). All HRs are per unit of blood product transfused. No increased risk was found for patients undergoing a combined procedure. CONCLUSIONS: No significant risk for long-term mortality was associated with transfusion of red blood cells during the study period. However, the transfusion of plasma was associated with increased mortality. PMID- 23816420 TI - The dynamic triple peak impact factor in traumatic brain injury influences native protein structures in gray and white matter as measured with computational simulation. AB - BACKGROUND: Traumatic brain injuries (TBIs) cause a substantial burden to the patient, relatives, and the society as a whole. Much experience and knowledge during the last two decades have improved the neurosurgical treatment as well as the outcome. However, there is still much debate on what actually happens when external kinetic energy is transferred to the head immediately after a TBI. Better knowledge about the cascades of mechanical events at the time of accident is a prerequisite to further reduce the burden in all categories and improve the neurosurgical care of TBI patients. METHODS: In the present study, we use the finite element modeling of the human brain to numerically simulate impact velocities of 10, 6, and 2 m/s to clarify some of the immediate consequences of the external kinetic energy transfer focusing on the gray (GM) and white matters (WM). RESULTS: The numerical simulation was focused on the external kinetic energy transfer with a level of 227.3 J reaching the head, intracranial pressure (ICP), strain energy density, 1st principal strain level, and their respective impacts on the brain tissue. The results show that, for a 10 m/s impact, a total internal potential energy of 208.6 J was absorbed, of which 14.3% (29.81 J) was absorbed by the scalp, 22.05% (46.0 J) by the outer compact bone, 17.12% (35.72 J) by the porous bone, 27.44% (57.23 J) by the inner compact bone, and 7.31% (15.24 J) by the facial bone. The rest of the internal potential energy was defined to reach the GM (3.6%, 7.51 J) and the WM 1.59% (3.31 J). Also, the ICP, strain energy density, and 1st principal strain levels, defined as the dynamic triple peak impact factor, influenced the GM and WM with their own impact peaks during the first 10 ms after the accident and were the highest for the 10 and 6 m/s impacts, while the 2 m/s impact had only a slight influence on the GM and WM structures. CONCLUSIONS: The present study shows for the first time that following an impact of 10 m/s, 88.31% of the calculated external kinetic energy was absorbed by the external parts of the head before the remaining energy of 5.19% reached the GM and WM. GM absorbed about twice as much of the energy compared to the WM. It is suggested that the dynamic triple peak impact factor may have a profound effect on native protein structures in the cerebral metabolism after a TBI. PMID- 23816421 TI - Insights into solar TiO2-assisted photocatalytic oxidation of two antibiotics employed in aquatic animal production, oxolinic acid and oxytetracycline. AB - In this study, solar driven TiO2-assisted heterogeneous photocatalytic experiments in a pilot-plant with compound parabolic collectors (CPCs) were carried out to study the degradation of two authorized veterinary antibiotics with particular relevance in finfish aquaculture, oxolinic acid (OXA) and oxytetracycline (OTC), using pure solutions of individual or mixed antibiotics. Firstly, the influence of natural solar photolysis was assessed for each antibiotic. Secondly, photocatalytic degradation kinetic rate constants for individual and mixed antibiotics were compared, using a catalyst load of 0.5 g L( 1) and an initial pH around 7.5. Thirdly, for individually photocatalytic-treated OXA and OTC in the same conditions, the growth inhibition of Escherichia coli DSM 1103 was followed, and the mineralization extent was assessed by the residual dissolved organic carbon (DOC), low-molecular-weight carboxylate anions and inorganic ions concentration. Finally, the effect of inorganic ions, such as chlorides, sulfates, nitrates, phosphates, ammonium and bicarbonates, on the photocatalytic degradation of individual solutions of OXA and OTC was also evaluated and the formation of different reactive oxygen species were probed using selective scavengers. The removal profiles of each antibiotic, both as single component or in mixture were similar, being necessary 2.5 kJ L(-1) of solar UV energy to fully remove them, and 18 kJ(UV) L(-1) to achieve 73% and 81% mineralization, for OXA and OTC, respectively. The remaining organic carbon content was mainly due to low-molecular-weight carboxylate anions. After complete removal of the antibiotics, the remaining degradation by-products no longer showed antibacterial activity. Also, 10% and 55% of the nitrogen content of each antibiotic was converted to ammonium, while no conversion to nitrite or nitrate was detected. The presence of phosphates hindered considerably the removal of both antibiotics, whereas the presence of other inorganic ions did not substantially altered the antibiotics photocatalytic degradation kinetics. PMID- 23816422 TI - A new approach to predicting environmental transfer of radionuclides to wildlife: a demonstration for freshwater fish and caesium. AB - The application of the concentration ratio (CR) to predict radionuclide activity concentrations in wildlife from those in soil or water has become the widely accepted approach for environmental assessments. Recently both the ICRP and IAEA have produced compilations of CR values for application in environmental assessment. However, the CR approach has many limitations, most notably, that the transfer of most radionuclides is largely determined by site-specific factors (e.g. water or soil chemistry). Furthermore, there are few, if any, CR values for many radionuclide-organism combinations. In this paper, we propose an alternative approach and, as an example, demonstrate and test this for caesium and freshwater fish. Using a Residual Maximum Likelihood (REML) mixed-model regression we analysed a dataset comprising 597 entries for 53 freshwater fish species from 67 sites. The REML analysis generated a mean value for each species on a common scale after REML adjustment taking account of the effect of the inter-site variation. Using an independent dataset, we subsequently test the hypothesis that the REML model outputs can be used to predict radionuclide, in this case radiocaesium, activity concentrations in unknown species from the results of a species which has been sampled at a specific site. The outputs of the REML analysis accurately predicted (137)Cs activity concentrations in different species of fish from 27 Finnish lakes; these data had not been used in our initial analyses. We recommend that this alternative approach be further investigated for other radionuclides and ecosystems. PMID- 23816423 TI - Comparison of microwave assisted, ultrasonic assisted and Soxhlet extractions of N-nitrosamines and aromatic amines in sewage sludge, soils and sediments. AB - This paper describes a cost-effective and sensitive method for the gas chromatographic determination of 10 aliphatic and aromatic N-nitrosamines and 14 aromatic amines (including aniline, several chloroanilines and 2-nitroaniline) in various soil matrices, after microwave-assisted extraction (MAE) combined with continuous solid-phase extraction. A systematic comparison of MAE with ultrasonic assisted and Soxhlet extraction alternatives showed that MAE provided the highest extraction efficiency (94-96%) with the shortest extraction time (3 min). The method developed provides a linear response throughout the concentration range 0.1-150 ng g(-1) and features low limits of detection (0.03-0.35 ng g(-1)) and good precision. The method was successfully applied to study the occurrence of the analytes in sewage sludge, agricultural soils, and river and pond sediments. Aniline and chloroanilines were the amines most frequently detected (0.4-5.4 ng g(-1)), whereas N-nitrosodimethylamine, N-nitrosodiethylamine and N nitrosomorpholine were only found in two of the urban sewage sludge samples analyzed (0.4-1.6 ng g(-1)). PMID- 23816424 TI - Biochemical changes accompanying apoptotic cell death in retinoblastoma cancer cells treated with lipogenic enzyme inhibitors. AB - Retinoblastoma (RB) is a malignant intra-ocular neoplasm that affects children (usually below the age of 5years). In addition to conventional chemotherapy, novel therapeutic strategies that target metabolic pathways such as glycolysis and lipid metabolism are emerging. Fatty acid synthase (FASN), a lipogenic multi enzyme complex, is over-expressed in retinoblastoma cancer. The present study evaluated the biochemical basis of FASN inhibition induced apoptosis in cultured Y79 RB cells. FASN inhibitors (cerulenin, triclosan and orlistat) significantly inhibited FASN enzyme activity (P<0.05) in Y79 RB cells. This was accompanied by a decrease in palmitate synthesis (end-product depletion), and increased malonyl CoA levels (substrate accumulation). Differential lipid profile was biochemically estimated in neoplastic (Y79 RB) and non-neoplastic (3T3) cells subjected to FASN inhibition. The relative proportion of phosphatidyl choline to neutral lipids (triglyceride+total cholesterol) in Y79 RB cancer cells was found to be higher than the non-neoplastic cells, indicative of altered lipid distribution and utilization in tumor cells. FASN inhibitor treated Y79 RB and fibroblast cells showed decrease in the cellular lipids (triglyceride, cholesterol and phosphatidyl choline) levels. Apoptotic DNA damage induced by FASN inhibitors was accompanied by enhanced lipid peroxidation. PMID- 23816425 TI - To strive...and not to yield: a radiologist's response to hard times. PMID- 23816427 TI - Overview of white papers of the ACR incidental findings committee ii on adnexal, vascular, splenic, nodal, gallbladder, and biliary findings. AB - This paper summarizes the background, objectives, and process for developing 4 new white papers on adnexal, vascular, splenic, nodal, gallbladder, and biliary incidental findings and CT and MRI. This work was performed under the auspices of the ACR through its Incidental Findings Committee II. This summary should be used as a reference for definitions of terms used throughout these white papers and for understanding the structure and color scheme of flowcharts used in 2 of them. PMID- 23816426 TI - Bacterial contamination of radiologist workstations: results of a pilot study. AB - PURPOSE: The aim of this study was to quantify and characterize bacterial contamination of radiologist workstations. METHODS: Dictation microphones and computer mice at the most frequently used radiologist workstations from 2 inpatient and 2 outpatient reading rooms at 2 teaching hospitals in 2 states were sampled for bacteria. Reference toilet seat and doorknob sampling was performed in the 4 restrooms nearest those reading rooms. One microphone and one mouse in each reading room were sampled again after quick disinfection with an inexpensive, commercially available antiseptic pad. Sampling was performed using direct trypticase soy agar plating, with sampled areas uniformly approximating 50 cm(2). Colonies were quantified and additionally characterized after 24 hours using mannitol salt agar and MacConkey agar. RESULTS: All sampled radiologist computer workstation and restroom sites were contaminated with bacteria. Mean colony counts were 69.4 +/- 38.7 (range, 15-123) for microphones, 46.1 +/- 58.1 (range, 1-173) for mice, 10.5 +/- 9.7 (range, 1-22) for toilet seats, and 14.8 +/ 16.0 (range, 1-36) for restroom doorknobs. Of all workstation sites, 64.3% (9 of 14) grew Staphylococcus aureus, and 21.4% (3 of 14) grew enteric organisms. Overall microphone and mouse bacterial contamination was significantly higher than that of nearby restroom toilets and doorknobs (57.8 +/- 49.0 vs 12.6 +/- 12.5, P = .005). Microphone and mouse bacterial counts were nearly completely eliminated after brief antiseptic swabbing (from 76.9 +/- 53.2 to 0.3 +/- 0.7, P = .002). CONCLUSIONS: Bacterial contamination of microphones and computer mice at radiologist workstations is common, with colonization significantly greater than nearby restroom toilet seats and doorknobs. Simple, rapid, and inexpensive disinfection techniques nearly completely eradicate workstation bacterial contamination. The clinical implications of colonization merits further study. PMID- 23816428 TI - The social impact of Parkinson's disease in Spain: Report by the Spanish Foundation for the Brain. AB - INTRODUCTION: Understanding the social and economic impact of Parkinson's disease is essential for resource planning and raising social awareness. DEVELOPMENT: Researchers reviewed the data published to date on epidemiology, morbidity and mortality, dependency, and economic impact of Parkinson's disease in Spain. In addition, a study has been carried out in order to define the public and private health care resources of Spanish patients affected by Parkinson's disease by means of an e-mail survey of all neurologists specialising in this disease and belonging to the Spanish Society of Neurology's study group for movement disorders. CONCLUSIONS: The incidence and prevalence rates of Parkinson's disease in Spain are similar to those in the rest of Europe. According to current population estimates, there are at least 300.000 patients with Parkinson's disease and one new case per 10.000 habitants per year in Spain. This has a major impact on the patient's quality of life and nearly doubles patient mortality. In addition, the disease generates sizeable costs for the country that may exceed 17.000? per year per patient; costs will rise due to the ageing of the population and the new therapies employed. Healthcare professionals and administrators dedicate their efforts to providing quality care to patients. Despite the above, we still have a long way to go in order to provide quality, efficient, multidisciplinary, and universal healthcare. PMID- 23816429 TI - Probing the association between dexamethasone-induced cortisol suppression and serotonin transporter availability among drug-free patients with major depressive disorder--a small-sample SPECT study with [123I]ADAM. AB - The association between hypothalamo-pituitary-adrenal (HPA) axis function and the serotonergic system could be involved in the mechanism of depression. However, neuroimaging evidence is scarce. The aim of the present study was to probe the association between dexamethasone suppression test response and serotonin transporter (SERT) availability in drug-free patients with major depressive disorder (MDD). Seventeen MDD patients (five males and twelve females) were recruited. SPECT with [(123)I] ADAM was used to measure the midbrain SERT availability, and HPA axis function was measured by the dexamethasone suppression test (DST). The association was significant when considering all participants (rho=0.69, p=0.002). This association may have clinical implications for the treatment of MDD. PMID- 23816430 TI - Antiviral therapies targeting host ER alpha-glucosidases: current status and future directions. AB - Endoplasmic reticulum (ER)-resident alpha-glucosidases I and II sequentially trim the three terminal glucose moieties on N-linked glycans attached to nascent glycoproteins. These reactions are the first steps of N-linked glycan processing and are essential for proper folding and function of many glycoproteins. Because most viral envelope glycoproteins contain N-linked glycans, inhibition of ER alpha-glucosidases with derivatives of 1-deoxynojirimycin (DNJ) or castanospermine (CAST), two well-studied pharmacophores of alpha-glucosidase inhibitors, efficiently disrupts the morphogenesis of a broad spectrum of enveloped viruses. Moreover, both DNJ and CAST derivatives have been demonstrated to prevent the death of mice infected with several distinct flaviviruses and filoviruses and suppress the multiplication of several other species of viruses in infected animals. N-Butyl derivative of DNJ (NB-DNJ) and 6 O-bytanoyl prodrug of CAST (Bu-CAST) have been evaluated in human clinical trials for their antiviral activities against human immunodeficiency virus and hepatitis C virus, and there is an ongoing trial of treating dengue patients with Bu-CAST. This article summarizes the current status of ER alpha-glucosidase-targeted antiviral therapy and proposes strategies for development of more efficacious and specific ER alpha-glucosidase inhibitors as broad-spectrum, drug resistance-refractory antiviral therapeutics. These host function-targeted, broad-spectrum antiviral agents do not rely on time-consuming etiologic diagnosis, and should therefore be particularly promising in the management of viral hemorrhagic fever and respiratory tract viral infections, medical conditions that can be caused by many different enveloped RNA viruses, with a short window for medical intervention. PMID- 23816431 TI - Investigation of Diospyros Kaki L.f husk extracts as corrosion inhibitors and bactericide in oil field. AB - BACKGROUND: Hydrochloric acid is used in oil-well acidizing commonly for improving the crude oil production of the low-permeable reservoirs, while it is a great challenge for the metal instruments involved in the acidification. Developing natural products as oilfield chemicals is a straight way to find less expensive, green and eco-friendly materials. The great plant resources in Qin ling and Ba-shan Mountain Area of Shannxi Province enable the investigating of new green oil field chemicals. Diospyros Kaki L.f (persimmon), a famous fruit tree is widely planted in Qin-ling and Ba-shan Mountain Area of Shaanxi Province. It has been found that the crude persimmon extracts are complex mixtures containing vitamins, p-coumaric acid, gallic acid, catechin, flavonoids, carotenoids and condensed tannin and so on, which indicates the extracts of persimmon husk suitable to be used as green and eco-friendly corrosion inhibitors. FINDINGS: Extracts of persimmon husk were investigated, by using weight loss and potentiodynamic polarisation techniques, as green and eco friendly corrosion inhibitors of Q235A steel in 1M HCl. The inhibition efficiency of the extracts varied with extract concentration from 10 to 1,000 mg/L. There are some synergistic effects between the extracts and KI, KSCN and HMTA. Potentiodynamic polarization studies indicate that extracts are mixed-type inhibitors. Besides, the extracts were screened for antibacterial activity against oil field microorganisms, and they showed good to moderate activity against SRB, IB and TGB. CONCLUSIONS: The inhibition efficiency of the extracts varied with extract concentration from 10 to 1,000 mg/L, and the highest reaches to 65.1% with the con concentration of 1,000 mg/L WE. KI, KSCN and HMTA they can enhance the IE of WE effectively to 97.3% at most, but not effective for KI and KSCN to AE. Tafel polarisation measurements indicate the extracts behave as mixed type inhibitor. Investigation of the antibacterial activity against oil field microorganism showed the extracts can inhibit SRB, IB and TGB with moderate to highly efficiency under 1,000 mg/L, which makes extracts potential to be used as bifunctional oil field chemicals. PMID- 23816432 TI - Reduced cerebrovascular reactivity in posterior cerebral arteries in patients with primary open-angle glaucoma. AB - PURPOSE: To evaluate the hemodynamics and vasoreactivity in the posterior cerebral artery (PCA) in patients with primary open-angle glaucoma (POAG). DESIGN: Case-control study. PARTICIPANTS: Thirteen POAG patients (age range, 40 60 years) with marked visual field loss (mean deviation [MD], <-6 dB); a preserved, mostly normal, central visual field of at least 5 degrees ; and best corrected visual acuity of at least 20/40 formed the study group. Exclusion criterion was presence or history of any systemic disorder including cardiovascular diseases. The control group consisted of 12 healthy subjects matched for age and sex with the study group. METHODS: Applying transcranial Doppler sonography, we measured hemodynamic parameters in both PCAs at baseline, under monocular reversing checkerboard stimulation, and under hyperventilation. The eye with more marked visual field loss was selected in glaucoma patients, whereas in controls, the tested eye was chosen randomly. Ipsilateral and contralateral PCA were defined according to the tested eye. MAIN OUTCOME MEASURES: Peak systolic velocity (PSV), end-diastolic velocity, mean velocity (MV), MV change percentage (MV%), resistivity index (RI), pulsatility index (PI). RESULTS: At baseline, RI (0.55 +/- 0.04 vs. 0.52 +/- 0.03; P = 0.04) and PI (0.88 +/- 0.11 vs. 0.80 +/- 0.07; P = 0.04) in the ipsilateral PCA were significantly higher in glaucoma patients than in controls. During checkerboard stimulation, MV% in both PCAs were significantly smaller in the glaucoma group than in controls (19.7 +/- 7.2% and 19.0 +/- 8.3% vs. 30.7 +/- 7.9% and 27.5+/-9.0%, respectively; P = 0.001 and 0.02, respectively). During hyperventilation, glaucoma patients showed significantly lower MV% in the contralateral PCA than control subjects (-39.8 +/- 9.6% versus -47.4 +/- 7.0%; P = 0.03). Perimetric pattern standard deviation (PSD) in the tested eye was correlated significantly with RI and PI of the ipsilateral PCA during checkerboard stimulation (P = 0.003, r = -0.76; and P = 0.002, r = -0.76). The MV% of contralateral PCA was correlated inversely with PSD in the fellow eye (P = 0.02, r = -0.64). The difference in MV% between both PCAs was correlated positively with the difference in MD between 2 eyes (P = 0.003, r = 0.75). Under hyperventilation, PSV in the contralateral PCA was correlated negatively with the PSD in the fellow eye (P = 0.03, r = -0.60). CONCLUSIONS: Vascular insufficiency in the PCAs may be associated with POAG. Changes in the vasoreactivity of PCAs to central visual stimulation may precede marked central visual field loss. PMID- 23816433 TI - Differential proteomics of Aedes albopictus salivary gland, midgut and C6/36 cell induced by dengue virus infection. AB - The interaction between dengue virus (DENV) and vector mosquitoes are still poorly understood at present. In this study, 2-D DIGE combined with MS was used to analyze the differential proteomes of Aedes albopictus salivary gland, midgut and C6/36 cells induced by DENV-2. Our results indicated that the virus infection regulated several functional classes of proteins. Among them, 26 were successfully analyzed by real-time RT-PCR. The mRNA levels of 15 were the highest in salivary gland, 2 in midgut and none in C6/36 cells, however, 18 were the least in fat body compared to other organs. Interestingly, the changes of differential proteins mRNA were the most obvious in fat body post-infection. Chaperone, cytoskeleton and energy metabolism enzyme were the most down- or up- regulated proteins after DENV-2 infection. The abundant expression of these proteins in salivary gland may relate to its high susceptibility. PMID- 23816434 TI - Role of the vaccinia virus O3 protein in cell entry can be fulfilled by its Sequence flexible transmembrane domain. AB - The vaccinia virus O3 protein, a component of the entry-fusion complex, is encoded by all chordopoxviruses. We constructed truncation mutants and demonstrated that the transmembrane domain, which comprises two-thirds of this 35 amino acid protein, is necessary and sufficient for interaction with the entry fusion complex and function in cell entry. Nevertheless, neither single amino acid substitutions nor alanine scanning mutagenesis revealed essential amino acids within the transmembrane domain. Moreover, replication-competent mutant viruses were generated by randomization of 10 amino acids of the transmembrane domain. Of eight unique viruses, two contained only two amino acids in common with wild type and the remainder contained one or none within the randomized sequence. Although these mutant viruses formed normal size plaques, the entry fusion complex did not co-purify with the mutant O3 proteins suggesting a less stable interaction. Thus, despite low specific sequence requirements, the transmembrane domain is sufficient for function in entry. PMID- 23816436 TI - Longitudinal analysis of heart and liver iron in thalassemia major patients according to chelation treatment. AB - Iron chelators and nuclear magnetic resonance imaging (MRI) techniques for assessing iron loading in liver and heart have greatly improved survival of thalassemic patients suffering iron overload-associated cardiomyopathy. However, the correlation between liver iron concentration and myocardial siderosis is ambiguous. Using an objective metric of time delay, scientists have demonstrated a lag in the loading and unloading of cardiac iron with respect to that of the liver. In the present study, we further tested this hypothesis with different chelation treatments. We analyzed the effect of three chelating treatment approaches on liver and cardiac iron content in 24 highly compliant patients who underwent 3 or more MRIs under each chelation treatment. Of the 84 MRIs considered, 32 were performed on deferoxamine (DFO - 8 patients), 24 on deferiprone (DFP - 7 patients), and 28 on combined therapy (DFO+DFP - 9 patients). In patients treated with DFO, changes in cardiac iron significantly lagged changes in liver iron but the opposite pattern was observed in patients treated with DFP (p=0.005), while combined therapy showed a pattern in-between DFO and DFP. We conclude that the temporality of changes of cardiac and liver iron is chelator-dependent, so that chelation therapy can be tailored to balance iron elimination from the liver and the heart. PMID- 23816435 TI - Hepatic glycogen cycling contributes to glucose lowering effects of the glucokinase activator LCZ960. AB - Glucokinase (GK) acts as a glucose sensor by facilitating glucose phosphorylation into glucose-6-phosphate (G6P) in the liver and pancreas, the two key target tissues. LCZ960, a glucokinase activator exerts a stimulatory effect on GK activity in hepatocytes in vitro. This study aimed to verify in vivo that LCZ960 stimulates glucose uptake primarily through a mechanism involving hepatic GK activation. Acute and chronic LCZ960 treatment-induced changes in glycemia and hepatic glucose turnover were measured in high fat diet-induced obese (DIO) mice and rats. G6P production and glycogen cycling were quantified by (13)C-MR spectroscopy during a [1-(13)C]glucose infusion, followed by a pulse-chase with [(12)C]glucose to mimic postprandial conditions in rats. Acute treatment with LCZ960 dose-dependently reduced blood glucose without causing hypoglycemia in DIO mice. Chronic LCZ960 treatment maintained normoglycemia and improved glucose tolerance without increased insulin secretion in DIO mice and rats. In rats, LCZ960 stimulated a 240% increase (P<0.05) in the glycogen synthase flux. However, due to a much higher glycogen breakdown (LCZ960: 48 +/- 15 vs control: 4 +/- 1MUmol/kg/min, P<0.05), this translated to only a 46% (ns) increase in glycogen storage (Vsyn net, LCZ960: 64+/-26 vs control: 43 +/- 6 MUmol/kg/min). Despite a 4-fold increase in hepatic glycogen turnover (LCZ960: 36.0 +/- 5.5% vs control: 8.3 +/- 2.0%), LCZ960 did not impact glucose-stimulated G6P accumulation. LCZ960 did not cause hypoglycemia in DIO rodents. Under hyperglycemic conditions, LCZ960 induced a robust increase in hepatic glycogen cycling. Since net hepatic glycogen storage is diminished in type 2 diabetes patients, stimulation of glycogen synthesis may contribute to the anti hyperglycemic properties of glucokinase activation. PMID- 23816438 TI - Age-related variations of appetite sensations of fullness and satisfaction with different dietary energy densities in a large, free-living sample of Japanese adults. AB - BACKGROUND: The effective energy density (ED) diet model for customized meal plans has not been adequately explored, and the specific differences in appetite sensation among age groups remain unclear. DESIGN: A randomized, crossover study was conducted in 2010 to examine the effects of lunches with different dietary EDs on sensory properties across age groups. PARTICIPANTS/SETTING: In this experiment, 276 healthy Japanese subjects aged 22 to 59 years consumed packed lunches over six sessions. Using the control meal (150 g cooked rice, sauteed beef menu containing 40 g raw beef, and 240 g vegetable) as a reference, a high meat/low-rice meal, a low-vegetable meal, a medium-fat/low-vegetable meal, a high fat meal, and a high-fat/low-vegetable meal were served as modified test meals with varying macronutrient distribution and ED. MAIN OUTCOME MEASURES: Subjective levels of fullness and satisfaction were assessed over time by visual analogue scale ratings. STATISTICAL ANALYSES PERFORMED: Data were analyzed using analysis of variance with body mass index as a covariate followed by Bonferroni post hoc tests. RESULTS: Meals with high vegetable content resulted in greater fullness and satisfaction than meals with low vegetable content, regardless of the diner's age. Particularly among the 500-kcal low-ED meals, a high-meat meal resulted in greater fullness and satisfaction than a medium-fat/low-vegetable meal among participants aged 30 to 40 years. Postprandial fullness was significantly higher with control meal than with high-meat meal among participants aged 40 to 50 years. CONCLUSIONS: This study indicated that high vegetable content in the low ED diet model provided sufficient fullness and satisfaction despite the low energy content and increased rice content is more effective for satiety than increased meat content for Japanese adults aged around 40 years. PMID- 23816439 TI - Malignant arrhythmogenic right ventricular dysplasia/cardiomyopathy with a normal 12-lead electrocardiogram: a rare but underrecognized clinical entity. AB - BACKGROUND: In Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C), a normal electrocardiogram (ECG) is considered reassuring. However, some patients with ARVD/C experiencing ventricular arrhythmias have a normal ECG. OBJECTIVES: To estimate how often patients with ARVD/C experiencing ventricular arrhythmias have a normal ECG during sinus rhythm, and to provide a clinical profile of these patients. METHODS: We included 145 patients with ARVD/C experiencing a documented sustained ventricular arrhythmia. Conventional 12-lead sinus rhythm ECGs within 6 months of the event were reviewed for diagnostic Task Force Criteria (TFC). ECGs were classified as abnormal (>=1 TFC), nonspecific (abnormal, no TFC), or normal. Cardiologic investigations within 6 months of the event were evaluated as per TFC in those with a nonspecific or normal ECG. RESULTS: The ECG was nonspecific or normal in 17 of 145 (12%) subjects. Mean age of these patients was 41.3 +/- 12.4 years and 14 (82%) were men, comparable to those with an abnormal ECG. Most patients with a nonspecific or normal ECG showed >=1 TFC on Holter monitoring (n = 9 of 10) and signal-averaged ECG (n = 4 of 5), and all had nonsustained ventricular tachycardia recorded. Among 15 patients who underwent structural evaluation, 11 (73%) showed structural TFC (9 major and 2 minor). CONCLUSIONS: Although most patients with ARVD/C experiencing arrhythmias have an abnormal ECG, a nonspecific or normal ECG does not preclude ARVD/C diagnosis. All patients with a nonspecific or normal ECG had alternative evidence of disease expression. These results alert the physician not to rely exclusively on ECG in ARVD/C, but to assess arrhythmic risk by comprehensive clinical evaluation. PMID- 23816440 TI - Transvenous extraction of implantable cardioverter-defibrillator leads under advisory--a comparison of Riata, Sprint Fidelis, and non-recalled implantable cardioverter-defibrillator leads. AB - BACKGROUND: Comparative safety and efficacy associated with transvenous lead extraction (TLE) of recalled and non-recalled implantable cardioverter defibrillator (ICD) leads has not been well characterized. OBJECTIVES: To compare the indications, techniques, and procedural outcomes of recalled vs non-recalled ICD lead extraction procedures. METHODS: TLE procedures performed at our institution from June 2002 to June 2012 in which Riata, Sprint Fidelis, or non recalled ICD leads were extracted were included in the analysis. RESULTS: ICD lead extraction procedures were performed in 1079 patients, including 430 patients with recalled leads (121 Riata, 308 Sprint Fidelis, and 1 Riata and Sprint Fidelis) and 649 patients with non-recalled ICD leads. A total of 2056 chronic endovascular leads were extracted, of which 1215 (59.1%) were ICD leads. Overall, there was 96.8% complete procedural success, 99.1% clinical success, and 0.9% failure, with 3.9% minor complications and 1.5% major complications. Procedural outcomes for Riata and Sprint Fidelis TLE procedures were no different. Lead implant duration was significantly less in recalled than in non recalled ICD lead TLE procedures. Complete procedural success was higher in recalled (424 of 430 [98.6%]) than in non-recalled (621 of 649 [95.7%]; P = .007) ICD lead TLE procedures. Minor complications were lower in recalled (10 of 430 [2.3%]) than in non-recalled (32 of 649 [5.0%]; P = .030) ICD lead TLE procedures. Rates of clinical success, failure, and major complications were no different in the recalled and non-recalled ICD lead TLE procedures. CONCLUSION: In our experience, recalled ICD leads were extracted with safety and efficacy comparable to that of non-recalled ICD leads. PMID- 23816441 TI - Surface-enhanced infrared absorption spectroscopy (SEIRAS) to probe monolayers of membrane proteins. AB - Surface-enhanced infrared absorption spectroscopy (SEIRAS) represents a variation of conventional infrared spectroscopy and exploits the signal enhancement exerted by the plasmon resonance of nano-structured metal thin films. The surface enhancement decays in about 10nm with the distance from the surface and is, thus, perfectly suited to selectively probe monolayers of biomembranes. Peculiar to membrane proteins is their vectorial functionality, the probing of which requires proper orientation within the membrane. To this end, the metal surface used in SEIRAS is chemically modified to generate an oriented membrane protein film. Monolayers of uniformly oriented membrane proteins are formed by tethering His tagged proteins to a nickel nitrilo-triacetic acid (Ni-NTA) modified gold surface and SEIRAS commands molecular sensitivity to probe each step of surface modification. The solid surface used as plasmonic substrate for SEIRAS, can also be employed as an electrode to investigate systems where electron transfer reactions are relevant, like e.g. cytochrome c oxidase or plant-type photosystems. Furthermore, the interaction of these membrane proteins with water soluble proteins, like cytochrome c or hydrogenase, is studied on the molecular level by SEIRAS. The impact of the membrane potential on protein functionality is verified by monitoring light-dark difference spectra of a monolayer of sensory rhodopsin (SRII) at different applied potentials. It is demonstrated that the interpretations of all of these experiments critically depend on the orientation of the solid-supported membrane protein. Finally, future directions of SEIRAS including cellular systems are discussed. This article is part of a Special Issue entitled: FTIR in membrane proteins and peptide studies. PMID- 23816442 TI - Peptide and protein binding to lipid monolayers studied by FT-IRRA spectroscopy. AB - Lipid monolayers at the air-water interface represent half of a lipid bilayer and are therefore suitable model systems for studying the binding of peripheral proteins and polypeptides as well as proteins containing hydrophobic membrane anchors to membrane interfaces. Infrared reflection-absorption spectroscopy (IRRAS) of these monolayer films at the air-water interface provides information on the state of the lipid monolayers as well as on the conformational and orientational order of the film constituents. We will review shortly the experimental set-up and the possibilities for obtaining structural information before several applications of the method to lipid-protein monolayers will be described. We will focus on examples where the analysis of the protein and peptide bands for pure monolayers of these compounds are combined with experiments where the same compounds are bound to lipid monolayers. Combination of these experiments leads to detailed information about the conformational properties and the orientation of the molecules at the air-water interface in contrast to being bound to the lipid-water interface. This article is part of a Special Issue entitled: FTIR in membrane proteins and peptide studies. PMID- 23816444 TI - Comment on: Predictors and outcomes of adolescent bariatric support group attendance. PMID- 23816443 TI - Cognitive function predicts 24-month weight loss success after bariatric surgery. AB - BACKGROUND: Clinically significant cognitive impairment, particularly in attention/executive and memory function, is found in many patients undergoing bariatric surgery. These difficulties have previously been linked to decreased weight loss 12 months after surgery, but more protracted examination of this relationship has not yet been conducted. The present study prospectively examined the independent contribution of cognitive function to weight loss 24 months after bariatric surgery. Given the rapid rate of cognitive improvement observed after surgery, postoperative cognitive function (i.e., cognition 12 weeks after surgery, controlling for baseline cognition) was expected to predict lower body mass index (BMI) and higher percent total weight loss (%WL) at 24-month follow up. METHODS: Data were collected by 3 sites of the Longitudinal Assessment of Bariatric Surgery (LABS) parent project. Fifty-seven individuals enrolled in the LABS project who were undergoing bariatric surgery completed cognitive evaluation at baseline, 12 weeks, and 24 months. BMI and %WL were calculated for 24-month postoperative follow-up. RESULTS: Better cognitive function 12 weeks after surgery predicted higher %WL and lower BMI at 24 months, and specific domains of attention/executive and memory function were robustly related to decreased BMI and greater %WL at 24 months. CONCLUSIONS: Results show that cognitive performance shortly after bariatric surgery predicts greater long-term %WL and lower BMI 24 months after bariatric surgery. Further work is needed to clarify the degree to which this relationship is mediated by adherence to postoperative guidelines. PMID- 23816445 TI - Contrast profiles of bullying in Peru and Spain. PMID- 23816446 TI - Characterization and immunolocalization of mutated ornithine decarboxylase antizyme from Angiostrongylus cantonensis. AB - Ornithine decarboxylase antizyme (OAZ), a prominent regulator of cell proliferation, DNA/RNA transformation and tumorigenesis, can bind to ornithine decarboxylase (ODC) and facilitate its degradation. Expression of OAZ requires a unique ribosomal frame shift that is regulated by levels of polyamine in the cell. In this study, we cloned an OAZ gene with the +1 ribosomal frame-shift from a fourth-stage larvae cDNA library of Angiostrongylus cantonensis. We removed one nucleotide to express the gene without polyamine. The sequence analysis showed that the deleted-mutation ornithine decarboxylase antizyme (DM-AcOAZ) contained a conservative domain related to other species OAZ. Quantitative real-time PCR revealed that DM-AcOAZ was expressed in L3 and L4 stages and adult female worms. More notably the expression level is the highest in the adult female stage. Immunohistochemical studies indicated that DM-AcOAZ was specifically localized in the uterus, oocyte and intestine in adult female worms. MTT assays showed that in DM-AcOAZ transfected HeLa cells, cell proliferation is inhibited. In conclusion, DM-AcOAZ may be a female-enriched protein and may involved in the cell proliferation in A. cantonensis. PMID- 23816447 TI - Vagus nerve stimulation for chronic major depressive disorder: 12-month outcomes in highly treatment-refractory patients. AB - BACKGROUND: There are limited treatment options for patients with chronic, treatment-refractory major depression who do not respond to routinely-available treatments. Vagus Nerve Stimulation (VNS) may represent an alternative to ablative neurosurgery for a specific group of patients. METHODS: 12-month response rates for 28 patients with chronic (>=2 years) major depression who had failed to respond to >=4 adequate treatment trials in the D03 European open clinical trial of VNS were described along with response rates for 13 consecutive patients who underwent VNS within the neurosurgical treatment programme in Dundee. RESULTS: In the D03 cohort (N=28), the response rate at 12 months (defined as a 50% reduction in symptom score) was 35.7%. In the Dundee VNS case series (N=13), the equivalent response rate was 30.8%. LIMITATIONS: These data are from unblinded and open studies, and there is no control group. Other factors may have contributed to some of the improvement seen, although this is unlikely in very chronic populations. Outcomes are not reported beyond 12 months. CONCLUSION: Response rates at 12 months for patients with chronic and highly refractory major depression are broadly consistent with previously published results in more heterogeneous and less refractory clinical trial populations. In highly treatment-resistant patients, the rate of response with VNS at 12 m is at least twice that anticipated with 'treatment-as-usual'. PMID- 23816448 TI - Is structured group psychoeducation for bipolar patients effective in ordinary mental health services? A controlled trial in Italy. AB - BACKGROUND: Recent reviews of evidence-based guidelines for the clinical management of Bipolar Disorders (BD) have recommended that "all patients with BD be offered group or individual psychoeducation" to prevent relapse, improve treatment adherence, quality of life, and functioning. The present study evaluated the effectiveness of psychoeducation in routine mental health services in reducing number of hospitalisations and number of days spent in hospital, at a 1-year follow-up. METHODS: A total of 102 outpatients were recruited from two Italian Departments of Mental Health. Inclusion criteria were a lifetime BD type I or II diagnosis, assessed with SCID, and >= 3 months of euthymia. Exclusion criteria were DSM-IV Axis I comorbidity, mental retardation (IQ<70), organic brain damage, or deafness. All participants received standard psychiatric care, including standard pharmacological treatment; the experimental group also received 21 group psychoeducation sessions, weekly held and conducted according to Colom and Vieta's model. RESULTS: The number of patients hospitalised during the 1-year follow-up, the mean number of hospitalisations per patient, and the mean number of hospitalisation days were significantly lower for psychoeducated patients. CONCLUSION: Our findings support the view that group psychoeducation is an effective way to prevent hospitalisation and decrease hospital days in pharmacologically treated patients with bipolar disorder also in routine clinical settings. The results confirm that psychoeducation promotes improvement in illness course by preventing acute phases and enhancing mood stability, and consequently, improvement in the quality of life for people with BD. PMID- 23816449 TI - Breastfeeding, retinoids, and postpartum depression: a new theory. AB - Postpartum depression (PPD) is an international public health problem affecting at least 1 in 8 mothers. Known risk factors include: giving birth to a preterm or low birth weight infant, babies with greater symptoms of illness at age 4-6 weeks, formula feeding, younger maternal age, smoking, and fatigue. Prolonged breastfeeding is associated with a reduced risk of PPD but the mechanisms are not well understood. Interventions for PPD focusing on psychosocial risk factors have been largely unsuccessful, suggesting that the condition has a mainly biological basis. The hypothesis proposed for consideration is that breastfeeding protects against PPD by maintaining endogenous retinoids (vitamin A-related compounds) below a threshold concentration. In fact, breast milk is rich in retinoids; pregnant women accumulate retinoids in liver and breast in preparation for lactation; there is increasing evidence that retinoids in higher concentration are associated with cognitive disturbances and mood disorders, including depression and suicide; and prolonged lactation reduces maternal stores of retinoids. Consistent with this hypothesis, it is estimated that an amount of vitamin A is transferred from mother to infant during the first six months of exclusive breastfeeding equivalent to 76% of a dose known to cause acute vitamin A poisoning in an adult. Breastfeeding may thus have evolutionary-adaptive functions for both mother and infant, transferring vital nutrients to an infant unable to feed itself, yet at the same time providing a natural means of reducing potentially toxic concentrations of retinoids in the mother. PMID- 23816451 TI - Relationship between heavy metals concentrations in egret species, their environment and food chain differences from two Headworks of Pakistan. AB - Concentration of ten metals (Cd, Cr, Co, Cu, Fe, Li, Mn, Ni, Pb and Zn) were analyzed in the egg contents, prey and soil samples of little egret (Egretta garzetta) and cattle egret (Bubulcus ibis) from two Headworks to determine habitat and species-specific differences; to assess the importance of prey and habitat contamination as an exposure source for heavy metals. Concentration of Cu, Mn, Cr and Pb in egg contents, Fe, Co, Cu, Mn, Zn in prey and Fe, Co, Cu, Ni, Li in surface soils were significantly different (P<0.05). Mean metal concentrations of Cr, Pb and Cd were relatively higher in little egret whereas Cu and Mn were higher in the egg contents of cattle egret. The mean concentrations of Cu, Mn and Zn were higher in prey samples of cattle egrets and Cr, Cd and Pb in prey samples of little egrets. In soil samples collected from little egret heronries metal concentrations were higher except Cu and Ni. Correlation Analysis and Hierarchical Agglomerative Cluster Analysis (HACA) identified relatively similar associations of metals and their source identification. Metals such as Fe, Cu, Mn, and Li were related with geochemical origin from parent rock material as well as anthropogenic input whereas Cr, Cd, Pb, Ni, Co and Zn were associated mostly with anthropogenic activities. The study suggested that eggs are useful bio-monitor of local heavy metal contamination. PMID- 23816450 TI - Photoreactivity of hydroxylated multi-walled carbon nanotubes and its effects on the photodegradation of atenolol in water. AB - In spite of the increasing concerns about the fate of pharmaceuticals and personal care products (PPCPs) and the nanomaterial pollution in aquatic ecosystem, the effects of carbon nanotubes on the photochemical transformation of PPCPs are less considered. In this study, the photochemical production of reactive oxygen species (ROS) were examined in colloidal dispersions of hydroxylated multi-walled carbon nanotubes (MWNT-OH) under simulated solar irradiation using a Xenon lamp. Two kinds of ROS, (1)O2 and OH, were confirmed by their molecular probes, furfuryl alcohol (FFA) and p-chlorobenzoic acid (PCBA). The steady-state concentrations of (1)O2 and OH were calculated as 1.30*10(-14) M and 5.02*10(-16) M, respectively. The effects of MWNT-OH on photodegradation of atenolol (ATL) were investigated in the presence of natural water components, i.e., dissolved organic matters (DOMs), nitrate (NO3(-)) and ferric ions (Fe(3+)). Photoproducts of atenolol were identified by solid phase extraction liquid chromatography-mass spectrometry (SPE-LC-MS) analysis techniques. Three potential photochemical pathways of atenolol, including the hydroxylation on aromatic ring, the loss of amide group and the cleavage of ether oxygen bond as well as di-polymerization of reaction intermediates were tentatively proposed. Using the radical quenching method, reaction with OH was determined as the major photolysis pathway of atenolol in irradiated MWNT-OH suspensions. These findings of the production of ROS and their effects on the photodegradation of organic contaminants provided useful information for assessing environmental risk of MWNT OH. PMID- 23816452 TI - Transcriptional and proteomic stress responses of a soil bacterium Bacillus cereus to nanosized zero-valent iron (nZVI) particles. AB - Nanosized zero valent iron (nZVI) is emerging as an option for treating contaminated soil and groundwater even though the potentially toxic impact exerted by nZVI on soil microorganisms remains uncertain. In this work, we focus on nanotoxicological studies performed in vitro using commercial nZVI and one common soil bacterium (Bacillus cereus). Results showed a negative impact of nZVI on B. cereus growth capability, consistent with the entrance of cells in an early sporulation stage, observed by TEM. Despite no changes at the transcriptional level are detected in genes of particular relevance in cellular activity (narG, nirS, pykA, gyrA and katB), the proteomic approach used highlights differentially expressed proteins in B. cereus under nZVI exposure. We demonstrate that proteins involved in oxidative stress-response and tricarboxilic acid cycle (TCA) modulation are overexpressed; moreover proteins involved in motility and wall biosynthesis are repressed. Our results enable to detect a molecular-level response as early warning signal, providing new insight into first line defense response of a soil bacterium after nZVI exposure. PMID- 23816453 TI - Effects of untreated hospital effluents on the accumulation of toxic metals in sediments of receiving system under tropical conditions: case of South India and Democratic Republic of Congo. AB - Physicochemical and ecotoxicological analyses have been performed to assess the quality of sediments receiving untreated hospital effluents from Indian and Democratic Republic of Congo (DRC) hospitals. The sediments were collected monthly and characterized for grain size, organic matter, total organic carbon, total carbon, nitrogen, phosphorus, toxic metals and ecotoxicity. The results highlight the high concentration of toxic metals from the Indian hospital effluent receiving systems, especially for Cr, Cu, As, Zn and Hg. On the other hand, the metal concentrations in the sediment receiving system from DRC are low (e.g. maximum Hg and Zn concentration were 0.46 and 48.84 mg kg(-1) respectively). Ostracods exposed to sediment samples H2 (September month sample) and H3 (June and September month samples) were found dead after 6d of exposure whereas the higher mortality rate for Congo sediments was 23% but was accompanied with 33 +/- 7% of growth inhibition. The results of this study show the variation of sediment composition on toxic metal levels as well as toxicity related to both, the type of hospitals and the sampling period. Additionally, hospital effluent disposal practices at the study sites can lead to the pollution of water resources and may generate risks for aquatic organisms and human health. PMID- 23816454 TI - Vapor-phase concentrations of PAHs and their derivatives determined in a large city: correlations with their atmospheric aerosol concentrations. AB - Thirteen PAHs, five nitro-PAHs and two hydroxy-PAHs were determined in 55 vapor phase samples collected in a suburban area of a large city (Madrid, Spain), from January 2008 to February 2009. The data obtained revealed correlations between the concentrations of these compounds and a series of meteorological factors (e.g., temperature, atmospheric pressure) and physical-chemical factors (e.g., nitrogen and sulfur oxides). As a consequence, seasonal trends were observed in the atmospheric pollutants. A "mean sample" for the 14-month period would contain a total PAH concentration of 13835+/-1625 pg m(-3) and 122+/-17 pg m(-3) of nitro PAHs. When the data were stratified by season, it emerged that a representative sample of the coldest months would contain 18900+/-2140 pg m(-3) of PAHs and 150+/-97 pg m(-3) of nitro-PAHs, while in an average sample collected in the warmest months, these values drop to 9293+/-1178 pg m(-3) for the PAHs and to 97+/-13 pg m(-3) for the nitro-PAHs. Total vapor phase concentrations of PAHs were one order of magnitude higher than concentrations detected in atmospheric aerosol samples collected on the same dates. Total nitro-PAH concentrations were comparable to their aerosol concentrations whereas vapor phase OH-PAHs were below their limits of the detection, indicating these were trapped in airborne particles. PMID- 23816455 TI - Reply to comment on "A computational study on enzymatically driven oxidative coupling of chlorophenols: an indirect dehalogenation reaction [Szatkowski and Dybala-Defratyka, Chemosphere 91 (2013) 258-264]". PMID- 23816456 TI - CYP1A1 genetic polymorphism and polycyclic aromatic hydrocarbons on pulmonary function in the elderly: haplotype-based approach for gene-environment interaction. AB - Lung function may be impaired by environmental pollutants not only acting alone, but working with genetic factors as well. Few epidemiologic studies have been conducted to explore the interplay of polycyclic aromatic hydrocarbons (PAHs) exposure and genetic polymorphism on lung function in the elderly. For genetic polymorphism, haplotype is considered a more informative unit than single nucleotide polymorphism markers. Therefore, we examined the role of haplotype based-CYP1A1 polymorphism in the effect of PAHs exposure on lung function in 422 participants from a community-based panel of elderly adults in Seoul, Korea. Linear mixed effect models were fit to evaluate the association of PAH exposure markers (urinary 1-hydroxypyrene and 2-naphthol) with FVC, FEV1, FEV1/FVC, and FEF25-75, and then the interaction with CYP1A1 haplotype constructed from three single nucleotide polymorphisms of the gene (rs4646421/rs4646422/rs1048943). Urinary 1-hydroxypyrene levels were inversely associated with FEV1/FVC (p<0.05), whereas urinary 2-naphthol levels failed to show associations with lung function. Urinary 1-hydroxypyrene was significantly associated with decrease in FEV1/FVC among participants with rs4646421 variants (CT+TT), rs4646422 wild-type (GG), and rs1048943 wild-type (AA). At least one TGA haplotype predicted a 0.88% (95% confidence interval, 0.31-1.45%) reduction in FEV1/FVC with an interquartile range increase in 1-hydroxypyrene, whereas no relationship was observed in participants without TGA haplotype (p for interaction=0.045). Similar patterns were also observed in FEF25-75. We did not find any main effects of CYP1A1 genetic polymorphisms on lung functions. Our findings suggest that PAH exposure producing 1-hydroxypyrene as a metabolite compromises lung function in the elderly, and that haplotype-based CYP1A1 polymorphism modifies the risk. PMID- 23816457 TI - Cognitive impairment and antiphospholipid syndrome: is paradoxical embolism the rule? AB - OBJECTIVE: Although cognitive decline (CD) is described in antiphospholipid syndrome (APS), its physiopathology is unknown. Paradoxical embolization (PE) is related to CD in Alzheimer disease. The objective of this study was to determine whether PE plays a role in CD in APS patients through a significant right-to-left shunt (sRLS). METHODS: A total of 27 patients diagnosed with APS without a history of stroke were tested for the presence of an sRLS using a contrast enhanced transcranial Doppler (cTCD) ultrasound. Cognitive decline was assessed using the mini mental state examination (MMSE), the Montreal cognitive assessment (MoCA), and a battery of neuropsychological tests. RESULTS: Of the 27 patients, 19 (70%) had a non-sRLS condition (<= 10 high-intensity transient signs [HITS] on cTCD), and 8 (30%) had an sRLS. Patients with more than 10 years of scholarship performed significantly better on both the MMSE (P = 0.048) and MoCA (P = 0.03). Individuals of the non-sRLS group with more than 10 years of scholarship had better performances on the five-point test (FPT) when compared with the sRLS group (P = 0.01). CONCLUSIONS: Patients without sRLS and with more years of education exhibited a better performance in cognitive tests than sRLS patients. PMID- 23816458 TI - Ghrelin and its interactions with growth hormone, leptin and orexins: implications for the sleep-wake cycle and metabolism. AB - Several studies have shown that ghrelin administration promotes wakefulness in rodents, while in human males it induces sleep but has no effect in women. Ghrelin also plays an important role in metabolism and appetite regulation, and as described in this review may participate in the energy balance during sleep. In this review, we summarize some of the effects induced by ghrelin administration on the sleep-wake cycle in relation to the effects of other hormones, such as growth hormone, leptin, and orexin. Finally we discuss the relationship between sleep deprivation, obesity and ghrelin secretion pattern. PMID- 23816459 TI - 3D brain tumor segmentation in multimodal MR images based on learning population- and patient-specific feature sets. AB - Brain tumor segmentation is a clinical requirement for brain tumor diagnosis and radiotherapy planning. Automating this process is a challenging task due to the high diversity in appearance of tumor tissue among different patients and the ambiguous boundaries of lesions. In this paper, we propose a method to construct a graph by learning the population- and patient-specific feature sets of multimodal magnetic resonance (MR) images and by utilizing the graph-cut to achieve a final segmentation. The probabilities of each pixel that belongs to the foreground (tumor) and the background are estimated by global and custom classifiers that are trained through learning population- and patient-specific feature sets, respectively. The proposed method is evaluated using 23 glioma image sequences, and the segmentation results are compared with other approaches. The encouraging evaluation results obtained, i.e., DSC (84.5%), Jaccard (74.1%), sensitivity (87.2%), and specificity (83.1%), show that the proposed method can effectively make use of both population- and patient-specific information. PMID- 23816460 TI - Low-dose computed tomography via spatially adaptive Monte-Carlo reconstruction. AB - Low-dose computed tomography (CT) reduces radiation exposure but decreases signal to-noise ratio (SNR) and diagnostic capabilities. Noise compensation can improve SNR so low-dose CT can provide valuable information for diagnosis without risking patient radiation exposure. In this study, a novel noise-compensated CT reconstruction method that uses spatially adaptive Monte-Carlo sampling to produce noise-compensated reconstructions is investigated. By adapting to local noise statistics, a non-parametric estimation of the noise-free image is computed that successfully handles non-stationary noise found in low-dose CT images. Using phantom and real low-dose CT images, effective noise suppression is shown to be accomplished while maintaining structures and details. PMID- 23816461 TI - DNA damage and oxidative stress modulatory effects of glyphosate-based herbicide in freshwater fish, Channa punctatus. AB - The present study was undertaken to evaluate the genotoxic and oxidative stress modulatory effects of commercial formulation of glyphosate-based herbicide (Roundup((r))) in freshwater fish Channa punctatus. Three sublethal test concentrations of the herbicide viz., SL-I (1/10th of LC50=~3.25mgL(-1)), SL-II (1/8th of LC50=~4.07mgL(-1)) and SL-III (1/5th of LC50=~6.51mgL(-1)) were calculated using 96-LC50 value and the test specimens were exposed to these concentrations. Blood and gill cells of the exposed specimens were sampled on day 1, 7, 14, 21, 28 and 35 to examine the DNA damage using comet assay and to assess the alteration in lipid peroxidation and antioxidant enzymes activities. The highest DNA damage was observed on day 14 at all test concentrations followed by gradual non-linear decline. Induction of oxidative stress in the blood and gill cells were evidenced by increased lipid peroxidation level, while antioxidants namely superoxide dismutase, catalase and glutathione reductase responded in a concentration-dependent manner. The results supported the integrated use of comet and antioxidant assays in determining the toxicity of water pollutants which could be used as part of monitoring programs. PMID- 23816462 TI - How gravity and muscle action control mediolateral center of mass excursion during slow walking: a simulation study. AB - Maintaining mediolateral (ML) balance is very important to prevent falling during walking, especially at very slow speeds. The effect of walking speed on support and propulsion of the center of mass (COM) has been focus of previous studies. However, the influence of speed on ML COM control and the associated coupling with sagittal plane control remains unclear. Simulations of walking at very slow and normal speeds were generated for twelve healthy subjects. Our results show that gluteus medius (GMED) contributions to ML stability decrease, while its contributions to sagittal plane accelerations increase during very slow compared to normal walking. Simultaneously the destabilizing influence of gravity increases in ML direction at a very slow walking speed. This emphasizes the need for a tight balance between gravity and gluteus medius action to ensure ML stability. When walking speed increases, GMED has a unique role in controlling ML acceleration and therefore stabilizing ML COM excursion. Contributions of other muscles decrease in all directions during very slow speed. Increased contributions of these muscles are therefore required to provide for both stability and propulsion when walking speed increases. PMID- 23816463 TI - Prevalence and etiology of onychomycosis in the HIV-infected Mexican population. AB - Onychomycosis is a fungal infection of the nail caused by dermatophytes, yeasts, and non-dermatophyte molds. Human immunodeficiency virus (HIV)-infected patients are predisposed to this infection. In a cross-sectional study, we estimated the prevalence of onychomycosis and the frequency of fungal agents among HIV-infected patients in Mexico. We enrolled HIV-infected patients diagnosed clinically with onychomycosis from 2008 to 2010. Samples were collected from 300 (84% men) HIV positive patients by scraping of subungual hyperkeratotic debris and nail plate clipping. All specimens were subjected to culture on Sabouraud agar, MycoselTM agar, direct microscopy with potassium hydroxide (KOH) and the cultures were incubated at 35 degrees C for 4 weeks. The prevalence and the 95% binomial confidence intervals were calculated. The mean age (+/- SD) was 37 +/- 9 years. One hundred and twenty-four patients (41%) had clinical signs of onychomycosis and 51 (17%) produced a positive culture. Candida parapsilosis was the most frequently isolated microorganism (13 patients, 20%), followed by Trichophyton rubrum (11 patients, 17%). PMID- 23816464 TI - Central insulin-angiotensin II interaction in blood pressure regulation in fructose overloaded rats. AB - The aim of the present study was to determine if insulin is able to modulate the pressor response to intracerebroventricularly administered angiotensin II in insulin resistant fructose overloaded rats. Male Sprague-Dawley rats were divided into two groups: 1) Control group (C) with tap water to drink for 6 weeks (n=36); and 2) fructose treated (F), with fructose solution (10% w/v) to drink for 6 weeks (n=36). On the day of the experiment, anesthetized male C and F rats were intracerebroventricularly infused with insulin (12 mU/h, n=15) or Ringer's solution as vehicle (n=15) for 2h. Immediately, changes in mean arterial pressure (MAP) in response to an intracerebroventricular subpressor dose of angiotensin II (5 pmol, n=10) or vehicle (n=5) were measured for 10 min. Then, hypothalami were removed and Akt and ERK1/2 phosphorylation levels were determined. In a subset of C (n=10) and F (n=20) animals, PD98059 (p44/42 MAPK inhibitor) or vehicle was administered intracerebroventricularly at a flow rate of 5 MUl/min for 1 min. Ten minutes later, insulin (12 mU/h, n=5 for each group) or vehicle (Ringer's solution, only in the F group, n=5) was perfused for 2h at a flow rate of 4 MUl/h, and cardiovascular parameters were measured every 15 min. Immediately, changes in MAP and HR in response to a subpressor dose of Ang II (5 pmol/2 MUl) were evaluated for 10 min (n=5 for each group). In other subset of animals (n=6 for each group), AT1 and AT2 hypothalamic receptor levels were measured by Western blotting. Intracerebroventricular insulin pre-treatment increased the pressor response to angiotensin II in C rats. In F rats (with or without insulin pretreatment), the pressor response to angiotensin II was higher than that in vehicle pre-treated C animals, but similar to that observed in C after insulin infusion. In C rats phospho-ERK 1/2 hypothalamic levels significantly increased after angiotensin II injection in insulin pretreated animals compared to vehicle pre-treated rats, suggesting that MAPK activation might be involved in insulin potentiation of blood pressure response to angiotensin II in the brain. Phospho ERK 1/2 hypothalamic levels were significantly increased in vehicle treated F rats compared to C, suggesting that basal MAPK activation might play a role in the enhanced response to angiotensin II observed in these animals. Finally, in F rats, either after vehicle or insulin infusion, angiotensin II injection was associated with a similar increase in phospho-ERK 1/2 hypothalamic levels, comparable to that observed after angiotensin II injection in insulin pre-treated C animals. ERK 1/2 blockade significantly reduced MAP in F rats compared to C. Moreover, ERK 1/2 inhibition completely abolished the Ang II pressor response in F rats and in insulin pre-treated C animals. All these findings suggest that insulin-angiotensin II interaction at hypothalamic level might be involved in the increase in blood pressure observed in the insulin resistant state. PMID- 23816465 TI - Leptin modulates enteric neurotransmission in the rat proximal colon: an in vitro study. AB - Leptin has been shown to modulate gastrointestinal functions including nutrient absorption, growth, and inflammation and to display complex effects on gut motility. Leptin receptors have also been identified within the enteric nervous system (ENS), which plays a crucial role in digestive functions. Although leptin has recently been shown to activate neurons in the ENS, the precise mechanisms involved are so far unknown. Therefore, the aim of the present study was to determine the effects of leptin on rat proximal colon smooth muscle and enteric neuron activities. The effects of exogenous leptin on tone and on responses to transmural nerve stimulation (TNS) of isolated circular smooth muscle of proximal colon in rats were investigated using an organ bath technique. The effects of a physiological concentration (0.1 MUM) of leptin were also studied on tone and TNS induced relaxation in the presence of atropine, hexamethonium, L-N(G) nitroarginine methyl ester (L-NAME) and capsazepine. Leptin caused a slight but significant decrease in tone, TNS-induced relaxation and contraction in a concentration-dependent manner in colonic preparations. Cholinergic antagonists abolished the effects of 0.1 MUM leptin on TNS-induced relaxation. This concentration of leptin had no further effect on relaxation in the presence of L NAME. In the presence of capsazepine, leptin had no further effect either on tone or relaxation compared to the drug alone. In conclusion, leptin modulates the activity of enteric inhibitory and excitatory neurons in proximal colon. These effects may be mediated through nitrergic neurons. Intrinsic primary afferent neurons may be involved. PMID- 23816466 TI - Increased thymosin beta4 levels in the serum and SF of knee osteoarthritis patients correlate with disease severity. AB - OBJECTIVE: Thymosin beta4, a member of a large family of thymic proteins, plays an important role in the process of articular cartilage degeneration which is a common cause of osteoarthritis (OA). This study aims to determine thymosin beta4 levels in the serum and synovial fluid (SF) of patients with knee OA and analyze the correlation of thymosin beta4 levels with the radiographic severity of OA. METHODS: This study consisted of 216 patients with knee OA and 152 healthy controls. OA progression was classified based on Kellgren-Lawrence by evaluating x-ray changes observed in anteroposterior knee radiography. Thymosin beta4 levels in the serum and SF were measured by enzyme-linked immunosorbent assay method. RESULTS: The knee OA patients had higher levels of serum thymosin beta4 than the healthy controls. Knee OA patients with KL grade 4 showed significantly elevated thymosin beta4 levels in the serum and SF compared with those with KL grades 2 and 3. Knee OA patients with KL grade 3 had significantly higher SF levels of thymosin beta4 than those with KL grade 2. Thymosin beta4 levels in the serum and SF of knee OA patients were significantly correlated with disease severity according to KL grading criteria. CONCLUSION: The thymosin beta4 levels in the serum and SF may serve as effective biomarkers for the severity of OA. PMID- 23816467 TI - Effect of short- and long-term physical activities on circulating granin protein levels. AB - BACKGROUND: The classic chromogranin-secretogranin (granin) proteins are produced in the myocardium and throughout the neuroendocrine system, but while chromogranin (Cg) A and B levels are high in the adrenal medulla, secretogranin (Sg) II production is higher in the pituitary gland. Whether these differences may influence the response to physical activity is not known. METHODS: We measured circulating granin proteins during (1) a short-term maximal bicycle exercise stress test and (2) a 7 day military ranger course of continuous physical activity and sleep and energy deprivation. RESULTS: In 9 healthy subjects performing the exercise stress test (7 male, age 45+/-5 y [mean+/-SEM], duration 10.13+/-1.14 min), CgB levels increased from before to immediately after the test: 1.20+/-0.12 vs. 1.45+/-0.09 nmol/L, p=0.013. Metabolic equivalents, representing an index of performed work, were closely associated with the change (?) in CgB levels during stress testing and explained 74% of the variability in ?CgB levels (p=0.004). CgA and SgII levels were not increased after exercise stress testing. In the second cohort of 8 male subjects (age 25+/-1 y) participating in the ranger course, CgB levels increased from day 1 and were significantly elevated on days 5 and 7. CgA also increased gradually with levels significantly elevated on day 7, while SgII was markedly increased on day 5 whereas levels on days 3 and 7 were unchanged compared to baseline levels. CONCLUSION: We demonstrate a heterogeneous response to short- and long-term physical activities among circulating granin proteins with the most potent effect on CgB levels. PMID- 23816468 TI - Angiotensin-converting enzyme 2 attenuates oxidative stress and VSMC proliferation via the JAK2/STAT3/SOCS3 and profilin-1/MAPK signaling pathways. AB - Angiotensin (Ang) II plays a vital role in vascular smooth muscle cell (VSMC) growth and proliferation. Angiotensin-converting enzyme 2 (ACE2) is a specific Ang II-degrading enzyme but its role in VSMC proliferation remains largely unknown. We hypothesized that ACE2 might suppress Ang II-mediated oxidative stress and VSMC proliferation. Human umbilical artery smooth muscle cells (HUASMCs) were pretreated with Ang II (100nM) for 6h and 24h, respectively. Exposure to Ang II resulted in significant increases in suppressor of cytokine signaling 3 (SOCS3) expression and phosphorylation levels of JAK2, STAT3 and ERK1/2 linked with elevated superoxide production and cell proliferation in HUASMCs. These changes were strikingly prevented by administration of ERK1/2 inhibitor PD98059 (10MUM) and JAK/STAT inhibitor WP1066 (5 MUM) but were largely aggravated by ACE2 inhibitor DX600 (0.5 MUM). More importantly, treatment with human recombinant ACE2 (hrACE2; 1mg/ml) dramatically prevented Ang II-mediated SOCS3 expression and the JAK2-STAT3 and ERK1/2 signaling, and resulted in attenuation of superoxide production and cell proliferation in HUASMCs. Intriguingly, downregulation of profilin-1 with profilin-1 siRNA (50 nM) was able to abolish Ang II-induced upregulations of profilin-1 expression, ERK1/2 phosphorylation and superoxide production with attenuation of VSMC proliferation. In conclusion, treatment with hrACE2 prevents Ang II-mediated activation of the JAK2/STAT3/SOCS3 and profilin-1/MAPK signaling pathways, contributing to attenuation of superoxide generation and cell proliferation in HUASMCs, suggesting a protective mechanism of ACE2 against Ang II-mediated oxidative stress and VSMC proliferation. ACE2 may represent a potential candidate to prevent and treat vascular disorders. PMID- 23816469 TI - Plasminogen activator inhibitor (PAI)-1 suppresses inhibition of gastric emptying by cholecystokinin (CCK) in mice. AB - The intestinal hormone cholecystokinin (CCK) delays gastric emptying and inhibits food intake by actions on vagal afferent neurons. Recent studies suggest plasminogen activator inhibitor (PAI)-1 suppresses the effect of CCK on food intake. In this study we asked whether PAI-1 also modulated CCK effects on gastric emptying. Five minute gastric emptying of liquid test meals was studied in conscious wild type mice (C57BL/6) and in transgenic mice over-expressing PAI 1 in gastric parietal cells (PAI-1H/Kbeta mice), or null for PAI-1. The effects of exogenous PAI-1 and CCK8s on gastric emptying were studied after ip administration. Intragastric peptone delayed gastric emptying in C57BL/6 mice by a mechanism sensitive to the CCK-1 receptor antagonist lorglumide. Peptone did not delay gastric emptying in PAI-1-H/Kbeta mice. Exogenous CCK delayed gastric emptying of a control test meal in C57BL/6 mice and this was attenuated by administration of PAI-1; exogenous CCK had no effect on emptying in PAI-1-H/Kbeta mice. Prior administration of gastrin to increase gastric PAI-1 inhibited CCK dependent effects on gastric emptying in C57BL/6 mice but not in PAI-1 null mice. Thus, both endogenous and exogenous PAI-1 inhibit the effects of CCK (whether exogenous or endogenous) on gastric emptying. The data are compatible with emerging evidence that gastric PAI-1 modulates vagal effects of CCK. PMID- 23816470 TI - Alpha-calcitonin gene-related peptide is protective against pressure overload induced heart failure. AB - The sensory neuropeptide, alpha-calcitonin gene-related peptide (alpha-CGRP) is protective against hypertension-induced heart damage and cardiac ischemia/reperfusion injury. To determine whether this neuropeptide is also cardioprotective in heart failure, this study examined whether the absence of alpha-CGRP exacerbated the adverse cardiac remodeling, dysfunction and mortality in pressure overload heart failure induced by transverse aortic constriction (TAC). Male alpha-CGRP knockout (KO) and wild type (WT) mice had TAC or sham surgery at day 0 and were studied on days 3, 14, 21, and 28. The survival rate of TAC alpha-CGRP KO mice was lower than the TAC WT mice over the duration of the protocol. Left ventricular alpha-CGRP content in TAC WT mice was higher at days 3, 14, and 21 than sham WT mice. Echocardiography demonstrated greater adverse cardiac remodeling and dysfunction in the TAC alpha-CGRP KO compared to the TAC WT mice. The lung/body weight ratios and left ventricular masses were higher in TAC alpha-CGRP KO compared to the TAC WT mice. While there was increased cardiac fibrosis in the TAC WT mice compared to shams, the TAC alpha-CGRP KO mice had markedly increased fibrosis above that of the TAC WT mice. TAC WT mice had greater cardiac inflammation, cell death, and adaptive angiogenesis compared to sham mice. Importantly, the TAC alpha-CGRP KO mice had greater inflammation, cell death, and attenuation of angiogenesis compared to TAC WT hearts. Thus, alpha CGRP plays a significant protective role in TAC-induced heart failure which may be mediated by decreased inflammation, cell death, and fibrosis. PMID- 23816471 TI - Beta-arrestin2 is involved in the increase of distal colonic contraction in diabetic rats. AB - Colonic dysmotility occurs in diabetes and the patients exhibit diarrhea or constipation. The pathogenetic mechanisms underlying colonic dysmotility in diabetic patients remain poorly understood. The effects of beta-arrestin2 on colonic contraction in diabetic rats were investigated for the first time. Male SD rats were treated with a single intraperitoneally injected dose of streptozotocin, and those displaying sustained high blood glucose were selected as diabetes mellitus models. Longitudinal muscle strips of the distal colon were prepared to monitor contraction of the colon in vitro. Expression of beta arrestin2 was investigated by Western blot analysis. Anti-beta-arrestin2 antibody had no direct effect on the contraction of distal colonic strips in both normal and diabetic rats. Carbachol-induced contractions of distal colonic strips were higher in diabetic rats than in normal rats. Anti-beta-arrestin2 antibody partly blocked carbachol-induced increases of distal colonic strips in diabetic rats. The expression level of beta-arrestin2 protein in the colon was higher in diabetic rats than in normal rats. These results suggest that beta-arrestin2 is involved in the increase of distal colonic contraction in diabetic rats. PMID- 23816472 TI - Perceived drinking norms among black college students: the race of reference group members. AB - Social norms have been consistently shown to influence alcohol use among college students. Much of the research in this area is focused on mostly White samples. This study sought to expand our understanding of social norms theory by examining perceptions of normative alcohol use among Black students and determining the impact of the race of reference group members on personal alcohol use. Participants (N=130; 73.8% female) completed an online questionnaire. Results of repeated measures of analysis of variance indicated that participants perceived all referent groups (i.e., White, same race, typical student) as drinking significantly more than they did. Results of hierarchical regression analysis indicated that perceptions of typical student drinking significantly predicted personal alcohol use. Implications for practice and research are discussed. PMID- 23816474 TI - Will nanomedicine deliver on its promise of changing therapeutics or remain an interesting and important research tool in cell biology and physiology? PMID- 23816473 TI - Smoking in European adolescents: relation between media influences, family affluence, and migration background. AB - Seeing smoking depictions in movies has been identified as a determinant of smoking in adolescents. Little is known about how such media influences interact with other social risk factors. Differences in smoking rates in different socio economic status groups might be explainable by differences in media exposure. There might also be differences in the average response to movie smoking exposure. We tested this hypothesis within a cross-national study conducted in six European countries. A total of 16,551 pupils from Germany, Iceland, Italy, Netherlands, Poland, and Scotland with a mean age of 13.4years (SD=1.18) were recruited from 114 state funded schools. Using previously validated methods, exposure to smoking depictions in movies was estimated for each student and related to ever smoking. The analysis was stratified by level of family affluence (low, medium, high) and migration history of parents (yes vs. no), controlling for a number of covariates like age, gender, school performance, television screen time, sensation seeking and rebelliousness and smoking within the social environment (peers, parents, siblings). We found a significant association for each category of family affluence and ethnicity between ever smoking and movie smoking exposure, also significant adjusted odds ratios for age, school performance, sensation seeking, peer smoking, mother smoking, and sibling smoking. This relationship between movie smoking and adolescent smoking was not moderated by family affluence or ethnicity. Although we used a very broad measure of economic status and migration history, the results suggest that the effects of exposure to movie smoking can be generalized to the population of youths across European countries. PMID- 23816475 TI - Clinical outcomes and mortality in peritoneal dialysis patients: a 10-year retrospective analysis in a single center. AB - AIM: To evaluate the clinical outcome, identify predictors of patient and technique survival in our peritoneal dialysis (PD) patients in the western region of Turkey. METHODS: We included all patients who initiated therapy between 2001 and 2010. Socio-demographic characteristics such as who helped to administer the PD as well as conditions under which PD was chosen by patients were investigated from patients' files. Hemodialysis (HD) history and duration, additional systemic diseases, and end-stage renal disease etiologies of all patients were recorded. Clinical data such as blood pressure, amount of ultrafiltration, and laboratory parameters were evaluated before initiation of PD and during the last monitoring period. Infectious complications and their incidences were investigated. Patient and technique survival were investigated for every patient. RESULTS: 322 patients started PD treatment during the study period. 23 patients were excluded. Data from the remaining 299 patients (167 female, mean follow-up time 38.5 +/- 26.8 months, mean age 44.7 +/- 15.9 years) were evaluated retrospectively. It was determined that 87.3% of the patients made their PD exchanges without help from anyone. 79.9% of patients chose PD as their personal preference. 48 patients had HD history before PD. Peritonitis incidences and catheter exit site/tunnel infection attacks were 27 +/- 23 and 32.3 +/- 24.9 patient-months, respectively. During the follow-up period, 199 patients (80 patients transferred to HD, 78 patients died and, 41 patients had transplantation) were withdrawn from PD. The most frequent causes of death were cardiovascular events and peritonitis and/or sepsis, whereas most frequent causes of transfer to HD were peritonitis and/or sepsis. Mean survival time was 49.9 +/- 2.6 months. The estimation of survival rate was 85.2%, 66.5% and 45.3% at 1, 3, and 5 years, respectively. Preference for PD (RR: 4.77, p < 0.001), presence of HD history (RR: 2.08, p = 0.04), presence of diabetes mellitus (RR: 2.13, p = 0.01), low pretreatment serum albumin (RR: 0.32, p < 0.001), and low serum parathormone levels at last visit (RR: 0.99, p = 0.04) were predictors of mortality. Mean technique survival duration was 48.5 +/- 2.4 months. The estimation of technique survival by Kaplan Meier analyses was 92%, 67% and 43% at 1, 3, and 5 years, respectively. Technique survival was associated with preference for PD (RR: 0.45, p < 0.001), presence of diabetes mellitus (RR: 1.92, p = 0.003), and pretreatment serum albumin levels (RR: 0.58, p = 0.003). CONCLUSION: Patient survival in the presented institute is similar to that reported in Western countries. Compulsory choice of PD, presence of HD history, presence of diabetes, low pretreatment serum albuminm, and low serum parathormone levels at last visit were the strongest predictors of death. Risk factors for technique failure were compulsory choice of PD, presence of diabetes, low pretreatment serum albumin. PMID- 23816476 TI - The role of renal damage on cardiac remodeling in patients with diabetic nephropathy. AB - BACKGROUND: Cardiovascular damage and diabetic nephropathy are major complications in patients with Type 2 diabetic nephropathy (T2DN); however, the role of renal damage on cardiac remodeling is not yet fully known. METHODS: A retrospective research was conducted in 254 T2DN patients. All were divided into three groups according to urinary albumin excretion (UAE): the normoalbuminuria group (UAE < 30 mg/g, n = 18), the microalbuminuria group (UAE 30 - 300 mg/g, n = 99) and the macroalbuminuria group (UAE > 300 mg/g, n = 137). The parameters of cardiac remodeling, left atrial diameter (LAD), left ventricular diameter at the end of diastole (LVDd), interventricular septum (IVS), posterior wall of left ventricle (PWLV) and ejection fraction (EF), were determined by Doppler echocardiography. The effects of renal damage on cardiac remodeling were analyzed. RESULTS: Among the 254 patients, LAD and LVDd enlargement was found in 180 (70.86%) and 53 (20.86%) patients, respectively; 46 cases (18.11%) suffered from both LAD and LVDd enlargement. Compared with normal LAD/LVDd groups, creatinine clearance (Ccr) and hemoglobin (Hb) were significantly lower in the left atrial (LA) and left ventricular (LV) dilated groups. LAD was positively correlated with mesangial sclerosis, tubular-interstitial lesions, interstitial fibrosis, as well as tubular basement membrane thickness (r = 0.273, 0.208, 0.176, 0.155, p < 0.05, respectively). Moreover, in comparison to patients with LA enlargement, more severe renal damage was detected in patients with LV enlargement. CONCLUSION: There is a strong correlation between echocardiographic parameters and kidney lesions in patients with T2DN in China; the more severe the renal damage, the more severe the cardiac structural alteration. Renal damage contributes to cardiac remodeling, which may provide new insights into the pathogenesis of cardiovascular complications ,in diabetes mellitus. PMID- 23816477 TI - Pravastatin and cardiovascular outcomes stratified by baseline eGFR in the lipid- lowering component of ALLHAT. AB - BACKGROUND/AIMS: The role of statins in preventing cardiovascular outcomes in patients with chronic kidney disease (CKD) is unclear. This paper compares cardiovascular outcomes with pravastatin vs. usual care, stratified by baseline estimated glomerular filtration rate (eGFR). METHODS: Post-hoc analyses of a prospective randomized open-label clinical trial; 10,151 participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (lipid-lowering component) were randomized to pravastatin 40 mg/day or usual care. Mean follow-up was 4.8 years. RESULTS: Through Year 6, total cholesterol declined in pravastatin (-20.7%) and usualcare groups (-11.2%). Use of statin therapy in the pravastatin group was 89.8% (Year 2) and 87.0% (Year 6). Usual care group statin use increased from 8.2% (Year 2) to 23.5% (Year 6). By primary intention-to-treat analyses, no significant differences were seen between groups for coronary heart disease (CHD), total mortality or combined cardiovascular disease; findings were consistent across eGFR strata. In exploratory "as-treated" analyses (patients actually using pravastatin vs. not using), pravastatin therapy was associated with lower mortality (HR = 0.76 (0.68 - 0.85), p<0.001) and lover CHD (HR=0.84 (0.73-0.97), p=0.01), but not combined cardiovascular disease (HR=0.95 (0.88-1.04), p=0.30). Total cholesterol reduction of 10 mg/dl from baseline to Year 2 was associated with 5% lower CHD risk. CONCLUSIONS: In hypertensive patients with moderate dyslipidemia, pravastatin was not superior to usual care in preventing total mortality or CHD independent of baseline eGFR level. However, exploratory "as-treated" analyses suggest improved mortality and CHD risk in participants using pravastatin, and decreased CHD events associated with achieved reduction in total cholesterol. Potential benefit from statin therapy may depend on degree of reduction achieved in total and LDL-cholesterol and adherence to therapy. PMID- 23816478 TI - Disseminated adenoviral infection masquerading as lower urinary tract voiding dysfunction in a kidney transplant recipient. AB - Viral infections continue to cause significant morbidity in immunosuppressed kidney transplant patients. Although cytomegalovirus, Epstein-Barr virus and polyoma "BK" virus are more frequently encountered, the Adenovirus can cause multi-organ system infections, and may be difficult to diagnose because it is not often considered in the initial work up in kidney transplant recipients. We present an unusual case of a kidney recipient 1 year post-transplant with disseminated adenoviral infection, who had an initial presentation of lower urinary tract voiding dysfunction with hematuria and sterile pyuria. This progressed to a severe tubulointerstitial nephritis and acute kidney injury that improved with reduction of immunosuppression. Serial blood viral loads are useful for monitoring the course of infection. Urinary adenoviral infection should be considered in the differential diagnosis whenever a kidney transplant recipient presents with unexplained lower tract voiding dysfunction, hematuria, and sterile pyuria. The allograft kidney and bladder can be targets of viral proliferation. Early diagnosis with reduction of immunosuppressive therapy is essential to clear the virus and maintain allograft function. PMID- 23816479 TI - Hourly oral sodium chloride for the rapid and predictable treatment of hyponatremia. AB - Hypertonic NaCl is first-line therapy for acute, severe and symptomatic hyponatremia; however, its use is often restricted to the intensive care unit (ICU). A 35-year-old female inpatient with an optic chiasm glioma and ventriculoperitoneal shunt for hydrocephalus developed acute hyponatremia (sodium 122 mEq/l) perhaps coinciding with haloperidol treatment. The sum of her urinary sodium and potassium concentrations was markedly hypertonic vis-a-vis plasma; it was inferred that serum sodium concentration would continue to fall even in the complete absence of fluid intake. Intravenous (i.v.) 3% NaCl was recommended; however, a city-wide public health emergency precluded her transfer to the ICU. She was treated with hourly oral NaCl tablets in a dose calculated to deliver the equivalent of 0.5 ml/kg/h of 3% NaCl with an objective of increasing the serum sodium concentration by 6 mEq/l. She experienced a graded and predictable increase in serum sodium concentration. A slight overshoot to 129 mEq/l was rapidly corrected with 0.25 l of D5W, and she stabilized at 127 mEq/l. We conclude that hourly oral NaCl, in conjunction with careful monitoring of the serum sodium concentration, may provide an attractive alternative to i.v. 3% NaCl for selected patients with severe hyponatremia. PMID- 23816480 TI - Intramuscular fat in the longissimus muscle is reduced in lambs from sires selected for leanness. AB - Selection for lean growth through Australian Sheep Breeding Values (ASBVs) for post weaning weight (PWWT), eye muscle depth (PEMD) and c-site fat depth (PFAT) raises concerns regarding declining intramuscular fat (IMF) levels. Reducing PFAT decreased IMF by 0.84% for Terminal sired lambs. PEMD decreased IMF by 0.18% across all sire types. Female lambs had higher IMF levels and this was unexplained by total carcass fatness. The negative phenotypic association between measures of muscling (shortloin muscle weight, eye muscle area) and IMF, and positive association between fatness and IMF, was consistent with other literature. Hot carcass weight increased IMF by 2.08% between 12 and 40 kg, reflective of development of IMF as lambs approach maturity. Selection objectives with low PFAT sires will reduce IMF, however the lower impact of PEMD and absence of a PWWT effect, will enable continued selection for lean growth without influencing IMF. Alternatively, the negative impact of PFAT could be off-set by inclusion of an IMF ASBV. PMID- 23816481 TI - Mentoring student nurses and the educational use of self: a hermeneutic phenomenological study. AB - BACKGROUND: In the United Kingdom, pre-registration nurse education relies on workplace mentors to support and assess practice learning. Despite research to clarify expectations and develop support structures, mentors nevertheless report being overwhelmed by the responsibility of mentoring alongside their clinical work. Understanding of their lived experience appears limited. OBJECTIVES: The aim of the study was to achieve a deeper understanding of the lived experience of mentoring, searching for insights into how mentors can be better prepared and supported. DESIGN: The mentor lifeworld was explored utilizing a hermeneutic phenomenological methodology drawing on Heidegger. SETTINGS AND PARTICIPANTS: Twelve mentors, who worked in a range of clinical settings in England were recruited via purposive and snowball sampling. METHOD: Participants described their experiences of mentoring through in-depth interviews and event diaries which included 'rich pictures'. Analysis involved the application of four lifeworld existentials proposed by van Manen - temporality, spatiality, corporeality and relationality. FINDINGS: The essence of being a mentor was 'the educational use of self'. Temporality featured in the past self and moving with daily/work rhythms. Spatiality evoked issues of proximity and accountability and the inner and outer spaces of patients' bodies. Mentor corporeality revealed using the body for teaching, and mentors revealed their relationality in providing a 'good educational experience' and sustaining their 'educational selves'. CONCLUSIONS: 'The educational use of self' offers insight into the lived experience of mentors, and exposes the potentially hidden elements of mentoring experience, which can inform mentor preparation and support. PMID- 23816482 TI - Skin test reactivity to female sex hormones in women with primary unexplained recurrent pregnancy loss. AB - The objective was to examine the hypothesis that primary unexplained recurrent pregnancy loss might be associated with an inappropriate immunologically mediated response to progesterone and/or estrogen. This prospective study included 47 women with two or more documented consecutive early pregnancy losses of unknown etiology, and no previous history of deliveries. Intradermal skin testing was performed in the luteal phase of the cycle (days 16-20) using estradiol benzoate, progesterone, and a placebo of refined sesame oil. Immediate (20 min) and late (24h and 1 week) skin test readings for all cases were compared with those of 12 parous women of comparable age with no history of spontaneous miscarriages, premenstrual disorders, pregnancy, or sex hormone-related allergic or autoimmune diseases. Main outcome measure was skin test reactivity to estradiol and/or progesterone. Immediate skin test reactivity to both hormones was observed among half of the cases at 20 min. A papule after 24h, which persisted for up to 1 week, was observed among 32 (68.1%) and 34 (72.3%) cases at the sites of estrogen and progesterone injection, respectively. 55.3% of cases had combined skin test reactivity to both estradiol and progesterone at 1 week. All women in the control group showed absence of skin test reactivity for both estradiol and progesterone at 20 min, 24h, and 1 week. None of the subjects in either group showed skin test reactivity to placebo. There is an association between primary unexplained recurrent pregnancy loss and skin test reactivity to female sex hormones. PMID- 23816483 TI - Overriding role of parent over daughter vessel dimension in size ratio detection performance of bifurcation aneurysms ruptured status. AB - OBJECTIVE: Aneurysm-to-vessel size ratio (SR) predicts rupture status based on the premise that large aneurysms on small vessels are more likely to rupture compared to small aneurysms on larger vessels. While simpler for sidewall-type (function of proximal vessel [PV] only), SR methodology for bifurcation aneurysms requires the overhead of daughter vessels measurement. This study sets to evaluate SR performance on bifurcation aneurysms, and determine the added value of including daughters' measurements. METHODS: Catheter 3D-rotational angiograms of 154 bifurcation aneurysms (54 ruptured) were available. Aneurysms were evaluated for height (H) and maximal size (Dmax). Vessel size was evaluated as PV, daughter vessels average (DV), and parent and daughter vessels average (PDV). First, SR was evaluated as SR1(PDV) = H/PDV and SR2(PDV) = Dmax/PDV. Second, SR function of the parent vessel only was evaluated as SR1(PV) = H/PV and SR2(PV) = Dmax/PV. Statistical significance was assumed for P < 0.05. Area under the curve (AUC) was evaluated. RESULTS: Unexpectedly, parent vessel only definitions, SR1(PV) (P < 0.001, AUC = 0.69) and SR2(PV) (P = 0.002, AUC = 0.64), performed marginally better as rupture status discriminators compared to the corresponding parent and daughter vessels definitions, SR1(PDV) (P = 0.001, AUC = 0.67) and SR2(PDV) (P = 0.01, AUC = 0.63), respectively. Parameters including daughter vessel measurements (DV, PDV, DV/PV) were not significant. CONCLUSION: Not only is the inclusion of daughter measurements not statistically justified, it may be detrimental to SR performance. Parent-only SR definitions simplify the aneurysmal morphological evaluation at no performance loss. It is reasonable to employ a unified approach regardless of sidewall/bifurcation labeling, by defining SR as aneurysm size to parent vessel ratio and omitting the measurements of the daughter branches. PMID- 23816484 TI - Enhanced NIR downconversion luminescence by precipitating nano Ca5(PO4)3F crystals in Eu2+-Yb3+ co-doped glass. AB - Eu(2+)-Yb(3+) co-doped transparent glass-ceramic containing nano-Ca5(PO4)3F (FAP) was prepared in reducing atmosphere. XRD and TEM analysis indicated that nano-FAP about 40 nm precipitated homogeneously in glass matrix after heat treatment. Confirmed by spectroscopy measurements, the crystal-like absorption and emission of Eu(2+) indicated the partition of Eu(2+) into FAP nanocrystals in glass ceramic. NIR emission due to the transition (2)F5/2->(2)F7/2 of Yb(3+) ions (about 980-1100 nm) was observed from glasses under ultraviolet excitation, ascribed to downconversion from Eu(2+) to Yb(3+), which can be enhanced by precipitating nano-FAP crystals. The results indicated that Eu(2+)-Yb(3+) co doped glass-ceramic embedding with nano-FAP is a promising candidate as downconversion materials for enhancing conversion efficiency of solar cells. PMID- 23816485 TI - Chemical composition and binary mixture of human urinary stones using FT-Raman spectroscopy method. AB - In the present study the human urinary stones were observed in their different chemical compositions of calcium oxalate monohydrate, calcium oxalate dihydrate, calcium phosphate, struvite (magnesium ammonium phosphate), uric acid, cystine, oxammite (ammonium oxalate monohydrate), natroxalate (sodium oxalate), glushinkite (magnesium oxalate dihydrate) and moolooite (copper oxalate) were analyzed using Fourier Transform-Raman (FT-Raman) spectroscopy. For the quantitative analysis, various human urinary stone samples are used for ratios calculation of binary mixtures compositions such as COM/COD, HAP/COD, HAP/COD, Uric acid/COM, uric acid/COD and uric acid/HAP. The calibration curve is used for further analysis of binary mixture of human urinary stones. For the binary mixture calculation the various intensities bands at 1462 cm(-1) (I(COM)), 1473 cm(-1) (I(COD)), 961 cm(-1) (I(HAP)) and 1282 cm(-1) (I(UA)) were used. PMID- 23816486 TI - Ultraviolet and infrared absorption spectra of Cr2O3 doped-sodium metaphosphate, lead metaphosphate and zinc metaphosphate glasses and effects of gamma irradiation: a comparative study. AB - The effects of gamma irradiation on spectral properties of Cr2O3-doped phosphate glasses of three varieties, namely sodium metaphosphate, lead metaphosphate and zinc metaphosphate have been investigated. Optical spectra of the undoped samples reveal strong UV absorption bands which are attributed to the presence of trace iron impurities in both the sodium and zinc phosphate glasses while the lead phosphate glass exhibits broad UV near visible bands due to combined absorption of both trace iron impurities and divalent lead ions. The effect of chromium oxide content has been investigated. The three different Cr2O3-doped phosphate glasses reveal spectral visible bands varying in their position and intensity and splitting due to the different field strengths of the Na(+), Pb(2+), Zn(2+) cations, together with the way they are housed in the network and their effects on the polarisability of neighboring oxygens ligands. The effects of gamma irradiation on the optical spectral properties of the various glasses have been compared. The different effects for lead and zinc phosphate are related to the ability of Pb(2+), and Zn(2+) to form additional structural units causing stability of the network towards gamma irradiation. Also, the introduction of the transition metal chromium ions reveals some shielding behavior towards irradiation. Infrared absorption spectra of the three different base phosphate glasses show characteristic vibrations due to various phosphate groups depending on the type of glass and Cr2O3 is observed to slightly affect the IR spectra. Gamma irradiation causes minor variations in some of the intensities of the IR spectra but the main characteristic bands due to phosphate groups remain in their number and position. PMID- 23816487 TI - Functional recovery in lumbar spine surgery: a controlled trial of health behavior change counseling to improve outcomes. AB - In 2001, the Institute of Medicine issued a challenge to the American health care system to improve the quality of care by focusing on six major areas: safety, effectiveness, patient-centeredness, timeliness, efficiency, and equity. The patient-centered model of care directly addresses important limits of surgical care of the lumbar spine, i.e., the lack of effective methods for increasing patient participation and engagement in post-operative follow-up. Recent evidence indicates that post-surgical outcomes are better among those with higher patient activation. We therefore developed an intervention based on the principles of motivational interviewing to increase patient activation: the Functional Recovery in Lumbar Spine Surgery Health Behavior Change Counseling (HBCC) intervention. The HBCC was designed to maximize post-operative engagement and participation in physical therapy and home exercise, to improve functional recovery, and to decrease pain in individuals undergoing elective lumbar spine surgery. From December 2009 through October 2012, 120 participants were recruited and divided into two groups: those receiving (intervention group, 60) and not receiving (control group, 60) the HBCC intervention. The current manuscript provides a detailed description of the theoretical framework and study design of the HBCC and describes the implementation of this health behavior intervention in a university-based spine service. The HBCC provides a model for conducting health behavioral research in a real-world setting. PMID- 23816488 TI - Considerations and lessons learned from designing a motivational interviewing obesity intervention for young people attending dental practices: a study protocol paper. AB - BACKGROUND: With the prevalence of child obesity increasing worldwide, and the consumption of sugar-sweetened beverages identified as a major contributor to obesity in adolescents, there is a need for effective interventions aimed at dietary behaviour change in this group. Primary dental care settings are in an ideal position to influence adolescents' dietary behaviours, yet have been under utilised for this purpose. Motivational Interviewing (MI) has shown promise in influencing other health behaviours. However, there is lack of published methodologies on which to base the design of such interventions, and limited evidence on its effectiveness in influencing dietary change. We undertook a study to test the feasibility of a MI intervention aimed at reducing soft drink consumption in adolescents attending dental surgeries. We present the study design for the development and evaluation of the intervention. METHOD: Ten dental practices in north London were randomised into control or intervention. Adolescent participants in control settings received routine advice and intervention participants received a brief MI intervention. The intervention was designed using comprehensive stakeholder engagement and consisted of 3-4 short MI sessions and a maintenance phase delivered by trained researchers through the use of age-specific resources. Process evaluation was carried out using qualitative and quantitative methods to assess intervention feasibility in a primary dental care setting. DISCUSSION: By focussing on the development and evaluation of the intervention, this paper contributes to the limited available knowledge and identifies methodological considerations for undertaking a MI intervention for dietary change in adolescents in primary dental care settings. PMID- 23816489 TI - Optimizing the scientific yield from a randomized controlled trial (RCT): evaluating two behavioral interventions and assessment reactivity with a single trial. AB - Randomized controlled trials (RCTs) remain the gold standard for evaluating intervention efficacy but are often costly. To optimize their scientific yield, RCTs can be designed to investigate multiple research questions. This paper describes an RCT that used a modified Solomon four-group design to simultaneously evaluate two, theoretically-guided, health promotion interventions as well as assessment reactivity. Recruited participants (N = 1010; 56% male; 69% African American) were randomly assigned to one of four conditions formed by crossing two intervention conditions (i.e., general health promotion vs. sexual risk reduction intervention) with two assessment conditions (i.e., general health vs. sexual health survey). After completing their assigned baseline assessment, participants received the assigned intervention, and returned for follow-ups at 3, 6, 9, and 12 months. In this report, we summarize baseline data, which show high levels of sexual risk behavior; alcohol, marijuana, and tobacco use; and fast food consumption. Sexual risk behaviors and substance use were correlated. Participants reported high satisfaction with both interventions but ratings for the sexual risk reduction intervention were higher. Planned follow-up sessions, and subsequent analyses, will assess changes in health behaviors including sexual risk behaviors. This study design demonstrates one way to optimize the scientific yield of an RCT. PMID- 23816490 TI - Healthy Homes/Healthy Kids: a randomized trial of a pediatric primary care-based obesity prevention intervention for at-risk 5-10 year olds. AB - Pediatric primary care is an important setting in which to address obesity prevention, yet relatively few interventions have been evaluated and even fewer have been shown to be effective. The development and evaluation of cost-effective approaches to obesity prevention that leverage opportunities of direct access to families in the pediatric primary care setting, overcome barriers to implementation in busy practice settings, and facilitate sustained involvement of parents is an important public health priority. The goal of the Healthy Homes/Healthy Kids (HHHK 5-10) randomized controlled trial is to evaluate the efficacy of a relatively low-cost primary care-based obesity prevention intervention aimed at 5 to 10 year old children who are at risk for obesity. Four hundred twenty one parent/child dyads were recruited and randomized to either the obesity prevention arm or a Contact Control condition that focuses on safety and injury prevention. The HHHK 5-10 obesity prevention intervention combines brief counseling with a pediatric primary care provider during routine well child visits and follow-up telephone coaching that supports parents in making home environmental changes to support healthful eating, activity patterns, and body weight. The Contact Control condition combines the same provider counseling with telephone coaching focused on safety and injury prevention messages. This manuscript describes the study design and baseline characteristics of participants enrolled in the HHHK 5-10 trial. PMID- 23816491 TI - Rationale and design of a multicenter randomized clinical trial of extended release gabapentin in provoked vestibulodynia and biological correlates of response. AB - INTRODUCTION: Few randomized controlled trials (RCTs) have been conducted to establish evidence-based management protocols for provoked vestibulodynia (PVD), a chronic vulvar pain condition affecting approximately 14 million women in the U.S. We describe the rationale and design of an NIH funded multicenter clinical trial utilizing an extended release formulation of gabapentin (G-ER), an intervention that preliminary data suggest may be efficacious for this condition. OBJECTIVES: 1) to determine if pain from tampon insertion (primary outcome measure) is lower in PVD patients when treated with G-ER compared to when treated with placebo and 2) to determine if G-ER reduces vulvar mechanical hyperalgesia, vaginal muscle pain to palpation, the number and intensity of somatic tenderpoints, spontaneous and provoked pain to intradermal capsaicin with an accompanying increase in cardiac beat-to-beat variability and to identify mechanistically-based PVD subtypes. Additional outcomes include subject reported intercourse pain and summative 24-hour pain. METHODS: This 16-week, randomized, double-blind, placebo-controlled, crossover study will enroll 120 women 18 years and older who report tenderness localized to the vulvar vestibule, pain with tampon insertion, and, when sexually active, insertional dyspareunia. Electronically entered daily diaries will be used to determine if pain is lower in PVD subjects when treated with G-ER (up to 3000 mg/d) compared to when treated with placebo. Psychophysiological measures will be obtained at baseline and after 2 weeks at the maximum tolerated dose. CONCLUSION: We will conduct the first multicenter RCT to confirm efficacy of an agent that is currently used in clinical practice for treating PVD. PMID- 23816492 TI - Personalized medicine in Alzheimer's disease and depression. AB - Latest research in the mental health field brings new hope to patients and promises to revolutionize the field of psychiatry. Personalized pharmacogenetic tests that aid in diagnosis and treatment choice are now becoming available for clinical practice. Amyloid beta peptide biomarkers in the cerebrospinal fluid of patients with Alzheimer's disease are now available. For the first time, radiologists are able to visualize amyloid plaques specific to Alzheimer's disease in live patients using Positron Emission Tomography-based tests approved by the FDA. A novel blood-based assay has been developed to aid in the diagnosis of depression based on activation of the HPA axis, metabolic, inflammatory and neurochemical pathways. Serotonin reuptake inhibitors have shown increased remission rates in specific ethnic subgroups and Cytochrome P450 gene polymorphisms can predict antidepressant tolerability. The latest research will help to eradicate "trial and error" prescription, ushering in the most personalized medicine to date. Like all major medical breakthroughs, integration of new algorithms and technologies requires sound science and time. But for many mentally ill patients, diagnosis and effective therapy cannot happen fast enough. This review will describe the newest diagnostic tests, treatments and clinical studies for the diagnosis and treatment of Alzheimer's disease and unipolar, major depressive disorder. PMID- 23816494 TI - Initial perceptions of key stakeholders in Ontario regarding independent prescriptive authority for pharmacists. AB - BACKGROUND: A number of jurisdictions, both in Canada and internationally, have recently expanded pharmacists' scope of practice to allow prescriptive authority. OBJECTIVE: To ascertain the initial perceptions of the Ontario government and health professional stakeholder groups regarding the prospect of prescriptive authority for pharmacists. METHODS: Qualitative research methods were used; data sources were policy documents and semi-structured interviews with key informants from the Ontario government and pharmacy and medical professional organizations. Purposive and snowball sampling strategies were used to identify 17 key informants. Fifty-one relevant policy documents were retrieved through searches of organizational websites and interviewee suggestions. Interview transcripts and documents were content analyzed independently by 2 researchers; and once consensus was achieved on key themes, the primary investigator analyzed the remainder. RESULTS: Pharmacy organizations and Ontario government representatives both expressed support for pharmacist prescriptive authority, suggesting that it would enhance patient access to primary care. Medical organizations were opposed to this expanded pharmacist role, arguing that pharmacists' lack of training and experience in diagnosis and prescribing would endanger patient safety. Other concerns were fragmentation of care and pharmacists' lack of access to patient clinical information. Some government and pharmacy informants felt that pharmacist prescribing would decrease health system costs through substitution of cheaper health professionals for physicians, while others felt that costs would increase due to increased utilization of services. Medical organizations preferred delegated medical authority as the policy alternative to pharmacist prescribing. CONCLUSIONS: Widely different views were expressed by the Ontario government and pharmacy organizations on the one hand and medical professional organizations on the other hand, regarding the potential impact of pharmacist prescribing on patient safety and access to primary care. This is likely due, at least in part, to the lack of evidence on the expected impact of this expanded pharmacist role. More research is needed to help inform discussions regarding this issue. PMID- 23816496 TI - Letter of response to correspondence regarding article "Defining professional pharmacy services in community pharmacy". PMID- 23816493 TI - Optimizing PMTCT service delivery in rural North-Central Nigeria: protocol and design for a cluster randomized study. AB - Nigeria has more HIV-infected women who do not receive needed services for the prevention of mother-to-child transmission of HIV (PMTCT) than any other nation in the world. To meet the UNAIDS/WHO goal of eliminating mother-to-child HIV transmission by 2015, multiple interventions will be required to scale up PMTCT services, especially to lower-level, rural health facilities. To address this, we are conducting a cluster-randomized controlled study to evaluate the impact and cost-effectiveness of a novel, family-focused integrated package of PMTCT services. A systematic re-assignment of patient care responsibilities coupled with the adoption of point-of-care CD4 + cell count testing could facilitate the ability of lower-cadre health providers to manage PMTCT care, including the provision and scale-up of antiretroviral therapy (ART) to pregnant women in rural settings. Additionally, as influential community members, male partners could support their partners' uptake of and adherence to PMTCT care. We describe an innovative approach to scaling up PMTCT service provision that incorporates considerations of where and from whom women can access services (task-shifting), ease of obtaining a CD4 + cell count result (point-of-care testing), the degree of HIV service integration for HIV-infected women and their infants, and the level of family and community involvement (specifically male partner involvement). This systematic approach, if proven feasible and effective, could be scaled up in Nigeria and similar resource-limited settings as a means to accelerate progress toward eliminating mother-to-child transmission of HIV and help women with HIV infection take ART and live long, healthy lives (Trial registration: NCT01805752). PMID- 23816495 TI - Using the theory of planned behavior to examine pharmacists' intention to utilize a prescription drug monitoring program database. AB - BACKGROUND: Prescription drug monitoring programs (PDMPs) are state-operated electronic databases that contain patients' controlled drug histories. Most states provide these data to pharmacists via online web portals to combat prescription drug abuse and diversion. OBJECTIVES: The objectives of this study were to: 1) explore the theory of planned behavior's (TPB) utility in predicting Texas pharmacists' intention to utilize an online accessible PDMP; 2) to determine the contribution of each construct, attitude (A), subjective norm (SN) and perceived behavioral control (PBC) in predicting pharmacists' intention; and 3) test whether the addition of perceived obligation (PO) is significantly related to pharmacists' intention. METHODS: A cross-sectional, 36-item questionnaire was developed from focus groups and literature of pharmacists' views regarding prescription drug abuse. A total of 998 practicing Texas community pharmacists were surveyed to collect data on their intention to utilize a PDMP database. Descriptive statistics, multivariate and hierarchical logistic regression analyses were used to address the study objectives. RESULTS: The response rate was 26.2% (261/998). TPB constructs were significant predictors of pharmacists' high intention to utilize the PDMP. Pharmacists with positive attitudes were almost twice as likely to have high intention (odds ratio [OR] = 1.8, 95% confidence interval [CI] = 1.2-2.8). SN was the strongest predictor of pharmacists' high intention (OR = 2.2, 95% CI = 1.4-3.3). Pharmacists with high PBC were also twice as likely to have high intention (OR = 1.9, 95% CI = 1.2 3.0). Additionally, pharmacists' PO contributed to the prediction of high intention (OR = 1.8, 95% CI = 1.0-3.1) above that explained by the TPB model constructs (X(2) = 4.14, P < 0.05). CONCLUSIONS: TPB with the addition of PO was useful in predicting pharmacists' high intention to utilize a PDMP database. Interventions that address pharmacists' A, SN, PBC, and PO may be valuable to increase pharmacists' high intention. Pharmacists' utilization of PDMPs may lead to a decrease in the morbidity and mortality associated with prescription drug abuse. Future studies that assess whether intention to use PDMPs translates to actual usage are needed to strengthen these findings. PMID- 23816497 TI - Biofilm switch and immune response determinants at early stages of infection. AB - Biofilm development is recognized as a major virulence factor underlying most chronic bacterial infections. When a biofilm community is established, planktonic cells growing in the surroundings of a tissue switch to a sessile lifestyle and start producing a biofilm matrix. The initial steps of in vivo biofilm development are poorly characterized and difficult to assess experimentally. A great amount of in vitro evidence has shown that accumulation of high levels of cyclic dinucleotides (c-di-NMPs) is the most prevalent hallmark governing the initiation of biofilm development by bacteria. As mentioned above, recent studies also link detection of c-di-NMPs by host cells with the activation of a type I interferon immune response against bacterial infections. We discuss here c-di-NMP signaling and the host immune response in the context of the initial steps of in vivo biofilm development. PMID- 23816498 TI - Pyoderma gangrenosum and concomitant hidradenitis suppurativa--rapid response to canakinumab (anti-IL-1beta). PMID- 23816499 TI - Antitussive, expectorant and bronchodilating effects of ethanol extract of Sorghum bicolor (L.) Moench roots. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Root of Sorghum bicolor (L.) Moench (RSB) is an herbal medicine in Traditional Chinese Medicine, still used in some rural areas in Central China as an alternative remedy to treat cough and asthma. AIM OF THE STUDY: The study was aimed at evaluating the antitussive, expectorant and bronchodilating effects of ethanol extract of RSB, support its folk use with scientific evidence, and lay a foundation for its further researches. MATERIALS AND METHODS: RSB was extracted with 80% ethanol aqueous in reflux conditions, solutions were concentrated in reduced pressure, and lyophilized in vacuum to yield the RSB extract. Antitussive evaluations were carried out with three different models including ammonia liquor induced mice cough, capsaicin induced mice cough, and citric acid induced guinea pigs cough; phenol red secretion experiments in mice were performed to evaluate the expectorant ability; bronchodilating effects were evaluated with a bronchoconstrictive challenge induced by acetylcholine chloride and histamine in guinea pigs. RESULTS: In all the three antitussive tests, treatment of RSB significantly inhibited the frequency of cough, and prolonged the cough latent period in animals. And high dose of RSB (200mg/kg in mice and 100mg/kg in guinea pigs) created therapeutic activities as good as standard antitussive drug codeine phosphate (20mg/kg). In the expectorant evaluation, 50, 100 and 200mg/kg RSB treatment had significantly increased the amount of phenol red output for 0.39, 1.18, and 1.96 folds in mice tracheas. In the bronchodilating test, RSB treatment at 100mg/kg extended the preconvulsive time for 44.84% compared with that of before treatment in guinea pigs. CONCLUSIONS: RSB is an effective alternative medicine for the treatment of cough with potent antitussive, expectorant and bronchodilating activities. PMID- 23816500 TI - Antimycobacterial activity of Citrullus colocynthis (L.) Schrad. against drug sensitive and drug resistant Mycobacterium tuberculosis and MOTT clinical isolates. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Citrullus colocynthis (Cucurbitaceae), a folk herbal medicine and traditionally used natural remedy for tuberculosis in India has been studied to validate its antitubercular activity against drug sensitive and drug resistant (including multidrug resistant) Mycobacterium tuberculosis and Mycobacterium other than tuberculosis (MOTT) bacilli. MATERIALS AND METHODS: Inhibitory and bactericidal activities of crude extracts, fractions and compounds of Citrullus colocynthis plant, consisting of aerial parts and ripe deseeded fruits were performed against the drug sensitive standard strain of Mycobacterium tuberculosis H37Rv (ATCC 27294), 16 drug resistant strains of Mycobacterium tuberculosis and two MOTT strains, using radiometric BACTEC 460TB system. RESULTS: Methanolic extract of ripe deseeded fruit of Citrullus colocynthis has shown good activity (MIC <= 62.5 ug/ml), whereas among the bioactive fractions, FC IX demonstrated the best activity (MIC 31.2 ug/ml) against Mycobacterium tuberculosis H37Rv. Bioactive FC III, IX and X also inhibited 16 clinical isolates of Mycobacterium tuberculosis consisting of seven non-multidrug resistants, eight multidrug resistants, one extensively drug resistant and two of MOTTs with MICs in the range of 50-125, 31.2-125 and 62.5-125 ug/ml, respectively. Ursolic acid and cucurbitacin E 2-0-beta-d-glucopyranoside were identified as the main biomarkers active against Mycobacterium tuberculosis H37Rv (MICs 50 and 25 ug/ml respectively), as well as against the 18 clinical isolates. FC III and FC IX showed better inhibition of drug resistant and MOTT clinical isolates. Minimal bactericidal concentrations of extracts, fractions and compound C-2 were >= two-fold MIC values. CONCLUSIONS: The study provides a scientific rationale for the traditional use of Citrullus colocynthis fruit in the treatment of tuberculosis. In addition, the study elucidates a broad spectrum antimycobacterial action of Citrullus colocynthis fruit, which can contribute to the development of improved preparation of an antitubercular natural drug for the treatment of drug resistant tuberculosis and MOTT infection as well. PMID- 23816501 TI - Ojeok-san, a traditional Korean herbal medicine attenuates airway inflammation and pulmonary fibrosis induced by repeated ovalbumin challenge. AB - ETHNOPHARMACOLOGICAL EVIDENCE: Ojeok-san, a traditional Korean herbal medicine, is widely used in China, Japan and Korea for treatment of the common cold, pain and fever. AIM OF THE STUDY: In this study, we investigated the protective effects of Ojeok-san aqueous extract (OJS) against pulmonary fibrosis using a chronic asthma murine model. METHODS: Mice were sensitized by intraperitoneal injection of ovalbumin (OVA), followed 1 weeks later by an airway challenge with OVA delivered three times a week for 4 weeks. OJS (50mg/kg or 100mg/kg) was also administered by oral gavage once a day for 4 weeks. RESULTS: OJS significantly reduced interleukin (IL)-4, IL-13, eotaxin, immunoglobulin E and the number of inflammatory cells in bronchoalveolar lavage fluid; in addition, it reduced inflammatory cell infiltration and mucus production in the respiratory tract. We found that OJS also attenuated the OVA-induced increase in vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-beta1 and Smad3 protein in lung tissue, as determined by Western analysis and immunohistochemistry. These inhibitory effects of OJS were accompanied by a reduction in pulmonary fibrosis, consistent with the histopathology of lung tissue stained with Masson's trichrome. CONCLUSION: Administration of OJS reduced the airway inflammation and pulmonary fibrosis, as well as the level of T helper type 2 cytokines and VEGF and TGF-beta1/Smad3 expressions in lung tissue. These results suggest that OJS might represent a useful new oral therapy for the treatment of chronic asthma. PMID- 23816502 TI - Organizational structure, leadership and readiness for change and the implementation of organizational cultural competence in addiction health services. AB - Increasing representation of racial and ethnic minorities in the health care system and on-going concerns about existing health disparities have pressured addiction health services programs to enhance their cultural competence. This study examines the extent to which organizational factors, such as structure, leadership and readiness for change contribute to the implementation of community, policy and staffing domains representing organizational cultural competence. Analysis of a randomly selected sample of 122 organizations located in primarily Latino and African American communities showed that programs with public funding and Medicaid reimbursement were positively associated with implementing policies and procedures, while leadership was associated with staff having greater knowledge of minority communities and developing a diverse workforce. Moreover, program climate was positively associated with staff knowledge of communities and having supportive policies and procedures, while programs with graduate staff and parent organizations were negatively associated with knowledge of and involvement in these communities. By investing in funding, leadership skills and a strategic climate, addiction health services programs may develop greater understanding and responsiveness of the service needs of minority communities. Implications for future research and program planning in an era of health care reform in the United States are discussed. PMID- 23816503 TI - Mesangial immunoglobulin (Ig)A glomerulonephritis in a patient with rheumatoid arthritis treated with abatacept. AB - We report observations of a 47-year-old seropositive woman with rheumatoid arthritis (RA) suffering from mesangial immunoglobulin (Ig)A glomerulonephritis (GN) after initiation of abatacept, a selective T-cell co-stimulation modulator cytotoxic T-lymphocyte antigen 4 (CTLA4)-Ig. She was initially treated by corticosteroids, followed by methotrexate associated with a TNF inhibitor (adalimumab then switched to etanercept), finally switched to abatacept monotherapy, after secondary failure of these two forms of TNF inhibitors. Due to a progressively increased hematuria and proteinuria after abatacept therapy initiation, a renal biopsy was performed highlighting GN with mesangial IgA deposits, with necrosis and extracapillary crescent formations. IgA GN as a possible adverse event to abatacept was considered. Abatacept was stopped and a treatment by corticosteroids was initiated. Proteinuria decreased a couple of months after abatacept interruption. The short term between abatacept induction and IgA GN onset, as well as GN improvement since abatacept discontinuation, lend weight to the argument that CTLA4-Ig may play a crucial role in IgA GN pathogenesis. The possibility of a drug postponed adverse event justifies a long term renal surveillance in RA patients treated by abatacept. PMID- 23816504 TI - DRESS syndrome. AB - Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, initially recognized as a serious form of cutaneous drug adverse reaction, is now viewed as a drug-related syndrome that can cause life-threatening organ dysfunctions. Characteristic features include a long time interval from first drug exposure to symptom onset and a prolonged course, often with flares, even after discontinuation of the causal drug. The pathophysiology of DRESS syndrome remains incompletely understood but involves reactivation of herpes viruses (HHV-6, HHV 7, EBV, and CMV), against which the body mounts a strong immune response. The culprit drugs may not only affect epigenetic control mechanisms, thereby promoting viral reactivation, but also induce an antiviral T-cell response by interacting with the major histocompatibility complex receptor in individuals with genetic susceptibility factors. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome is a potentially life-threatening form of cutaneous drug adverse reaction. The severity of this syndrome is related to the systemic manifestations, which can result in multiorgan failure. DRESS syndrome is characterized by highly specific features, most notably regarding the timing of the manifestations. New insights into the underlying pathophysiological mechanisms indicate a role for immunogenetic susceptibility factors and for reactivation of human herpes viruses (HHVs), chiefly HHV-6. We report a typical case of DRESS syndrome and discuss recent data about this condition. PMID- 23816505 TI - Hyperosmolarity-induced up-regulation of claudin-4 mediated by NADPH oxidase dependent H2O2 production and Sp1/c-Jun cooperation. AB - Claudin-4 is exclusively localized in the tight collecting ducts in the renal tubule. We examined what molecular mechanism is involved in the regulation of claudin-4 expression. In Madin-Darby canine kidney cells, hyperosmolarity increased the expression level of claudin-4 and the production of reactive oxygen species, which were inhibited by diphenyleneiodonium (DPI), an NADPH oxidase inhibitor, and manganese (III) tetrakis (4-benzoic acid)porphyrin (MnTBAP), a scavenger of H2O2. Both hyperosmolarity and H2O2 increased p-ERK1/2 and p-JNK, which were inhibited by U0126, a MEK inhibitor, and SP600125, a JNK inhibitor, respectively. Immunoprecipitation assay showed that hyperosmolarity increased the association of nuclear Sp1 with c-Jun, which was inhibited by U0126 and SP600125. In mouse inner medullary collecting duct cells and rat kidney slices, hyperosmolarity increased the expression level of claudin-4, which was inhibited by DPI, MnTBAP, U0126, and SP600125. Hyperosmolarity increased luciferase reporter activity of claudin-4, which was inhibited by U0126, SP600125, Sp1 siRNA, and c-Jun siRNA. The activity was inhibited by the mutation in the Sp1 binding site. Chromatin immunoprecipitation assay and avidin-biotin conjugated DNA assay showed that Sp1 and c-Jun are associated with the Sp1 binding site. These results suggest that hyperosmolarity increases nuclear Sp1/c-Jun complex and the association of the complex with the Sp1 binding site, resulting in the segment-specific expression of claudin-4 in the kidney. PMID- 23816506 TI - Male mosquitoes make waves in paradise. PMID- 23816507 TI - Antibiotics for human toxoplasmosis: a systematic review of randomized trials. AB - The efficacy of different treatment regimens in clinical syndromes of toxoplasmosis were assessed by conducting a systematic review of published randomized clinical trials through extensive searches in MEDLINE, EMBASE, and SCOPUS with no date limits, as well as manual review of journals. Outcome measures varied depending on the clinical entity of toxoplasmosis. Risk of bias was evaluated and quality of evidence was graded. Fourteen randomized trials were included of which one was a non-comparative study. One well-designed trial showed that trimethoprim-sulphamethoxazole was more effective than placebo for clinical recovery of toxoplasmic lymphadenopathy in immunocompetent hosts. For toxoplasmic encephalopathy, efficacy of pyrimethamine+sulphadiazine and trimethoprim+sulphamethoxazole were similar, whereas pyrimethamine+sulphadiazine versus pyrimathamine+clindamycin showed no difference, irrespective of the outcome. Intravitreal clindamycin+dexamethasone and conventional treatment with oral pyrimethamine+sulphadiazine had similar efficacy with regard to all outcome measures in ocular toxoplasmosis, and intravitreal therapy was found to be safe. Adverse effects seemed more common with pyrimethamine+sulphadiazine. Most trials for encephalitis and ocular manifestations had a high risk of bias and were of poor methodological quality. There were no trials evaluating drugs for toxoplasmosis in pregnancy, or for congenital toxoplasmosis. Pyrimethamine+sulphadiazine is an effective therapy for treatment of toxoplasmic encephalitis; trimethoprim+sulphamethoxazole and pyrimethamine+clindamycin are possible alternatives. Treatment with either oral or intravitreal antibiotics seems reasonable for ocular toxoplasmosis. Overall, trial evidence for the efficacy of these drugs for toxoplasmosis is poor, and further well-designed trials are needed. PMID- 23816509 TI - Development and evaluation of a 28S rRNA gene-based nested PCR assay for P. falciparum and P. vivax. AB - The 28S rRNA gene was amplified and sequenced from P. falciparum and P. vivax isolates collected from northwest India. Based upon the sequence diversity of the Plasmodium 28SrRNA gene in comparison with its human counterpart, various nested polymerase chain reaction (PCR) primers were designed from the 3R region of the 28SrRNA gene and evaluated on field isolates. This is the first report demonstrating the utility of this gene for species-specific diagnosis of malaria for these two species, prevalent in India. The initial evaluation on 363 clinical isolates indicated that, in comparison with microscopy, which showed sensitivity and specificity of 85.39% and 100% respectively, the sensitivity and specificity of the nested PCR assay was found to be 99.08% and 100% respectively. This assay was also successful in detecting mixed infections that are undetected by microscopy. Our results demonstrate the utility of the 28S rRNA gene as a diagnostic target for the detection of the major plasmodial species infecting humans. PMID- 23816510 TI - Prevalence of Toxoplasma gondii infection among individuals with severe mental illness in Nigeria: a case control study. AB - BACKGROUND: While the aetiology for most psychotic disorders is unknown, a strong association has been observed between Toxoplasma gondii infection and psychosis. The proportion of individuals with psychotic disorders who have current or past infection with toxoplasma has been varied. Reports from the African continent have however been scanty. METHODS: A case control study of patients with a psychotic disorder presenting for the first time to a regional psychiatric facility was undertaken and compared to age and sex-matched healthy controls. In addition to socio-demographic and clinical characteristics, seroprevalence (IgG and IgM) of T. gondii was undertaken using an immunoassay test kit. RESULTS: IgG seropositivity was significantly higher among cases (30.7% vs 17.85%, OR = 2.04, 95% CI = 1.12-3.74, P<0.02). In contrast, IgM seropositivity was significantly lower among the cases (7.14% vs 8.57%, OR = 0.82, 95% CI = 0.31-2.16, P = 0.82). Cases who were IgG seropositive to T. gondii were more likely to be older (P<0.001) and female (P<0.001). There was no statistically significant difference in terms of T. gondii infection and, eaten poorly cooked meat (0.88), and diagnostic group (P = 0.53). Though there was a trend towards exposure to cats, this failed to reach significance (P = 0.08). CONCLUSION: T. gondii (IgG) infection is common among individuals with severe mental illness sampled and significantly higher compared to controls. PMID- 23816508 TI - Genetic control of Aedes mosquitoes. AB - Aedes mosquitoes include important vector species such as Aedes aegypti, the major vector of dengue. Genetic control methods are being developed for several of these species, stimulated by an urgent need owing to the poor effectiveness of current methods combined with an increase in chemical pesticide resistance. In this review we discuss the various genetic strategies that have been proposed, their present status, and future prospects. We focus particularly on those methods that are already being tested in the field, including RIDL and Wolbachia based approaches. PMID- 23816511 TI - Cutaneous and post kala-azar dermal leishmaniasis caused by Leishmania infantum in endemic areas of visceral leishmaniasis, northwestern Iran 2002-2011: a case series. AB - Visceral leishmaniasis (VL) is endemic in Northwest and southern Iran. Reports of cutaneous leishmaniasis (CL) in Northwest areas are rare, and its etiological agents are unknown. In the current study, we report six CL and two post kala-azar dermal leishmaniasis (PKDL) cases caused by Leishmania infantum from endemic areas of VL in the Northwest. Smears were made from skin lesions of 30 suspected patients in 2002-2011, and CL was determined by microscopy or culture. Leishmania spp. were identified by nested-PCR assay. The disease was confirmed in 20 out of 30 (66%) suspected patients by parasitological examinations. L. infantum was identified in eight and Leishmania major in 12 CL cases by nested-PCR. Cutaneous leishmaniasis patients infected with L. major had the history of travel to CL endemic areas. L. infantum antibodies were detected by direct agglutination test (DAT) at titers of 1:3200 in two cases with history of VL. Results of this study indicated that L. infantum is a causative agent of CL as well as PKDL in the VL endemic areas. PMID- 23816512 TI - CD4+ T cell subsets and Tax expression in HTLV-1 associated diseases. AB - Human T lymphotropic virus type 1 (HTLV-1) infection displays variable clinical manifestations. These include inflammatory diseases such as HTLV-1 associated myelopathy (HAM) or immunosuppressive conditions such as Strongyloides stercoralis hyperinfection. The viral protein, Tax causes activation and proliferation of T cells. We hypothesize that the expression of Tax in T cell subsets characterizes the clinical manifestations of HTLV-1. To test this hypothesis, we measured T helper 1 effector cells and regulatory T cells (Tregs) among Tax expressing lymphocytes from peripheral blood mononuclear cells (PBMCs) of 32 HTLV-1 infected patients with HAM, with S. stercoralis co-infection or with asymptomatic infection. We observed increased ratios of Th1/Treg among Tax expressing lymphocytes in HAM patients. These data suggest that the expression of Tax among the different target cells may explain the variable presentation of HTLV-1. PMID- 23816513 TI - Efficacy of different albendazole and mebendazole regimens against heavy intensity Trichuris trichiura infections in school children, Jimma Town, Ethiopia. AB - Recent studies have shown that the efficacy of benzimidazole drugs is influenced by the intensity of trichuriasis. Therefore, the objective of this study was to determine the efficacy of albendazole (ALB) and mebendazole (MBZ) administered randomly for 1 (ALB*1 and MBZ*1) or 2 days (ALB*2 and MBZ*2) to 385 school children with heavy-intensity trichuriasis (mean faecal egg counts (FEC) >1000 eggs per gram of stool (epg)) in Jimma Town, Ethiopia. The efficacies (95% confidence intervals) by means of reduction in faecal egg counts (FECs) were 29.3% (-9.9-56.2), 60.0% (48.5-70.9), 73.5% (64.2-81.3), and 87.1% (81.4-91.2) for ALB*1, MBZ*1, ALB*2, and MBZ*2, respectively. These observations highlight that assessment of the anthelmintic efficacy of existing or new compounds against Trichuris trichiura should be assessed under varying levels of infection intensity. PMID- 23816514 TI - Clinical spectrum and treatment outcome of severe malaria caused by Plasmodium vivax in 18 children from northern India. AB - OBJECTIVE: The study was intended to document the clinical profile and treatment outcome of severe malaria caused by Plasmodium vivax (P.vivax) in children hospitalized in a tertiary care centre of northern India. METHODS: This prospective observational study was performed among children admitted with severe malaria at a tertiary care referral hospital of northern India from January 2012 to December 2012. Information was recorded pertaining to clinical symptoms at presentation, examination findings, biochemical and hematological investigation, and treatment outcome. Presence of malarial parasite on thick and thin smears and/or positive parasite lactate dehydrogenase (p-LDH) based rapid malaria antigen test was considered diagnostic of 'malaria'. Based on the etiology, children were categorized into three groups: P.vivax, Plasmodium falciparum (P. falciparum) and mixed infection. Children diagnosed with 'severe malaria' (World Health Organization, 2000), were started on intravenous artesunate followed by artemether-lumefantrine combination. RESULTS: Thirty-five children with a diagnosis of severe malaria were enrolled [18 (51.4%) P. vivax, nine (25.7%) mixed infection, eight (22.8%) P. falciparum]. Clinical features of severe vivax malaria (n = 18) were abnormal sensorium [9 (50%)], multiple seizures [8 (44.4%)], jaundice [5 (27.8%)], severe anaemia [5 (27.8%)], and shock [3 (16.7%)]. Two children [2/18 (11.1%)] infected with P. vivax had died of cerebral malaria, acute respiratory distress syndrome, shock, and metabolic acidosis. The clinical presentation and outcome of severe vivax malaria was found to be similar to severe malaria caused by P. falciparum and mixed infection, except for higher chances of severe anaemia among the children infected with P. falciparum (P = 0.04). CONCLUSION: The present study highlights P. vivax as an increasingly recognized causative agent for severe malaria in children from Rohtak, with similar clinical presentation and outcome to that caused by P. falciparum. PMID- 23816516 TI - Factors affecting dry-cured ham consumer acceptability. AB - The objectives of the present study were (1) to compare the relative importance of price, processing time, texture and intramuscular fat in purchase intention of dry-cured ham through conjoint analysis, (2) to evaluate the effect of dry-cured ham appearance on consumer expectations, and (3) to describe the consumer sensory preferences of dry-cured ham using external preference mapping. Texture and processing time influenced the consumer preferences in conjoint analysis. Red colour intensity, colour uniformity, external fat and white film presence/absence influenced consumer expectations. The consumer disliked hams with bitter and metallic flavour and with excessive saltiness and piquantness. Differences between expected and experienced acceptability were found, which indicates that the visual preference of consumers does not allow them to select a dry-cured ham that satisfies their sensory preferences of flavour and texture. PMID- 23816515 TI - A unique access for the ablation catheter to treat electrical storm in a patient with extracorporeal life support. AB - AIMS: Extracorporeal membrane oxygenation (ECMO) is a very effective bridging therapy in patients with cardiogenic shock. To perform coronary angiography in these patients our group developed an unique system to get urgent vascular access with minimal additional vascular complication risk. The 6 Fr coronary catheters are introduced through a standard Y-connector, which is inserted into the arterial cannula of the ECMO-line close to the patient, the blind end of which is then equipped with a haemostatic valve (Check-Flo Performer accessory adapter, Cook Medical, USA). To the best of our knowledge, we here present the first patient, in whom this system had been used to insert an 8 Fr radiofrequency ablation catheter to treat incessant ventricular fibrillation. METHODS AND RESULTS: A 66-year-old patient had been transferred with electrical storm 5 days after an acute MI. After failed interventional and medical therapies an ECMO system had been inserted (right femoral artery cannula 15 Fr, left femoral vein cannula 21 Fr) and an electrophysiological study had been performed because of incessant ventricular fibrillation episodes, which always were induced by the same ventricular premature beat (VPB). During this first EP study over the left femoral artery the VPB could be targeted and successfully ablated. Unfortunately the VPB recovered again after some days so a second EP study had to be performed. This time the left femoral artery could not be used because of a postinterventional complication so we used the arterial cannula of the ECMO system as the access for the ablation catheter using a Y-connector. Using this way again a successful ablation procedure could be performed, after getting familiar with manipulation the ablation catheter over the ECMO cannula and with the help of different curved ablation catheters. The issue of compromising of the effective lumen of the arterial cannula by the ablation catheter's cross sectional area could be overcome with increasing the rotational speed of the V-A ECMO. CONCLUSION: Ablation of ventricular arrhythmias using a Y-connector to insert the ablation catheter into the arterial cannula is feasible in patients with a V-A ECMO system avoiding additional arterial puncture with potentially major vascular complications in critically ill patients. Manipulation of the catheter is not as easy as using a standard sheath but can well be performed after a short habituation. PMID- 23816517 TI - Childhood trauma and dissociation in first-episode psychosis, chronic schizophrenia and community controls. AB - Increasing evidence supports the role of childhood trauma in the etiology of psychosis but underlying mechanisms are poorly understood. Early maltreatment has been linked to dissociative symptoms in psychosis patients. We explored associations between childhood trauma (Childhood Trauma Questionnaire) and dissociation (Dissociative Experiences Scale) in first-episode psychotic patients (n=62), chronic psychotic patients (n=43), and non-psychotic community controls (n=66). Multivariate analyses of covariance were used to test associations between childhood trauma and dissociation by group while controlling for sex. Chronic patients reported the highest level of dissociation. More severe childhood trauma was associated with greater dissociative symptoms in all groups although most strongly in chronic patients. Emotional abuse showed the strongest associations with dissociation, with these being strongest for chronic patients, followed by first-episode patients--and least for controls. Men showed a stronger association between physical neglect and dissociation than women, irrespective of group. There were no significant group by sex interactions. Our findings replicate the strong association between childhood trauma and dissociative symptoms in chronic and first-episode psychotic patients relative to non psychotic control subjects. We also demonstrate the salience of emotional abuse in explaining variance in dissociation, especially in chronic patients. PMID- 23816518 TI - Predictors of performance improvements within a cognitive remediation program for schizophrenia. AB - Cognitive impairment is regarded a core feature of schizophrenia and is associated with low psychosocial functioning. There is rich evidence that cognitive remediation can improve cognitive functions in patients with schizophrenia. However, little is known about what predicts individual remediation success. Some studies suggest that baseline cognitive impairment might be a limiting factor for training response. Aim of the current study was to further examine the role of cognitive and symptom variables as predictors of remediation success. We studied a total sample of 32 patients with schizophrenia and schizoaffective disorder who were engaged in a computer-based cognitive training program (CogPack). A pre-training test battery provided cognitive measures of selective attention, executive functioning, processing speed, verbal memory, and verbal intelligence along with measures for positive and negative symptoms. Training response was defined as improvement on training tasks. Correlation analyses revealed no significant relationship between any of the baseline cognitive or symptom measures and improvement rates. However, better baseline cognition was associated with a higher percentage of tasks with initial ceiling effects. We conclude that not carefully tailoring task difficulty to patients' cognitive abilities constitutes a much more severe threat to cognitive remediation success than cognitive impairment itself. PMID- 23816519 TI - Correlation between clinical findings and CT scan parameters for shoulder deformities in birth brachial plexus palsy. AB - PURPOSE: The shoulder is the most common site of secondary deformities after birth brachial plexus palsy. The severity and the pattern of deformity vary in patients and have implications for clinical decision making. This study aimed to find the correlation between clinical findings and computed tomography (CT) scan parameters for these deformities. METHODS: This prospective study included 75 patients aged 3 to 23 years. The clinical parameters included age, extent of involvement (nerve roots affected), degree of shoulder abduction, active and passive external rotation, and Mallet score. These were correlated with 3 CT scan parameters: elevation of the scapula above the clavicle, relative glenoid version, and percentage of the humeral head anterior to the scapular line. RESULTS: There was a significant correlation between lack of active and passive external rotation and relative glenoid version and humeral head subluxation. There was a significant correlation between active abduction and elevation of the scapula above the clavicle. There was no significant correlation between age or Mallet score with any of the CT scan parameters. CONCLUSIONS: These results suggest that presence of active and passive external rotation beyond 10 degrees is associated with significantly lesser shoulder deformity irrespective of the degree of shoulder abduction. Hence, a patient with more than 10 degrees external rotation does not need a screening CT scan evaluation regardless of the degree of shoulder abduction present. Conversely, a lack of external rotation beyond 10 degrees strongly suggests relative glenoid retroversion and posterior subluxation of the humeral head and should be considered a clinical indicator of shoulder deformation. TYPE STUDY/LEVEL OF EVIDENCE: Diagnostic II. PMID- 23816520 TI - Patient and hospital characteristics are associated with cost of hospitalizations in children with epilepsy. AB - We assessed patient and hospital characteristics and cost of hospitalizations in children with epilepsy, using the United States (U.S.) Kids' Inpatient Database (KID2009). There were 114,256 pediatric admissions for epilepsy in 2009. Admission rate was highest in those with the lowest household income. Private, urban teaching, and nonchildren's hospitals and hospitals in the Southern U.S. admitted the most patients. The average length of hospitalization was 5.4days, and adjusted cost was $6656/day of admission. The cost of hospitalizations was higher in those with the highest household income versus in those with lower income, private versus Medicare/Medicaid insurance, admissions to private versus public hospitals, urban teaching versus nonteaching or rural hospitals, and children's versus nonchildren's hospitals. Epilepsy comorbidities did not increase the cost of hospitalization. We found that the number and cost of hospitalizations in children with epilepsy vary by patient and hospital characteristics. Such findings are essential for informing future health plans and policy decisions on resource allocation. PMID- 23816521 TI - Pax6 is expressed in subsets of V0 and V2 interneurons in the ventral spinal cord in mice. AB - The embryonic spinal cord in mice is organized into eleven progenitor domains. Cells in each domain first produce neurons and then switch to specifying glia. Five of these domains known as p3, pMN, p2, p1 and p0 are located in the ventral spinal cord and each expresses a unique code of transcription factors (TFs) that define the molecular profile of progenitor cells. This code is largely responsible for determining the subtype specification of neurons generated from each domain. Pax6 codes for a homedomain-containing TF that plays a central role in defining the molecular boundaries between the two ventral-most domains, p3 and pMN. Using fate mapping and gene expression studies we show that PAX6, in addition to each patterning function, is expressed in a group of late born interneurons that derive from the p2 and p0 domains. The p2-derived neurons represent a subset of late born V2b interneurons and their specification depends on Notch signaling. The V0 neurons represent V0v ventral neurons expressing Pax2. Our data demonstrate that interneuron diversity in the ventral spinal cord is more complex than originally appreciated and point to the existence of additional mechanisms that determine interneuron diversity, particularly in the p2 domain. PMID- 23816522 TI - Expression of NOL1/NOP2/sun domain (Nsun) RNA methyltransferase family genes in early mouse embryogenesis. AB - The NOL1/NOP2/sun domain-containing genes encode the RNA methyltransferases Nsun2, 3, 4, 5, 6 and 7. Methylated RNA pervades the transcriptome, yet the function of RNA methyltransferases is poorly understood. Nsun2 and Nsun4 participate in cell proliferation and differentiation, protein biosynthesis and cancer. In addition, Nsun2 and Nsun7 dysfunction might cause intellectual disability and male sterility, respectively. The functions of Nsun3, Nsun5 and Nsun6 are unknown. Given the widespread distribution of RNA methylation, it is possible that Nsun genes participate in a broader range of relevant biological processes including the regulation of embryogenesis. Here, we describe the expression pattern of Nsun genes during mouse embryo development. In situ hybridization showed developmentally regulated Nsun gene expression. Nsun genes express broadly during gastrulation, but enrich in specific tissues as embryogenesis proceeds. Nsun transcripts enrich in the developing brain, consistent with proposed functions in neurocognitive development. In addition, Nsun transcripts enrich in the developing ear, eye, olfactory epithelium, branchial arches, heart and limb, suggesting possible overlapping functions of NSUN proteins in neural, craniofacial, cardiac, and limb morphogenesis. Furthermore, Nsun2 and Nsun6 enrich in the caudal neural tube and newly formed somites, suggesting possible functions in body axis extension. These results suggest possible overlapping functions of NSUN proteins and RNA methylation in broad aspects of embryonic development. PMID- 23816523 TI - Dopamine quinone modifies and decreases the abundance of the mitochondrial selenoprotein glutathione peroxidase 4. AB - Oxidative stress and mitochondrial dysfunction are known to contribute to the pathogenesis of Parkinson's disease. Dopaminergic neurons may be more sensitive to these stressors because they contain dopamine (DA), a molecule that oxidizes to the electrophilic dopamine quinone (DAQ) which can covalently bind nucleophilic amino acid residues such as cysteine. The identification of proteins that are sensitive to covalent modification and functional alteration by DAQ is of great interest. We have hypothesized that selenoproteins, which contain a highly nucleophilic selenocysteine residue and often play vital roles in the maintenance of neuronal viability, are likely targets for the DAQ. Here we report the findings of our studies on the effect of DA oxidation and DAQ on the mitochondrial antioxidant selenoprotein glutathione peroxidase 4 (GPx4). Purified GPx4 could be covalently modified by DAQ, and the addition of DAQ to rat testes lysate resulted in dose-dependent decreases in GPx4 activity and monomeric protein levels. Exposing intact rat brain mitochondria to DAQ resulted in similar decreases in GPx4 activity and monomeric protein levels as well as detection of multiple forms of DA-conjugated GPx4 protein. Evidence of both GPx4 degradation and polymerization was observed following DAQ exposure. Finally, we observed a dose-dependent loss of mitochondrial GPx4 in differentiated PC12 cells treated with dopamine. Our findings suggest that a decrease in mitochondrial GPx4 monomer and a functional loss of activity may be a contributing factor to the vulnerability of dopaminergic neurons in Parkinson's disease. PMID- 23816525 TI - Differing risk of cancer death among patients with pathologic T3a renal cell carcinoma: identification of risk categories according to fat infiltration and renal vein thrombosis. AB - OBJECTIVES: The study objectives were to evaluate the prognostic impact of fat infiltration and renal vein thrombosis in patients with pT3a renal cell carcinoma (RCC) and to identify new prognostic groups. MATERIAL AND METHODS: We analyzed 122 consecutive patients with pT3a who underwent radical nephrectomy for RCC between 2000 and 2011 at the University of Bologna. Cancer-specific survival (CSS) rates were estimated using Kaplan-Meier survival curves; univariable and multivariable analyses were performed with Cox analysis. RESULTS: The mean follow up was 41.7 +/- 35.4 months. Patients with peritumoral/hilar fat infiltration (n = 63) and patients with renal vein thrombosis (n = 18) experienced comparable CSS rates, whereas patients with both fat infiltration plus renal vein thrombosis (n = 41) showed worse survival outcomes than the first group (P = .026). Patients were divided in 2 groups: group A, with fat invasion or renal vein thrombosis, and group B, with concomitant fat invasion and renal vein invasion. Group B showed worse cancer-specific survival than group A (P = .024). At multivariate analysis, this new risk-group stratification was found to be an independent prognostic predictor of CSS (P < .05). CONCLUSIONS: Patients with T3a RCC with both fat invasion and renal vein thrombosis experience worse survival rates when compared with those patients with only 1 prognostic factor. The TNM classification should consider the concomitant presence of those parameters as a different prognostic predictor. PMID- 23816524 TI - Oxidative inhibition of the vascular Na+-K+ pump via NADPH oxidase-dependent beta1-subunit glutathionylation: implications for angiotensin II-induced vascular dysfunction. AB - Glutathionylation of the Na(+)-K(+) pump's beta1-subunit is a key molecular mechanism of physiological and pathophysiological pump inhibition in cardiac myocytes. Its contribution to Na(+)-K(+) pump regulation in other tissues is unknown, and cannot be assumed given the dependence on specific beta-subunit isoform expression and receptor-coupled pathways. As Na(+)-K(+) pump activity is an important determinant of vascular tone through effects on [Ca(2+)]i, we have examined the role of oxidative regulation of the Na(+)-K(+) pump in mediating angiotensin II (Ang II)-induced increases in vascular reactivity. beta1-subunit glutathione adducts were present at baseline and increased by exposure to Ang II in rabbit aortic rings, primary rabbit aortic vascular smooth muscle cells (VSMCs), and human arterial segments. In VSMCs, Ang II-induced glutathionylation was associated with marked reduction in Na(+)-K(+)ATPase activity, an effect that was abolished by the NADPH oxidase inhibitory peptide, tat-gp91ds. In aortic segments, Ang II-induced glutathionylation was associated with decreased K(+) induced vasorelaxation, a validated index of pump activity. Ang II-induced oxidative inhibition of Na(+)-K(+) ATPase and decrease in K(+)-induced relaxation were reversed by preincubation of VSMCs and rings with recombinant FXYD3 protein that is known to facilitate deglutathionylation of beta1-subunit. Knock-out of FXYD1 dramatically decreased K(+)-induced relaxation in a mouse model. Attenuation of Ang II signaling in vivo by captopril (8 mg/kg/day for 7 days) decreased superoxide-sensitive DHE levels in the media of rabbit aorta, decreased beta1-subunit glutathionylation, and enhanced K(+)-induced vasorelaxation. Ang II inhibits the Na(+)-K(+) pump in VSMCs via NADPH oxidase-dependent glutathionylation of the pump's beta1-subunit, and this newly identified signaling pathway may contribute to altered vascular tone. FXYD proteins reduce oxidative inhibition of the Na(+)-K(+) pump and may have an important protective role in the vasculature under conditions of oxidative stress. PMID- 23816526 TI - Glasgow prognostic score as a prognostic factor in metastatic castration resistant prostate cancer treated with docetaxel-based chemotherapy. AB - BACKGROUND: The modified Glasgow Prognostic Score (mGPS), derived from C-reactive protein (CRP) and albumin levels, and the neutrophil-lymphocyte ratio (NLR) have demonstrated prognostic significance in a number of malignancies. PATIENTS AND METHODS: Baseline mGPS and NLR were calculated in a prospective cohort of chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC) (AT-101-CS-205 trial) who received docetaxel and prednisone +/- AT101. Cox proportional hazards regression models estimated their effects on overall survival (OS). RESULTS: Of 220 eligible patients, mGPS and neutrophil and lymphocyte counts were available for 184, 193, and 112 patients, respectively. Albumin (hazard ratio [HR], 0.28; 95% confidence interval [CI]: 0.14-0.56; P < .001) and CRP (HR, 1.22; 95% CI, 1.00-1.48; P = .048) were independently prognostic for OS. An association between mGPS and OS was found (HR, 1.87; 95% CI, 1.35-2.59; P < .001; median survival, 23.5 months at mGPS 0 vs. 9.8 months at mGPS 2). mGPS was significant after controlling for 3 previously published nomograms or NLR (P <= .001). NLR was not prognostic for OS (HR, 0.98; P = .91), and no association between mGPS and toxicity was noted. CONCLUSION: Our results demonstrate the prognostic role of the mGPS in mCRPC over variables previously identified. mGPS is inexpensive, easily measured, and could be incorporated into routine clinical testing if our results are confirmed in a subsequent validation study. The utility of the NLR in mCRPC remains uncertain despite evidence in other malignancies. PMID- 23816527 TI - Adjuvant treatment for resected renal cell carcinoma: are all strategies equally negative? Potential implications for trial design with targeted agents. AB - BACKGROUND: Although data from ongoing trials with targeted agents are awaited, we used a meta-analytical approach to explore whether cytokines (CK), vaccines (VAX), or other therapies may differentially influence patients' outcomes. MATERIALS AND METHODS: The objective was to determine whether significant interactions exist according to treatment (CK vs. VAX vs. other), in the context of a literature-based meta-analysis. Fourteen trials (3380 patients) were identified, with 10 randomized clinical trials (RCTs) (2257 patients) providing data for the primary outcome--5-year relapse-free survival (RFS). The primary selected end point was 5-year RFS; secondary end points were 5- and 2-year overall survival (OS) and 2-year RFS. Event-based relative risk (RR) ratios with 95% confidence intervals (CI) were extracted and cumulated according to a random effect model from articles/presentations. Testing for heterogeneity was performed as well. RESULTS: Although not statistically significant, an effect in favor of a qualitative interaction according to treatment was found for 5-year RFS, with a likely detrimental effect in CK (P = .42) in contrast to that found in VAX subpopulation (P = .76). For the secondary end points, a similar effect in favor of a quantitative significant interaction according to treatment was found for 5 year OS, regardless of the approach adopted, with a different magnitude of treatment effect. In addition, a borderline significant (P = .05) detrimental effect in terms of 2-year OS against the use of adjuvant treatment was determined in the CK subpopulation (RR, 1.24; 95% CI, 0.99, 1.54). CONCLUSION: The effect in favor of a qualitative interaction according to the adopted strategy is intriguing and suggests potential implications for trial design with targeted agents. PMID- 23816528 TI - Decreased PITX1 gene expression in human cutaneous malignant melanoma and its clinicopathological significance. AB - BACKGROUND: The pituitary homeobox 1 (PITX1) protein is a member of the bicoid related homeobox transcription factors and has essential roles in human development. Recently, the PITX1 gene has been considered as a tumor suppressor gene in various human cancers. OBJECTIVE: This study examined the expression of PITX1 in the development and progression of human cutaneous malignant melanoma. MATERIALS & METHODS: Immunohistochemical and/or immunofluorescence analyses were performed to examine the histological expression of PITX1 in healthy skin and 40 cutaneous malignant melanoma cases, including 10 melanoma in situ cases. RESULTS: Expression of PITX1 was shown in nuclei of melanocytes in normal skin. PITX1 expression was positive (labeling index: >=10%) in 21 (52.5%) cases and negative (labeling index: <10%) in 19 (47.5%) of 40 cases of primary cutaneous malignant melanoma. The mean tumor thickness in PITX1-negative cases (7.11 +/- 10.3 mm) was significantly higher than that in the positive cases (1.90 +/- 3.19 mm) (P<0.01). The numbers of cases showing metastasis were 1 (4.76%) of 21 cases in PITX1 positive cases and 7 (36.8%) of 19 cases in PITX1-negative cases; the frequency was significantly higher in PITX1-negative cases than the positive cases (P = 0.012). Moreover, the reduction in PITX1 expression correlated significantly with clinical stage (P<0.001). Interestingly, PITX1 expression was inversely correlated with cell proliferation of cutaneous malignant melanoma (P<0.001). CONCLUSIONS: Down-regulation of PITX1 expression might contribute to the progression of cutaneous malignant melanoma via promoting cell proliferative activity. PMID- 23816529 TI - An acoustic switch. AB - The benefits derived from the development of acoustic transistors which act as switches or amplifiers have been reported in the literature. Here we propose a model of acoustic switch. We theoretically demonstrate that the device works: the input signal is totally restored at the output when the switch is on whereas the output signal nulls when the switch is off. The switch, on or off, depends on a secondary acoustic field capable to manipulate the main acoustic field. The model relies on the attenuation effect of many oscillating bubbles on the main travelling wave in the liquid, as well as on the capacity of the secondary acoustic wave to move the bubbles. This model evidences the concept of acoustic switch (transistor) with 100% efficiency. PMID- 23816530 TI - Measurement of the strength of iodine-125 seed moving at unknown speed during implantation in brachytherapy. AB - The aim of this study is to demonstrate the feasibility of estimating the strength of the moving radiation source during patient implantation. The requirement for the counting time was investigated by comparing the results of the measurements for the static source with those for the source moving at 2, 5, 10 and 20 cm s(-1). The utilized source was (125)I with an air-kerma strength of 0.432 U (MUGym(2)h(-1)). The detector utilized was a plastic scintillation detector (8 cm * 5 cm * 2 cm in thickness) set at 8 cm away from the needle to guide the source. Experiments were conducted in order to determine the most desirable counting time. Analysis using the maximum of the measured values while the source passed through the needle indicated that the results for the moving source increased more than those for the static source as the counting time decreased. The combined standard uncertainty, with the coverage factor of 1, was within 4% at the counting time of 100 ms. This investigation supported the feasibility of the method proposed for estimating the source strength during the implantation procedure, regardless of the source speed. The method proposed is a potential option for reducing the risk of accidental replacements of sources with those of incorrect strengths. PMID- 23816531 TI - Rapid assay for detecting gyrA and parC mutations associated with fluoroquinolone resistance in Enterobacteriaceae. AB - We developed a PCR-RFLP assay to detect mutations in the quinolone-resistance determining regions of gyrA and parC associated with fluoroquinolone resistance in Enterobacteriaceae. The assay detected mutations associated with reduced susceptibility to fluoroquinolones and may therefore serve as a specific, rapid, inexpensive, and simple testing alternative. PMID- 23816532 TI - Evaluation of MALDI-TOF mass spectroscopy methods for determination of Escherichia coli pathotypes. AB - It is rapidly becoming apparent that many E. coli pathotypes cause a considerable burden of human disease. Surveillance of these organisms is difficult because there are few or no simple, rapid methods for detecting and differentiating the different pathotypes. MALDI-TOF mass spectroscopy has recently been rapidly and enthusiastically adopted by many clinical laboratories as a diagnostic method because of its high throughput, relatively low cost, and adaptability to the laboratory workflow. To determine whether the method could be adapted for E. coli pathotype differentiation the Bruker Biotyper methodology and a second methodology adapted from the scientific literature were tested on isolates representing eight distinct pathotypes and two other groups of E. coli. A total of 136 isolates was used for this study. Results confirmed that the Bruker Biotyper methodology that included extraction of proteins from bacterial cells was capable of identifying E. coli isolates from all pathotypes to the species level and, furthermore, that the Bruker extraction and MALDI-TOF MS with the evaluation criteria developed in this work was effective for differentiating most pathotypes. PMID- 23816533 TI - IRE1alpha dissociates with BiP and inhibits ER stress-mediated apoptosis in cartilage development. AB - Bone morphogenetic protein 2 is known to activate unfolded protein response signaling molecules, including XBP1S, BiP and IRE1alpha. Endoplasmic reticulum stress is induced in chondrogenesis and activates IRE1alpha signal pathway, which is associated with ER stress-mediated apoptosis. However, the influence on IRE1alpha and BiP in BMP2-induced chondrocyte differentiation has not yet been elucidated; the molecular mechanism remains unexplored. In this study, we demonstrate that IRE1alpha interacts with BiP in unstressed cells and dissociates from BiP in the course of cartilage development. Induction of ER stress responsive proteins (XBP1S, IRE1alpha, BiP) was also observed in differentiating cells. IRE1alpha inhibition ER stress-mediated apoptosis lies in the process of chondrocyte differentiation. Furthermore, knockdown of IRE1alpha expression by way of the RNAi approach accelerates ER stress-mediated apoptosis in chondrocyte differentiation induced by BMP2, as revealed by enhanced expressions of cleaved caspase3, CHOP and p-JNK1; and this IRE1alpha inhibition effect on ER stress mediated apoptosis is required for BiP in chondrogenesis. Collectively, the ER stress sensors were activated during apoptosis in cartilage development, suggesting that selective activation of ER stress signaling was sufficient for induction of apoptosis. These findings reveal a novel critical role of IRE1alpha in ER stress-mediated apoptosis and the molecular mechanisms involved. These results suggest that activation of p-JNK1, caspase3 and CHOP was detected in developing chondrocytes and that specific ER stress signaling leads to naturally occurring apoptosis during cartilage development. PMID- 23816535 TI - Selective inhibition of tumor necrosis factor-alpha converting enzyme attenuates liver toxicity in a murine model of concanavalin A induced auto-immune hepatitis. AB - Emerging evidence suggest that tumor necrosis factor (TNF)-alpha plays a major role in pathogenesis of auto-immune hepatitis (AIH) induced liver injury. Blockade of TNF-alpha synthesis or bio-activity protects against experimental AIH. TNF-alpha converting enzyme (TACE) is a member of the ADAM (a disintegrin and metalloproteinase) family which processes precursor TNF-alpha to release soluble TNF-alpha. We hypothesized that selective inhibition of TACE might protect AIH. To investigate this, we studied the effects of a selective TACE inhibitor DPC-333 on murine model of liver injury and fibrosis induced with concanavalin A (Con A). Pre-treatment with DPC-333 significantly suppressed plasma alanine transaminase, aspartate transaminase and cytokines such as TNF alpha, interferon (IFN)-gamma, interleukin (IL)-2 and IL-6 levels due to acute Con A challenge. Interestingly; DPC-333 inhibited liver poly (ADP-ribose) polymerase (PARP)-1 activity which was associated with reduced number of necrotic hepatocytes in histological examination and mortality associated with Con A. In fibrosis study, repeated Con A administration significantly up-regulated liver collagen deposition as assessed by measurement of hydroxyproline content which was further confirmed in liver histology with Masson's trichrome staining. Treatment with 30mg/kg of DPC-333 was able to suppress liver hydroxyproline and fibrous tissue proliferation which corroborated well with inhibition in expression of pro-fibrotic genes such as tissue inhibitor of metalloproteinase (TIMP)-1 and transforming growth factor (TGF)-beta1. These observations suggest that selective TACE inhibition is an effective approach for the treatment of both immune mediated hepatic inflammation and fibrosis. PMID- 23816534 TI - Modification of p115RhoGEF Ser(330) regulates its RhoGEF activity. AB - p115RhoGEF is a member of a family of Rho-specific guanine nucleotide exchange factors that also contains a regulator of G protein signaling homology domain (RH RhoGEFs) that serves as a link between Galpha13 signaling and RhoA activation. While the mechanism of regulation of p115RhoGEF by Galpha13 is becoming well known, the role of other regulatory mechanisms, such as post-translational modification or autoinhibition, in mediating p115RhoGEF activity is less well characterized. Here, putative phosphorylation sites on p115RhoGEF are identified and characterized. Mutation of Ser(330) leads to a decrease in serum response element-mediated transcription as well as decreased activation by Galpha13 in vitro. Additionally, this study provides the first report of the binding kinetics between full-length p115RhoGEF and RhoA in its various nucleotide states and examines the binding kinetics of phospho-mutant p115RhoGEF to RhoA. These data, together with other recent reports on regulatory mechanisms of p115RhoGEF, suggest that this putative phosphorylation site serves as a means for initiation or relief of autoinhibition of p115RhoGEF, providing further insight into the regulation of its activity. PMID- 23816536 TI - Betulinic acid and betulin ameliorate acute ethanol-induced fatty liver via TLR4 and STAT3 in vivo and in vitro. AB - Ethanol consumption leads to many kinds of liver injury and suppresses innate immunity, but the molecular mechanisms have not been fully delineated. The present study was conducted to determine whether betulinic acid (BA) or betulin (BT) would ameliorate acute ethanol-induced fatty liver in mice, and to characterize whether Toll like receptor 4 (TLR4) and signal transducer and activator of transcription 3 (STAT3) were involved in ethanol-stimulated hepatic stellate cells (HSCs). EtOH (5mg/kg) and BA or BT (20 or 50mg/kg) were applied in vivo, while EtOH (50mM) and BA or BT (12.5 or 25MUM) were applied in vitro. Administration of BA or BT significantly prevented the increases of serum ALT and AST caused by ethanol, as well as serum TG. Supplement of BA or BT prevented ethanol-induced acidophilic necrosis, increased hepatocyte nuclei and stromal inflammation infiltration as indicated by liver histopathological studies. Administration of BA or BT significantly decreased CYP2E1 activities and expression of SREBP-1caused by ethanol, however, lower dosage of BA or BT showed slight effects on CYP2E1 activity or expression of SREBP-1c. BA or BT administration significantly decreased the expression of TLR4, and increased the phosphorylation of STAT3. In vitro, BA or BT treatment reduced the expressions of alpha-SMA and collagen-I in ethanol-stimulated HSCs via regulation of TLR4 and STAT3, coincided with in vivo. All of these findings demonstrated that BA or BT might ameliorate acute ethanol-induced fatty liver via TLR4 and STAT3 in vivo and in vitro, promising agents for ethanol-induced fatty liver therapies. PMID- 23816537 TI - Immunostimulatory effects and characterization of a glycoprotein fraction from rice bran. AB - Many natural resources obtained from plants have been studied for their utility as host defense potentiators. In the present study, we investigated whether a glycoprotein fraction from rice (Oryza sativa) bran (GFRB) could modulate immune responses such as the production of nitric oxide (NO), tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and IL-10 in the RAW 264.7 macrophage cell line. GFRB, which contained 65.7% of protein and 7.7% of total sugar, was prepared by treating an aqueous extract of rice bran with 80% (NH4)2SO4 and the extraction yield was 4.9%. GFRB consisted of 5 bands with varying molecular weights by SDS-PAGE and remarkably improved production of NO in RAW 264.7 murine macrophage cells, up to approximately 10-fold compared to the normal control at 100MUg/mL concentration. In RAW 264.7 cells treated with 50MUg/mL GFRB, released levels of various cytokines such as TNF-alpha, IL-1beta, IL-6, and IL-10 were 2824.4+/-90.7, 224.5+/-4.0, 524.3+/-4.8, and 143.0+/-9.5pg/mL, respectively, which were higher than the levels in normal controls. Moreover, GFRB exhibited no cytotoxicity. According to the results of region-selective enzyme hydrolysis, the immune responses against GFRB were elicited by the glycans in the GFRB. These results show the potential of GFRB as a functional therapeutic agent with demonstrable immunostimulatory activity. PMID- 23816538 TI - Dual role of lipoxin A4 in pneumosepsis pathogenesis. AB - Lipoxin A4 (LXA4) is an endogenous lipid mediator with potent anti-inflammatory actions but its role in infectious processes is not well understood. We investigated the involvement of LXA4 and its receptor FPR2/ALX in the septic inflammatory dysregulation. Pneumosepsis was induced in mice by inoculation of Klebsiella pneumoniae. LXA4 levels and FPR2/ALX expression in the infectious focus as well as the effects of treatment with receptor agonists (LXA4 and BML 111) and antagonists (BOC-2 and WRW(4)) in early (1h) and late (24h) sepsis were studied. Sepsis induced an early increase in LXA4, FPR2/ALX lung expression, local and systemic infection and inflammation, and mortality. Treatment with BOC 2 in early sepsis increased leukocyte migration to the focus, and reduced bacterial load and dissemination. Inhibition of 5- and 15-lipoxygenase in early sepsis also increased leukocyte migration. Early treatment with WRW(4) and BOC-2 improved survival. Treatment with authentic LXA4 or BML-111 in early sepsis decreased cell migration and worsened the infection. In late sepsis, treatment with BOC-2 had no effect, but LXA4 improved the survival rate by reducing the excessive inflammatory response, this effect being abolished by pretreatment with BOC-2. Thus, the anti-inflammatory and pro-resolution mediator LXA4 and its receptor FPR2/ALX levels were increased in the early phase of sepsis, contributing to the septic inflammatory dysregulation. In addition, LXA4 has a dual role in sepsis and that its beneficial or harmful effects are critically dependent on the time. Therefore, a proper interference with LXA4 system may be a new therapeutic avenue to treat sepsis. PMID- 23816540 TI - Combination of high-sensitivity C-reactive protein and homocysteine predicts the short-term outcomes of Chinese patients with acute ischemic stroke. AB - BACKGROUND: Ischemic stroke is one of the most common causes of death worldwide. Early and accurate prediction of outcome in acute ischemic stroke (AIS) is important and influences risk-optimized therapeutic strategies. We investigated the changes in high-sensitivity C-reactive protein (Hs-CRP) and homocysteine (HCY) levels, two of the risk factors, during the acute period of AIS and evaluated the relationship between these levels and short-term prognosis. METHODS: We prospectively studied 189 patients with AIS who were admitted within 24 hours after the onset of symptoms. Serum Hs-CRP, HCY levels, and National Institutes of Health Stroke Scale (NIHSS) were measured at the time of admission. Short-term functional outcome was measured by the modified Rankin scale (mRS), 90 days after admission. RESULTS: The median serum Hs-CRP and HCY levels were significantly higher in AIS patients as compared to normal controls (P < 0.0001, respectively). High-sensitivity C-reactive protein and HCY were independent prognostic markers of functional outcome and death (adjusted for age and the NIHSS) in patients with AIS. In receiver operating characteristic curve analysis, the prognostic accuracy of the combined model (HCY and Hs-CRP) was higher compared to all measured biomarkers individually and the NIHSS score. CONCLUSION: High-sensitivity C-reactive protein and HCY are independent predictors of short term outcome and mortality after AIS. The combined model may provide additional general prognostic information. PMID- 23816539 TI - Differing lifestyles of Staphylococcus epidermidis as revealed through Bayesian clustering of multilocus sequence types. AB - Staphylococcus epidermidis is part of the normal bacterial flora of human skin and a leading cause of infections associated with indwelling medical devices. Previous phylogenetic analyses of subgenomic data have been unable to distinguish between S. epidermidis strains with nosocomial or commensal lifestyles, despite the identification of specific phenotypes and accessory genes that may contribute to such lifestyles. To attempt to better define the population structure of this species, the international S. epidermidis multilocus sequence typing database was analyzed with the Bayesian clustering programs STRUCTURE and BAPS. A total of six genetic clusters (GCs) were identified. A local population of S. epidermidis from clinical specimens was classified according to these six GCs, and further characterized for antibiotic susceptibilities, biofilm, and various genetic markers. GC5 was abundant and significantly enriched for isolates that were resistant to four classes of antibiotics, high biofilm production, and positive for the virulence markers icaA, IS256, and sesD/bhp, indicating its potential clinical relevance. In contrast, GC2 was rare and contained the only isolates positive for the putative commensal marker, fdh. GC1 and GC6 were abundant but not significantly associated with any of the examined characteristics, except for sesF/aap and GC6. GC3 was rare and identified as a potential genetic sink that received, but did not donate, core genetic material from other GCs. In conclusion, population genetics analyses were essential for identifying clusters of strains that may differ in their adaptation to nosocomial or commensal lifestyles. These results provide a new, population genetics framework for studying S. epidermidis. PMID- 23816541 TI - Resonance versus linear responses to alternating electric fields induce mechanistically distinct mammalian cell death. AB - Alternating electric (AC) fields are known to activate tumor cell death, but the underlying cellular mechanisms are poorly understood. We thus combined live-cell imaging with computational modeling to investigate the dynamic interactions between AC fields and cultured mammalian cells. Our results showed extensive cell death activated via two distinct mechanisms. At frequency range of 100-300 kHz and 800-1000 kHz, AC fields triggered prolonged mitotic arrest followed by apoptosis, and the cell death kinetics showed linear dependence on both field frequency and intensity. However, at intermediate frequencies, from 300 kHz to 800 kHz, cells died as a result of field-induced surface detachment, and the process exhibited a resonance frequency. Based on models of induced dielectric polarization and charge oscillation, we simulated the functional dependence of cell death kinetics on field frequency and intensity for both the linear and resonance response regimes. By comparing the simulated and experimental results, we not only determined the crucial electrical properties of mammalian cells that govern their interaction with AC fields but also acquired novel mechanistic understanding of the resulting cell death processes, which provides important new insight for potentially utilizing AC fields as an alternative anti-tumor remedy. PMID- 23816542 TI - Correlation between Breslow thickness and Technetium-99m-sestamibi uptake in cutaneous melanoma. AB - BACKGROUND: Technetium-99m-sestamibi (MIBI) is a radiopharmaceutical that has well-known tumor-seeking properties. We evaluated the correlation between Breslow thickness and MIBI uptake by cutaneous melanoma (CM). MATERIAL AND METHODS: Patients with suspicious melanocytic lesions received intravenous injections of 740-1,110 Mbq of MIBI. Using a gamma probe, the number of radioactive counts in the skin was considered to determinate the MIBI uptake intensity. SPECT imaging of the lesion site and respective lymph node region was obtained. RESULTS: There was a strong positive correlation between MIBI uptake intensity and Breslow thickness (rs = 0.74, P = 0.003). There was a statistically significant difference (P <0.001) between lesions with Breslow thickness <1 mm (MIBI uptake intensity = 1.23 +/- 0.28 radioactive counts) and Breslow thickness >1 mm (MIBI uptake intensity = 2.32 +/- 0.32 radioactive counts). DISCUSSION: The possibility of correlating MIBI uptake intensity with Breslow categories may facilitate surgical procedures, reducing morbidity and costs. PMID- 23816543 TI - Association of the Val66Met polymorphism of the BDNF gene with primary cranial cervical dystonia patients from South-west China. AB - BACKGROUND: The etiology of primary dystonia remains unclear. Recent genetic studies suggest that the Val66Met polymorphism of the BDNF gene is a genetic modifier in cranial-cervical dystonia in Caucasians. However, the finding is not consistent. PATIENTS AND METHODS: A total of 193 patients with primary cranial cervical dystonia from the Department of Neurology, West China Hospital of Sichuan University was included. From the same region, 216 healthy individuals were recruited as a control group. The Val66Met SNP was identified by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: In the present study, cervical dystonia (59.59%) was the most common type of primary cranial cervical dystonia. No significant difference was found in the genotype and minor allele frequencies between all patients and controls, between cervical dystonia patients and controls, and between craniocervical dystonia patients and controls. However, significant differences were found in the genotype and minor allele frequencies of Val66Met SNP between blepharospasm (BSP) patients and controls (P=0.0080 and P=0.0042, respectively), and between BSP patients and patients with craniocervical derived from BSP (P=0.0010 and P=0.0002, respectively). CONCLUSION: Minor allele "A" of BDNF Val66Met SNP may increase the risk for developing BSP and may be a protective factor for preventing BSP progressing to craniocervical dystonia. More association studies involving a larger number of participants are needed to confirm the present findings. PMID- 23816544 TI - Comparison of exhaled endogenous particles from smokers and non-smokers using multivariate analysis. AB - BACKGROUND: Smoking, along with many respiratory diseases, has been shown to induce airway inflammation and alter the composition of the respiratory tract lining fluid (RTLF). We have previously shown that the phospholipid and protein composition of particles in exhaled air (PEx) reflects that of RTLF. In this study, we hypothesized that the composition of PEx differs between smokers and non-smokers, reflecting inflammation in the airways. OBJECTIVE: It was the aim of this study to identify differences in the phospholipid composition of PEx from smokers and non-smokers. METHODS: PEx from 12 smokers and 13 non-smokers was collected using a system developed in-house. PEx was analysed using time-of flight secondary ion mass spectrometry, and the mass spectral data were evaluated using multivariate analysis. Orthogonal partial least squares (OPLS) was used to relate smoking status, lung function and pack years to the chemical composition of RTLF. The discriminating ions identified by OPLS were then used as explanatory variables in traditional regression analysis. RESULTS: There was a clear discrimination between smokers and non-smokers according to the chemical composition, where phospholipids from smokers were protonated and sodiated to a larger extent. Poor lung function showed a strong association with higher response from all molecular phosphatidylcholine species in the samples. Furthermore, the accumulated amount of tobacco consumed was associated with variations in mass spectra, indicating a dose-response relationship. CONCLUSION: The chemical composition of PEx differs between smokers and non-smokers, reflecting differences in the RTLF. The results from this study may suggest that the composition of RTLF is affected by smoking and may be of importance for lung function. PMID- 23816545 TI - Lessons from natural and artificial polyploids in higher plants. AB - Polyploidy in higher plants is a major source of genetic novelty upon which selection may act to drive evolution, as evidenced by the widespread success of polyploid species in the wild. However, research into the effects of polyploidy can be confounded by the entanglement of several processes: genome duplication, hybridisation (allopolyploidy is frequent in plants) and subsequent evolution. The discovery of the chemical agent colchicine, which can be used to produce artificial polyploids on demand, has enabled scientists to unravel these threads and understand the complex genomic changes involved in each. We present here an overview of lessons learnt from studies of natural and artificial polyploids, and from comparisons between the 2, covering basic cellular and metabolic consequences through to alterations in epigenetic gene regulation, together with 2 in-depth case studies in Senecio and Glycine. See also the sister article focusing on animals by Arai and Fujimoto in this themed issue. PMID- 23816547 TI - Facial purpura associated with Capnocytophaga canimorsus septicaemia; role of sunlight? PMID- 23816550 TI - Proceedings of the 17th Conference of the European Society for Clinical Hemorheology and Microcirculation (ESCHM), Jul 6-9, 2013, Pecs, Hungary. PMID- 23816546 TI - Determinants of urinary bisphenol A concentrations in Mexican/Mexican--American pregnant women. AB - Prenatal exposure to bisphenol A (BPA) may be associated with adverse health effects in the developing fetus; however, little is known about predictors of BPA exposure during pregnancy. We examined BPA exposure in 491 pregnant women from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) cohort and explored the role of living in the United States on significant dietary predictors of BPA exposure. Women provided urine samples up to two times during pregnancy (n=866 total samples). We computed the intraclass correlation coefficient (ICC) to evaluate variability in concentrations between collections and used generalized estimating equation (GEE) models to assess predictors of exposure. Geometric mean (GSD) BPA concentrations were 0.9 (2.8)MUg/L and 1.0 (2.6)MUg/L at the first and second prenatal visits, respectively. We observed greater within- than between-woman variability in urinary BPA concentrations (ICC=0.22). GEE models suggest that women who lived in the United States their entire life had 38% (CI: -0.1, 89.3) higher urinary BPA concentrations compared with other immigrant women. Additionally, women who consumed >=3 sodas per day or hamburgers three times a week or more had 58% (CI: 18.0, 112.1) and 20% (CI: -0.2, 45.2) higher urinary BPA concentrations, respectively, compared with women who consumed no sodas or hamburgers. A higher percentage of women who lived their entire life in the United States reported increased consumption of sodas and hamburgers compared with other immigrant women. Independent of other factors, BPA urinary concentrations were slightly higher when the sample was collected later in the day. As in previous studies, high within-woman variability in urinary BPA concentrations confirms that several samples are needed to properly characterize exposure during pregnancy. Results also suggest that some factors could be modified to minimize exposures during pregnancy in our study participants (e.g., reducing soda and hamburger intake) and that factors associated with acculturation might increase BPA concentrations. PMID- 23816555 TI - Lymphoma and cerebral vasculitis in association with X-linked lymphoproliferative disease. AB - Lymphoma is seen in up to 30% of patients with X-linked lymphoproliferative disease (XLP), but cerebral vasculitis related with XLP after cure of Burkitt lymphoma is rarely reported. We describe a case of a 5-year-old boy with XLP who developed cerebral vasculitis two years after cure of Burkitt lymphoma. He had Burkitt lymphoma at the age of 3 years and received chemotherapy (non-Hodgkin's lymphoma-Berlin-Frankfurt-Milan-90 protocol plus rituximab), which induced complete remission over the following two years. At the age of 5 years, the patient first developed headache, vomiting, and then intellectual and motorial retrogression. His condition was not improved after anti-infection, dehydration, or dexamethasone therapy. No tumor cells were found in his cerebrospinal fluid. Magnetic resonance imaging showed multiple non-homogeneous, hypodense masses along the bilateral cortex. Pathology after biopsy revealed hyperplasia of neurogliocytes and vessels, accompanied by lymphocyte infiltration but no tumor cell infiltration. Despite aggressive treatment, his cognition and motor functions deteriorated in response to progressive cerebral changes. The patient is presently in a vegetative state. We present this case to inform clinicians of association between lymphoma and immunodeficiency and explore an optimal treatment for lymphoma patients with compromised immune system. PMID- 23816556 TI - Clinical findings and imaging features of 67 nasopharyngeal carcinoma patients with postradiation nasopharyngeal necrosis. AB - Postradiation nasopharyngeal necrosis is an important late effect of radiotherapy that affects prognosis in patients with nasopharyngeal carcinoma. In the present study, we reviewed the clinical and imaging features of 67 patients with pathologically diagnosed postradiation nasopharyngeal necrosis who were treated at Sun Yat-sen University Cancer Center between June 2006 and January 2010. Their clinical manifestations, endoscopic findings, and imaging features were analyzed. Early nasopharyngeal necrosis was limited to a local site in the nasopharyngeal region, and the tissue defect was not obvious, whereas deep parapharyngeal ulcer or signs of osteoradionecrosis in the basilar region was observed in serious cases. Those with osteoradionecrosis and/or exposed carotid artery had a high mortality. In conclusion, Postradiation nasopharyngeal necrosis has characteristic magnetic resonance imaging appearances, which associate well with clinical findings, but pathologic examination is essential to make the diagnosis. PMID- 23816557 TI - Re-evaluation of ABO gene polymorphisms detected in a genome-wide association study and risk of pancreatic ductal adenocarcinoma in a Chinese population. AB - Pancreatic cancer is a fatal malignancy with an increasing incidence in Shanghai, China. A genome-wide association study (GWAS) and other work have shown that ABO alleles are associated with pancreatic cancer risk. We conducted a population based case-control study involving 256 patients with pathologically confirmed pancreatic ductal adenocarcinoma (PDAC) and 548 healthy controls in Shanghai, China, to assess the relationships between GWAS-identified ABO alleles and risk of PDAC. Carriers of the C allele of rs505922 had an increased cancer risk [adjusted odds ratio (OR) = 1.42, 95% confidence interval (CI): 1.02-1.98] compared to TT carriers. The T alleles of rs495828 and rs657152 were also significantly associated with an elevated cancer risk (adjusted OR = 1.58, 95% CI: 1.17-2.14; adjusted OR = 1.51, 95% CI: 1.09-2.10). The rs630014 variant was not associated with risk. We did not find any significant gene-environment interaction with cancer risk using a multifactor dimensionality reduction (MDR) method. Haplotype analysis also showed that the haplotype CTTC was associated with an increased risk of PDAC (adjusted OR = 1.46, 95% CI: 1.12-1.91) compared with haplotype TGGT. GWAS-identified ABO variants are thus also associated with risk of PDAC in the Chinese population. PMID- 23816558 TI - The impact of both platinum-based chemotherapy and EGFR-TKIs on overall survival of patients with advanced non-small cell lung cancer. AB - Both platinum-based doublet chemotherapy (PBC) and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) prolong the survival of patients with advanced non-small cell lung cancer (NSCLC). In early studies, most patients underwent PBC as first-line treatment, but not all patients could afford EGFR TKIs as second-line treatment. To understand the impact of PBC and EGFR-TKIs on NSCLC prognosis, we evaluated the association between the receipt of both regimens and overall survival (OS). Using MEDLINE and EMBASE, we identified prospective, randomized, controlled phase III clinical trials in advanced NSCLC that met the inclusion criteria: in general population with advanced NSCLC, the percentage of patients treated with both PBC and EGFR-TKIs was available in the trial and OS was reported. After collecting data from the selected trials, we correlated the percentage of patients treated with both PBC and EGFR-TKIs with the reported OS, using a weighted analysis. Fifteen phase III clinical trials- involving 11,456 adult patients in 32 arms--were included in the analysis, including 6 trials in Asian populations and 9 in non-Asian (predominantly Caucasian) populations. The OS was positively correlated with the percentage of patients treated with both PBC and EGFR-TKIs (r = 0.797, P < 0.001). The correlation was obvious in the trials in Asian populations (r = 0.936, P < 0.001) but was not statistically significant in the trials in predominantly Caucasian populations (r = 0.116, P = 0.588). These results suggest that treatment with PBC and EGFR-TKIs may provide a survival benefit to patients with advanced NSCLC, highlighting the importance of having both modalities available for therapy. PMID- 23816559 TI - Ubiquitin at the crossroad of cell death and survival. AB - Ubiquitination is crucial for cellular processes, such as protein degradation, apoptosis, autophagy, and cell cycle progression. Dysregulation of the ubiquitination network accounts for the development of numerous diseases, including cancer. Thus, targeting ubiquitination is a promising strategy in cancer therapy. Both apoptosis and autophagy are involved in tumorigenesis and response to cancer therapy. Although both are categorized as types of cell death, autophagy is generally considered to have protective functions, including protecting cells from apoptosis under certain cellular stress conditions. This review highlights recent advances in understanding the regulation of apoptosis and autophagy by ubiquitination. PMID- 23816560 TI - Vasculogenic mimicry: a novel target for glioma therapy. AB - Anti-angiogenic therapy has shown promising but insufficient efficacy on gliomas. Recent studies suggest that vasculogenic mimicry (VM), or the formation of non endothelial, tumor-cell-lined microvascular channels, occurs in aggressive tumors, including gliomas. There is also evidence of a physiological connection between the endothelial-lined vasculature and VM channels. Tumor cells, by virtue of their high plasticity, can form vessel-like structures themselves, which may function as blood supply networks. Our previous study on gliomas showed that microvessel density was comparably less in VM-positive tumors than in VM-negative tumors. Thus, VM may act as a complement to ensure tumor blood supply, especially in regions with less microvessel density. Patients with VM-positive gliomas survived a shorter period of time than did patients with VM-negative gliomas. Although the detailed molecular mechanisms for VM are not fully understood, glioma stem cells might play a key role, since they are involved in tumor tissue remodeling and contribute to neovascularization via transdifferentiation. In the future, successful treatment of gliomas should involve targeting both VM and angiogenesis. In this review, we summarize the progress and challenges of VM in gliomas. PMID- 23816561 TI - Randomized study of sinusoidal chronomodulated versus flat intermittent induction chemotherapy with cisplatin and 5-fluorouracil followed by traditional radiotherapy for locoregionally advanced nasopharyngeal carcinoma. AB - Neoadjuvant chemotherapy plus radiotherapy is the most common treatment regimen for advanced nasopharyngeal carcinoma (NPC). Whether chronomodulated infusion of chemotherapy can reduce its toxicity is unclear. This study aimed to evaluate the toxic and therapeutic effects of sinusoidal chronomodulated infusion versus flat intermittent infusion of cisplatin (DDP) and 5-fluorouracil (5-FU) followed by radiotherapy in patients with locoregionally advanced NPC. Patients with biopsy diagnosed untreated stages III and IV NPC (according to the 2002 UICC staging system) were randomized to undergo 2 cycles of sinusoidal chronomodulated infusion (Arm A) or flat intermittent constant rate infusion (Arm B) of DDP and 5 FU followed by radical radiotherapy. Using a "MELODIE" multi-channel programmed pump, the patients were given 12-hour continuous infusions of DDP (20 mg/m2) and 5-FU (750 mg/m2) for 5 days, repeated every 3 weeks for 2 cycles. DDP was administered from 10:00 am to 10:00 pm, and 5-FU was administered from 10:00 pm to 10:00 am each day. Chronomodulated infusion was performed in Arm A, with the peak deliveries of 5-FU at 4:00 am and DDP at 4:00 pm. The patients in Arm B underwent a constant rate of infusion. Radiotherapy was initiated in the fifth week, and both arms were treated with the same radiotherapy techniques and dose fractions. Between June 2004 and June 2006, 125 patients were registered, and 124 were eligible for analysis of response and toxicity. The major toxicity observed during neoadjuvant chemotherapy was neutropenia. The incidence of acute toxicity was similar in both arms. During radiotherapy, the incidence of stomatitis was significantly lower in Arm A than in Arm B (38.1% vs. 59.0%, P = 0.020). No significant differences were observed for other toxicities. The 1-, 3-, and 5 year overall survival rates were 88.9%, 82.4%, and 74.8% for Arm A and 91.8%, 90.2%, and 82.1% for Arm B. The 1-, 3-, and 5-year progression-free survival rates were 91.7%, 88.1%, and 85.2% for Arm A and 100%, 94.5%, and 86.9% for Arm B. The 1-, 3-, and 5-year distant metastasis-free survival rates were 82.5%, 79.1%, and 79.1% for Arm A and 90.2%, 85.2%, and 81.7% for Arm B. Chronochemotherapy significantly reduced stomatitis but was not superior to standard chemotherapy in terms of hematologic toxicities and therapeutic response. PMID- 23816562 TI - Early holistic face-like processing of Arcimboldo paintings in the right occipito temporal cortex: evidence from the N170 ERP component. AB - The properties of the face-sensitive N170 component of the event-related brain potential (ERP) were explored through an orientation discrimination task using natural faces, objects, and Arcimboldo paintings presented upright or inverted. Because Arcimboldo paintings are composed of non-face objects but have a global face configuration, they provide great control to disentangle high-level face like or object-like visual processes at the level of the N170, and may help to examine the implication of each hemisphere in the global/holistic processing of face formats. For upright position, N170 amplitudes in the right occipito temporal region did not differ between natural faces and Arcimboldo paintings but were larger for both of these categories than for objects, supporting the view that as early as the N170 time-window, the right hemisphere is involved in holistic perceptual processing of face-like configurations irrespective of their features. Conversely, in the left hemisphere, N170 amplitudes differed between Arcimboldo portraits and natural faces, suggesting that this hemisphere processes local facial features. For upside-down orientation in both hemispheres, N170 amplitudes did not differ between Arcimboldo paintings and objects, but were reduced for both categories compared to natural faces, indicating that the disruption of holistic processing with inversion leads to an object-like processing of Arcimboldo paintings due to the lack of local facial features. Overall, these results provide evidence that global/holistic perceptual processing of faces and face-like formats involves the right hemisphere as early as the N170 time-window, and that the local processing of face features is rather implemented in the left hemisphere. PMID- 23816563 TI - Measurement of free carnitine and acylcarnitines in plasma by HILIC-ESI-MS/MS without derivatization. AB - Measurement of carnitine and acylcarnitines in plasma is important in diagnosis of fatty acid beta-oxidation disorders and organic acidemia. The usual method uses flow injection tandem mass spectrometry (FIA-MS/MS), which has limitations. A rapid and more accurate method was developed to be used for high-risk screening and diagnosis. Carnitine and acylcarnitines were separated by hydrophilic interaction liquid chromatography (HILIC) without derivatization and detected with a QTRAP MS/MS System. Total analysis time was 9.0min. The imprecision of within- and between-run were less than 6% and 17%, respectively. Recoveries were in the range of 85-110% at three concentrations. Some acylcarnitine isomers could be separated, such as dicarboxylic and hydroxyl acylcarnitines. The method could also separate interferent to avoid false positive results. 216 normal samples and 116 patient samples were detected with the validated method, and 49 patients were identified with fatty acid oxidation disorders or organic acidemias. PMID- 23816564 TI - Recent advances in the application of metabolomics to Alzheimer's Disease. AB - The pathophysiological changes associated with Alzheimer's Disease (AD) begin decades before the emergence of clinical symptoms. Understanding the early mechanisms associated with AD pathology is, therefore, especially important for identifying disease-modifying therapeutic targets. While the majority of AD clinical trials to date have focused on anti-amyloid-beta (Abeta) treatments, other therapeutic approaches may be necessary. The ability to monitor changes in cellular networks that include both Abeta and non-Abeta pathways is essential to advance our understanding of the etiopathogenesis of AD and subsequent development of cognitive symptoms and dementia. Metabolomics is a powerful tool that detects perturbations in the metabolome, a pool of metabolites that reflects changes downstream of genomic, transcriptomic and proteomic fluctuations, and represents an accurate biochemical profile of the organism in health and disease. The application of metabolomics could help to identify biomarkers for early AD diagnosis, to discover novel therapeutic targets, and to monitor therapeutic response and disease progression. Moreover, given the considerable parallel between mouse and human metabolism, the use of metabolomics provides ready translation of animal research into human studies for accelerated drug design. In this review, we will summarize current progress in the application of metabolomics in both animal models and in humans to further understanding of the mechanisms involved in AD pathogenesis. PMID- 23816565 TI - Sphingosine kinase-1 inhibition protects primary rat hepatocytes against bile salt-induced apoptosis. AB - Sphingosine kinases (SphKs) and their product sphingosine-1-phosphate (S1P) have been reported to regulate apoptosis and survival of liver cells. Cholestatic liver diseases are characterized by cytotoxic levels of bile salts inducing liver injury. It is unknown whether SphKs and/or S1P play a role in this pathogenic process. Here, we investigated the putative involvement of SphK1 and S1P in bile salt-induced cell death in hepatocytes. Primary rat hepatocytes were exposed to glycochenodeoxycholic acid (GCDCA) to induce apoptosis. GCDCA-exposed hepatocytes were co-treated with S1P, the SphK1 inhibitor Ski-II and/or specific antagonists of S1P receptors (S1PR1 and S1PR2). Apoptosis and necrosis were quantified. Ski II significantly reduced GCDCA-induced apoptosis in hepatocytes (-70%, P<0.05) without inducing necrosis. GCDCA increased the S1P levels in hepatocytes (P<0.05). GCDCA induced [Ca(2+)] oscillations in hepatocytes and co-treatment with the [Ca(2+)] chelator BAPTA repressed GCDCA-induced apoptosis. Ski-II inhibited the GCDCA-induced intracellular [Ca(2+)] oscillations. Transcripts of all five S1P receptors were detected in hepatocytes, of which S1PR1 and S1PR2 appear most dominant. Inhibition of S1PR1, but not S1PR2, reduced GCDCA-induced apoptosis by 20%. Exogenous S1P also significantly reduced GCDCA-induced apoptosis (-50%, P<0.05), however, in contrast to the GCDCA-induced (intracellular) SphK1 pathway, this was dependent on S1PR2 and not S1PR1. Our results indicate that SphK1 plays a pivotal role in mediating bile salt-induced apoptosis in hepatocytes in part by interfering with intracellular [Ca(2+)] signaling and activation of S1PR1. PMID- 23816566 TI - Egr1 regulates lithium-induced transcription of the Period 2 (PER2) gene. AB - A growing body of evidence suggests that the circadian molecular system is involved in the pathogenic and therapeutic mechanisms underlying bipolar disorders. Lithium, a representative mood stabilizer, has been reported to induce the Period 2 (PER2) gene; however, the underlying molecular mechanisms require further study. We found that lithium upregulated PER2 expression at the transcriptional level in neuronally differentiated SH-SY5Y human neuroblastoma cells. Promoter reporter analyses using serial deletions of the PER2 promoter revealed that two early growth response 1 (Egr1)-binding sites (EBS) between positions -180 and -100 are required for maximal activation of the PER2 promoter by lithium. Ectopic expression of Egr1 enhanced lithium-induced PER2 promoter activity, while a point mutation in EBS abolished it. Electrophoretic mobility shift assays and chromatin immunoprecipitation indicated that Egr1 bound directly to the PER2 promoter. Stimulation of the extracellular-signal regulated kinase (ERK)1/2/Elk1 pathway by lithium was functionally linked to PER2 expression through Egr1 induction, and lithium-induced PER2 expression was strongly attenuated by depletion of Egr1 by siRNA. Lithium also upregulated the expression of Per2 and Egr1 in mouse frontal cortex. Induction of Per2 by lithium was attenuated in Egr1(-/-) mice. In conclusion, lithium stimulates PER2 transcription through the ERK/Elk1/Egr1 pathway in neuronal cells, indicating a connection between the ERK-Egr1 pathway and a circadian gene system in the mechanism of action of lithium. PMID- 23816567 TI - Phosphorylation and degradation of S6K1 (p70S6K1) in response to persistent JNK1 Activation. AB - S6K (ribosomal S6 kinase p70, p70S6K) activation requires phosphorylation at two stages. The first phosphorylation is independent of insulin stimulation and mediated by an unknown kinase. The second phosphorylation is mediated by mTOR in insulin dependent manner. In this study, we identified JNK1 (c-Jun N-terminal kinase 1) as a kinase in the first phosphorylation. S6K protein was phosphorylated by JNK1 at S411 and S424 in the carboxyl terminal autoinhibitory domain. The phosphorylation was observed in kinase assay with purified S6K as a substrate, and in cells after JNK1 activation by TNF-alpha or MEKK1 expression. The phosphorylation was detected in JNK2 null cells, but not in JNK1 null cells after TNF-alpha treatment. When JNK1 activation was inhibited by MKK7 knockdown, the phosphorylation was blocked in cells. The phosphorylation led to S6K protein degradation in NF-kappaB deficient cells. The degradation was blocked by inhibition of proteasome activity with MG132. In wide type cells, the phosphorylation did not promote S6K degradation when IKK2 (IKKbeta, IkappaB kinase beta) was activated. Instead, the phosphorylation allowed S6K activation by mTOR, which stabilizes S6K protein. In IKK2 null cells or cells treated by IKK2 inhibitor, the phosphorylation led to S6K degradation. These data suggest that S6K is phosphorylated by JNK1 and the phosphorylation makes S6K protein unstable in the absence of IKK2 activation. This study provides a mechanism for regulation of S6K protein stability. PMID- 23816569 TI - Reactive arthritis induced by intravesical BCG therapy for bladder cancer: our clinical experience and systematic review of the literature. AB - OBJECTIVE: Intravesical instillation of BCG (ivBCG) is an effective and safe immunotherapy of bladder carcinoma but it may have, as side effect, a reactive arthritis (ReA). The authors describe 5 cases observed during their own clinical experience along with the updated review of the literature on this topic. METHODS: Seventy-three papers were present in the world literature, each reporting almost 1 case for a total of 112 patients. However, the review focused on 61 papers, selected on the basis of reporting suitable for a correct clinical evaluation; thus, a total of 89 patients, including the cases observed in our clinic, were carefully analyzed. RESULTS: Among the 89 patients identified 73 were males and 16 females. Europe is the geographical area with the higher number of reports, namely 80.6% of the papers including 74.2% of the patients. The Mediterranean area accounts for 62.9% of the papers and 59.6% of the cases. The symptoms of ReA appeared after a mean number of instillations of 5.8. Polyarthritis was present in 55.1%, oligoarthritis in 37.0% and monoarthritis in 7.9%. Polyarthritis was symmetric in 51.0% and asymmetric in 49.0% of the cases; oligoarthritis was symmetric in 33.3% and asymmetric in 66.7% of the cases. Overall, an asymmetric distribution of arthritis was present in 59.6%. Knee and ankle were the joints most frequently involved. The antigen HLA B27 was positive in 42.6%. The synovial fluid analysis was defined as flogistic-aseptic in 71.9% of the patients. Arthritis was recovered within 6months in 93.2% of the cases and in 70.5% of the patients within the first two months. NSAIDs and corticosteroids, alone or in conjunction with other drugs, are used in 65.1% and in 40.4% of the cases, respectively. The clinical features of ivBCG ReA are compared with ReA from other triggering agents, from which it differs for some clinical aspects and overlaps for others. CONCLUSIONS: Compared with a previous report, this review allows to modify some figures of this topic as a reduced prevalence of polyarthritis (from 70% to 55.1%) and of spinal and sacroiliac involvement; polyarthritis remains the more frequent clinical pattern of ivBCG ReA that, however, is characterized by rather asymmetrical distribution and involvement of the large joints of lower limbs. A definite linkage to HLA B27 is present, although without prognostic value. Moreover, arthritis is aseptic, has a latency time from antigen exposure, and is associated with extra-articular features as commonly observed in ReA from other triggering agents. Arthritis is usually benign and rarely develops into a chronic form. NSAIDs and/or corticosteroids are largely effective. Noteworthy, the overall clinical picture of arthritis triggered by ivBCG emerging from this updated review is comparable to that of ReA from other bacterial agents. PMID- 23816570 TI - Stent, balloon-assisted coiling and double microcatheter for treating wide-neck aneurysms in anterior cerebral circulation. AB - OBJECTIVE: To investigate the clinical application of adjuvant coiling techniques in treating anterior-circulation wide-necked aneurysms. METHODS: Over 4.5 years, 93 anterior-circulation wide-neck aneurysms in 81 patients were treated with different endovascular techniques: balloon-assisted, stent-assisted, and double microcatheter coiling. Demographic, clinical, and angiographic data were reviewed retrospectively. RESULTS: Of the 93 aneurysms, 45 were treated using stent, 28 using balloon, and 20 using double microcatheter. The proportion of ruptured aneurysms was significantly lower in the stent group (53.3%) than in the balloon (71.4%) or the double-microcatheter group (75%). Stent embolization was used for 61.1% of aneurysms located in the internal carotid artery, whereas aneurysms in the anterior communicating and middle cerebral arteries were mainly treated with balloon remodeling (42.9%) and double microcatheter (52.4%). The majority of aneurysms with neck ? 7 mm (87.5%) and all aneurysms with a dome/neck ratio < 1.0 (100%) were treated by stent-assisted coiling. For aneurysms with neck < 4 mm, the mean dome/neck ratio was 0.93 in the stent group, 1.08 in the balloon group, and 1.16 in the double-microcatheter group. Total occlusion was achieved in 21 cases (46.7%), with the rates for stent being significantly lower than for balloon (78.6%) or double microcatheter (75.0%). Clinical outcome was favorable in 73 cases (Glasgow Outcome Scale (GOS) 4-5) and fair in 4 (GOS 3), while 2 were severely disabled (GOS 2) and 2 others died (GOS 1). CONCLUSION: Double microcatheter was better for distal aneurysms with dome/neck ratio of 1.1-1.2, while stent was better for proximal aneurysms with an extremely wide neck (>= 7 mm) and for loudspeaker-shaped aneurysms (dome/neck ratio < 1.0) with poor vessel condition. For emergency cases, both balloon remodeling and double microcatheter are better choices than stent. PMID- 23816571 TI - Prepubertal children with growth hormone deficiency treated for four years with growth hormone experience dose-dependent increase in height, but not in the rate of puberty initiation. AB - BACKGROUND/AIMS: Limited data exist on long-term dose response to recombinant human growth hormone (rhGH) in prepubertal GH-deficient (GHD) children. The effect of low, intermediate, and high-dose rhGH (25, 50, and 100 MUg/kg/day, respectively) on growth and puberty in children with GHD was investigated for 48 months. METHODS: A prospective, dose-response study in 111 patients (aged 3-16 years) evaluated growth velocity (cm/year), height standard deviation score (HSDS), corrected HSDS, bone age/chronologic age ratio, body mass index SDS, and the percentage starting puberty. RESULTS: Dose-related increases were observed in growth velocity (p < 0.001), HSDS (p < 0.001), and corrected HSDS (p < 0.001) from baseline to 48 months. Increases in the bone age/chronologic age ratio (p = 0.043) and body mass index SDS (p = 0.018) occurred up to 36 months at intermediate and high doses versus low-dose rhGH; increases at 48 months were not significant. No significant differences in growth were found between intermediate and high doses of rhGH. Percentages of rhGH-treated patients starting puberty at each dose were equivalent (p = 0.607). CONCLUSIONS: rhGH, 50 and 100 MUg/kg/day, induced greater growth than 25 MUg/kg/day without altering the proportion of children starting puberty. The maximum approved dose for pubertal patients (100 MUg/kg/day) is not required or recommended for prepubertal children with GHD. PMID- 23816568 TI - Amyloid beta-induced glycogen synthase kinase 3beta phosphorylated VDAC1 in Alzheimer's disease: implications for synaptic dysfunction and neuronal damage. AB - Glycogen synthase kinase 3 (GSK3) is a serine/threonine protein kinase that is involved in the multiple signaling processes of a cell. Increasing evidence suggests that GSK3beta plays a key role in multiple cellular processes in the progression of diabetes, obesity, Alzheimer's disease (AD), Parkinson's disease (PD), inflammatory diseases, schizophrenia, bipolar and several mood disorders, and mitochondrial diseases. Recent research has found that increased GSK3beta activity is linked to the pathogenesis of AD through amyloid beta (Abeta), phosphorylated tau and mitochondrial dysfunction. Recent research has also revealed that GSK3beta is elevated in AD-affected tissues and is critically involved in dissociating the voltage-dependent anion channel 1 (VDAC1) protein from hexokinases, and causing disrupted glucose metabolism, mitochondrial dysfunction and activating apoptotic cell death. The purpose of this article is to review recent research that is elucidating the role of GSK3beta in AD pathogenesis. We discuss the involvement of GSK3beta in the phosphorylation of VDAC1 and dissociation of VADC1 with hexokinases in AD neurons. PMID- 23816572 TI - Do growth-stimulated retinal ganglion cell axons find their central targets after optic nerve injury? New insights by three-dimensional imaging of the visual pathway. AB - Retinal ganglion cells (RGCs) do not normally regenerate injured axons. However, several strategies to transform RGCs into a potent regenerative state have been developed in recent years. Intravitreal CNTF application combined with conditional PTEN and SOCS3 deletion or zymosan-induced inflammatory stimulation together with cAMP analogue injection and PTEN-deletion in RGCs induce long distance regeneration into the optic nerve of adult mice. A recent paper by the Benowitz group (de Lima et al.) claimed that the latter treatment enables full length regeneration, with axons correctly navigating to their central target zones and partial recovery of visual behaviors. To gain a more detailed view of the extent and the trajectories of regenerating axons, Luo et al. applied a tissue clearing method and fluorescent microscopy to allow the tracing of naive and regenerating RGC axons in whole ON and all the way to their brain targets. Using this approach, the authors found comparable axon regeneration in the optic nerve after both above-mentioned experimental treatments. Regeneration was accompanied by prevalent aberrant axon growth in the optic nerve and significant axonal misguidance at the optic chiasm. Less than 120 axons per animal reached the optic chiasm and only few entered the correct optic tract. Importantly, no axons reached visual targets in the olivary pretectal nucleus, the lateral geniculate nucleus or the superior colliculus, thereby contradicting and challenging previous claims by the Benowitz group. The data provided by Luo et al. rather suggest that potent stimulation of axonal growth per se is insufficient to achieve functional recovery and underscore the need to investigate regeneration-relevant axon guidance mechanisms in the mature visual system. PMID- 23816573 TI - Comparison of percutaneous nephrolithotomy, shock wave lithotripsy, and retrograde intrarenal surgery for lower pole renal calculi 10-20 mm. AB - OBJECTIVE: To compare the results of percutaneous nephrolithotomy (PCNL), shock wave lithotripsy (SWL), and retrograde intrarenal surgery (RIRS) for 1- to 2-cm lower pole kidney stones. PATIENTS AND METHODS: This retrospective study was based on data collected from the files of patients between January 2007 and May 2012. The files of 383 patients (221 SWL, 144 PCNL, 38 RIRS) were evaluated. The groups were compared for stone size, success rate, and complication rate using the modified Clavien grading system. RESULTS: The stone burdens of the groups were similar (p = 0.36). The success rates were 76, 94, and 73%, respectively, in SWL, PCNL, and RIRS. The highest stone-free rate was in the PNL group (p < 0.05). When the complication rates were evaluated using the Clavien grading system, they were determined to be 13% in PCNL, 3% in SWL, and 5% in RIRS. Especially GII and GIII complications were more common in the PCNL group (p < 0.05). CONCLUSION: PCNL seems to be the most successful but most invasive method. However, with relatively low complication rates, SWL and RIRS are other techniques to keep in mind. To determine the first-line treatment, prospective randomized studies with larger series are needed. PMID- 23816574 TI - Total energy expenditure of 16 Chinese young men measured by the doubly labeled water method. AB - OBJECTIVE: Doubly labeled water (DLW) method is the gold standard for measuring total energy expenditure (TEE). We used this method to measure TEE in Chinese young men. METHODS: Sixteen healthy young men age 23+/-1 years with body mass index 22.0+/-1.4 kg/m2 were recruited. TEE was measured by the DLW method, and basal energy expenditure (BEE) was determined by indirect calorimetry. We also conducted 24-h activity, energy balance and factorial approach to estimate energy requirements of the subjects. RESULTS: TEE of subjects by DLW method was 9.45+/ 0.57 MJ/day (2258+/-180 kcal/day). The 24-h activity was 10.80+/-0.33 MJ/day (2582+/-136 kcal/day). The energy requirement, derived from energy balance observations, was 9.93+/-1.32 MJ/day (2373+/-315 kcal/day). The BEE of 6.65+/ 0.28 MJ/day (1589+/-67 kcal/day), calculated by the adjusted Schofield equation, was significantly higher (P<0.001) than that measured by indirect calorimetry, 5.99+/-0.66 MJ/day (1433+/-158 kcal/day). The TEE derived from the factorial approach was 10.31+/-0.43 MJ/day (2463+/-104 kcal/day). CONCLUSION: The TEE of Chinese young men measured by the DLW method was about 10% lower than the current recommended nutrient intake (RNI), suggesting that the RNI for Chinese men maybe overestimated. Further studies are warranted to determine the value of the estimated energy requirement. PMID- 23816575 TI - Dietary exposure of the Chinese population to acrylamide. AB - OBJECTIVE: To assess the current status of the acrylamide in the Chinese food supply, the dietary acrylamide exposure in the Chinese population and to estimate the public health risks of the current consumption. METHODS: The acrylamide content in the total diet study (TDS) food samples was analyzed using an LC-MS/MS method. Based on the analytical results, the dietary exposure calculations were performed using a deterministic method, combining mean acrylamide concentrations from the food group composite with their associated food consumptions. RESULTS: Acrylamide was detected in 43.7% of all samples collected and acrylamide concentration varied from ND to 526.6 ug/kg. The estimated dietary intakes of acrylamide among Chinese general population given as the mean and the 95th percentile (P95) were 0.286 and 0.490 ug*kg(-1) bw*day(-1), respectively. The margins of exposure (MOEs) for the population calculated using both benchmark dose lower confidence limit for a 10% extra risk of tumors in animals (BMDL10) 0.31 and 0.18 ug*kg(-1) bw*day(-1), were 1069 and 621 for the mean dietary exposure, and 633 and 367 for the high dietary exposure respectively. CONCLUSION: These MOE values might indicate a human health concern on acrylamide for Chinese population. Efforts should continue to reduce acrylamide levels in food in order to reduce the dietary risks to the human health. PMID- 23816576 TI - Characterization of Staphylococcus aureus isolated from clinical specimens by matrix assisted laser desorption/ionization time-of-flight mass spectrometry. AB - OBJECTIVE: To develop a matrix assisted laser desorption/ionization time-of flight mass spectrometry (MALDI-TOF-MS) approach to identify Staphylococcus aureus (S. aureus) and differentiate methicillin-resistant S. aureus (MRSA) from methicillin-sensitive S. aureus (MSSA). METHODS: A total of 100 S. aureus strains isolated from clinical specimens and farm workers were collected and analyzed by MALDI-TOF-MS. And data obtained were interpreted with biotyper software. RESULTS: Ninety-two strains were identified by MALDI-TOF-MS as S. aureus at a level of secure genus and probable species, and 4 strains were identified at probable genus after their cultivation, spectral collection and data preprocessing. One strain was identified as S. aureus with lower score. It was revealed that identification of S. aureus by MALDI-TOF-MS was highly correlated with typing by biochemical and serological methods with an accuracy as high as 97%. The biotyper cluster analysis showed that 100 isolates were divided into 2 types at the distance level of 400. Higher peak intensity in the mass of both 3784 Da and 5700 Da was observed in MRSA, whereas that was absent from MSSA. CONCLUSION: MALDI-TOF MS is considered a simple, rapid and highly reproducible technique with high throughput and accuracy for the identification of S. aureus and it can reliably differentiate MRSA from MSSA. PMID- 23816577 TI - The association of overweight and obesity with blood pressure among Chinese children and adolescents. AB - OBJECTIVE: To examine the association between obesity and high blood pressure (BP) in Chinese children and adolescents. METHODS: Body mass index (BMI) and blood pressure measurements of 197 191 children aged 7-17 years were obtained from a Chinese national survey in 2010. Obesity and high BP were defined according to the reference values for Chinese children. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of different BMI categories for high BP, as well as the population attributable risk percent (PAR%), were also calculated. RESULTS: The prevalence of high BP was 16.1% for boys and 12.9% for girls in 2010. Overweight and obese children had a significantly higher prevalence of high BP than non-overweight children in both boys and girls in each age group. ORs (95% CI) for high BP were 4.1 (3.9, 4.4) in obese boys and 4.0 (3.7, 4.3) in obese girls. The overall PAR% for high BP due to overweight and obesity was 14.4%. CONCLUSION: Overweight and obese children have a significantly higher risk of high BP than non-overweight children. Eliminating overweight and obesity could reduce 14.4% of high BP cases. PMID- 23816578 TI - Impact of sub-chronic aluminium-maltolate exposure on catabolism of amyloid precursor protein in rats. AB - OBJECTIVE: To investigate the impact of sub-chronic Aluminium-maltolate [Al(mal)3] exposure on the catabolism of amyloid precursor protein (APP) in rats. METHODS: Forty adult male Sprague-Dawley (SD) rats were randomly divided into five groups: the control group, the maltolate group (7.56 mg/kg BW), and the Al(mal)3 groups (0.27, 0.54, and 1.08 mg/kg BW, respectively). Control rats were administered with 0.9% normal saline through intraperitoneal (i.p.) injection. Maltolate and Al(mal)3 were administered to the rats also through i.p. injections. Administration was conducted daily for two months. Rat neural behavior was examined using open field tests (OFT). And the protein expressions and their mRNAs transcription related with APP catabolism were studied using enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (RT-PCR). RESULTS: The expressions of APP, beta-site APP cleaving enzyme 1 (BACE1) and presenilin-1 (PS1) proteins and their mRNAs transcription increased gradually with the increase of Al(mal)3 doses (P<0.05). The enzyme activity of BACE1 in the 0.54 and 1.08 mg/kg Al(mal)3 groups increased significantly (P<0.05). The expression of beta-amyloid protein (Abeta) 1-40 gradually decreased while the protein expression of Abeta1-42 increased gradually with the increase of Al(mal)3 doses (P<0.05). CONCLUSION: Result from our study suggested that one of the possible mechanisms that Al(mal)3 can cause neurotoxicity is that Al(mal)3 can increase the generation of Abeta1-42 by facilitating the expressions of APP, beta-, and gamma-secretase. PMID- 23816579 TI - Socio-economic and psychosocial determinants of smoking and passive smoking in older adults. AB - OBJECTIVE: To determine the associations of socio-economic and psychosocial factors with active and passive smoking in older adults. METHODS: Using a standard interview method, we examined random samples of 6071 people aged?60 years in 5 provinces of China during 2007-2009. RESULTS: World age-standardised prevalence for current and former smoking in men was 45.6% and 20.5%, and in women 11.1% and 4.5%. Current smoking reduced with older age but increased with men, low socioeconomic status (SES), alcohol drinking, being never-married, pessimistic and depressive syndromes. Former smoking was associated with men, secondary school education, a middle-high income, being a businessman, being widowed, less frequencies of visiting children/relatives and friends, and worrying about children. Among 3774 never-smokers, the prevalence of passive smoking was 31.5%, and the risk increased with women, low SES, alcohol drinking, being married, having a religious believe, and daily visiting children/relatives. There were sex differences in the associations, and an interaction effect of education and income on smoking and passive smoking. CONCLUSION: Older Chinese had a higher level of smoking and passive smoking than those in high income countries, reflecting China's failures in controlling smoking. The associations with low SES and different psychosocial aspects and sex differences suggest preventative strategies for active and passive smoking. PMID- 23816580 TI - Effectiveness analysis on the physical activity and the health benefit of a community population based program. AB - OBJECTIVE: To evaluate the community-based health promotion effect of physical activity. METHODS: The residents aged 18 and above from two communities in Gongshu District of Hangzhou City, Zhejiang province, were randomly selected and recruited for the multi-strategy and comprehensive physical activity intervention. Questionnaire survey, physical check up and blood biochemistry were conducted. RESULTS: After this two-year intervention, the time of the participant spent on weekly physical activity of moderate intensity increased from 464 min to 542 min (P<0.05), with an average increase of 78 min. Time spent in walking every week increased from 533 min to 678 min (P<0.05), with an average increase of 145 min. The body weight, waistline, blood pressure and heart rate all reduced significantly (P<0.05); the vital capacity increased significantly (P<0.05); and the related biochemical indicators were also improved. CONCLUSION: Comprehensive and evidence-based physical activity interventions targeting community population can improve the levels of physical activity, related body measurement and biochemical indicators. PMID- 23816581 TI - Effects of environmental lead pollution on blood lead and sex hormone levels among occupationally exposed group in an E-waste dismantling area. AB - OBJECTIVE: To study the effects of environmental multi-media lead pollution on blood lead and sex hormone levels among lead exposed males engaged in E-waste dismantling, and the correlation between confounding factors and sex hormone levels. METHODS: An E-waste dismantling area in Taizhou of Zhejiang Province was selected as the research site. One hundred and fifty two samples were collected from the groundwater, soil, rice, corn, chicken, and pork in the dismantling area. The effects of the multi-media lead pollution on the male blood lead and sex hormone levels of FSH, LH, and T, as well as the correlation with confounding factors, were studied. RESULTS: The blood lead concentrations in the males aged under 31, from 31 to 45 and from 46 to 60 were 98.55, 100.23, and 101.45 MUg/L, respectively. Of all the environmental media lead exposures, the groundwater, rice and soil were main contributing factors to the lead accumulation in humans. FSH and LH levels increased with the age while the T levels decreased with the age instead. There was a significant correlation between the FSH and LH levels and wearing masks. CONCLUSION: There was correlation between the FSH, LH, and T levels, and the mean values of lead concentrations in environmental media, and the sex hormone levels were correlated with the confounding factor of wearing masks. PMID- 23816582 TI - BMI, WC, WHtR, VFI and BFI: which indictor is the most efficient screening index on type 2 diabetes in Chinese community population. AB - OBJECTIVE: Obesity is a major risk factor for type 2 diabetes, many indexes can be used to describes obesity and predict diabetes. This research attempts to identify the best indicator of obesity to screening diabetes in Chinese population. METHODS: A cross-sectional data of 8121 subjects aged 35-60 years were included in this research belongs to the Diabetes Appropriate Technology Intervention Study. Anthropometric indicators including body weight, height, waist circumferences (WC), body fat index (BFI) and visceral fat index (VFI) and blood biochemical indicators after an overnight fast [fasting blood glucose, total cholesterol, high-density lipoprotein (HDL) cholesterol, and triacylglycerol] were measured. BMI (body mass index) and Weight to Height Ratio was calculated. RESULTS: Subjects with obesity had a higher risk of physician diagnosed diabetes (OR=2.50, 95% CI 1.83-3.43), new diagnosed diabetes (OR=4.23, 95% CI 2.91-6.15) and pre-diabetes (OR=1.75, 95% CI 1.31-2.34) compared to those with normal Body mass index (BMI). There was a significant trend of increased risk of all diabetes status with increased waist circumference (WC). The waist-to height ratio (WHtR) yielded the most significant association with new diagnosed diabetes and physician diagnosed diabetes than other indices. CONCLUSION: Central obesity is significantly correlated with diabetes. VFI was most correlated with pre-diabetes while WHtR is an efficient screening index than BMI and WC in Chinese community diabetes screening. PMID- 23816583 TI - Age-related infection with Cryptosporidium species and genotype in pigs in China. AB - OBJECTIVE: Pigs, as hosts of zoonotic Cryptosporidium species/genotypes, are domestic animals with public health significance. The present study was to characterize the infection rate and species/genotype of Cryptosporidium in pre weaned and post-weaned pigs from Shanghai and Shaoxing, China. METHODS: A total of 208 fecal samples (42 from pre-weaned piglets, and 166 from post-weaned pigs) were examined by nested PCR of the 18S rRNA gene and analyzed by phylogenetic DNA fragment sequencing of secondary PCR products. RESULTS: Infection was detected in 79 samples (19/42 pre-weaned piglets, and 60/166 post-weaned pigs). C. suis (14/79) and Cryptosporidium pig genotype II (65/79) were identified; piglets were more susceptible to the former (13/14) and post-weaned pigs to the latter (59/65). CONCLUSION: Infection of Cryptosporidium spp. in pigs was age-specific; piglets were more susceptible to C. suis while pigs were more susceptible to Cryptosporidium pig genotype II. These findings combined with the isolation of the two Cryptosporidium from water suggest that pigs may be a source of zoonotic Cryptosporidium water pollution. Improvements in pig feeding practices, sewage discharge, feces disposal and field worker protection are therefore important to prevent potential public health problems. PMID- 23816584 TI - A better instrument for screening diabetes in rural areas of China: an equation developed from multivariate logistic regression or a simplified scoring form. PMID- 23816585 TI - Correlation of inferior vena cava respiratory variability index with central venous pressure and hemodynamic parameters in ventilated pigs with septic shock. PMID- 23816586 TI - Molecular typing of Brucella suis collected from 1960s to 2010s in China by MLVA and PFGE. PMID- 23816587 TI - Analysis of paraquat intoxication epidemic (2002-2011) within China. PMID- 23816588 TI - Establishment of occupational exposure limit for warfarin in China. AB - This study aims to establish the occupational exposure limit (OEL) in the air for workplace of warfarin based on the available toxicological studies and field investigations by using questionnaire and air monitoring. The clinical therapeutic dose was used as lowest observed effect level (LOEL), and no observed effect level (NOEL) was achieved by using a safety factor. The highest concentration of warfarin monitored in the worksite of centrifuge washing, drying and packing were 0.029 mg/m3, 0.051 mg/m3 respectively, which did not exceed the OEL 0.1 mg/m3 recommended by NIOSH and ACGIH. Considering its feasibility for enforcement and protection for workers, we recommend OEL 0.1 mg/m3 of warfarin in China. PMID- 23816589 TI - A selective and sensitive UPLC-MS/MS approach for trace level quantification of four potential genotoxic impurities in zolmitriptan drug substance. AB - The pivotal task of pharmaceutical industry is to separate and quantify the potential genotoxic impurities (PGIs) rising from the process of drug production. For trace level quantification of these PGIs we need to develop sensitive and selective analytical methods. APP, NPA, NPP and MNA have been highlighted as PGIs in zolmitriptan. A sensitive and selective UPLC-MS/MS method has developed for identification and quantification of four PGIs viz. APP, NPA, NPP and MNA in zolmitriptan. The method utilizes Hypersil BDS C8 column (50 mm * 4.6 mm, 3.0 MUm) with electrospray ionization in selected ion recording (SIR) mode for quantitation of four PGIs. The method was validated as per International Conference on Harmonization (ICH) guidelines and is able to quantitate APP at 0.1 ppm and NPA, NPP and MNA at 0.15 ppm with respect to 5.0mg/mL of zolmitriptan. The proposed method is specific, linear, accurate and precise. The method is linear in the range of 0.1-2.0 ppm for APP and 0.15-2.0 ppm for NPA, NPP and MNA, which matches the range of LOQ-200% of estimated permitted level (1.0 ppm). The correlation coefficient obtained was >0.999 in each case. The impurities were not present in the studied three pure and formulation batches of zolmitriptan. The accuracy of the method was ranged between 98.1 and 102.8% for four PGIs. This method is a good quality control tool for quantitation of four APP, NPA, NPP and MNA PGIs at very low levels in zolmitriptan. PMID- 23816590 TI - Adaptive testing for psychological assessment: how many items are enough to run an adaptive testing algorithm? AB - Although the principles of adaptive testing were established in the psychometric literature many years ago (e.g., Weiss, 1977), and practice of adaptive testing is established in educational assessment, it not yet widespread in psychological assessment. One obstacle to adaptive psychological testing is a lack of clarity about the necessary number of items to run an adaptive algorithm. The study explores the relationship between item bank size, test length and measurement precision. Simulated adaptive test runs (allowing a maximum of 30 items per person) out of an item bank with 10 items per ability level (covering .5 logits, 150 items total) yield a standard error of measurement (SEM) of .47 (.39) after an average of 20 (29) items for 85-93% (64-82%) of the simulated rectangular sample. Expanding the bank to 20 items per level (300 items total) did not improve the algorithm's performance significantly. With a small item bank (5 items per ability level, 75 items total) it is possible to reach the same SEM as with a conventional test, but with fewer items or a better SEM with the same number of items. PMID- 23816591 TI - DIF Cancellation in the Rasch Model. AB - Differential item functioning (DIF) cancellation occurs when the cumulative effect of an item or set of items exhibiting DIF against one subgroup cancels with other items that exhibit DIF against the comparison group and hence results in non-existent DIF at the test level. This paper investigates DIF cancellation in the context of Rasch measurement. It is shown that this phenomenon is not a property of the Rasch model, but rather, a function of the manner in which item parameters are estimated and the way that DIF impacts these estimates. The conditions under which DIF cancellation would exist when using the Rasch model are suggested and a proof is provided to support this suggestion. Empirical examples are provided to refute prior suggestions that DIF cancellation always exists if the Rasch model is used. PMID- 23816592 TI - A multidimensional diagnostic perspective on academic achievement goal orientation structure, using the Rasch measurement models. AB - This study is designed to investigate a multidimensional structure of academic achievement goal orientations from a diagnostic perspective, using the Rasch measurement models. A data set of Korean students who responded to the Patterns of Adaptive Learning Survey (PALS) was analyzed. Both consecutive unidimensional and multidimensional Rasch measurement models were applied for comparative purposes. Each goal orientation dimension (i.e., the attitude) was standardized and then classified into three categorical levels, i.e., low, middle and high. These categorizations of goal dimensions were used to examine the role of students' performance-approach goals on mathematics achievement in relation with the other achievement goals. Results indicate that the multidimensional partial credit model was the best model with respect to the fit of the data to the models. Findings of the current study also demonstrate that practitioners who need specific feedback for instruction and/or intervention can benefit from the multidimensional approach. PMID- 23816593 TI - An extension of a bayesian approach to detect differential item functioning. AB - The application of the existing test statistics to determine differential item functioning (DIF) requires large samples, but test administrators often face the challenge of detecting DIF with small samples. One advantage of a Bayesian approach over a frequentist approach is that the former can incorporate, in the form of a prior distribution, existing information on the inference problem at hand. Sinharay, Dorans, Grant, and Blew (2009) suggested the use of information from past data sets as a prior distribution in a Bayesian DIF analysis. This paper suggests an extension of the method of Sinharay et al. (2009). The suggested extension is compared to the existing DIF detection methods in a realistic simulation study. PMID- 23816594 TI - The development of the de morton mobility index (DEMMI) in an older acute medical population: item reduction using the Rasch model (part 1). AB - The DEMMI (de Morton Mobility Index) is a new and advanced instrument for measuring the mobility of all older adults across clinical settings. It overcomes practical and clinimetric limitations of existing mobility instruments. This study reports the process of item reduction using the Rasch model in the development of the DEMMI. Prior to this study, qualitative methods were employed to generate a pool of 51 items for potential inclusion in the DEMMI. The aim of this study was to reduce the item set to a unidimensional subset of items that ranged across the mobility spectrum from bed bound to high levels of independent mobility. Fifty-one physical performance mobility items were tested in a sample of older acute medical patients. A total of 215 mobility assessments were performed. Seventeen mobility items that spanned the mobility spectrum were selected for inclusion in the new instrument. The 17 item scale fitted the Rasch model. Items operated consistently across the mobility spectrum regardless of patient age, gender, cognition, primary language or time of administration during hospitalisation. Using the Rasch model, an interval level scoring system was developed with a score range of 0 to 100. PMID- 23816595 TI - A comparison of confirmatory factor analysis and multidimensional Rasch models to investigate the dimensionality of test-taking motivation. AB - Using a scale of test-taking motivation designed to have multiple factors, results are compared from a confirmatory factor analysis (CFA) using LISREL and a multidimensional Rasch partial credit model using ConQuest. Both types of analyses work with latent factors and allow the comparison of nested models. CFA models most typically model a linear relationship between observed and latent variables, while Rasch models specify a non-linear relationship between observed and latent variables. The CFA software provides many more measures of overall fit than ConQuest, which is focused more on the fit of individual items. Despite the conceptual differences in these techniques, the results were similar. The data fit a three-dimensional model better than the one-dimensional or two-dimensional models also hypothesized, although some misfit remained. PMID- 23816596 TI - Measuring alternative learning outcomes: dispositions to study in higher education. AB - In this paper we describe the validation of two scales constructed to measure pre university students' changing disposition (i) to enter Higher Education (HE) and (ii) to further study mathematically-demanding subjects. Items were selected drawing on interview data, and on a model of disposition as socially- as well as self- attributed. Rasch analyses showed that the two scales each produce robust one-dimensional measures on what we call a 'strength of commitment to enter HE' and 'disposition to study mathematically-demanding subjects further' respectively. However, the former scale was initially found to suffer psychometrically from a ceiling effect, which we 'corrected' by adding some harder items at a later data point, and revised the scale according to our interpretation of subsequent results. We finally discuss the potential significance of the constructed measures of learning outcomes, as variables in monitoring or even explaining students' progress into different subjects in HE. PMID- 23816597 TI - Relationship between vitreous temperature and posterior vitreous detachment. AB - The aim of this study is to examine the relationship between vitreous temperature and posterior vitreous detachment (PVD). 30 porcine eyes were hemisected to form eyecups. In 10 eyes, the vitreous was warmed to 37 +/- 1 degrees C for 1 min and cooled down to room temperature. In 10 eyes, the vitreous was warmed to 44 +/- 1 degrees C for 1 min and cooled down to room temperature. 10 eyes were kept at room temperature. The vitreous was then removed surgically by forceps. In the eyes that were kept at room temperature (n=10), and in the eyes that the vitreous was warmed to 37 +/- 1 degrees C (n=10), the vitreous removal caused significant retinal damage, detachment and fold, and choroidal detachment. In the eyes that the vitreous was warmed to 44 +/- 1 degrees C (n=10), the vitreous removal did not cause any observable changes in the retina and choroid. Therefore, the vitreous separates from the retina after warming to 44 +/- 1 degrees C. The effect is likely irreversible through vitreous liquefaction. Thermal effect might have caused PVD in some patients. Since cell death occurs at above 55-58 degrees C, the effect can potentially be safe and beneficial in surgical separation of the vitreous. Evidence is provided to show that this technique could be safely performed in vivo in humans, and that it would lead to safer removal of the vitreous during vitrectomy with fewer post-operative complications. PMID- 23816598 TI - The emerging role of the parabrachial complex in the generation of wakefulness drive and its implication for respiratory control. AB - The parabrachial complex is classically seen as a major neural knot that transmits viscero- and somatosensory information toward the limbic and thalamic forebrain. In the present review we summarize recent findings that imply an emerging role of the parabrachial complex as an integral part of the ascending reticular arousal system, which promotes wakefulness and cortical activation. The ascending parabrachial projections that target wake-promoting hypothalamic areas and the basal forebrain are largely glutamatergic. Such fast synaptic transmission could be even more significant in promoting wakefulness and its characteristic pattern of cortical activation than the cholinergic or mono aminergic ascending pathways that have been emphasized extensively in the past. A similar role of the parabrachial complex could also apply for its more established function in control of breathing. Here the parabrachial respiratory neurons may modulate and adapt breathing via the control of respiratory phase transition and upper airway patency, particularly during respiratory and non respiratory behavior associated with wakefulness. PMID- 23816601 TI - Predictors of phase III slope of nitrogen single-breath washout in COPD. AB - The nitrogen (N2) single-breath washout (SBW) test is a measure of ventilation distribution inhomogeneity and also a small airway function that offers complementary information to spirometry; however, the relevance to the forced oscillation technique (FOT) and pulmonary emphysema in COPD is not fully understood. We hypothesized that pulmonary functions, forced oscillatory parameters, and emphysema extent would contribute independently to the results of the SBW test. In this cross-sectional study we assessed the relationship between the phase III slope (delta N2) derived from N2 SBW and these parameters. Spirometry, lung volumes, N2 SBW, and the broadband frequency FOT were performed in 56 patients with COPD. Emphysema extent was measured by high-resolution computed tomography and scored. In multiple regression analyses, the delta N2 was independently predicted by forced vital capacity, resonant frequency, and emphysema score (R(2)=0.57, p<0.0001). The degree of ventilation inhomogeneity derived from N2 SBW is independently predicted by spirometry, lung mechanics, and the degree of emphysema. PMID- 23816602 TI - Reprint of: Nanocarrier systems for oral drug delivery: do we really need them? AB - In particular since the last two decades there is constantly increasing interest in nanocarrier systems. They are utilized in order to overcome the major challenges being associated with this route of administration - namely poor solubility (I), poor permeability (II) and poor GI-stability (III). In order to improve drug solubility nanonization of the API, the use of solid lipid nanoparticles and porous adsorbent particles have shown great potential. Nanocrystals and selfnanoemulsifying drug delivery systems (SNEDDS) resulted already in numerous marketed drug products. Moreover, proof-of-principle studies for nanocarrier systems providing enhanced oral drug uptake are available. By providing a comparatively more intimate contact with the absorption membrane, a prolonged GI-residence time and/or exhibiting permeation enhancing properties, oral absorption can be strongly improved. Likely because of safety considerations and because of insufficiently high bioavailability improvements (<5-fold), however, a commercial interest in these systems is limited. Poor GI-stability can be overcome by incorporating the drug in nanocarrier systems providing a protective effect towards an enzymatic attack in the GI-tract. Furthermore, as nanocarrier systems can at least to some extent diffuse into the mucus gel layer releasing their payload there, a presystemic metabolism of the drug on the way between the delivery system and the absorption membrane can be excluded. Future trends are mainly focusing on carrier systems capable of not just improving solubility but providing also controlled drug release as well as on nanocarrier systems capable of efficiently permeating the mucus gel layer without destroying it. PMID- 23816600 TI - Breathing challenges in Rett syndrome: lessons learned from humans and animal models. AB - Breathing disturbances are a major challenge in Rett Syndrome (RTT). These disturbances are more pronounced during wakefulness; but irregular breathing occurs also during sleep. During the day patients can exhibit alternating bouts of hypoventilation and irregular hyperventilation. But there is significant individual variability in severity, onset, duration and type of breathing disturbances. Research in mouse models of RTT suggests that different areas in the ventrolateral medulla and pons give rise to different aspects of this breathing disorder. Pre-clinical experiments in mouse models that target different neuromodulatory and neurotransmitter receptors and MeCP2 function within glia cells can partly reverse breathing abnormalities. The success in animal models raises optimism that one day it will be possible to control or potentially cure the devastating symptoms also in human patients with RTT. PMID- 23816599 TI - Inactivity-induced respiratory plasticity: protecting the drive to breathe in disorders that reduce respiratory neural activity. AB - Multiple forms of plasticity are activated following reduced respiratory neural activity. For example, in ventilated rats, a central neural apnea elicits a rebound increase in phrenic and hypoglossal burst amplitude upon resumption of respiratory neural activity, forms of plasticity called inactivity-induced phrenic and hypoglossal motor facilitation (iPMF and iHMF), respectively. Here, we provide a conceptual framework for plasticity following reduced respiratory neural activity to guide future investigations. We review mechanisms giving rise to iPMF and iHMF, present new data suggesting that inactivity-induced plasticity is observed in inspiratory intercostals (iIMF) and point out gaps in our knowledge. We then survey conditions relevant to human health characterized by reduced respiratory neural activity and discuss evidence that inactivity-induced plasticity is elicited during these conditions. Understanding the physiological impact and circumstances in which inactivity-induced respiratory plasticity is elicited may yield novel insights into the treatment of disorders characterized by reductions in respiratory neural activity. PMID- 23816603 TI - Chronic idiopathic acrocyanosis and methylenetetrahydrofolate reductase C677T (p.Ala222Val) and A1298C (p.Glu429Ala) polymorphisms. AB - BACKGROUND: Chronic idiopathic acrocyanosis is a common acrosyndrome. Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in the metabolism of folate. Two functional polymorphisms of MTHFR have been identified, C677T and A1298C. OBJECTIVE: To compare the prevalence of these two MTHFR polymorphisms in patients with chronic idiopathic acrocyanosis to a control group. MATERIALS AND METHODS: The study was conducted on 43 consecutive patients with acrocyanosis and on 100 controls. RESULTS: The risk of acrocyanosis was significantly higher in patients homozygous for the mutation c.677C>T compared to those with no mutation (OR = 4.8 (95%CI 1.5-14.9)). The homozygosity TT was associated with an increased homocysteine level. CONCLUSION: On the basis of our findings, acrocyanosis could be considered as a cutaneous sign of a "latent" cardiovascular risk. This should be taken into account particularly when acrocyanosis is associated either to other medical conditions that determine vessel wall damage or to conditions that predispose to the risk of thromboembolism. PMID- 23816604 TI - Lack of evidence for an interaction between Buchnera GroEL and Banana bunchy top virus (Nanoviridae). AB - Circulative plant viruses such as luteovirids and geminiviruses have been shown to bind to GroEL proteins produced by endosymbiotic bacteria harboured within hemipteran vectors. These interactions seem to prevent the degradation of the viral particles in the aphid's haemocoel. Similarly to luteovirids and geminiviruses, Banana bunchy top virus (BBTV), a member of the Nanoviridae family, is transmitted in a persistent, circulative manner and can be detected in the haemolymph of the aphid vector, Pentalonia nigronervosa. To date, it is not known if BBTV can interact with GroEL. In this study, we localised and inferred the phylogeny of a Buchnera aphidicola endosymbiont inhabiting P. nigronervosa. Furthermore, we predicted the 3D structure of Buchnera GroEL and detected the protein in the haemolymph of P. nigronervosa. Interactions were tested using 3 different assays: immunocapture PCR, dot blot, and far-western blot assays; however, none of them showed evidence of a BBTV-GroEL interaction. We concluded that it was unlikely that BBTV interacted with Buchnera GroEL either in vitro or in vivo and we discuss possible alternatives by which BBTV viral particles are able to avoid the process of degradation in the aphid haemocoel. PMID- 23816605 TI - Evidence suggesting that HCV p7 protects E2 glycoprotein from premature degradation during virus production. AB - The hepatitis C virus (HCV) genome encodes a 63 amino acid (aa) protein, p7, which is located between the structural and non-structural proteins. p7 localizes to endoplasmic reticulum membranes and is composed of two transmembrane domains (TM1 and TM2) and a cytoplasmic loop. While its exact role is unknown, p7 is crucial for assembly and/or release of infectious virus production in cell culture, as well as infectivity in chimpanzees. The contribution of p7 to the HCV life cycle may result from at least two distinct roles. Firstly, several studies have shown that p7 acts as an ion channel, the functionality of which is critical for infection. Secondly, p7 interacts with NS2 in a manner that may regulate the targeting of other structural proteins during the assembly process. In this study, we observed that mutations in TM1 and the cytoplasmic loop of p7 decreased infectious virus production in a single-cycle virus production assay. Analysis of intra- and extracellular virus titers indicated that p7 functions at a stage prior to generation of infectious particles. These effects were not due to altered RNA replication since no effects on levels of NS3 or NS5A protein were observed, and were not a consequence of altered recruitment of core protein to lipid droplets. Similarly, these mutations seemingly did not prevent nucleocapsid oligomerization. Importantly, we found that an alanine triplet substitution including the two basic residues of the cytoplasmic loop, which is integral to p7 ion channel function, significantly reduced E2 glycoprotein levels. A time course experiment tracking E2 levels indicated that E2 was degraded over time, as opposed to being synthesized in reduced quantities. The results of this study provide strong evidence that one of the functions of p7 is to protect HCV glycoproteins from premature degradation during virion morphogenesis. PMID- 23816606 TI - Practical issues and challenges in idiopathic pulmonary fibrosis. PMID- 23816607 TI - Surgical trials in head & neck cancer - are you serious? PMID- 23816608 TI - Double-deleted vaccinia virus in virotherapy for refractory and metastatic pediatric solid tumors. AB - BACKGROUND: Previous studies have shown successful antitumor effects of systemically delivered double-deleted vaccinia virus (vvDD) against a number of adult tumor models, including glioma, colon and ovarian cancers. The purpose of this study was to investigate the oncolytic potential of vvDD against a panel of cell lines representative of pediatric solid tumors that are currently difficult to cure. METHODS: Cell lines derived from central nervous system atypical teratoid rhabdoid tumor (AT/RT) (BT12, BT16 and KCCF1), sarcoma (143B, HOS, RD and RH30), and neuroblastoma (SKNAS, SKNBE2, IMR-5 and IMR-32) were examined for vvDD mediated cytotoxicity defined by virus expansion followed by loss of tumor cell viability. The normal human fibroblast cell line HS68 was used as a control. Next, relevant orthotopic, subcutaneous and lung metastasis xenograft models were treated with intravenous doses of live vvDD or killed virus controls (DV). Tumor growth inhibition and viral replication were quantified and survival outcomes of these animals were assessed. RESULTS: vvDD was able to infect and kill nine of eleven of the pediatric tumor cells (81.8%) in vitro. In xenograft models, intravenous administration of a single dose of vvDD significantly inhibited the growth of tumors and prolonged the survival of intracranial and metastatic tumors. CONCLUSIONS: Oncolytic vvDD administered i.v. shows activity in preclinical models of pediatric malignancies that are resistant to many currently available treatments. Our data support further evaluation of vvDD virotherapy for refractory pediatric solid tumors. PMID- 23816610 TI - Discontinuation of antiplatelet study medication and risk of recurrent stroke and cardiovascular events: results from the PRoFESS study. AB - BACKGROUND: Several case control studies have reported an increased risk of cardiovascular events following discontinuation of antiplatelet agents in high risk patients. We therefore sought to investigate the risk of recurrent stroke and cardiovascular events following discontinuation of antiplatelet study medication in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial, a large randomized secondary stroke prevention study. METHODS: The recurrent stroke and cardiovascular event rates following discontinuation of aspirin plus extended-release dipyridamole (ASA + ERDP) or clopidogrel were compared to the event rates in the on-treatment populations (patients who had discontinued their antiplatelet medication due to an outcome event were kept in the on-treatment population in order not to underestimate the on-treatment stroke rate). RESULTS: In 7,212 treated ASA + ERDP patients, the stroke incidence rate for the on-treatment group was 729 strokes with an average exposure of 17,048 person-years (0.12 per 1,000 person-days). For 7,864 treated clopidogrel patients, the stroke incidence rate for the on-treatment group was 737 strokes with an average exposure of 18,715 person-years (0.11 per 1,000 person-days). ASA + ERDP was discontinued in 2,843 patients (in 57.7% due to an adverse event, 28.2% noncompliance, 1.4% loss to follow-up, 4.5% withdrawal of consent and 8.1% other/nonspecified reasons) and clopidogrel was permanently discontinued in 2,176 patients (49.0% due to an adverse event, 34.2% noncompliance, 1.8% loss to follow up, 5.3% withdrawal of consent and 9.7% other/nonspecified reasons). Within 30 days, a recurrent stroke occurred in 31 patients (0.37 per 1,000 person-days) after discontinuation of ASA + ERDP and in 15 patients (0.24 per 1,000 person days) after discontinuation of clopidogrel. This corresponds to an absolute excess risk of 0.77% within 30 days after discontinuation of ASA + ERDP and 0.40% within 30 days after discontinuation of clopidogrel compared with the on treatment study populations. A combined vascular endpoint (stroke, myocardial infarction, vascular death) occurred in 68 patients (0.82 per 1,000 person-days) within 30 days after discontinuation of ASA + ERDP and in 47 patients (0.75 per 1,000 person-days) within 30 days after discontinuation of clopidogrel. This corresponds to an absolute excess risk of 2.02% within 30 days after discontinuation of ASA + ERDP and 1.83% within 30 days after discontinuation of clopidogrel compared with the on-treatment study populations. CONCLUSION: Discontinuation of antiplatelet medication after ischemic stroke should be advocated only when the risk and severity of bleeding clearly outweigh the risk of cardiovascular events. PMID- 23816609 TI - Through the open door: Preferential binding of dasatinib to the active form of BCR-ABL unveiled by in silico experiments. AB - Dasatinib is a second-generation BCR-ABL inhibitor approved for the treatment of patients with chronic myeloid leukemia, both in the frontline and in the imatinib resistant/intolerant settings. The high affinity of dasatinib for the protein is currently assumed to result from its ability to bind both the active and inactive conformations of the BCR-ABL kinase. In the present work, using state of the art molecular simulation techniques we prove that dasatinib exhibits a highly selective preference for the active (open) BCR-ABL conformation. By using three different BCR-ABL conformations (active, inactive, and intermediate inactive) we show that, from a thermodynamic standpoint, the affinity of dasatinib for BCR-ABL drastically decreases in the order: active > alternative inactive > inactive, as a result of differential contributions from the single residues lining the kinase binding pocket and the concomitant stabilization/destabilization of the kinase hydrophobic spine. Molecule-pulling experiments also corroborate this trend as significantly lower forces and smaller times are required to extract dasatinib from its inactive BCR-ABL complexes with respect to the active complex counterparts. Importantly, our results support recent NMR solution results demonstrating no evidence of dasatinib bound to the inactive form of BCR-ABL. PMID- 23816612 TI - Rasch modeling of accuracy and confidence measures from cognitive tests. AB - The use of IRT models has not been rigorously applied in studies of the relationship between test-takers' confidence and accuracy. This study applied the Rasch measurement models to investigate the relationship between test-takers' confidence and accuracy on English proficiency tests, proposing potentially useful measures of under or overconfidence. The Rasch approach provided the scaffolding to formulate indices that can assess the discrepancy between confidence and accuracy at the item or total test level, as well as at particular ability levels locally. In addition, a "disattenuated" measure of association between accuracy and confidence, which takes measurement error into account, was obtained through a multidimensional Rasch modeling of the two constructs where the latent variance-covariance structure is directly estimated from the data. The results indicate that the participants tend to show overconfidence bias in their own cognitive abilities. PMID- 23816611 TI - The Development of the de Morton Mobility Index (DEMMI) in an independent sample of older acute medical patients: refinement and validation using the Rasch model (part 2). AB - This study describes the refinement and validation of the 17-item DEMMI in an independent sample of older acute medical patients. Instrument refinement was based on Rasch analysis and input from clinicians and researchers. The refined DEMMI was tested on 106 older general medical patients and a total of 312 mobility assessments were conducted. Based on the results of this study a further 2 items were removed and the 15 item DEMMI was adopted. The Rasch measurement properties of the DEMMI were consistent with estimates obtained from the instrument development sample. No differential item functioning was identified and an interval level scoring system was established. The DEMMI is the first mobility instrument for older people to be developed, refined and validated using the Rasch model. This study confirms that the DEMMI provides clinicians and researchers with a unidimensional instrument for measuring and monitoring changes in mobility of hospitalised older acute medical patients. PMID- 23816613 TI - Baselines for the Pan-Canadian science curriculum framework. AB - Using a Canadian student achievement assessment database, the Science Achievement Indicators Program (SAIP), and employing the Rasch partial credit measurement model, this study estimated the difficulties of items corresponding to the learning outcomes in the Pan-Canadian science curriculum framework and the latent abilities of students of grades 7, 8, 10, 11, 12 and OAC (Ontario Academic Course). The above estimates serve as baselines for validating the Pan-Canadian science curriculum framework in terms of the learning progression of learning outcomes and expected mastery of learning outcomes by grades. It was found that there was no statistically significant progression in learning outcomes from grades 4-6 to grades 7-9, and from grades 7-9 to grades 10-12; the curriculum framework sets mastery expectation about 2 grades higher than students' potential abilities. In light of the above findings, this paper discusses theoretical issues related to deciding progression of learning outcomes and setting expectation of student mastery of learning outcomes, and highlights the importance of using national assessment data to establish baselines for the above purposes. This paper concludes with recommendations for further validating the Pan-Canadian science curriculum frameworks. PMID- 23816614 TI - An experimental study using Rasch analysis to compare absolute magnitude estimation and categorical rating scaling as applied in survey research. AB - Limited research has applied a measurement model to compare the rating scale functioning of categorical rating scaling (CRS) and absolute magnitude estimation scaling (MES) when rating subjective stimuli. We used an experimental design and applied the Rasch model to the survey data, with each respondent rating items using MES and one of four commonly used agreement-disagreement rating scales. The results indicated that the CRS and MES data were comparable in person and item separation and reliability when the respondents' scales were known. MES had lower standard error for people and items; however MES had disordered step calibrations. Finally, the respondents reported preference of CRS to MES. PMID- 23816615 TI - Developing of two instruments to measure attitudes of Vietnamese parents and students toward schooling. AB - The attitudes of parents and students towards schooling are often considered to be important factors associated with students' educational outcomes. This article presents the process of constructing and calibrating two scales to measure the attitudes of students and parents in Vietnam, and then linking these two scales to compare the two groups. A set of items that covered both development and opportunity aspects of education was designed. After the items were trialled, a final version of 13 items was compiled. The two scales yielded scores that were shown to have logical, face, content and construct validity. PMID- 23816616 TI - The tendency of individuals to respond to high-stakes tests in idiosyncratic ways. AB - It has been frequently suggested that personal characteristics (e.g., language deficiencies, atypical schooling) may be responsible for the tendency of individuals to answer with aberrant response patterns to high stakes tests. This has not, however, been adequately validated using empirical data. This research uses datasets from seven mathematics, English and science papers to investigate the consistency with which individuals respond aberrantly across papers. Pupils who responded aberrantly on one paper were more likely to do so on other papers on the same subject. Also, pupils who responded aberrantly on one paper of one subject were more likely to do so on papers of another subject. Logistic multilevel models using the generation of aberrant response patterns as a dependent variable have suggested non-negligible intra-pupil and intra-school correlations. PMID- 23816617 TI - Development and validation of the sense of competence scale - revised. AB - The purpose of this study was to develop an instrument to measure the sense of competence of traditional age college students across the dimensions that define the construct. The Sense of Competence Scale-Revised (SCS-R) was developed to provide a measure of Chickering's (1969) first vector, an important psychosocial construct. Administrators can use data from the instrument to modify an institution's academic and social environment to enhance the development of the intellectual, physical, and interpersonal competencies of college students. During the development and validation, various aspects of the SCS-R were examined in accordance with the validity framework outlined by Messick (1995). Of the six types of validity evidence proposed by Messick (1995), four were the primary focus: content, substantive, structural and generalizability. The evidence generated from the study suggested that the chosen items for the SCS-R support the validity of estimates of a student's personal assessment of their sense of competence. PMID- 23816618 TI - beta-Catenin protects the epidermis from mechanical stresses. AB - Many tissues in our body experience mechanical stresses caused by both internal and external forces. The skin, for example, must tolerate diverse mechanical insults. In this paper, we report a role for beta-catenin in providing stability to epithelia under stress. Loss of beta-catenin during epidermal development caused perinatal lethality. Mutant embryos up-regulated stress responses at sites of active morphogenesis, which became more widespread after the stresses associated with birth. In addition, selective loss of tight junctions occurred in focal regions. This was recapitulated in cultured beta-catenin-null cells exposed to externally applied forces. In addition, mutant cells were defective in tension induced engagement of adherens junctions. We found that beta-catenin was required to recruit vinculin to the cell cortex and to strengthen the junction's association with the underlying cytoskeleton in response to tension. These data demonstrate that a complete understanding of the functions of cell adhesion proteins must take into account their roles in response to mechanical stresses. PMID- 23816620 TI - Augmin-dependent microtubule nucleation at microtubule walls in the spindle. AB - The formation of a functional spindle requires microtubule (MT) nucleation from within the spindle, which depends on augmin. How augmin contributes to MT formation and organization is not known because augmin-dependent MTs have never been specifically visualized. In this paper, we identify augmin-dependent MTs and their connections to other MTs by electron tomography and 3D modeling. In metaphase spindles of human cells, the minus ends of MTs were located both around the centriole and in the body of the spindle. When augmin was knocked down, the latter population of MTs was significantly reduced. In control cells, we identified connections between the wall of one MT and the minus end of a neighboring MT. Interestingly, the connected MTs were nearly parallel, unlike other examples of end-wall connections between cytoskeletal polymers. Our observations support the concept of augmin-dependent MT nucleation at the walls of existing spindle MTs. Furthermore, they suggest a mechanism for maintaining polarized MT organization, even when noncentrosomal MT initiation is widespread. PMID- 23816619 TI - The centriolar satellite protein SSX2IP promotes centrosome maturation. AB - Meiotic maturation in vertebrate oocytes is an excellent model system for microtubule reorganization during M-phase spindle assembly. Here, we surveyed changes in the pattern of microtubule-interacting proteins upon Xenopus laevis oocyte maturation by quantitative proteomics. We identified the synovial sarcoma X breakpoint protein (SSX2IP) as a novel spindle protein. Using X. laevis egg extracts, we show that SSX2IP accumulated at spindle poles in a Dynein-dependent manner and interacted with the gamma-tubulin ring complex (gamma-TuRC) and the centriolar satellite protein PCM-1. Immunodepletion of SSX2IP impeded gamma-TuRC loading onto centrosomes. This led to reduced microtubule nucleation and spindle assembly failure. In rapidly dividing blastomeres of medaka (Oryzias latipes) and in somatic cells, SSX2IP knockdown caused fragmentation of pericentriolar material and chromosome segregation errors. We characterize SSX2IP as a novel centrosome maturation and maintenance factor that is expressed at the onset of vertebrate development. It preserves centrosome integrity and faithful mitosis during the rapid cleavage division of blastomeres and in somatic cells. PMID- 23816622 TI - Probing the depths of cellular senescence. AB - Cellular senescence is a state of irreversible cell cycle arrest that has been documented to both suppress cancer and promote aging. Although not well understood, extensive nuclear changes, including the remodeling of chromatin, take place as cells become senescent. In this issue, Ivanov et al. (2013. J. Cell Biol. http://dx.doi.org/jcb.201212110) report that chromatin fragments are released from the nuclei of senescent cells and are subsequently targeted for processing through the autophagy/lysosomal pathway. PMID- 23816621 TI - Lysosome-mediated processing of chromatin in senescence. AB - Cellular senescence is a stable proliferation arrest, a potent tumor suppressor mechanism, and a likely contributor to tissue aging. Cellular senescence involves extensive cellular remodeling, including of chromatin structure. Autophagy and lysosomes are important for recycling of cellular constituents and cell remodeling. Here we show that an autophagy/lysosomal pathway processes chromatin in senescent cells. In senescent cells, lamin A/C-negative, but strongly gamma H2AX-positive and H3K27me3-positive, cytoplasmic chromatin fragments (CCFs) budded off nuclei, and this was associated with lamin B1 down-regulation and the loss of nuclear envelope integrity. In the cytoplasm, CCFs were targeted by the autophagy machinery. Senescent cells exhibited markers of lysosomal-mediated proteolytic processing of histones and were progressively depleted of total histone content in a lysosome-dependent manner. In vivo, depletion of histones correlated with nevus maturation, an established histopathologic parameter associated with proliferation arrest and clinical benignancy. We conclude that senescent cells process their chromatin via an autophagy/lysosomal pathway and that this might contribute to stability of senescence and tumor suppression. PMID- 23816624 TI - Antiproliferative effects of palladium(II) complexes of 5-nitrosopyrimidines and interactions with the proteolytic regulatory enzymes of the renin-angiotensin system in tumoral brain cells. AB - Seventeen new palladium(II) complexes of general formulaes PdCl2L, PdCl(LH 1)(solvent) and PdCl2(PPh3)2L containing pyrimidine ligands derived from 6-amino 5-nitrosouracil and violuric acid have been prepared and characterized by elemental analysis, IR and NMR ((1)H and (13)C) methods and, two of them, PdCl(DANUH-1)(CH3CN)].1/2H2O and [PdCl(2MeOANUH-1)(CH3CN)] by X-ray single crystal diffraction (DANU: 6-amino-1,3-dimethyl-5-nitrosouracil; 2MeOANU: 6-amino 2-methoxy-5-nitroso-3H-pyrimidin-4-one). The coordination environment around palladium is nearly square planar in the two compounds with different supramolecular arrangements. Crystallographic and spectral data are consistent with a bidentate coordination mode through N5 and O4 atoms when the ligands act in neutral form and N5 and N6 atoms in the monodeprotonated ones. The cytotoxicity of the complexes against human neuroblastoma (NB69) and human glioma (U373-MG) cell lines has been tested showing a considerable antiproliferative activity. Also, the study of the effects of palladium(II) complexes on the renin angiotensin system (RAS) regulating proteolytic regulatory enzymes aminopeptidase A (APA), aminopeptidase N (APN) and insulin-regulated aminopeptidase (IRAP) shows a strong dependence on the compound tested and the tumoral cell type, also affecting different catalytic routes; the compounds affect in a different way the activities of enzymes of the RAS system, changing their functional roles as initiators of cell proliferation in tumors as autocrine/paracrine mediators. PMID- 23816623 TI - The STIM1 CTID domain determines access of SARAF to SOAR to regulate Orai1 channel function. AB - Ca(2+) influx by store-operated Ca(2+) channels (SOCs) mediates all Ca(2+) dependent cell functions, but excess Ca(2+) influx is highly toxic. The molecular components of SOC are the pore-forming Orai1 channel and the endoplasmic reticulum Ca(2+) sensor STIM1. Slow Ca(2+)-dependent inactivation (SCDI) of Orai1 guards against cell damage, but its molecular mechanism is unknown. Here, we used homology modeling to identify a conserved STIM1(448-530) C-terminal inhibitory domain (CTID), whose deletion resulted in spontaneous clustering of STIM1 and full activation of Orai1 in the absence of store depletion. CTID regulated SCDI by determining access to and interaction of the STIM1 inhibitor SARAF with STIM1 Orai1 activation region (SOAR), the STIM1 domain that activates Orai1. CTID had two lobes, STIM1(448-490) and STIM1(490-530), with distinct roles in mediating access of SARAF to SOAR. The STIM1(448-490) lobe restricted, whereas the STIM1(490-530) lobe directed, SARAF to SOAR. The two lobes cooperated to determine the features of SCDI. These findings highlight the central role of STIM1 in SCDI and provide a molecular mechanism for SCDI of Orai1. PMID- 23816625 TI - Validation of the Chinese Handwriting Analysis System (CHAS) for primary school students in Hong Kong. AB - There are more children diagnosed with specific learning difficulties in recent years as people are more aware of these conditions. Diagnostic tool has been validated to screen out this condition from the population (SpLD test for Hong Kong children). However, for specific assessment on handwriting problem, there seems a lack of standardized and objective evaluation tool to look into the problems. The objective of this study was to validate the Chinese Handwriting Analysis System (CHAS), which is designed to measure both the process and production of handwriting. The construct validity, convergent validity, internal consistency and test-retest reliability of CHAS was analyzed using the data from 734 grade 1-6 students from 6 primary schools in Hong Kong. Principal Component Analysis revealed that measurements of CHAS loaded into 4 components which accounted for 77.73% of the variance. The correlation between the handwriting accuracy obtained from HAS and eyeballing was r=.73. Cronbach's alpha of all measurement items was .65. Except SD of writing time per character, all the measurement items regarding handwriting speed, handwriting accuracy and pen pressure showed good to excellent test-retest reliability (r=.72-.96), while measurement on the numbers of characters which exceeded grid showed moderate reliability (r=.48). Although there are still ergonomic, biomechanical or unspecified aspects which may not be determined by the system, the CHAS can definitely assist therapists in identifying primary school students with handwriting problems and implement interventions accordingly. PMID- 23816626 TI - Autism in community pre-schoolers: developmental profiles. AB - Autism is often a complex developmental disorder. The aim of the present study was to describe the developmental characteristics of 129 1-4-year-old children (102 boys, 27 girls) referred for clinical assessment (mean age 2.9 years) due to suspicion of autism spectrum disorder (ASD) after community screening at Child Health Care centers. All children were clinically assessed at the Child Neuropsychiatry Clinic (CNC) in Gothenburg by a research team (neurodevelopmental examination, structured interviews and general cognitive and language examinations). Of the 129 children, 100 met diagnostic criteria for ASD (69 with autistic disorder, and 31 with atypical autism/pervasive developmental disorder not otherwise specified). The remaining 29 children had a variety of developmental disorders, most often attention-deficit/hyperactivity disorder (ADHD), language disorder, borderline intellectual functioning, and intellectual developmental disorder (IDD) with (n=25) or without (n=4) autistic traits (AT). IDD was found in 36% of the 100 children with ASD, and in 4% of the 25 children with AT. Of the children with ASD, 56% had language disorder with no or just a few words at the initial assessment at the CNC, many of whom in combination with IDD. Hyperactivity was found in 37% of those with ASD and in 40% of those with AT. Epilepsy was found in 6% of the total group and in 7% of those with a diagnosis of ASD. Of the latter group 11% had a history of regression, while none of the AT cases had a similar background. When results were compared with a non screened preschool ASD group of 208 children, referred for ASD intervention at a mean age of 3.4 years, very similar developmental profiles were seen. In conclusion, early community ASD screening appears to systematically identify those children who are in need of intervention and follow-up. PMID- 23816627 TI - Understanding macrographia in children with autism spectrum disorders. AB - It has been consistently reported that children with autism spectrum disorders (ASD) show considerable handwriting difficulties, specifically relating to accurate and consistent letter formation, and maintaining appropriate letter size. The aim of this study was to investigate the underlying factors that contribute to these difficulties, specifically relating to motor control. We examined the integrity of fundamental handwriting movements and contributions of neuromotor noise in 26 children with ASD aged 8-13 years (IQ>75), and 17 typically developing controls. Children wrote a series of four cursive letter l's using a graphics tablet and stylus. Children with ASD had significantly larger stroke height and width, more variable movement trajectory, and higher movement velocities. The absolute level of neuromotor noise in the velocity profiles, as measured by power spectral density analysis, was significantly higher in children with ASD; relatively higher neuromotor noise was found in bands >3 Hz. Our findings suggest that significant instability of fundamental handwriting movements, in combination with atypical biomechanical strategies, contribute to larger and less consistent handwriting in children with ASD. PMID- 23816628 TI - Handwriting speed in children with Developmental Coordination Disorder: are they really slower? AB - Handwriting difficulties are often included in descriptions of Developmental Coordination Disorder (DCD). They are cited as the most common reason for referral to health professionals following parent and teacher concerns about slow and untidy writing. The aim of this study was to compare handwriting performance in English children with and without DCD across a range of writing tasks, to gain a better understanding of the nature of 'slowness' so commonly reported. Twenty eight 8-14 year-old children with a diagnosis of DCD participated in the study, with 28 typically developing age and gender matched controls. Participants completed the four handwriting tasks from the Detailed Assessment of Speed of Handwriting (DASH) and wrote their own name; all on a digitising writing tablet. The number of words written, speed of pen movements and the time spent pausing during the tasks were calculated. The findings confirmed what many professionals report, that children with DCD produce less text than their peers. However, this was not due to slow movement execution, but rather a higher percentage of time spent pausing. Discussion centres on the understanding of the pausing phenomenon in children with DCD and areas for further research. PMID- 23816629 TI - Cognitive and behavioral trajectories in 22q11DS from childhood into adolescence: a prospective 6-year follow-up study. AB - Patients with 22q11DS are at risk of behavioral problems and cognitive impairment. Recent studies suggest a possible intellectual decline in 22q11DS children. To date it is unknown if cognitive development is related to the behavioral problems in 22q11DS. We studied 53 children with 22q11DS who underwent cognitive and behavioral assessments at 9.5 years (T1) and 15.3 years (T2). In about one third, IQ data obtained at 7.5 years (T0) were also available. Results showed that internalizing behaviors intensified while externalizing behaviors decreased. Simultaneously, in about a third a significant decline in IQ was found, which, surprisingly, was unrelated to the behavioral changes. It can be concluded that children with 22q11DS follow a unique developmental trajectory. Cognitive deterioration is severe in some but does not appear to predict behavioral problems in early adolescence. PMID- 23816630 TI - Relationships among cognitive deficits and component skills of reading in younger and older students with developmental dyslexia. AB - Processing speed deficits along with phonological awareness deficits have been identified as risk factors for dyslexia. This study was designed to examine the behavioral profiles of two groups, a younger (6-8 years) and an older (10-15 years) group of dyslexic children for the purposes of (1) evaluating the degree to which phonological awareness and processing speed deficits occur in the two developmental cohorts; (2) determining the strength of relationships between the groups' respective mean scores on cognitive tasks of phonological awareness and processing speed and their scores on component skills of reading; and (3) evaluating the degree to which phonological awareness and processing speed serve as concurrent predictors of component reading skills for each group. The mean scaled scores for both groups were similar on all but one processing speed task. The older group was significantly more depressed on a visual matching test of attention, scanning, and speed. Correlations between reading skills and the cognitive constructs were very similar for both age-groups. Neither of the two phonological awareness tasks correlated with either of the two processing speed tasks or with any of the three measures of reading. One of the two processing speed measures served as a concurrent predictor of word- and text-level reading in the younger, however, only the rapid naming measure functioned as a concurrent predictor of word reading in the older group. Conversely, phonological processing measures did not serve as concurrent predictors for word-level or text-level reading in either of the groups. Descriptive analyses of individual subjects' deficits in the domains of phonological awareness and processing speed revealed that (1) both linguistic and nonlinguistic processing speed deficits in the younger dyslexic children occurred at higher rates than deficits in phonological awareness and (2) cognitive deficits within and across these two domains were greater in the older dyslexic children. Our findings underscore the importance of using rapid naming measures when testing school-age children suspected of having a reading disability and suggest that processing speed measures that do not reply on verbal responses may serve as predictors of reading disability in young children prior to their development of naming automaticity. PMID- 23816632 TI - Parent inclusion in early intensive behavior interventions for young children with ASD: a synthesis of meta-analyses from 2009 to 2011. AB - This paper presents a comprehensive synthesis of six meta-analyses of early intensive behavioral interventions (EIBI) for young children with autism spectrum disorders published from 2009 to 2011. Analysis was conducted in three steps to account for different formats of treatment delivery and the extent to which parents took part in treatment. The three components of the synthesis were (a) descriptive analysis, (b) effect size analysis, and (c) mediator analysis via partial correlation and linear regressions. We completed the analysis by obtaining standardized mean difference effect sizes for 13 comparative studies ordered by comparison study type and 22 mean change effect sizes ordered by treatment delivery type. Results suggest that EIBI leads generally to positive medium-to-large effects for three available outcome measures: intellectual functioning, language skills and adaptive behaviors. Although favorable effects were apparent across comparative studies, analysis by type of delivery format revealed that EIBI programs that include parents in treatment provision are more effective. Mediator analyses suggest that treatment variables and child characteristics impact program effectiveness when accounting for the extent of parent inclusion. Clinical implications toward individualized treatment tailoring are discussed. PMID- 23816631 TI - Technology-aided recreation and communication opportunities for post-coma persons affected by lack of speech and extensive motor impairment. AB - This study assessed technology-aided intervention programs for two post-coma men who had re-acquired consciousness, but were unable to engage in personally or socially relevant occupations, given their lack of functional speech and their extensive motor disabilities. The microswitches used for accessing the program contents consisted of (a) a pressure sensor fixed in the palm of the first man's hand that could be activated with a small hand closure movement, and (b) an optic sensor fixed under the chin of the second man that could be activated by mouth opening movements. The programs' content consisted of recreation and communication options, which involved activating music, videos, and basic requests, sending and receiving (listening to) text messages, and placing phone calls. The results showed that the men (a) used the technology-aided programs successfully to manage the recreation and communication options available and (b) showed consistent preference for the sessions with the technology-aided program over other daily events. Family and staff members interviewed about the participants' programs (seven members for each participant) thought that the participants enjoyed the intervention sessions with the programs and that the programs had beneficial effects for them. Implications of the findings are discussed. PMID- 23816633 TI - Prenatal, perinatal and neonatal risk factors of Autism Spectrum Disorder: a comprehensive epidemiological assessment from India. AB - Incidence of Autism Spectrum Disorder (ASD) is increasing across the globe and no data is available from India regarding the risk factors of ASD. In this regard a questionnaire based epidemiological assessment was carried out on prenatal, perinatal and neonatal risk factors of ASD across 8 cities in India. A retrospective cohort of 942 children was enrolled for the study. 471 children with ASD, under age of 10, were analyzed for pre-, peri-, and neonatal factors and were compared with the observations from equal number of controls. The quality control of the questionnaire and data collection was done thoroughly and the observations were computed statistically. A total of 25 factors were evaluated by unadjusted and adjusted analysis in this study. Among the prenatal factors considered, advanced maternal age, fetal distress and gestational respiratory infections were found to be associated with ASD and had an odds ratio of 1.8. Evaluation of perinatal and neonatal risk factors showed labor complications, pre-term birth, neonatal jaundice, delayed birth cry and birth asphyxia to be associated with ASD with an odds ratio greater than 1.5. This important study, first of its kind in Indian population gives a firsthand account of the relation of pre-, peri- and neonatal risk factors on ASD from an ethnically and socially diverse country like India, the impact of which was unknown earlier. This advocates additional focused investigations on physiological and genetic changes contributed by these risk factor inducing environments. PMID- 23816634 TI - Precision grip control, sensory impairments and their interactions in children with hemiplegic cerebral palsy: a systematic review. AB - Children with hemiplegic cerebral palsy (HCP) exhibit long-term functional deficits. One of the most debilitating is the loss of prehension since this may impair functional independence. This loss of prehension could be partly due to sensory deficits. Identifying the underlying causes of prehension deficits and their potential link with sensory disorders is important to better adapt neurorehabilitation. Here we provide an overview of precision grip and sensory impairments in individuals with HCP, and the relation between them, in order to determine whether the sensory impairments influence the type and magnitude of deficits as measured by studies of prehensile force control. Pubmed and Scopus databases were used to search studies from 1990 to 2012, using combinations of the following keywords: fingertip force; grip force; precision grip; sensory deficit; sensory impairment; tactile discrimination; with cerebral palsy. Of the 190 studies detected through the systematic search; 38 were finally included in the systematic part of this review. This review shows that sensory deficits are common and are likely underestimated using standard clinical assessments in HCP. Some studies suggest these deficits are the basis of predictive motor control impairments in these individuals. However, children with HCP retain some ability to use predictive control, even if it is impaired in the more affected hand. Intensive practice and initial use of the less affected hand, which has only subtle sensory deficits, has been shown to remediate impairments in anticipatory motor control during subsequent use of the more affected hand. Implications for motor and sensory rehabilitation of individuals with HCP are discussed. PMID- 23816636 TI - Philosophy of science and the diagnostic process. AB - This is an overview of the principles that underpin philosophy of science and how they may provide a framework for the diagnostic process. Although philosophy dates back to antiquity, it is only more recently that philosophers have begun to enunciate the scientific method. Since Aristotle formulated deduction, other modes of reasoning including induction, inference to best explanation, falsificationism, theory-laden observations and Bayesian inference have emerged. Thus, rather than representing a single overriding dogma, the scientific method is a toolkit of ideas and principles of reasoning. Here we demonstrate that the diagnostic process is an example of science in action and is therefore subject to the principles encompassed by the scientific method. Although a number of the different forms of reasoning are used readily by clinicians in practice, without a clear understanding of their pitfalls and the assumptions on which they are based, it leaves doctors open to diagnostic error. We conclude by providing a case example from the medico-legal literature in which diagnostic errors were made, to illustrate how applying the scientific method may mitigate the chance for diagnostic error. PMID- 23816635 TI - The role of innate immunity in promoting SaeR/S-mediated virulence in Staphylococcus aureus. AB - The ability of Staphylococcus aureus to infect tissues is dependent on precise control of virulence through gene-regulatory systems. While the SaeR/S two component system has been shown to be a major regulator of S. aureus virulence, the influence of the host environment on SaeR/S-regulated genes (saeR/S targets) remains incompletely defined. Using QuantiGene 2.0 transcriptional assays, we examined expression of genes with the SaeR binding site in USA300 exposed to human and mouse neutrophils and host-derived peptides and during subcutaneous skin infection. We found that only some of the saeR/S targets, as opposed to the entire SaeR/S virulon, were activated within 5 and 10 min of interacting with human neutrophils as well as alpha-defensin. Furthermore, mouse neutrophils promoted transcription of saeR/S targets despite lacking alpha-defensin, and the murine skin environment elicited a distinctive expression profile of saeR/S targets. These findings indicate that saeR/S-mediated transcription is unique to and dependent on specific host stimuli. By using isogenic USA300DeltasaeR/S and USA300Deltaagr knockout strains, we also determined that SaeR/S is the major regulator of virulence factors, while Agr, a quorum-sensing two-component system, has moderate influence on transcription of the saeR/S targets under the tested physiological conditions. PMID- 23816637 TI - Replacement of reduced highly unsaturated fatty acids (HUFA deficiency) in dilative heart failure: dosage of EPA/DHA and variability of adverse peroxides and aldehydes in dietary supplement fish oils. AB - OBJECTIVES: To explore the rationale for omega-3 fatty acids in heart failure treatment, the dosage of EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) for replacing low levels of highly unsaturated fatty acids (HUFA deficiency) was examined. To judge the usefulness of various EPA/DHA preparations, their content of peroxides and aldehydes was determined. METHODS: In 298 patients with dilative heart failure, the serum HUFA level was assessed by gas chromatography. In omega-3-acid ethyl esters 90 (Omacor/Lovaza, approved by the Food and Drug Administration and the European Medicines Agency) and 63 dietary supplement fish oils, oxidation products were determined by photometry. RESULTS: Increasing serum HUFA from the lower (4.3 +/- 1.0%) to the upper (9.5 +/ 1.5%) tertile would be associated with an increased left ventricular (LV) ejection fraction (34.1 +/- 9.9 vs. 28.3 +/- 9.5%, p < 0.01) and reduced LV enddiastolic diameter (63.5 +/- 7.1 vs. 66.9 +/- 7.4 mm) requiring at least 2 g EPA/DHA daily. In fish oils, the peroxide and alkenal level varied greatly, i.e. peroxide value <= 5 mEq/kg in only 7 and <= 10 mEq/kg in 38 fish oils. Compared with equivalent doses of omega-3-acid ethyl esters 90, the mean peroxide intake would be 8.6 +/- 6.1 and the alkenal intake 10.9 +/- 4.4 times higher in fish oils. CONCLUSIONS: Levels of adverse oxidation products should be considered when targeting HUFA deficiency or treating patients with myocardial infarction or high triglycerides. PMID- 23816638 TI - Cognitive impairment among different clinical courses of multiple sclerosis. AB - BACKGROUND: As of yet, no consensus has been reached regarding cognitive impairment profiles in multiple sclerosis (MS) patients based on the MS type and disease duration. The main objective of this study was to describe cognitive impairment at the early stages of MS. The secondary objective was to compare cognitive performances in patients with relapsing remitting multiple sclerosis (RRMS), secondary progressive (SP) MS and primary progressive (PP) MS. METHODS: The study included 128 MS patients and 63 healthy controls (HC). The study constituted five groups: early RR (ERR) (<3 years); late RR (LRR) (>10 years), SP, PP, and healthy Controls (HC). A neuropsychological assessment was performed including information processing speed (IPS), working memory, verbal episodic memory and executive functions. RESULTS: Compared to HC, only impairment in phonemic fluency was observed in ERR. Slowing IPS, impairment in working memory and phonemic fluency were shown in LRR. In progressive forms, deficits were observed in verbal episodic memory, in working memory, in flexibility, in semantic and phonemic fluencies, with a slowing IPS. CONCLUSION: Verbal fluency is impaired at early stage of RRMS, in this form of MS, impairment increased with MS duration, and distinct cognitive profiles were observed between chronic and progressive forms. PMID- 23816639 TI - In vivo distribution and antitumor activity of doxorubicin-loaded N isopropylacrylamide-co-methacrylic acid coated mesoporous silica nanoparticles and safety evaluation. AB - The objective of this study was to develop and evaluate the antitumor activity and the safety of a delivery system containing mesoporous silica nanoparticles (MSN) coated with pH-responsive poly (N-isopropylacrylamide-co-methacrylic acid; P NIPAM-co-MAA) for doxorubicin (DOX) delivery (P-MSN-DOX) in vitro and in vivo. We reported that P-MSN-DOX nanoparticles (190 +/- 30 nm) offered a DOX-loading coefficient of more than 20%. DOX release from the P-MSN-DOX formulation was pH dependent with enhanced antitumor effects in vitro compared with traditional MSN DOX, which was weakly cytotoxic due to negligible drug release at tested pHs. P MSN-DOX circulated longer, with less cardiac and renal accumulation as shown by pharmacokinetics and biodistribution studies in vivo. Also, the P-MSN-DOX delivery system had greater antitumor activity in mice bearing a murine sarcoma S 180 cell line. This finding was correlated with both in vitro and in vivo. Subacute toxicity tests revealed a low P-MSN-DOX toxicity in vivo, as well. Thus, P-MSN-DOX appears to be an efficacious and safe cancer treatment strategy. PMID- 23816640 TI - Digoxin net secretory transport in bronchial epithelial cell layers is not exclusively mediated by P-glycoprotein/MDR1. AB - The impact of P-glycoprotein (MDR1, ABCB1) on drug disposition in the lungs as well as its presence and activity in in vitro respiratory drug absorption models remain controversial to date. Hence, we characterised MDR1 expression and the bidirectional transport of the common MDR1 probe (3)H-digoxin in air-liquid interfaced (ALI) layers of normal human bronchial epithelial (NHBE) cells and of the Calu-3 bronchial epithelial cell line at different passage numbers. Madin Darby Canine Kidney (MDCKII) cells transfected with the human MDR1 were used as positive controls. (3)H-digoxin efflux ratio (ER) was low and highly variable in NHBE layers. In contrast, ER=11.4 or 3.0 were measured in Calu-3 layers at a low or high passage number, respectively. These were, however, in contradiction with increased MDR1 protein levels observed upon passaging. Furthermore, ATP depletion and the two MDR1 inhibitory antibodies MRK16 and UIC2 had no or only a marginal impact on (3)H-digoxin net secretory transport in the cell line. Our data do not support an exclusive role of MDR1 in (3)H-digoxin apparent efflux in ALI Calu-3 layers and suggest the participation of an ATP-independent carrier. Identification of this transporter might provide a better understanding of drug distribution in the lungs. PMID- 23816642 TI - Serum levels of LH, FSH, estradiol and progesterone in female rats experimentally infected by Trypanosoma evansi. AB - The goal of this study was to evaluate reproductive hormones in sera samples of female rats experimentally infected by Trypanosoma evansi during different phases of the estrous cycle. For that, 64 animals were divided into two groups: 24 rats for the control group (uninfected), and 40 animals were infected by T. evansi. These groups were divided into subgroups according to the time of infection (days 5 and 15 post-infection; PI) and the phase of the estrous cycle (proestrus, estrus, metestrus and diestrus). Serum was collected at days 5 and 15 PI and the levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), progesterone and estradiol were assessed by enzyme immunoassay technique. The concentration of nitrite/nitrate (NOx), advanced oxidation protein products (AOPP), and thiobarbituric acid reactive substances (TBARS) were measured in ovaries and uteruses in these same periods. Infected females showed significant decrease (P<0.05) of LH, FSH, estradiol and progesterone in different periods and phases of the estrous cycle when compared to uninfected rats. In addition, it was observed an increase in the concentration of NOx, AOPP, and TBARS in the ovaries, which is indicative of cell damage. Therefore, our experimental study showed that T. evansi infection in female rats may cause changes in LH, FSH, estradiol, and progesterone levels regardless of the time of infection or phase of the estrous cycle. PMID- 23816641 TI - Proteolytically activated anti-bacterial hydrogel microspheres. AB - Hydrogels are finding increased clinical utility as advances continue to exploit their favorable material properties. Hydrogels can be adapted for many applications, including surface coatings and drug delivery. Anti-infectious surfaces and delivery systems that actively destroy invading organisms are alternative ways to exploit the favorable material properties offered by hydrogels. Sterilization techniques are commonly employed to ensure the materials are non-infectious upon placement, but sterilization is not absolute and infections are still expected. Natural, anti-bacterial proteins have been discovered which have the potential to act as anti-infectious agents; however, the proteins are toxic and need localized release to have therapeutic efficacy without toxicity. In these studies, we explore the use of the glutathione s transferase (GST) to anchor the bactericidal peptide, melittin, to the surface of poly(ethylene glycol) diacrylate (PEGDA) hydrogel microspheres. We show that therapeutic levels of protein can be anchored to the surface of the microspheres using the GST anchor. We compared the therapeutic efficacy of recombinant melittin released from PEGDA microspheres to melittin. We found that, when released by an activating enzyme, thrombin, recombinant melittin efficiently inhibits growth of the pathogenic bacterium Streptococcus pyogenes as effectively as melittin created by solid phase peptide synthesis. We conclude that a GST protein anchor can be used to immobilize functional protein to PEGDA microspheres and the protein will remain immobilized under physiological conditions until the protein is enzymatically released. PMID- 23816643 TI - Leishmania braziliensis: cytotoxic, cytostatic and chemotactic effects of poly lysine-methotrexate-conjugates. AB - Chemotactic responses play a significant role during Leishmania differentiation, as well as in the course of parasite-host-cell interaction, a process that precedes a successful infection. The present study uses the modified "two-chamber capillary assay" to quantitatively evaluate the chemotactic properties and the toxic activities of methotrexate containing branched chain polymeric polypeptide conjugates in Leishmania. Our results demonstrate that this methodology quantitatively determines the taxis of Leishmania towards/against gradients of compounds. They also demonstrate that chemotaxis produced by the polypeptide methotrexate conjugates depends on specific chemical characteristics. For example, the N-terminal amino acid (Ser or Glu) location at the branch significantly influences the elicited chemotaxis. Furthermore, the use of different attachment sites in the methotrexate conjugates (alpha- or gamma carboxylic groups) affect their chemotactic activity. Specific cytotoxic activities and cytostatic effects of the conjugates on parasites and on murine and human cells of the macrophage/monocyte system respectively, suggest that these ligands may be used as a group of anti-Leishmania substances acting selectively on Leishmania and different hosts. PMID- 23816644 TI - Activity of recombinant and natural defensins from Vigna unguiculata seeds against Leishmania amazonensis. AB - Antimicrobial peptides (AMPs), which are differentiated from other antibiotic peptides, such as gramicidins and polymyxins, because they are synthesized by large enzymatic complex and bear modified amino acids including d-amino acids, are short polymers of l-amino acids synthesized by ribosomes upon which all living organisms rely to defend themselves from invaders or competitor microorganisms. AMPs have received a great deal of attention from the scientific community as potential new drugs for neglected diseases such as Leishmaniasis. In plants, they include several families of compounds, including the plant defensins. The aim of the present study was to improve the expression of recombinant defensin from Vigna unguiculata seeds (Vu-Defr) and to test its activity against Leishmania amazonensis promatigotes. Recombinant expression was performed in LB and TB media and under different conditions. The purification of Vu-Defr was achieved by immobilized metal ion affinity and reversed-phase chromatography. The purified Vu-Defr was analyzed by circular dichroism (CD), and its biological activity was tested against L. amazonenis promastigotes. To demonstrate that the recombinant production of Vu-Defr did not interfere with its fold and biological activity, the results of all experiments were compared with the results from the natural defensin (Vu-Def). The CD spectra of both peptides presented good superimposition indicating that both peptides present very similar secondary structure and that the Vu-Defr was correctly folded. L. amazonensis treated with Vu-Defr led to the elimination of 54.3% and 46.9% of the parasites at 24 and 48h of incubation time, respectively. Vu-Def eliminated 50% and 54.8% of the parasites at 24 and 48 h, respectively. Both were used at a concentration of 100 MUg/mL. These results suggested the potential for plant defensins to be used as new antiparasitic substances. PMID- 23816645 TI - Docetaxel-loaded nanoparticles based on star-shaped mannitol-core PLGA-TPGS diblock copolymer for breast cancer therapy. AB - A star-shaped biodegradable polymer, mannitol-core poly(d,l-lactide-co-glycolide) d-alpha-tocopheryl polyethylene glycol 1000 succinate (M-PLGA-TPGS), was synthesized in order to provide a novel nanoformulation for breast cancer chemotherapy. This novel copolymer was prepared by a core-first approach via three stages of chemical reaction, and was characterized by nuclear magnetic resonance, gel permeation chromatography and thermogravimetric analysis. The docetaxel-loaded M-PLGA-TPGS nanoparticles (NPs), prepared by a modified nanoprecipitation method, were observed to be near-spherical shape with narrow size distribution. Confocal laser scanning microscopy showed that the uptake level of M-PLGA-TPGS NPs was higher than that of PLGA NPs and PLGA-TPGS NPs in MCF-7 cells. A significantly higher level of cytotoxicity was achieved with docetaxel-loaded M-PLGA-TPGS NPs than with commercial Taxotere(r), docetaxel loaded PLGA-TPGS and PLGA NPs. Examination of the drug loading and encapsulation efficiency proved that star-shaped M-PLGA-TPGS could carry higher levels of drug than linear polymer. The in vivo experiment showed docetaxel-loaded M-PLGA-TPGS NPs to have the highest anti-tumor efficacy. In conclusion, the star-like M-PLGA TPGS copolymer shows potential as a promising drug-loaded biomaterial that can be applied in developing novel nanoformulations for breast cancer therapy. PMID- 23816646 TI - Dissolving polymer microneedle patches for rapid and efficient transdermal delivery of insulin to diabetic rats. AB - This study presents a dissolving microneedle patch, composed of starch and gelatin, for the rapid and efficient transdermal delivery of insulin. The microneedles completely dissolve after insertion into the skin for 5 min, quickly releasing their encapsulated payload into the skin. A histological examination shows that the microneedles have sufficient mechanical strength to be inserted in vitro into porcine skin to a depth of approximately 200 MUm and in vivo into rat skin to 200-250 MUm depth. This penetration depth does not induce notable skin irritation or pain sensation. To evaluate the feasibility of using these dissolving microneedles for diabetes treatment insulin-loaded microneedles were administered to diabetic rats using a homemade applicator. Pharmacodynamic and pharmacokinetic results show a similar hypoglycemic effect in rats receiving insulin-loaded microneedles and a subcutaneous injection of insulin. The relative pharmacological availability and relative bioavailability of insulin were both approximately 92%, demonstrating that insulin retains its pharmacological activity after encapsulation and release from the microneedles. Storage stability analysis confirms that more than 90% of the insulin remained in the microneedles even after storage at 25 or 37 degrees C for 1 month. These results confirm that the proposed starch/gelatin microneedles enable stable encapsulation of bioactive molecules and have great potential for transdermal delivery of protein drugs in a relatively painless, rapid, and convenient manner. PMID- 23816647 TI - Composite hydrogels as a vehicle for releasing drugs with a wide range of hydrophobicities. AB - Many vitamins, bioactive lipids and over 40% of newly developed drugs are hydrophobic, and their poor water solubility limits their delivery using conventional formulations. In this work we investigated a composite gel system formulated from microemulsions embedded in alginate hydrogels, and showed that it is capable of loading several hydrophobic compounds with a wide range of aqueous solubility. All gels were clear, with no precipitations, indicating the solubility of the drugs in the gels. The release behavior was similar for different microemulsion formulations, various drugs and increasing concentrations of a drug. These findings indicate that our system could potentially act as a generic system, where the properties of the release do not depend on the drug but rather on the attributes of the gel. The structure of composite gels was investigated using small-angle scattering of X-rays and neutrons (SAXS and SANS, respectively). SANS showed more sensitivity to the structure of the microemulsion in the composite gel than SAXS did. SAXS and SANS plots of the composite gels show that both the droplets and the gel network preserve their structure when mixed together. PMID- 23816648 TI - Specific VEGF sequestering to biomaterials: influence of serum stability. AB - Vascular endothelial growth factor (VEGF) was originally discovered as a tumor derived factor that is able to induce endothelial cell behavior associated with angiogenesis. It has been implicated during wound healing for the induction of endothelial cell proliferation, tube formation and blood vessel remodeling. However, previous investigations into the biological effect of VEGF concluded that a particular range of growth factor concentrations are required for healthy vasculature to form, motivating recent studies to regulate VEGF activity via molecular sequestering to biomaterials. Numerous VEGF sequestering strategies have been developed, and they have typically relied on extracellular matrix mimicking moieties that are not specific for VEGF and can affect many growth factors simultaneously. We describe here a strategy for efficient, specific VEGF sequestering with poly(ethylene glycol) (PEG) microspheres, using peptides designed to mimic VEGF receptor type 2 (VEGFR2). By immobilizing two distinct peptides with different serum stabilities, we examined the effect of serum on the specific interaction between peptide-containing PEG microspheres and VEGF. We addressed the hypothesis that VEGF sequestering in serum-containing solutions would be influenced by the serum stability of the VEGF-binding peptide. We further hypothesized that soluble VEGF could be sequestered in serum-containing cell culture media, resulting in decreased VEGF-dependent proliferation of human umbilical vein endothelial cells. We show that soluble VEGF concentration can be effectively regulated in serum-containing environments via specific molecular sequestering, which suggests potential clinical applications. PMID- 23816649 TI - Combining decellularized human adipose tissue extracellular matrix and adipose derived stem cells for adipose tissue engineering. AB - Repair of soft tissue defects resulting from lumpectomy or mastectomy has become an important rehabilitation process for breast cancer patients. This study aimed to provide an adipose tissue engineering platform for soft tissue defect repair by combining decellularized human adipose tissue extracellular matrix (hDAM) and human adipose-derived stem cells (hASCs). To derive hDAM incised human adipose tissues underwent a decellularization process. Effective cell removal and lipid removal were proved by immunohistochemical analysis and DNA quantification. Scanning electron microscopic examination showed a three-dimensional nanofibrous architecture in hDAM. The hDAM included collagen, sulfated glycosaminoglycan, and vascular endothelial growth factor, but lacked major histocompatibility complex antigen I. hASC viability and proliferation on hDAM were proven in vitro. hDAM implanted subcutaneously in Fischer rats did not cause an immunogenic response, and it underwent remodeling, as indicated by host cell infiltration, neovascularization, and adipose tissue formation. Fresh fat grafts (Coleman technique) and engineered fat grafts (hDAM combined with hASCs) were implanted subcutaneously in nude rats. The implanted engineered fat grafts maintained their volume for 8 weeks, and the hASCs contributed to adipose tissue formation. In summary, the combination of hDAM and hASCs provides not only a clinically translatable platform for adipose tissue engineering, but also a vehicle for elucidating fat grafting mechanisms. PMID- 23816650 TI - pH-dependent antibacterial effects on oral microorganisms through pure PLGA implants and composites with nanosized bioactive glass. AB - Biomaterials made of biodegradable poly(alpha-hydroxyesters) such as poly(lactide co-glycolide) (PLGA) are known to decrease the pH in the vicinity of the implants. Bioactive glass (BG) is being investigated as a counteracting agent buffering the acidic degradation products. However, in dentistry the question arises whether an antibacterial effect is rather obtained from pure PLGA or from BG/PLGA composites, as BG has been proved to be antimicrobial. In the present study the antimicrobial properties of electrospun PLGA and BG45S5/PLGA fibres were investigated using human oral bacteria (specified with mass spectrometry) incubated for up to 24 h. BG45S5 nanoparticles were prepared by flame spray synthesis. The change in colony-forming units (CFU) of the bacteria was correlated with the pH of the medium during incubation. The morphology and structure of the scaffolds as well as the appearance of the bacteria were followed bymicroscopy. Additionally, we studied if the presence of BG45S5 had an influence on the degradation speed of the polymer. Finally, it turned out that the pH increase induced by the presence of BG45S5 in the scaffold did not last long enough to show a reduction in CFU. On the contrary, pure PLGA demonstrated antibacterial properties that should be taken into consideration when designing biomaterials for dental applications. PMID- 23816651 TI - Serum-free culture of rat proximal tubule cells with enhanced function on chitosan. AB - The proximal tubule performs a variety of important renal functions and is the major site for nutrient reabsorption. The purpose of this study is to culture rat renal proximal tubule cells (PTCs) on chitosan without serum to maintain a transcellular pathway to transport water and ions effectively without loss of highly differentiated cell function. The effect of chitosan, which is structurally similar to glycosaminoglycans, in the absence of serum on the primary cultured PTCs was compared that of collagen with or without serum. Two days after seeding, more tubule fragments and higher PTC viability were observed on chitosan than on collagen with or without serum. Proliferation marker Ki-67 immunostaining and phosphorylated extracellular-regulated kinase (ERK) expression results displayed similar proliferation capability of PTCs established on chitosan without serum and collagen with 2% fetal bovine serum after 4 days of incubation. When grown to confluence, PTCs formed a monolayer with well-organized tight junctions and formation of domes on chitosan without serum. Moreover, evaluation of the transepithelial electrical resistance showed that both chitosan and serum were involved in the modification of water and ion transport in confluent cells. By showing the direct suppression of PTC growth and dome formation treated with heparinase, we demonstrated that the interaction between cell surface heparin sulfate proteoglycan and chitosan played an important role in PTC proliferation and differentiation. A successful primary culture of PTCs has now been produced on chitosan in serum-free culture condition, which offers potential applications for chitosan in renal tissue engineering. PMID- 23816652 TI - Carboxymethylation of ulvan and chitosan and their use as polymeric components of bone cements. AB - Ulvan, extracted from the green algae Ulva lactuca, and chitosan, extracted from Loligo forbesis squid-pen, were carboxymethylated, yielding polysaccharides with an average degree of substitution of ~98% (carboxymethyl ulvan, CMU) and ~87% (carboxymethyl chitosan, N,O-CMC). The carboxymethylation was confirmed by Fourier transform infrared spectroscopy and quantified by conductimetric titration and 1H nuclear magnetic resonance. The average molecular weight increased with the carboxymethylation (chitosan, Mn 145->296 kDa and Mw 227->416 kDa; ulvan, Mn 139->261 kDa and Mw 368->640 kDa), indicating successful chemical modifications. Mixtures of the modified polysaccharides were tested in the formulation of polyacrylic acid-free glass-ionomer bone cements. Mechanical and in vitro bioactivity tests indicate that the inclusion of CMU in the cement formulation, i.e. 0.50:0.50 N,O-CMC:CMU, enhances its mechanical performance (compressive strength 52.4+/-8.0 MPa and modulus 2.3+/-0.3 GPa), generates non cytotoxic cements and induces the diffusion of Ca and/or P-based moieties from the surface to the bulk of the cements. PMID- 23816653 TI - Biomimetic coating of magnesium alloy for enhanced corrosion resistance and calcium phosphate deposition. AB - Degradable metals have been suggested as biomaterials with revolutionary potential for bone-related therapies. Of these candidate metals, magnesium alloys appear to be particularly attractive candidates because of their non-toxicity and outstanding mechanical properties. Despite their having been widely studied as orthopedic implants for bone replacement/regeneration, their undesirably rapid corrosion rate under physiological conditions has limited their actual clinical application. This study reports the use of a novel biomimetic peptide coating for Mg alloys to improve the alloy corrosion resistance. A 3DSS biomimetic peptide is designed based on the highly acidic, bioactive bone and dentin extracellular matrix protein, phosphophoryn. Surface characterization techniques (scanning electron microscopy, energy dispersive X-ray spectroscopy and diffuse-reflectance infrared spectroscopy) confirmed the feasibility of coating the biomimetic 3DSS peptide onto Mg alloy AZ31B. The 3DSS peptide was also used as a template for calcium phosphate deposition on the surface of the alloy. The 3DSS biomimetic peptide coating presented a protective role of AZ31B in both hydrogen evolution and electrochemical corrosion tests. PMID- 23816657 TI - Inflammatory patterns in upper airway disease in the same geographical area may change over time. AB - BACKGROUND: Inflammatory patterns of nasal polyps (NPs) may vary. Changes over time have not been investigated so far. This study was designed to evaluate the inflammatory patterns of NPs in Thailand at two time points 12 years apart, explore differences in Staphylococcus aureus (SA) mucosal carriage rates over time, and the latter's relationship with the inflammatory patterns. METHODS: Formalin-fixed nasal tissue was obtained from 89 (47 in 1999 and 42 in 2011) patients suffering from chronic rhinosinusitis with NPs (CRSwNPs). Tissues were evaluated for eosinophils, neutrophils, IgE(+) cells, IgE and macrophage mannose receptors, interleukin (IL)-5 and IL-17 cytokine profile, and the presence of SA, using automated immunohistochemistry and peptide nucleic acid-fluorescence in situ hybridization. RESULTS: We found a significant increase in the absolute values of eosinophils and IgE(+) cells in the 2011 CRSwNP tissue series compared with 1999 and a significant but smaller increase in neutrophils. Semiquantitative evaluation revealed significantly higher mean values of positive cells for all studied inflammatory markers in the 2011 group of patients, except for the high affinity IgE receptor. This "eosinophilic shift" of inflammation was accompanied by higher SA carriage, as well as higher frequencies of SA invasion (54.8% versus 10.6%; p < 0.001) in the 2011 compared with 1999 subjects. Patients with asthma were more likely to have higher SA carriage rates compared with nonasthmatic patients. CONCLUSION: There was a shift from predominantly neutrophilic to eosinophilic CRSwNPs in Thai patients within 12 years, with an increase in various inflammatory markers including IgE, which is associated with an increase in intramucosal presence of SA. PMID- 23816658 TI - The impact of nail disorders on quality of life. AB - BACKGROUND: Nail disorders have considerable psychological impact and may limit activity by impairing functionality of both fingers and toes. OBJECTIVE: To evaluate the impact of nails disorders on quality of life (QoL). METHODS: 1063 patients with nail disorders completed an anonymous nail-specific QoL questionnaire consisting of 24 and 16 questions, respectively, for fingernails and toenails with five possible responses to each question. A score of 1-5 was given to each response and the final score was adjusted on a percentile scale. The subjects were classified in groups according to nail disorders. Statistical analysis was carried out using T-test to compare the means between two groups and ANOVA analysis of variance to compare the impact of quality of life on the different types of nail disorders. RESULTS: Comparison between groups showed a statistically significant higher impact for trauma, onychomycosis, other infections, structure abnormalities, psoriasis, other inflammatory diseases and paronychia and a lower impact for chromonychias and tumours. QoL was statistically significantly more affected in patients having multiple nails involved, women, and in people aged 60-79 years. There was no statistically significant difference on the QoL impact between patients having only fingernails or only toenails involved. CONCLUSION: Even though published literature tends to focus on the impact of nail psoriasis and onychomycosis on QoL, other nail disorders cause similar frustration to patients. A possible explanation for this is that appearance of the nail has a more significant impact on QoL than the severity of the disorder. PMID- 23816659 TI - GASZ promotes germ cell derivation from embryonic stem cells. AB - Primordial germ cells (PGCs) are the first germ-line population that forms from the proximal epiblast of the developing embryo. Despite their biological importance, the regulatory networks whereby PGCs arise, migrate, and differentiate into gametes during embryonic development remains elusive, largely due to the limited number of germ cells in the early embryo. To elucidate the molecular mechanisms that govern early germ cell development, we utilized an in vitro differentiation model of embryonic stem cells (ESCs) and screened a series of candidate genes with specific expression in the adult reproductive organs. We discovered that gain of function of Gasz, a gene previously reported to participate in meiosis of postnatal spermatocytes, led to the most robust upregulation of PGC formation from both human and murine ESCs. In contrast, Gasz deficiency resulted in pronounced reduction of germ cells during ESC differentiation and decreased expression of MVH and DAZL in genital ridges during early embryonic development. Further analyses demonstrated that GASZ interacted with DAZL, a key germ cell regulator, to synergistically promote germ cell derivation from ESCs. Thus, our data reveal a potential role of GASZ during embryonic germ cell development and provide a powerful in vitro system for dissecting the molecular pathways in early germ cell formation during embryogenesis. PMID- 23816660 TI - A theoretical account of lexical and semantic naming deficits in bilingual aphasia. AB - PURPOSE: The purpose of this study was to examine premorbid language proficiency and lexical and semantic processing deficits in bilingual aphasia and develop a theoretical account of bilingual language processing. METHOD: Nineteen Spanish English patients with bilingual aphasia completed a language use questionnaire (LUQ) and were administered Spanish and English standardized language assessments. The authors analyzed the data to (a) identify patterns of lexical and semantic processing deficits and conceptualize a theoretical framework that accounts for language deficits, (b) determine LUQ measures that predict poststroke language deficits, and (c) evaluate the relationship between predictive LUQ measures and poststroke language deficits in order to identify impairment patterns. RESULTS: On the basis of the results, the authors obtained significant correlations on several measures between language input and output. They identified prestroke language ability rating as the strongest predictor of poststroke outcomes. On the basis of these data, 2 distinct groups were identified: (a) patients who lost the same amount of language in Spanish and English and (b) patients who lost different amounts of Spanish and English. CONCLUSIONS: These findings suggest that it is possible to identify relationships between language patterns and deficits in patients with bilingual aphasia and that these trends will be instrumental in clinical assessments of this understudied population. PMID- 23816661 TI - The Communicative Participation Item Bank (CPIB): item bank calibration and development of a disorder-generic short form. AB - PURPOSE: The purpose of this study was to calibrate the items for the Communicative Participation Item Bank (CPIB; Baylor, Yorkston, Eadie, Miller, & Amtmann, 2009; Yorkston et al., 2008) using item response theory (IRT). One overriding objective was to examine whether the IRT item parameters would be consistent across different diagnostic groups, thereby allowing creation of a disorder-generic instrument. The intended outcomes were the final item bank and a short form ready for clinical and research applications. METHOD: Self-report data were collected from 701 individuals representing 4 diagnoses: multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis, and head and neck cancer. Participants completed the CPIB and additional self-report questionnaires. CPIB data were analyzed using the IRT graded response model. RESULTS: The initial set of 94 candidate CPIB items were reduced to an item bank of 46 items demonstrating unidimensionality, local independence, good item fit, and good measurement precision. Differential item functioning analyses detected no meaningful differences across diagnostic groups. A 10-item, disorder-generic short form was generated. CONCLUSIONS: The CPIB provides speech-language pathologists with a unidimensional, self-report outcomes measurement instrument dedicated to the construct of communicative participation. This instrument may be useful to clinicians and researchers wanting to implement measures of communicative participation in their work. PMID- 23816662 TI - Learning to fail in aphasia: an investigation of error learning in naming. AB - PURPOSE: To determine whether the naming impairment in aphasia is influenced by error learning and whether error learning is related to type of retrieval strategy. METHOD: Nine participants with aphasia and 10 neurologically intact controls named familiar proper noun concepts. When experiencing tip-of-the-tongue naming failure (TOT) in an initial TOT-elicitation phase, participants were instructed to adopt phonological or semantic self-cued retrieval strategies. In the error learning manipulation, items evoking TOT states during TOT elicitation were randomly assigned to a short or long time condition in which participants were encouraged to continue to try to retrieve the name for either 20 s (short interval) or 60 s (long). The incidence of TOT on the same items was measured on a post-test after 48 hr. Error learning was defined as a higher rate of recurrent TOTs (TOT at both TOT elicitation and post-test) for items assigned to the long (versus short) time condition. RESULTS: In the phonological condition, participants with aphasia showed error learning, whereas controls showed a pattern opposite to error learning. There was no evidence for error learning in the semantic condition for either group. CONCLUSION: Error learning is operative in aphasia but is dependent on the type of strategy used during naming failure. PMID- 23816663 TI - Factors that influence fast mapping in children exposed to Spanish and English. AB - PURPOSE: The purpose of this study was to determine whether children exposed to 2 languages would benefit from the phonotactic probability cues of a single language in the same way as monolingual peers and to determine whether crosslinguistic influence would be present in a fast-mapping task. METHOD: Two groups of typically developing children (monolingual English and bilingual Spanish-English) took part in a computer-based fast-mapping task that manipulated phonotactic probability. Children were preschool-aged (N = 50) or school-aged (N = 34). Fast mapping was assessed through name-identification and naming tasks. Data were analyzed using mixed analyses of variance with post hoc testing and simple regression. RESULTS: Bilingual and monolingual preschoolers showed sensitivity to English phonotactic cues in both tasks, but bilingual preschoolers were less accurate than monolingual peers in the naming task. School-aged bilingual children had nearly identical performance to monolingual peers. CONCLUSION: Knowing that children exposed to two languages can benefit from the statistical cues of a single language can help inform ideas about instruction and assessment for bilingual learners. PMID- 23816666 TI - Methyl sulfone manifests anticancer activity in a metastatic murine breast cancer cell line and in human breast cancer tissue--part I: murine 4T1 (66cl-4) cell line. AB - BACKGROUND: The spread of cancer (metastasis) is usually associated with death. We have identified a new approach that may be useful for treating metastatic cancer. METHODS: Here we studied the murine breast cancer cell line 66cl-4, because these cells are highly aggressive, potent inducers of metastasis and estrogen receptor negative. RESULTS: We found that 200 mM methyl sulfone did not induce apoptosis in cancerous cells but instead decreased cell proliferation and DNA synthesis, inhibited migration of cells through an extracellular matrix and induced contact inhibition and anchorage-dependent growth. Methyl sulfone promoted proper wound healing, reversed the epithelial to mesenchymal transition associated with metastatic disease and increased expression of alpha-smooth muscle actin, a differentiation protein of breast myoepithelial cells. CONCLUSION: Methyl sulfone did not kill the cancer cells but instead decreased metastatic phenotypes and increased normal differentiated phenotypes. PMID- 23816664 TI - Afferent and efferent aspects of mandibular sensorimotor control in adults who stutter. AB - PURPOSE: Individuals who stutter show sensorimotor deficiencies in speech and nonspeech movements. For the mandibular system, the authors dissociated the sense of kinesthesia from the efferent control component to examine whether kinesthetic integrity itself is compromised in stuttering or whether deficiencies occur only when generating motor commands. METHOD: The authors investigated 11 stuttering and 11 nonstuttering adults' kinesthetic sensitivity threshold and kinesthetic accuracy for passive jaw movements as well as their minimal displacement threshold and positioning accuracy for active jaw movements. They also investigated the correlation with an anatomical index of jaw size. RESULTS: The groups showed no statistically significant differences on sensory measures for passive jaw movements. Although some stuttering individuals performed more poorly than any nonstuttering participants on the active movement tasks, between-group differences for active movements were not statistically significant. Unlike fluent speakers, however, the stuttering group showed a statistically significant correlation between mandibular size and performance in the active and passive near-threshold tasks. CONCLUSIONS: Previously reported minimal-movement differences were not replicated. Instead, stuttering individuals' performance varied with anatomical properties. These correlational results are consistent with the hypothesis that stuttering participants generate and perceive movements on the basis of less accurate internal models of the involved neuromechanical systems. PMID- 23816667 TI - Idiopathic pulmonary fibrosis: diagnosis and prognostic evaluation. AB - Idiopathic pulmonary fibrosis (IPF) is the most common type of idiopathic interstitial pneumonia and has a dismal prognosis. Median age at IPF onset is 60 70 years and it is mainly related to cigarette smoke exposure. Its clinical profile is heterogeneous and different clinical phenotypes are now better defined: familial IPF, slow and rapid progressors, combined pulmonary fibrosis and emphysema, anti-neutrophil cytoplasmic antibodies/microscopic polyangiitis and IPF, and IPF associated with lung cancer. Acute exacerbation associated with rapid functional decline is an event that does not happen infrequently and affects survival. Diagnosis requires a typical usual interstitial pneumonia (UIP) pattern on computed tomography in the appropriate clinical setting or morphological confirmation of the UIP pattern when imaging findings are not characteristic enough. Surgical lung biopsy is the gold standard to obtain valuable information for histological analysis. However, less invasive procedures (transbronchial lung biopsy or even improved transbronchial lung biopsy by cryoprobes) are now under consideration. Prognostic indicators are mainly derived by pulmonary function tests. Recently, staging systems have been proposed. PMID- 23816668 TI - The value of database and data interpretation. PMID- 23816669 TI - The application of European system for cardiac operative risk evaluation II (EuroSCORE II) and Society of Thoracic Surgeons (STS) risk-score for risk stratification in Indian patients undergoing cardiac surgery. AB - AIMS AND OBJECTIVES: To validate European system for cardiac operative risk evaluation II (EuroSCORE II) and Society of Thoracic Surgeons (STS) risk-score for predicting mortality and STS risk-score for predicting morbidity in Indian patients after cardiac surgery. MATERIALS AND METHODS: EuroSCORE II and STS risk scores were obtained pre-operatively for 498 consecutive patients. The patients were followed for mortality and various morbidities. The calibration of the scoring systems was assessed using Hosmer-Lemeshow test. The discriminative capacity was estimated by area under receiver operating characteristic (ROC) curves. RESULTS: The mortality was 1.6%. For EuroSCORE II and STS risk-score C statics of 5.43 and 6.11 were obtained indicating satisfactory model fit for both the scores. Area under ROC was 0.69 and 0.65 for EuroSCORE II and STS risk-score with P values of 0.068 and 0.15, respectively, indicating poor discriminatory power. Good fit and discrimination was obtained for renal failure, long-stay in hospital, prolonged ventilator support and deep sternal wound infection but the scores failed in predicting risk of reoperation and stroke. Mortality risk was correctly estimated in low (< 2%) and moderate (2-5%) risk patients, but over estimated in high-risk (> 5%) patients by both scoring systems. CONCLUSIONS: EuroSCORE II and STS risk-scores have satisfactory calibration power in Indian patients but their discriminatory power is poor. Mortality risk was over estimated by both the scoring systems in high-risk patients. The present study highlights the need for forming a national database and formulating risk stratification tools to provide better quality care to cardiac surgical patients in India. PMID- 23816670 TI - Epidural catheterization in cardiac surgery: the 2012 risk assessment. AB - AIMS AND OBJECTIVES: The risk assessment of epidural hematoma due to catheter placement in patients undergoing cardiac surgery is essential since its benefits have to be weighed against risks, such as the risk of paraplegia. We determined the risk of the catheter-related epidural hematoma in cardiac surgery based on the cases reported in the literature up to September 2012. MATERIALS AND METHODS: We included all reported cases of epidural catheter placement for cardiac surgery in web and in literature from 1966 to September 2012. Risks of other medical and non-medical activities were retrieved from recent reviews or national statistical reports. RESULTS: Based on our analysis the risk of catheter-related epidural hematoma is 1 in 5493 with a 95% confidence interval (CI) of 1/970-1/31114. The risk of catheter-related epidural hematoma in cardiac surgery is similar to the risk in the general surgery population at 1 in 6,628 (95% CI 1/1,170-1/37,552). CONCLUSIONS: The present risk calculation does not justify not offering epidural analgesia as part of a multimodal analgesia protocol in cardiac surgery. PMID- 23816671 TI - Efficacy of perioperative pregabalin in acute and chronic post-operative pain after off-pump coronary artery bypass surgery: a randomized, double-blind placebo controlled trial. AB - AIMS AND OBJECTIVES: We evaluated the efficacy of perioperative pregabalin on acute and chronic post-operative pain after off-pump coronary artery bypass (OPCAB) surgery. MATERIALS AND METHODS: Forty patients undergoing elective OPCAB surgery were randomized to pregabalin and control groups. Pregabalin group received 150 mg pregabalin 2 h prior to induction of anesthesia and 75 mg twice daily for 2 post-operative days whereas the control group received placebo at similar timings; pregabalin and placebo were administered by an anesthesiologist blinded to the drugs. Pain scores (visual analogue scale [VAS]) and sedation scores were observed at 0, 4, 6, 12, 24, 36 and 48 h after extubation. Time to extubation, tramadol consumption and side-effects were noted. VAS score was analyzed by Mann-Whitney U test. The analysis of variance test for repeated measures was used for comparison of the means of continuous variables. Group comparisons were made using the Chi-square-test. RESULTS: Pain-scores at 6, 12, 24 and 36 h from extubation at rest and at deep breath were less in pregabalin treated patients ( P < 0.05). Tramadol consumption was reduced by 60% in pregabalin group ( P < 0.001). Extent of sedation, extubation times and incidence of nausea were comparable. The effect on chronic post-operative pain was not significant. CONCLUSIONS: Perioperative pregabalin reduced pain scores at rest and deep breath and reduced consumption of tramadol in the post-operative period without delaying extubation and causing excessive sedation. PMID- 23816672 TI - Coronary angiography findings in lung injured patients with sulfur mustard compared to a control group. AB - AIMS AND OBJECTIVES: We evaluated the incidence of coronary artery disease (CAD) in Sulfur mustard (SM) exposed veterans. We also evaluated the relationship between exposure to SM and angiography findings and compared angiography findings of SM exposed individuals with unexposed ones after two decades from the time of exposure to SM. MATERIALS AND METHODS: A case-control study was conducted on 200 consecutive patients (100 SM exposed vs. 100 unexposed) undergoing angiographic assessments due to CAD. RESULTS: The coronary angiography findings between two groups were significantly different ( P < 0.001). Ninety two (92%) patients in SM exposed group and 82 (82%) in unexposed group had abnormal findings in their coronary arteries ( P = 0.031). CONCLUSIONS: The incidence of CAD and angiographic changes were significantly increased with exposure to SM. Further studies on cardiovascular effects of SM are needed. PMID- 23816673 TI - New orally active anticoagulants in critical care and anesthesia practice: the good, the bad and the ugly. AB - With the adoption of dabigatran, rivaroxaban, and apixaban into clinical practice, a new era has arrived in the practice of oral anticoagulants. Venous thromboembolism (VTE) has traditionally been underdiagnosed and under treated in Asia. With increasing longevity, the diagnosis and the need for management of atrial fibrillation (AF) and VTE is likely to increase significantly. The new orally active anticoagulants (NOACs) have reasonably filled the lacunae that clinicians traditionally faced when treating patients with vitamin K antagonist (VKA). Unlike VKA, NOACs do not need frequent monitoring. Therefore, more patients are likely to get therapeutic effects of anticoagulation and thus reduce morbidity and mortality associated with VTE and AF. However, the clinicians need to be circumspect and exercise caution in use of these medications. In particular (in geriatric population), the clinicians should look out for drug-drug interactions and underlying renal insufficiency. This would ensure therapeutic efficacy and minimize bleeding complications. Here, it is important to note that the antidote for NOACs is not available and is a major concern if emergency surgical procedure is required in their presence. PMID- 23816674 TI - Use of dopamine infusion improved oxygenation in a patient of Ebstein's anomaly with atrial septal defect. AB - We present the successful perioperative management of an adult patient with Ebstein's anomaly for abdominal rectopexy surgery. The patient developed mild hypotension and a fall in peripheral oxygen saturation (SpO 2 ) after administration of a graded epidural block. Correction of the fall in the blood pressure; however, did not improve the SpO 2 . The patient was administered an intravenous infusion of dopamine to improve the cardiac output and this led to improvement in the SpO 2 . PMID- 23816675 TI - Emergent cardiopulmonary bypass during pectus excavatum repair. AB - Pectus excavatum is a chest wall deformity that produces significant cardiopulmonary disability and is typically seen in younger patients. Minimally invasive repair of pectus excavatum or Nuss procedure has become a widely accepted technique for adult and pediatric patients. Although it is carried out through a thoracoscopic approach, the procedure is associated with a number of potential intraoperative and post-operative complications. We present a case of cardiac perforation requiring emergent cardiopulmonary bypass in a 29-year-old male with Marfan syndrome and previous mitral valve repair undergoing a Nuss procedure for pectus excavatum. This case illustrates the importance of vigilance and preparation by the surgeons, anesthesia providers as well as the institution to be prepared with resources to handle the possible complications. This includes available cardiac surgical backup, perfusionist support and adequate blood product availability. PMID- 23816676 TI - Idiopathic left ventricular outflow tract pseudoaneurysm. AB - Left ventricular outflow tract (LVOT) pseudoaneurysm is a rare occurrence and may produce clinically unpredictable symptoms. A very few cases of LVOT pseudoaneurysm are reported and there has always been a predisposing factor in these reported cases such as history of infective endocarditis, myocardial infarction, prosthetic aortic valve replacement or chest trauma. Our patient did not have the above predisposing conditions. Intra operative transesophageal echocardiography helped patient management and guided the surgical team in securing and isolation of the aneurysmal sac from the LVOT. PMID- 23816677 TI - Levosimendan in a neonate with severe coarctation of aorta and low cardiac output syndrome. AB - We report successful use of levosimendan after failed balloon angioplasty in a critically ill neonate with coarctation of aorta (CoA) and severe low cardiac output syndrome (LCOS). Treatment with levosimendan improved left heart function, and decreased lactate and brain natriuretic peptide levels. To our knowledge, this is the first report on the safe and successful use of levosimendan in the management of LCOS due to severe CoA in a neonate awaiting surgical repair. PMID- 23816678 TI - Cardiac surgery in a patient with severe thrombocytopenia: how low is too low? AB - Platelets play a very important role in hemostasis, especially after cardiac surgery. Excessive bleeding after such surgery may lead to increased need for transfusion and its incumbent increase in post-operative morbidity and mortality. Although most cardiac surgeons will offer a surgical option to a patient with moderate thrombocytopenia (platelet count around 70 * 10 9 /L), successful cardiac surgery has not been reported in patients with significantly lower platelets counts (less than 40 * 10 9 /L). We report a case of severe thrombocytopenia (19 * 10 9 /L) where coronary artery bypass grafting was performed with minimal blood loss post-operatively, discuss the patient's management and provide insights while dealing with such patients. PMID- 23816679 TI - How standard transesophageal echocardiography views change with dextrocardia. AB - Dextrocardia with situs inversus is a rare condition. Situs inversus with dextrocardia is also called as "situs inversus totalis". Transesophageal echocardiography (TEE) views in dextrocardia patient are not discussed in the literature. The cardiac position and the cardiac chambers are mirror image of the normal anatomy. Because of this positional change, certain TEE probe and multiplane angle manipulations are required to obtain the recommended views. PMID- 23816680 TI - Mobile left atrial mass. PMID- 23816681 TI - Necklace shadow in the neck after surgery. PMID- 23816682 TI - Anatomical landmark technique for internal jugular vein cannulation in patients with cyanotic congenital heart disease: a word of caution. PMID- 23816683 TI - False diagnosis of acute Type A dissection. PMID- 23816684 TI - In response to, aortic dissection: to be or not to be? PMID- 23816685 TI - Perioperative management of emergency aortic valve replacement for infective endocarditis after liver transplantation. PMID- 23816686 TI - Anaphylaxis during intravenous administration of amiodarone. PMID- 23816687 TI - Asystole during pulmonary artery catheter sheath removal: a rare occurance. PMID- 23816689 TI - Synthetic biology as red herring. AB - It has become commonplace to say that with the advent of technologies like synthetic biology the line between artifacts and living organisms, policed by metaphysicians since antiquity, is beginning to blur. But that line began to blur 10,000 years ago when plants and animals were first domesticated; and has been thoroughly blurred at least since agriculture became the dominant human subsistence pattern many millennia ago. Synthetic biology is ultimately only a late and unexceptional offshoot of this prehistoric development. From this perspective, then, synthetic biology is a red herring, distracting us from more thorough philosophical consideration of the most truly revolutionary human practice-agriculture. In the first section of this paper I will make this case with regard to ontology, arguing that synthetic biology crosses no ontological lines that were not crossed already in the Neolithic. In the second section I will construct a parallel case with regard to cognition, arguing that synthetic biology as biological engineering represents no cognitive advance over what was required for domestication and the new agricultural subsistence pattern it grounds. In the final section I will make the case with regard to human existence, arguing that synthetic biology, even if wildly successful, is not in a position to cause significant existential change in what it is to be human over and above the massive existential change caused by the transition to agriculture. I conclude that a longer historical perspective casts new light on some important issues in philosophy of technology and environmental philosophy. PMID- 23816690 TI - Effects of granulosa cells on steroidogenesis, proliferation and apoptosis of stromal cells and theca cells derived from the goat ovary. AB - The aim of this study was to investigate the effect of granulosa cells from small antral follicles on steroidogenesis, proliferation and apoptosis of goat ovarian stromal and theca cells in vitro. Using Transwell co-culture system, we evaluated androgen production, LH responsiveness, cell proliferation and apoptosis and some molecular expression regarding steroidogenic enzyme and apoptosis-related genes in stromal and theca cells. The results indicated that the co-culture with granulosa cells increased steroidogenesis, LH responsiveness and bcl-2 gene expression as well as decreased apoptotic bax and bad expressions in stromal and theca cells. Thus, granulosa cells had a capacity of promoting steroidogenesis in stromal cell and LH responsiveness in cortical stromal cells, maintaining steroidogenesis in theca cells, inhibiting apoptosis of cortical stromal cells and improving anti-apoptotic abilities of stromal and theca cells. PMID- 23816691 TI - A lines-of-defense model for managing health threats: a review. AB - As older individuals face challenges of progressive disease and increasing disability and approach the end of their lives, their capacity for controlling their environment and own health and functioning declines. The Lines-of-Defense Model is based on the Motivational Theory of Life-Span Development and proposes that individuals can adjust their control striving to the progressive physical decline in distinctly organized cycles of goal engagement and goal disengagement that reflect sequentially organized lines of defense. This organized process allows individuals to hold onto and defend still feasible levels of physical health and functioning in activities of daily living, while adjusting to increasing impairments. As physical constraints become more severe towards the end of life, avoiding psychological suffering becomes the focus of individuals' strivings for control. The Lines-of-Defense Model can also be applied to the inverse process of growth in functioning during recovery and rehabilitation. PMID- 23816692 TI - Primary intestinal B-cell lymphoma: a prospective multicentre clinical study of 91 cases. AB - BACKGROUND & AIMS: Clinical presentation, diagnosis and prognosis of different primary intestinal lymphomas have not been well described and compared so far. Our aim was to prospectively analyse a series of consecutive patients presenting different types of B-cell primary intestinal lymphomas. METHODS: Adult patients with primary intestinal lymphoma, collected between 1991 and 2000 within the multicenter national study in France were evaluated and followed up prospectively. Clinical features and treatment outcomes were analyzed and compared among different groups of lymphomas. RESULTS: Among 91 cases of B-cell primary intestinal lymphomas identified, 38 (41%) were diffuse large B cell lymphomas, 34 (37%) mantle cell lymphomas, 12 (13%) follicular lymphomas, 5 (5%) marginal zone MALT-lymphomas, and 2 (3%) Burkitt's lymphomas. A differential diagnosis could be made on the basis of tumour cell morphology and phenotype assessed by immunohistochemistry. Clinical presentation of the different types of lymphomas varied with respect to age, symptoms, circumstances of diagnosis, and stage. Overall survival was the poorest for mantle cell lymphomas while diffuse large B cell lymphomas could be cured if in complete remission after first line treatment. CONCLUSIONS: This study underlines the existence, within the B-cell primary intestinal lymphomas, of several distinct entities with different clinico pathological features and prognosis, whose identification is important for choosing appropriate therapeutic strategy. PMID- 23816693 TI - Comment to "serum osteopontin levels as a predictor of portal inflammation in patients with nonalcoholic fatty liver disease". PMID- 23816694 TI - Massive gastrointestinal dilatation in a case of hereditary hollow visceral myopathy. PMID- 23816695 TI - Metabolic syndrome after liver transplantation: short-term prevalence and pre- and post-operative risk factors. AB - BACKGROUND: The metabolic syndrome is a common condition among liver transplanted patients and contributes to morbidity and mortality by favouring the development of cardiovascular diseases. AIMS: This prospective study assessed the prevalence of metabolic syndrome in the first year after orthotopic liver transplantation, the associated pre-operative and post-operative risk factors and the influence of nutritional factors. METHODS: 84 cirrhotic patients (75% male, mean age 53.9+/ 9.3 years) were evaluated at baseline and after liver transplantation. Metabolic syndrome was defined according to 2004 Adult Treatment Panel-III criteria. Nutritional habits were assessed using 3-day food records. RESULTS: Prevalence of metabolic syndrome before orthotopic liver transplantation was 14/84 (16.6%); at 3, 6 and 12 months post-orthotopic liver transplantation it was 27/84 (32.1%), 30/84 (35.7%), and 32/81 (39.5%), respectively. Diabetes, family history of diabetes, and excess body weight at baseline independently correlated with incidence of metabolic syndrome. After orthotopic liver transplantation, patients with metabolic syndrome showed a higher increase in the intake of total energy and saturated fats and a higher prevalence of complications, especially cardiovascular events, than subjects without metabolic syndrome. CONCLUSION: Occurrence of metabolic syndrome is an early phenomenon after liver transplantation. Pre-operative and post-operative factors predispose patients to metabolic syndrome, which may be reduced by controlling modifiable risk factors, such as body weight and dietary intake. PMID- 23816696 TI - C/EBPalpha inhibits hepatocellular carcinoma by reducing Notch3/Hes1/p27 cascades. AB - BACKGROUND AND AIMS: CCAAT/enhancer binding protein alpha is one of the key transcription factors of the hepatocyte nuclear factors family, which plays a critical role in liver cell proliferation and differentiation. However, the role of CCAAT/enhancer binding protein alpha in hepatocarcinogenesis remains to be defined. METHODS: A recombinant adenovirus carrying the C/EBPalpha gene was constructed to determine its effect on hepatocarcinogenesis in vitro and in vivo. RESULTS: We demonstrated that overexpression of CCAAT/enhancer binding protein alpha inhibited the tumourigenicity of Huh7 cells, re-established the expression of certain liver-specific genes and induced G0/G1 arrest. Overexpression of CCAAT/enhancer binding protein alpha significantly suppressed the proliferation of primary hepatocarcinogenesis cells and tumour associated fibroblasts in vitro. Additionally, intratumoural injection of adenovirus carrying the C/EBPalpha reduced the growth of subcutaneous hepatocarcinogenesis xenografts in nude mice. Systemic administration of adenovirus carrying the C/EBPalpha resulted in the eradication of orthotopic liver hepatocarcinogenesis nodules in nude mice. Further, up-regulation of CCAAT/enhancer binding protein alpha reduced the expression of Notch3, thereby suppressing Hes1 transactivation activity and leading to decreased p27 expression. Overexpression of Hes1 partially abolished the anti-proliferation effect of CCAAT/enhancer binding protein alpha on Huh7 cells. CONCLUSION: These results suggested that the effect of CCAAT/enhancer binding protein alpha on hepatocarcinogenesis is partially through by reducing Notch3/Hes1/p27 cascades and CCAAT/enhancer binding protein alpha may possess a novel therapeutic potential for human hepatocarcinogenesis. PMID- 23816697 TI - Agreement between indirect calorimetry and traditional tests of lactose malabsorption. AB - BACKGROUND: Lactose malabsorption occurs frequently and the variable consequent intolerance may seriously impair quality of life. No reliable and convenient test method is in routine clinical practice. A recent animal study showed that the respiratory quotient changed significantly after ingestion of sucrose and lactose in naturally lactase-deficient rats. AIMS: This exploratory study evaluated the relevance of monitoring the respiratory quotient after lactose ingestion to detect malabsorption. METHODS: Healthy volunteers were identified and classified lactose absorbers and malabsorbers by a lactose tolerance test (25 g). After an overnight fast, a second lactose challenge was performed to monitor hydrogen excretion and respiratory quotient kinetics over 4h. Participants also completed questionnaires to score and localise their gastrointestinal symptoms. RESULTS: 20 subjects were enrolled (10 per group, 60% males, mean age 34 +/- 4 years). Respiratory quotient kinetics were different between absorbers and malabsorbers during the first 100 min after lactose ingestion (p<0.01) and during the initial 30-50 min period. Respiratory quotient was significantly, positively correlated to peak glycaemia (R=0.74) and negatively correlated to hydrogen excretion (R= 0.51) and symptoms score (R=-0.46). CONCLUSIONS: Indirect calorimetry could improve the reliability of lactose malabsorption diagnosis. Studies on larger populations are needed to confirm the validity of this test and propose a simplified measurement. PMID- 23816698 TI - Skills and requirements of a transplant hepatologist: board certification of the Italian Association for the Study of the Liver (AISF). AB - Liver transplantation has indeed evolved from an experimental procedure in the early 1980s to the most effective treatment for patients with advanced liver cirrhosis and for selected patients with hepatocellular carcinoma and fulminant hepatic failure. In this new scenario, the transplant hepatologist plays a crucial clinical role, with essential duties and skills to manage the complexities encountered in waitlisted patients or transplant recipients. The clinical tasks of the transplant hepatologist include the management of patients with end-stage liver disease who are candidates for liver transplantation and/or on the waiting list, as well as the care of transplant recipients, in both the in and outpatient setting. Starting in 2013, the Italian Association of the Study of the Liver, with the endorsement of the National Transplant Centre, will be offering a formal certification process for transplant hepatologists, implemented in accordance to Union Europeenne des Medecins Specialistes-European Board of Transplant Medicine procedures. The Special Article outlines the requirements for board certification of the Italian Association for the Study of the Liver transplant hepatologist. PMID- 23816699 TI - Inter-centre variability of the adenoma detection rate: a prospective, multicentre study. AB - BACKGROUND: Suboptimal colonoscopy quality is related to a higher risk of interval cancer. Aim of our study was to explore the variability in detection rate of neoplasia among different endoscopic centres in an unselected population. METHODS: Consecutive patients referred for colonoscopy in 28 Italian centres were included. Detection rate for polyp, neoplasia and advanced neoplasia was assessed at both the individual and centre level. Inter-centre variability in detection rate of colorectal lesions was explored after adjusting for patient-related factors at multivariate analysis. RESULTS: 3150 patients were included. Median detection rates for polyp, neoplasia and advanced neoplasia were 35%, 26% and 13%. At multivariate analysis, patient-related factors associated with neoplasia detection were age, sex, alcohol and smoking history. After adjusting for these variables, a statistically significant difference in the observed/expected ratio among different centres was observed (Chi-squared test: p<0.01). Among non patient-related factors, documentation of withdrawal time was associated with neoplasia detection. However, a statistically significant inter-centre variability also remained after adjusting for this variable. CONCLUSIONS: A wide variability was present in the detection rate of neoplasia and advanced neoplasia at the level of endoscopic centres in an unselected population. The adoption of a centre-related neoplasia detection rate could be suggested as a performance indicator. PMID- 23816700 TI - A patient with situs inversus totalis and pancreatic head cancer. PMID- 23816701 TI - Combining analyses of basophil allergen threshold sensitivity, CD-sens, and IgE antibodies to hydrolyzed wheat, omega-5 gliadin and timothy grass enhances the prediction of wheat challenge outcome. AB - BACKGROUND: Wheat is a common food causing allergy which has implications on the quality of life. The diagnosis of IgE-mediated wheat allergy is based on the clinical history and presence of IgE antibodies (IgE-Ab) in skin or blood, and the results of an oral food challenge which is time consuming and associated with risks. An improved diagnostic workup is needed for wheat allergy. The objective was to examine the relationship between wheat challenge, CD-sens and IgE-Ab to related allergens in wheat-allergic children and investigate if a combination of different markers could enhance the prediction of challenge outcome. METHOD: Twenty-four children (aged 1-15 years) with a wheat allergy diagnosis underwent an open wheat challenge. CD-sens and IgE-Ab to wheat, hydrolyzed wheat protein (HWP), omega-5 gliadin and timothy grass were analyzed and related to the challenge outcome. RESULTS: A positive challenge was seen in 12/24 children. Children reacting to the challenge had higher IgE-Ab concentrations to wheat, omega-5 gliadin and HWP (p < 0.01) and a tendency to higher wheat CD-sens values (p = 0.08) than nonreacting children. Combining wheat CD-sens >150 and IgE-Ab to wheat >20 kUA/l, or omega-5 gliadin >0.1 kUA/l predicted the challenge outcome in 83% of the patients. Most children with IgE-Ab to wheat also had IgE-Ab to timothy. Seven of 9 challenge-positive children had a positive CD-sens to HWP and IgE-Ab to HWP >8 kUA/l. CONCLUSION: Combining CD-sens and IgE-Ab to wheat or wheat components could be useful in the diagnosis and follow-up of wheat-allergic children. PMID- 23816702 TI - Circulating platelet derived microparticles are not increased in patients with cirrhosis. PMID- 23816703 TI - Reply to: "Circulating platelet derived microparticles are not increased in patients with cirrhosis". PMID- 23816705 TI - Combined antihypertensive therapy and sexual dysfunction: terra incognita. PMID- 23816704 TI - Identification of alpha-taxilin as an essential factor for the life cycle of hepatitis B virus. AB - BACKGROUND & AIMS: alpha-taxilin was identified as binding partner of syntaxins and is supposed to regulate vesicular trafficking. However, the physiological functions of alpha-taxilin and its potential relevance for the life cycle of hepatitis B virus (HBV) are still poorly understood. METHODS: Transfected hepatoma cells, infected primary human hepatocytes, and liver tissue of HBV infected patients were used to study the expression of alpha-taxilin. Subcellular localization and colocalization were analyzed by confocal laser scanning microscopy (CLSM). Protein-protein interactions were further investigated by co immunoprecipitations. Silencing of alpha-taxilin expression was performed by lentiviral gene transfer. RESULTS: HBV producing cells show a significant higher level of alpha-taxilin. HBV induces alpha-taxilin expression, by its regulatory proteins HBx and LHBs via c-Raf. This indicates that alpha-taxilin is essential for the release of HBV particles. CLSM and co-immunoprecipitations demonstrated that the PreS1PreS2 domain of LHBs interacts with alpha-taxilin. alpha-taxilin harbors a YXXL motif that represents a classic late domain. In accordance with this, it was found by co-immunoprecipitations that alpha-taxilin interacts with the ESCRT I component tsg101. CLSM revealed that a fraction of alpha-taxilin colocalizes with LHBs and tsg101. CONCLUSIONS: alpha-taxilin plays an essential role for release of HBV-DNA containing particles. It might act as an adapter that binds, on the one hand, to LHBs and, on the other hand, to tsg101 and thereby helps recruit the ESCRT machinery to the viral envelope proteins. PMID- 23816707 TI - Chemical and genomic evolution of enzyme-catalyzed reaction networks. AB - There is a tendency that a unit of enzyme genes in an operon-like structure in the prokaryotic genome encodes enzymes that catalyze a series of consecutive reactions in a metabolic pathway. Our recent analysis shows that this and other genomic units correspond to chemical units reflecting chemical logic of organic reactions. From all known metabolic pathways in the KEGG database we identified chemical units, called reaction modules, as the conserved sequences of chemical structure transformation patterns of small molecules. The extracted patterns suggest co-evolution of genomic units and chemical units. While the core of the metabolic network may have evolved with mechanisms involving individual enzymes and reactions, its extension may have been driven by modular units of enzymes and reactions. PMID- 23816706 TI - Methylerythritol phosphate pathway to isoprenoids: kinetic modeling and in silico enzyme inhibitions in Plasmodium falciparum. AB - The methylerythritol phosphate (MEP) pathway of Plasmodium falciparum (P. falciparum) has become an attractive target for anti-malarial drug discovery. This study describes a kinetic model of this pathway, its use in validating 1 deoxy-d-xylulose 5-phosphate reductoisomerase (DXR) as drug target from the systemic perspective, and additional target identification, using metabolic control analysis and in silico inhibition studies. In addition to DXR, 1-deoxy-d xylulose 5-phosphate synthase (DXS) can be targeted because it is the first enzyme of the pathway and has the highest flux control coefficient followed by that of DXR. In silico inhibition of both enzymes caused large decrement in the pathway flux. An added advantage of targeting DXS is its influence on vitamin B1 and B6 biosynthesis. Two more potential targets, 2-C-methyl-d-erythritol 2,4 cyclodiphosphate synthase and 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate synthase, were also identified. Their inhibition caused large accumulation of their substrates causing instability of the system. This study demonstrates that both types of enzyme targets, one acting via flux reduction and the other by metabolite accumulation, exist in P. falciparum MEP pathway. These groups of targets can be exploited for independent anti-malarial drugs. PMID- 23816708 TI - Cardiac autonomic impairment during sleep as a marker of human prion diseases: a preliminary report. PMID- 23816709 TI - Constantin N. Arseni (1912-1994) centenary: the birth of modern neurosurgery in Romania. AB - Prof. Dr. Constantin N. Arseni and his mentor, Prof. Dr. D. Bagdasar, are revered by later generations of doctors as the forefathers of Romanian neurosurgery. In 2012, we have celebrated 100 years since Prof. Arseni's birth in a small village within a deprived area of the country. Through his talents and perseveration, he rose to be a neurosurgical school creator and one of the most prominent figures in 20th-century Eastern European neurosurgery. This historical vignette is a modest tribute to his legacy and tells the story of his titanic endeavor. PMID- 23816710 TI - Surgical intervention of pilonidal sinus: impact on patients' postoperative satisfaction and return to work time. AB - BACKGROUND: Pilonidal sinus (PS) is a chronic inflammatory process accompanied by psychological strain and a high rate of work incapacity. OBJECTIVES: To analyze the impact of PS surgery on individual patients' satisfaction (SAT) and economic impacts on work capability. PATIENTS AND METHODS: We retrospectively analyzed 40 PS patients regarding SAT and return to work time (RTW) in relation to various factors, using multivariate analysis and Pearson's correlation test. RESULTS: We found a significant negative correlation between SAT and RTW (p<0.01), both correlated equally strongly with duration between first diagnosis and surgery (p<0.01) and with loss of weight (p<0.05). RTW correlated with duration of painkiller intake (p<0.01). SAT correlated with gender (p<0.01), smoking cessation (p<0.05) and quantity of painkiller intake (p<0.01). Satisfaction correlated with gender (p<0.01), smoking cessation (p<0.05), and quantity of painkiller intake (p<0.05). CONCLUSION: RTW after PS surgery is influenced by factors that can be influenced prior to surgery, leading to better economic results for patients and employers as well as society. PMID- 23816712 TI - Methyl sulfone manifests anticancer activity in a metastatic murine breast cancer cell line and in human breast cancer tissue--part 2: human breast cancer tissue. AB - BACKGROUND: Methyl sulfone is a small molecule that reverses cancerous phenotypes of a melanoma cell line. Here, we sought to determine whether methyl sulfone was effective against human breast cancer tissue. METHODS: We studied normal and cancerous breast tissue obtained from 17 patients. RESULTS: Methyl sulfone introduced structural order, with cancer tissue taking on the morphology of normal in vivo breast tissue; this structural order was sustainable over long term culture. Methyl sulfone promoted proper wound healing, including migration of cells into wounded areas and establishment of stable contact inhibition once wounds were covered. Methyl sulfone decreased expression of two breast stem cell marker proteins, HCAM and OCT3/4, which are associated with aberrantly rapid migration of metastatic cells. Finally, normal and cancerous primary breast cells remained viable and healthy in methyl sulfone culture for at least 90 days. CONCLUSION: Methyl sulfone reintroduced a normal structural phenotype to human breast cancer tissues. PMID- 23816713 TI - Impact of donor age on outcome of kidney transplantation from controlled donation after cardiac death. AB - Previous reports regarding donation after cardiac death (DCD) have called for caution in extending the age of kidney donors beyond 60 years due to the risk of poor graft function. The aim of this study was to determine the impact of donor age on renal transplantation from DCD in one center. All DCD transplants from 2005 to 2009 were included in the study. Immunosuppression and recipient follow up were as per unit protocol. Donor and recipient details were entered prospectively into a renal database and analyzed for graft outcome. Of the 147 renal transplants, 102 were from donors <60 years old and 45 were from donors >=60 years old. The incidence of delayed graft function varied significantly according to donor-recipient age groups (P = 0.01). The mean glomerular filtration rate at 12 months was 50.3 mL/min for transplants from young donors compared with 39.3 mL/min for transplants from old donors (P = 0.001). The cumulative graft survival rates at 1 and 5 years were 88% and 79% for young donors, while for old donors these were 78% and 72%, respectively (P = 0.101). By transplanting kidneys from old DCD donors into elderly patients, their survival is improved compared with dialysis, and organs from younger donors are made available for younger recipients. PMID- 23816714 TI - Outcomes following renal transplantation in patients with chronic hepatitis C based on severity of fibrosis on pre-transplant liver biopsy. AB - Data regarding long-term outcomes following renal transplantation in patients with hepatitis C virus (HCV) infection have been controversial. Our aim was to determine whether there is a difference in outcomes between patients with HCV and more advanced fibrosis on pretransplant biopsy and those with minimal or no fibrosis. Patients were divided according to the severity of fibrosis and their outcomes (including acute rejection, chronic rejection, re-initiation of dialysis, progression of liver disease and mortality) were compared. Thirty-one patients with minimal or no fibrosis (Scheuer stages 0 and 1: Group-A) and 10 patients with more advanced fibrosis (Scheuer stages 2 and 3: Group-B) were included in the final data analysis. Acute rejection occurred in 29% (9/31) of the patients with minimal and 30% (3/10) of the patients with advanced fibrosis (P = 0.95), while chronic allograft nephropathy occurred in 6.5% (2/31) of the patients without and 50% (5/10) of the patients with fibrosis (P = 0.006). None of the patients without fibrosis required re-initiation of dialysis compared with 50% (5/10) of the patients with fibrosis (P <0.05). Median graft survival was 46 months and 18 months for patients with minimal and advanced fibrosis, respectively. There were four deaths among patients with advanced and three deaths among patients with minimal fibrosis (P = 0.04). Our data suggests that patients with chronic HCV and more advanced fibrosis on liver biopsy who undergo a renal transplant have a higher incidence of chronic rejection, graft failure and mortality following renal transplant compared with those with minimal fibrosis. PMID- 23816715 TI - Tumor necrosis factor-alfa and monocyte chemoattractant protein-1 gene polymorphisms in kidney transplant recipients. AB - Tumor necrosis factor-alfa (TNF-alpha) gene polymorphism is supposed to have a significant influence on the incidence of acute rejection in renal transplantation. The monocyte chemoattractant protein-1 (MCP-1) is another factor supposed to modulate graft rejection. We studied TNF-alpha and MCP-1 gene polymorphisms in 84 kidney allograft recipients with polymerase chain reaction and restriction fragment length polymorphism and their serum levels by enzyme linked immunosorbent assay. The patients were classified into two groups based on their outcomes: Group I (n = 47) recipients with stable graft function as the control group and group II (n=37) recipients who experienced acute graft rejection episodes in the first 30 days post-transplantation. A significantly higher incidence of TNF 2 /TNF 2 genotype was observed among patients with acute graft rejection in comparison with the control group (40.5% and 19.2% respectively, P <0.05), while no statistically significant differences were observed in the TNF 1 /TNF 1 genotype between the groups (59.4% and 80.8%, respectively, P >0.05). A significant elevation of serum TNF-alpha levels was found in group II than group I and between TNF 2 genotype compared with that of TNF1 genotype within group II recipients. Distribution of MCP-1 genotypes in patients with and without acute rejection episodes was not significantly different (70.2% and 76.6% for MCP-1 A/A and 29.7% and 23.4% for MCP-1 G/G, respectively, P >0.05). The serum MCP-1 levels were not significantly different between the groups and between MCP-1 G/G genotype and MCP-1 A/A genotype in group II recipients. In conclusion, TNF-alpha gene polymorphism or its serum levels may identify patients at risk of acute rejection, where patients with TNF 2 /TNF 2 genotype or high serum TNF-alpha levels are more likely to have acute rejection episodes, while there was no relation between MCP-1 genotype or its serum levels and acute rejection. PMID- 23816716 TI - Outcome of second kidney transplant: a single center experience. AB - Nowadays, a repeat transplantation is considered to confer a better survival advantage to patients over dialysis. The cost-effectiveness of transplantation for end-stage renal disease patients shows benefits over dialysis even for re transplanted patients. This retrospective single center ten-year study was undertaken to evaluate patient/graft survival, function vis-a-vis serum creatinine (SCr) and rejection episodes in 62 re-transplanted patients. Sixty-two patients underwent a second renal transplant (24 living related, 38 deceased donors) at our center between 2000 to 2009. The mean recipient age was 41.9 +/- 12.27 years. Fifty-three recipients were male and nine recipients were female. Recipients had negative acceptable lymphocyte cross-matching using anti-human globulin complement-dependent cytotoxicity tests and flow cytometric cross-match before transplant. All recipients except those who were hepatitis C virus or hepatitis B surface antigen positive received single-dose rabbit-anti-thymocyte globulin induction and steroids, calcineurin inhibitor +/- mycophenolate mofetil/azathioprine for maintenance immunosuppression. Of the 62 patients, 38 patients received kidneys from deceased donors and 24 patients received kidneys from live donors. Over the mean follow-up of 4.03 +/- 2.93 years, the 1-year, 5 year and 10-year patient survival rates were 85.33%, 66.7% and 66.7%, respectively, and the graft survival rates were 96.7%, 79.7% and 79.7%, respectively. The acute rejection rates were 17.6%, with a mean SCr of 1.92 +/- 0.5 mg/dL. There was unexplained interstitial fibrosis with tubular atrophy in 11.2% patients (n = 7), all leading to graft loss eventually. Overall, 25% (n = 16) of the patients were lost, mainly to infectious complications. Re transplantation has acceptable graft and patient survival over a ten-year follow up period and should be encouraged for better quality of life as compared with dialysis. PMID- 23816717 TI - Association between pruritus and serum concentrations of parathormone, calcium and phosphorus in hemodialysis patients. AB - Chronic renal disorders have a progressive course in most cases, and finally result in end-stage renal disease (ESRD). Hemodialysis (HD) is one of the mainstays in the treatment of these patients. Disturbance in calcium (Ca) and phosphorus (P) metabolism and alteration of serum levels of parathormone (PTH) are observed in these patients. One of the most common cutaneous manifestations in patients on HD is pruritus. The aim of this study is to evaluate the association between pruritus and serum concentrations of Ca, P and PTH in patients with chronic renal disease. This analytic, descriptive, cross-sectional study was performed on 120 patients on HD at the Fifth-Azar Hospital in Gorgan, Iran, in 2010. Information related to the patients, including age, gender, pruritus, time of pruritus and duration on dialysis, was extracted from questionnaires. Serum concentrations of intact PTH, Ca and P were measured. Data were analyzed by the chi-square test and SPSS-16 software. A P-value less than 0.05 was considered statistically significant. Among the 120 study patients, 50% were male and the mean age (+/-SD) was 49 +/- 12.3 years. Sixty percent of the patients had pruritus, of whom 33.3% had PTH levels above the normal range. Among the 40% of the patients who did not have pruritus, 39.6% had PTH levels higher than the normal levels. The mean serum Ca and P levels were 8.44 +/- 1.65 mg/dL and 5.48 +/- 1.81 mg/dL, respectively. The mean (+/-SD) Ca-P product was 55.46 +/ 47.16 and the mean PTH concentration was 274.34 +/- 286.53 pg/mL. No significant association was found between pruritus and age, sex, serum PTH and P levels as well as Ca-P product. However, the association between serum Ca levels and pruritus was significant (P = 0.03). Our study showed that most patients with pruritus had serum Ca levels in the abnormal range (lower or higher), and there was no significant correlation between serum iPTH level and pruritis. Thus, good control of serum Ca levels is important to reduce pruritus in these patients. PMID- 23816718 TI - Ultrasound-guided internal jugular vein access: comparison between short axis and long axis techniques. AB - The use of real-time ultrasound (US) is advantageous in the insertion of central venous catheters (CVCs) in adults, especially in whom difficulties are anticipated for various reasons. The aim of the present study was to compare two different real-time 2-dimensional US-guided techniques [short axis view/out-of plane approach (SAX OOP approach) versus long axis view/in-plane approach (LAX IP approach)] for internal jugular vein (IJV) cannulation. In this prospective study, 90 critical care and hemodialysis patients were assigned for insertion of CVCs using either the real-time US-guided (SAX OOP approach or LAX IP approach) or landmark technique (control group). Failed catheter placement, risk of complications from placement, failure on first attempt at placement, number of attempts until successful catheterization, time to successful catheterization, incidence of central line-associated blood stream infection (CLA-BSI) and demographics of each patient were recorded. There were no significant differences in patient's demographic characteristics, side of cannulation (right or left) or presence of risk factors for difficult venous cannulation between the three groups of patients. Cannulation of the IJV was achieved in all patients by using US (SAX OOP and LAX IP approaches) and in 27 of the patients (90%) by using the landmark technique (P = 0.045). Average access time (skin to vein) and number of attempts were comparable between the SAX OOP and the LAX IP approaches while significantly reduced in both US groups of patients compared with the landmark group (P <0.001). In the landmark group, puncture of the carotid artery occurred in 16.7% of the patients, hematoma in 23.3% of the patients, pneumothorax in 3.3% of the patients and CLA-BSI in 20% of the patients, which were all significantly increased compared with the US group (P <0.05). The findings of this study suggest that the SAX OOP and LAX IP approaches were comparable for cannulation of IJV in critical care and hemodialysis patients. Furthermore, both US-guided techniques were superior to the landmark technique for insertion of CVCs. PMID- 23816719 TI - Sleep quality assessment using polysomnography in children on regular hemodialysis. AB - Studies examining sleep patterns in children on hemodialysis (HD) are lacking. This cross-sectional, control-matched group study was performed to assess the sleep quality in children on HD. The assessment was made using a subjective sleep assessment and sleep questionnaire and objective analysis was made using full night polysomnography. A total of 25 children with end-stage renal disease (ESRD) on HD were compared with 15 age- and sex-matched controls. The average age of the cases was 14 +/- 4 years, 52% were males and the mean body mass index was 20 +/- 3.8 kg/m2. The average duration on dialysis was 2.6 +/- 2 years. Analysis of subjective data revealed markedly affected sleep quality in HD patients, as evidenced by excessive day time sleepiness (P <0.005), night awakening (P <0.005), difficult morning arousal (P <0.005) and limb pains (P <0.005). Objective analysis showed differences in sleep architecture, less slow wave sleep in HD children, similar rapid eye movement and non-rapid eye movement, more sleep disordered breathing (P <0.0001) and more periodic limb movement disorders (P <0.0001). Our study suggests that children on regular HD have markedly affected objective as well as subjective quality of sleep. PMID- 23816720 TI - The use of continuous ambulatory peritoneal dialysis for patients with end-stage renal disease and pre-existing advanced liver disease. AB - End-stage renal disease (ESRD) associated with pre-existing advanced liver disease (ALD) has increased the risk of morbidity and mortality. The aim of this study is to assess the outcome following the use of continuous ambulatory peritoneal dialysis (CAPD) in ESRD patients with ALD. A retrospective case controlled study was performed on 16 patients with ALD and ESRD (ESRD-ALD) and 27 control patients with ESRD but without liver disease (ESRD); both groups were started on CAPD during the same period. No major complications were observed in either group in the immediate post-surgical period and, after an average break in period of 11.3 days, the cases and controls were started on regular CAPD. The average duration of follow-up was 8 +/- 2.3 months in the ESRD-ALD group compared with 20 +/- 1.3 months in the ESRD group. The overall peritonitis rates were 1.26/treatment year in the ESRD-ALD group and 0.63 in the ESRD group. The 6- and 12-month survivals among ESRD-ALD patients were 63.75% and 38.75%, respectively. Patients with ESRD-ALD had significantly lower baseline serum protein and albumin levels at the time of initiation of CAPD. On follow-up, the hemoglobin levels improved in both the groups along with an improvement in the serum protein and albumin levels. Fourteen of the 16 ESRD-ALD patients died at the end of the 3 year follow-up period; deaths were due to terminal liver failure in nine patients and peritonitis in five patients. Patients who died in the ESRD-ALD group had lower serum albumin, lower body mass index (BMI) (median BMI 18.2 vs. 25.6) and higher grades of liver disease [child Pugh grade B (8), grade C (6) vs. grade B (2)] at initiation of CAPD. Our study suggests that CAPD is a safe modality in patients with ESRD-ALD and that it does not carry any major risk for bleeding tendencies, technique failure or worsening of nutritional status. Low serum albumin, lower BMI and higher grade of liver disease at initiation are associated with higher mortality in these patients. PMID- 23816721 TI - Renal cortical necrosis in tropics. AB - The aim of this study is to review cases of renal cortical necrosis (RCN) that were seen on renal biopsy at our center over a period of seven years. All renal biopsy records over seven years at the Osmania General Hospital were reviewed to identify patients with histologically proven RCN. The demographic, clinical, laboratory investigations and follow-up data were noted. There were a total of 105 patients with RCN. The mean age was 28.13 +/- 12.40 years. Forty-one cases (39.04%) resulted from obstetric complications. The most common histology type of RCN was patchy cortical necrosis in 65 patients (62%). All patients required dialysis, and the mean duration of dialysis was 3 +/- 1 weeks. Thirty-three (31.42%) patients progressed to end-stage kidney disease while three patients underwent renal transplantation. Ten (9.5%) patients succumbed to acute kidney injury. The remaining patients recovered sufficient renal function and were dialysis-independent till the last follow-up. RCN is an important cause of chronic kidney disease. Obstetric complications are the leading cause of RCN in our setting. An early renal biopsy, especially in cases of anuric renal failure, helps in establishing the diagnosis. PMID- 23816722 TI - Urinary endothellin-1 level in children with pyelonephritis and hydronephrosis. AB - Hydronephrosis is a common finding in patients with urinary tract infection (UTI). Endothellin-1 (ET-1) is a potent vasoactive peptide that has vasoconstrictive effects. It has been shown that urinary ET-1 increases in urinary obstructions. In this study, we measured the urinary ET-1 level in patients with UTI and hydronephrosis of various causes. In this case-control study, we evaluated the urinary ET-1 level in 45 patients who had UTI and hydronephrosis, serving as a case group, and 45 patients who had UTI without hydronephrosis, serving as a control group. Urinary ET-1 was quantified using enzyme-linked immunosorbent assay and urinary creatinine (Cr) by Jaffe method. To rule out the effect of urinary flow rate, the urinary ET-1 to Cr correlation was considered for analysis of the results. The mean age of the patients in the case and control groups was 36.5 +/- 27.2 and 26.2 +/- 15.5 months, respectively (P >0.01). The mean urinary ET-1 was 89.6 +/- 41.7 pg/dL in the case group and 29.3 +/- 26 pg/dL in the control group, P <0.001. The mean urinary ET-1 was 121 +/- 55.4 pg/dL in patients who had grade 4 hydronephrosis. We conclude that urinary ET-1 was significantly higher in the obstructed than in non-obstructed cases. Urinary ET-1 could be a useful marker that can be utilized in young children for diagnosis of hydronephrosis, especially obstructive cases. PMID- 23816723 TI - Comparative evaluation of fosinopril and herbal drug Dioscorea bulbifera in patients of diabetic nephropathy. AB - Worldwide, diabetic nephropathy is one of the leading causes of end-stage renal failure. This hospital-based single-center prospective open-label randomized case control interventional study was performed to evaluate and compare the native drug Dioscorea bulbifera with fosinopril in the management of diabetic nephropathy. Patients with diabetic nephropathy with proteinuria >500 mg/day or albuminuria >300 mg/ day, S Cr <=2.5 mg/dL and hypertension controlled with a single drug were included into the study and were divided into three groups according to the interventional drugs that they were given; group A (n = 46) on fosinopril (5-40 mg/day), group B (n = 45) on Dioscorea bulbifera (500 mg BD) and group C (n = 46) on neither of these drugs. All necessary laboratory investigations needed to assess the effect of both the drugs were carried out. Patients were followed-up for six months. The study included 137 patients (M:F 2.61:1) with an age range of 19-76 years. At the sixth-month follow-up, a significant decrease in the systolic blood pressure was noted in all three groups whereas the diastolic blood pressure decreased significantly only in group B. There was significantly better control of both systolic and diastolic blood pressures in group B than in the other groups. Although fasting blood sugar was poorly controlled in the initial visit in all three groups, there was a significant decrease at the sixth-month follow-up in all three groups. Moreover, the decrease was significantly more pronounced in group B than in the other two groups. Low-density lipoprotein decreased significantly only in group B. Proteinuria, serum transforming growth factor-beta, interleukin-6 (IL-6) and C reactive protein decreased in both group A and group B, more so in the latter, but the differences between the groups were not statistically significant. Importantly, proteinuria and serum IL-6 showed an increasing trend in group C. It can be concluded that Dioscorea bulbifera was more effective than fosinopril in controlling blood pressure, glycemia, cholesterolemia and inflammatory state in diabetic nephropathy. Both agents decreased proteinuria. However, creatinine clearance significantly decreased with both the drugs, more so with Dioscera, and thus further evaluation with a larger trial is needed. PMID- 23816724 TI - Alveolar hemorrhage and kidney disease: characteristics and therapy. AB - Anti-neutrophil cytoplasmic antibody-associated vasculitis and Goodpasture's glomerular basement membrane disease are the most common causes of diffuse alveolar hemorrhage, a life-threatening disease. Systemic lupus erythematosus and the antiphospholipid syndrome are also causes of alveolar hemorrhage. We retrospectively reviewed 15 cases of diffuse alveolar hemorrhage (DAH) associated with renal diseases. Diagnosis of DAH was based on the presence of bloody bronchoalveolar lavage fluid. There were three men and 12 women, with a mean age of 50.5 years (extremes: 24-74 years). Proteinuria and hematuria were observed, respectively, in 15 and 14 cases. Six patients revealed arterial hypertension. Crescentic glomerulonephritis was diagnosed with kidney biopsies in ten cases. The etiology of renal disease was microscopic polyangiitis (MPA) in seven cases, Wegener disease in four cases, systemic lupus erythematous in one case, cryoglobulinemia in one case, myeloma in one case and propyl-thiouracil-induced MPA in one case. Hemoptysis occurred in 14 cases. The mean serum level of hemoglobin was 7.1 g/dL (5.1-10 g/dL). The mean serum creatinine concentration was 7.07 mg/dL (2.4-13.7 mg/dL). Gas exchange was severely compromised, with an oxygenation index <80 mmHg in 14 patients and <60 mmHg in seven patients. Bronchoalveolar lavage was performed in 11 cases, and had positive findings for hemorrhage in all. Methylprednisolone pulses and cyclophosphamide were used in 14 patients. Plasmapheresis was performed in three cases. One patient received cycles of Dexamethasome-Melphalan. Three patients died as a result of DAH. The mortality rate in our study was 20%. PMID- 23816725 TI - Immuno-histochemistry analysis of Helicobacter pylori antigen in renal biopsy specimens from patients with glomerulonephritis. AB - This study was conducted to investigate the relationship between Helicobacter pylori infection and three varieties of glomerulonephritis. Renal biopsy specimens from patients with Henoch Schonlein Purpura nephritis (HSPN; n = 10), membranous nephropathy (MN; n = 9) and lupus nephritis (LN; n = 27) were studied using immuno-histochemical labeling to clarify the etiological significance of H. pylori antigen in this disease. Immuno-histochemical labeling was performed using a mixture of anti-H. pylori-antibody-positive serum from nine volunteers; a mixture of anti-H. pylori-antibody-negative serum from nine volunteers was used as control. Staphylococci protein-A labeled by horseradish peroxidase was used as the second antibody in this study. A total of 34 of the 48 specimens revealed positive reaction with the anti-H. pylori-positive serum and five of the 48 specimens revealed positive reaction with the anti-H. pylori-negative serum. Positive reaction against anti-H. pylori-positive serum was seen in 10/10 patients with HSPN, six of nine patients with MN and 18/27 patients with LN. Statistical analysis showed that the difference of the positive reaction between anti-H. pylori-positive and negative sera was significant (chi 2 = 36.318, P = 0.000). Our study indicates that H. pylori infection may be associated with the development and/or progression of HSPN, MN and LN. PMID- 23816726 TI - The effect of Helicobacter pylori on vitamin B 12 blood levels in chronic renal failure patients: a single blind control trial. AB - Helicobacter pylori (HP) is a common infection worldwide and has been associated with severe morbidity. The level of vitamin B 12 in HP-infected chronic kidney disease (CKD) patients is reported to be lower than in the general population. The present study has been designed to evaluate the vitamin B 12 level in HP infected CKD patients. We assessed the serum levels of vitamin B 12 in 50 CKD patients with positive HP serology, one and three months after the eradication of HP infection. There were significant differences between the serum levels of vitamin B 12 in the study patients before (806.98 +/- 466.82) and after (760.36 +/- 433.93) eradication treatment (P <0.001). We conclude that our study suggests the correlation between vitamin B 12 deficiency in CKD patients and the HP infection status. PMID- 23816727 TI - Esophageal histoplasmosis in a renal allograft recipient. AB - Histoplasmosis is a progressive granulomatous disease caused by the intracellular dimorphic fungus Histoplasma capsulatum. We report a rare case of esophageal histoplasmosis in a renal allograft recipient. A 55-year-old male who received a live, unrelated renal allograft 20 years ago presented with complaints of recurrent fever for ten to 12 months, weight loss over six months, progressive dysphagia more for solids for five to six months and joint pain and swelling involving the bilateral metacarpo-phalangeal and proximal interphalangeal joints. Biopsy from the esophageal ulcers revealed dense inflammation infiltrated with lymphocytes and macrophages with clusters of strongly positive intracellular fungal spores with a clear area or "halo-like" zone suggestive of Histoplasma capsulatum invasion. The patient was treated with intravenous liposomal amphotericin B for ten days and later switched over to oral itraconazole. Repeated endoscopy revealed significant improvement of the lesions. PMID- 23816728 TI - Rhino-orbitocerebral mucormycosis in a patient with idiopathic crescentic glomerulonephritis. AB - Mucormycosis, caused by mucorales, is an acute, rapidly progressive infection associated with high mortality. Rhino-orbitocerebral infection is the most common variant and is generally seen in association with immune deficiency syndromes. Prompt medical treatment of this infection and debridement decreases the mortality rate. We describe a 47-year-old man with crescentic glomerulonephritis on maintenance prednisolone therapy. He had earlier received steroid and cyclophosphamide pulse therapies. Renal functions improved following immunosuppressive treatment. In the third month of maintenance therapy, he presented to us with left-sided facial swelling and bloody nasal discharge. He had high blood sugar and acidic blood pH (ketoacidosis), probably due to steroid therapy. Magnetic resonance imaging of the head and sinuses showed inflammation and mass in the ethmoid sinus and nose with partial septal destruction, proptosis, global destruction of the left eye, brain infarction and carotid artery obliteration. Endoscopic biopsy of the sinuses revealed severe tissue necrosis. Samples of nasal discharge and biopsy tissue showed aseptate hyphae on light microscopy and culture, compatible with Rhizopus. The patient was treated with amphotericin B and multiple wound debridements along with ethmoidectomy and enucleation of the left eye. He was discharged in good general condition but with mild right hemiparesis. On follow-up examination at one year, there were no signs of fungal infection or renal dysfunction. PMID- 23816729 TI - Crossed fused renal ectopia with a single ureter: a rare anomaly. AB - A rare case of crossed fused renal ectopia is presented where the fused kidneys were present on the right side and there was a single ureter opening into the right side of the bladder. To the best of our knowledge, this variant of crossed fused ectopia has not been reported previously. This case challenges the embryological theory that deviation of one of the ureteric buds to the opposite side results in crossed fused renal ectopia. PMID- 23816730 TI - Profound nephrotic syndrome in a patient with ovarian teratoma. AB - The nephrotic syndrome (NS) has been associated with a variety of malignancies in a number of reports in the literature, but has been reported in only nine cases associated with ovarian neoplasms. Membranous nephropathy is the most common glomerular pathology causing the NS in patients with solid tumors. There has been only one report of an ovarian neoplasm associated with minimal change disease (MCD). We describe the case of a 36-year-old woman who presented with the NS secondary to biopsy-proven MCD, likely secondary to mature ovarian teratoma. Treatment by tumor removal and prednisone led to remission of the NS. To the best of our knowledge, this is the first report of an ovarian teratoma and the second report of an ovarian neoplasm associated with MCD. PMID- 23816731 TI - Double-positive Goodpasture's syndrome with concomitant active pulmonary tuberculosis. AB - Anti-glomerular basement membrane (anti-GBM) disease usually presents as rapidly progressive glomerulonephritis, and, when accompanied with pulmonary hemorrhage, it is called Goodpasture's syndrome. Anti-neutrophilic cytoplasmic antibodies (ANCA) may co-exist with anti-GBM antibodies. In most of these "double positive" cases, ANCA is specific for myeloperoxidase (p-ANCA). We report a rare case of a critically ill patient c-ANCA-associated double-positive Goodpasture's syndrome with concomitant tuberculosis that was successfully treated with immunosuppression, plasmapheresis and anti-tuberculous therapy (ATT). A 32-year old gentleman with a 15 pack-year smoking history presented with massive hemoptysis, respiratory failure and oliguria. Laboratory investigation revealed anemia, elevated creatinine and active urinary sediment. Chest X-ray revealed bilateral pulmonary infiltrates. Broad-spectrum antibiotics and intravenous corticosteroids were started. Bronchoscopy showed alveolar hemorrhage and smears from bronchial lavage from both lungs were positive for acid fast bacillus (AFB). Vasculitis work-up revealed high titers of c-ANCA and anti-GBM antibodies. Kidney biopsy revealed crescents in >50% glomeruli on light microscopy. Immunofluorescence showed linear deposition of IgG and C3. The patient received pulse methylprednisone for three days followed by oral prednisone and ATT. In addition, he also underwent nine sessions of plasmapheresis. Oral Cyclophosphamide was added on Day 10. The patient showed remarkable recovery as his lung fields cleared and his kidney function got stabilized. Cyclophosphamide was continued for three months and then switched to azathioprine. At six months, the creatinine is 1.2 mg/dL, with minimal proteinuria and a normal chest X-ray. To the best of our knowledge, this is the only reported case of double-positive Goodpasture's syndrome (c-ANCA and anti GBM) with active tuberculosis treated successfully. PMID- 23816732 TI - Renal cell carcinoma presenting as mandibular metastasis. AB - Renal clear cell carcinoma (RCC) has different manifestations, including uncommon metastasis and paraneoplastic syndromes. Here we report a rare case of RCC presenting as metastasis to the mandible. A 57-year-old patient with mandibular swelling was referred to the dentist. After necessary evaluations, an incisional biopsy of mandible showed metastatic RCC. The patient was referred to the urologist. The patient underwent right radical nephrectomy. Pathological examination showed clear renal cell carcinoma. Every abnormal bone lesion in the oral cavity should be evaluated carefully and the possibility of a malignant lesion should always be considered. PMID- 23816733 TI - Renal transplantation in idiopathic thrombocytopenic purpura. PMID- 23816734 TI - Renal transplantation in obese patients. PMID- 23816735 TI - Geophagia masquerading as urolithiasis. PMID- 23816736 TI - A clinicopathological study of renal biopsies in glomerular diseases. PMID- 23816737 TI - Narrowing the margins of errors intrinsic to the estimations made from uACR and uPCR by introducing simple correction factors. PMID- 23816738 TI - The magnitude of chronic kidney diseases among primary health care attendees in Gezira state, Sudan. PMID- 23816739 TI - Bilateral pyonephrosis and end-stage renal disease secondary to pelvic organ prolapse. PMID- 23816740 TI - Clinical characteristics and outcomes of patients with acute kidney injury: a single-center study. PMID- 23816741 TI - Primary renal lymphoma: is prognosis really that bad? PMID- 23816742 TI - Accountable kidney care: role of telemedicine in a developing country. PMID- 23816743 TI - Histomorphological classification of focal segmental glomerulosclerosis: a critical evaluation of the clinical, histologic and morphometric features. PMID- 23816744 TI - Effect of relative hypoparathyroidism on the responsiveness to recombinant human erythropoietin in chronic hemodialysis patients: a single Saudi center experience. AB - Anemia is a common concomitant disorder in dialysis patients. The responsiveness to recombinant human erythropoietin in hemodialysis (HD) patients with relative hypoparathyroidism [4 <= intact parathyroid hormone (iPTH) <=16.5 pmol/L] remains undetermined. We retrospectively studied 70 chronic hemodialysis patients who were divided into two groups: Group A (32 patients) had 16.5 <= iPTH levels <33.5 pmol/L and Group B (38 patients) had 4 >= iPTH<=16.5 pmol/L during the preceding six months without 1- (OH) Vitamin D3 administration. The percentage of female gender was significantly higher in Group B compared with Group A (P = 0.018). In Groups A and B, the mean weekly recombinant human erythropoietin dose (U/kg/ week) was 227.96 +/- 95.24 vs. 154.1 +/- 84.9 (P = 0.001) and the mean hemoglobin level was 11.15 +/- 0.63 g/dL versus 11.62 +/- 0.63 g/dL (P = 0.008). There was no significant statistical difference regarding the other biochemical markers (serum ferritin, iron saturation, serum Ca, serum alkaline phosphatase, C reactive protein, serum B12, serum folate levels, residual renal function and Kt/v) between the groups. If other factors related to anemia are excluded in chronic HD patients, the lower the iPTH level (relative hypoparathyroidism) the better the responsiveness to recombinant human erythropoietin. PMID- 23816745 TI - Prevalence of patients with end-stage renal disease on dialysis in the West Bank, Palestine. AB - This study was conducted to determine the point prevalence of patients with end stage renal disease (ESRD) on dialysis in the West Bank, Palestine. As part of this study, the following parameters were studied: District, gender, age and presumed cause. This cross-sectional study was undertaken during the period 26-30 December 2010 at all dialysis units in the West Bank, and included all cases of ESRD on dialysis. The total prevalence of patients with ESRD on dialysis during the study period was 240.3 per million population (PMP). The highest prevalence was seen in Jericho city. There were 57.7% males and 42.4% females in the study. The majority of patients (62.3%) were living in villages, while 28.8% were living in cities and 8.9% were living in refugee camps. Most of the patients (45%) were aged between 45 and 64 years. The vast majority of patients were either diabetic (22.5%) or hypertensive (11.1%) or both at the same time (10.6%). There were a considerable number of patients in whom the cause was undetermined (27.6%). The majority of recorded cases of congenital causes were from the Hebron, Jenin and Tubas districts. The prevalence of ESRD noted in our study is comparable with other regional countries but far below the rate recorded in industrialized countries. In the Palestinian territories, there is a general lack of national statistics and surveys, particularly in the public health section. Increased efforts and awareness should be focused on the prevention and treatment of diabetes mellitus and hypertension as they are the main causes of ESRD. There should also be an additional enhancement and implementation of strategies for the registration of data in order to conduct periodic comparisons and analytical studies to improve the management and quality of life of ESRD patients. PMID- 23816746 TI - Metabolic evaluation in first-time renal stone formers in North India: a single center study. AB - The risk of stone recurrence in first-time stone formers (FTSF) varies from 26% to 53%. There is no consensus regarding metabolic evaluation in these individuals. We evaluated the metabolic abnormalities in first-time renal stone forming patients in North India. Thirty-nine patients, (29 males and 10 females with mean age 39.3 +/- 12.9 years) who presented with nephrolithiasis for the first time were evaluated. We evaluated the calcium homeostasis [serum corrected total calcium, phosphorous, creatinine, alkaline phosphatase, albumin, parathormone (iPTH), 25-hydroxy cholecalciferol (25(OH)D 3 ), 1-25 di-hydroxy cholecalciferol (1,25(OH) 2 D 3 )] and performed the calcium load test also. Two 24-h urine collections were taken for citrate, oxalate, calcium and uric acid. Ammonium chloride loading test for diagnosis of distal renal tubular acidosis was performed in all patients. For each of the diagnostic categories, descriptive statistics were computed for all biochemical variables. A two-tailed P-value <0.05 was regarded as significant. Metabolic abnormalities were detected in 92.3% of the patients (n = 39) studied. Of them, almost 60% had two or more metabolic abnormalities. The most common metabolic abnormality was hypo-citraturia (82%), followed by hyper-oxaluria (56%) and hyper-calciuria (41%). Five percent of the patients had incomplete renal tubular acidosis, signifying the importance of the ammonium chloride loading test in patients with renal stones. None of the study patients were detected to have primary hyperparathyroidism. In three patients, the etiology could not be detected. Our findings suggest that an underlying disorder is present in majority of first-time renal stone formers. Intervention with appropriate treatment can prevent recurrences. Hence, comprehensive metabolic evaluation is recommended in all FTSF. PMID- 23816747 TI - Clinical analysis of hypertension in children: an urban Indian study. AB - Hypertension in children, although an uncommon entity, is associated with end organ damage. We tried to study the clinical profile of hypertension in children presented to our hospital. The medical records from January 1990 to December 2010 of all children aged 18 years and younger with hypertension were studied. The patients were divided into four age groups (infants, pre-school age, school age and adolescents) Presenting symptoms and other clinical parameters were thoroughly evaluated. The results were compared with previous studies on hypertension in children. A total of 135 patients were selected (male:female 103:32), with mean age of 0.4 +/- 2.1 years (range: six months to 17 years). The most common age group affected was the adolescents group (42.9%). The most common clinical feature at presentation was dizziness (30.3%), followed by headache and chest discomfort (22.9%). Transient hypertension was detected in 34 patients (25.2%), and was most common in the adolescent age group, whereas sustained hypertension was noticed in 101 patients (74.8%) and was the most common in the school age group (36/45, 80%). Forty-two patients (31.1%) presented with hypertensive crisis. Nine patients were considered to have essential hypertension. The chief causes included chronic glomerulonephritis in 56 (41.5%), endocrine disorders in 21 (15.5%), obstructive uropathy in 16 (11.8%), reflux nephropathy in 12 (8.8%) and renovascular disease in 5 (3.7%). Takayasu's disease was the most common cause of renovascular hypertension. Coarctation of aorta was the most common cause of hypertension in infancy, being present in 40% of the cases. Hypertension in children may be easily underestimated but is a potentially life-threatening problem. Most of them are asymptomatic and a large chunk has an underlying etiology. Primary care clinicians should promptly identify patients with hypertension and treat them immediately and appropriately to prevent damage to the cardiovascular organs. PMID- 23816748 TI - New therapeutic options for allergic rhinitis: back to the future with intranasal corticosteroid aerosols. AB - BACKGROUND: Under current guidelines, intranasal corticosteroids (INSs) are considered the most effective first-line therapy to improve allergic rhinitis (AR) symptoms and burden of disease. In the late 1980s-1990s, chlorofluorocarbon (CFC)-propelled corticosteroid aerosol nasal sprays formed the standard of care for the treatment of AR. Because of environmental concerns, CFC aerosols were gradually phased out, and aqueous INS formulations of nasal sprays became the standard of care. Although many aqueous INS sprays are available, specific product-related factors can reduce patient adherence to an INS and subsequently reduce treatment efficacy. The purpose of this paper was to review the evolution of AR therapeutics and drug devices and how it may have an effect on patient adherence/compliance and patient satisfaction with current available therapies and show the unmet need to improve INS delivery systems. METHODS: Although aqueous INSs are effective and well tolerated, use in some patients may be compromised because of patient sensory perception and device preference. A historical review of the evolution of intranasal delivery of INSs was undertaken to provide further insight into improving treatment options for patients with AR. RESULTS: Although the various approved INSs appear to be equivalent in terms of reducing AR disease burden, the method in which an INS is delivered to a patient has significant bearing on the overall success of each specific drug product. CONCLUSION: Hydrofluoroalkane-propelled INS drug products offer a back-to-the future delivery approach that may be further tailored to the individual patient's needs. Past experiences and the development of new devices are paving the way toward further therapy choices, ultimately affording health care providers access to the most effective treatments for patients with AR. PMID- 23816749 TI - [Early onset seronegative generalised myasthenia gravis. Case report]. PMID- 23816750 TI - Technical difficulties and its remedies in laparoscopic cholecystectomy in situs inversus totalis: A rare case report. AB - INTRODUCTION: Laparoscopic cholecystectomy is considered to be the gold standard surgical procedure for cholelithiasis and is one of the commonest surgical procedures in the world today. However, in rare cases of previously undiagnosed situs inversus totalis (with dextrocardia), the presentation of the cholecystitis, its diagnosis and the operative procedure can pose problems. We present here one such case and discuss how the diagnosis was made and difficulties encountered during surgery and how they were coped with. PRESENTATION OF CASE: A 35 year old female presented with left hypochondrium pain and dyspepsia, for 2 years. A diagnosis of cholelithiasis with situs inversus was confirmed after thorough clinical examination, abdominal and chest X-rays and ultrasonography of the abdomen. Laparoscopic cholecystectomy, which is the standard treatment, was performed with numerous modifications in the positioning of the monitor, insufflator, ports and the position of the members of the surgical team and the laparoscopic instruments. The patient had an uneventful recovery. DISCUSSION: Situs inversus totalis is itself a rare condition and when associated with cholelithiasis poses a challenge in the management of the condition. We must appreciate the necessity of setting up the operating theatre, the positioning of the ports, the surgical team and the instruments. CONCLUSION: Therefore, it becomes important for the right handed surgeons to modify their techniques and establish a proper hand eye coordination to adapt to the mirror image anatomy of the Calot's triangle in a patient of situs inversus totalis. PMID- 23816751 TI - P2X7R/cryopyrin inflammasome axis inhibition reduces neuroinflammation after SAH. AB - Neuroinflammation contributes to the pathogenesis of early brain injury (EBI) after subarachnoid hemorrhage (SAH). Cytotoxic events following SAH, such as extracellular accumulation of adenosine triphosphate (ATP), may activate the P2X purinoceptor 7 (P2X7R)/cryopyrin inflammasome axis, thus inducing the proinflammatory cytokine IL-1beta/IL-18 secretion. We therefore hypothesized that inhibition of P2X7R/cryopyrin inflammasome axis would ameliorate neuroinflammation after SAH. In the present study, SAH was induced by the endovascular perforation in rats. Small interfering RNAs (siRNAs) of P2X7R or cryopyrin were administered intracerebroventricularly 24h before SAH. Brilliant blue G (BBG), a non-competitive antagonist of P2X7R, was administered intraperitoneally 30min following SAH. Post-assessments including SAH severity score, neurobehavioral test, brain water content, Western blot and immunofluorescence, were performed. Administration of P2X7R and cryopyrin siRNA as well as pharmacologic blockade of P2X7R by BBG ameliorated neurological deficits and brain edema at 24h following SAH. Inhibition of P2X7R/cryopyrin inflammasome axis suppressed caspase-1 activation, which subsequently decreased maturation of IL-1beta/IL-18. To investigate the link between P2X7R and cryopyrin inflammasome in vivo, Benzoylbenzoyl-ATP (BzATP), a P2X7R agonist, was given to lipopolysaccharide (LPS) primed naive rats with scramble or cryopyrin siRNAs. In LPS-primed naive rats, BzATP induced caspase-1 activation and mature IL-1beta release were neutralized by cryopyrin siRNA. Thus, the P2X7R/cryopyrin inflammasome axis may contribute to neuroinflammation via activation of caspase-1 and thereafter mature IL-1beta/IL-18 production following SAH. Therapeutic interventions targeting P2X7R/cryopyrin pathway may be a novel approach to ameliorate EBI following SAH. PMID- 23816752 TI - The 70 kDa heat shock protein protects against experimental traumatic brain injury. AB - Traumatic brain injury (TBI) causes disruption of the blood brain barrier (BBB) leading to hemorrhage which can complicate an already catastrophic illness. Matrix metalloproteinases (MMPs) involved in the breakdown of the extracellular matrix may lead to brain hemorrhage. We explore the contribution of the 70 kDa heat shock protein (Hsp70) to outcome and brain hemorrhage in a model of TBI. Male, wildtype (Wt), Hsp70 knockout (Ko) and transgenic (Tg) mice were subjected to TBI using controlled cortical impact (CCI). Motor function, brain hemorrhage and lesion size were assessed at 3, 7 and 14 days. Brains were evaluated for the effects of Hsp70 on MMPs. In Hsp70 Tg mice, CCI led to smaller brain lesions, decreased hemorrhage and reduced expression and activation of MMPs compared to Wt. CCI also significantly decreased right-biased swings and corner turns in the Hsp70 Tg mice. Conversely, Hsp70 Ko mice had significantly increased lesion size, worsened brain hemorrhage and increased expression and activation of MMPs with worsened behavioral outcomes compared to Wt. Hsp70 is protective in experimental TBI. To our knowledge, this is the direct demonstration of brain protection by Hsp70 in a TBI model. Our data demonstrate a new mechanism linking TBI-induced hemorrhage and neuronal injury to the suppression of MMPs by Hsp70, and support the development of Hsp70 enhancing strategies for the treatment of TBI. PMID- 23816753 TI - Neuropilin-1 modulates vascular endothelial growth factor-induced poly(ADP ribose)-polymerase leading to reduced cerebrovascular apoptosis. AB - Cerebral ischemia is encompassed by cerebrovascular apoptosis, yet the mechanisms behind apoptosis regulation are not fully understood. We previously demonstrated inhibition of endothelial apoptosis by vascular endothelial growth factor (VEGF) through upregulation of poly(ADP-ribose)-polymerase (PARP) expression. However, PARP overactivation through oxidative stress can lead to necrosis. This study tested the hypothesis that neuropilin-1 (NP-1), an alternative VEGF receptor, regulates the response to cerebral ischemia by modulating PARP expression and, in turn, apoptosis inhibition by VEGF. In endothelial cell culture, NP-1 colocalized with VEGF receptor-2 (VEGFR-2) and acted as its coreceptor. This significantly enhanced VEGF-induced PARP mRNA and protein expression demonstrated by receptor specific inhibitors and VEGF-A isoforms. NP-1 augmented the inhibitory effect of VEGF/VEGFR-2 interaction on apoptosis induced by adhesion inhibition through the alphaV-integrin inhibitor cRGDfV. NP-1/VEGFR-2 signal transduction involved JNK and Akt. In rat models of permanent and temporary middle cerebral artery occlusion, the ischemic cerebral hemispheres displayed endothelial and neuronal apoptosis next to increased endothelial NP-1 and VEGFR-2 expression compared to non-ischemic cerebral hemispheres, sham-operated or untreated controls. Increased vascular superoxide dismutase-1 and catalase expression as well as decreased glycogen reserves indicated oxidative stress in the ischemic brain. Of note, protein levels of intact PARP remained stable despite pro-apoptotic conditions through increased PARP mRNA production during cerebral ischemia. In conclusion, NP-1 is upregulated in conditions of imminent cerebrovascular apoptosis to reinforce apoptosis inhibition and modulate VEGF-dependent PARP expression and activation. We propose that NP-1 is a key modulator of VEGF maintaining cerebrovascular integrity during ischemia. Modulating the function of NP-1 to target PARP could help to prevent cellular damage in cerebrovascular disease. PMID- 23816755 TI - The effect of combined antihypertensive treatment (felodipine with either irbesartan or metoprolol) on erectile function: a randomized controlled trial. AB - OBJECTIVES: This study aimed to determine whether combining a calcium channel blocker with either an angiotensin II receptor blocker or a beta-blocker would have similar effects on sexual function in men with hypertension. METHODS: This prospective, randomized study (ClinicalTrials.gov: NCT01238705) included 218 male participants with untreated hypertension. Patients were randomized to treatment with felodipine combined with irbesartan or metoprolol for 48 weeks. Sexual function was evaluated at baseline and after 48 weeks of therapy. The levels of serum sex hormones and markers of oxidative stress were measured at the same time. RESULTS: There was no significant difference in the prevalence of erectile dysfunction before and after treatment in either group (p > 0.05). There were also no differences in the levels of serum testosterone, sex hormone-binding globulin or 4-hydroxynonenal before and after treatment in either group (p > 0.05). In the felodipine-irbesartan group, sexual desire scores rose after treatment (p = 0.022) and the concentrations of serum 8-hydroxy-2'-deoxyguanosine and malondialdehyde declined (p < 0.001 and p = 0.002, respectively). The between group differences for 8-hydroxy-2'-deoxyguanosine and malondialdehyde were not significant (p > 0.05, respectively). CONCLUSION: The results suggest that felodipine-irbesartan may be more beneficial to the sexual desire of hypertensive male patients than felodipine-metoprolol. This effect was possibly relevant to irbesartan, which prevents oxidative stress to some extent. PMID- 23816756 TI - Time of day effects on the regulation of food consumption after activation of health goals. AB - Previous research has found that while self-regulation is a resource that can be depleted, enhanced motivation to do so can help people successfully self regulate. The aim of this research was to determine whether activating health goals-either via laboratory priming techniques or via advertisements-can help people regulate food intake later in the day, when self-regulation resources are typically depleted. In two experimental studies, participants completed goal activation tasks in the morning or in the afternoon while they had a snack food (M&M's candies) available for consumption. In study 1, 121 participants viewed television shows with either healthy food ads, indulgent food ads, or non-food ads embedded within the program. In study 2, 149 participants completed a supraliminal but nonconscious goal priming exercise, in which they searched for health, indulgence, or control words in a puzzle. In both studies, activation of health goals led to decreased consumption of the snack food in the afternoon. In contrast, activation of health goals did not change consumption in the morning, when self-regulatory resources are typically high, due to replenishment after rest. These results suggest that activating health goals-either via classic laboratory goal-priming paradigms or via "real world primes," such as ads for healthy foods-helps people to overcome failures in curbing food consumption due to depleted self-regulatory resources later in the day. PMID- 23816754 TI - Complex I inhibition in the visual pathway induces disorganization of the node of Ranvier. AB - Mitochondrial defects can have significant consequences on many aspects of neuronal physiology. In particular, deficiencies in the first enzyme complex of the mitochondrial respiratory chain (complex I) are considered to be involved in a number of human neurodegenerative diseases. The current work highlights a tight correlation between the inhibition of complex I and the state of axonal myelination of the optic nerve. Exposing the visual pathway of rats to rotenone, a complex I inhibitor, resulted in disorganization of the node of Ranvier. The structure and function of the node depend on specific cell adhesion molecules, among others, CASPR (contactin associated protein) and contactin. CASPR and contactin are both on the axonal surfaces and need to be associated to be able to anchor their myelin counterpart. Here we show that inhibition of mitochondrial complex I by rotenone in rats induces reactive oxygen species, disrupts the interaction of CASPR and contactin couple, and thus damages the organization and function of the node of Ranvier. Demyelination of the optic nerve occurs as a consequence which is accompanied by a loss of vision. The physiological impairment could be reversed by introducing an alternative NADH dehydrogenase to the mitochondria of the visual system. The restoration of the nodal structure was specifically correlated with visual recovery in the treated animal. PMID- 23816757 TI - Exhaled nitric oxide as screening tool in subjects with suspected asthma without reversibility. AB - BACKGROUND: As fractional exhaled nitric oxide (FeNO) has been evaluated only in certain settings for asthma diagnosis, we investigated whether FeNO values could predict positive methacholine challenge testing (expressed as PD20) in subjects with suspected asthma but without spirometric reversibility. METHODS: Subjects with asthma-like symptoms and negative bronchodilation test were initially evaluated to undergo FeNO measurement and methacholine bronchial challenge. Diagnostic performance of FeNO to predict PD20 to methacholine <800 MUg was examined by constructing receiver-operating characteristic curves. RESULTS: A total of 112 subjects met the inclusion criteria. In all subjects, FeNO >32 ppb was associated with a sensitivity of 0.47 and a specificity of 0.85 for the identification of the PD20 <800 MUg (AUC = 0.691, 95% CI = 0.6-0.775, p = 0.00002). In smokers, FeNO >11 ppb was associated with a sensitivity of 0.85 and a specificity of 0.5 for the identification of PD20 <800 MUg (AUC = 0.625, 95% CI = 0.45-0.772, p = 0.18), while in atopics a FeNO level >26 ppb was associated with a sensitivity of 0.55 and a specificity of 0.85 (AUC = 0.677, 95% CI = 0.53 0.8, p = 0.02). CONCLUSIONS: In subjects with symptoms compatible with asthma but without spirometric reversibility, specific cutoff levels for FeNO levels significantly predict the positive methacholine challenge, with significant confounding factors being atopy and current smoking. PMID- 23816758 TI - Dermoscopy of melanocytic lesions in patients affected by oculocutaneous albinism: a case series. AB - BACKGROUND: Although the majority of skin cancers in albino patients consists of squamous and basal cell carcinomas, malignant melanomas have also been described, albeit less frequently. OBJECTIVE: The aim of our study was to evaluate melanocytic lesions in albino patients to look for any recurrent dermoscopic pattern. METHODS: We enrolled 12 consecutive albino patients presenting to our department and examined each patient for the presence of melanocytic nevi with the unaided eye and then with dermoscopy. Melanocytic lesions with suspicious clinical or dermoscopic features were excised and histopathologically evaluated. RESULTS: Analysis of the recorded images permitted us to find two main dermoscopic patterns in this group of patients. The first one was represented by a homogeneous light-brown yellowish pattern associated with comma-like and dotted vessels; the second one consisted of a classical brown reticular pattern frequently associated with central depigmentation and with comma-like vessels. Moreover, based on some atypical dermoscopic features, in 2 patients we excised 3 melanomas in situ (in the same patient) and a thick melanoma (3.2 mm). CONCLUSIONS: Dermoscopy may represent a useful tool for the evaluation of melanocytic lesions in albino patients, permitting an early diagnosis of melanoma. PMID- 23816759 TI - The association of red meat, poultry, and egg consumption with risk of hip fractures in elderly Chinese: a case-control study. AB - BACKGROUND/PURPOSE: The epidemiological evidence that the consumption of red meat, poultry or eggs may be associated with the risk of hip fractures is inconsistent and no studies have differentiated between types of red meat or poultry. We evaluated the association between the consumption of red meat, poultry or eggs and the risk of hip fracture. METHODS: A 1:1 age- (+/-3years) and gender-matched case-control study of 646 pairs (female/male: 484/162) of elderly Chinese was conducted between June 2009 and January 2013 in Guangdong, China. Information on meat and egg consumption was collected using a 79-item food frequency questionnaire administered in face-to-face interviews. Conditional logistic regression was used to test the relationship between intake of red meat, poultry, and eggs and the risk of hip fracture. Multivariate ORs and their 95% CIs were estimated. RESULTS: After adjusting for potential confounders, risk of hip fracture was found to be positively associated with total red meat consumption (P for trend <0.001), but not with total poultry or egg consumption. The adjusted ORs (95% CIs) for hip fractures, comparing extreme quartiles, were 2.94 (1.82, 4.76) for total red meat, 1.11 (0.74, 1.66) for total poultry, and 0.99 (0.63, 1.56) for eggs. Subtype analyses indicated that the unfavorable effect of total red meat was primarily associated with the consumption of fatty pork and organ meat, whereas fatty and lean poultry had opposite effects. Men with higher fatty pork intake tended to have greater risk than women (P interaction=0.019). CONCLUSIONS: Our findings suggest that greater consumption of fatty, but not lean, red meat and poultry may increase the risk of hip fracture. These results provide preliminary evidence for the feasibility of a dietary program for the prevention of hip fractures, which should be confirmed by further studies. PMID- 23816760 TI - Feasibility study of adjuvant chemotherapy of S-1 and carboplatin for completely resected non-small cell lung cancer. AB - BACKGROUND: The purpose of this study was to evaluate the feasibility and compliance of adjuvant chemotherapy of S-1 plus carboplatin for patients with completely resected non-small cell lung cancer (NSCLC) of pathological stage IB IIIB. METHODS: S-1 was given orally at a dose of 80 mg/m2/day for 2 weeks, followed by a 2-week period of no treatment. Carboplatin was given intravenously on day 8 at an area under the curve of 6. This regimen was repeated for four to six 28-day courses. RESULTS: Seventeen patients were enrolled in this study. Fourteen of them completed at least 4 cycles of chemotherapy. Nine patients had grade 2 and three patients had grade 3 thrombocytopenia, respectively. Severe nonhematologic toxicities were uncommon. Treatment was delayed in a few patients because of prolonged thrombocytopenia. CONCLUSION: We concluded that the regimen was feasible and tolerable for patients with completely resected NSCLC as adjuvant chemotherapy. PMID- 23816761 TI - Peripheral blood stem cell transplantation from human leukocyte antigen-matched sibling donors and unrelated donors in acute myeloid leukemia patients. AB - There have been rare comparative studies of hematopoietic stem cell transplantation from matched sibling donors (MSDs) and unrelated donors (URDs) with regard to peripheral blood stem cell transplantation (PBSCT). We performed a retrospective study of 104 consecutive acute myeloid leukemia (AML) patients who had received an allogeneic PBSCT from an MSD or a URD in order to compare transplant outcomes and posttransplant complications between the 2 groups of patients. The cumulative incidence of grade 2-4 acute graft-versus-host disease (aGVHD) at 100 days (22.6% with MSD vs. 35.3% with URD; p = 0.107) and that of chronic GVHD (cGVHD) at 2 years (72.9% with MSD vs. 56.1% with URD; p = 0.153) was not significantly different between the 2 groups. Multivariate analysis also indicated that a URD was not an independent predictor of grade 2-4 aGVHD or cGVHD. No statistically significant differences were observed in terms of relapse incidence (p = 0.371), nonrelapse mortality (p = 0.473), disease-free survival (p = 0.925) or overall survival (p = 0.534) at 2 years. URDs are comparable with MSDs as a donor type for PBSCT in AML patients if risk-stratified GVHD prophylaxis is adopted. PMID- 23816762 TI - Identification of a candidate single-nucleotide polymorphism related to chemotherapeutic response through a combination of knowledge-based algorithm and hypothesis-free genomic data. AB - Inter-individual variations in drug responses among patients are known to cause serious problems in medicine. Genome-wide association study (GWAS) is powerful for examining single-nucleotide polymorphisms (SNPs) and their relationships with drug response variations. However, no significant SNP has been identified using GWAS due to multiple testing problems. Therefore, we propose a combination method consisting of knowledge-based algorithm, two stages of screening, and permutation test for identifying SNPs in the present study. We applied this method to a genome-wide pharmacogenomics study for which 109,365 SNPs had been genotyped using Illumina Human-1 BeadChip for 119 gastric cancer patients treated with fluoropyrimidine. We identified rs2293347 in epidermal growth factor receptor (EGFR) is as a candidate SNP related to chemotherapeutic response. The p value for the rs2293347 was 2.19 * 10(-5) for Fisher's exact test, and the p value was 0.00360 for the permutation test (multiple testing problems are corrected). Additionally, rs2293347 was clearly superior to clinical parameters and showed a sensitivity value of 55.0% and specificity value of 94.4% in the evaluation by using multiple regression models. Recent studies have shown that combination chemotherapy of fluoropyrimidine and EGFR-targeting agents is effective for gastric cancer patients highly expressing EGFR. These results suggest that rs2293347 is a potential predictive factor for selecting chemotherapies, such as fluoropyrimidine alone or combination chemotherapies. PMID- 23816763 TI - Construction of a stable plasmid vector for industrial production of poly(3 hydroxybutyrate-co-3-hydroxyhexanoate) by a recombinant Cupriavidus necator H16 strain. AB - A new stable plasmid vector (pCUP3) was developed for high and stable production of poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBH) using Cupriavidus necator H16 as the host strain. In pCUP3, it was found that the plasmid partition and replication region of the megaplasmid pMOL28 in the Cupriavidus metallidurans CH34 strain plays an important role in plasmid stability in C. necator H16. Moreover, the partition locus (comprising parA28 and parB28 and the parS28 region) is essential for plasmid maintenance under high-PHBH-accumulation. PHBH productivity by the C. necator H16/ds strain (phaC1 deactivated mutant strain) harboring a phaCAc NSDG within pCUP3 was identical to the productivity of poly(3 hydroxybutyrate) by the C. necator H16 strain when palm kernel oil was used as the sole carbon source without any antibiotics. This new vector is important for industrial mass production of polyhydroxyalkanoates using the C. necator H16 strain as the host, dispensing the necessity of the application of selective pressure such as antibiotics. PMID- 23816765 TI - A consensus endocrine profile for chronically stressed wild animals does not exist. AB - Given the connection between chronic stress and health, there has been a growing emphasis on identifying chronically stressed wild animals, especially in relation to anthropogenic disturbances. There is considerable confusion, however, in how to identify chronically stressed wild animals, but the most common assumption is that measures of glucocorticoid (GC) function will increase. In an attempt to determine an "endocrine profile" of a chronically stressed wild animal, this review collected papers from the literature that measured baseline GC, stress induced GC, measures of integrated GC, negative feedback, hypothalamic-pituitary adrenal axis sensitivity, and/or body weight in chronically stressed animals. The collected studies encompassed laboratory and field studies, numerous diverse species, and multiple techniques for inducing chronic stress. Each paper was ranked according to its relevance to wild animals and scored as to whether the measured response increased, decreased, or stayed the same after exposure to chronic stress. The analyses uncovered so much variation between studies that the literature does not support a generalized endocrine profile in how wild animals respond to chronic stress. The common predictions appear to be based almost entirely on theoretical models rather than empirical data. The three most important variables affecting GC responses were the stressors used to induce chronic stress, the potential for those stressors to induce habituation, and the taxon of the focal species. The best approach for identifying a chronically stressed population appears to be documentation of changes at multiple levels of GC regulation, but the direction of the change (increase or decrease) may be relatively unimportant compared to the fact that the response changes at all. The conclusion is that a consistent, predictable, endocrine response to chronic stress, regardless of the protocol used to induce chronic stress and the species under study, does not exist. PMID- 23816766 TI - Effects of magnesium pretreatment on the levels of T helper cytokines and on the severity of reperfusion syndrome in patients undergoing living donor liver transplantation. AB - OBJECTIVES: Magnesium has protective effects in ischaemia-reperfusion injury, and is involved in immunomodulation. We investigated the effects of magnesium pretreatment on the secretion of T helper (Th) cytokines and on the severity of post-reperfusion syndrome (PRS) in patients undergoing living donor liver transplantation (LDLT). METHODS: forty patients were allocated to two groups of 20 (magnesium and saline groups). Blood samples for cytokine analysis were collected before infusion of the study solution at the end of anhepatic phase (time point 1), as well as five min and 30 min after allograft reperfusion (time points 2 and 3, respectively). Levels of cytokines were quantified using a sandwich enzyme immunoassay test kit. RESULTS: The duration of PRS was shorter in the magnesium group (p = 0.038). The level of interferon (IFN)-gamma released from Th1 was lower in the magnesium group at time point 3 (p = 0.009). Of the cytokines released from Th2 cells, interleukin (IL)-6 was present in higher concentrations in the magnesium group at time points 2 and 3 (p<0.05). The concentrations of IL-4 and IL-10, which were secreted from Th2 cells, were also higher in the magnesium group at time point 3 (p<0.05). The IFN-gamma /IL-6, IFN gamma /IL-4 and IFN-gamma /IL-10 ratios were lower in the magnesium group after allograft reperfusion. CONCLUSIONS: Magnesium pretreatment attenuated PRS and reinforced Th2 cell activity, shifting the Th1-to-Th2 cytokine balance towards Th2 in patients undergoing LDLT. PMID- 23816767 TI - 12-month observation of testosterone replacement effectiveness in a general population of men. AB - BACKGROUND: Testosterone decline becomes more prevalent as men age and symptomatic testosterone deficiency is associated with potentially serious comorbidities. Despite limitations, registries can provide an opportunity to accumulate data regarding disease management in a typical patient population, including diagnosis, treatment, and outcomes. MATERIALS AND METHODS: The Testim Registry in the United States (TRiUS) was a prospective, 12-month, observational cohort registry of men prescribed Testim(r) (1% testosterone gel; Auxilium Pharmaceuticals, Inc.) for the first time; patients previously on other forms of testosterone replacement therapy (TRT) were eligible to participate in the study as well. The registry recorded total testosterone (TT) and free testosterone (FT) levels, prostate-specific antigen (PSA), sexual function, mood/depression, and cardiometabolic and anthropometric criteria before and after TRT. Changes over time were analyzed by analysis of variance, and linear regression and Pearson product-moment correlation coefficients were used to examine relationships between variables. RESULTS: At baseline, 849 patients from 72 sites were enrolled, with 743 of 849 started on 5 g gel/day (50 mg testosterone/day) and 106 of 849 started on 10 g gel/day (100 mg testosterone/day). Mean TT and FT levels increased significantly after 3 months of TRT (TT level, 16.8 +/- 9.87 nmol/L [485 +/- 284 ng/dL], P < 0.001; FT level, 286.3 +/- 224.9 pmol/L [82.5 +/- 64.8 pg/mL], P < 0.001) and were maintained at eugonadal levels. Mean PSA levels increased significantly (P = 0.004) from 1.12 +/- 1.11 MUg/L (1.12 +/- 1.11 ng/mL) at baseline to 1.26 +/- 1.22 MUg/L (1.26 +/- 1.22 ng/mL) after 12 months of TRT, although changes were well within guidelines (< 1.4 MUg/L/year increase). Significant improvements were seen in sexual function and mood/depression at 3 months and in metabolic parameters at 12 months. CONCLUSION: Testosterone deficiency symptoms improved with TRT use in men; sexual function and mood/depression improvements were seen before metabolic improvements. Prostate specific antigen levels increased, although increases were within guideline determined safety limits. PMID- 23816768 TI - Testosterone replacement therapy in men with hypogonadism and HIV/AIDS: results from the TRiUS registry. AB - BACKGROUND: Although hypogonadism is common in men with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), testosterone levels after testosterone replacement therapy (TRT) in this population have not been reported. METHODS: The Testim Registry in the United States (TRiUS) was the first prospective, observational registry of men with hypogonadism who were prescribed TRT. The TRiUS cohorts with (n = 82) and without (n = 767) HIV/AIDS were followed during 12 months of treatment with Testim(r) (1% testosterone gel; Auxilium Pharmaceuticals, Inc.). Total testosterone (TT) and free testosterone levels, symptoms of depression, sexual function, body composition profiles, and prostate specific antigen levels were evaluated. RESULTS: The HIV/AIDS and non-HIV/AIDS cohorts differed at baseline in age (48.3 vs 52.5 years), TT level (13.0 vs 9.6 nmol/L), duration of hypogonadism (27.1 vs 14.6 months), prior TRT (36.6% vs 22.6%), body mass index (26.5 vs 32.0 kg/m2), and antidepressant (29% vs 15%) and opioid (20% vs 10%) use (P <= 0.01 for all comparisons). During the 12 months, both cohorts experienced significant elevations in TT and free testosterone levels to within normal ranges. Sexual function and depression scores improved and antidepressant medication use decreased in both cohorts. Body composition profiles improved significantly (P <= 0.05) in men without HIV/AIDS and remained stable in men with HIV/AIDS during the 12 months of follow-up. CONCLUSION: This 12-month, non-placebo-controlled, observational study of Testim(r) use in men with and without HIV/AIDS suggests that TRT may provide clinical benefits irrespective of the patient's HIV/AIDS status. This conclusion is supported by the higher testosterone levels, better sexual function, lower depression scores, and better body composition profiles found in both groups. However, given the loss of patients to follow-up, these results may reflect a bias toward drug responders. PMID- 23816769 TI - Optimal diagnostic measures and thresholds for hypogonadism in men with HIV/AIDS: comparison between 2 transdermal testosterone replacement therapy gels. AB - OBJECTIVES: To determine the incidence of hypogonadism in men with human immunodeficiency virus (HIV)/acquired immunodeficiency virus (AIDS), the most useful serum testosterone measurement and threshold for diagnosing hypogonadism, and the comparative efficacy of 2 testosterone replacement therapy (TRT) 1% gels (AndroGel(r) [Abbott Laboratories] and Testim(r) [Auxilium Pharmaceuticals, Inc.]). DESIGN AND SUBJECTS: This was a 2-stage observational study. In stage 1, patient records from 2 medical practices specializing in HIV/AIDS were reviewed. Eligible patients were aged >= 18 years; had HIV-seropositive status confirmed by enzyme-linked immunosorbent assay and western blot test or HIV-1 viremia confirmed by HIV-1 RNA polymerase chain reaction; and had prior baseline testosterone assessments for hypogonadism (ie, presence of signs/symptoms of hypogonadism as well as total testosterone [TT] and free testosterone [FT] level measurements). Stage 2 included the evaluation of patients from stage 1 who were treated with 5 to 10 g/day of TRT. The stage 2 inclusion criteria were a diagnosis of low testosterone (defined as TT level < 300 ng/dL and/or FT level < 50 pg/mL, as per The Endocrine Society guidelines and presence/absence of hypogonadal signs and symptoms); >= 12 months of evaluable sign and symptom assessments and TT/FT level measurements while on TRT with either Testim(r) or AndroGel(r); and >= 4 weeks on initial TRT if the initial TRT was switched or discontinued. RESULTS: Four hundred one of 422 patients met the stage 1 inclusion criteria and 167 of 401 patients (AndroGel(r), n = 92; Testim(r), n = 75) met the stage 2 inclusion criteria. Total testosterone level < 300 ng/dL alone identified 24% (94 of 390) of patients as hypogonadal, but failed to diagnose an additional 111 patients (67.7%) with FT levels < 100 pg/mL and hypogonadal symptoms. Through month 12, AndroGel(r) increased mean TT levels by +42.8% and FT levels by +66.9%, compared with +178.7% (P = 0.017) and +191% (P = 0.039), respectively, for Testim(r). Patients treated with Testim(r) showed significantly greater improvements in libido, sexual performance, nighttime energy, focus/concentration, and abdominal girth, and trends for greater improvement in fatigue and erectile dysfunction than patients treated with AndroGel(r). No patients discontinued therapy due to adverse events. CONCLUSION: The most useful serum testosterone measurement and threshold for diagnosing hypogonadism in men with HIV/AIDS was FT level < 100 pg/mL, which identified 64% of men as hypogonadal with the presence of >= 1 hypogonadal symptom. This is above currently accepted thresholds. Criteria using TT level < 300 ng/dL and FT level < 50 pg/mL only diagnosed 24% and 19% of patients, respectively, as having hypogonadism. Testim(r) was more effective than AndroGel(r) in increasing TT and FT levels and improving hypogonadal symptoms. PMID- 23816770 TI - Comorbidities in patients with irritable bowel syndrome with constipation or chronic idiopathic constipation: a review of the literature from the past decade. AB - BACKGROUND: Irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) are common functional bowel disorders. Patients with IBS-C or CIC often present with >= 1 comorbidity that coincides with either of these conditions. These comorbidities may make underappreciated contributions to the patient's overall disease burden. OBJECTIVE: To identify the comorbidities that are the most frequently reported in patients with IBS-C or CIC in the medical literature. METHODS: A literature search (January 2001-March 2012) was performed using the Medline and Medline In-Process databases. Studies of adult patients with IBS-C or CIC were selected, and the prevalence rates of the comorbidities were extracted and analyzed according to the body system affected. RESULTS: A total of 70 distinct comorbidities were identified from 35 published studies. These comorbidities involved several body systems, including the gastrointestinal, genitourinary, psychiatric, endocrine, and allergic or immunologic systems. Functional dyspepsia and depression were the most common comorbidities in patients with IBS-C, whereas functional dyspepsia, diabetes, and depression were the most common comorbidities in patients with CIC. CONCLUSION: Patients with IBS-C or CIC frequently experience a wide range of comorbidities that contribute to their disease burden. Thus, we believe that medical professionals should consider common comorbidities when diagnosing and treating patients with IBS-C or CIC. PMID- 23816771 TI - Psychosocial therapy in the treatment of adults with attention deficit/hyperactivity disorder. AB - Optimal management of attention-deficit/hyperactivity disorder (ADHD) requires a comprehensive treatment approach that reduces symptoms and improves quality of life. Psychosocial therapy, an important adjunct to pharmacotherapy for patients with ADHD, enables patients to improve functional performance across domains of life and maximizes the benefits of symptom reduction achieved via medication. This article evaluates the main types of psychosocial therapies used in the treatment of adult ADHD and discusses treatment goals within the context of skill acquisition and strength optimization. Factors influencing the success of psychosocial therapy and the role of a comprehensive treatment approach are also examined. The sequenced presentation of symptom reduction and skill acquisition plays a key role in coordinating psychosocial therapy and pharmacotherapy in a multimodal strategy for the effective treatment of adult ADHD. PMID- 23816772 TI - Variability in intravenous immunoglobulin G regimens for autoimmune neuromuscular disorders. AB - AIMS: We reviewed the intravenous immunoglobulin G (IVIG) dispensing records of a specialty pharmacy to characterize the IVIG treatment regimens used for chronic inflammatory demyelinating polyneuropathy (CIDP) and myasthenia gravis (MG) in community practice. METHODS: Anonymized records were selected based on International Classification of Diseases, Ninth Revision (ICD-9) codes and IVIG treatment for > 1 month. Each patient's immunoglobulin G (IgG) dose per infusion (mg/kg/dose) was multiplied by the number of doses per month (30.5 days divided by the dosing interval in days) to yield the total monthly dose (mg/kg/month). Data were analyzed and summarized using descriptive statistics. RESULTS: Forty six patients (median age, 56.5 years; range, 8-86 years) fulfilled the inclusion criteria. Thirty-one patients with CIDP received IgG at 7- to 92-day intervals (mean [standard deviation (SD)], 28 [16] days). The mean (SD) IgG dose was 75 (60) g/dose, equivalent to 866 (623) mg/kg/dose and 1145 (778) mg/kg/month. Six patients with stable MG received IVIG or subcutaneous IgG at 3.5- to 61-day intervals (28 [20] days) at a mean (SD) IgG dose of 39 (15) g/dose, equivalent to 405 (108) mg/kg/dose and 783 (680) mg/kg/month. Nine patients with MG with acute exacerbations received IgG at 7- to 42-day intervals (22 [12] days) at a mean (SD) dose of 40 (21) g/dose, equivalent to 403 (172) mg/kg/dose and 641 (288) mg/kg/month. One patient with CIDP and 4 patients with MG were treated with weekly subcutaneous IgG injections. CONCLUSION: Although patients with CIDP and MG are treated with mean total monthly IgG doses similar to those approved by the US Food and Drug Administration, the individual doses and intervals vary considerably, suggesting that physicians may be adjusting IgG dosing according to each patient's clinical condition and treatment response. Further study is necessary to determine the criteria used to adjust IgG treatment regimens and whether these adjustments optimize clinical outcomes while limiting overall costs. PMID- 23816773 TI - Impact of metastatic colorectal cancer stage and number of treatment courses on patient health care costs and utilization. AB - BACKGROUND: Advances in colorectal cancer (CRC) treatment and improved survival rates have led to higher costs associated with treating CRC. OBJECTIVE: To examine health care costs and utilization by initial CRC stage at diagnosis and the number of lines of treatment received by patients with metastatic CRC. METHODS: Adult patients with a diagnosis of CRC made from January 1, 2005 to May 31, 2010 were identified from the Oncology Management registry. Patients with stage IV CRC at initial diagnosis or who had advanced to stage IV CRC at the time of the study were included. Registry data included initial CRC stage and the date of diagnosis. Linked health care claims from a large US health insurance database affiliated with Optum were used to identify health care costs and patient characteristics. Multivariate regression analysis was used to estimate total 4 year health care costs stratified by stage and adjusted for patient characteristics. Follow-up ended at patient death, disenrollment from the health care plan, or study end (November 30, 2010). RESULTS: A total of 598 patients, followed for an average of 653 days after first evidence of metastasis, were included. At initial diagnosis, 91 patients had stages 0 to III CRC, 310 patients had stage IV CRC, and 197 patients had an unknown stage of CRC. The mean unadjusted total cost per patient (medical + pharmaceutical costs) was $252 200; outpatient hospital visits (excluding radiation and surgery) contributed most to the total cost, at a mean cost of $71 334. Hospitalization costs, with or without surgery (mean, $56 862), accounted for 33% of the $176 135 unadjusted mean cost for medical services (ambulatory visits [office and outpatient], emergency department visits, laboratory/radiology services, and inpatient admission). Chemotherapy and biologics were also costly (mean, $31 112 and $38 276, respectively). A general linear model analysis of estimated 4-year total costs showed that both CRC stage at diagnosis and the number of lines of treatment after metastasis had a statistically significant association with cost (P < 0.001). CONCLUSION: Variables that had a statistically significant association with cost (P < 0.05) were sex, age group, and follow-up Charlson Comorbidity Index score after metastases. After adjusting for the number of lines of treatment received, total 4-year costs were highest among patients who presented with stage IV CRC and lowest among patients who presented with stage III CRC and developed metastatic disease. PMID- 23816774 TI - Comparison of different adjuvant therapies for 9 resectable cancer types. AB - PURPOSE: The objective of this study was to compare the clinical benefit across adjuvant therapies for cancer treatment, including adjuvant imatinib, and to quantify the results using the number-needed-to-treat (NNT) approach. METHOD: We reviewed studies meeting the following criteria: 1) US and European randomized clinical trial populations consisting of patients with cancer who underwent surgical resection of the primary tumor and were considered cancer free; 2) comparators were either placebo or no treatment; and 3) recurrence-free survival (RFS) and overall survival (OS) rates were reported and showed benefit with the experimental treatment. The NNT was calculated as the inverse of the difference in event rate between the study groups in each trial. RESULTS: We identified 26 adjuvant treatment trials in 9 cancer types. With longer follow-up (3 years vs 1 year), 62.5% of treatments compared with placebo showed a decreased RFS NNT, including imatinib (7 vs 4). The largest relative decrease in RFS NNT over time was 91% (with trastuzumab or cyclophosphamide therapy). Approximately 25% of the treatments resulted in an increase in RFS NNT over time. The RFS NNT for imatinib was lower than that for all other treatments at 3 years of follow-up and lower than that for all but 2 treatments at 1 year. At both year 1 and year 3, the NNT for OS ranged from 6 to 100. Imatinib had an OS NNT of 31 at 3 years. CONCLUSION: With longer follow-up duration, most adjuvant cancer treatments showed a decreased NNT. Imatinib had one of the lowest NNTs among the adjuvant treatments at 1 and 3 years of follow-up using the RFS data. PMID- 23816775 TI - Natural history and malignant risk factors of solid pseudopapillary tumors of the pancreas. AB - BACKGROUND AND AIM: Solid pseudopapillary tumors (SPTs) of the pancreas are unusual neoplasms of uncertain prognosis. Most patients with SPTs have a good prognosis after undergoing surgical resection, but there are rare cases in which a locally infiltrative growth pattern and metastatic variety are exhibited, or recurrence of the disease after surgery occurs; these cases have been reported with very poor clinical outcomes. Our study investigated the natural history of SPTs and delineated the clinicopathologic features that may predict the malignancy potential of the disease. METHODS: A total of 100 patients with suspected SPTs were enrolled in our study and 77 patients underwent surgical resection. A resulting 60 tumors were pathologically proven to be SPTs and the affected patients were followed-up regularly after surgery. Clinical and pathologic data for all 100 patients were analyzed. RESULTS: Of the 60 total patients with histologically positive SPTs, 55 (92%) were women and 5 (8%) were men. The median patient age was 34 years (range, 13-77 years). Among the 60 patients, 9 had malignant SPTs and 51 had benign SPTs. Deep parenchymal invasion into the surrounding tissue was the most frequent pathologic feature suggesting malignancy (75%) among the 60 patients who underwent surgical resection. Patient clinicopathologic characteristics and demographic factors were compared between those who had benign SPTs and those who had malignant SPTs. There were no significant differences in the various patient features between the 2 groups, including age, sex, symptoms, tumor size, tumor location, internal tumor composition, pattern of tumor calcification, tumor necrosis, hemorrhage, and immunohistochemical tumor tissue patterns. There were 2 patients who had distant metastasis; 1 presented with distal metastasis in the liver and the other patient had recurrence of cancer with a peritoneal mass after surgery. Metastasectomy was performed on the 2 patients and there was no mortality or disease progression during the follow-up period (median, 143 months; range, 53-319 months). CONCLUSION: Solid pseudopapillary tumors are low-grade tumors that have a generally good prognosis. However, the clinical development and malignancy potential of SPTs are neither fully understood nor predictable, even with histologically benign tumors. Further investigations in tumor biology, along with long-term patient follow-up, may provide insight into the disease process and clinical development of SPTs. PMID- 23816776 TI - Treatment, outcomes, costs, and quality of life of women and men with acute coronary syndromes who have undergone percutaneous coronary intervention: results from the antiplatelet therapy observational registry. AB - BACKGROUND: Treatment, outcomes, costs, and quality of life after percutaneous coronary intervention (PCI) were compared between women and men with acute coronary syndromes (ACS) using data from the Antiplatelet Therapy Observational Registry (APTOR). METHODS: Fourteen European countries participated in this noninterventional, prospective, observational cohort registry, which enrolled patients with ACS who underwent PCI from 2007 to 2009. The 12-month outcomes included bleeding, cardiovascular events, and mortality. Quality of life was measured using the EQ-5DTM (EuroQol Group) health index and the visual analog scale. RESULTS: The APTOR registry included 4546 patients, of whom 1047 (23%) were women and 3499 (77%) were men. The women were older (mean age, 67 vs 61 years) and had higher rates of diabetes mellitus and hypertension. A greater proportion of the men were smokers (40% vs 30%). Approximately 70% of the patients underwent PCI on the day of the qualifying ACS event. Women and men received similar medications at the time of PCI, hospital discharge, and 12-month follow-up visit. Bleeding, cardiovascular events, and mortality occurred at higher rates in women than in men, but the differences were not statistically significant. At 12 months post-PCI, women reported lower quality-of-life scores on the EQ-5DTM health index and the visual analog scale than did men. The mean total cost of care was L6252 (?7189) for women and L5841 (?6717) for men; the differences may be driven by resource use after discharge from the hospital. CONCLUSION: Women with ACS tended to be older and had more comorbidities than men, but both sexes experienced similar outcomes after 1 year. This study indicated no differences in treatment between sexes. PMID- 23816777 TI - Carotid intima-media thickness testing as an asymptomatic cardiovascular disease identifier and method for making therapeutic decisions. AB - Cardiovascular disease (CVD) is the leading cause of death and disability in the United States. Although current therapies can reduce the risk for CVD, they are only given to patients who are considered to be at risk, and are therefore only beneficial if a patient's risk is accurately predicted before he or she sustains a cardiovascular (CV) event. Unfortunately, even relatively accurate risk factor analyses, such as the Reynolds Risk Score algorithm, fail to identify some patients who will sustain a CV event within 10 years. In contrast, the presence of an atheroma is an absolute predictor for the potential of an atherothrombotic event to occur, and it is therefore reasonable to anchor clinical decisions based on this knowledge. Carotid intima-media thickness (CIMT) testing via B-mode ultrasound is a safe, simple, and inexpensive method for evaluating CV risk by measuring the combined thickness of the intimal and medial layers of the arterial wall. Use of CIMT testing can also detect marked thickening of the arterial wall, possibly indicating plaques or atheromas that are associated with accelerated atherosclerotic disease and increased risk for coronary artery disease, myocardial infarction, and stroke. These characteristics make CIMT a practical supplemental method that physicians can use when making decisions. Moreover, the ability of CIMT testing to identify and quantify atherosclerotic disease has led to the adoption of CIMT as a surrogate endpoint in clinical trials, allowing the efficacy of new drugs to be assessed much more rapidly than would be possible by focusing solely on CV event or mortality rates. To date, several trials have provided evidence to indicate that some CVD therapies slow, stop, or reverse the progression of CIMT. Although many of these studies show that changes in CIMT predict future CV events, the value of CIMT testing in CVD risk assessment is still vigorously debated. In this article, we clarify the utility of CIMT testing for risk classification and reexamine its usefulness as a method for assessing therapeutic efficacy. PMID- 23816778 TI - Efficacy of amlodipine/olmesartan medoxomil +/- hydrochlorothiazide in patients aged >= 65 or < 65 years with uncontrolled hypertension on prior monotherapy. AB - Our subanalysis evaluated the efficacy of an amlodipine/olmesartan medoxomil (AML/OM)-based titration regimen to achieve blood pressure (BP) goals among patients aged >= 65 years. In this dose-titration study, 999 patients (228 of whom were aged >= 65 years) with uncontrolled BP after >= 1 month of monotherapy were switched to fixed-dose AML/OM 5/20 mg and uptitrated every 4 weeks to AML/OM 5/40 and 10/40 mg to achieve BP < 120/70 mm Hg. Patients were subsequently uptitrated every 4 weeks to AML/OM 10/40 mg + hydrochlorothiazide (HCTZ) 12.5 mg and AML/OM 10/40 mg + HCTZ 25 mg to achieve BP < 125/75 mm Hg. The primary efficacy endpoint (ie, the cumulative percentage of patients achieving the seated cuff systolic BP goal of < 140 mm Hg [or < 130 mm Hg for patients with type 2 diabetes mellitus] during first 12 weeks of treatment) was achieved by 76.7% and 75.6% of patients aged >= 65 (ie, 65-80) years and < 65 (ie, 18-64) years, respectively. For patients aged >= 65 and < 65 years, mean seated cuff BP changes from baseline during the titration periods ranged from -14.5/-7.8 mm Hg and 14.1/-7.7 mm Hg, respectively, for AML/OM 5/20 mg, to -28.5/-12.4 and -24.5/-14.0 mm Hg for AML/OM 10/40 mg + HCTZ 25 mg (all P < 0.0001). By week 20, the cumulative BP threshold of < 140/90 mm Hg was achieved by 86.8% and 84.2% of patients aged >= 65 and < 65 years, respectively. Among patients aged >= 65 years who underwent ambulatory BP monitoring, mean 24-hour, daytime, and nighttime ambulatory BP all decreased from baseline at weeks 12 and 20 (all P < 0.0001). At weeks 12 and 20, the mean 24-hour American Heart Association-recommended ambulatory BP target of < 130/80 mm Hg was achieved in 80.4% and 97.4% of patients aged >= 65 years, respectively, and in 71.3% and 88.8% of patients aged < 65 years, respectively. The majority of adverse events were mild to moderate in intensity and the incidence of treatment-emergent adverse events determined by clinical laboratory evaluation was low. The incidence of drug-related hypotension and orthostatic hypotension in patients aged >= 65 years was 2.2% and 0.0%, respectively, and in patients aged < 65 years, was 2.3% and 0.3%, respectively. Fixed-dose AML/OM +/- HCTZ combination therapy effectively lowered BP and achieved BP goals in patients aged >= 65 and < 65 years with hypertension previously uncontrolled on monotherapy. The treatment regimen was well tolerated irrespective of patient age. PMID- 23816779 TI - Laboratory monitoring of anticoagulant medications: focus on novel oral anticoagulants. AB - Novel oral anticoagulants, direct thrombin inhibitors, and factor Xa inhibitors are being introduced into clinical practice. In contrast to vitamin K antagonists, such as warfarin, these novel agents, because of their relatively wide therapeutic range and predictable pharmacokinetics, have been evaluated in clinical trials and approved for clinical use without the need for routine coagulation monitoring. On occasion, it will be important to assess the anticoagulant status of patients treated with these agents. As a result of their targeted mechanisms of action, they affect standard coagulation assays differently than vitamin K antagonists and heparins, and such assay results may not provide clinically useful information. Thus, less commonly used coagulation assays (eg, chromogenic anti-factor Xa activity assays, diluted thrombin time, and ecarin-based clotting tests) may be introduced into clinical practice. These assays are currently limited by the absence of validated therapeutic targets and lack of standardization across laboratories, vendors, and medication classes. This article provides an overview of the coagulation assays and their potential role in determining the anticoagulant status of patients treated with the emerging anticoagulants. PMID- 23816780 TI - Alternatives to warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a look back at the state of the field in 2012. AB - Stroke is the most feared complication among patients with atrial fibrillation. Oral anticoagulation therapy with vitamin K antagonists (VKAs) has been the gold standard for stroke prevention for the past 60 years. However, VKA therapy has many downsides, including risk for bleeding, a narrow therapeutic window, and the need for frequent monitoring, as well as numerous diet and lifestyle considerations that make its use cumbersome. Thus, development of new drugs that can preserve the benefits of VKAs while eliminating the negative aspects of VKA therapy has been enthusiastically sought. This article reviews the anticoagulant agents that are clinically available or under development as alternatives to VKAs for stroke prevention in patients with nonvalvular atrial fibrillation. PMID- 23816781 TI - Perinatal air pollutant exposures and autism spectrum disorder in the children of Nurses' Health Study II participants. AB - OBJECTIVE: Air pollution contains many toxicants known to affect neurological function and to have effects on the fetus in utero. Recent studies have reported associations between perinatal exposure to air pollutants and autism spectrum disorder (ASD) in children. We tested the hypothesis that perinatal exposure to air pollutants is associated with ASD, focusing on pollutants associated with ASD in prior studies. METHODS: We estimated associations between U.S. Environmental Protection Agency-modeled levels of hazardous air pollutants at the time and place of birth and ASD in the children of participants in the Nurses' Health Study II (325 cases, 22,101 controls). Our analyses focused on pollutants associated with ASD in prior research. We accounted for possible confounding and ascertainment bias by adjusting for family-level socioeconomic status (maternal grandparents' education) and census tract-level socioeconomic measures (e.g., tract median income and percent college educated), as well as maternal age at birth and year of birth. We also examined possible differences in the relationship between ASD and pollutant exposures by child's sex. RESULTS: Perinatal exposures to the highest versus lowest quintile of diesel, lead, manganese, mercury, methylene chloride, and an overall measure of metals were significantly associated with ASD, with odds ratios ranging from 1.5 (for overall metals measure) to 2.0 (for diesel and mercury). In addition, linear trends were positive and statistically significant for these exposures (p < .05 for each). For most pollutants, associations were stronger for boys (279 cases) than for girls (46 cases) and significantly different according to sex. CONCLUSIONS: Perinatal exposure to air pollutants may increase risk for ASD. Additionally, future studies should consider sex-specific biological pathways connecting perinatal exposure to pollutants with ASD. PMID- 23816782 TI - Effective inhibition of bacterial respiration and growth by CuO microspheres composed of thin nanosheets. AB - This study describes the synthesis, characterization and biocidal potential of copper oxide micro-spheres composed of thin sheets (CuOMSs-Ths). Microscopic observations of synthesized CuOMSs-Ths revealed the clusters of thin sheets arranged in small flower like micro-spheres. Diameter of each micro-sphere was determined in the range of 2-3 MUm, whereas the size of each sheet was ~ 80 nm. These micro-flowers like nanostructures were synthesized using copper nitrate hexahydrate and sodium hydroxide via solution process. The CuOMSs-Ths exhibited a broad-spectrum anti-bacterial activity involving significant growth inhibition of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Micrococcus luteus. The IC50 values of these engineered NPs against E. coli, P. aeruginosa, S. aureus and M. luteus were determined to be 195, 200, 131 and 184 MUg/ml, respectively. Also, the respiration of Gram+ ve organisms (M. luteus and S. aureus) was inhibited significantly (p value < 0.005) at relatively lower concentrations of 12.5 and 50 MUg/ml, respectively, as compared to the Gram- ve bacteria (E. coli and P. aeruginosa), where the growth inhibition occurred at a much greater concentration of 100 MUg/ml. The results explicitly demonstrated anti-microbial activity of CuOMSs-Ths with a higher level of toxicity against the Gram+ ve vis-a-vis Gram- ve bacteria. PMID- 23816783 TI - A novel model of invasive fungal rhinosinusitis in rats. AB - BACKGROUND: Invasive fungal rhinosinusitis (IFRS) is a life-threatening inflammatory disease that affects immunocompromised patients, but animal models of the disease are scarce. This study aimed to develop an IFRS model in neutropenic rats. METHODS: The model was established in three consecutive steps: unilateral nasal obstruction with Merocel sponges, followed by administration of cyclophosphamide (CPA), and, finally, nasal inoculation with Aspergillus fumigatus. Fifty healthy Wistar rats were randomly divided into five groups, with group I as the controls, group II undergoing unilateral nasal obstruction alone, group III undergoing nasal obstruction with fungal inoculation, group IV undergoing nasal obstruction with administration of CPA, and group V undergoing nasal obstruction with administration of CPA and fungal inoculation. Hematology, histology, and mycology investigations were performed. RESULTS: The changes in the rat absolute neutrophil counts (ANCs) were statistically different across the groups. The administration of CPA decreased the ANCs, whereas nasal obstruction with fungal inoculation increased the ANCs, and nasal obstruction did not change them. Histological examination of the rats in group V revealed the hyphal invasion of sinus mucosa and bone, thrombosis, and tissue infarction. No pathology indicative of IFRS was observed in the remaining groups. Positive rates of fungal culture in tissue homogenates from the maxillary sinus (62.5%) and lung (25%) were found in group V, whereas groups I, II, III, and IV showed no fungal culture in the homogenates. CONCLUSION: A rat IFRS model was successfully developed through nasal obstruction, CPA-induced neutropenia, and fungal inoculation. The disease model closely mimics the pathophysiology of anthropic IFRS. PMID- 23816784 TI - Integrated detection of natural antisense transcripts using strand-specific RNA sequencing data. AB - Pairs of RNA molecules transcribed from partially or entirely complementary loci are called cis-natural antisense transcripts (cis-NATs), and they play key roles in the regulation of gene expression in many organisms. A promising experimental tool for profiling sense and antisense transcription is strand-specific RNA sequencing (ssRNA-seq). To identify cis-NATs using ssRNA-seq, we developed a new computational method based on a model comparison framework that incorporates the inherent variable efficiency of generating perfectly strand-specific libraries. Applying the method to new ssRNA-seq data from whole-root and cell-type-specific Arabidopsis libraries confirmed most of the known cis-NAT pairs and identified 918 additional cis-NAT pairs. Newly identified cis-NAT pairs are supported by polyadenylation data, alternative splicing patterns, and RT-PCR validation. We found 209 cis-NAT pairs that have opposite expression levels in neighboring cell types, implying cell-type-specific roles for cis-NATs. By integrating a genome wide epigenetic profile of Arabidopsis, we identified a unique chromatin signature of cis-NATs, suggesting a connection between cis-NAT transcription and chromatin modification in plants. An analysis of small-RNA sequencing data showed that ~4% of cis-NAT pairs produce putative cis-NAT-induced siRNAs. Taken together, our data and analyses illustrate the potential for multifaceted regulatory roles of plant cis-NATs. PMID- 23816785 TI - Antibody humanization by redesign of complementarity-determining region residues proximate to the acceptor framework. AB - Antibodies are key components of the adaptive immune system and are well established protein therapeutic agents. Typically high-affinity antibodies are obtained by immunization of rodent species that need to be humanized to reduce their immunogenicity. The complementarity-determining regions (CDRs) contain the residues in a defined loop structure that confer antigen binding, which must be retained in the humanized antibody. To design a humanized antibody, we graft the mature murine CDRs onto a germline human acceptor framework. Structural defects due to mismatches at the graft interface can be fixed by mutating some framework residues to murine, or by mutating some residues on the CDRs' backside to human or to a de novo designed sequence. The first approach, framework redesign, can yield an antibody with binding better than the CDR graft and one equivalent to the mature murine, and reduced immunogenicity. The second approach, CDR redesign, is presented here as a new approach, yielding an antibody with binding better than the CDR graft, and immunogenicity potentially less than that from framework redesign. Application of both approaches to the humanization of anti-alpha4 integrin antibody HP1/2 is presented and the concept of the hybrid humanization approach that retains "difficult to match" murine framework amino acids and uses de novo CDR design to minimize murine amino acid content and reduce cell-mediated cytotoxicity liabilities is discussed. PMID- 23816786 TI - Monitoring intracellular oxidative events using dynamic spectral unmixing microscopy. AB - There is increasing interest in using live cell imaging to monitor not just individual intracellular endpoints, but to investigate the interplay between multiple molecular events as they unfold in real time within the cell. A major impediment to simultaneous acquisition of fluorescent signals from multiple probes is that emission spectra of many fluorophores overlap, often with maxima that are only a few nanometers apart. Spectral acquisition of mixed fluorescence signals captured within a dedicated scanning range can be used to quantitatively separate signals into component spectra. We report here the development of a novel live cell application of spectral unmixing for the simultaneous monitoring of intracellular events reported by closely-emitting fluorophores responding dynamically to external stimuli. We validate the performance of dynamic spectral unmixing microscopy (DynSUM) using genetically encoded sensors to simultaneously monitor changes in glutathione redox potential (Egsh) and H2O2 production in living cells exposed to oxidizing and reducing agents. We further demonstrate the utility of the DynSUM approach to observe the relationship between the increases in Egsh and H2O2 generation induced in airway epithelial cells exposed to an environmental electrophile. PMID- 23816787 TI - Kraken: a set of tools for quality control and analysis of high-throughput sequence data. AB - New sequencing technologies pose significant challenges in terms of data complexity and magnitude. It is essential that efficient software is developed with performance that scales with this growth in sequence information. Here we present a comprehensive and integrated set of tools for the analysis of data from large scale sequencing experiments. It supports adapter detection and removal, demultiplexing of barcodes, paired-end data, a range of read architectures and the efficient removal of sequence redundancy. Sequences can be trimmed and filtered based on length, quality and complexity. Quality control plots track sequence length, composition and summary statistics with respect to genomic annotation. Several use cases have been integrated into a single streamlined pipeline, including both mRNA and small RNA sequencing experiments. This pipeline interfaces with existing tools for genomic mapping and differential expression analysis. PMID- 23816788 TI - Design and use of transgenic reporter strains for detecting activity of signaling pathways in Xenopus. AB - Embryos and larvae of vertebrate species with external development are ideal subjects for investigating the dynamic spatiotemporal activity of developmental signaling pathways. The availability of efficient transgene technologies in Xenopus and zebrafish and the translucency and/or transparency of their embryos and larvae make these two species attractive for direct in vivo imaging of reporter gene expression. In this article we describe the design of efficient signaling reporters, using the Wnt/beta-catenin pathway as a representative example. We define methods for validating the reporter constructs and describe how they can be used to generate stable transgenic lines in Xenopus. We provide efficient methods used in our laboratory for raising the tadpoles and froglets rapidly to sexual maturity. We further discuss how the reporter lines can be used for delineating the dynamic activity of a signaling pathway and how modulators of the pathway can be scrutinized via chemical intervention and the micro-injection of synthetic RNAs or morpholinos. The strategic outline discussed in this paper provides a template for studying other developmental signaling pathways in Xenopus. PMID- 23816789 TI - Use of lentiviral vectors to deliver and express bicistronic transgenes in developing chicken embryos. AB - The abilities of lentiviral vectors to carry large transgenes (~8kb) and to efficiently infect and integrate these genes into the genomes of both dividing and non-dividing cells make them ideal candidates for transport of genetic material into cells and tissues. Given the properties of these vectors, it is somewhat surprising that they have seen only limited use in studies of developing tissues and in particular of the developing nervous system. Over the past several years, we have taken advantage of the large capacity of these vectors to explore the expression characteristics of several dual promoter and 2A peptide bicistronic transgenes in developing chick neural retina, with the goal of identifying transgene designs that reliably express multiple proteins in infected cells. Here we summarize the activities of several of these transgenes in neural retina and provide detailed methodologies for packaging lentivirus and delivering the virus into the developing neural tubes of chicken embryos in ovo, procedures that have been optimized over the course of several years of use in our laboratory. Conditions to hatch injected embryos are also discussed. The chicken specific techniques will be of highest interest to investigators using avian embryos, development and packaging of lentiviral vectors that reliably express multiple proteins in infected cells should be of interest to all investigators whose experiments demand manipulation and expression of multiple proteins in developing cells and tissues. PMID- 23816790 TI - NanoVelcro Chip for CTC enumeration in prostate cancer patients. AB - Circulating tumor cells (CTCs) are one of the most crucial topics in rare cell biology and have become the focus of a significant and emerging area of cancer research. While CTC enumeration is a valid biomarker in prostate cancer, the current FDA-approved CTC technology is unable to detect CTCs in a large portion of late stage prostate cancer patients. Here we introduce the NanoVelcro CTC Chip, a device composed of a patterned silicon nanowire substrate (SiNW) and an overlaid polydimethylsiloxane (PDMS) chaotic mixer. Validated by two institutions participating in the study, the NanoVelcro Chip assay exhibits very consistent efficiency in CTC-capture from patient samples. The utilized protocol can be easily replicated at different facilities. We demonstrate the clinical utility of the NanoVelcro Chip by performing serial enumerations of CTCs in prostate cancer patients after undergoing systemic therapy. Changes in CTC numbers after 4-10 weeks of therapy were compared with their clinical responses. We observed a statistically significant reduction in CTCs counts in the clinical responders. We performed long-term follow up with serial CTC collection and enumeration in one patient observing variations in counts correlating with treatment response. This study demonstrates the consistency of the NanoVelcro Chip assay over time for CTC enumeration and also shows that continuous monitoring of CTC numbers can be employed to follow responses to different treatments and monitor disease progression. PMID- 23816791 TI - Combination of a modified block PCR and endonuclease IV-based signal amplification system for ultra-sensitive detection of low-abundance point mutations. AB - By combination of a modified block PCR and endonuclease IV-based signal amplification system, we have developed a novel approach for ultra-sensitive detection of point mutations. The method can effectively identify mutant target sequence immersed in a large background of wild-type sequences with abundance down to 0.03% (for C->A) and 0.005% (for C->G). This sensitivity is among the highest in comparison with other existing approaches and the operating procedures are simple and time saving. The method holds great potential for future application in clinical diagnosis and biomedical research. PMID- 23816792 TI - Gated CW-STED microscopy: a versatile tool for biological nanometer scale investigation. AB - Stimulation emission depletion (STED) microscopy breaks the spatial resolution limit of conventional light microscopy while retaining its major advantages, such as working under physiological conditions. These properties make STED microscopy a perfect tool for investigating dynamic sub-cellular processes in living organisms. However, up to now, the massive dissemination of STED microscopy has been hindered by the complexity and cost of its implementation. Gated CW-STED (gCW-STED) substantially helps solve this problem without sacrificing spatial resolution. Here, we describe a versatile gCW-STED microscope able to speedily image the specimen, at a resolution below 50 nm, with light intensities comparable to the more complicated all-pulsed STED system. We show this ability on calibration samples as well as on biological samples. PMID- 23816793 TI - Isolation and culture of mouse proepicardium using serum-free conditions. AB - The proepicardium (PE) is an embryonic tissue that gives rise to multipotent vascular progenitors. Most notably the PE gives rise to the epicardium, cardiac fibroblasts, myocardium, and coronary vessels including both vascular smooth muscle and vascular endothelium. Much attention has been given to epicardial derived cells that show the capacity to differentiate into a wide variety of vascular progenitors including cardiomyocytes. However, it is the PE itself that possesses the greatest potential as a source of multipotent vascular progenitors. We show here a simple method to manually isolate mouse PE at the ninth day of mouse embryonic development and culture highly pure PE tissue in serum-free conditions. This PE culture method allows for the ex vivo analysis of specific growth factors on PE and epicardial development with greater efficiency and precision than existing epicardial culture methods. PMID- 23816794 TI - Endothelin-1 release during the early phase of reperfusion is a mediator of myocardial reperfusion injury. AB - PURPOSE: In acute myocardial infarction, left ventricular (LV) unloading reduces endothelin-1 (ET-1) release. We tested that endogenous ET-1 released during acute myocardial infarction might mediate ischemia/reperfusion (I/R) injury by stimulating increased intracellular calcium concentration, [Ca(2+)]i, and apoptosis. METHODS: Rabbits were subjected to 1 h of coronary artery occlusion followed by 3 h of reperfusion. Unloading was initiated 15 min prior to reperfusion and was maintained during reperfusion. The control group was subjected to reperfusion. Animals were treated with ET-1 receptor antagonist BQ123. In parallel, isolated rabbit cardiomyocytes subjected to simulated I/R with or without ET-1 or BQ123, intracellular Ca(2+) and cell death were assessed with flow cytometry. RESULTS: LV unloading prior to reperfusion reduced myocardial ET-1 release at 2 h of reperfusion. Infarct size was reduced in unloaded and BQ123 groups versus controls. LV unloading and BQ123 treatment reduced the percentage of apoptotic cells associated with increases in Bcl-2 protein levels in ischemic regions. BQ123 reduced both ET-1-induced [Ca(2+)]i increase and cell death for myocytes subjected to stimulated I/R. CONCLUSION: We propose that components of reperfusion injury involve ET-1 release which stimulates calcium overload and apoptosis. Intravenous ET-1 receptor blockade prior to reperfusion may be a protective adjunct to reperfusion therapy in acute myocardial infarction patients. PMID- 23816795 TI - Intermedin enhances sympathetic outflow via receptor-mediated cAMP/PKA signaling pathway in nucleus tractus solitarii of rats. AB - Direct administration of intermedin (IMD) into the brain elicits cardiovascular effects different from the systemic administration. Nucleus tractus solitarii (NTS) is an important region for the cardiovascular regulation. The present study was designed to determine the effect of IMD on modulating the sympathetic outflow and its related molecular mechanism in the NTS. Renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded in anesthetized rats. Site specific microinjection of IMD (20pmol) bilaterally into the NTS significantly increased RSNA and MAP. IMD-evoked increases of RSNA and MAP were almost abolished by pretreatment with receptor antagonist ADM22-52, an adenylyl cyclase (AC) inhibitor SQ22536, or a protein kinase A (PKA) inhibitor Rp-cAMP. However, pretreatment with another receptor antagonist calcitonin gene-related peptide (CGRP)8-37 did not suppress the increases of RSNA and MAP induced by IMD. Furthermore, IMD increased the cyclic adenosine monophosphate (cAMP) level, which was inhibited by ADM22-52 pretreatment in the NTS. These results suggest that IMD participates in the sympathetic nerve activity and central regulation of the cardiovascular system and a receptor-mediated cAMP/PKA signaling pathway is involved in IMD-induced effects in the NTS. PMID- 23816796 TI - Possible involvement of neuropeptide Y Y1 receptors in antidepressant like effect of agmatine in rats. AB - Agmatine and neuropeptide Y (NPY) are widely distributed in central nervous system and critically involved in modulation of depressive behavior in experimental animals. However their mutual interaction, if any, in regulation of depression remain largely unexplored. In the present study we explored the possible interaction between agmatine and neuropeptide Y in regulation of depression like behavior in forced swim test. We found that acute intracerebroventricular (i.c.v.) administration of agmatine (20-40MUg/rat), NPY (5 and 10MUg/rat) and NPY Y1 receptor agonist, [Leu(31), Pro(34)]-NPY (0.4 and 0.8ng/rat) dose dependently decreased immobility time in forced swim test indicating their antidepressant like effects. In combination studies, the antidepressant like effect of agmatine (10MUg/rat) was significantly potentiated by NPY (1 and 5MUg/rat, icv) or [Leu(31), Pro(34)]-NPY (0.2 and 0.4ng/rat, icv) pretreatment. Conversely, pretreatment of animals with NPY Y1 receptor antagonist, BIBP3226 (0.1ng/rat, i.c.v.) completely blocked the antidepressant like effect of agmatine (20-40MUg/rat) and its synergistic effect with NPY (1MUg/rat, icv) or [Leu(31), Pro(34)]-NPY (0.2ng/rat, icv). The results of the present study showed that, agmatine exerts antidepressant like effects via NPYergic system possibly mediated by the NPY Y1 receptor subtypes and suggest that interaction between agmatine and neuropeptide Y may be relevant to generate the therapeutic strategies for the treatment of depression. PMID- 23816797 TI - Ghrelin in ocular pathophysiology: from the anterior to the posterior segment. AB - Ghrelin is a 28 amino acid acylated peptide produced in several organs that binds the growth hormone secretagogues receptor type 1a (GHSR-1a). It acts over a wide range of systems, e.g. the endocrine, cardiovascular, musculoskeletal and immune systems and the eye. The aim of this work is to review the physiologic and pathologic implications of the ghrelin-GHSR-1a in the eye. A systematic revision of studies published between 2000 and 2013 in English, Spanish or Portuguese in MEDLINE, EMBASE and Scopus was performed. Search words used included: ghrelin, GHSR-1a, ocular production, iris muscular kinetics, ciliary body, glaucoma, retinopathy and uvea. The production of ghrelin by the ocular tissue has been detected both in the anterior and posterior segments, as well as the presence of GHSR-1a. This peptide promotes the relaxation of the iris sphincter and dilator muscles, being this effect independent from GHSR-1a and dependent on prostaglandins release in the first case and dependent on GHSR-1a in the second. Regarding ocular pathology, ghrelin levels in the aqueous humor appear to be decreased in individuals with glaucoma. Moreover, ghrelin has been shown to decrease the intraocular pressure in animal models of ocular hypertension through GHSR-1a. In the posterior segment, the ghrelin-GHSR-1a system interferes with the development of oxygen-induced retinopathy, being protective in the vaso obliterative phase and deleterious in the vaso-proliferative stage of the disease. Thus, the ghrelin-GHSR-1a system presents as a possible local regulatory mechanism in the eye, with pathophysiological implications, constituting a target for future clinical and therapeutic research and interventions. PMID- 23816798 TI - PYY(3-36) into the arcuate nucleus inhibits food deprivation-induced increases in food hoarding and intake. AB - Central administration of neuropeptide Y (NPY) increases food intake in laboratory rats and mice, as well as food foraging and hoarding in Siberian hamsters. The NPY-Y1 and Y5 receptors (Rs) within the hypothalamus appear sufficient to account for these increases in ingestive behaviors. Stimulation of NPY-Y2Rs in the Arcuate nucleus (Arc) has an anorexigenic effect as shown by central or peripheral administration of its natural ligand peptide YY (3-36) and pharmacological NPY-Y2R antagonism by BIIE0246 increases food intake. Both effects on food intake by NPY-Y2R agonism and antagonism are relatively short lived lasting ~4h. The role of NPY-Y2Rs in appetitive ingestive behaviors (food foraging/hoarding) is untested, however. Therefore, Siberians hamsters, a natural food hoarder, were housed in a semi-natural burrow/foraging system that had (a) foraging requirement (10 revolutions/pellet), no free food (true foraging group), (b) no running wheel access, free food (general malaise control) or (c) running wheel access, free food (exercise control). We microinjected BIIE0246 (antagonist) and PYY(3-36) (agonist) into the Arc to test the role of NPY-Y2Rs there on ingestive behaviors. Food foraging, hoarding, and intake were not affected by Arc BIIE0246 microinjection in fed hamsters 1, 2, 4, and 24h post injection. Stimulation of NPY-Y2Rs by PYY(3-36) inhibited food intake at 0-1 and 1-2h and food hoarding at 1-2h without causing general malaise or affecting foraging. Collectively, these results implicate a sufficiency, but not necessity, of the Arc NPY-Y2R in the inhibition of food intake and food hoarding by Siberian hamsters. PMID- 23816800 TI - Optimizing the use of a skin prick test device on children. AB - BACKGROUND: Studies comparing skin prick test (SPT) devices have revealed varying results in performance and there is little known about their use on children. METHODS: We performed 2 complementary studies to test the sensitivity, reproducibility and acceptability of commercially available SPT devices (Stallerpoint, Antony, France) using different application techniques. In the first part, histamine/saline was put on as a drop by use of a vial (V), and in the second part it was transferred from a well with the aid of the test device (W). The techniques were as follows: apply vertical pressure (Stallerpoint-VP or Stallerpoint-WP), apply vertical pressure with 90 degrees clockwise rotation (Stallerpoint-VC or Stallerpoint-WC) and apply vertical pressure with 90 degrees clockwise and counter-clockwise rotations (Stallerpoint-VCC or Stallerpoint-WCC). For comparison, ALK Lancet was used with a technique of 'drop and apply vertical pressure'. RESULTS: In the first part, sensitivities of the Stallerpoint-VC (96.6%), Stallerpoint-VCC (95.5%) and ALK Lancet (93.2%) techniques were superior (p < 0.001) to the other Stallerpoint-VP and Stallerpoint-WP techniques (76.1 and 46.6%). Intrapatient coefficient of variation (CV) values were 15.0, 18.9, 15.4, 22.4 and 48.5%, respectively. Interpatient CV ranged between 22.8 and 55.1%. In the second part, the Stallerpoint-WC (98.8%), WCC (97.5%) and ALK Lancet (98.8%) techniques yielded high sensitivities, whereas the sensitivity of Stallerpoint-WP (28.7%) was very low. There were false-positive reactions in the Stallerpoint-VCC and WCC techniques. CONCLUSION: In children, the SPT technique was found to be as important as the testing device. Stallerpoint-VC and WC techniques are reliable, tolerable and comparable with the ALK Lancet technique. PMID- 23816799 TI - Association between reported elder abuse and rates of admission to skilled nursing facilities: findings from a longitudinal population-based cohort study. AB - BACKGROUND: Elder abuse is common and is a frank violation of an older adult's fundamental rights to be safe and free of violence. Our prior study indicates elder abuse is independently associated with mortality. This study aims to quantify the relationship between overall elder abuse and specific subtypes of elder abuse and rate of admission to skilled nursing facilities (SNF). METHODS: A prospective population-based study conducted in Chicago of community-dwelling older adults who participated in the Chicago Health and Aging Project (CHAP). Of the 6,674 participants in the CHAP study, 106 participants were reported to the social services agency for elder abuse. The primary predictor was elder abuse reported to the social services agency. The outcome of interest was the annual rate of admission to SNF obtained from the Center for Medicare and Medicaid Services. Poisson regression models were used to assess these longitudinal relationships. RESULTS: The average annual rate of SNF for those without elder abuse was 0.14 (0.58) and for those with elder abuse was 0.66 (1.63). After adjusting for sociodemographic and socioeconomic variables, medical comorbidities, cognitive and physical function, and psychosocial wellbeing, older adults who have been abused had higher rates of SNF admission (RR 4.60 (2.85 7.42)). Psychological abuse (RR 2.31 (1.17-4.56)), physical abuse (RR 2.36 (1.19 4.66)), financial exploitation (RR 2.81 (1.53-5.17)) and caregiver neglect (RR 4.73 (3.03-7.40)) were associated with increased rates of admission to SNF, after considering the same confounders. Elder abuse is associated with a higher rate of SNF stay longer than 30 days (RR 6.27 (3.68-10.69)). CONCLUSION: Elder abuse was associated with increased rates of admission to SNF in this community population. Specific subtypes of elder abuse had a differential association with an increased rate of admission to SNF. PMID- 23816802 TI - New pieces of the Trichinella puzzle. AB - Contrary to our understanding of just a few decades ago, the genus Trichinella now consists of a complex assemblage of no less than nine different species and three additional genotypes whose taxonomic status remains in flux. New data and methodologies have allowed advancements in detection and differentiation at the population level which in turn have demonstrably advanced epidemiological, immunological and genetic investigations. In like manner, molecular and genetic studies have permitted us to hypothesise biohistorical events leading to the worldwide dissemination of this genus, and to begin crystalising the evolution of Trichinella on a macro scale. The identification of species in countries and continents otherwise considered Trichinella-free has raised questions regarding host adaptation and associations, and advanced important findings on the biogeographical histories of its members. Using past reviews as a backdrop, we have ventured to present an up-to-date assessment of the taxonomy, phylogenetic relationships and epidemiology of the genus Trichinella with additional insights on host species, survival strategies in nature and the shortcomings of our current understanding of the epidemiology of the genus. In addition, we have begun compiling information available to date on genomics, proteomics, transcriptomics and population studies of consequence in the hope we can build on this in years to come. PMID- 23816801 TI - Epigenomic control of the innate immune response. AB - Toll-like receptors (TLRs) play important roles in initiation of innate immune responses and promotion of pathological forms of inflammation. Recent technological advances have enabled the visualization of transcription factor binding and histone modifications in response to TLR signaling at genome-wide levels. Findings emerging from these studies are beginning to provide a picture of how signal-dependent transcription factors regulate the inflammatory response in a cell-specific manner by controlling the recruitment of nucleosome remodeling factors and histone modifying enzymes. Of particular interest, new small molecule inhibitors have been developed that influence inflammatory responses by altering the reading or erasure of histone modifications required for inflammatory gene activation. These findings suggest new approaches for treatment of inflammatory diseases. PMID- 23816803 TI - Effects of combined treatment with ambroxol and ciprofloxacin on catheter associated Pseudomonas aeruginosa biofilms in a rat model. AB - BACKGROUND: Pseudomonas aeruginosa is an opportunistic pathogen that causes potentially devastating infections in immunocompromised patients. These infections are particularly difficult to treat if a biofilm forms, which is likely if foreign bodies are present. OBJECTIVE: This study aimed to investigate the effect of ambroxol combined with ciprofloxacin on P. aeruginosa biofilm in a rat model. METHODS: A rat model of acute lung infection was created by endotracheal (ET) intubation with a tube covered with a P. aeruginosa biofilm. The rats were treated with ciprofloxacin alone, ambroxol alone, or a combination of both for 7 days. The microstructure of the biofilm on the tube was assessed by scanning electron microscopy (SEM). The numbers of bacterial colonies in the lungs and on the ET tube were measured on agar plates. Pathological changes in the lungs were observed with hematoxylin and eosin staining. RESULTS: Changes in the microstructure of the biofilm after combined treatment were demonstrated by SEM. Ambroxol combined with ciprofloxacin significantly reduced the number of bacteria in the lungs and ET tube compared to the single treatments (p < 0.05). The pathological changes in the lungs were also mildest after the combined treatment. CONCLUSION: The combination treatment of ambroxol with ciprofloxacin has a high ability to eradicate P. aeruginosa biofilms in vivo. These initial results provide the basis of a new strategy for the treatment of P. aeruginosa infections. PMID- 23816804 TI - Development of a novel antimicrobial film based on chitosan with LAE (ethyl N(alpha)-dodecanoyl-l-arginate) and its application to fresh chicken. AB - Chitosan (CS) films incorporating the antimicrobial compound ethyl-N(alpha) dodecanoyl-l-arginate (LAE) were developed for food packaging applications. Cast chitosan films were made with 1, 5 or 10% LAE and 20% glycerol in the film forming solution. Optical properties, release of LAE and antimicrobial activity of developed films was determined. The minimum inhibitory concentration (MIC) and the minimum biocide concentration (MBC) of LAE were determined. CS films with LAE were transparent and uniform, without discontinuities or visible particles and no visual differences could be perceived between CS and CS-LAE films. When in contact with an aqueous food simulant, the agent was fully released following a Fickian behavior in a few hours at 4 and 28 degrees C. Antimicrobial activity of films against mesophiles, psychrophiles, Pseudomonas spp., colifoms, lactic acid bacteria, hydrogen sulfide-producing bacteria, yeast and fungi, was evaluated at two, six and eight days for its application on chicken breast fillets. Films were active against bacteria, yeasts and fungi in liquid and solid media. CS films evidenced antimicrobial activity in the range 0.47-2.96 log reductions, while CS 5%LAE film produced 1.78-5.81 log reduction. Results highlighted that LAE incorporation in a chitosan-based packaging structure may provide a relevant antimicrobial activity that could improve the stability of fresh poultry products. PMID- 23816805 TI - Self-limited effusion large B-cell lymphoma: two cases of effusion lymphoma maintaining remission after drainage alone. AB - We report two cases of human herpesvirus-8 (HHV-8)-negative large B-cell lymphoma involving pericardial and/or pleural effusion that regressed after drainage alone. Case 1 is a 70-year-old man showing massive pericardial effusion. Cytology of the drained effusion showed monotonous infiltration of CD3-, CD20+, CD79a+, and CD138- large B-cells. Monoclonality was shown by Southern blot analysis. Case 2 is a 70-year-old man with massive pericardial and bilateral pleural effusion. Cytology of pericardial effusion showed infiltration of CD20+, CD45RO-, CD138-, immunoglobulin lambda chain+, and kappa chain- large B cells. In both cases, effusion resolved after drainage and no relapse has been observed. HHV-8 was not demonstrated in either case. Clinical presentation of our two cases resembled primary effusion lymphoma (PEL), but cytomorphology, immunophenotype, and prognosis were clearly distinct from those of PEL. HHV-8-negative effusion lymphomas might include prognostically favorable self-limited tumors that could regress without any cytotoxic therapy. PMID- 23816806 TI - The road against fatalities: infrastructure spending vs. regulation?? AB - The road safety literature is typified by a high degree of compartmentalization between studies that focus on infrastructure and traffic conditions and those devoted to the evaluation of public policies and regulations. As a result, few studies adopt a unified empirical framework in their attempts at evaluating the road safety performance of public interventions, thus limiting our understanding of successful strategies in this regard. This paper considers both types of determinants in an analysis of a European country that has enjoyed considerable success in reducing road fatalities. After constructing a panel data set with road safety outcomes for all Spanish provinces between 1990 and 2009, we evaluate the role of the technical characteristics of infrastructure and recent infrastructure spending together with the main regulatory changes introduced. Our results show the importance of considering both types of determinants in a unified framework. Moreover, we highlight the importance of maintenance spending given its effectiveness in reducing fatalities and casualties in the current economic context of austerity that is having such a marked impact on investment efforts in Spain. PMID- 23816807 TI - Food from earth: sustainable farming in action. PMID- 23816808 TI - A hybrid approach to determining cornea mechanical properties in vivo using a combination of nano-indentation and inverse finite element analysis. AB - An analysis of the material properties of porcine corneas has been performed. A simple stress relaxation test was performed to determine the viscoelastic properties and a rheological model was built based on the Generalized Maxwell (GM) approach. A validation experiment using nano-indentation showed that an isotropic GM model was insufficient for describing the corneal material behaviour when exposed to a complex stress state. A new technique was proposed for determining the properties, using a combination of nano-indentation experiment, an isotropic and orthotropic GM model and inverse finite element method. The good agreement using this method suggests that this is a promising technique for measuring material properties in vivo and further work should focus on the reliability of the approach in practice. PMID- 23816809 TI - Angiographic and clinical characteristics according to intracoronary acetylcholine dose in patients with myocardial bridge. AB - OBJECTIVES: It is well known that myocardial bridge (MB) is a risk factor of vasospastic angina. However, clinical and angiographic characteristics according to different acetylcholine (ACh) dose in patients with MB are not clarified yet. METHODS: A total 483 consecutive patients who had angiographically proven MB underwent the intracoronary ACh provocation test. ACh was injected by incremental doses of 20, 50 and 100 MUg into the left coronary artery. We evaluated the clinical and angiographic characteristics of patients with MB according to 3 different ACh doses. RESULTS: The baseline clinical and procedural characteristics are well balanced among the three groups. The MB patients who responded to the lower ACh dose (20 MUg) had higher incidence of baseline spasm, severe vasospasm and diffuse long spasms (>30 mm) than those who responded to the higher doses (50 and 100 MUg). The incidence of 12-month mortality and recurrent chest pain was higher in the lower ACh dose group (20 MUg). CONCLUSION: The patients with MB significantly reacting at the low ACh dose had more pronounced baseline spasm, severe and diffuse long coronary artery spasm, higher 12-month mortality and recurrent chest pain than those reacting with the higher ACh doses, suggesting that more intensive medical therapy will be required. PMID- 23816810 TI - FAST-Mag protocol with or without mild hypothermia (35 degrees C) does not improve outcome after permanent MCAO in rats. AB - The current study assessed the neuroprotective efficacy of magnesium using a FAST Mag trial treatment protocol alone, and in combination with mild hypothermia, in Sprague Dawley rats subjected to permanent, middle cerebral artery occlusion (MCAO). Treatment with magnesium (MgSO4.7H2O) consisted of an intravenous loading dose (LD: 360 MUmol/kg) and a 24 hour infusion (120 MUmol/kg/h), while mild hypothermia at 35 degrees C was maintained for 24 hours. Treatment groups consisted of animals receiving: i) saline; ii) magnesium LD/infusion at 1.5 h/2.5 h post-MCAO; iii) magnesium LD/infusion at 1.5 h/2.5 h post-MCAO and hypothermia commencing at 2.5 h post-MCAO; iv) magnesium LD and hypothermia at 1.5 h and magnesium infusion at 2.5 h post-MCAO; v) hypothermia commencing at 1.5 h post MCAO and magnesium LD/infusion at 2.5 h post-MCAO; and vi/vii) hypothermia commencing at 1.5 h or 2.5 h post-MCAO. No treatment significantly reduced infarct volumes or improved adhesive tape removal time when measured 48 hours after MCAO. These findings indicate that FAST-Mag treatment alone or with mild hypothermia may not provide benefit after ischemic stroke, associated with permanent cerebral artery occlusion. PMID- 23816811 TI - Management of brain metastases from germ cell tumors: a single center experience. AB - BACKGROUND: Brain metastases from germ cell tumors (GCT) are rare and treatment has not yet been standardized. METHODS: The clinical data of men with brain metastases from GCT treated in a single cancer hospital from January 1993 to September 2007 were reviewed. Patients with primary central nervous system GCT were excluded. RESULTS: Thirteen patients had brain metastases at initial diagnosis. All patients received cisplatin-based chemotherapy. Three also received radiotherapy and 1 underwent surgery. Eight of the patients died. Median survival was 19 months (95% CI 0.84-not reached). Twenty-two patients developed brain metastases at recurrence. Median time from initial diagnosis to brain metastases was 8.25 months (3-17.5 months). Five patients received radiotherapy alone, 3 received chemotherapy alone and 3 received supportive care only. Nine patients were operated on: 6 received postoperative chemotherapy and 1 received postoperative radiotherapy. Only 1 patient is still alive. Median survival was 5.1 months (95% CI: 2.2-10.5 months). CONCLUSIONS: Patients with GCT who present with brain metastases at diagnosis tend to do better than patients who develop them at relapse. Chemotherapy can be adequate treatment for initial brain metastases. Treatment for patients with brain metastases at relapse is still not optimal. PMID- 23816812 TI - Single-cell lysis for visual analysis by electron microscopy. AB - The stochastic nature of biological systems makes the study of individual cells a necessity in systems biology. Yet, handling and disruption of single cells and the analysis of the relatively low concentrations of their protein components still challenges available techniques. Transmission electron microscopy (TEM) allows for the analysis of proteins at the single-molecule level. Here, we present a system for single-cell lysis under light microscopy observation, followed by rapid uptake of the cell lysate. Eukaryotic cells were grown on conductively coated glass slides and observed by light microscopy. A custom designed microcapillary electrode was used to target and lyse individual cells with electrical pulses. Nanoliter volumes were subsequently aspirated into the microcapillary and dispensed onto an electron microscopy grid for TEM inspection. We show, that the cell lysis and preparation method conserves protein structures well and is suitable for visual analysis by TEM. PMID- 23816813 TI - Antidepressant-like effect of alpha-tocopherol in a mouse model of depressive like behavior induced by TNF-alpha. AB - Taking into account that pro-inflammatory cytokines and oxidative and nitrosative stress are implicated in the pathogenesis of depression and that alpha-tocopherol has antidepressant, anti-inflammatory and antioxidant properties, this study investigated the ability of alpha-tocopherol to abolish the depressive-like behavior induced by i.c.v. administration of TNF-alpha in the mouse TST. Additionally, we investigated the occurrence of changes in the levels of Bcl2 and Bax and phosphorylation of GSK-3beta (Ser9) in the hippocampus of mice. The administration of TNF-alpha (0.001fg/site, i.c.v.) increased the immobility time in the TST, which was prevented by the administration of alpha-tocopherol at the doses of 10, 30 and 100mg/kg (p.o.). Subeffective doses of alpha-tocopherol (10mg/kg, p.o.) and/or the antidepressants fluoxetine (5mg/kg, p.o.), imipramine (0.1mg/kg, p.o.) and bupropion (1mg/kg, p.o.), the NMDA receptor antagonist MK 801 (0.001mg/kg, p.o.) or the neuronal nitric oxide synthase inhibitor 7 nitroindazole (25mg/kg, i.p.) prevented the depressive-like effect induced by TNF alpha. None of the treatments altered the locomotor activity of mice. Treatment with TNF-alpha and/or alpha-tocopherol did not alter the levels of Bax and Bcl2 or the phosphorylation of GSK-3beta in the hippocampus of mice. Together, our results show a synergistic antidepressant-like effect of alpha-tocopherol with antidepressants against the depressive-like behavior induced by an inflammatory insult, suggesting that this vitamin may be useful to optimize conventional pharmacotherapy of depression, including depressive states associated with inflammatory conditions. PMID- 23816814 TI - Randomized double-blind study of prophylactic treatment with an antihistamine for seasonal allergic rhinitis. AB - BACKGROUND: The efficacy of prophylactic treatment before the start of pollen dispersal for prevention of aggravation of symptoms is unclear. The aim of the present study was to examine the efficacy of prophylactic treatment with an antihistamine for seasonal allergic rhinitis (SAR) using an environmental challenge chamber (ECC). METHODS: The study was performed in a randomized double blind manner with a 3-way crossover design. The subjects were 50 patients with SAR caused by Japanese cedar pollen who were randomized for treatment with levocetirizine hydrochloride 5 mg (Xyzal(r)) or placebo as follows: administration of placebo for 8 days (treatment A), single administration of levocetirizine on day 8 after placebo for 7 days (treatment B) or administration of levocetirizine for 8 days (treatment C). Efficacy in each treatment arm was evaluated based on cedar pollen exposure for 3 h on day 9 in an ECC, following 1 hour exposure on day 8. The primary endpoint was the total nasal symptom score for 12 h on day 9. Other nasal and ocular symptoms were secondary endpoints. RESULTS: The evaluation was performed in 45 subjects. The total nasal symptom score on day 9 was significantly lower with treatment B compared with treatment A. Treatment C did not show superior efficacy compared with treatment B. CONCLUSIONS: Our results suggest that early intervention with levocetirizine soon after onset of symptoms may attenuate these symptoms as effectively as prophylactic treatment before pollen dispersal. These results are important from the perspective of patient convenience and reduction of medical costs. PMID- 23816815 TI - Efficacy and safety of tadalafil monotherapy for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a meta-analysis. AB - OBJECTIVE: To evaluate the efficacy and safety of tadalafil monotherapy for lower urinary tract symptoms secondary to benign prostatic hyperplasia (LUTS/BPH). METHODS: A comprehensive search was done to identify randomized controlled trials comparing the efficacy and safety of tadalafil for LUTS/BPH with placebos. Meta analytical techniques were applied to evaluate the differences in the study results. RESULTS: Eight studies were identified and analyzed. Compared with placebo, tadalafil was associated with significant improvements in the International Prostate Symptom Score (IPSS) (mean difference = -2.19, p < 0.00001) and the International Index of Erectile Function (IIEF) score (mean difference = +4.66, p < 0.00001), despite the concomitant presence of erectile dysfunction. Significant differences were also observed in the IPSS irritative and obstructive subscores, IPSS quality of life index and BPH impact index. After pooling four doses (2.5, 5, 10 and 20 mg), tadalafil failed to produce a significant outcome in maximal urinary flow rate (Qmax) (mean difference = +0.26 ml/s, p = 0.14), but 5 mg of tadalafil significantly improved Qmax (mean difference = +0.63 ml/s, p = 0.04). No significant difference was detected in the incidence of serious adverse events (risk ratio = 1.00, p = 1.00) after tadalafil treatment. CONCLUSIONS: Tadalafil showed good efficacy and safety for improving LUTS and erectile dysfunction in men with BPH, and 5 mg of tadalafil significantly improved Qmax. PMID- 23816816 TI - Casticin induces human glioma cell death through apoptosis and mitotic arrest. AB - BACKGROUND: Malignant gliomas are the leading cause of morbidity and mortality in brain and central nervous system tumors. Recently, casticin has drawn wide attention to its critical role in tumor progression. However, the effect of casticin on glioma remains undefined. METHODS: Following treatment with casticin, cell viability, apoptosis, and cell cycle arrest were examined in U251 glioma cells. Additionally, the involved molecular mechanism was assessed by western blotting and flow cytometry. RESULTS: Casticin triggered an obvious dose dependent decrease in U251, U87 and U373 glioma cell viability, and the growth inhibitory effect of casticin was correlated with cell cycle arrest and cell apoptosis. Further mechanistic analysis indicated that casticin induced G2/M phase arrest by attenuating the polymerization of tubulin. Furthermore, striking apoptosis was also confirmed, accompanied by the up-regulation of caspase-3, p53 and proapoptotic protein Bax. These effects were absent when the caspase inhibitor z-VAD-fmk or p53 inhibitor PFTalpha were applied, suggesting that casticin could trigger cell apoptosis in a caspase-3 and p53-dependent manner. CONCLUSION: These findings provide a prominent insight into how casticin abrogates the pathogenesis of glioma, and support its potential clinical prospect for further development of anti-brain cancer therapy. PMID- 23816817 TI - Interactions among bone, liver, and adipose tissue predisposing to diabesity and fatty liver. AB - Growing epidemiological evidence connects obesity and its complications, including metabolic syndrome, diabetes, and nonalcoholic fatty liver disease (NAFLD) to reduced bone health and osteoporosis. Parallel to human studies, experimental data disclosed a complex network of interaction among adipose tissue, the liver, and the bone, which reciprocally modulate the function of each other. The main mediators of such crosstalk include hormonal/cytokine signals from the bone (osteopontin, osteocalcin, and osteoprotegerin), the liver (fetuin A), and adipose tissue [leptin, tumor necrosis factor-alpha (TNF-alpha), and adiponectin]. Dysregulation of this network promotes the development of diabesity, NAFLD, and osteoporosis. We will review recent advances in understanding the mechanisms of bone-liver-adipose tissue interaction predisposing to obesity, diabetes, NAFLD, and osteoporosis and their potential clinical implications. PMID- 23816818 TI - Acute promyelocytic leukemia with Flt3-TKD and WT1 mutations relapsing in a testicle and followed by systemic relapse. AB - Extramedullary relapse is a rare phenomenon in patients with acute promyelocytic leukemia (APL), especially that derived from urogenital systems like the testicles. In this report, we describe an APL patient who had received standard induction/maintenance therapy resulting in durable remission for 4.5 years, when he presented with a unilateral testicular mass confirmed as myeloid sarcoma; this was followed by systemic relapse of APL. Retrospective analysis of the involved blood and bone marrow samples at the time of the initial diagnosis revealed a rare point mutation of FLT3-TKD and a novel mutation of WT1. These mutations were detected recurrently throughout the course of the disease. After reinduction therapy with arsenic trioxide and all-trans retinoic acid combined with daunorubicin, complete hematological remission was achieved for the ensuing salvage allogeneic hematopoietic stem cell transplant. PMID- 23816819 TI - The role of CT pulmonary angiography in the investigation of unilateral pleural effusions. AB - BACKGROUND: Pulmonary embolism (PE) is frequently cited as a common primary cause of unilateral pleural effusion, but in clinical practice appears to be uncommon. OBJECTIVES: In order to evaluate this observation, CT pulmonary angiography (CTPA) was performed in consecutive patients presenting to a single centre with a new uninvestigated unilateral pleural effusion and no clear cause and was supplemented by delayed-phase thoracic CT, optimized for visualization of the pleura. METHODS: All patients underwent standard clinical assessment and pleural investigations in line with recent national guidelines and were followed up for a minimum of 1 year or until histological/microbiological diagnosis. RESULTS: One hundred and fifty patients were recruited, and of these, 141 had a CTPA. PEs were detected in 9/141 (6.4%) patients, and of these, 8/9 were subsequently diagnosed with pleural malignancy. In only 1 case was PE clinically suspected and in no case was PE the primary cause of effusion; 9.8% (8/82) of patients who were ultimately diagnosed with pleural malignancy had PE at presentation. CONCLUSIONS: This study indicates that PE is a frequent concomitant finding in patients with malignant effusions but uncommon as a primary cause of unilateral effusion. In addition, it highlights the known difficulty of clinical diagnosis of PE in the context of malignancy. In view of this, we recommend that CTPA combined with pleural-phase thoracic CT should be considered at presentation when investigating patients with suspected malignant pleural effusion. PMID- 23816820 TI - Application of plant derived compounds to control fungal spoilage and mycotoxin production in foods. AB - Food decay by spoilage fungi causes considerable economic losses and constitutes a health risk for consumers due to the potential for fungi to produce mycotoxins. The indiscriminate use of synthetic antifungals has led to the development of resistant strains which has necessitated utilization of higher concentrations, with the consequent increase in toxic residues in food products. Numerous studies have demonstrated that plant extracts contain diverse bioactive components that can control mould growth. The metabolites produced by plants are a promising alternative because plants generate a wide variety of compounds, either as part of their development or in response to stress or pathogen attack. The aim of this article is to summarize the results from the literature on in vitro and in vivo experiments regarding the effects of plant-derived products for controlling fungal growth. Data from research work on the mode of action of these metabolites inside the fungal cell and the influence of abiotic external factors such as pH and temperature are also covered in the present review. Furthermore, an analysis on how the stress factor derived from the presence of plant extracts and essential oils affects secondary metabolism of the fungus, specifically mycotoxin synthesis, is developed. Finally, the effectiveness of using plant-derived compounds in combination with other natural antimicrobials and its application in food using novel technologies is discussed. PMID- 23816821 TI - Emerging dangers: deadly effects of an emergent parasite in a new pollinator host. AB - There is growing concern about the threats facing many pollinator populations. Emergent diseases are one of the major threats to biodiversity and a microsporidian parasite, Nosema ceranae, has recently jumped host from the Asian to the Western honeybee, spreading rapidly worldwide, and contributing to dramatic colony losses. Bumblebees are ecologically and economically important pollinators of conservation concern, which are likely exposed to N. ceranae by sharing flowers with honeybees. Whilst a further intergeneric jump by N. ceranae to infect bumblebees would be potentially serious, its capacity to do this is unknown. Here we investigate the prevalence of N. ceranae in wild bumblebees in the UK and determine the infectivity of the parasite under controlled conditions. We found N. ceranae in all seven wild bumblebee species sampled, and at multiple sites, with many of the bees having spores from this parasite in their guts. When we fed N. ceranae spores to bumblebees under controlled conditions, we confirmed that the parasite can infect bumblebees. Infections spread from the midgut to other tissues, reduced bumblebee survival by 48% and had sub-lethal effects on behaviour. Although spore production appeared lower in bumblebees than in honeybees, virulence was greater. The parasite N. ceranae therefore represents a real and emerging threat to bumblebees, with the potential to have devastating consequences for their already vulnerable populations. PMID- 23816822 TI - Podoplanin and clusterin are reliable markers of nonneoplastic synovium at various sites. AB - INTRODUCTION: Clusterin (CLU) has been noted to mark synovium adjacent to tenosynovial tumors, and studies suggest that podoplanin (PP) is upregulated in inflammatory arthritis. Characterization of synovial staining with CLU and PP in various nonneoplastic disease states has not been described. METHODS: A microarray was created from paraffin-embedded human synovium, including 19 normal/noninflammatory (10 weight-bearing joints, 8 non-weight-bearing joints), 9 rheumatoid arthritis, 10 synovial cysts, and 3 osteoarthritis and stained with PP (D2-40) and CLU. Staining intensity was graded semiquantitatively (0-3+). RESULTS: PP and CLU stained synovium in 88% and 95% cases, respectively. PP and CLU showed moderate to strong (3+) staining in 26% and 19% of noninflammatory and 44% and 0% of inflammatory synovia, respectively (P < .01). CONCLUSIONS: PP and CLU are reliable markers of human synovium and can confirm its presence in limited specimens. Although CLU was more sensitive, PP may be more useful in the setting of chronic inflammation. PMID- 23816823 TI - Renal Anastomosing Hemangiomas With a Diverse Morphologic Spectrum: Report of Two Cases and Review of Literature. AB - Benign vascular lesions have a diverse appearance and can be extremely difficult to classify. We present renal anastomosing hemangiomas from 2 patients that exemplify the potential diverse range of appearances that can occur in this recently described, rare variant of capillary hemangioma. The lesion from one patient was an intravenous hemangioma with closely packed, fenestrated vascular channels that were reminiscent of the splenic red pulp. Also, the endothelial cells contained hyaline globules. On the other hand, the second patient had multifocal tumor. The lesions showed more extensive hyalinization and vascular ectasia reminiscent of cavernous hemangioma. Extramedullary hematopoiesis was a feature in all the tumors, particularly in the second patient where numerous immature blasts were present within vascular spaces. PMID- 23816824 TI - Pediatric renal solitary fibrous tumor: report of a rare case and review of the literature. AB - Solitary fibrous tumors (SFTs) are unusual spindle cell neoplasms initially described in the pleura but have since been discovered in many extrapleural locations. SFT of the kidney is extremely rare, the majority occurring in middle aged adults. To date, only two pediatric cases of renal SFT have been reported. We report a case of large SFT in the kidney of a 3-year-old boy that was clinically and radiologically thought to be a nephroblastoma. This case is the first pediatric renal SFT to be reported with detailed histopathologic and cytogenetic analyses. SFT should be included in the differential diagnosis of pediatric renal tumors. PMID- 23816825 TI - Transitional cell carcinoma of the retrorectal space arisen in tailgut cyst: a case report and review of the literature. AB - Tailgut cysts, also known as retrorectal cystic hamartomas, are congenital lesions derived by an abnormal remnant of the postanal primitive hindgut, consisting of unilocular or multilocular cysts usually lined by squamous, transitional, or glandular epithelium. Malignant transformation is an uncommon event, and it mainly involves the neuroendocrine or glandular epithelium; other histotypes are sporadic. Here, we report, for the first time, the clinicopathological features of a transitional cell carcinoma that arose in a tailgut cyst. PMID- 23816826 TI - Nanosilver: weighing the risks and benefits. PMID- 23816827 TI - Apoptosis and abundance of Bcl-2 family and transforming growth factor beta1 signaling proteins in canine myxomatous mitral valves. AB - OBJECTIVES: To determine the percentage of cells undergoing apoptosis within canine myxomatous valves and to evaluate whether TGFbeta1 can be implicated as an anti-apoptosic signal through the Bcl-2 family of signaling proteins. ANIMALS: Post-mortem mitral valve leaflets harvested from 5 normal dogs, 5 dogs with early stage myxomatous mitral valve disease (MMVD), and 5 dogs with late-stage MMVD. MATERIALS AND METHODS: The number of cells expressing cleaved caspase-3, DNA fragmentation (TUNEL marker) and apoptotic bodies were evaluated as a measure of apoptosis. To evaluate the relationship between TGFbeta1 signaling and apoptosis, the abundance of activated TGFbeta1 signaling protein, phosphorylated Smad 2/3 (p Smad 2/3), and Bcl-2 family proteins (pro-apoptotic Bax and anti-apoptotic Bcl-2) was determined by immunohistochemistry. RESULTS: Cells in normal and both stages of MMVD expressed the TUNEL marker and cleaved caspase-3, but not apoptotic bodies. The percentage of TUNEL marker and cleaved caspase-3 positive nuclei was not significantly different between groups of dogs (p > 0.05). P-Smad 2/3 and Bax were more abundant in myxomatous mitral valves while Bcl-2 was less abundant. P Smad 2/3 primarily increased in the atrialis layer and was abundantly increased only in late-stage MMVD. CONCLUSIONS: These data suggest that interstitial cells in MMVD are in a pro-apoptotic condition; however, they do not execute apoptosis. Thus, apoptosis does not explain differences in cellular density in canine MMVD. TGFbeta1 signaling through the canonical SMAD pathway is increased in myxomatous mitral valves, but does not apparently mediate interstitial cell apoptosis in canine MMVD. PMID- 23816828 TI - A study of inflammation-based predictors of tumor response to neoadjuvant chemoradiotherapy for locally advanced rectal cancer. AB - BACKGROUND: The ability of pretreatment laboratory markers of acute-phase inflammatory reactions like serum albumin level (SAL), hemoglobin (Hb), and absolute blood cell counts to predict complete pathological response (CPR) to neoadjuvant chemoradiotherapy (NACRT) in patients with locally advanced rectal cancer (LARC) has not yet been fully studied. METHODS: We retrospectively examined the relation between SAL, Hb and absolute blood cell counts, and CPR rates in 140 LARC patients treated with NACRT. RESULTS: Univariate analysis showed a significantly higher probability of CPR to NACRT in patients with clinical stage (CS) III LARC who had SAL >3.5 mg/dl (OR = 2.39; p = 0.04) and a neutrophil-to-lymphocyte ratio (NLR) value <5 (OR = 2.86; p = 0.03). The relation of CPR with SAL (OR = 2.11; p = 0.048) and NLR (OR = 2.54; p = 0.04) was confirmed by multivariate analysis in the same subset of patients. None of the parameters studied predicted CPR in patients with CS II disease. Patients who achieved CPR to NACRT had a higher probability of 5-year overall survival (HR 0.48; p = 0.01) and 5-year disease-free survival (HR 0.33; p = 0.003). CONCLUSIONS: Our data indicate that SAL >3.5 mg/dl and NLR <5 may be positively related to CPR after NACRT in patients with CS III LARC. Hypoalbuminemia and a high NLR may be considered an indication for a more aggressive approach to NACRT and postoperative adjuvant chemotherapy in this subset of patients. This hypothesis requires confirmation in a randomized study. PMID- 23816829 TI - Magnesium deficiency regulates vitamin D metabolizing enzymes and type II sodium phosphate cotransporter mRNA expression in rats. AB - A magnesium (Mg) deficiency induces changes in calcium (Ca) and phosphorus (P) metabolism; however, the mechanisms responsible for these effects remain unclear. Since 1,25-dihydroxyvitamin D3 and type II sodium-phosphate (Na/Pi) cotransporters are essential regulators of Ca and P metabolism, this study examined the effects of Mg deficiency on the mRNA expression of vitamin D metabolizing enzymes (25-hydroxyvitamin D-1alpha-hydroxylase (1alpha(OH)ase) and 25-hydroxyvitamin D-24-hydroxylase (24(OH)ase)), and Na/Pi cotransporters (type IIa and IIc) in the rat kidney. Rats were divided into two groups and fed a control diet (Mg concentration: 0.05%) or a Mg-deficient diet (Mg concentration: Mg-free) for 21 days. 1alpha(OH)ase mRNA levels were significantly decreased in rats fed the Mg-deficient diet, while 24(OH)ase mRNA levels were significantly increased, compared to rats fed the control diet. Type IIa and IIc Na/Pi cotransporter mRNA levels in rats fed the Mg-deficient diet were significantly decreased compared to rats fed the control diet. These results suggest that Mg deficiency induces downregulation of 1alpha(OH)ase and type IIa and IIc Na/Pi cotransporters, and upregulation of 24(OH)ase in the kidney. PMID- 23816830 TI - A case of severe Rh (D) alloimmunization pregnant woman delivery an infant with limited treatment. AB - A 35-year-old woman with histories of frequent failed pregnancies was pregnant after having five plasma exchange procedures during which she was given Rh (D) positive plasma as replacement and her anti-D antibody titer went from 512 to 1024. Antenatal surveillance of the fetus showed no abnormality. At 36 weeks gestation she delivered an infant who initially had no significant clinical problems but was severely anemic on the following days. Using exchange transfusion and blood transfusions the infant's hemoglobin was normal at 4 months of age. Thus, the Rh (D) status of donor plasma should be considered when used as the replacement in plasma exchange for Rh (D) negative women. Severe Rh (D) alloimmunization pregnant woman may delivery an infant who seem in good condition at birth. If severe Rhesus isoimmunisation of the infant is confirmed, whole blood exchange should be done as early as possible and the infant must be considered to be at risk for late anemia. Clinical judgment plays a vital role in the decision to transfuse red cells or not. PMID- 23816831 TI - Incidence and clinical significance of aberrant T-cell marker expression on diffuse large B-cell lymphoma cells. AB - INTRODUCTION: Aberrant expression of T-cell markers is occasionally observed in B cell lymphomas. We conducted a retrospective study to establish its incidence and to determine its relationship with clinical features of patients with diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS: We reviewed DLBCL patients diagnosed between January 2002 and April 2009. Patients fulfilled the following criteria: (1) age >18 years, (2) HIV negative, (3) B-cell lymphoma confirmed by restricted expression of surface immunoglobulin light chains by flow cytometry (FCM). Aberrant T-cell marker expression (ATCME) was defined as positivity for CD2, CD3, CD4, CD7, and/or CD8 on DLBCL cells by FCM. Phenotyping was also performed by immunohistochemistry (IHC). Patients were grouped according to positive or negative ATCME and their clinical features including survival were compared. RESULTS: Of 150 patients, 11 (7.3%) showed ATCME; CD2 and CD7 were most often expressed. ATCME was less often detected and the signal was weaker using IHC. There were no statistically significant differences in clinical features between the two groups. CONCLUSIONS: FCM may be useful to detect ATCME in a small amount of lymphoma cells. The mechanism responsible for ATCME, and whether it contributes in any way to the pathogenesis of B-cell neoplastic transformation, requires clarification. PMID- 23816832 TI - gamma-Tocotrienol induced cell cycle arrest and apoptosis via activating the Bax mediated mitochondrial and AMPK signaling pathways in 3T3-L1 adipocytes. AB - This study aimed to examine the anti-proliferative effects of alpha-, gamma- and delta-tocotrienols (alphaT3, gammaT3 and deltaT3), and alpha-tocopherol on 3T3-L1 adipocytes. Results showed that compared with other vitamin E analogues, gammaT3 demonstrated the most potent anti-proliferative effect on 3T3-L1 cells. It significantly caused a reduction in mitochondrial membrane potential (Deltapsim) and an increase in ROS formation, as well as inducing cell apoptosis and cell cycle arrest at S phase. Further studies showed that it down-regulated Bcl-2 and PPAR-gamma expression, suppressed Akt and ERK activation and phosphorylation, and caused cytochrome c release from mitochondria to cytosol, whereas it up-regulated CD95 (APO-1/CD95) and Bax expression, and caused caspase-3 and JNK activation, PARP cleavage and AMPK phosphorylation. Pretreatments with caspase-3 (z-DEVD-fmk) and AMPK (CC) inhibitors significantly suppressed the gammaT3-induced ROS production and cell death. Caspase-3 inhibitor also efficiently blocked CD95 (APO 1/CD95) and Bax expression, caspase-3 activation and PARP cleavage, whereas antioxidant N-acetyl-l-cysteine, AMPK inhibitor and AMPK siRNA effectively blocked the AMPK phosphorylation. Taken together, these results conclude that the potent anti-proliferative and anti-adipogenic effects of gammaT3 on 3T3-L1 adipocytes could be through the Bax-mediated mitochondrial and AMPK signaling pathways. PMID- 23816833 TI - Scientific evaluation of the subchronic toxicity of Musca domestica larvae extracts in Sprague Dawley rats. AB - Musca domestica larvae extracts (MDLE) is a potential drug used to treat lipopolysaccharide-induced atherosclerosis pro-inflammatory responses. The purpose of the study was to evaluate the safety of MDLE via a 13-week repeated dose subchronic toxicity test in rats. Both male and female Sprague Dawley rats were divided into four groups, eight animals each from the control and high-dose group (33.0 g/kg) were allocated into recovery groups. The four groups of rats were administrated with MDLE (0, 13.2, 22.0, 33.0 g/kg) in the diet for 13weeks respectively. During the experimental period, the rats were observed for symptoms and signs of gross toxicity daily, food consumption and body weight were measured weekly. Urinalysis, thrombotest, blood biochemical and hematological analyses were performed regularly; Expression of peroxide dismutase gene in liver was quantified and a histopathological examination was also performed. There were no MDLE-induced abnormalities in any of the groups during or after the 13 weeks except the relative weight of liver of high-dose group and middle-dose group was significantly higher than that of control group in male rats (P<0.05). The results indicate a no observed adverse effect level for MDLE is 13.2 and 33.0 g/kg bw/day in male and female rats, respectively. PMID- 23816834 TI - Acute encephalopathy with unilateral cortical-subcortical lesions in two unrelated kindreds treated with glucocorticoids prenatally for congenital adrenal hyperplasia due to 21-hydroxylase deficiency: established facts and novel insight. AB - BACKGROUND: Prenatal glucocorticoid (GC) treatment of the female fetus with 21 hydroxylase deficiency (21-OHD) may prevent genital virilization and androgen effects on the brain, but prenatal GC therapy is controversial because of possible adverse effects on fetal programming, the cardiovascular system and the brain. CASE REPORTS: We report 2 patients with congenital adrenal hyperplasia (CAH) due to 21-OHD who were treated prenatally with dexamethasone, suffered from an acute encephalopathy and showed focal and multifocal cortical and subcortical diffusion restrictions in early MRI and signs of permanent alterations in the follow-up neuroimaging studies. Both patients recovered from the acute episode. Whereas the first patient recovered without neurological sequelae the second patient showed hemianopsia and spastic hemiplegia in the neurological follow-up examination. CONCLUSION: These are 2 children with CAH, both treated prenatally with high doses of dexamethasone to prevent virilization. The question arises whether prenatal high-dose GC treatment in patients with CAH might represent a risk factor for brain lesions in later life. Adverse effects/events should be reported systematically in patients undergoing prenatal GC treatment and long term follow-up studies involving risk factors for cerebrovascular disease should be performed. PMID- 23816835 TI - Severe and morbid obesity in Crohn's disease patients: prevalence and disease associations. AB - BACKGROUND: Crohn's disease (CD) is frequently associated with weight loss and malnutrition. However, as the prevalence of obesity increases worldwide, it may become a clinical problem even in CD. AIM: To assess the prevalence of severe/morbid obesity in CD patients and to compare their disease characteristics to nonobese CD patients. METHODS: A retrospective analysis of a computerized CD patient database was performed to identify severely/morbidly obese patients (BMI >35). Prevalence was compared to data of the general population. Severely/morbidly obese CD patients were then compared to randomly selected nonobese CD patients (BMI <30) in a 1:3 ratio. RESULTS: Thirteen severely/morbidly obese patients out of 560 CD patients were found (2.3%), which is significantly lower than the prevalence in the general population (5.6%, p = 0.001). When compared to 39 nonobese CD patients, colonic disease was significantly more common among severely/morbidly obese CD patients (odds ratio: 6, 95% CI: 1.35-26.3, p = 0.02), while there was no difference in other disease parameters. Interestingly, 4 morbidly obese CD patients had undergone laparoscopic sleeve gastrectomy for treatment of morbid obesity with a favorable surgical course. CONCLUSION: CD in severely/morbidly obese patients is more often colonic, but otherwise no different than CD in nonobese patients. Sleeve gastrectomy is a viable therapeutic option for morbidly obese CD patients. PMID- 23816836 TI - 1alpha,25-Dihydroxycholecalciferol (Vitamin D3) induces NO-dependent endothelial cell proliferation and migration in a three-dimensional matrix. AB - BACKGROUND/AIMS: The 1alpha,25-dihydroxycholecalciferol (Vit. D) induces eNOS dependent nitric oxide (NO) production in human umbilical vein endothelial cells (HUVEC). To our knowledge, there are no reports directly relating Vit. D induced NO production to proliferation and/or migration in endothelial cells (EC). The aim of this study was to evaluate whether Vit. D addition to porcine EC could affect their proliferation and/or migration in a three-dimensional matrix via NO production. MATERIALS AND METHODS: Porcine aortic endothelial cells (PAE) were used to evaluate Vit. D effects on cell proliferation and migration in a three dimensional matrix. RESULTS: Vit. D induced NO production in PAE cells. Moreover, it induced a significant increase in cellular proliferation and migration in a three-dimensional matrix. These effects were NO dependent, as inhibiting eNOS activity by L-NAME PAE migration was abrogated. This effect was strictly related to MMP-2 expression and apparently dependent on Vit. D and NO production. CONCLUSIONS: Vit. D can promote both endothelial cells proliferation and migration in a three-dimensional matrix via NO-dependent mechanisms. These findings cast new light on the role of Vit. D in the angiogenic process, suggesting new applications for Vit. D in such fields as tissue repair and wound healing. PMID- 23816837 TI - Substrate specificity and oligomerization of human GMP synthetase. AB - Guanine monophosphate (GMP) synthetase is a bifunctional two-domain enzyme. The N terminal glutaminase domain generates ammonia from glutamine and the C-terminal synthetase domain aminates xanthine monophosphate (XMP) to form GMP. Mammalian GMP synthetases (GMPSs) contain a 130-residue-long insert in the synthetase domain in comparison to bacterial proteins. We report here the structure of a eukaryotic GMPS. Substrate XMP was bound in the crystal structure of the human GMPS enzyme. XMP is bound to the synthetase domain and covered by a LID motif. The enzyme forms a dimer in the crystal structure with subunit orientations entirely different from the bacterial counterparts. The inserted sub-domain is shown to be involved in substrate binding and dimerization. Furthermore, the structural basis for XMP recognition is revealed as well as a potential allosteric site. Enzymes in the nucleotide metabolism typically display an increased activity in proliferating cells due to the increased need for nucleotides. Many drugs used as immunosuppressants and for treatment of cancer and viral diseases are indeed nucleobase- and nucleoside-based compounds, which are acting on or are activated by enzymes in this pathway. The information obtained from the crystal structure of human GMPS might therefore aid in understanding interactions of nucleoside-based drugs with GMPS and in structure based design of GMPS-specific inhibitors. PMID- 23816839 TI - Ethnicity-specific birthweight distributions improve identification of term newborns at risk for short-term morbidity. AB - OBJECTIVE: We aimed to determine whether ethnicity-specific birthweight distributions more accurately identify newborns at risk for short-term neonatal morbidity associated with small for gestational age (SGA) birth than population based distributions not stratified on ethnicity. STUDY DESIGN: We examined 100,463 singleton term infants born to parents in Washington State between Jan. 1, 2006, and Dec. 31, 2008. Using multivariable logistic regression models, we compared the ability of an ethnicity-specific growth distribution and a population-based growth distribution to predict which infants were at increased risk for Apgar score <7 at 5 minutes, admission to the neonatal intensive care unit, ventilation, extended length of stay in hospital, hypothermia, hypoglycemia, and infection. RESULTS: Newborns considered SGA by ethnicity specific weight distributions had the highest rates of each of the adverse outcomes assessed-more than double those of infants only considered SGA by the population-based standards. When controlling for mother's age, parity, body mass index, education, gestational age, mode of delivery, and marital status, newborns considered SGA by ethnicity-specific birthweight distributions were between 2 and 7 times more likely to suffer from the adverse outcomes listed above than infants who were not SGA. In contrast, newborns considered SGA by population-based birthweight distributions alone were at no higher risk of any adverse outcome except hypothermia (adjusted odds ratio, 2.76; 95% confidence interval, 1.68 4.55) and neonatal intensive care unit admission (adjusted odds ratio, 1.40; 95% confidence interval, 1.18-1.67). CONCLUSION: Ethnicity-specific birthweight distributions were significantly better at identifying the infants at higher risk of short-term neonatal morbidity, suggesting that their use could save resources and unnecessary parental anxiety. PMID- 23816840 TI - In vitro fertilization and late preterm preschoolers' neuropsychological outcomes: the PETIT study. AB - OBJECTIVE: In vitro fertilization (IVF) is considered a generally safe procedure, although associated with a higher incidence of preterm birth. The literature is inconsistent about the psychological impact of IVF, and we found no reports about outcome in late preterm (LPT) children. Our objective was to study neuropsychological and behavioral outcomes in a cohort of preschoolers born LPT between 2004 and 2007. STUDY DESIGN: Participants were 397 LPT children (mean age, 3.8 years) conceived assisted by IVF (n = 105) or non-IVF (n = 292). Standardized performance-based tests of general conceptual ability (intelligence quotient), executive function, focused/selective attention, visual-spatial perception, visual-motor skill, manual dexterity, learning, and memory were administered. Parents completed behavioral and executive function questionnaires. RESULTS: IVF group characteristics included older maternal age (P < .001), lower birthweight (P < .001), and higher maternal education (P < .001). No main-effect significant group differences were found for any variable after controlling for these variables. However, sex differences were demonstrated for the neuropsychological variables in copying (P > .001), nonverbal reasoning (P = .001), manual dexterity (P = .001), and inhibitory capacity (P = .006), all favoring girls. CONCLUSION: Birth following IVF-assisted conception did not increase the risk of intellectual, neuropsychological, or behavioral deficit in LPT preschoolers. As shown in earlier gestational-age participants, girls have selective advantages. These findings should be reassuring for parents who conceive through IVF and deliver infants 1-3 weeks before term gestational age. Future study of these children at elementary school age may detect subtle impairments not yet apparent at age 3 years. PMID- 23816841 TI - WITHDRAWN: Discussion: 'Adherence to hormonal contraception among women veterans,' by Borrero et al. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, DOI of original article: http://dx.doi.org/10.1016/j.ajog.2013.06.032. The duplicate article has therefore been withdrawn. PMID- 23816838 TI - Guided by RNAs: X-inactivation as a model for lncRNA function. AB - The recent revolution in sequencing technology has helped to reveal a large transcriptome of long non-coding RNAs (lncRNAs). A major challenge in the years to come is to determine what biological functions, if any, they serve. Although the purpose of these transcripts is largely unknown at present, existing examples suggest that lncRNAs play roles in a wide variety of biological processes. Exemplary cases are lncRNAs within the X-inactivation center. Indeed, lncRNAs dominate control of random X-chromosome inactivation (XCI). The RNA-based regulatory mechanisms of XCI include recruitment of chromatin modifiers, formation of RNA-based subnuclear compartments, and regulation of transcription by antisense transcription. XCI and lncRNAs now also appear to be very relevant in the development and progression of cancer. This perspective focuses on new insights into lncRNA-dependent regulation of XCI, which we believe serve as paradigms for understanding lncRNA function more generally. PMID- 23816842 TI - Costs of unnecessary admissions and treatments for "threatened preterm labor". AB - OBJECTIVE: Cervical length (CL) of 3 cm or greater has been shown to have a 97 99% negative predictive value for preterm delivery in women with threatened preterm labor. Consequently, hospitalization and treatment are not indicated in these patients. We analyzed how often patients with a CL of 3 cm or greater are still being admitted and treated for preterm labor and how much this contributes to the economic burden of preterm labor hospitalizations. STUDY DESIGN: Twelve month hospitalizations for preterm labor at less than 34 weeks at a single institution were reviewed and patients with a CL of 3 cm or greater were identified. We chose to use patients' hospital charges as a surrogate for health care costs, recognizing that charges are not synonymous with the final patient bill and also do not reflect additional costs such as the cost of treatment at the referring facility, transportation, physician fees, and other such costs as lost wages, need for additional child care, etc. RESULTS: Between July 2009 and June 2010, 139 patients were admitted and treated for preterm labor at our level III center. Fifty of these patients (36%) had a CL of 3 cm or greater. None of them delivered preterm. Total hospital charges for the management of these patients were $1,018 589 (mean, $20,372; median, $14,444). CONCLUSION: Unnecessary admissions and treatments for threatened preterm labor are part of clinical practice and contribute to exploding health care costs. Using currently available diagnostics, these costs could be lowered significantly without jeopardizing outcome. PMID- 23816843 TI - Abnormal vaginal bleeding after epidural steroid injection: a paired observation cohort study. AB - OBJECTIVE: The use of epidural steroid injections has increased dramatically, but knowledge of potential adverse effects is lacking. An association between steroid injection and subsequent abnormal vaginal bleeding has been suspected clinically, but evidence has been limited to anecdotal reports. STUDY DESIGN: Paired observational retrospective cohort study using electronic medical records from a large integrated health care system. Participants were all nonhysterectomized women who underwent epidural steroid injections in 2011. For each steroid injection, encounters for abnormal vaginal bleeding during the 60 days preceding and 60 days after the injection were compared as paired observations. For women found to have bleeding, medical records review was performed to examine menopausal status and bleeding evaluation outcomes. RESULTS: Among 8166 epidural steroid injection procedures performed on 6926 nonhysterectomized women, 201 (2.5%) procedures were followed by at least 1 outpatient visit for abnormal vaginal bleeding. Women were 2.8 times more likely to present with abnormal vaginal bleeding during the postinjection period compared with the preinjection period (P < .0001). Of the 197 women with postinjection bleeding, 137 (70%) were premenopausal and 60 (30%) were postmenopausal. Postinjection bleeding prompted endometrial biopsy evaluation in 103 (52%) cases, with benign findings for 100% of premenopausal women (59/59) and 95% of postmenopausal women (42/44). CONCLUSION: Epidural steroid injections are associated with subsequent abnormal vaginal bleeding for both premenopausal and postmenopausal women. Women undergoing epidural steroid injection should be advised of abnormal bleeding as a potential adverse effect and providers should be aware of this association when evaluating abnormal bleeding. PMID- 23816845 TI - Use of the Bakri postpartum balloon in a patient with intractable pelvic floor hemorrhage: when other methods failed to stop postcesarean bleeding, physicians tried something new. AB - Massive pelvic floor hemorrhage is a potentially life-threatening condition associated with complicated obstetrical and gynecological procedures. Sometimes, the bleeding cannot be controlled by conventional methods. This report demonstrates the effectiveness of the Bakri balloon as a pelvic pressure pack for the control of intractable pelvic floor hemorrhage following cesarean section. PMID- 23816844 TI - Markedly different rates of incident insulin treatment based on universal gestational diabetes mellitus screening in a diverse HMO population. AB - OBJECTIVE: We sought to evaluate population gestational diabetes mellitus (GDM) screening results and risk for incident insulin treatment. STUDY DESIGN: Among 64,687 pregnant women universally screened for GDM from 1995 through 2010 in 2 regions of a large US health plan, we stratified women requiring insulin treatment during their pregnancy by GDM screening results (50-g glucose challenge test [GCT]), followed by a 3-hour, 100-g oral glucose tolerance test if GCT was positive. Women with GCT >200 mg/dL were evaluated separately. RESULTS: Overall, 2% of all pregnant women required insulin treatment, ranging from 0.1% (normal GCT) to 49.9% (GCT >200 mg/dL; P for trend < .0001). Women with GCT >200 mg/dL had a much higher rate of insulin treatment than women with GDM (odds ratio, 3.7; 95% confidence interval, 3.1-4.4). Risk factors for higher insulin treatment rates with GDM or GCT >200 mg/dL included obesity, race/ethnicity, and diagnosed <=16 weeks' gestation. CONCLUSION: Our results indicate women with GCT >200 mg/dL could be reasonably treated as GDM without requiring additional oral glucose tolerance test for diagnosis. PMID- 23816846 TI - Label-free detection of single-nucleotide polymorphisms associated with myeloid differentiation-2 using a nanostructured biosensor. AB - House dust mites are the major source of indoor allergens that are responsible for asthma. The major dust mite allergen is the group II allergen, Der p2. Myeloid differentiation-2 (MD-2) acts as an essential component in the CD14-TLR4 (toll-like receptor)/MD-2 receptor complex for Der p2 recognition. Mutations of the MD-2 associated gene on chromosome 8 degrade a human's innate responses. In this study, we report the effective detection of mutations to the MD-2 gene promoter, using a sensitive nanostructured biosensor with a sensing electrode of gold nanoparticles (GNPs) uniformly deposited in a nanohemisphere array. The 70 mer MD-2 expressed gene fragment was used to probe gene mutation. The complementary target, containing 156 mer nucleotide, was prepared using the fresh blood from patients with allergic disease. A total of 37 target samples, including 19 gene mutated samples and 18 normal samples, were prepared by a 20 cycles PCR process, and used for discrimination experiments. Experimental results illustrated that the nanostructured biosensor clearly discriminates between mutated and non-mutated MD-2 allergy genes. PMID- 23816847 TI - A new type of glucose biosensor based on surface acoustic wave resonator using Mn doped ZnO multilayer structure. AB - This work reports a high-performance Mn-doped ZnO multilayer structure Love mode surface acoustic wave (SAW) biosensor for the detection of blood sugar. The biosensor was functionalized via immobilizing glucose oxidase onto a pH-sensitive polymer which was attached on Mn-doped ZnO biosensor. The fabricated SAW glucose biosensor is highly sensitive, accurate and fast with good anti-interference. The sensitivity of the SAW glucose biosensor is 7.184 MHz/mM and the accuracy is 6.96 * 10(-3)mM, which is sensitive and accurate enough for glucose monitoring. A good degree of reversibility and stability of the glucose sensor is also demonstrated, which keeps a constant differential frequency shift up to 32 days. Concerning the time response to human serum, the glucose sensor shows a value of 4.6 +/- 0.4 min when increasing glucose concentrations and 7.1 +/- 0.6 min when decreasing, which is less than 10 min and reach the fast response requirement for medical applications. The Mn-doped ZnO Love mode SAW biosensor can be fully integrated with CMOS Si chips and developed as a portable, passive and wireless real time detection system for blood sugar monitoring in human serum. PMID- 23816848 TI - Highly-efficient peroxidase-like catalytic activity of graphene dots for biosensing. AB - In recent years, considerable efforts have been devoted to the construction of efficient enzyme mimetics, which have significant advantages of simple synthesis, good stability and design flexibility. In this paper, we described that graphene dots (GDs) possess highly-efficient peroxidase-like catalytic activity, and its activity is much higher than graphene oxide (GO) with large size. They can catalyze the oxidation of peroxidase substrate 3,3,5,5-tetramethylbenzidine (TMB) in the presence of H2O2 to produce a blue product, which can be used for H2O2 detection by measuring the absorbance change. This catalytic reaction can be also used for other analyte detection by monitoring the generation or consumption of H2O2, such as glucose and reduced glutathione (GSH). The GDs-based system permits detection of as low as 10nM H2O2, which is much lower than that of other nanomaterials-catalyzed methods. Meanwhile, the detection limit of this system is 0.5 MUM for glucose and 0.5 MUM for GSH, respectively. Furthermore, the proposed system also shows high selectivity and is capable of sensing in complicated biological samples such as cell lysate. Due to their high catalytic activity, high diffusion and excellent biocompatibility, GDs can be expected to be applied in various fields, such as biotechnology, medical diagnostics and environmental monitoring. PMID- 23816849 TI - Replacement of cetyltrimethylammoniumbromide bilayer on gold nanorod by alkanethiol crosslinker for enhanced plasmon resonance sensitivity. AB - Surface modification of gold nanorods (GNRs) is often problematic due to tightly packed cetyltrimethylammoniumbromide (CTAB) bilayer. Herein, we performed a double phase transfer ligand exchange to achieve displacement of CTAB on nanorods. During the removal, 11-mercaptoundecanoic acid (MUDA) crosslinker is simultaneously assembled on nanorod surfaces to prevent aggregation. The resulting MUDA-GNRs retain the shape and position of plasmon peaks similar to CTAB-capped GNRs. The introduction of carboxyl groups allows covalent conjugation of biological receptors in a facile fashion to construct a robust, label-free biosensor based on localized surface plasmon resonance (LSPR) transduction of biomolecular interaction. More importantly, smaller MUDA layer on the GNRs reduces the distance of target binding to the plasmonic nanostructure interface, leading to a significant enhancement in LSPR assay sensitivity and specificity. Compared to modification using conventional electropolymer adsorption, MUDA coated gold nanosensor exhibits five times lower detection limit for cardiac troponin I assay with a high selectivity. PMID- 23816850 TI - Electrochemical sensor based on direct electron transfer of HIV-1 virus at Au nanoparticle modified ITO electrode. AB - In this study, for the first time, an electrochemical detection method was proposed to detect direct electron transfer signal from HIV-1 Virus. Au nanoparticles were fabricated on the Indium Tin Oxide coated glass (ITO) electrode by electrochemical deposition to improve the surface area to provide better electron-transfer kinetics, and higher background charging current. On the Au nanoparticle modified ITO electrode, antibody fragment was immobilized by self assembly method with gold-thiol interaction and different concentrations of HIV-1 Virus like particles (VLPs) were applied for the direct determination. Due to the advantage of fabricated Au nanoparticle's excellent electrical and mechanical properties, HIV-1 VLPs were successfully detected from 600 fg/mL to 375 pg/mL. Furthermore, since the proposed electrochemical virus sensor is designed for direct determination without any labeling structure, the electrochemical communication between redox target and electrode surface will reduce interference reactions and simplifies the detection system with small amount of reagent and better stability. Therefore, highly sensitive virus sensor was developed to detect HIV-1 Virus in a label free system. PMID- 23816851 TI - Flagellins of Salmonella Typhi and nonpathogenic Escherichia coli are differentially recognized through the NLRC4 pathway in macrophages. AB - Flagellin is recognized by both Toll-like receptor (TLR)5 and NAIP5/NLRC4 inflammasome receptors. We hypothesized that the flagellins derived from different bacteria might differentially activate TLR5 and/or NAIP5/NLRC4 signal pathways. To test this, the immune recognition of recombinant flagellins derived from pathogenic Salmonella Typhi (SF) and the nonpathogenic Escherichia coli K12 strain MG1655 (KF) were examined by the activation of TLR5 and NLRC4 pathways in various cell types. While flagellins SF and KF were not distinguishable in activating the TLR5 pathway, KF induced significantly less interleukin-1beta production and pyroptotic cell death in peritoneal macrophages than SF, and showed markedly lower efficiency in activating caspase-1 through the NLRC4 pathway than SF. Macrophages may differentially recognize flagellins by intracellular sensors and thereby initiate the immune response to invading pathogenic bacteria. Our findings suggest an active role of flagellin as an important determinant in host differential immune recognition and for the control of bacteria infection. PMID- 23816852 TI - Analysis of the prevalence of and risk factors for atopic dermatitis using an ISAAC questionnaire in 8,750 Korean children. AB - BACKGROUND: Since 1995, epidemiologic studies of atopic disorders using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire have been performed in many countries, including the Republic of Korea. The prevalence, burden and risk factors of atopic dermatitis were surveyed in these studies, which helped to enhance their comparability among different areas and age groups, as well as to clarify the nature of atopic dermatitis and other atopic disorders. METHODS: From 21 facilities, 8,750 children were enrolled in this cross-sectional study. The data were collected via the Internet using a questionnaire based on the Korean-language version of the ISAAC study format. RESULTS: The prevalence of atopic dermatitis over the previous 12 months was 14.4%. The prevalence in preschool children was significantly higher than in elementary school children. Family history of atopic diseases, diagnosis of allergic conjunctivitis and diagnosis of food allergy were positively associated with atopic dermatitis in both preschool and elementary school children. In addition, raising pets was positively associated with atopic dermatitis in preschool children. In elementary school children, female gender, secondhand smoking, breastfeeding, changing the parents' house to a newly built one during the first year of life, diagnosis of asthma and diagnosis of allergic rhinitis were positively associated with atopic dermatitis. CONCLUSION: The prevalence of atopic dermatitis in preschool and elementary school children in Korea is similar to that of children in other developing countries. The risk factors for atopic dermatitis are different in preschool and elementary school children. More detailed strategies will be necessary to reduce atopic dermatitis in both age groups. PMID- 23816853 TI - Lung cancer stigma, anxiety, depression and symptom severity. AB - OBJECTIVES: Compared to other cancers, lung cancer patients report the highest levels of psychological distress and stigma. Few studies have examined the relationship between lung cancer stigma (LCS) and symptom burden. This study was designed to investigate the relationship between LCS, anxiety, depression and physical symptom severity. METHODS: This study employed a cross-sectional, correlational design to recruit patients online from lung cancer websites. LCS, anxiety, depression and physical symptoms were measured by patient self-report using validated scales via the Internet. Hierarchical multiple regression was performed to investigate the individual contributions of LCS, anxiety and depression to symptom severity. RESULTS: Patients had a mean age of 57 years; 93% were Caucasian, 79% were current or former smokers, and 74% were female. There were strong positive relationships between LCS and anxiety (r = 0.413, p < 0.001), depression (r = 0.559, p < 0.001) and total lung cancer symptom severity (r = 0.483, p < 0.001). Although its contribution was small, LCS provided a unique and significant explanation of the variance in symptom severity beyond that of age, anxiety and depression, by 1.3% (p < 0.05). CONCLUSIONS: Because LCS is associated with psychosocial and physical health outcomes, research is needed to develop interventions to assist patients to manage LCS and to enhance their ability to communicate effectively with clinicians. PMID- 23816854 TI - Deep parallel sequencing reveals conserved and novel miRNAs in gill and hepatopancreas of giant freshwater prawn. AB - MicroRNAs (miRNAs) are ~20-22 nucleotides, non protein-coding RNA regulatory genes that post-transcriptionally regulate many protein-coding genes, influencing critical biological and metabolic processes. While the number of known microRNA is increasing, there is currently no published data for miRNA from giant freshwater prawns, Macrobrachium rosenbergii (M. rosenbergii), a commercially cultured and economically important food species. In this study, we identified novel miRNAs in the gill and hepatopancreas of M. rosenbergii. Through a deep parallel sequencing analysis and an in silico data analysis approach, 327 miRNA families were identified from small RNA libraries with reference to both the de novo transcriptome of M. rosenbergii obtained from RNA-Seq and to miRBase (Release 18.0, November 2012). Based on the identified mature miRNA and recovered precursor sequences that form appropriate hairpin structures, three conserved miRNA (miR125, miR750, miR993) and 27 novel miRNA candidates encoding messenger like non-coding RNA were identified. miR-125, miR-750, G-m0002/H-m0009, G-m0005, G-m0008/H-m0016, G-m0011/H-m0027 and G-m0015 were selected for experimental validation with stem-loop quantitative RT-PCR and were found to be coherent with the expression profile of deep sequencing data as evaluated with Pearson's correlation coefficient (r = 0.835178 for miRNA in gill, r = 0.724131 for miRNA in hepatopancreas). Using a combinatorial approach of pathway enrichment analysis and inverse expression relationship of miRNA and mRNA, four co-expressed novel miRNA candidates (G-m0005, G-m0008/H-m0016, G-m0011/H-m0027, and G-m0015) were found to be associated with energy metabolism. In addition, the expression of the three novel miRNA candidates (G-m0005, G-m0008/H-m0016, and G-m0011/H-m0027) were also found to be significantly reduced at 9 and 24 h post infection in M. rosenbergii challenged with infectious hypodermal and hematopoietic necrosis virus, suggesting a functional role of these miRNAs in crustacean immune defense. PMID- 23816855 TI - Arsenical association: inorganic arsenic may accumulate in the meat of treated chickens. PMID- 23816856 TI - [Management of spinal cord compression in Togo]. AB - PURPOSE: The aim of this study was to describe the epidemiologic, clinical, diagnostic and therapeutic aspects of spinal cord compression at the Lome-Campus teaching hospital. MATERIAL AND METHOD: We retrospectively analyzed the files of all patients hospitalized for spinal cord compression at Lome-Campus teaching hospital from January 1, 1998, through December 31, 2007. RESULTS: 39 files were selected, mostly of men (77%). The mean age was 53 years (range: 22 to 79). Median time from the start of symptoms to hospital admission was 14.9 +/- 24.5 weeks. The spinal cord compression was confirmed by myeloscan in 35 cases (90%), myelography in 2 (5%) and magnetic resonance imaging in 2 cases (5%). The thoracic spine was the most common site of involvement. The principal cause was malignant neoplasm (17 cases: 44%), followed by cervical spondylotic myelopathy (9 cases: 23%) and Pott's disease (7 cases: 18%). Only one patient underwent surgery. CONCLUSION: Spinal cord compression appears to be a rare condition in Togo. It is a true medical emergency and immediate intervention is required. Its management remains precarious and its prognosis poor. PMID- 23816857 TI - Cardiovascular risk assessment using high-sensitivity C-reactive protein in patients with erectile dysfunction. AB - BACKGROUND: Erectile dysfunction (ED) is associated with cardiovascular events. High-sensitivity C-reactive protein (hsCRP) is a cardiovascular risk marker. The aim of this study is to determine whether hsCRP is useful in evaluating ED. METHODS: In 121 patients with ED, age, ED type and severity, time since onset of ED, weight, height, BMI, body fat percentage, waist and hip circumference, hsCRP and hormone profile were studied. Patients were classified as low or moderate high cardiovascular risk based on hsCRP levels. A descriptive and univariate study was performed. A logistic regression was used to establish factors associated with low versus moderate-high cardiovascular risk and hsCRP. RESULTS: Most patients had moderate-severe ED (70%). 74% had a moderate-high cardiovascular risk based on hsCRP levels, and 33.9 and 34.7% had hypogonadism according to total (TT) and free testosterone. In the univariate analysis, a relationship between hsCRP and TT and physical examination variables was observed (p < 0.05). In the multivariate analysis, TT was found to be a predictor (OR: 0.676; 95% CI: 0.491-0.029). Higher cardiovascular risk was found in the hypogonadic group (OR: 5.51; 95% CI: 1.185-25.662) and waist- to-hip ratio (p = 0.008; OR: 1.361; 95% CI: 1.075-1.612). CONCLUSIONS: A majority of patients with ED have high cardiovascular risk based on hsCRP levels and there is an association with hypogonadism and obesity. PMID- 23816858 TI - MicroRNA-124 suppresses breast cancer cell growth and motility by targeting CD151. AB - BACKGROUND: CD151 is highly expressed in breast cancer cells and has been shown to accelerate breast cancer by enhancing cell growth and motility, but its regulation is poorly understood. To explore post-translation regulation of CD151, for example microRNAs, will be of great importance to claim the mechanism. METHODS: A luciferase reporter assay was used to determine whether CD151 was a target of miR-124. The levels of CD151 mRNA were detected by real-time PCR and CD151 protein expression was measured by western blot and flow cytometry. The effects of miR-124 expression on growth, apoptosis, cell cycle and motility of breast cancer cells were determined. RESULTS: We discovered that miR-124 directly targets the 3' untranslated region (3'-UTR) of CD151 mRNAs and suppresses its mRNA expression and protein translation. Both siRNA of CD151 and miR-124 mimics could significantly inhibit proliferation of breast cancer cell lines via cell cycle arrest but does not induce apoptosis. Meanwhile, miR-124 mimics significantly inhibited the motility of breast cancer cells. CONCLUSION: miR-124 plays a critical role in inhibiting the invasive and metastatic potential of breast cancer cells, probably by directly targeting the CD151 genes. Our findings highlight an important role of miR-124 in the regulation of invasion and metastasis by breast cancer cells and suggest a potential application for miR-124 in breast cancer treatment. PMID- 23816859 TI - Cultural psychiatry: a general perspective. AB - The current scene in the field of cultural psychiatry shows a vigorous growth, multifaceted conceptual and research developments and more relevant clinical presence. After a pertinent definition of the discipline, this chapter examines the contribution of cultural psychiatry to the etiopathogenesis of mental disorders, to the variations of clinical presentations in numerous entities, to psychiatric diagnosis and treatment and to the relatively unexplored rubric of preventive psychiatry. Advanced concepts of neurosciences and technology-based research can find a place in the realm of biocultural correlates. The role of culture in the definition of mental illness, the renewed notions of the old 'culture-bound syndromes', hope, cognition and culture in psychiatric treatments (including the so-called 'cultural therapies'), and resiliency are areas duly examined and discussed. Cultural psychiatry has re-emerged as a reliable body of knowledge aimed at a comprehensive assessment of human beings as patients. PMID- 23816861 TI - Trends in cultural psychiatry in the United kingdom. AB - Cultural psychiatry in the United Kingdom exhibits unique characteristics closely related to its history as a colonial power, its relationship with Commonwealth countries and the changing socio-demographic characteristics of its diverse population throughout the centuries. It is not surprising, therefore, that the emergence of this discipline was centred around issues of race and religion. After a brief historical review of the development of cultural psychiatry and the mention of pioneering intellectual and academic figures, as well as the evolvement of the field in organizations such as the Royal College of Psychiatrists, this chapter examines the need of a critical cultural psychiatry, more than a narrative social science distanced from the realities of clinical practice. In such context, issues such as policies and experience with efforts to delivering race equality, and address inequities in a renewed public health approach seem to confer British cultural psychiatry with a defined socially active role aimed at the pragmatic management, understanding and improvement of diverse and alternative systems of care and care practices. PMID- 23816860 TI - Culture and psychiatric diagnosis. AB - Since the publication of DSM-IV in 1994, neurobiologists and anthropologists have criticized the rigidity of its diagnostic criteria that appear to exclude whole classes of alternate illness presentations, as well as the lack of attention in contemporary psychiatric nosology to the role of contextual factors in the emergence and characteristics of psychopathology. Experts in culture and mental health have responded to these criticisms by revising the very process of diagnosis for DSM-5. Specifically, the DSM-5 Cultural Issues Subgroup has recommended that concepts of culture be included more prominently in several areas: an introductory chapter on Cultural Aspects of Psychiatric Diagnosis - composed of a conceptual introduction, a revised Outline for Cultural Formulation, a Cultural Formulation Interview that operationalizes this Outline, and a glossary on cultural concepts of distress - as well as material directly related to culture that is incorporated into the description of each disorder. This chapter surveys these recommendations to demonstrate how culture and context interact with psychiatric diagnosis at multiple levels. A greater appreciation of the interplay between culture, context, and biology can help clinicians improve diagnostic and treatment planning. PMID- 23816862 TI - Opening up mental health service delivery to cultural diversity: current situation, development and examples from three northern European countries. AB - There are inequalities in health among migrants and local populations in Europe. Due to migration, Germany, Norway and Sweden have become ethnic culturally diverse nations. There are barriers to mental health care access for refugees, migrants and minorities, and problems with quality of culturally sensitive care in the three countries. This is despite tax-funded health care systems based on equity in service provision. There is a need to develop culturally sensitive mental health services that respond to the increasing diversity of the populations. In this chapter, we will take a closer look at cultural diversity in the countries in question, discuss challenges and give examples of current work to open up mental health services to cultural diversity. The German example will focus on the movement of Interkulturelle Offnung (cross-cultural opening of the health care system) and work on creating national guidelines and quality standards. From Norway, the work of the National Centre for Mental Health for the indigenous Sami population will be presented. The Swedish example will focus on the work carried out by the Transcultural Centre. The latter is a competence centre supporting development of culturally sensitive care as an integrated part of the regional health and mental health care system in Stockholm. Finally, the relevance of mental health care for a culturally diverse population, as a part of the larger social project of building tolerant multicultural societies, will be discussed. PMID- 23816863 TI - Cultural psychiatry in the French-speaking world. AB - For the last five centuries, France's international influence has been constant. This has been particularly evident in the areas of general culture, history and science. In psychiatry, the role of Pinel during the French Revolution, and the discovery of the first psychotropic agent, chlorpromazine, by Delay and Deniker are two outstanding historical facts. This chapter examines the contributions of French social scientists in the understanding of the sequelae of colonial exploitation, racism and political oppression. The establishment of a multi ethnic society in France and Francophile regions of the world has led to the gradual creation of a cultural psychiatry rich in terminological influences, clinical understanding, training programs and research. Closer connections between French psychiatric thought and Anglophile psychiatry is likely to produce beneficial effects. PMID- 23816864 TI - Transcultural aspects of somatic symptoms in the context of depressive disorders. AB - Somatic symptoms are a common presentation of mental disorders or psychological distress worldwide, and may often coexist with depressive and anxiety symptoms, thus accounting for what might be the most frequent psychiatric syndrome in primary care. Indeed, physical symptoms accompanying the clinical presentations of a variety of mental disorders may be considered as universal 'idioms of distress' that may vary across cultures, depending on attitudes and explanations embedded in each one of them. These variations in symptom presentations are the result of various interacting factors that ultimately determine how individuals identify and classify bodily sensations, perceive illness, and seek medical attention. This chapter examines the impact of culture on the experiencing of somatic symptoms, based on an inclusive review of the topic from ethnic, nosological, clinical and social perspectives. Particular attention is paid to the association of somatic symptoms with mood symptoms, since depressive disorders appear to be the most common, costly and disabling psychiatric entities worldwide. The review shows that racial/ethnic variations in somatic symptoms in the context of depression are common, and seem to be related to depression severity. Sociocultural factors, particularly stigma, may influence the unique emphasis placed on somatic symptoms within depression, and may account for some racial/ethnic differences in somatic symptom reporting. PMID- 23816865 TI - Culture and demoralization in psychotherapy. AB - In most societies, members of a culture have attempted to help each other in times of trouble with various types of healing methods. Demoralization - an individual experience related to a group phenomenon - responds to certain elements shared by all psychotherapies. This article has three objectives: (1) to review the theoretical background leading to our current views on culture and demoralization in psychotherapy, (2) to discuss the methodological challenges faced in the cross-cultural study of demoralization and psychotherapy, and (3) to describe the clinical applications and research prospects of this area of inquiry. Demoralization follows a shattering of the individual's assumptive world and it is different from homeostatic responses to a stressful situation or from depressive disorders. Only a few comparative studies of this construct across cultures have been undertaken. The presentation of distress may vary widely from culture to culture and even within the same culture. To avoid 'category fallacy', it is important to understand the idioms of distress peculiar to a cultural group. A cultural psychiatrist or psychotherapist would have to identify patient's values and sentiments, reconstruct his/her personal and collective ambient worlds, and only then study demoralization. The limitations of our current diagnostic systems have resulted in methodological challenges. Cultural clinicians should consider using a combination of both 'clinimetric' and 'perspectivistic' approaches in order to arrive at a diagnosis and identify the appropriate intervention. The presenting problem has to be understood in the context of the patient's individual, social and cultural background, and patients unfamiliar with Western-type psychotherapies have to be prepared to guide their own expectations before the former are used. Future research should identify the gaps in knowledge on the effectiveness of cultural psychotherapy at reversing or preventing demoralization. PMID- 23816866 TI - Ethnopsychopharmacology and pharmacogenomics. AB - Significant differences in response to psychotropic drugs are observed in various ethnic and cultural groups. Ethnopsychiatry is the study of how culture and genetic differences in human groups determine and influence the response to psychotropic agents. Meanwhile, pharmacogenomics studies the influence of genetic variations in the response of patients to different drugs. Pharmacogenetic tests are used to predict drug response and the potential for adverse effects. There are important genetic variations that influence the metabolism and action of psychotropic drugs in different ethnic groups. As examples, the frequencies of CYP2D6 polymorphisms and of the long and short alleles of the promoter region of the serotonin transporter are analyzed. Studies found significant differences in the frequency of polymorphisms of both genes in different countries and ethnic groups. On the basis of this review, the importance of considering ethnic and cultural factors in the prescription of drugs and in the need of further pharmacogenetic studies in different countries and geographical regions is reaffirmed. PMID- 23816867 TI - Cultural psychiatry: research strategies and future directions. AB - This chapter reviews some key aspects of current research in cultural psychiatry and explores future prospects. The first section discusses the multiple meanings of culture in the contemporary world and their relevance for understanding mental health and illness. The next section considers methodological strategies for unpacking the concept of culture and studying the impact of cultural variables, processes and contexts. Multiple methods are needed to address the many different components or dimensions of cultural identity and experience that constitute local worlds, ways of life or systems of knowledge. Quantitative and observational methods of clinical epidemiology and experimental science as well as qualitative ethnographic methods are needed to capture crucial aspects of culture as systems of meaning and practice. Emerging issues in cultural psychiatric research include: cultural variations in illness experience and expression; the situated nature of cognition and emotion; cultural configurations of self and personhood; concepts of mental disorder and mental health literacy; and the prospect of ecosocial models of health and culturally based interventions. The conclusion considers the implications of the emerging perspectives from cultural neuroscience for psychiatric theory and practice. PMID- 23816868 TI - Bioethical dimensions of cultural psychosomatics: the need for an ethical research approach. AB - Contemporary psychosomatics is a research-based technical discipline and its social power depends on how scientific knowledge is obtained and applied in practice, considering cultural contexts. This article presents the view that the dialogical principles on which bioethical discourse is based are more inclusive than professional ethics and philosophical reflection. The distinction is advanced between rule-guided behavior and norm-justifiable acts (substantiation and justification). The practical implications of good practices in the generation of valid, reliable, generalizable and applicable knowledge are emphasized. For practitioners and researchers, the need to reflect on the distinction between patient and research participant can avoid the therapeutic misunderstanding, a form of abuse of the doctor-patient relationship. In addition, in resource-poor settings, the dilemma presented by the know-do gap (inapplicability of research results due to financial or social constraints) is part of the ethics' realm of the profession. Future prospects include a wider use of research results in practice, but avoidance of the know-do gap (the disparity between what is known and what can be done, particularly in settings with limited resources) requires a synthetic and holistic approach to medical ethics, combining moral reflection, theoretical analysis and empirical data. PMID- 23816869 TI - Epilogue. PMID- 23816871 TI - Is vertebral artery hypoplasia a predisposing factor for posterior circulation cerebral ischemic events? A comprehensive review. AB - Vertebral artery hypoplasia is not currently considered an independent risk factor for stroke. Emerging evidence suggest that vertebral artery hypoplasia may contribute to posterior circulation ischemic events, especially when other risk factors coexist. In the present literature review, we present published data to discuss the relationship between a hypoplastic vertebral artery and posterior circulation cerebral ischemia. Despite difficulties and controversies in the accurate definition and prevalence estimation of vertebral artery hypoplasia, ultrasound studies reveal that the reduced blood flow observed ipsilateral to the hypoplastic vertebral artery may result in local cerebral hypoperfusion and subsequent focal neurological symptomatology. That risk of cerebral ischemia is related to the severity of the hypoplasia, suggesting that the smaller of paired arteries are more vulnerable to occlusion. Existing cohort studies further support clinical observations that hypoplastic vertebral artery enhances synergistically the vascular risk for posterior circulation ischemic events and is closely associated with both atherosclerotic and prothrombotic processes. PMID- 23816872 TI - Cell-free expression of a mammalian olfactory receptor and unidirectional insertion into small unilamellar vesicles (SUVs). AB - Although the identification of the multigene family encoding mammalian olfactory receptors were identified more than 20 years ago, we are far from understanding olfactory perception because of the difficulties in functional expression of these receptors in heterologous cell systems. Cell-free (CF) or in vitro expression systems offer an elegant alternative route to cell based protein expression, as the functional expression of membrane proteins can be directly achieved from the genetic template without the need of cell cultivation and protein isolation. Here we investigated in detail the cell-free expression and membrane insertion of the olfactory receptor OR5 in dependence of different experimental conditions like probing different origins of the cell-free expression system (from bacteria, via plants and insects toward mammalian system) and lipid composition of the respective extracts. We provided substantial biochemical indications by radioactive labeling based on [(35)S]-methionine, followed by proteolytic digestion, and we found that the insertion of the olfactory receptor OR5 into liposomes resulted in an unidirectional orientation with the binding side exposed into the aqueous space, resembling the native orientation in the cilia of the olfactory neurons. We report the different results in synthesis capacity for the different in vitro systems employed as we like to demonstrate the first in vitro kit toward and ex situ and ex vivo odorant receptor array. PMID- 23816873 TI - Myocardial ER chaperone activation and protein degradation occurs due to synergistic, not individual, cold and hypoxic stress. AB - Environmental stress at high altitude affects the myocardium at the physiological and molecular level. Characterized by hypobaric hypoxia and low temperatures, the cumulative impact of these stressors on the protein folding homeostasis in the heart is yet unexplored. The present study evaluates the collective effect of cold and hypoxia on the myocardial protein oxidation and activation of the endoplasmic reticulum (ER) stress response. Adult rats were exposed to either a singular acute stress of cold (10 degrees C; C), hypobaric hypoxia (7620 m; H) or simultaneously to both cold and hypobaric hypoxia (CH) for 6 h. Hypoxic stress amplified the free radical generation in H and CH groups, leading to enhanced HIF 1alpha expression. Coupled to cold stress, reduced oxygen availability caused substantial protein oxidative modifications, as well as cardiac tissue injury and matrix remodeling, evident in the histological staining. Presence of oxidized proteins caused a significant upregulation in expression of ER chaperones GRP78 and PDI in the cold hypoxia exposed animals. Enhanced proteolytic activity signaled the removal of misfolded proteins. Linked intricately to cellular stress response, cell survival kinases were expressed higher in CH group; however apoptotic CHOP (C/EBP homologous protein) expression remained unaltered. Administration of ER stress inducer, tunicamycin along with cold hypoxic stress, caused a discernible increase in protein oxidation and GRP78 expression, along with a significant elevation in proteasome and apoptotic activity. Highlighting the significance of a synergistic, rather than individual, effect of low oxygen and temperature on the protein folding machinery, our study provides evidence for the activation of ER stress response in the myocardium under acute high altitude stress. PMID- 23816874 TI - Antifungal property of hibicuslide C and its membrane-active mechanism in Candida albicans. AB - In this study, the antifungal activity and mode of action(s) of hibicuslide C derived from Abutilon theophrasti were investigated. Antifungal susceptibility testing showed that hibicuslide C possessed potent activities toward various fungal strains and less hemolytic activity than amphotericin B. To understand the antifungal mechanism(s) of hibicuslide C in Candida albicans, flow cytometric analysis with propidium iodide was done. The results showed that hibicuslide C perturbed the plasma membrane of the C. albicans. The analysis of the transmembrane electrical potential with 3,3'-dipropylthiacarbocyanine iodide [DiSC3(5)] indicated that hibicuslide C induced membrane depolarization. Furthermore, model membrane studies were performed with calcein encapsulating large unilamellar vesicles (LUVs) and FITC-dextran (FD) loaded LUVs. These results demonstrated that the antifungal effects of hibicuslide C on the fungal plasma membrane were through the formation of pores with radii between 2.3 nm and 3.3 nm. Finally, in three dimensional flow cytometric contour plots, a reduced cell sizes by the pore-forming action of hibicuslide C were observed. Therefore, the present study suggests that hibicuslide C exerts its antifungal effect by membrane-active mechanism. PMID- 23816875 TI - Phase II study of topotecan and bevacizumab in advanced, refractory non--small cell lung cancer. AB - BACKGROUND: This clinical trial evaluated whether topotecan in combination with bevacizumab improved progression-free survival (PFS) in patients with advanced, refractory non--small-cell lung cancer in a second-line setting. PATIENT AND METHODS: Patients aged 18 years old and older received topotecan (4.0 mg/m(2)) on days 1, 8, and 15, and bevacizumab (10 mg/kg) on days 1 and 15 as intravenous infusions on a 28-day treatment cycle. Available tumor specimens were analyzed for ISG15 gene expression as a biomarker of response to topotecan. RESULTS: Forty two patients were enrolled in the study, with a median age of 62.5 years and a median of 3 (range, 1-7) prior treatment regimens. Almost half (n = 18, 42.9%) of the patients received prior bevacizumab therapy. PFS was 5.1 months (95% CI, 3.7 7.8 months), and overall survival was 11.5 months (95% CI, 6.8-15.5 months). Response rates were as follows: 14.3% partial response, 54.8% stable disease, and 28.6% progressive disease. Hematologic toxicities included grade 3 thrombocytopenia (n = 7, 16.7%), neutropenia (n = 4, 9.5%), and anemia (n = 2, 4.8%). One toxic death occurred due to pulmonary hemorrhage, and one patient experienced a grade 4 pulmonary embolism. Grade 3 nonhematologic adverse events were uncommon (< 8%). There was a trend for improved median PFS, 3.5 months vs. 1.8 months (P = .26), in patients with high ISG15 expression. CONCLUSION: Bevacizumab in combination with topotecan as a salvage therapy for metastatic non -small-cell lung cancer is well tolerated and is worthy of further investigation. PMID- 23816877 TI - Aptamer--nanoparticle-based chemiluminescence for p53 protein. AB - A simple colorimetric biosensing technique based on the interaction of gold nanoparticles (AuNPs) with the aptamer was developed for detection of p53, a tumor suppressor protein, in the current study. Aggregation of AuNPs was induced by desorption of the p53 binding RNA aptamer from the surface of AuNPs as a result of the aptamer target interaction leading to the color change of AuNPs from red to purple. The detection limit of p53 protein by the colorimetric approach was 0.1 ng/ml after successful optimization of the amount of aptamer, AuNPs, salts, and incubation time. Furthermore, the catalytic activity of the aggregated AuNPs was greatly enhanced by chemiluminescence (CL) reaction, where the detection limit was enhanced to 10 pg/ml with a regression coefficient of R2 = 0.9907. Here the sensitivity was increased by 10-fold compared with the AuNP based colorimetric method. Hence, the sensitivity of detection was increased by employing CL, by using the catalytic activity of aggregated AuNPs, on the luminol hydrogen peroxide reaction. Thus, the combination of colorimetric and CL-based aptasensor can be of great advantage in increasing the sensitivity of detection for any target analyte. PMID- 23816876 TI - Predicting lymph node output efficiency using systems biology. AB - Dendritic cells (DCs) capture pathogens and foreign antigen (Ag) in peripheral tissues and migrate to secondary lymphoid tissues, such as lymph nodes (LNs), where they present processed Ag as MHC-bound peptide (pMHC) to naive T cells. Interactions between DCs and T cells result, over periods of hours, in activation, clonal expansion and differentiation of antigen-specific T cells, leading to primed cells that can now participate in immune responses. Two-photon microscopy (2PM) has been widely adopted to analyze lymphocyte dynamics and can serve as a powerful in vivo assay for cell trafficking and activation over short length and time scales. Linking biological phenomena between vastly different spatiotemporal scales can be achieved using a systems biology approach. We developed a 3D agent-based cellular model of a LN that allows for the simultaneous in silico simulation of T cell trafficking, activation and production of effector cells under different antigen (Ag) conditions. The model anatomy is based on in situ analysis of LN sections (from primates and mice) and cell dynamics based on quantitative measurements from 2PM imaging of mice. Our simulations make three important predictions. First, T cell encounters by DCs and T cell receptor (TCR) repertoire scanning are more efficient in a 3D model compared with 2D, suggesting that a 3D model is needed to analyze LN function. Second, LNs are able to produce primed CD4+T cells at the same efficiency over broad ranges of cognate frequencies (from 10(-5) to 10(-2)). Third, reducing the time that naive T cells are required to bind DCs before becoming activated will increase the rate at which effector cells are produced. This 3D model provides a robust platform to study how T cell trafficking and activation dynamics relate to the efficiency of T cell priming and clonal expansion. We envision that this systems biology approach will provide novel insights for guiding vaccine development and understanding immune responses to infection. PMID- 23816878 TI - Use of 65Zn as a tracer for the assessment of purification in the 68Ga-DOTANOC synthesis. AB - In the last years (68)Ga has got into the focus of researchers and clinicians especially for radio-labeling of biomolecules; an important characteristic of this positron emitting isotope is its availability via the (68)Ge/(68)Ga generator system: the long-lived (68)Ge (t1/2=270.8 d) produces the short-lived (68)Ga (t1/2=67.63 min) which decays to stable (68)Zn. (68)Ge breakthrough compromises (68)Ga radionuclidic purity, while (68)Zn might affect the specific activity of the radiopharmaceutical. In this paper we investigated the weight of these impurities in (68)Ga-DOTANOC synthesis. (65)Zn (t1/2=244.26d; decay mode: EC 98.3%, beta(+) 1.7%) was used as a radiotracer of stable (68)Zn; samples of the purification columns, wastes and product were recovered and measured with a calibrated HPGe gamma-ray spectrometry system. The results showed that (68)Zn competes with (68)Ga in labeling DOTANOC with a (95+/-2)% labeling yield; they also proved the effectiveness of the STRATA X-C cationic post-processing of the generator eluate in lowering the amount of this impurity to less than 1%. Moreover this approach, along with the purification of the final product through a STRATA X cartridge, effectively removes (68)Ge breakthrough providing a (68)Ga DOTANOC radionuclidic purity of (99.9999986+/-0.0000006)%, superior to 99.9% required by the Pharmacopoeia Monograph on (68)Ga Edotreotide injection. PMID- 23816879 TI - Design of an electrochemically assisted radiation sensor for alpha-spectrometry of actinides traces in water. AB - We describe a new approach for the detection and identification of actinides at low activity levels directly in aqueous solution. The measurement consists initially, in immobilizing alpha emitters in the form of insoluble hydroxides onto the entrance window of an immersed alpha particles detector. For this, a boron doped diamond detector window is negatively polarized to produce a basic layer on its surface by water decomposition. Actinides elements that are known to be very sensitive to hydrolysis are precipitated as solid hydroxides onto the entrance window of the sensor. Due to the absence of an air layer between the radioactive source and the detector, there is no need for vacuum during the alpha spectrometry measurement. After analysis, the detector can be easily cleaned by anodization in the aqueous medium to be reused at once. The minimum detectable activity concentration (MDA) of the system has been evaluated with (241)Am at 0.5 Bq/L for a 0.33 cm(2) area Si PIN diode. PMID- 23816880 TI - Antiparasitic hybrids of Cinchona alkaloids and bile acids. AB - A series of 16 hybrids of Cinchona alkaloids and bile acids (4a-h, 5a-h) was prepared by means of a Barton-Zard decarboxylation reaction. Quinine, quinidine, cinchonine and cinchonidine were functionalized at position C-2 of the quinoline nucleus by radical attack of a norcholane substituent. The newly synthesized hybrids were evaluated in vitro for their antitrypanosomal, antileishmanial and antiplasmodial activities, along with their cytotoxicity against WI38, a normal human fibroblast cell line. Seven compounds (4d, 4f, 4h, 5b, 5d, 5f, 5h) showed promising trypanocidal activity with IC50 values in the same range as the commercial drug suramine. Moreover all the 16 hybrids showed antiplasmodial activity (IC50 <= 6 MUg/ml), particularly those containing a nor chenodeoxycholane moiety (4b, 4d, 4f, 4h, 5b, 5d, 5f, 5h) with IC50 values comparable to those of the natural alkaloids, and selectivity indices in the range of 5.6-15.7. PMID- 23816881 TI - The casein kinase 2-nrf1 axis controls the clearance of ubiquitinated proteins by regulating proteasome gene expression. AB - Impairment of the ubiquitin-proteasome system (UPS) has been implicated in the pathogenesis of human diseases, including neurodegenerative disorders. Thus, stimulating proteasome activity is a promising strategy to ameliorate these age related diseases. Here we show that the protein kinase casein kinase 2 (CK2) regulates the transcriptional activity of Nrf1 to control the expression of the proteasome genes and thus the clearance of ubiquitinated proteins. We identify CK2 as an Nrf1-binding protein and find that the knockdown of CK2 enhances the Nrf1-dependent expression of the proteasome subunit genes. Real-time monitoring of proteasome activity reveals that CK2 knockdown alleviates the accumulation of ubiquitinated proteins upon proteasome inhibition. Furthermore, we identify Ser 497 of Nrf1 as the CK2 phosphorylation site and demonstrate that its alanine substitution (S497A) augments the transcriptional activity of Nrf1 and mitigates proteasome dysfunction and the formation of p62-positive juxtanuclear inclusion bodies upon proteasome inhibition. These results indicate that the CK2-mediated phosphorylation of Nrf1 suppresses the proteasome gene expression and activity and thus suggest that the CK2-Nrf1 axis is a potential therapeutic target for diseases associated with UPS impairment. PMID- 23816882 TI - CTGF mediates Smad-dependent transforming growth factor beta signaling to regulate mesenchymal cell proliferation during palate development. AB - Transforming growth factor beta (TGF-beta) signaling plays crucial functions in the regulation of craniofacial development, including palatogenesis. Here, we have identified connective tissue growth factor (Ctgf) as a downstream target of the TGF-beta signaling pathway in palatogenesis. The pattern of Ctgf expression in wild-type embryos suggests that it may be involved in key processes during palate development. We found that Ctgf expression is downregulated in both Wnt1 Cre; Tgfbr2(fl/fl) and Osr2-Cre; Smad4(fl/fl) palates. In Tgfbr2 mutant embryos, downregulation of Ctgf expression is associated with p38 mitogen-activated protein kinase (MAPK) overactivation, whereas loss of function of Smad4 itself leads to downregulation of Ctgf expression. We also found that CTGF regulates its own expression via TGF-beta signaling. Osr2-Cre; Smad4(fl/fl) mice exhibit a defect in cell proliferation similar to that of Tgfbr2 mutant mice, as well as cleft palate. We detected no alteration in bone morphogenetic protein (BMP) downstream targets in Smad4 mutant palates, suggesting that the reduction in cell proliferation is due to defective transduction of TGF-beta signaling via decreased Ctgf expression. Significantly, an exogenous source of CTGF was able to rescue the cell proliferation defect in both Tgfbr2 and Smad4 mutant palates. Collectively, our data suggest that CTGF regulates proliferation as a mediator of the canonical pathway of TGF-beta signaling during palatogenesis. PMID- 23816883 TI - Histone variant H2A.Z functions in sister chromatid cohesion in Saccharomyces cerevisiae. AB - H2A.Z is a highly conserved variant of histone H2A with well-characterized roles in transcriptional regulation. We previously reported that H2A.Z and Mcd1, a subunit of the cohesin complex, regulate the establishment of transcriptional silencing at telomeres in Saccharomyces cerevisiae and that H2A.Z broadly dissociated from chromatin during the anaphase-to-telophase transition, coincident with the dissociation of Mcd1 from chromosomes and dissolution of cohesion. In this study, we show that depletion of H2A.Z causes precocious loss of sister chromatid cohesion in yeast without loss of Mcd1 from chromosomes. H2A.Z is deposited into chromatin by the SWR1 complex and is subject to acetylation of its four N-terminal tail lysine residues by the NuA4 and SAGA histone acetyltransferase complexes. We found that cells compromised for function of the SWR1 complex were defective in cohesion, as were cells expressing a form of H2A.Z not subject to acetylation. Finally, inactivation of H2A.Z in metaphase blocked cells led immediately to cohesion defects, suggesting a direct role for H2A.Z in the maintenance of sister chromatid cohesion. PMID- 23816884 TI - The THO ribonucleoprotein complex is required for stem cell homeostasis in the adult mouse small intestine. AB - RNA processing and transport are mediated by cotranscriptionally assembled ribonucleoprotein (RNP) complexes. RNPs have been postulated to help specify coordinated gene expression, but the requirements for specific RNP complexes in mammalian development and tissue homeostasis have not been extensively evaluated. THO is an evolutionarily conserved RNP complex that links transcription with nuclear export. THO is not essential for Saccharomyces cerevisiae viability, but it is essential for early mouse embryonic development. Embryonic lethality has limited the characterization of THO requirements in adult tissues. To overcome this limitation, a mouse model has been generated that allows widespread inducible deletion of Thoc1, which encodes an essential protein subunit of THO. Widespread Thoc1 deletion disrupts homeostasis within the small intestine but does not have detectable effects in other epithelial tissues such as the related mucosa of the large intestine. Thoc1 loss compromises the proliferation and lineage-generating capacity of small intestinal stem cells, disrupting the supply of differentiated cells in this rapidly renewing tissue. These findings demonstrate that the effects of THO deficiency in the adult mouse are tissue and cell type dependent. PMID- 23816885 TI - An insertion peptide in yeast glycyl-tRNA synthetase facilitates both productive docking and catalysis of cognate tRNAs. AB - The yeast Saccharomyces cerevisiae possesses two distinct glycyl-tRNA synthetase (GlyRS) genes: GRS1 and GRS2. GRS1 is dually functional, encoding both cytoplasmic and mitochondrial activities, while GRS2 is dysfunctional and not required for growth. The protein products of these two genes, GlyRS1 and GlyRS2, are much alike but are distinguished by an insertion peptide of GlyRS1, which is absent from GlyRS2 and other eukaryotic homologues. We show that deletion or mutation of the insertion peptide modestly impaired the enzyme's catalytic efficiency in vitro (with a 2- to 3-fold increase in Km and a 5- to 8-fold decrease in kcat). Consistently, GRS2 can be conveniently converted to a functional gene via codon optimization, and the insertion peptide is dispensable for protein stability and the rescue activity of GRS1 at 30 degrees C in vivo. A phylogenetic analysis further showed that GRS1 and GRS2 are paralogues that arose from a gene duplication event relatively recently, with GRS1 being the predecessor. These results indicate that GlyRS2 is an active enzyme essentially resembling the insertion peptide-deleted form of GlyRS1. Our study suggests that the insertion peptide represents a novel auxiliary domain, which facilitates both productive docking and catalysis of cognate tRNAs. PMID- 23816886 TI - MYC degradation under low O2 tension promotes survival by evading hypoxia-induced cell death. AB - Cells encounter oxygen deprivation (hypoxia) in various physiological and pathological contexts. Adaptation to hypoxic stress occurs in part by suppressing MYC, a key regulator of cellular metabolism, proliferation, and survival. Hypoxia has been reported to inhibit MYC through multiple means, including disruption of MYC transcriptional complexes and decreased MYC protein abundance. Here we identify enhanced proteasomal degradation and cathepsin-mediated proteolysis as important mechanisms for hypoxic MYC inhibition in human colon carcinoma cells. MYC protein levels were similarly reduced in hypoxic primary keratinocytes. Increased MYC turnover at low O2 tension was dependent on the E3 ubiquitin ligases FBXW7 and DDB1, as well as hypoxic induction of cathepsins D and S. Reduced MYC protein levels coincided with hypoxic inhibition of RNA polymerase III-dependent MYC target genes, which MYC regulates independently of its binding partner MAX. Finally, MYC overexpression in hypoxic cells promoted cell cycle progression but also enhanced cell death via increased expression of the proapoptotic genes NOXA and PUMA. Collectively, these results indicate that hypoxic cells promote MYC degradation as an adaptive strategy to reduce proliferation, suppress biosynthetic processes, and promote cell survival under low O2 tension. PMID- 23816888 TI - Skull asymmetry as an unusual presentation of an intracranial tumour. PMID- 23816889 TI - [Primary focal segmental glomerular sclerosis in children: epidemiology and prognosis]. AB - Focal segmental glomerulosclerosis (FSGS) is the morphologic description of a glomerular lesion which is "focal", meaning a few but not all of the total sampled glomeruli have and "segmental" solidification of the tuft that is an accumulation of extracellular matrix with obliteration of the capillary lumina (sclerosis). It represents 20% of nephrotic syndrome in children and adults. To study the role of epidemiology, clinical presentation, histology, and treatment in the prognosis of HSF child, we retrospectively analyzed 23 children with primary focal segmental glomerulosclerosis (FSGS) hospitalized in pediatric nephrology unit of Children's Hospital Harrouchi Abderrahim, CHU Ibn Rochd Casablanca from January 2000 to December 2012. The main age at onset was 7.5 years with a male predominance. Hematuria was seen in 22% of patients, hypertension in 48% of patients, and moderate renal insufficiency in one patient at presentation. According to the histological classification of Columbia, 40% of patients have a non-specific HSF (NOS), including six patients who have responded to treatment and one patient progressed to renal failure, 13% have a perihilar HSF (PH) with a good prognosis, 8% have a HSF cell (CELL), which evolved to renal failure, 35% of HSF was a tubular pole (TIP) including five patients responded to treatment and 4% was a HSF collapsing (COL) having a renal failure at admission. The FSGS's prognosis is related to several predictive factors. PMID- 23816887 TI - Sestrin 2 and AMPK connect hyperglycemia to Nox4-dependent endothelial nitric oxide synthase uncoupling and matrix protein expression. AB - Mesangial matrix accumulation is an early feature of glomerular pathology in diabetes. Oxidative stress plays a critical role in hyperglycemia-induced glomerular injury. Here, we demonstrate that, in glomerular mesangial cells (MCs), endothelial nitric oxide synthase (eNOS) is uncoupled upon exposure to high glucose (HG), with enhanced generation of reactive oxygen species (ROS) and decreased production of nitric oxide. Peroxynitrite mediates the effects of HG on eNOS dysfunction. HG upregulates Nox4 protein, and inhibition of Nox4 abrogates the increase in ROS and peroxynitrite generation, as well as the eNOS uncoupling triggered by HG, demonstrating that Nox4 functions upstream from eNOS. Importantly, this pathway contributes to HG-induced MC fibronectin accumulation. Nox4-mediated eNOS dysfunction was confirmed in glomeruli of a rat model of type 1 diabetes. Sestrin 2-dependent AMP-activated protein kinase (AMPK) activation attenuates HG-induced MC fibronectin synthesis through blockade of Nox4-dependent ROS and peroxynitrite generation, with subsequent eNOS uncoupling. We also find that HG negatively regulates sestrin 2 and AMPK, thereby promoting Nox4-mediated eNOS dysfunction and increased fibronectin. These data identify a protective function for sestrin 2/AMPK and potential targets for intervention to prevent fibrotic injury in diabetes. PMID- 23816890 TI - The negative predictive value of typing safe local anesthetics. AB - BACKGROUND: Although allergy to local anesthetics (LA) is rare, patients often report unwanted reactions after their administration. A history of anaphylaxis or an atypical reaction related to LA is an indication for typing a safe anesthetic for future surgical or dental procedures. AIM: The aim of the study was to determine the negative predictive value (NPV) of typing safe LA. METHODS: A total of 154 patients with a history of an unwanted reaction to LA were enrolled into the study. Stepwise typing of a safe anesthetic included skin prick tests (SPT) and intracutaneous tests (ICT) with two or three of the following LA: lidocaine, bupivacaine, mepivacaine, and articaine. Skin tests were followed by provocations with one or two LA. Telephone follow-up visits were performed 4-12 months after drug typing. On the basis of follow-up questionnaire results, the NPV of the protocol was calculated. RESULTS: The full protocol was performed in 148 patients. Positive results of SPT were observed in 2, of ICT in 19 and of provocations in 11 cases. Lidocaine was found safe in 44, bupivacaine in 14, mepivacaine in 34 and articaine in 61 patients. The drug typed at the clinical visit was administered in 78 patients, and 76 reported no reactions (NPV = 97%). CONCLUSION: Stepwise approach including SPT, ICT and provocations is safe and allows typing a safe anesthetic in a vast majority of patients. PMID- 23816891 TI - [Role of continuous subcutaneous glucose monitoring in intensive care]. AB - Critical care associated with stress hyperglycaemia has gained a new view in the last decade since the demonstration of the beneficial effects of strong glycaemic control on the mortality in intensive care units. Strong glycaemic control may, however, induce hypoglycaemia, resulting in increased mortality, too. Pediatric population has an increased risk of hypoglycaemia because of the developing central nervous system. In this view there is a strong need for close monitoring of glucose levels in intensive care units. The subcutaneous continuous glucose monitoring developed for diabetes care is an alternative for this purpose instead of regular blood glucose measurements. It is important to know the limitations of subcutaneous continuous glucose monitoring in intensive care. Decreased tissue perfusion may disturb the results of subcutaneous continuous glucose monitoring, because the measurement occurs in interstitial fluid. The routine use of subcutaneous continuous glucose monitoring in intensive care units is not recommended yet until sufficient data on the reliability of the system are available. The Medtronic subcutaneous continuous glucose monitoring system is evaluated in the review partly based on the authors own results. PMID- 23816892 TI - [New tendencies in hand surgery]. AB - The author summarizes the new therapeutic tendencies in hand surgery at the past one and a half decade. He discusses the development of hand surgery, as an independent field, in a form of a short historical summary, then he reviews in detail new therapeutic methods considered important such as rehabilitation procedures after tendon injuries, present position of complete hand transplantation, new operations of regeneration of the injured skin and repair of nerve damages, as well as the conservative therapeutic options of Dupuytren's disease. Finally he outlines the modified, new operative procedures in bone and joint injuries of the hand. He concludes that constant development of hand surgical knowledge will likely result in further novel therapeutic methods. PMID- 23816893 TI - [Khat (Catha edulis): is it "coffee" or "cocaine"?]. AB - Regular consumption of khat's (Catha edulis) fresh leaves seriously affects the health, the social and economic life of the subject. Therefore, it is hazardous both to the individual and to the community. According to the latest reports, consumption of chat may exert some unknown and unreported gastrointestinal and hepatic effects. On the basis of studies performed by the authors, it seems that khat (cathinone) has no gastric or duodenal ulcerogenic effect. However, it does cause a significant enlargement of the hepatic mitochondria. In addition, a concern arose recently that the profit of illegal traffic of the plant may reach some illegal (terrorist) organisations. Therefore it seems that the so-called "khat-problem" needs further and more effective control. PMID- 23816894 TI - [Hepatitis C virus recurrence after liver transplantation in Hungary. Trends over the past 10 years]. AB - INTRODUCTION: Management of hepatitis C virus recurrence is a challenge after liver transplantation. AIM: The aim of the authors was to analyse the outcome of liver transplantation performed in hepatitis C virus positive patients during the past ten years and to compare recent data with a previous report of the authors. METHOD: The authors retrospectively evaluated the data (donors, recipients, perioperative characteristics, patient and graft survival, serum titer of hepatitis C virus RNA, histology) of 409 patients who underwent liver transplantation between 2003 and 2012. RESULTS: 156 patients were transplanted due to hepatitis C virus associated liver cirrhosis (38%). Worse outcome was observed in these patients in comparison to hepatitis C virus negative recipients. The cumulative patient survival rates at 1, 5, and 10 year were 80%, 61%, 51% in the hepatitis C virus positive group and 92%, 85%, 79% in the hepatitis C virus negative group, respectively (p<0.001). The cumulative graft survival rates at 1, 5 and 10 year were 79%, 59% and 50% in hepatitis C virus positive and 89%, 80% and 70% in hepatitis C virus negative patients (p<0.001). Hepatitis C virus recurrence was observed in the majority of the patients (132 patients, 85%), mainly within the first year (83%). The authors observed recurrence within 6 months in 71 patients (56%), and within 3 months in 26 patients (20%). The mean hepatitis C virus recurrence free survival was 243 days. Higher rate of de novo diabetes was detected in case of early recurrence. The cumulative patient survival rates at 1, 3, 5, 10 years were 98%, 89.5%, 81% and 65% when hepatitis C virus recurrence exceeded 3 months and 64%, 53%, 30.5% and 30.5% in patients with early recurrence (p<0.001). CONCLUSIONS: Poor outcome of liver transplantation in hepatitis C virus positive patients is still a challenge. Hepatitis C virus recurrence is observed earlier after liver transplantation in comparison with a previous report of the authors. De novo diabetes occurs more frequently in case of early recurrence. Despite an immediate start of antiviral treatment, early recurrence has a significant negative impact on the outcome of transplantation. PMID- 23816897 TI - Filling in the blanks on solid fuel use: new model illustrates trends, highlights needs. PMID- 23816895 TI - [The "dress" makes the neuron -- different forms of the extracellular matrix in the central nervous system of vertebrates]. AB - INTRODUCTION: Extracellular matrix is a key component of most connective tissues. For decades, the presence of this chemically heterogeneous interface has been largely ignored or even denied in the central nervous system. It was not until the end of the last century that scientists turned their attention to this enigmatic substance and unravelled its versatile roles in the developing as well as the adult nervous system. AIM: The aim of the authors was to characterize different parts of the human central nervous system: the hippocampus, the lateral geniculate nucleus and the spinal cord. In addition they looked for connections between brain plasticity and extracellular matrix indifferent animal models. METHOD: The authors used two perfusion fixed human brain and spinal cord samples, 23 further human brain samples for disease-related investigations, 16 adult rat brains and 18 chicken brains of hatchlings, 13 days or three months of age. They visualized the extracellular matrix via lectin- and immunohistochemistry. RESULTS: It was demonstrated that the human central nervous system shows a bewildering phenotypic versatility in its various parts. The human spinal cord harbours perineuronal nets around long-range projection neurons whilst peri synaptic coats are enriched in the dorsal horn. Periaxonal coats protect functional synapses in neurodegeneration. In the rat thalamus, perineuronal matrix is enriched in less plastic territories and develops in accordance with its linked cortical region. In the chicken, perineuronal matrix is well established already at birth and its further development is not functionally dependent. CONCLUSIONS: In human, the perineuronal matrix shows a large diversity depending on regional distribution and function. The authors argue that the development and differentiation of extracellular matrix is strongly linked to those of neurons. This observation was based on findings in the domestic chick which exhibits an immediate maturity after hatching as well as on observations in rat thalamic nuclei which reflect the plasticity of their corresponding cortical fields. PMID- 23816898 TI - A stabilization device to improve the quality of cardiopulmonary resuscitation during ambulance transportation: a randomized crossover trial. AB - BACKGROUND: The quality of cardiopulmonary resuscitation (CPR) during ambulance transportation is suboptimal, and therefore measures that can improve the quality are desirable. PURPOSE: To evaluate whether the use of a stabilization device can improve the quality of CPR during ambulance transportation. METHODS: This randomized controlled crossover trial enrolled 22 experienced ambulance officers. Each participant performed CPR in an ambulance under three conditions with 72 h apart, each condition for 10 min: non-moving (NM), moving without device (MND), and moving with device (MD). The sequences of conditions were randomized. The primary outcomes were effective chest compressions recorded by the Laerdal Resusci-Anne Skill-reporter manikin. The secondary outcomes included the severity of back pain scored using the Brief Pain Inventory short-form, the physiology parameter before and after CPR, and the changes in postural stability which was represented by the sway index (SI) of lower back measured using a goniometer. RESULTS: The overall effective compressions in 10 min were 87.0+/-17% for NM, 59.0+/-19% for MND, and 69.0+/-23% for MD (p<0.001). Compared to MND, MD had a lower no-flow fraction while driving on curved sections (0.04 vs. 0.29, p<0.001). Whereas the pain severity and social interference scores were similar under all conditions, MND had a higher SI than MD and NM. CONCLUSIONS: The use of a stabilization device can improve the quality of CPR and posture stability during ambulance transportation, although the effects on the severity of back pain were not significant. PMID- 23816899 TI - Extracorporeal life support associated with hypothermia and normoxemia in refractory cardiac arrest. AB - AIM: We describe a 1-year experience with extracorporeal cardiopulmonary resuscitation (ECPR) for in-hospital (IHCA) and out-of-hospital cardiac arrest (OHCA) associated with intra-arrest hypothermia and normoxemia. METHODS: Since January 1st 2012, ECPR has been applied in our hospital to all patients less than 65 years of age and without major co-morbidities who develop refractory cardiac arrest (CA) with bystander CPR. Over a 1-year period of observation, we recorded 28-day survival with intact neurological outcome and the rate of organ donation. RESULTS: During the observational period, 24 patients were treated with ECPR, with a median age of 48 years. Ten patients had IHCA. Acute coronary syndrome and/or major arrhythmias were the main cause of arrest. Intra-arrest cooling was used in 17 patients; temperature on ECMO initiation in these patients was 32.9 degrees C [32-34]. The time from collapse to ECPR was 58 min [45-70] and was shorter in survivors than in non-survivors (41 min [39-58] vs. 60 min [55-77], p=0.059). Non-survivors were more likely to have coagulopathy and received more blood transfusions. Six patients (25%) survived with good neurological outcome at day 28. Four patients with irreversible brain damage had organ function suitable for donation. CONCLUSION: ECPR provided satisfactory survival rates with good neurologic recovery in refractory CA for both IHCA and OHCA. ECMO may help rapidly stabilise systemic haemodynamic status and restore organ function. PMID- 23816900 TI - Virtual arterial blood pressure feedback improves chest compression quality during simulated resuscitation. AB - INTRODUCTION: Quality chest compressions (CC) are the most important factor in successful cardiopulmonary resuscitation. Adjustment of CC based upon an invasive arterial blood pressure (ABP) display would be theoretically beneficial. Additionally, having one compressor present for longer than a 2-min cycle with an ABP display may allow for a learning process to further maximize CC. Accordingly, we tested the hypothesis that CC can be improved with a real-time display of invasively measured blood pressure and with an unchanged, physically fit compressor. METHODS: A manikin was attached to an ABP display derived from a hemodynamic model responding to parameters of CC rate, depth, and compression decompression ratio. The area under the blood pressure curve over time (AUC) was used for data analysis. Each participant (N=20) performed 4 CPR sessions: (1) No ABP display, exchange of compressor every 2 min; (2) ABP display, exchange of compressor every 2 min; (3) no ABP display, no exchange of the compressor; (4) ABP display, no exchange of the compressor. Data were analyzed by ANOVA. Significance was set at a p-value<0.05. RESULTS: The average AUC for cycles without ABP display was 5201 mm Hgs (95% confidence interval (CI) of 4804-5597 mm Hgs), and for cycles with ABP display 6110 mm Hgs (95% CI of 5715-6507 mm Hgs) (p<0.0001). The average AUC increase with ABP display for each participant was 20.2+/-17.4% 95 CI (p<0.0001). CONCLUSIONS: Our study confirms the hypothesis that a real-time display of simulated ABP during CPR that responds to participant performance improves achieved and sustained ABP. However, without any real-time visual feedback, even fit compressors demonstrated degradation of CC quality. PMID- 23816901 TI - The key role of psychosocial risk on therapeutic outcome in obese children and adolescents. Results from a longitudinal multicenter study. AB - OBJECTIVE: Childhood obesity is high on the global public health agenda. Although risk factors are well known, the influence of social risk on the therapeutic outcome of lifestyle intervention is poorly examined. This study aims to investigate the influence of migration background, low education, and parental unemployment. METHODS: 62,147 patients participated in multidimensional lifestyle intervention programs in 179 pediatric obesity centers. Data were collected using standardized software for longitudinal multicenter documentation. 12,305 (19.8%) attended care for 6-24 months, undergoing an intensive therapy period and subsequent follow-ups for up to 3 years. A cumulative social risk score was calculated based on different risk indicators. RESULTS: Migration background, low education, and parental employment significantly influenced the outcome of lifestyle intervention. The observed BMI-SDS reduction was significantly higher in the subgroup with low social risks factors (Delta BMI-SDS -0.19) compared to those presenting moderate (Delta BMI-SDS -0.14) and high social risk (Delta BMI SDS -0.11). CONCLUSION: Our data underline the effect of children's social setting on the outcome of multidimensional lifestyle intervention. The presence of a high social risk burden is a negative predictor for successful weight loss. Specific therapeutic programs need to be developed for disadvantaged children and adolescents. PMID- 23816902 TI - Phylogenetic relationships and Y genome origin in Elymus L. sensu lato (Triticeae; Poaceae) based on single-copy nuclear Acc1 and Pgk1 gene sequences. AB - To estimate the origin and genomic relationships of the polyploid species within Elymus L. sensu lato, two unlinked single-copy nuclear gene (Acc1 and Pgk1) sequences of eighteen tetraploids (StH and StY genomes) and fourteen hexaploids (StStH, StYP, StYH, and StYW genomes) were analyzed with those of 35 diploid taxa representing 18 basic genomes in Triticeae. Sequence and phylogenetic analysis suggested that: (1) the St, H, W, and P genomes were donated by Pseudoroegneria, Hordeum, Australopyrum, and Agropyron, respectively, while the Y genome is closely related to the Xp genome in Peridictyon sanctum; (2) different hexaploid Elymus s.l. species may derived their StY genome from different StY genome tetraploid species via independent origins; (3) due to incomplete lineage sorting and/or hybridization events, the genealogical conflict between the two gene trees suggest introgression involving some Elymus s.l. species, Pseudoroegneria, Agropyron and Aegilops/Triticum; (4) it is reasonable to recognize the StH genome species as Elymus sensu stricto, the StY genome species as Roegneria, the StYW genome species as Anthosachne, the StYH genome species as Campeiostachys, and the StYP genome species as Kengyilia. The occurrence of multiple origin and introgression could account for the rich diversity and ecological adaptation of Elymus s.l. species. PMID- 23816903 TI - Designing artificial photosynthetic devices using hybrid organic-inorganic modules based on polyoxometalates. AB - Artificial photosynthesis aims at capturing solar energy and using it to produce storable fuels. However, while there is reason to be optimistic that such approaches can deliver higher energy conversion efficiencies than natural photosynthetic systems, many serious challenges remain to be addressed. Perhaps chief among these is the issue of device stability. Almost all approaches to artificial photosynthesis employ easily oxidized organic molecules as light harvesters or in catalytic centres, frequently in solution with highly oxidizing species. The 'elephant in the room' in this regard is that oxidation of these organic moieties is likely to occur at least as rapidly as oxidation of water, meaning that current device performance is severely curtailed. Herein, we discuss one possible solution to this problem: using self-assembling organic polyoxometalate hybrid structures to produce compartments inside which the individual component reactions of photosynthesis can occur without such a high incidence of deleterious side reactions. PMID- 23816904 TI - Silicon solar cells: state of the art. AB - The vast majority of photovoltaic (PV) solar cells produced to date have been based on silicon wafers, with this dominance likely to continue well into the future. The surge in manufacturing volume over the last decade has resulted in greatly decreased costs. Multiple companies are now well below the US$1 W-1 module manufacturing cost benchmark that was once regarded as the lowest possible with this technology. Despite these huge cost reductions, there is obvious scope for much more, as the polysilicon source material becomes more competitively priced, the new 'quasi-mono' and related controlled crystallization directional solidification processes are brought fully online, the sizes of ingot produced this way increase, wafer slicing switches to much quicker diamond impregnated approaches and cell conversion efficiencies increase towards the 25 per cent level. This makes the US Government's 'SunShot' target of US$1 W-1 installed system cost by 2020 very achievable with silicon PVs. Paths to lower cost beyond this point are also explored. PMID- 23816905 TI - Polymer solar cells. AB - This article reviews the motivations for developing polymer-based photovoltaics and describes some of the material systems used. Current challenges are identified, and some recent developments in the field are outlined. In particular, recent work to image and control nanostructure in polymer-based solar cells is reviewed, and very recent progress is described using the unique properties of organic semiconductors to develop strategies that may allow the Shockley-Queisser limit to be broken in a simple photovoltaic cell. PMID- 23816906 TI - Prospects for conversion of solar energy into chemical fuels: the concept of a solar fuels industry. AB - There is, at present, no solar fuels industry anywhere in the world despite the well-publicized needs to replace our depleting stock of fossil fuels with renewable energy sources. Many obstacles have to be overcome in order to store sunlight in the form of chemical potential, and there are severe barriers to surmount in order to produce energy on a massive scale, at a modest price and in a convenient form. It is also essential to allow for the intermittent nature of sunlight, its diffusiveness and variability and to cope with the obvious need to use large surface areas for light collection. Nonetheless, we have no alternative but to devise viable strategies for storage of sunlight as biomass or chemical feedstock. Simple alternatives, such as solar heating, are attractive in terms of quick demonstrations but are not the answer. Photo-electrochemical devices might serve as the necessary machinery by which to generate electronic charge but the main problem is to couple these charges to the multi-electron catalysis needed to drive energy-storing chemical reactions. Several potential fuels (CO, H2, HCOOH, NH3, O2, speciality organics, etc.) are possible, but the photochemical reduction of CO2 deserves particular mention because of ever-growing concerns about overproduction of greenhouse gases. The prospects for achieving these reactions under ambient conditions are considered herein. PMID- 23816907 TI - Roles of cocatalysts in semiconductor-based photocatalytic hydrogen production. AB - A photocatalyst is defined as a functional composite material with three components: photo-harvester (e.g. semiconductor), reduction cocatalyst (e.g. for hydrogen evolution) and oxidation cocatalyst (e.g. for oxidation evolution from water). Loading cocatalysts on semiconductors is proved to be an effective approach to promote the charge separation and transfer, suppress the charge recombination and enhance the photocatalytic activity. Furthermore, the photocatalytic performance can be significantly improved by loading dual cocatalysts for reduction and oxidation, which could lower the activation energy barriers, respectively, for the two half reactions. A quantum efficiency (QE) as high as 93 per cent at 420 nm for H2 production has been achieved for Pt-PdS/CdS, where Pt and PdS, respectively, act as reduction and oxidation cocatalysts and CdS as a photo-harvester. The dual cocatalysts work synergistically and enhance the photocatalytic reaction rate, which is determined by the slower one (either reduction or oxidation). This work demonstrates that the cocatalysts, especially the dual cocatalysts for reduction and oxidation, are crucial and even absolutely necessary for achieving high QEs in photocatalytic hydrogen production, as well as in photocatalytic water splitting. PMID- 23816908 TI - Solar energy in the context of energy use, energy transportation and energy storage. AB - Taking the UK as a case study, this paper describes current energy use and a range of sustainable energy options for the future, including solar power and other renewables. I focus on the area involved in collecting, converting and delivering sustainable energy, looking in particular detail at the potential role of solar power. Britain consumes energy at a rate of about 5000 watts per person, and its population density is about 250 people per square kilometre. If we multiply the per capita energy consumption by the population density, then we obtain the average primary energy consumption per unit area, which for the UK is 1.25 watts per square metre. This areal power density is uncomfortably similar to the average power density that could be supplied by many renewables: the gravitational potential energy of rainfall in the Scottish highlands has a raw power per unit area of roughly 0.24 watts per square metre; energy crops in Europe deliver about 0.5 watts per square metre; wind farms deliver roughly 2.5 watts per square metre; solar photovoltaic farms in Bavaria, Germany, and Vermont, USA, deliver 4 watts per square metre; in sunnier locations, solar photovoltaic farms can deliver 10 watts per square metre; concentrating solar power stations in deserts might deliver 20 watts per square metre. In a decarbonized world that is renewable-powered, the land area required to maintain today's British energy consumption would have to be similar to the area of Britain. Several other high-density, high-consuming countries are in the same boat as Britain, and many other countries are rushing to join us. Decarbonizing such countries will only be possible through some combination of the following options: the embracing of country-sized renewable power-generation facilities; large-scale energy imports from country-sized renewable facilities in other countries; population reduction; radical efficiency improvements and lifestyle changes; and the growth of non-renewable low-carbon sources, namely 'clean' coal, 'clean' gas and nuclear power. If solar is to play a large role in the future energy system, then we need new methods for energy storage; very-large-scale solar either would need to be combined with electricity stores or it would need to serve a large flexible demand for energy that effectively stores useful energy in the form of chemicals, heat, or cold. PMID- 23816909 TI - Prospects and performance limitations for Cu-Zn-Sn-S-Se photovoltaic technology. AB - While cadmium telluride and copper-indium-gallium-sulfide-selenide (CIGSSe) solar cells have either already surpassed (for CdTe) or reached (for CIGSSe) the 1 GW yr-1 production level, highlighting the promise of these rapidly growing thin film technologies, reliance on the heavy metal cadmium and scarce elements indium and tellurium has prompted concern about scalability towards the terawatt level. Despite recent advances in structurally related copper-zinc-tin-sulfide-selenide (CZTSSe) absorbers, in which indium from CIGSSe is replaced with more plentiful and lower cost zinc and tin, there is still a sizeable performance gap between the kesterite CZTSSe and the more mature CdTe and CIGSSe technologies. This review will discuss recent progress in the CZTSSe field, especially focusing on a direct comparison with analogous higher performing CIGSSe to probe the performance bottlenecks in Earth-abundant kesterite devices. Key limitations in the current generation of CZTSSe devices include a shortfall in open circuit voltage relative to the absorber band gap and secondarily a high series resistance, which contributes to a lower device fill factor. Understanding and addressing these performance issues should yield closer performance parity between CZTSSe and CdTe/CIGSSe absorbers and hopefully facilitate a successful launch of commercialization for the kesterite-based technology. PMID- 23816910 TI - Concentrating solar thermal power. AB - In addition to wind and photovoltaic power, concentrating solar thermal power (CSP) will make a major contribution to electricity provision from renewable energies. Drawing on almost 30 years of operational experience in the multi megawatt range, CSP is now a proven technology with a reliable cost and performance record. In conjunction with thermal energy storage, electricity can be provided according to demand. To date, solar thermal power plants with a total capacity of 1.3 GW are in operation worldwide, with an additional 2.3 GW under construction and 31.7 GW in advanced planning stage. Depending on the concentration factors, temperatures up to 1000 degrees C can be reached to produce saturated or superheated steam for steam turbine cycles or compressed hot gas for gas turbine cycles. The heat rejected from these thermodynamic cycles can be used for sea water desalination, process heat and centralized provision of chilled water. While electricity generation from CSP plants is still more expensive than from wind turbines or photovoltaic panels, its independence from fluctuations and daily variation of wind speed and solar radiation provides it with a higher value. To become competitive with mid-load electricity from conventional power plants within the next 10-15 years, mass production of components, increased plant size and planning/operating experience will be accompanied by technological innovations. On 30 October 2009, a number of major industrial companies joined forces to establish the so-called DESERTEC Industry Initiative, which aims at providing by 2050 15 per cent of European electricity from renewable energy sources in North Africa, while at the same time securing energy, water, income and employment for this region. Solar thermal power plants are in the heart of this concept. PMID- 23816911 TI - Concentrated solar power in the future of electricity generation: a synthesis of reasons. PMID- 23816912 TI - The use and misuse of photosynthesis in the quest for novel methods to harness solar energy to make fuel. AB - This short review will illustrate that photosynthesis can provide a real contribution towards our sustain- able, green fuel requirements in the future. However, it is argued that the focus on biofuels is misplaced and that, in the longer term, investment in artificial photosynthesis will prove much more beneficial. PMID- 23816913 TI - The use of solar energy can enhance the conversion of carbon dioxide into energy rich products: stepping towards artificial photosynthesis. AB - The need to cut CO2 emission into the atmosphere is pushing scientists and technologists to discover and implement new strategies that may be effective for controlling the CO2 atmospheric level (and its possible effects on climate change). One option is the capture of CO2 from power plant flue gases or other industrial processes to avoid it entering the atmosphere. The captured CO2 can be either disposed in natural fields (geological cavities, spent gas or oil wells, coal beads, aquifers; even oceans have been proposed) or used as a source of carbon in synthetic processes. In this paper, we present the options for CO2 utilization and make an analysis of possible solutions for the conversion of large volumes of CO2 by either combining it with H2, that must be generated from water, or by directly converting it into fuels by electrolysis in water using solar energy. A CO2-H2-based economy may address the issue of reducing the environmental burden of energy production, also saving fossil carbon for future generations. The integration of CO2 capture and utilization with CO2 capture and storage would result in a more economically and energetically viable practice of CO2 capture. PMID- 23816914 TI - Molecular approaches to solar energy conversion: the energetic cost of charge separation from molecular-excited states. AB - This review starts with a brief overview of the technological potential of molecular-based solar cell technologies. It then goes on to focus on the core scientific challenge associated with using molecular light-absorbing materials for solar energy conversion, namely the separation of short-lived, molecular excited states into sufficiently long-lived, energetic, separated charges capable of generating an external photocurrent. Comparisons are made between different molecular-based solar cell technologies, with particular focus on the function of dye-sensitized photoelectrochemical solar cells as well as parallels with the function of photosynthetic reaction centres. The core theme of this review is that generating charge carriers with sufficient lifetime and a high quantum yield from molecular-excited states comes at a significant energetic cost-such that the energy stored in these charge-separated states is typically substantially less than the energy of the initially generated excited state. The role of this energetic loss in limiting the efficiency of solar energy conversion by such devices is emphasized, and strategies to minimize this energy loss are compared and contrasted. PMID- 23816915 TI - Can solar power deliver? AB - Solar power represents a vast resource which could, in principle, meet the world's needs for clean power generation. Recent growth in the use of photovoltaic (PV) technology has demonstrated the potential of solar power to deliver on a large scale. Whilst the dominant PV technology is based on crystalline silicon, a wide variety of alternative PV materials and device concepts have been explored in an attempt to decrease the cost of the photovoltaic electricity. This article explores the potential for such emerging technologies to deliver cost reductions, scalability of manufacture, rapid carbon mitigation and new science in order to accelerate the uptake of solar power technologies. PMID- 23816916 TI - Realizing solar power's potential in the European Union. AB - The European Union aims at largely decarbonizing its energy system by 2050. In this context, this paper reviews the status of the solar electricity technologies that can exploit our largest renewable energy resource. Although substantial progress is being made, the possibility, for instance, to more than double the efficiency of photovoltaic systems underlines the continued need for coordinated R&D efforts, aimed also at promoting European expertise and industrial competiveness. In parallel, it is important to expand the market by developing integrated building products and by demonstrating the viability of very large scale systems for both technologies. PMID- 23816917 TI - Solar power. Preface. PMID- 23816918 TI - Communication in the initial paediatric consultation. AB - The first time a paediatrician meets with a patient, either with or without parents or caretakers, there are generally two aims with this consultation. Aside from exchanging relevant information for diagnosis, a relationship develops. This relationship is an important factor in the encounter: it can facilitate or impede collaboration between the partners in the consultation. The paediatrician can influence this relationship so that it becomes beneficial in the diagnostic process and in creating a collaborative atmosphere in the consultation, which in turn will prove useful for adherence. This paper addresses this second aim: how can we use the relationship between the patients (with or without parents) and their doctors to enhance the quality and effectiveness of the encounter. Below we will first address why investing in a relationship is beneficial. Next we will describe how this can be done. The review will continue with a discussion of three important pitfalls and how to avoid them, and a small epilogue will provide a brief summary. PMID- 23816919 TI - Survey and census of hoolock gibbon (Hoolock hoolock) in the Inner-Line Reserve Forest and the adjoining areas of Cachar district, Assam, India. AB - A detailed survey of Hoolock hoolock was carried out in the Inner-Line Reserve Forest and the adjoining areas of Cachar district of southern Assam, India, from July 2010 to December 2011. About 150 km2 of the area was covered. In direct sighting, groups and individuals were counted in 7 localities (39.7 km2). Only 3.96 km2 of the actual forest area were occupied by these gibbons. Nine family groups and a solitary subadult, 33 individuals in all, made up the total count. Of these, adult males and females comprised 54.5% of the population while the subadults, juveniles and infants comprised 27.3, 12.1 and 6.1%, respectively. Each family group's home range was 0.31-0.51 km2. Of the 7 localities, only 1 had more than 1 family group. Habitat destruction and diverse threats to the hoolock gibbon in this area are examined in this paper. PMID- 23816920 TI - Immunologic effects of omalizumab in children with severe refractory atopic dermatitis: a randomized, placebo-controlled clinical trial. AB - BACKGROUND: Severe refractory atopic dermatitis (AD) is a chronic, debilitating condition that is associated with elevated serum immunoglobulin E (IgE) levels. Thymic stromal lymphopoietin (TSLP), thymus and activation-regulated chemokine (TARC) and OX40 ligand (OX40L) are important immunologic factors involved in the pathogenesis of AD. Omalizumab, an anti-IgE antibody indicated for use in allergic asthma, is implicated in regulating allergen presentation by dendritic cells and the T cell response during the effector phases of allergic disease. We investigated if anti-IgE therapy modulates the allergen-specific responses mediated by the TSLP pathway in young patients with severe refractory AD. METHODS: This was a randomized, double-blind, placebo-controlled study of 8 patients between the ages of 4 and 22 years (mean = 11.6 years) with severe refractory AD (clinical trials.gov NCT01678092). Serum IgE ranged from 218 to 1,890 (mean = 1,068 IU/ml). Subjects received omalizumab (n = 4) or placebo (n = 4) every 2-4 weeks over 24 weeks using a regimen extrapolated from the package insert. TSLP, TARC, OX40L and other cytokines involved in AD were measured by using cytometric bead arrays. RESULTS: All patients receiving omalizumab had strikingly decreased levels of TSLP, OX40L, TARC (involved in Th2 polarization) and interleukin (IL)-9 compared to placebo. In addition, there was a marked increase in IL-10, a tolerogenic cytokine, in the omalizumab-treated group. Patients on anti-IgE therapy had an improvement in clinical outcomes as measured by the SCORAD system; however, these effects were comparable to improvements in the control group. CONCLUSIONS: Anti-IgE therapy with omalizumab decreases levels of cytokines that are involved in Th2 polarization and allergic inflammation, including TSLP, TARC and OX40L. PMID- 23816921 TI - Electrically induced resistance training in individuals with motor complete spinal cord injury. AB - OBJECTIVE: To examine the effects of 16 weeks of electrically induced resistance training on insulin resistance and glucose tolerance, and changes in muscle size, composition, and metabolism in paralyzed muscle. DESIGN: Pre-post intervention. SETTING: University-based trial. PARTICIPANTS: Participants (N=14; 11 men and 3 women) with chronic (>2y post spinal cord injury), motor complete spinal cord injury. INTERVENTION: Home-based electrically induced resistance exercise training twice weekly for 16 weeks. MAIN OUTCOME MEASURES: Plasma glucose and insulin throughout a standard clinical oral glucose tolerance test, thigh muscle and fat mass via dual-energy x-ray absorptiometry, quadriceps and hamstrings muscle size and composition via magnetic resonance imaging, and muscle oxidative metabolism using phosphorus magnetic resonance spectroscopy. RESULTS: Muscle mass increased in all participants (mean +/- SD, 39%+/-27%; range, 5%-84%). The mean change +/- SD in intramuscular fat was 3%+/-22%. Phosphocreatine mean recovery time constants +/- SD were 102+/-24 and 77+/-18 seconds before and after electrical stimulation-induced resistance training, respectively (P<.05). There was no improvement in fasting blood glucose levels, homeostatic model assessment calculated insulin resistance, 2-hour insulin, or 2-hour glucose. CONCLUSIONS: Sixteen weeks of electrical stimulation-induced resistance training increased muscle mass, but did not reduce intramuscular fat. Similarly, factors associated with insulin resistance or glucose tolerance did not improve with training. We did find a 25% improvement in mitochondrial function, as measured by phosphocreatine recovery rates. Larger improvements in mitochondrial function may translate into improved glucose tolerance and insulin resistance. PMID- 23816922 TI - Examination of sustained gait speed during extended walking in individuals with chronic stroke. AB - OBJECTIVES: To determine if individuals with chronic stroke were able to sustain their peak gait speed during the 6-minute walk test (6MWT), and to explore this sustainability across community ambulation potential subgroups. DESIGN: Prospective cross-sectional study. SETTING: University-based research laboratory, hospitals, and stroke support groups. PARTICIPANTS: A sample of individuals with chronic stroke (N=48) completed a series of questionnaires and physical outcome measures, including gait mat assessment, during a single visit. INTERVENTIONS: Not applicable; 1-time cross-sectional data collection. MAIN OUTCOME MEASURES: During the 6MWT, we measured peak gait speed and end gait speed to assess sustainability, along with beginning gait speed, total distance walked, and rating of perceived exertion. We also assessed maximum gait speed during the 10 meter walk test (10MWT). Finally, we examined these gait outcomes across the subgroups. RESULTS: During the 6MWT, peak gait speed declined from .89m/s (SD=.38) to an end speed of .82m/s (SD=.36), whereas perceived exertion increased from 7.7 (SD=2.6) to 11.8 (SD=3.6). This peak gait speed was slower than the 10MWT maximum speed of 1.06m/s (SD=.51), but faster than the 6MWT beginning speed of .81m/s (SD=.34). The unlimited community ambulator subgroup was the primary contributor to sustainability differences. CONCLUSIONS: Predicting community ambulation potential based on the discrete gait speed from the 10MWT and endurance based on the average from the 6MWT might be incomplete if gait speed sustainability is not also assessed. PMID- 23816923 TI - What is the relation between fear of falling and physical activity in older adults? AB - OBJECTIVE: To describe the association between fear of falling (FOF) and total daily activity in older adults. DESIGN: Cross-sectional observational study. SETTING: Ambulatory clinical research training center. PARTICIPANTS: Community dwelling older adults aged >=64 years (N=78), who were independent in ambulation with or without an assistive device. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: FOF was defined by self-reported fear ratings using the Survey of Activities and Fear of Falling in the Elderly and self-reported fear status determined by response to the following question: Are you afraid of falling? Physical function was assessed using the Late Life Function and Disability Instrument. Physical activity was recorded using an accelerometer worn on the waist for 7 consecutive days, and mean daily counts of activity per minute were averaged over the 7-day period. RESULTS: Fear ratings were related to total daily activity (r=-.26, P=.02). The relation was not as strong as the relation of function and physical activity (r=.45, P<.001). When stratified by exercise status or functional status, fear was no longer related to total daily activity. Physical function explained 19% of the variance in physical activity, whereas the addition of fear status did not add to the explained variance in physical activity. CONCLUSIONS: FOF is related to total daily physical activity; however, FOF was not independently associated with physical activity when accounting for physical function. Some FOF may be reported as a limitation in function. PMID- 23816924 TI - Case report: endurance electrical stimulation training improves skeletal muscle oxidative capacity in chronic spinal cord injury. AB - OBJECTIVE: To describe the use of a novel neuromuscular electrical stimulation (NMES) endurance exercise protocol and its effects on skeletal muscle oxidative capacity. DESIGN: Case report, pre/post intervention. SETTING: University-based trial. PARTICIPANT: A 39-year-old man who suffered a motor complete spinal cord injury (C5-6, ASIA Impairment Scale grade A). INTERVENTION: Twenty-four weeks of endurance NMES that consisted of progressive increases in the twitch frequency, duration of sessions, and sessions per week. MAIN OUTCOME MEASURE: Mitochondrial capacity was measured, in vivo, as the rate of recovery of muscle oxygen consumption using near-infrared spectroscopy. RESULTS: The rate of recovery of muscle oxygen consumption increased approximately 3-fold from 0.52 to 1.43, 1.46, and 1.40/min measured on 3 separate occasions during week 12 of training, and 1.57/min after 24 weeks of NMES endurance training. CONCLUSION: The findings of this study suggest that NMES endurance training using twitches can increase mitochondrial capacity to comparable levels measured in nonparalyzed muscles of sedentary able-bodied controls. PMID- 23816925 TI - Spontaneous knot formation in the peritoneal catheter: a rare cause of ventriculoperitoneal shunt malfunction. AB - Ventriculoperitoneal shunt malfunction is a relatively common problem encountered in shunted hydrocephalic patients and is attributed most frequently to mechanical obstruction of the ventricular catheter. We present the case of a rare cause of mechanical obstruction of the peritoneal catheter due to the spontaneous formation of a knot just underneath the abdominal wound. This occurred 1 year after shunt implantation and is thought to have been caused by a combination of plastic material memory and bowel peristaltic movements. This case brings for discussion the role of radiographic investigation of the shunt system in children who present with suspected shunt obstruction. Radiographic investigation is warranted in children who have unusual shunt arrangements (e.g., Y-connectors and multiple catheters) in order to exclude disconnections or those who develop shunt problems years after implantation, to exclude material fracture in the neck or migration of any kind. In shunt systems which have been implanted for shorter time periods, the need for radiographs is less apparent. Some surgeons proclaim that when clinical circumstances fall outside the realms of obvious possible proximal obstruction, radiographic evaluation of the shunt system should be considered. PMID- 23816926 TI - On the existence of the positive steady states of weakly reversible deficiency one mass action systems. AB - In this paper we prove that there exists a positive steady state in each positive stoichiometric class for every weakly reversible deficiency-one mass action system. This qualitative property does not depend on the values of the rate coefficients. Since not all weakly reversible deficiency-one mass action systems satisfy the assumptions of the Deficiency-One Theorem, our result contributes to the theory of deficiency-one mass action systems. PMID- 23816927 TI - Joint distribution of first exit times of a two dimensional Wiener process with jumps with application to a pair of coupled neurons. AB - Motivated by a neuronal modeling problem, a bivariate Wiener process with two independent components is considered. Each component evolves independently until one of them reaches a threshold value. If the first component crosses the threshold value, it is reset while the dynamics of the other component remains unchanged. But, if this happens to the second component, the first one has a jump of constant amplitude; the second component is then reset to its starting value and its evolution restarts. Both processes evolve once again until one of them reaches again its boundary. In this work, the coupling of the first exit times of the two connected processes is studied. PMID- 23816928 TI - Overexpression of Arachis hypogaea NAC3 in tobacco enhances dehydration and drought tolerance by increasing superoxide scavenging. AB - Drought stress can severely affect plant growth and substantially diminish crop yields. We previously isolated Arachis hypogaea NAC3 (AhNAC3), a dehydration induced NAM/ATAF/CUC (NAC) gene from peanut. In this study, to examine the role of AhNAC3 in stress tolerance, we constructed transgenic tobacco lines overexpressing AhNAC3. The transgenic plants showed hyper-resistance to dehydration and drought stresses and accumulated more proline and less superoxide anion (O2(-)) than wild type under dehydration and drought conditions. Moreover, the transgenic plants showed upregulation of four functional genes, superoxide dismutase (SOD), pyrroline-5-carboxylate synthetase (P5SC), late embryogenic abundant proteins (LEA), and early response to drought 10 (ERD10C). Protein localization and transactivation analysis suggested that AhNAC3 activates its specific targets in the nucleus. These results suggest that AhNAC3 is a dehydration-induced transcription factor that improves water stress tolerance by increasing superoxide scavenging and promoting the accumulation of various protective molecules. PMID- 23816929 TI - Prevalence, awareness, treatment and control of hypertension among adults in rural north-western China: a cross-sectional population survey. AB - OBJECTIVE: To assess rates and determinants of prevalence, awareness, treatment and control of hypertension in rural north-western China. METHODS: Adults were recruited from five surveillance areas in Gansu Province using a three-stage cluster sampling plan. A combination of household and community-based surveys was employed and two methods of surveillance (questionnaire and physical measurement) were undertaken. RESULTS: A total of 3000 subjects were included; 1100 (36.7%) had hypertension. Hypertension was associated with older age, lower educational levels and being overweight or obese. Only 407 (37%) subjects with hypertension were aware of their condition. Multiple logistic regression showed significant correlations between hypertension awareness and age, obesity and central obesity. Antihypertensive treatment was received by 31.2% of participants with hypertension. Obesity, smoking and older age were associated with treatment. Blood pressure was controlled in 18.1% of participants receiving antihypertensive treatment and in 5.6% of subjects with hypertension overall. CONCLUSION: In conclusion, prevalence of hypertension is rapidly increasing in rural north western China. Rates of awareness and treatment of hypertension remain low and blood pressure is poorly controlled. PMID- 23816930 TI - Toll-like receptor 9 (TLR9) gene polymorphisms associated with increased susceptibility of human papillomavirus-16 infection in patients with cervical cancer. AB - OBJECTIVES: To investigate the association between toll-like receptor 9 (TLR9) single nucleotide polymorphisms (SNPs) and human papillomavirus (HPV) infection among Chinese Han women with cervical cancer. METHODS: TLR9 -1486 and 2848 SNPs were investigated in patients with cervical cancer and controls using polymerase chain reaction (PCR)-restriction fragment length polymorphism. HPV16 E6 and E7 infections were assessed using PCR. RESULTS: Of 120 patients with cervical cancer and 100 controls, there was a significant association between TLR9 2848 SNP and cervical cancer risk, but there was no such association with TLR9 -1486 SNP. Frequency of the TLR9 2848 GA genotype was significantly higher in patients with cervical cancer than in controls. There was no statistically significant between group difference in presence of HPV16 infection. Presence of HPV infection with TLR9 2848 (rs352140) GA/AA genotype increased the risk of cervical cancer 13.8 fold compared with the GG genotype. CONCLUSIONS: The TLR9 2848 G/A polymorphism in Chinese Han women was associated with increased risk of cervical cancer in the presence of HPV16 infection. Further studies are necessary to uncover the functional aspect of this TLR9 2848 polymorphism. PMID- 23816931 TI - Neuroendocrine and haemodynamic changes in single-lead atrial pacing and dual chamber pacing modes. AB - OBJECTIVES: Neuroendocrine and haemodynamic changes were compared between single lead atrial (AAI) or dual-chamber (DDD) pacing modes in patients with sick sinus syndrome, in a crossover study. METHODS: Inpatients scheduled for their first pacemaker implantation were screened for the following inclusion criteria: sick sinus syndrome; intact atrioventricular conduction; normal QRS interval. All study patients were implanted with a dual-chamber pacemaker, programmed for AAI or DDD pacing mode. Patients were allocated randomly to AAI followed by DDD pacing or to DDD followed by AAI pacing, each mode being applied for 72 h. Echocardiographic, electrocardiographic and neuroendocrine parameters were tested at the end of each pacing mode. RESULTS: From 152 inpatients screened for inclusion, 28 were selected for treatment. Plasma levels of atrial natriuretic peptide (ANP), endothelin, aldosterone and angiotension II were significantly lower, and aortic flow velocity-time integral was significantly higher, in AAI mode than in DDD mode. Aortic pre-ejection interval, interventricular mechanical delay and QRS duration were significantly higher in DDD than in AAI mode. CONCLUSIONS: In patients with sick sinus syndrome, DDD pacing mode can induce neuroendocrine system activation, and left ventricular dysfunction and dyssynchrony. These findings discourage the routine use of DDD pacing in patients with sick sinus syndrome. PMID- 23816932 TI - Functional -141C Ins/Del polymorphism in the dopamine D2 receptor gene promoter and schizophrenia in a Chinese Han population. AB - OBJECTIVE: The association between a putative functional promoter polymorphism, 141C insertion/deletion (Ins/Del), in the dopamine receptor D2 gene (DRD2) and schizophrenia was investigated in a Chinese Han population. METHODS: The polymorphism was studied in unrelated schizophrenia patients and unrelated healthy controls. Linkage relationships were explored in core families of the schizophrenic patients using the transmission disequilibrium test. The Positive and Negative Syndrome Scale was used to evaluate the severity of the disorder. RESULTS: The Del allele was significantly less frequently found in patients (13/120; 11%) than in controls (18/100; 18%). In the 32 core families studied, 16 parents were Ins/Del heterozygotes. Parents transmitted the Ins and Del alleles to their children in 10 and six cases, respectively. Data from core families did not demonstrate linkage. Age, age at onset of schizophrenia and sex were not significantly different between carriers of the Ins and Del alleles. The group with the Ins allele had a significantly higher positive symptom score (75.3 +/- 23.4 versus 53.9 +/- 21.9) and excitement score (83.6 +/- 16.8 versus 50.3 +/- 24.6) than the Del group. Groups did not differ significantly in negative symptom and general psychopathology scores. CONCLUSIONS: The DRD2 -141C Ins/Del polymorphism may affect susceptibility to schizophrenia in a Chinese Han population. PMID- 23816933 TI - Increased expression of estrogen receptor alpha-36 by breast cancer oncogene IKKepsilon promotes growth of ER-negative breast cancer cells. AB - BACKGROUND/AIMS: The expression of estrogen receptor-alpha (ERalpha) is one of the most important diagnostic and prognostic factors of breast cancer. Recently, ERalpha-36 has been identified as a novel variant of ER-alpha. ERalpha-36 lacks intrinsic transcription activity and mainly mediates non-genomic estrogen signaling. The noncanonical IKK family member IKKepsilon is essential for regulating antiviral signaling pathways and is recently discovered as a breast cancer oncogene. IKKepsilon interacts with and phosphorylates ERalpha on serine 167, induces ERalpha transactivation activity and enhances ERalpha binding to DNA in ER-positive breast cancer cells. However, the correlation between IKKepsilon and the ERalpha-36 signaling pathway in ER-negative breast cancer cells remains unclear. METHODS AND RESULTS: In this study, we show that IKKepsilon interacts with ERalpha-36 and increases its expression in breast cancer cells. As shown by western blot assays, the upregulation of ERalpha-36 by IKKepsilon was significant. In MDA-MB-231 cells which are ER-negative, IKKepsilon was able to increase the expression of ERalpha-36 in a dose-dependent manner, and the RNA interference assay indicated the correlation between IKKepsilon and ERalpha-36 expression. Moreover, IKKepsilon enhanced the growth of MDA-MB-231 and MDA-MB-436 cells. CONCLUSIONS: These results suggest that IKKepsilon increases ERalpha-36 expression and is involved in ERalpha-36 mediated non-genomic estrogen signaling. PMID- 23816934 TI - Tox21 to date: steps toward modernizing human hazard characterization. PMID- 23816935 TI - Polycystic ovary syndrome: clinical presentation in normal-weight compared with overweight adolescents. AB - OBJECTIVE: To characterize polycystic ovary syndrome (PCOS) in adolescents and determine whether a distinct clinical presentation differentiates normal-weight (NW) from overweight (OW) PCOS. METHODS: Retrospective chart review of patients seen in a tertiary care center from 1998-2008 who met the National Institutes of Health and/or Rotterdam criteria for PCOS (N = 211; NW = 43, OW = 168). We collected data on clinical features, biochemical markers, and ultrasound findings. RESULTS: Patient age ranged from 11.3 to 20.3 years (mean, 15.7 +/- 1.7 years), and body mass index (BMI) from 17.4 to 64.2 kg/m2 (mean, 31.7 +/- 7.7 kg/m2). Seventy-one percent of patients were Caucasian, 85% had irregular menses, 69% reported hirsutism, 18% had moderate to severe acne, 91% had a high free androgen index (FAI), and 8% had abnormal thyroid-stimulating hormone (TSH) levels. The BMI-standard deviation (SD) score was 0.1 +/- 0.5 in NW and 3.4 +/- 1.8 in OW girls. NW girls were older at diagnosis (16.4 +/- 1.4 years vs. 15.5 +/ 1.7 years; P = .0006) than OW girls, less likely to have a family history of obesity (22% vs. 65%; P<.0001), and less likely to have acanthosis nigricans (11% vs. 68%; P<.0001). NW girls were more likely to have polycystic ovaries on ultrasound (88% vs. 52%; P = .01) and a lower FAI (7.3 +/- 4.5 vs. 17.4 +/- 12.9; P<.0001). The BMI-SD score was negatively associated with sex hormone binding globulin (r(s) = -0.52; P<.0001) and positively associated with FAI (r(s) = 0.42; P<.0001). CONCLUSION: NW girls are more likely to be older at diagnosis and have polycystic ovaries. Other differences in presentation between groups were attributable to differences in weight. NW PCOS is likely part of a continuous spectrum of clinical PCOS rather than a distinct entity. PMID- 23816938 TI - Calcium and vitamin D intake in women with low bone mass referred to an endocrine clinic for bone health evaluation. PMID- 23816939 TI - Preoperative acetazolamide SPECT is useful for predicting outcome of shunt operation in idiopathic normal pressure hydrocephalus patients. AB - PURPOSE OF THE REPORT: Good outcome of shunt surgery for idiopathic normal pressure hydrocephalus (iNPH) patients are highly dependent on accurate preoperative assessments. Acetazolamide ethylcysteinate-dimer-single photon emission computer tomography (SPECT) was applied to iNPH patients for more exact preoperative evaluation. PATIENTS AND METHODS: Sixty-five patients were categorized into 3 groups: group I (normals, n = 30), group II (with ventriculomegaly due to age-relating changes, n = 10), and group III (who underwent shunt surgery based on the diagnosis of iNPH, n = 25). Acetazolamide SPECT was performed in all patients, and mini-mental state examination (MMSE) was performed before and 1 month after the surgery in group III. RESULTS: Acetazolamide SPECT study demonstrated normal increase of cerebral blood flow (CBF, more than 40%) in groups I and II. Group III was classified into 2 subgroups on the examination; a mean increasing percentage (%increase) of CBF was less than 20% in group IIIa and more than 40% in group IIIb. One month after the surgery, acetazolamide SPECT showed normal %increase of CBF in IIIa, and the increase in postoperative MMSE score was significantly greater in group IIIa than IIIb (P < 0.05). In iNPH patients, less than 20% increase in preoperative acetazolamide SPECT predicted improvement of MMSE score with 100% sensitivity and 60% specificity. CONCLUSIONS: Poor %increase of CBF by acetazolamide implies a low capacity for vasodilation in the brain due to compression and stretching by ventriculomegaly. Acetazolamide SPECT study is not an absolute examination but one of the valuable supplementary objective examinations to determine the surgical indication in iNPH-suspected patients. PMID- 23816937 TI - American Association of Clinical Endocrinologists' comprehensive diabetes management algorithm 2013 consensus statement--executive summary. PMID- 23816940 TI - Tumor localization in ectopic Cushing syndrome using combined PET/CT imaging. AB - Diagnosis of ectopic Cushing syndrome is challenging. The best imaging approach for localizing ectopic ACTH-secreting tumors is not defined. Here, we report on a 68-year-old woman with new-onset hypertension (>200/90 mm Hg) who was referred to our institution with suspicion of ectopic ACTH-secreting tumor for further work up. Combined FDG PET/CT as a whole-body imaging modality revealed a neuroendocrine tumor of the pancreatic tail confirmed by surgical exploration. PMID- 23816941 TI - 18F-fluoride PET/CT scan for quantification of bone metabolism in the inner ear in patients with otosclerosis--a pilot study. AB - BACKGROUND: In otosclerosis, CT of the temporal bone is used to confirm the diagnosis. Whereas CT is a static diagnostic tool displaying the demineralization caused by otosclerosis, imaging of bone metabolism by (18)F-fluoride PET may provide quantitative information. This could be useful for prognosis and stratification of patients. The aim of this study was to assess (18)F-fluoride activity in patients with otosclerosis and to evaluate its use as a complementary diagnostic tool. METHODS: All patients with otosclerosis underwent a PET/CT scan. Audiometric data were collected. The severity of otosclerosis was assessed using a recognized radiological classification. The control group consisted of patients who had undergone (18)F-fluoride PET/CT scan for orthopedic purpose. Regions of interest were drawn on PET scans which corresponded to standardized anatomical sites as defined on CT, to measure bone metabolism using standardized uptake values (SUV(max) and SUV(mean)). RESULTS: Group 1 consisted of 11 otosclerosis patients (16 eligible temporal bones) and group 2 consisted of 5 control patients (10 temporal bones). On PET scan, visual assessment of temporal bones with otosclerosis showed increased metabolic activity in the otic capsule in 11/16 cases. The SUV(max) in the entire otic capsule was significantly higher in otosclerosis patients compared to control subjects. Significant differences in SUV(mean) were found between otosclerosis and control subjects in the fenestral and saccule area. Moreover, metabolic activity in these regions significantly correlated with hearing loss and CT classification. CONCLUSIONS: (18)F-Fluoride PET scanning using SUV measurements has the potential to be a diagnostic tool in otosclerosis. PMID- 23816942 TI - Evaluation of 18F-FDG excretion patterns in malignant obstructive uropathy. AB - OBJECTIVES: This study aims to evaluate whether (18)F-FDG excretion patterns reflect renal function in malignant obstructive uropathy and to evaluate if these patterns predict internal ureteral stent success. METHODS: One hundred twelve patients who underwent PET/CT for abdominal tumors and displayed hydronephrosis on CT and 59 patients who underwent PET/CT for cancer screening were included in a retrospective study. Hydronephrosis was graded by initial CT and correlated with visual analysis of (18)F-FDG renal parenchymal uptake and excretion patterns. Stent insertion was performed for 84 patients after PET. Follow-up CT was reviewed for hydronephrosis improvement. RESULTS: There were 4 PET patterns in obstructive hydronephrosis which correlated linearly with hydronephrosis severity and serum creatinine levels. Patients with no parenchymal retention and renal excretion (PET pattern 1) showed 97% (28/29) hydronephrosis improvement after stent insertion, and patients with no parenchymal retention and no renal excretion showed 0% (0/9) hydronephrosis improvement after stent insertion. Multivariate analysis showed creatinine levels and PET pattern predicted stent success, but CT hydronephrosis did not. CONCLUSIONS: There are 4 PET patterns of obstructive hydronephrosis which correlated with hydronephrosis grade and creatinine levels. Some of these PET patterns can be useful in the prediction of hydronephrosis improvement after stent insertion. Recognition of these patterns in obstructive hydronephrosis may be helpful in improving patient prognosis and quality of life. PMID- 23816943 TI - Increased FDG uptake along dermatome on PET in a patient with herpes zoster. AB - This is a 66-year-old female patient being treated for diffuse large B-cell lymphoma. She reported to her physician in late January 2012 with a left flank pruritic painful rash. She was diagnosed with herpes zoster and treated with antiviral medication. Her chemotherapy regimen was delayed due to the zoster infection. In March 2012, the patient underwent a PET/CT as a lymphoma surveillance scan prior to reinstituting the chemotherapy treatment. As an incidental finding, the PET showed increased metabolic activity in a dermatomal distribution along the left flank, which corresponded to the patient's zoster infection. PMID- 23816944 TI - Usefulness of PET/CT for the differentiation and characterization of periampullary lesions. AB - PURPOSE: At present, there is no ideal imaging modality for the diagnosis of periampullary lesions. We prospectively evaluated the preoperative diagnostic usefulness of PET/CT for differentiating malignant from benign periampullary lesions. METHODS: A total of 62 patients aged 27-86 years with periampullary lesions scheduled for surgical resection were consecutively recruited. Dual-phase (18)F-FDG PET/CT was performed in all patients. An additional 3'-deoxy-3' [(18)F]fluorothymidine (FLT) scan was performed in 21 patients (33.9%). The relationship of visual interpretation, SUV, and lesion to background ratio (LBR) with surgical histopathology diagnosis was evaluated. RESULTS: There were 36 patients with malignancies, 15 with benign neoplasms, and 11 with benign non neoplasms. Using visual analysis, FDG PET/CT had good sensitivity (86.1%; 31/36), lower specificity (57.7%; 15/26), and fair accuracy (74.2%; 46/62). Regional lymph node metastases were identified in 7 of 11 patients by FDG PET/CT and only in 1 patient by abdominal CT. On the other hand, hepatic metastasis was detected in 1 patient by FDG PET/CT. Dual-phase FDG (P < 0.001) and FLT (P < 0.05) SUV(max) and LBR were significantly higher in malignant than in benign lesions, and in malignant neoplasms than in benign neoplasms. Although average FLT SUV(max) was significantly lower than the average FDG SUV(max) (P < 0.001), the specificity and accuracy of the former were significantly better. CONCLUSION: FDG PET/CT may help identify patients with periampullary malignancy. FDG SUV(max) and LBR appear to aid in the differential diagnosis and add diagnostic confidence. In addition, higher specificity and diagnostic accuracy may be achieved by additional FLT PET/CT. PMID- 23816945 TI - Is 18F-FDG PET/CT useful for distinguishing between primary thyroid lymphoma and chronic thyroiditis? AB - PURPOSE: This study aims to investigate the usefulness of (18)F-FDG PET/CT for distinguishing between primary thyroid lymphoma (PTL) and chronic thyroiditis. METHODS: We retrospectively reviewed the data of 196 patients with diffuse (18)F FDG uptake of the thyroid gland and enrolled patients who were diagnosed as having PTL or chronic thyroiditis based on the medical records, pathological findings, and laboratory data. The enrolled patients comprised 10 PTL patients (M/F = 4:6) and 51 chronic thyroiditis patients (M/F = 8:43). Images had been acquired on a PET/CT scanner at 100 minutes after intravenous injection of (18)F FDG. RESULTS: The PTL group consisted of 7 patients with diffuse large B-cell lymphoma (DLBCL) and 3 with mucosa-associated lymphoid tissue (MALT) lymphoma. The maximum standardized uptake value (SUV(max)) was significantly higher in the PTL group than that in the chronic thyroiditis group (25.3 +/- 8.0 and 7.4 +/- 3.2, P < 0.001). On the other hand, the CT density (Hounsfield unit: HU) was significantly lower in the PTL group than that in the chronic thyroiditis group (46.1 +/- 7.0 HU and 62.1 +/- 6.9 HU, P < 0.001). Within the PTL group, the SUV(max) was significantly higher in the cases of DLBCL than in those of MALT lymphoma (29.0 +/- 6.4 and 16.7 +/- 2.3, P = 0.017). CONCLUSIONS: The SUV(max) was significantly higher and the CT density was significantly lower in PTL as compared with those in chronic thyroiditis. Thus, (18)F-FDG PET/CT may be useful for distinguishing between PTL and chronic thyroiditis. PMID- 23816946 TI - Complete normalization of severe brain 18F-FDG hypometabolism following electroconvulsive therapy in a major depressive episode. AB - We describe a patient with a complex neuropsychiatric disorder who presented a severe and diffuse cerebral glucose hypometabolism on (18)F-FDG PET initially which, in the clinical setting, was suspicious of an advanced neurodegenerative disease. Further evaluation suggested a major depressive episode with agitation and poor response to medication. Electroconvulsive therapy (ECT) brought excellent results. A follow-up cerebral (18)F-FDG PET was completely normal, thus illustrating the potential for complete recovery and normalization of brain metabolism in major depressive episode following ECT. It also shows the risk of false interpretation of brain PET in patients with depression. PMID- 23816947 TI - Abdominal lymph node metastasis in patients with non-small-cell lung cancer as shown by PET/CT. AB - PURPOSE: The aim of this study is to investigate the frequency and the spread of abdominal lymph node metastasis in patients with non-small-cell lung cancer (NSCLC) by (18)F-FDG PET/CT. PATIENTS AND METHODS: Retrospective evaluation of the (18)F-FDG PET/CT examinations of 1191 patients diagnosed with NSCLC was performed. The metastatic abdominal lymph nodes of the patients were classified as inside the routine imaging field (covering the field of chest CT including adrenal glands) and outside the field. RESULTS: Seventy-four patients (6 F, 68 M; mean: 61 +/- 11 years old) among 1191 patients (6%) were identified to have abdominal lymph node metastases. These abdominal lymph node metastasis changed management in 10 out of 74 patients (14%), and there were lymph node metastases outside the routine conventional imaging field in 43 (58%) patients. CONCLUSION: (18)F-FDG PET/CT provided identification of the distant metastatic lymph nodes out of conventional imaging field in more than half of NSCLC patients with abdominal metastasis which changed patient management in 14% of the patients due to abdominal lymph node metastasis outside the routine imaging field. This study shows the necessity of imaging NSCLC patients with an imaging protocol with larger imaging field like PET/CT. PMID- 23816948 TI - Metastatic prostate cancer proven by 18F-FCH PET/CT staging scan in patient with normal PSA but high PSA doubling time. AB - A 59-year-old man presented with frequent urination. Six months ago, his prostate specific antigen (PSA) was 1.56 ng/mL; currently it is 3.5 ng/mL (PSA doubling time = 6 months; PSA velocity = 0.19 ng/mL/mo). Biopsy revealed aggressive prostate cancer (Gleason score 5 + 5). Staging with (18)F-fluorocholine PET/CT ((18)F-FCH PET/CT) demonstrated lymph node metastasis. After 6 months of hormonal therapy with goserelin, PSA decreased to 0.38 ng/mL. A (18)F-FCH PET/CT restaging scan demonstrated a global reduction of (18)F-FCH lesion uptake with disappearance of some mediastinal and iliac pelvic lymph node activity. PMID- 23816949 TI - Reduced abuse, therapeutic errors, and diversion following reformulation of extended-release oxycodone in 2010. AB - This study evaluated changes in abuse exposures, therapeutic error exposures, and diversion into illegal markets associated with brand extended-release oxycodone (ERO) following introduction of reformulated ERO. Original ERO and reformulated ERO street prices also were compared. Data from the Poison Center and Drug Diversion programs of the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) System were used. Quarterly rates 2 years prior to introduction of reformulated ERO (October 2008 through September 2010) were compared to quarterly rates after introduction (October 2010 through March 2012) using negative binomial regression. Street prices were compared using a mixed effects linear regression model. Following reformulated ERO introduction, poison center ERO abuse exposures declined 38% (95% confidence interval [CI]: 31-45) per population and 32% (95% CI: 24-39) per unique recipients of dispensed drug. Therapeutic error exposures declined 24% (95% CI: 15-31) per population and 15% (95% CI: 6-24) per unique recipients of dispensed drug. Diversion reports declined 53% (95% CI: 41-63) per population and 50% (95% CI: 39-59) per unique recipients of dispensed drug. Declines exceeded those observed for other prescription opioids in aggregate. After its introduction, the street price of reformulated ERO was significantly lower than original ERO. PERSPECTIVE: This article indicates that the abuse, therapeutic errors, and diversion of ERO declined following the introduction of a tamper-resistant reformulation of the product. Reformulating abused prescription opioids to include tamper-resistant properties may be an effective approach to reduce abuse of such products. PMID- 23816950 TI - Long-term antidepressant treatment inhibits neuropathic pain-induced CREB and PLCgamma-1 phosphorylation in the mouse spinal cord dorsal horn. AB - The effect of long-term administration of imipramine, a tricyclic antidepressant, on the phosphorylation status of cyclic adenosine monophosphate-responsive element-binding protein (CREB), mitogen-activated protein kinase family members, and phospholipase gamma-1 (PLCgamma-1) was investigated in the dorsal horn of the spinal cord following peripheral nerve lesion. Nerve injury induced an ipsilateral long-lasting increased phosphorylation of CREB and PLCgamma-1 but not extracellular signal-regulated kinase (ERK1,2), p38, and c-Jun N-terminal kinase. Daily administration of imipramine (5, 10, or 30 mg/kg) for 21 days progressively reduced both tactile-induced neuropathic pain hypersensitivity and thermal hyperalgesia. After withdrawal of treatment, the antinociceptive effect of imipramine was gradually abolished but still remained for at least 3 weeks. Conversely, no analgesic effect was observed with short-term imipramine treatment. Moreover, imipramine therapy reversed nerve injury-induced CREB and PLCgamma-1 phosphorylation but had no effect on ERK1,2, p38, and c-Jun N-terminal kinase activity. These results indicate that long-term administration of imipramine may prevent some of the harmful changes in the spinal cord dorsal horn following nerve injury. However, imipramine analgesic effect takes time to develop and mature, which might explain in part why the clinical analgesic effect of tricyclic antidepressants develops with a delay after the beginning of treatment. Our data also provide evidence that prolonged imipramine treatment may induce antinociception in neuropathic pain conditions because of its action on the PLCgamma-1/CREB-signaling pathway. PERSPECTIVE: This article demonstrates that long-term treatment with imipramine reverses some of the marked effects induced by peripheral nerve injury in the spinal dorsal horn that contribute to long-term maintenance of sensory disorder, providing a new view to the mechanisms of action of these drugs. PMID- 23816951 TI - Core disgust and moral disgust are related to distinct spatiotemporal patterns of neural processing: an event-related potential study. AB - Core disgust is thought to rely more on sensory and perceptual processes, whereas moral disgust is thought to rely more on social evaluation processes. However, little is known about the neurocognitive mechanisms underlying these two types of disgust. We recorded event-related potentials (ERPs) from participants while they performed a lexical decision task in which core- and moral-disgust words were intermixed with neutral words and pseudowords. Lexical judgment was faster for coredisgust words and slower for moral-disgust words, relative to the neutral words. Core-disgust words, relative to neutral words, elicited a larger early posterior negative (EPN), a larger N320, a smaller N400, and a larger late positive component (LPC), whereas moral disgust words elicited a smaller N320 and a larger N400 than neutral words. These results suggest that the N320 and N400 components are particularly sensitive to the neurocognitive processes that overlap in processing both core and moral disgust, whereas the EPN and LPC may reflect process that are particularly sensitive to core disgust. PMID- 23816952 TI - Carbon dioxide inhalation as a human experimental model of panic: the relationship between emotions and cardiovascular physiology. AB - Inhaling carbon dioxide (CO2)-enriched air induces fear and panic symptoms resembling real-life panic attacks, the hallmark of panic disorder. The present study aimed to describe the emotional and cardiovascular effects evoked by inhaling CO2, taking shortcomings of previous studies into account. Healthy volunteers underwent a double inhalation of 0, 9, 17.5, and 35% CO2, according to a randomized, cross-over design. In addition to fear, discomfort, and panic symptom ratings, blood pressure and heart rate were continuously monitored. Results showed a dose-dependent increase in all self-reports. Systolic and diastolic blood pressure rose with increasing CO2 concentration, whereas heart rate results were less consistent. Diastolic blood pressure and heart rate variation correlated with fear and discomfort. Based on this relationship and the observation that the diastolic blood pressure most accurately mimicked the degree of self-reported emotions, it might serve as a putative biomarker to assess the CO2-reactivity in the future. PMID- 23816953 TI - Are we really doing hematopoietic stem cell transplantations? PMID- 23816954 TI - Clonal mast cell activation syndrome with anaphylaxis to sulfites. AB - Sulfites are rarely suspected as causative agents of immediate-type hypersensitivity. We report on a 49-year-old male patient who developed recurrent severe hypotension after food ingestion. A diagnosis of monoclonal mast cell activation syndrome was established. In the double-blind, placebo-controlled food challenge, the patient reacted to potassium metabisulfite with anaphylaxis. PMID- 23816955 TI - Molecular dynamics simulations reveal highly permeable oxygen exit channels shared with water uptake channels in photosystem II. AB - Photosystem II (PSII) catalyzes the oxidation of water in the conversion of light energy into chemical energy in photosynthesis. Water delivery and oxygen removal from the oxygen evolving complex (OEC), buried deep within PSII, are critical requirements to facilitate the reaction and minimize reactive oxygen damage. It has often been assumed that water and oxygen travel through separate channels within PSII, as demonstrated in cytochrome c oxidase. This study describes all atom molecular dynamics simulations of PSII designed to investigate channels by fully characterizing the distribution and permeation of both water and oxygen. Interestingly, most channels found in PSII were permeable to both oxygen and water, however individual channels exhibited different energetic barriers for the two solutes. Several routes for oxygen diffusion within PSII with low energy permeation barriers were found, ensuring its fast removal from the OEC. In contrast, all routes for water showed significant energy barriers, corresponding to a much slower permeation rate for water through PSII. Two major factors were responsible for this selectivity: (1) hydrogen bonds between water and channel amino acids, and (2) steric restraints. Our results reveal the presence of a shared network of channels in PSII optimized to both facilitate the quick removal of oxygen and effectively restrict the water supply to the OEC to help stabilize and protect it from small water soluble inhibitors. PMID- 23816956 TI - Oxidized low-density lipoprotein induces inflammatory responses in cultured human mast cells via Toll-like receptor 4. AB - BACKGROUND/AIMS: Oxidized low-density lipoprotein (ox-LDL) is a powerful atherogen. Toll-like receptor 4 (TLR4) has a pathophysiological role in regulating inflammatory responses and atherosclerosis. Mast cells can infiltrate into the atheromatous plaque and secrete various pro-inflammatory cytokines, which significantly amplify the atherogenic processes and promote plaque vulnerability. Small interfering RNA (siRNA) is an effective method to silence the target genes. We evaluated whether ox-LDL-induced inflammation depended in part on the activation of TLR4-dependent signaling pathways in a cultured human mast cell line (HMC-1). METHOD: HMC-1 cells were cultured, and treated with ox LDL, TLR4-specific siRNA, or inhibitors of phosphorylation of mitogen-activated protein kinase (MAPKs), and nuclear factor-kappaB (NF-kappaB), a critical mediator of inflammation. The expression of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6) was measured subsequently. RESULTS: Ox-LDL increased the expression of TLR4 and secretion of MCP-1, TNF-alpha and IL-6. Moreover, ox-LDL stimulated the translocation of NF-kappaB, from the cytoplasm to nucleus. Additionally, phosphorylation of MAPK was greatly increased. These ox-LDL-induced alterations were significantly attenuated by pretreatment with TLR4-specific siRNA. CONCLUSION: Ox-LDL induced inflammatory responses in cultured HMC-1 cells including NF-kappaB nuclear translocation and phosphorylation of MAPKs, a process mediated in part by TLR4. PMID- 23816957 TI - Differential neural mechanisms underlying exogenous attention to peripheral and central distracters. AB - Mechanisms underlying exogenous attention to central and peripheral distracters were temporally and spatially explored while 30 participants performed a digit categorization task. Neural (event-related potentials-ERPs-, analyzed both at the scalp and at the voxel level) and behavioral indices of exogenous attention were analyzed. Distracters were either biologically salient or neutral, in order to test whether the exogenous attention bias to the former observed in previous studies is independent of, or interacts with, distracter eccentricity. Two subcomponents of the N2 component of the ERPs, N2olp and N2ft, reflected processes related to peripheral distracters processing. N2olp effects, located in the dorsal attention network (supplementary motor area), were probably related to covert reorientation to peripheral distracters. N2ft effects, located in the default mode network (posterior cingulate cortex), appeared to reflect less effort in the ongoing task when peripheral distracters were presented. N2ft also showed a biological saliency effect which was independent of eccentricity and was located in the polar/ventral prefrontal cortex. P3 showed greater amplitudes to centrally presented distracters. These latter effects were located in TEO (visual cortex), and would be functionally associated with spatial interference between the target and central distracters. Behavior showed the relevance of both central and peripheral distracters in exogenous attention. These results indicate that exogenous attention to peripheral distracters differed in temporal and spatial terms from exogenous attention to central distracters and that it is biased towards biologically salient events irrespective of their eccentricity. PMID- 23816958 TI - An fMRI examination of the effects of acoustic-phonetic and lexical competition on access to the lexical-semantic network. AB - The current study explored how factors of acoustic-phonetic and lexical competition affect access to the lexical-semantic network during spoken word recognition. An auditory semantic priming lexical decision task was presented to subjects while in the MR scanner. Prime-target pairs consisted of prime words with the initial voiceless stop consonants /p/, /t/, and /k/ followed by word and nonword targets. To examine the neural consequences of lexical and sound structure competition, primes either had voiced minimal pair competitors or they did not, and they were either acoustically modified to be poorer exemplars of the voiceless phonetic category or not. Neural activation associated with semantic priming (Unrelated-Related conditions) revealed a bilateral fronto-temporo parietal network. Within this network, clusters in the left insula/inferior frontal gyrus (IFG), left superior temporal gyrus (STG), and left posterior middle temporal gyrus (pMTG) showed sensitivity to lexical competition. The pMTG also demonstrated sensitivity to acoustic modification, and the insula/IFG showed an interaction between lexical competition and acoustic modification. These findings suggest the posterior lexical-semantic network is modulated by both acoustic-phonetic and lexical structure, and that the resolution of these two sources of competition recruits frontal structures. PMID- 23816959 TI - Hypericin encapsulated in solid lipid nanoparticles: phototoxicity and photodynamic efficiency. AB - The hydrophobicity of some photosensitizers can induce aggregation in biological systems, which consequently reduces photodynamic activity. The conjugation of photosensitizers with nanocarrier systems can potentially be used to overcome this problem. The objective of this study was to prepare and characterise hypericin-loaded solid lipid nanoparticles (Hy-SLN) for use in photodynamic therapy (PDT). SLN were prepared using the ultrasonication technique, and their physicochemical properties were characterised. The mean particle size was found to be 153 nm, with a low polydispersity index of 0.28. One of the major advantages of the SLN formulation is its high entrapment efficiency (EE%). Hy-SLN showed greater than 80% EE and a drug loading capacity of 5.22% (w/w). To determine the photodynamic efficiency of Hy before and after encapsulation in SLN, the rate constants for the photodecomposition of two (1)O2 trapping reagents, DPBF and AU, were determined. These rate constants exhibited an increase of 60% and 50% for each method, respectively, which is most likely due to an increase in the lifetime of the triplet state caused by the increase in solubility. Hy-SLN presented a 30% increase in cell uptake and a correlated improvement of 26% in cytotoxicity. Thus, all these advantages suggest that Hy loaded SLN has potential for use in PDT. PMID- 23816961 TI - Frequency of non-cancer-related pain in patients with cancer. PMID- 23816960 TI - Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. AB - PURPOSE: The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation-positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS). PATIENTS AND METHODS: In this phase III study, eligible patients with stage IIIB/IV lung adenocarcinoma were screened for EGFR mutations. Mutation-positive patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian) before two-to one random assignment to 40 mg afatinib per day or up to six cycles of cisplatin plus pemetrexed chemotherapy at standard doses every 21 days. The primary end point was PFS by independent review. Secondary end points included tumor response, overall survival, adverse events, and patient-reported outcomes (PROs). RESULTS: A total of 1,269 patients were screened, and 345 were randomly assigned to treatment. Median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy (hazard ratio [HR], 0.58; 95% CI, 0.43 to 0.78; P = .001). Median PFS among those with exon 19 deletions and L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001). The most common treatment-related adverse events were diarrhea, rash/acne, and stomatitis for afatinib and nausea, fatigue, and decreased appetite for chemotherapy. PROs favored afatinib, with better control of cough, dyspnea, and pain. CONCLUSION: Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations. PMID- 23816962 TI - Comparison of PAM50 risk of recurrence score with oncotype DX and IHC4 for predicting risk of distant recurrence after endocrine therapy. AB - PURPOSE: Risk of distant recurrence (DR) among women with estrogen receptor (ER) positive early breast cancer is the major determinant of recommendations for or against chemotherapy. It is frequently estimated using the Oncotype DX recurrence score (RS). The PAM50 risk of recurrence (ROR) score provides an alternative approach, which also identifies intrinsic subtypes. PATIENTS AND METHODS: mRNA from 1,017 patients with ER-positive primary breast cancer treated with anastrozole or tamoxifen in the ATAC trial was assessed for ROR using the NanoString nCounter. Likelihood ratio (LR) tests and concordance indices (c indices) were used to assess the prognostic information provided beyond that of a clinical treatment score (CTS) by RS, ROR, or IHC4, an index of DR risk derived from immunohistochemical assessment of ER, progesterone receptor, human epidermal growth factor receptor 2 (HER2), and Ki67. RESULTS: ROR added significant prognostic information beyond CTS in all patients (Delta LR-chi(2) = 33.9; P < .001) and in all four subgroups: node negative, node positive, HER2 negative, and HER2 negative/node negative; more information was added by ROR than by RS. C indices in the HER2-negative/node-negative subgroup were 0.73, 0.76, and 0.78 for CTS, CTS plus RS, and CTS plus ROR, respectively. More patients were scored as high risk and fewer as intermediate risk by ROR than by RS. Relatively similar prognostic information was added by ROR and IHC4 in all patients but more by ROR in the HER2-negative/node-negative group. CONCLUSION: ROR provides more prognostic information in endocrine-treated patients with ER-positive, node negative disease than RS, with better differentiation of intermediate- and higher risk groups. PMID- 23816963 TI - LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. AB - PURPOSE: New molecular targeted agents are needed for patients with non-small cell lung cancer (NSCLC) who progress while receiving erlotinib, gefitinib, or both. Afatinib, an oral irreversible ErbB family blocker, has preclinical activity in epidermal growth factor receptor (EGFR [ErbB1]) mutant models with EGFR-activating mutations, including T790M. PATIENTS AND METHODS: This was a Japanese single-arm phase II trial conducted in patients with stage IIIB to IV pulmonary adenocarcinoma who progressed after >= 12 weeks of prior erlotinib and/or gefitinib. Patients received afatinib 50 mg per day. The primary end point was objective response rate (complete response or partial response) by independent review. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Of 62 treated patients, 45 (72.6%) were EGFR mutation positive in their primary tumor according to local and/or central laboratory analyses. Fifty-one patients (82.3%) fulfilled the criteria of acquired resistance to erlotinib and/or gefitinib. Of 61 evaluable patients, five (8.2%; 95% CI, 2.7% to 18.1%) had a confirmed objective response rate (partial response). Median PFS was 4.4 months (95% CI, 2.8 to 4.6 months), and median OS was 19.0 months (95% CI, 14.9 months to not achieved). Two patients had acquired T790M mutations: L858R + T790M, and deletion in exon 19 + T790M; they had stable disease for 9 months and 1 month, respectively. The most common afatinib-related adverse events (AEs) were diarrhea (100%) and rash/acne (91.9%). Treatment-related AEs leading to afatinib discontinuation were experienced by 18 patients (29%), of whom four also had progressive disease. CONCLUSION: Afatinib demonstrated modest but noteworthy efficacy in patients with NSCLC who had received third- or fourth-line treatment and who progressed while receiving erlotinib and/or gefitinib, including those with acquired resistance to erlotinib, gefitinib, or both. PMID- 23816964 TI - Serum androgens as prognostic biomarkers in castration-resistant prostate cancer: results from an analysis of a randomized phase III trial. AB - PURPOSE: In the phase III study COU-AA-301, abiraterone acetate (AA) plus prednisone (P) prolonged overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) after docetaxel administration. In this article, we investigate the relationship between baseline serum androgen (SA) levels and OS. PATIENTS AND METHODS: COU-AA-301 is a randomized, double blind study of AA (1,000 mg every day) plus P (5 mg by mouth twice daily; n = 797) versus P alone (n = 398). Randomization was stratified by Eastern Cooperative Oncology Group performance status (0 to 1 v 2), pain (Brief Pain Inventory-Short Form over past 24 hours: 4 to 10, present; v 0 to 3, absent), prior chemotherapy (1 v 2), and progression (prostate-specific antigen v radiographic). Association of baseline SA (testosterone, androstenedione, dehydroepiandrosterone sulfate), was measured by ultrasensitive liquid-liquid extraction or protein precipitation and two-dimensional liquid chromatography coupled to mass spectrometry, with OS determined by bivariate and multivariable Cox models. OS was examined with SA as greater than median and less than or equal to the median. RESULTS: Median survival increased with each quartile increase in testosterone level regardless of treatment arm. SA levels at baseline strongly associated with survival (P < .0001) in bivariate and multivariable analyses. Longer survival was observed for patients with SA above median compared with below median in both the AA and P arms (eg, testosterone, AA; hazard ratio, 0.64; 95% CI, 0.53 to 0.77; P < .0001). Treatment with AA led to longer survival versus P alone in the above- or below-median group for all androgens. CONCLUSION: SA, measured with a novel ultrasensitive assay in COU-AA-301, is prognostic for OS and may be useful for risk stratification in mCRPC clinical trials. PMID- 23816965 TI - Association between red and processed meat intake and mortality among colorectal cancer survivors. AB - PURPOSE: Red and processed meat intake is convincingly associated with colorectal cancer (CRC) incidence, but its impact on prognosis after CRC diagnosis is unknown. We examined associations of red and processed meat consumption, self reported before and after cancer diagnosis, with all-cause and cause-specific mortality among men and women with invasive, nonmetastatic CRC. PATIENTS AND METHODS: Participants in the Cancer Prevention Study II Nutrition Cohort reported information on diet and other factors at baseline in 1992-1993, 1999, and 2003. Participants with a verified CRC diagnosis after baseline and up to June 30, 2009, were observed for mortality through December 31, 2010. RESULTS: Among 2,315 participants diagnosed with CRC, 966 died during follow-up (413 from CRC and 176 from cardiovascular disease [CVD]). In multivariable-adjusted Cox proportional hazards regression models, red and processed meat intake before CRC diagnosis was associated with higher risks of death as a result of all causes (top v bottom quartile, relative risk [RR], 1.29; 95% CI, 1.05 to 1.59; Ptrend = .03) and from CVD (RR, 1.63; 95% CI, 1.00 to 2.67; Ptrend = .08) but not CRC (RR, 1.09; 95% CI, 0.79 to 1.51; Ptrend = 0.54). Although red and processed meat consumption after CRC diagnosis was not associated with mortality, survivors with consistently high (median or higher) intakes before and after diagnosis had a higher risk of CRC specific mortality (RR, 1.79; 95% CI, 1.11 to 2.89) compared with those with consistently low intakes. CONCLUSION: This study suggests that greater red and processed meat intake before diagnosis is associated with higher risk of death among patients with nonmetastatic CRC. PMID- 23816966 TI - Elevated pulmonary pressure in survivors of pediatric cancer: a physiologic finding, not a specific disease. PMID- 23816967 TI - Symptom control and quality of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. AB - PURPOSE: Patient-reported symptoms and health-related quality of life (QoL) benefits were investigated in a randomized, phase III trial of afatinib or cisplatin/pemetrexed. PATIENTS AND METHODS: Three hundred forty-five patients with advanced epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma were randomly assigned 2:1 to afatinib 40 mg per day or up to six cycles of cisplatin/pemetrexed. Lung cancer symptoms and health-related QoL were assessed every 21 days until progression using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and Lung Cancer-13 questionnaires. Analyses of cough, dyspnea, and pain were preplanned, including percentage of patients who improved on therapy, time to deterioration of symptoms, and change in symptoms over time. RESULTS: Questionnaire compliance was high. Compared with chemotherapy, afatinib significantly delayed the time to deterioration for cough (hazard ratio [HR], 0.60; 95% CI, 0.41 to 0.87; P = .007) and dyspnea (HR, 0.68; 95% CI, 0.50 to 0.93; P = .015), but not pain (HR, 0.83; 95% CI, 0.62 to 1.10; P = .19). More patients on afatinib (64%) versus chemotherapy (50%) experienced improvements in dyspnea scores (P = .010). Differences in mean scores over time significantly favored afatinib over chemotherapy for cough (P < .001) and dyspnea (P < .001). Afatinib showed significantly better mean scores over time in global health status/QoL (P = .015) and physical (P < .001), role (P = .004), and cognitive (P = .007) functioning compared with chemotherapy. Fatigue and nausea were worse with chemotherapy, whereas diarrhea, dysphagia, and sore mouth were worse with afatinib (all P < .01). CONCLUSION: In patients with lung adenocarcinoma with EGFR mutations, first line afatinib was associated with better control of cough and dyspnea compared with chemotherapy, although diarrhea, dysphagia, and sore mouth were worse. Global health status/QoL was also improved over time with afatinib compared with chemotherapy. PMID- 23816968 TI - Staging of ciliary body and choroidal melanomas based on anatomic extent. AB - PURPOSE: To refine the anatomic classification and staging of ciliary body and choroidal melanomas in the TNM classification. PATIENTS AND METHODS: Tumor largest basal diameter and thickness of 7,369 patients were analyzed based on registry data from five ocular oncology centers. T categories were derived empirically by dividing data into blocks representing 3- * 3-mm fractions. Blocks with similar survival were grouped together so that no T category comprised a large majority of tumors, and each was uniform in survival, using randomly drawn 60% building and 40% validation data sets. Presence of ciliary body involvement (CBI) and extraocular extension (EXE) was analyzed among 5,403 patients to define T subcategories. Stages were generated by iteratively combining subcategories with similar survival. RESULTS: Of the 7,369 tumors analyzed, 24% were classified as T1, 33% as T2, 31% as T3, and 12% as T4. Ten-year Kaplan-Meier survival estimates for the T categories were 89%, 77%, 58%, and 39%, respectively (P < .001). Survival of patients in four subcategories based on presence or absence of CBI and EXE differed significantly within each T category (P = .018 for T1; P < .001 for T2 to T4). EXE exceeding 5 mm in largest diameter carried a worse prognosis than smaller extensions (P < .001) and was assigned a separate subcategory. Ten-year Kaplan-Meier survival estimates for stages I, IIA to IIB, and IIIA to IIIC were 88%, 80%, 67%, 45%, 27%, 10%, respectively (P < .001). CONCLUSION: This evidence-based anatomic classification provides a basis for staging ciliary body and choroidal melanomas in the seventh edition of the Cancer Staging Manual of the American Joint Committee on Cancer. PMID- 23816969 TI - We are what we eat, or are we? PMID- 23816970 TI - Assessment of tocilizumab in the treatment of cancer cachexia. PMID- 23816971 TI - Outdoor smoking areas: does the science support a ban? PMID- 23816972 TI - Health Care Costs Associated With Parent-Reported ADHD: A Longitudinal Australian Population-Based Study. AB - OBJECTIVE: To examine the health care costs associated with ADHD within a nationally representative sample of children. METHOD: Data were from Waves 1 to 3 (4-9 years) of the Longitudinal Study of Australian Children ( N = 4,983). ADHD was defined by previous diagnosis and a measure of ADHD symptoms (Strengths and Difficulties Questionnaire [SDQ]). Participant data were linked to administrative data on health care costs. Analyses controlled for demographic factors and internalizing and externalizing comorbidities. RESULTS: Costs associated with health care attendances and medications were higher for children with parent reported ADHD at each age. Cost differences were highest at 8 to 9 years for both health care attendances and medications. Persistent symptoms were associated with higher costs ( p < .001). Excess population health care costs amounted to Aus$25 to Aus$30 million over 6 years, from 4 to 9 years of age. CONCLUSION: ADHD is associated with significant health care costs from early in life. Understanding the costs associated with ADHD is an important first step in helping to plan for service-system changes. PMID- 23816973 TI - Clinicians' attitudes toward general screening of the Ashkenazi-Jewish population for prevalent founder BRCA1/2 and LRRK2 mutations. AB - AIMS: Advances in genomics may eventually lead to genetic susceptibility screening of the general population, regardless of a personal or familial history of the disease in question. Yet, little is known about clinicians' attitudes toward such programs. We explored attitudes of family practitioners, medical geneticists and genetic counselors toward genetic screening of the general Ashkenazi-Jewish population for the common founder mutations in BRCA1/2 and LRRK2 genes (which increase the risk of hereditary breast/ovarian cancers and Parkinson's disease, respectively). METHODS: Participants (n = 204) completed a specially designed questionnaire, distributed by e-mail, regular mail or in person. RESULTS: Slightly more than half (52%) were in favor of BRCA screening, while the vast majority (86%) opposed to LRRK2 screening. About two-thirds (68%) of the respondents supported pre-test genetic counseling. Attitudes were largely independent of professional background and sociodemographic characteristics, though a correlation was found with personal interest in genetic self-testing for the above genes. Adverse psychological impact and discrimination in insurance and employment were the major concerns cited by respondents with regard to screening programs. CONCLUSION: Our findings suggest that the availability of measures for prevention and/or treatment is a major factor in the attitudes of healthcare providers toward population screening for late-onset conditions. PMID- 23816974 TI - Predictive biochemical-markers for the development of brain metastases from lung cancer: clinical evidence and future directions. AB - BACKGROUND: Brain metastases are a common complication of patients with lung cancer and lung cancer is one of the most common causes of brain metastases. The occurrence of brain metastases is associated with poor prognosis and high morbidity, even after intensive multimodal therapy. Therefore, identifying lung cancer patients with who are at high risk of developing brain metastases and applying effect intervention is important to reduce or delay the incidence of brain metastases. Biochemical-markers may meet an unmet need for following patients' mechanisms of brain metastases. METHODS: Data for this review were identified by searches of Pubmed and Cochrane databases, and references from relevant articles using the search terms "lung cancer" and "brain metastasis". Meeting abstracts, unpublished reports and review articles were not considered. RESULTS: Clinical results for pathological and circulating markers including cancer molecular subtypes, miRNA, single nucleotide polymorphisms, and other markers are presented. However, these biochemical-markers are not yet established surrogate assessments for prediction of brain metastases. CONCLUSIONS: Biochemical-markers reported allowed physicians to identify which patients with lung cancer are at high risk for brain metastases. Prospective randomized clinical studies are needed to further assess the utility of these biochemical markers. PMID- 23816976 TI - Who is who in the journal. PMID- 23816975 TI - Fatty acids and other risk factors for sudden cardiac death in patients starting hemodialysis. AB - BACKGROUND: Little is known about risk factors for sudden cardiac death in hemodialysis patients during the high-risk first year of dialysis. We therefore undertook to identify such risk factors in a nationally representative cohort and were able to include baseline levels of blood fatty acids, some of which influence arrhythmogenicity and sudden cardiac death risk. DESIGN: The study cohort included 100 patients who died of sudden cardiac death during the first year of hemodialysis and 300 frequency-matched controls. Using the elastic net statistical method, numerous demographic and clinical characteristics were included with baseline total serum levels for 11 major fatty acids (model 1) and with serum phospholipid fractions of these same fatty acids (model 2). Final models included only covariates that had a non-zero coefficient. RESULTS: In model 1, serum albumin [odds ratio (95% CI): 0.55 (0.33-0.93); p = 0.03] and total serum long-chain n-3 docosapentaenoic acid [0.70 (0.51-0.97); p = 0.03] were inversely associated with the odds of sudden cardiac death, while the total serum saturated fatty acid level had a direct association [1.01 (1.00-1.02); p = 0.03]. In model 2, serum albumin and docosapentaenoic acid remained inversely associated with sudden cardiac death in a similar manner as in model 1. Pulse pressure also had an inverse association [0.96 (0.93-1.00); p < 0.05]. CONCLUSIONS: Several factors, including blood content of docosapentaenoic acid and saturated fatty acids, were associated with the odds of sudden cardiac death during year one of hemodialysis. These results raise the possibility that dietary modification may reduce sudden death risk. PMID- 23816977 TI - A randomized, double-blind, placebo-controlled study to test the efficacy of topical 2-hydroxypropyl-Beta-cyclodextrin in the prophylaxis of recurrent herpes labialis. AB - Herpes labialis affects one third of the population. We evaluated the topical application of an antiviral compound, hydroxypropyl-beta-cyclodextrin (2 HPbetaCD), in reducing herpes labialis relapses. In this double-blind, randomized, placebo-controlled trial, 40 patients were randomized to a polyethylene glycol (PEG) formulation containing 20% 2-HPbetaCD or to a vehicle control arm. The gel was applied to the lips twice daily for 6 months. The primary objective was reducing herpes relapses. Surprisingly, the drug group had significantly more relapses than the vehicle group (p = 0.003). While the median numbers of relapses in the preceding year were 12 in the vehicle group and 10 in the drug group, both groups experienced very few relapses during the 6-month treatment period, with a median of 0 in the vehicle group and a median of 2 in the drug group. The impressive reduction of relapses in both groups may be due to a placebo effect or due to the topical treatment with PEG. PMID- 23816978 TI - Advances in intrathecal drug delivery. AB - PURPOSE OF REVIEW: Targeted intrathecal drug delivery systems (IDDS) are an option in algorithms for the treatment of patients with moderate-to-severe chronic refractory pain. This article is intended to review the literature regarding IDDS published over the last year, with special attention to the Polyanalgesic Consensus Conference 2012. RECENT FINDINGS: The recommendations made by the Polyanalgesic Consensus Conference 2012 are reviewed. Separate considerations of intrathecal drug therapy for neuropathic and nociceptive pain syndromes and the new concept of 'microdosing' are discussed in this article. SUMMARY: This review includes the recommendations for the use of IDDS, trialing, and recent reports of complications (especially, the occurrence of granulomas). In addition, the latest documents on cerebrospinal fluid and potential lines of future development are discussed. PMID- 23816980 TI - Exposures from nuclear medicine diagnostic procedures: the dose impact on the Aosta Valley population. AB - The present work evaluates the per-procedure, annual collective and per-capita effective doses to the Aosta Valley region population from nuclear medicine (NM) examinations performed from 2005 to 2011 at the regional NM department. Based on its demographical and socioeconomics characteristics, this area can be considered as representative of the level I countries, as defined by the United Nations Scientific Committee on the Effects of Atomic Radiation. The NM per-procedures effective doses were within the range of 0.018-35 mSv. A steady frequency per 10 000 inhabitants has been observed, together with a decrease for thyroid and whole body bone scintigraphy. Myocardial and bone scintigraphy studies were the major contributors to the total collective effective dose. The mean annual collective and per-capita effective doses to the population were 15 man Sv y(-1) and 120 uSv y(-1), respectively. The NM contribution to the total per-capita effective dose accounts for 5.9 % of that due to the medical ionising radiation examinations overall. PMID- 23816979 TI - Internet use frequency and patient-centered care: measuring patient preferences for participation using the health information wants questionnaire. AB - BACKGROUND: The Internet is bringing fundamental changes to medical practice through improved access to health information and participation in decision making. However, patient preferences for participation in health care vary greatly. Promoting patient-centered health care requires an understanding of the relationship between Internet use and a broader range of preferences for participation than previously measured. OBJECTIVE: To explore (1) whether there is a significant relationship between Internet use frequency and patients' overall preferences for obtaining health information and decision-making autonomy, and (2) whether the relationships between Internet use frequency and information and decision-making preferences differ with respect to different aspects of health conditions. METHODS: The Health Information Wants Questionnaire (HIWQ) was administered to gather data about patients' preferences for the (1) amount of information desired about different aspects of a health condition, and (2) level of decision-making autonomy desired across those same aspects. RESULTS: The study sample included 438 individuals: 226 undergraduates (mean age 20; SD 2.15) and 212 community-dwelling older adults (mean age 72; SD 9.00). A significant difference was found between the younger and older age groups' Internet use frequencies, with the younger age group having significantly more frequent Internet use than the older age group (younger age group mean 5.98, SD 0.33; older age group mean 3.50, SD 2.00; t436=17.42, P<.01). Internet use frequency was positively related to the overall preference rating (gamma=.15, P<.05), suggesting that frequent Internet users preferred significantly more information and decision making than infrequent Internet users. The relationships between Internet use frequency and different types of preferences varied: compared with infrequent Internet users, frequent Internet users preferred more information but less decision making for diagnosis (gamma=.57, P<.01); more information and more decision-making autonomy for laboratory test (gamma=.15, P<.05), complementary and alternative medicine (gamma=.32, P<.01), and self-care (gamma=.15, P<.05); and less information but more decision-making autonomy for the psychosocial (gamma=-.51, P<.01) and health care provider (gamma=-.27, P<.05) aspects. No significant difference was found between frequent and infrequent Internet users in their preferences for treatment information and decision making. CONCLUSIONS: Internet use frequency has a positive relationship with the overall preferences for obtaining health information and decision-making autonomy, but its relationship with different types of preferences varies. These findings have important implications for medical practice. PMID- 23816981 TI - Surface temperature changes in response to handling in domestic chickens. AB - Stress-induced hyperthermia (SIH) occurs in numerous species and is characterised by an increase in core body temperature, and a decrease in surface temperature, of between 0.5 and 1.5 degrees C within 10 to 15 min of the onset of "emotional stress". The aim of the current study was to ascertain whether the husbandry relevant procedure of handling resulted in measurable changes in surface body temperature in chickens, as measured using infrared thermography. Baseline temperatures for 19 domestic hens were compared to temperatures immediately, and up to 20 min following handling (catching and brief restraint by a human). Surface head, eye and comb temperatures were plotted to investigate the pattern of temperature change. In response to handling, comb temperature decreased significantly, showing a rapid 2 degrees C drop. Eye temperature showed an initial decrease then rose to levels significantly higher than handling. Head temperature increased over the 20 min post-handling period, to reach levels significantly higher than baseline. It can be concluded that surface temperature changes assessed using infrared thermography, in particular of the hen's comb, are sensitive to husbandry procedures such as handling and represent a potentially useful method for assessing stress-induced hyperthermia in chickens. PMID- 23816982 TI - Influence of fatigue, stress, muscle soreness and sleep on perceived exertion during submaximal effort. AB - The aim of this study was to assess the effects of the Hooper's Index variations (i.e., self-ratings of fatigue, stress, delayed onset muscle soreness (DOMS), and sleep) on rating of perceived exertion during a 10 min submaximal exercise training session (RPE-10 min) and then check the stability and the internal consistency of RPE-10 min. Seventeen junior soccer players took part in this study. The individual Hooper's indices taken before each training session were correlated with RPE-10 min during a constant intensity and duration effort (10 min) using Pearson product moment correlation. Intraclass correlation (ICC) was used to assess the internal consistency of the RPE-10 min. All individual correlations between RPE-10 min and quality of sleep and quantity of fatigue, stress, and DOMS were non-significant (p>0.05). No significant correlations were resulted between RPE-10 min and Hooper's Index in all athletes. The ICC of RPE-10 min was 0.77 thus demonstrating internal consistency. The results of the present study demonstrated the objectivity and utility of RPE as a psychological tool for monitoring training during traditional soccer training. Therefore, the results of the present study suggest that fatigue, stress, DOMS and sleep are not major contributors of perceived exertion during traditional soccer training without excessive training loads. It seems that psychobiological factors other than fatigue, stress, DOMS and sleep may have mediated the 10 min exercise perceptual intensity. PMID- 23816983 TI - Maternal immune activation affects litter success, size and neuroendocrine responses related to behavior in adult offspring. AB - It is increasingly evident that influences other than genetics can contribute to offspring phenotype. In particular, maternal influences are an important contributing factor to offspring survival, development, physiology and behavior. Common environmental pathogens such as viral or bacterial microorganisms can induce maternal immune responses, which have the potential to alter the prenatal environment via multiple independent pathways. The effects of maternal immune activation on endocrine responses and behavior are less well studied and provide the basis for the current study. Our approach in the current study was two pronged: 1) quantify sickness responses during pregnancy in adult female hamsters experiencing varying severity of immune responsiveness (i.e., differing doses of lipopolysaccharide [LPS]), and 2) assess the effects of maternal immune activation on offspring development, immunocompetence, hormone profiles, and social behavior during adulthood. Pregnancy success decreased with increasing doses of LPS, and litter size was reduced in LPS dams that managed to successfully reproduce. Unexpectedly, pregnant females treated with LPS showed a hypothermic response in addition to the more typical anorexic and body mass changes associated with sickness. Significant endocrine changes related to behavior were observed in the offspring of LPS-treated dams; these effects were apparent in adulthood. Specifically, offspring from LPS treated dams showed significantly greater cortisol responses to stressful resident-intruder encounters compared with offspring from control dams. Post-behavior cortisol was elevated in male LPS offspring relative to the offspring of control dams, and was positively correlated with the frequency of bites during agonistic interactions, and cortisol levels in both sexes were related to defensive behaviors, suggesting that changes in hypothalamo-pituitary-adrenal axis responsiveness may play a regulatory role in the observed behavioral differences. Overall, the results of this study provide evidence that maternal immune activation can exert marked effects on offspring physiology and behavior. PMID- 23816984 TI - Central administration of prolactin-releasing peptide shifts the utilities of metabolic fuels from carbohydrate to lipids in chicks. AB - We have recently identified prolactin (PRL)-releasing peptides (PrRPs) and their stimulating effects on feeding behavior in chicks. To investigate further metabolic functions of PrRP, the present study was performed to clarify whether intracerebroventricular (ICV) injection of PrRP31, an active form of PrRP in chicks, affects heat production (HP), respiratory quotient (RQ) and plasma concentrations of metabolic fuels in chicks. The ICV injection of PrRP31 (94 and 375 pmol) did not affect HP but significantly lowered RQ. The change in RQ implies that PrRP31 shifted the utility of metabolic fuels in the body. This idea was confirmed by subsequent results in which ICV injection of PrRP31 significantly reduced glucose but increased non-esterified fatty acid concentrations in plasma. These shifts in blood metabolic fuels would not be through the increased plasma insulin, because the ICV injection of PrRP31 significantly decreased plasma insulin concentration. On the other hand, ICV injection of another orexigenic peptide, neuropeptide Y (NPY) also induced the insulin release and the metabolic effects were similar to those of PrRP31. Because ICV injection of PrRP31 increased NPY mRNA in the diencephalon, the NPY may mediate the metabolic functions of PrRP31. In summary, the present study suggests that central PrRP31 shifts the utilities of peripheral energy sources, which is not via hyperinsulinemia but via the diencephalon. PMID- 23816985 TI - The validity and utility of the M. D. Anderson Symptom Inventory in patients with breast cancer: evidence from the symptom outcomes and practice patterns data from the eastern cooperative oncology group. AB - BACKGROUND: The M. D. Anderson Symptom Inventory (MDASI) is a psychometrically validated patient-reported outcome measurement that assesses the severity and impact of multiple symptoms related to cancer and its treatment. With the MDASI, patients rate 13 common "core" symptoms and 6 items that reflect symptom interference with functioning. Several MDASI modules (core symptom and interference items plus additional symptoms specific to a particular cancer type or treatment modality) have been developed. Although the original MDASI validation study encompassed various cancer types, the instrument's psychometric properties have not been examined in a homogenous sample of patients with breast cancer in a national multicenter study. MATERIALS AND METHODS: We performed a secondary analysis of data from an Eastern Cooperative Oncology Group study to establish the reliability, validity, and sensitivity of the MDASI in a large sample of patients with breast cancer (n = 1544), 78% of whom were receiving treatment. The instrument was administered twice, approximately 1 month apart. RESULTS: Internal consistency and test-retest reliability were adequate, with Cronbach alpha values >= 0.85 and intraclass correlations >= 0.76 for all subscales. Known-group validity was evaluated by using performance status, tumor response, and disease stage. Sensitivity to change in patient-reported quality of life was established. CONCLUSION: The MDASI is a valid, reliable, and sensitive symptom-assessment instrument that can enhance descriptive and clinical studies of symptom status in patients with breast cancer. Future studies might include cognitive debriefing and qualitative interviews to identify additional disease specific items for inclusion in a MDASI breast cancer module. PMID- 23816986 TI - The activation of HO-1/Nrf-2 contributes to the protective effects of diallyl disulfide (DADS) against ethanol-induced oxidative stress. AB - BACKGROUND: Diallyl disulfide (DADS) is a garlic-derived organosulfur compound. The current study is designed to evaluate the protective effects of DADS against ethanol-induced oxidative stress, and to explore the underlying mechanisms by examining the HO-1/Nrf-2 pathway. METHODS: We investigated whether or not DADS could activate the HO-1 in normal human liver cell LO2, and then evaluated the protective effects of DADS against ethanol-induced damage in LO2 cells and in acute ethanol-intoxicated mice. The biochemical parameters were measured using commercial kits. HO-1 mRNA level was determined by RT-PCR. Histopathology and immunofluorescence assay were performed with routine methods. Protein levels were measured by western blot. RESULTS: DADS significantly increased the mRNA and protein levels of HO-1, stimulated the nuclear translocation of Nrf-2 and increased the phosphorylation of MAPK in LO2 cells. The nuclear translocation of Nrf-2 was abrogated by MAPK inhibitors. DADS significantly suppressed ethanol induced elevation of lactate dehydrogenase (LDH) and aspartate transaminase (AST) activities, decrease of glutathione (GSH) level, increase of malondialdehyde (MDA) levels, and apoptosis of LO2 cells, which were all blocked by ZnPPIX. In mice, DADS effectively suppressed acute ethanol-induced elevation of aminotransferase activities, and improved liver histopathological changes, which might be associated with HO-1 activation. CONCLUSION: These results demonstrate that DADS could induce the activation of HO-1/Nrf-2 pathway, which may contribute to the protective effects of DADS against ethanol-induced liver injury. GENERAL SIGNIFICANCE: DADS may be beneficial for the prevention and treatment of ALD due to significant activation of HO-1/Nrf-2 pathway. PMID- 23816987 TI - The combined effect of retinoic acid and LSD1 siRNA inhibition on cell death in the human neuroblastoma cell line SH-SY5Y. AB - AIMS: Retinoic acid (RA) is used pharmacologically to treat neuroblastoma (NB), but its mechanism of action is unclear and it has limited use against refractory disease. This study investigated the expression of LSD1 (also known as KDM1A) in tumors, and assessed the efficacy of combining RA treatment with the inhibition of LSD1 expression. METHODS: LSD1 protein expression levels were assessed semi quantitatively in specimens of NB and ganglioneuroblastoma (GNB), along with the apoptosis markers, Bcl-2 and Bax. The combined effect of RA and LSD1 siRNA inhibition on cell death was then assessed in the human neuroblastoma cell line, SH-SY5Y. RESULTS: LSD1 expression was higher in NB compared to GNB, and LSD1 overexpression directly correlated with Bcl-2 expression and inversely correlated with Bax expression. RA treatment or LSD1 siRNA inhibition alone inhibited the growth of SH-SY5Y cells, but did not cause significant apoptosis or cell death. Combined treatment led to higher rates of SH-SY5Y cell death, as reflected by an increased Bax/Bcl-2 ratio. CONCLUSIONS: The combined effect of RA and LSD1 siRNA inhibition had a synergistic effect on promoting the apoptosis of NB cells. This novel approach may improve the clinical treatment of NB. PMID- 23816988 TI - Activated cyclin-dependent kinase 5 promotes microglial phagocytosis of fibrillar beta-amyloid by up-regulating lipoprotein lipase expression. AB - Amyloid plaques are crucial for the pathogenesis of Alzheimer disease (AD). Phagocytosis of fibrillar beta-amyloid (Abeta) by activated microglia is essential for Abeta clearance in Alzheimer disease. However, the mechanism underlying Abeta clearance in the microglia remains unclear. In this study, we performed stable isotope labeling of amino acids in cultured cells for quantitative proteomics analysis to determine the changes in protein expression in BV2 microglia treated with or without Abeta. Among 2742 proteins identified, six were significantly up-regulated and seven were down-regulated by Abeta treatment. Bioinformatic analysis revealed strong over-representation of membrane proteins, including lipoprotein lipase (LPL), among proteins regulated by the Abeta stimulus. We verified that LPL expression increased at both mRNA and protein levels in response to Abeta treatment in BV2 microglia and primary microglial cells. Silencing of LPL reduced microglial phagocytosis of Abeta, but did not affect degradation of internalized Abeta. Importantly, we found that enhanced cyclin-dependent kinase 5 (CDK5) activity by increasing p35-to-p25 conversion contributed to LPL up-regulation and promoted Abeta phagocytosis in microglia, whereas inhibition of CDK5 reduced LPL expression and Abeta internalization. Furthermore, Abeta plaques was increased with reducing p25 and LPL level in APP/PS1 mouse brains, suggesting that CDK5/p25 signaling plays a crucial role in microglial phagocytosis of Abeta. In summary, our findings reveal a potential role of the CDK5/p25-LPL signaling pathway in Abeta phagocytosis by microglia and provide a new insight into the molecular pathogenesis of Alzheimer disease. PMID- 23816989 TI - Soluble and catalytically active endothelin converting enzyme-1 is present in cerebrospinal fluid of subarachnoid hemorrhage patients. AB - Endothelin converting Enzyme-1 (ECE-1) is essential for the production of Endothelin-1 (ET-1), which is associated with vasospasm following subarachnoid hemorrhage (SAH). We have previously demonstrated the presence of a catalytically active soluble form of ECE-1 in the media of endothelial cells. We aimed to determine if this form of ECE-1 exists in vivo, in cerebrospinal fluid (CSF) of SAH patients. We examined CSF taken from SAH subjects for the presence of soluble ECE-1 using a bradykinin based quenched fluorescent substrate assay. We obtained further confirmation by characterizing the CSF mediated cleavage products of BigET-1 and BigET18-34 (6 MUg/ml) using mass spectrometry. The specificity of cleavage was confirmed using the ECE-1 inhibitor CGS35066 5 nmol/L. SAH CSF samples had mean ECE-1 activity of 0.127 +/- 0.037 MUmols of substrate cleaved/MUl of CSF/24 h. The C-terminal peptides generated upon the cleavage of BigET-1 and BigET18-34 were detected 48 h after incubation of these substrates with CSF. Cleavage of these substrates was inhibited by CGS35066. Results of Western blots also produced strong evidence for the presence of truncated soluble ECE-1 in CSF. These results strongly suggest the presence of a truncated but catalytically active form of ECE-1 in the CSF of SAH subjects. Further studies are necessary to determine the biological significance of soluble ECE-1 in CSF of SAH subjects, including an association with vasospasm after SAH. PMID- 23816990 TI - The Rhesus macaque (Macaca mulatta) sperm proteome. AB - Mass spectrometry based proteomics has facilitated sperm composition studies in several mammalian species but no studies have been undertaken in non-human primate species. Here we report the analysis of the 1247 proteins that comprise the Rhesus macaque (Macaca mulatta) sperm proteome (termed the MacSP). Comparative analysis with previously characterized mouse and human sperm proteomes reveals substantial levels of orthology (47% and 40% respectively) and widespread overlap of functional categories based on Gene Ontology analyses. Approximately 10% of macaque sperm genes (113/1247) are significantly under expressed in the testis as compared with other tissues, which may reflect proteins specifically acquired during epididymal maturation. Phylogenetic and genomic analyses of three MacSP ADAMs (A-Disintegrin and Metalloprotease proteins), ADAM18-, 20- and 21-like, provides empirical support for sperm genes functioning in non-human primate taxa which have been subsequently lost in the lineages leading to humans. The MacSP contains proteasome proteins of the 20S core subunit, the 19S proteasome activator complex and an alternate proteasome activator PA200, raising the possibility that proteasome activity is present in mature sperm. Robust empirical characterization of the Rhesus sperm proteome should greatly expand the possibility for targeted molecular studies of spermatogenesis and fertilization in a commonly used model species for human infertility. PMID- 23816991 TI - Exploration of binary virus-host interactions using an infectious protein complementation assay. AB - A precise mapping of pathogen-host interactions is essential for comprehensive understanding of the processes of infection and pathogenesis. The most frequently used techniques for interactomics are the yeast two-hybrid binary methodologies, which do not recapitulate the pathogen life cycle, and the tandem affinity purification mass spectrometry co-complex methodologies, which cannot distinguish direct from indirect interactions. New technologies are thus needed to improve the mapping of pathogen-host interactions. In the current study, we detected binary interactions between influenza A virus polymerase and host proteins during the course of an actual viral infection, using a new strategy based on trans complementation of the Gluc1 and Gluc2 fragments of Gaussia princeps luciferase. Infectious recombinant influenza viruses that encode a Gluc1-tagged polymerase subunit were engineered to infect cultured cells transiently expressing a selected set of Gluc2-tagged cellular proteins involved in nucleocytoplasmic trafficking pathways. A random set and a literature-curated set of Gluc2-tagged cellular proteins were tested in parallel. Our assay allowed the sensitive and accurate recovery of previously described interactions, and it revealed 30% of positive, novel viral-host protein-protein interactions within the exploratory set. In addition to cellular proteins involved in the nuclear import pathway, components of the nuclear pore complex such as NUP62 and mRNA export factors such as NXF1, RMB15B, and DDX19B were identified for the first time as interactors of the viral polymerase. Gene silencing experiments further showed that NUP62 is required for efficient viral replication. Our findings give new insights regarding the subversion of host nucleocytoplasmic trafficking pathways by influenza A viruses. They also demonstrate the potential of our infectious protein complementation assay for high-throughput exploration of influenza virus interactomics in infected cells. With more infectious reverse genetics systems becoming available, this strategy should be widely applicable to numerous pathogens. PMID- 23816992 TI - N- and O-glycosylation in the murine synaptosome. AB - We present the first large scale study characterizing both N- and O-linked glycosylation in a site-specific manner on hundreds of proteins. We demonstrate that a lectin-affinity fractionation step using wheat germ agglutinin enriches not only peptides carrying intracellular O-GlcNAc, but also those bearing ER/Golgi-derived N- and O-linked carbohydrate structures. Liquid chromatography MS (LC/MS) analysis with high accuracy precursor mass measurements and high sensitivity ion trap electron-transfer dissociation (ETD) were utilized for structural characterization of glycopeptides. Our results reveal both the identity of the precise sites of glycosylation and information on the oligosaccharide structures possible on these proteins. We report a novel iterative approach that allowed us to interpret the ETD data set directly without making prior assumptions about the nature and distribution of oligosaccharides present in our glycopeptide mixture. Over 2500 unique N- and O-linked glycopeptides were identified on 453 proteins. The extent of microheterogeneity varied extensively, and up to 19 different oligosaccharides were attached at a given site. We describe the presence of the well-known mucin-type structures for O-glycosylation, an EGF-domain-specific fucosylation and a rare O-mannosylation on the transmembrane phosphatase Ptprz1. Finally, we identified three examples of O-glycosylation on tyrosine residues. PMID- 23816993 TI - A comparison of three different physiotherapy modalities used in the physiotherapy of burns. AB - The present study compared the effectiveness of matrix rhythm therapy, ultrasound treatment (UT), laser treatment (LT) used in the physiotherapy of burns. The study was conducted at the Wound and Burn Healing Center, Dr. Lutfi Kirdar Kartal Education and Research Hospital (Turkey) from June 2009 to January 2012. The case series comprised 39 individuals with second- and third-degree upper-limb burns, whose burn traumas ended approximately 1 to 3 months previously. Participants were separated into three groups: matrix rhythm treatment (MRT), UT and LT; each group was also applied a treatment protocol including whirlpool and exercise. Pain, range of motion (ROM), muscular strength, skin elasticity, and sensory functions were evaluated before and after the treatment. Pressure sense and passive ROM were higher in the MRT group than in the LT group (P < .05). Pain was lower in the LT group than in the UT group, and passive ROM was higher in the UT group than the in LT group (P < .05). Active ROM was found to increase in all treatment groups, whereas passive ROM increased only in the MRT and UT groups; pressure sense increased only in the MRT group, and pain decreased only in the LT group (P < .05). MRT was found to be more effective in the restoration of sensory functions than LT, whereas LT was more effective in reducing pain than UT. No significant difference was observed in terms of skin elasticity according to the results of three treatment modalities. It is suggested that further research with more cases should be conducted to examine the long-term effect of treatment modalities. PMID- 23816994 TI - Nonsurgical scar management of the face: does early versus late intervention affect outcome? AB - Special emphasis is placed on the clinical management of facial scarring because of the profound physical and psychological impact of facial burns. Noninvasive methods of facial scar management include pressure therapy, silicone, massage, and facial exercises. Early implementation of these scar management techniques after a burn injury is typically accepted as standard burn rehabilitation practice, however, little data exist to support this practice. This study evaluated the timing of common noninvasive scar management interventions after facial skin grafting in children and the impact on outcome, as measured by scar assessment and need for facial reconstructive surgery. A retrospective review of 138 patients who underwent excision and grafting of the face and subsequent noninvasive scar management during a 10-year time frame was conducted. Regression analyses were used to show that earlier application of silicone was significantly related to lower Modified Vancouver Scar Scale scores, specifically in the subscales of vascularity and pigmentation. Early use of pressure therapy and implementation of facial exercises were also related to lower Modified Vancouver Scar Scale vascularity scores. No relationship was found between timing of the interventions and facial reconstructive outcome. Early use of silicone, pressure therapy, and exercise may improve scar outcome and accelerate time to scar maturity. PMID- 23816996 TI - Pediatric toxic epidermal necrolysis: an institutional review of patients admitted to an intensive care unit. AB - Stevens Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare debilitating mucocutaneuous diseases most commonly associated with severe drug reactions. A review of SJS/TEN cases was undertaken to describe the etiology, patient characteristics, treatment, and outcome in children affected at a large tertiary pediatric hospital. A retrospective chart review examined SJS/TEN cases admitted to a pediatric intensive care unit (PICU) between 2001 and 2011. Data concerning total body surface area (TBSA) involvement, causative agents, length of stay, and treatment were reviewed. PICU mortality predictors including Severity-of-Illness Score for Toxic Epidermal Necrolysis (SCORTEN), Pediatric Index of Mortality 2 scores, and Pediatric Logistic Organ Dysfunction scores were also reviewed. Nutritional feeding information was collected and compared with calculated and measured (calorimetry) requirements. There were 10 SJS/TEN pediatric patients (mean age = 6.6 years) with significant skin involvement (mean TBSA = 42.2%) requiring PICU admission. Prescription drugs were the most common causative factor (n = 7). Intravenous immunoglobulin and corticosteroids were used for treatment in eight and two of the cases, respectively. The mean length of stay in the PICU was 10.2 days. There were no mortalities, and all mortality scores predicted high likelihood of survival. Actual feeds (n = 9) were uniformly lower than the calculated feeding requirements (mean = 1059 kcal/day vs mean = 2027 kcal/day). This data will help to provide insight into the management of SJS/TEN in an intensive care setting, and will help form the best treatment approach for future cases in a pediatric population. PMID- 23816995 TI - Increased expression of atrogenes and TWEAK family members after severe burn injury in nonburned human skeletal muscle. AB - Severe burn induces rapid skeletal muscle proteolysis after the injury, which persists for up to 1 year and results in skeletal muscle atrophy despite dietary and rehabilitative interventions. The purpose of this research was to determine acute changes in gene expression of skeletal muscle mass regulators postburn injury. Specimens were obtained for biopsy from the vastus lateralis of a nonburned leg of eight burned subjects (6M, 2F: 34.8 +/- 2.7 years: 29.9 +/- 3.1% TBSA burn) at 5.1 +/- 1.1 days postburn injury and from matched controls. mRNA expression of cytokines and receptors in the tumor necrosis factor-alpha (TNF alpha) and interleukin-6 (IL-6) families, and the ubiquitin proteasome E3 ligases, atrogin-1 and MuRF-1, was determined. TNF receptor 1A was over 3.5-fold higher in burn. Expression of TNF-like weak inducer of apoptosis and its receptor were over 1.6 and 6.0-fold higher in burn. IL-6, IL-6 receptor, and glycoprotein 130 were elevated in burned subjects with IL-6 receptor over 13-fold higher. The level of suppressor of cytokine signaling-3 was also increased nearly 6-fold in burn. Atrogin-1 and MuRF-1 were more than 4- and 3-fold higher in burn. These results demonstrate for the first time that severe burn in humans has a remarkable impact on gene expression in skeletal muscle of a nonburned limb of genes that promote inflammation and proteolysis. Because these changes likely contribute to the acute skeletal muscle atrophy in areas not directly affected by the burn, in the future it will be important to determine the responsible systemic cues. PMID- 23816997 TI - Exercise behaviors after burn injury. AB - The purpose of this study was to investigate exercise behaviors in adult burn survivors and to identify barriers to exercise in this population. A two-page questionnaire developed by the authors was administered on a single occasion to adults attending the ambulatory burns clinic at a metropolitan hospital. Data from 68 adult burn survivors were analyzed. Within this cohort, 59% of subjects reported exercising several times per week or more and the remaining 41% exercised once per week or less. There was no correlation among exercise frequency and age, TBSA, or hospital length of stay. Walking was the most common type of exercise, and subjects reported lower compliance with stretching and strengthening exercises. Physical condition and motivation were identified as the main barriers to exercise. Although this preliminary study reveals that a higher proportion of burn survivors engage in exercise compared with their healthy counterparts, a substantial number are exercising just once per week or less, below the recommended guidelines to improve physical fitness. Physical and occupational therapists play an important role in providing exercise prescription and education, as well as addressing barriers to exercise in burn survivors. The potential for further research into physical activity across all domains of life using a validated questionnaire is identified. PMID- 23816998 TI - Evaluation of the effect of thymoquinone treatment on wound healing in a rat burn model. AB - Thymoquinone (TQ) is a plant extract that has been shown to have antimicrobial, anti-inflammatory, and antioxidant effects. Because of these activities, the authors hypothesized that TQ would reduce inflammation and oxidative stress and accelerate wound closure in a rat model of deep second-degree burns. For the purposes of this study, 40 Sprague-Dawley rats were divided into five groups of eight rats each. Group 1 was the control group, group 2 was the silver sulfadiazine group, group 3 was treated with systemic TQ, group 4 received topical TQ, and group 5 was administered topical and systemic TQ. After the deep second-degree burn damage was created, daily dressing changes and TQ administration were continued in the study groups for a period of 21 days. Systemic TQ was administered intraperitoneally at a dose of 2 mg/kg/day, whereas the topical treatment was applied using a 0.5% solution. The changes in the wound site were observed macroscopically, histopathologically, microbiologically, and biochemically in all groups. The smallest necrotic areas were observed at the end of the study in the groups that were administered a combination of systemic and topical TQ, or solely topical TQ (6.1 +/- 1.6 cm and 6.7 +/- 0.4 cm, respectively), whereas the largest necrotic areas were observed in the control group (11.2 +/- 1.2cm). The total antioxidant state levels in the control group were significantly lower than in the other groups (P < .05), whereas the total oxidative stress levels were lower in the TQ groups compared with the control group (P < .05). The lowest bacterial counts were observed in the groups treated with both topical and systemic TQ (P < .05). TQ given systemically and/or topically reduced inflammation and oxidative stress and accelerated the rate of wound closure or reepithelialization. PMID- 23816999 TI - Comparative Analysis of Early Excision and Grafting vs Delayed Grafting in Burn Patients in a Developing Country. AB - The present study attempts to compare how the patients who undergo early excision and grafting behave as compared with patients who are treated along usual conservative lines of management in centers where the resources are less than optimal. The data of 20 female patients were analyzed. Age of the patients ranged between 20 and 30 years, percentage area burn ranged between 20 and 40%, and percentage area resurfaced by skin grafting 5 to 10%. The patients were divided into two groups of 10 patients each. Group I included those patients who underwent early excision and grafting within 5 days of burn injury. Group II included those patients who were treated conservatively and the residual raw area was grafted 3 weeks or more after sustaining the burn. The two groups were compared for the amount of blood loss, transfusion requirement, graft take, and the total hospital stay. Statistical significance was tested by the application of Mann-Whitney U test. The mean percentage area burn was 29.1 +/- 5.6% in group I and 24.7 +/- 4.9% in group II. Mean percentage area resurfaced by skin grafting in group I was 9.4 +/- 2.3% and 8.1 +/- 1.6% in group II. Graft take in group I was 90 +/- 7.8%, whereas that in group II was 95 +/- 6.7%. Mean blood loss in group I and group II was 346 +/- 17.6 ml and 241 +/- 14.7 ml respectively. (P = .001). Mean transfusion requirement in the perioperative period was 1.6 pints in group I and 1.1 pints in group II. The mean hospital stay in the patients who underwent early excision and grafting was 15.1 +/- 4.1 days, whereas that in the patients who underwent delayed grafting was 36.2 +/- 6.3 days (P = .001). Early excision and grafting decreases the hospital stay of burn patients. The present study suggests that it has a definite applicability even in places where the resources might be less than optimal. PMID- 23817000 TI - Pseudomonas aeruginosa bacteremia after burn injury: the impact of multiple-drug resistance. AB - To evaluate the clinical impact of multiple-drug resistance in burn patients with Pseudomonas aeruginosa (Pa) bacteremia. A retrospective cohort study in a 10-bed burn intensive care unit (BICU) was performed. Univariate and multivariate analyses were used to analyze the influence of multiple-drug resistance on mortality and length of BICU stay in Pa bacteremic patients. During a 21-year study period (1989-2009), 87 patients with Pa bacteremia were identified; 45 patients had multiple-drug resistant (MDR) strains and 42 susceptible strains. On comparison of the two populations, one with multiple-drug resistant strains and the other with the susceptible strains, the following parameters were found to be significantly different in the univariate analysis: age (32.7 vs 43.6 years; P = .013), sex (males: 91.1 vs 66.7%; P = .005), intubation status on admission (75.6 vs. 54.8%; P = .041), escharotomy (57.8 vs 33.3%; P = .022), burn size (51.0 vs 35.3% of TBSA; P = .002) and Abbreviated Burn Severity Index score (9.2 vs 8.1; P = .048). In terms of outcome parameters, multiple-drug resistance was not significantly related to mortality (adjusted odds ratio 1.076; 95% confidence interval [CI] 0.356-3.254; P = .897) and length of BICU stay after Pa bacteremia (Kaplan-Meier analysis log-rank test P = .945; Cox's proportional hazards regression hazards ratio, 0.994; 95% CI 0.513-1.925; P = .985) in the univariate and multivariate analyses. The data from this study suggest that multiple-drug resistance is not associated with significant increases in mortality and length of BICU stay among burn patients with Pa bacteremia. PMID- 23817001 TI - Disaster planning: the past, present, and future concepts and principles of managing a surge of burn injured patients for those involved in hospital facility planning and preparedness. AB - The 9/11 attacks reframed the narrative regarding disaster medicine. Bypass strategies have been replaced with absorption strategies and are more specifically described as "surge capacity." In the succeeding years, a consensus has coalesced around stratifying the surge capacity into three distinct tiers: conventional, contingency, and crisis surge capacities. For the purpose of this work, these three distinct tiers were adapted specifically to burn surge for disaster planning activities at hospitals where burn centers are not located. A review was conducted involving published plans, other related academic works, and findings from actual disasters as well as modeling. The aim was to create burn specific definitions for surge capacity for hospitals where a burn center is not located. The three-tier consensus description of surge capacity is delineated in their respective stratifications by what will hereinafter be referred to as the three "S's"; staff, space, and supplies (also referred to as supplies, pharmaceuticals, and equipment). This effort also included the creation of a checklist for nonburn center hospitals to assist in their development of a burn surge plan. Patients with serious burn injuries should always be moved to and managed at burn centers, but during a medical disaster with significant numbers of burn injured patients, there may be impediments to meeting this goal. It may be necessary for burn injured patients to remain for hours in an outlying hospital until being moved to a burn center. This work was aimed at aiding local and regional hospitals in developing an extemporizing measure until their burn injured patients can be moved to and managed at a burn center(s). PMID- 23817002 TI - An open, prospective, randomized pilot investigation evaluating pain with the use of a soft silicone wound contact layer vs bridal veil and staples on split thickness skin grafts as a primary dressing. AB - An open, prospective, randomized, pilot investigation was implemented to evaluate the pain, cost-effectiveness, ease of use, tolerance, efficacy, and safety of a soft silicone wound contact layer (Mepitel One) vs Bridal Veil and staples used on split thickness skin grafts in the treatment of deep partial or full-thickness thermal burns. Individuals aged between 18 and 70 years with deep partial or full thickness thermal burns (1-25% TBSA) were randomized into two groups and treated for 14 days or until greater than 95% graft take was achieved, whichever occurred first. Data were obtained and analyzed on pain experienced before, during, and after dressing removal. Secondary considerations included the overall cost (direct), graft take and healing, the ease of product use, overall experience of the dressing, and adverse events. A total of 43 subjects were recruited. There were no significant differences in burn area profiles within the groups. The pain level during dressing removal was significant between the groups (P = .0118) with the removal of Mepitel One being less painful. The staff costs were lower in the group of patients treated with Mepitel One (P = .0064) as reflected in the shorter time required for dressing removal (P = .0005), with Mepitel One taking on average less than a quarter of the time to remove. There was no significant difference in healing between the two groups, with 99.0% of the Mepitel One group and 93.1% of the Bridal Veil and staples group showing greater than 95% graft take at post-op day 7 (+/-1) (P = .2373). Clinicians reported that the soft silicone dressing was easier to use, more conformable, and demonstrated better ability to stay in place, compared with the Bridal Veil and staples regime. Both treatments were well tolerated, with no serious adverse events in either treatment group. Mepitel One was at least as effective in the treatment of patients as the standard care (Bridal Veil and staples). In addition, the group of patients treated with the soft silicone dressing demonstrated decreased pain and lower costs associated with treatment. PMID- 23817003 TI - Disaster planning: transportation resources and considerations for managing a burn disaster. AB - A disaster scenario with a significant number of burn-injured patients creates a tremendous challenge for disaster planners. Directing the transport of patients to the most appropriate receiving facility as soon as reasonably possible remains the aim. This review focused on both the overall process as well as an analysis of one specific state (as an example). This included the capability and limitations of the intrastate and interstate resources should a burn disaster occur. Although the results for one state may be interesting, it is the process that is essential for those involved in burn disaster planning. An overview of the quantity and quality of available ambulances and how to access these resources is provided. Ground-based ambulances have an array of capacities and levels of services ranging from basic life support to advanced (paramedic) services and include ambulance buses. This review also included private and hospital-based specialty care ambulances and aeromedical services. Finally, the review identified military or federal resources that may be an option as well. There are various local, state, and federal resources that can be called upon to meet the transportation needs of these critically injured patients. Yet, there are barriers to access and limitations to their response. It is just as important to know both availability and capability as it is to know how to access these resources. A disaster is not the time to realize these hurdles. PMID- 23817004 TI - Disaster preparedness: are we ready? PMID- 23817006 TI - Assessment of prosthetic valve function and para-valvular regurgitation after trans-catheter aortic valve replacement. AB - PURPOSE OF REVIEW: To review the current literature on prosthetic valve function and para-valvular regurgitation (PVR) after trans-catheter aortic valve replacement (TAVR). TAVR is a new alternative for the treatment of severe aortic stenosis in patients at high risk for surgical aortic valve replacement and nonsurgical candidates. RECENT FINDINGS: The innovations in three-dimensional trans-esophageal echocardiography have made it an integral part of the TAVR procedure. PVR is more frequent with TAVR than surgical aortic valve replacement and is associated with worse cardiovascular outcomes. Recent publications focus on echocardiographic techniques to better assess the structural components of aortic valve complex, and begin to define the mechanism and risks of PVR after TAVR. SUMMARY: Imaging innovations before, during, and after TAVR may lead to improved patient selection, accelerated development of TAVR prostheses, and ultimately a fuller characterization of the performance and potential limitations of a new generation of prosthetic heart valves. PMID- 23817007 TI - Effects of pirfenidone on increased cough reflex sensitivity in guinea pigs. AB - Pirfenidone, an antifibrotic drug with anti-inflammatory and antioxidant effects, delays fibrosis in idiopathic pulmonary fibrosis (IPF). Patients with IPF have a greater cough reflex sensitivity to inhaled capsaicin than healthy people, and cough is an independent predictor of IPF disease progression; however, the effects of pirfenidone on cough reflex sensitivity are unknown. After challenge with an aerosolized antigen in actively sensitized guinea pigs, pirfenidone was administered intraperitoneally, and the cough reflex sensitivity was measured at 48 h after the challenge. Bronchoalveolar lavage (BAL) was performed, and the tracheal tissue was collected. Pirfenidone suppressed the capsaicin-induced increase in cough reflex sensitivity in a dose-dependent manner. Additionally, increased levels of prostaglandin E2, substance P, and leukotriene B4, but not histamine, in the BAL fluid were dose dependently suppressed by pirfenidone. The decrease in neutral endopeptidase activity in the tracheal tissue was also alleviated by pirfenidone treatment. The total number of cells and components in the BAL fluid was not influenced. These results suggest that pirfenidone ameliorates isolated cough based on increased cough reflex sensitivity associated with allergic airway diseases, and potentially relieve chronic cough in IPF patients who often have increased cough reflex sensitivity. Prospective studies on cough-relieving effects of pirfenidone in patients with IPF are therefore warranted. PMID- 23817008 TI - Endoscopic management of bile duct stones: residual bile duct stones after surgery, cholangitis, and "difficult stones". AB - Endoscopic treatment has become, according to the latest recommendations, the standard treatment for common bile duct stones (CBDS), although in certain situations, surgical clearance of the common duct at the time of laparoscopic cholecystectomy is still considered a possible alternative. The purpose of this article is not to compare endoscopic with surgical treatment of CBDS, but to describe the various techniques of endoscopic treatment, detailing their preferential indications and the various treatment options that must sometimes be considered when faced with "difficult calculi" of the CBD. The different techniques of lithotripsy and the role of biliary drainage with plastic or metallic stents will be detailed as well as papillary balloon dilatation and particularly the technique of sphincterotomy with macrodilatation of the sphincter of Oddi (SMSO), a recently described approach that has changed the strategy for endoscopic management of CBDS. Finally, the overall strategy for endoscopic management of CBDS, with description of different techniques, will be exposed. PMID- 23817009 TI - Mitochondrial membrane permeabilisation by amyloid aggregates and protection by polyphenols. AB - Alzheimer's disease and Parkinson's disease are neurodegenerative disorders characterised by the misfolding of proteins into soluble prefibrillar aggregates. These aggregate complexes disrupt mitochondrial function, initiating a pathophysiological cascade leading to synaptic and neuronal degeneration. In order to explore the interaction of amyloid aggregates with mitochondrial membranes, we made use of two in vitro model systems, namely: (i) lipid vesicles with defined membrane compositions that mimic those of mitochondrial membranes, and (ii) respiring mitochondria isolated from neuronal SH-SY5Y cells. External application of soluble prefibrillar forms, but not monomers, of amyloid-beta (Abeta42 peptide), wild-type alpha-synuclein (alpha-syn), mutant alpha-syn (A30P and A53T) and tau-441 proteins induced a robust permeabilisation of mitochondrial like vesicles, and triggered cytochrome c release (CCR) from isolated mitochondrial organelles. Importantly, the effect on mitochondria was shown to be dependent upon cardiolipin, an anionic phospholipid unique to mitochondria and a well-known key player in mitochondrial apoptosis. Pharmacological modulators of mitochondrial ion channels failed to inhibit CCR. Thus, we propose a generic mechanism of thrilling mitochondria in which soluble amyloid aggregates have the intrinsic capacity to permeabilise mitochondrial membranes, without the need of any other protein. Finally, six small-molecule compounds and black tea extract were tested for their ability to inhibit permeation of mitochondrial membranes by Abeta42, alpha-syn and tau aggregate complexes. We found that black tea extract and rosmarinic acid were the most potent mito-protectants, and may thus represent important drug leads to alleviate mitochondrial dysfunction in neurodegenerative diseases. PMID- 23817010 TI - Differential sensitivity to detergents of actin cytoskeleton from nerve endings. AB - Detergent-resistant membranes (DRM), an experimental model used to study lipid rafts, are typically extracted from cells by means of detergent treatment and subsequent ultracentrifugation in density gradients, Triton X-100 being the detergent of choice in most of the works. Since lipid rafts are membrane microdomains rich in cholesterol, depletion of this component causes solubilization of DRM with detergent. In previous works from our group, the lack of effect of cholesterol depletion on DRM solubilization with Triton X-100 was detected in isolated rat brain synaptosomes. In consequence, the aim of the present work is to explore reasons for this observation, analyzing the possible role of the actin cytoskeleton, as well as the use of an alternative detergent, Brij 98, to overcome the insensitivity to Triton X-100 of cholesterol-depleted DRM. Brij 98 yields Brij-DRM that are highly dependent on cholesterol, since marker proteins (Flotillin-1 and Thy-1), as well as actin, appear solubilized after MCD treatment. Pretreatment with Latrunculin A results in a significant increase in Flotillin-1, Thy-1 and actin solubilization by Triton X-100 after cholesterol depletion. Studies with transmission electron microscopy show that combined treatment with MCD and Latrunculin A leads to a significant increase in solubilization of DRM with Triton X-100. Thus, Triton-DRM resistance to cholesterol depletion can be explained, at least partially, thanks to the scaffolding action of the actin cytoskeleton, without discarding differential effects of Brij 98 and Triton X-100 on specific membrane components. In conclusion, the detergent of choice is important when events that depend on the actin cytoskeleton are going to be studied. PMID- 23817011 TI - FTIR spectroscopy is a powerful tool. PMID- 23817012 TI - Associate editor Kurt Blaser? PMID- 23817013 TI - Unilateral squamous cell carcinoma of the renal pelvis with hydronephrosis in a cat. AB - A 4-year-old female neutered domestic shorthair cat was presented for evaluation of gradual onset of lethargy and anorexia. Physical examination revealed moderate abdominal distension. Investigations performed included complete blood count, serum biochemistry, urinalysis, pyelocentesis, abdominal fluid analysis, abdominal ultrasonography and exploratory celiotomy. Nephrectomy was performed on the hydronephrotic kidney and a sample of the omentum was also taken, as it was grossly abnormal. No other abnormalities were found in the remainder of the abdominal organs. Findings were consistent with unilateral hydronephrosis and squamous cell carcinoma of the renal pelvis with abdominal carcinomatosis. The patient was given supportive treatment while the results of the biopsies from the renal tissue and the omentum were pending. The patient deteriorated a short time after surgical intervention and was euthanased. This is the first report of a squamous cell carcinoma arising from the renal pelvis in a cat. A comparison with the disease presentation in humans is also discussed. PMID- 23817014 TI - Partial hydatidiform mole diagnosis in a cat: a case report. AB - A case of a stillborn Norwegian Forest kitten characterised in the course of anatomopathological and genetic examination is reported. The hydatidiform mole was diagnosed by delayed development, low birth weight of the kitten and abnormal placental development. Anatomopathological diagnosis was confirmed in genetic tests based on the amplification of highly heterozygous microsatellite sequences located on the X (FCA311) and autosomal chromosomes (FCA506, FCA532 and FCA178), as well as the sex-specific Sry and amelogenin (Amel) genes. The presence of two microsatellite alleles of paternal origin and one allele of maternal origin was observed in all analysed tissues (kidney, liver, brain, heart and spleen) of the stillborn kitten. The kitten's sex was diagnosed by the presence of the paternal Sry gene, and maternal and paternal products of Amel, as well as one maternal and one paternal X chromosome FCA311 microsatellite allele. The results thus confirmed that the haploid egg was fertilised by two sperm, yielding a triploid karyotype. In summary, the successful application of genetic markers in postnatal diagnosis of this condition in the cat confirms considerable usefulness of these techniques, especially in cases where cytogenetic diagnosis is insufficient or impossible. PMID- 23817015 TI - Cardiac-specific adipose triglyceride lipase overexpression protects from cardiac steatosis and dilated cardiomyopathy following diet-induced obesity. AB - BACKGROUND: Although obesity increases the risk of developing cardiomyopathy, the mechanisms underlying the development of this cardiomyopathy are incompletely understood. As obesity is also associated with increased intramyocardial triacylglycerol (TAG) deposition, also referred to as cardiac steatosis, we hypothesized that alterations in myocardial TAG metabolism and excess TAG accumulation contribute to obesity-induced cardiomyopathy. OBJECTIVE AND DESIGN: To test if increased TAG catabolism could ameliorate obesity-induced cardiac steatosis and dysfunction, we utilized wild-type (WT) mice and mice with cardiomyocyte-specific overexpression of adipose triglyceride lipase (MHC-ATGL mice), which regulates cardiac TAG hydrolysis. WT and MHC-ATGL mice were fed either regular chow (13.5 kcal% fat) or high fat-high sucrose (HFHS; 45 kcal% fat and 17 kcal% sucrose) diet for 16 weeks to induce obesity and mice were subsequently studied at the physiological, biochemical and molecular level. RESULTS: Obese MHC-ATGL mice were protected from increased intramyocardial TAG accumulation, despite similar increases in body weight and systemic insulin resistance as obese WT mice. Importantly, analysis of in vivo cardiac function using transthoracic echocardiography showed that ATGL overexpression protected from obesity-induced systolic and diastolic dysfunction and ventricular dilatation. Ex vivo working heart perfusions revealed impaired cardiac glucose oxidation following obesity in both WT and MHC-ATGL mice, which was consistent with similar impaired cardiac insulin signaling between genotypes. However, hearts from obese MHC-ATGL mice exhibited reduced reliance on palmitate oxidation when compared with the obese WT, which was accompanied by decreased expression of proteins involved in fatty acid uptake, storage and oxidation in MHC-ATGL hearts. CONCLUSION: These findings suggest that cardiomyocyte-specific ATGL overexpression was sufficient to prevent cardiac steatosis and decrease fatty acid utilization following HFHS diet feeding, leading to protection against obesity-induced cardiac dysfunction. PMID- 23817016 TI - Dysregulation of brain olfactory and taste receptors in AD, PSP and CJD, and AD related model. AB - Recently, we have shown the expression of novel chemoreceptors corresponding to the olfactory receptor (OR) and taste receptor (TASR) families in the human brain. We have also shown dysregulation of ORs and TASRs in the cerebral cortex in Parkinson's disease. The present study demonstrates the presence of OR mRNA and mRNA of obligated downstream components of OR signaling adenylyl cyclase 3 (ADYLC3) and olfactory G protein (Gnal) in the cerebral cortex of the mouse. Dysregulation of selected ORs and TASRs has been found in the entorhinal cortex and frontal cortex in Alzheimer's disease (AD) in a gradient compatible with Braak and Braak staging; frontal cortex in terminal stages of Progressive Supranuclear Palsy; and frontal cortex and cerebellum in Creutzfeldt-Jakob disease subtypes methionine/methionine at codon 129 of PRNP (MM1) and valine/valine at codon 129 of PRNP (VV2). Altered OR, ADYLC3 and Gnal mRNA expression with disease progression has also been found in APP/PS1 transgenic mice, used as a model of AD. The function of these orphan receptors is not known, but probably related to cell signaling pathways responding to unidentified ligands. Variability in the drift, either down- or up-regulation, of dysregulated genes, suggests that central ORs and TASRs are vulnerable to variegated neurodegenerative diseases with cortical involvement, and that altered expression of ORs and TASRs is not a mere reflection of neuronal loss but rather a modulated pathological response. PMID- 23817017 TI - Dynamic and dual effects of glycated hemoglobin on estimated glomerular filtration rate in type 2 diabetic outpatients. AB - BACKGROUND: Diabetic nephropathy is the leading cause of incident end-stage renal disease in Taiwan. Previous studies on the consistent benefits of glycemic control in diabetic nephropathy focused primarily on delaying microalbuminuria. However, this effect on glomerular filtration rate (GFR) remains controversial. This study aims to establish a model that explains the controversial effects of glycated hemoglobin (HbA1C) on GFR. METHODS: This retrospective cohort study followed subjects with type 2 diabetes mellitus, who were enrolled between June 2006 and December 2006, for 4 years. The effects of HbA1C on estimated GFR (eGFR) were examined both cross-sectionally and longitudinally. The dual effects of HbA1C on eGFR, and how renal function interferes with these effects, were investigated. RESULTS: Of the 1,992 subjects enrolled, 1,699 completed the follow up. HbA1C was positively correlated with eGFR in the cross-sectional study (beta coefficient = 1.44, 95% CI: 0.71-2.17, p = 0.0001). In the longitudinal study, higher baseline HbA1C resulted in a greater decline in eGFR. The annual eGFR decline rates were -1.89, -1.29, and -0.68 ml/min/1.73 m(2)/year for baseline HbA1C >9, 7 to <=9, and <=7%, respectively. The eGFR value was simultaneously affected by concurrent (beta coefficient = 0.78, 95% CI: 0.48-1.08, p < 0.0001) and preceding HbA1C (-0.52, -0.82 to -0.23, p < 0.0001). The positive effects of concurrent HbA1C on eGFR reached statistical significance at all stages of chronic kidney disease (CKD); however, the negative effects of preceding HbA1C only applied to CKD stages 3 and 4. CONCLUSIONS: We developed a new model that demonstrates how preceding and concurrent HbA1C simultaneously affect eGFR in opposing ways. The dynamic effects varied among different CKD stages. The deterioration in eGFR at CKD stages 3 and 4 may be postponed by intensive glycemic control. Further prospective studies may be necessary to clarify the specific CKD stage(s) that will benefit from intensive glycemic control. PMID- 23817018 TI - Simvastatin attenuates TGF-beta1-induced epithelial-mesenchymal transition in human alveolar epithelial cells. AB - BACKGROUND: Transforming growth factor-beta1 (TGF-beta1)-induced epithelial mesenchymal transition (EMT) of alveolar epithelial cells (AEC) may contribute to idiopathic pulmonary fibrosis (IPF). TGF-beta1-induced EMT in A549 cells (a human AEC cell line) resulted in the adoption of mesenchymal responses that were predominantly mediated via the TGF-beta1-Smad2/3 signaling pathway. Simvastatin (Sim), a 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitor, has been previously reported to inhibit EMT in human proximal tubular epithelial cells and porcine lens epithelial cells and to suppress Smad2/3 phosphorylation in animal models. However, whether Sim can attenuate TGF-beta1-induced EMT in A549 cells and its underlying mechanisms remains unknown. METHODS: Cells were incubated with TGF-beta1 in the presence or absence of Sim. The epithelial marker E-cadherin (E Cad) and the mesenchymal markers, alpha-smooth muscle actin (alpha-SMA), vimentin (Vi) and fibronectin (FN), were detected using western blotting analyses and immunofluorescence. Phosphorylated Smad2 and Smad3 levels and connective tissue growth factor (CTGF) were analyzed using western blotting. In addition, a cell migration assay was performed. Moreover, the levels of matrix metalloproteinase (MMP)-2 and -9 in the culture medium were examined using ELISA. RESULTS: Sim significantly attenuated the TGF-beta1-induced decrease in E-Cad levels and elevated the levels of alpha-SMA, Vi and FN via the suppression of Smad2 and Smad3 phosphorylation. Furthermore, Sim inhibited the mesenchymal-like responses in A549 cells, including cell migration, CTGF expression and secretion of MMP-2 and -9. However, Sim failed to reverse the cell morphologial changes induced by TGF-beta1 in A549 cells. CONCLUSION: Sim attenuated TGF-beta1-induced EMT in A549 cells and might be a promising therapeutic agent for treating IPF. PMID- 23817019 TI - Exchanging the minimal cell binding fragments of tetanus neurotoxin in botulinum neurotoxin A and B impacts their toxicity at the neuromuscular junction and central neurons. AB - The modular four domain structure of clostridial neurotoxins supports the idea to reassemble individual domains from tetanus and botulinum neurotoxins to generate novel molecules with altered pharmacological properties. To treat disorders of the central nervous system drug transporter molecules based on catalytically inactive clostridial neurotoxins circumventing the passage of the blood-brain barrier are desired. Such molecules can be produced based on the highly effective botulinum neurotoxin serotype A incorporating the retrograde axonal sorting property of tetanus neurotoxin which is supposed to be encoded within its C terminal cell binding domain HC. The corresponding exchange of the tetanus neurotoxin HC-fragment in botulinum neurotoxin A yielded the novel hybrid molecule AATT which displayed decreased potency at the neuromuscular junction like tetanus neurotoxin but exerted equal activity in cortical neurons compared to botulinum neurotoxin A wild-type. Minimizing the tetanus neurotoxin cell binding domain to its N- or C-terminal half drastically reduced the potencies of AATA and AAAT in cortical neurons indicating that the structural motif mediating sorting of tetanus neurotoxin is predominantly encoded within the entire HC fragment. However, the reciprocal exchange resulted in TTAA which showed a similar potency as tetanus neurotoxin at the neuromuscular junction indicating that the tetanus neurotoxin portion prevents a high potency as observed for botulinum neurotoxins. In conclusion, clostridial neurotoxin based inactivated drug transporter for targeting central neurons should contain the cell binding domain of tetanus neurotoxin to exert its tropism for the central nervous system. PMID- 23817020 TI - ARF regulates the stability of p16 protein via REGgamma-dependent proteasome degradation. AB - The cell-cycle regulatory gene INK4A-ARF (CDKN2A) has two alternative transcripts that produce entirely different proteins, namely p14(ARF) and p16, which have complementary functions as regulators of p53 and pRB tumor suppressor pathways, respectively. The unusual organization of INK4A-ARF has long led to speculation of a need for coordinated regulation of p14(ARF) and p16. We now show that p14(ARF) (ARF) regulates the stability of p16 protein in human cancer cell lines, as well as in mouse embryonic fibroblasts (MEFs). In particular, ARF promotes rapid degradation of p16 protein, which is mediated by the proteasome and, more specifically, by interaction of ARF with one of its subunits, REGgamma. Furthermore, this ARF-dependent destabilization of p16 can be abrogated by knockdown of REGgamma or by pharmacologic blockade of its nuclear export. Thus, our findings have uncovered a novel crosstalk of 2 key tumor suppressors mediated by a REGgamma-dependent mechanism. The ability of ARF to control p16 stability may influence cell-cycle function. IMPLICATIONS: The ability of ARF to control p16 stability may influence cell cycle function. Visual Overview: http://mcr.aacrjournals.org/content/current. PMID- 23817021 TI - ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss. AB - Studies of ETS-mediated prostate oncogenesis have been hampered by a lack of suitable experimental systems. Here we describe a new conditional mouse model that shows robust, homogenous ERG expression throughout the prostate. When combined with homozygous Pten loss, the mice developed accelerated, highly penetrant invasive prostate cancer. In mouse prostate tissue, ERG markedly increased androgen receptor (AR) binding. Robust ERG-mediated transcriptional changes, observed only in the setting of Pten loss, included the restoration of AR transcriptional output and upregulation of genes involved in cell death, migration, inflammation and angiogenesis. Similarly, ETS variant 1 (ETV1) positively regulated the AR cistrome and transcriptional output in ETV1 translocated, PTEN-deficient human prostate cancer cells. In two large clinical cohorts, expression of ERG and ETV1 correlated with higher AR transcriptional output in PTEN-deficient prostate cancer specimens. We propose that ETS factors cause prostate-specific transformation by altering the AR cistrome, priming the prostate epithelium to respond to aberrant upstream signals such as PTEN loss. PMID- 23817022 TI - Origin and function of myofibroblasts in kidney fibrosis. AB - Myofibroblasts are associated with organ fibrosis, but their precise origin and functional role remain unknown. We used multiple genetically engineered mice to track, fate map and ablate cells to determine the source and function of myofibroblasts in kidney fibrosis. Through this comprehensive analysis, we identified that the total pool of myofibroblasts is split, with 50% arising from local resident fibroblasts through proliferation. The nonproliferating myofibroblasts derive through differentiation from bone marrow (35%), the endothelial-to-mesenchymal transition program (10%) and the epithelial-to mesenchymal transition program (5%). Specific deletion of Tgfbr2 in alpha-smooth muscle actin (alphaSMA)(+) cells revealed the importance of this pathway in the recruitment of myofibroblasts through differentiation. Using genetic mouse models and a fate-mapping strategy, we determined that vascular pericytes probably do not contribute to the emergence of myofibroblasts or fibrosis. Our data suggest that targeting diverse pathways is required to substantially inhibit the composite accumulation of myofibroblasts in kidney fibrosis. PMID- 23817025 TI - Fluids are drugs: type, dose and toxicity. AB - PURPOSE OF REVIEW: We discuss the formulation of a prescription for intravenous (i.v.) fluid therapy (a 'volume prescription') for critically ill patients: pros/cons of different fluid types; accurate dosing; and qualitative and quantitative toxicities. Updated physiologic concepts are invoked and results of recent major clinical trials on i.v. fluid therapy in the acutely ill are interpreted. RECENT FINDINGS: Context is vital and any fluid can be harmful if dosed incorrectly. When contrasting 'crystalloid versus colloid', differences in efficacy are modest, but differences in safety are significant. Differences in chloride load and strong ion difference appear to be clinically important. Quantitative toxicity is mitigated when dosing is based on dynamic parameters that predict volume responsiveness. Qualitative toxicity for colloids (even with newer hydroxyethyl starch 130/0.4 solutions) and isotonic saline remain a concern. SUMMARY: Similar to any drug used in acutely ill patients, clinicians ordering a volume prescription must recognize that context is crucial. Physiologically balanced crystalloids may be the 'default' fluid for acutely ill patients, and the role for colloids is unclear. Optimal dosing involves assessment of volume responsiveness. PMID- 23817023 TI - Liver receptor homolog-1 is essential for pregnancy. AB - Successful pregnancy requires coordination of an array of signals and factors from multiple tissues. One such element, liver receptor homolog-1 (Lrh-1), is an orphan nuclear receptor that regulates metabolism and hormone synthesis. It is strongly expressed in granulosa cells of ovarian follicles and in the corpus luteum of rodents and humans. Germline ablation of Nr5a2 (also called Lrh-1), the gene coding for Lrh-1, in mice is embryonically lethal at gastrulation. Depletion of Lrh-1 in the ovarian follicle shows that it regulates genes required for both steroid synthesis and ovulation. To study the effects of Lrh-1 on mouse gestation, we genetically disrupted its expression in the corpus luteum, resulting in luteal insufficiency. Hormone replacement permitted embryo implantation but was followed by gestational failure with impaired endometrial decidualization, compromised placental formation, fetal growth retardation and fetal death. Lrh-1 is also expressed in the mouse and human endometrium, and in a primary culture of human endometrial stromal cells, reduction of NR5A2 transcript abundance by RNA interference abrogated decidualization. These findings show that Lrh-1 is necessary for maintenance of the corpus luteum, for promotion of decidualization and for formation of the placenta. It therefore has multiple, indispensible roles in establishing and sustaining pregnancy. PMID- 23817024 TI - Temporal stability and moderating effects of age and sex on CNTRaCS task performance. AB - Research in schizophrenia has increasingly focused on incorporating measures from cognitive neuroscience, but little is known about their psychometric characteristics. Here, we extend prior research by reporting on temporal stability, as well as age and sex effects, for cognitive neuroscience paradigms optimized as part of the Cognitive Neuroscience Test Reliability and Clinical applications for Schizophrenia consortium. Ninety-nine outpatients with schizophrenia and 131 healthy controls performed 5 tasks assessing 4 constructs at 3 sessions. The constructs were (1) Goal maintenance (Dot Probe Expectancy [DPX] and AX continuous performance tasks [AX-CPT]); (2) Episodic memory (Relational and Item-Specific Encoding and Retrieval task [RiSE]); (3) Visual integration (Jittered Orientation Visual Integration task [JOVI]); and (4) Perceptual gain control (Contrast-Contrast Effect Task [CCE]). Patients performed worse than controls on all but the CCE, and the magnitude of these group differences was stable across sessions, with no sex differences observed. Improvements over sessions were seen for the AX-CPT, the DPX, and the JOVI though practice effects for the AX-CPT and the DPX were primarily present in older participants. For the AX-CPT and the JOVI, practice effects were larger for T1 to T2 than for T2 to T3. Age was associated with poor associative recognition on the RiSE and accuracy on the JOVI. Test-rest reliability ranged from poor for the JOVI threshold score to adequate to good for the DPX, AX-CPT, and JOVI accuracy measures, with RiSE and CCE measures in the moderate range. These results suggest that group differences in DPX, AX-CPT, RiSE, and JOVI are robust and consistent across repeated testing. PMID- 23817026 TI - Using procalcitonin-guided algorithms to improve antimicrobial therapy in ICU patients with respiratory infections and sepsis. AB - PURPOSE OF REVIEW: In patients with systemic bacterial infections hospitalized in ICUs, the inflammatory biomarker procalcitonin (PCT) has been shown to aid diagnosis, antibiotic stewardship, and risk stratification. Our aim is to summarize recent evidence about the utility of PCT in the critical care setting and discuss the potential benefits and limitations of PCT when used for clinical decision-making. RECENT FINDINGS: A growing body of evidence supports PCT use to differentiate bacterial from viral respiratory infections (including influenza), to help risk stratify patients, and to guide decisions about optimal duration of antibiotic therapy. Different PCT protocols were evaluated for these and similar purposes in randomized controlled trials in patients with varying severities of predominantly respiratory tract infection and sepsis. These trials demonstrated effectiveness of monitoring PCT to de-escalate antibiotic treatment earlier without increasing rates of relapsing infections or other adverse outcomes. Although serial PCT measurement has shown value in risk stratification of ICU patients, PCT-guided antibiotic escalation protocols have not yet shown benefit for patients. SUMMARY: Inclusion of PCT data in clinical algorithms improves individualized decision-making regarding antibiotic treatment in patients in critical care for respiratory infections or sepsis. Future research should focus on use of repeated PCT measurements to risk-stratify patients and guide treatment to improve their outcomes. PMID- 23817027 TI - Blood component transfusion in critically ill patients. AB - PURPOSE OF REVIEW: This review summarizes the current evidence base for commonly transfused blood components with a particular focus on the nonacutely bleeding patient. RECENT FINDINGS: There remains little definitive evidence to guide transfusion practices in the critically ill. The most rigorous evidence to guide red blood cell (RBC) transfusion practice is derived from the Transfusion in Critical Care Trial (TRICC Trial) that was published in 1999. Specific subgroups of patients may be at particular risk of the adverse effects of anemia, and require further study. There are no randomized controlled trials addressing clinically important outcomes evaluating frozen plasma, platelet thresholds, or impaired platelet activity in the critically ill. SUMMARY: As all blood components have some level of risk, the general approach to transfusion should be one of minimization. For the nonacutely bleeding critically ill patient, a RBC transfusion trigger of 70 g/l is clinically acceptable. For patients at potentially higher risk of adverse effects related to anemia such as those with septic shock, severe and/or acute ischemic heart disease, or brain injury, a higher threshold (80-90 g/l) may be considered. There is insufficient evidence to recommend specific thresholds for transfusion of frozen plasma or platelets in the critically ill. PMID- 23817028 TI - The postoperative airway: unique challenges? AB - PURPOSE OF REVIEW: The review is focused on the challenge of managing airway and ventilation in the intraoperative and postoperative period. RECENT FINDINGS: In past years, a lot of attention was focused on tracheal intubation in difficult airway, whereas only in recent years extubation time of difficult airway is also covering an important role. Protective ventilation strategies have been studied in acute respiratory distress syndrome and then in general anesthesia, either for thoracic or bariatric surgery, whereas in general abdominal surgery, in healthy lung, few studies are present demonstrating the effective protective role of low tidal volume, lung recruitment maneuvers (LRM) and positive end-expiratory pressure (PEEP). In the early postoperative period, the role of noninvasive ventilation is growing as it reduces postoperative pulmonary complications, postoperative length of stay and costs. SUMMARY: The combination of planning extubation of predicted and unpredicted difficult airway, both intraoperative low tidal volume and low FiO2 with LRM and PEEP at different points of surgery and postoperative noninvasive ventilation should be considered in patients undergoing surgery to decrease the rate of postoperative pulmonary complications and major fatal complications such as brain damage and death. PMID- 23817029 TI - Optimizing perioperative hemodynamics: what is new? AB - PURPOSE OF REVIEW: Using perioperative goal-directed therapy (GDT) or peroperative hemodynamic optimization significantly reduces postoperative complications and risk of death in patients undergoing noncardiac major surgeries. In this review, we discuss the main changes in the field of perioperative optimization over the last few years. RECENT FINDINGS: One of the key aspects that has changed in the last decade is the shift from invasive monitoring with pulmonary artery catheters (PACs) to less or minimally invasive monitoring systems. The evaluation of intravascular fluid volume deficits has also changed dramatically from the use of static indices to the assessment of fluid responsiveness using either dynamic indices or functional hemodynamic. Finally, attention has been directed toward more restrictive strategies of crystalloids as maintenance fluids. SUMMARY: GDT is safe and more likely to tailor the amount of fluids given to the amount of fluids actually needed. This approach includes assessment of fluid responsiveness and, if necessary, the use of inotropes; moreover, this approach can be coupled with a restrictive strategy for maintenance fluids. These strategies have been increasingly incorporated into protocols for perioperative hemodynamic optimization in high-risk patients undergoing major surgery, resulting in more appropriate use of fluids, vasopressors, and inotropes. PMID- 23817030 TI - Perioperative fluids: a clear road ahead? AB - PURPOSE OF REVIEW: There is significant controversy for perioperative fluid management. This review discusses the evidence from clinical studies, basic research, and systematic reviews to provide a summary of the current best practice in this area. RECENT FINDINGS: Recent evidence has challenged the long held contention that use of colloids results in substantially less fluid volumes to achieve resuscitation endpoints. Meanwhile, evidence that hydroxyethyl starch does carry a risk of renal toxicity is now strong. Mounting evidence also points to a hazard, especially for the kidney, when large volumes of saline are used. A patient's clinical condition may also determine the deposition of infused fluids in the body. Total positive fluid balance is an indicator of adverse clinical outcomes, though a cause-effect relationship has not been firmly established. The optimal perioperative fluid management requires a balance of the beneficial and adverse effects of intravenous fluid. SUMMARY: Although potentially life-saving, evidence points to significant hazards associated with various types and use strategies for intravenous fluids. Like other drugs, intravenous fluids should be used with caution for specific indications, in specific amounts, and with careful attention to potential adverse effects associated with various products. An individualized approach to perioperative fluid therapy is recommended. PMID- 23817031 TI - Reducing perioperative cardiac morbidity and mortality: is this the right goal? AB - PURPOSE OF REVIEW: One million people die annually following noncardiac surgery and 4% of patients suffer an adverse cardiac event after surgery. As the number of people having surgery grows, our ability to risk stratify patients becomes more important, particularly in the setting of perioperative myocardial ischemia/necrosis. RECENT FINDINGS: In recent publications, an increased troponin following noncardiac surgery has been associated with a higher morbidity/mortality in the perioperative setting. The level of troponin elevation associated with increased morbidity/mortality is now believed to be far lower than was previously considered to be pathologic. SUMMARY: The presence of troponin elevations following noncardiac surgery, particularly in at-risk patients, may enable practitioners to better identify high-risk patients in the postoperative setting. After recognizing those patients at increased risk for poor outcomes, practitioners can then make interventions, which may decrease the patients' in-hospital, 30-day and potentially long-term mortality. PMID- 23817032 TI - The long-term effects of postoperative complications. AB - PURPOSE OF REVIEW: This review examines the long-term influence of postoperative complications on survival. Although it is intuitive that complications after surgery worsen short-term outcomes, it is not clear to what extent and why a longer-term relationship may exist. RECENT FINDINGS: Most studies have focused on outcomes after cancer surgery. Despite mixed results in smaller cohorts, large multicentre analyses consistently identify an association between postoperative complications and long-term mortality. In part, this phenomenon may be due to unmeasured confounding factors or insufficient separation of short and long-term consequences. Nevertheless, functional and biological imprints established during postoperative complications are likely to be relevant, and are the subject of ongoing research. SUMMARY: Patients that develop postoperative complications and survive the immediate risk period, demonstrate worsened long-term mortality. The field of perioperative medicine is increasingly mandated to identify vulnerable individuals, develop and implement strategies to prevent and treat complications, and provide better care pathways after hospital discharge. PMID- 23817033 TI - Sexual dimorphism of the electrosensory system: a quantitative analysis of nerve axons in the dorsal anterior lateral line nerve of the blue-spotted Fantail Stingray (Taeniura lymma). AB - Quantitative studies of sensory axons provide invaluable insights into the functional significance and relative importance of a particular sensory modality. Despite the important role electroreception plays in the behaviour of elasmobranchs, to date, there have been no studies that have assessed the number of electrosensory axons that project from the peripheral ampullae to the central nervous system (CNS). The complex arrangement and morphology of the peripheral electrosensory system has a significant influence on its function. However, it is not sufficient to base conclusions about function on the peripheral system alone. To fully appreciate the function of the electrosensory system, it is essential to also assess the neural network that connects the peripheral system to the CNS. Using stereological techniques, unbiased estimates of the total number of axons were obtained for both the electrosensory bundles exiting individual ampullary organs and those entering the CNS (via the dorsal root of the anterior lateral line nerve, ALLN) in males and females of different sizes. The dorsal root of the ALLN consists solely of myelinated electrosensory axons and shows both ontogenetic and sexual dimorphism. In particular, females exhibit a greater abundance of electrosensory axons, which may result in improved sensitivity of the electrosensory system and may facilitate mate identification for reproduction. Also presented are detailed morphological data on the peripheral electrosensory system to allow a complete interpretation of the functional significance of the sexual dimorphism found in the ALLN. PMID- 23817034 TI - Innate immune responses to Proteus mirabilis flagellin in the urinary tract. AB - Flagella are bacterial virulence factors allowing microorganisms to move over surfaces. Flagellin, the structural component of flagella, is sensed by the host via Toll and NOD-like receptors and triggers pro-inflammatory responses. The use of Toll-like receptors agonists to modulate innate immune responses has aroused great interest as an alternative to improve the treatment of diverse infectious diseases. Proteus mirabilis is a Gram negative bacterium that causes urinary tract infections in humans. In the present work we used different approaches to study the ability of P. mirabilis flagellin to induce an innate immune response. We demonstrated that P. mirabilis flagellin has the ability to induce pro inflammatory chemokines expression in T24 bladder cultures cells and in the mouse bladder after instillation. It was evidenced also that flagellin from different P. mirabilis strains differed in their capacity to induce an innate immune response in the CacoCCL20-Luc system. Also, flagellin elicited inflammation, with recruitment of leukocytes to the bladder epithelium. Flagellin instillation before an experimental P. mirabilis infection showed that the inflammatory response due to flagellin did not help to clear the infection but favored bacterial colonization. Thus, induction of inflammatory response in the bladder did not contribute to P. mirabilis infection neutralization. PMID- 23817035 TI - Central venous catheter infections in outpatients with pulmonary hypertension treated with continuous iloprost. AB - BACKGROUND: Intravenous prostanoid therapy is one cornerstone of therapy for patients with pre-capillary pulmonary hypertension (PH). Long-term central venous catheters expose patients to infectious complications. OBJECTIVES: We report the incidence of catheter-related infection (CRI) and the spectrum of bacteria for ambulatory PH patients treated with iloprost via non-tunnelled central venous catheters from our Swiss referral centre in Zurich. METHODS: Data from 15 PH patients treated with intravenous iloprost between May 2000 and June 2012 were reviewed. RESULTS: We found 11 CRI in 4 cases by two different organisms. Pathogens found were Brevibacterium (55%), Micrococcus luteus (18%), coagulase negative Staphylococcus (9%) and Staphylococcus aureus (9%), as well as unusual organisms such as Agrobacterium tumefaciens or Delftia tsuruhatensis. The overall CRI rate was 1.28 per 1,000 catheter days, or 0.47 per year. CONCLUSIONS: The incidence of CRI using long-term, non-tunnelled central venous catheters in PH patients treated with iloprost is low. Uncommon, rare pathogens causing CRI were found in a substantial number of patients. PMID- 23817036 TI - Working together: research- and science-based regulation of BPA. PMID- 23817037 TI - Location- and sex-specific differences in weight and motor coordination in two commonly used mouse strains. AB - Several studies have shown that environmental factors can affect the outcome of behavioral experiments, shedding doubts on the inter-laboratory reproducibility of behavioral test results. When our laboratory moved from the University of Rochester, Rochester, NY, to Sanford Research in Sioux Falls, SD, our mouse colony was also transferred and the new environment caused strain-dependent changes in the weight, motor coordination and motor learning capability of mice. Here we report the observed changes for two wild type mouse strains commonly used in transgenic studies, C57BL/6J and 129S6/SvEv, and show that the type of rodent diet is partially responsible for the geographical location-specific differences. We also found sex-specific differences in weight and motor coordination in both mouse strains. Our results show that environmental factors specific to a geographical location can change the body weight, motor coordination and motor learning capability of wild type mice commonly used as controls in transgenic studies. PMID- 23817038 TI - Monocytic expression of osteoclast-associated receptor (OSCAR) is induced in atherosclerotic mice and regulated by oxidized low-density lipoprotein in vitro. AB - The osteoclast-associated receptor (OSCAR), primarily described as a co stimulatory regulator of osteoclast differentiation, represents a potential link between bone metabolism and vascular biology. Previously, we identified OSCAR as an endothelial cell-derived target of the proatherogenic factor oxidized low density lipoprotein (oxLDL). Since monocytes play an important role in the progression of atherosclerosis, we assessed whether atherogenic stimuli also regulate the expression of OSCAR on monocytes. Four-week-old male wild-type (WT), apolipoprotein e knockout (apoe KO), and LDL receptor knockout (ldlr KO) mice were fed a high-fat diet or normal chow for 6weeks. Peripheral blood mononuclear cells (PBMCs) isolated from the spleen were stained with antibodies against CD14 and OSCAR for subsequent flow cytometric analysis. OSCAR surface expression on CD14-positive monocytes increased 2-fold in PBMCs from apoe KO mice compared to WT mice. Feeding a high-fat diet further increased OSCAR surface expression 1.5 fold in apoe KO mice compared to normal diet. Moreover, OSCAR-positive macrophages were detected in atherosclerotic plaques of apoe KO mice. Interestingly, monocytic OSCAR expression was not altered in ldlr KO mice. In the murine macrophage cell line RAW 264.7, TNFalpha and oxLDL induced OSCAR mRNA expression by 2-fold and 5-fold (p<0.01), respectively. Blocking the oxLDL receptor LOX-1 and inhibiting the NF-kappaB pathway prevented OSCAR induction. In conclusion, OSCAR expression in monocytic cells is regulated by proatherogenic stimuli further pointing towards a role in vascular inflammation or plaque vulnerability during atherosclerosis. PMID- 23817039 TI - PKB/SGK-dependent GSK3-phosphorylation in the regulation of LPS-induced Ca2+ increase in mouse dendritic cells. AB - The function of dendritic cells (DCs) is modified by glycogen synthase kinase GSK3 and GSK3 inhibitors have been shown to protect against inflammatory disease. Regulators of GSK3 include the phosphoinositide 3 kinase (PI3K) pathway leading to activation of protein kinase B (PKB/Akt) and serum and glucocorticoid inducible kinase (SGK) isoforms, which in turn phosphorylate and thus inhibit GSK3. The present study explored, whether PKB/SGK-dependent inhibition of GSK3 contributes to the regulation of cytosolic Ca(2+) concentration following stimulation with bacterial lipopolysaccharides (LPS). To this end DCs from mutant mice, in which PKB/SGK-dependent GSK3alpha,beta regulation was disrupted by replacement of the serine residues in the respective SGK/PKB-phosphorylation consensus sequence by alanine (gsk3(KI)), were compared to DCs from respective wild type mice (gsk3(WT)). According to Western blotting, GSK3 phosphorylation was indeed absent in gsk3(KI) DCs. According to flow cytometry, expression of antigen-presenting molecule major histocompatibility complex II (MHCII) and costimulatory molecule CD86, was similar in unstimulated and LPS (1MUg/ml, 24h) stimulated gsk3(WT) and gsk3(KI) DCs. Moreover, production of cytokines IL-6, IL 10, IL-12 and TNFalpha was not significantly different in gsk3(KI) and gsk3(WT) DCs. In gsk3(WT) DCs, stimulation with LPS (1MUg/ml) within 10min led to transient phosphorylation of GSK3. According to Fura2 fluorescence, LPS (1MUg/ml) increased cytosolic Ca(2+) concentration, an effect significantly more pronounced in gsk3(KI) DCs than in gsk3(WT) DCs. Conversely, GSK3 inhibitor SB216763 (3-[2,4 Dichlorophenyl]-4-[1-methyl-1H-indol-3-yl]-1H-pyrrole-2,5-dione, 10MUM, 30min) significantly blunted the increase of cytosolic Ca(2+) concentration following LPS exposure. In conclusion, PKB/SGK-dependent GSK3alpha,beta activity participates in the regulation of Ca(2+) signaling in dendritic cells. PMID- 23817040 TI - Knockdown of TIGAR by RNA interference induces apoptosis and autophagy in HepG2 hepatocellular carcinoma cells. AB - Apoptosis and autophagy are crucial mechanisms regulating cell death, and the relationship between apoptosis and autophagy in the liver has yet to be thoroughly explored. TIGAR (TP53-induced glycolysis and apoptosis regulator), which is a p53-inducible gene, functions in the suppression of ROS (reactive oxygen species) and protects U2OS cells from undergoing cell death. In this study, silencing TIGAR by RNAi (RNA interference) in HepG2 cells down-regulated both TIGAR mRNA (~75%) and protein levels (~80%) and led to the inhibition of cell growth (P<0.01) by apoptosis (P<0.001) and autophagy. We demonstrated that TIGAR can increase ROS levels in HepG2 cells. The down-regulation of TIGAR led to the induction of LC-3 II (specific autophagic marker), the formation of the autophagosome, and increased Beclin-1 expression. 3-MA (3-Methyladenine), an inhibitor of autophagic sequestration blocker, inhibited TIGAR siRNA-enhanced autophagy, as indicated by the decrease in LC-3 II levels. Consequently, these data provide the first evidence that targeted silencing of TIGAR induces apoptotic and autophagic cell death in HepG2 cells, and our data raise hope for the future successful application of TIGAR siRNA in patients with hepatocellular carcinoma (HCC). PMID- 23817041 TI - Earliest hematopoietic progenitors at embryonic day 9 preferentially generate B-1 B cells rather than follicular B or marginal zone B cells. AB - The lymphoid potential of the hematopoietic system is observed as early as embryonic day 9 (E9) before transplantable hematopoietic stem cells (HSCs) appear at E11 in mice. However, it is largely unknown as to which cell fraction is responsible for the initial wave of lymphopoiesis and whether these earliest lymphocytes make any contributions to the adult lymphoid system. We previously isolated the earliest hematolymphoid progenitors at E9 that had CD45(+)c Kit(+)AA4.1(+) phenotypes. In this study, the differentiation potency into B cell subsets of the E9 hematolymphoid progenitors was examined in detail. In culture, E9 hematolymphoid progenitors produced B220(-/low) B cell progenitors in striking contrast to adult BM c-Kit(+)Sca-1(+)Lin(-) cells. Upon in vivo transplantation, B cell progenitors derived from E9 hematolymphoid progenitors preferentially differentiated into the B-1 B lymphocyte subset, whereas their differentiation into B-2 B lymphocyte subsets [follicular B (FoB), marginal zone B (MZB) cells] was inefficient. Of note, these donor B lymphocytes permanently repopulated in host mice, even if adult mice were used as recipients. These results suggest that B cell progenitors produced from an initial wave of definitive hematopoiesis before authentic HSCs appear could be a permanent source for, at least, the B-1 B lymphocyte subset. PMID- 23817042 TI - Identification of methyl violet 2B as a novel blocker of focal adhesion kinase signaling pathway in cancer cells. AB - The focal adhesion kinase (FAK) signaling cascade in cancer cells was profoundly inhibited by methyl violet 2B identified with the structure-based virtual screening. Methyl violet 2B was shown to be a non-competitive inhibitor of full length FAK enzyme vs. ATP. It turned out that methyl violet 2B possesses extremely high kinase selectivity in biochemical kinase profiling using a large panel of kinases. Anti-proliferative activity measurement against several different cancer cells and Western blot analysis showed that this substance is capable of suppressing significantly the proliferation of cancer cells and is able to strongly block FAK/AKT/MAPK signaling pathways in a dose dependent manner at low nanomolar concentration. Especially, phosphorylation of Tyr925-FAK that is required for full activation of FAK was nearly completely suppressed even with 1nM of methyl violet 2B in A375P cancer cells. To the best of our knowledge, it has never been reported that methyl violet possesses anti-cancer effects. Moreover, methyl violet 2B significantly inhibited FER kinase phosphorylation that activates FAK in cell. In addition, methyl violet 2B was found to induce cell apoptosis and to exhibit strong inhibitory effects on the focal adhesion, invasion, and migration of A375P cancer cells at low nanomolar concentrations. Taken together, these results show that methyl violet 2B is a novel, potent and selective blocker of FAK signaling cascade, which displays strong anti proliferative activities against a variety of human cancer cells and suppresses adhesion/migration/invasion of tumor cells. PMID- 23817043 TI - The significance of p53 immunoexpression with different clones (DO-7 and PAb-240) in oral squamous cell carcinoma. AB - BACKGROUND/AIM: The TP53 gene is a tumor suppressor gene. Its product is a nuclear protein that regulates cell cycle arrest, apoptosis and DNA repair. Anti p53 clones DO-7 and PAb-240 recognize the amino acid sequences 21-25 and 213-217, respectively. This study aimed to evaluate the expression of these clones and their relationship with clinicopathological features and survival analysis in oral squamous cell carcinomas (OSCC). METHODS: Information on 53 primary OSCC was collected at the Brazilian National Cancer Institute. An immunohistochemical method was applied to evaluate p53 expression (DO-7 and PAb-240). Their expression was analyzed quantitatively and correlated with clinicopathological features. Kaplan-Meier survival curves and log rank test were used. RESULTS: Immunopositivity for DO-7 was present in 64% of the cases, while 58% were positive for PAb-240. There was no correlation between immunoexpression of both antibodies and clinicopathological features or survival analysis. DO-7 expression was significantly higher (p = 0.001) than that of PAb-240. CONCLUSIONS: There were quantitative differences between the expression of the antibodies studied, which may reflect a different specificity of each one. To confirm immunohistochemical results and estimate the true prognostic role of TP53 in OSCC, it is important to perform mutation analysis. PMID- 23817044 TI - Associate editor Jean Bousquet. PMID- 23817045 TI - Hypothesis-generating research and predictive medicine. AB - Genomics has profoundly changed biology by scaling data acquisition, which has provided researchers with the opportunity to interrogate biology in novel and creative ways. No longer constrained by low-throughput assays, researchers have developed hypothesis-generating approaches to understand the molecular basis of nature-both normal and pathological. The paradigm of hypothesis-generating research does not replace or undermine hypothesis-testing modes of research; instead, it complements them and has facilitated discoveries that may not have been possible with hypothesis-testing research. The hypothesis-generating mode of research has been primarily practiced in basic science but has recently been extended to clinical-translational work as well. Just as in basic science, this approach to research can facilitate insights into human health and disease mechanisms and provide the crucially needed data set of the full spectrum of genotype-phenotype correlations. Finally, the paradigm of hypothesis-generating research is conceptually similar to the underpinning of predictive genomic medicine, which has the potential to shift medicine from a primarily population- or cohort-based activity to one that instead uses individual susceptibility, prognostic, and pharmacogenetic profiles to maximize the efficacy and minimize the iatrogenic effects of medical interventions. PMID- 23817047 TI - Comparative genomics as a tool to understand evolution and disease. AB - When the human genome project started, the major challenge was how to sequence a 3 billion letter code in an organized and cost-effective manner. When completed, the project had laid the foundation for a huge variety of biomedical fields through the production of a complete human genome sequence, but also had driven the development of laboratory and analytical methods that could produce large amounts of sequencing data cheaply. These technological developments made possible the sequencing of many more vertebrate genomes, which have been necessary for the interpretation of the human genome. They have also enabled large-scale studies of vertebrate genome evolution, as well as comparative and human medicine. In this review, we give examples of evolutionary analysis using a wide variety of time frames-from the comparison of populations within a species to the comparison of species separated by at least 300 million years. Furthermore, we anticipate discoveries related to evolutionary mechanisms, adaptation, and disease to quickly accelerate in the coming years. PMID- 23817046 TI - From human genome to cancer genome: the first decade. AB - The realization that cancer progression required the participation of cellular genes provided one of several key rationales, in 1986, for embarking on the human genome project. Only with a reference genome sequence could the full spectrum of somatic changes leading to cancer be understood. Since its completion in 2003, the human reference genome sequence has fulfilled its promise as a foundational tool to illuminate the pathogenesis of cancer. Herein, we review the key historical milestones in cancer genomics since the completion of the genome, and some of the novel discoveries that are shaping our current understanding of cancer. PMID- 23817048 TI - Insights into neural crest development and evolution from genomic analysis. AB - The neural crest is an excellent model system for the study of cell type diversification during embryonic development due to its multipotency, motility, and ability to form a broad array of derivatives ranging from neurons and glia, to cartilage, bone, and melanocytes. As a uniquely vertebrate cell population, it also offers important clues regarding vertebrate origins. In the past 30 yr, introduction of recombinant DNA technology has facilitated the dissection of the genetic program controlling neural crest development and has provided important insights into gene regulatory mechanisms underlying cell migration and differentiation. More recently, new genomic approaches have provided a platform and tools that are changing the depth and breadth of our understanding of neural crest development at a "systems" level. Such advances provide an insightful view of the regulatory landscape of neural crest cells and offer a new perspective on developmental as well as stem cell and cancer biology. PMID- 23817050 TI - Reduction of histamine H1 receptor binding induced by high-fat diet can be prevented by DHA and dietary fiber in specific brain areas of male rats. AB - High-fat (HF) diet and obesity are risk factors for a number of mental health problems including depression, cognitive dysfunction, dementia, and neurodegenerative diseases. Histamine H1 receptors (H1Rs) are involved in many of these conditions. This study examined H1R receptor binding density in the brain of male rats fed a high-saturated fat (HF) diet, as well as the effect of docosahexaenoic acid (DHA), galacto-oligosaccharide (GOS) and resistant starch (RS) supplementation of HF diet. Alterations of H1R expression in the post-mortem rat brain were detected by [(3)H]-pyrilamine binding autoradiography. We found that HF diet significantly decreased H1R binding densities in the substantia nigra (SN), caudate putamen (CPu), hypothalamic arcuate nucleus (Arc), ventral tegmental area (VTA), piriform cortex (Pir) and primary motor cortex (M1), compared with low-fat fed rats, and the suppression of receptor binding density ranged from 31% to 48%. Interestingly, supplementing the HF diet with 0.5% n-3 polyunsaturated docosahexaenoic acid (DHA) prevented reduction of H1R binding densities in the SN and CPu. Addition of galacto-oligosaccharide (GOS) and resistant starch (RS) to the diet blunted HF induced reduction of H1R ligand binding in the SN and Pir, respectively. In conclusion this study showed that HF diet can alter H1R binding densities in various brain regions, and many of these changes can be prevented by adding DHA, GOS or RS to the diet. PMID- 23817049 TI - Understanding the regulatory and transcriptional complexity of the genome through structure. AB - An expansive functionality and complexity has been ascribed to the majority of the human genome that was unanticipated at the outset of the draft sequence and assembly a decade ago. We are now faced with the challenge of integrating and interpreting this complexity in order to achieve a coherent view of genome biology. We argue that the linear representation of the genome exacerbates this complexity and an understanding of its three-dimensional structure is central to interpreting the regulatory and transcriptional architecture of the genome. Chromatin conformation capture techniques and high-resolution microscopy have afforded an emergent global view of genome structure within the nucleus. Chromosomes fold into complex, territorialized three-dimensional domains in concert with specialized subnuclear bodies that harbor concentrations of transcription and splicing machinery. The signature of these folds is retained within the layered regulatory landscapes annotated by chromatin immunoprecipitation, and we propose that genome contacts are reflected in the organization and expression of interweaved networks of overlapping coding and noncoding transcripts. This pervasive impact of genome structure favors a preeminent role for the nucleoskeleton and RNA in regulating gene expression by organizing these folds and contacts. Accordingly, we propose that the local and global three-dimensional structure of the genome provides a consistent, integrated, and intuitive framework for interpreting and understanding the regulatory and transcriptional complexity of the human genome. PMID- 23817051 TI - Characterization and predicted role of the microRNA expression profile in amnion from obese pregnant women. AB - Maternal obesity and nutrient excess in utero increase the risk of future metabolic diseases. The mechanisms underlying this process are poorly understood, but probably include genetic, epigenetic alterations and changes in fetal nutrient supply. We have studied the microRNA (miRNA) expression profile in amnion from obese and control women at delivery to investigate if a specific miRNA signature is associated with obesity. The expression profile of 365 human miRNAs was evaluated with the TaqMan Array in amnion from 10 obese and 5 control (prepregnancy body mass index (BMI) >30 and <25 kg m(-2), respectively) women at delivery. Target genes and miRNA-regulated pathways were predicted by bioinformatics. Anthropometric and biochemical parameters were also measured in mothers and newborns. Seven miRNAs were expressed only in obese women (miR-422b, miR-219, miR-575, miR-523, miR-579, miR-618 and miR-659), whereas 13 miRNAs were expressed at a higher level and 12 miRNAs at a lower level in obese women than in controls. MicroRNAs significantly downregulated the neurotrophin, cancer/ErbB, mammalian target of rapamycin, insulin, adipocytokine, actin cytoskeleton and mitogen-activated protein kinase signaling pathways. In conclusion, we show that the miRNA profile is altered in amnion during obesity and hypothesize that this could affect pathways important for placental growth and function, thereby contributing to an increase in the newborn's risk of future metabolic diseases. PMID- 23817052 TI - Transmembrane potential of red blood cells under low ionic strength conditions. AB - BACKGROUND/AIMS: In a variety of investigations described in the literature it was not clear to what extent the transmembrane potential red blood cells (RBCs) was changed after the cells have been transferred into low ionic strength (LIS) solutions. Another open question was to find out how fast the transmembrane potential of RBCs in LIS solution will change and which final new equilibrium value will be reached. METHODS: The transmembrane potential of human and bovine RBCs was investigated using the potential-sensitive fluorescent dye DIBAC4(3) (bis(1,3-dibutylbarbituric acid) trimethine oxonol) as well as the CCCP (carbonylcyanide-m-chlorophenylhydrazone) method. RESULTS: Under physiological conditions the transmembrane potential was about -10 mV in agreement with literature data. However, when the RBCs were transferred into an isosmotic low ionic strength medium containing sucrose the transmembrane potential increased to +73 mV and +81 mV for human and bovine RBCs, respectively. In case of human RBCs it continuously decreased reaching finally an equilibrium state of -10 mV again after 30 - 60 min. For bovine RBCs the transmembrane potential declined more slowly reaching a value of +72 mV after 30 min. CONCLUSIONS: Investigations of parameters of RBCs depending on transmembrane potential cannot be performed with human RBCs in LIS media. PMID- 23817053 TI - Close relations between podocyte injuries and membranous proliferative glomerulonephritis in autoimmune murine models. AB - BACKGROUND: Membranous proliferative glomerulonephritis (MPGN) is a major primary cause of chronic kidney disease (CKD). Podocyte injury is crucial in the pathogenesis of glomerular disease with proteinuria, leading to CKD. To assess podocyte injuries in MPGN, the pathological features of spontaneous murine models were analyzed. METHODS: The autoimmune-prone mice strains BXSB/MpJ-Yaa and B6.MRL (D1Mit202-D1Mit403) were used as the MPGN models, and BXSB/MpJ-Yaa(+) and C57BL/6 were used as the respective controls. In addition to clinical parameters and glomerular histopathology, the protein and mRNA levels of podocyte functional markers were evaluated as indices for podocyte injuries. The relation between MPGN pathology and podocyte injuries was analyzed by statistical correlation. RESULTS: Both models developed MPGN with albuminuria and elevated serum anti double-strand DNA (dsDNA) antibody levels. BXSB/MpJ-Yaa and B6.MRL showed severe proliferative lesions with T and B cell infiltrations and membranous lesions with T cell infiltrations, respectively. Foot process effacement and microvillus-like structure formation were observed ultrastructurally in the podocytes of both MPGN models. Furthermore, both MPGN models showed a decrease in immune-positive areas of nephrin, podocin and synaptopodin in the glomerulus, and in the mRNA expression of Nphs1, Nphs2, Synpo, Actn4, Cd2ap, and Podxl in the isolated glomerulus. Significant negative correlations were detected between serum anti dsDNA antibody levels and glomerular Nphs1 expression, and between urinary albumin-to-creatinine ratio and glomerular expression of Nphs1, Synpo, Actn4, Cd2ap, or Podxl. CONCLUSION: MPGN models clearly developed podocyte injuries characterized by the decreased expression of podocyte functional markers with altered morphology. These data emphasized the importance of regulation of podocyte injuries in MPGN. PMID- 23817054 TI - Estrogenic influences in pain processing. AB - Gonadal hormones not only play a pivotal role in reproductive behavior and sexual differentiation, they also contribute to thermoregulation, feeding, memory, neuronal survival, and the perception of somatosensory stimuli. Numerous studies on both animals and human subjects have also demonstrated the potential effects of gonadal hormones, such as estrogens, on pain transmission. These effects most likely involve multiple neuroanatomical circuits as well as diverse neurochemical systems and they therefore need to be evaluated specifically to determine the localization and intrinsic characteristics of the neurons engaged. The aim of this review is to summarize the morphological as well as biochemical evidence in support for gonadal hormone modulation of nociceptive processing, with particular focus on estrogens and spinal cord mechanisms. PMID- 23817055 TI - Growth in preterm infants until six months postterm: the role of insulin and IGF I. AB - BACKGROUND/AIMS: Since insulin-like growth factor type I (IGF-I) and insulin regulate growth in term infants, they were studied in relation to nutrient intake and growth until 6 months corrected age (CA) in preterm infants. METHODS: In 138 preterm infants (51% male, gestational age (expressed as median (IQR)) 30.6 (1.9) weeks, birth weight 1,368 (389) g) weight SDS, length SDS, IGF-I, and insulin were measured at term age, 3 and 6 months CA. RESULTS: IGF-I and insulin at term age were associated with weight SDS and length SDS at term age and 3 months CA. IGF-I and insulin at 3 months CA were associated with weight SDS and length SDS at 3 and 6 months CA. IGF-I and insulin at term age were negatively associated with gain in weight SDS and gain in length SDS between term age and 6 months CA (IGF-I: beta = -1.03, 95% CI -1.65;-0.41, p = 0.001 and beta = -0.78, 95% CI 1.32;-0.23, p = 0.005; insulin: beta = -0.19, 95% CI -0.37;-0.01, p = 0.044 and beta = -0.18, 95% CI -0.35;-0.01, p = 0.035). Nutrient intake was not associated with IGF-I or insulin. CONCLUSIONS: The present study suggests that IGF-I and insulin are important growth regulators in preterm infants until 6 months CA, independent of nutrient intake. PMID- 23817056 TI - An introduction to toothpaste - its purpose, history and ingredients. AB - Toothpaste is a paste or gel to be used with a toothbrush to maintain and improve oral health and aesthetics. Since their introduction several thousand years ago, toothpaste formulations have evolved considerably - from suspensions of crushed egg shells or ashes to complex formulations with often more than 20 ingredients. Among these can be compounds to combat dental caries, gum disease, malodor, calculus, erosion and dentin hypersensitivity. Furthermore, toothpastes contain abrasives to clean and whiten teeth, flavors for the purpose of breath freshening and dyes for better visual appeal. Effective toothpastes are those that are formulated for maximum bioavailability of their actives. This, however, can be challenging as compromises will have to be made when several different actives are formulated in one phase. Toothpaste development is by no means complete as many challenges and especially the poor oral substantivity of most active ingredients are yet to overcome. PMID- 23817057 TI - Fluorides and non-fluoride remineralization systems. AB - Caries develops when the equilibrium between de- and remineralization is unbalanced favoring demineralization. De- and remineralization occur depending on the degree of saturation of the interstitial fluids with respect to the tooth mineral. This equilibrium is positively influenced when fluoride, calcium and phosphate ions are added favoring remineralization. In addition, when fluoride is present, it will be incorporated into the newly formed mineral which is then less soluble. Toothpastes may contain fluoride and calcium ions separately or together in various compounds (remineralization systems) and may therefore reduce demineralization and promote remineralization. Formulating all these compounds in one paste may be challenging due to possible premature calcium-fluoride interactions and the low solubility of CaF2. There is a large amount of clinical evidence supporting the potent caries preventive effect of fluoride toothpastes indisputably. The amount of clinical evidence of the effectiveness of the other remineralization systems is far less convincing. Evidence is lacking for head to head comparisons of the various remineralization systems. PMID- 23817058 TI - Antiplaque and antigingivitis toothpastes. AB - Dentifrices are a general term used to describe preparations that are used together with a toothbrush with the purpose to clean and/or polish the teeth. Active toothpastes were first formulated in the 1950s and included ingredients such as urea, enzymes, ammonium phosphate, sodium lauryl sarcosinate and stannous fluoride. Later, therapeutic agents were included. Today's toothpastes have two objectives: to help the toothbrush in cleaning the tooth surface and to provide a therapeutic effect. The therapeutic effect may have an antiplaque or anti inflammatory basis when the nature of the agents is antimicrobial. Plaque inhibitory and antiplaque activity of toothpastes used for chemical plaque control is evaluated in distinct consecutive stages, the last being home use randomized clinical trials of at least 6 months' duration. In this chapter, the scientific evidence supporting the use of the most common antiplaque agents, included in toothpaste formulations, is reviewed, with a special emphasis on 6 month clinical trials, and systematic reviews with meta-analyses of the mentioned studies. Among the active agents, the following have been included in toothpastes: enzymes, amine alcohols, herbal or natural products, triclosan, bisbiguanides (chlorhexidine), quaternary ammonium compounds (cetylpyridinium chloride) and different metal salts (zinc salts, stannous fluoride, stannous fluoride with amine fluoride). Dentifrices are the ideal vehicles for any active ingredient used as an oral health preventive measure since they are used in combination with toothbrushing, which is the most frequently employed oral hygiene method. The most important indications of dentifrices with active ingredients are associated with long-term use to prevent bacterial biofilm formation, mostly in gingivitis patients or in patients on supportive periodontal therapy. PMID- 23817059 TI - The role of toothpastes in oral malodor management. AB - One out of four people suffers from persistent bad breath. In most of the cases, the cause can be found in the mouth, with the presence of tongue coating as the leading factor, followed by gingivitis and periodontitis, and it is referred to as oral malodor. Because oral malodor is the result of the degradation of organic substrates by anaerobic bacteria of the oral cavity, the management is mostly done by masking the odorous compounds or eliminating the cause (bacteria and their substrates) either mechanically or chemically. Toothpaste formulations have been modified to carry antimicrobial and oxidizing agents with an impact on the process of oral malodor formation. We performed extensive literature search regarding the effect of dedicated toothpastes in the management of oral malodor. The main characteristics of the in vitro and in vivo investigations and their most relevant findings are presented for discussion. Even though the amount of publications regarding this topic is far smaller than for others such as caries, plaque control and whitening, antibacterial ingredients such as triclosan and metal ions like stannous and zinc appear to be effective in the control of oral malodor. On the other hand, data supporting the use of hydrogen peroxide, baking soda, essential oils and flavors in the management of oral malodor are rather few and inconclusive. PMID- 23817060 TI - Anti-calculus and whitening toothpastes. AB - In terms of novel formulations, there seems to have been a shift in emphasis from anti-caries/anti-gingivitis to anti-calculus/whitening toothpastes in recent years. The anti-calculus and whitening effects of toothpastes are to some extent based on the same active ingredients: compounds of high affinity for tooth mineral. Due to this affinity, crystal growth may be hindered (anti-calculus) and chromophores be displaced (whitening). Besides these common ingredients, both types of toothpaste may contain agents specifically aimed at each condition. Clinical studies have shown that these active ingredients can be successfully formulated in fluoride toothpastes to give significant reductions in supragingival calculus and stain formation and facilitate their removal. Some of the ingredients are formulated in toothpastes that additionally contain anti plaque and anti-gingivitis ingredients, making these toothpastes (together with the fluoride) truly multi-functional. The development of these products is not straightforward because of interaction between formulation components and because the active ingredients must maintain their beneficial characteristics during the shelf life of the paste. Neither a therapeutic benefit (in terms of less gingivitis or less caries) nor a societal benefit (in terms of less treatment demand) has been demonstrated as a result of the anti-calculus and whitening effects of toothpastes. PMID- 23817061 TI - The role of toothpaste in the aetiology and treatment of dentine hypersensitivity. AB - Dentine hypersensitivity (DH) is a common, painful dental condition with a multi factorial aetiology. The hydrodynamic mechanism theory to explain dentine sensitivity also appears to fit DH: lesions exhibiting large numbers of open dentinal tubules at the surface and patent to the pulp. By definition, DH can only occur when dentine becomes exposed (lesion localisation) and tubules opened (lesion initiation), thus permitting increased fluid flow in tubules on stimulation. Erosion, particularly from dietary acids appears to play a dominant role in both processes. Toothbrushing with most toothpaste products alone cause clinically insignificant wear of enamel but are additive, even synergistic, to erosive enamel loss. Additionally, toothbrushing with toothpaste is implicated in 'healthy' gingival recession. Toothbrushing with most toothpastes removes the smear layer to expose tubules and again can exacerbate erosive loss of dentine. These findings thereby implicate toothbrushing with toothpaste in the aetiology of DH. Management of the condition should have secondary prevention at the core of treatment and therefore, must consider first and foremost the aetiology. Fluoride toothpaste at present appears to provide little primary or secondary preventive benefits to DH; additional ingredients can provide therapeutic benefits. Potassium-based products to block pulpal nerve response have caused much debate and are considered by many as unproven, which should not translate to ineffective. Several toothpaste technologies formulated to block tubules are from studies in vitro, in situ and controlled clinical trials considered proven for the treatment of DH. PMID- 23817062 TI - Toothpaste and erosion. AB - Dental erosion develops from the chronic exposure to non-bacterial acids resulting in bulk mineral loss with a partly demineralised surface of reduced micro-hardness. Clinical features are loss of surface structures with shallow lesions on smooth surfaces and cupping and flattening of cusps; already in early stages, coronal dentine often is exposed. Not only enamel, but also dentine is therefore an important target tissue for anti-erosion strategies. The main goal of active ingredients against erosion is to increase the acid resistance of tooth surfaces or pellicles. The challenge with toothpastes is that abrasives, otherwise beneficial in terms of cleaning properties, may counteract the effects of active ingredients. Fluoride toothpastes offer a degree of protection, but in order to design more effective formulations, active ingredients in addition to, or other than, fluorides have been suggested. Polyvalent metal cations, Ca/P salts in nano-form, phosphates, proteins, and various biopolymers, e.g. chitosan, are substances under study. The complex combined action of active ingredients and abrasives on the dental hard tissues, and the role of excipients of complex toothpaste formulations are not yet fully understood. Current evidence is flawed by the diversity of experimental designs, and there is no knowledge from clinical studies with patients so far. However, research results indicate that there is potential to develop effective toothpastes in this field. As the prevalence of initial erosive lesions particularly in younger age groups is high in some countries, such strategies would be of great importance for maintaining oral health. PMID- 23817063 TI - Abrasivity testing of dentifrices - challenges and current state of the art. AB - Abrasivity potential of dentifrices is assessed mostly in vitro due to practical, scientific, and ethical reasons. The two most used evaluation methods are based on the measurement of radioactive dentin release or dentin surface profile changes, after simulation of toothbrushing with dentifrices. The radiotracer method known as radioactive or relative dentin abrasivity (RDA) was developed decades ago and is the most frequently used today (the 'gold standard' for many). The RDA is a reasonably robust method considered a useful tool for the determination of the relative abrasive level of dentifrices and abrasive powders. Studying the level of abrasivity of dentifrices under laboratory conditions is important to develop new formulations, to evaluate quality control of production, and to obtain a rough estimate of its potential clinical abrasivity. However, it is inappropriate to use RDA values alone to determine clinical safety when considering that dental wear is multifactorial and in vitro dentifrice abrasivity level is only one of the variables potentially affecting this outcome. It is important to remember that individuals present significant behavioral differences when brushing that could dramatically affect the potential of abrasion of a particular dentifrice. RDA values should be just one of the multiple variables being taken into consideration by professionals when providing recommendations to prevent dental wear. PMID- 23817064 TI - Laboratory and human studies to estimate anticaries efficacy of fluoride toothpastes. AB - Much more than mechanical biofilm removal, toothbrushing with fluoride toothpastes is an effective way of increasing the availability of fluoride in the oral cavity to reduce demineralization and enhance remineralization of enamel and dentine. These effects of fluoride toothpastes have been estimated by a wide range of laboratory and human studies, which have helped to develop anticaries effective formulations and understand their mechanism of action. These studies have focused on the availability of fluoride in the toothpaste formulations, its bioavailability in saliva and remnants of disturbed biofilm, its reaction with the dental substrate to form loosely bound reservoirs as well as the ultimate reduction of mineral loss and increase in mineral and fluoride content of caries lesions. The specifics of these modes of action and their application in in vitro, in situ and in vivo preclinical tests is presented and discussed. PMID- 23817065 TI - Pharmacokinetics in the oral cavity: fluoride and other active ingredients. AB - Modern commercial toothpastes contain therapeutic ingredients to combat various oral conditions, for example, caries, gingivitis, calculus and tooth stain. The efficient delivery and retention of such ingredients in the mouth is essential for good performance. The aim of this chapter is to review the literature on the oral pharmacokinetics of, primarily, fluoride but also other active ingredients, mainly anti-plaque agents. Elevated levels of fluoride have been found in saliva, plaque and the oral soft tissues after use of fluoridated toothpaste, which persist at potentially active concentrations for hours. Both experiment and mathematical modelling suggest that the soft tissues are the main oral reservoir for fluoride. Qualitatively similar observations have been made for anti-plaque agents such as triclosan and metal cations, though their oral substantivity is generally greater. Scope for improved retention and subsequent efficacy exists. PMID- 23817066 TI - After-brush rinsing protocols, frequency of toothpaste use: fluoride and other active ingredients. AB - The intra-oral retention or substantivity of active ingredients in toothpastes is important for their effectiveness, and this is influenced by product-related and user-related factors. Product-related factors include the formulation and the compatibility of active and other agents in the toothpaste and the concentration of the active ingredient. User-related factors include biological aspects such as salivary flow and salivary clearance, and behavioural aspects, such as frequency and duration of brushing, amount of toothpaste used and post-brushing rinsing behaviour. To date, product-related factors have dominated the research agenda for toothpastes, but user-related factors have the potential to significantly enhance or reduce the effectiveness of toothpaste. In this chapter, we will focus on two of the user-related factors that have been most widely studied: (1) frequency of toothbrushing and (2) post-brushing rinsing behaviour. We will then provide an overview of how evidence on these two behaviours has been used to produce guidance both for the profession and for the public, and make suggestions for the future direction of research in this area. PMID- 23817067 TI - Engineered nanostructured beta-sheet peptides protect membrane proteins. AB - We designed beta-strand peptides that stabilize integral membrane proteins (IMPs). beta-strand peptides self-assemble in solution as filaments and become restructured upon association with IMPs; resulting IMP-beta-strand peptide complexes resisted aggregation when diluted in detergent-free buffer and were visible as stable, single particles with low detergent background in electron micrographs. beta-strand peptides enabled clear visualization of flexible conformations in the highly dynamic ATP-binding cassette (ABC) transporter MsbA. PMID- 23817068 TI - TALE-mediated modulation of transcriptional enhancers in vivo. AB - We tested whether transcription activator-like effectors (TALEs) could mediate repression and activation of endogenous enhancers in the Drosophila genome. TALE repressors (TALERs) targeting each of the five even-skipped (eve) stripe enhancers generated repression specifically of the focal stripes. TALE activators (TALEAs) targeting the eve promoter or enhancers caused increased expression primarily in cells normally activated by the promoter or targeted enhancer, respectively. This effect supports the view that repression acts in a dominant fashion on transcriptional activators and that the activity state of an enhancer influences TALE binding or the ability of the VP16 domain to enhance transcription. In these assays, the Hairy repression domain did not exhibit previously described long-range transcriptional repression activity. The phenotypic effects of TALER and TALEA expression in larvae and adults are consistent with the observed modulations of eve expression. TALEs thus provide a novel tool for detection and functional modulation of transcriptional enhancers in their native genomic context. PMID- 23817069 TI - Heritable genome editing in C. elegans via a CRISPR-Cas9 system. AB - We report the use of clustered, regularly interspaced, short palindromic repeats (CRISPR)-associated endonuclease Cas9 to target genomic sequences in the Caenorhabditis elegans germ line using single-guide RNAs that are expressed from a U6 small nuclear RNA promoter. Our results demonstrate that targeted, heritable genetic alterations can be achieved in C. elegans, providing a convenient and effective approach for generating loss-of-function mutants. PMID- 23817070 TI - Cell-selective labeling using amino acid precursors for proteomic studies of multicellular environments. AB - We report a technique to selectively and continuously label the proteomes of individual cell types in coculture, named cell type-specific labeling using amino acid precursors (CTAP). Through transgenic expression of exogenous amino acid biosynthesis enzymes, vertebrate cells overcome their dependence on supplemented essential amino acids and can be selectively labeled through metabolic incorporation of amino acids produced from heavy isotope-labeled precursors. When testing CTAP in several human and mouse cell lines, we could differentially label the proteomes of distinct cell populations in coculture and determine the relative expression of proteins by quantitative mass spectrometry. In addition, using CTAP we identified the cell of origin of extracellular proteins secreted from cells in coculture. We believe that this method, which allows linking of proteins to their cell source, will be useful in studies of cell-cell communication and potentially for discovery of biomarkers. PMID- 23817071 TI - LipidBlast in silico tandem mass spectrometry database for lipid identification. AB - Current tandem mass spectral libraries for lipid annotations in metabolomics are limited in size and diversity. We provide a freely available computer-generated tandem mass spectral library of 212,516 spectra covering 119,200 compounds from 26 lipid compound classes, including phospholipids, glycerolipids, bacterial lipoglycans and plant glycolipids. We show platform independence by using tandem mass spectra from 40 different mass spectrometer types including low-resolution and high-resolution instruments. PMID- 23817072 TI - Pharmacists as an underutilized resource for improving community-level support of breastfeeding. AB - With their highly visible roles in the community, frequent interactions with soon to-be and new parents, and knowledge of medication safety, pharmacists can be a key component in breastfeeding promotion and support. A review of the literature showed that pharmacists have poor knowledge but positive attitudes toward breastfeeding and that pharmacy practices are variable and mostly guided by personal experience. A review of 58 health professional organizations' English language infant feeding/breastfeeding policy statements showed that no US pharmacists' association has a position statement, as exists for professional pharmacist organizations in Canada and Australia. We explored pharmacists' interactions with mothers before and after birth and possible opportunities to expand pharmacists' roles in the promotion and support of breastfeeding. Barriers to meeting unmet needs of breastfeeding mothers were identified in order to plan strategies for implementing programs to address these barriers. Through input obtained from pharmacy and breastfeeding experts and from information available in the published literature, good matches between unmet needs and capabilities were identified in (a) provision of health promotion resources and public awareness campaigns, (b) assistance with purchase of breastfeeding products and pumps, and (c) provision of information, support, and referral related to commonly encountered difficulties as well as medication use during lactation. Absence of adequate breastfeeding knowledge was identified as a crucial barrier. Leveraging pharmacists to address unmet preventive health needs is especially important as we strive to align resources to support healthy behaviors in our current health care delivery environment. PMID- 23817073 TI - Transbronchial needle aspiration: a systematic review on predictors of a successful aspirate. AB - BACKGROUND: Transbronchial needle aspiration (TBNA) is a safe and useful sampling technique for the diagnosis of mediastinal adenopathies/masses, but its accuracy seems to be influenced by selected clinical and procedural aspects. OBJECTIVES: We performed a systematic review to identify the main predictors of a successful transbronchial aspirate according to different clinical settings. METHODS: We searched Medline and Embase for all studies evaluating predictors of TBNA diagnostic yield, published up to February 2012. Two authors reviewed all titles/abstracts and retrieved the full text of articles that are potentially relevant to identify studies according to predefined selection criteria. The methodological quality of studies was assessed through the revised Quality Assessment of Diagnostic Accuracy Studies tool. Evidence synthesis was graded according to overall number of studies, patients involved and methodological features. RESULTS: Fifty-three studies, involving more than 8,000 patients and evaluating 23 potential predictive factors, were included. Major predictors in an unselected population, as well as in patients with suspected/known lung cancer, included lymph node size (short axis length >= 2 cm), presence of abnormal endoscopic findings, subcarinal and right paratracheal location, and the use of histological needle by an experienced bronchoscopist. Stage I and sampling of more than one lymph node stations were the only predictors of a successful TBNA result in patients with suspected sarcoidosis. CONCLUSIONS: The diagnostic yield of TBNA depends on selected clinical and procedural features. Knowledge of factors that predict a positive TBNA result may help optimize the diagnostic success of the procedure in different clinical settings. PMID- 23817074 TI - Geometrical and volume changes of the membranous vestibular labyrinth in guinea pigs with endolymphatic hydrops. AB - OBJECTIVE: To evaluate geometrical and volume changes of membranous vestibular labyrinths in guinea pigs after endolymphatic hydrops (EH). METHODS: The membranous labyrinths of normal guinea pigs and of those with EH for 4 and 8 weeks were reconstructed after being scanned using micro-computed tomography subseqent to being stained in osmium tetroxide (OsO4). The diameters and volumes of the semicircular ducts, ampullae, utricles and saccules were measured based on the three-dimensional models. RESULTS: The diameters of the ampullae and utricles of EH guinea pigs were greater than those of the normal guinea pigs, while there were no significant differences in the diameters of the semicircular ducts among all groups. The volumes of ampullae, utricles and saccules of the EH groups were greater than those of the control group, but there were no changes in volumes of semicircular ducts after EH. CONCLUSION: The dilations of the membranous vestibular labyrinth in guinea pigs with EH mainly occur at the ampullae, utricles and saccules. PMID- 23817075 TI - Feeding the deoxyribonucleoside salvage pathway to rescue mitochondrial DNA. AB - Mutations in an increasing number of nuclear genes involved in deoxyribonucleotide homeostasis cause disorders associated with somatic mitochondrial DNA (mtDNA) abnormalities. Dysfunction of the products of these genes leads to limited availability of substrates for mtDNA replication and results in mtDNA depletion, multiple deletions or point mutations; mtDNA depletion is the molecular feature linked to greatest clinical severity. In this review, we discuss recent results demonstrating that enhancement of the salvage pathways by increasing the availability of deoxyribonucleosides needed for each specific genetic defect prevents mtDNA depletion. Hence, we propose administration of selected deoxyribonucleosides and/or inhibitors of their catabolism as a pharmacological strategy to treat these diseases. PMID- 23817076 TI - Image-guided drug delivery to the brain using nanotechnology. AB - Targeting across the blood-brain barrier (BBB) for treatment of central nervous system (CNS) diseases represents the most challenging aspect of, as well as one of the largest growing fields in, neuropharmaceutics. Combining nanotechnology with multiple imaging techniques has a unique role in the diagnosis and treatment (theranostics) of CNS disease. Such imaging techniques include anatomical imaging modalities, such as magnetic resonance imaging (MRI), ultrasound (US), X-ray computed tomography (CT), positron emission tomography (PET), single-photon emission computed tomography (SPECT), electron microscopy, autoradiography and optical imaging as well as thermal images. In this review, we summarize and discuss recent advances in formulations, current challenges and possible hypotheses concerning the use of such theranostics across the BBB. PMID- 23817077 TI - Animal models of disease: pre-clinical animal models of cancer and their applications and utility in drug discovery. AB - Preclinical models of human cancers are indispensable in the drug discovery and development process for new cancer drugs, small molecules and biologics. They are however imperfect facsimiles of human cancers given the genetic and epigenetic heterogeneity of the latter and the multiplicity of dysregulated survival and growth-regulatory pathways that characterize this spectrum of diseases. This review discusses pre-clinical tumor models - traditional ectopic xenografts, orthotopic xenografts, genetically engineered tumor models, primary human tumorgrafts, and various multi-stage carcinogen-induced tumor models - their advantages, limitations, physiological and pathological relevance. Collectively, these animal models represent a portfolio of test systems that should be utilized at specific stages in the drug discovery process in a pragmatic and hierarchical manner of increasing complexity, physiological relevance, and clinical predictability of the human response. Additionally, evaluating the efficacy of novel therapeutic agents emerging from drug discovery programs in a variety of pre-clinical models can better mimic the heterogeneity of human cancers and also aid in establishing dose levels, dose regimens and drug combinations for use in clinical trials. Nonetheless, despite the sophistication and physiological relevance of these human cancer models (e.g., genetically engineered tumor models and primary human tumografts), the ultimate proof of concept for efficacy and safety of novel oncology therapeutics lies in humans. The judicious interpretation and extrapolation of data derived from these models to humans, and a correspondingly greater emphasis placed on translational medical research in early stage clinical trials, are essential to improve on the current clinical attrition rates for novel oncology therapeutic agents. PMID- 23817079 TI - Post-sandy preparedness policies lag as sea levels rise. PMID- 23817080 TI - Associate editor A. Wesley Burks. PMID- 23817078 TI - A Penicillium sp. F33 metabolite and its synthetic derivatives inhibit acetyl CoA:1-O-alkyl-sn-glycero-3-phosphocholine acetyltransferase (a key enzyme in platelet-activating factor biosynthesis) and carrageenan-induced paw edema in mice. AB - Acetyl-CoA:1-O-alkyl-sn-glycero-3-phosphocholine (lyso-PAF) acetyltransferase is a key enzyme in the biosynthesis of 1-O-alkyl-2-acetyl-sn-glycero-3 phosphocholine (PAF) in inflammatory cells. Substances which inhibit this enzyme are of therapeutic interest. In this study, we screened for new inhibitors of lyso-PAF acetyltransferase with anti-inflammatory effects. In a metabolite from Penicillium sp. F33, we isolated an acetyltransferase inhibitor identified as dihydrofumigatin (2-methoxy-1,3,4-trihydroxy-5-methylbenzene) from high resolution mass spectrometer and NMR data. Dihydrofumigatin had strong acetyltransferase inhibitory activity, but was not stable in aqueous solution. Thus, we chemically synthesized its oxidized form fumigatin (3-hydroxy-2-methoxy 5-methyl-1,4-benzoquinone) and derivatives thereof, and evaluated their inhibitory effects. Strong inhibitory activity was observed for saturated fatty acid esters of fumigatin; the order of inhibition was 3-decanoyloxy-2-methoxy-5 methyl-1,4-benzoquinone (termed FUD-7, IC50 = 3 MUM)>2-methoxy-5-methyl-3 tetradecanoyloxy-1,4-benzoquinone (termed FUD-8, IC50 = 20 MUM)>3-hexanoyloxy-2 methoxy-5-methyl-1,4-benzoquinone (IC50 = 139 MUM). Interestingly, these compounds also significantly suppressed the gene expression of lyso-PAF acetyltransferase/LPCAT2 in mouse bone marrow-derived macrophages stimulated by lipopolysaccharide (LPS). We further evaluated the effect of these substances on anti-inflammatory activity in vivo using the carrageenan-induced mouse paw edema test. FUD-7 and FUD-8 at 2.5 mg/kg showed significant, 47.9-51.7%, inhibition stronger than that of prednisolone at 10 mg/kg (41.9%). These results suggest that FUD-7 and FUD-8 are potent inhibitors with anti-inflammatory activity. PMID- 23817081 TI - Large-range control of the microstructures and properties of three-dimensional porous graphene. AB - Graphene-based three-dimensional porous macrostructures are believed of great importance in various applications, e.g. supercapacitors, photovoltaic cells, sensors and high-efficiency sorbents. However, to precisely control the microstructures and properties of this material to meet different application requirements in industrial practice remains challenging. We herein propose a facile and highly effective strategy for large-range tailoring the porous architecture and its properties by a modified freeze casting process. The pore sizes and wall thicknesses of the porous graphene can be gradually tuned by 80 times (from 10 to 800 MUm) and 4000 times (from 20 nm to 80 MUm), respectively. The property experiences the changing from hydrophilic to hydrophobic, with the Young's Modulus varying by 15 times. The fundamental principle of the porous microstructure evolution is discussed in detail. Our results demonstrate a very convenient and general protocol to finely tailor the structure and further benefit the various applications of porous graphene. PMID- 23817083 TI - Class III beta-tubulin, a novel biomarker in the human melanocyte lineage. AB - It is generally thought that class III beta-tubulin expression is limited to cells of the neural lineage and is therefore often used to identify neurons amongst other cell types, both in vivo and in vitro. Melanocytes are derived from the neural crest and share both morphological features and functional characteristics with peripheral neurons. Here, we show that these similarities extend to class III beta-tubulin (TUBB3) expression, and that human melanocytes express this protein both in vivo and in vitro. In addition, we studied the expression of class III beta-tubulin in two murine melanogenic cell lines and show that expression of this protein starts as melanoblasts mature into melanocytes. Melanin bleaching experiments revealed close proximity between melanin and TUBB3 proteins. In vitro stimulation of primary human melanocytes by alpha-MSH indicated separate regulatory mechanisms for melanogenesis and to TUBB3 expression. Together, these observations imply that human melanocytes express TUBB3 and that this protein should be recognized as a wider marker for multiple neural crest-derived cells. PMID- 23817082 TI - 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). PMID- 23817084 TI - Melanoma genotypes and phenotypes get personal. AB - Traditionally, the diagnosis of metastatic melanoma was terminal to most patients. However, the advancements towards understanding the fundamental etiology, pathophysiology, and treatment have raised melanoma to the forefront of contemporary medicine. Indeed, the evidence of durable remissions are being heard ever more frequently in clinics around the globe. Despite having more gene mutations per cell than any other type of cancer, investigators are overcoming complex genomic landscapes, signaling pathways, and immune checkpoints by generating novel technological methods and clinical protocols with breath-taking speed. Significant progress in deciphering molecular genetics, epigenetics, kinase-driven networks, metabolomics, and immune-enhancing pathways to achieve personalized and positive outcomes has truly provided new hope for melanoma patients. However, obstacles requiring breakthroughs include understanding the influence of sunlight exposure on melanoma etiology, and overcoming all too frequently acquired drug resistance, complicating targeted therapy. Pathologists continue to have critically important roles in advancing the field, particularly in the area of transitioning from microscope-based diagnostic reports to pharmacogenomics through molecularly informed tumor boards. Although melanoma is no longer considered just 'one disease', pathologists will continue this rapidly progressing and exciting journey to identify tumor subtypes, to utilize tumorgraft or so-called patient-derived xenograft (PDX) models, and to develop companion diagnostics to keep pace with the bewildering breakthroughs occurring on a regular basis. Exactly which combination of drugs will ultimately be required to eradicate melanoma cells remains to be determined. However, it is clear that pathologists who are as dedicated to melanoma as the pioneering pathologist Dr Sidney Farber was committed to childhood cancers, will be required as the battle against melanoma continues. In this review, we describe what sets melanoma apart from other tumors, and demonstrate how lessons learned in the melanoma clinic are being transferred to many other types of aggressive neoplasms. PMID- 23817085 TI - Chronic administration of EP4-selective agonist exacerbates albuminuria and fibrosis of the kidney in streptozotocin-induced diabetic mice through IL-6. AB - Diabetic nephropathy is currently the most common cause of end-stage renal disease in the western world. Exacerbated inflammation of the kidney is known to contribute acceleration of nephropathy. Despite increased COX-2-mediated production of prostanoid metabolite PGE2, knowledge on its involvement in the progression of diabetic kidney disease is not complete. Here, we show the cross talk of the PGE2-EP4 pathways and IL-6 in inducing albuminuria and fibrosis in an animal model of type 1 diabetes. Hyperglycemia causes enhanced COX-2 expression and PGE2 production. Administration of PGE2 receptor EP4-selective agonist ONO AE1-329 for 12 weeks exacerbated fibrosis and albuminuria. Diabetes-induced expression of inflammatory cytokines TNFalpha and TGFbeta1 was enhanced in EP4 agonist-treated mice kidney. In addition, urinary excretion of cytokines (TNFalpha and IL-6) and chemokines (MCP-1 and IP-10) were significantly more in EP4-treated mice than vehicle-treated diabetes. Diabetes-induced collagen I and CTGF expression were also significantly higher in EP4-treated mice. However, EP4 agonist did not alter macrophage infiltration but increased cytokine and chemokine production in RAW264.7 cells. Interestingly, EP4-induced IL-6 expression in the kidney was localized in proximal and distal tubular epithelial cells. To confirm further whether EP4 agonist increases fibrosis and albuminuria through an increase in IL-6 expression, IL-6-knockout mice were administered with EP4 agonist. IL-6-knockout mice were resistant to EP4-induced exacerbation of albuminuria and diabetes and EP4-induced fibrosis. Our data suggest that EP4 agonist through IL-6 induces glomerulosclerosis and interstitial fibrosis, and IL 6 represents a new factor in the EP4 pathway. PMID- 23817086 TI - Fibroblasts endocytose and degrade transthyretin aggregates in transthyretin related amyloidosis. AB - Transthyretin (TTR)-related amyloidosis is a fatal disorder characterized by systemic extracellular deposition of TTR amyloid fibrils. Mutations in the TTR gene cause an autosomal dominant form of the disease-familial amyloidotic polyneuropathy (FAP). Wild-type (WT) TTR can also form amyloid fibrils in elderly patients with senile systemic amyloidosis. Regression of amyloid deposits in FAP patients who undergo liver transplantation to remove the main source of mutant TTR suggests the existence of mechanisms for the clearance of TTR deposits from the extracellular matrix (ECM), but the precise mechanisms are largely unknown. Because fibroblasts are abundant, playing a central role in the maintenance of the ECM and because the skin is one of the major sites of soluble TTR catabolism, in the present study, we analyzed their role in clearance of TTR aggregates. In vitro studies with a fibroblast cell line revealed that fibroblasts endocytosed and degraded aggregated TTR. Subcutaneous injection of soluble and aggregated TTR into WT mice showed internalization and clearance over time by both fibroblasts and macrophages. Immunohistochemical studies of skin biopsies from V30M patients, asymptomatic carriers, recipients of domino FAP livers as well as transgenic mice for human V30M showed intracellular TTR immunoreactivity in fibroblasts and macrophages that increased with clinical status and with age in transgenic mice. Overall, the present in vitro and in vivo data show that fibroblasts endocytose and degrade TTR aggregates. The function or dysfunction of TTR clearance by fibroblasts may have important implications for the development, progression, and regression of TTR deposition in the ECM. PMID- 23817087 TI - Podoplanin-mediated cell adhesion through extracellular matrix in oral squamous cell carcinoma. AB - Podoplanin (PDPN), one of the representative mucin-like type-I transmembrane glycoproteins specific to lymphatic endothelial cells, is expressed in various cancers including squamous cell carcinoma (SCC). On the basis of our previous studies, we have developed the hypothesis that PDPN functions in association with the extracellular matrix (ECM) from the cell surface side. The aim of this study was to elucidate the molecular role of PDPN in terms of cell adhesion, proliferation, and migration in oral SCC cells. Forty-four surgical specimens of oral SCC were used for immunohistochemistry for PDPN, and the expression profiles were correlated with their clinicopathological properties. Using ZK-1, a human oral SCC cell system, and five other cell systems, we examined PDPN expression levels by immunofluorescence, western blotting, and real-time PCR. The effects of transient PDPN knockdown by siRNA in ZK-1 were determined for cellular functions in terms of cell proliferation, adhesion, migration, and invasion in association with CD44 and hyaluronan. Cases without PDPN-positive cells were histopathologically classified as less-differentiated SCC, and SCC cells without PDPN more frequently invaded lymphatics. Adhesive properties of ZK-1 were significantly inhibited by siRNA, and PDPN was shown to collaborate with CD44 in cell adhesion to tether SCC cells with hyaluronan-rich ECM of the narrow intercellular space as well as with the stromal ECM. There was no siRNA effect in migration. We have demonstrated the primary function of PDPN in cell adhesion to ECM, which is to secondarily promote oral SCC cell proliferation. PMID- 23817089 TI - Meiosis and its deviations in polyploid plants. AB - Meiosis is a fundamental process in all sexual organisms that ensures fertility and genome stability and creates genetic diversity. For each of these outcomes, the exclusive formation of crossovers between homologous chromosomes is needed. This is more difficult to achieve in polyploid species which have more than 2 sets of chromosomes able to recombine. In this review, we describe how meiosis and meiotic recombination 'deviate' in polyploid plants compared to diploids, and give an overview of current knowledge on how they are regulated. See also the sister article focusing on animals by Stenberg and Saura in this themed issue. PMID- 23817088 TI - Depression, antidepressants, and falls among community-dwelling elderly people: the MOBILIZE Boston study. AB - BACKGROUND: The mechanisms linking falls and depression are still unknown. The aim of the study is to examine the association between depression and antidepressants, with indoor and outdoor falls, and to investigate how antidepressants mediate this relationship. METHODS: The study included 763 men and women aged 70 and older with baseline measures for depression and antidepressant use are captured with prospective data on falls from the "Maintenance of Balance, Independent Living, Intellect and Zest in the Elderly" (MOBILIZE) Boston study, which is a population-based longitudinal study (from 2005 to 2009). RESULTS: Overall, the rate of falls was 26 falls/100 person-years. Seventeen percent of participants had clinically significant depressive symptoms (CSDS), and 12% used antidepressants. CSDS increased the risk of indoor and outdoor falls (incidence rate ratio [IRR] = 1.6, 95% confidence interval [CI] = 1.2-2.3, p < .01; IRR = 1.6, 95% CI = 1.2-2.2, p < .01). Antidepressant use increased the risk of outdoor falls by 70% and partially mediated the association between CSDS and outdoor falls (IRR = 1.7, 95% CI = 1.2-2.5, p < .05). There was no relationship between antidepressant use and indoor falls. Similar results were observed when depression was considered as a continuous variable. CONCLUSIONS: Depression increased the risk of indoor and outdoor falls. Antidepressant use among older adults with CSDS increased the risk of outdoor, but not indoor falls. Clinicians should carefully consider the role of antidepressants among older adults with CSDS and their potential increase for the risk of outdoor falls. PMID- 23817090 TI - Chemical composition and physicochemical properties of barley dietary fiber by chemical modification. AB - Chemical modification of dietary fiber (DF), extracted from whole grain barley, was carried out to obtain cross-linked (CL) DF, carboxymethyl (CM) DF, and hydroxypropyl (HP) DF. The DF components, physicochemical properties, and subsequent influence on the in vitro digestibility of wheat starch gels were comparatively investigated. The redistribution of fiber components from chemically modified DF was observed. An increase in the total DF (TDF) content of CL- and HP-DF was observed, which was mainly due to an increase of insoluble DF. Carboxymethylation led to an appreciable increase of soluble DF (1.17-6.20%) but TDF contents slightly decreased. Chemical modification of barley DF led to increases in arabinose (7.1-11.5%) and xylose (10.7-17.5%), but glucose contents decreased (67.4-79.9%). The treatments, especially carboxymethylation, effectively (P<0.05) increased hydration properties (e.g. water solubility, swelling power, and water absorption index). Substitution of 5% wheat starch with CL-, and HP-DF led to decreased in vitro digestibility in comparison to the control starch. Our results suggest that chemical modification improve the DF characteristics of barley and to exploit its potential application as a functional ingredient in fiber-rich products. PMID- 23817091 TI - Response surface modeling and analysis of barrier and optical properties of maize starch edible films. AB - In this work, four factors with three level Box-Behnken response surface design was employed to investigate the influence of process variables (maize starch, sorbitol, agar and Tween-80) on the barrier (water vapor permeability, oxygen permeability, thickness, moisture content and solubility) and optical (transparency) properties of the maize starch based edible films. Casting method was employed to prepare the edible films. The results showed that, addition of sorbitol and Tween-80 reduces the water vapor and oxygen permeability of the films, its due to the reduction of molecular mobility between polymer matrixes, where as, it also increases the thickness, moisture content, solubility and transparency of the films. The results were analyzed using Pareto analysis of variance (ANOVA) and second-order polynomial models are developed for all responses in order to predict the effect of process variables over the barrier and optical properties of the films. PMID- 23817092 TI - Encapsulation in alginate and alginate coated-chitosan improved the survival of newly probiotic in oxgall and gastric juice. AB - This study was undertaken to develop an optimum composition model for the microencapsulation of a newly probiotic on sodium alginate using response surface methodology. The individual and interactive effects of three independent variables, namely sodium alginate concentration, biomass concentration, and hardening time, were investigated using Box-Behnken design experiments. A second ordered polynomial model was fitted and optimum conditions were estimated. The optimal conditions identified were 2% for sodium alginate, 10(10)UFC/ml for biomass, and 30 min for hardening time. The experimental value obtained for immobilized cells under these conditions was about 80.98%, which was in close agreement with the predicted value of 82.6%. Viability of microspheres (96%) was enhanced with chitosan as coating materials. The survival rates of free and microencapsulated Lactobacillus plantarum TN8 during exposure to artificial gastrointestinal conditions were compared. The results revealed that the encapsulated cells exhibited significantly higher resistances to artificial intestinal juice (AIJ) and artificial gastric juice (AGJ). Microencapsulation was also noted to effectively protect the strain from heating at 65 degrees C and refrigerating at 4 degrees C. Taken together, the findings indicated that microencapsulation conferred important protective effects to L. plantarum against the gastrointestinal conditions encountered during the transit of food. PMID- 23817093 TI - Selective adsorption of Pb(II), Cd(II), and Ni(II) ions from aqueous solution using chitosan-MAA nanoparticles. AB - Chitosan-MAA nanoparticles (CS-MAA) with an average size of 10-70 nm were prepared by polymerizing chitosan with methacrylic acid in aqueous solution. The physicochemical properties of nanoparticles were investigated using Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), X ray photoelectron spectroscopy (XPS), dynamic light scattering (DLS) and nuclear magnetic resonance (NMR). The adsorption of Pb(II), Cd(II) and Ni(II) from aqueous solution on CS-MAA was studied in a batch system. The effects of the solution pH, initial metal concentration, contact time, and dosage of the adsorbent on the adsorption process were examined. The experimental data were analyzed using the pseudo-second-order kinetic equations and the Langmuir, Freundlich and Redlish-Peterson isotherms. The maximum adsorption capacity was 11.30, 1.84, and 0.87 mg/g for Pb(II), Cd(II) and Ni(II) ions, respectively, obtained by the Langmuir isotherm. However, the adsorption isotherm was better explained by the Freundlich rather than by the Langmuir model, as the high correlation coefficients (R(2)>0.99) were obtained at a higher confidence level. PMID- 23817094 TI - Preparation of D-glucosamine by hydrolysis of chitosan with chitosanase and beta D-glucosaminidase. AB - Crude enzymes including chitosanase and beta-D-glucosaminidase were obtained by centrifugal separation from the fermentation broth of Microbacterium sp. OU01. Then the crude enzymes are used to hydrolyze chitosan for producing D-glucosamine (GlcN). The effects of temperature, pH, substrate concentration, the ratio of enzyme to chitosan, and hydrolysis time on the productivity of GlcN were discussed. The experimental result showed that the optimal conditions were temperature 50 degrees C, pH 5.8, substrate concentration 20 mg/mL, the optimum ratio of enzyme to chitosan 1.5 U/60 mg. Under above conditions, chitosan was completely hydrolyzed in 5 h. These results provide a scientific material for the optimization process of enzymatic production of GlcN. What is more, thin layer chromatography and high performance liquid chromatography were used to analyze hydrolytic product, which was proved to be GlcN. PMID- 23817095 TI - Astragalus polysaccharide improves muscle atrophy from dexamethasone- and peroxide-induced injury in vitro. AB - Astragalus polysaccharide (APS) is an important bioactive component of Astragalus membranaceus Bunge (Leguminosae) that has been used in traditional Chinese medicine for treating muscle wasting, a serious complication with complex mechanism manifested as myofibers atrophy and satellite cells apoptosis. In this study, the anti-atrophy and anti-apoptotic activity of Astragalus polysaccharide (APS) was characterized in C2C12 skeletal muscle myotubes and myoblasts. APS inhibited dexamethasone-induced atrophy by restoring phosphorylation of Akt, m TOR, P70s6k, rpS6 and FoxO3A/FoxO1. The targets that protected C2C12 myoblasts from damage by H2O2 were promoting cells proliferation and inhibiting cells apoptosis. The protective mechanisms involved mitochondrial pathway and death receptor pathway. Moreover, Antioxidant effect of APS was also detected in this work. Our findings suggested that APS could be explored as a protective and perhaps as a therapeutic agent in the management of muscle wasting. PMID- 23817096 TI - Emulsification properties of a novel hydrocolloid (Angum gum) for d-limonene droplets compared with Arabic gum. AB - In this study, the emulsification properties of a native biopolymer namely Angum gum (Ang) for use as a food flavor encapsulant in spray drying encapsulation was investigated and the results were compared with Arabic gum (Arg) stabilized emulsions. After gum extraction, gum dispersions with maltodextrin were prepared in water (in 1-5% concentrations) and emulsified with 5 and 10% d-limonene using high pressure homogenization. Statistical analysis of emulsion droplet size data revealed a significant difference between flavor level, gum type and droplet size at alpha=0.05. The results showed that increasing the Arg level leads to a decrease in emulsion droplet size, while increasing Ang content results in bigger droplet sizes. However, no significant differences were observed in droplet size. Also, droplet size data revealed that Ang-emulsified droplets at 2% gum and 5% flavor level had the lowest d32, d43 and the highest specific surface area by high-pressure homogenizer which could be mentioned as the optimum level of this native gum. PMID- 23817097 TI - Brown seaweed fucoidan: biological activity and apoptosis, growth signaling mechanism in cancer. AB - Seaweeds, being abundant sources of bioactive components have much interest in recent times. The complex polysaccharides from the brown, red and green seaweeds possess broad spectrum therapeutic properties. The sulfated polysaccharides are routinely used in biomedical research and have known biological activities. Fucoidan, a fucose-rich polysaccharide extracted from brown seaweed has various biological functions including anticancer effects. Cellular damage induces growth arrest and tumor suppression by inducing apoptosis, the mechanism of cell death depends on the magnitude of DNA damage following exposure to anticancer agents. Apoptosis is mainly regulated by cell growth signaling molecules. Number of research studies evidenced that fucoidan shown to induce cytotoxicity of various cancer cells, induces apoptosis, and inhibits invasion, metastasis and angiogenesis of cancer cells. There are few articles discussing on fucoidan biological activity but no specific review on cancer and its signaling mechanism. Hence, this review discusses the brown seaweed fucoidan structure and some biological function and role in apoptosis, invasion, metastasis, angiogenesis and growth signal mechanism on cancer. PMID- 23817098 TI - Characterization of Lycium barbarum polysaccharide and its effect on human hepatoma cells. AB - To investigate structure-bioactivity relationship of LBP, Lycium barbarum polysaccharide (LBP) was extracted and separated into five fractions using ultrafiltration membrane method. Then the effects of these polysaccharide fractions on human liver cancer cells (SMMC-7721) were observed by MTT assay, LSCM and FCM. And the components, molecular weight and conformation of LBP fractions were analyzed by GC, HPLC and AFM. The results showed that LBP-a8, LBP a3, LBP-a1 and LBP-a4 could inhibit the proliferation of SMMC-7721 cells in a concentration and time dependent manner. But LBP-p8 could promote the growth of SMMC-7721 cells. LBP-a4 (10.2 kDa), which consists of uronic acid (11.5%), protein (0.34%) and neutral sugar (39.02%), could arrest SMMC-7721 cells at G0/G1 phase and enhance the intracellular Ca(2+) concentration significantly. Nevertheless, LBP-p8 (6.50*10(3) kDa), which consists of uronic acid (13.4%), protein (4.77%) and neutral sugar (26.26%), did not change the cell cycle and Ca(2+) concentration in cytoplasm significantly. The molecular conformation of LBP-a4 and LBP-p8 was spherical and flocculent molecular shape, respectively, suggesting that spherical molecular shape was benefit to LBP's apoptosis inducing activity while flocculent molecular shape did not have that function. PMID- 23817099 TI - Effects of degumming conditions on electro-spinning rate of regenerated silk. AB - Electro-spun silk webs are potentially good candidates as tissue engineering scaffolds owing to their good bio- and cyto-compatibility. However, the low fabrication rate of electro-spun silk mats has been one of the obstacles in the mass production of such nanofibrous silk mats in applications to the biomedical field. In this study, the effects of degumming ratio and silk concentration on the electro-spinning process were investigated by using regenerated silk with different residual sericin contents and different silk concentrations in terms of the morphology and structure of the electro-spun silk web. The rate of production of electro-spun silk mats could be increased by approximately 5 fold at a degumming ratio of 19.5%. The electro-spinning rate of silk was affected by two main factors: (1) dope solution viscosity and (2) degumming ratio of silk. The conductivity of the silk dope solution, however, had little effects on the electro-spinning of regenerated silk. A constant spun fiber morphology was observed within the electro-spinning rate range (0.3-1.4 ml/h). Fourier transform infrared spectroscopy showed that partial beta-sheet crystallization occurred during electro-spinning. The molecular conformation was relatively unaffected by the electro-spinning rate of silk. PMID- 23817100 TI - Scrutinizing the different pectin types on stability of an Iranian traditional drink "Doogh". AB - Doogh is a fermented dairy drink which is highly consumed by Iranian people. Stability of this healthy drink was investigated in terms of sedimentation rate, viscosity, density and particle size characteristics including surface-weighted mean diameter (D32), Span and particle uniformity. Eight treatments were performed as randomized complete block design (RCBD) with three replications. Three types of pectin (high methoxyl pectin (HMP), grapefruit-seed extract pectin (GSEP) and amidated pectin (Ceamsa pectin (CSP)) at a constant concentration (0.35%w/w), three levels of salt (0.50, 0.75 and 1.00%w/w) and two dry matter contents (DMCs, 4 and 5% w/w) were used to produce the Dooghs. The results showed that the maximum stability and viscosity, and the minimum D32 were obtained by application of CSP, GSEP and HMP, respectively (p<0.05). Pectin type had no significant difference on the density values of Dooghs. The lowest sedimentation rate, viscosity, density and D32 were achieved in the minimum concentrations of salt and dry matter. The ANOVA analysis also revealed that the interaction of pectin type, salt concentration and DMC had a significant effect on the Span and particle uniformity. A maximum physical stability was found for the prepared samples with 0.35%w/w CSP, 0.5%w/w salt and 4%w/w dry matter. Evaluation of sensory attributes also confirmed that this formulation had the highest overall acceptability value. PMID- 23817101 TI - Porous hyaluronic acid/sodium alginate composite scaffolds for human adipose derived stem cells delivery. AB - The aim of this study is to evaluate the feasibility of hyaluronic acid/sodium alginate (HA/SA) scaffold-based interpenetrating polymeric network (IPN) for the proliferation and chondrogenic differentiation of the human adipose-derived stem cells (hADSCs). The hADSCs cultured in HA/SA IPN scaffold exhibited enhanced cell adhesion and proliferation compared to the HA scaffold. Superior chondrogenic differentiation of hADSCs in HA/SA IPN scaffold, compared to HA-based scaffold, was confirmed by measuring expression levels of chondrogenic markers. These results suggested that HA/SA IPN scaffold could provide a desirable environment for the cell adhesion, proliferation and chondrogenic differentiation of hADSCs. PMID- 23817102 TI - Response surface optimization of enzyme-assisted extraction polysaccharides from Dictyophora indusiata. AB - An enzyme-assisted procedure for the extraction of the water-soluble polysaccharides from the stipe of Dictyophora indusiata was investigated using response surface methodology. The orthogonal array design was employed to optimize the concentration of three kinds of enzyme (cellulase, papain and pectolyase) and the optimal cellulose, papain and pectolyase concentration were 2.0% (wt.% of D. indusiata powder), 2.0% and 1.5%, respectively. And then the effect such as temperature, time and pH was studied based on a three-level three factor Box-Behnken design. The optimized conditions were as follows: extraction temperature 52.5 degrees C, extraction time 105 min and pH 5.25. Under these conditions, the experimental yield of polysaccharides was 9.77+/-0.18%, which was well matched with the predictive yield of 9.87%. As it turned out, enzyme assisted procedure was an effective method. PMID- 23817103 TI - Enzymatic degradation and bioactivity evaluation of C-6 oxidized chitosan. AB - C-6 oxidized chitosan was produced from chitosan by performing selective oxidation with NaOCl and NaBr using 2,2,6,6-tetramethylpiperidine-1-oxy radical (TEMPO) as catalyst. Endocellulase, Celluclast 1.5 L, Glucanex((r)), Macerozyme R 10, hyaluronidase, hyaluronate lyase, red scorpionfish chitinase, glucuronan lyase and a protein mix from Trichoderma reesei were used to degrade the C-6 oxidized chitosan. Glucanex((r)), the crude extract from T. reesei IHEM 4122 and Macerozyme R-10 validated the enzymatic degradation through final hydrolysis yields of the derivative respectively close to 36.4, 20.3 and 12.9% (w/w). The best initial reaction velocity (2.41 U/mL) was observed for Glucanex((r)). The antileishmanial activity of the derivative was evaluated against Leishmania infantum LIPA 137. The antibacterial activities against Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853 were also tested. Results showed an antileishmanial activity (IC50: 125 MUg/mL) of the obtained derivatives against L. infantum LIPA 137. PMID- 23817104 TI - Central composite rotatable design for investigation of microwave-assisted extraction of okra pod hydrocolloid. AB - Microwave-assisted extraction (MAE) technique was employed to extract the hydrocolloid from okra pods (OPH). The optimal conditions for microwave-assisted extraction of OPH were determined by response surface methodology. A central composite rotatable design (CCRD) was applied to evaluate the effects of three independent variables (microwave power (X1: 100-500 W), extraction time (X2: 30 90 min), and extraction temperature (X3: 40-90 degrees C)) on the extraction yield of OPH. The correlation analysis of the mathematical-regression model indicated that quadratic polynomial model could be employed to optimize the microwave extraction of OPH. The optimal conditions to obtain the highest recovery of OPH (14.911+/-0.27%) were as follows: microwave power, 395.56 W; extraction time, 67.11 min and extraction temperature, 73.33 degrees C. Under these optimal conditions, the experimental values agreed with the predicted ones by analysis of variance. It indicated high fitness of the model used and the success of response surface methodology for optimizing OPH extraction. After method development, the DPPH radical scavenging activity of the OPH was evaluated. MAE showed obvious advantages in terms of high extraction efficiency and radical scavenging activity of extract within the shorter extraction time. PMID- 23817105 TI - Ionizing radiation-induced gene expression changes in TP53 proficient and deficient glioblastoma cell lines. AB - The genetic heterogeneity presented by different cell lines derived from glioblastoma (GBM) seems to influence their responses to antitumoral agents. Although GBM tumors present several genomic alterations, it has been assumed that TP53, frequently mutated in GBM, may to some extent be responsible for differences in cellular responses to antitumor agents, but this is not clear yet. To directly determine the impact of TP53 on GBM response to ionizing radiation, we compared the transcription profiles of four GBM cell lines (two with wild-type (WT) TP53 and two with mutant (MT) TP53) after 8Gy of gamma-rays. Transcript profiles of cells analyzed 30 min and 6h after irradiation showed that WT TP53 cells presented a higher number of modulated genes than MT TP53 cells. Our findings also indicate that there are several pathways (apoptosis, DNA repair/stress response, cytoskeleton organization and macromolecule metabolic process) in radiation responses of GBM cell lines that were modulated only in WT TP53 cells (30 min and 6h). Interestingly, the majority of differentially expressed genes did not present the TP53 binding site, suggesting secondary effects of TP53 on transcription. We conclude that radiation-induced changes in transcription profiles of irradiated GBM cell lines mainly depend on the functional status of TP53. PMID- 23817106 TI - Genotoxic effects of exposure to radiofrequency electromagnetic fields (RF-EMF) in HL-60 cells are not reproducible. AB - Conflicting results have been published regarding the induction of genotoxic effects by exposure to radiofrequency electromagnetic fields (RF-EMF). Various results indicating a genotoxic potential of RF-EMF were reported by the collaborative EU-funded REFLEX (Risk Evaluation of Potential Environmental Hazards From Low Energy Electromagnetic Field Exposure Using Sensitive in vitro Methods) project. There has been a long-lasting scientific debate about the reliability of the reported results and an attempt to reproduce parts of the results obtained with human fibroblasts failed. Another part of the REFLEX study was performed in Berlin with the human lymphoblastoid cell line HL-60; genotoxic effects of RF-EMF were measured by means of the comet assay and the micronucleus test. The plausibility and reliability of these results were also questioned. In order to contribute to a clarification of the biological significance of the reported findings, a repeat study was performed, involving scientists of the original study. Comet-assay experiments and micronucleus tests were performed under the same experimental conditions that had led to genotoxic effects in the REFLEX study. Here we report that the attempts to reproduce the induction of genotoxic effects by RF-EMF in HL-60 cells failed. No genotoxic effects of RF-EMF were measured in the repeat experiments. We could not find an explanation for the conflicting results. However, the negative repeat experiments suggest that the biological significance of genotoxic effects of RF-EMF reported by the REFLEX study should be re-assessed. PMID- 23817107 TI - Differences in the expression profile of connexin 43 between keratoacanthomas and squamous cell carcinomas of the skin. PMID- 23817127 TI - Improved tools for the Brainbow toolbox. AB - In the transgenic multicolor labeling strategy called 'Brainbow', Cre-loxP recombination is used to create a stochastic choice of expression among fluorescent proteins, resulting in the indelible marking of mouse neurons with multiple distinct colors. This method has been adapted to non-neuronal cells in mice and to neurons in fish and flies, but its full potential has yet to be realized in the mouse brain. Here we present several lines of mice that overcome limitations of the initial lines, and we report an adaptation of the method for use in adeno-associated viral vectors. We also provide technical advice about how best to image Brainbow-expressing tissue. PMID- 23817128 TI - Protein kinase Calpha and P-type Ca channel CaV2.1 in red blood cell calcium signalling. AB - BACKGROUND/AIMS: Protein kinase Calpha (PKCalpha) is activated by an increase in cytosolic Ca(2+) in red blood cells (RBCs). Previous work has suggested that PKCalpha directly stimulates the CaV2.1 channel, whereas other studies revealed that CaV2.1 is insensitive to activation by PKC. The aim of this study was to resolve this discrepancy. METHODS: We performed experiments based on a single cell read-out of the intracellular Ca(2+) concentration in terms of Fluo-4 fluorescence intensity and phosphatidylserine exposure to the external membrane leaflet. Measurement modalities included flow cytometry and live cell imaging. RESULTS: Treatment of RBCs with phorbol 12-myristate 13-acetate (PMA) led to two distinct populations of cells with an increase in intracellular Ca(2+): a weak responding and a strong-responding population. The EC50 of PMA for the number of cells with Ca(2+) elevation was 2.7+/-1.2 uM; for phosphatidylserine exposure to the external membrane surface, it was 2.8+/-0.5 uM; and for RBC haemolysis, it was 2.9+/-0.5 uM. Using pharmacological manipulation with the CaV2.1 inhibitor omega-agatoxin TK and the broad protein kinase C inhibitor Go6983, we are able to show that there are two independent PMA-activated Ca(2+) entry processes: the first is independent of CaV2.1 and directly PKCalpha-activated, while the second is associated with a likely indirect activation of CaV2.1. Further studies using lysophosphatidic acid (LPA) as a stimulation agent have provided additional evidence that PKCalpha and CaV2.1 are not directly interconnected in a signalling chain. CONCLUSION: Although we provide evidence for a lack of interaction between PKCalpha and CaV2.1 in RBCs, further studies are required to decipher the signalling relationship between LPA, PKCalpha and CaV2.1. PMID- 23817129 TI - Unexpected distribution of cKIT and BRAF mutations among southern Italian patients with sinonasal melanoma. AB - BACKGROUND: Racial and geographic factors seem to affect the incidence of cutaneous and mucosal melanoma. OBJECTIVE: To investigate the occurrence of BRAF and cKIT impairments in patients with sinonasal melanoma in Southern Italy. METHODS: Eleven sinonasal melanomas were screened for BRAF mutations and cKIT alterations by immunohistochemistry (CD117), fluorescence in situ hybridization and sequencing analyses. RESULTS: A high prevalence (4/11; 36%) of BRAF mutations and lack of cKIT mutations were observed. Amplification of cKIT was found in 18% of cases; cKIT expression was detectable in 18% non-overlapping cases. No correlation between CD117 and cKIT alterations was observed. One (6%) cKIT and two (12%) BRAF mutations were detected in an additional series of 17 acral/mucosal melanomas from the same geographic areas. CONCLUSION: Mutations of cKIT are infrequent in sinonasal melanoma in Southern Italy. PMID- 23817130 TI - Pharmacokinetics of macitentan in caucasian and Japanese subjects: the influence of ethnicity and sex. AB - BACKGROUND/AIMS: Macitentan is a novel dual endothelin receptor antagonist with sustained receptor binding in clinical development for pulmonary arterial hypertension. The present study compared the pharmacokinetics and safety of macitentan in healthy Caucasian and Japanese subjects and explored the potential sex differences. METHODS: In this single-center, open-label, phase I study 10 healthy subjects of each ethnic origin with a male/female ratio of 1:1 in each group were administered a single oral 10-mg dose of macitentan. Blood samples were taken to determine plasma levels of macitentan and its pharmacologically active metabolite, ACT-132577, and safety and tolerability were monitored using standard assessments. RESULTS: For both macitentan and its metabolite, values for Cmax were similar but a shorter half-life was determined in Japanese subjects resulting in an exposure to both compounds being approximately 15% lower in Japanese when compared to Caucasian subjects. The exposure to macitentan was similar in Japanese males and females whereas Caucasian females had an approximately 25% higher exposure than Caucasian males. In both ethnic groups, females had an approximately 15% higher exposure to ACT-132577 than male subjects. Macitentan was well tolerated in both ethnic groups. There were no clinically significant differences in adverse event profile, clinical laboratory, electrocardiographic parameters, and vital signs between both groups. CONCLUSION: The data suggest that the minor differences in pharmacokinetics between the two groups are not clinically relevant and no dose adjustment of macitentan based on Japanese ethnic origin or sex is necessary. PMID- 23817131 TI - Wharton's jelly stem cells: a novel cell source for oral mucosa and skin epithelia regeneration. AB - Perinatal stem cells such as human umbilical cord Wharton's jelly stem cells (HWJSCs) are excellent candidates for tissue engineering because of their proliferation and differentiation capabilities. However, their differentiation potential into epithelial cells at in vitro and in vivo levels has not yet been reported. In this work we have studied the capability of HWJSCs to differentiate in vitro and in vivo to oral mucosa and skin epithelial cells using a bioactive three-dimensional model that mimics the native epithelial-mesenchymal interaction. To achieve this, primary cell cultures of HWJSCs, oral mucosa, and skin fibroblasts were obtained in order to generate a three-dimensional heterotypical model of artificial oral mucosa and skin based on fibrin-agarose biomaterials. Our results showed that the cells were unable to fully differentiate to epithelial cells in vitro. Nevertheless, in vivo grafting of the bioactive three-dimensional models demonstrated that HWJSCs were able to stratify and to express typical markers of epithelial differentiation, such as cytokeratins 1, 4, 8, and 13, plakoglobin, filaggrin, and involucrin, showing specific surface patterns. Electron microscopy analysis confirmed the presence of epithelial cell-like layers and well-formed cell-cell junctions. These results suggest that HWJSCs have the potential to differentiate to oral mucosa and skin epithelial cells in vivo and could be an appropriate novel cell source for the development of human oral mucosa and skin in tissue engineering protocols. PMID- 23817132 TI - Concise review: the involvement of SOX2 in direct reprogramming of induced neural stem/precursor cells. AB - Since induced pluripotent stem cells were first generated from mouse embryonic fibroblasts in 2006, somatic cell reprogramming has become a powerful and valuable tool in many fields of biomedical research, with the potential to lead to the development of in vitro disease models, cell-based drug screening platforms, and ultimately novel cell therapies. Recent research has now demonstrated the direct conversion of fibroblasts into stem, precursor, or mature cell types that are committed in their fate within a specific lineage, such as hematopoietic precursors or mature neurons. This has been achieved by ectopic expression of defined, tissue-specific transcription factors. Several studies have demonstrated direct reprogramming of mouse and human fibroblasts into immature neural stem or precursor cells, either by transient expression of the four pluripotency genes OCT3/4, KLF4, SOX2, and C-MYC or by application of different combinations of up to 11 neural transcription factors. Interestingly, in all of these studies SOX2 was introduced alone or in combination with other transcription factors. In this review we discuss the different combinations of ectopic transcription factors used to generate neural stem/precursor cells from somatic cells, with particular emphasis on SOX2 and its potential to act as a master regulator for reprogramming to a neural precursor state. PMID- 23817134 TI - Plastic fantastic: Schwann cells and repair of the peripheral nervous system. AB - Repair in the peripheral nervous system (PNS) depends upon the plasticity of the myelinating cells, Schwann cells, and their ability to dedifferentiate, direct axonal regrowth, remyelinate, and allow functional recovery. The ability of such an exquisitely specialized myelinating cell to revert to an immature dedifferentiated cell that can direct repair is remarkable, making Schwann cells one of the very few regenerative cell types in our bodies. However, the idea that the PNS always repairs after injury, in contrast to the central nervous system, is not true. Repair in patients after nerve trauma can be incredibly variable, depending on the site and type of injury, and only a relatively small number of axons may fully regrow and reinnervate their targets. Recent research has shown that it is an active process that drives Schwann cells back to an immature state after injury and that this requires activity of the p38 and extracellular regulated kinase 1/2 mitogen-activated protein kinases, as well as the transcription factor cJun. Analysis of the events after peripheral nerve transection has shown how signaling from nerve fibroblasts forms Schwann cells into cords in the newly generated nerve bridge, via Sox2 induction, to allow the regenerating axons to cross the gap. Understanding these pathways and identifying additional mechanisms involved in these processes raises the possibility of both boosting repair after PNS trauma and even, possibly, blocking the inappropriate demyelination seen in some disorders of the peripheral nervous system. PMID- 23817135 TI - GLUT1 regulation of the pro-sclerotic mediators of diabetic nephropathy. AB - Diabetic glomerulosclerosis is characterized by accumulation of extracellular matrix proteins, mesangial expansion, and tubulointerstitial fibrosis. Hyperglycemia accelerates development of the disease, a direct result of increased intracellular glucose availability. The facilitative glucose transporter GLUT1 mediates mesangial cell glucose flux which leads to activation of signaling cascades favoring glomerulosclerosis, including pathways mediated by angiotensin II (Ang II), transforming growth factor beta (TGF-beta), connective tissue growth factor (CTGF), and vascular endothelial growth factor (VEGF). Ang II has both hemodynamic and metabolic effects directly inducing GLUT1 and/or matrix protein synthesis through diacyl glycerol (DAG) or protein kinase C (PKC) induction, mesangial cell stretch, and/or through transactivation of the epidermal growth factor receptor, the platelet-derived growth factor receptor, and the insulin-like growth factor-1 receptor, all of which may stimulate GLUT1 synthesis via an ERK-mediated pathway. Conversely, inhibition of Ang II effects suppresses GLUT1 and cellular glucose uptake. GLUT1-mediated glucose flux leads to metabolism of glucose via glycolysis, with induction of DAG, PKC, TGF-beta1, CTGF and VEGF. VEGF in turn triggers both GLUT1 and matrix synthesis. New roles for GLUT1-mTOR and GLUT1-mechano-growth factor interactions in diabetic glomerulosclerosis have also recently been suggested. Recent mouse models confirmed roles for GLUT1 in vivo in stimulating glomerular growth factor expression, growth factor receptors and development of glomerulosclerosis. GLUT1 may therefore act in concert with cytokines and growth factors to induce diabetic glomerulosclerosis. Further clarification of the pathways involved may prove useful for the therapy of diabetic nephropathy. New directions for investigation are discussed. PMID- 23817133 TI - Concise review: immunological properties of ocular surface and importance of limbal stem cells for transplantation. AB - Cornea transplantation has been considered to be different from other solid organ transplantation because of the assumed immune-privileged state of the anterior chamber of the eye. Three major lines of thought regarding the molecular mechanisms of immune privilege in the eye are as follows: (a) anatomical, cellular, and molecular barriers in the eye; (b) anterior chamber-associated immune deviation; and (c) immunosuppressive microenvironment in the eye. However, cornea transplants suffer allograft rejection when breached by vascularization. In recent developments, cellular corneal transplantation from cultivated limbal epithelial cells has shown impressive advances as a future therapy. The limbal stem cell niche contains stem cells that promote proliferation and migration and have immunosuppressive mechanisms to protect them from immunological reactions. Limbal stem cells are also noted to display an enhanced expression of genes for the antiapoptotic proteins, a property that is imperative for the survival of transplanted tissues. Further investigation of the molecular mechanisms regulating the immune regulation of limbal stem cells is relevant in the clinical setting to promote the survival of whole corneal and limbal stem cell transplantation. PMID- 23817136 TI - Rapid thinning of the Late Pleistocene Patagonian Ice Sheet followed migration of the Southern Westerlies. AB - Here we present the first reconstruction of vertical ice-sheet profile changes from any of the Southern Hemisphere's mid-latitude Pleistocene ice sheets. We use cosmogenic radio-nuclide (CRN) exposure analysis to record the decay of the former Patagonian Ice Sheet (PIS) from the Last Glacial Maximum (LGM) and into the late glacial. Our samples, from mountains along an east-west transect to the east of the present North Patagonian Icefield (NPI), serve as 'dipsticks' that allow us to reconstruct past changes in ice-sheet thickness, and demonstrates that the former PIS remained extensive and close to its LGM extent in this region until ~19.0 ka. After this time rapid ice-sheet thinning, initiated at ~18.1 ka, saw ice at or near its present dimension by 15.5 ka. We argue this rapid thinning was triggered by a combination of the rapid southward migration of the precipitation bearing Southern Hemisphere (SH) westerlies and regional warming. PMID- 23817137 TI - Modulation of pancreatic exocrine and endocrine secretion. AB - PURPOSE OF REVIEW: Recent advances in the regulation of pancreatic secretion by secretagogues, modulatory proteins and neural pathways are discussed. RECENT FINDINGS: Downstream events involved in secretagogue stimulation of pancreatic secretion have been elucidated through characterization of the Src kinase pathway. An additional mechanism regulating vagus nerve effects on the pancreas involves Group II and III metabotropic glutamate receptors that are located presynaptically on certain vagal pancreas-projecting neurons. Hypothalamic neurons perceive glucose and regulate insulin release by direct communication with islets, and activation of proopiomelanocortin neurons by leptin enhances insulin secretion and modulates glucose but not energy homeostasis. Ghrelin and somatostatin mediate glucose-stimulated insulin secretion by differential receptor signaling that is dependent on the amount of ghrelin and state of receptor heterodimerization. Endoplasmic reticulum (ER) stress and loss-of function mutations of a key ER stress protein are associated with disruption of membrane translocation and reduction in insulin secretion. The importance of hormones, neuropeptides, amino acids, cytokines and regulatory proteins in pancreatic secretion and the pathophysiology of type 2 diabetes are also discussed. SUMMARY: The biomolecular pathways regulating pancreatic secretions are still not fully understood. New secretagogues and mechanisms continue to be identified and this information will aid in drug discovery and development of new and improved therapy for pancreatic disorders. PMID- 23817138 TI - Associate editor David Dombrowicz. PMID- 23817139 TI - Animal models of chronic kidney disease: useful but not perfect. AB - Animal models of chronic kidney disease (CKD) approximate the human condition and are keys to understanding its pathogenesis and to developing rational treatment strategies. The ethical use of animals requires a detailed understanding of the strengths and limitations of each species and the disease model, and the way in which findings can be translated from animals to humans. While not perfect, the careful use of animal experiments offers the opportunity to examine individual mechanisms in an accelerated time frame. PMID- 23817140 TI - A serine proteinase PmClipSP2 contributes to prophenoloxidase system and plays a protective role in shrimp defense by scavenging lipopolysaccharide. AB - Serine proteinases (SPs) participate in various biological processes and play vital role in immunity. In this study, we investigated the function of PmClipSP2 from shrimp Penaeus monodon in defense against bacterial infection. PmClipSP2 was identified as a clip-domain SP and its mRNA increased in response to infection with Vibrio harveyi. PmClipSP2-knockdown shrimp displayed a significantly reduced phenoloxidase (PO) activity and increased susceptibility to V. harveyi infection. Injection of LPS and/or beta-1,3-glucan induced a dose-dependent mortality and a significant decrease in the number of total hemocytes, with clear morphological changes in the hemocyte surface, of the PmClipSP2-knockdown shrimp. Recombinant PmClipSP2 was shown to bind to LPS and beta-1,3-glucan and to activate PO activity. These results reveal that PmClipSP2 acts as a pattern-recognition protein, binding to microbial polysaccharides and likely activating the proPO system, whilst it may play an essential role in the hemocyte homeostasis by scavenging LPS and neutralizing its toxicity. PMID- 23817141 TI - Characterization of the CCR3 and CCR9 genes in miiuy croaker and different selection pressures imposed on different domains between mammals and teleosts. AB - The innate immune system can recognize non-self through pattern recognition receptors and provides a first line of antimicrobial host defense. Thus innate immunity plays a very important role in resistance against major bacterial disease in vertebrates. In the innate immune responses, the chemokine receptors act as the main receptors of chemokines which are released at the sites of infection, inflammation and injury. In this study, the Miichthys miiuy CCR3 and CCR9 genes were cloned and characterized, showing that MIMI-CCR3 possesses a highly conserved DRYLA motif similar to that of other fishes. MIMI-CCR3 and CCR9 were ubiquitously expressed in all tested tissues and the expressions were significantly up-regulated after infection with Vibrio anguillarum except that of CCR9 in spleen. Evolutionary analysis showed that all the ancestral lineages of CCR3 and CCR9 in mammals and teleosts underwent positive selection, indicating that the ancestor of terrestrial animals further evolved to adapt to terrestrial environments and the continuous intrusion of microbes stimulated the evolution of CCR genes in the ancestor of teleost. Multiple ML methods were used to detect the robust candidates for sites under positive selection. In total, 11 and 8 positively selected sites were found in the subsets of current mammal and teleost CCR3 genes, and 3 and 2 sites were detected in the subsets of current mammals and teleosts in CCR9. Interestingly, for mammal CCR3 and CCR9 genes, the robust candidates of positively selected sites were mainly located in the extracellular domains which were the ligand binding and pathogen interaction regions. For teleost CCR3 and CCR9 genes, the positively selected sites were not only located in the extracellular domains but also in the C-terminal and intracellular domains, indicating mammals and teleosts experienced different selection pressures upon their N-terminus, C-terminus and intracellular loops of CCRs. PMID- 23817142 TI - Shrimp hemocytes release extracellular traps that kill bacteria. AB - Extracellular traps (ETs) are formed from the DNA, histones and cytoplasmic antimicrobial proteins that are released from a range of vertebrate immune-cells in response to pathogenic stimulation. This novel defense mechanism has not been demonstrated in invertebrates. In this study, we investigated the formation of ETs in the crustacean Litopenaeus vannamei. We found that stimulation of shrimp hemocytes with phorbol myristate acetate (PMA), lipopolysaccharide (LPS) and live Escherichia coli all led to the formation of the characteristic ET fibers made from host cell DNA. After E. coli stimulation, we found that histone proteins were co-localized with these extracellular DNA fibers. The results further showed that E. coli were trapped by these ET-like fibers and that some of the trapped bacteria were permeabilized. All of these results are characteristic of the ETs that are seen in vertebrates and we therefore conclude that shrimp are also capable of forming extracellular traps. PMID- 23817143 TI - Isolation of gamma-interferon-inducible lysosomal thiol reductase (GILT) from the Yangtze finless porpoise. AB - In this study, we isolated the cDNA of a gamma-interferon-inducible lysosomal thiol reductase (GILT), which is critical for innate immune regulation, from the Yangtze finless porpoise (FpGILT). This gene encoded a protein with 244 amino acids and a predicted molecular weight of 28 kDa. The amino acid sequence of FpGILT includes an active-site CXXC motif, a GILT signature sequence, CQHGX2ECX2NX4C, and three N-linked glycosylation sites. Phylogenetic analysis showed that FpGILT and other GILT family members were derived from a common ancestor and finless porpoises are closely related to artiodactyla. Recombinant protein (FpsGILT) was then efficiently expressed and purified, and thiol reductase activity assays suggested that FpGILT catalyses disulfide bond reduction. These findings provide a basis for understanding the characteristics of immunity in the finless porpoise and other aquatic mammals. PMID- 23817144 TI - A pilot study: the effect of healing touch on anxiety, stress, pain, pain medication usage, and physiological measures in hospitalized sickle cell disease adults experiencing a vaso-occlusive pain episode. AB - PURPOSE: This pilot study was conducted to determine the effectiveness of Healing Touch on anxiety, stress, pain, pain medication usage, and selected physiological measures of hospitalized adults with sickle cell disease experiencing a vaso occlusive pain episode. DESIGN: Healing Touch sessions were administered for 30 minutes on four consecutive days, and the self-reported data on anxiety, stress, pain, and the selected physiological data were collected while controlling for music and presence. METHOD: A parallel-group randomized control trial comparing the effects of Healing Touch with Music (HTM) to Attention Control with Music (ACM). FINDINGS: Due to the small sample size, there were no statistically significant changes in any between-group comparisons, except for present pain on Day 4 for the ACM group. For both groups, the within-group comparison showed a nonsignificant reduction in physiological parameters, a statistically significant reduction in anxiety and stress for the ACM group after Day 4, and a statistically significant reduction in stress in the HTM group after Days 2 and 4. The pre- to postintervention reductions in present pain were greater in the HTM group across all 4 days, but the only statistically significant within groups findings were in the HTM group (p < .01) on Day 1. CONCLUSIONS: Further research is needed. PMID- 23817145 TI - Mind-body therapies for sleep disturbances in women at midlife. AB - Multiple factors contribute to sleep disturbances in women at midlife. Poor sleep is a common occurrence in women transitioning through midlife and is associated with significant morbidity. Factors that are known to disturb sleep in women at midlife include vasomotor symptoms, nocturia, sleep apnea, and stress. Stress in particular has a significant impact on sleep. Various treatments, pharmacologic and nonpharmacologic, are available to treat sleep disturbances. One nonpharmacologic option includes mind-body medicine, which encompasses several therapies. Practices within this realm have been shown to moderate the experience of stress and help restore sleep quality. Each woman's experience of disturbed sleep and transition through midlife is unique. By having a broad awareness of all evidence-based therapeutics, the clinician is able to present a diverse set of options for women at midlife who are affected by poor sleep. PMID- 23817147 TI - Likelihood ratios to apply for nasal bone, ductus venosus and tricuspid flow at the 11-13 weeks' scan in down syndrome screening. AB - OBJECTIVE: To assess the feasibility of nasal bone (NB), ductus venosus (DV) and tricuspid flow (TF) at the 11-13 weeks' scan, calculate likelihood ratios for each of the markers and evaluate their efficacy in expanded and contingent screening strategies for Down syndrome. MATERIAL AND METHODS: NB, DV and TF were assessed in 11,261 singleton fetuses undergoing first trimester combined screening. For each marker, Down syndrome detection rate (DR), false positive rate (FPR), positive, negative and isolated likelihood ratios (PLR, NLR and iLR) were calculated. Likelihood ratios were multiplied to the combined test risk either to the entire population or to the intermediate risk group (expanded and sequential strategies, respectively). RESULTS: Down syndrome was diagnosed in 101 pregnancies. Feasibility for marker assessment ranged from 71 to 97%, DRs for isolated markers from 20 to 54% and FPRs from 1.3 to 5.3%. PLR ranged from 10 to 15, NLR from 0.5 to 0.8 and iLR from 3.9 to 5.6. When ultrasound markers were added to both strategies, a significant FPR reduction was observed. CONCLUSION: The application of NB, DV and TF likelihood ratios to the combined test risk, either in an expanded or contingent strategy, result in a FPR reduction. PMID- 23817146 TI - Small molecule drug screening in Drosophila identifies the 5HT2A receptor as a feeding modulation target. AB - Dysregulation of eating behavior can lead to obesity, which affects 10% of the adult population worldwide and accounts for nearly 3 million deaths every year. Despite this burden on society, we currently lack effective pharmacological treatment options to regulate appetite. We used Drosophila melanogaster larvae to develop a high-throughput whole organism screen for drugs that modulate food intake. In a screen of 3630 small molecules, we identified the serotonin (5 hydroxytryptamine or 5-HT) receptor antagonist metitepine as a potent anorectic drug. Using cell-based assays we show that metitepine is an antagonist of all five Drosophila 5-HT receptors. We screened fly mutants for each of these receptors and found that serotonin receptor 5-HT2A is the sole molecular target for feeding inhibition by metitepine. These results highlight the conservation of molecular mechanisms controlling appetite and provide a method for unbiased whole organism drug screens to identify novel drugs and molecular pathways modulating food intake. PMID- 23817149 TI - Physician examine thyself. PMID- 23817150 TI - The medical alliance: from placebo response to alliance effect. AB - The natural human response to illness is to seek to understand what is happening and to look for help from others. In all cultures, one finds healers, who provide explanations and offer care. Their interventions often have a placebo effect through activation of natural healing processes in the patient. Although placebo effects are relatively large and robust, physicians generally consider placebo treatment prescientific and deceptive. We review the determinants of the placebo response and show how a particular professional alliance between a patient and a caregiver is apt to equally affect treatment outcome. We distinguish the alliance effect from the placebo effect. We develop a comprehensive model of the medical alliance, on the basis of the concept of concordance, and review its relevance for clinical practice and medical education. The alliance effect represents a professional and ethical way of activating a patient's natural healing mechanisms. PMID- 23817151 TI - Clinicians' attitudes toward the use of long-acting injectable antipsychotics. AB - Depot formulations are not widely used in everyday practice. This study aimed to assess psychiatrists' attitudes toward the use of long-acting injectable (LAI) antipsychotics in schizophrenia. We interviewed 113 French psychiatrists about the factors that influenced their prescription of LAI antipsychotics. Multidimensional and cluster analyses were used to detect correlations. The most important factor against the use of LAI antipsychotics is a sufficient estimated compliance with the oral formulation. For first-generation LAI, the main factor is the risk for extrapyramidal symptoms; and for second-generation LAI, it is the unavailability of the equivalent oral formulation. Four factors incite the psychiatrists to prescribe LAI. Two different clusters of patients can also be identified. Most factors influencing the clinicians' attitudes toward the use of LAI antipsychotics are shared in many countries. Conversely, some attitudes related to organizational aspects, particularly the relevance of health care costs, may vary from one country to another. PMID- 23817152 TI - Stalking by patients: doctors' experiences in a Canadian urban area (Part II)- physician responses. AB - Stalking involves recurrent unwanted communication, harassment, and intrusive behaviors. The aim of this study was to examine physicians' experiences of being stalked by their patients, with particular attention to the emotional impact on the physicians and their actions taken. A questionnaire designed to study the nature and the impact of stalking experiences among physicians was sent to 3159 randomly chosen physicians in the Greater Toronto Area. Approximately 15% (14.9%) of the 1190 physicians who responded reported having been stalked. The physicians reported feeling angry, frustrated, anxious, frightened, lacking control, and helpless. The physicians coped in a number of ways including terminating the physician-patient relationship, but many just ignored the problem. Most had no previous knowledge about stalking. Physicians experience a range of emotions as a result of being a victim of stalking. In view of the prevalence and the impact, physicians may benefit from education to help prepare them for the possibility of being stalked. PMID- 23817153 TI - Residential placement for veterans with addiction: American Society of Addiction Medicine criteria vs. a veterans homeless program. AB - The goal of this study was to compare placements of patients with addiction undertaken by a) a unidimensional, protocol-driven, independent "permanent" housing "wet" program versus b) a multidimensional, patient-individualized, contingency-based housing approach. The sample consisted of eight veterans in a single team's panel admitted to a housing program and eight matched veterans on the verge of homelessness placed by the team according to the American Society of Addiction Medicine (ASAM) criteria. The two groups (matched for sex, race ethnicity, and age [SD, 5 years]) were similar on demography, substance disorder, and psychiatric comorbidity. Measures consisted of a) description of the placements, b) 12-month postplacement outcomes using a 12-item scale, and c) a Drug Abuse Research Project-based 10-item scale to assess recovery processes at two 6-month preplacement and two 6-month postplacement intervals. The veterans in the housing program escalated drinking and/or drug use; all were readdicted by the end of 12 months after placement. In the ASAM-criteria group, five of the eight patients had brief slips lasting 2 days or less, but none were readdicted at 12 months. The housing program group experienced five nontrivial outcomes: three imprisonments for felonies, one life-threatening medical complication, and one death. In conclusion, the findings support close monitoring and relevant contingencies using the ASAM criteria in the treatment of substance use disorder. PMID- 23817154 TI - The association between combat exposure and negative behavioral and psychiatric conditions. AB - This study evaluated the association between cumulative combat exposures and negative behavioral and psychiatric conditions. A total of 6128 active-duty soldiers completed a survey approximately 6 months after their unit's most recent combat deployment. The soldiers self-reported combat exposures and behavioral and psychiatric conditions. Multivariable logistic regression was used to assess the association between cumulative combat exposures and behavioral and psychiatric outcomes. In comparison with the referent group of soldiers not previously deployed, the soldiers categorized as having the highest cumulative combat exposures were significantly associated with self-reporting a history of behavioral and psychiatric diagnoses, problematic alcohol misuse, aggression, criminal behavior, and physical altercations with a significant other. The magnitude and the consistency of the association among the soldiers with the highest number of combat exposures suggest that the number of cumulative combat deployment exposures is an important consideration for identifying and treating high-risk soldiers and units returning from combat. PMID- 23817155 TI - The association between adult attachment style, mental disorders, and suicidality: findings from a population-based study. AB - Attachment theory categorically assesses how a person perceives and experiences interpersonal relationships. Attachment style is linked to numerous physical and psychological phenomena; however, there is a paucity of research examining its relationship to suicide ideation and attempt in adults. Our study addresses this and investigates the relationship of adult attachment style and mental disorders in a nationally representative sample. Using data from the National Comorbidity Survey Replication (N = 5692, aged >18 years), multiple logistic regression analyses were conducted to examine these relationships. After adjusting for confounding variables, insecure attachment styles were associated with greater reporting of suicidal ideation, attempt, and all mental disorder categories analyzed (adjusted odds ratio range, 1.13-1.81). Secure attachment styles were associated with a decreased likelihood of reporting suicidal ideation, attempt, and any anxiety disorder (adjusted odds ratio range, 0.67-0.91). Clinicians should be aware of attachment issues in their patients to ensure better health outcomes and more effective physician-patient relationships. PMID- 23817156 TI - Asthma and suicidal ideation and behavior among Puerto Rican older children and adolescents. AB - There is growing evidence of a positive association between asthma and suicidal ideation and behavior in the general community, although information on this potential association is scarce among older children and adolescents and Puerto Ricans, groups at risk for both conditions. Data came from wave 3 of the Boricua Youth Study, a longitudinal study of youth in the Bronx and San Juan conducted from 2000 to 2004. Logistic regressions for correlated data (Generalized Estimating Equation) were conducted, with asthma predicting suicidal ideation and behavior among participants 11 years or older. After adjustment for survey design; age; sex; poverty; Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, mental disorders; cigarette smoking; and stressful life events, asthma was positively associated with suicidal ideation and behavior among the Puerto Rican older children and adolescents. Public health interventions targeting Puerto Rican older children and adolescents with asthma and future studies investigating potential biological and psychological mechanisms of association are warranted. PMID- 23817157 TI - Quality of life impairment and the attitudinal and behavioral features of eating disorders. AB - We examined the relative contribution of different forms of eating disorder (ED) pathology to impairment in mental and physical health-related quality of life (QOL) in women with a wide range of ED symptoms. Female participants from an outpatient ED clinic (n = 53) and the local community (n = 214) completed measures of ED features and mental and physical health-related QOL. Across the sample, ED features were significantly associated with most mental and physical domains of QOL. In multiple regression analyses controlling for age and body mass index, ED features significantly predicted impairment in mental and physical QOL. Extreme shape and weight concern significantly and independently predicted most QOL subscales (beta range = 0.19-0.44). The prominent contribution of shape and weight concern to both mental and physical QOL impairment underlines the importance of addressing body dissatisfaction in the treatment and prevention of EDs. PMID- 23817158 TI - Parental perceptions of academic performance and attainment of children diagnosed with attention deficit hyperactivity disorder. AB - We examined parental perceptions of academic performance and attainment of children with attention deficit hyperactivity disorder (ADHD) according to both parent and child gender along with the interaction of parent and child gender. The current study adds to the body of research by examining the perceptions of parents of children with ADHD according to both parent and child gender. The results indicate that fathers, on the whole, seemed less likely to consider ADHD to have negative academic implications for their children as compared with mothers. With regard to child gender, the fathers seemed less likely to consider ADHD to have negative academic implications for their sons over their daughters. The results suggest that interventions for parents of children with ADHD should be targeted to fathers with sons with ADHD. PMID- 23817159 TI - Birth weight, domestic violence, coping, social support, and mental health of young Iranian mothers in Tehran. AB - The aim of this study was to investigate associations of birth weight with sociodemographic variables, domestic violence, ways of coping, social support, and general mental health of Iranian mothers. Six hundred mothers aged 15 to 29 years participated between June 2009 and November 2010. t-Test, analysis of variance, Spearman's correlation, and multiple regression were used. The results showed that there was no significant association between birth weight and general mental health of the mothers. Prenatal care visits, the mothers' history of having children with low birth weight (LBW), and weight gain during pregnancy were significantly associated with birth weight. The women who reported physical abuse during pregnancy had infants with lower birth weight. Satisfaction with social support and use of positive reappraisal were significantly associated with higher birth weight. In conclusion, a high quality of prenatal care and screening of pregnant women are recommended. Social environments good enough during pregnancy have protective effects against LBW. PMID- 23817160 TI - Change in defense mechanisms and coping patterns during the course of 2-year-long psychotherapy and psychoanalysis for recurrent depression: a pilot study of a randomized controlled trial. AB - Very little research has been conducted so far to study the potential mechanisms of change in long-term active psychological treatments of recurrent depression. The present pilot randomized controlled trial aimed to determine the feasibility of studying the change process occurring in patients during the course of 2-year long dynamic psychotherapy, psychoanalysis, and cognitive therapy, as compared with clinical management. In total, eight outpatients presenting with recurrent depression, two patients per treatment arm, were included. All patients were randomly assigned to one of the four treatment conditions. Defense mechanisms and coping patterns were assessed using validated observer-rated methodology based on transcribed, semistructured follow-along independent dynamic interviews. The results indicated that, whereas some patients in the active treatments changed on the symptomatic levels, some others remained unchanged during the course of their 2-year-long treatment. However, with regard to potential mechanisms of change in these patients, changes in defense mechanisms and coping patterns were revealed to be important processes over time in successful therapies and, to a lesser extent, in less successful treatments. No change was found either on outcome or on the process measure for the control condition, that is, clinical management. These results are discussed along with previous data comparing change in defense mechanisms and coping during the course of treatments. PMID- 23817161 TI - Depersonalization experiences are strongly associated with dizziness and vertigo symptoms leading to increased health care consumption in the German general population. AB - This study investigated the association of depersonalization (DP) experiences with dizziness and its impact on subjective impairment and health care use. Trained interviewers surveyed a representative sample of 1287 persons using standardized self-rating questionnaires on dizziness, DP, and mental distress. Symptoms of dizziness were reported by 15.8% (n = 201). Thereof, 62.7% endorsed at least one symptom of DP, 40% reported impairment by symptoms of DP, and 8.5% reported clinically significant DP. Regression analyses identified DP as a significant, independent predictor for dizziness symptom severity, health care use, and impairment by dizziness. With regard to the Vertigo Symptom Scale, DP explained 34.1% (p < 0.001) of the variance for severity of symptoms of dysfunction in the balance system. In conclusion, symptoms of DP, highly prevalent in patients complaining of dizziness and vertigo, were independently associated with increased impairment and health care use. The presence of DP symptoms should actively be explored in patients complaining of dizziness. PMID- 23817162 TI - Wading through the flood of nontraditional therapies. PMID- 23817163 TI - Intranasal insulin to treat and protect against posttraumatic stress disorder. PMID- 23817164 TI - Psychometric evaluation of the Brown Assessment of Beliefs Scale in body dysmorphic disorder. AB - The Brown Assessment of Beliefs Scale (BABS) is a widely used measure that assesses insight/delusionality-an important dimension of psychopathology-both dimensionally and categorically (e.g., delusional versus nondelusional). The BABS has been shown to have good psychometric properties in a number of disorders, but sample sizes were small. In the present study, 327 subjects with body dysmorphic disorder (BDD) were interviewed with the BABS to assess insight regarding appearance beliefs. Other measures were administered. Intraclass correlation coefficients demonstrated excellent interrater reliability and test-retest reliability; internal consistency was strong. Principal components factor analysis identified one factor accounting for 60% of the variance. Analyses with measures of severity of BDD, depressive symptoms, and general psychopathology indicated good discriminant validity. Among the treated subjects, the BABS was sensitive to change but not identical to improvement in symptom severity. These findings provide further evidence that the BABS is a reliable and valid measure of insight/delusionality. PMID- 23817165 TI - Role of CB2 cannabinoid receptors in the rewarding, reinforcing, and physical effects of nicotine. AB - This study was aimed to evaluate the involvement of CB2 cannabinoid receptors (CB2r) in the rewarding, reinforcing and motivational effects of nicotine. Conditioned place preference (CPP) and intravenous self-administration experiments were carried out in knockout mice lacking CB2r (CB2KO) and wild-type (WT) littermates treated with the CB2r antagonist AM630 (1 and 3 mg/kg). Gene expression analyses of tyrosine hydroxylase (TH) and alpha3- and alpha4-nicotinic acetylcholine receptor subunits (nAChRs) in the ventral tegmental area (VTA) and immunohistochemical studies to elucidate whether CB2r colocalized with alpha3- and alpha4-nAChRs in the nucleus accumbens and VTA were performed. Mecamylamine precipitated withdrawal syndrome after chronic nicotine exposure was evaluated in CB2KO mice and WT mice treated with AM630 (1 and 3 mg/kg). CB2KO mice did not show nicotine-induced place conditioning and self-administered significantly less nicotine. In addition, AM630 was able to block (3 mg/kg) nicotine-induced CPP and reduce (1 and 3 mg/kg) nicotine self-administration. Under baseline conditions, TH, alpha3-nAChR, and alpha4-nAChR mRNA levels in the VTA of CB2KO mice were significantly lower compared with WT mice. Confocal microscopy images revealed that CB2r colocalized with alpha3- and alpha4-nAChRs. Somatic signs of nicotine withdrawal (rearings, groomings, scratches, teeth chattering, and body tremors) increased significantly in WT but were absent in CB2KO mice. Interestingly, the administration of AM630 blocked the nicotine withdrawal syndrome and failed to alter basal behavior in saline-treated WT mice. These results suggest that CB2r play a relevant role in the rewarding, reinforcing, and motivational effects of nicotine. Pharmacological manipulation of this receptor deserves further consideration as a potential new valuable target for the treatment of nicotine dependence. PMID- 23817167 TI - Coastal proximity, health and well-being: results from a longitudinal panel survey. AB - Analysis of English census data revealed a positive association between self reported health and living near the coast. However that analysis was based on cross-sectional data and was unable to control for potential selection effects (e.g. generally healthier, personality types moving to coastal locations). In the current study we have used English panel data to explore the relationship between the proximity to the coast and indicators of generic and mental health for the same individuals over time. This allowed us to control for both time-invariant factors such as personality and compare the strength of any relationship to that of other relationships (e.g. employment vs. unemployment). In support of cross sectional analysis, individuals reported significantly better general health and mental health when living nearer the coast, controlling for both individual (e.g. employment status) and area (e.g. green space) level factors. No coastal effect on life satisfaction was found. Although individual level coastal proximity effects for general health and mental health were small, their cumulative impact at the community level may be meaningful for policy makers. PMID- 23817166 TI - Down-regulation of TRPM8 in pulmonary arteries of pulmonary hypertensive rats. AB - BACKGROUND: Pulmonary hypertension (PH) is characterized by profound vascular remodeling and alterations in Ca(2+) homeostasis in pulmonary arterial smooth muscle cells (PASMCs). Multiple transient receptor potential melastatin-related (TRPM) subtypes have been identified in vascular tissue. However, the changes in the expression and function of TRPM channels in pulmonary hypertension have not been characterized in detail. METHODS: We examined the expression of TRPM channels and characterized the functions of the altered TRPM channels in two widely used rat models of chronic hypoxia (CH)- and monocrotaline (MCT)-induced PH. RESULTS: CH-exposed and MCT-treated rats developed severe PH and right ventricular hypertrophy, with a significant decrease in TRPM8 mRNA and protein expression in pulmonary arteries (PAs). The downregulation of TRPM8 was associated with significant reduction in menthol-induced cation-influx. Time profiles showed that TRPM8 down-regulation occurred prior to the increase of right ventricular systolic pressure (RVSP) and right ventricular mass index (RVMI) in CH-exposed rats, but these changes were delayed in MCT-treated rats. The TRPM8 agonist menthol induced vasorelaxation in phenylephrine-precontracted PAs, and the vasorelaxing effects were significantly attenuated in PAs of both PH rat models, consistent with decreased TRPM8 expression. CONCLUSION: Downregulation of TRPM8 may contribute to the enhanced vasoreactivity in PH. PMID- 23817168 TI - 1-[2-(2-Methoxyphenylamino)ethylamino]-3-(naphthalene-1-yloxy)propan-2-ol as a potential anticancer drug. AB - The aim of the present study was to assess the anticancer effect of several naftopidil analogues on human malignant mesothelioma cell lines NCI-H28, NCI H2052, NCI-H2452, and MSTO-211H, human lung cancer cell lines A549, SBC-3, and Lu 65, human hepatoma cell lines HepG2 and HuH-7, human gastric cancer cell lines MKN-28 and MKN-45, and human bladder cancer cell lines 253J, 5637, KK-47, TCCSUP, T24, and UM-UC-3, human prostate cancer cell lines DU145, LNCap, and PC-3, and human renal cancer cell lines ACHN, RCC4-VHL, and 786-O. We newly synthesized 21 naftopidil analogues, and of them 1-[2-(2-methoxyphenylamino)ethylamino]-3 (naphthalene-1-yloxy)propan-2-ol (HUHS1015) most efficiently reduced cell viability for all the investigated malignant mesothelioma cell lines in a concentration (1-100 MUmol/l)-dependent manner. HUHS1015 reduced cell viability for all other investigated cancer cell lines, to an extent similar to that for malignant mesothelioma cell lines. HUHS1015 activated caspase-3 and -4, without activating caspase-8 and -9, in malignant mesothelioma cell lines. The results of the present study, thus, indicate that HUHS1015 induces apoptosis in a variety of cancer cells, possibly by activating caspase-4 and the effector caspase-3. PMID- 23817169 TI - Hemostatic abnormalities in sickle cell disease. AB - PURPOSE OF REVIEW: Although it has long been recognized that sickle cell disease (SCD) and other hemoglobinopathies are associated with a state of chronic hyperactivation of coagulation, the study of the epidemiology of venous thromboembolic (VTE) complications in SCD is only now beginning to evolve. In parallel, mechanistic studies of the hypercoagulable state in humans and mouse models implicate an increasingly important causative role of hemolysis. RECENT FINDINGS: The case for SCD as a thrombophilic state has been strengthened by the recent literature. In an attempt to better understand the underlying mechanism(s), global assays of coagulation (thromboelastography and thrombin generation assays) have been utilized by several groups, but thus far, the results have been inconsistent, probably because of the technical differences. However, global assays continue to support the case for an important role of peripheral blood cells and their derived microparticles in promoting coagulation activation. SUMMARY: VTE is an underappreciated and potentially morbid complication of SCD. The mechanisms underlying this hypercoagulable state are complex. A greater understanding of these pathways may lead to the rational selection of therapies that not only prevent thrombosis, but also impact on many of the other vaso-occlusive complications of SCD. PMID- 23817171 TI - Simultaneous determination of beta-agonists and psychiatric drugs in feeds by LC MS-MS. AB - A method was developed for the simultaneous determination of nine beta-agonists (cimaterol, ractopamine, terbutaline, zilpaterol, salbutamol, clenbuterol, mabuterol, bambuterol and brombuterol) and six psychiatric drugs (diazepam, nitrazepam, oxazepam, chlorpromazine, promethazine and perphenazine) in animal feed by using solid-phase extraction (SPE) followed by liquid chromatography tandem mass spectrometry (LC-MS-MS). Conditions were optimized for the extraction of the target analytes from animal feed and for clean-up with MCX SPE cartridges. The eluent was evaporated to dryness under nitrogen, and the residue was dissolved in a solution of acetonitrile and 1% formic acid (2:8, v/v) and analyzed by LC-MS-MS using an isotopic internal standard for quantification. Under the optimum conditions, the recovery values of the target analytes were between 70.1 and 110%, with coefficients of variation between 1.9 and 18.4%. The method was very reliable for the simultaneous determination of nine beta-agonists and six psychiatric drugs in animal feed. PMID- 23817170 TI - Mechanisms of thrombosis in obesity. AB - PURPOSE OF REVIEW: Obesity has become a worldwide epidemic that is driving increased morbidity and mortality from thrombotic disorders such as myocardial infarction, stroke, and venous thromboembolism. Effective prevention and treatment of thrombosis in obese patients is limited by an incomplete understanding of the underlying prothrombotic mechanisms and by uncertainties about risks, benefits, and dosing of anticoagulant drugs in this patient population. RECENT FINDINGS: This review summarizes our current understanding of established and emerging mechanisms contributing to the obesity-induced prothrombotic state. The mechanistic impact of chronic inflammation and impaired fibrinolysis in mediating obesity-associated thrombosis is highlighted. Recent data demonstrating the aberrant expression of adipokines and microRNAs, which appear to function as key modulators of proinflammatory and prothrombotic pathways in obesity, are also reviewed. Finally, some challenges and new approaches to the prevention and management of thrombotic disorders in obese and overweight patients are discussed. SUMMARY: Obesity-driven chronic inflammation and impaired fibrinolysis appear to be major effector mechanisms of thrombosis in obesity. The proinflammatory and hypofibrinolytic effects of obesity may be exacerbated by dysregulated expression and secretion of adipokines and microRNAs, which further increase the risk of thrombosis and suggest new potential targets for therapy. PMID- 23817175 TI - Acetylcholinesterase inhibition in the basolateral amygdala plays a key role in the induction of status epilepticus after soman exposure. AB - Exposure to nerve agents induces intense seizures (status epilepticus, SE), which cause brain damage or death. Identification of the brain regions that are critical for seizure initiation after nerve agent exposure, along with knowledge of the physiology of these regions, can facilitate the development of pretreatments and treatments that will successfully prevent or limit the development of seizures and brain damage. It is well-established that seizure initiation is due to excessive cholinergic activity triggered by the nerve agent induced irreversible inhibition of acetylcholinesterase (AChE). Therefore, the reason that when animals are exposed to lethal doses of a nerve agent, a small proportion of these animals do not develop seizures, may have to do with failure of the nerve agent to inhibit AChE in brain areas that play a key role in seizure initiation and propagation. In the present study, we compared AChE activity in the basolateral amygdala (BLA), hippocampus, and piriform cortex of rats that developed SE (SE rats) after administration of the nerve agent soman (154MUg/kg) to AChE activity in these brain regions of rats that received the same dose of soman but did not develop SE (no-SE rats). The levels of AChE activity were measured at the onset of SE in SE rats, 30min after soman administration in no-SE rats, as well as in controls which received saline in place of soman. In the control group, AChE activity was significantly higher in the BLA compared to the hippocampus and piriform cortex. Compared to controls, AChE activity was dramatically lower in the hippocampus and the piriform cortex of both the SE rats and the no-SE rats, but AChE activity in the BLA was reduced only in the SE rats. Consistent with the notion that soman-induced neuropathology is due to intense seizures, rather than due to a direct neurotoxic effect of soman, no-SE rats did not present any neuronal loss or degeneration, 7 days after exposure. The results suggest that inhibition of AChE activity in the BLA is necessary for the generation of seizures after nerve agent exposure, and provide strong support to the view that the amygdala is a key brain region for the induction of seizures by nerve agents. PMID- 23817176 TI - Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms. AB - The mechanisms involved in the progression from monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) to malignant multiple myeloma (MM) and plasma cell leukemia (PCL) are poorly understood but believed to involve the sequential acquisition of genetic hits. We performed exome and whole-genome sequencing on a series of MGUS (n=4), high-risk (HR)SMM (n=4), MM (n=26) and PCL (n=2) samples, including four cases who transformed from HR-SMM to MM, to determine the genetic factors that drive progression of disease. The pattern and number of non-synonymous mutations show that the MGUS disease stage is less genetically complex than MM, and HR-SMM is similar to presenting MM. Intraclonal heterogeneity is present at all stages and using cases of HR-SMM, which transformed to MM, we show that intraclonal heterogeneity is a typical feature of the disease. At the HR-SMM stage of disease, the majority of the genetic changes necessary to give rise to MM are already present. These data suggest that clonal progression is the key feature of transformation of HR-SMM to MM and as such the invasive clinically predominant clone typical of MM is already present at the SMM stage and would be amenable to therapeutic intervention at that stage. PMID- 23817177 TI - RUNX1 meets MLL: epigenetic regulation of hematopoiesis by two leukemia genes. AB - A broad range of human leukemias carries RUNX1 and MLL genetic alterations. Despite such widespread involvements, the relationship between RUNX1 and MLL has never been appreciated. Recently, we showed that RUNX1 physically and functionally interacts with MLL, thereby regulating the epigenetic status of critical cis-regulatory elements for hematopoietic genes. This newly unveiled interaction between the two most prevalent leukemia genes has solved a long standing conundrum: leukemia-associated RUNX1 N-terminal point mutants that exhibit no obvious functional abnormalities in classical assays for the assessment of transcriptional activities. These mutants turned out to be defective in MLL interaction and subsequent epigenetic modifications that can be examined by the histone-modification status of cis-regulatory elements in the target genes. RUNX1/MLL binding confirms the importance of RUNX1 function as an epigenetic regulator. Recent studies employing next-generation sequencing on human hematological malignancies identified a plethora of mutations in epigenetic regulator genes. These new findings would enhance our understanding on the mechanistic basis for leukemia development and may provide a novel direction for therapeutic applications. This review summarizes the current knowledge about the epigenetic regulation of normal and malignant hematopoiesis by RUNX1 and MLL. PMID- 23817178 TI - CXCR4-SERINE339 regulates cellular adhesion, retention and mobilization, and is a marker for poor prognosis in acute myeloid leukemia. AB - The CXCR4 receptor is a major regulator of hematopoietic cell migration. Overexpression of CXCR4 has been associated with poor prognosis in acute myelogenous leukemia (AML). We have previously shown that ligand-mediated phosphorylation of the Serine339 (CXCR4-S339) residue of the intracellular domain by PIM1 is implicated in surface re-expression of this receptor. Here, we report that phosphorylation of CXCR4-S339 in bone marrow (BM) biopsies correlated with poor prognosis in a cohort of AML patients. To functionally address the impact of CXCR4-S339 phosphorylation, we generated cell lines-expressing CXCR4 mutants that mimic constitutive phosphorylation (S339E) or abrogate phosphorylation (S339A). Whereas the expression of CXCR4 significantly increased, both CXCR4-S339E and the CXCR4-S339A mutants significantly reduced the BM homing and engraftment of Kasumi 1 AML cells in immunodeficient mice. In contrast, only expression of the CXCR4 S339E mutant increased the BM retention of the cells and resistance to cytarabine treatment, and impaired detachment capacity and AMD3100-induced mobilization of engrafted leukemic cells. These observations suggest that the poor prognosis in AML patients displaying CXCR4-S339 phosphorylation can be the consequence of an increased retention to the BM associated with an enhanced chemoresistance of leukemic cells. Therefore, CXCR4-S339 phosphorylation could serve as a novel prognostic marker in human AML. PMID- 23817179 TI - Spurious electrolyte disorders: a diagnostic challenge for clinicians. AB - Spurious electrolyte disorders refer to an artifactually elevated or decreased serum electrolyte values that do not correspond to their actual systemic levels. When a clinician is confronted with a case of electrolyte disturbance, the first question should be whether it is an artifact. Spurious electrolyte disorders (pseudohyponatremia, pseudohypernatremia, pseudohypokalemia, pseudohyperkalemia, pseudohypomagnesemia, pseudohypophosphatemia, pseudohyperphosphatemia, pseudohypocalcemia and pseudohypercalcemia) are not infrequently observed in clinical practice. The recognition that an electrolyte disturbance may be an artifact may prevent inappropriate therapeutic interventions that could potentially have unfavorable outcomes. Clinicians must be alert to the possibility of spurious laboratory abnormalities when faced with conflicting laboratory values or measurements that are discordant with the clinical presentation. Moreover, in the presence of conditions that predispose to spurious electrolyte disorders, the normal measured electrolyte levels should raise the suspicion that true electrolyte disorders may be present. PMID- 23817180 TI - Associate editor Holger Garn. PMID- 23817181 TI - Conservative approach in the treatment of renal trauma in children. AB - OBJECTIVE: Our aim was to evaluate the role of a conservative approach in the treatment of renal trauma in the pediatric age group. MATERIALS AND METHODS: A total of 31 pediatric patients with renal trauma (male = 25, female = 6) in whom we used a conservative approach in our clinic between the years 2002 and 2010 were included in the study. Patients were assessed according to the type of trauma, type of treatment, findings of radiological imaging, concomitant other organ injuries and complications occurring during follow-up. RESULTS: Surgery was required in just 4 of 31 pediatric patients who were treated with the conservative approach. Of the patients who underwent surgery, only one child needed nephrectomy. No complications were detected in the clinical and radiological follow-up of the patients who received the conservative approach. CONCLUSIONS: The main objective in the treatment of renal trauma occurring in childhood is to protect the kidneys. If the hemodynamic findings are stable, a conservative approach should be the first preferred method of treatment in every grade of renal trauma that can occur in childhood. PMID- 23817182 TI - The outcome of isolated primary fetal hydrothorax: a 10-year review from a tertiary center. AB - INTRODUCTION: The management of primary fetal pleural effusion remains a challenge for clinicians given the paucity of clinical information to guide practice. MATERIALS AND METHODS: A retrospective descriptive study of cases referred for management to our fetal therapy center over a 10-year period. Survival to hospital discharge was evaluated against case characteristics and prenatal intervention. For this study, we categorized the severity of the pleural effusion at diagnosis as mild, moderate or severe, and the clinical course as regression, stable or progression. RESULTS: Forty-five of the 103 pregnancies complicated by fetal pleural effusions during the study period were managed for primary effusions. Termination of pregnancy was requested in 6 cases. Thirty-nine pregnancies continued management, with 14 undergoing prenatal intervention. The overall survival rate to hospital discharge was 51%, including 7 survivors after prenatal intervention. The rate of survival was low if the effusion was categorized as severe at diagnosis or if there was progression of the clinical course. CONCLUSIONS: Case characteristics at the time of diagnosis and clinical course can be used to guide patient counseling and decision-making regarding fetal therapy. Prenatal intervention may improve the chance of survival in cases with characteristics associated with a poor prognosis. PMID- 23817183 TI - The trend in SLD enrollments and the role of RTI. AB - Based on the latest U.S. Department of Education data, this article presents the enrollment figures for students identified with specific learning disabilities (SLD) under the Individuals with Disabilities Education Act (IDEA) for the school years from 1995-1996 to 2011-2012. The figures for each year are (a) the number of students with SLD ages 6 to 21, (b) the percentage in relation to students classified under all of the IDEA classifications, and (c) the percentage in relation to total K-12 school enrollments. The discussion examines these trends and explores the possible reasons for them. PMID- 23817184 TI - Crosstalk between PI3 kinase/PDK1/Akt/Rac1 and Ras/Raf/MEK/ERK pathways downstream PDGF receptor. AB - BACKGROUND/AIMS: Our earlier studies suggested crosstalk between IRS/PI3 kinase/PDK1/Akt/Rac1/ROCK and (Shc2/Grb2/SOS)/Ras/Raf/MEK/ERK pathways downstream PDGF-betabeta receptor responsible for chemotaxis and proliferation of malignant mesothelioma cells. The present study was conducted to obtain evidence for this. METHODS: To assess activation of Akt, MEK, and ERK, Western blotting was carried out on MSTO-211H malignant mesothelioma cells using antibodies against phospho Thr308-Akt, phopho-Ser473-Akt, Akt, phospho-MEK, MEK, phopho-ERK1/2, and ERK1/2. To knock-down Akt, PI3 kinase, PDK1, and Rac1, siRNAs silencing each-targeted gene were constructed and transfected into cells. To monitor Rac1 activity, FRET monitoring was carried out on living and fixed cells. RESULTS: ERK was activated under the basal conditions in MSTO-211H cells, and the activation was prevented by inhibitors for PI3 kinase, PDK1, Akt, and Rac1 or by knocking-down PI3 kinase, PDK1, Akt, and Rac1. Akt was also activated under the basal conditions, and the activation was suppressed by a MEK inhibitor and an ERK1/2 inhibitor. In the FRET analysis, Rac1 was activated under the basal conditions, and the activation was inhibited by a MEK inhibitor and an ERK1/2 inhibitor. CONCLUSION: The results of the present study show that ERK could be activated by PI3 kinase, PDK1, Akt, and Rac1 and that alternatively, Akt and Rac1 could be activated by MEK and ERK in MSTO-211H cells. PMID- 23817185 TI - Dyslipidaemia: Risks of statin and antibiotic coprescription. PMID- 23817186 TI - Reply: Optimal renin-angiotensin-aldosterone system blockade--wish fulfilled. PMID- 23817187 TI - Coronary artery disease: Frequent somatic symptoms in CHD. PMID- 23817189 TI - Public health: Cardiovascular disease insights--something new out of Africa. AB - Adverse trends in blood pressure, diabetes mellitus, and other cardiometabolic risk factors, together with population growth and ageing, are contributing to the burden of cardiovascular diseases in Africa. This increasing problem, coupled with inadequate access to effective interventions for prevention, diagnosis, and treatment, is creating major public-health challenges across the continent. PMID- 23817188 TI - Presentation, management, and outcomes of ischaemic heart disease in women. AB - Scientific interest in ischaemic heart disease (IHD) in women has grown considerably over the past 2 decades. A substantial amount of the literature on this subject is centred on sex differences in clinical aspects of IHD. Many reports have documented sex-related differences in presentation, risk profiles, and outcomes among patients with IHD, particularly acute myocardial infarction. Such differences have often been attributed to inequalities between men and women in the referral and treatment of IHD, but data are insufficient to support this assessment. The determinants of sex differences in presentation are unclear, and few clues are available as to why young, premenopausal women paradoxically have a greater incidence of adverse outcomes after acute myocardial infarction than men, despite having less-severe coronary artery disease. Although differential treatment on the basis of patient sex continues to be described, the extent to which such inequalities persist and whether they reflect true disparity is unclear. Additionally, much uncertainty surrounds possible sex-related differences in response to cardiovascular therapies, partly because of a persistent lack of female-specific data from cardiovascular clinical trials. In this Review, we assess the evidence for sex-related differences in the clinical presentation, treatment, and outcome of IHD, and identify gaps in the literature that need to be addressed in future research efforts. PMID- 23817190 TI - Optimal renin-angiotensin system blockade-wishful thinking? PMID- 23817191 TI - Anticoagulation therapy: Dabigatran--a RELY-ABLE therapy? PMID- 23817192 TI - Valvular disease: TAVI safe and effective for patients with a bicuspid aortic valve. PMID- 23817193 TI - Safety and efficacy of stereotactic body radiotherapy for stage 1 non-small-cell lung cancer in routine clinical practice: a patterns-of-care and outcome analysis. AB - INTRODUCTION: To evaluate safety and efficacy of stereotactic body radiotherapy (SBRT) for stage I non-small-cell lung cancer (NSCLC) in a patterns-of-care and patterns-of-outcome analysis. METHODS: The working group "Extracranial Stereotactic Radiotherapy" of the German Society for Radiation Oncology performed a retrospective multicenter analysis of practice and outcome after SBRT for stage I NSCLC. Sixteen German and Austrian centers with experience in pulmonary SBRT were asked to participate. RESULTS: Data of 582 patients treated at 13 institutions between 1998 and 2011 were collected; all institutions, except one, were academic hospitals. A time trend to more advanced radiotherapy technologies and escalated irradiation doses was observed, but patient characteristics (age, performance status, pulmonary function) remained stable over time. Interinstitutional variability was substantial in all treatment characteristics but not in patient characteristics. After an average follow-up of 21 months, 3 year freedom from local progression (FFLP) and overall survival (OS) were 79.6% and 47.1%, respectively. The biological effective dose was the most significant factor influencing FFLP and OS: after more than 106 Gy biological effective dose as planning target volume encompassing dose (N = 164), 3-year FFLP and OS were 92.5% and 62.2%, respectively. No evidence of a learning curve or improvement of results with larger SBRT experience and implementation of new radiotherapy technologies was observed. CONCLUSION: SBRT for stage I NSCLC was safe and effective in this multi-institutional, academic environment, despite considerable interinstitutional variability and time trends in SBRT practice. Radiotherapy dose was identified as a major treatment factor influencing local tumor control and OS. PMID- 23817194 TI - New methods for ALK status diagnosis in non-small-cell lung cancer: an improved ALK immunohistochemical assay and a new, Brightfield, dual ALK IHC-in situ hybridization assay. AB - INTRODUCTION: The demonstration of anaplastic lymphoma kinase (ALK) positivity in non-small-cell lung cancer (NSCLC) has been hindered by the technical complexity and interpretative challenges of fluorescence in situ hybridization methods for detection of ALK gene rearrangement and by the inadequate sensitivity of existing immunohistochemistry (IHC) methods for ALK protein detection. In this study, we sought to increase the sensitivity of ALK IHC detection and to develop a brightfield assay for concurrent detection of ALK protein expression and ALK gene rearrangement. METHODS: We developed a horseradish peroxidase-based IHC detection system using the novel, nonendogenous hapten 3-hydroxy-2-quinoxaline (HQ) and tyramide. We also developed a dual gene protein ALK assay combining a brightfield break-apart in situ hybridization ALK assay with another sensitive IHC method using the novel, nonendogenous hapten 5-nitro-3-pyrazole. We examined the sensitivity and accuracy of these methods using surgically resected NSCLC cases examined with ALK fluorescence in situ hybridization. RESULTS: The new HQ tyramide IHC detection system offered readily interpretable staining with substantially greater sensitivity than conventional ALK IHC, and produced heterogeneous and homogeneous patterns of ALK protein staining among ALK-positive NSCLC surgical cases. The new 5-nitro-3-pyrazole-based IHC detection system was similar in ALK detection sensitivity to the HQ-tyramide IHC system and was compatible with the brightfield in situ hybridization assay. CONCLUSION: The new HQ-tyramide IHC reagent system allows more sensitive assessment of ALK protein status in NSCLC cases. The new ALK gene-protein assay allows the concurrent visualization of ALK gene and ALK protein status in single cells, allowing more accurate ALK status determination even in heterogeneous specimens. PMID- 23817195 TI - DNA methylation regulated nucleosome dynamics. AB - A strong correlation between nucleosome positioning and DNA methylation patterns has been reported in literature. However, the mechanistic model accounting for the correlation remains elusive. In this study, we evaluated the effects of specific DNA methylation patterns on modulating nucleosome conformation and stability using FRET and SAXS. CpG dinucleotide repeats at 10 bp intervals were found to play different roles in nucleosome stability dependent on their methylation states and their relative nucleosomal locations. An additional (CpG)5 stretch located in the nucleosomal central dyad does not alter the nucleosome conformation, but significant conformational differences were observed between the unmethylated and methylated nucleosomes. These findings suggest that the correlation between nucleosome positioning and DNA methylation patterns can arise from the variations in nucleosome stability dependent on their sequence and epigenetic content. This knowledge will help to reveal the detailed role of DNA methylation in regulating chromatin packaging and gene transcription. PMID- 23817197 TI - Docosahexaenoic acid augments hypothermic neuroprotection in a neonatal rat asphyxia model. AB - BACKGROUND: In neonatal rats, early post-hypoxia-ischemia (HI) administration of the omega-3 fatty acid docosahexaenoic acid (DHA) improves sensorimotor function, but does not attenuate brain damage. OBJECTIVE: To determine if DHA administration in addition to hypothermia, now standard care for neonatal asphyxial brain injury, attenuates post-HI damage and sensorimotor deficits. METHODS: Seven-day-old (P7) rats underwent right carotid ligation followed by 90 min of 8% O2 exposure. Fifteen minutes later, pups received injections of DHA 2.5 mg/kg (complexed to 25% albumin) or equal volumes of albumin. After a 1-hour recovery, pups were cooled (3 h, 30 degrees C). Sensorimotor and pathology outcomes were initially evaluated on P14. In subsequent experiments, sensorimotor function was evaluated on P14, P21, and P28; histopathology was assessed on P28. RESULTS: At P14, left forepaw function scores (normal: 20/20) were near normal in DHA + hypothermia-treated animals (mean +/- SD 19.7 +/- 0.7 DHA + hypothermia vs. 12.7 +/- 3.5 albumin + hypothermia, p < 0.0001) and brain damage was reduced (mean +/- SD right hemisphere damage 38 +/- 17% with DHA + hypothermia vs. 56 +/- 15% with albumin + hypothermia, p = 0.003). Substantial improvements on three sensorimotor function measures and reduced brain damage were evident up to P28. CONCLUSION: Unlike post-HI treatment with DHA alone, treatment with DHA + hypothermia produced both sustained functional improvement and reduced brain damage after neonatal HI. PMID- 23817198 TI - The promises of PCSK9 inhibition. AB - PURPOSE OF REVIEW: In the past 10 years, the LDL receptor inhibitor proprotein convertase subtilisin kexin type 9 (PCSK9) has emerged as a validated target for lowering plasma LDL cholesterol levels. Here we review the most recent reports on PCSK9 out of a total of 500 publications published in print or online before March 2013 and indexed on PubMed. RECENT FINDINGS: All published in 2012, phase I and II clinical trials demonstrate that fully human monoclonal antibodies targeting PCSK9 dramatically reduce LDL-C and enable patients to reach their target goals, without severe or serious safety issues. SUMMARY: This review summarizes the discovery of PCSK9, its original mode of action as a secreted inhibitor of the LDL receptor, as well as its genetic regulation by statins. We then focus on the major results from the 2012 phase I and II PCSK9 inhibitor clinical trials. We also review the recent in-vivo studies demonstrating the potential cardiovascular benefits of long-term PCSK9 inhibition and discuss its potential side-effects. PMID- 23817199 TI - Smad2 and myocardin-related transcription factor B cooperatively regulate vascular smooth muscle differentiation from neural crest cells. AB - RATIONALE: Vascular smooth muscle cell (VSMC) differentiation from neural crest cells (NCCs) is critical for cardiovascular development, but the mechanisms remain largely unknown. OBJECTIVE: Transforming growth factor-beta (TGF-beta) function in VSMC differentiation from NCCs is controversial. Therefore, we determined the role and mechanism of a TGF-beta downstream signaling intermediate Smad2 in NCC differentiation to VSMCs. METHODS AND RESULTS: By using Cre/loxP system, we generated a NCC tissue-specific Smad2 knockout mouse model and found that Smad2 deletion resulted in defective NCC differentiation to VSMCs in aortic arch arteries during embryonic development and caused vessel wall abnormality in adult carotid arteries where the VSMCs are derived from NCCs. The abnormalities included 1 layer of VSMCs missing in the media of the arteries with distorted and thinner elastic lamina, leading to a thinner vessel wall compared with wild-type vessel. Mechanistically, Smad2 interacted with myocardin-related transcription factor B (MRTFB) to regulate VSMC marker gene expression. Smad2 was required for TGF-beta-induced MRTFB nuclear translocation, whereas MRTFB enhanced Smad2 binding to VSMC marker promoter. Furthermore, we found that Smad2, but not Smad3, was a progenitor-specific transcription factor mediating TGF-beta-induced VSMC differentiation from NCCs. Smad2 also seemed to be involved in determining the physiological differences between NCC-derived and mesoderm-derived VSMCs. CONCLUSIONS: Smad2 is an important factor in regulating progenitor-specific VSMC development and physiological differences between NCC-derived and mesoderm derived VSMCs. PMID- 23817201 TI - Skepinone-L, a novel potent and highly selective inhibitor of p38 MAP kinase, effectively impairs platelet activation and thrombus formation. AB - BACKGROUND/AIMS: Platelets are critically important for primary haemostasis and the major players in thrombotic vascular occlusion. Platelets are activated by agonists, such as thrombin and collagen-related peptide as well as second-wave mediators including thromboxane A2 via different intracellular signaling pathways resulting in degranulation, aggregation and thrombus formation. Platelet activation is paralleled by phosphorylation and activation of p38 MAPK. The limited specificity of hitherto known p38 MAPK inhibitors precluded safe conclusions on the precise role of p38 MAPK in the regulation of platelet function. The present study examined the impact of Skepinone-L, a novel and highly selective inhibitor of p38 mitogen-activated protein kinase (p38 MAPK), on platelet activation and thrombus formation. METHODS: Experiments were performed in freshly isolated human platelets. Protein phosphorylation was quantified by Western blotting, thromboxane B2 synthesis by enzyme immunoassay, ATP release by ChronoLume luciferin assay, cytosolic Ca(2+) concentration by Fura-2 fluorescence measurements, platelet aggregation by a light transmissions measurement and in vitro thrombus formation by a flow chamber. RESULTS: Skepinone-L (1 MUM) virtually abrogated the phosphorylation of platelet p38 MAPK substrate Hsp27 following stimulation with CRP (1 MUg/ml), thrombin (5 mU/ml) or thromboxane A2 analogue U-46619 (1 MUM). Furthermore, Skepinone-L significantly blunted activation-dependent platelet secretion and aggregation following threshold concentrations of CRP, thrombin and thromboxane A2 analogue U-46619. Skepinone-L did not impair platelet Ca(2+) signaling but prevented agonist-induced thromboxane A2 synthesis through abrogation of p38 MAPK-dependent phosphorylation of platelet cytosolic phospholipase A2 (cPLA2). Skepinone-L further markedly blunted thrombus formation under low (500-s) and high (1700-s) arterial shear rates. CONCLUSIONS: The present study discloses a powerful inhibiting effect of p38 MAPK-blocker Skepinone-L on platelet activation and thrombus formation. PMID- 23817202 TI - Melanoma-related mortality and productivity losses in the USA, 1990-2008. AB - Melanoma remains among the deadliest cancers in the USA, ranking presently as the leading cause of death from skin disease in this country. The present analysis presents national statistics on the health burden (mortality) and productivity losses attributable to this cancer over a 19-year period. Melanoma-related deaths and mortality rates from 1990 through 2008 were identified and calculated using multiple-cause-of-death data and data from the 2000 US Census. Productivity losses were estimated using previously published methods that accounted for life expectancy, labor force participation, productivity growth, and the imputed values of caregiving and housekeeping activities. A total of 155,571 melanoma related deaths occurred during 1990-2008, resulting in 1,811,701 years of potential life lost. Age-adjusted mortality rates stratified by sex and race/ethnicity revealed differences: whites had the highest rate (3.55 per 100 000 population; 95% confidence interval 3.54, 3.57) and male individuals were 2.21 times more likely than female individuals to succumb to the disease. Cumulatively, the numbers of death for blacks, Hispanics, Asian/Pacific Islanders, and American Indians/Alaskan Natives exceeded 6000 deaths. The total productivity losses attributable to melanoma-related mortality during the sampled period were ~$66.9 billion. The burden and economic consequences of melanoma related deaths in the USA are not inconsequential. Understanding the mortality trends and productivity losses attributed to this skin cancer is important for evaluating the feasibility and trade-offs of public health and behavioral counseling interventions that focus on promoting skin cancer prevention. PMID- 23817200 TI - Inhibitor kappaB kinase 2 is a myosin light chain kinase in vascular smooth muscle. AB - RATIONALE: Myosin light chain (MLC) phosphorylation determines vascular contractile status. In addition to the classic Ca2+-dependent MLC kinase (MLCK), another unidentified kinase(s) also contributes to MLC phosphorylation in living cells. Inhibitor kappaB kinase 2 (IKK2)-deficient mouse embryonic fibroblasts demonstrate abnormal morphology and migration, suggesting that IKK2 may be involved in MLC phosphorylation. OBJECTIVE: Therefore, we tested whether IKK2 is an MLCK in living cells and the role of IKK2 in mediating vasoconstriction and blood pressure regulation. METHODS AND RESULTS: In the present study, we showed that recombinant IKK2-phosphorylated MLC and intact myosin in vitro, and the kinetic parameters were comparable with those of the classic MLCK. Overexpression of IKK2 increased cellular MLC phosphorylation level, and pharmacological inhibition of IKK2 markedly decreased vascular smooth muscle cell MLC phosphorylation, suggesting that IKK2 is an MLCK in living cells. IKK2 inhibitors dose- and time-dependently attenuated vasoconstriction elicited by diverse agonists, suggesting the physiological importance of IKK2 as an MLCK. Vascular smooth muscle cell-specific IKK2-deficient mice had decreased aortic contractile responses, and reduced hypertensive responses to several vasoconstrictors, compared with wild-type mice, confirming the physiological importance of IKK2 as an MLCK. CONCLUSIONS: Our data provide a novel mechanism whereby IKK2 regulates MLC phosphorylation as an MLCK and, thus, vascular function and blood pressure. PMID- 23817203 TI - Iron homeostasis and serum hepcidin-25 levels in obese children and adolescents: relation to body mass index. AB - BACKGROUND/AIMS: The etiology of the hypoferremia of obesity is unclear. Hepcidin is the body's main regulator of systemic iron (Fe) and has been reported to be elevated in obese patients. Thus, we aimed to assess Fe status and serum hepcidin 25 levels and their relationship with body mass index (BMI) in obese Egyptian children and adolescents. METHODS: Fifty obese children were compared to 50 age-, sex- and pubertal stage- matched controls. All subjects were subjected to history and anthropometric assessment and measurement of serum Fe, total iron binding capacity (TIBC), ferritin, transferrin saturation (TS), soluble transferrin receptor (sTfR) and hepcidin. RESULTS: Fe, TS and TIBC were lower, while ferritin, sTfR and hepcidin-25 were higher in obese patients than controls. BMI standard deviation score (SDS) correlated negatively with Fe (r = -0.82, p < 0.01), TS (r = -0.79, p = 0.02) and TIBC (r = -0.69, p = 0.02), and positively with ferritin (r = +0.73, p < 0.001), sTfR (r = +0.80, p < 0.01) and hepcidin (r = +0.95, p < 0.001). Higher BMI SDS and hepcidin were risk factors for iron deficiency (ID). CONCLUSIONS: Hypoferremia and elevated hepcidin-25 are prevalent in obese children and correlated with BMI SDS. The connection between hepcidin and inflammation could explain the association of ID with obesity. PMID- 23817204 TI - Macrolide therapy decreases chronic obstructive pulmonary disease exacerbation: a meta-analysis. AB - BACKGROUND: Macrolide antibiotics have anti-inflammatory effects, and long-term administration may reduce chronic obstructive pulmonary disease (COPD) exacerbations. OBJECTIVE: To investigate the effects of long-term treatment of macrolide therapy for COPD. METHODS: We searched the PubMed and Embase databases to identify randomized controlled trials that evaluated the effect of macrolide therapy (of at least 2 weeks) for COPD. The primary outcome assessed was the frequency of acute exacerbations during follow-up. RESULTS: Six trials involving 1,485 COPD patients were included in the analysis. Analysis of the pooled data of all 6 trials showed that macrolide administration reduced the frequency of acute exacerbations of COPD [risk ratio (RR) = 0.62; 95% CI 0.43-0.89, p = 0.01]. Subgroup analysis showed that only erythromycin might be associated with decreased COPD exacerbations (erythromycin: p = 0.04, azithromycin: p = 0.22, clarithromycin: p = 0.18). Moreover, macrolide therapy for 3 months did not significantly reduce the number of exacerbations (p = 0.18), whereas a beneficial effect was conclusive in the 6-month (p = 0.009) and 12-month (p = 0.03) treatment subgroups. In addition, nonfatal adverse events were more frequent in the macrolide treatment groups than in the controls (RR = 1.32; 95% CI 1.06-1.64, p = 0.01). However, related clinical factors had no influence on the overall result (p = 0.19). There was no publication bias among the included trials. CONCLUSIONS: Macrolide therapy was effective and safe in decreasing the frequency of exacerbations in patients with COPD. Treatment might provide a significant benefit but only when therapy lasts more than 6 months. PMID- 23817205 TI - A single intravenous rAAV injection as late as P20 achieves efficacious and sustained CNS Gene therapy in Canavan mice. AB - Canavan's disease (CD) is a fatal pediatric leukodystrophy caused by mutations in aspartoacylase (AspA) gene. Currently, there is no effective treatment for CD; however, gene therapy is an attractive approach to ameliorate the disease. Here, we studied progressive neuropathology and gene therapy in short-lived (<= 1 month) AspA(-/-) mice, a bona-fide animal model for the severest form of CD. Single intravenous (IV) injections of several primate-derived recombinant adeno associated viruses (rAAVs) as late as postnatal day 20 (P20) completely rescued their early lethality and alleviated the major disease symptoms, extending survival in P0-injected rAAV9 and rAAVrh8 groups to as long as 2 years thus far. We successfully used microRNA (miRNA)-mediated post-transcriptional detargeting for the first time to restrict therapeutic rAAV expression in the central nervous system (CNS) and minimize potentially deleterious effects of transgene overexpression in peripheral tissues. rAAV treatment globally improved CNS myelination, although some abnormalities persisted in the content and distribution of myelin-specific and -enriched lipids. We demonstrate that systemically delivered and CNS-restricted rAAVs can serve as efficacious and sustained gene therapeutics in a model of a severe neurodegenerative disorder even when administered as late as P20. PMID- 23817206 TI - Adeno-associated virus-mediated rescue of neonatal lethality in argininosuccinate synthetase-deficient mice. AB - Viral vectors based on adeno-associated virus (AAV) are showing exciting promise in gene therapy trials targeting the adult liver. A major challenge in extending this promise to the pediatric liver is the loss of episomal vector genomes that accompanies hepatocellular proliferation during liver growth. Hence maintenance of sufficient transgene expression will be critical for success in infants and children. We therefore set out to explore the therapeutic efficacy and durability of liver-targeted gene transfer in the challenging context of a neonatal lethal urea cycle defect, using the argininosuccinate synthetase deficient mouse. Lethal neonatal hyperammonemia was prevented by prenatal and early postnatal vector delivery; however, hyperammonemia subsequently recurred limiting survival to no more than 33 days despite vector readministration. Antivector antibodies acquired in milk from vector-exposed dams were subsequently shown to be blocking vector readministration, and were avoided by crossfostering vector-treated pups to vector-naive dams. In the absence of passively acquired antivector antibodies, vector redelivery proved efficacious with mice surviving to adulthood without recurrence of significant hyperammonemia. These data demonstrate the potential of AAV vectors in the developing liver, showing that vector readministration can be used to counter growth-associated loss of transgene expression provided the challenge of antivector humoral immunity is addressed. PMID- 23817207 TI - Organic chemicals in diesel exhaust particles enhance picryl chloride-induced atopic dermatitis in NC/Nga mice. AB - BACKGROUND: Diesel exhaust particles (DEP) have been reported to worsen allergic airway inflammation in mice. Recently, the organic chemical components of DEP (DEP-OC) were found to be important contributors to the aggravation of allergic airway inflammation in mice. The purpose of this study was to examine the effects of DEP-OC on atopic dermatitis (AD)-like skin lesions induced by picryl chloride (PiCl) in NC/Nga mice. METHODS: DEP were extracted with benzene/ethanol, and the soluble organic fraction formed the DEP-OC. NC/Nga male mice received simultaneous application of DEP-OC and/or PiCl on their ears once a week for 9 or 3 weeks. We evaluated skin lesions by noting scaling, eruption, excoriation, erosion, hemorrhage, pathologic changes, production of cytokines, and IgE level in the serum. RESULTS: PiCl application alone produced progressively severe AD like skin lesions. The application of PiCl plus DEP-OC resulted in a marked worsening of skin lesions in the early stages of AD. Moreover, mast cell counts significantly increased in the subcutaneous tissue. Administration of PiCl combined with DEP-OC resulted in a greater increase in the local expression of interleukin-4, keratinocyte chemoattractant, and neutrophils in subcutaneous tissue compared with PiCl treatment alone. In contrast, the combination treatment produced lower levels of IFN-gamma compared with PiCl treatment alone. CONCLUSIONS: DEP-OC application to the skin aggravated PiCl-induced AD. This aggravation may be due to activation of the Th2-associated immune responses by the organic chemicals in DEP. PMID- 23817208 TI - Autoimmune inner ear disease: a retrospective review of forty-seven patients. AB - The purpose of this retrospective study was to characterize and further define autoimmune inner ear disease (AIED) using the Harris AIED classification. A retrospective review was conducted at two tertiary medical centers for 47 patients who were diagnosed with AIED. The overall patient response rate to oral prednisone treatment was 69.7%. The sensitivity of the test for a serum antibody against heat-shock protein 70 (HSP70) was 54.5% and the specificity was 42.9%. Therefore, the clinical utility of the HSP70 antibody test appeared to be limited with respect to the diagnosis of AIED. Vertigo, tinnitus and aural fullness improved significantly with both of the newly developed adalimumab (Humira(r)) and rituximab (Rituxan(r)). However, hearing loss did not improve in the present study. PMID- 23817209 TI - Time to positivity as prognostic tool in patients with Pseudomonas aeruginosa bloodstream infection. AB - OBJECTIVES: The time to positivity (TTP), measured as the time span between the start of incubation and the alert signal from the blood culture device, has been described as useful tool of prognosis in patients suffering from blood stream infection with Staphylococcus aureus, Escherichia coli and Klebsiella pneumonia. The present study investigates the relationship between TTP and in-hospital mortality in patients with monomicrobial Pseudomonas aeruginosa blood stream infection (PA-BSI). METHODS: From 2006 until 2012 a retrospective cohort study was undertaken in 3 hospitals in the region surrounding Tubingen, Germany. Seventy-four patients with monomicrobial PA-BSI were studied. TTP and clinical parameters were determined and analyzed by receiver operating characteristic (ROC) analysis and Cox regression. RESULTS: The in-hospital mortality of our clinical cohort was 33.78%. In multivariate Cox regression, a TTP <= 18 h proved to be independently associated with mortality (HR 3.83, P = 0.012) along with SAPS II score (HR 1.04, P = 0.006), cardiac disease (HR 0.33, P = 0.008) and appropriate definitive antimicrobial treatment (HR 0.21, P = 0.013). CONCLUSIONS: TTP is an easy-to-measure laboratory tool for prognosis in patients with monomicrobial PA-BSI, providing useful information in addition to clinical parameters. PMID- 23817211 TI - Identification of new pillared-layered carbon nitride materials at high pressure. AB - The compression of the layered carbon nitride C6N9H3 . HCl was studied experimentally and with density functional theory (DFT) methods. This material has a polytriazine imide structure with Cl(-) ions contained within C12N12 voids in the layers. The data indicate the onset of layer buckling accompanied by movement of the Cl(-) ions out of the planes beginning above 10-20 GPa followed by an abrupt change in the diffraction pattern and c axis spacing associated with formation of a new interlayer bonded phase. The transition pressure is calculated to be 47 GPa for the ideal structures. The new material has mixed sp(2)-sp(3) hybridization among the C and N atoms and it provides the first example of a pillared-layered carbon nitride material that combines the functional properties of the graphitic-like form with improved mechanical strength. Similar behavior is predicted to occur for Cl-free structures at lower pressures. PMID- 23817213 TI - Deep brain stimulation for Parkinson's disease and other movement disorders. AB - PURPOSE OF REVIEW: Deep brain stimulation (DBS) is now widely used in the treatment of Parkinson's disease, tremor, and dystonia. This review examines recent developments in the application of DBS to the management of movement disorders. RECENT FINDINGS: In Parkinson's disease, recent work has demonstrated that early DBS may have a significant benefit on quality of life and motor symptoms while permitting a decrease in levodopa equivalent dosage. Thalamic DBS continues to be a well established target for the treatment of tremor, although recent work suggests that alternative targets such as the posterior subthalamic area may be similarly efficacious. The treatment of primary dystonia with DBS has been established in multiple recent trials, demonstrating prolonged symptomatic benefit. SUMMARY: DBS is now an established symptomatic treatment modality for Parkinson's disease and other movement disorders. Future work will undoubtedly involve establishing new indications and targets in the treatment of movement disorders with further refinements to existing technology. Ultimately, these methods combined with biologically based therapies may catalyze a shift from symptomatic treatment to actually modifying the natural history of neurodegenerative diseases such as Parkinson's disease. PMID- 23817215 TI - Adeno-associated virus 9 mediated FKRP gene therapy restores functional glycosylation of alpha-dystroglycan and improves muscle functions. AB - Mutations in the FKRP gene are associated with a wide range of muscular dystrophies from mild limb-girdle muscular dystrophy (LGMD) 2I to severe Walker Warburg syndrome and muscle-eye-brain disease. The characteristic biochemical feature of these diseases is the hypoglycosylation of alpha-dystroglycan (alpha DG). Currently there is no effective treatment available. In this study, we examined the adeno-associated virus serotype 9 vector (AAV9)-mediated gene therapy in the FKRP mutant mouse model with a proline to leucine missense mutation (P448L). Our results showed that intraperitoneal administration of AAV9 FKRP resulted in systemic FKRP expression in all striated muscles examined with the highest levels in cardiac muscle. Consistent with our previous observations, FKRP protein is localized in the Golgi apparatus in myofibers. Expression of FKRP consequently restored functional glycosylation of alpha-DG in the skeletal and cardiac muscles. Significant improvement in dystrophic pathology, serum creatine kinase levels and muscle function was observed. Only limited FKRP transgene expression was detected in kidney and liver with no detectable toxicity. Our results provided evidence for the utility of AAV-mediated gene replacement therapy for FKRP-related muscular dystrophies. PMID- 23817217 TI - Single-port laparoscopic retroperitoneal surgery using a modified single-port device in urology. AB - OBJECTIVES: To investigate the use of a flexible instrument platform in performing single-port laparoscopic retroperitoneal urologic surgeries and to verify the safety and feasibility of these surgeries. METHODS: The homemade instrument platform consisted of two control loops and a powder-free surgical glove to form multichannels. 56 patients underwent this kind of single-port surgery for different urologic diseases, including radical nephrectomy in 31 patients, nephroureterectomy in 7 patients, partial nephrectomy in 8 patients, living donor nephrectomy in 4 patients, adrenalectomy in 3 patients, renal cyst surgery in 2 patients and ureterolithotomy in 1 patient. RESULTS: All surgeries were completed successfully with no switch to conventional laparoscopic or open surgery. The mean hospital stay was 13.13 days (range 6-36). All patients were satisfied without major complications. CONCLUSIONS: Retroperitoneal laparoendoscopic single-site surgery using our cost-effective homemade instrument platform appears to be a feasible and safe surgical strategy to perform retroperitoneal laparoscopic urologic surgery. PMID- 23817216 TI - An infection-enhanced oncolytic adenovirus secreting H. pylori neutrophil activating protein with therapeutic effects on neuroendocrine tumors. AB - Helicobacter pylori neutrophil-activating protein (HP-NAP) is a major virulence factor involved in H. pylori infection. HP-NAP can mediate antitumor effects by recruiting neutrophils and inducing Th1-type differentiation in the tumor microenvironment. It therefore holds strong potential as a therapeutic gene. Here, we armed a replication-selective, infection-enhanced adenovirus with secretory HP-NAP, Ad5PTDf35-[Delta24-sNAP], and evaluated its therapeutic efficacy against neuroendocrine tumors. We observed that it could specifically infect and eradicate a wide range of tumor cells lines from different origin in vitro. Insertion of secretory HP-NAP did not affect the stability or replicative capacity of the virus and infected tumor cells could efficiently secrete HP-NAP. Intratumoral administration of the virus in nude mice xenografted with neuroendocrine tumors improved median survival. Evidence of biological HP-NAP activity was observed 24 hours after treatment with neutrophil infiltration in tumors and an increase of proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha and MIP2-alpha in the systemic circulation. Furthermore, evidence of Th1-type immune polarization was observed as a result of increase in IL-12/23 p40 cytokine concentrations 72 hours postvirus administration. Our observations suggest that HP-NAP can serve as a potent immunomodulator in promoting antitumor immune response in the tumor microenvironment and enhance the therapeutic effect of oncolytic adenovirus. PMID- 23817214 TI - The pallidopyramidal syndromes: nosology, aetiology and pathogenesis. AB - PURPOSE OF REVIEW: The aims of this review is to suggest a new nomenclature and classification system for the diseases currently categorized as neurodegeneration with brain iron accumulation (NBIA) or dystonia-parkinsonism, and to discuss the mechanisms implicated in the pathogenesis of these diseases. RECENT FINDINGS: NBIA is a disease category encompassing syndromes with iron accumulation and prominent dystonia-parkinsonism. However, as there are many diseases with similar clinical presentations but without iron accumulation and/or known genetic cause, the current classification system and nomenclature remain confusing. The pathogenetic mechanisms of these diseases and the causes of gross iron accumulation and significant burden of neuroaxonal spheroids are also elusive. Recent genetic and functional studies have identified surprising links between NBIA, Parkinson's disease and lysosomal storage disorders (LSD) with the common theme being a combined lysosomal-mitochondrial dysfunction. We hypothesize that mitochondria and lysosomes form a functional continuum with a predominance of mitochondrial and lysosomal pathways in NBIA and LSD, respectively, and with Parkinson's disease representing an intermediate form of disease. SUMMARY: During the past 18 months, important advances have been made towards understanding the genetic and pathological underpinnings of the pallidopyramidal syndromes with important implications for clinical practice and future treatment developments. PMID- 23817218 TI - Urine erythropoietin level is associated with kidney and brain injury in critically ill neonates. AB - BACKGROUND: Erythropoietin (EPO) is a glycoprotein hormone produced predominantly in the kidneys. The protective effect of exogenous EPO in hypoxic-ischemic brain injury has been thoroughly examined in neonates. However, the metabolism of endogenous EPO in neonates remains unclear. OBJECTIVES: We aimed to evaluate the concentration of urinary EPO (uEPO) in critically ill neonates and to identify possible clinical and laboratory variables that may be associated with uEPO levels. METHODS: The concentrations of EPO, cystatin-C, microalbumin, and alpha1 microglobulin in the first available urine sample during the initial 72 h of life were measured in 103 critically ill neonates. Clinical and laboratory data were collected for each neonate. RESULTS: There was a positive correlation between uEPO levels and urinary levels of cystatin-C (r = 0.265, p = 0.008), microalbumin (r = 0.422, p < 0.001), and alpha1-microglobulin (r = 0.421, p < 0.001). The concentration of uEPO was elevated in neonates who developed acute kidney injury (AKI) during the first week of life compared with those without AKI (p = 0.002) and was also elevated in neonates with brain injury, as demonstrated by ultrasound or magnetic resonance imaging, compared to neonates without brain injury (p = 0.008). An increased log10 uEPO level was associated with the occurrence of AKI (OR 2.70, p = 0.007) and brain injury (OR 2.33, p = 0.016). CONCLUSIONS: An increased urinary EPO level in the early postnatal period is significantly associated with kidney and brain injury in critically ill neonates. PMID- 23817219 TI - Temporal profile of matrix metalloproteinases and their inhibitors in a human endothelial cell culture model of cerebral ischemia. AB - BACKGROUND: Matrix metalloproteinases (MMPs) are key players in proteolytic blood brain barrier (BBB) disruption during ischemic stroke, leading to vascular edema, hemorrhagic transformation and infiltration by leukocytes. Their effect is dampened by the endogenous tissue inhibitors of metalloproteinases (TIMPs). The respective cellular source of specific MMPs and TIMPs during BBB breakdown is still under investigation. METHODS: We analyzed the MMP and TIMP release of human brain microvascular endothelial cells (BMECs) under oxygen glucose deprivation (OGD). Cultured human BMECs (the hCMEC/D3 cell line) were subjected to OGD (6, 12, 18 and 24 h). Gene expression of MMP-2, MMP-9, TIMP-1 and TIMP-2 were serially measured by quantitative real time-PCR and compared to ELISA-detected cell culture medium levels. RESULTS: OGD induced a significant and long-lasting increase in MMP-2 gene expression, reaching a plateau after 12 h. Medium protein levels of MMP-2 were correspondingly elevated at 12 h of OGD. The MMP-9 synthesis rate was detectable at very low levels and remained unaffected by OGD. TIMP-1 gene expression and secretion declined under OGD, whereas both expression and secretion of TIMP-2 remained stable. Contrary to the respective gene expression rate, medium levels of MMP-2, TIMP-1 and TIMP-2 started a simultaneous decline after 12 h of OGD. This is most likely due to an impaired synthesis and enhanced consumption rate under OGD. CONCLUSIONS: The objective of our study was to determine the contribution of human BMECs to the MMP metabolism under in vitro OGD conditions simulating ischemic stroke. Our results suggest that human BMECs switch to a proinflammatory state by means of an enhanced production of MMP-2, attenuated release of TIMP-1, and unaffected production of TIMP-2. Thus, human BMECs might participate in the MMP-mediated BBB breakdown during ischemic stroke. However, our data does not support human BMECs to be a source of MMP-9. PMID- 23817221 TI - Frequency and activation of CD4+CD25 FoxP3+ regulatory T cells in peripheral blood from children with atopic allergy. AB - BACKGROUND: Atopic allergy is among the immune tolerance-related disorders resulting from a failure of the regulatory network. Regulatory T cells (Tregs) play a leading role in the development of homeostasis in the immune system. The aim of this study was to determine the role of Tregs in the pathogenesis of atopic diseases in children by exploring the relationship between Treg frequency, activation markers and the clinical manifestations of the disease. METHODS: Twenty allergic and 50 healthy children were enrolled to the study. Peripheral blood mononuclear cells were stained with monoclonal antibodies (anti-CD25-CD4 CD127-FoxP3-CD69-CD71) and evaluated using flow cytometry. Tregs were identified as CD4+CD25(+/high)FoxP3+CD127- T cells. RESULTS: The percentage of Tregs in allergic patients (2.3%) was significantly decreased in comparison to healthy controls (4.6%, p = 0.003). The frequency of Tregs in patients with symptoms of atopic dermatitis and/or food allergy (1.7%) was significantly lower than in patients without these symptoms (2.9%, p = 0.04). A significant correlation between the percentage of Tregs and the sIgE serum concentration was observed (p = 0.037). Relative fluorescence intensities of FoxP3 expression in allergic patients were higher than in healthy controls (p = 0.00004). The frequency of CD4+CD25(high)CD127-CD71+ cells did not differ between the groups. CONCLUSIONS: Tregs display substantial deficiencies in atopic children, especially in children with multiorgan involvement, compared to patients with single organ manifestations. Additionally, there is an association between Tregs and the sIgE serum concentration. Better identification and characterization of Tregs in allergy is needed as they limit responses to foreign antigens, thereby minimizing T cell-mediated immunopathology in allergic diseases. PMID- 23817222 TI - Association of common gene variants in the WNT/beta-catenin pathway with colon cancer recurrence. AB - Wnt/beta-catenin signaling has a central role in the development and progression of most colon cancers (CCs). Germline variants in Wnt/beta-catenin pathway genes may result in altered gene function and/or activity, thereby causing inter individual differences in relation to tumor recurrence capacity and chemoresistance. We investigated germline polymorphisms in a comprehensive panel of Wnt/beta-catenin pathway genes to predict time to tumor recurrence (TTR) in patients with stage III and high-risk stage II CC. A total of 234 patients treated with 5-fluorouracil-based chemotherapy were included in this study. Whole blood samples were analyzed for putative functional germline polymorphisms in SFRP3, SFRP4, DKK2, DKK3, Axin2, APC, TCF7L2, WNT5B, CXXC4, NOTCH2 and GLI1 genes by PCR-based restriction fragment-length polymorphism or direct DNA sequencing. Polymorphisms with statistical significance were validated in an independent study cohort. The minor allele of WNT5B rs2010851 T>G was significantly associated with a shorter TTR (10.7 vs 4.9 years; hazard ratio: 2.48; 95% CI, 0.96-6.38; P=0.04) in high-risk stage II CC patients. This result remained significant in multivariate Cox's regression analysis. This study shows that the WNT5B germline variant rs2010851 was significantly identified as a stage dependent prognostic marker for CC patients after 5-fluorouracil-based adjuvant therapy. PMID- 23817223 TI - Possible mechanisms involved in subthalamotomy-induced dyskinesia in patients with Parkinson's disease. AB - BACKGROUND/AIMS: Operation-induced dyskinesia (OID) occurs in approximately 10% of patients submitted to subthalamotomy. The goal of the authors was to determine the possible causes of this feared complication. METHODS: The 54 patients who underwent unilateral subthalamotomy were divided into two groups: the OID group (OIDG), composed of 6 patients who developed dyskinesia following the operation, and the control group (CG), consisting of 48 patients who did not present this complication. The two groups were compared regarding age; sex; presence of levodopa-induced dyskinesia (LID) and/or stimulation-induced dyskinesia (SID); side of the operation; territories of the subthalamic nucleus (STN) involved by the lesion, and degree of lesion extension towards the zona incerta (ZI). RESULTS: The lesion involved the dorsolateral territory of the STN and was almost completely restricted to this nucleus in all patients of the OIDG, while it spread to the ZI in all but 1 patient of the CG. SID was significantly (p < 0.05) more frequent in the OIDG. There was also a strong trend favoring LID (p = 0.055). CONCLUSIONS: Damage to the dorsolateral territory of the STN and sparing of the ZI seem to be essential for the development of OID. SID and, to a lesser extent, LID are apparently significant risk factors for the development of this complication. PMID- 23817224 TI - Polyploidy in animals: effects of gene expression on sex determination, evolution and ecology. AB - Polyploidy is rarer in animals than in plants. Why? Since Muller's observation in 1925, many hypotheses have been proposed and tested, but none were able to completely explain this intriguing fact. New genomic technologies enable the study of whole genomes to explain the constraints on or consequences of polyploidization, rather than focusing on specific genes or life history characteristics. Here, we review a selection of old and recent literature on polyploidy in animals, with emphasis on the consequences of polyploidization for gene expression patterns and genomic network interactions. We propose a conceptual model to contrast various scenarios for changes in genomic networks, which may serve as a framework to explain the different evolutionary dynamics of polyploidy in animals and plants. We also present new insights of genetic sex determination in animals and our emerging understanding of how animal sex determination systems may hamper or enable polyploidization, including some recent data on haplodiploids. We discuss the role of polyploidy in evolution and ecology, using a gene regulation perspective, and conclude with a synopsis regarding the effects of whole genome duplications on the balance of genomic networks. See also the sister articles focusing on plants by Ashman et al. and Madlung and Wendel in this themed issue. PMID- 23817225 TI - Visible light-induced OH radicals in Ga2O3: an EPR study. AB - Reactive oxygen species (ROS) were found to exist in water suspensions of several metal oxide nanoparticles (NPs), such as CuO, TiO2 and ZnO. Visible light irradiation enhanced the capability of TiO2 and ZnO NPs to generate ROS, thus increasing their antibacterial effects. Because of the possible toxic effects on the host tissue it is desired to find nano-metal oxides which do not produce ROS under room light, but only upon a strong external stimulus. Using the technique of electron-spin resonance (ESR) coupled with spin trapping, we examined the ability of Ga2O3 submicron-particle suspensions in water to produce reactive oxygen species with and without visible light irradiation. We found that in contrast to ZnO and TiO2 NPs, no ROS are produced by Ga2O3 under room light. Nevertheless blue light induced hydroxyl radical formation in Ga2O3. This finding might suggest that NPs of Ga2O3 could be used safely for infected skin sterilization. PMID- 23817227 TI - In memoriam. Professor Antonio Liuzzi (1939-2013). PMID- 23817226 TI - Enhancement of autophagy by simvastatin through inhibition of Rac1-mTOR signaling pathway in coronary arterial myocytes. AB - BACKGROUND/AIMS: In addition to their action of lowering blood cholesterol levels, statins modulate biological characteristics and functions of arterial myocytes such as viability, proliferation, apoptosis, survival and contraction. The present study tested whether simvastatin, as a prototype statin, enhances autophagy in coronary arterial myocytes (CAMs) to thereby exert their beneficial effects in atherosclerosis. METHODS AND RESULTS: Using flow cytometry, we demonstrated that simvastatin significantly increased the autophagsome formation in CAMs. Western blot analysis confirmed that simvastatin significantly increased protein expression of typical autophagy markers LC3B and Beclin1 in these CAMs. Confocal microscopy further demonstrated that simvastatin increased fusion of autophagosomes with lysosomes, which was blocked by autophagy inhibitor 3 methyladenine or silencing of Atg7 genes. Simvastatin reduced mammalian target of rapamycin (mTOR) activity, which was reversed by Rac1-GTPase overexpression and the mTOR agonist phosphatidic acid. Moreover, both Rac1-GTPase overexpression and activation of mTOR by phosphatidic acid drastically blocked simvastatin-induced autophagosome formation in CAMs. Interestingly, simvastatin increased protein expression of a contractile phenotype marker calponin in CAMs, which was blocked by autophagy inhibitor 3-methyladenine. Simvastatin markedly reduced proliferation of CAMs under both control and proatherogenic stimulation. However, this inhibitory effect of simvastatin on CAM proliferation was blocked by by autophagy inhibitor 3-methyladenine or silencing of Atg7 genes. Lastly, animal experiments demonstrated that simvastatin increased protein expression of LC3B and calponin in mouse coronary arteries. CONCLUSION: Our results indicate that simvastatin inhibits the Rac1-mTOR pathway and thereby increases autophagy in CAMs which may stabilize CAMs in the contractile phenotype to prevent proliferation and growth of these cells. PMID- 23817228 TI - Fatty acid-binding protein 2 Ala54Thr genotype is associated with insulin resistance and leptin levels changes after a high monounsaturated fat diet in obese non-diabetic patients. AB - BACKGROUND: It has been found that the expression of fatty acid binding protein 2 (FABP2) mRNA is under dietary control. This polymorphism was associated with high insulin resistance, and fasting insulin concentrations. OBJECTIVE: The aim of our study was to investigate the influence of Thr54 polymorphism in the FABP2 gene on metabolic response, weight loss and serum adipokine levels secondary to a high monounsaturated fat hypocaloric diet. DESIGN: A sample of 122 obese patients was analyzed in a prospective way. The hypocaloric diet had 1342 kcal, 46.6% of carbohydrates, 34.1% of lipids and 19.2% of proteins, with a 67.5% of monounsaturated fats, and lasted 3 months. RESULTS: Fifty-five patients (45.1%) had the genotype Ala54/Ala54 (wild group) and 67 (64.9%) patients a mutant genotype, Ala54/Thr54 (54 patients, 44.3%) or Thr54/Thr54 (13 patients, 10.7%). In wild group, body mass index (-1.5+/-1.2 kg/m2), weight (-4.1+/-3.6 kg), fat mass (-3.6+/-3.3 kg), waist circumference (-4.9+/-2.9 cm), insulin (-1.7+/-3.6 mUI/l), homeostasis model assessment of insulin resistance (HOMA-IR) (-0.6+/-1.8 units) and leptin levels decreased (-7.6+/-7.1 ng/ml). In mutant group, anthropometric parameters improved, without changes in biochemical parameters. CONCLUSION: Carriers of Thr54 allele have a different response than wild type obese, with a lack of decrease of insulin levels, leptin levels and HOMA-IR. PMID- 23817229 TI - Insulin autoimmune syndrome induced by methimazole in a patient with Graves' disease. PMID- 23817230 TI - The outcomes of laparoscopic resection of bowel endometriosis. AB - PURPOSE OF REVIEW: To present the outcome of laparoscopic resection for bowel endometriosis. RECENT FINDINGS: In the last 12 months, numerous articles have been published to demonstrate and underline the efficiency and feasibility of the laparoscopic approach in the treatment of bowel endometriosis. SUMMARY: Endometriosis is a common condition that can affect women in their reproductive age. It can have an intestinal involvement, and when it occurs rectum and rectosigmoid junction are the most frequent sites; other lesser frequent sites are the appendix, the distal ileum, and the cecum. It is widely agreed that surgical management is the primary treatment for symptomatic bowel endometriosis. Laparoscopic bowel resection has become increasingly popular because it represents a well tolerated and feasible technique. PMID- 23817231 TI - Computed tomography and echocardiography together reveal more high-risk findings than echocardiography alone in the diagnostics of stroke etiology. AB - BACKGROUND: Cardioembolic stroke carries a major risk of stroke recurrence, which can be markedly reduced by early initiation of appropriate secondary prevention. We investigate whether combined examination of the heart, aorta, and cervicocranial arteries with computed tomography (CACC-CT) may improve the diagnosis of stroke etiology. METHODS: Patients with suspected cardiogenic ischemic stroke or transient ischemic attack (n = 140; mean age 60 +/- 10 years; 95 males) underwent CACC-CT and standard diagnostics including transthoracic and transesophageal echocardiography (TTE/TEE). Patients with atrial fibrillation were excluded because cardiac imaging will not affect to anticoagulant treatment. Imaging findings with a potential cardioembolic source were analyzed. Aortic and cardiac risk findings were evaluated independently. Consensus reading of 2 experts using the findings of both approaches and complemented by cardiac MRI when needed served as the reference standard. RESULTS: In 101 patients (72%) the clinical diagnosis was stroke, and transient ischemic attack was confirmed in the remaining patients. Imaging findings associated with highly increased cardioembolic risk were detected in 22 patients (16%). Nine high-risk findings in 140 patients were found by TTE/TEE and this number rose to 25 high after performing both echocardiography and CACC-CT. No difference was found between CACC-CT and TTE/TEE in detecting patients with of at least one high-risk findings (sensitivity 68 vs. 41%, p = 0.052; specificity 98 vs. 99%; overall accuracy 94 vs. 90%). Combined use of CACC-CT and TTE/TEE was more sensitive than TTE/TEE alone for detecting patients with at least one cardiac or aortic high-risk finding (sensitivity 91 vs. 41%, p < 0.001; specificity 98 vs. 99%; overall accuracy 97 vs. 90%). TTE/TEE was insufficient for diagnosing myocardial infarction with left ventricular aneurysm, whereas the accuracy of CACC-CT was high. In 9 patients (6%) with normal or mild hypokinesia in TTE/TEE, CACC-CT and MRI showed myocardial infarction large enough to indicate anticoagulant therapy. In contrast, CACC-CT was not suitable for diagnosing small left artrial thrombi, patent foramen ovale or to measure left ventricular ejection fraction. CONCLUSION: CACC-CT and TTE/TEE alone show limited accuracy for the diagnostics of stroke etiology. Therefore, CACC-CT could be a valuable tool in patients with cryptogenic stroke despite standard stroke diagnostics. PMID- 23817232 TI - Cerebral aspects of neonatal extracorporeal membrane oxygenation: a review. AB - BACKGROUND: Neonatal extracorporeal membrane oxygenation (ECMO) is a lifesaving therapeutic approach in newborns suffering from severe, but potentially reversible, respiratory insufficiency, mostly complicated by neonatal persistent pulmonary hypertension. However, cerebral damage, intracerebral hemorrhage as well as ischemia belong to the most devastating complications of ECMO. OBJECTIVES: The objectives are to give insights into what is known from the literature concerning cerebral damage related to neonatal ECMO treatment for pulmonary reasons. METHODS: A short introduction to ECMO indications and technical aspects of ECMO are provided for a better understanding of the process. The remainder of this review focuses on outcome and especially on (potential) risk factors for cerebral hemorrhage and ischemia during ECMO treatment. RESULTS: Although neonatal ECMO treatment shows improved outcome compared to conservative treatment in cases of severe respiratory insufficiency, it is related to disturbances in various aspects of neurodevelopmental outcome. Risk factors for cerebral damage are either related to the patient's disease, EMCO treatment itself, or a combination of both. CONCLUSION: It is of ongoing importance to further understand pathophysiological mechanisms resulting in cerebral hemorrhage and ischemia due to ECMO and to develop neuroprotective strategies and approaches. PMID- 23817234 TI - A wake-up call for hibernating tumour cells. AB - Disseminated tumour cells (DTCs) can adopt a state of long-term dormancy. However, when and why they emerge from quiescence has remained unclear. Distinct microvascular niches are now shown to regulate this process. Mature blood vessels produce signals that sustain tumour cell quiescence, whereas sprouting microvasculature provides stimuli that reactivate DTCs, leading to metastatic relapse. PMID- 23817233 TI - Emerging regulation and functions of autophagy. AB - Autophagy maintains cell, tissue and organism homeostasis through degradation. Complex post-translational modulation of the Atg (autophagy-related) proteins adds additional entry points for crosstalk with other cellular processes and helps define cell-type-specific regulations of autophagy. Beyond the simplistic view of a process exclusively dedicated to the turnover of cellular components, recent data have uncovered unexpected functions for autophagy and the autophagy related genes, such as regulation of metabolism, membrane transport and modulation of host defenses--indicating the novel frontiers lying ahead. PMID- 23817235 TI - Finding the shape-shifter genes. AB - Cell morphological plasticity is controlled by intracellular signalling pathways. By combining large-scale imaging with quantitative analysis, an RNA interference (RNAi) screen in Drosophila melanogaster haemocytes reveals that most targeted genes regulate transitions between discrete shapes. Loss of gene function changes shape frequencies or reduces diversity, rather than producing new morphologies. PMID- 23817236 TI - Sequential addition of reprogramming factors improves efficiency. AB - Addition of a specific set of transcription factors reprograms somatic cell nuclei to a pluripotent state. Sequential addition of these factors, rather than the simultaneous exposure used in standard protocols, improves reprogramming efficiency. This sequential method favours a transition through a state with enhanced mesenchymal characteristics before driving an epithelial transformation on the way to the pluripotent state. PMID- 23817237 TI - ULK1 targets Beclin-1 in autophagy. AB - The substrates of mammalian ULK1/2 and its yeast homologue Atg1 in autophagy have remained elusive. The class III phosphatidylinositol 3-kinase component Beclin-1 has now been identified as a physiological substrate of the ULK kinases in autophagy following amino acid starvation, therefore suggesting a critical molecular link between the upstream kinases and the autophagy core machinery. PMID- 23817242 TI - Insights into the evolutionary history of the X-linked sex reversal mutation in mus minutoides: clues from sequence analyses of the Y-linked Sry gene. AB - The African pygmy mouse, Mus minutoides, is one of the very few mammal species that deviates from the classical mammalian XX/XY sex chromosome system by presenting a high proportion of fully fertile sex-reversed females. Since the still unknown sex reversal mutation is X-linked (X*), they are designated as X*Y females. Until now, X*Y females had only been identified in Southern Africa, but data were lacking for the rest of the vast sub-Saharan distribution range of this species. In this study, the PCR genotyping of the Y-linked Sry gene on 72 females from Western Africa (Guinea, Ivory Coast and Ghana) uncovered 10 sex-reversed females distributed in the 3 countries. This expands our understanding of the geographical distribution and temporal origin (dated at 0.9 mya) of the sex reversal mutation. In addition, we sequenced and analyzed a fragment of the Sry gene (including the complete high-mobility group, i.e. HMG box, and the partial C terminal region). The results demonstrate the presence of multiple polymorphic copies of the gene as reported in other rodent species and reveal, more unexpectedly, an extremely high proportion of amino acid replacement within the HMG box. In effect, the predicted HMG box protein sequence similarity between some populations of M. minutoides is as low as 94.9%, and at the interspecific level (within genus), it drops to only 91.1% between M. minutoides and M. musculus. PMID- 23817243 TI - First-principles studies on transport properties and contact effects of Cu(111)/ZnO-nanobelt(1010)/Cu(111) systems. AB - The transport properties of ZnO nanobelts along the (101-0) non-polarized direction coupled with Cu electrodes were studied via non-equivalent Greens functions method and density functional theory formalism. The transport properties were greatly affected by interfacial spacing and nanobelt widths. The conductance decreased exponentially with the widths of the nanobelts. Ohmic behavior was found in narrow nanobelts, while rectifying characteristics were observed in wide nanobelts. In the case of narrow belts, the current-voltage characteristics were changed from ohmic type to rectifying characteristics as the interspace increased, corresponding to the contacts transforming from chemical to physical interactions. However, the conductance in the wider nanobelts declined exponentially as the interfacial distance increased. The change of metal induced gap states (MIGS) depends strongly on the interfacial distance but not significantly on the thickness of ZnO nanobelts. An n-type Schottky barrier between copper and ZnO nanobelts is induced by interfacial polarization effects. The Schottky barrier heights for the narrowest and widest nanobelts with equilibrium interfacial spacing were 0.37 eV and 0.44 eV, respectively, which is in good agreement with the experimental values. Additionally, the Schottky barrier heights increased almost linearly as the width of the nanobelts changed from 0.34 nm to 1.2 nm. PMID- 23817244 TI - Brains to comprehend. PMID- 23817245 TI - [Physicians' ethical dilemmas]. PMID- 23817246 TI - [Alternative interpretation of the term patient]. PMID- 23817247 TI - [The patient concept from the view of the patient]. PMID- 23817248 TI - [E. Hem replies]. PMID- 23817249 TI - [Acute phase proteins and/or iron storage]. PMID- 23817250 TI - [R. J. Ulvik replies]. PMID- 23817252 TI - [Application based internship--who should get the job?]. PMID- 23817253 TI - [Expert statements and judgment in the 22 July case--what can we learn?]. PMID- 23817254 TI - [Public health compromise]. PMID- 23817255 TI - [Do donor children need to know?]. PMID- 23817256 TI - [Unexplained syncopes]. PMID- 23817257 TI - [Is the role of the family too comprehensive?]. PMID- 23817259 TI - Cultural and musical activity among Norwegian doctors. AB - BACKGROUND: The cultural and musical activity of Norwegian doctors was studied in 1993. We wished to re-examine their cultural and musical activity, analyse the development and study the correlation with satisfaction, health and other leisure activities. MATERIAL AND METHOD: In the autumn of 2010, a survey was undertaken among a representative sample of economically active Norwegian doctors. The survey asked the same questions as in 1993, and the responses were also compared to the population studies conducted by Statistics Norway. We also used a cultural index that we have developed ourselves. RESULTS: Altogether 1,019 doctors (70%) responded to the survey. They reported a higher level of cultural activity in 2010 than in 1993, measured in terms of reading of non-medical literature and visits to the cinema, theatre and concerts. The doctors engaged in musical activity of their own especially frequently: 58% reported to be able to play an instrument, and 21% reported to play on a regular basis, which is more than among other academic professions. We found a significant correlation between the doctors' level of cultural activity and their job satisfaction, general satisfaction, self-reported health and physical activity. The doctors who engage most frequently in cultural activities are thus most satisfied with their work and with life in general. Furthermore, they also have better self-reported health. INTERPRETATION: Norwegian doctors give priority to cultural and musical activities. The assertion that doctors are particularly fond of music is more than just a myth. PMID- 23817260 TI - Moral distress and professional freedom of speech among doctors. AB - BACKGROUND: Previous studies indicate that Norwegian doctors experience distress in their encounter with differing and partly contradictory ideals, such as the obligation to criticise unethical and inappropriate practices. The objective of this study was to investigate the perception of moral distress and professional freedom of speech among Norwegian doctors as of today, as well as identify changes that have occurred since the previous study undertaken in 2004. MATERIAL AND METHODS: A total of 1,522 economically active doctors received a questionnaire listing various statements describing the perception of moral distress and professional freedom of speech. The responses were compared to responses to the 2004 study. RESULTS: Altogether 67% of the doctors responded to the questionnaire. The proportion who reported "fairly strong" or "strong" moral distress varied from 24% to 70% among the different statements. On the whole, the "rank and file" hospital doctors reported the highest degree of moral distress. Nevertheless, a decrease in the scores for moral distress could be observed from 2004 to 2010. During the same period, the perception of professional freedom of speech increased slightly. INTERPRETATION: A reduced level of distress associated with ethical conflicts in working life may be due to improved methods for handling distressing situations, or because the consequences of the health services reorganisations are perceived as less threatening now than in 2004, immediately after the introduction of the hospital reform. However, the perceived lower distress level may also be due to professional and ethical resignation. These findings should be followed up by a qualitative study. PMID- 23817261 TI - [Minimal head injury that got acutely worse]. PMID- 23817262 TI - [Treatment with statins]. PMID- 23817263 TI - A man in his 60s with chest pain and pareses. PMID- 23817264 TI - When every minute counts. PMID- 23817265 TI - [New knowledge about narcolepsy in children]. PMID- 23817266 TI - Time for new thinking on psychiatric diagnoses. PMID- 23817267 TI - [Andre Bjerke and psychoanalysis]. PMID- 23817268 TI - [Two children in Kristin Lavransdatter monastery]. PMID- 23817269 TI - [Magpie's nest and a Marna 8-12 gas engine]. PMID- 23817270 TI - [Where are you?]. PMID- 23817271 TI - [The Rosenborg case and physicians' roles in financial claims]. PMID- 23817274 TI - Digital compressive chemical quantitation and hyperspectral imaging. AB - Digital compressive detection, implemented using optimized binary (OB) filters, is shown to greatly increase the speed at which Raman spectroscopy can be used to quantify the composition of liquid mixtures and to chemically image mixed solid powders. We further demonstrate that OB filters can be produced using multivariate curve resolution (MCR) to pre-process mixture training spectra, thus facilitating the quantitation of mixtures even when no pure chemical component samples are available for training. PMID- 23817275 TI - Mapping of the immunodominant regions of shrimp tropomyosin Pan b 1 by human IgE binding and IgE receptor crosslinking studies. AB - BACKGROUND: Epitope mapping of an allergen is generally done by IgE-binding assays with short synthetic peptides, but this provides little information about which domains are responsible for IgE receptor crosslinking on effector cells. Our aim was to map the immunodominant regions of shrimp tropomyosin by both IgE binding and IgE-receptor crosslinking studies. METHODS: Five overlapping fragments covering Pandalus borealis tropomyosin were cloned, expressed in Escherichia coli and characterized by circular dichroism spectroscopy, native PAGE and bis(sulfosuccinimidyl) suberate-crosslinking. IgE binding was detected by Western blot, indirect ELISA and inhibition ELISA, and IgE receptor crosslinking was investigated by basophil activation test and skin prick test with Norwegian shrimp allergic adults. RESULTS: The N- and C-terminal fragments of tropomyosin showed the highest amount of secondary structure. Western blot studies showed preferential binding to the terminal fragments, while indirect and inhibition ELISA studies showed binding to all fragments, but with individual variations. Basophil CD63 expression was upregulated by all fragments at high concentrations (1 ug/ml) and showed individual variations comparable to ELISA results. A mixture of the fragments with equal molar ratios induced comparably strong CD63 activation as for tropomyosin. Skin prick test studies showed positive responses to the terminal and middle fragments and increased responses to the fragment mixture compared to whole tropomyosin. CONCLUSIONS: The terminal and middle fragments of tropomyosin had the highest IgE reactivity, but overall no clear immunodominant region was observed in this study. These results correlated well with previous studies with short peptides. Dividing shrimp tropomyosin into five fragments did not reduce the allergenicity of the protein. PMID- 23817276 TI - Cutaneous adverse drug reaction to oral acetazolamide and skin tests. AB - BACKGROUND: Few cases of cutaneous adverse drug reactions (CADR) to oral acetazolamide, a non-antimicrobial sulfonamide, have been previously reported, and the interest of acetazolamide skin tests has never been studied. OBJECTIVES: We report a series of ten patients with oral acetazolamide CADR and skin tests. PATIENTS AND METHODS: The files of ten patients with CADR secondary to oral acetazolamide prescribed for cataract surgery in most cases referred between 2001 and 2011 in four French dermatology and allergy departments were retrospectively reviewed. Skin tests with acetazolamide were performed in nine patients and twelve controls. Other sulfonamides were tested in five of ten patients. RESULTS: Seven patients developed maculopapular exanthema and four had acute generalized exanthematous pustulosis. Patch tests were positive for 8/9 patients, prick tests for 2/4 and intradermal tests for 3/3. Patch and prick or intradermal test results were concordant in 2/3 positive subjects. Patch tests for other sulfonamides were negative, as were patch tests in controls. CONCLUSIONS: We report the largest series of CADR to oral acetazolamide (maculopapular exanthema or acute generalized exanthematous pustulosis). A drug eruption after cataract surgery should be investigated for accountability of acetazolamide. In view of this retrospective study, skin tests and particularly intradermal tests appear to be an important contribution to demonstrate accountability. PMID- 23817277 TI - The inhibition of inwardly rectifying K+ channels by memantine in macrophages and microglial cells. AB - BACKGROUND/AIMS: Memantine (MEM) can block N-methyl-D-aspartate receptors non competitively and is recognized to exert anti-inflammatory action. Whether MEM and other related compounds produce any effects on K(+) currents in macrophages and in microglial cells is largely unknown. In this study, we investigated the effects of MEM and other related compounds on inwardly rectifying K(+) current (IK(IR)) in RAW 264.7 macrophages and in BV2 microglial cells. METHODS: Patch clamp recordings under whole-cell, cell-attached or inside-out configuration were performed in standard patch-clamp technique. MEM suppressed the IK(IR) amplitude in a concentration-dependent manner with an IC50 value of 12 uM. RESULTS: This agent significantly slowed the inactivation time rate of IK(IR) evoked with membrane hyperpolarization. In cells dialyzed spermine (10 uM), MEM-mediated inhibition of IK(IR) no longer existed. MEM-suppressed activity is associated with a decrease in the slow component of mean open time and an increase in mean closed time, despite no detectable change in single-channel conductance of inwardly rectifying K(+) (Kir) channels. Under current-clamp conditions, the addition of MEM resulted in membrane depolarization of RAW 264.7 cells. Similarly, in BV2 microglial cells, addition of MEM suppressed IK(IR) as well as depolarized the membrane. However, neither C6 astrocytic cells nor Jurkat T lymphoces were noted to display IK(IR). CONCLUSION: The block by MEM of Kir2.1 channels is thus one of the important mechanisms underlying its actions on the functional activities of either macrophages or microglial cells, if similar findings occur in vivo. PMID- 23817278 TI - Nursing research and the global burden of noncommunicable diseases. PMID- 23817280 TI - Impact of patient-level risk adjustment on the findings about nurse staffing and 30-day mortality in veterans affairs acute care hospitals. AB - BACKGROUND: Studies about nurse staffing and patient outcomes often lack adequate risk adjustment because of limited access to patient information. OBJECTIVE: The aim of this study was to examine the impact of patient-level risk adjustment on the associations of unit-level nurse staffing and 30-day inpatient mortality. METHODS: This retrospective cross-sectional study included 284,097 patients discharged during 2007-2008 from 446 acute care nursing units at 128 Veterans Affairs medical centers. The association of nurse staffing with 30-day mortality was assessed using hierarchical logistic models under three levels of risk adjustment conditions: using no patient information (low), using patient demographics and diagnoses (moderate), or using patient demographics and diagnoses plus physiological measures (high). RESULTS: Discriminability of the models improved as the level of risk adjustment increased. The c-statistics for models of low, moderate, and high risk adjustment were 0.64, 0.74, and 0.88 for non-ICU patients and 0.66, 0.76, and 0.88 for ICU patients. For non-ICU patients, higher RN skill mix was associated with lower 30-day mortality across all three levels of risk adjustment. For ICU patients, higher total nursing hours per patient day was strongly associated with higher mortality with moderate risk adjustment (p = .0002), but this counterintuitive association was not significant with low or high risk adjustment. DISCUSSION: Inadequate risk adjustment may lead to biased estimates about nurse staffing and patient outcomes. Combining physiological measures with commonly used administrative data is a promising risk adjustment approach to reduce potential biases. PMID- 23817279 TI - Daytime observed emotional expressions of people with dementia. AB - BACKGROUND: Emotional expression among people with dementia (PWD) may inform person-centered approaches to care and improvements in dementia-related quality of life. OBJECTIVES: The aim of this study was to examine frequency and variability of positive and negative emotional expressions, personal factors influencing positive and negative emotional expressions, and trajectories of emotional expression among PWD during daytime hours. METHODS: We conducted a secondary analysis of daytime positive and negative emotional expressions of 30 PWD living in residential long-term care who completed twelve 20-minute observation periods occurring hourly as part of a multi-site study of wandering behavior. Hierarchical linear modeling was used to examine relationships between influencing factors and frequency of emotional expressions; group-based trajectory analysis was applied to identify clusters of individuals with similar daytime patterns of emotional expression. RESULTS: Time of day (rate ratio [RR] = 1.05) and impaired mobility (RR = 1.37) significantly influenced positive emotional expression; gender (RR = 1.85), age (RR = 1.03), and education (RR = 0.54) were significantly related to negative emotional expression. Three distinct trajectory groups were identified for positive emotional expression: a low stable group, a fluctuating group displaying afternoon peaking, and a fluctuating group displaying morning peaking. Two trajectory groups were identified for negative emotional expression: a consistent pattern and an inconsistent pattern. DISCUSSION: PWD showed a broad range of emotional expression and significant within-person variation in daytime positive and negative emotional expressions. Observed emotional display is a promising measure of psychological well-being among PWD that, if more fully understood, could guide care approaches to improve quality of life. PMID- 23817281 TI - Cumulative poor psychosocial and behavioral health among low-income women at 6 weeks postpartum. AB - BACKGROUND: During the postpartum period, women may experience unfavorable psychosocial and behavioral health in multiple domains with adverse effects on parenting and maternal and infant health. Yet, little is known about the accumulation of poor health across the domains of depressive symptoms; body image; diet and physical activity; substance use including smoking and alcohol; and general self-care at 6 weeks postpartum, the usual end of maternity care. OBJECTIVES: The aims of this study were to evaluate relationships among the domains comprising psychosocial and behavioral health and to examine the distribution and risk factors associated with cumulative poor psychosocial and behavioral health at 6 weeks postpartum. METHODS: This study was a secondary analysis of cumulative poor health assessed by self-report scales for depressive symptoms, body image dissatisfaction, diet and exercise, substance use, and general self-care among 419 low-income White, African American, and Hispanic women at 6 weeks postpartum. Multivariable Poisson and logistic regression were used in key analyses. RESULTS: The correlation among psychosocial and behavioral domains had a range of r = .50-.00. In this sample of women, 45% had two or more domains in which they had poor health. The model testing risk factors for cumulative poor health was significant (likelihood ratio chi-square = 39.26, df = 11, p < 0.05), with two significant factors: not exclusively breastfeeding (odds ratio [OR] = 1.459, 95% confidence interval [CI] [1.119, 1.901]) and Hispanic ethnicity (OR = 0.707, 95% CI [0.582, 0.858], psuedo-R = .029). Within individual domains, significant risk factors (body mass index, not exclusively breastfeeding, ethnicity, education level, and parity) varied by domain. DISCUSSION: Many low-income women postpartum have poor psychosocial and behavioral health in multiple domains, which constitute areas for health promotion and early disease prevention. PMID- 23817282 TI - Pretreatment predictors of short-term nonadherence to oral hormonal therapy for women with breast cancer. AB - BACKGROUND: Adjuvant treatment with oral hormonal therapy improves clinical outcomes for breast cancer, but women have difficulty adhering to the 5-year regimen. OBJECTIVE: The aim of this study was to explore pretreatment predictors of short-term nonadherence to oral hormonal therapy for women with early-stage breast cancer from the pretreatment assessment to 6 months after initiation of hormonal therapy. METHODS: A secondary analysis was performed using data collected from 198 women enrolled in one of two longitudinal studies. Nonadherence was defined as the percentage of prescribed doses of hormonal therapy not taken during the first 6 months of therapy measured using electronic medication event monitoring. Information on predictor variables was measured at pretreatment using self-report and medical record review. Linear regression analysis was performed to examine associations between predictor variables and 6 month nonadherence in a bivariate manner to first identify candidate predictors variables at p < .20 and then multivariately considering candidate predictors identified through stepwise and backward elimination regression methods. RESULTS: Participants were White (98.3%), well educated (M = 15.0; SD = 2.9 years of schooling), and on average, 59.1 years old (SD = 7.5 years old). Mean nonadherence was 11.3%. Stepwise and backward elimination modeling algorithms identified a similar set of predictors associated with 6-month nonadherence and explained 13.0% of the variance (adjusted R = .11, standard error of the estimate = 0.28). Ductal carcinoma in situ tumor type (p = .004) and higher weight concern scores (p = .003) were associated with nonadherence. DISCUSSION: The findings suggest that additional examinations of associations of tumor type and symptom burden with nonadherence are indicated. PMID- 23817283 TI - Obese women's perceptions and experiences of healthcare and primary care providers: a phenomenological study. AB - BACKGROUND: Nearly two thirds of the adult population in the United States is overweight or obese. Adults who are overweight or obese require the same high quality healthcare from their providers as any other adult. Unfortunately, stigma is a reality experienced by individuals who are overweight or obese, and healthcare professionals' views have sometimes been reported to be biased against individuals who are overweight or obese. However, there are gaps and inconsistencies in the literature regarding the types of experiences and perceptions of obese women receiving healthcare and whether stigma is present. OBJECTIVE: The aim of this study was to describe the experiences and perceptions of obese women with regard to stigma in healthcare and from their healthcare provider. METHODS: A phenomenological research approach using the Colaizzi method was utilized to examine and describe the lived experience of overweight and obese women with healthcare. Semistructured interviews were conducted with a diverse, purposive sample of 26 English-speaking women with a body mass index of over 30 kg/m. Participants were asked to describe their perceptions and experiences with regard to healthcare and their relationship with their healthcare providers. RESULTS: Four themes emerged from the analysis of the data: (a) perceptions of health and healthcare, (b) respect me as a person, (c) establishing a healthcare connection, and (d) assertiveness is necessary. Although stigma was not named by women in this study, all acknowledged some negative treatment by healthcare providers. DISCUSSION: Discussion relating to the current professional literature is presented. Implications for nursing education and research are discussed. PMID- 23817284 TI - Nurse care coordination and technology effects on health status of frail older adults via enhanced self-management of medication: randomized clinical trial to test efficacy. AB - BACKGROUND: Self-management of complex medication regimens for chronic illness is challenging for many older adults. OBJECTIVES: The purpose of this study was to evaluate health status outcomes of frail older adults receiving a home-based support program that emphasized self-management of medications using both care coordination and technology. DESIGN: This study used a randomized controlled trial with three arms and longitudinal outcome measurement. SETTING: Older adults having difficulty in self-managing medications (n = 414) were recruited at discharge from three Medicare-certified home healthcare agencies in a Midwestern urban area. METHODS: All participants received baseline pharmacy screens. The control group received no further intervention. A team of advanced practice nurses and registered nurses coordinated care for 12 months to two intervention groups who also received either an MD.2 medication-dispensing machine or a medplanner. Health status outcomes (the Geriatric Depression Scale, Mini Mental Status Examination, Physical Performance Test, and SF-36 Physical Component Summary and Mental Component Summary) were measured at baseline and at 3, 6, 9, and 12 months. RESULTS: After covariate and baseline health status adjustment, time * group interactions for the MD.2 and medplanner groups on health status outcomes were not significant. Time * group interactions were significant for the medplanner and control group comparisons. DISCUSSION: Participants with care coordination had significantly better health status outcomes over time than those in the control group, but addition of the MD.2 machine to nurse care coordination did not result in better health status outcomes. PMID- 23817285 TI - Cost effectiveness analysis for nursing research. AB - BACKGROUND: With ever-increasing pressure to reduce costs and increase quality, nurses are faced with the challenge of producing evidence that their interventions and care provide value. Cost effectiveness analysis (CEA) is a tool that can be used to provide this evidence by comparative evaluation of the costs and consequences of two or more alternatives. OBJECTIVES: The aim of this article is to introduce the essential components of CEA to nurses and nurse researchers with the protocol of a recently funded cluster randomized controlled trial as an example. METHODS: This article provides (a) a description of the main concepts and key steps in CEA and (b) a summary of the background and objectives of a CEA designed to evaluate a nursing-led pain and symptom management intervention in rural communities compared with the current usual care. DISCUSSION: As the example highlights, incorporating CEA into nursing research studies is feasible. The burden of the additional data collection required is offset by quantitative evidence of the given intervention's cost and impact using humanistic and economic outcomes. At a time when U.S. healthcare is moving toward accountable care, the information provided by CEA will be an important additional component of the evidence produced by nursing research. PMID- 23817286 TI - Survey methods and response rates among rural community dwelling older adults. AB - BACKGROUND: Rural older adults are not often targeted for surveys, and little is known about survey response rates in this population. Because overall numbers of rural older adults are small, it is important to consider techniques to improve their survey response rates. OBJECTIVES: The purpose of this study was to work with community partners to determine whether rural older adults participating in a rural county home-delivered meals program were more likely to respond to an injury risk survey hand-delivered via the postal service or hand-delivered by the home-delivered meals drivers. METHODS: All home-delivered meals clients older than 65 years old were randomized to one of two groups. One group (n = 70) received the following via the postal service: a prenotice letter, a survey packet containing a description of the survey, the survey, a stamped and addressed return envelope, and a reminder/thank-you card. Older adults in the other group (n = 69) were personally handed the survey packet by the home delivered meals driver. RESULTS: The overall survey response rate was 43.9%. Older adults who were handed the survey packets by the home-delivered meals drivers were older and significantly more likely to return the survey (57%) compared with those who received survey materials in the mail (31%). Only 27% of respondents agreed to be contacted regarding participation in future face-to-face interviews. When taking into account response rates, postage costs alone were over five times higher for the postal-delivered surveys compared with the hand delivered surveys. DISCUSSION: By working with community partners, we were able to determine that older adults in a rural community were more likely to respond to surveys personally handed to them by someone they knew. PMID- 23817287 TI - Nutrition: Are mild maternal iodine deficiency and child IQ linked? PMID- 23817288 TI - Metabolism: gut microbiota modulates diurnal secretion of glucocorticoids. AB - A new study has identified the sophisticated communication between the gut microbiota and intestinal epithelial cells that controls diurnal variations in the secretion of corticosteroids in mice. The absence of gut bacteria disrupts this communication and contributes to hypertriglyceridaemia, hyperglycaemia and insulin resistance. PMID- 23817289 TI - Diabetes: Human beta-cell proliferation by promoting Wnt signalling. PMID- 23817291 TI - Thyroid gland: Mutations identified in thyroid cancer. PMID- 23817290 TI - Current and future applications of GnRH, kisspeptin and neurokinin B analogues. AB - Reproductive hormones affect all stages of life from gamete production, fertilization, fetal development and parturition, neonatal development and puberty through to adulthood and senescence. The reproductive hormone cascade has, therefore, been the target for the development of numerous drugs that modulate its activity at many levels. As the central regulator of the cascade, gonadotropin-releasing hormone (GnRH) agonists and antagonists have found extensive applications in treating a wide range of hormone-dependent diseases, such as precocious puberty, prostate cancer, benign prostatic hyperplasia, endometriosis and uterine fibroids, as well as being an essential component of in vitro fertilization protocols. The neuroendocrine peptides that regulate GnRH neurons, kisspeptin and neurokinin B, have also been identified as therapeutic targets, and novel agonists and antagonists are being developed as modulators of the cascade upstream of GnRH. Here, we review the development and applications of analogues of the major neuroendocrine peptide regulators of the reproductive hormone cascade: GnRH, kisspeptin and neurokinin B. PMID- 23817292 TI - Cancer: Novel target to enhance radioiodine uptake in thyroid cancer. PMID- 23817293 TI - Soft tissue reconstruction of the oral cavity: a review of current options. AB - PURPOSE OF REVIEW: This article provides an overview of the principles of soft tissue reconstruction of the oral cavity, and reviews the recent clinical outcomes for described options. RECENT FINDINGS: For small defects of the oral cavity, healing by secondary intention and primary closure are both excellent options and may provide functionally superior results. In defects where a split thickness skin graft is appropriate, acellular dermis may provide results that are at least as good at lower cost. Free flaps, particularly the radial forearm and the anterolateral thigh, have become the mainstays of oral cavity soft tissue reconstruction for larger defects. Recent clinical series suggest that relatively novel regional flaps provide a reasonable alternative to free flap reconstructions for moderate and some large soft tissue defects. SUMMARY: Soft tissue reconstruction of the oral cavity is a complex task with significant functional implications. There are a large number of reconstructive options available. Systematic appraisal of the defect and options allows the reconstructive surgeon to optimize functional potential by choosing the most appropriate reconstructive option. PMID- 23817294 TI - Cytogenetic Nomenclature: Changes in the ISCN 2013 Compared to the 2009 Edition. AB - The latest edition of the International System for Human Cytogenetic Nomenclature, ISCN 2013, has recently been published following a thorough revision of the 2009 issue and the incorporation of suggestions from the community by the current standing committee. This review will highlight the multiple nomenclature changes in the respective chapters of the 2013 version compared to the previous version of the ISCN published in 2009. These highlights are meant as a guide for the cytogeneticist to assist in the transition in the use of this updated nomenclature for describing cytogenetic and molecular cytogenetic findings in both clinical and research reports. PMID- 23817295 TI - The effects of oral carvacrol treatment against H2O2 induced injury on isolated pancreas islet cells of rats. AB - Pancreatic islet transplantation is an alternative treatment of insulin replacement therapy in diabetes mellitus, but the islets are exposed to many chemical, mechanical damages, and oxidative stress before transplantation. Carvacrol is a well-known essential oil for its antioxidant, antimicrobial, antifungal and antiinflammatory properties. The aim of this study was to investigate the possible protective effects of carvacrol against H 2O 2 induced cellular injury on isolated pancreas islets. After carvacrol (20, 40 and 80 mg/kg/day) treatment, the pancreas islets were isolated by enzyme digestion. The isolated islets were incubated within 0, 150 and 300 uM H 2O 2 containing medium at +4 degrees C for 15 min. Then, the islets were examined with fluorescein diacetate and propidium iodide mixture stains for viability. A number of islets were stored for lipid peroxidation, protein oxidation and DNA fragmentation analysis. The cell viability ratio of Carvacrol 20 mg/kg/day group was increased in comparison to control and vehicle (DMSO) groups. Additionally, carvacrol application protected the cells from lipid peroxidation and protein oxidation induced by H 2O 2. H 2O 2 caused tissue injury and DNA fragmentation. There was only one DNA fragmentation band from islet cells of 20 mg/kg/day carvacrol treated group, however there were more than one bands from control and DMSO groups. In conclusion, carvacrol treatment ameliorates islet cell injury induced by H 2O 2. However, the dose of carvacrol is important and our results suggest that 20 mg/kg/day dose is more effective than doses of 40 or 80 mg/kg/day. PMID- 23817296 TI - Evidence for the involvement of GPR40 and NADPH oxidase in palmitic acid-induced superoxide production and insulin secretion. AB - G protein coupled receptor 40 (GPR40) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex have been shown to be involved in the fatty acid amplification of glucose-stimulated insulin secretion (GSIS). The effect of palmitic acid on superoxide production and insulin secretion by INS-1E cells and the possible involvement of GPR40 and NADPH oxidase in these processes were examined in this study. Cells were incubated during 1 h with palmitic acid in low and high glucose concentrations, a GPR40 agonist (GW9508) and inhibitors of NADPH oxidase (diphenyleneiodonium, DPI) and PKC (calphostin C). GW9508 induced superoxide production at 2.8 and 5.6 mM glucose concentrations and stimulated insulin secretion at 16.7 mM glucose concentration involving both PKC and NADPH oxidase activation. Palmitic acid induced superoxide production through NADPH oxidase and GPR40-dependent pathways and the stimulation of insulin secretion in the presence of a high glucose concentration was reduced by knockdown of GPR40 using siRNA. Our results suggest that palmitic acid induces superoxide production and potentiates GSIS through NADPH oxidase and GPR40 pathways in pancreatic ? cells. PMID- 23817297 TI - Stability issues in Pd-based catalysts: the role of surface Pt in improving the stability and oxygen reduction reaction (ORR) activity. AB - Carbon-supported Pd and Pd3Co catalysts have been electrochemically characterized in 0.1 M HClO4 solution and we found that both catalysts were unstable. On repeated potential cycling, the electrochemical surface area of the catalysts decreases and the oxygen reduction reaction (ORR) activity suffers. To stabilize surface Pd atoms of both Pd and Pd3Co catalysts, we deposited Pt using adsorbed hydrogen on the catalytically active Pd sites. The Pt : Pd ratio of Pt-coated Pd and Pt-coated Pd3Co catalysts suggests half-a-monolayer coverage of Pt (two hydrogen atoms required for reducing a Pt(2+) ion). The Pt : Pd ratio of Pt coated Pd3Co catalyst obtained from the simple geometrical hard sphere model, energy-dispersive X-ray spectroscopy (EDS) line scan and bulk EDS agrees very well with that calculated from the hydrogen desorption (H(des)) charge of Pd3Co. At the same time, the Pt : Pd ratio of Pt-coated Pd calculated from the H(des) charge of Pd catalyst is significantly lower than the ratio obtained from the other methods. Thus, the Pt : Pd ratio of the Pt-coated Pd catalyst estimated from the H(des) region of Pd is an underestimation of the composition. This suggests that Pd forms an electrochemically inactive species from the H(upd) region itself and Co in Pd3Co seems to stabilize Pd against oxidation by delaying the formation of electrochemically inactive species to higher potentials above the H(upd) region. The voltammograms along with the peroxide formation characteristics of the catalysts support the above observations. The deposited Pt on the surface of the Pd and Pd3Co catalysts masks active Pd sites from the electrochemical environment and even partial coverage with Pt improves the stability and ORR activity of the catalysts when compared to that of the respective Pt-free counterparts. PMID- 23817298 TI - Hyperperfusion syndrome after carotid endarterectomy and carotid stenting. AB - BACKGROUND: Hyperperfusion syndrome (HS) is a relatively rare but possibly serious complication of carotid revascularization procedures. Impaired cerebral autoregulation and postrevascularization changes in cerebral blood flow are the main mechanisms involved in the development of HS. Most up-to-date studies addressing this issue are retrospective and tend to concentrate on carotid endarterectomy (CEA), neglecting carotid stenting (CAS). Our aim was to compare the frequency of clinical signs of HS and hyperperfusion detected by transcranial Doppler (TCD) in patients undergoing CAS or CEA due to carotid stenosis. METHODS: In this prospective observational study, we evaluated 61 patients scheduled for routine CAS or CEA. Each patient was examined by a neurologist before and after the revascularization procedure to assess the clinical status. Severe headache, ocular or facial pain, confusion, visual disturbances, epileptic seizures or any focal deficits not caused by cerebral ischemia were considered clinical signs of HS. Peak systolic velocity (PSV), end-diastolic velocity, mean velocity (MV), and pulsatility index were measured by TCD once before and twice after the intervention (within 6 h after and 2-5 days after the procedure). Hyperperfusion was defined as a >100% increase in the middle cerebral artery (MCA) blood velocity, evaluated separately for PSV and MV after the procedure compared with the baseline value. Cerebrovascular reactivity (CVR) was evaluated with a TCD acetazolamide test before the intervention. RESULTS: CAS (n = 33) and CEA (n = 28) patients were included in the study. There was no difference between the groups in the frequency of clinical signs of HS (21.2 vs. 21.4%) and ratio of TCD hyperperfusion (12.1 vs. 14.3%). In the CAS group, ipsilateral MCA velocity significantly increased directly after the intervention and 2-5 days later, while it increased in the CEA group only 2-5 days after the intervention. The sensitivity and specificity of hyperperfusion, defined by MV, for HS signs were 38.5 and 93.8%, respectively, whereas those defined by PSV were 30.8 and 89.6%, respectively. The sensitivity and specificity of impaired CVR (<25%) for HS signs were 63.6 and 73.5%, respectively. CONCLUSIONS: There is no difference in the frequency of HS clinical signs and hyperperfusion detected by TCD between patients after CAE and CAS. Clinical signs suggested HS does not always correspond with TCD hyperperfusion. However, both the CVR test and TCD measurements of MCA velocity can help identify patients at high risk for HS. PMID- 23817299 TI - Neuroendocrine neoplasms of the stomach. AB - BACKGROUND: Gastric neuroendocrine neoplasms of type 1 and type 3 are different entities and as such require different therapeutical strategies. The aim of this study was to define and distinguish these two tumour subtypes with clearly different biological properties and patient survival. As shown, serum gastrin is an important diagnostic tool for differentiating the less malignant type 1 "hypergastrinemia non-related" tumor from malignant type 3, along with other parameters of malignant potential such as proliferation index and depth of invasion. METHODS: The biological behaviour, tumour marker status, symptomatology, survival and therapeutical strategy were assessed and compared in 18 consecutive patients with type 1 and 7 with type 3 gastric neuroendocrine tumours. RESULTS: All 18 patients with type 1 gastric carcinoids survived long term. 17/18 patients were treated with endoscopic tumour removal. The prognosis for patients with generalized type 3 neuroendocrine neoplasms was poor, with short-term survival. No statistically significant differences between the types were found in urine 5-hydroxyindolacetic acid concentration or serum chromogranin A concentration. Significant differences were found in serum gastrin with high levels even in localized type 1 tumors and normal levels in generalized type 3 neoplasm. Further, high neuron-specific enolase levels were found in type 3. CONCLUSIONS: Type 1 tumour should be preferably treated with endoscopic tumour removal. Recently, favourable tumoristatic effects have been reported in somatostatin analogs. Surgery is a treatment option for type 3 neuroendocrine carcinoma with normal gastrinemia. Serum gastrin is suitable for assessment of the biological properties of both neuroendocrine neoplasm types. It serves, among other factors, as a predictor of prognosis and an indicator for the selection of optimal therapeutical strategy. PMID- 23817300 TI - Neurosarcoidosis: two case reports with multiple cranial nerve involvement and review of the literature. AB - BACKGROUND: Involvement of the central nervous system is registered in a relatively small number of patients with sarcoidosis. In this article we present two cases with various neurological symptoms that fulfill criteria for neurosarcoidosis (NS). In addition, we review the literature on NS with special attention to isolated cranial nerve involvement. METHODS AND RESULTS: First patient: Neurological examination identified multiple cranial neuropathy, moderate right-sided hemiparesis, polyradiculoneuritis of the lower limbs and positive meningeal signs. Laboratory tests showed serum and cerebrospinal fluid (CSF) inflammatory abnormalities, with increased values of the angiotensin converting enzyme (ACE). CSF analysis also showed presence of 9 oligoclonal IgG bands. Brain and spine magnetic resonance imaging (MRI) revealed diffuse meningopathy, and focal granulomatous lesion in the body of the L5 vertebra. Lung sarcoidosis was confirmed by additional diagnostic procedures. The patient was treated with Methylprednisolone and a tapering course of oral Prednisone, which reduced the pain in the back and legs and improved the strength of the right leg. However, the other neurological deficiencies remained. After confirming lung sarcoidosis, the patient received Methotrexate in addition to Prednisone but during the following 2 years the patient's condition progressively worsened and ended in death. Second patient: Neurological findings showed weakness of the right n. oculomotorius and the right n. trochlearis, as well as the right-side face weakness. We found raised level of the ACE in serum and CSF. Thorax high definition computed tomography (HDCTT) showed ribbon-like domains of discrete changes in the pulmonary parenchyma. MRI of the brain showed multiple white matter lesions. This patient also received Methylprednisolone followed by Prednisone, and after two months, ocular motility normalized. CONCLUSION: The diagnosis of NS is always a challenge. For this rerason definitive diagnosis requires the exclusion of other causes of neuropathy. Multiple cranial neuropathies should always arouse suspicion of NS. PMID- 23817301 TI - Neonatal hypercalcemia due to a homozygous mutation in the calcium-sensing receptor: failure of cinacalcet. AB - A neonate affected by a novel inactivating mutation in the calcium-sensing receptor (CASR) gene is presented. This mutation is homozygously inherited and has not been previously described. A deletion in exon 5 (c.1392_1404del13) of the gene causes a loss of function of the receptor, which results in neonatal severe hyperparathyroidism and an ensuing extreme hypercalcemia. In a case of homozygosis of the CASR gene, the use of cinacalcet is the second reported calcimimetic treatment attempt and the first treatment attempt prior to surgery. However, because of the type of mutation, parathyroid surgery was necessary at 4 months of age after therapeutic failure. Because there are multiple mutations that affect the CASR gene in different ways, treatment with cinacalcet as an alternative to surgery may be valuable in homozygous cases that are caused by different mutations than the reported case. PMID- 23817302 TI - Endometriosis for the primary care physician. AB - PURPOSE OF REVIEW: This review will empower the primary care provider (PCP) to evaluate, manage, and refer as needed adolescents with dysmenorrhea and/or chronic pelvic pain (CPP) who are suspected to have endometriosis. RECENT FINDINGS: Endometriosis is a common cause of CPP in adolescents who do not respond to primary medical treatment. The presentation in adolescents is unique, causing high rates of misdiagnosis or delayed treatment. Endometriosis-related pain has a marked negative impact on social and mental health. Simple treatments that are available in the primary care setting can alleviate pain and improve quality of life for these young women if initiated in a timely fashion. SUMMARY: Adolescents usually turn to their PCP for evaluation of dysmenorrhea and CPP. By maintaining a high index of suspicion, initiating treatment, and referring when needed, the PCP can have a tremendous effect on the patient's present and future quality of life. PMID- 23817303 TI - Bariatric surgical management of adolescents with morbid obesity. AB - PURPOSE OF REVIEW: Adolescent obesity continues to be a significant public health issue. To date, there are no medical therapies that provide significant, durable weight loss. Bariatric surgery has been shown in the adult and now the adolescent population to provide a reasonable alternative for weight loss. RECENT FINDINGS: Recent publications have focused on the revision of the current guidelines for bariatric surgery in adolescents to more closely align with their well established adult counterparts. These guidelines now introduce the establishment of multidisciplinary teams for the care of this subset of adolescent surgical patients. Numerous manuscripts in the past 2-3 years have demonstrated the overall effectiveness of Roux-en-Y gastric bypass, adjustable gastric banding, and most recently sleeve gastrectomy for both significant weight loss and comorbidity reduction with safety profiles similar to those found in adults. Despite these data, a recently published study showed that the trend for adolescent bariatric surgery has been stagnant over a 6-year period. There is also an ongoing shift in the type of procedure performed for morbid obesity in the United States toward sleeve gastrectomy and away from the adjustable gastric band. SUMMARY: With the growing number of morbidly obese adolescents in the United States coupled with the relative ineffectiveness of medical therapy in this group of patients, bariatric surgery consistently provides a means for significant weight loss and the resolution of substantial comorbidities. Its approval is slowly increasing, and the growing fund of knowledge in regard to complication rates and the efficacy of bariatric surgery will ultimately result in its more widespread acceptance. PMID- 23817304 TI - Update on pediatric photosensitivity disorders. AB - PURPOSE OF REVIEW: Although rare in the pediatric population, photosensitive dermatoses may begin prior to adulthood. The causes of photosensitivity are diverse, ranging from primary, immunologically mediated disorders of photosensitivity to inherited genetic or metabolic disorders. This review will highlight the key features of these disorders to familiarize the pediatric practitioner with their symptoms and any associated extracutaneous clinical or laboratory findings that may accompany them. RECENT FINDINGS: New developments in the field of pediatric photosensitivity have been scant over recent years. While mechanisms of photosensitivity and genetic underpinnings associated with various conditions such as xeroderma pigmentosum continue to be uncovered, the literature on disorders of photosensitivity has been otherwise without many recent significant advances. SUMMARY: Although the differential diagnosis of pediatric photosensitivity disorders is broad, it is often possible to establish the diagnosis by following an algorithmic approach. Once the correct diagnosis is rendered, this will guide any further workup that needs to be performed as well as specific management strategies. PMID- 23817305 TI - Anisakis allergy component-resolved diagnosis: clinical and immunologic differences between patients from Italy and Spain. AB - BACKGROUND: Anisakissimplex is the main organism responsible for the zoonotic disease anisakiasis which follows the ingestion of live larvae present in raw or undercooked marine fish. Clinical features include severe epigastric pain, frequently accompanied by severe allergic reactions. We investigated the prevalence of immunoglobulin E (IgE) specific for 5 Anisakis allergens in Italian patients sensitized or allergic to the parasite. The results were compared with those obtained previously in a similar Spanish population. PATIENTS AND METHODS: We conducted a descriptive, cross-sectional validation study. Asymptomatic Anisakis-sensitized subjects (15 Italian and 17 Spanish) and Anisakis allergic patients (42 Italian and 35 Spanish) were studied by ImmunoCAP, Western-blotting with nAni s 4 and dot-blotting with rAni s 1, rAni s 5, rAni s 9 and rAni s 10. RESULTS: Anisakis IgE CAP classes 1 or 2 were associated with a high probability of asymptomatic sensitization (66.7%) while CAP classes 4 or above, were associated with a very high probability of allergy to Anisakis (95.2%). The most frequently detected allergen among Italian and Spanish allergic patients was Ani s 1. All of the Spanish patients versus 76.2% of the Italian patients recognized at least one of the allergens tested. Patients suffering from gastrointestinal symptoms only were significantly more frequent among the Italians whereas the Spanish presented more frequently with urticaria, angioedema or anaphylaxis. CONCLUSIONS: Anisakis hypersensitivity shows different immunological patterns in different European countries. Allergen component diagnosis might help us to better understand this complex entity. Anisakis-specific IgE levels may have moderate prognostic significance. PMID- 23817306 TI - Facile template free synthesis of Gd2O(CO3)2.H2O chrysanthemum-like nanoflowers and luminescence properties of corresponding Gd2O3:RE3+ spheres. AB - Trivalent rare-earth (RE(3+) = Eu(3+), Tb(3+), Dy(3+), and Sm(3+)) ions activated Gd2O(CO3)2.H2O chrysanthemum-like flowers are prepared by a modified urea-based homogeneous precipitation via a template free hydrothermal synthesis route. Subsequently, Gd2O3 monodispersed spheres were obtained after calcining at 750 degrees C. The growth mechanism of the Gd2O(CO3)2.H2O:RE(3+) chrysanthemum-like morphology (homogeneous precipitation) and their transformation to monodispersed spheres (heterogeneous nucleation) are established by taking scanning electron microscope and transmission electron microscope images of the intermediate products. The thermogravimetric analysis, Fourier transform infrared analyses confirmed the decomposition of CO2 and OH groups, and the corresponding XRD patterns exhibited the Gd2O(CO3)2.H2O and cubic Gd2O3 phases. The photoluminescence measurements are used to explore the emission behavior of different RE(3+) ions activated Gd2O3 spheres. The Gd2O3:Eu(3+) shows gorgeous red emission with high purity red color as compared to the commercial Y2O3:Eu(3+) phosphors. Gd2O3:Tb(3+), Gd2O3:Dy(3+) and Gd2O3:Sm(3+) exhibit green, yellow and rich orange emissions, respectively. The Tb(3+)/Eu(3+) co-doped sample shows warm white light by controlling the energy transfer. At minimal parameters, the cathodoluminescence intensity of Gd2O3:Eu(3+) is beyond the experimental limit for 5 kV of accelerating voltage. The CIE chromaticity coordinates were also calculated from the PL and CL spectra of RE(3+) ions to establish their color richness. PMID- 23817307 TI - A complex chromosome rearrangement involving four chromosomes, nine breakpoints and a cryptic 0.6-Mb deletion in a boy with cerebellar hypoplasia and defects in skull ossification. AB - Constitutional complex chromosomal rearrangements (CCRs) are considered rare cytogenetic events. Most apparently balanced CCRs are de novo and are usually found in patients with abnormal phenotypes. High-resolution techniques are unveiling genomic imbalances in a great percentage of these cases. In this paper, we report a patient with growth and developmental delay, dysmorphic features, nervous system anomalies (pachygyria, hypoplasia of the corpus callosum and cerebellum), a marked reduction in the ossification of the cranial vault, skull base sclerosis, and cardiopathy who presents a CCR with 9 breakpoints involving 4 chromosomes (3, 6, 8 and 14) and a 0.6-Mb deletion in 14q24.1. Although the only genomic imbalance revealed by the array technique was a deletion, the clinical phenotype of the patient most likely cannot be attributed exclusively to haploinsufficiency. Other events must also be considered, including the disruption of critical genes and position effects. A combination of several different investigative approaches (G-banding, FISH with different probes and SNP array techniques) was required to describe this CCR in full, suggesting that CCRs may be more frequent than initially thought. Additionally, we propose that a chain chromosome breakage mechanism may have occurred as a single rearrangement event resulting in this CCR. This study demonstrates the importance of applying different cytogenetic and molecular techniques to detect subtle rearrangements and to delineate the rearrangements at a more accurate level, providing a better understanding of the mechanisms involved in CCR formation and a better correlation with phenotype. PMID- 23817308 TI - Synthesis and characterization of the crystal structure and magnetic properties of the hydroxyfluoride MnF(2-x)(OH)x (x ~ 0.8). AB - The new compound MnF(2-x)(OH)x (x ~ 0.8) was synthesized by a hydrothermal route from a 1 : 1 molar ratio of lithium fluoride and manganese acetate in an excess of water. The crystal structure was determined using the combination of single crystal X-ray and neutron powder diffraction measurements. The magnetic properties of the title compound were characterized by magnetic susceptibility and low-temperature neutron powder diffraction measurements. MnF(2-x)(OH)x (x ~ 0.8) crystallizes with orthorhombic symmetry, space group Pnn2 (no. 34), a = 4.7127(18), b = 5.203(2), c = 3.2439(13) A, V = 79.54(5) A(3) and Z = 2. The crystal structure is a distorted rutile-type with [Mn(F,O)4] infinite edge sharing chains along the c-direction. The protons are located in the channels and form O-HF bent hydrogen bonds. The magnetic susceptibility measurements indicate an antiferromagnetic ordering at ~70 K and the neutron powder diffraction measurements at 3 K show that the ferromagnetic chains with spins parallel to the c-axis are antiferromagnetically coupled to each other, similarly to the magnetic structure of tetragonal rutile-type MnF2 with isoelectronic Mn(2+). MnF(2-x)(OH)x (x ~ 0.8) is expected to be of great interest as a positive electrode for Li cells if the protons could be exchanged for lithium. PMID- 23817309 TI - From promises to practical strategies in epigenetic epidemiology. AB - The epigenome has been heralded as a key 'missing piece' of the aetiological puzzle for complex phenotypes across the biomedical sciences. The standard research approaches developed for genetic epidemiology, however, are not necessarily appropriate for epigenetic studies of common disease. Here, we discuss the optimal execution of population-based studies of epigenetic variation, which will contribute to the emerging field of 'epigenetic epidemiology' and emphasize the importance of establishing a causal role in pathology for disease-associated epigenetic changes. We propose that improved understanding of the molecular mechanisms underlying human health and disease are best achieved through carrying out studies of epigenetics in populations as a part of an integrated functional genomics strategy. PMID- 23817311 TI - Complex traits: Sequencing for disease architecture. PMID- 23817312 TI - Epigenetics: X inactivation by titration. PMID- 23817313 TI - Surface-enhanced charge-density-wave instability in underdoped Bi2Sr(2 x)La(x)CuO(6+delta). AB - Neutron and X-ray scattering experiments have provided mounting evidence for spin and charge ordering phenomena in underdoped cuprates. These range from early work on stripe correlations in Nd-LSCO to the latest discovery of charge-density-waves in YBa2Cu3O(6+x). Both phenomena are characterized by a pronounced dependence on doping, temperature and an externally applied magnetic field. Here, we show that these electron-lattice instabilities exhibit also a previously unrecognized bulk surface dichotomy. Surface-sensitive electronic and structural probes uncover a temperature-dependent evolution of the CuO2 plane band dispersion and apparent Fermi pockets in underdoped Bi2 Sr(2-x) La(x) CuO(6+delta) (Bi2201), which is directly associated with an hitherto-undetected strong temperature dependence of the incommensurate superstructure periodicity below 130 K. In stark contrast, the structural modulation revealed by bulk-sensitive probes is temperature independent. These findings point to a surface-enhanced incipient charge-density wave instability, driven by Fermi surface nesting. This discovery is of critical importance in the interpretation of single-particle spectroscopy data, and establishes the surface of cuprates and other complex oxides as a rich playground for the study of electronically soft phases. PMID- 23817310 TI - Adult-specific functions of animal microRNAs. AB - MicroRNAs (miRNAs) are ~22 nt RNAs that coordinate vast regulatory networks in animals and thereby influence myriad processes. This Review examines evidence that miRNAs have continuous roles in adults in ways that are separable from developmental control. Adult-specific activities for miRNAs have been described in various stem cell populations, in the context of neural function and cardiovascular biology, in metabolism and ageing, and during cancer. In addition to reviewing recent results, we also discuss methods for studying miRNA activities specifically in adults and evaluate their relative strengths and weaknesses. A fuller understanding of continuous functions of miRNAs in adults has bearing on efforts and opportunities to manipulate miRNAs for therapeutic purposes. PMID- 23817314 TI - An aptasensing platform for simultaneous detection of multiple analytes based on the amplification of exonuclease-catalyzed target recycling and DNA concatemers. AB - In the present study, an ultrasensitive electrochemical aptasensor for the simultaneous detection of thrombin (TB) and ochratoxin A (OTA) was fabricated by using exonuclease-catalyzed target recycling and DNA concatemers for signal amplification. The previously hybridized double-stranded DNAs (SH-cTBA/TBA and SH cOBA/OBA) were self-assembled on a gold electrode. In the presence of targets, the formation of aptamer-target complexes would lead to not only the dissociation of aptamers (TBA and OBA) from the double-stranded DNAs but also the transformation of the complementary DNAs (SH-cTBA and SH-cOBA) into hairpin structures. Subsequently, owing to employment of RecJf exonuclease, which is a single-stranded DNA-specific exonuclease to selectively digest the appointed DNAs (TBA and OBA), the targets could be liberated from the aptamer-target complexes for recycling of the analytes. Thereafter, probe DNAs (T1 and T2) were employed to hybridize with SH-cTBA and SH-cOBA respectively to provide primers for the concatemer reaction. After that, when four auxiliary DNA strands S1, anthraquinone-2-carboxylic acid (AQ)-labeled S2, S3, S4, as well as hemin were introduced, extended dsDNA polymers with lots of AQ moieties and hemin-G quadruplex complexes could form on the electrode surface. Then, based on the signal of the AQ and hemin-G-quadruplex complex, an electrochemical aptasensor for the simultaneous detection of TB and OTA was successfully fabricated. PMID- 23817315 TI - Anti-rPru p 3 IgE levels are inversely related to the age at onset of peach induced severe symptoms reported by peach-allergic adults. AB - Sensitisation to peach lipid transfer protein (LTP; Pru p 3) is significantly associated with severe allergic symptoms in adults, but little is known about the age at onset of peach allergy. We investigated a possible correlation between specific IgE levels to Pru p 3 and the age at onset of peach allergy. One hundred and forty-eight patients allergic to peach were divided into 6 classes according to the age at onset. Sera were analyzed for IgE antibodies to peach, rPru p 3, rPru p 1, rPru p 4, rBet v 1, rBet v 2, total IgE titre, and tryptase; all collected data were statistically analysed. A significant inverse correlation was found between the age at onset of peach allergy and anti-rPru p 3 IgE levels at diagnosis (p < 0.0005; Spearman's rho = -0.3833). In contrast, the age at onset was directly correlated with both anti-rPru p 1 IgE levels (p = 0.0001; Spearman's rho = 0.3197) and anti-rBet v 1 IgE levels (p = 0.0006; Spearman's rho = 0.2914) at diagnosis. No correlations were detected between the reported age at onset and anti-peach, anti-rPru p 4, anti-rBet v 2 IgE and total IgE values and serum tryptase levels. At diagnosis, when peach allergy starts at a younger age, it is likely associated with Pru p 3 sensitisation, and the younger the onset, the higher the IgE titres. When peach allergy starts at an older age, it is more likely the result of cross-reactivity to Bet v1. PMID- 23817316 TI - Periventricular leukomalacia and less invasive surfactant administration in extremely preterm infants. Concerning the article by k. Klebermass-schrehof et Al.: less invasive surfactant administration in extremely preterm infants: impact on mortality and morbidity [neonatology 2013;103:252-258]. PMID- 23817318 TI - Letter from the editor. PMID- 23817317 TI - The changing landscape in metastatic castration-resistant prostate cancer. AB - PURPOSE OF REVIEW: The treatment landscape in metastatic castration-resistant prostate cancer (mCRPC) has significantly changed in the recent years. We provide an updated summary of the new therapeutic agents in this disease and discuss open questions and future challenges. RECENT FINDINGS: mCRPC is now known to frequently retain sensitivity to hormonal manipulation even after the development of castration resistance, and both the androgen synthesis inhibitor abiraterone and the androgen-receptor antagonist enzalutamide have recently shown to prolong survival in mCRPC patients after chemotherapy. Cabazitaxel, a new-generation antitubulin chemotherapeutic, and the radionuclide radium-223 chloride have also been shown to prolong survival. The biological agent cabozantinib, an orally bioavailable tyrosine kinase inhibitor with activity against Met and vascular endothelial growth factor receptor 2, demonstrated promising results in a phase II trial and is currently being assessed in two large randomized phase 3 controlled trials. SUMMARY: This recent progress is unprecedented and has already translated to a significant increase in the available armamentarium of drugs for mCRPC. Nonetheless, there are still significant unresolved questions as to the proper sequencing of these novel drugs along the disease continuum. Moreover, the problem of drug resistance, either primary of acquired, continues to be a major therapeutic obstacle. PMID- 23817319 TI - Two therapeutic HPV vaccine candidates successful in phase 1. PMID- 23817320 TI - Profile: ImmunoCellular Therapeutics Ltd. PMID- 23817322 TI - Gut microbiota: Obesity-induced microbial metabolite promotes HCC. PMID- 23817321 TI - Epidemiology and natural history of HCV infection. AB - Worldwide, an estimated 130-170 million people have HCV infection. HCV prevalence is highest in Egypt at >10% of the general population and China has the most people with HCV (29.8 million). Differences in past HCV incidence and current HCV prevalence, together with the generally protracted nature of HCV disease progression, has led to considerable diversity in the burden of advanced liver disease in different countries. Countries with a high incidence of HCV or peak incidence in the recent past will have further escalations in HCV-related cirrhosis and hepatocellular carcinoma (HCC) over the next two decades. Acute HCV infection is difficult to detect because of the generally asymptomatic nature of the disease and the marginalization of at-risk populations. Around 25% of patients with acute HCV infection undergo spontaneous clearance, with increased rates among those with favourable IL28B genotypes, acute symptoms and in women. The remaining 75% of patients progress to chronic HCV infection and are subsequently at risk of progression to hepatic fibrosis, cirrhosis and HCC. Chronic hepatitis C generally progresses slowly in the initial two decades, but can be accelerated during this time as a result of advancing age and co-factors such as heavy alcohol intake and HIV co-infection. PMID- 23817323 TI - Drug-drug interactions during antiviral therapy for chronic hepatitis C. AB - The emergence of direct-acting antiviral agents (DAAs) for HCV infection represents a major advance in treatment. The NS3 protease inhibitors, boceprevir and telaprevir, were the first DAAs to receive regulatory approval. When combined with PEG-IFN and ribavirin, these agents increase rates of sustained virologic response in HCV genotype 1 to ~70%. However, this treatment regimen is associated with several toxicities. In addition, both boceprevir and telaprevir are substrates for and inhibitors of the drug transporter P-glycoprotein and the cytochrome P450 enzyme 3A4 and are, therefore, prone to clinically relevant drug interactions. Several new DAAs for HCV are in late stages of clinical development and are likely to be approved in the near future. These include the protease inhibitors, simeprevir and faldaprevir, the NS5A inhibitor, daclatasvir, and the nucleotide polymerase inhibitor, sofosbuvir. Herein, we review the clinical pharmacology and drug interactions of boceprevir, telaprevir and these investigational DAAs. Although boceprevir and telaprevir are involved in many interactions, these interactions are manageable if health-care providers proactively identify and adjust treatments. Emerging DAAs seem to have a reduced potential for drug interactions, which will facilitate their use in the treatment of HCV. PMID- 23817324 TI - IBD: Antibodies to anti-TNF therapy--consequences for IBD management. PMID- 23817326 TI - TiO2-graphene composites with exposed {001} facets produced by a one-pot solvothermal approach for high performance photocatalyst. AB - TiO2-graphene (TOG) composites with exposed TiO2 {001} facets were prepared by a solvothermal approach without any addition of surfactants or capping agents, only using titanium isopropoxide and graphene oxide ethanol suspension as the precursors. Graphene was covered uniformly and densely with anatase TiO2 nanoparticles, exposing the {001} facets. The X-ray photoelectron spectroscopy, photoluminescence spectroscopy and photocurrent measurements show the presence of electron transfer between TiO2 and graphene. The electron transfer between TiO2 and graphene will greatly retard the recombination of photoinduced charge carriers and prolong electron lifetime, which will contribute to the enhancement of photocatalytic performance. Accordingly, the TOG composites show high photocatalytic activity of methyl orange under UV light, likely due to the effective separation of photoinduced charge, exposure of highly reactive {001} facets and great adsorptivity of dyes. PMID- 23817327 TI - A detailed kinetic analysis of rhodium-catalyzed alkyne hydrogenation. AB - Continuous monitoring using electrospray ionisation mass spectrometry (ESI-MS) shows that Wilkinson's catalyst hydrogenates a charge-tagged alkyne to the corresponding alkene, and at only a marginally slower rate, to the alkane. No rhodium-containing intermediates were observed during the reaction, consistent with the established mechanism which points at the initial dissociation of triphenylphosphine from Rh(PPh3)3Cl as being the key step in the reaction. A numerical model was constructed that the closely matched the experimental data, and correctly predicted the response of the reaction to the addition of excess PPh3. PMID- 23817325 TI - The liver-brain axis in liver failure: neuroinflammation and encephalopathy. AB - Systemic inflammation is common in liver failure and its acquisition is a predictor of hepatic encephalopathy severity. New studies provide convincing evidence for a role of neuroinflammation (inflammation of the brain per se) in liver failure; this evidence includes activation of microglia, together with increased synthesis in situ of the proinflammatory cytokines TNF, IL-1beta and IL 6. Liver-brain signalling mechanisms in liver failure include: direct effects of systemic proinflammatory molecules, recruitment of monocytes after microglial activation, brain accumulation of ammonia, lactate and manganese, and altered permeability of the blood-brain barrier. Ammonia and cytokines might act synergistically. Existing strategies to reduce ammonia levels (including lactulose, rifaximin and probiotics) have the potential to dampen systemic inflammation, as does albumin dialysis, mild hypothermia and N-acetylcysteine, the latter two agents acting at both peripheral and central sites. Minocycline, an agent with potent central anti-inflammatory properties, reduces neuroinflammation, brain oedema and encephalopathy in liver failure, as does the anti-TNF agent etanercept. PMID- 23817328 TI - Systematic study of terahertz time-domain spectra of historically informed black inks. AB - The potential of terahertz-time domain spectroscopy (THz-TDS) as a diagnostic tool for studies of inks in historical documents is investigated in this paper. Transmission mode THz-TDS was performed on historically informed model writing and drawing inks. Carbon black, bistre and sepia inks show featureless spectra between 5 and 75 cm(-1) (0.15-2.25 THz); however, their analysis still provided useful information on the interaction of terahertz radiation with amorphous materials. On the other hand, THz-TDS can be used to distinguish different iron gall inks with respect to the amount of iron(II) sulfate contained, as sharp spectral features are observed for inks containing different ratios of iron(II) sulfate to tannic or gallic acid. Additionally, copper sulfate was found to modify the structure of iron(II) precipitate. Furthermore, Principal Component Analysis (PCA) applied to THz-TDS spectra, highlights changes in iron gall inks during thermal degradation, during which a decrease in the sharp spectral bands associated with iron(II) sulfate is observed. ATR-FTIR spectroscopy combined with THz-TDS of dynamically heated ink samples indicate that this phenomenon is due to dehydration of iron(II) sulfate heptahydrate. While this research demonstrates the potential of THz-TDS to improve monitoring of the chemical state of historical documents, the outcomes go beyond the heritage field, as it also helps to develop the theoretical knowledge on interactions between terahertz radiation and matter, particularly in studies of long-range symmetry (polymorphism) in complex molecular structures and the role played by the surrounding matrix, and also indicates the potential of THz-TDS for the optimization of contrast in terahertz imaging. PMID- 23817329 TI - Interlaboratory agreement of pulsed-field gel electrophoresis identification of Leptospira serovars. AB - Leptospirosis may be caused by > 250 Leptospira serovars. Serovar classification is a complex task that most laboratories cannot perform. We assessed the interlaboratory reproducibility of a pulsed-field gel electrophoresis (PFGE) identification technique developed by the Centers for Disease Control and Prevention (CDC). Blinded exchange of 93 Leptospiraceae strains occurred between San Antonio Military Medical Center (SAMMC) and the CDC. PFGE was performed and gel images were analyzed and compared with patterns present in each laboratory's database (CDC database: > 800 strain patterns; SAMMC database: > 300 strain patterns). Overall, 93.7% (74 of 79) of strains present in each receiving laboratory's database were correctly identified. Five isolates were misidentified, and two isolates did not match serovar PFGE patterns in the receiving laboratory's database. Patterns for these seven isolates were identical between laboratories; four serovars represented misidentified reference strains. The PFGE methodology studied showed excellent interlaboratory reproducibility, enabling standardization and data sharing between laboratories. PMID- 23817331 TI - Adult malaria chemoprophylaxis prescribing patterns in the military health system from 2007-2011. AB - The Military Health System (MHS), with 9.7 million beneficiaries, represents an enormous pool of potential travelers requiring malaria prevention measures. A systematic search of the MHS electronic pharmacy record was performed for prescriptions of atovaquone-proguanil (AP), chloroquine (CQ), doxycycline (DC), mefloquine (MQ), primaquine (PQ) to adult patients from 2007 through 2011. Over 1,000,000 were identified, including 161,341 primary prophylaxis prescriptions originating from civilian facilities. Military facility prescription volume rose from 50,128 (PQ < 1%, AP 4%, CQ 6%, DC 53%, MQ 36%) in 2007 to 166,649 (PQ < 1%, AP 3%, CQ < 1%, DC 94%, MQ 2%) in 2011. Mefloquine use diminished in all clinics over time. The majority of military facility prescriptions originated from primary care clinics (83%); primary care clinics predominantly and increasingly prescribed DC, whereas specialty travel clinics predominantly and increasingly prescribed AP. Prescribing patterns in the MHS varied by time, practice setting, beneficiary status, and provider specialty. These changes, including among non active duty military patients, are temporally associated with policy changes intended for the active duty force. PMID- 23817330 TI - Clinical and immunological aspects of post-kala-azar dermal leishmaniasis in Bangladesh. AB - We conducted active surveillance for kala-azar and post-kala-azar dermal leishmaniasis (PKDL) in a population of 24,814 individuals. Between 2002 and 2010, 1,002 kala-azar and 185 PKDL cases occurred. Median PKDL patient age was 12 years; 9% had no antecedent kala-azar. Cases per 10,000 person-years peaked at 90 for kala-azar (2005) and 28 for PKDL (2007). Cumulative PKDL incidence among kala azar patients was 17% by 5 years. Kala-azar patients younger than 15 years were more likely than older patients to develop PKDL; no other risk factors were identified. The most common lesions were hypopigmented macules. Of 98 untreated PKDL patients, 48 (49%) patients had resolution, with median time of 19 months. Kala-azar patients showed elevated interferon-gamma (IFNgamma), tumor necrosis factor-alpha (TNFalpha), and interleukin 10 (IL-10). Matrix metalloproteinase 9 (MMP9) and MMP9/tissue inhibitor of matrix metalloproteinase-1 (TIMP1) ratio were significantly higher in PKDL patients than in other groups. PKDL is frequent in Bangladesh and poses a challenge to the current visceral leishmaniasis elimination initiative in the Indian subcontinent. PMID- 23817332 TI - Blood glucose as a predictor of mortality in children admitted to the hospital with febrile illness in Tanzania. AB - Data from a prospective study of 3,319 children ages 2 months to 5 years admitted with febrile illness to a Tanzanian district hospital were analyzed to determine the relationship of blood glucose and mortality. Hypoglycemia (blood sugar < 2.5 mmol/L and < 45 mg/dL) was found in 105 of 3,319 (3.2%) children at admission, and low-normal blood glucose (2.5-5 mmol/L and 45-90 mg/dL) was found in 773 of 3,319 (23.3%) children. Mortality was inversely related to admission blood sugar; compared with children with an admission blood glucose of > 5 mmol/L, the adjusted odds of dying were 3.3 (95% confidence interval = 2.1-5.2) and 9.8 (95% confidence interval = 5.1-19.0) among children with admission blood glucose 2.5-5 and < 2.5 mmol/L, respectively. Receiver operating characteristic (ROC) analysis suggested an optimal cutoff for admission blood sugar of < 5 mmol/L in predicting mortality (sensitivity = 57.7%, specificity = 75.2%). A cutoff for admission blood glucose of < 5 mmol/L represents a simple and clinically useful predictor of mortality in children admitted with severe febrile illness to hospital in resource-poor settings. PMID- 23817333 TI - Sequence analyses of 2012 West Nile virus isolates from Texas fail to associate viral genetic factors with outbreak magnitude. AB - In 2012, Texas experienced the largest outbreak of human West Nile encephalitis (WNE) since the introduction of West Nile virus (WNV) in 2002. Despite the large number of WNV infections, data indicated the rate of reported WNE among human cases was no higher than in previous years. To determine whether the increase in WNV human cases could have been caused by viral genetic changes, the complete genomes of 17 isolates made from mosquito pools in Dallas and Montgomery Counties in 2012 were sequenced. The 2012 Texas isolates were found to be composed of two distinct clades, both circulating in Dallas and Montgomery Counties despite a 5 fold higher disease incidence in the former. Although minor genetic differences existed between Dallas and Montgomery WNV populations, there was weak support for population subdivision or adaptive changes. On the basis of these data, alternative explanations for increased WNV disease incidence in 2012 are proposed. PMID- 23817334 TI - Severity of diarrhea and malnutrition among under five-year-old children in rural Bangladesh. AB - Enteric pathogens are commonly associated with diarrhea among malnourished children. This study aimed to determine the association between the severity of diarrheal illnesses and malnutrition among under 5-year-old children. During 2010 and 2011, we studied 2,324 under 5-year-old diarrheal children with mild disease (MD) and moderate-to-severe disease (MSD) attending a hospital in Bangladesh. Children with MSD were more likely to be malnourished compared with children with MD (35% versus 24%, P < 0.001). In multivariate analysis, malnutrition (odds ratio [95% confidence interval] = 1.53 [1.22, 1.92]), age of the child (24-59 months; 1.67 [1.28, 2.19]), fever (1.65 [1.28, 2.12]), abdominal pain (1.87 [1.48, 2.37]), straining (5.93 [4.80, 7.33]), and infection with Shigella (3.26 [2.38, 4.46]) and Vibrio cholerae (2.21 [1.07, 4.58]) were shown to be significantly associated with MSD. Factors significantly associated with malnutrition were disease severity (1.56 [1.24, 1.95]), age (24-59 months; 1.75 [1.38, 2.22]), mother's schooling (1.54 [1.16, 2.04]), and monthly household income (1.71 [1.42, 2.07]). Childhood malnutrition was associated with dysentery and dehydrating diarrhea. PMID- 23817335 TI - Free-ranging chickens in households in a periurban shantytown in Peru--attitudes and practices 10 years after a community-based intervention project. AB - Free-ranging chickens are often found in periurban communities in developing countries, and their feces can pose a significant public health sanitation problem. Corralling chickens raised in these periurban areas in chicken coops has been proposed previously as an intervention to address this problem. Aims of this study were to revisit households in a corralling intervention study conducted in 2000-2001 to compare poultry-raising practices and investigate current attitudes regarding the impact of raising chickens in a periurban environment. Sociobehavioral questionnaires were given sequentially to all study participants; 30 families (58%) ceased raising poultry of any kind, whereas 42 (81%) do not raise chickens in their home. This finding indicates a significant reduction in poultry-raising in our study population since 2000-2001, possibly because of acculturation and/or change in socioeconomic status. However, attitudes about corral use for raising poultry were overwhelmingly positive, and the most common reason cited was cleanliness of the home. PMID- 23817337 TI - A review of settings-based health promotion with applications to sports clubs. AB - Sports clubs have a long and traditional history in many countries, yet they remain underdeveloped and underutilized settings for health promotion. Leisure time settings, in general, have been in minor role among settings-based health promotion initiatives. Current health concerns in western countries, such as sedentary lifestyles and obesity, have aroused a need to expand health promotion to include also settings with greater potential to reach and engage children and adolescents in more vigorous activity. To develop these alternative, most often non-institutional, settings to the level of the established ones, it is important to review what has been done, what has been accepted and what is known from research, theory and practice to have contributed to health. Given that settings approaches have been implemented with diverse scope and without close cooperation between different initiatives, the first aim of this paper is, on the basis of a review of commonly used theories and practices, to propose a mutual definition for the settings approach to health promotion. The second is to examine the applicability of the theoretical basis to youth sports club settings. Sports clubs are used as a reflective setting when reviewing the traditional ones. PMID- 23817336 TI - Community diarrhea incidence before and after rotavirus vaccine introduction in Nicaragua. AB - We estimated the incidence of watery diarrhea in the community before and after introduction of the pentavalent rotavirus vaccine in Leon, Nicaragua. A random sample of households was selected before and after rotavirus vaccine introduction. All children < 5 years of age in selected households were eligible for inclusion. Children were followed every 2 weeks for watery diarrhea episodes. The incidence rate was estimated as numbers of episodes per 100 child-years of exposure time. A mixed effects Poisson regression model was fit to compare incidence rates in the pre-vaccine and vaccine periods. The pre-vaccine cohort (N = 726) experienced 36 episodes per 100 child-years, and the vaccine cohort (N = 826) experienced 25 episodes per 100 child-years. The adjusted incidence rate ratio was 0.60 (95% confidence interval [CI] 0.40, 0.91) during the vaccine period versus the pre-vaccine period, indicating a lower incidence of watery diarrhea in the community during the vaccine period. PMID- 23817338 TI - A spontaneous Cdt1 mutation in 129 mouse strains reveals a regulatory domain restraining replication licensing. AB - Cdt1 is required for loading the replicative DNA helicase MCM2/7, a process known as DNA replication licensing. Here we show that 129 mouse strains express a Cdt1 mutated allele with enhanced licensing activity. The mutation, named Delta(6)PEST, involves a six-amino acid deletion within a previously uncharacterized PEST-like domain. Cdt1 Delta(6)PEST and more extensive deletions exhibit increased re-replication and transformation activities that are independent of the Geminin and E3 ligase pathways. This PEST domain negatively regulates cell cycle-dependent chromatin recruitment of Cdt1 in G2/M phases of the cell cycle. Mass spectrometry analysis indicates that Cdt1 is phosphorylated at sites within the deleted PEST domain during mitosis. This study reveals a conserved new regulatory Cdt1 domain crucial for proper DNA licensing activity and suggests a mechanism by which the presence of Cdt1 in G2/M phases does not lead to premature origin licensing. These results also question the usage of 129 mouse strains for knockout analyses. PMID- 23817339 TI - Rapid defervescence after doxycycline treatment of macrolide-resistant Mycoplasma pneumoniae-associated community-acquired pneumonia in children. AB - We did a retrospective review of children with Mycoplasma pneumoniae infection hospitalized from March 2010 to March 2013. Mycoplasma-resistant M. pneumoniae constituted 70% of the total M. pneumoniae-associated community-acquired pneumonia. Doxycycline was significantly more effective than macrolide for treatment of Mycoplasma-resistant M. pneumoniae-associated community-acquired pneumonia in terms of achievement of rapid defervescence within 24 hours. PMID- 23817341 TI - A novel co-precipitation method for one-pot fabrication of a Co-Ni multiphase composite electrode and its application in high energy-density pseudocapacitors. AB - A multiphase composite film composed of nickel(II) hydroxide and cobalt(II) hydroxide was synthesized by a novel co-precipitation method. The film exhibited high capacitance and stable cyclic retention because of its 3D network nanostructure and high conductivity due to CoOOH evolved during cycling. PMID- 23817340 TI - A randomized controlled trial of a vancomycin loading dose in children. AB - BACKGROUND: Despite its frequent use, the optimal dosing regimen of intravenous vancomycin remains controversial. Achievement of therapeutic trough early in the course of illness may be beneficial. Our objective was to assess whether a loading dose of vancomycin would increase the proportion of children reaching target trough concentrations 8 hours after initiation of therapy. METHODS: We enrolled hospitalized children aged 2-18 years prescribed vancomycin at Boston Children's Hospital between February 2011 and January 2012. Participants were randomized to receive a loading dose (30 mg/kg) or a conventional initial dose (20 mg/kg). These were followed by a 20 mg/kg/dose every 8 hours in both groups. Serum vancomycin concentrations were measured before the second and third doses. Pharmacokinetic parameters were calculated using individual and population pharmacokinetic models. RESULTS: Two of nineteen (11%) loading dose recipients had a trough 15-20 mg/L before the second dose, compared with 0 of 27 in the conventional dose group (P=0.17). However, the median area under the curve/minimum inhibitory concentration estimates (for a hypothetical minimum inhibitory concentration=1 mg/L) were above 400 in both groups. Red man syndrome incidence was higher in loading dose recipients (48% vs. 24%, P=0.06). CONCLUSIONS: A vancomycin loading dose did not result in earlier achievement of therapeutic trough concentrations in this study. However, the systemic exposure to vancomycin in children administered 60 mg/kg/day was adequate, despite lower than recommended measured trough levels. Therefore, the need for higher target trough concentrations should be questioned. PMID- 23817342 TI - Thermoelectric performance of PbSe quantum dot films. AB - The thermoelectric (TE) performance of films of colloidal lead selenide (PbSe) quantum dots (QDs) with metal-chalcogenide complex ligands is seen to change with QD size and temperature. Films of smaller QDs have higher Seebeck coefficient magnitudes, indicating stronger quantum confinement, and lower electrical and thermal conductivities. The thermoelectric figure of merit ZT is ~0.5 at room temperature and increases with temperature to 1.0-1.37 at ~400 K, where it is larger for smaller QD films. This is better than previous results for solution prepared QD TE materials at these elevated temperatures. PMID- 23817343 TI - The gaseous structure of closo-9,12-(SH)2-1,2-C2B10H10, a modifier of gold surfaces, as determined using electron diffraction and computational methods. AB - The molecular structure of closo-9,12-(SH)2-1,2-C2B10H10 has been determined by the concerted use of quantum chemical calculations and gas electron diffraction (GED). For the purposes of GED, the architecture of the carbaborane cage was simplified to allow it to have C2v symmetry, while the positioning of the thiol groups means that the molecule had overall C1 symmetry. The accuracy of the experimental structure, as well as that calculated at the MP2(full)/6 311++G(3df,3pd) level, has been gauged by comparison of experimental (11)B NMR chemical shifts with those calculated using gauge-invariant atomic orbitals (GIAO) methods. The inclusion of electron correlation in the magnetic property calculations (GIAO-MP2) gave superior results to those carried out using GIAO-HF. The electronic structure of this derivative, with respect to its directional interaction with a metal surface, is outlined. PMID- 23817344 TI - Clinical outcomes after percutaneous coronary intervention in patients with mild versus moderate renal insufficiency at 30-day and 1-year follow-up. AB - Percutaneous coronary intervention (PCI) is a standard of care in the management of coronary artery disease in patients with renal insufficiency (RI). However, outcomes of PCI in these patients remain suboptimal with high cardiovascular morbidity and mortality. The studies comparing target vessel revascularization (TVR) after PCI in patients with mild and moderate RI have shown conflicting results. Hence, a meta-analysis of these studies comparing 30-day and 1-year outcomes after PCI was performed. A systematic review of literature revealed 5 studies involving 16,262 patients. Based on the creatinine clearance (CrCl), patients were divided into 2 groups (mild RI, CrCl > 60 mL/min and moderate RI, CrCl of 30-60 mL/min). End points extracted were all-cause mortality, TVR, myocardial infarction, and major adverse cardiac events at 30-day and 1-year follow-up. Combined relative risks (RR) across all the studies and 95% confidence intervals (CIs) were computed. A 2-sided alpha error of <0.05 was considered statistically significant. Both groups had similar baseline characteristics. Rate of TVR at 30 days was significantly lower in the mild RI group than in the moderate RI group (RR, 1.45; 95% CI, 1.04-2.02; P < 0.05). However, rate of TVR at 1-year follow-up was similar in both groups (RR, 1.02; 95% CI, 0.94-1.11; P, nonsignificant). Incidence of all-cause mortality, TVR, myocardial infarction, and major adverse cardiac events remained higher in the moderate RI group both at 30-day and 1-year follow-up (P < 0.05 for all outcomes). Patients with moderate RI have higher morbidity and mortality at 30 days and 1 year after PCI compared with patients with mild RI. However, there is no difference in the incidence of TVR after PCI at 1 year between the 2 groups. PMID- 23817345 TI - An echo-guided case report of rapid regression of unstable mobile thrombus aortic atheroma after aggressive statin and antiplatelet combination therapy. AB - We describe a case report that documented the efficacy and safety of medical therapy in stabilizing and resolving a complex and unstable aortic atheroma after a relatively short period. The patient had a large protruding, mobile, calcified nonulcerated atheroma involving the descending aorta and was therefore treated with aggressive combination therapy with high statin dosages (atorvastatin = 80 mg) and dual antiplatelet treatment (clopidogrel = 75 mg and aspirin = 100 mg). At follow-up, the echocardiogram showed a significant regression in the atheroma volume, with no signs suggestive of ulceration on its surface with the complete mobile component resolution. PMID- 23817346 TI - Effect of ofloxacin and norfloxacin on rifampicin pharmacokinetics in man. AB - The in vivo effects of norfloxacin (NXC) and ofloxacin (OXC) on rifampicin (RIF) pharmacokinetics were investigated in 5 apparently healthy volunteers aged 18-39 years after informed consent. The study was carried out in 3 phases with an interval drug washout period of at least 1 week in between the phases. In phase 1 (RIF alone), the subject received 600 mg of RIF. In phase 2 (RIF + OXC), 600 mg of RIF was coadministered with 200 mg of OXC. In phase 3 (RIF + NXC), each subject received 600 mg of RIF together with 400 mg of NXC after 1 week drug washout period. Drugs were taken orally with 350 mL of water after an overnight fast, and the subjects fasted 3 hours after the administration of drug. Plasma, saliva, and urine concentration of RIF were predetermined at 0 hour and then hourly until the 8th, 12th, 24th, and 48th hour. The urine samples were further collected at 72 hours after drug(s) administration using validated methods. Various pharmacokinetics parameters were calculated. NXC reduced the extent and rate of absorption of RIF. Various pharmacokinetic parameters of RIF significantly differ when administered alone or in combination with OXC and NXC. The mean saliva to plasma ratio of RIF concentration was approximately 0.15. The bioavailability indices of RIF in the saliva and plasma were similar in all the groups. Several pharmacokinetic parameters could be calculated using different body fluid concentrations of RIF. The determination of RIF levels in saliva may be useful in therapeutic drug monitoring and pharmacokinetic studies. PMID- 23817347 TI - Gaps in pre-rituximab hepatitis B screening: an institutional experience. AB - The aim of the study was to evaluate the pretreatment workup of patients referred to our tertiary care center with low-grade lymphoma for compliance with National Comprehensive Cancer Network guidelines. This was a retrospective chart review. The study included all new patients with low-grade lymphoma who were diagnosed and treated at our center from January 1, 2005, to December 30, 2011. All the major facets of pretreatment workup were examined, including bone marrow biopsy, lactate dehydrogenase, hepatitis B screening, performance status of the patient, and diagnostic radiological studies. A total of 53 new patients were identified, of whom 36 (68%) had pretreatment workup and treatment at our center. The median age at diagnosis was 67. Fifty-four percent of the patients had bone marrow biopsy done. Radiological diagnostic studies were conducted in 97% of the patients. Hepatitis B screening was done in 19% of the total patients and 25% of the patients who received rituximab. Lactate dehydrogenase levels were checked in 72% of the patients. A significant deviation from the National Comprehensive Cancer Network guidelines for low-grade lymphoma pretreatment workup was observed for hepatitis B screening. Measures to ensure that patients have hepatitis B screening before rituximab were implemented. Studies such as these help to improve patient care. PMID- 23817348 TI - Hilar clamping versus off-clamp laparoscopic partial nephrectomy for T1b tumors. AB - PURPOSE OF REVIEW: An off-clamp, or zero-ischemia, approach to laparoscopic partial nephrectomy has been a proposed means of preserving global renal function by preventing ischemia to normal renal parenchyma. However, for clinical stage T1b tumors this provides a unique challenge as the large size of these tumors further complicates an already difficult procedure. This review provides an overview of outcomes for laparoscopic partial nephrectomies performed with or without hilar clamping for clinical stage T1b tumors. RECENT FINDINGS: There is a paucity of data for laparoscopic partial nephrectomies for this larger tumor size. The feasibility of performing laparoscopic partial nephrectomy for renal tumors 4-7 cm in size has clearly been demonstrated. Not unexpectedly, using an off-clamp technique during laparoscopic partial nephrectomy has variably shown increased intraoperative blood loss when compared to hilar controlled procedures. This does not, however, seem to translate into increased risk of transfusion or loss of visualization leading to compromise in oncologic outcomes. Lastly, some data suggest improved short-term and long-term preservation of renal function as estimated by estimated glomerular filtration rate. SUMMARY: With accumulating data pointing to the long-term health benefits of nephron sparing surgery over radical nephrectomy and its oncologic equivalency confirmed, there is an increased push to perform partial nephrectomy for larger tumors. As demonstrated in the setting of a solitary kidney, every minute of warm ischemia counts and ischemia is an important modifiable variable that impacts renal function. As such, off-clamp dissection has potential advantages. The reviewed data show that foregoing hilar clamping for T1b tumors is not only feasible, but is likely beneficial with respect to renal function and does not appear to carry an increased risk of transfusion despite increased blood loss. PMID- 23817351 TI - Neuro-oncology: in search of molecular markers of glioma in elderly patients. PMID- 23817349 TI - Chronic low back pain: pharmacological, interventional and surgical strategies. AB - Chronic low back pain (CLBP) is a highly prevalent, costly and disabling condition that is associated with high levels of health-care resource utilization. Over the past few decades, there has been a paradigm shift in our understanding of CLBP. Nowadays, this condition is accepted as a biopsychosocial phenomenon in which anatomical injury interplays with psychosocial factors. The considerable progress made in elucidating the aetiology of low back pain and the sharp increase in related health-care costs have not translated into a decreased prevalence of CLBP or the development of therapies with markedly improved efficacy and safety. Classic medical-technical interventions for CLBP always need to be placed in a broader therapeutic framework comprising physical, psychosocial and behavioural strategies, and must address the patient's welfare in a holistic context. A common key finding in the literature on these interventions for CLBP is their disappointing magnitude of pain reduction and gain in functionality. This Review summarizes general concepts of CLBP and focuses on evidence supporting the classic medical-technical approaches to CLBP; that is, pharmacotherapy, interventional pain management and surgery. PMID- 23817350 TI - New treatments for mitochondrial disease-no time to drop our standards. AB - Mitochondrial dysfunction is a common cause of inherited multisystem disease that often involves the nervous system. Despite major advances in our understanding of the pathophysiology of mitochondrial diseases, clinical management of these conditions remains largely supportive. Using a systematic approach, we identified 1,039 publications on treatments for mitochondrial diseases, only 35 of which included observations on more than five patients. Reports of a positive outcome on the basis of a biomarker of unproven clinical significance were more common in nonrandomized and nonblinded studies, suggesting a publication bias toward positive but poorly executed studies. Although trial design is improving, there is a critical need to develop new biomarkers of mitochondrial disease. In this Perspectives article, we make recommendations for the design of future treatment trials in mitochondrial diseases. Patients and physicians should no longer rely on potentially biased data, with the associated costs and risks. PMID- 23817352 TI - Ground tit genome reveals avian adaptation to living at high altitudes in the Tibetan plateau. AB - The ground tit (Parus humilis) is endemic to the Tibetan plateau. It is a member of family Paridae but it was long thought to be related to the ground jays because of their morphological similarities. Here we present the ground tit's genome and re-sequence two tits and one ground jay, to clarify this controversially taxonomic status and uncover its genetic adaptations to the Tibetan plateau. Our results show that ground tit groups with two tits and it diverges from them between 7.7 and 9.9 Mya. Compared with other avian genomes, ground tit shows expansion in genes linked to energy metabolism and contractions in genes involved in immune and olfactory perception. We also found positively selected and rapidly evolving genes in hypoxia response and skeletal development. These results indicated that ground tit evolves basic strategies and 'tit-to-jay' change for coping with the life in an extreme environment. PMID- 23817353 TI - The love song of the headless fatty and other observations. PMID- 23817355 TI - Reynolds numbers influence the directionality of self-propelled microjet engines in the 10(-4) regime. AB - The motion directionality of self-propelled bubble-jet microengines is influenced by their velocities and/or viscosity of the media in which they move. The influence of the fuel concentration from 1 to 3 wt% of H2O2 in 0.5% steps and of the glycerol fraction from 0 to 64% in aqueous solution on the directionality of the microjets motions is examined systematically. We show that with decreasing Reynolds numbers of the system (that is, with increasing viscosity or decreasing velocity of the microjets), the directionality of the motion shifts from circular to linear motion. This translates to a shorter travel time towards a designated target for the microjets despite moving at a slower speed, since the movements are linear instead of circular. We show that such dependence of trajectories of microjets on Re is a general issue. This observation has a strong implication for the real-world applications of microjets. PMID- 23817354 TI - Major blunt trauma evokes selective upregulation of oxidative enzymes in circulating leukocytes. AB - Tissue injury, such as burns or inflammation, can lead to the generation of oxidized lipids capable of regulating hemodynamic, pulmonary, immune, and neuronal responses. However, it is not known whether traumatic injury leads to a selective upregulation of transcripts encoding oxidative enzymes capable of generating these mediators. Here, we analyzed microarrays taken from circulating leukocytes of 187 trauma subjects compared with 97 control volunteers for changes in the expression of 105 oxidative enzymes and related receptors. The results indicate that major blunt trauma triggers a selective change in gene expression, with some transcripts undergoing highly significant upregulation (e.g., CYP2C19), while others display significantly reduced expression (e.g., CYP2U1). This pattern in gene expression was maintained for up to 28 days after injury. In addition, the level of expression of CYP2A7, CYP2B7P1, CYP2C19, CYP2E1, CYP4A11, CYP4F3, CYP8B1, CYP19A1, CYP20A1, CYP51A1, HMOX2, NCF1, NCF2, and NOX1 and the receptors PTGER2 and ESR2 were correlated with clinical trauma indices such as APACHE II, Max Denver Scale, and the Injury Severity Score. Demonstration of a selective alteration in expression of transcripts encoding oxidative enzymes reveals a complex molecular response to major blunt trauma in circulating leukocytes. Furthermore, the association between changes in gene expression and clinical trauma scores suggests an important role in integrating pathophysiologic responses to blunt force trauma. PMID- 23817356 TI - [Primary prevention with enhancer substances for a longer and healthier life]. PMID- 23817357 TI - [Association between mood characteristics and polymorphisms of glial cell line derived neurotrophic factor (GNDF) in patients with depression]. AB - Glial cell line-derived neurotrophic factor (GNDF) plays an important role in the development and synaptic plasticity of dopaminergic neurons, thus it could be an important therapeutic factor in Parkinson's disease. Results from candidate gene studies of GDNF in psychiatric disorders are contradictory. Moreover, the possible association between GDNF polymorphisms and major- or bipolar depression has not been studied to date. Recently, our research group has published an association between two GDNF polymorphisms (rs3812047, rs3096140) and the individual variability of anxiety measured by the Hospital Anxiety and Depression Scale (HADS) on a non-clinical sample. In the present study we further analyzed this association on a sample with major- and bipolar depression: we used data from 183 MDD, 116 BP, and 1172 control subjects and tested effect of GDNF rs3812047 and rs3096140 polymorphisms on mood disorders. The case control design did not show significant differences in the genotype distribution of BP or MDD versus control patients. However, in the bipolar group subjects with rs3812047 A allele showed a significantly higher anxiety and depression mean score then subjects with G allele (p=0.043). This result supports our previous findings demonstrated on a non-clinical sample. Interestingly we found an opposite effect of the rs3812047 using data from MDD patients: subjects with the G allele had higher depression scores (p=0.012). An interaction effect of patient subgroups and genetic variants of the rs3812047 was observed for both HADS subscales (anxiety: p=0.029; depression: 0.004). In summary, we confirmed the previously published association between the rs3812047 A allele and mood characteristics on the bipolar sample, and an effect in the opposite direction was detected in the patient group with major depression. PMID- 23817358 TI - [Quality of life of patients with attention-deficit/hyperactivity disorder: systematic review of the past 5 years]. AB - AIMS: Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent childhood disorders which continues into adulthood in 30-60%. Many studies are interested in the examination of the impact of ADHD on QoL. The aim of the current study is to provide a systematic review of QoL studies in both children and adults with ADHD published in the past five years focusing on three domains: 1. The impact of ADHD on QoL 2. The impact of ADHD on QoL regarding age 3. The impact of ADHD on QoL regarding gender. METHOD: A systematic literature search was conducted using the following databases: sciencedirect.com and MEDLINE from 2008 to 2012. The following keywords were searched: quality of life, QoL, attention deficit/hyperactivity disorder, ADHD, gender differences, gender related, age differences, age-related. We included studies into our review which investigated both adults and children. Papers in English, German and Hungarian were included. RESULTS: Fourteen relevant articles were identified, among them 13 articles were in English, one in German and there were no articles in Hungarian. All of the 14 articles confirmed the negative effects of ADHD on QoL. Four studies dealt with the effects of ADHD on QoL regarding age: one paper claimed that older people with ADHD have more impairments, but have better lefi expectations than younger people with ADHD, one study claimed that increasing age raises the odds of poor QoL, while two studies did not find any changes on QoL of patients with ADHD regarding age. Three studies dealt with the effect of ADHD on QoL regarding the gender: two studies did not find difference on QoL of patients with ADHD, while one study found that women with ADHD have lower QoL. CONCLUSIONS: Based on the studies published in the last 5 years, patients with ADHD have lower QoL than healthy people; moreover, they have lower QoL in many areas than patients with several somatic or other mental illnesses. More studies are needed regarding the effects of ADHD on QoL by age and gender. PMID- 23817359 TI - [Pharmacological treatment in alcohol-, drug- and benzodiazepine-dependent patients - the significance of trazodone]. AB - Currently detoxification of drug and alcohol dependent patients is pharmacologically unresolved, and long-term treatment following the acute phase is also not very successful including a high number of relapses. We would need medications that on the short term cease: the severe vegetative symptoms, the pain, the extremely distressing psychosyndrome characterised by restlessness, anxiety or acute depressive symptoms, and the craving. The optimal would be if there was one medication capable of simultaneously alleviating or diminishing all the above symptoms without causing dependency and preventing relapse in the long term. Dependency is almost all cases accompanied by primary and/or secondary mood disorder or sleep disorder which should also be treated. It should be considered, however, that following withdrawal of the agent benzodiazepine dependency often develops. The serotonin antagonist and reuptake inhibitor (SARI) trazodone is effective in the treatment of depression accompanied by sleeping disorder and it has also shown efficacy in alcohol and benzodiazepine-dependency. Its administration may improve the efficacy of detoxification and treatment of following conditions, may decrease medication load and the risk of the development of benzodiazepine dependency. In our clinical practice we frequently use this agent to treat our patients simultaneously suffering from depression and addiction problems, gaining experience comparing it to other pharmacotherapies (benzodiazepines or other antidepressants). The medication is not approved for alcohol and drug dependence, however, treatment t of comorbid conditions is not against to the official recommendations. Our aim was, in addition to reviewing the literature, to share our experience which, although cannot be considered an evidence based study, we deemed worthy of publishing. We cannot, at this point, put forward a protocol addressing all related scientific problems and problems of off-label treatment, and we could not so far treat enough patients with trazodone so that our results would be statistically proven. "Acute" and long term treatment of dependency is not sufficiently effective with a substantial relapse rate, which is in part related to the lack of specific medication also for long term treatment. Among the available psychopharmacons, trazodone is a possible choice, since, as based on patients' reports and clinical observations, improvement of their depressive conditions and sleep problems potentially decreases the risk of relapse of drug and alcohol dependence. PMID- 23817360 TI - [Adult psychiatric aspects of Niemann-Pick disease]. AB - Niemann-Pick disease (NPD) is a group of distinct rare disorders (i.e. NPD-A; NPD B; NPD-C) - with autosomal recessive inheritance pattern - within the class of the inborn disorders of the sphingolipid metabolism (called sphingolipidoses). Since patients with NPD-A do not survive into adulthood and most patients with NPD-B are free from neuropsychiatric symptoms we discuss only briefly type-A and B NPD and mainly constrict our review discussing the neuropsychiatric symptoms along with the pathomechanism and the treatment of NPD-C. NPD-C is clinically heterogeneous, with notable variations in age at onset, course and symptoms. Along with systemic signs, neurologic and psychiatric symptoms are quite frequent in NPD-C and in its adult form sometimes psychiatric symptoms are the first ones appearing. Unfortunately, the majority of clinicans (including adult psychiatrists and neurologists) are not aware of the symptom group characteristic to NPD-C so patients with this disorder are frequently misdiagnosed in the clinical practice. Since neuropsychiatric manifestations of NPD-C may be treated with a substrate reduction agent (miglustat) with greater awareness of the identification of neuropsychiatric symptoms in due course is the prerequisite of proper and early diagnosis and treatment. PMID- 23817361 TI - [Olanzapine pamoate injection -- experience and case reports from Hungarian clinical practice]. AB - When treating schizophrenia and other psychotic disorders, clinicians often encounter the problems of non-adherence, which is almost the most common drawback of achieving remission and a better quality of life. The uncertain oral drug taking habits may lead to relapses and rehospitalizations. Using second generation long acting injectables we have more possibilities to avoid these problems. This review attempts to present and describe the pharmacological background of the modern long acting injectables including patient cases where olanzapine pamoate long acting injectable provided remission and better quality of life for the patients. PMID- 23817362 TI - Psychiatric intensive care of dementia praecox. AB - 33 year old British male's first presentation to mental health services was prompted by florid paranoid psychosis and volatile aggression. The patient developed agitated catatonia which eventually improved after 12 courses of ECT. The ongoing psychopharmacological management includes a second generation antipsychotic, a mood stabilizer antiepileptic and an anxiolytic. All investigations including blood tests, CSF analysis, urine and hair drug screen, CT and MRI scans with multidisciplinary medical consultations excluded any underlying pathology. The working diagnosis is an enduring paranoid psychosis with prominent signs of cognitive decline, all of which conclude to Kraepelin's Dementia Praecox. PMID- 23817363 TI - Autotransplantation of cryopreserved ovarian tissue in cancer survivors and the risk of reintroducing malignancy: a systematic review. AB - BACKGROUND The risk of recurrent oncological disease due to the reintroduction of cancer cells via autotransplantation of cryopreserved ovarian tissue is unknown. METHODS A systematic review of literature derived from MEDLINE, EMBASE and the Cochrane Library was conducted. Studies on follow-up after autotransplantation; detection of cancer cells in ovarian tissue from oncological patients by histology, polymerase chain reaction or xenotransplantation; and epidemiological data on ovarian metastases were included. RESULTS A total of 289 studies were included. Metastases were repeatedly detected in ovarian tissue obtained for cryopreservation purposes from patients with leukaemia, as well as in one patient with Ewing sarcoma. No metastases were detected in ovarian tissue from lymphoma and breast cancer patients who had their ovarian tissue cryopreserved. Clinical studies indicated that one should be concerned about autotransplantation safety in patients with colorectal, gastric and endometrial cancer. For patients with low-stage cervical carcinoma, clinical data were relatively reassuring, but studies focused on the detection of metastases were scarce. Oncological recurrence has been described in one survivor of cervical cancer and one survivor of breast cancer who had their ovarian tissue autotransplanted, although these recurrences may not be related to the transplantation. CONCLUSIONS It is advisable to refrain from ovarian tissue autotransplantation in survivors of leukaemia. With survivors of all other malignancies, current knowledge regarding the safety of autotransplantation should be discussed. The most reassuring data regarding autotransplantation safety were found for lymphoma patients. PMID- 23817364 TI - Two types of tetranuclear phosphanegold(I) cations as dimers of dinuclear units, [{(Au{P(p-RPh)3})2(MU-OH)}2]2+ (R = Me, F), synthesized by polyoxometalate mediated clusterization. AB - Novel intercluster compounds [{(Au{P(p-RPh)3})2(MU-OH)}2]3[alpha-PM12O40]2.nEtOH (R = Me, M = W for 1; R = Me, M = Mo for 2; R = F, M = Mo for 3) were synthesized by the polyoxometalate (POM)-mediated clusterization of monomeric phosphanegold(I) complexes, and unequivocally characterized by elemental analysis, TG/DTA, FTIR, X-ray crystallography, and (1)H and (31)P{(1)H} NMR. In each cluster cation, two digold(I) units, {Au{P(p-RPh)3})2(MU-OH)}(+), dimerized to form the tetragold(I) cluster cation by interdimer aurophilic interactions, i.e., a dimer of dinuclear units, and these cations showed different forms of structural dimerization, i.e., a crossed-edge arrangement for 1 and 2 and a parallel-edge arrangement for 3, depending upon the substituent on the aryl group of triarylphosphanes. The dimerization of digold(I) cations was affected by not only the type of the POMs, but also the phosphane ligand of the monomeric phosphanegold(I) precursors. PMID- 23817365 TI - In vitro antifungal activity of naftifine hydrochloride against dermatophytes. AB - The incidence of superficial dermatophytoses is high in developed countries, and there remains a need for effective topical antifungals. In this study, we evaluated the in vitro antifungal activity of naftifine hydrochloride, the active ingredient in naftifine hydrochloride cream and gel 1% and 2%, against dermatophytes. The MICs and minimum fungicidal concentrations (MFCs) of naftifine hydrochloride against 350 clinical strains, including Trichophyton rubrum, T. mentagrophytes, T. tonsurans, Epidermophyton floccosum, and Microsporum canis, were determined using the CLSI methodology. Subsets from this test panel were subsequently tested in a time-kill assay at 0.125*, 0.25*, 0.5*, and 1* the MFC for each isolate. CFU counts were performed over a period of 48 h of incubation. Additionally, in order to determine the potential for resistance development, six strains were subjected to 15 serial passages in concentrations higher than the MIC for each strain. MICs were determined following each passage. The MIC range against the dermatophyte isolates tested was 0.015 to 1.0 MUg/ml, with naftifine hydrochloride being fungicidal against 85% of the Trichophyton species. The time kill assay showed dose-dependent activity, with the greatest reduction in the numbers of CFU corresponding to the highest drug concentration. There was no increase in MIC for any strains following repeated exposure to naftifine hydrochloride. Naftifine hydrochloride demonstrated potent activity against all dermatophytes tested, and none of the isolates within this test panel demonstrated the potential for the development of resistance. Thus, future clinical studies of naftifine hydrochloride against dermatophytes may be warranted for the treatment of superficial dermatophytoses. PMID- 23817366 TI - Hyperthermia sensitizes Rhizopus oryzae to posaconazole and itraconazole action through apoptosis. AB - The high mortality rate of mucormycosis with currently available monotherapy has created interest in studying novel strategies for antifungal agents. With the exception of amphotericin B (AMB), the triazoles (posaconazole [PCZ] and itraconazole [ICZ]) are fungistatic in vitro against Rhizopus oryzae . We hypothesized that growth at a high temperature (42 degrees C) results in fungicidal activity of PCZ and ICZ that is mediated through apoptosis. R. oryzae had high MIC values for PCZ and ICZ (16 to 64 MUg/ml) at 25 degrees C; in contrast, the MICs for PCZ and ICZ were significantly lower at 37 degrees C (8 to 16 MUg/ml) and 42 degrees C (0.25 to 1 MUg/ml). Furthermore, PCZ and ICZ dose dependent inhibition of germination was more pronounced at 42 degrees C than at 37 degrees C. In addition, intracellular reactive oxygen species (ROS) increased significantly when fungi were exposed to antifungals at 42 degrees C. Characteristic cellular changes of apoptosis in R. oryzae were induced by the accumulation of intracellular reactive oxygen species. Cells treated with PCZ or ICZ in combination with hyperthermia (42 degrees C) exhibited characteristic markers of early apoptosis: phosphatidylserine externalization visualized by annexin V staining, membrane depolarization visualized by bis-[1,3 dibutylbarbituric acid] trimethine oxonol (DiBAC) staining, and increased metacaspase activity. Moreover, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assay and DAPI (4',6-diamidino-2 phenylindole) staining demonstrated DNA fragmentation and condensation, respectively. The addition of N-acetylcysteine increased fungal survival, prevented apoptosis, reduced ROS accumulation, and decreased metacaspase activation. We concluded that hyperthermia, either alone or in the presence of PCZ or ICZ, induces apoptosis in R. oryzae. Local thermal delivery could be a therapeutically useful adjunct strategy for these refractory infections. PMID- 23817367 TI - Identification of an aminothiazole with antifungal activity against intracellular Histoplasma capsulatum. AB - As eukaryotes, fungi possess relatively few molecules sufficiently unique from mammalian cell components to be used as drug targets. Consequently, most current antifungals have significant host cell toxicity. Primary fungal pathogens (e.g., Histoplasma) are of particular concern, as few antifungals are effective in treating them. To identify additional antifungal candidates for the treatment of histoplasmosis, we developed a high-throughput platform for monitoring Histoplasma growth and employed it in a phenotypic screen of 3,600 commercially available compounds. Seven hit compounds that inhibited Histoplasma yeast growth were identified. Compound 41F5 has fungistatic activity against Histoplasma yeast at micromolar concentrations, with a 50% inhibitory concentration (IC50) of 0.87 MUM, and has the greatest selectivity for yeast (at least 62-fold) relative to host cells. Structurally, 41F5 consists of an aminothiazole core with an alicyclic substituent at the 2-position and an aromatic substituent at the 5 position. 41F5 inhibits Histoplasma growth in liquid culture and similarly inhibits yeast cells within macrophages, the actual host environment of this fungal pathogen during infection. Importantly, 41F5 protects infected host cells from Histoplasma-induced macrophage death, making this aminothiazole hit compound an excellent candidate for development as an antifungal for Histoplasma infections. PMID- 23817368 TI - Rapid emergence of echinocandin resistance in Candida glabrata resulting in clinical and microbiologic failure. AB - We report a case of Candida glabrata candidemia that developed resistance to micafungin within 8 days of initiation of therapy in a patient without previous echinocandin exposure or other known risk factors for clinical or microbiological failure. Pre- and postresistant isolates were confirmed to be isogenic, and sequencing of hot spots known to confer echinocandin resistance revealed a phenylalanine deletion at codon 659 within FKS2. PMID- 23817369 TI - Tigecycline induction of phenol-soluble modulins by invasive methicillin resistant Staphylococcus aureus strains. AB - We examined the effects of tigecycline on three types of exoproteins, alpha-type phenol-soluble modulins (PSMalpha1 to PSMalpha4), alpha-hemolysin, and protein A, in 13 methicillin-resistant Staphylococcus aureus isolates compared to those of clindamycin and linezolid. Paradoxical increases in PSMalphas occurred in 77% of the isolates with tigecycline at 1/4 and 1/8 MICs and clindamycin at 1/8 MIC compared to only 23% of the isolates with linezolid at 1/8 MIC. Induction was specific to PSMalpha1 to PSMalpha4, as protein A and alpha-hemolysin production was decreased under the same conditions by all of the antibiotics used. PMID- 23817370 TI - Characterization of Tn5801.Sag, a variant of Staphylococcus aureus Tn916 family transposon Tn5801 that is widespread in clinical isolates of Streptococcus agalactiae. AB - Tn5801, originally detected in Staphylococcus aureus Mu50, is a Tn916 family element in which a unique int gene (int5801) replaces the int and xis genes in Tn916 (int916 and xis916). Among 62 tet(M)-positive tetracycline-resistant Streptococcus agalactiae isolates, 43 harbored Tn916, whereas 19 harbored a Tn5801-like element (Tn5801.Sag, ~20.6 kb). Tn5801.Sag was characterized (PCR mapping, partial sequencing, and chromosomal integration) and compared to other Tn5801-like elements. Similar to Tn5801 from S. aureus Mu50, tested in parallel, Tn5801.Sag was unable to undergo circularization and conjugal transfer. PMID- 23817371 TI - Human beta-defensin 2 induces extracellular accumulation of adenosine in Escherichia coli. AB - Human beta-defensins are host defense peptides performing antimicrobial as well as immunomodulatory functions. The present study investigated whether treatment of Escherichia coli with human beta-defensin 2 could generate extracellular molecules of relevance for immune regulation. Mass spectrometry analysis of bacterial supernatants detected the accumulation of purine nucleosides triggered by beta-defensin 2 treatment. Other cationic antimicrobial peptides tested presented variable outcomes with regard to extracellular adenosine accumulation; human beta-defensin 2 was the most efficient at inducing this response. Structural and biochemical evidence indicated that a mechanism other than plain lysis was involved in the observed phenomenon. By use of isotope ((13)C) labeling, extracellular adenosine was found to be derived from preexistent RNA, and a direct interaction between the peptide and bacterial nucleic acid was documented for the first time for beta-defensin 2. Taken together, the data suggest that defensin activity on a bacterial target may alter local levels of adenosine, a well-known immunomodulator influencing inflammatory processes. PMID- 23817372 TI - Role of 6-gingerol in reduction of cholera toxin activity in vitro and in vivo. AB - Vibrio cholerae is one of the major bacterial pathogens responsible for the devastating diarrheal disease called cholera. Chemotherapy is often used against V. cholerae infections; however, the emergence of V. cholerae with multidrug resistance (MDR) toward the chemotherapeutic agents is a serious clinical problem. This scenario has provided us with the impetus to look into herbal remediation, especially toward blocking the action of cholera toxin (CT). Our studies were undertaken to determine the antidiarrheal potential of 6-gingerol (6G) on the basis of its effect on CT, the virulence factor secreted by V. cholerae. We report here that 6G binds to CT, hindering its interaction with the GM1 receptor present on the intestinal epithelial cells. The 50% inhibitory concentration (IC50) was determined to be 10 MUg/ml. The detailed mechanistic study was conducted by enzyme-linked immunosorbent assay (ELISA), fluorescence spectroscopy, and isoelectric focusing. These results were validated with in vitro studies performed with the CHO, HeLa, and HT-29 cell lines, whereas a rabbit ileal loop assay was done to estimate the in vivo action, which confirms the efficacy of 6G in remediation of the choleragenic effects of CT. Thus, 6G can be an effective adjunctive therapy with oral rehydration solution for severe CT mediated diarrhea. PMID- 23817373 TI - Synergistic effects of anti-CmeA and anti-CmeB peptide nucleic acids on sensitizing Campylobacter jejuni to antibiotics. AB - The CmeABC efflux pump in Campylobacter jejuni confers resistance to structurally divergent antimicrobials, and inhibition of CmeABC represents a promising strategy to control antibiotic-resistant Campylobacter. Antisense peptide nucleic acids (PNAs) targeting the three components of CmeABC were evaluated for inhibition of CmeABC expression. The result revealed a synergistic effect of the PNAs targeting CmeA and CmeB on sensitizing C. jejuni to antibiotics. This finding further demonstrates the feasibility of using PNAs to potentiate antibiotics against antibiotic-resistant Campylobacter. PMID- 23817374 TI - OqxAB, a quinolone and olaquindox efflux pump, is widely distributed among multidrug-resistant Klebsiella pneumoniae isolates of human origin. PMID- 23817375 TI - Effect of prednisone on the pharmacokinetics of the integrase inhibitor dolutegravir. AB - Prednisone, a corticosteroid frequently used to treat common AIDS-related illnesses and comorbidities, has been shown to induce drug metabolism. This study was performed to determine whether prednisone coadministration affected the pharmacokinetics of dolutegravir (DTG). In this open-label, repeat-dose study, 12 healthy subjects were administered DTG at 50 mg daily alone for 5 days and then with concomitant prednisone for 10 days (prednisone at 60 mg daily for 5 days, followed by a 5-day taper). Serial blood sampling and safety assessments were performed during the trial. Pharmacokinetic parameters were determined using noncompartmental methods and geometric least-square mean ratios, and 90% confidence intervals were generated. Coadministration of DTG and 5-day high-dose prednisone with a 5-day taper had a modest effect on DTG exposure. The area under the DTG plasma concentration-time curve, maximum observed DTG concentration, and 24-hour postdose DTG concentration were increased by 11%, 6%, and 17%, respectively, on day 10 of the combination. Similar results were observed after 5 days of DTG and prednisone. Dolutegravir and prednisone coadministration was well tolerated. The changes in plasma exposures of DTG in healthy individuals as a result of prednisone dosing were not clinically significant. No dose adjustment is required for DTG coadministered with prednisone. (This study has been registered at ClinicalTrials.gov under registration no. NCT01425099.). PMID- 23817376 TI - Establishment of a method to rapidly assay bacterial persister metabolism. AB - Bacterial persisters exhibit an extraordinary tolerance to antibiotics that is dependent on their metabolic state. Although persister metabolism promises to be a rich source of antipersister strategies, there is relatively little known about the metabolism of these rare and transient phenotypic variants. To address this knowledge gap, we explored the use of several techniques, and we found that only one measured persister metabolism. This assay was based on the phenomenon of metabolite-enabled aminoglycoside killing of persisters, and we used it to characterize the metabolic heterogeneity of different persister populations. From these investigations, we determined that glycerol and glucose are the most ubiquitously used carbon sources by various types of Escherichia coli persisters, suggesting that these metabolites might prove beneficial to deliver in conjunction with aminoglycosides for the treatment of chronic and recurrent infections. In addition, we demonstrated that the persister metabolic assay developed here is amenable to high-throughput screening with the use of phenotype arrays. PMID- 23817377 TI - The equine antimicrobial peptide eCATH1 is effective against the facultative intracellular pathogen Rhodococcus equi in mice. AB - Rhodococcus equi, the causal agent of rhodococcosis, is a major pathogen of foals and is also responsible for severe infections in immunocompromised humans. Of great concern, strains resistant to currently used antibiotics have emerged. As the number of drugs that are efficient in vivo is limited because of the intracellular localization of the bacterium inside macrophages, new active but cell-permeant drugs will be needed in the near future. In the present study, we evaluated, by in vitro and ex vivo experiments, the ability of the alpha-helical equine antimicrobial peptide eCATH1 to kill intracellular bacterial cells. Moreover, the therapeutic potential of the peptide was assessed in experimental rhodococcosis induced in mice, while the in vivo toxicity was evaluated by behavioral and histopathological analysis. The study revealed that eCATH1 significantly reduced the number of bacteria inside macrophages. Furthermore, the bactericidal potential of the peptide was maintained in vivo at doses that appeared to have no visible deleterious effects for the mice even after 7 days of treatment. Indeed, daily subcutaneous injections of 1 mg/kg body weight of eCATH1 led to a significant reduction of the bacterial load in organs comparable to that obtained after treatment with 10 mg/kg body weight of rifampin. Interestingly, the combination of the peptide with rifampin showed a synergistic interaction in both ex vivo and in vivo experiments. These results emphasize the therapeutic potential that eCATH1 represents in the treatment of rhodococcosis. PMID- 23817378 TI - Immunoactivating peptide p4 augments alveolar macrophage phagocytosis in two diverse human populations. AB - New treatment strategies are urgently needed to overcome early mortality in acute bacterial infections. Previous studies have shown that administration of a novel immunoactivating peptide (P4) alongside passive immunotherapy prevents the onset of septicemia and rescues mice from lethal invasive disease models of pneumococcal pneumonia and sepsis. In this study, using two diverse populations of adult volunteers, we determined whether P4 treatment of human alveolar macrophages would upregulate phagocytic killing of Streptococcus pneumoniae ex vivo. We also measured macrophage intracellular oxidation, cytokine secretion, and surface marker expression following stimulation. Peptide treatment showed enhanced bacterial killing in the absence of nonspecific inflammation, consistent with therapeutic potential. This is the first demonstration of P4 efficacy on ex vivo-derived human lung cells. PMID- 23817379 TI - The BpeEF-OprC efflux pump is responsible for widespread trimethoprim resistance in clinical and environmental Burkholderia pseudomallei isolates. AB - Trimethoprim-sulfamethoxazole (co-trimoxazole) is the primary drug used for oral eradication therapy of Burkholderia pseudomallei infections (melioidosis). Here, we demonstrate that trimethoprim resistance is widespread in clinical and environmental isolates from northeast Thailand and northern Australia. This resistance was shown to be due to BpeEF-OprC efflux pump expression. No dihydrofolate reductase target mutations were involved, although frequent insertion of ISBma2 was noted within the putative folA transcriptional terminator. All isolates tested remained susceptible to trimethoprim sulfamethoxazole, suggesting that resistance to trimethoprim alone in these strains probably does not affect the efficacy of co-trimoxazole therapy. PMID- 23817380 TI - Evaluation of the Carba NP test for rapid detection of carbapenemase-producing Enterobacteriaceae and Pseudomonas aeruginosa. AB - The Carba NP test was evaluated against a panel of 244 carbapenemase- and non carbapenemase-producing Enterobacteriaceae and Pseudomonas aeruginosa isolates. We confirmed the 100% specificity and positive predictive value of the test, but the sensitivity and negative predictive value were 72.5% and 69.2%, respectively, and increased to 80% and 77.3%, respectively, using a more concentrated bacterial extract. False-negative results were associated with mucoid strains or linked to enzymes with low carbapenemase activity, particularly OXA-48-like, which has emerged globally in enterobacteria. PMID- 23817381 TI - Bacterial peritonitis due to Acinetobacter baumannii sequence type 25 with plasmid-borne new delhi metallo-beta-lactamase in Honduras. AB - A carbapenem-resistant Acinetobacter baumannii strain was isolated from the peritoneal fluid of a patient with complicated intra-abdominal infection and evaluated at the Multidrug-resistant Organism Repository and Surveillance Network by whole-genome sequencing and real-time PCR. The isolate was sequence type 25 and susceptible to colistin and minocycline, with low MICs of tigecycline. blaNDM 1 was located on a plasmid with >99% homology to pNDM-BJ02. The isolate carried numerous other antibiotic resistance genes, including the 16S methylase gene, armA. PMID- 23817382 TI - Relationship between trough plasma and epithelial lining fluid concentrations of voriconazole in lung transplant recipients. AB - Trough (predose) voriconazole concentrations in plasma and pulmonary epithelial lining fluid (ELF) of lung transplant recipients receiving oral voriconazole preemptive treatment were determined. The mean (+/- standard deviation [SD]) ELF/plasma ratio was 12.5 +/- 6.3. A strong positive linear relationship was noted between trough plasma and ELF voriconazole concentrations (r(2) = 0.87), suggesting the feasibility of using trough plasma voriconazole concentration as a surrogate to estimate the corresponding concentration in ELF of lung transplant recipients. PMID- 23817383 TI - Antibiotic reduction campaigns do not necessarily decrease bacterial resistance: the example of methicillin-resistant Staphylococcus aureus. AB - Interventions designed to reduce antibiotic consumption are under way worldwide. While overall reductions are often achieved, their impact on the selection of antibiotic-resistant selection cannot be assessed accurately from currently available data. We developed a mathematical model of methicillin-sensitive and methicillin-resistant Staphylococcus aureus (MSSA and MRSA) transmission inside and outside the hospital. A systematic simulation study was then conducted with two objectives: to assess the impact of antibiotic class-specific changes during an antibiotic reduction period and to investigate the interactions between antibiotic prescription changes in the hospital and the community. The model reproduced the overall reduction in MRSA frequency in French intensive-care units (ICUs) with antibiotic consumption in France from 2002 to 2003 as an input. However, the change in MRSA frequency depended on which antibiotic classes changed the most, with the same overall 10% reduction in antibiotic use over 1 year leading to anywhere between a 69% decrease and a 52% increase in MRSA frequency in ICUs and anywhere between a 37% decrease and a 46% increase in the community. Furthermore, some combinations of antibiotic prescription changes in the hospital and the community could act in a synergistic or antagonistic way with regard to overall MRSA selection. This study shows that class-specific changes in antibiotic use, rather than overall reductions, need to be considered in order to properly anticipate the impact of an antibiotic reduction campaign. It also highlights the fact that optimal gains will be obtained by coordinating interventions in hospitals and in the community, since the effect of an intervention in a given setting may be strongly affected by exogenous factors. PMID- 23817384 TI - Resistance of human cytomegalovirus to cyclopropavir maps to a base pair deletion in the open reading frame of UL97. AB - Human cytomegalovirus (HCMV) is a widespread pathogen in the human population, affecting many immunologically immature and immunocompromised patients, and can result in severe complications, such as interstitial pneumonia and mental retardation. Current chemotherapies for the treatment of HCMV infections include ganciclovir (GCV), foscarnet, and cidofovir. However, the high incidences of adverse effects (neutropenia and nephrotoxicity) limit the use of these drugs. Cyclopropavir (CPV), a guanosine nucleoside analog, is 10-fold more active against HCMV than GCV (50% effective concentrations [EC50s] = 0.46 and 4.1 MUM, respectively). We hypothesize that the mechanism of action of CPV is similar to that of GCV: phosphorylation to a monophosphate by viral pUL97 protein kinase with further phosphorylation to a triphosphate by endogenous kinases, resulting in inhibition of viral DNA synthesis. To test this hypothesis, we isolated a CPV resistant virus, sequenced its genome, and discovered that bp 498 of UL97 was deleted. This mutation caused a frameshift in UL97 resulting in a truncated protein that lacks a kinase domain. To determine if this base pair deletion was responsible for drug resistance, the mutation was engineered into the wild-type viral genome, which was then exposed to increasing concentrations of CPV. The results demonstrate that the engineered virus was approximately 72-fold more resistant to CPV (EC50 = 25.8 +/- 3.1 MUM) than the wild-type virus (EC50 = 0.36 +/- 0.11 MUM). We conclude, therefore, that this mutation is sufficient for drug resistance and that pUL97 is involved in the mechanism of action of CPV. PMID- 23817386 TI - Improvement of LATE-PCR to allow single-cell analysis by pyrosequencing. AB - Nucleic acid analysis in a single cell is very important, but the extremely small amount of template in a single cell requires a detection method more sensitive than the conventional method. In this paper, we describe a novel assay allowing a single cell genotyping by coupling improved linear-after-the-exponential-PCR (imLATE-PCR) on a modified glass slide with highly sensitive pyrosequencing. Due to the significantly increased yield of ssDNA in imLATE-PCR amplicons, it is possible to employ pyrosequencing to sequence the products from 1 MUL chip PCR which directly used a single cell as the starting material. As a proof-of concept, the 1555A>G mutation (related to inherited deafness) on mitochondrial DNA and the SNP 2731C>T of the BRCA1 gene on genomic DNA from a single cell were successfully detected, indicating that our single-cell-pyrosequencing method has high sensitivity, simple operation and is low cost. The approach has promise to be of efficient usage in the fields of diagnosis of genetic disease from a single cell, for example, preimplantation genetic diagnosis (PGD). PMID- 23817385 TI - Discovery of novel small-molecule HIV-1 replication inhibitors that stabilize capsid complexes. AB - The identification of novel antiretroviral agents is required to provide alternative treatment options for HIV-1-infected patients. The screening of a phenotypic cell-based viral replication assay led to the identification of a novel class of 4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6-one (pyrrolopyrazolone) HIV 1 inhibitors, exemplified by two compounds: BI-1 and BI-2. These compounds inhibited early postentry stages of viral replication at a step(s) following reverse transcription but prior to 2 long terminal repeat (2-LTR) circle formation, suggesting that they may block nuclear targeting of the preintegration complex. Selection of viruses resistant to BI-2 revealed that substitutions at residues A105 and T107 within the capsid (CA) amino-terminal domain (CANTD) conferred high-level resistance to both compounds, implicating CA as the antiviral target. Direct binding of BI-1 and/or BI-2 to CANTD was demonstrated using isothermal titration calorimetry and nuclear magnetic resonance (NMR) chemical shift titration analyses. A high-resolution crystal structure of the BI 1:CANTD complex revealed that the inhibitor bound within a recently identified inhibitor binding pocket (CANTD site 2) between CA helices 4, 5, and 7, on the surface of the CANTD, that also corresponds to the binding site for the host factor CPSF-6. The functional consequences of BI-1 and BI-2 binding differ from previously characterized inhibitors that bind the same site since the BI compounds did not inhibit reverse transcription but stabilized preassembled CA complexes. Hence, this new class of antiviral compounds binds CA and may inhibit viral replication by stabilizing the viral capsid. PMID- 23817387 TI - Nanomaterial modified electrodes: evaluating oxygen reduction catalysts. AB - Intense current research is directed at the evaluation of nanomaterials as catalysts for the oxygen reduction reaction. This is commonly undertaken by means of voltammetric measurements supported on an electrode surface presumed inert other than for providing electrical contact. At their basis these factors usually involve measurement of a current or current density, measured at a fixed potential. However we now report that the current/current density at a fixed potential can vary with the surface coverage of the nanoparticles in the catalyst, without any change in fundamental kinetic or thermodynamic parameters, even though the voltammetric signal shows that the reduction is fully transport controlled. This finding leads us to the conclusion that caution should be expressed when comparing catalysts in this way. In particular the essential need is emphasised for characterising the coverage, porosity and particle size, when inferring inherent electrochemical activity and using a suitable physical model to extract catalytic parameters. PMID- 23817388 TI - The effect of the molecular structures of dicyanomethylene compounds on their supramolecular assembly, photophysical and electrochemical properties. AB - Two series of flexible dicyanomethylene compounds, specifically, class 1 and class 2 compounds, have been designed and synthesised. In class 1 compounds, the dicyanomethylene groups are separated by glycol chain spacers of different lengths, whereas, in class 2 compounds, the spacers are alkyl linkers of different lengths. The notion underlying the design of these compounds is that in class 1 molecules, the spacers contain donor oxygen atoms that could not only form hydrogen bonds during the course of crystal packing but also promote withdrawing effects that modify the photophysical and electrochemical properties of these molecules in solution; in contrast, these effects would be absent for class 2 molecules. However, this study revealed that, with respect to crystal packing, the size of the spacers and their even and odd numbers of atoms are more important than their chemical nature. All of the synthesised compounds exhibited blue emission in the solid state and in CH2Cl2 solutions. The photophysical and electrochemical properties of these compounds in solution were not significantly affected by the type and length of the spacer that was used in each molecule. In the solid state, however, the compound with the shortest spacer showed the highest Stokes shift. The electronic transitions for the synthesized compounds in solution were explained by density functional theory and time-dependent density functional theory calculations, which indicated that the methylene moieties control the properties of both classes of compounds and that the spacers do not conjugate with the end groups. These two series of flexible dicyanomethylene compounds could be utilised as molecular building blocks for the development of new solids with novel properties. PMID- 23817389 TI - Children, stigma, and obesity. PMID- 23817390 TI - Ceragenin CSA-13 induces cell cycle arrest and antiproliferative effects in wild type and p53 null mutant HCT116 colon cancer cells. AB - Antimicrobial peptides of the cathelicidin family play a central role in the host defense system. Our group has reported previously that cathelicidin-related or cathelicidin-modified antimicrobial peptides, such as FF/CAP-18, have antiproliferative effects on the squamous cell carcinoma cell line SAS-H1 and colon cancer-derived cell line HCT116. Ceragenin CSA-13, which mimics the hydrophobic and cationic morphology of cathelicidin-related peptides, was developed to reduce synthetic costs and resolve stability issues in the presence of proteases. In this study, we evaluated the antiproliferative effect of CSA-13 on HCT116 cells. We evaluated the effects of CSA-13 in HCT116 cells by measuring cell growth, detecting apoptosis, analyzing the cell cycle, and examining mitochondrial membrane depolarization. Treatment with CSA-13 suppressed HCT116 cell proliferation in a dose-dependent manner, increasing the incidence of apoptosis detected by the binding of Annexin V. Furthermore, cell cycle analysis showed that the cell cycle of CSA-13-treated wild-type and p53 null mutant HCT116 cells was arrested at the G1/S phase, indicating that CSA-13 affects the cell cycle by a p53-independent pathway. Our study showed that CSA-13 exerts an antiproliferative effect in cancer cells similar to that of FF/CAP-18, suggesting that membrane-permeabilizing capability is the common underlying mechanism for anticancer and antimicrobial effects of CSA-13 and anitimicrobial peptides. PMID- 23817391 TI - Obesity-related complications: few biochemical phenomena with reference to tumorigenesis. AB - Overweight or obesity is currently a common health problem in westernized societies globally. Obesity is linked with a sizeable number of disease aetiologies, notably type-2 diabetes, cardiovascular disorders and certain cancers, perhaps through some common mechanisms that favor persistent low-grade inflammation. Both epidemiological and laboratory studies have demonstrated that the pathogenesis of certain cancers and the related prognosis are influenced by obesity. Clinically, a complex situation is present in obesity, which usually shows higher blood levels of various biomolecules, e.g., lipids like triglycerides, hormones like insulin, and fat cell-secreted adipokines like leptin. On the contrary, obesity is associated with lower concentrations of substances like sex hormone-binding globulin and adiponectin. Many of these biochemical compounds are used routinely for clinical diagnosis and assessment during the follow-up period. Nonetheless, approximately one-fifth of the total cancer burden is associated with obesity. Excess adipose tissue and different hormonal substances possibly play a significant role in this complex obesity related carcinogenesis. A precise understanding of the pertinent pathological processes is definitely useful in early diagnosis, clinical management, and designing of novel pharmaceutical agents. PMID- 23817392 TI - Cellular mechanisms of emerging applications of mesenchymal stem cells. AB - Mesenchymal stem cells (MSC) are multipotent, self-renewing cells that can be found mainly in the bone marrow, and other post-natal organs and tissues. The ease of isolation and expansion, together with the immunomodulatory properties and their capability to migrate to sites of inflammation and tumours make them a suitable candidate for therapeutic use in the clinical settings. We review here the cellular mechanisms underlying the emerging applications of MSC in various fields. PMID- 23817393 TI - SNP array technology: an array of hope in breast cancer research. AB - Breast cancer is the most common malignancy in women worldwide. The incidence of breast cancer in Malaysia is lower compared to international statistics, with peak occurrence in the age group between 50 to 59 years of age and mortality rates of 18.6%. Despite current diagnostic and prognostic methods, the outcome for individual subjects remain poor. This is in part due to breast cancers' wide genetic heterogeneity. Various platforms for genetics studies are now employed to determine the identity of these genetic abnormalities, including microarray methods like high density single-nucleotide-polymorphism (SNP) oligonucleotide arrays which combine the power of chromosomal comparative genomic hybridization (cCGH) and loss of heterozygosity (LOH) in the offering of higher-resolution mappings. These platforms and their applications in highlighting the genomic alteration frameworks manifested in breast carcinoma will be discussed. PMID- 23817394 TI - Pattern of hMLH1, hMSH2 and hMSH6 expression and clinical characteristics in a sample of Malaysian colorectal carcinoma cases. AB - Malignant transformation from normal colonic mucosa to carcinomas may be accelerated by genetic loss or inactivation of genes of the DNA mismatch repair system. The aim of the study was to determine the local incidence and pattern of immunohistochemical expression of mismatch repair proteins namely: hMLH1, hMSH2 and hMSH6 in a series of colorectal carcinomas (CRCs) and correlate this to their clinical and pathological features. Forty-three out of 298 cases of CRCs (14.4%) showed abnormal staining pattern for mismatch repair proteins with a majority (65.1%) showing single hMLH1 loss. Tumours with mismatch repair defect (MMR-d) were frequently found at the right side of colon (p<0.001), poorly differentiated carcinomas (p<0.001), produced more mucin (p=0.007), exophytic growth (p=0.007) and were bigger (p=0.002) than tumours with no mismatch repair defect. Immunohistochemical stains for mismatch repair proteins could be done in local laboratories on these selected cases before referring for the expensive molecular test. PMID- 23817395 TI - Importance of screening for macroprolactin in all hyperprolactinaemic sera. AB - INTRODUCTION: Prolactin (PRL) exists in different forms in human serum. The predominant form is monomeric PRL (molecular mass 23 kDa) with smaller amounts of big PRL (molecular mass 50-60 kDa) and at times macroprolactin (molecular mass 150-170 kDa). Macroprolactin, generally considered to be biologically inactive, accounts for the major part of prolactin in some patients. Different immunoassays for prolactin differ in reactivity with this macromolecular complex. AIM: The present study was undertaken to assess the incidence of macroprolactinaemia in our cohort of hyperprolactinemic patients. METHOD: 204 samples with hyperprolactinemia were evaluated for macroprolactinemia by polyethylene glycol (PEG) precipitation and gel filtration chromatography (GFC). Recoveries <=60% after PEG precipitation were considered to have macroprolactinaemia. RESULTS: A total of 43 (21%) of these patients had less than 60% recovery after PEG precipitation. GFC confirmed that in seven of these patients macroprolactin was the major part of the prolactin. Recoveries were < 40% PEG precipitation in these samples. Combined macro and hyperprolactinemia was observed in two samples and the recovery after PEG precipitation was >40% but <=50%. The incidence of macroprolactinemia in our cohort of hyperprolactinaemic patients was noted to be 4.4%. CONCLUSION: Macroprolactin is a significant cause of misdiagnosis, unnecessary investigation, and inappropriate treatment and hence it is useful to screen all patients with high PRL levels with PEG precipitation and to apply GFC to samples with recoveries <50%. PMID- 23817396 TI - HLA DR/DQ type in a Malay population in Kelantan, Malaysia. AB - The human leucocyte antigen (HLA) has been documented to be involved in various disease susceptibilities or in resistance against certain diseases. An important element in susceptibility and resistance to disease is ethnic genetic constitution. Cognizant of this, the present study aimed at studying the prevalence of particular HLA class II in a normal healthy Malay population which may serve as a guide for further genetic and immunological studies related to the Malay Malaysian population. The study involved 40 normal healthy Malay persons in Kelantan. HLA typing was conducted on venous blood samples through a polymerase chain reaction-sequence specific primer method (low resolution Olerup SSP(c) HLA Typing Kits). The study found HLA DR12 and HLA DQ8 to be the most frequent HLA class II type. HLA DQ5 was significantly associated with female subjects. PMID- 23817397 TI - Review of patients with Strongyloides stercoralis infestation in a tertiary teaching hospital, Kelantan. AB - Strongyloides stercoralis is an intestinal nematode infecting humans. The actual prevalence of infestation with this parasite in our setting is not well established. Thus, this study was conducted to determine the age, sex and co morbid conditions among patients with S. stercoralis infestation as well as to study the common manifestations of strongyloidiasis in our patients. Records of patients with positive S. stercoralis larvae from January 2000 to December 2012 in Hospital Universiti Sains Malaysia, Kubang Kerian, Kelantan were reviewed. Ten patients were male and two were female. Their ages ranged from 19 to 78 years old. The majority (92%) of cases, presented with intestinal symptoms and 50% with moderate to severe anaemia. Thirty percent of cases had extraintestinal manifestations such as cough, sepsis and pleural effusion. Ninety-two percent of the patients had a comorbid illness. Most patients were immunocompromised, with underlying diabetes mellitus, retroviral disease, lymphoma and steroid therapy contributing to about 58% of cases. Only 58% were treated with anti-helminthic drugs. Strongyloidiasis is present in our local setting, though the prevalence could be underestimated. PMID- 23817398 TI - Post mortem changes in relation to different types of clothing. AB - Post mortem changes are important in estimating post mortem interval (PMI). This project's aim was to study the effect of burial and type of clothing on rate of decomposition, which can contribute to estimating PMI for victims. 12 rabbits (Oryctolagus cuniculus) carcasses were separated into 3 groups: no clothing, light clothing and heavy clothing. Control subjects were placed on the ground surface while test subjects were buried at 30 cm depth graves. Soil samples prior and after decomposition were collected for soil pH and moisture analysis. Post mortem change was assessed using a Total Body Score system. The head, neck and limb regions were found to decay faster than the body trunk region. Mummifi cation occurred on body parts that were exposed directly to the atmosphere while adipocere formed on some buried subjects. Burial delayed decomposition due to lower insect activity and lower soil temperature. The soil layer also blocked the accessibility of majority of the arthropods, causing further delay in decomposition. Clothing enhanced decay for bodies on ground surface because it provided protection for maggots and retained moisture on tissues. However, clothing delayed decomposition in buried bodies because it physically separated the bodies from soil and arthropods. Higher sun exposure and repetitive exhumation showed acceleration of decomposition. The decomposition process increased soil pH and moisture percentage values. Soil pH initially increased until pH 8.0-8.4 followed by a slight decrease while soil moisture percentage changed inconsistently. Burial was significant in affecting post mortem change, F(1,11)=12.991, p<0.05 while type of clothing was not significant, F(2,9)=0.022, p=0.978 and combination of both type of clothing and burial factors were also not significant, F(2,3)=0.429, p=0.686. For validation, an accuracy of 83.33% was achieved based on soil pH and soil moisture percentage analysis. PMID- 23817399 TI - Bone cement implantation syndrome. AB - Bone cement implantation syndrome (BCIS) is characterized by hypoxia, hypotension, cardiac arrhythmias, increased pulmonary vascular resistance and cardiac arrest. It is a known cause of morbidity and mortality in patients undergoing cemented orthopaedic surgeries. The rarity of the condition as well as absence of a proper definition has contributed to under-reporting of cases. We report a 59-year-old woman who sustained fracture of the neck of her left femur and underwent an elective hybrid total hip replacement surgery. She collapsed during surgery and was revived only to succumb to death twelve hours later. Post mortem findings showed multiorgan disseminated microembolization of bone marrow and amorphous cement material. PMID- 23817400 TI - Giant labial fibroepithelial stromal polyp. AB - We report an18-year-old girl with a four-year history of a slow-growing labial mass with a sudden increase in size in the last year. Examination revealed a large fleshy 20 cm perineal mass centering on the left labia majora and attached to it by a 1cm pedicle. It was associated with pain, ulceration and discharge. The lesion was excised via diathermy at the base of the stalk. The excised specimen weighed 1.112kg and measured 20.5 x 17 x 5cm. The lesion showed a solid, soft whitish, cut surface. Histology revealed a hypocellular tumour with focally oedematous fibrous stroma in which were scattered large and small blood vessels, mast cells and other chronic inflammatory cells. True myxoid matrix was not observed. The stromal cells had a spindle to stellate morphology. There was no significant cytological atypia, mitotic activity or necrosis. The tumour cells were negative for SMA, desmin, CD34, S100 protein, EMA and PR. The diagnosis was clinically and histologically challenging because various vulvovaginal soft tissue tumours often have overlapping clinicopathological features. However, based on strict histological criteria and the absence of worrisome cytological features, a diagnosis of fi broepithelial stromal polyp was rendered despite the unusual size. A review of the literature shows that whilst vulvovaginal fibroepithelial stromal polyps are well described, giant variants are rare. Awareness of the extraordinary size that can be attained by such polyps can facilitate swift clinical and histological diagnosis. PMID- 23817401 TI - Mucinous cystadenocarcinoma arising in an ectopic kidney simulating a retroperitoneal dermoid cyst: a rare tumour presenting as a diagnostic dilemma. AB - Primary mucinous cystic neoplasms are rare tumours of the kidney, with a very few case reports in the literature. They arise from metaplasia of renal pelvic urothelium. We describe here a 45-year-old male who presented with pain in the abdomen and a lump in the left iliac fossa for two months. Ultrasound and CT scan showed a large, complex, heterogenous mass in the central abdomen and left iliac fossa, suggesting the possibility of dermoid cyst. Excision of the mass showed an enlarged multicystic kidney filled with mucin, destruction of renal parenchyma and a small viable area of grey white tumour. Histopathology revealed a peripherally located mucinous cystadenocarcinoma arising in the background of chronic pyelonephritis and mucinous metaplasia. We report this case for the rarity of the lesion and the associated clinical and radiological diagnostic dilemma. PMID- 23817402 TI - Neurogenous hyperplasia in the oesophagus. AB - Leiomyoma and gastrointestinal stromal tumours take first place among mesenchymal tumours of the oesophagus, where tumours of peripheral nerve origin are rarely seen. Schwann and enterochromaffi n cell proliferation occur in neurogenous hyperplasia, an entity observed in the appendix which has not been reported in the oesophagus in the medical literature. Oesophagogastroscopy of a 58-year-old woman showed linear erosions and nodularity at the gastroesophageal junction. The microscopic examination of biopsies taken from this area revealed proliferation of spindle cells with oval-round nuclei forming focal fascicular arrangement in the lamina propria. These cells stained positive for synaptophysin and S100 protein, while immunohistochemistry for smooth muscle actin and CD117 were negative. The case was diagnosed as neurogenous hyperplasia with these findings. Control endoscopic biopsies showed no evidence of neurogenous hyperplasia. Neurogenous hyperplasia can be considered as a distinct entity which might also be observed in the oesophagus as in the appendix. PMID- 23817403 TI - Emphysematous pyelonephritis in a diabetic leading to renal destruction: pathological aspects of a rare case. AB - Emphysematous pyelonephritis is a severe, potentially fatal necrotizing pyelonephritis with a variable clinical presentation, ranging from mild abdominal pain to septic shock. The majority of cases occur in diabetics with poor glycemic control, while a small percentage may be due to urinary tract obstruction. We present a case of a 57 year old male patient, diabetic on treatment, presenting with left flank pain and poor stream of urine since one week. Laboratory tests revealed that the patient had electrolyte imbalance, ketoacidosis and high blood sugar. Urine culture was positive for Escherichia coli with a signifi cant colony count. Radiological examination gave a diagnosis of Left Type 1 Emphysematous Pyelonephritis. Inspite of giving vigorous resuscitation and antibiotics with nephrostomy, the patient had to undergo nephrectomy due to extensive renal parenchymal destruction. The nephrectomy specimen was studied in detail to know the histopathological findings in a case of diabetic patient with emphysematous pyelonephritis. We present this case not only because of it being a rare complication of diabetes, but also to focus on the histopathological findings of the same, documentation of which is limited in literature. PMID- 23817404 TI - Liquid-liquid transition in a strong bulk metallic glass-forming liquid. AB - Polymorphic phase transitions are common in crystalline solids. Recent studies suggest that phase transitions may also exist between two liquid forms with different entropy and structure. Such a liquid-liquid transition has been investigated in various substances including water, Al2O3-Y2O3 and network glass formers. However, the nature of liquid-liquid transition is debated due to experimental difficulties in avoiding crystallization and/or measuring at high temperatures/pressures. Here we report the thermodynamic and structural evidence of a temperature-induced weak first-order liquid-liquid transition in a bulk metallic glass-forming system Zr(41.2)Ti(13.8)Cu(12.5)Ni10Be(22.5) characterized by non- (or weak) directional bonds. Our experimental results suggest that the local structural changes during the transition induce the drastic viscosity changes without a detectable density anomaly. These changes are correlated with a heat capacity maximum in the liquid. Our findings support the hypothesis that the 'strong' kinetics (low fragility) of a liquid may arise from an underlying lambda transition above its glass transition. PMID- 23817405 TI - Solvothermal synthesis of antimony sulfide dendrites for electrochemical detection of dopamine. AB - Sb2S3 dendrites composed of 1-dimensional rods were prepared by a facile solvothermal reaction. The dosage of the poly(acrylic acid) (PAA) morphology controlling reagent and the reaction temperature are key factors determining the final morphology of the product. Temporal experiments revealed that the formation of Sb2S3 dendrites experienced successive stages including precipitate reaction, crystallization and tip splitting. The as-prepared Sb2S3 dendrites were further employed as sensing material for electrochemical detection of dopamine (DA). A cyclic voltammogram (CV) showed that an Sb2S3 dendrite modified electrode enables the selective electro-oxidation of DA in the presence of ascorbic acid (AA). The constructed biosensor demonstrated a linear response range of 0.125-160 MUM and a detection limit of 0.1 MUM, which suggests that the Sb2S3 dendrites are promising sensing materials in the electrochemical analysis of DA. PMID- 23817407 TI - Stones: reducing radiation during PCNL. PMID- 23817409 TI - Prostate cancer: the growing evidence supporting mid-life PSA testing. PMID- 23817408 TI - Neuromodulation for overactive bladder. AB - Overactive bladder (OAB) affects millions of people worldwide yet first-line treatments are often poorly tolerated and compliance rates are low. Neuromodulation works via afferent nerve modulation and offers a minimally invasive and reversible alternative treatment option for patients with OAB who have failed first-line therapy. Neuromodulation has revolutionized the management of OAB and is now well established as a safe and effective treatment for those refractory to conservative treatments. Multiple neuroanatomical pathways have been described for sacral neuromodulation including the S3 nerve root, pudendal nerve and tibial nerve. The S3 nerve root is currently the main treatment target and has the most long-term data on safety and efficacy to support its use. However, studies on neuromodulation at the pudendal nerve or posterior tibial nerve have been positive and their role in treatment continues to evolve. Most urologists who are experienced in voiding dysfunction can become proficient in each technique. Patient selection, surgical techniques and postoperative management differ slightly between approaches and urologists should familiarize themselves with these differences. Treatment of OAB should progress from the least to most invasive modality, and neuromodulation provides an attractive option owing to its minimally invasive approach, tolerability, positive outcomes and reversibility. PMID- 23817410 TI - Differential impact of age and cytomegalovirus infection on the gammadelta T cell compartment. AB - gammadelta T cells represent a subset of unconventional T lymphocytes that are known for their reactivity against different pathogens and considered as intermediate mediators between adaptive and innate immunity. We provide in this paper further insights underlying the changes that affect the gammadelta T cell compartment with advanced age in humans. We show that both aging and CMV infection impact independently on the gammadelta T cell compartment. Most gammadelta T cells are significantly affected by age and present a decreased frequency in the elderly. The decline of the gammadelta T cell pool appears to be independent from the activity of the thymus, arguing in favor of an extrathymic site of gammadelta T cell production in humans. Of note, CMV infection, which is directly associated with the activation of the pool of Vdelta2(-) gammadelta T cells, promotes nonetheless the inflation of this compartment throughout life. CMV seropositivity accentuates further the accumulation of highly differentiated lymphocytes in Vdelta2(-) gammadelta T cell subsets with time, in contrast to Vdelta2(+) gammadelta T cells, which maintain a less differentiated phenotype. This is similar to the effect of CMV on alphabeta T cells and suggests that gammadelta T cells may vary in differentiation phenotype according to distinct stimuli or pathogens. PMID- 23817411 TI - Ficolin-1-PTX3 complex formation promotes clearance of altered self-cells and modulates IL-8 production. AB - The long pentraxin 3 (PTX3) has been shown to be important in maintaining internal tissue homeostasis and in protecting against fungal Aspergillus fumigatus infection. However, the molecular mechanisms of how these functions are elicited are poorly delineated. Ficolin-1 is a soluble pattern recognition molecule that interacts with PTX3. We hypothesized that heterocomplexes between ficolin-1 and PTX3 might mediate the signals necessary for sequestration of altered self-cells and A. fumigatus. We were able to show that ficolin-1 interacts with PTX3 via its fibrinogen-like domain. The interaction was affected in a pH- and divalent cation-sensitive manner. The primary binding site for ficolin-1 on PTX3 was located in the N-terminal domain portion of PTX3. Ficolin-1 and PTX3 heterocomplex formation occurred on dying host cells, but not on A. fumigatus. The heterocomplex formation was a prerequisite for enhancement of phagocytosis by human monocyte-derived macrophages and downregulation of IL-8 production during phagocytosis. On A. fumigatus, PTX3 exposed the C-terminal portion of the molecule, probably resulting in steric hindrance of ficolin-1 interaction with PTX3. These results demonstrate that ficolin-1 and PTX3 heterocomplex formation acts as a noninflammatory "find me and eat me" signal to sequester altered-host cells. The fact that the ficolin-1-PTX3 complex formation did not occur on A. fumigatus shows that PTX3 uses different molecular effector mechanisms, depending on which domains it exposes during ligand interaction. PMID- 23817412 TI - The archaic roles of the amphioxus NF-kappaB/IkappaB complex in innate immune responses. AB - NF-kappaB transcription factors play important roles in immune responses and the development of the immune system. Many aspects of NF-kappaB signaling differ significantly among distinct species, although many similarities in signaling exist in flies and humans. Thus, to understand the functional refinement of the NF-kappaB cascade from invertebrates to vertebrates, the Rel and NF-kappaB proteins, identified as bbtRel and bbtp105, were characterized in a basal chordate amphioxus. Consistent with the sequence similarities, bbtRel was found to interact with a mammalian kappaB response element, to move into the nucleus when activated, and to be inhibited by the NF-kappaB-specific inhibitor helenalin. Similar to the other class I members, bbtp105 could be cleaved into the mature form p58. Such endoproteolysis depends on the GRR sequence and requires both protease degradation and caspase 8 cleavage. Furthermore, we found that bbtIkappaB and the unprocessed bbtp105 can inhibit the transcriptional activity of bbtRel, whereas bbtp58 forms homodimers or heterodimers with bbtRel to create a mature NF-kappaB complex. Finally, we found that the survival rate and the expression of bbtIkappaB and TNF-alpha-like genes were decreased when adult amphioxus were treated with helanalin before immune challenge, suggesting the archaic roles for NF-kappaB signaling in innate immune responses in a basal chordate. The presence of the NF-kappaB-IkappaB cascade in amphioxus indicates that it is a significant feature linking invertebrates to vertebrates and is refined in vertebrates through the expansion and divergence of genes involved in the cascade. PMID- 23817413 TI - Histamine h2 receptor signaling in the pathogenesis of sepsis: studies in a murine diabetes model. AB - Type 1 diabetes enhances susceptibility to infection and favors the sepsis development. In addition, diabetic mice produced higher levels of histamine in several tissues and in the blood after LPS stimulation than nondiabetic mice. In this study, we aimed to explore the role of mast cells (MCs) and histamine in neutrophil migration and, consequently, infection control in diabetic mice with mild sepsis (MS) induced by cecum ligation and puncture. We used female BALB/c, MC-sufficient (WB/B6), MC-deficient (W/W(v)), and NOD mice. Diabetic mice given MS displayed 100% mortality within 24 h, whereas all nondiabetic mice survived for at least 5 d. The mortality rate of diabetic mice was reduced to 57% after the depletion of MC granules with compound 48/80. Moreover, this pretreatment increased neutrophil migration to the focus of infection, which reduced systemic inflammatory response and bacteremia. The downregulation of CXCR2 and upregulation of G protein-coupled receptor kinase 2 in neutrophils was prevented by pretreatment of diabetic mice given MS with compound 48/80. In addition, blocking the histamine H2 receptor restored neutrophil migration, enhanced CXCR2 expression, decreased bacteremia, and improved sepsis survival in alloxan-induced diabetic and spontaneous NOD mice. Finally, diabetic W/W(v) mice had neutrophil migration to the peritoneal cavity, increased CXCR2 expression, and reduced bacteremia compared with diabetic WB/B6 mice. These results demonstrate that histamine released by MCs reduces diabetic host resistance to septic peritonitis in mice. PMID- 23817414 TI - Cutting edge: the NLRP3 inflammasome links complement-mediated inflammation and IL-1beta release. AB - The complement system is a potent component of the innate immune response, promoting inflammation and orchestrating defense against pathogens. However, dysregulation of complement is critical to several autoimmune and inflammatory syndromes. Elevated expression of the proinflammatory cytokine IL-1beta is often linked to such diseases. In this study, we reveal the mechanistic link between complement and IL-1beta secretion using murine dendritic cells. IL-1beta secretion occurs following intracellular caspase-1 activation by inflammasomes. We show that complement elicits secretion of both IL-1beta and IL-18 in vitro and in vivo via the NLRP3 inflammasome. This effect depends on the inflammasome components NLRP3 and ASC, as well as caspase-1 activity. Interestingly, sublethal complement membrane attack complex formation, but not the anaphylatoxins C3a and C5a, activated the NLRP3 inflammasome in vivo. These findings provide insight into the molecular processes underlying complement-mediated inflammation and highlight the possibility of targeting IL-1beta to control complement-induced disease and pathological inflammation. PMID- 23817415 TI - Y14 positively regulates TNF-alpha-induced NF-kappaB transcriptional activity via interacting RIP1 and TRADD beyond an exon junction complex protein. AB - Although Y14 is known to be a component of the exon junction complex, we previously reported that Y14 regulates IL-6-induced STAT3 activation. In this study, we showed that endogenous Y14 positively regulated TNF-alpha-induced IL-6 expression in HeLa cells. Small interfering RNA-mediated Y14-knockdown reduced TNF-alpha-induced and NF-kappaB-mediated transcriptional activity, phosphorylation/degradation of IkappaBalpha, and nuclear localization of NF kappaB/p65. As in the case of IL-6 stimuli, Y14 enhanced TNF-alpha-induced STAT3 phosphorylation, which is important for its nuclear retention. However, our manipulation of Y14 expression indicated that it is involved in TNF-alpha-induced IL-6 expression via both STAT3-dependent and -independent mechanisms. We screened signaling molecules in the TNF-alpha-NF-kappaB pathway and found that Y14 endogenously associated with receptor-interacting protein 1 (RIP1) and TNFR associated death domain (TRADD). Overexpression of RIP1, but not TRADD, restored TNF-alpha-induced NF-kappaB activation in Y14-knockdown cells, and Y14 overexpression restored TNF-alpha-induced NF-kappaB activation in TRADD-knockdown cells, but not in RIP1-knockdown cells, indicating that Y14 lies downstream of TRADD and upstream of RIP1. Of importance, Y14 significantly enhanced the binding between RIP1 and TRADD, and this is a possible new mechanism for Y14-mediated modification of TNF-alpha signals. Although Y14 associates with MAGOH in the exon junction complex, Y14's actions in the TNF-alpha-NF-kappaB pathway are unlikely to require MAGOH. Therefore, Y14 positively regulates signals for TNF-alpha induced IL-6 production at multiple steps beyond an exon junction complex protein. PMID- 23817417 TI - Synovial fibroblasts directly induce Th17 pathogenicity via the cyclooxygenase/prostaglandin E2 pathway, independent of IL-23. AB - Th17 cells are critically involved in autoimmune disease induction and severity. Recently, we showed that Th17 cells from patients with rheumatoid arthritis (RA) directly induced a proinflammatory loop upon interaction with RA synovial fibroblasts (RASF), including increased autocrine IL-17A production. To unravel the mechanism driving this IL-17A production, we obtained primary CD4(+)CD45RO(+)CCR6(+) (Th17) cells and CD4(+)CD45RO(+)CCR6(-) (CCR6(-)) T cells from RA patients or healthy individuals and cocultured these with RASF. IL-1beta, IL-6, IL-23p19, and cyclooxygenase (COX)-2 expression and PGE2 production in Th17 RASF cultures were higher than in CCR6(-) T cell-RASF cultures. Cytokine neutralization showed that IL-1beta and IL-6, but not IL-23, contributed to autocrine IL-17A induction. Importantly, treatment with celecoxib, a COX-2 inhibitor, resulted in significantly lower PGE2 and IL-17A, but not IFN-gamma, production. Combined celecoxib and TNF-alpha blockade more effectively suppressed the proinflammatory loop than did single treatment, as shown by lower IL-6, IL-8, matrix metalloproteinase-1 and matrix metalloproteinase-3 production. These findings show a critical role for the COX-2/PGE2 pathway in driving Th17-mediated synovial inflammation in an IL-23- and monocyte-independent manner. Therefore, it would be important to control PGE2 in chronic inflammation in RA and potentially other Th17-mediated autoimmune disorders. PMID- 23817416 TI - Regulation of adaptive immunity by the fractalkine receptor during autoimmune inflammation. AB - Fractalkine, a chemokine anchored to neurons or peripheral endothelial cells, serves as an adhesion molecule or as a soluble chemoattractant. Fractalkine binds CX3CR1 on microglia and circulating monocytes, dendritic cells, and NK cells. The aim of this study is to determine the role of CX3CR1 in the trafficking and function of myeloid cells to the CNS during experimental autoimmune encephalomyelitis (EAE). Our results show that, in models of active EAE, Cx3cr1( /-) mice exhibited more severe neurologic deficiencies. Bone marrow chimeric mice confirmed that CX3CR1 deficiency in bone marrow enhanced EAE severity. Notably, CX3CR1 deficiency was associated with an increased accumulation of CD115(+)Ly6C( )CD11c(+) dendritic cells into EAE-affected brains that correlated with enhanced demyelination and neuronal damage. Furthermore, higher IFN-gamma and IL-17 levels were detected in cerebellar and spinal cord tissues of CX3CR1-deficient mice. Analyses of peripheral responses during disease initiation revealed a higher frequency of IFN-gamma- and IL-17-producing T cells in lymphoid tissues of CX3CR1 deficient as well as enhanced T cell proliferation induced by CX3CR1-deficient dendritic cells. In addition, adoptive transfer of myelin oligodendrocyte glycoprotein35-55-reactive wild-type T cells induced substantially more severe EAE in CX3CR1-deficient recipients when compared with wild-type recipients. Collectively, the data demonstrate that besides its role in chemoattraction, CX3CR1 is a key regulator of myeloid cell activation contributing to the establishment of adaptive immune responses. PMID- 23817418 TI - Active caspase-3 is stored within secretory compartments of viable mast cells. AB - Caspase-3 is a main executioner of apoptotic cell death. The general notion is that, in viable cells, caspase-3 is found as a cytosolic inactive proenzyme and that caspase-3 activation is largely confined to processes associated with cell death. In this study, we challenge this notion by showing that enzymatically active caspase-3 is stored in viable mast cells. The enzymatically active caspase 3 was undetectable in the cytosol of viable cells, but was recovered in subcellular fractions containing secretory granule-localized proteases. Moreover, active caspase-3 was rapidly released into the cytosolic compartment after permeabilization of the secretory granules. Using a cell-permeable substrate for caspase-3, the presence of active caspase-3-like activity in granule-like compartments close to the plasma membrane was demonstrated. Moreover, it was shown that mast cell activation caused release of the caspase-3 to the cell exterior. During the course of mast cell differentiation from bone marrow cells, procaspase-3 was present in cells of all stages of maturation. In contrast, active caspase-3 was undetectable in bone marrow precursor cells, but increased progressively during the process of mast cell maturation, its accumulation coinciding with that of a mast cell-specific secretory granule marker, mouse mast cell protease 6. Together, the current study suggests that active caspase-3 can be stored within secretory compartments of viable mast cells. PMID- 23817419 TI - Deficiency of phospholipase A2 receptor exacerbates ovalbumin-induced lung inflammation. AB - Secretory phospholipase A2 (sPLA2) plays a critical role in the genesis of lung inflammation through proinflammatory eicosanoids. A previous in vitro experiment showed a possible role of cell surface receptor for sPLA2 (PLA2R) in the clearance of extracellular sPLA2. PLA2R and groups IB and X sPLA2 are expressed in the lung. This study examined a pathogenic role of PLA2R in airway inflammation using PLA2R-deficient (PLA2R(-/-)) mice. Airway inflammation was induced by immunosensitization with OVA. Compared with wild-type (PLA2R(+/+)) mice, PLA2R(-/-) mice had a significantly greater infiltration of inflammatory cells around the airways, higher levels of groups IB and X sPLA2, eicosanoids, and Th2 cytokines, and higher numbers of eosinophils and neutrophils in bronchoalveolar lavage fluid after OVA treatment. In PLA2R(-/-) mice, intratracheally instilled [(125)I]-labeled sPLA2-IB was cleared much more slowly from bronchoalveolar lavage fluid compared with PLA2R(+/+) mice. The degradation of the instilled [(125)I]-labeled sPLA2-IB, as assessed by trichloroacetic acid soluble radioactivity in bronchoalveolar lavage fluid after instillation, was lower in PLA2R(-/-) mice than in PLA2R(+/+) mice. In conclusion, PLA2R deficiency increased sPLA2-IB and -X levels in the lung through their impaired clearance from the lung, leading to exaggeration of lung inflammation induced by OVA treatment in a murine model. PMID- 23817420 TI - Comparison of induced versus natural regulatory T cells of the same TCR specificity for induction of tolerance to an environmental antigen. AB - Recent evidence shows that natural CD25(+)Foxp3(+) regulatory T cells (nTreg) and induced CD25(+)Foxp3(+) regulatory T cells (iTreg) both contribute to tolerance in mouse models of colitis and asthma, but there is little evidence regarding their relative contributions to this tolerance. We compared the abilities of nTreg and iTreg, both from OVA-TCR-transgenic OTII mice, to mediate tolerance in OVA-asthmatic C57BL/6 mice. The iTreg were differentiated from Th2 effector T cells by exposure to IL-10-differentiated dendritic cells (DC10) in vitro or in vivo, whereas we purified nTreg from allergen-naive mice and exposed them to DC10 before use. Each Treg population was subsequently repurified and tested for its therapeutic efficacy in vitro and in vivo. DC10 engaged the nTreg in a cognate fashion in Forster (or fluorescence) resonance energy transfer assays, and these nTreg reduced in vitro OVA-asthmatic Th2 effector T cell responses by 41-56%, whereas the comparator iTreg reduced these responses by 72-86%. Neutralization of IL-10, but not TGF-beta, eliminated the suppressive activities of iTreg but not nTreg. Delivery of 5 * 10(5) purified nTreg reduced allergen challenge-induced airway IL-4 (p <= 0.03) and IL-5 (p <= 0.001) responses of asthmatic recipients by <= 23% but did not affect airway hyperresponsiveness or IgE levels, whereas equal numbers of iTreg of identical TCR specificity reduced all airway responses to allergen challenge by 82-96% (p <= 0.001) and fully normalized airway hyperresponsiveness. These data confirm that allergen-specific iTreg and nTreg have active roles in asthma tolerance and that iTreg are substantially more tolerogenic in this setting. PMID- 23817421 TI - A diametric role for OX40 in the response of effector/memory CD4+ T cells and regulatory T cells to alloantigen. AB - OX40 is a member of the TNFR superfamily that has potent costimulatory properties. Although the impact of blockade of the OX40-OX40 ligand (OX40L) pathway has been well documented in models of autoimmune disease, its effect on the rejection of allografts is less well defined. In this article, we show that the alloantigen-mediated activation of naive and memory CD4(+) T cells results in the induction of OX40 expression and that blockade of OX40-OX40L interactions prevents skin allograft rejection mediated by either subset of T cells. Moreover, a blocking anti-OX40 had no effect on the activation and proliferation of T cells; rather, effector T cells failed to accumulate in peripheral lymph nodes and subsequently migrate to skin allografts. This was found to be the result of an enhanced degree of cell death among proliferating effector cells. In clear contrast, blockade of OX40-OX40L interactions at the time of exposure to alloantigen enhanced the ability of regulatory T cells to suppress T cell responses to alloantigen by supporting, rather than diminishing, regulatory T cell survival. These data show that OX40-OX40L signaling contributes to the evolution of the adaptive immune response to an allograft via the differential control of alloreactive effector and regulatory T cell survival. Moreover, these data serve to further highlight OX40 and OX40L as therapeutic targets to assist the induction of tolerance to allografts and self-Ags. PMID- 23817423 TI - IL-16 induces intestinal inflammation via PepT1 upregulation in a pufferfish model: new insights into the molecular mechanism of inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) has long been a worldwide health care problem with a persistently increasing incidence. Although its clinical features have been well described, its etiology and pathogenesis remain unclear. IL-16 is a chemoattractant cytokine with various effects on cellular activities and diseases. However, the involvement of IL-16 in IBD remains poorly understood. In this study, to our knowledge we report for the first time the mechanism by which IL-16 induces intestinal inflammation by upregulating the expression of oligopeptide transporter member 1 (PepT1) in a Tetraodon nigroviridis fish model. The dextran sodium sulfate-induced colitis model in this species revealed that IL 16 levels significantly increase accompanied by elevations in PepT1 in the colon. Moreover, the signs of colitis were dramatically attenuated by IL-16 depletion using anti-IL-16 Abs. In vivo IL-16 administration induced remarkable intestinal inflammation with typical ulcerative colitis-like features, including histologic damage, inflammatory cell infiltration, increased myeloperoxidase activity, and proinflammatory cytokines expression, which corresponded with significant PepT1 upregulation in the colon. The IL-16-induced PepT1 expression and its upregulated fMLF transport were also demonstrated in vitro. To our knowledge, our study provides the first evidence of the connection between IL-16 and PepT1, which provides new insights into the molecular mechanism underlying IBD development. Additionally, this study suggests that fish species are an attractive model for studying IBD. By providing a better understanding of IL-16 biology from fish to mammals, this study should aid the development of IL-16-based therapies for IBD. PMID- 23817422 TI - Antigen-free adjuvant assists late effector CD4 T cells to transit to memory in lymphopenic hosts. AB - The events controlling the transition of T cells from effector to memory remain largely undefined. Many models have been put forth to account for the origin of memory precursors, but for CD4 T cells initial studies reported that memory T cells derive from IFN-gamma-nonproducing effectors, whereas others suggested that memory emanates from highly activated IFN-gamma-producing effectors. In this study, using cell proliferation, expression of activation markers, and production of IFN-gamma as a measure of activation, we defined two types of effector CD4 T cells and investigated memory generation. The moderately activated early effectors readily transit to memory, whereas the highly activated late effectors, regardless of their IFN-gamma production, develop minimal memory. Boosting with Ag-free adjuvant, however, rescues late effectors from cell death and sustains both survival and IFN-gamma cytokine responses in lymphopenic hosts. The adjuvant mediated memory transition of late effectors involves the function of TLRs, most notably TLR9. These findings uncover the mechanism by which late effector CD4 T cells are driven to transit to memory and suggest that timely boosts with adjuvant may enhance vaccine efficacy. PMID- 23817425 TI - The encephalitogenic, human myelin oligodendrocyte glycoprotein-induced antibody repertoire is directed toward multiple epitopes in C57BL/6-immunized mice. AB - Although Abs specific for myelin oligodendrocyte glycoprotein (MOG) have been detected in patients with multiple sclerosis (MS), their contribution to pathogenesis remains poorly understood. Immunization of C57BL/6 mice with recombinant human MOG (hMOG) results in experimental autoimmune encephalomyelitis involving MOG-specific, demyelinating Abs. This model is therefore informative for understanding anti-MOG humoral responses in MS. In the current study, we have characterized the hMOG-specific Ab repertoire in immunized C57BL/6 mice using both in vitro and in vivo approaches. We demonstrate that hMOG-specific mAbs are not focused on one specific region of MOG, but instead target multiple epitopes. Encephalitogenicity of the mAbs, assessed by the ability of the mAbs to exacerbate experimental autoimmune encephalomyelitis in mice, correlates with the activity of the mAbs in binding to CNS tissue sections, but not with other in vitro assays. The targeting of different MOG epitopes by encephalitogenic Abs has implications for disease pathogenesis, because it could result in MOG cross linking on oligodendrocytes and/or immune complex formation. These studies reveal several novel features concerning pathogenic, humoral responses that may have relevance to human MS. PMID- 23817424 TI - Corticosteroids block autophagy protein recruitment in Aspergillus fumigatus phagosomes via targeting dectin-1/Syk kinase signaling. AB - Aspergillus fumigatus is the predominant airborne fungal pathogen in immunocompromised patients. Genetic defects in NADPH oxidase (chronic granulomatous disease [CGD]) and corticosteroid-induced immunosupression lead to impaired killing of A. fumigatus and unique susceptibility to invasive aspergillosis via incompletely characterized mechanisms. Recent studies link TLR activation with phagosome maturation via the engagement of autophagy proteins. In this study, we found that infection of human monocytes with A. fumigatus spores triggered selective recruitment of the autophagy protein LC3 II in phagosomes upon fungal cell wall swelling. This response was induced by surface exposure of immunostimulatory beta-glucans and was mediated by activation of the Dectin-1 receptor. LC3 II recruitment in A. fumigatus phagosomes required spleen tyrosine kinase (Syk) kinase-dependent production of reactive oxygen species and was nearly absent in monocytes of patients with CGD. This pathway was important for control of intracellular fungal growth, as silencing of Atg5 resulted in impaired phagosome maturation and killing of A. fumigatus. In vivo and ex vivo administration of corticosteroids blocked LC3 II recruitment in A. fumigatus phagosomes via rapid inhibition of phosphorylation of Src and Syk kinases and downstream production of reactive oxygen species. Our studies link Dectin-1/Syk kinase signaling with autophagy-dependent maturation of A. fumigatus phagosomes and uncover a potential mechanism for development of invasive aspergillosis in the setting of CGD and corticosteroid-induced immunosupression. PMID- 23817426 TI - Tumor-derived lactate modifies antitumor immune response: effect on myeloid derived suppressor cells and NK cells. AB - In this study, we explore the hypothesis that enhanced production of lactate by tumor cells, because of high glycolytic activity, results in inhibition of host immune response to tumor cells. Lactate dehydrogenase-A (LDH-A), responsible for conversion of pyruvate to lactate, is highly expressed in tumor cells. Lentiviral vector-mediated LDH-A short hairpin RNA knockdown Pan02 pancreatic cancer cells injected in C57BL/6 mice developed smaller tumors than mice injected with Pan02 cells. A decrease occurred in the frequency of myeloid-derived suppressor cells (MDSCs) in the spleens of mice carrying LDH-A-depleted tumors. NK cells from LDH A-depleted tumors had improved cytolytic function. Exogenous lactate increased the frequency of MDSCs generated from mouse bone marrow cells with GM-CSF and IL 6 in vitro. Lactate pretreatment of NK cells in vitro inhibited cytolytic function of both human and mouse NK cells. This reduction of NK cytotoxic activity was accompanied by lower expression of perforin and granzyme in NK cells. The expression of NKp46 was decreased in lactate-treated NK cells. These studies strongly suggest that tumor-derived lactate inhibits NK cell function via direct inhibition of cytolytic function as well as indirectly by increasing the numbers of MDSCs that inhibit NK cytotoxicity. Depletion of glucose levels using a ketogenic diet to lower lactate production by glycolytic tumors resulted in smaller tumors, decreased MDSC frequency, and improved antitumor immune response. These studies provide evidence for an immunosuppressive role of tumor-derived lactate in inhibiting innate immune response against developing tumors via regulation of MDSC and NK cell activity. PMID- 23817428 TI - Dendritic cells regulate high-speed interstitial T cell migration in the lymph node via LFA-1/ICAM-1. AB - T lymphocytes vigorously migrate within the paracortex of lymph nodes (LNs) in search of cognate Ags that are presented by dendritic cells (DCs). However, the mechanisms that support T cells to exert the highest motility in a densely packed LN microenvironment are not fully understood. Two-photon microscopy using LN tissue slices revealed that LFA-1 and ICAM-1 were required for high-velocity migration (>10 MUm/min) with relatively straight movement. Importantly, ICAM-1 expressed by myeloid lineages, most likely DCs, but not stromal cells or lymphocytes, was sufficient to support the high-velocity migration. Visualizing DCs in the LN from CD11c-EYFP mice showed that T cells traveled over thin dendrites and the body of DCs. Interestingly, DCs supported T cell motility in vitro in chemokine- and ICAM-1-dependent manners. Moreover, an acute lymphopenic environment in the LN significantly increased LFA-1 dependency for T cell migration, indicating that lymphocyte density modulates the use of LFA-1. Therefore, our results indicate that LFA-1/ICAM-1-dependent interactions between T cells and DCs play a crucial role not only in supporting firm arrest during Ag recognition but also in facilitating the Ag scanning processes. PMID- 23817427 TI - A protective Hsp70-TLR4 pathway in lethal oxidant lung injury. AB - Administering high levels of inspired oxygen, or hyperoxia, is commonly used as a life-sustaining measure in critically ill patients. However, prolonged exposures can exacerbate respiratory failure. Our previous study showed that TLR4 confers protection against hyperoxia-induced lung injury and mortality. Hsp70 has potent cytoprotective properties and has been described as a TLR4 ligand in cell lines. We sought to elucidate the relationship between TLR4 and Hsp70 in hyperoxia induced lung injury in vitro and in vivo and to define the signaling mechanisms involved. Wild-type, TLR4(-/-), and Trif(-/-) (a TLR4 adapter protein) murine lung endothelial cells (MLECs) were exposed to hyperoxia. We found markedly elevated levels of intracellular and secreted Hsp70 from wild-type mice lungs and MLECs after hyperoxia. We confirmed that Hsp70 and TLR4 coimmunoprecipitate in lung tissue and MLECs. Hsp70-mediated NF-kappaB activation appears to depend upon TLR4. In the absence of TLR4, Hsp70 loses its protective effects in endothelial cells. Furthermore, these protective properties of Hsp70 are TLR4 adapter Trif dependent and MyD88 independent. Hsp70-deficient mice have increased mortality during hyperoxia, and lung-targeted adenoviral delivery of Hsp70 effectively rescues both Hsp70-deficient and wild-type mice. To our knowledge, our studies are the first to define an Hsp70-TLR4-Trif cytoprotective axis in the lung and endothelial cells. This pathway is a potential therapeutic target against a range of oxidant-induced lung injuries. PMID- 23817429 TI - Cutting edge: Direct recognition of infected cells by CD4 T cells is required for control of intracellular Mycobacterium tuberculosis in vivo. AB - Effector T cells control intracellular infection by secreting cytokines and through contact-dependent cytolysis. Because cytokines can diffuse and act at a distance, we determined whether cytokine diffusion is sufficient to control Mycobacterium tuberculosis or whether direct recognition of infected cells by CD4 T cells is required. Using MHC class II (MHC II) mixed bone marrow chimeras, we compared the bacterial burdens in lung myeloid cells that were capable (MHC II(+/+)) or not (MHC II(-/-)) of being recognized by CD4 T cells. MHC II(+/+) cells had lower bacterial burdens than did MHC II(-/-) cells. CD4 T cell depletion increased the number of bacteria associated with MHC II(+/+)cells but not MHC II(-/-) cells, indicating that direct recognition of infected cells by CD4 T cells is required for control of intracellular M. tuberculosis. These results show that the effector mechanisms required for CD4 T cell control of distinct intracellular pathogens differ and that long-range cytokine diffusion does not contribute to control of M. tuberculosis. PMID- 23817431 TI - Adipocytes modulate the phenotype of human macrophages through secreted lipids. AB - Previous studies have shown accumulation and an enhanced proinflammatory profile of macrophages in adipose tissue of obese mice, indicating the presence of an interaction between adipocytes and macrophages in this tissue. However, the consequences of this interaction in humans are yet incompletely understood. In this study, we explored the modulating effects of adipocytes on the phenotype of macrophages in humans and studied the possible molecular pathways involved. Adipocyte-conditioned media (ACM) treatment of macrophages for 48 h strongly reduced the LPS-induced IL-12p40 secretion by macrophages, whereas the production of TNF-alpha and other cytokines remained largely unaffected. This effect was independent of the source of adipocytes. Interestingly, the level of inhibition correlated directly with body mass index (BMI) of the adipocyte donor. Because adipocytes release many different cytokines, adipokines, and lipids, we have separated the protein and lipid fractions of ACM, to obtain insight into the molecular nature of the soluble mediators underlying the observed effect. These experiments revealed that the inhibitory effect resided predominantly in the lipid fraction. Further studies revealed that PGE2 and linoleic and oleic acid were potent inhibitors of IL-12p40 secretion. Interestingly, concentrations of these ACM-derived lipids increased with increase in BMI of the adipocyte donor, suggesting that they could mediate the BMI-dependent effects of ACM. To our knowledge, these results provide first evidence that obesity-related changes in adipose tissue macrophage phenotype could be mediated by adipocyte-derived lipids in humans. Intriguingly, these changes appear to be different from those in murine obesity. PMID- 23817430 TI - Francisella tularensis SchuS4 and SchuS4 lipids inhibit IL-12p40 in primary human dendritic cells by inhibition of IRF1 and IRF8. AB - Induction of innate immunity is essential for host survival of infection. Evasion and inhibition of innate immunity constitute a strategy used by pathogens, such as the highly virulent bacterium Francisella tularensis, to ensure their replication and transmission. The mechanism and bacterial components responsible for this suppression of innate immunity by F. tularensis are not defined. In this article, we demonstrate that lipids enriched from virulent F. tularensis strain SchuS4, but not attenuated live vaccine strain, inhibit inflammatory responses in vitro and in vivo. Suppression of inflammatory responses is associated with IkappaBalpha-independent inhibition of NF-kappaBp65 activation and selective inhibition of activation of IFN regulatory factors. Interference with NF kappaBp65 and IFN regulatory factors is also observed following infection with viable SchuS4. Together these data provide novel insight into how highly virulent bacteria selectively modulate the host to interfere with innate immune responses required for survival of infection. PMID- 23817433 TI - Reproductive and hormonal factors, family history, and breast cancer according to the hormonal receptor status. AB - The aim of this study was to investigate the association between breast cancer risk, reproductive factors, and family history of breast cancer by the estrogen receptor (ER) and progesterone receptor (PR) status. We analyzed data from an Italian case-control study including 1075 women with incident breast cancer and 1477 hospital controls. We estimated the odds ratios (ORs) of breast cancer using unconditional logistic regression models including major recognized risk factors for breast cancer. Stronger associations with ER+ than with ER- breast cancer were observed for parity (OR: 0.7 vs. 0.9 for >= 3 births vs. nulliparae), age at first birth (OR: 1.6 vs. 1.2 for age >= 30 vs. <25 years), menopausal status (OR: 0.7 vs. 0.8 for postmenopause vs. pre/perimenopause), age at menopause (OR: 1.3 vs. 1.2 for menopause at age >= 50 vs. <50 years), and family history of breast cancer (OR: 2.2 vs. 1.4). Among the ER+ patients, the presence of PR+ did not appreciably modify any of the risk estimates. The association with age at menarche and hormone replacement therapy use was neither significant nor heterogeneous across ER and PR subtypes. In conclusion, we found stronger associations with selected menstrual and reproductive factors for ER+ (PR+) than for ER- (PR-) breast cancers, though in the absence of significant heterogeneity. PMID- 23817432 TI - Censoring of self-reactive B cells by follicular dendritic cell-displayed self antigen. AB - In the secondary lymphoid organs, intimate contact with follicular dendritic cells (FDCs) is required for B cell retention and Ag-driven selection during the germinal center response. However, selection of self-reactive B cells by Ag on FDCs has not been addressed. To this end, we generated a mouse model to conditionally express a membrane-bound self-antigen on FDCs and to monitor the fate of developing self-reactive B cells. In this article, we show that self antigen displayed on FDCs mediates effective elimination of self-reactive B cells at the transitional stage. Notwithstanding, some self-reactive B cells persist beyond this checkpoint, showing evidence of Ag experience and intact proximal BCR signaling, but they are short-lived and unable to elicit T cell help. These results implicate FDCs as an important component of peripheral B cell tolerance that prevents the emergence of naive B cells capable of responding to sequestered self-antigens. PMID- 23817434 TI - Label-free optical detection of cells grown in 3D silicon microstructures. AB - We demonstrate high aspect-ratio photonic crystals that could serve as three dimensional (3D) microincubators for cell culture and also provide label-free optical detection of the cells. The investigated microstructures, fabricated by electrochemical micromachining of standard silicon wafers, consist of periodic arrays of silicon walls separated by narrow deeply etched air-gaps (50 MUm high and 5 MUm wide) and feature the typical spectral properties of photonic crystals in the wavelength range 1.0-1.7 MUm: their spectral reflectivity is characterized by wavelength regions where reflectivity is high (photonic bandgaps), separated by narrow wavelength regions where reflectivity is very low. In this work, we show that the presence of cells, grown inside the gaps, strongly affects light propagation across the photonic crystal and, therefore, its spectral reflectivity. Exploiting a label-free optical detection method, based on a fiberoptic setup, we are able to probe the extension of cells adherent to the vertical silicon walls with a non-invasive direct testing. In particular, the intensity ratio at two wavelengths is the experimental parameter that can be well correlated to the cell spreading on the silicon wall inside the gaps. PMID- 23817435 TI - An unrecognized, preventable cause of syncope, malignant arrhythmia, and cardiac death. PMID- 23817436 TI - Caesium accumulation in yeast and plants is selectively repressed by loss of the SNARE Sec22p/SEC22. AB - The non-essential cation caesium (Cs(+)) is assimilated by all organisms. Thus, anthropogenically released radiocaesium is of concern to agriculture. Cs(+) accumulates owing to its chemical similarity to the potassium ion (K(+)). The apparent lack of a Cs(+)-specific uptake mechanism has obstructed attempts to manipulate Cs(+) accumulation without causing pleiotropic effects. Here we show that the SNARE protein Sec22p/SEC22 specifically impacts Cs(+) accumulation in yeast and in plants. Loss of Saccharomyces cerevisiae Sec22p does not affect K(+) homeostasis, yet halves Cs(+) concentration compared with the wild type. Mathematical modelling of the uptake time course predicts a compromised vacuolar Cs(+) deposition in sec22Delta. Biochemical fractionation confirms this and indicates a new feature of Sec22p in enhancing non-selective cation deposition. A developmentally controlled loss-of-function mutant of the orthologous Arabidopsis thaliana SEC22 phenocopies the reduced Cs(+) uptake without affecting plant growth. This finding provides a new strategy to reduce radiocaesium entry into the food chain. PMID- 23817437 TI - PAH concentration gradients and fluxes through sand cap test cells installed in situ over river sediments containing coal tar. AB - Short-term performance of permeable sand cap test cells, installed over sediment containing liquid coal tar was monitored on the Grand Calumet River (Hammond, Indiana, USA). The sand cap test cells included two sand-only cells, two test cells containing a sand/peat mixed layer, two test cells containing a sand/organoclay mixed layer, and two sediment control cells. In each test cell, six monocyclic and twelve polycyclic aromatic hydrocarbons (MAHs and PAHs) were monitored over an 18 month period, and interfacial water flow was monitored periodically. Seepage velocities ranged from 3.8 cm per day into the sediments to 3.2 cm per day out of the sediments, with discharge out of the sediments being observed more often. A ferric iron test indicated that stratified oxic-anaerobic layers were formed in the caps. Within the sand caps, concentrations of MAHs and PAHs fluctuated with time, and this fluctuation was more significant near the bottom. Near the top, most of the MAHs and PAHs were attenuated above 95% in the first year of the study, but their attenuation rates decreased in the second year due to recontamination of the surface of the caps by the surrounding sediments. Functional genes involved in PAH degradation were detected by polymerase chain reaction (PCR) in upper and lower sections of the caps for each of the three treatments. Bacterial communities were characterized by PCR amplification of 16s rRNA genes and denaturing gradient gel electrophoresis (DGGE). The results indicate that the rate and direction of sediment porewater flow is an important factor for properly designing any remedial sand cap, and that biodegradation of many of the MAH and PAH compounds was likely a major removal mechanism leading to attenuation through the test cells. PMID- 23817439 TI - Factors influencing long-term quality of life and depression in German liver transplant recipients: a single-centre cross-sectional study. AB - BACKGROUND: Health-related quality of life (HRQOL) following orthotopic liver transplantation (OLT) has become increasingly important. Therefore, we aimed to identify factors affecting HRQOL after OLT. MATERIAL AND METHODS: This cross sectional, single-centre study surveyed 281 OLT patients. Survey tools included the Short Form (SF-36) Health Survey, the Patient Health Questionnaire 9 (PHQ9), and a self-designed employment questionnaire. Patient medical records were reviewed. RESULTS: Participants included 187 men (mean age at OLT: 50 [+/- 11; 13 69] years). Primary indications for OLT were viral hepatitis (28%), alcoholic liver disease (35%), cholestatic liver disease (11%), and others (26%). Follow-up ranged from 2 to 136 months. Clinical factors associated with improved HRQOL were age <= 45 years at OLT and current MELD score <=<= 13. Time after OLT and indication for transplantation affected SF-36 HRQOL. SF-36 physical component summary scales plateaued at 3-years post-OLT and then stabilized. For the SF-36 HRQOL, scores were the lowest in all domains for OLT recipients transplanted for chronic viral hepatitis and for unemployed patients, whereas sex and number of transplantations showed no significant differences. The PHQ9 results showed that depression was significantly more frequent among patients with current MELD score >= 13 or impaired liver function and those transplanted for chronic viral hepatitis or unemployed patients. Age and sex did not influence PHQ9 results. CONCLUSIONS: Medical and psychosocial support is crucial for long-term HRQOL after OLT. Developing multidisciplinary interventions to address issues such as employment, age, MELD score, and liver function may improve long-term HRQOL in these patients. PMID- 23817438 TI - Amyloid deposition and cognition in older adults: the effects of premorbid intellect. AB - Although amyloid deposition remains a marker of the development of Alzheimer's disease, results linking amyloid and cognition have been equivocal. Twenty-five community-dwelling non-demented older adults were examined with (18)F flutemetamol, an amyloid imaging agent, and a cognitive battery, including an estimate of premorbid intellect and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). In the first model, (18)F-flutemetamol uptake significantly correlated with the Delayed Memory Index of the RBANS (r = -.51, p = .02) and premorbid intellect (r = .43, p = .03). In the second model, the relationship between (18)F-flutemetamol and cognition was notably stronger when controlling for premorbid intellect (e.g., three of the five RBANS Indexes and its Total score significantly correlated with (18)F-flutemetamol, r's = -.41 to .58). Associations were found between amyloid-binding (18)F-flutemetamol and cognitive functioning in non-demented older adults. These associations were greatest with delayed memory and stronger when premorbid intellect was considered, suggesting that cognitive reserve partly compensates for the symptomatic expression of amyloid pathology in community-dwelling elderly. PMID- 23817440 TI - Comparision of benefits of early, delayed, and no administration of G-CSF after autologous peripheral blood stem cell transplantation in lymphoma patients. AB - BACKGROUND: Autologous peripheral blood stem cell transplantation (PBSCT) is commonly used in the treatment of lymphoma patients. G-CSF is widely used to boost white blood cell recovery. However, there are no clear data indicating which strategy of using G-CSF provides the most benefit. The aim of our study was to compare 3 strategies of G-CSF administration: from day +1, from day +5, and no administration. MATERIAL AND METHODS: Data from 211 patients treated at 3 centers were gathered retrospectively. The patients in the 3 analyzed groups were not different in regard to type of disease, age, sex, and number of CD34+ cells received. RESULTS: The 3 strategies of G-CSF dosage had very similar results. G CSF boosted the recovery of white blood cells and shortened the time of neutropenia. However, there were no differences in confirmed infections and the duration of hospitalization after transplantation. CONCLUSIONS: Our results question the use of G-CSF in a post-PBSCT setting, as it does not provide significant benefits in reducing the number of infections or shortening the duration of hospitalization. PMID- 23817441 TI - Chemosis secondary to anterograde episcleral (sub-tenon) spread of local anesthetic during retrobulbar eye block. PMID- 23817442 TI - Template-free synthesis of uniform single-crystal hollow cerium dioxide nanocubes and their catalytic activity. AB - Monodisperse single-crystal hollow cerium dioxide nanocubes with exposed (001) facets have been synthesized with the assistance of ammonium chloride (NH4Cl) and polyvinylpyrrolidone (PVP) in a water and ethanol system. A series of experiments indicate that ammonium ion plays an important role in the formation of the hollow structure and PVP plays a key role in the formation of a cubic shape. The hollow cerium dioxide nanocubes exhibit excellent CO catalytic oxidation activity. PMID- 23817443 TI - The spatial distribution of overweight and obesity among a birth cohort of young adult Filipinos (Cebu Philippines, 2005): an application of the Kulldorff spatial scan statistic. AB - OBJECTIVES: The objectives of the study were to test for spatial clustering of obesity in a cohort of young adults in the Philippines, to estimate the locations of any clusters, and to relate these to neighborhood-level urbanicity and individual-level socioeconomic status (SES). SUBJECTS: Data are from a birth cohort of young adult (mean age 22 years) Filipino males (n=988) and females (n=820) enrolled in the Cebu Longitudinal Health and Nutrition Survey. METHODS: We used the Kulldorff spatial scan statistic to detect clusters associated with unusually low or high prevalences of overweight or obesity (defined using body mass index, waist circumference and body fat percentage). Cluster locations were compared to neighborhood-level urbanicity, which was measured with a previously validated scale. Individual-level SES was adjusted for using a principal components analysis of household assets. RESULTS: High-prevalence clusters were typically centered in urban areas, but often extended into peri-urban and even rural areas. There were also differences in clustering by both sex and the measure of obesity used. Evidence of clustering in males, but not females, was much weaker after adjustment for SES. PMID- 23817445 TI - Optimization of non-periodic plasmonic light-trapping layers for thin-film solar cells. AB - Non-periodic arrangements of nanoscale light scatterers allow for the realization of extremely effective broadband light-trapping layers for solar cells. However, their optimization is challenging given the massive number of degrees of freedom. Brute-force, full-field electromagnetic simulations are computationally too time intensive to identify high-performance solutions in a vast design space. Here we illustrate how a semi-analytical model can be used to quickly identify promising non-periodic spatial arrangements of nanoscale scatterers. This model only requires basic knowledge of the scattering behaviour of a chosen nanostructure and the waveguiding properties of the semiconductor layer in a cell. Due to its simplicity, it provides new intuition into the ideal amount of disorder in high performance light-trapping layers. Using simulations and experiments, we demonstrate that arrays of nanometallic stripes featuring a limited amount of disorder, for example, following a quasi-periodic or Fibonacci sequence, can substantially enhance solar absorption over perfectly periodic and random arrays. PMID- 23817446 TI - Skin discoloration caused by iron salts. PMID- 23817447 TI - Adalimumab for Crohn's disease after infliximab treatment failure: a systematic review. AB - The tumor necrosis factor inhibitors infliximab and adalimumab are effective treatments for Crohn's disease (CD); however, some patients treated with infliximab experience a loss of efficacy. There is a lack of high-quality evidence available on whether adalimumab is an effective treatment for patients who have failed infliximab treatment. A systematic review was carried out to examine the efficacy and safety of adalimumab for the treatment of CD in patients who have failed infliximab treatment. PubMed, Google Scholar, and the Cochrane Library were searched using the terms 'adalimumab AND infliximab AND Crohn's'. Randomized-controlled trials and cohort studies were included if they involved patients treated with adalimumab after failing infliximab. Outcomes were response and remission rates, adverse event (AE) rate, and the rate of discontinuations because of AEs. Ten studies (one randomized-controlled trial and nine cohort studies) involving 1009 patients were included. Luminal disease remission rates ranged from 12 to 67% during induction and 29 to 72% during maintenance therapy. Fistulizing disease remission rates ranged from 5 to 50% during induction and 27 to 68% during maintenance therapy. Luminal disease response rates ranged from 29 to 83% during induction and 31 to 59% during maintenance therapy. Fistulizing disease response rates ranged from 15 to 44% during induction and 41 to 56% during maintenance therapy. The overall AE rate ranged from 13 to 69%. Most AEs were mild to moderate in severity. The rate of discontinuation because of AEs ranged from 0 to 14%. The findings reported in the current literature support adalimumab as an efficacious and safe treatment for CD in patients who have failed infliximab treatment. PMID- 23817448 TI - Ventricular thrombosis during sorafenib therapy for advanced hepatocellular carcinoma. PMID- 23817449 TI - Bipolar disorder and interferon treatment: how to manage? PMID- 23817451 TI - The mechanistic influence of aligned nanofibers on cell shape, migration and blebbing dynamics of glioma cells. AB - Investigating the mechanistic influence of the tumor microenvironment on cancer cell migration and membrane blebbing is crucial in the understanding and eventual arrest of cancer metastasis. In this study, we investigate the effect of suspended and aligned nanofibers on the glioma cytoskeleton, cell shape, migration and plasma membrane blebbing dynamics using a non-electrospinning fiber manufacturing platform. Cells attached in repeatable shapes of spindle on single fibers, rectangular on two parallel fibers and polygonal on intersecting fibers. Structural stiffness (N m(-1)) of aligned and suspended nanofibers (average diameter: 400 nm, length: 4, 6, and 10 mm) was found to significantly alter the migration speed with higher migration on lower stiffness fibers. For cells attached to fibers and exhibiting blebbing, an increase in cellular spread area resulted in both reduced bleb count and bleb size with an overall increase in cell migration speed. Blebs no longer appeared past a critical cellular spread area of approximately 1400 MUm(2). Our results highlighting the influence of the mechanistic environment on the invasion dynamics of glioma cells add to the understanding of how biophysical components influence glioma cell migration and blebbing dynamics. PMID- 23817452 TI - Spontaneous preoperative microembolic signals detected with transcranial Doppler are associated with vulnerable carotid plaque characteristics. AB - AIM: Carotid plaque composition is associated with ipsilateral cerebrovascular events. Among patients with carotid artery stenosis, presence of microembolic signals (MES) detected with transcranial Doppler (TCD) is associated with increased stroke risk. We aimed to investigate whether MES detected with TCD in the outpatient clinic among patients scheduled for carotid endarterectomy, was associated with underlying carotid plaque composition. METHODS: TCD was used to detect MES among 38 symptomatic patients scheduled for carotid endarterectomy. Measurements were performed for 30 minutes. Carotid plaques harvested during CEA were subjected to histopathological examination. Plaques from patients without spontaneous MES were compared with plaques from patients with >=1 MES. RESULTS: Median time between TCD and surgery was 4 days. At least 1 MES was detected in 10/38 (26%) patients. Five of ten (50%) patients with spontaneous MES had lipid rich plaques, compared with 5/28 (17.2%) plaques from patients without MES (P=0.048). Luminal thrombus was observed in 6/10 (60.0%) of plaques from patients with MES compared with 7/28 (25.0%) of plaques from patients without MES (P=0.045). CONCLUSION: Spontaneous MES were detected in 26% of symptomatic patients scheduled for CEA and were associated with unstable carotid plaque characteristics. TCD might be a useful tool to help identify patients with vulnerable plaques. PMID- 23817453 TI - The problem of overuse. PMID- 23817454 TI - Improved performance of graphene doped with pyridinic N for Li-ion battery: a density functional theory model. AB - The performance of N-doped graphene on Li-ion battery has been investigated systematically by means of a density functional theory method. Pyridinic N doping, graphitic N atoms and 5-8-5 double vacancies have been selected as the functional defects to study their influence on Li storage compared to the pristine graphene. It has been confirmed that introducing pyridinic N atoms with p-type doping is a suitable method, especially for graphene doped with 4 pyridinic N atoms, whose structural distortion induced by Li intercalation is small and supplies strong force for Li adsorption. The diffusion barrier for this model is lower than for pristine graphene, both for the side and center diffusion routes, contributing to the high mobility. In addition, we point out that the strong catch force for Li will cause more Li to stay on the pyridinic N-doped graphene during the charge-discharge cycles, leading to a faster decrease of capacity compared to pristine graphene. PMID- 23817455 TI - Trimetallic Ag@AuPt Neapolitan nanoparticles. AB - Trimetallic Ag@AuPt Neapolitan nanoparticles were prepared by two sequential galvanic exchange reactions of 1-hexanethiolate-capped silver nanoparticles (AgC6, 5.70 +/- 0.82 nm in diameter) with gold(I)-thiomalic acid (Au(I)TMA) and platinum(II)-hexanethiolate (Pt(II)C6) complexes. The first reaction was carried out at the air-water interface by the Langmuir method where the AgC6 nanoparticles formed a compact monolayer and water-soluble Au(I)TMA was injected into the water subphase; the nanoparticles were then deposited onto a substrate surface in the up-stroke fashion and immersed into an acetone solution of Pt(II)C6. As both reactions were confined to an interface, the Au and Pt elements were situated on two opposite poles of the original Ag nanoparticles. The tripatchy structure was clearly manifested in elemental mapping of the nanoparticles, and consistent with the damping and red-shift of the nanoparticle surface plasmon resonance. Further characterizations by X-ray photoelectron spectroscopy showed that the reactions were mostly confined to the top layers of the Ag metal cores, and contact angle and infrared spectroscopic measurements confirmed the incorporation and segregated distribution of the organic capping ligands on the nanoparticle surface. PMID- 23817456 TI - Pectoralis major myocutaneous flap for reconstruction of circumferential pharyngeal defects. AB - BACKGROUND: A 270-degree partially tubed pectoralis major myocutaneous flap (PMMF) is an excellent option for total circumferential pharyngoesophageal defects in patients who are not candidates for more complex reconstructions. METHODS: Patients undergoing circumferential pharyngoesophageal reconstruction with partially tubed PMMF were reviewed. End points were stricture, fistula, resumption of oral intake, perioperative death, and recurrence. RESULTS: Eleven patients underwent 270-degree PMMF for reconstruction: 6 (55%) were men and 5 (45%) were women (mean, 62 years; range, 42-78 years). Three patients (27%) developed fistulas and 2 (18%) developed stenosis. Ten patients (91%) were able to resume adequate nutrition via oral intake. There were no perioperative deaths. CONCLUSIONS: Patients with severe comorbidities, metastatic disease, a lack of donor vessels, or a potentially hostile abdomen may not be ideal candidates for free tissue transfer. For these patients, partially tubed PMMF using the prevertebral fascia provides a reliable alternative for reconstruction with excellent functional results. PMID- 23817457 TI - Limited incision with thorough elevation palatoplasty: technical evolution for superior results in cleft repair of the secondary palate. AB - BACKGROUND: All kinds of palatoplasty emphasize elongating the soft palate and reconstructing the velar musculature without complication. We present the limited incision with thorough elevation (LITE) palatoplasty that leaves the anterior margin of the hard palate intact, achieving a fully movable bipedicled flap for complete closure and an adequate functioning velar muscular sling. METHODS: Fifty six patients consecutively underwent the LITE palatoplasty. The patients were diagnosed with varying degrees of cleft of the secondary palate. The length of the soft palate was measured, preoperatively and postoperatively, to quantify the lengthening effect of the surgical procedure. The LITE palatoplasty lengthens the soft palate by full mobilization of the velar musculature and reconstruction of the muscles. The LITE palatoplasty also completely repairs the hard palate and leaves no raw surfaces, which can be disadvantageous to the maxillary growth. RESULTS: The average length of soft palate was 18.5+/-3.1 mm preoperatively, and the increased length of the soft palate was 5.06+/-2.41 mm (27.3+/-17.4%). There were no complications including fistula formation, hematoma, or wound problems. After 2 years of operation, only 2 patients who had multiple congenital problems showed grade 1 hypernasality in speech assessment. CONCLUSIONS: The LITE palatoplasty gives satisfactory results in elongating the soft palate and reconstructing a functional velar sling without leaving any raw surfaces that can be detrimental to healing and facial growth. And there was a better speech outcome without complications. PMID- 23817458 TI - The effects of botulinum toxin A on survival of rat TRAM flap with vertical midline scar. AB - The transverse rectus abdominis musculocutaneous (TRAM) flap has been widely used in various reconstructive surgeries. Recently, there have been reports regarding the positive effect of botulinum toxin A (BoTA) on flap survival. We hypothesized that pretreatment with BoTA could augment the survival of pedicled TRAM flaps with a vertical midline scar. Twenty-four Sprague-Dawley rats were randomly divided into 2 groups, namely, control group and BoTA group. Five days after a vertical midline incision, the BoTA group was pretreated with BoTA, whereas the control group was pretreated with normal saline. Ten days after the initial incision, the TRAM flap was harvested. We evaluated the gross flap survival and analyzed the overall histologic change, lumen area of pedicle, and microvessel density with immunohistochemistry. Reverse transcription polymerase chain reaction was performed for the evaluation of angiogenesis-related factors. In the BoTA group, the gross flap survival rate was significantly higher than that in the control group on both ipsilateral and contralateral sides (P < 0.001). In the BoTA group, a significant increase in pedicle lumen area was observed (P < 0.001). In the control group, mild to moderate epidermal necrosis was seen; microvessels were relatively small compared with those of the BoTA group. According to immunohistochemistry, the number of CD31 positively stained vessels was significantly higher on the contralateral side in the control group compared to that in the BoTA group (P < 0.001). The relative messenger RNA (mRNA) expression of CD31 was significantly lower in the BoTA group than that in the control group on both ipsilateral and contralateral sides (P < 0.001). Meanwhile, the relative mRNA expression of VEGF was significantly higher in the BoTA group than in the control group on both ipsilateral and contralateral sides (P < 0.001).We believe that preoperative BoTA therapy is a feasible method to improve circulation of the rat TRAM flap with a vertical midline incision scar. PMID- 23817459 TI - Reconstruction of a large external hemipelvectomy defect after chordoma resection using a 5-component chimeric rotational flap. AB - Management of complex lumbosacral neoplastic disease presents unique challenges and requires a multidisciplinary approach. Large pelvic tumors may require external hemipelvectomy where an entire lower extremity including the hemipelvis is removed with disarticulation of the sacroiliac joint and symphysis pubis. When external hemipelvectomy is performed, the reconstructive surgeon must consider osseous reconstruction for structural pelvic support, the elimination of dead space, protection of implanted hardware, intra-abdominal support, and skin coverage. Reconstruction must minimize wound healing morbidity, operative time and the number of operative sites, and maximize the potential for rehabilitation. We present a case demonstrating use of a rotational chimeric flap for the reconstruction of an external hemipelvectomy defect. PMID- 23817460 TI - Predictive factors of wound complications after sarcoma resection requiring plastic surgeon involvement. AB - INTRODUCTION: The most effective management of a patient with sarcoma is surgical resection. Often the resection is performed, the wound is irradiated, adjuvant chemotherapy is administered, and the wound is closed without plastic surgery consultation. Wound complications, after these treatment protocols, often require plastic surgery involvement and the treatment may require more advanced reconstructive techniques with higher rates of complications than if involvement occurred earlier. METHODS: A retrospective review of all patients who underwent sarcoma excision from 2001 to 2011 was performed. Factors such as tumor size, radiation, chemotherapy, delayed reconstruction (>3 weeks), and immediate reconstruction (<3 weeks) were analyzed for their correlation with wound complications or flap loss. RESULTS: A total of 127 patients underwent sarcoma resection. Wound complications occurred in 49 (38%) patients. All 15 delayed reconstructions had a wound complication, whereas only 11 (37%) of immediate reconstructions had a wound complication. Wound complications with tissue excision less than 500 g occurred in 18 (26%) patients and occurred in 31 (54%) patients with excision greater than 500 g. Seventy-two patients underwent radiation with a wound complication rate of 46% compared with 29% for patients who were not radiated. Chemotherapy was used in 35 patients with a wound complication rate of 49%. CONCLUSIONS: The most predictive factor of sarcoma complication is whether the procedure was a delayed or immediate reconstruction. The second most predictive factor is the amount of tissue excised, greater than 500 g of tissue excised was associated with significantly higher complication rates. Other aspects of sarcoma treatment that may be correlated with higher incidence of wound complications are radiation and the use of adjuvant chemotherapy. Early plastic surgery involvement can help with preoperative planning and reduce the complication rates in patients with sarcoma resection. PMID- 23817461 TI - The prognostic value of miR-21 and miR-155 in non-small-cell lung cancer: a meta analysis. AB - OBJECTIVE: miR-21 and miR-155 have been implicated in the prognosis of non-small cell lung cancer, but the results are controversial. To resolve this issue, we performed a meta-analysis on miR-21 and miR-155 and non-small-cell lung cancer prognosis and lymphoid metastasis. METHODS: Eligible data were extracted and the correlation between miR-21 and miR-155 and non-small-cell lung cancer survival was analyzed by calculating a pooled hazard ratio and sensitivity analysis. The heterogeneity was detected by Q statistic and I-squared statistic, and the publication bias was tested by funnel plots and Egger's test. RESULTS: Nineteen studies were included. High miR-21 level (hazard ratio = 2.00, 95% confidence interval = 1.38-2.89, P = 0.000 for heterogeneity test, I(2) = 84.9%) and high miR-155 level (hazard ratio = 1.65, 95% confidence interval = 1.11-2.44, P = 0.004 for heterogeneity test, I(2) = 68.3%) were significantly associated with worse non-small-cell lung cancer survival. Furthermore, a high miR-21 level was associated with an increased risk of lymphoid infiltration for non-small-cell lung cancer (odds ratio = 1.93; 95% confidence interval = 1.31-2.85). Funnel plot and Egger's test suggested that there was no publication bias in the current meta analysis. CONCLUSIONS: This meta-analysis provides evidence that miR-21 and miR 155 are predicting factors for non-small-cell lung cancer prognosis and lymphoid infiltration. PMID- 23817462 TI - Comparison of proxy ratings of main family caregivers and physicians on the quality of dying of terminally ill cancer patients. AB - OBJECTIVE: Proxy data collection is a prevalent and important source of information in palliative medicine, and few studies have evaluated the level of agreement between different types of proxies. METHODS: A study was conducted to compare the agreement in quality of dying of terminally ill cancer patients from the perspective of (i) the main family caregiver and (ii) the main caregiving physician. The Kappa statistic was applied to measure agreement between the proxies in a prospective study. Using the good death scale and the audit scales, 126 dyads (70%) were compared from a tertiary medical center in Taiwan. RESULTS: In general, the physicians rated quality of dying higher than did family caregivers. The kappa ranged from 0 to 0.232 for the five items, indicating marginal agreement. The prevalence index was applied to correct the Kappa statistic and showed the data to be asymmetrically distributed. Both proxies tended to agree at higher scores (Pneg = 0.745-0.996) in all five items and the total good death scale. For the audit scale, both proxies tended to agree at higher scores in most of the 12 items, except 'alleviation of anxiety', 'resolution of depression' and 'fulfillment of last wishes'. CONCLUSION: The observed agreement between the two proxies was good, except the psychological aspects, demonstrating the validity of proxy rating of patients between physicians and main caregivers. More communications toward the end-of-life issues should be encouraged and conducted in this population. Further research is needed to determine how to best use proxy assessments to evaluate the quality of the dying process. PMID- 23817463 TI - The thermodynamic patterns of eukaryotic genes suggest a mechanism for intron exon recognition. AB - The essential cis- and trans-acting elements required for RNA splicing have been defined, however, the detailed molecular mechanisms underlying intron-exon recognition are still unclear. Here we demonstrate that the ratio between stability of mRNA/DNA and DNA/DNA duplexes near 3'-spice sites is a characteristic feature that can contribute to intron-exon differentiation. Remarkably, throughout all transcripts, the most unstable mRNA/DNA duplexes, compared with the corresponding DNA/DNA duplexes, are situated upstream of the 3' splice sites and include the polypyrimidine tracts. This characteristic instability is less pronounced in weak alternative splice sites and disease associated cryptic 3'-splice sites. Our results suggest that this thermodynamic pattern can prevent the re-annealing of mRNA to the DNA template behind the RNA polymerase to ensure access of the splicing machinery to the polypyrimidine tract and the branch point. In support of this mechanism, we demonstrate that RNA/DNA duplex formation at this region prevents pre-spliceosome A complex assembly. PMID- 23817464 TI - Plastic antibody for DNA damage: fluorescent imaging of BPDE-dG adducts in genomic DNA. AB - Exogenous and endogenous genotoxic carcinogens and their in vivo metabolites may result in DNA damage and cause adverse health effects. It is very difficult to specifically detect trace DNA damage in the presence of a large excess of unmodified nucleosides. Here we report a molecularly imprinted polymer (MIP) nanocomposite, namely nanoMIP, which can be used as a "plastic antibody" for specific recognition of benzo[a]pyrene diol epoxide (BPDE)-DNA adduct. Enhanced binding affinity (880 nM) of nanoMIPs was achieved by using two tailor-made functional monomers. The property of binding kinetics was greatly improved in virtue of the well-defined nanostructure, which was fabricated by initiators for continuous activator regeneration-atom transfer radical polymerization (ICAR ATRP). The BPDE-adducted DNA can be specifically captured by synthetic nanoMIP. By taking advantage of this antibody-mimicking behavior, we further developed a fluorescently imaged particle counting immunoassay (FIPCIA) method for ultrasensitive detection of BPDE-ssDNA adducts using a laser scanning confocal microscope (LSCM). The number of countable fluorescent dots is proportional to the content of BPDE-ssDNA adducts in the DNA sample. The proposed plastic antibody-based FIPCIA method can detect traces of BPDE-DNA adducts as low as 18 pM in human lung carcinoma A549 cells. This highly-sensitive detection of DNA lesions offers a promising alternative to immunogenic antibody-based immunoassays for genomics and DNA modification analysis. PMID- 23817467 TI - Modeling the functioning of YtvA in the general stress response in Bacillus subtilis. AB - The blue-light photoreceptor YtvA activates the general stress response (GSR) of Bacillus subtilis by activating a large protein complex (the stressosome). We have constructed a model for the YtvA's photocycle, and derived an equation for the fraction of YtvA in the light-induced signaling state at a given light intensity. The model was verified experimentally in vitro on wild type YtvA and on an R63K mutant with faster recovery kinetics. Application of the model to the activation of the GSR at various light intensities in vivo revealed that the GSR is more sensitive to light than would be expected based on YtvA's in vitro kinetics. These results were confirmed with the R63K mutant and a slower recovering V28I mutant. Additionally, we have demonstrated the presence of a near UV-light-induced branching reaction that converts the signaling state of YtvA to the dark state. Extension of the model with this reaction shows that it does not contribute significantly to the in vivo blue-light response. The model represents an important step towards a complete systems biology model of the GSR. PMID- 23817466 TI - More targets, more pathways and more clues for mutant p53. AB - Mutations in the transcription factor p53 are among the most common genetic alterations in human cancer, and missense p53 mutations in cancer cells can lead to aggressive phenotypes. So far, only few studies investigated transcriptional reprogramming under mutant p53 expression as a means to identify deregulated targets and pathways. A review of the literature was carried out focusing on mutant p53-dependent transcriptome changes with the aims of (i) verifying whether different p53 mutations can be equivalent for their effects, or whether there is a mutation-specific transcriptional reprogramming of target genes, (ii) understanding what is the main mechanism at the basis of upregulation or downregulation of gene expression under the p53 mutant background, (iii) identifying novel candidate target genes of WT and/or mutant p53 and (iv) defining cellular pathways affected by the mutant p53-dependent gene expression reprogramming. Nearly 600 genes were consistently found upregulated or downregulated upon ectopic expression of mutant p53, regardless of the specific p53 mutation studied. Promoter analysis and the use of ChIP-seq data indicate that, for most genes, the expression changes could be ascribed to a loss both of WT p53 transcriptional activation and repressor functions. Pathway analysis indicated changes in the metabolism/catabolism of amino acids such as aspartate, glutamate, arginine and proline. Novel p53 candidate target genes were also identified, including ARID3B, ARNT2, CLMN, FADS1, FTH1, KPNA2, LPHN2, PARD6B, PDE4C, PIAS2, PRPF40A, PYGL and RHOBTB2, involved in the metabolism, xenobiotic responses and cell differentiation. PMID- 23817468 TI - Extent of preoperative false lumen thrombosis does not influence long-term survival in patients with acute type A aortic dissection. AB - BACKGROUND: Partial thrombosis of the false lumen has been related to aortic growth, reoperations, and death in the chronic phase of type B and repaired type A aortic dissections. The impact of preoperative false lumen thrombosis has not been studied previously. We used data from a contemporary, multinational database on aortic dissections to evaluate whether different degrees of preoperative false lumen thrombosis influenced long-term prognosis. METHODS AND RESULTS: We examined the records of 522 patients with surgically treated acute type A aortic dissections who survived to discharge between 1996 and 2011. At the preoperative imaging, 414 (79.3%) patients had patent false lumens, 84 (16.1%) had partial thrombosis of the false lumen, and 24 (4.6%) had complete thrombosis of the false lumen. The annual median (interquartile range) aortic growth rates were 0.5 (-0.3 to 2.0) mm in the aortic arch, 2.0 (0.2 to 4.0) mm in the descending thoracic aorta, and similar regardless of the degree of false lumen thrombosis. The overall 5-year survival rate was 84.7%, and it was not influenced by false lumen thrombosis (P=0.86 by the log-rank test). Independent predictors of long-term mortality were age >70 years (hazard ratio [HR], 2.34; 95% confidence interval [CI], 1.20 to 4.56, P=0.012) and postoperative cerebrovascular accident, coma, and/or renal failure (HR, 2.62; 95% CI, 1.40 to 4.92, P=0.003). CONCLUSIONS: Patients with acute type A aortic dissection who survive to discharge have a favorable prognosis. Preoperative false lumen thrombosis does not influence long term mortality, reintervention rates, or aortic growth. PMID- 23817469 TI - Loss of Apelin exacerbates myocardial infarction adverse remodeling and ischemia reperfusion injury: therapeutic potential of synthetic Apelin analogues. AB - BACKGROUND: Coronary artery disease leading to myocardial ischemia is the most common cause of heart failure. Apelin (APLN), the endogenous peptide ligand of the APJ receptor, has emerged as a novel regulator of the cardiovascular system. METHODS AND RESULTS: Here we show a critical role of APLN in myocardial infarction (MI) and ischemia-reperfusion (IR) injury in patients and animal models. Myocardial APLN levels were reduced in patients with ischemic heart failure. Loss of APLN increased MI-related mortality, infarct size, and inflammation with drastic reductions in prosurvival pathways resulting in greater systolic dysfunction and heart failure. APLN deficiency decreased vascular sprouting, impaired sprouting of human endothelial progenitor cells, and compromised in vivo myocardial angiogenesis. Lack of APLN enhanced susceptibility to ischemic injury and compromised functional recovery following ex vivo and in vivo IR injury. We designed and synthesized two novel APLN analogues resistant to angiotensin converting enzyme 2 cleavage and identified one analogue, which mimicked the function of APLN, to be markedly protective against ex vivo and in vivo myocardial IR injury linked to greater activation of survival pathways and promotion of angiogenesis. CONCLUSIONS: APLN is a critical regulator of the myocardial response to infarction and ischemia and pharmacologically targeting this pathway is feasible and represents a new class of potential therapeutic agents. PMID- 23817471 TI - Writing and reading with American Psychological Association style. PMID- 23817470 TI - Docosahexaenoic acid supplementation, vascular function and risk factors for cardiovascular disease: a randomized controlled trial in young adults. AB - BACKGROUND: A high consumption of omega-3 long-chain polyunsaturated fatty acids, and particularly docosahexaenoic acid (DHA), has been suggested to reduce the risk of cardiovascular disease (CVD). However, while DHA supplementation may have benefits for secondary prevention, few studies have investigated the role of DHA in the primary prevention of CVD. Here, we tested the hypothesis that DHA supplementation improves endothelial function and risk factors for CVD. METHODS AND RESULTS: Healthy volunteers (n=328), aged 18 to 37 years, were randomly assigned to 1.6 g DHA/day (from a microalgae source) together with 2.4 g/day carrier oil (index group) or to 4.0 g/day olive oil (control) (both given in eight 500-mg capsules/day for 16 weeks). Flow-mediated endothelium-dependent vasodilation (FMD) of the brachial artery (primary outcome) was measured before and after the intervention (n=268) using high-resolution vascular ultrasound. FMD was the same in both groups at randomization (mean, SD; 0.27, 0.1 mm), but postintervention was higher in the control group (0.29, 0.1 mm) compared with the DHA-supplemented group (0.26, 0.1 mm; mean difference -0.03 mm; 95% CI -0.005 to 0.06 mm; P=0.02). Of other outcomes, only triglyceride (mean difference -28%, 95% CI -40% to -15%; P<0.0001) and very low-density lipoprotein concentrations were significant lower in DHA-supplemented individuals compared with controls. CONCLUSIONS: DHA supplementation did not improve endothelial function in healthy, young adults. Nevertheless, lower triglyceride concentrations with DHA supplementation was consistent with previous reports and could have benefits for the prevention of CVD. PMID- 23817473 TI - Spirituality in nursing: nurses' perceptions about providing spiritual care. AB - Providing spiritual care is an important foundation of nursing and is a requirement mandated by accreditation organizations. Spiritual care is essential in all clinical areas but particularly in home care and hospice. Clinicians may be unable to respond to spiritual needs because of inadequate education or the assumption that spiritual needs should be addressed by clergy, chaplains, or other "spiritual" care providers. In reality, clinicians in the home may be in the best position to offer spiritual support when caring for patients at home at end of life. The purpose of this pilot study was to examine relationships between spirituality and nurses' providing spiritual care. Professional nurses (n = 69) working in 2 large healthcare organizations completed the Perceptions of Spiritual Care Questionnaire. Approximately, 33% of the nurses worked in home care. Significant correlations were found among those nurses whose reported nursing education programs adequately prepared them to meet spiritual needs and taught ways to incorporate spiritual care into practice and those who did not. PMID- 23817474 TI - Identifying urinary incontinence in the home setting. Part 2: treatment and related care of incontinence. AB - This is Part 2 of a 2-part series for treating urinary incontinence in the home care setting. Part 1 addresses the assessment, diagnosis, and strategies in the treatment of urinary incontinence; including a case study. PMID- 23817476 TI - Improving fall risk assessment in home care: interdisciplinary use of the Timed Up and Go (TUG). AB - The Timed Up and Go (TUG) is a popular, effective, and valid test of functional mobility and fall risk that is often completed by registered nurses (RNs) and physical therapists (PTs) throughout the course of a home care episode. As reimbursement becomes tied to outcomes, it is essential that all disciplines are consistent in their methods when administering the TUG. Results of this study confirm the hypothesis that test-specific training will significantly improve reliability of the TUG when completed by 2 different disciplines. The purpose of this article is to describe an initiative that provided tool-specific training to all clinical staff at our home care agency. The inter-rater reliability between PTs and RNs improved significantly from 0.77 to 0.86 (p = 0.001) after standardized training on administration of the TUG. PMID- 23817478 TI - Evolution ensures survival ... and success. PMID- 23817479 TI - Acute localized exanthematous pustulosis on inguinal area secondary to piperacillin/tazobactam. PMID- 23817481 TI - Blood pressure and cholesterol control in hypertensive hypercholesterolemic patients: national health and nutrition examination surveys 1988-2010. AB - BACKGROUND: Hypertension doubles coronary heart disease (CHD) risk. Treating hypertension only reduces CHD risk ~25%. Treating hypercholesterolemia in hypertensive patients reduces residual CHD risk >35%. METHODS AND RESULTS: To assess progress in concurrent hypertension and hypercholesterolemia control, National Health and Nutrition Examination Surveys 1988 to 1994, 1999 to 2004, and 2005 to 2010 were analyzed. Hypertension was defined by blood pressure >=140/>=90 mm Hg, current medication treatment, and 2-told hypertension status; blood pressure <140/<90 defined control. Hypercholesterolemia was defined by ATP III criteria based on 10-year CHD risk, low-density lipoprotein cholesterol (LDL-C), and non-high-density lipoprotein cholesterol; values below diagnostic thresholds defined control. Across surveys, 60.7% to 64.3% of hypertensives were hypercholesterolemic. From 1988 to 1994 to 2005 to 2010, control of LDL-C rose (9.2% [95% confidence interval (CI), 6.6%-11.9%] to 45.4% [95% CI, 42.6%-48.3%]), concomitant hypertension and LDL-C (5.0% [95% CI, 3.3%-6.7%] to 30.7% [95% CI, 27.9%-33.4%]), and combined hypertension, LDL-C, and non-high-density lipoprotein cholesterol (1.8% [95% CI, 0.4%-3.2%] to 26.9% [95% CI, 24.4%-29.5%]). By multivariable logistic regression, factors associated with concomitant hypertension, LDL-C, and non-high-density lipoprotein cholesterol control (odds ratio [95% CI]) were statin (10.7 [8.1-14.3]) and antihypertensive (3.32 [2.45 4.50]) medications, age (0.77 [0.69-0.88]/10-year increase), >=2 healthcare visits/yr (1.90 [1.26-2.87]), black race (0.59 [0.44-0.80]), Hispanic ethnicity (0.62 [0.43-0.90]), cardiovascular disease (0.44 [0.34-0.56]), and diabetes mellitus (0.54 [0.42-0.70]). CONCLUSIONS: Despite progress, opportunities for improving concomitant hypertension and hypercholesterolemia control persist. Prescribing antihypertensive and antihyperlipidemic medications to achieve treatment goals, especially for older, minority, diabetic, and cardiovascular disease patients, and accessing healthcare at least biannually could improve concurrent risk factor control and CHD prevention. PMID- 23817482 TI - Management of low levels of high-density lipoprotein-cholesterol. PMID- 23817483 TI - The electrocardiogram at a crossroads. PMID- 23817484 TI - ECG Challenge: July 2, 2013. PMID- 23817485 TI - By a Hair's Breadth. PMID- 23817486 TI - Transcatheter closure of giant ruptured sinus of valsalva aneurysm. PMID- 23817487 TI - Letter by Lensen et al regarding article, "anti-tumor necrosis factor-alpha therapy reduces aortic inflammation and stiffness in patients with rheumatoid arthritis". PMID- 23817488 TI - Genetic testing for inherited heart disease. PMID- 23817489 TI - Letter by Winnik et Al regarding article, "conversion of cardiovascular conference abstracts to publications". PMID- 23817490 TI - Nonsurgical treatments for urinary incontinence in women: summary of primary findings and conclusions. PMID- 23817491 TI - Female-specific hypertension loci on rat chromosome 13. AB - A 3.7-Mb region of rat chromosome 13 (45.2-49.0 Mb) affects blood pressure (BP) in females only, indicating the presence of sex-specific BP loci in close proximity to the Renin locus. In the present study, we used a series of Dahl salt sensitive/Mcwi-13 Brown Norway congenic rat strains to further resolve BP loci within this region. We identified 3 BP loci affecting female rats only, of which the 2 smaller loci (line9BP3 and line9BP4) were functionally characterized by sequence and expression analysis. Compared with SS (SS/HsdMcwiCrl), the presence of a 591-kb region of BN (BN/NHsdMcwi) chromosome 13 (line9BP3) significantly lowered BP by 21 mm Hg on an 8% NaCl diet (153 +/- 7 versus 174 +/- 5 mm Hg; P<0.001). Unexpectedly, the addition of 23 kb of Brown Norway chromosome 13 (line9BP4) completely erased the female-specific BP protection on 8% NaCl diet, suggesting that BN hypertensive allele(s) reside in this region. The congenic interval of the protective line 9F strain contains 3 genes (Optc, Prelp, and Fmod), and the hypertensive line 9E contains 1 additional gene (Btg2). Sequence analysis of the 2 BP loci revealed a total of 282 intergenic variants, with no coding variants. Analysis of gene expression by quantitative real-time polymerase chain reaction revealed strain- and sex-specific differences in Prelp, Fmod, and Btg2 expression, implicating these as novel candidate genes for female-specific hypertension. PMID- 23817492 TI - miR-30a regulates endothelial tip cell formation and arteriolar branching. AB - Microvascular rarefaction increases vascular resistance and pressure in systemic arteries and is a hallmark of fixed essential hypertension. Preventing rarefaction by activation of angiogenic processes could lower blood pressure. Endothelial tip cells in angiogenic sprouts direct branching of microvascular networks; the process is regulated by microRNAs, particularly the miR-30 family. We investigated the contribution of miR-30 family members in arteriolar branching morphogenesis via delta-like 4 (Dll4)-Notch signaling in a zebrafish model. The miR-30 family consists of 5 members (miR-30a-e). Loss-of-function experiments showed that only miR-30a reduced growth of intersegmental arterioles involving impaired tip cell function. Overexpression of miR-30a stimulated tip cell behavior resulting in augmented branching of intersegmental arterioles. In vitro and in vivo reporter assays showed that miR-30a directly targets the Notch ligand Dll4, a key inhibitor of tip cell formation. Coadministration of a Dll4 targeting morpholino in miR-30a morphants rescued the branching defects. Conversely, conditional overexpression of Notch intracellular domain restored arteriolar branching in miR-30a gain-of-function embryos. In human endothelial cells, loss of miR-30a increased DLL4 protein levels, activated Notch signaling as indicated in Notch reporter assays, and augmented Notch downstream effector, HEY2 and EFNB2 (ephrin-B2), expression. In spheroid assays, miR-30a loss- and gain-of-function affected tip cell behavior, consistent with miR-30a targeting Dll4. Our data suggest that miR-30a stimulates arteriolar branching by downregulating endothelial Dll4 expression, thereby controlling endothelial tip cell behavior. These findings could have relevance to the rarefaction process and, therefore, to hypertension. PMID- 23817493 TI - Gestational hypoxia induces preeclampsia-like symptoms via heightened endothelin 1 signaling in pregnant rats. AB - Preeclampsia is a life-threatening pregnancy disorder. However, its pathogenesis remains unclear. We tested the hypothesis that gestational hypoxia induces preeclampsia-like symptoms via heightened endothelin-1 (ET-1) signaling. Time dated pregnant and nonpregnant rats were divided into normoxic and hypoxic (10.5% O2 from the gestational day 6-21) groups. Chronic hypoxia had no significant effect on blood pressure or proteinuria in nonpregnant rats but significantly increased blood pressure on day 12 (systolic blood pressure, 111.7 +/- 6.1 versus 138.5 +/- 3.5 mm Hg; P=0.004) and day 20 (systolic blood pressure, 103.4 +/- 4.6 versus 125.1 +/- 6.1 mm Hg; P=0.02) in pregnant rats and urine protein (MUg/MUL)/creatinine (nmol/MUL) ratio on day 20 (0.10 +/- 0.01 versus 0.20 +/- 0.04; P=0.04), as compared with the normoxic control group. This was accompanied with asymmetrical fetal growth restriction. Hypoxia resulted in impaired trophoblast invasion and uteroplacental vascular remodeling. In addition, plasma ET-1 levels, as well as the abundance of prepro-ET-1 mRNA, ET-1 type A receptor and angiotensin II type 1 receptor protein in the kidney and placenta were significantly increased in the chronic hypoxic group, as compared with the control animals. Treatment with the ET-1 type A receptor antagonist, BQ123, during the course of hypoxia exposure significantly attenuated the hypoxia induced hypertension and other preeclampsia-like features. The results demonstrate that chronic hypoxia during gestation induces preeclamptic symptoms in pregnant rats via heightened ET-1 and ET-1 type A receptor-mediated signaling, providing a molecular mechanism linking gestational hypoxia and increased risk of preeclampsia. PMID- 23817494 TI - Carotid artery intima-media thickness and distensibility in children and adolescents: reference values and role of body dimensions. AB - Carotid intima-media thickness (cIMT) and carotid artery distensibility are reliable screening methods for vascular alterations and the assessment of cardiovascular risk in adult and pediatric cohorts. We sought to establish an international reference data set for the childhood and adolescence period and explore the impact of developmental changes in body dimensions and blood pressure (BP) on carotid wall thickness and elasticity. cIMT, the distensibility coefficient, the incremental modulus of elasticity, and the stiffness index beta were assessed in 1155 children aged 6 to 18 years and sex-specific reference charts normalized to age or height were constructed from 1051 nonobese and nonhypertensive children. The role of body dimensions, BP, and family history, as well as the association between cIMT and distensibility, was investigated. cIMT increased and distensibility decreased with age, height, body mass index, and BP. A significant sex difference was apparent from the age of 15 years. Age- and height-normalized cIMT and distensibility values differed in children who are short or tall for their age. By stepwise multivariate analysis, standardized systolic BP and body mass index were independently positively associated with cIMT SD scores (SDS). Systolic BP SDS independently predicted all distensibility measures. Distensibility coefficient SDS was negatively and beta SDS positively associated with cIMT SDS, whereas incremental modulus of elasticity was independent of cIMT. Morphological and functional aspects of the common carotid artery are particularly influenced by age, body dimensions, and BP. The reference charts established in this study allow to accurately compare vascular phenotypes of children with chronic conditions with those of healthy children. PMID- 23817495 TI - Preeclampsia is associated with the presence of transcriptionally active placental fragments in the maternal lung. AB - Preeclampsia is associated with increased levels of the circulating antiangiogenic factor sFlt-1 and with an excessive shedding of placenta-derived multinucleated syncytial aggregates into the maternal circulation. However, it remains unclear whether these aggregates are transcriptionally active in the maternal organs and can, therefore, contribute to the systemic manifestations of preeclampsia. In this study, we measured placental soluble fms-like tyrosine kinase-1 (sFlt-1) mRNA levels in preeclamptic- and control placentas and performed RNA in situ hybridization to localize the main placental expression site of sFlt-1 mRNA. Because the maternal lung is the first capillary bed that circulating syncytial aggregates traverse, we studied the presence and persistence of placental material in lungs of preeclamptic and control subjects. To confirm the placental origin of these aggregates in maternal lungs, immunohistochemistry for the placenta-specific marker hCG (human chorionic ghonadotropin) and Y chromosome in situ hybridization were performed. Using human placental tissue, we found that syncytial knots are the principal site of expression of the antiangiogenic factor sFlt-1. In addition, autopsy material obtained from women with preeclampsia (n=9) showed significantly more placenta derived syncytial aggregates in the lungs than in control subjects (n=26). Importantly, these aggregates still contained the antiangiogenic factor sFlt-1 after their entrapment in the maternal lungs. The current study confirms the important role of syncytial knots in placental sFlt-1 mRNA production. In addition, it shows a significant association between preeclampsia and larger quantities of sFlt-1 containing syncytial aggregates in maternal lungs, suggesting that the transfer of syncytial aggregates to the maternal compartment may contribute to the systemic endothelial dysfunction that characterizes preeclampsia. PMID- 23817496 TI - Translational examination of changes in baroreflex function after renal denervation in hypertensive rats and humans. AB - Renal denervation has shown promise in the treatment of resistant hypertension, although the mechanisms underlying the blood pressure (BP) reduction remain unclear. In a translational study of spontaneously hypertensive rats (n=7, surgical denervation) and resistant hypertensive human patients (n=8; 5 men, 33 71 years), we examined the relationship among changes in BP, sympathetic nerve activity, and cardiac and sympathetic baroreflex function after renal denervation. In humans, mean systolic BP (SBP; sphygmomanometry) and muscle sympathetic nerve activity (microneurography) were unchanged at 1 and 6 months after renal denervation (P<0.05). Interestingly, 4 of 8 patients showed a 10% decrease in SBP at 6 months, but sympathetic activity did not necessarily change in parallel with SBP. In contrast, all rats showed significant and immediate decreases in telemetric SBP and lumbar sympathetic activity (P<0.05), 7 days after denervation. Despite no change in SBP, human cardiac and sympathetic baroreflex function (sequence and threshold techniques) showed improvements at 1 and 6 months after denervation, particularly through increased sympathetic baroreflex sensitivity to falling BP. This was mirrored in spontaneously hypertensive rats; cardiac and sympathetic baroreflex sensitivity (spontaneous sequence and the Oxford technique) improved 7 days after denervation. The more consistent results in rats may be because of a more complete (>90% reduction in renal norepinephrine content) denervation. We conclude that (1) renal denervation improves BP in some patients, but sympathetic activity does not always change in parallel, and (2) baroreflex sensitivity is consistently improved in animals and humans, even when SBP has not decreased. Determining procedural success will be crucial in advancing this treatment modality. PMID- 23817497 TI - A versatile electrochemical cell for the preparation and characterisation of model electrocatalytic systems. AB - An electrochemical cell for the controllable modification and comprehensive electrochemical characterisation of model electro-catalytic surfaces has been developed. In-depth electrochemical characterisation of stationary electrodes as well as rotating disc electrode (RDE) measurements in hanging meniscus configuration becomes possible. Additionally, the temperature of the electrodes in contact with electrolytes can be accurately controlled between room temperature and 70-80 degrees C. It is of particular importance for model electro-catalytic studies that in one experimental set-up (i) electrochemical metal and non-metal deposition to adjust the amount of the foreign atoms at the surface, (ii) controllable thermal treatment to vary the position of these atoms at the surface and subsurface regions, and (iii) state-of-the-art techniques common in electrocatalysis to characterise the resulting samples are possible. The deposition and annealing procedures under various atmospheres allow accurate control over the position of the foreign atoms at the electrode surface as overlayers, surface alloys and sub-surface (or near-surface) alloys, where the solute element is preferentially located in the second atomic layer of the host metal. The cell enables us to perform all operations without exposing the samples to the laboratory atmosphere at any of the experimental stages. To demonstrate the performance and advantages of the developed cell, we use model experiments with Pt(111) single crystal electrodes and Pt(111) surfaces modified with (sub)monolayer amounts of copper. PMID- 23817498 TI - Is prostate cancer a Lynch syndrome cancer? PMID- 23817499 TI - Cistanche deserticola decoction alleviates the testicular toxicity induced by hydroxyurea in male mice. AB - This study aimed to evaluate testicular toxicity induced by hydroxyurea (HU) and the possible counteracting effect of an aqueous extract of Cistanche deserticola (CD). HU is an antineoplastic drug that has potential reproductive toxicity, and Herba Cistanche has been used as a tonic for the reproductive system for thousands of years. Sixty mice were randomly divided into five groups. Except mice in normal group, the rest received HU (400 mg kg(-1) body weight) intragastrically. Meanwhile, mice in normal and HU control groups received purified water, and the rest received intragastrically three doses of CD decoctions (1.5, 3.0 and 6.0 g crude drug kg(-1) body weight, respectively) daily for 4 weeks. Severe testes lesions were observed, testes weight (P<0.01) and serum luteinising hormone levels (P<0.01) were also decreased significantly, in the HU groups. Three doses of CD decoctions alleviated the spermatogenetic cell degeneration induced by HU and modulated the serum sex hormones levels to some extent. PMID- 23817500 TI - The effectiveness of the TAX 327 nomogram in predicting overall survival in Chinese patients with metastatic castration-resistant prostate cancer. AB - Based on the results of TAX 327, a nomogram was developed to predict the overall survival of metastatic castration-resistant prostate cancer (mCRPC) after first line chemotherapy. The nomogram, however, has not been validated in an independent dataset, especially in a series out of clinical trials. Thus, the objective of the current study was to validate the TAX 327 nomogram in a community setting in China. A total of 146 patients with mCRPC who received first line chemotherapy (docetaxel or mitoxantrone) were identified. Because clinical trials are limited in mainland China, those patients did not receive investigational treatment after the failure of first-line chemotherapy. The predicted overall survival rate was calculated from the TAX 327 nomogram. The validity of the model was assessed with discrimination, calibration and decision curve analysis. The median survival of the cohort was 21 months (docetaxel) and 19 months (mitoxantrone) at last follow-up. The predictive c-index of the TAX 327 nomogram was 0.66 (95% CI: 0.54-0.70). The calibration plot demonstrated that the 2-year survival rate was underestimated by the nomogram. Decision curve analysis showed a net benefit of the nomogram at a threshold probability greater than 30%. In conclusion, the present validation study did not confirm the predictive value of the TAX 327 nomogram in a contemporary community series of men in China, and further studies with a large sample size to develop or validate nomograms for predicting survival and selecting therapies in advanced prostate cancer are necessary. PMID- 23817501 TI - Erectile function and late-onset hypogonadism symptoms related to lower urinary tract symptom severity in elderly men. AB - The aim of this study was to evaluate the relationship between lower urinary tract symptoms (LUTSs), erectile dysfunction (ED) and symptomatic late-onset hypogonadism (SLOH) in ageing men in the Aegean region of Turkey. Five hundred consecutive patients >40 years old who had been in a steady sexual relationship for the past 6 months and were admitted to one of six urology clinics were included in the study. Serum prostate-specific antigen and testosterone levels and urinary flow rates were measured. All patients filled out the International Prostate Symptom Score and Quality of Life (IPSS-QoL), International Index of Erectile Function (IIEF) and Aging Males' Symptoms (AMS) scale forms. Of the patients, 23.9% had mild LUTSs, 53.3% had moderate LUTSs and 22.8% had severe LUTSs. The total testosterone level did not differ between groups. Additionally, 69.6% had ED. The presence of impotence increased with increasing LUTS severity. Symptomatic late-onset hypogonadism (AMS >27) was observed in 71.2% of the patients. The prevalence of severe hypogonadism symptoms increased with the IPSS scores. A correlation analysis revealed that all three questionnaire scores were significantly correlated. In conclusion, LUTS severity is an age-independent risk factor for ED and SLOH. LUTS severity and SLOH symptoms appear to have a strong link that requires etiological and biological clarification in future studies. PMID- 23817503 TI - Somatic DNA copy number alterations and their potential clinical utility for predicting lethal prostate cancer. PMID- 23817502 TI - Semen analysis standardization: is there any problem in Polish laboratories? AB - The aim of the study was to determine the degree of compliance of Polish laboratories with World Health Organization (WHO) recommendations, with regard to semen analysis methodology. A survey requesting information about methods of semen analysis was distributed to employees of 55 laboratories. Respondents who had participated in external seminological workshops (31%) were termed certified respondents (CR), the remaining (69%)-non-certified respondents (NCR). Only one laboratory (6%) in the CR group and none in the NCR were compliant with WHO guidelines for methods and equipment used to evaluate seminal volume, sperm motility, concentration, vitality and morphology. Most problems were of volume measurement (weighing method was reported by 17% of CR and 10% of NCR) and staining method for sperm morphology (Papanicolau or Diff-Quik were found in 33% of CR and 23% of NCR). A three- or four-point grading of sperm motility was used by the majority of respondents; however, 17% of CR and 37% of NCR did not use a laboratory counter to tally spermatozoa. Although a haemocytometer method was used by 80% of laboratories in each group, the improved Neubauer chamber was used only by 42% of CR and 19% of NCR. In each group, 24% of laboratories did not perform a vitality test. Procedural errors and the interchangeable utilization of two or even three methods to analyse a given parameter was observed in both groups. The results indicate a need for standardisation of the methods and continuous, unified training in semen analysis in Polish laboratories. PMID- 23817505 TI - Outcome of sacral nerve stimulation for fecal incontinence at 5 years. AB - OBJECTIVE: This study aimed to evaluate the outcome of sacral nerve stimulation (SNS) for fecal incontinence at 5 years after implantation and to identify predictors of sustained efficacy. BACKGROUND: There is a lack of knowledge about the long-term outcome of SNS for fecal incontinence. METHODS: Prospectively collected data from patients who underwent implantation of an SNS device between 2001 and 2006 were reviewed. RESULTS: One hundred and one patients were available for outcome evaluation at 5 years. Sixty of 101 patients [42.6% on intention-to treat (ITT) and 55.6% per protocol (PP)] reported a favorable outcome, 41 patients (ITT 29.1%; PP 38.0%) reported an unfavorable outcome, of whom 24 patients (ITT 17.0%; PP 22.2%) had their device explanted or permanently switched off before 5 years. Wexner incontinence scores improved significantly from a baseline median of 16 (range 6-20) to a median of 6 (range 0-20) at 3 months (P < 0.0001), and the improvement compared with baseline was maintained throughout the 5-year follow-ups (P < 0.0001).Age was a negative predictive factor [odds ratio (OR): 0.96 each year increase, 95% confidence interval (CI): 0.92-0.99; P = 0.016]. Positive predictors included improvement of urge incontinence episodes during percutaneous nerve evaluation (OR: 10.8; 95% CI: 1.72-132; P = 0.036), improvement of incontinence scores at 6 months from baseline (OR: 6.29; 95% CI: 1.33-34.3; P = 0.025), particularly improvement of incontinence scores from 3 to 6 months (OR: 41.5; 95% CI: 3.51-811; P = 0.007). Overall, 521 reportable events were recorded from 94 patients (93.1%). CONCLUSIONS: On an ITT analysis, 42.6% of patients reported favorable outcomes at 60 months. Patient's age, improvement of urge incontinence during PNE, and sustained efficacy during the first 6 months after implantation are some of the predictors identified. PMID- 23817504 TI - Cellular metabolic regulators: novel indicators of low-grade inflammation in humans. AB - OBJECTIVE: The Toll-like receptor 4 (TLR4) ligand endotoxin triggers robust systemic inflammatory responses in humans at doses equal to or greater than 1 ng/kg. In this study, we tested the hypothesis that evidence of TLR4-induced responses would be detectable in leukocytes challenged with endotoxin doses that are below the threshold needed to trigger a characteristic systemic inflammatory phenotype in humans. METHODS: Subjects were challenged with endotoxin at 1, 0.5, or 0.1 ng/kg (n = 5 per dose). Systemic responses were monitored for 24 hours. Blood samples, collected at designated intervals, were used to determine plasma cytokines levels, total and differential leukocyte counts, expression of leukocyte cell surface receptors, and changes in the leukocyte transcriptome. Western blotting was used to determine changes in leukocyte protein expression. RESULTS: We found that in vivo endotoxin at doses below 1.0 ng/kg triggers weak and variable responses in humans. In marked contrast, we show that endotoxin at a concentration as low as 0.1 ng/kg triggers a transient decline in cellular ATP levels in leukocytes. This is associated with the appearance of a unique protein expression signature in leukocytes. The protein expression signature includes 3 prominent features: (i) AMP-activated protein kinase subunit alpha (AMPKalpha) degradation, (ii) increased hypoxia inducible factor-1 (HIF-1) alpha expression, and (iii) autophagy, collectively indicative of a regulated metabolic response. An indistinguishable response phenotype was observed in human leukocytes treated with endotoxin in vitro. CONCLUSIONS: These data demonstrate for the first time in humans that a TLR4 ligand concentration that is below the threshold needed to trigger clinically evident systemic inflammatory manifestations initiates a transient decline in ATP levels, AMPKalpha degradation, HIF-1alpha expression, and autophagy in leukocytes. This establishes that low-grade TLR4 activation exerts control over leukocyte metabolism in the absence of systemic inflammatory indicators. PMID- 23817506 TI - Effect of simvastatin on physiological and biological outcomes in patients undergoing esophagectomy: a randomized placebo-controlled trial. AB - OBJECTIVE: To test whether simvastatin improves physiological and biological outcomes in patients undergoing esophagectomy. BACKGROUND: One-lung ventilation during esophagectomy is associated with inflammation, alveolar epithelial and systemic endothelial injury, and the development of acute lung injury (ALI). Statins that modify many of the underlying processes are a potential therapy to prevent ALI. METHODS: We conducted a randomized double-blind placebo-controlled trial in patients undergoing esophagectomy. Patients received simvastatin 80 mg or placebo enterally for 4 days preoperatively and 7 days postoperatively. The primary end point was pulmonary dead space (Vd/Vt) at 6 hours after esophagectomy or before extubation. Inflammation was assessed by plasma cytokines and intraoperative exhaled breath condensate pH; alveolar type 1 epithelial injury was assessed by plasma receptor for advanced glycation end products and systemic endothelial injury by the urine albumin-creatinine ratio. RESULTS: Thirty-nine patients were randomized; 8 patients did not undergo surgery and were excluded. Fifteen patients received simvastatin and 16 received placebo. There was no difference in Vd/Vt or other physiological outcomes. Simvastatin resulted in a significant decrease in plasma MCP-1 on day 3 and reduced exhaled breath condensate acidification. Plasma receptor for advanced glycation end products was significantly lower in the simvastatin-treated group, as was the urine albumin creatinine ratio on day 7 postsurgery. ALI developed in 4 patients in the placebo group and no patients in the simvastatin group although this difference was not statistically significant (P=0.1). CONCLUSIONS: In this proof of concept study, pretreatment with simvastatin in esophagectomy decreased biomarkers of inflammation as well as pulmonary epithelial and systemic endothelial injury. PMID- 23817507 TI - A novel approach to assessing technical competence of colorectal surgery residents: the development and evaluation of the Colorectal Objective Structured Assessment of Technical Skill (COSATS). AB - OBJECTIVE: To develop and evaluate an objective method of technical skills assessment for graduating subspecialists in colorectal (CR) surgery-the Colorectal Objective Structured Assessment of Technical Skill (COSATS). BACKGROUND: It may be reasonable for the public to assume that surgeons certified as competent have had their technical skills assessed. However, technical skill, despite being the hallmark of a surgeon, is not directly assessed at the time of certification by surgical boards. METHODS: A procedure-based, multistation technical skills examination was developed to reflect a sample of the range of skills necessary for CR surgical practice. These consisted of bench, virtual reality, and cadaveric models. Reliability and construct validity were evaluated by comparing 10 graduating CR residents with 10 graduating general surgery (GS) residents from across North America. Expert CR surgeons, blinded to level of training, evaluated performance using a task-specific checklist and a global rating scale. The mean global rating score was used as the overall examination score and a passing score was set at "borderline competent for CR practice." RESULTS: The global rating scale demonstrated acceptable interstation reliability (0.69) for a homogeneous group of examinees. Both the overall checklist and global rating scores effectively discriminated between CR and GS residents (P < 0.01), with 27% of the variance attributed to level of training. Nine CR residents but only 3 GS residents were deemed competent. CONCLUSIONS: The Colorectal Objective Structured Assessment of Technical Skill effectively discriminated between CR and GS residents. With further validation, the Colorectal Objective Structured Assessment of Technical Skill could be incorporated into the colorectal board examination where it would be the first attempt of a surgical specialty to formally assess technical skill at the time of certification. PMID- 23817508 TI - Hospital center effect for laparoscopic colectomy among elderly stage I-III colon cancer patients. AB - OBJECTIVE: To investigate hospital-level variation in short-term laparoscopic colectomy outcomes among stage I-III elderly colon cancer patients. BACKGROUND: Surgical outcomes are associated with patient and surgeon characteristics. If outcomes are also impacted by the hospital where the surgery occurs, there is a hospital center effect (HCE). METHODS: Surveillance, Epidemiology, and End Results (SEER)-Medicare data was used to identify stage I-III colon cancer patients treated with laparoscopic colectomies. Multilevel regressions were utilized to study potential HCE for length of stay (LOS), 30-day rehospitalization, and in-hospital mortality, adjusting for patient, surgeon, and hospital-level characteristics. To quantify HCE, we calculated the median instantaneous rate ratio (MIRR) for LOS and median odds ratio (MOR) for in hospital mortality and 30-day rehospitalization. Sensitivity analyses were conducted for high volume/medical school affiliated hospitals and colorectal surgeons. RESULTS: The multilevel analyses based on 4617 patients from 465 hospitals documented statistically significant HCEs for LOS (MIRR = 1.35; P < 0.001) and in-hospital mortality (MOR = 1.69; P = 0.032), but no HCE for 30-day rehospitalization. Sensitivity analyses confirmed our findings. HCE was significant for LOS in all sensitivity analyses and was significant for in hospital mortality for high volume/medical school affiliated hospitals. CONCLUSIONS: HCE exists for LOS and in-hospital mortality of laparoscopic colectomy, which suggests that the choice of hospital affects outcomes independently of other confounding variables. Reducing the variation in outcomes associated with HCE may improve the quality of cancer care. PMID- 23817509 TI - The involvement of CD36 in monocyte activation by antiphospholipid antibodies. AB - BACKGROUND: CD36, known as a scavenger receptor, is a transmembrane glycoprotein expressed on monocytes, platelets and endothelial cells, recognizes multiple ligands, including phosphatidylserine, and regulates atherogenesis and thrombosis. The objective of this study is to investigate the possible involvement of CD36 in the pathophysiology of thrombosis in patients with antiphospholipid syndrome (APS). METHODS: First, rs3765187, a missense mutation linked to CD36 deficiency, was investigated by TaqMan polymerase chain reaction (PCR) genotyping method in 819 Japanese, including 132 patients with APS, 265 with systemic lupus erythematosus (SLE) in the absence of APS, and 422 healthy subjects. Then, the involvement of CD36 in antiphospholipid antibody (aPL) induced tissue factor (TF) expression was examined using CD36-null mice or anti CD36. Purified IgG from patients with APS and a monoclonal phosphatidylserine dependent antiprothrombin antibody were used in these experiments. TF expression was tested by real-time PCR and flow cytometry. RESULTS: Minor allele carrier of rs3765187 was less frequent in patients with APS (3.8% p=0.032), but not in patients with SLE in the absence of APS (7.9% p=0.32), compared with healthy subjects (10.2%). The aPL-induced TF expression was significantly suppressed on peritoneal macrophages from CD36-null mice compared to wild type and significantly inhibited by anti-CD36 on human monocytes. CONCLUSIONS: The gene mutation linked to CD36 deficiency was less frequent in patients with APS. The deficient or suppressed CD36 function significantly reduced aPL-induced TF expression in vitro. Taken together, in a susceptible background CD36 scavenger receptor function may be involved in the thrombotic pathophysiology in patients with APS. PMID- 23817510 TI - Pristane-induced lupus as a model of human lupus arthritis: evolvement of autoantibodies, internal organ and joint inflammation. AB - OBJECTIVE: Arthritis is frequently seen in human lupus, but rarely in lupus models. Pristane-induced lupus (PIL) can be induced in various mouse strains such as BALB/c and C57BL/6. We herein characterize clinical and histological features of arthritis in the context of systemic lupus and provide a prudent comparison with models of rheumatoid arthritis (RA). METHODS: A total of 57 BALB/c mice received pristane (PIL group) and were analyzed for serum autoantibodies (anti chromatin-, -histone, -Sm, -dsDNA), as well as for clinical features and histopathology of joints, lungs and kidneys. Joint pathology was quantified by image analysis and tissue cytometry. Ten C57BL/6 mice (Bl/6-PIL) and historical groups of two different RA models were analyzed accordingly. RESULTS: In BALB/c PIL, clinical arthritis started at three months, occurred finally in 79% of PIL (but not in controls, p<0.001) and correlated with areas of inflammation, erosion, cartilage damage, osteoclast numbers and total severity score (for all: r>0.7, p<0.001). After eight months, 58% of PIL (but no controls, p<0.001) had mild-erosive arthritis. In contrast to RA, the most frequent inflammatory cell type of the pannus was granulocytes (17.7%), PIL had lower numbers of osteoclasts, erosions rarely affected both layers of the cortical bone and there was no progression to complete joint destruction (even after one year of observation). Serum autoantibodies (auto-abs) preceded arthritis and became significantly elevated in all PIL; affected joints showed increased deposits of IgG (and IgM) within the inflammatory tissue, indicative of an ab-mediated process. PIL mice with arthritis also showed signs of pulmonary (100%) and renal (46%) lupus. In contrast to BALB/c, Bl/6-PIL mice did not develop any signs of arthritis. CONCLUSION: PIL in BALB/c mice is characterized by severe organ involvement, typical autoabs and by a mild-erosive arthritis with similarities to, but also with distinct differences from, RA. PIL may help to study arthritis along with other key features of systemic lupus erythematosus after therapeutic interventions or in knock-out models based on a BALB/c but not on a C57BL/6 background. PMID- 23817511 TI - Limitations of current treatments for systemic lupus erythematosus: a patient and physician survey. AB - An independent cross-sectional survey assessed systemic lupus erythematosus (SLE) disease and treatment burden. Variables included medication classes prescribed, disease activity, flare occurrences, treatment satisfaction, and validated measures of health-related quality of life (HRQoL), fatigue and work productivity. Of 886 eligible patients (mean age 41.3 years, 89% female), 515 completed the survey. One-third reported moderate-to-severe disease activity, and 31% had flared in the last 12 months. Higher severity of disease activity (moderate-to-severe) was associated with >= 2 medication classes prescribed and treatment regimens that included corticosteroids (CS) (both p<0.0001). Patients receiving CS reported lower EQ-5D scores (p=0.0019) and higher fatigue levels (p<0.001), and both patients (p=0.0019) and physicians (p=0.0001) were less likely to report satisfaction with treatment regimens including CS. Among responders eligible for work (n=456), severity of disease activity (moderate-to severe vs. mild) was associated with unemployment (52.9% vs. 40.8%; p=0.0189), greater impairment in work productivity (36% vs. 21%; p=0.0003) and participation in daily activities (41% vs. 21%; p<0.0001). This survey confirms that SLE and current treatment options substantially impair patients' health status and work productivity. Physician- and patient-reported satisfaction with current treatment regimens, despite poorly controlled disease activity, indicate they are resigned to the limitations of available SLE treatment regimens. PMID- 23817512 TI - Aspirin resistance in systemic lupus erythematosus. A pilot study. AB - Systemic lupus erythematosus (SLE) patients are at increased risk of thrombosis and cardiovascular diseases. Aspirin is an effective treatment option for these patients. The aim of this study was to investigate the presence of aspirin resistance in SLE patients. We studied aspirin resistance in 33 SLE patients and nine healthy controls by using a Multiplate(r) impedance aggregometer (Dynabyte GmbH, Munich, Germany). Twenty-six SLE patients were on regular aspirin treatment. Aspirin resistance was found in five (19.2%) out of 26 patients who were on aspirin treatment. When the tests were repeated by adding acetylsalicylic acid in the medium, all of these patients became responsive to the aspirin. SLE disease activity, body mass index, smoking status, and the presence of anticardiolipin antibodies or positive lupus anticoagulant test results were no different in patients with or without aspirin resistance. (p>0.05 for all). Our results suggest that there may be a considerable number of SLE patients with aspirin resistance. PMID- 23817514 TI - Deoxynucleoside triphosphates bearing histamine, carboxylic acid, and hydroxyl residues--synthesis and biochemical characterization. AB - Modified nucleoside triphosphates (dA(Hs)TP, dU(POH)TP, and dC(Val)TP) bearing imidazole, hydroxyl, and carboxylic acid residues connected to the purine and pyrimidine bases through alkyne linkers were prepared. These modified dN*TPs were excellent substrates for various DNA polymerases in primer extension reactions. Moreover, the combined use of terminal deoxynucleotidyl transferase (TdT) and the modified dNTPs led to efficient tailing reactions that rival those of natural counterparts. Finally, the triphosphates were tolerated by polymerases under PCR conditions, and the ensuing modified oligonucleotides served as templates for the regeneration of unmodified DNA. Thus, these modified dN*TPs are fully compatible with in vitro selection methods and can be used to develop artificial peptidases based on DNA. PMID- 23817516 TI - Evolution of longitudinally extensive transverse myelitis in an aquaporin-4 IgG positive patient. PMID- 23817517 TI - Neurologic disability: a hidden epidemic for India. PMID- 23817518 TI - Impairment of JCV-specific T-cell response by corticotherapy: effect on PML-IRIS management? PMID- 23817521 TI - Opinion & Special Articles: neurologist: specialized primary care provider vs consultant. AB - As per the Centers for Medicare and Medicaid Services (CMS) current proposal, many specialties including neurology are not eligible for the increase in Medicare reimbursements that will be allocated to other cognitive specialties, such as the 7% increase for family physicians, 5% for internists, and 4% for geriatric specialists.(1,2) Other specialties such as anesthesiology, radiology, and cardiology are scheduled for a 3%-4% decrease in reimbursement in order to pay for the increases outlined above. Current estimates show that neurologists provide a significant amount of primary care for complex patients and yet these services are not eligible for increased payments. It is estimated that up to 60% of neurologists' services to these complex patients are ineligible for increased payments.(3.) PMID- 23817522 TI - Teaching NeuroImages: diagnostic utility of FDG-PET in neurolymphomatosis. PMID- 23817523 TI - Teaching Video NeuroImages: a teenager with a rare movement disorder. PMID- 23817524 TI - Breast cancer normalization induced by embryonic mesenchyme is mediated by extracellular matrix biglycan. AB - Some epithelial cancers can be induced to revert to quiescent differentiated tissue when combined with embryonic mesenchyme; however, the mechanism of this induction is unknown. Here we combine tissue engineering, developmental biology, biochemistry and proteomics approaches to attack this problem. Using a synthetic reconstitution system, we show that co-culture of breast cancer cells with embryonic mesenchyme from early stage (E12.5-13.5) mammary glands decreases tumor cell proliferation while stimulating acinus differentiation, whereas cancer associated fibroblasts (CAFs) fail to produce these normalizing effects. When insoluble extracellular matrices (ECMs) were isolated from cultured early stage (E12.5-13.5) embryonic mammary mesenchyme cells or E10 tooth mesenchyme and recombined with mammary tumor cells, they were found to be sufficient to induce breast cancer normalization including enhanced expression of estrogen receptor alpha (ER-alpha). In contrast, ECM from later stage (E14.5) mammary mesenchyme and conditioned medium isolated from mesenchymal cell cultures were ineffective. Importantly, when the inductive ECMs produced by early stage embryonic mammary mesenchyme were scraped from dishes and injected into fast-growing breast tumors in mice, they significantly inhibited cancer expansion. Proteomics analysis of the detergent insoluble ECM material revealed several matrix components that were preferentially expressed in the embryonic ECMs. Analysis of two of these molecules previously implicated in cancer regulation--biglycan and tenascin C- revealed that addition of biglyan can mimic the tumor normalization response, and that siRNA knockdown of its expression in cultured embryonic mesenchyme results in loss of the ECM's inductive activity. These studies confirm that embryonic mesenchyme retains the ability to induce partial breast cancer reversion, and that its inductive capability resides at least in part in the ECM protein biglycan that it produces. PMID- 23817525 TI - Temperature and magnetic field dependence of a Kondo system in the weak coupling regime. AB - The Kondo effect arises due to the interaction between a localized spin and the electrons of a surrounding host. Studies of individual magnetic impurities by scanning tunneling spectroscopy have renewed interest in Kondo physics; however, a quantitative comparison with theoretical predictions remained challenging. Here we show that the zero-bias anomaly detected on an organic radical weakly coupled to a Au (111) surface can be described with astonishing agreement by perturbation theory as originally developed by Kondo 60 years ago. Our results demonstrate that Kondo physics can only be fully conceived by studying both temperature and magnetic field dependence of the resonance. The identification of a spin 1/2 Kondo system is of relevance not only as a benchmark for predictions for Kondo physics but also for correlated electron materials in general. PMID- 23817526 TI - Not better but quite good: effects on work loss of combination treatment for rheumatoid arthritis with and without biological agents. PMID- 23817527 TI - In vitro cytokine expression by peripheral mononuclear cells in herbal drug induced skin eruption. AB - Herbal medicine is widely used worldwide and is associated with side-effects such as skin eruptions. Herbal drugs are often produced by combining multiple crude drugs, mostly of plant origin. Determining which medi-cinal plants are associated with the herbal drugs that induce skin eruptions can therefore be difficult. This study investigated mRNA expression of several cytokines in peripheral mononuclear cells (PBMCs) from two patients with herbal drug-induced skin eruptions; one reacted to keishi-bukuryo-gan (KBG), composed of 5 medicinal plants, and the other patient reacted to senna. PBMCs (1*106) from the 2 patients were cultured for 24 h with the supernatant from the medicinal plants from KBG or senna in various concentrations, and a reverse transcription-polymerase chain reaction (RT PCR) analysis was performed. A high mRNA level of interleukin (IL)-4 and IL-5 was detected in PBMCs stimulated by KBG and two of its components. Senna stimulated a high level of IL-4 and IL-5 mRNA levels in PBMCs from patient with senna-induced drug reaction. PMID- 23817528 TI - Examining the relationship between health-related quality of life in individuals with spinal cord injury and the mental health of their caregivers in Colombia, South America. AB - Although considerable research has been carried out on family caregivers of individuals with various types of disabilities, spinal cord injury (SCI) caregivers have received considerably less attention in terms of research, especially in regions such as Latin America. This study examined the relationship between health-related quality of life (HRQOL) in individuals with SCI and their family caregiver's mental health in Neiva, Colombia. Thirty-four individuals with SCI and their primary caregivers (34 dyads; n=68) from the Foundation for the Integral Development of People with Disabilities in Neiva, Colombia, were included in this study. Individuals with SCI completed eight subscales of the SF 36 that assessed HRQOL. Five aspects of caregiver mental health were assessed, including burden (Zarit Burden Interview), satisfaction with life (Satisfaction with Life Scale), depression (Patient Health Questionnaire-9), self-esteem (Rosenberg Self-Esteem Scale), and anxiety (State Trait Anxiety Inventory). A series of multiple regressions uncovered strong associations among the HRQOL of individuals with SCI and various aspects of caregiver mental health. In these regressions, patient physical functioning and pain were independently related to caregiver burden; patient pain and general health were independently related to caregiver satisfaction with life; and patient pain was independently related to caregiver anxiety. HRQOL in individuals with SCI was robustly related to their caregiver's mental health, suggesting that the two sets of variables are closely linked. These findings suggest that caregiver mental health should be a central part of SCI rehabilitation interventions, especially in Latin America. PMID- 23817529 TI - Ab initio calculations of the optical absorption spectra of C60-conjugated polymer hybrids. AB - A recently developed linear-scaling density-functional theory (LS-DFT) formalism is used to calculate optical absorption spectra of hybrids of C60 and the conjugated polymers poly(para-phenylene) (PPP) and poly(para-phenylene vinylene) (PPV). The use of a LS formalism allows calculations on large systems with realistic proportions of C60, which has been of interest for the use of such materials in photovoltaics. Two different bonding structures are tested for the hybrid PPP and for both systems additional peaks are present in the absorption spectra below the original onset of absorption. By identifying the eigenstates involved in the relevant transitions, a weighted density difference is formed, demonstrating the transfer of charge between the polymer chain and the C60, in agreement with experiment. For the hybrid PPV, no additional peaks are observed in the absorption spectrum. PMID- 23817530 TI - Spatiotemporally controlled induction of autophagy-mediated lysosome turnover. AB - Lysosomes are the major degradative compartments within cells, harbouring a wide variety of hydrolytic enzymes within their lumen. Release of lysosomal hydrolases from lysosomes into the cell cytoplasm results in cell death. Here we report that damaged lysosomes undergo autophagic turnover. Using a light-induced lysosome impairing scheme that can be controlled spatially and temporally within a cell, we show that damaged lysosomes are selectively ubiquitinated, recruit autophagic proteins and are eventually incorporated into autolysosomes for degradation. We propose that autophagic removal of lysosomes, which we term lysophagy, is a surveillance mechanism that alleviates cells from the adverse effects of lysosomal damage. We envision our method to induce lysosomal damage will enable detailed molecular studies of the lysophagy pathway in the future. PMID- 23817531 TI - Sperm quality assessment via separation and sedimentation in a microfluidic device. AB - A major reason for infertility is due to male factors, including the quality of spermatozoa, which is a primary factor and often difficult to assess, particularly the total sperm concentration and its motile percentage. This work presents a simple microfluidic device to assess sperm quality by quantifying both total and motile sperm counts. The key design feature of the microfluidic device is two channels separated by a permeative phase-guide structure, where one channel is filled with raw semen and the other with pure buffer. The semen sample was allowed to reach equilibrium in both chambers, whereas non-motile sperms remained in the original channel, and roughly half of the motile sperms would swim across the phase-guide barrier into the buffer channel. Sperms in each channel agglomerated into pellets after centrifugation, with the corresponding area representing total and motile sperm concentrations. Total sperm concentration up to 10(8) sperms per ml and motile percentage in the range of 10 70% were tested, encompassing the cutoff value of 40% stated by World Health Organization standards. Results from patient samples show compact and robust pellets after centrifugation. Comparison of total sperm concentration between the microfluidic device and the Makler chamber reveal they agree within 5% and show strong correlation, with a coefficient of determination of R(2) = 0.97. Motile sperm count between the microfluidic device and the Makler chamber agrees within 5%, with a coefficient of determination of R(2) = 0.84. Comparison of results from the Makler Chamber, sperm quality analyzer, and the microfluidic device revealed that results from the microfluidic device agree well with the Makler chamber. The sperm microfluidic chip analyzes both total and motile sperm concentrations in one spin, is accurate and easy to use, and should enable sperm quality analysis with ease. PMID- 23817532 TI - Chemoselective synthesis of tetrasubstituted furans via intramolecular Wittig reactions: mechanism and theoretical analysis. AB - An efficient synthesis of tetrasubstituted furans was achieved from the corresponding alpha,beta-unsaturated ketone derivatives, acid chlorides, and Bu3P in the presence of Et3N via a chemoselective intramolecular Wittig reaction as the key step. The presence of an additional electron-withdrawing group in the alpha-position of Michael acceptors controlled the chemoselectivities of presumable phosphorus ylides in the intramolecular Wittig reactions, and their mechanisms were also investigated by DFT calculations. PMID- 23817533 TI - Gut-on-a-Chip microenvironment induces human intestinal cells to undergo villus differentiation. AB - Existing in vitro models of human intestinal function commonly rely on use of established epithelial cell lines, such as Caco-2 cells, which form polarized epithelial monolayers but fail to mimic more complex intestinal functions that are required for drug development and disease research. We show here that a microfluidic 'Gut-on-a-Chip' technology that exposes cultured cells to physiological peristalsis-like motions and liquid flow can be used to induce human Caco-2 cells to spontaneously undergo robust morphogenesis of three dimensional (3D) intestinal villi. The cells of that line these villus structures are linked by tight junctions, and covered by brush borders and mucus. They also reconstitute basal proliferative crypts that populate the villi along the crypt villus axis, and form four different types of differentiated epithelial cells (absorptive, mucus-secretory, enteroendocrine, and Paneth) that take characteristic positions similar to those observed in living human small intestine. Formation of these intestinal villi also results in exposure of increased intestinal surface area that mimics the absorptive efficiency of human intestine, as well enhanced cytochrome P450 3A4 isoform-based drug metabolizing activity compared to conventional Caco-2 cell monolayers cultured in a static Transwell system. The ability of the human Gut-on-a-Chip to recapitulate the 3D structures, differentiated cell types, and multiple physiological functions of normal human intestinal villi may provide a powerful alternative in vitro model for studies on intestinal physiology and digestive diseases, as well as drug development. PMID- 23817534 TI - Gluteal blood flow and oxygenation during electrical stimulation-induced muscle activation versus pressure relief movements in wheelchair users with a spinal cord injury. AB - BACKGROUND: Prolonged high ischial tuberosities pressure (IT pressure), decreased regional blood flow (BF) and oxygenation (%SO2) are risk factors for developing pressure ulcers (PUs) in patients with spinal cord injury (SCI). Electrical stimulation (ES)-induced gluteal and hamstring muscle activation may improve pressure distribution by changing the shape of the buttocks while sitting and also increase BF and %SO2. OBJECTIVE: To compare acute effects of ES-induced gluteal and hamstring muscle activation with pressure relief movements (PRMs) on IT pressure, BF and %SO2. PARTICIPANTS AND METHODS: Twelve men with SCI performed PRMs - push-ups, bending forward and leaning sideward - and received surface ES (87+/-19 mA) to the gluteal and hamstring muscles while sitting in their wheelchair. Ischial tuberosities pressure was measured using a pressure mapping system; (sub)cutaneous BF and %SO2 were measured using reflection spectroscopy and laser Doppler, respectively. RESULTS: Compared with rest (156+/-26 mm Hg), IT pressure was significantly lower during all other conditions (push-ups 19+/-44; bending forward 56+/-33; leaning sideward 44+/-38; ES 67+/-45 mm Hg). For the whole group, all PRMs significantly augmented BF (+39 to -96%) and %SO2 (+6.0 to 7.9%-point), whereas ES-induced muscle activation did only for peak BF. In all, 63% of the participants showed an increased BF (average 52%) with ES. CONCLUSION: PRMs acutely reduced IT pressure and improved oxygenation and BF in SCI. The currently used ES method cannot replace PRMs, but it may be used additionally. ES induced muscle activation is not as effective for acute pressure relief, but the frequency of stimulation is much higher than the performance of PRMs and can therefore be more effective in the long term. PMID- 23817535 TI - A few comments on a few articles. PMID- 23817536 TI - Spinal cord injury-related chronic pain in victims of the 2008 Sichuan earthquake: a prospective cohort study. AB - STUDY DESIGN: Prospective cohort. OBJECTIVES: To characterize spinal cord injury (SCI)-related pain and treatment in victims of the 2008 Sichuan earthquake. SETTING: Mianzhu County, China. METHODS: Twenty-six patients who sustained SCI in the 2008 Sichuan earthquake and who were treated in the same hospital were enrolled. Data was collected on pain severity with a visual analog scale, depression with Patient Health Questionnaire-9, quality of life (QoL) with World Health Organization Quality of Life-BREF and social participation with the Craig Hospital Handicap Assessment and Reporting Technique Short Form at three assessment points. Detailed pain descriptions including therapeutic interventions were elicited at the fourth assessment. Pain determinants were analyzed with a longitudinal Tobit regression, and Pearson's correlations of pain severity with depression, QoL and social participation stratified by measurement point were calculated. RESULTS: SCI-related pain was highly prevalent and prevalence of neuropathic pain was nearly twice that of nociceptive pain. Most patients reported pain since the onset and severity was not significantly reduced over time. Cervical injury, complete lesions and education level were significant pain determinants. Depression and QoL scores were highly correlated with pain at the first two assessments points but not at the third measurement. Most patients did not seek treatment because they regarded pain as either a normal condition after SCI or were afraid of drug dependency. CONCLUSION: This initial longitudinal assessment and characterization of SCI-related pain in earthquake victims provides a foundation for further exploration of the biological and psychosocial determinants of pain severity and of the correlation of chronic pain with other outcomes of interest in this population. Patient pain-treatment-seeking behavior and therapeutic interventions should be evaluated concurrently. PMID- 23817537 TI - Acute spinal cord injury could cause activation of autophagy in dorsal root ganglia. AB - OBJECTIVES: Dorsal root ganglia (DRGs) have an important role in the peripheral mechanism of sensation by primary afferent neurons, which are widely used to research the processes of cell death, axonal regeneration, signal transmission of growth factors and the mechanism of pain. METHODS: In the present study, we investigated the activation of autophagy in DRGs in a rat model of acute spinal cord injury at different time points. RESULTS: Expression of microtubule associated protein light chain 3, a marker of autophagy was increased after 8 h in DRGs, peaked after 3 days, and then gradually decreased after 7 days. Furthermore, the toluidine blue staining has proven that after acute spinal cord injury, the myelin sheathes of DRGs undergo histopathological changes over time, with axonal swellings, disorderly arrangement and uneven distribution. CONCLUSION: Potential treatment aimed at recovery of behavioral locomotor and sensory perception should target the process of autophagy in DRGs. PMID- 23817539 TI - New perspectives on potential hydrogen storage materials using high pressure. AB - In addressing the global demand for clean and renewable energy, hydrogen stands out as the most suitable candidate for many fuel applications that require practical and efficient storage of hydrogen. Supplementary to the traditional hydrogen storage methods and materials, the high-pressure technique has emerged as a novel and unique approach to developing new potential hydrogen storage materials. Static compression of materials may result in significant changes in the structures, properties and performance that are important for hydrogen storage applications, and often lead to the formation of unprecedented phases or complexes that have profound implications for hydrogen storage. In this perspective article, 22 types of representative potential hydrogen storage materials that belong to four major classes--simple hydride, complex hydride, chemical hydride and hydrogen containing materials--were reviewed. In particular, their structures, stabilities, and pressure-induced transformations, which were reported in recent experimental works together with supporting theoretical studies, were provided. The important contextual aspects pertinent to hydrogen storage associated with novel structures and transitions were discussed. Finally, the summary of the recent advances reviewed and the insight into the future research in this direction were given. PMID- 23817541 TI - Serum levels of angiopoietin-2, but not angiopoietin-1, are elevated in patients with erythrodermic cutaneous T-cell lymphoma. AB - Angiogenesis is a crucial process in the growth and progression of cancer, correlating with the metastatic potential of tumour cells. Angiopoietins are ligands for the endothelium-specific tyrosine kinase Tie2 receptor, which comprise 4 structurally related proteins, termed angiopoietin (Ang)-1, Ang-2, Ang 3 and Ang-4. The roles of Ang-1 and Ang-2 have recently been clarified as crucial in angiogenesis. In this report, we measured serum Ang-1 and Ang-2 levels in patients with cutaneous T-cell lymphoma (CTCL). Serum levels of Ang-2, but not Ang-1, in patients with Sezary syndrome were significantly higher than those in patch mycosis fungoides (MF), plaque/tumour MF, and healthy controls. In patients with CTCL, serum Ang-2 correlated with disease activity. Moreover, the numbers of Ang-2+ cells in lesional skin of CTCL were significantly larger than those in normal skin. These results suggest that Ang-2 may have important roles in the development of CTCL. PMID- 23817542 TI - A clinical protocol for intraoral digital impression of screw-retained CAD/CAM framework on multiple implants based on wavefront sampling technology. AB - PURPOSE: To obtain an accurate CAD/CAM metal framework over 6 implants using a Chairside Intraoral Scanner based on the principle of active (optical) wavefront sampling. MATERIAL AND METHODS: Six prototype cylindrical scan bodies screwed in the implants were used to obtain an intraoral digital impression. A conventional resin tooth try-in was fabricated and digitized with an extraoral scanner, and this dataset was merged to the digital data obtained from the intraoral impression to calculate the best framework design with advanced CAD software. The framework was fabricated with a 5-axis computer numerical control milling unit. Three clinical tests (saliva intrusion, Sheffield test, and screw resistance test) were performed to assess the fit of the framework. RESULTS: Under 3 clinical tests, an accurate fit was observed. CONCLUSION: The case presented in this report proposes a new clinical protocol for obtaining accurate digital impressions of multiple implants. PMID- 23817543 TI - No rest for the weary...or the sick. PMID- 23817544 TI - Hemeoxygenase-1 mediated hypercoagulability in a patient with thyroid cancer. AB - Thyroid cancers can cause significant regional thrombotic morbidity and mortality. Of interest, thyroid cancer cell lines can have upregulation of the carbon monoxide-producing enzyme, hemeoxygenase-1. Carbon monoxide has been demonstrated to markedly enhance plasmatic coagulation in vitro and in vivo via enhancement of fibrinogen's substrate properties by binding to a fibrinogen associated heme group(s). We present a patient undergoing removal of a malignant thyroid tumour who was serendipitously found to have abnormally increased carboxyhaemoglobin concentration (2.4%) and plasmatic hypercoagulability with a carbon monoxide-mediated clot strength as determined by a thrombelastographic method. This initial observation serves as a rationale to further investigate the role played by hemeoxygenase-1 upregulation in the setting of cancers associated with increased endogenous carbon monoxide production. PMID- 23817545 TI - Cortical activation of accumbens hyperpolarization-active NMDARs mediates aversion-resistant alcohol intake. AB - Compulsive drinking despite serious adverse medical, social and economic consequences is a characteristic of alcohol use disorders in humans. Although frontal cortical areas have been implicated in alcohol use disorders, little is known about the molecular mechanisms and pathways that sustain aversion-resistant intake. Here, we show that nucleus accumbens core (NAcore) NMDA-type glutamate receptors and medial prefrontal (mPFC) and insula glutamatergic inputs to the NAcore are necessary for aversion-resistant alcohol consumption in rats. Aversion resistant intake was associated with a new type of NMDA receptor adaptation, in which hyperpolarization-active NMDA receptors were present at mPFC and insula but not amygdalar inputs in the NAcore. Accordingly, inhibition of Grin2c NMDA receptor subunits in the NAcore reduced aversion-resistant alcohol intake. None of these manipulations altered intake when alcohol was not paired with an aversive consequence. Our results identify a mechanism by which hyperpolarization active NMDA receptors under mPFC- and insula-to-NAcore inputs sustain aversion resistant alcohol intake. PMID- 23817547 TI - Goal-dependent dissociation of visual and prefrontal cortices during working memory. AB - To determine the specific contribution of brain regions to working memory, human participants performed two distinct tasks on the same visually presented objects. During the maintenance of visual properties, object identity could be decoded from extrastriate, but not prefrontal, cortex, whereas the opposite held for nonvisual properties. Thus, the ability to maintain information during working memory is a general and flexible cortical property, with the role of individual regions being goal-dependent. PMID- 23817546 TI - Arl13b-regulated cilia activities are essential for polarized radial glial scaffold formation. AB - The construction of cerebral cortex begins with the formation of radial glia. Once formed, polarized radial glial cells divide either symmetrically or asymmetrically to balance appropriate production of progenitor cells and neurons. Following birth, neurons use the processes of radial glia as scaffolding for oriented migration. Radial glia therefore provide an instructive structural matrix to coordinate the generation and placement of distinct groups of cortical neurons in the developing cerebral cortex. We found that Arl13b, a cilia-enriched small GTPase that is mutated in Joubert syndrome, was critical for the initial formation of the polarized radial progenitor scaffold. Using developmental stage specific deletion of Arl13b in mouse cortical progenitors, we found that early neuroepithelial deletion of ciliary Arl13b led to a reversal of the apical-basal polarity of radial progenitors and aberrant neuronal placement. Arl13b modulated ciliary signaling necessary for radial glial polarity. Our findings indicate that Arl13b signaling in primary cilia is crucial for the initial formation of a polarized radial glial scaffold and suggest that disruption of this process may contribute to aberrant neurodevelopment and brain abnormalities in Joubert syndrome-related ciliopathies. PMID- 23817548 TI - Bidirectional effects of aversive learning on perceptual acuity are mediated by the sensory cortex. AB - Although emotional learning affects sensory acuity, little is known about how these changes are facilitated in the brain. We found that auditory fear conditioning in mice elicited either an increase or a decrease in frequency discrimination acuity depending on how specific the learned response was to the conditioned tone. Using reversible pharmacological inactivation, we found that the auditory cortex mediated learning-evoked changes in acuity in both directions. PMID- 23817549 TI - Inhibition of inhibition in visual cortex: the logic of connections between molecularly distinct interneurons. AB - Cortical inhibitory neurons contact each other to form a network of inhibitory synaptic connections. Our knowledge of the connectivity pattern underlying this inhibitory network is, however, still incomplete. Here we describe a simple and complementary interaction scheme between three large, molecularly distinct interneuron populations in mouse visual cortex: parvalbumin-expressing interneurons strongly inhibit one another but provide little inhibition to other populations. In contrast, somatostatin-expressing interneurons avoid inhibiting one another yet strongly inhibit all other populations. Finally, vasoactive intestinal peptide-expressing interneurons preferentially inhibit somatostatin expressing interneurons. This scheme occurs in supragranular and infragranular layers, suggesting that inhibitory networks operate similarly at the input and output of the visual cortex. Thus, as the specificity of connections between excitatory neurons forms the basis for the cortical canonical circuit, the scheme described here outlines a standard connectivity pattern among cortical inhibitory neurons. PMID- 23817551 TI - Chemical synthesis of beta-arabinofuranosyl containing oligosaccharides derived from plant cell wall extensins. AB - Extensins are plant-derived glycoproteins that are densely modified by oligo arabinofuranosides linked to hydroxyproline residues. These glycoproteins have been implicated in many aspects of plant growth and development. Here, we describe the chemical synthesis of a tetrameric beta(1-2)-linked arabinofuranoside that is capped by an alpha(1-3)-arabinofuranoside and a similar trisaccharide lacking the capping moiety. The challenging beta(1-2)-linked arabinofuranosides were installed by using an arabinofuranosyl donor protected with 3,5-O-(di-tert-butylsilane) and a C-2 2-methylnaphthyl (Nap) ether. It was found that the cyclic silane-protecting group of the glycosyl donor greatly increased beta-anomeric selectivity. It was, however, imperative to remove the silane-protecting group of an arabinosyl acceptor to achieve optimal anomeric selectivities. The anomeric linker of the synthetic compounds was modified by a biotin moiety for immobilization of the compounds to microtiter plates coated with streptavidine. The resulting microtiter plates were employed to screen for binding against a panel of antibodies elicited against plant cell wall polysaccharides. PMID- 23817550 TI - The fat mass and obesity associated gene (Fto) regulates activity of the dopaminergic midbrain circuitry. AB - Dopaminergic (DA) signaling governs the control of complex behaviors, and its deregulation has been implicated in a wide range of diseases. Here we demonstrate that inactivation of the Fto gene, encoding a nucleic acid demethylase, impairs dopamine receptor type 2 (D2R) and type 3 (D3R) (collectively, 'D2-like receptor')-dependent control of neuronal activity and behavioral responses. Conventional and DA neuron-specific Fto knockout mice show attenuated activation of G protein-coupled inwardly-rectifying potassium (GIRK) channel conductance by cocaine and quinpirole. Impaired D2-like receptor-mediated autoinhibition results in attenuated quinpirole-mediated reduction of locomotion and an enhanced sensitivity to the locomotor- and reward-stimulatory actions of cocaine. Analysis of global N(6)-methyladenosine (m(6)A) modification of mRNAs using methylated RNA immunoprecipitation coupled with next-generation sequencing in the midbrain and striatum of Fto-deficient mice revealed increased adenosine methylation in a subset of mRNAs important for neuronal signaling, including many in the DA signaling pathway. Several proteins encoded by these mRNAs had altered expression levels. Collectively, FTO regulates the demethylation of specific mRNAs in vivo, and this activity relates to the control of DA transmission. PMID- 23817552 TI - Adenosine-A3 receptors in neutrophil microdomains promote the formation of bacteria-tethering cytonemes. AB - The A3-adenosine receptor (A3AR) has recently emerged as a key regulator of neutrophil behaviour. Using a fluorescent A3AR ligand, we show that A3ARs aggregate in highly polarized immunomodulatory microdomains on human neutrophil membranes. In addition to regulating chemotaxis, A3ARs promote the formation of filipodia-like projections (cytonemes) that can extend up to 100 MUm to tether and 'reel in' pathogens. Exposure to bacteria or an A3AR agonist stimulates the formation of these projections and bacterial phagocytosis, whereas an A3AR selective antagonist inhibits cytoneme formation. Our results shed new light on the behaviour of neutrophils and identify the A3AR as a potential target for modulating their function. PMID- 23817553 TI - How high frequency trading affects a market index. AB - The relationship between a market index and its constituent stocks is complicated. While an index is a weighted average of its constituent stocks, when the investigated time scale is one day or longer the index has been found to have a stronger effect on the stocks than vice versa. We explore how this interaction changes in short time scales using high frequency data. Using a correlation-based analysis approach, we find that in short time scales stocks have a stronger influence on the index. These findings have implications for high frequency trading and suggest that the price of an index should be published on shorter time scales, as close as possible to those of the actual transaction time scale. PMID- 23817554 TI - A luminescent-water soluble inorganic co-crystal for a selective pico-molar range arsenic(III) sensor in water medium. AB - The water solution of an intriguing luminescent 'Inorganic Co-crystal' of Cu(II) monomeric and dimeric units shows extremely selective sensing ability towards inorganic arsenic(III) in water medium in the pico-molar concentration range even in the presence of other cations. PMID- 23817555 TI - The effect of secondary structures on the NLO properties of single chain oligopeptides: a comparison between beta-strand and alpha-helix polyglycines. AB - The evolution of the electronic first-order longitudinal hyperpolarizability (betazzz) and the hyperpolarizability aligned along the direction of the dipole moment (betaMU) of the alpha-helix and beta-strand single chain H2N-(CH2-CO-NH)n CH2-COOH (n = 1-9) oligoglycines, were investigated. For this purpose we have used Hartree-Fock, second-order Moller-Plesset perturbation theory and Coulomb attenuating Density Functional Theory computations. For the longest chain, betaMU(beta-strand) is one order of magnitude greater than betaMU(alpha-helix), due to the cooperative effect of the alpha-helices being unfavourable for the NLO properties. The betazzz and betaMU values per unit cell of the beta-strand conformation were determined, extrapolating the properties in the limit of the polymer. The calculated betazzz values were elucidated using the two-state model involving the characteristic pi-pi* NV1 electronic transition of peptides. Single chain beta-strand polyglycines can be discriminated from the alpha-helices using second-order NLO effects. PMID- 23817556 TI - Lanthanides: new metallic cathode materials for organic photovoltaic cells. AB - Organic photovoltaics (OPVs) are compliant with inexpensive, scalable, and environmentally benign manufacturing technologies. While substantial attention has been focused on optimization of active layer chemistry, morphology, and processing, far less research has been directed to understanding charge transport at the interfaces between the electrodes and the active layer. Electrical properties of these interfaces not only impact efficiency, but also play a central role in stability of organic solar cells. Low work function metals are the most widely used materials for the electron transport layer with Ca being the most common material. In bulk heterojunction OPV devices, low work function metals are believed to mirror the role they play in OLEDs, where such metals are used to control carrier selectivity, transport, extraction, and blocking, as well as interface band bending. Despite their advantages, low work function materials are generally prone to reactions with water, oxygen, nitrogen, and carbon dioxide from air leading to rapid device degradation. Here we discuss the search for a new metallic cathode interlayer material that increases device stability and still provides device efficiency similar to that achieved with a Ca interlayer. PMID- 23817558 TI - Severe auto-immune hemolytic anemia in a fingolimod-treated multiple sclerosis patient. PMID- 23817562 TI - Olopatadine hydrochloride decreases tissue interleukin-31 levels in an atopic dermatitis mouse model. PMID- 23817563 TI - Mouse neutrophils express the decoy type 2 interleukin-1 receptor (IL-1R2) constitutively and in acute inflammatory conditions. AB - The proinflammatory activities of IL-1 are tightly controlled at different levels. IL-1R2 acts as a decoy receptor and has been shown to regulate the biological effects of IL-1 in vitro and in vivo. However, little is known about its natural expression in the mouse in physiologic and pathologic conditions. In this study, we examined IL-1R2 mRNA and protein expression in isolated cells and tissues in response to different stimulatory conditions. Data obtained using ex vivo CD11b(+)Ly6G(+) peripheral blood cells and in vitro-differentiated CD11b(+)Ly6G(+) BMG indicated that neutrophils are the major source of constitutively expressed IL-1R2 in the mouse. The expression of IL-1R2 on BMG and ex vivo Ly6G(+) peripheral blood cells was highly up-regulated by HC. IL-1R2 pull down experiments showed that mouse rIL-1beta binds to BMG IL-1R2, whereas binding of IL-1Ra could not be detected. Furthermore, LPS treatment induced shedding of IL-1R2 from the neutrophil membrane in vitro and in vivo, executed mainly by ADAM17. Finally, in in vivo models of inflammation, including thioglycolate induced acute peritonitis and acute lung injury, infiltrating Ly6G(+) neutrophils, expressed IL-1R2. Our data show that in the mouse, neutrophils mainly express the decoy receptor IL-1R2 under naive and inflammatory conditions. These data suggest that neutrophils may contribute to the resolution of acute inflammation. PMID- 23817565 TI - Tolerance induction by hair-specific keratins in murine alopecia areata. AB - AA is a presumptive autoimmune disease, severely damaging the hair follicle. Hair and nail-specific keratins are discussed as potential candidates, which we controlled in C3H/HeJ mice that develop AA spontaneously or after skin transplantation. From nine keratins, K71 and K31 peptides supported T cell activation when presented by DCs to syngeneic naive T cells, and young C3H/HeJ mice receiving s.c. injections of peptide-loaded DC developed AA. The frequency of K71- and K31-specific CD4(+) and CD8(+) T cells increased four- to fivefold by vaccination, which corresponds with the frequency seen in skin transplantation induced AA mice. Also, accessory molecule expression, the cytokine profile with a dominance of IFN-gamma-expressing T cells, the proliferative response against AA lysate or peptide-loaded DCs, as well as peptide-specific cytotoxic T cells were similar in keratin peptide- and skin transplantation-induced AA. Instead, vaccination with soluble K71 or K31 peptides significantly retarded AA induction and prevented progression. Soluble peptide vaccination did not provoke immunosuppression but induced long-lasting T cell anergy with unresponsiveness to DC-presented K71 and K31 peptides. Thus, keratins K71 and K31 contribute to AA induction, and peptide application in a nonimmunogenic form serves as an efficient therapeutic. PMID- 23817564 TI - Cocaine exposure enhances permissiveness of quiescent T cells to HIV infection. AB - In vivo and in vitro exposure to stimulants has been associated with increased levels of HIV infection in PBMCs. Among these lymphocyte subsets, quiescent CD4(+) T cells make up the majority of circulating T cells in the blood. Others and we have demonstrated that HIV infects this population of cells inefficiently. However, minor changes in their cell state can render them permissive to infection, significantly impacting the viral reservoir. We have hypothesized that stimulants, such as cocaine, may perturb the activation state of quiescent cells enhancing permissiveness to infection. Quiescent T cells isolated from healthy human donors were exposed to cocaine and infected with HIV. Samples were harvested at different time-points to assess the impact of cocaine on their susceptibility to infection at various stages of the HIV life cycle. Our data show that a 3-day exposure to cocaine enhanced infection of quiescent cells, an effect that appears to be mediated by sigma1R and D4R. Overall, our results indicate that cocaine-mediated effects on quiescent T cells may increase the pool of infection-susceptible T cells. The latter underscores the impact that stimulants have on HIV-seropositive individuals and the challenges posed for treatment. PMID- 23817566 TI - Regulation of miR-155 affects pancreatic cancer cell invasiveness and migration by modulating the STAT3 signaling pathway through SOCS1. AB - In the present study, we investigated the effects of miR-155 on pancreatic cancer cell invasion and migration in vitro, underlying gene expression, expression of miR-155 and its target genes in pancreatic cancer tissues, and their association with metastasis and clinical stage. miR-155 mimics and an inhibitor were transfected into Panc-1 and Capan-2 cells in order to regulate the expression of miR-155. qPCR and western immunoblotting were performed in order to detect gene expression. Transwell assays were performed to characterize the invasion and migration of pancreatic cancer cells in vitro. Immunohistochemical analysis and in situ hybridization were used to detect the expression of protein and microRNA in pancreatic cancer tissue. miR-155 mimics and an inhibitor upregulated and downregulated, respectively, the expression of miR-155 in pancreatic cancer cells. The invasion and migration of pancreatic cancer cells increased or decreased along with miR-155 expression in vitro. Suppressor of cytokine signaling 1 (SOCS1) protein expression was upregulated when miR-155 was inhibited and downregulated when miR-155 was increased. However, the expression of P-signal transducer and activator of transcription-3 (STAT3) was synchronized with that of miR-155. Transcription of SOCS1 and STAT3 was unchanged by miR-155 regulation. miR-155 expression was high in pancreatic cancer tissues and SOCS1 expression was high in tumor-adjacent tissues. There was no relationship between these genes in cancer and tumor-adjacent tissues. In addition, miR-155 expression was associated with lymph node metastasis and clinical stage. In conclusion, miR-155 plays an important role in the regulation of pancreatic cancer cell invasion and migration by modulating the STAT3 signaling pathway and reducing SOCS1 expression in pancreatic cancer cells. PMID- 23817567 TI - The influence of hyperglycemia on the therapeutic effect of exercise on glycemic control in patients with type 2 diabetes mellitus. PMID- 23817568 TI - An atlas of over 90,000 conserved noncoding sequences provides insight into crucifer regulatory regions. AB - Despite the central importance of noncoding DNA to gene regulation and evolution, understanding of the extent of selection on plant noncoding DNA remains limited compared to that of other organisms. Here we report sequencing of genomes from three Brassicaceae species (Leavenworthia alabamica, Sisymbrium irio and Aethionema arabicum) and their joint analysis with six previously sequenced crucifer genomes. Conservation across orthologous bases suggests that at least 17% of the Arabidopsis thaliana genome is under selection, with nearly one quarter of the sequence under selection lying outside of coding regions. Much of this sequence can be localized to approximately 90,000 conserved noncoding sequences (CNSs) that show evidence of transcriptional and post-transcriptional regulation. Population genomics analyses of two crucifer species, A. thaliana and Capsella grandiflora, confirm that most of the identified CNSs are evolving under medium to strong purifying selection. Overall, these CNSs highlight both similarities and several key differences between the regulatory DNA of plants and other species. PMID- 23817569 TI - A genome-wide association meta-analysis of self-reported allergy identifies shared and allergy-specific susceptibility loci. AB - Allergic disease is very common and carries substantial public-health burdens. We conducted a meta-analysis of genome-wide associations with self-reported cat, dust-mite and pollen allergies in 53,862 individuals. We used generalized estimating equations to model shared and allergy-specific genetic effects. We identified 16 shared susceptibility loci with association P<5*10(-8), including 8 loci previously associated with asthma, as well as 4p14 near TLR1, TLR6 and TLR10 (rs2101521, P=5.3*10(-21)); 6p21.33 near HLA-C and MICA (rs9266772, P=3.2*10( 12)); 5p13.1 near PTGER4 (rs7720838, P=8.2*10(-11)); 2q33.1 in PLCL1 (rs10497813, P=6.1*10(-10)), 3q28 in LPP (rs9860547, P=1.2*10(-9)); 20q13.2 in NFATC2 (rs6021270, P=6.9*10(-9)), 4q27 in ADAD1 (rs17388568, P=3.9*10(-8)); and 14q21.1 near FOXA1 and TTC6 (rs1998359, P=4.8*10(-8)). We identified one locus with substantial evidence of differences in effects across allergies at 6p21.32 in the class II human leukocyte antigen (HLA) region (rs17533090, P=1.7*10(-12)), which was strongly associated with cat allergy. Our study sheds new light on the shared etiology of immune and autoimmune disease. PMID- 23817570 TI - A genome-wide association study identifies two new cervical cancer susceptibility loci at 4q12 and 17q12. AB - To identify new genetic risk factors for cervical cancer, we conducted a genome wide association study in the Han Chinese population. The initial discovery set included 1,364 individuals with cervical cancer (cases) and 3,028 female controls, and we selected a 'stringently matched samples' subset (829 cases and 990 controls) from the discovery set on the basis of principal component analysis; the follow-up stages included two independent sample sets (1,824 cases and 3,808 controls for follow-up 1 and 2,343 cases and 3,388 controls for follow up 2). We identified strong evidence of associations between cervical cancer and two new loci: 4q12 (rs13117307, Pcombined, stringently matched=9.69*10(-9), per allele odds ratio (OR)stringently matched=1.26) and 17q12 (rs8067378, Pcombined, stringently matched=2.00*10(-8), per-allele ORstringently matched=1.18). We additionally replicated an association between HLA-DPB1 and HLA-DPB2 (HLA-DPB1/2) at 6p21.32 and cervical cancer (rs4282438, Pcombined, stringently matched=4.52*10(-27), per-allele ORstringently matched=0.75). Our findings provide new insights into the genetic etiology of cervical cancer. PMID- 23817573 TI - Boron-doped graphene and boron-doped diamond electrodes: detection of biomarkers and resistance to fouling. AB - Doped carbon materials are of high interest as doping can change their properties. Here we wish to contrast the electrochemical behaviour of two carbon allotropes - sp(3) hybridized carbon as diamond and sp(2) hybridized carbon as graphene - doped by boron. We show that even though both materials exhibit similar heterogeneous electron transfer towards ferro/ferricyanide, there are dramatic differences towards the oxidation of biomolecules, such as ascorbic acid, uric acid, dopamine and beta-nicotinamide adenine dinucleotide (NADH). The boron-doped graphene exhibits much lower oxidation potentials than boron-doped diamond. The stability of the surfaces towards NADH oxidation product fouling has been studied and in the long term, there is no significant difference among the studied materials. The proton/electron coupled reduction of dopamine and nitroaromatic explosive (TNT) takes place on boron-doped graphene, while it is not observable at boron-doped diamond. These findings show that boron-doped sp(2) graphene and sp(3) diamond behave, in many aspects, dramatically differently and this shall have a profound influence upon their applicability as electrochemical materials. PMID- 23817572 TI - Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. AB - Pilocytic astrocytoma, the most common childhood brain tumor, is typically associated with mitogen-activated protein kinase (MAPK) pathway alterations. Surgically inaccessible midline tumors are therapeutically challenging, showing sustained tendency for progression and often becoming a chronic disease with substantial morbidities. Here we describe whole-genome sequencing of 96 pilocytic astrocytomas, with matched RNA sequencing (n = 73), conducted by the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. We identified recurrent activating mutations in FGFR1 and PTPN11 and new NTRK2 fusion genes in non-cerebellar tumors. New BRAF-activating changes were also observed. MAPK pathway alterations affected all tumors analyzed, with no other significant mutations identified, indicating that pilocytic astrocytoma is predominantly a single-pathway disease. Notably, we identified the same FGFR1 mutations in a subset of H3F3A-mutated pediatric glioblastoma with additional alterations in the NF1 gene. Our findings thus identify new potential therapeutic targets in distinct subsets of pilocytic astrocytoma and childhood glioblastoma. PMID- 23817571 TI - Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization. AB - Allergen-specific immunoglobulin E (present in allergic sensitization) has a central role in the pathogenesis of allergic disease. We performed the first large-scale genome-wide association study (GWAS) of allergic sensitization in 5,789 affected individuals and 10,056 controls and followed up the top SNP at each of 26 loci in 6,114 affected individuals and 9,920 controls. We increased the number of susceptibility loci with genome-wide significant association with allergic sensitization from three to ten, including SNPs in or near TLR6, C11orf30, STAT6, SLC25A46, HLA-DQB1, IL1RL1, LPP, MYC, IL2 and HLA-B. All the top SNPs were associated with allergic symptoms in an independent study. Risk associated variants at these ten loci were estimated to account for at least 25% of allergic sensitization and allergic rhinitis. Understanding the molecular mechanisms underlying these associations may provide new insights into the etiology of allergic disease. PMID- 23817574 TI - Comprehensive cardiac magnetic resonance imaging and spectroscopy reveal a high burden of myocardial disease in HIV patients. AB - BACKGROUND: HIV infection continues to be endemic worldwide. Although treatments are successful, it remains controversial whether patients receiving optimal therapy have structural, functional, or biochemical cardiac abnormalities that may underlie their increased cardiac morbidity and mortality. The purpose of this study was to characterize myocardial abnormalities in a contemporary group of HIV infected individuals undergoing combination antiretroviral therapy. METHODS AND RESULTS: Volunteers with HIV who were undergoing combination antiretroviral therapy and age-matched control subjects without a history of cardiovascular disease underwent cardiac magnetic resonance imaging and spectroscopy for the determination of cardiac function, myocardial fibrosis, and myocardial lipid content. A total of 129 participants were included in this analysis. Compared with age-matched control subjects (n=39; 30.23%), HIV-infected subjects undergoing combination antiretroviral therapy (n=90; 69.77%) had 47% higher median myocardial lipid levels (P <0.003) and 74% higher median plasma triglyceride levels (both P<0.001). Myocardial fibrosis, predominantly in the basal inferolateral wall of the left ventricle, was observed in 76% of HIV infected subjects compared with 13% of control subjects (P<0.001). Peak myocardial systolic and diastolic longitudinal strain were also lower in HIV infected individuals than in control subjects and remained statistically significant after adjustment for available confounders. CONCLUSIONS: Comprehensive cardiac imaging revealed cardiac steatosis, alterations in cardiac function, and a high prevalence of myocardial fibrosis in a contemporary group of asymptomatic HIV-infected subjects undergoing combination antiretroviral therapy. Cardiac steatosis and fibrosis may underlie cardiac dysfunction and increased cardiovascular morbidity and mortality in subjects with HIV. PMID- 23817575 TI - Factor Xa activation of factor V is of paramount importance in initiating the coagulation system: lessons from a tick salivary protein. AB - BACKGROUND: Generation of active procoagulant cofactor factor Va (FVa) and its subsequent association with the enzyme activated factor X (FXa) to form the prothrombinase complex is a pivotal initial event in blood coagulation and has been the subject of investigative effort, speculation, and controversy. The current paradigm assumes that FV activation is initiated by limited proteolysis by traces of (meizo) thrombin. METHODS AND RESULTS: Recombinant tick salivary protein TIX-5 was produced and anticoagulant properties were studied with the use of plasma, whole blood, and purified systems. Here, we report that TIX-5 specifically inhibits FXa-mediated FV activation involving the B domain of FV and show that FXa activation of FV is pivotal for plasma and blood clotting. Accordingly, tick feeding is impaired on TIX-5 immune rabbits, displaying the in vivo importance of TIX-5. CONCLUSIONS: Our data elucidate a unique molecular mechanism by which ticks inhibit the host's coagulation system. From our data, we propose a revised blood coagulation scheme in which direct FXa-mediated FV activation occurs in the initiation phase during which thrombin-mediated FV activation is restrained by fibrinogen and inhibitors. PMID- 23817576 TI - Tick spit shines a light on the initiation of coagulation. PMID- 23817577 TI - Direct quantitative assessment of the peripheral artery collateral circulation in patients undergoing angiography. AB - BACKGROUND: Despite the fact that numerous studies have pursued the strategy of improving collateral function in patients with peripheral artery disease, there is currently no method available to quantify collateral arterial function of the lower limb. METHODS AND RESULTS: Pressure-derived collateral flow index (CFIp, calculated as (occlusive pressure-central venous pressure)/(aortic pressure central venous pressure); pressure values in mm Hg) of the left superficial femoral artery was obtained in patients undergoing elective coronary angiography using a combined pressure/Doppler wire (n=30). Distal occlusive pressure and toe oxygen saturation (Sao2) were measured for 5 minutes under resting conditions, followed by an exercise protocol (repetitive plantar-flexion movements in supine position; n=28). In all patients, balloon occlusion of the superficial femoral artery over 5 minutes was painless under resting conditions. CFIp increased during the first 3 minutes from 0.451+/-0.168 to 0.551+/-0.172 (P=0.0003), whereas Sao2 decreased from 98+/-2% to 93+/-7% (P=0.004). Maximal changes of Sao2 were inversely related to maximal CFIp (r(2)=0.33, P=0.003). During exercise, CFIp declined within 1 minute from 0.560+/-0.178 to 0.393+/-0.168 (P<0.0001) and reached its minimum after 2 minutes of exercise (0.347+/-0.176), whereas Sao2 declined to a minimum of 86+/-6% (P=0.002). Twenty-five patients (89%) experienced pain or cramps/tired muscles, whereas 3 (11%) remained symptom-free for an occlusion time of 10 minutes. CFIp values were positively related to the pain-free time span (r(2)=0.50, P=0.002). CONCLUSIONS: Quantitatively assessed collateral arterial function at rest determined in the nonstenotic superficial femoral artery is sufficient to prevent ischemic symptoms during a total occlusion of 5 minutes. During exercise, there is a decline in CFIp that indicates a supply-demand mismatch via collaterals or, alternatively, a steal phenomenon. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. UNIQUE IDENTIFIER: NCT01742455. PMID- 23817578 TI - Transcription factor Bach2 balances tolerance and immunity. PMID- 23817581 TI - Tobacco smoking in adolescence predicts maladaptive coping styles in adulthood. AB - INTRODUCTION: To examine the extent to which cigarette smoking in adolescence is associated with maladaptive versus adaptive coping behaviors in adulthood. METHOD: The data came from a longitudinal study of New Zealand adolescents followed into adulthood at age 32 years. Using structural equation modeling (SEM), we examined the predictive association between daily smoking of cigarettes and symptoms of tobacco dependence from 18 to 26 years of age and later coping at age 32 years. We included pathways from childhood family disadvantage in addition to both adolescent stress-worry and adult coping in the model. RESULTS: SEM revealed that cigarette smoking had a small but direct inverse effect on later adaptive coping (-.14) and a direct effect on maladaptive coping (.23) independent of the relationships between adolescent coping and stress-worry and later adult coping. CONCLUSIONS: The findings are consistent with the hypothesis that tobacco smoking may inhibit the development of self-efficacy or one's ability to act with appropriate coping behaviors in any given situation. PMID- 23817579 TI - Host genetic background impacts modulation of the TLR4 pathway by RON in tissue associated macrophages. AB - Toll-like receptors (TLRs) enable metazoans to mount effective innate immune responses to microbial and viral pathogens, as well as to endogenous host-derived ligands. It is understood that genetic background of the host can influence TLR responsiveness, altering susceptibility to pathogen infection, autoimmunity and cancer. Macrophage stimulatory protein (MSP), which activates the receptor tyrosine kinase recepteur d'origine nantais (RON), promotes key macrophage functions such as motility and phagocytic activity. MSP also acts via RON to modulate signaling by TLR4, which recognizes a range of pathogen or endogenous host-derived molecules. Here, we show that RON exerts divergent control over TLR4 activity in macrophages from different mouse genetic backgrounds. RON potently modulated the TLR4 response in macrophages from M2-prone FVB mice, as compared with M1-skewed C57Bl6 mice. Moreover, global expression analysis revealed that RON suppresses the TLR4-dependent type-I interferon gene signature only in FVB macrophages. This leads to attenuated production of the potent inflammatory mediator, tumor necrosis factor-alpha. Eliminating RON kinase activity markedly decreased carcinogen-mediated tumorigenesis in M2/Th2-biased FVB mice. We propose that host genetic background influences RON function, thereby contributing to the variability in TLR4 responsiveness in rodents and, potentially, in humans. These findings provide novel insight into the complex interplay between genetic context and immune function. PMID- 23817582 TI - Gradual and immediate nicotine reduction result in similar low-dose nicotine self administration. AB - INTRODUCTION: Food and Drug Administration-mandated product standards that drastically reduce nicotine content in cigarettes aim to decrease smoking and thus improve health outcomes for millions of U.S. smokers. Researchers have suggested that nicotine reduction should be implemented gradually, but a gradual nicotine reduction may shift the minimum level of nicotine required to reinforce behavior or may result in different levels of compensatory smoking behavior. METHOD: Rats were given the opportunity to acquire nicotine self-administration at 60 ug/kg/infusion nicotine with a cocktail of other tobacco constituents included as the vehicle. Rats were subsequently assigned to one of six immediate dose reductions (30, 15, 7.5, 3.75, 1.875, or 0.0 ug/kg/infusion) for 10 sessions (n = 9-15). Rats in the 30 ug/kg/infusion reduction group continued to have their nicotine dose reduced by half after at least 10 sessions at each dose until reaching 1.875 ug/kg/infusion (i.e., gradual reduction). RESULTS: For both methods of reduction, reduction to 3.75 ug/kg/infusion resulted in significant decreases in behavior. Reduction to doses above 3.75 ug/kg/infusion resulted in only limited compensation. The largest compensation was temporary. There was no compensation following reduction to 3.75 ug/kg/infusion or below. CONCLUSION: This study suggests that reduction to the same nicotine dose will result in similar reductions in behavior for both gradual and immediate reductions, and both methods result in similar compensation. Future studies using humans should investigate differences in other outcomes such as withdrawal and craving. PMID- 23817583 TI - A practical way to estimate retail tobacco sales violation rates more accurately. AB - PURPOSE: U.S. states annually estimate retailer propensity to sell adolescents cigarettes, which is a violation of law, by staging a single purchase attempt among a random sample of tobacco businesses. The accuracy of single-visit estimates is unknown. We examined this question using a novel test-retest protocol. METHOD: Supervised minors attempted to purchase cigarettes at all retail tobacco businesses located in 3 Colorado counties. The attempts observed federal standards: Minors were aged 15-16 years, were nonsmokers, and were free of visible tattoos and piercings, and were allowed to enter stores alone or in pairs to purchase a small item while asking for cigarettes and to show or not show genuine identification (ID, e.g., driver's license). Unlike federal standards, stores received a second purchase attempt within a few days unless minors were firmly told not to return. Separate violation rates were calculated for first visits, second visits, and either visit. RESULTS: Eleven minors attempted to purchase cigarettes 1,079 times from 671 retail businesses. One sixth of first visits (16.8%) resulted in a violation; the rate was similar for second visits (15.7%). Considering either visit, 25.3% of businesses failed the test. Factors predictive of violation were whether clerks asked for ID, whether the clerks closely examined IDs, and whether minors included snacks or soft drinks in cigarette purchase attempts. CONCLUSION: A test-retest protocol for estimating underage cigarette sales detected half again as many businesses in violation as the federally approved one-test protocol. Federal policy makers should consider using the test-retest protocol to increase accuracy and awareness of widespread adolescent access to cigarettes through retail businesses. PMID- 23817584 TI - Medicinal nicotine nonuse: smokers' rationales for past behavior and intentions to try medicinal nicotine in a future quit attempt. AB - INTRODUCTION: Nicotine replacement therapy (NRT) is a proven smoking cessation treatment. Previous research has reported low rates of NRT use among quit attempters. This study analyzed population-level nonuse rates and reasons for not using NRT. METHODS: Data were from the 2008 adult Colorado Tobacco Attitudes and Behaviors Survey (TABS), a population-based, random-digit-dialed telephone survey (n = 14,156). Primary measures were past NRT nonuse and future intentions regarding NRT use among current smokers intending to quit. Multiple logistic regression was used to identify reasons for past NRT nonuse associated with intention to use NRT in the future, adjusted for factors known to influence NRT use. RESULTS: Nearly, 80% of 1,095 current smokers who intended to quit had never used NRT. The most common reasons for nonuse were belief that "willpower" alone is sufficient for cessation (21.5%), perceived lack of NRT effectiveness (15.6%), and cost (14.3%). Willpower was more widely reported among Hispanics than Anglos (36.9% vs. 14.7%) and nondaily versus daily smokers (30.4% vs. 12.5%). Most previous NRT nonusers reported they would use cold turkey (65.2%) in their next quit attempt; NRT was the next most common choice (15.0%). In multivariate analysis, smokers identifying cost or willpower as a reason for previous nonuse had significantly lower odds of planning to use NRT in a future quit attempt. CONCLUSIONS: The majority of smokers have never used NRT and do not plan to use it in the future. Cost and belief in willpower alone are significant barriers to using NRT in future smoking cessation attempt. PMID- 23817586 TI - Broadband light absorption enhancement in dye-sensitized solar cells with Au-Ag alloy popcorn nanoparticles. AB - In this paper, we present an investigation on the use of Au-Ag alloy popcorn shaped nanoparticles (NPs) to realise the broadband optical absorption enhancement of dye-sensitized solar cells (DSCs). Both simulation and experimental results indicate that compared with regular plasmonic NPs, such as nano-spheres, irregular popcorn-shaped alloy NPs exhibit absorption enhancement over a broad wavelength range due to the excitation of localized surface plasmons (LSPs) at different wavelengths. The power conversion efficiency (PCE) of DSCs is enhanced by 16% from 5.26% to 6.09% by incorporating 2.38 wt% Au-Ag alloy popcorn NPs. Moreover, by adding a scattering layer on the exterior of the counter electrode, the popcorn NPs demonstrate an even stronger ability to increase the PCE by 32% from 5.94% to 7.85%, which results from the more efficient excitation of the LSP mode on the popcorn NPs. PMID- 23817585 TI - Diagnostic utility of craving in predicting nicotine dependence: impact of craving content and item stability. AB - INTRODUCTION: Craving is useful in the diagnosis of drug dependence, but it is unclear how various items used to assess craving might influence the diagnostic performance of craving measures. This study determined the diagnostic performance of individual items and item subgroups of the 32-item Questionnaire on Smoking Urges (QSU) as a function of item wording, level of craving intensity, and item stability. METHODS: Nondaily and daily smokers (n = 222) completed the QSU on 6 separate occasions, and item responses were averaged across the administrations. Nicotine dependence was assessed with the Wisconsin Inventory of Smoking Dependence Motives. The discriminative performance of the QSU items was evaluated with receiver-operating characteristic curves and area under the curve statistics. RESULTS: Although each of the QSU items and selected subgroups of items significantly discriminated dependent from nondependent smokers, certain item subgroups outperformed others. There was no difference in discriminative performance between use of the specific terms urge and crave or between items assessing intention to smoke relative to those assessing desire to smoke, but there were significant differences in the two major factors represented on the QSU and in craving items reflecting more intense relative to less intense craving. Stability of the item scores was strongly related to the discriminative performance of craving. CONCLUSIONS: Items indexing stable, high-intensity aspects of craving that reflect the negative reinforcing effects of smoking will likely be most useful for diagnostic purposes. Future directions and implications are discussed. PMID- 23817587 TI - Enantioselective access to benzannulated spiroketals using a chiral sulfoxide auxiliary. AB - This article describes our efforts to develop an asymmetric synthesis of bisbenzannulated spiroketals using a chiral sulfoxide auxiliary. Our primary focus was on the synthesis of the 3H-spiro[benzofuran-2,2'-chroman] ring system, the spirocyclic core of the rubromycin family. Our strategy employed the use of lithium-halogen exchange on a racemic bromospiroketal in order to attach a chiral sulfoxide, thus producing two diastereomers. The diastereomers were separable, enabling isolation of each spiroketal enantiomer. Subsequent cleavage of the sulfoxide group from each diastereomer yielded the respective parent spiroketal in high enantiopurity. PMID- 23817588 TI - An electrochemiluminescence sensor for adrenaline assay based on the tyrosinase/SiC/chitosan modified electrode. AB - An electrochemiluminescence sensor for adrenaline based on a tyrosinase/SiC/chitosan film modified glassy carbon electrode was fabricated, and the proposed sensor showed high sensitivity and excellent biocompatibility. PMID- 23817591 TI - Na3V2O2(PO4)2F/graphene sandwich structure for high-performance cathode of a sodium-ion battery. AB - A Na3V2O2(PO4)2F/reduced-graphene-oxide (RGO) sandwich structure has been synthesized by a facile one-step solvothermal method. Cubic Na3V2O2(PO4)2F nanoparticles are homogeneously trapped between conductive RGO sheets during its growth and assembled into a compact sandwich structure, which allows the electrically insulating Na3V2O2(PO4)2F nanoparticles to be wired up to a current collector through the underlying graphene conducting layers. As a sodium insertion cathode material, the structure exhibits a high reversible capacity of 120 mA h g(-1) at a discharge rate of C/20 with a capacity retention of 100.4 mA h g(-1) at 1 C and an excellent cyclic retention of 91.4% after the 200th cycle at C/10. These results highlight the importance of anchoring Na3V2O2(PO4)2F on a conducting scaffold for maximum utilization of the electrochemically active Na3V2O2(PO4)2F particles in a high-performance sodium-ion battery. PMID- 23817592 TI - Increased expression of alpha-actinin-4 is associated with unfavorable pathological features and invasiveness of bladder cancer. AB - In the present study, the association between clinicopathological parameters and alpha-actinin-4 (ACTN4) expression in bladder cancer specimens was evaluated, and the functional role of ACTN4 in bladder cancer cells was investigated. Immunohistochemistry using anti-ACTN4 antibody was performed in bladder cancer specimens (53 superficial and 42 muscle-invasive cases) from 95 patients who underwent radical cystectomy (n=46) or transurethral resection (TUR) only (n=49). We divided the levels of ACTN4 expression into 2 groups (low or high) by comparing the staining intensity in each specimen with that of the vascular endothelial cells in the same specimen, and we evaluated the correlations between these levels and pathological parameters, recurrence and prognosis. We also investigated the effects of ACTN4 suppression by siRNA on the invasive ability and proliferation of T24 and KU19-19 cells. High ACTN4 expression was significantly associated with higher tumor grade and higher pT stage. In patients with superficial bladder cancer treated only by TUR, the rate of intravesical recurrence did not differ significantly between patients with high ACTN4 expression and patients with low ACTN4 expression. In patients who had muscle invasive tumors and underwent radical cystectomy, high ACTN4 expression was associated with neither recurrence nor poor prognosis. Nonetheless, high ACTN4 expression was shown by a large percentage (81%) of patients with muscle-invasive bladder cancer and by a small percentage (17%) of patients with superficial bladder cancer. Furthermore, the leading edges of the invasive bladder cancer showed increased ACTN4 expression. ACTN4 suppression significantly reduced the number of invading bladder cancer cells but unexpectedly increased the proliferation of bladder cancer cells. ACTN4 suppression increased the phosphorylation of ERKs but not AKT or STAT3, suggesting that the increased proliferation due to ACTN4 suppression was mediated in part by the ERK pathway. ACTN4 expression may suppress the proliferation of bladder cancer cells and may produce conditions which facilitate cancer cell invasion. PMID- 23817593 TI - Analysis of contact allergens in korean polysensitized patients by patch testing: a pilot study. PMID- 23817594 TI - Therapeutic touch is not therapeutic for procedural pain in very preterm neonates: a randomized trial. AB - BACKGROUND: Preterm neonates below 30 weeks' gestational age undergo numerous painful procedures. Many management approaches are not appropriate for this population. Therapeutic Touch, an alternative approach based on the theory of energy medicine, has been shown to promote physiological stability in preterm neonates and reduce pain in some adult studies. The objective was to determine whether Therapeutic Touch is efficacious in decreasing pain in preterm neonates. METHODS: Infants < 30 weeks' gestational age participated in a randomized control trial in 2 level III neonatal intensive care units. All evaluations, analyses, and heel lance procedure were conducted with only the therapist knowing the group assignment. Immediately before and after the heel lance procedure, the therapist performed nontactile Therapeutic Touch (n = 27) with infant behind curtains, leaving the curtained area for the heel lance, performed by another. In the sham condition (n = 28), the therapist stood by the incubator with hands by her side. The Premature Infant Pain Profile was used for pain response and time for heart rate to return to baseline for recovery. Heart rate variability and stress response were secondary outcomes. RESULTS: There were no group differences in any of the outcomes. Mean Premature Infant Pain Profile scores across 2 minutes of heel lance procedure in 30-second blocks ranged from 7.92 to 8.98 in the Therapeutic Touch group and 7.64 to 8.46 in the sham group. INTERPRETATION: Therapeutic Touch given immediately before and after heel lance has no comforting effect in preterm neonates. Other effective strategies involving actual touch should be considered. PMID- 23817595 TI - Dyslipidemia and hyperinsulinemia in children and adolescents with chronic liver disease: relation to disease severity. AB - BACKGROUND: Lipid metabolism is profoundly disturbed in chronic liver diseases (CLD). Moreover, patients with cirrhosis displayed chronically elevated serum insulin (SI) concentrations. OBJECTIVES: The aim of this work was to assess fasting lipid profile (FLP) and SI levels among Egyptian patients with CLD and their relation to severity of liver disease. METHODS: A total of 40 Egyptian children with CLD were compared with 30 age-, sex-, and pubertal stage-matched controls. All subjects were subjected to history and auxological assessment; their FLP, fasting blood glucose (FBG) and SI were measured; and their fasting glucose/insulin (G/I) ratios were calculated. RESULTS: Total cholesterol (TC, p=0.006), triglycerides (TG, p=0.03), low density lipoproteins (LDL, p=0.034), and SI (p<0.001) were significantly higher while high density lipoproteins (HDL, p<0.001) and G/I ratio (p<0.001) were significantly lower as serum albumin decreased; these were also lower among cases with a progressive decrease going from child A to C. Of the 40 studied cases, eight (20%) had hypercholesterolemia, 13 (32.5%) had hypertriglyceridemia, 17 (42.5%) had low HDL and 9 (22.5%) had high LDL, 32 (80%) had hyperinsulinemia (HI), and 11 (27.5%) had insulin resistance (IR). CONCLUSIONS: Dyslipidemia and HI were frequent findings in patients with CLD, which worsened with increased severity of CLD. PMID- 23817596 TI - Prevalence of metabolic syndrome in obese Chilean children and association with gene variants of the leptin-melanocortin system. AB - Metabolic syndrome (MS) related to adult type 2 diabetes mellitus and cardiovascular disease is prevalent among obese children/adolescents. Genetic variants of the leptin-melanocortin system have been associated with components of MS. The aim of our study is to estimate the prevalence of MS (according to Cook's criteria) in a Chilean cross-sectional sample of 259 obese children (47.1% girls, aged 6-12 years), and to assess the association between common genetic variants of leptin-melanocortin pathway genes (LEP, LEPR, POMC, MC3R and MC4R) with components of the MS using logistic regression. We observed an overall MS prevalence of 26.3% (32.2% in girls and 21.1% in boys) in obese Chilean children. No associations were detected between genetic variants of leptin-melanocortin genes and MS components. MS prevalence among our obese children sample is similar to those previously described in Chile, demonstrating the increased risk of diseases in adulthood that obese children carry. PMID- 23817597 TI - Concomitant autoantibodies in newly diagnosed diabetic children with transient celiac serology or proven celiac disease. AB - BACKGROUND: We previously demonstrated that children with Type 1 Diabetes Mellitus (T1DM) may have transiently elevated tissue transglutaminase antibodies (TTG) on a gluten-containing diet. This study aimed to examine if the presence of autoantibodies in newly diagnosed T1DM differs between patients with celiac disease and those with transient celiac serology. METHODS: Forty children were identified who had been diagnosed with T1DM between 2003 and 2009 and who had elevated serum IgA-TTG antibody levels at diagnosis. Blood samples were collected for measurement of insulin (IA-2A) antibodies, islet cell antigen (ICA) antibodies, glutamic acid decarboxylase (GAD) antibodies, thyroglobulin (TgAb) antibodies, and thyroid peroxidase (TPO) antibodies. Children diagnosed with celiac disease (CD; group 1, n=23) and children in whom TTG antibody levels spontaneously normalized over time (group 2, n=17) were compared. RESULTS: No significant differences in positivity rates between groups 1 and 2 were found for any of the autoantibodies tested. The respective findings were as follows: IA-2A 50% and 47.1% (p=0.855); ICA 77.3% and 76.5% (p=0.953); GAD 27.3% and 52.9% (p=0.102). Thyroid antibodies were found positive in a limited number of patients: TgAb 4.5% and 11.8%; TPO 4.5% and 11.8%. In addition, antibody titer levels did not differ significantly for all autoantibodies. Difference in occurrence of clinical or subclinical thyroid disease did not reach significance (4.3% vs. 29.4%; p=0.07). Age was positively correlated with the presence of thyroglobulin and thyroid peroxidase antibodies, and negatively correlated with the presence of insulin antibody. CONCLUSION: Neither the number of concomitant autoantibodies nor their titers in newly diagnosed T1DM differed between patients with proven CD and those with transient TTG serology. PMID- 23817598 TI - Vitamin D status is associated with early markers of cardiovascular disease in prepubertal children. AB - BACKGROUND: The associations of 25-hydroxyvitamin D [25(OH)D], non-high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL), and related markers of early cardiovascular disease (CVD) are unclear in prepubertal children. OBJECTIVE: To investigate the association of 25(OH)D with markers of CVD. The hypothesis was that 25(OH)D would vary inversely with non-HDL-C. SUBJECTS AND METHODS: A prospective cross-sectional study of children (n=45; 26 males, 19 females) of mean age 8.3 +/- 2.5 years to investigate the relationships between 25(OH)D and glucose, insulin, high-sensitivity C-reactive protein, and lipids. Vitamin D deficiency was defined as 25(OH)D <20 ng/mL; overweight as body mass index (BMI) >= 85 th but <95th percentile; and obesity as BMI >95th percentile. RESULTS: Twenty subjects (44.4%) had BMI <85%, and 25 had BMI of >= 85%. Eleven participants (24.4%) had 25(OH)D of <20 ng/mL, and 10 (22.2%) had 25(OH)D of >30 ng/mL. Patients with 25(OH)D of <20 ng/mL had significantly elevated non-HDL-C (136.08 +/- 44.66 vs. 109.88 +/- 28.25, p=0.025), total cholesterol (TC)/HDL ratio (3.89 +/- 1.20 vs. 3.21 +/- 0.83, p=0.042), and triglycerides (TG) (117.09 +/- 71.27 vs. 73.39 +/- 46.53, p=0.024), while those with 25(OH)D of >30 ng/mL had significantly lower non-HDL-C, TC/HDL, TG, and LDL (82.40 +/- 18.03 vs. 105.15 +/- 28.38, p=0.006). Multivariate analysis showed significant inverse correlations between 25(OH)D and non-HDL cholesterol (beta=-0.337, p=0.043), and TC/HDL ratio (beta=-0.339, p=0.028), and LDL (beta=-0.359, p=0.016), after adjusting for age, race, sex, BMI, and seasonality. CONCLUSIONS: Vitamin D varied inversely with non-HDL, TC/HDL, and LDL. A 25(OH)D level of 30 ng/mL is associated with optimal cardioprotection in children. PMID- 23817599 TI - Serum dipeptidyl peptidase 4 activity in children with type 1 diabetes mellitus. AB - BACKGROUND: It is poorly understood whether dipeptidyl peptidase 4 (DPP4) activity is altered and how DPP4 contributes to glycemic control in patients with type 1 diabetes mellitus (T1DM). AIM: The aim of this study was to measure serum DPP4 activity and to assess its relationships to metabolic variables in T1DM children. METHODS: Serum DPP4 activity was determined using a fluorometric assay in 43 T1DM and 26 control children. RESULTS: Serum DPP4 activity was significantly higher in T1DM children than in controls (3.57 +/- 0.99 vs. 2.67 +/ 0.77 U/mL, p<0.001). In the T1DM children, DPP4 activity was not correlated with HbA1c, blood glucose, or diabetes duration. A significant negative correlation was found between DPP4 activity and serum adiponectin levels in the T1DM group (r=-0.35, p<0.05). CONCLUSIONS: Serum DPP4 activity was increased in the T1DM children, whereas it was not associated with glycemic control. Given the negative correlation between serum DPP4 and adiponectin levels, further investigations are warranted to elucidate the role of DPP4 on insulin sensitivity in T1DM children. PMID- 23817600 TI - The evaluation of the hypoglycemic effect of soft drink leaf extract of Phyllanthus amarus (Euphorbiaceae) in rats. AB - BACKGROUND: Phyllanthus amarus has been used in traditional medicine in Nigeria to treat some disease conditions. This study evaluated the soft drink extract (SDE) of the plant for antidiabetic activities in rats. METHODS: Standard phytochemical methods were used to test for the presence of phytoactive compounds in the plant. Acute toxicity was carried out in mice to determine safe doses for this plant extract. The antidiabetic activities of the SDE of the plant were assessed using some standard tests as well as histological changes in liver, kidney and pancreas. Diabetes mellitus was induced in rats using alloxan, whereas glibenclamide at 0.2 mg/kg was the reference drug used in this study. RESULTS: The SDE at 200 and 400 mg/kg body weight caused a significant reduction of fasting blood glucose, a significant change in the oral glucose tolerance test, a marked effect in the hypoglycemic activity test, and a pronounced reduction in the glucose, cholesterol and triglyceride levels of diabetic rats. Histopathologically, the liver of the diabetic nontreated and glibenclamide treated groups showed widespread vacuolar change in the hepatocytes, but there was no visible lesion seen in the kidney and pancreas of extract-treated and glibenclamide-treated groups. No lesion was also seen in the liver of the SDE treated group. CONCLUSIONS: The results from this study may have validated the traditional basis for the use of P. amarus as antidiabetic agent with the pharmacological activities attributed to the presence of flavonoids and other phenolics contained in this plant. At the doses used, SDE also appeared safer than glibenclamide even though the latter is more potent. PMID- 23817601 TI - Use of mercaptophenylboronic acid functionalized gold nanoparticles in a sensitive and selective dynamic light scattering assay for glucose detection in serum. AB - A highly sensitive dynamic light scattering (DLS) assay for glucose detection without interference from ascorbic acid was demonstrated based on mercaptophenylboronic acid functionalized gold nanoparticles (MPBA-AuNPs). The stable, water-solubility MPBA-AuNPs were synthesized using facile and mild method. In the presence of glucose, specific binding between glucose and boronic acids resulted in the aggregation of MPBA-AuNPs. Thus, glucose could be detected by monitoring the average particle size change of the assay solution using DLS analysis. The detection limit was estimated to be around 10 nM. This assay also showed good selectivity, and glucose could be detected without interference even if 1 mM ascorbic acid was present. Furthermore, glucose in human serum was successfully detected here. Therefore, this sensitive and selective approach has the potential to become a new key for glucose detection. PMID- 23817602 TI - A prospective study of nighttime vital sign monitoring frequency and risk of clinical deterioration. PMID- 23817603 TI - The role of ear stone size in hair cell acoustic sensory transduction. AB - Hearing and bodily balance are different sensations initiated by a common mechanism. Both sound- and head movement-dependent mechanical displacement are converted into electrical signals by the sensory hair cells. The saccule and utricle inner ear organs, in combination with their central projections to the hindbrain, are considered essential in fish for separating auditory and vestibular stimuli. Here, we established an in vivo method in larval zebrafish to manipulate otolith growth. We found that the saccule containing a large otolith is necessary to detect sound, whereas the utricle containing a small otolith is not sufficient. Otolith removal and relocation altered otolith growth such that utricles with experimentally enlarged otoliths acquired the sense of sound. These results show that otolith biomineralization occurs in a region-specific manner, and suggest that regulation of otolith size in the larval zebrafish ear is crucial to differentially sense auditory and vestibular information. PMID- 23817607 TI - Enhancing excess electron transport in DNA. AB - The efficiency of excess electron transport in duplex DNA can be enhanced by limiting the pathways available for migration and using a donor of moderate strength that suppresses radical recombination through selective electron transfer to distal pyrimidines rather than proximal purines. PMID- 23817606 TI - Diagnosis of recurrent deep vein thrombosis. AB - Deep vein thrombosis is a chronic disease with a continuing risk of recurrence. In a patient with recurrence long term prognosis and treatment are significantly altered both carrying their own risks not only in the acute phase but mainly in the long term perspective. Thus, accurate diagnosis of recurrence is of utmost importance for the fate of the patient. Diagnosis of a first DVT episode is well established and follows an algorithm including clinical prediction rules, D-Dimer testing and compression ultrasound. Due to the previous episode the efficiency of all three elements is impaired in a patient with suspected recurrence. This opens up areas of uncertainty which have to be filled by individual clinical judgement. Guidelines reflect this difficulty by providing mainly weak recommendations based on sparse data. The present review summarizes what is known about the performance of tools for DVT diagnosis, discusses recent guidelines, and finally gives personally weighed recommendations how to deal with this peculiar diagnostic situation. In conclusion, it will turn out that the well accepted diagnostic algorithm for a first DVT may be applied as well if the lower efficiency is regarded. Compression ultrasound largely benefits from a baseline assessment at the end of the previous episode. The order of tests may be discussed according to local and regional attitudes. PMID- 23817604 TI - Diversity and antibacterial activity of the bacterial communities associated with two Mediterranean sea pens, Pennatula phosphorea and Pteroeides spinosum (Anthozoa: Octocorallia). AB - A description of the bacterial communities associated with the Mediterranean pennatulids (sea pens) Pennatula phosphorea and Pteroeides spinosum from the Straits of Messina (Italy) is reported. The automated ribosomal intergenic spacer analysis showed a marked difference between coral (tissues and mucus) and non coral (underlying sediment and surrounding water) habitats. The diversity of the coral-associated communities was more deeply analysed by sequencing the 16S rRNA genes of bacterial clones. P. phosphorea and P. spinosum harbour distinct bacterial communities, indicating the occurrence of species-specific coral associated bacteria. In addition, only few phylotypes were shared between mucus and tissues of the same pennatulid species, suggesting that there might be a sort of microhabitat partitioning between the associated microbial communities. The predominance of Alphaproteobacteria was observed for the communities associated with both tissues and mucus of P. phosphorea (84 and 58.2 % of total sequences, respectively). Conversely, the bacterial community in the mucus layer of P. spinosum was dominated by Alphaproteobacteria (74.2 %) as opposed to the tissue library that was dominated by the Gammaproteobacteria and Mollicutes (40.6 and 35.4 %, respectively). The antibacterial activity of 78 bacterial isolates against indicator organisms was assayed. Active isolates (15.4 %), which predominantly affiliated to Vibrio spp., were mainly obtained from coral mucus. Results from the present study enlarge our knowledge on the composition and antibacterial activity of coral-associated bacterial communities. PMID- 23817610 TI - The effect of dimensionality of nanostructured carbon on the architecture of organic-inorganic hybrid materials. AB - The natural tendency of carbon nanotubes (CNTs) to agglomerate is an underlying reason that prevents the realization of their full potential. On the other hand, covalent functionalization of CNTs to control dispersion leads to disruption of pi-conjugation in CNTs and the non-covalent functionalization leads to a weak CNT polymer interface. To overcome these challenges, we describe the characteristics of fostering of direct nucleation of polymers on nanostructured carbon (CNTs of diameters (~2-200 nm), carbon nanofibers (~200-300 nm), and graphene), which culminates in interfacial adhesion, resulting from electrostatic and van der Waals interaction in the hybrid nanostructured carbon-polymer architecture. Furthermore, the structure is tunable through a change in undercooling. High density polyethylene and polypropylene were selected as two model polymers and two sets of experiments were carried out. The first set of experiments was carried out using CNTs of diameter ~2-5 nm to explore the effect of undercooling and polymer concentration. The second set of experiments was focused on studying the effect of dimensionality on geometrical confinements. The periodic crystallization of polyethylene on small diameter CNTs is demonstrated to be a consequence of the geometrical confinement effect, rather than epitaxy, such that petal-like disks nucleate on large diameter CNTs, carbon nanofibers, and graphene. The application of the process is illustrated in terms of fabricating a system for cellular uptake and bioimaging. PMID- 23817611 TI - Severity of allergic airway disease due to house dust mite allergen is not increased after clinical recovery of lung infection with Chlamydia pneumoniae in mice. AB - Chlamydia pneumoniae is associated with chronic inflammatory lung diseases like bronchial asthma and chronic obstructive pulmonary disease. The existence of a causal link between allergic airway disease and C. pneumoniae is controversial. A mouse model was used to address the question of whether preceding C. pneumoniae lung infection and recovery modifies the outcome of experimental allergic asthma after subsequent sensitization with house dust mite (HDM) allergen. After intranasal infection, BALB/c mice suffered from pneumonia characterized by an increased clinical score, reduction of body weight, histopathology, and a bacterial load in the lungs. After 4 weeks, when infection had almost resolved clinically, HDM allergen sensitization was performed for another 4 weeks. Subsequently, mice were subjected to a methacholine hyperresponsiveness test and sacrificed for further analyses. As expected, after 8 weeks, C. pneumoniae specific antibodies were detectable only in infected mice and the titer was significantly higher in the C. pneumoniae/HDM allergen-treated group than in the C. pneumoniae/NaCl group. Intriguingly, airway hyperresponsiveness and eosinophilia in bronchoalveolar lavage fluid were significantly lower in the C. pneumoniae/HDM allergen-treated group than in the mock/HDM allergen-treated group. We did observe a relationship between experimental asthma and chlamydial infection. Our results demonstrate an influence of sensitization to HDM allergen on the development of a humoral antibacterial response. However, our model demonstrates no increase in the severity of experimental asthma to HDM allergen as a physiological allergen after clinically resolved severe chlamydial lung infection. Our results rather suggest that allergic airway disease and concomitant cellular changes in mice are decreased following C. pneumoniae lung infection in this setting. PMID- 23817612 TI - Identification of genes involved in Neisseria meningitidis colonization. AB - Neisseria meningitidis is a worldwide cause of meningitis and septicemia leading at least to 50,000 deaths every year. Nevertheless, N. meningitidis is also a commensal bacterium that asymptomatically colonizes the epithelial cells of the nasopharynx of 10 to 30% of healthy individuals. Occasionally, N. meningitidis crosses the nasopharyngeal barrier and enters the bloodstream. During bacteremia, N. meningitidis may adhere to endothelial cells of brain vessels and invade meninges. To identify the genes required for meningococcal host colonization, we screened a signature-tagged transposon mutagenesis library using an innovative in vitro colonization model in order to identify mutants displaying decreased capacity to colonize human epithelial cells. Approximately 1,600 defined insertion mutants of invasive serogroup C strain NEM8013 were screened. Candidate mutants were tested individually for quantification of bacterial biomass with confocal microscope and COMSTAT software. Five mutants were demonstrated to exhibit significantly decreased colonization ability. The identified genes, including narP and estD, appeared to be involved in adaptation to hypoxic conditions and stress resistance. Interestingly, the genes fadD1, nnrS, and NMV_2034 (encoding a putative thioredoxin), prior to this study, had not been shown to be involved in colonization. Therefore, we provide here insights into the meningococcal functions necessary for the bacterium to adapt to growth on host cells. PMID- 23817613 TI - Identification and characterization of Cryptosporidium parvum Clec, a novel C type lectin domain-containing mucin-like glycoprotein. AB - Cryptosporidium species are waterborne apicomplexan parasites that cause diarrheal disease worldwide. Although the mechanisms underlying Cryptosporidium host cell interactions are not well understood, mucin-like glycoproteins of the parasite are known to mediate attachment and invasion in vitro. We identified C. parvum Clec (CpClec), a novel mucin-like glycoprotein that contains a C-type lectin domain (CTLD) and has orthologs in C. hominis and C. muris. CTLD containing proteins are ligand-binding proteins that function in adhesion and signaling and are present in a wide range of organisms, from humans to viruses. However, this is the first report of a CTLD-containing protein in protozoa and in Apicomplexa. CpClec is predicted to be a type 1 membrane protein, with a CTLD, an O-glycosylated mucin-like domain, a transmembrane domain, and a cytoplasmic tail containing a YXX sorting motif. The predicted structure of CpClec displays several characteristics of canonical CTLD-containing proteins, including a long loop region hydrophobic core associated with calcium-dependent glycan binding as well as predicted calcium- and glycan-binding sites. CpClec expression during C. parvum infection in vitro is maximal at 48 h postinfection, suggesting that it is developmentally regulated. The 120-kDa mass of native CpClec is greater than predicted, most likely due to O-glycosylation. CpClec is localized to the surface of the apical region and to dense granules of sporozoites and merozoites. Taken together, these findings, along with the known functions of C. parvum mucin-like glycoproteins and of CTLD-containing proteins, strongly implicate a significant role for CpClec in Cryptosporidium-host cell interactions. PMID- 23817614 TI - Functional features of TonB energy transduction systems of Acinetobacter baumannii. AB - Acinetobacter baumannii is an opportunistic pathogen that causes severe nosocomial infections. Strain ATCC 19606(T) utilizes the siderophore acinetobactin to acquire iron under iron-limiting conditions encountered in the host. Accordingly, the genome of this strain has three tonB genes encoding proteins for energy transduction functions needed for the active transport of nutrients, including iron, through the outer membrane. Phylogenetic analysis indicates that these tonB genes, which are present in the genomes of all sequenced A. baumannii strains, were acquired from different sources. Two of these genes occur as components of tonB-exbB-exbD operons and one as a monocistronic copy; all are actively transcribed in ATCC 19606(T). The abilities of components of these TonB systems to complement the growth defect of Escherichia coli W3110 mutants KP1344 (tonB) and RA1051 (exbBD) under iron chelated conditions further support the roles of these TonB systems in iron acquisition. Mutagenesis analysis of ATCC 19606(T) tonB1 (subscripted numbers represent different copies of genes or proteins) and tonB2 supports this hypothesis: their inactivation results in growth defects in iron-chelated media, without affecting acinetobactin biosynthesis or the production of the acinetobactin outer membrane receptor protein BauA. In vivo assays using Galleria mellonella show that each TonB protein is involved in, but not essential for, bacterial virulence in this infection model. Furthermore, we observed that TonB2 plays a role in the ability of bacteria to bind to fibronectin and to adhere to A549 cells by uncharacterized mechanisms. Taken together, these results indicate that A. baumannii ATCC 19606(T) produces three independent TonB proteins, which appear to provide the energy-transducing functions needed for iron acquisition and cellular processes that play a role in the virulence of this pathogen. PMID- 23817615 TI - MntABC and MntH contribute to systemic Staphylococcus aureus infection by competing with calprotectin for nutrient manganese. AB - During infection, vertebrates limit access to manganese and zinc, starving invading pathogens, such as Staphylococcus aureus, of these essential metals in a process termed "nutritional immunity." The manganese and zinc binding protein calprotectin is a key component of the nutrient-withholding response, and mice lacking this protein do not sequester manganese from S. aureus liver abscesses. One potential mechanism utilized by S. aureus to minimize host-imposed manganese and zinc starvation is the expression of the metal transporters MntABC and MntH. We performed transcriptional analyses of both mntA and mntH, which revealed increased expression of both systems in response to calprotectin treatment. MntABC and MntH compete with calprotectin for manganese, which enables S. aureus growth and retention of manganese-dependent superoxide dismutase activity. Loss of MntABC and MntH results in reduced staphylococcal burdens in the livers of wild-type but not calprotectin-deficient mice, suggesting that these systems promote manganese acquisition during infection. During the course of these studies, we observed that metal content and the importance of calprotectin varies between murine organs, and infection leads to profound changes in the anatomical distribution of manganese and zinc. In total, these studies provide insight into the mechanisms utilized by bacteria to evade host-imposed nutrient metal starvation and the critical importance of restricting manganese availability during infection. PMID- 23817616 TI - Edwardsiella tarda Ivy, a lysozyme inhibitor that blocks the lytic effect of lysozyme and facilitates host infection in a manner that is dependent on the conserved cysteine residue. AB - Edwardsiella tarda is a Gram-negative bacterial pathogen with a broad host range that includes fish and humans. In this study, we examined the activity and function of the lysozyme inhibitor Ivy (named IvyEt) identified in the pathogenic E. tarda strain TX01. IvyEt possesses the Ivy signature motif CKPHDC in the form of (82)CQPHNC(87) and contains several highly conserved residues, including a tryptophan (W55). For the purpose of virulence analysis, an isogenic TX01 mutant, TXivy, was created. TXivy bears an in-frame deletion of the ivyEt gene. A live infection study in a turbot (Scophthalmus maximus) model showed that, compared to TX01, TXivy exhibited attenuated overall virulence, reduced tissue dissemination and colonization capacity, an impaired ability to replicate in host macrophages, and decreased resistance against the bactericidal effect of host serum. To facilitate functional analysis, recombinant IvyEt (rIvy) and three mutant proteins, i.e., rIvyW55A, rIvyC82S, and rIvyH85D, which bear Ala, Ser, and Asp substitutions at W55, C82, and H85, respectively, were prepared. In vitro studies showed that rIvy, rIvyW55A, and rIvyH85D were able to block the lytic effect of lysozyme on a Gram-positive bacterium, whereas rIvyC82S could not do so. Likewise, rIvy, but not rIvyC82S, inhibited the serum-facilitated killing effect of lysozyme on E. tarda. In vivo analysis showed that rIvy, but not rIvyC82S, restored the lost pathogenicity of TXivy and enhanced the infectivity of TX01. Together these results indicate that IvyEt is a lysozyme inhibitor and a virulence factor that depends on the conserved C82 for biological activity. PMID- 23817617 TI - Donor CD8+ T cells prevent Toxoplasma gondii de-encystation but fail to rescue the exhausted endogenous CD8+ T cell population. AB - Functional exhaustion of CD8(+) T cells due to increased expression of inhibitory molecule PD-1 (Programmed Death-1) causes reactivation of latent disease during later phases of chronic toxoplasmosis. Onset of disease recrudescence results in decreased parasite cyst burden concomitant with parasites undergoing stage conversion from a primarily encysted, quiescent bradyzoite to a fast-replicating, highly motile tachyzoite. Thus, reduced cyst burden is one of the early hallmarks of disease recrudescence. This was further validated by depleting gamma interferon (IFN-gamma), a cytokine known to control latent toxoplasmosis, in chronically infected prerecrudescent mice. Since CD8(+) T cells (an important source of IFN-gamma) lose their functionality during the later phases of chronic toxoplasmosis, we next examined if adoptive transfer of functional CD8(+) T cells from acutely infected donors to the chronically infected prerecrudescent hosts could impede parasite de-encystation and rescue exhausted CD8(+) T cells. While the transfer of immune CD8(+) T cells temporarily restricted the breakdown of cysts, the exhausted endogenous CD8(+) T cell population was not rescued. Over time, the donor population got deleted, resulting in parasite de-encystation and host mortality. Considering that donor CD8(+) T cells fail to become long-lived, one of the cardinal features of memory CD8(+) T cells, it bears the implication that memory CD8 differentiation is impaired during chronic toxoplasmosis. Moreover, our data strongly suggest that while adoptive immunotherapy can prevent parasite de-encystation transiently, reduced antigen burden in the chronic phase by itself is insufficient for rescue of exhausted CD8(+) T cells. The conclusions of this study have profound ramifications in designing immunotherapeutics against chronic toxoplasmosis. PMID- 23817618 TI - Role of the zinc uptake ABC transporter of Moraxella catarrhalis in persistence in the respiratory tract. AB - Moraxella catarrhalis is a human respiratory tract pathogen that causes otitis media in children and lower respiratory tract infections in adults with chronic obstructive pulmonary disease. We have identified and characterized a zinc uptake ABC transporter that is present in all strains of M. catarrhalis tested. A mutant in which the znu gene cluster is knocked out shows markedly impaired growth compared to the wild type in medium that contains trace zinc; growth is restored to wild-type levels by supplementing medium with zinc but not with other divalent cations. Thermal-shift assays showed that the purified recombinant substrate binding protein ZnuA binds zinc but does not bind other divalent cations. Invasion assays with human respiratory epithelial cells demonstrated that the zinc ABC transporter of M. catarrhalis is critical for invasion of respiratory epithelial cells, an observation that is especially relevant because an intracellular reservoir of M. catarrhalis is present in the human respiratory tract and this reservoir is important for persistence. The znu knockout mutant showed marked impairment in its capacity to persist in the respiratory tract compared to the wild type in a mouse pulmonary clearance model. We conclude that the zinc uptake ABC transporter mediates uptake of zinc in environments with very low zinc concentrations and is critical for full virulence of M. catarrhalis in the respiratory tract in facilitating intracellular invasion of epithelial cells and persistence in the respiratory tract. PMID- 23817619 TI - Immunosuppressive property within the Streptococcus pneumoniae cell wall that inhibits generation of T follicular helper, germinal center, and plasma cell response to a coimmunized heterologous protein. AB - We previously demonstrated that intact, inactivated Streptococcus pneumoniae (unencapsulated strain R36A) inhibits IgG responses to a number of coimmunized soluble antigens (Ags). In this study, we investigated the mechanism of this inhibition and whether other extracellular bacteria exhibited similar effects. No inhibition was observed if R36A was given 24 h before or after immunization with soluble chicken ovalbumin (cOVA), indicating that R36A acts transiently during the initiation of the immune response. Using transgenic cOVA-specific CD4(+) T cells, we observed that R36A had no significant effect on T-cell activation (24 h) or generation of regulatory T cells (day 7) and only a modest effect on T-cell proliferation (48 to 96 h) in response to cOVA. However, R36A mediated a significant reduction in the formation of Ag-specific splenic germinal center T follicular helper (GC Tfh) and GC B cells and antibody-secreting cells in the spleen and bone marrow in response to cOVA or cOVA conjugated to 4-hydroxy-3 nitrophenylacetyl hapten (NP-cOVA). Of note, the inhibitory effect of intact R36A on the IgG anti-cOVA response could be reproduced using R36A-derived cell walls. In contrast to R36A, neither inactivated, unencapsulated, intact Neisseria meningitidis nor Streptococcus agalactiae inhibited the OVA-specific IgG response. These results suggest a novel immunosuppressive property within the cell wall of Streptococcus pneumoniae. PMID- 23817620 TI - Histone deacetylase 4 mediates SMAD family member 4 deacetylation and induces 5 fluorouracil resistance in breast cancer cells. AB - Histone deacetylases (HDACs) have been shown to play important roles in the regulation of chromatin remodeling by histone deacetylation, and their expression is induced in several types of cancer. In addition, they are known to be associated with resistance to anticancer drugs. However, the relevance of HDAC4 in chemoresistance remains unclear. Therefore, we investigated the interaction between HDAC4 expression and chemoresistance in breast cancer cells. We found that increased HDAC4 expression in MDA-MB-231 cells was associated with resistance to the anticancer drug 5-fluorouracil (5-FU). To verify these results, a cell line stably overexpressing HDAC4 was generated using MCF-7 cells (HDAC4OE). This cell line displayed increased 5-FU resistance, and HDAC4 knockdown in HDAC4OE cells restored 5-FU sensitivity. Consequently, we concluded that HDAC4 is a critical gene associated with 5-FU chemoresistance. Further investigation using a microarray approach revealed that 355 genes were differentially expressed following HDAC4 overexpression. Based on functional annotation of the array results, HDAC4 overexpression was found to downregulate genes related to the transforming growth factor (TGF) beta signaling pathway, including SMAD4, SMAD6, bone morphogenetic protein 6, inhibitor of DNA binding 1 and TGFbeta2. We also found that HDAC4 expression regulates SMAD4 expression by inducing deacetylation of histone H3 in the SMAD4 promoter region. In addition, SMAD4 knockdown in MCF-7 cells increased 5-FU resistance. In summary, our data suggest that HDAC4-mediated deacetylation of the SMAD4 promoter may lead to 5-FU resistance in breast cancer cells. PMID- 23817621 TI - Identification and characterization of a twist ortholog in the polychaete annelid Platynereis dumerilii reveals mesodermal expression of Pdu-twist. AB - The basic helix-loop-helix transcription factor twist plays a key role during mesoderm development in Bilateria. In this study, we identified a twist ortholog in the polychaete annelid Platynereis dumerilii and analyze its expression during larval development, postlarval growth up to the adult stage, and caudal regeneration after amputation of posterior segments. At late larval stages, Pdu twist is expressed in the mesodermal anlagen and in developing muscles. During adulthood and caudal regeneration, Pdu-twist is expressed in the posterior growth zone, in mesodermal cells within the newly forming segments and budding parapodia. Our results indicate that Pdu-twist is involved in mesoderm formation during larval development, posterior growth, and caudal regeneration. PMID- 23817622 TI - Synthesis of [PtCl2(4,4'-dialkoxy-2,2'-bipyridine)] complexes and their in vitro anticancer properties. AB - A series of [Pt(II)Cl2(4,4'-dialkoxy-2,2'-bipyridine)] complexes of the general formula of [Pt(II)Cl2(4,4'-bis(RO)-2,2'-bipyridine)] (where R = -(CH2)n-1CH3, n = 2-6, 8) were synthesized and characterized using (1)H NMR, (13)C NMR spectroscopy, elemental analysis, mass spectroscopy, and differential scanning calorimetry measurements. The in vitro anti-proliferative activities of these compounds were evaluated against human cancer cell lines A549 (lung adenocarcinoma), DU145 (prostate carcinoma), MCF-7 (breast adenocarcinoma), and MDA-MB-435 (melanoma) using the MTS cell proliferation assay. Several Pt(II) coordination compounds were found to have greatly enhanced activity compared to cisplatin after a one hour treatment in all cell lines tested. A structure activity relationship was observed, that is, the activity increases as the carbon chain length of the alkyl group increases. The activity was maximum when the carbon chain length reached four or five carbons and decreased with the longer carbon chain length. Fluorescence microscopy and flow cytometry data indicate that the main mode of cell death is through apoptosis with some necrotic responses. PMID- 23817625 TI - Quantitative analysis of molecular-level DNA crystal growth on a 2D surface. AB - Crystallization is an essential process for understanding a molecule's aggregation behavior. It provides basic information on crystals, including their nucleation and growth processes. Deoxyribonucleic acid (DNA) has become an interesting building material because of its remarkable properties for constructing various shapes of submicron-scale DNA crystals by self-assembly. The recently developed substrate-assisted growth (SAG) method produces fully covered DNA crystals on various substrates using electrostatic interactions and provides an opportunity to observe the overall crystallization process. In this study, we investigated quantitative analysis of molecular-level DNA crystallization using the SAG method. Coverage and crystal size distribution were studied by controlling the external parameters such as monomer concentration, annealing temperature, and annealing time. Rearrangement during crystallization was also discussed. We expect that our study will provide overall picture of the fabrication process of DNA crystals on the charged substrate and promote practical applications of DNA crystals in science and technology. PMID- 23817626 TI - Easy and cheap fabrication of ordered pyramidal-shaped plasmonic substrates for detection and quantitative analysis using surface-enhanced Raman spectroscopy. AB - In this work we present a simple approach for the fabrication of periodically ordered pyramidal-shaped metallic nanostructures and demonstrate their efficiency as SERS active substrates. Our method for the fabrication of the plasmonic substrate is based on nanoimprint lithography and exploits the thermal properties of two classes of polymers, thermoplastics and hydrogels. During the heating process the thermoplastic polymers will start to melt whereas the hydrogel polymers will form a solid due to the evaporation of water molecules adsorbed during the dissolving process. Using this approach we fabricate highly ordered pyramidal-shaped nanostructures using the texture of a commercial DVD as the initial mold. This technique represents a low-cost alternative to the classical lithography techniques, allowing the fabrication over large areas (~cm(2)) of periodically ordered nanostructures in a controlled and reproducible manner. The SERS efficiency of the fabricated substrate is demonstrated through the detection of urea molecules found in the fingerprint. In addition, due to the periodicity of the pyramidal-shaped structures, the fabricated substrate can be successfully employed to correlate the intensity of the specific SERS peak of urea with the molecules concentration, offering thus the possibility of developing a quantitative SERS renal sensor. PMID- 23817627 TI - Generalized granulomatous dermatitis accompanied by myelodysplastic syndrome. PMID- 23817628 TI - Induction and translocation of tissue transglutaminase isoforms increased phosphorylation in retinoic acid treated erythroleukemia cells. AB - Tissue transglutaminase (TGC, TG2, 80 kDa) is inactive in cross-linking reactions and is converted in vitro and in vivo to the TG (55 kDa) active isoform (Fraij in J Cell Biochem 112:2469-2489, 2011). Two isoforms of human TGC were cloned from human erythroleukemia (HEL) cells induced with retinoic acid (RA) and termed TGH, 63 kDa (Fraij et al. in J Biol Chem 267:22616-22673, 1992) and TGH2, 37 kDa. The purified TGC isoforms exhibited GTPase activity and TGH and TGH2 showed higher activities than the native TGC protein. In all normal cells examined, TGC was found in membrane fractions several fold higher than the supernatant fractions; however, in the natural tumor cell line HEL the TGC cellular distribution was reversed. Although TGC is the major enzyme in normal human erythrocytes, its expression level was significantly decreased in HEL cells. RA treatment induced a sevenfold increase in the level of TGC protein in HEL cells and was accompanied by its translocation to cell membranes. When isolated membrane and supernatant fractions from normal human foreskin (CF3), normal human embryonic lung (WI-38), and HEL cells treated with or without RA were incubated with [(32)P]-ATP at 37 degrees C for 1 h, more radio-labeled proteins were detected in the membrane fractions than the cytosolic fractions. More labeled protein bands were detected in RA treated HEL cells in comparison to control HEL cell extracts. Radio labeled proteins coimmunoprecipitated with the TGC isoforms in RA treated HEL membrane fractions thereby confirming that the radio-labeled material consists of endogenous proteins associated with TGC isoforms. Protein phosphorylation is related to the induction and translocation of the isoforms in RA treated cells. These results show that the TGC isoforms complexes with proteins in vivo and that the phosphorylation of these proteins is catalyzed directly by TGC kinase activity or indirectly by the TGC phosphorylation of other protein kinases. PMID- 23817629 TI - Cross-sectional relatedness between sentences in breast radiology reports: development of an SVM classifier and evaluation against annotations of five breast radiologists. AB - Introduce the notion of cross-sectional relatedness as an informational dependence relation between sentences in the conclusion section of a breast radiology report and sentences in the findings section of the same report. Assess inter-rater agreement of breast radiologists. Develop and evaluate a support vector machine (SVM) classifier for automatically detecting cross-sectional relatedness. A standard reference is manually created from 444 breast radiology reports by the first author. A subset of 37 reports is annotated by five breast radiologists. Inter-rater agreement is computed among their annotations and standard reference. Thirteen numerical features are developed to characterize pairs of sentences; the optimal feature set is sought through forward selection. Inter-rater agreement is F-measure 0.623. SVM classifier has F-measure of 0.699 in the 12-fold cross-validation protocol against standard reference. Report length does not correlate with the classifier's performance (correlation coefficient = -0.073). SVM classifier has average F-measure of 0.505 against annotations by breast radiologists. Mediocre inter-rater agreement is possibly caused by: (1) definition is insufficiently actionable, (2) fine-grained nature of cross-sectional relatedness on sentence level, instead of, for instance, on paragraph level, and (3) higher-than-average complexity of 37-report sample. SVM classifier performs better against standard reference than against breast radiologists's annotations. This is supportive of (3). SVM's performance on standard reference is satisfactory. Since optimal feature set is not breast specific, results may transfer to non-breast anatomies. Applications include a smart report viewing environment and data mining. PMID- 23817631 TI - Biological vs. conventional combination treatment and work loss in early rheumatoid arthritis: a randomized trial. AB - IMPORTANCE: The introduction of biological tumor necrosis factor inhibitors has improved the treatment of rheumatoid arthritis (RA) but at a substantial cost. These drugs have been shown to lead to superior radiological outcomes compared with a combination of conventional disease-modifying antirheumatic drugs over 2 years. OBJECTIVE: To investigate whether radiological superiority translates into better work loss outcomes. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, 2-arm, parallel, randomized, active-controlled, open-label trial. Patients with early RA (symptom duration <1 year) were recruited from 15 rheumatology clinics in Sweden from October 1, 2002, through December 31, 2005. The study population was restricted to working-age patients (aged <63 years). INTERVENTIONS: Patients who did not achieve low disease activity after 3 to 4 months of methotrexate therapy were randomized to receive additional biological treatment with infliximab or conventional combination treatment with sulfasalazine plus hydroxychloroquine. MAIN OUTCOMES AND MEASURES: Monthly sick leave and disability pension days 21 months after randomization retrieved from the nationwide Swedish Social Insurance Office register. Main analyses were by intention to treat, including all patients, and adjusted for baseline sick leave and disability pension. RESULTS: Of 204 eligible patients, 105 were randomized to biological and 99 to conventional treatment. Seven patients in the biological and 4 in the conventional treatment group never received the study drug, and 72 and 52 patients, respectively, followed the study per protocol for 21 months. The baseline mean (SD) work loss was 17 (13) d/mo (median, 16 d/mo) in both groups (mean difference, 0.6 d/mo; 95% CI, -3.0 to 3.9). The mean changes in work loss at 21 months were -4.9 d/mo in the biological and -6.2 d/mo in the conventional treatment group (adjusted mean difference, 1.6 d/mo; 95% CI, -1.2 to 4.4). Including only patients receiving at least 1 dose of assigned treatment, the adjusted mean difference was 1.5 d/mo (95% CI, -1.5 to 4.4), and in per-protocol analysis the adjusted mean difference was 0.3 d/mo (95% CI, -2.8 to 3.8). CONCLUSIONS AND RELEVANCE: The radiological superiority of biological compared with conventional combination therapy did not translate into better work loss outcomes in patients with early RA who had experienced an insufficient response to methotrexate. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00764725. PMID- 23817632 TI - 3D graphene-Fe3O4 nanocomposites with high-performance microwave absorption. AB - 3D Fe3O4-graphene nanocomposites were conveniently prepared via a direct hydrothermal grafting method. On the basis of the unique properties of both single-crystalline Fe3O4 and 3D chemically reduced graphene oxide, with characteristics such as ultralow density and high surface area, the as-prepared graphene-Fe3O4 nanocomposites showed high-performance microwave absorption ability and have the potential for application as advanced microwave absorbers. PMID- 23817633 TI - NRPSs and amide ligases producing homopoly(amino acid)s and homooligo(amino acid)s. AB - Microorganisms are capable of producing a wide variety of biopolymers. Homopoly(amino acid)s and homooligo(amino acid)s, which are made up of only a single type of amino acid, are relatively rare; in fact, only two homopoly(amino acid)s have been known to occur in nature: poly(epsilon-L-lysine) (epsilon-PL) and poly(gamma-glutamic acid) (gamma-PGA). Bacterial enzymes that produce homooligo(amino acid)s, such as L-beta-lysine-, L-valine-, L-leucine-, L isoleucine-, L-methionine-, and L-glutamic acid-oligopeptides and poly(alpha-l glutamic acid) (alpha-PGA) have recently been identified, as well as epsilon-PL synthetase and gamma-PGA synthetase. This article reviews the current knowledge about these unique enzymes producing homopoly(amino acid)s and homooligo(amino acid)s. PMID- 23817634 TI - Nicotine interferes with purinergic signaling in smooth muscle cells isolated from urinary bladders of patients with lower urinary tract symptoms. AB - In patients with outlet obstruction, the contraction of the base is reduced compared to that of healthy individuals, while the contraction of the dome is not affected. Here, we investigated the cellular mechanisms that might be responsible for cholinergic effects blocking non-adrenergic non-cholinergic contractions in the base of the urinary bladder. Smooth muscle cells either from the base or from the dome of human urinary bladders were cultured to determine the contribution of cholinergic and purinergic mechanisms to their Ca2+ homeostasis. While ATP evoked Ca2+ transients in all the cells, nicotine and carbachol induced Ca2+ transients only in 56% and 44% of the cells, respectively. When ATP was administered together with nicotine or carbachol, the amplitudes of the Ca2+ transients recorded from cells prepared from the base of bladders were significantly smaller (42 +/- 6% with nicotine and 56 +/- 9% with carbachol) than those evoked by ATP alone. This inhibition was much less apparent in the dome of bladders. The inhibition between the cholinergic and purinergic signaling pathways reported in this work may decrease the strength of the contraction of the base of the urinary bladder in patients with outlet obstruction during voiding. PMID- 23817635 TI - Apolipoprotein E genotype may influence urinary gammacarboxyglutamate (Gla) concentrations in young individuals. AB - Upon degradation of vitamin K-dependent proteins (known as Gla-proteins) the free aminoacid Gla cannot be re-utilized and is excreted in the urine, where it can be used as an overall marker for vitamin K status. We report the urinary Gla excretion values in first morning void urine for healthy young Romanian subjects from birth, childhood and young adulthood. In these subjects we have evaluated age, gender and apo E genotype as potential confounders. The urinary free Gla/creat ratio (Gla/creat, mg/g) was highest in newborns (34.8 +/- 19.5; p < 0.001), than fell in the group 4 to 48 months old (13.1 +/- 11.1) to levels that were not significantly different from the young adult group (18.3 +/- 5.5). No gender-related differences were observed in Gla/creat in newborns and young children, but Gla excretion in women was higher than in men (28.6%; p < 0.029). Remarkably, Gla excretion in subjects bearing the apo epsilon2+ allele was significantly lower (11.9 +/- 4.2) than in those bearing combinations of the epsilon3+ and epsilon4+ alleles (20.3 +/- 4.1). The novelty of this study resides in the evaluation of urinary Gla excretion in relation with apo E genotype, suggesting that apo epsilon2 allele is a risk factor for developing vitamin K insufficiency. PMID- 23817637 TI - A miniature microdrive for recording auditory evoked potentials from awake anurans. AB - Electrical activity recording from the brains of awake animals is a corner stone in the study of the neurophysiological basis of behavior. To meet this need, a microelectrode driver suitable for the animal of interest has to be developed. In the present study a miniature microdrive was developed specifically for the leopard toad, Bufo regularis, however, it can be used for other small animals. The microdrive was designed to meet the following requirements: small size, light weight, simple and easy way of attaching and removing, advancing and withdrawing of microelectrode in the animal brain without rotation, can be reused and made from inexpensive materials. To assess the performance of the developed microdrive, we recorded auditory evoked potentials from different auditory centers in the toad's brain. The potentials were obtained from mesencephalic, diencephalic and telencephalic auditory sensitive areas in response to simple and complex acoustic stimuli. The synthetic acoustical tones introduced to the toad were carrying the dominant frequencies of their mating calls. PMID- 23817636 TI - The effect of photodynamic treatment on the morphological and mechanical properties of the HeLa cell line. AB - High resolution imaging of biological structures and changes induced by various agents such as drugs and toxins is commonly performed by fluorescence and electron microscopy (EM). Although high-resolution imaging is possible with EM, the requirements for fixation and staining of samples for image contrast severely limits the study of living organisms. Atomic force microscopy (AFM), on the other hand, is capable of simultaneous nanometer spatial resolution and piconewton force detection, allowing detailed study of cell surface morphology and monitoring cytomechanical information. We present a method that images and studies mechanically characterized cells using AFM. We used a HeLa cell line (cervix carcinoma cell), which is sensitive to photodynamic treatment (PDT); growth media as a scanning surrounding; atomic force microscopy NT-MDT Aura for cytomechanical measurement; and scanning electron microscope Hitachi Su 6600 for control images of the cells. The modulus of elasticity for intact and photodynamically damaged cells can indicate mechanical changes to the main properties of cells. Cell elasticity changes can provide information on the degree or value of cell damage, for example after PDT. Measurements were carried out on approximately sixty cells, including three independent experiments on a control group and on sixty cells in a photodamaged group. Cells before PDT show higher elasticity: the median of Young's modulus on the nucleus was 35.283 kPa and outside of the nucleus 107.442 kPa. After PDT, the median of Young's modulus on the nucleus was 61.144 kPa and outside of the nucleus was 193.605 kPa. PMID- 23817638 TI - Epilobium angustifolium extract demonstrates multiple effects on dermal fibroblasts in vitro and skin photo-protection in vivo. AB - Stress-induced fibroblast senescence is thought to contribute to skin aging. Ultraviolet light (UV) radiation is the most potent environmental risk factor in these processes. An Epilobium angustifolium (EA) extract was evaluated for its capacity to reverse the senescent response of normal human dermal fibroblasts (NHDF) in vitro and to exhibit skin photo-protection in vivo. The HPLC-UV-MS analysis of the EA preparation identified three major polyphenol groups: tannins (oenothein B), phenolic acids (gallic and chlorogenic acids) and flavonoids. EA extract increased the cell viability of senescent NHDF induced by serum deprivation. It diminished connective tissue growth factor and fibronectin gene expressions in senescent NHDF. Down-regulation of the UV-induced release of both matrix metalloproteinase-1 and -3 and the tissue inhibitor of matrix metalloproteinases-1 and -2, and also down-regulation of the gene expression of hyaluronidase 2 were observed in repeatedly UV-irradiated NHDF after EA extract treatment. Interestingly, EA extract diminished the down-regulation of sirtuin 1 dampened by UV-irradiation. The application of EA extract using a sub-irritating dose protected skin against UV-induced erythema formation in vivo. In summary, EA extract diminished stress-induced effects on NHDF, particularly on connective tissue growth factor, fibronectin and matrix metalloproteinases. These results collectively suggest that EA extract may possess anti-aging properties and that the EA polyphenols might account for these benefits. PMID- 23817640 TI - The guinea pig atrial A1 adenosine receptor reserve for the direct negative inotropic effect of adenosine. AB - Although the A1 adenosine receptor (A1 receptor), the main adenosine receptor type in cardiac muscle, is involved in powerful cardioprotective processes such as ischemic preconditioning, the atrial A1 receptor reserve has not yet been quantified for the direct negative inotropic effect of adenosine. In the present study, adenosine concentration-effect (E/c) curves were constructed before and after pretreatment with FSCPX (8-cyclopentyl-N3-[3-(4 (fluorosulfonyl)benzoyloxy)propyl]-N1-propylxanthine), an irreversible A1 receptor antagonist, in isolated guinea pig atria. To prevent the intracellular elimination of the administered adenosine, NBTI (S-(2-hydroxy-5-nitrobenzyl)-6 thioinosine), a nucleoside transport inhibitor, was used. As expected, NBTI alone and FSCPX-pretreatment alone shifted the adenosine E/c curve to the left and right, respectively. However, in the presence of NBTI, FSCPX-pretreatment appeared to increase the maximal response to adenosine. By means of the receptorial responsiveness method (RRM), our recently developed procedure, adenosine E/c curves generated in the presence of NBTI were corrected for the bias caused by the endogenous adenosine accumulated by NBTI. The corrected curves indicate a substantial A1 receptor reserve for the direct negative inotropy evoked by adenosine. In addition, our results suggest that accumulation of an endogenous agonist may bias the E/c curve constructed with the same or similar agonist that can lead to seemingly paradoxical results. PMID- 23817639 TI - Isoproterenol accelerates apoptosis through the over-expression of the sodium/calcium exchanger in HeLa cells. AB - Apoptosis induction causes over-expression of the Na+/Ca2+ exchanger of type 1 (NCX1) in the HeLa cell line. During induction of apoptosis and in the presence of isoproterenol hydrochloride (I; beta-adrenergic agonist), increase in the NCX1 is even more pronounced. Anti-apoptotic Bcl-2 mRNA and protein is markedly reduced during apoptosis and in the presence of I, which causes a rapid increase in the Bax/Bcl-2 ratio. During apoptosis induction by apoptosis inducing kit (A), both with and without I, the active form of caspase-3, which is the executive enzyme in apoptosis, becomes visible on Western blots. Silencing NCX1 resulted in the reversal of the Bax/Bcl-2 ratio, it prevented a decrease in mitochondrial membrane potential compared to the AI group and it decreased the level of AI induced apoptosis in HeLa cells. Based on the experiments with single apoptotic inducers camptothecin, cycloheximide and dexamethasone, it might be proposed that potentiated apoptotic effect in I-treated cells is due to the inhibition of nuclear topoisomerase. As illustrated in immunofluorescence and Western blot analysis, calnexin increased significantly during induction of the apoptosis in the presence of I. In addition, further decrease in sarco/endoplasmic ATPase 2 (SERCA2), decrease in reticular calcium and mitochondrial membrane potential was observed, which suggests development of the endoplasmic reticulum (ER) stress. Based on these results, we propose that I further enhanced NCX1 expression in apoptotic cells through the development of ER stress. PMID- 23817641 TI - Increased production of IL-6 and IL-17 in lipopolysaccharide-stimulated peripheral mononuclears from patients with rheumatoid arthritis. AB - TLR4-mediated inflammatory responses are important for innate immune functions, thus their alterations may participate in the pathogenesis of rheumatoid arthritis (RA). Cortisol is one of the most potent immunomodulatory hormones involved in control of inflammation. In this study, we analyzed TLR4-mediated responses and cortisol effects on the process in peripheral blood mononuclear cells (PBMC) from RA patients. Lipopolysaccharide-stimulated PBMC from 23 female patients and 15 healthy controls were cultured in the presence or absence of cortisol (1 MUM) for 24 h. A panel of 17 inflammatory cytokines was analyzed in the cell culture supernatants. Higher (p < 0.05) concentrations of IL-6, IL-17 and MCP-1 were found in lipopolysaccharide-stimulated PBMC from RA patients compared to controls. After normalization of stimulated cytokine secretion to unstimulated cells, a significantly higher (p < 0.05) IL-6 and G-CSF production was found in RA PBMC. Cortisol induced stronger (p < 0.05) suppression of lipopolysaccharide-stimulated secretion of IL-1beta, IL-6, IL-17 and G-CSF in RA group compared to controls. The observed higher production of the key inflammatory cytokines by RA PBMC to lipopolysaccharide stimulation supports involvement of TLR4-mediated processes in RA pathogenesis. The higher sensitivity of LPS-stimulated RA PBMC to immunosuppressive effects of cortisol may reflect adaptive processes to chronic inflammation. PMID- 23817642 TI - Effect of aging on formation of reactive oxygen species by mitochondria of rat heart. AB - Mitochondrial electron transport chain is thought to be a major source of reactive oxygen species (ROS) during aging. However, this view is supported mainly by accumulation of mitochondrial oxidative damage with age and the exact sites of ROS formation remains unknown. In the present study, we measured rate of ROS formation using 2',7'-dichlorofluorescein (DCF) probe in cardiac mitochondria from adult (6-month-old), old (15-month-old) and senescent (26-month-old) rats. In mitochondria oxidizing complex II substrate, succinate, the rate of ROS formation progressively increased with age. In the presence of complex I inhibitor rotenone or complex III inhibitor antimycin A, the rate ROS formation significantly decreased, but even the combination of inhibitors could not fully prevent generation of ROS. Age-dependent increase of ROS formation was accompanied by a loss of thiol groups, tryptophan degradation and increased lipid peroxidation. These data suggest that in addition to complex I and complex II other mitochondrial sites can contribute to accelerated ROS generation and oxidative damage during aging. PMID- 23817643 TI - [Mathematical modelling of the propagation of infectious diseases: where we came from, and where we are going]. AB - This work deals with the study of the use of mathematical models to simulate the spreading of infectious diseases. There is no doubt about the importance of the use of computational tools that allow the health staff to model and predict the spreading of an infectious disease. Using such tools one can establish and simulate disease control strategies. The development of such technologies is a multidisciplinary issue; in this sense, the mathematical algorithms -that must be computationally implemented- play a central role. The main goal of this work is to highlight among health community the increasing importance of the use of mathematical models for epidemic disease spreading. Consequently, the main features of such models are introduced and their classification is stated taking into account the behavior, the basic population unit or the mathematical objects used. An exhaustive search of related papers through the most important databases (Medline and Web of Science) are performed. The main conclusion obtained from this work is the central role that mathematical models can play in the simulation of epidemic spreading; moreover,some ideas about the future research are stated. PMID- 23817644 TI - [Incidence and susceptibility of Campylobacter jejuni in pediatric patients: involvement in bacteremia]. AB - INTRODUCTION: Invasive disease as a result Campylobacter spp. is rarely reported. Bloodstream infections have been reported in patients with immune deficiency or other serious underlying conditions. We conducted a prospective study to know the incidence of Campylobacter jejuni bacteremia in pediatric patients and its susceptibility to erythromycin and ciprofloxacin. METHODS: The identification of Campylobacter isolates was based on routine culture methods. Antimicrobial susceptibility was performed using a disk diffusion method. RESULTS: During April 2010-June 2012, at Hospital Nino Jesus of Madrid, Campylobacter spp. was isolated from 171 stool specimens in 154 patients. The median age was 2 years (3 months-21 year). One hundred and one (66%) isolates were identified as C. jejuni. Nine patients with enteritis due C. jejuni (9%) were immunocompromised. Erythromycin resistance was observed in 5% of the isolates. The resistance to ciprofloxacin was 88%. Blood cultures were obtained of 19 patients infected with C. jejuni (19%). Of these, one had C. jejuni bacteremia. During the study period, other episode of C. jejuni bacteremia was detected in one patient different without positive stool culture for C. jejuni (0.34% of all bloodstreams infections). Both patients were immunocompromised. CONCLUSIONS: Campylobacter spp. is an uncommon cause of bloodstream infection in our serie occurring in pediatric patients with immune deficiency as predisposing factor. In our institution, empirical use of fluoroquinolones for Campylobacter infections should not be recommended by the high rate of resistance. Moreover in our study the resistance to erythromycin is low, however is advisable its surveillance. PMID- 23817645 TI - [Biofilm score: is it a differential element within gram negative bacilli?]. AB - The aim of the study was to investigate biofilm formation in Gram negative bacteria and to quantify biofilm production applying a new developed technique that made possible to compare results about biofilm formation within the different Gram negative bacteria species. A total of 153 Gram negative strains corresponding to 12 different bacterium species were studied applying a variation of the optic density measurement technique reported by Stepanovic et al. Data obtained with optic density analysis allow to classify microorganisms in strong biofilm developers, moderate biofilm developers, weak biofilm developers and no biofilm developers. The results were expressed in two ways, using in both cases the same statistical method: without standardization, where controls were different depending on the day optic density measurements were performed, and standardized using a correction factor, using the same control for every strain of all our bacterium species in our study, which allows result homogenization. The obtained results in our study after data analysis and standardization show that over the 153 Gram negative strains in our study, 105 of them were no biofilm developers, representing 63.75% of all the studied bacterium genera. We consider that standardization and quantification of biofilm development in Gram negative bacteria can be useful in clinical practice, because biofilm development ability can lead or focus the gold treatment of pathologies produced by these microorganisms. PMID- 23817646 TI - [Reasons for the introduction of darunavir in the antirretroviral treatment in HIV-infected patients]. AB - INTRODUCTION: In 2009 a deep change in ARV treatment took place in Spain with the introduction of new ARV drugs. The principal objective of the study was to determine the clinical situation of the patients in which DRV/r was introduced in the ARV therapy. METHODS: Observational, cross sectional and multicentre study in which 91 reference hospitals participated. Patient's enrollment was carried out between 2008 and 2009. Data were collected retrospectively considering standard clinical practice. RESULTS: 719 medical records were reviewed. Patients had a different clinical situation compared to nowadays with predominance of multiresistant virus which leaded to virologic failure. The principal reason for introducing DRV/r in the ARV regimen was the virologic failure (54.2%). CONCLUSIONS: Considering this situation, DRV/r became a therapeutic option which represented a change in the ARV paradigm in that period. PMID- 23817647 TI - [Serological markers of Spanish and immigrant pregnant women in the south of Madrid during the period 2007-2010]. AB - OBJECTIVE: The prevalence and evolution of the markers including in the serologic profile of pregnant woman was studied in our hospital during a period of 4 years. MATERIAL AND METHODS: A retrospective study of the prevalence of antibodies against Treponema pallidum, human immunodeficiency virus (HIV), Toxoplasma gondii, rubeola virus and hepatitis B virus (HBV), was performed in our hospital among Spanish and immigrant pregnant women, from January 2007 to December 2010. RESULTS: A total of 8,012 pregnant were studied, 2,752 (34.2%) of them were foreign. The non-treponemal tests (RPR) were positive in 40 (0.49%) women, being the prevalence slightly superior in foreigners than in natives (0.8 as opposed to 0.3%). The IgG anti-T. gondii global prevalence was 23,35% (1,874 patients). In Spanish pregnant this prevalence was 18%, and 33.8% in the immigrant women. Almost the total of Spanish pregnant (99.5%) displayed IgG antibodies against rubeola virus whereas in the foreigners this rate was 61.6%. The presence of HBsAg for HBV was tested in 86.6% of pregnant women (6,939/8,012), being positive the 0.75% (59 patients), with a prevalence in foreigners greater than in Spanish (1.65 as opposed to 0.4%). Antibodies anti-HVI were detected in 22 patients (0.22%), being the prevalence 0.15% among the Spanish and 0.51% among the foreigners. PMID- 23817648 TI - [Emergence of high-level resistance to gentamicin and streptomycin in Streptococcus agalactiae in Buenos Aires, Argentina]. AB - INTRODUCTION: Streptococcus agalactiae has become recognized as a cause of serious illness in newborns, pregnant women, and adults with chronic medical conditions. Optimal antimicrobial therapy for serious infections requires the use of synergistic combinations of a cell wall-active agent, such as a penicillin, with an aminoglycoside, which results in bactericidal activity against this organism. The synergistic effect is eliminated by the acquisition of high-level resistance (HLR) to aminoglycosides. The aim of our study was to determine the prevalence of HLR to gentamicin (GEN) and streptomycin (EST).The ability to detect HLR using a standard agar screen plate and high-content discs was investigated. METHODS: This study was conducted with 141 strains of S. agalactiae isolated from vaginal and rectal swabs of pregnant women at term. Minimum inhibitory concentrations (MICs) to GEN and STR were determined by the E-test method. Disks of GEN (120 MUg) and STR (300 MUg) were used to detect HLR. Agar screening plates were performed with GEN 100 mg/L, GEN 500 mg/L and STR 2000 mg/L. RESULTS: The HLR to GEN and STR was detected in 13.5% and 16.3% of the isolates respectively. Among 141 strains, 7.8% were simultaneously resistant to GEN and STR. With 120-MUg GEN and 300-MUg STR disks, strains for which MICs were >= 512 mg/L and >= 1024 mg/L had no zones of inhibition. Isolates with inhibitory zones for GEN and STR of >=13 mm showed a MICs <= 64 mg/L and <= 512 mg/L. All the screening plates were negative for these isolates. HLR to aminoglycosides was associated (83.9%) with resistance to erythromycin and/or clindamycin. CONCLUSIONS: This study highlights the emergence of strains with HLR to aminoglycosides. The disk-agar diffusion test performed with high-content aminoglycoside disks and screening plates can provide laboratories with a convenient and reliable method for detecting S. agalactiae isolates that are resistant to aminoglycoside-betalactam synergy. PMID- 23817649 TI - [Accuracy of Etest method to study Campylobacter spp. susceptibility to erythromycin, ciprofloxacin and tetracycline]. AB - INTRODUCTION: In industrialized countries Campylobacter jejuni is the enteropathogen most frequently isolated from the feces of patients with gastroenteritis. The Etest accuracy to categorize Campylobacter spp. susceptibility to erythromycin, ciprofloxacin and tetracycline was evaluated. METHODS: Ninety strains were studied. The Etest(r) was performed following the manufacturer's instructions on commercial plates of Mueller-Hinton blood. The breakpoints were those recommended by the Clinical Laboratory Standards Institute (CLSI) for broth microdilution. The gold standard was the broth microdilution method as recommended by CLSI. RESULTS: The Etest agreement with the reference method was 100%, 97% and 98% for erythromycin, ciprofloxacin and tetracycline, respectively. No major or very major errors were found. CONCLUSIONS: The Etest results are equivalent to those obtained using the gold standard. The Etest is a valid method to determine susceptibility to tetracycline. It is also a suitable method to categorize strains classified as non-resistant to erythromycin and ciprofloxacin by the diffusion method. PMID- 23817650 TI - [Bacteraemia at a second level hospital: epidemiological study, analysis of pronostic factors associated to mortality and economic cost estimation]. AB - INTRODUCTION: Bacteraemia (B) accounts for a considerable proportion (0.36%) of all hospital admissions due to infections diseases and it is associated to increased hospital costs. The aim of this study is to describe a cohort of patients with bacteraemia at a second level hospital, to analyze factors associated to mortality and its economical impact during hospital admission. PATIENTS AND METHODS: Observational study of a cohort of adult patients with bacteraemia admitted at a second level hospital during 2010. Data collection from clinical records has been done according to a standard protocol: epidemiological and clinical variables and factors associated to mortality were analysed. Total economical cost per patient was estimated. RESULTS: 148 patients were included: 80 community B (55.4%), 23 health care associated B (15.5%) and 45 nosocomial B (28.5%). The incidence was 9 cases 10.000 persons/year. Mean age was 69 years and the global mortality was 24%. In bivariate analysis smoking, diabetes mellitus, McCabe Jackson score type I-II, Pitt Index >= 3, APACHE >= 20, Glasgow <= 9, shock, respiratory distress, invasive procedures, nosocomial bacteraemia and inadequate empiric or definitive antibiotic treatment were associated to mortality (p<0.05). Factors associated to mortality in multivariate analysis included McCabe Jackson score type I-II (OR 4.95; 95% CI 1.095-22.38), haemodialysis during acute stage (OR 7.8; 95% CI 2.214-27.773) and inadequate empiric antibiotic treatment (OR 7.68; 95% CI 19.82-29.77). Admission economic cost per patient was 9,459 ? for community acquired bacteriemia, 5,656 ? for health care associated bacteraemia and 41,680? for nosocomial bacteraemia. CONCLUSIONS: Comorbidity, inadequate empiric antibiotic treatment and haemodialysis during acute phase are statistically significantly in our cohort of patients with bacteraemia. PMID- 23817651 TI - A rare case of Meleney's ulcer after partial chemical matricectomy. AB - BACKGROUND: Meleney's ulcer is a rare, but potentially deadly infection that often occurs in post-surgical sites. This type of ulcer has not previously been reported in the toenail after phenol matricectomy. PATIENT CASE: A female patient underwent partial phenolization of the medial nail matrix of the hallux, but after 2 months had a recurrent spicula that caused Meleney's ulcers. RESULTS: The ulcers remained after treatment with antibiotics, and further surgery was required to fully clear the infection. CONCLUSION: This case and review of Meleney's ulcer highlights the deceptively benign initial presentation of necrotizing fasciitis at the hallux after partial chemical matricectomy surgery using a phenol-based approach. PMID- 23817653 TI - Direct hemoperfusion with polymyxin B-immobilized cartridge in severe sepsis due to intestinal perforation: hemodynamic findings and clinical considerations in anticoagulation therapy. AB - BACKGROUND: High levels of endotoxin have been reported as a risk factor for mortality in critical patients. Toraymyxin(r) is a column designed to remove circulating blood endotoxin by direct hemoperfusion widely used in Japan. OBJECTIVES: To evaluate the effect of direct hemoperfusion with Toraymyxin(r) (DHP-PMX) as an adjuvant treatment in patients with severe sepsis due to intestinal perforation in terms of hemodynamic function and coagulation abnormalities. METHODS: Prospective cohort study with a historical control group. Cohort 1: prospective cohort undergoing two sessions of DHP-PMX (n=14). Cohort 2: retrospective historical cohort (n=7). The anticoagulation regime was used according to the protocol of each centre and to the special conditions of each patient. RESULTS: Mean norepinephrine dose was significantly reduced (0.9 +/- 0.5 MUg/kg/min pre-first DHP-PMX vs 0.3 +/- 0.4 MUg/kg/min post-second DHP-PMX treatment, p<0.05). Central venous pressure (CVP) and stroke volume variation (SVV) remained without significant changes during the study, as well as cardiac index (CI) in patients with initial CI >= 2.5 L/min/m2. CI significantly increased in patients with initial CI<2.5 L/min/m2 (2.1 +/- 0.4 pre-first DHP-PMX vs 3.4 +/- 0.4 pre-second DHP-PMX session, p=0.01). Mean platelet count pre-first and post-second DHP-PMX decreased significantly (213.9 x 10(3) +/- 138.5 x 10(3) platelets/mm3 vs 91.0 x 10(3) +/- 53.5 x 10(3) platelets/mm3, p=0.03), without significant changes during each DHP-PMX treatment. Patients did not experience bleeding nor complications derived from DHP-PMX treatments. Survival rates at 28 and 56 days did not differ significantly between cohort 1 and 2 (21.4% vs 42.9%; 42.9% vs 57.1%; respectively). CONCLUSIONS: Performing two sessions of DHP-PMX treatment in a cohort of patients with abdominal sepsis is a feasible adjuvant therapeutic approach, safe in terms of coagulation abnormalities, can be done with different anticoagulation protocols, improves hemodynamic status and may impact on survival. PMID- 23817654 TI - [Is it possible to handle genitourinary system infections in our area with empirical treatment, following recommendations from recent guidelines?]. PMID- 23817655 TI - [Isolation of Salmonella enterica serovar Typhi in a mesenteric adenopathy]. PMID- 23817652 TI - EPICO PROJECT. Development of educational recommendations using the DELPHI technique on invasive candidiasis in non- neutropenic critically ill adult patients. AB - INTRODUCTION: Although there has been an improved management of Invasive Candidiasis in the last decade, controversial issues still remain, especially in the diagnostic and therapeutic approaches. OBJECTIVES: We sought to identify the core clinical knowledge and to achieve high level agreement recommendations required to care for critically ill adult patients with Invasive Candidiasis. METHODS: Prospective Spanish survey reaching consensus by the Delphi technique, anonymously conducted by electronic e-mail in a first term to 25 national multidisciplinary experts in invasive fungal infections from five national scientific societies, including Intensivists, Anesthesiologists, Microbiologists, Pharmacologists and Infectious Disease Specialists, responding to 47 questions prepared by a coordination group after a strict review of the literature in the last five years. The educational objectives spanned five categories, including epidemiology, diagnostic tools, prediction rules, and treatment and de-escalation approaches. The level of agreement achieved among the panel experts in each item should exceed 75% to be selected. In a second term, after extracting recommendations from the selected items, a face to face meeting was performed where more than 80 specialists in a second round were invited to validate the preselected recommendations. MEASUREMENTS AND MAIN RESULTS: In the first term, 20 recommendations were preselected (Epidemiology 4, Scores 3, Diagnostic tools 4, TREATMENT 6 and De-escalation approaches 3). After the second round, the following 12 were validated: EPIDEMIOLOGY: Think about Candidiasis in your ICU and do not forget that non-albicans species also exist. DIAGNOSTIC TOOLS: Blood cultures should be performed under suspicion every 2-3 days and, if positive, every 3 days until obtaining the first negative result. Obtain sterile fluid and tissue, if possible (direct examination of the sample is important). Use nonculture based methods of microbiological tools, whenever possible. Determination of antifungal susceptibility is mandatory. SCORES: As screening tool, use the Candida Score and determine multicolonization in high risk patients. TREATMENT: Start early. Choose Echinocandins. Withdraw the catheter. Fundoscopy is needed. DE-ESCALATION: Only applied when knowing susceptibility determinations and after 3 days of clinical stability. The higher rate of agreement was achieved in the optimization of microbiological tools and the withdrawal of the catheter, whereas the lower rate corresponded to de-escalation therapy and the use of scores. CONCLUSIONS: The management of invasive candidiasis in ICU patients requires the application of a broad range of knowledge and skills that our summarized in our recommendations. These recommendations may help to identify the potential patients, standardize their global management and improve their outcomes, based on the DELPHI methodology. PMID- 23817656 TI - [Keratitis due to Moraxella lacunata: a case report]. PMID- 23817657 TI - [Coagulase-negative Staphylococcus bacteraemia]. PMID- 23817658 TI - [Tropheryma wipplei endocarditis: a report of 3 cases]. PMID- 23817659 TI - [Urinary infection by Shigella dysenteriae]. PMID- 23817660 TI - Epidemiology, diagnosis and treatment of fungal respiratory infections in the critically ill patient. AB - OBJECTIVE: To elaborate practical recommendations based on scientific evidence, when available, or on expert opinions for the diagnosis, treatment and prevention of fungal respiratory infections in the critically ill patient, including solid organ transplant recipients. METHODS: Twelve experts from two scientific societies (The Spanish Society for Chemotherapy and The Spanish Society of Intensive Care and Coronary Units) reviewed in a meeting held in March 2012 epidemiological issues and risk factors as basis for a document about prevention, diagnosis and treatment of respiratory fungal infections caused by Candida spp., Aspergillus spp or Zygomycetes. RESULTS: Despite the frequent isolation of Candida spp. from respiratory tract samples, antifungal treatment is not recommended since pneumonia by this fungal species is exceptional in non neutropenic patients. In the case of Aspergillus spp., approximately 50% isolates from the ICU represent colonization, and the remaining 50% cases are linked to invasive pulmonary aspergillosis (IPA), an infection of high mortality. Main risk factors for invasive disease in the ICU are previous treatment with steroids and chronic obstructive pulmonary disease (COPD). Collection of BAL sample is recommended for culture and galactomannan determination. Voriconazole and liposomal amphotericin B have the indication as primary therapy while caspofungin has the indication as salvage therapy. Although there is no solid data supporting scientific evidence, the group of experts recommends combination therapy in the critically ill patient with sepsis or severe respiratory failure. Zygomycetes cause respiratory infection mainly in neutropenic patients, and liposomal amphotericin B is the elective therapy. CONCLUSIONS: Presence of fungi in respiratory samples from critically ill patients drives to different diagnostic and clinical management approaches. IPA is the most frequent infection and with high mortality. PMID- 23817661 TI - Phylogenetic perspectives on the evolution of functional hermaphroditism in teleost fishes. AB - Hermaphroditism is taxonomically widespread among teleost fishes and takes on many forms including simultaneous, protogynous, and protandrous hermaphroditism, bidirectional sex change, and androdioecy. The proximate mechanisms that influence the timing, incidence, and forms of hermaphroditism in fishes are supported by numerous theoretical and empirical studies on their mating systems and sexual patterns, but few have examined aspects of sex-allocation theory or the evolution of hermaphroditism for this group within a strict phylogenetic context. Fortunately, species-level phylogenetic reconstructions of the evolutionary history of many lineages of fishes have emerged, providing opportunities for understanding fine-scale evolutionary pathways and transformations of sex allocation. Examinations of several families of fishes with adequate data on phylogeny, patterns of sex allocation, mating systems, and with some form of hermaphroditism reveal that the evolution and expression of protogyny and other forms of sex allocation show little evidence of phylogenetic inertia within specific lineages but rather are associated with particular mating systems in accordance with prevalent theories about sex allocation. Transformations from protogyny to gonochorism in groupers (Epinephelidae), seabasses (Serranidae), and wrasses and parrotfishes (Labridae) are associated with equivalent transformations in the structure of mating groups from spawning of pairs to group spawning and related increases in sperm competition. Similarly, patterns of protandry, androdioecy, simultaneous hermaphroditism, and bidirectional sex change in other lineages (Aulopiformes, Gobiidae, and Pomacentridae) match well with particular mating systems in accordance with sex allocation theory. Unlike other animals and plants, we did not find evidence that transitions between hermaphroditism and gonochorism required functional intermediates. Two instances in which our general conclusions might not hold include the expression of protandry in the Sparidae and the distribution of simultaneous hermaphroditism. In the Sparidae, the association of hypothesized mating systems and patterns of sex allocation were not always consistent with the size-advantage model (SAM), in that certain protandric sparids show evidence of intense sperm competition that should favor the expression of gonochorism. In the other case, simultaneous hermaphroditism does not occur in some groups of monogamous fishes, which are similar in ecology to the hermaphroditic serranines, suggesting that this form of sex allocation may be more limited by phylogenetic inertia. Overall, this work strongly supports sexual lability within teleost fishes and confirms evolutionary theories of sex allocation in this group of vertebrates. PMID- 23817663 TI - Internal and Emergency Medicine (IEM) has obtained its fourth impact factor. PMID- 23817662 TI - Application of PCR methods to evaluate EGFR, KRAS and BRAF mutations in a small number of tumor cells in cytological material from lung cancer patients. AB - The epidermal growth factor receptor (EGFR) mutation status in the tyrosine kinase domain is known to be a predictor of the response to gefitinib or erlotinib in lung cancer; thus, a non-surgical procedure of tumor specimen collection is critical for mutation analysis. The aim of the present study was to analyze the EGFR, KRAS and BRAF status in limited cytological material. To the best of our knowledge, this is the first time that the quantitative scale of tumor cells and the percentage of tumor cells in cytological material were evaluated at the early stages of pathomorphological material qualification for EGFR, KRAS and BRAF mutation analysis. Our results revealed that even 100-1,000 tumor cells from fine needle aspiration (FNA) samples provided reliable results of mutation analysis when sensitive real-time polymerase chain reaction (PCR) methods were used. EGFR mutations were detected in 10% (7/71) and KRAS mutations were detected in 35% (19/54) of the lung adenocarcinoma cases. In addition, we reported the most common inhibiting mutation (p.T790M) found in coexistence with p.L858R in an FNA sample from a patient, for whom short-term improvement after erlotinib treatment was observed before further progression of the disease. Subsequently, mutual exclusion of EGFR and KRAS mutations was observed. Cytological samples with a small number of tumor cells obtained via FNA, endobronchial ultrasound (EBUS)-transbronchial needle aspiration (TBNA) or brushing are suggested to be used for diagnostic purposes after careful selection by cytopathologists and analysis using a validated, sensitive real-time PCR method. PMID- 23817664 TI - Identification of 1-chloro-2-formyl indenes and tetralenes as novel antistaphylococcal agents exhibiting sortase A inhibition. AB - Tetralene and indene compounds have shown inhibitory activity against human pathogen, Mycobacterium tuberculosis. Their potential use as antistaphylococcal agent against drug-resistant Staphylococcus aureus has not been explored so far. We determined in vitro antistaphylococcal activity and mechanism of action of these compounds as sortase A inhibitors through in silico analysis followed by biological assays. Tetralene and indene series were tested against S. aureus strains MTCC96, MRSA, and VA30. Three compounds showed significant reduction in MIC in both wild-type and drug-resistant S. aureus strains. In silico absorption, distribution, metabolism, excretion, and toxicity analysis of identified leads and cytotoxicity testing with colorimetric method using Vero and WRL-68 cell lines showed no significant cytotoxic effects. Molecular docking of these molecules with sortase A (PDB: 2KID) showed H-bond interaction with functional site residue Arg197 of sortase A. Sortase A inhibition assay was developed by expressing SrtA?N from S. aureus strain MTCC96. Tetralene and indene compounds were found to have sortase A inhibitory potential. S. aureus strain MTCC96 treated with these compounds showed surface-sorting inhibition of fibronectin binding protein and reduction in adherence to host extracellular matrix protein, fibronectin. 1-Chloro, 2-formyl, 6-methoxy, 1-tetralene (Tet-5), 1,5-dichloro, 2 formyl, 1-indene (Tet-20) and 1-chloro, 2-formyl, 5,6-methylenedioxy, and 1 indene (Tet-21) exhibited antistaphylococcal activity along with sortase A inhibition. The results also indicate the possible role of these leads in other reactions essential for cell viability. PMID- 23817666 TI - Bioactive natural products derived from the Central African flora against neglected tropical diseases and HIV. AB - This review discusses the medicinal potential of bioactive metabolites isolated from medicinal plants in Central Africa for the treatment of neglected tropical diseases and HIV. A correlation is established between the biological activities of the isolated compounds and the uses of the plants in traditional medicine. Insight is provided on how secondary metabolites from medicinal plants in Central Africa could be exploited for drug discovery. PMID- 23817665 TI - beta-Elemene enhances susceptibility to cisplatin in resistant ovarian carcinoma cells via downregulation of ERCC-1 and XIAP and inactivation of JNK. AB - beta-Elemene is a promising new plant-derived drug with broad-spectrum anticancer activity. It also increases cisplatin cytotoxicity and enhances cisplatin sensitivity in resistant human carcinoma cells. However, little is known about the mechanism of its action. To explore the potential therapeutic application of beta-elemene as a drug-resistance modulator, this study investigated the underlying mechanism of beta-elemene activity in cisplatin-resistant ovarian cancer cells. beta-Elemene enhanced cisplatin sensitivity to a much greater extent in chemoresistant A2780/CP70 and MCAS human ovarian carcinoma cells compared to the chemosensitive parental cell line A2780. The dose-modifying factors for cisplatin were between 35 and 60 for A2780/CP70 cells and between 1.6 and 2.5 for A2780 cells. In the cisplatin-resistant ovarian carcinoma cells, beta elemene abrogated cisplatin-induced expression of excision repair cross complementation group-1 (ERCC-1), a marker gene in the nucleotide excision repair pathway that repairs cisplatin-caused DNA damage. In addition, beta-elemene not only reduced the level of X-linked inhibitor of apoptosis protein (XIAP), but also downregulated cisplatin-mediated XIAP expression in chemoresistant cells. Furthermore, beta-elemene blocked the cisplatin-stimulated increase in the level of phosphorylated c-Jun NH2-terminal kinase (JNK) in these cells. These novel findings suggest that the beta-elemene enhancement of cisplatin sensitivity in human chemoresistant ovarian cancer cells is mediated at least in part through the impairment of DNA repair activity and the activation of apoptotic signaling pathways, thereby making resistant ovarian cancer cells susceptible to cisplatin induced cell death. PMID- 23817669 TI - Correlates of repeat lipid testing in patients with coronary heart disease. AB - IMPORTANCE: Understanding the frequency and correlates of redundant lipid testing could identify areas for quality improvement initiatives aimed at improving the efficiency of cholesterol care in patients with coronary heart disease (CHD). OBJECTIVE: To determine the frequency and correlates of repeat lipid testing in patients with CHD who attained low-density lipoprotein cholesterol (LDL-C) goals and received no treatment intensification. DESIGN, SETTING, AND PARTICIPANTS: We assessed the proportion of patients with LDL-C levels of less than 100 mg/dL and no intensification of lipid-lowering therapy who underwent repeat lipid testing during an 11-month follow-up period. We performed logistic regression analyses to evaluate facility, provider, and patient characteristics associated with repeat testing. In total, we analyzed 35,191 patients with CHD in a Veterans Affairs network of 7 medical centers with associated community-based outpatient clinics. MAIN OUTCOMES AND MEASURES: Frequency and correlates of repeat lipid testing in patients having CHD with LDL-C levels of less than 100 mg/dL and no further treatment intensification with lipid-lowering therapies. RESULTS: Of 27,947 patients with LDL-C levels of less than 100 mg/dL, 9200 (32.9%) had additional lipid assessments without treatment intensification during the following 11 months (12 ,686 total additional panels; mean, 1.38 additional panel per patient). Adjusting for facility-level clustering, patients with a history of diabetes mellitus (odds ratio [OR], 1.16; 95% CI, 1.10-1.22), a history of hypertension (OR, 1.21; 95% CI, 1.13-1.30), higher illness burden (OR, 1.39; 95% CI, 1.23-1.57), and more frequent primary care visits (OR, 1.32; 95% CI, 1.25 1.39) were more likely to undergo repeat testing, whereas patients receiving care at a teaching facility (OR, 0.74; 95% CI, 0.69-0.80) or from a physician provider (OR, 0.93; 95% CI, 0.88-0.98) and those with a medication possession ratio of 0.8 or higher (OR, 0.75; 95% CI, 0.71-0.80) were less likely to undergo repeat testing. Among 13,114 patients who met the optional LDL-C target level of less than 70 mg/dL, repeat lipid testing was performed in 8177 (62.4% of those with LDL-C levels of <70 mg/dL) during 11 follow-up months. CONCLUSIONS AND RELEVANCE: One-third of patients having CHD with LDL-C levels at goal underwent repeat lipid panels. Our results highlight areas for quality improvement initiatives to reduce redundant lipid testing. These efforts would be more important if the forthcoming cholesterol guidelines adopt a medication dose-based approach in place of the current treat-to-target approach. PMID- 23817670 TI - Quantitative mapping of the local and extrinsic sources of GABA and Reelin to the layer Ia neuropil in the adult rat neocortex. AB - Inputs to apical dendritic tufts have been considered to be crucial for associative learning, attention and similar ''feedback'' interactions and are located in neocortical layer Ia. Excitatory thalamic projections to apical tufts in layer Ia have been well characterized and their role in the cortical circuit has been emphasized. In addition, the neuropil and the extracellular matrix surrounding apical tufts are highly reactive to GABA and to the glycoprotein Reelin, respectively. Recently it has been shown that the GABA inhibition on apical dendrites can reduce the output of pyramidal cells in layer V, however, the origin of 89% of the symmetric synapses in layer I still remains unknown. In the present study we have systematically analyzed the origin of the GABAergic neuropil in neocortical layer Ia in a qualitative and quantitative manner, and investigated the possible extrinsic origin of the rich extracellular Reelin content of the same layer. We show that the inhibitory inputs in a given spot in layer I come from cortical projections and arise mainly from Martinotti cells located directly under that same spot. Double bouquet and bipolar cells may also project to layer Ia although to a lesser extent and the external globus pallidus and zona incerta provide the remaining inhibitory inputs. Finally, our results suggest that Martinotti cells are also the main source of Reelin in layer Ia. The present data will help in the understanding of the cortical circuit and why it changes in pathological conditions. PMID- 23817675 TI - Computational study of peptide bond formation in the gas phase through ion molecule reactions. AB - A computational study of peptide bond formation from gas-phase ion-molecule reactions has been carried out. We have considered the reaction between protonated glycine and neutral glycine, as well as the reaction between two neutral glycine molecules for comparison purposes. Two different mechanisms, concerted and stepwise, were studied. Both mechanisms show significant energy barriers for the neutral reaction. The energy requirements for peptide bond formation are considerably reduced upon protonation of one of the glycine molecules. For the reaction between neutral glycine and N-protonated glycine the lowest energy barrier is observed for the concerted mechanism. For the reaction between neutral glycine and protonated glycine at carbonyl oxygen, the preferred mechanism is the stepwise one, with a relatively small energy barrier (23 kJ mol( 1) at 0 K) and leading to the lowest-lying protonated glycylglycine isomer. In the case that the reaction could be initiated by protonated glycine at hydroxyl oxygen the process would be barrier-free and clearly exothermic. In that case peptide bond formation could take place even under interstellar conditions if glycine is present in space. PMID- 23817671 TI - Factors involved in the response to change of agitation rate during cellulase production from Penicillium decumbens JUA10-1. AB - Improvement of agitation is a commonly used approach for the optimization of fermentation processes. In this report, the response to improving agitation rate from 150 to 250 rpm on cellulase production from Penicillium decumbens JUA10-1 was investigated. It was shown that the production of all the major components of the cellulase mixture increased following improved agitation. Further investigations showed that at least three factors are involved in this improvement: the improved biomass accumulation, proportion of active/mature cellulases, and cellulase transcription level. The transcription levels of the cellulase repressing transcription factor ace1 and the cellulase activating transcription factor xlnR, however, both declined when a higher agitation was applied. These observations, along with our analysis of the carbon catabolite repressor CreA, lead to the suggestion that the molecular mechanism underlying improved cellulase transcription is the competition of two concurrent effects following improved agitation: CreA-mediated derepression induced by the downregulation of ace1, and CreA-mediated deactivation induced by the downregulation of xlnR. PMID- 23817674 TI - Rapamycin suppresses brain aging in senescence-accelerated OXYS rats. AB - Cellular and organismal aging are driven in part by the MTOR (mechanistic target of rapamycin) pathway and rapamycin extends life span inC elegans, Drosophila and mice. Herein, we investigated effects of rapamycin on brain aging in OXYS rats. Previously we found, in OXYS rats, an early development of age-associated pathological phenotypes similar to several geriatric disorders in humans, including cerebral dysfunctions. Behavioral alterations as well as learning and memory deficits develop by 3 months. Here we show that rapamycin treatment (0.1 or 0.5 mg/kg as a food mixture daily from the age of 1.5 to 3.5 months) decreased anxiety and improved locomotor and exploratory behavior in OXYS rats. In untreated OXYS rats, MRI revealed an increase of the area of hippocampus, substantial hydrocephalus and 2-fold increased area of the lateral ventricles. Rapamycin treatment prevented these abnormalities, erasing the difference between OXYS and Wister rats (used as control). All untreated OXYS rats showed signs of neurodegeneration, manifested by loci of demyelination. Rapamycin decreased the percentage of animals with demyelination and the number of loci. Levels of Tau and phospho-Tau (T181) were increased in OXYS rats (compared with Wistar). Rapamycin significantly decreased Tau and inhibited its phosphorylation in the hippocampus of OXYS and Wistar rats. Importantly, rapamycin treatment caused a compensatory increase in levels of S6 and correspondingly levels of phospo-S6 in the frontal cortex, indicating that some downstream events were compensatory preserved, explaining the lack of toxicity. We conclude that rapamycin in low chronic doses can suppress brain aging. PMID- 23817676 TI - Evaluating hyperglycaemia in the hospitalised patient: towards an improved system for classification and treatment. AB - BACKGROUND: Hyperglycaemia is common amongst hospitalised patients. Some of this is due to pre-existing diabetes (either previously diagnosed or not), but a proportion is due to stress hyperglycaemia, a transient state of high blood sugars related to the underlying illness. AIMS: We aimed to estimate the prevalence of hyperglycaemia in an Irish hospital setting, including an assessment of what contribution is made by cases of stress hyperglycaemia. METHODS: Over a 9-day period, all bedside glucometer-measured point of care blood glucoses performed in medical and surgical wards in University Hospital Galway were examined. Medical case notes and our diabetes computerised database were analysed to identify individuals with pre-existing diabetes. Glycosylated haemoglobin (HbA1c) was measured on the remainder of patients, to differentiate between pre-existing diabetes (HbA1c >= 48 mmol/mol) and stress hyperglycaemia (HbA1c < 48 mmol/mol). RESULTS: A total of 1,637 glucose readings were performed on 262 in-patients, of which 164 (63 %) were in the hyperglycaemic range. Of the 126 eligible for study inclusion, 92 (73 %) had pre-existing diabetes and 11 (9 %) had previously undiagnosed diabetes. The remaining 20 patients (16 %) had stress hyperglycaemia. CONCLUSIONS: We report a high prevalence of hyperglycaemia (including stress hyperglycaemia) in an in-patient cohort in whom testing was undertaken at the discretion of the treating physician. Our data illustrate the utility of HbA1c measurement in this setting to help differentiate between pre existing diabetes and stress hyperglycaemia. Much work remains to be done on how to best identify and treat in-patient hyperglycaemia. PMID- 23817677 TI - Impact of chronic respiratory symptoms in a rural area of sub-Saharan Africa: an in-depth qualitative study in the Masindi district of Uganda. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD), once regarded as a disease of developed countries, is now recognised as a common disease in low- and middle-income countries. No studies have been performed to examine how the community in resource poor settings of a rural area in sub-Saharan Africa lives with chronic respiratory symptoms. AIMS: To explore beliefs and attitudes concerning health (particularly respiratory illnesses), use of biomass fuels, tobacco smoking, and the use of health services. METHODS: A qualitative study was undertaken in a rural area of Masindi district in Uganda, using focus group discussions with 10-15 members of the community in 10 randomly selected villages. RESULTS: Respiratory symptoms were common among men, women, and children. In several communities respiratory symptoms were stigmatised and often associated with tuberculosis. Almost all the households used firewood for cooking and the majority cooked indoors without any ventilation. The extent of exposure to tobacco and biomass fuel smoke was largely determined by their cultural tradition and gender, tribal origin and socioeconomic factors. Many people were unaware of the damage to respiratory health caused by these risk factors, notably the disproportionate effect of biomass smoke in women and children. CONCLUSIONS: The knowledge of chronic respiratory diseases, particularly COPD, is poor in the rural community in sub-Saharan Africa. The lack of knowledge has created different beliefs and attitudes concerning respiratory symptoms. Few people are aware of the relation between smoke and respiratory health, leading to extensive exposure to mostly biomass-related smoke. PMID- 23817678 TI - Assessing the risk of attack in the management of asthma: a review and proposal for revision of the current control-centred paradigm. AB - Asthma guidelines focus on day-to-day control of symptoms. However, asthma attacks remain common. They continue to cause mortality and considerable morbidity, and are a major financial burden to the UK National Health Service (NHS) and the wider community. Asthma attacks have chronic consequences, being associated with loss of lung function and significant psychological morbidity. In this article we argue that addressing daily symptom control is only one aspect of asthma treatment, and that there should be a more explicit focus on reducing the risk of asthma attacks. Management of future risk by general practitioners is already central to other conditions such as ischaemic heart disease and chronic renal impairment. We therefore propose a revised approach that separately considers the related domains of daily control and future risk of asthma attack. We believe this approach will have advantages over the current 'stepwise' approach to asthma management. It should encourage individualised treatment, including non-pharmacological measures, and thus may lead to more efficacious and less harmful management strategies. We speculate that this type of approach has the potential to reduce morbidity and healthcare costs related to asthma attacks. PMID- 23817679 TI - miR-21 and its target gene CCL20 are both highly overexpressed in the microenvironment of colorectal tumors: significance of their regulation. AB - Recently, we reported a functional interaction between miR-21 and its identified chemokine target CCL20 in colorectal cancer (CRC) cell lines. Here, we investigated whether such functional interactions are permitted at the cellular level which would require an inverse correlation of expression and also co expression of miR-21 and CCL20 in the same cell. Expression profiling was performed using qPCR, and ELISA, in situ hybridization and immunohistochemistry were applied for the presentation of their cellular localization. We demonstrated that miR-21 as well as CCL20 were both significantly upregulated in CRC tissues; thus, showing no antidromic expression pattern. This provided an initial clue that miR-21 and CCL20 may not be expressed in the same cell. In addition, we located miR-21 expression at the cellular level predominantly in stromal cells such as tumor-associated fibroblasts and to a minor degree in immune cells such as macrophages and lymphocytes. Likewise, CCL20 expression was primarily detected in tumor-infiltrating immune cells. Thus, investigating the cellular localization of miR-21 and its target CCL20 revealed that both molecules are expressed predominantly in the microenvironment of CRC tumors. PMID- 23817680 TI - Endoscopic vein harvesting is influenced by patient-related risk factors and may be of specific benefit in female patients. AB - OBJECTIVES: The standard of care regarding endoscopic vein harvesting (EVH) is still inhomogeneous across Europe. The current study aimed at elucidating patient related factors favouring its application and procedure-related outcome in a tertiary care centre. METHODS: All patients who underwent coronary artery bypass grafting with or without concomitant valve procedures between 2008 and 2011 were included. Emergency surgery and all arterial revascularization patients were excluded. RESULTS: A total of 262 endoscopically harvested patients and 623 open vein harvested patients were included. Mortality, perfusion time and cross-clamp time were not significantly different. Peripheral artery disease predisposed open vein harvesting (odds ratio [OR] 1.9; P = 0.001); diabetes and a higher number of diseased coronary vessels favoured EVH (OR 0.6; P = 0.003 and 0.002). Further, the number of bypass grafts was significantly increased in the endoscopic group, but these patients required less periprocedural blood transfusions (1.4 +/- 1.8 vs 1.8 +/- 3.0; P = 0.035). Minor wound healing complications were more common in the open group (10.3 vs 3.8%; P = 0.001). Severe complications in the leg requiring surgical revision occured in 2.4% of open vein harvested patients compared with 1.1% for endoscopic patients (P = ns). After a multivariate regression analysis, only female gender remained as a significant risk factor for impaired wound healing (OR 2.4; P = 0.001), whereas EVH reduced the risk of wound healing complications (OR 0.4; P = 0.008). CONCLUSIONS: EVH dramatically reduced postoperative would healing complications. Women were more likely to develop mild and severe leg wound complications. Therefore, women may benefit even more from EVH. In general, the favourable outcomes of EVH should result in a more widespread use of this technology in men and women. PMID- 23817682 TI - Comparison of lung lesion biopsies between low-dose CT-guided and conventional CT guided techniques. AB - BACKGROUND: The low-dose computed tomography (CT) technique has been widely used because it decreases the potential risk of radiation exposure, as well as enabling low-dose CT-guided lung lesion biopsy. However, uncertainties remain regarding diagnostic accuracy, radiation dose, complication rate, and image quality. PURPOSE: To compare the diagnostic accuracy, radiation dose, complication rate, and image quality of lung lesion biopsy between conventional CT-guided and low-dose CT-guided techniques. MATERIAL AND METHODS: A total of 90 patients were prospectively enrolled and randomized into two groups (group A: 120 kv; 200 mA; thickness, 2.0 mm; pitch, 16 mm/rot; n = 44; group B: 120 kv;10 mA; thickness, 2.0 mm; pitch, 23 mm/rot; n = 46). Sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV), radiation dose, image quality, and complication rate were compared. All variables between the two groups were analyzed using chi-square and Student's t tests. A P value of < 0.05 was considered statistically significant. RESULTS: The sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) for diagnosing lung lesions were 96.88%, 100%, 97.5%, 100%, and 88.89% in group A, respectively. In group B, the values were 96.67%, 100%, 97.5%, 100%, and 90.91%, respectively (P > 0.05). The mean weighted CT dose index (CTDIw) and dose length product (DLP) were 29.29 +/- 3.93 mGy and 211.74 +/- 37.89 mGy*cm in group A and 1.55 +/- 0.15 mGy and 10.98 +/- 1.56 mGy*cm in group B (P < 0.001). Image quality satisfied the need for a coaxial biopsy. Complications in group A and group B were observed in 27.28% and 23.91% of the patients, respectively (P > 0.05). CONCLUSION: Compared to conventional CT-guided biopsies, lung lesion biopsies guided by the low-dose CT biopsy protocol showed dramatically lower CTDIw and DLP levels. In contrast, the diagnostic yield of the procedures did not differ significantly, which is a recommended technique in certain populations. PMID- 23817683 TI - An assessment of the dynamic of religious ritualism in sporting environments. AB - The main focus of this study is the analysis of the link between sport, leisure and the behavior, and phenomenon of religion. From the qualitative point of view of social anthropology, fieldwork has been carried out with different informers from different sporting environments. Rather than directly show the fieldwork itself, we have decided to present an interpretation of it through an analysis of the environments, behaviors, attitudes, the discourse of leisure and sport and its relationship with market forces, advertising and the media. In this regard, we point out a reality which for some people is their conscience or reason for being, opening new directions of study and viewpoints in this area of sporting and health studies. PMID- 23817684 TI - Comparison of integrated whole-body [11C]choline PET/MR with PET/CT in patients with prostate cancer. AB - PURPOSE: To evaluate the performance of conventional [(11)C]choline PET/CT in comparison to that of simultaneous whole-body PET/MR. METHODS: The study population comprised 32 patients with prostate cancer who underwent a single injection dual-imaging protocol with PET/CT and subsequent PET/MR. PET/CT scans were performed applying standard clinical protocols (5 min after injection of 793 +/- 69 MBq [(11)C]choline, 3 min per bed position, intravenous contrast agent). Subsequently (52 +/- 15 min after injection) PET/MR was performed (4 min per bed position). PET images were reconstructed iteratively (OSEM 3D), scatter and attenuation correction of emission data and regional allocation of [(11)C]choline foci were performed using CT data for PET/CT and segmented Dixon MR, T1 and T2 sequences for PET/MR. Image quality of the respective PET scans and PET alignment with the respective morphological imaging modality were compared using a four point scale (0-3). Furthermore, number, location and conspicuity of the detected lesions were evaluated. SUVs for suspicious lesions, lung, liver, spleen, vertebral bone and muscle were compared. RESULTS: Overall 80 lesions were scored visually in 29 of the 32 patients. There was no significant difference between the two PET scans concerning number or conspicuity of the detected lesions (p not significant). PET/MR with T1 and T2 sequences performed better than PET/CT in anatomical allocation of lesions (2.87 +/- 0.3 vs. 2.72 +/- 0.5; p = 0.005). The quality of PET/CT images (2.97 +/- 0.2) was better than that of the respective PET scan of the PET/MR (2.69 +/- 0.5; p = 0.007). Overall the maximum and mean lesional SUVs exhibited high correlations between PET/CT and PET/MR (rho = 0.87 and rho = 0.86, respectively; both p < 0.001). CONCLUSION: Despite a substantially later imaging time-point, the performance of simultaneous PET/MR was comparable to that of PET/CT in detecting lesions with increased [(11)C]choline uptake in patients with prostate cancer. Anatomical allocation of lesions was better with simultaneous PET/MR than with PET/CT, especially in the bone and pelvis. These promising findings suggest that [(11)C]choline PET/MR might have a diagnostic benefit compared to PET/CT in patients with prostate cancer, and now needs to be further evaluated in prospective trials. PMID- 23817685 TI - Effect of emaciation and obesity on small-animal internal radiation dosimetry for positron-emitting radionuclides. AB - PURPOSE: Rats are widely used in biomedical research involving molecular imaging and therefore the radiation dose to animals has become a concern. The weight of laboratory animals might change through emaciation or obesity as a result of their use in various research experiments including those investigating different diet types. In this work, we evaluated the effects of changes in body weight induced by emaciation and obesity on the internal radiation dose from common positron-emitting radionuclides. METHODS: A systematic literature review was performed to determine normal anatomical parameters for adult rats and evaluate how organs change with variations in total body weight. The ROBY rat anatomical model was then modified to produce a normal adult rat, and mildly, moderately and severely emaciated and obese rats. Monte Carlo simulations were performed using MCNPX to estimate absorbed fractions, specific absorbed fractions (SAFs) and S values for these models using different positron-emitting radionuclides. The results obtained for the different models were compared to corresponding estimates from the normal rat model. RESULTS: The SAFs and S-values for most source-target pairs between the various anatomical models were not significantly different, except where the intestine and the total body were considered as source regions. For the intestine, irradiating other organs in the obese model, the SAFs in organs in the anterior region of the splanchnocoele (e.g. kidney, liver and stomach) increased slightly, whereas the SAFs in organs in the posterior region of the splanchnocoele (e.g. bladder and testes) decreased owing to the increase in the distance separating the intestine and posterior abdominal organs because of the rat epididymal fat pad. For the total body, irradiating other organs, the SAFs and S-values were inversely related to body weight. CONCLUSION: The effect of obesity on internal radiation dose is insignificant in most conditions for common positron-emitting radionuclides. Emaciation increases the cross-absorbed dose to organs from surrounding tissues, which might be a notable issue in laboratory animal internal dosimetry. PMID- 23817686 TI - PET/MRI with a 68Ga-PSMA ligand for the detection of prostate cancer. PMID- 23817688 TI - Defining risks of taxane neuropathy: insights from randomized clinical trials. AB - Sensory neuropathy is a common but difficult to quantify complication encountered during treatment of various cancers with taxane-containing regimens. Docetaxel, paclitaxel, and its nanoparticle albumin-bound formulation have been extensively studied in randomized clinical trials comparing various dose and schedules for the treatment of breast, lung, and ovarian cancers. This review highlights differences in extent of severe neuropathies encountered in such randomized trials and seeks to draw conclusions in terms of known pharmacologic factors that may lead to neuropathy. This basic knowledge provides an essential background for exploring pharmacogenomic differences among patients in relation to their susceptibility of developing severe manifestations. In addition, the differences highlighted may lead to greater insight into drug and basic host factors (such as age, sex, and ethnicity) contributing to axonal injury from taxanes. PMID- 23817689 TI - Genomic heterogeneity of translocation renal cell carcinoma. AB - PURPOSE: Translocation renal cell carcinoma (tRCC) is a rare subtype of kidney cancer involving the TFEB/TFE3 genes. We aimed to investigate the genomic and epigenetic features of this entity. EXPERIMENTAL DESIGN: Cytogenomic analysis was conducted with 250K single-nucleotide polymorphism microarrays on 16 tumor specimens and four cell lines. LINE-1 methylation, a surrogate marker of DNA methylation, was conducted on 27 cases using pyrosequencing. RESULTS: tRCC showed cytogenomic heterogeneity, with 31.2% and 18.7% of cases presenting similarities with clear-cell and papillary RCC profiles, respectively. The most common alteration was a 17q gain in seven tumors (44%), followed by a 9p loss in six cases (37%). Less frequent were losses of 3p and 17p in five cases (31%) each. Patients with 17q gain were older (P=0.0006), displayed more genetic alterations (P<0.003), and had a worse outcome (P=0.002) than patients without it. Analysis comparing gene-expression profiling of a subset of tumors bearing 17q gain and those without suggest large-scale dosage effects and TP53 haploinsufficiency without any somatic TP53 mutation identified. Cell line-based cytogenetic studies revealed that 17q gain can be related to isochromosome 17 and/or to multiple translocations occurring around 17q breakpoints. Finally, LINE-1 methylation was lower in tRCC tumors from adults compared with tumors from young patients (71.1% vs. 76.7%; P=0.02). CONCLUSIONS: Our results reveal genomic heterogeneity of tRCC with similarities to other renal tumor subtypes and raise important questions about the role of TFEB/TFE3 translocations and other chromosomal imbalances in tRCC biology. PMID- 23817692 TI - Substitution of anti-androgens and tegafur-uracil combination therapy for castration-resistant prostate cancer: results of a multi-center randomized phase II study. AB - We conducted this study to determine whether substitution with anti-androgen (SOA) and tegafur-uracil (a pro-drug of 5-FU) combination therapy is more effective than SOA alone after relapse from initial hormonal therapy. Patients who were histologically confirmed and relapsed after initial hormonal therapy were included. All patients were randomly allocated into two groups: SOA alone (group A) or SOA combined with tegafur-uracil (group B). The mRNA expression of four enzymes, including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phospho-ribosyltransferase (OPRT) and thymidine phosphorylase (TP), in prostate cancer cells was analyzed by quantitative reverse transcription polymerase chain reaction. Fifty-two patients were enrolled in this study. The median age was 77 (range: 47-92) years. The PSA response rate in group B (61.5%) tended to be higher compared to that in group A (34.6%) (p=0.095). Group B (median: 15.9 months) had a significantly longer time to PSA progression (TTP) compared to group A (6.4 months) (p=0.014). In patients with a lower TS expression or a higher OPRT expression, group B demonstrated a higher PSA response rate compared to group A (p=0.019 and p=0.041, respectively). In addition, in the patients with a lower TS expression, group B demonstrated a significantly longer TTP compared to group A (p=0.018). There were no severe adverse events in either treatment group. After relapse from initial hormonal therapy, SOA combined with tegafur-uracil is effective and well tolerated. The TS mRNA expression level may be a predictive factor for this combination therapy. PMID- 23817691 TI - GSTT1 and GSTM1 polymorphisms and prostate cancer risk in Asians: a systematic review and meta-analysis. AB - Glutathione S-transferases (GSTs) enzymes are involved in conjugation of electrophilic compounds to glutathione, and glutathione S-transferase T 1 (GSTT1) and glutathione S-transferase M 1 (GSTM1) polymorphisms have been implicated as risk factors for prostate cancer. We conducted a systematic review and meta analysis to define the effect of GSTM1 and GSTT1 null genotypes on prostate cancer risk in Asians. We searched the PubMed and Wanfang Medical databases to identify published case-control studies investigating the associations of GSTM1 and GSTT1 null genotypes with risk of prostate cancer in Asians. Heterogeneity was assessed using Cochran's Q statistic and odds ratios (OR) with corresponding 95 % confidence intervals (95 % CI) from individual studies were pooled using fixed or random effects models according to the heterogeneity. There were 18 studies (2,046 cases, 2,876 controls) on GSTM1 polymorphism, 15 studies (1,677 cases, 2,431 controls) on GSTT1 polymorphism, and 6 studies (675 cases, 853 controls) on GSTM1/GSTT1 interaction analysis. Overall, GSTM1 null genotype was significantly associated with increased risk of prostate cancer in Asians (random effects OR 1.80, 95 % CI 1.48-2.18, P < 0.001), and GSTT1 null genotype was also significantly associated with increased risk of prostate cancer in Asians (random effects OR 1.40, 95 % CI 1.10-1.80, P < 0.001). In addition, the GSTM1/GSTT dual null genotype was associated with higher risk of prostate cancer in Asians (random effects OR 2.14, 95 % CI 1.59-2.89, P = 0.007). In conclusion, GSTM1 and GSTT1 null genotypes are associated with increased risk of prostate cancer in Asians, and GSTM1 and GSTT1 null genotypes are risk factors for the development of prostate cancer. PMID- 23817693 TI - What makes wild chimpanzees wake up at night? AB - I examined the possible cause of night awakening among wild chimpanzees (Pan troglodytes) in Mahale Mountains National Park, Tanzania. Chimpanzee vocalizations and activity-related sounds (CVSs) were used to indicate awakening because I was unable to visually observe them. Over a 5-night observation period, CVSs (n = 128) were heard every night, and most (n = 91) were observed within 5 min of previous CVSs. Chimpanzees use CVSs as social communication to maintain spatial contact with other chimpanzees who occasionally travel at night. The first sound in a sequence of CVSs (CVS bout) was heard immediately following the vocalization or sound of another animal (n = 11), defecation or urination by a chimpanzee (n = 7), or unknown (n = 19). CVS bouts were longer when preceded by defecation or urination than when preceded by the vocalization or sound of other animals or an unknown factor. This suggests that the degree of wakefulness varies according to the possible cause of the disturbance. CVSs at night may be provoked by various factors, and awakening during the night is probably common among diurnal primates. PMID- 23817694 TI - A patient-derived xenograft mouse model generated from primary cultured cells recapitulates patient tumors phenotypically and genetically. AB - BACKGROUND: Preclinical trials of cancer therapeutics require both in vitro and in vivo evaluations. Recently, a patient-derived xenograft model in immunodeficient mice has been reported as a valuable in vivo evaluation system. In our current study, we aimed to establish a more efficient and accurate system for preclinical trials by generating primary cancer cells from patients and performing xenograft transfers of these cells into mice. METHODS: Human lung cancer specimens (n = 4) obtained from chemo-naive patients were cultured in bronchiolar epithelial basal medium supplemented with growth factors, followed by inoculation into non-obese diabetic/severe combined immunodeficient mice. The generated tumors in the mice were validated phenotypically and genetically using the original specimen and primary cancer cells. RESULTS: Immunohistochemical analysis of marker proteins, including cytokeratin 7, cytokeratin 20, epidermal growth factor receptor, thyroid transcription factor-1, CD56, chromogranin, and synaptophysin, demonstrated that the xenograft tumors were originated from the patient tumors. Moreover, mutation profiling using the OncoMap System, which analyzes mutations at 440 sites in 41 tumor-related genes, showed the same patterns in both the patient and xenograft tumors. CONCLUSIONS: These results indicate that our animal system is suitable for the amplification of patient tumors and will therefore be beneficial for both in vivo and in vitro assessments and preclinical trials of chemotherapeutics. This has the potential to provide a very effective tool for future personalized therapy and for conducting translational lung cancer research. PMID- 23817695 TI - Complementary medicine in guidelines of the German Guideline Program in Oncology: comparison of the evidence base between complementary and conventional therapy. huebner@med.uni-frankfurt.de. AB - INTRODUCTION: The German Guideline Program in Oncology (GGPO) comprises guidelines aiming at epidemiology, prevention, diagnosis, treatment and aftercare of different types of cancer. As many patients in Germany use complementary and alternative medicine (CAM), the aim of our study was to assess the information on CAM presented in these guidelines compared to conventional, supportive and psychosocial therapy. METHODS: We assessed all recommendations and statements from guidelines published from 2010 to 2012 from the program according to level of evidence (LoE) as given in the guideline. We differentiated between conventional cancer treatment, conventional supportive treatment, psychosocial interventions and complementary treatment. RESULTS: A total of 9 guidelines (ovarian, colorectal, pancreatic, gastric, breast, prostate, oral cancer, melanoma and Hodgkin lymphoma) were included in our analysis. The total number of statements is highly diverse, ranging from 35 to 150. Only few statements and recommendations are given regarding supportive, psychosocial or complementary therapy. Regarding conventional treatments, only two guidelines (ovarian and oral cancer) have more than 50 % statements and recommendations on level 1. Considering supportive treatments, the LoE is lower, except the guideline on pancreatic cancer (40 % level 1). In breast cancer, all statements are based on expert consensus. Four guidelines do not include any statement at all. All guidelines beside that on Hodgkin lymphoma include at least one statement or recommendation on psychosocial therapy. Most recommendations are GCP.CAM is discussed in 8 guidelines; LoE is low with GCP statements dominating. DISCUSSION: There may be different reasons for the low number of statements and recommendations on supportive, psychosocial and CAM therapies. Often, these topics are considered less important, and evidence is assumed as being low. In the GGPO, guidelines focusing on psychosocial and supportive therapy are under development. Thus, cancer-specific guidelines will be able to refer to these guidelines and only include recommendations on psychosocial care and supportive therapy which are specific for the type of cancer. A national guideline on CAM would close the gap of information for physicians and patients. In case of missing or low evidence, a transparent description of this uncertainty would be valuable information to professionals and patients. PMID- 23817696 TI - Estrogen receptor beta 2 is associated with poor prognosis in estrogen receptor alpha-negative breast carcinoma. AB - PURPOSE: Our aim was to examine the prognostic significance of ERbeta1 and ERbeta2 expression in ERalpha-negative breast carcinomas. MATERIALS AND METHODS: We evaluated nuclear and cytoplasmic expression of ERbeta1 and ERbeta2 by immunohistochemistry in a group of 95 patients with long follow-up. ERbeta1 and ERbeta2 status was correlated with clinicopathological parameters and disease outcome. Univariate and multivariate analyses of ERbeta1 and ERbeta2 as independent markers of disease-free survival (DFS) were carried out using the Cox proportional hazards model. RESULTS: Nuclear ERbeta1 (nERbeta1) and nERbeta2 status was positively correlated (p = 0.01). nERbeta1 positivity was associated with low histological grade (p = 0.01) in all patients and in the nERbeta2 positive subgroup (p = 0.03) but not in the nERbeta2-negative (p = 0.27). nERbeta2 positivity was associated with lymph node involvement and tumor relapse in all cases (p < 0.00 and p < 0.00, respectively) and in the nERbeta1-negative subgroup (p < 0.00 and p < 0.00, respectively) but not in the nERbeta1-positive (p = 0.09 and p = 0.20, respectively). nERbeta2 positivity was associated with poor DFS in all patients (log-rank p <0.00), in the post-menopausal patient subgroup (log-rank p = 0.02) and in the HER2-negative (triple-negative) subgroup (log-rank p = 0.04). Cox multivariate analysis including ERbeta1, ERbeta2 and established clinicopathological variables highlighted ERbeta2 as an independent marker of early disease recurrence (hazard ratio 4.87; 95 % confidence interval 1.07-22.3; p = 0.04). CONCLUSION: High nERbeta2 is an independent marker of early relapse in ERalpha-negative breast carcinoma, and in particular, in the nERbeta1 negative, the post-menopausal patient and the triple-negative subgroups. These findings suggest that inhibition of expression and/or function of ERbeta2 could improve disease outcome. PMID- 23817697 TI - Differential expression of microRNAs in plasma of patients with laryngeal squamous cell carcinoma: potential early-detection markers for laryngeal squamous cell carcinoma. AB - PURPOSE: Altered microRNA (miRNA) expression has been found in many cancers, including lung, breast, prostate, bladder and colorectal cancer. Many recent studies have demonstrated that aberrant plasma miRNAs were also found in various types of cancers. However, the alteration in plasma miRNA expressions in laryngeal squamous cell carcinoma (LSCC) remains unclear. The present study aimed to investigate the alterations in plasma miRNAs in LSCC. METHODS: In the present study, the expression profiles of 738 miRNAs in plasma from 20 patients and 44 healthy subjects were evaluated using high-throughput real-time quantitative polymerase chain reaction. RESULTS: Our results demonstrated that expression levels of 17 miRNAs were significantly upregulated in patients with LSCCs when compared to control group (p < 0.05). Expression levels of nine miRNAs were found significantly downregulated in LSCC patients (p < 0.05). In addition, 17 miRNAs were expressed only in LSCC group, and five of these miRNAs (miR-331-3p, 603, 1303, 660-5p and 212-3p) are LSCC specific and never seen before in plasma of any human subject. CONCLUSION: In conclusion, our study suggests that detecting these LSCC-specific miRNAs in plasma might serve as novel noninvasive biomarkers for LSCC. PMID- 23817698 TI - MicroRNAs targeting EGFR signalling pathway in colorectal cancer. AB - MicroRNAs (miRNAs) are short, 18-25-nucleotide long, non-coding single-stranded RNAs, which are capable to regulate gene expression on post-transcriptional level through binding to their target protein-encoding mRNAs. miRNAs regulate individual components of multiple oncogenic pathways. One of them is epidermal growth factor receptor (EGFR) signalling pathway that regulates cell proliferation, differentiation, migration, angiogenesis and apoptosis. All these processes are deregulated in colorectal cancer (CRC). Moreover, EGFR has been validated as the therapeutic target in CRC, and monoclonal antibodies cetuximab and panitumumab are used in the therapy of patients with metastatic CRC. Because of the extensive involvement of miRNAs in the regulation of EGFR signalling, it seems they could also serve as promising predictive biomarkers to anti-EGFR therapy. In this review, we summarize current knowledge about miRNAs targeting EGFR signalling pathway, their functioning in CRC pathogenesis and potential usage as biomarkers. PMID- 23817700 TI - Prevalence of advanced colorectal neoplasia in white and black patients undergoing screening colonoscopy in a safety-net hospital. AB - Chinese translation BACKGROUND: Black persons are more likely than white persons to be diagnosed with colorectal cancer and to die from it. The extent to which genetic or biological factors versus disparities in screening rates explain this variance remains controversial. OBJECTIVE: To define the prevalence and location of presymptomatic advanced colorectal neoplasia (ACN) among white and black persons undergoing screening colonoscopy, controlling for other epidemiologic risk factors. DESIGN: Cross-sectional survey between 22 March 2005 and 31 January 2012. SETTING: Urban, open-access, academic, safety-net hospital in Massachusetts. PARTICIPANTS: Asymptomatic, average-risk white (n = 1172) and black (n = 1681) persons aged 50 to 79 years undergoing screening colonoscopy. MEASUREMENTS: Adjusted prevalence and location of ACN, defined as a tubular adenoma 10 mm or more in size, any adenoma with villous features or high-grade dysplasia, any dysplastic serrated lesion, or invasive cancer. RESULTS: The prevalence of ACN was higher among white patients than black patients (6.8% vs. 5.0%; P = 0.039) but varied by sex (white vs. black men, 9.3% vs. 5.7%; white vs. black women, 3.5% vs. 4.3%; interaction P = 0.034). After controlling for many risk factors, black men were 41% less likely than white men (adjusted odds ratio [AOR], 0.59 [95% CI, 0.39 to 0.89]) to have ACN. No statistically significant difference was seen for women (AOR, 1.32 [CI, 0.73 to 2.40]). Black patients with ACN had a higher percentage of proximal disease (52% vs. 39%) after adjustment for age and sex (P = 0.055). LIMITATION: Single-institution study with inadequate statistical power for subgroup analyses and recall bias. CONCLUSION: Black men are less likely than white men to have ACN at screening colonoscopy in a safety net health care setting. Disparities in access to screening and differential exposure to modifiable risk factors rather than genetic or biological factors may be largely responsible for the higher incidence of CRC among black men. Genetic or biological factors may explain the predilection for proximal disease. PMID- 23817699 TI - Salicylate (salsalate) in patients with type 2 diabetes: a randomized trial. AB - BACKGROUND: Short-duration studies show that salsalate improves glycemia in type 2 diabetes mellitus (T2DM). OBJECTIVE: To assess 1-year efficacy and safety of salsalate in T2DM. DESIGN: Placebo-controlled, parallel trial; computerized randomization and centralized allocation, with patients, providers, and researchers blinded to assignment. (ClinicalTrials.gov: NCT00799643). SETTING: 3 private practices and 18 academic centers in the United States. PATIENTS: Persons aged 18 to 75 years with fasting glucose levels of 12.5 mmol/L or less (<=225 mg/dL) and hemoglobin A1c (HbA1c) levels of 7.0% to 9.5% who were treated for diabetes. INTERVENTION: 286 participants were randomly assigned (between January 2009 and July 2011) to 48 weeks of placebo (n = 140) or salsalate, 3.5 g/d (n = 146), in addition to current therapies, and 283 participants were analyzed (placebo, n = 137; salsalate, n = 146). MEASUREMENTS: Change in hemoglobin A1c level (primary outcome) and safety and efficacy measures. RESULTS: The mean HbA1c level over 48 weeks was 0.37% lower in the salsalate group than in the placebo group (95% CI, -0.53% to -0.21%; P < 0.001). Glycemia improved despite more reductions in concomitant diabetes medications in salsalate recipients than in placebo recipients. Lower circulating leukocyte, neutrophil, and lymphocyte counts show the anti-inflammatory effects of salsalate. Adiponectin and hematocrit levels increased more and fasting glucose, uric acid, and triglyceride levels decreased with salsalate, but weight and low-density lipoprotein cholesterol levels also increased. Urinary albumin levels increased but reversed on discontinuation; estimated glomerular filtration rates were unchanged. LIMITATION: Trial duration and number of patients studied were insufficient to determine long-term risk-benefit of salsalate in T2DM. CONCLUSION: Salsalate improves glycemia in patients with T2DM and decreases inflammatory mediators. Continued evaluation of mixed cardiorenal signals is warranted. PMID- 23817702 TI - Pressure ulcer risk assessment and prevention: a systematic comparative effectiveness review. AB - BACKGROUND: Pressure ulcers are associated with substantial health burdens but may be preventable. PURPOSE: To review the clinical utility of pressure ulcer risk assessment instruments and the comparative effectiveness of preventive interventions in persons at higher risk. DATA SOURCES: MEDLINE (1946 through November 2012), CINAHL, the Cochrane Library, grant databases, clinical trial registries, and reference lists. STUDY SELECTION: Randomized trials and observational studies on effects of using risk assessment on clinical outcomes and randomized trials of preventive interventions on clinical outcomes. DATA EXTRACTION: Multiple investigators abstracted and checked study details and quality using predefined criteria. DATA SYNTHESIS: One good-quality trial found no evidence that use of a pressure ulcer risk assessment instrument, with or without a protocolized intervention strategy based on assessed risk, reduces risk for incident pressure ulcers compared with less standardized risk assessment based on nurses' clinical judgment. In higher-risk populations, 1 good-quality and 4 fair-quality randomized trials found that more advanced static support surfaces were associated with lower risk for pressure ulcers compared with standard mattresses (relative risk range, 0.20 to 0.60). Evidence on the effectiveness of low-air-loss and alternating-air mattresses was limited, with some trials showing no clear differences from advanced static support surfaces. Evidence on the effectiveness of nutritional supplementation, repositioning, and skin care interventions versus usual care was limited and had methodological shortcomings, precluding strong conclusions. LIMITATION: Only English-language articles were included, publication bias could not be formally assessed, and most studies had methodological shortcomings. CONCLUSION: More advanced static support surfaces are more effective than standard mattresses for preventing ulcers in higher-risk populations. The effectiveness of formal risk assessment instruments and associated intervention protocols compared with less standardized assessment methods and the effectiveness of other preventive interventions compared with usual care have not been clearly established. PMID- 23817701 TI - Borrelia miyamotoi infection presenting as human granulocytic anaplasmosis: a case report. AB - BACKGROUND: The diverse tickborne infections of the northeastern United States can present as undifferentiated flu-like illnesses. In areas endemic for Lyme and other tickborne diseases, patients presenting with acute febrile illness with myalgia, headache, neutropenia, thrombocytopenia, and elevated hepatic aminotransferase levels are presumptively diagnosed as having human granulocytic anaplasmosis (HGA). OBJECTIVE: To assign a cause for illness experienced by 2 case patients who were initially diagnosed with HGA but did not rapidly defervesce with doxycycline treatment and had no laboratory evidence of Anaplasma phagocytophilum infection. DESIGN: Case report. SETTING: 2 primary care medical centers in Massachusetts and New Jersey. PATIENTS: 2 case patients acutely presenting with fever. MEASUREMENTS: Identification of the causative agent by polymerase chain reaction and DNA sequencing. RESULTS: Molecular diagnostic assays detected Borrelia miyamotoi in the peripheral blood of both patients. There was no evidence of infection with other tickborne pathogens commonly diagnosed in the referral areas. LIMITATION: One of the case patients may have had concurrent Lyme disease. CONCLUSION: The presence of B. miyamotoi DNA in the peripheral blood and the patients' eventual therapeutic response to doxycycline are consistent with the hypothesis that their illness was due to this newly recognized spirochete. Samples from tick-exposed patients acutely presenting with signs of HGA but who have a delayed response to doxycycline therapy or negative confirmatory test results for HGA should be analyzed carefully for evidence of B. miyamotoi infection. PMID- 23817704 TI - Borrelia miyamotoi: a lesson in disease discovery. PMID- 23817705 TI - Trust but verify: trial registration and determining fidelity to the protocol. PMID- 23817703 TI - Pressure ulcer treatment strategies: a systematic comparative effectiveness review. AB - BACKGROUND: Pressure ulcers affect as many as 3 million Americans and are major sources of morbidity, mortality, and health care costs. PURPOSE: To summarize evidence comparing the effectiveness and safety of treatment strategies for adults with pressure ulcers. DATA SOURCES: MEDLINE, EMBASE, CINAHL, Evidence Based Medicine Reviews, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, and Health Technology Assessment Database for English- or foreign-language studies; reference lists; gray literature; and individual product packets from manufacturers (January 1985 to October 2012). STUDY SELECTION: Randomized trials and comparative observational studies of treatments for pressure ulcers in adults and noncomparative intervention series (n > 50) for surgical interventions and evaluation of harms. DATA EXTRACTION: Data were extracted and evaluated for accuracy of the extraction, quality of included studies, and strength of evidence. DATA SYNTHESIS: 174 studies met inclusion criteria and 92 evaluated complete wound healing. In comparison with standard care, placebo, or sham interventions, moderate-strength evidence showed that air-fluidized beds (5 studies [n = 908]; high consistency), protein-containing nutritional supplements (12 studies [n = 562]; high consistency), radiant heat dressings (4 studies [n = 160]; moderate consistency), and electrical stimulation (9 studies [n = 397]; moderate consistency) improved healing of pressure ulcers. Low-strength evidence showed that alternating-pressure surfaces, hydrocolloid dressings, platelet derived growth factor, and light therapy improved healing of pressure ulcers. The evidence about harms was limited. LIMITATION: Applicability of results is limited by study quality, heterogeneity in methods and outcomes, and inadequate duration to assess complete wound healing. CONCLUSION: Moderate-strength evidence shows that healing of pressure ulcers in adults is improved with the use of air fluidized beds, protein supplementation, radiant heat dressings, and electrical stimulation. PMID- 23817706 TI - Once upon a July (saved). PMID- 23817708 TI - Legacy. PMID- 23817709 TI - Treatment of moderate to severe hidradenitis suppurativa. PMID- 23817710 TI - Treatment of moderate to severe hidradenitis suppurativa. PMID- 23817711 TI - Accuracy of electronically reported "meaningful use" clinical quality measures. PMID- 23817712 TI - Accuracy of electronically reported "meaningful use" clinical quality measures. PMID- 23817713 TI - Discontinuation of statins in routine care settings. PMID- 23817714 TI - Discontinuation of statins in routine care settings. PMID- 23817715 TI - Discontinuation of statins in routine care settings. PMID- 23817716 TI - Discontinuation of statins in routine care settings. PMID- 23817717 TI - Successful treatment of the postpartum atypical hemolytic uremic syndrome with eculizumab. PMID- 23817718 TI - Summaries for patients. Salsalate for type 2 diabetes mellitus. PMID- 23817719 TI - Summaries for patients. Screening for HIV: U.S. Preventive Services Task Force Recommendation Statement. PMID- 23817720 TI - In the clinic. Care of returning military personnel. PMID- 23817721 TI - Therapeutic vaccination against autologous cancer stem cells with mRNA transfected dendritic cells in patients with glioblastoma. AB - BACKGROUND: The growth and recurrence of several cancers appear to be driven by a population of cancer stem cells (CSCs). Glioblastoma, the most common primary brain tumor, is invariably fatal, with a median survival of approximately 1 year. Although experimental data have suggested the importance of CSCs, few data exist regarding the potential relevance and importance of these cells in a clinical setting. METHODS: We here present the first seven patients treated with a dendritic cell (DC)-based vaccine targeting CSCs in a solid tumor. Brain tumor biopsies were dissociated into single-cell suspensions, and autologous CSCs were expanded in vitro as tumorspheres. From these, CSC-mRNA was amplified and transfected into monocyte-derived autologous DCs. The DCs were aliquoted to 9-18 vaccines containing 10(7) cells each. These vaccines were injected intradermally at specified intervals after the patients had received a standard 6-week course of post-operative radio-chemotherapy. The study was registered with the ClinicalTrials.gov identifier NCT00846456. RESULTS: Autologous CSC cultures were established from ten out of eleven tumors. High-quality RNA was isolated, and mRNA was amplified in all cases. Seven patients were able to be weaned from corticosteroids to receive DC immunotherapy. An immune response induced by vaccination was identified in all seven patients. No patients developed adverse autoimmune events or other side effects. Compared to matched controls, progression-free survival was 2.9 times longer in vaccinated patients (median 694 vs. 236 days, p = 0.0018, log-rank test). CONCLUSION: These findings suggest that vaccination against glioblastoma stem cells is safe, well-tolerated, and may prolong progression-free survival. PMID- 23817722 TI - Identification of HLA ligands and T-cell epitopes for immunotherapy of lung cancer. AB - INTRODUCTION: Lung cancer is the most common cancer worldwide. Every year, as many people die of lung cancer as of breast, colon and rectum cancers combined. Because most patients are being diagnosed in advanced, not resectable stages and therefore have a poor prognosis, there is an urgent need for alternative therapies. Since it has been demonstrated that a high number of tumor- and stromal-infiltrating cytotoxic T cells (CTLs) is associated with an increased disease-specific survival in lung cancer patients, it can be assumed that immunotherapy, e.g. peptide vaccines that are able to induce a CTL response against the tumor, might be a promising approach. METHODS: We analyzed surgically resected lung cancer tissues with respect to HLA class I- and II-presented peptides and gene expression profiles, aiming at the identification of (novel) tumor antigens. In addition, we tested the ability of HLA ligands derived from such antigens to generate a CTL response in healthy donors. RESULTS: Among 170 HLA ligands characterized, we were able to identify several potential targets for specific CTL recognition and to generate CD8+ T cells which were specific for peptides derived from cyclin D1 or protein-kinase, DNA-activated, catalytic polypeptide and lysed tumor cells loaded with peptide. CONCLUSIONS: This is the first molecular analysis of HLA class I and II ligands ex vivo from human lung cancer tissues which reveals known and novel tumor antigens able to elicit a CTL response. PMID- 23817723 TI - Large excited state two photon absorptions in the near infrared region of surprisingly stable radical cations of (ferrocenyl)indenes. AB - Multiphoton absorptions are important non-linear optical processes which allow us to explore excited states with low energy photons giving rise to new possibilities for photoinduced processes. Among these processes, multiphoton absorptions from excited states are particularly interesting because of the large susceptibilities characteristic of excited states. Here we explore the nonlinear transmission measurements recorded with 9 ns laser pulses at 1064 nm of the radical cations of (2-ferrocenyl)indene and of (2-ferrocenyl)-hexamethylindene, two interesting very stable molecules. The non-linear transmission data can be interpreted with a multiphoton sequence of three photon absorptions, the first being a one photon absorption related to the intramolecular charge transfer and the second a two photon absorption from the excited state created with the first process. The two photon absorption cross section is found to be several orders of magnitude larger than those usually found for two photon absorbing systems excited from the ground state. PMID- 23817724 TI - Heart failure readmissions. AB - OPINION STATEMENT: Heart failure readmissions (HFR) represent a personal burden for patients and a large financial burden for the healthcare system. As such, strategies to decrease HFR are avidly sought and studied. There are many reasons for HFR that challenge programs aimed to reduce the frequency of HFR. Large pharmacological and device trials often incorporate hospital admission as an endpoint, and many programs have been developed in varied settings to address HFR. Some of the most successful programs use a multidisciplinary team approach, intensive patient education and system commitment. Many risk factors for HFR have been identified although prediction tools are limited. The reduction of HFR should incorporate a multidisciplinary approach with 1) evidenced-based physician guided medical and device therapy; 2) institutional programs for effective care transitions; 3) strategies aimed to improve disease management; and 4) engage patients in self-care. PMID- 23817725 TI - The Role of Cardiovascular Magnetic Resonance (CMR) and Computed Tomography (CCT) in Facilitating Heart Failure Management. AB - OPINION STATEMENT: Cardiovascular magnetic resonance (CMR) and cardiac computed tomography (CCT) offer advantages for detecting left or right ventricular dysfunction in patients with or suspected of heart failure. CMR does not expose patients to ionizing radiation, and thus is well-suited for functional assessments and serial studies. CCT provides high spatial resolution, making it useful for the identification of coronary arteriosclerosis associated with ischemic cardiomyopathy. In this review, the clinical applications of CMR and CCT are individually discussed, with comparisons made between them to examine the strengths of each modality. The major techniques for each modality are outlined, as well as their uses for the evaluation of cardiomyopathy in heart failure patients with reduced left ventricular ejection fraction, preserved left ventricular ejection fraction, and valvular heart disease. Finally, we review the utility of CMR and CCT in determining which patients will benefit from cardiac resynchronization therapy. PMID- 23817726 TI - Prevention of recurrent preterm birth: role of the neonatal follow-up program. AB - Preterm birth (PTB) is a public health crisis in need of effective preventative strategies. Multi-disciplinary Neonatal Follow-up Programs (NFPs) provide health services to preterm infants at high risk for developmental problems after discharge from US newborn intensive care units. We aimed to determine whether NFPs are a potentially effective venue for specialized maternal counseling and intervention aimed at reducing the high rate of recurrent PTB in this population. This prospective case series enrolled women with preterm children evaluated in the Utah Department of Health NFP, 2010-2012. Women were interviewed, received Maternal Fetal Medicine (MFM) counseling services, and maternal and neonatal records were abstracted. We assessed maternal demographics, medical history, and characteristics of the index pregnancy. We calculated the proportion of women with knowledge of PTB recurrence risk and available prevention strategies, and assessed current contraceptive use and reproductive plans. Ninety-six women with a history of early PTB (<=26 weeks and/or birth weight < 1,250 g) were evaluated. Nearly 1 in 5 women (19.8 %) evaluated reported sexual activity, desire to avoid pregnancy, and no current contraceptive use, and were therefore at imminent risk of unintended pregnancy. Of women without permanent contraception, only 24.3 % were aware of their individual PTB recurrence risk. Of women with a history of spontaneous PTB, only 4 % were aware of effective pharmacologic preventative strategies. Introduction of MFM consultation as part NFP multi-disciplinary services is a novel approach with the potential to reduce recurrent PTB in an exceptionally high-risk population. PMID- 23817729 TI - Reforming the payment system for medical oncology. PMID- 23817728 TI - Recent health insurance trends for US families: children gain while parents lose. AB - In the past decade, political and economic changes in the United States (US) have affected health insurance coverage for children and their parents. Most likely these policies have differentially affected coverage patterns for children (versus parents) and for low-income (versus high-income) families. We aimed to examine--qualitatively and quantitatively--the impact of changing health insurance coverage on US families. Primary data from interviews with Oregon families (2008-2010) were analyzed using an iterative process. Qualitative findings guided quantitative analyses of secondary data from the nationally representative Medical Expenditure Panel Survey (MEPS) (1998-2009); we used Joinpoint Regression to assess average annual percent changes (AAPC) in health insurance trends, examining child and parent status and type of coverage stratified by income. Interviewees reported that although children gained coverage, parents lost coverage. MEPS analyses confirmed this trend; the percentage of children uninsured all year decreased from 9.6 % in 1998 to 6.1 % in 2009; AAPC = -3.1 % (95 % confidence interval [CI] from -5.1 to -1.0), while the percentage of parents uninsured all year rose from 13.6 % in 1998 to 17.1 % in 2009, AAPC = 2.7 % (95 % CI 1.8-3.7). Low-income families experienced the most significant changes in coverage. Between 1998 and 2009, as US children gained health insurance, their parents lost coverage. Children's health is adversely affected when parents are uninsured. Investigation beyond children's coverage rates is needed to understand how health insurance policies and changing health insurance coverage trends are impacting children's health. PMID- 23817727 TI - Parental perceptions and childhood dietary quality. AB - The early years represent a critical period of growth and development of health behaviours. While optimal child growth is associated with a complex set of factors, the importance of diet quality is undeniable. The objective of this narrative review is to examine contributors to child diet quality and parental perception and how such perceptions might affect child diet quality. An extensive literature search was conducted, generating a variety of sources including research trials (randomized and non-randomized), lab-based studies, cohort studies, topical reviews, government or NGO reports and grey literature. In addition, reflection and opinion, accrued through regular interaction with families, regarding some of the potential links has also been included. Parental perception of diet quality is influenced by many different social, biological economical and psychological factors. Research suggests that diet quality of today's children is sub-optimal and a parent's perception of their child's diet may not accurately reflect this reality. Various parental attitudes and perceptions/misperceptions are important to address as knowledge awareness and beliefs can impact diet quality as can parental practices, and family structure. Issues related to socioeconomics and convenience, and a child's preferences and their peer and/or social environment are also potential factors impacting child diet quality. Knowing that parents play such an integral role in the development and maintenance of their child's health behaviours, addressing misconceptions and unhealthy parental beliefs about diet quality may be an important area for early intervention and prevention work in childhood obesity. PMID- 23817731 TI - [Peritoneal dialysis--an ideal initial dialysis mode]. AB - Peritoneal dialysis (PD) has become an established dialysis modality besides hemodialysis (HD). Although PD is an equal form of dialysis compared to HD, patients numbers on PD remain low worldwide. There are several reasons for this fact. The medical staff in some centers is not used to PD, so there is not enough information about the different dialysis methods available for the patients and the staff doesn't get the training that would be necessary to get familiar with PD. There are some concerns about offering PD to certain groups of patients despite excellent results as to quality of dialysis, good preservation of residual renal function, low costs compared to HD and better quality of life than on HD. However, PD should be offered to all patients requiring dialysis with very few exeptions as an ideal initial dialysis method. This includes patients with diabetes, patients with kidney transplant failure, patients with congestive heart failure and older patients. PMID- 23817732 TI - [Surgical aspects of peritoneal dialysis]. AB - Peritoneal dialysis (PD) has wide clinical range since die 70ies. Clinical data report a significantly higher 2 year survival rate for PD compared to patients treated with hemodialysis. Nevertheless, currently only about 10 % of patients suffering from end-stage renal disease are treated with PD. Long-term function of the catheter is based on patient's compliance as well as optimal surgical catheter implantation. Beside the classic "open" surgical approach by mini laparotomy new minimal invasive techniques of catheter implantation were developed during the last years. Advantages of laparoscopic techniques are the possibility for combined intraperitoneal procedures and optimal placement of the catheter. Most of surgery-related complications are caused by leakage or migration, infection is very rare. Several studies did not find an advantage of minimal invasive procedures regarding complications.This review should give an overview on currently established surgical techniques for PD-catheter implantation. PMID- 23817733 TI - [Routine data in psychiatry - who has the interpretative power?]. PMID- 23817734 TI - [Recovery is an illusion - pro & contra]. PMID- 23817735 TI - [Recovery is an illusion - pro & contra]. PMID- 23817736 TI - [On the death of Christian Muller, a Swiss reformer in psychiatry]. PMID- 23817737 TI - [Presentations from the National Conference of German Clinics of Psychiatry and Psychotherapy (BDK)]. PMID- 23817738 TI - Skeletal muscle mitochondrial uncoupling in a murine cancer cachexia model. AB - Approximately half of all cancer patients present with cachexia, a condition in which disease-associated metabolic changes lead to a severe loss of skeletal muscle mass. Working toward an integrated and mechanistic view of cancer cachexia, we investigated the hypothesis that cancer promotes mitochondrial uncoupling in skeletal muscle. We subjected mice to in vivo phosphorous-31 nuclear magnetic resonance (31P NMR) spectroscopy and subjected murine skeletal muscle samples to gas chromatography/mass spectrometry (GC/MS). The mice used in both experiments were Lewis lung carcinoma models of cancer cachexia. A novel 'fragmented mass isotopomer' approach was used in our dynamic analysis of 13C mass isotopomer data. Our 31P NMR and GC/MS results indicated that the adenosine triphosphate (ATP) synthesis rate and tricarboxylic acid (TCA) cycle flux were reduced by 49% and 22%, respectively, in the cancer-bearing mice (p<0.008; t-test vs. controls). The ratio of ATP synthesis rate to the TCA cycle flux (an index of mitochondrial coupling) was reduced by 32% in the cancer-bearing mice (p=0.036; t test vs. controls). Genomic analysis revealed aberrant expression levels for key regulatory genes and transmission electron microscopy (TEM) revealed ultrastructural abnormalities in the muscle fiber, consistent with the presence of abnormal, giant mitochondria. Taken together, these data suggest that mitochondrial uncoupling occurs in cancer cachexia and thus point to the mitochondria as a potential pharmaceutical target for the treatment of cachexia. These findings may prove relevant to elucidating the mechanisms underlying skeletal muscle wasting observed in other chronic diseases, as well as in aging. PMID- 23817739 TI - Biofabrication of multi-material anatomically shaped tissue constructs. AB - Additive manufacturing in the field of regenerative medicine aims to fabricate organized tissue-equivalents. However, the control over shape and composition of biofabricated constructs is still a challenge and needs to be improved. The current research aims to improve shape, by converging a number of biocompatible, quality construction materials into a single three-dimensional fiber deposition process. To demonstrate this, several models of complex anatomically shaped constructs were fabricated by combined deposition of poly(vinyl alcohol), poly(epsilon-caprolactone), gelatin methacrylamide/gellan gum and alginate hydrogel. Sacrificial components were co-deposited as temporary support for overhang geometries and were removed after fabrication by immersion in aqueous solutions. Embedding of chondrocytes in the gelatin methacrylamide/gellan component demonstrated that the fabrication and the sacrificing procedure did not affect cell viability. Further, it was shown that anatomically shaped constructs can be successfully fabricated, yielding advanced porous thermoplastic polymer scaffolds, layered porous hydrogel constructs, as well as reinforced cell-laden hydrogel structures. In conclusion, anatomically shaped tissue constructs of clinically relevant sizes can be generated when employing multiple building and sacrificial materials in a single biofabrication session. The current techniques offer improved control over both internal and external construct architecture underscoring its potential to generate customized implants for human tissue regeneration. PMID- 23817742 TI - Liquid crystalline thermotropic and lyotropic nanohybrids. AB - This review is meant to give the reader an insight into hybrids incorporating different types of nanoparticles, e.g. metallic or metal oxides, within different types of lyotropic and thermotropic liquid crystals, from relatively small calamitic molecules to the larger discotics and polymers. In particular, this review highlights the importance of nanoparticle-liquid crystal interactions in accessing hybrid materials that exhibit synergetic properties. PMID- 23817741 TI - Light-dependent phosphorylation of Bardet-Biedl syndrome 5 in photoreceptor cells modulates its interaction with arrestin1. AB - Arrestins are dynamic proteins that move between cell compartments triggered by stimulation of G-protein-coupled receptors. Even more dynamically in vertebrate photoreceptors, arrestin1 (Arr1) moves between the inner and outer segments according to the light conditions. Previous studies have shown that the light driven translocation of Arr1 in rod photoreceptors is initiated by rhodopsin through a phospholipase C/protein kinase C (PKC) signaling cascade. The purpose of this study is to identify the PKC substrate that regulates the translocation of Arr1. Mass spectrometry was used to identify the primary phosphorylated proteins in extracts prepared from PKC-stimulated mouse eye cups, confirming the finding with in vitro phosphorylation assays. Our results show that Bardet-Biedl syndrome 5 (BBS5) is the principal protein phosphorylated either by phorbol ester stimulation or by light stimulation of PKC. Via immunoprecipitation of BBS5 in rod outer segments, Arr1 was pulled down; phosphorylation of BBS5 reduced this co precipitation of Arr1. Immunofluorescence and immunoelectron microscopy showed that BBS5 principally localizes along the axonemes of rods and cones, but also in photoreceptor inner segments, and synaptic regions. Our principal findings in this study are threefold. First, we demonstrate that BBS5 is post-translationally regulated by phosphorylation via PKC, an event that is triggered by light in photoreceptor cells. Second, we find a direct interaction between BBS5 and Arr1, an interaction that is modulated by phosphorylation of BBS5. Finally, we show that BBS5 is distributed along the photoreceptor axoneme, co-localizing with Arr1 in the dark. These findings suggest a role for BBS5 in regulating light-dependent translocation of Arr1 and a model describing its role in Arr1 translocation is proposed. PMID- 23817744 TI - Correcting a bent septum by a k-wire stabilization during an extracorporeal septal reconstruction. AB - BACKGROUND: Extracorporeal septoplasty has been successfully employed in difficult cases of septal deviation. A novel technique of wire fixation during extracorporeal septoplasty is presented. METHODS: All patients had complete or near complete nasal airway blockage. The quadrangular cartilage was entirely removed through an open approach. The bent areas were scored, and K-wires were placed to fix the cartilage in the straightened position. The cartilage was replaced and fixated to the bony septum, upper lateral cartilages, and anterior maxillary crest. The K-wire was removed after 6 weeks. RESULTS: Fifteen of 17 patients retained straightness of the septum, and 13 of 17 achieved subjective improvement in nasal breathing. There was one skin infection which was treated with oral antibiotics with complete resolution. Two wires required a percutaneous incision to remove. CONCLUSIONS: The presented technique of extracorporeal septoplasty with wire fixation can be successfully employed for extreme septal deviations. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23817740 TI - Neuroimaging, nutrition, and iron-related genes. AB - Several dietary factors and their genetic modifiers play a role in neurological disease and affect the human brain. The structural and functional integrity of the living brain can be assessed using neuroimaging, enabling large-scale epidemiological studies to identify factors that help or harm the brain. Iron is one nutritional factor that comes entirely from our diet, and its storage and transport in the body are under strong genetic control. In this review, we discuss how neuroimaging can help to identify associations between brain integrity, genetic variations, and dietary factors such as iron. We also review iron's essential role in cognition, and we note some challenges and confounds involved in interpreting links between diet and brain health. Finally, we outline some recent discoveries regarding the genetics of iron and its effects on the brain, suggesting the promise of neuroimaging in revealing how dietary factors affect the brain. PMID- 23817745 TI - Self-made compressive dressing for vaginoplasty. PMID- 23817746 TI - The fetal porcine aorta and mesenteric acellular matrix as small-caliber tissue engineering vessels and microvasculature scaffold. AB - BACKGROUND: The extracellular matrix (ECM) is characterized by not only well preserved scaffolds of organs and vascularized tissues, but also by extremely low immunogenicity during allo- or xeno-implantation. This study aimed to establish a model of a composite microvasculature network scaffold with a small-caliber dominant vascular pedicle by decellularizing fetal porcine aorta and the conterminous mesentery. METHODS: The aorta and the conterminous mesenteric vascular system originating from the inferior mesenteric artery were harvested from fetal pigs at late gestation. All of the cellular components were removed by sequential treatment with Triton X-100 and sodium dodecyl sulfate. After the degree of decellularization was assessed, the fetal porcine aorta and mesenteric acellular matrix (FPAMAM) were transplanted into dogs. RESULTS: Gross and histologic examination demonstrated the removal of cellular constituents with preservation of ECM architecture, including macrochannels and microchannels. The residual DNA content in the FPAMAM was less than 2 %. The aorta and microchannels were perfused well, and the fetal porcine aorta had good patency for more than 3 months. CONCLUSIONS: The integrity of the FPAMAM provided a scaffold for the reconstruction of a rich vascular network with numerous segmentally radiating branches. Decellularized fetal porcine vascular tissue might be a potential alternative for xenogeneic transplantation based on its optimized properties and low immunogenicity. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23817747 TI - A tool for computer-controlled lipoaspirate deposition in autologous fat grafting. AB - BACKGROUND: In autologous fat grafting applied for tissue regeneration and morphologic/volumetric restoration, clinical evidence suggests that the uniformity of tissue distribution in the receiver site may influence regenerative outcomes and rates of complications. METHODS: This technical report describes the prototype of a computer-assisted deposition tool designed to maximize deposition uniformity. This is obtained by modulating the lipoaspirate flow through the cannula of the syringe as a function of the tool withdrawal speed by means of a DC motor that controls the movement of the syringe plunger. Although simpler technologies for speed detection may be applied, the authors' prototype features a wireless connection with an infrared (IR) motion-tracking system for real-time detection of position, orientation, and speed of the surgical tool. The integrated motion-tracking instrumentation grants combined computer-controlled lipoaspirate deposition and real-time surgical navigation to maximize fat tissue uniformity along a planned, patient-specific insertion pattern. CONCLUSIONS: The presented tool ensures the uniformity of tissue deposition through integration of the plunger motion with control of the tool movement, allowing for reduced onset of postintervention complications. EBM level 5 LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23817748 TI - Micro- and macroscopic tissue modifications after bariatric surgery: effects of different procedures-a pilot study. AB - The most effective treatment for morbid obesity has demonstrated to be bariatric surgery. Despite enormous benefits, skin tissue aberrations are inevitable consequences. Our study was focused on micro- and macroscopic modifications in patients who had previously undergone gastric bypass. These preliminary data suggest that tissue alterations, partly responsible for high wound complications rate, may differ among patients undergoing both different and same weight loss procedures. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23817750 TI - Cosmetic surgery National Data Bank: statistics 2012. PMID- 23817752 TI - What the ACGME's next accreditation system means to you. PMID- 23817753 TI - Commonalities, differences, and challenges with patient-derived outcome measurement tools: function/activity scales. AB - BACKGROUND: There is a critical need to evaluate the success of orthopaedic treatments through valid outcome measures. Previous attempts to express patient outcomes using a single aggregate score led to scores that were ambiguous, often insensitive to change, and poorly correlated with the patient's assessment of the outcome of surgical procedures. WHERE ARE WE NOW?: Numerous patient-reported outcome measurement tools have been developed for assessment of patients' level of activity and functional status, especially after joint arthroplasty. However, most tools assume an idealized set of prescribed activities independent of the age, activity level, and lifestyle of each individual. Few instruments are designed to capture the priorities of individual patients, especially those involved in high-demand sporting and recreational activities. WHERE DO WE NEED TO GO?: We need valid outcome measures that provide a meaningful, individualized assessment of the functional status of each patient, taking into account the lifestyle and expectation of each individual. This advance in outcome measurement will allow clinicians to individualize treatment and provide patients with an accurate estimate of the outcome of alternative treatments and procedures. HOW DO WE GET THERE?: Much more comprehensive information is needed to characterize the activities, abilities, and physical aspirations of individual patients. This could form a database for the development of predictive models relating individual characteristics to functional outcomes. Statistical tools are needed to minimize the burden on patients in completing questionnaires to access predictive data and to ensure that all outcome assessments are psychometrically valid. PMID- 23817754 TI - Preliminary results suggest tranexamic acid is safe and effective in arthroplasty patients with severe comorbidities. AB - BACKGROUND: Tranexamic acid (TXA) reduces blood loss and transfusion after total joint arthroplasty (TJA) but concerns remain that patients with severe medical comorbidities might be at increased risk for thromboembolic complications. QUESTIONS/PURPOSES: Among patients undergoing primary TJA with severe systemic medical disease, (1) was TXA associated with increased symptomatic thromboembolic events; (2) was TXA associated with decreased blood transfusion rates; and (3) were there differences in symptomatic thromboembolism or transfusions in the subset of patients with a history of, or risk factors for; thromboembolic disease? METHODS: We performed a retrospective review of 1131 primary TJAs in 1002 patients with American Society of Anesthesiologists score III or IV. Of these, 402 had at least one of seven risk factors for thromboembolic events and were designated as high risk; 240 of those patients received TXA. Outcome measures included 30-day postoperative symptomatic thromboembolic events and postoperative transfusion. RESULTS: There were no differences in symptomatic thromboembolic events within 30 days of surgery between patients who received TXA and those who did not (2.5% versus 2.6%, p = 0.97). Fewer patients treated with TXA received transfusions (11% with versus 41% without; p < 0.0001). In high-risk patients, TXA was not associated with an increase in symptomatic thromboembolic events (6.7% with versus 4.3% without; p = 0.27) and was associated with a decrease in transfusion rates (17% with versus 48% without; p = 0.001). CONCLUSIONS: Although TXA seemed safe and effective in this database review of patients with severe medical comorbidities, a larger prospective trial is warranted to confirm these results. PMID- 23817755 TI - Aspirin: an alternative for pulmonary embolism prophylaxis after arthroplasty? AB - BACKGROUND: The most effective agent for prophylaxis against venous thromboembolic disease after total joint arthroplasty (TJA) remains unknown. The paucity of literature comparing different methods of pulmonary embolism (PE) prophylaxis and fear of litigation make it difficult for surgeons to abandon the use of aggressive chemical prophylaxis. QUESTIONS/PURPOSES: We compared the (1) overall frequency of symptomatic PE, (2) risk of symptomatic PE after propensity matching that adjusted for potentially confounding variables, and (3) other complications and length of stay before and after propensity matching in patients undergoing TJA at our institution who received either aspirin or warfarin prophylaxis. METHODS: A total of 28,923 patients underwent TJA between January 2000 and June 2012 at our institution, had either aspirin (325 mg twice daily; 2800 patients) or warfarin prophylaxis (26,123 patients), and were registered in our institutional electronic database. The incidence of symptomatic PE, symptomatic deep vein thrombosis (DVT), hematoma formation, infection, wound complications, and mortality up to 90 days postoperatively was collected from the database. We performed multivariate analysis and 3:1 and 5:1 propensity score matching for comorbid and demographic variables. RESULTS: The overall symptomatic PE rate was lower (p < 0.001) in patients receiving aspirin (0.14%) than in the patients receiving warfarin (1.07%). This difference did not change after matching. The aspirin group also had significantly fewer symptomatic DVTs and wound-related problems and shorter hospital stays, which did not change after matching. CONCLUSIONS: After publication of the American Academy of Orthopaedic Surgeons' guidelines, some surgeons have utilized aspirin as thromboprophylaxis after TJA. Based on our findings from a large institutional database, aspirin offers suitable prophylaxis against symptomatic PE in selected patients. PMID- 23817756 TI - Muscle strength and functional recovery during the first year after THA. AB - BACKGROUND: Patients undergoing total hip arthroplasty (THA) often are satisfied with the decrease in pain and improvement in function they achieve after surgery. Even so, strength and functional performance deficits persist after recovery, but these remain poorly characterized; knowledge about any ongoing strength or functional deficits may allow therapists to design rehabilitation programs to optimize recovery after THA. QUESTIONS/PURPOSES: The purposes of this study were to (1) evaluate postoperative muscle strength, function, and quality of life during the first year after THA; and (2) compare strength and function in patients 1 year after THA with a cohort of healthy peers. METHODS: Twenty-six patients undergoing THA were assessed 1, 3, 6, and 12 months postoperatively, and 19 adults with no hip pathology were tested as a control group. Isometric muscle strength (hip flexors, extensors, abductors, knee extensors, and flexors), functional performance (stair climbing, five times sit-to-stand, timed-up-and-go, 6-minute walk, and single-limb stance tests), and self-reported function (Hip Disability and Osteoarthritis Score, SF-36, and UCLA activity score) were compared. RESULTS: One month after THA, patients had 15% less hip flexor and extensor torque, 26% less abductor torque, 14% less knee extensor and flexor torque, and worse performance on the stair climbing, timed-up-and-go, single-limb stance, and 6-minute walk. Compared with healthy adults, patients 12 months after THA had 17% less knee extensor and 23% less knee flexor torque; however, the functional testing (including stair climbing, five times sit-to-stand, and the 6 minute walk) showed no significant differences with the patient numbers available between individuals undergoing THA and healthy control subjects. SF-36 Physical Component Scores, although significantly improved from preoperative levels, were significantly worse than healthy adults 1 year after THA (p < 0.01). CONCLUSIONS: Patients experience early postoperative strength losses and decreased functional capacity after THA, yet strength deficits may persist after recovery. This may suggest that rehabilitation may be most effective in the first month after surgery. PMID- 23817757 TI - Are cementless stems more durable than cemented stems in two-stage revisions of infected total knee arthroplasties? AB - BACKGROUND: The routine use of stems in revision TKA improves survival rates by enhancing the stability of the prosthesis. The ideal method of stem fixation (cemented or uncemented) in two-stage reimplantation remains controversial. QUESTIONS/PURPOSES: The purpose of this study was to answer the following questions: (1) Are rerevision rates for aseptic loosening comparable between cemented stems and uncemented stems in two-stage reimplantation? (2) Is the reinfection rate comparable between antibiotic-impregnated cemented stems and uncemented stems for two-stage reimplantation? (3) Are there any differences in Knee Society radiographic scores between stem techniques? METHODS: A retrospective analysis was performed in all patients who underwent two-stage reimplantation between 1990 and 2010 at Anderson Orthopaedic Research Institute (AORI) and OrthoCarolina (OC). One hundred fourteen patients with 228 stems met the inclusion criteria. Of these 228 stems, 102 stems were cemented and 126 stems were uncemented. The indication for stem fixation was largely institution specific; AORI used cementless stems 92% (118) of the time, whereas OC used a cemented stem 92% (92) of the time. A 2-year minimum radiographic and clinical followup was required for inclusion into the study. Radiographic evaluations were performed using a modification of the Knee Society radiographic score. RESULTS: Rerevision rates for aseptic loosening were comparable with three cemented and three cementless stem constructs. The reinfection rate was also comparable between cemented and cementless stems (p = 0.86). Using post hoc analysis, 32% of cemented stems were radiographically classified as loose or closely observe (33 of 102) compared with 17% of the cementless stem group (21 of 126; p = 0.006). Patients with good bone quality had a significantly lower rate of radiographic loosening compared with patients with poor bone quality (p = 0.01). There was no significant correlation with radiographic loosening and level of constraint (p = 0.90) or use of articulating versus static antibiotic spacer (p = 0.06). CONCLUSIONS: In this retrospective study, cementless diaphyseal-engaging stems had a lower rate of radiographic failure than did cemented stems in two-stage reimplantation. Reinfection rates remain similar despite the absence of antibiotic cement in the cementless constructs. At this time we believe the use of hybrid, cementless diaphyseal-engaging stems should be considered as a possible option at the time of reimplantation. PMID- 23817758 TI - Knee pain in a 9-year-old girl. PMID- 23817759 TI - New model of subconjunctival tumor development in rabbits. AB - Conjunctival squamous cell carcinoma (SCC) is an uncommon disease. However, SCC has recently become an important clinical problem due the identification of a significantly high incidence of SCC among a group of black African patients with AIDS. However, basic research concerning SCC, including both intraepithelial and invasive squamous neoplasia, is limited due to the lack of an ocular tumor animal model. Specifically, current ocular imaging and treatment modalities are insufficient for investigating currently available small animal models, because the conjunctival space is not comparable to that of humans. We describe the development of a reproducible model of subconjunctival squamous carcinoma in moderate-sized immunocompetent rabbits. Under optical coherence tomography guidance, 1*107 VX2 carcinoma cells are inoculated into the subconjunctival space of 3 to 4-kg New Zealand white rabbits. Malignant tumor involvement developed on the subconjunctival space after an average of 1 to 2 weeks. This subconjunctival tumor model induction method will likely facilitate a broad range of investigation of subconjunctival cancer diagnostics and therapeutics. PMID- 23817760 TI - Photoacoustic needle: minimally invasive guidance to biopsy. AB - We introduce a needle probe based on photoacoustics (PA) to extend the scope of optical needle methods in guiding biopsies. Pulsed light is coupled to an optical fiber in a needle to be inserted in tissue, and PA signals are detected using an ultrasound imager used for needle guidance. This PA needle samples large volumes and possesses an imaging component so that sites forward and off-axis of the fiber are surveyed. This allows navigation of those regions for optical characterization and direct biopsy in a subsequent step. The concept is explored on simple phantoms and biological specimens. PMID- 23817762 TI - Hollow steel tips for reducing distal fiber burn-back during thulium fiber laser lithotripsy. AB - The use of thulium fiber laser (TFL) as a potential alternative laser lithotripter to the clinical holmium:YAG laser is being studied. The TFL's Gaussian spatial beam profile provides efficient coupling of higher laser power into smaller core fibers without proximal fiber tip degradation. Smaller fiber diameters are more desirable, because they free up space in the single working channel of the ureteroscope for increased saline irrigation rates and allow maximum ureteroscope deflection. However, distal fiber tip degradation and "burn back" increase as fiber diameter decreases due to both excessive temperatures and mechanical stress experienced during stone ablation. To eliminate fiber tip burn back, the distal tip of a 150-MUm core silica fiber was glued inside 1-cm-long steel tubing with fiber tip recessed 100, 250, 500, 1000, or 2000 MUm inside the steel tubing to create the hollow-tip fiber. TFL pulse energy of 34 mJ with 500 MUs pulse duration and 150-Hz pulse rate was delivered through the hollow-tip fibers in contact with human calcium oxalate monohydrate urinary stones during ex vivo studies. Significant fiber tip burn-back and degradation was observed for bare 150-MUm core-diameter fibers. However, hollow steel tip fibers experienced minimal fiber burn-back without compromising stone ablation rates. A simple, robust, compact, and inexpensive hollow fiber tip design was characterized for minimizing distal fiber burn-back during the TFL lithotripsy. Although an increase in stone retropulsion was observed, potential integration of the hollow fiber tip into a stone basket may provide rapid stone vaporization, while minimizing retropulsion. PMID- 23817761 TI - Overconstrained library-based fitting method reveals age- and disease-related differences in transcutaneous Raman spectra of murine bones. AB - Clinical diagnoses of bone health and fracture risk typically rely on measurements of bone density or structure, but the strength of a bone is also dependent on its chemical composition. Raman spectroscopy has been used extensively in ex vivo studies to measure the chemical composition of bone. Recently, spatially offset Raman spectroscopy (SORS) has been utilized to measure bone transcutaneously. Although the results are promising, further advancements are necessary to make noninvasive, in vivo measurements of bone with SORS that are of sufficient quality to generate accurate predictions of fracture risk. In order to separate the signals from bone and soft tissue that contribute to a transcutaneous measurement, we developed an overconstrained extraction algorithm that is based on fitting with spectral libraries. This approach allows for accurate spectral unmixing despite the fact that similar chemical components (e.g., type I collagen) are present in both bone and soft tissue. The algorithm was utilized to transcutaneously detect biochemical differences in the tibiae of wild-type mice between 1 and 7 months of age and between the tibiae of wild-type mice and a mouse model of osteogenesis imperfecta. These results represent the first diagnostically sensitive, transcutaneous measurements of bone using SORS. PMID- 23817763 TI - The management of esophageal achalasia: from diagnosis to surgical treatment. AB - The goal of this review is to illustrate our approach to patients with achalasia in terms of preoperative evaluation and surgical technique. Indications, patient selection and management are herein discussed. Specifically, we illustrate the pathogenetic theories and diagnostic algorithm with current up-to-date techniques to diagnose achalasia and its manometric variants. Finally, we focus on the therapeutic approaches available today: medical and surgical. A special emphasis is given on the surgical treatment of achalasia and we provide the reader with a detailed description of our pre and postoperative management. PMID- 23817764 TI - Force corridors of post mortem human surrogates in oblique side impacts from sled tests. AB - To develop region-specific force corridors in side impacts under oblique loadings using post mortem human surrogates (PMHS). Unembalmed PMHS were positioned on a sled. Surrogates contacted a segmented, modular/ scalable load-wall to isolate region-specific forces (shoulder, thorax, abdomen, pelvis). Heights and widths of segmented load-wall plates were adjustable in sagittal and coronal planes to accommodate anthropometry variations. Load cells were used to gather region specific forces. Tests were conducted at 6.7 m/s. Peak forces and times of attainments, and standard corridors (mean +/- 1 SD) are given for the four torso regions and summated forces. The mean age, stature, and total body mass of the five male PMHS were: 56.6 +/- 4.4 years, 183 +/- 3.5 cm and 70.6 +/- 9.0 kg. Peak pelvis forces were the greatest, followed by thorax, abdomen and shoulder. Sequence of times of attainments of peak forces initiating from pelvis increased rostrally to abdomen to thorax and shoulder regions. Corridors were tight in all regions, except shoulder. As previous force corridors were based solely on pure lateral impacts and region-specific forces were not extracted, the present oblique responses using anthropometry-specific load-wall design can be used to develop injury criteria and evaluate the biofidelity of dummies. PMID- 23817765 TI - Topology of blood transport in the human left ventricle by novel processing of Doppler echocardiography. AB - Novel processing of Doppler-echocardiography data was used to study blood transport in the left ventricle (LV) of six patients with dilated cardiomyopathy and six healthy volunteers. Bi-directional velocity field maps in the apical long axis of the LV were reconstructed from color-Doppler echocardiography. Resulting velocity field data were used to perform trajectory-based computation of Lagrangian coherent structures (LCS). LCS were shown to reveal the boundaries of blood injected and ejected from the heart over multiple beats. This enabled qualitative and quantitative assessments of blood transport patterns and residence times in the LV. Quantitative assessments of stasis in the LV are reported, as well as characterization of LV vortex formations from E-wave and A wave filling. PMID- 23817766 TI - A technical assessment of pulse wave velocity algorithms applied to non-invasive arterial waveforms. AB - Non-invasive assessment of arterial stiffness through pulse wave velocity (PWV) analysis is becoming common clinical practice. However, the effects of measurement noise, temporal resolution and similarity of the two waveforms used for PWV calculation upon accuracy and variability are unknown. We studied these effects upon PWV estimates given by foot-to-foot, least squared difference, and cross-correlation algorithms. We assessed accuracy using numerically generated blood pressure and flow waveforms for which the theoretical PWV was known to compare with the algorithm estimates. We assessed variability using clinical measurements in 28 human subjects. Wave shape similarity was quantified using a cross correlation-coefficient (CCCoefficient), which decreases with increasing distance between waveform measurements sites. Based on our results, we propose the following criteria to identify the most accurate and least variable algorithm given the noise, resolution and CCCoefficient of the measured waveforms. (1) Use foot-to-foot when the noise-to-signal ratio <=10%, and/or temporal resolution >=100 Hz. Otherwise (2) use a least squares differencing method applied to the systolic upstroke. PMID- 23817768 TI - Aortic outflow cannula tip design and orientation impacts cerebral perfusion during pediatric cardiopulmonary bypass procedures. AB - Poor perfusion of the aortic arch is a suspected cause for peri- and post operative neurological complications associated with cardiopulmonary bypass (CPB). High-speed jets from 8 to 10FR pediatric/neonatal cannulae delivering ~1 L/min of blood can accrue sub-lethal hemolytic damage while also subjecting the aorta to non-physiologic flow conditions that compromise cerebral perfusion. Therefore, we emphasize the importance of cannulation strategy and hypothesize engineering better CPB perfusion through a redesigned aortic cannula tip. This study employs computational fluid dynamics to investigate novel diffuser-tipped aortic cannulae for shape sensitivity to cerebral perfusion, in an in silico cross-clamped aortic arch model modeled with fixed outflow resistances. 17 parametrically altered configurations of an 8FR end-hole and several diffuser cone angled tips in combination with jet incidence angles toward or away from the head-neck vessels were studied. Experimental pressure-flow characterizations were also conducted on these cannula tip designs. An 8FR end-hole aortic cannula delivering 1 L/min along the transverse aortic arch was found to give rise to backflow from the brachicephalic artery (BCA), irrespective of angular orientation, for the chosen ascending aortic insertion location. Parametric alteration of the cannula tip to include a diffuser cone angle (tested up to 7 degrees ) eliminated BCA backflow for any tested angle of jet incidence. Experiments revealed that a 1 cm long 10 degrees diffuser cone tip demonstrated the best pressure-flow performance improvement in contrast with either an end hole tip or diffuser cone angles greater than 10 degrees . Performance further improved when the diffuser was preceded by an expanded four-lobe swirl inducer attachment-a novel component. In conclusion, aortic cannula orientation is crucial in determining net head-neck perfusion but precise angulations and insertion-depths are difficult to achieve practically. Altering the cannula tip to include a diffuser cone angle has been shown for the first time to have potential in ensuring a net positive outflow at the BCA. Cannula insertion distanced from the BCA inlet may also avoid backflow owing to the Venturi effect, but the diffuser tipped cannula design presents a promising solution to mitigate this issue irrespective of in vivo cannula tip orientation. PMID- 23817767 TI - Age-dependent ascending aorta mechanics assessed through multiphase CT. AB - Quantification of the age- and gender-specific in vivo mechanical characteristics of the ascending aorta (AA) will allow for identification of abnormalities aside from changes brought on by aging alone. Multiphase clinical CT scans of 45 male patients between the ages of 30 and 79 years were analyzed to assess age dependent in vivo AA characteristics. The three-dimensional AA geometry for each patient was reconstructed from the CT scans for 9-10 phases throughout the cardiac cycle. The AA circumference was measured during each phase and was used to determine the corresponding diameter, circumferential strain, and wall tension at each phase. The pressure-strain modulus was also determined for each patient. The mean diastolic AA diameter was significantly smaller among young (42.6 +/- 5.2 years) at 29.9 +/- 2.8 mm than old patients (69.0 +/- 5.2 years) at 33.2 +/- 3.2 mm. The circumferential AA strain from end-diastole to peak-systole decreased from 0.092 +/- 0.03 in young to 0.056 +/- 0.03 in old patients. The pressure strain modulus increased two-fold from 68.4 +/- 30.5 kPa in young to 162.0 +/- 93.5 kPa in old patients, and the systolic AA wall tension increased from 268.5 +/- 31.3 kPa in young to 304.9 +/- 49.2 kPa in old patients. The AA dilates and stiffens with aging which increases the vessel wall tension, likely predisposing aneurysm and dissection. PMID- 23817769 TI - Development and validation of a 10-year-old child ligamentous cervical spine finite element model. AB - Although a number of finite element (FE) adult cervical spine models have been developed to understand the injury mechanisms of the neck in automotive related crash scenarios, there have been fewer efforts to develop a child neck model. In this study, a 10-year-old ligamentous cervical spine FE model was developed for application in the improvement of pediatric safety related to motor vehicle crashes. The model geometry was obtained from medical scans and meshed using a multi-block approach. Appropriate properties based on review of literature in conjunction with scaling were assigned to different parts of the model. Child tensile force-deformation data in three segments, Occipital-C2 (C0-C2), C4-C5 and C6-C7, were used to validate the cervical spine model and predict failure forces and displacements. Design of computer experiments was performed to determine failure properties for intervertebral discs and ligaments needed to set up the FE model. The model-predicted ultimate displacements and forces were within the experimental range. The cervical spine FE model was validated in flexion and extension against the child experimental data in three segments, C0-C2, C4-C5 and C6-C7. Other model predictions were found to be consistent with the experimental responses scaled from adult data. The whole cervical spine model was also validated in tension, flexion and extension against the child experimental data. This study provided methods for developing a child ligamentous cervical spine FE model and to predict soft tissue failures in tension. PMID- 23817770 TI - Prevalence of incidental narrowing of the superior segment of the internal jugular vein in patients without multiple sclerosis. AB - PURPOSE: Internal jugular vein (IJV) narrowing superiorly is likely relatively frequent. IJV narrowing has been proposed as a potential pathophysiologic component for multiple sclerosis (MS). Our purpose was to investigate the prevalence of incidental superior IJV narrowing in patients imaged with neck computed tomography angiography (CTA) for reasons unrelated to IJV pathology or MS. METHODS: We retrospectively identified 164 consecutive adult patients who had undergone neck CTA in which at least one IJV superior segment was opacified (158 right, 155 left IJVs). At the narrowest point of the upper IJV, each IJV was assessed for dominance, graded (shape and narrowing), measured (diameter and area), and located (axially and craniocaudally). Associations were analyzed using Spearman rank correlations (p < 0.05 significant). Medical records were reviewed for MS. RESULTS: Among 164 patients, at least one IJV was: absent/pinpoint in 15 % (25/164), occluded/nearly occluded in 26 % (43/164). Shape, narrowing, and the three measurements all correlated with each other (all p < 0.01). Lateral location with respect to C1 transverse foramen correlated with subjectively and objectively smaller IJVs (p < 0.01). The most common craniocaudal location was at the C1 transverse process (79 % (125/158) of right and 81 % (126/155) of left IJVs). No patient had a diagnosis of MS. CONCLUSIONS: The appearance of the superior IJV is variable, with an occlusive/near-occlusive appearance present in approximately one-quarter of patients without known MS undergoing CTA. Radiologists should be aware of and cautious to report or ascribe clinical significance to this frequent anatomic variant. PMID- 23817771 TI - Aortic mispuncture during routine catheterization requires emergency cardiac operation. AB - Transseptal puncture for left heart catheter or left atrial appendage occlusion is a highly standardized routine intervention in interventional cardiology. However, mispuncture is rare but can be life threatening at worst. Here, we report the case of a combined mispuncture of the right atrium and the ascending aorta resulting in a pericardial effusion with a hemodynamic effective tamponade requiring urgent cardiac operation for successful life saving. PMID- 23817772 TI - The Mosaic bioprosthesis in the aortic position: 17 years' results. AB - BACKGROUND: The Mosaic bioprosthesis (Medtronic Inc., Minneapolis, Minnesota, United States), a stented porcine aortic valve, combines glutaraldehyde fixation with zero-pressure, root-pressure techniques and antimineralization treatment with amino-oleic acid for improved hemodynamics and tissue durability. The first device has been implanted worldwide at the authors' institution in September 1993. The aim of the present study was to collect mid- to long-term data of the prosthesis. MATERIALS AND METHODS: A total of 272 patients (124 males and 148 females) underwent isolated aortic valve replacement with the Mosaic bioprosthesis between September 1993 and August 2007. Median age at implant was 76.8 years (range, 31.3 to 90.7). Median follow-up was 12.0 years (range, 0 to 17.2 years); follow-up was complete for 223 (82%) patients. RESULTS: Early mortality (30 days) was 4% (12 patients). Overall survival at 5, 10, 15, and 17 years was 68.6% +/- 3.1%, 36.4% +/- 3.3%, 17.1% +/- 3.6%, and 10.7% +/- 4.3%, respectively. Eleven late deaths (5%) were cardiac related. There were 24 thromboembolic events, 1 hemorrhagic, and 6 reoperations/explants. At a median follow-up of 12 years, freedom from any cause of death was 27.0% +/- 3.2% acting as a competing risk for the incidence of thromboembolic events (16.4% +/- 3.5%), hemorrhage (0.5% +/- 0.5%), and reoperation/explant (4.1% +/- 1.8%). Two redos were due to structural valve deterioration (SVD), two for nonstructural dysfunction (paravalvular leakage), one for thrombosed prosthesis, and one for endocarditis. CONCLUSIONS: Performance and late outcome of the Mosaic bioprosthesis was satisfactory during 17 years after clinical introduction. The Mosaic bioprosthesis showed low incidence of SVD or need for reoperation in the long term. PMID- 23817773 TI - Distinctive microRNA expression signatures in proton-irradiated mice. AB - Proton particles comprise the most abundant ionizing radiation (IR) in outer space. These high energy particles are known to cause frequent double- and single stranded DNA lesions that can lead to cancer and tumor formation. Understanding the mechanism of cellular response to proton-derived IR is vital for determining health risks to astronauts during space missions. Our understanding of the consequences of these high energy charged particles on microRNA (miRNA) regulation is still in infancy. miRNAs are non-coding, single-stranded RNAs of ~22 nucleotides that constitute a novel class of gene regulators. They regulate diverse biological processes, and each miRNA can control hundreds of gene targets. To investigate the effect of proton radiation on these master regulators, we examined the miRNA expression in selected mice organs that had been exposed to whole-body proton irradiation (2 Gy), and compared this to control mice (0 Gy exposure). RNA was isolated from three tissues (testis, brain, and liver) from treated and control mice and subjected to high-throughput small RNA sequencing. Bioinformatics analysis of small RNA sequencing data revealed dysregulation of (p < 0.05; 20 up- and 10 down-regulated) 14 mouse testis, 8 liver, and 8 brain miRNAs. The statistically significant and unique miRNA expression pattern found among three different proton-treated mouse tissues indicates a tissue-specific response to proton radiation. In addition to known miRNAs, sequencing revealed differential expression of 11 miRNAs in proton irradiated mice that have not been previously reported in association with radiation exposure and cancer. The dysregulation of miRNAs on exposure to proton radiation suggest a possible mechanism of proton particles involvement in the onset of cell tumorgenesis. In summary, we have established that specific miRNAs are vulnerable to proton radiation, that such differential expression profile may depend upon the tissue, and that there are more miRNAs affected by proton radiation than have been previously observed. PMID- 23817775 TI - Additive effects of exotic plant abundance and land-use intensity on plant pollinator interactions. AB - The continuing spread of exotic plants and increasing human land-use are two major drivers of global change threatening ecosystems, species and their interactions. Separate effects of these two drivers on plant-pollinator interactions have been thoroughly studied, but we still lack an understanding of combined and potential interactive effects. In a subtropical South African landscape, we studied 17 plant-pollinator networks along two gradients of relative abundance of exotics and land-use intensity. In general, pollinator visitation rates were lower on exotic plants than on native ones. Surprisingly, while visitation rates on native plants increased with relative abundance of exotics and land-use intensity, pollinator visitation on exotic plants decreased along the same gradients. There was a decrease in the specialization of plants on pollinators and vice versa with both drivers, regardless of plant origin. Decreases in pollinator specialization thereby seemed to be mediated by a species turnover towards habitat generalists. However, contrary to expectations, we detected no interactive effects between the two drivers. Our results suggest that exotic plants and land-use promote generalist plants and pollinators, while negatively affecting specialized plant-pollinator interactions. Weak integration and high specialization of exotic plants may have prevented interactive effects between exotic plants and land-use. Still, the additive effects of exotic plants and land-use on specialized plant-pollinator interactions would have been overlooked in a single-factor study. We therefore highlight the need to consider multiple drivers of global change in ecological research and conservation management. PMID- 23817774 TI - UVB irradiation-induced dysregulation of plasma membrane calcium ATPase1 and intracellular calcium homeostasis in human lens epithelial cells. AB - Ultraviolet B (UVB) could lead to the apoptosis of human lens epithelial cell and be hypothesized to be one of the important factors of cataractogenesis. In the human lens, Ca(2+)-ATPase is a major determinant of calcium homeostasis. Plasma membrane calcium ATPase1 (PMCA1) is a putative "housekeeping" isoform and is widely expressed in all tissues and cells, which plays an important role in calcium homeostasis. However, the effects of UVB-irradiation on the expression of PMCA1 and the cellular calcium homeostasis are still unclear. In the present study, we cultured human lens epithelial cells (HLE B-3) in vitro and investigated the effects of UVB irradiation on the expression of PMCA1 and the intracellular calcium homeostasis using real-time cell electronic sensing system, flow cytometry, fluo-3/AM probes, real-time quantitative PCR, and enzyme-linked immunosorbent assay techniques. We found that UVB irradiation could induce human lens epithelial cell death, cause intracellular calcium ion (Ca(2+)) elevation, inhibit Ca(2+)-ATPase activity and decrease the expression of PMCA1 at gene and protein levels, suggesting that the downregulation of PMCA1 and the disruption of calcium homeostasis may play important roles in UVB-induced HLE B-3 cell apoptosis. PMID- 23817776 TI - The impact of climate on the geographical distribution of phytoplankton species in boreal lakes. AB - Here, we use a novel space-by-time approach to study large-scale changes in phytoplankton species distribution in Swedish boreal lakes in response to climate variability. Using phytoplankton samples from 27 lakes, evenly distributed across Sweden, all relatively unimpacted by anthropogenic disturbance and sampled annually between 1996 and 2010, we found significant shifts in the geographical distribution of 18 species. We also found significant changes in the prevalence of 45 species (33 became more common and 12 less common) over the study period. Using species distribution models and phytoplankton samples from 60 lakes sampled at least twice between 1992 and 2010, we evaluated the importance of climate variability and other environmental variables on species distribution. We found that temperature (e.g., extreme events and the duration of the growing season) was the most important predictor for species detections. Many cyanobacteria, chlorophytes, and, to a lesser extent, diatoms and zygnematophytes, showed congruent and positive responses to temperature. In contrast, precipitation explained little variation and was important only for a few taxa (e.g., Staurodesmus spp., Trachelomonas volvocina). At the community level, our results suggest a change in community composition at temperatures over 20 degrees C and growing seasons longer than 40 days. We conclude that climate is an important driver of the distributional patterns of individual phytoplankton species and may drive changes in community composition in minimally disturbed boreal lakes. PMID- 23817778 TI - Facile synthesis of porous worm-like Pd nanotubes with high electrocatalytic activity and stability towards ethylene glycol oxidation. AB - A facile method was developed for large-scale preparation of porous worm-like Pd nanotubes based on the reduction of PdO nanotubes, which were obtained by calcining the complex precipitate of [Pd(dimethylglyoxime)2]n. The Pd catalyst showed excellent electrocatalytic activity and stability towards ethylene glycol oxidation. PMID- 23817777 TI - 'Decoy' and 'non-decoy' functions of DcR3 promote malignant potential in human malignant fibrous histiocytoma cells. AB - Decoy receptor 3 (DcR3) is a soluble secreted protein that belongs to the tumor necrosis factor receptor (TNFR) superfamily. DcR3 inhibits the Fas ligand (FasL)/Fas apoptotic pathway by binding to FasL, competitively with Fas receptor. Previous studies have reported that overexpression of DcR3 has been detected in various human malignancies and that DcR3 functions as a 'decoy' for FasL to inhibit FasL-induced apoptosis. In addition, recent studies have revealed that DcR3 has 'non-decoy' functions to promote tumor cell migration and invasion, suggesting that DcR3 may play important roles in tumor progression by decoy and non-decoy functions. We have previously reported that overexpression of DcR3 was observed in human malignant fibrous histiocytoma (MFH), however, the roles of DcR3 in MFH have not been studied. In the present study, to elucidate the roles of DcR3 in tumor progression of MFH, we examined the effects of DcR3 inhibition on cell apoptosis, migration and invasion in human MFH cells. siRNA knockdown of DcR3 enhanced the FasL-induced apoptotic activity and significantly decreased cell migration and invasion with a decrease in the activation of phosphatidylinositol 3 kinase (PI3K)/Akt and matrix metalloproteinase (MMP)-2. The findings in this study strongly suggest that DcR3 plays important roles in tumor progression of human MFH by decoy as well as non-decoy functions and that DcR3 may serve as a potent therapeutic target for human MFH. PMID- 23817779 TI - The role of C-reactive protein in prostate cancer. PMID- 23817780 TI - Designer coordination polymers: dimensional crossover architectures and proton conduction. AB - Coordination polymers (CPs) have large degrees of freedom in framework compositions and in the structures and environment of the inner pores. This review focuses on the recent significant progress achieved by controlling these degrees of freedom. Two breakthroughs are reviewed for constructing sophisticated structures of CP frameworks, especially in dimensional crossover regions. The first is the synthesis of quasi one-dimensional halogen-bridged coordinative tubes by applying state-of-the-art techniques of coordination chemistry. The electronic state of the coordinative tube was studied by structural, spectroscopic and theoretical methods and found to be distinct from conventional one-dimensional systems. The second breakthrough is the achievement of a quasi two-dimensional architecture by combining Langmuir-Blodgett and layer-by-layer methods. Two-dimensional LB CP films were prepared on liquid; the films were stacked layer by layer, and a crystalline quasi-two-dimensional structure was constructed. This review also covers the design of the environment of the inner pore, where hydrogen bond networks with various acidic sites were modified. By appropriate design of the hydrogen bond network, proton-conductive CPs are invented, which are summarized in this review. Types of proton donor sites are discussed and classified, and superprotonic conductive CPs were achieved in these investigations. These results will provide new strategies for constructing functional materials for smart devices. PMID- 23817782 TI - The "flying saucer" sign on spectral domain optical coherence tomography in chloroquine retinopathy. PMID- 23817781 TI - Long non-coding RNAs: novel targets for nervous system disease diagnosis and therapy. AB - The human genome encodes tens of thousands of long non-coding RNAs (lncRNAs), a novel and important class of genes. Our knowledge of lncRNAs has grown exponentially since their discovery within the last decade. lncRNAs are expressed in a highly cell- and tissue-specific manner, and are particularly abundant within the nervous system. lncRNAs are subject to post-transcriptional processing and inter- and intra-cellular transport. lncRNAs act via a spectrum of molecular mechanisms leveraging their ability to engage in both sequence-specific and conformational interactions with diverse partners (DNA, RNA, and proteins). Because of their size, lncRNAs act in a modular fashion, bringing different macromolecules together within the three-dimensional context of the cell. lncRNAs thus coordinate the execution of transcriptional, post-transcriptional, and epigenetic processes and critical biological programs (growth and development, establishment of cell identity, and deployment of stress responses). Emerging data reveal that lncRNAs play vital roles in mediating the developmental complexity, cellular diversity, and activity-dependent plasticity that are hallmarks of brain. Corresponding studies implicate these factors in brain aging and the pathophysiology of brain disorders, through evolving paradigms including the following: (i) genetic variation in lncRNA genes causes disease and influences susceptibility; (ii) epigenetic deregulation of lncRNAs genes is associated with disease; (iii) genomic context links lncRNA genes to disease genes and pathways; and (iv) lncRNAs are otherwise interconnected with known pathogenic mechanisms. Hence, lncRNAs represent prime targets that can be exploited for diagnosing and treating nervous system diseases. Such clinical applications are in the early stages of development but are rapidly advancing because of existing expertise and technology platforms that are readily adaptable for these purposes. PMID- 23817784 TI - Influence of inoculum source and pre-incubation on bio-methane potential of chicken manure and corn stover. AB - In order to investigate the effects of inoculum source and pre-incubation on methane production performance of chicken manure (CM) and corn stover (CS), two sets of bio-methane potential tests using non- and pre-incubated inocula (digested sludge from a municipal wastewater treatment plant (DSMW) and digested sludge from a chicken manure treatment plant (DSCM)) were conducted at 37 degrees C. Modified Gompertz and first-order models were used to evaluate the kinetic parameters. The results revealed that DSMW was better than DSCM in digesting organic substrates (CM and CS), since the average ultimate methane yields were 351 mL g(-1) volatile solid (VS)added for CM and 300 mL g(-1) VSadded for CS when DSMW was used as inoculum, and 298 mL g(-1) VSadded for CM and 218 mL g(-1) VSadded for CS when DSCM was used as inoculum, respectively. Nevertheless, there was no significant difference (p > 0.05) in the ultimate methane yields between non- and pre-incubated inoculum for digesting CM and CS, regardless of the inoculum source. However, when evaluating the kinetic parameters of anaerobic digestion, the correlation coefficient, maximal methane production rate, and hydrolysis rate constant were slightly higher using pre-incubated inoculum as compared to non-incubated inoculum. PMID- 23817783 TI - Postnatal developmental expression of regulator of G protein signaling 14 (RGS14) in the mouse brain. AB - Regulator of G protein signaling 14 (RGS14) is a multifunctional scaffolding protein that integrates G protein and mitogen-activated protein kinase (MAPK) signaling pathways. In the adult mouse brain, RGS14 mRNA and protein are found almost exclusively in hippocampal CA2 neurons. We have shown that RGS14 is a natural suppressor of CA2 synaptic plasticity and hippocampal-dependent learning and memory. However, the protein distribution and spatiotemporal expression patterns of RGS14 in mouse brain during postnatal development are unknown. Here, using a newly characterized monoclonal anti-RGS14 antibody, we demonstrate that RGS14 protein immunoreactivity is undetectable at birth (P0), with very low mRNA expression in the brain. However, RGS14 protein and mRNA are upregulated during early postnatal development, with protein first detected at P7, and both increasing over time until reaching highest sustained levels throughout adulthood. Our immunoperoxidase data demonstrate that RGS14 protein is expressed in regions outside of hippocampal CA2 during development including the primary olfactory areas, the anterior olfactory nucleus and piriform cortex, and the olfactory associated orbital and entorhinal cortices. RGS14 is also transiently expressed in neocortical layers II/III and V during postnatal development. Finally, we show that RGS14 protein is first detected in the hippocampus at P7, with strongest immunoreactivity in CA2 and fasciola cinerea and sporadic immunoreactivity in CA1; labeling intensity in hippocampus increases until adulthood. These results show that RGS14 mRNA and protein are upregulated throughout postnatal mouse development, and RGS14 protein exhibits a dynamic localization pattern that is enriched in hippocampus and primary olfactory cortex in the adult mouse brain. PMID- 23817785 TI - Carbohydrate binding and unfolding of Spatholobus parviflorus lectin: fluorescence and circular dichroism spectroscopic study. AB - Biophysical and carbohydrate binding studies have been carried out on a lectin of Spatholobus parviflorus (SPL) seeds isolated by affinity chromatography on cross linked guar gum. It agglutinated erythrocytes of all ABO blood groups. SDS-PAGE, both in reducing and non-reducing conditions, showed two bands with MW of 29 and 31 kDa. MALDI TOF analysis revealed two peaks at 60 and 120 kDa, indicating that SPL is a hetero-dimeric tetramer. Temperature and pH stability studies revealed that SPL is a thermostable protein and its lectin activity is unaffected in the temperature range of 0-70 degrees C. Its activity was maximal in the pH range of 7-8. Unfolding studies with different denaturants like urea and guanidine hydrochloride indicated its globular nature and the presence of tryptophan in the highly hydrophobic area, which could be correlated to the results of fluorescence spectroscopic studies. The effect of carbohydrate binding on the lectin, shown by circular dichroism spectra, indicated the changes in its secondary and tertiary structures. SPL exerted anti-fungal activity against Aspergillus sp. PMID- 23817786 TI - A chemiluminescence microarray based on catalysis by CeO(2) nanoparticles and its application to determine the rate of removal of hydrogen peroxide by human erythrocytes. AB - In this work, cerium oxide nanoparticles are capable of strongly enhancing the chemiluminescence (CL) of the luminol-hydrogen peroxide (H2O2) system. Based on this, a microarray CL method for the determination of the removal rate constant of H2O2 by human erythrocytes has been developed. It is providing direct evidence for a H2O2-removing enzyme in human erythrocytes that acts as the predominant catalyst. A reaction mechanism is discussed. The proposed microarray CL method is sensitive, selective, simple and time-saving, and has good reproducibility and high throughput. Relative CL intensity is linearly related to the concentration of H2O2 in the range from 0.01 to 50 MUM. The limit of detection is as low as 6.5 * 10(-11) M (3sigma), and the relative standard deviation is 2. 1 % at 1 MUM levels of H2O2 (for n = 11). PMID- 23817787 TI - Cultured preadipocytes undergoing stable transfection with cyclooxygenase-1 in the antisense direction accelerate adipogenesis during the maturation phase of adipocytes. AB - The arachidonate cyclooxygenase (COX) pathway is involved in the generation of several types of endogenous prostaglandins (PGs) with opposite effects on adipogenesis at different life stages of adipocytes. However, the specific role of COX isoforms, the rate-limiting enzymes for the pathway, remains elusive in the regulation of the endogenous synthesis of PGs. This study was aimed at the selective suppression of the constitutive COX-1 in cultured preadipocytes by the isolation of cloned preadipocytes transfected stably with a mammalian expression vector harboring cDNA encoding mouse COX-1 in the antisense direction. The gene expression analysis revealed that the transcript and protein levels of the constitutive COX-1 were substantially suppressed in the isolated cloned transfectants with antisense COX-1. By contrast, the expression of the inducible COX-2 was not affected in the stable transfectants with antisense COX-1. All of the cloned stable transfectants with antisense COX-1 exhibited a significant reduction in the immediate synthesis of PGE2 serving as an anti-adipogenic factor. The sustained expression of COX-1 in the antisense direction induced the appreciable stimulation of fat storage in adipocytes during the maturation phase, which was associated with the higher expression levels of adipocyte-specific genes, indicating the positive regulation of adipogenesis program. Moreover, the up-regulation of adipogenesis is accompanied by a higher production of J2 series PGs including 15-deoxy-Delta(12,14)-PGJ2 and Delta(12)-PGJ2, known as pro adipogenic factors by the transfectants with antisense COX-1. The results suggest that the inducible COX-2 can contribute to the endogenous synthesis of PGJ2 derivatives acting as autocrine mediators to simulate adipogenesis during the maturation phase by way of compensation for the suppressed expression of the constitutive COX-1. PMID- 23817788 TI - Improving the activity of cytochrome P450 BM-3 catalyzing indole hydroxylation by directed evolution. AB - Cytochrome P450 BM-3 (A74G/F87V/L188Q) could catalyze indole to produce indigo. To further improve this capability, random mutagenesis was performed on the heme domain of P450 BM-3 (A74G/F87V/L188Q) with error-prone PCR. A single mutant V445A was selected out from the error-prone library and exhibited the highest specific activity toward indole among the mutants obtained. The kinetic parameters of V445A were also highly improved. Compared with the parent enzyme, the turnover rate (k cat) of V445A was increased by 7.5 times, while its K m value decreased by 9.2 %. Consequently, the catalytic efficiency (k cat/K m) of V445A was raised to 8.2 times than that of the parent enzyme. Moreover, alanine was confirmed as the best amino acid substitution by saturated mutagenesis in Val445 position. Three-dimensional structure analysis was also used to rationalize the effect on the enzyme properties of the mutation. This study showed that random mutagenesis was efficient to identify mutants with potential values in industry and increased our insight into P450 BM-3. PMID- 23817789 TI - Yeasts and lactic acid bacteria mixed-specie biofilm formation is a promising cell immobilization technology for ethanol fermentation. AB - We previously found that some Saccharomyces cerevisiae and Lactobacillus plantarum remarkably formed mixed-specie biofilm in a static co-culture and deduced that this biofilm had potential as immobilized cells. We investigated the application of mixed-specie biofilm formed by S. cerevisiae BY4741 and L. plantarum HM23 for ethanol fermentation in repeated batch cultures. This mixed specie biofilm was far abundantly formed and far resistant to washing compared with S. cerevisiae single biofilm. Adopting mixed-specie biofilm formed on cellulose beads as immobilized cells, we could produce enough ethanol from 10 or 20 % glucose during ten times repeated batch cultures for a duration of 10 days. Cell numbers of S. cerevisiae and L. plantarum during this period were stable. In mixed-specie biofilm system, though ethanol production was slightly lower compared to S. cerevisiae single-culture system due to by-production of lactate, pH was stably maintained under pH 4 without artificial control suggesting high resistance to contamination. Inoculated model contaminants, Escherichia coli and Bacillus subtilis, were excluded from the system in a short time. From the above results, it was indicated that the mixed-specie biofilm of S. cerevisiae and L. plantarum was a promising immobilized cell for ethanol fermentation for its ethanol productivity and robustness due to high resistance to contamination. PMID- 23817790 TI - Atmospheric pressure plasma pretreatment of sugarcane bagasse: the influence of moisture in the ozonation process. AB - Sugarcane bagasse samples were pretreated with ozone via atmospheric O2 pressure plasma. A delignification efficiency of approximately 80 % was observed within 6 h of treatment. Some hemicelluloses were removed, and the cellulose was not affected by ozonolysis. The quantity of moisture in the bagasse had a large influence on delignification and saccharification after ozonation pretreatment of the bagasse, where 50 % moisture content was found to be best for delignification (65 % of the cellulose was converted into glucose). Optical absorption spectroscopy was applied to determine ozone concentrations in real time. The ozone consumption as a function of the delignification process revealed two main reaction phases, as the ozone molecules cleave the strong carbon-carbon bonds of aromatic rings more slowly than the weak carbon-carbon bonds of aliphatic chains. PMID- 23817791 TI - PET-CT and the detection of the asymptomatic recurrence or second primary lesions in the treated head and neck cancer patient. AB - OBJECTIVES/HYPOTHESIS: The role of follow-up and the detection of recurrent or new primary disease in cancer management remains to be defined. Specifically, the effectiveness and impact on survival of imaging studies that detects disease before it is symptomatic or noted on exam is unknown. STUDY DESIGN: Retrospective chart review. METHODS: A retrospective review was performed on a series of head and neck cancer patients (n = 123), at a single institution from February 18, 2004 to July 9, 2007, who had undergone nonstaging 18F-fluorodeoxyglucose positron emission tomography-computing tomography (FDG PET-CT) scans as an integral part of the patient's follow-up after definitive treatment. Each scan (n = 308) was evaluated by a board-certified nuclear medicine physician, and final scan readings from each patient's medical record were reviewed for this study. RESULTS: Of the 123 patients in the study, 24 (20%) were noted to have asymptomatic lesions (either recurrent or new primaries) indicated on PET/CT (8% of surveillance scans) at an average interval of 35.7 weeks posttreatment. Asymptomatic lesions were detected most frequently at distant sites, with 50% being thoracic, but also included were primary (9%), regional (9%), and other distant (32%) sites. At last follow-up of the 24 patients in whom an asymptomatic lesion was detected, 14 patients have died of disease; 10 patients remain alive, four with disease; and one patient had a subsequent recurrence treated and is currently disease-free. CONCLUSION: PET-CT scanning is an effective tool for detecting asymptomatic disease in patients previously treated for head and neck cancer. Unfortunately, even with early detection of recurrent disease, the mortality rate remains high. PMID- 23817792 TI - The social ecology of resolving family conflict among West African immigrants in New York: a grounded theory approach. AB - The current study employs a grounded theory approach to examine West African immigrants' resolution of parent-child conflict and intimate partner conflict. Data from 59 participants present an interactive social ecological framework, where a lack of resolution at one level results in attempts to resolve problems at higher levels. Four levels are identified within West African immigrants' problem solving ecology, each with specific actors in positions of authority: individual/dyadic (parents and spouses), extended family (which includes distant relatives and relatives living in home countries), community leadership (non family elders and religious leaders), and state authorities. From participants' descriptions of family challenges emerged a picture of a social ecology in flux, with traditional, socially conservative modes of resolving family conflict transposed across migration into the more liberal and state-oriented familial context of the United States. This transposition results in a loss spiral for the traditional social ecology, differentially affecting individual actors within families. Implications for helping professionals working with new immigrant communities include identifying variability in openness to adapting structures that are not working well (e.g., patriarchal protection of abusive husbands) and supporting structures known to be associated with well being (e.g., collective monitoring of youth). PMID- 23817793 TI - Physiology: a world perspective. PMID- 23817794 TI - Physiology's impact: discovering life. PMID- 23817795 TI - Physiology in perspective: addressing cardiovascular health and disease. PMID- 23817796 TI - Role of beta-adrenergic receptors and nitric oxide signaling in exercise-mediated cardioprotection. AB - Exercise promotes cardioprotection in both humans and animals not only by reducing risk factors associated with cardiovascular disease but by reducing myocardial infarction and improving survival following ischemia. This article will define the role that nitric oxide and beta-adrenergic receptors play in mediating the cardioprotective effects of exercise in the setting of ischemia reperfusion injury. PMID- 23817797 TI - Elucidating immune mechanisms causing hypertension during pregnancy. AB - Preeclampsia is associated with hypertension and increased infant and maternal morbidity and mortality. The underlying cause of preeclampsia is largely unknown, but it is clear that an immunological component plays a key pathophysiological role. This review will highlight immunological key players in the pathology of preeclampsia and discuss their role in the pathophysiology observed in the reduced placental perfusion (RUPP) rat model of preeclampsia. PMID- 23817800 TI - Activating autoantibodies and cardiovascular disease. AB - Stimulating antibodies against G-protein-coupled receptors, including the beta1- and beta2-adrenergic receptors, the alpha1-adrenergic receptor, and the angiotensin II AT1 receptor, have been described, as well as activating antibodies directed at the platelet-derived growth factor receptor tyrosine kinase. Their existence and actions appear to be established. Lacking are mechanistic studies of receptor activation and translational studies to document receptor-stimulating antibodies as worthwhile therapeutic targets. PMID- 23817799 TI - Darkness at the end of the tunnel: poststenotic kidney injury. AB - Renal artery stenosis remains an important contributor to renal failure in the elderly population, but uncertainty continues to surround the mechanisms underlying progressive renal dysfunction. Here, we present the current understanding of the pathogenic mechanisms responsible for renal injury in these patients, with emphasis on those involved in disease progression. PMID- 23817801 TI - Modulation of soluble guanylate cyclase for the treatment of erectile dysfunction. AB - Nitric oxide (NO) is the principal mediator of penile erection, and PDE-5 inhibitors are the first-line agents used to treat erectile dysfunction (ED). When NO formation or bioavailability is decreased by oxidative stress and PDE-5 inhibitors are no longer effective, a new class of agents called soluble guanylate cyclase (sGC) stimulators like BAY 41-8543 will induce erection. sGC stimulators bind to the normally reduced, NO-sensitive form of sGC to increase cGMP formation and promote erection. The sGC stimulators produce normal erectile responses when NO formation is inhibited and the nerves innervating the corpora cavernosa are damaged. However, with severe oxidative stress, the heme iron on sGC can be oxidized, rendering the enzyme unresponsive to NO or sGC stimulators. In this pathophysiological situation, another newly developed class of agents called sGC activators can increase the catalytic activity of the oxidized enzyme, increase cGMP formation, and promote erection. The use of newer agents that stimulate or activate sGC to promote erection and treat ED is discussed in this brief review article. PMID- 23817798 TI - Hypertension: what's sex got to do with it? AB - Hypertension is a complex and multifaceted disease, and there are well established sex differences in many aspects of blood pressure (BP) control. The intent of this review is to highlight recent work examining sex differences in the molecular mechanisms of BP control in hypertension to assess whether the "one size-fits-all" approach to BP control is appropriate with regard to sex. PMID- 23817802 TI - [Influence of comorbidities and delay in surgical treatment on mortality following femoral neck fracture]. AB - BACKGROUND: Hip fractures typically occur in geriatric patients representing an increasing medical as well as socioeconomic challenge. PATIENTS AND METHODS: In order to reveal the influence of considerable comorbidities and the time of surgery in the treatment of geriatric hip fractures we analysed patients treated between 1993 and 2008 at a level I trauma centre. RESULTS: 654 patients with isolated hip fractures were included. Surgical treatment was performed with osteosynthetic stabilisation in 55.5 % (n = 363) and with endoprosthetic implants in 44.5 % (n = 291). The presence of pulmonary, psychiatric and metabolic/endocrinological comorbidities resulted in delayed treatment. If an early surgical treatment was performed within the first 12 hours after hospital admission, long-term survival was significantly improved (p = 0.02). A regression analysis revealed a statistical trend towards an increased mortality of 0.2 % per hour delay after hospital admission. The presence of considerable comorbidities and surgical treatment with endoprosthetic implants (odds ratio 1.611) were proven as independent mortality factors. CONCLUSION: The present study supports the guideline of early surgical treatment of geriatric hip fractures. Emphasising the incidence of in-hospital complications and the mortality after endoprosthetic treatment, osteosynthetic fracture stabilisation should be considered in the presence of considerable morbidity and pre-surgical immobilisation. PMID- 23817803 TI - [Pseudarthrosis following surgically treated forearm fractures in children and adolescents]. AB - AIM: Due to the changing attitude of treating paediatric forearm fractures increasingly towards the surgical stabilisation rather than conservatively by the method of elastic stable intramedullary nailing (ESIN), we are confronted with complications which have not been described in childhood previously. Pseudarthrosis following surgically treated forearm fractures in children is only found in single reports with none in the German-speaking area. The goal of this study is to define predisposing factors which may lead to pseudarthrosis after surgery for forearm fractures. METHOD: From 1990 to 2011 all children having sustained a pseudarthrosis following forearm fractures treated in our institution were included. All children who did not demonstrate a complete consolidation of the forearm fractures after 6 months from injury were considered for the study. Those pseudarthroses which were caused through systemic diseases were excluded. RESULTS: During the time period of 21 years, fourteen children were treated who fulfilled the criteria of having a pseudarthrosis. Nine of the fourteen children had primarily been treated in an outside hospital, five in our institution. The average age was 10.8 years (7-15 years). There were thirteen ulnar shaft and one radius shaft pseudarthroses. In 11 children the pseudarthrosis was located in the middle third and there was one child each with a pseudarthrosis in the proximal and distal third of the ulna. There were 13 ulnar shaft fractures and one monteggia lesion. Twelve of the fractures were primarily closed and there were two open cases. In nine cases an open reduction of the ulna was necessary, the radius was openly reduced in four patients. In five children technical mistakes of the osteosynthesis were identified to contribute to the formation of the pseudarthrosis. Five of the 14 children had experienced a re-fracture. Nine children had revision surgery. These children were treated by plate osteosynthesis or ESIN. In five patients the pseudarthrosis healed spontaneously without interference. There were 13 hypertrophic and one hypotrophic pseudarthroses. CONCLUSION: Pseudarthrosis of the forearm following surgical treatment of forearm fractures in children and adolescents mainly occurred in the middle third of the ulna. In primarily open fractures or in cases which needed to be openly reduced the risk of pseudarthrosis formation was higher. Inadequate osteosynthetic stabilisation is another factor to contribute to difficulties in fracture healing. Despite of the possibility of pseudarthrosis, the indication to ESIN treatment in paediatric forearm fractures is not doubted. It is important to keep the surgical trauma as small as possible if open reduction is required in order to not disturb the perfusion of the bone. PMID- 23817804 TI - [Complication analysis of spinal interventions in adult central movement disorders and scoliosis]. AB - BACKGROUND: Adult central movement disorders, malpostures, and scolioses can have their cause in various neurological underlying diseases such as Morbus Parkinson, Pisa syndrome, or segmental dystonia. Important clinical characteristics are marked postural distortions such as camptocormia (bent spine) or laterocollis. In cases of these adult scolioses, surgical spine treatment puts high demands on the surgeon. Surgery in Parkinson's disease, for example, is associated with serious surgery-specific as well as general complications. The more rarely occurring Pisa syndrome is an entity primarily requiring medical therapy. PATIENTS AND METHODS: A series of ten case reports of patients with Morbus Parkinson and Pisa syndrome who underwent spinal surgery is presented and discussed. From these reports, treatment recommendations have been derived and complemented by references from the literature. An extensive MEDLINE search was performed for this purpose. RESULTS AND CONCLUSION: In patients suffering from Parkinson's disease, even minor surgical interventions can lead to instability of whole spine segments or even the entire spine. Implant loosening, adjacent segment instability, general perioperative complications, and progressive malposture due to disease progress can bring forth disastrous treatment courses. Spinal fixation should be performed long-segmented in combination with ventral stabilisation. Due to osteoporosis, pedicle screw cement augmentation is recommended in this collective. If the diagnosis of Pisa syndrome is established, an optimised preoperative preparation should be initiated in close cooperation with neurologists. In many cases medical therapy is sufficient and surgical interventions can be avoided. PMID- 23817806 TI - Oropharyngeal Dysphagia in patients with obstructive sleep apnea syndrome. AB - Although previous studies demonstrated that patients with obstructive sleep apnea syndrome (OSAS) may present subclinical manifestations of dysphagia, in not one were different textures and volumes systematically studied. The aim of this study was to analyze the signs and symptoms of oropharyngeal dysphagia using fiberoptic endoscopic evaluation of swallowing (FEES) with boluses of different textures and volumes in a large cohort of patients with OSAS. A total of 72 OSAS patients without symptoms of dysphagia were enrolled. The cohort was divided in two groups: 30 patients with moderate OSAS and 42 patients with severe OSAS. Each patient underwent a FEES examination using 5, 10 and 20 ml of liquids and semisolids, and solids. Spillage, penetration, aspiration, retention, and piecemeal deglutition were considered. The penetration-aspiration scale (PAS), pooling score (PS), and dysphagia outcome and severity scale (DOSS) were used for quantitative analysis. Each patient completed the SWAL-QOL questionnaire. Forty six patients (64 %) presented spillage, 20 (28 %) piecemeal deglutition, 26 (36 %) penetration, and 30 (44 %) retention. No differences were found in the PAS, PS, and DOSS scores between patients with moderate and severe OSAS. Patients with severe OSAS scored higher General Burden and Food selection subscales of the SWAL QOL. Depending on the DOSS score, the cohort of patients was divided into those with and those without signs of dysphagia. Patients with signs of dysphagia scored lower in the General Burden and Symptoms subscales of the SWAL-QOL. OSAS patients show signs of swallowing impairment in about half of the population; clinicians involved in the management of these patients should include questions on swallowing when taking the medical history. PMID- 23817807 TI - Bile duct confluence: anatomic variations and its classification. AB - Accurate knowledge of the anatomy of the bile ducts is critical for successfully hepato-biliary surgery. We describe the anatomical variations of the confluence of the bile ducts, their branches patterns, frequency and classification. From 1996 to 2011, we have collected data of the bile duct confluence. 2,032 and 1,014 anatomical variations of right and left bile ducts, respectively, were reviewed and classified according to the branching pattern. The frequencies of each type of the right hepatic duct (RHD) were as follows: Type A1-1,247 (61.3%); Type A2 296 (14.5%); Type A3-272 (13.3%); Type A4-124 (6.1%); Type A5-21 (1%) and others 72 (3.5%) and, for the left hepatic duct (LHD) was as follows: Type B1-773 (76.2%); Type B2-153 (15%); Type B3-38 (3.7%); Type B4-9 (0.8%); Type B5-29 (2.8%) and others-12 (1.1%). Atypical branching patterns of both the right and left hepatic ducts were found in 14 and 8%, respectively. The two most common variations of the RHD were right anterior and posterior hepatic ducts join together to form the RHD and trifurcation where the RHD is absent and right anterior and posterior hepatic ducts join directly to the confluence with the LHD to form the common hepatic duct. The two most common variations in the LHD were segment IV drainage to the left and right hepatic ducts. PMID- 23817808 TI - EMMPRIN expression positively correlates with WHO grades of astrocytomas and meningiomas. AB - High-grade primary brain tumors possessed poor outcome due to invasiveness. Extracellular matrix metalloproteinase inducer (EMMPRIN) stimulates peri-tumoral fibroblasts to secrete matrix metalloproteinase and promote invasiveness. This study hypothesized that high-grade brain tumors overexpress EMMPRIN. Analyzing the public delinked database from the Gene Expression Omnibus profile, the results showed that the EMMPRIN mRNA level was higher in WHO grade IV (n = 81) than in grade III (n = 19, p < 0.0005) astrocytomas and non-tumor brain tissue controls (n = 23, p < 0.00001). The results of tissue microarray-based immunohistochemical (IHC) staining revealed that EMMPRIN levels positively correlated with WHO grades for astrocytomas (p = 0.008) and meningiomas (p = 0.048). EMMPRIN mRNA levels in conventional glioma cell lines (n = 36) was not less than those in glioma primary culture cells (n = 27) and glioblastoma stem like cells (n = 12). The GBM8401, U87MG, and LN229 human glioma cell lines also overexpressed EMMPRIN. Hematoxylin and eosin, IHC, and immunofluorescence staining of xenografts confirmed that high-grade brain tumors overexpressed EMMPRIN. Lastly, Kaplan-Meier analysis revealed poorer survival in WHO grade IV (n = 56) than in grade III astrocytomas (n = 21, by log-rank test; p = 0.0001, 95 % CI: 1.842-3.053). However, in high-grade astrocytomas, there was no difference in survival between high and low EMMPRIN mRNA levels. Thus, this study identified that high-grade brain tumors overexpress EMMPRIN, which positively correlates with WHO grades in human astrocytomas and meningiomas, and suggests that EMMPRIN may be a therapeutic target of brain tumor. PMID- 23817809 TI - A population-based study of low-grade gliomas and mutated isocitrate dehydrogenase 1 (IDH1). AB - Low-grade gliomas (LGG) have a slow growth rate, but transformations into malignant gliomas with a rapid deterioration occur in many patients. The aim of this study was to evaluate clinical prognostic factors in a population-based cohort of patients with LGG. In addition we investigated the expression and prognostic value of the isocitrate dehydrogenase 1 (IDH1) R132H mutation. Seventy four patients diagnosed between 2005 and 2009 in the Region of Southern Denmark were identified using the Danish Cancer Register and The Danish Pathology Databank. Survival analysis using Cox regression was performed in 52 patients with tumor samples useable for immunohistochemical evaluation of IDH1 status. Patients with a contrast enhancing tumor, neurological deficits, headache, an astrocytic tumor and PS 2-4 had an increased risk of recurrence. In univariate analysis age > 50 years (HR 2.14, 95 % CI 1.08-4.24), having neurological deficit (HR 2.28, 95 % CI 1.15-4.52), receiving post-surgical treatment (HR 2.52, 95 % CI 1.19-5.32), being in performance status 2-4 (HR 1.44, 95 % CI 1.15-1.81), and having an astrocytic tumor (HR 3.79, 95 % CI 1.64-8.73) were associated with poor survival. Mutated IDH1 (mIDH1) was identified in 46 % of the patients and was significantly correlated to a good survival in both univariate (HR 0.24, 95 % CI 0.11-0.53) and in multivariate analysis (HR 0.40, 95 % CI 0.17-0.91). The other clinical variables were not significant when adjusted for the effect of mIDH1 status. We find that young age, the absence of neurologic deficit, PS 0-1 and oligodendroglial histology were associated with better survival. IDH1 status showed independent prognostic information when adjusting for classical prognostic factors, and should be validated in a larger patient population. PMID- 23817810 TI - Phosphorylated insulin-like growth factor-1 receptor (pIGF1R) is a poor prognostic factor in brain metastases from lung adenocarcinomas. AB - A greater understanding of brain metastases is imperative for developing novel therapeutic strategies. Our previous study showed that insulin-like growth factor (IGF) signaling pathway was activated in brain-tropic cancer cells. In this study, we investigated the clinical relevance of activated (phosphorylated) IGF-1 receptor (pIGF1R) expression in brain metastases originating from lung adenocarcinomas. All pathologically confirmed brain metastases from lung adenocarcinomas, with available archived specimens from January 1998 to December 2009 at National Taiwan University Hospital, were assessed immunohistochemically for pIGF1R expression using H-score criteria. A median H-score was used as a cutoff point to define high or low pIGF1R expression. The mutation status in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) was examined using direct sequencing. The prognostic significance of pIGF1R expression, its correlations with clinicopathological characteristics, and EGFR status were evaluated. In the 86 cases, high membranous/cytoplasmic pIGF1R expression in brain metastases correlated with a shorter median survival (10.8 vs 27.8 mo, P = 0.003). This correlation was more significant in patients with EGFR mutations [hazard ratio (HR) 2.38, 95 % confidence interval (CI) 1.19-4.77 for EGFR mutations; HR 1.99, 95 % CI 0.95-4.15 for EGFR wild type] and remained statistically significant in multivariate analysis after adjusting for the effects of other potential prognostic factors, including the graded prognostic assessment score, solitary brain metastasis, extracranial metastatic status, EGFR mutations, and treatment using EGFR tyrosine kinase inhibitors. Although we also identified nuclear pIGF1R expression, this result was prognostically non significant. Our study results showed that high membranous/cytoplasmic pIGF1R expression in brain metastases was a poor prognostic factor, more significantly in patients with EGFR mutations than in those with wild-type EGFRs. PMID- 23817811 TI - Quality of life among adult patients with neurofibromatosis 1, neurofibromatosis 2 and schwannomatosis: a systematic review of the literature. AB - The aim of this study was to review the literature on quality of life among adult patients with neurofibromatosis 1, neurofibromatosis 2 and schwannomatosis, and to identify the specific aspects of quality of life that were studied and reported in this population. We also set out to report predictors of quality of life. Published research reports were included if they described quality of life in this population and met methodological quality according to a list of predefined criteria. Eight studies (7 in NF1, 1 in NF2, 0 in schwannomatosis), conducted between 2001 and 2013, met inclusion criteria. The methodological quality of the eight studies was mostly high according to ratings by predefined criteria. Most studies reported that patients with NF experience decreased quality of life when compared to the general population. Visibility and disease severity were strong predictors of skin-specific quality of life in NF1 patients. However, the majority of findings regarding predictors of quality of life were weak or inconclusive. Given the decreased quality of life in NF patients, it is important to examine more comprehensively the psychosocial factors in this population, especially in patients with NF2 and schwannomatosis. Mind body interventions that address these domains may provide comprehensive and efficacious long term treatment. PMID- 23817812 TI - Papillary tumor of the pineal region with anaplastic small cell component. PMID- 23817813 TI - Conflict management in the intensive care unit. PMID- 23817814 TI - Take action to diminish moral distress in critical care nurses. PMID- 23817815 TI - Education may help decrease nurses' moral distress. PMID- 23817817 TI - Parallel paths to improve heart failure outcomes: evidence matters. AB - Gaps and disparities in delivery of heart failure education by nurses and performance in accomplishing self-care behaviors by patients with advanced heart failure may be factors in clinical decompensation and unplanned consumption of health care. Is nurse-led education effectively delivered before hospital discharge? Nurse leaders must understand the strength of nurses' knowledge base related to self-care principles and important barriers to best practice. Nurses may not be comfortable teaching patients about dry weight, meal planning, heart failure medications, or progressive steps of activity and exercise. Further, clinical nurses may not have time to provide in-depth education to patients before discharge. Equally important, research is needed to learn about factors that enhance patients' adherence to heart failure self-care behaviors, because adherence to recommendations of national, evidence-based, heart failure guidelines improves clinical outcomes. Thus, nurses and patients are on parallel paths related to setting the foundation for improved self-care adherence in advanced heart failure. Through research, we found that nurses were not adequately prepared as heart failure educators and that patients did not believe they were able to control heart failure. In 2 educational intervention studies that aimed to help patients understand that they could control fluid management and follow a strict daily fluid limit, patients had improved clinical outcomes. Thus, misperceptions about heart failure can be overcome with interventions that move beyond communicating "what" self-care behaviors are recommended. Research results reflect that evidence matters! Systems and processes are needed to support nurses' knowledge, comfort, and frequency in delivering self-care education before discharge, increase the accuracy of patients' beliefs about controlling heart failure, and enhance patients' desire to adhere to guideline recommended heart failure self-care behaviors. This article describes the development of the parallel paths of nurse and patient programs of research and explores translation of findings into practice and development of clinical translational research. PMID- 23817818 TI - Accuracy of stop-cursor method for determining systolic and pulse pressure variation. AB - BACKGROUND: Functional hemodynamic indicators (systolic pressure variation [SPV and SPV%] and pulse pressure variation [PPV%]) are sensitive and specific indicators of fluid responsiveness. It was unknown if these indicators could be accurately measured directly from the bedside monitor. OBJECTIVE: Determine the accuracy of SPV, SPV%, and PPV% measurements by using a stop-cursor method compared with a digitized analog strip (gold standard). METHODS: A prospective observational study using a convenience sample of 30 adult patients in a medical surgical intensive care unit who were receiving mechanical ventilation and had no spontaneous breaths during 3 sequential ventilator breaths and had an optimized arterial catheter. The peak and nadir arterial pressure values for a ventilator cycle were simultaneously obtained by using the stop-cursor method on the bedside monitor and a hardcopy strip. The indicators were averaged over 3 breaths, and the difference between methods was calculated. RESULTS: Data were analyzed from 29 patients (1 patient excluded) on assist control ventilation (mean [SD] for tidal volume, 7.5 [2] mL/kg; positive end-expiratory pressure, 7 [4] cm H2O). For SPV, the mean bias was 0.4 (SD, 0.9) mm Hg (95% limits of agreement [LOA], -1.4 to 2.2 mm Hg); for SPV%, 0.3 (SD, 0.9; 95% LOA, -1.5% to 2.1%); for PPV%, 1.0 (SD, 3.3; 95% LOA, -5.5% to 7.5%). In only 1 case (PPV%) was there disagreement on fluid response characterization. CONCLUSIONS: Statistically significant small differences in SPV and SPV% were detected. The differences in SPV, SPV%, and PPV% were not clinically significant, suggesting that functional hemodynamic indicators can be obtained accurately with the stop-cursor method. PMID- 23817820 TI - Sex and mortality of hospitalized adults after admission to an intensive care unit. AB - BACKGROUND: After admission to intensive care, women have higher mortality rates than do men. The reasons for the greater mortality in women are not fully understood. OBJECTIVE: To determine if increased mortality in women was due to delays in the recognition of critical illness or to delays in timely admission to intensive care. METHODS: A total of 241 consecutive admissions to intensive care from medical and surgical units during a 12-month period were analyzed retrospectively. Patients' demographics, illness severity, and delay between the time the patients would have fulfilled criteria for calling a medical emergency team and consultation with and admission to intensive care were analyzed. RESULTS: Delay from fulfillment of criteria for calling a medical emergency team and consultation with intensive care and from consultation to admission to intensive care did not differ between sexes. Despite similar delays in admission to intensive care, women had a higher 30-day mortality than did men (44.9% vs 30.5%; P = .02). The increased mortality was more pronounced in the medical patients (53% vs 34%; P = .02). Multivariate analysis of mortality data yielded a mortality odds ratio of 0.35 (95% CI, 0.16-0.74) for men, significantly different from values for women (P = .006). CONCLUSION: After admission to intensive care from medical or surgical units, women had higher mortality rates than did men, and the difference was more pronounced in medical patients. The difference in mortality between sexes was not explained by delayed recognition of critical illness or delayed admission to intensive care. PMID- 23817819 TI - Relationship between nursing documentation and patients' mortality. AB - BACKGROUND: Nurses alter their monitoring behavior as a patient's clinical condition deteriorates, often detecting and documenting subtle changes before physiological trends are apparent. It was hypothesized that a nurse's behavior of recording optional documentation (beyond what is required) reflects concern about a patient's status and that mining data from patients' electronic health records for the presence of these features could help predict patients' mortality. METHODS: Data-mining methods were used to analyze electronic nursing documentation from a 15-month period at a large, urban academic medical center. Mortality rates and the frequency of vital sign measurements (beyond required) and optional nursing comment documentation were analyzed for a random set of patients and patients who experienced a cardiac arrest during their hospitalization. Patients were stratified by age-adjusted Charlson comorbidity index. RESULTS: A total of 15,000 acute care patients and 145 cardiac arrest patients were studied. Patients who died had a mean of 0.9 to 1.5 more optional comments and 6.1 to 10 more vital signs documented within 48 hours than did patients who survived. A higher frequency of comment and vital sign documentation was also associated with a higher likelihood of cardiac arrest. Of patients who had a cardiac arrest, those with more documented comments were more likely to die. CONCLUSIONS: For the first time, nursing documentation patterns have been linked to patients' mortality. Findings were consistent with the hypothesis that some features of nursing documentation within electronic health records can be used to predict mortality. With future work, these associations could be used in real time to establish a threshold of concern indicating a risk for deterioration in a patient's condition. PMID- 23817821 TI - Thematic analysis of cardiac care patients' explanations for declining contribution to a genomic research-based biobank. AB - BACKGROUND: Health care delivery systems increasingly ask patients to contribute biological samples for future genomic-based health research during critical care admissions, as the result of genome-based research requirements of unprecedented large sample sizes. Few reports describe patients' perceptions and responses to actual biobanking approaches in clinical settings. A qualitative study was conducted to explore 568 cardiac care patients' explanations of why they declined to contribute their samples to a future genomic research biobank. OBJECTIVES: To (1) identify themes emerging from explanations for declining contribution to the research biobanking initiative and (2) determine how the content informs the stewardship conceptual framework that addresses evidence-based clinical ethics practices in genomic and genetic research biobanking. METHODS: This qualitative study used an analytic method that combines inductive and deductive approaches to identify themes in patients' explanations for declining to contribute to a research biobank initiative. The hybrid design has relevance to health services research that seeks to develop taxonomy, themes, and theory. RESULTS: Inductive approaches showed that themes of intrusion and autonomy dominated explanations. Deductive approaches affirmed previously proposed elements of a stewardship conceptual framework that addresses ethics in biobanking. CONCLUSION: Research in understanding patients' perceptions can guide nursing and biobank practices in developing best practices. PMID- 23817823 TI - Physiological responses to passive exercise in adults receiving mechanical ventilation. AB - BACKGROUND: Critical illness may weaken muscles, with long-term consequences. OBJECTIVE: To assess physiological responses to an early standardized passive exercise protocol to prevent muscle weakness in adults receiving mechanical ventilation. METHODS: A quasi-experimental within-subjects repeated-measures design was used. Within 72 hours of intubation, 30 patients had 20 minutes of bilateral passive leg movement delivered by continuous-passive-motion machines at a standardized rate and flexion-extension. Heart rate, mean blood pressure, oxygen saturation, and cytokine levels were measured before, during, and after the intervention. The Behavioral Pain Scale was used to measure patients' comfort. Repeated-measures analysis of variance was used to analyze the effect of the exercise on independent variables. RESULTS: Patients were mostly white men with a mean age of 56.5 years (SD, 16.9) with moderate mortality risk and illness severity. Heart rate, mean blood pressure, and oxygen saturation did not differ from baseline at any time measured. Pain scores were significantly reduced (F(2.43,70.42) = 4.08; P = .02) 5 and 10 minutes after exercise started and remained reduced at the end of exercise and 1 hour later. Interleukin 6 levels were significantly reduced (F(1.60,43.1) = 4.35; P = .03) at the end of exercise but not after the final rest period. Interleukin 10 levels did not differ significantly. Ratios of interleukin 6 to interleukin 10 decreased significantly (F(1.61,43.38) = 3.42; P = .05) at the end of exercise and again after 60 minutes' rest. CONCLUSION: The exercise was well tolerated, and comfort improved during and after the intervention. Cytokine levels provided physiological rationale for benefits of early exercise. PMID- 23817822 TI - Thirst in critically ill patients: from physiology to sensation. AB - Critically ill patients often report distressful episodes of severe thirst, but the complex biochemical, neurohormonal mechanisms that regulate this primal sensation still elude clinicians. The most potent stimuli for thirst are subtle increases in plasma osmolality. These minute changes in osmolality stimulate central osmoreceptors to release vasopressin (also known as antidiuretic hormone). Vasopressin in turn acts on the kidneys to promote the reabsorption of water to correct the increased osmolality. If this compensatory mechanism fails to decrease osmolality, then thirst is triggered to motivate drinking. In contrast, thirst induced by marked volume loss, or hypovolemic thirst, is subject to the tight osmoregulation of the renin-angiotensin aldosterone system and accompanying adrenergic agonists. Understanding the essential role that thirst plays in salt and water regulation can provide clinicians with a better appreciation for the complex physiology that underlies this intense sensation. PMID- 23817824 TI - Early passive mobility. PMID- 23817825 TI - Asking for parents' permission to enroll their child into a clinical trial: best practices. PMID- 23817826 TI - Do earplugs and eye masks affect sleep and delirium outcomes in the critically ill? PMID- 23817827 TI - Syncope and cardiac rhythms. PMID- 23817828 TI - A cluster of fulminant, fatal necrotizing community-associated methicillin resistant Staphylococcus aureus pneumonias. AB - Community-associated methicillin-resistant Staphylococcus aureus is a frequent cause of skin and soft-tissue infections and is increasingly identified as a cause of pneumonia in immunocompetent patients. Panton-Valentine leukocidin, one of several leukocytotoxic peptides secreted by these cocci, is associated with increased virulence. A cluster of 3 unrelated patients with fatal pneumonia presumably caused by community-associated methicillin-resistant S aureus positive for Panton-Valentine leukocidin were treated in a 3-week period. Despite aggressive care and appropriate, timely administration of antibiotics, all 3 patients died. This article reviews the clinical and laboratory features suggestive of this lethal isolate, including unique findings on Gram stains of sputum. PMID- 23817830 TI - Nonlinear optical properties of boron doped single-walled carbon nanotubes. AB - Single-walled carbon nanotubes (SWCNTs) exhibit excellent nonlinear optical (NLO) properties due to the delocalized pi electron states present along their tube axis. Using the open aperture Z-scan method in tandem with X-ray photoelectron spectroscopy (XPS) and Raman spectroscopy, we demonstrate the simultaneous tailoring of both electronic and NLO properties of SWCNTs, from ultrafast (femtosecond) to relatively slow (nanosecond) timescales, by doping with a single substituent, viz., boron. SWCNTs were doped via a wet chemical method using B2O3, and the boron content and bonding configurations were identified using XPS. While in the ns excitation regime, the nonlinear absorption was found to increase with increasing boron concentration in the SWCNTs (due to the increasing disorder and enhanced metallicity of the SWCNTs), the saturation intensity in the fs excitation regime decreased. We attribute this counter-intuitive behavior to excited state absorption on ns timescales, and saturable absorption combined with weak two-photon transitions on fs timescales between van Hove singularities. PMID- 23817832 TI - Binding of Dopamine to Alpha-Synuclein is Mediated by Specific Conformational States. AB - Parkinson's disease is the second most common neurodegenerative disorder, in which both alpha-synuclein (alpha-syn) and dopamine (DA) have a critical role. alpha-Syn is known to be natively unstructured in equilibrium with subpopulations of more compact structures. It is these compact structures that are thought to be linked to amyloid formation. In the presence of DA, alpha-syn yields a diverse range of SDS-resistant, non-amyloid oligomers, however the precursor state conformation has not been established. Here, three DA molecules have been observed to bind per alpha-syn monomer by electrospray-ionization-ion mobility spectrometry-mass spectrometry (ESI-IMS-MS). Each of these DA molecules binds exclusively to the extended conformation of alpha-syn, and binding is not observed in the compact state of the protein. Measurements of collisional cross sectional areas show that the incremental uptake of DA pushes the protein towards a highly extended population, becoming fully populated upon the binding of three DA ligands. Tyrosine (Tyr) as a closely related structural analog, exhibited limited binding to the protein as compared with DA, with a maximum of two ligands being observed. Those Tyr ligands that do bind were observed as adducts to the extended conformation akin to DA. These findings suggest DA is able to modulate alpha-syn self-assembly by inducing the population of a highly extended state. PMID- 23817833 TI - Gas-phase synthesis of singly and multiply charged polyoxovanadate anions employing electrospray ionization and collision induced dissociation. AB - Electrospray ionization mass spectrometry (ESI-MS) combined with in-source fragmentation and tandem mass spectrometry (MS/MS) experiments were used to generate a wide range of singly and multiply charged vanadium oxide cluster anions including VxOy(n-) and VxOyCl(n-) ions (x = 1-14, y = 2-36, n = 1-3), protonated clusters, and ligand-bound polyoxovanadate anions. The cluster anions were produced by electrospraying a solution of tetradecavanadate, V14O36Cl(L)5 (L = Et4N(+), tetraethylammonium), in acetonitrile. Under mild source conditions, ESI-MS generates a distribution of doubly and triply charged VxOyCl(n-) and VxOyCl(L)((n-1)-) clusters predominantly containing 14 vanadium atoms as well as their protonated analogs. Accurate mass measurement using a high-resolution LTQ/Orbitrap mass spectrometer (m/Deltam = 60,000 at m/z 410) enabled unambiguous assignment of the elemental composition of the majority of peaks in the ESI-MS spectrum. In addition, high-sensitivity mass spectrometry allowed the charge state of the cluster ions to be assigned based on the separation of the major from the much less abundant minor isotope of vanadium. In-source fragmentation resulted in facile formation of smaller VxOyCl((1-2)-) and VxOy ((1-2)-) anions. Collision-induced dissociation (CID) experiments enabled systematic study of the gas-phase fragmentation pathways of the cluster anions originating from solution and from in-source CID. Surprisingly simple fragmentation patterns were obtained for all singly and doubly charged VxOyCl and VxOy species generated through multiple MS/MS experiments. In contrast, cluster anions originating directly from solution produced comparatively complex CID spectra. These results are consistent with the formation of more stable structures of VxOyCl and VxOy anions through low-energy CID. Furthermore, our results demonstrate that solution-phase synthesis of one precursor cluster anion combined with gas-phase CID is an efficient approach for the top-down synthesis of a wide range of singly and multiply charged gas-phase metal oxide cluster anions for subsequent investigations of structure and reactivity using mass spectrometry and ion spectroscopy techniques. PMID- 23817831 TI - Fragmentation of neutral amino acids and small peptides by intense, femtosecond laser pulses. AB - High power femtosecond laser pulses have unique properties that could lead to their application as ionization or activation sources in mass spectrometry. By concentrating many photons into pulse lengths approaching the timescales associated with atomic motion, very strong electric field strengths are generated, which can efficiently ionize and fragment molecules without the need for resonant absorption. However, the complex interaction between these pulses and biomolecular species is not well understood. To address this issue, we have studied the interaction of intense, femtosecond pulses with a number of amino acids and small peptides. Unlike previous studies, we have used neutral forms of these molecular targets, which allowed us to investigate dissociation of radical cations without the spectra being complicated by the action of mobile protons. We found fragmentation was dominated by fast, radical-initiated dissociation close to the charge site generated by the initial ionization or from subsequent ultrafast migration of this charge. Fragments with lower yields, which are useful for structural determinations, were also observed and attributed to radical migration caused by hydrogen atom transfer within the molecule. PMID- 23817834 TI - Bioreduction of para-chloronitrobenzene in a hydrogen-based hollow-fiber membrane biofilm reactor: effects of nitrate and sulfate. AB - A continuous-stirred, hydrogen-based, hollow-fiber membrane biofilm reactor (HFMBfR) that was active in nitrate and sulfate reductions was shown to be effective for degradation or detoxification of para-chloronitrobenzene (p-CNB) in water by biotransforming it first to para-chloroaniline (nitro-reduction) and then to aniline (reductive dechlorination) with hydrogen (H2) as an electron donor. A series of short-term experiments examined the effects of nitrate and sulfate on p-CNB bioreduction. The results obtained showed both higher nitrate and sulfate concentration declined the p-CNB bioreduction in the biofilm, and this suggests the competition for H2 caused less H2 available for the p-CNB bioreduction when the H2 demand for the reductions was larger. Denitrification and sulfate reduction intermediates were thought to be potential factors inhibiting the p-CNB bioreduction. Analysis of electron-equivalent fluxes and reaction orders in the biofilm further demonstrated both denitrification and sulfate reduction competed more strongly for H2 availability than p-CNB bioreduction. These findings have significant implications for the HFMBfR used for degrading p-CNB under denitrifying and/or sulfate reducing conditions. PMID- 23817835 TI - Hybrid NS ligands supported Cu(I)/(II) complexes for azide-alkyne cycloaddition reactions. AB - Three copper complexes of nitrogen-sulfur donor ligands, [CuBr2(L1)] (1), [CuCl2(L2)2] (2) and [Cu2I2(L3)]n (3) (L1 = bis(2-cyclohexylsulfanylethyl)amine, L2 = 2-(benzylsulfanylmethyl)pyridine and L3 = 2-(4 pyridylsulfanylmethyl)pyridine), have been synthesized and characterized by single-crystal X-ray diffraction (XRD), powder XRD and TGA analysis. Complexes 1 and 2 are mononuclear Cu(II) complexes and are EPR active with distorted square pyramidal and octahedral geometry, respectively. Complex 3 is a two-dimensional tetrahedral Cu(I) coordination polymer with 16- and 20-membered metallocycles. These complexes show good catalytic activities for one-pot azide-alkyne cycloaddition reactions in CH3OH-H2O. PMID- 23817836 TI - Crackling noise during failure of alumina under compression: the effect of porosity. AB - We study acoustic emission avalanches during the process of failure of porous alumina samples (Al2O3) under compression. Specimens with different porosities ranging from 30% to 59% have been synthesized from a mixture of fine-grained alumina and graphite. The compressive strength as well as the characteristics of the acoustic activity have been determined. The statistical analysis of the recorded acoustic emission pulses reveals, for all porosities, a broad distribution of energies with a fat tail, compatible with the existence of an underlying critical point. In the region of 35%-55% porosity, the energy distributions of the acoustic emission signals are compatible with a power-law behaviour over two decades in energy with an exponent epsilon = 1.8 +/- 0.1. PMID- 23817837 TI - Mucin-like peptides from Echinococcus granulosus induce antitumor activity. AB - There is substantial evidence suggesting that certain parasites can have antitumor properties. We evaluated mucin peptides derived from the helminth Echinococcus granulosus (denominated Egmuc) as potential inducers of antitumor activity. We present data showing that Egmuc peptides were capable of inducing an increase of activated NK cells in the spleen of immunized mice, a fact that was correlated with the capacity of splenocytes to mediate killing of tumor cells. We demonstrated that Egmuc peptides enhance LPS-induced maturation of dendritic cells in vitro by increasing the production of IL-12p40p70 and IL-6 and that Egmuc-treated DCs may activate NK cells, as judged by an increased expression of CD69. This evidence may contribute to the design of tumor vaccines and open new horizons in the use of parasite-derived molecules in the fight against cancer. PMID- 23817838 TI - Should patients with papillary microcarcinoma undergo radioiodine ablation? PMID- 23817840 TI - Serum concentrations of fully and undercarboxylated osteocalcin do not vary between estrous cycle stages in Sprague-Dawley rats. PMID- 23817839 TI - Anti-hypertensive treatment in pheochromocytoma and paraganglioma: current management and therapeutic features. AB - Pheochromocytoma (PH) and paraganglioma (PG) are neuroendocrine neoplasms arising from chromaffin cells of the adrenal medulla and the sympathetic ganglia, respectively. Although are unusual cause of hypertension (HT) accounting for at most 0.1-0.2 % of cases, they may lead to severe and potentially lethal hypertensive crisis due to the effects of the released catecholamines. However, both PH and PG may be asymptomatic as ~30 % of subjects are normotensive or have orthostatic hypotension and in these cases the 24 h ambulatory blood pressure (BP) monitoring is an important toll to diagnose and treat HT. HT treatment may be difficult when PH or PG occurs in pregnancy or in the elderly subjects and in these cases a multidisciplinary team is required. When surgical excision is mandatory the perioperative management requires the administration of selective alpha1-adrenergic blocking agents (i.e., doxazosin, prazosin or terazosin) followed by a beta-adrenergic blockade (i.e., propranolol, atenolol). This latter should never be started first because blockade of vasodilatory peripheral beta adrenergic receptors with unopposed alpha-adrenergic receptor stimulation can lead to a further elevation of BP. Although labetalol is traditionally considered the ideal agent due to its alpha- and beta-adrenergic antagonism, experimental studies do not support its use in this clinical setting. As second regimen, the administration of vasodilators as calcium channel blockers (i.e., nicardipine, nifedipine) may be required to control BP. Oral and sublingual short-acting nifedipine are potentially dangerous in patients with hypertensive emergencies and are not recommend. The latest evidences into the diagnosis and treatment of hypertensive crisis due to PH and PG are reviewed here. PMID- 23817841 TI - Increased risk of breast cancer associated with long-term shift work in Canada. AB - OBJECTIVES: Long-term night work has been suggested as a risk factor for breast cancer; however, additional studies with more comprehensive methods of exposure assessment to capture the diversity of shift patterns are needed. As well, few previous studies have considered the role of hormone receptor subtype. METHODS: Relationships between night shift work and breast cancer were examined among 1134 breast cancer cases and 1179 controls, frequency-matched by age in Vancouver, British Columbia, and Kingston, Ontario. Self-reported lifetime occupational histories were assessed for night shift work, and hormone receptor status obtained from tumour pathology records. RESULTS: With approximately one-third of cases and controls ever employed in night shift work, associations with duration demonstrated no relationship between either 0-14 or 15-29 years, while an association was apparent for >=30 years (OR=2.21, 95% CI 1.14 to 4.31). This association with long-term night shift work is robust to alternative definitions of prolonged shift work, with similar results for both health and non-health care workers. CONCLUSIONS: Long-term night shift work in a diverse mix of occupations is associated with increased breast cancer risk and not limited to nurses, as in most previous studies. PMID- 23817842 TI - Influence of variable native arterial diameter and vasculature status on coronary diagnostic parameters. AB - In current practice, diagnostic parameters, such as fractional flow reserve (FFR) and coronary flow reserve (CFR), are used to determine the severity of a coronary artery stenosis. FFR is defined as the ratio of hyperemic pressures distal (p(rh)) and proximal (p(ah)) to a stenosis. CFR is the ratio of flow at hyperemic and basal condition. Another diagnostic parameter suggested by our group is the pressure drop coefficient (CDP). CDP is defined as the ratio of the pressure drop across the stenosis to the upstream dynamic pressure. These parameters are evaluated by invasively measuring flow (CFR), pressure (FFR), or both (CDP) in a diseased artery using guidewire tipped with a sensor. Pathologic state of artery is indicated by lower CFR (<2). Similarly, FFR lower than 0.75 leads to clinical intervention. Cutoff for CDP is under investigation. Diameter and vascular condition influence both flow and pressure drop, and thus, their effect on FFR and CDP was studied. In vitro experiment coupled with pressure-flow relationships from human clinical data was used to simulate pathophysiologic conditions in two representative arterial diameters, 2.5 mm (N1) and 3 mm (N2). With a 0.014 in. (0.35 mm) guidewire inserted, diagnostic parameters were evaluated for mild (~64% area stenosis (AS)), intermediate (~80% AS), and severe (~90% AS) stenosis for both N1 and N2 arteries, and between two conditions, with and without myocardial infarction (MI). Arterial diameter did not influence FFR for clinically relevant cases of mild and intermediate stenosis (difference < 5%). Stenosis severity was underestimated due to higher FFR (mild: ~9%, intermediate: ~ 20%, severe: ~ 30%) for MI condition because of lower pressure drops, and this may affect clinical decision making. CDP varied with diameter (mild: ~20%, intermediate: ~24%, severe: by 2.5 times), and vascular condition (mild: ~35%, intermediate: ~14%, severe: ~ 9%). However, nonoverlapping range of CDP allowed better delineation of stenosis severities irrespective of diameter and vascular condition. PMID- 23817843 TI - [Anesthesiological aspects of deep brain stimulation : special features of implementation and dealing with brain pacemaker carriers]. AB - Deep brain stimulation (DBS) provides a very effective treatment for a number of neurological diseases including Parkinson's disease, movement disorders and epilepsy. In DBS microelectrodes are positioned in defined cerebral target areas and connected to a pacemaker. It is most often performed as an awake craniotomy with intraoperative testing. Various anesthesiological regimes are used to protect the patient from surgical stress on the one hand and to achieve ideal test conditions on the other. They include local anesthesia or scalp blocks, intermittent general anesthesia or analgosedation with or without airway protection; however, anesthetic agents interfere with hemodynamic stability and ventilation, with vigilance and cooperation and in addition with the symptoms and microelectrode recording. Guidance and communication have a pivotal impact on patient needs for pharmacological interventions. With increasing numbers of DBS procedures, anesthesiologists are more often faced with patients carrying brain pacemakers. For anesthesia the characteristics of the disease as well as the respective long-term medication have to be considered. In addition, the rules for handling patients with pacemakers need to be followed to avoid both dysfunction of the generator and tissue damage due to overheating of the electrodes. PMID- 23817844 TI - [Medicine from the computer]. AB - Small molecules can have a significant effect on human metabolic processes. Computational drug design aims at constructing specialized small molecules that selectively and efficiently address specific proteins. The basic ideas of computational molecular design are presented and it will be shown how a virtual protein can be computer designed. This virtual protein can be used to predict the binding affinity of given small molecules without having to synthesize them in a laboratory. Modern computational drug design goes far beyond the lock and key principle. Possible future developments are discussed and a current successful example of computational drug design in the field of painkiller medication is demonstrated. PMID- 23817845 TI - Nicotinamide adenine dinucleotide (NAD+) repletion attenuates bupivacaine-induced neurotoxicity. AB - Bupivacaine is one of the most toxic local anesthetics but the mechanisms underlying its neurotoxicity are still unclear. Intracellular nicotinamide adenine dinucleotide (NAD(+)) depletion has been demonstrated to play an essential role in neuronal injury. In the present study, we investigated whether intracellular NAD(+) depletion contributes to bupivacaine-induced neuronal injury and whether NAD(+) repletion attenuates the injury in SH-SY5Y cells. First, we evaluated the intracellular NAD(+) content after bupivacaine exposure. We also examined the cellular NAD(+) level after pretreatment with exogenous NAD(+). We next determined cell viability and the apoptosis rate after bupivacaine treatment in the presence or absence of NAD(+) incubation. Finally, cell injuries such as nuclear injury, reactive oxygen species (ROS) production, and mitochondrial depolarization were detected after bupivacaine treatment with or without NAD(+) pretreatment. Bupivacaine caused intracellular NAD(+) depletion in a time- and concentration-dependent manner. Cellular NAD(+) replenishment prevented cell death and apoptosis induced by bupivacaine. Importantly, exogenous NAD(+) attenuated bupivacaine-induced nuclear injury, ROS production, and mitochondrial depolarization. Our results suggest that NAD(+) depletion is necessary for bupivacaine-induced neuronal necrosis and apoptosis, and that NAD(+) repletion attenuates neurotoxicity resulting from bupivacaine-treatment. PMID- 23817846 TI - Status epilepticus induces long lasting increase in S100A6 expression in astrocytes. AB - In the present work we examined expression and localization of the S100A6 protein in rat brain in a model of epilepsy induced by Status Epilepticus evoked by amygdala stimulation. We demonstrate, through the use of the reverse transcriptase-polymerase chain reaction technique, that mRNA level of S100A6 was increased in cortex while, as found by immunoblotting, the level of the S100A6 protein was significantly higher in the cortex and in the CA1 area of the hippocampus at day 14 after stimulation. Immunohistochemical studies performed on rat brain slices indicated that S100A6 immunoreactivity was elevated in GFAP positive astrocytes in the hippocampus and cortex starting from day 1, and further increased at day 4 and 14 after stimulation. Interestingly, in a subpopulation of astrocytes, up-regulation of S100A6 was associated with an increased level of beta-catenin, a protein involved in regulation of S100A6 expression. Altogether, our data show a widespread and prolonged up-regulation of S100A6 in the epileptic brain and indicate that an increase in S100A6 immunoreactivity is related to astrogliosis. PMID- 23817851 TI - Newborn with mild, self-resolving respiratory distress. PMID- 23817852 TI - What is meant by "increased risk for suicide"? PMID- 23817853 TI - Are active video games useful in increasing physical activity and addressing obesity in children? PMID- 23817854 TI - What is meant by "increased risk for suicide"?--Reply. PMID- 23817855 TI - Are active video games useful in increasing physical activity and addressing obesity in children? PMID- 23817856 TI - Are active video games useful in increasing physical activity and addressing obesity in children?--Reply. PMID- 23817857 TI - JAMA pediatrics patient page. Transition of care from pediatric to adult clinics. PMID- 23817858 TI - An African PTSD proverb? PMID- 23817859 TI - Covert clozapine overdose: Clozapine toxicity in a naive patient. PMID- 23817860 TI - Compulsory treatment: rights, reforms and the role of realism. PMID- 23817861 TI - Effects of guideline-oriented pharmacotherapy in patients with newly diagnosed COPD: a prospective study. AB - BACKGROUND: Whether guideline-oriented pharmacotherapy prevents the decline in pulmonary function or reduces systemic inflammation associated with chronic obstructive pulmonary disease (COPD) is uncertain. OBJECTIVES: The aim of this study was to assess the outcome of COPD in clinical practice under real-world conditions in Taiwan as measured by pulmonary function and systemic inflammation parameters (C-reactive protein (CRP) or white blood cell (WBC)) after initiation of guideline-oriented pharmacotherapy. METHODS: Newly diagnosed COPD patients were enrolled and prospectively observed in real-world outpatient practice following initiation of pharmacotherapy of COPD. Pulmonary function, WBC and neutrophil counts, and CRP level of COPD patients were assessed annually. This study enrolled 566 patients and 263 returned for follow-up visits. RESULTS: Significantly higher postbronchodilator FVC, FEV1, and FEV1/FVC but lower DLCO were found at 1 year compared to baseline values. During 4-year follow-up period, FVC and FEV1 remained stable. DLCO progressively declined compared to baseline. No significant changes were seen in CRP and neutrophil count over a 3-year period. Values of CRP, WBC, and neutrophil count correlated inversely with FEV1, FVC, FEV1/FVC, and DLCO. CONCLUSIONS: Guideline-oriented pharmacotherapy of COPD improves airflow limitation but does not prevent the alveolar destruction and systemic inflammation under real-world conditions in Taiwan. PMID- 23817862 TI - The early prediction of neonatal morbidity and mortality in singleton small for gestational age infants with a birthweight < 1,500 g. AB - OBJECTIVE: Identify factors for discrimination of "high" and "low risk" small for gestational age infants. STUDY DESIGN: Singleton infants born small for gestational age with a birthweight <1,500 g between 1999 and 2007 were included. Maternal, placental, and infant related factors were analyzed with regard to mortality and morbidity. Patients who died or suffered from complications were defined "high risk" as opposed to "low risk". Parameters associated with "high risk" were identified and an equation established to predict the minimal expected probability to die or suffer from neonatal morbidity. RESULTS: Around 231 patients showed a mortality rate of 12.6 %, respiratory distress syndrome in 35.5 %, necrotizing enterocolitis in 8.2 % and neurological morbidities in 6.5 %. Of these, 58.9 % survived without complications. The factors for discrimination of "high" and "low risk" were Z-score of birth weight, gestational age, and pH. CONCLUSION: We facilitate prognostication by classifying small for gestational age preterms into "low" and "high risk". PMID- 23817863 TI - Coronary subclavian steal syndrome: an extracoronary cause of acute coronary syndrome. AB - Significant atherosclerotic changes of the coronary arteries are the common cause of cardiac chest pain. We report the case of an 80-year-old woman suffering from unstable angina caused by extracoronary atherosclerosis. The patient had an extensive medical history with severe coronary heart disease and cardiac bypass surgery (LIMA to LAD, two venous bypass grafts). An urgent coronary angiography was performed. The angiogram displayed the already known three-vessel disease, the bypass grafts were in a good functional condition. Subsequently, a stenosis of the proximal segment of the left subclavian artery was detected. Measurement of the pullback pressure gradient confirmed the significance of the stenosis. We suspected a "steal phenomenon" concerning the bypass graft LIMA to LAD. An ad hoc PTA with consecutive stenting (self-expandable stent) enabled a successful revascularization of the left subclavian artery without any adverse effects to the vertebral arteries. Cardiac chest pain did not occur any more. Coronary Subclavian Steal Syndrome should be considered a rare but important differential diagnosis in acute coronary syndrome after bypass surgery. PMID- 23817864 TI - Internal structure-mediated ultrafast energy transfer in self-assembled polymer blend dots. AB - Applications of polymeric semiconductors in organic electronics and biosensors depend critically on the nature of energy transfer in these materials. Important questions arise as to how this long-range transport degrades in amorphous condensed solids which are most amenable to low-cost optoelectronic devices and how fast energy transfer could occur. Here, we address these in disordered, densely packed nanoparticles made from green-light-harvesting host polymers (PFBT) and deep-red-emitting dopant polymers (PF-DBT5). By femtosecond selective excitation of donor (BT) units, we study in detail the internal structure mediated energy transfer to uniformly distributed, seldom acceptor (DBT) units. It has been unambiguously demonstrated that the creation of interchain species is responsible for the limitation of bulk exciton diffusion length in polymer materials. This interchain Forster resonance energy transfer (FRET) becomes a preferred and dominant channel, and near 100% energy transfer efficiency could be achieved at high acceptor concentrations (>10 wt%). Side-chain carboxylic acid groups in functionalized polymer-blend dots slightly slow down the FRET rate, but it could not affect the Forster radius and FRET efficiency. These findings imply that a greater understanding of the role of interchain species could be an efficient approach to improve the cell efficiency. PMID- 23817865 TI - Effects of a comprehensive intervention program, including hot bathing, on physical function in community-dwelling healthy older adults: a pilot randomized controlled trial. AB - BACKGROUND AND AIMS: To study the effects of a comprehensive intervention program comprising exercise, diet, and hot bathing in community-dwelling older adults by using a randomized controlled trial. METHODS: The program included 61 community dwelling healthy older adults (mean [SD] age, 69.9 [5.3] years) who were using a hot bath facility. The participants were randomly assigned to four groups as follows: an exercise, diet, and hot bath intervention group (A); an exercise and diet intervention group (B); a hot bath intervention group (C); and a control group (D). Individuals in groups A and B participated in a comprehensive intervention program (including exercise and diet classes) twice a week for 3 months, and those in groups A and C took hot baths. RESULTS: After 3 months, the participants in groups A and B showed a significantly greater improvement in their timed up and go test and stepping test scores than the participants in groups C and D. However, the participants in groups A and C did not show any dependent or independent effects of hot bathing. Three months after the intervention, a follow-up assessment indicated that the group A participants maintained the effect of the intervention and showed improved lower extremity function and health-related quality of life. CONCLUSIONS: The present study suggests that a comprehensive intervention program involving hot bathing may improve lower extremity function and that its effects can be maintained even in healthy older adults. However, the dependent or independent effects of hot bathing may not be expected for healthy older adults. PMID- 23817866 TI - Return to work after spinal stenosis surgery and the patient's quality of life. AB - INTRODUCTION: The return to work of patients who undergo spinal surgery poses important medical and social challenge. OBJECTIVES: 1) To establish whether patients who undergo spinal stenosis surgery later return to work. 2) To establish the patient's attitude towards employment. 3) To assess the quality of life of the patients and its influence on their attitude to work. MATERIALS AND METHODS: The study population consisted of 58 patients aged from 21 to 80 years (the mean age was 52.33+/-14.12). There were 29 women (50%) and 29 men (50%) in the group. The patients' quality of life was measured by the use of the WHOQOL BREF instrument. Individual interviews were conducted 3 to 8 months (a mean of 5.72 months +/-1.6) after the surgery. RESULTS: 1) Although 13 patients (22.3%) returned to work, 44 (75.9%) did not, these being manual workers of vocational secondary education. 2) Almost half of the patients (27 patients, i.e. 44%) intend to apply for disability pension, 16 patients (27.6%) consider themselves unfit to work, 22 patients (37.9%) do not feel like working again. 3) The quality of life of the patients decreased. Domain scores for the WHOQOL-BREF are transformed to a 0-100 scale. The mean physical health amounted to 60.67 (+/ 16.31), the mean psychological health was 58.78 (+/-16.01), while the mean social relations with family and friends were 59.91 (+/-20.69), and the mean environment 59.62 (+/-12.48). CONCLUSIONS: 1) A total of 75% of the patients operated for lumbar spinal stenosis do not return to their preoperative work. Difficulties in returning to work and decreased quality of life are associated with female sex, lower-level education, hard physical work and low income. 2) Physical health, psychological health, social relations and environment decreased to the mean of approximately 60. 3) The quality of life of the patients who did return to work was similar to that of healthy people. PMID- 23817867 TI - Analysis of job stress in workers employed by three public organizations in Serbia. AB - OBJECTIVES: The present study analyzes job stress in terms of education, age and the presence of cardiovascular and endocrine/metabolic diseases. MATERIAL AND METHODS: A total of 411 workers employed by three public organizations completed the Job Content Questionnaire to classify their jobs based on the job strain model. Data about health condition, education and habits was obtained by the use of medical examinations and an interview. RESULTS: The analysis of the completed Job Content Questionnaires indicates that workers with high education have significantly higher decision latitude (DL) than low-educated workers (one-way ANOVA, p < 0.0001). DL was also different between age groups (one-way ANOVA, p < 0.0001) - the highest DL values were observed in the oldest group, while the lowest DL mean was found in the youngest group. Psychological job demands (PJD) and social support (SS) were not significantly different between educational and age groups. The frequency of job stress categories was significantly different between low and highly-educated workers (chi(2) test, df = 3, p < 0.0001) and also between different age groups (chi(2) test, df = 6, p < 0.0001). The majority of highly-educated men were exposed to "active" jobs (high PJD and high DL). Most frequently, men older than 45 years experienced jobs with high DL ("active" and "low strain"), men aged 35 to 45 years were exposed to jobs with high PJD ("high strain" and "active") while the majority of men younger than 35 years were exposed to jobs with low DL ("high strain" and "passive"). No association between cardiovascular and endocrine/metabolic disorders and different job stress categories was observed. CONCLUSION: "High strain" and "passive" jobs were most frequently identified among low-educated and young men. Despite the absence of association between job stress and cardiovascular and endocrine/metabolic diseases, we recommend prevention of work stress, particularly in the case of low educated workers and workers younger than 45 years exposed to unfavorable job stress categories. PMID- 23817868 TI - Voice amplification for primary school teachers with voice disorders: a randomized clinical trial. AB - OBJECTIVES: Several studies have demonstrated a high prevalence of voice disorders in teachers, together with the personal, professional and economical consequences of the problem. Good primary prevention should be based on 3 aspects: 1) amelioration of classroom acoustics, 2) voice care programs for future professional voice users, including teachers and 3) classroom or portable amplification systems. The aim of the study was to assess the benefit obtained from the use of portable amplification systems by female primary school teachers in their occupational setting. MATERIALS AND METHODS: Forty female primary school teachers attended a course about professional voice care, which comprised two theoretical lectures, each 60 min long. Thereafter, they were randomized into 2 groups: the teachers of the first group were asked to use a portable vocal amplifier for 3 months, till the end of school-year. The other 20 teachers were part of the control group, matched for age and years of employment. All subjects had a grade 1 of dysphonia with no significant organic lesion of the vocal folds. RESULTS: Most teachers of the experimental group used the amplifier consistently for the whole duration of the experiment and found it very useful in reducing the symptoms of vocal fatigue. In fact, after 3 months, Voice Handicap Index (VHI) scores in "course + amplifier" group demonstrated a significant amelioration (p = 0.003). The perceptual grade of dysphonia also improved significantly (p = 0.0005). The same parameters changed favourably also in the "course only" group, but the results were not statistically significant (p = 0.4 for VHI and p = 0.03 for perceptual grade). CONCLUSIONS: In teachers, and particularly in those with a constitutional weak voice and/or those who are prone to vocal fold pathology, vocal amplifiers may be an effective and low-cost intervention to decrease potentially damaging vocal loads and may represent a necessary form of prevention. PMID- 23817869 TI - Hepatitis B and C infection: is it a problem in Polish healthcare workers? AB - OBJECTIVES: Hepatitis B (HBV) and C viruses (HCV) are among the most frequent blood borne pathogens. According to WHO, 5% of healthcare workers (in central Europe), are exposed to at least one sharps injury contaminated with HBV per year, 1,7% - contaminated with HCV. AIMS: The aims of the study were to determine prevalence of HCV and HBV infections, vaccination efficacy against hepatitis B and usefulness of alanine aminotransferase (ALT) testing in prophylactic examinations in healthcare workers (HCWs). MATERIAL AND METHODS: In a group of 520 healthcare workers, a survey, laboratory and serologic tests such as ALT, HBsAg, anti-HBs, anti-HBcT and anti-HCV were carried out. RESULTS: The study revealed a low rate of workers with presence of HBsAg and anti-HCV (1,2% and 0,8% respectively). Anti-HBcT was found in 99 subjects (19%) without a significant association with experiencing an occupational percutaneous injury. Being vaccinated against HBV was declared by 90% of the subjects. There was no relationship between ALT level rise and positive HBsAg, anti-HCV and anti-HBcT tests. CONCLUSION: A seroprevalence of HBV and HCV markers in HCWs found in the study is low and similar to the one found in general population. Current or past hepatitis B infections were independent of needle stick injuries. Vaccination against HBV coverage, although found to be high, should improve to 100%. Occupational prophylactic medical examinations found performing ALT test (obligatory in Poland for HCWs) not helpful. It seems that determination of anti HBcT and anti-HCV status would be essential in pre-employment medical examinations. PMID- 23817870 TI - Survival impact of serum uric acid levels in children and adolescents. AB - Evidence is limited on the association between hyperuricaemia and mortality in children and adolescents. This study was to investigate this association in the paediatric population. The study included children and adolescents who had undergone serum uric acid (SUA) measurement at the Chang Gung Memorial Hospital between 1997 and 2008. The survival status and cause of death of the included were ascertained by examining the National Death Registry of Taiwan. Hyperuricaemia was defined as a SUA level greater than 7.0 mg/dL. We included 13,241 patients (male, n = 7,454; female, n = 5,787) of mean age 14.3 +/- 4.9 years. During the 82,800 person-years of follow-up, 455 deaths were identified, which corresponded to a crude mortality rate of 5.50 deaths per 1,000 person years. Compared with individuals with a SUA <6.0 mg/dL, those with a SUA of 6.0 8.9, 9.0-11.9 and >=12 mg/dL had an age- and sex-adjusted HR (95% CI) of 1.02 (0.82-1.26), 1.48 (1.08-2.02) and 4.73 (2.67-8.37). After adjustment for age, sex and history of diabetes mellitus and hypertension, hyperuricaemia was found to be associated with a HR (95% CI) of 1.38 (1.13-1.69; p < 0.001) for all-cause mortality. Hyperuricaemia was associated with an increased risk of mortality due to cardiovascular diseases (HR, 5.0; 95% CI 1.79-13.94; p = 0.001) and kidney diseases (11.71; 3.13-43.78; p < 0.001). Paediatric patients with hyperuricaemia were at increased risk of mortality, especially due to kidney and cardiovascular diseases. PMID- 23817871 TI - Risk factors for and prevalence of knee osteoarthritis in the rural areas of Shanxi Province, North China: a COPCORD study. AB - The purpose of this study is to investigate the prevalence of knee osteoarthritis (OA) in the rural areas of Shanxi Province, North China. A total of 7,126 permanent residents aged from 16 to 90 years were surveyed using Community Oriented Program for the Control of Rheumatic Diseases methodology. Diagnosis of knee OA was reached according to the examination results by 3 rheumatologists. Possible risk factors for knee OA were analyzed. Among the 7,126 participants, 983 cases were diagnosed with knee OA. Of the 983 cases, 446 were male (12.4%) and 537 were female (15.3%). The overall prevalence of knee OA was 13.8%. The prevalence rate of knee pain was significantly higher in women than in men. There was a tendency of increased knee OA prevalence with age, especially after 40 years old. Participants with higher body mass index (BMI) showed a higher prevalence rate of knee OA than those with lower BMI. Multivariable analysis indicates age, gender, dietary bias, underground work history, BMI, waist-to-hip ratio (WHR), and concomitant cardiovascular diseases (CSDs) are risk factors for knee OA in rural Shanxi. The prevalence of knee OA in the rural areas of Shanxi Province is high. Age, gender, dietary bias, underground work history, BMI, WHR, and CSDs are risk factors for knee OA. Primary and secondary prevention programs aimed at improving ventilation condition, reducing obesity, and treating concomitant cardiovascular diseases are required. PMID- 23817873 TI - No slackers in tourniquet use to stop bleeding. AB - BACKGROUND: Tourniquets on casualties in war have been loose in 4%?9% of uses, and such slack risks death from uncontrolled bleeding. A tourniquet evidence gap persists if there is a mechanical slack?performance association. OBJECTIVE: The purpose of the present study was to determine the results of tourniquet use with slack in the strap versus no slack before windlass turning, in order to develop best practices. METHODS: The authors used a tourniquet manikin 254 times to measure tourniquet effectiveness, windlass turns, time to stop bleeding, and blood volume lost at 5 degrees of strap slack (0mm, 25mm, 50mm, 100mm, and 200mm maximum). RESULTS: When comparing no slack (0mm) to slack (any positive amount), there were increases with slack in windlass turns (p < .0001, 3-fold), time to stop bleeding (p < .0001, 2-fold), and blood volume lost (p < .0001, 2-fold). When comparing no slack to 200mm slack, the median results showed an increase in slack for windlass turns (p < .0001), time to stop bleeding (p < .0001), and blood volume lost (p < .0001). CONCLUSIONS: Any slack presence in the strap impaired tourniquet performance. More slack had worse results. Trainers can now instruct tourniquet users with concrete guidance. PMID- 23817874 TI - Quality of care assessment in forward detection of extremity compartment syndrome in war. AB - BACKGROUND: Recent efforts to improve the quality of care in the Afghanistan theater have focused on extremity compartment syndrome, a common, disabling, and costly problem. To identify opportunities to improve care, the present survey was undertaken to observe the use of two standard methods?the traditional, improvised method and the common, off-the-shelf method?for determining intracompartmental pressures in the lower extremities of combat casualties. METHODS: As part of a quality of care improvement effort during Operation Enduring Freedom, all combat casualties presenting to a forward surgical team at Forward Operating Base Shank from August to November 2011 with lower-extremity major trauma were evaluated for signs and symptoms of compartment syndrome. RESULTS: Ten casualties had pressure measurement surveyed simultaneously using both methods. A two one-sided test analysis demonstrated a mean difference of ?0.13 (90% confidence interval, ?0.36 to 0.096), which indicated that the methods were similar. A repeated-measures analysis yielded a p value of .72, indicating no statistical difference between the methods. The receiver operating characteristic curve demonstrated excellent agreement within the prespecified limits (?2mm Hg, area under the curve 1.0), which indicated that the methods were similar. CONCLUSION: The main finding of the quality of care effort was that clinicians received similar information from use of two standard methods for far forward measurement of pressures to detect extremity compartment syndrome. This finding may help clinicians improve the quality of care in the theater in detecting, diagnosing, and monitoring compartment syndrome. PMID- 23817872 TI - Omega-3 in SLE: a double-blind, placebo-controlled randomized clinical trial of endothelial dysfunction and disease activity in systemic lupus erythematosus. AB - Accelerated atherosclerosis remains a major cause of death in late systemic lupus erythematosus (SLE). Omega-3 has been reported to have benefit for endothelial dysfunction, one of the earliest stages of atherosclerosis, and to reduce disease activity in SLE. We performed a randomized, double-blind placebo-controlled trial to examine the effect of Omega-3 on endothelial function, disease activity, inflammatory markers and lipids in SLE. SLE patients (n = 85, mean age 47, 55% Caucasian, 38% African-American, 94% female) were randomly assigned to 3 g of Omega-3 (Lovaza, GSK) versus placebo for 12 weeks. Endothelial function was measured at baseline and at 12 weeks using flow-mediated dilation, calculated using high-resolution B-mode ultrasound of the brachial artery diameter in response to vasoactive stimuli (hyperemia). Disease activity was measured using the physician global assessment and SELENA-SLEDAI score. Inflammatory markers (sICAM-1, sVCAM-1, IL-6) and fasting lipid profile were done at baseline and 12 week follow-up. There was no difference between the treatment groups with respect to changes in flow-mediated dilation parameters or disease activity. An average increase in LDL cholesterol of 3.11 mg/dL (+/-21.99) was found with Omega-3 versus a decrease of 1.87 mg/dL (+/-18.29) with placebo (p = 0.0266). In this trial, Omega-3 did not improve endothelial function, disease activity, nor reduce inflammatory markers in SLE. Longer trials might be required if there are delayed clinical effects. There was evidence that Omega-3 may increase LDL cholesterol, but not the LDL/HDL ratio. PMID- 23817875 TI - An Introduction to Survival, Evasion, Resistance, and Escape (SERE) Medicine. AB - When an individual finds himself/herself in a survival, evasion, resistance, or escape (SERE) scenario, the ability to treat injuries/illnesses can be the difference between life and death. SERE schools are responsible for preparing military members for these situations, but the concept of SERE medicine is not particularly well defined. To provide a comprehensive working description of SERE medicine, operational and training components were examined. Evidence suggests that SERE medicine is diverse, injury/illness patterns are situationally dependent, and treatment options often differ from conventional clinical medicine. Ideally, medical lessons taught in SERE training are based on actual documented events. Unfortunately, the existing body of literature is dated and does not appear to be expanding. In this article, four distinct facets of SERE medicine are presented to establish a basis for future discussion and research. Recommendations to improve SERE medical curricula and data-gathering processes are also provided. PMID- 23817876 TI - Endovascular resuscitation techniques for severe hemorrhagic shock and traumatic arrest in the presurgical setting. AB - Novel aortic catheter-based resuscitation interventions aimed at control of noncompressible torso hemorrhage and resuscitative perfusion are undergoing active research and development. These methods have been reported as resuscitative endovascular balloon occlusion of the aorta, selective aortic arch perfusion, and profound hypothermia (emergency preservation and resuscitation). These interventions are advanced options to treat noncompressible torso hemorrhage and hemorrhage-induced traumatic cardiac arrest in the presurgical environment. However, to achieve maximum potential benefit, such interventions need to be initiated as soon as possible. This means that these advanced interventions should be adapted for use in austere military treatment facilities and, when feasible, initiated at the point of injury. This report argues for the feasibility of advanced endovascular resuscitation interventions in the austere military theater. PMID- 23817877 TI - Priorities for a 21st-century defense: aligning u.s. Army environmental science and engineering officer resources with the department of defense strategic guidance. AB - The recently published Department of Defense (DoD) strategic guidance highlights the need to ?shape a joint force for the future.? Supporting requirements to shape the joint force while the overall DoD force structure is reduced will be challenging. Fortunately, based on its unique training and experience, the Army Environmental Science and Engineering Officer (ESEO) profession is positioned today to fill anticipated joint public health requirements. Obtaining the U.S. Army Medical Department (AMEDD) approval to meet these requirements will have near-term consequences for the ESEO profession as some existing (albeit antiquated) authorizations may go unfilled. However, long-term dividends for the Medical Service Corps (MSC), AMEDD, Army, and DoD will be achieved by realigning critical resources to future joint and interagency requirements. Assigning ESEOs now to organizations such as the Theater Special Operations Commands (TSOCs), U.S. Agency for International Development (USAID), and the North Atlantic Treaty Organization (NATO) with perceived and real joint force health protection/public health requirements through unique means will ensure our profession remains relevant today and supports the joint force of tomorrow. PMID- 23817878 TI - CBRNE TC3: A Hybrid Approach to Casualty Care in the CBRNE Environment. AB - The implementation of Tactical Combat Casualty Care (TCCC) guidelines for the Operation Enduring Freedom and Operation Iraqi Freedom contingency operations has dramatically reduced preventable combat deaths. A study of these principles and their application to medical treatment in the chemical, biological, radiological, nuclear, and high-yield explosives (CBRNE), weapons of mass destruction (WMD) environment is presented as a potential readiness and force multiplier for units engaged in this area of operations. Preparing medical operators for support of WMD sampling and mitigation missions requires extensive preventive medicine and post-exposure and downrange trauma threat preparedness. Training and equipping CBRN operators with treatment skills and appropriate interventional material requires pre-implementation planning specific to WMD threats (e.g., anthrax, radiation, organophosphates, and contaminated trauma). A scenario-based study reveals the tactics, techniques, and procedures for training, resourcing, and fielding the CBRN operator of the future. PMID- 23817879 TI - Recent consideration in tactical medicine. AB - A philosophical approach to tactical and remote medicine should be reflected in the gear (e.g., equipment and technology) chosen as well as the protocols used. The gear needs to be lightweight and small volume. Asmuch as possible, it should have multiple uses, and there should be no redundancy with other items. When modern technology (e.g., hemostatic gauze, pulse oximeters, etc.) allows it to have unique applications, it should be used. Otherwise, if simple basic gear works, it should remain a staple (e.g., cravats). Protocols should reflect the goal to provide thorough care in an efficient manner. They should be straightforward and scaleable and be capable of being trained in a fashion that will allow them to become automatic under duress. These guiding principles establish a basis from which the Special Operations Forces/Tactical Medic or PJ can operate to maximal effectiveness. This article will describe current thinking in Pararescue as it relates to gear and protocols. PMID- 23817880 TI - Vector-borne disease surveillance in puerto rico: pathogen prevalence rates in canines ? Implications for public health and the u.s. Military ? Applying the one health concept. AB - Vector-borne diseases (VBDs) make up a large number of emerging infectious and zoonotic diseases. Vectors such as ticks, fleas, and mosquitoes parasitize dogs, thus making canine populations adequate reservoirs for infectious disease and zoonoses. The U.S. military deploys its personnel and Military Working Dogs (MWDs) throughout the world with possible risk of exposure to VBDs. Canine VBDs continue to have veterinary and public health significance for the host nations as well as for deployed U.S. personnel and MWDs. Thus, ongoing and consistent disease surveillance is an essential component to preserve health. The purpose of this study was to survey dogs from multiple cities and varying regions throughout Puerto Rico to determine the prevalence of ehrlichiosis (Ehrlichia canis), anaplasmosis (Anaplasma phagocytophilum), Lyme disease (Borrelia burgdorferi), and heartworm disease (Dirofilaria immitis) from May to July 2012. Canine blood samples (1?3 ml) from the cities of San Juan (n = 629), Guaynabo (n = 50), Ponce (n = 20) and Vieques Island (n = 53) were obtained and tested on-site using an IDEXX SNAP? 4Dx? (enzyme-linked immunosorbent assay) test kit. Prevalence for single or multiple disease status was calculated for each site. The overall period prevalence of VBD in Puerto Rico in the shelter population was 57.7% (71/123). In Guaynabo, the VBD prevalence was 30% (15/50); 2 (13%) of these positive dogs had VBD co-infection. In the coastal port city of Ponce, it was 60% (12/20); 6 (50%) dogs were infected by two or more VBDs. On Vieques Island, it was 83% (44/53); 27 (61%) dogs were coinfected. Conversely, samples collected at the Fort Buchanan Veterinary Clinic in the capitol city of San Juan resulted in a VBD prevalence of 8.9% (56/629). Lyme disease was not detected in any sample. This study showed the presence of D. immitis, E. canis, and A. phagocytophilum in all four sites of Puerto Rico, emphasizing the value of surveillance for VBDs to determine disease prevalence, complete risk assessments, and impleme t timely preventive medicine and other preventive measures. The lower VBD prevalence rate in the canine samples from Fort Buchanan demonstrates the value of responsible pet ownership and importance of preventive medicine and public health. PMID- 23817881 TI - Dengue infections. AB - BACKGROUND: Dengue fever is one of the most common mosquito-borne viral illnesses in the world. It is usually transmitted to humans through the bite of an infected Aedes aegypti or Aedes albopictus mosquito. Dengue infections are caused by four antigenically distinct but closely related viruses (DEN 1?4). Infection with any one of the viruses is thought to provide lifetime immunity to future infections from the same virus but only short-term cross-immunity to the other types, leading to the possibility of secondary infections. Dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), more severe types of dengue infections, sometimes result when an individual is subsequently infected with a second virus serotype during their lifetime. The most commonly accepted theory for the development of these more severe dengue infections is that of antibody-dependent enhancement, although other factors likely play a role. Infections complicated by DHF/DSS in areas where dengue is endemic are most often seen in the later half of the first year of life, when waning maternal antibodies may enhance the development of a more severe infection, and in young school-age children experiencing secondary infections. Widespread infections are most commonly seen during the rainy season of endemic areas when the breeding habitat of the Aedes mosquito is most favorable. PMID- 23817882 TI - Medical mission to dominican republic: one dermatology group?s experiences. AB - The intents of this article are to share our experiences during a medical mission in the Dominican Republic and to provide the reader with a cross-sectional view of conditions seen and an overview of interesting and challenging cases encountered. We also discuss treatments and techniques used and share lessons learned. PMID- 23817883 TI - Fetuses respond to father's voice but prefer mother's voice after birth. AB - Fetal and newborn responding to audio-recordings of their father's versus mother's reading a story were examined. At home, fathers read a different story to the fetus each day for 7 days. Subsequently, in the laboratory, continuous fetal heart rate was recorded during a 9 min protocol, including three, 3 min periods: baseline no-sound, voice (mother or father), postvoice no-sound. Following a 20 min delay, the opposite voice was delivered. Newborn head-turning was observed on 20 s trials: three no-sound, three voice (mother or father), three opposite voice, three no-sound trials with the same segment of each parent's recording. Fetuses showed a heart rate increase to both voices which was sustained over the voice period. Consistent with prior reports, newborns showed a preference for their mother's but not their father's voice. The characteristics of voice stimuli that capture fetal attention and elicit a response are yet to be identified. PMID- 23817884 TI - Intrinsic to extrinsic phonon lifetime transition in a GaAs-AlAs superlattice. AB - We have measured the lifetimes of two zone-center longitudinal acoustic phonon modes, at 320 and 640 GHz, in a 14 nm GaAs/2 nm AlAs superlattice structure. By comparing measurements at 296 and 79 K we separate the intrinsic contribution to phonon lifetime determined by phonon-phonon scattering from the extrinsic contribution due to defects and interface roughness. At 296 K, the 320 GHz phonon lifetime has approximately equal contributions from intrinsic and extrinsic scattering, whilst at 640 GHz it is dominated by extrinsic effects. These measurements are compared with intrinsic and extrinsic scattering rates in the superlattice obtained from first-principles lattice dynamics calculations. The calculated room-temperature intrinsic lifetime of longitudinal phonons at 320 GHz is in agreement with the experimentally measured value of 0.9 ns. The model correctly predicts the transition from predominantly intrinsic to predominantly extrinsic scattering; however the predicted transition occurs at higher frequencies. Our analysis indicates that the 'interfacial atomic disorder' model is not entirely adequate and that the observed frequency dependence of the extrinsic scattering rate is likely to be determined by a finite correlation length of interface roughness. PMID- 23817885 TI - The road not taken: antigen-specific therapy and neuroinflammatory disease. PMID- 23817886 TI - Early life factors and adult mammographic density. AB - PURPOSE: Early life factors have shown to be related to breast cancer risk. The pathophysiological link could be mammographic density, a strong risk factor for breast cancer. Mammary gland development already starts in utero and early life factors might affect the number of mammary cells at risk. In this study, we investigated the association between early life factors and mammographic density in adulthood. METHODS: The study was conducted within 2,588, mainly postmenopausal women of the Prospect-European Prospective Investigation into Cancer and Nutrition cohort. This ongoing study recruited breast cancer screening participants who filled out extensive questionnaires. Information on the early life factors birth weight, gestational age, maternal and paternal age, multiple births, birth rank, exposure to parental smoking, and leg length as a proxy for growth at childhood was obtained using questionnaires. Generalized linear models and linear regression models were used to study the relation between early life factors and mammographic density. Analyses were adjusted for potential confounders. RESULTS: Women who had an older mother (p = 0.06) or father (p = 0.002) at birth tended to have a higher mammographic density. Furthermore, greater leg length seemed to be related to higher mammographic density, although not statistically significantly (p = 0.16). After adjustment for confounders, none of the early life factors showed any statistically significant relationship with mammographic density in adulthood. CONCLUSION: Although we cannot exclude small effects that go undetected due to measurement error in recall of early life factors, the results suggest that mammographic density is not a major pathway in any observed relationship between these early life events and breast cancer risk. PMID- 23817887 TI - Synaptic behavior and STDP of asymmetric nanoscale memristors in biohybrid systems. AB - We fabricate and characterize asymmetric memristors which show a very strong single-sided hysteresis. When biased in one direction there is hysteresis and in the opposite direction there is a lack of hysteresis. We demonstrate that this apparent lack is actually hysteresis on a much faster time-scale. We further demonstrate that this form of asymmetric behavior correlates very well to the asymmetric structure and function of an actual synapse. The asymmetric memristor device presented here is necessary to correctly implement spike-timing-dependent plasticity STDP in mixed memristor/neuron hybrid systems as an artificial synapse. These devices show the required characteristics for implementing the asymmetric form of long-term potentiation (LTP) and long-term depression (LTD) of a synapse between two neurons, where symmetric memristor devices do not. Signals from a presynaptic neuron are sent via its axon across the synapse to the dendrite of a postsynaptic neuron. Postsynaptic neuron signals sent to subsequent neurons have an influence on the strength of any further presynaptic neuron signals received by the postsynaptic neuron across the synapse. These signals are grouped into spike triplets within the framework of STDP and, as we experimentally show here, can be implemented with asymmetric memristors, not standard symmetric memristors. PMID- 23817888 TI - Quantification of median lobe protrusion and its impact on the base surgical margin status during robot-assisted laparoscopic prostatectomy. AB - PURPOSE: Protrusion of the median lobe (PML) is thought to add technical difficulty during robot-assisted laparoscopic prostatectomy (RALP). Thus, we quantified PML using preoperative magnetic resonance imaging (MRI) and evaluated its impact on base surgical margin (BSM) status during RALP. METHODS: The clinical data of consecutive patients who underwent RALP were retrieved from a prospectively registered database. Of the 655 eligible men, 9 patients were excluded because they did not undergo MRI. PML was measured in a T2-weighted mid sagittal scan. We performed univariate and multiple logistic regression analyses. RESULTS: The mean PML was 8.3 +/- 3.6 mm. The rate of positive surgical margins was 17.3 % (73/423) in pathologic stage T2 and 34.6 % (226/646) in all cases. The BSMs were positive in 10.1 % (66/646) of cases. A logistic regression analysis revealed that PML was significantly correlated with BSM positivity in all cases (odds ratio [OR] 1.080, p = 0.026). In particular, they had a stronger correlation with pathologic stage T3 or higher (OR 1.1143, p = 0.004). PML was an independent predictor of BSM positivity (OR 1.113, p = 0.046) in pathologic stage T3 or higher, as were preoperative prostate-specific antigen, prostate size, and pathologic stage. Cases with 10 mm or higher PML had significantly more BSM positivity than cases with <10 mm PML (35.9 vs. 20.1 %, p = 0.012). CONCLUSIONS: Protrusion of the median lobe measured using preoperative MRI was significantly correlated with positive BSMs during RALP. Surgeons should pay more attention to patients with 10 mm or higher PML and advanced stages. PMID- 23817889 TI - Oncological outcomes of robotic-assisted radical prostatectomy after more than 5 years. AB - INTRODUCTION: In the last 10 years, robotic-assisted radical prostatectomy (RARP) has become increasingly popular as witnessed by an increased number of publications. However, there is still little known about the long-term oncologic outcomes of this technique. The aim of this study is to assess the oncologic outcomes of patients who underwent RARP at least 5 years ago, with an emphasis on biochemical recurrence-free survival (BCRFS). MATERIALS AND METHODS: In 2004, RARP was introduced at our institutions. Records of all patients having RARP were prospectively collected in a dedicated database as part of the NUVOLA-BAUS project. For the present study, we selected only patients who had a follow-up of at least 5 years. Endpoints were BCRFS rate and 5-year cancer-specific survival (CSS). RESULTS: Overall, we identified 175 patients; 61.7 % of patients had Gleason 7-9 disease and 26.9 % had pT >= 3 disease at final pathology. Eight patients (4.5 %) had biochemical recurrence at follow-up. Overall 5-year BCRFS rate was 95.4 %, while it was 97.6, 91 and 50 % in pT2, pT3 and pT4 diseases, respectively. Among the patients who recurred, the mean time to recurrence was 22.1 +/- 8.8 months. These patients received salvage external beam radiation treatment combined with hormonal therapy (anti-androgen + LHRH analogue) or hormonal therapy alone. 5-year CSS was 98.3 % (172/175): in 2 cases, the specimen showed pT4 cancer, while lymph node metastasis was noted in one case. CONCLUSION: The 5-year BCRFS and CSS after RARP are encouraging even in a population with significant high-risk disease. PMID- 23817890 TI - Laparoscopic radical cystectomy with extracorporeal ileal neobladder for muscle invasive urothelial carcinoma of the bladder: technique and short-term outcomes. AB - OBJECTIVES: To report the surgical outcomes of laparoscopic radical cystectomy (LRC) with extracorporeal orthotopic ileal neobladder (OIN) in patients with muscle-invasive urothelial carcinoma of the bladder (UCB). MATERIALS AND METHODS: Between October 2009 and December 2011, 37 patients with muscle-invasive UCB underwent a LRC with OIN. Indications included (a) muscle-invasive UCB T2-4a, N0 Nx, M0; (b) high-risk and recurrent non-muscle-invasive tumors; (c) T1G3 plus CIS; and (d) extensive non-muscle-invasive disease that could not be controlled by transurethral resection and intravesical therapy. Demographic data, perioperative, and postoperative variables were recorded and analyzed. RESULTS: The median operating time was 330 min, with a median estimated blood loss of 410 ml. Median length of stay was 12 days, and the mean length of the skin incision to extract the specimen and for the configuration of the neobladder was 7 +/- 1 cm. The complication rate was 21.6 % (Clavien II). No Clavien III-V complications were reported. Daytime and nocturnal continence were preserved in 95 and 78 %, respectively. No local recurrence or port site metastasis occurred. Median time to disease recurrence was 14 months (IQR 9-24), and 1-year cancer-specific survival was 91.9 %. CONCLUSIONS: Laparoscopic radical cystectomy with extracorporeal ileal neobladder is a challenging procedure but technically feasible, allowing low morbidity and oncological safety. Long-term oncological results are required to definitely recognize this procedure as a standard treatment for bladder cancer. PMID- 23817891 TI - Comparative survival following different treatment modalities for stage T2 bladder cancer in octogenarians. AB - PURPOSE: A higher rate of comorbidities and an anticipated higher operative risk in octogenarians may influence urologists in opting for less aggressive and less effective treatment modalities for muscle-invasive bladder cancer. This study was performed to compare survival after different treatment modalities in octogenarians with stage T2 bladder cancer. METHODS: Patients that were 80 years or older with a diagnosis of transitional cell carcinoma of the bladder were identified using the Surveillance, Epidemiology, and End Results-17 registry database between 1988 and 2007. Patients were analyzed for treatment method and outcomes, including overall survival (OS) and cancer-specific survival (CSS). RESULTS: A total of 3,232 patients met inclusion criteria. Of these, 69 % (N = 2,216) underwent only transurethral resection (TURBT), 23 % (N = 733) underwent pelvic radiation therapy (RT), and 9 % (N = 283) underwent definitive surgical therapy. The 3-, 5-, and 10-year OS rates were 22.2, 15.0, and 4.4 %, respectively, for TURBT; 27.8, 18.3, and 3.5 % for RT; and 52.7, 39.1, and 17.2 % for definitive surgery. The 3-, 5-, and 10-year CSS rates were 38.3, 33.4, and 27.4 %, respectively, for TURBT; 41.6, 35.0, and 27.2 % for RT; and 66.6, 55.5, and 49.9 % for definitive surgery. Both partial and radical cystectomy had significantly longer CSS rates at 3 and 5 years when compared to RT (p <= 0.001). CONCLUSIONS: Compared to other treatment modalities, surgery, either radical cystectomy or partial cystectomy, offers the best OS and CSS for men aged 80 years or older with T2 bladder cancer. PMID- 23817892 TI - Antioxidant extracts of African medicinal plants induce cell cycle arrest and differentiation in B16F10 melanoma cells. AB - African ethnomedicine is essentially based on the traditional use of vegetal extracts. Since these natural drugs have shown health giving properties, in the present study we increased further the scientific basis supporting these data. We investigated the effects, on murine B16F10 melanoma cells, of plant extracts that were directly obtained by a Cameroon 'traditional healer'. After a preliminary study on the antioxidant functions of these compounds, already abundant in literature, Moringa oleifera Lam., Eremomastax speciosa (Hochst.) Cufod and Aframomum melegueta K. Schum extracts were individually analyzed. We performed laboratory assessments on these medicinal preparations in order to clearly demonstrate their antineoplastic features. All the treatments caused in tumor cells a great reduction in growth and proliferation rate, cell cycle arrest, increase of p53, p21WAF1/Cip1 and p27Kip1 protein levels and induction of differentiation. These results, on the bioactivity and the biochemical characteristics of African plant extracts, may increase the comprehension of indigenous therapeutic practices and represent the first step for the individuation of new inexpensive and natural drugs able to prevent and contrast cancer onset. PMID- 23817893 TI - Allele-dose association of the C5orf30 rs26232 variant with joint damage in rheumatoid arthritis. AB - OBJECTIVE: There is increasing evidence to indicate that genetic factors contribute significantly to radiologic joint damage in rheumatoid arthritis (RA). The aim of the present study was to determine whether genotypes of 10 recently identified RA susceptibility loci are associated with radiologic severity. METHODS: A 2-stage study was performed using 3 Northern European RA populations: a British cross-sectional population (discovery cohort; n=885) and the Leiden Early Arthritis Clinic (EAC) cohort (n=581) and Yorkshire Early Arthritis Register (YEAR) cohort (n=418) (validation cohorts). Radiologic damage was assessed using a modified Larsen method for scoring radiographs (in the discovery cohort) or modified Sharp/van der Heijde score (in the 2 validation cohorts). A meta-analysis was performed to bring together the evidence from the 3 studies, using data on radiologic severity of joint damage from a single time point. RESULTS: An allele-dose association of rs26232 was present in the discovery population (P=4*10(-4)); the median modified Larsen scores of radiologic joint damage per genotype were 31 (for those with CC), 27 (for those with CT), and 16 (for those with TT). The allele-dose association of rs26232 was replicated in both the Leiden EAC cohort during the initial 7 years of RA (P=0.04) and the YEAR cohort (P=0.039). In a fixed-effects meta-analysis of all 3 studies, the per T allele effect on the ratio of radiologic severity scores was 0.90 (95% confidence interval 0.84, 0.96; P=0.004). CONCLUSION: The variant rs26232, in the first intron of the C5orf30 locus, is associated with the severity of radiologic damage in RA and is independent of established prognostic biomarkers. The biologic activities of C5orf30 are unknown, but our genetic data suggest that it is involved in mediating joint damage in RA. PMID- 23817894 TI - Basal ganglia engagement during feedback processing after a substantial delay. AB - The striatum has been shown to play an important role in learning from performance-related feedback that is presented shortly after each response. However, less is known about the neural mechanisms supporting learning from feedback that is substantially delayed from the original response. Since the consequences of one's actions often do not become known until after a delay, it is important to understand whether delayed feedback can produce neural responses similar to those elicited by immediate-feedback presentation. We investigated this issue by using functional magnetic resonance imaging (fMRI) as participants performed a paired-associate learning task with 180 distinct trials. Feedback indicating response accuracy was presented immediately, after a delay of 25 min, or not at all. Both immediate and delayed feedback led to significant gains in accuracy on a posttest, relative to no feedback. Replicating previous work, we found that the caudate nuclei showed greater activation for positive feedback than for negative feedback when the feedback was presented immediately. In addition, delayed feedback also led to differential caudate activity to positive versus negative feedback. Delayed negative feedback also produced significant activation of the putamen and globus pallidus (the lentiform nucleus), relative to no feedback and delayed positive feedback. This suggests that the caudate nucleus is sensitive to the affective nature of feedback, across different time scales, while the lentiform nucleus may be particularly involved in processing the information carried by negative feedback after a substantial delay. PMID- 23817896 TI - [Clinical infectious diseases : interdisciplinary and unique]. PMID- 23817895 TI - Pituicytoma with gelsolin amyloid deposition. AB - Pituicytoma is a rare low-grade (WHO grade I) sellar region glioma. Among sellar tumors, pituitary adenomas, mainly prolactinomas, may show amyloid deposits. Gelsolin is a ubiquitous calcium-dependent protein that regulates actin filament dynamics. Two known gene point mutations result in gelsolin amyloid deposition, a characteristic feature of a rare type of familial amyloid polyneuropathy (FAP), the Finnish-type FAP, or hereditary gelsolin amyloidosis (HGA). HGA is an autosomal-dominant systemic amyloidosis, characterized by slowly progressive neurological deterioration with corneal lattice dystrophy, cranial neuropathy, and cutis laxa. A unique case of pituicytoma with marked gelsolin amyloid deposition in a 67-year-old Chinese woman is described. MRI revealed a 2.6-cm well-circumscribed, uniformly contrast-enhancing solid sellar mass with suprasellar extension. Histologically, the lesion was characterized by solid sheets and fascicles of spindle cells with slightly fibrillary cytoplasm and oval nuclei with pinpoint nucleoli. Surrounding brain parenchyma showed marked reactive piloid gliosis. Remarkably, conspicuous amyloid deposits were identified as pink homogeneous spherules on light microscopy that showed apple-green birefringence on Congo red with polarization. Mass spectrometric-based proteomic analysis identified the amyloid as gelsolin type. Immunohistochemically, diffuse reactivity to S100 protein and TTF1, focal reactivity for GFAP, and no reactivity to EMA, synaptophysin, and chromogranin were observed. HGA-related mutations were not identified in the tumor. No recurrence was noted 14 months after surgery. To the knowledge of the authors, amyloid deposition in pituicytoma or tumor associated gelsolin amyloidosis has not been previously described. This novel finding expands the spectrum of sellar tumors that may be associated with amyloid deposition. PMID- 23817897 TI - [Severe infections : causes and management of sepsis]. AB - The sepsis syndrome has only recently been defined as a clinical syndrome but despite its unspecific definition it has evolved rapidly into an important concept. Although specific therapeutic interventions targeting the inflammatory pathway have not yet been effective in treating sepsis, a better understanding of mechanisms leading to organ dysfunction has led to better management of patients with sepsis. Clinical signs of systemic inflammatory response syndrome (SIRS) or sepsis are hallmarks for the definition of severe infections. Current guidelines are presented for the management of a number of severe infectious syndromes. PMID- 23817898 TI - Role of plasma membrane estrogen receptors in mediating the estrogen induction of progesterone receptors in hypothalamic ventromedial neurons. AB - Progesterone is well known for its role in the modulation of sexual behavior. In the ventromedial nucleus (VMN), a part of the mediobasal hypothalamus that regulates sexual behavior in female rodents, estrogens induce the expression of progesterone receptors (PRs). This effect is known to be dependent on the activation of nuclear estrogen receptors (ERs). However, recent studies have documented estrogen activation of genomic transcription triggered by protein protein phosphorylation cascades initiated at membrane receptors. The aim of this study was to examine if membrane-initiated estradiol (E2 ) stimulation is able to induce PR expression in the VMN or, at least, to modulate nuclear ER action. To achieve this goal, 2-month-old ovariectomized Wistar rats were injected bilaterally, in the vicinity of VMN, with free E2 and with E2 conjugated with bovine serum albumin (E2 BSA), alone or in sequence, by using a two-pulse injection paradigm. Stereological methods and western blot analysis were used to estimate the total number of PR-immunoreactive neurons in the VMN and the PR protein content of the VMN, respectively. The results showed that the administration of E2 BSA alone increases the number of PR-immunoreactive neurons and the expression level of PR protein to values similar to those resulting from E2 administration. They also showed that the sequential administration of E2 and E2 BSA potentiates the effects resulting from the injection of E2 or E2 BSA alone. These data provide the first evidence that membrane-initiated E2 stimulation is able to induce and to potentiate the genomic activation of PR expression in the VMN. PMID- 23817899 TI - An overview of the clubhouse model of psychiatric rehabilitation. AB - OBJECTIVE: The aim of this article is to provide an overview of the clubhouse model and its capacity to assist people with severe mental illness. METHOD: The paper uses a sample vignette (with all identifying information removed) and survey of literature describing clubhouses over the last 15 years. RESULTS: Strengths of the clubhouse model include its ability to provide a safe environment, supportive relationships and supported employment activities. Criticisms include its failure to provide onsite psychiatry clinics and a risk of promoting service dependence. CONCLUSIONS: Modern clubhouses continue to provide useful models of psychiatric rehabilitation which are popular worldwide. Studying and describing the model is challenging due to its complexity. Mixed methodological approaches and recovery-orientated measurement tools may assist future research and development. PMID- 23817900 TI - Well-controlled ring-opening polymerization of cyclic esters initiated by dialkylaluminum beta-diketiminates. AB - A series of aluminum alkyl complexes nacnacRAlMe2 (2a-2h) bearing aliphatic N substituted beta-diketiminate ligands (nacnacRH = N,N'-dialkyl-2-amino-4 iminopent-2-enes), were prepared from the reaction of trialkyl aluminum and the corresponding beta-diketimines. All these aluminum complexes were characterized by NMR, elemental analysis and HRMS spectroscopy. The molecular structures of complexes 2a, 2c and 2h were confirmed by single-crystal X-ray diffraction. These aluminum alkyl complexes show notable activity towards the ring-opening polymerization of epsilon-caprolactone in the absence and presence of alcohol, and the resulting polymers have narrow molecular weight distributions. PMID- 23817902 TI - Evidence-based design and the fields of human factors and ergonomics: complementary systems-oriented approaches to healthcare design. PMID- 23817901 TI - Effect of thrombomodulin on the development of monocrotaline-induced pulmonary hypertension. AB - PURPOSE: The purpose of the present study was to investigate whether thrombomodulin (TM) prevents the development of pulmonary hypertension (PH) in monocrotaline (MCT)-injected rats. METHODS: Human recombinant TM (3 mg/kg/2 days) or saline were given to MCT-injected male Sprague-Dawley rats for 19 (n = 14) or 29 (n = 11) days. Control rats (n = 6) were run for 19 days. The mean pulmonary artery pressure (mPAP), right ventricular hypertrophy (RVH), percentages of muscularized peripheral arteries (%muscularization), and medial wall thickness of small muscular arteries (%MWT) were measured. To determine inflammatory and coagulation responses, broncho-alveolar lavage fluid (BALF) was analyzed in another set of rats (n = 29). Western blotting for endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS (peNOS) in the lung tissue was performed in separate rats (n = 13). Survival was determined in 60 rats. RESULTS: MCT increased mPAP, RVH, %muscularization, and %MWT. TM treatment significantly reduced mPAP, %muscularization, and %MWT in peripheral arteries with an external diameter of 50-100 MUm in 19 days after MCT injection, but the effect was lost after 29 days. MCT increased the levels of tumor necrosis factor alpha, monocyte chemoattractant protein-1, and thrombin-antithrombin complex in BALF. Expression of eNOS increased in MCT rats, while peNOS decreased. The relative amount of peNOS to total eNOS increased in MCT/TM rats compared to MCT/Vehicle rats. A Kaplan-Meier survival curve showed no difference with and without TM. CONCLUSION: Although the administration of TM might slightly delay the progression of MCT induced PH, the physiological significance for treatment is limited, since the survival rate was not improved. PMID- 23817903 TI - Considering human factors when designing for safety. PMID- 23817904 TI - Examination of overbed tables: healthcare provider and user preferences. AB - OBJECTIVE: This exploratory study examined the preferences of healthcare providers and patients with respect to overbed table features and functions, as well as how the devices tend to be used. BACKGROUND: In order to improve the design of overbed tables, it is important to understand which features and functions of existing models are valued by healthcare providers and patients. METHODS: A sample of overbed table models was presented to volunteers, who were asked to choose which models' implementation of specific features and functions they preferred. Structured interviews incorporating both forced choice and free response questions were administered to the volunteers-healthcare providers and patients at a rehabilitation hospital. RESULTS: While the overbed tabletop and extendable tray are heavily used, all other features of the overbed table models are rarely used. Usability of the models exhibits the potential for improvement. Healthcare providers' and patients' feature preferences differ and occasionally conflict. CONCLUSIONS: Existing overbed tables are valued primarily for the top surface. Other features and functions of the overbed table present opportunities for refinement of design, durability, and usability. There are strong patterns of agreement and disagreement in the preferences of healthcare providers and patients with respect to overbed table design, use, features, and functionality. There is potential to improve overbed table designs from both the perspectives of the staff and the patient. KEYWORDS: Evidence-based design, hospital, human factors, patient-centered care, quality care, technology. PMID- 23817905 TI - Design of admission medication reconciliation technology: a human factors approach to requirements and prototyping. AB - OBJECTIVE: Our objectives were to (1) develop an in-depth understanding of the workflow and information flow in medication reconciliation, and (2) design medication reconciliation support technology using a combination of rapid-cycle prototyping and human-centered design. BACKGROUND: Although medication reconciliation is a national patient safety goal, limitations both of physical environment and in workflow can make it challenging to implement durable systems. We used several human factors techniques to gather requirements and develop a new process to collect a medication history at hospital admission. METHODS: We completed an ethnography and time and motion analysis of pharmacists in order to illustrate the processes used to reconcile medications. We then used the requirements to design prototype multimedia software for collecting a bedside medication history. We observed how pharmacists incorporated the technology into their physical environment and documented usability issues. RESULTS: Admissions occurred in three phases: (1) list compilation, (2) order processing, and (3) team coordination. Current medication reconciliation processes at the hospital average 19 minutes to complete and do not include a bedside interview. Use of our technology during a bedside interview required an average of 29 minutes. The software represents a viable proof-of-concept to automate parts of history collection and enhance patient communication. However, we discovered several usability issues that require attention. CONCLUSIONS: We designed a patient centered technology to enhance how clinicians collect a patient's medication history. By using multiple human factors methods, our research team identified system themes and design constraints that influence the quality of the medication reconciliation process and implementation effectiveness of new technology. KEYWORDS: Evidence-based design, human factors, patient-centered care, safety, technology. PMID- 23817906 TI - The design and testing of interactive hospital spaces to meet the needs of waiting children. AB - OBJECTIVE: To design an innovative interactive media display in a pediatric hospital clinic waiting space that addresses the growing demand for accessible, contact-surface-free options for play. BACKGROUND: In healthcare settings, waiting can be anxiety provoking for children and their accompanying family members. Opportunities for positive distraction have been shown to reduce waiting anxiety, leading to positive health outcomes. METHODS: An interactive media display, ScreenPlay, was created and evaluated using a participatory design approach and a combination of techniques including quality function deployment and mixed data elicitation methods (questionnaires, focus groups, and observations). The user and organizational design requirements were established and used to review contemporary strategies for positive distraction in healthcare waiting spaces and to conceptualize and test ScreenPlay. Ten staff members, 11 children/youths, and 6 parents participated in the design and evaluation of ScreenPlay. RESULTS: ScreenPlay provided a positive, engaging experience without the use of contact surfaces through which infections can be spread. It was accessible to children, youth, and adults of all motor abilities. All participants strongly agreed that the interactive media display would improve the healthcare waiting experience. CONCLUSIONS: ScreenPlay is an interactive display that is the result of a successful model for the design of healthcare waiting spaces that is collaborative, interdisciplinary, and responsive to the needs of its community. KEYWORDS: Design process, healing environments, hospital, interdisciplinary, pediatric. PMID- 23817907 TI - Clinician perceptions of a changing hospital environment. AB - OBJECTIVE: The purposes of this study were to describe how a move into a new hospital influenced the work environment, how long it takes clinicians to adjust to such a significant change, and how much a new hospital work environment helps the practice shift toward patient- and family-centered care (PFCC). BACKGROUND: Creating a healthy work environment to keep patients safe and staff engaged in the mission of the organization is perhaps one of the most important roles of hospital administrators and nursing leaders. METHODS: A descriptive and comparative design was used to investigate how clinicians perceive, evaluate, and adjust to a new hospital environment, and how much a healthy work environment helps the practice shift toward patient- and family-centered care. RESULTS: Perceived stress was significantly higher than baseline 15 months after the move into the new hospital (p < 0.0000), and employees with 3 or more years of service had significantly higher stress than others (p < 0.000). Nurses had the second lowest mean stress score (x = 12.5). The PFCC score increased significantly (p < 0.007). CONCLUSIONS: The single-patient room model increased the workload of many clinicians, and their stress increased after 15 months. There were additional burdens not measured that also may have added to the stress of the participants. The new hospital enabled a significant practice shift toward PFCC. KEYWORDS: Healing environments, organizational transformation, patient-centered care, pediatric, satisfaction. PMID- 23817908 TI - Role of a service corridor in ICU noise control, staff stress, and staff satisfaction: environmental research of an academic medical center. AB - OBJECTIVE: To investigate the role of a dedicated service corridor in intensive care unit (ICU) noise control and staff stress and satisfaction. BACKGROUND: Shared corridors immediately adjacent to patient rooms are generally noisy due to a variety of activities, including service deliveries and pickups. The strategy of providing a dedicated service corridor is thought to reduce noise for patient care, but the extent to which it actually contributes to noise reduction in the patient care environment and in turn improves staff performance has not been previously documented. METHODS: A before-and-after comparison was conducted in an adult cardiac ICU. The ICU was relocated from a traditional hospital environment to a new addition with a dedicated service corridor. A total of 118 nursing staff participated in the surveys regarding pre-move and post-move environmental comfort, stress, and satisfaction in the previous and new units. Acoustical measures of noise within the new ICU and a control environment of the previous unit were collected during four work days, along with on-site observations of corridor traffic. RESULTS: Independent and paired sample t-tests of survey data showed that the perceived noise level was lower and staff reported less stress and more satisfaction in the new ICU (p < 0.01). Analyses of acoustical data confirmed that the new ICU was significantly quieter (p < 0.02). Observations revealed how the service corridor impacted patient care services and traffic. CONCLUSIONS: The addition of a dedicated service corridor works in the new unit for improving noise control and staff stress and satisfaction. KEYWORDS: Critical care/intensive care, noise, satisfaction, staff, work environment. PMID- 23817910 TI - Design collaboration: practice and academic perspectives. PMID- 23817909 TI - The role of flooring as a design element affecting patient and healthcare worker safety. AB - OBJECTIVE: The objective of this study was to review, identify, and synthesize the literature on patient and healthcare worker safety related to flooring. The topic of flooring in the design of healthcare facilities is complex: healthcare associated infections, push/pull limitations, falls and fall injuries, and noise as a contributing factor to quality of care. BACKGROUND: Most hospitals have not been explicitly designed to enhance patient safety. Recommendations from the Agency for Healthcare Research and Quality (AHRQ) include preventing patient falls, reducing infections, and preventing medication errors as the areas of emphasis of evidence-based design to improve patient safety and quality of care. METHODS: A review of the literature was conducted through search engines using a predefined list of keywords to identify studies about flooring and the safety of patients and healthcare workers. Inclusion criteria included peer-reviewed theoretical and empirical studies published in English from 1982 to 2012. Final inclusion was obtained based on an analysis of research design. RESULTS: Of those 27 articles that met inclusion, 7 focused on healthcare associated infections; 9 focused on slips, trips and falls; 7 articles focused on noise; and 4 focused on fatigue. The studies are profiled in tables and organized by environmental variable. CONCLUSIONS: Though a limited number of studies met the criteria for this review, the evidence base is emerging to design for safety. Recommendations for future research and practical application of design are provided. KEYWORDS: Evidence-based design, literature review, patients, safety, staff. PMID- 23817911 TI - Advancing Translational Research through Facility Design in Non-AMC Hospitals. AB - OBJECTIVE: This article aims to explore the future of translational research and its physical design implications for community hospitals and hospitals not attached to large centralized research platforms. BACKGROUND: With a shift in medical services delivery focus to community wellness, continuum of care, and comparative effectiveness research, healthcare research will witness increasing pressure to include community-based practitioners. METHODS: The roundtable discussion group, comprising 14 invited experts from 10 institutions representing the fields of biomedical research, research administration, facility planning and design, facility management, finance, and environmental design research, examined the issue in a structured manner. The discussion was conducted at the Washington Hospital Center, MedStar Health, Washington, D.C. CONCLUSIONS: Institutions outside the AMCs will be increasingly targeted for future research. Three factors are crucial for successful research in non-AMC hospitals: operational culture, financial culture, and information culture. An operating culture geared towards creation, preservation, and protection of spaces needed for research; creative management of spaces for financial accountability; and a flexible information infrastructure at the system level that enables complete link of key programmatic areas to academic IT research infrastructure are critical to success of research endeavors. KEYWORDS: Hospital, interdisciplinary, leadership, planning, work environment. PMID- 23817912 TI - Clinic exam room design: present and future. AB - OBJECTIVE: This article aims to deconstruct various design qualities and strategies of clinic exam rooms, and discuss how they influence users' interaction and behavior in the space. Relevant literature supports the advantages and disadvantages of different design strategies. Annotated exam room prototypes illustrate the design qualities and strategies discussed. BACKGROUND: Advancements in technology and medicine, along with new legislative policies, are influencing the way care providers deliver care and ultimately clinic exam room designs. The patient-centered medical home model has encouraged primary care providers to make patients more active leaders of their health plan which will influence the overall functionality and configuration of clinic exam rooms. Specific design qualities discussed include overall size, location of doors and privacy curtains, positioning of exam tables, influence of technology in the consultation area, types of seating, and placement of sink and hand sanitizing dispensers. In addition, future trends of exam room prototypes are presented. CONCLUSIONS: There is a general lack of published evidence to support design professionals' design solutions for outpatient exam rooms. Future research should investigate such topics as the location of exam tables and privacy curtains as they relate to patient privacy; typical size and location of consultation table as it relates to patient connection and communication; and placement of sinks and sanitization dispensers as they relate to frequency and patterns of usage. KEYWORDS: Literature review, outpatient, technology, visual privacy. PMID- 23817913 TI - Methodological issues in conducting post-occupancy evaluations to support design decisions. PMID- 23817914 TI - Human factors and ergonomics in health care and patient safety, second edition. PMID- 23817915 TI - Letter to the editors: lighting for different healthcare settings. PMID- 23817916 TI - The association of plasma lactate with incident cardiovascular outcomes: the ARIC Study. AB - We examined the association of plasma lactate at rest, a marker of oxidative capacity, with incident cardiovascular outcomes in 10,006 participants in the Atherosclerosis Risk in Communities (ARIC) Study visit 4 (1996-1998). We used Cox proportional-hazards models to estimate hazard ratios of incident coronary heart disease, stroke, heart failure, and all-cause mortality by quartiles of plasma lactate (Q1, <=5.3 mg/dL; Q2, 5.4-6.6; Q3, 6.7-8.6; and Q4 >=8.7). During a median follow-up time of 10.7 years, there were 1,105 coronary heart disease cases, 379 stroke cases, 820 heart failure cases, and 1,408 deaths. A significant graded relation between lactate level and cardiovascular events was observed in the demographically adjusted model (all P for trend < 0.001). After further adjustment for traditional and other potential confounders, the association remained significant for heart failure (Q4 vs. Q1: hazard ratio (HR) = 1.35, 95% confidence interval (CI): 1.07, 1.71) and all-cause mortality (HR = 1.27, 95% CI: 1.07, 1.51) (P for trend < 0.02 for these outcomes) but not for coronary heart disease (HR = 1.02, 95% CI: 0.84, 1.24) and stroke (HR = 1.26, 95% CI: 0.91, 1.75). The results for heart failure were robust across multiple subgroups, after further adjustment for N-terminal pro-B-type natriuretic peptide and after exclusion of participants with incident heart failure within 3 years. The independent associations of plasma lactate with heart failure and all-cause mortality suggest an important role for low resting oxidative capacity. PMID- 23817917 TI - Association of age at menarche with increasing number of fibroids in a cohort of women who underwent standardized ultrasound assessment. AB - Age at menarche has been associated with several reproductive conditions, and frequencies differ by race. Racial disparities also impact fibroid risk. We comprehensively examined the relationship between age at menarche, fibroid characteristics, and race. Women were enrolled in Right From the Start (2001 2010), a multistate study that systematically screened for fibroids during very early pregnancy. Endovaginal ultrasounds were conducted, and fibroid presence, number, type, volume, and diameter were recorded according to standardized definitions. Generalized estimating equations adjusted for correlations within study site were used to estimate associations between age at menarche and fibroid status and to test for interactions with race. Of 5,023 participants, 11% had a fibroid. Seven percent underwent menarche before 11 years of age and 11% at 15 years or later. We did not observe interactions between age at menarche and race. A 1-year increase in age at menarche was inversely associated with fibroids (adjusted risk ratio = 0.87, 95% confidence interval: 0.82, 0.91). Early age at menarche had a similar positive association in individual analyses with fibroid size, type, and location but was stronger for multiple fibroids (adjusted risk ratio = 0.75, 95% confidence interval: 0.68, 0.83). Our findings confirm other reports of an association between age at menarche and fibroid development (regardless of characteristics), demonstrate no effect modification by race, and suggest a stronger association for women with multiple fibroids, possibly reflecting a stronger association for early-onset disease. PMID- 23817918 TI - Smoking and diabetes: does the increased risk ever go away? AB - Recent studies reported that smoking cessation leads to higher short-term risk of type 2 diabetes than continuing to smoke. However, the duration of increased diabetes risk following smoking cessation needs further investigation. We followed 135,906 postmenopausal women aged 50-79 years enrolled in the Women's Health Initiative between September 1, 1993, and December 31, 1998, over an average of 11 years to examine the association between smoking cessation and risk of diabetes using Cox proportional hazard multivariable-adjusted regression models. Compared with that for never smokers, the risk for diabetes was significantly elevated in current smokers (hazard ratio = 1.28, 95% confidence interval: 1.20, 1.36) but was even higher in women who quit smoking during the first 3 years of follow-up (hazard ratio = 1.43, 95% confidence interval: 1.26, 1.63). Among former smokers, the risk of diabetes decreased significantly as the time since quitting increased and was equal to that of never smokers following a cessation period of 10 years. In new quitters with low cumulative exposure (<20 pack-years), diabetes risk was not elevated following smoking cessation. In conclusion, the risk of diabetes in former smokers returns to that in never smokers 10 years after quitting, and even more quickly in lighter smokers. PMID- 23817920 TI - Low-temperature thermal properties of a hyperaged geological glass. AB - We have measured the specific heat of amber from the Dominican Republic, an ancient geological glass about 20 million years old, in the low-temperature range 0.6 K <= T <= 26 K, in order to assess the effects of its natural stabilization (hyperageing) process on the low-temperature glassy properties, i.e. boson peak and two-level systems. We have also conducted modulated differential scanning calorimetry experiments to characterize the thermodynamic state of our samples. We found that calorimetric curves exhibit a huge ageing signal DeltaH ~ 5 J g(-1) in the first upscan at the glass transition Tg = 389 K, that completely disappears after heating up (rejuvenating) the sample to T = 395 K for 3 h. To independently evaluate the phonon contribution to the specific heat, Brillouin spectroscopy was performed in the temperature range 80 K <= T <= 300 K. An expected increase in the Debye level was observed after rejuvenating the Dominican amber. However, no significant change was observed in the low temperature specific heat of glassy amber after erasing its thermal history: both its boson peak (i.e., the maximum in the Cp/T(3) representation) and the density of tunnelling two-level systems (i.e., the Cp ~ T contribution at the lowest temperatures) remained essentially the same. Also, a consistent analysis using the soft-potential model of our Cp data and earlier thermal-conductivity data found in the literature further supports our main conclusion, namely, that these glassy 'anomalous' properties at low temperatures remain essentially invariant after strong relaxational processes such as hyperageing. PMID- 23817919 TI - Cigarette, cigar, and pipe smoking and the risk of head and neck cancers: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. AB - Cigar and pipe smoking are considered risk factors for head and neck cancers, but the magnitude of effect estimates for these products has been imprecisely estimated. By using pooled data from the International Head and Neck Cancer Epidemiology (INHANCE) Consortium (comprising 13,935 cases and 18,691 controls in 19 studies from 1981 to 2007), we applied hierarchical logistic regression to more precisely estimate odds ratios and 95% confidence intervals for cigarette, cigar, and pipe smoking separately, compared with reference groups of those who had never smoked each single product. Odds ratios for cigar and pipe smoking were stratified by ever cigarette smoking. We also considered effect estimates of smoking a single product exclusively versus never having smoked any product (reference group). Among never cigarette smokers, the odds ratio for ever cigar smoking was 2.54 (95% confidence interval (CI): 1.93, 3.34), and the odds ratio for ever pipe smoking was 2.08 (95% CI: 1.55, 2.81). These odds ratios increased with increasing frequency and duration of smoking (Ptrend <= 0.0001). Odds ratios for cigar and pipe smoking were not elevated among ever cigarette smokers. Head and neck cancer risk was elevated for those who reported exclusive cigar smoking (odds ratio = 3.49, 95% CI: 2.58, 4.73) or exclusive pipe smoking (odds ratio = 3.71, 95% CI: 2.59, 5.33). These results suggest that cigar and pipe smoking are independently associated with increased risk of head and neck cancers. PMID- 23817921 TI - Transdermal application of myelin peptides in multiple sclerosis treatment. AB - IMPORTANCE: Demonstration of efficacious antigen-specific therapy in multiple sclerosis. OBJECTIVE: To assess the safety and efficacy of transdermally applied myelin peptides in patients with relapsing-remitting multiple sclerosis. DESIGN: One-year double-blind, placebo-controlled cohort study. SETTING: Referral center. PARTICIPANTS: Thirty outpatients aged 18 to 55 years with relapsing-remitting multiple sclerosis. INTERVENTION: Skin patch with a mixture of 3 myelin peptides, MBP85-99, MOG35-55, and PLP139-155. MAIN OUTCOMES AND MEASURES Cumulative number of active gadolinium-enhanced (Gd+) lesions per patient per scan, mean volume of Gd+ lesions, cumulative number of new T2 lesions, and T2 lesion and T1 lesion volume change from baseline to the end of the study. Total number of relapses during the year of the study per patient (annual relapse rate), proportion of relapse-free patients, and proportion of patients with 3 months of confirmed disability worsening on the Expanded Disability Status Scale at month 12. RESULTS: All patients completed the study. Compared with placebo, treatment with a myelin peptide skin patch (1 mg) showed a 66.5% reduction in the cumulative number of Gd+ lesions (P = .02) during the 12 months of the study. The annual relapse rate in patients treated with a mixture of myelin peptides (1 mg) was significantly lower compared with the placebo group (0.43 vs 1.4; P = .007). Treatment with a myelin peptide skin patch was well tolerated and no serious adverse events were reported. CONCLUSIONS AND RELEVANCE: In patients with relapsing-remitting multiple sclerosis, treatment with a myelin peptide skin patch significantly reduced both magnetic resonance imaging and clinically defined measures of disease activity and was safe and well tolerated. PMID- 23817922 TI - Benefit of enactment over oral repetition of verbal instruction does not require additional working memory during encoding. AB - For this research, we used a dual-task approach to investigate the involvement of working memory in following written instructions. In two experiments, participants read instructions to perform a series of actions on objects and then recalled the instructions either by spoken repetition or performance of the action sequence. Participants engaged in concurrent articulatory suppression, backward-counting, and spatial-tapping tasks during the presentation of the instructions, in order to disrupt the phonological-loop, central-executive, and visuospatial-sketchpad components of working memory, respectively. Recall accuracy was substantially disrupted by all three concurrent tasks, indicating that encoding and retaining verbal instructions depends on multiple components of working memory. The accuracy of recalling the instructions was greater when the actions were performed than when the instructions were repeated, and this advantage was unaffected by the concurrent tasks, suggesting that the benefit of enactment over oral repetition does not cost additional working memory resources. PMID- 23817923 TI - Infliximab for the treatment of granulomatous peritonitis. PMID- 23817924 TI - Relationship between 13C-aminopyrine breath test and the MELD score and its long term prognostic use in patients with cirrhosis. AB - BACKGROUND: (13)C-Aminopyrine breath test ((13)C-ABT) is a non-invasive, dynamic, quantitative liver function test, and the model for end-stage liver disease (MELD) is a recognised biochemical score used to predict survival in patients with cirrhosis. AIMS: The purpose of this study was to evaluate the relationship between the (13)C-ABT and MELD score in a cohort of cirrhotic patients and, moreover, to assess the prognostic value of (13)C-ABT results in the same group of patients. PATIENTS AND METHODS: Forty-six patients with cirrhosis and without hepatocellular carcinoma who underwent (13)C-ABT and who had at least 1-year follow-up were prospectively included in this study. MELD score was calculated at entry into the study in all patients. End-points of the study were 1-year liver related death or liver transplantation. RESULTS: (13)C-ABT %dose/h at 30 min (%dose/h30) results showed significant, inverse correlation with MELD scores (r = -0.414, P = 0.004). During 1-year follow-up nine patients died (19.6 %) and two were transplanted (4.3 %). Median (13)C-ABT %dose/h30 results (3.2 vs. 1.8) were significantly higher in patients who survived as compared to those who died or underwent transplantation (P = 0.04). Receiver operating characteristics curves showed that a (13)C-ABT %dose/h30 cut-off of 2.0 had the best accuracy (c-index = 0.717) in assessing 1-year prognosis. CONCLUSIONS: We observed a correlation between a flow-independent quantitative liver function test and the MELD score, and found that the (13)C-ABT may accurately provide long-term prognostic information in cirrhotic patients. PMID- 23817925 TI - Regional hepatic regeneration after liver resection correlates well with preceding changes in the regional portal circulation in humans. AB - BACKGROUND AND AIMS: While portal hemodynamics largely affects the liver regeneration after partial hepatectomy, whether the remnant liver homogeneously regenerates is unclear, especially in humans. We hypothesized that change in flow distribution varies in each remnant portal branch after liver resection in humans and the liver consequently regenerates heterogeneously. METHODS: Twenty-two patients who underwent anatomical hepatic resection preserving intact drainage veins were analyzed. Based on perioperative contrast-enhanced computed tomography, the regional hepatic regeneration in each segment was analyzed using a region growing software. The perioperative change in the distribution of blood flow in each portal branch was assessed using the computational flow dynamics technique. The correlation between the change in the portal flow distribution and the later regional hepatic regeneration was investigated. RESULTS: The distribution of portal blood flow in each remnant branch largely changed at 2 weeks (71-389 %). Each remnant segment also heterogeneously regenerated at 3 months (85-204 %). Meanwhile, a good correlation between the regional regeneration rate at 3 months and the relative change in the flow distribution in each circulating portal branch at 2 weeks was detected in each patient (r = 0.74 0.99). CONCLUSIONS: After partial hepatectomy, the change in blood flow varies in each remnant portal branch and the liver heterogeneously regenerates in humans. The good correlation between the earlier change in the portal flow distribution and the later regional hepatic regeneration strongly suggests that the portal venous flow most likely regulates the non-uniform liver regeneration after hepatic resection in humans. PMID- 23817926 TI - Post-colonoscopy recommendations after inadequate bowel preparation: all in the timing. PMID- 23817927 TI - Activation of signaling pathways following intestinal resection: turning it up a Notch? PMID- 23817928 TI - Helicobacter pylori and gastritis: the role of extracellular matrix metalloproteases, their inhibitors, and the disintegrins and metalloproteases--a systematic literature review. AB - Helicobacter pylori (H. pylori) is the etiologic agent of gastritis; it has been estimated that 50 % of the world's population could be infected by this bacteria. Gastritis may progress to chronic atrophic gastritis, a condition associated with the development of gastric cancer (GC). Several matrix metalloproteases (MMP) and tissue inhibitors of MMPs (TIMP) as well as disintegrins and metalloproteases (ADAM) have been reported as being involved in gastritis. Among other processes, these protein families participate in remodeling the extracellular matrix, cell signaling, immune response, angiogenesis, inflammation and epithelial mesenchymal transition. This systematic review analyzes the scientific evidence surrounding the relationship between members of the MMP, TIMP and ADAM families and infection by H. pylori in gastritis, considering both in vitro and in vivo studies. Given the potential clinical value of certain members of the MMP, TIMP and ADAM families as molecular markers in gastritis and the association of gastritis with GC, the need for further study is highlighted. PMID- 23817929 TI - Microcantilever sensors coated with doped polyaniline for the detection of water vapor. AB - In the present work, PANI (polyaniline) emeraldine salt (doped) and base (dedoped) were used as the sensitive layer of a silicon microcantilever, and the mechanical response (deflection) of the bimaterial (coated microcantilever) was investigated under the influence of humidity. PANI in the emeraldine base oxidation state was obtained by interfacial synthesis and was deposited on the microcantilever surface by spin-coating (dedoped). Next, the conducting polymer was doped with 1 M HCl (hydrochloric acid). A four-quadrant AFM head with an integrated laser and a position-sensitive detector (AFM Veeco Dimension V) was used to measure the optical deflection of the coated microcantilever. The deflection of the coated (doped and undoped PANI) and uncoated microcantilever was measured under different humidities (in triplicate) at room pressure and temperature in a closed chamber to evaluate the sensor's sensitivity. The relative humidity (RH) in the chamber was varied from 20% to 70% using dry nitrogen as a carrier gas, which was passed through a bubbler containing water to generate humidity. The results showed that microcantilevers coated with sensitive layers of doped and undoped PANI films were sensitive (12,717 +/- 6% and 6,939 +/ 8%, respectively) and provided good repeatability (98.6 +/- 0.015% and 99 +/- 0.01%, respectively) after several cycles of exposure to RH. The microcantilever sensor without a PANI coating (uncoated) was not sensitive to humidity. The strong effect of doping on the sensitivity of the sensor was attributed to an increased adsorption of water molecules dissociated at imine nitrogen centers, which improves the performance of the coated microcantilever sensor. Moreover, microcantilever sensors coated with a sensitive layer provided good results in several cycles of exposure to RH (%). PMID- 23817930 TI - Ultrasound-targeted microbubble destruction enhances gene transduction of adeno associated virus in a less-permissive cell type, NIH/3T3. AB - Adeno-associated virus (AAV) is a common vector utilized in gene therapy. The NIH/3T3 cell line, which is a potential induced pluripotent stem (iPS) cell type, was identified to be a less-permissive cell type to AAV due to its defective endosomal processing. Ultrasound-targeted microbubble destruction (UTMD) enhanced the gene transduction of AAV in permissive cells. However, there are no data concerning UTMD enhancement in less-permissive cells, and the exact mechanism of UTMD enhancement in cellular uptake is unclear. Greater knowledge concerning the rate-limiting steps in NIH/3T3 cells would aid in the elucidation of the mechanism of UTMD enhancement in the gene transduction of AAV. In the present study, UTMD enhanced the gene transduction of AAV in NIH/3T3 cells, suggesting that UTMD-enhanced AAV-mediated gene transduction may be beneficial for gene therapy in iPS cells. The dose dependence of UTMD enhancement indicated that mechanisms other than sonoporation were involved in the cellular uptake of AAV. However, UTMD did not greatly increase the gene transduction of AAV in NIH/3T3 cells. Additionally, the similar degree of enhancement in the two cell types resulted in no correlation between UTMD and endosomal processing. Future studies on UTMD-mediated AAV transduction in other non- or less-permissive cell types may aid in elucidating the exact mechanism of UTMD enhancement in cellular uptake. PMID- 23817931 TI - Spontaneous laryngeal reinnervation following chronic recurrent laryngeal nerve injury. AB - OBJECTIVES/HYPOTHESIS: To enhance understanding of spontaneous laryngeal muscle reinnervation following severe recurrent laryngeal nerve injury by testing the hypotheses that 1) nerve fibers responsible for thyroarytenoid muscle reinnervation can originate from multiple sources and 2) superior laryngeal nerve is a source of reinnervation. STUDY DESIGN: Prospective, controlled, animal model. METHODS: A combination of retrograde neuronal labeling techniques, immunohistochemistry, electromyography, and sequential observations of vocal fold mobility were employed in rat model of chronic recurrent laryngeal nerve injury. The current study details an initial set of experiments in sham surgical and denervated group animals and a subsequent set of experiments in a denervated group. RESULTS: At 3 months after recurrent laryngeal nerve resection, retrograde brainstem neuronal labeling identified cells in the characteristic superior laryngeal nerve cell body location as well as cells in a novel caudal location. Regrowth of neuron fibers across the site of previous recurrent laryngeal nerve resection was seen in 87% of examined animals in the denervated group. Electromyographic data support innervation by both the superior and recurrent laryngeal nerves following chronic recurrent laryngeal nerve injury. CONCLUSIONS: Following chronic recurrent laryngeal nerve injury in the rat, laryngeal innervation is demonstrated through the superior laryngeal nerve from cells both within and outside of the normal cluster of cells that supply the superior laryngeal nerve. The recurrent laryngeal nerve regenerates across a surgically created gap, but functional significance of regenerated nerve fibers is unclear. PMID- 23817932 TI - Antenatal care: paradigm changes over the years. PMID- 23817933 TI - Breast milk DHA levels in Sri Lankan mothers vary significantly in three locations that have different access to dietary fish. AB - INTRODUCTION: Long-chain polyunsaturated fatty acids (LCPUFA) notably docosahexaenoeic acid (DHA) and arachidonic acid (ARA) are important for the optimum growth and development of the infant. DHA and ARA levels in breast-milk are thought to be influenced both by direct nutritional intake, and by the genetic variation of the FA desaturase enzymes. OBJECTIVES: To assess the fatty acid distribution in mothers' milk and their babies' blood, in three areas of Sri Lanka, with different access to sea-fish, and to see how the availability of dietary fish would affect fatty acid levels. METHODS: 6-12 week-old mother-baby pairs were recruited and mother's dietary intake assessed. Packed RBC from infants and breast milk (BM) from mothers were transported on dry ice to the Nutrition Laboratory, University of Otago, New Zealand for fatty acids extraction and quantification. RESULTS: We studied 136 mothers in three locations in Sri Lanka - Matara, Colombo, and Kandy. The breastmilk DHA levels were high in all three locations (0.79%, 0.53% and 0.37% respectively), and correlated with fish consumption. ARA levels did not vary significantly. In the 119 mother-infant pairs studied, infant erythrocyte DHA levels did not correlate significantly with BM DHA. CONCLUSIONS: Even the modest access to sea fish in the most inland site, resulted in BM-DHA levels higher than those found in any infant formula. Higher BM-DHA levels in the two other sites with greater access to fish did not lead to further increase in infant RBC-DHA levels. Where access to sea fish is limited, mothers should be encouraged to actively increase their fish intake as this would improve their DHA status, and also that of their breast milk. PMID- 23817934 TI - A multi centre laboratory study of Gram negative bacterial blood stream infections in Sri Lanka. AB - INTRODUCTION: Data on causative agents and antibiotic susceptibility patterns of blood stream infections in Sri Lanka is scarce. Information on trends of antibiotic resistance is necessary for the prescribers to treat patients effectively and policy makers to develop policies and guidelines. OBJECTIVES: To lay the foundation for a national data base on antimicrobial resistance in Sri Lanka. METHODS: A prospective study was carried out in seven hospitals to study the Gram negative aetiological agents and their susceptibility patterns in patients suspected of having bacteraemia. We reviewed 817 patients with clinically significant blood cultures including both adults and children. RESULTS: Data were complete for analysis in 733 Gram negative isolates only. Of the 733 isolates, 488 were from adults (> 12 years), 109 were from children (1-12 years) and 136 were from infants (<1 year). Intensive care units represented 18.4% of the isolates (123 adult patients and 27 paediatric patients). The highest number of isolates (33.7%) was from patients with septicaemia of unknown origin. Enteric fever, pyelonephritis and respiratory tract infections accounted for 20% of the isolates. Bacteraemia with underline malignancies were responsible for 24.5% of infections. Salmonella paratyphi A was the commonest cause of enteric fever in adults with 92% resistance to ciprofloxacin. The prevalence of extended spectrum beta lactamase (ESBL) producing Escherichia coli and Klebsiella pneumoniae was high in this study population. CONCLUSIONS: It is essential to introduce multidisciplinary interventions to reduce the inappropriate use of antibiotics to increase the lifespan of precious antibiotics. Introduction of a National antibiotic policy with strict implementation and a well-planned stewardship programme is essential to control antimicrobial resistance in our country. PMID- 23817935 TI - Sri Lankan fetal/ birthweight charts: validation of global reference for fetal weight and birthweight percentiles. AB - INTRODUCTION: Small for gestational age (SGA) is defined as birthweight below the tenth centile at a particular gestational week. Birthweight centiles for different populations are varied. Generic reference for fetal weight and birthweight that could be adapted to local populations was recently described. The purpose of this study was to validate the reference for birthweights adapted to the local population. METHODS: This was a prospective validation study done between January 2012 and July 2012 in well dated pregnancies at General Hospital, Ampara. Observed frequencies of birthweights of 5th, 10th, 50th, 90th and 95th percentiles for Hadlock formula, World Health Organization (WHO) global survey data for Sri Lanka and India were calculated. The expected frequencies for each birthweight centile of our study were compared with observed frequencies. RESULTS: A total of 411 patients were recruited and 207 delivered at 40 weeks (40+0-40+6). The mean birth-weight (SD) at 40 weeks of gestation was 3140g (432g). Hadlock formula and WHO reference data for India overestimate and underestimate most of the birthweights respectively. WHO generic reference adapted to Sri Lanka fitted well with our data. The mean birthweight of our population is similar, and the adapted reference range would identify most of the small fetuses correctly. It would also identify almost all the babies with weight above the 90th centile. CCONCLUSIONS: The findings of the study show that the observed distribution of birthweight fitted well with the reference range derived from the WHO global reference range adapted to Sri Lankan population. WHO reference charts can be used effectively in Sri Lankan population. PMID- 23817936 TI - Factor structure and normative data of the Sinhalese version of self reported Strength and Difficulties Questionnaire (SDQ) for adolescents. AB - OBJECTIVES: To describe the normative data, factor structure and the internal consistency of the Sinhalese, self reported version of SDQ for adolescents. METHODS: The present study was carried out in eight provinces in Sri Lanka. A sample of school going adolescents aged 12-16 years were selected from Sinhalese medium schools using a multi stage cluster sampling technique with probability proportionate to size. The component structure of the SDQ was examined using principal component analysis. Normative banding and the cut off values were determined, based on the distribution of raw data in this non-clinical sample. RESULTS: The study sample consisted of 535 (45.3%) boys and 645 (54.5%) girls. Mean total difficulty score for girls (10.66+/-5.440) was significantly (p=0.014) higher than that for boys (9.93+/-4.671). Mean scores for emotional (2.97+/ 2.009), conduct (2.11+/-1.755) and peer (2.24+/-1.760) subscales were also significantly higher among girls than that of boys (2.7+/-1.915, 1.78+/-1.406 and 2.04+/-1.383 respectively). In the factor analysis, only factor that was loaded with all five items in the original subscale was "emotional" and the loading values were more than .445 for all five items. None of the other extracted factors contained more than 3 items from one subscale. Internal consistency (Cronbach's alpha) for total difficulties was satisfactory in the total sample as well as in boys and girls separately (>.71). However, in all five subscales, Chrobach's alpha was less than six, showing a low homogeneity. CONCLUSIONS: Factor structure and internal consistency of the current Sinhalese version of the self reported SDQ is not satisfactory. Revalidation of this version of SDQ is recommended to capture the intended objectives of the SDQ. PMID- 23817937 TI - Validity of BMI, hip and waist circumferences as surrogate measures of obesity in a cohort of Sri Lankan premenopausal women. AB - INTRODUCTION: BMI, hip and waist circumferences (HC and WC) are being used as clinical surrogates of obesity. Unceratinities exist regarding the cut-off values, which are recommonded for Western countries. OBJECTIVES: We conducted a study to determine cut-off values for Sri Lankan women. METHODS: Healthy premenopausal women (n=128) aged 25 to 50 years were selected randomly, from local MOH area and stratified into four groups (32 in each) according to their BMI. Those who were pregnant, breast feeding, or on long-term medications were excluded. Body weight and height, hip circumference (HC) and waist circumference (WC) were measured, using standard protocols. Lean and fat mass, were measured by DXA and percentage FM (%FM) was calculated (FM/body weight x100). Women with %FM> 30% were considered obese. RESULTS: BMI moderately correlated (r = 0.41) with %FM and BMI accounted for only 16% (r2 = 0.16) of %FM variation. Regression equations were used to estimate the cut-off values that corresponded to %FM of 30. Those cut-off values for BMI, WC, and HC were 24.4 Kg/m2, 92 cm, and 78 cm, respectively. CONCLUSION: BMI, WC and HC values of 24 kg/m2, 92 cm and 78 cm can be considered appropriate cut-off values when detecting central obesity in premenopausal women. PMID- 23817938 TI - Prevalence of postpartum anal incontinence: a cross sectional study in Northern Sri Lanka. AB - OBJECTIVES: To estimate the prevalence of postpartum anal incontinence (AI) and to highlight associated factors that account for variation in the prevalence in Vavuniya district in Northern Sri Lanka. METHODS: A community based cross sectional study was conducted. Sample included all mothers (hospital and home deliveries) who had completed postpartum period between 1st August and 30th September 2007. Participants were identified from the "expected date of delivery" registers maintained by public health midwives. Data were collected by trained public health midwives at the respondents' houses using an interviewer administered questionnaire. RESULTS: The mean age of the 540 postpartum mothers interviewed was 28 years (range: 16 - 44). Majority 78% (n=423) were Sri Lankan Tamils, 13% (n=68) Sinhalese and remaining 9% (n=49) Moors. Thirty nine percent (n=209) were primi parous, 81% (n=435) had a normal vaginal delivery and 79% (n=344) had an episiotomy. Out of 540 mothers, 16.5% (95% CI: 13.4 - 19.6) reported anal incontinence. Among them only 39.3% (n=35) had consulted a health worker for the symptom. In the bivariate analysis the following factors were significantly associated with anal incontinence: parity, history of an episiotomy, duration of labour >12hrs, mode of delivery (vaginal), family income and maternal age (teenage). But the multiple logistic regression analysis revealed only the episiotomy status as an independent risk factor (adjusted odd ratio: 3.4 (95% CI: 1.28 - 8.9). CONCLUSINS: Anal incontinence is not an uncommon symptom in postpartum mothers and majority of affected individuals avoided seeking medical attention. Factors associated with increased risk of anal sphincter damage should be considered during delivery and an attempt should be made to reduce it. PMID- 23817939 TI - N-acetylcysteine in children with acute liver failure complicating dengue viral infection. AB - OBJECTIVES: To describe the outcome after administration of N-acetylcysteine (NAC) to seven children with nonparacetamol induced acute liver failure (ALF) complicating dengue infection. METHODS: Clinical records of children with non paracetamol induced acute liver failure complicating severe dengue viral infection, were retrospectively analysed for clinical and biochemical outcome following treatment with NAC. RESULTS: Seven patients between ages six months to twelve years with plasma leakage and circulatory compromise complicating dengue infection developed ALF. Three were exposed to prolonged shock prior to hospitalisation. NAC infusion (100 mg/kg) was administered as soon as ALF was diagnosed, based on low GCS scores, raised transaminases and prolonged prothrombin/INR. Full clinical and biochemical recovery occurred in all patients. CONCLUSIONS: A successful outcome followed early administration of NAC to children with ALF complicating severe dengue infection. PMID- 23817940 TI - Rate of stunting among a sample of postwar resettled families in the Vanni Region: a study from the Mullaitivu District. AB - The Department of Family Medicine, University of Kelaniya conducted a health camp in Puthukudiyiruppu in March 2011. Height and weight measurements were carried out and data of 303 participants were analysed. The rate of stunting among children below six years in this population was 62% compared to 19.3% nationally. Thirty four percent of children and adolescents (6-18yrs) were underweight and 21.4% of adults had a BMI less than 18.5kg/m2. PMID- 23817941 TI - Fatal pulmonary haemorrhage following adenovirus infection. PMID- 23817942 TI - Acquired pure red cell aplasia due to anti-erythropoietin antibodies in a patient with end stage chronic kidney disease. PMID- 23817943 TI - Megaloblastic anaemia in non secretory multiple myeloma: a rare presentation. PMID- 23817944 TI - An incidental finding of congenital methaemoglobinaemia in a patient with an allergy. PMID- 23817945 TI - Effect of stacking faults on the magnetocrystalline anisotropy of hcp Co: a first principles study. AB - In terms of the fully relativistic screened Korringa-Kohn-Rostoker method we investigate the effect of stacking faults on the magnetic properties of hexagonal close-packed (hcp) cobalt. In particular, we consider the formation energy and the effect on the magnetocrystalline anisotropy energy (MAE) of four different stacking faults in hcp cobalt-an intrinsic growth fault, an intrinsic deformation fault, an extrinsic fault and a twin-like fault. We find that the intrinsic growth fault has the lowest formation energy, in good agreement with previous first-principles calculations. With the exception of the intrinsic deformation fault which has a positive impact on the MAE, we find that the presence of a stacking fault generally reduces the MAE of bulk Co. Finally, we consider a pair of intrinsic growth faults and find that their effect on the MAE is not additive, but synergic. PMID- 23817946 TI - Relatedness communicated in lemur scent. AB - Lemurs are the most olfactory-oriented of primates, yet there is still only a basic level of understanding of what their scent marks communicate. We analyzed scent secretions from Milne-Edwards' sifakas (Propithecus edwardsi) collected in their natural habitat of Ranomafana National Park, Madagascar. We sought to test whether the scent mark could signal genetic relatedness in addition to species, sex, season, and individuality. We not only found correlations (r (2) = 0.38, P = 0.017) between the total olfactory fingerprint and genetic relatedness but also between relatedness and specific components of the odor, despite the complex environmental signals from differences in diet and behavior in a natural setting. To the best of our knowledge, this is the first demonstration of an association between genetic relatedness and chemical communication in a wild primate population. Furthermore, we found a variety of compounds that were specific to each sex and each sampling period. This research shows that scent marks could act as a remote signal to avoid inbreeding, optimize mating opportunities, and potentially aid kin selection. PMID- 23817947 TI - Effects of exotic fish farms on bird communities in lake and marine ecosystems. AB - Salmon farming is a widespread activity around the world, also known to promote diverse environmental effects on aquatic ecosystems. However, information regarding the impact of salmon farming on bird assemblages is notably scarce. We hypothesize that salmon farming, by providing food subsidies and physical structures to birds, will change their local community structure. To test this hypothesis, we conducted a seasonal monitoring of bird richness, abundance, and composition at paired salmon pen and control plots in two marine and two lake sites in southern Chile, from fall 2002 to summer 2004. Overall, salmon farming had no significant effects on species richness, but bird abundance was significantly and noticeably higher in salmon pens than in controls. Such aggregation was mainly accounted for by the trophic guilds of omnivores, diving piscivores, carrion eaters, and perching piscivores, but not by invertebrate feeders, herbivores, and surface feeders. Species composition was also significantly and persistently different between salmon pens and controls within each lake or marine locality. The patterns described above remained consistent across environment types and seasons indicating that salmon farming is changing the community structure of birds in both lake and marine habitats by promoting functional and aggregation responses, particularly by favoring species with broader niches. Such local patterns may thus anticipate potential threats from the ongoing expansion of the salmon industry to neighboring areas in Chile, resulting in regional changes of bird communities, toward a less diverse one and dominated by opportunistic, common, and generalist species such as gulls, vultures, and cormorants. PMID- 23817948 TI - Efficacy of taurolidine on the prevention of catheter-related bloodstream infections in patients on home parenteral nutrition. AB - PURPOSE: To assess the efficacy of taurolidine (TauroLockTM) line locks on the prevention of catheter-related bloodstream infections (CRBSI) in patients on home parenteral nutrition (HPN). METHODS: In our unit, any patient with >=2 CRBSIs in six months is considered for TauroLockTM (2% taurolidine and 4% citrate) line locks. All such patients from May 2007 until January 2012 were identified, along with associated CRBSI rates. CRBSI was defined by differential time to positivity for positive blood cultures. CRBSIs were grouped into pre-taurolidine use and post-taurolidine commencement for each patient and the infection rate per 1000 catheter days calculated. Results were analyzed using Wilcoxon two-sided test. RESULTS: A total of nine patients were included (two men and seven women) with a median age of 51 (range 43-82) years. Infection rates after commencing taurolidine decreased markedly in all patients studied. The median CRBSI rate prior to taurolidine use was 6.39 per 1000 catheter days. This decreased to a median CRBSI rate of 0 per 1000 catheter days after commencing taurolidine. CONCLUSIONS: Taurolidine is no substitute for careful aseptic technique. However, it is clearly effective at preventing CRBSIs and should be used in patients with recurrent infections to reduce morbidity. PMID- 23817949 TI - Internal jugular vein cannulation: why ultrasound guidance should be expanded as much as possible. PMID- 23817950 TI - Morphologic and functional vessels characteristics assessed by ultrasonography for prediction of radiocephalic fistula maturation. AB - PURPOSE: Although native radiocephalic arteriovenous fistula (RCAVF) is the best vascular access for hemodialysis (HD), a major obstacle to increase its use is high frequency of fistulas that fail to mature. The aim of this study was to investigate and define cut-off values of morphologic and functional vessel parameters influencing successful RCAVF maturation using ultrasound. METHODS: A prospective, observational study was performed on 122 patients (66 men) who underwent primary RCAVF creation. Internal diameters of cephalic vein (CVd) and radial artery (ARd), venous distensibility (VD), resistance index (RI) and endothelial function by flow mediated dilatation (FMD) were determined by ultrasound examination before AVF placement. AVF maturation was observed by measuring blood flow (Qa) and CVd 0, 14 and 28 days after creation. Depending on the time when AVFs attained maturity (Qa >=500 mL/min, CVd >=5 mm), patients were divided into three groups: (i) successful maturation (after four weeks), (ii) prolonged maturation (within eight weeks) and (iii) failure to mature. RESULTS: Only 11% of patients failed to achieve a mature RCAVF. Successful AVF maturation occurred in 53% of patients and prolonged maturation in 36% of patients. ROC analysis defined the limits of variables relevant for RCAVF success (CVd >1.8 mm, ARd >1.6 mm, VD >0.4 mm). Female sex was associated with prolonged maturation (OR 0.35, 95% CI=0.17-0.72; P=0.005) having a significantly smaller ARd (1.83 vs. 2.01 mm, P=0.01) but better FMD (2981.5 vs. 2689.5, P=0.02) compared to men. CONCLUSIONS: ARd <=1.6 mm, CVd <=1.8 mm and VD <=0.4 mm are exact cut-off points, which best predict nonmaturation of RCAVF. Women need extended time for adequately matured AVF. PMID- 23817951 TI - Central venous catheters in neonates: old territory, new frontiers. Invited commentary to peripherally inserted central venous catheters in critically ill premature neonates, by Ozkiraz et al, J Vasc Access 2013;14(4):320-324. PMID- 23817952 TI - Peripherally inserted central venous catheters in critically ill premature neonates. AB - PURPOSE: To evaluate the safety of peripherally inserted central venous catheters (PICCs) and their complications in critically ill premature neonates. METHODS: A retrospective collection of data of infants with very low birth weight (VLBW) who underwent PICC placement over a 2-year period. Gestational age, birth weight (BW), sex, site of catheter placement, reason for catheter removal, duration of the catheter use, proven sepsis, type of the reported organism and the rate of complications were collected. The infants were classified into two groups according to BWs: Group 1-VLBW infants (BW between 1,000 and 1,500 g) and Group 2 BW <1,000 g (extremely low birth weight, ELBW group). RESULTS: During the study period, 90 VLBW infants were admitted to the neonatal intensive care unit. PICCs were attempted in 71 patients. A PICC was successfully inserted into 62 patients (87.3%). Totally, 68 PICCs were inserted into 62 infants. PICCs placed in either the upper or the lower extremity have no differences in complication rates. The median time of catheter insertion was 10 (1-22) days for Group 1 and 16 (1-47) days for Group 2 (p=0.001). The median duration of PICCs was 9 (2-18) and 12.0 (3 30) days, respectively (p=0.012). There were no significant differences between groups for the reasons for removal (p=0.859). CONCLUSIONS: PICCs are convenient for the administration of long course antibiotics and parenteral nutrition for both VLBW and ELBW infants. The risk of catheter complications did not increase in ELBW infants. Although the technique of insertion is easy and using PICCs has many benefits, serious and fatal complications may occur in premature neonates in critical states. PMID- 23817953 TI - Arteriovenous fistula aneurysms in patients with Alport's. AB - PURPOSE: Alport's syndrome is a rare but important cause of renal failure. It is characterized by Type IV collagen mutations resulting in connective tissue disorders and renal and cochlear dysfunction. Vascular basement membrane also contains collagen IV and the effect on arteriovenous fistulas (AVFs) is not reported. Anecdotally, we observed a high rate of aneurysm formation in Arteriovenous fistulas (AVF) of patients with Alport's and sought to determine whether this was the case within our population. METHODS: All patients with a diagnosis of Alport's were identified from a contemporaneously maintained database. AVFs formed in patients with Alport's were identified to define the incidence of aneurysms in this group. RESULTS: A total of 40 patients with a diagnosis of Alport's were identified. Of these, 20 patients had undergone AVF formation, the remainder opting for CAPD as renal replacement or had undergone pre-emptive transplantation. Of the 20 patients identified, 11 had an AVF and of these the rate of aneurysm formation was high (55%). CONCLUSIONS: While this finding of high rate of aneurysmal AVF in Alport's patients is a purely observational finding within our population further population study would be extremely interesting and could support enhanced surveillance or alternative dialysis modalities in Alport's syndrome patients. PMID- 23817954 TI - Central vascular catheters versus peripherally inserted central catheters in nurse anesthesia. A perspective within the Greek health system. AB - PURPOSE: We present a study comparing the insertion of central vascular catheter (CVC) and peripherally inserted central catheter (PICC) by an anesthesia nurse at 2 Greek University Hospitals. METHODS: Eighty patients, aged 20-80 years, were enrolled in the study. Patients were divided into 2 groups. In group A (41 patients), a CVC was inserted in the internal jugular vein. In group B (39 patients), a pressure-injectable PICC was inserted in the basilica vein. RESULTS: Correlations between the methods applied, the patients' characteristics, the procedures' characteristics and the overall satisfaction scores for each procedure were examined. The final results show that the patients of group B (PICC method) were more satisfied with the procedure than the patients of group A (CVC method), at the statistical significance level of a=0.01. Also, according to the results of the analysis, the PICC method offers significantly more comfort and relative satisfaction than the CVC method, at the statistical significance level of a=0.01. The satisfaction scores of "physicians" were statistically more significant, at a=0.01, for the patients of group A (classic CVCs) mainly because of the insufficient flow rate of the PICCs when compared with the CVCs and especially if one considers the fact that the physicians did not have any experience with the PICC method at all. CONCLUSIONS: PICCs under ultrasound guidance constitute the solution of choice for patients and they definitely surpass the CVCs focusing mainly on the improvement of the quality of life and the satisfaction of patients. PMID- 23817955 TI - External jugular vein cross-over as a new technique for percutaneous central venous port access in case of left central venous occlusion. AB - PURPOSE: To report the cross-over venous catheter technique in case of left-sided central venous (internal jugular, subclavian and innominate veins) occlusion and right-sided central vein patency. METHODS: A 60-year-old right breast cancer patient presented with a local recurrence requiring chemotherapy. He presented with a left-sided catheter-related central venous occlusion and radiodermatitis of the right chest and neck. The nonsymptomatic side of insertion was defined as the patient's left side. Successful percutaneous left-to-right external jugular vein (EJV) cross-over access tips and tricks are reported. They include performing (a) the EJV access at the lower neck, (b) the 0.032 hydrophilic guidewire (GW) catheterization of the venous curves, (c) the GW anchor technique into the inferior vena cava, (d) the GW + Glidecath catheter stiffening technique and (e) the over-the-stiff wire implantable catheter push. RESULTS: The cross over technique was successful by using real-time ultrasonography/X-ray monitoring and interventional radiology tools (hydrophilic 0.032 in. and stiff 0.0035 in. GW and "J-shaped" Glidecath catheter) and the five-step technique. CONCLUSIONS: In case of left innominate vein occlusion and necessity of left neck venous access, percutaneous EJV access should be attempted under real-time ultrasound/X-ray monitoring when other standard (subclavian venous port and internal jugular vein) routes are no longer available. PMID- 23817956 TI - Non contrast-enhanced MRA versus ultrasound blood vessel assessment to determine the choice of hemodialysis vascular access. AB - PURPOSE: The aim of this work was to establish the relationship between traditional blood vessel mapping for vascular access (VA) creation by B-mode ultrasound (US) and novel non contrast-enhanced magnetic resonance angiography ?(NCE-MRA), and to study the potential influence of the diameter assessment technique on the choice of hemodialysis vascular access. METHODS: A total of 27 end-stage renal-disease patients were included. They received routine US and a NCE-MRA examination of the upper extremity. Diameters were measured manually on US and semi-automatically on NCE-MRA. These measurements were statistically compared for the arteries and veins and for each measurement location. Furthermore, sensitivity and specificity of both modalities to predict VA location was investigated by comparison with an experienced surgeon. This analysis gave insight into the potential influence of vessel mapping modality on decision-making. RESULTS: Comparison of NCE-MRA with US for the arteries and veins, demonstrated a bias of 9% (limits -33%-78%) and 38% (limits -36%-198%), respectively. Statistically significant differences between the modalities on the individual locations were mainly found for the venous locations. The sensitivity and specificity for US to predict VA location was 1.0 and 0.74, respectively, while for NCE-MRA this was 0.88 and 0.39, respectively. CONCLUSIONS: The results obtained indicate that extreme caution should be exercised when replacing one diameter measurement modality with the other. A further need exists to improve both vessel mapping protocols to obtain a geometric description of the upper extremity vasculature regardless of acquisition modality. PMID- 23817957 TI - Glucosinolates profile and antioxidant capacity of Romanian Brassica vegetables obtained by organic and conventional agricultural practices. AB - The profile of glucosinolates in relation to the antioxidant capacity of five Brassica vegetables (Broccoli, Cauliflower, Kohlrabi, White and Red Cabbage) grown by organic and conventional agricultural practices in Transylvania region Romania, were determined and compared. The qualitative and quantitative compositions of glucosinolates were determined by HPLC-PDA technique. The antioxidant capacity was comparatively determined by ABTS, DPPH, FRAP and Folin Ciocalteu assays. The highest glucosinolates levels were found in the Broccoli samples grown under conventional practices (14.24 MUmol/g dry weight), glucoraphanin, glucobrassicin and neo-glucobrassicin being the major components. The total glucosinolates content was similar in Kohlrabi and Cauliflower (4.89 and 4.84 MUmol/g dry weight, respectively), the indolyl glucosinolates were predominant in Kohlrabi, while the aliphatic derivatives (sinigrin and glucoiberin) were major in Cauliflower. In Cabbage samples, the aliphatic glucosinolates were predominat against indolyl derivatives, glucoraphanin and glucoiberin being the main ones in Red Cabbage. The principal component analysis was applied to discriminate among conventional and organic samples and demonstrated non-overlaps between these two agricultural practices. Meanwhile it was shown that glucosinolates may represent appropriate molecular markers of Brassica vegetables, their antioxidant capacity being higher in organic crops, without significant differences among different Brassica varieties. PMID- 23817958 TI - Proinflammatory stimuli induce galectin-9 in human mesenchymal stromal cells to suppress T-cell proliferation. AB - Human multipotent mesenchymal stromal cells (MSCs) are clinically applied to treat autoimmune diseases and graft-versus-host disease due to their immunomodulatory properties. Several molecules have been identified to mediate these effects, including constitutively expressed galectin-1. However, there are indications in the literature that MSCs exert enhanced immunosuppressive functions after interaction with an inflammatory environment. Therefore, we analyzed how inflammatory stimuli influence the expression of the galectin network in MSCs and functionally tested the relevance for the immunomodulatory effects of MSCs. We found that galectin-9 was strongly induced in MSCs upon interaction with activated PBMCs. Proinflammatory cytokines, such as interferon gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha), and also ligands of the Toll-like receptors (TLRs) TLR2, TLR3, and TLR4 elicited similar induction of galectin-9 in activated PBMCs. Galectin-9 was not only upregulated intracellularly, but also released by MSCs in significant amounts into the supernatant after exposure to proinflammatory stimuli. In proliferation assays, MSCs with a galectin-9 knockdown lost a significant portion of their antiproliferative effects on T cells. In conclusion, we found that unlike constitutively expressed galectin-1, galectin-9 is induced by several proinflammatory stimuli and released by MSCs. Thus, galectin-9 contributes to the inducible immunomodulatory functions of MSCs. PMID- 23817959 TI - Unique protein signature of circulating microparticles in systemic lupus erythematosus. AB - OBJECTIVE: To characterize the unique qualities of proteins associated with circulating subcellular material in systemic lupus erythematosus (SLE) patients compared with healthy controls and patients with other chronic autoimmune diseases. METHODS: Using differential centrifugation and high-sensitivity nano liquid chromatography tandem mass spectrometry, we systematically profiled proteins of microparticles (MPs) from SLE patients (n=12), systemic sclerosis (SSc) patients (n=6), and rheumatoid arthritis (RA) patients (n=6), as well as healthy controls (n=12). RESULTS: We identified 531 unique proteins and showed that the differences between healthy controls and patients with SLE with regard to the abundance of 248 proteins were highly statistically significant. Almost half of the proteins that were increased by >2-fold were complement proteins and Ig (increased by 100-4,000 times). MP Ig and complement loads also distinguished SLE from RA and SSc and correlated strongly with clinical SLE severity. Subsets of microtubule proteins, fibronectin, 14-3-3eta, and desmosomal proteins as well as ficolin 2 and galectin 3 binding protein were also highly increased. In SLE MPs, levels of cytoskeletal, mitochondrial, and organelle proteins, including lysosome-associated membrane protein 1 and transforming growth factor beta1, were decreased. CONCLUSION: The data show that SLE patients have increased numbers of MPs that are heavily tagged for removal and fewer MPs with normal protein composition. SLE MPs are unique and specific proteins that represent novel leads for our understanding of SLE and for the development of new treatments of the disease. PMID- 23817960 TI - Dynamic changes in the dural sac of patients with lumbar canal stenosis evaluated by multidetector-row computed tomography after myelography. AB - PURPOSE: Some reported studies have evaluated the dural sac in patients with lumbar spinal stenosis (LSS) by computed tomography (CT) after conventional myelography or magnetic resonance imaging (MRI). But they have been only able to evaluate static factors. No reports have described detailed dynamic changes in the dural sac during flexion and extension observed by multidetector-row computed tomography (MDCT). The aim of this study was to elucidate or demonstrate, in detail, the influence of dynamic factors on the severity of stenosis. METHODS: One hundred patients with LSS were enrolled in this study. All underwent MDCT in both flexion and extension positions after myelography, in addition to undergoing MRI. The anteroposterior diameter (AP-distance) and cross-sectional area of the dural sac (D-area) were measured at each disc level between L1-2 and L5-S1. The dynamic change in the D-area was defined as the absolute value of the difference between flexion and extension. The rate of dynamic change (dynamic change in D area/D-area at flexion) in the dural sac at each disc level was also calculated. RESULTS: The average AP-distance in flexion/extension (mm) was 9.2/7.4 at L3-4 and 8.3/7.4 at L4-5. The average D-area in flexion/extension (mm(2)) was 96.3/73.6 at L3-4 and 72.3/61.0 at L4-5. The values were significantly lower in extension than in flexion at all disc levels from L1-2 to L5-S1. AP-distance was narrowest and D-area smallest at L4-5 during extension. The rates of dynamic changes at L2-3 and L3-4 were higher than those at L4-5. CONCLUSIONS: MDCT clearly elucidated the dynamic changes in the lumbar dural sac. Before surgery, MDCT after myelography should be used to evaluate the dynamic change during flexion and extension, especially at L2-3, L3-4, and L4-5. PMID- 23817961 TI - Prehospital triage to primary stroke centers and rate of stroke thrombolysis. AB - IMPORTANCE: Implementation of prehospital stroke triage is a public policy intervention that can have an immediate impact on acute stroke care in a region. OBJECTIVE To evaluate the impact that a citywide policy recommending prehospital triage of patients with suspected stroke to the nearest primary stroke center had on intravenous tissue plasminogen activator (tPA) use in Chicago, Illinois. DESIGN: Retrospective multicenter cohort study from September 1, 2010, to August 31, 2011 (6 months before and after intervention that began March 1, 2011). SETTING: Ten primary stroke center hospitals in Chicago. PATIENTS: All admitted patients with stroke and transient ischemic attack. INTERVENTION Prehospital triage policy of patients with stroke to primary stroke centers. MAIN OUTCOMES AND MEASURES: Intravenous tPA use (measured as a fraction of patients with ischemic strokes arriving through the emergency department). RESULTS There were 1075 stroke and transient ischemic attack admissions in the pretriage period and 1172 in the posttriage period. Patient demographic characteristics including age, sex, and risk factors were similar between the 2 periods (mean age, 65 years; 53% female). Compared with the pretriage period, use of emergency medical services increased from 30.2% to 38.1% (P < .001) and emergency medical services prenotification increased from 65.5% to 76.5% (P = .001) after implementation. Rates of intravenous tPA use were 3.8% and 10.1% (P < .001) and onset-to treatment times decreased from 171.7 to 145.7 minutes (P = .03) in the pretriage and posttriage periods, respectively. Stroke unit admission, symptomatic intracranial hemorrhage rates, and in-hospital mortality were not significantly different between periods. Adjusting for mode of arrival, prehospital notification, and onset-to-arrival time, the posttriage period was independently associated with increased tPA use for patients with ischemic stroke presenting through the emergency department (adjusted odds ratio = 2.21; 95% CI, 1.34-3.64). CONCLUSIONS AND RELEVANCE: Implementation of a prehospital stroke triage policy in Chicago resulted in significant improvements in emergency medical services use and prenotification and more than doubled intravenous tPA use at primary stroke centers. PMID- 23817963 TI - A highly porous 4,4-paddlewheel-connected NbO-type metal-organic framework with a large gas-uptake capacity. AB - A highly porous 4,4-paddlewheel-connected NbO-type metal-organic framework (HNUST 2, HNUST represents Hunan University of Science and Technology) has been designed and synthesized by self-assembling [Cu2(COO)4] SBUs with a nanosized tetracarboxylate ligand prolonged by alkyne groups, 5,5'-(naphthalene-1,4 diylbis(ethyne-2,1-diyl))diisophthalic acid (H4NDED). HNUST-2 exhibits high structural stability, a porous non-interpenetration framework with open metal sites and excellent gas-uptake capacity. This MOF material possesses a high BET surface area of 2366 m2 g-1, a large unsaturated excess and total H2 uptake of 4.57 wt% and 5. 20 wt% at 20 bar and 77 K, respectively. Meanwhile, HNUST-2 also exhibits an excellent adsorption capacity for CO2 (18.07 mmol g-1 at 20 bar and 298 K) and CH4 (85.6 cm3 cm-3 at 20 bar and 298 K) with a high selectivity for CO2 over N2 (22.9) and CH4 (4.9) at 298 K. PMID- 23817962 TI - Analysis of the delay components in the treatment of status epilepticus. AB - BACKGROUND: The factors comprising the delays in management of status epilepticus (SE) have not been systematically studied. METHODS: We studied retrospectively all adult patients (N = 82) diagnosed with SE in Helsinki University Central Hospital emergency room over a 2-year period. We analyzed prehospital, diagnostic, treatment, and treatment response delays based on medical records and quantitatively evaluated data availability and accuracy. RESULTS: SE manifested mostly without any warning symptoms, but every fifth case presented a pre-status period. Median prehospital delay was 2 h 4 min, including delays in emergency call, ambulance arrival, and patient transportation. Median delay of diagnosing SE was 2 h 10 min. EEG-based diagnosis was significantly delayed compared to clinical diagnosis. Median delay in recording EEG was 22 h 2 min. Median delay of the first medication was 35 min, and those of second- and third-stage medications were 3 h and 2 h 55 min, respectively. We applied stepwise definition for treatment response and counted delays accordingly: total convulsion period 5 h 52 min, Burst-suppression (BS) 17 h 30 min and return of consciousness 47 h 40 min. Median treatment period in intensive care unit was 2.7 days. Mortality over treatment period (median 7.7 days) was 8.5 %. No post-discharge follow-up was performed. CONCLUSION: Our study reveals unexpectedly and unacceptably long delays in SE management, stressing the importance of commitment to acknowledged management protocol. Delays in the treatment can and need to be shortened markedly by several strategies discussed in this article. PMID- 23817964 TI - MiR-124 inhibits the growth of glioblastoma through the downregulation of SOS1. AB - Glioblastoma multiforme (GBM) is a lethal brain tumor in adults. Despite advances in treatments, such as surgery, radiotherapy and chemotherapy, high-grade glioma remains fatal. The molecular and cellular mechanisms for GBM are not entirely clear and further studies are required to elucidate these. MicroRNAs (miRNAs) are small, non-coding, endogenous RNAs that are involved in cell differentiation and proliferation, and have been suggested to play a role in a variety of types of cancer. In this study, we investigated the role of miR-124 in the inhibition of proliferation of GBM cells. The downregulation of miR-124 in human GBM tumor cell lines was detected using quantitative RT-PCR. To assess the function of miR-124, we constructed stable cell lines, U87-124 and U373-124, which overexpressed miR 124 using lentiviral vectors. Overexpression of miR-124 inhibited the proliferation of GBM cancer cells in vitro. Using integrated bioinformatics analysis, SOS1 was found to be a direct target for miR-124, which is frequently upregulated in gliomas. Dual-luciferase reporter assays confirmed that the SOS1 mRNA 3'-untranslated regions (UTR) was directly targeted by miR-124 and that the mutated 3'UTR was not affected. This was revealed to be mechanistically associated with the induction of SOS/Ras/Raf/ERK and the suppression of ERK activity, which was achieved by silencing SOS1. This study therefore indicates an important role for miR-124 in the regulation of growth in the molecular etiology of GBM, and offers a potential strategy for the use of miR-124 in cancer treatment. PMID- 23817965 TI - Spatial resolution of an eye containing a grouped retina: ganglion cell morphology and tectal physiology in the weakly electric fish Gnathonemus petersii. AB - The retina of the weakly electric fish Gnathonemus petersii is a so-called grouped retina where photoreceptors are bundled. These bundles are regarded as functional units and this type of retinal specialization is uniquely found in teleosts. To understand how this anatomical organization influences visual information processing we investigated the morphology and distribution of retinal ganglion cells (GCs) and the response properties of retinal afferents terminating in the major retinorecipient area, the optic tectum. GCs were classified based on their dendritic morphology (dendritic field diameters <90-100 MUm: narrow-field GCs; 110-280 MUm: widefield GCs; >280 MUm: giant GCs). Within these classes subtypes were distinguished based on the ramification patterns of the dendrites in the sublaminae of the inner plexiform layer. Properties of presumed optic nerve terminals were investigated in the optic tectum using extracellular recordings. Physiological classes could be observed based on their response to visual stimuli (on; off; on-off, and fast units). Receptive field sizes and spatiotemporal properties were classified and the topographical representation of the visual space was mapped in the tectum. Gratings of low spatial frequencies were best responded to and followed up to high temporal frequencies (>30 Hz). Most of the recorded units were directionally selective. No evidence of distorted topographies in the tectum was found, i.e., no overrepresentation of the retina was seen in the tectum opticum. The grouped retina of G. petersii seems to be optimized for the detection of large, fast objects in an environment of low optical quality. PMID- 23817966 TI - [Metastasis of the ciliary body and iris from an oropharyngeal carcinoma]. AB - Uveal metastases are the most common intraocular malignancies. The choroid is the most common site for uveal involvement and metastases to the ciliary body and iris are much less common. We describe for the first time a patient with a metastatic tumor of the ciliary body and the iris originating from a squamous cell carcinoma of the oropharynx and demonstrate the clinical and histopathological characteristics. PMID- 23817972 TI - Human dental mesenchymal stem cells and neural regeneration. AB - Nerve tissue presents inherent difficulties for its effective regeneration. Stem cell transplantation is considered an auspicious treatment for neuronal injuries. Recently, human dental mesenchymal stem cells (DMSCs) have received extensive attention in the field of regenerative medicine due to their accessibility and multipotency. Since their origin is within the neural crest, they can be differentiated into neural crest-derived cells including neuron and glia cells both in vitro and in vivo. DMSCs are also able to secrete a wide variety of neurotrophins and chemokines, which promote neuronal cells to survival and differentiation. Experimental evidence has shown that human DMSCs engraftment recovered neuronal tissue damage in animal models of central nervous system injuries. Human DMSCs can be a new hope for treatment of nervous system diseases and deficits such as spinal cord injury, stroke and Parkinson's disease. PMID- 23817973 TI - Phase II clinical study of modified FOLFOX7 (intermittent oxaliplatin administration) plus bevacizumab in patients with unresectable metastatic colorectal cancer-CRAFT study. AB - PURPOSE: Continuous treatment with FOLFOX therapy is associated with peripheral nerve toxicity, and to improve this inconvenient side effect various methods of administration are being investigated. A regimen of intermittent oxaliplatin administration by continuous infusion therapy, i.e., modified FOLFOX7 (mFOLFOX7) + bevacizumab, was designed with the goal of alleviating severe peripheral nerve disorders and hematological toxicity. A phase II clinical study was conducted to evaluate the efficacy and safety of this regimen. METHODS: Previously untreated patients were assigned to mFOLFOX7 (oxaliplatin 85 mg/m(2), levofolinate [l-LV] 200 mg/m(2), 5-fluorouracil [5-FU] 2400 mg/m(2)) + bevacizumab (5 mg/kg) administered every 2 weeks for 8 cycles, maintenance without oxaliplatin for 8 cycles, and reintroduction of mFOLFOX7 + bevacizumab for 8 cycles or until disease progression. Progression free survival (PFS) following the first dose (PFS 1) and following reintroduction of oxaliplatin (PFS 2) were used as indices for assessing the efficacy of intermittent administration. RESULTS: Fifty-two patients were enrolled, with median age of 64 years (range, 36-74). Median PFS 1 was 11.8 months (95 % confidence interval [CI], 9.5 to 13.7), median time to treatment failure was 10.3 months (95 % CI, 5.6 to 12.1), percentage of patients with neutropenia of grade 3 or higher was 7.8 %, and percentage with peripheral nerve disorders was 3.9 %. Response rate was 50 %, and 84.4 % of patients who started modified simplified LV5FU2 + bevacizumab were reintroduced to oxaliplatin. CONCLUSION: By excluding 5-FU bolus administration and administering bevacizumab continuously the mFOLFOX7 + bevacizumab regimen with preplanned withdrawal of oxaliplatin showed high tolerability and prevented severe peripheral neuropathy and neutropenia without reducing efficacy. PMID- 23817974 TI - Phase 1 dose-escalation, pharmacokinetic, and cerebrospinal fluid distribution study of TAK-285, an investigational inhibitor of EGFR and HER2. AB - INTRODUCTION: This phase 1 study assessed safety, maximum tolerated dose (MTD), pharmacokinetics, cerebrospinal fluid (CSF) distribution, and preliminary clinical activity of the receptor tyrosine kinase inhibitor TAK-285. METHODS: Patients with advanced, histologically confirmed solid tumors and Eastern Cooperative Oncology Group performance status <=2 received daily oral TAK-285; daily dose was escalated within defined cohorts until MTD and recommended phase 2 dose (RP2D) were determined. Eleven patients were enrolled into an RP2D cohort. Blood samples were collected from all cohorts; CSF was collected at pharmacokinetic steady-state from RP2D patients. Tumor responses were assessed every 8 weeks per Response Evaluation Criteria in Solid Tumors. RESULTS: Fifty four patients were enrolled (median age 60; range, 35-76 years). The most common diagnoses were cancers of the colon (28 %), breast (17 %), and pancreas (9 %). Escalation cohorts evaluated doses from 50 mg daily to 500 mg twice daily; the MTD/RP2D was 400 mg twice daily. Dose-limiting toxicities included diarrhea, hypokalemia, and fatigue. Drug absorption was fast (median time of maximum concentration was 2-3 h), and mean half-life was 9 h. Steady-state average unbound CSF concentration (geometric mean 1.54 [range, 0.51-4.27] ng/mL; n = 5) at the RP2D was below the 50 % inhibitory concentration (9.3 ng/mL) for inhibition of tyrosine kinase activity in cells expressing recombinant HER2. Best response was stable disease (12 weeks of nonprogression) in 13 patients. CONCLUSIONS: TAK-285 was generally well tolerated at the RP2D. Distribution in human CSF was confirmed, but the free concentration of the drug was below that associated with biologically relevant target inhibition. PMID- 23817975 TI - Use of dithiothreitol to improve the diagnosis of prosthetic joint infections. AB - Diagnosis of prosthetic joint infections (PJIs) remains a challenge for microbiologists, despite new techniques for bacteria isolation have been developed in recent years. A widely recognized standard method has not yet been indicated mainly because of limitations due difficult procedures and need of dedicated instrumentation. We evaluated the ability of a sulfhydryl compound routinely used in microbiology laboratories, dithiothreitol (DTT), to dislodge bacteria from biofilm, keeping them alive and cultivable for identification and antibiotic susceptibility testing. We compared DTT treatment against sonication of prosthesis and culture of periprosthetic tissues, in order to establish if it could be introduced in routine microbiological diagnosis of PJIs. The study was conducted on 76 patients, 34 with aseptic loosening of their prosthesis and 42 who were diagnosed for PJI. DTT treatment gave results similar to sonication in terms of bacterial yielding. Sonication provided higher sensitivity (71.4%) and specificity (94.1%) respect to periprosthetic tissue culture, while DTT showed the same specificity of sonication but a better sensitivity (85.7%), especially when the causative microorganism was Staphylococcus epidermidis. In conclusion, we demonstrated that DTT could be used for PJIs diagnosis, thanks to its ease of use and its high sensitivity and specificity. PMID- 23817976 TI - Effects of repetitive trascranial magnetic stimulation on repetitive facilitation exercises of the hemiplegic hand in chronic stroke patients. AB - OBJECTIVE: To investigate whether multiple sessions of 1-Hz repetitive transcranial magnetic stimulation (rTMS) facilitates the effect of repetitive facilitation exercises on hemiplegic upper-limb function in chronic stroke patients. DESIGN: Randomized double-blinded crossover study. PATIENTS: Eighteen patients with hemiplegia of the upper limb. METHODS: Patients were assigned to 2 groups: a motor-before-sham rTMS group, which performed motor rTMS sessions for 2 weeks followed by sham rTMS sessions for 2 weeks; or a motor-following-sham rTMS group, which performed sham rTMS sessions for 2 weeks followed by motor rTMS sessions for 2 weeks. Patients received 1-Hz rTMS to the unaffected motor cortex for 4 min and performed repetitive facilitation exercises for 40 min during motor rTMS sessions. The Fugl-Meyer Assessment, Action Research Arm Test (ARAT) and Simple Test for Evaluating Hand Function were used to evaluate upper-limb function. The Modified Ashworth Scale and F-wave were measured to evaluate spasticity. RESULTS: Motor function improved significantly during the motor, but not sham, rTMS sessions. ARAT score gains were 1.5 (0-4.0) (median, interquartile range) during the motor rTMS session, and 0 (-0.8-1.8) during the sham rTMS session (p = 0.04). Spasticity did not significantly change during either session. CONCLUSION: Multiple sessions of 1-Hz rTMS facilitated the effects of repetitive facilitation exercises in improving motor function of the affected upper limb, but did not change spasticity. PMID- 23817977 TI - High electrical conductance enhancement in Au-nanoparticle decorated sparse single-wall carbon nanotube networks. AB - We report high electrical conductance enhancement in sparse single-walled carbon nanotube networks by decoration with Au nanoparticles. The optimized hybrid network exhibited a sheet resistance of 650 Omega sq(-1), 1/1500 of the resistance of the host undecorated network, with a negligible optical transmission penalty (>90% transmittance at 550 nm wavelength). The electrical transport at room temperature in the host and decorated networks was dominated by two-dimensional variable range hopping. The high conductance enhancement was due to positive charge transfer from the decorating Au nanoparticles in intimate contact with the host network causing a Fermi energy shift into the high density of states at a van Hove singularity and enhanced electron delocalization relative to the host network which beneficially modifies the hopping parameters in such a way that the network behaves as an integral whole. The effect is most pronounced when the nanoparticle diameter is comparable to the electron mean free path in the bulk material at room temperature and there is minimum nanoparticle agglomeration. For higher than optimal values of nanoparticle coverage or nanoparticle diameter, the conductance enhancement is countered by metallic inclusions in the current pathways that are of higher resistance than the variable range hopping-controlled elements. PMID- 23817978 TI - Tryptophan 46 is a site for ethanol and ivermectin action in P2X4 receptors. AB - ATP-gated purinergic P2X4 receptors (P2X4Rs) are the most alcohol-sensitive P2XR subtype. We recently reported that ivermectin (IVM), an antiparasitic used in animals and humans, antagonized ethanol inhibition of P2X4Rs. Furthermore, IVM reduced ethanol intake in mice. The first molecular model of the rat P2X4R, built onto the X-ray crystal structure of zebrafish P2X4R, revealed an action pocket for both ethanol and IVM formed by Asp331, Met336 in TM2 and Trp46, and Trp50 in TM1 segments. The role of Asp331 and Met336 was experimentally confirmed. The present study tested the hypothesis that Trp46 plays a role in ethanol and IVM modulation of P2X4Rs. Trp46 was mutated to residues with different physicochemical properties and the resultant mutants tested for ethanol and IVM responses using Xenopus oocyte expression system and two-electrode voltage clamp. Nonaromatic substitutions at position 46 reduced ethanol inhibition at higher concentrations and switched IVM potentiation to inhibition. Simultaneous substitution of alanine at positions Trp46 and Met336 also resulted in similar changes in ethanol and IVM responses. Furthermore, a new molecular model based on the open pore conformation of zebrafish P2X4R suggested a role for Tyr42 that was further supported experimentally. Our previous and current findings, combined with our preliminary evidence of increased ethanol consumption in P2X4R knockout mice, suggest that the ethanol and IVM action pocket in P2X4Rs formed by positions 42, 46, 331, and 336 presents a potential target for medication development for alcohol use disorders. PMID- 23817980 TI - Connexin 43 and hearing: possible implications for retrocochlear auditory processing. AB - OBJECTIVES/HYPOTHESIS: To examine the relationship between hearing and connexin 43, a dominant gap junctional protein in the central nervous system. STUDY DESIGN: Original research. METHODS: Connexin 43 heterozygous mice are used to assess its mutational effect on hearing. Results are compared to controls consisting of connexin 43, wild type and CBA/J mice. Hearing is assessed using auditory brainstem response and distortion product otoacoustic emissions tests. Distribution of connexin 43 in the organ of Corti and the retrocochlear auditory centers (eight nerve, cochlear nucleus, olivary complex, lateral lemniscus, inferior colliculus, respectively) is examined. Fluorescent markers are used to elucidate cell types. RESULTS: Mean click auditory brainstem response threshold for the young connexin 43 heterozygous mice (3-4 months) was 36.7 +/- 12.6 dB compared to 25 +/- 0 dB for control mice (P < 0.05). Mean threshold difference became more pronounced (68 +/- 7.5 dB vs. 31 +/- 2.2 dB) at 10 months (P < 0.05). Tonal auditory brainstem response testing showed elevated thresholds (>60 dB) at all frequencies (4-32 kHz) compared to the controls. Distortion product otoacoustic emissions (DPOAE) were present in all the mice, although the older connexin 43 heterozygous mice responded at higher thresholds. The pattern of connexin 43 immunoreactivity was distinctive from connexin 26 and 30, showing minimal presence in the organ of Corti but robustly present in the retrocochlear centers. CONCLUSION: Connexin 43 heterozygous mice demonstrated greater degree of hearing loss compared to age-matched controls. It is abundantly found in the retrocochlear auditory centers. The mechanism of hearing loss in these mice does not appear to be related to hair cell loss. PMID- 23817979 TI - Sputum autoantibodies in patients with established rheumatoid arthritis and subjects at risk of future clinically apparent disease. AB - OBJECTIVE: To evaluate the generation of rheumatoid arthritis (RA)-related autoantibodies in the lung. METHODS: Simultaneous collection of serum and induced sputum was performed in 21 healthy controls, 49 at-risk subjects without inflammatory arthritis but at risk of RA due to family history or seropositivity for anti-citrullinated protein antibodies, and 14 subjects with early RA. Samples were tested for anti-cyclic citrullinated peptide 2 (anti-CCP2), anti-CCP3, anti CCP3.1, rheumatoid factor isotypes IgM, IgG, and IgA, and total IgM, IgG, and IgA. RESULTS: One or more autoantibodies were present in sputum of 39% of at-risk seronegative subjects, 65% of at-risk seropositive subjects, and 86% of subjects with early RA. In at-risk seronegative subjects, the rate of anti-CCP3.1 positivity and the median number of autoantibodies were elevated in sputum versus serum. In subjects with early RA, the rate of positivity for several individual autoantibodies and the median number of autoantibodies were higher in serum than in sputum. Results in at-risk seropositive subjects were intermediate between these groups. In at-risk subjects with autoantibody positivity in sputum, the ratios of autoantibody to total Ig were higher in sputum than in serum, suggesting that these autoantibodies are generated or sequestered in the lung. CONCLUSION: RA-related autoantibodies are detectable in sputum in subjects at risk of RA and in subjects with early RA. In a subset of at-risk subjects, the presence of sputum autoantibodies in the absence of seropositivity, and the increased autoantibody-to-total Ig ratios in sputum, suggest that the lung may be a site of autoantibody generation in the early development of RA. These findings suggest an important role of the lung in the pathogenesis of RA. PMID- 23817981 TI - New bisphosphomide ligands, 1,3-phenylenebis((diphenylphosphino)methanone) and (2 bromo-1,3-phenylene)bis((diphenylphosphino)methanone): synthesis, coordination behavior, DFT calculations and catalytic studies. AB - The bisphosphomide, 1,3-{Ph2PC(O)}2C6H4 (1), was prepared by the reaction of isophthaloyl chloride with diphenylphosphine in the presence of triethylamine. The corresponding bromo-derivative, 2-Br-1,3-{Ph2PC(O)}2C6H3 (2), was obtained by the reaction of 2-bromoisophthaloyl chloride with diphenylphosphine. The reaction of 1 with elemental sulfur or selenium yielded the bis(chalcogenides), 1,3 {Ph2P(S)C(O)}2C6H4 (3) and {1,3-Ph2P(Se)C(O)}2C6H4 (4). The reaction between 1 and [Ru(eta(6)-p-cymene)Cl2]2 and [Pd(eta(3)-C3H5)Cl]2 in 1 : 1 stoichiometry yielded the corresponding binuclear complexes, [Ru2(eta(6)-p-cymene)2Cl4{1,3 {Ph2PC(O)}2(C6H4)}] (5) and [Pd2(eta(3)-C3H5)2Cl2{1,3-{Ph2PC(O)}2(C6H4)}] (6). The reaction of 1 with AgClO4 followed by the addition of [Pd(COD)Cl2] at room temperature resulted in the formation of a pincer complex [PdCl{2,6 {Ph2PC(O)}2(C6H3)}] (9), via transmetallation. Pincer complex formation through C H activation requires drastic conditions and yields are generally moderate. The oxidative addition reaction between 2 and [Ni(COD)2] gave a pincer complex [NiBr{2,6-{Ph2PC(O)}2(C6H3)}] (8), whereas the 2:1 reaction of 2 with [Pd2(dba)3] yielded the palladium analogue [PdBr{2,6-{Ph2PC(O)}2(C6H3)}] (9) in quantitative yield. The reaction between 1 and CuX in a 1:1 molar ratio produced binuclear complexes, [Cu2(MU-X)2{1,3-{Ph2PC(O)}2(C6H4)}2] (10, X = Cl; 11, X = Br; 12, X = I), whereas the reaction between 1 and [Cu(NCCH3)4]BF4 led to the isolation of a spirocyclic complex, [Cu(CH3CN)2{1,3-{Ph2PC(O)}2(C6H4)}]BF4 (13). The silver complexes [Ag2(MU-ClO4)2{1,3-{Ph2PC(O)}2(C6H4)}2] (14), [Ag2(MU-OTf)2{1,3 {Ph2PC(O)}2(C6H4)}2] (15) and [Ag2X2{1,3-{Ph2PC(O)}2(C6H4)}] (16, X = ClO4; 17, X = OTf) were obtained by treating 1 with AgClO4 or AgOTf in 1:1 or 1:2 molar ratios. The reactions of 1 with [AuCl(SMe2)] in 1 : 1 and 1 : 2 molar ratios afforded mono- and binuclear complexes, [AuCl{1,3-{Ph2PC(O)}2(C6H4)}2] (18) and [Au2Cl2{1,3-{Ph2PC(O)}2(C6H4)}AuCl] (19), in good yield. The structures of complexes 5, 7-10, 12 and 14a were confirmed by single-crystal X-ray diffraction studies. DFT calculations were performed in order to gain additional insights into the structure and bonding of the pincer complexes. An additional analysis of the orbital interactions in the case of palladium complex 9 is also included. The in situ generated rhodium complex of bisphosphomide 1 showed moderate to good selectivity in the hydroformylation of hex-1-ene and styrene derivatives. PMID- 23817983 TI - [Interpersonal psychotherapy for work-related stress depressive disorders]. AB - In general work involves health promoting functions but can also have hazardous impacts on well-being. Due to a massive change in working conditions it has become increasingly more recognized that depressive disorders are highly prevalent at the workplace and that work stress belongs to the most common triggers of depressive disorders, particularly in men. It is relevant to differentiate between subjectively experienced burnout and clinical depression. The best investigated psychosocial work stressors include increased job demands in connection with low control possibilities and lack of gratification, interpersonal conflicts, role stress and social isolation. For the treatment of work-related clinical depression, an additional focus of interpersonal psychotherapy (IPT) of depression, namely "work-related stress and burnout experience" was conceptualized based on a vulnerability-stress model and the fact that work usually takes place in an interpersonal context. This new problem area focuses on role stress and conflicts at work and the reduction of stressful working conditions. Interpersonal psychotherapy has so far been useful for the treatment of depression due to problems at work; however, further studies are needed to evaluate the efficacy of this newly designed problem area. PMID- 23817982 TI - Insulinoma-released exosomes activate autoreactive marginal zone-like B cells that expand endogenously in prediabetic NOD mice. AB - Exosomes (EXOs) are nano-sized secreted microvesicles that can function as potent endogenous carriers of adjuvant and antigens. To examine a possible role in autoimmunity for EXOs, we studied EXO-induced immune responses in nonobese diabetic (NOD) mice, an autoimmune-prone strain with tissue-specific targeting at insulin-secreting beta cells. EXOs released by insulinoma cells can activate various antigen-presenting cells to secrete several proinflammatory cytokines and chemokines. A subset of B cells responded to EXO stimulation in culture by proliferation, and expressed surface markers representing marginal zone B cells, which was independent of T helper cells. Importantly, splenic B cells from prediabetic NOD mice, but not diabetic-resistant mice, exhibited increased reactivity to EXOs, which was correlated with a high level of serum EXOs. We found that MyD88-mediated innate TLR signals were essential for the B-cell response; transgenic B cells expressing surface immunoglobulin specific for insulin reacted to EXO stimulation, and addition of a calcineurin inhibitor FK506 abrogated the EXO-induced B-cell response, suggesting that both innate and antigen-specific signals may be involved. Thus, EXOs may contribute to the development of autoimmunity and type 1 diabetes in NOD mice, partially via activating autoreactive marginal zone-like B cells. PMID- 23817984 TI - [Do neurologists need the head impulse test?]. PMID- 23817985 TI - The alterations of matrix metalloproteinase-9 in mouse brainstem during herpes simplex virus type 1-induced facial palsy. AB - The aim of this study is to explore the changes of matrix metalloproteinase-9 (MMP9) in the mouse brainstem during the development of facial paralysis induced by herpes simplex virus type 1 (HSV-1) and the inhibitory effect of methylprednisolone sodium succinate (MPSS) on MMP9 expression. HSV-1 was inoculated into the surface of posterior auricle of mouse to establish a paralyzed animal model. The paralyzed mice were divided randomly into three groups. In one group without any treatment, mice were killed at different time points of 6 h, 1, 2, 3, and 7 days post-induction of facial paralysis; in the other two groups, mice were injected daily with MPSS and a combination of MPSS and glucocorticoid receptor blocker (RU486) for 2 days, respectively. The expression of MMP9 in the facial nucleus of brainstem was detected by Western blot, quantitative real-time polymerase chain reaction, and immunofluorescence technique. A total of 52.07 % of mice developed unilateral facial paralysis after inoculated with HSV-1. Both mRNA and protein expression of MMP9 were present at low levels in normal facial nucleus of brainstem and were increased significantly after facial paralysis with its peak time at 2 days post-induction of facial paralysis. Expression of MMP9 of paralyzed mice was inhibited by MPSS, and the inhibition could be blocked by RU486. Our findings suggest that MMP9 in mouse brainstem is involved in the evolution of facial palsy induced by HSV-1 and may play an important role in the pathogenesis of this disease. MPSS might effectively relieve HSV-1-mediated damages by inhibitory effect on expression of MMP9 in HSV-1-induced facial paralysis. PMID- 23817986 TI - Upcoming challenges for neurologists in the United States. PMID- 23817988 TI - Glenohumeral relationships: subchondral mineralization patterns, thickness of cartilage, and radii of curvature. AB - Subchondral mineralization represents the loading history of a joint and can be measured in vivo using computed tomography osteoabsorptiometry. Different mineralization patterns in the glenohumeral joint have been explained by the principle of physiologic incongruence. We sought to support this explanation by measurement of mineralization, radii, and cartilage thickness in 18 fresh shoulder specimens. We found three mineralization patterns: bicentric, monocentric anterior, and monocentric central. Mean radii of the glenoids were 27.4 mm for bicentric glenoids, 27.3 mm for monocentric anterior, and 24.8 mm for monocentric central glenoids. Cartilage thickness measurement revealed the highest values in anterior parts; the thinnest cartilage was found centrally. Our findings support the principle of a physiologic incongruence in the glenohumeral joint. Bicentric mineralization patterns exist in joints consisting of more flat glenoids compared to the corresponding humeral head. Monocentric distribution with a central maximum was found in specimens with glenoids being more curved, indicating higher degrees of congruence, which might represent an early stage of degenerative disease. The obtained information might also be important for implant fixation in resurfacing procedures or to achieve the best possible fit of an osteochondral allograft in the repair of cartilage defects. PMID- 23817987 TI - Cloning and molecular characterization of cationic amino acid transporter y+LAT1 in grass carp (Ctenopharyngodon idellus). AB - The solute carrier family 7A, member 7 gene encodes the light chain- y+L amino acid transporter-1 (y+LAT1) of the heterodimeric carrier responsible for cationic amino acid (CAA) transport across the basolateral membranes of epithelial cells in intestine and kidney. Rising attention has been given to y+LAT1 involved in CAA metabolic pathways and growth control. The molecular characterization and function analysis of y+LAT1 in grass carp (Ctenopharyngodon idellus) is currently unknown. In the present study, full-length cDNA (2,688 bp), which encodes y+LAT1 and contains a 5'-untranslated region (319 bp), an open reading frame (1,506 bp) and a 3'-untranslated region (863 bp), has been cloned from grass carp. Amino acid sequence of grass carp y+LAT1 contains 11 transmembrane domains and shows 95 %, 80 % and 75 % sequence similarity to zebra fish, amphibian and mammalian y+LAT1, respectively. The tissue distribution and expression regulation by fasting of y+LAT1 mRNA were analyzed using real-time PCR. Our results showed that y+LAT1 mRNA was highly expressed in midgut, foregut and spleen while weakly expressed in hindgut, kidney, gill, brain, heart, liver and muscle. Nutritional status significantly influenced y+LAT1 mRNA expression in fish tissues, such as down-regulation of y+LAT1 mRNA expression after fasting (14 days). PMID- 23817989 TI - Changes in cognitive function associated with syndrome changes on two five-factor models of the Positive and Negative Syndrome Scale. AB - OBJECTIVE: This study aims to examine the association between neuropsychological function and symptom changes over time on two five-factor models, pentagonal (PM) and Van der Gaag (VDG), of the Positive and Negative Syndrome Scale (PANSS) and to determine the added value of these syndrome models for interpreting neuropsychological changes. METHODS: Data were collected in a randomized controlled trial comparing second-generation and conventional antipsychotic medications for 108 adult patients diagnosed with schizophrenia and monitored prospectively for 12 months using standard neuropsychological instruments and the PANSS. Random-effects regression was used to estimate the change over time in neuropsychological function and the association of PANSS covariates. RESULTS: Improvements in positive, negative, and cognitive syndromes were significant predictors of change on nine neuropsychological measures. The neuropsychological function was worsening on five of these measures. The PM model represented the best set of predictors examining positive and negative syndrome covariates, whereas the VDG model consistently represented the best predictors examining cognitive syndrome covariates. CONCLUSIONS: The PM positive and negative syndrome factors and the VDG disorganized thoughts syndrome factor are differentially associated with changes in neuropsychological function over time. Clinical investigators may want to target their use of these factors from the PANSS according to the outcome variables being measured. PMID- 23817990 TI - Sphingosine kinase-1 mediates endotoxemia-induced hyperinflammation in aged animals. AB - Sepsis is a serious issue in the geriatric population due to its association with high mortality rates in the elderly. The increase in mortality in the elderly correlates with inflammation. We have previously demonstrated that the inflammatory response is exacerbated in a rodent endotoxemia model of sepsis in aged rats compared with young rats. However, the molecular mediators associated with this hyperinflammatory response in aged rats have not been completely determined. Sphingosine kinase-1 (Sphk-1), an enzyme present in neutrophils and macrophages, regulates proinflammatory responses associated with endotoxemia and sepsis. To determine whether Sphk-1 is a molecular mediator associated with the observed hyperinflammatory response in aging, Sphk-1 mRNA expression was examined in hepatic tissues of young and aged rats subjected to endotoxemia. A significant increase in Sphk-1 mRNA was observed in endotoxemic aged rats compared with young rats. This increase was correlated with a significant increase in TNF-alpha mRNA levels in the liver. CD14 is a receptor component for lipopolysaccharide (LPS) and therefore, CD14 mRNA expression in hepatic tissues of endotoxemic young and aged rats was examined. Of note, CD14 mRNA was significantly upregulated in endotoxemic aged rats. Sphk-1 mRNA expression was significantly elevated in LPS treated Kupffer cells and this increase correlated with an increase in CD14 mRNA expression. Results of the present study indicated that increased Sphk-1 expression in the liver in response to endotoxemia mediates the hyperinflammatory state observed in aged animals. PMID- 23817992 TI - Diffusion tensor imaging of the superior cerebellar peduncle identifies patients with posterior fossa syndrome. AB - INTRODUCTION: Posterior fossa tumors are the most common brain tumor of children. Aggressive resection correlates with long-term survival. A high incidence of posterior fossa syndrome (PFS), impairing the quality of life in many survivors, has been attributed to damage to bilateral dentate nucleus or to cerebellar output pathways. Using diffusion tensor imaging (DTI), we examined the involvement of the dentothalamic tracts, specifically the superior cerebellar peduncle (SCP), in patients with posterior fossa tumors and the association with PFS. METHODS: DTI studies were performed postoperatively in patients with midline (n = 12), lateral cerebellar tumors (n = 4), and controls. The location and visibility of the SCP were determined. The postoperative course was recorded, especially with regard to PFS, cranial nerve deficits, and oculomotor function. RESULTS: The SCP travels immediately adjacent to the lateral wall of the fourth ventricle and just medial to the middle cerebellar peduncle. Patients with midline tumors that still had observable SCP did not develop posterior fossa syndrome (N = 7). SCPs were absent, on either preoperative (N = 1, no postoperative study available) or postoperative studies (N = 4), in the five patients who developed PFS. Oculomotor deficits of tracking were observed in patients independent of PFS or SCP involvement. CONCLUSION: PFS can occur with bilateral injury to the outflow from dentate nuclei. In children with PFS, this may occur due to bilateral injury to the superior cerebellar peduncle. These tracts sit immediately adjacent to the wall of the ventricle and are highly vulnerable when an aggressive resection for these tumors is performed. PMID- 23817993 TI - A bony human tail causing tethered cord syndrome: case report. AB - INTRODUCTION: Dorsal cutaneous appendages, sometimes referred to as "human tails," are considered to be markers of underlying occult spinal dysraphism. Rarely, these tail-like structures can themselves be the cause of tethered cord syndrome. However, to date, a "bony human tail" causing tethered cord has not been reported in the literature. One such rare lesion is being reported. DISCUSSION: A 2-days-old female child was brought for neurosurgical consultation with a skin-covered bony protuberance in the lower back. Examination of the child did not reveal any neurological deficits. Plain radiographic and CT evaluation showed a dorsal bony protuberance arising from the posterior elements of L1 vertebra. MRI showed the cord to be displaced posteriorly and adherent to the undersurface of the bony tail through a lipoma. During surgery, the bony "tail" was excised, and the cord was untethered with excision of the lipoma, which was tethering the cord to the bony "tail." When examined 1 year later, the child was developing normally without any focal neurological deficits. CONCLUSIONS: This case is being reported for its rarity and to highlight the hitherto unreported occurrence of "bony human tail" causing tethered cord syndrome. PMID- 23817991 TI - IB4-binding sensory neurons in the adult rat express a novel 3' UTR-extended isoform of CaMK4 that is associated with its localization to axons. AB - Calcium/calmodulin-dependent protein kinase 4 (gene and transcript: CaMK4; protein: CaMKIV) is the nuclear effector of the Ca(2+) /calmodulin kinase (CaMK) pathway where it coordinates transcriptional responses. However, CaMKIV is present in the cytoplasm and axons of subpopulations of neurons, including some sensory neurons of the dorsal root ganglia (DRG), suggesting an extranuclear role for this protein. We observed that CaMKIV was expressed strongly in the cytoplasm and axons of a subpopulation of small-diameter DRG neurons, most likely cutaneous nociceptors by virtue of their binding the isolectin IB4. In IB4+ spinal nerve axons, 20% of CaMKIV was colocalized with the endocytic marker Rab7 in axons that highly expressed CAM-kinase-kinase (CAMKK), an upstream activator of CaMKIV, suggesting a role for CaMKIV in signaling though signaling endosomes. Using fluorescent in situ hybridization (FISH) with riboprobes, we also observed that small-diameter neurons expressed high levels of a novel 3' untranslated region (UTR) variant of CaMK4 mRNA. Using rapid amplification of cDNA ends (RACE), reverse-transcription polymerase chain reaction (RT-PCR) with gene-specific primers, and cDNA sequencing analyses we determined that the novel transcript contains an additional 10 kb beyond the annotated gene terminus to a highly conserved alternate polyadenylation site. Quantitative PCR (qPCR) analyses of fluorescent-activated cell sorted (FACS) DRG neurons confirmed that this 3'-UTR extended variant was preferentially expressed in IB4-binding neurons. Computational analyses of the 3'-UTR sequence predict that UTR-extension introduces consensus sites for RNA-binding proteins (RBPs) including the embryonic lethal abnormal vision (ELAV)/Hu family proteins. We consider the possible implications of axonal CaMKIV in the context of the unique properties of IB4-binding DRG neurons. PMID- 23817994 TI - Rosette-forming glioneuronal tumor of the fourth ventricle with neurocytoma component. AB - Rosette-forming glioneuronal tumor (RGNT) was first published in 2002 and was described as a benign and indolent tumor. It was also included in the 2007 World Health Organization (WHO) classification of tumors as a grade 1 tumor for its benign clinical behavior and the possibility of surgical cure. Pathologically, RGNT is a mixed neuronal-glial tumor which consists of two distinct histological components-one with uniform neurocytes forming rosettes and/or perivascular pseudorosettes and the other being astrocytic in nature resembling pilocytic astrocytoma (biphasic pattern). We present the clinical course and pathological findings of two distinctively different cases. The first one was a 4-year-old girl with head trauma and a tumor which was incidentally found by CT. Pathology revealed that the tumor contained neurocytoma components and areas of relatively high proliferative ability with the first report of the presence of midsized bright elliptic cells. The other case was a 19-year-old girl whose imaging studies showed hydrocephalus and a brain stem tumor. She underwent endoscopic third ventriculostomy and biopsy, followed by observation. An MRI taken 6 months later showed progression of the tumor and she subsequently had the tumor excised. We are considering the possibility for our RGNT cases to correspond to a higher WHO grade as they have shown rapid progression, contrary to the already established, and their character, origin, differential diagnosis, and treatment plans have been discussed. PMID- 23817995 TI - Intracranial pial arteriovenous fistula in infancy: a case report and literature review. AB - Intracranial pial arteriovenous fistulas (AVF) are rare vascular malformation especially in the first 2 years of life. The pathology in this age group is associated with greater morbidity and mortality. We report a rare case of 36-day old male infant with a pial AVF associated with an arterial aneurysm, who presented with intraventricular hemorrhage and hydrocephalus. In addition, an online review of the literatures on pediatric pial AVF was performed using PubMed on published case reports and articles from 1980 to April 2013. PMID- 23817996 TI - Topical herbal formulae in the management of psoriasis: systematic review with meta-analysis of clinical studies and investigation of the pharmacological actions of the main herbs. AB - This systematic review and meta-analysis of randomized controlled trials (RCTs) examined the topical use of multi-herbal formulations for the management of psoriasis vulgaris. Studies were identified from PubMed, Cochrane library, EMBASE, and the Chinese databases CNKI and CQVIP. Methods were according to the Cochrane Handbook and meta-analyses used RevMan 5.1. Nine studies met the inclusion/exclusion criteria. The comparisons were with placebo and/or anti psoriatic pharmacotherapy (APP) with two studies having three arms. The pooled meta-analysis data indicated the topical herbal formulae improved overall clinical efficacy (defined as 50% improvement or greater) when compared with: topical placebo (plus oral herbal co-intervention); topical APP alone; and topical APP (plus pharmaceutical co-intervention). Improvement was evident in Modified Psoriasis Area and Severity Index (PASI) score when topical herbal formula was compared to placebo (plus oral herbal co-intervention). No serious adverse events were reported. The most commonly used herbs were Sophora flavescens root and Lithospermum erythrorhizon root. Experimental studies reported that these herbs and/or their constituents have anti-inflammatory, anti proliferative, anti-angiogenic, and tissue repair actions. These actions may at least partially explain the apparent benefits of the topical multi-herbal formulations in psoriasis. PMID- 23817997 TI - Recent trend of pylephlebitis in Taiwan: Klebsiella pneumoniae liver abscess as an emerging etiology. AB - BACKGROUND AND AIMS: Pylephlebitis (septic thrombophlebitis of the portal venous system) is a rare complication of intra-abdominal infection. We aimed to investigate the recent trend of its etiology, clinical manifestation, and prognosis. METHODS: We retrospectively studied the etiology, clinical manifestation, and outcome by reviewing the medical records of all imaging confirmed pylephlebitis cases diagnosed during the period 2002-2011 in a university hospital in Taiwan. To identify the risk factors for pylephlebitis, we randomly selected 160 patients with intra-abdominal infections but without pylephlebitis as the comparison group. RESULTS: We identified 35 cases of pylephlebitis. Most patients were men [29/35 (83 %)]. The median age of the patients was 57 years (range 35-90 years). Unspecified abdominal pain (18/35) and fever (10/35) were the most common clinical manifestations. Klebsiella pneumoniae liver abscess (7/35) and cholangitis (7/35) were the most common etiologies. Liver abscess was a risk factor for pylephlebitis (13/35 vs. 27/160, P = 0.01). With antibiotic therapy, there was no in-hospital mortality, but pylephlebitis was still associated with an excess hospital stay (22.2 +/- 17.6 vs. 9.8 +/- 7.1 days, P < 0.001). CONCLUSIONS: Our study results suggested a different pattern of pylephlebitis from previous Western literature. K. pneumoniae liver abscess (7/35) is an emerging etiology of pylephlebitis in Taiwan. PMID- 23817998 TI - The range and intensity of backscattered electrons for use in the creation of high fidelity electron beam lithography patterns. AB - We present a set of universal curves that predict the range and intensity of backscattered electrons which can be used in conjunction with electron beam lithography to create high fidelity nanoscale patterns. The experimental method combines direct write dose, backscattered dose, and a self-reinforcing pattern geometry to measure the dose provided by backscattered electrons to a nanoscale volume on the substrate surface at various distances from the electron source. Electron beam lithography is used to precisely control the number and position of incident electrons on the surface of the material. Atomic force microscopy is used to measure the height of the negative electron beam lithography resist. Our data shows that the range and the intensity of backscattered electrons can be predicted using the density and the atomic number of any solid material, respectively. The data agrees with two independent Monte Carlo simulations without any fitting parameters. These measurements are the most accurate electron range measurements to date. PMID- 23817999 TI - Germinal center kinase-like kinase overexpression in T cells as a novel biomarker in rheumatoid arthritis. AB - OBJECTIVE: Germinal center kinase-like kinase (GLK; also called MAPKKKK-3) activates protein kinase Ctheta (PKCtheta) during T cell activation and controls autoimmunity in lupus patients. Intracellular kinases are involved in the pathogenesis of rheumatoid arthritis (RA). We undertook this study to determine the role of GLK in RA. METHODS: The severity of collagen-induced arthritis (CIA) was studied in GLK-deficient mice. Expression levels of GLK from RA patients were determined by Western blotting, flow cytometry, real-time polymerase chain reaction, and immunohistochemical staining. Localization of GLK in T cells was identified by confocal microscopy. RA disease activity was assessed using the Disease Activity Score in 28 joints. RESULTS: GLK-deficient mice displayed impaired CIA development and decreased inflammatory cytokine levels. Local T cell infiltration and collagen restimulation responses were impaired by GLK deficiency. RA patients showed significantly higher GLK protein and messenger RNA levels in peripheral blood T cells than did healthy controls. GLK-overexpressing T cells in synovial fluid and synovial tissue samples from RA patients were increased compared with those from osteoarthritis patients. Confocal microscopy and flow cytometry showed that GLK colocalized and coexisted with phosphorylated PKCtheta in T cells from RA patients. Frequencies of GLK-expressing T cells were significantly correlated with RA disease activity. CONCLUSION: GLK overexpression in T cells contributes to the pathogenesis of RA, indicating that GLK is a novel biomarker for autoimmune disease severity and a potential therapeutic target for RA. PMID- 23818000 TI - The effect of over-commitment and reward on trapezius muscle activity and shoulder, head, neck, and torso postures during computer use in the field. AB - BACKGROUND: Because of reported associations of psychosocial factors and computer related musculoskeletal symptoms, we investigated the effects of a workplace psychosocial factor, reward, in the presence of over-commitment, on trapezius muscle activity and shoulder, head, neck, and torso postures during computer use. METHODS: We measured 120 office workers across four groups (lowest/highest reward/over-commitment), performing their own computer work at their own workstations over a 2-hr period. RESULTS: Median trapezius muscle activity (P = 0.04) and median neck flexion (P = 0.03) were largest for participants reporting simultaneously low reward and high over-commitment. No differences were observed for other muscle activities or postures. CONCLUSIONS: These data suggest that the interaction of reward and over-commitment can affect upper extremity muscle activity and postures during computer use in the real work environment. This finding aligns with the hypothesized biomechanical pathway connecting workplace psychosocial factors and musculoskeletal symptoms of the neck and shoulder. PMID- 23818001 TI - Structured outpatient peritoneal dialysis catheter insertion is safe and cost saving. AB - BACKGROUND: Data about outcomes and costs for peritoneal catheter insertion on an outpatient basis are scarce. METHODS: Using patient files, all peritoneal dialysis (PD) catheter insertions performed between 2004 and 2009 in a single center tertiary care institution for adult patients were located. Patient demographics, complications, hospitalizations, survival, and treatment modality changes were recorded. Procedure-related expenses were valued as actual production costs. RESULTS: During the study period, 106 PD catheters were inserted. In 46 cases, the patients were admitted electively for catheter insertion; 19 catheters were placed during admission for other medical reasons; and 41 catheters were placed on an outpatient basis. Among the study patients (54.7 +/- 16.0 years of age), 45% were diabetic. Early (<30 days) catheter related complications occurred in 22% of patients. The incidences of technique failure and any complication within 90 days were 10% and 38% respectively. The occurrence of complications was not statistically significantly different for outpatients and electively admitted patients. Average costs for catheter insertion were higher in electively hospitalized patients than in outpatients (?2320 +/- ?960 vs ?1346 +/- ?208, p < 0.000). CONCLUSIONS: Compared with an inpatient procedure, outpatient insertion of a PD catheter results in similar outcomes at a lower cost. PMID- 23818002 TI - Patient education and care for peritoneal dialysis catheter placement: a quality improvement study. AB - BACKGROUND AND OBJECTIVES: Peritoneal dialysis catheter (PDC) complications are an important barrier to peritoneal dialysis (PD) utilization. Practice guidelines for PDC placement exist, but it is unknown if these recommendations are followed. We performed a quality improvement study to investigate this issue. ? METHODS: A prospective observational study involving 46 new patients at a regional US PD center was performed in collaboration with a nephrology fellowship program. Patients completed a questionnaire derived from the International Society for Peritoneal Dialysis (ISPD) catheter guidelines and were followed for early complications. ? RESULTS: Approximately 30% of patients reported not being evaluated for hernias, not being asked to visualize their exit site, or not receiving catheter location marking before placement. After insertion, 20% of patients reported not being given instructions for follow-up care, and 46% reported not being taught the warning signs of PDC infection. Directions to manage constipation (57%), immobilize the PDC (68%), or leave the dressing undisturbed (61%) after insertion were not consistently reported. Nearly 40% of patients reported that their PDC education was inadequate. In 41% of patients, a complication developed, with 30% of patients experiencing a catheter or exit-site problem, 11% developing infection, 13% needing PDC revision, and 11% requiring unplanned transfer to hemodialysis because of catheter-related problems. ? CONCLUSIONS: There were numerous deviations from the ISPD guidelines for PDC placement in the community. Patient satisfaction with education was suboptimal, and complications were frequent. Improving patient education and care coordination for PDC placement were identified as specific quality improvement needs. PMID- 23818003 TI - Non-candidal fungal peritonitis in Far North Queensland: a case series. AB - BACKGROUND: Fungal peritonitis is a recognized complication in patients with end stage renal failure treated with peritoneal dialysis (PD). Most infections are attributable to Candida species. In approximately one third of cases, the causative fungus is a non-Candida species. Recent reports in the literature show a rising incidence of non-candidal fungal peritonitis (NCFP). We report a case series of NCFP, together with two hitherto unreported species of fungi causing peritonitis, from a tropical geographic area (Far North Queensland). METHODS: This series of 10 cases of NCFP was identified from the PD peritonitis database in Far North Queensland between 1998 and 2010. All 10 patients were from the Aboriginal and Torres Strait Islander ethnic group, 8 of whom lived in remote locations. All but 1 patient had type 2 diabetes mellitus. Of the 10 cases, 7 occurred while the patients received continuous ambulatory PD. Only 1 patient avoided catheter removal, and 5 patients were permanently transferred to hemodialysis. No patient died as a result of the fungal infection. All 10 fungi represented different species. Most (6 of 10) were saprophytic; only 2 were normal skin flora. Two of the causative species (Chaetomium and Beauveria) have rarely been associated with any form of human infection. In 7 patients, the infection occurred during the wet season (November - April). All cases met clinical criteria for peritonitis. DISCUSSION AND CONCLUSIONS: The NCFP cases described in this series involved a variety of previously known fungal species and also two new species that have not been reported to cause disease in humans. Indigenous patients from Far North Queensland are particularly predisposed to infection with these exotic fungi as a result of environmental and social factors. Further understanding is desirable to help devise preventive strategies to avoid the consequences of catheter failure. PMID- 23818004 TI - Nutrition changes in conservatively treated patients with encapsulating peritoneal sclerosis. AB - BACKGROUND: Encapsulating peritoneal sclerosis (EPS), a rare but serious complication of long-term PD, is characterized by nausea, abdominal pain, weight loss, anorexia, and constipation. It can cause a significant deterioration in a patient's nutrition status. In the present study we examined changes in nutrition status and outcomes for patients with EPS treated conservatively without the use of surgical intervention. METHODS: Patients diagnosed with EPS at our institution between December 2006 and December 2010 were identified, and data on demographics, nutrition, and symptoms were collected every 2 months for 12 months and then at 18 and 24 months. RESULTS: Of the 15 patients identified, 12 were malnourished or at risk of malnutrition according to their subjective global assessment score, with 11 of the 15 presenting with more than 10% weight loss in the 6 months before diagnosis. Furthermore, symptom burden was high, with 11 of 15 patients reporting 2 or more gastrointestinal symptoms. Of the 15 patients, 12 required parenteral nutrition for a median of 4.5 months, and 5 died within the first 12 months after diagnosis. In the 10 survivors, albumin and C-reactive protein significantly improved over the 24 months after diagnosis. Improving trends in weight and symptoms were also observed in those patients. CONCLUSIONS: In some patients with EPS, a conservative approach without surgical intervention, and with regular dietetic input and aggressive nutrition support, can lead to improved nutrition status and symptoms. PMID- 23818005 TI - Correlation between glycemic control and the incidence of peritoneal and catheter tunnel and exit-site infections in diabetic patients undergoing peritoneal dialysis. AB - BACKGROUND: Diabetes mellitus, especially if complicated by poor glycemic control, portends an increased risk of infection. The significance of this association in the case of diabetic patients undergoing peritoneal dialysis (PD) has not been assessed. METHODS: Using a retrospective observational design, we analyzed the association between glycemic control at the start of PD (estimated from glycosylated hemoglobin levels) and the risk of peritoneal and catheter tunnel and exit-site infections during follow-up in 183 incident patients on PD. We used the median value of glycosylated hemoglobin to classify patients into good (group A) or poor (group B) glycemic control groups. We applied multivariate strategies of analysis to control for other potential predictors of PD-related infection. RESULTS: Groups A and B differed significantly in age, dialysis vintage, use of insulin, and rate of Staphylococcus aureus carriage. Neither the incidence (0.60 episodes in group A vs 0.56 episodes in group B per patient-year) nor the time to a first peritoneal infection (median: 42 months vs 38 months) differed significantly between the study groups. In contrast, group B had a significantly higher incidence of catheter tunnel and exit-site infections (0.23 episodes vs 0.12 episodes per patient-year) and shorter time to a first infection episode (64 months vs 76 months, p = 0.004). The difference persisted in multivariate analysis (adjusted hazard ratio: 2.65; 95% confidence interval: 1.13 to 6.05; p = 0.013). We observed no differences between the study groups in the spectrum of causative organisms or in the outcomes of PD-related infections. CONCLUSIONS: Poor glycemic control is a consistent predictor of subsequent risk of catheter tunnel and exit-site infection, but not of peritoneal infection, among diabetic patients starting PD therapy. PMID- 23818006 TI - 68Ga-triacetylfusarinine C and 68Ga-ferrioxamine E for Aspergillus infection imaging: uptake specificity in various microorganisms. AB - PURPOSE: (68)Ga-triacetylfusarinine C ((68)Ga-TAFC) and (68)Ga-ferrioxamine E ((68)Ga-FOXE) showed excellent targeting properties in Aspergillus fumigatus rat infection model. Here, we report on the comparison of specificity towards different microorganisms and human lung cancer cells (H1299). PROCEDURES: The in vitro uptake of (68)Ga-TAFC and (68)Ga-FOXE was studied in various fungal, bacterial and yeast cultures as well as in H1299 cells. The in vivo imaging was studied in fungal and bacterial rat infection and inflammation models. RESULTS: (68)Ga-TAFC and (68)Ga-FOXE showed rapid uptake in A. fumigatus cultures, significantly lower in other fungal species and almost no uptake in other microorganisms and H1299 cells, except for (68)Ga-FOXE in Staphylococcus aureus. (68)Ga-TAFC and (68)Ga-FOXE revealed rapid uptake in the lungs of A. fumigatus infected rats, low accumulation in sterile inflammation and no uptake in bacterial abscess. CONCLUSIONS: We have shown that (68)Ga-FOXE and (68)Ga-TAFC have high uptake in A. fumigatus both in vitro and in vivo. (68)Ga-TAFC showed higher specificity, while (68)Ga-FOXE showed higher sensitivity. PMID- 23818007 TI - Prognostic implication of extrarenal metabolic tumor burden in advanced renal cell carcinoma treated with targeted therapy after nephrectomy. AB - OBJECTIVE: In the era of targeted therapy for advanced renal cell carcinoma (RCC), appropriate prognosis prediction is necessary for optimal therapy with or without cytoreductive surgery. We evaluated prognostic implication of extrarenal metabolic tumor burden in nephrectomized patients with advanced RCC. METHODS: Forty-four patients with advanced RCC who underwent (18)F-fluorodeoxyglucose PET/CT were retrospectively enrolled. The patients were treated with nephrectomy and targeted therapy. On PET/CT image of each patient, maximal standardized uptake value (SUVmax) of lesions were measured, and metabolic tumor burden was measured as total lesion glycolysis (TLG) by multiplying tumor volume and mean SUV. An overall TLG was calculated as the sum of those of all lesions. The prognostic value of PET parameters (SUVmax and TLG), and established major clinical factors (serum hemoglobin and corrected calcium, and number of metastatic sites) were tested with regard to overall survival. RESULTS: Among 44 patients, 8 died during mean follow-up time of 21.9 +/- 17.7 months. On FDG PET/CT, a total of 250 lesions were analyzed. In univariate analyses, SUVmax, TLG, number of metastatic sites, serum hemoglobin and corrected calcium were significant prognostic factors. Among them, TLG remained as an independent prognostic factor in a multivariate analysis (P = 0.038). In subgroup analyses, TLG was still a significant prognostic factor in patients treated with sunitinib only and in patients on the first staging as well as restaging. CONCLUSIONS: Extrarenal metabolic tumor burden is a significant prognostic factor in advanced RCC patients treated with targeted therapy. In selection of candidates for cytoreductive surgery, the measurement of metabolic tumor burden may be effective. PMID- 23818008 TI - Positron emission mammography (PEM): reviewing standardized semiquantitative method. AB - PURPOSE: To validate semiquantitative analysis of positron emission mammography (PEM). METHODS: Fifty women with histologically confirmed breast lesions were retrospectively enrolled. Semiquantitative uptake values (4 methods), the maximum PEM uptake value (PUVmax), and the lesion-to-background (LTB) value (3 methods) were measured. LTB is a ratio of the lesion's PUVmax to the mean background; LTB1, LTB2, and LTB3 (which were calculated on different background) were used to designate the three values measured. Interobserver reliability between two readers for PUVmax and the LTBs was tested using the interobserver correlation coefficient (ICC). The likelihood ratio test was used to evaluate the relationship between ICCs. Receiver operating characteristic (ROC) curves were calculated for all methods. Diagnostic accuracy in differentiating benign tissue from malignant tissue was compared between PUVmax and LTB1. RESULTS: The ICC rate was 0.971 [95 % confidence interval (CI) 0.943-0.986] for PUVmax, 0.873 (95 % CI 0.758-0.935) for LTB1, 0.965 (95 % CI 0.925-0.983) for LTB2, and 0.895 (95 % CI 0.799-0.946) for LTB3. However, there were some technical difficulties in the practical use of LTB2 and LTB3. The likelihood ratio test between PUVmax and LTB1 was statistically significant (p < 0.001). ROC curves of the 4 methods had similar characteristics. The median PUVmax was 1.39 for benign lesions and 3.70 for malignant lesions. LTB1 was 1.92 for benign lesions and 4.78 for malignant lesions. Significant differences (p < 0.001) in both PUVmax and LTB1 were observed between groups. CONCLUSION: Due to its simplicity and reproducibility, PUVmax is superior to LTB as an indicator for PEM in semiquantitative analysis. PMID- 23818009 TI - Immunolocalization of estrogen and progesterone receptors in ewe mammary glands. AB - Immunopresence of estrogen receptor alpha (ERalpha), beta (ERbeta) and progesterone receptor (PR) were examined in the ewe mammary gland from prepubertal stage to involution. Immunolocalization of ERalpha revealed a strong positive staining in nuclei of cells composing terminal ductular units (TDUs) in prepubertal ewes. A mild immunoreactivity was identified in early lactating gland. During late lactation immunoreactive product to ERalpha was observed in the cytoplasm of glandular epithelial cells in all alveoli. In mammary glands at involution ERalpha positivity was clearly nuclear, with weak to moderate cytoplasmic staining. Cytoplasmic strong immunostaining for ERbeta was detected in cells of TDUs, whereas some stromal cells exhibited nuclear staining. A nuclear ERbeta immunostaining was observed at early lactation, instead during late lactation, the positivity for ERbeta showed only a moderate cytoplasmic distribution. At involution, ERbeta positivity was very moderate and detected just in the cytoplasm of shrunken alveoli. Scattered nuclear staining of PR was observed just in mammary glands at early lactation. These results showed that in the mammary glands of sheep both estrogen receptor isoforms were displayed during lactation cycle and that PR appeared just at early lactation, reflecting their regulatory role in alveolar cells. PMID- 23818010 TI - Respiratory infections in early life and the development of islet autoimmunity in children at increased type 1 diabetes risk: evidence from the BABYDIET study. AB - IMPORTANCE: There is evidence for a role of infections within the pathogenesis of islet autoimmunity and type 1 diabetes mellitus (T1D), but previous studies did not allow assessment of potential critical time windows in this context. OBJECTIVE: To examine whether early, short-term, or cumulative exposures to episodes of infection and fever during the first 3 years of life were associated with the initiation of persistent islet autoimmunity in children at increased T1D risk. DESIGN: Prospective cohort study with daily infection records and regular assessment of islet autoimmunity. SETTING: Diabetes Research Institute, Munich, Germany. PARTICIPANTS: A total of 148 children at high T1D risk with documentation of 1245 infectious events in 90,750 person-days during their first 3 years of life. MAIN OUTCOMES AND MEASURES: Hazard ratios (HRs) for seroconversion to persistent islet autoantibodies were assessed in Cox regression models with numbers of respiratory, gastrointestinal, and other infections, adjusting for sex, delivery mode, intervention group, season of birth, and antibiotic use. RESULTS: An increased HR of islet autoantibody seroconversion was associated with respiratory infections during the first 6 months of life (HR = 2.27; 95% CI, 1.32-3.91) and ages 6.0 to 11.9 months (HR = 1.32; 95% CI, 1.08 1.61). During the second year of life, no meaningful effects were detected for any infectious category. A higher number of respiratory infections in the 6 months prior to islet autoantibody seroconversion was also associated with an increased HR (HR = 1.42; 95% CI, 1.12-1.80). CONCLUSIONS AND RELEVANCE: Respiratory infections in early childhood are a potential risk factor for the development of T1D. PMID- 23818011 TI - IFN-gamma production by CD27+ NK cells exacerbates Listeria monocytogenes infection in mice by inhibiting granulocyte mobilization. AB - Natural killer (NK) cells are key components of the immune system involved in several immune reactions, including the clearance of intracellular pathogens. When activated, NK cells rapidly secrete particular cytokines that activate innate immunity and facilitate development of adaptive responses. Conflicting reports on the role of NK cells during infection by Listeria monocytogenes can be found in the literature. Here, we demonstrate that during lethal infection by L. monocytogenes, activation of NK cells via the costimulatory molecule CD27 leads to excessive IFN-gamma production. This impairs innate anti-bacterial host defenses by inducing downregulation of CXCR2 on granulocytes and consequently inhibiting their recruitment to the sites of infection. The use of antibodies to block CD27 signaling or to deplete IFN-gamma was sufficient to rescue mice from lethal challenge by L. monocytogenes. Our findings contribute to a better understanding of the importance of CD27 signaling in activation of NK cells and should provide new ways of interfering with infections. PMID- 23818012 TI - Erythrocyte glutathione transferase activity: a possible early biomarker for blood toxicity in uremic diabetic patients. AB - Erythrocyte glutathione transferase (e-GST) displays increased activity in patients with renal damage and positive correlation with homocysteine (Hcy) in patients under maintenance hemodialysis. Here, we determined e-GST, Hcy, and erythrocyte catalase (e-CAT) in 328 patients affected by type 2 diabetes mellitus (T2DM), 61 diabetic non-nephropathic patients and 267 affected by diabetes and by chronic kidney disease (CKD) under conservative therapy subdivided into four stages according to K-DOQI lines. e-GST activity was significantly higher in all T2DM patients compared to the control group (7.90 +/- 0.26 vs. 5.6 +/- 0.4 U/g(Hb)), and we observed an enhanced activity in all subgroups of CKD diabetic patients. No significant correlation or increase has been found for e-CAT in all patients tested. Mean Hcy in diabetic patients is higher than that in healthy subjects (33.42 +/- 1.23 vs. 13.6 +/- 0.8 MUM), and Hcy increases in relation to the CKD stage. As expected, a significant correlation was found between e-GST and Hcy levels. These findings suggest that e-GST hyperactivity is not caused directly by diabetes but by its consequent renal damage. e-GST, as well as Hcy, may represent an early biomarker of renal failure. PMID- 23818013 TI - [Functional MRI of speech]. AB - Speech is a multifactorial term. In relationship with our central organ, speech is a communication medium which in a complex manner includes the production and perception of verbal information. Even within this limitation, imaging exploration of the neuronal basis of verbal communication offers an extensive investigative field which can only be presented in this article as highlights. The main focus is on the technical hurdles of investigations into speech production using functional magnetic resonance imaging (fMRI) and solution options will be presented. The difficulties contained in this aspect are that spoken words can only be poorly assessed in the noise level of the measurements and that the movements of the mouth necessary for speech motoric can lead to technical imaging artefacts. Investigation techniques and designs will be discussed which allow a representation of speech-relevant brain centers despite these problems. PMID- 23818014 TI - [On the diversity of applications for ultrasound]. PMID- 23818015 TI - Editorial: RSV, dendritic cells, and allergens--a bad combination. PMID- 23818016 TI - Editorial: mouse eosinophils expressing Cre recombinase: endless "flox"ibilities. PMID- 23818017 TI - Possible new modifications for the McDonald 2010 criteria for the diagnosis of primary progressive multiple sclerosis. PMID- 23818018 TI - Preventing brain atrophy should be the gold standard of effective therapy in MS (after the first year of treatment): Yes. PMID- 23818019 TI - Preventing brain atrophy should be the gold standard of effective theraphy in MS (after the first year of treatment): No. PMID- 23818020 TI - Preventing brain atrophy should be the gold standard of effective therapy in multiple sclerosis (after the first year of treatment): Commentary. PMID- 23818021 TI - A sandwich-type triple-decker lanthanide complex with mixed phthalocyanine and Schiff base ligands. AB - A new triple-decker dinuclear sandwich-type dysprosium complex based on both the phthalocyanine ligand and the tetradentate Schiff base ligand was synthesized, which is of interest for synthetic chemistry and also shows single-molecule magnetic behaviour. PMID- 23818022 TI - Uterine massage for preventing postpartum haemorrhage. AB - BACKGROUND: Postpartum haemorrhage (PPH) (bleeding from the genital tract after childbirth) is a major cause of maternal mortality and disability, particularly in under-resourced areas. In these settings, uterotonics are often not accessible. There is a need for simple, inexpensive techniques which can be applied in low-resourced settings to prevent and treat PPH. Uterine massage is recommended as part of the routine active management of the third stage of labour. However, it is not known whether it is effective. If shown to be effective, uterine massage would represent a simple intervention with the potential to have a major effect on PPH and maternal mortality in under-resourced settings. OBJECTIVES: To determine the effectiveness of uterine massage after birth and before or after delivery of the placenta, or both, to reduce postpartum blood loss and associated morbidity and mortality. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 April 2013). SELECTION CRITERIA: All published, unpublished and ongoing randomised controlled trials comparing uterine massage alone or in addition to uterotonics before or after delivery of the placenta, or both, with non-massage. DATA COLLECTION AND ANALYSIS: Two researchers independently considered trials for eligibility, assessed risk of bias and extracted the data using the agreed form. Data were checked for accuracy. The effect of uterine massage commenced before or after placental delivery were first assessed separately, and then the combined for an overall result. MAIN RESULTS: This review included two randomised controlled trials. The first trial included 200 women who were randomised to receive uterine massage or no massage following delivery of the placenta, after active management of the third stage of labour including use of oxytocin. The numbers of women with blood loss more than 500 mL was small, with no statistically significant difference (risk ratio (RR) 0.52, 95% confidence interval (CI) 0.16 to 1.67). There were no cases of retained placenta in either group. The mean blood loss was significantly less in the uterine massage group at 30 minutes (mean difference (MD) -41.60 mL, 95% CI -75.16 to -8.04) and 60 minutes after trial entry (MD 77.40 mL, 95% CI -118.71 to -36.09). The need for additional uterotonics was significantly reduced in the uterine massage group (RR 0.20, 95% CI 0.08 to 0.50).For use of uterine massage before and after delivery of the placenta, one trial recruited 1964 women in Egypt and South Africa. Women were assigned to receive oxytocin, uterine massage or both after delivery of the baby but before delivery of the placenta. There was no added benefit for uterine massage plus oxytocin over oxytocin alone as regards blood loss greater than or equal to 500 mL (average RR 1.56, 95% CI 0.44, 5.49; random-effects) or need for additional use of uterotonics (RR 1.02, 95% CI 0.56 to 1.85).The two trials were combined to examine the effect of uterine massage commenced either before or after delivery of the placenta. There was substantial heterogeneity with respect to the blood loss 500 mL or more after trial entry. The average effect using a random-effects model found no statistically significant differences between groups (average RR 1.14, 95% CI 0.39 to 3.32; random-effects). AUTHORS' CONCLUSIONS: The results of this review are inconclusive, and should not be interpreted as a reason to change current practice. Due to the limitations of the included trials, more trials with sufficient numbers of women are needed in order to estimate the effects of sustained uterine massage. All the women compared in this review received oxytocin as part of the active management of labour. Recent research suggests that once an oxytocic has been given, there is limited scope for further reduction in postpartum blood loss. Trials of uterine massage in settings where uterotonics are not available, and which measure women's experience of the procedure, are needed. PMID- 23818023 TI - Lack of association between the haplotype GCC/ATA polymorphism in the IL-10 promoter and SLE risk: evidence from a meta-analysis. AB - Numerous studies have investigated the association between the interleukin (IL) 10 promoter haplotype GCC/ATA (at the - 1082, - 819 and - 592 positions of the IL 10 gene) polymorphism and systemic lupus erythematosus (SLE) risk, but the results were inconsistent. We performed the current meta-analysis to assess precisely the association by comparing the GCC haplotype with the ATA haplotype. A literature search was conducted using Pubmed and Web of Science databases. Twelve studies including 1765 cases and 2444 controls were included in this meta analysis. The overall odds ratios (total and stratified by ethnicity: Asian or Caucasian) were 1.042 (95 % confidence interval [CI] 0.893-1.216; p = 0.599), 0.790 (95 % CI 0.528-1.182; p = 0.251), and 1.093 (95 % CI 0.919-1.300; p = 0.317), respectively. The results indicated that the GCC haplotype revealed no statistically significant association with SLE risk; thus, the haplotype GCC/ATA polymorphism of the IL-10 promoter is not likely to be involved in SLE susceptibility. PMID- 23818024 TI - The pediatric polytrauma patient: current concepts. PMID- 23818025 TI - A welcome to ownership. PMID- 23818026 TI - Shoulder arthroscopy in children and adolescents. AB - Arthroscopy is increasingly being used to manage a wide range of pathologies in the pediatric population. Knee arthroscopy is an efficacious treatment method for skeletally immature patients, and an increasing number of shoulder conditions can be managed with minimally invasive techniques. Special considerations are needed with regard to anatomy, anesthetic technique, equipment, and patient positioning when performing shoulder arthroscopy in a child or an adolescent. Several shoulder ailments can be managed arthroscopically in this patient population, including infection, contractures resulting from brachial plexus palsy, traumatic instability, atraumatic multidirectional instability, hemophilia, and rotator cuff injuries. PMID- 23818027 TI - Triceps surae contracture: implications for foot and ankle surgery. AB - Restricted ankle dorsiflexion secondary to contracture of the gastrocnemius soleus complex is frequently encountered in patients with foot and ankle pain and is well documented in the literature. During gait, decreased dorsiflexion shifts weight-bearing pressures from the heel to the forefoot, which may result in or exacerbate one of several pathologic conditions. Modest success has been achieved with nonsurgical management of triceps surae contracture, including splinting and stretching exercises. Surgical lengthening of the gastrocnemius-soleus complex at multiple levels has been described, and early clinical results have been promising. Additional research is required to further elucidate the long-term outcomes of various lengthening techniques. PMID- 23818028 TI - Blount disease. AB - In 1937, Blount described progressive tibial varus deformity observed in otherwise healthy children and adolescents. Although he called the condition "osteochondrosis deformans tibiae," the disorder is most frequently referred to as Blount disease. Two distinct clinical and radiographic forms have been recognized: infantile and adolescent. A third form, which was called "juvenile" Blount disease by Thompson, is recognized by some authors and is intermediate in severity and age of onset. The etiology of Blount disease is unknown. If the condition remains unresolved, it can lead to progressive varus deformity, with or without associated deformities of the distal femur and/or tibia; leg length inequality; and significant articular distortion, leading to premature osteoarthritis of the knee. A strong, but not universal, association exists between Blount disease and childhood obesity, increasing the prevalence and making effective treatment of this condition a challenge. Infantile Blount disease may resolve, respond to nonsurgical treatment, or be relentlessly progressive, so the surgeon must be astute in recognizing the features of true infantile Blount disease to determine effective treatment options. PMID- 23818029 TI - Defining the value of spine care. AB - The increased cost and frequency of spine-related procedures, expanding indications, and regional variation in care has led to a shift toward delivery of value-based spine care. In this model, payers show preference for interventions and treatments with proven value and incentivize providers who use such interventions and demonstrate value in their practices. Thus, spine care providers must understand how to determine the value of interventions and treatments. Determining value (ie, cost and quality of care, measured over time) can be challenging in the setting of spine care. Data collection and reporting are complicated by variation in diagnostic coding and surgical techniques. Typically, outcomes in spine care are based on subjective patient-reported measures that are influenced by concomitant orthopaedic, medical, and psychological disease. Health utility is a preferable measure of quality that can be converted into quality-adjusted life years and used in cost-effectiveness analysis. Although no standard currently exists, estimates of cost should include both direct and indirect costs of care over an adequate time horizon. PMID- 23818030 TI - Total elbow arthroplasty: current options. AB - Total elbow arthroplasty (TEA) has changed considerably in the past three decades. Based on the good long-term results with TEA in patients with rheumatoid arthritis, the indications expanded to include management of acute traumatic and posttraumatic conditions in young, higher-demand patients. Today, unlinked, linked semiconstrained, and convertible devices are available. The high complication rate with earlier surgeries led to surgical advances such as new cementing technique and a focus on managing the triceps. Complications such as infection, aseptic loosening, polyethylene wear, periprosthetic fracture, triceps insufficiency, wound breakdown, and ulnar nerve injury will continue to spur the evolution of surgical technique and implant design. Refinement of surgical indications and improvement in implant fixation, polyethylene design, component implantation, and pathology-specific implants will determine the future success of TEA. PMID- 23818031 TI - How do statistical differences in matrix-sensitive magnetic resonance outcomes translate into clinical assignment rules? PMID- 23818032 TI - Using Computational Simulation for Analysis and Development of Next-generation Orthopaedic Devices. PMID- 23818033 TI - Systemic treatment with the sphingosine-1-phosphate analog FTY720 does not improve fracture healing in mice. AB - Sphingosine-1-phosphate (S1P) has recently been recognized as a crucial coupling molecule of osteoclast and osteoblast activity provoking osteoanabolic effects. Targeting S1P receptors could, therefore, be a potential strategy to support bone formation in osteopenic diseases or in fracture repair. Here we investigated whether systemic treatment with the S1P analog FTY720 (Fingolimod) could improve fracture healing. Twelve-week-old, female C57BL/6 mice received an osteotomy of the femur, which was stabilized using an external fixator. The mice received a daily subcutaneous injection of either FTY720 (6 mg/kg) or vehicle from the third postoperative day. Fracture healing was evaluated after 10 and 21 days using biomechanical testing, u-computed tomography, and histomorphometry. Because FTY720 is supposed to influence osteoclast recruitment, osteoclasts were identified in the fracture callus by staining for tartrate resistant acid phosphatase (TRAP). There were no significant differences in callus mechanical properties, tissue composition and osteoclast number between the groups, suggesting that systemically applied FTY720 did not influence bone regeneration in this model of regular fracture healing. Even if further studies should test the potency of FTY720 under unfavorable healing conditions, we conclude that the effect of systemically applied FTY720 on fracture healing might be inferior compared to other anabolic treatments. (c) 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:1845-1850, 2013. PMID- 23818034 TI - Neuropeptidome of Tribolium castaneum antennal lobes and mushroom bodies. AB - Neuropeptides are a highly diverse group of signaling molecules that affect a broad range of biological processes in insects, including development, metabolism, behavior, and reproduction. In the central nervous system, neuropeptides are usually considered to act as neuromodulators and cotransmitters that modify the effect of "classical" transmitters at the synapse. The present study analyzes the neuropeptide repertoire of higher cerebral neuropils in the brain of the red flour beetle Tribolium castaneum. We focus on two integrative neuropils of the olfactory pathway, the antennal lobes and the mushroom bodies. Using the technique of direct peptide profiling by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry, we demonstrate that these neuropils can be characterized by their specific neuropeptide expression profiles. Complementary immunohistological analyses of selected neuropeptides revealed neuropeptide distribution patterns within the antennal lobes and the mushroom bodies. Both approaches revealed consistent differences between the neuropils, underlining that direct peptide profiling by mass spectrometry is a fast and reliable method to identify neuropeptide content. PMID- 23818035 TI - Structural and electronic properties of graphene-ZnO interfaces: dispersion corrected density functional theory investigations. AB - Detailed first-principles computations were performed on the geometric and electronic properties of the interfaces between graphene and ZnO polar surfaces. A notable van der Waals force exists at the interface, and charge transfer occurs between graphene and ZnO as a result of the difference in their work functions. The Dirac point of graphene remains intact despite its adsorption on ZnO, implying that its interaction with ZnO does not affect the superior conductivity of graphene. Excited electrons within the energy range of 0-3 eV (versus Fermi energy) in the hybrid systems are mainly accumulated on graphene. The computations provide a theoretical explanation for the good performance of graphene/ZnO hybrid materials in photocatalysts and solar cells. PMID- 23818036 TI - Effect of multivitamins on plasma homocysteine in patients with the 5,10 methylenetetrahydrofolate reductase C677T homozygous state. AB - The role of hyperhomocysteinemia (HHcy) as a cardiovascular risk factor remains a matter of debate, while it correlates with folates, it demonstrates inverse correlation with plasma homocysteine (Hcy) levels and vitamin B12 levels and reduces plasma Hcy levels following supplementation with multivitamins. The purpose of this study was to demonstrate that administering multivitamins at specific doses for 90 days restores normal plasma Hcy levels in women who are homozygous for the thermolabile variant of 5,10 methylenetetrahydrofolate reductase (MTHFR C677T). We enrolled 106 healthy females aged between 30 and 42 years, who were non-smokers, non-vegetarian, normotensive and who had no history of food abuse in the previous months. Only females were enrolled in order to rule out any bias due to the variation in Hcy plasma concentrations between males and females. Patient blood sampling was performed in order to determine plasma Hcy, serum folic acid and vitamin B12 levels. Furthermore, molecular characterization of the C677T polymorphism present in the MTHFR gene, was also performed. The results of this study demonstrated that supplementation with specific multivitamins restores normal plasma Hcy levels, regardless of the MTHFR genotype. Furthermore, it is unnecessary to adminster high doses of folate to reduce plasma Hcy levels, and administering high doses of folate may cause pro inflammatory and pro-proliferative effects. PMID- 23818037 TI - A job-exposure matrix for research and surveillance of occupational health and safety in Spanish workers: MatEmESp. AB - BACKGROUND: In this study we describe a general-population job-exposure matrix (MatEmESp) for Spanish workers covering the period 1996-2005. METHODS: The Finnish job-exposure matrix (FINJEM) provided the default value estimates for occupational exposure to chemical, physical and biological agents. These estimates were adapted to Spanish working conditions by local experts. Spanish surveys were used to obtain exposure estimates for ergonomic and psychosocial risk factors. Employment and socio-demographic conditions for Spanish workers were obtained from the Spanish National Statistics Institute. RESULTS: MatEmESp provides a large amount of national and occupation-specific data on the major occupational exposures in Spain. As some examples, the data show that the most prevalent occupational hazards are repetitive movements and a lack of support from co-workers. In addition, 10% of the Spanish working population perform night shifts, and bricklayers and concrete workers are the job titles with the highest risk of exposure to quartz dust. CONCLUSIONS: MatEmESp can be a useful tool for research and surveillance, and can help set priorities for occupational illness and injury prevention in Spain. PMID- 23818038 TI - Cancer, conflict, and the development of nuclear transplantation techniques. AB - The technique of nuclear transplantation - popularly known as cloning - has been integrated into several different histories of twentieth century biology. Historians and science scholars have situated nuclear transplantation within narratives of scientific practice, biotechnology, bioethics, biomedicine, and changing views of life. However, nuclear transplantation has never been the focus of analysis. In this article, I examine the development of nuclear transplantation techniques, focusing on the people, motivations, and institutions associated with the first successful nuclear transfer in metazoans in 1952. The conflict between embryologists and geneticists over the mechanisms of differentiation motivated Robert Briggs to pursue nuclear transplantation experiments as a way to resolve the debate. Briggs worked at the Lankenau Hospital Research Institute, a research facility devoted to the study of cancer. The goal of understanding cancer would play a role in the development of the technique, and the story of nuclear transplantation sheds light on the role that biomedical contexts play in biological research in the second half of the twentieth century. PMID- 23818039 TI - The effectiveness and safety of landiolol hydrochloride, an ultra-short-acting beta1-blocker, in postoperative patients with supraventricular tachyarrhythmias: a multicenter, randomized, double-blind, placebo-controlled study. AB - BACKGROUND: Persistent postoperative supraventricular tachyarrhythmias (SVTs) increase cardiac burden and aggravate cardiac hemodynamics. Therefore, for patients in unstable conditions after surgery, prompt and sustained control of heart rate is essential. The importance of beta-adrenoceptor antagonists (beta blockers) in controlling such postoperative atrial fibrillation or atrial flutter has been established, and the usefulness of ultra-short-acting beta1-blockers with high beta1 selectivity has been suggested based on their safety and efficacy under such circumstances. OBJECTIVES: Our objectives were to evaluate the effectiveness and safety of landiolol hydrochloride, an ultra-short-acting beta1 selective blocker, in the treatment of postoperative SVT in patients with a high risk of myocardial ischemia, or in patients after highly invasive surgery, in a multicenter, randomized, double-blind, placebo-controlled, group-comparative study. METHODS: A total of 165 patients were randomly allocated to three groups and received LM or MH doses of landiolol hydrochloride or placebo. LM group: dose L (1-min loading dose at a rate of 0.03 mg/kg/min, followed by a 10-min infusion at 0.01 mg/kg/min) followed by dose M (1-min loading at a rate of 0.06 mg/kg/min, followed by a 10-min infusion at 0.02 mg/kg/min); MH group: dose M followed by dose H (1-min loading dose at a rate of 0.125 mg/kg/min, followed by a 10-min infusion at 0.04 mg/kg/min); placebo (PP) group: dose P (1-min loading dose at a rate of 0 mg/kg/min, followed by a 10-min infusion at 0 mg/kg/min) followed by another round of dose P. If the targeted heart-rate reduction was not obtained at the end of the first 10-min infusion, the higher dose was started. The primary endpoint was the percentage of patients who met the heart-rate reduction criteria (>=20 % reduction and <100 beats/min). The safety endpoint was the incidence of adverse events in each of the three groups. RESULTS: The percentages of patients who met the heart-rate reduction criteria (>=20 % reduction and <100 beats/min) were 0.0, 60.4, and 42.0 % in the PP, LM, and MH groups, respectively. There were significant differences in the LM and MH groups relative to the PP group, but there was no significant difference between the LM and MH groups. No significant difference was observed in the incidence of adverse events among the three groups: 29.6 % in the PP group, 45.5 % in the LM group, and 43.1 % in the MH group. CONCLUSION: Landiolol hydrochloride is effective and safe for patients with postoperative SVT. PMID- 23818040 TI - Anti-tumor necrosis factor and new bone formation in ankylosing spondylitis: the controversy continues. PMID- 23818041 TI - Three daily servings of reduced-fat milk: an evidence-based recommendation? PMID- 23818042 TI - Screening for type 2 diabetes in a high-risk population: effects of a negative screening test after 4 years follow-up. AB - BACKGROUND: A negative diabetes screening test may unintentionally provide reassurance, resulting in reduced incentive to follow a healthy lifestyle. PURPOSE: The purpose of this study is to assess negative test result effects on lifestyle and risk perception at 4 years follow-up. METHODS: Risk perception and changes in smoking, physical activity, body mass index (BMI), and waist circumference were compared between 706 high-risk participants with a negative test result and 706 high-risk participants not offered screening (controls) in a randomized controlled trial of diabetes screening. RESULTS: Negative-screened individuals experienced a small but significant increase in BMI and waist circumference, but there was no significant difference with controls. The negative-screened group had significantly higher perception of risk of developing diabetes (p = 0.009) than controls, but no differences were observed in perceived personal control, worry, and optimistic bias. CONCLUSION: Screening negative for diabetes did not lead to overt long-term changes in lifestyle, despite a high perception of risk of developing diabetes. (ISRCTN75983009.). PMID- 23818044 TI - Directed manipulation of a flavoprotein photocycle. PMID- 23818043 TI - The Cag pathogenicity island and interaction between TLR2/NOD2 and NLRP3 regulate IL-1beta production in Helicobacter pylori infected dendritic cells. AB - Helicobacter pylori colonization of the stomach affects about half of the world population and is associated with the development of gastritis, ulcers, and cancer. Polymorphisms in the IL1B gene are linked to an increased risk of H. pylori associated cancer, but the bacterial and host factors that regulate interleukin (IL)-1beta production in response to H. pylori infection remain unknown. Using murine BM-derived DCs, we show that the bacterial virulence factors cytotoxin-associated genes pathogenicity island and CagL, but not vacuolating cytotoxin A or CagA, regulate the induction of pro-IL-1beta and the production of mature IL-1beta in response to H. pylori infection. We further show that the host receptors, Toll-like receptor 2 (TLR2) and nucleotide-binding oligomerization domain 2 (NOD2), but not NOD1, are required for induction of pro IL-1beta and NOD-like receptor pyrin domain containing 3 (NLRP3) in H. pylori infected DCs. In contrast, NLRP3 and the adaptor ASC were essential for the activation of caspase-1, processing of pro-IL-1beta into IL-1beta, and IL-1beta secretion. Finally, we show that mice deficient in caspase-1, IL-1beta, and IL-1 receptor, but not NLRP3, are impaired in the clearance of CagA-positive H. pylori from the stomach when compared with WT mice. These studies identify bacterial cag pathogenicity island and the cooperative interaction among host innate receptors TLR2, NOD2, and NLRP3 as important regulators of IL-1beta production in H. pylori infected DCs. PMID- 23818045 TI - Resilience and depressive symptoms in mainland Chinese immigrants to Hong Kong. AB - PURPOSE: Immigrants are highly vulnerable to the development of psychological problems such as depressive symptoms, which calls for further study of immigration in the Eastern context. Identification of factors that protect against depressive symptoms would inform interventions to enhance immigrant adaptation. METHODS: This survey recruited 1,205 individuals who are adult immigrants from mainland China to Hong Kong. The Patient Health Questionnaire-9 (PHQ-9) was used to screen them for depressive symptoms. Participants also completed assessments for acculturative stress, discrimination and rejection, and personal and family resilience. RESULTS: The results showed that participants reported considerable depressive symptoms. After controlling for socio demographic characteristics, acculturative stress, and discrimination and rejection, personal resilience was associated with fewer depressive symptoms. Family resilience added significant explanation of variance to predict depressive symptoms over and above the individual variables, including personal resilience. CONCLUSIONS: Our findings draw attention to the role of resilience as a protective factor against mental distress when facing adversities, while highlighting the central importance of family as an emotional resource for immigrant adjustment in the Chinese context. As personal resilience can increase with interventions, our results can inform trials to enhance adaptation among mainland Chinese immigrants in Hong Kong. PMID- 23818046 TI - Acetaminophen (paracetamol) for the common cold in adults. AB - BACKGROUND: Acetaminophen is frequently prescribed for treating patients with the common cold, but there is little evidence as to whether it is effective. OBJECTIVES: To determine the efficacy and safety of acetaminophen in the treatment of the common cold in adults. SEARCH METHODS: We searched CENTRAL 2013, Issue 1, Ovid MEDLINE (1950 to January week 5, 2013), EMBASE (1980 to February 2013), CINAHL (1982 to February 2013) and LILACS (1985 to February 2013). SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing acetaminophen to placebo or no treatment in adults with the common cold. Studies were included if the trials used acetaminophen as one ingredient of a combination therapy. We excluded studies in which the participants had complications. Primary outcomes included subjective symptom score and duration of common cold symptoms. Secondary outcomes were overall well being, adverse events and financial costs. DATA COLLECTION AND ANALYSIS: Two review authors independently screened studies for inclusion, assessed risk of bias and extracted data. We performed standard statistical analyses. MAIN RESULTS: We included four RCTs involving 758 participants. We did not pool data because of heterogeneity in study designs, outcomes and time points. The studies provided sparse information about effects longer than a few hours, as three of four included studies were short trials of only four to six hours. Participants treated with acetaminophen had significant improvements in nasal obstruction in two of the four studies. One study showed that acetaminophen was superior to placebo in decreasing rhinorrhoea severity, but was not superior for treating sneezing and coughing. Acetaminophen did not improve sore throat or malaise in two of the four studies. Results were inconsistent for some symptoms. Two studies showed that headache and achiness improved more in the acetaminophen group than in the placebo group, while one study showed no difference between the acetaminophen and placebo group. None of the included studies reported the duration of common cold symptoms. Minor side effects (including gastrointestinal adverse events, dizziness, dry mouth, somnolence and increased sweating) in the acetaminophen group were reported in two of the four studies. One of them used a combination of pseudoephedrine and acetaminophen. AUTHORS' CONCLUSIONS: Acetaminophen may help relieve nasal obstruction and rhinorrhoea but does not appear to improve some other cold symptoms (including sore throat, malaise, sneezing and cough). However, two of the four included studies in this review were small and allocation concealment was unclear in all four studies. The data in this review do not provide sufficient evidence to inform practice regarding the use of acetaminophen for the common cold in adults. Further large-scale, well-designed trials are needed to determine whether this intervention is beneficial in the treatment of adults with the common cold. PMID- 23818047 TI - Complete genome sequence of a novel dsRNA mycovirus isolated from the phytopathogenic fungus Verticillium dahliae Kleb. AB - A novel double-stranded RNA (dsRNA) mycovirus, designated Verticillium dahliae partitivirus 1 (VdPV1), was isolated from a strain of the fungus Verticillium dahliae. The VdPV1 genome has two dsRNA genome segments. The larger segment (1768 bp) has a single open reading frame (ORF) with a conserved RNA-dependent RNA polymerase (RdRP) domain. The smaller segment (1587 bp) contains a single ORF encoding a putative coat protein. Analysis of its genomic structure indicated that VdPV1 is a new member of the genus Partitivirus. We report the full-length sequence of this partitivirus that infects Verticillium dahliae, the causal agent of verticillium wilt of cotton. PMID- 23818048 TI - Gender effects of the COMT Val 158 Met genotype on verbal fluency in healthy adults. AB - Cognitive performance in healthy individuals is associated with gender differences in specific tests; a female advantage has been demonstrated in language tests, whereas a male advantage has been demonstrated in spatial relation examinations. The prefrontal cortex (PFC) mediates important cognitive domains and is influenced by dopamine (DA) activity. The single nucleotide polymorphism (SNP) rs4680 in the catechol-O-methyltransferase (COMT) gene results in an amino acid substitution from valine (Val) to methionine (Met). The Met allele has been demonstrated to decrease COMT enzyme activity and improve PFC cognitive function. COMT regulates DA activity in the PFC and exhibits gender effects. The aim of the present study was to investigate the gender-specific effects of the COMT genotype on cognition in healthy young adults. Seventy-six healthy subjects were genotyped for COMT rs4680 and submitted to an extensive range of neuropsychological tests assessing aspects of PFC function. The COMT Met allele influenced the performance of executive function. The results revealed gender effects of the COMT rs4680 Met allele on verbal fluency, with positive effects in males and negative effects in females. This suggested that DA activity affects cognitive function in different ways, according to gender. PMID- 23818049 TI - Variable tunneling barriers in FEBID based PtC metal-matrix nanocomposites as a transducing element for humidity sensing. AB - The development of simple gas sensing concepts is still of great interest for science and technology. The demands on an ideal device would be a single-step fabrication method providing a device which is sensitive, analyte-selective, quantitative, and reversible without special operating/reformation conditions such as high temperatures or special environments. In this study we demonstrate a new gas sensing concept based on a nanosized PtC metal-matrix system fabricated in a single step via focused electron beam induced deposition (FEBID). The sensors react selectively on polar H2O molecules quantitatively and reversibly without any special reformation conditions after detection events, whereas non polar species (O2, CO2, N2) produce no response. The key elements are isolated Pt nanograins (2-3 nm) which are embedded in a dielectric carbon matrix. The electrical transport in such materials is based on tunneling effects in the correlated variable range hopping regime, where the dielectric carbon matrix screens the electric field between the particles, which governs the final conductivity. The specific change of these dielectric properties by the physisorption of polar gas molecules (H2O) can change the tunneling probability and thus the overall conductivity, allowing their application as a simple and straightforward sensing concept. PMID- 23818050 TI - The usefulness of anthropometric measures. PMID- 23818053 TI - Capillary electrophoresis for analysis of deletion and duplication in exon 44-55 of Duchenne muscular dystrophy gene. AB - In this study, a genotyping CGE method was established for analysis of Duchenne muscular dystrophy (DMD) gene deletions and duplications in exon 44-55. A total of 12 DMD exons (exon 44-55) and 2 internal standard gene fragments were simultaneously amplified by using a universal multiplex PCR (UMPCR) and determined by CGE. The conditions of UMPCR and CGE were optimized, including the kinds of polymerase, temperatures in UMPCR, separation matrix, separation temperature, and voltage. Finally, the separation was performed by 1.2% poly(ethylene oxide) in 1* TBE buffer at -6 kV and 25 degrees C. After validation, our results showed the peak patterns for differentiation of genetic deletion or duplication in 27 DMD patients and normal subjects, according to the peak height ratios by comparison of two internal standard peaks. Among the 27 subjects, 23 cases are deletion type and four are duplication type. The data of two patients analyzed by this CGE-PCR method were different from that of multiplex ligation dependent probe amplification method, and the sequencing results demonstrated that our results were correct. This UMPCR-CGE method was considered better than the multiplex ligation dependent probe amplification method. Furthermore, this method can be used for eugenics in clinical applications. PMID- 23818054 TI - Safety representatives' views on their interaction with workers in a context of unequal power relations: an exploratory qualitative study in Barcelona (Spain). AB - BACKGROUND: The interaction between workers and safety representatives (SRs), a factor that determines SRs' effectiveness, is an unexplored issue within occupational health research. METHODS: We undertook a qualitative exploratory interpretative-descriptive study by means of semi-structured interviews with SRs from Barcelona (Spain) to analyze the SRs' perspective on the interaction with workers and its determinants RESULTS: SRs' interaction with workers is mainly limited to information processes and to identifying occupational hazards. Prominent factors determining this interaction are associated with the way SRs understand and carry out their role, the firm sector and size, and workers' fear of dismissal, exacerbated by changes in the labor market and the current economic crisis. CONCLUSIONS: Interaction with workers is influenced by a more prevalent technical-legal view of the SRs' role and by unequal power relations between workers and management. Poor interaction with workers might lead to decreasing SRs' effectiveness. PMID- 23818055 TI - Porphyromonas gingivalis lipopolysaccharide activates canonical Wnt/beta-catenin and p38 MAPK signalling in stem cells from the apical papilla. AB - As dental precursor cells, stem cells from the apical papilla (SCAP) are capable of forming roots and undergoing apexogenesis, which are impaired upon exposure to bacterial infection. Porphyromonas gingivalis is a common Gram-negative bacterium that is involved in pulpal and periapical infection. The purpose of this study was to investigate the effects of P. gingivalis lipopolysaccharide (LPS) on the Wnt/beta-catenin and p38 mitogen-activated protein kinase (MAPK) signalling pathways in SCAP. As indicated by the IL-1beta and TNF-alpha mRNA levels, P. gingivalis LPS induced the expression of pro-inflammatory cytokines in a dose dependent manner. In addition, activation of the p38 MAPK and Wnt/beta-catenin pathways was confirmed by the augmentation of phospho-p38 and beta-catenin protein expression and increased expression of c-myc and cyclin D1 mRNA. Despite no significant increase in beta-catenin mRNA expression, increased phosphorylation of glycogen synthase kinase (GSK)-3beta suggested that GSK-3beta was responsible for the accumulation of beta-catenin in the cytoplasm and translocation to the nucleus. Previous studies have shown that GSK-3beta plays a critical role in crosstalk between the Wnt/beta-catenin and p38 MAPK pathways. In the present study, we showed that the level of p38 phosphorylation decreased upon pretreatment with a p38 MAPK inhibitor for 1 h before stimulating SCAP with 10 MUg/ml P. gingivalis LPS. However, the levels of GSK-3beta and beta-catenin phosphorylation in the cytoplasm and nucleus were not significantly altered. Our results suggest that the p38 MAPK and canonical Wnt/beta-catenin signalling pathways are activated by P. gingivalis LPS in SCAP, but we have no evidence that p38 MAPK is upstream of GSK-3beta in the Wnt/beta-catenin signalling pathway. PMID- 23818056 TI - Sorafenib and thyroid cancer. AB - Sorafenib (Nexavar) is a multikinase inhibitor, which has demonstrated both anti proliferative and anti-angiogenic properties in vitro and in vivo, inhibiting the activity of targets present in the tumor cell [c-RAF (proto-oncogene serine/threonine-protein kinase), BRAF, (V600E)BRAF, c-KIT, and FMS-like tyrosine kinase 3] and in tumor vessels (c-RAF, vascular endothelial growth factor receptor-2, vascular endothelial growth factor receptor-3, and platelet-derived growth factor receptor beta). For several years, sorafenib has been approved for the treatment of hepatocellular carcinoma and advanced renal cell carcinoma. After previous studies showing that sorafenib was able to inhibit oncogenic RET mutants, (V600E)BRAF, and angiogenesis and growth of orthotopic anaplastic thyroid cancer xenografts in nude mice, some clinical trials demonstrated the effectiveness of sorafenib in advanced thyroid cancer. Currently, the evaluation of the clinical safety and efficacy of sorafenib for the treatment of advanced thyroid cancer is ongoing. This article reviews the anti-neoplastic effect of sorafenib in thyroid cancer. Several completed (or ongoing) studies have evaluated the long-term efficacy and tolerability of sorafenib in patients with papillary and medullary aggressive thyroid cancer. The results suggest that sorafenib is a promising therapeutic option in patients with advanced thyroid cancer that is not responsive to traditional therapeutic strategies. PMID- 23818057 TI - Estrogen receptor beta expression in the mouse forebrain: age and sex differences. AB - Estrogen receptors regulate multiple brain functions, including stress, sexual, and memory-associated behaviors as well as controlling neuroendocrine and autonomic function. During development, estrogen signaling is involved in programming adult sex differences in physiology and behavior. Expression of estrogen receptor alpha changes across development in a region-specific fashion. By contrast, estrogen receptor beta (ERbeta) is expressed in many brain regions, yet few studies have explored sex and developmental differences in its expression, largely because of the absence of selective reagents for anatomical localization of the protein. This study utilized bacterial artificial chromosome transgenic mice expressing ERbeta identified by enhanced green fluorescent protein (EGFP) to compare expression levels and distribution of ERbeta in the male and female mouse forebrain on the day of birth (P0), on postnatal day 4 (P4), and on P21. By using qualitative analysis, we mapped the distribution of ERbeta-EGFP and found developmental alterations in ERbeta expression within the cortex, hippocampus, and hypothalamic regions including the arcuate, ventromedial, and paraventricular nuclei. We also report a sex difference in ERbeta in the bed nucleus of the stria terminalis, with males showing greater expression at P4 and P21. Another sex difference was found in the anteroventral periventricular nucleus of P21, but not P0 or P4, mice, in which ERbeta-EGFP immunoreactive cells were densely clustered near the third ventricle in females but not males. These developmental changes and sex differences in ERbeta indicate a mechanism through which estrogens might differentially affect brain functions or program adult physiology at select times during development. PMID- 23818059 TI - ChenPhos: highly modular P-stereogenic C1-symmetric diphosphine ligands for the efficient asymmetric hydrogenation of alpha-substituted cinnamic acids. PMID- 23818058 TI - Mechanical properties of the extra-fibrillar matrix of human annulus fibrosus are location and age dependent. AB - The mechanical behavior of the annulus fibrosus (AF) of the intervertebral disc can be modeled as a mixture of fibers, extra-fibrillar matrix (EFM), ions, and fluid. However, the properties of the EFM have not been measured directly. We measured mechanical properties of the human EFM at several locations, determined the effect of age and degeneration, and evaluated whether changes in EFM properties correspond to AF compositional changes. EFM mechanical properties were measured using a method that combines osmotic loading and confined compression. AF samples were dissected from several locations, and mechanical properties were correlated with age, degeneration, and composition. EFM modulus was found to range between 10 and 50 kPa, increasing nonlinearly with compression magnitude and being highest in the AF outer-anterior region. EFM properties were not correlated with composition or degeneration. However, the EFM modulus, its relative contribution to tissue modulus, and model parameters were correlated with age. These measurements will result in more accurate predictions of deformations in the intervertebral disc. Additionally, parameters such as permeability and diffusivity used for biotransport analysis of glucose and other solutes depend on EFM deformation. Consequently, the accuracy of biotransport simulations will be greatly improved. PMID- 23818060 TI - Si-Si and Si-O bond activation at platinum: stepwise formation of a SiH3 complex. PMID- 23818061 TI - Chromium phytotoxicity in radish (Raphanus sativus): effects on metabolism and nutrient uptake. AB - In the present investigation, chromium (VI) induced toxicity on metabolic activity and translocations of nutrients in radish were evaluated under controlled glass house conditions. Chromium was found to induce toxicity and significantly affect plant growth and metabolic activity. Excess of chromium (0.4 mM) caused a decrease in the concentration of iron in leaves (from 134.3 to 71.9 MUg g(-1) dw) and significant translocation of sulphur, phosphorus and zinc. Translocation of manganese, copper and boron were less affected from root to stem. After 15 days of Cr exposure, maximum accumulation of Cr was found in roots (327.6 MUg g(-1) dw) followed by stems (186.8 MUg g(-1) dw) and leaves (116.7 MUg g(-1) dw) at 0.4 mM Cr concentration. Therefore, Cr may affect negatively not only production, but also the nutritive quality of the radish; likewise, higher Cr content may cause health hazards for humans. PMID- 23818062 TI - Artesunate exerts specific cytotoxicity in retinoblastoma cells via CD71. AB - Retinoblastoma (RB) is an intraocular cancer that affects young children. There is an ongoing effort to find new agents for RB management that are effective, specific and with few side-effects. In the present study, we tested artesunate (ART), a synthetic derivative from the herbal drug artemisinin, used in the clinic for the treatment of malaria. We analyzed ART cytotoxicity in an RB cell line (RB-Y79) and in a retinal epithelial cell line (hTERT-RPE1) by flow cytometric analysis (FCM). We related the effect of ART to the expression of transferrin receptor 1 (TfR-1, also known as CD71) by knocking down CD71 with RNAi and analyzing cell cycle variables by FCM. We found that the cytotoxic action of ART is specific for RB cells in a dose-dependent manner, with low toxicity in normal retina cells. ART is more effective in RB than carboplatin with a markedly strong cytotoxic effect on carboplatin-resistant RB cells. RB had higher CD71 levels at the membrane compared to normal retinal cells. We showed that ART internalization in RB cells is dependent upon the expression of the CD71. In addition, ART blocked the cell cycle progression at the G1 phase, even at low doses, and decreased the proportion of RB cells in the S phase. In conclusion, we showed that ART is a promising drug exhibiting high selective cytotoxicity even against multidrug-resistant RB cells. Thus, we suggest that ART could be used in the treatment of RB. PMID- 23818063 TI - Incidence of osteoporotic fractures in Sado, Japan in 2010. AB - We conducted a survey of fracture incidences associated with senile osteoporosis in 2010 in Sado City, Niigata Prefecture, Japan, including compression vertebral fractures, hip fractures, distal radius fractures, and fractures of the proximal end of the humerus. We previously conducted a similar survey from 2004-2006 in Sado City. The purpose of the current study was to determine the incidence of osteoporotic fractures in Sado City in 2010 and to examine changes over time. We calculated the incidence of each fracture per 100,000 person-years based on the population of Sado City. Hip and vertebral fractures showed marked increases from 2004-2006, but a similar increase was not found from 2006-2010. The average age at injury increased in 2010 compared to 2004, except for fractures of the radius. Among the subjects with hip fractures, 14 % had a history of contralateral hip fracture. The percentage of patients taking medication for osteoporosis before injury was higher in 2010 compared with 2004, but these percentages were still only 7 and 13 % for those with subsequent hip and vertebral fractures, respectively. PMID- 23818064 TI - Interstitial fluid drainage is impaired in ischemic stroke and Alzheimer's disease mouse models. AB - The interstitial fluid (ISF) drainage pathway has been hypothesized to underlie the clearance of solutes and metabolites from the brain. Previous work has implicated the perivascular spaces along arteries as the likely route for ISF clearance; however, it has never been demonstrated directly. The accumulation of amyloid beta (Abeta) peptides in brain parenchyma is one of the pathological hallmarks of Alzheimer disease (AD), and it is likely related to an imbalance between production and clearance of the peptide. Abeta drainage along perivascular spaces has been postulated to be one of the mechanisms that mediate the peptide clearance from the brain. We therefore devised a novel method to visualize solute clearance in real time in the living mouse brain using laser guided bolus dye injections and multiphoton imaging. This methodology allows high spatial and temporal resolution and revealed the kinetics of ISF clearance. We found that the ISF drains along perivascular spaces of arteries and capillaries but not veins, and its clearance exhibits a bi-exponential profile. ISF drainage requires a functional vasculature, as solute clearance decreased when perfusion was impaired. In addition, reduced solute clearance was observed in transgenic mice with significant vascular amyloid deposition; we suggest the existence of a feed-forward mechanism, by which amyloid deposition promotes further amyloid deposition. This important finding provides a mechanistic link between cerebrovascular disease and Alzheimer disease and suggests that facilitation of Abeta clearance along the perivascular pathway should be considered as a new target for therapeutic approaches to Alzheimer disease and cerebral amyloid angiopathy. PMID- 23818066 TI - Probing alloy composition gradient and nanometer-scale carrier localization in single AlGaN nanowires by nanocathodoluminescence. AB - The optical properties of single AlGaN nanowires grown by plasma-assisted molecular beam epitaxy have been studied by nanocathodoluminescence. Optical emission was found to be position-dependent and to occur in a wide wavelength range, a feature which has been assigned to a composition gradient along the nanowire growth axis, superimposed on local composition fluctuations at the nanometer scale. This behavior is associated with the growth mode of such AlGaN nanowires, which is governed by kinetics, leading to the successive formation of (i) a zone with strong local composition fluctuations followed by (ii) a zone with a marked composition gradient and, eventually, (iii) a zone corresponding to a steady state regime and the formation of a homogeneous alloy. PMID- 23818065 TI - Homozygosity for the C9orf72 GGGGCC repeat expansion in frontotemporal dementia. AB - An expanded hexanucleotide repeat in the C9orf72 gene is the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). We now report the first description of a homozygous patient and compare it to a series of heterozygous cases. The patient developed early-onset frontotemporal dementia without additional features. Neuropathological analysis showed c9FTD/ALS characteristics, with abundant p62-positive inclusions in the frontal and temporal cortices, hippocampus and cerebellum, as well as less abundant TDP-43 positive inclusions. Overall, the clinical and pathological features were severe, but did not fall outside the usual disease spectrum. Quantification of C9orf72 transcript levels in post-mortem brain demonstrated expression of all known C9orf72 transcript variants, but at a reduced level. The pathogenic mechanisms by which the hexanucleotide repeat expansion causes disease are unclear and both gain- and loss-of-function mechanisms may play a role. Our data support a gain-of function mechanism as pure homozygous loss of function would be expected to lead to a more severe, or completely different clinical phenotype to the one described here, which falls within the usual range. Our findings have implications for genetic counselling, highlighting the need to use genetic tests that distinguish C9orf72 homozygosity. PMID- 23818067 TI - Identifying critical regions for spike propagation in axon segments. AB - Morphological reconstructions of axon segments reveal the abundance of geometrical ultrastructures that can dramatically affect the propagation of Action Potentials (AP). Moreover, deformations and swellings in axons resulting from brain traumas are associated to many neural dysfunctions and disorders. Our aim is to develop a computational framework to distinguish between geometrical enlargements that lead to minor changes in propagation from those that result in critical phenomenon such as reflection or blockage of the original traveling spike. We use a few geometrical parameters to model a prototypical shaft enlargement and explore the parameter space characterizing all possible propagation regimes and dynamics in an unmylienated AP model. Contrary to earlier notions that large diameter increases mostly lead to blocking, we demonstrate transmission is stable provided the geometrical changes occur in a slow manner. Our method also identifies a narrow range of parameters leading to a reflection regime. The distinction between these three regimes can be evaluated by a simple function of the geometrical parameters inferred through numerical simulations. We suggest that evaluating this function along axon segments can detect regions most susceptible to (i) transmission failure due to perturbations, (ii) structural plasticity, (iii) critical swellings caused by brain traumas and/or (iv) neurological disorders associated with the break down of spike train propagation. PMID- 23818069 TI - Acupuncture for stress urinary incontinence in adults. AB - BACKGROUND: The use of acupuncture for stress urinary incontinence is increasing in frequency, especially in Asian area. However, its effectiveness and side effects have not been evaluated. OBJECTIVES: To assess the effectiveness and side effects of acupuncture for stress urinary incontinence in adults. SEARCH METHODS: We searched the Cochrane Incontinence Group Specialised Register (searched 28 January 2013), EMBASE, AMED, Chinese Biomedical Literature Database (CBM), Chinese Acupuncture Trials Register and China National Knowledge Infrastructure (CNKI) (all searched 20 February 2013). In addition, we searched the reference lists of relevant articles and contacted authors and trialists in the field. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials of acupuncture interventions without other treatments for the management of stress urinary incontinence for adults. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility, trial quality and extracted data. We meta analysed data where appropriate. MAIN RESULTS: We identified 17 possibly eligible studies but only one small trial with 60 women met our inclusion criteria. The trial compared acupuncture versus midodrine, a drug for treating hypotension. The risk of bias was high as there was no concealment of randomised allocation, and there was no blinding of assessment of outcome. In addition, it was not possible to blind participants or health providers to the interventions. The statistical methods were not described.More women improved in the acupuncture group (73% with acupuncture versus 33% with midodrine; risk ratio (RR) 2.20, 95% confidence interval (CI) 1.27 to 3.81) but the cure rates were low and not statistically significantly different (13% versus 7%; RR 2.00, 95% CI 0.40 to 10.11). There were adverse events in the drug group only. AUTHORS' CONCLUSIONS: The effect of acupuncture for stress urinary incontinence for adults is uncertain. There is not enough evidence to determine whether acupuncture is more effective than drug treatment. PMID- 23818068 TI - A single functional model of drivers and modulators in cortex. AB - A distinction is commonly made between synaptic connections capable of evoking a response ("drivers") and those that can alter ongoing activity but not initiate it ("modulators"). Here it is proposed that, in cortex, both drivers and modulators are an emergent property of the perceptual inference performed by cortical circuits. Hence, it is proposed that there is a single underlying computational explanation for both forms of synaptic connection. This idea is illustrated using a predictive coding model of cortical perceptual inference. In this model all synaptic inputs are treated identically. However, functionally, certain synaptic inputs drive neural responses while others have a modulatory influence. This model is shown to account for driving and modulatory influences in bottom-up, lateral, and top-down pathways, and is used to simulate a wide range of neurophysiological phenomena including surround suppression, contour integration, gain modulation, spatio-temporal prediction, and attention. The proposed computational model thus provides a single functional explanation for drivers and modulators and a unified account of a diverse range of neurophysiological data. PMID- 23818070 TI - Evaluation of B. subtilis SPB1 biosurfactants' potency for diesel-contaminated soil washing: optimization of oil desorption using Taguchi design. AB - Low solubility of certain hydrophobic soil contaminants limits remediation process. Surface-active compounds can improve the solubility and removal of hydrophobic compounds from contaminated soils and, consequently, their biodegradation. Hence, this paper aims to study desorption efficiency of oil from soil of SPB1 lipopeptide biosurfactant. The effect of different physicochemical parameters on desorption potency was assessed. Taguchi experimental design method was applied in order to enhance the desorption capacity and establish the best washing parameters. Mobilization potency was compared to those of chemical surfactants under the newly defined conditions. Better desorption capacity was obtained using 0.1% biosurfacatnt solution and the mobilization potency shows great tolerance to acidic and alkaline pH values and salinity. Results show an optimum value of oil removal from diesel-contaminated soil of about 87%. The optimum washing conditions for surfactant solution volume, biosurfactant concentration, agitation speed, temperature, and time were found to be 12 ml/g of soil, 0.1% biosurfactant, 200 rpm, 30 degrees C, and 24 h, respectively. The obtained results were compared to those of SDS and Tween 80 at the optimal conditions described above, and the study reveals an effectiveness of SPB1 biosurfactant comparable to the reported chemical emulsifiers. (1) The obtained findings suggest (a) the competence of Bacillus subtilis biosurfactant in promoting diesel desorption from soil towards chemical surfactants and (b) the applicability of this method in decontaminating crude oil-contaminated soil and, therefore, improving bioavailability of hydrophobic compounds. (2) The obtained findings also suggest the adequacy of Taguchi design in promoting process efficiency. Our findings suggest that preoptimized desorption process using microbial-derived emulsifier can contribute significantly to enhancement of hydrophobic pollutants' bioavailability. This study can be complemented with the investigation of potential role in improving the biodegradation of the diesel adsorbed to the soil. PMID- 23818071 TI - Nutrient and enzymatic changes of hydrolysed tannery solid waste treated with epigeic earthworm Eudrilus eugeniae and phytotoxicity assessment on selected commercial crops. AB - Animal fleshing (ANFL) is the predominant proteinaceous solid waste generated during processing of leather and it is confronting disposal problems. The aim of this study was to assess the potential of epigeic earthworm Eudrilus eugeniae to utilize and transform the fermented ANFL in the solid state (SSF) and submerged state (SmF) into a value added product along a low residence period (25 days). A total of six treatment units containing different waste mixture compositions were established. Fifty healthy and non-clitellated earthworms were introduced in three different treatment containers: control, SSF, and SmF (+worm). Another set of treatment mixtures (control, SSF, SmF) was established without earthworms ( worm) to compare the results. The products were characterized for physico chemical, enzymatic analysis and seedling growth parameters to compare the differences in the process with and without earthworms. The changes observed in the analytical parameters were in the following order: SSF > SmF > control mixtures (p < 0.05). The vermicompost showed a significant reduction in heavy metals, total organic carbon and an increase in total Kjeldhal nitrogen as compared to the product untreated by earthworms. The maximum enzymatic activities were observed after 21 days of vermicomposting. The relative seed germination of vermicompost extracts were in the order of tomato (Lycopersicon esculentum) > green gram (Vigna radiata) > cucumber (Cucumis sativus) > bottle gourd (Lagenaria siceraria (Mol.) Standl.) and showed no phytotoxicity effects. The results indicated that the combination of both ANFL hydrolysis through fermentation and vermicomposting is a good alternative to the management of this kind of waste. PMID- 23818072 TI - Phytostabilization potential of evening primrose (Oenothera glazioviana) for copper-contaminated sites. AB - A field investigation, field experiment, and hydroponic experiment were conducted to evaluate feasibility of using Oenothera glazioviana for phytostabilization of copper-contaminated soil. In semiarid mine tailings in Tongling, Anhui, China, O. glazioviana, a copper excluder, was a dominant species in the community, with a low bioaccumulation factor, the lowest copper translocation factor, and the lowest copper content in seed (8 mg kg(-1)). When O. glazioviana was planted in copper-polluted farmland soil in Nanjing, Jiangsu, China, its growth and development improved and the level of gamma-linolenic acid in seeds reached 17.1%, compared with 8.73% in mine tailings. A hydroponic study showed that O. glazioviana had high tolerance to copper, low upward transportation capacity of copper, and a high gamma-linolenic acid content. Therefore, it has great potential for the phytostabilization of copper-contaminated soils and a high commercial value without risk to human health. PMID- 23818073 TI - Determination of phenols and pharmaceuticals in municipal wastewaters from Polish treatment plants by ultrasound-assisted emulsification-microextraction followed by GC-MS. AB - A method combining ultrasound-assisted emulsification-microextraction (USAEME) with gas chromatography-mass spectrometry (GC-MS) was developed for simultaneous determination of four acidic pharmaceuticals, ibuprofen, naproxen, ketoprofen, and diclofenac, as well as four phenols, 4-octylphenol, 4-n-nonylphenol, bisphenol A, and triclosan in municipal wastewaters. Conditions of extraction and simultaneous derivatization were optimized with respect to such aspects as type and volume of extraction solvent, volume of derivatization reagent, kind and amount of buffering salt, location of the test tube in the ultrasonic bath, and extraction time. The average correlation coefficient of the calibration curves was 0.9946. The LOD/(LOQ) values in influent and effluent wastewater were in the range of 0.002-0.121/(0.005-0.403) MUg L(-1) and 0.002-0.828/(0.006-2.758) MUg L( 1), respectively. Quantitative recoveries (>=94%) and satisfactory precision (average RSD 8.2%) were obtained. The optimized USAEME/GC-MS method was applied for determination of the considered pharmaceuticals and phenols in influents and treated effluents from nine Polish municipal wastewater treatment plants. The average concentration of acidic pharmaceuticals in influent and effluent wastewater were in the range of 0.06-551.96 MUg L(-1) and 0.01-22.61 MUg L(-1), respectively, while for phenols were in the range of 0.03-102.54 MUg L(-1) and 0.02-10.84 MUg L(-1), respectively. The removal efficiencies of the target compounds during purification process were between 84 and 99%. PMID- 23818074 TI - Spectroscopic Raman study of sulphate precipitation sequence in Rio Tinto mining district (SW Spain). AB - Acidic waters and sulphate-rich precipitates are typical by-products of mining activity such as in Rio Tinto (Huelva, SW Spain). This river drains pyrite mines situated in the Iberian Pyrite Belt which have been in operation since the Bronze Age and probably constitutes the oldest continuously operating mining activity over the world. In the present work, we have used Raman spectroscopy to study a wide range of natural mineral samples collected at Rio Tinto which origin is related to evaporation and mineral transformation processes in a wet and extreme acidic environment. In addition, we simulated the phenomenon of mineral precipitation in controlled conditions by using a simulator developed at the laboratory evaporating natural water collected at Rio Tinto. Also, a series of experiments using the same waters as small droplets have been carried out using micro-Raman technique. The droplets were placed on substrates with different chemical composition and reactivity. The results reveal that the precipitation sequence occurred in Rio Tinto mainly comprises copiapite and coquimbite group minerals followed by several other low hydrated iron sulphates. The experiments carried out on droplets allow estimating with higher accuracy the precipitation sequence. PMID- 23818075 TI - Pacific oyster (Crassostrea gigas) hemocyte are not affected by a mixture of pesticides in short-term in vitro assays. AB - Pesticides are frequently detected in estuaries among the pollutants found in estuarine and coastal areas and may have major ecological consequences. They could endanger organism growth, reproduction, or survival. In the context of high mortality outbreaks affecting Pacific oysters, Crassostrea gigas, in France since 2008, it appears of importance to determine the putative effects of pesticides on oyster susceptibility to infectious agents. Massive mortality outbreaks reported in this species, mainly in spring and summer, may suggest an important role played by the seasonal use of pesticides and freshwater input in estuarine areas where oyster farms are frequently located. To understand the impact of some pesticides detected in French waters, their effects on Pacific oyster hemocytes were studied through short-term in vitro experiments. Bivalve immunity is mainly supported by hemocytes eliminating pathogens by phagocytosis and producing compounds including lysosomal enzymes and antimicrobial molecules. In this study, oyster hemocytes were incubated with a mixture of 14 pesticides and metaldehyde alone, a molecule used to eliminate land mollusks. Hemocyte parameters including dead/alive cells, nonspecific esterase activities, intracytoplasmic calcium, lysosome number and activity, and phagocytosis were monitored by flow cytometry. No significant effect of pesticides tested at different concentrations was reported on oyster hemocytes maintained in vitro for short-term periods in the present study. It could be assumed that these oyster cells were resistant to pesticide exposure in tested conditions and developing in vivo assays appears as necessary to better understand the effects of pollutants on immune system in mollusks. PMID- 23818076 TI - The role of Mn oxide doping in phosphate removal by Al-based bimetal oxides: adsorption behaviors and mechanisms. AB - This study investigated the behaviors and mechanisms of phosphate adsorbed onto manganese (Mn) oxide-doped aluminum (Al) oxide (MODAO). The isotherm results demonstrated that the maximum amount of phosphorus (P) adsorbed onto MODAO was 59.8 mg/g at T = 298 K (pH 6.0). This value was nearly twice the amount of singular AlOOH and could increase with rising temperatures. The kinetic results illustrated that most of the P was adsorbed onto MODAO within 5 h, which was shorter than the equilibrium time of phosphate adsorption onto AlOOH. The Elovich model effectively described the adsorption kinetic data of MODAO because of its heterogeneous surface. The optimal solution pH for phosphate removal was approximately 5.0 because of electrostatic interaction effects. Meanwhile, the decrease in P uptake with increasing ion strength suggested that phosphate adsorption occurred through an outer-sphere complex. Phosphates would compete for adsorption sites on the surface of MODAO in the presence of fluoride ion or sulfate. In addition, the spectroscopic analysis results of Fourier transform infrared spectroscopy and X-ray photoemission spectroscopy indicated that removal mechanisms of phosphate primarily include adhesion to surface hydroxyl groups and ligand exchange. PMID- 23818077 TI - Degradation of the potential rodent contraceptive quinestrol and elimination of its estrogenic activity in soil and water. AB - Quinestrol has shown potential for use in the fertility control of the plateau pika population of the Qinghai-Tibet Plateau. However, the environmental safety and fate of this compound are still obscure. Our study investigated degradation of quinestrol in a local soil and aquatic system for the first time. The results indicate that the degradation of quinestrol follows first-order kinetics in both soil and water, with a dissipation half-life of approximately 16.0 days in local soil. Microbial activity heavily influenced the degradation of quinestrol, with 41.2% removal in non-sterile soil comparing to 4.8% removal in sterile soil after incubation of 10 days. The half-lives in neutral water (pH 7.4) were 0.75 h when exposed to UV light (lambda = 365 nm) whereas they became 2.63 h when exposed to visible light (lambda > 400 nm). Acidic conditions facilitated quinestrol degradation in water with shorter half-lives of 1.04 and 1.47 h in pH 4.0 and pH 5.0 solutions, respectively. Moreover, both the soil and water treatment systems efficiently eliminated the estrogenic activity of quinestrol. Results presented herein clarify the complete degradation of quinestrol in a relatively short time. The ecological and environmental safety of this compound needs further investigation. PMID- 23818078 TI - Dietary arsenic consumption and urine arsenic in an endemic population: response to improvement of drinking water quality in a 2-year consecutive study. AB - We assessed the association between arsenic intake through water and diet, and arsenic levels in first morning-void urine under variable conditions of water contamination. This was done in a 2-year consecutive study in an endemic population. Exposure of arsenic through water and diet was assessed for participants using arsenic-contaminated water (>=50 MUg L(-1)) in a first year (group I) and for participants using water lower in arsenic (<50 MUg L(-1)) in the next year (group II). Participants with and without arsenical skin lesions were considered in the statistical analysis. Median dose of arsenic intake through drinking water in groups I and II males was 7.44 and 0.85 MUg kg body wt.(-1) day(-1) (p <0.0001). In females, it was 5.3 and 0.63 MUg kg body wt.(-1) day(-1) (p <0.0001) for groups I and II, respectively. Arsenic dose through diet was 3.3 and 2.6 MUg kg body wt.(-1) day(-1) (p = 0.088) in males and 2.6 and 1.9 MUg kg body wt.(-1) day(-1) (p = 0.0081) in females. Median arsenic levels in urine of groups I and II males were 124 and 61 MUg L(-1) (p = 0.052) and in females 130 and 52 MUg L(-1) (p = 0.0001), respectively. When arsenic levels in the water were reduced to below 50 MUg L(-1) (Indian permissible limit), total arsenic intake and arsenic intake through the water significantly decreased, but arsenic uptake through the diet was found to be not significantly affected. Moreover, it was found that drinking water mainly contributed to variations in urine arsenic concentrations. However, differences between male and female participants also indicate that not only arsenic uptake, but also many physiological factors affect arsenic behavior in the body and its excretion. As total median arsenic exposure still often exceeded 3.0 MUg kg body wt.(-1) day( 1) (the permissible lower limit established by the Joint Expert Committee on Food Additives) after installation of the drinking water filters, it can be concluded that supplying the filtered water only may not be sufficient to minimize arsenic availability for an already endemic population. PMID- 23818079 TI - Niosomal gel of lornoxicam for topical delivery: in vitro assessment and pharmacodynamic activity. AB - Lornoxicam is a potent oxicam class of non steroidal anti-inflammatory agent, prescribed for mild to moderate pain and inflammation. Niosomal gel of lornoxicam was developed for topical application. Lornoxicam niosomes (Lor-Nio) were fabricated by thin film hydration technique. Bilayer composition of niosomal vesicles was optimized. Lor-Nio dispersion was characterized by DSC, XRD, and FT IR. Morphological evaluation was performed by scanning electron microscopy (SEM). Lor-Nio dispersion was incorporated into a gel using 2% w/w Carbopol 980 NF. Rheological and texture properties of Lor-Nio gel formulation showed suitability of the gel for topical application. The developed formulation was evaluated for in vitro skin permeation and skin deposition studies, occlusivity test and skin irritation studies. Pharmacodynamic activity of the Lor-Nio gel was performed by carragenan-induced rat paw model. Optimized Lor-Nio comprised of Span 60 and cholesterol in a molar ratio of 3:1 with 30 MUM dicetyl palmitate as a stabilizer. It had particle size of 1.125 +/- 0.212 MUm (d 90), with entrapment efficiency of 52.38 +/- 2.1%. DSC, XRD, and IR studies showed inclusion of Lor into niosomal vesicles. SEM studies showed spherical closed vesicular structure with particles in nanometer range. The in vitro skin permeation studies showed significant improvement in skin permeation and skin deposition for Lor-Nio gel (31.41 +/- 2.24 MUg/cm(2), 30.079 +/- 1.2 MUg/cm(2)) over plain lornoxicam gel (7.37 +/- 1.27 MUg/cm(2), 6.6 +/- 2.52 MUg/cm(2)). The Lor-Nio gel formulation showed enhanced anti-inflammatory activity by exhibiting mean edema inhibition (87.69 +/- 1.43%) which was significantly more than the plain lornoxicam gel (53.84 +/- 2.21%). PMID- 23818081 TI - Note on the measurement of bulk density and tapped density of powders according to the European Pharmacopeia. AB - The apparent volume and compressibility index of commonly used excipients were evaluated according to European Pharmacopeia monograph (seventh edition) in order to study the influence of the procedure conditions. The results suggested that the leveling of the powder inside the cylinder ought to be avoided. PMID- 23818080 TI - Preparation and characterization of PEGylated amylin. AB - Amylin is a pancreatic hormone that plays important roles in overall metabolism and in glucose homeostasis. The therapeutic restoration of postprandial and basal amylin levels is highly desirable for patients with diabetes who need to avoid glucose excursions. Protein conjugation with polyethylene glycol (PEG) has long been known to be a convenient approach for extending the biological effects of biopharmaceuticals. We have investigated the reactivity of amylin with methoxy polyethylene glycol succinimidyl carbonate and methoxy polyethylene glycol succinimidyl propionate, which have an average molecular weight of 5 kDa. The reaction, which was conducted in both aqueous and organic (dimethyl sulfoxide) solvents, occurred within a few minutes and resulted in at least four detectable products with distinct kinetic phases. These results suggest a kinetic selectivity for PEGylation by succinimidyl derivatives; these derivatives exhibit enhanced reactivity with primary amine groups, as indicated by an evaluation of the remaining amino groups using fluorescamine. The analysis of tryptic fragments from mono- and diPEGylated amylin revealed that conjugation occurred within the 1 11 amino acid region, most likely at the two amine groups of Lys(1). The reaction products were efficiently separated by C-18 reversed phase chromatography. Binding assays confirmed the ability of mono- and diPEGylated amylin to interact with the amylin co-receptor receptor activity-modifying protein 2. Subcutaneous administration in mice revealed the effectiveness of monoPEG-amylin and diPEG amylin in reducing glycemia; both compounds exhibited prolonged action compared to unmodified amylin. These features suggest the potential use of PEGylated amylin to restore basal amylin levels. PMID- 23818083 TI - Hemophilia: in review. AB - Hemophilia A (deficiency in factor [F] VIII) and hemophilia B (deficiency in FIX) are the most common serious congenital coagulation factor deficiencies. (Based on strong evidence) Hemophilia is a genetic disorder inherited in an Xlinked fashion. Both diseases cause similar bleeding diatheses, with the hallmark being hemarthroses. (Based on strong evidence) The optimal treatment is recombinant factor replacement to prevent bleeding; however, this treatment has many barriers. (Based on strong evidence) The most serious complication of treatment is the development of inhibitors to factor products. (Based on strong evidence) Care for patients with hemophilia is most appropriate in a comprehensive care setting. (Based on strong evidence). PMID- 23818082 TI - Motion sensitivity and caloric responsiveness in vestibular migraine and Meniere's disease. AB - OBJECTIVES/HYPOTHESIS: We examined whether scores on a motion sensitivity questionnaire (MSQ) could distinguish between vestibular migraine (VM) and Meniere's disease (MD). As a secondary goal, we examined whether scores on the MSQ correlated with results from caloric testing. STUDY DESIGN: This study administered a telephone questionnaire to subjects who met clinical criteria for vestibular migraine, Meniere's disease, and controls. METHODS: A MSQ was administered to 20 subjects meeting American Academy of Otolaryngology (AAO) criteria for MD, 30 subjects meeting Neuhauser criteria for both probable vestibular migraine (pVM) and definite vestibular migraine (dVM), and 22 controls. RESULTS: The average score on the MSQ was 5.9 for VM, 4.25 for MD, and 0.4 for controls. Both the VM and MD scored significantly higher than the controls (P = 0.0001), but results were not statistically different from each other (P = 0.17). However, the average score for subjects with dVM was 7.1, which was significantly higher than subjects with pVM whose average score was 4.2 (P = 0.045) and higher than subjects with MD (P = 0.048). When each question of the MSQ was analyzed, motion sensitivity to riding in a car was found to be significantly different between VM (average score 1.1) and MD (average score 0.5), with P value of 0.048. Scores of MSQ did not correlate with the total eye speed (TES) on caloric testing. CONCLUSIONS: Subjects with VM and MD had elevated levels of motion sensitivity compared to controls. Subjects with VM had more motion sensitivity to riding in a car than those with MD, but their TES was not different. LEVEL OF EVIDENCE: 3b. PMID- 23818084 TI - Psychosis in children and youth: focus on early-onset schizophrenia. AB - On the basis of strong research evidence (1)(3) very early onset (VEOS) and early onset schizophrenia (EOS) carry significant morbidity and mortality risks for children and adolescents. On the basis of strong research evidence, the pathogenesis of EOS is linked to a dysregulation of dopamine and morphologic brain changes. (6)(7) On the basis of some research evidence and consensus, development of schizophrenia is the result of the interplay between genetic and environmental risk factors. (4) On the basis of strong research evidence, antipsychotic medications are the cornerstones of treatment for EOS. (11)(12)(13) On the basis of some research evidence and consensus, (13) treatment for schizophrenia should be timely, multimodal and multidisciplinary, including both pharmacologic and nonpharmacologic modalities tooptimize recovery. PMID- 23818085 TI - Vomiting. AB - Vomiting can be the presenting symptom of a variety of disorders, ranging from self-limited diseases to life-threatening diseases. The causes of vomiting vary with age of presentation, and pediatricians should develop the skill to identify serious conditions at the earliest stage based on the age of presentation. Bilious emesis at any age is a sign of intestinal obstruction until proven otherwise and needs immediate attention. Vomiting is not always due to a GI disorder, and pediatricians should look for causes outside the GI tract if no GI disease is identified. PMID- 23818086 TI - Index of suspicion. Case 1: abdominal pain, distension, hard stool, and diarrhea in an 11-year-old boy. Case 2: recurrent otitis media in a 4-year-old boy. Case 3: gynecomastia and galactorrhea in a 15-year-old boy. PMID- 23818087 TI - Wilms tumor. PMID- 23818088 TI - Visual diagnosis: newborn who has unilateral color change. Diagnosis: Harlequin color change. AB - HCC is a benign, transient, self-limited condition encountered in neonates. Prompt recognition is required to avoid unnecessary diagnostic testing. No treatment is needed, and parental reassurance is adequate. PMID- 23818089 TI - The impact of gene expression analysis on evolving views of avian brain organization. AB - Recent studies have presented data on adult and developing avian brain organization. Jarvis et al. ([2013] J Comp Neurol. 521:3614-3665) identify four pallial and two subpallial gene expression domains and demonstrate that the mesopallium and adjoining divisions of the hyperpallium (hyperpallium intercalatum and hyperpallium densocellulare), have very similar gene expression profiles to each other, distinct from those of the nidopallium, the arcopallium, and the more distant divisions of the hyperpallium (hyperpallium apicale). The study proposes an update of the current nomenclature (Jarvis et al. [2005] Nat Rev Neurosci. 6:151-159). The authors perform densitometric quantifications of the in situ expression of 50 selected genes, use correlations of distances between vectors that represent these gene expression patterns within the 23 avian brain regions of their study, and group them according to similarity in their expression profiles. The generated cluster tree further supports their argument for a new terminology. The authors hypothesize that the mesopallium and adjoining divisions of the hyperpallium have a common developmental origin, and in the accompanying paper (Chen et al. [2013] J Comp Neurol. 521:3666-3701) show that these structures/subdivisions initially form continuous gene expression domains. With subsequent development these domains fold into distinct subdivisions in the dorsal and ventral avian pallium, forming mirror images to each other. Jarvis et al. ([2013] J Comp Neurol. 521:3614-3665) also demonstrate interesting principles of the functional organization of the avian brain by showing that specific sensory stimulation or motor behavior elicits gene expression in functional units perpendicular to the axis of the gene expression reversal and compare their arrangements and cell types with mammalian cortical columns. PMID- 23818091 TI - Venom of the ectoparasitoid, Nasonia vitripennis, influences gene expression in Musca domestica hemocytes. AB - Insect hosts have evolved potent innate immunity against invasion by parasitoid wasps. Host/parasitoids live in co-evolutionary relationships. Nasonia vitripennis females inject venom into their dipteran hosts just prior to laying eggs on the host's outer integument. The parasitoid larvae are ectoparasitoids because they feed on their hosts within the puparium, but do not enter the host body. We investigated the influence of N. vitripennis venom on the gene expression profile of hemocytes of their hosts, pupae of the housefly, Musca domestica. We prepared venom by isolating venom glands and treated experimental host pupae with venom. We used suppression subtractive hybridization (SSH) to determine the influence of venom on hemocyte gene expression. At 1 h post treatment, we recorded decreases in transcript levels of 133 EST clones derived from forward a subtractive library of host hemocytes and upregulation in transcript levels of 111 EST clones from the reverse library. These genes are related to immune and stress response, cytoskeleton, cell cycle and apoptosis, metabolism, transport, and transcription/translation regulation. We verified the reliability of our data with reverse transcription quantitative real-time PCR analysis of randomly selected genes, and with assays of enzyme activities. These analyses showed that the expression level of all selected genes were downregulated after venom treatment. Outcomes of our experiments support the hypothesis that N. vitripennis venom influences the gene expression in host hemocytes. We conclude that the actions of venom on host gene expression influence host biology in ways that benefit the development and emergence of the next generation of parasitoids. PMID- 23818090 TI - Differences in cytochrome p450-mediated pharmacokinetics between chinese and caucasian populations predicted by mechanistic physiologically based pharmacokinetic modelling. AB - BACKGROUND: International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines emphasize the need for better understanding of the influence of ethnicity on drug response to minimize duplication of clinical studies, thereby expediting drug approval. OBJECTIVES: We have developed a Chinese database for the prediction of differences in the population kinetics of drugs mainly metabolized by cytochromes P450 (CYPs) relative to Caucasian populations. Such predictions should help to inform the need for duplication of in vivo pharmacokinetic studies in the two ethnic groups and the design of such studies. METHODS: Demographic and physiological data for Chinese, along with information on CYP abundances and the frequencies of associated genetic polymorphisms in Chinese, were collated from literature sources and incorporated within the Simcyp Population-based Simulator((r)) (v11.1). Default Simcyp parameter values for a virtual Caucasian population and for model compounds metabolized principally by specific CYPs were used as the point of reference. The drugs and the main CYPs involved in their metabolism were phenacetin (CYP1A2), desipramine (CYP2D6), tolbutamide (CYP2C9), omeprazole (CYP2C19), and alprazolam and midazolam (CYP3A). Hydroxy bupropion formation was used as a more sensitive marker of CYP2B6 activity than bupropion kinetics. Observed plasma drug concentration-time profiles and pharmacokinetic parameters after oral and, where possible, intravenous dosing were obtained from published in vivo studies in both Chinese and Caucasian subjects. Virtual subjects generated within Simcyp were matched to the subjects used in the in vivo studies with respect to age, sex, dosage and, where possible, CYP phenotype frequency. Predicted and observed plasma drug concentrations and weight normalized clearances were compared between the ethnic groups. RESULTS: Significant differences were identified between Chinese and Caucasian populations in the frequency of CYP2C19 poor metabolizers (PMs) [Chinese 13 %; Caucasian 2.4 %], CYP2D6 PMs and intermediate metabolizers (IMs) [Chinese PMs 0.3 %, IMs 39 %; Caucasian PMs 8 %, IMs <1 %], the hepatic abundance of CYP2C19 (mean values: Chinese 8 pmol/mg; Caucasian 14 pmol/mg) and liver weight (mean values: Chinese 1198 g; Caucasian 1603 g). The observed plasma drug concentration-time profiles and weight-normalized clearances were predicted with reasonable accuracy (100 % within twofold; 89 % within 1.5-fold) in both ethnic groups. The predicted phenacetin, tolbutamide, omeprazole, desipramine, midazolam (intravenous), midazolam (oral), alprazolam (intravenous) and alprazolam (oral) clearances were 36, 25, 51, 43, 24, 17, 21 and 22 % lower, respectively, in Chinese than in Caucasians; the observed clearances were 28, 2, 75, 42, 19, 62, 20 and 21 % lower, respectively. Predicted and observed formation of hydroxy bupropion was lower in Caucasians than in Chinese (6 and 20 %, respectively). Differences between ethnic groups were less after normalization for body weight. CONCLUSION: The results of this study indicate the value of simulation based on mechanistic physiologically based pharmacokinetic modelling (PBPK) in anticipating the likely extent of any differences in the kinetics of CYP substrates in Chinese and Caucasian populations arising from demographic, physiological and genetic differences. PMID- 23818092 TI - Spinal gout presenting as acute low back pain. PMID- 23818093 TI - Early blood lactate area as a prognostic marker in pediatric septic shock. AB - PURPOSE: We attempted to evaluate whether the early lactate area is useful as an early prognostic marker of mortality in pediatric septic shock patients. METHODS: We performed a retrospective study of pediatric patients with septic shock who were admitted to the pediatric intensive care unit of Asan Medical Center, Seoul, Korea. Serial arterial lactate levels were obtained immediately and then every 6 h after admission for a total of 24 h. The lactate area (mmol/lh) was defined as the sum of the area under the curve (AUC) of serial lactate levels measured during the 24 h following admission. We compared the lactate-associated parameters as a predictor of mortality. RESULTS: A total of 65 patients were included in this study, and the overall 28-day mortality of these patients was 26.2%. Survivors compared with non-survivors had an initial lactate level of 3.13 +/- 2.79 vs. 6.16 +/- 4.87 mmol/l, a lactate clearance of 32.8 +/- 63.4 vs. -30.8 +/- 75.6%, and a lactate area of 59.7 +/- 56.0 vs. 168.0 +/- 107.0 mmol/lh (p < 0.05 for all variables). Receiver operating characteristic curves indicated a strong predictive power for the lactate area (AUC = 0.828), which demonstrated the largest AUC in comparison with the AUCs of the initial lactate level (0.699) or the 24-h lactate clearance (0.719). Using multivariate logistic regression analysis, the lactate area was a significant prognostic factor. CONCLUSION: The early lactate area is a potentially feasible and clinically useful predictor of mortality in pediatric septic shock patients. PMID- 23818094 TI - Total synthesis of vinigrol. PMID- 23818095 TI - Diisopinocampheylborane-mediated reductive aldol reactions: highly enantio- and diastereoselective synthesis of syn aldols from N-acryloylmorpholine. PMID- 23818096 TI - The natural place to begin: the ethnoprimatology of the Waorani. AB - Ethnoprimatology is an important and growing discipline, studying the diverse relationships between humans and primates. However there is a danger that too great a focus on primates as important to humans may obscure the importance of other animal groups to local people. The Waorani of Amazonian Ecuador were described by Sponsel [Sponsel (1997) New World Primates: Ecology, evolution and behavior. New York: Aldine de Gruyter. p 143-165] as the "natural place" for ethnoprimatology, because of their close relationship to primates, including primates forming a substantial part of their diet. Therefore they are an ideal group in which to examine contemporary perceptions of primates in comparison to other types of animal. We examine how Waorani living in Yasuni National Park name and categorize primates and other common mammals. Although there is some evidence that the Waorani consider primates a unique group, the non-primate kinkajou and olingo are also included as part of the group "monkeys," and no evidence was found that primates were more important than other mammals to Waorani culture. Instead, a small number of key species, in particular the woolly monkey (Lagothrix poeppigii) and white-lipped peccary (Tayassu pecari), were found to be both important in the diet and highly culturally salient. These results have implications for both ethnoprimatologists and those working with local communities towards broader conservation goals. Firstly, researchers should ensure that they and local communities are referring to the same animals when they use broad terms such as "monkey," and secondly the results caution ethnoprimatologists against imposing western taxonomic groups on indigenous peoples, rather than allowing them to define themselves which species are important. PMID- 23818097 TI - Ionic strength-dependent conformations of a ubiquitin-like small archaeal modifier protein (SAMP1) from Haloferax volcanii. AB - Eukaryotic ubiquitin and ubiquitin-like systems play crucial roles in various cellular biological processes. In this work, we determined the solution structure of SAMP1 from Haloferax volcanii by NMR spectroscopy. Under low ionic conditions, SAMP1 presented two distinct conformations, one folded beta-grasp and the other disordered. Interestingly, SAMP1 underwent a conformational conversion from disorder to order with ion concentration increasing, indicating that the ordered conformation is the functional form of SAMP1 under the physiological condition of H. volcanii. Furthermore, SAMP1 could interact with proteasome-activating nucleotidase B, supposing a potential role of SAMP1 in the protein degradation pathway mediated by proteasome. PMID- 23818098 TI - Actinic keratosis among seafarers. AB - The aim of this study was to assess the prevalence of UV-induced actinic keratosis and further skin lesions. A newly developed questionnaire about lifetime UV radiation exposure was completed by 514 seafarers. An experienced dermatologist inspected the whole-body skin status of all participants. The questionnaire revealed a pre-employment UV radiation exposure in 104 seafarers, sunbed use in 26 subjects and a median work-related UV radiation exposure at sea of 20 years. The diagnosis of actinic keratoses was made in 94 seafarers and the clinical diagnosis of skin cancers in 48 seafarers (28 basal cell carcinoma, 11 squamous cell carcinoma, 9 malignant melanoma). After age standardisation according to a European reference population, the male European seafarers in this study had a 1.80-fold increased risk of actinic keratosis. Actinic keratoses [OR 1.03 (1.01-1.05)] and squamous cell carcinoma [OR 1.07 (1.01-1.13)] were related to the duration of seafaring time in years. A significant association was also found between actinic keratosis/squamous cell carcinoma and sunlight exposure during home leave [OR 1.67 (1.03-2.81) and OR 6.19 (1.18-32.40)]. Furthermore, the engine room personnel-especially the technical officers-were at higher risk of developing actinic keratosis. Due to the high prevalence of actinic keratosis especially among older seafarers with fair skin, with longer duration of seafaring employment at sea and with higher UV exposure during home leave, more intensive advice should be given on sun protection both at sea and ashore. PMID- 23818099 TI - Sterol regulatory element-binding protein 1 is required for ovarian tumor growth. AB - Re-programming of lipogenic signaling is one of the most significant alterations of tumor cell pathology. Consistent with a large demand for lipids, tumor cells express high levels of lipogenic enzymes, most of which are transcriptional targets of sterol regulatory element-binding protein 1 (SREBP1). However, the expression levels and the function of SREBP1 in ovarian cancer are largely unknown. Our study aimed to assess the oncogenic potential of SREBP1 in ovarian cancer. In this study, we showed that the SREBP1 protein expression was significantly higher in human ovarian cancer compared to benign and borderline ovarian tumors by immunohistochemical staining. Knockdown of SREBP1 by small hairpin RNA (shRNA) in ovarian cancer cells retarded cell growth, migration and invasion and enhanced cell apoptosis without significant effects on cell cycle distribution. In a xenograft SCID mouse model, SREBP1 silencing inhibited tumor growth in vivo and reduced the expression of SREBP1 downstream lipogenic genes at both the protein and mRNA levels. Taken together, the results from this study demonstrate a crucial role of SREBP1 in ovarian cancer growth, which establish SREBP1 as a novel therapeutic target for antitumor therapy. PMID- 23818100 TI - Thiamine for prevention and treatment of Wernicke-Korsakoff Syndrome in people who abuse alcohol. AB - BACKGROUND: Autopsy studies suggest that Wernicke-Korsakoff syndrome (WKS) is not a rare disorder, particularly in individuals who abuse alcohol. Thiamine has been established as the treatment of choice for over 50 years, but uncertainty remains about appropriate dosage and duration. Current practice guidelines are based on case reports and clinical experience. This is an update of a review first published in 2004 and last updated in 2008. OBJECTIVES: * To assess the efficacy of thiamine in preventing and treating the manifestations of WKS due to excess alcohol consumption. * To determine the optimum form, dose and duration of thiamine treatment for this indication. SEARCH METHODS: ALOIS, the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (CDCIG), The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL and LILACS were searched on 6 September 2012 using the term thiamine OR aneurine. ALOIS contains records from all major health care databases (The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS) as well as from many trial databases and grey literature sources. SELECTION CRITERIA: Any randomised trials comparing thiamine with alternative interventions or comparing different thiamine regimens (varying in formulation, dose or duration of administration). DATA COLLECTION AND ANALYSIS: All abstracts were independently inspected by two reviewers (ED and PWB), and relevant articles were retrieved and assessed for methodological quality using criteria provided in the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: Two studies were identified that met the inclusion criteria, but only one contained sufficient data for quantitative analysis. Ambrose (2001) randomly assigned participants (n = 107) to one of five doses of intramuscular thiamine and measured outcomes after 2 days of treatment. We compared the lowest dose (5 mg/day) with each of the other four doses. A significant difference favoured 200 mg/day compared with the 5-mg/day dose in determining the number of trials needed to meet inclusion criteria on a delayed alternation test (mean difference (MD) 17.90, 95% confidence interval (CI) -35.4 to -0.40, P = 0.04). No significant differences emerged when the other doses were compared with 5 mg/day. The pattern of results did not reflect a simple dose-response relationship. The study had methodological shortcomings in design and in the presentation of results that limited further analysis. AUTHORS' CONCLUSIONS: Evidence from randomised controlled clinical trials is insufficient to guide clinicians in determining the dose, frequency, route or duration of thiamine treatment for prophylaxis against or treatment of WKS due to alcohol abuse. PMID- 23818101 TI - A candidate gene approach for virally induced cancer with application to HIV related Kaposi's sarcoma. AB - Like other members of the gamma-herpesvirus family, human herpes virus 8, the etiologic agent of classic and HIV-related Kaposi's sarcoma (HIV-KS) acquired and evolved several human genes with key immune modulatory and cellular growth control functions. The encoded viral homologs substitute for their human counterparts but escape cellular regulation, leading to uncontrolled cell proliferation. We postulated that DNA variants in the human homologs of viral genes that potentially alter the expression or the binding of the encoded factors controlling the antiviral response may facilitate viral interference. To test whether cellular homologs are candidate susceptibility genes, we evaluated the association of DNA variants in 92 immune-related genes including seven cellular homologs with the risk for HIV-KS in a matched case and control study nested in the Multicenter AIDS Cohort Study. Low- and high-risk gene-by-gene interactions were estimated by multifactor dimensionality reduction and used as predictors in conditional logistic models. Among the most significant gene interactions at risk (OR=2.84-3.92; Bonferroni- adjusted p=9.9 * 10(-3) - 2.6 * 10(-4) ), three comprised human homologs of two latently expressed viral genes, cyclin D1 (CCND1) and interleukin-6 (IL-6), in conjunction with angiogenic genes (VEGF, EDN-1 and EDNRB). At lower significance thresholds (adjusted p < 0.05), human homologs related to apoptosis (CFLAR) and chemotaxis (CCL2) emerged as candidates. This "proof of concept" study identified human homologs involved in the regulation of type I interferon-induced signaling, cell cycle and apoptosis potentially as important determinants of HIV-KS. PMID- 23818102 TI - The self and its resting state in consciousness: an investigation of the vegetative state. AB - Recent studies have demonstrated resting-state abnormalities in midline regions in vegetative state/unresponsive wakefulness syndrome and minimally conscious state patients. However, the functional implications of these resting-state abnormalities remain unclear. Recent findings in healthy subjects have revealed a close overlap between the neural substrate of self-referential processing and the resting-state activity in cortical midline regions. As such, we investigated task related neural activity during active self-referential processing and various measures of resting-state activity in 11 patients with disorders of consciousness (DOC) and 12 healthy control subjects. Overall, the results revealed that DOC patients exhibited task-specific signal changes in anterior and posterior midline regions, including the perigenual anterior cingulate cortex (PACC) and posterior cingulate cortex (PCC). However, the degree of signal change was significantly lower in DOC patients compared with that in healthy subjects. Moreover, reduced signal differentiation in the PACC predicted the degree of consciousness in DOC patients. Importantly, the same midline regions (PACC and PCC) in DOC patients also exhibited severe abnormalities in the measures of resting-state activity, that is functional connectivity and the amplitude of low-frequency fluctuations. Taken together, our results provide the first evidence of neural abnormalities in both the self-referential processing and the resting state in midline regions in DOC patients. This novel finding has important implications for clinical utility and general understanding of the relationship between the self, the resting state, and consciousness. PMID- 23818104 TI - MicroRNA-339 and microRNA-556 regulate Klotho expression in vitro. AB - Klotho is an anti-aging protein with direct effects on life-span in mice. Klotho functions to regulate pathways classically associated with longevity including insulin/IGF1 and Wnt signaling. Decreased Klotho protein expression is observed throughout the body during the normal aging process. While increased methylation of the Klotho promoter is reported, other epigenetic mechanisms could contribute to age-related downregulation of Klotho expression, including microRNA-mediated regulation. Following in silico identification of potential microRNA binding sites within the Klotho 3' untranslated region, reporter assays reveal regulation by microRNA-339, microRNA-556, and, to a lesser extent, microRNA-10 and microRNA 199. MicroRNA-339 and microRNA-556 were further found to directly decrease Klotho protein expression indicating that, if upregulated in aging tissue, these microRNA could play a role in age-related downregulation of Klotho messenger RNA. These microRNAs are differentially regulated in cancer cells compared to normal cells and may imply a role for microRNA-mediated regulation of Klotho in cancer. PMID- 23818103 TI - Physical capability and subsequent positive mental wellbeing in older people: findings from five HALCyon cohorts. AB - Objective measures of physical capability are being used in a growing number of studies as biomarkers of healthy ageing. However, very little research has been done to assess the impact of physical capability on subsequent positive mental wellbeing, the maintenance of which is widely considered to be an essential component of healthy ageing. We aimed to test the associations of grip strength and walking, timed get up and go and chair rise speeds (assessed at ages 53 to 82 years) with positive mental wellbeing assessed using the Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS) 5 to 10 years later. Data were drawn from five British cohorts participating in the Healthy Ageing across the Life Course research collaboration. Data from each study were analysed separately and then combined using random-effects meta-analyses. Higher levels of physical capability were consistently associated with higher subsequent levels of wellbeing; for example, a 1SD increase in grip strength was associated with an age and sex-adjusted mean difference in WEMWBS score of 0.81 (0.25, 1.37), equivalent to 10 % of a standard deviation (three studies, N = 3,096). When adjusted for body size, health status, living alone, socioeconomic position and neuroticism the associations remained albeit attenuated. The finding of these consistent modest associations across five studies, spanning early and later old age, highlights the importance of maintaining physical capability in later life and provides additional justification for using objective measures of physical capability as markers of healthy ageing. PMID- 23818105 TI - Diagnostic criteria for sarcopenia and physical performance. AB - Relative and absolute muscle mass and muscle strength are used as diagnostic criteria for sarcopenia. We aimed to assess which diagnostic criteria are most associated with physical performance in 180 young (18-30 years) and 281 healthy old participants (69-81 years) of the European study MYOAGE. Diagnostic criteria included relative muscle mass (total or appendicular lean mass (ALM) as percentage of body mass), absolute muscle mass (ALM/height squared and total lean mass), knee extension torque, and handgrip strength. Physical performance comprised walking speed, Timed Up and Go test (TUG), and in a subgroup physical fitness. Diagnostic criteria for sarcopenia and physical performance were standardized, and the associations were analyzed using linear regression models stratified by age category, with adjustments for age, gender, and country. In old participants, relative muscle mass was associated with faster walking speed, faster TUG, and higher physical fitness (all p < 0.001). Absolute muscle mass was not associated with physical performance. Knee extension torque and handgrip strength were associated with faster walking speed (both p <= 0.003). Knee extension torque was associated with TUG (p = 0.001). Knee extension torque and handgrip strength were not associated with physical fitness. In young participants, there were no significant associations between diagnostic criteria for sarcopenia and physical performance, except for a positive association between relative muscle mass and physical fitness (p < 0.001). Relative muscle mass, defined as lean mass or ALM percentage, was most associated with physical performance. Absolute muscle mass including ALM/height squared was not associated with physical performance. This should be accounted for when defining sarcopenia. PMID- 23818106 TI - Effect of blood bank storage on the rheological properties of male and female donor red blood cells. AB - It was previously demonstrated that red blood cell (RBC) deformability progressively decreases during storage along with other changes in RBC mechanical properties. Recently, we reported that the magnitude of changes in RBC mechanical fragility associated with blood bank storage in a variety of additive solutions was strongly dependent on the donor gender [15]. Yet, the potential dependence of changes in the deformability and relaxation time of stored blood bank RBCs on donor gender is not known. The objective of this study was to determine the effects of donor gender and blood bank storage on RBC deformability and relaxation time through the measurement of RBC suspension viscoelasticity. Packed RBC units preserved in AS-5 solution from 12 male and 12 female donors (three from each ABO group) were obtained from the local blood center and tested at 1, 4 and 7 weeks of storage at 1-6 degrees C. At each time point, samples were aseptically removed from RBC units and hematocrit was adjusted to 40% before assessment of cell suspension viscoelasticity. RBC suspensions from both genders demonstrated progressive increases (p < 0.05) in viscosity, elasticity and relaxation time at equivalent shear rates over seven weeks of storage indicating a decrease in RBC deformability. No statistically significant differences in RBC deformability or relaxation time were observed between male and female RBCs at any storage time. The decrease in RBC deformability during blood bank storage may reduce tissue perfusion and RBC lifespan in patients receiving blood bank RBCs. PMID- 23818107 TI - Molecular analysis of fungal diversity associated with three bryophyte species in the Fildes Region, King George Island, maritime Antarctica. AB - The fungal communities associated with three bryophytes species (the liverwort Barbilophozia hatcheri, the mosses Chorisodontium aciphyllum and Sanionia uncinata) in the Fildes Region, King George Island, maritime Antarctica, were studied using clone library analysis. Fungal communities showed low diversity; the 680 clones belonged to 93 OTUs. Of these, 78 belonged to the phylum Ascomycota, 13 to the phylum Basidiomycota, 1 to the phylum Zygomycota, and 1 to an unknown phylum. Among the OTUs, the most common orders in the Ascomycota were Helotiales (42 OTUs) and Chaetothyriales (14 OTUs) and the most common orders in the Basidiomycota were Sebacinales (3 OTUs) and Platygloeales (3 OTUs). Most OTUs clustered within clades that contained phylotypes identified from samples in Antarctic or Arctic ecosystems or from bryophytes in other ecosystems. In addition, we found that host-related factor may shape the fungal communities associated with bryophytes in this region. This is the first systematic study of the fungal community in Antarctic bryophytes to be performed using culture independent method and the results may improve understanding of the endophytic fungal evolution and ecology in the Antarctic ecosystem. PMID- 23818108 TI - A new treatment paradigm for trigeminal neuralgia using Botulinum toxin type A. AB - OBJECTIVES: To review the current data for the use of Botulinum toxin type A (BoNT-A) in trigeminal neuralgia (TN) and to describe the preferred injection technique of BoNT-A in TN. To propose a new treatment paradigm for TN incorporating the use BoNT-A. DATA SOURCES: MEDLINE and Google Scholar databases. REVIEW METHODS: The current data on BoNT-A for TN were reviewed and analyzed for outcomes. RESULTS: Seven studies examining the use of BoNT-A were identified: Two randomized double-blind, placebo-controlled studies and five prospective case series. All studies found BoNT-A to be an effective treatment in the majority of patients; and the results of the two randomized double-blind placebo-controlled study showed significant benefit over placebo. The majority of studies used an intradermal or subcutaneous injection technique. The most common side effect was transient facial paresis. CONCLUSIONS: BoNT-A offers a safe, effective, local treatment for TN that is nonablative in nature. BoNT-A should be considered in patients who have failed, become refractory to, or are unable to tolerate first line pharmacologic treatments. LEVEL OF EVIDENCE: N/A. PMID- 23818109 TI - The impact of tumor necrosis factor alpha inhibitors on radiographic progression in ankylosing spondylitis. AB - OBJECTIVE: To study the effect of tumor necrosis factor alpha (TNFalpha) inhibitors on progressive spinal damage in patients with ankylosing spondylitis (AS). METHODS: All AS patients meeting the modified New York criteria who had been monitored prospectively and had at least 2 sets of spinal radiographs a minimum of 1.5 years apart were included in the study (n=334). The patients received standard therapy, which included nonsteroidal antiinflammatory drugs and TNFalpha inhibitors. Radiographic severity was assessed by the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Patients with a rate of AS progression that was >=1 mSASSS unit/year were considered progressors. Univariable and multivariable regression analyses were done. Propensity score matching and sensitivity analysis were performed. A zero-inflated negative binomial (ZINB) model was used to analyze the effect of TNFalpha inhibitors on the change in the mSASSS with varying followup periods. Potential confounders, such as disease activity (as assessed by the Bath Ankylosing Spondylitis Disease Activity Index), the erythrocyte sedimentation rate, C-reactive protein level, HLA-B27 positivity, sex, age at onset, smoking burden (number of pack-years), and baseline damage, were included in the model. RESULTS: TNFalpha inhibitor treatment was associated with a 50% reduction in the odds of progression, with an odds ratio (OR) of 0.52 (95% confidence interval [95% CI] 0.30-0.88, P=0.02). Patients with a delay of >10 years in starting therapy were more likely to experience progression as compared to those who started earlier (OR 2.4 [95% CI 1.09-5.3], P=0.03). In the ZINB model, the use of TNFalpha inhibitors significantly reduced disease progression when the gap between radiographs was >3.9 years. The protective effect of TNFalpha inhibitors was stronger after propensity score matching. CONCLUSION: Treatment with TNFalpha inhibitors appears to reduce radiographic progression in AS patients, especially with early initiation and with longer duration of followup. PMID- 23818110 TI - Different responses of two highly permissive cell lines upon HCV infection. AB - The construction of the first infectious clone JFH-1 speeds up the research on hepatitis C virus (HCV). However, Huh7 cell line was the only highly permissive cell line for HCV infection and only a few clones were fully permissive. In this study, two different fully permissive clones of Huh7 cells, Huh7.5.1 and Huh7 Lunet-CD81 (Lunet-CD81) cells were compared for their responses upon HCV infection. The virus replication level was found slightly higher in Huh7.5.1 cells than that in Lunet-CD81 cells. Viability of Huh7.5.1 cells but not of Lunet CD81 cells was reduced significantly after HCV infection. Further analysis showed that the cell cycle of infected Huh7.5.1 cells was arrested at G1 phase. The G1/S transition was blocked by HCV infection in Huh7.5.1 cells as shown by the cell cycle synchronization analysis. Genes related to cell cycle regulation was modified by HCV infection and gene interaction analysis in GeneSpring GX in Direct Interactions mode highlighted 31 genes. In conclusion, the responses of those two cell lines were different upon HCV infection. HCV infection blocked G1/S transition and cell cycle progress, thus reduced the cell viability in Huh7.5.1 cells but not in Lunet-CD81 cells. Lunet-CD81 cells might be suitable for long term infection studies of HCV. PMID- 23818113 TI - Ruthenium-NHC-catalyzed asymmetric hydrogenation of flavones and chromones: general access to enantiomerically enriched flavanones, flavanols, chromanones, and chromanols. PMID- 23818111 TI - TRIM22 inhibits the TRAF6-stimulated NF-kappaB pathway by targeting TAB2 for degradation. AB - Tripartite motif containing 22 (TRIM22), a member of the TRIM/RBCC family, has been reported to activate the nuclear factor-kappa B (NF-kappaB) pathway in unstimulated macrophage cell lines, but the detailed mechanisms governing this activation remains unclear. We investigated this mechanism in HEK293T cells. We found that overexpression of TRIM22 could activate the NF-kappaB pathway and conversely, could inhibit the tumor necrosis factor receptor-associated factor 6 (TRAF6)-stimulated NF-kappaB pathway in HEK293T cells. Further experiments showed that TRIM22 could decrease the self-ubiquitination of TRAF6, and interact with and degrade transforming growth factor-beta activated kinase 1 binding protein 2 (TAB2), and that these effects could be partially rescued by a TRIM22 RING domain deletion mutant. Collectively, our data indicate that overexpression of TRIM22 may negatively regulate the TRAF6-stimulated NF-kappaB pathway by interacting with and degrading TAB2. PMID- 23818114 TI - Near-infrared-emitting Cd(x)Hg(1-x)Se nanorods fabricated by ion exchange in an aqueous medium. AB - Whereas CdSe nanorods that are grown in organic solution have a hexagonal wurtzite structure, which is the limiting case for exchange, HgSe is more commonly encountered as a cubic zinc blende system. An exchange process was performed at room temperature and at atmospheric pressure in an aqueous environment after phase transfer of the original CdSe nanorods, which reinforced the tendency for the endpoint of HgSe to be cubic. Consequently, we observed that under ambient conditions, the exchange process terminated with an average composition of only Cd(0.9)Hg(0.1)Se. Following the changes during the process by optical spectroscopy and high angle annular dark field (HAADF) scanning transmission electron microscopy (STEM), we observed that the Hg(2+) ions diffused into the rods to a point limited by the formation of stacking faults due to the different lattice structures of the two limiting cases of zinc blende and wurtzite. HAADF-STEM and energy dispersive spectroscopy analyses also confirmed that the Hg substitution did not occur uniformly throughout the individual nanorods, as Hg-poor and Hg-rich regions coexist around the stacking faults. The formation of near-infrared-emitting alloyed Cd(x)Hg(1-x)Se nanorods in an aqueous medium highlights the subtle dependence of the ion-exchange process on the differences in the crystal structures of the two endpoint lattices. PMID- 23818115 TI - Laryngotracheal reconstruction with autogenous rib cartilage graft for complex laryngotracheal stenosis and/or anterior neck defect. AB - To study the effectiveness of laryngotracheal reconstruction with rib cartilage graft for complex laryngotracheal stenosis and/or anterior neck defect, 62 patients with complex laryngotracheal stenosis and/or anterior neck defect underwent laryngotracheal reconstruction with autogenous rib cartilage graft. The surgical procedures were laryngotracheotomy with rib cartilage graft interposition and silicon-tube stent placed in the region of laryngotracheal stenosis and/or anterior neck defect for the period of between 10 days and 12 months. Three patients with complex subglottic stenosis and anterior neck defects underwent a single-stage reconstruction with a combined rib cartilage graft interposition and fasciocutaneous flap reparation. One patient with a complex subglottic and superior thoracic tracheal stenosis underwent a staged operation. Of the 62 patients, 46 patients (74.1%) were successfully decannulated. One patient had combined subglottic stenosis, which was healed, and superior thoracic tracheal stenosis, which is undergoing treatment. 15 patients (24.2%) had failure in decannulation due to either wound infection followed by rib cartilage necrosis, or granulation tissue formation and restenosis. Of these 15 patients, ten required revision operations and delayed healing. The duration of follow-up ranged from 1 to 10 years. Of 46 patients, who were successfully decannulated, 36 had a satisfactory airway and a functional voice; two had restenosis due to partial laryngectomy for laryngocarcinoma recurrence 1 year after decannulation; eight were lost to follow-up after successfully decannulated. We conclude that this method can provide effective treatment for complex laryngotracheal stenosis and/or anterior neck defects. It is relatively simple with a high decannulation rate in selected patients. PMID- 23818116 TI - Polysensitisation to pollen due to profilin and calcium-binding protein: distribution of IgE antibodies to marker allergens in grass and birch pollen allergic rhinitis patients in southern Germany. AB - Allergen-specific immunotherapy for grass pollen allergy has been reported to be effective in up to 85% of patients. Sensitisation to profilin and calcium-binding protein (CBP) can possibly influence treatment results and may thus be a reason for treatment failures. During a study period of 3 years, the distribution patterns of antibodies to marker allergens were continuously investigated in all blood serum samples with a level of immunoglobulin E antibodies to timothy and birch pollen higher than 0.7 kUA/l (n = 556). Sensitisation to timothy grass pollen alone was found in 33% of the cases, to birch pollen alone in 19%, and to both in 48%. The group of polysensitised patients showed an inhomogenous distribution of antibodies to marker allergens. IgE against minor allergens was detected in 40%. Sensitisation to major allergens, especially to the major birch allergen, was not present in 13% of the polysensitised patients. Of the patients who were sensitised to minor allergens, 82% were sensitised to profilin, 11% to CBP, and 8% to both profilin and CBP. Profilin and CBP frequently cause polysensitisations to pollen. The data obtained justify the measurement of serum levels of antibodies to marker allergens in patients who are sensitised to more than one group of allergens. PMID- 23818117 TI - Persistent benign paroxysmal positional vertigo: our experience and proposal for an alternative treatment. AB - Benign paroxysmal positional vertigo (BPPV) is the most common cause of vertigo. Despite the great efficacy of canalith repositioning procedures (CRPs), BPPV may persist (PBPPV). The aim of the study was to evaluate whether a prolonged and self-assessed temporal bone vibration (TBV) could change the outcome of PBPPV after 12 months of repeated treatments, in order to avoid further invasive and/or drug therapies. This evaluation was also conducted with respect to the entire BPPV population treated with CRPs. Seventy-two patients affected by PBPPV were enrolled in the study: 51 and 21 of them suffering from posterior semicircular canal (PSC) and lateral semicircular canal (LSC), respectively. PBPPV patients underwent a twice-a-day self-assessed TBV, using a common low-intensity massaging cushion. Patients were re-tested 1 week later and they were considered free from disease as the results of the positioning tests continued to be negative after 1 month. 70.6 % of PSC PBPPV and 61.9 % of LSC PBPPV patients had positive and statistically significant (P < 0.01) outcomes not biased by "age" and "gender" variables. The recurrence rate of BPPV (RBPPV) was also studied in the BPPV and PBPPV groups after a 12/24-month follow-up and any statistically significant result was found in multiple regression analysis between nuisance variables and RBPPV patients previously treated by CRPs or TBV. The present study suggests that the self-assessed and prolonged TBV could be an alternative treatment in patients affected by PBPPV otherwise addressed to undergo more invasive procedures and pharmacological treatment that are not completely side effects free. PMID- 23818118 TI - Is fat talking a causal risk factor for body dissatisfaction? A systematic review and meta-analysis. AB - OBJECTIVE: Fat talking has been assumed to be a causal risk factor for body dissatisfaction in a number of prevention programs and body confidence campaigns. The aim of this paper was to assess whether fat talking meets three criteria necessary for causal risk factors, namely whether fat talking is: (a) cross sectionally associated with body dissatisfaction; (b) prospectively associated with changes in body dissatisfaction; and (c) associated with changes in body dissatisfaction in experimental studies. METHOD: A systematic literature review was conducted using electronic databases and hand searching of relevant journals. Meta-analyses provided pooled effect size estimates, and meta-regressions were used to determine whether age, gender or risk of bias were effect modifiers of the relationship. RESULTS: Searches revealed 24 studies. There was a significant cross-sectional association (r = 0.297, 95% CI = 0.225-0.349), which differed in strength between age groups and genders. There was a prospective association between fat talking and changes in body dissatisfaction in long term (r = 0.144, 95% CI = 0.050-0.234), but not in short-term studies (r = 0.022, 95% CI = -0.131 0.174). One study showed that experimental exposure to fat talking was associated with increases in body dissatisfaction (d = 0.124). DISCUSSION: As such, there is good evidence that fat talking is a correlate of body dissatisfaction. The few prospective and experimental studies give an initial indication that fat talking is a causal risk factor for body dissatisfaction. Further work is needed to support this position. PMID- 23818119 TI - Highly-accelerated Bloch-Siegert |B1+| mapping using joint autocalibrated parallel image reconstruction. AB - PURPOSE: To reconstruct accurate single- and multichannel Bloch-Siegert transmit radiofrequency (|B(1)(+)|) field maps from highly accelerated data. THEORY AND METHODS: The approach is based on the fact that the |B(1)(+)|-to-phase encoding pulse for each transmit coil and off-resonance frequency applies a unique phase shift to the same underlying image. This enables joint reconstruction of all images in a Bloch-Siegert acquisition from an augmented set of virtual receive coils, using any autocalibrated parallel imaging reconstruction method. RESULTS: Simulations with an eight channel transmit/receive array head coil at 7T show that accurate |B(1)(+)| maps can be produced at acceleration factors of 16* and 6* for Cartesian and spiral sampling, respectively. A phantom experiment with a six channel transverse electromagnetic (TEM) transceive array coil allowed accurate reconstruction at 16* acceleration. 7T in vivo experiments performed using 32 channel receive and two-channel transmit coils further demonstrate the proposed method's ability to produce high-quality |B(1)(+)| maps at accelerations of 32* and 8* for Cartesian and spiral trajectories, respectively. Reconstruction accuracy is improved using disjoint k-space sampling patterns between acquisitions. CONCLUSION: The proposed approach allows high acceleration factors in Bloch-Siegert |B(1)(+)| mapping and can significantly reduce the scan time requirements for mapping the |B(1)(+)| fields of transmit arrays. PMID- 23818120 TI - Steroids for idiopathic sudden sensorineural hearing loss. AB - BACKGROUND: This is an update of a Cochrane review first published in The Cochrane Library in Issue 1, 2006 and previously updated in 2009.Idiopathic sudden sensorineural hearing loss (ISSHL) is a clinical diagnosis characterised by a sudden deafness of cochlear or retrocochlear origin in the absence of a clear precipitating cause. Steroids are commonly prescribed to treat this condition. There is no consensus on their effectiveness. OBJECTIVES: To determine whether steroids in the treatment of ISSHL a) improve hearing (primary) and b) reduce tinnitus (secondary).To determine the incidence of significant side effects from the medication. SEARCH METHODS: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was 22 April 2013. SELECTION CRITERIA: We identified all randomised controlled trials (with or without blinding) in which steroids were evaluated in comparison with either no treatment or a placebo. We considered trials including the use of steroids in combination with another treatment if the comparison control group also received the same other treatment. The two authors reviewed the full-text articles of all the retrieved trials of possible relevance and applied the inclusion criteria independently. DATA COLLECTION AND ANALYSIS: We graded trials for risk of bias using the Cochrane approach. The data extraction was performed in a standardised manner by one author and rechecked by the other author. Where necessary we contacted investigators to obtain the missing information. Meta-analysis was neither possible nor considered appropriate because of the heterogeneity of the populations studied and the differences in steroid formulations, dosages and duration of treatment. We analysed and reported the quality of the results of each study individually. A narrative overview of the results is presented. MAIN RESULTS: Only three trials, involving 267 participants, satisfied the inclusion criteria and all three studies were at high risk of bias. One trial showed a lack of effect of oral steroids in improving hearing compared with the placebo control group. The second trial showed a significant improvement of hearing in 61% of the patients receiving oral steroid and in only 32% of the patients from the control group (combination of placebo-treated group and untreated control group). The third trial also showed a lack of effect of oral steroids in improving hearing compared with the placebo control. However, this trial did not follow strict inclusion criteria for participant selection and analysis of data was limited by significant exclusion of participants from the final analysis and lack of participant compliance to the treatment protocol. No clear evidence was presented in two trials about any harmful side effects of the steroids. Only one study declared that no patients suffered from adverse effects of the steroid treatment. AUTHORS' CONCLUSIONS: The value of steroids in the treatment of idiopathic sudden sensorineural hearing loss remains unclear since the evidence obtained from randomised controlled trials is contradictory in outcome, in part because the studies are based upon too small a number of patients. PMID- 23818121 TI - Acute changes in electromechanical parameters during different pacing configurations using a quadripolar left ventricular lead. AB - PURPOSE: Quadripolar left ventricular (LV) leads allow for several pacing configurations in candidates for cardiac resynchronization therapy (CRT). Whether different pacing configurations may affect LV dyssynchrony and systolic function is not completely known. We aimed to evaluate the acute effects of different pacing vectors on LV electromechanical parameters in patients implanted with a quadripolar LV lead. METHODS: In this two-centre study, within 1 month of implantation 21 CRT patients (65 +/- 8 years, 76 % men, 38 % ischemic) receiving a quadripolar LV lead (Quartet 1458Q, St Jude Medical) underwent LV capture threshold assessment, intracardiac electrogram optimization, and two-dimensional echocardiography during four pacing configurations: D1-P4, P4-RV coil, D1-RV coil, and P4-M2. LV dyssynchrony and contractile function were expressed by septal-to-lateral delay and global longitudinal strain (GLS). RESULTS: LV capture threshold varied between the configurations (P < 0.001), showing higher values in the configurations P4-RV coil and P4-M2. Septal-to-lateral delay decreased in the configurations D1-P4 and D1-RV coil (P = 0.003 and P = 0.033 vs. spontaneous rhythm, respectively). GLS improved significantly vs. spontaneous rhythm only in the configuration D1-P4 (from -8.6 +/- 3.5 to -11.0 +/- 3.2 %, P = 0.001). Accordingly, an increase in stroke volume and a decrease in mitral regurgitation were observed in the configuration D1-P4 (P <= 0.001 vs. spontaneous rhythm). CONCLUSIONS: In CRT patients receiving a quadripolar LV lead, significant variations in electromechanical parameters were observed by changing pacing vector. Individually targeting the optimal pacing site may enhance the acute haemodynamic response to CRT. PMID- 23818123 TI - Factors associated with lymph node metastasis in radically resected rectal carcinoids: a systematic review and meta-analysis. AB - BACKGROUND: Although various guidelines regarding neuroendocrine tumors were released, treatment for rectal neuroendocrine tumors with size between 1 and 2 cm has not been explicitly elucidated. The determinant factor of the choice between endoscopic resection and radical surgery is whether lymph node involvement exists. AIM: This study aims to explore factors associated with lymph node involvement in rectal neuroendocrine tumors by conducting a meta-analysis. METHODS: A broad literature research of Pubmed, Embase&Medline, and The Cochrane Library was performed, and systematic review and meta-analysis about factors associated with lymph node involvement were conducted. RESULTS: Seven studies were included in this meta-analysis. Tumor size > 1 cm (odds ratio (OR) 6.72, 95% confidence interval (CI) [3.23, 14.02]), depth of invasion (OR 5.06, 95% CI [2.30, 11.10]), venous invasion (OR 5.92, 95% CI [2.21, 15.87]), and central depression (OR 3.00, 95% CI [1.07, 8.43]) were significantly associated with lymph node involvement. CONCLUSION: The available clinical evidence suggests that tumor size > 1 cm, invasion of muscularis properia, venous invasion, and central depression could be risk factors of lymph node involvement, while other factors reported by few studies need further research. PMID- 23818122 TI - Global view of the functional molecular organization of the avian cerebrum: mirror images and functional columns. AB - Based on quantitative cluster analyses of 52 constitutively expressed or behaviorally regulated genes in 23 brain regions, we present a global view of telencephalic organization of birds. The patterns of constitutively expressed genes revealed a partial mirror image organization of three major cell populations that wrap above, around, and below the ventricle and adjacent lamina through the mesopallium. The patterns of behaviorally regulated genes revealed functional columns of activation across boundaries of these cell populations, reminiscent of columns through layers of the mammalian cortex. The avian functionally regulated columns were of two types: those above the ventricle and associated mesopallial lamina, formed by our revised dorsal mesopallium, hyperpallium, and intercalated hyperpallium; and those below the ventricle, formed by our revised ventral mesopallium, nidopallium, and intercalated nidopallium. Based on these findings and known connectivity, we propose that the avian pallium has four major cell populations similar to those in mammalian cortex and some parts of the amygdala: 1) a primary sensory input population (intercalated pallium); 2) a secondary intrapallial population (nidopallium/hyperpallium); 3) a tertiary intrapallial population (mesopallium); and 4) a quaternary output population (the arcopallium). Each population contributes portions to columns that control different sensory or motor systems. We suggest that this organization of cell groups forms by expansion of contiguous developmental cell domains that wrap around the lateral ventricle and its extension through the middle of the mesopallium. We believe that the position of the lateral ventricle and its associated mesopallium lamina has resulted in a conceptual barrier to recognizing related cell groups across its border, thereby confounding our understanding of homologies with mammals. PMID- 23818124 TI - An envirogenomic signature is associated with risk of IBD-related surgery in a population-based Crohn's disease cohort. AB - BACKGROUND AND AIMS: Crohn's disease (CD) is an inflammatory bowel disease (IBD) caused by a combination of genetic, clinical, and environmental factors. Identification of CD patients at high risk of requiring surgery may assist clinicians to decide on a top-down or step-up treatment approach. METHODS: We conducted a retrospective case-control analysis of a population-based cohort of 503 CD patients. A regression-based data reduction approach was used to systematically analyse 63 genomic, clinical and environmental factors for association with IBD-related surgery as the primary outcome variable. RESULTS: A multi-factor model was identified that yielded the highest predictive accuracy for need for surgery. The factors included in the model were the NOD2 genotype (OR = 1.607, P = 2.3 * 10(-5)), having ever had perianal disease (OR = 2.847, P = 4 * 10(-6)), being post-diagnosis smokers (OR = 6.312, P = 7.4 * 10(-3)), being an ex-smoker at diagnosis (OR = 2.405, P = 1.1 * 10(-3)) and age (OR = 1.012, P = 4.4 * 10(-3)). Diagnostic testing for this multi-factor model produced an area under the curve of 0.681 (P = 1 * 10(-4)) and an odds ratio of 3.169, (95% CI P = 1 * 10(-4)) which was higher than any factor considered independently. CONCLUSIONS: The results of this study require validation in other populations but represent a step forward in the development of more accurate prognostic tests for clinicians to prescribe the most optimal treatment approach for complicated CD patients. PMID- 23818125 TI - Extent of lymphadenectomy does not predict survival in patients treated with primary esophagectomy. AB - BACKGROUND: The number of lymph nodes resected and its impact on survival for patients with esophageal cancer remains undefined. Current guidelines recommend extended lymphadenectomy in patients not receiving neoadjuvant therapy. We reviewed our single institutional experience with nodal harvest for esophageal cancer in a non-neoadjuvant therapy setting. METHODS: Patients who underwent esophagectomy as primary therapy were indentified from a prospectively maintained database consisting of 704 patients who underwent esophagectomy. Patients were stratified by number of lymph nodes (LN) resected: >5, 10, 12, 15, or 20. Survival, clinical, and pathologic parameters were analyzed with Kaplan-Meier curves, chi-square, or Fisher's exact tests where appropriate. RESULTS: We identified 246 patients who underwent esophagectomy as initial treatment. The mean age was 65 +/-10 years. The majority of patients were male (87%). Ivor-Lewis esophagectomy was performed for 71%, minimally invasive esophagectomy for 15%, transhiatal esophagectomy for 12%, and three-field esophagectomy for 2%. At 60 months follow-up, there was no statistically significant difference in overall survival (OS) or disease-free survival (DFS) between patients with < vs. >5 LN resected (p = 0.74 and p = 0.67, respectively) or in the < vs. >10 (p = 0.33, p = 0.11), 12 (p = 0.82, p = 0.90), 15 (p = 0.45, p = 0.79), or 20 (p = 0.72, p = 0.86) resected LN groups. Patients were then subdivided into node-positive and node-negative cohorts and stratified by nodal harvest. In the subgroups of patients with node-negative and node-positive disease, OS and DFS also did not significantly differ between groups with respect to number of nodes resected (p > 0.05). A total of 49 (20%) patients developed recurrent disease; however, recurrence was not statistically associated with number of LN resected (p > 0.05). CONCLUSION: We found no impact of extent of lymphadenectomy on overall or disease-free survival in patients treated with esophagectomy without neoadjuvant therapy. In addition, the number of nodes resected at esophagectomy did not affect recurrence rates. Current recommendations for increased nodal resection during esophagectomy in patients not receiving neoadjuvant therapy may not improve patient outcomes, and this phenomenon warrants further investigation. PMID- 23818126 TI - Biliary dyskinesia: does it exist? If so, how do we diagnose it? Is laparoscopic cholecystectomy effective or a sham operation? PMID- 23818127 TI - Patient recall 6 weeks after surgical consent for midurethral sling using mesh. AB - INTRODUCTION AND HYPOTHESIS: We aimed to determine patient recall of specific surgical risks and benefits discussed during consent for midurethral sling (MUS) surgery immediately after consent and at 6 weeks follow-up. Specifically we sought to determine whether or not women recalled specific risks related to the placement of mesh. METHODS: Surgeons consented patients for MUS in their usual fashion during audio recorded consent sessions. After consent and again at 6 weeks postoperatively, women completed a checklist of risks, benefits, alternatives, and general procedural items covered during consent. In addition, women completed the Decision Regret Scale for Pelvic Floor Disorders (DRS-PFD). Audio files were used to verify specific risks, benefits, alternatives, and procedural items discussed at consent. Recall of specific risks, benefits, and alternatives were correlated with DRS-PFD scores. RESULTS: Sixty-three women completed checklists immediately post consent and at 6 weeks postoperatively. Six week recall of benefits, alternatives, and description of the operation did not change. Surgical risk recall as measured by the patient checklist deteriorated from 92 % immediately post consent to 72 % at 6 weeks postoperatively (p < .001). Recall of the risk for mesh erosion declined from 91 to 64 % (p < .001). Recall that mesh was placed during the MUS procedure declined from 98 to 84 % (p = .01). DRS-PFD scores were correlated with poorer surgical risk recall and surgical complications (r = .31, p = .02). CONCLUSIONS: Recall of MUS surgery risks deteriorated over time. Specifically, women forgot that mesh was placed or might erode. Further investigations into methods and measures of adequate consent that promote recall of long-term surgical risks are needed. PMID- 23818128 TI - Perineal trauma in women undergoing vaginal delivery following intra-uterine fetal demise: a case-control analysis. AB - INTRODUCTION AND HYPOTHESIS: This study aimed to evaluate any differences in the incidence of perineal trauma in women undergoing vaginal delivery following intrauterine fetal death (IUFD) versus live-births. This information would be of interest in evaluating the possible effect of fetal demise on the mechanism of labour in the second stage and thus may provide invaluable insights to contribute to our understanding of the impact of fetal tone on the mechanics of labour and delivery. METHODS: 323 women who delivered vaginally following IUFD were matched with 1,000 women with a live-birth for age, parity, gestation and birth weight. Women undergoing assisted vaginal delivery and/or episiotomy were excluded. RESULTS: Women with an IUFD had a significantly lower risk of perineal trauma overall (relative risk 0.16) as well as a lower risk of obstetric anal sphincter injury specifically (RR 0.12). CONCLUSIONS: Women delivering vaginally after IUFD have a lower incidence of perineal trauma compared with women delivering a live infant. This may be due to differences in biomechanics following an IUFD. PMID- 23818129 TI - Lower urinary tract dysfunction and quality of life in cervical cancer survivors after concurrent chemoradiation versus radical hysterectomy. AB - INTRODUCTION AND HYPOTHESIS: Lower urinary tract dysfunction (LUTD) is a common morbidity. Due to the different pathophysiology of LUT injury, we compared LUTD between patients who received concurrent chemoradiation (CCRT) and radical hysterectomy (RH). METHODS: Seventy cervical cancer survivors were evaluated with multichannel urodynamic studies. The CCRT group received a total dose of 54 Gy pelvic radiation with 2-3 high-dose-rate brachytherapy, concurrent with platinum based chemotherapy. The RH group underwent type III RH without pre- or postoperative radiation. RESULTS: Overall, LUTD was insignificantly different between CCRT and RH (60 % and 68.6 %). Voiding dysfunction was significantly higher in RH, particularly high postvoid residual urine and void with abdominal straining. However, storage dysfunction, particularly low bladder compliance and increased bladder sensation, were significantly more prevalent in CCRT; urinary incontinence was not significantly different between groups. CONCLUSION: LUTD was prevalent in cervical cancer survivors. Different profiles of dysfunction were demonstrated. Voiding dysfunction was higher followng RH, but storage dysfunction was higher following CCRT. PMID- 23818130 TI - High risk of complications with a single incision pelvic floor repair kit: results of a retrospective case series. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to retrospectively assess the extent and severity of the post-operative complications associated with the Pinnacle Pelvic Floor Repair Kit. METHODS: This is a descriptive analysis of 23 consecutive women who had a prolapse repair with either an anterior (n = 19) or posterior (n = 4) Pinnacle kit. The clinical records of all these patients were available for analysis. Pre-operative data and intra-operative complications were noted. All post-operative complications and repeat surgical interventions were recorded. In addition to pelvic floor symptoms, we looked specifically for pelvic pain and mesh contraction, exposure, extrusion or erosion. Complications were classified according to the joint IUGA/ICS system. RESULTS: Seventy percent (n = 16) of our cohort experienced at least one complication. All, except one, were following an anterior Pinnacle. 10 patients (43 %) had a tender vaginal mesh prominence, including a contraction band anteriorly or at the vaginal apex. Six (26 %) complained of associated buttock, groin or vaginal pain, while the tenderness was only detected during vaginal examination in 4 (16 %) patients. Three (13 %) patients required vaginal mesh excision for severe pain and one required a second procedure. Three patients (13 %) had vaginal mesh exposure and 8 (35 %) developed de novo stress incontinence. Two patients (8 %) developed symptomatic recurrent prolapse, one following mesh excision owing to large mesh exposure. Another patient had an anterior compartment prolapse above and below a tender contracted anterior vaginal mesh. CONCLUSIONS: The Pinnacle kit was associated with a high incidence of post-operative complications in this small series. PMID- 23818134 TI - Association of aminoacyl-tRNA synthetases with cancer. AB - Although aminoacyl-tRNA synthetases (ARSs) and ARS-interacting multi-functional proteins (AIMPs) have long been recognized as housekeeping proteins, evidence indicating that they play a key role in regulating cancer is now accumulating. In this chapter we will review the conventional and non-conventional functions of ARSs and AIMPs with respect to carcinogenesis. First, we will address how ARSs and AIMPs are altered in terms of expression, mutation, splicing, and post translational modifications. Second, the molecular mechanisms for ARSs' and AIMPs' involvement in the initiation, maintenance, and progress of carcinogenesis will be covered. Finally, we will introduce the development of therapeutic approaches that target ARSs and AIMPs with the goal of treating cancer. PMID- 23818133 TI - Networks involved in olfaction and their dynamics using independent component analysis and unified structural equation modeling. AB - The study of human olfaction is complicated by the myriad of processing demands in conscious perceptual and emotional experiences of odors. Combining functional magnetic resonance imaging with convergent multivariate network analyses, we examined the spatiotemporal behavior of olfactory-generated blood-oxygenated level-dependent signal in healthy adults. The experimental functional magnetic resonance imaging (fMRI) paradigm was found to offset the limitations of olfactory habituation effects and permitted the identification of five functional networks. Analysis delineated separable neuronal circuits that were spatially centered in the primary olfactory cortex, striatum, dorsolateral prefrontal cortex, rostral prefrontal cortex/anterior cingulate, and parietal-occipital junction. We hypothesize that these functional networks subserve primary perceptual, affective/motivational, and higher order olfactory-related cognitive processes. Results provided direct evidence for the existence of parallel networks with top-down modulation for olfactory processing and clearly distinguished brain activations that were sniffing-related versus odor-related. A comprehensive neurocognitive model for olfaction is presented that may be applied to broader translational studies of olfactory function, aging, and neurological disease. PMID- 23818135 TI - Progress in the identification of plasma biomarkers of colorectal cancer. AB - Proteomic analysis of human tissue and plasma samples has been a useful tool in recent years for the identification of potential biomarkers to aid in the early diagnosis of colorectal cancer. However, biomarkers relating to the crucial transition between adenomatous lesions and invasive colorectal malignancy have not previously been described. The work of Choi et al. (Proteomics 2013, 13, 2361 2374) attempts to address this issue. Using plasma samples from age-matched patients with colorectal adenomas or invasive disease this group identified a range of plasma proteins and cytokines that were differentially expressed. This information not only provides insights into the biology of the adenoma to carcinoma progression sequence but it also represents a step towards the goal of achieving diagnostically accurate and clinically acceptable biomarkers in early colorectal cancer. PMID- 23818136 TI - Brief report: accelerated aging influences cardiovascular disease risk in rheumatoid arthritis. AB - OBJECTIVE: To determine whether the impact of aging on cardiovascular disease (CVD) risk in patients with rheumatoid arthritis (RA) differs from that in the general population (as estimated by the Framingham Risk Score [FRS]). METHODS: A population-based inception cohort of Olmsted County, Minnesota residents ages>=30 years who fulfilled the American College of Rheumatology 1987 criteria for RA in 1988-2008 was assembled and followed up until death, migration, or July 1, 2012. Data on CVD events were collected by medical records review. The 10-year FRS for CVD was calculated. Cox models adjusted for FRS were used to examine the influence of age on CVD risk. RESULTS: The study included 563 patients with RA without prior CVD (mean age 55 years, 72% women, and 69% seropositive [i.e., rheumatoid factor and/or anti-citrullinated protein antibody positive]). During a mean followup of 8.2 years, 98 patients developed CVD (74 seropositive and 24 seronegative), but the FRS predicted only 59.7 events (35.4 seropositive and 24.3 seronegative). The gap between observed and predicted CVD risk increased exponentially across age, and the effect of age on CVD risk in seropositive RA was nearly double its effect in the general population, with additional log(age) coefficients of 2.91 for women (P=0.002) and 2.06 for men (P=0.027). CONCLUSION: Our findings indicate that age exerts an exponentially increasing effect on CVD risk in seropositive RA, but no increased effect among seronegative patients. The causes of accelerated aging in patients with seropositive RA deserve further investigation. PMID- 23818137 TI - Electrorheological effect and electro-optical properties of side-on liquid crystalline polysiloxane in a nematic solvent. AB - The electrorheological (ER) effect and the electro-optical properties of a ''side on'' liquid crystalline polysiloxane (PS) are investigated. A large ER effect is observed and the response to the shear stress of neat PS in the nematic phase is shown to be affected by the shear rate. PS is also mixed with a low-molar nematic liquid crystal (5CB) in order to improve the response behavior to the applied electric field. The rheological properties of such mixtures are highly dependent on the concentration of 5CB. The composites respond faster to the applied electric field and have improved electro-optical properties. This study offers a new perspective on the development of liquid crystal materials for the ER effect. PMID- 23818138 TI - Hysterectomy and kidney cancer risk: a meta-analysis. AB - Recent cohort findings suggest that women who underwent a hysterectomy have an elevated relative risk of kidney cancer, although evidence from past studies has been inconsistent. We conducted a systematic review and meta-analysis of published cohort and case-control studies to summarize the epidemiologic evidence investigating hysterectomy and kidney cancer. Studies published from 1950 through 2012 were identified through a search of PubMed and of references from relevant publications. Meta-analyses were conducted using random-effects models to estimate summary relative risks (SRRs) and 95% confidence intervals (CIs) for hysterectomy, age at hysterectomy (<45, 45+ years) and time since hysterectomy (<10, 10+ years). The SRR for hysterectomy and kidney cancer for all published studies (seven cohort, six case-control) was 1.29 (95% CI, 1.16-1.43), with no evidence of between-study heterogeneity or publication bias. The summary effect was slightly weaker, although still significant, for cohorts (SRR, 1.26; 95% CI, 1.11-1.42) compared with case-control findings (1.37; 95% CI, 1.09-1.73) and was observed irrespective of age at hysterectomy, time since the procedure and model adjustment for body mass index, smoking status and hypertension. Women undergoing a hysterectomy have an approximate 30% increased relative risk of subsequent kidney cancer. Additional research is needed to elucidate the biological mechanisms underlying this association. PMID- 23818139 TI - Idiopathic subglottic stenosis: an evolving therapeutic algorithm. AB - OBJECTIVES/HYPOTHESIS: Idiopathic subglottic stenosis (ISS) is a rare type of airway stenosis of unclear etiology. Open resection, while effective, remains a complex surgery and requires a hospital stay. Endoscopic management is often preferred but has historically been associated with a high recurrence rate. We aimed to analyze our experience, consisting of a standardized endoscopic approach combined with an empiric medical treatment. STUDY DESIGN: Retrospective cohort study. METHODS: All patients with ISS managed with standardized endoscopic treatment at our institution between 1987 and 2012 were identified, and their electronic medical records were reviewed. The treatment consisted of CO2 laser resection without dilatation and local infiltration with steroids and application of mitomycin C. Patients were also treated with antireflux medications, inhaled corticosteroids, and occasionally trimethoprim-sulfamethoxazole. The influence of medical management on annual recurrence rate was analyzed using negative binomial logistic regression. RESULTS: A total of 110 patients treated with standardized endoscopic management were included in our analysis. The procedure was well tolerated by all patients without complications. Recurrences were observed in approximately 60% of patients at 5 years. There was a trend suggesting an association between aggressive medical treatment and a reduction in the rate of recurrence/person/year (relative risk = 0.52, P = 0.051). CONCLUSION: A standardized endoscopic management of ISS consisting of CO2 laser vaporization of the fibrotic scar appears effective in symptom control, with 40% of patients not requiring retreatment in the follow-up period, and with recurrence noted in a majority of patients. Aggressive medical treatment may have a role, but further prospective studies are required to confirm these findings. LEVEL OF EVIDENCE: 4. PMID- 23818140 TI - Location and morphometry of the thyroid isthmus in adult Korean cadavers. AB - The thyroid isthmus has different measurements in its width, height, and thickness, and its location with respect to the tracheal rings has been inconsistent, among the anatomical literature. This study was performed to clarify the location and morphometric characteristics of the thyroid isthmus. One hundred thyroid isthmuses of adult Korean cadavers (gender 58 males and 42 females, mean age 62.9 years, range 19-94 years) were used for this study. The distances from the inferior border of the cricoid cartilage to the superior and inferior margins of the isthmus were 4.9 +/- 3.7 and 20.8 +/- 5.8 mm, respectively. The width, height, and thickness of the thyroid isthmus were 11.1 +/- 6.2, 15.9 +/- 5.8 and 3.4 +/- 1.7 mm, respectively. The thyroid isthmus was located on the 2nd to 4th, 1st to 3rd, and 1st to 4th tracheal rings, in 22, 18 and 18 % of the specimens, respectively. These results are expected to further the current knowledge of the location and morphometry of the thyroid isthmus and provide helpful information for surgical procedures in this region. PMID- 23818131 TI - The pharmacology of regenerative medicine. AB - Regenerative medicine is a rapidly evolving multidisciplinary, translational research enterprise whose explicit purpose is to advance technologies for the repair and replacement of damaged cells, tissues, and organs. Scientific progress in the field has been steady and expectations for its robust clinical application continue to rise. The major thesis of this review is that the pharmacological sciences will contribute critically to the accelerated translational progress and clinical utility of regenerative medicine technologies. In 2007, we coined the phrase "regenerative pharmacology" to describe the enormous possibilities that could occur at the interface between pharmacology, regenerative medicine, and tissue engineering. The operational definition of regenerative pharmacology is "the application of pharmacological sciences to accelerate, optimize, and characterize (either in vitro or in vivo) the development, maturation, and function of bioengineered and regenerating tissues." As such, regenerative pharmacology seeks to cure disease through restoration of tissue/organ function. This strategy is distinct from standard pharmacotherapy, which is often limited to the amelioration of symptoms. Our goal here is to get pharmacologists more involved in this field of research by exposing them to the tools, opportunities, challenges, and interdisciplinary expertise that will be required to ensure awareness and galvanize involvement. To this end, we illustrate ways in which the pharmacological sciences can drive future innovations in regenerative medicine and tissue engineering and thus help to revolutionize the discovery of curative therapeutics. Hopefully, the broad foundational knowledge provided herein will spark sustained conversations among experts in diverse fields of scientific research to the benefit of all. PMID- 23818141 TI - alpha-Boryl isocyanides enable facile preparation of bioactive boropeptides. PMID- 23818144 TI - Relaxation and guided imagery used with 12-year-olds during venipuncture in a school-based screening study. AB - Needle-related procedures are reported to be problematic for children. In a school-based celiac disease screening, 12-year-olds' experiences with relaxation and guided imagery (R-GI) during venipuncture were investigated. One group tried nurse-led R-GI (n = 60) and another group received standard care (SC; n = 49). A mixed method design was applied using short written narratives, facial affective scale (FAS), and visual analog scale (VAS) for pain intensity. Qualitative content analysis highlighted that diversity and contradictions when facing blood tests. FAS scores were significantly lower in the SC group before (p = 0.01), during (p = 0.01), and after (p = 0.01) venipuncture. VAS scores did not differ between the groups. The blood test was mostly experienced as unproblematic, and GI during venipuncture did not decrease pain or affect. However, the fact that a number of children scored high FAS indicates a need for effective methods to help children cope with needle-related school-based procedures. PMID- 23818143 TI - Brief communication: Adrenal androgens and aging: Female chimpanzees (Pan troglodytes) compared with women. AB - Ovarian cycling continues to similar ages in women and chimpanzees yet our nearest living cousins become decrepit during their fertile years and rarely outlive them. Given the importance of estrogen in maintaining physiological systems aside from fertility, similar ovarian aging in humans and chimpanzees combined with somatic aging differences indicates an important role for nonovarian estrogen. Consistent with this framework, researchers have nominated the adrenal androgen dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), which can be peripherally converted to estrogen, as a biomarker of aging in humans and other primates. Faster decline in production of this steroid with age in chimpanzees could help explain somatic aging differences. Here, we report circulating levels of DHEAS in captive female chimpanzees and compare them with published levels in women. Instead of faster, the decline is slower in chimpanzees, but from a much lower peak. Levels reported for other great apes are lower still. These results point away from slowed decline but toward increased DHEAS production as one of the mechanisms underlying the evolution of human longevity. PMID- 23818145 TI - Comparing the psychometric properties of the pediatric outcomes data collection instrument and the activities scales for kids: a review. AB - The aim of this study was to review and evaluate the psychometric properties of two general musculoskeletal outcome measures focusing on pediatric physical disability, namely, the Pediatric Outcomes Data Collection Instrument (PODCI) and the Activities Scales for Kids (ASK). Although this review reveals the psychometric superiority of ASK to PODCI, further research should confirm the psychometric properties of both the instruments. A number of psychometric issues need to be further addressed. Specifically, future studies should examine additional types of reliability and validity, for example, content, construct, criterion, and discriminant with more sophisticated statistical analyses, for example, Aiken's item content validity coefficient and confirmatory factor analysis. Until these issues are addressed, researchers should be cautious utilizing these instruments in children with musculoskeletal problems in a clinical setting. PMID- 23818142 TI - Splicing factor TRA2B is required for neural progenitor survival. AB - Alternative splicing of pre-mRNAs can rapidly regulate the expression of large groups of proteins. The RNA binding protein TRA2B (SFRS10) plays well-established roles in developmentally regulated alternative splicing during Drosophila sexual differentiation. TRA2B is also essential for mammalian embryogenesis and is implicated in numerous human diseases. Precise regulation of alternative splicing is critical to the development and function of the central nervous system; however, the requirements for specific splicing factors in neurogenesis are poorly understood. This study focuses on the role of TRA2B in mammalian brain development. We show that, during murine cortical neurogenesis, TRA2B is expressed in both neural progenitors and cortical projection neurons. Using cortex-specific Tra2b mutant mice, we show that TRA2B depletion results in apoptosis of the neural progenitor cells as well as disorganization of the cortical plate. Thus, TRA2B is essential for proper development of the cerebral cortex. PMID- 23818146 TI - An evaluation of physicians' engagement of children with asthma in treatment related discussions. AB - Our objectives were to examine whether providers engage children with asthma in treatment-related discussions at the level children prefer (engagement concordance) and to determine whether engagement concordance is related to child, caregiver, and provider characteristics. Children with asthma (n = 296) aged 8-16 years were recruited at five pediatric practices in North Carolina. Using audiotaped medical visit transcripts, we documented the number of treatment related questions the providers asked the children. Children reported their preferred level of provider engagement. A logistic generalized estimating equation was used to determine which variables predicted engagement concordance. Most children (96.6%) wanted to be involved in treatment-related discussions. One third of the providers did not ask children any treatment-related questions. Only 36.1% of provider-child dyads were concordant. Most discordant dyads were under engaged (83.1%). Better engagement concordance was observed among older children (odds ratio (OR) = 1.19, 95% confidence interval (CI) (1.07, 1.33)), male children (OR = 1.67, 95% CI (1.03, 2.70)), and among providers with fewer years in practice (OR = .97, 95% CI (.94, .99)). Providers engaged in treatment-related discussions with younger children and females less frequently than these children preferred. Providers should ask children how much they want to be involved in treatment-related discussions and then attempt to engage children at the level they prefer. PMID- 23818147 TI - Parenting and relationship characteristics in mothers with their children having atopic disease. AB - This study compared parental cognitions and relationship characteristics of mothers of children with atopic disease with those of mothers of children without atopic disease. These factors include child-rearing attitudes, parental locus of control, parental sense of competence, attachment security, and maternal sensitivity. Preplanned subanalyses were carried out according to specific disease, mothers' perception of disease severity, and presence of concurrent atopic diseases. The descriptive comparative study of 233 Korean mothers included 102 mothers of children aged six years or younger with atopic dermatitis, asthma, and/or allergic rhinitis. Data were collected from 2007 to 2008 from local clinics and day care centers. Parental cognitions and relationship characteristics did not differ significantly between groups of mothers, except that mothers of children with atopic dermatitis showed less affection. However, subanalyses showed that mothers who perceived their child's disease to be severe were less likely to encourage autonomy and had a lower sense of competence, more rejecting attitudes, and an external locus of control. Although we should be cautious in generalizing these results, special care plans are strongly recommended for mothers of children with severe atopic disease to provide support and education, help mothers develop an internal locus of control, and increase parental sense of competence. PMID- 23818148 TI - Out-of-school lives of physically disabled children and young people in the United Kingdom: a qualitative literature review. AB - Currently there appears to be few opportunities and little evidence of physically disabled children and young people (C&YP) participating in mainstream social activities. A qualitative review was undertaken to examine the factors affecting physically disabled C&YP (8-15 years) in the United Kingdom participating in out of-school activities. Views and experiences were explored from the perspective of the service users and providers to assess current provision and to determine the need for future research into factors that may affect participation. Searches were conducted across eight databases, the references of the included studies were checked and the websites were searched. Studies that used a qualitative design that examined the views relating to out-of-school activities were included. Nine papers were identified, which included three peer-reviewed papers and six pieces of grey literature and pertinent government documents to include views and experiences of out-of-school activity provision. The main themes emerging from the review were the need for social inclusion, out-of-school activities run by volunteers and accessibility, with threads throughout, which require further research including parental influence, provision, training and attitudes. This review highlights the absence of the service user's voice and sheds light on the limited provision and barriers affecting participation in out of-school activities. PMID- 23818149 TI - More than just clowns--Clown doctor rounds and their impact for children, families and staff. AB - Admission to hospital is recognised as a difficult time for children and families. This study explored clown doctor activities in an acute paediatric setting and the impact their activities have on children, their families, other health professionals and clown doctors themselves. We used observation, semi structured interviews and focus groups with children and parents and staff and clown doctors and results provide a rich description of the work of clown doctors. The major themes were 'the encounter - in the moment' of the interaction of the child and the clown doctor and 'beyond the encounter'. The findings show that the impact of clown doctor visits is experienced beyond the immediate interaction, and this has not been clearly articulated in previous studies. This study highlights the multifaceted and complex nature of the work of the clown doctors and the high level of skill required as they modify and interpret play, activities and environment based on individual need and response. PMID- 23818152 TI - The glutamate system as a therapeutic target and impact of genes on suicidality. PMID- 23818153 TI - Significantly different proliferative potential of oral mucosal epithelial cells between six animal species. AB - There has been an upsurge in regenerative medicine in recent years. In particular, because oral mucosal epithelial cells can be obtained noninvasively, cultured epithelial cell sheets have been used in a number of ectopic transplantations. Additionally, the verification of the properties of experimental animals' cultured cells has accelerated the application of regenerative medicine. In the present study, the properties of oral mucosal epithelial cells were compared between six animal species. The human and pig epithelia were relatively thicker than the epithelia of the other species. The colony-forming efficiency of the rat was the highest, followed by those of the dog, human, rabbit, and pig, whereas the colonies of the mouse cells were all paraclone and uncountable in the colony-forming assay. We also found that the rabbit and pig cells proliferated poorly and were unable to form cell sheets without feeder layers. In contrast, even in the absence of feeder layers and cholera toxin, cultured dog and mouse cells formed contiguous sheets, when the cell seeding density was high. These results indicate that interspecies variation is considerable in oral mucosal epithelial cells and that specific experimental animal or human cells must be chosen according to the intended use. PMID- 23818154 TI - Prostate specific antigen enhances the innate defence of prostatic epithelium against Escherichia coli infection. AB - BACKGROUND: This study investigated whether the increase in serum prostate specific antigen (PSA) typically seen during male urinary tract infection (UTI) is incidental or reflects an innate defence mechanism of the prostate. The protective roles of the whey-acid-motif-4-disulphide core (WFDC) proteins, secretory leukoproteinase inhibitor (SLPI) and WFDC2, in the prostate were also examined. METHODS: UTI recurrence was assessed retrospectively in men following initial UTI by patient interview. PSA, SLPI, and WFDC2 gene expression were assessed using biopsy samples. LNCaP and DU145 in vitro prostate cell models were utilized to assess the effects of an Escherichia coli challenge on PSA and WFDC gene expression, and bacterial invasion of the prostate epithelium. The effects of PSA on WFDC antimicrobial properties were studied using recombinant peptides and time-kill assays. RESULTS: Men presenting with PSA >4 ng/ml at initial UTI were less likely to have recurrent (r) UTI than those with PSA <4 ng/ml [2/15 (13%) vs. 7/10 (70%), P < 0.01]. Genes encoding PSA, SLPI and WFDC2, were expressed in prostatic epithelium, and the PSA and SLPI proteins co-localized in vivo. Challenging LNCaP (PSA-positive) cells with E. coli increased PSA, SLPI, and WFDC2 gene expression (P < 0.05), and PSA synthesis (P < 0.05), and reduced bacterial invasion. Pre-incubation of DU145 (PSA-negative) cells with PSA also decreased bacterial invasion. In vitro incubation of recombinant SLPI and WFDC2 with PSA resulted in peptide proteolysis and increased E. coli killing. CONCLUSIONS: Increased PSA during UTI appears protective against rUTI and in vitro is linked to proteolysis of WFDC proteins supporting enhanced prostate innate defences. PMID- 23818156 TI - Mirabegron: a review of its use in patients with overactive bladder syndrome. AB - Mirabegron (YM178, MyrbetriqTM, Betanis((r)), BetmigaTM) is a beta3-adrenergic receptor agonist approved in several countries for the symptomatic treatment of adults with overactive bladder syndrome. In three 12-week, randomized, double blind, placebo-controlled, multinational trials in patients with overactive bladder syndrome, oral mirabegron 25 or 50 mg once daily significantly reduced the adjusted mean number of incontinence episodes per 24 h (in patients with incontinence at baseline) and the adjusted mean number of micturition episodes per 24 h (in full trial populations) [coprimary endpoints]. Across trials, mirabegron 50 mg once daily also consistently significantly reduced urgency episodes and increased the volume of urine voided per micturition, generally in association with improved health-related quality of life (HR-QOL) and treatment satisfaction. Based on descriptive analyses from a 12-month trial, once-daily mirabegron 50 mg and tolterodine extended-release (ER) 4 mg were both efficacious in reducing urinary symptoms and improving HR-QOL. Mirabegron was generally well tolerated in the trials. Over 12 weeks, the adverse event rate with mirabegron 50 mg once daily was similar to that with placebo. During 12 months of treatment, 2.8 % of mirabegron 50 mg once daily recipients reported dry mouth compared with 8.6 % with tolterodine ER 4 mg once daily recipients. Mirabegron 50 mg once daily carries a low risk of QT interval prolongation. Thus, mirabegron is an efficacious new treatment for overactive bladder syndrome with a favourable tolerability profile. PMID- 23818155 TI - Structure, function, and tethering of DNA-binding domains in sigma54 transcriptional activators. AB - We compare the structure, activity, and linkage of DNA-binding domains (DBDs) from sigma(54) transcriptional activators and discuss how the properties of the DBDs and the linker to the neighboring domain are affected by the overall properties and requirements of the full proteins. These transcriptional activators bind upstream of specific promoters that utilize sigma(54)-polymerase. Upon receiving a signal the activators assemble into hexamers, which then, through adenosine triphosphate (ATP) hydrolysis, drive a conformational change in polymerase that enables transcription initiation. We present structures of the DBDs of activators nitrogen regulatory protein C 1 (NtrC1) and Nif-like homolog 2 (Nlh2) from the thermophile Aquifex aeolicus. The structures of these domains and their relationship to other parts of the activators are discussed. These structures are compared with previously determined structures of the DBDs of NtrC4, NtrC, ZraR, and factor for inversion stimulation. The N-terminal linkers that connect the DBDs to the central domains in NtrC1 and Nlh2 were studied and found to be unstructured. Additionally, a crystal structure of full-length NtrC1 was solved, but density of the DBDs was extremely weak, further indicating that the linker between ATPase and DBDs functions as a flexible tether. Flexible linking of ATPase and DBDs is likely necessary to allow assembly of the active hexameric ATPase ring. The comparison of this set of activators also shows clearly that strong dimerization of the DBD only occurs when other domains do not dimerize strongly. PMID- 23818158 TI - Microscopic imaging mass spectrometry assisted by on-tissue chemical derivatization for visualizing multiple amino acids in human colon cancer xenografts. AB - Imaging MS combined with CE/MS serves as a method to provide semi-quantitative and spatial information of small molecular metabolites in tissue slices. However, not all metabolites including amino acids have fully been visualized, because of low-ionization efficiency in MALDI MS. This study aimed to acquire semi quantitative spatial information for multiple amino acids in frozen tissue slices. As a derivatization reagent, p-N,N,N-trimethylammonioanilyl N' hydroxysuccinimidyl carbamate iodide (TAHS) was applied to increase their ionization efficiency and detection sensitivity. Semi-quantitative MALDI-imaging MS allowed us to visualize and quantify free amino acid pools in human colon cancer xenografts using a model of liver metastases in super-immunodeficient NOD/scid/gamma(null) mice (NOG mice). Because the m/z values of several TAHS derivatized amino acids overlap with those of the 2,5-dihydroxybenzoic acid background and other endogenous compounds, we imaged them with tandem MS. The results indicated that regional contents of glutamate, glutamine, glycine, leucine/isoleucine/hydroxyproline, phenylalanine, and alanine were significantly elevated in metastatic tumors versus parenchyma of tumor-bearing livers. On tissue TAHS derivatization thus serves as a useful method to detect alterations in many amino acid levels in vivo, thereby enabling understanding of the spatial alterations of these metabolites under varied disease conditions including cancer. PMID- 23818159 TI - Randomized, controlled trial of a multimodal intervention to improve cancer screening rates in a safety-net primary care practice. AB - BACKGROUND: Cancer screening rates are suboptimal for low-income patients. OBJECTIVE: To assess an intervention to increase cancer screening among patients in a safety-net primary care practice. DESIGN: Patients at an inner-city family practice who were overdue for cancer screening were randomized to intervention or usual care. Screening rates at 1 year were compared using the chi-square test, and multivariable analysis was performed to adjust for patient factors. SUBJECTS: All average-risk patients at an inner-city family practice overdue for mammography or colorectal cancer (CRC) screening. Patients' ages were 40 to 74 years (mean 53.9, SD 8.7) including 40.8 % African Americans, 4.2 % Latinos, 23.2 % with Medicaid and 10.9 % without any form of insurance. INTERVENTION: The 6 month intervention to promote cancer screening included letters, automated phone calls, prompts and a mailed Fecal Immunochemical Testing (FIT) Kit. MAIN MEASURES: Rates of cancer screening at 1 year. KEY RESULTS: Three hundred sixty six patients overdue for screening were randomly assigned to intervention (n = 185) or usual care (n = 181). Primary analysis revealed significantly higher rates of cancer screening in intervention subjects: 29.7 % vs. 16.7 % for mammography (p = 0.034) and 37.7 % vs. 16.7 % for CRC screening (p = 0.0002). In the intervention group, 20 % of mammography screenings and 9.3 % of CRC screenings occurred at the early assessment, while the remainder occurred after repeated interventions. Within the CRC intervention group 44 % of screened patients used the mailed FIT kit. On multivariable analysis the CRC screening rates remained significantly higher in the intervention group, while the breast cancer screening rates were not statistically different. CONCLUSIONS: A multimodal intervention significantly increased CRC screening rates among patients in a safety-net primary care practice. These results suggest that relatively inexpensive letters and automated calls can be combined for a larger effect. Results also suggest that mailed screening kits may be a promising way to increase average-risk CRC screening. PMID- 23818160 TI - Reconsidering against medical advice discharges: embracing patient-centeredness to promote high quality care and a renewed research agenda. AB - Hospital discharges against medical advice (AMA) are common, costly, stigmatizing to patients, and are associated with excess morbidity and mortality. Achieving better quality care for patients discharged AMA has been limited both by the sparse research illuminating how best to care for this challenging patient population, as well as a lack of standards regarding this clinical practice. This paper will review elements of the AMA literature and highlight the gaps, including the predictors of AMA discharge, challenges to high quality informed consent in AMA discharges, problematic aspects of AMA discharge forms, and the stigma associated with patients discharged AMA. These gaps in the evidence base collectively limit the ability to adequately and completely address AMA discharges and improve health care quality. This paper will recommend future directions to answer remaining questions for the field, and offer guidance for providing ethically sound and high quality care for the affected population. Applying the widely accepted principles of patient-centered care and shared decision making to AMA discharges offers the opportunity to improve quality of care and promote ethical health care practice. PMID- 23818161 TI - Microwave-assisted synthesis of HKUST-1 and functionalized HKUST-1-@H3PW12O40: selective adsorption of heavy metal ions in water analyzed with synchrotron radiation. AB - A simple, rapid and efficient synthesis of the metal-organic framework (MOF) HKUST-1 [Cu3(1,3,5-benzene-tri-carboxilic-acid)2] by microwave irradiation is described, which afforded a homogeneous and highly selective material. The unusually short time to complete the synthesis by microwave irradiation is mainly attributable to rapid nucleation rather than to crystal growth rate. Using this method, HKUST-1-MW (MW=microwave) could be prepared within 20 min, whereas by hydrothermal synthesis, involving conventional heating, the preparation time is 8 h. Work efficiency was improved by the good performance of the obtained HKUST-1 MW which exhibited good selective adsorption of heavy metal ions, as well as a remarkably high adsorption affinity and adsorption capacity, but no adsorption of Hg(2+) under the same experimental conditions. Of particular importance is the preservation of the structure after metal-ion adsorption, which remained virtually intact, with only a few changes in X-ray diffraction intensity and a moderate decline in surface area. Synthesis of the polyoxometalate-containing HKUST-1-MW@H3PW12O40 afforded a MOF with enhanced stability in water, due to the introduced Keggin-type phosphotungstate, which systematically occluded in the cavities constituting the walls between the mesopores. Different Cu/W ratios were investigated according to the extrusion rate of cooper ions concentration, without significant structural changes after adsorption. The MOFs obtained feature particle sizes between 10-20 MUm and their structures were determined using synchrotron-based X-ray diffraction. The results of this study can be considered important for potentially wider future applications of MOFs, especially to attend environmental issues. PMID- 23818162 TI - Multilayer integral method for simulation of eddy currents in thin volumes of arbitrary geometry produced by MRI gradient coils. AB - PURPOSE: This article aims to present a fast, efficient and accurate multi-layer integral method (MIM) for the evaluation of complex spatiotemporal eddy currents in nonmagnetic and thin volumes of irregular geometries induced by arbitrary arrangements of gradient coils. METHODS: The volume of interest is divided into a number of layers, wherein the thickness of each layer is assumed to be smaller than the skin depth and where one of the linear dimensions is much smaller than the remaining two dimensions. The diffusion equation of the current density is solved both in time-harmonic and transient domain. RESULTS: The experimentally measured magnetic fields produced by the coil and the induced eddy currents as well as the corresponding time-decay constants were in close agreement with the results produced by the MIM. Relevant parameters such as power loss and force induced by the eddy currents in a split cryostat were simulated using the MIM. CONCLUSION: The proposed method is capable of accurately simulating the current diffusion process inside thin volumes, such as the magnet cryostat. The method permits the priori-calculation of optimal pre-emphasis parameters. The MIM enables unified designs of gradient coil-magnet structures for an optimal mitigation of deleterious eddy current effects. PMID- 23818163 TI - Identification of Enterobacteriaceae by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry using the VITEK MS system. AB - This multicenter study evaluated the accuracy of matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry identifications from the VITEK MS system (bioMerieux, Marcy l'Etoile, France) for Enterobacteriaceae typically encountered in the clinical laboratory. Enterobacteriaceae isolates (n = 965) representing 17 genera and 40 species were analyzed on the VITEK MS system (database v2.0), in accordance with the manufacturer's instructions. Colony growth (<=72 h) was applied directly to the target slide. Matrix solution (alpha-cyano-4-hydroxycinnamic acid) was added and allowed to dry before mass spectrometry analysis. On the basis of the confidence level, the VITEK MS system provided a species, genus only, or no identification for each isolate. The accuracy of the mass spectrometric identification was compared to 16S rRNA gene sequencing performed at MIDI Labs (Newark, DE). Supplemental phenotypic testing was performed at bioMerieux when necessary. The VITEK MS result agreed with the reference method identification for 96.7% of the 965 isolates tested, with 83.8% correct to the species level and 12.8% limited to a genus-level identification. There was no identification for 1.7% of the isolates. The VITEK MS system misidentified 7 isolates (0.7 %) as different genera. Three Pantoea agglomerans isolates were misidentified as Enterobacter spp. and single isolates of Enterobacter cancerogenus, Escherichia hermannii, Hafnia alvei, and Raoultella ornithinolytica were misidentified as Klebsiella oxytoca, Citrobacter koseri, Obesumbacterium proteus, and Enterobacter aerogenes, respectively. Eight isolates (0.8 %) were misidentified as a different species in the correct genus. The VITEK MS system provides reliable mass spectrometric identifications for Enterobacteriaceae. PMID- 23818164 TI - The role of broth enrichment in Staphylococcus aureus cultivation and transmission from the throat to newborn infants: results from the Swedish hygiene intervention and transmission of S. aureus study. AB - Staphylococcus aureus is detected by direct plating, whereas incubation in enrichment broth prior to plating to increase the proportion of positive samples has not been fully evaluated. S. aureus throat colonization has been suggested to be more common than colonization of the anterior nares, but no data are available on the transmission of S. aureus from the throat. Swab samples were collected from the anterior nares and umbilicus from newborn infants (n = 168), anterior nares, throat, skin lesions, and vagina from parents (n = 332), and anterior nares, throat, and skin lesions from healthcare workers (n = 231) at three maternity wards. spa typing was used to elucidate the transmission routes of S. aureus. The use of enrichment broth prior to plating increased the proportion of positive samples by 46%. The prevalence of S. aureus colonization in adults was 58%. Throat colonization (47%) was significantly more common than colonization in any of the other screened sites (p < 0.001). In total, 103 out of 168 (61%) newborn infants were colonized during their hospital stay. Overall, 124 S. aureus transmissions to newborn infants were detected. Although we detected an increased risk of transmission from the nares as compared to the throat, with an odds ratio of 4.8 [95% confidence interval (CI) 1.8-12.7], we detected a transmission rate of 7 % from the throat. We show that S. aureus throat colonization is more common than colonization in any of the other sites among the parents and staff. We also show evidence of transmission from the throat. PMID- 23818165 TI - Effect of upper torso inclination in Fowler's position on autonomic cardiovascular regulation. AB - The present study investigates autonomic cardiovascular regulation during postural changes while in Fowler's position. Respiratory sinus arrhythmia (RSA) and sequence baroreflex sensitivity (sBRS) were measured in 12 healthy individuals in three positions (Experiment 1). We also measured RSA, sBRS, tidal volume (TV), lung volume spectrum (LV spectrum), and transfer gain and phase between lung volume and RR interval (RSA-TF, RSATF-phase) in 11 healthy individuals in two positions (Experiment 2). All participants maintained respiratory frequency at 15 breaths/min. The three positions in Experiment 1 were 30 degrees , 45 degrees , and 60 degrees of upper torso inclination with a lower torso inclination of 30 degrees throughout all evaluations. The two positions in Experiment 2 were 30 degrees and 60 degrees of upper torso backrest inclination with a lower torso inclination of 30 degrees throughout all evaluations. The results of Experiment 1 showed significantly higher RSA and sBRS at 60 degrees and 45 degrees than at 30 degrees , whereas RR interval (RRI), systolic blood pressure (SBP), and diastolic blood pressure (DBP) did not differ significantly under any condition. The results of Experiment 2 showed that RSA, RSA-TF, sBRS, TV, and LV spectrum were significantly higher at 60 degrees than at 30 degrees , and that RRI, SBP, DBP, and the RSATF phase did not significantly differ under any condition. These findings suggested that slight flexion of the upper torso in Fowler's position activates respiratory function and increases the contribution of vagal nerve activity to the cardiovascular system in young participants under conditions of a fixed respiratory rate. PMID- 23818166 TI - Immobilization-induced hypersensitivity associated with spinal cord sensitization during cast immobilization and after cast removal in rats. AB - This study examined mechanical and thermal hypersensitivity in the rat hind paw during cast immobilization of the hind limbs for 4 or 8 weeks and following cast removal. Blood flow, skin temperature, and volume of the rat hind paw were assessed in order to determine peripheral circulation of the hind limbs. Sensitization was analyzed by measuring the expression of the calcitonin gene related peptide (CGRP) in the spinal dorsal horn following cast immobilization. Two weeks post immobilization, mechanical and thermal sensitivities increased significantly in all rats; however, peripheral circulation was not affected by immobilization. Cast immobilization for 8 weeks induced more serious hypersensitivity compared to cast immobilization for 4 weeks. Moreover, CGRP expression in the deeper lamina layer of the spinal dorsal horn increased in the rats immobilized for 8 weeks but not in those immobilized for 4 weeks. These findings suggest that immobilization-induced hypersensitivity develops during the immobilization period without affecting peripheral circulation. Our results also highlight the possibility that prolonged immobilization induces central sensitization in the spinal cord. PMID- 23818168 TI - Pig oocytes with a large perivitelline space matured in vitro show greater developmental competence after parthenogenesis and somatic cell nuclear transfer. AB - The objective of this study was to examine the developmental competence of pig oocytes in relation to the size of the perivitelline space (PVS) of oocytes matured in vitro. Immature oocytes were matured in medium 199 or porcine zygote medium (PZM)-3 containing 108 or 61.6 mM NaCl. In vitro-matured (IVM) oocytes were examined for intracellular glutathione (GSH) level; cyclin-dependent kinase 1 (CDK1), proliferating cell nuclear antigen (PCNA), and extracellular signal regulated kinase 2 (ERK2) mRNA levels; and developmental competence after parthenogenesis (PA) and somatic cell nuclear transfer (SCNT). IVM oocytes with a larger PVS had higher (P < 0.05) levels of intracellular GSH (1.00 pixels/oocyte vs. 0.57 pixels/oocyte) and blastocyst formation (54.3% vs. 37.3%) after PA than oocytes with a smaller PVS. Culturing oocytes for maturation in PZM-3 with reduced (61.6 mM) NaCl increased (P < 0.05) the size of the PVS (6.4 um vs. 2.8 um) compared to control oocytes that were matured in normal PZM-3 containing 108 mM NaCl. Moreover, oocytes with a larger PVS showed higher CDK1, PCNA, and ERK2 mRNA and intracellular GSH levels (1.6 pixels/oocyte vs. 1.2 pixels/oocyte) and increased blastocyst formation after PA (52.1% vs. 40.6%) and SCNT (31.8% vs. 18.2%) than control oocytes. Our results demonstrate that pig oocytes with a large PVS have greater developmental competence after PA and SCNT, which is attributed to improved cytoplasmic maturation based on the enhanced GSH level and transcription factor expression. Further, enlargement of the PVS by culturing in low-NaCl medium improves the developmental competence of pig oocytes. PMID- 23818167 TI - Alterations in white matter microstructure in women recovered from anorexia nervosa. AB - OBJECTIVE: A recent study of ill individuals with anorexia nervosa (AN) reported microstructural alterations in white matter integrity including lower fractional anisotropy and higher mean diffusivity. This study was designed to determine whether such alterations exist in long-term recovered AN individuals and to examine potential associations with underlying AN traits. METHOD: Twelve adult women recovered from restricting-type AN and 10 control women were studied using diffusion tensor imaging. RESULTS: Overall, there was no significant fractional anisotropy alteration in recovered AN, in contrast to a prior study reporting lower fractional anisotropy in ill AN. Further, recovered AN showed lower mean diffusivity in frontal, parietal and cingulum white matter relative to control women, contrary to elevated mean diffusivity previously reported in ill AN. Lower longitudinal diffusivity in recovered AN was associated with higher harm avoidance. However, more severe illness history was associated with worse white matter integrity after recovery in the same direction as reported in prior work. DISCUSSION: Our findings suggest that fractional anisotropy in recovered AN is not different from controls, however, a novel pattern of lower mean diffusivity was evidenced in recovered AN, and this alteration was associated with harm avoidance. Notably, severity of illness history may have long-term consequences, emphasizing the importance of aggressive treatment. PMID- 23818169 TI - Fecal immunochemical test accuracy in familial risk colorectal cancer screening. AB - There is little information on fecal immunochemical test (FIT) in familial risk colorectal cancer (CRC) screening. Our study assesses FIT accuracy, number needed to scope (NNS) and cost to detect a CRC and an advanced neoplasia (AN) in this setting. We performed a multicentric, prospective, double-blind study of diagnostic tests on individuals with first-degree relatives (FDRs) with CRC submitted to screening colonoscopy. Two stool samples were collected and fecal hemoglobin in the first sample (FIT1) and the highest in both samples (FITmax) were determined. Areas under the curve (AUC) for CRC and AN as well as the best FIT1 and FITmax cutoff value for CRC were determined. At this threshold, NNS and the cost per lesion detected were calculated. A total of 595 individuals were included (one FDR > 60 years, 413; two FDR or one <= 60 years, 182). AN and CRC were found in 64 (10.8%) and six (1%) patients, respectively. For CRC diagnosis, FIT1 AUC was 0.96 [95% confidence interval (CI): 0.95-0.98] and FITmax AUC was 0.95 (95% CI: 0.93-0.97). For AN diagnosis, FIT1 and FITmax AUC were 0.74 (95% CI: 0.66-0.82). The best cutoff point for CRC was 115. At this threshold, the NNS to detect a CRC was 5.67 and 7.67, and the cost per CRC was 1,064? and 1591.33? on FIT1 and FITmax strategies, respectively. FIT shows high accuracy to detect CRC in familial CRC screening. Performing two tests does not improve diagnostic accuracy, but increases cost and NNS to detect a lesion. PMID- 23818170 TI - In reference to what are the diagnostic criteria for migraine-associated vertigo? PMID- 23818172 TI - Organocatalytic diastereo- and enantioselective 1,3-dipolar cycloaddition of azlactones and methyleneindolinones. PMID- 23818171 TI - Lifting della repression of Arabidopsis seed germination by nonproteolytic gibberellin signaling. AB - DELLA repression of Arabidopsis (Arabidopsis thaliana) seed germination can be lifted either through DELLA proteolysis by the ubiquitin-proteasome pathway or through proteolysis-independent gibberellin (GA) hormone signaling. GA binding to the GIBBERELLIN-INSENSITIVE DWARF1 (GID1) GA receptors stimulates GID1-GA-DELLA complex formation, which in turn triggers DELLA protein ubiquitination and proteolysis via the SCF(SLY1) E3 ubiquitin ligase and 26S proteasome. Although DELLA cannot be destroyed in the sleepy1-2 (sly1-2) F-box mutant, long dry after ripening and GID1 overexpression can relieve the strong sly1-2 seed dormancy phenotype. It appears that sly1-2 seed dormancy results from abscisic acid (ABA) signaling downstream of DELLA, since dormant sly1-2 seeds accumulate high levels of ABA hormone and loss of ABA sensitivity rescues sly1-2 seed germination. DELLA positively regulates the expression of XERICO, an inducer of ABA biosynthesis. GID1b overexpression rescues sly1-2 germination through proteolysis-independent DELLA down-regulation associated with increased expression of GA-inducible genes and decreased ABA accumulation, apparently as a result of decreased XERICO messenger RNA levels. Higher levels of GID1 overexpression are associated with more efficient sly1 germination and increased GID1-GA-DELLA complex formation, suggesting that GID1 down-regulates DELLA through protein binding. After-ripening results in increased GA accumulation and GID1a-dependent GA signaling, suggesting that after-ripening triggers GA-stimulated GID1-GA-DELLA protein complex formation, which in turn blocks DELLA transcriptional activation of the XERICO inhibitor of seed germination. PMID- 23818173 TI - Death receptor 5-targeted depletion of interleukin-23-producing macrophages, Th17, and Th1/17 associated with defective tyrosine phosphatase in mice and patients with rheumatoid arthritis. AB - OBJECTIVE: Bidirectional interactions between granulocyte-macrophage colony stimulating factor-positive (GM-CSF+) T cells and interferon regulatory factor 5 positive (IRF-5+) macrophages play a major role in autoimmunity. In the absence of SH2 domain-containing phosphatase 1 (SHP-1), GM-CSF-stimulated cells are resistant to death receptor (DR)-mediated apoptosis. The objective of this study was to determine whether TRA-8, an anti-DR5 agonistic antibody, can eliminate inflammatory macrophages and CD4 T cells in the SHP-1-deficient condition. METHODS: Ubiquitous Cre (Ubc.Cre) human/mouse-chimeric DR5-transgenic mice were crossed with viable SHP-1-defective motheaten (mev/mev) mice. TRA-8 was administered weekly for up to 4 weeks. The clinical scores, histopathologic severity, and macrophage and CD4 T cell phenotypes were evaluated. The role of TRA-8 in depleting inflammatory macrophages and CD4 T cells was also evaluated, using synovial fluid obtained from patients with rheumatoid arthritis (RA). RESULTS: The levels of inflammatory macrophages (interleukin-23-positive [IL-23+] IRF-5+) and CD4 T cells (IL-17+ GM-CSF+) were elevated in mev/mev mice. In DR5 transgenic mev/mev mice, DR5 expression was up-regulated in these 2 cell populations. TRA-8 treatment depleted these cell populations and resulted in a significant reduction in inflammation and in the titers of autoantibodies. In synovial cells from patients with RA, the expression of IRF5 and DR5 was negatively correlated with the expression of PTPN6. TRA-8, but not TRAIL, suppressed RA inflammatory macrophages and Th17 cells under conditions in which the expression of SHP-1 is low. CONCLUSION: In contrast to TRAIL, which lacks the capability to counteract the survival signal in the absence of SHP-1, TRA-8 eliminated both IRF-5+ IL-23+ M1 macrophages and pathogenic GM-CSF+ IL-17+ CD4 T cells in a SHP-1-independent manner. The results of the current study suggest that TRA-8 can deplete inflammatory cell populations that result from a hyperactive GM-CSF/IRF-5 axis. PMID- 23818174 TI - Molecular profiling of the developing avian telencephalon: regional timing and brain subdivision continuities. AB - In our companion study (Jarvis et al. [2013] J Comp Neurol. doi: 10.1002/cne.23404) we used quantitative brain molecular profiling to discover that distinct subdivisions in the avian pallium above and below the ventricle and the associated mesopallium lamina have similar molecular profiles, leading to a hypothesis that they may form as continuous subdivisions around the lateral ventricle. To explore this hypothesis, here we profiled the expression of 16 genes at eight developmental stages. The genes included those that define brain subdivisions in the adult and some that are also involved in brain development. We found that phyletic hierarchical cluster and linear regression network analyses of gene expression profiles implicated single and mixed ancestry of these brain regions at early embryonic stages. Most gene expression-defined pallial subdivisions began as one ventral or dorsal domain that later formed specific folds around the lateral ventricle. Subsequently a clear ventricle boundary formed, partitioning them into dorsal and ventral pallial subdivisions surrounding the mesopallium lamina. These subdivisions each included two parts of the mesopallium, the nidopallium and hyperpallium, and the arcopallium and hippocampus, respectively. Each subdivision expression profile had a different temporal order of appearance, similar in timing to the order of analogous cell types of the mammalian cortex. Furthermore, like the mammalian pallium, expression in the ventral pallial subdivisions became distinct during prehatch development, whereas the dorsal portions did so during posthatch development. These findings support the continuum hypothesis of avian brain subdivision development around the ventricle and influence hypotheses on homologies of the avian pallium with other vertebrates. PMID- 23818175 TI - Motional timescale predictions by molecular dynamics simulations: case study using proline and hydroxyproline sidechain dynamics. AB - We propose a new approach for force field optimizations which aims at reproducing dynamics characteristics using biomolecular MD simulations, in addition to improved prediction of motionally averaged structural properties available from experiment. As the source of experimental data for dynamics fittings, we use (13) C NMR spin-lattice relaxation times T1 of backbone and sidechain carbons, which allow to determine correlation times of both overall molecular and intramolecular motions. For structural fittings, we use motionally averaged experimental values of NMR J couplings. The proline residue and its derivative 4-hydroxyproline with relatively simple cyclic structure and sidechain dynamics were chosen for the assessment of the new approach in this work. Initially, grid search and simplexed MD simulations identified large number of parameter sets which fit equally well experimental J couplings. Using the Arrhenius-type relationship between the force constant and the correlation time, the available MD data for a series of parameter sets were analyzed to predict the value of the force constant that best reproduces experimental timescale of the sidechain dynamics. Verification of the new force-field (termed as AMBER99SB-ILDNP) against NMR J couplings and correlation times showed consistent and significant improvements compared to the original force field in reproducing both structural and dynamics properties. The results suggest that matching experimental timescales of motions together with motionally averaged characteristics is the valid approach for force field parameter optimization. Such a comprehensive approach is not restricted to cyclic residues and can be extended to other amino acid residues, as well as to the backbone. PMID- 23818177 TI - Tumor necrosis factor alpha increases aerobic glycolysis and reduces oxidative metabolism in prostate epithelial cells. AB - BACKGROUND: Chronic inflammation promotes prostate cancer formation and progression. Furthermore, alterations in energy metabolism are a hallmark of prostate cancer cells. However, the actions of inflammatory factors on the energy metabolism of prostate epithelial cells have not been previously investigated. This is the first study to report on the effect of the inflammatory cytokine tumor necrosis factor alpha (TNFalpha) on the glycolytic and oxidative metabolism, and the mitochondrial function of widely used prostate epithelial cells. METHODS: Pre-malignant RWPE-1 and cancerous LNCaP and PC-3 cells were treated with low-dose TNFalpha. Glycolytic and oxidative metabolism was quantified by measuring extracellular acidification and oxygen consumption rates, respectively. ATP content and lactate export were measured by luminescence and fluorescence, respectively. Mitochondrial content and the expression of glucose transporter 1 (GLUT1), peroxisome proliferator-activated receptor co-activator 1 alpha (PGC-1alpha), and Cytochrome C were measured by flow cytometry. RESULTS: Our data suggest that TNFalpha increases glycolysis, ATP production, and lactate export, while it reduces oxidative metabolism and mitochondrial function in prostate epithelial cells. The highly aggressive PC-3 cells tend to be less responsive to the actions of TNFalpha than the pre-malignant RWPE-1 and the non aggressive LNCaP cells. CONCLUSIONS: Cellular energetics, that is, glycolytic and oxidative metabolism is significantly influenced by low-level inflammation in prostate epithelial cells. In widely used prostate epithelial cell models, the micro-environmental inflammatory cytokine TNFalpha induces aerobic glycolysis while inhibiting oxidative metabolism. This supports the hypothesis that low level inflammation can induce Warburg metabolism in prostate epithelial cells, which may promote cancer formation and progression. PMID- 23818179 TI - Propionic acidemia and optic neuropathy: a report of two cases. AB - INTRODUCTION: Propionic acidemia is a metabolic disease produced by a deficiency of the enzyme propionyl-CoA carboxylase. It can lead to coma, with severe neurologic encephalopathy or present later in life with vomiting, hypotonia, and seizures. An early diagnosis with adequate treatment helps to prevent the sequelae. Among the described complications is optic neuropathy, although not commonly reported, it is very disabling. OBJECTIVES: To describe two patients with propionic acidemia and optic neuropathy. PATIENTS AND METHODS: Patient 1: 16 years old, male, parents without consanguinity. He was diagnosed at 5 months of age because of hypotonia and seizures. Until the age of 9 years, he evolved satisfactorily; therefore, he stopped treatment. At 13 years, he presented bilateral optic neuropathy. Patient 2: 20 years, female, parents without consanguinity. She was diagnosed with PA at 11 months of age because of hypotonia and seizures. She evolved satisfactorily until the age of 9 years when she presented a metabolic decompensation followed by a bad metabolic control. At 18 years, she presented bilateral progressive optic neuropathy. RESULTS: Both patients have psychometric scores with borderline IQ 84-75 (WISC-R) beside optic neuropathy. They were evaluated by an ophthalmologist and also by neuroimaging (MRI of optic pathway). CONCLUSIONS: Pathophysiology of optic neuropathy is not completely understood. There is evidence that the damage is due to an accumulation of neurotoxic compounds secondary to the metabolic block increasing the oxidative stress. We suggest an annual ophthalmologic evaluation in the long term follow-up of organic acidurias with visual loss, in order to detect this disabling sequela at an earlier stage. PMID- 23818178 TI - Chromatin in a marine picoeukaryote is a disordered assemblage of nucleosomes. AB - Chromatin organization is central to many conserved biological processes, but it is generally unknown how the underlying nucleosomes are arranged in situ. Here, we have used electron cryotomography to study chromatin in the picoplankton Ostreococcus tauri, the smallest known free-living eukaryote. By visualizing the nucleosome densities directly, we find that O. tauri chromosomes do not arrange into discrete, compact bodies or any other higher level of order. In contrast to the textbook 30-nm fiber model, O. tauri chromatin resembles a disordered assemblage of nucleosomes akin to the polymer melt model. This disorganized nucleosome arrangement has important implications for potentially conserved functions in tiny eukaryotes such as the clustering of nonhomologous chromosomes at the kinetochore during mitosis and the independent regulation of closely positioned adjacent genes. PMID- 23818176 TI - A historical account of Hoogsteen base-pairs in duplex DNA. AB - In 1957, a unique pattern of hydrogen bonding between N3 and O4 on uracil and N7 and N6 on adenine was proposed to explain how poly(rU) strands can associate with poly(rA)-poly(rU) duplexes to form triplexes. Two years later, Karst Hoogsteen visualized such a noncanonical A-T base-pair through X-ray analysis of co crystals containing 9-methyladenine and 1-methylthymine. Subsequent X-ray analyses of guanine and cytosine derivatives yielded the expected Watson-Crick base-pairing, but those of adenine and thymine (or uridine) did not yield Watson Crick base-pairs, instead favoring "Hoogsteen" base-pairing. More than two decades ensued without experimental "proof" for A-T Watson-Crick base-pairs, while Hoogsteen base-pairs continued to surface in AT-rich sequences, closing base-pairs of apical loops, in structures of DNA bound to antibiotics and proteins, damaged and chemically modified DNA, and in polymerases that replicate DNA via Hoogsteen pairing. Recently, NMR studies have shown that base-pairs in duplex DNA exist as a dynamic equilibrium between Watson-Crick and Hoogsteen forms. There is now little doubt that Hoogsteen base-pairs exist in significant abundance in genomic DNA, where they can expand the structural and functional versatility of duplex DNA beyond that which can be achieved based only on Watson Crick base-pairing. Here, we provide a historical account of the discovery and characterization of Hoogsteen base-pairs, hoping that this will inform future studies exploring the occurrence and functional importance of these alternative base-pairs. PMID- 23818180 TI - Chiari 1 malformation and holocord syringomyelia in hunter syndrome. AB - Compressive cervical myelopathy is a well-known life-threatening complication in mucopolysaccharidosis (MPS) patients. Glycosaminoglycan accumulation in the growing cartilage results in dens dysplasia, atlanto-axial instability, and subsequent periodontoid fibrocartilaginous tissue deposition with upper cervical stenosis.Chiari malformation type 1 (CM1) is a congenital downward cerebellar tonsil ectopia determined by clivus and posterior cranial fossa underdevelopment, possibly leading to progressive spinal cord cavitation (syringomyelia) and severe neurological impairment.We present a boy affected with Hunter syndrome (MPS II) and cerebellar tonsil ectopia who developed a holocord syringomyelia at the age of 6 years. The child underwent atlanto-occipital decompressive surgery with rapid clinical and neuroimaging improvement.Sharing a primary mesenchymal involvement of the cervical-occipital region, the coexistence of CM1 in MPS might be not unexpected and complicate further the disease course. In these patients, strict monitoring and prompt treatment might be of foremost importance for preventing major neurological complications. PMID- 23818181 TI - Association between DRD2/DRD4 interaction and conduct disorder: a potential developmental pathway to alcohol dependence. PMID- 23818183 TI - Brief report: a human induced pluripotent stem cell model of cernunnos deficiency reveals an important role for XLF in the survival of the primitive hematopoietic progenitors. AB - Cernunnos (also known as XLF) deficiency syndrome is a rare recessive autosomal disorder caused by mutations in the XLF gene, a key factor involved in the end joining step of DNA during nonhomologous end joining (NHEJ) process. Human patients with XLF mutations display microcephaly, developmental and growth delays, and severe immunodeficiency. While the clinical phenotype of DNA damage disorders, including XLF Syndrome, has been described extensively, the underlying mechanisms of disease onset, are as yet, undefined. We have been able to generate an induced pluripotent stem cell (iPSC) model of XLF deficiency, which accurately replicates the double-strand break repair deficiency observed in XLF patients. XLF patient-specific iPSCs (XLF-iPSC) show typical expression of pluripotency markers, but have altered in vitro differentiation capacity and an inability to generate teratomas comprised of all three germ layers in vivo. Our results demonstrate that XLF-iPSCs possess a weak NHEJ-mediated DNA repair capacity that is incapable of coping with the DNA lesions introduced by physiological stress, normal metabolism, and ionizing radiation. XLF-iPSC lines are capable of hematopoietic differentiation; however, the more primitive subsets of hematopoietic progenitors display increased apoptosis in culture and an inability to repair DNA damage. Together, our findings highlight the importance of NHEJ mediated-DNA repair in the maintenance of a pristine pool of hematopoietic progenitors during human embryonic development. PMID- 23818182 TI - The K(+) channel GIRK2 is both necessary and sufficient for peripheral opioid mediated analgesia. AB - The use of opioid agonists acting outside the central nervous system (CNS) is a promising therapeutic strategy for pain control that avoids deleterious central side effects such as apnea and addiction. In human clinical trials and rat models of inflammatory pain, peripherally restricted opioids have repeatedly shown powerful analgesic effects; in some mouse models however, their actions remain unclear. Here, we investigated opioid receptor coupling to K(+) channels as a mechanism to explain such discrepancies. We found that GIRK channels, major effectors for opioid signalling in the CNS, are absent from mouse peripheral sensory neurons but present in human and rat. In vivo transgenic expression of GIRK channels in mouse nociceptors established peripheral opioid signalling and local analgesia. We further identified a regulatory element in the rat GIRK2 gene that accounts for differential expression in rodents. Thus, GIRK channels are indispensable for peripheral opioid analgesia, and their absence in mice has profound consequences for GPCR signalling in peripheral sensory neurons. PMID- 23818184 TI - Adult attachment and psychotic phenomenology in clinical and non-clinical samples: a systematic review. AB - OBJECTIVES: It has been argued that attachment theory could enhance our knowledge and understanding of psychotic phenomenology. DESIGN: We systematically reviewed and critically appraised research investigating attachment and psychotic phenomenology in clinical and non-clinical samples. METHODS: We searched databases Pub Med, PsycINFO, Medline and Web of Science using the keywords. Attachment, Adult Attachment, Psychosis, Schizotypy and Schizophrenia and identified 29 studies assessing adult attachment in combination with psychotic phenomenology. RESULT: The findings indicated that both insecure anxious and insecure avoidant attachment are associated with psychotic phenomenology. Insecurely attached individuals are more vulnerable to developing maladaptive coping strategies in recovering from psychosis. The importance of attachment experiences for processing social information, mentalization skills and developing social relationships, including therapeutic relationships, in samples with psychosis is also highlighted. CONCLUSION: Attachment style is a clinically relevant construct in relation to development, course and treatment of psychosis. PRACTITIONER POINTS: Understanding the role of attachment in symptoms may help to gain insight into the development or persistence of symptoms. Associations between attachment and recovery style suggest that it may be helpful to improve attachment security in a context of therapeutic relationships or other social relationships before encouraging people to explore their experiences of psychosis. Associations between insecure attachment and impaired mentalization skills may help in understanding interpersonal difficulties and this knowledge can be used to improve recovery. PMID- 23818185 TI - The burden of hip osteoarthritis in the United States: epidemiologic and economic considerations. AB - Osteoarthritis (OA) is a common and disabling disease. Because of improved treatment of chronic diseases and lower mortality from infectious diseases, the US population is aging, and older Americans are living with disabling conditions, including hip OA. The projected number of older adults with arthritis or other chronic musculoskeletal joint symptoms is expected to nearly double, from 21.4 million in 2005 to 41.1 million by 2030. The burden of hip OA is increasing due to the aging population and the obesity crisis; as a result, the need for total hip arthroplasty (THA) is expected to grow 174%, to 572,000 primary THAs per year by 2030 in the United States. Prior projections appear to have underestimated the actual number of primary and revision THAs that are in demand. PMID- 23818186 TI - Clinical diagnosis of femoroacetabular impingement. AB - The diagnosis of femoroacetabular impingement (FAI) syndrome is made based on a combination of clinical symptoms, physical examination findings, and imaging studies. A detailed assessment of each of these components is important to differentiate FAI from other intra- and extra-articular hip disorders. Clinical and physical examination findings must be viewed collectively because no single pathognomonic finding exists for FAI. Nevertheless, common components of the history and physical examination do suggest a diagnosis of FAI. PMID- 23818187 TI - Diagnostic imaging of femoroacetabular impingement. AB - Imaging studies play a key role in establishing the diagnosis of femoroacetabular impingement (FAI). When clinical examination is suggestive of FAI, radiographic evidence should confirm the diagnosis. Imaging findings must be evaluated in the context of the patient's clinical presentation and recreational activities. Plain radiographic evaluation remains the initial diagnostic modality. Three dimensional imaging such as MRI and CT often is obtained for the evaluation of labral and cartilage pathology, definition of bony anatomy, and surgical planning. PMID- 23818188 TI - Motion analysis, cartilage mechanics, and biology in femoroacetabular impingement: current understanding and areas of future research. AB - The effect and interplay of pathomorphology and joint kinematics is increasingly recognized as important in the study of femoroacetabular impingement (FAI). Hip joint kinematics consists of motion analysis at the macroscopic hip joint level. Although overall joint morphology and subject-specific kinematics are important, the cellular mechanobiology of cartilage and the biologic response to cartilage injury are poorly understood and require further study if surgeons are to understand how tissue damage actually occurs. A clearer understanding of these factors may provide the foundation for new treatments that could alter the joint injury associated with FAI. The purpose of this study group was to discuss the current evidence regarding the interaction of hip joint motion, cartilage mechanics, and cartilage biology with FAI and determine future priorities for research in these areas to expand the surgeon's ability to understand and manage this increasingly recognized clinical entity. Specific research needs were identified in four areas: motion analysis (how do muscle contributions to joint loading influence the disease process?), arthrokinematics (what happens at the joint level in vivo?), cartilage mechanics (how do cartilage cells respond to different mechanical stimuli?), and cartilage biology (need to identify biomarkers for cartilage degradation). PMID- 23818189 TI - Staging of hip osteoarthritis for clinical trials on femoroacetabular impingement. AB - Future clinical trials investigating the natural history and treatment of femoroacetabular impingement (FAI) will require multimodal staging systems for hip osteoarthritis because the optimal system will differ based on the size of the study population, the specific objective in question, and the time frame in which the investigator expects to see the specified end point. Plain radiographs are readily available, low in cost, and of unquestioned validity, but they are relatively insensitive to early joint damage. MRI allows assessment of both bony and soft-tissue pathology within the joint, and it is much more sensitive for early joint damage because cartilage is visualized directly. Biochemical imaging techniques such as delayed gadolinium-enhanced MRI of cartilage, T2 mapping, and T1rho offer the potential to identify biochemical damage to cartilage before the onset of irreversible tissue loss. In the future, biomarkers may allow earlier detection of osteoarthritis before the development of radiographic evidence of disease. PMID- 23818191 TI - Clinical trials in orthopaedics and the future direction of clinical investigations for femoroacetabular impingement. AB - Femoroacetabular impingement (FAI) represents a heterogeneous group of disorders that affect a diverse patient population. The natural history of the disease, the role of nonsurgical management, the indications for surgery, optimal surgical techniques, and the predictors of treatment outcomes need to be further defined. To date, clinical research reports have included primarily surgical case series. Future clinical investigations are needed to establish improved clinical evidence to guide patient care. Most urgent is the need to better understand the potential role of standardized nonsurgical treatment options for FAI and to define the predictors of surgical and nonsurgical outcomes. Future randomized controlled trials and large observational cohort studies targeted at these clinical research deficiencies will strengthen the evidence and improve informed decision making regarding the management of symptomatic FAI. PMID- 23818190 TI - Clinical outcomes assessment in clinical trials to assess treatment of femoroacetabular impingement: use of patient-reported outcome measures. AB - Patient-reported outcome measures are an important component of outcomes assessment in clinical trials to assess the treatment of femoroacetabular impingement (FAI). This review of disease-specific measures and instruments used to assess the generic quality of life and physical activity levels of patients with FAI found no conclusive evidence to support a single disease-specific questionnaire. Using a systematic review of study methodology, the Copenhagen Hip and Groin Outcome Score and the 33-item International Hip Outcome Tool scored the best. Nevertheless, both of these instruments were developed recently and have not been established in the literature. Although currently used generic and activity-level measures have limitations, as well, they should be considered, depending on the specific goals of the study. Additional research is needed to assess the properties of these measures fully when used to evaluate patients with FAI. PMID- 23818192 TI - Overview of treatment options, clinical results, and controversies in the management of femoroacetabular impingement. AB - The surgical management of symptomatic femoroacetabular impingement (FAI) generally is indicated after the failure of a trial of nonsurgical treatment. Surgical planning includes an assessment of the labrochondral pathology as well as of the acetabular and proximal femoral bony deformity. Advanced articular cartilage disease generally is associated with poorer outcomes. Surgical hip dislocation and hip arthroscopy have been used, with favorable early outcomes and low complication rates. Careful patient selection is important in predicting the success of the surgical management of symptomatic FAI. A trial of nonsurgical management generally is recommended, but limited information exists regarding its success. The early outcomes of both open and arthroscopic surgical techniques demonstrate significant improvement in most patients, with relatively low rates of complications. Because poorer clinical outcomes are associated with more advanced articular cartilage degeneration, improved strategies for the earlier identification and disease staging of symptomatic patients may enhance the long term outcomes of both nonsurgical and surgical management. PMID- 23818193 TI - Legg-Calve-Perthes disease and slipped capital femoral epiphysis: major developmental causes of femoroacetabular impingement. AB - Problematic femoroacetabular impingement frequently is seen following Legg-Calve Perthes disease (LCPD) in young children and following slipped capital femoral epiphysis (SCFE) in older children and adolescents. Although symptoms may be mild in adolescents and young adults, chondral damage following LCPD and SCFE deformity is cumulative and irreversible, which has led to a recent emphasis on the consideration of early treatment. The surgical dislocation approach and improved MRI and three-dimensional CT have revealed common patterns of deformity and structural damage. The surgical dislocation approach is a superb diagnostic tool unmatched in assessing complex dynamic impingement patterns, and it allows direct treatment of deformity through recontouring of the head and neck and, in unhealed SCFE, epiphyseal realignment. The contemporary hip-preserving management of deformity following LCPD and SCFE is changing rapidly, necessitating careful evaluation of new treatment methods. PMID- 23818194 TI - Femoroacetabular impingement: defining the condition and its role in the pathophysiology of osteoarthritis. AB - Femoroacetabular impingement (FAI) is an increasingly recognized cause of hip pain. It is best defined as a pathologic mechanical process by which morphologic abnormalities of the acetabulum and/or femur combined with vigorous hip motion lead to repetitive collisions that damage the soft-tissue structures within the joint itself. Based on cross-sectional studies in which FAI morphology was studied before the presence of radiographic osteoarthritis (OA), and on prevalence studies in younger, asymptomatic persons, it is clear that FAI and its morphologic risk factors are common in young adult hips and predispose to the later development of OA in certain patients. Longitudinal studies also support the assertion that, in middle-aged adults, the presence of cam deformities at baseline substantially increases the risk of developing OA and the need for total hip arthroplasty. More long-term data are needed to better define the natural history of pincer deformities as well as FAI in younger cohorts. PMID- 23818195 TI - Femoroacetabular impingement research symposium. PMID- 23818196 TI - The natural history of children with severe combined immunodeficiency: baseline features of the first fifty patients of the primary immune deficiency treatment consortium prospective study 6901. AB - The Primary Immune Deficiency Treatment Consortium (PIDTC) consists of 33 centers in North America. We hypothesized that the analysis of uniform data on patients with severe combined immunodeficiency (SCID) enrolled in a prospective protocol will identify variables that contribute to optimal outcomes following treatment. We report baseline clinical, immunologic, and genetic features of the first 50 patients enrolled, and the initial therapies administered, reflecting current practice in the diagnosis and treatment of both typical (n = 37) and atypical forms (n = 13) of SCID. From August 2010 to May 2012, patients with suspected SCID underwent evaluation and therapy per local center practices. Diagnostic information was reviewed by the PIDTC eligibility review panel, and hematopoietic cell transplantation (HCT) details were obtained from the Center for International Blood and Marrow Transplant Research. Most patients (92 %) had mutations in a known SCID gene. Half of the patients were diagnosed by newborn screening or family history, were younger than those diagnosed by clinical signs (median 15 vs. 181 days; P = <0.0001), and went to HCT at a median of 67 days vs. 214 days of life (P = <0.0001). Most patients (92 %) were treated with HCT within 1-2 months of diagnosis. Three patients were treated with gene therapy and 1 with enzyme replacement. The PIDTC plans to enroll over 250 such patients and analyze short and long-term outcomes for factors beneficial or deleterious to survival, clinical outcome, and T- and B-cell reconstitution, and which biomarkers are predictive of these outcomes. PMID- 23818198 TI - Regulations and guidelines should be strengthened urgently for re-evaluation on post-marketing medicines in China. AB - This paper reviewed the situation of regulations and guidelines on post-marketing medicines in the developed countries and in China. The developed countries have accumulated a lot of empirical principles and techniques on postmarketing surveillance (also named pharmacovigilance), therefore, their regulation systems are nearly perfect. In China, the regulations on post-marketing re-evaluation and relative technical guidelines do not cover the whole aspects, even lack in some important aspects, and long-term risk management mechanisms have not been established. So it is urgent to establish new regulations and improve the regulatory system in China based on the existing regulations and guidelines, by learning from the ideas of foreign advanced regulations, then fully integrating them with China's actual conditions, and cooperating with multidisciplinary researchers. PMID- 23818197 TI - Molecular diversity in rice blast resistance gene Pi-ta makes it highly effective against dynamic population of Magnaporthe oryzae. AB - Rice blast is one of the important diseases of rice which can be effectively managed by the deployment of resistance genes. Pi-ta is one of the major blast resistant genes effective against pathogen populations in different parts of India. We analysed allelic variants of Pi-ta from 48 rice lines selected after phenotyping of 529 rice landraces across three eco-geographical blast hot spot regions. Besides, Pi-ta orthologue sequences of 220 rice accessions belonging to wild and cultivated species of rice were also included in the study for a better evo-devo perspective of the diversity present in the gene and the selection pressures acting on this locus. We obtained high nucleotide variations (SNPs and insertion-deletions) in the intronic region. We also identified 64 haplotypes based on nucleotide polymorphism in these alleles. Pi-ta orthologues of Indian landraces were scattered in eight major haplotypes indicating its heterogenous nature. We identified a total of 47 different Pi-ta protein variants on the basis of deduced amino acid residues amongst the orthologues. Five unique and novel Pi ta variants were identified for the first time in rice landraces exhibiting different reaction types against the Magnaporthe oryzae population. A high value of Pi(non/syn) was observed only in the leucine-rich domain of the alleles cloned from Indian landraces, indicating strong selective forces acting on this region. The detailed molecular analysis of the Pi-ta orthologues provides insights to a high degree of inter- and intraspecific relationships amongst the Oryza species. We identified rice landraces possessing the effective alleles of this resistance gene which can be used in future blast resistance breeding programmes. PMID- 23818199 TI - Design and analysis of post-marketing research. AB - A post-marketing study is an integral part of research that helps to ensure a favorable risk-benefit profile for approved drugs used in the market. Because most of post-marketing studies use observational designs, which are liable to confounding, estimation of the causal effect of a drug versus a comparative one is very challenging. This article focuses on methodological issues of importance in designing and analyzing studies to evaluate the safety of marketed drugs, especially marketed traditional Chinese medicine (TCM) products. Advantages and limitations of the current designs and analytic methods for postmarketing studies are discussed, and recommendations are given for improving the validity of postmarketing studies in TCM products. PMID- 23818200 TI - Methodological approaches to developing and establishing the body of evidence on post-marketing Chinese medicine safety. AB - Evidence based medicine demands the highest form of scientific evidence to demonstrate the efficacy and clinical effectiveness for any therapeutic intervention in order to provide best care. It is however accepted that in the absence of scientific evidence, personal experience and expert opinion together with professional judgement are critical. Obtaining evidence for drug safety, postmarketing surveillance (PMS) has focussed on follow up of observational cohorts exposed to a particular drug in order to estimate the incidence of adverse drug reactions (ADRs). Evidence on PMS of Chinese herbal products is still limited, in particular for herbal injections. The aim of this article is to suggest a new model of ascertaining the safety of Chinese medicine using a more comprehensive approach for collecting data. To collect safety data on the Chinese herbal injection, Kudiezi, a mixed methods approach is proposed using 18 hospital information systems to detect ADRs in order to prospectively observe 30,000 patients over 3 years. Evidence will also be collected using a questionnaire survey and through a sample of semi structured interviews. This information based on the expert opinion and the experience of clinicians will produce additional data on the frequency and types of side effects in clinical practice. Furthermore semi structured interviews with a random sample of patients receiving the injection will be carried out to ascertain any potential side effects missed. It is hoped that this comprehensive approach to data collection will accumulate wider evidence based on individual traditional Chinese medicine care and treatment and provide important feedback to the national data collection system to ensure completeness of ADR data recording, monitoring and any potential wider effects through developing improved ADR guidelines. PMID- 23818201 TI - Efficacy of Gastrosis No.1 compound on functional dyspepsia of spleen and stomach deficiency-cold syndrome: a multi-center, double-blind, placebo-controlled clinical trial. AB - OBJECTIVE: To assess the efficacy and safety of Gastrosis No.1 compound in the treatment of functional dyspepsia with Spleen (Pi) and Stomach (Wei) deficiency cold syndrome. METHODS: A randomized, double-blind, placebo-controlled trial was performed in 5 centers. Patients with functional dyspepsia (FD) of Spleen deficiency and qi-stagnation syndrome (162 cases) were randomly assigned to groups given Chinese herbal medicine (CHM) Gastrosis No.1 compound or placebo in a 2:1 ratio. This trial included a 4-week treatment period and a 4-week follow-up period. The outcomes were the dyspepsia symptom scores (measured by total dyspepsia symptom scale and single dyspepsia symptom scale) and syndromes of traditional Chinese medicine score (measured by traditional Chinese medicine syndrome scale). The outcomes were noted at weeks 0, 4 and 8. RESULTS: Compared with patients in the placebo group, patients in the CHM group showed significant improvement in the dyspepsia symptom scores as rated by patients and investigators (P <0.01), and also showed improvement in syndromes of traditional Chinese medicine score (P <0.01). No serious adverse event was reported. Safety tests obtained after 4 weeks of treatment showed no abnormal values. CONCLUSION: CHM Gastrosis No.1 compound was effective and safe in the treatment of functional dyspepsia with Spleen and Stomach deficiency-cold syndrome. PMID- 23818202 TI - Clinical observation on treatment of clearing the Governor Vessel and refreshing the mind needling in neural development and remediation of children with cerebral palsy. AB - OBJECTIVE: To investigate the effects of clearing the Governor Vessel and refreshing the mind needling in neural development and remediation of children with cerebral palsy. METHODS: A total of 200 cases of children with cerebral palsy were randomly assigned to the treatment group (100 patients) and the control group (100 patients). The treatment group was given the combined therapy of acupuncture and rehabilitation training, and the chosen acupoints were 13 points of the Governor Vessel, Shenshu (BL 23), Taixi (KI 3), Yanglingquan (GB 34), Zusanli (ST 36) and Sanyinjiao (SP 6), and points of refreshing the mind were also selected, which included puncturing Shenting (GV 24) toward Qianding (GV 21), puncturing Qianding (GV 21) toward Baihui (GV 20), puncturing Baihui (GV 20) toward Naohu (GV 17) and Sishencong (Ex-HN 1). The control group was only treated with rehabilitation training. A contrastive analysis of the therapeutic effect between acupuncture combined with rehabilitation training and rehabilitation training alone was made after a treatment course of 3 months. The Gross Motor Function Measure (GMFM) and Beijing Gesell Developmental Scale were adopted to assess the neural development and rehabilitation outcomes of the two groups. In addition, skull CT/MRI was adopted to evaluate the plerosis of injured cerebral nerve after treatment. RESULTS: The total effective rate in treatment group was 87% (87/100), significantly higher than the 55% (55/100) in the control group. The children's development quotient (DQ) tested by Gesell Developmental Scale and scores tested by GMFM in the treatment group were obviously higher than those in the control group (P<0.01). The improving and curing rates presented by skull CT/MRI in the treatment group were higher than those in the control group (P<0.01). CONCLUSIONS: Clearing the Governor Vessel and refreshing the mind needling could accelerate the recovery of injured brain nerve and the reconstruction of brain function. The acupuncture therapy could ameliorate both the motor development and cognitive development. On the other hand, the forward curative effect of acupuncture combined with rehabilitation training was significantly better than the rehabilitation training alone. PMID- 23818203 TI - Paeonol induces vasodilatation in rat mesenteric artery via inhibiting extracellular Ca2+ influx and intracellular Ca2+ release. AB - OBJECTIVE: To investigate the vasodilative effect of paeonol in rat mesenteric artery and the mechanisms responsible for it. METHODS: Rats were anaesthetized and sacrificed. The superior mesenteric artery was removed, dissected free of adherent tissue and cut into 2.0 mm long cylindrical segments. Isometric tension of artery rings was recorded by a myograph system in vitro. Concentration relaxation curves of paeonol (17.8 MU mol/L to 3.16 mmol/L) were recorded on artery rings precontracted by potassium chloride (KCl) and concentration contraction curves of KCl, 5-hydroxytryptamine (5-HT), noradrenaline (NA) or calcium chloride (CaCl2) were recorded in the presence of paeonol (10(-4.5), 10( 3.8), 10(-3.5) mol/L) respectively. And also, concentration-relaxation curves of paeonol were recorded in the presence of different potassium channel inhibitors and propranolol on rings precontracted with KCl respectively. To investigate the role of intracellular Ca(2+) release from Ca(2+) store, the contraction induced by NA (100 MU mol/L) and CaCl2 (2 mmol/L) in Ca(2+) free medium was observed in the presence of paeonol respectively. RESULTS: Paeonol relaxed artery rings precontracted by KCl in a concentration-dependent manner and the vasodilatation effect was not affected by endothelium denudation. Paeonol significant decreased the maximum contractions (Emax) induced by KCl, CaCl2, NA and 5-HT, as well as Emax induced by NA and CaCl2 in Ca(2+) -free medium, suggesting that paeonol dilated the artery via inhibiting the extracellular Ca(2+) influx mediated by voltage-dependent calcium channel, and receptor-mediated Ca(2+)-influx and release. Moreover, none of glibenclamide, tetraethylammonium, barium chlorded and propranolol affected the paeonol-induced vasodilatation, indicating that the vasodilatation was not contributed to ATP sensitive potassium channel, calcium activated potassium channel, inwardly rectifying potassium channel, and beta adrenoceptor. CONCLUSION: Paeonol induces non-endothelium dependent vasodilatation in rat mesenteric artery via inhibiting voltage-dependent calcium channel-mediated extracellular Ca(2+) influx and receptor-mediated Ca(2+) influx and release. PMID- 23818204 TI - Effect of serum containing Jinmaitong Capsule on rats' Schwann cell apoptosis induced by high glucose concentration. AB - OBJECTIVE: To evaluate the effect of serum containing Jinmaitong Capsule (JMT) on apoptosis of Schwann cells (SCs) that are cultured in high glucose at the cellular and molecular levels. METHODS: SCs were cultured in Dulbecco's modified Eagle's medium (control group), high glucose (50 mmol/L) medium supplemented with 20% rat serum (HG group), and 50 mmol/L glucose medium supplemented with serum containing JMT (JMT group). SC apoptosis was detected using a terminal deoxynucleotidyl transferase dUTP nick end labeling kit. The expression of Bcl-2 and the caspase-3 p20 subunit in SCs were detected by realtime fluorogenic quantitative polymerase chain reaction and confocal laser scanning microscopy, respectively. RESULTS: No apoptosis was detected in SCs that were cultured in the control group. The percentage of apoptosis of SCs cultured in the HG group was much higher than that in the control group. The apoptosis of SCs in the JMT group was lower than that in the HG group. Fluorescence intensity of Bcl-2 and the expression of Bcl-2 mRNA in SCs that were cultured in the HG group were much lower than those in the control group and much higher than those in the JMT group (P<0.01). The fluorescence intensity of caspase-3 p20 and the expression of caspase-3 p20 mRNA in SCs that were cultured in the HG group were much higher than those in the control group (P<0.01), and they were remarkably lower in the JMT group (P<0.01). CONCLUSIONS: JMT effectively prevents SC apoptosis that is induced by high glucose. This effect may be because of increased expression of Bcl-2 mRNA and protein and decreased expression of caspase-3 p20 mRNA and protein. PMID- 23818205 TI - Regulation of C-type natriuretic peptides and natriuretic peptide receptor-B expression in diabetic rats renal treated by Tongluo Recipe. AB - OBJECTIVE: To investigate the expression of C-type natriuretic peptides (CNP) and natriuretic peptide receptor-B (NPR-B) receptor in diabetic rats renal cortex, and the regulation by Tongluo Recipe (TLR). METHODS: Sixty male SD rats were divided into 3 groups: the normal control group, diabetic model group and diabetic TLR group. Each group was further divided into two subgroups of ten in each, according to 4-week or 12-week observation period. Streptozotocin (STZ) induced diabetic rats were treated with TLR (1.0 g.kg(-1).d(-1)) for 4 and 12 weeks, respectively. (1) The essential information was collected for comparing renal mass, serum creatinine and 24 h urine albumen on each group was calculated. (2) CNP mRNA and NPR-B mRNA were detected by realtime-polymerase chain reaction (PCR) on rats renal cortex. (3) Concentration of CNP on renal cortex or serum were analyzed by enzyme-linked immunosorbent assay (ELISA). (4) Pathological evaluation and NPR-B immunostaining for renal tissue were also performed. RESULTS: (1) CNP and NPR-B mRNA levels were detected in each treated or untreated group, with slight elevated in untreated diabetes rats administrated with STZ after 4-week and CNP mRNA level remarkable elevated at 39.21 times higher than normal control group after 12 weeks, but NPR-B mRNA level showed a remarkably down-regulation at 98.07% after 12 weeks. CNP mRNA of TLR-treated group was also elevated after 12-week treatment, but less than untreated group. (2) Concentrations of CNP in renal cortex were obviously increased in treated or untreated diabetes rats, within these groups the treatment of TLR was found more significantly on prompting CNP concentration. Comparing to normal group, serum concentrations of CNP were also increased in treated or untreated diabetic groups, but there was no difference between these diabetic groups. (3) Renal lesions like glomerular volume increased are observed mostly in the relative early stage after 4 weeks. Although TLR treated group had no significant difference in their glomerular volume, the degrees of injury of glomerulus were ameliorated, as well as the NPR-B immunostaining enhanced in glomerulus. Weakly positive immunostaining of NPR-B are observed in glomerulus of normal control, and negative in glomerulus of untreated diabetes rats administrated with STZ after 12 weeks, whereas TLR-treatment groups showed a little enhancement. CONCLUSION: CNP and NPR-B showed different characteristic on renal cortex at different pathological period in diabetes rats, and TLR regulated their expression. PMID- 23818206 TI - Clinical study on treatment of cough variant asthma by Chinese medicine. AB - OBJECTIVE: To observe the clinical efficacy and the change of airway responsiveness to Chinese medicine (CM) in treating cough variant asthma (CVA). METHODS: Ninety-four patients who had confirmed the diagnosis of CVA were selected and randomly assigned to the treatment group and the control group by the blocked randomization method. The ratio of the two groups was 2:1. The treatment group had 63 patients that were treated by CM, lost in 10 cases, 53 patients had finished the trial. The control group had 31 patients that were treated by montelukast tablets and theophylline, lost in 5 cases, 26 patients had finished the trial, two weeks as one therapeutic course. The syndrome efficacy, cough efficacy, symptom score and the airway responsiveness between two groups were observed. RESULTS: The comparison of the syndrome efficacy: the total effective rate of the treatment group was 90.57% and the control group was 76.92%, and the two groups were significantly different (P<0.05). The comparison of the cough efficacy: the total effective rate of the treatment group was 98.11% and the control group was 80.77%, and the two groups were also significantly different (P<0.05). Syndrome scoring and cough scoring were all significantly lowered, but the airway responsiveness was not significantly lowered. CONCLUSIONS: The treatment of CM could ease the cough, improve the syndrome, and shows obvious advantages compared with the control group, which is worthy of extensive clinical application. PMID- 23818207 TI - Progress on the application of aquaporins in Chinese medicine. AB - Aquaporins are a group of membrane proteins, which are known as the passages of water molecules transforming through the biological membrane lipid bilayer and distributing in almost all of the organs and tissues of living creatures. Aquaporins play important roles in maintaining water balance and internal environment stability. As a new entry point, aquaporins are involved in the researches on water metabolism, physiological regulation and pathological essence in viscera-state more and more widely in recent years. The literature on traditional Chinese medical studies, which related to aquaporins and were published in the last decade, was reviewed and the progress on application of aquaporin in Chinese medicine was summarized in this paper. PMID- 23818208 TI - Epidemiology of fractures in Iceland and secular trends in major osteoporotic fractures 1989-2008. AB - The incidence of the most common fracture types in Iceland is reported based on individual data from the Reykjavik Study 1967-2008. Time trend is reported for the major osteoporotic fractures (MOS) 1989-2008. INTRODUCTION: This study aims to assess the incidence of all fractures in Iceland, with emphasis on the rate of hip fractures, and compare the incidence with other populations as well as examine the secular changes. METHODS: Individuals from the prospective population based cohort Reykjavik Study were examined between 1967 and 2008 (follow-up 26.5 years), which consisted of 9,116 men and 9,756 women born in 1907-1935, with age range 31-81 years. First fracture incidence was estimated using life table methods with age as the timescale. RESULTS: Fracture rate increased proportionally with age between the sexes for vertebral and proximal humerus but disproportionally for hip and distal forearm fractures. The ratio of first fracture incidence between the sexes varied considerably by site: 2.65 for hip fractures and the highest for distal forearm fractures at 4.83. By the age of 75, 36.7% of women and 21% of men had sustained a fracture, taking into account competing risk of death. The incidence of hip fractures was similar to results previously published from USA, Sweden, Norway, and Scotland. The incidence of MOS fractures in both sexes decreased over the last decade, except hip fractures in men, which remained unchanged, as reflected in the women/men ratio for the hip, which changed from 2.6 to 1.7. CONCLUSION: This study adds information to scarce knowledge on the relative fracture incidence of different fractures. The incidence of MOS fractures increased in the latter part of the last century in both sexes and declined during the last decade, less dramatically for men. This information is important for planning health resources. PMID- 23818210 TI - Application of ionomer cement onto the stapedial footplate: impact on the perilymphatic aluminum level. AB - OBJECTIVES/HYPOTHESIS: From an acoustic aspect, fixation of the medial end of an ossicular replacement prosthesis to the stapedial footplate would be desirable. Technically, ionomer cement seems an ideal material for this purpose. The objective was to determine the aluminum level of the perilymph after the application of ionomer cement on the stapedial footplate. STUDY DESIGN: An experimental study on rabbits. METHODS: A total of 25 Pannon White rabbits were divided into three groups. Five rabbits (group I) underwent sham operation; in 15 animals (group II) ionomer cement was applied onto the stapedial footplate; and in 5 cases (group III) the application of the cement onto the footplate was followed by opening of the vestibulum. In groups of 5, the animals were killed on day 1, 7, 30, 180, or 365 postoperatively. Fluid samples were taken from the vestibulum and their aluminum levels were determined. RESULTS: The average aluminum level in the fluid was insignificantly lower in group II than in group I, but significantly lower in groups I and II than in group III. CONCLUSION: As a glue, ionomer cement safely can be applied directly onto the footplate without the threat of raising the perilymphatic aluminum level, provided that there is no perilymph leakage. However, in the event of an open vestibulum, the application of cement onto the footplate is to be strongly discouraged due to the danger of a consequent increase in the aluminum level in the perilymph and the cerebrospinal fluid. LEVEL OF EVIDENCE: NA. PMID- 23818209 TI - Implications of local osteoporosis on the efficacy of anti-resorptive drug treatment: a 3-year follow-up finite element study in risedronate-treated women. AB - The existence of local osteoporosis necessitates patient-specific analysis. Lower and higher ranges of local buckling ratio were found at femoral necks for adequate and inadequate drug response groups, respectively (grouped based on fracture loads). Management of hip fracture risk should be targeted at local geometric abnormalities causing instability. INTRODUCTION: Hip fracture amongst the elderly is a growing concern especially with improvements in living standards and increasing lifespan. Approximately half of the total hip fractures result from those without osteoporosis. This escalates the need to observe local osteoporosis. By observing the local buckling ratio (BR) in the femoral neck in ten risedronate-treated subjects over 3 years, we discovered that subjects with improved fracture loads, as predicted by finite element (FE) analysis, were associated with lower local BR and vice versa. METHODS: The 3D models of the left proximal femurs were generated, and local BR values at 30 degrees intervals were obtained from femoral neck slices by measuring the respective mean cortical thickness and mean outer radius. Following geometric analysis, structural strength was examined with FE analysis where critical fracture loads (F cr) were acquired from sideways fall load simulations. RESULTS: We classified subjects in three groups according to the change in F cr: adequate (+20 %), inadequate (-22 %) and indefinite (-2 %) drug response groups. A common striking feature was that lower and higher ranges of local BR values (baseline year) were found for adequate (min = 2.14, max = 8.04) and inadequate (min = 1.72, max = 11.38) drug response groups, respectively. CONCLUSIONS: Subjects in the inadequate drug response group exhibited high local BR at the supero-anterior and supero posterior regions. These high local BR values coincided with FE-predicted critical strain regions, whereas subjects from the adequate drug response group showed significantly reduced strain regions. The superiority of coupling geometry (BR) with structure (F cr) over bone mineral density measurements alone by monitoring local osteoporosis has been illustrated. PMID- 23818211 TI - The antibody-based targeted delivery of interleukin-4 and 12 to the tumor neovasculature eradicates tumors in three mouse models of cancer. AB - Preclinical studies with recombinant murine interleukin 4 (IL4) in models of cancer have shown potent tumor growth inhibition. However, systemic administration of human IL4 to cancer patients exhibited modest antitumor activity and considerable toxicities. To improve the therapeutic index and reduce side effects of this cytokine, we developed of a novel "immunocytokine" based on sequential fusion of murine IL4 with the antibody fragment F8 (specific to the alternatively spliced extra-domain A of fibronectin, a marker for tumor angiogenesis) in diabody format. The resulting fusion protein, termed F8-IL4, retained full antigen-binding activity and cytokine bioactivity and was able to selectively localize on solid tumors in vivo. When used as single agent, F8-IL4 inhibited tumor growth in three different immunocompetent murine cancer models (F9 teratocarcinoma, CT26 colon carcinoma and A20 lymphoma). Furthermore, F8-IL4 showed synergistic effects when coadministered with immunocytokines based on IL2 and IL12. Indeed, combination therapy with an IL12-based immunocytokine yielded complete tumor eradication, in spite of the fact that IL4 and IL12 display opposite immunological mechanisms of action in terms of their polarization of T cell based responses. No weight loss or any signs of toxicity were observed in treated mice, both in monotherapy and in combination, indicating a good tolerability of the immunocytokine treatment. Interestingly, mice cured from CT26 tumors acquired a durable protective antitumor immunity. Depletion experiments indicated that the antitumor activity was mediated by CD8+ T cells and by NK cells. PMID- 23818213 TI - Massive transfusion and adverse postoperative outcomes: the message behind the drama. PMID- 23818212 TI - Three-dimensional magnetization-prepared imaging using a concentric cylinders trajectory. AB - PURPOSE: To develop new magnetization-prepared imaging schemes based on a three dimensional (3D) concentric cylinders trajectory. METHODS: The 3D concentric cylinders trajectory, which is robust to off-resonance effects and timing delays while requiring fewer excitations than a comparable 3D Cartesian (3DFT) sequence, is used as the readout for magnetization-prepared sequences exploiting its inherently centric-ordered structure. Two applications: (i) T1 -weighted brain imaging with an inversion-recovery-prepared radiofrequency-spoiled gradient-echo (IR-SPGR) sequence, (ii) non-contrast-enhanced (NCE) peripheral angiography with a magnetization-prepared balanced steady-state free precession (bSSFP) sequence are presented to demonstrate the effectiveness of the proposed method. For peripheral angiography, the scan efficiency is further improved by interleaving different preparations at different rates and by carefully designing the sampling geometry for an efficient parallel imaging method. RESULTS: In vivo brain scans with an IR-SPGR sequence and lower extremity scans with a magnetization-prepared bSSFP sequence for NCE peripheral angiography both demonstrate that the proposed sequences with concentric cylinders effectively capture the transient magnetization-prepared contrast with faster scan times than a corresponding 3DFT sequence. The application of peripheral angiography also shows the feasibility of the proposed interleaving schemes and parallel imaging method. CONCLUSION: The 3D concentric cylinders trajectory is a robust and efficient readout that is well suited for magnetization-prepared imaging. PMID- 23818214 TI - Cardiac rehabilitation after myocardial infarction: what influences patients' intentions to attend? AB - BACKGROUND: Cardiac rehabilitation (CR) programmes have increased their availability and expanded their eligibility criteria. This study sought to identify current predictors and reasons influencing myocardial infarction patients' pre-discharge intentions to attend CR. METHODS: Patients in this longitudinal, prospective, five site study completed questionnaires that surveyed their intentions to attend, attendance and main reasons for non-attendance at CR. RESULTS: 84% of the 1172 patients indicated that they intended to attend CR. Multivariate analyses revealed that age, employment and earlier history of myocardial infarction were significant predictors of intention to attend CR, yet contributed to only a small proportion of the variance. The main reasons given for not intending to attend CR were lack of interest and perception that the programme would not be beneficial. Other obstacles included work, transport or time. A total of 708 (60%) patients responded at 12 months, and of these, 44% who did not intend to attend CR had attended. CONCLUSION: Patient sociodemographic and clinical profile, although significant, are not major predictors of intention to attend CR. Lack of interest and misconceptions regarding CR are cited as key barriers. Some of these seem to have been addressed post discharge as a good proportion of patients who had not intended to attend CR did change their minds and attended. Motivation of patients to participate in CR, including the identification of barriers and the provision of comprehensive information about the purpose and varied formats of CR programmes, could be used to help further address barriers to attendance. PMID- 23818215 TI - Relationship of health-related quality of life with fatigue and exercise capacity in patients with coronary artery disease. AB - OBJECTIVE: The study objective was to evaluate the relationship of health-related quality of life (HRQoL) with fatigue and exercise capacity in coronary artery disease (CAD) patients. METHODS: A total of 1072 consecutive CAD patients on admission to a cardiac rehabilitation program were evaluated for HRQoL (36-item Short Form Medical Outcome Questionnaire; SF-36), body mass index, clinical characteristics (New York Heart Association (NYHA) class, angina pectoris class, coronary interventions, treatment with beta blockers, hypertension and diabetes), symptoms of depression and anxiety (Hospital Anxiety and Depression Scale), fatigue (Multidimensional Fatigue Inventory-20; MFI-20), and exercise capacity (bicycle ergometer test). RESULTS: In univariate regression analyses lower scores on all SF-36 domains were associated with greater scores on all MFI-20 subscales. Exercise capacity was associated with all SF-36 domains, except for social functioning and mental health domains. In multivariate regression analyses, after adjusting for age, gender, body mass index, NYHA class, angina pectoris class, hypertension, diabetes, coronary interventions, treatment with betablockers, and symptoms of depression and anxiety, greater limitation due to physical and due to emotional problems, poor social functioning, decreased energy/vitality, worse general health perception, reduced mental component summary and lower global SF 36 score were independently associated with higher MFI-20 general fatigue score. Reduced physical functioning, greater pain, and reduced physical component summary SF-36 scores were associated with greater MFI-20 physical fatigue score. Lower SF-36 mental health score was associated, with greater MFI-20 mental fatigue score. CONCLUSION: In CAD patients undergoing rehabilitation, poor HRQoL is associated with greater fatigue and decreased exercise capacity independently from mental distress and CAD severity score. PMID- 23818216 TI - Weak operator binding enhances simulated Lac repressor-mediated DNA looping. AB - The 50th anniversary of Biopolymers coincides closely with the like celebration of the discovery of the Escherichia coli (lac) lactose operon, a classic genetic system long used to illustrate the influence of biomolecular structure on function. The looping of DNA induced by the binding of the Lac repressor protein to sequentially distant operator sites on DNA continues to serve as a paradigm for understanding long-range genomic communication. Advances in analyses of DNA structures and in incorporation of proteins in computer simulations of DNA looping allow us to address long-standing questions about the role of protein mediated DNA loop formation in transcriptional control. Here we report insights gained from studies of the sequence-dependent contributions of the natural lac operators to Lac repressor-mediated DNA looping. Novel superposition of the ensembles of protein-bound operator structures derived from NMR measurements reveals variations in DNA folding missed in conventional structural alignments. The changes in folding affect the predicted ease with which the repressor induces loop formation and the ways that DNA closes between the protein headpieces. The peeling of the auxiliary operators away from the repressor enhances the formation of loops with the 92-bp wildtype spacing and hints of a structural reason behind their weak binding. PMID- 23818217 TI - Biomimetic dehydrogenative Diels-Alder cycloadditions: total syntheses of brosimones A and B. PMID- 23818219 TI - Your new neighbor. AB - Accountable care organizations (ACOs) are popping up in Texas as physicians and hospitals join the latest effort to control costs and ensure quality health care. Health system reform's focus on accountable care, coupled with employers' and payers' desire for value-based care, could mean more ACOs are in store. PMID- 23818218 TI - Brief report: deficient thymic output in rheumatoid arthritis despite abundance of prethymic progenitors. AB - OBJECTIVE: To determine the frequencies of common lymphoid progenitors (CLPs) and recent thymic emigrants (RTEs) in patients with rheumatoid arthritis (RA) and healthy control subjects. METHODS: Flow cytometry was performed to determine the frequencies of CLPs and RTEs in the peripheral blood of 101 control subjects and 51 patients with RA. Thirteen of these patients were also analyzed longitudinally for 6 months after initiation of treatment with a tumor necrosis factor (TNF) inhibitor. RESULTS: A significant correlation between the frequencies of CLPs and RTEs was observed in healthy control subjects. The frequencies of both CLPs and RTEs decreased with age and correlated inversely with absolute lymphocyte numbers in peripheral blood. In patients with RA, the frequencies of RTEs were significantly decreased compared with the frequencies in control subjects. Importantly, the frequencies of CLPs were significantly higher in patients with RA compared with control subjects. Therapeutic TNF blockade further increased the frequency of CLPs, thereby normalizing thymic output, as indicated by an increase in the number of RTEs. CONCLUSION: Thymic insufficiency in RA is not attributable to an inadequate supply of progenitor cells to the thymus. Thus, insufficient numbers of RTEs could result from inadequate thymic T cell neogenesis, or alternatively, could be a consequence of high CD4+ T cell turnover, homeostatic proliferation, and subsequent dilution of the RTE population. PMID- 23818220 TI - A painful process. AB - Selecting and implementing the right electronic health record (EHR) system due diligence by physicians, buy-in by all practitioners and staff, commitment to training, and willingness to start from scratch and learn a new way of documentation. PMID- 23818222 TI - Taking control. PMID- 23818221 TI - The night West blew up. AB - The April 17 fertilizer plant explosion that killed 15 people and injured more than 160 in the Central Texas town of West put the state's disaster response system to the test. Area health professionals and emergency responders mobilized quickly to care for the injured and prevent more deaths. PMID- 23818224 TI - Tubulin-interactive stilbene derivatives as anticancer agents. AB - Microtubules are dynamic polymers that occur in eukaryotic cells and play important roles in cell division, motility, transport and signaling. They form during the process of polymerization of alpha- and beta-tubulin dimers. Tubulin is a significant and heavily researched molecular target for anticancer drugs. Combretastatins are natural cis-stilbenes that exhibit cytotoxic properties in cultured cancer cells in vitro. Combretastatin A-4 (3'-hydroxy-3,4,4',5 tetramethoxy-cis-stilbene; CA-4) is a potent cytotoxic cis-stilbene that binds to beta-tubulin at the colchicine-binding site and inhibits tubulin polymerization. The prodrug CA-4 phosphate is currently in clinical trials as a chemotherapeutic agent for cancer treatment. Numerous series of stilbene analogs have been studied in search of potent cytotoxic agents with the requisite tubulin-interactive properties. Microtubule-interfering agents include numerous CA-4 and transresveratrol analogs and other synthetic stilbene derivatives. Importantly, these agents are active in both tumor cells and immature endothelial cells of tumor blood vessels, where they inhibit the process of angiogenesis. Recently, computer-aided virtual screening was used to select potent tubulin-interactive compounds. This review covers the role of stilbene derivatives as a class of antitumor agents that act by targeting microtubule assembly dynamics. Additionally, we present the results of molecular modeling of their binding to specific sites on the alpha- and beta-tubulin heterodimer. This has enabled the elucidation of the mechanism of stilbene cytotoxicity and is useful in the design of novel agents with improved anti-mitotic activity. Tubulin-interactive agents are believed to have the potential to play a significant role in the fight against cancer. PMID- 23818223 TI - Characterization of the 5'-flanking region of the mouse asparagine-linked glycosylation 12 homolog gene. AB - Recently, we characterized multiple roles of the endoplasmic reticulum stress responsive element (ERSE) in the promotion of a unique head-to-head gene pair: mammalian asparagine-linked glycosylation 12 homolog (ALG12) and cysteine-rich with EGF-like domains 2 (CRELD2). This bidirectional promoter, which consists of fewer than 400 base pairs, separates the two genes. It has been demonstrated that the ALG12 promoter shows less transcriptional activity through ERSE, but its basic regulatory mechanism has not been characterized. In this study, we focused on well-conserved binding elements for the transcription factors for ATF6, NF-Y and YY1 and the Sp1 and Ets families in the 5'-flanking region of the mouse ALG12 gene. We characterized their dominant roles in regulating ALG12 promoter activities using several deletion and mutation luciferase reporter constructs. The ALG12 gene is expressed in three distinct cell lines: Neuro2a, C6 glioma and HeLa cells. The reporter activity in each cell line decreased similarly with serial deletions of the mouse ALG12 promoter. Mutations in the ERSE and adjacent NF-Y-binding element slightly affected reporter activity. Each of the mutations in the GC-rich sequence and YY1-binding element reduced ALG12 promoter activity, and the combination of these mutations additively decreased reporter activity. Each mutation in the tandem-arranged Ets-family consensus sequences partially attenuated ALG12 promoter activity, and mutations of all three Ets-binding elements decreased promoter activity by approximately 40%. Mutation of the three conserved regulatory elements (GC-rich, YY1 and Ets) in the ALG12 promoter decreased reporter activity by more than 90%. Our results suggest that the promoter activity of the mouse ALG12 gene is regulated in a similar manner in the three cell lines tested in this study. The well-conserved consensus sequences in the promoter of this gene synergistically contribute to maintaining basal gene expression. PMID- 23818225 TI - Protein kinase C gamma interneurons in the rat medullary dorsal horn: distribution and synaptic inputs to these neurons, and subcellular localization of the enzyme. AB - The gamma isoform of protein kinase C (PKCgamma), which is concentrated in interneurons in the inner part of lamina II (IIi ) of the dorsal horn, has been implicated in the expression of tactile allodynia. Lamina IIi PKCgamma interneurons were shown to be activated by tactile inputs and to participate in local circuits through which these inputs can reach lamina I, nociceptive output neurons. That such local circuits are gated by glycinergic inhibition and that A- and C-fibers low threshold mechanoreceptors (LTMRs) terminate in lamina IIi raise the general issue of synaptic inputs to lamina IIi PKCgamma interneurons. Combining light and electron microscopic immunochemistry in the rat spinal trigeminal nucleus, we show that PKCgamma-immunoreactivity is mostly restricted to interneurons in lamina IIi of the medullary dorsal horn, where they constitute 1/3 of total neurons. The majority of synapses on PKCgamma-immunoreactive interneurons are asymmetric (likely excitatory). PKCgamma-immunoreactive interneurons appear to receive exclusively myelinated primary afferents in type II synaptic glomeruli. Neither large dense core vesicle terminals nor type I synaptic glomeruli, assumed to be the endings of unmyelinated nociceptive terminals, were found on these interneurons. Moreover, there is no vesicular glutamate transporter 3-immunoreactive bouton, specific to C-LTMRs, on PKCgamma immunoreactive interneurons. PKCgamma-immunoreactive interneurons contain GABAA ergic and glycinergic receptors. At the subcellular level, PKCgamma immunoreactivity is mostly concentrated on plasma membranes, close to, but not within, postsynaptic densities. That only myelinated primary afferents were found to contact PKCgamma-immunoreactive interneurons suggests that myelinated, but not unmyelinated, LTMRs play a critical role in the expression of mechanical allodynia. PMID- 23818226 TI - The transfer of host MHC class I protein protects donor cells from NK cell and macrophage-mediated rejection during hematopoietic stem cell transplantation and engraftment in mice. AB - Human hematopoietic stem cell engraftment has been studied extensively using xenograft transplant models with immunocompromised mice. It is standard practice to incorporate mouse models, such as the limiting dilution assay, to accurately assess the number of repopulating stem cells in bone marrow or umbilical cord blood collections or to confirm the long-term repopulating ability of cultured hematopoietic stem cells. In a previous study using a standard NOD/SCID mouse model to assess human hematopoietic stem cell engraftment we observed that all human cells had mouse MHC class I protein on their surface, suggesting that this is a mechanism adopted by the cells to evade host immune surveillance. To determine whether this was a xenograft phenomenon we studied host MHC transfer in an intraspecies mouse model and observed similar results. The transfer of MHC class I proteins has implications for antigen presentation and immune modulation. In this report, we used a standard mouse model of bone marrow transplantation to demonstrate that surface protein transfer between cells plays an important role in protecting donor hematopoietic cells from NK cell and macrophage-mediated rejection. The transfer of intact MHC class I antigens from host cells to transplanted donor cells confers a self identity on these otherwise foreign cells. This gives them the ability to evade detection by the host NK cells and macrophages. Once full donor chimerism is established, transplanted cells no longer require host MHC class I protein transfer to survive. PMID- 23818227 TI - The glaucoma detection capability of spectral-domain OCT and GDx-VCC deviation maps in early glaucoma patients with localized visual field defects. AB - PURPOSE: To evaluate and compare the glaucoma detection capabilities afforded by retinal nerve fiber layer (RNFL) thickness and deviation maps obtained using Cirrus spectral domain optical coherence tomography (Cirrus OCT), and GDx employing variable corneal compensation (GDx-VCC) in glaucoma patients with early, localized visual field (VF) loss. METHODS: This prospective controlled, comparative study was performed on 42 eyes with localized VF defects, and 42 age/refractive error-matched healthy eyes. All participants were imaged by both imaging devices at the same visit. The area of the RNFL defect in each deviation map, corresponding to a VF defect, was analyzed by direct counting of color-coded superpixels in each device. Receiver operating characteristic (ROC) curves were constructed and compared between Cirrus OCT and GDx-VCC. RESULTS: The areas under the ROCs (AUCs) of RNFL quadrant thicknesses in hemifields with visual field (VF) defects did not differ significantly (Cirrus OCT; 0.961, GDx-VCC; 0.919, P = 0.07). However, Cirrus OCT afforded a better diagnostic ability, by deviation map analysis, than did GDx-VCC (0.972 vs 0.887, P = 0.02). CONCLUSIONS: The RNFL thicknesses assessed by either Cirrus OCT or GDx-VCC were comparable in terms of early glaucoma diagnostic capability. However, when areas containing RNFL defects were analyzed via deviation mapping, Cirrus OCT was better than GDx-VCC. PMID- 23818229 TI - Identification of perivascular mesenchymal stromal/stem cells by flow cytometry. AB - Mesenchymal stem/stromal cells (MSCs) are adult multipotent progenitors of great promise for cell therapy. MSCs can mediate tissue regeneration, immunomodulation, and hematopoiesis support. Despite the unique properties of MSCs and their broad range of potential clinical applications, the very nature of these cells has been uncertain. Furthermore, MSCs are heterogeneous and only defined subpopulations of these are endowed with the particular abilities to sustain hematopoietic stem cells, regulate immune responses, or differentiate into mesodermal cell lineages. It is becoming evident that current criteria used to define cultured polyclonal MSCs (expression of nonspecific markers and in vitro mesodermal differentiation) are not sufficient to fully understand and exploit the potential of these cells. Here, we describe how flow cytometry has been used to reveal a perivascular origin of MSCs. As a result, the prospective purification of MSCs and specialized subsets thereof is now possible, and the clinical use of purified autologous MSCs is now within reach. PMID- 23818230 TI - Robust abdominal imaging with incomplete breath-holds. AB - PURPOSE: Breath-holding is an established strategy for reducing motion artifacts in abdominal imaging. However, the breath-holding capabilities of patients are often overstrained by scans with large coverage and high resolution. In this work, a new strategy for coping with resulting incomplete breath-holds in abdominal imaging is suggested. METHODS: A sampling pattern is designed to support image reconstruction from undersampled data acquired up to any point in time using compressed sensing and parallel imaging. In combination with a navigator-based detection of the onset of respiration, it allows scan termination and thus reconstruction only from consistent data, which suppresses motion artifacts. The spatial resolution is restricted by a lower bound of the sampling density and is increased over the scan, to strike a compromise with the signal-to noise ratio and undersampling artifacts for any breath-hold duration. RESULTS: The sampling pattern is optimized in phantom experiments and is successfully applied in abdominal gradient-echo imaging including water-fat separation on volunteers. CONCLUSIONS: The new strategy provides images in which motion artifacts are minimized independent of the breath-holding capabilities of patients, and which enhance in terms of spatial resolution, signal-to-noise ratio, and undersampling artifacts with the a priori unknown breath-hold duration actually achieved in a particular scan. PMID- 23818228 TI - The ZEB1 pathway links glioblastoma initiation, invasion and chemoresistance. AB - Glioblastoma remains one of the most lethal types of cancer, and is the most common brain tumour in adults. In particular, tumour recurrence after surgical resection and radiation invariably occurs regardless of aggressive chemotherapy. Here, we provide evidence that the transcription factor ZEB1 (zinc finger E-box binding homeobox 1) exerts simultaneous influence over invasion, chemoresistance and tumourigenesis in glioblastoma. ZEB1 is preferentially expressed in invasive glioblastoma cells, where the ZEB1-miR-200 feedback loop interconnects these processes through the downstream effectors ROBO1, c-MYB and MGMT. Moreover, ZEB1 expression in glioblastoma patients is predictive of shorter survival and poor Temozolomide response. Our findings indicate that this regulator of epithelial mesenchymal transition orchestrates key features of cancer stem cells in malignant glioma and identify ROBO1, OLIG2, CD133 and MGMT as novel targets of the ZEB1 pathway. Thus, ZEB1 is an important candidate molecule for glioblastoma recurrence, a marker of invasive tumour cells and a potential therapeutic target, along with its downstream effectors. PMID- 23818231 TI - Motor functions in trumpet playing-a real-time MRI analysis. AB - INTRODUCTION: The function of the orofacial and pharyngeal musculature for sound generation in brass instruments is insufficiently investigated. The contribution of muscles defying direct observation remains poorly understood. Time-resolved magnetic resonance imaging (MRI) allows visualization of muscle function as well as changes of the oropharyngeal cavities during muscle activation. METHODS: We used fast 3-T MRI imaging to analyze motor activation during sound generation in brass instruments. Twelve professional trumpeters were analyzed at different pitch, loudness and dynamic. MR images were analyzed for position of the mouthpiece to lips and teeth, pivoting, nasopharyngeal closure and changes in the area of oral and pharyngeal cavity. RESULTS: Of the 12 subjects, eight positioned the mouthpiece mainly to the upper lip, three in equal parts to upper and lower lip, and only one mostly to the lower lip. The last turned out to be the only subject with upward pivoting. All subjects had a complete velopharyngeal closure. Measurements of the oral and pharyngeal cavities showed an increase when subjects were playing higher pitches. The increase in areas of oral and pharyngeal cavity was present also when switching from lower to higher loudness and when performing crescendo to decrescendo. Enlargement of the oral and pharyngeal cavity was less pronounced with increasing loudness. But no general difference in change of oral and pharyngeal cavity could be observed. CONCLUSIONS: The present study shows that it is possible to measure motor function and its implications on oral as well as pharyngeal cavities during sound generation in brass instruments. These changes seem to follow a reproducible pattern. PMID- 23818232 TI - Low frequency of TERT promoter somatic mutation in 313 sporadic esophageal squamous cell carcinomas. PMID- 23818233 TI - Crystal structure of the N-terminal domain of EccA1 ATPase from the ESX-1 secretion system of Mycobacterium tuberculosis. AB - EccA1 is an important component of the type VII secretion system (T7SS) that is responsible for transport of virulence factors in pathogenic mycobacteria. EccA1 has an N-terminal domain of unknown function and a C-terminal AAA+ (ATPases associated with various cellular activities) domain. Here we report the crystal structure of the N-terminal domain of EccA1 from Mycobacterium tuberculosis, which shows an arrangement of six tetratricopeptide repeats that may mediate interactions of EccA1 with secreted substrates. Furthermore, the size and shape of the N-terminal domain suggest its orientation in the context of a hexamer model of full-length EccA1. PMID- 23818234 TI - Computational design of RNAs with complex energy landscapes. AB - RNA has become an integral building material in synthetic biology. Dominated by their secondary structures, which can be computed efficiently, RNA molecules are amenable not only to in vitro and in vivo selection, but also to rational, computation-based design. While the inverse folding problem of constructing an RNA sequence with a prescribed ground-state structure has received considerable attention for nearly two decades, there have been few efforts to design RNAs that can switch between distinct prescribed conformations. We introduce a user friendly tool for designing RNA sequences that fold into multiple target structures. The underlying algorithm makes use of a combination of graph coloring and heuristic local optimization to find sequences whose energy landscapes are dominated by the prescribed conformations. A flexible interface allows the specification of a wide range of design goals. We demonstrate that bi- and tri stable "switches" can be designed easily with moderate computational effort for the vast majority of compatible combinations of desired target structures. RNAdesign is freely available under the GPL-v3 license. PMID- 23818235 TI - Colorectal cancer is reliably excluded in the frail and elderly population by minimal preparation CT. AB - BACKGROUND: This study aimed to retrospectively assess the accuracy of minimal preparation computed tomography (MPCT) in the detection of colorectal cancer (CRC) within the frail and elderly population and to evaluate the relevance of extra-colonic findings (ECF). METHODS: Radiology reports, clinical notes and follow-up reports from 207 patients who underwent MPCT to investigate for CRC between 2005 and 2009 were analysed. Patients were scanned following the administration of oral contrast for 48 h, without bowel preparation or colonic insufflation. MPCT results were measured against patient outcomes, with a minimum of 2 years of follow-up. RESULTS: Twelve cases of clinically relevant CRC were confirmed (5.8 %). MPCT correctly identified 11 of these lesions (sensitivity 91.6 %). Thirty-one patients had a possible CRC identified by MPCT, which was not confirmed by further examination (specificity 84.1 %). This results in a positive predictive value of 26.2 % and a negative predictive value of 99.4 %. Five of the patients with colon cancer underwent curative surgery. Sixty-eight clinically relevant ECF were confirmed, including 14 previously undiagnosed extra-colonic malignancies. ECF were considered to account for the presenting complaint in 15.0 % (31/207) of all patients. CONCLUSIONS: Minimal preparation computed tomography is an effective and reliable investigation for the exclusion of clinically relevant CRC in this population. It provides clinicians with a valuable and pragmatic alternative to colonoscopy and CT colonography when invasive examination or cathartic bowel preparation will be poorly tolerated and small polyps are of limited significance. MPCT has an advantage over purely luminal imaging in the detection of extra-colonic pathology and appears to have an equally important role in the detection of CRC. PMID- 23818236 TI - Value of open horizontal glottectomy in the treatment for T1b glottic cancer with anterior commissure involvement. AB - BACKGROUND: The aim of the study was to evaluate the treatment outcomes in the group of 108 T1b glottic cancer patients with the anterior commissure involvement treated with open horizontal glottectomy and to compare them with transoral laser microsurgery (TLM) or primary radiotherapy (XRT) results from the literature review. METHODS: Status of surgical margins, local and nodal recurrence, organ preservation and survival rates, functional outcomes were major end points of interest. RESULTS: Recurrence rate was 16.7% and was correlated with histologically confirmed prelaryngeal node metastases. Salvage laryngectomy was performed in 10 patients, organ preservation rate was 90.7%. Mean survival was 41.9 months, while 5-year overall survival 97.2%. CONCLUSIONS: Local control and survival rates presented by the authors are comparable or even better than in TLM procedures or XRT outcomes from the literature. Positive prelaryngeal lymph nodes constituted a significant prognostic factor for nodal and local recurrence in the analyzed group. PMID- 23818237 TI - Adherence to home physiotherapy treatment in children and young people with joint hypermobility: a qualitative report of family perspectives on acceptability and efficacy. AB - OBJECTIVE: Joint hypermobility can lead to pain and motor developmental problems in children and young people (CYP). Exercise programmes may help CYP with joint hypermobility strengthen core muscle groups. Non- adherence to home physiotherapy is common. The present study aimed to understand how families experienced an intensive multidisciplinary intervention. METHOD: This was a qualitative study nested within a randomized controlled trial of a multidisciplinary treatment intervention, including physiotherapy, for children aged five to 17 years. Twenty eight families were recruited following the intervention. Semi-structured interviews were used to examine the views and expectations of parents and CYP, and examine adherence to the exercise programme. Thematic analysis of data was used to develop findings. RESULTS: Parents and CYP reported that exercise reduced the symptoms of hypermobility. Parental motivation, adapting family routines, making exercise a family activity and seeing benefit increased adherence to exercise. Non-adherence to exercise was linked to lower levels of parental supervision, not understanding the treatment, not seeing benefit and not having specific time to dedicate to doing the exercises. CONCLUSION: Even when exercise is seen to benefit a child's well-being, families experience challenges in adhering to a physiotherapy programme for hypermobility. Therapists can utilize findings on what enhances adherence to help CYP effectively exercise in the home setting. PMID- 23818238 TI - Structural and optical properties of Cu-doped ZnS nanoparticles formed in chitosan/sodium alginate multilayer films. AB - Chitosan/alginate multilayers were fabricated using a spin-coating method, and ZnS:Cu nanoparticles were generated within the network of two natural polysaccharides, chitosan and sodium alginate. The synthesized nanoparticles were characterized using an X-ray diffractometer (XRD), transmission electron microscopy (TEM), energy dispersive spectroscopy (EDS) and atomic force microscopy (AFM). The results showed that cubic zinc blende-structured ZnS:Cu nanoparticles with an average crystal size of ~ 3 nm were uniformly distributed. UV-vis spectra indicate a large quantum size effect and the absorption edge for the ZnS:Cu nanoparticles slightly shifted to longer wavelengths with increasing Cu ion concentrations. The photoluminescence of the Cu-doped ZnS nanoparticles reached a maximum at a 1% doping level. The ZnS:Cu nanoparticles form and are distributed uniformly in the composite multilayer films with a surface average height of 25 nm. PMID- 23818239 TI - Effect of bariatric surgery on bone mineral density: comparison of gastric bypass and sleeve gastrectomy. AB - The aim of our study was to compare bone mineral density (BMD) a year after Roux en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) in age- and body mass index-matched women. In 33 morbidly obese women undergoing RYGB and 33 undergoing SG, plasma determinations of calcium, parathyroid hormone (PTH), 25 hydroxyvitamin D (25(OH) D3), and insulin-like growth factor-I (IGF-I) were made prior to and at 12 months after surgery. Dual-energy X-ray absorptiometry was performed in all patients 1 year after surgery. BMD at the femoral neck and the lumbar spine 1 year after surgery was similar in women undergoing RYGB and SG (1.01 +/- 0.116 vs. 1.01 +/- 0.122 g/cm(2), p = 0.993; 1.05 +/- 0.116 vs. 1.08 +/ 0.123 g/cm(2), p = 0.384). The percentage of patients with osteopenia and osteoporosis was not different between groups. In the linear regression analysis, age (beta = -0.628, p = 0.034) and lean mass 12 months after surgery (beta = 0.424, p = 0.021) were found to be the main determinants of femoral neck BMD. Age (beta = -0.765, p = 0.025), menopause (beta = -0.898, p = 0.033), and lean mass (beta = 0.615, p = 0.023) were determinants of BMD at the lumbar spine. No influence was found between low bone mass and type of surgery, plasma PTH, 25(OH) D3, or IGF-I. The effect of RYGB and SG on BMD was comparable a year after surgery. Menopausal women were at a higher risk of having low bone mass, but the presence of osteoporosis was uncommon. PMID- 23818241 TI - Rosai-Dorfman disease with extranodal involvement. AB - Rosai-Dorfman disease is a rare condition of marrow hematopoietic stem-cell origin. Patients can show extranodal involvement as well as lymphatic involvement, but only about 5% of extranodal cases involve intracranial lesions. A 53-year-old male was admitted to our hospital with bilateral cervical lymphadenopathy. Intracranial tumors and bone lesions were also detected. Cervical lymph node biopsy and intracranial tumor resection were performed, and histopathological examination revealed Rosai-Dorfman disease. The patient showed good clinical course without significant enlargement of the tumor. This study describes the case of a patient with Rosai-Dorfman disease presenting with massive cervical lymphadenopathy mimicking malignant neoplasm. PMID- 23818242 TI - [Accidental destruction of stone trapping baskets: new knowledge on the interaction of baskets, stone trapping devices, guide wires and lithotriptors - a brief review]. AB - There is a rise in the incidence of stone disease in the industrial nations. Due to this, the number of endurological procedures will also rise. Sometimes endourological instruments will be fragmented accidentally together with the destruction of the stone. A search for articles on this subject was performed. The aim of this article is to provide a review about the literature on this subject and how this subject can be managed today and in the future. PMID- 23818240 TI - SGTA: a new player in the molecular co-chaperone game. AB - Small glutamine-rich tetratricopeptide repeat-containing protein alpha (SGTA) is a steroid receptor molecular co-chaperone that may substantially influence hormone action and, consequently, hormone-mediated carcinogenesis. To date, published studies describe SGTA as a protein that is potentially critical in a range of biological processes, including viral infection, cell division, mitosis, and cell cycle checkpoint activation. SGTA interacts with the molecular chaperones, heat shock protein 70 (HSP70) and HSP90, and with steroid receptor complexes, including those containing the androgen receptor. Steroid receptors are critical for maintaining cell growth and differentiation in hormonally regulated tissues, such as male and female reproductive tissues, and also play a role in disease states involving these tissues. There is growing evidence that, through its interactions with chaperones and steroid receptors, SGTA may be a key player in the pathogenesis of hormonally influenced disease states, including prostate cancer and polycystic ovary syndrome. Research into the function of SGTA has been conducted in several model organisms and cell types, with these studies showing that SGTA functionality is cell-specific and tissue-specific. However, very few studies have been replicated in multiple cell types or experimental systems. Although a broad range of functions have been attributed to SGTA, there is a serious lack of mechanistic information to describe how SGTA acts. In this review, published evidence linking SGTA with hormonally regulated disease states is summarized and discussed, highlighting the need for future research to more clearly define the biological function(s) of this potentially important co chaperone. PMID- 23818243 TI - Detection of B-cell populations with monotypic light chain expression in cerebrospinal fluid specimens from patients with multiple sclerosis by polychromatic flow cytometry. AB - BACKGROUND: Flow cytometric immunophenotyping is an established method for the detection of occult leptomeningeal disease in patients with aggressive B-cell non Hodgkin lymphoma, and is increasingly being used in the evaluation of patients without an established diagnosis of lymphoma who present with signs and/or symptoms referable to the central nervous system. However, the specificity of flow cytometric immunophenotyping in the identification of monoclonal B-cell populations in cerebrospinal fluid (CSF) has not been systematically evaluated. METHODS: We searched a consecutive series of CSF specimens submitted to our laboratory for polychromatic (8-color) flow cytometric immunophenotyping between June, 2010 and December, 2012 for cases in which a B-cell population with monotypic immunoglobulin light chain expression was detected in patients without clinical or radiographic evidence of lymphoma. RESULTS: A B-cell population with monotypic light chain expression was identified in CSF specimens from three patients whose subsequent clinical and radiologic evaluation provided no evidence for lymphoma. In all three patients, a diagnosis of multiple sclerosis was ultimately rendered upon completion of the clinical evaluation. CONCLUSIONS: We conclude that the detection of a B-cell population with monotypic light chain expression in CSF by polychromatic flow cytometry is not diagnostic of occult leptomeningeal involvement by a B-cell non-Hodgkin lymphoma. Moreover, these findings suggest that monotypic B-cell populations detectable by polychromatic flow cytometry may be prevalent in patients with multiple sclerosis, and highlight the importance of clinicopathologic correlation in this application of polychromatic flow cytometry. PMID- 23818244 TI - Ex vivo porcine model to measure pH dependence of chemical exchange saturation transfer effect of glycosaminoglycan in the intervertebral disc. AB - PURPOSE: Studies have linked low pH and loss of glycosaminoglycan (GAG) in the intervertebral discs (IVDs) of patients with discogenic back pain. The purpose of this study is to determine whether the chemical exchange saturation transfer (CEST) effect of GAG (gagCEST) is pH dependent and whether it can be used to detect pH changes in IVD specimens. Iopromide, a Food and Drug Administration approved agent for CT/X-Ray, was also evaluated as a pH-sensitive CEST probe to explore the agents' potential to measure IVD pH. METHODS: The pH dependency of the CEST effect of chondroitin sulfate (containing GAG) and Iopromide phantoms was investigated at 7 T. Z-spectra from porcine IVD specimens were acquired before and after manipulating the pH with sodium lactate. Iopromide was injected into the specimens and the calibration curve was used to determine the pH status. RESULTS: Chondroitin sulfate showed a non-linear dependence of gagCEST effect with pH and gagCEST signal differences were detected in the specimens. The CEST effect of Iopromide resulted in a sigmoidal relation with pH and was used to measure pH. CONCLUSION: gagCEST is sensitive to pH and enables investigation of the IVD pH status. Iopromide CEST is independent of the local GAG concentration and has the potential for measuring pH in the IVD. PMID- 23818245 TI - Food and beverage advertising on children's web sites. AB - BACKGROUND: Food marketing contributes to childhood obesity. Food companies commonly place display advertising on children's web sites, but few studies have investigated this form of advertising. OBJECTIVES: Document the number of food and beverage display advertisements viewed on popular children's web sites, nutritional quality of advertised brands and proportion of advertising approved by food companies as healthier dietary choices for child-directed advertising. METHODS: Syndicated Internet exposure data identified popular children's web sites and food advertisements viewed on these web sites from July 2009 through June 2010. Advertisements were classified according to food category and companies' participation in food industry self-regulation. The percent of advertisements meeting government-proposed nutrition standards was calculated. RESULTS: 3.4 billion food advertisements appeared on popular children's web sites; 83% on just four web sites. Breakfast cereals and fast food were advertised most often (64% of ads). Most ads (74%) promoted brands approved by companies for child-directed advertising, but 84% advertised products that were high in fat, sugar and/or sodium. Ads for foods designated by companies as healthier dietary choices appropriate for child-directed advertising were least likely to meet independent nutrition standards. CONCLUSIONS: Most foods advertised on popular children's web sites do not meet independent nutrition standards. Further improvements to industry self-regulation are required. PMID- 23818246 TI - Sorafenib relieves cell-intrinsic and cell-extrinsic inhibitions of effector T cells in tumor microenvironment to augment antitumor immunity. AB - Sorafenib, a multitargeted antiangiogenic tyrosine kinase inhibitor, is the standard of care for patients with advanced hepatocellular carcinoma (HCC). Cumulating evidence suggests that sorafenib differentially affects immune cells; however, whether this immunomodulatory effect has any impact on antitumor immune responses is unknown. Using an orthotopic mouse model of HCC and tumor-free mice, we investigated the effects of sorafenib on antitumor immunity and characterized the underlying mechanisms. Sorafenib treatment inhibited tumor growth and augmented antitumor immune responses in mice bearing established orthotopic HCC. The tumor-specific effector T cell functions were upregulated, while the proportion of PD-1-expressing CD8(+) T cells and regulatory T cells (Tregs) was reduced in tumor microenvironment of sorafenib-treated mice. Mechanistically, the sorafenib-mediated effects on Tregs could be independent of its direct tumor suppressing activities. Sorafenib treatment reduced Treg numbers by inhibiting their proliferation and inducing apoptosis. Moreover, sorafenib inhibited the function of Tregs, characterized by diminished expression of Treg-associated molecules important for their function and by their impaired suppressive capacity. These data reveal that sorafenib treatment enhanced functions of tumor specific effector T cells as well as relieved PD-1-mediated intrinsic and Treg mediated non-cell-autonomous inhibitions in tumor microenvironment leading to effective antitumor immune responses. In addition to the well-known tumor inhibiting activity of sorafenib, its enhancement of antitumor immunity may also contribute to the clinical efficacy. Our findings uncover a previously unrecognized mechanism of action of sorafenib and indicate that sorafenib represents a potential targeted agent suitable to be combined with immunotherapeutic approaches to treat cancer patients. PMID- 23818247 TI - A new technique to perform pelvic osteotomy using Gigli saw. PMID- 23818249 TI - Security analysis and improvement of a privacy authentication scheme for telecare medical information systems. AB - Nowadays, patients can gain many kinds of medical service on line via Telecare Medical Information Systems(TMIS) due to the fast development of computer technology. So security of communication through network between the users and the server is very significant. Authentication plays an important part to protect information from being attacked by malicious attackers. Recently, Jiang et al. proposed a privacy enhanced scheme for TMIS using smart cards and claimed their scheme was better than Chen et al.'s. However, we have showed that Jiang et al.'s scheme has the weakness of ID uselessness and is vulnerable to off-line password guessing attack and user impersonation attack if an attacker compromises the legal user's smart card. Also, it can't resist DoS attack in two cases: after a successful impersonation attack and wrong password input in Password change phase. Then we propose an improved mutual authentication scheme used for a telecare medical information system. Remote monitoring, checking patients' past medical history record and medical consultant can be applied in the system where information transmits via Internet. Finally, our analysis indicates that the suggested scheme overcomes the disadvantages of Jiang et al.'s scheme and is practical for TMIS. PMID- 23818248 TI - Reversing bone loss by directing mesenchymal stem cells to bone. AB - Bone regeneration by systemic transplantation of mesenchymal stem cells (MSCs) is problematic due to the inability to control the MSCs' commitment, growth, and differentiation into functional osteoblasts on the bone surface. Our research group has developed a method to direct the MSCs to the bone surface by conjugating a synthetic peptidomimetic ligand (LLP2A) that has high affinity for activated alpha4beta1 integrin on the MSC surface, with a bisphosphonates (alendronate) that has high affinity for bone (LLP2A-Ale), to direct the transplanted MSCs to bone. Our in vitro experiments demonstrated that mobilization of LLP2A-Ale to hydroxyapatite accelerated MSC migration that was associated with an increase in the phosphorylation of Akt kinase and osteoblastogenesis. LLP2A-Ale increased the homing of the transplanted MSCs to bone as well as the osteoblast surface, significantly increased the rate of bone formation and restored both trabecular and cortical bone loss induced by estrogen deficiency or advanced age in mice. These results support LLP2A-Ale as a novel therapeutic option to direct the transplanted MSCs to bone for the treatment of established bone loss related to hormone deficiency and aging. PMID- 23818251 TI - Removal of collagen nerve conduits (NeuraGen) after unsuccessful implantation: focus on histological findings. AB - Nerve conduits are nonneural, hollow tubular structures designed to bridge the gap of a sectioned nerve, to protect the nerve from scar formation, and to guide the regenerating fibers into the distal nerve stump. In the 8-year experience of our department, four patients aged 14 to 50 years had an unsuccessful implantation of a nerve conduit (NeuraGen, Integra, Plainsboro, NJ). In these four patients, the collagen tubes were replaced by an autogenous nerve graft. The histological specimens showed characteristic histological findings of a scar neuroma without any signs of foreign body reaction in three cases and with minimal foreign body reaction in one case. The collagen nerve tube was completely resorbed in all cases after a time period of 6 to 17 months and could not be detected marco- or microscopically.To our knowledge, this is the first report in the English and German literature describing the histological characteristics of explanted collagen nerve tubes in humans. PMID- 23818250 TI - Extension of the germinal center stage of B cell development promotes autoantibodies in BXD2 mice. AB - OBJECTIVE: Regulator of G protein signaling (RGS) proteins inhibit chemokine signaling by desensitizing G protein-coupled receptor signals. This study was undertaken to determine the mechanisms by which RGS13 promotes the generation of pathogenic autoantibodies in germinal centers (GCs), using BXD2-Rgs13-/- mice. METHODS: Confocal and light microscopy imaging techniques were used to determine the location of cells that express RGS13 and activation-induced cytidine deaminase (AID) in the mouse spleen, and the number of plasmablasts. The levels of GC and plasma cell program transcripts in GC B cells were determined by real time quantitative polymerase chain reaction (qPCR). Differential interleukin-17 (IL-17)-mediated expression of RGS13 in GC versus non-GC B cells was analyzed using A20 and 70Z/3 B cells. RESULTS: In the spleens of BXD2 mice, RGS13 was mainly expressed by GC B cells and was stimulated by IL-17 but not IL-21. IL-17 up-regulated RGS13 in A20 GC cells but not 70Z/3 non-GC B cells. BXD2- Rgs13-/- mice exhibited smaller GCs and lower AID levels, suggesting lower somatic hypermutation and affinity maturation. However, GC B cells from BXD2- Rgs13-/- mice showed increased levels of IgMbright plasmablasts, up-regulation of the genes encoding plasma program, including interferon regulatory factor 4, B lymphocyte-induced maturation protein 1, and X-box binding protein 1 and the p CREB target genes Fosb and Obf1, and down-regulation of the GC program genes Aid, Pax5, and Bach2 compared to BXD2 mice. BXD2-Rgs13-/- mice had lower titers of IgG autoantibodies and IgG deposits in the glomeruli, suggesting reduced autoantibody pathogenicity. CONCLUSION: RGS13 deficiency is associated with a reduction in GC program genes and the exit of fewer pathogenic IgM plasmablasts in BXD2 mice. Our findings indicate that prolonged GC program, mediated by up-regulation of RGS13, enhances AID expression and enables the generation of pathogenic autoantibodies in autoreactive GCs. PMID- 23818252 TI - LyMPHA and the prevention of lymphatic injuries: a rationale for early microsurgical intervention. PMID- 23818253 TI - Cross-face nerve grafting for reanimation of incomplete facial paralysis: quantitative outcomes using the FACIAL CLIMA system and patient satisfaction. AB - Although in most cases Bell palsy resolves spontaneously, approximately one-third of patients will present sequela including facial synkinesis and paresis. Currently, the techniques available for reanimation of these patients include hypoglossal nerve transposition, free muscle transfer, and cross-face nerve grafting (CFNG). Between December 2008 and March 2012, eight patients with incomplete unilateral facial paralysis were reanimated with two-stage CFNG. Gender, age at surgery, etiology of paralysis denervation time, donor and recipient nerves, presence of facial synkinesis, and follow-up were registered. Commissural excursion and velocity and patient satisfaction were evaluated with the FACIAL CLIMA and a questionnaire, respectively. Mean age at surgery was 33.8 +/- 11.5 years; mean time of denervation was 96.6 +/- 109.8 months. No complications requiring surgery were registered. Follow-up period ranged from 7 to 33 months with a mean of 19 +/- 9.7 months. FACIAL CLIMA showed improvement of both commissural excursion and velocity greater than 75% in 4 patients, greater than 50% in 2 patients, and less than 50% in the remaining two patients. Qualitative evaluation revealed a high grade of satisfaction in six patients (75%). Two-stage CFNG is a reliable technique for reanimation of incomplete facial paralysis with a high grade of patient satisfaction. PMID- 23818255 TI - Integrity of stent polymer layer after drug-eluting stent implantation: in vivo comparison of sirolimus-, paclitaxel-, zotarolimus- and everolimus-eluting stents. AB - Few data exist with regard to the polymer integrity of drug-eluting stents (DES) in vivo. This study aims to investigate the integrity of the polymer layer of 4 polymer-coated DES in vivo. We assessed the morphology of the polymer layer of sirolimus-eluting stent (SES; Cypher SelectTM), paclitaxel-eluting stent (PES; Taxus LiberteTM), zotarolimus-eluting stent (ZES; Endeavour RXTM) and everolimus eluting stent (EES; Xience VTM) by scanning electron microscopy after balloon expansion at nominal and high pressures in the coronary arteries of 3 pigs. Effects of kissing balloon procedure were also explored. The polymer layer of SES, PES and EES were damaged in less than 3 % of the surface area with high pressure procedures, whereas the damaged area reached 38.0 +/- 2.6 % in ZES (P < 0.01). The polymer integrity differed greatly among DES after balloon inflation in vivo. This should be taken into account when placing DES in tortuous vessels, calcified, as well as bifurcation lesions because the polymer layer may be easily damaged in these lesions. PMID- 23818254 TI - Disease-causing mutations in the XIAP BIR2 domain impair NOD2-dependent immune signalling. AB - X-linked Inhibitor of Apoptosis (XIAP) is an essential ubiquitin ligase for pro inflammatory signalling downstream of the nucleotide-binding oligomerization domain containing (NOD)-1 and -2 pattern recognition receptors. Mutations in XIAP cause X-linked lymphoproliferative syndrome type-2 (XLP2), an immunodeficiency associated with a potentially fatal deregulation of the immune system, whose aetiology is not well understood. Here, we identify the XIAP baculovirus IAP repeat (BIR)2 domain as a hotspot for missense mutations in XLP2. We demonstrate that XLP2-BIR2 mutations severely impair NOD1/2-dependent immune signalling in primary cells from XLP2 patients and in reconstituted XIAP-deficient cell lines. XLP2-BIR2 mutations abolish the XIAP-RIPK2 interaction resulting in impaired ubiquitylation of RIPK2 and recruitment of linear ubiquitin chain assembly complex (LUBAC) to the NOD2-complex. We show that the RIPK2 binding site in XIAP overlaps with the BIR2 IBM-binding pocket and find that a bivalent Smac mimetic compound (SMC) potently antagonises XIAP function downstream of NOD2 to limit signalling. These findings suggest that impaired immune signalling in response to NOD1/2 stimulation is a general defect in XLP2 and demonstrate that the XIAP BIR2 RIPK2 interaction may be targeted pharmacologically to modulate inflammatory signalling. PMID- 23818256 TI - Synthesis of chiral aliphatic amines through asymmetric hydrogenation. PMID- 23818258 TI - Juvenile recurrent parotitis: a retrospective comparison of sialendoscopy versus conservative therapy. AB - OBJECTIVES/HYPOTHESIS: There are several therapeutic approaches to treat juvenile recurrent parotitis. The aim of this study was to compare sialendoscopy, including prophylactic cortisone irrigation, with observation and a conservative approach of antibiotic therapy alone. STUDY DESIGN: Retrospective study, tertiary clinical center. METHODS: The charts of patients treated for juvenile recurrent parotitis between November 2004 and June 2011 were reviewed. Initial acute flares were always treated with a course of antibiotics. Subsequent treatment consisted of either salivary gland endoscopy including cortisone irrigation or additional pure antibiotic therapy. Patients treated with salivary endoscopy were compared to patients treated with antibiotics alone with regard to the number of inflammatory episodes and pain intensity pre- and posttreatment. RESULTS: Thirty six patients were treated during the period of study, 15 with salivary endoscopy with cortisone irrigation and 21 with antibiotic therapy alone. A significant reduction in recurrent episodes and pain intensity following therapy was found in both groups. With respect to these two outcomes, the comparison showed two therapeutic options of equal merit. CONCLUSIONS: Salivary gland endoscopy is an option in the management of juvenile recurrent parotitis that helps in confirming the diagnosis and that also provides therapeutic intervention. However, although there are further advantages, the definitive value of salivary gland endoscopy requires ongoing evaluation in further prospective studies. LEVEL OF EVIDENCE: 4. PMID- 23818257 TI - Antimicrobial prophylaxis to prevent perioperative infection in urological surgery: a multicenter study. AB - We prospectively investigated the rates of incidence of surgical site infection (SSI), urinary tract infection (UTI), and remote infection (RI) in 4,677 patients who underwent urological surgery from January to December 2010, including 2,507 endourological cases, 1,276 clean cases, 807 clean-contaminated cases, and 87 contaminated cases involving bowel segments. A single dose of antimicrobial prophylaxis (AMP) was administered in the endourological, clean, and clean contaminated surgery cases, except for patients who underwent transurethral resection of the prostate (TURP) or percutaneous nephrolithotripsy (PNL). AMP was administered within 72 h in TURP and PNL, and AMP was administered within 48 h in contaminated surgery cases. In cases of endourological surgery, UTI was observed in 4% and RI in 0%, and SSI, UTI, and RI were seen in 1%, 1%, and 1%, respectively, of clean surgery cases, in 3%, 3%, and 2%, respectively, of clean contaminated surgery cases, and in 17%, 30%, and 10%, respectively, of contaminated surgery cases. In multivariate analysis of the risk factors for infection, operative time was a significant risk factor for UTI in endourological surgery, and American Society of Anesthesiologists score and operative time were significant risk factors for RI in clean surgery. No significant risk factor was found in analyses of clean-contaminated and contaminated surgery cases. A single dose AMP regimen was shown to be effective and feasible for prevention of perioperative infection in urological surgery. PMID- 23818259 TI - Specific attitudes which predict psychology students' intentions to seek help for psychological distress. AB - OBJECTIVE: Although many postgraduate psychology programs address students' mental health, there are compelling indications that earlier, undergraduate, interventions may be optimal. We investigated specific attitudes that predict students' intentions to seek treatment for psychological distress to inform targeted interventions. METHOD: Psychology students (N = 289; mean age = 19.75 years) were surveyed about attitudes and intentions to seek treatment for stress, anxiety, or depression. RESULTS: Less than one quarter of students reported that they would be likely to seek treatment should they develop psychological distress. Attitudes that predicted help-seeking intentions related to recognition of symptoms and the benefits of professional help, and openness to treatment for emotional problems. CONCLUSIONS: The current study identified specific attitudes which predict help-seeking intentions in psychology students. These attitudes could be strengthened in undergraduate educational interventions promoting well being and appropriate treatment uptake among psychology students. PMID- 23818260 TI - Modification of cysteine residues by cyclopentenone prostaglandins: interplay with redox regulation of protein function. AB - Cyclopentenone prostaglandins (cyPG) are endogenous lipid mediators involved in the resolution of inflammation and the regulation of cell proliferation and cellular redox status. Upon exogenous administration they have shown beneficial effects in models of inflammation and tissue injury, as well as potential antitumoral actions, which have raised a considerable interest in their study for the development of therapeutic tools. Due to their electrophilic nature, the best known mechanism of action of these mediators is the covalent modification of proteins at cysteine residues through Michael addition. Identification of cyPG targets through proteomic approaches, including MS/MS analysis to pinpoint the modified residues, is proving critical to characterize their mechanisms of action. Among the targets of cyPG are proinflammatory transcription factors, proteins involved in cell defense, such as the regulator of the antioxidant response Keap1 and detoxifying enzymes like GST, and key signaling proteins like Ras proteins. Moreover, cyPG may interact with redox-active small molecules, such as glutathione and hydrogen sulfide. Much has been learned about cyPG in the past few years and this knowledge has also contributed to clarify both pharmacological actions and signaling mechanisms of these and other electrophilic lipids. Given the fact that many cyPG targets are involved in or are targets for redox regulation, there is a complex interplay with redox-induced modifications. Here we address the modification of protein cysteine residues by cyPG elucidated by proteomic studies, paying special attention to the interplay with redox signaling. PMID- 23818261 TI - A network of interorganellar communications underlies cellular aging. AB - Organelles within a eukaryotic cell respond to age-related intracellular stresses and environmental factors by altering their functional states to generate, direct and process the flow of interorganellar information that is essential for establishing a pro- or antiaging cellular pattern. The scope of this review is to critically analyze recent progress in understanding how various intercompartmental (i.e., organelle-organelle and organelle-cytosol) communications regulate cellular aging in evolutionarily distant eukaryotes. Our analysis suggests a model for an intricate network of intercompartmental communications that underly cellular aging in eukaryotic organisms across phyla. This proposed model posits that the numerous directed, coordinated and regulated organelle-organelle and organelle-cytosol communications integrated into this network define the long-term viability of a eukaryotic cell and, thus, are critical for regulating cellular aging. PMID- 23818262 TI - How catalase recognizes H2O2 in a sea of water. AB - Monofunctional heme-catalases have been studied for many decades but there is still an incomplete understanding of why such a large tetrameric protein with deeply buried active sites is required to accomplish such a simple reaction as H2 O2 dismutation. Catalase accomplishes this reaction at a high rate although water at 55 M is expected to compete with H2 O2 for the enzyme's active site. Using molecular dynamics simulations we addressed the question as to how catalase selects H2 O2 in water. Selection is accomplished through different mechanisms: higher residence time of H2 O2 in the vicinity of certain prevalent amino acid residues at the protein surface and substrate channel, coordinated motion of the main passage amino acids that is increased in the presence of H2 O2 , a gate valve mechanism consisting of the motion of two contiguous phenylalanine residues that drive water molecules out of the final section of the substrate channel, a hydrophobic barrier before the active site that was crossed more easily by H2 O2 which kept most of its hydrogen bonds while passing, and finally an increased residence time for H2 O2 at the active site. These mechanisms, based on the physicochemical differences between H2 O2 and water, provide an explanation as to why such a large tetrameric protein with deeply buried active sites is required to accomplish efficient H2 O2 dismutation. PMID- 23818263 TI - High disease activity: an independent factor for reduced immunogenicity of the pandemic influenza a vaccine in patients with juvenile systemic lupus erythematosus. AB - OBJECTIVE: Recent findings demonstrated a reduced immunogenicity of the influenza A H1N1/2009 vaccine in juvenile rheumatic diseases. However, a point of concern is whether the vaccine could induce disease flares. The aim of this study was to assess the disease safety of and the possible influence of disease parameters and therapy on nonadjuvant influenza A H1N1 vaccine response of juvenile systemic lupus erythematosus (SLE) patients. METHODS: One hundred eighteen juvenile SLE patients and 102 healthy controls of a comparable age were vaccinated. Seroprotection rate, seroconversion rate, and factor increase in geometric mean titer (GMT) were calculated and effective immune response was defined by the Food and Drug Administration and the European Committee for Proprietary Medicinal Products vaccine immunologic standards. Disease parameters, treatment, and adverse events were evaluated. RESULTS: Age was comparable in juvenile SLE patients and controls (mean +/- SD 16.0 +/- 3.5 versus 15.9 +/- 4.5 years; P = 0.26). Three weeks after immunization, seroprotection rate (73.7% versus 95.1%; P < 0.001), seroconversion rate (63.6% versus 91.2%; P < 0.001), GMT (90.8 versus 273.3; P < 0.001), and factor increase in GMT (8.1 versus 19.9; P < 0.001) were significantly lower in juvenile SLE patients versus controls. Nonseroconversion was associated with a higher frequency of patients with a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score >=8 (48.8% versus 24%; P = 0.008) and a higher mean +/- SD current glucocorticoid dosage (18 +/- 21.4 versus 10.5 +/- 12.5 mg/day; P = 0.018). Multivariate logistic regression including a SLEDAI-2K score >=8 revealed that only the SLEDAI-2K remained a significant factor for nonseroconversion (odds ratio 0.42, 95% confidence interval 0.18-0.98; P = 0.045). Disease parameters remained stable throughout the study and no severe vaccine adverse events were observed. CONCLUSION: The present study demonstrated adequate disease safety and is the first to discriminate that high disease activity impairs influenza A H1N1/2009 vaccine antibody production in juvenile SLE, in spite of an overall immune response within recommended levels. PMID- 23818268 TI - Assessment of dermal safety of Scutellaria baicalensis aqueous extract topical application on skin hypersensitivity. AB - Scutellaria baicalensis has been used as a traditional herbal medicine for bronchitis, hepatitis, and allergic diseases. The root of Scutellaria baicalensis contains active flavonoid components, including baicalin, baicalein, wogonoside, and wogonin, which have pharmaceutical properties. In the present study, the antiallergic properties of a standardized aqueous extract of S. baicalensis were evaluated, and the skin toxicity of its dermal application was also determined. The in vivo and in vitro assays were performed by using the beta-hexosaminidase assay in rat basophilic leukemia cells (RBL-2H3) and cutaneous skin reaction in BALB/c mice, respectively. In addition, the acute dermal irritation/corrosion test was carried out in New Zealand white rabbits, and the skin sensitization test was conducted by Buhler's method in Hartley guinea pigs to estimate the safety of the standardized aqueous extract of S. baicalensis for topical application. beta-Hexosaminidase release in RBL-2H3 was markedly decreased following treatment with the standardized aqueous extract of S. baicalensis. It also ameliorated antigen-induced ear swelling compared with the control group in BALB/c mice. In the toxicological studies, it did not induce any dermal irritation/corrosion in rabbits or skin sensitization in guinea pigs. Although still limited, these results concerning the toxicological effects of S. baicalensis could be an initial step toward the topical application of S. baicalensis extracts on hypersensitive skin. PMID- 23818269 TI - New 23-spirocholestane derivatives from Ypsilandra thibetica. AB - Three new unusual 23-spirocholestane derivatives, ypsilanogenin (1), ypsilanogenin 3-O-beta-D-glucopyranoside (2), and 4'-acetylypsilanogenin 3-O-beta D-glucopyranoside (3), were isolated from the whole plants of Ypsilandra thibetica. The structures of compounds 1-3 were deduced by spectroscopic and chemical methods, and the structure of 1 was further confirmed by a single crystal diffraction analysis. All isolates were evaluated for their inhibitory activities against HIV-1. PMID- 23818270 TI - Embryonic stem cells neural differentiation qualifies the role of Wnt/beta Catenin signals in human telencephalic specification and regionalization. AB - Wnt-ligands are among key morphogens that mediate patterning of the anterior territories of the developing brain in mammals. We qualified the role of Wnt signals in regional specification and subregional organization of the human telencephalon using human pluripotent stem cells (hPSCs). One step neural conversion of hPSCs using SMAD inhibitors leads to progenitors with a default rostral identity. It provides an ideal biological substrate for investigating the role of Wnt signaling in both anteroposterior and dorso-ventral processes. Challenging hPSC-neural derivatives with Wnt-antagonists, alone or combined with sonic hedgehog (Shh), we found that Wnt-inhibition promote both telencephalic specification and ventral patterning of telencephalic neural precursors in a dose dependent manner. Using optimal Wnt-antagonist and Shh-agonist signals we produced human ventral-telencephalic precursors, committed to differentiation into striatal projection neurons both in vitro and in vivo after homotypic transplantation in quinolinate-lesioned rats. This study indicates that sequentially organized Wnt-signals play a key role in the development of human ventral telencephalic territories from which the striatum arise. In addition, the optimized production of hPSC-derived striatal cells described here offers a relevant biological resource for exploring and curing Huntington disease. PMID- 23818271 TI - alpha-mangostin: one of the best dietary supplements. PMID- 23818275 TI - New design concept of monopole antenna array for UHF 7T MRI. AB - PURPOSE: We have developed and evaluated a monopole antenna array that can increase sensitivity at the center of the brain for 7T MRI applications. METHODS: We have developed a monopole antenna array that has half the length of a conventional dipole antenna with eight channels for brain imaging with a 7T MRI. The eight-channel monopole antenna array and conventional eight-channel transceiver surface coil array were evaluated and compared in terms of transmit properties, specific absorption ratio (SAR), and sensitivity. The sensitivity maps were generated by dividing the SNR map by the flip angle distribution. RESULTS: A single surface coil provides asymmetric sensitivity resulting in reduced sensitivity at the center of the brain. In contrast, a single monopole antenna provides higher sensitivity at the center of the brain. Moreover, the monopole antenna array provides uniform sensitivity over the entire brain, and the sensitivity gain was 1.5 times higher at the center of the brain compared with the surface coil array. CONCLUSION: The monopole antenna array is a promising candidate for MRI applications, especially for brain imaging in a 7T MRI because it provides increased sensitivity at the center of the brain. PMID- 23818276 TI - Brief report: the IL23R nonsynonymous polymorphism rs11209026 is associated with radiographic sacroiliitis in spondyloarthritis. AB - OBJECTIVE: Spondyloarthritis (SpA) is a group of inflammatory articular disorders sharing a genetic background. The nonsynonymous single-nucleotide polymorphism (SNP) rs11209026 (Arg381Gln) in the IL23R gene has reproducibly been shown to be associated with ankylosing spondylitis (AS). We undertook this study to examine the association between rs11209026 and SpA as a whole, with particular attention devoted to genotype/phenotype correlation. METHODS: The SNP rs11209026 was genotyped in a French cohort of 415 patients/372 controls, with replication analysis performed in 383 "trios," each consisting of 1 patient with SpA and both parents. Association analysis was carried out in SpA as a whole group and then separately in AS and non-AS patients. Phenotype/genotype correlations were examined using logistic regression analysis. RESULTS: A significant association between rs11209026 and SpA overall was identified only in the familial data set (odds ratio 0.57, P=0.028). Strong association with AS was observed in both the case-control and familial data sets (P=4.5*10(-4) and P=4.0*10(-3), respectively). In contrast, such association was not detected in the non-AS group. Furthermore, rs11209026 frequency was significantly different between AS and non-AS patients (P=1.5*10(-3)). Phenotype/genotype correlation study revealed that both radiographic sacroiliitis and early age at onset were independently associated with a lower frequency of the rare protective rs11209026 allele A in patients (P=9*10(-3) and P=8*10(-3), respectively). CONCLUSION: Our study replicated the robust association between rs11209026 and AS in the French population. However, such association was restricted to AS, as compared to SpA without radiographic sacroiliitis. The fact that it was independently conditional on radiographic sacroiliitis and age at onset suggests that rs11209026 could affect disease severity rather than susceptibility. PMID- 23818277 TI - Voice disorders in the workplace: productivity in spasmodic dysphonia and the impact of botulinum toxin. AB - OBJECTIVES/HYPOTHESIS: The impact of the disordered voice on standard work productivity measures and employment trends is difficult to quantify; this is in large part due to the heterogeneity of the disease processes. Spasmodic dysphonia (SD), a chronic voice disorder, may be a useful model to study this impact. Self reported work measures (worked missed, work impairment, overall work productivity, and activity impairment) were studied among patients receiving botulinum toxin (BTX) treatments for SD. It was hypothesized that there would be a substantial difference in work-related measures between the best and worst voicing periods. In addition, job types, employment shifts, and vocal requirements during the course of vocal disability from SD were investigated for each individual, and the impact of SD on these patterns was studied. STUDY DESIGN: A total of 145 patients with SD, either adductor or abductor, who were established in routine therapeutic BTX injections agreed to participate in a self administered questionnaire study. Seventy-two participants were currently working and provided highly detailed information on work-related measures. Their answers characterized the effect of SD on their employment status, productivity at work, activity impairment outside of work, employment retention or change, and whether the individual perceived that BTX therapy affected these measures. Patients were asked to complete the Work Productivity and Activity Impairment (WPAI) instrument to determine these measures for their best and worst voicing weeks over the duration since their previous BTX injection. Voice-specific quality of life instruments (Voice Handicap Index-10) and perceptual assessments (Consensus Auditory Perceptual Evaluation of Voice) were elicited to provide correlations of work measures with patient-perceived voice handicap and clinician-perceived voice quality. METHODS: Cross-sectional analysis using self-administered questionnaire. RESULTS: A total of 108 patients reported ever working during their diagnosis and treatment of SD, and 72 patients were currently working and had undergone BTX therapy for at least 1 year at the time of the analysis. Currently employed patients reported a mean 4.4% decrease in work missed (absenteeism), a 28.1% decrease in work impairment (presenteeism), a 29.4% decrease in work productivity, and a 21.4% decrease in activity impairment (P <.001) in their best, as compared to their worst voicing period over their last BTX injection cycle. Presenteeism accounted for the major component of the percent work productivity impairment calculation. There was neither apparent shift in job categories nor any change in the vocal demands of their employment over the course of their disease. Among patients that have worked during their diagnosis of SD, greater than 98% report that BTX injections helped them at work. CONCLUSIONS: Patients with SD reported that their vocal dysfunction caused a significant negative effect on work productivity and increase in activity impairment. There was a significant improvement in their voice-related work parameters from their worst to best voicing periods over their last BTX injection cycle. Patients undergoing long-term BTX treatment report a positive effect of this treatment in their workplace. Spasmodic dysphonia is a meaningful model in which to study the effects of voice disorders on work productivity and employment patterns. PMID- 23818278 TI - Pressure-induced polyamorphism and formation of 'aragonitic' amorphous calcium carbonate. PMID- 23818279 TI - Chiral enol oxazolines and thiazolines as auxiliary ligands for the asymmetric synthesis of ruthenium-polypyridyl complexes. AB - Various ligands, such as (Z)-1-phenyl-2-[(4S)-4-phenyl-4,5-dihydro-1,3-oxazol-2 yl]ethen-1-ol ((S)-1a) and (Z)-1-phenyl-2-[(4S)-4-phenyl-4,5-dihydro-1,3-thiazol 2-yl]ethen-1-ol ((S)-1c), were investigated as auxiliaries for the asymmetric synthesis of chiral ruthenium(II) complexes. The reaction of these chiral auxiliary ligands with [RuCl2(dmso)4], 2,2'-bipyridine (bpy, 2.2 equiv), and triethylamine (10 equiv) in DMF/PhCl (1:8) at 140 degrees C for several hours diastereoselectively provided the complexes Lambda-[Ru(bpy)2{(S)-1a-H}] (Lambda (S)-2a, 52 % yield, 56:1 d.r.) and Lambda-[Ru(bpy)2{(S)-1c-H}] (Lambda-(S)-2c, 48 % yield, >100:1 d.r.) in a single step after purification. Both Lambda-(S)-2a and Lambda-(S)-2c could be converted into Lambda-[Ru(bpy)3](PF6)2 by replacing the bidentate enolato ligands with bpy, under retention of configuration, induced by either NH4PF6 as a weak acid (from Lambda-(S)-2a: 73 % yield, 22:1 e.r.; from Lambda-(S)-2c: 77 % yield, 22:1 e.r.), TFA as a strong acid (from Lambda-(S)-2a: 72 % yield, 52:1 e.r.; from Lambda-(S)-2c: 85 % yield, 25:1 e.r.), methylation with Meerwein's salt (from Lambda-(S)-2a: 59 % yield, 46:1 e.r.; from Lambda-(S) 2c: 86 % yield, 37:1 e.r.), ozonolysis (from Lambda-(S)-2a: 56 % yield, 22:1 e.r.; from Lambda-(S)-2c: 43 % yield, 6.3:1 e.r.), or oxidation with a peroxy acid (from Lambda-(S)-2a: 72 % yield, 45:1 e.r.; from Lambda-(S)-2c: 79 % yield, 8.5:1 e.r.). This study shows that, except for the reaction with NH4PF6, oxazoline-enolato complex Lambda-(S)-2a provides Lambda-[Ru(bpy)3](PF6)2 with higher enantioselectivities than analogous thiazoline-enolato complex Lambda-(S) 2c, which might be due to the higher coordinative stability of the thiazoline enolato complex, thus requiring more prolonged reaction times. Thus, this study provides attractive new avenues for the asymmetric synthesis of non-racemic ruthenium(II)-polypyridyl complexes without the need for using a strong acid or a strong methylating reagent, as has been the case in all previously reported auxiliary methods from our group. PMID- 23818280 TI - Association between fee-for-service expenditures and morbidity burden in primary care. AB - BACKGROUND: In primary care, fee-for-services (FFS) tariffs are often based on political negotiation rather than costing systems. The potential for comprehensive measures of patient morbidity to explain variation in negotiated FFS expenditures has not previously been examined. OBJECTIVES: To examine the relative explanatory power of morbidity measures and related general practice (GP) clinic characteristics in explaining variation in politically negotiated FFS expenditures. METHODS: We applied a multilevel approach to consider factors that explain FFS expenditures among patients and GP clinics. We used patient morbidity characteristics such as diagnostic markers, multimorbidity casemix adjustment based on resource utilisation bands (RUB) and related GP clinic characteristics for the year 2010. Our sample included 139,527 patients visiting GP clinics. RESULTS: Out of the individual expenditures, 31.6% were explained by age, gender and RUB, and around 18% were explained by RUB. Expenditures increased progressively with the degree of resource use (RUB0-RUB5). Adding more patient specific morbidity measures increased the explanatory power to 44%; 3.8-9.4% of the variation in expenditures was related to the GP clinic in which the patient was treated. CONCLUSIONS: Morbidity measures were significant patient-related FFS expenditure drivers. The association between FFS expenditure and morbidity burden appears to be at the same level as similar studies in the hospital sector, where fees are based on average costing. However, our results indicate that there may be room for improvement of the association between politically negotiated FFS expenditures and morbidity in primary care. PMID- 23818281 TI - An empirical analysis of the multimarket contact theory in pharmaceutical markets. AB - Multimarket contact theory predicts that firms will optimally reduce prices in markets where collusive prices are sustainable and allocate the slack of the corresponding incentive compatibility to increase prices in markets where collusion is not sustainable. Binding price caps in collusive markets will have different effects over the multimarket contact mechanism depending on the severity of the cap. Setting a price cap close to the unregulated case will increase the size of the redistribution of market power whereas stronger regulation will even reduce prices in unregulated markets. Therefore, price regulations aiming at capping prices in a specific market will also affect markets that are not subject to specific mandatory price regulations. We find evidence of the theory predictions using information for nine OECD countries for pharmaceutical markets. Unregulated US markets are shown to respond to the redistribution effect; Canadian markets, known to be subject to soft price regulations, with respect to the former, are shown to be consistent with a stronger redistribution effect. EU markets and Japan are either consistent with the effect of a medium regulation or strong regulation. In this last case multimarket contact cannot explain prices, and these are expected to be lower compared to the unregulated benchmark. PMID- 23818282 TI - [Socio-demographic, biological and clinical profile of patients living with HIV during screening in a voluntary counselling and screening centre in a rural area of Mbanza-Ngungu, Democratic Republic of Congo, in 2006-2011]. AB - AIDS remains a public health problem in the Democratic Republic of Congo (DRC). However, there is little information on the medical situation of the disease in rural areas. The objective of this study is to describe the HIV infection in a rural zone in the province of Bas-Congo, DRC. The medical records of patients with a diagnosis of HIV/AIDS, followed in the centre of voluntary counselling and testing (VCT) of the general hospital Nsona-Nkulu in the city of Mbanza-Ngungu, DRC, from January 2006 to June 2011, were retrospectively reviewed. Socio demographic profile, laboratory data and mode of detection were analyzed. During this study, 167 patients were identified as HIV positive (112 females and 54 males). The majority of patients were aged between 30 and 44 years and two out of three patients were not married; 77.3% had primary schooling. Testing for HIV was performed in 78% of patients during an episode of illness. Screening for unprotected sex was a rare event (0.7%). Co-infection with tuberculosis was present in 32% of our patients while 26% had shingles and 44.5% had sexually transmitted infection. Smoking was found slightly (14%) and alcoholism was reported in 37% of patients. Weight loss greater than 10% was found in 61% of patients. Over 80% of people tested positive for HIV were in later stages (stages 3 and 4). This study demonstrates that HIV infection remains a serious public health problem in rural zone. The factors militating for the use of awareness program for preventive measures need to be urgently addressed. PMID- 23818283 TI - Progress on the development of rapid methods for antimicrobial susceptibility testing. AB - Antimicrobial susceptibility testing is essential for guiding the treatment of many types of bacterial infections, especially in the current context of rising rates of antibiotic resistance. The most commonly employed methods rely on the detection of phenotypic resistance by measuring bacterial growth in the presence of the antibiotic being tested. Although these methods are highly sensitive for the detection of resistance, they require that the bacterial pathogen is isolated from the clinical sample before testing and must employ incubation times that are sufficient for differentiating resistant from susceptible isolates. Knowledge regarding the molecular determinants of antibiotic resistance has facilitated the development of novel approaches for the rapid detection of resistance in bacterial pathogens. PCR-based techniques, mass spectrometry, microarrays, microfluidics, cell lysis-based approaches and whole-genome sequencing have all demonstrated the ability to detect resistance in various bacterial species. However, it remains to be determined whether these methods can achieve sufficient sensitivity and specificity compared with standard phenotypic resistance testing to justify their use in routine clinical practice. In the present review, we discuss recent progress in the development of methods for rapid antimicrobial susceptibility testing and highlight the limitations of each approach that still remain be addressed. PMID- 23818284 TI - NDM-1 carbapenemase-producing Salmonella enterica subsp. enterica serovar Corvallis isolated from a wild bird in Germany. PMID- 23818285 TI - Neutrophil gelatinase-associated lipocalin, a marker of tubular dysfunction, is not increased in long-term virologically controlled patients receiving a tenofovir/emtricitabine + nevirapine regimen. AB - OBJECTIVES: Tenofovir may be associated with nephrotoxicity. Several studies have shown that an early increase in urinary neutrophil gelatinase-associated lipocalin (NGAL) may predict the occurrence of acute kidney injury. We investigated urine and plasma NGAL in patients on long-term treatment with nevirapine associated with either tenofovir/emtricitabine or abacavir/lamivudine. PATIENTS AND METHODS: We studied 40 virologically controlled Caucasian patients on stable treatment (median >4 years) with tenofovir/emtricitabine + nevirapine (n = 20) or abacavir/lamivudine + nevirapine (n = 20), and no history of kidney disease, high blood pressure or diabetes. Plasma immunovirological parameters (NGAL and C-reactive protein) and urinary NGAL, beta2-microglobulin and alpha1 microglobulin were measured during a routine clinical visit. RESULTS: Median concentrations of NGAL were in the normal range, but were significantly higher in the abacavir/lamivudine group compared with the tenofovir/emtricitabine group both in the plasma, at 74.9 and 66.0 ng/mL (P = 0.032), respectively, and in the urine, at 36.1 and 12.8 ng/mL (P = 0.017), respectively. CONCLUSIONS: Plasma and urinary NGAL concentrations remained in the normal range in this long-term virologically controlld population without any overt renal disease. The usefulness of NGAL in detecting sub-clinical renal dysfunction appears to be very limited. PMID- 23818286 TI - Knowledge and attitude of dental trauma among mothers in Iraq. AB - AIM: To evaluate the knowledge and attitude of Iraqi mothers regarding dental trauma prevention and management. STUDY DESIGN AND METHODS: Mothers (n = 231) that visited two professional dental centres in Mosul, Iraq, were interviewed and asked to answer a three-part questionnaire containing questions about demographic variables, attitudes and knowledge of dental trauma. STATISTICS: The relationships of the demographic variables with the total knowledge score of the correct responses were analysed using two-sample t tests. The number of correct responses regarding management of avulsed teeth compared to that of fractured teeth was evaluated using a paired t test. A 5 % level of statistical significance was applied for the analyses. RESULTS: The mean knowledge score was 5.2 (on a scale of 0-10). No significant differences were found in knowledge score with respect to mothers' age, educational level, working status, personal experience with dental trauma or first aid training (p > 0.05). Mothers with either at least a high school education or previous experience with dental trauma were more likely to recommend that their children wear mouth guards during sports (p = 0.02 and p = 0.03, respectively). Mothers who were 35 years of age and older were more likely to know how to correctly carry an avulsed tooth to a dentist. Mothers' knowledge regarding management of fractured teeth was significantly higher than that of avulsed teeth (p < 0.0001). CONCLUSIONS: Mothers in Mosul, Iraq, did not have sufficient knowledge about the prevention and management of traumatic dental injuries. Intervention programmes should be considered to increase mothers' awareness regarding dental injuries. PMID- 23818287 TI - Interarm differences in systolic blood pressure and mortality among US army veterans: aetiological associations and risk prediction in the Vietnam Experience Study. AB - BACKGROUND: Differences between the arms in systolic blood pressure (SBP) of >=10 mmHg have been associated with an increased risk of mortality in patients with hypertensive and chronic renal disease. For the first time, we examined these relationships in a non-clinical population. DESIGN: Cohort study. METHODS: Participants were 4419 men (mean age 38.37 years) from the Vietnam Experience Study. Bilateral SBP and diastolic BP (DBP), serum lipids, fasting glucose, erythrocyte sedimentation rate, metabolic syndrome, and ankle brachial index were assessed in 1986. RESULTS: Ten per cent of men had an interarm difference of >=10 and 2.4% of >=15 mmHg. A 15-year follow-up period gave rise to 246 deaths (64 from cardiovascular disease, CVD). Interarm differences of >=10 mmHg were associated with an elevated risk of all-cause mortality (hazard ratio, HR, 1.49, 95% confidence interval, CI, 1.04-2.14) and CVD mortality (HR 1.93, 95% CI 1.01 3.69). After adjusting for SBP, DBP, lipids, fasting glucose, and erythrocyte sedimentation rate, associations between interarm differences of >=10 mmHg and all-cause mortality (HR 1.35, 95% CI 0.94-1.95) and CVD mortality (1.62, 95% CI 0.84-3.14) were significantly attenuated. CONCLUSIONS: In this non-clinical cohort study, interarm differences in SBP were not associated with mortality after accounting for traditional CVD risk factors. Interarm differences might not be valuable as an additional risk factor for mortality in populations with a low risk of CVD. PMID- 23818288 TI - Heart rate and blood pressure interactions in the development of erectile dysfunction in high-risk cardiovascular patients. AB - AIMS: Erectile dysfunction (ED) is associated with cardiovascular risk factors as elevated systolic blood pressure (SBP), resting high heart rate (HR), and endothelial dysfunction and predicts cardiovascular events. However, the interaction between high HR and SBP and the development of ED remains unclear. METHODS AND RESULTS: We evaluated 1015 male patients enrolled in the ED substudy of ONTARGET and TRANSCEND, examining the influence of mean HR and mean SBP obtained over all study visits (mean 10.9+/-1.4 study visits) and their interaction with ED. In patients without pre-existing ED, new onset ED was detected in 29% of patients below, and 41% of patients above, the median of mean HR (OR 1.72, 95% CI 1.8-2.5, p = 0.0047). In patients with pre-existing ED, high HR had no add-on effect. With or without pre-existing ED, high SBP had no influence after adjustment for covariates (OR 1.03, 95% CI 0.66-1.59, p = 0.91). In a continuous model, it was shown that effects of high HR were prominent at low Kolner (Cologne) Evaluation of Erectile Function (KEED) score baseline values and in the presence of SBP above the median. CONCLUSIONS: In patients at risk for cardiovascular events, high HR is associated with ED, whereas the effect of high SBP was not significant. High resting HR might represent a cardiovascular risk indicator. Whether HR represents a potential treatment target to improve ED in high-risk individuals must be scrutinized in prospective trials. PMID- 23818289 TI - Use of mindful reappraisal coping among meditation practitioners. AB - OBJECTIVE: By enhancing positive affect and cognitive flexibility, mindfulness practice may promote reappraisal of stressors. We hypothesized that coping through mindful reappraisal would be common among mindfulness practitioners from an array of traditions. METHOD: A sample of 118 meditation practitioners completed an online survey comprising assessments of the prevalence and frequency of mindful reappraisal, as well as measures of well-being and distress. RESULTS: Regular use of mindful reappraisal was reported by over half of the sample and was significantly correlated with years of meditation practice (r = .31, p = .01), meditation practice days per month (r = .30, p = .001), and meditation hours per week (r = .30, p = .001). Controlling for frequency of meditation practice and trait mindfulness, mindful reappraisal frequency explained significant portions of variance in well-being (P <.001) and distress (P <.001). CONCLUSIONS: Meditation practitioners commonly employ mindful reappraisal coping as a positive emotion regulatory strategy in stressful contexts. PMID- 23818290 TI - Fisetin protects against hepatosteatosis in mice by inhibiting miR-378. AB - SCOPE: Lipid homeostasis in vertebrates is regulated at many levels including synthesis, degradation, and distribution. MicroRNAs (miRNAs) are key regulators of lipid homeostasis. The use of phytochemicals to target miRNA (miR) could provide new therapeutic approaches to human diseases. Thus, we investigated the regulation of lipid metabolism by the flavonoid fisetin during experimental analysis of hepatic miRs in mice. METHODS AND RESULTS: Mice were separated into three groups. One group was maintained on the normal diet and the other two groups were fed either a high-fat (HF) diet or HF supplemented with fisetin. We found that fisetin lowered hepatic fat accumulation in HF mice and reversed abnormal expressions of lipid metabolism genes. The co-expression of miR-378 and its host gene PGC-1beta was significantly induced by HF, whereas fisetin prevented the induction of both genes. We also identified nuclear respiratory factor-1 (NRF-1), a critical regulator of the mitochondrial function, as a direct target of miR-378. CONCLUSION: Dietary fisetin protects against hepatosteatosis in association with modulation of lipid metabolism genes and miR-378 in mice. These observations suggest that the use of fisetin to target miRs could be an effective prevention or intervention against metabolic diseases. PMID- 23818292 TI - [Understanding ventilator-induced diaphragmatic dysfunction (VIDD): progress and advances]. AB - There is rising evidence that ventilator-induced diaphragmatic dysfunction (VIDD) is not just an artifactual finding from animal studies, but actually occurs in humans undergoing invasive mechanical ventilation. Initial research findings in humans have demonstrated that periods of controlled invasive mechanical ventilation lasting just 18 - 69 hours can lead to a marked reduction in diaphragmatic myofibers. More recently, it has been shown that even short periods (e. g. two-hours) of controlled invasive mechanical ventilation are sufficient to initiate VIDD. The evidence available at present suggests that VIDD is most likely based on increased proteolysis of the respiratory muscles. Moreover, VIDD seems not to be part of a general muscle wasting process, as suggested by the fact that e. g. the human latissimus dorsi and the pectoralis major muscles seem not to be subjected to early muscle fiber atrophy when directly compared to the human diaphragm. Novel in vivo data have also revealed that VIDD in humans is associated with a reduction in diaphragmatic force generation after only one day of controlled invasive mechanical ventilation. This impairment was observed to progress further over the one-week investigation period. The introduction of a simple bedside ultrasound measurement of diaphragmatic function is of great importance to the clinician, as it may serve as a surrogate measure for VIDD, with high predictive value. Regarding potential therapeutic interventions against VIDD, the primary aim should be to encourage sufficient diaphragmatic use in susceptible patients so as to avoid VIDD; this approach remains in fundamental contrast to that of reducing respiratory muscle load by (invasive) mechanical ventilation. PMID- 23818291 TI - IGF-1-mediated osteoblastic niche expansion enhances long-term hematopoietic stem cell engraftment after murine bone marrow transplantation. AB - The efficiency of hematopoietic stem cell (HSC) engraftment after bone marrow (BM) transplantation depends largely on the capacity of the marrow microenvironment to accept the transplanted cells. While radioablation of BM damages osteoblastic stem cell niches, little is known about their restoration and mechanisms governing their receptivity to engraft transplanted HSCs. We previously reported rapid restoration and profound expansion of the marrow endosteal microenvironment in response to marrow radioablation. Here, we show that this reorganization represents proliferation of mature endosteal osteoblasts which seem to arise from a small subset of high-proliferative, relatively radio resistant endosteal cells. Multiple layers of osteoblasts form along the endosteal surface within 48 hours after total body irradiation, concomitant with a peak in marrow cytokine expression. This niche reorganization fosters homing of the transplanted hematopoietic cells to the host marrow space and engraftment of long-term-HSC. Inhibition of insulin-like growth factor (IGF)-1-receptor tyrosine kinase signaling abrogates endosteal osteoblast proliferation and donor HSC engraftment, suggesting that the cytokine IGF-1 is a crucial mediator of endosteal niche reorganization and consequently donor HSC engraftment. Further understanding of this novel mechanism of IGF-1-dependent osteoblastic niche expansion and HSC engraftment may yield clinical applications for improving engraftment efficiency after clinical HSC transplantation. PMID- 23818293 TI - Role of endothelin A receptor in colon cancer metastasis: in vitro and in vivo evidence. AB - The endothelin (ET)-1/endothelin A receptor (ETAR) axis is reportedly involved in tumor cell invasion, survival, and metastasis. However, the role of ETAR in colon cancer metastasis and the underlying mechanisms have not been defined. In the present study, we assessed the role of ETAR in colon cancer metastasis in vitro and in vivo. Overexpression and knockdown of ETAR were respectively performed in SW480 and SW620 human colon cancer cells. Overexpression of ETAR in SW480 cells significantly increased cell survival against cisplatin, cell invasion, and matrix metalloproteinase (MMP)-2 expression, which was strengthened by exogenous ET-1 and abolished by selective ETAR antagonist BQ123 and phosphatidylinositol 3 kinase (PI3K) inhibitor LY294002. Knockdown of ETAR in SW620 cells markedly decreased cell survival against cisplatin, cell invasion, and MMP-2 expression, which was strengthened by BQ123 and LY294002, and partially rescued by exogenous ET-1. In a colon cancer liver metastasis mouse model, while ETAR overexpression promoted colon cancer liver metastases, ETAR knockdown markedly decreased liver metastases. In conclusion, our in vitro data demonstrate that ETAR mediates the promoting effects of ET-1 on colon cancer cell survival, invasion and MMP-2 expression by a PI3K-mediated mechanism. Our in vivo data indicate that ETAR markedly promotes colon cancer liver metastasis. This study provides direct evidence for a critical role of ETAR in colon cancer metastasis, which suggests that ETAR antagonism could benefit patients with metastatic colon cancer. PMID- 23818294 TI - Molecular dynamics of (E)-6-acetyl-3-(2-hydroxy-5-methylphenyl)-5-styryl cyclohex 2-en-1-one and (E)-6-ethylcarboxylate-3-(2-hydroxy-5-methylphenyl)-5-styryl cyclohex-2-en-1-one in a solution studied by NMR spectroscopy. AB - Molecular dynamics of cyclohexenone derivatives of (2E,4E)-1-(2-hydroxy-5 methylphenyl)-5-phenyl-2,4-pentadiene-1-one (chalcone) has been investigated in solutions using NMR. The results confirm the formation of O-H...O intramolecular hydrogen bond and the presence of keto-enol tautomeric transitions in the (E)-6 acetyl-3-(2-hydroxy-5-methylphenyl)-5-styryl cyclohex-2-en-1-one. The free energy of activation for the keto-enol tautomeric transitions has been calculated. The keto-enol tautomerism in the investigated compound has been also confirmed by chemical method. PMID- 23818296 TI - Improved wound healing of postischemic cutaneous flaps with the use of bone marrow-derived stem cells. AB - OBJECTIVES/HYPOTHESIS: To determine if the intravascular delivery of mesenchymal stem cells improves wound healing and blood perfusion to postischemic cutaneous flap tissues. STUDY DESIGN: Randomized controlled study. METHODS: A murine model of a cutaneous flap was created based on the inferior epigastric vessels. Mice (n = 14) underwent 3.5 hours of ischemia followed by reperfusion. Bone marrow stromal cells (BMSCs) 1 * 10(6) were injected intravenously. Wound healing was then assessed measuring percent flap necrosis, flap perfusion, and tensile strength of the flap after a period of 14 days. Localization of BMSCs was determined with radiolabeled and fluorescent labeled BMSCs. RESULTS: Postischemic cutaneous flap tissues treated with BMSCs demonstrated significantly less necrosis than control flaps (P <0.01). Beginning on postoperative day 5, BMSC treated flaps demonstrated greater blood perfusion than untreated flaps (P <0.01). Tensile strength of BMSC-treated cutaneous flaps was significantly higher (P <0.01), with a mean strength of 283.4 +/- 28.4 N/m than control flaps with a mean of 122.4 +/- 23.5 N/m. Radiolabeled BMSCs localized to postischemic flaps compared to untreated tissues (P = 0.001). Fluorescent microscopy revealed incorporation of BMSCs into endothelial and epithelial tissues of postischemic flaps. CONCLUSIONS: This study demonstrates that the intravascular delivery of BMSCs increases wound healing and promotes flap survival following ischemia reperfusion injury of cutaneous tissue flaps. PMID- 23818298 TI - Three-dimensional near-surface imaging of chirality domains with circularly polarized X-rays. PMID- 23818297 TI - Interleukin-6 trans-signaling exacerbates inflammation and renal pathology in lupus-prone mice. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease that is characterized by the production of antinuclear antibodies (ANAs) and leads to immune complex deposition in the kidneys and nephritis. Lyn tyrosine kinase is a regulator of antibody-mediated autoimmune disease, as evidenced by studies in gene-targeted mice and as suggested in genome-wide association studies in SLE. Like SLE patients, Lyn-deficient mice have increased levels of interleukin-6 (IL-6). Deletion of IL-6 from Lyn-deficient mice abrogates levels of inflammation, pathogenic autoantibodies, and nephritis. The purpose of this study was to assess the role of IL-6 trans-signaling in autoimmune disease by overexpressing soluble gp130Fc (sgp130Fc) in a mouse model. METHODS: The effect of overexpression of sgp130Fc on immune cell phenotypes was determined by flow cytometry in young and aged mice with lupus, and ANAs were measured by enzyme linked immunosorbent assay. Glomerulonephritis was assessed by histopathologic analysis, by measuring the glomerular area and the blood urea nitrogen concentration, and by immunohistochemistry. Immunofluorescence defined renal immune complex and complement deposition. The acute-phase response was determined by quantitative real-time polymerase chain reaction. RESULTS: In contrast to removing IL-6, impaired IL-6 trans-signaling had little effect on many immune cell abnormalities in Lyn-/- mice. Pathogenic ANAs and kidney deposition of immune complexes were also unaltered by sgp130Fc. However, sgp130Fc overexpression led to diminished macrophage expansion, reduced glomerular leukocyte infiltration, reduced complement fixation, significantly attenuated glomerulonephritis, and improved renal function in Lyn-deficient mice. CONCLUSION: Our results reveal key roles of leukocytes, complement, and the innate immune system in mediating glomerulonephritis, and they implicate IL-6 trans-signaling in this process. We suggest that targeting this pathway may be an effective adjunct to B cell depletion in SLE treatment. PMID- 23818299 TI - Brief report: SRF-dependent MiR-210 silences the sonic hedgehog signaling during cardiopoesis. AB - Serum response factor (SRF) wields potent gene silencing activity through its regulation over numerous microRNAs (miRs). Here, SRF directs embryonic stem cell (ESC) progenitor cell lineage specification in part by silencing genes through miR-210. Viral expression of miR-210 in murine ESCs-derived embryoid bodies (EBs) inhibited cell growth and inhibited the appearance of cardiac progenitor markers Nkx2.5 and Gata4 and terminal differentiated contractile proteins Mlc2v and betaMHC. Knockdown of miR-210 expression via antisense RNA activated cardiac progenitor gene activity. miR-210 inhibitory activity was attributed to silencing of the Sonic hedgehog (Shh) signaling pathway, which fosters the cardiac progenitor program. miR-210 directly silenced Shh via targeting of the Shh 3'UTR, comparable to the chemical Shh inhibitor, cyclopamine. miR-210 silencing of Shh/Gli1 signaling also blocked expression of the cell cycle regulators Cyclin D1 and Cyclin D2, and EB cell expansion. Absence of SRF expression in SRF null EBs blocked miR-210 expression, coincident with enhanced Shh, and Gli1 gene activity. Thus, SRF-dependent miR-210 expression may operate as a novel silencer of the Shh signaling pathway. PMID- 23818300 TI - MDM2 promoter polymorphism and p53 codon 72 polymorphism in chronic myeloid leukemia: the association between MDM2 promoter genotype and disease susceptibility, age of onset, and blast-free survival in chronic phase patients receiving imatinib. AB - The genetic or functional inactivation of the p53 pathway plays an important role with regards to disease progression from the chronic phase (CP) to blast phase (BP) and imatinib treatment response in chronic myeloid leukemia (CML). Two functional single nucleotide polymorphisms (SNPs), p53 R72P and MDM2 SNP309, are associated with alternation of p53 activity, however the association regarding CML susceptibility and BP transformation under imatinib treatment is unclear. The MDM2 SNP309 genotype was determined by polymerase chain reaction-restriction fragment length polymorphism and confirmed by direct sequencing from 116 CML patients, including 104 in the CP at diagnosis, and 162 healthy Taiwanese controls. The p53 R72P polymorphism was examined in all CML patients. The SNP309 G/G genotype was associated with an increased risk of CML susceptibility (OR: 1.82, 95% CI: 1.03-3.22, P = 0.037), and an earlier age of disease onset (log rank P = 0.005) compared with the T/T + T/G genotypes. Higher MDM2 mRNA expression was found in G/G genotype compared with T/T (P = 0.034) and T/T + T/G (P = 0.056) genotypes. No associations were found between the p53 R72P genotypes and clinical parameters and survival outcomes. Among 62 CP patients receiving imatinib as first-line therapy, the G/G genotype was associated with a shorter blast-free survival (log-rank P = 0.048) and more clonal evolution compared with the T/T + T/G genotypes. In patients with advanced diseases at diagnosis, the G/G genotype was associated with a poor overall survival (log-rank P = 0.006). Closely monitoring CML patients harboring the G/G genotype and further large scale studies are warranted. PMID- 23818301 TI - Is a fluorescence navigation system with indocyanine green effective enough to detect liver malignancies? AB - BACKGROUND: Although several reports have shown the efficacy of a fluorescence navigation system (FNS) with indocyanine green (ICG) to detect liver malignancies during hepatectomy, the real accuracy of this procedure is not yet clear. This study aimed to analyze the actual efficacy of ICG-FNS in cirrhotic and non cirrhotic livers. METHODS: Ten cirrhotic whole livers explanted from liver transplant recipients and 23 non-cirrhotic livers from patients who underwent hepatectomy for various kinds of liver tumors were investigated with ICG-FNS. All surgical specimens were analyzed macroscopically and pathologically. RESULTS: In the patients with a cirrhotic liver, most nodules illuminated by ICG-FNS were diagnosed as regenerative nodules pathologically. The positive predictive value was 5.4%. There was a significant difference in positive predictive value to detect malignant liver tumors between cirrhotic liver and non-cirrhotic liver (5.4% vs 100%, P < 0.0001). In the non-cirrhotic livers, 11 of 33 (32.4%) tumors were not recognized by ICG-FNS through the liver surface before resection. There was a significant difference in the depth from the liver surface to tumor between illuminated nodules and non-illuminated nodules (1.5 mm vs 11.6 mm, P < 0.01). CONCLUSIONS: It is necessary to know the limitation of ICG-FNS when detecting liver malignancies in both cirrhotic and non-cirrhotic livers. PMID- 23818302 TI - Measurement of operator exposure to chlorpyrifos. AB - BACKGROUND: To date, no research has been conducted to establish exposure levels for occupational pesticide operators under typical use scenarios in China. Through surrogate skin techniques (the whole-body method), the authors monitored dermal and inhalation exposure of pesticide applicators in China. In addition, the exposure of pesticide mixers was analysed. RESULTS: The total dermal exposure of inexperienced and experienced applicators was respectively 4037 and 536 mg kg( 1) of active ingredient (AI) handled for application to maize that was <80 cm in height. The exposure level was highest on hands; the closer to the hands, the lower arms and the upper legs, the higher the exposure. The unit exposure of mixers differed according to the formulation; exposure to emulsifiable concentrate (EC) and oil-in-water emulsion (EW) was greater than exposure to wettable powder (WP) or wettable dispersible granules (WG). The unit exposure of mixers via inhalation was significantly greater than that of applicators when chlorpyrifos (48% EC) was used (P < 0.0001). CONCLUSIONS: The main objectives of this study were to provide an indication of the realistic exposure risk of mixers and applicators, and to contribute useful information for risk mitigation and management and epidemiological studies in China. PMID- 23818305 TI - Use of diffusion-ordered NMR spectroscopy and HPLC-UV-SPE-NMR to identify undeclared synthetic drugs in medicines illegally sold as phytotherapies. AB - The informal (and/or illegal) e-commerce of pharmaceutical formulations causes problems that governmental health agencies find hard to control, one of which concerns formulas sold as natural products. The purpose of this work was to explore the advantages and limitations of DOSY and HPLC-UV-SPE-NMR. These techniques were used to identify the components of a formula illegally marketed in Brazil as an herbal medicine possessing anti-inflammatory and analgesic properties. DOSY was able to detect the major components present at higher concentrations. Complete characterization was achieved using HPLC-UV-SPE-NMR, and 1D and 2D NMR analyses enabled the identification of known synthetic drugs. These were ranitidine and a mixture of orphenadrine citrate, piroxicam, and dexamethasone, which are co-formulated in a remedy called Rheumazim that is used to relieve severe pain, but it is prohibited in Brazil because of a lack of sufficient pharmacokinetic and pharmacodynamic information. PMID- 23818303 TI - High body mass index is associated with increased diurnal strains in the articular cartilage of the knee. AB - OBJECTIVE: Obesity is an important risk factor for osteoarthritis (OA) and is associated with changes in both the biomechanical and inflammatory environments within the joint. However, the relationship between obesity and cartilage deformation is not fully understood. The goal of this study was to determine the effects of body mass index (BMI) on the magnitude of diurnal cartilage strain in the knee. METHODS: Three-dimensional maps of knee cartilage thickness were developed from 3T magnetic resonance images of the knees of asymptomatic age- and sex-matched subjects with normal BMI (18.5-24.9 kg/m2) or high BMI (25-31 kg/m2). Site-specific magnitudes of diurnal cartilage strain were determined using aligned images recorded at 8:00 AM and 4:00 PM on the same day. RESULTS: Subjects with high BMI had significantly thicker cartilage on both the patella and femoral groove, as compared to subjects with normal BMI. Diurnal cartilage strains were dependent on location in the knee joint, as well as BMI. Subjects with high BMI, compared to those with normal BMI, exhibited significantly higher compressive strains in the tibial cartilage. Cartilage thickness on both femoral condyles decreased significantly from the AM to the PM time point; however, there was no significant effect of BMI on diurnal cartilage strain in the femur. CONCLUSION: Increased BMI is associated with increased diurnal strains in articular cartilage of both the medial and lateral compartments of the knee. The increased cartilage strains observed in individuals with high BMI may, in part, explain the elevated risk of OA associated with obesity or may reflect alterations in the cartilage mechanical properties in subjects with high BMI. PMID- 23818306 TI - Longitudinal positron emission tomography imaging for monitoring myelin repair in the spinal cord. AB - OBJECTIVE: Novel therapeutic interventions aimed at myelin repair are now under development for neuroprotection as well as functional recovery of patients with multiple sclerosis. However, development of myelin repair therapy necessitates a noninvasive approach for measuring changes in myelin content in vivo in a quantitative fashion not yet possible using magnetic resonance imaging. For this reason, we developed a novel positron emission tomography (PET) probe, termed [11C]MeDAS, that is capable of longitudinally imaging central nervous system myelin content. METHODS: The binding properties of [11C]MeDAS for myelin were systematically evaluated by in vitro and in situ fluorescent staining of the spinal cord and the brain, and by in vivo competitive blocking studies. Longitudinal PET studies were conducted in 3 rat models involving acute focal neuroinflammation in the brain, lysophosphatidylcholine (LPC)-induced focal demyelination in the spinal cord, and experimental autoimmune encephalomyelitis (EAE). Image-guided myelin repair therapy was conducted in an LPC rat model using a mesenchymal stem cell-based hepatocyte growth factor (HGF). Biodistribution and acute toxicity studies of [11C]MeDAS were also conducted. RESULTS: MeDAS selectively stains myelin in the spinal cord and brain. Neuroinflammation did not affect [11C]MeDAS uptake in the brain as long as the myelin sheaths remained intact. Longitudinal PET studies in LPC and EAE rat models demonstrate that [11C]MeDAS uptake changes correlate with associated myelin loss in the spinal cord. Furthermore, using [11C]MeDAS-PET, the efficacy of myelin repair therapy with HGF was longitudinally monitored in vivo. INTERPRETATION: [11C]MeDAS-PET is a promising imaging marker for monitoring myelin pathology in vivo, future applications of which in humans should be achievable. PMID- 23818307 TI - Dietary resistant starch improves selected brain and behavioral functions in adult and aged rodents. AB - Resistant starch (RS) is a dietary fiber that exerts multiple beneficial effects. The current study explored the effects of dietary RS on selected brain and behavioral functions in adult and aged rodents. Because glucokinase (GK) expression in hypothalamic arcuate nucleus and area postrema of the brainstem is important for brain glucose sensing, GK mRNA was measured by brain nuclei microdissection and PCR. Adult RS-fed rats had a higher GK mRNA than controls in both brain nuclei, an indicator of improved brain glucose sensing. Next, we tested whether dietary RS improve selected behaviors in aged mice. RS-fed aged mice exhibited (i) an increased eating responses to fasting, a behavioral indicator of improvement in aged brain glucose sensing; (ii) a longer latency to fall from an accelerating rotarod, a behavioral indicator of improved motor coordination; and (iii) a higher serum active glucagon-like peptide-1 (GLP-1). Then, GLP-1 receptor null (GLP-1RKO) mice were used to test the role of GLP-1 in brain glucose sensing, and they exhibited impaired eating responses to fasting. We conclude that in rodents (i) dietary RS improves two important indicators of brain function: glucose sensing and motor coordination, and (ii) GLP-1 is important in the optimal feeding response to a fast. PMID- 23818309 TI - Variable clinical outcome of ABCA3 deficiency in two siblings. AB - This case report describes an unusual outcome of ABCA3 deficiency with resolution of symptoms, normalization of chest imaging and lung function in a 9-year-old child whose sibling died of the same disease in infancy. PMID- 23818308 TI - Visual pigments and opsin expression in the juveniles of three species of fish (rainbow trout, zebrafish, and killifish) following prolonged exposure to thyroid hormone or retinoic acid. AB - Thyroid hormone (TH) and retinoic acid (RA) are powerful modulators of photoreceptor differentiation during vertebrate retinal development. In the embryos and young juveniles of salmonid fishes and rodents, TH induces switches in opsin expression within individual cones, a phenomenon that also occurs in adult rodents following prolonged (12 week) hypothyroidism. Whether changes in TH levels also modulate opsin expression in the differentiated retina of fish is unknown. Like TH, RA is essential for retinal development, but its role in inducing opsin switches, if any, has not been studied. Here we investigate the action of TH and RA on single-cone opsin expression in juvenile rainbow trout, zebrafish, and killifish and on the absorbance of visual pigments in rainbow trout and zebrafish. Prolonged TH exposure increased the wavelength of maximum absorbance (lambdamax ) of the rod and the medium (M, green) and long (L, red) wavelength visual pigments in all fish species examined. However, unlike the opsin switch that occurred following TH exposure in the single cones of small juvenile rainbow trout (alevin), opsin expression in large juvenile rainbow trout (smolt), zebrafish, or killifish remained unchanged. RA did not induce any opsin switches or change the visual pigment absorbance of photoreceptors. Neither ligand altered cone photoreceptor densities. We conclude that RA has no effect on opsin expression or visual pigment properties in the differentiated retina of these fishes. In contrast, TH affected both single-cone opsin expression and visual pigment absorbance in the rainbow trout alevin but only visual pigment absorbance in the smolt and in zebrafish. The latter results could be explained by a combination of opsin switches and chromophore shifts from vitamin A1 to vitamin A2. PMID- 23818310 TI - Current incidence of duplicate publication in otolaryngology. AB - OBJECTIVES/HYPOTHESIS: Duplicate publication--deemed highly unethical--is the reproduction of substantial content in another article by the same authors. In 1999, Rosenthal et al. identified an 8.5% incidence of duplicate articles in two otolaryngology journals. We explored the current incidence in three otolaryngology journals in North America and Europe. STUDY DESIGN: Retrospective literature review. METHODS: Index articles in 2008 in Archives of Otolaryngology Head and Neck Surgery, Laryngoscope, and Clinical Otolaryngology were searched using MEDLINE. Potential duplicate publications in 2006 through 2010 were identified using the first, second, and last authors' names. Three authors independently investigated suspected duplicate publications--classifying them by degree of duplication. RESULTS: Of 358 index articles screened, 75 (20.9%) had 119 potential duplicates from 2006 to 2010. Full review of these 119 potential duplicates revealed a total of 40 articles with some form of redundancy (33.6% of the potential duplicates) involving 27 index articles (7.5% of 358 index articles); one (0.8%) "dual" publication (identical or nearly identical data and conclusions to the index article); three (2.5%) "suspected" dual publications (less than 50% new data and same conclusions); and 36 (30.3%) publications with "salami-slicing" (portion of the index article data repeated) were obtained. Further analysis compared the likelihood of duplicate publication by study source and subspecialty within otolaryngology. CONCLUSIONS: The incidence of duplicate publication has not significantly changed over 10 years. "Salami-slicing" was a concerning practice, with no cross-referencing in 61% of these cases. Detecting and eliminating redundant publications is a laborious task, but it is essential in upholding the journal quality and research integrity. PMID- 23818311 TI - Effect of starters and ripening time on the physicochemical, nitrogen fraction and texture profile of goat's cheese coagulated with a vegetable coagulant (Cynara cardunculus). AB - BACKGROUND: The increase in the demand for goat's cheese throughout the world has encouraged research into the development of new related products with different textural characteristics. The aim of this work was to study the effect of three commercial starter cultures through the assessment of physicochemical and textural characteristics of goat's milk cheeses made with vegetable coagulant (Cynara cardunculus) during ripening. RESULTS: Use of the different starter cultures produced a significant effect (P < 0.05) on moisture, proteins, pH, nitrogen fractions and hardness of the cheeses. Results show that the addition of mesophilic starters ensures the correct acidification rate and produced cheeses with lower pH values and greater hardness. Use of thermophilic starter cultures produces cheeses with less instrumental hardness and the use of mixed cultures produced less proteolysis. CONCLUSION: These results are found useful for selecting the most suitable starter for the development of new goat's cheeses. PMID- 23818295 TI - Standard care versus protocol based therapy for new onset Pseudomonas aeruginosa in cystic fibrosis. AB - RATIONALE: The Early Pseudomonal Infection Control (EPIC) randomized trial rigorously evaluated the efficacy of different antibiotic regimens for eradication of newly identified Pseudomonas (Pa) in children with cystic fibrosis (CF). Protocol based therapy in the trial was provided based on culture positivity independent of symptoms. It is unclear whether outcomes observed in the clinical trial were different than those that would have been observed with historical standard of care driven more heavily by respiratory symptoms than culture positivity alone. We hypothesized that the incidence of Pa recurrence and hospitalizations would be significantly reduced among trial participants as compared to historical controls whose standard of care preceded the widespread adoption of tobramycin inhalation solution (TIS) as initial eradication therapy at the time of new isolation of Pa. METHODS: Eligibility criteria from the trial were used to derive historical controls from the Epidemiologic Study of CF (ESCF) who received standard of care treatment from 1995 to 1998, before widespread availability of TIS. Pa recurrence and hospitalization outcomes were assessed over a 15-month time period. RESULTS: As compared to 100% of the 304 trial participants, only 296/608 (49%) historical controls received antibiotics within an average of 20 weeks after new onset Pa. Pa recurrence occurred among 104/298 (35%) of the trial participants as compared to 295/549 (54%) of historical controls (19% difference, 95% CI: 12%, 26%, P < 0.001). No significant differences in the incidence of hospitalization were observed between cohorts. CONCLUSIONS: Protocol-based antimicrobial therapy for newly acquired Pa resulted in a lower rate of Pa recurrence but comparable hospitalization rates as compared to a historical control cohort less aggressively treated with antibiotics for new onset Pa. PMID- 23818312 TI - Reversible switching of the luminescence of a photoresponsive gadolinium(III) complex. PMID- 23818313 TI - Combined linkage and association analyses identify a novel locus for obesity near PROX1 in Asians. AB - OBJECTIVE: Although genome-wide association studies (GWAS) have substantially contributed to understanding the genetic architecture, unidentified variants for complex traits remain an issue. One of the efficient approaches is the improvement of the power of GWAS scan by weighting P values with prior linkage signals. Our objective was to identify the novel candidates for obesity in Asian populations by using genemapping strategies that combine linkage and association analyses. DESIGN AND METHODS: To obtain linkage information for body mass index (BMI) and waist circumference (WC), we performed a multipoint genome-wide linkage study in an isolated Mongolian sample of 1,049 individuals from 74 families. Next, a family-based GWAS, which integrates within- and between-family components, was performed using the genotype data of 756 individuals of the Mongolian sample, and P values for association were weighted using linkage information obtained previously. RESULTS: For both BMI (LOD = 3.3) and WC (LOD = 2.6), the highest linkage peak was discovered at chromosome 10q11.22. In family based GWAS combined with linkage information, six single-nucleotide polymorphisms (SNPs) for BMI and five SNPs for WC reached a significant level of association (linkage weighted P < 1 * 10(-5) ). Of these, only one of the SNPs associated with WC (rs1704198) was replicated in 327 Korean families comprising 1,301 individuals. This SNP was located in the proximity of the prosperorelated homeobox 1 (PROX1) gene, the function of which was validated previously in a mouse model. CONCLUSION: Our powerful strategic analysis enabled the discovery of a novel candidate gene, PROX1, associated with WC in an Asian population. PMID- 23818314 TI - The changing dielectric properties of CHO cells can be used to determine early apoptotic events in a bioprocess. AB - To ensure maximum productivity of recombinant proteins it is desirable to prolong cell viability during a mammalian cell bioprocess, and therefore important to carefully monitor cell density and viability. In this study, five different and independent methods of monitoring were applied to Chinese hamster ovary (CHO) cells grown in a batch culture in a controlled bioreactor to determine cell density and/or cell viability. They included: a particle counter, trypan blue exclusion (Cedex), an in situ bulk capacitance probe, an off-line fluorescent flow cytometer, and a prototype dielectrophoretic (DEP) cytometer. These various techniques gave similar values during the exponential growth phase. However, beyond the exponential growth phase the viability measurements diverged. Fluorescent flow cytometry with a range of fluorescent markers was used to investigate this divergence and to establish the progress of cell apoptosis: the cell density estimates by the intermediate stage apoptosis assay agreed with those obtained by the bulk capacitance probe and the early stage apoptosis assay viability measurements correlated well with the DEP cytometer. The trypan blue assay showed higher estimates of viable cell density and viability compared to the capacitance probe or the DEP cytometer. The DEP cytometer measures the dielectric properties of individual cells and identified at least two populations of cells, each with a distinct polarizability. As verified by comparison with the Nexin assay, one population was associated with viable (non-apoptotic) cells and the other with apoptotic cells. From the end of the exponential through the stationary and decline stages there was a gradual shift of cell count from the viable into the apoptotic population. However, the two populations maintained their individual dielectric properties throughout this shift. This leads to the conclusion that changes in bulk dielectric properties of cultures might be better modeled as shifts in cells between different dielectric sub-populations, rather than assuming a homogeneous dielectric population. This shows that bulk dielectric probes are sensitive to the early apoptotic changes in cells. DEP cytometry offers a novel and unique technology for analyzing and characterizing mammalian cells based on their dielectric properties, and suggests a potential application of the device as a low-cost, label-free, electronic monitor of physiological changes in cells. PMID- 23818315 TI - [Is obesity an addiction?]. PMID- 23818316 TI - [Assessing common factors in psychotherapy: psychometric properties of a new time economic instrument (WIFA-k)]. AB - Research on common and differential factors in the therapeutic process is impeded by the lack of instruments suitable for assessing common change mechanisms. This study presents the psychometric properties of a newly developed time-economic instrument (WIFA-k), which was designed to assess common factors of psychotherapy as designed by Grawe. Within a multi-center study comparing the efficacy of cognitive therapy and psychodynamic therapy in the treatment of social phobia, 6 raters assessed 25 randomly selected, videotaped therapy sessions of each treatment approach, and evaluated common factors using the Wifa-k. Interrater reliability was found to be high for the items "resource activation", "motivational clarification" and "mastery" and low for the items "therapeutic relationship" and "problem activation". Ways to increase reliability and validity of the scale are discussed. PMID- 23818317 TI - [Standardized reporting of scientific research]. PMID- 23818318 TI - [Messages from the German College of Psychosomatic Medicine]. PMID- 23818319 TI - Clinical and epidemiologic profile of lower respiratory tract infections associated with human bocavirus. AB - BACKGROUND: Acute viral bronchiolitis (AVB) remains the leading cause of lower respiratory tract infection (LRTI) in infants under 2 years of age. Advances in molecular methods for virus detection have led to the identification of new infectious agents implicated in the development of AVB, such as human bocavirus (HBoV). OBJECTIVES: To ascertain the frequency, seasonality, and clinical behavior of HBoV detection in a series of episodes of LRTI. STUDY DESIGN: The frequency of HBoV was assessed in children with LRTI episodes, aged 1-24 months, seen at the emergency department of Hospital da Crianca Santo Antonio, Porto Alegre, Brazil, between May 2007 and July 2008. Virus-specific polymerase chain reaction was used for detection. RESULTS: A total of 455 nasal secretion samples were collected from 433 patients over a 14-month period. Of these, 60 were positive for HBoV (13.2%). Mean age was 7.9 months and 55% of patients were male. Just over half of patients were under 6 months of age (53.3%). Wheezing was the presenting respiratory complaint in 51.7%. Of the 60 patients, 80% were admitted to a pediatric ward. Diarrhea was present in nine patients (18%). Co-detection was a frequent finding in our sample, occurring in 95% of cases. In our series, the distribution of HBoV was clearly seasonal and was influenced by temperature, relative humidity, and precipitation. CONCLUSIONS: We conclude that HBoV detection in infants with AVB and recurrent wheezing of viral etiology in Brazil is similar to that reported in other countries. The clinical course of HBoV detection is no different from that of other respiratory viruses commonly found in this age range. PMID- 23818320 TI - Effects of hypoxia-induced gill remodelling on the innervation and distribution of ionocytes in the gill of goldfish, Carassius auratus. AB - The presence of an interlamellar cell mass (ILCM) on the gills of goldfish acclimated to 7 degrees C leads to preferential distribution of branchial ionocytes to the distal edges of the ILCM, where they are likely to remain in contact with the water and hence remain functional. Upon exposure to hypoxia, the ILCM retracts, and the ionocytes become localized to the lamellar surfaces and on the filament epithelium, owing to their migration and the differentiation of new ionocytes from progenitor cells. Here we demonstrate that the majority of the ionocytes receive neuronal innervation, which led us to assess the consequences of ionocyte migration and differentiation during hypoxic gill remodelling on the pattern and extent of ionocyte neuronal innervation. Normoxic 7 degrees C goldfish (ILCM present) possessed significantly greater numbers of ionocytes/mm(2) (951.2 +/- 94.3) than their 25 degrees C conspecifics (ILCM absent; 363.1 +/- 49.6) but a statistically lower percentage of innervated ionocytes (83.1% +/- 1.0% compared with 87.8% +/- 1.3%). After 1 week of exposure of goldfish to hypoxia, the pool of branchial ionocytes was composed largely of pre-existing migrating cells (555.6 +/- 38.1/mm(2)) and to a lesser extent newly formed ionocytes (226.7 +/- 15.1/mm(2)). The percentage of new (relative to pre existing) ionocytes remained relatively constant (at ~30%) after 1 or 2 weeks of normoxic recovery. After hypoxia, pre-existing ionocytes expressed a greater percentage of innervation than newly formed ionocytes in all treatment groups; however, their percentage innervation steadily decreased over 2 weeks of normoxic recovery. PMID- 23818322 TI - Commentary on "Adaptive deep brain stimulation in advanced Parkinson disease". PMID- 23818321 TI - Irritability in child and adolescent anxiety disorders. AB - BACKGROUND: Our objective was to compare self- and parent-reported irritability in youths with anxiety disorders, healthy youths, and those with mood disorders characterized by irritability. Irritability is a common but relatively understudied psychiatric symptom in child and adolescent anxiety disorders. In anxious youths, little is known about the severity of irritability, its impact on functioning, or the effect of informant source on reports of irritability. METHODS: We compared parent- and self-report forms of the Affective Reactivity Index (ARI), a validated measure of irritability, in youths ages 8-17 years with no psychopathology (healthy comparison, HC; n = 38), anxiety disorders (ANX; n = 42), bipolar disorder (BD; n = 35), or severe mood dysregulation (SMD; n = 61; a phenotype characterized by chronic, severely impairing irritability). RESULTS: Irritability was significantly higher in ANX than HC youths by both parent and self-report (partial eta(2) = 0.24 and 0.22, respectively, P's < 0.001). Informant effects differed among ANX, BD, and SMD. Overall, parent-reported irritability was higher in BD with comorbid anxiety disorders and SMD with or without comorbid anxiety disorders than ANX (P's < 0.007), but self-reported irritability was not significantly different among the three patient groups. DISCUSSION: By both parent and self-report, youths with anxiety disorders exhibit significantly more irritability and associated impairment than healthy subjects. Self-reported irritability in youths with anxiety disorders is comparable to that observed in youths with severe mood disorders, although parental reports of irritability differ among the disorders. Future research should examine the pathophysiology of anxiety-associated irritability, as well as its prognostic and treatment implications. PMID- 23818323 TI - Public hospital autonomy in China in an international context. AB - Following decades of change in health care structures and modes of funding, China has recently been making pilot reforms to the governance of its public hospitals, primarily by increasing the autonomy of public hospitals and redefining the roles of the health authorities. In this paper, we analyse the historical evolution and current situation of public hospital governance in China, focussing the range of governance models being tried out in pilot cities across China. We then draw on the experiences of public hospital governance reform in a wide range of other countries to consider the nature of the Chinese pilots. We find that the key difference in China is that the public hospitals in the pilot schemes do not receive sufficient funding from government and are able to distribute profits to staff. This creates incentives to charge patients for excessive treatment. This situation has undermined public service orientation in Chinese public hospitals. We conclude that the pilot reforms of governance will not be sufficient to remedy all the problems facing these hospitals, although they are a step in the right direction. PMID- 23818324 TI - Hypoxia regulates the sperm associated antigen 4 (SPAG4) via HIF, which is expressed in renal clear cell carcinoma and promotes migration and invasion in vitro. AB - Hypoxia leads to the upregulation of a variety of genes mediated largely via the hypoxia inducible transcription factor (HIF). Prominent HIF-regulated target genes such as the vascular endothelial growth factor (VEGF), the glucose transporter 1 (Glut-1), or erythropoietin (EPO) help to assure survival of cells and organisms in a low oxygenated environment. Here, we are the first to report the hypoxic regulation of the sperm associated antigen 4 (SPAG4). SPAG4 is a member of the cancer testis (CT) gene family and to date little is known about its physiological function or its involvement in tumor biology. A number of CT family candidate genes are therefore currently being investigated as potential cancer markers, due to their predominant testicular expression pattern. We analyzed RNA and protein expression by RNAse protection assay, immunofluorescent as well as immunohistological stainings. To evaluate the influence of SPAG4 on migration and invasion capabilities, siRNA knockdown as well as transient overexpression was performed prior to scratch or invasion assay analysis. The hypoxic regulation of SPAG4 is clearly mediated in a HIF-1 and VHL dependent manner. We furthermore show upregulation of SPAG4 expression in human renal clear cell carcinoma (RCC) and co-localization within the nucleolus in physiological human testis tissue. SPAG4 knockdown reduces the invasion capability of RCC cells in vitro and overexpression leads to enhancement of tumor cell migration. Together, SPAG4 could possibly play a role in the invasion capability and growth of renal tumors and could represent an interesting target for clinical intervention. PMID- 23818325 TI - Dual requirement of ectodermal Smad4 during AER formation and termination of feedback signaling in mouse limb buds. AB - BMP signaling is pivotal for normal limb bud development in vertebrate embryos and genetic analysis of receptors and ligands in the mouse revealed their requirement in both mesenchymal and ectodermal limb bud compartments. In this study, we genetically assessed the potential essential functions of SMAD4, a mediator of canonical BMP/TGFbeta signal transduction, in the mouse limb bud ectoderm. Msx2-Cre was used to conditionally inactivate Smad4 in the ectoderm of fore- and hindlimb buds. In hindlimb buds, the Smad4 inactivation disrupts the establishment and signaling by the apical ectodermal ridge (AER) from early limb bud stages onwards, which results in severe hypoplasia and/or aplasia of zeugo- and autopodal skeletal elements. In contrast, the developmentally later inactivation of Smad4 in forelimb buds does not alter AER formation and signaling, but prolongs epithelial-mesenchymal feedback signaling in advanced limb buds. The late termination of SHH and AER-FGF signaling delays distal progression of digit ray formation and inhibits interdigit apoptosis. In summary, our genetic analysis reveals the temporally and functionally distinct dual requirement of ectodermal Smad4 during initiation and termination of AER signaling. PMID- 23818326 TI - Stereoselective nickel-catalyzed [2+2+2] cycloadditions and alkenylative cyclizations of ene-allenes and alkenes. PMID- 23818327 TI - Prevalence of pediatric periodic leg movements of sleep after initiation of PAP therapy. AB - INTRODUCTION: Positive-airway-pressure (PAP) is a treatment for obstructive-sleep apnea (OSA). In adults, initiation of PAP-therapy may unmask periodic-limb movements-of-sleep (PLMS). We present a series of children in whom PLMS was aggravated or induced following initiation of PAP therapy. METHODS: Retrospective analysis was performed on children who had PAP-studies performed over a 3-year period. Children with OSA without significant PLMS on baseline studies and who then showed a periodic-limb-movement-index (PLMI) (>5/hr) during titration with PAP-therapy were identified. Charts were reviewed for demographics, OSA severity based on apnea hypopnea index (AHI), PLMI, PLM-arousal-index (PLMAI) and pressures titrated. RESULTS: Two hundred fourteen PAP-titration studies (151 on continuous positive airway pressure [CPAP] and 63 on bilevel positive airway pressure [BiPAP]) were done. Eleven (10 on CPAP, 1 on BiPAP) met study criteria. Eight patients were boys. The median age was 12 years (range 6 months-18 years). On baseline studies, median AHI was 5/hr (range 1.5-32/hr), median PLMI was 1/hr (range 0-4/hr) and median PLMAI 0.3/Hr (range 0-2/hr). On titration studies, pressures ranged from 4 to 14 cm of water, median AHI was 0.5/hr (range 0-1), median PLMI was 12/hr (range 5-55/hr) and median PLMAI 9/hr (range 0-25). PLMS were seen predominantly during N1, N2 sleep and on PAP of >7 cm of water. One patient had resolution of PLMS at 1-year follow-up. CONCLUSION: PLMS were seen in 5.1% of children after initiation of PAP. OSA may mask PLMS, which appears as breathing improves. Alternatively, PAP may unmask or induce PLMS. PLMS may potentially be a cause of treatment failure in children on recent-onset PAP therapy. PMID- 23818329 TI - Longitudinal weight gain in women identified with polycystic ovary syndrome: results of an observational study in young women. AB - OBJECTIVE: Polycystic ovary syndrome (PCOS) affects 6-18% of women. The natural history of weight gain in women with PCOS has not been well described. Here we aimed to examine longitudinal weight gain in women with and without PCOS and to assess the association between obesity and PCOS prevalence. DESIGN AND METHODS: The observational study was set in the general community. Participants were women randomly selected from the national health insurance scheme (Medicare) database. Mailed survey data were collected by the Australian Longitudinal Study on Women's Health. Data from respondents to survey 4, aged 28-33 years (2006, n = 9,145) were analyzed. The main outcome measures were PCOS prevalence and body mass index (BMI). RESULTS: Self-reported PCOS prevalence was 5.8% (95% CI: 5.3%-6.4%). Women reporting PCOS had higher weight, mean BMI [2.5 kg/m(2) (95% CI: 1.9-3.1)], and greater 10-year weight gain [2.6 kg (95% CI: 1.2-4.0)]. BMI was the strongest correlate of PCOS status with every BMI increment increasing the risk of reporting PCOS by 9.2% (95% CI: 6%-12%). CONCLUSIONS: This community based observational study with longitudinal reporting of weight shows that weight, BMI, and 10-year weight gain were higher in PCOS. We report the novel finding that obesity and greater weight gain are significantly associated with PCOS status. Considering the prevalence, major health and economic burden of PCOS, the increasing weight gain in young women, and established benefits of weight loss, these results have major public health implications. PMID- 23818330 TI - Development of the cerebellar afferent system in the shark Scyliorhinus canicula: insights into the basal organization of precerebellar nuclei in gnathostomes. AB - The cerebellum is recognized as an evolutionary innovation of jawed vertebrates, whose most primitive group is represented by the chondrichthyans, or cartilaginous fishes. A comprehensive knowledge of cerebellar connections in these fishes might shed light on the basal organization of the cerebellar system. Although the organization of the precerebellar system is known in adults, developmental studies are essential for understanding the origin and evolution of precerebellar nuclei. In the present work we performed a developmental study of cerebellar connections in embryos and juveniles of an advanced shark species, Scyliorhinus canicula, by application of tract tracing in combination with immunohistochemical techniques. Main precerebellar cell populations were located in the diencephalon (pretectum and thalamus), mesencephalon (reticular formation and nucleus ruber), rhombencephalon (cerebellar nucleus, reticular formation, and inferior olive), and spinal cord (ventral horn). The order of arrival of cerebellar afferent projections throughout development revealed a common pattern with other jawed vertebrates, which was helpful for comparison of stages of cerebellar development. The neurochemical study of the inferior olive and other precerebellar nuclei revealed many shared features with other gnathostomes. Furthermore, because many precerebellar nuclei originate from rhombic lips, the first analysis of neuronal migrations from these lips was performed with markers of neuroblasts. The shared features of development and organization of precerebellar connections observed between sharks and amniotes suggest that their basic pattern was established early in gnathostome evolution. PMID- 23818328 TI - Nutritional lipidomics: molecular metabolism, analytics, and diagnostics. AB - The field of lipidomics is providing nutritional science a more comprehensive view of lipid intermediates. Lipidomics research takes advantage of the increase in accuracy and sensitivity of mass detection of MS with new bioinformatics toolsets to characterize the structures and abundances of complex lipids. Yet, translating lipidomics to practice via nutritional interventions is still in its infancy. No single instrumentation platform is able to solve the varying analytical challenges of the different molecular lipid species. Biochemical pathways of lipid metabolism remain incomplete and the tools to map lipid compositional data to pathways are still being assembled. Biology itself is dauntingly complex and simply separating biological structures remains a key challenge to lipidomics. Nonetheless, the strategy of combining tandem analytical methods to perform the sensitive, high-throughput, quantitative, and comprehensive analysis of lipid metabolites of very large numbers of molecules is poised to drive the field forward rapidly. Among the next steps for nutrition to understand the changes in structures, compositions, and function of lipid biomolecules in response to diet is to describe their distribution within discrete functional compartments lipoproteins. Additionally, lipidomics must tackle the task of assigning the functions of lipids as signaling molecules, nutrient sensors, and intermediates of metabolic pathways. PMID- 23818331 TI - Changes in biocrust cover drive carbon cycle responses to climate change in drylands. AB - Dryland ecosystems account for ca. 27% of global soil organic carbon (C) reserves, yet it is largely unknown how climate change will impact C cycling and storage in these areas. In drylands, soil C concentrates at the surface, making it particularly sensitive to the activity of organisms inhabiting the soil uppermost levels, such as communities dominated by lichens, mosses, bacteria and fungi (biocrusts). We conducted a full factorial warming and rainfall exclusion experiment at two semiarid sites in Spain to show how an average increase of air temperature of 2-3 degrees C promoted a drastic reduction in biocrust cover (ca. 44% in 4 years). Warming significantly increased soil CO2 efflux, and reduced soil net CO2 uptake, in biocrust-dominated microsites. Losses of biocrust cover with warming through time were paralleled by increases in recalcitrant C sources, such as aromatic compounds, and in the abundance of fungi relative to bacteria. The dramatic reduction in biocrust cover with warming will lessen the capacity of drylands to sequester atmospheric CO2 . This decrease may act synergistically with other warming-induced effects, such as the increase in soil CO2 efflux and the changes in microbial communities to alter C cycling in drylands, and to reduce soil C stocks in the mid to long term. PMID- 23818332 TI - Biliary complications adversely affect patient and graft survival after liver retransplantation. AB - Inferior outcomes are consistently observed for recipients of liver retransplantation (re-LT) versus recipients of primary transplants. Few studies have examined the incidence and impact of biliary complications (BCs) on outcomes after re-LT. The aim of this study was to compare patient and graft survival for re-LT recipients with BCs (BC(+) ) and re-LT recipients without BCs (BC(-) ). Additional aims were to determine the impact of biliary reconstruction on the incidence of BCs and to identify risk factors for BCs after re-LT. A single center, retrospective analysis of all re-LT recipients over a decade was performed. Univariate analyses were performed, and survival was compared with the log-rank method. A multivariate Cox regression analysis was performed to determine independent predictors of death and graft failure. The BC rate was 20.9% (n = 23) for 110 re-LT cases. The average follow-up was 55 months. The survival rates for BC(-) recipients at 3 months and 1, 3, and 5 years were 95.3%, 91.7%, 85.4%, and 80.9%, respectively, whereas BC(+) patients had survival rates of 64.3%, 49.7%, 34.8%, and 29.8%, respectively (P < 0.001, log-rank). The graft survival rates at 3 months and 1, 3, and 5 years were 92.0%, 88.5%, 82.4%, and 78.0%, respectively, for the BC(-) group and 60.9%, 43.5%, 30.4%, and 26.1%, respectively, for the BC(+) group (P < 0.001, log-rank). BCs, a length of stay >= 12 days, and donor age were strongly associated with death and graft failure in a regression analysis, whereas retransplant indications other than chronic rejection and recurrent disease also affected graft failure. In conclusion, BCs significantly affected both patient and graft survival, with an increased risk of death and graft loss among BC(+) recipients. Early recognition, appropriate interventions, and preventative measures for BCs are critical in the clinical management of re-LT recipients. PMID- 23818333 TI - How do hospitalization experience and institutional characteristics influence inpatient satisfaction? A multilevel approach. AB - Over the last several years, interest in benchmarking health services' quality- particularly patient satisfaction (PS)--across organizations has increased. Comparing patient experiences of care across hospitals requires risk adjustment to control for important differences in patient case-mix and provider characteristics. This study investigates the individual-level and organizational level determinants of PS with public hospitals by applying hierarchical models. The analysis focuses on the effect of hospital characteristics, such as self discharges, on overall evaluations and on across hospital variation in scores. Sociodemographics, admission mode, place of residence, hospitalization ward and continuity of care were statistically significant predictors of inpatient satisfaction. Interestingly, it was observed that hospitals with a higher percentage of Patients Leaving Against Medical Advice (PLAMA) received lower scores. The latter result suggests that the percentage of PLAMA may provide a useful measure of a hospital's inability to meet patient needs and a proxy indicator of PS with hospital care. PMID- 23818334 TI - Strategies for expanding colorectal cancer screening at community health centers. AB - Community health centers are uniquely positioned to address disparities in colorectal cancer (CRC) screening as they have addressed other disparities. In 2012, the federal Health Resources and Services Administration, which is the funding agency for the health center program, added a requirement that health centers report CRC screening rates as a standard performance measure. These annually reported, publically available data are a major strategic opportunity to improve screening rates for CRC. The Patient Protection and Affordable Care Act enacted provisions to expand the capacity of the federal health center program. The recent report of the Institute of Medicine on integrating public health and primary care included an entire section devoted to CRC screening as a target for joint work. These developments make this the ideal time to integrate lifesaving CRC screening into the preventive care already offered by health centers. This article offers 5 strategies that address the challenges health centers face in increasing CRC screening rates. The first 2 strategies focus on improving the processes of primary care. The third emphasizes working productively with other medical providers and institutions. The fourth strategy is about aligning leadership. The final strategy is focused on using tools that have been derived from models that work. PMID- 23818335 TI - Recent developments in esophageal adenocarcinoma. AB - Answer questions and earn CME/CNE Esophageal adenocarcinoma (EAC) is characterized by 6 striking features: increasing incidence, male predominance, lack of preventive measures, opportunities for early detection, demanding surgical therapy and care, and poor prognosis. Reasons for its rapidly increasing incidence include the rising prevalence of gastroesophageal reflux and obesity, combined with the decreasing prevalence of Helicobacter pylori infection. The strong male predominance remains unexplained, but hormonal influence might play an important role. Future prevention might include the treatment of reflux or obesity or chemoprevention with nonsteroidal antiinflammatory drugs or statins, but no evidence-based preventive measures are currently available. Likely future developments include endoscopic screening of better defined high-risk groups for EAC. Individuals with Barrett esophagus might benefit from surveillance, at least those with dysplasia, but screening and surveillance strategies need careful evaluation to be feasible and cost-effective. The surgery for EAC is more extensive than virtually any other standard procedure, and postoperative survival, health-related quality of life, and nutrition need to be improved (eg, by improved treatment, better decision-making, and more individually tailored follow-up). Promising clinical developments include increased survival after preoperative chemoradiotherapy, the potentially reduced impact on health-related quality of life after minimally invasive surgery, and the new endoscopic therapies for dysplastic Barrett esophagus or early EAC. The overall survival rates are improving slightly, but poor prognosis remains a challenge. PMID- 23818337 TI - A crystal-to-crystal synthesis of triazolyl-linked polysaccharide. PMID- 23818336 TI - miR-155 as a multiple sclerosis-relevant regulator of myeloid cell polarization. AB - OBJECTIVE: To define the functional significance of increased miR-155 expression in myeloid cells in multiple sclerosis (MS). METHODS: miR-155 expression levels were measured in CD14+ monocytes from untreated relapsing-remitting MS patients and compared to healthy controls. Similar microRNA (miRNA) analyses were performed in laser-captured CD68+ cells from perivascular (blood-derived macrophages) and parenchymal (microglia) brain regions in both active MS lesions and noninflammatory cases. Using human adult blood-derived macrophages and brain derived microglia, in vitro experiments were performed to demonstrate how miR-155 influences the polarization state, phenotype, and functional properties of myeloid cells, in addition to their ability to subsequently impact adaptive T cell responses. RESULTS: In MS, miR-155 expression was significantly increased in both peripheral circulating CD14+ monocytes and active lesions (CD68+ cells) compared to control donor monocytes and parenchymal microglia, respectively. In vitro, miR-155 was significantly increased in both M1-polarized primary human macrophages and microglia. Transfection of an miR-155 mimic increased proinflammatory cytokine secretion and costimulatory surface marker expression in both cell types; an miR-155 inhibitor decreased proinflammatory cytokine expression. Coculture experiments demonstrated that allogeneic T-cell responses were significantly enhanced in the presence of miR-155-transfected myeloid cells compared to controls. INTERPRETATION: Our results demonstrate that miR-155 regulates proinflammatory responses in both blood-derived and central nervous system (CNS)-resident myeloid cells, in addition to impacting subsequent adaptive immune responses. Differential miRNA expression may therefore provide insight into mechanisms responsible for distinct phenotypic and functional properties of myeloid cells, thus impacting their ability to influence CNS injury and repair. PMID- 23818338 TI - Chemical and genetic characterization of bacteriocins: antimicrobial peptides for food safety. AB - Antimicrobial peptides are produced across all domains of life. Among these diverse compounds, those produced by bacteria have been most successfully applied as agents of biocontrol in food and agriculture. Bacteriocins are ribosomally synthesized, proteinaceous compounds that inhibit the growth of closely related bacteria. Even within the subcategory of bacteriocins, the peptides vary significantly in terms of the gene cluster responsible for expression, and chemical and structural composition. The polycistronic gene cluster generally includes a structural gene and various combinations of immunity, secretion, and regulatory genes and modifying enzymes. Chemical variation can exist in amino acid identity, chain length, secondary and tertiary structural features, as well as specificity of active sites. This diversity posits bacteriocins as potential antimicrobial agents with a range of functions and applications. Those produced by food-grade bacteria and applied in normally occurring concentrations can be used as GRAS-status food additives. However, successful application requires thorough characterization. PMID- 23818339 TI - Breast cancer and pregnancy; overview of international bibliography. AB - Breast cancer constitutes the first gynaecological malignancy in pregnancy with a frequency of 1 : 3,000 - 10,000 pregnancies. Pregnancy itself does not seem to affect the odds of developing breast cancer or its prognosis. Breast ultrasonography constitutes the diagnostic method of choice, whereas magnetic resonance imaging (MRI) can be used as adjunct. As main staging tests, thoracic X ray and abdominal ultrasonography are recommended. The therapy of choice is modified radical mastectomy for the first two trimesters and lumpectomy or partial mastectomy followed by radiation therapy after childbirth for patients diagnosed in the 3(rd) trimester of pregnancy. The administration of chemotherapy is deemed acceptable in the 2(nd) and 3(rd) trimester, whereas hormonal therapy should be avoided for reasons of safety of the foetus. PMID- 23818340 TI - Sequential adjuvant docetaxel and anthracycline chemotherapy for node positive breast cancers: a retrospective study. AB - PURPOSE: Anthracyclines and taxanes are the most active agents in the adjuvant treatment of breast cancer (BC). They can be used simultaneously or sequentially. The optimal schedule and duration for their administration is unknown. We analyzed the efficacy of sequential adjuvant anthracycline and docetaxel administration in node positive BC patients. METHODS: Node positive BC patients (N=539) from 6 medical oncology centers in Turkey who received sequential adjuvant anthracycline-based regimens and taxane chemotherapy were included in this study between 2006 - 2010. One-hundred and thirty-eight (25%) patients received 3 cycles of anthracycline-based chemotherapy followed by 3 cycles of docetaxel (3+3) and 401 (75%) patients received 4 cycles of anthracycline-based chemotherapy followed by 4 cycles of docetaxel (4+4). Prognostic factors analyzed were estrogen receptor (ER), progesterone receptor (PR), HER2, tumor grade, and nodal status in relation to disease free survival (DFS) and HER2 status in relation to overall survival (OS). RESULTS: The patient median age was 48 years (range 18-79). Most common grade 3-4 toxicities were neutropenia, mucositis and arthralgia. No treatment-related toxic deaths were seen. With a median follow up of 26 months (range 1-115) 61 (11.3%) recurrences and 11 (2%) deaths were registered. Three-year DFS was 81% and OS 96% for all patients. There was no statistically significant difference between 3+3 and 4+4 groups in terms of survival (3-year DFS 88% and 79% [p=0.28] and OS 97% and 95% [p=0.60), respectively). CONCLUSION: Sequential chemotherapy with 4+4 cycles of anthracycline and docetaxel every 3 weeks is an acceptable regimen for adjuvant treatment of node positive BC patients. Duration of chemotherapy should be planned depending on prognostic factors. In this study there was no difference between 3+3 and 4+4 groups in DFS and OS despite the presence of good prognostic factors in the 3+3 group. PMID- 23818341 TI - Change of influence of prognostic markers on metastasis free interval during and after adjuvant tamoxifen therapy in breast cancer patients. AB - PURPOSE: To evaluate the influence of molecular biomarkers (estrogen receptor - ER, progesterone receptor - PR, and human epidermal growth factor receptor2 - HER2) and pathological parameters on metastasis free interval (MFI) in adjuvantly tamoxifen-treated breast cancer patients, during different follow up periods (0 2.5 years, 2.5-5 years and 5-12 years). METHODS: The study included 113 postmenopausal breast cancer patients with known pathological parameters. Steroid receptors were determined by ligand-binding assay and HER2 amplification status by chromogenic in situ hybridization (CISH). RESULTS: During the first 2.5 years of therapy patients with ER <5 fmol/mg, PR <5 fmol/mg or pT2 (>=2cm) tumors had higher probability of distant metastasis. For the period between 2.5-5 years, analysis of MFI according to pathological parameters and molecular biomarkers, separately, did not show any statistically significant difference. Patients with pT>=2 cm and HER2 amplification had much greater chance of developing distant metastasis when compared to other phenotypes (HER2-negative/pT1, HER2 negative/pT2 and HER2-positive/pT1). Patiens with ER >=160 fmol/mg and PR >=45 fmol/mg had good prognosis after 5 years of tamoxifen therapy. CONCLUSION: Our study indicates that there is a change of influence of the analyzed pathological parameters on MFI, depending on different follow up periods. Steroid receptor status, tumor size and HER2 status (alone or in combination) are significant parameters for the course of disease of postmenopausal ER-positive breast cancer patients, but during different periods of follow up. PMID- 23818342 TI - Breast cancer in octogenarian women: clinical characteristics and outcome. AB - PURPOSE: Breast cancer incidence increases in the elderly but data on treatment and outcomes of elderly patients is limited. We assessed the clinicopathological features and outcomes of our patients with breast cancer aged >=80 years in comparison with their younger postmenopausal counterparts. METHODS: The records of 83 patients diagnosed with breast cancer after the age of 80 (group 1) between 2003 and 2011 in 4 different centers were retrospectively evaluated and the clinicopathological features and outcomes were assessed in comparison with a control group (group 2) of 249 patients aged between 60-70 years. RESULTS: Median ages at diagnosis were 82 years (range 80-95) and 64 years (range 60-70) for group 1 and group 2, respectively. The incidence of invasive cancers other than ductal or lobular type was higher in group 1 than in group 2 (20 vs 8%; p=0.0177rpar;. More patients in group 1 had Charlson Comorbidty scores >=1 than those in group 2 (49 vs 36%; p=0.011). Patients in group 1 had more conservative operations and less axillary node dissections (ALND) and they received chemotherapy, trastuzumab or radiotherapy less frequently compared to their younger counterparts in group 2. Median follow up period was 36 months (range 1 178) in group 1 and 24 months (range 12-217) in group 2. Five-year disease free survival (DFS) was 53.7 and 75.9) (p=0.005), 5-year overall survival (OS) was 61.9% and 80.47percnt; in group 1 and group 2 (p=0.001), respectively. Advanced stage (stage IV vs stage I, II, III, p=0.051) and cerbB2 positivity (p<0.001) were found to be associated with shorter DFS in patients >=80 years of age. CONCLUSION: Although the majority of patients were undertreated in our study according to the current guidelines, mortality rates were quite low. Different biology of the disease in the elderly might explain this difference. PMID- 23818343 TI - The prognostic impact of obesity on molecular subtypes of breast cancer in premenopausal women. AB - PURPOSE: The increasing incidence of obesity throughout the world will result in expansion of the number of women at risk for developing breast cancer. Obesity is associated with adverse outcomes in postmenopausal women with breast cancer. In premenopausal women, the association is less clear. We investigated the impact of obesity on tumor features, hormonal status, recurrence and mortality in premenopausal breast cancer patients, classified according to molecular subtypes. METHODS: 818 premenopausal women with nonmetastatic breast cancer were analysed. Patients were classified into 3 groups according to body mass index (BMI): i) normal body weight (BMI: 18.5-24.9 kg/m(2)); ii) overweight (BMI: 25-29.9 kg/ m(2)); and iii) obese (BMI:>30 kg/ m(2)). Clinocopathologic characteristics and survival rates were analyzed for triple negative, HER-2 overexpressing and luminal subtypes. RESULTS: Obese patients compared with normal-weight women were older at diagnosis (p<0.001) and more often had high grade tumor (57.1 vs 42.3%; p=0.04) with lymphovascular invasion (79.5 vs 63.9%; p=0.03). The median follow up period after diagnosis was 29 months. According to the molecular subtypes, overall survival (OS) and disease free survival (DFS) were significantly shorter in obese patients with triple negative breast cancer (TNBC) (p=0.001 and p=0.006, respectively). Obesity (HR 1.4; 95% CI 1.0-2.1; p=0.04) and lymphovascular invasion (HR 2.1; 95% CI 1.3- 3.3; p=0.02) were found to be independent prognostic factors for TNBC mortality. CONCLUSION: Obesity is associated with estrogen (ER) and progesterone receptor (PR) negative tumors and poor OS in premenopausal women with breast cancer. PMID- 23818344 TI - Estimation of maspin's subcellular localization in invasive ductal breast cancer via light microscopy and computerized image analysis: a comparative study. AB - PURPOSE: Contradictory results have been reported concerning the role of maspin and its cellular distribution in breast cancer. The purpose of this study was to examine the subcellular localization (nuclear-cytoplasmic) of maspin in breast cancer and to compare the evaluation of maspin immunostaining via light microscopy (LM) to the estimation via computerized image analysis (CIA) system. We also examined correlations between maspin expression and several clinicopathological parameters. METHODS: The sample consisted of 48 primary invasive ductal carcinomas (IDC) of the breast. Maspin immunostaining was quantified and graded via LM by two pathologists, separately in the nuclear and cytoplasmic compartments. Total maspin expression was also estimated via CIA system. Univariate non-parametric statistics and stepwise multivariate ordinal logistic regression were performed. RESULTS: Both maspin components (nuclear and cytoplasmic) were closely associated with each other (p<0.001). Total maspin score was positively and closely associated with nuclear maspin (p<0.001) and cytoplasmic maspin (p<0.001). Total maspin , nuclear maspin and cytoplasmic maspin did not correlate significantly with either age, grade, T, N and M status, stage, micro vessel density (MVD) (CD34), ki-67, p53, estrogen receptor (ER) and HER-2 status, or with any of the 4 groups of the molecular classification. The only factor that showed a borderline inverse correlation with nuclear maspin (p=0.059) was progesterone receptors (PR) positivity. CONCLUSION: The cytoplasmic and nuclear fractions of maspin seem to be closely interwoven. Evidently, both mutually intertwined counterparts were independently reflected upon the total maspin levels measured by CIA. Future studies should ideally encompass all three approaches (nuclear, cytoplasmic, total) adopted herein. PMID- 23818345 TI - The role of ThinPrep cytology in the investigation of ki-67 index, p53 and HER-2 detection in fine-needle aspirates of breast tumors. AB - PURPOSE: The aim of the current study was to compare the immunocytochemical expression of ki-67, HER-2 and p53 on ThinPrep (TP)-processed smears, obtained by preoperative fine-needle aspiration (FNA) biopsies from primary breast carcinoma with the immunohistochemical results obtained on the corresponding surgical samples. METHODS: FNA biopsies were collected from 119 female patients during a 31-month period. Subsequently, these patients underwent surgical resection of the tumors. RESULTS: The overall accuracy (OA) of the TP cytology for ki-67, p53 and HER-2 expression was 96, 99 and 97%, respectively. There was a strong positive correlation between immunohistochemistry and immunocytochemistry results for ki 67 (Spearman's test 0.875) for p53 (Cramer's phi test 0.965) and HER-2 (Kendall's tau test 0.891). CONCLUSION: This pilot study demonstrates that it is possible to monitor multiple molecular markers by using the TP cytology. Sample collection and storage is simple and permits the assortment of the FNA sample for both morphologic diagnosis and ancillary studies. The accuracy of TP technique in the evaluation of ki-67, p53 and HER-2 expression is comparable to those of the histological evaluation, and could be of paramount importance for the preoperative planning of treatment. PMID- 23818347 TI - Evaluation of changes in biologic markers ER, PR, HER 2 and Ki-67 index in breast cancer with administration of neoadjuvant dose dense doxorubicin, cyclophosphamide followed by paclitaxel chemotherapy. AB - PURPOSE: The aim of this study was to assess the changes in biologic markers of breast cancer ER, PR, HER 2 and Ki-67 in locally advanced breast cancer patients after neoadjuvant chemotherapy. METHODS: Data from 63 locally advanced breast cancer patients (stage II or III), whose histological diagnosis was made by core biopsies were retrospectively evaluated. The patients were given 4 cyles of 600 mg/m(2) cyclophosphamide, 60 mg/m(2) doxorubicin every 15 days followed by 4 cycles of paclitaxel 175 mg/m(2) every 15 days, and they underwent surgery within two weeks after the last chemotherapy cycle. Expressions in the preoperative and postoperative status of ER, PR, HER 2 and Ki-67 were compared. RESULTS: The patient mean age was 49.2 +/-10.7 years and most (57.1%) were premenopausal. Clinical stages of patients ranged between T2N1 and T3N2. The pathological complete response (pCR) rate was 14.9 % (N=9). Two (5.7%) patients who were ER positive prior to treatment showed ER negativity after treatment. In 7 (21.17percnt;) patients PR became negative after neoadjuvant chemotherapy and in 3 (9.0%) patients PR became positive. Changes in ER and PR receptors were not statistically significant (ER p=0.500 and PR p=0.549, respectively), whereas in 2 (5. 8%) patients hormonal status changed significantly when compared to initial biopsies (p=0.003). In addition, median value for PR intensity decreased from 20 to 10% (p=0.003) and Ki-67 values decreased from 10 to 1% (p<0.001) following neoadjuvant therapy. Six (17%) patients exhibited some changes in HER 2 staining. HER 2 expression became 2+ in 3 patients who were HER 2 negative prior to treatment, and HER 2 expression became negative in two patients with HER 2 1+ and 2+ prior to treatment following neoadjuvant chemotherapy. CONCLUSION: The biological markers ER, PR, HER 2 and Ki- 67 index demonstrated differences after neoadjuvant treatment in breast cancer patients. These changes may affect the treatment decision. PMID- 23818346 TI - Prognostic significance of estrogen receptor, progesterone receptor, HER2/neu, Ki 67, and nm23 expression in patients with invasive breast cancer. AB - PURPOSE: To determine the prognostic significance of estrogen receptor (ER), progesterone receptor (PR), HER2/neu, Ki-67, and nm23 immunohistochemical expression with respect to progression free survival (PFS) and overall survival (OS) in Turkish patients with invasive breast cancer (IBC). METHODS: Patients with IBC (n = 81; mean age = 51.9 +/- 11.1 years) were prospectively enrolled at the Department of Oncology, Uludag University Medical Center, Bursa, Turkey. Immunohistochemistry was performed on formalin- fixed, paraffin-embedded tissue sections. RESULTS: We did not find any significant association between immunohistochemical expression of ER, PR, HER2/ neu, Ki-67, and nm23 and the baseline characteristics of IBC patients. The median patient PFS was 30 months (range 22-45), and the median OS was 32 months (range 23-46). Stratification of the patient population according to nm23 immunohistochemical expression revealed a statistically significant difference in terms of both OS (p < 0.05) and DFS (p < 0.05). Multivariate Cox regression analysis indicated that tumor grade, axillary lymph node status, and nm23 immunohistochemical expression were the 3 main independent prognostic factors for PFS and OS in IBC patients. CONCLUSION: Reduced nm23 immunohistochemical expression is an independent negative prognostic factor for OS and PFS. Patients with negative nm23 expression may require a more intensive follow-up. PMID- 23818348 TI - Evaluation of the efficacy of adjuvant chemotherapy in patients with high-risk stage II colon cancer. AB - PURPOSE: This study aimed at comparing the disease-free survival (DFS) in high risk TNM stage II colon cancer patients who had been subjected to adjuvant chemotherapy and TNM low-risk stage II patients who did not receive chemotherapy. METHODS: We retrospectively reviewed the medical records of stage II colon cancer patients between January 2006 and December 2011. High-risk patients were defined those with any colonic obstruction/perforation, mucinous histology, inadequate lymph node sampling, T4 disease, lymphatic/ vascular or perineural invasion, preoperatively elevated carcinoembryonic antigen (CEA) and high-grade tumor. All patients with high-risk features received adjuvant chemotherapy. RESULTS: There were 42 patients in the high-risk treatment group and 21 patients in the non treatment (observation) group. There were no significant differences in terms of gender, tumor size, tumor localization, or the number of excised lymph nodes between the groups. The median follow- up time was 33.9 months in the treatment group and 29.3 months in the non-treatment group. Recurrence developed in 4 patients (6.3%), 3 of which were in the treatment group. DFS in both groups was statistically similar. CONCLUSION: Adjuvant chemotherapy in the high-risk patients resulted in similar DFS as that in the low-risk patients. Although the role of adjuvant chemotherapy for stage II colon cancer is unclear, it is rational to offer adjuvant chemotherapy to patients with high-risk stage II colon cancer. PMID- 23818349 TI - A modified DCF regimen as primary treatment for patients with metastatic gastric cancer. AB - PURPOSE: To retrospectively assess the efficacy and toxity of a modified docetaxel, cisplatin, fluorouracil (mDCF) regimen as primary treatment in patients with metastatic gastric cancer (MGC). METHODS: mDCF included folinic acid 400 mg/m(2) (day 1) + 5-fluorouracil (5-FU) 400 mg/m(2) i.v. bolus (day 1) + 5-FU 2400 mg/m(2) 46-h infusion (days 1 and 2) + docetaxel 60 mg/m(2) (day 1) + cisplatin 50 mg/m(2) (day 1) and was administered once every two weeks in MGC patients. RESULTS: Eighty-nine patients (median age 59 years, range 31-79) were enrolled. The median number of courses was 6 (range 2-12), and the total number was 492. The median follow-up duration was 8.6 months (range 2-14). Three (3.3%) patients showed complete response, 21 (23.6%) partial response, 36 (40.4%) stable disease, and progression was observed in 29 (32.6%) patients. The median progression- free survival (PFS) rate was 7 months (95% CI 5.7-8.2), and the median overall survival (OS) rate was 11 months (95% CI 9.7-12.2). The most common toxicity was neutropenia, which was observed in 52 (58.4%) patients. CONCLUSION: mDCF with reduced drug doses, given every two weeks, is a rather efficient regimen for MGC patients. PMID- 23818350 TI - Preoperative chemoradiotherapy improves local recurrence free survival in locally advanced rectal cancer. AB - PURPOSE: Preoperative chemoradiotherapy (pre-CRT) followed by total mesorectal excision (TME) is the recommended therapy for patients with locally advanced rectal cancer (LARC). The primary aim of this study was to compare the rates of local and distant recurrence and overall survival (OS) in LARC patients who received pre-CRT vs postoperative (post) CRT. METHODS: The medical records of 158 rectal cancer patients with clinical stage T3, T4 or N positive disease who received either pre-CRT or post-CRT between 2000-2009 were retrospectively analysed. Pre-CRT employed protracted 5-fluorouracil (5FU) infusion, whereas post CRT included bolus 5FU and leucovorin concurrently with radiation therapy (RT). Radiation dose was 50.4 Gy in 82% and 45 Gy in 18% of the patients. RESULTS: 158 patients (65 females, 93 males) were analysed. Median age was 56.5 years (range 19-78). Fifty-three (34%) patients received pre-CRT and 105 (66%) post-CRT. Median follow-up was 43.3 months (range 8-182) and 47.6 months (range 9-194) in pre-CRT and post-CRT patients, respectively. After pre-CRT, significant downstaging was achieved. However, the type of surgical resection was not influenced by the administration of pre-CRT in tumors >=5 cm distant from the anal verge (p=0.3). Pathologic complete response was achieved in 20% of the patients in the pre-CRT group. Local recurrence free survival (LRFS) at 5-years was 89.2% in the pre-CRT and 74.8% in the post-CRT group (p=0.04). Distant recurrence free survival (DRFS) at 5-years was 81.7% and 68.5 % in pre-CRT and post-CRT groups, respectively (p=0.1). OS was similar in the two groups (71.4 vs 64.4%, p=0.9). CONCLUSION: Treatment of LARC with pre-CRT followed by surgery improved LRFS as compared to surgery followed by post-CRT, but failed to improve DRFS or OS in our patient population. PMID- 23818351 TI - D-dimer is a marker of response to chemotherapy in patients with metastatic colorectal cancer. AB - PURPOSE: D-dimer, LDH and tumor markers are usually overexpressed in colorectal carcinomas (CRC). Our purpose was to assess the prognostic role of D-dimer, lactate dehydrogenase (LDH), CEA, CA19-9 and CA72-4 in patients with metastatic CRC treated with XELOX chemotherapy. METHODS: Thirty-eight CRC patients who had evidence of distant metastasis were enrolled in the study and blood samples were taken before chemotherapy for estimation of the tumor markers CEA, CA19-9 and CA72-4, and for D-dimer and LDH. Patients were randomized into 3 groups: those with partial response (PR), stable disease (SD), and progressive disease (PD) according to their clinical and radiologic evaluation after 3 cycles of XELOX chemotherapy. All parameters were reevaluated after the 3rd cycle of chemotherapy. RESULTS: Eighteen patients (47.3%) achieved PR, 10 (26.3%) SD, and 10 (26.3%) showed PD. After 3 cycles of XELOX CEA (20.55 vs 11.97 ng7sol;ml; p=0.002), LDH (357.50 vs 214.0 U7sol; lt; p=0.001) and D-dimer (1.56 vs 1.17 MUgFEU/ml; p=0.022) levels were significantly decreased in the PR group. D-dimer levels were also notably decreased (1.36 vs 0.77 MUgFEU/ml; p=0.021) in the SD group. In the PD group a considerable increase was seen in CA 19-9 (119.5 vs 243.09 U/ml; p=0.025), CA 72-4 (5.18 vs 25.8 U/ml; p=0.036) and D-dimer levels (1.77 vs 1.88 MUgFEU/ml; p=0.012). CONCLUSION: This study demonstrated that D dimer, LDH and tumor markers can be helpful in determining CRC prognosis in patients with metastatic disease. D-dimer, LDH and tumor markers provided unique prognostic information in advanced CRC patients. PMID- 23818352 TI - Prognostic significance of vascular endothelial growth factor expression in esophageal carcinoma: a meta-analysis. AB - PURPOSE: The purpose of this study was to comprehensively and quantitatively review eligible published studies to explore the prognostic significance of vascular endothelial growth factor (VEGF) expression in patients with esophageal carcinoma (EC). METHODS: PubMed and Embase databases were searched until September 11, 2011. A meta-analysis was performed to demonstrate any relationship between VEGF and 5-year overall survival (OS) in EC patients. RESULTS: The final analysis included 1453 patients from 19 studies. The studies were grouped by patient source, histology, VEGF isoform and cutoff value. The estimated risk of death suggested that VEGF positivity had negative impact on prognosis of patients with EC, esophageal squamous cell carcinoma (ESCC) and Asian patients. The risk ratios (RR) and 95% confidence interval (95% CI) were 1.26 (1.16-1.37) in EC patients, 1.28 (1.16-1.40) in ESCC patients and 1.35 (1.24-1.48) in Asian patients. Furthermore, when the cutoff value was set at 10% in 6 studies, the RR (95% CI) was 1.48 in the VEGF positive group (1.27-1.73). In addition, VEGFC was also correlated with patient poor prognosis with a RR (95% CI) of 1.30 (1.15 1.48). However, EC patients from non-Asian countries and cutoff value at 30% showed no significant correlation with survival. Data were not sufficient to determine the prognostic value of VEGF expression in esophageal adenocarcinoma (EA) patients and VEGFD expression. CONCLUSIONS: VEGF positivity indicated poor prognosis in patients with EC, ESCC and of Asian origin. Cutoff value at 10% may be a more appropriate standard to define VEGF positivity. VEGFC also correlated with poor prognosis in EC patients. PMID- 23818353 TI - A weekly hypofractionated radiotherapeutic schedule for bladder carcinoma in elderly patients: local response, acute and late toxicity, dosimetric parameters and pain relief. AB - PURPOSE: To investigate the early and late toxicity of a hypofractionated radiotherapy (RT) schedule to treat muscle- invasive bladder cancer in relation to radiation parameters according to the organs at risk. METHODS: Forty-three patients with T2-T3 bladder carcinoma were irradiated with a weekly hypofractionated schedule with a total dose of 36 Gy in 6 fractions. Included in this study were elderly patients with poor performance status or unfit for surgery, while they complained of daily pain on urination. Pain evaluation was assessed with the use of the visual analogue scale (VAS) of pain, acute and late toxicities were assessed using the combined RTOG/EORTC criteria by using a dose of 50 Gy (D50), and the relapse free survival (RFS) was estimated from the date of recurrence. RESULTS: No acute side effects were observed in the majority of the patients. Grade I rectal toxicity was registered in 67.4% of the patients, while grade II and III were noted in 30.25% and 2.37percnt; of the patients, respectively. The worst late rectal toxicity was grade I in 30.2% of the patients. The VAS score of pain showed a significant improvement after the hypofractionated schedule. There was a significant correlation between acute and late toxicity on the one hand and the D50 dosimetric parameter on the other. The Kaplan-Meier plot showed a median RFS of 15 months, while age did not have any impact on RFS in patients above or under 75 years of age. CONCLUSION: The performed hypofractionated schedule permitted delivery of an increased radiation dose without increased toxicity, and with a high probability of local control for elderly patients with low survival perspective. PMID- 23818354 TI - The association of hematologic parameters on the prognosis of patients with metastatic renal cell carcinoma. AB - PURPOSE: Metastatic renal cell carcinoma (mRCC) bears a poor prognosis. We investigated the prognostic significance of some hematologic parameters of patients with mRCC. METHODS: We retrospectively reviewed the records of 53 patients with mRCC . The mean follow up time was 34 months (range 5-142).We assessed the prognostic value of hematologic parameters (leukocytes ,neutrophils, lymphocytes, platelets, neutrophil to lymphocyte ratio/NLR, platelet to lymphocyte ratio/PLR), and other clinical parameters with univariate and multivariate analysis. RESULTS: Memorial Sloan-Kettering Cancer Center (MSKCC) risk group , lung metastases, sunitinib treatment, lymphocyte count, NLR, and anemia significantly correlated with median overall survival (OS) on univariate analysis. The median OS in patients with a NLR < 3.4 was 32.2 months , significantly higher than the 13.9 months in patients with a ratio >= 3.4 (p = 0.006). Multivariate analysis revealed that MSKCC risk group and the NLR were independent predictors of OS. CONCLUSION: Hematologic parameters may be associated with OS in mRCC. However, further studies are needed to establish their routine use. PMID- 23818355 TI - Relationship of TP53 and Ki67 expression in bladder cancer under WHO 2004 classification. AB - PURPOSE: Tumor markers TP53 and Ki67 are currently common labels used in the diagnosis of bladder cancer throughout the world. In light of the co-existence of both WHO1973 and 2004 classifications for bladder cancer, it is necessary to establish different quantification standards for both labels to better cater for the grading and staging. METHODS: We investigated the immunohistochemical profiles of 280 bladder cancer samples classified under WHO 2004 standards. TP53 was scored semi-quantitatively whilst Ki67 was scored by label index. RESULTS: We found that expression of TP53 was not correlated to either grade or stage, a finding that doesn't agree with most of the literature. Expression of Ki67 was correlated with grade and stage. Expressions of TP53 and Ki67 were correlated with each other. Interestingly, Ki67 expression was higher in females. CONCLUSION: The expression of TP53 could be modified to better suit the WHO 2004 classification. PMID- 23818356 TI - Adjuvant chemotherapy after reduced craniospinal irradiation dose in children with average-risk medulloblastoma: a 5-year follow-up study. AB - PURPOSE: This study was undertaken to determine the effect of adjuvant chemotherapy combined with reduced-dose craniospinal irradiation (CSI) on survival and neurocognitive sequelae of radiotherapy (RT) in patients with average- risk medulloblastoma above the age of 3 years. METHODS: Thirty-three children between 3 and 10 years of age with average-risk medulloblastoma were treated with postoperative reduced-dose CSI (24.0 Gy) and 30.6 Gy of local RT (total of 54.6 Gy) and then with adjuvant chemotherapy consisting of cisplatin, vincristine, and cyclophosphamide every 4 weeks for 8 cycles. RESULTS: At 5 years, event-free survival (EFS) was 79%, while overall survival (OS) was 85%. Sites of relapse were local in 3%, neuraxis in 9% and both local and neuraxis in 9% of the patients. Chemotherapy was well tolerated. Hematopoietic toxicity was the most predominant side effect followed by vomiting and ototoxicity. No grade III or IV nephrotoxicity or neurotoxicity and no treatment-related deaths were encountered. Insignificant decline of intelligence quotient (IQ) was reported in 28.6% of the patients. CONCLUSION: The preliminary results of adjuvant chemotherapy after reduced-dose CSI in average-risk medulloblastoma patients are encouraging and effective, and can be applied safely with acceptable toxicity. PMID- 23818357 TI - Prognostic value of peritumoral edema and angiogenesis in intracranial meningioma surgery. AB - PURPOSE: In a series of 78 consecutive patients we analyzed the influence of peritumoral edema (PTE) and angiogenesis (vascular endothelial growth factor/ VEGF expression) on the prognosis of morbidity and postoperative complications after intracranial meningioma surgery. METHODS: A retrospective analysis was performed of clinical, neuroradiological and histological data of 78 microsurgically treated patients with intracranial supratentorial meningioma, with follow-up period of at least one year. RESULTS: The severity of PTE showed significant correlation with VEGF expression, and all patients with large PTE (>40 mm) had strong VEGF expression (>50%). Treatment outcome was significantly better in patients with low VEGF expression (p<0.05). All of the monitored postoperative complications were more frequent in the group with PTE.The duration of intensive care treatment in the group with PTE (mean 6.85 days) was significantly longer than in the group without PTE (mean 3.68 days) (p=0.003). In the group without PTE, the outcome was significantly better than in patients with PTE (p<0.01). CONCLUSION: PTE in intracranial meningiomas has significant influence on the prognosis in surgically treated patients in terms of increased risk of morbidity and postoperative complications. VEGF expression is strongly correlated with PTE formation, which also affects the outcome in the management of patients with intracranial meningioma. PMID- 23818358 TI - miR-17 in imatinib resistance and response to tyrosine kinase inhibitors in chronic myeloid leukemia cells. AB - PURPOSE: In this study we examined the expression levels of miR-17 which possesses oncogenic activities through downregulation of CDKN1A, p21 and E2F1 tumor suppressor genes, in imatinib sensitive and resistant chronic myeloid leukemia (CML) cells. On the other hand, we also determined the expression levels of miR-17 in response to tyrosine kinase inhibitors imatinib, nilotinib and dasatinib used for the treatment of CML. METHODS: The expression profiles of miR 17 were analysed by Stem-Loop reverse transcription (RT) polymerase chain reaction (PCR). RESULTS: The results revealed significant increase in the expression levels of miR-17 in imatinib sensitive and resistant cells compared to peripheral blood mononuclear cells (PBMCs). On the other hand, significant decrease was observed in miR-17 levels in response to imatinib, nilotinib and dasatinib. CONCLUSION: These results may imply that miR-17 can be used for diagnosis and treatment of CML. PMID- 23818359 TI - The evaluation of minimal residual disease in multiple myeloma by fluorescent molecular beacons in real time PCR of IgH gene rearrangements and correlation with flow cytometry. AB - PURPOSE: Multiple myeloma (MM) patients relapse after a period of time despite longer disease-free survival due to novel treatment options. In this study we aimed to assess the value of real-time polymerase chain reaction (RT-PCR) for detecting the immunoglobulin heavy chain (IgH) gene rearrangement using allele specific molecular beacons as fluorescence probes to quantify minimal residual disease (MRD) and also to correlate post-treatment flow cytometric detection of plasma cells' (PCs) expression of CD19, CD38, CD45, CD56 and CD138 in MM. METHODS: After diagnosis of 17 MM patients, the CDR1, CDR2 and CDR3 regions of the IgH gene were analysed and sequenced to identify IgH's clonal nature. Unique sequences of the clonal IgH rearrangement were used to design specific molecular beacon probes for each MM patient. Examined were also the co-expression of CD19, CD38, CD45, CD56, and CD138 molecules in bone marrow aspirates of patients with MM by flow cytometry. RESULTS: Detection of MRD was positive in 13 (76%) of 17 patients by RT-PCR. The infiltration ratio was significantly correlated with CD138 expression (p=0.009). Significant correlation was also found between RT-PCR detection of MRD and CD138 expression (p=0.006). Nevertheless, no correlation was observed among other surface antigens (CD38, CD45, CD56). CONCLUSION: Our results indicated that RT-PCR with specific molecular beacons provide a feasible, accurate and reproducible method for the determination of MRD in MM. Flow cytometry detection of CD138 expression may be used as a disease marker in addition to RT-PCR. PMID- 23818360 TI - Multiple myeloma in association with second malignancy. AB - PURPOSE: To look at the frequency of second primary malignancies (SECMAL) in patients with multiple myeloma (MM). METHODS: The medical files of 332 patients with MM (whole group), diagnosed and treated at the University Multiprofile Hospital for Active Treatment "Sv. Georgi" and the Comprehensive Oncology Hospital (Plovdiv) for a 20-year period (1990-2010) were retrospectively analyzed. MM patients with SECMAL constituted the study group. A control group comprised patients with solid tumors associated with SECMAL. This group derived from a sample of 21768 patients with solid tumors. RESULTS: In the study group, SECMAL was diagnosed in 4.52% (N=15) of the patients, while in the control group this figure was 5.09% (N=1108) (p>0.05). The diagnosis of MM preceded the occurrence of SECMAL in 35.71% of the study group patients, the median interval being 6.6 years (range 5-14). More frequently the diagnosis of the solid tumor preceded the occurrence of MM (66.67%). Breast cancer and gastric cancer were encountered with the highest frequency (26.67% each). The median survival (77.2 months, range 44-129) was significantly longer in the group with MM and SECMAL compared to the whole group with MM (median 38.6 months, range 10-58; p<0.05). CONCLUSION: The rate of MM with other malignant diseases is comparable with the frequency of SECMAL in other lymphoproliferative disorders and solid tumors. The occurrence of SECMAL during the clinical course of MM is not a frequent event and is expected in the rare cases with longer survival. PMID- 23818361 TI - Who may benefit from prophylactic cranial irradiation amongst stage III non-small cell lung cancer patients? AB - PURPOSE: To identify a high risk group of non-small cell lung cancer (NSCLC) patients who may benefit from preventive strategies in order to reduce the rate of brain metastasis. METHODS: Two-hundred stage IIIA (47.5%) and IIIB (52.5%) NSCLC patients were analysed (median age 61 years, range 29-82). Pathological diagnosis consisted of 27% adenocarcinomas, 48.5% squamous cell carcinomas, and 24.5% non-small cell lung carcinomas. Brain metastasis rate was calculated and compared in relation to age, gender, stage, histology, chemotherapy and surgery. RESULTS: Median follow-up was 15 months (range 2-65), and the 2-year survival rate was 35%. Two-year incidence of brain metastasis was 23%. In univariate analysis, 32.9% of the patients younger than 60 years of age developed brain metastasis, in contrast to 15.3% of those older than 60 years (p=0.003). Brain was the first metastatic site in younger patients (44.4%) which was significantly higher than in the older age group (23%) (p=0.03). Adenocarcinoma had higher risk (39.6%) than squamous cell carcinoma (15.7%) for brain metastasis (p<0.0001). Patients 60 years old or younger with adenocarcinoma (53.3%) had higher risk for brain metastasis than all the others (18%; p<0.0001). CONCLUSION: In locally advanced NSCLC patients, age and adenocarcinoma histology represent high risk factors for early development of brain metastasis. Many of the failures are isolated brain lesions and future studies are required to assess the benefit of preventive strategies in selected patients. PMID- 23818362 TI - Negative prognostic factors for head and neck cancer in the young. AB - PURPOSE: To evaluate the prognosis of head and neck (HN) squamous cell carcinoma (SCC) diagnosed in young people (<=40 years), and to compare it with the typical older patients. METHODS: The study population comprised 69 HN cancer patients below the age of 40 years. An equal-sized control group of older patients was pair-matched with the young cases. Cases and controls were compared for type and frequency of recurrence, in addition to survival. Tongue tumor specimens from 12 women of the study group (6 young and 6 old) were included in a pilot immunohistochemical analysis of estrogen receptors (ER) expression. RESULTS: Young patients with early (T1,T2) tongue cancer had shorter overall survival (OS) than their matched controls, but the finding was marginally non-significant (p=0.056). In the young population, late neck metastasis was a particularly aggravating factor for survival (p=0.004). In the case of tongue SCCs, young women were at the greatest risk of recurrence than any other gender-age combination (p=0.006). However, only 8.3% of tumors expressed ER. CONCLUSION: Early-stage tongue cancer, regional recurrence, and tongue SCCs in women are negative prognostic factors for young HN cancer patients. Treatment modifications targeting these subgroups might be beneficial. PMID- 23818363 TI - Expression of hPEBP4 negatively correlates with estrogen and progesterone receptors in endometrial carcinoma. AB - PURPOSE: To investigate the expression of human phosphatidylethanolamine- binding protein 4 (hPEBP4) in endometrial carcinoma and its relation with progesterone receptor (PR) and estrogen receptor (ER). METHODS: Forty-five samples of endometrioid endometrial carcinoma (EEC), 12 samples of atypical endometrial hyperplasia, and 30 samples of normal endometrium were examined. Samples were studied by immunohistochemistry for PR, ER and hPEBP4 expression. Expressions were statistically quantified and analyzed. RESULTS: Expressions of PR and ER were significantly higher in normal endometrium than in cancer. Expression of hPEBP4 was significantly lower in normal endometrium. The expression of hPEBP4 was significantly higher in advanced-stage endometrial cancer, whilst higher but insignificant trend was noticed in higher grade carcinoma. Statistically insignificant trend of negative ER and PR expression with higher grade or stage was noticed. The expression of hPEBP4 was negatively correlated to ER and PR in EEC. CONCLUSION: The expression pattern of hPEBP4 indicated that hPEBP4 interacted with ER and PR in EEC and could thus become a possible target for the development of novel treatment against this malignancy. PMID- 23818364 TI - Correlation of nuclear morphometry of primary melanoma of the skin with clinicopathological parameters and expression of tumor suppressor proteins (p53 and p16(INK4a)) and bcl-2 oncoprotein. AB - PURPOSE: To determine the correlation of nuclear morphometry of primary cutaneous malignant melanoma (CMM) with clinicopathological parameters and the expression of p53, p16INK4a, and bcl-2. METHODS: Image analysis and computerized nuclear morphometry were used in a series of 53 primary CMM (nodular melanoma/NM, N=33, and superficially spreading melanoma/SSM, N=20). The clinicopathological parameters determined for each tumor were histological type, maximal tumor diameter, Breslow thickness, Clark level, ulceration, mitotic index (MI) and pathological disease stage. Measured nuclear features included size, shape and optical density (OD). The results were correlated with the expression of p53, p16INK4a and bcl-2. RESULTS: Significant differences between NM and SSM were found for the nuclear area, OD, and perimeter (p<0.05). MI showed significant correlations with nuclear area, perimeter and Feret diameter (p<0.05). In relation to the Clark level, significant differences were found for OD (p<0.01) and circularity of nuclei (p<0.05) between levels II and IV, while the Breslow thickness was not significantly correlated with nuclear morphometric variables. Significantly negative correlations were observed between OD and the expression of p53 and bcl-2, while significant positive correlation was found between the nuclear circularity and p53 immunoreaction intensity. There was no significant correlation between the expression of p16INK4a protein and karyometric variables. CONCLUSION: OD and circularity are significantly correlated with p53 and bcl-2, and nuclear area with MI. These karyometric variables may determine a more aggressive phenotype of melanoma cells. PMID- 23818365 TI - Triterpenoid pristimerin induced HepG2 cells apoptosis through ROS-mediated mitochondrial dysfunction. AB - PURPOSE: To investigate the anticancer properties implicated in a natural triterpenoid (pristimerin)-induced apoptosis and inhibited proliferation in human hepatocellular carcinoma (HCC) HepG2 cell line. METHODS: The cytotoxic activity of pristimerin in HepG2 cells was determined by MTT assay. Apoptotic morphology was observed by fluorescence microscope with Hoechst 33258 staining and percent apoptosis was measured by annexin V/PI double staining. DiOC6 for mitochondrial potential (DeltaPsim) and DCFH-DA for reactive oxygen species (ROS) were determined by flow cytometry. Changes of apoptotic- related proteins were analysed by Western blot. RESULTS: Pristimerin exerted a potent cytotoxic effect on HepG2 cells. After HepG2 cells were treated with pristimerin, typical apoptotic bodies, increasing the proportion of apoptotic annexin V-positive cells and activation of caspase-3 were detected in a dose-dependent manner. It was intriguing that pristimerin increased the generation of ROS with a collapse of the mitochondrial membrane potential in the cells. In addition, there was significant change in other mitochondrial membrane proteins triggered by pristimerin, such as Bcl-2 and Bax. Pristimerin also effectively induced subsequent release of cytochrome C from mitochondria into the cytosol, downregulated EGFR protein expression and inhibited downstream signaling pathways in HepG2 cells. Pretreatment with N-acetylcysteine (NAC) blocked ROS generation and resulted in loss of mitochondrial membrane potential, release of cytochrome C and apoptosis induced by pristimerin. CONCLUSION: These data indicate that ROS play an essential role in the induction of apoptosis by pristimerin in HepG2 cells. PMID- 23818366 TI - Influence of polymorphisms in ERCC5, XPA and MTR DNA repair and synthesis genes in B-cell lymphoma risk. A case-control study in Spanish population. AB - PURPOSE: Functions pertaining to DNA repair and synthesis are believed to play a critical role in cancer development and seem to be affected by genetic polymorphisms. Herein we performed a case-control study evaluating the influence of three single nucleotide polymorphisms (SNPs) in XPA, ERCC5 and MTR [rs1800975 (G-4A), rs17655 (Asp1104His) and rs1805087 (A2756G), respectively] in lymphoma risk. METHODS: Genotype distributions were studied in 213 lymphoma Caucasian patients (193 non-Hodgkin/NHL and 20 Hodgkin lymphoma/HL) and 214 controls, residents in a region of Southeast Spain. RESULTS: No significant differences were observed in the genotype distributions between cases and controls for the studied SNPs. This lack of association was also observed when stratifying for gender or lymphoma type. CONCLUSION: Our results suggest that the rs1800975, rs17655 and rs1805087 SNPs in DNA repair and synthesis of genes do not seem to play a major role in lymphoma susceptibility. PMID- 23818367 TI - The Euphorbia lunulata Bge extract inhibits proliferation of human hepatoma HepG2 cells and induces apoptosis. AB - PURPOSE: The purpose of this study was to determine the effect of Euphorbia lunulata Bge extract on the proliferation of human hepatoma HepG2 cell line. METHODS: Different dilutions of Euphorbia lunulata Bge extract were used to treat human hepatoma HepG2 cells. Hoechst 33258 and PI-staining fluorescence microscopy were utilized to observe the nuclear morphological changes of apoptotic cells. Flow cytometry was used to detect the rates of apoptosis and apoptotic peaks. Western blotting was performed to analyze the subcellular distribution of cytochrome C. RESULTS: The Euphorbia lunulata Bge extract was found to inhibit the proliferation of human hepatoma HepG2 cells via a time and concentration dependent manner. CONCLUSION: Altogether, the results suggest that the Euphorbia lunulata Bge extract is effective in inhibiting the proliferation of human hepatoma HepG2 cells and inducing cell apoptosis. The mechanism may be related to the mitochondrial pathways or cellular apoptosis pathways. PMID- 23818368 TI - Cemented versus cementless endoprostheses for lower limb salvage surgery. AB - PURPOSE: To determine the survival and failures of cemented vs cementless endoprostheses. METHODS: We retrospectively studied 232 patients treated with lower limb salvage surgery and reconstruction using cementless and cemented endoprostheses from 2002 to 2007. We compared survival and failures of the endoprostheses regarding age, gender, body mass index (BMI), diagnosis, site of reconstruction, radiation therapy, chemotherapy, and stem fixation. RESULTS: The mean patient follow-up was 28 months (median 24; range 12-84). The overall survival of cemented and cementless endoprostheses at 60 months was 64 and 78%, respectively (p=0.0078). Survival at 60 months of cemented and cementless endoprostheses to infection was 68 and 82%, respectively (p=0.0248). Survival of cemented and cementless endoprostheses to aseptic loosening at 60 months was 94 and 96%, respectively (p=0.1493). The only significant univariate and multivariate predictor of survival was the cementless type of stem fixation. CONCLUSION: Cementless endoprostheses have higher overall survival and survival to infection compared to cemented endoprostheses. Survival to aseptic loosening is not different. Stem fixation is the only significant variable for survival. PMID- 23818369 TI - GE132+Natural: Novel promising dietetic supplement with antiproliferative influence on prostate, colon, and breast cancer cells. AB - PURPOSE: Natural products have been investigated for promising new leads in pharmaceutical development. The purpose of this study was to analyze the biological effect of GE132+Natural, a novel supplement consisting of 5 compounds: Resveratrol, Ganoderma lucidum, Sulforaphane, Lycopene and Royal jelly. METHODS: The antiproliferative activity of GE132+Natural was tested on 3 different human cancer cell lines: MCF7 (breast cancer cells), PC3 (prostate cancer cells), and SW480 (colon cancer cells), as well as on EA.hy 926 (normal human endothelial cell line). In addition, the cytotoxicity of GE132+- Natural on the proliferation of primary human mesenchymal stem cells isolated from dental pulp (DP=MSC), along with its in vitro impact on different peripheral blood parameters, was determined. RESULTS: The results revealed high antiproliferative activity of GE132+Natural on all tested cancer cell lines (PC3, MCF7 and SW480), as well as on the EA.hy 926 endothelial cell line in a dose-dependent manner. However, applied in a wide range of concentrations GE132+Natural did not affect both the proliferation of primary mesenchymal stem cells and the peripheral blood cells counts. CONCLUSION: The data obtained demonstrated that GE132+Natural is effective in inhibiting cancer cell proliferation, indicating its potential beneficial health effects. In addition, the results pointed that adult mesenchymal stem cells might be valuable as a test system for evaluating the toxicity and efficacy of new medicines or chemicals. PMID- 23818370 TI - Perception about influenza and pneumococcal vaccines and vaccination coverage among patients with malignancies and their family members. AB - PURPOSE: Although influenza and pneumococcal vaccinations for high-risk populations are recommended by current guidelines, vaccination coverage rate (VCR) is still low in patients with malignancies and the family members living with them. METHODS: During the 2011-2012 seasonal influenza (SI), we surveyed 359 patients with solid or hematological malignancies Data were recorded in an especially designed questionnaire after face to face interview. RESULTS: The median patient age was 57 years (range 18-90) and 177 (49.3%) patients were female. Overall vaccination rate was 17% and 4.2% for influenza and pneumococcus, respectively. VCR among family members was 21.2%. The most common causes for not getting vaccinated were lack of knowledge for indication by the patients (33.5%), getting chemotherapy (22.1%), fear of side effects (12.5%), lack of efficacy (12.1%), and not advised by the attending physician (5.9%). CONCLUSION: VCR was very low among patients with cancer and their family members. To eliminate misconceptions and improve vaccination coverage in this population, educational programs for patients and for physicians focusing on safety and efficacy of vaccine are needed. PMID- 23818371 TI - Disclosure of cancer diagnosis: the Greek experience. AB - PURPOSE: To analyze the attitude of Greek health professionals towards truth disclosure and factors that may influence it. METHODS: Through a self-completed questionnaire, we studied the attitudes over the initial disclosure of cancer diagnosis to cancer patients of 132 doctors and 123 nurses, partly involved in cancer patients' care, in 5 general hospitals of Crete, Greece. RESULTS: Eighty nine percent of the participants considered information as patient's right and 88% as professional's ethical duty, 64% believed that the whole truth should be revealed, 90% avoided the word "cancer" in the communication and 39% disclosed cancer diagnosis at patient's direct asking. Respondents informed 1/10 of their new cancer patients, mainly due to perceived limited responsibility (23%), patient's low cognitive state (22%), fear of harming the patient (17%) and relatives' objection (15%). Sixteen percent of fellows acknowledged to themselves the responsibility to inform patients. Cooperation, compliance and arrangement of patient's personal issues were considered as benefits from accurate disclosure (88%, 83% and 75%, respectively), the latter more among doctors than nurses (p=0.01) and medical than surgical professionals (p=0.03). Thirty-six percent of the respondents considered the presence of a psychologist necessary during disclosure, nurses more than doctors (p<0.001). CONCLUSION: Despite adequate theoretical background, Greek non-cancer specialists, doctors and nurses, initially inform accurately a small part of their cancer patients. Appropriate training programs for doctors and non-medical health professionals involved in cancer patients' management are required to upgrade professional-patient communication. PMID- 23818372 TI - Informing cancer patient based on his type of personality: the avoidant patient. AB - Imparting bad news to a cancer patient is considered an arduous task, but it seems to be facilitated by the use of the empathic approach. Indeed, doctors who are trained to adhere to a cancer patient informing protocol argue that the hardest step to take is the empathic approach. The usual questions asked are: To tell the diagnosis or not? How much information should we give? Should the patient know or has the right not to know? Is it possible to determine who should say, what, when, and how. The aim of this article was to describe the avoidant character or type of personality, so that any physician can make a diagnosis and tailor the information strategy to the patient's needs. As method of research was used the qualitative method through groups with doctors and nurses, while research within groups lasted for 5 years. The degree of informing the avoidant personality in the range "minimal - small - medium - large - very large" is : The degree of denial varies between "small" and "medium", while the degree of informing varies between "medium" and "small" in order to reach "large" later. Informing the family: The patient reacts to a common approach with the family as he is concerned about inflicting a blow to his image. PMID- 23818373 TI - High-dose tamoxifen in breast cancer bone metastasis. AB - High-dose tamoxifen was used as a treatment for bone metastasis in 16 patients with breast cancer. All of them had been pretreated with hormonal therapy, including lowdose tamoxifen. The results were extremely positive with clinical amelioration and also disappearance of osteolysis in 5 patients. PMID- 23818375 TI - The treatment of melanoma at Westminster Hospital in the 20th century. AB - At Saint Dunstan's Coffee House in 1715 four London men met to form "A charitable proposal for Relieving the Poor and Needy and Other Distressed Persons". The proposal marked the beginnings of Westminster Hospital in London. Following the admission of the first patient in 1720, Westminster Hospital and later Westminster Medical School dominated the medical scene of London for over two and a half centuries until its closure in 1993 and transfer to the new Chelsea and Westminster Hospital. The Hospital and Medical school are credited with pioneering work in the fields of anaesthesia, immunology, bone marrow transplantation and the treatment of cancer. In the 20th century Westminster became a centre of tertiary referrals for cancer and under the leadership of Sir Stanford Cade and later of Gerald Westbury and Kenneth Newton the hospital pioneered the multidisciplinary management of malignant disease exemplified by the internationally- famous Wednesday afternoon clinics where the patients' best interests were discussed and served by a multitude of surgical and medical specialists. This paper focuses on the treatment of melanoma at Westminster Hospital in the 20th Century, placing in perspective the latest therapeutic developments based on the genetics of this cancer. PMID- 23818374 TI - Only particular cytogenetic events are related to disease progression in sequential cytogenetic studies in myelodysplastic syndromes. AB - We performed prospective sequential cytogenetic studies in 76 patients with myelodysplastic syndromes (MDS) followed up to 82 months. Their karyotypes were followed routinely, regardless of clinical status. The incidence of evolutive karyotypes was similar in patients with a normal karyotype at referral and in patients with clonal abnormalities at diagnosis (24.5 and 26.1%, respectively). We did not find association between karyotype evolution and leukemic transformation or reduced survival, since the majority of secondary cytogenetic changes in evolutive karyotypes of our patients were aberrations with good or intermediate prognosis. Therefore, we concluded that only particular cytogenetic events are related to disease progression, while others represent secondary changes of little biologic and prognostic significance. PMID- 23818376 TI - Tyrosine kinase inhibitors may change the metastatic pattern. PMID- 23818377 TI - Vemurafenib-induced hypertension: is it real? PMID- 23818378 TI - A case of thoracic ancient schwannoma with a challenging approach. PMID- 23818379 TI - Adult Langerhans' cell histiocytosis: a rare cause of parotid gland enlargement. PMID- 23818380 TI - Etoposide hypersensitivity. PMID- 23818381 TI - Fertility sparing surgery for early cervical cancer. PMID- 23818382 TI - Granulocyte colony stimulating factor-induced tumor lysis-like syndrome: leucolysis. PMID- 23818383 TI - The distinguished surgeon Bertrand Becane (1728-1802?) and the syphilitic theory of cancer. AB - Bertrand Becane, Professor of surgery in Toulouse Medical School, is considered an eminent precursor of oncology, influencing the 18th century medicine with his syphilitic theory of cancer. PMID- 23818385 TI - Lipidomics of essential fatty acids and oxygenated metabolites. AB - Polyunsaturated fatty acids in mammals may be oxygenated into a myriad of bioactive products through di- and monooxygenases, products that are rapidly degraded to control their action. To evaluate the phenotypes of biological systems regarding this wide family of compounds, a lipidomics approach in function of time and compartments would be relevant. The current review takes into consideration most of the diverse oxygenated metabolites of essential fatty acids at large and their immediate degradation products. Their biological function and life span are considered. Overall, this is a fluxolipidomics approach that is emerging. PMID- 23818386 TI - Bullying and victimization in early adolescence: relations to social information processing patterns. AB - There is a gap in the literature on the social information processing (SIP) patterns of adolescents exposed to victimization in school. Therefore, we examine the SIP patterns of young adolescents characterized by their teachers and by their own reports as victims, bullies, bullies/victims, and neither bullies nor victims. The 105 adolescents participating in this study were asked to respond to hypothetical social scenarios in which a protagonist is either rebuffed or provoked by peers. The scenarios were ambiguous in nature and thus could have been processed in different ways. Indeed, distinctive processing patterns were found for each of these groups: victims tended to avoid challenging social situations while expecting others to be purposefully hostile or ignoring; bullies tended to interpret others as purposefully hostile and stated their desire to retaliate; bullies/victims showed patterns more similar to those of the bullies than the victims; and those who were neither victims nor bullies tended to view the same challenging social situations as non hostile and more likely to end well for them. We conclude by discussing the theoretical and practical implications of these findings. PMID- 23818388 TI - The influence of social relationships on obesity: sex differences in a longitudinal study. AB - OBJECTIVE: To investigate the effect of five dimensions of social relationships on obesity and potential sex differences in these associations. DESIGN AND METHODS: This study used longitudinal data from the Swedish Level of Living Surveys (LNU) in 1991 and 2000. The sample included 3,586 individuals. The dimensions of social relationships examined in this study include emotional support, frequency of visiting friends, marital status, marital status changes, and a Social Relationships Index (SRI). Obesity status was based on BMI (kg/m(2)) and calculated with self-reported measurements. The association between social relationships and the incidence of obesity after 9 years of follow-up was evaluated through Poisson regressions. RESULTS: After controlling for confounders, we found that the lack of emotional support (RR = 1.98; 95% CI, 1.1 4.6) influenced the incidence of obesity among men. In addition, men with the lowest levels of SRI (RR = 2.22; 95% CI, 1.1-4.4) had an increased risk of being obese. Among women, SRI was not significantly associated with obesity. Women who changed their marital status from married to unmarried had lower risk of obesity (RR = 0.39; 95% CI, 0.2-0.9). CONCLUSIONS: This study provides evidence for the effect of social relationships on the incidence of obesity, with significant differences by sex. PMID- 23818387 TI - Distribution of language-related Cntnap2 protein in neural circuits critical for vocal learning. AB - Variants of the contactin associated protein-like 2 (Cntnap2) gene are risk factors for language-related disorders including autism spectrum disorder, specific language impairment, and stuttering. Songbirds are useful models for study of human speech disorders due to their shared capacity for vocal learning, which relies on similar cortico-basal ganglia circuitry and genetic factors. Here we investigate Cntnap2 protein expression in the brain of the zebra finch, a songbird species in which males, but not females, learn their courtship songs. We hypothesize that Cntnap2 has overlapping functions in vocal learning species, and expect to find protein expression in song-related areas of the zebra finch brain. We further expect that the distribution of this membrane-bound protein may not completely mirror its mRNA distribution due to the distinct subcellular localization of the two molecular species. We find that Cntnap2 protein is enriched in several song control regions relative to surrounding tissues, particularly within the adult male, but not female, robust nucleus of the arcopallium (RA), a cortical song control region analogous to human layer 5 primary motor cortex. The onset of this sexually dimorphic expression coincides with the onset of sensorimotor learning in developing males. Enrichment in male RA appears due to expression in projection neurons within the nucleus, as well as to additional expression in nerve terminals of cortical projections to RA from the lateral magnocellular nucleus of the nidopallium. Cntnap2 protein expression in zebra finch brain supports the hypothesis that this molecule affects neural connectivity critical for vocal learning across taxonomic classes. PMID- 23818389 TI - Larval carry-over effects from ocean acidification persist in the natural environment. AB - An extensive body of work suggests that altered marine carbonate chemistry can negatively influence marine invertebrates, but few studies have examined how effects are moderated and persist in the natural environment. A particularly important question is whether impacts initiated in early life might be exacerbated or attenuated over time in the presence or absence of other stressors in the field. We reared Olympia oyster (Ostrea lurida) larvae in laboratory cultures under control and elevated seawater pCO2 concentrations, quantified settlement success and size at metamorphosis, then outplanted juveniles to Tomales Bay, California, in the mid intertidal zone where emersion and temperature stress were higher, and in the low intertidal zone where conditions were more benign. We tracked survival and growth of outplanted juveniles for 4 months, halfway to reproductive age. Survival to metamorphosis in the laboratory was strongly affected by larval exposure to elevated pCO2 conditions. Survival of juvenile outplants was reduced dramatically at mid shore compared to low shore levels regardless of the pCO2 level that oysters experienced as larvae. However, juveniles that were exposed to elevated pCO2 as larvae grew less than control individuals, representing a larval carry-over effect. Although juveniles grew less at mid shore than low shore levels, there was no evidence of an interaction between the larval carry-over effect and shore level, suggesting little modulation of acidification impacts by emersion or temperature stress. Importantly, the carry-over effects of larval exposure to ocean acidification remained unabated 4 months later with no evidence of compensatory growth, even under benign conditions. This latter result points to the potential for extended consequences of brief exposures to altered seawater chemistry with potential consequences for population dynamics. PMID- 23818390 TI - Physicians differ on the use of sentinel lymph node biopsy for melanoma: published data receive various interpretations. PMID- 23818391 TI - Link between high-fat dairy consumption and poor breast cancer survival. PMID- 23818392 TI - Heart-healthy diet also has cancer benefits. PMID- 23818393 TI - Cytotoxic, antioxidant, antimicrobial properties and chemical composition of rose petals. AB - BACKGROUND: Rosa rugosa petals are used for production of teas, jams, wines and juices. Despite the wide availability of rose cultivars, comprehensive information on petal chemical composition and healthful properties is still lacking. Therefore, the aim of this study was analysis of cytotoxic, antioxidant and antimicrobial activity and chemical composition of rugosa rose petals. RESULTS: Petals of R. rugosa were evaluated for their cytotoxic effect against cervical (HeLa) and breast cancer (T47D) cell lines and for antiradical activity (with DPPH*). As a result, significant cytotoxic (up to 100% of dead cells) and antiradical properties (IC50 1.33-0.08 mg mg-1 DPPH*) were demonstrated. Moreover, notable antimicrobial activity against eight bacterial (i.e. Staphylococcus. epidermidis, S. aureus, Bacillus subtilis, Micrococcus luteus, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis) and two yeast strains (Candida. albicans, C. parapsilosis) was shown. Total phenolic, flavonoid, phenolic acid, tannin, carotenoid and polysaccharide content in petals was determined using spectrophotometric methods. Liquid chromatography-electrospray ionization-tandem mass spectrometry was used to thoroughly analyze phenolic acids and flavonoid glycosides in the methanolic extract and fractions obtained after its separation. Five phenolic acids and six flavonoids previously not reported in the plant material were identified. CONCLUSION: This is the first such detailed report on chemical composition and biological activity of R. rugosa petals. PMID- 23818394 TI - Synthesis and radical scavenging activities of resveratrol analogs. AB - Highly substituted polyhydroxylated (E)-stilbenes were synthesized by Mizoroki Heck reactions and tested for their ability to act as radical scavenger. One of the 56 stilbenes included in this study and investigated in DPPH assays gave an SC50 value of 11.0 MUM, hence exhibiting an about 9.3 times higher activity than resveratrol. As shown in a photometric SRB assay using mouse NiH 3T3 fibroblasts, this compound is not cytotoxic up to concentrations of <30 MUM. PMID- 23818395 TI - Stress and paediatric obesity: what we know and where to go. AB - Childhood obesity is a public health epidemic and is associated with substantial negative physical and psychosocial health consequences. Stress is thought to be one contributor to the development and maintenance of obesity in children and adolescents, yet the linkage between stress and paediatric obesity is a poorly understood phenomenon. This paper furthers the understanding of stress in the context of paediatric obesity by firstly presenting a focused review of what is known about links between chronic and acute stress and paediatric obesity risk and then synthesizing important areas from the literature. These critical areas of focus include the following: (1) physiological stress reactivity; (2) stress induced eating; (3) stress and physical activity; (4) parent and family influences; and (5) stress in at-risk populations. This review is geared toward facilitating future research on the stress-obesity connection in youth. PMID- 23818396 TI - Reversible insertion of unactivated alkenes into silicon(II)-tin bonds. PMID- 23818397 TI - Responses of aquatic macrophyte cover and productivity to flooding variability on the Amazon floodplain. AB - Macrophyte net primary productivity (NPP) is a significant but understudied component of the carbon budget in large Amazonian floodplains. Annual NPP is determined by the interaction between stem elongation (vertical growth) and plant cover changes (horizontal expansion), each affected differently by flood duration and amplitude. Therefore, hydrological changes as predicted for the Amazon basin could result in significant changes in annual macrophyte NPP. This study investigates the responses of macrophyte horizontal expansion and vertical growth to flooding variability, and its possible effects on the contribution of macrophytes to the carbon budget of Amazonian floodplains. Monthly macrophyte cover was estimated using satellite imagery for the 2003-2004 and 2004-2005 hydrological years, and biomass was measured in situ between 2003 and 2004. Regression models between macrophyte variables and river-stage data were used to build a semiempirical model of macrophyte NPP as a function of water level. Historical river-stage records (1970-2011) were used to simulate variations in NPP, as a function of annual flooding. Vertical growth varied by a factor of ca. 2 over the simulated years, whereas minimum and maximum annual cover varied by ca. 3.5 and 1.5, respectively. Results suggest that these processes act in opposite directions to determine macrophyte NPP, with larger sensitivity to changes in vertical growth, and thus maximum flooding levels. Years with uncommonly large flooding amplitude resulted in the highest NPP values, as both horizontal expansion and vertical growth were enhanced under these conditions. Over the simulated period, annual NPP varied by ca. 1.5 (1.06-1.63 TgC yr(-1) ). A small increasing trend in flooding amplitude, and by extension NPP, was observed for the studied period. Variability in growth rates caused by local biotic and abiotic factors, and the lack of knowledge on macrophyte physiological responses to extreme hydrological conditions remain the major sources of uncertainty. PMID- 23818399 TI - Single-vesicle patterning of uniform, giant polymersomes into microarrays. AB - Giant, cell-sized polymersomes are functionalized and patterned at the single vesicle level. Microfluidic methods are employed to generate uniform diameter vesicles with high loading efficiencies and microcontact printing is used to generate patterns of adhesive ligand. A simple sensory capability is demonstrated with the immobilized array of vesicles. PMID- 23818400 TI - Effect of fructose vs. glucose on acylation stimulating protein, leptin, and adiponectin lacks relevance. PMID- 23818401 TI - The association between C-reactive protein (CRP) level and biochemical failure free survival in patients after radiation therapy for nonmetastatic adenocarcinoma of the prostate. AB - BACKGROUND: C-reactive protein (CRP) has been associated with outcomes in patients with metastatic adenocarcinoma of the prostate. Associations between prostate adenocarcinoma-specific endpoints and CRP in patients who are treated for localized disease remain unknown. METHODS: In total, 206 patients who received radiation therapy for adenocarcinoma of the prostate had at least 1 CRP measured in follow-up and were analyzed. The primary outcome was biochemical failure-free survival. In addition, associations were examined between CRP and prostate-specific antigen (PSA). RESULTS: On univariate analysis, higher CRP levels were associated significantly with shorter biochemical failure-free survival for patients who received radiation therapy after undergoing radical prostatectomy. For patients who were managed with definitive radiation therapy alone, higher CRP levels also were associated significantly with shorter biochemical failure-free survival on univariate and multivariable analyses (hazard ratio, 2.03; 95% confidence interval, 1.19-3.47; P = .009). In addition, CRP levels were associated significantly with PSA after radical prostatectomy for patients who had Gleason scores >= 8 (P = .037), for high-risk patients (P = .008), and for those with pretreatment PSA levels > 20 ng/mL (P = .05). In patients who received definitive radiation therapy, CRP levels also were associated with PSA both for those with pretreatment PSA levels > 20 ng/mL (P < .001), and for the intermediate-risk (P = .029) and high-risk (P = .009) subgroups. CONCLUSIONS: A higher CRP level was associated with shorter biochemical failure-free survival on univariate and multivariable analyses in patients who received definitive radiation therapy. CRP was also associated with PSA in exploratory subgroups. These findings warrant further exploration in a prospectively enrolled patient cohort. PMID- 23818402 TI - Harmonization of legislation and regulations to achieve food safety: US and Canada perspective. AB - Trade in food and food ingredients among the nations of the world is rapidly expanding and, with this expansion, new supply chain partners, from globally disparate geographic regions, are being enrolled. Food and food ingredients are progressively sourced more from lesser developed nations. Food safety incidents in the USA and Canada show a high unfavorable correlation between illness outbreaks and imported foods. In the USA, for example, foodborne disease outbreaks caused by imported food appeared to rise in 2009 and 2010, and nearly half of the outbreaks, associated with imported food, implicated foods imported from areas which previously had not been associated with outbreaks. Projecting supply chains into new geographical regions raises serious questions about the capacity of the new supply chain partners to provide the requisite regulatory framework and sufficiently robust public health measures for ensuring the safety of the foods and foodstuffs offered for international trade. The laws, regulation and legislation among the many nations participating in the global food trade are, at best, inconsistent. These inconsistencies frequently give rise to trade disputes and cause large quantities of food to be at risk of destruction on the often dubious pretext that they are not safe. Food safety is often viewed through a political or normative lens. Often as not, this lens has been wrought absent scientific precision. Harmonization of food safety legislation around sound scientific principles, as advocated by the US Food Safety Modernization Act (FSMA), would ultimately promote trade and likely provide for incremental improvement in public health. Among the priority roles of most national governments are the advancement of commerce and trade, preservation of public health and ensuring domestic tranquility. Achieving these priorities is fundamental to creating and preserving the wealth of nations. Countries such as the Netherlands, Canada, Germany, Japan and the USA, for example, have very stable governments, are leaders in trade and commerce and enjoy high standards of public health. It is not by accident or coincidence that these nations are also among the world's wealthiest. Attainment of national priorities, especially those related to promoting trade in foodstuffs and also in preserving public health (food safety), would benefit greatly from international efforts in harmonizing food safety regulations and legislation. PMID- 23818403 TI - Sequential development among dimensions of job burnout and engagement among IT employees. AB - The current study examined the sequential development of job burnout and job engagement and their related antecedents (job demands, job resources and personality) using a three-wave longitudinal design. We collected usable responses from 160 Information Technology employees in China. Using M-plus 5.0, we compared four models: the exhaustion-cynicism-inefficacy model of burnout and the vigour-dedication-absorption model of engagement, the exhaustion-cynicism inefficacy model of burnout and the dedication-absorption-vigour model of engagement, the cynicism-inefficacy-exhaustion model of burnout and the dedication-absorption-vigour model of engagement and the cynicism-inefficacy exhaustion model of burnout and the vigour-dedication- absorption model of engagement. The results of the model comparisons revealed that the last model had the best fit with the data. In addition, we found that job demands, job resources and personality influenced burnout and engagement in different ways. The results showed that the pathways from job demands/job resources to burnout/engagement were robust and direct, whereas personality had both a direct influence and an indirect influence (through job demands/resources) on burnout/engagement. PMID- 23818406 TI - N-heterocyclic carbene catalyzed [4+3] annulation of enals and o-quinone methides: highly enantioselective synthesis of benzo-epsilon-lactones. PMID- 23818407 TI - Self-assembled poly(N-methylaniline)-lignosulfonate spheres: from silver-ion adsorbent to antimicrobial material. AB - Self-assembled poly(N-methylaniline)-lignosulfonate (PNMA-LS) composite spheres with reactive silver-ion adsorbability were prepared from N-methylaniline by using lignosulfonate (LS) as a dispersant. The results show that the PNMA-LS composite consisted of spheres with good size distribution and an average diameter of 1.03-1.27 MUm, and the spheres were assembled by their final nanofibers with an average diameter of 19-34 nm. The PNMA-LS composite spheres exhibit excellent silver-ion adsorption; the maximum adsorption capacity of silver ions is up to 2.16 g g(-1) at an adsorption temperature of 308 K. TEM and wide-angle X-ray results of the PNMA-LS composite spheres after absorption of silver ions show that silver ions are reduced to silver nanoparticles with a mean diameter of about 11.2 nm through a redox reaction between the PNMA-LS composite and the silver ions. The main adsorption mechanism between the PNMA-LS composite and the silver ions is chelation and redox adsorption. In particular, a ternary PNMA-LS-Ag composite achieved by using the reducing reaction between PNMA-LS composite spheres and silver ions can be used as an antibacterial material with high bactericidal rate of 99.95 and 99.99% for Escherichia coli and Staphylococcus aureus cells, respectively. PMID- 23818408 TI - Effect of a local vibration stimulus training programme on postural sway and gait in chronic stroke patients: a randomized controlled trial. AB - OBJECTIVE: To investigate the effect of a local vibration stimulus training programme on postural sway and gait in stroke patients. DESIGN: A randomized controlled trial with two groups: a local vibration stimulus training programme group and a sham group. SETTING: Inpatient rehabilitation centre. SUBJECTS: Thirty-one chronic stroke patients. INTERVENTIONS: Both groups underwent a standard rehabilitation programme. The local vibration stimulus training programme group (n = 16) participated in the local vibration stimulus training programme for 30 minutes a day, five times a week, for six weeks. The sham group (n = 15) participated in a sham local vibration stimulus training programme for 30 minutes a day, five times a week, for six weeks. MAIN MEASURES: A forceplate was used to measure postural sway under two conditions: standing with eyes open and eyes closed. Gait ability was measured using the GAITRite system. RESULTS: In postural sway, greater improvements in the postural sway distance with eyes-open (-11.91 vs. 0.80) and eyes-closed (-20.67 vs. -0.34) conditions and postural sway velocity with eyes-open (-0.40 vs. 0.03) and eyes-closed (-0.69 vs. -0.01) conditions were observed in the local vibration stimulus training programme group, compared with the sham group (P < 0.05). In gait ability, greater improvement in gait speed (15.06 vs. 2.85), cadence (8.46 vs. 1.55), step length (7.90 vs. 3.64), and single limb support time (0.12 vs. 0.01) were observed in the local vibration stimulus training programme group, compared with the sham group (P < 0.05). CONCLUSIONS: These findings suggest that local vibration stimulus training programme is an effective method for improvement of the postural sway and gait ability of chronic stroke patients. PMID- 23818409 TI - Modified constraint-induced movement therapy versus intensive bimanual training for children with hemiplegia - a randomized controlled trial. AB - OBJECTIVE: To clarify whether modified constraint-induced movement therapy provides greater improvement than intensive bimanual training both for motor functions and spontaneous use of the paretic arm and hand in everyday life activities. DESIGN: Randomized controlled, single-blind trial. SETTING: Inpatient paediatric rehabilitation clinic. SUBJECTS: Forty-seven children with unilateral cerebral palsy or other non-progressive hemiplegia (aged 3.3-11.4 years) were randomly assigned to either a modified constraint-induced movement programme (kid CIMT) or intensive bimanual training. INTERVENTIONS: Patients in the kid-CIMT group received 60 hours of unilateral constraint-induced and 20 hours of bimanual training over four weeks. Patients in the bimanual treatment group received 80 hours of bimanual training over four weeks. MAIN OUTCOME MEASURES: Melbourne Assessment of Unilateral Upper Limb Function and Assisting Hand Assessment. RESULTS: Modified constraint-induced therapy provided a significantly better outcome for isolated motor functions of the paretic arm than bimanual training (gain in Melbourne Assessment, percent score: 6.6 vs. 2.3, P= 0.033). Regarding spontaneous use both methods led to similar improvement (gain in Assisting Hand Assessment, percent score: 6.2 vs. 4.6, P= 0.579). More-disabled children showed greater improvement than less-disabled ones (correlation with Assisting Hand Assessment pretreatment score r = -0.40). Age did not affect treatment outcome. CONCLUSIONS: Modified constraint-induced movement therapy can improve isolated functions of the hemiplegic arm better than intensive bimanual training, but regarding spontaneous hand use in everyday life both methods lead to similar improvement. Improvements are generally greater in more impaired children. Age does not affect outcome. PMID- 23818410 TI - Effects of a predefined mini-trampoline training programme on balance, mobility and activities of daily living after stroke: a randomized controlled pilot study. AB - OBJECTIVE: To investigate the effects of a predefined mini-trampoline therapy programme for increasing postural control, mobility and the ability to perform activities of daily living after stroke. DESIGN: Randomized non-blinded controlled pilot study. SETTING: Neurological rehabilitation hospital. SUBJECTS: First-time stroke; age 18-80 years; independent standing ability for a minimum of 2 minutes. INTERVENTION: Patients were randomized into two groups: the mini trampoline group (n = 20) received 10 sessions of balance training using the mini trampoline over three weeks. The patients of the control group (n =20) participated 10 times in a group balance training also over three weeks. MAIN MEASURES: Postural control (Berg Balance Scale, BBS), mobility and gait endurance (timed 'up and go' test, TUG; 6-minute walk test, 6MWT) and the ability to perform activities of daily living (Barthel Index, BI). Measurements were undertaken prior to and after the intervention period. RESULTS: Both groups were comparable before the study. The mini-trampoline group improved significantly more in the BBS (P = 0.003) compared to the control group. Mean or median differences of both groups showed improvements in the TUG 10.12 seconds/7.23 seconds, the 6MWT 135 m/75 m and the BI 20 points/13 points for the mini trampoline and control group, respectively. These outcome measurements did not differ significantly between the two groups. CONCLUSION: A predefined mini trampoline training programme resulted in significantly increased postural control in stroke patients compared to balance training in a group. Although not statistically significant, the mini-trampoline training group showed increased improvement in mobility and activities of daily living. These differences could have been statistically significant if we had investigated more patients (i.e. a total sample of 84 patients for the TUG, 98 patients for the 6MWT, and 186 patients for the BI). PMID- 23818411 TI - Experienced stigmatization reduced quality of life of patients with a neuromuscular disease: a cross-sectional study. AB - OBJECTIVE: To examine the influence of stigma on the quality of life of patients with a neuromuscular disease. DESIGN: Cross-sectional postal survey. SETTING: Outpatient clinic of the Department of Neurology, University Hospital Groningen, the Netherlands. SUBJECTS: Patients diagnosed with a neuromuscular disease. MEASURES: The Stigma Scale for Chronic Illness, the World Health Organization Quality of Life - abbreviated version questionnaires and some background and disease-related questions. The Stigma Scale for Chronic Illness was translated into Dutch according to international guidelines. The impact of stigma on quality of life was estimated using hierarchical multiple regression analysis after controlling for the extent of limitations and patient characteristics. RESULTS: In total 235 patients (75% response rate) were diagnosed with neuromuscular disease and represented all four categories of the approximately 600 neuromuscular diseases. Most patients (86%) reported self stigma, while 64% reported to experience enacted stigma. Experienced quality of life was moderate to good. Stigma contributed to a unique and substantial extent to all domains of quality of life: explained variance for the impact of stigma on quality ranged from 0.13 (social relations) to 0.34 (physical functioning) for self stigma and from 0.09 (social relations) to 0.11 (physical and psychological health, and quality of the environment). CONCLUSION: Self stigma was a stronger predictor for poorer quality of life compared with enacted stigma. In other words: patients suffered more from shame and fear for discrimination (self stigma) than from the really experienced discrimination and exclusion (enacted stigma). PMID- 23818412 TI - The effectiveness of aquatic physical therapy in the treatment of fibromyalgia: a systematic review with meta-analysis. AB - OBJECTIVE: To assess the effectiveness of aquatic physical therapy in the treatment of fibromyalgia. DATA SOURCES: The search strategy was undertaken using the following databases, from 1950 to December 2012: MEDLINE, EMBASE, CINAHL, LILACS, SCIELO, WEB OF SCIENCE, SCOPUS, SPORTDiscus, Cochrane Library Controlled Trials Register, Cochrane Disease Group Trials Register, PEDro and DARE. REVIEW METHODS: The studies were separated into groups: Group I - aquatic physical therapy * no treatment, Group II - aquatic physical therapy * land-based exercises and Group III - aquatic physical therapy * other treatments. RESULTS: Seventy-two abstracts were found, 27 of which met the inclusion criteria. For the functional ability (Fibromyalgia Impact Questionnaire), three studies were considered with a treatment time of more than 20 weeks and a mean difference (MD) of -1.35 [-2.04; -0.67], P = 0.0001 was found in favour of the aquatic physical therapy group versus no treatment. The same results were identified for stiffness and the 6-minute walk test where two studies were pooled with an MD of -1.58 [ 2.58; -0.58], P = 0.002 and 43.5 (metres) [3.8; 83.2], P = 0.03, respectively. CONCLUSION: Three meta-analyses showed statistically significant results in favour of the aquatic physical therapy (Fibromyalgia Impact Questionnaire, stiffness and the 6-minute walk test) during a period of longer than 20 weeks. Due to the low methodological rigor, the results were insufficient to demonstrate statistical and clinical differences in most of the outcomes. PMID- 23818413 TI - Combined effects of global climate change and regional ecosystem drivers on an exploited marine food web. AB - Changes in climate, in combination with intensive exploitation of marine resources, have caused large-scale reorganizations in many of the world's marine ecosystems during the past decades. The Baltic Sea in Northern Europe is one of the systems most affected. In addition to being exposed to persistent eutrophication, intensive fishing, and one of the world's fastest rates of warming in the last two decades of the 20th century, accelerated climate change including atmospheric warming and changes in precipitation is projected for this region during the 21st century. Here, we used a new multimodel approach to project how the interaction of climate, nutrient loads, and cod fishing may affect the future of the open Central Baltic Sea food web. Regionally downscaled global climate scenarios were, in combination with three nutrient load scenarios, used to drive an ensemble of three regional biogeochemical models (BGMs). An Ecopath with Ecosim food web model was then forced with the BGM results from different nutrient-climate scenarios in combination with two different cod fishing scenarios. The results showed that regional management is likely to play a major role in determining the future of the Baltic Sea ecosystem. By the end of the 21st century, for example, the combination of intensive cod fishing and high nutrient loads projected a strongly eutrophicated and sprat-dominated ecosystem, whereas low cod fishing in combination with low nutrient loads resulted in a cod dominated ecosystem with eutrophication levels close to present. Also, nonlinearities were observed in the sensitivity of different trophic groups to nutrient loads or fishing depending on the combination of the two. Finally, many climate variables and species biomasses were projected to levels unseen in the past. Hence, the risk for ecological surprises needs to be addressed, particularly when the results are discussed in the ecosystem-based management context. PMID- 23818414 TI - Ampelographic and chemical characterization of Reggio Emilia and Modena (northern Italy) grapes for two traditional seasonings: 'saba' and 'agresto'. AB - BACKGROUND: 'Saba' and 'agresto' are traditional Italian products both based on unfermented grape juices that are concentrated by heating. The former is obtained from ripe grapes and the latter from unripe grapes. In this work, we have characterized the main red-skinned (Ancellotta, Fortana, Lambrusco di Sorbara, Lambrusco grasparossa, Lambrusco salamino and Uva Tosca) and white-skinned (Lugliatica, Spergola, Trebbiano di Spagna and Trebbiano modenese) cultivars used for 'saba' and 'agresto' production, focusing on the variability expressed by ampelographic traits, physical and chemical parameters and anthocyanin profile. RESULTS: The cultivars examined were effectively discriminated on the basis of their different composition profile by analysis of variance and principal component analysis. In particular, a peculiar anthocyanin profile was traced by absolute and relative values for each cultivar. The identification of the main anthocyanins of some local cultivars, their chemical characterization and their ampelographic description were one of the main achievements of this work. CONCLUSION: The use of red grapes to obtain 'saba' seems more rational for the presence of higher amounts of antioxidant substances. Ancellotta showed several factors interesting for 'saba' production, such as the very high anthocyanin content, including anthocyanin antioxidants. A more detailed investigation on 'agresto' technology is required. PMID- 23818415 TI - Low-molecular-weight adiponectin and high-molecular-weight adiponectin levels in relation to diabetes. AB - OBJECTIVE: To evaluate the association between adiponectin complexes (high molecular-weight [HMW], middle-molecular-weight [MMW], and low-molecular-weight [LMW] adiponectin) and diabetes. DESIGN AND METHODS: We conducted a case-control study, based on a cohort in Saku, Japan. Among 2565 participants, 300 participants with diabetes and 300 matched controls (430 men and 170 women) were analyzed. RESULTS: After adjusting for age, physical activity, hypertension, family history, alcohol use, smoking, and menopausal status, total, HMW, and LMW, but not MMW adiponectin levels were inversely associated with diabetes: total adiponectin, odds ratio comparing the highest with the lowest quartiles, 0.46 (95% confidence interval, 0.25-0.82; P for trend = 0.046); HMW, 0.40 (95%CI, 0.22 0.72; P = 0.046); MMW, 1.04 (95%CI, 0.60-1.77; P = 0.81); and LMW, 0.51 (95%CI, 0.29-0.89; P = 0.01). The associations between total and HMW adiponectin and diabetes attenuated after adjustment for BMI (P = 0.15 and 0.13, respectively), but LMW remained (P = 0.04). When stratified by sex, LMW adiponectin levels were associated with diabetes in men only. None of the associations were significant after adjustment for HOMA-IR. CONCLUSIONS: Decreased LMW, total, and HMW adiponectin levels are associated with diabetes. These associations may be secondary to adiposity or insulin resistance. PMID- 23818417 TI - Association between child cortisol levels in saliva and neuropsychological development during the second year of life. AB - Exposure to highly elevated levels of cortisol has been linked with impairments in cognitive capacities in both children and adults. By contrast, moderate levels of cortisol may engender beneficial effects. The main aim of this study was to assess the association between child cortisol levels and neuropsychological development during the second year of life. A population-based birth cohort was established in the city of Sabadell (Catalonia, Spain) as part of the INMA (Environment and Childhood) Project. We assessed the cognitive and psychomotor development at the age of 14 months using the Bayley Scales of Infant Development (BSID). We included 302 children assessed during their second year of life for whom we had information on neuropsychological assessment and measurements of cortisol in saliva. Higher levels of cortisol were associated with better scores in BSID's mental scale. There was no association between cortisol levels and psychomotor test scores. We found a small positive association between duration of breastfeeding and child cortisol levels. This association was only found in boys. The results of this study suggest that moderate levels of cortisol in children could have small beneficial effects on their early neuropsychological development. PMID- 23818419 TI - Bis(sulfonylimide)ruthenium(VI) porphyrins: X-ray crystal structure and mechanism of C-H bond amination by density functional theory calculations. AB - The X-ray crystal structure of [Ru(VI) (NMs)2 (tmp)] (Ms=SO2 - p-MeOC6 H4 ; tmp=5,10,15,20-tetramesitylporphyrinato(2-)), a metal sulfonylimide complex that can undergo alkene aziridination and C-H bond amination reactions, shows a Ru=N distance of 1.79(3) A and Ru-N-S angle of 162.5(3) degrees . Density functional theory (DFT) calculations on the electronic structures of [Ru(VI) (NMs)2 (tmp)] and model complex [Ru(VI) (NMs)2 (por(0) )] (por(0) =unsubstituted porphyrinato(2 )) using the M06L functional gave results in agreement with experimental observations. For the amination of ethylbenzene by the singlet ground state of [Ru(VI) (NMs)2 (por(0))], DFT calculations using the M06L functional revealed an effectively concerted pathway involving rate-limiting hydrogen atom abstraction without a distinct radical rebound step. The substituent effect on the amination reactivity of ethylbenzene by [Ru(VI) (NX)2 (por(0) )] (X=SO2 -p-YC6 H4 with Y=MeO, Me, H, Cl, NO2 ) was examined. Electron-withdrawing Y groups lower the energy of the LUMOs of [Ru(VI) (NX)2 (por(0))], thus facilitating their interaction with the low-lying HOMO of the ethylbenzene C-H bond and hence increasing the reactivity of [Ru(VI) (NX)2 (por(0) )]. DFT calculations on the amination/aziridination reactions of [Ru(VI) (NSO2 C6 H5 )2 (por(0) )] with pent 4-enal, an aldehyde substrate bearing acyl, homoallylic, and allylic C-H bonds and a C=C bond, revealed a lower reaction barrier for the amination of the acyl C H bond than for both the amination of the other C-H bonds and aziridination of the C=C bond in this substrate. PMID- 23818418 TI - Ultrasound and early tape mobilization--a practical solution for treating postoperative voiding dysfunction. AB - AIMS: This study assessed the effectiveness of ultrasound in determining tape distance to urethra and the impact of early tape mobilization on outcomes in women with postoperative voiding dysfunction resulting from a too tightly positioned tension-free vaginal tape (TVT). METHODS: A prospective observational study was conducted with women experiencing voiding dysfunction caused by too tightly positioned tapes. Ultrasound was used to identify the cause of the dysfunction and measure the distance between tape and longitudinal smooth muscle layer (LSM) of the urethra. If the tape was too close to the LSM (<3 mm) and the residual volume was >100 ml, it was mobilized under local/analgosedation shortly after the initial TVT procedure. RESULTS: Seventy-one postoperative TVT mobilization procedures were conducted on 61 women, which was 4.1% (61/1501) of all suburethral tape procedures performed. Early tape mobilization restored normal micturition in 59 (96.7%) of the women at the time of discharge. Significant differences were found in residual volumes (P < 0.001) and tape-LSM distances (P < 0.001) pre- and post-mobilization. At 6-month follow-up visits, 58 (95.1%) women were cured of SUI, three were incontinent, and no additional voiding dysfunction occurred. CONCLUSIONS: Immediate postoperative ultrasound can reliably detect too tightly positioned tapes that can be promptly treated with tape mobilization, a short and safe procedure that does not compromise the outcome of the original procedure. PMID- 23818420 TI - Concise synthesis and antimalarial activity of all four mefloquine stereoisomers using a highly enantioselective catalytic borylative alkene isomerization. PMID- 23818422 TI - Nitroxyl radicals for studying electron transfer. PMID- 23818421 TI - Genotype and phenotype in Parkinson's disease: lessons in heterogeneity from deep brain stimulation. AB - Variation in the genetic risk(s) of developing Parkinson's disease (PD) undoubtedly contributes to the subsequent phenotypic heterogeneity. Although patients with PD who undergo deep brain stimulation (DBS) are a skewed population, they represent a valuable resource for exploring the relationships between heterogeneous phenotypes and PD genetics. In this series, 94 patients who underwent DBS were screened for mutations in the most common genes associated with PD. The consequent genetic subgroups of patients were compared with respect to phenotype, levodopa (l-dopa), and DBS responsiveness. An unprecedented number (29%) of patients tested positive for at least 1 of the currently known PD genes. Patients with Parkin mutations presented at the youngest age but had many years of disease before needing DBS, whereas glucocerebrosidase (GBA) mutation carriers reached the threshold of needing DBS earlier, and developed earlier cognitive impairment after DBS. DBS cohorts include large numbers of gene positive PD patients and can be clinically instructive in the exploration of genotype phenotype relationships. PMID- 23818424 TI - H1N1 was not all that scary: uncertainty and stressor appraisals predict anxiety related to a coming viral threat. AB - H1N1 reached pandemic proportions in 2009, yet considerable ambivalence was apparent concerning the threat presented and the inclination to be vaccinated. The present investigation assessed several factors, notably appraisals of the threat, intolerance of uncertainty, and familiarity with the virus, that might contribute to reactions to a potential future viral threat. Canadian adults (N = 316) provided with several scenarios regarding viral threats reported moderate feelings of anxiety, irrespective of whether the viral threat was one that was familiar versus one that was entirely unfamiliar to them (H1N1 recurrence, H5N1, a fictitious virus: D3N4). Participants appraised the stressfulness of the threats to be moderate and believed that they would have control in this situation. However, among individuals with high intolerance of uncertainty, the viral threat was accompanied by high levels of anxiety, which was mediated by aspects of appraisals, particularly control and stressfulness. In addition, among those individuals that generally appraised ambiguous life events as being stressful, the viral threat appraisals were accompanied by still greater anxiety. Given the limited response to potential viral threats, these results raise concerns that the public may be hesitant to heed recommendations should another pandemic occur. PMID- 23818423 TI - Dietary camphene attenuates hepatic steatosis and insulin resistance in mice. AB - OBJECTIVE: The aim of this study was to investigate the protective effects of camphene on high-fat diet (HFD)-induced hepatic steatosis and insulin resistance in mice and to elucidate its mechanism of action. DESIGN AND METHODS: Male C57BL/6N mice were fed with a normal diet, HFD (20% fat and 1% cholesterol of total diet), or HFD supplemented with 0.2% camphene (CPND) for 10 weeks. RESULTS: Camphene alleviated the HFD-induced increases in liver weight and hepatic lipid levels in mice. Camphene also increased circulating adiponectin levels. To examine the direct effects of camphene on adiponectin secretion, 3T3-L1 adipocytes were incubated with camphene. Consistent with in vivo result, camphene increased adiponectin expression and secretion in 3T3-L1 adipocytes. In HFD-fed mice, camphene increased hepatic adiponectin receptor expression and AMP activated protein kinase (AMPK) activation. Concordant with the activation of adiponectin-AMPK signaling, camphene increased hepatic expression of fatty acid oxidation-related genes and decreased those of lipogenesis-related genes in HFD fed mice. Moreover, camphene increased insulin-signaling molecules activation and stimulated glucose transporter-2translocation to the plasma membrane in the liver. CONCLUSIONS: These results suggest camphene prevents HFD-induced hepatic steatosis and insulin resistance in mice; furthermore, these protective effects are mediated via the activation of adiponectin-AMPK signaling. PMID- 23818425 TI - Rh-catalyzed highly enantioselective hydrogenation of nitroalkenes under basic conditions. PMID- 23818426 TI - Hofmeister salts recover a misfolded multiprotein complex for subsequent structural measurements in the gas phase. PMID- 23818427 TI - The individual determinants of care-seeking among middle-aged women reporting urinary incontinence: analysis of a 2273-woman cohort. AB - AIMS: Our main objective was to analyze individual determinants that lead middle aged women to seek medical care for urinary incontinence (UI). METHODS: Observational longitudinal study among GAZEL cohort participants: 2,640 women aged 50-62 completed a self-administered questionnaire at baseline. Eight years later (2008) 2,273 (86%) responded to a follow-up questionnaire. Seeking care for UI was defined as any consultation for UI during the 8-year follow-up period. Individual determinants considered in the regression analysis were social and demographic characteristics, social relations, UI type and severity, and other health factors. RESULTS: Among 1,192 women reporting incontinence at baseline, 24.4% had visited a physician at least once for UI during the follow-up period (56.0% of those reporting severe UI). The care-seeking rate increased with age at baseline. Multivariate analysis showed that women who reported severe UI (OR = 4.1; 95% CI 2.6-6.5), mixed UI (2.0; 1.3-3.0), or neurologic disease (1.6; 1.1 2.6), had weak social support (1.4; 1.0-2.0), or talked about their UI with close friends or family (1.5; 1.0-2.1) were more likely to seek care for UI. A model including these factors had a 78% probability of correctly differentiating women with incontinence who chose to seek care from those who did not. Our analysis could not take factors related to the organization of health services into account. CONCLUSIONS: Women do not always seek care for UI, even when it is severe. Besides UI severity and type, consultation is associated with aging, weak social support, conversation about it with close friends and family, and neurologic disorders. PMID- 23818428 TI - MRI of Thiel-embalmed human cadavers. AB - PURPOSE: To explain the observed considerable loss of signal and contrast when Thiel-embalmed human cadavers are imaged using clinical magnetic resonance imaging (MRI) sequences, especially those based on spin-echo MRI. MATERIALS AND METHODS: All cadavers were imaged with a medical 1.5T scanner using standard MRI sequences. Dual angle B1+ magnitude mapping and electromagnetic (EM) simulations that characterize the radiofrequency (RF) penetration in a male human body model (HBM) were carried out for a range of tissue conductivities. RESULTS: The EM simulations show that RF penetration issues begin to affect the image quality for values of electrical conductivity as low as 2.6 S/m. The electrical conductivity values of the embalming fluids were found to be within the range of 5-10.6 S/m, thus strongly suggesting that the observed loss in signal and contrast is due to diminished RF penetration inside the cadavers. Furthermore, it was demonstrated that gradient-echo (GRE)-based MRI sequences perform better than spin-echo (SE) based sequences, as they are less susceptible to imperfections in the flip angle that are inevitably present when imaging Thiel cadavers. CONCLUSION: The diminished signal and contrast observed when imaging Thiel-embalmed human cadavers may be attributed to the high conductivity of the embalming liquids. PMID- 23818430 TI - Regioselective o-hydroxylation of monosubstituted benzenes by P450 BM3. PMID- 23818429 TI - Lipid in skeletal muscle myotubes is associated to the donors' insulin sensitivity and physical activity phenotypes. AB - OBJECTIVE: This study investigated the relationship between in vitro lipid content in myotubes and in vivo whole body phenotypes of the donors such as insulin sensitivity, intramyocellular lipids (IMCL), physical activity, and oxidative capacity. DESIGN AND METHODS: Six physically active donors were compared to six sedentary lean and six T2DM. Lipid content was measured in tissues and myotubes by immunohistochemistry. Ceramides, triacylglycerols, and diacylglycerols (DAGs) were measured by LC-MS-MS and GC-FID. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp (80 mU min-1 m-2), maximal mitochondrial capacity (ATPmax) by 31P-MRS, physical fitness by VO2max and physical activity level (PAL) by accelerometers. RESULTS: Myotubes cultured from physically active donors had higher lipid content (0.047 +/- 0.003 vs. 0.032 +/- 0.001 and 0.033 +/- 0.001AU; P < 0.001) than myotubes from lean and T2DM donors. Lipid content in myotubes was not associated with IMCL in muscle tissue but importantly, correlated with in vivo measures of ATPmax (r = 0.74; P < 0.001), insulin sensitivity (r = 0.54; P < 0.05), type-I fibers (r = 0.50; P < 0.05), and PAL (r = 0.92; P < 0.0001). DAGs and ceramides in myotubes were inversely associated with insulin sensitivity (r = -0.55, r = -0.73; P < 0.05) and ATPmax (r = -0.74, r = -0.85; P < 0.01). CONCLUSIONS: These results indicate that cultured human myotubes can be used in mechanistic studies to study the in vitro impact of interventions on phenotypes such as mitochondrial capacity, insulin sensitivity, and physical activity. PMID- 23818431 TI - Cross-sectional and longitudinal relationships between perceived stress and C reactive protein in men and women. AB - To date, an examination of the longitudinal relationship between perceived stress and C-reactive protein (CRP) is limited. We explored the relationship between perceived stress and CRP concurrently and across 2 and 4 years in 383 men and women. Multiple linear regressions examined the cross-sectional and longitudinal relationships between baseline stress and counter-stress scores with CRP at baseline, 2 years after baseline and 4 years after baseline, while controlling for covariates (age, smoking status, anti-inflammatory use, oral contraceptive use, physical activity, menopausal status, years since onset of menopause, post menopausal hormone use and body mass index). Results indicate that stress and counter-stress were not related to CRP in either men or women at study baseline or 2 years later. Across a 4-year time frame, higher stress values were related to higher CRP values in women, but not men. Counter-stress was not related to CRP values in men or women across the 4 years. This study highlights the importance of examining the cross-sectional and longitudinal relationship between perceived stress and inflammation separately in men and women. PMID- 23818432 TI - A treatable new cause of chorea: beta-ketothiolase deficiency. PMID- 23818433 TI - Electrochemically driven cup-and-ball CuI and CuII complexes. AB - The conformation of copper "funnel" complexes that contains a coordinating appended arm can be electrochemically switched between endo, which corresponds to the self-coordination of the arm through the cavity, and exo positions. This process, which is reminiscent of a cup-and-ball device, is activated by an exogenous ligand for complexes that contain a hydroxy-terminated arm. The exchange is electrochemically triggered and is operated in either Cu(I) or Cu(II) redox states, depending on the exogenous ligand, that is, CO or n-butylamine, respectively. PMID- 23818434 TI - Risk-stratified imputation in survival analysis. AB - BACKGROUND: Censoring that is dependent on covariates associated with survival can arise in randomized trials due to changes in recruitment and eligibility criteria to minimize withdrawals, potentially leading to biased treatment effect estimates. Imputation approaches have been proposed to address censoring in survival analysis; while these approaches may provide unbiased estimates of treatment effects, imputation of a large number of outcomes may over- or underestimate the associated variance based on the imputation pool selected. PURPOSE: We propose an improved method, risk-stratified imputation, as an alternative to address withdrawal related to the risk of events in the context of time-to-event analyses. METHODS: Our algorithm performs imputation from a pool of replacement subjects with similar values of both treatment and covariate(s) of interest, that is, from a risk-stratified sample. This stratification prior to imputation addresses the requirement of time-to-event analysis that censored observations are representative of all other observations in the risk group with similar exposure variables. We compared our risk-stratified imputation to case deletion and bootstrap imputation in a simulated dataset in which the covariate of interest (study withdrawal) was related to treatment. A motivating example from a recent clinical trial is also presented to demonstrate the utility of our method. RESULTS: In our simulations, risk-stratified imputation gives estimates of treatment effect comparable to bootstrap and auxiliary variable imputation while avoiding inaccuracies of the latter two in estimating the associated variance. Similar results were obtained in analysis of clinical trial data. LIMITATIONS: Risk-stratified imputation has little advantage over other imputation methods when covariates of interest are not related to treatment. Risk stratified imputation is intended for categorical covariates and may be sensitive to the width of the matching window if continuous covariates are used. CONCLUSIONS: The use of the risk-stratified imputation should facilitate the analysis of many clinical trials, in which one group has a higher withdrawal rate that is related to treatment. PMID- 23818436 TI - Apparent total tract macronutrient and energy digestibility of 1- to- 3-day-old whole chicks, adult ground chicken, and extruded and canned chicken-based diets in African wildcats (Felis silvestris lybica). AB - Our objectives were to evaluate the composition of whole 1- to- 3-day-old chicks (Whole), ground adult chicken (Ground), chicken-based canned diet (Canned), and chicken-based extruded diet (Extruded); and evaluate apparent total tract energy and macronutrient digestibility of these diets by four captive African wildcats (Felis silvestrus lybica) utilizing a Latin Square design. We analyzed diets for macronutrient and mineral (Ca, P, K, Na, Mg, Fe, Cu, Mn, Zn, and S) composition, and screened for potentially pathogenic bacteria. Canned and Extruded diets tested negative for all microbes and met macronutrient and mineral recommendations for domestic cat foods [AAFCO (2012). Official publication. Oxford, IN: AAFCO]. Whole prey diets (Ground and Whole) met macronutrient requirements for domestic cats; however, they were below recommendations in some minerals [Mn, Cu, K, and Na; AAFCO (2012). Official publication. Oxford, IN: AAFCO], and tested positive for potentially pathogenic microorganisms (Salmonella, E. coli spp.). For all diets, apparent total tract organic matter digestibility was high (>85%). Organic matter digestibility was higher (P <= 0.05) for cats fed Ground (94%) compared to those fed Canned, Extruded, or Whole (87, 86, and 85%, respectively). Apparent total tract crude protein digestibility was lower than expected (i.e., <85%) for cats fed Extruded (81%) and fat digestibility was lower than expected (i.e., <90%) for cats fed Whole (82%). Cats fed whole prey items tested herein adequately maintained BW short-term; however, long-term studies are needed. These data indicate that there may be a need to monitor whole prey composition and when necessary, adjust the diet to account for potential deficiencies. PMID- 23818438 TI - Neurovascular anatomic relationships to arthroscopic posterior and transseptal portals in different knee positions. AB - BACKGROUND: No study exists that directly measures the distances between posterior portals and the popliteal artery under arthroscopic conditions. PURPOSE: To define the anatomic relationship between the neural structures and standard posterior arthroscopic portals and between the popliteal artery and posterior as well as transseptal portals in different knee positions. STUDY DESIGN: Descriptive laboratory study. METHODS: Seventeen fresh-frozen cadaveric knees were used. The posterolateral, posteromedial, and transseptal portals were established at 90 degrees of knee flexion. The popliteal artery was revealed using a shaver placed through the posteromedial portal. The distance from those portals to the popliteal artery was measured using a precision caliper. After the measurements were made, each specimen was dissected. The distance from a needle, blade, and cannula in each portal site to the adjacent neural structures was successively measured at 30 degrees , 90 degrees , and 120 degrees of knee flexion. RESULTS: The mean distance (in millimeters) from the posterolateral, posteromedial, and transseptal portals to the popliteal artery was significantly smaller at 30 degrees (32.1 +/- 4.6, 36.5 +/- 4.9, and 9.0 +/- 3.9, respectively) than at 90 degrees (40.7 +/- 5.1, 41.0 +/- 3.8, and 18.0 +/- 3.8, respectively) and 120 degrees (38.4 +/- 4.8, 38.7 +/- 6.0, and 21.0 +/- 4.0, respectively) of knee flexion. The mean distance from the posterolateral portal to the common peroneal nerve at 90 degrees of flexion (needle, 26.6 +/- 9.5; blade, 24.7 +/- 6.9; cannula, 22.1 +/- 6.9) was significantly greater than the distance at 30 degrees (needle, 23.4 +/- 6.5; blade, 21.4 +/- 6.4; cannula, 18.4 +/- 6.3) and 120 degrees (needle, 21.8 +/- 6.6; blade, 19.1 +/- 6.3; cannula, 17.4 +/- 6.7) of knee flexion. The mean distance between the posteromedial portal and the inferior infrapatellar branch of the saphenous nerve at 30 degrees (needle, 18.6 +/- 4.3; blade, 15.5 +/- 3.3; cannula, 13.7 +/- 5.8) of flexion was smaller than at 90 degrees (needle, 20.1 +/- 6.1; blade, 16.5 +/- 5.3; cannula, 14.3 +/- 4.4) and 120 degrees (needle, 21.1 +/- 3.6; blade, 17.7 +/- 4.9; cannula, 15.1 +/- 5.9) of flexion, but there was no statistical significance. The mean distance from the posteromedial portal to the sartorial branch of the saphenous nerve at 30 degrees (needle, 22.8 +/- 6.1; blade, 19.8 +/- 5.3; cannula, 17.7 +/- 6.2) of flexion was significantly smaller than that at 90 degrees (needle, 29.7 +/- 3.6; blade, 26.3 +/- 6.3; cannula, 23.1 +/- 4.7) and 120 degrees (needle, 31.5 +/- 3.9; blade, 28.9 +/- 4.1; cannula, 25.4 +/- 5.1) of flexion. Conclusion/ CLINICAL RELEVANCE: The position of 90 degrees of knee flexion is safe to establish posterior and transseptal arthroscopic portals. The position of 120 degrees of knee flexion is practically safe to establish posteromedial and transseptal portals, but it is unsafe to create a posterolateral portal because the risk of damaging the common peroneal nerve is high. The position of 30 degrees of knee flexion is not recommended to establish posterior arthroscopic portals. PMID- 23818435 TI - The epilepsy phenome/genome project. AB - BACKGROUND: Epilepsy is a common neurological disorder that affects approximately 50 million people worldwide. Both risk of epilepsy and response to treatment partly depend on genetic factors, and gene identification is a promising approach to target new prediction, treatment, and prevention strategies. However, despite significant progress in the identification of genes causing epilepsy in families with a Mendelian inheritance pattern, there is relatively little known about the genetic factors responsible for common forms of epilepsy and so-called epileptic encephalopathies. Study design The Epilepsy Phenome/Genome Project (EPGP) is a multi-institutional, retrospective phenotype-genotype study designed to gather and analyze detailed phenotypic information and DNA samples on 5250 participants, including probands with specific forms of epilepsy and, in a subset, parents of probands who do not have epilepsy. RESULTS: EPGP is being executed in four phases: study initiation, pilot, study expansion/establishment, and close-out. This article discusses a number of key challenges and solutions encountered during the first three phases of the project, including those related to (1) study initiation and management, (2) recruitment and phenotyping, and (3) data validation. The study has now enrolled 4223 participants. CONCLUSIONS: EPGP has demonstrated the value of organizing a large network into cores with specific roles, managed by a strong Administrative Core that utilizes frequent communication and a collaborative model with tools such as study timelines and performance-payment models. The study also highlights the critical importance of an effective informatics system, highly structured recruitment methods, and expert data review. PMID- 23818439 TI - Traditional and modified Latarjet techniques: letter to the editor. PMID- 23818440 TI - Platelet-rich plasma treatment for lateral epicondylitis: letter to the editor. PMID- 23818441 TI - Dynamic labral shear test in diagnosis of SLAP lesions: letter to the editor. PMID- 23818443 TI - Genomic test validation for incidental findings. PMID- 23818444 TI - Incremental prognostic value of biomarkers beyond the GRACE (Global Registry of Acute Coronary Events) score and high-sensitivity cardiac troponin T in non-ST elevation acute coronary syndrome. AB - BACKGROUND: Guidelines recommend the use of validated risk scores and a high sensitivity cardiac troponin assay for risk assessment in non-ST-elevation acute coronary syndrome (NSTE-ACS). The incremental prognostic value of biomarkers in this context is unknown. METHODS: We calculated the Global Registry of Acute Coronary Events (GRACE) score and measured the circulating concentrations of high sensitivity cardiac troponin T (hs-cTnT) and 8 selected cardiac biomarkers on admission in 1146 patients with NSTE-ACS. We used an hs-cTnT threshold at the 99th percentile of a reference population to define increased cardiac marker in the score. The magnitude of the increase in model performance when individual biomarkers were added to GRACE was assessed by the change (Delta) in the area under the receiver-operating characteristic curve (AUC), integrated discrimination improvement (IDI), and category-free net reclassification improvement [NRI(>0)]. RESULTS: Seventy-eight patients reached the combined end point of 6-month all-cause mortality or nonfatal myocardial infarction. The GRACE score alone had an AUC of 0.749. All biomarkers were associated with the risk of the combined end point and offered statistically significant improvement in model performance when added to GRACE (likelihood ratio test P <= 0.015). Growth differentiation factor 15 [DeltaAUC 0.039, IDI 0.049, NRI(>0) 0.554] and N terminal pro-B-type natriuretic peptide [DeltaAUC 0.024, IDI 0.027, NRI(>0) 0.438] emerged as the 2 most promising biomarkers. Improvements in model performance upon addition of a second biomarker were small in magnitude. CONCLUSIONS: Biomarkers can add prognostic information to the GRACE score even in the current era of high-sensitivity cardiac troponin assays. The incremental information offered by individual biomarkers varies considerably, however. PMID- 23818445 TI - Identification of complete hydatidiform mole pregnancy-associated microRNAs in plasma. PMID- 23818447 TI - Commentary. PMID- 23818446 TI - The syndrome of microcornea, myopic chorioretinal atrophy, and telecanthus (MMCAT) is caused by mutations in ADAMTS18. AB - One of us recently described an apparently novel ocular syndrome characterized by microcornea, myopic chorioretinal atrophy, and telecanthus (MMCAT) in a number of Saudi families. Consistent with the presumed pseudodominant inheritance in one of the original families, we show that MMCAT maps to a single autozygous locus on chr16q23.1 in which exome sequencing revealed a homozygous missense change in ADAMTS18. Direct sequencing of this gene in four additional probands with the same phenotype revealed three additional homozygous changes in ADAMTS18 including two nonsense mutations. Reassuringly, the autozygomes of all probands overlap on the same chr16q23.1 locus, further supporting the positional mapping of MMCAT to ADAMTS18. ADAMTS18 encodes a member of a family of metalloproteinases that are known for their role in extracellular matrix remodeling, and previous work has shown a strong expression of Adamts18 in the developing eye. Our data suggest that ADAMTS18 plays an essential role in early eye development and that mutations therein cause a distinct eye phenotype that is mainly characterized by microcornea and myopia. PMID- 23818449 TI - Phosphane-functionalized cycloheptatrienyl-cyclopentadienyl titanium sandwich complexes: phosphorus ligands with an integrated reducing agent for palladium(0) catalyst generation. PMID- 23818448 TI - Childhood cancer survivors exposed to total body irradiation are at significant risk for slipped capital femoral epiphysis during recombinant growth hormone therapy. AB - BACKGROUND: Childhood cancer survivors treated with cranial or total body irradiation (TBI) are at risk for growth hormone deficiency (GHD). Recombinant growth hormone (rhGH) therapy is associated with slipped capital femoral epiphysis (SCFE). We compared the incidence of SCFE after TBI versus cranial irradiation (CI) in childhood cancer survivors treated with rhGH. PROCEDURE: Retrospective cohort study (1980-2010) of 119 survivors treated with rhGH for irradiation-induced GHD (56 TBI; 63 CI). SCFE incidence rates were compared in CI and TBI recipients, and compared with national registry SCFE rates in children treated with rhGH for idiopathic GHD. RESULTS: Median survivor follow-up since rhGH initiation was 4.8 (range 0.2-18.3) years. SCFE was diagnosed in 10 subjects post-TBI and none after CI (P < 0.001). All 10 subjects had atypical valgus SCFE, and 7 were bilateral at presentation. Within TBI recipients, age at cancer diagnosis, sex, race, underlying malignancy, age at radiation, and age at initiation of rhGH did not differ significantly between those with versus without SCFE. The mean (SD) age at SCFE diagnosis was 12.3 (2.7) years and median duration of rhGH therapy to SCFE was 1.8 years. The SCFE incidence rate after TBI exposure was 35.9 per 1,000 person years, representing a 211-fold greater rate than reported in children treated with rhGH for idiopathic GH deficiency. CONCLUSIONS: The markedly greater SCFE incidence rate in childhood cancer survivors with TBI-associated GHD, compared with rates in children with idiopathic GHD, suggests that cancer treatment effects to the proximal femoral physis may contribute to SCFE. PMID- 23818450 TI - Inhibitory effects of nobiletin on hepatocellular carcinoma in vitro and in vivo. AB - Nobiletin (5, 6, 7, 8, 3' 4'-hexamethoxyflavone) is a major anticancer component in juice from zhishi (Rutaceae). This study aimed to investigate the inhibitory effect of Nobiletin on hepatic cancer cells both in vitro and in vivo. The 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), growth curve, and clonogenic assay showed that nobiletin inhibited the proliferation of SMMC-7721 cells in vitro. Hoechst staining observed the characteristics of cell apoptosis in nobiletin-treated cells, and the apoptotic rates of treated groups were increased in a dose-dependent manner. Flow cytometric analysis demonstrated that nobiletin could block the cell cycle arrested at G2 phase. Cell cycle analysis was performed using flow cytometry. Results showed that cell cycle phase distribution analysis showed G2 arrest. It was found that nobiletin downregulated the expressions of Bcl-2 and COX-2 and up-regulated the expressions of Bax and caspase-3 in SMMC-7721 cells by western blotting. The experiment in vivo demonstrated that nobiletin significantly inhibited the growth of H22 transplantable tumor, downregulated the expressions of COX-2, up-regulated the expressions of Bax and caspase-3 detected by immunohistochemistry and western blotting, and the ratios of Bcl-2/Bax were decreased. Our results suggest that nobiletin has significant inhibitory effects on hepatocellular carcinoma both in vitro and in vivo. PMID- 23818452 TI - Conductance switching and mechanisms in single-molecule junctions. PMID- 23818451 TI - Large numbers of genetic variants considered to be pathogenic are common in asymptomatic individuals. AB - It is now affordable to order clinically interpreted whole-genome sequence reports from clinical laboratories. One major component of these reports is derived from the knowledge base of previously identified pathogenic variants, including research articles, locus-specific, and other databases. While over 150,000 such pathogenic variants have been identified, many of these were originally discovered in small cohort studies of affected individuals, so their applicability to asymptomatic populations is unclear. We analyzed the prevalence of a large set of pathogenic variants from the medical and scientific literature in a large set of asymptomatic individuals (N = 1,092) and found 8.5% of these pathogenic variants in at least one individual. In the average individual in the 1000 Genomes Project, previously identified pathogenic variants occur on average 294 times (sigma = 25.5) in homozygous form and 942 times (sigma = 68.2) in heterozygous form. We also find that many of these pathogenic variants are frequently occurring: there are 3,744 variants with minor allele frequency (MAF) >= 0.01 (4.6%) and 2,837 variants with MAF >= 0.05 (3.5%). This indicates that many of these variants may be erroneous findings or have lower penetrance than previously expected. PMID- 23818453 TI - Biology of anterior cruciate ligament injury and repair: Kappa delta ann doner vaughn award paper 2013. AB - Anterior cruciate ligament (ACL) injuries are currently treated by removing the injured ligament and replacing it with a tendon graft. Recent studies have examined alternative treatment methods, including repair and regeneration of the injured ligament. In order to make such an approach feasible, a basic understanding of ACL biology and its response to injury is needed. Identification of obstacles to native ACL healing can then be identified and potentially resolved using tissue engineering strategies-first, with in vitro screening assays, and then with in vivo models of efficacy and safety. This Perspectives paper outlines this path of discovery for optimizing ACL healing using a bio enhanced repair technique. This journey required constructing indices of the functional tissue response, pioneering physiologically based methods of biomechanical testing, developing, and validating clinically relevant animal models, and creating and optimizing translationally feasible scaffolds, surgical techniques, and biologic additives. Using this systematic translational approach, "bio-enhanced" ACL repair has been advanced to the point where it may become an option for future treatment of acute ACL injuries and the prevention of subsequent post-traumatic osteoarthritis associated with this injury. PMID- 23818455 TI - Exposure assessment at 30 000 feet: challenges and future directions. AB - Few studies of cancer mortality and incidence among flight crew have included a detailed assessment of both occupational exposures and lifestyle factors that may influence the risk of cancer. In this issue, Kojo et al. (Risk factors for skin cancer among Finnish airline cabin crew. Ann Occup. Hyg 2013; 57: 695-704) evaluated the relative contributions of ultraviolet and cosmic radiation to the incidence of skin cancer in Finnish flight attendants. This is a useful contribution, yet the reason flight crew members have an increased risk of skin cancer compared with the general population remains unclear. Good policy decisions for flight crew will depend on continued and emerging effective collaborations to increase study power and improve exposure assessment in future flight crew health studies. Improving the assessment of occupational exposures and non-occupational factors will cost additional time and effort, which are well spent if the role of exposures can be clarified in larger studies. PMID- 23818454 TI - Wnt5a evokes cortical axon outgrowth and repulsive guidance by tau mediated reorganization of dynamic microtubules. AB - Wnt5a guides cortical axons in vivo by repulsion and in vitro evokes cortical axon outgrowth and repulsion by calcium signaling pathways. Here we examined the role of microtubule (MT) reorganization and dynamics in mediating effects of Wnt5a. Inhibiting MT dynamics with nocodazole and taxol abolished Wnt5a evoked axon outgrowth and repulsion of cultured hamster cortical neurons. EGFP-EB3 labeled dynamic MTs visualized in live cell imaging revealed that growth cone MTs align with the nascent axon. Wnt5a increased axon outgrowth by reorganization of dynamic MTs from a splayed to a bundled array oriented in the direction of axon extension, and Wnt5a gradients induced asymmetric redistribution of dynamic MTs toward the far side of the growth cone. Wnt5a gradients also evoked calcium transients that were highest on the far side of the growth cone. Calcium signaling and the reorganization of dynamic MTs could be linked by tau, a MT associated protein that stabilizes MTs. Tau is phosphorylated at the Ser 262 MT binding site by CaMKII, and is required for Wnt5a induced axon outgrowth and repulsive turning. Phosphorylation of tau at Ser262 is known to detach tau from MTs to increase their dynamics. Using transfection with tau constructs mutated at Ser262, we found that this site is required for the growth and guidance effects of Wnt5a by mediating reorganization of dynamic MTs in cortical growth cones. Moreover, CaMKII inhibition also prevents MT reorganization required for Wnt5a induced axon outgrowth, thus linking Wnt/calcium signaling to tau mediated MT reorganization during growth cone behaviors. PMID- 23818456 TI - Adiponectin in coronary heart disease and newly diagnosed impaired glucose tolerance. AB - OBJECTIVE: Adiponectin is produced by adipose tissue and regarded as protective hormone for diabetes and coronary heart disease (CHD). Its role in heart failure is discussed controversially. METHODS: In this study, 1015 consecutive patients admitted for acute (n = 149) or elective (n = 866) coronary angiography were enrolled. Patients with known diabetes mellitus (DM) were excluded. All patients were classified by oral glucose tolerance test (oGTT) according to World Health Organization (WHO) criteria and by the results of coronary angiography as no/minor coronary heart disease (CHD), single-vessel disease (1-VD), double vessel disease (2-VD) or triple-vessel disease (3-VD), by New York Heart Association (NYHA) criteria and by echocardiography for heart failure. Adiponectin and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were measured in all patients. RESULTS: Adiponectin was higher in patients with normal glucose tolerance (NGT) (13.65 +/- 10.31 mg/l) compared to impaired glucose tolerance (IGT) (11.12 +/- 7.5, p < 0.001) or diabetes (11.22 +/- 7.63, p < 0.001). There was a stepwise decrease in adiponectin from no CHD (18.16 +/- 12.49 mg/L) to minor CHD (16.01 +/- 11.42) to 1-VD (12.18 +/- 8.8, p < 0.001 to no/minor CHD) to 2- and 3-VD (10.68 +/- 7.5, p < 0.001 to no/minor CHD, p = 0.004 to 1-VD). Patients with heart failure NYHA III (17.4 +/- 10.27) had higher adiponectin levels compared to NYHA II (12.94 +/- 9.41, p < 0.001 to NYHA III) and NYHA I (10.3 +/- 7.75, p < 0.001 to NYHA III/II). In this line, adiponectin levels were positively correlated to NT-proBNP levels (r = 0.303), and patients with ejection fraction (EF) < 50% had higher adiponectin levels than those with EF > 50% (14.96 +/- 4.35 to 11.78 +/- 3.71, p = 0.006). CONCLUSION: Adiponectin levels are inversely correlated to progressing CHD and glucose intolerance but positively correlated to increasing heart failure. PMID- 23818457 TI - Feasibility of high pressure freezing with freeze substitution after long-term storage in chemical fixatives. AB - Fixation of biological samples is an important process especially related to histological and ultrastructural studies. Chemical fixation was the primary method of fixing tissue for transmission electron microscopy for many years, as it provides adequate preservation of the morphology of cells and organelles. High pressure freezing (HPF) and freeze substitution (FS) is a newer alternative method that rapidly freezes non-cryoprotected samples that are then slowly heated in the FS medium, allowing penetration of the tissue to insure adequate fixation. This study addresses several issues related to tissue preservation for electron microscopy. Using mice liver tissue as model the difference between samples fixed chemically or with HPF immediately after excision, or stored before chemical or HPF fixation were tested with specific focus on the nuclear membrane. Findings are that immediate HPF is the method of choice compared to chemical fixation. Of the chemical fixatives, immediate fixation with 2.5% glutaraldehyde (GA)/formaldehyde (FA) is the best in preserving membrane morphology, 2.5% GA can be used as alternative for stored and then chemically processed samples, with 10% formalin being suitable as a storage medium only if followed by HPF fixation. Overall, storage leads to lower ultrastructural preservation, but HPF with FS can minimize these artifacts relative to other processing protocols. PMID- 23818458 TI - Mapping cytoskeletal protein function in cells by means of nanobodies. AB - Nanobodies or VHHs are single domain antigen binding fragments derived from heavy chain antibodies naturally occurring in species of the Camelidae. Due to their ease of cloning, high solubility and intrinsic stability, they can be produced at low cost. Their small size, combined with high affinity and antigen specificity, enables recognition of a broad range of structural (undruggable) proteins and enzymes alike. Focusing on two actin binding proteins, gelsolin and CapG, we summarize a general protocol for the generation, cloning and production of nanobodies. Furthermore, we describe multiple ways to characterize antigen nanobody binding in more detail and we shed light on some applications with recombinant nanobodies. The use of nanobodies as intrabodies is clarified through several case studies revealing new cytoskeletal protein properties and testifying to the utility of nanobodies as intracellular bona fide protein inhibitors. Moreover, as nanobodies can traverse the plasma membrane of eukaryotic cells by means of the enteropathogenic E. coli type III protein secretion system, we show that in this promising way of nanobody delivery, actin pedestal formation can be affected following nanobody injection. PMID- 23818459 TI - Controlled polymer-brush growth from microliter volumes using sacrificial-anode atom-transfer radical polymerization. PMID- 23818460 TI - Biomechanical comparison of 4 different lateral plate constructs for distal fibula fractures. AB - BACKGROUND: Displaced lateral malleolar fractures are often treated with reduction and surgical stabilization. However, there has not been a comprehensive laboratory comparison to determine the most appropriate device for treating these patients. This study subjected a range of contemporary lateral fibular plates to a series of mechanical tests designed to reveal performance differences. METHODS: Forty fresh frozen lower extremities were divided into 4 groups. A Weber B distal fibula fracture was simulated with an osteotomy and stabilized using 1 of 4 plate systems: a standard Synthes one-third tubular plate with interfragmentary lag screw, a Synthes LCP locking plate with lag screw, an Orthohelix MaxLock Extreme low-profile locking plate with lag screw, or a TriMed Sidewinder nonlocking plate. Controlled monotonic bending and cyclic torsional loading were applied and bending stiffness, torsional stiffness, and fracture site motion were quantified. Resistance to cyclic torsional loading was determined by quantifying the number of loads withstood before excessive rotation occurred. Correlation between bone mineral density and each of the mechanical measures was determined. RESULTS: There was no difference in angulation or bending stiffness between plates. All plates except the LCP showed greater lateral deflection than in the other bending directions. Bending stiffness was lowest in lateral distal fragment deflection for all 4 plates. There was a positive correlation between bone mineral density and bending stiffness for all plate types. There was no difference in fracture site rotation between plate types in internal or external torsion, but internal rotation of the distal fragment consistently exceeded external rotation. Torsional stiffness in external rotation exceeded stiffness in internal rotation in nearly all specimens. LCP plates performed relatively poorly under cyclic torsion. CONCLUSIONS: Significant differences in plate performance were not demonstrated. The effects of bone quality variability and differences in interfragmentary screw purchase resulted in data dispersion that confounded absolute ranking of plate performance. CLINICAL RELEVANCE: Identification of an optimal lateral fibular plating system has the potential to improve the clinical outcome of malleolar fracture fixation, particularly when patient conditions are unfavorable. PMID- 23818461 TI - Endocortical bone loss in osteoporosis: the role of bone surface availability. AB - Age-related bone loss and postmenopausal osteoporosis are due to a dysregulation of bone remodelling in which less bone is reformed than resorbed. This dysregulation of bone remodelling does not occur with equal strength in all bone regions. Loss of bone is more pronounced near the endocortical surface. This leads to thinning of the cortical wall proceeding from the endosteum, a process sometimes called 'trabecularisation'. In this paper, we investigate the influence of the nonuniform distribution of bone surface within bone tissue for osteoporotic bone losses. We use a spatio-temporal computational model of bone remodelling in which microstructural changes of bone tissue are represented by a phenomenological relationship between bone specific surface and bone porosity. The simulation of an osteoporotic condition by our model shows that the evolution of bone porosity within a bone cross section is significantly influenced by the nonuniform availability of bone surface. Greater bone loss occurs near the endocortical wall, leading to cortical wall thinning and to an expansion of the medullary cavity similar to cross-sectional observations from human femur midshafts. Our model suggests that the rate of cortical wall thinning is fast/slow in the presence/absence of an adjacent trabecular or trabecularised bone compartment. PMID- 23818462 TI - A systematic review and meta-analysis of asthma outcomes following endoscopic sinus surgery for chronic rhinosinusitis. AB - BACKGROUND: Patients suffering from both chronic rhinosinusitis (CRS) and asthma demonstrate improved asthma outcomes when upper airway inflammation is controlled with medications. It is unclear if similar benefits exist when the upper airway is treated surgically. This study presents a systematic review and meta-analysis to assess the effects of endoscopic sinus surgery (ESS) on asthma outcomes. METHODS: Ovid MEDLINE and the Cochrane databases were searched to identify studies examining asthma outcomes in patients with CRS following ESS. Included studies involved a cohort of at least 5 patients and reported at least 1 postoperative asthma outcome. RESULTS: Twenty-two studies involving a total of 891 patients were identified. Mean follow-up across all studies was 26.4 months. Patients reported improved overall asthma control in 76.1% (95% confidence interval [CI], 71.9% to 80.3%) of cases. The frequency of asthma attacks decreased in 84.8% (95% CI, 76.6% to 93.0%) of patients and the number of hospitalizations decreased in 64.4% (95% CI, 53.3% to 75.6%). Decreased use of oral corticosteroids was seen in 72.8% (95% CI, 67.5% to 78.1%) of patients; inhaled corticosteroid use decreased in 28.5% (95% CI, 22.6% to 34.5%) and bronchodilator use decreased in 36.3% (95% CI, 28.9% to 43.7%) of patients. Mean improvement in predicted forced expiratory volume at 1 second (FEV1 ) was 1.62%, but was not statistically significant (p = 0.877). CONCLUSION: ESS in patients with concomitant bronchial asthma improves clinical asthma outcome measures, but not lung function testing. Difficulty conducting controlled clinical trials of ESS limits the strength of conclusions which can be reached. PMID- 23818463 TI - Fostering resilience among urban youth exposed to violence: a promising area for interdisciplinary research and practice. AB - Most studies to date have examined negative effects of exposure to community violence, in line with the deficit-based perspective. However, given that most youth exposed to community violence demonstrate positive adaptation or resilience over time, we suggest a shift in perspective, practices, and policies across systems toward identifying and building individual, family, and community assets and strengths that may more effectively support youth who have been exposed to community violence and related risks into competent, caring, and thriving adults. In this article, we review how resilience has been conceptualized and operationalized within the context of community violence, highlight gaps in literature, and offer directions for future public health research and practice. We illustrate this review with practice-based examples from public health work in the San Francisco Bay Area. Future multidisciplinary longitudinal studies that identify protective processes and successful trajectories and rigorous evaluations of strength-based policies, programs, and protective processes are needed. PMID- 23818464 TI - Words: what do they really mean? PMID- 23818465 TI - Community suffering. PMID- 23818466 TI - Nightingale's environmental theory. AB - This author extracts the environmental theory from Florence Nightingale's writings and recorded experiences. As Nightingale's experiences broadened to other cultures and circumstances, she generated an ever-widening commitment to redress unjust social policies imperiling human health. She mobilized collaborators, shaped public awareness, and championed the cause of those suffering as a result of unjust policies. Nightingale challenged nurses to create environments where population health is a realistic expectation. PMID- 23818467 TI - In the zeal to synthesize: a call for congruency. AB - In this column, the author provides a clear explanation of the nature of meta analysis, systematic reviews, integrative reviews, meta-synthesis, and meta summary along with a discussion of the paradigms that support each. Also the appropriateness of these methods of synthesis and a recommendation as to their use is discussed in terms of the utility of research. PMID- 23818468 TI - Suffering. AB - Human suffering is a significant yet elusive phenomenon that is frequently a topic of discussion in nursing and contemporary healthcare literature. Definitions and notions elaborating the potential meaning of human suffering are commonly linked with the concept of pain. The author here illuminates possible ethical meanings of human suffering. The ethical enduring truths embedded in the human becoming nursing theoretical perspective under girds the ethical discussion and significance for advancing disciplinary knowledge, practice, and education. PMID- 23818469 TI - The power of suffering. PMID- 23818470 TI - Strengthening a praxis of suffering: teaching-learning practices. AB - Suffering involves the loss of acceptable meaning and nourishing connection. How nurses are present to those who suffer makes a significant difference. In a context where sustained engagement with the sufferer is crucial but often neglected, important questions for educators arise. These include how to cultivate moral courage and compassion among our students and how to select philosophical and pedagogical approaches that can guide teaching and learning. This article presents the challenges raised in a graduate-level nursing course aimed at advancing a praxis of suffering as well as our experience integrating interpretive phenomenological and narrative-based approaches. PMID- 23818471 TI - Is nursing its own worst enemy? AB - In a thought-provoking interview, one nurse theorist poses a question related to nurses. She asks nurses to defend their profession as a profession rather than as a trade. This question should give rise to a resounding response that nursing is a professional discipline. Over the years many nurses have fought to be recognized as a profession by doing the real work of building a foundation to ensure nursing's future. Unfortunately, over the last few decades, the building of nursing science has taken a back seat to other concerns such as creating more layers of practice, continuing to confuse the public and our patients about who nurses really are and what nursing really does. PMID- 23818472 TI - Life as a nurse metatheorist. PMID- 23818473 TI - Creating an epiphany with Martha E. Rogers. AB - Creating an epiphany or integral manifestation with Martha Rogers is discussed in the context of her science of unitary human beings, Barrett's power theory, and yinyang. It is shown how Martha's science is related to an epiphany with her. Questions are raised and speculations are made about an epiphany with Martha living in the universe and about gender. PMID- 23818474 TI - Feeling at home: a humanbecoming living experience. AB - In this article, the author reports a Parse research study on the experience of feeling at home with 10 participants living in community. The central finding of the study is the structure: Feeling at home is quietude amid potential adversity, as uplifting certitude arises with the penetrable reverence of cherished affiliations. The findings are discussed in relation to the humanbecoming school of thought and extant literature. PMID- 23818475 TI - A comparison of the prenatal health behaviors of women from four cultural groups in Turkey: an ethnonursing study. AB - This research was conducted to uncover women's health behaviors during prenatal periods using a transcultural approach. The qualitative ethnonursing method was used, and the research was conducted at the family health center in Bornova District in Izmir. The data were collected between November 2007 and August 2008 using the purposive sampling method. Eighteen pregnant women were included in the study and in-depth face-to-face semi-structured interviews were recorded on an audio recording device. A thematic analysis revealed four main themes: family, social learning-tradition transfer, perceptions, and behavioral changes. PMID- 23818476 TI - A different drum: an arts-based educational program. AB - The authors in this article describe the background and development of a drama based educational initiative for student nurses in the United Kingdom (UK) Forty five student nurses from Adult and Mental-Health fields of study took part in a one-day experience where they worked alongside individuals with learning disabilities to produce art, dance, and drama sketches. The workshop was evaluated using a validated questionnaire to explore the experience from the students' perspectives. Students felt challenged as they were pushed beyond the comfort zone of a regular classroom environment. Moreover, a greater understanding of core concepts such as empathy, dignity, stigma, and social exclusion were identified as key outcomes of the experience. The focus for future work in this field is to explore the ways in which arts-based learning and teaching initiatives can be developed within mainstream curricula. PMID- 23818477 TI - Stories of suffering with leprosy and cancer in Korea. AB - The authors in this article tell the story of the experience of suffering of three persons with cancer in South Korea. Two of the stories are about men who early in their lives were diagnosed with Leprosy (Hansen's disease) and forced to live most of their lives in a prison- like treatment facility. The third story is of a woman with advanced cancer who ended up in a similar place because she lost both of her children and husband. Parse's humanbecoming theory and thoughts on human dignity provide the theoretical perspective for this discussion. The conclusion of the article is that largely because of ignorance and fear, people with Hansen's disease in Korea, as elsewhere, suffer a unique form of betrayal and shame; what they deserve is honor and reverence as they struggle to retain a sense of awe about being human. PMID- 23818478 TI - Social determinants of health in nursing education, research, and health policy. AB - The adoption of the Patient Protection and Affordable Care Act and the recent Institute of Medicine report, The Future of Nursing: Leading Change, Advancing Health, have brought about a resurgence of interest in the social determinants of health as the basis for healthcare decisions in nursing education, research, and health policy. Nurses are positioned to be at the forefront of crucial healthcare reform to affect health outcomes and reduce health disparities profoundly. However, for nurses of the 21st century to improve the health of U.S. citizens and promote health equity effectively, we must first intently address the social determinants of health in our current nursing educational models, research agendas, and public health policies. PMID- 23818479 TI - Thoughts about conceptual models, theories, and literature reviews. AB - This essay focuses on various types of literature reviews, including scoping reviews, realist reviews, and integrative reviews. As contributions to understanding the state of nursing science about a particular topic, each literature review should be but rarely is guided by a nursing conceptual model, and the research findings should be but rarely are interpreted as theories that were generated or tested. Examples that are exceptions to usual literature reviews are given. PMID- 23818483 TI - Knot-free suture medialization of the middle turbinate. PMID- 23818484 TI - Footprints of neutrophil extracellular traps as predictors of cardiovascular risk. PMID- 23818485 TI - Elevated levels of circulating DNA and chromatin are independently associated with severe coronary atherosclerosis and a prothrombotic state. AB - OBJECTIVE: Aberrant neutrophil activation occurs during the advanced stages of atherosclerosis. Once primed, neutrophils can undergo apoptosis or release neutrophil extracellular traps. This extracellular DNA exerts potent proinflammatory, prothrombotic, and cytotoxic properties. The goal of this study was to examine the relationships among extracellular DNA formation, coronary atherosclerosis, and the presence of a prothrombotic state. APPROACH AND RESULTS: In a prospective, observational, cross-sectional cohort of 282 individuals with suspected coronary artery disease, we examined the severity, extent, and phenotype of coronary atherosclerosis using coronary computed tomographic angiography. Double-stranded DNA, nucleosomes, citrullinated histone H4, and myeloperoxidase-DNA complexes, considered in vivo markers of cell death and NETosis, respectively, were established. We further measured various plasma markers of coagulation activation and inflammation. Plasma double-stranded DNA, nucleosomes, and myeloperoxidase-DNA complexes were positively associated with thrombin generation and significantly elevated in patients with severe coronary atherosclerosis or extremely calcified coronary arteries. Multinomial regression analysis, adjusted for confounding factors, identified high plasma nucleosome levels as an independent risk factor of severe coronary stenosis (odds ratio, 2.14; 95% confidence interval, 1.26-3.63; P=0.005). Markers of neutrophil extracellular traps, such as myeloperoxidase-DNA complexes, predicted the number of atherosclerotic coronary vessels and the occurrence of major adverse cardiac events. CONCLUSIONS: Our report provides evidence demonstrating that markers of cell death and neutrophil extracellular trap formation are independently associated with coronary artery disease, prothrombotic state, and occurrence of adverse cardiac events. These biomarkers could potentially aid in the prediction of cardiovascular risk in patients with chest discomfort. PMID- 23818486 TI - Overexpression of the Escherichia coli TolQ protein leads to a null-FtsN-like division phenotype. AB - Mutations involving the Tol-Pal complex of Escherichia coli result in a subtle phenotype in which cells chain when grown under low-salt conditions. Here, the nonpolar deletion of individual genes encoding the cytoplasmic membrane associated components of the complex (TolQ, TolR, TolA) produced a similar phenotype. Surprisingly, the overexpression of one of these proteins, TolQ, resulted in a much more overt phenotype in which cells occurred as elongated rods coupled in long chains when grown under normal salt conditions. Neither TolR nor TolA overexpression produced a phenotype, nor was the presence of either protein required for the TolQ-dependent phenotype. Consistent with their native membrane topology, the amino-terminal domain of TolQ specifically associated in vivo with the periplasmic domain of FtsN in a cytoplasm-based two-hybrid analysis. Further, the concomitant overexpression of FtsN rescued the TolQ-dependent phenotype, suggesting a model wherein the overexpression of TolQ sequesters FtsN, depleting this essential protein from the divisome during Gram-negative cell division. The role of the Tol-Pal system in division is discussed. PMID- 23818487 TI - Combating child obesity: impact of HENRY on parenting and family lifestyle. AB - BACKGROUND: One-quarter of children in England are overweight/obese at school entry. We investigated the impact of a programme designed to provide parents of infants and preschool children with the skills required for a healthier family lifestyle. METHOD: A cohort of families was followed across the 8-week HENRY (Health Exercise Nutrition for the Really Young) parent course at nine locations in England. Seventy-seven parents enrolled on the course, of which 71 agreed to complete questionnaires addressing eating behaviours, dietary intake and parental self-efficacy. Pre- and post-course data was available from 60 (84.5%) parents (8 week follow-up data from 58 parents) and was analysed using repeated measures analyses. RESULTS: Significant changes were observed, with most sustained at follow-up. Parents reported increased self-efficacy and ability to encourage good behaviour (P < 0.001). Increased consumption of fruits and vegetables was reported in both children and adults, together with reduced consumption of sweets, cakes and fizzy drinks in adults (all P < 0.01). There were also positive changes in eating behaviours (e.g., frequency of family mealtimes and eating while watching television or in response to negative emotion [P < 0.01] ) and reduced screen time in adults (P < 0.001). DISCUSSION: The results build upon earlier evaluation, indicating that the HENRY intervention has a beneficial impact upon the families of infants and preschool children. Furthermore, the findings suggest that positive changes inspired by the programme can be maintained beyond its completion. Such changes may serve to protect against later obesity. PMID- 23818489 TI - Positional dependency and surgical success of relocation pharyngoplasty among patients with severe obstructive sleep apnea. AB - OBJECTIVE: To examine the effect of positional dependency on surgical success among patients with severe obstructive sleep apnea (OSA) following modified uvulopalatopharyngoplasty, known as relocation pharyngoplasty. STUDY DESIGN: Case series with planned data collection. SETTING: Tertiary referred center. SUBJECTS AND METHODS: Standard nocturnal polysomnography was used to compare the apnea hypopnea index (AHI) in different sleep positions before and after relocation pharyngoplasty in 47 consecutive patients with severe OSA (AHI, 59.5 +/- 18.2 events/hour; Epworth Sleepiness Scale [ESS] scores, 12.2 +/- 4.4) who failed continuous positive airway pressure therapy. Positional (dependency) OSA was defined when the supine:non-supine AHI ratio was >2, otherwise it was defined as nonpositional OSA. Surgical success was defined as a >=50% reduction in AHI and a postoperative AHI of <=20 events/hour. Polysomnographic parameters, ESS, and surgical success following surgery were recorded. RESULTS: Of the 47 patients, 27 (57%) had positional OSA and 20 (43%) nonpositional OSA. The nonpositional OSA patients had higher AHI and ESS scores than the positional OSA patients (P = .002 and .104, respectively). Relocation pharyngoplasty significantly improved AHI and ESS scores in both positional and nonpositional OSA groups 6 months postoperatively (P < .05). The overall surgical success rate was 49%; however, positional OSA patients had a significantly higher success rate than nonpositional OSA patients (67% vs 25%, P = .008). CONCLUSION: The presence of positional dependency at baseline was a favorable outcome predictor of surgical success among severe OSA patients undergoing relocation pharyngoplasty. PMID- 23818488 TI - Does topical anesthesia using aerosolized lidocaine inhibit the superior laryngeal nerve reflex? AB - OBJECTIVE: This study was designed to evaluate the effectiveness of topical lidocaine in attenuating the laryngeal reflex and blunting hemodynamic response by inhibition of the superior laryngeal nerve in laryngeal microsurgery, which would be helpful in preventing potential complications. STUDY DESIGN: A prospective, randomized, double-blind study. SETTING: Tertiary medical center. SUBJECTS AND METHODS: Fifty-four patients requiring glottic and supraglottic laryngeal microsurgery were randomly assigned to 1 of 2 groups, with equal numbers. Before surgery, 10% lidocaine was topically applied to the laryngeal surface of the epiglottis and vocal folds under direct vision in the study group and saline aerosol was applied in the control group. Heart rates, arterial blood pressure, and SPO2 were recorded at baseline, after induction, immediately before and after intubation, during the surgery, and upon extubation. Laryngospasm, agitation, and coughing were recorded during the recovery period. RESULTS: Heart rates, arterial pressure, and SPO2 did not differ significantly from baseline to postintubation period among the groups. SPO2 values measured similar in the remaining study. Heart rates and blood pressures were slightly decreased in the study group after lidocaine administration, but only blood pressure at pre- and post-extubation was significantly decreased in the study group (P < .05). Also laryngospasm and coughing were not statistically different between the 2 groups. There was an obvious gap between the 2 groups for agitation. Study group agitation was noted significantly lower (P < .05). CONCLUSION: These findings indicate that preoperative topical lidocaine application may be helpful in attenuating airway-circulatory reflexes in laryngeal microscopic surgery. PMID- 23818490 TI - Compensatory responses to insulin resistance in obese African-American and Latina girls. AB - PURPOSE: Insulin responses to oral and intravenous glucose markedly differ by ethnicity. This study examined whether ethnic differences in pancreatic insulin secretion, hepatic insulin extraction and clearance explain these disparate findings in 35 obese African-American and 41 Latina girls (Tanner Stages: IV-V; ages: 14-18; body mass index percentile: 85.9-99.8%). METHODS: Pancreatic insulin secretion, hepatic insulin extraction and clearance were estimated by C-peptide and insulin modeling during an oral glucose tolerance test. Insulin sensitivity (SI), acute insulin response to glucose (AIRG ) and disposition index were derived from a frequently sampled intravenous glucose tolerance test. RESULTS: Compared to Latinas, obese African-American adolescents had lower pancreatic insulin secretion (21.3%; P < 0.01), glucose incremental area under the curve (IAUC) (41.7%, P = 0.02), C-peptide IAUC (25.1%, P < 0.01) and SI (33.7%; P < 0.01). There were no ethnic differences in hepatic insulin extraction and clearance (P's > 0.05). CONCLUSIONS: Compensatory mechanisms to insulin resistance do not appear to explain the ethnic differences in insulin responses to oral and intravenous glucose in obese African-American and Latina girls. PMID- 23818491 TI - Evaluating template-based and template-free protein-protein complex structure prediction. AB - We compared the performance of template-free (docking) and template-based methods for the prediction of protein-protein complex structures. We found similar performance for a template-based method based on threading (COTH) and another template-based method based on structural alignment (PRISM). The template-based methods showed similar performance to a docking method (ZDOCK) when the latter was allowed one prediction for each complex, but when the same number of predictions was allowed for each method, the docking approach outperformed template-based approaches. We identified strengths and weaknesses in each method. Template-based approaches were better able to handle complexes that involved conformational changes upon binding. Furthermore, the threading-based and docking methods were better than the structural-alignment-based method for enzyme inhibitor complex prediction. Finally, we show that the near-native (correct) predictions were generally not shared by the various approaches, suggesting that integrating their results could be the superior strategy. PMID- 23818492 TI - Identifying driver mutations from sequencing data of heterogeneous tumors in the era of personalized genome sequencing. AB - Distinguishing driver mutations from passenger mutations is critical to the understanding of the molecular mechanisms of carcinogenesis and for identifying prognostic and diagnostic markers as well as therapeutic targets. We reviewed the current approaches and software for identifying driver mutations from passenger mutations including both biology-based approaches and machine-learning-based approaches. We also reviewed approaches to identify driver mutations in the context of pathways or gene sets. Finally, we discussed the challenges of predicting driver mutations considering the complexities of inter- and intra tumor heterogeneity as well as the evolution and progression of tumors. PMID- 23818493 TI - Mitochondria, Mb, and Hb have electrical, mechanical, thermal, and CO2 positive feedbacks from the contracting sarcomeres for the ATP, PCR, and O2 supply. PMID- 23818494 TI - Reply toPancheva, Panchev, and Pancheva. PMID- 23818495 TI - Biological function of nuclear receptor tyrosine kinase action. AB - Receptor tyrosine kinases (RTKs) were believed until recently to act at the cell membrane in a singular fashion (i.e., binding of ligands on the extracellular domain would activate the intrinsic tyrosine kinase activity in the intracellular domain), which would then start a cascade involving other intracellular signaling molecules that would act as effectors. However, new evidence indicates that some RTKs can signal through a different modality; they can move into the nucleus where they directly exert their actions. Although some studies have showed that the proteolytically released intracellular domain of several RTKs can move to the nucleus where they influence gene expression and cell function, others suggest that RTKs can also move to the nucleus as holoproteins. The identification of this novel signaling mechanism calls for a critical reevaluation of the mechanisms of action of RTKs and their biological roles. PMID- 23818496 TI - MET: a critical player in tumorigenesis and therapeutic target. AB - Since its discovery more than 25 years ago, numerous studies have established that the MET receptor is unique among tyrosine kinases. Signaling through MET is necessary for normal development and for the progression of a wide range of human cancers. MET activation has been shown to drive numerous signaling pathways; however, it is not clear how MET signaling mediates diverse cellular responses such as motility, invasion, growth, and angiogenesis. Great strides have been made in understanding the pleotropic aspects of MET signaling using three dimensional molecular structures, cell culture systems, human tumors, and animal models. These combined approaches have driven the development of MET-targeted therapeutics that have shown promising results in the clinic. Here we examine the unique features of MET and hepatocyte growth factor/scatter factor (HGF/SF) structure and signaling, mutational activation, genetic mouse models of MET and HGF/SF, and MET-targeted therapeutics. PMID- 23818497 TI - Principles and concepts of DNA replication in bacteria, archaea, and eukarya. AB - The accurate copying of genetic information in the double helix of DNA is essential for inheritance of traits that define the phenotype of cells and the organism. The core machineries that copy DNA are conserved in all three domains of life: bacteria, archaea, and eukaryotes. This article outlines the general nature of the DNA replication machinery, but also points out important and key differences. The most complex organisms, eukaryotes, have to coordinate the initiation of DNA replication from many origins in each genome and impose regulation that maintains genomic integrity, not only for the sake of each cell, but for the organism as a whole. In addition, DNA replication in eukaryotes needs to be coordinated with inheritance of chromatin, developmental patterning of tissues, and cell division to ensure that the genome replicates once per cell division cycle. PMID- 23818498 TI - Biology of extreme radiation resistance: the way of Deinococcus radiodurans. AB - The bacterium Deinococcus radiodurans is a champion of extreme radiation resistance that is accounted for by a highly efficient protection against proteome, but not genome, damage. A well-protected functional proteome ensures cell recovery from extensive radiation damage to other cellular constituents by molecular repair and turnover processes, including an efficient repair of disintegrated DNA. Therefore, cell death correlates with radiation-induced protein damage, rather than DNA damage, in both robust and standard species. From the reviewed biology of resistance to radiation and other sources of oxidative damage, we conclude that the impact of protein damage on the maintenance of life has been largely underestimated in biology and medicine. PMID- 23818499 TI - Mitochondrial biogenesis through activation of nuclear signaling proteins. AB - The dynamics of mitochondrial biogenesis and function is a complex interplay of cellular and molecular processes that ultimately shape bioenergetics capacity. Mitochondrial mass, by itself, represents the net balance between rates of biogenesis and degradation. Mitochondrial biogenesis is dependent on different signaling cascades and transcriptional complexes that promote the formation and assembly of mitochondria--a process that is heavily dependent on timely and coordinated transcriptional control of genes encoding for mitochondrial proteins. In this article, we discuss the major signals and transcriptional complexes, programming mitochondrial biogenesis, and bioenergetic activity. This regulatory network represents a new therapeutic window into the treatment of the wide spectrum of mitochondrial and neurodegenerative diseases characterized by dysregulation of mitochondrial dynamics and bioenergetic deficiencies. PMID- 23818501 TI - Plant mobile small RNAs. AB - In plants, RNA silencing is a fundamental regulator of gene expression, heterochromatin formation, suppression of transposable elements, and defense against viruses. The sequence specificity of these processes relies on small noncoding RNA (sRNA) molecules. Although the spreading of RNA silencing across the plant has been recognized for nearly two decades, only recently have sRNAs been formally demonstrated as the mobile silencing signals. Here, we discuss the various types of mobile sRNA molecules, their short- and long-range movement, and their function in recipient cells. PMID- 23818500 TI - Epigenetics in Saccharomyces cerevisiae. AB - Saccharomyces cerevisiae provides a well-studied model system for heritable silent chromatin, in which a nonhistone protein complex--the SIR complex- represses genes by spreading in a sequence-independent manner, much like heterochromatin in higher eukaryotes. The ability to study mutations in histones and to screen genome-wide for mutations that impair silencing has yielded an unparalleled depth of detail about this system. Recent advances in the biochemistry and structural biology of the SIR-chromatin complex bring us much closer to a molecular understanding of how Sir3 selectively recognizes the deacetylated histone H4 tail and demethylated histone H3 core. The existence of appropriate mutants has also shown how components of the silencing machinery affect physiological processes beyond transcriptional repression. PMID- 23818503 TI - The personal experience of dysmenorrhoea: an interpretative phenomenological analysis. AB - This study explored six women's experiences of primary dysmenorrhoea using semi structured interviews analysed using interpretative phenomenological analysis. Rather than focusing on pain, participants broadened the study focus to coping with the menstrual process as a whole. This was seen to be mediated by menstrual taboos and by the theme of 'order', arising from a strong feeling of a menstrual timetable and the need for rational explanation. Another theme was pain as a separate entity, which was connected to the theme of order. Placing dysmenorrhoea in its context may be useful for health-care professionals treating women with the condition. PMID- 23818504 TI - Caloric expenditure assessment among older adults: criterion validity of a novel accelerometry device. AB - Criterion validity of a novel accelerometry device that measures caloric expenditure (Fitbit) was evaluated against a self-report estimation of caloric expenditure (Community Healthy Activities Model Program for Seniors) in older adults. Community Health Activities Model Program for Seniors and Fitbit estimates of total caloric expenditure per day were significantly correlated (r = .61, p < .05). Bland-Altman plots indicated that 70 percent of participants' data were within 1 standard deviation of the mean difference between measures. These preliminary findings suggest that the Fitbit may be considered a viable instrument for measuring daily caloric expenditure among older adults. However, further work is required to determine the optimal measurement technique for caloric expenditure among older adults. PMID- 23818502 TI - Regulatory T cells and immune tolerance in the intestine. AB - A fundamental role of the mammalian immune system is to eradicate pathogens while minimizing immunopathology. Instigating and maintaining immunological tolerance within the intestine represents a unique challenge to the mucosal immune system. Regulatory T cells are critical for continued immune tolerance in the intestine through active control of innate and adaptive immune responses. Dynamic adaptation of regulatory T-cell populations to the intestinal tissue microenvironment is key in this process. Here, we discuss specialization of regulatory T-cell responses in the intestine, and how a breakdown in these processes can lead to chronic intestinal inflammation. PMID- 23818506 TI - Somatic symptoms in those with performance and interaction anxiety. AB - This study (n = 304) examined the relationship between somatic symptoms and social anxiety. Significant differences in the experience of somatic symptoms were found among four groups (i.e. performance anxious, interaction anxious, generalized socially anxious, and controls). Post hoc analyses revealed that those who exceeded the clinical cutoff for generalized social anxiety exhibited more somatic symptoms than those who exceeded the clinical cutoff in the other two social anxiety domains or controls. Individuals in each group exhibited more somatic symptoms than controls, but subtypes did not differ in the amount of somatic symptoms experienced. Additionally, regression analyses revealed that type of somatic symptoms experienced varied depending on subtype. PMID- 23818505 TI - Writing about life goals: effects on rumination, mood and the cortisol awakening response. AB - Rumination is a vulnerability factor for the onset and maintenance of emotional distress. This study examined whether writing about life goals is associated with a decrease in ruminative thinking and a reduced cortisol awakening response. 68 healthy participants either wrote about their personal life goals or a control topic. Writing about life goals was associated with a modest decrease in ruminative thinking and a reduced cortisol awakening response at the post intervention assessment. Results provide initial evidence that writing about life goals can be a helpful aid in decreasing rumination and physiological stress reactivity. PMID- 23818507 TI - Subjective social status, self-rated health and tobacco smoking: Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). AB - Using baseline data from ELSA-Brasil (N = 15,105), we investigated whether subjective social status, measured using three 10-rung "ladders," is associated with self-rated health and smoking, independently of objective indicators of social position and depression symptoms. Additionally, we explored whether the magnitude of these associations varies according to the reference group. Subjective social status was independently associated with poor self-rated health and weakly associated with former smoking. The references used for social comparison did not change these associations significantly. Subjective social status, education, and income represent distinct aspects of social inequities, and the impact of each of these indicators on health is different. PMID- 23818508 TI - Measurement properties of the Danish version of the Illness Perception Questionnaire-Revised for patients with colorectal cancer symptoms. AB - The aim of this study was to validate the measurement properties of the Danish version of the Illness Perception Questionnaire-Revised adapted to measure symptom representations among patients with colorectal cancer symptoms. A total of 488 colorectal cancer patients completed a questionnaire derived from the Illness Perception Questionnaire-Revised to retrospectively assess cognitive and emotional representations of experienced symptoms. A confirmatory factor analysis indicated no good comparative fit with the Illness Perception Questionnaire Revised. Using exploratory factor analysis, a 7-factor structure was conducted, which fairly supported the Illness Perception Questionnaire-Revised. The modified Illness Perception Questionnaire-Revised is a promising tool for measuring symptom representations among Danish colorectal cancer patients. PMID- 23818509 TI - Age and sexual risk among Black men who have sex with men in South Africa: the mediating role of attitudes toward condoms. AB - The results of research linking age and sexual risk among men who have sex with men have been inconsistent. This study assessed the relationship between age and sexual risk among 193 Black men who have sex with men in Pretoria. Older men who have sex with men reported engaging in more frequent unprotected insertive anal intercourse. We examined whether components of Information-Motivation-Behavioral Skills model mediated this relationship. Results showed that (1) older age predicts less positive attitudes toward condoms, (2) less positive attitudes predict more frequent unprotected insertive anal intercourse, and (3) attitudes mediate the relationship between age and frequency of unprotected insertive anal intercourse. We consider two possible explanations for these findings: a developmental trajectory and a cohort effect. PMID- 23818510 TI - Does the 'Teddy Bear Hospital' enhance preschool children's knowledge? A pilot study with a pre/post-case control design in Germany. AB - The 'Teddy Bear Hospital' is a medical students' project, which has been increasingly established in many countries. To evaluate this concept, we examined the effects of a German Teddy Bear Hospital on children's knowledge relating to their body, health and disease. Using a quasi-experimental pre/post design, we examined 131 preschool children from 14 German kindergartens with pictorial interview-based scales. The analysis of covariance revealed that the children who visited the Teddy Bear Hospital had a significantly better knowledge concerning their body, health and disease than the children from the control group. This German Teddy Bear Hospital is a good health education vehicle for preschool children. PMID- 23818511 TI - The mediator role of psychological morbidity in patients with chronic low back pain in differentiated treatments. AB - This study analyzed the mediating role of psychological morbidity and the variables that discriminated low versus high disability, in patients receiving physiotherapy and acupuncture. A total of 203 patients answered measures of illness and medication representations, coping, depression, anxiety, quality of life, and functional disability. Morbidity was a mediator between functional disability and quality of life. Treatment consequences and quality of life, in the acupuncture group, and emotional representations, quality of life, depression, anxiety, and active strategies for pain relief, in the physiotherapy group, discriminated patients with low versus high disability. These results have important implications for identifying high-risk patients. PMID- 23818512 TI - BNFinder2: Faster Bayesian network learning and Bayesian classification. AB - SUMMARY: Bayesian Networks (BNs) are versatile probabilistic models applicable to many different biological phenomena. In biological applications the structure of the network is usually unknown and needs to be inferred from experimental data. BNFinder is a fast software implementation of an exact algorithm for finding the optimal structure of the network given a number of experimental observations. Its second version, presented in this article, represents a major improvement over the previous version. The improvements include (i) a parallelized learning algorithm leading to an order of magnitude speed-ups in BN structure learning time; (ii) inclusion of an additional scoring function based on mutual information criteria; (iii) possibility of choosing the resulting network specificity based on statistical criteria and (iv) a new module for classification by BNs, including cross-validation scheme and classifier quality measurements with receiver operator characteristic scores. AVAILABILITY AND IMPLEMENTATION: BNFinder2 is implemented in python and freely available under the GNU general public license at the project Web site https://launchpad.net/bnfinder, together with a user's manual, introductory tutorial and supplementary methods. PMID- 23818513 TI - Cystic fibrosis transmembrane regulator correctors and potentiators. AB - Cystic fibrosis (CF) is caused by loss-of-function mutations in the CF transmembrane conductance regulator (CFTR) protein, a cAMP-regulated anion channel expressed primarily at the apical plasma membrane of secretory epithelia. Nearly 2000 mutations in the CFTR gene have been identified that cause disease by impairing its translation, cellular processing, and/or chloride channel gating. The fundamental premise of CFTR corrector and potentiator therapy for CF is that addressing the underlying defects in the cellular processing and chloride channel function of CF-causing mutant CFTR alleles will result in clinical benefit by addressing the basic defect underlying CF. Correctors are principally targeted at F508del cellular misprocessing, whereas potentiators are intended to restore cAMP dependent chloride channel activity to mutant CFTRs at the cell surface. This article reviews the discovery of CFTR potentiators and correctors, what is known regarding their mechanistic basis, and encouraging results achieved in clinical testing. PMID- 23818514 TI - Concepts and mechanisms: crossing host barriers. AB - The human body is bordered by the skin and mucosa, which are the cellular barriers that define the frontier between the internal milieu and the external nonsterile environment. Additional cellular barriers, such as the placental and the blood-brain barriers, define protected niches within the host. In addition to their physiological roles, these host barriers provide both physical and immune defense against microbial infection. Yet, many pathogens have evolved elaborated mechanisms to target this line of defense, resulting in a microbial invasion of cells constitutive of host barriers, disruption of barrier integrity, and systemic dissemination and invasion of deeper tissues. Here we review representative examples of microbial interactions with human barriers, including the intestinal, placental, and blood-brain barriers, and discuss how these microbes adhere to, invade, breach, or compromise these barriers. PMID- 23818515 TI - The pneumococcus: epidemiology, microbiology, and pathogenesis. AB - The pneumococcus is the classic Gram-positive extracellular pathogen. The medical burden of diseases it causes is amongst the greatest in the world. Intense study for more than 100 years has yielded an understanding of fundamental aspects of its physiology, pathogenesis, and immunity. Efforts to control infection have led to the deployment of polysaccharide vaccines and an understanding of antibiotic resistance. The inflammatory response to pneumococci, one of the most potent in medicine, has revealed the double-edged sword of clearance of infection but at a cost of damage to host cells. In virtually every aspect of the infectious process, the pneumococcus has set the rules of the Gram-positive pathogenesis game. PMID- 23818517 TI - Cancer in the transplant recipient. AB - Malignancy has become one of the three major causes of death after transplantation in the past decade and is thus increasingly important in all organ transplant programs. Death from cardiovascular disease and infection are both decreasing in frequency from a combination of screening, prophylaxis, aggressive risk factor management, and interventional therapies. Cancer, on the other hand, is poorly and expensively screened for; risk factors are mostly elusive and/or hard to impact on except for the use of immunosuppression itself; and finally therapeutic approaches to the transplant recipient with cancer are often nihilistic. This article provides a review of each of the issues as they come to affect transplantation: cancer before wait-listing, cancer transmission from the donor, cancer after transplantation, outcomes of transplant recipients after a diagnosis of cancer, and the role of screening and therapy in reducing the impact of cancer in transplant recipients. PMID- 23818516 TI - Lymphodepletional strategies in transplantation. AB - Because lymphocytes were shown to mediate transplant rejection, their depletion has been studied as a mechanism of preventing rejection and perhaps inducing immunologic tolerance. Agents that profoundly deplete lymphocytes have included monoclonal antibodies, cytotoxic drugs, and radiation. We have studied several such agents but focused on antibodies that deplete not only peripheral blood lymphocytes, but also lymph node lymphocytes. Depletion of lymph node T lymphocytes appears to permit peripheral tolerance at least for T cells in animal models. Nevertheless, B-cell responses may be resistant to such approaches, and T memory cells are likewise relatively resistant to depleting antibodies. We review the experimental and clinical approaches to depletion strategies and outline some of the pitfalls of depletion, such as limitations of currently available agents, duration of tolerance, infection, and malignancy. It is notable that most tolerogenic strategies that have been attempted experimentally and clinically include depleting agents even when they are not named as the underlying strategy. Thus, there is an implicitly acknowledged role for reducing the precursor frequency of donor antigen-specific lymphocytes when approaching the daunting goal of transplant tolerance. PMID- 23818518 TI - Structure and catalytic mechanism of yeast 4-amino-4-deoxychorismate lyase. AB - Saccharomyces cerevisiae Abz2 is a pyridoxal 5'-phosphate (PLP)-dependent lyase that converts 4-amino-4-deoxychorismate (ADC) to para-aminobenzoate and pyruvate. To investigate the catalytic mechanism, we determined the 1.9 A resolution crystal structure of Abz2 complexed with PLP, representing the first eukaryotic ADC lyase structure. Unlike Escherichia coli ADC lyase, whose dimerization is critical to the formation of the active site, the overall structure of Abz2 displays as a monomer of two domains. At the interdomain cleft, a molecule of cofactor PLP forms a Schiff base with residue Lys-251. Computational simulations defined a basic clamp to orientate the substrate ADC in a proper pose, which was validated by site-directed mutageneses combined with enzymatic activity assays. Altogether, we propose a putative catalytic mechanism of a unique class of monomeric ADC lyases led by yeast Abz2. PMID- 23818519 TI - Non-receptor-tyrosine kinases integrate fast glucocorticoid signaling in hippocampal neurons. AB - Despite numerous descriptions of rapid effects of corticosterone on neuronal function, the intracellular mechanisms responsible for these changes remain elusive. The present comprehensive analysis reveals that signaling from a membrane-located G protein-coupled receptor activates PKC, Akt/PKB, and PKA, which subsequently trigger the phosphorylation of the tyrosine kinases Pyk2, Src, and Abl. These changes induce rapid cytoskeletal rearrangements (increased PSD-95 co-clustering) within the post-synaptic density; these events are accompanied by increased surface NMDA receptor expression, reflecting corticosterone-induced inhibition of NMDA receptor endocytosis. Notably, none of these signaling mechanisms require de novo protein synthesis. The observed up-regulation of ERK1/2 (downstream of NMDA receptor signaling) together with the fact that c-Abl integrates cytoplasmic and nuclear functions introduces a potential mechanism through which rapid signaling initiated at the plasma membrane may eventually determine the long term integrated response to corticosterone by impacting on the transcriptional machinery that is regulated by classical, nuclear mineralocorticoid, and glucocorticoid receptors. PMID- 23818520 TI - Structural and biochemical analyses of the eukaryotic heat shock locus V (HslV) from Trypanosoma brucei. AB - In many bacteria, heat shock locus V (HslV) functions as a protease, which is activated by heat shock locus U (HslU). The primary sequence and structure of HslV are well conserved with those of the beta-subunit of the 20 S proteasome core particle in eukaryotes. To date, the HslVU complex has only been characterized in the prokaryotic system. Recently, however, the coexistence of a 20 S proteasome with HslV protease in the same living organism has been reported. In Trypanosoma brucei, a protozoan parasite that causes human sleeping sickness in Africa, HslV is localized in the mitochondria, where it has a novel function in regulating mitochondrial DNA replication. Although the prokaryotic HslVU system has been studied extensively, little is known regarding its eukaryotic counterpart. Here, we report the biochemical characteristics of an HslVU complex from T. brucei. In contrast to the prokaryotic system, T. brucei possesses two potential HslU molecules, and we found that only one of them activates HslV. A key activating residue, Tyr(494), was identified in HslU2 by biochemical and mutational studies. Furthermore, to our knowledge, this study is the first to report the crystal structure of a eukaryotic HslV, determined at 2.4 A resolution. Drawing on our comparison of the biochemical and structural data, we discuss herein the differences and similarities between eukaryotic and prokaryotic HslVs. PMID- 23818521 TI - The bile acid receptor TGR5 does not interact with beta-arrestins or traffic to endosomes but transmits sustained signals from plasma membrane rafts. AB - TGR5 is a G protein-coupled receptor that mediates bile acid (BA) effects on energy balance, inflammation, digestion, and sensation. The mechanisms and spatiotemporal control of TGR5 signaling are poorly understood. We investigated TGR5 signaling and trafficking in transfected HEK293 cells and colonocytes (NCM460) that endogenously express TGR5. BAs (deoxycholic acid (DCA), taurolithocholic acid) and the selective agonists oleanolic acid and 3-(2 chlorophenyl)-N-(4-chlorophenyl)-N, 5-dimethylisoxazole-4-carboxamide stimulated cAMP formation but did not induce TGR5 endocytosis or recruitment of beta arrestins, as assessed by confocal microscopy. DCA, taurolithocholic acid, and oleanolic acid did not stimulate TGR5 association with beta-arrestin 1/2 or G protein-coupled receptor kinase (GRK) 2/5/6, as determined by bioluminescence resonance energy transfer. 3-(2-chlorophenyl)-N-(4-chlorophenyl)-N, 5 dimethylisoxazole-4-carboxamide stimulated a low level of TGR5 interaction with beta-arrestin 2 and GRK2. DCA induced cAMP formation at the plasma membrane and cytosol, as determined using exchange factor directly regulated by cAMP (Epac2) based reporters, but cAMP signals did not desensitize. AG1478, an inhibitor of epidermal growth factor receptor tyrosine kinase, the metalloprotease inhibitor batimastat, and methyl-beta-cyclodextrin and filipin, which block lipid raft formation, prevented DCA stimulation of ERK1/2. Bioluminescence resonance energy transfer analysis revealed TGR5 and EGFR interactions that were blocked by disruption of lipid rafts. DCA stimulated TGR5 redistribution to plasma membrane microdomains, as localized by immunogold electron microscopy. Thus, TGR5 does not interact with beta-arrestins, desensitize, or traffic to endosomes. TGR5 signals from plasma membrane rafts that facilitate EGFR interaction and transactivation. An understanding of the spatiotemporal control of TGR5 signaling provides insights into the actions of BAs and therapeutic TGR5 agonists/antagonists. PMID- 23818523 TI - Pigment epithelium-derived factor (PEDF) prevents retinal cell death via PEDF Receptor (PEDF-R): identification of a functional ligand binding site. AB - The extracellular pigment epithelium-derived factor (PEDF) displays retina survival activity by interacting with receptor proteins on cell surfaces. We have previously reported that PEDF binds and stimulates PEDF receptor (PEDF-R), a transmembrane phospholipase. However, the PEDF binding site of PEDF-R and its involvement in survival activity have not been identified. The purpose of this work is to identify a biologically relevant ligand-binding site on PEDF-R. PEDF bound the PEDF-R ectodomain L4 (Leu(159)-Met(325)) with affinity similar to the full-length PEDF-R (Met(1)-Leu(504)). Binding assays using synthetic peptides spanning L4 showed that PEDF selectively bound E5b (Ile(193)-Leu(232)) and P1 (Thr(210)-Leu(249)) peptides. Recombinant C-terminal truncated PEDF-R4 (Met(1) Leu(232)) and internally truncated PEDF-R and PEDF-R4 (DeltaHis(203)-Leu(232)) retained phospholipase activity of the full-length PEDF-R. However, PEDF-R polypeptides without the His(203)-Leu(232) region lost the PEDF affinity that stimulated their enzymatic activity. Cell surface labeling showed that PEDF-R is present in the plasma membranes of retina cells. Using siRNA to selectively knock down PEDF-R in retina cells, we demonstrated that PEDF-R is essential for PEDF mediated cell survival and antiapoptotic activities. Furthermore, preincubation of PEDF with P1 and E5b peptides blocked the PEDF.PEDF-R-mediated retina cell survival activity, implying that peptide binding to PEDF excluded ligand-receptor interactions on the cell surface. Our findings establish that PEDF-R is required for the survival and antiapoptotic effects of PEDF on retina cells and has determinants for PEDF binding within its L4 ectodomain that are critical for enzymatic stimulation. PMID- 23818522 TI - The complexity of thyroid transcription factor 1 with both pro- and anti oncogenic activities. AB - After the original identification of thyroid transcription factor 1 (TTF-1 or NKX2-1) biochemical activity as a transcriptional regulator of thyroglobulin in 1989, the bulk of the ensuing research has concentrated on elucidating the roles of NKX2-1 in the development of lung and thyroid tissues. Motivated by its specific expression pattern, pathologists adopted the NKX2-1 immunoreactivity to distinguish pulmonary from nonpulmonary nonthyroid adenocarcinomas. Interestingly, the concept of NKX2-1 as an active participant in lung tumorigenesis did not take hold until 2007. This minireview contrasts the recent advancements of NKX2-1-related observations primarily in the realm of pulmonary malignancies. PMID- 23818524 TI - Single-chain variable fragment albumin fusions bind the neonatal Fc receptor (FcRn) in a species-dependent manner: implications for in vivo half-life evaluation of albumin fusion therapeutics. AB - Albumin has a serum half-life of 3 weeks in humans. This has been utilized to extend the serum persistence of biopharmaceuticals that are fused to albumin. In light of the fact that the neonatal Fc receptor (FcRn) is a key regulator of albumin homeostasis, it is crucial to address how fusion of therapeutics to albumin impacts binding to FcRn. Here, we report on a detailed molecular investigation on how genetic fusion of a short peptide or an single-chain variable fragment (scFv) fragment to human serum albumin (HSA) influences pH dependent binding to FcRn from mouse, rat, monkey, and human. We have found that fusion to the N- or C-terminal end of HSA only slightly reduces receptor binding, where the most noticeable effect is seen after fusion to the C-terminal end. Furthermore, in contrast to the observed strong binding to human and monkey FcRn, HSA and all HSA fusions bound very poorly to mouse and rat versions of the receptor. Thus, we demonstrate that conventional rodents are limited as preclinical models for analysis of serum half-life of HSA-based biopharmaceuticals. This finding is explained by cross-species differences mainly found within domain III (DIII) of albumin. Our data demonstrate that although fusion, particularly to the C-terminal end, may slightly reduce the affinity for FcRn, HSA is versatile as a carrier of biopharmaceuticals. PMID- 23818526 TI - CHD@ZJU: a knowledgebase providing network-based research platform on coronary heart disease. AB - Coronary heart disease (CHD), the leading cause of global morbidity and mortality in adults, has been reported to be associated with hundreds of genes. A comprehensive understanding of the CHD-related genes and their corresponding interactions is essential to advance the translational research on CHD. Accordingly, we construct this knowledgebase, CHD@ZJU, which records CHD-related information (genes, pathways, drugs and references) collected from different resources and through text-mining method followed by manual confirmation. In current release, CHD@ZJU contains 660 CHD-related genes, 45 common pathways and 1405 drugs accompanied with >8000 supporting references. Almost half of the genes collected in CHD@ZJU were novel to other publicly available CHD databases. Additionally, CHD@ZJU incorporated the protein-protein interactions to investigate the cross-talk within the pathways from a multi-layer network view. These functions offered by CHD@ZJU would allow researchers to dissect the molecular mechanism of CHD in a systematic manner and therefore facilitate the research on CHD-related multi-target therapeutic discovery. Database URL: http://tcm.zju.edu.cn/chd/ PMID- 23818525 TI - Binding and movement of individual Cel7A cellobiohydrolases on crystalline cellulose surfaces revealed by single-molecule fluorescence imaging. AB - The efficient catalytic conversion of biomass to bioenergy would meet a large portion of energy requirements in the near future. A crucial step in this process is the enzyme-catalyzed hydrolysis of cellulose to glucose that is then converted into fuel such as ethanol by fermentation. Here we use single-molecule fluorescence imaging to directly monitor the movement of individual Cel7A cellobiohydrolases from Trichoderma reesei (TrCel7A) on the surface of insoluble cellulose fibrils to elucidate molecular level details of cellulase activity. The motion of multiple, individual TrCel7A cellobiohydrolases was simultaneously recorded with ~15-nm spatial resolution. Time-resolved localization microscopy provides insights on the activity of TrCel7A on cellulose and informs on nonproductive binding and diffusion. We measured single-molecule residency time distributions of TrCel7A bound to cellulose both in the presence of and absence of cellobiose the major product and a potent inhibitor of Cel7A activity. Combining these results with a kinetic model of TrCel7A binding provides microscopic insight into interactions between TrCel7A and the cellulose substrate. PMID- 23818527 TI - Incretin action in the pancreas: potential promise, possible perils, and pathological pitfalls. AB - Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones that control the secretion of insulin, glucagon, and somatostatin to facilitate glucose disposal. The actions of incretin hormones are terminated via enzymatic cleavage by dipeptidyl peptidase-4 (DPP-4) and through renal clearance. GLP-1 and GIP promote beta-cell proliferation and survival in rodents. DPP-4 inhibitors expand beta-cell mass, reduce alpha-cell mass, and inhibit glucagon secretion in preclinical studies; however, whether incretin based therapies sustain functional beta-cell mass in human diabetic subjects remains unclear. GLP-1 and GIP exert their actions predominantly through unique G protein-coupled receptors expressed on beta-cells and other pancreatic cell types. Accurate localization of incretin receptor expression in pancreatic ductal or acinar cells in normal or diabetic human pancreas is challenging because antisera used for detection of the GLP-1 receptor often are neither sufficiently sensitive nor specific to yield reliable data. This article reviews recent advances and controversies in incretin hormone action in the pancreas and contrasts established mechanisms with areas of uncertainty. Furthermore, methodological challenges and pitfalls are highlighted and key areas requiring additional scientific investigation are outlined. PMID- 23818529 TI - Cone beam CT: a current overview of devices. AB - The purpose of this study was to review and compare the properties of all the available cone beam CT (CBCT) devices offered on the market, while focusing especially on Europe. In this study, we included all the different commonly used CBCT devices currently available on the European market. Information about the properties of each device was obtained from the manufacturers' official available data, which was later confirmed by their representatives in cases where it was necessary. The main features of a total of 47 CBCT devices that are currently marketed by 20 companies were presented, compared and discussed in this study. All these CBCT devices differ in specific properties according to the companies that produce them. The summarized technical data from a large number of CBCT devices currently on the market offer a wide range of imaging possibilities in the oral and maxillofacial region. PMID- 23818530 TI - ICD-11 should not repeat the mistakes made by DSM-5. AB - Having two systems of psychiatric diagnosis creates unnecessary confusion therefore it would be desirable to achieve increased consistency between ICD-11 and DSM-5. Unfortunately, however, DSM-5 has included many controversial suggestions that have weak scientific support and insufficient risk-benefit analysis. As a result ICD-11 should learn from the DSM-5 mistakes rather than repeating them. PMID- 23818531 TI - Mixed features of depression: why DSM-5 is wrong (and so was DSM-IV). AB - The DSM system has never acknowledged a central position for mixed states; thus, mixed depressions have been almost completely neglected for decades. Now, DSM-5 is proposing diagnostic criteria for depression with mixed features that will lead to more misdiagnosis and inadequate treatment of this syndrome. Different criteria, based on empirically stronger evidence than exists for the DSM-5 criteria, should be adopted. PMID- 23818532 TI - Tardive dyskinesia in schizophrenia. AB - Sarro et al report grey matter deficits associated with tardive dyskinesia in schizophrenia. Much evidence suggests that the intrinsic pathophysiology of schizophrenia contributes to predisposition to tardive dyskinesia. The possibility that antipsychotics might play a causal role in the grey matter deficits cannot be excluded, but the evidence is tenuous. PMID- 23818533 TI - Lack of interventions for anxiety in older people. AB - Although anxiety disorders are common in later life, only a minority of patients receive appropriate treatment. The scarcity of clinical trials and decreasing effectiveness of current treatment modalities with advancing age, as shown by Wetherell and colleagues in this issue, argue for more clinical trials and development of age-specific psychotherapeutic techniques. PMID- 23818534 TI - Socioeconomic status as a risk factor for dementia death: individual participant meta-analysis of 86 508 men and women from the UK. AB - BACKGROUND: Life-course socioeconomic factors may have a role in dementia aetiology but there is a current paucity of studies. Meta-analyses of individual participant data would considerably strengthen this evidence base. AIMS: To examine the association between socioeconomic status in early life and adulthood with later dementia death. METHOD: Individual participant meta-analysis of 11 prospective cohort studies (1994-2004, n = 86 508). RESULTS: Leaving full-time education at an earlier age was associated with an increased risk of dementia death in women (fully adjusted hazard ratio (HR) for age <=14 v. age >=16: HR = 1.76, 95% CI 1.23-2.53) but not men. Occupational social class was not statistically significantly associated with dementia death in men or women. CONCLUSIONS: Lower educational attainment in women was associated with an increased risk of dementia-related death independently of common risk behaviours and comorbidities. PMID- 23818535 TI - Messages from Manchester: pilot randomised controlled trial following self-harm. AB - Studies of therapeutic contact following self-harm have had mixed results. We carried out a pilot randomised controlled trial comparing an intervention (information leaflet listing sources of help, two telephone calls soon after presentation and a series of letters over 12 months) to usual treatment alone in 66 adults presenting with self-harm to two hospitals. We found that our methodology was feasible, recruitment was challenging and repeat self-harm was more common in those who received the intervention (12-month repetition rate 34.4% v. 12.5%). PMID- 23818536 TI - Antidepressants in rapid-cycling bipolar disorder. PMID- 23818537 TI - Clinical practice guideline: tympanostomy tubes in children--executive summary. AB - The American Academy of Otolaryngology-Head and Neck Surgery Foundation (AAO HNSF) has published a supplement to this issue featuring the new Clinical Practice Guideline: Tympanostomy Tubes in Children. To assist in implementing the guideline recommendations, this article summarizes the rationale, purpose, and key action statements. The 12 recommendations developed address patient selection, surgical indications for and management of tympanostomy tubes in children. The development group broadly discussed indications for tube placement, perioperative management, care of children with indwelling tubes, and outcomes of tympanostomy tube surgery. Given the lack of current published guidance on surgical indications, the group focused on situations in which tube insertion would be optional, recommended, or not recommended. Additional emphasis was placed on opportunities for quality improvement, particularly regarding shared decision making and care of children with existing tubes. PMID- 23818538 TI - Clinical consensus statement: tracheostomy care. PMID- 23818539 TI - In response to the letter to the editor: "Clinical consensus statement: tracheostomy care". PMID- 23818540 TI - Comparison of intratympanic methylprednisolone and gentamicin for Meniere's disease may be misleading. PMID- 23818541 TI - Response to: Comparison of intratympanic methylprednisolone and gentamicin for Meniere's disease may be misleading. PMID- 23818543 TI - Clinical practice guideline: Tympanostomy tubes in children. AB - OBJECTIVE: Insertion of tympanostomy tubes is the most common ambulatory surgery performed on children in the United States. Tympanostomy tubes are most often inserted because of persistent middle ear fluid, frequent ear infections, or ear infections that persist after antibiotic therapy. Despite the frequency of tympanostomy tube insertion, there are currently no clinical practice guidelines in the United States that address specific indications for surgery. This guideline is intended for any clinician involved in managing children, aged 6 months to 12 years, with tympanostomy tubes or being considered for tympanostomy tubes in any care setting, as an intervention for otitis media of any type. PURPOSE: The primary purpose of this clinical practice guideline is to provide clinicians with evidence-based recommendations on patient selection and surgical indications for and management of tympanostomy tubes in children. The development group broadly discussed indications for tube placement, perioperative management, care of children with indwelling tubes, and outcomes of tympanostomy tube surgery. Given the lack of current published guidance on surgical indications, the group focused on situations in which tube insertion would be optional, recommended, or not recommended. Additional emphasis was placed on opportunities for quality improvement, particularly regarding shared decision making and care of children with existing tubes. ACTION STATEMENTS: The development group made a strong recommendation that clinicians should prescribe topical antibiotic eardrops only, without oral antibiotics, for children with uncomplicated acute tympanostomy tube otorrhea. The panel made recommendations that (1) clinicians should not perform tympanostomy tube insertion in children with a single episode of otitis media with effusion (OME) of less than 3 months' duration; (2) clinicians should obtain an age-appropriate hearing test if OME persists for 3 months or longer (chronic OME) or prior to surgery when a child becomes a candidate for tympanostomy tube insertion; (3) clinicians should offer bilateral tympanostomy tube insertion to children with bilateral OME for 3 months or longer (chronic OME) and documented hearing difficulties; (4) clinicians should reevaluate, at 3- to 6-month intervals, children with chronic OME who did not receive tympanostomy tubes until the effusion is no longer present, significant hearing loss is detected, or structural abnormalities of the tympanic membrane or middle ear are suspected; (5) clinicians should not perform tympanostomy tube insertion in children with recurrent acute otitis media (AOM) who do not have middle ear effusion in either ear at the time of assessment for tube candidacy; (6) clinicians should offer bilateral tympanostomy tube insertion to children with recurrent AOM who have unilateral or bilateral middle ear effusion at the time of assessment for tube candidacy; (7) clinicians should determine if a child with recurrent AOM or with OME of any duration is at increased risk for speech, language, or learning problems from otitis media because of baseline sensory, physical, cognitive, or behavioral factors; (8) in the perioperative period, clinicians should educate caregivers of children with tympanostomy tubes regarding the expected duration of tube function, recommended follow-up schedule, and detection of complications; (9) clinicians should not encourage routine, prophylactic water precautions (use of earplugs, headbands; avoidance of swimming or water sports) for children with tympanostomy tubes. The development group provided the following options: (1) clinicians may perform tympanostomy tube insertion in children with unilateral or bilateral OME for 3 months or longer (chronic OME) and symptoms that are likely attributable to OME including, but not limited to, vestibular problems, poor school performance, behavioral problems, ear discomfort, or reduced quality of life and (2) clinicians may perform tympanostomy tube insertion in at-risk children with unilateral or bilateral OME that is unlikely to resolve quickly as reflected by a type B (flat) tympanogram or persistence of effusion for 3 months or longer (chronic OME). PMID- 23818544 TI - Soluble GARP has potent antiinflammatory and immunomodulatory impact on human CD4+ T cells. AB - Glycoprotein A repetitions predominant (GARP) is expressed on the surface of activated human regulatory T cells (Treg) and regulates the bioavailability of transforming growth factor-beta (TGF-beta). GARP has been assumed to require membrane anchoring. To investigate the function of GARP in more detail, we generated a soluble GARP protein (sGARP) and analyzed its impact on differentiation and activation of human CD4+ T cells. We demonstrate that sGARP efficiently represses proliferation and differentiation of naive CD4+ T cells into T effector cells. Exposure to sGARP induces Foxp3, decreases proliferation and represses interleukin (IL)-2 and interferon-gamma production, resulting in differentiation of naive T cells into induced Treg. This is associated with Smad2/3 phosphorylation and partially inhibited by blockade of TGF-beta signaling. Furthermore, in the presence of the proinflammatory cytokines IL-6 and IL-23, sGARP facilitates the differentiation of naive T cells into Th17 cells. More important, in a preclinical humanized mouse model of xenogeneic graft-versus host disease (GVHD), sGARP prevents T cell-mediated destructive inflammation by enhancing Treg and inhibiting T effector cell activity. These results demonstrate a crucial role of sGARP in modulation of peripheral tolerance and T effector cell function, opening the possibility to use sGARP as a potent immunomodulator of inflammatory diseases including transplant rejection, autoimmunity, and allergy. PMID- 23818545 TI - Multiparameter single-cell profiling of human CD4+FOXP3+ regulatory T-cell populations in homeostatic conditions and during graft-versus-host disease. AB - Understanding the heterogeneity of human CD4+FOXP3+ regulatory T cells (Tregs) and their potential for lineage reprogramming is of critical importance for moving Treg therapy into the clinics. Using multiparameter single-cell analysis techniques, we explored the heterogeneity and functional diversity of human Tregs in healthy donors and in patients after allogeneic hematopoietic stem cell transplantation (alloHSCT). Human Tregs displayed a level of complexity similar to conventional CD4+ effector T cells with respect to the expression of transcription factors, homing receptors and inflammatory cytokines. Single-cell profiling of the rare Treg producing interleukin-17A or interferon-gamma showed an overlap of gene expression signatures of Th17 or Th1 cells and of Tregs. To assess whether Treg homeostasis is affected by an inflammatory and lymphopenic environment, we characterized the Treg compartment in patients early after alloHSCT. This analysis suggested a marked depletion of Treg with a naive phenotype in patients developing acute graft-versus-host disease, compared with tolerant patients. However, single-cell profiling showed that CD4+FOXP3+ T cells maintain the Treg gene expression signature and Treg-suppressive activity was preserved. Our study establishes that heterogeneity at the single-cell level, rather than lineage reprogramming of CD4+FOXP3+ T cells, explains the remarkable complexity and functional diversity of human Tregs. PMID- 23818546 TI - Murine NK-cell licensing is reflective of donor MHC-I following allogeneic hematopoietic stem cell transplantation in murine cytomegalovirus responses. AB - Natural killer (NK) cells express inhibitory receptors with varied binding affinities to specific major histocompatibility complex class I (MHC-I) haplotypes. NK cells can be classified as licensed or unlicensed based on their ability or inability to bind MHC-I, respectively. The role of donor vs host MHC on their development after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is not known. Following reciprocal MHC-disparate allogeneic transplants and during de novo NK-cell recovery, depletion of the licensed and not unlicensed population of NK cells as determined by the licensing patterns of donor MHC-I haplotypes, resulted in significantly increased susceptibility to murine cytomegalovirus (MCMV) infection. A corresponding expansion of the licensed Ly49H(+) NK cells occurred with greater interferon gamma production by these cells than unlicensed NK cells in the context of donor MHC-I. Thus, NK licensing behavior to MCMV corresponds to the donor, and not recipient, MHC haplotype after allo-HSCT in mice. PMID- 23818548 TI - Interim 18F-FDG PET in Hodgkin lymphoma: would PET-adapted clinical trials lead to a paradigm shift? AB - Hodgkin lymphoma (HL) is a curable disease with currently available chemotherapy regimens. Major late morbidities can potentially be avoided in most limited-stage HL patients if the treatment can be adapted to the patient's early response profile. The therapy efficacy can also be increased early during therapy in nonresponding HL patients with the addition of involved-field radiation therapy or a switch to an escalated therapy protocol, particularly in advanced-stage or unfavorable-risk patients. (18)F-FDG PET is a well-established surrogate for tumor chemosensitivity early during therapy. The ongoing PET-adaptive clinical trials are testing the hypothesis that a decision can reliably be made on escalating or deescalating therapy based on interim PET results. Discussed in this review is the integral role of interim (18)F-FDG PET in HL, challenges, critical issues to improve its accuracy, and the observations from completed interim PET studies and ongoing PET-adaptive clinical trials. PMID- 23818559 TI - Access to HIV drugs should be widened, says WHO. PMID- 23818558 TI - Analysis of the systematic reviews process in reports of network meta-analyses: methodological systematic review. AB - OBJECTIVE: To examine whether network meta-analyses, increasingly used to assess comparative effectiveness of healthcare interventions, follow the key methodological recommendations for reporting and conduct of systematic reviews. DESIGN: Methodological systematic review of reports of network meta-analyses. DATA SOURCES: Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Medline, and Embase, searched from inception to 12 July 2012. REVIEW METHODS: All network meta-analyses comparing clinical efficacy of three or more interventions based on randomised controlled trials, excluding meta-analyses with an open loop network of three interventions. We assessed the reporting of general characteristics and key methodological components of the systematic review process using two composite outcomes. For some components, if reporting was adequate, we assessed their conduct quality. RESULTS: Of 121 network meta analyses covering a wide range of medical areas, 100 (83%) assessed pharmacological interventions and 11 (9%) non-pharmacological interventions; 56 (46%) were published in journals with a high impact factor. The electronic search strategy for each database was not reported in 88 (73%) network meta-analyses; for 36 (30%), the primary outcome was not clearly identified. Overall, 61 (50%) network meta-analyses did not report any information regarding the assessment of risk of bias of individual studies, and 103 (85%) did not report any methods to assess the likelihood of publication bias. Overall, 87 (72%) network meta analyses did not report the literature search, searched only one database, did not search other sources, or did not report an assessment of risk of bias of individual studies. These methodological components did not differ by publication in a general or specialty journal or by public or private funding. CONCLUSIONS: Essential methodological components of the systematic review process-conducting a literature search and assessing risk of bias of individual studies-are frequently lacking in reports of network meta-analyses, even when published in journals with high impact factors. PMID- 23818547 TI - Pim2 is required for maintaining multiple myeloma cell growth through modulating TSC2 phosphorylation. AB - Multiple myeloma (MM) is the second most common hematologic malignancy. Despite recent treatment advances, it remains incurable. Here, we report that Pim2 kinase expression is highly elevated in MM cells and demonstrate that it is required for MM cell proliferation. Functional interference of Pim2 activity either by short hairpin RNAs or by a potent and selective small-molecule inhibitor leads to significant inhibition of MM cell proliferation. Pim inhibition results in a significant decrease of mammalian target of rapamycin C1 (mTOR-C1) activity, which is critical for cell proliferation. We identify TSC2, a negative regulator of mTOR-C1, as a novel Pim2 substrate and show that Pim2 directly phosphorylates TSC2 on Ser-1798 and relieves the suppression of TSC2 on mTOR-C1. These findings support Pim2 as a promising therapeutic target for MM and define a novel Pim2 TSC2-mTOR-C1 pathway that drives MM proliferation. PMID- 23818560 TI - Private medicine's real manifesto. PMID- 23818561 TI - A pain in the bottom. PMID- 23818562 TI - GP is suspended for failing to provide shared care for child over nine year period. PMID- 23818563 TI - Great Ormond Street Hospital gagged doctor who raised safety concerns. PMID- 23818564 TI - Educational "events" have only a small part in how doctors learn, conference is told. PMID- 23818565 TI - Peers call for UK to harness "enormous" potential of regenerative medicine. PMID- 23818566 TI - Prognostic impact of the extracapsular lymph node involvement on disease-free survival according to the 7th edition of American Joint Committee on Cancer Staging System. AB - OBJECTIVES: The 7th edition of American Joint Committee on Cancer (AJCC) staging system of oesophageal cancer and gastro-oesophageal junction has re-staged positive nodes into N1-3 according to the number of invaded lymph nodes (LNs). However, this new classification does not consider the potential negative impact of the extracapsular breakthrough on survival. This study aims at assessing prognosis according to whether LN involvement is intracapsular (ICLNI) or extracapsular (ECLNI) on disease-free survival (DFS) among the three sub-groups of LN-positive patients. METHODS: Four hundred and sixteen consecutive R0 patients who underwent transthoracic oesophagectomy for cancer between 1996 and 2011 were retrospectively re-classified using the latest AJCC TNM classification. Among them, 230 (55%) patients have received a neoadjuvant chemoradiotherapy. Prognostic impact of ICLNI and ECLNI on DFS was assessed according to their new LN status. Multivariate analysis was drawn to determine factors affecting DFS. RESULTS: Among the 416 patients, there were 138 (33%) patients with positive LN: 79 (57%) with ICLNI and 59 (43%) with ECLNI. The proportion of ECLNI was 21 of 73 (28%), 21 of 41 (51%) and 17 of 24 (70%) in N1, N2 and N3 patients, respectively. In N1 patients, median DFS was 48 months in ICLNI and 13 months in ECLNI (P = 0.068). In N2 patients, median DFS was 19 months in ICLNI and 9 months in ECLNI (P = 0.07). In N3 patients, median DFS was not reached in ICLNI and was 6 months in ECLNI (P = 0.002). On multivariate analysis, the ECLNI (P < 0.001, hazard ratio, HR: 2.51) and the post-T stage (P = 0.03, HR: 1.62) were the two independent factors affecting DFS. CONCLUSIONS: Based on our limited study population, the existence of an ECLNI seems to have an additive negative impact on DFS, regardless of the pN stage. This suggests that extracapsular breakthrough status should be added to the new TNM staging system. This information has to be validated by further investigations. PMID- 23818567 TI - No ring at all in mitral valve repair: indications, techniques and long-term outcome. AB - OBJECTIVES: In mitral valve (MV) repair, we adhere to a biological concept of preservation of the native valves and avoidance of any prosthetic materials except for sutures whenever possible. Untreated autologous pericardium is the biological tissue of choice we use to support the repair. We report our 25-year institutional experience with no-ring MV repair in terms of indications, repair techniques and long-term results. METHODS: Patients with ruptured chordae or posterior leaflet prolapse from degenerative MV disease, active infective endocarditis (IE), ischaemic mitral incompetence (IMI), annular dilatation with or without ruptured chordae along the posterior leaflet, and various lesions of the MV and its subvalvar apparatus underwent suture-repair techniques tailored to their valve morphology. These are personal series of modified Gerbode-Hetzer posterior leaflet plication and modified Paneth-Hetzer posterior annulus shortening techniques. Indications for the use of each technique and technical details are described in this report. RESULTS: Modified Gerbode-Hetzer posterior leaflet plication: mean duration of the follow-up is 15.84+/-0.58 years. Overall freedoms from reoperation and cumulative survival rate are 55.4+/-4.7 and 44.7+/ 5.4%, respectively. Freedom from reoperation is 83.5+/-4.3%, in ruptured chordae from degenerative disease (n=161), 74.4+/-10.1% in active infectious endocarditis (IE) (n=22) and 100% from both ruptured chordae of ischaemic origin (n=10) and deceleration trauma (n=1), respectively. Likewise, freedoms from reoperation at a mean duration of the follow-up of 11.2+/-7.2 years in 62 children stratified based on age groups are: <3 months: 61.4+/-2.7%; 3 months to 2 years: 78.7+/ 3.7%; 2-18 years: 97.1+/-2.4%. Modified Paneth-Hetzer posterior annulus shortening: Mean duration of the follow-up is 11.98+/-1.14 years. Overall freedoms from reoperation and cumulative survival rate in 179 patients are 82.95+/-4.1 and 63.4+/-8.5%, respectively. Freedom from reoperation is 85.9+/ 13.9% in patients with annular dilatation from any form of cardiomyopathy (n=81), 78.4+/-5.6% in those with IMI (n=75) and 100% in those who underwent asymmetric valve repair (n=23). In IMI, mean New York Heart Association functional class, ejection fraction and degree of mitral incompetence (MI) were significantly abated (P=0.001). In 78 children, freedoms from reoperation at a mean duration of the follow-up of 11.2+/-7.2 years stratified based on age groups are as follows: <3 months: 82.79+/-3.5%; 3 months to 2 years: 71.6+/-5.3%; 2-18 years: 85.1+/ 4.4%. CONCLUSIONS: No-ring MV repair using the aforementioned techniques in patients with MI resulting from chordal rupture, degenerative valve disease, IE, annular dilatation and posterior leaflet prolapse and from IMI as well as various MV lesions in children offers excellent long-term functional results with satisfactory freedom from reoperation. PMID- 23818568 TI - Assessment of aortic valve pressure overload and leaflet functions in an ex vivo beating heart loaded with a continuous flow cardiac assist device. AB - OBJECTIVES: Aortic valve regurgitation, fusion and thrombosis are commonly reported clinical complications after continuous flow ventricular assist device implantations; however, the complex interaction between reduced pulsatile flow physiology and aortic valve functions has not been studied experimentally. To address this, a continuous flow left ventricular assist device was implanted in four swine ex vivo beating hearts and then operated at baseline (device off, no flow) and at device speeds ranging between 8500 and 11,500 rpm under healthy and experimentally created failing heart conditions. METHODS: At baseline and after each speed increase, aortic, left ventricular, left atrial and pulse pressure signals were monitored to assess the haemodynamic status of the ex vivo heart, aortic valve opening time and the transvalvular pressure changes. Aortic root and device flows were recorded with flow probes. Left ventricular pressure-volume loops were measured with a conductance catheter. Changes in aortic leaflet motion and end-diastolic aortic root diameter were recorded with epicardial echocardiography. RESULTS: A two-chamber healthy and failing ex vivo beating heart model was successfully created. At increasing device flows, aortic valve open time steadily decreased from 36+/-7% of the baseline cardiac cycle to 0% at 11,500 rpm in the healthy heart and from 18+/-16 to 0% in failing heart mode (P<0.05). Aortic transvalvular pressure increased from 25+/-5 mmHg (baseline) to 67+/-7 mmHg (11,500 rpm) in the healthy heart and from 10+/-9 mmHg (baseline) to 73+/-8 mmHg (11,500 rpm) in failing heart mode (P<0.05). Aortic root diameters were significantly increased at speeds exceeding 10 500 rpm in the healthy heart mode (P<0.05 vs baseline) and approached statistical significance in failing hearts. CONCLUSIONS: Increasing assist device flows resulted in pressure overload above the aortic leaflets, impaired leaflet functions, caused aortic root dilatation and altered leaflet coaptation at the central portion of the aortic valve in both modes. We conclude that the deleterious effect of the reduced pulsatile flow on the aortic valve functions and haemodynamics is immediate and such an insult may explain the structural changes of the aortic valve causing leaflet fusion and/or regurgitation in the chronic phase. PMID- 23818569 TI - Results of rapid-response extracorporeal cardiopulmonary resuscitation in children with refractory cardiac arrest following cardiac surgery. AB - OBJECTIVES: Survival of children having cardiac arrest refractory to conventional cardiopulmonary resuscitation (CPR) is very poor. We sought to examine current era outcomes of extracorporeal CPR (ECPR) support for refractory arrest following surgical correction of congenital heart disease. METHODS: Demographic, anatomical, clinical, surgical and support details of children requiring postoperative ECPR (2007-12) were included in multivariable logistic regression models to determine the factors associated with survival. RESULTS: Thirty-nine children, median age 44 days (4 days-10 years), required postoperative ECPR at a median interval of 1 day (up to 15 days) after surgery. Thirteen (33%) children had single-ventricle pathology; Risk Adjustment in Congenital Heart Surgery (RACHS)-1 categories were 2, 3, 4 and 6 in 6, 15, 13 and 5 patients, respectively. Median CPR duration was 34 (8-125) min, while median support duration was 4 (1-17) days. Seven (18%) patients underwent cardiac re-operation, 28 (72%) survived >24 h after support discontinuation and 16 (41%) survived. Survival rates in neonates, infants and older children were 53, 39 and 17% (P=0.13). Survival rates for single- vs two-ventricle pathology patients were 54 and 35%, (P=0.25) and 50, 47, 23 and 60% in RACHS-1 2, 3, 4 and 6 patients, respectively (P=0.37). Survivors had shorter CPR duration (25 vs 34 min, P=0.05), lower pre-arrest lactate (2.6 vs 4.6 mmol/l, P=0.05) and postextracorporeal membrane oxygenation (ECMO) peak lactate (15.4 vs 20.0 mmol/l, P<0.001). On multivariable analysis, factors associated with death were higher immediate post ECMO lactate (odds ratio, OR 1.34 per mmol/l, P=0.008) and renal failure requiring haemodialysis (OR 14.1, P=0.01). CONCLUSIONS: ECPR plays a valuable role in children having refractory postoperative cardiac arrest. Survival is unrelated to cardiac physiology or surgical complexity. Timely support prior to the emergence of end-organ injury and surgical correction of residual cardiac lesions might enhance survival. PMID- 23818570 TI - The Snoopy sign. PMID- 23818571 TI - Adverse results of a decellularized tissue-engineered pulmonary valve in humans assessed with magnetic resonance imaging. AB - OBJECTIVES: Matrix P(r) and Matrix P plus(r) tissue-engineered pulmonary valves (TEPV) were offered as an improvement for pulmonary valve replacement (PVR) because of recellularization by host cells. The high frequency of graft failure gave reason to evaluate the underlying morphological substrate using magnetic resonance imaging (MRI) and histology. METHODS: Between June 2006 and August 2008, 17 Matrix P(r) and 10 Matrix P plus(r) TEPVs were implanted in 26 patients with a median age of 12.4 (range: 0.8-38.7, interquartile range: 6.1-18.1) years. The grafts were studied by MRI, and underwent histological examination when explantation was required. RESULTS: Surgical (n = 13) or transcatheter (n = 1) TEPV replacement because of graft failure was needed in 14 cases (52%) 19 (0.5 53) months after implantation. MRI detected significant TEPV stenosis with mild insufficiency (V(max) = 3.7 +/- (standard deviation) 0.5 m/s, regurgitant fraction (RGF) = 10 +/- 3%) and stenosis with moderate-to-severe insufficiency (V(max) = 3.5 +/- 0.8 m/s, RGF = 38 +/- 10%) in 6 patients, respectively, and severe insufficiency (RGF = 40%) in 1 patient. In patients with graft failure, MRI showed hyperenhancement and TEPV wall thickening. Histology revealed severe inflammation, increased fibrous tissue and foreign-body reaction against valve leaflets and fascial tissue, while TEPV endothelialization was not detected in any case. CONCLUSIONS: The high frequency of Matrix P(r) and Matrix P plus(r) graft failure can be related to inflammation and fibrosis revealed by MRI and histology. Our results do not support the use of these valves for PVR and suggest careful follow-up examinations, including MRI for early detection of graft inflammation and fibrosis. PMID- 23818572 TI - Common gene pathways and families altered by DNA methylation in breast and prostate cancers. AB - Epigenetic modifications, such as DNA methylation, are widely studied in cancer as they are stable and easy to measure genome wide. DNA methylation changes have been used to differentiate benign from malignant tissue and to predict tumor recurrence or patient outcome. Multiple genome wide DNA methylation studies in breast and prostate cancers have identified genes that are differentially methylated in malignant tissue compared with non-malignant tissue or in association with hormone receptor status or tumor recurrence. Although this has identified potential biomarkers for diagnosis and prognosis, what is highlighted by reviewing these studies is the similarities between breast and prostate cancers. In particular, the gene families/pathways targeted by DNA methylation in breast and prostate cancers have significant overlap and include homeobox genes, zinc finger transcription factors, S100 calcium binding proteins, and potassium voltage-gated family members. Many of the gene pathways targeted by aberrant methylation in breast and prostate cancers are not targeted in other cancers, suggesting that some of these targets may be specific to hormonal cancers. Genome wide DNA methylation profiles in breast and prostate cancers will not only define more specific and sensitive biomarkers for cancer diagnosis and prognosis but also identify novel therapeutic targets, which may be direct targets of agents that reverse DNA methylation or which may target novel gene families that are themselves DNA methylation targets. PMID- 23818574 TI - Doctors in India defy guidelines on generic drugs. PMID- 23818573 TI - IGF2 revs the steroidogenesis engine. AB - Molecular understanding of how prostate cancers evade hormone therapy greatly increased over the last several years, and the realization that de novo steroidogenesis plays a significant role in tumor progression and therapeutic bypass has led to development of promising new therapeutics. In the April 2013 issue of Endocrine-Related Cancer, Lubik et al. revealed a new molecular pathway by which the IGF2 can ignite the de novo steroidogenesis engine and promote molecular events associated with tumor progression. PMID- 23818575 TI - US court ruling gives broad free speech protection to scientific articles. PMID- 23818576 TI - Dementia experts are optimistic despite decline in hope for effective drugs. PMID- 23818577 TI - Bomb-curve radiocarbon measurement of recent biologic tissues and applications to wildlife forensics and stable isotope (paleo)ecology. AB - Above-ground thermonuclear weapons testing from 1952 through 1962 nearly doubled the concentration of radiocarbon ((14)C) in the atmosphere. As a result, organic material formed during or after this period may be radiocarbon-dated using the abrupt rise and steady fall of the atmospheric (14)C concentration known as the bomb-curve. We test the accuracy of accelerator mass spectrometry radiocarbon dating of 29 herbivore and plant tissues collected on known dates between 1905 and 2008 in East Africa. Herbivore samples include teeth, tusks, soft tissue, hair, and horn. Tissues formed after 1955 are dated to within 0.3-1.3 y of formation, depending on the tissue type, whereas tissues older than ca. 1955 have high age uncertainties (>17 y) due to the Suess effect. (14)C dating of tissues has applications to stable isotope (paleo)ecology and wildlife forensics. We use data from 41 additional samples to determine growth rates of tusks, molars, and hair, which improve interpretations of serial stable isotope data for (paleo)ecological studies. (14)C dating can also be used to calculate the time interval represented in periodic histological structures in dental tissues (i.e., perikymata), which in turn may be used as chronometers in fossil teeth. Bomb curve (14)C dating of confiscated animal tissues (e.g., ivory statues) can be used to determine whether trade of the item is legal, because many Convention of International Trade of Endangered Species restrictions are based on the age of the tissue, and thus can serve as a powerful forensic tool to combat illegal trade in animal parts. PMID- 23818528 TI - The prediction of type 1 diabetes by multiple autoantibody levels and their incorporation into an autoantibody risk score in relatives of type 1 diabetic patients. AB - OBJECTIVE: We assessed whether a risk score that incorporates levels of multiple islet autoantibodies could enhance the prediction of type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: TrialNet Natural History Study participants (n = 784) were tested for three autoantibodies (GADA, IA-2A, and mIAA) at their initial screening. Samples from those positive for at least one autoantibody were subsequently tested for ICA and ZnT8A. An autoantibody risk score (ABRS) was developed from a proportional hazards model that combined autoantibody levels from each autoantibody along with their designations of positivity and negativity. RESULTS: The ABRS was strongly predictive of T1D (hazard ratio [with 95% CI] 2.72 [2.23-3.31], P < 0.001). Receiver operating characteristic curve areas (with 95% CI) for the ABRS revealed good predictability (0.84 [0.78-0.90] at 2 years, 0.81 [0.74-0.89] at 3 years, P < 0.001 for both). The composite of levels from the five autoantibodies was predictive of T1D before and after an adjustment for the positivity or negativity of autoantibodies (P < 0.001). The findings were almost identical when ICA was excluded from the risk score model. The combination of the ABRS and the previously validated Diabetes Prevention Trial-Type 1 Risk Score (DPTRS) predicted T1D more accurately (0.93 [0.88-0.98] at 2 years, 0.91 [0.83-0.99] at 3 years) than either the DPTRS or the ABRS alone (P <= 0.01 for all comparisons). CONCLUSIONS: These findings show the importance of considering autoantibody levels in assessing the risk of T1D. Moreover, levels of multiple autoantibodies can be incorporated into an ABRS that accurately predicts T1D. PMID- 23818578 TI - Skeletal muscle-specific T-tubule protein STAC3 mediates voltage-induced Ca2+ release and contractility. AB - Excitation-contraction (EC) coupling comprises events in muscle that convert electrical signals to Ca(2+) transients, which then trigger contraction of the sarcomere. Defects in these processes cause a spectrum of muscle diseases. We report that STAC3, a skeletal muscle-specific protein that localizes to T tubules, is essential for coupling membrane depolarization to Ca(2+) release from the sarcoplasmic reticulum (SR). Consequently, homozygous deletion of src homology 3 and cysteine rich domain 3 (Stac3) in mice results in complete paralysis and perinatal lethality with a range of musculoskeletal defects that reflect a blockade of EC coupling. Muscle contractility and Ca(2+) release from the SR of cultured myotubes from Stac3 mutant mice could be restored by application of 4-chloro-m-cresol, a ryanodine receptor agonist, indicating that the sarcomeres, SR Ca(2+) store, and ryanodine receptors are functional in Stac3 mutant skeletal muscle. These findings reveal a previously uncharacterized, but required, component of the EC coupling machinery of skeletal muscle and introduce a candidate for consideration in myopathic disorders. PMID- 23818579 TI - Phase separation explains a new class of self-organized spatial patterns in ecological systems. AB - The origin of regular spatial patterns in ecological systems has long fascinated researchers. Turing's activator-inhibitor principle is considered the central paradigm to explain such patterns. According to this principle, local activation combined with long-range inhibition of growth and survival is an essential prerequisite for pattern formation. Here, we show that the physical principle of phase separation, solely based on density-dependent movement by organisms, represents an alternative class of self-organized pattern formation in ecology. Using experiments with self-organizing mussel beds, we derive an empirical relation between the speed of animal movement and local animal density. By incorporating this relation in a partial differential equation, we demonstrate that this model corresponds mathematically to the well-known Cahn-Hilliard equation for phase separation in physics. Finally, we show that the predicted patterns match those found both in field observations and in our experiments. Our results reveal a principle for ecological self-organization, where phase separation rather than activation and inhibition processes drives spatial pattern formation. PMID- 23818581 TI - Human placental trophoblasts confer viral resistance to recipient cells. AB - Placental trophoblasts form the interface between the fetal and maternal environments and serve to limit the maternal-fetal spread of viruses. Here we show that cultured primary human placental trophoblasts are highly resistant to infection by a number of viruses and, importantly, confer this resistance to nonplacental recipient cells by exosome-mediated delivery of specific microRNAs (miRNAs). We show that miRNA members of the chromosome 19 miRNA cluster, which are almost exclusively expressed in the human placenta, are packaged within trophoblast-derived exosomes and attenuate viral replication in recipient cells by the induction of autophagy. Together, our findings identify an unprecedented paracrine and/or systemic function of placental trophoblasts that uses exosome mediated transfer of a unique set of placental-specific effector miRNAs to directly communicate with placental or maternal target cells and regulate their immunity to viral infections. PMID- 23818583 TI - Large population solution of the stochastic Luria-Delbruck evolution model. AB - Luria and Delbruck introduced a very useful and subsequently widely adopted framework for quantitatively understanding the emergence of new cellular lineages. Here, we provide an analytical treatment of the fully stochastic version of the model, enabled by the fact that population sizes at the time of measurement are invariably very large and mutation rates are low. We show that the Lea-Coulson generating function describes the "inner solution," where the number of mutants is much smaller than the total population. We find that the corresponding distribution function interpolates between a monotonic decrease at relatively small populations, (compared with the inverse of the mutation probability), whereas it goes over to a Levy alpha-stable distribution in the very large population limit. The moments are completely determined by the outer solution, and so are devoid of practical significance. The key to our solution is focusing on the fixed population size ensemble, which we show is very different from the fixed time ensemble due to the extreme variability in the evolutionary process. PMID- 23818580 TI - Inverse modulation of plant immune and brassinosteroid signaling pathways by the receptor-like cytoplasmic kinase BIK1. AB - Maintaining active growth and effective immune responses is often costly for a living organism to survive. Fine-tuning the shared cross-regulators is crucial for metazoans and plants to make a trade-off between growth and immunity. The Arabidopsis regulatory receptor-like kinase BAK1 complexes with the receptor kinases FLS2 in bacterial flagellin-triggered immunity and BRI1 in brassinosteroid (BR)-mediated growth. BR homeostasis and signaling unidirectionally modulate FLS2-mediated immune responses at multiple levels. We have shown previously that BIK1, a receptor-like cytoplasmic kinase, is directly phosphorylated by BAK1 and associates with FLS2/BAK1 complex in transducing flagellin signaling. In contrast to its positive role in plant immunity, we report here that BIK1 acts as a negative regulator in BR signaling. The bik1 mutant displays various BR hypersensitive phenotypes accompanied with increased accumulation of de-phosphorylated BES1 proteins and transcriptional regulation of BZR1 and BES1 target genes. BIK1 associates with BRI1, and is released from BRI1 receptor upon BR treatment, which is reminiscent of FLS2-BIK1 complex dynamics in flagellin signaling. The ligand-induced release of BIK1 from receptor complexes is associated with BIK1 phosphorylation. However, in contrast to BAK1-dependent FLS2-BIK1 dissociation, BAK1 is dispensable for BRI1-BIK1 dissociation. Unlike FLS2 signaling which depends on BAK1 to phosphorylate BIK1, BRI1 directly phosphorylates BIK1 to transduce BR signaling. Thus, BIK1 relays the signaling in plant immunity and BR-mediated growth via distinct phosphorylation by BAK1 and BRI1, respectively. Our studies indicate that BIK1 mediates inverse functions in plant immunity and development via dynamic association with specific receptor complexes and differential phosphorylation events. PMID- 23818582 TI - Nutrient enrichment, biodiversity loss, and consequent declines in ecosystem productivity. AB - Anthropogenic drivers of environmental change often have multiple effects, including changes in biodiversity, species composition, and ecosystem functioning. It remains unknown whether such shifts in biodiversity and species composition may, themselves, be major contributors to the total, long-term impacts of anthropogenic drivers on ecosystem functioning. Moreover, although numerous experiments have shown that random losses of species impact the functioning of ecosystems, human-caused losses of biodiversity are rarely random. Here we use results from long-term grassland field experiments to test for direct effects of chronic nutrient enrichment on ecosystem productivity, and for indirect effects of enrichment on productivity mediated by resultant species losses. We found that ecosystem productivity decreased through time most in plots that lost the most species. Chronic nitrogen addition also led to the nonrandom loss of initially dominant native perennial C4 grasses. This loss of dominant plant species was associated with twice as great a loss of productivity per lost species than occurred with random species loss in a nearby biodiversity experiment. Thus, although chronic nitrogen enrichment initially increased productivity, it also led to loss of plant species, including initially dominant species, which then caused substantial diminishing returns from nitrogen fertilization. In contrast, elevated CO2 did not decrease grassland plant diversity, and it consistently promoted productivity over time. Our results support the hypothesis that the long-term impacts of anthropogenic drivers of environmental change on ecosystem functioning can strongly depend on how such drivers gradually decrease biodiversity and restructure communities. PMID- 23818584 TI - Earliest floral grave lining from 13,700-11,700-y-old Natufian burials at Raqefet Cave, Mt. Carmel, Israel. AB - Flowering plants possess mechanisms that stimulate positive emotional and social responses in humans. It is difficult to establish when people started to use flowers in public and ceremonial events because of the scarcity of relevant evidence in the archaeological record. We report on uniquely preserved 13,700 11,700-y-old grave linings made of flowers, suggesting that such use began much earlier than previously thought. The only potentially older instance is the questionable use of flowers in the Shanidar IV Neanderthal grave. The earliest cemeteries (ca. 15,000-11,500 y ago) in the Levant are known from Natufian sites in northern Israel, where dozens of burials reflect a wide range of inhumation practices. The newly discovered flower linings were found in four Natufian graves at the burial site of Raqefet Cave, Mt. Carmel, Israel. Large identified plant impressions in the graves include stems of sage and other Lamiaceae (Labiatae; mint family) or Scrophulariaceae (figwort family) species; accompanied by a plethora of phytoliths, they provide the earliest direct evidence now known for such preparation and decoration of graves. Some of the plant species attest to spring burials with a strong emphasis on colorful and aromatic flowers. Cave floor chiseling to accommodate the desired grave location and depth is also evident at the site. Thus, grave preparation was a sophisticated planned process, embedded with social and spiritual meanings reflecting a complex preagricultural society undergoing profound changes at the end of the Pleistocene. PMID- 23818585 TI - The mTOR pathway negatively controls ATM by up-regulating miRNAs. AB - The ataxia telangiectasia mutated (ATM) checkpoint is the central surveillance system that maintains genome integrity. We found that in the context of childhood sarcoma, mammalian target of rapamycin (mTOR) signaling suppresses ATM by up regulating miRNAs targeting ATM. Pharmacological inhibition or genetic down regulation of the mTOR pathway resulted in increase of ATM mRNA and protein both in mouse sarcoma xenografts and cultured cells. mTOR Complex 1 (mTORC1) suppresses ATM via S6K1/2 signaling pathways. microRNA-18a and microRNA-421, both of which target ATM, are positively controlled by mTOR signaling. Our findings have identified a negative feedback loop for the signaling between ATM and mTOR pathways and suggest that oncogenic growth signals may promote tumorigenesis by dampening the ATM checkpoint. PMID- 23818586 TI - Identification of a MU-delta opioid receptor heteromer-biased agonist with antinociceptive activity. AB - G protein-coupled receptors play a pivotal role in many physiological signaling pathways. Mounting evidence suggests that G protein-coupled receptors, including opioid receptors, form dimers, and dimerization is necessary for receptor maturation, signaling, and trafficking. However, the physiological role of dimerization in vivo has not been well-explored because of the lack of tools to study these dimers in endogenous systems. To address this problem, we previously generated antibodies to MU-delta opioid receptor (MUOR-deltaOR) dimers and used them to study the pharmacology and signaling by this heteromer. We also showed that the heteromer exhibits restricted distribution in the brain and that its abundance is increased in response to chronic morphine administration. Thus, the MUOR-deltaOR heteromer represents a potentially unique target for the development of therapeutics to treat pain. Here, we report the identification of compounds targeting MUOR-deltaOR heteromers through high-throughput screening of a small molecule library. These compounds exhibit activity in MUOR-deltaOR cells but not MUOR or deltaOR cells alone. Among them, CYM51010 was found to be a MUOR-deltaOR biased ligand, because its activity is blocked by the MUOR-deltaOR heteromer antibody. Notably, systemic administration of CYM51010 induced antinociceptive activity similar to morphine, and chronic administration of CYM51010 resulted in lesser antinociceptive tolerance compared with morphine. Taken together, these results suggest that CYM51010, a MUOR-deltaOR-biased ligand, could serve as a scaffold for the development of a unique type (heteromer-biased) of drug that is more potent and without the severe side effects associated with conventional clinical opioids. PMID- 23818587 TI - Dysregulation of PAD4-mediated citrullination of nuclear GSK3beta activates TGF beta signaling and induces epithelial-to-mesenchymal transition in breast cancer cells. AB - Peptidylarginine deiminase 4 (PAD4) is a Ca(2+)-dependent enzyme that converts arginine and methylarginine residues to citrulline, with histone proteins being among its best-described substrates to date. However, the biological function of this posttranslational modification, either in histones or in nonhistone proteins, is poorly understood. Here, we show that PAD4 recognizes, binds, and citrullinates glycogen synthase kinase-3beta (GSK3beta), both in vitro and in vivo. Among other functions, GSK3beta is a key regulator of transcription factors involved in tumor progression, and its dysregulation has been associated with progression of human cancers. We demonstrate that silencing of PAD4 in breast cancer cells leads to a striking reduction of nuclear GSK3beta protein levels, increased TGF-beta signaling, induction of epithelial-to-mesenchymal transition, and production of more invasive tumors in xenograft assays. Moreover, in breast cancer patients, reduction of PAD4 and nuclear GSK3beta is associated with increased tumor invasiveness. We propose that PAD4-mediated citrullination of GSK3beta is a unique posttranslational modification that regulates its nuclear localization and thereby plays a critical role in maintaining an epithelial phenotype. We demonstrate a dynamic and previously unappreciated interplay between histone-modifying enzymes, citrullination of nonhistone proteins, and epithelial-to-mesenchymal transition. PMID- 23818588 TI - Mn(II,III) oxidation and MnO2 mineralization by an expressed bacterial multicopper oxidase. AB - Reactive Mn(IV) oxide minerals are ubiquitous in the environment and control the bioavailability and distribution of many toxic and essential elements and organic compounds. Their formation is thought to be dependent on microbial enzymes, because spontaneous Mn(II) to Mn(IV) oxidation is slow. Several species of marine Bacillus spores oxidize Mn(II) on their exosporium, the outermost layer of the spore, encrusting them with Mn(IV) oxides. Molecular studies have identified the mnx (Mn oxidation) genes, including mnxG, encoding a putative multicopper oxidase (MCO), as responsible for this two-electron oxidation, a surprising finding because MCOs only catalyze single-electron transfer reactions. Characterization of the enzymatic mechanism has been hindered by the lack of purified protein. By purifying active protein from the mnxDEFG expression construct, we found that the resulting enzyme is a blue (absorption maximum 590 nm) complex containing MnxE, MnxF, and MnxG proteins. Further, by analyzing the Mn(II)- and (III)-oxidizing activity in the presence of a Mn(III) chelator, pyrophosphate, we found that the complex facilitates both electron transfers from Mn(II) to Mn(III) and from Mn(III) to Mn(IV). X-ray absorption spectroscopy of the Mn mineral product confirmed its similarity to Mn(IV) oxides generated by whole spores. Our results demonstrate that Mn oxidation from soluble Mn(II) to Mn(IV) oxides is a two-step reaction catalyzed by an MCO-containing complex. With the purification of active Mn oxidase, we will be able to uncover its mechanism, broadening our understanding of Mn mineral formation and the bioinorganic capabilities of MCOs. PMID- 23818589 TI - Importance of trivalency and the e(g)(1) configuration in the photocatalytic oxidation of water by Mn and Co oxides. AB - Prompted by the early results on the catalytic activity of LiMn2O4 and related oxides in the photochemical oxidation of water, our detailed study of several manganese oxides has shown that trivalency of Mn is an important factor in determining the catalytic activity. Thus, Mn2O3, LaMnO3, and MgMn2O4 are found to be very good catalysts with turnover frequencies of 5 * 10(-4) s(-1), 4.8 * 10( 4) s(-1), and 0.8 * 10(-4) s(-1), respectively. Among the cobalt oxides, Li2Co2O4 and LaCoO3--especially the latter--exhibit excellent catalytic activity, with the turnover frequencies being 9 * 10(-4) s(-1) and 1.4 * 10(-3) s(-1), respectively. The common feature among the catalytic Mn and Co oxides is not only that Mn and Co are in the trivalent state, but Co(3+) in the Co oxides is in the intermediate t2g(5)e(g)(1) state whereas Mn(3+) is in the t2g(3e(g)(1) state. The presence of the e(g)(1) electron in these Mn and Co oxides is considered to play a crucial role in the photocatalytic properties of the oxides. PMID- 23818590 TI - Regulation of ubiquitin-dependent cargo sorting by multiple endocytic adaptors at the plasma membrane. AB - Endocytic protein trafficking is directed by sorting signals on cargo molecules that are recognized by cytosolic adaptor proteins. However, the steps necessary to segregate the variety of cargoes during endocytosis remain poorly defined. Using Caenorhabditis elegans, we demonstrate that multiple plasma membrane endocytic adaptors function redundantly to regulate clathrin-mediated endocytosis and to recruit components of the endosomal sorting complex required for transport (ESCRT) machinery to the cell surface to direct the sorting of ubiquitin-modified substrates. Moreover, our data suggest that preassembly of cargoes with the ESCRT 0 complex at the plasma membrane enhances the efficiency of downstream sorting events in the endolysosomal system. In the absence of a heterooligomeric adaptor complex composed of FCHO, Eps15, and intersectin, ESCRT-0 accumulation at the cell surface is diminished, and the degradation of a ubiquitin-modified cargo slows significantly without affecting the rate of its clathrin-mediated internalization. Consistent with a role for the ESCRT machinery during cargo endocytosis, we further show that the ESCRT-0 complex accumulates at a subset of clathrin-coated pits on the surface of human cells. Our findings suggest a unique mechanism by which ubiquitin-modified cargoes are sequestered into the endolysosomal pathway. PMID- 23818591 TI - Family-based training program improves brain function, cognition, and behavior in lower socioeconomic status preschoolers. AB - Using information from research on the neuroplasticity of selective attention and on the central role of successful parenting in child development, we developed and rigorously assessed a family-based training program designed to improve brain systems for selective attention in preschool children. One hundred forty-one lower socioeconomic status preschoolers enrolled in a Head Start program were randomly assigned to the training program, Head Start alone, or an active control group. Electrophysiological measures of children's brain functions supporting selective attention, standardized measures of cognition, and parent-reported child behaviors all favored children in the treatment program relative to both control groups. Positive changes were also observed in the parents themselves. Effect sizes ranged from one-quarter to half of a standard deviation. These results lend impetus to the further development and broader implementation of evidence-based education programs that target at-risk families. PMID- 23818592 TI - Formation of hexagonal and cubic ice during low-temperature growth. AB - From our daily life we are familiar with hexagonal ice, but at very low temperature ice can exist in a different structure--that of cubic ice. Seeking to unravel the enigmatic relationship between these two low-pressure phases, we examined their formation on a Pt(111) substrate at low temperatures with scanning tunneling microscopy and atomic force microscopy. After completion of the one molecule-thick wetting layer, 3D clusters of hexagonal ice grow via layer nucleation. The coalescence of these clusters creates a rich scenario of domain boundary and screw-dislocation formation. We discovered that during subsequent growth, domain boundaries are replaced by growth spirals around screw dislocations, and that the nature of these spirals determines whether ice adopts the cubic or the hexagonal structure. Initially, most of these spirals are single, i.e., they host a screw dislocation with a Burgers vector connecting neighboring molecular planes, and produce cubic ice. Films thicker than ~20 nm, however, are dominated by double spirals. Their abundance is surprising because they require a Burgers vector spanning two molecular-layer spacings, distorting the crystal lattice to a larger extent. We propose that these double spirals grow at the expense of the initially more common single spirals for an energetic reason: they produce hexagonal ice. PMID- 23818593 TI - Stoichiometry of SecYEG in the active translocase of Escherichia coli varies with precursor species. AB - We have established a reconstitution system for the translocon SecYEG in proteoliposomes in which 55% of the accessible translocons are active. This level corresponds to the fraction of translocons that are active in vitro when assessed in their native environment of cytoplasmic membrane vesicles. Assays using these robust reconstituted proteoliposomes and cytoplasmic membrane vesicles have revealed that the number of SecYEG units involved in an active translocase depends on the precursor undergoing transfer. The active translocase for the precursor of periplasmic galactose-binding protein contains twice the number of heterotrimeric units of SecYEG as does that for the precursor of outer membrane protein A. PMID- 23818594 TI - EGF shifts human airway basal cell fate toward a smoking-associated airway epithelial phenotype. AB - The airway epithelium of smokers acquires pathological phenotypes, including basal cell (BC) and/or goblet cell hyperplasia, squamous metaplasia, structural and functional abnormalities of ciliated cells, decreased number of secretoglobin (SCGB1A1)-expressing secretory cells, and a disordered junctional barrier. In this study, we hypothesized that smoking alters airway epithelial structure through modification of BC function via an EGF receptor (EGFR)-mediated mechanism. Analysis of the airway epithelium revealed that EGFR is enriched in airway BCs, whereas its ligand EGF is induced by smoking in ciliated cells. Exposure of BCs to EGF shifted the BC differentiation program toward the squamous and epithelial-mesenchymal transition-like phenotypes with down-regulation of genes related to ciliogenesis, secretory differentiation, and markedly reduced junctional barrier integrity, mimicking the abnormalities present in the airways of smokers in vivo. These data suggest that activation of EGFR in airway BCs by smoking-induced EGF represents a unique mechanism whereby smoking can alter airway epithelial differentiation and barrier function. PMID- 23818595 TI - MST1 functions as a key modulator of neurodegeneration in a mouse model of ALS. AB - Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder characterized by loss of motor neurons. Dominant mutations in the gene for superoxide dismutase 1 (SOD1) give rise to familial ALS by an unknown mechanism. Here we show that genetic deficiency of mammalian sterile 20-like kinase 1 (MST1) delays disease onset and extends survival in mice expressing the ALS-associated G93A mutant of human SOD1. SOD1(G93A) induces dissociation of MST1 from a redox protein thioredoxin-1 and promotes MST1 activation in spinal cord neurons in a reactive oxygen species-dependent manner. Moreover, MST1 was found to mediate SOD1(G93A)-induced activation of p38 mitogen-activated protein kinase and caspases as well as impairment of autophagy in spinal cord motoneurons of SOD1(G93A) mice. Our findings implicate MST1 as a key determinant of neurodegeneration in ALS. PMID- 23818596 TI - LNK genes integrate light and clock signaling networks at the core of the Arabidopsis oscillator. AB - Light signaling pathways and the circadian clock interact to help organisms synchronize physiological and developmental processes with periodic environmental cycles. The plant photoreceptors responsible for clock resetting have been characterized, but signaling components that link the photoreceptors to the clock remain to be identified. Here we describe a family of night light-inducible and clock-regulated genes (LNK) that play a key role linking light regulation of gene expression to the control of daily and seasonal rhythms in Arabidopsis thaliana. A genomewide transcriptome analysis revealed that most light-induced genes respond more strongly to light during the subjective day, which is consistent with the diurnal nature of most physiological processes in plants. However, a handful of genes, including the homologous genes LNK1 and LNK2, are more strongly induced by light in the middle of the night, when the clock is most responsive to this signal. Further analysis revealed that the morning phased LNK1 and LNK2 genes control circadian rhythms, photomorphogenic responses, and photoperiodic dependent flowering, most likely by regulating a subset of clock and flowering time genes in the afternoon. LNK1 and LNK2 themselves are directly repressed by members of the TIMING OF CAB1 EXPRESSION/PSEUDO RESPONSE REGULATOR family of core clock genes in the afternoon and early night. Thus, LNK1 and LNK2 integrate early light signals with temporal information provided by core oscillator components to control the expression of afternoon genes, allowing plants to keep track of seasonal changes in day length. PMID- 23818597 TI - Nicotinic alpha7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex. AB - The cognitive function of the highly evolved dorsolateral prefrontal cortex (dlPFC) is greatly influenced by arousal state, and is gravely afflicted in disorders such as schizophrenia, where there are genetic insults in alpha7 nicotinic acetylcholine receptors (alpha7-nAChRs). A recent behavioral study indicates that ACh depletion from dlPFC markedly impairs working memory [Croxson PL, Kyriazis DA, Baxter MG (2011) Nat Neurosci 14(12):1510-1512]; however, little is known about how alpha7-nAChRs influence dlPFC cognitive circuits. Goldman Rakic [Goldman-Rakic (1995) Neuron 14(3):477-485] discovered the circuit basis for working memory, whereby dlPFC pyramidal cells excite each other through glutamatergic NMDA receptor synapses to generate persistent network firing in the absence of sensory stimulation. Here we explore alpha7-nAChR localization and actions in primate dlPFC and find that they are enriched in glutamate network synapses, where they are essential for dlPFC persistent firing, with permissive effects on NMDA receptor actions. Blockade of alpha7-nAChRs markedly reduced, whereas low-dose stimulation selectively enhanced, neuronal representations of visual space. These findings in dlPFC contrast with the primary visual cortex, where nAChR blockade had no effect on neuronal firing [Herrero JL, et al. (2008) Nature 454(7208):1110-1114]. We additionally show that alpha7-nAChR stimulation is needed for NMDA actions, suggesting that it is key for the engagement of dlPFC circuits. As ACh is released in cortex during waking but not during deep sleep, these findings may explain how ACh shapes differing mental states during wakefulness vs. sleep. The results also explain why genetic insults to alpha7 nAChR would profoundly disrupt cognitive experience in patients with schizophrenia. PMID- 23818598 TI - Genetic loss or pharmacological blockade of testes-expressed taste genes causes male sterility. AB - TAS1R taste receptors and their associated heterotrimeric G protein gustducin are involved in sugar and amino acid sensing in taste cells and in the gastrointestinal tract. They are also strongly expressed in testis and sperm, but their functions in these tissues were previously unknown. Using mouse models, we show that the genetic absence of both TAS1R3, a component of sweet and amino acid taste receptors, and the gustducin alpha-subunit GNAT3 leads to male-specific sterility. To gain further insight into this effect, we generated a mouse model that expressed a humanized form of TAS1R3 susceptible to inhibition by the antilipid medication clofibrate. Sperm formation in animals without functional TAS1R3 and GNAT3 is compromised, with malformed and immotile sperm. Furthermore, clofibrate inhibition of humanized TAS1R3 in the genetic background of Tas1r3(-/ ), Gnat3(-/-) doubly null mice led to inducible male sterility. These results indicate a crucial role for these extraoral "taste" molecules in sperm development and maturation. We previously reported that blocking of human TAS1R3, but not mouse TAS1R3, can be achieved by common medications or chemicals in the environment. We hypothesize that even low levels of these compounds can lower sperm count and negatively affect human male fertility, which common mouse toxicology assays would not reveal. Conversely, we speculate that TAS1R3 and GNAT3 activators may help infertile men, particularly those that are affected by some of the mentioned inhibitors and/or are diagnosed with idiopathic infertility involving signaling pathway of these receptors. PMID- 23818599 TI - Real-time observation of fluctuations at the driven-dissipative Dicke phase transition. AB - We experimentally study the influence of dissipation on the driven Dicke quantum phase transition, realized by coupling external degrees of freedom of a Bose Einstein condensate to the light field of a high-finesse optical cavity. The cavity provides a natural dissipation channel, which gives rise to vacuum-induced fluctuations and allows us to observe density fluctuations of the gas in real time. We monitor the divergence of these fluctuations over two orders of magnitude while approaching the phase transition, and observe a behavior that deviates significantly from that expected for a closed system. A correlation analysis of the fluctuations reveals the diverging time scale of the atomic dynamics and allows us to extract a damping rate for the external degree of freedom of the atoms. We find good agreement with our theoretical model including dissipation via both the cavity field and the atomic field. Using a dissipation channel to nondestructively gain information about a quantum many-body system provides a unique path to study the physics of driven-dissipative systems. PMID- 23818600 TI - Body wall development in lamprey and a new perspective on the origin of vertebrate paired fins. AB - Classical hypotheses regarding the evolutionary origin of paired appendages propose transformation of precursor structures (gill arches and lateral fin folds) into paired fins. During development, gnathostome paired appendages form as outgrowths of body wall somatopleure, a tissue composed of somatic lateral plate mesoderm (LPM) and overlying ectoderm. In amniotes, LPM contributes connective tissue to abaxial musculature and forms ventrolateral dermis of the interlimb body wall. The phylogenetic distribution of this character is uncertain because lineage analyses of LPM have not been generated in anamniotes. We focus on the evolutionary history of the somatopleure to gain insight into the tissue context in which paired fins first appeared. Lampreys diverged from other vertebrates before the acquisition of paired fins and provide a model for investigating the preappendicular condition. We present vital dye fate maps that suggest the somatopleure is eliminated in lamprey as the LPM is separated from the ectoderm and sequestered to the coelomic linings during myotome extension. We also examine the distribution of postcranial mesoderm in catshark and axolotl. In contrast to lamprey, our findings support an LPM contribution to the trunk body wall of these taxa, which is similar to published data for amniotes. Collectively, these data lead us to hypothesize that a persistent somatopleure in the lateral body wall is a gnathostome synapomorphy, and the redistribution of LPM was a key step in generating the novel developmental module that ultimately produced paired fins. These embryological criteria can refocus arguments on paired fin origins and generate hypotheses testable by comparative studies on the source, sequence, and extent of genetic redeployment. PMID- 23818601 TI - A thioredoxin-like/beta-propeller protein maintains the efficiency of light harvesting in Arabidopsis. AB - The light-harvesting complexes of plants have evolved the ability to switch between efficient light harvesting and quenching forms to optimize photosynthesis in response to the environment. Several distinct mechanisms, collectively termed "nonphotochemical quenching" (NPQ), provide flexibility in this response. Here we report the isolation and characterization of a mutant, suppressor of quenching 1 (soq1), that has high NPQ even in the absence of photosystem II subunit S (PsbS), a protein that is necessary for the rapidly reversible component of NPQ. The formation of NPQ in soq1 was light intensity-dependent, and it exhibited slow relaxation kinetics and other characteristics that distinguish it from known NPQ components. Treatment with chemical inhibitors or an uncoupler, as well as crosses to mutants known to affect other NPQ components, showed that the NPQ in soq1 does not require a transthylakoid pH gradient, zeaxanthin formation, or the phosphorylation of light-harvesting complexes, and it appears to be unrelated to the photosystem II damage-and-repair cycle. Measurements of pigments and chlorophyll fluorescence lifetimes indicated that the additional NPQ in soq1 is the result of a decrease in chlorophyll excited-state lifetime and not pigment bleaching. The SOQ1 gene was isolated by map-based cloning, and it encodes a previously uncharacterized thylakoid membrane protein with thioredoxin-like and beta-propeller domains located in the lumen and a haloacid-dehalogenase domain exposed to the chloroplast stroma. We propose that the role of SOQ1 is to prevent formation of a slowly reversible form of antenna quenching, thereby maintaining the efficiency of light harvesting. PMID- 23818603 TI - Quorum sensing allows T cells to discriminate between self and nonself. AB - T cells orchestrate pathogen-specific adaptive immune responses by identifying peptides derived from pathogenic proteins that are displayed on the surface of infected cells. Host cells also display peptide fragments from the host's own proteins. Incorrectly identifying peptides derived from the body's own proteome as pathogenic can result in autoimmune disease. To minimize autoreactivity, immature T cells that respond to self-peptides are deleted in the thymus by a process called negative selection. However, negative selection is imperfect, and autoreactive T cells exist in healthy individuals. To understand how autoimmunity is yet avoided, without loss of responsiveness to pathogens, we have developed a model of T-cell training and response. Our model shows that T cells reliably respond to infection and avoid autoimmunity because collective decisions made by the T-cell population, rather than the responses of individual T cells, determine biological outcomes. The theory is qualitatively consistent with experimental data and yields a criterion for thymic selection to be adequate for suppressing autoimmunity. PMID- 23818602 TI - Rickettsia Sca2 has evolved formin-like activity through a different molecular mechanism. AB - Sca2 (surface cell antigen 2) is the only bacterial protein known to promote both actin filament nucleation and profilin-dependent elongation, mimicking eukaryotic formins to assemble actin comet tails for Rickettsia motility. We show that Sca2's functional mimicry of formins is achieved through a unique mechanism. Unlike formins, Sca2 is monomeric, but has N- and C-terminal repeat domains (NRD and CRD) that interact with each other for processive barbed-end elongation. The crystal structure of NRD reveals a previously undescribed fold, consisting of helix-loop-helix repeats arranged into an overall crescent shape. CRD is predicted to share this fold and might form together with NRD, a doughnut-shaped formin-like structure. In between NRD and CRD, proline-rich sequences mediate the incorporation of profilin-actin for elongation, and WASP-homology 2 (WH2) domains recruit actin monomers for nucleation. Sca2's alpha-helical fold is unusual among Gram-negative autotransporters, which overwhelmingly fold as beta-solenoids. Rickettsia has therefore "rediscovered" formin-like actin nucleation and elongation. PMID- 23818604 TI - Highly multiplexed single-cell analysis of formalin-fixed, paraffin-embedded cancer tissue. AB - Limitations on the number of unique protein and DNA molecules that can be characterized microscopically in a single tissue specimen impede advances in understanding the biological basis of health and disease. Here we present a multiplexed fluorescence microscopy method (MxIF) for quantitative, single-cell, and subcellular characterization of multiple analytes in formalin-fixed paraffin embedded tissue. Chemical inactivation of fluorescent dyes after each image acquisition round allows reuse of common dyes in iterative staining and imaging cycles. The mild inactivation chemistry is compatible with total and phosphoprotein detection, as well as DNA FISH. Accurate computational registration of sequential images is achieved by aligning nuclear counterstain derived fiducial points. Individual cells, plasma membrane, cytoplasm, nucleus, tumor, and stromal regions are segmented to achieve cellular and subcellular quantification of multiplexed targets. In a comparison of pathologist scoring of diaminobenzidine staining of serial sections and automated MxIF scoring of a single section, human epidermal growth factor receptor 2, estrogen receptor, p53, and androgen receptor staining by diaminobenzidine and MxIF methods yielded similar results. Single-cell staining patterns of 61 protein antigens by MxIF in 747 colorectal cancer subjects reveals extensive tumor heterogeneity, and cluster analysis of divergent signaling through ERK1/2, S6 kinase 1, and 4E binding protein 1 provides insights into the spatial organization of mechanistic target of rapamycin and MAPK signal transduction. Our results suggest MxIF should be broadly applicable to problems in the fields of basic biological research, drug discovery and development, and clinical diagnostics. PMID- 23818605 TI - Far upstream element-binding protein 1 and RNA secondary structure both mediate second-step splicing repression. AB - Splicing of mRNA precursors consists of two steps that are almost invariably tightly coupled to facilitate efficient generation of spliced mRNA. However, we described previously a splicing substrate that is completely blocked after the first step. We have now investigated the basis for this unusual second-step inhibition and unexpectedly elucidated two independent mechanisms. One involves a stem-loop structure located downstream of the 3'splice site, and the other involves an exonic splicing silencer (ESS) situated 3' to the structure. Both elements contribute to the second-step block in vitro and also cause exon skipping in vivo. Importantly, we identified far upstream element-binding protein 1 (FUBP1), a single-stranded DNA- and RNA-binding protein not previously implicated in splicing, as a strong ESS binding protein, and several assays implicate it in ESS function. We demonstrate using depletion/add-back experiments that FUBP1 acts as a second-step repressor in vitro and show by siRNA-mediated knockdown and overexpression assays that it modulates exon inclusion in vivo. Together, our results provide additional insights into splicing control, and identify FUBP1 as a splicing regulator. PMID- 23818606 TI - Crystal structure and versatile functional roles of the COP9 signalosome subunit 1. AB - The constitutive photomorphogenesis 9 (COP9) signalosome (CSN) plays key roles in many biological processes, such as repression of photomorphogenesis in plants and protein subcellular localization, DNA-damage response, and NF-kappaB activation in mammals. It is an evolutionarily conserved eight-protein complex with subunits CSN1 to CSN8 named following the descending order of molecular weights. Here, we report the crystal structure of the largest CSN subunit, CSN1 from Arabidopsis thaliana (atCSN1), which belongs to the Proteasome, COP9 signalosome, Initiation factor 3 (PCI) domain containing CSN subunit family, at 2.7 A resolution. In contrast to previous predictions and distinct from the PCI-containing 26S proteasome regulatory particle subunit Rpn6 structure, the atCSN1 structure reveals an overall globular fold, with four domains consisting of helical repeat I, linker helix, helical repeat-II, and the C-terminal PCI domain. Our small angle X-ray scattering envelope of the CSN1-CSN7 complex agrees with the EM structure of the CSN alone (apo-CSN) and suggests that the PCI end of each molecule may mediate the interaction. Fitting of the CSN1 structure into the CSN Skp1-Cul1-Fbox (SCF) EM structure shows that the PCI domain of CSN1 situates at the hub of the CSN for interaction with several other subunits whereas the linker helix and helical repeat-II of CSN1 contacts SCF using a conserved surface patch. Furthermore, we show that, in human, the C-terminal tail of CSN1, a segment not included in our crystal structure, interacts with IkappaBalpha in the NF-kappaB pathway. Therefore, the CSN complex uses multiple mechanisms to hinder NF-kappaB activation, a principle likely to hold true for its regulation of many other targets and pathways. PMID- 23818608 TI - Fat cells directly sense temperature to activate thermogenesis. AB - Classic brown fat and inducible beige fat both dissipate chemical energy in the form of heat through the actions of mitochondrial uncoupling protein 1. This nonshivering thermogenesis is crucial for mammals as a defense against cold and obesity/diabetes. Cold is known to act indirectly through the sympathetic nervous systems and beta-adrenergic signaling, but here we report that cool temperature (27-33 degrees C) can directly activate a thermogenic gene program in adipocytes in a cell-autonomous manner. White and beige fat cells respond to cool temperatures, but classic brown fat cells do not. Importantly, this activation in isolated cells is independent of the canonical cAMP/Protein Kinase A/cAMP response element-binding protein pathway downstream of the beta-adrenergic receptors. These findings provide an unusual insight into the role of adipose tissues in thermoregulation, as well as an alternative way to target nonshivering thermogenesis for treatment of obesity and metabolic diseases. PMID- 23818607 TI - TET1 plays an essential oncogenic role in MLL-rearranged leukemia. AB - The ten-eleven translocation 1 (TET1) gene is the founding member of the TET family of enzymes (TET1/2/3) that convert 5-methylcytosine to 5 hydroxymethylcytosine. Although TET1 was first identified as a fusion partner of the mixed lineage leukemia (MLL) gene in acute myeloid leukemia carrying t(10,11), its definitive role in leukemia is unclear. In contrast to the frequent down-regulation (or loss-of-function mutations) and critical tumor-suppressor roles of the three TET genes observed in various types of cancers, here we show that TET1 is a direct target of MLL-fusion proteins and is significantly up regulated in MLL-rearranged leukemia, leading to a global increase of 5 hydroxymethylcytosine level. Furthermore, our both in vitro and in vivo functional studies demonstrate that Tet1 plays an indispensable oncogenic role in the development of MLL-rearranged leukemia, through coordination with MLL-fusion proteins in regulating their critical cotargets, including homeobox A9 (Hoxa9)/myeloid ecotropic viral integration 1 (Meis1)/pre-B-cell leukemia homeobox 3 (Pbx3) genes. Collectively, our data delineate an MLL fusion/Tet1/Hoxa9/Meis1/Pbx3 signaling axis in MLL-rearranged leukemia and highlight TET1 as a potential therapeutic target in treating this presently therapy-resistant disease. PMID- 23818609 TI - Efficient viral delivery system for unnatural amino acid mutagenesis in mammalian cells. AB - Here we report the development of a baculovirus-based delivery system that enables the efficient incorporation of unnatural amino acids into proteins in mammalian cells. We have exploited the large cargo-capacity (>30 kb) and stability of the double-stranded DNA genome of baculovirus to deliver to a variety of cell types all of the components required to genetically incorporate novel amino acids. These include the engineered tRNA/aminoacyl-tRNA synthetase pair and the nonsense mutant of the target gene. Mammalian cell transduction efficiency of baculovirus was significantly improved by incorporating genetic elements from mammalian viruses. Two polyspecific tRNA/aminoacyl-tRNA synthetase pairs were inserted into this expression system, enabling the site-specific incorporation of a variety of unnatural amino acids with novel chemical and biological properties into proteins. PMID- 23818610 TI - Diacylglycerol promotes centrosome polarization in T cells via reciprocal localization of dynein and myosin II. AB - Centrosome reorientation to the immunological synapse maintains the specificity of T-cell effector function by facilitating the directional release of cytokines and cytolytic factors toward the antigen-presenting cell. This polarization response is driven by the localized accumulation of diacylglycerol, which recruits multiple protein kinase (PK)C isozymes to the synaptic membrane. Here, we used T-cell receptor (TCR) photoactivation and imaging methodology to demonstrate that PKCs control centrosome dynamics through the reciprocal localization of two motor complexes, dynein and nonmuscle myosin (NM)II. Dynein accumulated in the region of TCR stimulation, whereas NMII clustered in the back of the cell, behind the polarizing centrosome. PKC activity, which shaped both dynein and NMII accumulation within this framework, controlled NMII localization directly by phosphorylating inhibitory sites within the myosin regulatory light chain, thereby suppressing NMII clustering in the region of TCR stimulation. Concurrently, phosphorylation of distinct sites within myosin regulatory light chain by Rho kinase drove NMII clustering in areas behind the centrosome. These results reveal a role for NMII in T-cell polarity and demonstrate how it is regulated by upstream signals. PMID- 23818611 TI - Two independent pathways of regulated necrosis mediate ischemia-reperfusion injury. AB - Regulated necrosis (RN) may result from cyclophilin (Cyp)D-mediated mitochondrial permeability transition (MPT) and receptor-interacting protein kinase (RIPK)1 mediated necroptosis, but it is currently unclear whether there is one common pathway in which CypD and RIPK1 act in or whether separate RN pathways exist. Here, we demonstrate that necroptosis in ischemia-reperfusion injury (IRI) in mice occurs as primary organ damage, independent of the immune system, and that mice deficient for RIPK3, the essential downstream partner of RIPK1 in necroptosis, are protected from IRI. Protection of RIPK3-knockout mice was significantly stronger than of CypD-deficient mice. Mechanistically, in vivo analysis of cisplatin-induced acute kidney injury and hyperacute TNF-shock models in mice suggested the distinctness of CypD-mediated MPT from RIPK1/RIPK3-mediated necroptosis. We, therefore, generated CypD-RIPK3 double-deficient mice that are viable and fertile without an overt phenotype and that survived prolonged IRI, which was lethal to each single knockout. Combined application of the RIPK1 inhibitor necrostatin-1 and the MPT inhibitor sanglifehrin A confirmed the results with mutant mice. The data demonstrate the pathophysiological coexistence and corelevance of two separate pathways of RN in IRI and suggest that combination therapy targeting distinct RN pathways can be beneficial in the treatment of ischemic injury. PMID- 23818612 TI - Spatial interactions among ecosystem services in an urbanizing agricultural watershed. AB - Understanding spatial distributions, synergies, and tradeoffs of multiple ecosystem services (benefits people derive from ecosystems) remains challenging. We analyzed the supply of 10 ecosystem services for 2006 across a large urbanizing agricultural watershed in the Upper Midwest of the United States, and asked the following: (i) Where are areas of high and low supply of individual ecosystem services, and are these areas spatially concordant across services? (ii) Where on the landscape are the strongest tradeoffs and synergies among ecosystem services located? (iii) For ecosystem service pairs that experience tradeoffs, what distinguishes locations that are "win-win" exceptions from other locations? Spatial patterns of high supply for multiple ecosystem services often were not coincident; locations where six or more services were produced at high levels (upper 20th percentile) occupied only 3.3% of the landscape. Most relationships among ecosystem services were synergies, but tradeoffs occurred between crop production and water quality. Ecosystem services related to water quality and quantity separated into three different groups, indicating that management to sustain freshwater services along with other ecosystem services will not be simple. Despite overall tradeoffs between crop production and water quality, some locations were positive for both, suggesting that tradeoffs are not inevitable everywhere and might be ameliorated in some locations. Overall, we found that different areas of the landscape supplied different suites of ecosystem services, and their lack of spatial concordance suggests the importance of managing over large areas to sustain multiple ecosystem services. PMID- 23818613 TI - Structural and functional analysis of the yeast N-acetyltransferase Mpr1 involved in oxidative stress tolerance via proline metabolism. AB - Mpr1 (sigma1278b gene for proline-analog resistance 1), which was originally isolated as N-acetyltransferase detoxifying the proline analog L-azetidine-2 carboxylate, protects yeast cells from various oxidative stresses. Mpr1 mediates the L-proline and L-arginine metabolism by acetylating L-Delta(1)-pyrroline-5 carboxylate, leading to the L-arginine-dependent production of nitric oxide, which confers oxidative stress tolerance. Mpr1 belongs to the Gcn5-related N acetyltransferase (GNAT) superfamily, but exhibits poor sequence homology with the GNAT enzymes and unique substrate specificity. Here, we present the X-ray crystal structure of Mpr1 and its complex with the substrate cis-4-hydroxy-L proline at 1.9 and 2.3 A resolution, respectively. Mpr1 is folded into alpha/beta structure with eight-stranded mixed beta-sheets and six alpha-helices. The substrate binds to Asn135 and the backbone amide of Asn172 and Leu173, and the predicted acetyl-CoA-binding site is located near the backbone amide of Phe138 and the side chain of Asn178. Alanine substitution of Asn178, which can interact with the sulfur of acetyl-CoA, caused a large reduction in the apparent kcat value. The replacement of Asn135 led to a remarkable increase in the apparent Km value. These results indicate that Asn178 and Asn135 play an important role in catalysis and substrate recognition, respectively. Such a catalytic mechanism has not been reported in the GNAT proteins. Importantly, the amino acid substitutions in these residues increased the L-Delta(1)-pyrroline-5-carboxylate level in yeast cells exposed to heat stress, indicating that these residues are also crucial for its physiological functions. These studies provide some benefits of Mpr1 applications, such as the breeding of industrial yeasts and the development of antifungal drugs. PMID- 23818614 TI - Voltage sensor interaction site for selective small molecule inhibitors of voltage-gated sodium channels. AB - Voltage-gated sodium (Nav) channels play a fundamental role in the generation and propagation of electrical impulses in excitable cells. Here we describe two unique structurally related nanomolar potent small molecule Nav channel inhibitors that exhibit up to 1,000-fold selectivity for human Nav1.3/Nav1.1 (ICA 121431, IC50, 19 nM) or Nav1.7 (PF-04856264, IC50, 28 nM) vs. other TTX-sensitive or resistant (i.e., Nav1.5) sodium channels. Using both chimeras and single point mutations, we demonstrate that this unique class of sodium channel inhibitor interacts with the S1-S4 voltage sensor segment of homologous Domain 4. Amino acid residues in the "extracellular" facing regions of the S2 and S3 transmembrane segments of Nav1.3 and Nav1.7 seem to be major determinants of Nav subtype selectivity and to confer differences in species sensitivity to these inhibitors. The unique interaction region on the Domain 4 voltage sensor segment is distinct from the structural domains forming the channel pore, as well as previously characterized interaction sites for other small molecule inhibitors, including local anesthetics and TTX. However, this interaction region does include at least one amino acid residue [E1559 (Nav1.3)/D1586 (Nav1.7)] that is important for Site 3 alpha-scorpion and anemone polypeptide toxin modulators of Nav channel inactivation. The present study provides a potential framework for identifying subtype selective small molecule sodium channel inhibitors targeting interaction sites away from the pore region. PMID- 23818615 TI - Genome-wide association study identifies vitamin B5 biosynthesis as a host specificity factor in Campylobacter. AB - Genome-wide association studies have the potential to identify causal genetic factors underlying important phenotypes but have rarely been performed in bacteria. We present an association mapping method that takes into account the clonal population structure of bacteria and is applicable to both core and accessory genome variation. Campylobacter is a common cause of human gastroenteritis as a consequence of its proliferation in multiple farm animal species and its transmission via contaminated meat and poultry. We applied our association mapping method to identify the factors responsible for adaptation to cattle and chickens among 192 Campylobacter isolates from these and other host sources. Phylogenetic analysis implied frequent host switching but also showed that some lineages were strongly associated with particular hosts. A seven-gene region with a host association signal was found. Genes in this region were almost universally present in cattle but were frequently absent in isolates from chickens and wild birds. Three of the seven genes encoded vitamin B5 biosynthesis. We found that isolates from cattle were better able to grow in vitamin B5-depleted media and propose that this difference may be an adaptation to host diet. PMID- 23818616 TI - Matrix-dependent adhesion mediates network responses to physiological stimulation of the osteocyte cell process. AB - Osteocytes are bone cells that form cellular networks that sense mechanical loads distributed throughout the bone tissue. Interstitial fluid flow in the lacunar canalicular system produces focal strains at localized attachment sites around the osteocyte cell process. These regions of periodic attachment between the osteocyte cell membrane and its canalicular wall are sites where pN-level fluid flow induced forces are generated in vivo. In this study, we show that focally applied forces of this magnitude using a newly developed Stokesian fluid stimulus probe initiate rapid and transient intercellular electrical signals in vitro. Our experiments demonstrate both direct gap junction coupling and extracellular purinergic P2 receptor signaling between MLO-Y4 cells in a connected bone cell network. Intercellular signaling was initiated by pN-level forces applied at integrin attachment sites along both appositional and distal unapposed cell processes, but not initiated at their cell bodies with equivalent forces. Electrical coupling was evident in 58% of all cell pairs tested with appositional connections; coupling strength increased with the increasing number of junctional connections. Apyrase, a nucleotide-degrading enzyme, suppressed and abolished force-induced effector responses, indicating a contribution from ATP released by the stimulated cell. This work extends the understanding of how osteocytes modulate their microenvironment in response to mechanical signals and highlights mechanisms of intercellular relay of mechanoresponsive signals in the bone network. PMID- 23818617 TI - Analysis of Dll4 regulation reveals a combinatorial role for Sox and Notch in arterial development. AB - The mechanisms by which arterial fate is established and maintained are not clearly understood. Although a number of signaling pathways and transcriptional regulators have been implicated in arterio-venous differentiation, none are essential for arterial formation, and the manner in which widely expressed factors may achieve arterial-specific gene regulation is unclear. Using both mouse and zebrafish models, we demonstrate here that arterial specification is regulated combinatorially by Notch signaling and SoxF transcription factors, via direct transcriptional gene activation. Through the identification and characterization of two arterial endothelial cell-specific gene enhancers for the Notch ligand Delta-like ligand 4 (Dll4), we show that arterial Dll4 expression requires the direct binding of both the RBPJ/Notch intracellular domain and SOXF transcription factors. Specific combinatorial, but not individual, loss of SOXF and RBPJ DNA binding ablates all Dll4 enhancer-transgene expression despite the presence of multiple functional ETS binding sites, as does knockdown of sox7;sox18 in combination with loss of Notch signaling. Furthermore, triple knockdown of sox7, sox18 and rbpj also results in ablation of endogenous dll4 expression. Fascinatingly, this combinatorial ablation leads to a loss of arterial markers and the absence of a detectable dorsal aorta, demonstrating the essential roles of SoxF and Notch, together, in the acquisition of arterial identity. PMID- 23818618 TI - Transformation of odor selectivity from projection neurons to single mushroom body neurons mapped with dual-color calcium imaging. AB - Although the response properties of most neurons are, to a large extent, determined by the presynaptic inputs that they receive, comprehensive functional characterization of the presynaptic inputs of a single neuron remains elusive. Toward this goal, we introduce a dual-color calcium imaging approach that simultaneously monitors the responses of a single postsynaptic neuron together with its presynaptic axon terminal inputs in vivo. As a model system, we applied the strategy to the feed-forward connections from the projection neurons (PNs) to the Kenyon cells (KCs) in the mushroom body of Drosophila and functionally mapped essentially all PN inputs for some of the KCs. We found that the output of single KCs could be well predicted by a linear summation of the PN input signals, indicating that excitatory PN inputs play the major role in generating odor selective responses in KCs. When odors failed to activate KC output, local calcium transients restricted to individual postsynaptic sites could be observed in the KC dendrites. The response amplitudes of the local transients often correlated linearly with the presynaptic response amplitudes, allowing direct assay of the strength of single synaptic sites. Furthermore, we found a scaling relationship between the total number of PN terminals that a single KC received and the average synaptic strength of these PN-KC synapses. Our strategy provides a unique perspective on the process of information transmission and integration in a model neural circuit and may be broadly applicable for the study of the origin of neuronal response properties. PMID- 23818619 TI - Targeting global conservation funding to limit immediate biodiversity declines. AB - Inadequate funding levels are a major impediment to effective global biodiversity conservation and are likely associated with recent failures to meet United Nations biodiversity targets. Some countries are more severely underfunded than others and therefore represent urgent financial priorities. However, attempts to identify these highly underfunded countries have been hampered for decades by poor and incomplete data on actual spending, coupled with uncertainty and lack of consensus over the relative size of spending gaps. Here, we assemble a global database of annual conservation spending. We then develop a statistical model that explains 86% of variation in conservation expenditures, and use this to identify countries where funding is robustly below expected levels. The 40 most severely underfunded countries contain 32% of all threatened mammalian diversity and include neighbors in some of the world's most biodiversity-rich areas (Sundaland, Wallacea, and Near Oceania). However, very modest increases in international assistance would achieve a large improvement in the relative adequacy of global conservation finance. Our results could therefore be quickly applied to limit immediate biodiversity losses at relatively little cost. PMID- 23818620 TI - Rotavirus mRNAS are released by transcript-specific channels in the double layered viral capsid. AB - Rotaviruses are the single most common cause of fatal and severe childhood diarrheal illness worldwide (>125 million cases annually). Rotavirus shares structural and functional features with many viruses, such as the presence of segmented double-stranded RNA genomes selectively and tightly packed with a conserved number of transcription complexes in icosahedral capsids. Nascent transcripts exit the capsid through 12 channels, but it is unknown whether these channels specialize in specific transcripts or simply act as general exit conduits; a detailed description of this process is needed for understanding viral replication and genomic organization. To this end, we developed a single molecule assay for capturing and identifying transcripts extruded from transcriptionally active viral particles. Our findings support a model in which each channel specializes in extruding transcripts of a specific segment that in turn is linked to a single transcription complex. Our approach can be extended to study other viruses and transcription systems. PMID- 23818622 TI - Quantum of optical absorption in two-dimensional semiconductors. AB - The optical absorption properties of free-standing InAs nanomembranes of thicknesses ranging from 3 nm to 19 nm are investigated by Fourier transform infrared spectroscopy. Stepwise absorption at room temperature is observed, arising from the interband transitions between the subbands of 2D InAs nanomembranes. Interestingly, the absorptance associated with each step is measured to be ~1.6%, independent of thickness of the membranes. The experimental results are consistent with the theoretically predicted absorptance quantum, AQ = pialpha/nc for each set of interband transitions in a 2D semiconductor, where alpha is the fine structure constant and nc is an optical local field correction factor. Absorptance quantization appears to be universal in 2D systems including III-V quantum wells and graphene. PMID- 23818621 TI - BET proteins promote efficient murine leukemia virus integration at transcription start sites. AB - The selection of chromosomal targets for retroviral integration varies markedly, tracking with the genus of the retrovirus, suggestive of targeting by binding to cellular factors. gamma-Retroviral murine leukemia virus (MLV) DNA integration into the host genome is favored at transcription start sites, but the underlying mechanism for this preference is unknown. Here, we have identified bromodomain and extraterminal domain (BET) proteins (Brd2, -3, -4) as cellular-binding partners of MLV integrase. We show that purified recombinant Brd4(1-720) binds with high affinity to MLV integrase and stimulates correct concerted integration in vitro. JQ-1, a small molecule that selectively inhibits interactions of BET proteins with modified histone sites impaired MLV but not HIV-1 integration in infected cells. Comparison of the distribution of BET protein-binding sites analyzed using ChIP-Seq data and MLV-integration sites revealed significant positive correlations. Antagonism of BET proteins, via JQ-1 treatment or RNA interference, reduced MLV-integration frequencies at transcription start sites. These findings elucidate the importance of BET proteins for MLV integration efficiency and targeting and provide a route to developing safer MLV-based vectors for human gene therapy. PMID- 23818624 TI - Superconductivity in highly disordered dense carbon disulfide. AB - High pressure plays an increasingly important role in both understanding superconductivity and the development of new superconducting materials. New superconductors were found in metallic and metal oxide systems at high pressure. However, because of the filled close-shell configuration, the superconductivity in molecular systems has been limited to charge-transferred salts and metal-doped carbon species with relatively low superconducting transition temperatures. Here, we report the low-temperature superconducting phase observed in diamagnetic carbon disulfide under high pressure. The superconductivity arises from a highly disordered extended state (CS4 phase or phase III[CS4]) at ~6.2 K over a broad pressure range from 50 to 172 GPa. Based on the X-ray scattering data, we suggest that the local structural change from a tetrahedral to an octahedral configuration is responsible for the observed superconductivity. PMID- 23818623 TI - Anti-VEGF- and anti-VEGF receptor-induced vascular alteration in mouse healthy tissues. AB - Systemic therapy with anti-VEGF drugs such as bevacizumab is widely used for treatment of human patients with various solid tumors. However, systemic impacts of such drugs in host healthy vasculatures remain poorly understood. Here, we show that, in mice, systemic delivery of an anti-VEGF or an anti-VEGF receptor (VEGFR)-2 neutralizing antibody caused global vascular regression. Among all examined tissues, vasculatures in endocrine glands, intestinal villi, and uterus are the most affected in response to VEGF or VEGFR-2 blockades. Thyroid vascular fenestrations were virtually completely blocked by VEGF blockade, leading to marked accumulation of intraendothelial caveolae vesicles. VEGF blockade markedly increased thyroid endothelial cell apoptosis, and withdrawal of anti-VEGF resulted in full recovery of vascular density and architecture after 14 d. Prolonged anti-VEGF treatment resulted in a significant decrease of the circulating level of the predominant thyroid hormone free thyroxine, but not the minimal isoform of triiodothyronine, suggesting that chronic anti-VEGF treatment impairs thyroid functions. Conversely, VEGFR-1-specific blockade produced virtually no obvious phenotypes. These findings provide structural and functional bases of anti-VEGF-specific drug-induced side effects in relation to vascular changes in healthy tissues. Understanding anti-VEGF drug-induced vascular alterations in healthy tissues is crucial to minimize and even to avoid adverse effects produced by currently used anti-VEGF-specific drugs. PMID- 23818625 TI - P(II) signal transduction proteins are ATPases whose activity is regulated by 2 oxoglutarate. AB - P(II) proteins are one of the most widespread families of signal transduction proteins in nature, being ubiquitous throughout bacteria, archaea, and plants. In all these organisms, P(II) proteins coordinate many facets of nitrogen metabolism by interacting with and regulating the activities of enzymes, transcription factors, and membrane transport proteins. The primary mode of signal perception by P(II) proteins derives from their ability to bind the effector molecules 2 oxoglutarate (2-OG) and ATP or ADP. The role of 2-OG as an indicator of cellular nitrogen status is well understood, but the function of ATP/ADP binding has remained unresolved. We have now shown that the Escherichia coli P(II) protein, GlnK, has an ATPase activity that is inhibited by 2-OG. Hence, when a drop in the cellular 2-OG pool signals nitrogen sufficiency, 2-OG depletion of GlnK causes bound ATP to be hydrolyzed to ADP, leading to a conformational change in the protein. We propose that the role of ATP/ADP binding in E. coli GlnK is to effect a 2-OG-dependent molecular switch that drives a conformational change in the T loops of the P(II) protein. We have further shown that two other P(II) proteins, Azospirillum brasilense GlnZ and Arabidopsis thaliana P(II), have a similar ATPase activity, and we therefore suggest that this switch mechanism is likely to be a general property of most members of the P(II) protein family. PMID- 23818627 TI - Improved El Nino forecasting by cooperativity detection. AB - Although anomalous episodic warming of the eastern equatorial Pacific, dubbed El Nino by Peruvian fishermen, has major (and occasionally devastating) impacts around the globe, robust forecasting is still limited to about 6 mo ahead. A significant extension of the prewarning time would be instrumental for avoiding some of the worst damages such as harvest failures in developing countries. Here we introduce a unique avenue toward El Nino prediction based on network methods, inspecting emerging teleconnections. Our approach starts from the evidence that a large-scale cooperative mode--linking the El Nino basin (equatorial Pacific corridor) and the rest of the ocean--builds up in the calendar year before the warming event. On this basis, we can develop an efficient 12-mo forecasting scheme, i.e., achieve some doubling of the early-warning period. Our method is based on high-quality observational data available since 1950 and yields hit rates above 0.5, whereas false-alarm rates are below 0.1. PMID- 23818626 TI - Kinetic response of a photoperturbed allosteric protein. AB - By covalently linking an azobenzene photoswitch across the binding groove of a PDZ domain, a conformational transition, similar to the one occurring upon ligand binding to the unmodified domain, can be initiated on a picosecond timescale by a laser pulse. The protein structures have been characterized in the two photoswitch states through NMR spectroscopy and the transition between them through ultrafast IR spectroscopy and molecular dynamics simulations. The binding groove opens on a 100-ns timescale in a highly nonexponential manner, and the molecular dynamics simulations suggest that the process is governed by the rearrangement of the water network on the protein surface. We propose this rearrangement of the water network to be another possible mechanism of allostery. PMID- 23818628 TI - How psychological framing affects economic market prices in the lab and field. AB - A fundamental debate in social sciences concerns how individual judgments and choices, resulting from psychological mechanisms, are manifested in collective economic behavior. Economists emphasize the capacity of markets to aggregate information distributed among traders into rational equilibrium prices. However, psychologists have identified pervasive and systematic biases in individual judgment that they generally assume will affect collective behavior. In particular, recent studies have found that judged likelihoods of possible events vary systematically with the way the entire event space is partitioned, with probabilities of each of N partitioned events biased toward 1/N. Thus, combining events into a common partition lowers perceived probability, and unpacking events into separate partitions increases their perceived probability. We look for evidence of such bias in various prediction markets, in which prices can be interpreted as probabilities of upcoming events. In two highly controlled experimental studies, we find clear evidence of partition dependence in a 2-h laboratory experiment and a field experiment on National Basketball Association (NBA) and Federation Internationale de Football Association (FIFA World Cup) sports events spanning several weeks. We also find evidence consistent with partition dependence in nonexperimental field data from prediction markets for economic derivatives (guessing the values of important macroeconomic statistics) and horse races. Results in any one of the studies might be explained by a specialized alternative theory, but no alternative theories can explain the results of all four studies. We conclude that psychological biases in individual judgment can affect market prices, and understanding those effects requires combining a variety of methods from psychology and economics. PMID- 23818629 TI - Dynamics of mechanosensing in the bacterial flagellar motor. AB - Mechanosensing by flagella is thought to trigger bacterial swarmer-cell differentiation, an important step in pathogenesis. How flagellar motors sense mechanical stimuli is not known. To study this problem, we suddenly increased the viscous drag on motors by a large factor, from very low loads experienced by motors driving hooks or hooks with short filament stubs, to high loads, experienced by motors driving tethered cells or 1-MUm latex beads. From the initial speed (after the load change), we inferred that motors running at very low loads are driven by one or at most two force-generating units. Following the load change, motors gradually adapted by increasing their speeds in a stepwise manner (over a period of a few minutes). Motors initially spun exclusively counterclockwise, but then increased the fraction of time that they spun clockwise over a time span similar to that observed for adaptation in speed. Single-motor total internal reflection fluorescence imaging of YFP-MotB (part of a stator force-generating unit) confirmed that the response to sudden increments in load occurred by the addition of new force-generating units. We estimate that 6-11 force-generating units drive motors at high loads. Wild-type motors and motors locked in the clockwise or counterclockwise state behaved in a similar manner, as did motors in cells deleted for the motor protein gene fliL or for genes in the chemotaxis signaling pathway. Thus, it appears that stators themselves act as dynamic mechanosensors. They change their structure in response to changes in external load. How such changes might impact cellular functions other than motility remains an interesting question. PMID- 23818630 TI - Controlled insertional mutagenesis using a LINE-1 (ORFeus) gene-trap mouse model. AB - A codon-optimized mouse LINE-1 element, ORFeus, exhibits dramatically higher retrotransposition frequencies compared with its native long interspersed element 1 counterpart. To establish a retrotransposon-mediated mouse model with regulatable and potent mutagenic capabilities, we generated a tetracycline (tet) regulated ORFeus element harboring a gene-trap cassette. Here, we show that mice expressing tet-ORFeus broadly exhibit robust retrotransposition in somatic tissues when treated with doxycycline. Consistent with a significant mutagenic burden, we observed a reduced number of double transgenic animals when treated with high-level doxycycline during embryogenesis. Transgene induction in skin resulted in a white spotting phenotype due to somatic ORFeus-mediated mutations that likely disrupt melanocyte development. The data suggest a high level of transposition in melanocyte precursors and consequent mutation of genes important for melanoblast proliferation, differentiation, or migration. These findings reveal the utility of a retrotransposon-based mutagenesis system as an alternative to existing DNA transposon systems. Moreover, breeding these mice to different tet-transactivator/reversible tet-transactivator lines supports broad functionality of tet-ORFeus because of the potential for dose-dependent, tissue specific, and temporal-specific mutagenesis. PMID- 23818632 TI - Antibodies that bind complex glycosaminoglycans accumulate in the Golgi. AB - Light (L) chains that edit anti-DNA heavy (H) chains rescue B-cell development by suppressing DNA binding. However, exceptional editor L chains allow B cells to reach splenic compartments even though their B-cell receptors remain autoreactive. Such incompletely edited B cells express multireactive antibodies that accumulate in the Golgi and are released as insoluble, amyloid-like immune complexes. Here, we examine examples of incomplete editing from the analysis of variable to joining (VJ) gene junction of the variable (Vlambdax) editor L chain. When paired with the anti-DNA heavy chain, VH56R, the Vlambdax variants yield antibodies with differing specificities, including glycosaminoglycan reactivity. Our results implicate these specificities in the evasion of receptor editing through intracellular sequestration of IgM and the release of insoluble IgM complexes. Our findings can be extrapolated to human L chains and have implications for understanding a latent component of the Ig repertoire that could exert pathogenic and protective functions. PMID- 23818631 TI - Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma. AB - Current therapy for glioblastoma multiforme is insufficient, with nearly universal recurrence. Available drug therapies are unsuccessful because they fail to penetrate through the region of the brain containing tumor cells and they fail to kill the cells most responsible for tumor development and therapy resistance, brain cancer stem cells (BCSCs). To address these challenges, we combined two major advances in technology: (i) brain-penetrating polymeric nanoparticles that can be loaded with drugs and are optimized for intracranial convection-enhanced delivery and (ii) repurposed compounds, previously used in Food and Drug Administration-approved products, which were identified through library screening to target BCSCs. Using fluorescence imaging and positron emission tomography, we demonstrate that brain-penetrating nanoparticles can be delivered to large intracranial volumes in both rats and pigs. We identified several agents (from Food and Drug Administration-approved products) that potently inhibit proliferation and self-renewal of BCSCs. When loaded into brain-penetrating nanoparticles and administered by convection-enhanced delivery, one of these agents, dithiazanine iodide, significantly increased survival in rats bearing BCSC-derived xenografts. This unique approach to controlled delivery in the brain should have a significant impact on treatment of glioblastoma multiforme and suggests previously undescribed routes for drug and gene delivery to treat other diseases of the central nervous system. PMID- 23818633 TI - Posttranslational modification of CENP-A influences the conformation of centromeric chromatin. AB - Centromeres are chromosomal loci required for accurate segregation of sister chromatids during mitosis. The location of the centromere on the chromosome is not dependent on DNA sequence, but rather it is epigenetically specified by the histone H3 variant centromere protein A (CENP-A). The N-terminal tail of CENP-A is highly divergent from other H3 variants. Canonical histone N termini are hotspots of conserved posttranslational modification; however, no broadly conserved modifications of the vertebrate CENP-A tail have been previously observed. Here, we report three posttranslational modifications on human CENP-A N termini using high-resolution MS: trimethylation of Gly1 and phosphorylation of Ser16 and Ser18. Our results demonstrate that CENP-A is subjected to constitutive initiating methionine removal, similar to other H3 variants. The nascent N terminal residue Gly1 becomes trimethylated on the alpha-amino group. We demonstrate that the N-terminal RCC1 methyltransferase is capable of modifying the CENP-A N terminus. Methylation occurs in the prenucleosomal form and marks the majority of CENP-A nucleosomes. Serine 16 and 18 become phosphorylated in prenucleosomal CENP-A and are phosphorylated on asynchronous and mitotic nucleosomal CENP-A and are important for chromosome segregation during mitosis. The double phosphorylation motif forms a salt-bridged secondary structure and causes CENP-A N-terminal tails to form intramolecular associations. Analytical ultracentrifugation of phospho-mimetic CENP-A nucleosome arrays demonstrates that phosphorylation results in greater intranucleosome associations and counteracts the hyperoligomerized state exhibited by unmodified CENP-A nucleosome arrays. Our studies have revealed that the major modifications on the N-terminal tail of CENP A alter the physical properties of the chromatin fiber at the centromere. PMID- 23818634 TI - Size distribution dynamics reveal particle-phase chemistry in organic aerosol formation. AB - Organic aerosols are ubiquitous in the atmosphere and play a central role in climate, air quality, and public health. The aerosol size distribution is key in determining its optical properties and cloud condensation nucleus activity. The dominant portion of organic aerosol is formed through gas-phase oxidation of volatile organic compounds, so-called secondary organic aerosols (SOAs). Typical experimental measurements of SOA formation include total SOA mass and atomic oxygen-to-carbon ratio. These measurements, alone, are generally insufficient to reveal the extent to which condensed-phase reactions occur in conjunction with the multigeneration gas-phase photooxidation. Combining laboratory chamber experiments and kinetic gas-particle modeling for the dodecane SOA system, here we show that the presence of particle-phase chemistry is reflected in the evolution of the SOA size distribution as well as its mass concentration. Particle-phase reactions are predicted to occur mainly at the particle surface, and the reaction products contribute more than half of the SOA mass. Chamber photooxidation with a midexperiment aldehyde injection confirms that heterogeneous reaction of aldehydes with organic hydroperoxides forming peroxyhemiacetals can lead to a large increase in SOA mass. Although experiments need to be conducted with other SOA precursor hydrocarbons, current results demonstrate coupling between particle-phase chemistry and size distribution dynamics in the formation of SOAs, thereby opening up an avenue for analysis of the SOA formation process. PMID- 23818635 TI - Transorganellar complementation redefines the biochemical continuity of endoplasmic reticulum and chloroplasts. AB - Tocopherols are nonpolar compounds synthesized and localized in plastids but whose genetic elimination specifically impacts fatty acid desaturation in the endoplasmic reticulum (ER), suggesting a direct interaction with ER-resident enzymes. To functionally probe for such interactions, we developed transorganellar complementation, where mutated pathway activities in one organelle are experimentally tested for substrate accessibility and complementation by active enzymes retargeted to a companion organelle. Mutations disrupting three plastid-resident activities in tocopherol and carotenoid synthesis were complemented from the ER in this fashion, demonstrating transorganellar access to at least seven nonpolar, plastid envelope-localized substrates from the lumen of the ER, likely through plastid:ER membrane interaction domains. The ability of enzymes in either organelle to access shared, nonpolar plastid metabolite pools redefines our understanding of the biochemical continuity of the ER and chloroplast with profound implications for the integration and regulation of organelle-spanning pathways that synthesize nonpolar metabolites in plants. PMID- 23818636 TI - Characterization and comparison of human nuclear and cytosolic editomes. AB - We developed a robust computational statistical framework to identify RNA editing events from RNA-Seq data with high specificity. Our approach handles several outstanding challenges of genome-wide editing analyses, including the effect of editing on read alignment and the utilization of redundant reads. By applying this framework, we characterized the nuclear and cytosolic editomes of seven human cell lines. We found that 93.8-99.2% of the editing events are A-to-G (or A to-I). Nuclear transcriptomes contain many more editing events than cytosolic transcriptomes. Most of the sites exhibiting nucleus-specific editing are in introns or novel intergenic transcripts that are preferentially localized in the nucleus regardless of their editing status, arguing against the role of editing in nuclear retention. In contrast, many sites that exhibit cytosol-specific editing show comparable nuclear and cytosolic expression, suggesting the differential subcellular compartmentalization of the edited and the unedited alleles. We found that RNA editing is globally associated with the modification of microRNA regulation in 3' untranslated regions, whereas editing events in coding regions are rare and tend to be synonymous. Interestingly, A-to-G editing at derived alleles in the human lineage tends to result in reversion back to the ancestral forms at the RNA level. This suggests that editing can mediate RNA memory on evolutionary time-scales to maintain ancestral genetic information. PMID- 23818637 TI - Transgene- and locus-dependent imprinting reveals allele-specific chromosome conformations. AB - When positioned into the integrin alpha-6 gene, an Hoxd9lacZ reporter transgene displayed parental imprinting in mouse embryos. While the expression from the paternal allele was comparable with patterns seen for the same transgene when present at the neighboring HoxD locus, almost no signal was scored at this integration site when the transgene was inherited from the mother, although the Itga6 locus itself is not imprinted. The transgene exhibited maternal allele specific DNA hypermethylation acquired during oogenesis, and its expression silencing was reversible on passage through the male germ line. Histone modifications also corresponded to profiles described at known imprinted loci. Chromosome conformation analyses revealed distinct chromatin microarchitectures, with a more compact structure characterizing the maternally inherited repressed allele. Such genetic analyses of well-characterized transgene insertions associated with a de novo-induced parental imprint may help us understand the molecular determinants of imprinting. PMID- 23818638 TI - Activation of dimeric ABA receptors elicits guard cell closure, ABA-regulated gene expression, and drought tolerance. AB - Abscisic acid (ABA) is an essential molecule in plant abiotic stress responses. It binds to soluble pyrabactin resistance1/PYR1-like/regulatory component of ABA receptor receptors and stabilizes them in a conformation that inhibits clade A type II C protein phosphatases; this leads to downstream SnRK2 kinase activation and numerous cellular outputs. We previously described the synthetic naphthalene sulfonamide ABA agonist pyrabactin, which activates seed ABA responses but fails to trigger substantial responses in vegetative tissues in Arabidopsis thaliana. Here we describe quinabactin, a sulfonamide ABA agonist that preferentially activates dimeric ABA receptors and possesses ABA-like potency in vivo. In Arabidopsis, the transcriptional responses induced by quinabactin are highly correlated with those induced by ABA treatments. Quinabactin treatments elicit guard cell closure, suppress water loss, and promote drought tolerance in adult Arabidopsis and soybean plants. The effects of quinabactin are sufficiently similar to those of ABA that it is able to rescue multiple phenotypes observed in the ABA-deficient mutant aba2. Genetic analyses show that quinabactin's effects in vegetative tissues are primarily mediated by dimeric ABA receptors. A PYL2 quinabactin-HAB1 X-ray crystal structure solved at 1.98-A resolution shows that quinabactin forms a hydrogen bond with the receptor/PP2C "lock" hydrogen bond network, a structural feature absent in pyrabactin-receptor/PP2C complexes. Our results demonstrate that ABA receptors can be chemically controlled to enable plant protection against water stress and define the dimeric receptors as key targets for chemical modulation of vegetative ABA responses. PMID- 23818639 TI - Role of a microcin-C-like biosynthetic gene cluster in allelopathic interactions in marine Synechococcus. AB - Competition between phytoplankton species for nutrients and light has been studied for many years, but allelopathic interactions between them have been more difficult to characterize. We used liquid and plate assays to determine whether these interactions occur between marine unicellular cyanobacteria of the genus Synechococcus. We have found a clear growth impairment of Synechococcus sp. CC9311 and Synechococcus sp. WH8102 when they are cultured in the presence of Synechococcus sp. CC9605. The genome of CC9605 contains a region showing homology to genes of the Escherichia coli Microcin C (McC) biosynthetic pathway. McC is a ribosome-synthesized peptide that inhibits translation in susceptible strains. We show that the CC9605 McC gene cluster is expressed and that three genes (mccD, mccA, and mccB) are further induced by coculture with CC9311. CC9605 was resistant to McC purified from E. coli, whereas strains CC9311 and WH8102 were sensitive. Cloning the CC9605 McC biosynthetic gene cluster into sensitive CC9311 led this strain to become resistant to both purified E. coli McC and Synechococcus sp. CC9605. A CC9605 mutant lacking mccA1, mccA2, and the N terminal domain of mccB did not inhibit CC9311 growth, whereas the inhibition of WH8102 was reduced. Our results suggest that an McC-like molecule is involved in the allelopathic interactions with CC9605. PMID- 23818640 TI - Modulation of B-cell exosome proteins by gamma herpesvirus infection. AB - The human gamma herpesviruses, Kaposi sarcoma-associated virus (KSHV) and EBV, are associated with multiple cancers. Recent evidence suggests that EBV and possibly other viruses can manipulate the tumor microenvironment through the secretion of specific viral and cellular components into exosomes, small endocytically derived vesicles that are released from cells. Exosomes produced by EBV-infected nasopharyngeal carcinoma cells contain high levels of the viral oncogene latent membrane protein 1 and viral microRNAs that activate critical signaling pathways in recipient cells. In this study, to determine the effects of EBV and KSHV on exosome content, quantitative proteomics techniques were performed on exosomes purified from 11 B-cell lines that are uninfected, infected with EBV or with KSHV, or infected with both viruses. Using mass spectrometry, 871 proteins were identified, of which ~360 were unique to the viral exosomes. Analysis by 2D difference gel electrophoresis and spectral counting identified multiple significant changes compared with the uninfected control cells and between viral groups. These data predict that both EBV and KSHV exosomes likely modulate cell death and survival, ribosome function, protein synthesis, and mammalian target of rapamycin signaling. Distinct viral-specific effects on exosomes suggest that KSHV exosomes would affect cellular metabolism, whereas EBV exosomes would activate cellular signaling mediated through integrins, actin, IFN, and NFkappaB. The changes in exosome content identified in this study suggest ways that these oncogenic viruses modulate the tumor microenvironment and may provide diagnostic markers specific for EBV and KSHV associated malignancies. PMID- 23818641 TI - Systematic profiling of Caenorhabditis elegans locomotive behaviors reveals additional components in G-protein Galphaq signaling. AB - Genetic screens have been widely applied to uncover genetic mechanisms of movement disorders. However, most screens rely on human observations of qualitative differences. Here we demonstrate the application of an automatic imaging system to conduct a quantitative screen for genes regulating the locomotive behavior in Caenorhabditis elegans. Two hundred twenty-seven neuronal signaling genes with viable homozygous mutants were selected for this study. We tracked and recorded each animal for 4 min and analyzed over 4,400 animals of 239 genotypes to obtain a quantitative, 10-parameter behavioral profile for each genotype. We discovered 87 genes whose inactivation causes movement defects, including 50 genes that had never been associated with locomotive defects. Computational analysis of the high-content behavioral profiles predicted 370 genetic interactions among these genes. Network partition revealed several functional modules regulating locomotive behaviors, including sensory genes that detect environmental conditions, genes that function in multiple types of excitable cells, and genes in the signaling pathway of the G protein Galphaq, a protein that is essential for animal life and behavior. We developed quantitative epistasis analysis methods to analyze the locomotive profiles and validated the prediction of the gamma isoform of phospholipase C as a component in the Galphaq pathway. These results provided a system-level understanding of how neuronal signaling genes coordinate locomotive behaviors. This study also demonstrated the power of quantitative approaches in genetic studies. PMID- 23818642 TI - Enhanced transcription rates in membrane-free protocells formed by coacervation of cell lysate. AB - Liquid-liquid phase transitions in complex mixtures of proteins and other molecules produce crowded compartments supporting in vitro transcription and translation. We developed a method based on picoliter water-in-oil droplets to induce coacervation in Escherichia coli cell lysate and follow gene expression under crowded and noncrowded conditions. Coacervation creates an artificial cell like environment in which the rate of mRNA production is increased significantly. Fits to the measured transcription rates show a two orders of magnitude larger binding constant between DNA and T7 RNA polymerase, and five to six times larger rate constant for transcription in crowded environments, strikingly similar to in vivo rates. The effect of crowding on interactions and kinetics of the fundamental machinery of gene expression has a direct impact on our understanding of biochemical networks in vivo. Moreover, our results show the intrinsic potential of cellular components to facilitate macromolecular organization into membrane-free compartments by phase separation. PMID- 23818643 TI - Evaluation of mixed-source, low-template DNA profiles in forensic science. AB - Enhancements in sensitivity now allow DNA profiles to be obtained from only tens of picograms of DNA, corresponding to a few cells, even for samples subject to degradation from environmental exposure. However, low-template DNA (LTDNA) profiles are subject to stochastic effects, such as "dropout" and "dropin" of alleles, and highly variable stutter peak heights. Although the sensitivity of the newly developed methods is highly appealing to crime investigators, courts are concerned about the reliability of the underlying science. High-profile cases relying on LTDNA evidence have collapsed amid controversy, including the case of Hoey in the United Kingdom and the case of Knox and Sollecito in Italy. I argue that rather than the reliability of the science, courts and commentators should focus on the validity of the statistical methods of evaluation of the evidence. Even noisy DNA evidence can be more powerful than many traditional types of evidence, and it can be helpful to a court as long as its strength is not overstated. There have been serious shortcomings in statistical methods for the evaluation of LTDNA profile evidence, however. Here, I propose a method that allows for multiple replicates with different rates of dropout, sporadic dropins, different amounts of DNA from different contributors, relatedness of suspected and alternate contributors, "uncertain" allele designations, and degradation. R code implementing the method is open source, facilitating wide scrutiny. I illustrate its good performance using real cases and simulated crime scene profiles. PMID- 23818644 TI - Natural killer cells in HIV controller patients express an activated effector phenotype and do not up-regulate NKp44 on IL-2 stimulation. AB - Control of HIV replication in elite controller (EC) and long-term nonprogressor (LTNP) patients has been associated with efficient CD8(+)cytotoxic T-lymphocyte function. However, innate immunity may play a role in HIV control. We studied the expression of natural cytotoxicity receptors (NKp46, NKp30, and NKp44) and their induction over a short time frame (2-4 d) on activation of natural killer (NK) cells in 31 HIV controller patients (15 ECs, 16 LTNPs). In EC/LTNP, induction of NKp46 expression was normal but short (2 d), and NKp30 was induced to lower levels vs. healthy donors. Notably, in antiretroviral-treated aviremic progressor patients (TAPPs), no induction of NKp46 or NKp30 expression occurred. More importantly, EC/LTNP failed to induce expression of NKp44, a receptor efficiently induced in activated NK cells in TAPPs. The specific lack of NKp44 expression resulted in sharply decreased capability of killing target cells by NKp44, whereas TAPPs had conserved NKp44-mediated lysis. Importantly, conserved NK cell responses, accompanied by a selective defect in the NKp44-activating pathway, may result in lack of killing of uninfected CD4(+)NKp44Ligand(+) cells when induced by HIVgp41 peptide-S3, representing a relevant mechanism of CD4(+) depletion. In addition, peripheral NK cells from EC/LTNP had increased NKG2D expression, significant HLA-DR up-regulation, and a mature (NKG2A-CD57(+)killer cell Ig-like receptor(+)CD85j(+)) phenotype, with cytolytic function also against immature dendritic cells. Thus, NK cells in EC/LTNP can maintain substantially unchanged functional capabilities, whereas the lack of NKp44 induction may be related to CD4 maintenance, representing a hallmark of these patients. PMID- 23818645 TI - Aryl hydrocarbon receptor-mediated induction of the microRNA-132/212 cluster promotes interleukin-17-producing T-helper cell differentiation. AB - Aryl hydrocarbon receptor (AHR) plays critical roles in various autoimmune diseases such as multiple sclerosis by controlling interleukin-17 (IL-17) producing T-helper (TH17) and regulatory T cells. Although various transcription factors and cytokines have been identified as key participants in TH17 generation, the role of microRNAs in this process is poorly understood. In this study, we found that expression of the microRNA (miR)-132/212 cluster is up regulated by AHR activation under TH17-inducing, but not regulatory T-inducing conditions. Deficiency of the miR-132/212 cluster prevented the enhancement of TH17 differentiation by AHR activation. We also identified B-cell lymphoma 6, a negative regulator of TH17 differentiation, as a potential target of the miR-212. Finally, we investigated the roles of the miR-132/212 cluster in experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis. Mice deficient in the miR-132/212 cluster exhibited significantly higher resistance to the development of experimental autoimmune encephalomyelitis and lower frequencies of both TH1 and TH17 cells in draining lymph nodes. Our findings reveal a unique mechanism of AHR-dependent TH17 differentiation that depends on the miR-132/212 cluster. PMID- 23818646 TI - Massively parallel in vivo enhancer assay reveals that highly local features determine the cis-regulatory function of ChIP-seq peaks. AB - Transcription factors (TFs) recognize short sequence motifs that are present in millions of copies in large eukaryotic genomes. TFsmust distinguish their target binding sites from a vast genomic excess of spurious motif occurrences; however, it is unclear whether functional sites are distinguished from nonfunctional motifs by local primary sequence features or by the larger genomic context in which motifs reside. We used a massively parallel enhancer assay in living mouse retinas to compare 1,300 sequences bound in the genome by the photoreceptor transcription factor Cone-rod homeobox (Crx), to 3,000 control sequences. We found that very short sequences bound in the genome by Crx activated transcription at high levels, whereas unbound genomic regions with equal numbers of Crx motifs did not activate above background levels, even when liberated from their larger genomic context. High local GC content strongly distinguishes bound motifs from unbound motifs across the entire genome. Our results show that the cis-regulatory potential of TF-bound DNA is determined largely by highly local sequence features and not by genomic context. PMID- 23818648 TI - Coronary microvascular dysfunction is an early feature of cardiac involvement in patients with Anderson-Fabry disease. AB - AIMS: Male patients with Anderson-Fabry disease (AFD) often exhibit cardiac involvement, characterized by LV hypertrophy (LVH), associated with severe coronary microvascular dysfunction (CMD). Whether CMD is present in patients without LVH, particularly when female, remains unresolved. The aim of the study was to investigate the presence of CMD by positron emission tomography (PET) in AFD patients of both genders, with and without evidence of LVH. METHODS AND RESULTS: We assessed myocardial blood flow following dipyridamole infusion (Dip MBF) with 13N-labelled ammonia by PET in 30 AFD patients (age 51 +/- 13 years; 18 females) and in 24 healthy controls. LVH was defined as echocardiographic maximal LV wall thickness >=13 mm. LVH was present in 67% of patients (n = 20; 10 males and 10 females). Dip-MBF was reduced in all patients compared with controls (1.8 +/- 0.5 and 3.2 +/- 0.5 mL/min/g, respectively, P < 0.001). For both genders, flow impairment was most severe in patients with LVH (1.4 +/- 0.5 mL/min/g in males and 1.9 +/- 0.5 mL/min/g in females), but was also evident in those without LVH (1.8 +/- 0.3 mL/min/g in males and 2.1 +/- 0.4 mL/min/g in females; overall P = 0.064 vs. patients with LVH). Analysis of variance (ANOVA) for the 17 LV segments showed marked regional heterogeneity of MBF in AFD (F = 4.46, P < 0.01), with prevalent hypoperfusion of the apical region. Conversely, controls showed homogeneous LV perfusion (F = 1.25, P = 0.23). CONCLUSIONS: Coronary microvascular function is markedly impaired in AFD patients irrespective of LVH and gender. CMD may represent the only sign of cardiac involvement in AFD patients, with potentially important implications for clinical management. PMID- 23818649 TI - Right ventricular hypertrophy and failure abolish cardioprotection by ischaemic pre-conditioning. AB - AIMS: We aimed to investigate the response to ischaemia-reperfusion (IR) and ischaemic pre-conditioning (IPC) in the hypertrophic and failing right heart. METHODS AND RESULTS: Male Wistar rats underwent sham operation, moderate pulmonary trunk banding (mPTB), or severe PTB (sPTB). Four weeks after surgery, hearts were quick-frozen (n = 28) for biochemical analysis of key salvage pathways or isolated and perfused in a Langendorff set-up (n = 46). We randomized perfused hearts to IPC (2 * 5 min of global ischaemia) or no preceding ischaemia (CON), before 40 min of global ischaemia and 120 min of reperfusion. The infarct size/area at risk (IS/AAR) ratio and post-ischaemic right ventricular (RV) function were used to evaluate the effect of IPC. mPTB induced compensated RV hypertrophy and sPTB induced RV hypertrophy with failure. Hypertrophy of the right ventricle increased IS in hearts from mPTB and sPTB animals compared with sham (IS/AAR, 73.1 +/- 2.9% and 59.3 +/- 2.4% vs. 35.6 +/- 2.9%, P < 0.0001). IPC reduced IS in sham and mPTB hearts (IS/AAR, 35.6 +/- 2.9% vs. 17.4 +/- 1.2% and 73.1 +/- 2.9% vs. 56.9 +/- 3.5%, P < 0.01) and improved recovery of RV contractile function. IPC did not alter IS/AAR (59.3 +/- 2.4% and 59.3 +/- 2.9%, P = 0.999) or haemodynamic recovery in sPTB hearts. RV cyclic guanosine monophosphate (cGMP) and the cGMP-dependent protein kinase were increased after sPTB. CONCLUSION: Right ventricular hypertrophy increases IR injury. Cardioprotection by IPC is abolished in the failing but not the compensated hypertrophic right ventricle of the rat heart. PMID- 23818650 TI - To remove or to replace traditional electronic games? A crossover randomised controlled trial on the impact of removing or replacing home access to electronic games on physical activity and sedentary behaviour in children aged 10-12 years. AB - OBJECTIVE: To evaluate the impact of (1) the removal of home access to traditional electronic games or (2) their replacement with active input electronic games, on daily physical activity and sedentary behaviour in children aged 10-12 years. DESIGN: Crossover randomised controlled trial, over 6 months. SETTING: Family homes in metropolitan Perth, Australia from 2007 to 2010. PARTICIPANTS: 10-year-old to 12-year-old children were recruited through school and community media. From 210 children who were eligible, 74 met inclusion criteria, 8 withdrew and 10 had insufficient primary outcome measures, leaving 56 children (29 female) for analysis. INTERVENTION: A counterbalanced randomised order of three conditions sustained for 8 weeks each: no home access to electronic games, home access to traditional electronic games and home access to active input electronic games. MAIN OUTCOME MEASURES: Primary outcome was accelerometer assessed moderate/vigorous physical activity (MVPA). Secondary outcomes included sedentary time and diary assessed physical activity and sedentary behaviours. RESULTS: Daily MVPA across the whole week was not significantly different between conditions. However, compared with home access to traditional electronic games, removal of all electronic games resulted in a significant increase in MVPA (mean 3.8 min/day, 95% CI 1.5 to 6.1) and a decrease in sedentary time (4.7 min/day, 0.0 to 9.5) in the after-school period. Similarly, replacing traditional games with active input games resulted in a significant increase in MVPA (3.2 min/day, 0.9 to 5.5) and a decrease in sedentary time (6.2 min/day, 1.4 to 11.4) in the after-school period. Diary reports supported an increase in physical activity and a decrease in screen-based sedentary behaviours with both interventions. CONCLUSIONS: Removal of sedentary electronic games from the child's home and replacing these with active electronic games both resulted in small, objectively measured improvements in after-school activity and sedentary time. Parents can be advised that replacing sedentary electronic games with active electronic games is likely to have the same effect as removing all electronic games. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Registry (ACTRN 12609000279224). PMID- 23818651 TI - One without the other: seeing relationships in everyday objects. AB - People often make multiple choices at the same time, choosing a snack and drink or a cell phone and case, only to learn that some of their choices are unavailable. Do they take the available item (or items) or something else entirely? Culture-as-situated-cognition theory predicts that this choice is determined by one's accessible cultural mind-set. An accessible collectivist (vs. individualist) mind-set should heighten sensitivity to an emergent relationship among items chosen together so that having some is not acceptable if not all can be obtained. Indeed, we found that Latinos (but not Anglos) refuse chosen items if not all can be obtained (Study 1a). Further, making a collectivist mind-set accessible reproduces this between-groups difference (Study 1b), increases people's willingness to pay to complete sets (Study 1b), and shifts choice to previously undesired items if no set-completing option is provided (Studies 2-4). Finally, we found that increased sensitivity to an emergent relationship among chosen items mediates these effects (Studies 3 and 4). PMID- 23818652 TI - Unstable identity compatibility: how gender rejection sensitivity undermines the success of women in science, technology, engineering, and mathematics fields. AB - Although the perceived compatibility between one's gender and science, technology, engineering, and mathematics (STEM) identities (gender-STEM compatibility) has been linked to women's success in STEM fields, no work to date has examined how the stability of identity over time contributes to subjective and objective STEM success. In the present study, 146 undergraduate female STEM majors rated their gender-STEM compatibility weekly during their freshman spring semester. STEM women higher in gender rejection sensitivity, or gender RS, a social-cognitive measure assessing the tendency to perceive social-identity threat, experienced larger fluctuations in gender-STEM compatibility across their second semester of college. Fluctuations in compatibility predicted impaired outcomes the following school year, including lower STEM engagement and lower academic performance in STEM (but not non-STEM) classes, and significantly mediated the relationship between gender RS and STEM engagement and achievement in the 2nd year of college. The week-to-week changes in gender-STEM compatibility occurred in response to negative academic (but not social) experiences. PMID- 23818653 TI - The nature and nurture of high IQ: an extended sensitive period for intellectual development. AB - IQ predicts many measures of life success, as well as trajectories of brain development. Prolonged cortical thickening observed in individuals with high IQ might reflect an extended period of synaptogenesis and high environmental sensitivity or plasticity. We tested this hypothesis by examining the timing of changes in the magnitude of genetic and environmental influences on IQ as a function of IQ score. We found that individuals with high IQ show high environmental influence on IQ into adolescence (resembling younger children), whereas individuals with low IQ show high heritability of IQ in adolescence (resembling adults), a pattern consistent with an extended sensitive period for intellectual development in more-intelligent individuals. The pattern held across a cross-sectional sample of almost 11,000 twin pairs and a longitudinal sample of twins, biological siblings, and adoptive siblings. PMID- 23818654 TI - Look before you leap: sensory memory improves decision making. AB - Simple decisions require the processing and evaluation of perceptual and cognitive information, the formation of a decision, and often the execution of a motor response. This process involves the accumulation of evidence over time until a particular choice reaches a decision threshold. Using a random-dot-motion stimulus, we showed that simply delaying responses after the stimulus offset can almost double accuracy, even in the absence of new incoming visual information. However, under conditions in which the otherwise blank interval was filled with a sensory mask or concurrent working memory load was high, performance gains were lost. Further, memory and perception showed equivalent rates of evidence accumulation, suggesting a high-capacity memory store. We propose an account of continued evidence accumulation by sequential sampling from a simultaneously decaying memory trace. Memories typically decay with time, hence immediate inquiry trumps later recall from memory. However, the results we report here show the inverse: Inspecting a memory trumps viewing the actual object. PMID- 23818655 TI - Explaining the increasing heritability of cognitive ability across development: a meta-analysis of longitudinal twin and adoption studies. AB - Genes account for increasing proportions of variation in cognitive ability across development, but the mechanisms underlying these increases remain unclear. We conducted a meta-analysis of longitudinal behavioral genetic studies spanning infancy to adolescence. We identified relevant data from 16 articles with 11 unique samples containing a total of 11,500 twin and sibling pairs who were all reared together and measured at least twice between the ages of 6 months and 18 years. Longitudinal behavioral genetic models were used to estimate the extent to which early genetic influences on cognition were amplified over time and the extent to which innovative genetic influences arose with time. Results indicated that in early childhood, innovative genetic influences predominate but that innovation quickly diminishes, and amplified influences account for increasing heritability following age 8 years. PMID- 23818656 TI - Perceived aggressiveness predicts fighting performance in mixed-martial-arts fighters. AB - Accurate assessment of competitive ability is a critical component of contest behavior in animals, and it could be just as important in human competition, particularly in human ancestral populations. Here, we tested the role that facial perception plays in this assessment by investigating the association between both perceived aggressiveness and perceived fighting ability in fighters' faces and their actual fighting success. Perceived aggressiveness was positively associated with the proportion of fights won, after we controlled for the effect of weight, which also independently predicted perceived aggression. In contrast, perception of fighting ability was confounded by weight, and an association between perceived fighting ability and actual fighting success was restricted to heavyweight fighters. Shape regressions revealed that aggressive-looking faces are generally wider and have a broader chin, more prominent eyebrows, and a larger nose than less aggressive-looking faces. Our results indicate that perception of aggressiveness and fighting ability might cue different aspects of success in male-male physical confrontation. PMID- 23818657 TI - Age, actuarial risk, and long-term recidivism in a national sample of sex offenders. AB - Age at release has become an increasing focus of study with regard to evaluating risk in the sex offender population and has been repeatedly shown to be an important component of the risk assessment equation. This study constitutes an extension of a study of sex offender outcomes prepared for the Evaluation Branch, Correctional Service of Canada. The entire cohort of 2,401 male federally incarcerated sexual offenders who reached their warrant expiry date (WED) within 1997/1998, 1998/1999, and 1999/2000 fiscal years were reviewed for the study. Sexual and violent reconviction information was obtained from CPIC criminal records over an average of 12.0 years (SD = 1.7) follow-up. This study focused upon the cohort of sex offenders who were 50 years or older at time of release (N = 542). They were stratified according to risk using a brief actuarial scale (BARS) comprising six binary variables. For the most part, older offenders showed low base rates of sexual recidivism regardless of the risk band into which they fell. The exception was a small group of elderly offenders (n = 20) who fell into the highest risk band, and who showed high levels of sexual recidivism. The results of this combination of cross-sectional and longitudinal analyses of elderly sexual offenders may have important implications for offender management, particularly in light of the increasing numbers of offenders in Canada who fall into the over 50 age cohort. PMID- 23818658 TI - Update on platelet glycoprotein IIb/IIIa inhibitors: recommendations for clinical practice. AB - Antiplatelet therapy is the cornerstone of treatment for patients with acute coronary syndrome (ACS) and undergoing percutaneous coronary intervention (PCI). Glycoprotein IIb/IIIa receptors mediate platelet aggregation, representing the final common pathway of platelet-mediated thrombosis. Therefore, agents blocking this pathway may be desirable for the treatment of patients with ACS and PCI. Glycoprotein IIb/IIIa receptor inhibitors have been widely investigated and have been key to the pharmacological advancements in the field. However, although GPIs have been important to reduce ischemic complications, their elevated risk of bleeding complications remains a major limitation. The poor prognostic implications, including increased mortality, associated with bleeding complication underscores the need for alternative treatment options. Over the past years there have been several advancements in antithrombotic pharmacology which have led to changes in recommendations for GPI usage in clinical practice. This is an overview of the most recent clinical trial data on GPIs, and provides practical insight on their modern day use in ACS therapy. PMID- 23818659 TI - Images in vascular medicine. Calcific uremic arteriolopathy of the penis. PMID- 23818660 TI - Is goal-directed attentional guidance just intertrial priming? A review. AB - According to most models of selective visual attention, our goals at any given moment and saliency in the visual field determine attentional priority. But selection is not carried out in isolation--we typically track objects through space and time. This is not well captured within the distinction between goal directed and saliency-based attentional guidance. Recent studies have shown that selection is strongly facilitated when the characteristics of the objects to be attended and of those to be ignored remain constant between consecutive selections. These studies have generated the proposal that goal-directed or top down effects are best understood as intertrial priming effects. Here, we provide a detailed overview and critical appraisal of the arguments, experimental strategies, and findings that have been used to promote this idea, along with a review of studies providing potential counterarguments. We divide this review according to different types of attentional control settings that observers are thought to adopt during visual search: feature-based settings, dimension-based settings, and singleton detection mode. We conclude that priming accounts for considerable portions of effects attributed to top-down guidance, but that top down guidance can be independent of intertrial priming. PMID- 23818661 TI - Imaging and manipulating calcium transients in developing Xenopus spinal neurons. AB - Many forms of electrical excitability expressed in the embryonic nervous system depend on Ca(2+) influx. This discovery has stimulated investigation of the functions of spontaneous elevations of intracellular Ca(2+) and their roles in neuronal development. We present a protocol for imaging different classes of intracellular Ca(2+) transients in embryonic Xenopus (amphibian) spinal neurons grown in dissociated cell culture and in the intact neural tube (the developing spinal cord), focusing on early stages of neuronal differentiation around the time of neural tube closure. The protocol describes methods for gain-of-function and loss-of-function experiments to reveal the functions of these Ca(2+) transients. The methods can also be applied to explant and organotypic cultures. The procedures are sufficiently simple that they can be further adapted for dissociated neuronal cell cultures from other developing embryos, embryonic spinal cords of vertebrates such as zebrafish, and ganglia in the developing nervous systems of invertebrates. PMID- 23818662 TI - Immunoblotting histones from yeast whole-cell protein extracts. AB - Histones are small basic proteins that are core components of chromatin. As such, they are essential for cell viability and genomic stability and their levels are tightly controlled. In addition, histone tails are subject to extensive posttranslational modifications, including acetylation, methylation, phosphorylation and ubiquitylation, that play critical roles in many cellular processes. To quickly screen for alterations in histone levels and/or their modifications in yeast mutants under different growth conditions, we present a fast and reliable protocol for whole-cell protein extract preparation and immunoblotting. PMID- 23818663 TI - Purification and culture of retinal ganglion cells. AB - Retinal ganglion cells (RGCs) are the neurons that extend axons through the optic nerve, connecting and transmitting information from the retina to the brain. In mammals, RGCs receive information from bipolar and amacrine cells and synapse onto target cells in the lateral geniculate nucleus (LGN) as well as the superior colliculus. Methods for acute purification of RGCs from rodent retina by immunopanning followed by culture in a serum-free medium have facilitated the study of neuronal biology and function in a defined environment. These methods are introduced here, and modifications for achieving optimal RGC purity and culture are described. PMID- 23818664 TI - Counting and measuring ultrastructural features of biological samples. AB - Ultrastructural features of cells can be fractions of a micrometer in diameter, and electron microscopy is needed to resolve them to a degree that is compatible with stereological techniques. Because the focal depth of transmission electron microscopy (TEM) images is thousands of times greater than the thickness of the sections used with TEM, virtual sectioning of sections suitable for TEM is not possible, as it is with light microscopy and the optical disector probe. With features the size of neuronal synapses, for example, this necessitates the use of physical sections and physical disectors. Regardless of how the imaging is performed, the design of stereological studies for quantifying ultrastructural features will be essentially the same as that used in the example described here, which uses physically separated ultrathin sections viewed with conventional TEM to estimate the number and size of synapses in a particular brain region. PMID- 23818665 TI - Live cell imaging of cytoplasmic Ca2+ dynamics in Arabidopsis guard cells. AB - This protocol describes a classical method for measuring cytoplasmic Ca(2+) dynamics in Arabidopsis thaliana guard cells. The Forster (fluorescence) resonance energy transfer (FRET)-based genetically modified Ca(2+) indicator Yellow Cameleon YC3.6, under the control of the guard cell-specific promoter GC1, is used for Ca(2+) measurements. PMID- 23818666 TI - High-resolution imaging of cytoplasmic Ca2+ dynamics in Arabidopsis roots. AB - This protocol describes a method for imaging cytoplasmic Ca(2+) dynamics in roots with high resolution using confocal laser scanning microscopy (CLSM). The Forster (fluorescence) resonance energy transfer (FRET)-based genetically modified Ca(2+) indicator Yellow Cameleon YC3.6, stably expressed in plants under the control of the ubiquitin promoter UBQ10, is used for Ca(2+) measurements. This protocol enables imaging of 5- to 7-d-old seedlings with high-magnification objectives (25*, 40*, and 63*). PMID- 23818667 TI - Purification and culture of retinal ganglion cells from rodents. AB - Here we describe methods for acute purification of retinal ganglion cells (RGCs) from rodent retina by immunopanning, followed by culture in serum-free medium. Though the method was initially established and verified with rats, we have included modifications for the purification of mouse RGCs. This protocol is written for isolation of cells from one litter of pups. All of the volumes and numbers of panning plates should be scaled according to the number of litters used, particularly for rat RGCs. PMID- 23818668 TI - Culturing hybridoma cell lines for monoclonal antibody production. AB - This protocol describes how to culture hybridoma cell lines (e.g., Thy1.1) for monoclonal antibody production. Supernatants harvested from such cultures can be used to purify various rodent neural cell types by immunopanning. PMID- 23818669 TI - Measuring interstitial pH and pO2 in mouse tumors. AB - This protocol outlines methods to measure two extravascular parameters, interstitial pH and partial pressure of oxygen (pO2), in mouse tumors. The method for measuring interstitial pH uses fluorescence ratio imaging microscopy (FRIM) of the pH-sensitive fluorescent dye 2',7'-bis-(2-carboxyethyl)-5,6 carboxyfluorescein (BCECF). The method for measuring interstitial pO2 is based on the oxygen-dependent quenching of the phosphorescence of albumin-bound palladium meso-tetra(4-carboxyphenyl)porphyrin, and can be used to measure microvascular as well as interstitial pO2. In addition, the two methods can be used sequentially to measure both pH and pO2 in the same tissues. PMID- 23818670 TI - Measuring interstitial diffusion, convection, and binding parameters in mouse tumors. AB - Noninvasive techniques have been developed for the assessment of various parameters in normal and diseased tissues of mice. This protocol describes the measurement of extravascular parameters, including interstitial diffusion, convection, and binding parameters, in mouse tumors. A fluorescently labeled molecule of interest is infused into the tumor interstitium, followed by imaging using single-photon microscopy or multiphoton laser-scanning microscopy (MPLSM). Fluorescence recovery after photobleaching (FRAP) with spatial Fourier analysis is performed. To measure interstitial diffusion coefficients, multiphoton FRAP is performed. PMID- 23818671 TI - Measuring membrane voltage with fluorescent proteins. AB - Measuring signal transduction in large numbers of cells with high spatial and temporal resolution is fundamental to studying information processing in the nervous system. DNA-encoded sensors have an advantage in that they can be introduced into an organism noninvasively and targeted to specific brain regions, cell types, or subcellular compartments. A variety of chimeric proteins that report transmembrane voltage have been developed. The prototype sensor, FlaSh, is a green fluorescent protein fused to a voltage-sensitive K(+) channel, where voltage-dependent rearrangements in the channel induce changes in the protein's fluorescence. Subsequent sensors have refined this basic design using a monomeric voltage-sensing phosphatase domain from Ciona intestinalis and pairs of fluorescent proteins to produce a larger fluorescent signal. These sensors and their uses are discussed here. PMID- 23818672 TI - Dehydration and clearing of adult Drosophila for ultramicroscopy. AB - This protocol describes the preparation of adult flies for ultramicroscopy (UM), a powerful imaging technique that achieves precise and accurate three-dimensional (3D) reconstructions of intact macroscopic specimens with micrometer resolution. In UM, a specimen in the size range of ~1-15 mm is illuminated perpendicular to the observation pathway by two thin counterpropagating sheets of laser light. Thus, specimens for UM need to be sufficiently transparent, which requires chemical clearing in most cases. In this protocol, Drosophila melanogaster adults are fixed, dehydrated in ethanol, and then cleared in a solution of benzyl alcohol and benzyl benzoate. PMID- 23818673 TI - Dehydration and clearing of whole mouse brains and dissected hippocampi for ultramicroscopy. AB - This protocol describes the preparation of whole mouse brains and dissected hippocampi for ultramicroscopy (UM), a powerful imaging technique that achieves precise and accurate three-dimensional (3D) reconstructions of intact macroscopic specimens with micrometer resolution. In UM, a specimen in the size range of ~1 15 mm is illuminated perpendicular to the observation pathway by two thin counterpropagating sheets of laser light. Thus, specimens for UM need to be sufficiently transparent, which requires chemical clearing in most cases. In this protocol, mouse brains and hippocampi are carefully dissected and dehydrated, and then cleared in a solution of benzyl benzoate and benzyl alcohol. PMID- 23818674 TI - The fundamentals of RNA purification. AB - The ability to purify, analyze, and manipulate RNA is now essential for many laboratories working in the life sciences; however, the skills and practices required to work with RNA are not present in every laboratory, and initiating RNA research can be intimidating. In this article, we provide an overview of RNA purification procedures and discuss strategies to prevent RNA degradation, so that any competent researcher can confidently purify RNA and use it to perform meaningful experiments from the most basic to the highly sophisticated. PMID- 23818675 TI - Creating an miR30-based shRNA vector. AB - Generating expression constructs for artificial microRNAs (miRNAs) is relatively straightforward. This protocol describes the creation of miR-30-based short hairpin RNA (shRNA) cassettes that are compatible with a number of standard vector systems. The principles outlined here can also be easily applied to other miRNA scaffolds or to simple snapback shRNAs. It is important to note that one must understand the processing of the artificial scaffold and be able to predict precisely the small RNAs that will be generated. Otherwise, no design principles can be effectively applied and the probability that any individual shRNA clone will work effectively will be greatly reduced. PMID- 23818676 TI - Electrophoretic mobility-shift assays. AB - In an electrophoretic mobility-shift assay (EMSA, or simply "gel shift"), a (32)P labeled DNA fragment containing a specific DNA site is incubated with a cognate DNA-binding protein. The protein-DNA complexes are separated from free (unbound) DNA by electrophoresis through a nondenaturing polyacrylamide gel. The protein retards the mobility of the DNA fragments to which it binds. Thus, the free DNA will migrate faster than the DNA-protein complex. An image of the gel is used to reveal the positions of the free and bound radiolabeled DNAs. PMID- 23818677 TI - Saccadic brightness decisions do not use a difference model. AB - Eye movements are the most frequent (~3 per second), shortest-latency (~150-250 ms), and biomechanically simplest (1 joint, no inertial complexities) voluntary motor behavior in primates, providing a model sensorimotor decision-making system. Current computational "difference" models of choice behavior utilize a single decision variable encoding the difference between two alternate signals, often implemented as a log-likelihood ratio. Alternatively, the oculomotor literature describes a "race" mechanism, in which two separate decision variables encoding the two alternate signals race against one another independently. These two models make two qualitatively distinct predictions, which can be tested empirically with a two-alternative forced-choice task. Unlike the race model, a decision variable based upon a differencing operation predicts strong mirror image correlations between response time (RT) and the signal strengths of the selected and unselected stimuli (because differencing creates equal and opposite correlations). In a saccadic brightness discrimination task, we observed positive correlations between response rate (1/RT) and the strength of both the selected and unselected stimulus, a simple qualitative prediction of race models that applies to any 2AFC task but which is fundamentally at odds with the most basic prediction of any difference model. Our data are, however, qualitatively consistent with a mechanism in which two competing motor plans co-exist and their two corresponding neural decision variables race to a threshold to drive the saccadic decision. PMID- 23818678 TI - Remapping time across space. AB - Multiple lines of evidence indicate that visual attention's temporal properties differ between the left and right visual fields (LVF and RVF). Notably, recent electroencephalograph recordings indicate that event-related potentials peak earlier for LVF than for RVF targets on bilateral-stream rapid serial visual presentation (RSVP) identification tasks. Might this hastened neural response render LVF targets perceptually available sooner than RVF targets? If so, how might the visual system reconcile these timing differences to estimate simultaneity across the LVF and RVF? We approached these questions by presenting bilateral-stream RSVP displays that contained opposite-hemifield targets and requiring participants to judge both the targets' temporal order and simultaneity. The temporal order judgments (TOJs) revealed that participants perceived LVF targets ~134 ms sooner than RVF targets. This LVF hastening approximates a full cycle of visual attention's canonical ~10 Hz (~100 ms) temporal resolution. In contrast, performance on the simultaneity task did not exhibit the LVF hastening observed on the TOJ task, despite identical retinal stimulation across the two tasks. This finding rules out a stimulus-driven "bottom-up" explanation for the task-specific behavior. Moreover, error patterns across the two tasks revealed that, within the decision stage of simultaneity judgments, participants remapped LVF targets, but not RVF targets, to a later time in the RSVP sequence. Such hemifield-specific remapping would effectively compensate for the cross-hemifield asymmetries in neural response latencies that could otherwise impair simultaneity estimates. PMID- 23818679 TI - Evidence-based assessment of childhood injuries and physical risk-taking behaviors. AB - OBJECTIVE: To offer a critical evidence-based review and summary of assessment methods of childhood injuries and physical risk-taking behaviors. METHODS: A literature review was conducted to identify methodologies for assessing injury events and physical risk-taking behaviors. Methodologies reviewed included self- or parent-report scales, behavioral observations, and participant event monitoring. We classified methodologies according to published criteria of "well established," "approaching well-established," or "promising." RESULTS: 7 methodologies were classified as "well-established", 9 were classified as "approaching well-established", and 8 were classified as "promising." CONCLUSIONS: Several approaches to assessing injuries or physical risk-taking behaviors have strong psychometric properties. Opportunities for further psychometric validation of techniques are noted. It is hoped that this review inspires researchers throughout the fields of pediatric and clinical child psychology to adopt assessments of injury and physical risk-taking in their ongoing research efforts. PMID- 23818680 TI - Vitamin and mineral supplement adherence in pediatric inflammatory bowel disease. AB - OBJECTIVE: Although vitamin and mineral supplementation for nutritional deficiencies is a common component of pediatric inflammatory bowel disease (IBD) management, little is known about supplement adherence in this group. This study described adherence to multivitamin, iron, and calcium supplements among 49 youth aged 11-18 years with IBD. Additionally, the study examined relationships between supplement knowledge and adherence. METHODS: Participants completed supplement adherence ratings using a validated interview. Knowledge was assessed using an open-ended question from the same interview; responses were later categorized into 1 of 3 knowledge sophistication categories (low, moderate, or high). RESULTS: Mean adherence rates ranged from 32 to 44% across supplements. Youth who did not know the reason for supplementation (approximately 25% of the sample) displayed substantially poorer adherence than did those with moderate or high levels of knowledge, across all supplements. CONCLUSIONS: Findings highlight the importance of evaluating and addressing nonadherence to vitamin and mineral supplements in youth with pediatric IBD. PMID- 23818681 TI - Commentary: adherence matters. PMID- 23818682 TI - A new pyrroline compound selective for I1-imidazoline receptors improves metabolic syndrome in rats. AB - Symptoms of the metabolic syndrome (MetS), such as insulin resistance, obesity, and hypertension, have been associated with sympathetic hyperactivity. In addition, the adiponectin pathway has interesting therapeutic potentials in MetS. Our purpose was to investigate how targeting both the sympathetic nervous system and the adipose tissue (adiponectin secretion) with a drug selective for nonadrenergic I1-imidazoline receptors (I1Rs) may represent a new concept in MetS pharmacotherapy. LNP599 [3-chloro-2-methyl-phenyl)-(4-methyl-4,5-dihydro-3H pyrrol-2-yl)-amine hydrochloride], a new pyrroline derivative, displaced the specific [(125)I]para-iodoclonidine binding to I1R with nanomolar affinity and had no significant affinity for a large set of receptors, transporters, and enzymes. In addition, it can cross the blood-brain barrier and has good intestinal absorption, permitting oral as well as intravenous delivery. The presence of I1Rs was demonstrated in 3T3-L1 adipocytes; LNP599 had a specific stimulatory action on adiponectin secretion in adipocytes. Short-term administration of LNP599 (10 mg/kg i.v.) in anesthetized Sprague-Dawley rats markedly decreased sympathetic activity, causing hypotension and bradycardia. Long-term treatment of spontaneously hypertensive heart failure rats with LNP599 (20 mg/kg PO) had favorable effects on blood pressure, body weight, insulin resistance, glucose tolerance, and lipid profile, and it increased plasma adiponectin. The pyrroline derivative, which inhibits sympathetic activity and stimulates adiponectin secretion, has beneficial effects on all the MetS abnormalities. The use of one single drug with both actions may constitute an innovative strategy for the management of MetS. PMID- 23818683 TI - Pharmacology at work for cardio-oncology: ranolazine to treat early cardiotoxicity induced by antitumor drugs. AB - Antitumor drugs may cause asymptomatic diastolic dysfunction that introduces a lifetime risk of heart failure or myocardial infarction. Cardio-oncology is the discipline committed to the cardiac surveillance and management of cancer patients and survivors; however, cardio-oncology teams do not always attempt to treat early diastolic dysfunction. Common cardiovascular drugs, such as beta blockers or angiotensin-converting enzyme inhibitors or others, would be of uncertain efficacy in diastolic dysfunction. This perspective describes the potential value of ranolazine, an antianginal drug that improves myocardial perfusion by relieving diastolic wall tension and dysfunction. Ranolazine acts by inhibiting the late inward sodium current, and pharmacological reasonings anticipate that antitumor anthracyclines and nonanthracycline chemotherapeutics might well induce anomalous activation of this current. These notions formed the rationale for a clinical study of the efficacy and safety of ranolazine in cancer patients. This study was not designed to demonstrate that ranolazine reduced the lifetime risk of cardiac events; it was designed as a short term proof-of-concept study that probed the following hypotheses: 1) asymptomatic diastolic dysfunction could be detected a few days after patients completed antitumor therapy, and 2) ranolazine was active and safe in relieving echocardiographic and/or biohumoral indices of diastolic dysfunction, measured at 5 weeks or 6 months of ranolazine administration. These facts illustrate the translational value of pharmacology, which goes from identifying therapeutic opportunities to validating hypotheses in clinical settings. Pharmacology is a key to the success of cardio-oncology. PMID- 23818684 TI - Trends in alcohol-attributable morbidity and mortality for Victoria, Australia from 2000/01 to 2009/10. AB - BACKGROUND: To examine trends in alcohol-attributable morbidity (AAMorb) (2000/01 2009/10) and mortality (AAMort) (2000-07) by age, sex and region. METHODS: Time series analyses of population data for Victoria, Australia. We used joinpoint regression to quantify trends by estimating quarterly percent change (QPC) for rates of morbidity and mortality. We present the average QPC (AQPC) as a weighted average of QPCs. A test of parallelism was used to examine pairwise differences. RESULTS: AAMorb increased significantly over time for Victoria (AQPC = 1.0%, 95% confidence interval 0.8-1.2). While females (1.6, 1.1-2.0), age groups 25-44 (1.0, 0.9-1.1) and 45-64 (1.2, 0.2-2.2), and metropolitan population (1.2, 0.5 1.9) were broad subgroups more at risk, multivariate analysis detected specific increases for metropolitan females aged 15-44 (1.8, 1.0-2.6) and 45+ (1.6, 0.2 3.0). Relatively greater increases in morbidity among metropolitan subgroups were widespread. AAMort remained stable for Victoria and for most subgroups, although significant declines in mortality were specifically experienced by metropolitan 15-24 (-2.0, -2.9 to -1.0) and 25-44 (-1.0, -1.7 to -0.3) age groups, and by regional males aged 45+ (-0.8, -1.3 to -0.3). Metropolitan males aged 45+ were a special high-risk population. DISCUSSION: Our study has identified overlooked subgroups as being at increasing risk for alcohol-attributable chronic harm necessitating their inclusion in future policies for harm reduction. PMID- 23818687 TI - On "Medicare mandate for claims-based functional data collection..." [editorial]. Resnik L. Phys Ther. 2013;93:587-588. PMID- 23818688 TI - Nursing home residents attending the emergency department: clinical characteristics and outcomes. AB - Nursing home (NH) residents represent the frailest group of older people, and providing gerontologically attuned care that addresses these frailties is often a challenge within the emergency department (ED). This study sought to prospectively profile acutely unwell NH residents in order to clarify some of the challenges of providing emergency care to this group. Over an 18-week period, we prospectively reviewed all NH residents presenting to the ED of an urban university teaching hospital. Relevant data were retrieved by direct physician review (as part of a comprehensive geriatric assessment in the ED), collateral history from NH staff and primary carers, and review of electronic records. There were 155 ED visits by 116 NH residents. Their mean age was 80.3 (+/-9.6) years. High pre-morbid levels of dependency were reflected by a mean Barthel Index of 34.1 (+/-20) and almost two-thirds had a pre-existing diagnosis of dementia. One third of visits were during 'normal' working hours. Patients were reviewed by their regular NH doctor pre-transfer for 36% of visits. Using accepted international criteria, over half of the visits were deemed 'potentially preventable'. Unwell NH residents have complex medical needs. The decision to refer these patients to the ED is often made by 'out of hours' general practitioners and their initial care in the ED is directed by physicians with limited experience in geriatric medicine. Most referrals to the ED are potentially preventable but this would require enhancements to the package of care available in NHs. PMID- 23818689 TI - Network interactions within the canine intrinsic cardiac nervous system: implications for reflex control of regional cardiac function. AB - The aims of the study were to determine how aggregates of intrinsic cardiac (IC) neurons transduce the cardiovascular milieu versus responding to changes in central neuronal drive and to determine IC network interactions subsequent to induced neural imbalances in the genesis of atrial fibrillation (AF). Activity from multiple IC neurons in the right atrial ganglionated plexus was recorded in eight anaesthetized canines using a 16-channel linear microelectrode array. Induced changes in IC neuronal activity were evaluated in response to: (1) focal cardiac mechanical distortion; (2) electrical activation of cervical vagi or stellate ganglia; (3) occlusion of the inferior vena cava or thoracic aorta; (4) transient ventricular ischaemia, and (5) neurally induced AF. Low level activity (ranging from 0 to 2.7 Hz) generated by 92 neurons was identified in basal states, activities that displayed functional interconnectivity. The majority (56%) of IC neurons so identified received indirect central inputs (vagus alone: 25%; stellate ganglion alone: 27%; both: 48%). Fifty per cent transduced the cardiac milieu responding to multimodal stressors applied to the great vessels or heart. Fifty per cent of IC neurons exhibited cardiac cycle periodicity, with activity occurring primarily in late diastole into isovolumetric contraction. Cardiac-related activity in IC neurons was primarily related to direct cardiac mechano-sensory inputs and indirect autonomic efferent inputs. In response to mediastinal nerve stimulation, most IC neurons became excessively activated; such network behaviour preceded and persisted throughout AF. It was concluded that stochastic interactions occur among IC local circuit neuronal populations in the control of regional cardiac function. Modulation of IC local circuit neuronal recruitment may represent a novel approach for the treatment of cardiac disease, including atrial arrhythmias. PMID- 23818690 TI - Normal mucus formation requires cAMP-dependent HCO3- secretion and Ca2+-mediated mucin exocytosis. AB - Evidence from the pathology in cystic fibrosis (CF) and recent results in vitro indicate that HCO3- is required for gel-forming mucins to form the mucus that protects epithelial surfaces. Mucus formation and release is a complex process that begins with an initial intracellular phase of synthesis, packaging and apical granule exocytosis that is followed by an extracellular phase of mucin swelling, transport and discharge into a lumen. Exactly where HCO3- becomes crucial in these processes is unknown, but we observed that in the presence of HCO3-, stimulating dissected segments of native mouse intestine with 5 hydroxytryptamine (5-HT) and prostaglandin E2 (PGE2) induced goblet cell exocytosis followed by normal mucin discharge in wild-type (WT) intestines. CF intestines that inherently lack cystic fibrosis transmembrane conductance regulator (CFTR)-dependent HCO3- secretion also demonstrated apparently normal goblet cell exocytosis, but in contrast, this was not followed by similar mucin discharge. Moreover, we found that even in the presence of HCO3-, when WT intestines were stimulated only with a Ca2+-mediated agonist (carbachol), exocytosis was followed by poor discharge as with CF intestines. However, when the Ca2+-mediated agonist was combined with a cAMP-mediated agonist (isoproterenol (isoprenaline) or vasoactive intestinal peptide) in the presence of HCO3- both normal exocytosis and normal discharge was observed. These results indicate that normal mucus formation requires concurrent activation of a Ca2+ mediated exocytosis of mucin granules and an independent cAMP-mediated, CFTR dependent, HCO3- secretion that appears to mainly enhance the extracellular phases of mucus excretion. PMID- 23818691 TI - Cardiac sodium channelopathy associated with SCN5A mutations: electrophysiological, molecular and genetic aspects. AB - Over the last two decades, an increasing number of SCN5A mutations have been described in patients with long QT syndrome type 3 (LQT3), Brugada syndrome, (progressive) conduction disease, sick sinus syndrome, atrial standstill, atrial fibrillation, dilated cardiomyopathy, and sudden infant death syndrome (SIDS). Combined genetic, electrophysiological and molecular studies have provided insight into the dysfunction and dysregulation of the cardiac sodium channel in the setting of SCN5A mutations identified in patients with these inherited arrhythmia syndromes. However, risk stratification and patient management is hindered by the reduced penetrance and variable disease expressivity in sodium channelopathies. Furthermore, various SCN5A-related arrhythmia syndromes are known to display mixed phenotypes known as cardiac sodium channel overlap syndromes. Determinants of variable disease expressivity, including genetic background and environmental factors, are suspected but still largely unknown. Moreover, it has become increasingly clear that sodium channel function and regulation is more complicated than previously assumed, and the sodium channel may play additional, as of yet unrecognized, roles in cardiac structure and function. Development of cardiac structural abnormalities secondary to SCN5A mutations has been reported, but the clinical relevance and underlying mechanisms are unclear. Increased insight into these issues would enable a major next step in research related to cardiac sodium channel disease, ultimately enabling improved diagnosis, risk stratification and treatment strategies. PMID- 23818692 TI - Skeletal muscle carnitine loading increases energy expenditure, modulates fuel metabolism gene networks and prevents body fat accumulation in humans. AB - Twelve weeks of daily l-carnitine and carbohydrate feeding in humans increases skeletal muscle total carnitine content, and prevents body mass accrual associated with carbohydrate feeding alone. Here we determined the influence of L carnitine and carbohydrate feeding on energy metabolism, body fat mass and muscle expression of fuel metabolism genes. Twelve males exercised at 50% maximal oxygen consumption for 30 min once before and once after 12 weeks of twice daily feeding of 80 g carbohydrate (Control, n=6) or 1.36 g L-carnitine + 80 g carbohydrate (Carnitine, n=6). Maximal carnitine palmitolytransferase 1 (CPT1) activity remained similar in both groups over 12 weeks. However, whereas muscle total carnitine, long-chain acyl-CoA and whole-body energy expenditure did not change over 12 weeks in Control, they increased in Carnitine by 20%, 200% and 6%, respectively (P<0.05). Moreover, body mass and whole-body fat mass (dual-energy X ray absorptiometry) increased over 12 weeks in Control by 1.9 and 1.8 kg, respectively (P<0.05), but did not change in Carnitine. Seventy-three of 187 genes relating to fuel metabolism were upregulated in Carnitine vs. Control after 12 weeks, with 'insulin signalling', 'peroxisome proliferator-activated receptor signalling' and 'fatty acid metabolism' as the three most enriched pathways in gene functional analysis. In conclusion, increasing muscle total carnitine in healthy humans can modulate muscle metabolism, energy expenditure and body composition over a prolonged period, which is entirely consistent with a carnitine-mediated increase in muscle long-chain acyl-group translocation via CPT1. Implications to health warrant further investigation, particularly in obese individuals who have a reduced reliance on muscle fat oxidation during low intensity exercise. PMID- 23818693 TI - Cholinergic modulation of neuronal excitability and recurrent excitation inhibition in prefrontal cortex circuits: implications for gamma oscillations. AB - Cholinergic neuromodulation in neocortical networks is required for gamma oscillatory activity associated with working memory and other cognitive processes. Importantly, the cholinergic agonist carbachol (CCh) induces gamma oscillations in vitro, via mechanisms that may be shared with in vivo gamma oscillations and that are consistent with the pyramidal interneuron network gamma (PING) model. In PING oscillations, pyramidal cells (PCs), driven by asynchronous excitatory input, recruit parvalbumin-positive fast-spiking interneurons (FSNs), which then synchronize the PCs via feedback inhibition. Whereas the PING model is favoured by current data, how cholinergic neuromodulation contributes to gamma oscillation production is poorly understood. We thus studied the effects of cholinergic modulation on circuit components of the PING model in mouse medial prefrontal cortex (mPFC) brain slices. CCh depolarized and evoked action potential firing in a fraction of PCs and increased excitatory synaptic input onto FSNs. In synaptically connected pairs, CCh reduced the short-term depression at FSN-PC and PC-FSN synapses, equalizing synaptic strength during repetitive presynaptic firing while simultaneously increasing the failure probability. Interestingly, when PCs or FSNs fired in response to gamma frequency oscillatory inputs, CCh increased the firing probability per cycle. Combined with the equalization of synaptic strength, an increase by CCh in the fraction of neurons recruited per oscillation cycle may support oscillatory synchrony of similar strength during relatively long oscillation episodes such as those observed during working memory tasks, suggesting a significant functional impact of cholinergic modulation of mPFC circuit components crucial for the PING model. PMID- 23818694 TI - Acetazolamide attenuates transvascular fluid flux in equine lungs during intense exercise. AB - During intense exercise in horses the transvascular fluid flux in the pulmonary circulation (Jv-a) represents 4% of cardiac output (Q). This fluid flux has been attributed to an increase in pulmonary transmural hydrostatic forces, increases in perfused microvascular surface area, and reversible alterations in capillary permeability under conditions of high flow and pressure. Erythrocyte fluid efflux, however, accounts for a significant fraction of Jv-a. In the lung the Jacobs-Stewart cycle occurs with diffusion of CO2 into alveolar space with possible accompanying chloride (Cl-) and water movement from the erythrocyte directly into the pulmonary interstitium. We hypothesised that inhibition of carbonic anhydrase in erythrocytes inhibits the Jacobs-Stewart cycle and attenuates Jv-a. Five horses were exercised on a treadmill until fatigue without (control) and with acetazolamide treatment (30 mg kg(-1) 30 min before exercise). Erythrocyte fluid efflux, plasma fluid flux across the lung and Jv-a were calculated using haemoglobin, haematocrit, plasma protein and Q. Fluid fluxes were used to calculate erythrocyte, plasma and whole blood Cl- fluxes across the lung. Cardiac output was not different between control and acetazolamide treatment. During exercise erythrocyte fluid efflux and Jv-a increased in control (9.3+/-3.3 and 11.0+/-4.4 l min(-1), respectively) and was higher than after acetazolamide treatment (3.8+/-1.6 and 1.2+/-1.2 l min(-1), respectively) (P<0.05). Plasma fluid flux did not change from rest in control and decreased after acetazolamide treatment (-4.5+/-1.5 l min(-1)) (P<0.05). Erythrocyte Cl- flux increased during exercise in control and after acetazolamide treatment (P<0.05). During exercise plasma Cl- flux across the lung did not change in control; however, it increased with acetazolamide treatment (P=0.0001). During exercise whole blood Cl- flux increased across the lung in control (P<0.05) but not after acetazolamide treatment. The results indicate that Jv-a in the lung is dependent on the Jacobs-Stewart cycle and mostly independent of transmural hydrostatic forces. It also appears that Jv-a is mediated by Cl- and water egress from erythrocytes directly into the interstitium without transit through plasma. PMID- 23818704 TI - Batteries and the brain. PMID- 23818695 TI - Cyclooxygenase-2, prostaglandin E2 glycerol ester and nitric oxide are involved in muscarine-induced presynaptic enhancement at the vertebrate neuromuscular junction. AB - Previous work has demonstrated that activation of muscarinic acetylcholine receptors at the lizard neuromuscular junction (NMJ) induces a biphasic modulation of evoked neurotransmitter release: an initial depression followed by a delayed enhancement. The depression is mediated by the release of the endocannabinoid 2-arachidonylglycerol (2-AG) from the muscle and its binding to cannabinoid type 1 receptors on the motor nerve terminal. The work presented here suggests that the delayed enhancement of neurotransmitter release is mediated by cyclooxygenase-2 (COX-2) as it converts 2-AG to the glycerol ester of prostaglandin E2 (PGE2-G). Using immunofluorescence, COX-2 was detected in the perisynaptic Schwann cells (PSCs) surrounding the NMJ. Pretreatment with either of the selective COX-2 inhibitors, nimesulide or DuP 697, prevents the delayed increase in endplate potential (EPP) amplitude normally produced by muscarine. In keeping with its putative role as a mediator of the delayed muscarinic effect, PGE2-G enhances evoked neurotransmitter release. Specifically, PGE2-G increases the amplitude of EPPs without altering that of spontaneous miniature EPPs. As shown previously for the muscarinic effect, the enhancement of evoked neurotransmitter release by PGE2-G depends on nitric oxide (NO) as the response is abolished by application of either N(G)-nitro-l-arginine methyl ester (l NAME), an inhibitor of NO synthesis, or carboxy-PTIO, a chelator of NO. Intriguingly, the enhancement is not prevented by AH6809, a prostaglandin receptor antagonist, but is blocked by capsazepine, a TRPV1 and TRPM8 receptor antagonist. Taken together, these results suggest that the conversion of 2-AG to PGE2-G by COX-2 underlies the muscarine-induced enhancement of neurotransmitter release at the vertebrate NMJ. PMID- 23818705 TI - FRETing over dopamine: single cell cAMP and protein kinase A responses to 100 ms dopamine application. PMID- 23818706 TI - Size matters: formation and function of giant synapses. PMID- 23818707 TI - A questionnaire using the modified 2010 American College of Rheumatology criteria for fibromyalgia: specificity and sensitivity in clinical practice. AB - OBJECTIVE: To determine the specificity and sensitivity of the Modified 2010 American College of Rheumatology (ACR) Diagnostic Criteria for Fibromyalgia (given as a self-administered questionnaire) in clinical practice. METHODS: A cohort of patients with widespread pain, referred by primary care physicians to rheumatologists, completed the questionnaire for the Modified ACR 2010 criteria. Prior to completion of the questionnaire, patients were diagnosed by at least 1 rheumatologist as either having fibromyalgia (FM) or not having FM, using the rheumatologist's clinical assessment as the gold standard for diagnosis of FM. The Modified ACR 2010 criteria were then applied to determine whether a diagnosis of FM was satisfied by the criteria. Sensitivity and specificity were determined, using the rheumatologist's clinical assessment as the gold standard. A score >= 12 on the Modified ACR 2010 criteria questionnaire was also tested as the criterion to satisfy a diagnosis of FM, and subsequently to determine sensitivity and specificity. We examined the effect of using a cutoff score >= 13, as previous research indicated that this may be a more useful cutoff value. RESULTS: A total of 451 subjects completed the questionnaire: 174 with an a priori diagnosis of FM by a rheumatologist and 277 with widespread pain who did not have an a priori clinical diagnosis of FM by a rheumatologist. The Modified ACR 2010 criteria were satisfied by 90.2% of patients with an a priori diagnosis of FM, and by 10.5% of subjects who had widespread pain, but were not diagnosed with FM when previously assessed by a rheumatologist. Thus, sensitivity and specificity are 90.2% and 89.5%, respectively, using the Modified ACR 2010 criteria. A score >= 12 on the Modified ACR 2010 criteria was observed in 97.4% of patients with an a priori diagnosis of FM, and 14.8% of subjects who had widespread pain, but were not diagnosed with FM when previously assessed by a rheumatologist. Thus, the sensitivity and specificity are 97.4% and 85.2%, respectively, using a cutoff score >= 12. Using a score of >= 13, however, the sensitivity was 93.1% and the specificity was 91.7%. CONCLUSION: The Modified ACR 2010 criteria questionnaire can be used in primary care as a tool to assist physicians in the diagnosis of FM with high specificity and sensitivity. Calculating the total score on a Modified ACR 2010 criteria questionnaire, and setting the value of >= 13 as the cutoff for a diagnosis of FM appears to be the most effective approach. The Modified ACR 2010 criteria may reduce the need for rheumatology referral simply for the diagnosis of FM. PMID- 23818708 TI - Dactylitis in psoriatic arthritis: prevalence and response to therapy in the biologic era. AB - OBJECTIVE: To determine the prevalence of acute dactylitis in patients with psoriatic arthritis (PsA) and to compare the response of new acute dactylitis to treatment with traditional disease-modifying antirheumatic drug (DMARD) and anti tumor necrosis factor-alpha (anti-TNF) agents in a longitudinal PsA cohort. METHODS: Patients with PsA followed at 6 months according to a standard protocol from January 2000 to January 2010 were included in our study. Acute dactylitis was defined as the presence of painful swelling of an entire digit. Response was defined as either complete resolution of dactylitis or > 50% improvement in the number of dactylitic digits. A multivariate generalized estimating equations analysis using a negative binomial model to account for repeated measures was conducted to determine predictors for response to treatment of dactylitis. RESULTS: Of the 752 patients seen in the clinic during this period, 294 had dactylitis in at least 1 visit, giving a prevalence of 39%. Patients with acute dactylitis and data available for response at 6 and 12 months (n = 252; 34% women, mean age 47 yrs, PsA duration 11 yrs) were included in the study on predictors of response to treatment. Multivariate analysis showed that treatment with anti-TNF agents was a significant predictor of improvement in dactylitis at 12 months (relative risk 0.528, 95% CI 0.283-0.985, p = 0.045). CONCLUSION: The prevalence of dactylitis on at least 1 visit was 39%. Treatment was associated with improvement of dactylitis. Patients treated with biologics had better response to treatment compared with those treated with nonbiologic DMARD alone. PMID- 23818709 TI - Canadian Pain Society and Canadian Rheumatology Association recommendations for rational care of persons with fibromyalgia: a summary report. AB - OBJECTIVE: To summarize the development of evidence-based guidelines for the clinical care of persons with fibromyalgia (FM), taking into account advances in understanding of the pathogenesis of FM, new diagnostic criteria, and new treatment options. METHODS: Recommendations for diagnosis, treatment, and patient followup were drafted according to the classification system of the Oxford Centre for Evidence-Based Medicine, and following review were endorsed by the Canadian Rheumatology Association and the Canadian Pain Society. RESULTS: FM is a polysymptomatic syndrome presenting a spectrum of severity, with a pivotal symptom of body pain. FM is a positive clinical diagnosis, not a diagnosis of exclusion, and not requiring specialist confirmation. There are no confirmatory laboratory tests, although some investigation may be indicated to exclude other conditions. Ideal care is in the primary care setting, incorporating nonpharmacologic and pharmacologic strategies in a multimodal approach with active patient participation. The treatment objective should be reduction of symptoms, but also improved function using a patient-tailored treatment approach that is symptom-based. Self-management strategies combining good lifestyle habits and fostering a strong locus of control are imperative. Medications afford only modest relief, with doses often lower than suggested, and drug combinations used according to clinical judgment. There is a need for continued reassessment of the risk-benefit ratio for any drug treatment. Outcome should be aimed toward functioning within a normal life pattern and any culture of disablement should be discouraged. CONCLUSION: These guidelines should provide the health community with reassurance for the global care of patients with FM with the aim of improving patient outcome by reducing symptoms and maintaining function. PMID- 23818710 TI - Do radiographic joint damage and disease activity influence functional disability through different mechanisms? Direct and indirect effects of disease activity in established rheumatoid arthritis. AB - OBJECTIVE: To explore the relationship between rheumatoid arthritis (RA) disease activity and functional disability over time, considering indirect (predictive) and direct (concurrent) associations as well as the influence of radiographic joint damage and treatment strategy. METHODS: Functional disability [Health Assessment Questionnaire (HAQ)], disease activity [28-joint Disease Activity Score (DAS28)], and radiographic joint damage [Sharp/van der Heijde score (SHS)] were measured in 4 consecutive randomized controlled trials with increasingly intensive (tight control) treatment strategies. Average followup time for the 3 cohorts was 97, 53, and 50 months, respectively. Next to current DAS28, the previous DAS28 was used to study the predictive effect of a change in DAS28 on progression of functional disability (HAQ). Finally, it was investigated whether SHS mediated the predictive effect of DAS28. RESULTS: In patients treated with intensive treatment strategies, the progression of HAQ over time was statistically significantly less (p < 0.0001). The predictive influence of DAS28 on HAQ progression increased over the duration of the disease. SHS was not found to influence HAQ progression and did not mediate the predictive effect of DAS28. In the less intensively treated patients, the direct effect of disease activity decreased with disease duration, and contrarily, SHS did influence HAQ progression, but was not found to (fully) mediate the predictive effect of DAS28. CONCLUSION: In patients with RA treated with modern treatment strategies, there is less functional decline over time. Further, disease activity does predict functional decline but joint damage does not. This might indicate that factors associated with cumulative disease activity but not visible on radiographs can influence functional decline in patients with RA. This further underlines the importance of disease activity as a treatment target in early RA and in established RA. PMID- 23818711 TI - Risk of diabetes in patients with rheumatoid arthritis: a 12-year retrospective cohort study. AB - OBJECTIVE: The incidence of type 2 diabetes (T2D) in adults with rheumatoid arthritis (RA) was investigated, and the results were compared with non-RA controls to confirm whether RA is a risk factor for diabetes mellitus (DM) in Taiwan. METHODS: We used a databank of 1 million individuals randomly selected from 23 million Taiwanese citizens covered by the National Health Insurance plan in 2005. All persons older than age 20 years in 1998 and not diagnosed with either RA or T2D before 1998 were included. They were divided into 2 cohorts, 1 with RA and the other without. Those who had T2D before RA were excluded. Each patient in the RA cohort was followed from the RA diagnosis until the end of 2009, or until dropping out of the insurance coverage. RA was ascertained by at least 3 visits using ICD-9 code 714.0, plus at least 2 visits with prescription of antirheumatic drugs in a period of 12 months. T2D was ascertained by at least 3 visits with diabetes codes within 1 year, while hypertension (HTN) and disorders of lipid metabolism (DLM) were determined by at least 3 visits using corresponding ICD codes during the study period. Kaplan-Meier plots, log-rank tests, and Cox regression were used to study the effects of age, sex, glucocorticoid use, HTN, DLM, and RA on T2D risk. RESULTS: The subjects include 600,695 adults. Of these, 4193 were diagnosed with RA, and among them 799 were diagnosed with T2D. The RA to non-RA risk ratio for T2D was 1.68 (95% CI 1.53 1.84) in men and 1.46 (95% CI 1.39-1.54) in women. CONCLUSION: RA appears to be associated with an increased risk for T2D in Taiwan. PMID- 23818713 TI - Magnetic resonance imaging compared to conventional radiographs for detection of chronic structural changes in sacroiliac joints in axial spondyloarthritis. AB - OBJECTIVE: We investigated the performance of magnetic resonance imaging (MRI) compared to conventional radiographs for detection of chronic structural changes in the sacroiliac joints (SIJ) in patients with axial spondyloarthritis (SpA). METHODS: We included 112 patients with definite axial SpA (68 with ankylosing spondylitis and 44 with nonradiographic axial SpA), for whom radiographs and MRI scans of the SIJ performed at the same time were available. Radiographs and MRI of the SIJ were scored for subchondral sclerosis (score 0-2), erosions (score 0 3), and joint space changes (score 0-5) in each SIJ. Readers provided an overall impression of the extent of damage according to the scoring system of the modified New York criteria. RESULTS: In total, 224 SIJ from 112 patients were available for analysis. There was rather low agreement between MRI and radiographs concerning definite erosions of SIJ (kappa = 0.11), moderate agreement for definite subchondral sclerosis (kappa = 0.46) and definite joint space abnormalities (kappa = 0.41), and almost perfect agreement for joint ankylosis (kappa = 0.85). MRI demonstrated a good overall performance in detection of definite "chronic" sacroiliitis, with a sensitivity of 84% and a specificity of 61%. For sacroiliitis fulfilling the modified New York criteria, MRI had a sensitivity of 81% and a specificity of 64% using radiographs as the reference method. CONCLUSION: MRI demonstrated good overall performance for detection of chronic structural changes in the SIJ as compared to radiographs. PMID- 23818712 TI - Response of pediatric uveitis to tumor necrosis factor-alpha inhibitors. AB - OBJECTIVE: To evaluate the outcome of tumor necrosis factor-alpha inhibition (anti-TNF) for pediatric uveitis. METHODS: We retrospectively assessed children (age <= 18 yrs) with noninfectious uveitis receiving anti-TNF at 5 uveitis centers and 1 pediatric rheumatology center. Incident treatment success was defined as minimal or no uveitis activity at >= 2 consecutive ophthalmological examinations >= 28 days apart while taking no oral and <= 2 eyedrops/day of corticosteroids. Eligible children had active uveitis and/or were taking higher corticosteroid doses. RESULTS: Among 56 eligible children followed over 33.73 person-years, 52% had juvenile idiopathic arthritis (JIA) and 75% had anterior uveitis (AU). The Kaplan-Meier estimated proportion achieving treatment success within 12 months was 75% (95% CI 62%-87%). Complete absence of inflammatory signs with discontinuation of all corticosteroids was observed in an estimated 64% by 12 months (95% CI 51%-76%). Diagnoses of JIA or AU were associated with greater likelihood of success, as was the oligoarticular subtype among JIA cases. In a multivariable model, compared to those with JIA-associated AU, those with neither or with JIA or AU alone had a 75%-80% lower rate of achieving quiescence under anti-TNF, independent of the number of immunomodulators previously or concomitantly prescribed. Uveitis reactivated within 12 months of achieving quiescence in 14% of those continuing anti-TNF (95% CI 6%-31%). The incidence of discontinuation for adverse effects was 8%/year (95% CI 1%-43%). CONCLUSION: Treatment with anti-TNF was successful and sustained in a majority of children with noninfectious uveitis, and treatment-limiting toxicity was infrequent. JIA associated AU may be especially responsive to anti-TNF. PMID- 23818714 TI - Decreased cartilage thickness in juvenile idiopathic arthritis assessed by ultrasonography. AB - OBJECTIVE: Juvenile idiopathic arthritis (JIA) may result in disability, which is caused primarily by degeneration of the osteocartilaginous structures, due to the synovial inflammatory process. It is essential to closely monitor structural damage during the disease course. We aimed to compare ultrasound (US) measurements of joint cartilage thickness in 5 joints in children with JIA to our findings in an age- and sex-related healthy cohort regarding disease duration, joint activity, JIA subtype, age, and sex. METHODS: We clinically examined joint activity in 95 patients with JIA and collected parent and physician global assessments. Joint cartilage thickness was assessed by greyscale US in knee, ankle, wrist, metacarpophalangeal, and proximal interphalangeal (PIP) joints. Measurements were compared to reference values of a healthy cohort from a previous study. Medical records were reviewed for JIA subtype, treatment, and disease duration. RESULTS: Joint cartilage thickness was decreased in the knee, wrist, and second PIP joint in children with JIA compared with the healthy cohort (p < 0.001 for all). Patients with oligoarticular JIA had thicker cartilage than patients with polyarticular and systemic JIA. We also found decreased joint cartilage thickness in joints not previously affected by arthritis in children with JIA compared to the same joint in the healthy cohort. We found decreasing cartilage thickness with age and thicker cartilage in boys than in girls. CONCLUSION: Children with JIA have reduced cartilage thickness compared with children who do not have JIA, and children with polyarticular and systemic JIA have thinner cartilage than children with oligoarticular JIA. PMID- 23818715 TI - The disconnect between better quality of glucocorticoid-induced osteoporosis preventive care and better outcomes: a population-based cohort study. AB - OBJECTIVE: The quality of glucocorticoid-induced osteoporosis (GIOP) care [defined by bone mineral density (BMD) testing or osteoporosis treatment] is suboptimal and has been targeted for improvement. The assumption that improvements in GIOP preventive care will lead to better outcomes has not been tested. METHODS: We used linked healthcare databases to conduct a population based study of all adults 20 years of age or older in Manitoba, Canada, who initiated longterm (> 90 days) systemic glucocorticoids (GC) between 1998 and 2008. High-quality GIOP care was defined by BMD testing or prescription osteoporosis treatment within 6 months. Outcomes were adjusted odds of major fractures within 1 year and 3 years. RESULTS: We studied 15,285 subjects who had just begun to take GC; 5804 (38%) were 70 years of age or older, 9185 (58%) were women, and 4755 (30%) received 10 mg or more prednisone equivalents daily. Overall, 3898 (25%) subjects received a BMD test or osteoporosis treatment within 6 months. Within 1 year of starting GC, there had been 206 major fractures (1%) and within 3 years, 553 major fractures (4%). High-quality GIOP preventive care was not associated with a reduced risk of major fractures within 1 year (adjusted OR 1.6, 95% CI 1.2-2.1) or within 3 years (adjusted OR 1.3, 95% CI 1.1-1.6). CONCLUSION: Three-quarters of those initiating GC received suboptimal osteoporosis care. Conventional administrative database analyses could not demonstrate that better GIOP preventive care was associated with reductions in medically attended fractures. Clinically rich databases and different analytic techniques are needed to better evaluate the effectiveness of GIOP preventive care. PMID- 23818716 TI - Attack rate of Chlamydia-induced reactive arthritis and effect of the CCR5-Delta 32 mutation: a prospective analysis. AB - OBJECTIVE: Factors that predispose patients to Chlamydia-induced reactive arthritis (CiReA) are poorly defined. Data indirectly suggest chemokine receptor 5 (CCR5)-delta-32 mutation might play a role in CiReA. We investigated the attack rate of CiReA and we hypothesized that the CCR5-delta-32 allele may modulate disease susceptibility. METHODS: Patients who tested positive for Chlamydia trachomatis after either (1) symptoms of an acute venereal disease or (2) sexual contact with an individual known to be positive for the same organism were followed in a prospective fashion. All patients were contacted at Week 6 after their acute infection and queried for symptoms of CiReA. Patients who had new onset symptoms suggestive of CiReA were followed at Weeks 12, 26, and 52. All subjects were tested for CCR5-delta-32 mutation. RESULTS: A total of 365 study participants were enrolled, with average age 24.4 years, 201 men (55%) and 164 women (45%). We followed up with 149 patients (41%) at Week 6. Twelve of 149 participants (8.1%) had symptoms suggestive of CiReA at Week 6. None of these 12 patients was positive for the CCR5-delta-32 mutation. Of the 12 patients that had symptoms at Week 6, we were able to follow up with 7 through Week 52. All 7 had complete resolution of their symptoms by Week 26. Overall, 25/365 (6.8%) subjects were positive for the CCR5-delta-32 mutation. CONCLUSION: The attack rate of CiReA in our study was higher than previously reported, but the CCR5-delta-32 mutation does not seem to play a role in CiReA disease susceptibility. PMID- 23818717 TI - Vitamin D deficiency, interleukin 17, and vascular function in rheumatoid arthritis. AB - OBJECTIVE: Vitamin D deficiency is associated with increased cardiovascular (CV) disease risk in the general population. We examined the association between vitamin D deficiency and CV risk in rheumatoid arthritis (RA). METHODS: We measured large artery compliance by pulse wave velocity and microvascular function by the reactive hyperemia index in patients with stable RA (n = 87). We quantified CV risk factors, serum 25-hydroxyvitamin D [25(OH)D], and interleukin 17 (IL-17), and RA disease activity by Disease Activity Score of 28 joints. We used linear regression to test associations between serum 25(OH)D and CV risk factors. RESULTS: The mean serum 25(OH)D level in the cohort was 27.1 +/- SD 13.6 ng/ml. Fifty-nine patients (68%) were vitamin D-insufficient (25(OH)D < 30 ng/ml; mean 20.2 +/- 5.9 ng/ml) and of these, 25 (29%) were vitamin D-deficient (25(OH)D < 20 ng/ml; mean 14.4 +/- 3.4 ng/ml). In the whole cohort and the vitamin D insufficient group, serum 25(OH)D was inversely associated with IL-17 (log IL-17; beta = -0.83, p = 0.04; beta = -0.63, p = 0.004, respectively) by univariate analysis, which persisted after adjustment for season, and in multivariate analysis after adjustment for confounders (log IL-17; beta = -0.74, p = 0.04; beta = -0.53, p = 0.02). In vitamin D-deficient patients, serum 25(OH)D was positively associated with microvascular function by univariate and multivariate analysis after adjustment for confounders (beta = 2.1, p = 0.04; beta = 2.7, p = 0.04). CONCLUSION: Vitamin D deficiency in RA may affect Th17 responses and microvascular function. Maintaining normal serum vitamin D levels may protect against IL-17-mediated inflammation and vascular dysfunction in RA. PMID- 23818718 TI - Clinical, functional, and radiographic benefits of longterm adalimumab plus methotrexate: final 10-year data in longstanding rheumatoid arthritis. AB - OBJECTIVE: To examine the longterm effectiveness and safety of adalimumab in patients with longstanding rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX), and to assess the effect of a 1-year delay in initiation of combination therapy. METHODS: DE019 was a 1-year randomized controlled trial (RCT) in which patients received adalimumab 20 mg weekly, adalimumab 40 mg every other week (eow), or placebo; all received concomitant MTX. Patients completing the RCT could receive open-label adalimumab 40 mg eow + MTX for an additional 9 years. Clinical, functional, and radiographic outcomes were assessed using composite measures of disease activity (e.g., American College of Rheumatology responses, 28-joint Disease Activity Score with C-reactive protein, Simplified Disease Activity Index), Health Assessment Questionnaire-Disability Index, and the modified total Sharp score (mTSS), respectively. RESULTS: Of the 619 patients randomized, 457 entered the open-label extension; 202 completed 10 years. At Year 10, patients demonstrated effective disease control and inhibition of radiographic progression. Differences in clinical and functional responses between adalimumab + MTX and placebo + MTX observed during the RCT became less apparent at Year 10. Still, patients who initially received adalimumab + MTX had significantly lower mean DeltamTSS at Year 10 compared with patients who initially received placebo + MTX. No new safety signals arose following up to 10 years of adalimumab + MTX exposure. CONCLUSION: During up to 10 years of treatment with adalimumab + MTX, patients with longstanding RA experienced effective disease control with no change to the expected safety profile. A 1-year delay in receipt of adalimumab + MTX was associated with reduced effectiveness, suggesting that a window of opportunity to prevent irreversible damage exists even in a population with established RA. PMID- 23818719 TI - Gain in quality-adjusted life-years in patients with rheumatoid arthritis during 1 year of biological therapy: a prospective study in clinical practice. AB - OBJECTIVE: The quality-adjusted life-year (QALY) is used to measure outcome in rheumatoid arthritis (RA) studies; identification of drivers of a gain in QALY might help predict a treatment response. We investigated how changes in components of the Disease Activity Score-28 joints (DAS28) were associated with the European League Against Rheumatism (EULAR) and European Quality of Life 5 Dimensions (EQ-5D) responses; and what baseline variables predicted the change in QALY following 1 year of biological therapy. METHODS: Data were collected at baseline and after 3, 6, and 12 months of biological therapy in Danish patients with RA and included bDAS28, sociodemographic data, comorbidity, Health Assessment Questionnaire (HAQ), and EQ-5D scored using the Danish algorithm. A cross-tabulation based on EULAR versus EQ-5D responses was performed, and the association of each DAS28 component across the EULAR/EQ-5D response groups was tested. Predictors of a change in QALY were assessed in a multiple regression model including baseline clinical and patient-reported data as explanatory variables. RESULTS: In total, 315 patients entered the study; 77% were women, 78% IgM rheumatoid factor-positive, with mean age 55 (SD 13) years, disease duration 10 (SD 8) years, mean DAS28 4.9 (SD 1.2), HAQ score 1.22 (SD 0.70), and EQ-5D score 0.60 (SD 0.19). Sixty-eight percent of patients gained QALY; the mean gain was 0.14 (SD 0.13). The patient global score was strongly correlated with both EULAR and EQ-5D responses. The gain in QALY increased with increasing patient global score and number of swollen joints, but not with C-reactive protein (CRP). CONCLUSION: The subjective patient global score was the best baseline predictor of gain in QALY following biological therapy, while the objective CRP measure had no predictive value. It seems that no sharp demarcation between objective and subjective measures could be determined. PMID- 23818720 TI - The value of studying clinical and serologic phenotypes in north american native populations with autoimmune disease. PMID- 23818721 TI - The ambitious goal of validating prognostic biomarkers for systemic sclerosis related interstitial lung disease. PMID- 23818722 TI - Juvenile idiopathic arthritis and pain -- more than simple nociception. PMID- 23818723 TI - More than meets the Wegener's eye. PMID- 23818724 TI - Amicrobial pustulosis of the folds. PMID- 23818725 TI - New onset of psoriasis in a patient with rheumatoid arthritis treated with rituximab. PMID- 23818726 TI - Treatment of relapsing polychondritis with tocilizumab. PMID- 23818727 TI - Psoriatic arthritis mutilans: case series and literature review. PMID- 23818728 TI - IgG4-related disease manifesting as pachymeningitis and aortitis. PMID- 23818729 TI - Clinical features and perforin A91V gene analysis in 31 patients with macrophage activation syndrome and systemic juvenile idiopathic arthritis in China. PMID- 23818730 TI - Septic oligoarthritis caused by Klebsiella pneumoniae and Acinetobacter baumannii. PMID- 23818734 TI - In vitro and in vivo experimental studies on trabecular meshwork degeneration induced by benzalkonium chloride (an American Ophthalmological Society thesis). AB - PURPOSE: Long-term antiglaucomatous drug administration may cause irritation, dry eye, allergy, subconjunctival fibrosis, or increased risk of glaucoma surgery failure, potentially due to the preservative benzalkonium chloride (BAK), whose toxic, proinflammatory, and detergent effects have extensively been shown experimentally. We hypothesize that BAK also influences trabecular meshwork (TM) degeneration. METHODS: Trabecular specimens were examined using immunohistology and reverse transcriptase-polymerase chain reaction. A trabecular cell line was stimulated by BAK and examined for apoptosis, oxidative stress, fractalkine and SDF-1 expression, and modulation of their receptors. An experimental model was developed with BAK subconjunctival injections to induce TM degeneration. Mass spectrometry (MS) imaging assessed BAK penetration after repeated instillations in rabbit eyes. RESULTS: Trabecular specimens showed extremely low densities of trabecular cells and presence of cells expressing fractalkine and fractalkine receptor and their respective mRNAs. Benzalkonium in vitro induced apoptosis, oxidative stress, and fractalkine expression and inhibited the protective chemokine SDF-1 and Bcl2, also inducing a sustained intraocular pressure (IOP) increase, with dramatic apoptosis of trabecular cells and reduction of aqueous outflow. MS imaging showed that BAK could access the TM at measurable levels after repeated instillations. CONCLUSION: BAK enhances all characteristics of TM degeneration typical of glaucoma-trabecular apoptosis, oxidative stress, induction of inflammatory chemokines-and causes degeneration in acute experimental conditions, potentially mimicking long-term accumulation. BAK was also shown to access the TM after repeated instillations. These findings support the hypothesis that antiglaucoma medications, through toxicity of their preservative, may cause further long-term trabecular degeneration and therefore enhance outflow resistance, reducing the impact of IOP-lowering agents. PMID- 23818735 TI - Histologic features of conjunctival melanoma predictive of metastasis and death (an American Ophthalmological thesis). AB - PURPOSE: In conjunctival melanoma, tumor thickness and nonlimbal location are associated with poor prognosis. However, other established high-risk features for cutaneous melanoma, including ulceration, mitotic figures, epithelioid cell type, and lymphovascular invasion, have not previously been studied extensively for their prognostic value in conjunctival melanoma. We examined the hypothesis that these features also predict regional nodal metastasis and death in conjunctival melanoma. METHODS: The medical records of 44 of 46 consecutive conjunctival melanoma patients treated between June 2003 and December 2009 were retrospectively reviewed; tumor tissue was not available for the two excluded patients. Demographic and clinicopathologic features, including tumor location, tumor thickness, ulceration, mitotic rate, histology, lymphovascular invasion, and microsatellitosis, were reviewed. Outcome measures included regional nodal metastasis, distant metastasis, and death. RESULTS: Twenty-six women and 18 men had a median age of 62 years. Regional nodal metastasis occurred in 7 patients (16%) and distant metastasis in 9 (20%). Median follow-up was 40 months. At last follow-up, 10 patients (23%) had died of disease. Tumor thickness>2.0 mm, ulceration, and mitotic figure>1/mm2 predicted regional nodal metastasis and death from disease. In addition to these three histologic features, vascular invasion, epithelioid cell type, and microsatellitosis significantly predicted death from disease. Tumor location (bulbar vs nonbulbar) was not correlated with regional nodal metastasis or death. CONCLUSIONS: In conjunctival melanoma, as in cutaneous melanoma, thicker tumor, ulceration, and higher mitotic rate are correlated with regional nodal metastasis. In addition, lymphovascular invasion, epithelioid cell type, and microsatellitosis are correlated with melanoma-related death. PMID- 23818736 TI - The association of neonatal dacryocystoceles and infantile dacryocystitis with nasolacrimal duct cysts (an American Ophthalmological Society thesis). AB - PURPOSE: To investigate whether neonatal dacryocystoceles and dacryocystitis are associated with nasolacrimal duct cysts, and to report the outcomes of treatment of these disorders. METHODS: This was a retrospective medical record review of two groups of infants with nasolacrimal duct (NLD) obstruction. The first group had dacryocystoceles with or without dacryocystitis. The second group had NLD obstruction with symptoms severe enough to require early NLD probing. All of the patients underwent NLD probing and nasal endoscopy. When present, NLD cysts were removed. RESULTS: In the first group, 33 infants had dacryocystoceles. Acute dacryocystitis was present in 16 patients, 12 had noninfected dacryocystoceles that did not resolve, and 5 had dacryocystoceles that resolved but severe symptoms persisted. All of the patients had NLD cysts that were surgically removed. The symptoms resolved after surgery in 31 patients (94%). In the second group, 27 infants less than 6 months old without dacryocystoceles underwent early NLD probing and endoscopy due to severity of symptoms. Twelve (44%) of these patients had NLD cysts. The symptoms resolved in 11 (92%) of 12 patients following NLD probing and cyst removal. CONCLUSIONS: Neonatal dacryocystoceles are almost always associated with NLD cysts. The success rate of NLD probing and endoscopic cyst removal in these patients is excellent. Nasolacrimal duct cysts also are present in many young infants with severe symptoms of NLD obstruction. Nasal endoscopy is an important adjunct to the management of these infants. PMID- 23818737 TI - Medical malpractice claims related to cataract surgery complicated by retained lens fragments (an American Ophthalmological Society thesis). AB - PURPOSE: To review malpractice claims associated with retained lens fragments during cataract surgery to identify ways to improve patient outcomes. METHODS: Retrospective, noncomparative, consecutive case series. Closed claims data related to cataract surgeries complicated by retained lens fragments (1989 through 2009) from an ophthalmic insurance carrier were reviewed. Factors associated with these claims and claims outcomes were analyzed. RESULTS: During the 21-year period, 117 (12.5%) of 937 closed claims associated with cataract surgery were related to retained lens fragments with 108 unique cataract surgeries, 97% against cataract surgeon and 3% against retinal surgeon. Twelve (11%) of 108 claims were resolved by a trial, 30 (28%) were settled, and 66 (61%) were dismissed. The defendant prevailed in 83% of trials. Indemnity payments totaling more than $3,586,000 were made in 32 (30%) of the claims (median payment, $90,000). The difference between the preoperative visual acuity and the final visual acuity was predictive of an indemnity payment (odds ratio [OR], 2.28; P=.001) and going to a trial (OR, 2.93; P=.000). Development of corneal edema was associated with an indemnity payment (OR, 3.50; P=.037). Timing of referral and elevated intraocular pressure (IOP) were statistically significant in univariate analyses but not in multivariate analyses for a trial. CONCLUSIONS: Whereas the majority of claims were dismissed, claims associated with greater visual acuity decline, corneal edema, or elevated IOP were more likely to result in a trial or payment. Ways to reduce significant vision loss, including improved management of corneal edema and IOP, and timely referral to a subspecialist should be considered. PMID- 23818738 TI - Evaluation of the reactive T-cell infiltrate in uveitis and intraocular lymphoma with flow cytometry of vitreous fluid (an American Ophthalmological Society thesis). AB - PURPOSE: To describe the reactive T-cell infiltrate in uveitis and intraocular lymphoma using flow cytometry of clinical intraocular specimens acquired during diagnostic pars plana vitrectomy. METHODS: This was a retrospective review of diagnostic vitreous specimens (1992-2011) obtained at a university-based, tertiary care center. Seventy-eight patients with uveitis or lymphoma undergoing pars plana vitrectomy were selected for intraocular testing based on clinical diagnostic uncertainty. Pars plana vitrectomy with flow cytometry, gene rearrangement studies, and cytology was performed. RESULTS: T-cell infiltrates were found in all diagnostic categories with limited power to discriminate between uveitis and T-lymphocyte reactive infiltrates in response to intraocular lymphoma. Statistically significant differences by two-sample test of means between group means were found between 35 uveitis and 35 B-cell lymphoma cases for T-cell markers CD2, 3, 4, 5, and 7, but not for CD8. The CD4:CD8 ratio had a higher mean value in the uveitis group (P=.0113), and 8 T-cell lymphomas had a statistically greater number of CD3+ lymphocytes compared to uveitis (P=.0199) by two-sample test of means. Likelihood ratios were highest for CD2, CD5, CD7, CD4:CD8 ratio, CD20, and CD22. CONCLUSIONS: Discrimination between uveitis and lymphoma based on cell identification by flow cytometry was limited because of the prevalence of T lymphocytes in all diagnostic categories, emphasizing the importance of a reactive T-cell infiltrate in B-cell lymphomas, which may impede diagnosis. Flow cytometry may allow identification of more cases of T-cell lymphoma than reported when it is combined with gene rearrangement and cytology. PMID- 23818739 TI - Ultrashort-pulse lasers treating the crystalline lens: will they cause vision threatening cataract? (An American Ophthalmological Society thesis). AB - PURPOSE: To demonstrate that ultrashort-pulse laser treatment in the crystalline lens does not form a focal, progressive, or vision-threatening cataract. METHODS: An Nd:vanadate picosecond laser (10 ps) with prototype delivery system was used. Primates: 11 rhesus monkey eyes were prospectively treated at the University of Wisconsin (energy 25-45 MUJ/pulse and 2.0-11.3M pulses per lens). Analysis of lens clarity and fundus imaging was assessed postoperatively for up to 41/2 years (5 eyes). Humans: 80 presbyopic patients were prospectively treated in one eye at the Asian Eye Institute in the Philippines (energy 10 MUJ/pulse and 0.45-1.45M pulses per lens). Analysis of lens clarity, best-corrected visual acuity, and subjective symptoms was performed at 1 month, prior to elective lens extraction. RESULTS: Bubbles were immediately seen, with resolution within the first 24 to 48 hours. Afterwards, the laser pattern could be seen with faint, noncoalescing, pinpoint micro-opacities in both primate and human eyes. In primates, long-term follow-up at 41/2 years showed no focal or progressive cataract, except in 2 eyes with preexisting cataract. In humans, <25% of patients with central sparing (0.75 and 1.0 mm radius) lost 2 or more lines of best spectacle-corrected visual acuity at 1 month, and >70% reported acceptable or better distance vision and no or mild symptoms. Meanwhile, >70% without sparing (0 and 0.5 mm radius) lost 2 or more lines, and most reported poor or severe vision and symptoms. CONCLUSIONS: Focal, progressive, and vision-threatening cataracts can be avoided by lowering the laser energy, avoiding prior cataract, and sparing the center of the lens. PMID- 23818740 TI - Establishment of a human conjunctival epithelial cell line lacking the functional TACSTD2 gene (an American Ophthalmological Society thesis). AB - PURPOSE: To report the establishment of a human conjunctival epithelial cell line lacking the functional tumor-associated calcium signal transducer 2 (TACSTD2) gene to be used as an in vitro model of gelatinous drop-like corneal dystrophy (GDLD), a rare disease in which the corneal epithelial barrier function is significantly compromized by the loss of function mutation of the TACSTD2 gene. METHODS: A small piece of conjunctival tissue was obtained from a GDLD patient. The conjunctival epithelial cells were enzymatically separated and dissociated from the tissue and immortalized by the lentiviral introduction of the SV40 large T antigen and human telomerase reverse transcriptase (hTERT) genes. Population doubling, protein expression, and transepithelial resistance (TER) analyses were performed to assess the appropriateness of the established cell line as an in vitro model for GDLD. RESULTS: The life span of the established cell line was found to be significantly elongated compared to nontransfected conjunctival epithelial cells. The SV40 large T antigen and hTERT genes were stably expressed in the established cell line. The protein expression level of the tight junction related proteins was significantly low compared to the immortalized normal conjunctival epithelial cell line. TER of the established cell line was found to be significantly low compared to the immortalized normal conjunctival epithelial cell line. CONCLUSIONS: Our conjunctival epithelial cell line was successfully immortalized and well mimicked several features of GDLD corneas. This cell line may be useful for the elucidation of the pathogenesis of GDLD and for the development of novel treatments for GDLD. PMID- 23818741 TI - Activation of protease-activated receptor 2-mediated signaling by mast cell tryptase modulates cytokine production in primary cultured astrocytes. AB - Protease-activated receptor 2 (PAR-2), which is abundantly expressed in astrocytes, is known to play major roles in brain inflammation. However, the influence of the natural agonist of PAR-2, tryptase, on proinflammatory mediator releasedfrom astrocytes remains uninvestigated. In the present study, we found that tryptase at lower concentrations modestly reduced intracellular ROS production but significantly increased IL-6 and TNF- alpha secretion at higher concentrations without affecting astrocytic viability and proliferation. The actions of tryptase were alleviated by specific PAR-2 antagonist FSLLRY-NH2 (FS), indicating that the actions of tryptase were via PAR-2. PI3K/AKT inhibitor LY294002 reversed the effect of tryptase on IL-6 production, whereas inhibitors specific for p38, JNK, and ERK1/2 abolished the effect of tryptase on TNF- alpha production, suggesting that different signaling pathways are involved. Moreover, tryptase-induced activation of MAPKs and AKT was eliminated by FS, implicating that PAR-2 is responsible for transmitting tryptase biosignals to MAPKs and AKT. Tryptase provoked also expression of TGF- beta and CNTF in astrocytes. The present findings suggest for the first time that tryptase can regulate the release of cytokines from astrocytes via PAR-2-MAPKs or PAR-2-PI3K/AKT signaling pathways, which reveals PAR-2 as a new target actively participating in the regulation of astrocytic functions. PMID- 23818742 TI - Local overexpression of interleukin-11 in the central nervous system limits demyelination and enhances remyelination. AB - Demyelination is one of the pathological hallmarks of multiple sclerosis (MS). To date, no therapy is available which directly potentiates endogenous remyelination. Interleukin-11 (IL-11), a member of the gp130 family of cytokines, is upregulated in MS lesions. Systemic IL-11 treatment was shown to ameliorate clinical symptoms in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. IL-11 modulates immune cells and protects oligodendrocytes in vitro. In this study, the cuprizone-induced demyelination mouse model was used to elucidate effects of IL-11 on de- and remyelination, independent of the immune response. Prophylactic-lentiviral- (LV-) mediated overexpression of IL-11 in mouse brain significantly limited acute demyelination, which was accompanied with the preservation of CC1(+) mature oligodendrocytes (OLs) and a decrease in microglial activation (Mac-2(+)). We further demonstrated that IL-11 directly reduces myelin phagocytosis in vitro. When IL-11 expressing LV was therapeutically applied in animals with extensive demyelination, a significant enhancement of remyelination was observed as demonstrated by Luxol Fast Blue staining and electron microscopy imaging. Our results indicate that IL-11 promotes maturation of NG2(+) OPCs into myelinating CC1(+) OLs and may thus explain the enhanced remyelination. Overall, we demonstrate that IL-11 is of therapeutic interest for MS and other demyelinating diseases by limiting demyelination and promoting remyelination. PMID- 23818743 TI - Monocytes, peripheral blood mononuclear cells, and THP-1 cells exhibit different cytokine expression patterns following stimulation with lipopolysaccharide. AB - THP-1 cells are widely applied to mimic monocytes in cell culture models. In this study, we compared the cytokine release from THP-1, peripheral blood mononuclear cells (PBMC), monocytes, or whole blood after stimulation with lipopolysaccharide (LPS) and investigated the consequences of different cytokine profiles on human umbilical vein endothelial cell (HUVEC) activation. While Pseudomonas aeruginosa stimulated (10 ng/mL) THP-1 secreted similar amounts of tumor necrosis factor alpha (TNF- alpha ) as monocytes and PBMC, they produced lower amounts of interleukin(IL)-8 and no IL-6 and IL-10. Whole blood required a higher concentration of Pseudomonas aeruginosa (1000 ng/mL) to induce cytokine release than isolated monocytes or PBMC (10 ng/mL). HUVEC secreted more IL-6 and IL-8 after stimulation with conditioned medium derived from whole blood than from THP 1, despite equal concentrations of TNF- alpha in both media. Specific adsorption of TNF- alpha or selective cytokine adsorption from the conditioned media prior to HUVEC stimulation significantly reduced HUVEC activation. Our findings show that THP-1 differ from monocytes, PBMC, and whole blood with respect to cytokine release after stimulation with LPS. Additionally, we could demonstrate that adsorption of inflammatory mediators results in reduced endothelial activation, which supports the concept of extracorporeal mediator modulation as supportive therapy for sepsis. PMID- 23818744 TI - Association between serum interleukin-6 concentration and mortality in patients with coronary artery disease. AB - OBJECTIVES: To evaluate whether serum interleukin-6 (IL-6) is associated with increased risk of mortality in coronary artery disease (CAD) patients. METHODS: We performed a prospective cohort study of 718 CAD patients from the Guangzhou Cardiovascular Disease Cohort (GCDC) study. Multivariable-adjusted Cox proportional hazards regression analyses were used to examine the association between serum IL-6 with all-cause and cardiovascular mortality. RESULTS: During the 1663 person-years of followup, the cumulative all-cause mortality and cardiovascular mortality were 6.5% (n = 47) and 3.3% (n = 24), respectively. The mean length of followup was 2.32 +/- 0.81 years. In the multivariable analyses, a one-SD increment in log-transformed serum IL-6 was positively associated with an increased risk of all-cause and cardiovascular mortality, with hazard ratios (HR) of 2.93 (95% CI, 2.11-4.08) and 2.04 (95% CI, 1.34-3.68) within the patients combined and 2.98 (95% CI, 2.12-4.18) and 3.10 (95% CI, 1.98-4.85) within males, respectively. Patients in the highest serum IL-6 tertile versus the lowest tertile were at higher risk of all-cause and cardiovascular mortality, with HR of 17.12 (95% CI 3.11-71.76) and 8.68 (95% CI, 1.88-37.51), respectively. CONCLUSIONS: In hospitalized patients with CAD, serum IL-6 is significantly associated with all-cause and cardiovascular mortality. PMID- 23818745 TI - Resolution of PMA-induced skin inflammation involves interaction of IFN-gamma and ALOX15. AB - BACKGROUND: Acute inflammation and its timely resolution play important roles in the body's responses to the environmental stimulation. Although IFN-gamma is well known for the induction of inflammation, its role in the inflammation resolution is still poorly understood. METHODOLOGY AND PRINCIPAL FINDINGS: In this study, we investigated the function of interferon gamma (IFN-gamma) during the resolution of PMA-induced skin inflammation in vivo. The results revealed that the expression levels of IL-6, TNF-alpha, and monocyte chemoattractant protein 1 (MCP 1) in skin decreased during the resolution stage of PMA-induced inflammation, while IFN-gamma is still maintained at a relatively high level. Neutralization of endogenous IFN-gamma led to accelerated reduction of epidermal thickness and decreased epithelial cell proliferation. Similarly, decreased infiltration of inflammatory cells (Gr1(+) or CD11b(+) cells) and a significant reduction of proinflammatory cytokines were also observed upon the blockade of IFN-gamma. Furthermore, neutralization of IFN-gamma boosted ALOX15 expression of the skin during inflammation resolution. In accordance, application of lipoxin A4 (LXA4, a product of ALOX15) obtained a proresolution effect similar to neutralization of IFN-gamma. These results demonstrated that through upregulating ALOX15-LXA4 pathway, blockage of IFN-gamma can promote the resolution of PMA-induced skin inflammation. PMID- 23818746 TI - Celecoxib improves host defense through prostaglandin inhibition during Histoplasma capsulatum infection. AB - Prostaglandins act as mediators of inflammation and, similar to cytokines, function as immune modulators during innate and adaptive immune responses. Therefore, using a pharmacological inhibitor, celecoxib, we investigated the role of prostaglandins in host defense against Histoplasma capsulatum infection in C57BL/6 mice. Our results showed that treatment with celecoxib inhibited cyclooxygenase 2, reduced the total fungal burden, and reduced the concentration of PGE2, cytokines, lymphocytes, neutrophils, and mononuclear cells in the bronchoalveolar space and lung parenchyma. In addition, celecoxib treatment increased the synthesis of nitric oxide, IFN- gamma, LTB4, and the phagocytic capacity of alveolar macrophages. Moreover, celecoxib treatment increased the survival of mice after infection with a lethal inoculum of H. capsulatum. These results suggest that prostaglandins alter the host immune response and play an important role in the pathogenesis of histoplasmosis. Thus, the inhibition of prostaglandins could be a valuable immunomodulatory strategy and antifungal therapy for histoplasmosis treatment. PMID- 23818747 TI - Diagnostic yield and safety of endoscopic ultrasound guided fine needle aspiration of central mediastinal lung masses. AB - Background and Aims. EUS-FNA is an accurate and safe technique to biopsy mediastinal lymph nodes. However, there are few data pertaining to the role of EUS-FNA to biopsy central lung masses. The aim of the study was to assess the diagnostic yield and safety of EUS-FNA of indeterminate central mediastinal lung masses. Methods. DESIGN: Retrospective review of a prospectively maintained database; noncomparative. SETTING: Tertiary referral center. From 10/2004 to 12/2010, all patients with a lung mass located within proximity to the esophagus were referred for EUS-FNA. MAIN OUTCOME MEASUREMENT: EUS-FNA diagnostic accuracy and safety. Results. 73 consecutive patients were included. EUS allowed detection in 62 (85%) patients with lack of visualization prohibiting FNA in 11 patients. Among sampled lesions, one patient (1/62 = 1.6%) had a benign lung mass (hamartoma), while the remaining 61 patients (61/62 = 98.4%) had a malignant mass (primary lung cancer: 55/61 = 90%; lung metastasis: 6/61 = 10%). The sensitivity, specificity, and accuracy of EUS-FNA were 96.7%, 100%, and 96.7%, respectively. The sensitivity was 80.8% when considering nonvisualized masses. One patient developed a pneumothorax (1/62 = 1.6%). Conclusions. EUS-FNA appears to be an accurate and safe technique for tissue diagnosis of central mediastinal lung masses. PMID- 23818748 TI - Comment on "The Molecular Evolutionary Patterns of the Insulin/FOXO Signaling Pathway". AB - Letter to the Editor on Wang M, Wang Q, Wang Z, Zhang X, Pan Y. The molecular evolutionary patterns of the insulin/FOXO signaling pathway. Evol Bioinform. 2013;9:1-16. doi: 10.4137/EBO.S10539. PMID- 23818749 TI - rbrothers: R Package for Bayesian Multiple Change-Point Recombination Detection. AB - Phylogenetic recombination detection is a fundamental task in bioinformatics and evolutionary biology. Most of the computational tools developed to attack this important problem are not integrated into the growing suite of R packages for statistical analysis of molecular sequences. Here, we present an R package, rbrothers, that makes a Bayesian multiple change-point model, one of the most sophisticated model-based phylogenetic recombination tools, available to R users. Moreover, we equip the Bayesian change-point model with a set of pre- and post- processing routines that will broaden the application domain of this recombination detection framework. Specifically, we implement an algorithm that forms the set of input trees required by multiple change-point models. We also provide functionality for checking Markov chain Monte Carlo convergence and creating estimation result summaries and graphics. Using rbrothers, we perform a comparative analysis of two Salmonella enterica genes, fimA and fimH, that encode major and adhesive subunits of the type 1 fimbriae, respectively. We believe that rbrothers, available at R-Forge: http://evolmod.r-forge.r-project.org/, will allow researchers to incorporate recombination detection into phylogenetic workflows already implemented in R. PMID- 23818750 TI - Subretinal angiostrongyliasis-induced optic neuritis. AB - A 27-year-old Thai male presented with progressive visual loss and a membrane like floater in the right eye that had persisted for 1 month. He had a history of eating raw foods, including snails. His initial visual acuity was counting fingers at 1 ft and he had a relative afferent pupillary defect. A movable larva with subretinal tracks was found in the subretinal space near a normal optic disc. Visually evoked potentials showed delayed latency, which indicated secondary retrobulbar optic neuritis. A diode laser was directly applied to the motile worm. The patient was subsequently prescribed oral prednisolone and albendazole. After treatment, his visual acuity was slightly improved at 2/60. Ocular manifestation is a very rare event resulting from parasitic infection. In only 1.1% of angiostrongyliasis cases is an Angiostrongylus cantonensis larva identified in the eye. Ocular angiostrongyliasis with optic neuritis may be secondary to mechanical injury and/or inflammatory reactions. Steroid treatment is recommended, although most patients have only slight visual improvement after treatment. PMID- 23818751 TI - Superselective intra-arterial melphalan therapy for newly diagnosed and refractory retinoblastoma: results from a single institution. AB - BACKGROUND: Intra-arterial administration of melphalan chemotherapy has shown promise in the treatment of retinoblastoma. This report describes our results using superselective intra-arterial melphalan in patients with newly diagnosed retinoblastoma and those who were treated for progression after systemic chemotherapy. METHODS: This is a retrospective review of all retinoblastoma patients treated with intra-arterial melphalan at the University of California, San Francisco from March 2010 to August 2012. Twenty eyes (16 patients) underwent 40 intra-arterial melphalan infusions, and dose was determined by age. Patients were treated at monthly intervals and received a range of 1-5 treatments. Response to therapy, toxicity, and procedural radiation exposure was assessed. RESULTS: All patients are alive without metastatic disease at a median follow-up of 14.5 (1-29) months. Treatment with enucleation or external beam radiation was avoided in 11/20 eyes (55%) overall [6/12 (50%) in newly diagnosed eyes and 5/8 (63%) in refractory/relapsed eyes]. Response rates (per the International Classification of Retinoblastoma) were as follows: 6/7 (86%) in groups A-C and 5/13 (38%) in groups D and E. Nonhematologic and hematologic toxicities were minimal and comparable with those in previous reports. The mean procedural radiation dose was 20.2 +/- 11.9 mGy per eye per procedure. CONCLUSION: Superselective intra-arterial melphalan therapy is effective for less advanced eyes but further modifications to therapy are required to improve results in eyes with advanced retinoblastoma. PMID- 23818752 TI - Rhegmatogenous retinal detachment in children 16 years of age or younger. AB - PURPOSE: To study the anatomical and visual outcomes and prognostic factors that may predict the outcomes of rhegmatogenous retinal detachment (RRD) in children. METHODS: A retrospective chart review was performed for patients 16 years of age or younger who underwent retinal reattachment surgery for RRD at the King Abdulaziz University Hospital from 1996 to 2005 and the King Khalid Eye Specialist Hospital from 2002 to 2006, Riyadh, Saudi Arabia. Good visual outcome was defined as >=20/200. The association between two categorical variables was evaluated with the Chi-squared test or the exact test, as appropriate. Predictors for RRD and good final visual acuity were identified by conducting stepwise logistic regression analysis. P < 0.05 was statistically significant. RESULTS: The study population comprised 148 patients (166 eyes). There were 104 (70%) males and 44 (30%) females. Mean age at presentation was 8.33 +/- 3.26 years (range 1.5-16 years). The retina was reattached after one surgical procedure in 106 (63.8%) eyes and reattached in 130 (78.3%) eyes after multiple surgeries. Factors predicting recurrence after the first surgery were myopia (P = 0.028), proliferative vitreoretinopathy (PVR) at presentation (P = 0.024), and total retinal detachment (P = 0.032). Good final visual outcome was achieved in 60 (44.4%) eyes. Predictors of good visual acuity were: good visual acuity at presentation (P < 0.001); absence of PVR at presentation (P < 0.001); one quadrant of retinal detachment (P = 0.0024); macula on (P = 0.0107); absence of primary repair of a ruptured globe (P = 0.0059); no pars plana vitrectomy (PPV) (P = 0.0123); clear phakic lens at follow-up (P < 0.001); absence of postoperative complications (P < 0.001); absence of recurrence of RRD (P < 0.001); and absence of epiretinal membrane (P = 0.0088). Logistic regression analysis indicated that recurrence of RRD was associated with myopia and previous congenital cataract surgery; good final visual outcome was associated with macula on detachment and poor visual outcome was associated with recurrence of RRD and occurrence of postoperative complications and previous repair of a ruptured globe. CONCLUSION: RRD in children is usually associated with a predisposing factor, a high rate of PVR, and total retinal detachment. Despite late diagnosis and the presence of PVR, favorable anatomical and visual outcomes can be achieved. PMID- 23818753 TI - Longstanding refractory pseudophakic cystoid macular edema resolved using intravitreal 0.7 mg dexamethasone implants. AB - BACKGROUND: Refractory pseudophakic cystoid macular edema (PCME) following cataract surgery has long posed a challenge to clinicians, but intravitreal injections with a sustained delivery 0.7 mg dexamethasone implant has emerged as a promising therapy for this condition. OBJECTIVE: To present a case of longstanding and refractory PCME with complete remission through 189 days of follow-up after two successive injections with intravitreal dexamethasone implants. CASE REPORT: A 59-year-old male had experienced metamorphopsia for approximately 4 years and had been diagnosed with PCME 15 months earlier. Since the time of the diagnosis, the condition had been refractory to both subtenon triamcinolone acetonide and a total of five injections with intravitreal ranibizumab. After the last injection with ranibizumab, central subfield mean thickness was 640 MUm, and the best corrected visual acuity was 78 Early Treatment Diabetic Retinopathy Study letters. Following an intravitreal injection with a dexamethasone implant, the macular edema resolved at the next follow-up. The macular edema returned 187 days after the first injection and was treated with another intravitreal dexamethasone implant. Again, the macular edema subsided completely, and best corrected visual acuity improved to 84 Early Treatment Diabetic Retinopathy Study letters, a condition which was maintained through an additional 189 days of follow-up. CONCLUSION: Chronic PCME is traditionally a difficult condition to treat, but we are encouraged by the optimal response experienced with intravitreal sustained release dexamethasone implants in our patient whose longstanding PCME had been refractory to previous treatments with both subtenon triamcinolone and intravitreal ranibizumab. In this case, the condition appeared to be fully reversible once inflammation was controlled, but the need for monitoring and repeated injections remains an issue of concern. PMID- 23818754 TI - Vancomycin-resistant Staphylococcus hominis endophthalmitis following cataract surgery. AB - We report a case of acute postoperative endophthalmitis caused by vancomycin resistant Staphylococcus hominis, treated at our hospital. An 80-year-old male presented 2 days after uncomplicated phacoemulsification and posterior chamber intraocular lens implantation, with a 24-hour history of progressive visual loss and redness in the operated (right) eye. On examination, best corrected visual acuity was counting fingers. Anterior segment examination revealed conjunctival injection, chemosis, corneal edema, and hypopyon. B-scan ultrasonography showed vitreous opacification, but no retinal detachment. Acute postoperative endophthalmitis was diagnosed. We performed vitrectomy with vancomycin in the irrigating solution, intraocular lens removal, and silicone oil tamponade. Culture of the vitreous grew Staphylococcus hominis. Antibiotic susceptibility testing showed the isolate was sensitive to trimethoprim/sulfamethoxazole and teicoplanin but resistant to ciprofloxacin, moxifloxacin, levofloxacin, cefazolin, and vancomycin. At 3 months, the visual acuity of the silicone oil treated eye was 20/400. PMID- 23818755 TI - A comparison of two approaches to managing acute primary angle closure in Asian eyes. AB - PURPOSE: To review the management regimes of acute primary angle closure (APAC) in two hospitals in Singapore, and to identify the incidence of and risk factors for progression to glaucomatous optic neuropathy. METHODS: We conducted a retrospective review of 40 patients from National University Hospital (NUH) and 52 patients from Singapore National Eye Centre (SNEC) who were diagnosed with APAC. Patients were treated with similar protocols of intensive medical therapy until laser peripheral iridotomy could be performed. In the event of failed medical treatment, patients at NUH only underwent laser iridoplasty. The 1-year outcomes were reviewed. RESULTS: The demographic features of patients and presenting intraocular pressures (IOP) were similar in both centers. More patients from NUH presented within 3 days of symptom onset, compared to those from SNEC (90.0% versus 71.2%, respectively) (P = 0.037). The mean +/- standard deviation time to break the attack was 18.2 +/- 32.9 hours at SNEC and 9.80 +/- 10.6 hours at NUH (P = 0.11). The mean follow up duration was 18.8 +/- 14.0 months. Nineteen patients (36.5%) from SNEC and six patients (22.5%) from NUH developed raised IOP (P = 0.032) within 1-year of the attack. Of these, glaucomatous optic neuropathy developed in thirteen patients (68.4%) from SNEC and all six patients (100%) from NUH. At final review, the mean IOP of the APAC eye was 14.8 +/- 4.3 mmHg from SNEC and 13.4 +/- 3.0 mmHg from NUH. There was no significant difference in final visual acuity or IOP between both groups. CONCLUSION: Treatment strategies in both centers were effective in aborting an APAC attack. The development of raised IOP appears to be associated with a longer period of attack suggesting that greater urgency in aborting APAC attacks may entail better long term outcomes. PMID- 23818756 TI - A novel platinum chromium everolimus-eluting stent for the treatment of coronary artery disease. AB - The development of coronary stents represents a major step forward in the treatment of obstructive coronary artery disease since the introduction of percutaneous coronary intervention. The initial enthusiasm for bare metal stents was, however, tempered by a significant incidence of in-stent restenosis, the manifestation of excessive neointima hyperplasia within the stented vessel segment, ultimately leading to target vessel revascularization. Later, drug eluting stents, with controlled local release of antiproliferative agents, consistently reduced this need for repeat revascularization. In turn, the long term safety of first-generation drug-eluting stents was brought into question with the observation of an increased incidence of late stent thrombosis, often presenting as myocardial infarction or sudden death. Since then, new drugs, polymers, and platforms for drug elution have been developed to improve stent safety and preserve efficacy. Development of a novel platinum chromium alloy with high radial strength and high radiopacity has enabled the design of a new, thin strut, flexible, and highly trackable stent platform, while simultaneously improving stent visibility. Significant advances in polymer coating, serving as a drug carrier on the stent surface, and in antiproliferative agent technology have further improved the safety and clinical performance of newer-generation drug eluting stents. This review will provide an overview of the novel platinum chromium everolimus-eluting stents that are currently available. The clinical data from major clinical trials with these devices will be summarized and put into perspective. PMID- 23818757 TI - Novel phytochemical-antibiotic conjugates as multitarget inhibitors of Pseudomononas aeruginosa GyrB/ParE and DHFR. AB - BACKGROUND: There is a dearth of treatment options for community-acquired and nosocomial Pseudomonas infections due to several rapidly emerging multidrug resistant phenotypes, which show resistance even to combination therapy. As an alternative, developing selective promiscuous hybrid compounds for simultaneous modulation of multiple targets is highly appreciated because it is difficult for the pathogen to develop resistance when an inhibitor has activity against multiple targets. METHODS: In line with our previous work on phytochemical antibiotic combination assays and knowledge-based methods, using a fragment combination approach we here report a novel drug design strategy of conjugating synergistic phytochemical-antibiotic combinations into a single hybrid entity for multi-inhibition of P. aeruginosa DNA gyrase subunit B (GyrB)/topoisomerase IV subunit B (ParE) and dihydrofolate reductase (DHFR) enzymes. The designed conjugates were evaluated for their multitarget specificity using various computational methods including docking and dynamic simulations, drug-likeness using molecular properties calculations, and pharmacophoric features by stereoelectronic property predictions. RESULTS: Evaluation of the designed hybrid compounds based on their physicochemical properties has indicated that they are promising drug candidates with drug-like pharmacotherapeutic profiles. In addition, the stereoelectronic properties such as HOMO (highest occupied molecular orbital), LUMO (lowest unoccupied molecular orbital), and MEP (molecular electrostatic potential) maps calculated by quantum chemical methods gave a good correlation with the common pharmacophoric features required for multitarget inhibition. Furthermore, docking and dynamics simulations revealed that the designed compounds have favorable binding affinity and stability in both the ATP-binding sites of GyrB/ParE and the folate-binding site of DHFR, by forming strong hydrogen bonds and hydrophobic interactions with key active site residues. CONCLUSION: This new design concept of hybrid "phyto-drug" scaffolds, and their simultaneous perturbation of well-established antibacterial targets from two unrelated pathways, appears to be very promising and could serve as a prospective lead in multitarget drug discovery. PMID- 23818758 TI - Early achievement and maintenance of stable asthma control using initially higher dose inhaled corticosteroids as part of combination therapy: an open-label pilot study. AB - BACKGROUND: Uncontrolled asthma is characterized by considerable variability. Well controlled asthma is associated with less unplanned use of health care resources and fewer acute exacerbations. In this study, we attempted to increase inhaled corticosteroid (ICS) doses initially in suboptimally controlled asthmatics, hypothesizing that early achievement of asthma control using this strategy would be associated positively with a higher level of stability. METHODS: This was a randomized, open-label, prospective study including patients with uncontrolled asthma who were randomized to receive higher-dose (HD) ICS in combination with a long-acting beta-agonist (LABA) for one month and then shifted to doses suggested in the practice guidelines (GD) or to receive GD therapy alone. Lung function, ie, forced expiratory volume in one second (FEV(1)), peak expiratory flow, Asthma Control Test scores, and frequency of acute exacerbations, was followed up for one year. RESULTS: Seventy-six patients were treated with the HD strategy and 80 with the GD strategy. The increase in FEV(1) from baseline was greater in the HD group than in the GD group, especially during the first month of treatment (304 +/- 49 mL versus 148 +/- 39 mL, respectively, P = 0.01). Numbers of patients with completely or well controlled asthma were higher in the HD group than in the GD group (92.1% versus 81.1%, respectively, P = 0.03). Further, there was a significant difference between the groups with regard to frequency of acute exacerbations (9.2% in the HD group versus 21.3% in the GD group, P = 0.02); this effect was more pronounced for patients in the HD group with partially controlled or uncontrolled asthma. CONCLUSION: Patients receiving HD therapy achieved asthma control more rapidly and maintained greater stability than those receiving GD therapy. This represents a novel strategy for gaining disease control in patients with uncontrolled asthma. PMID- 23818759 TI - Resistance to antivascular endothelial growth factor treatment in age-related macular degeneration. AB - Age-related macular degeneration (AMD) is the main cause of visual impairment and blindness in people aged over 65 years in developed countries. Vascular endothelial growth factor (VEGF) is a positive regulator of angiogenesis and its proven role in the pathological neovascularization in wet AMD has provided evidence for the use of anti-VEGF agents as potential therapies. In this study, we review the literature for the possible causes of failure after treatment with anti-VEGF agents and attempt to propose an algorithm of suggestive actions to increase the chances of successful management of such difficult cases. PMID- 23818760 TI - Drug-resistant colon cancer cells produce high carcinoembryonic antigen and might not be cancer-initiating cells. AB - PURPOSE: We evaluated the higher levels of carcinoembryonic antigen (CEA) secreted by the LoVo human colon carcinoma cells in a medium containing anticancer drugs. Drug-resistant LoVo cells were analyzed by subcutaneously xenotransplanting them into mice. The aim of this study was to evaluate whether the drug-resistant cells isolated in this study were cancer-initiating cells, known also as cancer stem cells (CSCs). METHODS: The production of CEA was investigated in LoVo cells that were cultured with 0-10 mM of anticancer drugs, and we evaluated the increase in CEA production by the LoVo cells that were stimulated by anticancer drug treatment. The expression of several CSC markers in LoVo cells treated with anticancer drugs was also evaluated. Following anticancer drug treatment, LoVo cells were injected subcutaneously into the flanks of severe combined immunodeficiency mice in order to evaluate the CSC fraction. RESULTS: Production of CEA by LoVo cells was stimulated by the addition of anticancer drugs. Drug-resistant LoVo cells expressed lower levels of CSC markers, and LoVo cells treated with any of the anticancer drugs tested did not generate tumors within 8 weeks from when the cells were injected subcutaneously into severe combined immunodeficiency mice. These results suggest that the drug-resistant LoVo cells have a smaller population of CSCs than the untreated LoVo cells. CONCLUSION: Production of CEA by LoVo cells can be stimulated by the addition of anticancer drugs. The drug-resistant subpopulation of LoVo colon cancer cells could stimulate the production of CEA, but these cells did not act as CSCs in in vivo tumor generation experiments. PMID- 23818761 TI - Reducing lung function decline in patients with idiopathic pulmonary fibrosis: potential of nintedanib. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic lung disease with no clear etiology and a paucity of therapeutic options. Nintedanib (previously known as BIBF 1120) is a tyrosine kinase receptor antagonist which inhibits a number of key receptors, including those for platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and fibroblast growth factor (FGF). These growth factors are profibrotic and each has been investigated as a potential standalone therapeutic target in IPF. Simultaneous inhibition of these receptors, with an analog of nintedanib, has proved to be effective in experimental animal models of pulmonary fibrosis. This observation, together with extensive safety and pharmacokinetic data from studies of nintedanib in malignancy, paved the way for the clinical development of this drug in IPF. The Phase IIb TOMORROW trial demonstrated that treatment with nintedanib may potentially slow decline in lung function, decrease the frequency of acute exacerbations, and improve quality of life in patients with IPF. While these observations are drawn from a single clinical trial, taken together with the preclinical data they suggest that nintedanib may yet become an important therapeutic option for individuals with IPF. The results of ongoing parallel, international, multicenter Phase III clinical trials are therefore eagerly awaited. PMID- 23818762 TI - The drug efficacy and adverse reactions in a mouse model of oral squamous cell carcinoma treated with oxaliplatin at different time points during a day. AB - BACKGROUND: Recent studies have shown that the growth and proliferation of cancer cells in vivo exhibit circadian rhythm, and the efficacy and adverse reactions of platinum-based anticancer drugs administered at different times of the day vary significantly on colon cancer. However, since the circadian rhythms of growth and proliferation of various cancer cells often differ, the question of whether the administration of platinum anticancer drugs at different times of the day exerts significantly different efficacy and adverse effects on oral cancers remains to be elucidated. This study has compared the efficacy and adverse effects of oxaliplatin (L-OHP) administration at different times during a day on oral squamous cell carcinoma in mice and has analyzed cellular circadian rhythms. METHODS: The mouse model for oral squamous cell carcinoma was established in 75 nude mice, housed in a 12 hour light/12 hour dark cycle environment. The mice were randomly divided into five groups; four experimental groups were intravenously injected with L-OHP at four time points within a 24-hour period (4, 10, 16, and 22 hours after lights on [HALO]). The control group was intravenously injected with the same volume of saline. Treatment efficacy and adverse reactions were compared on the seventh day after the injection, at 22 HALO. The existence of circadian rhythms was determined by cosine analysis. RESULTS: Only injections of L-OHP at 16 and 22 HALO significantly prolonged animal survival time. The adverse reactions in mice injected with L-OHP at 16 and 22 HALO were significantly less than those observed in mice administered L-OHP at 4 and 10 HALO. The cosine fitting curve showed that the survival time and adverse reactions exhibited circadian rhythm. CONCLUSION: The time factor should be considered when treating patients with oral squamous cell carcinoma with L-OHP in order to achieve better efficacy, reduce the adverse reactions, and improve the patients' survival time and quality of life. PMID- 23818763 TI - Profile of tivozanib and its potential for the treatment of advanced renal cell carcinoma. AB - Tivozanib is a novel vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGF TKI). Among other VEGF TKIs, tivozanib stands apart due to its selective kinase inhibitory properties as well as its high potency for inhibiting VEGF receptors 1 and 2. Tivozanib has been evaluated in several clinical trials including a Phase I and Phase II trial demonstrating safety and efficacy for patients with advanced clear cell renal cell carcinoma (RCC). A pivotal randomized Phase III trial comparing the front-line use of tivozanib to sorafenib in patients with metastatic clear cell RCC has been reported. The clinical development of tivozanib and results of these important studies will be reviewed. Also, the potential placement of tivozanib among currently US Food and Drug Administration approved agents for advanced RCC will be discussed. PMID- 23818764 TI - Do concomitant pain symptoms in patients with major depression affect quality of life even when taking into account baseline depression severity? AB - BACKGROUND: Patients with major depressive disorder (MDD) may suffer from concomitant pain symptoms. The aim of this study is to determine whether the presence of painful physical symptoms (PPS) influences quality of life when taking into account baseline depression severity. METHODS: Patients with a new or first episode of MDD (n = 909) were enrolled in a 3-month prospective observational study in East Asia. The Hamilton Depression Rating Scale, Clinical Global Impression-Severity score, Somatic Symptom Inventory, and EuroQoL questionnaire-5 Dimensions (EQ-5D) and EQ-Visual Analogue Scale (EQ-VAS) were assessed at baseline and 3 months' follow-up. The presence of PPS was defined as a mean score of >=2 on the Somatic Symptom Inventory pain-related items. Regression analyses determined predictors of quality of life at 3 months, adjusting for age, sex, depressive symptoms, overall severity, and quality of life at baseline. RESULTS: PPS were present (PPS+) at baseline in 52% of patients. During the 3-month follow-up, EQ-VAS scores improved from 47.7 (standard deviation [SD] 20.6) to 72.5 (SD 20.4), and EQ-5D improved from 0.48 (SD 0.34) to 0.80 (SD 0.26). At 3 months, mean EQ-VAS was 66.4 (SD 21.2) for baseline PPS+ patients versus 78.5 (SD 17.6) for baseline PPS- patients, and mean EQ-5D was 0.71 (SD 0.29) versus 0.89 (SD 0.18). PPS+ at baseline was a significant predictor of quality of life at 3 months after adjusting for sociodemographic and baseline clinical variables. CONCLUSION: The presence of painful physical symptoms is associated with less improvement in quality of life in patients receiving treatment for major depression, even when adjusting for depression severity. PMID- 23818765 TI - The occurrence of cerebrovascular atherosclerosis in Alzheimer's disease patients. AB - BACKGROUND: Both Alzheimer's disease (AD) and cerebrovascular atherosclerosis (CA) contributed to dementia in an aged population. Whether they share the same mechanism is unknown. AIM: Our goal was to explore the occurrence rates of CA in AD patients. METHOD: Here we examined the degree of CA in different groups of AD patients with contrast angiography. Ninety-three AD patients were recruited to the present study. Contrast computed tomography scanning and contrast angiography were performed for CA analyses. RESULT: We found that the cerebrovascular plaques were common in AD patients, which was partly correlated with the severity of AD (as determined by cognitive decline). CONCLUSION: We concluded that vascular dementia may partly correlate with AD pathology. PMID- 23818766 TI - Association of polymorphisms in FADS gene with age-related changes in serum phospholipid polyunsaturated fatty acids and oxidative stress markers in middle aged nonobese men. AB - BACKGROUND: To investigate the association of FADS gene polymorphisms with age related changes in polyunsaturated fatty acids (PUFAs) in serum phospholipids and oxidative stress markers. METHODS: We genotyped 122 nonobese men aged 35-59 years without any known diseases at baseline for rs174537 near FADS1 (FEN1 rs174537G > T), FADS2 (rs174575, rs2727270), and FADS3 (rs1000778), and followed them for 3 years. RESULTS: Among the four single-nucleotide polymorphisms, the minor variants of rs174537 and rs2727270 were significantly associated with lower concentrations of long-chain PUFAs. However, rs174537G > T showed stronger association. At baseline, men with the rs174537T allele had lower arachidonic acid (AA) and AA/linoleic acid (LA), and higher interleukin (IL)-6 levels than rs174537GG counterparts. After 3 years, rs174537GG men had significantly increased AA (P = 0.022), AA/dihomo-gamma-linolenic acid (DGLA) (P = 0.007), docosapentaenoic acid (DPA), low-density lipoprotein (LDL) cholesterol, and oxidized LDL (ox-LDL), but decreased eicosatrienoic acid. The rs174537T group showed significantly increased gamma-linolenic acid and ox-LDL, and decreased eicosadienoic acid, eicosapentaenoic acid (EPA)/alpha-linolenic acid (ALA), and IL-6. After 3 years, the rs174537T group had lower AA (P < 0.001), AA/DGLA (P = 0.019), EPA, DPA, EPA/ALA, and urinary 8-epi-prostaglandin F2alpha (8-epi PGF2alpha) (P = 0.011) than rs174537GG. Changes in AA (P = 0.001), AA/DGLA (P = 0.017), EPA, DPA, EPA/ALA, and urinary 8-epi-PGF2alpha (P < 0.001) were significantly different between the groups after adjusting for baseline values. Overall, changes in AA positively correlated with changes in urinary 8-epi PGF2alpha (r = 0.249, P = 0.007), plasma ox-LDL (r = 0.199, P = 0.045), and serum IL-6 (r = 0.289, P = 0.004). CONCLUSION: Our data show that FADS polymorphisms can affect age-associated changes in serum phospholipid long-chain PUFAs, Delta5 desaturase activity, and oxidative stress in middle-aged nonobese men. In particular, the rs174537T allele did not show the age-associated increases in AA and Delta5-desaturase activity seen with the rs174537GG genotype. PMID- 23818767 TI - Calcium and vitamin D intake by postmenopausal women with osteoporosis in Spain: an observational calcium and vitamin D intake (CaVIT) study. AB - BACKGROUND: Osteoporotic fractures are important causes of morbidity, mortality, and increased health care costs. However, the risk of osteoporotic fractures can be decreased, with clinical studies supporting the use of calcium and vitamin D supplements to promote bone health. Vitamin D insufficiency is widespread, particularly among postmenopausal women with osteoporosis, and this indicates that dietary intake is suboptimal, even though vitamin D supplements are widely available. METHODS: We conducted an observational study, using telephone surveys, to estimate vitamin D and calcium intake and the use of prescription osteoporosis medications in Spanish women aged >= 50 years with osteoporosis. RESULTS: Among the study participants, mean dietary calcium intake was 1239 mg/day and generally appeared sufficient in terms of the recommended daily intake guidance documents. Participants aged >= 75 years had a significantly lower mean dietary calcium intake (988 mg/day), thus one-half were below the level advised by the World Health Organization. Daily calcium intake was also lower in participants who were not taking prescription medications for bone health. Dietary vitamin D intake was 167 IU/day, which is well below both the established target dose (400 IU/day) and the more recent, higher guideline recommended for postmenopausal women (800-1300 IU/day). Dietary vitamin D intake was even lower for participants aged >= 75 years (120 IU/day) and was not related to the use of bone health prescription medications. CONCLUSION: These results support the need for greater promotion of the benefits of higher vitamin D intake in Spanish women with osteoporosis. PMID- 23818768 TI - Patients undergoing long-term treatment with antihypertensive eye drops responded positively with respect to their ocular surface disorder to oral supplementation with antioxidants and essential fatty acids. AB - BACKGROUND: Glaucoma and dry eye disorders (DEDs) are frequent comorbidities. The antioxidant and anti-inflammatory properties of essential polyunsaturated fatty acids have been extensively studied in relation to eye diseases. OBJECTIVE: Our objective was to determine the effects of oral supplementation with a combined formulation of antioxidants and essential polyunsaturated fatty acids on expression of cytokines and chemokines in tears from patients with DEDs or primary open-angle glaucoma (POAG). METHODS: Participants (n = 97) were distributed into three groups: (1) individuals with nonsevere DEDs (DEDG), (2) individuals with nonadvanced POAG (POAGG), and (3) healthy controls. These groups were randomized into two subgroups: one received a daily antioxidant and essential polyunsaturated fatty acid supplement (two pills) for 3 months (+S), and the other did not (-NS). Participants were interviewed and ophthalmologically examined. Concentrations of specific cytokines and chemokines in reflex tears were determined by multiplexed particle-based flow cytometry. The data were analyzed statistically (SPSS version 15.0). RESULTS: Comparison of the results from the DEDG and POAGG patients showed significant differences in tear expression of granulocyte-macrophage colony-stimulating factor (P = 0.008), tumor necrosis factor alpha (P = 0.005), vascular endothelial growth factor (P = 0.038), interleukin-4 (P = 0.030), and interleukin-6 (P = 0.044). The main signs and symptoms of dry eyes such as dryness, burning, photophobia, eye heaviness, and blurred vision, as well as positive changes in eyelashes, hair, nails and skin, were significantly improved in DEDG +S and POAGG +S patients relative to unsupplemented patients. CONCLUSION: Inflammation biomarkers were differentially expressed in glaucomatous tears, but the differences changed upon antioxidant/essential polyunsaturated fatty acid supplementation. Chronic instillation of antihypertensive eye drops must be considered for integrating protocols to glaucoma standards of care. PMID- 23818769 TI - High-level activities of daily living and disease-specific mortality during a 12 year follow-up of an octogenarian population. AB - BACKGROUND: Little is known about the relationship between disease-specific mortality and high-level activities of daily living in the elderly. We examined whether mortality is associated with high-level activities of daily living in an octogenarian population. METHODS: We conducted a population-based cross-sectional and prospective cohort study in 693 older persons aged 80 years and living in Japan's Fukuoka Prefecture. We then evaluated the association between 12-year disease-specific mortality and high-level functional capacity as measured by the Tokyo Metropolitan Institute of Gerontology Index of Competence, which is a standardized multidimensional 13-item instrument; items 1 through 5 are classified as instrumental self-maintenance activity, items 6 through 9 as intellectual activity, items 10 through 13 as social roles activity, and all 13 items together yield total functional capacity. RESULTS: By the 12-year follow-up of the 693 participants, 413 had died, 242 survived, and 38 were unable to be located. Of the 413 who died, 105 died of cardiovascular disease, 73 of respiratory tract disease, 71 of cancer, and 39 of senility. Of the other 125 deaths, 59 were due to other diseases, and the cause of death for 66 participants is not known. The hazard ratio (HR) for all-cause mortality, adjusted for confounding factors with multivariate Cox analyses, fell by 6% (HR 0.937, 95% confidence interval [CI] 0.899-0.978, P = 0.003) with each one-point increase in participants' scores on the Tokyo Metropolitan Institute of Gerontology Index of total functional capacity. With one-point increases in instrumental self maintenance activity and in intellectual activity, the HRs for all-cause mortality decreased by 14% (HR 0.856, 95% CI 0.787-0.930, P = 0.000) and 12% (HR 0.884, 95% CI 0.794-0.983, P = 0.023), respectively. Respiratory mortality with HR adjustment fell by 11% (HR 0.887, 95% CI 0.804-0.978, P = 0.016) and 24% (HR 0.760, 95% CI 0.627-0.922, P = 0.005) with one-point increases in the scores of total functional capacity and instrumental self-maintenance activity, respectively. Similarly, mortality due to senility fell by 16% (HR 0.838, 95% CI 0.743-0.946, P = 0.004), 29% (HR 0.707, 95% CI 0.564-0.886, P = 0.003), and 29% (HR 0.710, 95% CI 0.522-0.966, P = 0.029) with one-point increases in the scores of total functional capacity, instrumental self-maintenance activity, and intellectual activity, respectively. CONCLUSION: These findings suggest that high level activities of daily living may be an independent predictor of mortality due to all causes, respiratory disease and senility in older persons. PMID- 23818770 TI - 30-day hospital readmission of older adults using care transitions after hospitalization: a pilot prospective cohort study. AB - PURPOSE: Patients leaving the hospital are at increased risk of functional decline and hospital readmission. The Employee and Community Health service at Mayo Clinic in Rochester developed a care transition program (CTP) to provide home-based care services for medically complex patients. The study objective was to determine the relationship between CTP use, 30-day hospital readmission, and Emergency Room (ER) visits for adults over 60 years with high Elder Risk Assessment scores. PATIENTS AND METHODS: This was a pilot prospective cohort study that included 20 patients that used the CTP and 20 patients discharged from the hospital without using the CTP. The medically complex study patients were drawn from the department of Employee and Community Health population between October 14, 2011 and September 27, 2012. The primary outcomes were 30-day hospital readmission or ER visit after discharge from the hospital. The secondary outcomes were within-group changes in grip strength, gait speed, and quality of life (QOL). Patients underwent two study visits, one at baseline and one at 30 days postbaseline. The primary analysis included time-to-event from baseline to rehospitalization or ER visit. Paired t-tests were used for secondary outcomes, with continuous scores. RESULTS: Of the 40 patients enrolled, 36 completed all study visits. The 30-day hospital readmission rates for usual care patients were 10.5% compared with no readmissions for CTP patients. There were 31.6% ER visits in the UC group and 11.8% in the CTP group (P = 0.37). The secondary analysis showed some improvement in physical QOL scores (pre: 32.7; post: 39.4) for the CTP participants (P < 0.01) and no differences in gait speed or grip strength. CONCLUSION: Based on this pilot study of care transition, we found nonsignificant lower hospital and ER utilization rates and improved physical QOL scores for patients in the CTP group. However, the data leads us to recommend future studies with larger sample sizes (N = 250). PMID- 23818771 TI - Radiofrequency treatment has a beneficial role in reducing low back pain due to facet syndrome in octogenarians or older. AB - INTRODUCTION: Chronic low back pain is a disabling phenomenon that can cause a severe reduction in quality of life, especially in elderly patients. Surgical treatment is sometimes a big challenge for these elderly patients. Radiofrequency (RF) ablation is an increasingly popular method for treating low back pain caused by facet syndrome. The purpose of this study was to evaluate whether RF neurotomy is effective in terms of pain reduction and functional outcome in elderly patients. PATIENTS AND METHODS: Fifty-eight patients aged 80 years and older who had chronic mechanical low back pain were examined after they underwent RF heat lesion of the medial branch. Follow-up occurred 1, 3, 6, and 12 months after treatment. Pain was measured on the visual analog scale and functional outcome was measured using the Oswestry Disability Index. RESULTS: After 1 month, 43 patients (74%) were satisfied with the results. After 3 months, 38 patients (66%) had clinically significant pain relief. After 6 months, 33 patients (57%) had pain relief, and at the 1-year follow-up, 30 patients (52%) showed good results while 28 patients (48%) showed no effect. The Oswestry Disability Index score was substantially improved even after 1 year. Minor complications occurred in eleven patients (19%), who had transient discomfort and burning pain. CONCLUSION: RF is a safe and partially effective procedure for treating elderly patients with mechanical back pain due to facet syndrome. PMID- 23818772 TI - Nutrients for the aging eye. AB - The incidence of age-related eye diseases is expected to rise with the aging of the population. Oxidation and inflammation are implicated in the etiology of these diseases. There is evidence that dietary antioxidants and anti inflammatories may provide benefit in decreasing the risk of age-related eye disease. Nutrients of interest are vitamins C and E, beta-carotene, zinc, lutein, zeaxanthin, and the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid. While a recent survey finds that among the baby boomers (45-65 years old), vision is the most important of the five senses, well over half of those surveyed were not aware of the important nutrients that play a key role in eye health. This is evident from a national survey that finds that intake of these key nutrients from dietary sources is below the recommendations or guidelines. Therefore, it is important to educate this population and to create an awareness of the nutrients and foods of particular interest in the prevention of age related eye disease. PMID- 23818774 TI - Noninvasive mechanical ventilation with high pressure strategy remains a "double edged sword"? PMID- 23818773 TI - Polypharmacy in the HIV-infected older adult population. AB - The prevalence of human immunodeficiency virus (HIV) infection among people older than 50 years is increasing. Older HIV-infected patients are particularly at risk for polypharmacy because they often have multiple comorbidities that require pharmacotherapy. Overall, there is not much known with respect to both the impact of aging on medication use in HIV-infected individuals, and the potential for interactions with highly active antiretroviral therapy (HAART) and coadministered medications and its clinical consequences. In this review, we aim to provide an overview of polypharmacy with a focus on its impact on the HIV-infected older adult population and to also provide some clinical considerations in this high risk population. PMID- 23818775 TI - Infrared light-absorbing gold/gold sulfide nanoparticles induce cell death in esophageal adenocarcinoma. AB - Gold nanoparticles and near infrared-absorbing light are each innocuous to tissue but when combined can destroy malignant tissue while leaving healthy tissue unharmed. This study investigated the feasibility of photothermal ablation therapy for esophageal adenocarcinoma using chitosan-coated gold/gold sulfide (CS GGS) nanoparticles. A rat esophagoduodenal anastomosis model was used for the in vivo ablation study, and three human esophageal cell lines were used to study the response of cancer cells and benign cells to near infrared light after treatment with CS-GGS. The results indicate that both cancerous tissue and cancer cells took up more gold nanoparticles and were completely ablated after exposure to near infrared light. The benign tissue and noncancerous cells showed less uptake of these nanoparticles, and remained viable after exposure to near infrared light. CS-GGS nanoparticles could provide an optimal endoluminal therapeutic option for near infrared light ablation of esophageal cancer. PMID- 23818776 TI - Thymoquinone-loaded nanostructured lipid carriers: preparation, gastroprotection, in vitro toxicity, and pharmacokinetic properties after extravascular administration. AB - BACKGROUND: Nanostructured lipid carriers (NLCs), composed of solid and liquid lipids, and surfactants are potentially good colloidal drug carriers. Thymoquinone is the main bioactive compound of Nigella sativa. In this study, the preparation, gastroprotective effects, and pharmacokinetic (PK) properties of thymoquinone (TQ)-loaded NLCs (TQNLCs) were evaluated. METHOD: TQNLCs were prepared using hydrogenated palm oil (Softisan(r) 154), olive oil, and phosphatidylcholine for the lipid phase and sorbitol, polysorbate 80, thimerosal, and double distilled water for the liquid lipid material. A morphological assessment of TQNLCs was performed using various methods. Analysis of the ulcer index, hydrogen concentration, mucus content, and biochemical and histochemical studies confirmed that the loading of TQ into the NLCs significantly improved the gastroprotective activity of this natural compound against the formation of ethanol-induced ulcers. The safety of TQNLC was tested on WRL68 liver normal cells with cisplatin as a positive control. RESULTS: The average diameter of the TQNLCs was 75 +/- 2.4 nm. The particles had negative zeta potential values of -31 +/- 0.1 mV and a single melting peak of 55.85 degrees C. Immunohistochemical methods revealed that TQNLCs inhibited the formation of ethanol-induced ulcers through the modulation of heat shock protein-70 (Hsp70). Acute hepatotoxic effects of the TQNLCs were not observed in rats or normal human liver cells (WRL 68). After validation, PK studies in rabbits showed that the PK properties of TQ were improved and indicated that the drug behaves linearly. The Tmax, Cmax, and elimination half-life of TQ were found to be 3.96 +/- 0.19 hours, 4811.33 +/- 55.52 ng/mL, and 4.4933 +/- 0.015 hours, respectively, indicating that TQ is suitable for extravascular administration. CONCLUSION: NLCs could be a promising vehicle for the oral delivery of TQ and improve its gastroprotective properties. PMID- 23818778 TI - Combinatorial evaluation of in vivo distribution of polyanhydride particle-based platforms for vaccine delivery. AB - Several challenges are associated with current vaccine strategies, including repeated immunizations, poor patient compliance, and limited approved routes for delivery, which may hinder induction of protective immunity. Thus, there is a need for new vaccine adjuvants capable of multi-route administration and prolonged antigen release at the site of administration by providing a depot within tissue. In this work, we designed a combinatorial platform to investigate the in vivo distribution, depot effect, and localized persistence of polyanhydride nanoparticles as a function of nanoparticle chemistry and administration route. Our observations indicated that the route of administration differentially affected tissue residence times. All nanoparticles rapidly dispersed when delivered intranasally but provided a depot when administered parenterally. When amphiphilic and hydrophobic nanoparticles were administered intranasally, they persisted within lung tissue. These results provide insights into the chemistry- and route-dependent distribution and tissue-specific association of polyanhydride nanoparticle-based vaccine adjuvants. PMID- 23818777 TI - Treatment of neuroblastoma and rhabdomyosarcoma using RGD-modified liposomal formulations of patupilone (EPO906). AB - BACKGROUND: Patupilone (EPO906) is a microtubule stabilizer with a potent antitumor effect. Integrin alphaVbeta3-binding (RGD) liposomes were loaded with EPO906, and their antitumor efficacy was evaluated in two pediatric tumor models, ie, neuroblastoma and rhabdomyosarcoma. METHODS: Integrin alphaVbeta3 gene expression, RGD-liposome cellular association, and the effect of EPO906 and liposomal formulations of EPO906 on cell viability were assessed in vitro in human umbilical vein endothelial cells (HUVEC), in the RH-30 rhabdomyosarcoma cell line, and in the Kelly neuroblastoma cell line. In vivo, mice bearing neuroblastoma or rhabdomyosarcoma tumors were treated with EPO906, EPO906 liposomes, or EPO906-RGD-liposomes. Tumor growth, cumulative survival, and toxicity were monitored. RESULTS: Integrin alphaVbeta3 was highly expressed in HUVEC and RH-30, but not in Kelly cells. Accordingly, RGD-liposomes were highly associated with HUVEC and RH-30 cells in vitro, but not with the Kelly cells. EPO906 and its liposomal formulations inhibited HUVEC, RH-30, and Kelly cell viability to the same extent. In vivo, EPO906 1.5 mg/kg and liposomal EPO906 potently inhibited tumor growth in both xenograft models without triggering major toxicity. At this dose, liposomal EPO906 did not enhance the antitumor effect of EPO906 in neuroblastoma, but tended to have an increased antitumor effect in rhabdomyosarcoma. Using a lower dose of EPO906-RGD-liposomes significantly enhanced cumulative survival in rhabdomyosarcoma compared with EPO906 alone. CONCLUSION: EPO906 shows a strong antitumor effect in neuroblastoma and rhabdomyosarcoma, without triggering major side effects. Its liposomal encapsulation does not alter its activity, and enhances cumulative survival when EPO906-RGD-liposomes are used at low dose in rhabdomyosarcoma. PMID- 23818779 TI - A novel bone cement impregnated with silver-tiopronin nanoparticles: its antimicrobial, cytotoxic, and mechanical properties. AB - Post-operatory infections in orthopedic surgeries pose a significant risk. The common approach of using antibiotics, both parenterally or embedded in bone cement (when this is employed during surgery) faces the challenge of the rising population of pathogens exhibiting resistance properties against one or more of these compounds; therefore, novel approaches need to be developed. Silver nanoparticles appear to be an exciting prospect because of their antimicrobial activity and safety at the levels used in medical applications. In this paper, a novel type of silver nanoparticles capped with tiopronin is presented. Two ratios of reagents during synthesis were tested and the effect on the nanoparticles investigated through TEM, TGA, and UV-Vis spectroscopy. Once encapsulated in bone cement, only the nanoparticles with the highest amount of inorganic fraction conferred antimicrobial activity against methicillin resistant Staphylococcus aureus (MRSA) at concentrations as low as 0.1% w/w. No other characteristics of the bone cement, such as cytotoxicity or mechanical properties, were affected by the presence of the nanoparticles. Our work presents a new type of silver nanoparticles and demonstrates that they can be embedded in bone cement to prevent infections once the synthetic conditions are tailored for such applications. PMID- 23818780 TI - Apoptosis of THP-1 macrophages induced by protoporphyrin IX-mediated sonodynamic therapy. AB - BACKGROUND: Sonodynamic therapy (SDT) was developed as a localized ultrasound activated cytotoxic therapy for cancer. The ability of SDT to destroy target tissues selectively is especially appealing for atherosclerotic plaque, in which selective accumulation of the sonosensitizer, protoporphyrin IX (PpIX), had been demonstrated. Here we investigate the effects of PpIX-mediated SDT on macrophages, which are the main culprit in progression of atherosclerosis. METHODS AND RESULTS: Cultured THP-1 derived macrophages were incubated with PpIX. Fluorescence microscopy showed that the intracellular PpIX concentration increased with the concentration of PpIX in the incubation medium. MTT assay demonstrated that SDT with PpIX significantly decreased cell viability, and this effect increased with duration of ultrasound exposure and PpIX concentration. PpIX-mediated SDT induced both apoptosis and necrosis, and the maximum apoptosis to necrosis ratio was obtained after SDT with 20 MUg/mL PpIX and five minutes of sonication. Production of intracellular singlet oxygen and secondary disruption of the cytoskeleton were also observed after SDT with PpIX. CONCLUSION: PpIX mediated SDT had apoptotic effects on THP-1 macrophages via generation of intracellular singlet oxygen and disruption of the cytoskeleton. PpIX-mediated SDT may be a potential treatment to attenuate progression of atherosclerotic plaque. PMID- 23818781 TI - One-step detection of circulating tumor cells in ovarian cancer using enhanced fluorescent silica nanoparticles. AB - Ovarian cancer is the fifth-leading cause of cancer-related deaths among women as a result of late diagnosis. For survival rates to improve, more sensitive and specific methods for earlier detection of ovarian cancer are needed. This study presents the development of rapid and specific one-step circulating tumor cell (CTC) detection using flow cytometry in a whole-blood sample with fluorescent silica nanoparticles. We prepared magnetic nanoparticle (MNP)-SiO2(rhodamine B isothiocyanate [RITC]) (MNP-SiO2[RITC] incorporating organic dyes [RITC, emax(ex/em) = 543/580 nm]) in the silica shell. We then controlled the amount of organic dye in the silica shell of MNP-SiO2(RITC) for increased fluorescence intensity to overcome the autofluorescence of whole blood and increase the sensitivity of CTC detection in whole blood. Next, we modified the surface function group of MNP-SiO2(RITC) from -OH to polyethylene glycol (PEG)/COOH and conjugated a mucin 1 cell surface-associated (MUC1) antibody on the surface of MNP-SiO2(RITC) for CTC detection. To study the specific targeting efficiency of MUC1-MNP-SiO2(RITC), we used immunocytochemistry with a MUC1-positive human ovarian cancer cell line and a negative human embryonic kidney cell line. This technology was capable of detecting 100 ovarian cancer cells in 50 MUL of whole blood. In conclusion, we developed a one-step CTC detection technology in ovarian cancer based on multifunctional silica nanoparticles and the use of flow cytometry. PMID- 23818782 TI - Iron oxide nanoparticles and magnetic field exposure promote functional recovery by attenuating free radical-induced damage in rats with spinal cord transection. AB - BACKGROUND: Iron oxide nanoparticles (IONPs) can attenuate oxidative stress in a neutral pH environment in vitro. In combination with an external electromagnetic field, they can also facilitate axon regeneration. The present study demonstrates the in vivo potential of IONPs to recover functional deficits in rats with complete spinal cord injury. METHODS: The spinal cord was completely transected at the T11 vertebra in male albino Wistar rats. Iron oxide nanoparticle solution (25 MUg/mL) embedded in 3% agarose gel was implanted at the site of transection, which was subsequently exposed to an electromagnetic field (50 Hz, 17.96 MUT for two hours daily for five weeks). RESULTS: Locomotor and sensorimotor assessment as well as histological analysis demonstrated significant functional recovery and a reduction in lesion volume in rats with IONP implantation and exposure to an electromagnetic field. No collagenous scar was observed and IONPs were localized intracellularly in the immediate vicinity of the lesion. Further, in vitro experiments to explore the cytotoxic effects of IONPs showed no effect on cell survival. However, a significant decrease in H2O2-mediated oxidative stress was evident in the medium containing IONPs, indicating their free radical scavenging properties. CONCLUSION: These novel findings indicate a therapeutic role for IONPs in spinal cord injury and other neurodegenerative disorders mediated by reactive oxygen species. PMID- 23818783 TI - Mouse lymphatic endothelial cell targeted probes: anti-LYVE-1 antibody-based magnetic nanoparticles. AB - PURPOSE: To investigate the specific targeting property of lymphatic vessel endothelial hyaluronan receptor-1 binding polyethylene glycol-coated ultrasmall superparamagnetic iron oxide (LYVE-1-PEG-USPIO) nanoparticles to mouse lymphatic endothelial cells (MLECs). METHODS: A ligand specific target to lymphatic vessels was selected by immunohistochemical staining on the sections of a Lewis subcutaneous transplanted tumor. The z-average hydrodynamic diameter (HD), zeta potential, and the relaxivity of PEG-USPIO and LYVE-1-PEG-USPIO nanoparticles were determined with a laser particle analyzer and magnetic resonance T2 spin echo sequence, respectively. Prussian blue staining and transmission electron microscopy (TEM) of nanoparticle labeled cells were performed to determine the nanoparticles' binding form. Magnetic resonance imaging (MRI) was performed in vitro to evaluate the signal enhancement on the T2 spin echo sequence of the nanoparticle labeled cells. The iron content of the labeled cells after the Prussian blue staining and MRI scanning was determined by atomic absorption spectroscopy (AAS). RESULTS: The anti-LYVE-1 antibody was used as the specific ligand to synthesize the target probe to the MLECs. The mean z-average HDs of the LYVE-1-PEG-USPIO and PEG-USPIO nanoparticles were 57.42 +/- 0.31 nm and 47.91 +/- 0.73 nm, respectively, and the mean zeta potentials of the LYVE-1-PEG-USPIO and PEG-USPIO nanoparticles were 12.38 +/- 4.87 mV and 2.57 +/- 0.83 m V, respectively. The relaxivities of the LYVE-1-PEG-USPIO and PEG-USPIO nanoparticles were 185.48 mM(-1)s(-1) and 608.32 mM(-1)s(-1). Cells binding nanoparticles were visualized as blue granules in the Prussian blue staining. The TEM results of the labeled cells showed the specific localization of nanoparticles. The AAS results of labeled cells after the Prussian blue staining and MRI scanning showed that the LYVE-1-PEG-USPIO nanoparticles had good binding selectivity for MLECs. MRI results indicated that the PEG-USPIO and LYVE-1-PEG USPIO nanoparticles could generate contrast on T2-weighted imaging, and the correlation between R2 and the iron content of the labeled cells was significantly positive. CONCLUSION: This study demonstrated that LYVE-1-PEG-USPIO nanoparticles might potentially be used as an MRI contrast agent for targeting MLECs, and the magnetic properties of LYVE-1-PEG-USPIO nanoparticles were suitable for MRI. PMID- 23818784 TI - Understanding the link between leadership style, employee satisfaction, and absenteeism: a mixed methods design study in a mental health care institution. AB - BACKGROUND: In service oriented industries, such as the health care sector, leadership styles have been suggested to influence employee satisfaction as well as outcomes in terms of service delivery. However, how this influence comes into effect has not been widely explored. Absenteeism may be a factor in this association; however, no studies are available on this subject in the mental health care setting, although this setting has been under a lot of strain lately to provide their services at lower costs. This may have an impact on employers, employees, and the delivery of services, and absenteeism due to illness of employees tends to already be rather high in this particular industry. This study explores the association between leadership style, absenteeism, and employee satisfaction in a stressful work environment, namely a post-merger specialty mental health care institution (MHCI) in a country where MHCIs are under governmental pressure to lower their costs (The Netherlands). METHODS: We used a mixed methods design with quantitative as well as qualitative research to explore the association between leadership style, sickness absence rates, and employee satisfaction levels in a specialty MHCI. In depth, semi-structured interviews were conducted with ten key informants and triangulated with documented research and a contrast between four departments provided by a factor analysis of the data from the employee satisfaction surveys and sickness rates. Data was analyzed thematically by means of coding and subsequent exploration of patterns. Data analysis was facilitated by qualitative analysis software. RESULTS: Quantitative analysis revealed sickness rates of 5.7% in 2010, which is slightly higher than the 5.2% average national sickness rate in The Netherlands in 2010. A general pattern of association between low employee satisfaction, high sickness rates, and transactional leadership style in contrast to transformational leadership style was established. The association could be described best by: (1) communication between the manager and employees; (2) the application of sickness protocols by the managers; and (3) leadership style of the manager. CONCLUSION: We conclude that the transformational leadership style is best suited for attaining employee satisfaction, for adequate handling of sickness protocols, and for lower absenteeism, in a post-merger specialty mental health setting. PMID- 23818785 TI - Temporal changes in serum creatine kinase concentration and degree of muscle rigidity in 24 patients with neuroleptic malignant syndrome. AB - Neuroleptic malignant syndrome (NMS) is a dangerous adverse response to antipsychotic drugs. It is characterized by the four major clinical symptoms of hyperthermia, severe muscle rigidity, autonomic dysfunction, and altered mental state. Serum creatine kinase (CK) elevation occurs in over 90% of NMS cases. In the present study, the detailed temporal changes in serum CK and degree of muscle rigidity, and the relationship between CK concentration and degree of muscle rigidity over the time course from fever onset, were evaluated in 24 affected patients. The results showed that serum CK peaked on day 2 after onset of fever and returned to within normal limits at day 12. Mild muscle rigidity was observed before the onset of fever in 17 of 24 cases (71%). Muscle rigidity was gradually exacerbated and worsened until day 4 after onset of fever. These findings confirm physicians' empirical understanding of serum CK concentrations and muscle rigidity in NMS based on data accumulated from numerous patients with the syndrome, and they indicate that serum CK may contribute to the early detection of NMS. PMID- 23818786 TI - Efficacy of second-generation antipsychotics in patients at ultra-high risk and those with first-episode or multi-episode schizophrenia. AB - AIM: The aim of this study was to examine the speed of response, doses, and safety of treatment with second-generation antipsychotics (SGAs) in patients at ultra-high risk (UHR) compared to those with schizophrenia. METHODS: A 12-week open-label, prospective study of SGAs was performed in UHR patients and those with first-episode schizophrenia (FES) and multi-episode schizophrenia (MES). The subjects were 14-30 years old and were recruited at Zikei Hospital, Okayama, Japan from December 1, 2006 to December 1, 2011. Treatment was carried out in a natural setting in an open-label format, but clinical evaluation was performed blind. The clinical rating scales include the Global Assessment of Functioning (GAF), the Positive and Negative Syndrome Scale (PANSS), and the Clinical Global Impression-Severity scale (CGI-S). RESULTS: UHR (n = 17), FES (n = 23), and MES (n = 21) patients all showed significant improvements on the GAF, PANSS, and CGI S. However, the UHR patients showed significantly greater improvement on the GAF at weeks 4, 8, and 12 compared to the other groups, and a significantly lower modal dose of SGAs (chlorpromazine equivalent: 183 [201.1] mg/day, mean [SD]) was needed for improvement in the UHR group. Each group was also prescribed anticholinergic agents during the study period and the UHR group had significantly fewer extrapyramidal symptoms (only 6%) compared with the FES group. CONCLUSION: Our findings suggest that UHR patients have a better response to SGAs compared to patients with schizophrenia, and that these drugs can be given safely by minimizing the dosage of SGAs and using anticholinergic agents. PMID- 23818787 TI - Applicability of the Rivermead Behavioural Memory Test - Third Edition (RBMT-3) in Korsakoff's syndrome and chronic alcoholics. AB - PURPOSE: To examine the applicability of the newly developed Rivermead Behavioural Memory Test - Third Edition (RBMT-3) as an ecologically-valid memory test in patients with alcohol-related cognitive disorders. PATIENTS AND METHODS: An authorized Dutch translation of the RBMT-3 was developed, equivalent to the UK version, and administered to a total of 151 participants - 49 patients with amnesia due to alcoholic Korsakoff's syndrome, 49 patients with cognitive impairment and a history of chronic alcoholism, not fulfilling the Korsakoff criteria, and 53 healthy controls. Between-group comparisons were made at subtest level, and the test's diagnostic accuracy was determined. RESULTS: Korsakoff patients performed worse than controls on all RBMT-3 subtests (all P-values < 0.0005). The alcoholism group performed worse than controls on most (all P-values < 0.02), but not all RBMT-3 subtests. Largest effects were found between the Korsakoff patients and the controls after delayed testing. The RBMT-3 had good sensitivity and adequate specificity. CONCLUSION: The RBMT-3 is a valid test battery to demonstrate everyday memory deficits in Korsakoff patients and non Korsakoff patients with alcohol abuse disorder. Korsakoff patients showed an impaired performance on subtests relying on orientation, contextual memory and delayed testing. Our findings provide valuable information for treatment planning and adjustment in patients with alcohol-related cognitive impairments. PMID- 23818789 TI - Prevalence of parasomnia in autistic children with sleep disorders. AB - The prevalence of sleep related complaints is reported by questionnaire studies to be as high as 83.3% in children with autism spectrum disorders (ASD). Questionnaire studies report the presence of various parasomnia in ASD. However, no polysomnographic study reports non-REM parasomnias and only a single study reports REM related parasomnias in ASD. We investigated the prevalence and characteristics of sleep disorders by polysomnographic study and questionnaires in a cohort of 23 children with ASD and 23 age-matched children of a non-autistic comparison group. The results showed significantly more non-REM parasomnias in 14 children with ASD on polysomnograms (PSG) and 16 ASD children by questionnaire, a finding that was not associated with medication use, other comorbid medical or psychiatric disorders, or sleep disordered breathing. Of the 14 children with ASD who had PSG evidence of parasomnia, 11 of them had a history suggestive of parasomnia by questionnaire. There was a high sensitivity but a low specificity of parasomnia in ASD by questionnaire in predicting the presence of parasomnia in the PSG. Of the parasomnias recorded in the laboratory, 13 ASD children had Disorders of Partial Arousal, consistent with sleep terrors or confusional arousals. Furthermore, multiple episodes of partial arousal occurred in 11 of the 13 ASD children who had PSG evidence of Disorders of Partial Arousal. Of the 11 ASD children with multiple episodes of partial arousal, 6 ASD children had multiple partial arousals during both nights' PSG study. Sleep architecture was abnormal in children with ASD, characterized by increased spontaneous arousals, prolonged REM latency and reduced REM percentage. These results suggest a high prevalence of parasomnia in this cohort of children with ASD and a careful history intake of symptoms compatible with parasomnia could be prudent to diagnose parasomnia in ASD children when performing a PSG is not possible. PMID- 23818788 TI - Profile of vildagliptin in type 2 diabetes: efficacy, safety, and patient acceptability. AB - Vildagliptin is a selective and potent dipeptidyl peptidase-4 inhibitor that improves glycemic control by inhibiting the degradation of both endogenous glucagon-like peptide-1 and glucose-dependent insulinotropic peptide. This article is a comprehensive review of the safety and efficacy of vildagliptin in patients with type 2 diabetes. Clinical evidence has proven that it effectively decreases hemoglobin A1c with a low risk of hypoglycemia and is weight neutral. The addition of vildagliptin to metformin improves glucose control and significantly reduces gastrointestinal adverse events, particularly in patients inadequately controlled with metformin monotherapy. Its long-term advantages include preservation of beta-cell function, reduction in total cholesterol, decrease in fasting lipolysis in adipose tissue, and triglyceride storage in non fat tissues. Vildagliptin is well tolerated with a low incidence of AEs, and it does not increase the risk of cardiovascular/cerebrovascular (CCV) events. It can be taken before or after meals, and has little drug interaction, thus it will be well accepted. PMID- 23818790 TI - Association between polymorphisms in genes related to common adult diseases and fetal growth. AB - A close relationship between size at birth and occurrence of common adult diseases has been reported. As an explanation of this relationship, it has been hypothesized that the thrifty genotypes cause changes in growth efficiency during fetal period and diseases in later life. In the present study, we examined the association of fetal growth with genetic polymorphisms within the IGF2-INS-TH region and in the G protein gene. Analysis of the genes in the IGF2-INS-TH region suggests that thrifty genotype has the effect of accelerating fetal growth, but at the same time a genomic imprinting mechanism is also involved. Analysis of the G protein beta3 subunit gene unveiled that the 825T allele in the mother may exert influence on fetal metabolic environment. By extending the analysis to other genomic regions related to common adult diseases using the same technique, the detailed role of genetic polymorphisms may be elucidated. PMID- 23818791 TI - IgA nephropathy: a twenty year retrospective single center experience. AB - IgA nephropathy (IgAN) is a common glomerular disease whose etiology is unknown. Previous studies have described the clinical and laboratory features but none have specifically compared patients during different time periods. This 20 year retrospective study was performed to assess trends in the severity of IgAN from 1989-2008. We reviewed 57 patient charts that contained a confirmed biopsy diagnosis of IgAN and recorded data at the time of diagnosis and the final follow up appointment. Clinical data included physical examination, urine, and blood tests. Patients were separated into two cohorts, Cohort 1 1989-1998 and Cohort 2 1999-2008. An increase in severity was noted in Cohort 2 based on a significantly higher Up/c and lower serum albumin level. Other prognostic indicators including GFRe, hematocrit, and glomerular injury score also demonstrated a trend towards more severe disease over the past 20 years. The patients in both Cohorts received similar treatments and had comparable renal function at the last follow-up visit. Based on our findings, we suggest that although a kidney biopsy is required to diagnose IgAN, the procedure may not be necessary in patients clinically suspected of having the disease but who have normal kidney function and minimal urine abnormalities. PMID- 23818792 TI - Detection of Oxacillin Resistance in Staphylococcus aureus Isolated from the Neonatal and Pediatric Units of a Brazilian Teaching Hospital. AB - OBJECTIVE: To determine, by phenotypic and genotypic methods, oxacillin susceptibility in Staphylococcus aureus strains isolated from pediatric and neonatal intensive care unit patients seen at the University Hospital of the Botucatu School of Medicine. METHODS: A total of 100 S. aureus strains isolated from the following materials were studied: 25 blood cultures, 21 secretions, 12 catheters, 3 cannulae and one chest drain from 62 patients in the neonatal unit, and 36 blood cultures, one pleural fluid sample and one peritoneal fluid sample from 38 patients in the pediatric unit. Resistance of the S. aureus isolates to oxacillin was evaluated by the disk diffusion method with oxacillin (1 MUg) and cefoxitin (30 MUg), agar screening test using Mueller-Hinton agar supplemented with 6 MUg/ml oxacillin and 4% NaCl, and detection of the mecA gene by PCR. In addition, the isolates were tested for beta-lactamase production using disks impregnated with Nitrocefin and hyperproduction of beta-lactamase using amoxicillin (20 MUg) and clavulanic acid (10 MUg) disks. RESULTS: Among the 100 S. aureus strains included in the study, 18.0% were resistant to oxacillin, with 16.1% MRSA being detected in the neonatal unit and 21.0% in the pediatric unit. The oxacillin (1 MUg) and cefoxitin (30 MUg) disk diffusion methods presented 94.4% and 100% sensitivity, respectively, and 98.8% specificity. The screening test showed 100% sensitivity and 98.8% specificity. All isolates produced beta lactamase and one of these strains was considered to be a hyperproducer. CONCLUSIONS: The 30 MUg cefoxitin disk diffusion method presented the best result when compared to the 1 MUg oxacillin disk. The sensitivity of the agar screening test was similar to that of the cefoxitin disk diffusion method and higher than that of the oxacillin disk diffusion method. We observed variations in the percentage of oxacillin-resistant isolates during the study period, with a decline over the last years which might be related to improved nosocomial infection control and the rational use of antibiotics. PMID- 23818793 TI - Surgery for idiopathic scoliosis: currently applied techniques. AB - This review discusses the basic knowledge and recent innovation of surgical treatment for scoliosis. Surgical treatment for scoliosis is indicated, in general, for a curve exceeding 45 to 50 degrees by the Cobb's method on the basis that: Curves larger than 50 degrees progress even after skeletal maturity.Curves larger than 60 degrees cause loss of pulmonary function, and much larger curves cause respiratory failure.Greater the curve progression, the more difficult it is to treat with surgery. Posterior fusion with instrumentation has been the standard form of surgical treatment for scoliosis. In modern instrumentation systems, more anchors are used to connect the rod and the spine, resulting in better correction and less frequent implant failures. Segmental pedicle screw constructs or hybrid constructs using pedicle screws, hooks, and wires are the trend of today. Anterior instrumentation surgery was once the choice of treatment for thoracolumbar and lumbar scoliosis because better correction could be obtained with shorter fusion levels. But in the recent times, superiority of anterior surgery for the thoracolumbar and lumbar scoliosis has been questioned. Initial enthusiasm for anterior instrumentation for the thoracic curve using video assisted thoracoscopy has faded out. PMID- 23818795 TI - Body Fat Percentages by Dual-energy X-ray Absorptiometry Corresponding to Body Mass Index Cutoffs for Overweight and Obesity in Indian Children. AB - BACKGROUND: Indians are suspected to have higher body fat percent at a given body mass index (BMI) than their western counterparts. OBJECTIVE: To estimate percent body fat in apparently healthy Indian children and adolescents by dual-energy X ray absorptiometry (DXA) and explore linkages of BMI with body fat percent for better health risk assessment. METHODS: Age, weight, height of 316 boys and 250 girls (6-17 years) were recorded. Body composition was measured by dual-energy X ray absorptiometry (DXA). High adiposity was defined as body fat percent (BF%) > McCarthy's 85th percentile of body fat reference data. Receiver operating characteristic analysis (ROC) was carried out for CDC BMI Z score for it's ability to judge excess fatness. RESULTS: High BF% was seen in 38.5% boys and 54.0% girls (p < 0.05). Percentage of obese children as defined by the BMI cutoffs of International Obesity Task Force (IOTF) (2.1% for boys and 6.9% for girls) was lower than that using Indian (13.7% for boys and 20.9% for girls) and CDC (14.1% for boys and 20.9% for girls) cutoffs. The point closest to one on the ROC curves of CDC BMI Z-scores indicated high adiposity at BMI cutoff of 22 at the age of 17 yr in both the genders. CONCLUSIONS: Higher body fat percentage is associated with lower BMI values in Indian children. PMID- 23818794 TI - Role of gut microbiota in early infant development. AB - Early colonization of the infant gastrointestinal tract is crucial for the overall health of the infant, and establishment and maintenance of non-pathogenic intestinal microbiota may reduce several neonatal inflammatory conditions. Much effort has therefore been devoted to manipulation of the composition of the microbiota through 1) the role of early infant nutrition, particularly breast milk, and supplementation of infant formula with prebiotics that positively influence the enteric microbiota by selectively promoting growth of beneficial bacteria and 2) oral administration of probiotic bacteria which when administered in adequate amounts confer a health benefit on the host. While the complex microbiota of the adult is difficult to change in the long-term, there is greater impact of the diet on infant microbiota as this is not as stable as in adults. Decreasing excessive use of antibiotics and increasing the use of pre- and probiotics have shown to be beneficial in the prevention of several important infant diseases such as necrotizing enterocolitis and atopic eczema as well as improvement of short and long-term health. This review addresses how the composition of the gut microbiota becomes established in early life, its relevance to infant health, and dietary means by which it can be manipulated. PMID- 23818796 TI - Hydronephrosis in infants and children: natural history and risk factors for persistence in children followed by a medical service. AB - BACKGROUND: Infants with neonatal hydronephrosis and a normal voiding cystourethrogram (VCUG) are presumed to have ureteropelvic junction obstruction (UPJO). There is little current information about the natural history of children with hydronephrosis or clinical factors that predict resolution of the radiological abnormality. OBJECTIVE: To determine the time course until spontaneous resolution of neonatal hydronephrosis and define risk factors for persistence of the abnormality. METHODS: This retrospective single center review examined infants and children <5 years of age with hydronephrosis who were followed for at least 12 months. RESULTS: 136 children were identified (96 male:40 female). The mean age at diagnosis of hydronephrosis was 3.3 +/- 9.7 months and 76% of the patients were diagnosed at birth. The hydronephrosis was unilateral in 98 (72%) of cases, and hydronephrosis was at least moderate in severity in 22% of affected kidneys. At last follow-up at 30 +/- 10 months, the abnormality had resolved in 77 out of 115 (67%) available patients, 30 (26%) had been referred to urology, and 12 (10%) had persistent hydronephrosis. Severity of hydronephrosis was the only clinical feature that predicted persistence of the abnormality (P < 0.001). There was an association between detection at birth and lack of resolution of hydronephrosis. CONCLUSIONS: Children with hydronephrosis and presumed UPJO and normal kidney parenchyma can be followed for at least 2 years to allow for spontaneous resolution before referral to urology. Serial sonography can be performed at 6 month intervals in uncomplicated cases. More severe hydronephrosis and presence of the lesion at birth may predict infants and children requiring closer observation and referral for possible surgical correction of the hydronephrosis. PMID- 23818797 TI - Vertebral compression fractures: a review of current management and multimodal therapy. AB - Vertebral compression fractures are a prevalent disease affecting osteoporotic patients. When symptomatic, they cause significant pain and loss of function and have a high public health impact. In this paper we outline the diagnosis and management of these patients, with evidence-based review of treatment outcomes for the various therapeutic options. Diagnosis involves a clinical history focusing on the nature of the patient's pain as well as various imaging studies. Management is multimodal in nature and starts with conservative therapy consisting of analgesic medication, medication for osteoporosis, physical therapy, and bracing. Patients who are refractory to conservative management may be candidates for vertebral augmentation through either vertebroplasty or kyphoplasty. PMID- 23818798 TI - Transitions of care in anticoagulated patients. AB - Anticoagulation is an effective therapeutic means of reducing thrombotic risk in patients with various conditions, including atrial fibrillation, mechanical heart valves, and major surgery. By its nature, anticoagulation increases the risk of bleeding; this risk is particularly high during transitions of care. Established anticoagulants are not ideal, due to requirements for parenteral administration, narrow therapeutic indices, and/or a need for frequent therapeutic monitoring. The development of effective oral anticoagulants that are administered as a fixed dose, have low potential for drug-drug and drug-food interactions, do not require regular anticoagulation monitoring, and are suitable for both inpatient and outpatient use is to be welcomed. Three new oral anticoagulants, the direct thrombin inhibitor, dabigatran etexilate, and the factor Xa inhibitors, rivaroxaban and apixaban, have been approved in the US for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; rivaroxaban is also approved for prophylaxis and treatment of deep vein thrombosis, which may lead to pulmonary embolism in patients undergoing knee or hip replacement surgery. This review examines current options for anticoagulant therapy, with a focus on maintaining efficacy and safety during transitions of care. The characteristics of dabigatran etexilate, rivaroxaban, and apixaban are discussed in the context of traditional anticoagulant therapy. PMID- 23818799 TI - The clinical and economic burden of chronic obstructive pulmonary disease in the USA. AB - Chronic obstructive pulmonary disease (COPD) is the third most common cause of death in the USA. In 2010, the cost of COPD in the USA was projected to be approximately US$50 billion, which includes $20 billion in indirect costs and $30 billion in direct health care expenditures. These costs can be expected to continue to rise with this progressive disease. Costs increase with increasing severity of disease, and hospital stays account for the majority of these costs. Patients are diagnosed with COPD following a multifactorial assessment that includes spirometry, clinical presentation, symptomatology, and risk factors. Smoking cessation interventions are the most influential factor in COPD management. The primary goal of chronic COPD management is stabilization of chronic disease and prevention of acute exacerbations. Bronchodilators are the mainstay of COPD therapy. Patients with few symptoms and low exacerbation risk should be treated with a short-acting bronchodilator as needed for breathlessness. Progression of symptoms, as well as possible decline in forced expiratory volume in the first second of expiration (FEV1), warrant the use of long-acting bronchodilators. For patients with frequent exacerbations with or without consistent symptoms, inhaled corticosteroids should be considered in addition to a long-acting beta2-agonist (LABA) or long-acting muscarinic antagonist (LAMA) and may even consist of "triple therapy" with all three agents with more severe disease. Phosphodiesterase-4 inhibitors may be an option in patients with frequent exacerbations and symptoms of chronic bronchitis. In addition to a variety of novel ultra-LABAs, LAMAs and combination bronchodilator and inhaled corticosteroid (ICS) therapies, other bronchodilators with a variety of mechanisms are also being considered, to expand therapeutic options for the treatment of COPD. With more than 50 new medications in the pipeline for the treatment of COPD, optimal management will continue to evolve and grow more complex as benefits of therapy are balanced with the limitations and needs of each patient. PMID- 23818800 TI - Estimating the long-term effects of in vitro fertilization in Greece: an analysis based on a lifetime-investment model. AB - OBJECTIVE: To quantify the economic effects of a child conceived by in vitro fertilization (IVF) in terms of net tax revenue from the state's perspective in Greece. METHODS: Based on previous international experience, a mathematical model was developed to assess the lifetime productivity of a single individual and his/her lifetime transactions with governmental agencies. The model distinguished among three periods in the economic life cycle of an individual: (1) early life, when the government primarily contributes resources through child tax credits, health care, and educational expenses; (2) employment, when individuals begin returning resources through taxes; and (3) retirement, when the government expends additional resources on pensions and health care. The cost of a live birth with IVF was based on the modification of a previously published model developed by the authors. All outcomes were discounted at a 3% discount rate. The data inputs - namely, the economic or demographic variables - were derived from the National Statistical Secretariat of Greece and other relevant sources. To deal with uncertainty, bias-corrected uncertainty intervals (UIs) were calculated based on 5000 Monte Carlo simulations. In addition, to examine the robustness of our results, other one-way sensitivity analyses were also employed. RESULTS: The cost of IVF per birth was estimated at ?17,015 (95% UI: ?13,932-?20,200). The average projected income generated by an individual throughout his/her productive life was ?258,070 (95% UI: ?185,376-?339,831). In addition, his/her life tax contribution was estimated at ?133,947 (95% UI: ?100,126-?177,375), while the discounted governmental expenses for elderly and underage individuals were ?67,624 (95% UI: ?55,211-?83,930). Hence, the net present value of IVF was ?60,435 (95% UI: ?33,651-?94,330), representing a 182% net return on investment. Results remained constant under various assumptions for the main model parameters. CONCLUSION: State-funded IVF may represent good value for money in the Greek setting, since it has positive tax benefits for the government, notwithstanding its beneficial psychological effect on infertile couples. PMID- 23818801 TI - Hospitalizations for vaccine preventable pneumonias in patients with inflammatory bowel disease: a 6-year analysis of the Nationwide Inpatient Sample. AB - BACKGROUND: Pneumonias are among the most common causes of hospitalization among inflammatory bowel disease (IBD) patients. Guidelines published in 2004 advocate vaccination against Streptococcus pneumoniae and influenza virus. We sought to examine trends in hospitalizations for vaccine preventable pneumonias among IBD patients since the availability of published guidelines, and to identify whether Haemophilus influenzae is a causative organism for pneumonia hospitalizations among IBD patients. METHODS: This cross-sectional study on the Nationwide Inpatient Sample was used to identify admissions for pneumonias in patients with IBD between 2004 and 2009. A multivariate logistic regression analysis was performed comparing IBD patients to controls, accounting for potential confounders. RESULTS: There were more admissions for S. pneumoniae pneumonia than influenza virus or H. influenzae (787, 393, and 183 respectively). Crohn's disease (CD) as well as ulcerative colitis (UC) patients did not demonstrate increased adjusted odds of hospitalization for S. pneumoniae pneumonia (1.08; confidence interval [CI] 0.99-1.17 compared to 0.93; CI 0.82-1.06 respectively). Increased adjusted odds for hospitalization for pneumonias due to influenza virus were seen among UC patients in the bottom quartile of income (1.86; CI 1.46 2.37). Adjusted odds for H. influenzae pneumonia admission in patients with UC and CD patients were increased compared to controls (1.42; CI 1.13-1.79 and 1.28; CI 1.06-1.54, respectively). CONCLUSION: The study identified lowest income UC patients as having higher adjusted odds, and these patients should be targeted for influenza virus vaccination. Additionally, H. influenzae may be another vaccine preventable cause for pneumonia among IBD patients. PMID- 23818802 TI - Yi-gan san restores behavioral alterations and a decrease of brain glutathione level in a mouse model of schizophrenia. AB - The traditional Chinese herbal medicine yi-gan san has been used to cure neuropsychological disorders. Schizophrenia can be one of the target diseases of yi-gan san. We aimed at evaluating the possible use of yi-gan san in improving the schizophrenic symptoms of an animal model. Yi-gan san or distilled water was administered to mice born from pregnant mice injected with polyinosinic polycytidilic acid or phosphate buffered saline. The former is a model of schizophrenia based on the epidemiological data that maternal infection leads to psychotic disorders including schizophrenia in the offspring. Prepulse inhibition and sensitivity to methamphetamine in open field tests were analyzed and the total glutathione content of whole brains was measured. Yi-gan san reversed the decrease in prepulse inhibition, hypersensitivity to methamphetamine and cognitive deficits found in the model mice to the level of control mice. Total glutathione content in whole brains was reduced in the model mice but was restored to normal levels by yi-gan san treatment. These results suggest that yi gan san may have ameliorating effects on the pathological symptoms of schizophrenia. PMID- 23818803 TI - Teleradiology and emergency neurosurgery-presence in a small asian city state and need in a large canadian province. AB - Teleradiology involving the transfer of vital patient information such as scan images is an important technology to facilitate effective and efficient provision of neurosurgical care in the setting of scarce resources and geographic isolation. We review the implementation of teleradiology initiatives in the small city state of Singapore and its potential and need in the large province of Ontario and draw parallels in their strategic implementation. Although it may seem intuitive that teleradiology has greater applications in regions of vast geographical size, the technology has universal usefulness if applied appropriately in any neurosurgical or health care system. PMID- 23818804 TI - Emergency medical services support for acute ischemic stroke patients receiving thrombolysis at a primary stroke center. AB - BACKGROUND: Emergency Medical Services (EMS) is a vital link in the overall chain of stroke survival. A Primary Stroke Center (PSC) relies heavily on the 9-1-1 response system along with the ability of EMS personnel to accurately diagnose acute stroke. Other critical elements include identifying time of symptom onset, providing pre-hospital care, selecting a destination PSC, and communicating estimated time of arrival (ETA). PURPOSE: Our purpose was to evaluate the EMS component of thrombolysed acute ischemic stroke patient care at our PSC. METHODS: In a retrospective manner we retrieved electronic copies of the EMS incident reports for every thrombolysed ischemic stroke patient treated at our PSC from September 2001 to August 2005. The following data elements were extracted: location of victim, EMS agency, times of dispatch, scene, departure, emergency department (ED) arrival, recordings of time of stroke onset, blood pressure (BP), heart rate (HR), cardiac rhythm, blood glucose (BG), Glasgow Coma Scale (GCS), Cincinnati Stroke Scale (CSS) elements, emergency medical personnel field assessment, and transport decision making. RESULTS: Eighty acute ischemic stroke patients received thrombolysis during the study interval. Eighty-one percent arrived by EMS. Two EMS agencies transported to our PSC. Mean dispatch-to-scene time was 6 min, on-scene time was 16 min, transport time was 10 min. Stroke onset time was recorded in 68%, BP, HR, and cardiac rhythm each in 100%, BG in 81%, GCS in 100%, CSS in 100%, and acute stroke diagnosis was made in 88%. Various diagnostic terms were employed: cerebrovascular accident in 40%, unilateral weakness or numbness in 20%, loss of consciousness in 16%, stroke in 8%, other stroke terms in 4%. In 87% of incident reports there was documentation of decision-making to transport to the nearest PSC in conjunction with pre notification. CONCLUSION: The EMS component of thrombolysed acute ischemic stroke patients care at our PSC appeared to be very good overall. Diagnostic accuracy was excellent, field assessment, decision-making, and transport times were very good. There was still room for improvement in documentation of stroke onset and in employment of a common term for acute stroke. PMID- 23818805 TI - Identification of stroke mimics in the emergency department setting. AB - BACKGROUND AND PURPOSE: Previous studies have shown a stroke mimic rate of 9% 31%. We aimed to establish the proportion of stroke mimics amongst suspected acute strokes, to clarify the aetiology of stroke mimic and to develop a prediction model to identify stroke mimics. METHODS: This was a retrospective cohort observational study. Consecutive "stroke alert" patients were identified over nine months in a primary stroke centre. 31 variables were collected. Final diagnosis was defined as "stroke" or "stroke mimic". Multivariable regression analysis was used to define clinical predictors of stroke mimic. RESULTS: 206 patients were reviewed. 22% were classified as stroke mimics. Multivariable scoring did not help in identification of stroke mimics. 99.5% of patients had a neurological diagnosis at final diagnosis. DISCUSSION: 22% of patients with suspected acute stroke had a stroke mimic. The aetiology of stroke mimics was varied, with seizure, encephalopathy, syncope and migraine being commonest. Multivariable scoring for identification of stroke mimics is not feasible. 99.5% of patients had a neurological diagnosis. This strengthens the case for the involvement of stroke neurologists/stroke physicians in acute stroke care. PMID- 23818806 TI - Type d syndrome of inappropriate antidiuretic hormone secretion in a schizophrenia patient with polydipsia. AB - A 55-year-old man with schizophrenia developed water intoxication due to primary polydipsia. His manner of antidiuretic hormone secretion was investigated by water loading and infusion of hypertonic saline to clarify the form of the syndrome of inappropriate antidiuretic hormone secretion. The plasma antidiuretic hormone level, which may be involved in the occurrence of water intoxication, was consistently low in this patient, and linked to type D syndrome of inappropriate antidiuretic hormone secretion, designated "hypovasopressinemic antidiuresis". Although this type is not common, it should be considered as a pathophysiology for water intoxication in schizophrenia patients. PMID- 23818807 TI - Views of emergency physicians on thrombolysis for acute ischemic stroke. AB - BACKGROUND: The 3-hour window for treating stroke with intravenous tissue plasminogen activator (t-PA) requires well-organized, integrated efforts by emergency physicians and stroke neurologists. OBJECTIVE: To evaluate attitudes and knowledge of emergency physicians about intravenous t-PA for acute ischemic stroke, particularly in primary stroke centers (PSCs) with stroke neurology teams. METHODS: A 15-question pilot Internet survey administered by the Arizona College of Emergency Physicians. RESULTS: Between March and August 2005, 100 emergency physicians responded: 71 in Arizona and 29 in Missouri. Forty-eight percent practiced at PSCs; 48% thought t-PA was effective, 20% did not, and 32% were uncertain. PSC or non-PSC location of practice did not influence endorsement (odds ratio, 0.96; 95% confidence interval, 0.27-1.64). Of those opposing t-PA, 87% cited risk of hemorrhage. CONCLUSIONS: Most emergency physicians did not endorse t-PA. Improved collaboration between emergency physicians and stroke neurologists is needed. PMID- 23818808 TI - Telemedicine and Alzheimer's disease from studio-based videoconferencing to mobile handheld cell phones. AB - The use of Telemedicine in the assessment of cognitive impairment and Alzheimer's Disease is evolving with advances in Information and Communication Technology. This article outlines the course of evolution in Western Australia, a large state with a sparse population outside of the capital city. The starting point of the evolution, video-conferencing in Telehealth studios, is reviewed as well as the next stage, use of desktop technology, which enables the physician to consult from the office or clinic. A pilot study currently being undertaken to assess the validity of the latest stage in evolution of Telehealth-the use of handheld mobile cell phone video calling that allows the physician and patient to interact at locations convenient to both parties. The pitfalls and implications of the use of this stage, should it prove to be a valid approach, are discussed. PMID- 23818809 TI - Telesurgery of Microscopic Micromanipulator System "NeuRobot" in Neurosurgery: Interhospital Preliminary Study. AB - OBJECT: Robotic surgery can be applied as a novel technology. Our master-slave microscopic-micromanipulator system (NeuRobot), which has a rigid endoscope and three robot-arms, has been developed to perform neurosurgical procedures, and employed successfully in some clinical cases. Although the master and slave parts of NeuRobot are directly connected by wire, it is possible to separate each part and to apply it to telesurgery with some modifications. To evaluate feasibility of NeuRobot in telesurgery, some basic experiments were performed. METHODS: The quality of telemedicine network system between Shinshu University and one of the affiliated hospitals, which was completely separated from other public network systems, was investigated. The communication delay was calculated from the transmitting and the receiving records in the computers set in each hospital. The relationship between the change in communication delay from the master part to the slave part of NeuRobot (0, 100, 300, 500 and 700 ms) respectively and feasibility of NeuRobot was investigated. The task performance time in each time changing group was compared. Feasibility of NeuRobot in telesurgical usage was evaluated. The master part and the slave part of NeuRobot placed in each hospital were connected through private network system. Interhospitally connected NeuRobot was compared with directly connected one in terms of task performance time. RESULTS: Less than 1 ms was required for corresponding the data in a steady transmitting state. Within 2 seconds after connection, relative time delay (maximum 40 ms) and packet loss were sometimes observed. The mean task performance time was significantly longer in over 500 ms delayed group compared with directly connected NeuRobot. There was no significant difference in the task performance time between directly connected NeuRobot and interhospitally connected NeuRobot. CONCLUSION: Our results proved that telesurgical usage of NeuRobot was feasible. Telesurgical usage of telecontrolled manipulator system is recommended for application in a private network system in order to reduce technical and ethical problems. Some technical innovations will bring breakthrough to the telemedicine field. PMID- 23818810 TI - Capsule endoscopy in the diagnosis of Crohn's disease. AB - Crohn's disease is a chronic inflammatory disorder affecting any part of the gastrointestinal tract, but frequently involves the small and large bowel. Typical presenting symptoms include abdominal pain and diarrhea. Patients with this disorder may also have extraintestinal manifestations, including arthritis, uveitis, and skin lesions. The PillCamTMSB capsule is an ingestible disposable video camera that transmits high quality images of the small intestinal mucosa. This enables the small intestine to be readily accessible to physicians investigating for the presence of small bowel disorders, such as Crohn's disease. Four meta-analyses have demonstrated that capsule endoscopy identifies Crohn's disease when other methods are not helpful. It should be noted that it is the best noninvasive procedure for assessing mucosal status, but is not superior to ileocolonoscopy, which remains the gold standard for assessment of ileocolonic disease. Mucosal healing along the small bowel can only be demonstrated by an endoscopic procedure such as capsule endoscopy. Achievement of long-term mucosal healing has been associated with a trend towards a decreased need for hospitalization and a decreased requirement for corticosteroid treatment in patients with Crohn's disease. Recently, we have developed and validated the Capsule Endoscopy Crohn's Disease Activity Index (also known as the Niv score) for Crohn's disease of the small bowel. The next step is to expand our score to the colon, and to determine the role and benefit of a capsule endoscopy activity score in patients suffering from Crohn's ileocolitis and/or colitis. This scoring system will also serve to improve our understanding of the impact of capsule endoscopy, and therefore treatment, on the immediate outcome of this disorder. As the best procedure available for assessing mucosal status, capsule endoscopy will provide important information about the course and outcome of Crohn's disease. PMID- 23818811 TI - New neotropical species of Opiinae (Hymenoptera, Braconidae) reared from fruit infesting and leaf-mining Tephritidae (Diptera) with comments on the Diachasmimorpha mexicana species group and the genera Lorenzopius and Tubiformopius. AB - Four new species of opiine Braconidae are described from Mexico. These are Diachasmimorpha martinalujai Wharton reared from Rhagoletis infesting fruits of Crataegus spp., Diachasmimorpha norrbomi Wharton reared from Euphranta mexicana infesting fruits of Ribes pringlei, Eurytenes (Stigmatopoea) norrbomi Wharton reared from Trypeta concolor mining leaves of Barkleyanthus salicifolia and Eurytenes (Stigmatopoea) maya Wharton reared from Rhagoletis pomonella infesting apples and fruits of Crataegus spp. Morphological features of the first metasomal segment and occipital carina, useful for placement of these species, are discussed relative to the genera Diachasmimorpha, Eurytenes, Lorenzopius, Tubiformopius, and Opius s.l. Descriptions and diagnoses are referenced to the Hymenoptera Anatomy Ontology. The following represent new combinations: Diachasmimorpha hildagensis, Lorenzopius euryteniformis, and Tubiformopius tubibasis. Revised diagnoses are provided for Diachasmimorpha hildagensis, Diachasmimorpha mexicana, Diachasmimorpha sanguinea, Eurytenes (Stigmatopoea), Lorenzopius, Lorenzopius euryteniformis, Tubiformopius, Tubiformopius tubigaster, Tubiformopius tubibasis, Opius incoligma, and Opius rugicoxis. Two species groups are delineated within Lorenzopius and a key to species of Diachasmimorpha occurring in the New World is provided. PMID- 23818812 TI - Low-Grade Fibromyxoid Sarcoma: Incidence, Treatment Strategy of Metastases, and Clinical Significance of the FUS Gene. AB - Aim. The aim of this study was to assess the incidence of low-grade fibromyxoid sarcoma (LGFMS), present treatment results of metastatic LGFMS, and investigate the clinical significance of the FUS gene rearrangement. Methods. This study included 14 consecutive LGFMS patients treated at the Aarhus Sarcoma Centre in 1979-2010. Fluorescent in situ hybridization (FISH) analysis for FUS break-apart was performed for all patients. Results. The incidence of LGFMS was 0.18 per million, representing 0.6% of all soft tissue sarcomas. Four patients needed multiple biopsies/resections before the correct diagnosis was made. Four patients experienced local recurrence, and three patients developed metastases. The treatment of metastatic LGFMS varied from multiagent chemotherapy to repeated, selective surgery of operable metastases. The best response to chemotherapy was short-term stabilization of disease progression, seen with Trabectedin. The prevalence of the FUS break-apart was 21.4%. We found no significant difference in clinical characteristics and outcomes in correlation with the FUS break-apart. Conclusion. LGFMS is a rare disease with multiple challenges. The FUS break-apart was not associated with local recurrence or metastases in our study. To date the only treatment resulting in disease-free periods is surgery; however further investigation into the management of metastatic LGFMS is necessary. PMID- 23818813 TI - The Nitrosopumilus maritimus CdvB, but not FtsZ, assembles into polymers. AB - Euryarchaeota and Crenarchaeota are two major phyla of archaea which use distinct molecular apparatuses for cell division. Euryarchaea make use of the tubulin related protein FtsZ, while Crenarchaea, which appear to lack functional FtsZ, employ the Cdv (cell division) components to divide. Ammonia oxidizing archaeon (AOA) Nitrosopumilus maritimus belongs to another archaeal phylum, the Thaumarchaeota, which has both FtsZ and Cdv genes in the genome. Here, we used a heterologous expression system to characterize FtsZ and Cdv proteins from N. maritimus by investigating the ability of these proteins to form polymers. We show that one of the Cdv proteins in N. maritimus, the CdvB (Nmar_0816), is capable of forming stable polymers when expressed in fission yeast. The N. maritimus CdvB is also capable of assembling into filaments in mammalian cells. However, N. maritimus FtsZ does not assemble into polymers in our system. The ability of CdvB, but not FtsZ, to polymerize is consistent with a recent finding showing that several Cdv proteins, but not FtsZ, localize to the mid-cell site in the dividing N. maritimus. Thus, we propose that it is Cdv proteins, rather than FtsZ, that function as the cell division apparatus in N. maritimus. PMID- 23818814 TI - The effects of five-order nonlinear on the dynamics of dark solitons in optical fiber. AB - We study the influence of five-order nonlinear on the dynamic of dark soliton. Starting from the cubic-quintic nonlinear Schrodinger equation with the quadratic phase chirp term, by using a similarity transformation technique, we give the exact solution of dark soliton and calculate the precise expressions of dark soliton's width, amplitude, wave central position, and wave velocity which can describe the dynamic behavior of soliton's evolution. From two different kinds of quadratic phase chirps, we mainly analyze the effect on dark soliton's dynamics which different fiver-order nonlinear term generates. The results show the following two points with quintic nonlinearities coefficient increasing: (1) if the coefficients of the quadratic phase chirp term relate to the propagation distance, the solitary wave displays a periodic change and the soliton's width increases, while its amplitude and wave velocity reduce. (2) If the coefficients of the quadratic phase chirp term do not depend on propagation distance, the wave function only emerges in a fixed area. The soliton's width increases, while its amplitude and the wave velocity reduce. PMID- 23818815 TI - New models of emergency prehospital care that avoid unnecessary conveyance to emergency department: translation of research evidence into practice? AB - BACKGROUND: Achieving knowledge translation in healthcare is growing in importance but methods to capture impact of research are not well developed. We present an attempt to capture impact of a programme of research in prehospital emergency care, aiming to inform the development of EMS models of care that avoid, when appropriate, conveyance of patients to hospital for immediate care. METHODS: We describe the programme and its dissemination, present examples of its influence on policy and practice, internationally, and analyse routine UK statistics to determine whether conveyance practice has changed. RESULTS: The programme comprises eight research studies, to a value of > L4 m. Findings have been disseminated through 18 published papers, cited 274 times in academic journals. We describe examples of how evidence has been put into practice, including new models of care in Canada and Australia. Routine statistics in England show that, alongside rising demand, conveyance rates have fallen from 90% to 58% over a 12-year period, 2,721 million fewer journeys, with publication of key studies 2003-2008. COMMENT: We have set out the rationale, key features, and impact on practice of a programme of publicly funded research. We describe evidence of knowledge translation, whilst recognising limitations in methods for capturing impact. PMID- 23818816 TI - Application of scenario analysis and multiagent technique in land-use planning: a case study on Sanjiang wetlands. AB - Land-use planning has triggered debates on social and environmental values, in which two key questions will be faced: one is how to see different planning simulation results instantaneously and apply the results back to interactively assist planning work; the other is how to ensure that the planning simulation result is scientific and accurate. To answer these questions, the objective of this paper is to analyze whether and how a bridge can be built between qualitative and quantitative approaches for land-use planning work and to find out a way to overcome the gap that exists between the ability to construct computer simulation models to aid integrated land-use plan making and the demand for them by planning professionals. The study presented a theoretical framework of land-use planning based on scenario analysis (SA) method and multiagent system (MAS) simulation integration and selected freshwater wetlands in the Sanjiang Plain of China as a case study area. Study results showed that MAS simulation technique emphasizing quantitative process effectively compensated for the SA method emphasizing qualitative process, which realized the organic combination of qualitative and quantitative land-use planning work, and then provided a new idea and method for the land-use planning and sustainable managements of land resources. PMID- 23818817 TI - A comparative analysis of burned area datasets in Canadian boreal forest in 2000. AB - The turn of the new millennium was accompanied by a particularly diverse group of burned area datasets from different sensors in the Canadian boreal forests, brought together in a year of low global fire activity. This paper provides an assessment of spatial and temporal accuracy, by means of a fire-by-fire comparison of the following: two burned area datasets obtained from SPOT VEGETATION (VGT) imagery, a MODIS Collection 5 burned area dataset, and three different datasets obtained from NOAA-AVHRR. Results showed that burned area data from MODIS provided accurate dates of burn but great omission error, partially caused by calibration problems. One of the VGT-derived datasets (L3JRC) represented the largest number of fire sites in spite of its great overall underestimation, whereas the GBA2000 dataset achieved the best burned area quantification, both showing delayed and very variable fire timing. Spatial accuracy was comparable between the 5 km and the 1 km AVHRR-derived datasets but was remarkably lower in the 8 km dataset leading, us to conclude that at higher spatial resolutions, temporal accuracy was lower. The probable methodological and contextual causes of these differences were analyzed in detail. PMID- 23818818 TI - Measures of cultural competence in nurses: an integrative review. AB - BACKGROUND: There is limited literature available identifying and describing the instruments that measure cultural competence in nursing students and nursing professionals. DESIGN: An integrative review was undertaken to identify the characteristics common to these instruments, examine their psychometric properties, and identify the concepts these instruments are designed to measure. METHOD: There were eleven instruments identified that measure cultural competence in nursing. Of these eleven instruments, four had been thoroughly tested in either initial development or in subsequent testing, with developers providing extensive details of the testing. RESULTS: The current literature identifies that the instruments to assess cultural competence in nurses and nursing students are self-administered and based on individuals' perceptions. The instruments are commonly utilized to test the effectiveness of educational programs designed to increase cultural competence. CONCLUSIONS: The reviewed instruments measure nurses' self-perceptions or self-reported level of cultural competence but offer no objective measure of culturally competent care from a patient's perspective which can be problematic. Comparison of instruments reveals that they are based on a variety of conceptual frameworks and that multiple factors should be considered when deciding which instrument to use. PMID- 23818819 TI - Controlling the shannon entropy of quantum systems. AB - This paper proposes a new quantum control method which controls the Shannon entropy of quantum systems. For both discrete and continuous entropies, controller design methods are proposed based on probability density function control, which can drive the quantum state to any target state. To drive the entropy to any target at any prespecified time, another discretization method is proposed for the discrete entropy case, and the conditions under which the entropy can be increased or decreased are discussed. Simulations are done on both two- and three-dimensional quantum systems, where division and prediction are used to achieve more accurate tracking. PMID- 23818820 TI - A new logistic dynamic particle swarm optimization algorithm based on random topology. AB - Population topology of particle swarm optimization (PSO) will directly affect the dissemination of optimal information during the evolutionary process and will have a significant impact on the performance of PSO. Classic static population topologies are usually used in PSO, such as fully connected topology, ring topology, star topology, and square topology. In this paper, the performance of PSO with the proposed random topologies is analyzed, and the relationship between population topology and the performance of PSO is also explored from the perspective of graph theory characteristics in population topologies. Further, in a relatively new PSO variant which named logistic dynamic particle optimization, an extensive simulation study is presented to discuss the effectiveness of the random topology and the design strategies of population topology. Finally, the experimental data are analyzed and discussed. And about the design and use of population topology on PSO, some useful conclusions are proposed which can provide a basis for further discussion and research. PMID- 23818821 TI - Robustness of auditory Teager Energy Cepstrum Coefficients for classification of pathological and normal voices in noisy environments. AB - This paper focuses on a robust feature extraction algorithm for automatic classification of pathological and normal voices in noisy environments. The proposed algorithm is based on human auditory processing and the nonlinear Teager Kaiser energy operator. The robust features which labeled Teager Energy Cepstrum Coefficients (TECCs) are computed in three steps. Firstly, each speech signal frame is passed through a Gammatone or Mel scale triangular filter bank. Then, the absolute value of the Teager energy operator of the short-time spectrum is calculated. Finally, the discrete cosine transform of the log-filtered Teager Energy spectrum is applied. This feature is proposed to identify the pathological voices using a developed neural system of multilayer perceptron (MLP). We evaluate the developed method using mixed voice database composed of recorded voice samples from normophonic or dysphonic speakers. In order to show the robustness of the proposed feature in detection of pathological voices at different White Gaussian noise levels, we compare its performance with results for clean environments. The experimental results show that TECCs computed from Gammatone filter bank are more robust in noisy environments than other extracted features, while their performance is practically similar to clean environments. PMID- 23818822 TI - Synthesis and photocatalytic properties of ZnWO4 nanocrystals via a fast microwave-assisted method. AB - High crystallinity of ZnWO4 nanoparticles has been successfully synthesized via a highly effective and environmentally friendly microwave route by controlling the reaction time and temperature. The products were characterized by X-ray powder diffraction (XRD), transmission electron microscopy (TEM), and Fourier infrared spectrum (FT-IR). The crystallinity was enhanced with the increase of the reaction temperature and time. The photocatalytic activities of ZnWO4 nanocrystals were evaluated by testing the photodegradation of rhodamine B (RhB) dye under ultraviolet (UV) light irradiation. The results indicated that as prepared ZnWO4 was highly effective for the degradation of RhB. The degradation rate of RhB reached 98.01% after 6 h of UV illumination. PMID- 23818823 TI - Exp-function method for solving fractional partial differential equations. AB - We extend the Exp-function method to fractional partial differential equations in the sense of modified Riemann-Liouville derivative based on nonlinear fractional complex transformation. For illustrating the validity of this method, we apply it to the space-time fractional Fokas equation and the nonlinear fractional Sharma Tasso-Olver (STO) equation. As a result, some new exact solutions for them are successfully established. PMID- 23818824 TI - Antioxidant potential and oil composition of Callistemon viminalis leaves. AB - The present study was designed to investigate the antioxidant potential and oil composition of Callistemon viminalis leaves. GC-MS analysis of the n-hexane extract revealed the presence of 40 compounds. Leaves contained appreciable levels of total phenolic contents (0.27-0.85 GAE mg/g) and total flavonoid contents (2.25-7.96 CE mg/g). DPPH radical scavenging IC50 and % inhibition of linoleic acid peroxidation were found to be in the ranges of 28.4-56.2 MUg/ml and 40.1-70.2%, respectively. The haemolytic effect of the plant leaves was found in the range of 1.79-4.95%. The antioxidant activity of extracts was also studied using sunflower oil as an oxidative substrate and found that it stabilized the oil. The correlation between the results of different antioxidant assays and oxidation parameters of oil indicated that leaves' methanolic extract, exhibiting higher TPC and TFC and scavenging power, was also more potent for enhancing the oxidative stability of sunflower oil. PMID- 23818825 TI - Comparison of different methods for separation of haploid embryo induced through irradiated pollen and their economic analysis in Melon (Cucumis melo var. inodorus). AB - Irradiated pollen technique is the most successful haploidization technique within Cucurbitaceae. After harvesting of fruits pollinated with irradiated pollen, classical method called as "inspecting the seeds one by one" is used to find haploid embryos in the seeds. In this study, different methods were used to extract the embryos more easily, quickly, economically, and effectively. "Inspecting the seeds one by one" was used as control treatment. Other four methods tested were "sowing seeds direct nutrient media," "inspecting seeds in the light source," "floating seeds on liquid media," and "floating seeds on liquid media after surface sterilization." Y2 and Y3 melon genotypes selected from the third backcross population of Yuva were used as plant material. Results of this study show that there is no statistically significant difference among methods "inspecting the seeds one by one," "sowing seeds direct CP nutrient media," and "inspecting seeds in the light source," although the average number of embryos per fruit is slightly different. No embryo production was obtained from liquid culture because of infection. When considered together with labor costs and time required for embryo rescue, the best methods were "sowing seeds directly in the CP nutrient media" and "inspecting seeds in the light source." PMID- 23818826 TI - Developing an appropriate digital hearing aid for low-resource countries: a case study. AB - This paper reviews the development process and discusses the key findings which resulted from our multidisciplinary research team's effort to develop an alternative digital hearing suitable for low-resource countries such as Thailand. A cost-effective, fully programmable digital hearing aid, with its specifications benchmarking against WHO's recommendations, was systematically designed, engineered, and tested. Clinically it had undergone a full clinical trial that employed the outcome measurement protocol adopted from the APHAB, the first time implemented in Thai language. Results indicated that using the hearing aid improves user's satisfaction in terms of ease of communication, background noises, and reverberation, with clear benefit after 3 and 6 months, confirming its efficacy. In terms of engineering, the hearing aid also proved to be robust, passing all the designated tests. As the technology has successfully been transferred to a local company for the production phase, we also discuss other challenges that may arise before the device can be introduced into the market. PMID- 23818827 TI - Bioinformatics and biomedical informatics. PMID- 23818828 TI - One-pot synthesis of 2'-aminobenzothiazolo-arylmethyl-2-naphthols catalyzed by NBS under solvent-free conditions. AB - To develop a new facile protocol for the synthesis of 2'-aminobenzothiazolo arylmethyl-2-naphthol derivatives, N-bromosuccinimide (NBS) was used as an efficient catalyst for the one-pot synthesis of 2'-aminobenzothiazolo-arylmethyl 2-naphthols in excellent yields from beta -naphthol (1 mmol), aromatic aldehydes (1 mmol), and 2-aminobenzothiazole (1 mmol) at 60 degrees C under solvent-free conditions. PMID- 23818829 TI - High efficiency secondary somatic embryogenesis in Hovenia dulcis Thunb. through solid and liquid cultures. AB - Embryogenic callus was obtained from mature seed explants on medium supplemented with 2,4-dichlorophenoxyacetic acid. Primary somatic embryos (SEs) can only develop into abnormal plants. Well-developed SEs could be obtained through secondary somatic embryogenesis both in solid and liquid cultures. Temperature strongly affected induction frequency of secondary embryogenesis. Relatively high temperature (30 degrees C) and germinated SEs explants were effective for induction of secondary somatic embryos, and low temperature (20 degrees C) was more suitable for further embryo development, plantlet conversion, and transplant survival. Somatic embryos formed on agar medium had larger cotyledons than those of embryos formed in liquid medium. Supplementing 0.1 mg L(-1) 6-benzyladenine (BA) was effective for plant conversion; the rate of plant conversion was 43.3% in somatic embryos from solid culture and 36.5% in embryos from liquid culture. In vitro plants were successfully acclimatized in the greenhouse. The protocol established in this study will be helpful for large-scale vegetative propagation of this medicinal tree. PMID- 23818830 TI - SGC tests for influence of material composition on compaction characteristic of asphalt mixtures. AB - Compaction characteristic of the surface layer asphalt mixture (13-type gradation mixture) was studied using Superpave gyratory compactor (SGC) simulative compaction tests. Based on analysis of densification curve of gyratory compaction, influence rules of the contents of mineral aggregates of all sizes and asphalt on compaction characteristic of asphalt mixtures were obtained. SGC Tests show that, for the mixture with a bigger content of asphalt, its density increases faster, that there is an optimal amount of fine aggregates for optimal compaction and that an appropriate amount of mineral powder will improve workability of mixtures, but overmuch mineral powder will make mixtures dry and hard. Conclusions based on SGC tests can provide basis for how to adjust material composition for improving compaction performance of asphalt mixtures, and for the designed asphalt mixture, its compaction performance can be predicted through these conclusions, which also contributes to the choice of compaction schemes. PMID- 23818831 TI - A fragile zero watermarking scheme to detect and characterize malicious modifications in database relations. AB - We put forward a fragile zero watermarking scheme to detect and characterize malicious modifications made to a database relation. Most of the existing watermarking schemes for relational databases introduce intentional errors or permanent distortions as marks into the database original content. These distortions inevitably degrade the data quality and data usability as the integrity of a relational database is violated. Moreover, these fragile schemes can detect malicious data modifications but do not characterize the tempering attack, that is, the nature of tempering. The proposed fragile scheme is based on zero watermarking approach to detect malicious modifications made to a database relation. In zero watermarking, the watermark is generated (constructed) from the contents of the original data rather than introduction of permanent distortions as marks into the data. As a result, the proposed scheme is distortion-free; thus, it also resolves the inherent conflict between security and imperceptibility. The proposed scheme also characterizes the malicious data modifications to quantify the nature of tempering attacks. Experimental results show that even minor malicious modifications made to a database relation can be detected and characterized successfully. PMID- 23818832 TI - Optimal control for a parallel hybrid hydraulic excavator using particle swarm optimization. AB - Optimal control using particle swarm optimization (PSO) is put forward in a parallel hybrid hydraulic excavator (PHHE). A power-train mathematical model of PHHE is illustrated along with the analysis of components' parameters. Then, the optimal control problem is addressed, and PSO algorithm is introduced to deal with this nonlinear optimal problem which contains lots of inequality/equality constraints. Then, the comparisons between the optimal control and rule-based one are made, and the results show that hybrids with the optimal control would increase fuel economy. Although PSO algorithm is off-line optimization, still it would bring performance benchmark for PHHE and also help have a deep insight into hybrid excavators. PMID- 23818833 TI - Deadline-aware energy-efficient query scheduling in Wireless Sensor Networks with mobile sink. AB - Mobile sinks are proposed to save sensor energy spent for multihop communication in transferring data to a base station (sink) in Wireless Sensor Networks. Due to relative low speed of mobile sinks, these approaches are mostly suitable for delay-tolerant applications. In this paper, we study the design of a query scheduling algorithm for query-based data gathering applications using mobile sinks. However, these kinds of applications are sensitive to delays due to specified query deadlines. Thus, the proposed scheduling algorithm aims to minimize the number of missed deadlines while keeping the level of energy consumption at the minimum. PMID- 23818834 TI - Effects of IAA, IBA, NAA, and GA3 on rooting and morphological features of Melissa officinalis L. stem cuttings. AB - This study analyzed the potential of producing Melissa officinalis L. using stem cuttings. Four different hormones (IAA, IBA, NAA, and GA3) were applied to the cuttings, with and without buds, in two doses (1000 mg/L and 5000 mg/L), and after 60 days, 10 morphological characteristics of newly generated plants were detected, and a statistical analysis was carried out. The results of the study show that the cuttings with at least one bud must be used in order to produce M. officinalis using stem cuttings. Even though the auxin group hormones (IAA, IBA, and NAA) do not have an apparent effect on rooting percentage, these hormones were detected to affect the morphological characteristics of the newly generated plants, especially root generation. GA3 application has a considerable effect on stem height. PMID- 23818835 TI - The system power control unit based on the on-chip wireless communication system. AB - Currently, the on-chip wireless communication system (OWCS) includes 2nd generation (2G), 3rd-generation (3G), and long-term evolution (LTE) communication subsystems. To improve the power consumption of OWCS, a typical architecture design of system power control unit (SPCU) is given in this paper, which can not only make a 2G, a 3G, and an LTE subsystems enter sleep mode, but it can also wake them up from sleep mode via the interrupt. During the sleep mode period, either the real-time sleep timer or the global system for mobile (GSM) communication sleep timer can be used individually to arouse the corresponding subsystem. Compared to previous sole voltage supplies on the OWCS, a 2G, a 3G, or an LTE subsystem can be independently configured with three different voltages and frequencies in normal work mode. In the meantime, the voltage supply monitor, which is an important part in the SPCU, can significantly guard the voltage of OWCS in real time. Finally, the SPCU may implement dynamic voltage and frequency scaling (DVFS) for a 2G, a 3G, or an LTE subsystem, which is automatically accomplished by the hardware. PMID- 23818836 TI - Metals ions removal by polymer membranes of different porosity. AB - The effect of the amount of pore generating agent (polyvinylpyrrolidone) added to standard polymer membranes containing 18 wt.% of polyethersulfone on the physicochemical properties of the membranes and their capacity for removal of iron and copper ions from the liquid phase was studied. The membranes were obtained by the phase inversion method. The results have shown that the modification of polymer membranes by the use of different amounts of the pore forming agent in their syntheses leads to significant changes in porosity and has beneficial effect on equilibrium water content. The membranes studied were found to show different acid-base surface character, but for all membranes studied, a significant dominance of oxygen groups of acidic character was evidenced. The most effective were the membranes of the lowest content of polyvinylpyrrolidone, while the lowest values of resistance showed the membranes of the highest content of PVP, and so the ones of the greatest porosity. PMID- 23818837 TI - A comparative morphometrical study of the pecten oculi in different avian species. AB - In this study was investigated the structure of pecten oculi in the ostrich, duck, pigeon, turkey, and starling. The pecten oculi of the ostrich was vaned type and made up primary, secondary, and few tertiary lamellae. However, duck, pigeon, turkey and starling had a pleated-type pecten oculi which displayed folded structure. The numbers of pleats of the pectens were 12, 13-14, 21-22, and 17 in duck, pigeon, turkey, and starling, respectively. Light microscopic investigation demonstrated that pecten oculi is basically composed of numerous capillaries, large blood vessels, and pigment cells in all investigating avian species. Capillaries were 20.23, 14.34, 11.78, 12.58, and 12.78 MU m in diameter in ostrich, duck, pigeon, turkey, and starling, respectively. The capillaries are surrounded by thick basal membrane, and pigmented cells were observed around the capillaries. PMID- 23818838 TI - The ability of flux balance analysis to predict evolution of central metabolism scales with the initial distance to the optimum. AB - The most powerful genome-scale framework to model metabolism, flux balance analysis (FBA), is an evolutionary optimality model. It hypothesizes selection upon a proposed optimality criterion in order to predict the set of internal fluxes that would maximize fitness. Here we present a direct test of the optimality assumption underlying FBA by comparing the central metabolic fluxes predicted by multiple criteria to changes measurable by a (13)C-labeling method for experimentally-evolved strains. We considered datasets for three Escherichia coli evolution experiments that varied in their length, consistency of environment, and initial optimality. For ten populations that were evolved for 50,000 generations in glucose minimal medium, we observed modest changes in relative fluxes that led to small, but significant decreases in optimality and increased the distance to the predicted optimal flux distribution. In contrast, seven populations evolved on the poor substrate lactate for 900 generations collectively became more optimal and had flux distributions that moved toward predictions. For three pairs of central metabolic knockouts evolved on glucose for 600-800 generations, there was a balance between cases where optimality and flux patterns moved toward or away from FBA predictions. Despite this variation in predictability of changes in central metabolism, two generalities emerged. First, improved growth largely derived from evolved increases in the rate of substrate use. Second, FBA predictions bore out well for the two experiments initiated with ancestors with relatively sub-optimal yield, whereas those begun already quite optimal tended to move somewhat away from predictions. These findings suggest that the tradeoff between rate and yield is surprisingly modest. The observed positive correlation between rate and yield when adaptation initiated further from the optimum resulted in the ability of FBA to use stoichiometric constraints to predict the evolution of metabolism despite selection for rate. PMID- 23818839 TI - Integrative analysis of deep sequencing data identifies estrogen receptor early response genes and links ATAD3B to poor survival in breast cancer. AB - Identification of responsive genes to an extra-cellular cue enables characterization of pathophysiologically crucial biological processes. Deep sequencing technologies provide a powerful means to identify responsive genes, which creates a need for computational methods able to analyze dynamic and multi level deep sequencing data. To answer this need we introduce here a data-driven algorithm, SPINLONG, which is designed to search for genes that match the user defined hypotheses or models. SPINLONG is applicable to various experimental setups measuring several molecular markers in parallel. To demonstrate the SPINLONG approach, we analyzed ChIP-seq data reporting PolII, estrogen receptor alpha (ERalpha), H3K4me3 and H2A.Z occupancy at five time points in the MCF-7 breast cancer cell line after estradiol stimulus. We obtained 777 ERa early responsive genes and compared the biological functions of the genes having ERalpha binding within 20 kb of the transcription start site (TSS) to genes without such binding site. Our results show that the non-genomic action of ERalpha via the MAPK pathway, instead of direct ERa binding, may be responsible for early cell responses to ERalpha activation. Our results also indicate that the ERalpha responsive genes triggered by the genomic pathway are transcribed faster than those without ERalpha binding sites. The survival analysis of the 777 ERalpha responsive genes with 150 primary breast cancer tumors and in two independent validation cohorts indicated the ATAD3B gene, which does not have ERalpha binding site within 20 kb of its TSS, to be significantly associated with poor patient survival. PMID- 23818840 TI - How the dynamics and structure of sexual contact networks shape pathogen phylogenies. AB - The characteristics of the host contact network over which a pathogen is transmitted affect both epidemic spread and the projected effectiveness of control strategies. Given the importance of understanding these contact networks, it is unfortunate that they are very difficult to measure directly. This challenge has led to an interest in methods to infer information about host contact networks from pathogen phylogenies, because in shaping a pathogen's opportunities for reproduction, contact networks also shape pathogen evolution. Host networks influence pathogen phylogenies both directly, through governing opportunities for evolution, and indirectly by changing the prevalence and incidence. Here, we aim to separate these two effects by comparing pathogen evolution on different host networks that share similar epidemic trajectories. This approach allows use to examine the direct effects of network structure on pathogen phylogenies, largely controlling for confounding differences arising from population dynamics. We find that networks with more heterogeneous degree distributions yield pathogen phylogenies with more variable cluster numbers, smaller mean cluster sizes, shorter mean branch lengths, and somewhat higher tree imbalance than networks with relatively homogeneous degree distributions. However, in particular for dynamic networks, we find that these direct effects are relatively modest. These findings suggest that the role of the epidemic trajectory, the dynamics of the network and the inherent variability of metrics such as cluster size must each be taken into account when trying to use pathogen phylogenies to understand characteristics about the underlying host contact network. PMID- 23818841 TI - Non-genetic determinants of mosquito competence for malaria parasites. AB - Understanding how mosquito vectors and malaria parasites interact is of fundamental interest, and it also offers novel perspectives for disease control. Both the genetic and environmental contexts are known to affect the ability of mosquitoes to support malaria development and transmission, i.e., vector competence. Although the role of environment has long been recognized, much work has focused on host and parasite genetic effects. However, the last few years have seen a surge of studies revealing a great diversity of ways in which non genetic factors can interfere with mosquito-Plasmodium interactions. Here, we review the current evidence for such environmentally mediated effects, including ambient temperature, mosquito diet, microbial gut flora, and infection history, and we identify additional factors previously overlooked in mosquito-Plasmodium interactions. We also discuss epidemiological implications, and the evolutionary consequences for vector immunity and parasite transmission strategies. Finally, we propose directions for further research and argue that an improved knowledge of non-genetic influences on mosquito-Plasmodium interactions could aid in implementing conventional malaria control measures and contribute to the design of novel strategies. PMID- 23818842 TI - Rickettsia typhi possesses phospholipase A2 enzymes that are involved in infection of host cells. AB - The long-standing proposal that phospholipase A2 (PLA2) enzymes are involved in rickettsial infection of host cells has been given support by the recent characterization of a patatin phospholipase (Pat2) with PLA2 activity from the pathogens Rickettsia prowazekii and R. typhi. However, pat2 is not encoded in all Rickettsia genomes; yet another uncharacterized patatin (Pat1) is indeed ubiquitous. Here, evolutionary analysis of both patatins across 46 Rickettsia genomes revealed 1) pat1 and pat2 loci are syntenic across all genomes, 2) both Pat1 and Pat2 do not contain predicted Sec-dependent signal sequences, 3) pat2 has been pseudogenized multiple times in rickettsial evolution, and 4) ubiquitous pat1 forms two divergent groups (pat1A and pat1B) with strong evidence for recombination between pat1B and plasmid-encoded homologs. In light of these findings, we extended the characterization of R. typhi Pat1 and Pat2 proteins and determined their role in the infection process. As previously demonstrated for Pat2, we determined that 1) Pat1 is expressed and secreted into the host cytoplasm during R. typhi infection, 2) expression of recombinant Pat1 is cytotoxic to yeast cells, 3) recombinant Pat1 possesses PLA2 activity that requires a host cofactor, and 4) both Pat1 cytotoxicity and PLA2 activity were reduced by PLA2 inhibitors and abolished by site-directed mutagenesis of catalytic Ser/Asp residues. To ascertain the role of Pat1 and Pat2 in R. typhi infection, antibodies to both proteins were used to pretreat rickettsiae. Subsequent invasion and plaque assays both indicated a significant decrease in R. typhi infection compared to that by pre-immune IgG. Furthermore, antibody pretreatment of R. typhi blocked/delayed phagosomal escapes. Together, these data suggest both enzymes are involved early in the infection process. Collectively, our study suggests that R. typhi utilizes two evolutionary divergent patatin phospholipases to support its intracellular life cycle, a mechanism distinguishing it from other rickettsial species. PMID- 23818843 TI - HIV-1 vaccine-induced T-cell responses cluster in epitope hotspots that differ from those induced in natural infection with HIV-1. AB - Several recent large clinical trials evaluated HIV vaccine candidates that were based on recombinant adenovirus serotype 5 (rAd-5) vectors expressing HIV-derived antigens. These vaccines primarily elicited T-cell responses, which are known to be critical for controlling HIV infection. In the current study, we present a meta-analysis of epitope mapping data from 177 participants in three clinical trials that tested two different HIV vaccines: MRKAd-5 HIV and VRC-HIVAD014-00VP. We characterized the population-level epitope responses in these trials by generating population-based epitope maps, and also designed such maps using a large cohort of 372 naturally infected individuals. We used these maps to address several questions: (1) Are vaccine-induced responses randomly distributed across vaccine inserts, or do they cluster into immunodominant epitope hotspots? (2) Are the immunodominance patterns observed for these two vaccines in three vaccine trials different from one another? (3) Do vaccine-induced hotspots overlap with epitope hotspots induced by chronic natural infection with HIV-1? (4) Do immunodominant hotspots target evolutionarily conserved regions of the HIV genome? (5) Can epitope prediction methods be used to identify these hotspots? We found that vaccine responses clustered into epitope hotspots in all three vaccine trials and some of these hotspots were not observed in chronic natural infection. We also found significant differences between the immunodominance patterns generated in each trial, even comparing two trials that tested the same vaccine in different populations. Some of the vaccine-induced immunodominant hotspots were located in highly variable regions of the HIV genome, and this was more evident for the MRKAd-5 HIV vaccine. Finally, we found that epitope prediction methods can partially predict the location of vaccine-induced epitope hotspots. Our findings have implications for vaccine design and suggest a framework by which different vaccine candidates can be compared in early phases of evaluation. PMID- 23818844 TI - Adhesins and host serum factors drive Yop translocation by yersinia into professional phagocytes during animal infection. AB - Yersinia delivers Yops into numerous types of cultured cells, but predominantly into professional phagocytes and B cells during animal infection. The basis for this cellular tropism during animal infection is not understood. This work demonstrates that efficient and specific Yop translocation into phagocytes by Yersinia pseudotuberculosis (Yptb) is a multi-factorial process requiring several adhesins and host complement. When WT Yptb or a multiple adhesin mutant strain, DeltaailDeltainvDeltayadA, colonized tissues to comparable levels, DeltaailDeltainvDeltayadA translocated Yops into significantly fewer cells, demonstrating that these adhesins are critical for translocation into high numbers of cells. However, phagocytes were still selectively targeted for translocation, indicating that other bacterial and/or host factors contribute to this function. Complement depletion showed that complement-restricted infection by DeltaailDeltainvDeltayadA but not WT, indicating that adhesins disarm complement in mice either by prevention of opsonophagocytosis or by suppressing production of pro-inflammatory cytokines. Furthermore, in the absence of the three adhesins and complement, the spectrum of cells targeted for translocation was significantly altered, indicating that Yersinia adhesins and complement direct Yop translocation into neutrophils during animal infection. In summary, these findings demonstrate that in infected tissues, Yersinia uses adhesins both to disarm complement-dependent killing and to efficiently translocate Yops into phagocytes. PMID- 23818845 TI - Galectin-9 and IL-21 mediate cross-regulation between Th17 and Treg cells during acute hepatitis C. AB - Loss of CD4 T cell help correlates with virus persistence during acute hepatitis C virus (HCV) infection, but the underlying mechanism(s) remain unknown. We developed a combined proliferation/intracellular cytokine staining assay to monitor expansion of HCV-specific CD4 T cells and helper cytokines expression patterns during acute infections with different outcomes. We demonstrate that acute resolving HCV is characterized by strong Th1/Th17 responses with specific expansion of IL-21-producing CD4 T cells and increased IL-21 levels in plasma. In contrast, viral persistence was associated with lower frequencies of IL-21 producing CD4 T cells, reduced proliferation and increased expression of the inhibitory receptors T cell immunoglobulin and mucin-domain-containing-molecule-3 (Tim-3), programmed death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) on HCV-specific CD8 T cells. Progression to persistent infection was accompanied by increased plasma levels of the Tim-3 ligand Galectin-9 (Gal-9) and expansion of Gal-9 expressing regulatory T cells (Tregs). In vitro supplementation of Tim 3(high) HCV-specific CD8 T cells with IL-21 enhanced their proliferation and prevented Gal-9 induced apoptosis. siRNA-mediated knockdown of Gal-9 in Treg cells rescued IL-21 production by HCV-specific CD4 T cells. We propose that failure of CD4 T cell help during acute HCV is partially due to an imbalance between Th17 and Treg cells whereby exhaustion of both CD4 and CD8 T cells through the Tim-3/Gal-9 pathway may be limited by IL-21 producing Th17 cells or enhanced by Gal-9 producing Tregs. PMID- 23818846 TI - Novel polyomaviruses of nonhuman primates: genetic and serological predictors for the existence of multiple unknown polyomaviruses within the human population. AB - Polyomaviruses are a family of small non-enveloped DNA viruses that encode oncogenes and have been associated, to greater or lesser extent, with human disease and cancer. Currently, twelve polyomaviruses are known to circulate within the human population. To further examine the diversity of human polyomaviruses, we have utilized a combinatorial approach comprised of initial degenerate primer-based PCR identification and phylogenetic analysis of nonhuman primate (NHP) polyomavirus species, followed by polyomavirus-specific serological analysis of human sera. Using this approach we identified twenty novel NHP polyomaviruses: nine in great apes (six in chimpanzees, two in gorillas and one in orangutan), five in Old World monkeys and six in New World monkeys. Phylogenetic analysis indicated that only four of the nine chimpanzee polyomaviruses (six novel and three previously identified) had known close human counterparts. To determine whether the remaining chimpanzee polyomaviruses had potential human counterparts, the major viral capsid proteins (VP1) of four chimpanzee polyomaviruses were expressed in E. coli for use as antigens in enzyme linked immunoassay (ELISA). Human serum/plasma samples from both Cote d'Ivoire and Germany showed frequent seropositivity for the four viruses. Antibody pre adsorption-based ELISA excluded the possibility that reactivities resulted from binding to known human polyomaviruses. Together, these results support the existence of additional polyomaviruses circulating within the human population that are genetically and serologically related to existing chimpanzee polyomaviruses. PMID- 23818847 TI - Single cell analysis of lymph node tissue from HIV-1 infected patients reveals that the majority of CD4+ T-cells contain one HIV-1 DNA molecule. AB - Genetic recombination contributes to the diversity of human immunodeficiency virus (HIV-1). Productive HIV-1 recombination is, however, dependent on both the number of HIV-1 genomes per infected cell and the genetic relationship between these viral genomes. A detailed analysis of the number of proviruses and their genetic relationship in infected cells isolated from peripheral blood and tissue compartments is therefore important for understanding HIV-1 recombination, genetic diversity and the dynamics of HIV-1 infection. To address these issues, we used a previously developed single-cell sequencing technique to quantify and genetically characterize individual HIV-1 DNA molecules from single cells in lymph node tissue and peripheral blood. Analysis of memory and naive CD4(+) T cells from paired lymph node and peripheral blood samples from five untreated chronically infected patients revealed that the majority of these HIV-1-infected cells (>90%) contain only one copy of HIV-1 DNA, implying a limited potential for productive recombination in virus produced by these cells in these two compartments. Phylogenetic analysis revealed genetic similarity of HIV-1 DNA in memory and naive CD4(+) T-cells from lymph node, peripheral blood and HIV-1 RNA from plasma, implying exchange of virus and/or infected cells between these compartments in untreated chronic infection. PMID- 23818848 TI - Evidence for novel hepaciviruses in rodents. AB - Hepatitis C virus (HCV) is among the most relevant causes of liver cirrhosis and hepatocellular carcinoma. Research is complicated by a lack of accessible small animal models. The systematic investigation of viruses of small mammals could guide efforts to establish such models, while providing insight into viral evolutionary biology. We have assembled the so-far largest collection of small mammal samples from around the world, qualified to be screened for bloodborne viruses, including sera and organs from 4,770 rodents (41 species); and sera from 2,939 bats (51 species). Three highly divergent rodent hepacivirus clades were detected in 27 (1.8%) of 1,465 European bank voles (Myodes glareolus) and 10 (1.9%) of 518 South African four-striped mice (Rhabdomys pumilio). Bats showed anti-HCV immunoblot reactivities but no virus detection, although the genetic relatedness suggested by the serologic results should have enabled RNA detection using the broadly reactive PCR assays developed for this study. 210 horses and 858 cats and dogs were tested, yielding further horse-associated hepaciviruses but none in dogs or cats. The rodent viruses were equidistant to HCV, exceeding by far the diversity of HCV and the canine/equine hepaciviruses taken together. Five full genomes were sequenced, representing all viral lineages. Salient genome features and distance criteria supported classification of all viruses as hepaciviruses. Quantitative RT-PCR, RNA in-situ hybridisation, and histopathology suggested hepatic tropism with liver inflammation resembling hepatitis C. Recombinant serology for two distinct hepacivirus lineages in 97 bank voles identified seroprevalence rates of 8.3 and 12.4%, respectively. Antibodies in bank vole sera neither cross-reacted with HCV, nor the heterologous bank vole hepacivirus. Co-occurrence of RNA and antibodies was found in 3 of 57 PCR positive bank vole sera (5.3%). Our data enable new hypotheses regarding HCV evolution and encourage efforts to develop rodent surrogate models for HCV. PMID- 23818849 TI - Heterosubtypic immunity to influenza A virus infections in mallards may explain existence of multiple virus subtypes. AB - Wild birds, particularly duck species, are the main reservoir of influenza A virus (IAV) in nature. However, knowledge of IAV infection dynamics in the wild bird reservoir, and the development of immune responses, are essentially absent. Importantly, a detailed understanding of how subtype diversity is generated and maintained is lacking. To address this, 18,679 samples from 7728 Mallard ducks captured between 2002 and 2009 at a single stopover site in Sweden were screened for IAV infections, and the resulting 1081 virus isolates were analyzed for patterns of immunity. We found support for development of homosubtypic hemagglutinin (HA) immunity during the peak of IAV infections in the fall. Moreover, re-infections with the same HA subtype and related prevalent HA subtypes were uncommon, suggesting the development of natural homosubtypic and heterosubtypic immunity (p-value = 0.02). Heterosubtypic immunity followed phylogenetic relatedness of HA subtypes, both at the level of HA clades (p-value = 0.04) and the level of HA groups (p-value = 0.05). In contrast, infection patterns did not support specific immunity for neuraminidase (NA) subtypes. For the H1 and H3 Clades, heterosubtypic immunity showed a clear temporal pattern and we estimated within-clade immunity to last at least 30 days. The strength and duration of heterosubtypic immunity has important implications for transmission dynamics of IAV in the natural reservoir, where immune escape and disruptive selection may increase HA antigenic variation and explain IAV subtype diversity. PMID- 23818850 TI - Nitric oxide synthase dysfunction contributes to impaired cerebroarteriolar reactivity in experimental cerebral malaria. AB - Cerebrovascular dysfunction plays a key role in the pathogenesis of cerebral malaria. In experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA, cerebrovascular dysfunction characterized by vascular constriction, occlusion and damage results in impaired perfusion and reduced cerebral blood flow and oxygenation, and has been linked to low nitric oxide (NO) bioavailability. Here, we directly assessed cerebrovascular function in ECM using a novel cranial window method for intravital microscopy of the pial microcirculation and probed the role of NOS isoforms and phosphorylation patterns in the impaired vascular responses. We show that pial arteriolar responses to endothelial NOS (eNOS) and neuronal NOS (nNOS) agonists (Acetylcholine (ACh) and N-Methyl-D-Aspartate (NMDA)) were blunted in mice with ECM, and could be partially recovered by exogenous supplementation of tetrahydrobiopterin (BH4). Pial arterioles in non-ECM mice infected by Plasmodium berghei NK65 remained relatively responsive to the agonists and were not significantly affected by BH4 treatment. These findings, together with the observed blunting of NO production upon stimulation by the agonists, decrease in total NOS activity, augmentation of lipid peroxidation levels, upregulation of eNOS protein expression, and increase in eNOS and nNOS monomerization in the brain during ECM development strongly indicate a state of eNOS/nNOS uncoupling likely mediated by oxidative stress. Furthermore, the downregulation of Serine 1176 (S1176) phosphorylation of eNOS, which correlated with a decrease in cerebrovascular wall shear stress, implicates hemorheological disturbances in eNOS dysfunction in ECM. Finally, pial arterioles responded to superfusion with the NO donor, S-Nitroso-L-glutathione (GSNO), but with decreased intensity, indicating that not only NO production but also signaling is perturbed during ECM. Therefore, the pathological impairment of eNOS and nNOS functions contribute importantly to cerebrovascular dysfunction in ECM and the recovery of intrinsic functionality of NOS to increase NO bioavailability and restore vascular health represents a target for ECM treatment. PMID- 23818851 TI - An extracellular subtilase switch for immune priming in Arabidopsis. AB - In higher eukaryotes, induced resistance associates with acquisition of a priming state of the cells for a more effective activation of innate immunity; however, the nature of the components for mounting this type of immunological memory is not well known. We identified an extracellular subtilase from Arabidopsis, SBT3.3, the overexpression of which enhances innate immune responses while the loss of function compromises them. SBT3.3 expression initiates a durable autoinduction mechanism that promotes chromatin remodeling and activates a salicylic acid(SA)-dependent mechanism of priming of defense genes for amplified response. Moreover, SBT3.3 expression-sensitized plants for enhanced expression of the OXI1 kinase gene and activation of MAP kinases following pathogen attack, providing additional clues for the regulation of immune priming by SBT3.3. Conversely, in sbt3.3 mutant plants pathogen-mediated induction of SA-related defense gene expression is drastically reduced and activation of MAP kinases inhibited. Moreover, chromatin remodeling of defense-related genes normally associated with activation of an immune priming response appear inhibited in sbt3.3 plants, further indicating the importance of the extracellular SBT3.3 subtilase in the establishment of immune priming. Our results also point to an epigenetic control in the regulation of plant immunity, since SBT3.3 is up regulated and priming activated when epigenetic control is impeded. SBT3.3 represents a new regulator of primed immunity. PMID- 23818852 TI - Location of the CD8 T cell epitope within the antigenic precursor determines immunogenicity and protection against the Toxoplasma gondii parasite. AB - CD8 T cells protect the host from disease caused by intracellular pathogens, such as the Toxoplasma gondii (T. gondii) protozoan parasite. Despite the complexity of the T. gondii proteome, CD8 T cell responses are restricted to only a small number of peptide epitopes derived from a limited set of antigenic precursors. This phenomenon is known as immunodominance and is key to effective vaccine design. However, the mechanisms that determine the immunogenicity and immunodominance hierarchy of parasite antigens are not well understood. Here, using genetically modified parasites, we show that parasite burden is controlled by the immunodominant GRA6-specific CD8 T cell response but not by responses to the subdominant GRA4- and ROP7-derived epitopes. Remarkably, optimal processing and immunodominance were determined by the location of the peptide epitope at the C-terminus of the GRA6 antigenic precursor. In contrast, immunodominance could not be explained by the peptide affinity for the MHC I molecule or the frequency of T cell precursors in the naive animals. Our results reveal the molecular requirements for optimal presentation of an intracellular parasite antigen and for eliciting protective CD8 T cells. PMID- 23818853 TI - Direct proteolytic cleavage of NLRP1B is necessary and sufficient for inflammasome activation by anthrax lethal factor. AB - Inflammasomes are multimeric protein complexes that respond to infection by recruitment and activation of the Caspase-1 (CASP1) protease. Activated CASP1 initiates immune defense by processing inflammatory cytokines and by causing a rapid and lytic cell death called pyroptosis. Inflammasome formation is orchestrated by members of the nucleotide-binding domain and leucine-rich repeat (NLR) or AIM2-like receptor (ALR) protein families. Certain NLRs and ALRs have been shown to function as direct receptors for specific microbial ligands, such as flagellin or DNA, but the molecular mechanism responsible for activation of most NLRs is still poorly understood. Here we determine the mechanism of activation of the NLRP1B inflammasome in mice. NLRP1B, and its ortholog in rats, is activated by the lethal factor (LF) protease that is a key virulence factor secreted by Bacillus anthracis, the causative agent of anthrax. LF was recently shown to cleave mouse and rat NLRP1 directly. However, it is unclear if cleavage is sufficient for NLRP1 activation. Indeed, other LF-induced cellular events have been suggested to play a role in NLRP1B activation. Surprisingly, we show that direct cleavage of NLRP1B is sufficient to induce inflammasome activation in the absence of LF. Our results therefore rule out the need for other LF-dependent cellular effects in activation of NLRP1B. We therefore propose that NLRP1 functions primarily as a sensor of protease activity and thus could conceivably detect a broader spectrum of pathogens than just B. anthracis. By adding proteolytic cleavage to the previously established ligand-receptor mechanism of NLR activation, our results illustrate the remarkable flexibility with which the NLR architecture can be deployed for the purpose of pathogen-detection and host defense. PMID- 23818854 TI - The Th17/Treg ratio, IL-1RA and sCD14 levels in primary HIV infection predict the T-cell activation set point in the absence of systemic microbial translocation. AB - Impairment of the intestinal barrier and subsequent microbial translocation (MT) may be involved in chronic immune activation, which plays a central role in HIV pathogenesis. Th17 cells are critical to prevent MT. The aim of the study was to investigate, in patients with primary HIV infection (PHI), the early relationship between the Th17/Treg ratio, monocyte activation and MT and their impact on the T cell activation set point, which is known to predict disease progression. 27 patients with early PHI were included in a prospective longitudinal study and followed-up for 6 months. At baseline, the Th17/Treg ratio strongly negatively correlated with the proportion of activated CD8 T cells expressing CD38/HLA-DR or Ki-67. Also, the Th17/Treg ratio was negatively related to viral load and plasma levels of sCD14 and IL-1RA, two markers of monocyte activation. In untreated patients, the Th17/Treg ratio at baseline negatively correlated with CD8 T-cell activation at month 6 defining the T-cell activation set point (% HLA DR(+)CD38(+) and %Ki-67(+)). Soluble CD14 and IL-1RA plasma levels also predicted the T-cell activation set point. Levels of I-FABP, a marker of mucosal damages, were similar to healthy controls at baseline but increased at month 6. No decrease in anti-endotoxin core antibody (EndoCAb) and no peptidoglycan were detected during PHI. In addition, 16S rDNA was only detected at low levels in 2 out 27 patients at baseline and in one additional patient at M6. Altogether, data support the hypothesis that T-cell and monocyte activation in PHI are not primarily driven by systemic MT but rather by viral replication. Moreover, the "innate immune set point" defined by the early levels of sCD14 and IL-1RA might be powerful early surrogate markers for disease progression and should be considered for use in clinical practice. PMID- 23818855 TI - CD4+ T cell-derived IL-10 promotes Brucella abortus persistence via modulation of macrophage function. AB - Evasion of host immune responses is a prerequisite for chronic bacterial diseases; however, the underlying mechanisms are not fully understood. Here, we show that the persistent intracellular pathogen Brucella abortus prevents immune activation of macrophages by inducing CD4(+)CD25(+) T cells to produce the anti inflammatory cytokine interleukin-10 (IL-10) early during infection. IL-10 receptor (IL-10R) blockage in macrophages resulted in significantly higher NF-kB activation as well as decreased bacterial intracellular survival associated with an inability of B. abortus to escape the late endosome compartment in vitro. Moreover, either a lack of IL-10 production by T cells or a lack of macrophage responsiveness to this cytokine resulted in an increased ability of mice to control B. abortus infection, while inducing elevated production of pro inflammatory cytokines, which led to severe pathology in liver and spleen of infected mice. Collectively, our results suggest that early IL-10 production by CD25(+)CD4(+) T cells modulates macrophage function and contributes to an initial balance between pro-inflammatory and anti-inflammatory cytokines that is beneficial to the pathogen, thereby promoting enhanced bacterial survival and persistent infection. PMID- 23818856 TI - Dissection of antibody specificities induced by yellow fever vaccination. AB - The live attenuated yellow fever (YF) vaccine has an excellent record of efficacy and one dose provides long-lasting immunity, which in many cases may last a lifetime. Vaccination stimulates strong innate and adaptive immune responses, and neutralizing antibodies are considered to be the major effectors that correlate with protection from disease. Similar to other flaviviruses, such antibodies are primarily induced by the viral envelope protein E, which consists of three distinct domains (DI, II, and III) and is presented at the surface of mature flavivirions in an icosahedral arrangement. In general, the dominance and individual variation of antibodies to different domains of viral surface proteins and their impact on neutralizing activity are aspects of humoral immunity that are not well understood. To gain insight into these phenomena, we established a platform of immunoassays using recombinant proteins and protein domains that allowed us to dissect and quantify fine specificities of the polyclonal antibody response after YF vaccination in a panel of 51 vaccinees as well as determine their contribution to virus neutralization by serum depletion analyses. Our data revealed a high degree of individual variation in antibody specificities present in post-vaccination sera and differences in the contribution of different antibody subsets to virus neutralization. Irrespective of individual variation, a substantial proportion of neutralizing activity appeared to be due to antibodies directed to complex quaternary epitopes displayed on the virion surface only but not on monomeric E. On the other hand, DIII-specific antibodies (presumed to have the highest neutralizing activity) as well as broadly flavivirus cross-reactive antibodies were absent or present at very low titers. These data provide new information on the fine specificity as well as variability of antibody responses after YF vaccination that are consistent with a strong influence of individual specific factors on immunodominance in humoral immune responses. PMID- 23818857 TI - Extreme genetic fragility of the HIV-1 capsid. AB - Genetic robustness, or fragility, is defined as the ability, or lack thereof, of a biological entity to maintain function in the face of mutations. Viruses that replicate via RNA intermediates exhibit high mutation rates, and robustness should be particularly advantageous to them. The capsid (CA) domain of the HIV-1 Gag protein is under strong pressure to conserve functional roles in viral assembly, maturation, uncoating, and nuclear import. However, CA is also under strong immunological pressure to diversify. Therefore, it would be particularly advantageous for CA to evolve genetic robustness. To measure the genetic robustness of HIV-1 CA, we generated a library of single amino acid substitution mutants, encompassing almost half the residues in CA. Strikingly, we found HIV-1 CA to be the most genetically fragile protein that has been analyzed using such an approach, with 70% of mutations yielding replication-defective viruses. Although CA participates in several steps in HIV-1 replication, analysis of conditionally (temperature sensitive) and constitutively non-viable mutants revealed that the biological basis for its genetic fragility was primarily the need to coordinate the accurate and efficient assembly of mature virions. All mutations that exist in naturally occurring HIV-1 subtype B populations at a frequency >3%, and were also present in the mutant library, had fitness levels that were >40% of WT. However, a substantial fraction of mutations with high fitness did not occur in natural populations, suggesting another form of selection pressure limiting variation in vivo. Additionally, known protective CTL epitopes occurred preferentially in domains of the HIV-1 CA that were even more genetically fragile than HIV-1 CA as a whole. The extreme genetic fragility of HIV-1 CA may be one reason why cell-mediated immune responses to Gag correlate with better prognosis in HIV-1 infection, and suggests that CA is a good target for therapy and vaccination strategies. PMID- 23818858 TI - The genome of tolypocladium inflatum: evolution, organization, and expression of the cyclosporin biosynthetic gene cluster. AB - The ascomycete fungus Tolypocladium inflatum, a pathogen of beetle larvae, is best known as the producer of the immunosuppressant drug cyclosporin. The draft genome of T. inflatum strain NRRL 8044 (ATCC 34921), the isolate from which cyclosporin was first isolated, is presented along with comparative analyses of the biosynthesis of cyclosporin and other secondary metabolites in T. inflatum and related taxa. Phylogenomic analyses reveal previously undetected and complex patterns of homology between the nonribosomal peptide synthetase (NRPS) that encodes for cyclosporin synthetase (simA) and those of other secondary metabolites with activities against insects (e.g., beauvericin, destruxins, etc.), and demonstrate the roles of module duplication and gene fusion in diversification of NRPSs. The secondary metabolite gene cluster responsible for cyclosporin biosynthesis is described. In addition to genes necessary for cyclosporin biosynthesis, it harbors a gene for a cyclophilin, which is a member of a family of immunophilins known to bind cyclosporin. Comparative analyses support a lineage specific origin of the cyclosporin gene cluster rather than horizontal gene transfer from bacteria or other fungi. RNA-Seq transcriptome analyses in a cyclosporin-inducing medium delineate the boundaries of the cyclosporin cluster and reveal high levels of expression of the gene cluster cyclophilin. In medium containing insect hemolymph, weaker but significant upregulation of several genes within the cyclosporin cluster, including the highly expressed cyclophilin gene, was observed. T. inflatum also represents the first reference draft genome of Ophiocordycipitaceae, a third family of insect pathogenic fungi within the fungal order Hypocreales, and supports parallel and qualitatively distinct radiations of insect pathogens. The T. inflatum genome provides additional insight into the evolution and biosynthesis of cyclosporin and lays a foundation for further investigations of the role of secondary metabolite gene clusters and their metabolites in fungal biology. PMID- 23818859 TI - Integrated transcriptomic and epigenomic analysis of primary human lung epithelial cell differentiation. AB - Elucidation of the epigenetic basis for cell-type specific gene regulation is key to gaining a full understanding of how the distinct phenotypes of differentiated cells are achieved and maintained. Here we examined how epigenetic changes are integrated with transcriptional activation to determine cell phenotype during differentiation. We performed epigenomic profiling in conjunction with transcriptomic profiling using in vitro differentiation of human primary alveolar epithelial cells (AEC). This model recapitulates an in vivo process in which AEC transition from one differentiated cell type to another during regeneration following lung injury. Interrogation of histone marks over time revealed enrichment of specific transcription factor binding motifs within regions of changing chromatin structure. Cross-referencing of these motifs with pathways showing transcriptional changes revealed known regulatory pathways of distal alveolar differentiation, such as the WNT and transforming growth factor beta (TGFB) pathways, and putative novel regulators of adult AEC differentiation including hepatocyte nuclear factor 4 alpha (HNF4A), and the retinoid X receptor (RXR) signaling pathways. Inhibition of the RXR pathway confirmed its functional relevance for alveolar differentiation. Our incorporation of epigenetic data allowed specific identification of transcription factors that are potential direct upstream regulators of the differentiation process, demonstrating the power of this approach. Integration of epigenomic data with transcriptomic profiling has broad application for the identification of regulatory pathways in other models of differentiation. PMID- 23818860 TI - The NADPH metabolic network regulates human alphaB-crystallin cardiomyopathy and reductive stress in Drosophila melanogaster. AB - Dominant mutations in the alpha-B crystallin (CryAB) gene are responsible for a number of inherited human disorders, including cardiomyopathy, skeletal muscle myopathy, and cataracts. The cellular mechanisms of disease pathology for these disorders are not well understood. Among recent advances is that the disease state can be linked to a disturbance in the oxidation/reduction environment of the cell. In a mouse model, cardiomyopathy caused by the dominant CryAB(R120G) missense mutation was suppressed by mutation of the gene that encodes glucose 6 phosphate dehydrogenase (G6PD), one of the cell's primary sources of reducing equivalents in the form of NADPH. Here, we report the development of a Drosophila model for cellular dysfunction caused by this CryAB mutation. With this model, we confirmed the link between G6PD and mutant CryAB pathology by finding that reduction of G6PD expression suppressed the phenotype while overexpression enhanced it. Moreover, we find that expression of mutant CryAB in the Drosophila heart impaired cardiac function and increased heart tube dimensions, similar to the effects produced in mice and humans, and that reduction of G6PD ameliorated these effects. Finally, to determine whether CryAB pathology responds generally to NADPH levels we tested mutants or RNAi-mediated knockdowns of phosphogluconate dehydrogenase (PGD), isocitrate dehydrogenase (IDH), and malic enzyme (MEN), the other major enzymatic sources of NADPH, and we found that all are capable of suppressing CryAB(R120G) pathology, confirming the link between NADP/H metabolism and CryAB. PMID- 23818861 TI - Distinct and atypical intrinsic and extrinsic cell death pathways between photoreceptor cell types upon specific ablation of Ranbp2 in cone photoreceptors. AB - Non-autonomous cell-death is a cardinal feature of the disintegration of neural networks in neurodegenerative diseases, but the molecular bases of this process are poorly understood. The neural retina comprises a mosaic of rod and cone photoreceptors. Cone and rod photoreceptors degenerate upon rod-specific expression of heterogeneous mutations in functionally distinct genes, whereas cone-specific mutations are thought to cause only cone demise. Here we show that conditional ablation in cone photoreceptors of Ran-binding protein-2 (Ranbp2), a cell context-dependent pleiotropic protein linked to neuroprotection, familial necrotic encephalopathies, acute transverse myelitis and tumor-suppression, promotes early electrophysiological deficits, subcellular erosive destruction and non-apoptotic death of cones, whereas rod photoreceptors undergo cone-dependent non-autonomous apoptosis. Cone-specific Ranbp2 ablation causes the temporal activation of a cone-intrinsic molecular cascade highlighted by the early activation of metalloproteinase 11/stromelysin-3 and up-regulation of Crx and CoREST, followed by the down-modulation of cone-specific phototransduction genes, transient up-regulation of regulatory/survival genes and activation of caspase-7 without apoptosis. Conversely, PARP1+ -apoptotic rods develop upon sequential activation of caspase-9 and caspase-3 and loss of membrane permeability. Rod photoreceptor demise ceases upon cone degeneration. These findings reveal novel roles of Ranbp2 in the modulation of intrinsic and extrinsic cell death mechanisms and pathways. They also unveil a novel spatiotemporal paradigm of progression of neurodegeneration upon cell-specific genetic damage whereby a cone to rod non-autonomous death pathway with intrinsically distinct cell-type death manifestations is triggered by cell-specific loss of Ranbp2. Finally, this study casts new light onto cell-death mechanisms that may be shared by human dystrophies with distinct retinal spatial signatures as well as with other etiologically distinct neurodegenerative disorders. PMID- 23818862 TI - Survival response to increased ceramide involves metabolic adaptation through novel regulators of glycolysis and lipolysis. AB - The sphingolipid ceramide elicits several stress responses, however, organisms survive despite increased ceramide but how they do so is poorly understood. We demonstrate here that the AKT/FOXO pathway regulates survival in increased ceramide environment by metabolic adaptation involving changes in glycolysis and lipolysis through novel downstream targets. We show that ceramide kinase mutants accumulate ceramide and this leads to reduction in energy levels due to compromised oxidative phosphorylation. Mutants show increased activation of Akt and a consequent decrease in FOXO levels. These changes lead to enhanced glycolysis by upregulating the activity of phosphoglyceromutase, enolase, pyruvate kinase, and lactate dehydrogenase to provide energy. A second major consequence of AKT/FOXO reprogramming in the mutants is the increased mobilization of lipid from the gut through novel lipase targets, CG8093 and CG6277 for energy contribution. Ubiquitous reduction of these targets by knockdown experiments results in semi or total lethality of the mutants, demonstrating the importance of activating them. The efficiency of these adaptive mechanisms decreases with age and leads to reduction in adult life span of the mutants. In particular, mutants develop cardiac dysfunction with age, likely reflecting the high energy requirement of a well-functioning heart. The lipases also regulate physiological triacylglycerol homeostasis and are important for energy metabolism since midgut specific reduction of them in wild type flies results in increased sensitivity to starvation and accumulation of triglycerides leading to cardiac defects. The central findings of increased AKT activation, decreased FOXO level and activation of phosphoglyceromutase and pyruvate kinase are also observed in mice heterozygous for ceramide transfer protein suggesting a conserved role of this pathway in mammals. These data reveal novel glycolytic and non-autonomous lipolytic pathways in response to increased ceramide for sustenance of high energy demanding organ functions like the heart. PMID- 23818863 TI - Cohesin and polycomb proteins functionally interact to control transcription at silenced and active genes. AB - Cohesin is crucial for proper chromosome segregation but also regulates gene transcription and organism development by poorly understood mechanisms. Using genome-wide assays in Drosophila developing wings and cultured cells, we find that cohesin functionally interacts with Polycomb group (PcG) silencing proteins at both silenced and active genes. Cohesin unexpectedly facilitates binding of Polycomb Repressive Complex 1 (PRC1) to many active genes, but their binding is mutually antagonistic at silenced genes. PRC1 depletion decreases phosphorylated RNA polymerase II and mRNA at many active genes but increases them at silenced genes. Depletion of cohesin reduces long-range interactions between Polycomb Response Elements in the invected-engrailed gene complex where it represses transcription. These studies reveal a previously unrecognized role for PRC1 in facilitating productive gene transcription and provide new insights into how cohesin and PRC1 control development. PMID- 23818865 TI - Horizontally acquired glycosyltransferase operons drive salmonellae lipopolysaccharide diversity. AB - The immunodominant lipopolysaccharide is a key antigenic factor for Gram-negative pathogens such as salmonellae where it plays key roles in host adaptation, virulence, immune evasion, and persistence. Variation in the lipopolysaccharide is also the major differentiating factor that is used to classify Salmonella into over 2600 serovars as part of the Kaufmann-White scheme. While lipopolysaccharide diversity is generally associated with sequence variation in the lipopolysaccharide biosynthesis operon, extraneous genetic factors such as those encoded by the glucosyltransferase (gtr) operons provide further structural heterogeneity by adding additional sugars onto the O-antigen component of the lipopolysaccharide. Here we identify and examine the O-antigen modifying glucosyltransferase genes from the genomes of Salmonella enterica and Salmonella bongori serovars. We show that Salmonella generally carries between 1 and 4 gtr operons that we have classified into 10 families on the basis of gtrC sequence with apparent O-antigen modification detected for five of these families. The gtr operons localize to bacteriophage-associated genomic regions and exhibit a dynamic evolutionary history driven by recombination and gene shuffling events leading to new gene combinations. Furthermore, evidence of Dam- and OxyR dependent phase variation of gtr gene expression was identified within eight gtr families. Thus, as O-antigen modification generates significant intra- and inter strain phenotypic diversity, gtr-mediated modification is fundamental in assessing Salmonella strain variability. This will inform appropriate vaccine and diagnostic approaches, in addition to contributing to our understanding of host pathogen interactions. PMID- 23818864 TI - Genome-scale analysis of escherichia coli FNR reveals complex features of transcription factor binding. AB - FNR is a well-studied global regulator of anaerobiosis, which is widely conserved across bacteria. Despite the importance of FNR and anaerobiosis in microbial lifestyles, the factors that influence its function on a genome-wide scale are poorly understood. Here, we report a functional genomic analysis of FNR action. We find that FNR occupancy at many target sites is strongly influenced by nucleoid-associated proteins (NAPs) that restrict access to many FNR binding sites. At a genome-wide level, only a subset of predicted FNR binding sites were bound under anaerobic fermentative conditions and many appeared to be masked by the NAPs H-NS, IHF and Fis. Similar assays in cells lacking H-NS and its paralog StpA showed increased FNR occupancy at sites bound by H-NS in WT strains, indicating that large regions of the genome are not readily accessible for FNR binding. Genome accessibility may also explain our finding that genome-wide FNR occupancy did not correlate with the match to consensus at binding sites, suggesting that significant variation in ChIP signal was attributable to cross linking or immunoprecipitation efficiency rather than differences in binding affinities for FNR sites. Correlation of FNR ChIP-seq peaks with transcriptomic data showed that less than half of the FNR-regulated operons could be attributed to direct FNR binding. Conversely, FNR bound some promoters without regulating expression presumably requiring changes in activity of condition-specific transcription factors. Such combinatorial regulation may allow Escherichia coli to respond rapidly to environmental changes and confer an ecological advantage in the anaerobic but nutrient-fluctuating environment of the mammalian gut. PMID- 23818866 TI - Pervasive transcription of the human genome produces thousands of previously unidentified long intergenic noncoding RNAs. AB - Known protein coding gene exons compose less than 3% of the human genome. The remaining 97% is largely uncharted territory, with only a small fraction characterized. The recent observation of transcription in this intergenic territory has stimulated debate about the extent of intergenic transcription and whether these intergenic RNAs are functional. Here we directly observed with a large set of RNA-seq data covering a wide array of human tissue types that the majority of the genome is indeed transcribed, corroborating recent observations by the ENCODE project. Furthermore, using de novo transcriptome assembly of this RNA-seq data, we found that intergenic regions encode far more long intergenic noncoding RNAs (lincRNAs) than previously described, helping to resolve the discrepancy between the vast amount of observed intergenic transcription and the limited number of previously known lincRNAs. In total, we identified tens of thousands of putative lincRNAs expressed at a minimum of one copy per cell, significantly expanding upon prior lincRNA annotation sets. These lincRNAs are specifically regulated and conserved rather than being the product of transcriptional noise. In addition, lincRNAs are strongly enriched for trait associated SNPs suggesting a new mechanism by which intergenic trait-associated regions may function. These findings will enable the discovery and interrogation of novel intergenic functional elements. PMID- 23818867 TI - Integrative "omics"-approach discovers dynamic and regulatory features of bacterial stress responses. AB - Bacteria constantly face stress conditions and therefore mount specific responses to ensure adaptation and survival. Stress responses were believed to be predominantly regulated at the transcriptional level. In the phototrophic bacterium Rhodobacter sphaeroides the response to singlet oxygen is initiated by alternative sigma factors. Further adaptive mechanisms include post transcriptional and post-translational events, which have to be considered to gain a deeper understanding of how sophisticated regulation networks operate. To address this issue, we integrated three layers of regulation: (1) total mRNA levels at different time-points revealed dynamics of the transcriptome, (2) mRNAs in polysome fractions reported on translational regulation (translatome), and (3) SILAC-based mass spectrometry was used to quantify protein abundances (proteome). The singlet oxygen stress response exhibited highly dynamic features regarding short-term effects and late adaptation, which could in part be assigned to the sigma factors RpoE and RpoH2 generating distinct expression kinetics of corresponding regulons. The occurrence of polar expression patterns of genes within stress-inducible operons pointed to an alternative of dynamic fine-tuning upon stress. In addition to transcriptional activation, we observed significant induction of genes at the post-transcriptional level (translatome), which identified new putative regulators and assigned genes of quorum sensing to the singlet oxygen stress response. Intriguingly, the SILAC approach explored the stress-dependent decline of photosynthetic proteins, but also identified 19 new open reading frames, which were partly validated by RNA-seq. We propose that comparative approaches as presented here will help to create multi-layered expression maps on the system level ("expressome"). Finally, intense mass spectrometry combined with RNA-seq might be the future tool of choice to re annotate genomes in various organisms and will help to understand how they adapt to alternating conditions. PMID- 23818868 TI - ABI4 regulates primary seed dormancy by regulating the biogenesis of abscisic acid and gibberellins in arabidopsis. AB - Seed dormancy is an important economic trait for agricultural production. Abscisic acid (ABA) and Gibberellins (GA) are the primary factors that regulate the transition from dormancy to germination, and they regulate this process antagonistically. The detailed regulatory mechanism involving crosstalk between ABA and GA, which underlies seed dormancy, requires further elucidation. Here, we report that ABI4 positively regulates primary seed dormancy, while negatively regulating cotyledon greening, by mediating the biogenesis of ABA and GA. Seeds of the Arabidopsis abi4 mutant that were subjected to short-term storage (one or two weeks) germinated significantly more quickly than Wild-Type (WT), and abi4 cotyledons greened markedly more quickly than WT, while the rates of germination and greening were comparable when the seeds were subjected to longer-term storage (six months). The ABA content of dry abi4 seeds was remarkably lower than that of WT, but the amounts were comparable after stratification. Consistently, the GA level of abi4 seeds was increased compared to WT. Further analysis showed that abi4 was resistant to treatment with paclobutrazol (PAC), a GA biosynthesis inhibitor, during germination, while OE-ABI4 was sensitive to PAC, and exogenous GA rescued the delayed germination phenotype of OE-ABI4. Analysis by qRT-PCR showed that the expression of genes involved in ABA and GA metabolism in dry and germinating seeds corresponded to hormonal measurements. Moreover, chromatin immunoprecipitation qPCR (ChIP-qPCR) and transient expression analysis showed that ABI4 repressed CYP707A1 and CYP707A2 expression by directly binding to those promoters, and the ABI4 binding elements are essential for this repression. Accordingly, further genetic analysis showed that abi4 recovered the delayed germination phenotype of cyp707a1 and cyp707a2 and further, rescued the non germinating phenotype of ga1-t. Taken together, this study suggests that ABI4 is a key factor that regulates primary seed dormancy by mediating the balance between ABA and GA biogenesis. PMID- 23818869 TI - Evidence for two different regulatory mechanisms linking replication and segregation of vibrio cholerae chromosome II. AB - Understanding the mechanisms that coordinate replication initiation with subsequent segregation of chromosomes is an important biological problem. Here we report two replication-control mechanisms mediated by a chromosome segregation protein, ParB2, encoded by chromosome II of the model multichromosome bacterium, Vibrio cholerae. We find by the ChIP-chip assay that ParB2, a centromere binding protein, spreads beyond the centromere and covers a replication inhibitory site (a 39-mer). Unexpectedly, without nucleation at the centromere, ParB2 could also bind directly to a related 39-mer. The 39-mers are the strongest inhibitors of chromosome II replication and they mediate inhibition by binding the replication initiator protein. ParB2 thus appears to promote replication by out-competing initiator binding to the 39-mers using two mechanisms: spreading into one and direct binding to the other. We suggest that both these are novel mechanisms to coordinate replication initiation with segregation of chromosomes. PMID- 23818870 TI - Loss of catalytically inactive lipid phosphatase myotubularin-related protein 12 impairs myotubularin stability and promotes centronuclear myopathy in zebrafish. AB - X-linked myotubular myopathy (XLMTM) is a congenital disorder caused by mutations of the myotubularin gene, MTM1. Myotubularin belongs to a large family of conserved lipid phosphatases that include both catalytically active and inactive myotubularin-related proteins (i.e., "MTMRs"). Biochemically, catalytically inactive MTMRs have been shown to form heteroligomers with active members within the myotubularin family through protein-protein interactions. However, the pathophysiological significance of catalytically inactive MTMRs remains unknown in muscle. By in vitro as well as in vivo studies, we have identified that catalytically inactive myotubularin-related protein 12 (MTMR12) binds to myotubularin in skeletal muscle. Knockdown of the mtmr12 gene in zebrafish resulted in skeletal muscle defects and impaired motor function. Analysis of mtmr12 morphant fish showed pathological changes with central nucleation, disorganized Triads, myofiber hypotrophy and whorled membrane structures similar to those seen in X-linked myotubular myopathy. Biochemical studies showed that deficiency of MTMR12 results in reduced levels of myotubularin protein in zebrafish and mammalian C2C12 cells. Loss of myotubularin also resulted in reduction of MTMR12 protein in C2C12 cells, mice and humans. Moreover, XLMTM mutations within the myotubularin interaction domain disrupted binding to MTMR12 in cell culture. Analysis of human XLMTM patient myotubes showed that mutations that disrupt the interaction between myotubularin and MTMR12 proteins result in reduction of both myotubularin and MTMR12. These studies strongly support the concept that interactions between myotubularin and MTMR12 are required for the stability of their functional protein complex in normal skeletal muscles. This work highlights an important physiological function of catalytically inactive phosphatases in the pathophysiology of myotubular myopathy and suggests a novel therapeutic approach through identification of drugs that could stabilize the myotubularin-MTMR12 complex and hence ameliorate this disorder. PMID- 23818871 TI - Comprehensive high-resolution analysis of the role of an Arabidopsis gene family in RNA editing. AB - In flowering plants, mitochondrial and chloroplast mRNAs are edited by C-to-U base modification. In plant organelles, RNA editing appears to be generally a correcting mechanism that restores the proper function of the encoded product. Members of the Arabidopsis RNA editing-Interacting Protein (RIP) family have been recently shown to be essential components of the plant editing machinery. We report the use of a strand- and transcript-specific RNA-seq method (STS-PCRseq) to explore the effect of mutation or silencing of every RIP gene on plant organelle editing. We confirm RIP1 to be a major editing factor that controls the editing extent of 75% of the mitochondrial sites and 20% of the plastid C targets of editing. The quantitative nature of RNA sequencing allows the precise determination of overlapping effects of RIP factors on RNA editing. Over 85% of the sites under the influence of RIP3 and RIP8, two moderately important mitochondrial factors, are also controlled by RIP1. Previously uncharacterized RIP family members were found to have only a slight effect on RNA editing. The preferential location of editing sites controlled by RIP7 on some transcripts suggests an RNA metabolism function for this factor other than editing. In addition to a complete characterization of the RIP factors for their effect on RNA editing, our study highlights the potential of RNA-seq for studying plant organelle editing. Unlike previous attempts to use RNA-seq to analyze RNA editing extent, our methodology focuses on sequencing of organelle cDNAs corresponding to known transcripts. As a result, the depth of coverage of each editing site reaches unprecedented values, assuring a reliable measurement of editing extent and the detection of numerous new sites. This strategy can be applied to the study of RNA editing in any organism. PMID- 23818872 TI - Extensive intra-kingdom horizontal gene transfer converging on a fungal fructose transporter gene. AB - Comparative genomics revealed in the last decade a scenario of rampant horizontal gene transfer (HGT) among prokaryotes, but for fungi a clearly dominant pattern of vertical inheritance still stands, punctuated however by an increasing number of exceptions. In the present work, we studied the phylogenetic distribution and pattern of inheritance of a fungal gene encoding a fructose transporter (FSY1) with unique substrate selectivity. 109 FSY1 homologues were identified in two sub phyla of the Ascomycota, in a survey that included 241 available fungal genomes. At least 10 independent inter-species instances of horizontal gene transfer (HGT) involving FSY1 were identified, supported by strong phylogenetic evidence and synteny analyses. The acquisition of FSY1 through HGT was sometimes suggestive of xenolog gene displacement, but several cases of pseudoparalogy were also uncovered. Moreover, evidence was found for successive HGT events, possibly including those responsible for transmission of the gene among yeast lineages. These occurrences do not seem to be driven by functional diversification of the Fsy1 proteins because Fsy1 homologues from widely distant lineages, including at least one acquired by HGT, appear to have similar biochemical properties. In summary, retracing the evolutionary path of the FSY1 gene brought to light an unparalleled number of independent HGT events involving a single fungal gene. We propose that the turbulent evolutionary history of the gene may be linked to the unique biochemical properties of the encoded transporter, whose predictable effect on fitness may be highly variable. In general, our results support the most recent views suggesting that inter-species HGT may have contributed much more substantially to shape fungal genomes than heretofore assumed. PMID- 23818873 TI - H-NS can facilitate specific DNA-binding by RNA polymerase in AT-rich gene regulatory regions. AB - Extremely AT-rich DNA sequences present a challenging template for specific recognition by RNA polymerase. In bacteria, this is because the promoter -10 hexamer, the major DNA element recognised by RNA polymerase, is itself AT-rich. We show that Histone-like Nucleoid Structuring (H-NS) protein can facilitate correct recognition of a promoter by RNA polymerase in AT-rich gene regulatory regions. Thus, at the Escherichia coli ehxCABD operon, RNA polymerase is unable to distinguish between the promoter -10 element and similar overlapping sequences. This problem is resolved in native nucleoprotein because the overlapping sequences are masked by H-NS. Our work provides mechanistic insight into nucleoprotein structure and its effect on protein-DNA interactions in prokaryotic cells. PMID- 23818874 TI - Functional analysis of neuronal microRNAs in Caenorhabditis elegans dauer formation by combinational genetics and Neuronal miRISC immunoprecipitation. AB - Identifying the physiological functions of microRNAs (miRNAs) is often challenging because miRNAs commonly impact gene expression under specific physiological conditions through complex miRNA::mRNA interaction networks and in coordination with other means of gene regulation, such as transcriptional regulation and protein degradation. Such complexity creates difficulties in dissecting miRNA functions through traditional genetic methods using individual miRNA mutations. To investigate the physiological functions of miRNAs in neurons, we combined a genetic "enhancer" approach complemented by biochemical analysis of neuronal miRNA-induced silencing complexes (miRISCs) in C. elegans. Total miRNA function can be compromised by mutating one of the two GW182 proteins (AIN-1), an important component of miRISC. We found that combining an ain-1 mutation with a mutation in unc-3, a neuronal transcription factor, resulted in an inappropriate entrance into the stress-induced, alternative larval stage known as dauer, indicating a role of miRNAs in preventing aberrant dauer formation. Analysis of this genetic interaction suggests that neuronal miRNAs perform such a role partly by regulating endogenous cyclic guanosine monophosphate (cGMP) signaling, potentially influencing two other dauer-regulating pathways. Through tissue specific immunoprecipitations of miRISC, we identified miRNAs and their likely target mRNAs within neuronal tissue. We verified the biological relevance of several of these miRNAs and found that many miRNAs likely regulate dauer formation through multiple dauer-related targets. Further analysis of target mRNAs suggests potential miRNA involvement in various neuronal processes, but the importance of these miRNA::mRNA interactions remains unclear. Finally, we found that neuronal genes may be more highly regulated by miRNAs than intestinal genes. Overall, our study identifies miRNAs and their targets, and a physiological function of these miRNAs in neurons. It also suggests that compromising other aspects of gene expression, along with miRISC, can be an effective approach to reveal miRNA functions in specific tissues under specific physiological conditions. PMID- 23818875 TI - DeepSAGE reveals genetic variants associated with alternative polyadenylation and expression of coding and non-coding transcripts. AB - Many disease-associated variants affect gene expression levels (expression quantitative trait loci, eQTLs) and expression profiling using next generation sequencing (NGS) technology is a powerful way to detect these eQTLs. We analyzed 94 total blood samples from healthy volunteers with DeepSAGE to gain specific insight into how genetic variants affect the expression of genes and lengths of 3'-untranslated regions (3'-UTRs). We detected previously unknown cis-eQTL effects for GWAS hits in disease- and physiology-associated traits. Apart from cis-eQTLs that are typically easily identifiable using microarrays or RNA sequencing, DeepSAGE also revealed many cis-eQTLs for antisense and other non coding transcripts, often in genomic regions containing retrotransposon-derived elements. We also identified and confirmed SNPs that affect the usage of alternative polyadenylation sites, thereby potentially influencing the stability of messenger RNAs (mRNA). We then combined the power of RNA-sequencing with DeepSAGE by performing a meta-analysis of three datasets, leading to the identification of many more cis-eQTLs. Our results indicate that DeepSAGE data is useful for eQTL mapping of known and unknown transcripts, and for identifying SNPs that affect alternative polyadenylation. Because of the inherent differences between DeepSAGE and RNA-sequencing, our complementary, integrative approach leads to greater insight into the molecular consequences of many disease associated variants. PMID- 23818876 TI - The drive to strive: goal generation based on current needs. AB - Hungry animals are influenced by a multitude of different factors when foraging for sustenance. Much of the work on animal foraging has focused on factors relating to the amount of time and energy animals expend searching for and harvesting foods. Models that emphasize such factors have been invaluable in determining when it is beneficial for an animal to search for pastures new. When foraging, however, animals also have to determine how to direct their search. For what food should they forage? There is no point searching for more of a particular food when you are sated from eating it. Here we review work in macaques and humans that has sought to reveal the neural circuits critical for determining the subjective value of different foods and associated objects in our environment and tracking this value over time. There is mounting evidence that a network composed of the orbitofrontal cortex (OFC), amygdala, and medial thalamus is critical for linking objects in the environment with food value and adjusting those valuations in real time based on current biological needs. Studies using temporary inactivation methods have revealed that the amygdala and OFC play distinct yet complementary roles in this valuation process. Such a network for determining the subjective value of different foods and, by extension, associated objects, must interact with systems that determine where and for how long to forage. Only by efficiently incorporating these two factors into their decisions will animals be able to achieve maximal fitness. PMID- 23818877 TI - Visual encoding and fixation target selection in free viewing: presaccadic brain potentials. AB - In scrutinizing a scene, the eyes alternate between fixations and saccades. During a fixation, two component processes can be distinguished: visual encoding and selection of the next fixation target. We aimed to distinguish the neural correlates of these processes in the electrical brain activity prior to a saccade onset. Participants viewed color photographs of natural scenes, in preparation for a change detection task. Then, for each participant and each scene we computed an image heat map, with temperature representing the duration and density of fixations. The temperature difference between the start and end points of saccades was taken as a measure of the expected task-relevance of the information concentrated in specific regions of a scene. Visual encoding was evaluated according to whether subsequent change was correctly detected. Saccades with larger temperature difference were more likely to be followed by correct detection than ones with smaller temperature differences. The amplitude of presaccadic activity over anterior brain areas was larger for correct detection than for detection failure. This difference was observed for short "scrutinizing" but not for long "explorative" saccades, suggesting that presaccadic activity reflects top-down saccade guidance. Thus, successful encoding requires local scanning of scene regions which are expected to be task-relevant. Next, we evaluated fixation target selection. Saccades "moving up" in temperature were preceded by presaccadic activity of higher amplitude than those "moving down". This finding suggests that presaccadic activity reflects attention deployed to the following fixation location. Our findings illustrate how presaccadic activity can elucidate concurrent brain processes related to the immediate goal of planning the next saccade and the larger-scale goal of constructing a robust representation of the visual scene. PMID- 23818878 TI - Agency matters! Social preferences in the three-person ultimatum game. AB - In the present study EEG was recorded simultaneously while two participants were playing the three-person ultimatum game (UG). Both participants received different offers from changing proposers about how to split up a certain amount of money between the three players. One of the participants had no say, whereas the other, the responder, was able to harm the payoff of all other players. The aim of the study was to investigate how the outcomes of the respective other are evaluated by participants who were treated fairly or unfairly themselves and to what extent agency influences concerns for fairness. Analyses were focused on the medial frontal negativity (MFN) as an early index for subjective value assignment. Recipients with veto-power exhibited enhanced, more negative-going, MFN amplitudes following proposals that comprised a low share for both recipients, suggesting that responders favored offers with a fair amount to at least one of the two players. Though, the powerless players cared about the amount assigned to the responder, MFN amplitudes were larger following fair compared to unfair offers assigned to the responder. Similarly, concerns for fairness which determined the amplitude of the MFN, suggested that the powerless players exhibited negative and conversely the responders, positive social preferences. PMID- 23818879 TI - Behavioral evidence for inter-hemispheric cooperation during a lexical decision task: a divided visual field experiment. AB - HIGHLIGHTSThe redundant bilateral visual presentation of verbal stimuli decreases asymmetry and increases the cooperation between the two hemispheres.The increased cooperation between the hemispheres is related to semantic information during lexical processing.The inter-hemispheric interaction is represented by both inhibition and cooperation. This study explores inter-hemispheric interaction (IHI) during a lexical decision task by using a behavioral approach, the bilateral presentation of stimuli within a divided visual field experiment. Previous studies have shown that compared to unilateral presentation, the bilateral redundant (BR) presentation decreases the inter-hemispheric asymmetry and facilitates the cooperation between hemispheres. However, it is still poorly understood which type of information facilitates this cooperation. In the present study, verbal stimuli were presented unilaterally (left or right visual hemi field successively) and bilaterally (left and right visual hemi-field simultaneously). Moreover, during the bilateral presentation of stimuli, we manipulated the relationship between target and distractors in order to specify the type of information which modulates the IHI. Thus, three types of information were manipulated: perceptual, semantic, and decisional, respectively named pre lexical, lexical and post-lexical processing. Our results revealed left hemisphere (LH) lateralization during the lexical decision task. In terms of inter-hemisphere interaction, the perceptual and decision-making information increased the inter-hemispheric asymmetry, suggesting the inhibition of one hemisphere upon the other. In contrast, semantic information decreased the inter hemispheric asymmetry, suggesting cooperation between the hemispheres. We discussed our results according to current models of IHI and concluded that cerebral hemispheres interact and communicate according to various excitatory and inhibitory mechanisms, all which depend on specific processes and various levels of word processing. PMID- 23818880 TI - Spatial working memory deficits represent a core challenge for rehabilitating neglect. AB - Left neglect following right hemisphere injury is a debilitating disorder that has proven extremely difficult to rehabilitate. Traditional models of neglect have focused on impaired spatial attention as the core deficit and as such, most rehabilitation methods have tried to improve attentional processes. However, many of these techniques (e.g., visual scanning training, caloric stimulation, neck muscle vibration) produce only short-lived effects, or are too uncomfortable to use as a routine treatment. More recently, many investigators have begun examining the beneficial effects of prism adaptation for the treatment of neglect. Although prism adaptation has been shown to have some beneficial effects on both overt and covert spatial attention, it does not reliably alter many of the perceptual biases evident in neglect. One of the challenges of neglect rehabilitation may lie in the heterogeneous nature of the deficits. Most notably, a number of researchers have shown that neglect patients present with severe deficits in spatial working memory (SWM) in addition to their attentional impairments. Given that SWM can be seen as a foundational cognitive mechanism, critical for a wide range of other functions, any deficit in SWM memory will undoubtedly have severe consequences. In the current review we examine the evidence for SWM deficits in neglect and propose that it constitutes a core component of the syndrome. We present preliminary data which suggest that at least one current rehabilitation method (prism adaptation) has no effect on SWM deficits in neglect. Finally, we end by reviewing recent work that examines the effectiveness of SWM training and how SWM training may prove to be a useful avenue for future rehabilitative efforts in patients with neglect. PMID- 23818883 TI - Modeling speech imitation and ecological learning of auditory-motor maps. AB - Classical models of speech consider an antero-posterior distinction between perceptive and productive functions. However, the selective alteration of neural activity in speech motor centers, via transcranial magnetic stimulation, was shown to affect speech discrimination. On the automatic speech recognition (ASR) side, the recognition systems have classically relied solely on acoustic data, achieving rather good performance in optimal listening conditions. The main limitations of current ASR are mainly evident in the realistic use of such systems. These limitations can be partly reduced by using normalization strategies that minimize inter-speaker variability by either explicitly removing speakers' peculiarities or adapting different speakers to a reference model. In this paper we aim at modeling a motor-based imitation learning mechanism in ASR. We tested the utility of a speaker normalization strategy that uses motor representations of speech and compare it with strategies that ignore the motor domain. Specifically, we first trained a regressor through state-of-the-art machine learning techniques to build an auditory-motor mapping, in a sense mimicking a human learner that tries to reproduce utterances produced by other speakers. This auditory-motor mapping maps the speech acoustics of a speaker into the motor plans of a reference speaker. Since, during recognition, only speech acoustics are available, the mapping is necessary to "recover" motor information. Subsequently, in a phone classification task, we tested the system on either one of the speakers that was used during training or a new one. Results show that in both cases the motor-based speaker normalization strategy slightly but significantly outperforms all other strategies where only acoustics is taken into account. PMID- 23818881 TI - Connexin diversity in the heart: insights from transgenic mouse models. AB - Cardiac conduction is mediated by gap junction channels that are formed by connexin (Cx) protein subunits. The connexin family of proteins consists of more than 20 members varying in their biophysical properties and ability to combine with other connexins into heteromeric gap junction channels. The mammalian heart shows regional differences both in connexin expression profile and in degree of electrical coupling. The latter reflects functional requirements for conduction velocity which needs to be low in the sinoatrial and atrioventricular nodes and high in the ventricular conduction system. Over the past 20 years knowledge of the biology of gap junction channels and their role in the genesis of cardiac arrhythmias has increased enormously. This review focuses on the insights gained from transgenic mouse models. The mouse heart expresses Cx30, 30.2, 37, 40, 43, 45, and 46. For these connexins a variety of knock-outs, heart-specific knock outs, conditional knock-outs, double knock-outs, knock-ins and overexpressors has been studied. We discuss the cardiac phenotype in these models and compare Cx expression between mice and men. Mouse models have enhanced our understanding of (patho)-physiological implications of Cx diversity in the heart. In principle connexin-specific modulation of electrical coupling in the heart represents an interesting treatment strategy for cardiac arrhythmias and conduction disorders. PMID- 23818885 TI - Beliefs in conspiracy theories and the need for cognitive closure. AB - An important component of conspiracy theories is how they influence, and are influenced by, the evaluation of potential evidence. Some individuals may be more open minded regarding certain explanations for events whereas others may seek closure and thus cut off a conspiracy explanation. Two studies examined the relationship between the need for cognitive closure (NFCC), levels of belief in real world conspiracy theories, and the attribution of conspiracy theories to explain events. A first, small (N = 30) and preliminary study found no relationship between NFCC and beliefs in conspiracy theories, suggesting that both advocates and opponents of conspiracy explanations do not differ on this dimension. A second study (N = 86) revealed that evidence for and against conspiracy theories had an influence on attributions of the likelihood of a conspiracy to explain a novel event. Specifically, after reading evidence individuals with high levels of belief in conspiracy theories tended to rate a conspiracy explanation as more likely whereas those with low levels of belief rated it as less likely. However, when the need for cognitive closure (NFCC) was experimentally lowered the effects of prior beliefs in conspiracy theories diminished. PMID- 23818882 TI - The Interplay between the Hippocampus and Amygdala in Regulating Aberrant Hippocampal Neurogenesis during Protracted Abstinence from Alcohol Dependence. AB - The development of alcohol dependence involves elevated anxiety, low mood, and increased sensitivity to stress, collectively labeled negative affect. Particularly interesting is the recent accumulating evidence that sensitized extrahypothalamic stress systems [e.g., hyperglutamatergic activity, blunted hypothalamic-pituitary-adrenal (HPA) hormonal levels, altered corticotropin releasing factor signaling, and altered glucocorticoid receptor signaling in the extended amygdala] are evident in withdrawn dependent rats, supporting the hypothesis that pathological neuroadaptations in the extended amygdala contribute to the negative affective state. Notably, hippocampal neurotoxicity observed as aberrant dentate gyrus (DG) neurogenesis (neurogenesis is a process where neural stem cells in the adult hippocampal subgranular zone generate DG granule cell neurons) and DG neurodegeneration are observed in withdrawn dependent rats. These correlations between withdrawal and aberrant neurogenesis in dependent rats suggest that alterations in the DG could be hypothesized to be due to compromised HPA axis activity and associated hyperglutamatergic activity originating from the basolateral amygdala in withdrawn dependent rats. This review discusses a possible link between the neuroadaptations in the extended amygdala stress systems and the resulting pathological plasticity that could facilitate recruitment of new emotional memory circuits in the hippocampus as a function of aberrant DG neurogenesis. PMID- 23818886 TI - Commercial conspiracy theories: a pilot study. AB - There are many ways to categorise conspiracy theories. In the present study, we examined individual and demographic predictors of beliefs in commercial conspiracy theories among a British sample of over 300 women and men. Results showed many people were cynical and sceptical with regard to advertising tricks, as well as the tactics of organisations like banks and alcohol, drug and tobacco companies. Beliefs sorted into four identifiable clusters, labelled sneakiness, manipulative, change-the-rules and suppression/prevention. The high alpha for the overall scale suggested general beliefs in commercial conspiracy. Regressions suggested that those people who were less religious, more left-wing, more pessimistic, less (self-defined as) wealthy, less Neurotic and less Open-to Experience believed there was more commercial conspiracy. Overall the individual difference variables explained relatively little of the variance in these beliefs. The implications of these findings for the literature on conspiracy theories are discussed. Limitations of the study are also discussed. PMID- 23818884 TI - Beyond "somatization" and "psychologization": symptom-level variation in depressed Han Chinese and Euro-Canadian outpatients. AB - The finding that people of Chinese heritage tend to emphasize somatic rather than psychological symptoms of depression has frequently been discussed in the culture and mental health literature since the 1970s. Recent studies have confirmed that Chinese samples report more somatic and fewer psychological depression symptoms compared to "Western" samples. The question remains, however, as to whether or not these effects are attributable to variation in all the constituent symptoms or to a subset. If the latter, there is the additional possibility that some symptoms might show a divergent pattern. Such findings would have implications for how cultural variations in symptom presentation are interpreted, and would also inform the cultural study of affective experiences more broadly. The current study addressed these issues in Chinese (n = 175) and Euro-Canadian (n = 107) psychiatric outpatients originally described by Ryder et al. (2008). Differential item functioning (DIF) was used to examine whether specific somatic and psychological symptoms diverged from the overall patterns of cultural variation. Chi-square analyses were used to examine atypical somatic symptoms (e.g., hypersomnia), previously neglected in this literature. No DIF was observed for the typical somatic symptoms, but Euro-Canadians reported greater levels of atypical somatic symptoms, and showed higher rates of atypical depression. DIF was observed for psychological symptoms-the Chinese reported high levels of "suppressed emotions" and "depressed mood," relative to their overall psychological symptom reporting. Chinese outpatients also spontaneously reported "depressed mood" at similar levels as the Euro-Canadians, contrary to prevailing ideas about Chinese unwillingness to discuss depression. Overall, the findings provide a more nuanced picture of how culture shapes symptom presentation and point toward future studies designed to unpack cultural variation in narrower subsets of depressive symptoms. PMID- 23818887 TI - Neuropsychological functioning in late-life depression. AB - BACKGROUND: The literature describing neurocognitive function in patients with late-life depression (LLD) show inconsistent findings in regard to incidence and main deficits. Reduced information processing speed is in some studies found to explain deficits in higher order cognitive function, while other studies report specific deficits in memory and executive function. Our aim was to determine the characteristics of neuropsychological functioning in non-demented LLD patients. METHODS: A comprehensive neuropsychological battery was administered to a group of hospitalized LLD patients and healthy control (HC) subjects. Thirty-nine patients without dementia, 60 years or older meeting DSM-IV criteria for current episode of major depression, and 18 non-depressed control subjects were included. The patient group was characterized by having a long lasting current depressive episode of late-onset depression and by being non-responders to treatment with antidepressants. Neurocognitive scores were calculated for the domains of information processing speed, verbal memory, visuospatial memory, executive function, and language. Number of impairments (performance below the 10th percentile of the control group per domain) for each participant was calculated. RESULTS: Nearly half of the patients had a clinically significant cognitive impairment in at least one neurocognitive domain. Relative to HC subjects, LLD patients performed significantly poorer in the domains of information processing speed and executive function. Executive abilities were most frequently impaired in the patient group (39% of the patients). Even when controlling for differences in processing speed, patients showed more executive deficits than controls. CONCLUSIONS: Controlling for processing speed, patients still showed impaired executive function compared to HCs. Reduced executive function thus appears to be the core neurocognitive deficit in LLD. Executive function seems to be an umbrella concept for several connected but distinct cognitive functions. Further studies of neuropsychological functioning in LLD patients are needed to characterize more specific what kinds of executive impairments patients have. Additional studies of remitted LLD patients are needed to separate episode related and persistent impairments. PMID- 23818889 TI - Tomato fruits: a good target for iodine biofortification. AB - IODINE IS A TRACE ELEMENT THAT IS FUNDAMENTAL FOR HUMAN HEALTH: its deficiency affects about two billion people worldwide. Fruits and vegetables are usually poor sources of iodine; however, plants can accumulate iodine if it is either present or exogenously administered to the soil. The biofortification of crops with iodine has therefore been proposed as a strategy for improving human nutrition. A greenhouse pot experiment was carried out to evaluate the possibility of biofortifying tomato fruits with iodine. Increasing concentrations of iodine supplied as KI or KIO3 were administered to plants as root treatments and the iodine accumulation in fruits was measured. The influences of the soil organic matter content or the nitrate level in the nutritive solution were analyzed. Finally, yield and qualitative properties of the biofortified tomatoes were considered, as well as the possible influence of fruit storage and processing on the iodine content. Results showed that the use of both the iodized salts induced a significant increase in the fruit's iodine content in doses that did not affect plant growth and development. The final levels ranged from a few mg up to 10 mg iodine kg (-) (1) fruit fresh weight and are more than adequate for a biofortification program, since 150 MUg iodine per day is the recommended dietary allowance for adults. In general, the iodine treatments scarcely affected fruit appearance and quality, even with the highest concentrations applied. In contrast, the use of KI in plants fertilized with low doses of nitrate induced moderate phytotoxicity symptoms. Organic matter-rich soils improved the plant's health and production, with only mild reductions in iodine stored in the fruits. Finally, a short period of storage at room temperature or a 30-min boiling treatment did not reduce the iodine content in the fruits, if the peel was maintained. All these results suggest that tomato is a particularly suitable crop for iodine biofortification programs. PMID- 23818891 TI - Lipid signaling in plants. PMID- 23818890 TI - Integrating nitric oxide into salicylic acid and jasmonic acid/ ethylene plant defense pathways. AB - Plant defense against pests and pathogens is known to be conferred by either salicylic acid (SA) or jasmonic acid (JA)/ethylene (ET) pathways, depending on infection or herbivore-grazing strategy. It is well attested that SA and JA/ET pathways are mutually antagonistic allowing defense responses to be tailored to particular biotic stresses. Nitric oxide (NO) has emerged as a major signal influencing resistance mediated by both signaling pathways but no attempt has been made to integrate NO into established SA/JA/ET interactions. NO has been shown to act as an inducer or suppressor of signaling along each pathway. NO will initiate SA biosynthesis and nitrosylate key cysteines on TGA-class transcription factors to aid in the initiation of SA-dependent gene expression. Against this, S nitrosylation of NONEXPRESSOR OF PATHOGENESIS-RELATED PROTEINS1 (NPR1) will promote the NPR1 oligomerization within the cytoplasm to reduce TGA activation. In JA biosynthesis, NO will initiate the expression of JA biosynthetic enzymes, presumably to over-come any antagonistic effects of SA on JA-mediated transcription. NO will also initiate the expression of ET biosynthetic genes but a suppressive role is also observed in the S-nitrosylation and inhibition of S adenosylmethionine transferases which provides methyl groups for ET production. Based on these data a model for NO action is proposed but we have also highlighted the need to understand when and how inductive and suppressive steps are used. PMID- 23818888 TI - Thymic versus induced regulatory T cells - who regulates the regulators? AB - Physiological health must balance immunological responsiveness against foreign pathogens with tolerance toward self-components and commensals. Disruption of this balance causes autoimmune diseases/chronic inflammation, in case of excessive immune responses, and persistent infection/immunodeficiency if regulatory components are overactive. This homeostasis occurs at two different levels: at a resting state to prevent autoimmune disease, as autoreactive effector T-cells (Teffs) are only partially deleted in the thymus, and during inflammation to prevent excessive tissue injury, contract the immune response, and enable tissue repair. Adaptive immune cells with regulatory function ("regulatory T-cells") are essential to control Teffs. Two sets of regulatory T cell are required to achieve the desired control: those emerging de novo from embryonic/neonatal thymus ("thymic" or tTregs), whose function is to control autoreactive Teffs to prevent autoimmune diseases, and those induced in the periphery ("peripheral" or pTregs) to acquire regulatory phenotype in response to pathogens/inflammation. The differentiation mechanisms of these cells determine their commitment to lineage and plasticity toward other phenotypes. tTregs, expressing high levels of IL-2 receptor alpha chain (CD25), and the transcription factor Foxp3, are the most important, since mutations or deletions in these genes cause fatal autoimmune diseases in both mice and men. In the periphery, instead, Foxp3(+) pTregs can be induced from naive precursors in response to environmental signals. Here, we discuss molecular signatures and induction processes, mechanisms and sites of action, lineage stability, and differentiating characteristics of both Foxp3(+) and Foxp3(-) populations of regulatory T cells, derived from the thymus or induced peripherally. We relate these predicates to programs of cell-based therapy for the treatment of autoimmune diseases and induction of tolerance to transplants. PMID- 23818892 TI - Resistance to sap-sucking insects in modern-day agriculture. AB - Plants and herbivores have co-evolved in their natural habitats for about 350 million years, but since the domestication of crops, plant resistance against insects has taken a different turn. With the onset of monoculture-driven modern agriculture, selective pressure on insects to overcome resistances has dramatically increased. Therefore plant breeders have resorted to high-tech tools to continuously create new insect-resistant crops. Efforts in the past 30 years have resulted in elucidation of mechanisms of many effective plant defenses against insect herbivores. Here, we critically appraise these efforts and - with a focus on sap-sucking insects - discuss how these findings have contributed to herbivore-resistant crops. Moreover, in this review we try to assess where future challenges and opportunities lay ahead. Of particular importance will be a mandatory reduction in systemic pesticide usage and thus a greater reliance on alternative methods, such as improved plant genetics for plant resistance to insect herbivores. PMID- 23818894 TI - The role of the nervous system in aging and longevity. PMID- 23818895 TI - Corneal Sublayers Thickness Estimation Obtained by High-Resolution FD-OCT. AB - This paper presents a novel processing technique which can be applied to corneal in vivo images obtained with optical coherence tomograms across the central meridian of the cornea. The method allows to estimate the thickness of the corneal sublayers (Epithelium, Bowman's layer, Stroma, Endothelium, and whole corneal thickness) at any location, including the center and the midperiphery, on both nasal and temporal sides. The analysis is carried out on both the pixel and subpixel scales to reduce the uncertainty in thickness estimations. This technique allows quick and noninvasive assessment of patients. As an example of application and validation, we present the results obtained from the analysis of 52 healthy subjects, each with 3 scans per eye, for a total of more than 300 images. Particular attention has been paid to the statistical interpretation of the obtained results to find a representative assessment of each sublayer's thickness. PMID- 23818893 TI - The role of K(+) channels in uptake and redistribution of potassium in the model plant Arabidopsis thaliana. AB - Potassium (K(+)) is inevitable for plant growth and development. It plays a crucial role in the regulation of enzyme activities, in adjusting the electrical membrane potential and the cellular turgor, in regulating cellular homeostasis and in the stabilization of protein synthesis. Uptake of K(+) from the soil and its transport to growing organs is essential for a healthy plant development. Uptake and allocation of K(+) are performed by K(+) channels and transporters belonging to different protein families. In this review we summarize the knowledge on the versatile physiological roles of plant K(+) channels and their behavior under stress conditions in the model plant Arabidopsis thaliana. PMID- 23818896 TI - Radionuclide small intestine imaging. AB - The aim of this overview article is to present the current possibilities of radionuclide scintigraphic small intestine imaging. Nuclear medicine has a few methods-scintigraphy with red blood cells labelled by means of (99m)Tc for detection of the source of bleeding in the small intestine, Meckel's diverticulum scintigraphy for detection of the ectopic gastric mucosa, radionuclide somatostatin receptor imaging for carcinoid, and radionuclide inflammation imaging. Video capsule or deep enteroscopy is the method of choice for detection of most lesions in the small intestine. Small intestine scintigraphies are only a complementary imaging method and can be successful, for example, for the detection of the bleeding site in the small intestine, ectopic gastric mucosa, carcinoid and its metastasis, or inflammation. Radionuclide scintigraphic small intestine imaging is an effective imaging modality in the localisation of small intestine lesions for patients in whom other diagnostic tests have failed to locate any lesions or are not available. PMID- 23818897 TI - Comparison of efficiencies of michigan neuropathy screening instrument, neurothesiometer, and electromyography for diagnosis of diabetic neuropathy. AB - Aim. This study compares the effectiveness of Michigan Neuropathy Screening Instrument (MNSI), neurothesiometer, and electromyography (EMG) in detecting diabetic peripheral neuropathy in patients with diabetes type 2. Materials and Methods. 106 patients with diabetes type 2 treated at the outpatient clinic of Ankara Numune Education and Research Hospital Department of Endocrinology between September 2008 and May 2009 were included in this study. Patients were evaluated by glycemic regulation tests, MNSI (questionnaire and physical examination), EMG (for detecting sensorial and motor defects in right median, ulnar, posterior tibial, and bilateral sural nerves), and neurothesiometer (for detecting alterations in cold and warm sensations as well as vibratory sensations). Results. According to the MNSI score, there was diabetic peripheral neuropathy in 34 (32.1%) patients (score >=2.5). However, when the patients were evaluated by EMG and neurothesiometer, neurological impairments were detected in 49 (46.2%) and 79 (74.5%) patients, respectively. Conclusion. According to our findings, questionnaires and physical examination often present lower diabetic peripheral neuropathy prevalence. Hence, we recommend that in the evaluation of diabetic patients neurological tests should be used for more accurate results and thus early treatment options to prevent neuropathic complications. PMID- 23818898 TI - The ETS-Domain Transcription Factor Elk-1 Regulates COX-2 Gene Expression and Inhibits Glucose-Stimulated Insulin Secretion in the Pancreatic beta -Cell Line INS-1. AB - Cyclooxygenase-2 (COX-2) expression is associated with many aspects of physiological and pathological conditions, including pancreatic beta -cell dysfunction. Prostaglandin E2 (PGE2) production, as a consequence of COX-2 gene induction, has been reported to impair beta -cell function. The molecular mechanisms involved in the regulation of COX-2 gene expression are not fully understood. We previously demonstrated that transcription factor Elk-1 significantly upregulated COX-2 gene promoter activity. In this report, we used pancreatic beta -cell line (INS-1) to explore the relationships between Elk-1 and COX-2. We first investigated the effects of Elk-1 on COX-2 transcriptional regulation and expression in INS-1 cells. We thus undertook to study the binding of Elk-1 to its putative binding sites in the COX-2 promoter. We also analysed glucose-stimulated insulin secretion (GSIS) in INS-1 cells that overexpressed Elk 1. Our results demonstrate that Elk-1 efficiently upregulates COX-2 expression at least partly through directly binding to the -82/-69 region of COX-2 promoter. Overexpression of Elk-1 inhibits GSIS in INS-1 cells. These findings will be helpful for better understanding the transcriptional regulation of COX-2 in pancreatic beta -cell. Moreover, Elk-1, the transcriptional regulator of COX-2 expression, will be a potential target for the prevention of beta -cell dysfunction mediated by PGE2. PMID- 23818899 TI - Tissue banking, bioinformatics, and electronic medical records: the front-end requirements for personalized medicine. AB - Personalized medicine promises patient-tailored treatments that enhance patient care and decrease overall treatment costs by focusing on genetics and "-omics" data obtained from patient biospecimens and records to guide therapy choices that generate good clinical outcomes. The approach relies on diagnostic and prognostic use of novel biomarkers discovered through combinations of tissue banking, bioinformatics, and electronic medical records (EMRs). The analytical power of bioinformatic platforms combined with patient clinical data from EMRs can reveal potential biomarkers and clinical phenotypes that allow researchers to develop experimental strategies using selected patient biospecimens stored in tissue banks. For cancer, high-quality biospecimens collected at diagnosis, first relapse, and various treatment stages provide crucial resources for study designs. To enlarge biospecimen collections, patient education regarding the value of specimen donation is vital. One approach for increasing consent is to offer publically available illustrations and game-like engagements demonstrating how wider sample availability facilitates development of novel therapies. The critical value of tissue bank samples, bioinformatics, and EMR in the early stages of the biomarker discovery process for personalized medicine is often overlooked. The data obtained also require cross-disciplinary collaborations to translate experimental results into clinical practice and diagnostic and prognostic use in personalized medicine. PMID- 23818900 TI - Pressure shift freezing as potential alternative for generation of decellularized scaffolds. AB - Background. Protocols using chemical reagents for scaffold decellularization can cause changes in the properties of the matrix, depending on the type of tissue and the chemical reagent. Technologies using physical techniques may be possible alternatives for the production grafts with potential superior matrix characteristics. Material and Methods. We tested four different technologies for scaffold decellularization. Group 1: high hydrostatic pressure (HHP), 1 GPa; Group 2: pressure shift freezing (PSF); Group 3: pulsed electric fields (PEF); Group 4: control group: detergent (SDS). The degree of decellularization was assessed by histological analysis and the measurement of residual DNA. Results. Tissue treated with PSF showed a decellularization with a penetration depth (PD) of 1.5 mm and residual DNA content of 24% +/- 3%. HHD treatment caused a PD of 0.2 mm with a residual DNA content of 28% +/- .4%. PD in PEF was 0.5 mm, and the residual DNA content was 49% +/- 7%. In the SDS group, PD was found to be 5 mm, and the DNA content was determined at 5% +/- 2%. Conclusion. PSF showed promising results as a possible technique for scaffold decellularization. The penetration depth of PSF has to be optimized, and the mechanical as well as the biological characteristics of decellularized grafts have to be evaluated. PMID- 23818901 TI - Goiter and laryngeal sensory neuropathy. AB - Objective. Examining the prevalence of laryngeal sensory neuropathy (LSN) in goiter patients versus a control group. Study Design. Cross-sectional study. Methods. 33 Goiter patients were enrolled versus 25 age-matched controls. TSH levels, size of thyroid gland, and presence or absence of thyroid nodules were reported. Subjects were asked about the presence or absence of any of the following symptoms: cough, globus pharyngeus, and/or throat clearing that persistented for more than 6 weeks. The presence of one or more of these symptoms for at least six weeks in the absence of LPRD, allergy, asthma, ACE inhibitor intake, and psychogenic disorder was defined as LSN. Results. For goitrous patients mean age (years) was (41.73 +/- 9.47) versus (37.44 +/- 10.89) for controls. 82% goitrous patients had known nodules and 27% carried a simultaneous diagnosis of hypothyroidism. Among those with documented size (61%), mean total thyroid volume was 26.996 +/- 14.852 cm(3), with a range from 9.430 to 67.022 cm(3). The overall prevalence of LSN among goitrous patients was 42% versus 12% among controls (P = 0.0187). There was no correlation between LSN, size of thyroid gland, and TSH level. Conclusion. The prevalence of LSN in goitrous patients is significantly higher than that in a nongoitrous population. PMID- 23818902 TI - Sphingosine kinase: a novel putative target for the prevention of infection triggered preterm birth. AB - Preterm birth is defined as any delivery before 37 complete weeks of gestation. It is a universal challenge in the field of obstetrics owing to its high rate of mortality, long-term morbidity, associated human suffering and economic burden. In the United States, about 12.18% deliveries in 2009 were preterm, producing an exorbitant cost of $5.8 billion. Infection-associated premature rupture of membranes (PROM) accounts for 40% of extremely preterm births (<28 weeks of gestation). Major research efforts are directed towards improving the understanding of the pathophysiology of preterm birth and ways to prevent or at least postpone delivery. Endothelin-1 (ET-1) is a potent vasoconstrictor that plays a significant role in infection-triggered preterm birth. Its involvement in a number of pathological mechanisms and its elevation in preterm delivered amniotic fluid samples implicate it in preterm birth. Sphingosine kinase (SphK) is a ubiquitous enzyme responsible for the production of sphingosine-1-phosphate (S1P). S1P acts as second messenger in a number of cell proliferation and survival pathways. SphK is found to play a key role in ET-1 mediated myometrial contraction. This review highlights SphK as a prospective target with great potential to prevent preterm birth. PMID- 23818903 TI - The Rare Case of a Probably True IgE-Mediated Allergy to Local Anaesthetics. AB - The majority of immediate type adverse reactions to local anaesthetics seem to be non-IgE-mediated. We report a case of a 31-year-old woman, who developed conjunctivitis and conjunctival erythema immediately after intrauterine application of a local anaesthetic. Skin prick testing and intradermal testing were done with lidocaine, mepivacaine, and procaine. Intradermal testing showed positive reactions to mepivacaine (1 : 10), undiluted lidocaine, and procaine (1 : 10 and undiluted). Specific IgE could be detected against mepivacaine, but not against latex. Serum tryptase was in the normal range. In order to rule out the exceptional case of a true IgE-mediated reaction, allergy testing with local anaesthetics is still required in the workup of patients. PMID- 23818904 TI - Obstructive jaundice as an initial manifestation of non-hodgkin lymphoma: treatment dilemma and high mortality. AB - Introduction. Non Hodgkin lymphoma (NHL) presenting with obstructive jaundice is a rare occurrence. Because of rarity of combination, it is seldom considered in differential diagnosis of patients presenting with obstructive jaundice. It is considered treatable due to the chemosensitive nature of the disease and the recent advances in chemotherapy. Case Series. We present a case series of 2 patients with NHL presenting with obstructive jaundice as an initial manifestation. Both patients presented with obstructive jaundice and were diagnosed by CT guided liver biopsy. One patient died of sepsis and multiorgan failure before initiating chemotherapy and the second patient did not choose to undergo chemotherapy. Conclusion. Biliary obstruction is a sign of poor prognosis. The diagnosis of NHL needs to be considered in patients presenting with biliary obstruction. It can be associated with high mortality and poses treatment dilemma. PMID- 23818905 TI - Whole-Body (18) FDG-PET in an Arthritis Paraneoplastic Syndrome Revealed an Underlying Hematological Neoplasm. AB - We showed the first image of (18)FDG-PET, which leads to a diagnosis of lymphoma in an atypical polyarthritis. About 4% of patients with lymphoma or leukemia suffered from rheumatologic paraneoplastic symptoms like arthralgia and about 10% of the patients with rheumatologic or neurologic clinical symptoms develop a solid cancer or hematological neoplasm. (18)FDG-PET is an interesting exam to identify an underlying malignancy when a paraneoplastic syndrome is suspected; it can detect the primitive lesion and/or the metastasis lesions. The use of the (18)FDG-PET can help to detect earlier hematological neoplasm in cases of paraneoplastic syndrome without a determined cause and to treat more rapidly and specifically the patient. PMID- 23818906 TI - Primary dural repair in minimally invasive spine surgery. AB - We describe an effective surgical technique in primary repair of the spinal dura during minimally invasive spine surgery (MISS). Objective. Minimally invasive spine surgery includes the treatment of intradural lesions, and proper closure of the dura is necessary. However, primary dural closure can be difficult due to the restricted space of MIS retractors and the availability of appropriate surgical instrumentation. Methods. We describe the use of a needle already used in the pediatric neurosurgical arena that can facilitate easier and safer closure of spinal dura through MISS retractors in two illustrative intradural cases. Results and Discussion. The primary dural closure technique is described and patient demographics are included. The instruments specifically used for the intradural closure through MIS retractor systems include (1) 4-0 Surgilon braided nylon (Covidien, Dublin, Ireland) with a CV-20 taper 1/2 circle, 10 mm diameter needle; (2) Scanlan (Saint Paul, MN, USA) dura closure set. Conclusion. Successful primary dural repair can be performed on primary and incidental durotomies during minimally invasive spinal surgery. We describe the novel use of a 10 mm diameter needle to help surgeons safely and efficiently close the dura with more ease than previously described. PMID- 23818908 TI - Developing a New Two-Step Protocol to Generate Functional Hepatocytes from Wharton's Jelly-Derived Mesenchymal Stem Cells under Hypoxic Condition. AB - The shortage of donor livers and hepatocytes is a major limitation of liver transplantation. Thus, generation of hepatocyte-like cells may provide alternative choice for therapeutic applications. In this study, we developed a new method to establish hepatocytes from Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) cell lines named WJMSCs-SUT1 and WJMSCs-SUT2 under hypoxic condition. This new method could rapidly drive both WJ-MSCs cell lines into hepatic lineage within 18 days. The achievement of hepatogenic differentiation was confirmed by the characterization of both phenotypes and functions. More than 80% MSCs-derived hepatocyte-like cells (MSCDHCs) achieved functional hepatocytes including hepatic marker expressions both at gene and protein levels, glycogen storage, low-density lipoprotein uptake, urea production, and albumin secretion. This study highlights the establishment of new hepatogenic induction protocol under hypoxic condition in order to mimic hypoxic microenvironment in typical cell physiology. In conclusion, we present a simple, high-efficiency, and time saving protocol for the generation of functional hepatocyte-like cells from WJ MSCs in hypoxic condition. The achievement of this method may overcome the limitation of donor hepatocytes and provides a new avenue for therapeutic value in cell-based therapy for life-threatening liver diseases, regenerative medicine, toxicity testing for pharmacological drug screening, and other medical related applications. PMID- 23818907 TI - Intrinsic ability of adult stem cell in skeletal muscle: an effective and replenishable resource to the establishment of pluripotent stem cells. AB - Adult stem cells play an essential role in mammalian organ maintenance and repair throughout adulthood since they ensure that organs retain their ability to regenerate. The choice of cell fate by adult stem cells for cellular proliferation, self-renewal, and differentiation into multiple lineages is critically important for the homeostasis and biological function of individual organs. Responses of stem cells to stress, injury, or environmental change are precisely regulated by intercellular and intracellular signaling networks, and these molecular events cooperatively define the ability of stem cell throughout life. Skeletal muscle tissue represents an abundant, accessible, and replenishable source of adult stem cells. Skeletal muscle contains myogenic satellite cells and muscle-derived stem cells that retain multipotent differentiation abilities. These stem cell populations have the capacity for long term proliferation and high self-renewal. The molecular mechanisms associated with deficits in skeletal muscle and stem cell function have been extensively studied. Muscle-derived stem cells are an obvious, readily available cell resource that offers promise for cell-based therapy and various applications in the field of tissue engineering. This review describes the strategies commonly used to identify and functionally characterize adult stem cells, focusing especially on satellite cells, and discusses their potential applications. PMID- 23818909 TI - HLA-B*44 Is Associated with Dengue Severity Caused by DENV-3 in a Brazilian Population. AB - Human leukocyte antigen (HLA) alleles have been correlated with susceptibility or resistance to severe dengue; however, few immunogenetic studies have been performed in Latin American (LA) populations. We have conducted immunogenetic studies of HLA class I and II alleles in a cohort of 187 patients with DENV-3 infection and confirmed clinical diagnosis of either severe dengue, known as dengue hemorrhagic fever (DHF), or the less severe form, dengue fever (DF), in Recife, Pernambuco, Brazil. An association analysis was performed using Fisher's association test, with odds ratios (ORs) calculated using conditional maximum likelihood estimates. HLA-B*44 (P = 0.047, OR = 2.025, 95% CI = 0.97-4.24) was found to be associated with increased susceptibility to DHF in response to DENV-3 infection. In addition, HLA-B*07 (P = 0.048, OR = 0.501, one-sided 95% CI = 0 0.99) and HLA-DR*13 (P = 0.028, OR = 0.511, one-sided 95% CI = 0-0.91) were found to be associated with resistance to secondary dengue infection by DENV-3. These results suggest that HLA-B*44 supertype alleles and their respective T-cell responses might be involved in susceptibility to severe dengue infections, whereas the HLA-B*07 supertype alleles and DR*13 might be involved in cross dengue serotype immunity. PMID- 23818910 TI - A review of the epidemiological methods used to investigate the health impacts of air pollution around major industrial areas. AB - We performed a literature review to investigate how epidemiological studies have been used to assess the health consequences of living in the vicinity of industries. 77 papers on the chronic effects of air pollution around major industrial areas were reviewed. Major health themes were cancers (27 studies), morbidity (25 studies), mortality (7 studies), and birth outcome (7 studies). Only 3 studies investigated mental health. While studies were available from many different countries, a majority of papers came from the United Kingdom, Italy, and Spain. Several studies were motivated by concerns from the population or by previous observations of an overincidence of cases. Geographical ecological designs were largely used for studying cancer and mortality, including statistical designs to quantify a relationship between health indicators and exposure. Morbidity was frequently investigated through cross-sectional surveys on the respiratory health of children. Few multicenter studies were performed. In a majority of papers, exposed areas were defined based on the distance to the industry and were located from <2 km to >20 km from the plants. Improving the exposure assessment would be an asset to future studies. Criteria to include industries in multicenter studies should be defined. PMID- 23818911 TI - Health effects of coastal storms and flooding in urban areas: a review and vulnerability assessment. AB - Coastal storms can take a devastating toll on the public's health. Urban areas like New York City (NYC) may be particularly at risk, given their dense population, reliance on transportation, energy infrastructure that is vulnerable to flood damage, and high-rise residential housing, which may be hard-hit by power and utility outages. Climate change will exacerbate these risks in the coming decades. Sea levels are rising due to global warming, which will intensify storm surge. These projections make preparing for the health impacts of storms even more important. We conducted a broad review of the health impacts of US coastal storms to inform climate adaptation planning efforts, with a focus on outcomes relevant to NYC and urban coastal areas, and incorporated some lessons learned from recent experience with Superstorm Sandy. Based on the literature, indicators of health vulnerability were selected and mapped within NYC neighborhoods. Preparing for the broad range of anticipated effects of coastal storms and floods may help reduce the public health burden from these events. PMID- 23818913 TI - Dexamethasone preconditioning improves the response of collagen-induced arthritis to treatment with short-term lipopolysaccharide-stimulated collagen-loaded dendritic cells. AB - Background. Pharmacologically modulated dendritic cells (DCs) have been shown to restore tolerance in type II collagen-(CII-) induced arthritis (CIA). We examined the effect of dexamethasone (DXM) administration as a preconditioning agent, followed by an injection of lipopolysaccharide-(LPS-) stimulated and CII-loaded DCs on the CIA course. Methods. After CIA induction, mice pretreated with DXM were injected with 4-hour LPS-stimulated DCs loaded with CII (DXM/4hLPS/CII/DCs). Results. Mice injected with DXM/4hLPS/CII/DCs displayed significantly less severe clinical disease compared to animals receiving 4hLPS/CII/DCs alone or those in which only DXM was administered. Cytokine profile evaluation showed that CD4+ T cells from DXM/4hLPS/CII/DCs and 4hLPS/CII/DCs groups release higher IL-10 levels than those from mice receiving DXM alone or CIA mice. CD4+ T cells from all DC treated groups showed less IL-17 release when compared to the CIA group. On the contrary, CD4+ T cells from DXM/4hLPS/CII/DCs and 4hLPS/CII/DCs groups released higher IFN- gamma levels than those from CIA group. Conclusion. A combined treatment, including DXM preconditioning followed by an inoculation of short-term LPS-stimulated CII-loaded DCs, provides an improved strategy for attenuating CIA severity. Our results suggest that this benefit is driven by a modulation in the cytokine profile secreted by CD4+ T cells. PMID- 23818912 TI - Cellular mechanisms of multiple myeloma bone disease. AB - Multiple myeloma (MM) is a hematologic malignancy of differentiated plasma cells that accumulates and proliferates in the bone marrow. MM patients often develop bone disease that results in severe bone pain, osteolytic lesions, and pathologic fractures. These skeletal complications have not only a negative impact on quality of life but also a possible effect in overall survival. MM osteolytic bone lesions arise from the altered bone remodeling due to both increased osteoclast activation and decreased osteoblast differentiation. A dysregulated production of numerous cytokines that can contribute to the uncoupling of bone cell activity is well documented in the bone marrow microenvironment of MM patients. These molecules are produced not only by malignant plasma cells, that directly contribute to MM bone disease, but also by bone, immune, and stromal cells interacting with each other in the bone microenvironment. This review focuses on the current knowledge of MM bone disease biology, with particular regard on the role of bone and immune cells in producing cytokines critical for malignant plasma cell proliferation as well as in osteolysis development. Therefore, the understanding of MM pathogenesis could be useful to the discovery of novel agents that will be able to both restore bone remodelling and reduce tumor burden. PMID- 23818914 TI - FSH and TSH in the regulation of bone mass: the pituitary/immune/bone axis. AB - Recent evidences have highlighted that the pituitary hormones have profound effects on bone, so that the pituitary-bone axis is now becoming an important issue in the skeletal biology. Here, we discuss the topical evidence about the dysfunction of the pituitary-bone axis that leads to osteoporotic bone loss. We will explore the context of FSH and TSH hormones arguing their direct or indirect role in bone loss. In addition, we will focus on the knowledge that both FSH and TSH have influence on proinflammatory and proosteoclastogenic cytokine expression, such as TNF alpha and IL-1, underlining the correlation of pituitary bone axis to the immune system. PMID- 23818915 TI - Assessment of T regulatory cells and expanded profiling of autoantibodies may offer novel biomarkers for the clinical management of systemic sclerosis and undifferentiated connective tissue disease. AB - In order to identify disease biomarkers for the clinical and therapeutic management of autoimmune diseases such as systemic sclerosis (SSc) and undifferentiated connective tissue disease (UCTD), we have explored the setting of peripheral T regulatory (T reg) cells and assessed an expanded profile of autoantibodies in patients with SSc, including either limited (lcSSc) or diffuse (dcSSc) disease, and in patients presenting with clinical signs and symptoms of UCTD. A large panel of serum antibodies directed towards nuclear, nucleolar, and cytoplasmic antigens, including well-recognized molecules as well as less frequently tested antigens, was assessed in order to determine whether different antibody profiles might be associated with distinct clinical settings. Beside the well-recognized association between lcSSc and anti-centromeric or dcSSC and anti topoisomerase-I antibodies, we found a significative association between dcSSc and anti-SRP or anti-PL-7/12 antibodies. In addition, two distinct groups emerged on the basis of anti-RNP or anti-PM-Scl 75/100 antibody production among UCTD patients. The levels of T reg cells were significantly lower in patients with SSc as compared to patients with UCTD or to healthy controls; in patients with lcSSc, T reg cells were inversely correlated to disease duration, suggesting that their levels may represent a marker of disease progression. PMID- 23818916 TI - Different peripheral tissue injury induces differential phenotypic changes of spinal activated microglia. AB - The purpose of this study is to investigate the possible different cellular marker expression associated with spinal cord microglial activation in different pain models. Immunohistochemistry and western blotting analysis of CD45, CD68, and MHC class I antigen as well as CD11b and Iba-1 in the spinal cord were quantitatively compared among widely used three pain animal models, complete Freund's adjuvant (CFA) injection, formalin injection, and chronic constriction injury (CCI) models. The results showed that significant upregulated expressions of CD45 and MHC class I antigen in spinal microglia as well as morphological changes with increased staining with CD11b and Iba-1 were seen in CCI and formalin models and not found in CFA-induced inflammatory pain model. CD68 expression was only detected in CCI model. Our findings suggested that different peripheral tissue injuries produced differential phenotypic changes associated with spinal microglial activation; peripheral nerve injury might induce spinal microglia to acquire these immunomolecular phenotypic changes. PMID- 23818917 TI - Significance of semiquantitative assessment of preformed donor-specific antibody using luminex single bead assay in living related liver transplantation. AB - AIM: To analyze the risks of preoperatively produced donor-specific antibody (DSA) in liver transplantation. METHODS: DSA was assessed using direct complement dependent cytotoxicity (CDC) and anti-human globulin- (AHG-) CDC tests, as well as the Luminex Single Antigen assay. Among 616 patients undergoing blood type identical or compatible living donor liver transplantation (LDLT), 21 patients were positive for CDC or AHG-CDC tests, and the preserved serum from 18 patients was examined to determine targeted Class I and II antigens. The relationships between the mean fluorescence intensity (MFI) of DSA and the clinical outcomes were analyzed. RESULTS: Patients were divided into 3 groups according to the MFI of anti-Class I DSA: high (11 patients with MFI > 10,000), low (2 patients with MFI < 10,000), and negative (5 patients) MFI groups. Six of 11 patients with high Class-I DSA showed positive Class-II DSA. Hospital death occurred in 7 patients of the high MFI group. High MFI was a significant risk factor for mortality (P = 0.0155). Univariate analysis showed a significant correlation between MFI strength and C4d deposition (P = 0.0498). CONCLUSIONS: HLA Class I DSA with MFI > 10,000 had a significant negative effect on the clinical outcome of patients with preformed DSA in LDLT. PMID- 23818918 TI - Important developments in romanian propolis research. AB - The most important developments in propolis analysis and pharmacological properties are discussed. In order to help in the Romanian propolis standardization, different methodologies for chemical composition analysis (UV VIS, HP-TLC, and HPLC-DAD) are reviewed using new approaches and software (fuzzy divisive hierarchical clustering approach and ChromQuest software) and compared with international studies made until now in propolis research. Practical applications of Romanian propolis in medicinal therapy and cosmetics are reviewed, and quality criteria for further standardization are proposed. PMID- 23818919 TI - Biological Activities and Chemical Characterization of Cordia verbenacea DC. as Tool to Validate the Ethnobiological Usage. AB - Knowledge of medicinal plants is often the only therapeutic resource of many communities and ethnic groups. "Erva-baleeira", Cordia verbenacea DC., is one of the species of plants currently exploited for the purpose of producing a phytotherapeutic product extracted from its leaves. In Brazil, its major distribution is in the region of the Atlantic Forest and similar vegetation. The crude extract is utilized in popular cultures in the form of hydroalcoholic, decoctions and infusions, mainly as antimicrobial, anti-inflammatory and analgesic agents. The aim of the present study was to establish a chemical and comparative profile of the experimental antibacterial activity and resistance modifying activity with ethnopharmacological reports. Phytochemical prospecting and HPLC analysis of the extract and fractions were in agreement with the literature with regard to the presence of secondary metabolites (tannins and flavonoids). The extract and fraction tested did not show clinically relevant antibacterial activity, but a synergistic effect was observed when combined with antibiotic, potentiating the antibacterial effect of aminoglycosides. We conclude that tests of antibacterial activity and modulating the resistance presented in this work results confirm the ethnobotanical and ethnopharmacological information, serving as a parameter in the search for new alternatives for the treatment of diseases. PMID- 23818920 TI - Anti-Diabetic Activities of Jiaotaiwan in db/db Mice by Augmentation of AMPK Protein Activity and Upregulation of GLUT4 Expression. AB - Jiaotaiwan (JTW), which is composed of Coptis chinensis (CC) and cinnamon (CIN), is one of the most well-known traditional Chinese medicines. In this study, we investigated the antidiabetic effects and mechanism of JTW in db/db mice. Results showed that JTW significantly decreased the level of fasting blood glucose and improved glucose and insulin tolerance better than CC or CIN alone. JTW also effectively protected the pancreatic islet shape, augmented the activation of AMP activated protein kinase (AMPK) in the liver, and increased the expression of glucose transporter 4 (GLUT4) protein in skeletal muscle and white fat. AMPK and GLUT4 contributed to glucose metabolism regulation and had an essential function in the development of diabetes mellitus (DM). Therefore, the mechanisms of JTW may be related to suppressing gluconeogenesis by activating AMPK in the liver and affecting glucose uptake in surrounding tissues through the upregulation of GLUT4 protein expression. These findings provided a new insight into the antidiabetic clinical applications of JTW and demonstrated the potential of JTW as a new drug candidate for DM treatment. PMID- 23818921 TI - Acupuncture de qi in stable somatosensory stroke patients: relations with effective brain network for motor recovery. AB - Acupuncture has been widely used for treating stroke and De Qi may play an important role. In spite of its acceptance, the neural mechanism underlying acupuncture for motor recovery is still elusive. Particularly, by what extent De Qi sensations can reliably predict the therapeutical acupuncture effect on the mediating recovery from stroke is urgent to investigate. Nine stroke patients were assessed by De Qi, neurological examination, and scanned with acupuncture stimuli across two time points at an interval of two weeks. And we adopted multivariate Granger causality analysis to explore the interregional influences within motor executive brain network during post-acupuncture resting state. Our findings indicated that acupuncture at GB34 can enhance the recovery of stroke mainly by strengthening causal influences between the ipsilesional and contralesional motor cortex. Moreover, centrality of some motor-related regions correlated with clinical variables and thus served as a predictor of stroke recovery. Along the same line, the centrality of these motor-related regions has also high relations with the De Qi sensation. Our findings suggest that De Qi having relatively stable reliability may be essential and used as a predictor to the therapeutic effectiveness of acupuncture for stroke recovery. PMID- 23818922 TI - Antiobesity Effect of Codonopsis lanceolata in High-Calorie/High-Fat-Diet-Induced Obese Rats. AB - The antiobesity effects of Codonopsis lanceolata (CL) were evaluated in a high calorie/high-fat-diet (HFD-) induced obesity rat model and 3T3-L1 cells. The Sprague-Dawley male rats were fed a normal diet (ND) or a HFD for a period of 12 weeks. The rats were subdivided into groups: ND, ND + wild Codonopsis lanceolata (wCL) (900 mg/kg/day, p.o.), ND + cultivated Codonopsis lanceolata (cCL) (900 mg/kg/day, p.o.), HFD, HFD + wCL (100, 300, or 900 mg/kg/day, p.o.), HFD + cCL (100, 300, or 900 mg/kg/day, p.o.), and HFD + sibutramine. The body weight gains of the administered HFD + CL (wCL or CCL) were lower than those of the rats fed with only the HFD group. Moreover, the weight of adipose pads and the serum levels of triglycerides, total cholesterol, and low density lipoprotein cholesterol in the group administered HDL + CL were significantly lower than in the HFD group. The inhibitory effect of lipid accumulation in 3T3-L1 cells was measured by Oil Red O staining and reverse transcription-polymerase chain reaction (RT-PCR). Treatment of 3T3-L1 cells with wCL inhibited lipid accumulation and expression of C/EBPalpha and PPARgamma. These results suggest that CL has a great potential as a functional food with anti-obesity effects and as a therapeutic alternative in the treatment of obesity. PMID- 23818923 TI - Corporate culture assessments in integrative oncology: a qualitative case study of two integrative oncology centers. AB - The offer of "integrative oncology" is one option for clinics to provide safe and evidence-based complementary medicine treatments to cancer patients. As known from merger theories, corporate culture and integration models have a strong influence on the success of such integration. To identify relevant corporate culture aspects that might influence the success in two highly visible integrative oncology clinics, we interviewed physicians, nurses, practitioners, and managers. All interviews (11 in a German breast cancer clinic and 9 in an integrative medicine cancer service in the USA) were audio-recorded, transcribed and analyzed with content analysis. According to the theoretical framework of mergers, each clinic selected a different integration type ("best of both worlds" and "linking"). Nonetheless, each developed a similar corporate culture that has a strong focus on research and safe and evidence-based treatments, and fosters a holistic and patient-centered approach. Structured communication within the team and with other departments had high relevance. Research was highlighted as a way to open doors and to facilitate a more general acceptance within the hospital. Conventional physicians felt unburdened by the provision of integrative medicine service but also saw problems in the time required for scheduled treatments, which often resulted in long waiting lists. PMID- 23818924 TI - Factors contributing to de qi in acupuncture randomized clinical trials. AB - De qi is a core concept of acupuncture and is necessary to produce therapeutic effect. In 2010, de qi has been received as a term in the official extension of the CONSORT Statement. However, there are few articles that discuss which factors have influences on obtaining de qi in clinical trials. This paper aims to explore these factors and give advice on trial design in order to optimize de qi in acupuncture RCTs. PMID- 23818925 TI - Anthricin Isolated from Anthriscus sylvestris (L.) Hoffm. Inhibits the Growth of Breast Cancer Cells by Inhibiting Akt/mTOR Signaling, and Its Apoptotic Effects Are Enhanced by Autophagy Inhibition. AB - Anthricin (deoxypodophyllotoxin) is a natural product isolated from Anthriscus sylvestris (L.) Hoffm. (Apiaceae). Here, we investigated the effect of anthricin on autophagy and mammalian target of rapamycin (mTOR) signaling as anticancer actions in breast cancer cells. Many studies have supported the contention that the phosphoinositide 3-kinase (PI3K)/Akt/mTORC1 pathway is considerably deregulated in breast cancer and that autophagy plays important roles in the development of this type of cancer, although the exact underlying mechanisms remain unknown. Our data confirmed that anthricin markedly induced apoptosis in 2 breast cancer cell lines, MCF7 (estrogen receptor positive) and MDA-MB-231 (estrogen receptor, progesterone receptor, and Her2/Neu receptor negative). Anthricin treatment decreased the levels of phosphorylated Akt and mTORC1, followed by inhibition of cell growth. Interestingly, blockage of autophagy by a pharmacological inhibitor or genetic deletion of ULK1 and Atg13 accelerated anthricin-induced apoptosis, suggesting that autophagy has cytoprotective effects. Taken together, our results indicate that anthricin is an inhibitor of mTOR and that a combination of an autophagy inhibitor and anthricin may serve as a new promising strategy for the treatment of breast cancer cells. PMID- 23818926 TI - Paeonia lactiflora Extract Attenuating Cerebral Ischemia and Arterial Intimal Hyperplasia Is Mediated by Paeoniflorin via Modulation of VSMC Migration and Ras/MEK/ERK Signaling Pathway. AB - Paeonia lactiflora is a well-known traditional Chinese medicine. Paeoniflorin is an active component found in Paeonia lactiflora, which is used to treat smooth muscle spasms and pain and to protect the cardiovascular system. The objective of this study was to determine if Paeonia lactiflora would be protective in rodent models of cerebral ischemia and arterial intimal hyperplasia. Paeonia lactiflora extract (PLex) and paeoniflorin (PF) significantly attenuated cerebral infarction in ischemia/reperfusion injury rats and the severity of intimal hyperplasia in mice where the carotid artery was ligated. PLex and PF reduced PDGF-stimulated VSMC proliferation and migration in a dose-dependent manner by MTT, wound healing, and transwell assays. PF significantly reduced protein levels of Ras, MEK, p-MEK and p-ERK, but not MMP-2 and MMP-9. In summary, Paeonia lactiflora reduced cerebral ischemia and arterial intimal hyperplasia which were mainly made via the intermediary of PF. The protective effect of PF was related to the modulation of the Ras/MEK/ERK signaling pathway. PMID- 23818927 TI - Decursin and Doxorubicin Are in Synergy for the Induction of Apoptosis via STAT3 and/or mTOR Pathways in Human Multiple Myeloma Cells. AB - Background. Combination cancer therapy is one of the attractive approaches to overcome drug resistance of cancer cells. In the present study, we investigated the synergistic effect of decursin from Angelica gigas and doxorubicin on the induction of apoptosis in three human multiple myeloma cells. Methodology/Principal Findings. Combined treatment of decursin and doxorubicin significantly exerted significant cytotoxicity compared to doxorubicin or decursin in U266, RPMI8226, and MM.1S cells. Furthermore, the combination treatment enhanced the activation of caspase-9 and -3, the cleavage of PARP, and the sub G1 population compared to either drug alone in three multiple myeloma cells. In addition, the combined treatment downregulated the phosphorylation of mTOR and its downstream S6K1 and activated the phosphorylation of ERK in three multiple myeloma cells. Furthermore, the combined treatment reduced mitochondrial membrane potential, suppressed the phosphorylation of JAK2, STAT3, and Src, activated SHP-2, and attenuated the expression of cyclind-D1 and survivin in U266 cells. Conversely, tyrosine phosphatase inhibitor pervanadate reversed STAT3 inactivation and also PARP cleavage and caspase-3 activation induced by combined treatment of doxorubicin and decursin in U266 cells. Conclusions/Significance. Overall, the combination treatment of decursin and doxorubicin can enhance apoptotic activity via mTOR and/or STAT3 signaling pathway in multiple myeloma cells. PMID- 23818928 TI - Reconstructive Effects of Percutaneous Electrical Stimulation Combined with GGT Composite on Large Bone Defect in Rats. AB - Previous studies have shown the electromagnetic stimulation improves bone remodeling and bone healing. However, the effect of percutaneous electrical stimulation (ES) was not directly explored. The purpose of this study was to evaluate effect of ES on improvement of bone repair. Twenty-four adult male Sprague-Dawley rats were used for cranial implantation. We used a composite comprising genipin cross-linked gelatin mixed with tricalcium phosphate (GGT). Bone defects of all rats were filled with the GGT composites, and the rats were assigned into six groups after operation. The first three groups underwent 4, 8, and 12 weeks of ES, and the anode was connected to the backward of the defect on the neck; the cathode was connected to the front of the defect on the head. Rats were under inhalation anesthesia during the stimulation. The other three groups only received inhalation anesthesia without ES, as control groups. All the rats were examined afterward at 4, 8, and 12 weeks. Radiographic examinations including X-ray and micro-CT showed the progressive bone regeneration in the both ES and non-ES groups. The amount of the newly formed bone increased with the time between implantation and examination in the ES and non-ES groups and was higher in the ES groups. Besides, the new bone growth trended on bilateral sides in ES groups and accumulated in U-shape in non-ES groups. The results indicated that ES could improve bone repair, and the effect is higher around the cathode. PMID- 23818929 TI - Bees' honey attenuation of metanil-yellow-induced hepatotoxicity in rats. AB - The present study aims to investigate the protective effect of bees' honey against metanil-yellow-induced hepatotoxicity in rats. Rats were divided into 7 groups: control group; three groups treated with 50, 100, and 200 mg/kg metanil yellow, and three groups treated with metanil yellow plus 2.5 mg . kg(-1) . day( 1) bees' honey for 8 weeks. The obtained data showed that the antioxidant/anti inflammatory activity of bees' honey reduced the oxidative stress in the liver tissue and downregulated the inflammatory markers. In addition, the elevated levels of AGE and the activated NF- kappa B in the metanil-yellow-treated animals were significantly attenuated. Moreover, the levels of TNF- alpha and IL-1 beta were significantly attenuated as a result of bees' honey administration. Furthermore, the histopathological examination of the liver showed that bees' honey reduced fatty degeneration, cytoplasmic vacuolization, and necrosis in metanil-yellow-treated rats. In conclusion, the obtained data suggest that bees' honey has hepatoprotective effect on acute liver injuries induced by metanil yellow in vivo, and the results suggested that the effect of bees' honey against metanil yellow-induced liver damage is related to its antioxidant/anti inflammatory properties which attenuate the activation of NF- kappa B and its controlled genes like TNF- alpha and IL-1 beta . PMID- 23818930 TI - Lessons learnt from evidence-based approach of using chinese herbal medicines in liver cancer. AB - This paper is a systematic review of evidence-based studies of the effectiveness of Chinese herbal medicine (CHM) in the treatment of liver cancer. After a detailed analysis of the literature, five animal studies and four human clinical trials met the criteria for inclusion. Analysis revealed that results of the clinical trials, whilst encouraging, need to be interpreted with caution as problems with study designs may lead to apparent benefits being attributable to various forms of bias. However, as each of the CHM agents used in these studies appeared to be potentially beneficial, further well-designed and controlled randomized clinical trials are warranted. The second part of this review focused on the lessons learned from the relationships between Traditional Chinese Medicine (TCM) theory, TCM Syndrome Differentiation, and modern scientific understanding of mechanisms of action of CHM agents. The understanding of TCM Syndrome Differentiation may allow identification of different patterns of disharmony and may provide important guidance to the prescription of CHM. Furthermore, quality control using both biological and chemical fingerprinting of CHM is important to ensure batch-to-batch consistency to deliver sustained therapeutic benefit. Also, careful assessment of herb-drug interactions is paramount for safety and integrative use of western chemotherapeutic and CHM agents. PMID- 23818931 TI - A New Herbal Formula, KSG-002, Suppresses Breast Cancer Growth and Metastasis by Targeting NF- kappa B-Dependent TNF alpha Production in Macrophages. AB - Tumor-associated macrophages (TAMs) in tumor microenvironment regulate cancer progression and metastases. In breast cancer, macrophage infiltration is correlated with a poor prognosis. While metastatic breast cancer is poor prognostic with a severe mortality, therapeutic options are still limited. In this study, we demonstrate that KSG-002, a new herbal composition of radices Astragalus membranaceus and Angelica gigas, suppresses breast cancer via inhibiting TAM recruitment. KSG-002, an extract of radices Astragalus membranaceus and Angelica gigas at 3 : 1 ratio, respectively, inhibited MDA-MB 231 xenograft tumor growth and pulmonary metastasis in nude mice, while KSG-001, another composition (1 : 1 ratio, w/w), enhanced tumor growth, angiogenesis, and pulmonary metastasis, in vivo. KSG-002 further decreased the infiltrated macrophage numbers in xenograft tumor cohorts. In Raw264.7 cells, KSG-002 but not KSG-001 inhibited cell proliferation and migration and reduced TNF-alpha (TNF alpha ) production by inhibiting NF- kappa B pathway. Furthermore, a combinatorial treatment of KSG-002 with TNF alpha inhibited a proliferation and migration of both MDA-MB-231 and Raw264.7 cells. Taken together, we conclude that KSG-002 suppresses breast cancer growth and metastasis through targeting NF- kappa B-mediated TNF alpha production in macrophages. PMID- 23818932 TI - Exploring the ligand-protein networks in traditional chinese medicine: current databases, methods, and applications. AB - The traditional Chinese medicine (TCM), which has thousands of years of clinical application among China and other Asian countries, is the pioneer of the "multicomponent-multitarget" and network pharmacology. Although there is no doubt of the efficacy, it is difficult to elucidate convincing underlying mechanism of TCM due to its complex composition and unclear pharmacology. The use of ligand protein networks has been gaining significant value in the history of drug discovery while its application in TCM is still in its early stage. This paper firstly surveys TCM databases for virtual screening that have been greatly expanded in size and data diversity in recent years. On that basis, different screening methods and strategies for identifying active ingredients and targets of TCM are outlined based on the amount of network information available, both on sides of ligand bioactivity and the protein structures. Furthermore, applications of successful in silico target identification attempts are discussed in detail along with experiments in exploring the ligand-protein networks of TCM. Finally, it will be concluded that the prospective application of ligand-protein networks can be used not only to predict protein targets of a small molecule, but also to explore the mode of action of TCM. PMID- 23818933 TI - The mechanisms of chansu in inducing efficient apoptosis in colon cancer cells. AB - Chansu is one of the most widely used traditional Chinese medicines in China, Japan, and other Southeast Asian countries primarily for antipain, anti inflammation, and recently anticancer. Over 10 recipes and remedies contained Chansu, which are easily available in pharmacies and hospitals, but the mechanisms of action were not clearly articulated. In the present study, Cinobufagin (CBF), the major compound of Chansu, was employed as a surrogate marker to determine its ability in inducing cancer cell death. As expected, CBF has significant cancer-killing capacity for a range of cancers, but such ability differs markedly. Colon and prostate cancers are more sensitive than skin and lung cancers. Interestingly, cancer cells die through apoptotic pathway either being biphasic caspase-3-dependent (HCT116) or independent (HT29). Multipathway analysis reveals that CBF-induced apoptosis is likely modulated by the hypoxia inducing factor-1 alpha subunit (HIF-1 alpha ) as its inhibition was evident in vitro and in vivo. Taken together, these results demonstrate that CBF is a potent apoptotic inducer with potential for further development as a novel and effective anticancer agent for a range of cancers, especially colon cancer. PMID- 23818934 TI - Informal Trade of Psychoactive Herbal Products in the City of Diadema, SP, Brazil: Quality and Potential Risks. AB - The present study aimed to assess the quality and risks involved in the consumption of psychoactive herbal products (PHs) that are available through informal commerce in the city of Diadema, SP, Brazil. Methods of ethnography were used to conduct the fieldwork during which four dealers were selected to record the collection, handling, packaging, types of PHs marketed, and their therapeutic purposes. In addition, lots of the PHs selected were purchased from the dealers and analyzed using microbiology and pharmacognosy techniques. 217 PHs were recorded and categorized into two main groups: stimulants (67%) and depressants (27%) of the central nervous system; sixteen of them were selected, and their 52 lots were acquired. The deficiencies observed in handling and packaging these lots by dealers were confirmed by microbiological analysis; 80.8% of them presented risk according to the indicators defined by the Brazilian Pharmacopoeia. The pharmacognostic analysis confirmed the authenticity of only 9 to 16 PHs analyzed. In addition, descriptions of contraindications, adverse reactions, and drug interactions were found in the literature for the PHs. The results of this study allow the observation of the priorities for the sanitary adequacy of the popular trade of herbs. PMID- 23818935 TI - Ethanol Extract of Antrodia camphorata Grown on Germinated Brown Rice Suppresses Inflammatory Responses in Mice with Acute DSS-Induced Colitis. AB - The anti-inflammatory activity of Antrodia camphorata (AC) grown on germinated brown rice (CBR) extract was evaluated in vitro and in vivo. CBR suppressed the release of nitric oxide (NO) and prostaglandin (PG) E2 from lipopolysaccharide (LPS-)stimulated RAW264.7 cells. CBR inhibited the level of inducible nitric oxide synthase (iNOS) and cyclooxygenase-(COX-)2 proteins, and it activated p38 MAPK, extracellular signal-related kinases (ERK), and NF- kappa B in LPS stimulated RAW264.7 macrophages. LPS-induced tumor necrosis factor- alpha (TNF- alpha ) and interleukin-6 (IL-6) mRNA expression was reduced in CBR-treated RAW264.7 cells. In concert with in vitro data, CBR suppressed the levels of dextran-sulfate-sodium-(DSS-)induced iNOS and COX-2 proteins in the colon tissue. CBR treatment inhibited activated p38-MAPK, ERK, and NF- kappa B proteins in the colon tissue of DSS-induced mice. TNF- alpha and IL-6 mRNA expression was reduced in DSS+CBR-treated mice. The disease activity index and histological scores were significantly lower in CBR-treated mice (500 mg/kg/day) than in DSS-treated mice (P < 0.05 versus DSS). This is the first report of anti-inflammatory activity of CBR in DSS-induced acute colitis. These results suggest that CBR is a promising, potential agent for preventing acute colitis through the inhibition of NF- kappa B signaling and its upstream signaling molecules, including MAPKs. PMID- 23818936 TI - The efficacy study on si ni san freeze-dried powder on sleep phase in insomniac and normal rats. AB - Objectives. To investigate the effect of Si Ni San freeze-dried powder (SNSP) on sleep phase in insomniac and normal rats, to identify its mode of action in improving sleep, and to provide a reliable method for determining pharmacodynamic material basis of Si-Ni-San on improving sleep. Methods. Rats were deprived of sleep by using the footplate electrical stimulator to record the rats' electroencephalogram (EEG) and electromyogram (EMG) by using polysomnography (PSG) and copy insomnia model by the method of electric stimulation. Analysis on EEG and EMG was carried out to observe the effects of SNSP on the sleep phase of insomniac and normal rats. Results. Rats were treated by intragastric administration (i.g.) consecutively for seven days. The results showed that the total sleep time was extended; meanwhile, SWS2 (P < 0.01) and REMS (P < 0.05) were mainly prolonged for both insomniac and normal rats. The dates implied SNSP could significantly improve sleep. Conclusions. SNSP could prolong SWS2 and REMS, the experimental reproducibility is good, and the dates indicate that SNSP has the sedative function. Study on the effects of SNSP on sleep phases provided a basis for the further studies on effective constituents and the pharmacodynamic mechanism of SNSP. PMID- 23818937 TI - Nonlinear radon transform using Zernike moment for shape analysis. AB - We extend the linear Radon transform to a nonlinear space and propose a method by applying the nonlinear Radon transform to Zernike moments to extract shape descriptors. These descriptors are obtained by computing Zernike moment on the radial and angular coordinates of the pattern image's nonlinear Radon matrix. Theoretical and experimental results validate the effectiveness and the robustness of the method. The experimental results show the performance of the proposed method in the case of nonlinear space equals or outperforms that in the case of linear Radon. PMID- 23818938 TI - Clinical procedure for intraocular electrochemical lysis during endoresection. AB - Optimal clinical approaches to the treatment of large intraocular lesions located in the posterior pole of the eye remain controversial. In our opinion, the introduction of innovative techniques into the clinical practice of vitreoretinal surgery professionals as well as the implementation of new techniques designed to destroy tumour tissue will make endoresection one of the most promising alternative approaches to choroidal melanoma management, providing an encouraging high-potential eye-saving treatment option in the future. However, in view of a small number of treated cases and a short follow-up period, further research studies are required to evaluate the effectiveness of the electrochemical lysis procedure during endoresection. PMID- 23818939 TI - Filgrastim XM02 (Tevagrastim(r)) after autologous stem cell transplantation compared to lenograstim: favourable cost-efficacy analysis. AB - PURPOSE: Granulocyte colony-stimulating factors (G-CSFs), filgrastim and lenograstim, are recognised to be useful in accelerating engraftment after autologous stem cell transplantation. Several forms of biosimilar non glycosylated G-CSF have been approved by the European Medicines Agency, with limited published data supporting the clinical equivalence in peripheral blood stem cell mobilisation and recovery after autologous stem cell transplantation. METHOD: With the aim of comparing cost-effective strategies in the use of G-CSF after autologous stem cell transplantation, we retrospectively evaluated 32 patients consecutively treated with biosimilar filgrastim XM02 (Tevagrastim) and 26 with lenograstim. All patients received G-CSF (biosimilar or lenograstim) at a dosage of 5 mcg/kg/day subcutaneously from day 5 to absolute neutrophil count of 1500/mmc for three days. RESULTS: The median time to absolute neutrophil count engraftment was 11 days for the filgrastim XM02 group and 12 days for the lenograstim group. As for platelets recovery, the median time was 12 days in both groups. The median number of G-CSF vials used for patients was 9.5 for Tevagrastim and 10.5 for lenograstim, reflecting a mean estimated cost of about 556.1 euros for Tevagrastim versus 932.2 euros for lenograstim (p< 0.001). The median days of febrile neutropenia were 1.5 and 1 for filgrastim XM02 and lenograstim, respectively. No adverse event related to the use of XM02 filgrastim was recorded. CONCLUSION: In our experience, filgrastim XM02 and lenograstim showed comparable efficacy in shortening the period of neutropenia after cytoreduction and autologous stem cell transplantation, with a favourable cost effect for filgrastim XM02. PMID- 23818940 TI - Neuronal activation in the central nervous system of rats in the initial stage of chronic kidney disease-modulatory effects of losartan and moxonidine. AB - The effect of mild chronic renal failure (CRF) induced by 4/6-nephrectomy (4/6NX) on central neuronal activations was investigated by c-Fos immunohistochemistry staining and compared to sham-operated rats. In the 4/6 NX rats also the effect of the angiotensin receptor blocker, losartan, and the central sympatholyticum moxonidine was studied for two months. In serial brain sections Fos immunoreactive neurons were localized and classified semiquantitatively. In 37 brain areas/nuclei several neurons with different functional properties were strongly affected in 4/6NX. It elicited a moderate to high Fos-activity in areas responsible for the monoaminergic innervation of the cerebral cortex, the limbic system, the thalamus and hypothalamus (e.g. noradrenergic neurons of the locus coeruleus, serotonergic neurons in dorsal raphe, histaminergic neurons in the tuberomamillary nucleus). Other monoaminergic cell groups (A5 noradrenaline, C1 adrenaline, medullary raphe serotonin neurons) and neurons in the hypothalamic paraventricular nucleus (innervating the sympathetic preganglionic neurons and affecting the peripheral sympathetic outflow) did not show Fos-activity. Stress- and pain-sensitive cortical/subcortical areas, neurons in the limbic system, the hypothalamus and the circumventricular organs were also affected by 4/6NX. Administration of losartan and more strongly moxonidine modulated most effects and particularly inhibited Fos-activity in locus coeruleus neurons. In conclusion, 4/6NX elicits high activity in central sympathetic, stress- and pain related brain areas as well as in the limbic system, which can be ameliorated by losartan and particularly by moxonidine. These changes indicate a high sensitivity of CNS in initial stages of CKD which could be causative in clinical disturbances. PMID- 23818941 TI - Cytokine receptor-like factor 1 (CRLF1) protects against 6-hydroxydopamine toxicity independent of the gp130/JAK signaling pathway. AB - Oxidative stress is an important cause of cellular toxicity in the central nervous system and contributes to the pathology associated with neurodegenerative disorders including Parkinson's disease. As such, elucidation of cellular mechanisms that enhance neuronal resistance to oxidative stress may provide new avenues for therapy. In this study we employed a simple two-state cellular model to identify genes that are associated with resistance to oxidative stress induced by 6-hydroxydopamine (6-OHDA). In this model, undifferentiated neuroblastoma cells display higher sensitivity to 6-OHDA than differentiated cells. By comparing the gene expression between these two states, we identified several genes whose expression is altered concomitant with changes in 6-OHDA sensitivity. This gene set includes cytokine receptor-like factor 1 (CRLF1), which is up regulated during the differentiation process and has been previously implicated in neuroprotection. We show that the product of this gene is both necessary and sufficient for increased resistance to 6-OHDA in differentiated neuroblastoma cells, and that CRLF1 serves its protective role by a cell autonomous mechanism that is independent from its known role as a co-ligand for the ciliary neurotrophic factor receptor. These data provide an additional role for CRLF1 that could potentially explain its broad expression pattern and effects on cells lacking expression of this receptor. PMID- 23818942 TI - Evolution of cooperation in a heterogeneous graph: fixation probabilities under weak selection. AB - It has been shown that natural selection favors cooperation in a homogenous graph if the benefit-to-cost ratio exceeds the degree of the graph. However, most graphs related to interactions in real populations are heterogeneous, in which some individuals have many more neighbors than others. In this paper, we introduce a new state variable to measure the time evolution of cooperation in a heterogeneous graph. Based on the diffusion approximation, we find that the fixation probability of a single cooperator depends crucially on the number of its neighbors. Under weak selection, a cooperator with more neighbors has a larger probability of fixation in the population. We then investigate the average fixation probability of a randomly chosen cooperator. If a cooperator pays a cost for each of its neighbors (the so called fixed cost per game case), natural selection favors cooperation if the benefit-to-cost ratio is larger than the average degree. In contrast, if a cooperator pays a fixed cost and all its neighbors share the benefit (the fixed cost per individual case), cooperation is favored if the benefit-to-cost ratio is larger than the harmonic mean of the degree distribution. Moreover, increasing the graph heterogeneity will reduce the effect of natural selection. PMID- 23818943 TI - Effects of elevated CO2 and nitrogen deposition on ecosystem carbon fluxes on the Sanjiang plain wetland in Northeast China. AB - BACKGROUND: Increasing atmospheric CO2 and nitrogen (N) deposition across the globe may affect ecosystem CO2 exchanges and ecosystem carbon cycles. Additionally, it remains unknown how increased N deposition and N addition will alter the effects of elevated CO2 on wetland ecosystem carbon fluxes. METHODOLOGY/PRINCIPAL FINDINGS: Beginning in 2010, a paired, nested manipulative experimental design was used in a temperate wetland of northeastern China. The primary factor was elevated CO2, accomplished using Open Top Chambers, and N supplied as NH4NO3 was the secondary factor. Gross primary productivity (GPP) was higher than ecosystem respiration (ER), leading to net carbon uptake (measured by net ecosystem CO2 exchange, or NEE) in all four treatments over the growing season. However, their magnitude had interannual variations, which coincided with air temperature in the early growing season, with the soil temperature and with the vegetation cover. Elevated CO2 significantly enhanced GPP and ER but overall reduced NEE because the stimulation caused by the elevated CO2 had a greater impact on ER than on GPP. The addition of N stimulated ecosystem C fluxes in both years and ameliorated the negative impact of elevated CO2 on NEE. CONCLUSION/SIGNIFICANCE: In this ecosystem, future elevated CO2 may favor carbon sequestration when coupled with increasing nitrogen deposition. PMID- 23818944 TI - Facial and prosodic emotion recognition deficits associate with specific clusters of psychotic symptoms in schizophrenia. AB - BACKGROUND: Patients with schizophrenia perform significantly worse on emotion recognition tasks than healthy participants across several sensory modalities. Emotion recognition abilities are correlated with the severity of clinical symptoms, particularly negative symptoms. However, the relationships between specific deficits of emotion recognition across sensory modalities and the presentation of psychotic symptoms remain unclear. The current study aims to explore how emotion recognition ability across modalities and neurocognitive function correlate with clusters of psychotic symptoms in patients with schizophrenia. METHODS: 111 participants who met the DSM-IV diagnostic criteria for schizophrenia and 70 healthy participants performed on a dual-modality emotion recognition task, the Diagnostic Analysis of Nonverbal Accuracy 2-Taiwan version (DANVA-2-TW), and selected subscales of WAIS-III. Of all, 92 patients received neurocognitive evaluations, including CPT and WCST. These patients also received the PANSS for clinical evaluation of symptomatology. RESULTS: The emotion recognition ability of patients with schizophrenia was significantly worse than healthy participants in both facial and vocal modalities, particularly fearful emotion. An inverse correlation was noted between PANSS total score and recognition accuracy for happy emotion. The difficulty of happy emotion recognition and earlier age of onset, together with the perseveration error in WCST predicted total PANSS score. Furthermore, accuracy of happy emotion and the age of onset were the only two significant predictors of delusion/hallucination. All the associations with happy emotion recognition primarily concerned happy prosody. DISCUSSION: Deficits in emotional processing in specific categories, i.e. in happy emotion, together with deficit in executive function, may reflect dysfunction of brain systems underlying severity of psychotic symptoms, in particular the positive dimension. PMID- 23818945 TI - Real-time electrocardiogram transmission from Mount Everest during continued ascent. AB - The feasibility of a real-time electrocardiogram (ECG) transmission via satellite phone from Mount Everest to determine a climber's suitability for continued ascent was examined. Four Taiwanese climbers were enrolled in the 2009 Mount Everest summit program. Physiological measurements were taken at base camp (5300 m), camp 2 (6400 m), camp 3 (7100 m), and camp 4 (7950 m) 1 hour after arrival and following a 10 minute rest period. A total of 3 out of 4 climbers were able to summit Mount Everest successfully. Overall, ECG and global positioning system (GPS) coordinates of climbers were transmitted in real-time via satellite phone successfully from base camp, camp 2, camp 3, and camp 4. At each camp, Resting Heart Rate (RHR) was transmitted and recorded: base camp (54-113 bpm), camp 2 (94 130 bpm), camp 3 (98-115 bpm), and camp 4 (93-111 bpm). Real-time ECG and GPS coordinate transmission via satellite phone is feasible for climbers on Mount Everest. Real-time RHR data can be used to evaluate a climber's physiological capacity to continue an ascent and to summit. PMID- 23818946 TI - Effects of hydrostatic pressure on growth and luminescence of a moderately piezophilic luminous bacteria Photobacterium phosphoreum ANT-2200. AB - Bacterial bioluminescence is commonly found in the deep sea and depends on environmental conditions. Photobacterium phosphoreum ANT-2200 has been isolated from the NW Mediterranean Sea at 2200-m depth (in situ temperature of 13 degrees C) close to the ANTARES neutrino telescope. The effects of hydrostatic pressure on its growth and luminescence have been investigated under controlled laboratory conditions, using a specifically developed high-pressure bioluminescence system. The growth rate and the maximum population density of the strain were determined at different temperatures (from 4 to 37 degrees C) and pressures (from 0.1 to 40 MPa), using the logistic model to define these two growth parameters. Indeed, using the growth rate only, no optimal temperature and pressure could be determined. However, when both growth rate and maximum population density were jointly taken into account, a cross coefficient was calculated. By this way, the optimum growth conditions for P. phosphoreum ANT-2200 were found to be 30 degrees C and, 10 MPa defining this strain as mesophile and moderately piezophile. Moreover, the ratio of unsaturated vs. saturated cellular fatty acids was found higher at 22 MPa, in agreement with previously described piezophile strains. P. phosphoreum ANT-2200 also appeared to respond to high pressure by forming cell aggregates. Its maximum population density was 1.2 times higher, with a similar growth rate, than at 0.1 MPa. Strain ANT-2200 grown at 22 MPa produced 3 times more bioluminescence. The proposed approach, mimicking, as close as possible, the in situ conditions, could help studying deep-sea bacterial bioluminescence and validating hypotheses concerning its role into the carbon cycle in the deep ocean. PMID- 23818947 TI - How the visual cortex handles stimulus noise: insights from amblyopia. AB - Adding noise to a visual image makes object recognition more effortful and has a widespread effect on human electrophysiological responses. However, visual cortical processes directly involved in handling the stimulus noise have yet to be identified and dissociated from the modulation of the neural responses due to the deteriorated structural information and increased stimulus uncertainty in the case of noisy images. Here we show that the impairment of face gender categorization performance in the case of noisy images in amblyopic patients correlates with amblyopic deficits measured in the noise-induced modulation of the P1/P2 components of single-trial event-related potentials (ERP). On the other hand, the N170 ERP component is similarly affected by the presence of noise in the two eyes and its modulation does not predict the behavioral deficit. These results have revealed that the efficient processing of noisy images depends on the engagement of additional processing resources both at the early, feature specific as well as later, object-level stages of visual cortical processing reflected in the P1 and P2 ERP components, respectively. Our findings also suggest that noise-induced modulation of the N170 component might reflect diminished face-selective neuronal responses to face images with deteriorated structural information. PMID- 23818949 TI - Genetic diversity and molecular evolution of Chinese waxy maize germplasm. AB - Waxy maize (Zea mays L. var. certaina Kulesh), with many excellent characters in terms of starch composition and economic value, has grown in China for a long history and its production has increased dramatically in recent decades. However, the evolution and origin of waxy maize still remains unclear. We studied the genetic diversity of Chinese waxy maize including typical landraces and inbred lines by SSR analysis and the results showed a wide genetic diversity in the Chinese waxy maize germplasm. We analyzed the origin and evolution of waxy maize by sequencing 108 samples, and downloading 52 sequences from GenBank for the waxy locus in a number of accessions from genus Zea. A sharp reduction of nucleotide diversity and significant neutrality tests (Tajima's D and Fu and Li's F*) were observed at the waxy locus in Chinese waxy maize but not in nonglutinous maize. Phylogenetic analysis indicated that Chinese waxy maize originated from the cultivated flint maize and most of the modern waxy maize inbred lines showed a distinct independent origin and evolution process compared with the germplasm from Southwest China. The results indicated that an agronomic trait can be quickly improved to meet production demand by selection. PMID- 23818948 TI - Potentiating the efficacy of molecular targeted therapy for hepatocellular carcinoma by inhibiting the insulin-like growth factor pathway. AB - Insulin-like growth factor (IGF) signaling pathway is an important regulatory mechanism of tumorigenesis and drug resistance in many cancers. The present study explored the potential synergistic effects between IGF receptor (IGFR) inhibition and other molecular targeted agents (MTA) in HCC cells. HCC cell lines (Hep3B, PLC5, and SK-Hep1) and HUVECs were tested. The MTA tested included sorafenib, sunitinib, and the IGFR kinase inhibitor NVP-AEW541. The potential synergistic antitumor effects were tested by median dose effect analysis and apoptosis assay in vitro and by xenograft models in vivo. The activity and functional significance of pertinent signaling pathways and expression of apoptosis-related proteins were measured by RNA interference and Western blotting. We found that IGF can activate IGFR and downstream AKT signaling activities in all the HCC cells tested, but the growth-stimulating effect of IGF was most prominent in Hep3B cells. NVP-AEW541 can abrogate IGF-induced activation of IGFR and AKT signaling in HCC cells. IGF can increase the resistance of HCC cells to sunitinib. The apoptosis-inducing effects of sunitinib, but not sorafenib, were enhanced when IGFR signaling activity was inhibited by NVP-AEW541 or IGFR knockdown. Chk2 kinase activation was found contributory to the synergistic anti tumor effects between sunitinib and IGFR inhibition. Our data indicate that the apoptosis-potentiating effects of IGFR inhibition for HCC may be drug-specific. Combination therapy of IGFR inhibitors with other MTA may improve the therapeutic efficacy in HCC. PMID- 23818950 TI - Turbo-FLASH based arterial spin labeled perfusion MRI at 7 T. AB - Motivations of arterial spin labeling (ASL) at ultrahigh magnetic fields include prolonged blood T1 and greater signal-to-noise ratio (SNR). However, increased B0 and B1 inhomogeneities and increased specific absorption ratio (SAR) challenge practical ASL implementations. In this study, Turbo-FLASH (Fast Low Angle Shot) based pulsed and pseudo-continuous ASL sequences were performed at 7T, by taking advantage of the relatively low SAR and short TE of Turbo-FLASH that minimizes susceptibility artifacts. Consistent with theoretical predictions, the experimental data showed that Turbo-FLASH based ASL yielded approximately 4 times SNR gain at 7T compared to 3T. High quality perfusion images were obtained with an in-plane spatial resolution of 0.85*1.7 mm(2). A further functional MRI study of motor cortex activation precisely located the primary motor cortex to the precentral gyrus, with the same high spatial resolution. Finally, functional connectivity between left and right motor cortices as well as supplemental motor area were demonstrated using resting state perfusion images. Turbo-FLASH based ASL is a promising approach for perfusion imaging at 7T, which could provide novel approaches to high spatiotemporal resolution fMRI and to investigate the functional connectivity of brain networks at ultrahigh field. PMID- 23818951 TI - Genome-wide DNA methylation analysis reveals a potential mechanism for the pathogenesis and development of uterine leiomyomas. AB - BACKGROUND: The pathogenesis of uterine leiomyomas, the most common benign tumor in women, remains unclear. Since acquired factors such as obesity, hypertension and early menarche place women at greater risk for uterine leiomyomas, uterine leiomyomas may be associated with epigenetic abnormalities that are caused by unfavorable environmental exposures. PRINCIPAL FINDINGS: Profiles of genome-wide DNA methylation and mRNA expression were investigated in leiomyomas and in myometrium with and without leiomyomas. Profiles of DNA methylation and mRNA expression in the myometrium with and without leiomyomas were quite similar while those in leiomyomas were distinct. We identified 120 genes whose DNA methylation and mRNA expression patterns differed between leiomyomas and the adjacent myometrium. The biological relevance of the aberrantly methylated and expressed genes was cancer process, including IRS1 that is related to transformation, and collagen-related genes such as COL4A1, COL4A2 and COL6A3. We also detected 22 target genes of estrogen receptor (ER) alpha, including apoptosis-related genes, that have aberrant DNA methylation in the promoter, suggesting that the aberrant epigenetic regulation of ER alpha-target genes contributes to the aberrant response to estrogen. CONCLUSIONS: Aberrant DNA methylation and its related transcriptional aberration were associated with cancer processes, which may represent a critical initial mechanism that triggers transformation of a single tumor stem cell that will eventually develop into a monoclonal leiomyoma tumor. The aberrant epigenetic regulation of ER alpha-target genes also may contribute to the aberrant response to estrogen, which is involved in the development of uterine leiomyomas after menarche. PMID- 23818952 TI - Tripeptidyl peptidase II regulates sperm function by modulating intracellular Ca(2+) stores via the ryanodine receptor. AB - Recent studies have identified Ca(2+) stores in sperm cells; however, it is not clear whether these Ca(2+) stores are functional and how they are mobilized. Here, in vitro and in vivo, we determined that tripeptidyl peptidase II antagonists strongly activated the cAMP/PKA signaling pathway that drives sperm capacitation-associated protein tyrosine phosphorylation. We demonstrated that in the absence of Ca(2+), TPIII antagonists elevated the intracellular Ca(2+) levels in sperm, resulting in a marked improvement in sperm movement, capacitation, acrosome reaction, and the in vitro fertilizing ability. This antagonist-induced release of intracellular Ca(2+) could be blocked by the inhibitors of ryanodine receptors (RyRs) which are the main intracellular Ca(2+) channels responsible for releasing stored Ca(2+). Consistent with these results, indirect immunofluorescence assay using anti-RyR antibodies further validated the presence of RyR3 in the acrosomal region of mature sperm. Thus, TPPII can regulate sperm maturation by modulating intracellular Ca(2+) stores via the type 3 RyR. PMID- 23818953 TI - Neuropathy in Parkinson's disease patients with intestinal levodopa infusion versus oral drugs. AB - BACKGROUND: Severe polyneuropathy has been observed in a number of patients treated for Parkinson's disease with Levodopa/Carbidopa intestinal gel infusion. This may reflect a rare individual complication or a systematic side effect. OBJECTIVE: To investigate whether peripheral nerve function differed between patients with oral treatment versus Levodopa/Carbidopa intestinal gel infusion. METHODS: In an observational design, data from median, tibial, and peroneal neurography were prospectively assessed and compared between patients with conventional drug treatment (n = 15) and with Levodopa/Carbidopa intestinal gel infusion (n = 15). The groups were matched for age and disease duration. In view of the medical risk profile for polyneuropathy, comorbidity and basic serological parameters were assessed. RESULTS: Axonal neuropathy was common in both patient groups. However, although group differences in risk factors for polyneuropathy were not evident, neurographic abnormalities were more severe in the patients treated with Levodopa/Carbidopa intestinal gel infusion than in the orally treated patients. In the group with Levodopa/Carbidopa intestinal gel infusion, the degree of neuropathic change correlated with weight lost since therapy initiation and with the drug dose. In contrast to the axonal abnormalities, conduction velocity was found normal in both groups. CONCLUSION: The results are compatible with the promotion of axonal neuropathy by Levodopa/Carbidopa intestinal gel infusion. This could be due to the intrinsically high levodopa doses associated with the therapy and/or malnutritional effects from intestinal drug application. The results should be corroborated by a larger longitudinal and controlled trial. PMID- 23818954 TI - The negative influence of high-glucose ambience on neurogenesis in developing quail embryos. AB - Gestational diabetes is defined as glucose intolerance during pregnancy and it is presented as high blood glucose levels during the onset pregnancy. This condition has an adverse impact on fetal development but the mechanism involved is still not fully understood. In this study, we investigated the effects of high glucose on the developing quail embryo, especially its impact on the development of the nervous system. We established that high glucose altered the central nervous system mophologically, such that neural tube defects (NTDs) developed. In addition, we found that high glucose impaired nerve differentiation at dorsal root ganglia and in the developing limb buds, as revealed by neurofilament (NF) immunofluorescent staining. The dorsal root ganglia are normally derived from neural crest cells (NCCs), so we examine the delamination of NCCs from dorsal side of the neural tube. We established that high glucose was detrimental to the NCCs, in vivo and in vitro. High glucose also negatively affected neural differentiation by reducing the number and length of neurites emanating from neurons in culture. We established that high glucose exposure caused an increase in reactive oxidative species (ROS) generation by primary cultured neurons. We hypothesized that excess ROS was the factor responsible for impairing neuron development and differentiation. We provided evidence for our hypothesis by showing that the addition of vitamin C (a powerful antioxidant) could rescue the damaging effects of high glucose on cultured neurons. PMID- 23818955 TI - Using magnetically responsive tea waste to remove lead in waters under environmentally relevant conditions. AB - We report the use of a simple yet highly effective magnetite-waste tea composite to remove lead(II) (Pb(2+)) ions from water. Magnetite-waste tea composites were dispersed in four different types of water-deionized (DI), artificial rainwater, artificial groundwater and artificial freshwater-that mimic actual environmental conditions. The water samples had varying initial concentrations (0.16-5.55 ppm) of Pb(2+) ions and were mixed with the magnetite-waste tea composite for at least 24 hours to allow adsorption of the Pb(2+) ions to reach equilibrium. The magnetite-waste tea composites were stable in all the water samples for at least 3 months and could be easily removed from the aqueous media via the use of permanent magnets. We detected no significant leaching of iron (Fe) ions into the water from the magnetite-waste tea composites. The percentage of Pb adsorbed onto the magnetite-waste tea composite ranged from ~70% to 100%; the composites were as effective as activated carbon (AC) in removing the Pb(2+) ions from water, depending on the initial Pb concentration. Our prepared magnetite-waste tea composites show promise as a green, inexpensive and highly effective sorbent for removal of Pb in water under environmentally realistic conditions. PMID- 23818956 TI - Ocular injury by transient formaldehyde exposure in a rabbit eye model. AB - Formaldehyde (FA) is frequently used in sterilizing surgical instruments and materials. Exposure to FA is highly concerned for eye tissues. Rabbit corneal epithelial cells were examined for changes after FA exposure. Our results showed that cell survival decreased 7 days after transient 3 min exposure to more than 100 ppm FA by trypan blue staining while MTT assay detected significant decrease at 20 ppm at 24 hours observation. The decrease of cell survival rate was concentration (up to 600 ppm)- and observation time (1-7 day)- dependent. The cell number decreased after 100 ppm FA exposure for more than 10 min at 7-day observation. The FA treated cells showed increased apoptosis/necrosis and cell cycle accumulation at sub G1 phase as well as mitochondria clustering around nucleus. The in vivo rabbit eye exposure for tear production by Schirmer's test revealed that the FA-induced overproduction of tear also exhibited observation time (1-10 day)- and FA concentration (20-300 ppm for 5 min exposure)-dependent. Activated extracellular signal-regulated kinase (pERK2) in cornea explants by western blotting was reduced and increased c-Jun amino - terminal kinase (JNK) activation (pJNK) in cornea and conjunctiva was evident at 2 month after exposure to 50-200 ppm FA for 5 min. In conclusion, injury to the eye with transient exposure of up to 100 ppm FA for 3 min decreased corneal cell survival while a more sensitive MTT test detected the cell decrease at 20 ppm FA exposure. Morphology changes can be observed even at 5 ppm FA exposure for 3 min at 7 days after. The FA exposure also increased apoptotic/necrotic cells and sub-G1 phase in cell cycle. Long term effect (2 months after exposure) on the eye tissues even after the removal of FA can be observed with persistent JNK activation in cornea and conjunctiva. PMID- 23818957 TI - Eubacterial SpoVG homologs constitute a new family of site-specific DNA-binding proteins. AB - A site-specific DNA-binding protein was purified from Borrelia burgdorferi cytoplasmic extracts, and determined to be a member of the highly conserved SpoVG family. This is the first time a function has been attributed to any of these ubiquitous bacterial proteins. Further investigations into SpoVG orthologues indicated that the Staphylococcus aureus protein also binds DNA, but interacts preferentially with a distinct nucleic acid sequence. Site-directed mutagenesis and domain swapping between the S. aureus and B. burgdorferi proteins identified that a 6-residue stretch of the SpoVG alpha-helix contributes to DNA sequence specificity. Two additional, highly conserved amino acid residues on an adjacent beta-sheet are essential for DNA-binding, apparently by contacts with the DNA phosphate backbone. Results of these studies thus identified a novel family of bacterial DNA-binding proteins, developed a model of SpoVG-DNA interactions, and provide direction for future functional studies on these wide-spread proteins. PMID- 23818958 TI - Crystal structure, SAXS and kinetic mechanism of hyperthermophilic ADP-dependent glucokinase from Thermococcus litoralis reveal a conserved mechanism for catalysis. AB - ADP-dependent glucokinases represent a unique family of kinases that belong to the ribokinase superfamily, being present mainly in hyperthermophilic archaea. For these enzymes there is no agreement about the magnitude of the structural transitions associated with ligand binding and whether they are meaningful to the function of the enzyme. We used the ADP-dependent glucokinase from Thermococcus litoralis as a model to investigate the conformational changes observed in X-ray crystallographic structures upon substrate binding and to compare them with those determined in solution in order to understand their interplay with the glucokinase function. Initial velocity studies indicate that catalysis follows a sequential ordered mechanism that correlates with the structural transitions experienced by the enzyme in solution and in the crystal state. The combined data allowed us to resolve the open-closed conformational transition that accounts for the complete reaction cycle and to identify the corresponding clusters of aminoacids residues responsible for it. These results provide molecular bases for a general mechanism conserved across the ADP-dependent kinase family. PMID- 23818959 TI - Endosymbiotic and host proteases in the digestive tract of the invasive snail Pomacea canaliculata: diversity, origin and characterization. AB - Digestive proteases of the digestive tract of the apple snail Pomacea canaliculata were studied. Luminal protease activity was found in the crop, the style sac and the coiled gut and was significantly higher in the coiled gut. Several protease bands and their apparent molecular weights were identified in both tissue extracts and luminal contents by gel zymography: (1) a 125 kDa protease in salivary gland extracts and in the crop content; (2) a 30 kDa protease throughout all studied luminal contents and in extracts of the midgut gland and of the endosymbionts isolated from this gland; (3) two proteases of 145 and 198 kDa in the coiled gut content. All these proteases were inhibited by aprotinin, a serine-protease inhibitor, and showed maximum activity between 30 degrees C and 35 degrees C and pH between 8.5 and 9.5. Tissue L-alanine-N aminopeptidase activity was determined in the wall of the crop, the style sac and the coiled gut and was significantly higher in the coiled gut. Our findings show that protein digestion in P. canaliculata is carried out through a battery of diverse proteases originated from the salivary glands and the endosymbionts lodged in the midgut gland and by proteases of uncertain origin that occur in the coiled gut lumen. PMID- 23818960 TI - Emergence and phylodynamics of Citrus tristeza virus in Sicily, Italy. AB - Citrus tristeza virus (CTV) outbreaks were detected in Sicily island, Italy for the first time in 2002. To gain insight into the evolutionary forces driving the emergence and phylogeography of these CTV populations, we determined and analyzed the nucleotide sequences of the p20 gene from 108 CTV isolates collected from 2002 to 2009. Bayesian phylogenetic analysis revealed that mild and severe CTV isolates belonging to five different clades (lineages) were introduced in Sicily in 2002. Phylogeographic analysis showed that four lineages co-circulated in the main citrus growing area located in Eastern Sicily. However, only one lineage (composed of mild isolates) spread to distant areas of Sicily and was detected after 2007. No correlation was found between genetic variation and citrus host, indicating that citrus cultivars did not exert differential selective pressures on the virus. The genetic variation of CTV was not structured according to geographical location or sampling time, likely due to the multiple introduction events and a complex migration pattern with intense co- and re-circulation of different lineages in the same area. The phylogenetic structure, statistical tests of neutrality and comparison of synonymous and nonsynonymous substitution rates suggest that weak negative selection and genetic drift following a rapid expansion may be the main causes of the CTV variability observed today in Sicily. Nonetheless, three adjacent amino acids at the p20 N-terminal region were found to be under positive selection, likely resulting from adaptation events. PMID- 23818961 TI - Morbidity before and after the diagnosis of hyperthyroidism: a nationwide register-based study. AB - BACKGROUND: Hyperthyroidism has been linked with different morbidities, like atrial fibrillation, stroke and diabetes mellitus. However, our knowledge regarding the extent and temporal relation between hyperthyroidism and other diseases is fragmented. Here, we aimed at evaluating various morbidities before and after the diagnosis of hyperthyroidism. METHODS: Observational cohort study. From nationwide Danish health registers 2631 hyperthyroid singletons and 375 twin pairs discordant for hyperthyroidism were identified and followed for an average of 6 years (range 0-13). Data on the occurrence of cardiovascular diseases, lung diseases, diabetes mellitus, rheumatic diseases and malignant diseases was obtained by person-to-person record linkage with the National Danish Patient Register and/or the Danish National Prescription Registry (lung diseases and diabetes mellitus). Logistic and Cox regression models were used to assess the risk of morbidity before and after the diagnosis of hyperthyroidism, respectively. All Cox regression analyses were adjusted for the degree of co morbidity preceding the diagnosis of hyperthyroidism, using the Charlson score. RESULTS: Hyperthyroid individuals had a significantly higher risk of being diagnosed with cardiovascular diseases (odds ratio (OR) 1.65; 95% confidence interval (CI): 1.45-1.87), lung diseases (OR 1.53; 95% CI: 1.29-1.60), and diabetes mellitus (OR 1.43, 95% CI: 1.20-1.72), but not with malignant diseases (OR 1.16, 95% CI: 0.99-1.36) prior to the diagnosis of hyperthyroidism. After the diagnosis of hyperthyroidism, subjects had a significantly higher risk of being diagnosed with cardiovascular diseases (hazard ratio (HR) 1.34; 95% CI: 1.15 1.56), lung diseases (HR 1.28; 95% CI: 1.10-1.49), and diabetes mellitus (HR 1.46; 95% CI: 1.16-1.84), but not with rheumatic diseases (HR 1.39, 95% CI: 0.92 2.09) or malignant diseases (HR 1.18, 95% CI 0.97-1.42). CONCLUSIONS: We demonstrate a significantly increased burden of morbidity, both before and after the diagnosis of hyperthyroidism. PMID- 23818962 TI - Angiogenesis inhibitor bevacizumab increases the risk of ischemic heart disease associated with chemotherapy: a meta-analysis. AB - Concerns have arisen regarding the risk of ischemic heart disease with the novel antiangiogenic agent bevacizumab, a recombinant humanised monoclonal antibody to the vascular endothelial growth factor that is widely used in cancer treatment. Currently, the role of bevacizumab in ischemic heart disease is controversial. This meta-analysis was therefore performed to assess the overall risk of ischemic heart disease associated with the use of bevacizumab. The databases of PubMed, EMBASE and Web of Science were searched for English language studies of randomised controlled trials comparing bevacizumab with control therapy published through October 25, 2012. Summary incidence rates, relative risks (RRs) and 95% confidence intervals (CIs) were calculated using random-effects or fixed-effects models based on the heterogeneity of the included studies. A total of 4,617 patients from 7 randomised controlled trials were identified and included for analysis. Among those patients receiving bevacizumab, the summary incidence of ischemic heart disease was 1.0% (95% CI, 0.6%-1.4%). Patients treated with bevacizumab had a significantly increased risk of ischemic heart disease with an RR of 2.49 (95% CI, 1.37-4.52) compared with controls. In addition, both high doses and low doses of bevacizumab increased the risk of cardiac ischemia (low dose at 2.5 mg/kg per week: RR, 2.14 [95% CI, 1.09-4.19]; high dose at 5 mg/kg per week: RR, 4.81 [95% CI, 1.03-22.42]). Bevacizumab was also found to significantly increase the risk of cardiac ischemia in patients with colorectal cancer (RR, 2.13; 95% CI, 1.11-4.06) compared with controls. This meta-analysis shows the use of bevacizumab was associated with an increased risk of developing ischemic heart disease in colorectal cancer patients receiving this drug. Our conclusions are limited by the available data. Further evaluations of high quality RCTs are needed. PMID- 23818963 TI - Calreticulin-STAT3 signaling pathway modulates mitochondrial function in a rat model of furazolidone-induced dilated cardiomyopathy. AB - BACKGROUND: Calreticulin is a Ca(2+)-binding chaperone of the endoplasmic reticulum which regulates the signal transducer and activator of transcription 3 (STAT3). The effects of the calreticulin-STAT3 signaling pathway on cardiac mitochondria and on the progress of dilated cardiomyopathy (DCM) are still unclear. METHODS AND RESULTS: The DCM model was generated in rats by the daily oral administration of furazolidone. Echocardiographic and hemodynamic studies demonstrated enlarged LV dimensions and reduced systolic and diastolic functions at thirty weeks after the first furazolidone administration. Morphometric analysis showed significant myocardial degeneration, interstitial fibrosis, and mitochondrial swelling with fractured or dissolved cristae in the model group. Compared with the control group, the mitochondrial membrane potential (MMP) level of the freshly isolated cardiac mitochondria and the enzyme activities of cytochrome c oxidase and succinate dehydrogenase in the model group were significantly decreased (P<0.05). Real-time PCR and western-blot revealed the increased expression of calreticulin associated with decreased activity of STAT3 in the model group. When cultured neonatal rat cardiomyocytes were exposed to furazolidone, a dose-dependent decrease in cell viability and MMP, and the increase of apoptosis rate were observed. The mRNA and protein expression of CRT gradually increased with the increase of furazolidone concentration, associated with a gradual decrease of the STAT3 phosphorylation level both in the whole cell and mitochondrial fraction. When calreticulin was knocked down with siRNA in cardiomyocytes, these changes of cardiomyocytes and mitochondria induced by furazolidone were significantly attenuated. CONCLUSIONS: A rat model of DCM induced by furazolidone is successfully established. The calreticulin-STAT3 signaling pathway is involved in cardiac mitochondrial injury and the progress of furazolidone induced DCM. PMID- 23818964 TI - HIV and hepatitis C virus testing delays at methadone clinics in Guangdong Province, China. AB - In China, injection drug use is a major transmission route for HIV and hepatitis C virus (HCV) infection. Timely HIV and HCV testing among drug users is vital to earlier diagnosis, linkage to care, and retention. This study aimed to examine HIV and hepatitis C virus (HCV) testing delays at methadone clinics in Guangdong Province, China, and identify individual-level and clinic-level factors associated with delayed testing. Data from 13,270 individuals at 45 methadone clinics in Guangdong were abstracted from a national web-based surveillance database. A two-level binomial logit model was used to examine the association between individual- and clinic-level factors and delayed HIV and HCV testing, defined as receiving a test seven or more days after initial entry into the methadone system. Among 10,046 patients tested for HIV, 1882 (18.7%) had delayed testing; among 10,404 patients tested for HCV, 1542 (14.8%) had delayed testing. Among delayed testers, the median time to HCV testing was significantly longer than the median time to HIV testing (73 vs. 54 days, p<0.05). In the multivariate analysis, the likelihood of delayed HIV testing was higher among individuals with high school or greater education (adjusted odds ratio [aOR] 1.32, 95% confidence interval [CI] 1.02-1.72) and individuals enrolled at clinics with more patients (aOR 1.41, 95% CI 1.05-1.91, for each increase in 100). The likelihood of delayed HCV testing was higher among women (aOR 1.51, 95% CI 1.11-2.06) and employed individuals (aOR 1.21, 95% CI 1.02-1.43). Delayed testing for HIV and HCV is common among patients at methadone clinics in Guangdong, with many patients experiencing delays of two or more months. Structural interventions are needed to expedite testing once individuals enter the methadone maintenance program. PMID- 23818965 TI - Polymorphisms of glucose-regulated protein 78 and risk of colorectal cancer: a case-control study in southwest China. AB - Glucose-regulated protein 78 (GRP78), an endoplasmic reticulum chaperone, up regulation serves as an efficient mechanism to promote malignant transformation of colorectal cancer (CRC) and protect CRC cells against apoptosis. Recently, the analysis of GRP78 polymorphisms has already determined that GRP78 rs391957 polymorphism could predict clinical outcome in CRC patients. Thus, we tested whether GRP78 polymorphisms are related to the risk of CRC. In this study, we detected two GRP78 polymorphisms (rs391957 (C>T) and rs430397 (G>A)) in 414 CRC cases and 502 hospital-based cancer-free healthy controls in Southwest China using a polymerase chain reaction-restriction fragment length polymorphism technique. Compared with the CC genotype, carriers of CT and TT genotypes of rs391957 polymorphism had higher risks of CRC (odds ratio (OR) = 1.39, 95% confidence interval (CI) = 1.06-1.83 for CT genotype and OR = 2.10, 95% CI = 1.06 4.14 for TT genotype, respectively). In CRC cases, the variant T allele was significantly associated with tumor invasion stage (P = 0.030), but not with status of lymph nodes metastasis (P = 0.052). Compared with the GG genotype, carriers of GA and AA genotypes of rs430397 polymorphism had higher risks of CRC (OR = 1.63, 95% CI = 1.23-2.15 for GA genotype and OR = 2.92, 95% CI = 1.23-6.94 for AA genotype, respectively). The rs430397 polymorphism was not associated with the clinicopathological characteristics of CRC. These data provide the first evidence that GRP78 rs391957 and rs430397 polymorphisms could serve as markers to predict the risk of CRC. PMID- 23818966 TI - Volatile compound-mediated interactions between barley and pathogenic fungi in the soil. AB - Plants are able to interact with their environment by emitting volatile organic compounds. We investigated the volatile interactions that take place below ground between barley roots and two pathogenic fungi, Cochliobolus sativus and Fusarium culmorum. The volatile molecules emitted by each fungus, by non-infected barley roots and by barley roots infected with one of the fungi or the two of them were extracted by head-space solid phase micro extraction and analyzed by gas chromatography mass spectrometry. The effect of fungal volatiles on barley growth and the effect of barley root volatiles on fungal growth were assessed by cultivating both organisms in a shared atmosphere without any physical contact. The results show that volatile organic compounds, especially terpenes, are newly emitted during the interaction between fungi and barley roots. The volatile molecules released by non-infected barley roots did not significantly affect fungal growth, whereas the volatile molecules released by pathogenic fungi decreased the length of barley roots by 19 to 21.5% and the surface of aerial parts by 15%. The spectrum of the volatiles released by infected barley roots had no significant effect on F. culmorum growth, but decreased C. sativus growth by 13 to 17%. This paper identifies the volatile organic compounds emitted by two pathogenic fungi and shows that pathogenic fungi can modify volatile emission by infected plants. Our results open promising perspectives concerning the biological control of edaphic diseases. PMID- 23818967 TI - Modeling habitat split: landscape and life history traits determine amphibian extinction thresholds. AB - Habitat split is a major force behind the worldwide decline of amphibian populations, causing community change in richness and species composition. In fragmented landscapes, natural remnants, the terrestrial habitat of the adults, are frequently separated from streams, the aquatic habitat of the larvae. An important question is how this landscape configuration affects population levels and if it can drive species to extinction locally. Here, we put forward the first theoretical model on habitat split which is particularly concerned on how split distance - the distance between the two required habitats - affects population size and persistence in isolated fragments. Our diffusive model shows that habitat split alone is able to generate extinction thresholds. Fragments occurring between the aquatic habitat and a given critical split distance are expected to hold viable populations, while fragments located farther away are expected to be unoccupied. Species with higher reproductive success and higher diffusion rate of post-metamorphic youngs are expected to have farther critical split distances. Furthermore, the model indicates that negative effects of habitat split are poorly compensated by positive effects of fragment size. The habitat split model improves our understanding about spatially structured populations and has relevant implications for landscape design for conservation. It puts on a firm theoretical basis the relation between habitat split and the decline of amphibian populations. PMID- 23818968 TI - Lineage-specific expansion of IFIT gene family: an insight into coevolution with IFN gene family. AB - In mammals, IFIT (Interferon [IFN]-induced proteins with Tetratricopeptide Repeat [TPR] motifs) family genes are involved in many cellular and viral processes, which are tightly related to mammalian IFN response. However, little is known about non-mammalian IFIT genes. In the present study, IFIT genes are identified in the genome databases from the jawed vertebrates including the cartilaginous elephant shark but not from non-vertebrates such as lancelet, sea squirt and acorn worm, suggesting that IFIT gene family originates from a vertebrate ancestor about 450 million years ago. IFIT family genes show conserved gene structure and gene arrangements. Phylogenetic analyses reveal that this gene family has expanded through lineage-specific and species-specific gene duplication. Interestingly, IFN gene family seem to share a common ancestor and a similar evolutionary mechanism; the function link of IFIT genes to IFN response is present early since the origin of both gene families, as evidenced by the finding that zebrafish IFIT genes are upregulated by fish IFNs, poly(I:C) and two transcription factors IRF3/IRF7, likely via the IFN-stimulated response elements (ISRE) within the promoters of vertebrate IFIT family genes. These coevolution features creates functional association of both family genes to fulfill a common biological process, which is likely selected by viral infection during evolution of vertebrates. Our results are helpful for understanding of evolution of vertebrate IFN system. PMID- 23818969 TI - p21-activated kinase 3 (PAK3) is an AP-1 regulated gene contributing to actin organisation and migration of transformed fibroblasts. AB - Activating Protein 1 (AP-1) plays a vital role in cell proliferation, differentiation and apoptosis. While de-regulation of AP-1 has been linked to many cancers, little is known regarding its downstream transcriptional targets that associate with cellular transformation. Previous studies identified PAK3, a serine/threonine kinase, as a potential AP-1 target gene. PAK3 has been implicated in a variety of pathological disorders and over-expression of other PAK-family members has been linked to cancer. In this study, we investigate AP-1 regulation of PAK3 expression and the role of PAK3 in cJun/AP-1-associated cellular transformation. Our results showed elevated PAK3 expression at both the mRNA and protein level in cJun-over-expressing Rat1a fibroblasts, as well as in transformed human fibroblasts. Elevated PAK3 expression in cJun/AP-1 over expressing cells associated with a significant increase in PAK3 promoter activation. This increased promoter activity was lost when a single putative Jun binding site, which can bind AP-1 directly both in vitro and in vivo, was mutated. Further, inhibition of PAK3 using siRNA showed a regression in the cell morphology, migratory potential and actin organisation associated with AP-1 transformed cells. Our study is a first to describe a role for AP-1 in regulating PAK3 expression and suggest that PAK3 is an AP-1 target required for actin organization and migration observed in transformed cells. PMID- 23818970 TI - Do non-glycaemic markers add value to plasma glucose and hemoglobin a1c in predicting diabetes? Yuport health checkup center study. AB - BACKGROUND: Many markers have been indicated as predictors of type 2 diabetes. However, the question of whether or not non-glycaemic (blood) biomarkers and non blood biomarkers have a predictive additive utility when combined with glycaemic (blood) biomarkers is unknown. The study aim is to assess this additive utility in a large Japanese population. METHODS: We used data from a retrospective cohort study conducted from 1998 to 2002 for the baseline and 2002 to 2006 for follow up, inclusive of 5,142 men (mean age of 51.9 years) and 4,847 women (54.1 years) at baseline. The cumulative incidence of diabetes [defined either as a fasting plasma glucose (FPG) >=7.00 mmol/l or as clinically diagnosed diabetes] was measured. In addition to glycaemic biomarkers [FPG and hemoglobin A1c (HbA1c)], we examined the clinical usefulness of adding non-glycaemic biomarkers and non blood biomarkers, using sensitivity and specificity, and the area under the curve (AUC) of the receiver operating characteristics. RESULTS: The AUCs to predict diabetes were 0.874 and 0.924 for FPG, 0.793 and 0.822 for HbA1c, in men and women, respectively. Glycaemic biomarkers were the best and second-best for diabetes prediction among the markers. All non-glycaemic markers (except uric acid in men and creatinine in both sexes) predicted diabetes. Among these biomarkers, the highest AUC in the single-marker analysis was 0.656 for alanine aminotransferase (ALT) in men and 0.740 for body mass index in women. The AUC of the combined markers of FPG and HbA1c was 0.895 in men and 0.938 in women, which were marginally increased to 0.904 and 0.940 when adding ALT, respectively. CONCLUSIONS: AUC increments were marginal when adding non-glycaemic biomarkers and non-blood biomarkers to the classic model based on FPG and HbA1c. For the prediction of diabetes, FPG and HbA1c are sufficient and the other markers may not be needed in clinical practice. PMID- 23818971 TI - Effects of picoxystrobin and 4-n-nonylphenol on soil microbial community structure and respiration activity. AB - There is widespread use of chemical amendments to meet the demands for increased productivity in agriculture. Potentially toxic compounds, single or in mixtures, are added to the soil medium on a regular basis, while the ecotoxicological risk assessment procedures mainly follow a chemical by chemical approach. Picoxystrobin is a fungicide that has caused concern due to studies showing potentially detrimental effects to soil fauna (earthworms), while negative effects on soil microbial activities (nitrification, respiration) are shown to be transient. Potential mixture situations with nonylphenol, a chemical frequently occurring as a contaminant in sewage sludge used for land application, infer a need to explore whether these chemicals in mixture could alter the potential effects of picoxystrobin on the soil microflora. The main objective of this study was to assess the effects of picoxystrobin and nonylphenol, as single chemicals and mixtures, on soil microbial community structure and respiration activity in an agricultural sandy loam. Effects of the chemicals were assessed through measurements of soil microbial respiration activity and soil bacterial and fungal community structure fingerprints, together with a degradation study of the chemicals, through a 70 d incubation period. Picoxystrobin caused a decrease in the respiration activity, while 4-n-nonylphenol caused an increase in respiration activity concurring with a rapid degradation of the substance. Community structure fingerprints were also affected, but these results could not be directly interpreted in terms of positive or negative effects, and were indicated to be transient. Treatment with the chemicals in mixture caused less evident changes and indicated antagonistic effects between the chemicals in soil. In conclusion, the results imply that the application of the fungicide picoxystrobin and nonylphenol from sewage sludge application to agricultural soil in environmentally relevant concentrations, as single chemicals or in mixture, will not cause irreversible effects on soil microbial respiration and community structure. PMID- 23818972 TI - Bone mineral density, bone turnover markers and fractures in patients with systemic sclerosis: a case control study. AB - OBJECTIVE: The aim of our study was to elucidate the pathophysiology of systemic sclerosis-related osteoporosis and the prevalence of vertebral fragility fracture in postmenopausal women with systemic sclerosis (SSc). METHODOLOGY: Fifty-four postmenopausal women with scleroderma and 54 postmenopausal controls matched for age, BMI, and smoking habits were studied. BMD was measured by dual energy-x-ray absorptiometry at spine and femur, and by ultrasonography at calcaneus The markers of bone turnover included serum osteocalcin and urinary deoxypyridinoline. All subjects had a spine X-ray to ascertain the presence of vertebral fractures. RESULTS: bone mineral density at lumbar spine (BMD 0.78+/ 0.08 vs 0.88+/-0.07; p<0,001), femoral neck (BMD: 0.56+/-0.04 vs 0.72+/-0.07; p<0,001) and total femur (BMD: 0.57+/-0.04 vs 0.71+/-0.06; p<0,001) and ultrasound parameter at calcaneus (SI: 80.10+/-5.10 vs 94.80+/-6.10 p<0,001) were significantly lower in scleroderma compared with controls; bone turnover markers and parathyroid hormone level were significantly higher in scleroderma compared with controls, while serum of 25(OH)D3 was significantly lower. In scleroderma group the serum levels of 25(OH)D3 significantly correlated with PTH levels, BMD, stiffness index and bone turnover markers. One or more moderate or severe vertebral fractures were found in 13 patients with scleroderma, wherease in control group only one patient had a mild vertebral fracture. CONCLUSION: Our data shows, for the first time, that vertebral fractures are frequent in subjects with scleroderma, and suggest that lower levels of 25(OH)D3 may play a role in the risk of osteoporosis and vertebral fractures. PMID- 23818973 TI - Systematic examination of infant size and growth metrics as risk factors for overweight in young adulthood. AB - OBJECTIVE: To systematically examine infant size and growth, according to the 2006 WHO infant growth standards, as risk factors for overweight status in young adulthood in a historical cohort. Specifically, to assess: Whether accounting for length (weight-for-length) provides a different picture of risk than weight-for age, intervals of rapid growth in both weight-for-age and weight-for-length metrics, and what particular target ages for infant size and intervals of rapid growth associate most strongly with overweight as a young adult. PATIENTS/METHODS: Data analysis of 422 appropriate for gestational age white singleton infants enrolled in the Fels Longitudinal Study. Odds ratios (OR) for overweight and obesity in young adulthood (age 20-29) were calculated using logistic regression models for the metrics at each target age (0, 1, 3, 6, 9, 12, 18, 24 months) comparing >=85(th) v. <85(th) percentile, as well as rapid growth (Delta>=0.67 Z-score) through target age intervals. Models accounted for both maternal and paternal BMI. RESULTS: Infants >=85(th) percentile of weight-for-age at each target age (except 3 months) had a greater odds of being overweight as a young adult. After accounting for length (weight-for-length) this association was limited to 12, and 18 months. Rapid weight-for-age growth was infrequently associated with overweight as a young adult. Rapid weight-for-length growth from 0 to 24 months, 1 to 6, 9, 12, 18, and 24 months and from 3 to 9, 12, 18, and 24 months was strongly associated with overweight status as a young adult. CONCLUSIONS: The WHO weight-for-length metric associates differently with risk of being overweight as a young adult compared to weight-for-age. Intervals of rapid weight-for-length growth ranging from months (0-24), (1-12, 18, and 24) and (3-9, and 12) displayed the largest OR for being overweight as a young adult. PMID- 23818974 TI - The perception of dynamic and static facial expressions of happiness and disgust investigated by ERPs and fMRI constrained source analysis. AB - A recent functional magnetic resonance imaging (fMRI) study by our group demonstrated that dynamic emotional faces are more accurately recognized and evoked more widespread patterns of hemodynamic brain responses than static emotional faces. Based on this experimental design, the present study aimed at investigating the spatio-temporal processing of static and dynamic emotional facial expressions in 19 healthy women by means of multi-channel electroencephalography (EEG), event-related potentials (ERP) and fMRI-constrained regional source analyses. ERP analysis showed an increased amplitude of the LPP (late posterior positivity) over centro-parietal regions for static facial expressions of disgust compared to neutral faces. In addition, the LPP was more widespread and temporally prolonged for dynamic compared to static faces of disgust and happiness. fMRI constrained source analysis on static emotional face stimuli indicated the spatio-temporal modulation of predominantly posterior regional brain activation related to the visual processing stream for both emotional valences when compared to the neutral condition in the fusiform gyrus. The spatio-temporal processing of dynamic stimuli yielded enhanced source activity for emotional compared to neutral conditions in temporal (e.g., fusiform gyrus), and frontal regions (e.g., ventromedial prefrontal cortex, medial and inferior frontal cortex) in early and again in later time windows. The present data support the view that dynamic facial displays trigger more information reflected in complex neural networks, in particular because of their changing features potentially triggering sustained activation related to a continuing evaluation of those faces. A combined fMRI and EEG approach thus provides an advanced insight to the spatio-temporal characteristics of emotional face processing, by also revealing additional neural generators, not identifiable by the only use of an fMRI approach. PMID- 23818975 TI - Influence of approach velocity and mesh size on the entrainment and contact of a lowland river fish assemblage at a screened irrigation pump. AB - Fish screens can help prevent the entrainment or injury of fish at irrigation diversions, but only when designed appropriately. Design criteria cannot simply be transferred between sites or pump systems and need to be developed using an evidence-based approach with the needs of local species in mind. Laboratory testing is typically used to quantify fish responses at intake screens, but often limits the number of species that can studied and creates artificial conditions not directly applicable to screens in the wild. In this study a field-based approach was used to assess the appropriateness of different screen design attributes for the protection of a lowland river fish assemblage at an experimental irrigation pump. Direct netting of entrained fish was used along with sonar technology to quantify the probability of screen contact for a Murray Darling Basin (Australia) fish species. Two approach velocities (0.1 and 0.5 m.sec(-1)) and different sizes of woven mesh (5, 10 and 20 mm) were evaluated. Smaller fish (<150 mm) in the assemblage were significantly more susceptible to entrainment and screen contact, especially at higher approach velocities. Mesh size appeared to have little impact on screen contact and entrainment, suggesting that approach velocity rather than mesh size is likely to be the primary consideration when developing screens. Until the effects of screen contacts on injury and survival of these species are better understood, it is recommended that approach velocities not exceed 0.1 m.sec(-1) when the desire is to protect the largest range of species and size classes for lowland river fish assemblages in the Murray-Darling Basin. The field method tested proved to be a useful approach that could compliment laboratory studies to refine fish screen design and facilitate field validation. PMID- 23818976 TI - Changes in functional integration with the non-epileptic temporal lobe of patients with unilateral mesiotemporal epilepsy. AB - PURPOSE: To investigate epilepsy-induced changes in effective connectivity between the non-epileptic amygdalo-hippocampal complex (AHC) and the rest of the brain in patients with unilateral mesiotemporal lobe epilepsy (MTLE) associated with hippocampal sclerosis (HS). METHODS: Thirty-three patients with unilateral MTLE associated with HS (20 females, mean age: 36 years, 19 left HS) and 33 adult controls matched for age and gender underwent (18)F-Fluorodeoxyglucose positron emission tomography (FDG-PET). Right-HS patients' FDG-PET data were flipped to obtain a left-epileptic-focus-lateralized group of patients. Voxels of interest (VOI) were selected within the cytoarchitectonic probabilistic maps of the non epileptic AHC (probability level = 100%, SPM8 Anatomy toolbox v1.7). Patients and controls were compared using VOI metabolic activity as covariate of interest to search for epilepsy-induced changes in the contribution of the non-epileptic AHC to the level of metabolic activity in other brain areas. Age, gender, duration of epilepsy, seizure type and frequency were used as covariates of no interest for connectivity analyses. KEY FINDINGS: Significant decrease in effective connectivity was found between the non-epileptic AHC and ventral prefrontal cortical areas bilaterally, as well as with the temporal pole and the posterior cingulate cortex contralateral to HS. Significant increase in connectivity was found between the non-epileptic AHC and midline structures, such as the anterior cingulate and dorsal medial prefrontal cortices, as well as the temporo-parietal junction bilaterally. Connectivity analyses also revealed a preserved positive connectivity between the non-epileptic and the epileptic AHC in the patients' group. SIGNIFICANCE: This study evidences epilepsy-induced changes in connectivity between the non-epileptic AHC and some limbic and default mode network areas. These changes in connectivity probably account for emotional, cognitive and decision-making impairments frequently observed in MTLE patients. The preserved neurometabolic connectivity between the non-epileptic and the epileptic AHC in MTLE patients is pivotal to explain the epilepsy-induced changes found in this study. PMID- 23818977 TI - Characterization of pyruvate uptake in Escherichia coli K-12. AB - The monocarboxylate pyruvate is an important metabolite and can serve as sole carbon source for Escherichia coli. Although specific pyruvate transporters have been identified in two bacterial species, pyruvate transport is not well understood in E. coli. In the present study, pyruvate transport was investigated under different growth conditions. The transport of pyruvate shows specific activities depending on the growth substrate used as sole carbon source, suggesting the existence of at least two systems for pyruvate uptake: i) one inducible system and probably highly specific for pyruvate and ii) one system active under non-induced conditions. Using the toxic pyruvate analog 3 fluoropyruvate, a mutant was isolated unable to grow on and transport pyruvate. Further investigation revealed that a revertant selected for growth on pyruvate regained the inducible pyruvate transport activity. Characterization of pyruvate excretion showed that the pyruvate transport negative mutant accumulated pyruvate in the growth medium suggesting an additional transport system for pyruvate excretion. The here presented data give valuable insight into the pyruvate metabolism and transport of E. coli suggesting the presence of at least two uptake systems and one excretion system to balance the intracellular level of pyruvate. PMID- 23818978 TI - Powdery mildew resistance in tomato by impairment of SlPMR4 and SlDMR1. AB - Genetic dissection of disease susceptibility in Arabidopsis to powdery and downy mildew has identified multiple susceptibility (S) genes whose impairment results in disease resistance. Although several of these S-genes have been cloned and characterized in more detail it is unknown to which degree their function in disease susceptibility is conserved among different plant species. Moreover, it is unclear whether impairment of such genes has potential in disease resistance breeding due to possible fitness costs associated with impaired alleles. Here we show that the Arabidopsis PMR4 and DMR1, genes encoding a callose synthase and homoserine kinase respectively, have functional orthologs in tomato with respect to their S-gene function. Silencing of both genes using RNAi resulted in resistance to the tomato powdery mildew fungus Oidium neolycopersici. Resistance to O. neolycopersici by SlDMR1 silencing was associated with severely reduced plant growth whereas SlPMR4 silencing was not. SlPMR4 is therefore a suitable candidate gene as target for mutagenesis to obtain alleles that can be deployed in disease resistance breeding of tomato. PMID- 23818979 TI - A novel C-type lysozyme from Mytilus galloprovincialis: insight into innate immunity and molecular evolution of invertebrate C-type lysozymes. AB - A c-type lysozyme (named as MgCLYZ) gene was cloned from the mussel Mytilus galloprovincialis. Blast analysis indicated that MgCLYZ was a salivary c-type lysozyme which was mainly found in insects. The nucleotide sequence of MgCLYZ was predicted to encode a polypeptide of 154 amino acid residues with the signal peptide comprising the first 24 residues. The deduced mature peptide of MgCLYZ was of a calculated molecular weight of 14.4 kD and a theoretical isoelectric point (pI) of 8.08. Evolution analysis suggested that bivalve branch of the invertebrate c-type lysozymes phylogeny tree underwent positive selection during evolution. By quantitative real-time RT-PCR (qRT-PCR) analysis, MgCLYZ transcript was widely detected in all examined tissues and responded sensitively to bacterial challenge in hemocytes and hepatopancreas. The optimal temperature and pH of recombinant MgCLYZ (rMgCLYZ) were 20 degrees C and 4, respectively. The rMgCLYZ displayed lytic activities against Gram-positive bacteria including Micrococcus luteus and Staphyloccocus aureus, and Gram-negative bacteria including Vibrio anguillarum, Enterobacter cloacae, Pseudomonas putida, Proteus mirabilis and Bacillus aquimaris. These results suggest that MgCLYZ perhaps play an important role in innate immunity of M. galloprovincialis, and invertebrate c type lysozymes might be under positive selection in a species-specific manner during evolution for undergoing adaptation to different environment and diverse pathogens. PMID- 23818980 TI - Effect of mild hypothermia on the coagulation-fibrinolysis system and physiological anticoagulants after cardiopulmonary resuscitation in a porcine model. AB - The aim of this study was to evaluate the effect of mild hypothermia on the coagulation-fibrinolysis system and physiological anticoagulants after cardiopulmonary resuscitation (CPR). A total of 20 male Wuzhishan miniature pigs underwent 8 min of untreated ventricular fibrillation and CPR. Of these, 16 were successfully resuscitated and were randomized into the mild hypothermia group (MH, n = 8) or the control normothermia group (CN, n = 8). Mild hypothermia (33 degrees C) was induced intravascularly, and this temperature was maintained for 12 h before pigs were actively rewarmed. The CN group received normothermic post cardiac arrest (CA) care for 72 h. Four animals were in the sham operation group (SO). Blood samples were taken at baseline, and 0.5, 6, 12, 24, and 72 h after ROSC. Whole-body mild hypothermia impaired blood coagulation during cooling, but attenuated blood coagulation impairment at 72 h after ROSC. Mild hypothermia also increased serum levels of physiological anticoagulants, such as PRO C and AT-III during cooling and after rewarming, decreased EPCR and TFPI levels during cooling but not after rewarming, and inhibited fibrinolysis and platelet activation during cooling and after rewarming. Finally, mild hypothermia did not affect coagulation-fibrinolysis, physiological anticoagulants, or platelet activation during rewarming. Thus, our findings indicate that mild hypothermia exerted an anticoagulant effect during cooling, which may have inhibitory effects on microthrombus formation. Furthermore, mild hypothermia inhibited fibrinolysis and platelet activation during cooling and attenuated blood coagulation impairment after rewarming. Slow rewarming had no obvious adverse effects on blood coagulation. PMID- 23818981 TI - The impact of food viscosity on eating rate, subjective appetite, glycemic response and gastric emptying rate. AB - Understanding the impact of rheological properties of food on postprandial appetite and glycemic response helps to design novel functional products. It has been shown that solid foods have a stronger satiating effect than their liquid equivalent. However, whether a subtle change in viscosity of a semi-solid food would have a similar effect on appetite is unknown. Fifteen healthy males participated in the randomized cross-over study. Each participant consumed a 1690 kJ portion of a standard viscosity (SV) and a high viscosity (HV) semi-solid meal with 1000 mg acetaminophen in two separate sessions. At regular intervals during the three hours following the meal, subjective appetite ratings were measured and blood samples collected. The plasma samples were assayed for insulin, glucose dependent insulinotropic peptide (GIP), glucose and acetaminophen. After three hours, the participants were provided with an ad libitum pasta meal. Compared with the SV meal, HV was consumed at a slower eating rate (P = 0.020), with postprandial hunger and desire to eat being lower (P = 0.019 and P<0.001 respectively) while fullness was higher (P<0.001). In addition, consuming the HV resulted in lower plasma concentration of GIP (P<0.001), higher plasma concentration of glucose (P<0.001) and delayed gastric emptying as revealed by the acetaminophen absorption test (P<0.001). However, there was no effect of food viscosity on insulin or food intake at the subsequent meal. In conclusion, increasing the viscosity of a semi-solid food modulates glycemic response and suppresses postprandial satiety, although the effect may be short-lived. A slower eating rate and a delayed gastric emptying rate can partly explain for the stronger satiating properties of high viscous semi-solid foods. PMID- 23818982 TI - Possible secondary population-level effects of selective harvest of adult male muskoxen. AB - Selective harvest regimes are often focused on males resulting in skewed sex ratios, and for many ungulate species this strategy is sustainable. However, muskoxen (Ovibos moschatus) are very social and mature bulls (>=4 years old), particularly prime-age bulls (6-10 years old), play important roles in predator defense and recruitment. A year-round social structure incorporating large males into mixed-sex groups could make this species more susceptible to the effects of selective harvest if population composition and sex-ratios influence overall survival and reproductive success. Using detailed data collected on the muskox population occupying the Seward Peninsula, Alaska during 2002-2012, we formulated the hypothesis that the selective harvest of mature bulls may be related to documented changes in population composition and growth rates in this species. In addition, we reviewed existing published information from two other populations in Alaska, the Cape Thompson and Northeastern populations, to compare population growth rates among the three areas under differential harvest rates relative to our hypothesis. We found that on the Seward Peninsula, mature bull:adult cow ratios declined 4-12%/year and short-yearling:adult cow ratios (i.e., recruitment) declined 8-9%/year in the most heavily harvested areas. Growth rates in all 3 populations decreased disproportionately after increases in the number of bulls harvested, and calf:cow ratios declined in the Northeastern population as harvest increased. While lack of appropriate data prevented us from excluding other potential causes such as density dependent effects and changes in predator densities, our results did align with our hypothesis, suggesting that in the interest of conservation, harvest of mature males should be restricted until causal factors can be more definitively identified. If confirmed by additional research, our findings would have important implications for harvest management and conservation of muskoxen and other ungulate species with similar life histories. PMID- 23818984 TI - Homocysteine restricts copper availability leading to suppression of cytochrome C oxidase activity in phenylephrine-treated cardiomyocytes. AB - Cardiomyocyte hypertrophy induced by phenylephrine (PE) is accompanied by suppression of cytochrome c oxidase (CCO) activity, and copper (Cu) supplementation restores CCO activity and reverses the hypertrophy. The present study was aimed to understand the mechanism of PE-induced decrease in CCO activity. Primary cultures of neonatal rat cardiomyocytes were treated with PE at a final concentration of l00 uM in cultures for 72 h to induce cell hypertrophy. The CCO activity was determined by enzymatic assay and changes in CCO subunit COX IV as well as copper chaperones for CCO (COX17, SCO2, and COX11) were determined by Western blotting. PE treatment increased both intracellular and extracellular homocysteine concentrations and decreased intracellular Cu concentrations. Studies in vitro found that homocysteine and Cu form complexes. Inhibition of the intracellular homocysteine synthesis in the PE-treated cardiomyocytes prevented the increase in the extracellular homocysteine concentration, retained the intracellular Cu concentration, and preserved the CCO activity. PE treatment decreased protein concentrations of the COX-IV, and the Cu chaperones COX17, COX11, and SCO2. These PE effects were prevented by either inhibition of the intracellular homocysteine synthesis or Cu supplementation. Therefore, PE-induced elevation of homocysteine restricts Cu availability through its interaction with Cu and suppression of Cu chaperones, leading to the decrease in CCO enzyme activity. PMID- 23818983 TI - Application of high-density DNA resequencing microarray for detection and characterization of botulinum neurotoxin-producing clostridia. AB - BACKGROUND: Clostridium botulinum and related clostridia express extremely potent toxins known as botulinum neurotoxins (BoNTs) that cause severe, potentially lethal intoxications in humans. These BoNT-producing bacteria are categorized in seven major toxinotypes (A through G) and several subtypes. The high diversity in nucleotide sequence and genetic organization of the gene cluster encoding the BoNT components poses a great challenge for the screening and characterization of BoNT-producing strains. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we designed and evaluated the performances of a resequencing microarray (RMA), the PathogenId v2.0, combined with an automated data approach for the simultaneous detection and characterization of BoNT-producing clostridia. The unique design of the PathogenID v2.0 array allows the simultaneous detection and characterization of 48 sequences targeting the BoNT gene cluster components. This approach allowed successful identification and typing of representative strains of the different toxinotypes and subtypes, as well as the neurotoxin-producing C. botulinum strain in a naturally contaminated food sample. Moreover, the method allowed fine characterization of the different neurotoxin gene cluster components of all studied strains, including genomic regions exhibiting up to 24.65% divergence with the sequences tiled on the arrays. CONCLUSIONS/SIGNIFICANCE: The severity of the disease demands rapid and accurate means for performing risk assessments of BoNT-producing clostridia and for tracing potentials sources of contamination in outbreak situations. The RMA approach constitutes an essential higher echelon component in a diagnostics and surveillance pipeline. In addition, it is an important asset to characterise potential outbreak related strains, but also environment isolates, in order to obtain a better picture of the molecular epidemiology of BoNT-producing clostridia. PMID- 23818985 TI - Diabetic mouse model of orthopaedic implant-related Staphylococcus aureus infection. AB - BACKGROUND: Periprosthetic bacterial infections represent one of the most challenging orthopaedic complications that often require implant removal and surgical debridement and carry high social and economical costs. Diabetes is one of the most relevant risk factors of implant-related infection and its clinical occurrence is growing worldwide. The aim of the present study was to test a model of implant-related infection in the diabetic mouse, with a view to allow further investigation on the relative efficacy of prevention and treatment options in diabetic and non-diabetic individuals. METHODOLOGY: A cohort of diabetic NOD/ShiLtJ mice was compared with non-diabetic CD1 mice as an in vivo model of S. aureus orthopaedic infection of bone and soft tissues after femur intramedullary pin implantation. We tested control and infected groups with 1*10(3) colony forming units of S. aureus ATCC 25923 strain injected in the implant site. At 4 weeks post-inoculation, host response to infection, microbial biofilm formation, and bone damage were assessed by traditional diagnostic parameters (bacterial culture, C-reactive protein and white blood cell count), histological analysis and imaging techniques (micro computed tomography and scanning electron microscopy). RESULTS: Unlike the controls and the CD1 mice, all the diabetic mice challenged with a single inoculum of S. aureus displayed severe osteomyelitic changes around the implant. CONCLUSIONS: Our findings demonstrate for the first time that the diabetic mouse can be successfully used in a model of orthopaedic implant-related infection. Furthermore, the same bacteria inoculum induced periprosthetic infection in all the diabetic mice but not in the controls. This animal model of implant-related infection in diabetes may be a useful tool to test in vivo treatments in diabetic and non-diabetic individuals. PMID- 23818986 TI - Macrophage Resistance to HIV-1 Infection Is Enhanced by the Neuropeptides VIP and PACAP. AB - It is well established that host factors can modulate HIV-1 replication in macrophages, critical cells in the pathogenesis of HIV-1 infection due to their ability to continuously produce virus. The neuropeptides VIP and PACAP induce well-characterized effects on macrophages through binding to the G protein coupled receptors VPAC1, VPAC2 and PAC1, but their influence on HIV-1 production by these cells has not been established. Here, we describe that VIP and PACAP reduce macrophage production of HIV-1, acting in a synergistic or additive manner to decrease viral growth. Using receptor antagonists, we detected that the HIV-1 inhibition promoted by VIP is dependent on its ligation to VPAC1/2, whereas PACAP decreases HIV-1 growth via activation of the VPAC1/2 and PAC1 receptors. Specific agonists of VPAC2 or PAC1 decrease macrophage production of HIV-1, whereas sole activation of VPAC1 enhances viral growth. However, the combination of specific agonists mimicking the receptor preference of the natural neuropeptides reproduces the ability of VIP and PACAP to increase macrophage resistance to HIV 1 replication. VIP and PACAP up-regulated macrophage secretion of the beta chemokines CCL3 and CCL5 and the cytokine IL-10, whose neutralization reversed the neuropeptide-induced inhibition of HIV-1 replication. Our results suggest that VIP and PACAP and the receptors VPAC2 and PAC1 could be used as targets for developing alternative therapeutic strategies for HIV-1 infection. PMID- 23818987 TI - Nonsense-mediated mRNA decay and loss-of-function of the protein underlie the X linked epilepsy associated with the W356* mutation in synapsin I. AB - Synapsins are a family of neuronal phosphoproteins associated with the cytosolic surface of synaptic vesicles. Experimental evidence suggests a role for synapsins in synaptic vesicle clustering and recycling at the presynaptic terminal, as well as in neuronal development and synaptogenesis. Synapsin knock-out (Syn1(-/-) ) mice display an epileptic phenotype and mutations in the SYN1 gene have been identified in individuals affected by epilepsy and/or autism spectrum disorder. We investigated the impact of the c.1067G>A nonsense transition, the first mutation described in a family affected by X-linked syndromic epilepsy, on the expression and functional properties of the synapsin I protein. We found that the presence of a premature termination codon in the human SYN1 transcript renders it susceptible to nonsense-mediated mRNA decay (NMD). Given that the NMD efficiency is highly variable among individuals and cell types, we investigated also the effects of expression of the mutant protein and found that it is expressed at lower levels compared to wild-type synapsin I, forms perinuclear aggregates and is unable to reach presynaptic terminals in mature hippocampal neurons grown in culture. Taken together, these data indicate that in patients carrying the W356* mutation the function of synapsin I is markedly impaired, due to both the strongly decreased translation and the altered function of the NMD-escaped protein, and support the value of Syn1(-/-) mice as an experimental model mimicking the human pathology. PMID- 23818988 TI - Temperature induced syllable breaking unveils nonlinearly interacting timescales in birdsong motor pathway. AB - The nature of telencephalic control over premotor and motor circuits is debated. Hypotheses range from complete usurping of downstream circuitry to highly interactive mechanisms of control. We show theoretically and experimentally, that telencephalic song motor control in canaries is consistent with a highly interactive strategy. As predicted from a theoretical model of respiratory control, mild cooling of a forebrain nucleus (HVC) led to song stretching, but further cooling caused progressive restructuring of song, consistent with the hypothesis that respiratory gestures are subharmonic responses to a timescale present in the output of HVC. This interaction between a life-sustaining motor function (respiration) and telencephalic song motor control suggests a more general mechanism of how nonlinear integration of evolutionarily new brain structures into existing circuitry gives rise to diverse, new behavior. PMID- 23818989 TI - Ubiquitination and degradation of CFTR by the E3 ubiquitin ligase MARCH2 through its association with adaptor proteins CAL and STX6. AB - Golgi-localized cystic fibrosis transmembrane conductance regulator (CFTR) associated ligand (CAL) and syntaxin 6 (STX6) regulate the abundance of mature, post-ER CFTR by forming a CAL/STX6/CFTR complex (CAL complex) that promotes CFTR degradation in lysosomes. However, the molecular mechanism underlying this degradation is unknown. Here we investigated the interaction of a Golgi localized, membrane-associated RING-CH E3 ubiquitin ligase, MARCH2, with the CAL complex and the consequent binding, ubiquitination, and degradation of mature CFTR. We found that MARCH2 not only co-immunoprecipitated and co-localized with CAL and STX6, but its binding to CAL was also enhanced by STX6, suggesting a synergistic interaction. In vivo ubiquitination assays demonstrated the ubiquitination of CFTR by MARCH2, and overexpression of MARCH2, like that of CAL and STX6, led to a dose-dependent degradation of mature CFTR that was blocked by bafilomycin A1 treatment. A catalytically dead MARCH2 RING mutant was unable to promote CFTR degradation. In addition, MARCH2 had no effect on a CFTR mutant lacking the PDZ motif, suggesting that binding to the PDZ domain of CAL is required for MARCH2-mediated degradation of CFTR. Indeed, silencing of endogenous CAL ablated the effect of MARCH2 on CFTR. Consistent with its Golgi localization, MARCH2 had no effect on ER-localized DeltaF508-CFTR. Finally, siRNA-mediated silencing of endogenous MARCH2 in the CF epithelial cell line CFBE-CFTR increased the abundance of mature CFTR. Taken together, these data suggest that the recruitment of the E3 ubiquitin ligase MARCH2 to the CAL complex and subsequent ubiquitination of CFTR are responsible for the CAL-mediated lysosomal degradation of mature CFTR. PMID- 23818990 TI - Putting the biological species concept to the test: using mating networks to delimit species. AB - Although interfertility is the key criterion upon which Mayr's biological species concept is based, it has never been applied directly to delimit species under natural conditions. Our study fills this gap. We used the interfertility criterion to delimit two closely related oak species in a forest stand by analyzing the network of natural mating events between individuals. The results reveal two groups of interfertile individuals connected by only few mating events. These two groups were largely congruent with those determined using other criteria (morphological similarity, genotypic similarity and individual relatedness). Our study, therefore, shows that the analysis of mating networks is an effective method to delimit species based on the interfertility criterion, provided that adequate network data can be assembled. Our study also shows that although species boundaries are highly congruent across methods of species delimitation, they are not exactly the same. Most of the differences stem from assignment of individuals to an intermediate category. The discrepancies between methods may reflect a biological reality. Indeed, the interfertility criterion is an environment-dependant criterion as species abundances typically affect rates of hybridization under natural conditions. Thus, the methods of species delimitation based on the interfertility criterion are expected to give results slightly different from those based on environment-independent criteria (such as the genotypic similarity criteria). However, whatever the criterion chosen, the challenge we face when delimiting species is to summarize continuous but non uniform variations in biological diversity. The grade of membership model that we use in this study appears as an appropriate tool. PMID- 23818991 TI - Are introduced species better dispersers than native species? A global comparative study of seed dispersal distance. AB - We provide the first global test of the idea that introduced species have greater seed dispersal distances than do native species, using data for 51 introduced and 360 native species from the global literature. Counter to our expectations, there was no significant difference in mean or maximum dispersal distance between introduced and native species. Next, we asked whether differences in dispersal distance might have been obscured by differences in seed mass, plant height and dispersal syndrome, all traits that affect dispersal distance and which can differ between native and introduced species. When we included all three variables in the model, there was no clear difference in dispersal distance between introduced and native species. These results remained consistent when we performed analyses including a random effect for site. Analyses also showed that the lack of a significant difference in dispersal distance was not due to differences in biome, taxonomic composition, growth form, nitrogen fixation, our inclusion of non-invasive introduced species, or our exclusion of species with human-assisted dispersal. Thus, if introduced species do have higher spread rates, it seems likely that these are driven by differences in post-dispersal processes such as germination, seedling survival, and survival to reproduction. PMID- 23818992 TI - Drug administration errors in hospital inpatients: a systematic review. AB - CONTEXT: Drug administration in the hospital setting is the last barrier before a possible error reaches the patient. OBJECTIVES: We aimed to analyze the prevalence and nature of administration error rate detected by the observation method. DATA SOURCES: Embase, MEDLINE, Cochrane Library from 1966 to December 2011 and reference lists of included studies. STUDY SELECTION: Observational studies, cross-sectional studies, before-and-after studies, and randomized controlled trials that measured the rate of administration errors in inpatients were included. DATA EXTRACTION: Two reviewers (senior pharmacists) independently identified studies for inclusion. One reviewer extracted the data; the second reviewer checked the data. The main outcome was the error rate calculated as being the number of errors without wrong time errors divided by the Total Opportunity for Errors (TOE, sum of the total number of doses ordered plus the unordered doses given), and multiplied by 100. For studies that reported it, clinical impact was reclassified into four categories from fatal to minor or no impact. Due to a large heterogeneity, results were expressed as median values (interquartile range, IQR), according to their study design. RESULTS: Among 2088 studies, a total of 52 reported TOE. Most of the studies were cross-sectional studies (N=46). The median error rate without wrong time errors for the cross sectional studies using TOE was 10.5% [IQR: 7.3%-21.7%]. No fatal error was observed and most errors were classified as minor in the 18 studies in which clinical impact was analyzed. We did not find any evidence of publication bias. CONCLUSIONS: Administration errors are frequent among inpatients. The median error rate without wrong time errors for the cross-sectional studies using TOE was about 10%. A standardization of administration error rate using the same denominator (TOE), numerator and types of errors is essential for further publications. PMID- 23818993 TI - Direct and indirect effects of UV-B exposure on litter decomposition: a meta analysis. AB - Ultraviolet-B (UV-B) exposure in the course of litter decomposition may have a direct effect on decomposition rates via changing states of photodegradation or decomposer constitution in litter while UV-B exposure during growth periods may alter chemical compositions and physical properties of plants. Consequently, these changes will indirectly affect subsequent litter decomposition processes in soil. Although studies are available on both the positive and negative effects (including no observable effects) of UV-B exposure on litter decomposition, a comprehensive analysis leading to an adequate understanding remains unresolved. Using data from 93 studies across six biomes, this introductory meta-analysis found that elevated UV-B directly increased litter decomposition rates by 7% and indirectly by 12% while attenuated UV-B directly decreased litter decomposition rates by 23% and indirectly increased litter decomposition rates by 7%. However, neither positive nor negative effects were statistically significant. Woody plant litter decomposition seemed more sensitive to UV-B than herbaceous plant litter except under conditions of indirect effects of elevated UV-B. Furthermore, levels of UV-B intensity significantly affected litter decomposition response to UV-B (P<0.05). UV-B effects on litter decomposition were to a large degree compounded by climatic factors (e.g., MAP and MAT) (P<0.05) and litter chemistry (e.g., lignin content) (P<0.01). Results suggest these factors likely have a bearing on masking the important role of UV-B on litter decomposition. No significant differences in UV-B effects on litter decomposition were found between study types (field experiment vs. laboratory incubation), litter forms (leaf vs. needle), and decay duration. Indirect effects of elevated UV-B on litter decomposition significantly increased with decay duration (P<0.001). Additionally, relatively small changes in UV-B exposure intensity (30%) had significant direct effects on litter decomposition (P<0.05). The intent of this meta-analysis was to improve our understanding of the overall effects of UV-B on litter decomposition. PMID- 23818994 TI - Immunoprotection of mice against Schistosomiasis mansoni using solubilized membrane antigens. AB - BACKGROUND: Schistosomiasis continues to be one of the most prevalent parasitic diseases in the world. Despite the existence of a highly effective antischistosome drug, the disease is spreading into new areas, and national control programs do not arrive to complete their tasks particularly in low endemic areas. The availability of a vaccine could represent an additional component to chemotherapy. Experimental vaccination studies are however necessary to identify parasite molecules that would serve as vaccine candidates. In the present work, C57BL/6 female mice were subcutaneously immunized with an n-butanol extract of the adult worm particulate membranous fraction (AWBE) and its protective effect against a S. mansoni challenge infection was evaluated. METHODOLOGY AND FINDINGS: Water-saturated n-butanol release into the aqueous phase a set of membrane-associated (glyco)proteins that are variably recognized by antibodies in schistosome-infected patients; among the previously identified AWBE antigens there is Alkaline Phosphatase (SmAP) which has been associated with resistance to the infection in mice. As compared to control, a significantly lower number of perfuse parasites was obtained in the immunized/challenged mouse group (P<0.05, t test); and consequently, a lower number of eggs and granulomas (with reduced sizes), overall decreasing pathology. Immunized mice produced high levels of sera anti-AWBE IgG recognizing antigens of ~190-, 130-, 98-, 47-, 28 23, 14-, and 9-kDa. The ~130-kDa band (the AP dimer) exhibited in situ SmAP activity after addition of AP substrate and the activity was not apparently inhibited by host antibodies. A preliminary proteomic analysis of the 25-, 27-, and 28-kDa bands in the immunodominant 28-23 kDa region suggested that they are composed of actin. CONCLUSIONS: Immunization with AWBE induced the production of specific antibodies to various adult worm membrane molecules (including AP) and a partial (43%) protection against a challenging S. mansoni infection by mechanism(s) that still has to be elucidated. PMID- 23818995 TI - Bacillus thuringiensis-derived Cry5B has potent anthelmintic activity against Ascaris suum. AB - Ascaris suum and Ascaris lumbricoides are two closely related geo-helminth parasites that ubiquitously infect pigs and humans, respectively. Ascaris suum infection in pigs is considered a good model for A. lumbricoides infection in humans because of a similar biology and tissue migration to the intestines. Ascaris lumbricoides infections in children are associated with malnutrition, growth and cognitive stunting, immune defects, and, in extreme cases, life threatening blockage of the digestive tract and aberrant migration into the bile duct and peritoneum. Similar effects can be seen with A. suum infections in pigs related to poor feed efficiency and performance. New strategies to control Ascaris infections are needed largely due to reduced treatment efficacies of current anthelmintics in the field, the threat of resistance development, and the general lack of new drug development for intestinal soil-transmitted helminths for humans and animals. Here we demonstrate for the first time that A. suum expresses the receptors for Bacillus thuringiensis crystal protein and novel anthelmintic Cry5B, which has been previously shown to intoxicate hookworms and which belongs to a class of proteins considered non-toxic to vertebrates. Cry5B is able to intoxicate A. suum larvae and adults and triggers the activation of the p38 mitogen-activated protein kinase pathway similar to that observed with other nematodes. Most importantly, two moderate doses of 20 mg/kg body weight (143 nM/kg) of Cry5B resulted in a near complete cure of intestinal A. suum infections in pigs. Taken together, these results demonstrate the excellent potential of Cry5B to treat Ascaris infections in pigs and in humans and for Cry5B to work effectively in the human gastrointestinal tract. PMID- 23818996 TI - Ecology of Leptospira interrogans in Norway rats (Rattus norvegicus) in an inner city neighborhood of Vancouver, Canada. AB - BACKGROUND: Leptospira interrogans is a bacterial zoonosis with a worldwide distribution for which rats (Rattus spp.) are the primary reservoir in urban settings. In order to assess, monitor, and mitigate the risk to humans, it is important to understand the ecology of this pathogen in rats. The objective of this study was to characterize the ecology of L. interrogans in Norway rats (Rattus norvegicus) in an impoverished inner-city neighborhood of Vancouver, Canada. METHODOLOGY/PRINCIPAL FINDINGS: Trapping was performed in 43 city blocks, and one location within the adjacent port, over a 12 month period. Kidney samples were tested for the presence of L. interrogans using PCR and sequencing. A multivariable model was built to predict L. interrogans infection status in individual rats using season and morphometric data (e.g., weight, sex, maturity, condition, etc.) as independent variables. Spatial analysis was undertaken to identify clusters of high and low L. interrogans prevalence. The prevalence of L. interrogans varied remarkably among blocks (0-66.7%), and spatial clusters of both high and low L. interrogans prevalence were identified. In the final cluster controlled model, characteristics associated with L. interrogans-infection in rats included weight (OR = 1.14, 95% CI = 1.07-1.20), increased internal fat (OR = 2.12, 95% CI = 1.06-4.25), and number of bite wounds (OR = 1.20, 95% CI = 0.96 1.49). CONCLUSIONS/SIGNIFICANCE: Because L. interrogans prevalence varied with weight, body fat, and bite wounds, this study suggests that social structure and interactions among rats may influence transmission. The prevalence and distribution of L. interrogans in rats was also highly variable even over a short geographic distance. These factors should be considered in future risk management efforts. PMID- 23818997 TI - A review of preventative methods against human leishmaniasis infection. AB - BACKGROUND: Leishmaniasis is an intracellular parasitic infection transmitted to humans via the sandfly. Approximately 350 million people are at risk of contracting the disease and an estimated 1.6 million new cases occur annually. Of the two main forms, visceral and cutaneous, the visceral form is fatal in 85-90% of untreated cases. AIMS: This literature review aims to identify and evaluate the current evidence base for the use of various preventative methods against human leishmaniasis. METHODS: A literature search was performed of the relevant database repositories for primary research conforming to a priori inclusion and exclusion criteria. RESULTS: A total of 84 controlled studies investigating 12 outcome measures were identified, implementing four broad categories of preventative interventions: animal reservoir control, vector population control, human reservoir control and a category for multiple concurrently implemented interventions. The primary studies investigated a heterogeneous mix of outcome measures using a range of different methods. CONCLUSIONS: This review highlights an absence of research measuring human-specific outcomes (35% of the total) across all intervention categories. The apparent inability of study findings to be generalizable across different geographic locations, points towards gaps in knowledge regarding the biology of transmission of Leishmania in different settings. More research is needed which investigates human infection as the primary outcome measure as opposed to intermediate surrogate markers, with a focus on developing a human vaccine. PMID- 23818998 TI - Housefly population density correlates with shigellosis among children in Mirzapur, Bangladesh: a time series analysis. AB - BACKGROUND: Shigella infections are a public health problem in developing and transitional countries because of high transmissibility, severity of clinical disease, widespread antibiotic resistance and lack of a licensed vaccine. Whereas Shigellae are known to be transmitted primarily by direct fecal-oral contact and less commonly by contaminated food and water, the role of the housefly Musca domestica as a mechanical vector of transmission is less appreciated. We sought to assess the contribution of houseflies to Shigella-associated moderate-to severe diarrhea (MSD) among children less than five years old in Mirzapur, Bangladesh, a site where shigellosis is hyperendemic, and to model the potential impact of a housefly control intervention. METHODS: Stool samples from 843 children presenting to Kumudini Hospital during 2009-2010 with new episodes of MSD (diarrhea accompanied by dehydration, dysentery or hospitalization) were analyzed. Housefly density was measured twice weekly in six randomly selected sentinel households. Poisson time series regression was performed and autoregression-adjusted attributable fractions (AFs) were calculated using the Bruzzi method, with standard errors via jackknife procedure. FINDINGS: Dramatic springtime peaks in housefly density in 2009 and 2010 were followed one to two months later by peaks of Shigella-associated MSD among toddlers and pre-school children. Poisson time series regression showed that housefly density was associated with Shigella cases at three lags (six weeks) (Incidence Rate Ratio = 1.39 [95% CI: 1.23 to 1.58] for each log increase in fly count), an association that was not confounded by ambient air temperature. Autocorrelation-adjusted AF calculations showed that a housefly control intervention could have prevented approximately 37% of the Shigella cases over the study period. INTERPRETATION: Houseflies may play an important role in the seasonal transmission of Shigella in some developing country ecologies. Interventions to control houseflies should be evaluated as possible additions to the public health arsenal to diminish Shigella (and perhaps other causes of) diarrheal infection. PMID- 23819000 TI - Spatiotemporal patterns of Japanese encephalitis in China, 2002-2010. AB - OBJECTIVE: The aim of the study is to examine the spatiotemporal pattern of Japanese Encephalitis (JE) in mainland China during 2002-2010. Specific objectives of the study were to quantify the temporal variation in incidence of JE cases, to determine if clustering of JE cases exists, to detect high risk spatiotemporal clusters of JE cases and to provide evidence-based preventive suggestions to relevant stakeholders. METHODS: Monthly JE cases at the county level in mainland China during 2002-2010 were obtained from the China Information System for Diseases Control and Prevention (CISDCP). For the purpose of the analysis, JE case counts for nine years were aggregated into four temporal periods (2002; 2003-2005; 2006; and 2007-2010). Local Indicators of Spatial Association and spatial scan statistics were performed to detect and evaluate local high risk space-time clusters. RESULTS: JE incidence showed a decreasing trend from 2002 to 2005 but peaked in 2006, then fluctuated over the study period. Spatial cluster analysis detected high value clusters, mainly located in Southwestern China. Similarly, we identified a primary spatiotemporal cluster of JE in Southwestern China between July and August, with the geographical range of JE transmission increasing over the past years. CONCLUSION: JE in China is geographically clustered and its spatial extent dynamically changed during the last nine years in mainland China. This indicates that risk factors for JE infection are likely to be spatially heterogeneous. The results may assist national and local health authorities in the development/refinement of a better preventive strategy and increase the effectiveness of public health interventions against JE transmission. PMID- 23818999 TI - Phylogenetic analysis reveals a high prevalence of Sporothrix brasiliensis in feline sporotrichosis outbreaks. AB - Sporothrix schenckii, previously assumed to be the sole agent of human and animal sporotrichosis, is in fact a species complex. Recently recognized taxa include S. brasiliensis, S. globosa, S. mexicana, and S. luriei, in addition to S. schenckii sensu stricto. Over the last decades, large epidemics of sporotrichosis occurred in Brazil due to zoonotic transmission, and cats were pointed out as key susceptible hosts. In order to understand the eco-epidemiology of feline sporotrichosis and its role in human sporotrichosis a survey was conducted among symptomatic cats. Prevalence and phylogenetic relationships among feline Sporothrix species were investigated by reconstructing their phylogenetic origin using the calmodulin (CAL) and the translation elongation factor-1 alpha (EF1alpha) loci in strains originated from Rio de Janeiro (RJ, n = 15), Rio Grande do Sul (RS, n = 10), Parana (PR, n = 4), Sao Paulo (SP, n =3) and Minas Gerais (MG, n = 1). Our results showed that S. brasiliensis is highly prevalent among cats (96.9%) with sporotrichosis, while S. schenckii was identified only once. The genotype of Sporothrix from cats was found identical to S. brasiliensis from human sources confirming that the disease is transmitted by cats. Sporothrix brasiliensis presented low genetic diversity compared to its sister taxon S. schenckii. No evidence of recombination in S. brasiliensis was found by split decomposition or PHI-test analysis, suggesting that S. brasiliensis is a clonal species. Strains recovered in states SP, MG and PR share the genotype of the RJ outbreak, different from the RS clone. The occurrence of separate genotypes among strains indicated that the Brazilian S. brasiliensis epidemic has at least two distinct sources. We suggest that cats represent a major host and the main source of cat and human S. brasiliensis infections in Brazil. PMID- 23819001 TI - Is zinc concentration in toxic phase plasma related to dengue severity and level of transaminases? AB - OBJECTIVE: To determine the relationship between plasma zinc values and the severity of dengue viral infection (DVI) and DVI-caused hepatitis. METHODS: A prospective cohort study was conducted during 2008-2010 in hospitalized children aged <15 years confirmed with DVI. Complete blood count, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and zinc values (mcg/dL) were determined twice: first during the toxic phase (Zn1) and secondly two weeks after recovery (Zn2). RESULTS: 39 patients were enrolled with a mean age of 9.7 +/- 3.7 years, and 15/39 diagnosed with dengue shock syndrome (DSS). Zn1 values were lower than Zn2 values [median (IQR): 46.0 (37.0, 58.0) vs 65.0 (58.0, 81.0) mcg/dL, respectively, p <0.01]. Zn1 but not Zn2 values had a negative correlation with AST and ALT (rs = -0.33, p = 0.04 and rs = -0.31, p = 0.05, respectively). Patients with DSS had lower Zn1 but not Zn2 values compared with non-DSS patients [median (IQR) Zn1, 38.0 (30.0, 48.0) vs 52.5 (41.2, 58.7), p = 0.02; Zn2, 61.0 (56.0, 88.0) vs 65.0 (59.5, 77.5), respectively, p = 0.76]. Zn1 values showed a decreasing trend across increasing dengue severity groups (p = 0.02). Age <5 years and DVI-associated diarrhea were associated with low Zn1. CONCLUSION: Children who had a higher grade of dengue disease severity and liver cell injury had lower Zn1 values. Low Zn1 values were probably caused by loss from diarrhea and from zinc translocating to liver cells. PMID- 23819002 TI - Monocytes play an IL-12-dependent crucial role in driving cord blood NK cells to produce IFN-g in response to Trypanosoma cruzi. AB - We previously reported that foetuses congenitally infected with Trypanosoma cruzi, the agent of Chagas disease, mount an adult-like parasite-specific CD8(+) T-cell response, producing IFN-g, and present an altered NK cell phenotype, possibly reflecting a post-activation state supported by the ability of the parasite to trigger IFN-g synthesis by NK cells in vitro. We here extended our knowledge on NK cell activation by the parasite. We compared the ability of T. cruzi to activate cord blood and adult NK cells from healthy individuals. Twenty four hours co-culture of cord blood mononuclear cells with T. cruzi trypomastigotes and IL-15 induced high accumulation of IFN-g transcripts and IFN g release. TNF-a, but not IL-10, was also produced. This was associated with up regulation of CD69 and CD54, and down-regulation of CD62L on NK cells. The CD56(bright) NK cell subset was the major IFN-g responding subset (up to 70% IFN g-positive cells), while CD56(dim) NK cells produced IFN-g to a lesser extent. The response points to a synergy between parasites and IL-15. The neonatal response, observed in all newborns, remained however slightly inferior to that of adults. Activation of IL-15-sensitized cord blood NK cells by the parasite required contacts with live/intact parasites. In addition, it depended on the engagement of TLR-2 and 4 and involved IL-12 and cross-talk with monocytes but not with myeloid dendritic cells, as shown by the use of neutralizing antibodies and cell depletion. This work highlights the ability of T. cruzi to trigger a robust IFN-g response by IL-15-sensitized human neonatal NK cells and the important role of monocytes in it, which might perhaps partially compensate for the neonatal defects of DCs. It suggests that monocyte- and IL-12- dependent IFN g release by NK cells is a potentially important innate immune response pathway allowing T. cruzi to favour a type 1 immune response in neonates. PMID- 23819003 TI - [Isolated bone metastasis of the radius metachronous of colorectal cancer]. PMID- 23819004 TI - Case report: cranioplasty infection due to Roseomonas gilardii at a university hospital in Turkey. AB - Roseomonas is a pink-pigmented, nonfermentative, oxidative, Gram-negative coccobacilli that has clinical importance as opportunistic pathogen which can lead to infections especially in immunosuppressed individuals. It is relatively less reported in many centers. These microorganisms are detected after several days growth in culture environment, and typical pink, mucoid colonies are detected. We are reported a case of cranioplasty infection that took place in a patient with with cranial abscess formation due to Roseomonas gilardii at Izmir University School of Medicine Medicalpark Hospital. PMID- 23819005 TI - [An exceptional localization of spinal tuberculosis: sub-occipital Pott disease]. PMID- 23819006 TI - Dental caries and oral health practice among 12 year old school children from low socio-economic status background in Zimbabwe. AB - INTRODUCTION: Dental caries is one of the most prevalent chronic diseases affecting children in Sub-Saharan Africa. Previous studies show a higher prevalence of dental caries in children from low socio-economic status backgrounds. The purpose of this study was to determine the prevalence of dental caries among 12 year old children in urban and rural areas of Zimbabwe and establish preliminary baseline data. METHODS: A descriptive cross-sectional study was conducted among 12 year old children at primary schools in Harare and Bikita district. A Pre-tested questionnaire was administered to elicit information from the participants on tooth cleaning, dietary habits and dental experience. Dental caries status was assessed using the DMFT index following World Health Organization (WHO) guidelines. RESULTS: Our results showed a high prevalence of dental caries in both urban (59.5%) and rural (40.8%) children. The mean DMFT in urban and rural areas was 1.29 and 0.66, respectively. Furthermore, our data showed a general lack of knowledge on oral health issues by the participants. CONCLUSION: There is high prevalence of dental caries among 12 years old school children in both urban and rural areas of Zimbabwe. This calls for early preventive strategies and treatment services. We recommend incorporation of oral health education in the elementary school curricula. PMID- 23819007 TI - [Congenital adrenal hyperplasia of late revelation: about a rare case]. PMID- 23819008 TI - Calcified right atrial thrombus in HIV infected patient. AB - Calcified right atrial thrombi are rare cardiac masses that may be complicated by pulmonary embolism. Although they can be discovered by a transthoracic echocardiography, they may need histological examination to differentiate them from other cardiac masses. We report a case of a 44-year-old woman who presented with a calcified right atrial thrombus and progressive dyspnoea. PMID- 23819009 TI - The role of xanthine oxidase in hemodialysis-induced oxidative injury: relationship with nutritional status. AB - The role of xanthine oxidase (XOD) in patients undergoing chronic hemodialysis treatment (HD) is poorly understood. Geriatric nutritional risk index (GNRI) <= 90 could be linked with malnutrition-inflammation complex syndrome. This study measured XOD, myeloperoxidase (MPO), superoxide dismutase (SOD), lipid hydroperoxides, total free thiol groups, and advanced oxidation protein products (AOPP) in 50 HD patients before commencing (pre-HD) and immediately after completion of HD session (post-HD) and in 22 healthy controls. Pre-HD serum hydroperoxides, AOPP, XOD, and SOD were higher and total thiol groups were lower in patients than in controls (P < 0.05, resp.). Compared to baseline values, serum MPO activity was increased irrespective of GNRI status. Serum XOD activity was increasing during HD treatment in the group with GNRI <= 90 (P = 0.030) whilst decreasing in the group with GNRI > 90 (P = 0.002). In a multiple regression analysis, post-HD serum XOD activity was independently associated with GNRI <= 90 ( beta +/- SE: 0.398 +/- 0.151; P = 0.012) and HD vintage ( beta +/- SE: -0.349 +/- 0.139; P = 0.016). These results indicate that an upregulated XOD may be implicated in HD-induced oxidative injury contributing to accelerated protein damage in patients with GNRI <= 90. PMID- 23819010 TI - 17-beta-Estradiol counteracts the effects of high frequency electromagnetic fields on trophoblastic connexins and integrins. AB - We investigated the effect of high-frequency electromagnetic fields (HF-EMFs) and 17-beta-estradiol on connexins (Cxs), integrins (Ints), and estrogen receptor (ER) expression, as well as on ultrastructure of trophoblast-derived HTR-8/SVneo cells. HF-EMF, 17-beta-estradiol, and their combination induced an increase of Cx40 and Cx43 mRNA expression. HF-EMF decreased Int alpha1 and beta 1 mRNA levels but enhanced Int alpha5 mRNA expression. All the Ints mRNA expressions were increased by 17-beta-estradiol and exposure to both stimuli. ER-beta mRNA was reduced by HF-EMF but augmented by 17-beta-estradiol alone or with HF-EMF. ER beta immunofluorescence showed a cytoplasmic localization in sham and HF-EMF exposed cells which became nuclear after treatment with hormone or both stimuli. Electron microscopy evidenced a loss of cellular contact in exposed cells which appeared counteracted by 17-beta-estradiol. We demonstrate that 17-beta-estradiol modulates Cxs and Ints as well as ER-beta expression induced by HF-EMF, suggesting an influence of both stimuli on trophoblast differentiation and migration. PMID- 23819011 TI - Mitochondrial signaling: forwards, backwards, and in between. AB - Mitochondria are semiautonomous organelles that are a defining characteristic of almost all eukaryotic cells. They are vital for energy production, but increasing evidence shows that they play important roles in a wide range of cellular signaling and homeostasis. Our understanding of nuclear control of mitochondrial function has expanded over the past half century with the discovery of multiple transcription factors and cofactors governing mitochondrial biogenesis. More recently, nuclear changes in response to mitochondrial messaging have led to characterization of retrograde mitochondrial signaling, in which mitochondria have the ability to alter nuclear gene expression. Mitochondria are also integral to other components of stress response or quality control including ROS signaling, unfolded protein response, mitochondrial autophagy, and biogenesis. These avenues of mitochondrial signaling are discussed in this review. PMID- 23819012 TI - Roles nrf2 plays in myeloid cells and related disorders. AB - The Keap1-Nrf2 system protects animals from oxidative and electrophilic stresses. Nrf2 is a transcription factor that induces the expression of genes essential for detoxifying reactive oxygen species (ROS) and cytotoxic electrophiles. Keap1 is a stress sensor protein that binds to and ubiquitinates Nrf2 under unstressed conditions, leading to the rapid proteasomal degradation of Nrf2. Upon exposure to stress, Keap1 is modified and inactivated, which allows Nrf2 to accumulate and activate the transcription of a battery of cytoprotective genes. Antioxidative and detoxification activities are important for many types of cells to avoid DNA damage and cell death. Accumulating lines of recent evidence suggest that Nrf2 is also required for the primary functions of myeloid cells, which include phagocytosis, inflammation regulation, and ROS generation for bactericidal activities. In fact, results from several mouse models have shown that Nrf2 expression in myeloid cells is required for the proper regulation of inflammation, antitumor immunity, and atherosclerosis. Moreover, several molecules generated upon inflammation activate Nrf2. Although ROS detoxification mediated by Nrf2 is assumed to be required for anti-inflammation, the entire picture of the Nrf2-mediated regulation of myeloid cell primary functions has yet to be elucidated. In this review, we describe the Nrf2 inducers characteristic of myeloid cells and the contributions of Nrf2 to diseases. PMID- 23819013 TI - Role of lipid peroxidation-derived alpha, beta-unsaturated aldehydes in vascular dysfunction. AB - Vascular diseases are the most prominent cause of death, and inflammation and vascular dysfunction are key initiators of the pathophysiology of vascular disease. Lipid peroxidation products, such as acrolein and other alpha, beta unsaturated aldehydes, have been implicated as mediators of inflammation and vascular dysfunction. alpha, beta-Unsaturated aldehydes are toxic because of their high reactivity with nucleophiles and their ability to form protein and DNA adducts without prior metabolic activation. This strong reactivity leads to electrophilic stress that disrupts normal cellular function. Furthermore, alpha, beta-unsaturated aldehydes are reported to cause endothelial dysfunction by induction of oxidative stress, redox-sensitive mechanisms, and inflammatory changes such as induction of cyclooxygenase-2 and cytokines. This review provides an overview of the effects of lipid peroxidation products, alpha, beta unsaturated aldehydes, on inflammation and vascular dysfunction. PMID- 23819015 TI - A novel tetrapeptide derivative exhibits in vitro inhibition of neutrophil derived reactive oxygen species and lysosomal enzymes release. AB - Neutrophil infiltration plays a major role in the pathogenesis of myocardial injury. Oxidative injury is suggested to be a central mechanism of the cellular damage after acute myocardial infarction. This study is pertained to the prognostic role of a tetrapeptide derivative PEP1261 (BOC-Lys(BOC)-Arg-Asp Ser(tBu)-OtBU), a peptide sequence (39-42) of lactoferrin, studied in the modulation of neutrophil functions in vitro by measuring the reactive oxygen species (ROS) generation, lysosomal enzymes release, and enhanced expression of C proteins. The groundwork experimentation was concerned with the isolation of neutrophils from the normal and acute myocardial infarct rats to find out the efficacy of PEP1261 in the presence of a powerful neutrophil stimulant, phorbol 12-myristate 13 acetate (PMA). Stimulation of neutrophils with PMA resulted in an oxidative burst of superoxide anion and enhanced release of lysosomal enzymes and expression of complement proteins. The present study further demonstrated that the free radicals increase the complement factors in the neutrophils confirming the role of ROS. PEP1261 treatment significantly reduced the levels of superoxide anion and inhibited the release of lysosomal enzymes in the stimulated control and infarct rat neutrophils. This study demonstrated that PEP1261 significantly inhibited the effect on the ROS generation as well as the mRNA synthesis and expression of the complement factors in neutrophils isolated from infarct heart. PMID- 23819018 TI - Pleural abnormalities: thoracic ultrasound to the rescue! AB - Diaphragmatic hernias that are diagnosed in adulthood may be traumatic or congenital in nature. Therefore, respiratory specialists need to be aware of the presentation of patients with these conditions. In this report, we describe a case series of patients with congenital and traumatic diaphragmatic hernias and highlight a varied range of their presentations. Abnormalities were noted in the thorax on the chest radiographs, but it was unclear as to the nature of the anomaly. The findings on thoracic ultrasound conducted by a pulmonologist helped to direct appropriate investigations avoiding unnecessary interventions. Instead of pleural effusions, consolidation or collapse, thoracic computed tomography demonstrated diaphragmatic hernias which were managed either conservatively or by surgery. There is increasing evidence that pulmonary specialists should be trained in thoracic ultrasonography to identify pleural pathology as well as safely conducting pleural-based interventions. PMID- 23819014 TI - Resveratrol suppresses PAI-1 gene expression in a human in vitro model of inflamed adipose tissue. AB - Increased plasminogen activator inhibitor-1 (PAI-1) levels are associated with a number of pathophysiological complications; among them is obesity. Resveratrol was proposed to improve obesity-related health problems, but the effect of resveratrol on PAI-1 gene expression in obesity is not completely understood. In this study, we used SGBS adipocytes and a model of human adipose tissue inflammation to examine the effects of resveratrol on the production of PAI-1. Treatment of SGBS adipocytes with resveratrol reduced PAI-1 mRNA and protein in a time- and concentration-dependent manner. Further experiments showed that obesity associated inflammatory conditions lead to the upregulation of PAI-1 gene expression which was antagonized by resveratrol. Although signaling via PI3K, Sirt1, AMPK, ROS, and Nrf2 appeared to play a significant role in the modulation of PAI-1 gene expression under noninflammatory conditions, those signaling components were not involved in mediating the resveratrol effects on PAI-1 production under inflammatory conditions. Instead, we demonstrate that the resveratrol effects on PAI-1 induction under inflammatory conditions were mediated via inhibition of the NF kappa B pathway. Together, resveratrol can act as NF kappa B inhibitor in adipocytes and thus the subsequently reduced PAI-1 expression in inflamed adipose tissue might provide a new insight towards novel treatment options of obesity. PMID- 23819019 TI - Therapeutic advances in the management of chronic hepatitis B infection. AB - Hepatitis B virus (HBV) is a small nonenveloped DNA virus that is a member of the Hepadnaviridae family. Chronic HBV infection is estimated to effect more than 350 million people worldwide with over 2 billion people being exposed to the virus. Risk factors for chronic infection include age of exposure to the virus, concurrent immunosuppression and HIV infection. Individuals chronically infected are 200 times more likely to develop hepatocellular carcinoma (HCC) than uninfected individuals and are at risk of developing cirrhosis and the risks of decompensated liver disease. This article focuses on the recent therapeutic advances that reduce the risk of developing these complications, those that prevent the spread of HBV and strategies for the prevention of post-liver transplantation recurrence of HBV. PMID- 23819021 TI - Scaling Laws at the Nano Size: The Effect of Particle Size and Shape on the Magnetism and Relaxivity of Iron Oxide Nanoparticle Contrast Agents. AB - The magnetic properties of iron oxide nanoparticles govern their relaxivities and efficacy as contrast agents for MRI. These properties are in turn determined by their composition, size and morphology. Herein we present a systematic study of the effect of particle size and shape of magnetite nanocrystals synthesized by thermal decompositions of iron salts on both their magnetism and their longitudinal and transverse relaxivities, r1 and r2, respectively. Faceted nanoparticles demonstrate superior magnetism and relaxivities than spherical nanoparticles of similar size. For faceted nanoparticles, but not for spherical ones, r1 and r2 further increase with increasing particle size up to a size of 18 nm. This observation is in accordance with increasing saturation magnetization for nanoparticles increasing in size up to 12 nm, above which a plateau is observed. The NMRD (Nuclear Magnetic Resonance Dispersion) profiles of MIONs (Magnetic Iron Oxide Nanoparticles) display an increase in longitudinal relaxivity with decreasing magnetic field strength with a plateau below 1 MHz. The transverse relaxivity shows no dependence on the magnetic field strength between 20 MHz and 500 MHz. These observations translate to phantom MR images: in T1-weighted SWIFT (SWeep imaging with Fourier Transform) images MIONs have a positive contrast with little dependence on particle size, whereas in T2-weighted gradient-echo images MIONs create a negative contrast which increases in magnitude with increasing particle size. Altogether, these results will enable the development of particulate MRI contrast agents with enhanced efficacy for biomedical and clinical applications. PMID- 23819020 TI - Prevention of infection caused by immunosuppressive drugs in gastroenterology. AB - Immunosuppressive therapy is frequently used to treat gastrointestinal diseases such as inflammatory bowel disease, autoimmune hepatitis, IgG4-related disease (autoimmune pancreatitis and sclerosing cholangitis) and in the post transplantation setting. These drugs interfere with the immune system. The main safety concern with their use is the risk of infections. Certain infections can be prevented or their impact minimized. Physicians must adopt preventative strategies and should have a high degree of suspicion to recognize infections early and treat appropriately. This article reviews the risk factors for infections, the mechanism of action of immunosuppressive therapy and proposes preventive strategies. PMID- 23819022 TI - Breast cancer in young women - Special Issue. PMID- 23819023 TI - Breast cancer in the young: role of the geneticist. AB - The genetics professional plays an important role in the care of young women with breast cancer by providing counseling on issues specific to these young women. The issues addressed in counseling include hereditary predisposition to cancer, fertility and reproductive options in the context of hereditary cancer, and the impact and implications of their history of early breast cancer on close family members. A thorough risk assessment and counseling session address the patient's personal and family history, with particular attention paid to benign and malignant findings that suggest the need for genetic testing. Genetics professionals, especially genetic counselors, also address the physical and emotional implications of an increased risk of cancer with patients and family members. This review highlights the unique aspects of care provided by these specialized healthcare providers. PMID- 23819024 TI - Epidemiology and prognosis of breast cancer in young women. AB - Breast cancer is the most common malignancy in women with 6.6% of cases diagnosed in young women below the age of 40. Despite variances in risk factors, Age Standardized Incidence Rates of breast cancer in young women vary little between different countries. Review of modifiable risk factors shows that long-term use of oral contraceptives, low body mass index (BMI) and high animal fat diet consumption are associated with increased risk of premenopausal breast cancer. Decreased physical activity and obesity increase risks of breast cancer in postmenopausal women, but data on premenopausal women rather shows that high BMI is associated with decreased risk of breast cancer. Non-modifiable risk factors such as family history and genetic mutations do account for increased risks of breast cancer in premenopausal women. Breast cancer in young women is associated with adverse pathological factors, including high grade tumors, hormone receptor negativity, and HER2 overexpression. This has a significant negative impact on the rate of local recurrence and overall survival. Moreover, younger women often tend to present with breast cancer at a later stage than their older counterparts, which further explains worse outcome. Despite these factors, age per se is still being advocated as an independent role player in the prognosis. This entails more aggressive treatment modalities and the need for closer monitoring and follow-up. PMID- 23819025 TI - Bisphosphonates in the adjuvant treatment of young women with breast cancer: the estrogen rich is a poor candidate! AB - During the last 2 decades the role of bisphosphonates (BPs) to reduce skeletal related events from bone metastases in breast cancer has been well defined. Several preclinical studies have strongly suggested that BPs may also provide an anti-cancer effect in early breast cancer. Indeed, the use of adjuvant BPs represents a unique approach that attempts at eradicating occult tumor micro metastases residing in the bone marrow via targeting the bone microenvironment to render it less favorable for cancer cell growth. Although, this concept has been tested clinically for more than 15 years, no final consensus has been reached as for the routine use of BPs in the adjuvant phase of breast cancer, owing to conflicting results of randomized studies. Nevertheless, accumulating evidence from recent trials has indicated a therapeutic benefit of adjuvant BPs particularly zoledronic acid-in women with established menopause, with no or perhaps detrimental effects in premenopausal women. Indeed, this hypothesis has opened a new chapter on the role of estrogen-poor microenvironment as a potential pre-requisite for the anti-tumor effects of BPs in the adjuvant phase of breast cancer. In this review, we will emphasize the biological rational of using BPs to target bone microenvironment in patients with early breast cancer and we will explore mechanistic differences; related to bisphosphonates effects in premenopausal versus postmenopausal women and how the endocrine environment would influence the anticancer potential of these compounds. PMID- 23819026 TI - Hormonal therapies in young breast cancer patients: when, what and for how long? AB - Breast cancer in young women (<40 years) is a rare and complex clinical and psychosocial condition, which deserves multidisciplinary and personalized approaches. In young women with hormone-receptor positive disease, 5 years of adjuvant tamoxifen, with or without ovarian suppression/ablation, is considered the standard endocrine therapy. The definitive role of adjuvant aromatase inhibitors has still to be elucidated: the upcoming results of the Tamoxifen and EXemestane Trial (TEXT) and Suppression of Ovarian Function Trial (SOFT) trials will help understanding if we can widen our current endocrine therapeutic options. The optimal duration of adjuvant endocrine therapy in young women also remains an unresolved issue. The recently reported results of the ATLAS and aTToM trials represent the first evidence of a beneficial effect of extended endocrine therapy in premenopausal women and provide an important opportunity in high-risk young patients. In the metastatic setting, endocrine therapy should be the preferred choice for endocrine responsive disease, unless there is evidence of endocrine resistance or need for rapid disease and/or symptom control. Tamoxifen in combination with ovarian suppression/ablation remains the 1st-line endocrine therapy of choice. Aromatase inhibitors in combination with ovarian suppression/ablation can be considered after progression on tamoxifen and ovarian suppression/ablation. Fulvestrant has not yet been studied in pre-menopausal women. Specific age-related treatment side effects (i.e., menopausal symptoms, change in body image and weight gain, cognitive function impairment, fertility damage/preservation, long-term organ dysfunction, sexuality) and the social impact of diagnosis and treatment (i.e., job discrimination, family management) should be carefully addressed when planning long-lasting endocrine therapies in young women with hormone-receptor positive early and advanced breast cancer. PMID- 23819027 TI - Treatment of breast cancer in young women: do we need more aggressive therapies? AB - Breast cancer diagnosed in young patients has been reported to have a more aggressive biologic behaviour and to be associated with a more unfavorable prognosis compared with the disease in older patients. However controversies exist regarding the optimal treatment and if more aggressive therapies are really crucial in this population. Very young women with this disease are faced with personal, family, professional, and quality-of-life issues that further complicate the phase of treatment decision-making. Moreover it's mandatory in young patients to consider the impact of acute but also late toxicities in relation to long life-expectancy, too. Dose-dense and high-dose chemotherapy are two examples of more aggressive therapies that failed to show a clear beneficial in a feasible way compared to standard regimens also in young patients. The benefit evidenced in patients with ER-positive disease raises the hypothesis that efficacy of dose-intensive chemotherapy might simply be related to its endocrine effects. The study of the biology and of the oncogenic pathways should be a research priority so to aid management of young patients with breast cancer, and more important, to better tailor treatments that could be offered to young women or, simply to use better the modalities available today. For the time being, young age alone should not be a reason to prescribe more aggressive therapies and there are no evidence to recommend a specific chemotherapy regimen for young women. PMID- 23819028 TI - Premature menopause in young breast cancer: effects on quality of life and treatment interventions. AB - Many young women are at increased risk for premature menopause following adjuvant treatment for breast cancer. These women must deal with consequences of menopause, including loss of fertility and physiologic symptoms such as night sweats, hot flashes, vaginal dryness, and weight gain. These symptoms can be particularly distressing for young women and can adversely affect both health related and psychosocial quality of life (QOL). While there are a wide range of pharmacologic and non-pharmacologic interventions available to help with these symptoms and in turn, improve QOL, there is little data available about the use and efficacy of these interventions in younger women who become menopausal as a result of their breast cancer treatment. Future studies should focus on this vulnerable population, with the goal of identifying effective strategies to relieve symptoms and improve quality of life in young breast cancer survivors. PMID- 23819029 TI - Challenges in managing breast cancer during pregnancy. AB - Pregnancy-associated breast cancer (PABC) is defined as breast cancer occurring anytime during gestation, lactation or within one year after delivery. The optimal management of pregnant women with breast cancer is challenging and not well established; the main concern is the effect of the drugs on the developing fetus and long-term complications after in utero exposure to anti-cancer drugs. Surgical resection is the mainstay of treatment for early breast cancer diagnosed during pregnancy. Modified radical mastectomy is standard of care in first trimester, whereas breast-conserving surgery (lumpectomy with lymph node dissection) can be performed preferably in the second and third trimester. Of note, breast-conserving surgery is not contraindicated per se during the first trimester, but owing to the potential impact of delaying radiotherapy. Radiation therapy is not favored during pregnancy. Moreover, tamoxifen is contraindicated during pregnancy; the agent has been associated with birth defects in up to 20% of exposures. Chemotherapy is generally contraindicated during the first trimester because of the possible damage to organogenesis. Anthracyclines-based regimens are the most widely used is breast cancer treatment and were been shown to be associated with favourable safety profile when administered during pregnancy. As for taxanes, more limited data is available. The use of trastuzumab is contraindicated during pregnancy, given the apparent risk of oligo- and/or anhydramnios as well as the unknown long-term sequelae on the fetus. It is obvious that, diagnosis of breast cancer during pregnancy adds complexity to cancer treatment recommendations. In all cases, a multidisciplinary therapeutic approach among obstetricians, gynaecologists, surgical oncologists, radiation oncologists, medical oncologists, pediatricians and hematologists is clearly warranted. PMID- 23819031 TI - Sexuality and breast cancer: prime time for young patients. AB - Sexuality and sexual functioning is a cardinal domain of health-related quality of life in breast cancer patients, namely in the younger population. Young women below 40 years of age go through a time in their lives where sexual self-identity has recently matured, their professional obligations are demanding and they bear interpersonal and childbearing expectations, all of which can suffer a devastating turnaround with cancer diagnosis and its physical and psychological aftermath. Although these women's sexuality and directed interventions have remained largely unaddressed so far, concepts are evolving and treatment options are becoming diversified, chiefly on the field of non-hormonal pharmacological therapy of sexual dysfunction. This review will examine the definitions of female sexual dysfunction, the etiology of the disorders in young breast cancer patients, the assessment methods, the non-pharmacological and pharmacological treatment options and the challenges that lie ahead. PMID- 23819030 TI - Fertility counseling of young breast cancer patients. AB - Approximately 6% of women with breast cancer are diagnosed before the age of 40. Young age is an independent predictor of adverse outcome and most young breast cancer patients receive systemic treatment with chemotherapy, hormonal therapy or both. The loss or impairment of fertility is a potential side effect of antineoplastic treatments. Due to the rising trend to delaying pregnancy in life, an increasing proportion of young cancer patients who are yet to have a pregnancy will face the problem of iatrogenic menopause in the future. The incidence of anticancer-treatment-related ovarian failure depends on the type of chemotherapy regimen administered, the use of tamoxifen and the age of patients. It rises with increasing age, in the range of 22-61% and 61-97% in women aged <40 years and >40 years respectively. Although there is a clear trend to increasing incidence of ovarian failure with the rise in aging, there may be a small proportion of patients who became amenorrhoeic despite the very young age, thus indicating that also individual factors still unknown may affect the probability of treatment related ovarian failure. A prompt referral of patients to reproductive counseling and a multidisciplinary team including Oncology and Reproductive Units are essential to face the management of fertility issues in cancer patients. Fertility counseling should include a detailed description of all the available techniques to preserve fertility. The main available fertility preservation techniques, standard and experimental, for young breast cancer patients include: temporary ovarian suppression during chemotherapy with gonadotropin-releasing hormone analogues, embryo cryopreservation, cryopreservation of oocytes and cryopreservation of ovarian tissue. Research efforts are still necessary to improve the efficacy and safety of the available fertility preservation strategies as well as an efficient collaboration between oncologists and gynecologists is necessary to improve patients' access to the strategies themselves. PMID- 23819032 TI - Breast imaging in the young: the role of magnetic resonance imaging in breast cancer screening, diagnosis and follow-up. AB - Diagnosis of breast cancer in young individuals (younger than 40 years old) poses a real challenge to breast radiologists because their breast tissue is often denser than the breast tissue of older women. Magnetic Resonance Imaging (MRI) may be particularly helpful in such situations. The American Cancer Society (ACS) recommended breast MRI screening as an adjunct to mammography for: BRCA mutation carriers and their first-degree relatives; women with a lifetime breast cancer risk >=20% to 25%; women with a history of chest radiation between ages of 10 and 30 years; and women with predisposing genetic syndromes. Currently, breast MRI demonstrates a high sensitivity in the range of 93-100%. As many benign lesions also show enhancement or other atypical features on MRI, the primary weakness of contrast enhanced MRI remains in its low specificity, reported to be in the range of 37-97%. Breast MRI is helpful in demonstrating the true tumor size initially, as well as identifying residual tumor following the completion of neo-adjuvant therapy. In general, sensitivities ranging from 61% to 86% for detecting residual disease have been reported. The absence of enhancement virtually excludes a recurrence and the presence of enhancement is very specific for tumor even in the radiated breast. MRI is also the preferred modality for assessment of the breast after re- constructive surgery. The role of Magnetic Resonance Imaging (MRI) in breast diagnosis will continue to evolve as technology improves and clinical experience with new techniques expands. PMID- 23819033 TI - Transfer and Expression of Small Interfering RNAs in Mammalian Cells Using Lentiviral Vectors. AB - RNA interference is a convenient tool for modulating gene expression. The widespread application of RNA interference is made difficult because of the imperfections of the methods used for efficient target cell delivery of whatever genes are under study. One of the most convenient and efficient gene transfer and expression systems is based on the use of lentiviral vectors, which direct the synthesis of small hairpin RNAs (shRNAs), the precursors of siRNAs. The application of these systems enables one to achieve sustainable and long-term shRNA expression in cells. This review considers the adaptation of the processing of artificial shRNA to the mechanisms used by cellular microRNAs and simultaneous expression of several shRNAs as potential approaches for producing lentiviral vectors that direct shRNA synthesis. Approaches to using RNA interference for the treatment of cancer, as well as hereditary and viral diseases, are under active development today. The improvement made to the methods for constructing lentiviral vectors and the investigation into the mechanisms of processing of small interfering RNA allow one to now consider lentiviral vectors that direct shRNA synthesis as one of the most promising tools for delivering small interfering RNAs. PMID- 23819035 TI - The evolutionary pathway of x chromosome inactivation in mammals. AB - X chromosome inactivation is a complex process that occurs in marsupial and eutherian mammals. The process is thought to have arisen during the differentiation of mammalian sex chromosomes to achieve an equal dosage of X chromosome genes in males and females. The differences in the X chromosome inactivation processes in marsupial and eutherian mammals are considered, and the hypotheses on its origin and evolution are discussed in this review. PMID- 23819036 TI - Late replication of the inactive x chromosome is independent of the compactness of chromosome territory in human pluripotent stem cells. AB - Dosage compensation of the X chromosomes in mammals is performed via the formation of facultative heterochromatin on extra X chromosomes in female somatic cells. Facultative heterochromatin of the inactivated X (Xi), as well as constitutive heterochromatin, replicates late during the S-phase. It is generally accepted that Xi is always more compact in the interphase nucleus. The dense chromosomal folding has been proposed to define the late replication of Xi. In contrast to mouse pluripotent stem cells (PSCs), the status of X chromosome inactivation in human PSCs may vary significantly. Fluorescence in situ hybridization with a whole X-chromosome- specific DNA probe revealed that late replicating Xi may occupy either compact or dispersed territory in human PSCs. Thus, the late replication of the Xi does not depend on the compactness of chromosome territory in human PSCs. However, the Xi reactivation and the synchronization in the replication timing of X chromosomes upon reprogramming are necessarily accompanied by the expansion of X chromosome territory. PMID- 23819037 TI - Mycobacterium tuberculosis Transcriptome Profiling in Mice with Genetically Different Susceptibility to Tuberculosis. AB - Whole transcriptome profiling is now almost routinely used in various fields of biology, including microbiology. In vivo transcriptome studies usually provide relevant information about the biological processes in the organism and thus are indispensable for the formulation of hypotheses, testing, and correcting. In this study, we describe the results of genome-wide transcriptional profiling of the major human bacterial pathogen M. tuberculosis during its persistence in lungs. Two mouse strains differing in their susceptibility to tuberculosis were used for experimental infection with M. tuberculosis. Mycobacterial transcriptomes obtained from the infected tissues of the mice at two different time points were analyzed by deep sequencing and compared. It was hypothesized that the changes in the M. tuberculosis transcriptome may attest to the activation of the metabolism of lipids and amino acids, transition to anaerobic respiration, and increased expression of the factors modulating the immune response. A total of 209 genes were determined whose expression increased with disease progression in both host strains (commonly upregulated genes, CUG). Among them, the genes related to the functional categories of lipid metabolism, cell wall, and cell processes are of great interest. It was assumed that the products of these genes are involved in M. tuberculosis adaptation to the host immune system defense, thus being potential targets for drug development. PMID- 23819034 TI - Blood Clotting Factor VIII: From Evolution to Therapy. AB - Recombinant blood clotting factor VIII is one of the most complex proteins for industrial manufacturing due to the low efficiency of its gene transcription, massive intracellular loss of its proprotein during post-translational processing, and the instability of the secreted protein. Improvement in hemophilia A therapy requires a steady increase in the production of factor VIII drugs despite tightening standards of product quality and viral safety. More efficient systems for heterologous expression of factor VIII can be created on the basis of the discovered properties of its gene transcription, post translational processing, and behavior in the bloodstream. The present review describes the deletion variants of factor VIII protein with increased secretion efficiency and the prospects for the pharmaceutical development of longer acting variants and derivatives of factor VIII. PMID- 23819038 TI - Peculiarities of the Regulation of Gene Expression in the Ecl18kI Restriction Modification System. AB - Transcription regulation in bacterial restriction-modification (R-M) systems is an important process, which provides coordinated expression levels of tandem enzymes, DNA methyltransferase (MTase) and restriction endonuclease (RE) protecting cells against penetration of alien DNA. The present study focuses on (cytosine-5)-DNA methyltransferase Ecl18kI (M.Ecl18kI), which is almost identical to DNA methyltransferase SsoII (M.SsoII) in terms of its structure and properties. Each of these enzymes inhibits expression of the intrinsic gene and activates expression of the corresponding RE gene via binding to the regulatory site in the promoter region of these genes. In the present work, complex formation of M.Ecl18kI and RNA polymerase from Escherichia soli with the promoter regions of the MTase and RE genes is studied. The mechanism of regulation of gene expression in the Ecl18kI R-M system is thoroughly investigated. M.Ecl18kI and RNA polymerase are shown to compete for binding to the promoter region. However, no direct contacts between M.Ecl18kI and RNA polymerase are detected. The properties of M.Ecl18kI and M.SsoII mutants are studied. Amino acid substitutions in the N-terminal region of M.Ecl18kI, which performs the regulatory function, are shown to influence not only M.Ecl18kI capability to interact with the regulatory site and to act as a transcription factor, but also its ability to bind and methylate the substrate DNA. The loss of methylation activity does not prevent MTase from performing its regulatory function and even increases its affinity to the regulatory site. However, the presence of the domain responsible for methylation in the M.Ecl18kI molecule is necessary for M.Ecl18kI to perform its regulatory function. PMID- 23819039 TI - Factors Affecting Aggregate Formation in Cell Models of Huntington's Disease and Amyotrophic Lateral Sclerosis. AB - Most neurodegenerative pathologies stem from the formation of aggregates of mutant proteins, causing dysfunction and ultimately neuronal death. This study was aimed at elucidating the role of the protein factors that promote aggregate formation or prevent the process, respectively, glyceraldehyde-3-dehydrogenase (GAPDH) and tissue transglutaminase (tTG) and Hsp70 molecular chaperone. The siRNA technology was used to show that the inhibition of GAPDH expression leads to a 45-50% reduction in the aggregation of mutant huntingtin, with a repeat of 103 glutamine residues in a model of Huntington's disease (HD). Similarly, the blockage of GAPDH synthesis was found for the first time to reduce the degree of aggregation of mutant superoxide dismutase 1 (G93A) in a model of amyotrophic lateral sclerosis (ALS). The treatment of cells that imitate HD and ALS with a pharmacological GAPDH inhibitor, hydroxynonenal, was also shown to reduce the amount of the aggregating material in both disease models. Tissue transglutaminase is another factor that promotes the aggregation of mutant proteins; the inhibition of its activity with cystamine was found to prevent aggregate formation of mutant huntingtin and SOD1. In order to explore the protective function of Hsp70 in the control of the aggregation of mutant huntingtin, a cell model with inducible expression of the chaperone was used. The amount and size of polyglutamine aggregates were reduced by increasing the intracellular content of Hsp70. Thus, pharmacological regulation of the function of three proteins, GAPDH, tTG, and Hsp70, can affect the pathogenesis of two significant neurodegenerative diseases. PMID- 23819040 TI - Identification of Novel IGF1R Kinase Inhibitors by Molecular Modeling and High Throughput Screening. AB - The aim of this study was to identify small molecule compounds that inhibit the kinase activity of the IGF1 receptor and represent novel chemical scaffolds, which can be potentially exploited to develop drug candidates that are superior to the existing experimental anti-IGF1R therapeuticals. To this end, targeted compound libraries were produced by virtual screening using molecular modeling and docking strategies, as well as the ligand-based pharmacophore model. High throughput screening of the resulting compound sets in a biochemical kinase inhibition assay allowed us to identify several novel chemotypes that represent attractive starting points for the development of advanced IGF1R inhibitory compounds. PMID- 23819041 TI - Posterior lamellar graft preparation: a prospective review from an eye bank on current and future aspects. AB - Descemet membrane endothelial keratoplasty (DMEK) is a corneal surgical technique which selectively replaces the damaged posterior part of the cornea with a healthy donor graft retaining the rest of the tissue intact. There is a need to validate and standardize the donor tissue before grafting due to certain issues that can lead to consequences such as graft failure due to poor endothelial cell count, higher mortality, detachment of the graft, or increased surgical expenses, time, and effort. Thus, prospective potential surgeons and eye banks should now aim at developing new improved surgical techniques in order to prepare the best suited, validated, precut, preloaded, and easy to transplant tissue to reduce pre and postsurgical complications. This could be achieved by defining parameters like graft thickness, accepted mortality threshold of the endothelial cells, and behavior of grafts during preservation and transportation along with using more sophisticated instruments like microkeratome and femtosecond lasers for graft preparation. Thus, a rapport between the eye banks and the surgeons along with the advanced instruments can overcome this challenge to find the best possible solution for endothelial keratoplasty (EK). PMID- 23819042 TI - Prevalence rates of self-care behaviors and related factors in a rural hypertension population: a questionnaire survey. AB - The objective of this study was to investigate the self-care behaviors among hypertensive patients in primary care. A cross-sectional survey, with 318 hypertensive patients, was conducted in a rural area in Beijing, China, in 2012. Participants were mainly recruited from a community health clinic and completed questionnaires assessing their self-care behaviors, including data on adherence to a prescribed medication regimen, low-salt diet intake, smoking habits, alcohol consumption, blood pressure monitoring, and physical exercise. The logistic regression model was used for the analysis of any association between self-care behaviors and age, gender, duration of hypertension, self-rated health, marital status, education level, diabetes status, or body mass index. Subjects that adhered to their medication schedule were more likely to have hypertension for a long duration (OR, 3.44; 95% CI 1.99-5.97). Older participants (OR, 1.80; 95% CI 1.08-2.99) were more likely to monitor their blood pressure. Subjects who did not partake in physical exercise were more likely to be men, although the difference between genders was not significant (OR, 0.60; 95% CI 0.36-1.01). Patients with shorter history of hypertension, younger and being males have lower self-care behaviors. Primary care providers and public health practitioner should pay more attention to patients recently diagnosed with hypertension as well as younger male patients. PMID- 23819043 TI - Solvent-Free Synthesis of Flavour Esters through Immobilized Lipase Mediated Transesterification. AB - The synthesis of methyl butyrate and octyl acetate through immobilized Rhizopus oryzae NRRL 3562 lipase mediated transesterification was studied under solvent free conditions. The effect of different transesterification variables, namely, molarity of alcohol, reaction time, temperature, agitation, addition of water, and enzyme amount on molar conversion (%) was investigated. A maximum molar conversion of 70.42% and 92.35% was obtained in a reaction time of 14 and 12 h with the transesterification variables of 0.6 M methanol in vinyl butyrate and 2 M octanol in vinyl acetate using 80 U and 60 U immobilized lipase with the agitation speed of 200 rpm and 0.2% water addition at 32 degrees C and 36 degrees C for methyl butyrate and octyl acetate, respectively. The immobilized enzyme has retained good relative activity (more than 95%) up to five and six recycles for methyl butyrate and octyl acetate, respectively. Hence, the present investigation makes a great impingement in natural flavour industry by introducing products synthesized under solvent-free conditions to the flavour market. PMID- 23819044 TI - Are nutrition knowledge, attitudes, and beliefs associated with obesity among low income Hispanic and African American women caretakers? AB - The purposes of this descriptive study were to (1) describe nutrition knowledge, attitudes, beliefs (KAB), and self-efficacy among low-income African American and Hispanic women; (2) identify the associations these variables have on diet quality and weight status; (3) identify barriers to healthy eating. Data from three separate studies were combined and analyzed. The total sample included African Americans (N = 92) and Hispanics (N = 272). Descriptive statistics and bivariate analyses were used to identify associations between KAB and body mass index (BMI) and diet quality. The majority of African Americans had good knowledge in nutrition while Hispanics had fair knowledge. Attitudes toward eating a healthy diet were significantly associated with high fiber intake among African Americans and low fat consumption among Hispanics. A computed KAB score showed no significant relation to individuals' weight status or diet quality. However, attitudes and beliefs about healthy foods strongly correlated with participants' weight or diet consumption among Hispanics. The most common barrier to consuming a healthy diet reported by both groups was the cost of healthy foods. It is therefore recommended to address these variables when addressing obesity and poor dietary intake among low-income minority groups. PMID- 23819045 TI - Increased seizure latency and decreased severity of pentylenetetrazol-induced seizures in mice after essential oil administration. AB - The effect of pretreatment with essential oils (EOs) from eight aromatic plants on the seizure latency and severity of pentylenetetrazol- (PTZ-) induced seizures in mice was evaluated. Weight-dependent doses of Rosmarinus officinalis, Ocimum basilicum, Mentha spicata, Mentha pulegium, Lavandula angustifolia, Mentha piperita, Origanum dictamnus, and Origanum vulgare, isolated from the respective aromatic plants from NE Greece, were administered 60 minutes prior to intraperitoneal (i.p.) injection of a lethal dose of PTZ to eight respective groups of Balb-c mice. Control group received only one i.p. PTZ injection. Motor and behavioral activity of the animals after EOs administration, development of tonic-clonic seizures, seizure latency and severity, and percentage of survival after PTZ administration were determined for each group. All groups of mice treated with the EOs showed reduced activity and stability after the administration of the oil, except for those treated with O. vulgare (100% mortality after the administration of the oil). After PTZ administration, mice from the different groups showed increased latency and reduced severity of seizures (ranging from simple twitches to complete seizures). Mice who had received M. piperita demonstrated no seizures and 100% survival. The different drastic component and its concentration could account for the diversity of anticonvulsant effects. PMID- 23819046 TI - Oral care of hospitalised older patients in the acute medical setting. AB - Oral health care is an essential aspect of nursing care. There are many variances in the quality and frequency of the oral care that is delivered to patients by nursing staff, such as oral care being given a low priority when compared to other nursing care elements, oral care being neglected, and oral care delivery being dependent on the nurse's knowledge of oral hygiene. Additionally, there are some particular patient groups known to be at risk of oral health problems or who have existing oral diseases and conditions. As people age their susceptibility increases to chronic and life-threatening diseases, and they can be at increased risk of acute infections increases compromised by ageing immune systems. The aim of this literature review was to ignite the discussion related to the oral care practices of nurses for older acute medical hospitalised patients. The review revealed that nursing staff know that good nursing includes oral health care, but this knowledge does not always mean that oral health care is administered. Oral health care seems to be separated from other nursing activities and is not discussed when nursing care plans are written, only when oral problems are obvious. PMID- 23819047 TI - Conceptualizing and Treating Comorbid Chronic Pain and PTSD. AB - The purpose of this paper is to review the rationale for concurrent, evidence based treatment of chronic pain and posttraumatic stress disorder (PTSD). To meet this end, we review pertinent definitions and extant theories related to the two conditions and their correlations with each other. We then synthesize theoretical components into a proposal of a comprehensive conceptual framework for understanding the relationship and clinical complexity of overlapping chronic pain and PTSD. We conclude with an example of an integrated treatment model designed specifically to address a fundamental factor associated with pain and PTSD: avoidance. PMID- 23819048 TI - Comparison of Adaptive Behavior Measures for Children with HFASDs. AB - Adaptive behavior rating scales are frequently used to gather information on the adaptive functioning of children with high-functioning autism spectrum disorders (HFASDs), yet little is known about the extent to which these measures yield comparable results. This study was conducted to (a) document the parent-rated VABS-II, BASC-2, and ABAS-II adaptive behavior profiles of 6- to 11-year-olds with HFASDs (including relative strengths and weaknesses); (b) examine the extent to which these measures yielded similar scores on comparable scales; and (c) assess potential discrepancies between cognitive ability and adaptive behavior across the measures. All three adaptive measures revealed significant deficits overall for the sample, with the VABS-II and ABAS-II indicating relative weaknesses in social skills and strengths in academic-related skills. Cross measure comparisons indicated significant differences in the absolute magnitude of scores. In general, the VABS-II yielded significantly higher scores than the BASC-2 and ABAS-II. However, the VABS-II and ABAS-II yielded scores that did not significantly differ for adaptive social skills which is a critical area to assess for children with HFASDs. Results also indicated significant discrepancies between the children's average IQ score and their scores on the adaptive domains and composites of the three adaptive measures. PMID- 23819049 TI - Family Doctors Seen through the Eyes of Specialists: A Qualitative Study. AB - Germany is facing a shortage of young family doctors. In search of possible reasons the aim of this study was to explore the perception of specialists on family doctors. Within a qualitative study 16 medical specialists from different fields in hospital and outpatient care setting were interviewed. Interviews were analysed using qualitative content analysis according to Mayring. Most of the interviewed specialists have a positive view on family doctors although a certain depreciative assumption is resonated in a number of statements. According to the specialists, family doctors enjoy a high status in public, even if social processes of change may have a negative influence on their rather old-fashioned image. Specialists find that family medicine is underrepresented in university education suffering from an upgrading of specialized disciplines. Altogether the majority of the interviewed specialists certify family doctors in Germany a positive image. Lecturer in medical education and training should be aware of their key role in the career choices of young trainees and avoid degradation or upgrading of certain medical disciplines. Interlinked measures on different levels focusing on the improvement of working conditions and representation at the universities would be needed to regain attractiveness for the family doctor's profession as a career choice for young doctors. PMID- 23819050 TI - Effect of the Direct Renin Inhibitor Aliskiren on Urinary Albumin Excretion in Spontaneous Type 2 Diabetic KK-A (y) Mouse. AB - Objective. Although angiotensin II-mediated inflammation and extracellular matrix accumulation are considered to be associated with the progression of diabetic nephropathy, these processes have not yet been sufficiently clarified. The objective of this study was to determine whether the correction of the abnormal renal expression of MMPs and its inhibitors (MMPs/TIMPs) and cytokines following the administration of aliskiren to KK-A (y) mice results in a renoprotective effect. Methods. KK-A (y) mice were divided into two groups, that is, untreated (saline) and treated (aliskiren) groups. Systolic BP, HbA1c levels, and the albumin-creatinine ratio (ACR) were measured. The renal expression of MMPs/TIMPs, fibronectin, type IV collagen, MCP-1, and (pro)renin receptor ((P)RR) was examined using real-time PCR and/or immunohistochemical staining. Renal MAPK and NF- kappa B activity were also examined by Western blot analyses and ELISA, respectively. Results. Significant decreases in systolic BP and ACR levels were observed in treated KK-A (y) mice compared with the findings in untreated KK-A (y) mice. Furthermore, increases in MMPs/TIMPs, fibronectin, type IV collagen, MCP-1, and (P)RR expression, in addition to MAPK and NF- kappa B activity, were significantly attenuated by aliskiren administration. Conclusions. It appears that aliskiren improves albuminuria and renal fibrosis by regulating inflammation and the alteration of collagen synthesis and degradation. PMID- 23819051 TI - Age differences in long term outcomes of coronary patients treated with drug eluting stents at a tertiary medical center. AB - We evaluate differences in outcomes in younger (<65 years) and older (>=65 years) patients for target lesion failure (TLF) at 2-year follow-up in an unselected consecutive series of patients treated with the everolimus- (EES) and paclitaxel eluting (PES) stents at a tertiary medical center. 348 consecutive patients (younger 150; older 198) stented with the EES and PES were retrospectively analyzed. The primary endpoint was TLF (composite endpoint of cardiac death, non fatal myocardial infarction due to index vessel and target lesion revascularization (TLR)). At 2 years follow up, younger versus older patients had the following outcomes respectively: TLF 27.7% versus 25.5% (P = 0.71), TLR 24.8% versus 21.4% (P = 0.52), cardiac death 3.4% versus 2.5% (P = 0.75) and definite and probable stent thrombosis (2.0% versus 1.0%). Multivariate analysis showed that renal failure (odds ratio: 2.55, P = 0.045), number of stents per patient (odds ratio: 1.60, P = 0.001) and younger age (odds ratio: 0.97; P = 0.010), but not gender, diabetes or type of DES stent (EES versus PES) predicted TLF. We conclude that older age was not a predictor of TLF at 2-year follow-up after adjusting for renal insufficiency, number of stents used per patient, gender, diabetes and type of DES used. PMID- 23819052 TI - Assessment of myometrial concentrations of oestrogen and progesterone receptors in the lower uterine segment of full-term pregnancies in presence or absence of labour. AB - OBJECTIVE: To assess the concentration of progesterone (PRs) and oestrogen (ORs) receptors of myometrium of full-term pregnant women in the myometrium of lower segment of the uterus in relationship with presence or absence of labour. METHODS: This was a cross-sectional prospective study with 21 pregnant women, being 6 in labour (Group I) and 15 without labour (Group II). The biopsy of myometrium was realized during caesarian section, and the excised tissue was stained using immunohistochemical techniques for the quantification of the receptors, and with the aid of image-analysis software, the numbers of receptors for each hormone were determined spectrophotometrically. The Mann-Whitney test was used to compare the pregnant women in each study group with respect to the numbers of ORs and PRs. The Wilcoxon test was used to compare the concentration of ORs and PRs in each group separately. RESULTS: The mean of gestational age was 39 weeks, (range, 37 to 41 weeks). The medians of PRs and ORs in pregnant women in labour (Group I) were 29.3 (range, 24.6-30.2) and 32.3 (range, 22.9-49.0), respectively. The medians of PRs and ORs in pregnant women without labour (Group II) were 43.6 (range, 23.6-70) and 43.9 (range, 18.3-62.6), respectively. We did not observe significant differences of the number of ORs and PRs in both groups (P = 0.13 and 0.37, resp.). The number of ORs was statistically more than that of PRs in Group II (Z calculated = 16.00). CONCLUSION: The concentrations of PRs and ORs were similar in the myometrium of the lower uterine segment of pregnant women during and without labour, but the concentration of ORs was more than that of PRs in the myometrium of the lower uterine segment of pregnant women without labour. PMID- 23819053 TI - Mouse models of the skin: models to define mechanisms of skin carcinogenesis. PMID- 23819054 TI - Genotypic Characterization of Yersinia enterocolitica Biotype 4/O:3 Isolates from Pigs and Slaughterhouses Using SE-AFLP, ERIC-PCR, and PFGE. AB - Yersinia enterocolitica is a foodborne pathogen that causes illness in humans and animals. The biotype 4/O:3 has been commonly associated with yersiniosis and is characterized by the presence of chromosomal and extra-chromosomal virulence genes. Molecular typing methods have been successfully used to characterize Y. enterocolitica genetic heterogeneity and to study the epidemiology of the bacteria from different origins. In this study, 320 Y. enterocolitica biotype 4/O:3 isolates originating in pigs and slaughterhouses were characterized according to the virulence profile, and 61 isolates were typified through SE AFLP, ERIC-PCR, and PFGE techniques. The majority of the isolates originated from pigs, and the predominant virulence profile was ail+ virF+ rfbC+ ystA+, representing 83.4% of the tested isolates. All of the Y. enterocolitica 4/O:3 isolates were positive for at least ystA gene. The SE-AFLP and ERIC-PCR patterns were highly homogeneous. The SE-AFLP was more discriminative than the ERIC-PCR and tended to cluster isolates according to the slaughterhouse. Despite the limited genetic diversity of Y. enterocolitica 4/O:3, PFGE was shown to be the most discriminative technique considering one band of difference. Fattening pigs proved to be an important reservoir of Y. enterocolitica biotype 4/O:3 carrying virulence genes. PMID- 23819055 TI - Emerging molecularly targeted therapies in castration refractory prostate cancer. AB - Androgen deprivation therapy (ADT) with medical or surgical castration is the mainstay of therapy in men with metastatic prostate cancer. However, despite initial responses, almost all men eventually develop castration refractory metastatic prostate cancer (CRPC) and die of their disease. Over the last decade, it has been recognized that despite the failure of ADT, most prostate cancers maintain some dependence on androgen and/or androgen receptor (AR) signaling for proliferation. Furthermore, androgen independent molecular pathways have been identified as drivers of continued progression of CRPC. Subsequently, drugs have been developed targeting these pathways, many of which have received regulatory approval. Agents such as abiraterone, enzalutamide, orteronel (TAK-700), and ARN 509 target androgen signaling. Sipuleucel-T, ipilimumab, and tasquinimod augment immune-mediated tumor killing. Agents targeting classic tumorogenesis pathways including vascular endothelial growth factor, hepatocyte growth factor, insulin like growth factor-1, tumor suppressor, and those which regulate apoptosis and cell cycles are currently being developed. This paper aims to focus on emerging molecular pathways underlying progression of CRPC, and the drugs targeting these pathways, which have recently been approved or have reached advanced stages of development in either phase II or phase III clinical trials. PMID- 23819056 TI - Giant hepatic cyst with septal structure: diagnosis and management. AB - The hepatic cyst is a common benign liver tumor, and no surgical treatment is necessary. However, it is difficult to correctly diagnose the giant hepatic cyst containing the solid septal structures inside, from the malignant cystadenocarcinomas. The various imaging modalities such as computed tomography, magnetic resonance imaging, and ultrasonography, have been developed and are useful for the diagnosis of these liver tumors. Reviewing the other reports in this paper, the combination of more than 2 modalities will help to diagnose these tumors; however, the malignant potential is unable to be excluded if the tumor is huge. Therefore, the surgical resection should be considered for the huge hepatic cysts with septal structures if the correct diagnosis is unable to be made. For example, when the hemorrhages cause the granulation in the septa which often shows neovascularization, the imaging modalities are unable to define this situation from the malignant tissue with hypervascularity. Therefore, with the careful review of other reports, we conclude that if the imaging studies show the possible malignant potential or the sizing-up is marked, the surgical treatment should be considered with the consent from the patients. PMID- 23819057 TI - Rising Prevalence and Neighborhood, Social, and Behavioral Determinants of Sleep Problems in US Children and Adolescents, 2003-2012. AB - We examined trends and neighborhood and sociobehavioral determinants of sleep problems in US children aged 6-17 between 2003 and 2012. The 2003, 2007, and 2011 2012 rounds of the National Survey of Children's Health were used to estimate trends and differentials in sleep problems using logistic regression. Prevalence of sleep problems increased significantly over time. The proportion of children with <7 days/week of adequate sleep increased from 31.2% in 2003 to 41.9% in 2011 2012, whereas the prevalence of adequate sleep <5 days/week rose from 12.6% in 2003 to 13.6% in 2011-2012. Prevalence of sleep problems varied in relation to neighborhood socioeconomic and built-environmental characteristics (e.g., safety concerns, poor housing, garbage/litter, vandalism, sidewalks, and parks/playgrounds). Approximately 10% of children in neighborhoods with the most favorable social environment had serious sleep problems, compared with 16.2% of children in neighborhoods with the least-favorable social environment. Children in neighborhoods with the fewest health-promoting amenities or the greatest social disadvantage had 37%-43% higher adjusted odds of serious sleep problems than children in the most-favorable neighborhoods. Higher levels of screen time, physical inactivity, and secondhand smoke exposure were associated with 20%-47% higher adjusted odds of sleep problems. Neighborhood conditions and behavioral factors are important determinants of sleep problems in children. PMID- 23819058 TI - Prevalence and Risk Indicators for Anal Incontinence among Pregnant Women. AB - The aim of this study was to assess the prevalence and risk factors of anal incontinence in an unselected pregnant population at second trimester. A survey of pregnant women attending a routine ultrasound examination was conducted in a university hospital in Oslo, Norway. A questionnaire consisting of 105 items concerning anal incontinence (including St. Mark's score), urinary incontinence, medication use, and comorbidity was posted to women when invited to the ultrasound examination. Results. Prevalence of self-reported anal incontinence (St. Mark's score >= 3) was the lowest in the group of women with a previous cesarean section only (6.4%) and the highest among women with a previous delivery complicated by obstetric anal sphincter injury (24.4%). Among nulliparous women the prevalence of anal incontinence was 7.7% and was associated to low educational level and comorbidity. Prevalence of anal incontinence increased with increasing parity. Urinary incontinence was associated with anal incontinence in all parity groups. Conclusions. Anal incontinence was most frequent among women with a history of obstetric anal sphincter injury. Other obstetrical events had a minor effect on prevalence of anal incontinence among parous women. Prevention of obstetrical sphincter injury is likely the most important factor for reducing bothersome anal incontinence among fertile women. PMID- 23819059 TI - Angiogenic and inflammatory properties of psoriatic arthritis. AB - Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy associated with psoriasis and included in seronegative spondyloarthropathy. PsA has several unique characteristics different from rheumatoid arthritis (RA), such as enthesopathy, dactylitis, and abnormal bone remodeling. As compared with synovitis of RA (pannus), proliferation of PsA synovium is mild and characterized by hypervascularity and increased infiltration of polymorphonuclear leukocytes in the synovial tissues. Angiogenesis plays a crucial role in cutaneous psoriasis, and several angiogenic factors such as vascular endothelial growth factor, interleukin-8, angiopoietin, tumor necrosis factor- alpha and transforming growth factor-beta, are suggested to play an important role also in the pathophysiology of PsA. Further, IL-17 has various functions such as upregulation of proinflammatory cytokines, attraction of neutrophils, stimulation of keratinocytes, endothelial cell migration, and osteoclast formation via RANKL from activated synovial fibroblasts. Thus, IL-17 may be important in angiogenesis, fibrogenesis, and osteoclastogenesis in PsA. In this paper, roles of angiogenesis in the psoriatic synovium are discussed, which may strengthen the understanding of the pathogenesis of PsA. PMID- 23819060 TI - Determinants of oxygen therapy in childhood pneumonia in a resource-constrained region. AB - Childhood pneumonia is a leading cause of morbidity and mortality among underfives particularly in the resource-constraint part of the world. A high proportion of these deaths are due to lack of oxygen, thereby making oxygen administration a life-saving adjunctive when indicated. However, many primary health centres that manage most of the cases often lack the adequate manpower and facilities to decide which patient should be on oxygen therapy. Therefore, this study aimed to determine factors that predict hypoxaemia at presentation in children with severe pneumonia. Four hundred and twenty children aged from 2 to 59 months (40% infants) with severe pneumonia admitted to a health centre in rural Gambia were assessed at presentation. Eighty-one of them (19.30%) had hypoxaemia (oxygen saturation < 90%). Children aged 2-11 months, with grunting respiration, cyanosis, and head nodding, and those with cardiomegaly on chest radiograph were at higher risk of hypoxaemia (P < 0.05). Grunting respiration (OR = 5.210, 95% CI 2.287-7.482) and cyanosis (OR = 83.200, 95% CI 5.248-355.111) were independent predictors of hypoxaemia in childhood pneumonia. We conclude that children that grunt and are centrally cyanosed should be preferentially commenced on oxygen therapy even when there is no facility to confirm hypoxaemia. PMID- 23819061 TI - Stathmin Regulates Hypoxia-Inducible Factor-1alpha Expression through the Mammalian Target of Rapamycin Pathway in Ovarian Clear Cell Adenocarcinoma. AB - Stathmin, a microtubule-destabilizing phosphoprotein, is highly expressed in ovarian cancer, but the pathophysiological significance of this protein in ovarian carcinoma cells remains poorly understood. This study reports the involvement of stathmin in the mTOR/HIF-1 alpha /VEGF pathway in ovarian clear cell adenocarcinoma (CCA) during hypoxia. HIF-1 alpha protein and VEGF mRNA levels were markedly elevated in RMG-1 cells, a CCA cell line, cultured under hypoxic conditions. Rapamycin, an inhibitor of mTOR complex 1, reduced the level of HIF-1 alpha and blocked phosphorylation of ribosomal protein S6 kinase 1 (S6K), a transcriptional regulator of mTOR, demonstrating that hypoxia activates mTOR/S6K/HIF-1 alpha signaling in CCA. Furthermore, stathmin knockdown inhibited hypoxia-induced HIF-1 alpha and VEGF expression and S6K phosphorylation. The silencing of stathmin expression also reduced Akt phosphorylation, a critical event in the mTOR/HIF-1 alpha /VEGF signaling pathway. By contrast, stathmin overexpression upregulated hypoxia-induced HIF-1 alpha and VEGF expression in OVCAR-3 cells, another CCA cell line. In addition, suppression of Akt activation by wortmannin, a phosphoinositide 3-kinase (PI3K) inhibitor, decreased HIF-1 alpha and VEGF expression. These results illustrate that regulation of HIF-1 alpha through the PI3K/Akt/mTOR pathway is controlled by stathmin in CCA. Our findings point to a new mechanism of stathmin regulation during ovarian cancer. PMID- 23819062 TI - Investigating the value of abatacept in the treatment of rheumatoid arthritis: a systematic review of cost-effectiveness studies. AB - Background. Rheumatoid arthritis is a progressive inflammatory disease that affects greatly patients' quality of life and demands for aggressive management early on during the course of the disease. The discovery of biologics has equipped rheumatologists with evolutionary treatment tools but has also impacted greatly management costs. Objectives. To conduct a systematic review in order to evaluate the cost effectiveness of abatacept in the treatment of moderate to severe rheumatoid arthritis. Methods. Pubmed, the International Society for Pharmacoeconomics and Outcomes Research Outcomes Research Digest, the National Health System Economic Evaluation Database, and the Database of Abstracts of Reviews of Effects were searched. Results. In total 301 studies were identified and 42 met the inclusion criteria. Half of the selected studies evaluated abatacept in the treatment of rheumatoid arthritis, after failure of or intolerance to tumor necrosis factor alpha inhibitors. Of those, 82% were in favor of abatacept as a cost-effective or dominant strategy versus varying alternatives, whereas 18% favored other treatments. Conclusion. The majority of evidence from the published literature supports that abatacept can be a cost effective alternative in the treatment of moderate to severe rheumatoid arthritis, especially in patients that have demonstrated inadequate response or intolerance to anti-TNF agents or conventional disease modifying antirheumatic drugs. PMID- 23819064 TI - Efficacy and Safety of Enoxaparin for Preventing Venous Thromboembolic Events following Urologic Laparoscopic Surgery. AB - There is a paucity of definitive evidence that supports the use of enoxaparin to prevent venous thromboembolism (VTE) after urologic laparoscopic surgery. The purpose of this study was to evaluate the efficacy and safety of postoperative subcutaneous enoxaparin injection in patients who underwent urologic laparoscopic surgery. A total of 63 patients were evaluated from June 2010 to December 2012. All patients received postoperative prophylaxis with enoxaparin (2000 IU twice daily for 5 days). None of the patients treated with enoxaparin developed symptomatic VTE, but two cases (3.2%) of pulmonary embolism were noted before initial enoxaparin administration. Statistically significant differences were observed between the prothrombin time (PT) and activated partial thromboplastin time (APTT) values and D-dimer levels obtained at baseline and on day 7 after surgery; however, the PT and APTT values did not exceed the normal range. In addition, signs of any adverse events were not encountered in any of the patients treated with enoxaparin. The use of enoxaparin immediately after a surgery may confer valuable thromboprophylaxis benefits for urologic laparoscopic surgery. PMID- 23819065 TI - The effect of in vitro oxidative stress on the female rabbit bladder contractile response and antioxidant levels. AB - Introduction. There are several bladder dysfunctions that are associated with oxidative stress to the urinary bladder. Two experimental models are known to cause this type of bladder damage. The first is direct oxidative damage caused by hydrogen peroxide (H2O2). The second is oxidative damage caused by ischemia followed by reperfusion (I/R). The specific aim of this study is to directly compare these two models of oxidative stress. Methods. Six adult female NZW rabbits were divided into two groups of three rabbits each. Eight full thickness strips from three rabbit bladders were taken for in vitro ischemia/reperfusion physiological analysis, while eight strips from three rabbit bladders were taken for in vitro H2O2 physiological analysis. All tissue was analyzed for total antioxidant activity (AA) and malondialdehyde (MDA) levels. In addition, samples of the water baths were also analyzed for AA. Results. In vitro I/R reduced the response to field stimulation (FS) to a significantly greater extent than the inhibition of the response to carbachol. In vitro H2O2 decreased all responses to approximately the same degree. Total AA levels at higher concentrations of H2O2 for all bath fluids were significantly higher than controls. MDA levels were significantly elevated in both models of oxidative stress. PMID- 23819066 TI - Delayed onset malignant hyperthermia after sevoflurane. AB - Malignant hyperthermia is a hypermetabolic response to inhalation agents (such as halothane, sevoflurane, and desflurane), succinylcholine, vigorous exercise, and heat. Reactions develop more frequently in males than females (2 : 1). The classical signs of malignant hyperthermia are hyperthermia, tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, muscle rigidity and rhabdomyolysis. In this case report, we present a case of delayed onset malignant hyperthermia-like reaction after the second exposure to sevoflurane. PMID- 23819067 TI - Foreign body induced neuralgia: a diagnostic challenge. AB - Neuropathic pain is caused by neural injury or painful states associated with either peripheral or central nerve injury. One of the aetiologies of this type of pain is iatrogenic trauma. This case highlights the features of peripheral neuropathic pain caused by foreign body left in the mental foramen following a previous surgical procedure. The foreign body was detected on routine radiographic evaluation. Once the foreign body was removed by surgical intervention, the pain resolved. This stresses the importance of routine radiographic evaluation in proper diagnosis and treatment planning in the management of neuropathic pain. This paper also sheds light on the role of iatrogenic mechanical cause of peripheral neuropathic pain and warrants a tough degree of caution on the part of oral clinicians. PMID- 23819068 TI - Laser-Assisted Periodontal Management of Drug-Induced Gingival Overgrowth under General Anesthesia: A Viable Option. AB - Gingival overgrowth/hyperplasia can be attributed to several causes, but drug induced gingival overgrowth/hyperplasia arises secondarily to prolonged use of antihypertensive drugs, anticonvulsants and immunosuppressants. The management is complex in nature considering the multitude of factors involved such as substitution of drug strict plaque control along with excision of the tissue to be performed under local anesthesia as outpatient. In the recent times, the patient's psychological fear of the treatment with the use of surgical blade and multiple visits has developed the concept of single visit treatment under general anesthesia incorporating a laser as viable option. The present case highlights the new method of management of gingival overgrowth. PMID- 23819069 TI - Management of a severely submerged primary molar: a case report. AB - Ankylosis is a condition frequently associated with primary molars, wherein the ankylosed primary teeth remain in a fixed position, while the adjacent teeth continue to erupt, moving occlusally. In this case report, a five-year-old boy, who had a retained and submerged left lower second primary molar, was presented. Luxation of ankylosed primary molar was considered as a treatment approach. After four months, the tooth erupted to the occlusal level, and there was evidence of further development of a permanent successor in radiographic evaluation. After one year, tooth mobility, bone formation, and development of a permanent successor were in good condition. PMID- 23819070 TI - Cemento-ossifying fibroma in a patient with end-stage renal disease. AB - The presence of chronic renal disease (CRD) is a predisposing factor for the occurrence of soft and hard tissue lesions in the oral cavity. The cemento ossifying fibroma (COF) is an uncommon benign fibroosseous lesion composed of fibrocellular component and calcified materials like cementum and woven bone. A 37-year-old female patient undergoing chronic haemodialysis reported to our institution with a complaint of slow growing, nontender swelling of mandible of 6 month duration. Computed tomography disclosed an ill-defined lesion showing thinning and expansion of buccal as well as lingual cortical plate with flecks of radiopacity in centre. Incision biopsy revealed histological characteristics consistent with cemento-ossifying fibroma. The lesion was excised under local anesthesia. The histopathological examination revealed irregularly shaped bone and cementum-like hard tissue calcifications contained within hypercellular fibrous tissue stroma, leading to a confirmation of the diagnosis of cemento ossifying fibroma. This paper aims to provide light to the fact that the soft and hard tissues of the oral region may become susceptible to the development of pathological growths in case of some particular systemic conditions. PMID- 23819071 TI - Tension Pneumothorax, Pneumoperitoneum, and Cervical Emphysema following a Diagnostic Colonoscopy. AB - Colonoscopy is currently a widespread procedure used in screening for colorectal cancer. Iatrogenic colonic perforation during colonoscopy is a serious and potentially life-threatening complication that can cause significant morbidity and mortality. "Triple pneumo" (a combination of pneumothorax, pneumomediastinum, and pneumoperitoneum) following colonoscopy is a rare but a serious condition requiring immediate diagnosis and emergent intervention. In majority of these cases a colonic perforation is the initial injury that is followed by pneumothorax and pneumomediastinum through the potential anatomical connection with retroperitoneal and mediastinal spaces. In this rare case report we are presenting a case of "triple pneumo" with no evidence of colonic perforation. This patient developed a simultaneous pneumoperitoneum, pneumomediastinum, and a tension pneumothorax requiring immediate tube thoracostomy. This case may raise the awareness on the likelihood of these serious complications after colonoscopy. PMID- 23819063 TI - The role of chronic inflammation in obesity-associated cancers. AB - There is a strong relationship between metabolism and immunity, which can become deleterious under conditions of metabolic stress. Obesity, considered a chronic inflammatory disease, is one example of this link. Chronic inflammation is increasingly being recognized as an etiology in several cancers, particularly those of epithelial origin, and therefore a potential link between obesity and cancer. In this review, the connection between the different factors that can lead to the chronic inflammatory state in the obese individual, as well as their effect in tumorigenesis, is addressed. Furthermore, the association between obesity, inflammation, and esophageal, liver, colon, postmenopausal breast, and endometrial cancers is discussed. PMID- 23819072 TI - Citrullus colocynthis as the Cause of Acute Rectorrhagia. AB - Introduction. Citrullus colocynthis Schrad. is a commonly used medicinal plant especially as a hypoglycemic agent. Case Presentation. Four patients with colocynth intoxication are presented. The main clinical feature was acute rectorrhagia preceeded by mucosal diarrhea with tenesmus, which gradually progressed to bloody diarrhea and overt rectorrhagia within 3 to 4 hours. The only colonoscopic observation was mucosal erosion which was completely resolved in follow-up colonoscopy after 14 days. Conclusion. The membranolytic activity of some C. colocynthis ingredients is responsible for the intestinal damage. Patients and herbalists should be acquainted with the proper use and side effects of the herb. Clinicians should also be aware of C. colocynthis as a probable cause of lower GI bleeding in patients with no other suggestive history, especially diabetics. PMID- 23819073 TI - Acanthosis nigricans associated with an adrenocortical tumor in a pediatric patient. AB - Malignant acanthosis nigricans (AN) is a rare paraneoplastic syndrome seen primarily in adults with an underlying diagnosis of gastrointestinal adenocarcinoma. Malignant AN is characterized by hyperpigmentation and velvety hyperplasia of the epidermis. This condition is generally not associated with tumors in pediatric populations or in the adrenal gland. We present a case of malignant AN in a pediatric patient with a nonmalignant, functional adrenocortical tumor. PMID- 23819075 TI - Syndrome of inappropriate antidiuretic hormone secretion and Ibuprofen, a rare association to be considered: role of tolvaptan. AB - The association between the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and the use of nonsteroidal anti-inflammatory drugs (NSAIDs) is rare and has never been treated with an arginine vasopressin receptor antagonist. We report a unique case of SIADH associated with ibuprofen use and successfully treated with tolvaptan. A 76-year-old man came to our observation because of lumbar pain and epigastric discomfort. He was taking ibuprofen orally 400 mg bid as an analgesic treatment. Laboratory tests showed low levels of sodium (116 mmol/L) and chloride; a diagnosis of SIADH was formulated and ibuprofen was stopped immediately. Imaging tests allowed to rule out the presence of malignancies or cerebral and lung diseases. Slightly hypertonic saline infusion was administered for 3 days without significant sodium improvement; therefore, tolvaptan was started at the initial dose of 7.5 mg daily, doubled after 5 days. After 8 days of treatment the patient showed progressive increase of sodium levels up to normal values. In the following weeks tolvaptan was prescribed at progressively titrated dosage to full suspension; afterwards the sodium levels remained normal without any type of treatment. PMID- 23819074 TI - Pure androgen-secreting adrenal adenoma associated with resistant hypertension. AB - Pure androgen-secreting adrenal adenoma is very rare, and its diagnosis remains a clinical challenge. Its association with resistant hypertension is uncommon and not well understood. We present an 18-year-old female with a 10-year history of hirsutism that was accidentally diagnosed with an adrenal mass during the evaluation of a hypertensive crisis. She had a long-standing history of hirsutism, clitorimegaly, deepening of the voice, and primary amenorrhea. She was phenotypically and socially a male. FSH, LH, prolactin, estradiol, 17 hydroxyprogesterone, and progesterone were normal. Total testosterone and DHEA-S were elevated. Cushing syndrome, primary aldosteronism, pheochromocytoma, and nonclassic congenital adrenal hyperplasia were ruled out. She underwent adrenalectomy and pathology reported an adenoma. At 2-month followup, hirsutism and virilizing symptoms clearly improved and blood pressure normalized without antihypertensive medications, current literature of this unusual illness and it association with hypertension is presented and discussed. PMID- 23819076 TI - Acute gastric dilatation: a transient cause of hepatic portal venous gas-case report and review of the literature. AB - Gastric pneumatosis (GP) and hepatic portal venous gas (HPVG) have typically been thought of as an ominous radiological sign associated with a grave prognosis, and the observation of HPVG on plain abdominal radiography, ultrasonography, or computed tomography is viewed as a significant finding. It is often associated with severe or potentially lethal conditions warranting urgent diagnosis and possible surgical intervention. Early studies of HPVG based on plain abdominal radiography found an associated mortality rate of 75% primarily due to ischemic bowel. However, modern abdominal computed tomography (CT) has resulted in the detection of HPVG in an increased proportion of nonfatal and benign conditions. We report a nonfatal case of HPVG in a patient with Noonan's syndrome due to acute gastric dilatation in the setting of gastric outlet obstruction caused by a congenital band that is extremely rare in adults. PMID- 23819077 TI - Paecilomyces variotii as an Emergent Pathogenic Agent of Pneumonia. AB - Paecilomyces variotii is a commonly occurring species in air and food, and it is also associated with many types of human infections. Pneumonia due to Paecilomyces variotii has been rarely reported in the medical literature. The authors report a 48-year-old patient with refractory lymphoma who underwent allogenic hematopoietic cell transplantation and developed pneumonia due to Paecilomyces variotii. They also review the published case reports of pneumonia caused by this fungus. PMID- 23819078 TI - Nonspecific Erysipelothrix rhusiopathiae Bacteremia in a Patient with Subclinical Alcoholic Liver Disease. AB - Erysipelothrix rhusiopathiae, a pleomorphic gram-positive bacillus, is found widely in nature or as a commensal pathogen. It infects domestic animals such as swine, which may be the major reservoir of the organism. E. rhusiopathiae is primarily an occupational illness; 89% of the cases are linked to high-risk epidemiological situations. Humans that are infected by this bacillus typically present with one or a combination of the following symptoms: localized skin lesion (erysipeloid), diffuse cutaneous eruptions with systemic symptoms, or bacteremia, which is often followed by endocarditis. We report a case of E. rhusiopathiae bacteremia that was present without severe clinical illness such as endocarditis, arthritis, or skin lesions. The patient was a 64-year-old male with a complicated past medical history including subclinical alcoholic liver disease. Penicillin-G therapy completely resolved the patients bacteremia. The case presented has exceptional clinical merit due to 2 key factors: the patient does not fit the occupational demographic typically affected by this bacterium, and the patient presented with subclinical septicemia, which has a high correlation with fatal endocarditis. This case brings a new prospective to E. rhusiopathiae bacteremia. PMID- 23819079 TI - Surgical Site Infection by Corynebacterium macginleyi in a Patient with Neurofibromatosis Type 1. AB - Corynebacterium (C.) macginleyi is a gram positive, lipophilic rod, usually considered a colonizer of skin and mucosal surfaces. Several reports have associated C. macginleyi with ocular infections, such as conjunctivitis and endophthalmitis. However, even if rare, extraocular infections from C. macginleyi may occur, especially among immunocompromised patients and patients with indwelling medical devices. We report herein the first case of surgical site infection by C. macginleyi after orthopaedic surgery for the correction of kyphoscoliosis in a patient with neurofibromatosis type 1. Our patient developed a nodular granulomatous lesion of about two centimetres along the surgical scar, at the level of C4-C5, with purulent discharge and formation of a fistulous tract. Cervical magnetic resonance imaging showed the presence of a two centimetre fluid pocket in the subcutaneous tissue. Several swabs were collected from the borders of the lesion as well as from the exudate, with isolation of C. macginleyi. The isolate was susceptible to beta-lactams, cotrimoxazole, linezolid, and glycopeptides but resistant to quinolones, third-generation cephalosporins, and erythromycin. Two 30-day courses of antibiotic therapy with amoxicillin/clavulanate (1 g three times/day) and cotrimoxazole (800/160 mg twice a day) were administered, obtaining a complete healing of the lesion. PMID- 23819080 TI - Saccadic alterations in severe developmental dyslexia. AB - It is not sure if persons with dyslexia have ocular motor deficits in addition to their deficits in rapid visual information processing. A 15-year-old boy afflicted by severe dyslexia was submitted to saccadic eye movement recording. Neurological and ophthalmic examinations were normal apart from the presence of an esophoria for near and slightly longer latencies of pattern visual evoked potentials. Subclinical saccadic alterations were present, which could be at the basis of the reading pathology: (1) low velocities (and larger durations) of the adducting saccades of the left eye with undershooting and long-lasting postsaccadic onward drift, typical of the internuclear ophthalmoplegia; (2) saccades interrupted in mid-flight and fixation instability, which are present in cases of brainstem premotor disturbances. PMID- 23819081 TI - Neglected primary omental pregnancy after laparoscopic and medical treatment: a difficult diagnosis? AB - The following case report describes a rare case of omental pregnancy in a fertile 34-year-old woman at 5 + 3 weeks of gestation who presented with abdominal pain. Clinical examination, vital signs, and laboratory values were within normal limits, so the woman was hospitalized and monitored. Laparoscopic exploration was performed according to the preoperative diagnosis of tubal pregnancy, but it showed normal pelvic organs. In view of the growth of the beta-HCG value, a medical approach was attempted, without success. Due to hemodynamic instability, an emergency laparotomy was performed, and it showed an omental pregnancy, confirmed at the pathological examination. PMID- 23819082 TI - Use of FloSeal Sealant in the Surgical Management of Tubal Ectopic Pregnancy. AB - Background. Surgery is sometimes required for the management of tubal ectopic pregnancies. Historically, surgeons used electrosurgery to obtain hemostasis. Topical hemostatic sealants, such as FloSeal, may decrease the reliance on electrosurgery and reduce thermal injury to the tissue. Case. A 33-year-old G1 P0 received methotrexate for a right tubal pregnancy. The patient became symptomatic six days later and underwent a laparoscopic right salpingotomy. After multiple unsuccessful attempts to obtain hemostasis with electrocoagulation, FloSeal was used and hemostasis was obtained. Six weeks later, a hysterosalpingogram (HSG) confirmed tubal patency. The patient subsequently had an intrauterine pregnancy. Conclusion. FloSeal helped to achieve hemostasis during a laparoscopic salpingotomy and preserve tubal patency. FloSeal is an effective alternative and adjunct to electrosurgery in the surgical management of tubal pregnancy. PMID- 23819083 TI - Radiation-induced carotid artery stenosis in a patient with carcinoma of the oral floor. AB - Radiation-induced carotid artery stenosis (RI-CS), a life-threatening condition, can occur after external radiation for head and neck cancer. We here describe a case of asymptomatic RI-CS in a 73-year-old patient treated with chemoradiotherapy and radical neck dissection for a basaloid squamous cell carcinoma of the oral floor. Stenosis of the left carotid artery, diagnosed as RI CS, showed on an MRI performed 1.5 years after radiotherapy. Blood from the left side of the anterior cerebral artery and the middle anterior artery was flowing to the brain through the anterior and posterior communicating arteries, so no stent surgery or other treatment was necessary. The cancer has not recurred during approximately 5 years of followup after radiotherapy, and the patient has had no adverse effects from the RI-CS since it was diagnosed 3.5 years ago. This case emphasizes the necessity of early scrutiny for RI-CS in patients given radiotherapy for oral cancer. PMID- 23819084 TI - Choriocarcinoma syndrome: a case report and a literature review. AB - A 35-year-old Qatari man presented to our hospital with a 4-month history of mild abdominal pain, weight loss, and jaundice. He was found to have central intra abdominal mass and a single testis in the scrotum. His investigations showed cholestatic jaundice and very high level of beta -HCG (1131379 IU/L). CT scans of the chest and abdomen showed a huge pelvic-abdominal mass with extensive retroperitoneal lymphadenopathy, in addition to liver and lung metastases. CT guided Tru-Cut biopsy of the mass showed mixed germ cell tumor. Chemotherapy was refused by the patient and his family. In the following days, the patient bled from his liver metastases leading to hemorrhagic shock, hemorrhage from metastatic sites of choriocarcinoma containing tumors is named choriocarcinoma syndrome. He was transferred to the medical intensive care unit, where he was intubated and resuscitated. Embolization of the right hepatic artery was done, but failed to control the bleeding, which continued with development of disseminated intravascular coagulopathy and a severe abdominal compartment syndrome, and eventually the patient died. PMID- 23819085 TI - Bilateral ewing sarcoma/primitive neuroectodermal tumor of the breast: a very rare entity and review of the literature. AB - Peripheral primitive neuroectodermal tumors (PNET) are rare malignant tumors, affecting mostly children and adolescents and have been described in breast in eight case reports only. In this paper, we present a case of bilateral mammary ES/PNET where distinction between primary and metastatic diseases was discussed through a literature review. The aim of this work is to demonstrate that although rare, the possibility of PNET should be kept in mind while evaluating a palpable breast abnormality in a young female. PMID- 23819086 TI - Four-rod stabilization of severely destabilized lumbar spine caused by metastatic tumor. AB - We report a case of a 67-year-old female with severely destabilized lumbar spine caused by metastatic malignant tumor. The primary lesion was a thyroid follicular adenocarcinoma. Complete destruction of the L3, L4, and L5 vertebrae had resulted in severe instability, which left the patient with severe back pain and bed ridden. Since the vertebrae were so severely damaged at 3 levels, 4 rods were used to stabilize the spine. Following stabilization, the pain was alleviated and the patient's quality of life improved. We introduce here the 4-rod technique to stabilize the spine over 3 vertebral levels following severe destruction by metastatic tumor. PMID- 23819087 TI - Osteoid Osteoma with a Multicentric Nidus: Interstitial Laser Ablation under MRI Guidance. AB - Osteoid osteoma (OO) is a common benign tumor of the bone and is typically treated by thermal ablation with computed tomography (CT) guidance. Only a few cases of multicentric OO have been described. We here report the case of an 11 year-old boy with multicentric OO of the right femur treated with laser ablation under open high-field MRI guidance. The steps of the interventional MRI procedure are described, discussing the benefits and disadvantages of MRI versus CT guidance especially with regard to younger patients. PMID- 23819088 TI - Fatal Pulmonary Embolism following Achilles Tendon Repair: A Case Report and a Review of the Literature. AB - Deep venous thrombosis (DVT) is a significant source of morbidity in orthopaedic surgery. It can progress to a pulmonary embolism, a significant source of mortality. Up to date, patients with Achilles tendon rupture routinely do not receive DVT chemical prophylaxis. We are presenting a case of fatal pulmonary embolism after a surgically treated Achilles tendon rupture in a forty-two-year old male healthy patient. In the current body of the literature, the reported incidence of DVT after Achilles tendon rupture is highly variable ranging from less than 1% to 34%, and there is a disagreement in the international guidelines regarding the need of chemical DVT prophylaxis with this type of injury. Further research needs to be conducted to investigate the risks and benefits of chemical DVT prophylaxis following Achilles tendon rupture. For low-risk patients, the use of milder forms of prophylaxis such as aspirin should also be explored. PMID- 23819089 TI - Percutaneous method of management of simple bone cyst. AB - Introduction. Simple bone cyst or unicameral bone cysts are benign osteolytic lesions seen in metadiaphysis of long bones in growing children. Various treatment modalities with variable outcomes have been described in the literature. The case report illustrates the surgical technique of minimally invasive method of treatment. Case Study. A 14-year-old boy was diagnosed as active simple bone cyst proximal humerus with pathological fracture. The patient was treated by minimally invasive percutaneous curettage with titanium elastic nail (TENS) and allogenic bone grafting mixed with bone marrow under image intensifier guidance. Results. Pathological fracture was healed and allograft filled in the cavity was well taken up. The patient achieved full range of motion with successful outcome. Conclusion. Minimally invasive percutaneous method using elastic intramedullary nail gives benefit of curettage cyst decompression and stabilization of fracture. Allogenic bone graft fills the cavity and healing of lesion by osteointegration. This method may be considered with advantage of minimally invasive technique in treatment of benign cystic lesions of bone, and the level of evidence was therapeutic level V. PMID- 23819090 TI - A novel technique for closed reduction and fixation of paediatric calcaneal fracture dislocation injuries. AB - Paediatric calcaneal fractures are rare injuries usually managed conservatively or with open reduction and internal fixation (ORIF). Closed reduction was previously thought to be impossible, and very few cases are reported in the literature. We report a new technique for closed reduction using Ilizarov half rings. We report successful closed reduction and screwless fixation of an extra articular calcaneal fracture dislocation in a 7-year-old boy. Reduction was achieved using two Ilizarov half-ring frames arranged perpendicular to each other, enabling simultaneous application of longitudinal and rotational traction. Anatomical reduction was achieved with restored angles of Bohler and Gissane. Two K-wires were the definitive fixation. Bony union with good functional outcome and minimal pain was achieved at eight-weeks follow up. ORIF of calcaneal fractures provides good functional outcome but is associated with high rates of malunion and postoperative pain. Preservation of the unique soft tissue envelope surrounding the calcaneus reduces the risk of infection. Closed reduction prevents distortion of these tissues and may lead to faster healing and mobilisation. Closed reduction and screwless fixation of paediatric calcaneal fractures is an achievable management option. Our technique has preserved the soft tissue envelope surrounding the calcaneus, has avoided retained metalwork related complications, and has resulted in a good functional outcome. PMID- 23819091 TI - Ankle fracture surgery on a pregnant patient complicated by intraoperative emergency caesarian section. AB - We report the case of a woman in the third trimester of pregnancy who sustained an ankle fracture dislocation that could not be adequately closed reduced. After discussions with the patient, her obstetrician, and the anesthesiologists, she was indicated for surgical fixation. A heart tone monitor was used to assess fetal health during the procedure. During surgical incision, the fetus went into distress, and an emergency caesarian section was performed. After delivery of the infant and abdominal closer, surgery was completed. Due to a cohesive team effort, both the patient and her infant had excellent outcomes. There are many important considerations in the surgical management of the pregnant patient with traumatic orthopaedic injuries. Of especial importance to the orthopaedic surgeon is the impact of patient positioning on uteroplacental blood flow. This report discusses factors that should be taken into account by any orthopaedist who plans to operate on a pregnant patient. PMID- 23819092 TI - Fibroepithelial polyp of the external auditory canal: a case report and a literature review. AB - This paper reports the first case of fibroepithelial polyp arising independently of the external auditory canal. A 16-year-old female patient presented to our clinic for aural fullness of the left side. Physical examination revealed a papillomatous tumor at the posterior wall of the inlet of the left external auditory canal. After biopsy, which yielded a diagnosis of benign papilloma, the patient underwent tumor excision. Final diagnosis was fibroepithelial polyp. One week after resection, aural fullness had resolved. Fibroepithelial polyp is a benign lesion and occurs mainly in the skin, ureteropelvic system, and genitals. In the head and neck area, there are reports on fibroepithelial polyp of the tongue, piriform fossa, inferior nasal turbinate, and tonsil, in addition to the skin, but none on independent fibroepithelial polyp of the external auditory canal. Excision of fibroepithelial polyp of the external auditory canal is advisable, especially in the presence of any symptoms, and should be preceded by confirmation of nonmalignancy by biopsy, if possible. PMID- 23819093 TI - Sturge-weber syndrome with osteohypertrophy of maxilla. AB - Sturge-Weber syndrome is a rare nonhereditary developmental condition with neurological and skin disorder, characterized by presence of port wine stain on the face along with ocular disorders, oral manifestations and leptomeningeal angiomas. Here we present an unusual case of Sturge-Weber syndrome with osseous hypertrophy of maxilla. PMID- 23819094 TI - Perforated Meckel's Diverticulum Lithiasis: An Unusual Cause of Peritonitis. AB - Meckel's diverticulum is the commonest congenital malformation of gastrointestinal tract and represents a persistent remnant of the omphalomesenteric duct. Although it mostly remains silent, it can present as bleeding, perforation, intestinal obstruction, intussusception, and tumours. These complications, especially bleeding, tend to be more common in the paediatric group and intestinal obstruction in adults. Stone formation (lithiasis) in Meckel's diverticulum is rare. We report a case of Meckel's diverticulum lithiasis which presented as an acute abdomen in an otherwise healthy individual. The patient underwent an exploratory laparotomy which revealed a perforated Meckel's diverticulum with lithiasis; a segmental resection with end-to-end anastomosis of small bowel was performed. Patient recovery was delayed due to pneumonia, discharged on day 20 with no further complications at 6 months following surgery. PMID- 23819095 TI - Breakage of Needle during Intracavernosal Injection and Use of Portable Ultrasound Guidance for Removal. AB - Purpose. Intracavernosal self-injection (ICI) was first described in 1982, and remains a viable therapy for erectile dysfunction. However, intracorporal needle breakage can be a rare complication of therapy. We report a rare complication of intracorporal needle breakage and a retention of a 30-gauge needle in a 42-year old paraplegic man. We discuss our experience in using portable high-frequency ultrasound intraoperatively to visualize and guide removal of a retained ICI needle. Materials and Methods. Review of case and ultrasound technique are presented. Results. Using intraoperative ultrasound imaging, the retained intracorporal needle was successfully removed from the patient's penis without any complications. Follow-up ultrasonography and X-ray confirmed complete removal of the needle. Conclusions. We report on the successful implementation and use of a portable high-frequency ultrasound probe to visualize a retained intracorporal needle inside the penis and its use to guide removal. Given the rapid proliferation of portable ultrasound machines in the operating room and out in the field, we expect these imaging techniques to become routine, especially in urological emergencies. PMID- 23819096 TI - Modification of the No-Touch Technique during Renal Artery Stenting. AB - Renal artery stenting has been established as the primary form of renal artery stenosis revascularization procedure. The no-touch technique is proposed in order to avoid renal artery injury and atheroembolism during renal artery stenting. We describe a modification of the no-touch technique by using an over-the-wire (OTW) balloon or a Quickcross 0.014'' catheter with a 0.014'' coronary wire inside, instead of the rigid 0.035'' J wire. The reported technique, while it prevents direct contact of the guiding catheter with the aortic wall, at the same time it allows for a closer contact with the renal arterial ostium and a more favorable guiding catheter orientation, compared to what is achieved with the use of the more rigid 0.035'' J wire, thus improving visualization, reducing the amount of contrast required, and potentially decreasing complications. PMID- 23819097 TI - Socioeconomic assessment and impact of social security on outcome in patients admitted with suspected coronary chest pain in the city of salta, Argentina. AB - Low socioeconomic status is associated with increased mortality from coronary heart disease. We assessed total mortality, cardiac death, and sudden cardiac death (SCD) in relation to socioeconomic class and social security in 982 patients consecutively admitted with suspected coronary chest pain, living in the city of Salta, northern Argentina. Patients were divided into three socioeconomic classes based on monthly income, residential area, and insurance coverage. Five year follow-up data were analyzed accordingly, applying univariate and multivariate analyses. At follow-up, 173 patients (17.6%) had died. In 92 patients (9.4%) death was defined as cardiac, of whom 59 patients (6.0%) were characterized as SCD. In the multivariate analysis, the hazard ratios (HRs) for all-cause and cardiac mortality in the highest as compared to the lowest socioeconomic class were 0.42 (95% confidence interval (CI), 0.22-0.80), P = 0.008, and 0.39 (95% CI, 0.15-0.99), P = 0.047, respectively. Comparing patients in the upper socioeconomic class to patients without healthcare coverage, HRs were 0.46 (95% CI, 0.23-0.94), P = 0.032, and 0.37 (95% CI, 0.14-1.01), P = 0.054, respectively. In conclusion, survival was mainly tied to socioeconomic inequalities in this population, and the impact of a social security program needs further attention. PMID- 23819098 TI - Curbing inflammation in the ischemic heart disease. AB - A modern concept considers acute coronary syndrome as an autoinflammatory disorder. From the onset to the healing stage, an endless inflammation has been presented with complex, multiple cross-talk mechanisms at the molecular, cellular, and organ levels. Inflammatory response following acute myocardial infarction has been well documented since the 1940s and 1950s, including increased erythrocyte sedimentation rate, the C-reactive protein analysis, and the determination of serum complement. It is surprising to note, based on a wide literature overview including the following 30 years (decades of 1960, 1970, and 1980), that the inflammatory acute myocardium infarction lost its focus, virtually disappearing from the literature reports. The reversal of this historical process occurs in the 1990s with the explosion of studies involving cytokines. Considering the importance of inflammation in the pathophysiology of ischemic heart disease, the aim of this paper is to present a conceptual overview in order to explore the possibility of curbing this inflammatory process. PMID- 23819100 TI - Is the use of a drain for thyroid surgery realistic? A prospective randomized interventional study. AB - Background. The use of a suction drain in thyroid surgery is common practice in order to avoid hematomas or seromas. The aim of this study was to determine the efficacy of routine drainage after thyroid surgery. Methods. In this prospective randomized trial, 400 patients who underwent either a total thyroidectomy or lobectomy for thyroid disorders were randomly allocated to either the nondrainage (group 1) or the drainage (group 2) group. The volume of fluid collection in the operative bed, postoperative pain, complications, and length of hospital stay were then recorded. Results. Both groups were homogeneous according to age, gender, thyroid volume, type of procedure performed, and histopathological diagnosis. After assessment by USG, no significant difference was found between the groups in the fluid collection of the thyroid bed (P = 0.117), but the length of hospital stay was significantly reduced in group 1 (P = 0.004). Conclusions. In our experience, the use of drain for thyroid surgery is not a routine procedure. However, it should be used in the presence of extensive dead space, particularly when there is retrosternal or intrathoracic extension, or when the patient is on anticoagulant treatment. This trial was registered with clinical Trials.gov NCT01771523. PMID- 23819101 TI - Extralaryngeal terminal division of the inferior laryngeal nerve: anatomical classification by a surgical point of view. AB - Background. Complete anatomic knowledge including all variations of the inferior laryngeal nerve (ILN) is mandatory for thyroid surgeon. Extralaryngeal terminal division (ETD) of the ILN has significant importance for the safety of thyroidectomy. Material and Methods. Surgical dissection of 200 ILNs was performed on 100 cases. The presence of ETD of the nerve was determined intraoperatively. We propose by a surgical point of view a regional (segmental) classification of ETD of the ILN along its cervical course. Results. ETD has been observed in 54/200 nerves (27%). Great majority are bifurcated nerves (trifurcation 2%). Four types of ETD are classified. In type 1 (arterial; 46.3%), ETD has occurred near inferior thyroid artery (ITA). In type 2 (postarterial; 31.5%), division has been found on postarterial segment. In type 3 (prelaryngeal; 11%), division has been located very close to laryngeal entry point. In type 4 (prearterial; 11%), ETD has occurred before the nerve crossing the ITA. Conclusions. ETD of the ILN is a common anatomical variation. The bifurcation occurs in the ILN at various distances from laryngeal entry point. The classification increasing surgeons' awareness may help to simplify identification and exposure of terminal branches. Preservation of both extralaryngeal terminal branches of the ILN has paramount importance for the safety of thyroid operations. PMID- 23819102 TI - Prevalence of Swimming Puppy Syndrome in 2,443 Puppies during the Years 2006-2012 in Thailand. AB - The purpose of this study was to report on the prevalence of swimming puppy syndrome (SPS) and investigate predisposing factors. Data were recorded from 2,443 puppies (1,183 males and 1,260 females) in Thailand, October 2006-September 2012, including breed, sex, number of puppies per litter, type of nest floor, number of affected limbs, and occurrence of pectus excavatum. Fifty-two puppies (2.13%) were diagnosed with SPS. The breed most frequently affected was English Bulldog (8.33%). There was no significant difference (P > 0.05) between presence and absence of disease based on sex, breed, and nest floor type. The number of puppies per litter was associated with SPS; puppies from smaller litters (1.92 +/ 1.12) had a higher prevalence of the disease (P < 0.01) than puppies from larger litters (3.64 +/- 2.24). Moreover, 15.38% of puppies with affected limbs showed signs of pectus excavatum (8/52); this clinical sign was more prevalent (P < 0.01) in puppies with all four limbs affected with SPS. PMID- 23819099 TI - Blocking neurogenic inflammation for the treatment of acute disorders of the central nervous system. AB - Classical inflammation is a well-characterized secondary response to many acute disorders of the central nervous system. However, in recent years, the role of neurogenic inflammation in the pathogenesis of neurological diseases has gained increasing attention, with a particular focus on its effects on modulation of the blood-brain barrier BBB. The neuropeptide substance P has been shown to increase blood-brain barrier permeability following acute injury to the brain and is associated with marked cerebral edema. Its release has also been shown to modulate classical inflammation. Accordingly, blocking substance P NK1 receptors may provide a novel alternative treatment to ameliorate the deleterious effects of neurogenic inflammation in the central nervous system. The purpose of this paper is to provide an overview of the role of substance P and neurogenic inflammation in acute injury to the central nervous system following traumatic brain injury, spinal cord injury, stroke, and meningitis. PMID- 23819103 TI - Anna S. Tikhonenko: Electron microscopist extraordinary. AB - Anna Sergeyevna Tikhonenko (1925-2010) is to be remembered for the excellency of her electron microscopical work, particularly with bacteriophages. She published 113 articles and one book, Ultrastructure of Bacterial Viruses (Izdadelstvo Nauka, Moscow 1968; Plenum Press, New York, 1972). It included 134 micrographs and a complete overview of the 316 phages then examined by electron microscopy. Most micrographs were of exceptional quality. This book, a rarity in those days of strict separation of Soviet and Western research, was the first bacteriophage atlas in the literature and presented a morphological classification of phages into five categories of family level, similar to a scheme presented in 1965 by D.E. Bradley (J Royal Microsc Soc 84:257-316). Her book remains one of the fundamentals of phage research. PMID- 23819104 TI - Evolution of genetic switch complexity. AB - The circuitry of the phage lambda genetic switch determining the outcome of lytic or lysogenic growth is well-integrated and complex, raising the question as to how it evolved. It is plausible that it arose from a simpler ancestral switch with fewer components that underwent various additions and refinements, as it adapted to vast numbers of different hosts and conditions. We have recently identified a new class of genetic switches found in mycobacteriophages and other prophages, in which immunity is dependent on integration. These switches contain only three genes (integrase, repressor and cro) and represent a major departure from the lambda-like circuitry, lacking many features such as xis, cII and cIII. These small self-contained switches represent an unrealized, elegant circuitry for controlling infection outcome. In this addendum, we propose a model of possible events in the evolution of a complex lambda-like switch from a simpler integration-dependent switch. PMID- 23819105 TI - Phage therapy: Should bacterial resistance to phages be a concern, even in the long run? AB - Bacteriophage therapy, the use of viruses that infect bacteria as antimicrobials, has been championed as a promising alternative to conventional antibiotics. Although in the laboratory bacterial resistance against phages arises rapidly, resistance so far has been an only minor problem for the effectiveness of phage therapy. Resistance to antibiotics, however, has become a major issue after decades of extensive use. Should we expect similar problems after long-term use of phages as antimicrobials? Like antibiotics, phages are often noted to be drivers of bacterial evolution. Should we expect phage-treated pathogens to develop a general resistance to phages over time, a resistance against which only, for example, hypothetically co-evolved phages might be infective? Here we argue that the global infection patterns of phages suggest that this is not necessarily a concern as environmental phages often can infect bacteria with which those phages lack any recent co-evolutionary history. PMID- 23819106 TI - Lytic bacteriophages reduce Escherichia coli O157: H7 on fresh cut lettuce introduced through cross-contamination. AB - The role of lytic bacteriophages in preventing cross contamination of produce has not been evaluated. A cocktail of three lytic phages specific for E. coli O157:H7 (EcoShieldTM) or a control (phosphate buffered saline, PBS) was applied to lettuce by either; (1) immersion of lettuce in 500 ml of EcoShieldTM 8.3 log PFU/ml or 9.8 log PFU/ml for up to 2 min before inoculation with E. coli O157:H7; (2) spray-application of EcoShieldTM (9.3 log PFU/ml) to lettuce after inoculation with E. coli O157:H7 (4.10 CFU/cm2) following exposure to 50 MUg/ml chlorine for 30 sec. After immersion studies, lettuce was spot-inoculated with E. coli O157:H7 (2.38 CFU/cm2). Phage-treated, inoculated lettuce pieces were stored at 4 degrees C for and analyzed for E. coli O157:H7 populations for up to 7 d. Immersion of lettuce in 9.8 log PFU/ml EcoShieldTM for 2 min significantly (p < 0.05) reduced E. coli O157:H7 populations after 24 h when stored at 4 degrees C compared with controls. Immersion of lettuce in suspensions containing high concentrations of EcoShieldTM (9.8 log PFU/ml) resulted in the deposition of high concentrations (7.8 log log PFU/cm2) of bacteriophages on the surface of fresh cut lettuce, potentially contributing to the efficacy of the lytic phages on lettuce. Spraying phages on to inoculated fresh cut lettuce after being washed in hypochlorite solution was significantly more effective in reducing E. coli O157:H7 populations (2.22 log CFU/cm2) on day 0 compared with control treatments (4.10 log CFU/cm2). Both immersion and spray treatments provided protection from E. coli O157:H7 contamination on lettuce, but spray application of lytic bacteriophages to lettuce was more effective in immediately reducing E. coli O157:H7 populations fresh cut lettuce. PMID- 23819107 TI - Biocontrol of Escherichia coli O157: H7 on fresh-cut leafy greens. AB - The effect of a bacteriophage cocktail (EcoShieldTM) that is specific against Escherichia coli O157:H7 was evaluated against a nalidixic acid-resistant enterohemorrhagic E. coli O157:H7 RM4407 (EHEC) strain on leafy greens stored under either (1) ambient air or (2) modified atmosphere (MA; 5% O2/35% CO2/60% N2). Pieces (~2 * 2 cm2) of leafy greens (lettuce and spinach) inoculated with 4.5 log CFU/cm2 EHEC were sprayed with EcoShieldTM (6.5 log PFU/cm2). Samples were stored at 4 or 10 degrees C for up to 15 d. On spinach, the level of EHEC declined by 2.38 and 2.49 log CFU/cm2 at 4 and 10 degrees C, respectively, 30 min after phage application (p <= 0.05). EcoShieldTM was also effective in reducing EHEC on the surface of green leaf lettuce stored at 4 degrees C by 2.49 and 3.28 log units in 30 min and 2 h, respectively (p <= 0.05). At 4 degrees C under atmospheric air, the phage cocktail significantly (p <= 0.05) lowered the EHEC counts in one day by 1.19, 3.21 and 3.25 log CFU/cm2 on spinach, green leaf and romaine lettuce, respectively compared with control (no bacteriophage) treatments. When stored under MA at 4 degrees C, phages reduced (p <= 0.05) EHEC populations by 2.18, 3.50 and 3.13 log CFU/cm2, on spinach, green leaf and romaine lettuce. At 10 degrees C, EHEC reductions under atmospheric air storage were 1.99, 3.90 and 3.99 log CFU/cm2 (p <= 0.05), while population reductions under MA were 3.08, 3.89 and 4.34 logs on spinach, green leaf and romaine lettuce, respectively, compared with controls (p <= 0.05). The results of this study showed that bacteriophages were effective in reducing the levels of E. coli O157:H7 on fresh leafy produce, and that the reduction was further improved when produce was stored under the MA conditions. PMID- 23819108 TI - Biochemical insights into the function of phage G1 gp67 in Staphylococcus aureus. AB - Bacteriophage (phage) are among the most diverse and abundant life forms on Earth. Studies have recently used phage diversity to identify novel antimicrobial peptides and proteins. We showed that one such phage protein, Staphylococcus aureus (Sau) phage G1 gp67, inhibits cell growth in Sau by an unusual mechanism. Gp67 binds to the host RNA polymerase (RNAP) through an interaction with the promoter specificity sigma subunit, but unlike many other sigma-binding phage proteins, gp67 does not disrupt transcription at most promoters. Rather, gp67 prevents binding of another RNAP domain, the alpha-C-terminal domain, to upstream A/T-rich elements required for robust transcription at rRNA promoters. Here, we discuss additional biochemical insights on gp67, how phage promoters escape the inhibitory function of gp67, and methodological advancements that were foundational to our work. PMID- 23819109 TI - Phage-host interactions during pseudolysogeny: Lessons from the Pid/dgo interaction. AB - Although the study of phage infection has a long history and catalyzed much of our current understanding in bacterial genetics, molecular biology, evolution and ecology, it seems that microbiologists have only just begun to explore the intricacy of phage-host interactions. In a recent manuscript by Cenens et al. we found molecular and genetic support for pseudolysogenic development in the Salmonella Typhimurium-phage P22 model system. More specifically, we observed the existence of phage carrier cells harboring an episomal P22 element that segregated asymmetrically upon subsequent divisions. Moreover, a newly discovered P22 ORFan protein (Pid) able to derepress a metabolic operon of the host (dgo) proved to be specifically expressed in these phage carrier cells. In this addendum we expand on our view regarding pseudolysogeny and its effects on bacterial and phage biology. PMID- 23819110 TI - Bacteriophages for managing Shigella in various clinical and non-clinical settings. AB - The control of shigellosis in humans enjoys a prominent position in the history of bacteriophage therapy. d'Herelle first demonstrated the efficacy of phage therapy by curing 4 patients of shigellosis, and several subsequent studies confirmed the ability of phages to reduce Shigella based infection. Shigella spp continue to cause millions of illnesses and deaths each year and the use of phages to control the disease in humans and the spread of the bacteria within food and water could point the way forward to the effective management of an infectious disease with global influence. PMID- 23819111 TI - Cancer stem cells in pediatric sarcomas. AB - Sarcomas represent a clinically and biologically diverse group of malignant connective tissue tumors. Despite aggressive conventional therapy, a large proportion of sarcoma patients experience disease recurrence which will ultimately result in mortality. The presence of a unique population of cells, referred to as cancer stem cells (CSCs), have been proposed to be responsible for refractory responses to current chemotherapies as well underlying the basis for metastasis and relapse of disease - clinical corollaries to what has been termed the CSC hypothesis. The presence of CSCs have been suggested in a variety of hematologic and solid malignancies, and only more recently in sarcomas. Based on our current understanding of normal stem cell biology and evidence obtained from the study of malignant hematopoietic and solid tumors, researchers have identified candidate cell surface markers (CD133, CD117, Stro-1), biochemical markers (aldehyde dehydrogenase activity), and cytological characteristics (side population and spherical colony formation) that may identify putative sarcoma CSCs. In this review, we explore the current state of evidence that may suggest the existence of sarcoma CSCs. We present research in osteosarcoma, the Ewing's sarcoma family of tumors, rhabdomyosarcoma, as well as other sarcoma subtypes to describe commonly used molecular and biochemical markers, as well as techniques, used in the identification, isolation, and characterization of candidate sarcoma CSCs. We will also discuss the current controversies and challenges that face research in sarcoma CSC. PMID- 23819112 TI - Sex-biased differences in the effects of host individual, host population and environmental traits driving tick parasitism in red deer. AB - The interactions between host individual, host population, and environmental factors modulate parasite abundance in a given host population. Since adult exophilic ticks are highly aggregated in red deer (Cervus elaphus) and this ungulate exhibits significant sexual size dimorphism, life history traits and segregation, we hypothesized that tick parasitism on males and hinds would be differentially influenced by each of these factors. To test the hypothesis, ticks from 306 red deer-182 males and 124 females-were collected during 7 years in a red deer population in south-central Spain. By using generalized linear models, with a negative binomial error distribution and a logarithmic link function, we modeled tick abundance on deer with 20 potential predictors. Three models were developed: one for red deer males, another for hinds, and one combining data for males and females and including "sex" as factor. Our rationale was that if tick burdens on males and hinds relate to the explanatory factors in a differential way, it is not possible to precisely and accurately predict the tick burden on one sex using the model fitted on the other sex, or with the model that combines data from both sexes. Our results showed that deer males were the primary target for ticks, the weight of each factor differed between sexes, and each sex specific model was not able to accurately predict burdens on the animals of the other sex. That is, results support for sex-biased differences. The higher weight of host individual and population factors in the model for males show that intrinsic deer factors more strongly explain tick burden than environmental host seeking tick abundance. In contrast, environmental variables predominated in the models explaining tick burdens in hinds. PMID- 23819114 TI - Hip fracture surgery: does type of anesthesia matter? AB - BACKGROUND: Hip fracture surgery is a common procedure, and the geriatric population with its multiple comorbid conditions is at most at risk of developing anesthesia-related complications. Data on the impact of type anesthesia on postoperative morbidity and mortality is limited. The effects of regional and general anesthesia on postoperative outcomes need to be clearly elucidated. METHODS: In this study, all patients who underwent dynamic hip screw (DHS) fixation for intertrochanteric fractures, between January 2005 and December 2010, at the Aga Khan University Hospital, were included. Patients were divided into two groups; group A included those patients who received general anesthesia, and group B consisted of patients who had received regional anesthesia. The two groups were compared for differences in morbidity, mortality, and intraoperative complications based on the type of anesthesia administered. RESULTS: During this period, 194 patients underwent DHS fixation. One hundred and seven patients received general anesthesia whereas eighty-seven patients received regional anesthesia. The mean operative time was significantly lower in the group receiving regional anesthesia (1.25 +/- 0.39 hrs) as compared to those who received general anesthesia (1.54 +/- 0.6 hrs) (P < 0.05). There were no statistically significant differences in the rates of wound infections, length of hospital stay, postoperative ambulation status, intraoperative blood loss, postoperative complications, and mortality between the regional and general anesthesia groups. CONCLUSION: Even though administration of regional anesthesia was positively correlated with shorter operative duration, the type of anesthesia was not found to affect surgical outcomes in the two study groups. Based on these results, we recommend that anesthesia should be tailored to individual patient requirements. PMID- 23819113 TI - Emerging therapeutic biomarkers in endometrial cancer. AB - Although clinical trials of molecular therapies targeting critical biomarkers (mTOR, epidermal growth factor receptor/epidermal growth factor receptor 2, and vascular endothelial growth factor) in endometrial cancer show modest effects, there are still challenges that might remain regarding primary/acquired drug resistance and unexpected side effects on normal tissues. New studies that aim to target both genetic and epigenetic alterations (noncoding microRNA) underlying malignant properties of tumor cells and to specifically attack tumor cells using cell surface markers overexpressed in tumor tissue are emerging. More importantly, strategies that disrupt the cancer stem cell/epithelial-mesenchymal transition-dependent signals and reactivate antitumor immune responses would bring new hope for complete elimination of all cell compartments in endometrial cancer. We briefly review the current status of molecular therapies tested in clinical trials and mainly discuss the potential therapeutic candidates that are possibly used to develop more effective and specific therapies against endometrial cancer progression and metastasis. PMID- 23819115 TI - Association of atherosclerotic peripheral arterial disease with adiponectin genes SNP+45 and SNP+276: a case-control study. AB - OBJECTIVES: We hypothesized that adiponectin gene SNP+45 (rs2241766) and SNP+276 (rs1501299) would be associated with atherosclerotic peripheral arterial disease (PAD). Furthermore, the association between circulating adiponectin levels, fetuin-A, and tumoral necrosis factor-alpha (TNF-alpha) in patients with atherosclerotic peripheral arterial disease was investigated. METHOD: Several blood parameters (such as adiponectin, fetuin-A, and TNF-alpha) were measured in 346 patients, 226 with atherosclerotic peripheral arterial disease (PAD) and 120 without symptomatic PAD (non-PAD). Two common SNPs of the ADIPOQ gene represented by +45T/G 2 and +276G/T were also investigated. RESULTS: Adiponectin concentrations showed lower circulating levels in the PAD patients compared to non-PAD patients (P < 0.001). Decreasing adiponectin concentration was associated with increasing serum levels of fetuin-A in the PAD patients. None of the investigated adiponectin SNPs proved to be associated with the subjects' susceptibility to PAD (P > 0.05). CONCLUSION: The results of our study demonstrated that neither adiponectin SNP+45 nor SNP+276 is associated with the risk of PAD. PMID- 23819116 TI - Higher plasma pyridoxal phosphate is associated with increased antioxidant enzyme activities in critically ill surgical patients. AB - Critically ill patients experience severe stress, inflammation and clinical conditions which may increase the utilization and metabolic turnover of vitamin B 6 and may further increase their oxidative stress and compromise their antioxidant capacity. This study was conducted to examine the relationship between vitamin B-6 status (plasma and erythrocyte PLP) oxidative stress, and antioxidant capacities in critically ill surgical patients. Thirty-seven patients in surgical intensive care unit of Taichung Veterans General Hospital, Taiwan, were enrolled. The levels of plasma and erythrocyte PLP, serum malondialdehyde, total antioxidant capacity, and antioxidant enzyme activities (i.e., superoxide dismutase (SOD), glutathione S-transferase, and glutathione peroxidase) were determined on the 1st and 7th days of admission. Plasma PLP was positively associated with the mean SOD activity level on day 1 (r = 0.42, P < 0.05), day 7 (r = 0.37, P < 0.05), and on changes (Delta (day 7 - day 1)) (r = 0.56, P < 0.01) after adjusting for age, gender, and plasma C-reactive protein concentration. Higher plasma PLP could be an important contributing factor in the elevation of antioxidant enzyme activity in critically ill surgical patients. PMID- 23819118 TI - Actinomycetes: role in biotechnology and medicine. PMID- 23819117 TI - Flow cytometry total cell counts: a field study assessing microbiological water quality and growth in unchlorinated drinking water distribution systems. AB - The objective of this study was to evaluate the application of flow cytometry total cell counts (TCCs) as a parameter to assess microbial growth in drinking water distribution systems and to determine the relationships between different parameters describing the biostability of treated water. A one-year sampling program was carried out in two distribution systems in The Netherlands. Results demonstrated that, in both systems, the biomass differences measured by ATP were not significant. TCC differences were also not significant in treatment plant 1, but decreased slightly in treatment plant 2. TCC values were found to be higher at temperatures above 15 degrees C than at temperatures below 15 degrees C. The correlation study of parameters describing biostability found no relationship among TCC, heterotrophic plate counts, and Aeromonas. Also no relationship was found between TCC and ATP. Some correlation was found between the subgroup of high nucleic acid content bacteria and ATP (R (2) = 0.63). Overall, the results demonstrated that TCC is a valuable parameter to assess the drinking water biological quality and regrowth; it can directly and sensitively quantify biomass, detect small changes, and can be used to determine the subgroup of active HNA bacteria that are related to ATP. PMID- 23819119 TI - Intra- and interday reliability of spine rasterstereography. AB - To determine intra- and interday reliability of spine rasterstereographic system Formetric 4D with and without reflective markers. Twenty-six healthy volunteers (M group) had two markers placed in correspondence of vertebra prominens and intergluteal cleft, and 24 volunteers (NM group) were assessed without markers. All participants were analyzed two times in the same day and one time on a separate day. Trunk length, kyphotic angle, lordotic angle, pelvic inclination, kyphotic and lordotic apex, right and left lateral deviation, fleche cervicale and lombaire, trunk imbalance, pelvic tilt, inflection point, rotation correction, right and left surface rotation, pelvic torsion, and trunk torsion were measured. Intraclass correlation coefficient (ICC) and Cronbach Alpha (C alpha ) were calculated. In M group, for intra-, interday, and overall evaluations, the higher reliability coefficients were 0.971, 0.963, and 0.958 (ICC) and 0.987, 0.983, and 0.985 (C alpha ) for trunk length, kyphotic angle, and lordotic apex, respectively; while in NM group, they were 0.978, 0.982, and 0.972 and 0.989, 0.991, and 0.991 for trunk length. In M group, the lower values were 0.598, 0.515, and 0.534 (ICC) and 0.742, 0.682, and 0.784 (C alpha ) for trunk and pelvic torsion and in NM group 0.561, 0.537, and 0.461 and 0.731, 0.695, and 0.729 for left lateral deviation. The reliability of most parameters was excellent. PMID- 23819120 TI - Measurement of the silver ion concentration in wound fluids after implantation of silver-coated megaprostheses: correlation with the clinical outcome. AB - BACKGROUND: Tumor patients and patients after traumas are endangered by a reduced immune defense, and a silver coating on their megaprostheses may reduce their risks of infection. The aim of this study was to determine the silver ion concentration directly measured from the periprosthetic tissue and the influence on the clinical outcome. MATERIAL AND METHODS: Silver ions were evaluated in 5 mL wound fluids two days postoperatively and in blood patients 7 and 14 days after surgery using inductively coupled plasma emission spectrometry in 18 patients who underwent total joint replacement with a silver-coated megaendoprosthesis. RESULTS: The concentration of silver ions averaged 0.08 parts per million. Patients who showed an increased silver concentration in the blood postoperatively presented a lower silver concentration in the wound fluids and a delayed decrease in C-reactive protein levels. There were significantly fewer reinfections and shorter hospitalization in comparison with a group that did not receive a silver-coated megaprosthesis. CONCLUSION: An increased concentration of silver in the immediate surroundings of silver-coated prostheses was demonstrated for the first time in cohorts of patients with trauma or tumors. An elevated concentration of silver ions in the direct periprosthetic tissue may have reduced the infection rate. PMID- 23819122 TI - Use of a new ocular insert versus conventional mydriasis in cataract surgery. AB - BACKGROUND: To compare the efficacy and safety of a new ocular insert versus conventional mydriasis in cataract surgery. METHODS: We selected 70 patients undergoing cataract surgery. Thirty five patients (Group 1) received instillation of mydriatic drops (tropicamide 1%, phenylephrine 10%, and cyclopentolate 1%) prior to surgery, and 35 patients (Group 2) had a Mydriasert insert (Thea Pharma) (0.28 mg of tropicamide and 5.4 mg of phenylephrine hydrochloride) placed in the inferior fornix. Pupil size before and after surgery, blood pressure, and heart rate were measured. RESULTS: Before surgery, pupil diameter was 9.44 +/- 1.17 mm in Group 1 and 9.05 +/- 1.54 in Group 2 (P > 0.05). Twenty four hours after surgery, pupil diameter was 5.20 +/- 1.54 mm in Group 1 and 3.33 +/- 1.15 in Group 2 (P < 0.001). There were no statistically significant differences in blood pressure or heart rate between groups. CONCLUSIONS: The effect of the Mydriasert insert was similar to conventional mydriatic agents. Pupil size was restored to normal faster when using the Mydriasert insert compared with conventional mydriatic agents for pupil dilation. PMID- 23819121 TI - New therapeutics in promoting and modulating mandibular growth in cases with mandibular hypoplasia. AB - Children with mandibular growth deficiency may develop airway obstruction. The standard treatment of severe airway obstruction involves invasive procedures such as tracheostomy. Mandibular distraction osteogenesis has been proposed in neonates with mandibular deficiency as a treatment option to avoid tracheostomy procedure later in life. Both tracheostomy and distraction osteogenesis procedures suffer from substantial shortcomings including scarring, unpredictability, and surgical complications. Forward jaw positioning appliances have been also used to enhance mandible growth. However, the effectiveness of these appliances is limited and lacks predictability. Current and future approaches to enhance mandibular growth, both experimental and clinical trials, and their effectiveness are presented and discussed. PMID- 23819123 TI - Minimally invasive thoracic surgery in pediatric patients: the Taiwan experience. AB - Minimally invasive technology or laparoscopic surgery underwent a major breakthrough over the past two decades. The first experience of thoracoscopy in children was reported around 1980 for diagnosis of intrathoracic pathology and neoplasia. Up until the middle of the 1990s, the surgical community in Taiwan was still not well prepared to accept the coming era of minimally invasive surgery. In the beginning, laparoscopy was performed in only a few specialties and only relatively short or simple surgeries were considered. But now, the Taiwan's experiences over the several different clinical scenarios were dramatically increased. Therefore, we elaborated on the experience about pectus excavatum: Nuss procedure, primary spontaneous hemopneumothorax, thoracoscopic thymectomy, and empyema in Taiwan. PMID- 23819124 TI - Mouse prostate epithelial luminal cells lineage originate in the basal layer where the primitive stem/early progenitor cells reside: implications for identifying prostate cancer stem cells. AB - Prostate stem cells are thought to be responsible for generation of all prostate epithelial cells and for tissue maintenance. The lineage relationship between basal and luminal cells in the prostate is not well clarified. We developed a mouse model to trace cell fate and a mouse model with a slowly cycling cell label to provide insight into this question. The results obtained indicate that putative mouse prostate stem cells are likely to reside in the basal layer. PMID- 23819125 TI - High genetic diversity of Enterococcus faecium and Enterococcus faecalis clinical isolates by pulsed-field gel electrophoresis and multilocus sequence typing from a hospital in Malaysia. AB - Little is known on the genetic relatedness and potential dissemination of particular enterococcal clones in Malaysia. We studied the antibiotic susceptibility profiles of Enterococcus faecium and Enterococcus faecalis and subjected them to pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). E. faecium and E. faecalis displayed 27 and 30 pulsotypes, respectively, and 10 representative E. faecium and E. faecalis isolates (five each) yielded few different sequence types (STs): ST17 (2 isolates), ST78, ST203, and ST601 for E. faecium, and ST6, ST16, ST28, ST179, and ST399 for E. faecalis. Resistance to tazobactam-piperacillin and ampicillin amongst E. faecium isolates was highly observed as compared to E. faecalis isolates. All of the isolates were sensitive to vancomycin and teicoplanin. The presence of epidemic and nosocomial strains of selected E. faecium STs: 17, 78, and 203 and E. faecalis ST6 as well as high rates of resistance to multiple antibiotics amongst E. faecium isolates is of a particular concern. PMID- 23819126 TI - Alteration of 11beta-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptor by ethanol in rat liver and mouse hepatoma cells. AB - Alcohol is a potential risk factor of type 2 diabetes, but its underlying mechanism is unclear. To explore this issue, Wistar rats and mouse hepatoma cells (Hepa 1-6) were exposed to ethanol, 8 g.kg(-1) .d(-1) for 3 months and 100 mM for 48 h, respectively. Glucose and insulin tolerance tests in vivo were performed, and protein levels of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) and glucocorticoid receptor (GR) in liver and Hepa 1-6 cells were measured. Alterations of key enzymes of gluconeogenesis phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6 phosphatase (G6Pase), as well as glycogen synthase kinase 3a (GSK3 alpha ), were also examined. The results revealed that glucose levels were increased, and insulin sensitivity was impaired accompanied with liver injury in rats exposed to ethanol compared with controls. The 11beta-HSD1, GR, PEPCK, G6Pase, and GSK3 alpha proteins were increased in the liver of rats treated with ethanol compared with controls. Ethanol-exposed Hepa 1-6 cells also showed higher expression of 11beta-HSD1, GR, PEPCK, G6Pase, and GSK3 alpha proteins than control cells. After treatment of Hepa 1-6 cells exposed to ethanol with the GR inhibitor RU486, the expression of 11beta-HSD1 and GR was significantly decreased. At the same time the increases in PEPCK, G6Pase, and GSK3 alpha levels induced by ethanol in Hepa 1-6 cells were also attenuated by RU486. The results indicate that ethanol causes glucose intolerance by increasing hepatic expression of 11beta-HSD1 and GR, which leads to increased expression of gluconeogenic and glycogenolytic enzymes. PMID- 23819127 TI - Endothelial function in women with and without a history of glucose intolerance in pregnancy. AB - BACKGROUND/AIMS: Gestational diabetes mellitus (GDM) and milder gestational impaired glucose tolerance (GIGT) identify women who are at risk of developing cardiovascular disease. Endothelial dysfunction, as indicated by impaired flow mediated dilatation (FMD) on brachial artery ultrasound, is an early marker of vascular disease. Thus, we sought to evaluate endothelial function in women with and without recent glucose intolerance in pregnancy. METHODS: One-hundred and seventeen women underwent oral glucose tolerance testing (OGTT) in pregnancy, enabling stratification into those with normal gestational glucose tolerance (n = 59) and those with GDM or GIGT (n = 58). 6 years postpartum, they underwent a repeat of OGTT and brachial artery FMD studies, enabling assessment of FMD and 4 secondary vascular measures: FMD after 60 seconds (FMD60), baseline arterial diameter, peak shear rate, and reactive hyperemia. RESULTS: There were no differences between the normal gestational glucose tolerance and GDM/GIGT groups in FMD (mean 8.5 versus 9.3%, P = 0.61), FMD60 (4.1 versus 5.1%, P = 0.33), baseline diameter (3.4 versus 3.4 mm, P = 0.66), peak shear rate (262.6 versus 274.8 s(-1), P = 0.32), and reactive hyperemia (576.6 versus 496.7%, P = 0.07). After covariate adjustment, there were still no differences between the groups. CONCLUSION: Despite their long-term cardiovascular risk, women with glucose intolerance in pregnancy do not display endothelial dysfunction 6 years postpartum. PMID- 23819129 TI - Antibody-based antiangiogenic and antilymphangiogenic therapies to prevent tumor growth and progression. AB - Blood and lymphatic vessel formation is an indispensable factor for cancer progression and metastasis. Therefore, various strategies designed to block angiogenesis and lymphangiogenesis are being investigated in the hope to arrest and reverse tumor development. Monoclonal antibodies, owing to their unequalled diversity and specificity, might be applied to selectively inhibit the pathways that cancer cells utilize to build up a network of blood vessels and lymphatics. Among the possible targets of antibody-based therapies are proangiogenic and prolymphangiogenic growth factors from the VEGF family and the receptors to which they bind (VEGFRs). Here, we present molecular mechanisms of angiogenesis and lymphangiogenesis exploited by tumors to progress and metastasise, with examples of antibody-based therapeutic agents directed at interfering with these processes. The expanding knowledge of vascular biology helps to explain some of the problems encountered in such therapies, that arise due to the redundancy in signaling networks controlling the formation of blood and lymphatic vessels, and lead to tumor drug resistance. Nonetheless, combined treatments and treatments focused on newly discovered proangiogenic and prolymphangiogenic factors give hope that more prominent therapeutic effects might be achieved in the future. PMID- 23819128 TI - Metabolic syndrome in Iranian youths: a population-based study on junior and high schools students in rural and urban areas. AB - AIM: The present population-based study aimed to assess prevalence of metabolic syndrome and its related components in Iranian youth in the different sex, age, and residential subgroups. METHOD: Overall, 1039 junior high school and 953 high school students were selected using multistage random sampling. Fasting blood sugar, total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL C), and low-density lipoprotein cholesterol (LDL-C) levels were determined. Trained individuals measured waist circumference and blood pressure. Subjects with MetS were selected according to two definitions provided by the IDF and de Ferranti. RESULTS: Among girls in intervention area, hypertriglyceridemia was more prevalent in rural than in urban areas using IDF definition. Significant differences were observed between boys in rural and urban areas regarding some components of metabolic syndrome including hypertriglyceridemia and high waist circumference. Besides, boys who are residents in urban areas had higher blood pressure, as well as higher waist circumference, than boys in rural areas. CONCLUSION: Our youth population is at significant risk of developing metabolic syndrome, and the pattern of this phenomenon seems to be discrepant in boys as well as in rural and urban areas probably due to the different lifestyle aspects, genetic factors, and racial differences. PMID- 23819130 TI - Metastasis inhibition after proton beam, beta- and gamma-irradiation of melanoma growing in the hamster eye. AB - Standard ocular tumor treatment includes brachytherapy, as well as proton therapy, particularly for large melanoma tumors. However, the effects of different radiation types on the metastatic spread is not clear. We aimed at comparing ruthenium ((106)Ru, emitting beta electrons) and iodine ((125)I, gamma radiation) brachytherapy and proton beam therapy of melanoma implanted into the hamster eye on development of spontaneous lung metastases. Tumors of Bomirski Hamster Melanoma (BHM) implanted into the anterior chamber of the hamster eye grew aggressively and completely filled the anterior chamber within 8-10 days. Metastases, mainly in the lung, were found in 100% of untreated animals 30 days after enucleation. Tumors were irradiated at a dose of 3-10 Gy with a (106)Ru plaque and at a dose of 6-14 Gy using a (125)I plaque. The protons were accelerated using the AIC-144 isochronous cyclotron operating at 60 MeV. BHM tumors located in the anterior chamber of the eye were irradiated with 10 Gy, for the depth of 3.88 mm. All radiation types caused inhibition of tumor growth by about 10 days. An increase in the number of metastases was observed for 3 Gy of beta-irradiation, whereas at 10 Gy an inhibition of metastasis was found. gamma radiation reduced the metastatic mass at all applied doses, and proton beam therapy at 10 Gy also inhibited the metastastic spread. These results are discussed in the context of recent clinical and molecular data on radiation effects on metastasis. PMID- 23819132 TI - Breaking bad news. PMID- 23819131 TI - Neutrophil extracellular traps (NETs) - formation and implications. AB - Neutrophils are cells of the immune system which freely circulate in blood vessels and are recruited to the inflammation sites when the human organism responds to microbial infections. One of the mechanisms of neutrophil action is the formation of neutrophil extracellular traps (NETs) The process of NET generation, called netosis, is a specific type of cell death, different from necrosis and apoptosis. NETs are formed by neutrophils upon contact with various bacteria or fungi as well as with activated platelets or under the influence of numerous inflammatory stimuli, and this process is associated with dramatic changes in the morphology of the cells. The main components of NETs, DNA and granular antimicrobial proteins, determine their antimicrobial properties. The pathogens trapped in NETs are killed by oxidative and non-oxidative mechanisms. On the other hand, it was also discovered that chromatin and proteases released into the circulatory system during NET formation can regulate procoagulant and prothrombotic factors and take part in clot formation in blood vessels. NETs have also been detected in lungs where they are involved in chronic inflammation processes in ALI/ARDS patients. Moreover, DNA-proteins complexes have been found in the airway fluids of cystic fibrosis patients where they can increase the viscosity of the sputum and have a negative impact on the lung functions. The DNA complexed granular proteins and other proteins released by neutrophils during netosis lead to autoimmunity syndromes such as systemic lupus erythematosus (SLE), small-vessel vasculitis (SVV) or autoimmune diseases associated with the formation of autoantibodies against chromatin and neutrophil components. A possible involvement of NETs in metastasis is also considered. PMID- 23819133 TI - Seeking medicine for the soul. PMID- 23819134 TI - Our zip code may be more important than our genetic code: social determinants of health, law and policy. PMID- 23819135 TI - Social determinants of health: a view on theory and measurement. AB - The theory and measurement of the social determinants of health featured in a three-part seminar series on Social Determinants of Health, Law and Policy held at the Taubman Center for Public Policy, Brown University in February 2012. The seminar series represents a broader commitment to engage the public, health providers, researchers, and policy makers in dialogue for the purposes of identifying and addressing social determinants of health at community and state levels. This article summarizes and expands upon the first part of the series by defining social determinants of health and exploring methodological debates over their measurement, with a focus on income inequality, racism and discrimination, housing security, and food security. The authors of this article and the members of the seminar series represent the kind of interdisciplinary and applied work necessary for addressing the five key areas of social determinants of health identified in Healthy People 2020: economic stability, education, social and community context, health and health care, and neighborhood and environment. PMID- 23819136 TI - Social determinants of health and the Affordable Care Act. AB - Healthy living is mainly seen as a product of good genetics and holistic healthcare in the United States, but a growing field of research is also attributing well-being to social determinants of health (SDH), which are the compounded effects that arise from the concentration or lack of social capital. The Affordable Care Act (ACA) was enacted to promote the overall health of the country and its clauses are calling to attention the health disparities that come from social inequalities, the main sources for SDH. The ACA acknowledges that SDH affects marginalized communities in different ways, and to mitigate their effects, it localizes funding in hopes of empowering individuals and communities, but there is no integrated, multi-prong system for addressing SDH. PMID- 23819137 TI - Optimizing the health impacts of civil legal aid interventions: the public health framework of medical-legal partnerships. AB - Research documents the significance of the social determinants of health - the social and environmental conditions in which people live, work and play. A critical foundation of these social and environmental conditions are laws and regulations, which construct the environments in which individuals and populations live, influencing how and when people face disease. Increasingly, healthcare providers, public health professionals and lawyers concerned with social determinants are joining forces to form Medical-Legal Partnerships (MLPs) which offer a preventive approach to address the complex social, legal and systemic problems that affect the health of vulnerable populations. Now in more than 500 health and legal institutions across the country, including Rhode Island, MLP is a healthcare delivery model that integrates legal assistance as a vital component of healthcare. This article explores the many benefits of the MLP model for improving patient health, transforming medical and legal practice and institutions and generating policy changes that specifically address health disparities and social determinants. PMID- 23819138 TI - Health impact assessments. AB - Health Impact Assessment (HIA) serves as a tool for policymakers and planners when considering a new policy, project, or plan that will influence the health of people outside of the doctor's office. HIA is a series of steps that can be used to determine how a proposed plan, policy, or project may affect any number of social or environmental conditions, and ultimately health. HIA does not evaluate whether a project or plan should or should not be implemented, but rather serves to inform policymakers and planners on how to make a proposed plan, policy or project more likely to promote health and avoid potentially negative health outcomes. In this article, we present the steps, considerations needed to perform an HIA and illustrations of HIAs that have been done. PMID- 23819139 TI - Health in all policies: a start in Rhode Island. AB - In Rhode Island, health care access, whether measured as having a regular source of care or as having health insurance, is better than the U.S. average. However, health care access does not necessarily translate into better health outcomes. Rhode Island has not fared better than the rest of the nation in ending or decreasing health disparities across socioeconomic and racial demographics in spite of improved access to quality health insurance products. In June 2011, law RIGL 23-64.1 directed the establishment of a Commission of Heath Advocacy and Equity. It requires a cross-section of state agency and community members to focus on the social determinants of health, and prepare biennial reports with public participation. The law will serve to remind the government and the public that objectives for the well-being of the population are best achieved when all sectors include health as a key component of policy development. PMID- 23819140 TI - Environmental management of mosquito-borne viruses in Rhode Island. AB - West Nile Virus (WNV) and Eastern Equine Encephalitis Virus (EEEV) are both primarily bird viruses, which can be transmitted by several mosquito species. Differences in larval habitats, flight, and biting patterns of the primary vector species result in substantial differences in epidemiology, with WNV more common, primarily occurring in urban areas, and EEEV relatively rare, typically occurring near swamp habitats. The complex transmission ecology of these viruses complicates prediction of disease outbreaks. The Rhode Island Department of Environmental Management (DEM) and Department of Health (DoH) provide prevention assistance to towns and maintain a mosquito surveillance program to identify potential disease risk. Responses to potential outbreaks follow a protocol based on surveillance results, assessment of human risk, and technical consultation. PMID- 23819141 TI - Intramural esophageal dissection associated with esophageal perforation. AB - Intramural esophageal dissection (IED) is a rare clinical entity involving a mucosal injury and creation of a true and false lumen within the esophagus. We report on a case of IED caused by repeated vomiting due to a small bowel obstruction associated with a small amount of pneumomediastinum on CT. IED has traditionally been believed not to be associated with esophageal perforation. Our case adds to the few reported instances where IED has been associated with extraluminal air leakage, the mildest form of esophageal perforation and demonstrates imaging not previously published in the radiology literature. Our case was successfully managed conservatively. PMID- 23819142 TI - Lower urinary tract dysfunction: From basic science to clinical management. Foreword. PMID- 23819143 TI - Guest editorial: Special issue on noninvasive electromagnetic brain stimulation. PMID- 23819144 TI - Recent advances in the prevention and management of complications associated with routine lumbar spine surgery. PMID- 23819145 TI - A crowded calendar. PMID- 23819146 TI - Whole-genome sequencing in health care. Recommendations of the European Society of Human Genetics. PMID- 23819147 TI - Gender-based violence (GBV) is a worldwide problem that violates fundamental human rights and threatens the well-being of women and girls. Introduction. PMID- 23819148 TI - Response to effect of fenofibrate on vascular endothelial function: statistical appraisal and its validity. PMID- 23819149 TI - Response to role of the carotid body in obesity-related sympathoactivation. PMID- 23819150 TI - Response to mortality benefits from U.S. population-wide reduction in sodium consumption: projections from 3 modeling approaches. PMID- 23819151 TI - [Whiplash: "Active" therapy instead of cervical collar]. PMID- 23819152 TI - Francis report: the focus should be patients not policies. PMID- 23819153 TI - Francis report: the focus should be patients not policies. PMID- 23819154 TI - US Supreme Court strikes down anti-prostitution pledge. PMID- 23819155 TI - Response to Syria's health crisis--poor and uncoordinated. PMID- 23819156 TI - Ukraine at risk of polio outbreak. PMID- 23819157 TI - James Marsh and the poison panic. PMID- 23819158 TI - Retraction. PMID- 23819159 TI - Traumatic brain stem injury: evaluation by MRI. Author reply. PMID- 23819160 TI - Dynamic contrast-enhanced MR: importance of reaching the washout phase. Author reply. PMID- 23819161 TI - [The diabetes mellitus and pancreatic cancer]. PMID- 23819162 TI - [The appendicitis: etiology, pathogenesis, classification and variants of recurrent and chronic course of the disease]. PMID- 23819163 TI - [The evolution of surgical approach to the tumorous colonic obstruction]. PMID- 23819165 TI - Molecular mechanism of green microalgae, Dunaliella salina, involved in attenuating balloon injury-induced neointimal formation -- retraction. PMID- 23819164 TI - Colonic graft-versus-host disease (GVHD) manifesting as eosinophilic colitis following autologous hematopoietic stem cell transplantation. PMID- 23819166 TI - Retraction. "CRB2 expression in epithelial cancers and its relationship with clinical characteristics.". PMID- 23819167 TI - Research scientists: endemic fraud. PMID- 23819168 TI - Pirfenidone. First, do no harm. AB - Idiopathic pulmonary fibrosis is a rare disorder due to progressive, widespread fibrotic damage of the lung parenchyma. It usually occurs after the age of 50, and its cause is unknown. Symptoms include progressive shortness of breath and nonproductive cough. The course of the disease is marked by exacerbations. Death from respiratory failure occurs about 2 to 5 years after diagnosis. There are currently no drugs that can control or slow the fibrotic process. Pirfenidone, an immunosuppressant, has been authorised in the European Union for the treatment of mild to moderate idiopathic pulmonary fibrosis. Clinical evaluation is based on two double-blind randomised placebo-controlled trials lasting 72 weeks in a total of 779 patients. Mortality, the frequency of exacerbations and the number of lung transplants did not differ significantly between the pirfenidone and placebo groups in either trial. Decline in forced vital capacity was smaller with pirfenidone than with placebo, but the difference was statistically significant in only one of the trials. The small difference in this surrogate endpoint is of questionable clinical relevance. 14.8% of the patients taking pirfenidone 2403 mg/day (maintenance dose according to the marketing authorisation) discontinued treatment because of adverse events, versus 8.6% of patients in the placebo groups. Serious adverse effects included 3 cases of bladder cancer in the pirfenidone groups versus 1 case in the placebo groups. Photosensitivity and skin rash, cardiac arrhythmias and coronary artery disease were more frequent with pirfenidone 2403 mg/day than with placebo. Abnormal transaminase elevation occurred in 4.1% of patients on pirfenidone 2403 mg/day versus 0.6% of patients on placebo. A few cases of acute renal failure were also observed. In practice, there is no evidence that pirfenidone improves quality of life in patients with mild to moderate idiopathic pulmonary fibrosis, or that it slows the progression of pulmonary fibrosis. The adverse effect profile is already burdensome. Pending real therapeutic advance, it is best to avoid pirfenidone altogether and to focus on symptomatic treatment. PMID- 23819169 TI - Danitumumab adjunctive therapy. No place in either first- or second-line treatment of metastatic colorectal cancer. AB - Adding panitumumab to standard protocols does not prolong survival but provokes additional adverse effects. PMID- 23819170 TI - Vildagliptin monotherapy. To be avoided, like other DPP-4 inhibitors. PMID- 23819171 TI - Common stem -renone and cycline. PMID- 23819172 TI - Tegafur + gimeracil + oteracil. Just another fluorouracil precursor. AB - Patients with advanced-stage gastric cancer and inoperable locoregional extension rarely survive more than a few months. Chemotherapy based on intravenous fluorouracil or oral capecitabine slightly prolongs overall survival. An oral fixed-dose combination of tegafur + gimeracil + oteracil (Teysuno degrees, Nordic) has been approved in the European Union for the treatment of advanced gastric cancer. Like capecitabine, tegafur is a metabolic precursor of fluorouracil. It is combined with gimeracil in order to increase its bioavailability and with oteracil to try to reduce its gastrointestinal toxicity. In two randomised, controlled but unblinded trials including 91 and 129 patients with advanced gastric cancer, there was no significant difference in median overall survival times between patients who received the tegafur + gimeracil + oteracil combination and those who received oral capecitabine alone (about 9 and 13 months, respectively). However, the study populations were too small to rule out a noteworthy difference in survival between the 2 treatments. Another randomised, unblinded trial compared tegafur + gimeracil + oteracil versus flurorouracil monotherapy in 1029 patients with gastric cancer, which was often metastastic. However, the dose of concomitantly administered cisplatin was lower in the tegafur group, therefore skewing the results. Median overall survival was about 8 months in both groups, and median progression-free survival was about 5 months. Neither outcome differed significantly between the 2 treatments. Compared to capecitabine, the tegafur + gimeracil + oteracil combination appears to cause fewer cases of severe palmoplantar dysaesthesia but more serious gastrointestinal disorders. Like capecitabine, the tegafur + gimeracil + oteracil combination is administered orally twice daily. In practice, when oral therapy is preferred for a patient with advanced gastric cancer, capecitabine is still the best option because it carries a lower risk of serious gastrointestinal adverse effects. PMID- 23819173 TI - Anaphylactic reactions during anaesthesia: neuromuscular blocking agents, latex and antibiotics. AB - A French team investigated hypersensitivity reactions that occurred during locoregional or general anaesthesia over an 8-year period. They estimated that the incidence of anaphylactic reactions was about 1 per 10 000 anaesthetic procedures. Among the 1816 reports of anaphylactic reactions, the most commonly implicated drugs were neuromuscular blocking agents (1067 cases), latex (361 cases), and antibiotics (236 cases). Some anaphylactic reactions to neuromuscular blocking agents occurred in patients who had never previously been anaesthetised, suggesting cross-reactivity with other, poorly known, substances. Most reactions in children were due to latex, followed by neuromuscular blocking agents and antibiotics. In practice, exposure to latex devices should be minimised, or simply avoided when possible. A history of sensitization to substances sharing allergenic sites with neuromuscular blocking agents should be investigated, and measures should be taken to protect patients. PMID- 23819174 TI - Heparin-induced thrombocytopenia. AB - Patients can develop thrombocytopenia during heparin therapy.The most frequent form, type I heparin-induced thrombocytopenia, does not require cessation of therapy. Type II heparin-induced thrombocytopenia is immune-mediated. It can cause venous or arterial thrombosis, which may be fatal or require amputation. Type II thrombocytopenia typically develops 5 to 10 days after initiation of treatment, sometimes earlier in patients previously exposed to heparins. The recommendations on platelet-count monitoring during heparin therapy are not based on high-level evidence. The main risk factors for type II thrombocytopenia must be taken into account: unfractionated heparin, previous heparin exposure, surgery, female patient. For patients considered at high risk for heparin-induced thrombocytopenia, platelet-count monitoring is usually recommended at least twice a week for at least 2 weeks. The treatment of immune-mediated heparin-induced thrombocytopenia is based on stopping heparin and replacing it with danaparoid or argatroban. In practice, the decision to initiate treatment with unfractionated or low-molecular-weight heparin is not a trivial one. In addition to the bleeding risk, the risk of type II thrombocytopenia in the short- term, or during subsequent heparin therapy, should be taken into account when assessing the harm benefit balance. PMID- 23819175 TI - Weekly oral methotrexate therapy: raise awareness of fatal dosing errors. PMID- 23819176 TI - Fatal methotrexate overdose. PMID- 23819177 TI - Mephenesin: abuse and dependence. AB - Mephenesin is a muscle relaxant with poorly documented clinical value. Its sedative properties have been known since its introduction on the French market. Cases of abuse and dependence have been reported, particularly since the early 2010s. Some adults were reported to be taking up to 12 g of mephenesin per day, the equivalent of an entire box. Most of them had a history of dependence on various other psychotropic drugs. Withdrawal symptoms, including tremor, anxiety, and aggression, have been reported in 3 patients. A woman who was taking no other drugs died of bronchial aspiration following mephenesin overdose. Painful muscle spasm is sometimes relieved by a short rest period, or paracetamol. Repeated requests for mephenesin should alert health professionals to the possibility of abuse. It is best to avoid mephenesin altogether, especially when the patient has a history of abuse or dependence. PMID- 23819178 TI - Risperidone: rhabdomyolysis. PMID- 23819179 TI - Bisphosphonates: uveitis and scleritis. PMID- 23819180 TI - Dabigatran and mechanical valves: less effective and more risky than warfarin. PMID- 23819181 TI - Deep venous thrombosis and pulmonary embolism. Part 2--Prevention of recurrences: warfarin or low-molecular-weight heparin for at least 3 months. AB - In patients with deep venous thrombosis or pulmonary embolism, initial treatment with low-molecular-weight heparin (LMWH) is primarily aimed at preventing thrombus extension. After this initial phase, the goal of treatment is to prevent recurrences, which can be fatal. Is it better to continue treatment of deep venous thrombosis or pulmonary embolism with LMWH or switch to an oral anticoagulant? What is the optimal duration of treatment? To answer these questions, we conducted a review of the literature using the standard Prescrire methodology. In non-cancer patients, two meta-analyses of trials in which treatment was not double blinded showed that severe bleeding was slightly less frequent with LMWH than with a vitamin K antagonist, but no data on mortality or the recurrence rate were provided. In cancer patients, LMWH prevented more recurrences than vitamin K antagonists; LMWH did not reduce overall mortality and did not increase the risk of serious bleeding compared to vitamin K antagonists. Treatment with LMWH requires daily injections and renal monitoring.Treatment with warfarin, the standard vitamin K antagonist, requires regular INR monitoring. There is no evidence that rivaroxaban or dabigatran has a better harm-benefit balance than warfarin for long-term treatment. After a first episode of proximal deep venous thrombosis or pulmonary embolism associated with an identified reversible trigger, several meta-analyses support a 3-month course of anticoagulation. Prolonged anticoagulant therapy is generally considered when there is no identified trigger or in case of a recurrence. Two double-blind randomised placebo-controlled trials failed to establish whether or not aspirin based antiplatelet therapy given after discontinuation of anticoagulant therapy has a favourable harm-benefit balance. Various clinical practice guidelines published since 2006 recommend first-line treatment with a vitamin K antagonist for at least 3 months in patients without cancer, and continuation of LMWH therapy in patients with cancer. Overall, LMWH and warfarin have similar harm benefit balances. In practice, it is best to choose between these drugs on a case by-case basis, taking into account patient preferences, monitoring constraints, difficulty controlling the INR, the risk of bleeding and interactions, and the cost of treatment. PMID- 23819182 TI - Choosing a treatment for deep venous thrombosis and pulmonary embolism. PMID- 23819183 TI - Botulinum toxin type A and tension-type headache. PMID- 23819184 TI - 2012 drug packaging review: many dangerous, reportable flaws. AB - Drug packaging plays an important role in protecting and providing information to patients. The packaging examined by Prescrire in 2012, on the whole, still fails to perform all of these functions effectively. Two issues are especially worrisome. First, packaging too often poses a danger to children. In addition, too many patient leaflets provide incomplete information about adverse effects, thus failing to properly protect the most vulnerable patients. Yet, the method Prescrire used to analyse drug packaging shows that it is not difficult to detect and anticipate risks. It is up to healthcare professionals to take advantage of the method, to protect patients from, and report, dangerous packaging. PMID- 23819185 TI - Prescrire's packaging analysis. PMID- 23819186 TI - Exceptions to and deviations from the INN common stem system. AB - For various reasons, mainly related to the history of the drug and of drug nomenclature, some INNs lack a common stem. As INN nomenclature has evolved, some stems have been abandoned or their definition has been modified. Some common stems are difficult to interpret or fail to achieve their objective of designating coherent therapeutic groups. This problem tends to arise particularly when: several stems are used for the same therapeutic use; stems used to designate a particular structure or origin are shared by drugs with different properties; or several stems are used to represent drugs with the same properties but different structures. PMID- 23819187 TI - The FDA is spying on whistleblowers. PMID- 23819188 TI - Pain relievers: bad for your heart? People with heart disease should avoid prolonged use of certain anti-inflammatory drugs, Naproxen (Aleve) is safest. PMID- 23819189 TI - Prostate biopsy: what to expect. Here are the benefits, risks, and uncertainties of the only diagnostic procedure that can tell you whether you have prostate cancer. PMID- 23819190 TI - Mindful eating 101. Harness the powerful mind-body connection for healthier eating. PMID- 23819191 TI - Alzheimer's drug update. Harvard researchers help test new drugs that could strike at the root of Alzheimer's disease. Here's where things stand. PMID- 23819192 TI - Regular exercise reduces the risk of mental decline. PMID- 23819193 TI - Fish, not fish oil, prevents stroke. PMID- 23819194 TI - How long does quitting smoking extend life? PMID- 23819195 TI - In reply. PMID- 23819196 TI - Can simulated practice learning improve clinical competence? AB - The area of simulation within education is fast developing, with many educational providers striving to keep up with current advances in technology. Evaluation of simulation learning appears overwhelmingly positive (Moule et al, 2008; McCaughey and Traynor, 2010; Hope et al, 2011). However, when looking to generate financial support to develop simulation practices within education,little evidence exists regarding its impact within clinical practice.This paper details the findings of a scoping exercise undertaken to ascertain current simulation practice within nursing curricula,in order to identity good practices and a clear evidence-base for embedding and using simulation to enhance education and practice.The project found overwhelming support for simulated learning from students and facilitators. However, it was highlighted that no clear guidance or strategies were universally used to effectively incorporate simulation within curricula, nor to evaluate or audit its effect upon student competency within clinical practice. Further evidence to support the implementation of simulation within nurse education is therefore required to ensure effective implementation and transferability of learning into clinical care settings. PMID- 23819197 TI - Response to the letter to the editor on electronic billboards and driver distraction. PMID- 23819198 TI - Supporting patients following pelvic radiotherapy for endometrial cancer. AB - Endometrial cancer is the commonest gynaecological cancer in the UK. Affected women often live with long-term complex and debilitating side-effects of radiotherapy treatment, such as bowel toxicity, fatigue and psychosexual problems. Women also experience negative feelings around self-image and sexuality, which contribute to a decline in their quality of life. A review of the literature and national policy showed that women had unmet needs after completing radiotherapy treatment for endometrial cancers, and that cancer nurse specialists are in a prime position to deliver a holistic package of personalized care. Staff at a nurse-led gynaecology oncology clinic performed an audit that found the clinic was not meeting the longer-term needs of most women after radiotherapy for endometrial cancers, and that women were attending multiple appointments to access different services. The clinical nurse specialist reviewed local and national policy, carried out situational analysis and engaged with service users to identify where change was needed and to examine whether a new model of service provision, where patients could consult different professionals at one appointment, would help the move forward in life after treatment. PMID- 23819199 TI - [Cryoablation in the treatment of cardiac arrhythmias]. AB - Catheter ablation is currently the preferred treatment for various arrhythmias. Radiofrequency ablation has been shown to be efficacious and safe. Cryoablation provides better ablation catheter stability and reduces the risk of an inadvertent atrioventricular (AV) block when treating arrhythmia substrates near the normal conduction system. In our own seven year experience of cryoablation in 157 patients no serious complications occurred. In children and young patients, cryoablation has become the preferred method for AV nodal re-entrant tachycardia. Cryoablation is preferable for all tachycardia substrates near the normal conduction system in children, teenagers and adults. PMID- 23819200 TI - [FRAX fracture risk calculator in the diagnostics and treatment of osteoporosis]. AB - Screening, diagnostics and treatment of primary osteoporosis must take place on an outpatient basis. FRAX is a computer-based algorithm developed at WHO as a tool for outpatient care with the aim to recognize patients having an increased fracture risk and bring them within effective care. Special attention should be focused on secondary prevention for those having already had a fracture. Instead of replacing clinical evaluation or decision-making, FRAX serves as an aid for them. It is hoped that the use of the FRAX calculator will reduce the number of unnecessary bone density testings and "blind" initiations of osteoporosis treatments. PMID- 23819201 TI - [Significance of physical activity in childhood--a cardiometabolic view]. AB - Unfavorable diet and lack of physical activity are frequently underlying childhood and juvenile obesity. Recommendations for physical activity advise children under school age to move at least two hours per day and children of school age at least 1 to 2 hours per day. The fact that these recommendations are, however, not met among Finnish children, is reflected in physical activity also in adulthood. Immobility and obesity often develop into a mutually reinforcing vicious circle that predisposes to an increasingly early appearance of cardiometabolic risk factors. PMID- 23819202 TI - [Inappropriate medication use among the aged. Review of the criteria]. AB - Inappropriate medication use among the aged review of the criteria Several criteria have been developed to assess inappropriate prescribing among individuals aged > or = 65 years. The criteria are classified as explicit (criterion-based) or implicit (judgment-based) and most of them have been validated using consensus methods. The criteria are based on risk-benefit definition of appropriateness; benzodiazepines and anticholinergics being the most often listed inappropriate medications. Many criteria also list inappropriate medication use due to drug-disease or drug-syndrome interactions. Avoiding unnecessary duplication is mentioned in the newest criteria. Fimea's database of medication for the elderly has been developed to support rational geriatric pharmacotherapy in Finnish healthcare. In addition to Fimea's database national evidence-based Current Care Guidelines on geriatric pharmacotherapy are needed. PMID- 23819203 TI - [A systematic review for psychosocial risk factors of borderline personality disorder]. AB - Borderline personality disorder (BPD) is a serious personality disorder characterized by affective instability, impulsivity and interpersonal disturbance. Currently, intensive research is being conducted concerning the etiology of BPD. This study focuses on psychosocial risk factors to propose a conceptual model of the development of BPD. A systematic review of the literature focusing on evidence based psychosocial risk factors for BPD is provided. Utilizing this knowledge, a multi-pathway outbreak model is developed to illustrate how these data may be processed into a conceptual model of the development of BPD and used in the psychotherapy of BPD. PMID- 23819204 TI - [Mechanical thrombectomy in the treatment of acute disturbance of cerebral circulation]. AB - An essential aim of acute treatment of brain infarction is to restrict the size of the infarct by rapid and permanent recanalization of the obstructed artery. Thrombolytic therapy based on intravenous administration of alteplas (IV-tPA) exhibits the highest efficacy in the treatment of cerebral artery thrombi that are fairly small or intermediate in size. Intra-arterial thrombolysis (IA-tPA) and mechanical thrombectomy can be considered, if IV-tPA turns out to be ineffective or is contraindicated. In situations where the expected effect of IV tPA:n is modest per se, mechanical thrombectomy should be taken into account as part of the therapeutic strategy. PMID- 23819205 TI - [Combined technique in the removal of parotid gland stones]. AB - Sialendoscopy is used in the diagnostics and treatment of salivary gland swelling. Small intraductal stones can be removed with various instruments during sialendoscopy. In cases with larger fixed stones a combined technique can be applied. The stone is approached endoscopically, skin flap is raised or a small incision is made through the illuminated area and the stone is removed via the external route with minimal morbidity. In this series five out of seven patients treated by the combined technique became symptomless. Superficial parotidectomy was performed on one patient. The combined technique is recommended in the removal of stones that are large, fixed in the duct or located in the gland's hilus. PMID- 23819206 TI - [Posterior dislocation of the sternoclavicular joint]. AB - Posterior dislocation of the sternoclavicular joint is a rare injury. It can be associated with life-threatening complications. Computed tomography is the imaging modality of choice with which possible associated injuries can be detected. Acute injuries are managed with closed reduction under general anaesthesia. A fracture-dislocation is inherently more unstable than an isolated dislocation. Surgical treatment is advocated in cases of delayed diagnosis or failed closed reduction. With early diagnosis and treatment, the long-term outcome of this injury is good. PMID- 23819207 TI - [Update on current care guideline: dyslipidaemias]. AB - The updated guideline on the treatment of dyslipidaemias is in concordance with European guidelines on cardiovascular disease prevention. Treatment of dyslipidaemia aims to reduce the risk of atherosclerotic vascular diseases. Therapeutic targets for LDL cholesterol, determined by risk assessment, range from concentration < 1.8 mmol/l (very high risk), < 2.5 mmol/l (high risk) to < 3.0 mmol/l (moderate or low risk). Lifestyle (diet, including replacement of saturated with unsaturated fat, physical activity, nonsmoking, stress management) is the cornerstone of treatment. Drug therapy, mainly statins, is considered when risk-stratified LDL targets are not reached otherwise. PMID- 23819208 TI - [Effect of electroacupuncture on expression of myocardial PI 3 K, HIF-1alpha and VEGF in rats with cerebral-cardiac syndrome]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) on the expression of myocardial 1-phosphatidylinositol 3-kinase (PI 3 K), hypoxia-inducible factor 1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) in rats with cerebral-cardiac syndrome (CCS), so as to reveal its mechanism underlying reducing ischemic myocardial injury. METHODS: Forty SD rats were randomly and equally divided into sham-operation, model, EA and non-acupoint (the lateral superior side of the hip) groups (10 rats/group). CCS model was established by injection of collagenase (1 U/microL) and heparin (7 U/microL) into the right caudate nucleus. Following modeling, EA (1.5 mA, 2 Hz, 20 min) was applied to "Shuigou" (GV 26), "Fengfu" (GV 16), "Neiguan" (PC 6) and "Xinshu" (BL 15) acupoints, once daily for three consecutive days. The expression levels of PI 3 K,HIF-1alpha and VEGF in the myocardium were detected by immunohistochemistry. RESULTS: Compared with the sham-operation group, the expression levels of myocardial PI 3 K, HIF-1a and VEGF proteins were significantly increased in the model group (P<0.01). While in comparison with the model group, there were little increase in the non-acupoint group (P>0.05) and considerable increase in the expression levels of the 3 myocardial proteins in the EA group (P<0.05). CONCLUSION: EA intervention has a function in upregulating the expression of myocardial VEGF, HIF-1alpha and PI 3 K proteins in CCS rats, which maybe contribute to its protective effect on ischaemic myocardial injury. PMID- 23819209 TI - [Involvement of hippocampal NO/PKG signaling pathway in the accumulative analgesic effect of electroacupuncture stimulation of "Zusanli" (ST 36) "Yanglingquan"(GB 34) in chronic neuropathic pain rats]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) at "Zusanli"(ST 36) "Yanglingquan"(GB 34) on pain behavior and expression of hippocampal neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase(iNOS)and cGMP dependent protein kinase (PKG) mRNA in rats with chronic neuropathic pain so as to analyze its mechanism underlying analgesia. METHODS: Forty male Wistar rats were randomly divided into control, CCI model, EA-2 Hz, EA-2 Hz/15 Hz, EA-100 Hz groups, with 8 cases in each group. Chronic neuropathic pain model was established by ligature of the left sciatic nerve under anesthesia (Urethane + Alpha-Chloralose) except rats in the control group. EA(2 Hz, 2 Hz/15 Hz, 100 Hz, 1 mA) was applied to bilateral "Zusanli"(ST 36)-"Yanglingquan"(GB 34) for 30 min, once each day for 2 weeks. The thermal and mechanical paw withdrawal latencies (pain thresholds) of the bilateral limbs were detected before and after EA interventions. The hippocampal tissue of the rat was collected for detecting the expression levels of nNOS, INOS and PKG genes using quantitative real-time-PCR technique. RESULTS: In comparison with the control group, the thermal and mechanical pain thresholds of the model group were decreased obviously (P<0. 05).Compared with the model group, both thermal and mechanical pain thresholds of the EA-2 Hz, EA-2 Hz/15 Hz and EA-100 Hz groups were markedly increased after EA intervention for 3, 7, 10 and 14 days (P<0. 05). Compared with the control group, the expression levels of hippocampal nNOS and PKG mRNA were significantly and moderately up-regulated in the model group (P<0. 05). While in comparison with the model group, the expression levels of hippocampal nNOS and PKG mRNA in the EA 2 Hz, EA-2 Hz/15 Hz and EA-100 Hz groups were markedly down-regulated (P<0. 05). No significant differences were found among the EA-2 Hz, EA-2 Hz/15 Hz and EA-100 Hz groups in the analgesic effect and in down-regulating hippocampal nNOS and PKG mRNA expression (P>0.05). However, the recovery state of the pain reaction of both EA-2 Hz and EA-2 Hz/ 15 Hz groups was relatively better than that of the EA 100 Hz group from day 3 to 10 after EA intervention. CONCLUSION: EA stimulation of "Zusanli"(ST 36)-"Yanglingquan"(GB 34) at 2 Hz, 2 Hz/15 Hz and 100 Hz can significantly suppress chronic neuropathic pain induced in CCI rats, which may be closely associated with its effects in down-regulating hippocampal nNOS and PKG mRNA expression levels. PMID- 23819210 TI - [Effects of electroacupuncture stimulation of "Fenglong" (ST 40) on expression of liver ATP-binding cassette transporter A 1 mRNA and protein in rats with hyperlipidemia]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) at "Fenglong" (ST 40) on blood lipid levels and hepatic ATP binding cassette transporter A 1(ABCA 1) mRNA and protein expression in hyperlipidemia rats, so as to study its mechanism underlying improvement of HLP. METHODS: Forty SD rats were randomized into normal control, model,diet control, EA, and EA+ diet control groups, with 8 rats in each group. Hyperlipidemia model was established by feeding the animals with high fat forage for 28 days. After modeling, rats of the two diet control groups were fed with basal forage. EA (2 mA, 2 Hz/ 100 Hz) was applied to bilateral ST 40 for 30 min, once daily for 28 days. Plasma total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) contents were detected by automatic biochemistry analyzer, and the expression levels of ABCA 1 mRNA and protein in the liver tissue were assayed by in situ hybridization(lSH), RT-PCR and Western blot, respectively. RESULTS: Compared with the normal control group, the contents of plasma TC and LDL-C were apparently increased (P<0.01) and the expression levels of hepatic ABCA 1 mRNA (detected by both ISH and RT-PCR) and ABCA 1 protein were significantly decreased in the model group (P<0.01). In comparison with the model group, plasma TC and LDL-C contents were significantly decreased and the expression levels of hepatic ABCA 1 mRNA and protein were significantly up regulated in the EA group and EA+diet control group( P<0. 01). The effects of EA+ diet control were significantly superior to those of diet control in down regulating plasma TC and LDL-C levels and up-regulating hepatic ABCA 1 mRNA and protein expression levels(P<0. 01). CONCLUSION: EA stimulation of "Fenglong"(ST 40) can decrease the load of blood cholesterol and suppress the down-regulation of hepatic ABCA 1 mRNA and protein expression in hyperlipidemia rats, which may contribute to its effect in improving hyperlipidemia. PMID- 23819211 TI - [Influence of acupuncture intervention on neurologic deficits, cerebrocortical cell apoptosis and Protein kinase A expression in rats with focal cerebral ischemia]. AB - OBJECTIVE: To observe the influence of acupuncture intervention on expression of protein kinase A (PKAP in the cerebrocortex of rats with focal cerebral ischemia reperfusion injury(CI/RI), so as to explore its underlying neuroprotection mechanism on cerebral ischemia. METHODS: Ninety male SD rats were randomly and evenly divided into sham-operation (sham), model and acupuncture groups which were further randomized into 3, 7 and 14-days (d) subgroups (10 rats/subgroup). CI/RI model was established by occlusion of the left middle cerebral artery for 2 hours and reperfusion. Manual acupuncture stimulation was applied to "Baihui" (GV 20) and "Shuigou" (GV 26), as well as the right "Quchi" (LI 11), "Hegu" (LI 4), "Neig (PC 6), "Zusanli" (ST 36),"Sanyinjiao"(SP 6) and "Taichong" (LR 3) for 30 min, once daily for 3, 7 and 14 d respectively. Rats of the sham and model groups were restrained for 30 min each day. Neurological defects were assessed by ethologic scoring according to Bederson's neurologic assessment scales. Cellular apoptosis in the ischemic cortex was detected by flow cytometry and PKA expression determined by immunohistochemistry for calculating its PKA immunoreaction (IR)-positive cell rate, respectively. RESULTS: Compared with the sham group, the neurologic scores, cortical cellular apoptosis rates and PKA IR positive cell rates of the model group were significantly increased at the time points of day 3, 7 and 14 post-treatment (P<0. 05). In comparison with the model group, the neurologic scores and cortical cellular apoptosis rates of the acupuncture group at the time-points of day 3, 7 and 14 post-treatment were considerably down-regulated (P<0. 05), and the cortical PKA IR-positive cell rates of the acupuncture group were remarkably increased (P<0. 05). In addition, along with the increase of acupuncture treatment sessions, lower apoptosis rates and more PKA IR-positive cells were found, suggesting a cumulative effect. CONCLUSION: Acupuncture intervention can lower cellular apoptosis rate of the ischemic cerebrocortex and up-regulate cortical PKA expression level in CI/RI rats, which may be responsible for its effect in improving neurologic deficits. PMID- 23819212 TI - [Influence of electroacupuncture stimulation of delivery-facilitating acupoints with different stimulating parameters on serum endocrine hormones of late-stage pregnant rats]. AB - OBJECTIVE: To observe the influence of electroacupuncture (EA) stimulation of "Hegu" (LI 4) and "Sanyinjiao"(SP 6; a classical delivery-facilitating acupoint recipe) at different parameters on endocrine hormone levels of late-stage pregnant rats, so as to find the better stimulation parameters for delivery facilitation. METHODS: Ninety-six female Wistar rats were randomly divided into eight groups: normal control (normal), pregnancy (model), EA-15 Hz, EA-30 Hz, EA 50 Hz, EA-2 Hz/ 15 Hz, EA-2 Hz/30 Hz and EA-2 Hz/50 Hz, with 12 rats in each group except EA-30 Hz group (n = 10). EA stimulation (0.2 to 0. 3 mA) was delivered to bilateral LI 4 for 20 min and then bilateral SP 6 for 5 min (25 min). The contents of serum estradiol (E2), progesterone (P) and prostaglandin E2 (PGE2) were detected by ELISA. RESULTS: Compared with the normal group, serum E2, P and PGE2 contents were significantly increased in the pregnancy model group (P<0.01), and E2/ P level was downregulated mildly (P>0.05). Compared with the model group, the contents of serum E2 in the EA-15 Hz, EA-30 Hz, EA-50 Hz, EA-2 Hz/15 Hz and EA-2 Hz/50 Hz groups, serum PGE2 contents in the EA-15 Hz, EA-30 Hz and EA-2 Hz/50 Hz groups, and E2/P levels in the EA-15 Hz, EA-30 Hz, EA-50 Hz and EA-2 Hz/50 Hz groups were significantly increased (P<0.01, P<0.05), whereas serum P contents in the EA-15 Hz, EA-30 Hz, EA-50 Hz and EA-2 Hz/50 Hz groups were significantly down-regulated (P<0. 01, P<0. 05). The effects of EA-2 Hz/50 Hz group were significantly superior to those of EA-2 Hz/15 Hz and EA-2 Hz/ 30 Hz groups in raising serum E2 and E2/P levels (P<0.05, P<0.01). No significant differences were found among the EA-15 Hz, EA-30 Hz, EA-50 Hz and EA-2 Hz/50 Hz groups in raising serum E2, PGE2 and E2/P levels, and among the EA-30 Hz, EA-50 Hz and EA-2 Hz/50 Hz groups in lowering serum P levels (P>0. 05). It displayed that the effects of EA at 15 Hz, 30 Hz and 2 Hz/50 Hz on the abovementioned 4 indexes were relatively better. CONCLUSION: EA of LI 4 and SP 6 at 15 Hz, 30 Hz and 2 Hz/ 50 Hz can effectively up-regulate serum E2, PGE2 and E2/P levels and down-regulate serum P content in pregnancy rats, which may contribute to its effect in promoting labor. PMID- 23819213 TI - [Relationship between regional mast cell activity and peripheral nerve discharges during manual acupuncture stimulation of "Zusanli" (ST 36)]. AB - OBJECTIVE: To observe changes of discharges of the sciatic nerve branch and mast cell activities and collagen fibers in the acupoint area during manual acupuncture stimulation of "Zusanli"(ST 36), so as to reveal the relationship between peripheral nerve and mast cell activities. METHODS: A total of 30 male SD rats were divided into normal, acupuncture control (an acupuncture neidle was inserted into ST 36 without manipulation), manual acupuncture (MA), disodium cromoglycate (DSCG, suppressing mast cell activity) plus acupuncture (MA + DSCG) and col lagenase (dissolving the collagen fibers) plus acupuncture (MA+ collagenase) groups (6 rats/group). After dissection of a branch of the sciatic nerve innervating ST 36 region in the left hind-limb under anesthesia, the ipsilateral ST 36 was stimulated by manipulating the acupuncture needle for 20 min. Discharges of the sciatic nerve branch were recorded by using a pair of metal electrodes and data acquisition system (Power Lab). Skin and muscle tissues of ST 36 area were sampled, sliced and stained with Toluidine Blue for detecting the number of degranulated mast cells. RESULTS: Compared with the control group, the mean power spectrum of d ischarges of the sciatic nerve and the mean rates of the degranulated mast cells in "Zusanli" (ST 36) area in the MA group were significantly increased (P<0.01). Whereas the mean power spectrum of discharges of the sciatic nerve and the mean degranulation rates of mast cells were considerably lower in the MA + DSCG group and MA+ collagenase group than in the MA group (P<0.01). No significant differences were found between the normal and control groups, and between the MA+NDSCG and MA+collagenase groups in the mean power density and degranulation rates of mast cells (P>0.05). CONCLUSION: Manual acupuncture stimulation of Zuai"ST 36 can significantly potentiate the discharge activity of the sciatic nerve and induce degranulation of mast cells at the same time, suggesting an involvement of mast cells in initiating acupuncture signals by peripheral sensory nerve. PMID- 23819214 TI - [Effects of electroacupuncture intervention on blood lipid levels and expression of CD 40 L and MMP-9 in the coronary artery tissue in coronary heart disease rats]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) of "Neiguan" (PC 6) and "Xinshu" (BL 15) on levels of serum total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL) and low-density lipoprotein (LDL) and expression of T cell CD 40 L and matrix metalloproteinases-9 (MMP-9) in the coronary artery in coronary heart disease (CHD) rats, so as to reveal its mechanism underlying improvement of coronary atherosclerotic heart disease. METHODS: A total of 60 Wistar rats were randomly divided into normal control, model, EA-pretreatment, routine EA and medication groups (n = 12). Coronary atherosclerotic heart disease model was established by feeding the animals with high fat forage for 3 months and intraperitoneal injection of VD3 (2 mL/kg, 60 000 IU/100 g, once daily for 3 days). EA was applied to unilateral "Neiguan"(PC 6) and "Xinshu"(BL 15) once every other day for rats of the EA-pretreatment group from the 1st day of modeling on for 12 weeks, and once daily for rats of the routine EA group from successful modeling on for 2 weeks. Rats of the medication group were treated by intragastric administration of Atorvastatin 0. 25 mg . kg-1 . d-1 for 2 weeks. Serum TC, TG, HDL and LDL contents were detected by ELISA and the expression levels of CD 40 L and MMP-9 of the coronary artery tissue assayed by Western blot. RESULTS: Serum contents of TC, TG and LDL and expression levels of coronary arterial CD 40 L and MMP-9 in the model group were significantly higher than those of the normal control group( P<0.01), while serum HDL content was decreased considerably in the mo- del group (P<0. 01). In comparison with the model group, the contents of serum TC, TG, HDL and the expression levels of arterial CD 40 L and MMP-9 in both EA-pretreatment group and routine EA group were remarkably down-regulated (P<0. 01), and serum LDL content was obviously up regulated (P<0. 01). The effects of the EA-pretreatment group were significantly superior to those of the medication group in down-regulating the contents of serum TC, TG, HDL and decreasing the expression of coronary arterial CD 40 L and MMP-9 proteins (P<0. 01, P<0. 05). No significant differences were found between the EA-pretreatment and routine EA groups in all the 6 indexes (P>0. 05). CONCLUSION: Both EA-pretreatment and routine EA of PC 6 and BL 15 can down regulate blood TC, TG and HDL contents, raise serum HDL level and suppress the increased expression of CD 40 L and MMP-9 proteins of coronary artery tissue in rats with coronary atherosclerotic heart disease, which may contribute to their effect in improving CHD. PMID- 23819215 TI - [Effects of moxibustion intervention on inflammatory reactions and expression of suppressor of cytokine signaling proteins of synovium cells in rheumatoid arthritis rabbits]. AB - OBJECTIVE: To observe the effect of moxibustion intervention on inflammatory reactions and expression of suppressor of cyfokine signaling 1 (SOCS 1) and SOCS 2 [Which are involved in inhibition of the Janus Kinase-signal transducer and activator of transcrip-tion (JAK/STAT signaling pathway and in sffenuation of cytokine signaling)] in synovium cells of the hind-knee joint in rheumatoid arthritis (RA) rabbits, so as to study its mechanism underlying improvement of RA. METHODS: Forty-two Japanese big-ear white rabbits were randomized into control, model and moxibustion groups respectively, with 14 cases in each group. RA model was established by injection of Freund's Complete Adjuvant (0. 5 mL/kg) into the rabbits' bilateral hind-knee joint cavities. Moxibustion was applied to bilateral "Shenshu" (BL 23) areas, 5 cones every time, once daily for 3 weeks except the Sundays. The perimeters of rabbits' hind legs were measured before and after modeling and after the therapy. The synovial tissue of joint was sampled for analyzing the expression levels of SOCS 1 and SOCS 3 by immunohistochemistry. RESULTS: Before the therapy, the perimeters of bilateral knee joints of the control, model and moxibustion groups were of no statistical significance (P>0. 05). In comparison with the control group, the perimeters of bilateral knee joints were significantly increased on day 1, 7, 14 and 21 in the model group (P<0. 01). Compared with the model group, the perimeters of bilateral knee joints in the moxibustion group were significantly decreased (P<0. 05), suggesting an improvement of the inflammatory reaction after moxibustion intervention. Correspondingly, synovial SOCS 1 and SOCS 3 expression levels were remarkabely higher in the model group than in the control group (P<0. 01), and obviously decreased in the moxibustion group compared with the model group (P<0. 01). CONCLUSIONS: Moxibustion intervention has an anti-inflammatory and detumescent effects in RA rabbits, which may be closely associated with its effects in down regulating expression of SOCS 1 and SOCS 3 proteins by suppressing negative feedback regulatory JAK/STAT pathway in synovial cells. [KEY WORDS] Moxibustion; Rheumatoid arthritis; Inflammatory reactions; Synovial cells; Suppressor of cytokine signaling proteins; Negative-feedback regulatory factors PMID- 23819216 TI - [Effect of different types of moxibustion intervention on expression of inflammatory cytokines IL-1 and TNF-alpha in rabbits with rheumatoid arthritis]. AB - OBJECTIVE: To observe the effect of different moxibustion intervention on expression of interleukin-1 (IL-l) and tumor necrosis factor-alpha (TNF-alpha) in the synovial fluid of hind-knee joint in rheumatoid arthritis (RA) rabbits. METHODS: Forty Japanese big-ear white rabbits (half male and half female) were randomized into normal control, RA model, direct-moxibustion, ginger-partitioned moxibustion and warm moxibustion groups (n= 8). RA model was established by injection of Freund's Complete Adjuvant (0. 5 mL/kg) into the articular cavities of the rabbits' bilateral hind-limbs. Moxibustion intervention was applied to unilateral "Shenshu" (BL 23) and "Zusanli"(ST 36) regions alternatively for 20 min from the 7th day on after modeling, once daily for 3 weeks except Sundays. The circumference of the hindlimb-knee joint was measured using a tape measure and the contents of IL-1 and TNF-alpha in the synovial fluid of articular cavities were detected by ELISA. RESULTS: In comparison with the normal control group, the circumference values of the bilateral hind-knee joints, and the contents of IL-1 and TNF-alpha in the synovial fluid of articular cavities in the model group were significantly increased (P<0. 01). After the moxibustion treatment, compared with the model group, the circumference values of the bilateral hind-knee joints, and IL-1 and TNF-alpha contents of the synovial fluid in the warm moxibustion, direct moxibustion and ginger-partitioned moxibustion groups were remarkably reduced (P<0.01, P<0.05). The effects of the ginger partitioned group were significantly superior to those of both warm moxibustion and direct moxibustion groups in decreasing the swelled hind-knee joint circumference on day 21 after the treatment and down-regulating synovial fluid inflammatory cytokines IL-1 and TNF-alpha levels (P<0. 05). CONCLUSION: Warm, direct and ginger-separated moxibustion interventions all can reduce inflammatory reactions of the knee-joint and suppress inflammatory cytokine IL-1 and TNF-alpha levels of the synovial fluid in RA rabbits, which may contribute to its effect in improving RA in clinic. The therapeutic effect of ginger-partitioned muxibustion intervention is apparently better. PMID- 23819217 TI - [Effects of electroacupuncture intervention on behavior changes and hippocampal glucocorticoid receptor and mineralocorticoid receptor expression levels in post traumatic stress disorder rats]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) on behavior reactions and hippocampal glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) protein expression in rats with post-traumatic stress disorder (PTSD), so as to explore its mechanism underlying improvement of PTSD. METHODS: Thirty male Sprague-Dawley rats were randomly divided into control, model and EA groups (10 rats/group). PTSD model was established by single prolonged stress. EA (2 Hz, 1 mA) stimulation was applied to "Baihui" (GV 20) and bilateral "Zusanli" (ST 36) acupoints for 30 min, once a day for a week. Morris water maze test was used to measure the ability of spatial learning and memory. GR and MR protein expression levels in the hippocampus tissee were examined with immunohistochemistry. RESULTS: Compared with the control group, the animals' escape latency and the expression level of hippocampal GR protein were increased significantly, and the expression level of hippocampal MR protein, as well the ratio of MR/GR expression were down-regulated considerably in the model group (P<0.05). In comparison with the model group, the animals' escape latency and the expression level of hippocampal GR protein were shortened pronouncedly, and the expression level of hippocampal MR protein, as well the ratio of MR/GR immunoactivity were up regulated considerably (P<0. 05). CONCLUSION: EA of GV 20 and ST 36 can improve the learning-memory ability and regulate hippocampal MR and GR expression in PTSD rats, which may contribute to its effect in relieving PTSD in clinical practice. PMID- 23819218 TI - [Discussion on method for locating acupoint "Mingmen" (GV 4) in adult rats]. AB - "Mingmen" (GV 4) is one of the most frequently used acupoints in acupuncture clinic. In recent years, more and more experimental researches have been focusing on GV 4 or acupoint recipe containing GV 4 in rats. Accurate location of GV 4 is probably not only related to fully display its therapeutic effect, but also to help study its underlying mechanisms. However, there has been no unified standard about the accurate location of GV 4 in the adult rat at present. In the present paper, the authors review related literature about GV 4 location in experimental studies in recent 10 years, and put forward a practical method for locating GV 4 in the rat by combining their own experience. That is, GV 4 is taken according to the relative relationship of ilium and spinous process of the lumbar vertebra. In addition, the authors also recommend some matters needing attention in locating GV 4 in rats. PMID- 23819219 TI - [Randomized controlled clinical trials for treatment of external sty with ear apex blood-letting]. AB - OBJECTIVE: To observe the clinical therapeutic effect of ear-apex blood-letting for external sty. METHODS: A total 102 sty patients were randomized into ear-apex blood-letting group (n = 51) and routine treatment (medication) group (n = 51) according to computer-aided randomization procedure. Ear-apex-bloodletting (5-6 blood drops/time) was performed once daily for 3 times for the patients of blood letting group. Patients of the medication group were treated by local application of hydrochloric levofloxacin and erycin ointment to the affected eyelid lining. Additionally, local warm compress of the affected eyelid was given to patients of both groups. The therapeutic effect was assessed by measuring the size of the sty swell and visual analogue scale (VAS) was determined for evaluating pain severity changes. The outcomes were analyzed by researchers who did not know the grouping. RESULTS: Comparison between patients of the two groups showed that the difference vahees of the styrize and VAS score between pre- and post-treatment in the ear apex bloodletting group were significantly bigger than those of the medication group on day 3, 5 and 7 after treatment (P<0.05). The cure rates of the blood letting group and medication group were 64.7% and 41.2%, 90.2% and 62.7%, 94. 1% and 80.4%, respectively on day 3, 5 and 7 after the treatment. The therapeutic effects of blood-letting were significantly superior to those of the medication group in relieving external sty (P<0.05). CONCLUSION: Ear-apex blood-letting therapy for external sty is effective in relieving pain, reducing the size and shortening the duration of disease. PMID- 23819220 TI - [Influence of "Sancai" acupuncture treatment on plasma and urine SP, 5-HT levels of renal colic patients]. AB - OBJECTIVE: To observe the effect of "Sancai Needling" (superficial, medium and deep insertion of the acupuncture needle) combined with electroacupuncture ( EA) stimulation of Shenshu ( BL 23) on plasma and urine SP and 5- HT levels in renal colic patients, so as to study its mechanism underlying improvement of renal colic. METHODS: Sixty renal colic patients (lower-energizer stasis type) were randomly allocated to "Sancai Needling" -EA group, Ashi-point-EA group and routine EA treatment group, with 20 cases in each group. The "Sancai Needling"-EA meant that an acupuncture needle was inserted into the subcutaneous layer of BL 23 first and EA stimulation was given for 10 min; then the needle was inserted into the medium layer (muscle layer) and EA stimulation performed for 10 min; at last, the needle was further inserted into the periosteum-muscle layer and EA was performed for 10 min again. The procedures for Ashi-point-EA group were the same. For patients of the routine EA treatment group, EA was applied to BL 23 for 30 min. The therapeutic effect for pain was assessed according to McGill Pain Questionnaire. Plasma and urine SP and 5-HT contents were determined using enzyme labeled immunosorbent assay (ELISA) . RESULTS: In comparison with pre-treatment, pain scores, plasma and urine SP and 5-HT contents were remarkably decreased in renal colic patients of the "Sancai Needling"-EA group, Ashi-point-EA group and routine EA treatment group after the treatment ( P<0. 05). The effects of the "Sancai Needling"-EA group and Ashi-point-EA group were significantly superior to those of the routine EA treatment group in reducing pain score, plasma and urine SP and 5-HT contents( P<0. 05). No statistical differences were found between the "Sancai Needling"-EA group and Ashi-point-EA group in pain score, plasma and urine SP and 5-HT contents ( P>0. 05). CONCLUSION: "Sancai Needling"-EA treatment is effective in relieving renal colic in the patients, which may be closely associated with its effects in down-regulating plasma SP and 5-HT levels. PMID- 23819222 TI - [Discussion on existing problems of placebo acupuncture design based on acupuncture analgesia]. AB - In the present article, the authors made an overview about the existing problems of placebo acupuncture design in accordance with the neurological basis of acupuncture analgesia. The neuron-segmental and systemic mechanisms initiated by local somesthetic stimuli at different intensities are involved in acupuncture analgesia. When the local pain locus and the stimulated point are in the same spinal segmental region, stimuli of either higher intensity or lower intensity may produce an obvious anaIgesia effect. If the stimulation site is far from the pain locus (in remote spinal segment region), only higher intensity stimulation works. From this viewpoint, the placebo acupuncture design in current clinical trials for pain treatment exists some unreasonable aspects. Both pain focus and intensity of acupuncture stimulation should be taken into consideration together. The optimal placebo acupuncture design for the treatment of pain conditions is that lower intensity acupuncture stimulation is given for longer distance between the pain origin locus and the stimulated acupoint. PMID- 23819221 TI - [Clinical observation on electroacupuncture for arousing consciousness of comatose patients with severe trauma brain injury]. AB - OBJECTIVE: To observe the arousal effect of electroacupuncture (EA) stimulation of Baihui (GV 20), Shuigou (GV 26), etc. on severe craniocerebral injury patients. METHODS: A total of 90 cases of severe craniocerebral injury were randomly allocated to routine medication, naloxone and EA groups, with 30 cases in each group. For patients of the routine medication group, mild hypothermia therapy, medicines for dehydration, hormonal therapy, vascular dilation, cerebral nutrition supporting, anti-inflammation, etc. were given. For patients of the naloxone group, intravenous drip of naloxone 0.4 mg/kg in the first 3 days, 0.2 mg/kg for 7 days and 0. 1 mg/kg afterwards. For patients of the EA group, EA (1 Hz/50 Hz) was given for 30 min once daily. All the treatments were conducted once a day for 14 days. The Glasgow Coma Scale (GCS) and Glasgow Outcome Scale (GOS) were used for assessing the therapeutic effect. RESULTS: In comparison with pre treatment in each one of the routine medication, naloxone and EA groups, GCS scores were all obviously increased in the 3 groups following the treatment, and one month's follow-up (P<0. 05). The GCS scores of both naloxone and EA groups were significantly higher than those of the routine medication group (P<0.05). No significant difference was found between the naloxone group and EA group in GCS scores (P>0. 05). According to the GOS, one month's follow-up showed that of the three 30 cases in the routine medication, naloxone and EA groups, 6, 12 and 14 were improved, 8, 10 and 10 moderate handicap, 8, 3 and 2 severe handicap, 5, 3 and 2 vegetative state, and 3, 2 and 2 dead, with the arousal rates being 46. 66% , 73. 33% and 80. 00%, respectively. The therapeutic effects of both naloxone and EA groups were significantly superior to those of the routine medication group (P<0.05). CONCLUSION: EA intervention at early stage can promote the recovery of neurological function, accelerate the consciousness from coma and improve the outcomes of patients with severe traumatic brain injury. PMID- 23819223 TI - [Review of studies on Deqi of acupuncture mainly in foreign countries]. AB - Deqi (needle sensation), is closely related to clinical therapeutic effect of acupuncture in the treatment of different clinical conditions. In the present paper, the authors summarized various components or concepts of Deqi mainly in the foreign studies collected from Pubmed database. At present, foreign researches about Deqi mainly include 1) the subjects' subjective qualitative and quantitative descriptions about Deqi, 2) correlation between acupuncture stimulation induced Deqi and clinical therapeutic effects, and 3) responses of different brain regions or the connectivity of brain network shown by functional magnetic resonance imaging (fMRI) during Deqi by needling different acupoints. According to the current commonly used 6 questionnaires, aching, tingling, numbness, heaviness, dull pain, throbbing, and deep pressure sensation are the most frequently seen components of Deqi of acupuncture stimulation. The factors influencing Deqi are psychological state, personal previous experience and cultural background. Regarding the degree of Deqi and clinical effects or outcomes, the conclusions are controversial. RESULTS: of fMRI analysis shows that in spite of extensive deactivation of the limbic system has been found in many studies, and the connectivity of the intrinsic brain functional networks is increased during acupuncture-induced Deqi, the significance of activation or deactivation of some brain regions remains unclear, and the related mechanisms need to be studied further. No matter activation or deactivation of different brain regions during Deqi, the most important issue is the relationship between Deqi and clinical therapeutic effects. Further studies are definitely needed. PMID- 23819224 TI - [Lumbar disc herniation treated with qi pathway intervention and spinal adjustment: a randomized controlled trial]. AB - OBJECTIVE: To compare the efficacy difference in the treatment of lumbar disc herniation (LDH) between the comprehensive therapy of qi pathway intervention and the spinal adjustment and the conventional therapy of acupuncture and Tuina and explore the analgesic mechanism. METHODS: Seventy-one cases were randomized into a comprehensive therapy group (36 cases) and a conventional therapy group (35 cases). In the comprehensive therapy group, the acupoints in the region of abdominal qi pathway were selected and stimulated manually with both hands. In combination, the spinal adjustment therapy was applied. In the conventional therapy group, Shenshu (BL 23), Dachangshu (BL 25), Huantiao (GB 30) and Chengfu (BL 36) on the affected side were selected and stimulated with the conventional needling technique. Additionally, the routine Tuina therapy was applied. Before and after treatment, the visual analogue scale (VAS), Oswestry disability index (ODI) questionnaire, the health related quality of life (SF-36) questionnaire and the level of serum tumor necrosis factor (TNF-alpha) were adopted to determine analgesic effect and clinical efficacy. RESULTS: In the comprehensive therapy group, the curative and effective rate was 91.7% (33/36), which was apparently superior to 77.1% (27/35) in the conventional therapy group (P < 0.05). The analgesic effect in the first 10 treatments in the comprehensive therapy group was apparently superior to that in the conventional therapy group (P < 0.05). ODI after treatment was improved significantly in both groups (both P < 0.05), in which the result in the comprehensive therapy group was superior to that in the conventional therapy group (P < 0.05). After treatment, the SF-36 values of gener al health, bodily pain, physiological functioning, social functioning and emotional functioning in the comprehensive therapy group were superior to that in the conventional therapy group (all P < 0.05). After 15 treatments, the level of serum TNF-alpha in the comprehensive therapy group was lowered as compared with that before treatment and lower apparently than that in the conventional therapy group (P < 0.05); after 30 treatments, it was also lower than that in conventional therapy group (P < 0.05). CONCLUSION: In the guide of the theory of qi pathway, the comprehensive therapy of acupuncture and spinal adjustment intervention achieves the quick and good efficacy on LDH as compared with the conventional acupuncture and Tuina and improves the quality of life for the patients to certain extent. The analgesic effect of this therapy is relevant with the decrease of serum TNF-alpha. PMID- 23819225 TI - [Observation on the clinical efficacy of shoulder pain in post-stroke shoulder hand syndrome treated with floating acupuncture and rehabilitation training]. AB - OBJECTIVE: To compare the efficacy difference in the treatment of shoulder pain in post-stroke shoulder-hand syndrome among floating acupuncture, oral administration of western medicine and local fumigation of Chinese herbs. METHODS: Ninety cases of post-stroke shoulder-hand syndrome (stage I) were randomized into a floating acupuncture group, a western medicine group and a local Chinese herbs fumigation group, 30 cases in each one. In the floating acupuncture group, two obvious tender points were detected on the shoulder and the site 80-100 mm inferior to each tender point was taken as the inserting point and stimulated with floating needling technique. In the western medicine group, mobic 7.5 mg was prescribed for oral administration. In the local Chinese herbs fumigation group, the formula for activating blood circulation and relaxing tendon was used for local fumigation. All the patients in three groups received rehabilitation training. The floating acupuncture, oral administration of western medicine, local Chinese herbs fumigation and rehabilitation training were given once a day respectively in corresponding group and the cases were observed for 1 month. The visual analogue scale (VAS) and Takagishi shoulder joint function assessment were adopted to evaluate the dynamic change of the patients with shoulder pain before and after treatment in three groups. The modified Barthel index was used to evaluate the dynamic change of daily life activity of the patients in three groups. RESULTS: With floating acupuncture, shoulder pain was relieved and the daily life activity was improved in the patients with post stroke shoulder-hand syndrome, which was superior to the oral administration of western medicine and local Chinese herbs fumigation (P < 0.01). With local Chinese herbs fumigation, the improvement of shoulder pain was superior to the oral administration of western medicine. The difference in the improvement of daily life activity was not significant statistically between the local Chinese herbs fumigation and oral administration of western medicine, the efficacy was similar between these two therapies (P > 0.05). CONCLUSION: The floating acupuncture relieves shoulder pain of the patients with post-stroke shoulder-hand syndrome promptly and effectively, and the effects on shoulder pain and the improvements of daily life activity are superior to that of the oral administration of western medicine and local Chinese herbs fumigation. PMID- 23819226 TI - [Influence of moxibustion apparatus as adjuvant treatment for pulmonary tuberculosis and patient's immune function]. AB - OBJECTIVE: To verify efficacy of moxibustion apparatus on pulmonary tuberculosis (PT) and explore adjuvant treatment method for PT. METHODS: One hundred cases of PT were randomly divided into a moxibustion group and a routine treatment group, 50 cases in each one. The regular antituberculous therapy (2HRZE/4HRE) was applied in both groups. In addition, the moxibustion apparatus was used at Bailao (EX-HN 15), Feishu (BL 13), Gaohuang (BL 43), Qihai (CV 6), Zhongfu (LU 1), Danzhong (CV 17), Guanyuan (CV 4), Zusanli (ST 36) and so on in the moxibustion group. The change of lesion area in chest radiography, degradation rate of bacte rium in the sputum, T-lymphocyte subsets and natural kill (NK) cells were observed before and after treatment in two groups. RESULTS: After the treatment for 3 months, there were 45 cases (90.0%) in the moxibustion group with more than 45% of focal absorption in chest radiography, which was obviously higher than 72.0% (36/50) in the routine treatment group (P < 0.01). The degradation rate of bacterium in the sputum in the moxibustion group was higher than that in the routine treatment group [82.0% (41/50) vs 60.0% (30/50), P < 0.01]. The CD3+, CD4+/CD8+ ratio of T-lymphocyte subsets and NK cells in the moxibustion group were significantly higher than those in the routine treatment group (P < 0.05, P < 0.01). CONCLUSION: On the basis of regular antituberculous therapy, moxibustion apparatus could significantly improve clinical effect, promote focal absorption and boost immunity, which is considered as an adjuvant treatment for PT. PMID- 23819227 TI - [Efficacy observation on female chronic pyelonephritis treated with abdominal cluster-needling therapy]. AB - OBJECTIVE: To observe the difference in the clinical efficacy on female chronic pyelonephritis between abdominal cluster-needling therapy and western medicine so as to explore the optimal therapeutic method for the disease. METHODS: Seventy cases of female chronic pyelonephritis were randomized into an abdominal cluster needling group and levofloxacin group, 35 cases in each one. In the abdominal cluster-needling group, the lower abdominal point was selected in combination with Zusanli (ST 36), Sanyinjiao (SP 6) and Taixi (KI 3). The treatment was given once a day and 10 treatments made one session. In the levofloxacin group, levofloxacin capsules were prescribed for oral administration, once a day. Three months later, the clinical efficacy was observed before and after treatment in two groups. RESULTS: The curative rate was 65.7% (23/35) and the total effective rate was 100.0% (35/35) in the abdominal cluster-needling group. The curative rate was 22.9%, (8/35) and the total effective rate was 71.4% (25/35) in the levofloxacin group. The clinical efficacy in the abdominal cluster-needling group was superior to that in the levofloxacin group (P < 0.01, P < 0.05). CONCLUSION: The abdominal cluster-needling therapy achieves the significant efficacy on female chronic pyelonephritis and it is the optimal therapy for the disease. PMID- 23819228 TI - [Moxibustion at Baihui (GV 20) for intractable facial paralysis and its impacts on immunoglobulin]. AB - OBJECTIVE: To observe the efficacy of moxibustion at Baihui (GV 20) on intractable facial paraly sis and the impacts on immune globulin IgA, IgG and IgM. METHODS: One hundred and twenty cases of intractable facial paralysis that was in compliance with the inclusive criteria were randomized into a moxibustion group and an acupuncture group, 60 cases in each one. In the moxibustion group, moxibustion was applied at Baihui (GV 20). In the acupuncture group, the patients were treated with acupuncture, once a day, the treatment of 15 days made one session in two groups. Before treatment and after 2 sessions treatment, the levels of IgA, IgG and IgM were detected respectively for the patients in two groups and compared. RESULTS: The difference in the levels of IgA, IgG and IgM was not significant for the patients between two groups (all P > 0.05) before treatment, but the levels of all three indices were increased significantly as compared with the normal reference values (all P < 0.05). Componed before the treatment, the levels of IgA, IgG and IgM were reduced significantly in two groups after treatment, indicating the significant difference (all P < 0.05). In comparison between two groups after the treatment, the levels of IgA, IgG and IgM in the moxibustion group were lower significantly than those in the acupuncture group, presenting the significant difference after treatment (all P < 0.05). CONCLUSION: The ottack of intractable facial paralysis is relevant with the abnormal increase of immunoglobulin. Moxibustion at Baihui (GV 20) reduces significantly the levels of IgA, IgG and IgM for the patients with intractable facial paraly sis, which is probably one of the mechanisms in the treatment of intractable facial paralysis. PMID- 23819229 TI - [Controlled observation of the efficacy between floating acupuncture at Tianying point and warm-needling therapy for supraspinous ligament injury]. AB - OBJECTIVE: To compare the efficacy difference in the treatment of supraspinous ligament injury between floating acupuncture at Tianying point and the conventional warm needling therapy. METHODS: Ninety patients were randomized into a floating acupuncture group and a warm needling group, 45 cases in each one. In the floating acupuncture group, the floating needling technique was adopted at Tianying point. In the warm needling group, the conventional warm needling therapy was applied at Tianying point as the chief point in the prescription. The treatment was given 3 times a week and 6 treatments made one session. The visual analogue scale (VAS) was adopted for pain comparison before and after treatment of the patients in two groups and the efficacy in two groups were assessed. RESULTS: The curative and remarkably effective rate was 81.8% (36/44) in the floating acupuncture group and the total effective rate was 95.5% (42/44), which were superior to 44.2% (19/43) and 79.1% (34/43) in the warm needling group separately (P < 0.01, P < 0.05). VAS score was lower as compared with that before treatment of the patients in two groups (both P < 0.01) and the score in the floating acupuncture group was lower than that in the warm needling group after treatment (P < 0.01). Thirty-six cases were cured and remarkably effective in the floating acupuncture group after treatment, in which 28 cases were cured and remarkably effective in 3 treatments, accounting for 77.8 (28/36), which was apparently higher than 26.3 (5/19) in the warm-needling group (P < 0.01). CONCLUSION: The floating acupuncture at Tianying point achieves the quick and definite efficacy on supraspinous ligament injury and presents the apparent analgesic effect. The efficacy is superior to the conventional warm-needling therapy. PMID- 23819230 TI - [Xingjian (LR 2) penitrated to Yongquan (KI 1) for insomnia]. PMID- 23819231 TI - [Acupuncture at points Front-Mu and points Xiahe for 32 cases of diabetes complications]. PMID- 23819232 TI - [Point massage and cupping therapys for 31 cases of esophageal achalasia]. PMID- 23819233 TI - [Case of Lermoyez syndrome]. PMID- 23819234 TI - [The relationship between meridians and mental state discused from the treatment of depression with acupuncture and moxibustion]. AB - The acupoints and meridians selected in the treatment of depression with acupuncture and moxibustion recorded in the domestic clinical literatures from 2001 to 2011 were summarized and analyzed so as to provide the references for the treatment of depression with acupuncture and moxibustion and discuss the relationship between meridians and mental state. SPSS 17.0 statistical analyzing software was used and the statistical description of enumeration data was applied for statistical analysis. It was found that all of the twelve regular meridians and the eight extraordinary meridians were involved in the treatment of depression with acupuncture and moxibustion, of which the application frequency of the Governor Vessel was the highest and that of the Foot-Taiyang Meridian, Foot-Yangming Meridian, Foot-Shaoyang Meridian and the Conception Vessel were followed. It is concluded that depression is Yin disease treated by regulating Yang meridians and it is found that the Governor Vessel, three foot yang meridians and the Conception Vessel are closely related to mental disorders. PMID- 23819235 TI - [Discussion on necessity of standardization for nomenclature and location of extraordinary acupoints]. AB - With retrieval of articles on extraordinary acupoint that were published in domesticin recent five years, one hundred and eight articles of clinical application are screened out and one hundred and twenty-three extraordinary acupoints that are extensively recognized are collected. Of those acupoints, 23 acupoints are included in the latest national standard. Of the rest 100 extraordinary acupoints, 48 acupoints are located on the running courses of fourteen meridians, 4 acupoints are shared with the meridian points and the other 52 acupoints have not been clarified to be located on the running courses of meridians based on the literature data. It is found in the collection of these acupoints that there are many extraordinary acupoints that are extensively used in clinical practice. But the nomenclatures and locations of acupoints have not been unified. Hence, a further standardization on these aspects is anticipated. PMID- 23819236 TI - [Acupuncture at Xinshe point for 30 cases of intractable hiccups]. PMID- 23819237 TI - [Observation on the distribution of heat-sensitized acupoints in patients with primary trigeminal neuralgia]. AB - OBJECTIVE: To observe the distribution characteristics of heat-sensitized acupoints in the high incidence region of heat sensitization on the body surface of the patients with trigeminal neuralgia. METHODS: Sixty cases of trigeminal neuralgia were collected and 60 healthy subjects were in the control. With moxibustion sensitization method to detect the heat-sensitized acupoints, the probability of the heat-sensitized acupoints in the high incidence region of heat sensitization on the body surface was analyzed and the correlation between the heat-sensitized acupoints and trigeminal neuralgia was discussed. RESULTS: (1) The occurrence rate of the heat-sensitized acupoints in the high incidence region of heat sensitization in patients with trigeminal neuralgia was 83.3% (50/60). (2) The occurrence rate of the heat-sensitized acupoints was high in the site of Xiaguan (ST 7) and Sibai (ST 2), and was secondarily high in the site of Jiachengjiang (Extra), Fengchi (GB 20) and Yuyao (EX-HN 4) in the high incidence region of heat sensitization in patients with trigeminal neuralgia. CONCLUSION: The heat-sensitized acupoints are highly correlative with trigeminal neuralgia, which provides the evidence for the further study on prevention and treatment of trigeminal neuralgia with heat-sensitive moxibustion. PMID- 23819238 TI - [Bloodletting at Sifeng (EX-UE 10) for infantile diarrhea of damp-heat syndrome type]. PMID- 23819239 TI - [Influence of electroacupuncture on p38-mitogen activated protein kinase in substantia nigra cells of rats with Parkinson disease model]. AB - OBJECTIVE: To explore the role of inflammatory reaction mediated by p38-mitogen activated protein kinase (p38-MAPK) signal path on prevention and treatment of Parkinson disease (PD) model rats by electroacupuncture (EA). METHODS: Thirty-two healthy male SD rats were randomly divided into a normal group, a sham operation group, a model group and an EA group, eight rats in each one. The PD model was established in the model group and EA group by subcutaneous injection of rotenone in skin-back area (2 mg/kg, dissolved in sunflower oil, 2 mg/mL in density), while the injection of sunflower oil emulsion without rotenone at the same point and quantity as the model group was applied in the sham operation group. The normal group was not given any intervention. The EA treatment (continuous wave, 2 Hz in frequency, 1 mA in intensity, 20 min) was applied at "Fengfu" (GV 16) and "Taichong" (LR 3) in the EA group, once a day for continuously 14 days. No treatment was given in the other groups. The expression of tyrosine hydroxylase (TH), phosphorylated p38-MAPK, cyclooxygenase-2 (COX-2) in the substantia nigra were detected with immunohistochemical method. RESULTS: There was typical PD ethology change in the model group. Compared with the normal group and sham operation group, the expression of TH positive neuron in the substantia nigra in the model group was significantly decreased, while the expression of phosphorylated p38-MAPK and COX-2 were significantly increased (all P < 0.01). Compared with the model group, the expression of TH positive neuron in the EA group was apparently increased, while the expression of phosphorylated p38-MAPK and COX-2 were significantly decreased (all P < 0.01). CONCLUSION: The EA therapy could obviously reduce the expression of inflammation mediator COX-2, inhibit the phosphorylation of p38-MAPK, reduce the damage of dopaminergic neurons in the rats with PD, and this effect may be related with the impact of p38-MAPK signal path PMID- 23819240 TI - [Efficacy and safety evaluation of fire needling for rats with rheumatoid arthritis]. AB - OBJECTIVE: To explore the therapeutic effect and safety of fire needling on rat with rheumatoid arthritis. METHODS: Forty female Wistar rats were randomly divided into a normal group, a model group, a methotrexate (MTX) group and a fire needling group, 10 rats in each group. The 0.1 mL of normal saline was subcutaneously injected in rat's right back paw in the normal group, while the other groups received subcutaneous injection of 0.1 mL of complete Freund's adjuvant to establish the model. The pricking method was applied in the fire needling group at "Jiaji" (EX-B 2), "Zusanli" (ST 36) and Ashi points with a depth of 5 mm, once every three days, and totally eight times were required. In the MTX group, with intragastric administration of 2.0 mg/kg per rat, the treatment was given once every seven days, and totally four times were required. The weight, swelling rate of foot, joint pain score and polyarthritis index of rats in each group as well as the pathological change of liver tissue under light microscope were observed. RESULTS: The weight, swelling rate of foot, joint pain score and polyarthritis index in the model group were significantly higher than those in the normal group (P < 0.05, P < 0.01), after the treatment, the above mentioned indexes in the two treatment groups were obviouly dereased as componed with those in the model group (all P < 0.01), and there were statistical differences between the fire needling group and MTX group (P < 0.05, P < 0.01). Compared with the normal group, inflammatory cells were appeared with a cluster distribution in the liver cells of rats in the model group. The inflammatory cells were reduced in the MTX group and fire needling group, and liver cells had degenerative edema and cell nucleus were largen and deformed in the MTX group. CONCLUSION: The fire needling has significant efficacy for rats with adjuvant arthritis (AA) without any damage to the liver, which coud have a better control of disease progression of rheumatoid arthritis . PMID- 23819241 TI - [Influence of auricular point sticking on incidence of nausea and vomiting and analgesia effect after gynecological laparoscopy]. AB - OBJECTIVE: To observe the influence of auricular point sticking on incidence of nausea and vomiting and analgesia effect after gynecological laparoscopy, and provide evidence for clinical application of auricular point sticking. METHODS: One hundred and twenty cases of selective gynecological laparoscopy under general anesthesia were randomly divided into an auricular point sticking group and a placebo group, 60 cases in each group. In the auricular point sticking group, the auricular point sticking with vaccaria seeds was applied at Shenmen (TF 4), Wei (CO 4) and Jiaogan (AH 6a) before the operation and 1, 5, 9, 23 h after the operation, which were pressed 5 min each point each time. The two ears were proceeded at the same time. In the placebo group, the same point selection, sticking paste was used as the auricular point sticking group, but no sticking or pressing with vaccaria seeds was adopted. The incidence of nausea and vomiting, the usage rate of tropisetron and morphine within 24 hours of the operation, as well as the score of visual analogue scale (VAS) and other adverse reactions at 2, 6, 10, 24 h after the operation were observed respectively. RESULTS: Compared with the placebo group, the incidence of nausea and vomiting [31.7% (19/60), 16.7% (10/60) vs 58.3% (35/60), 35.0% (21/60)], the usage rate of tropisetron [21.7% (13/60) vs 48.3% (29/60)] and morphine [18.3% (11/60) vs 38.3% (23/60)], the VAS scores at all different time points in the auricular point sticking group were all decreased (all P < 0.05), and no adverse reaction was observed. CONCLUSION: The auricular point sticking could significantly decrease the incidence of nausea and vomiting in patients of gynecological laparoscopy and has positive analgesic effect. PMID- 23819242 TI - [Influence of acupoint injection with small dose of fentanyl-droperidol mixed liquor on labor analgesia and level of stress hormone in parturient]. AB - OBJECTIVE: To observe the clinical effect of acupoint injection with small dose of fentanyl-droperido mixed liquor at different time stages on labor analgesia, and explore its function mechanism. METHODS: One hundred and fifty cases of full term primiparas who were intended to take vaginal delivery were randomly divided into 3 groups, 50 cases in each one. The acupoint injection with fentanyl droperido mixed liquor at different time stages was applied in the group I, where Shenshu (BL 23) was selected in active phase and Ciliao (BL 32) was selected in the 2nd stage of labor. The subcutaneous injection with fentanyl-droperido mixed liquor was adopted in group II. The group III, which was considered as a control group, was treated with subcutaneous injection of 0.9% NaCl at the same time stage as group I and II. The blood pressure, VAS score and level of norepinephrine and adrenaline were observed at different time stages. RESULTS: Compared before the injection, the blood pressure of group III in the active phase and 2nd stage of labor was significantly increased (P < 0.05), and that in group II and III was obviously higher than that in the group I (P < 0.05). The VAS score of group I in the active phase and 2nd stage of labor was significantly lower than that in the group II and III (P < 0.01). After the injection, the level of NE and E was significantly decreased (P < 0.05), which was lower than that in the group II and III (P < 0.05). CONCLUSION: The acupoint injection with small dose of fentanyl-droperido mixed liquor at different time stages has positive effect on labor analgesia, and it could significantly relieve stress reaction of parturient during the labor. Its mechanism could be related to the reduction of stress hormone in parturient. PMID- 23819243 TI - [Case of pruritus ani]. PMID- 23819244 TI - [Clinical evaluation of stiletto needle for pain of knee osteoarthritis]. AB - OBJECTIVE: To objectively evaluate the clinical efficacy of stiletto needle for pain of knee osteoarthri tis (KOA), and analyze its function mechanism. METHODS: Seventy-six cases of KOA (76 knees) were selected. Under the guide of Jingjin theory in TCM, stiletto needle was applied at pain point of Jingjin in extra articular area to have a loose solution effect, 1 to 3 points were selected each time, 1 to 2 times of treatment were required. The results of tenderness measurement instrument was adopted as main evaluation index of joint pain, and all data of evaluation indices before and after the treatment were statistical analyzed. RESULTS: There were significant differences in visual analogue scale (VAS) score, tenderness score, HSS function score and movement range of joint before and after the treatment (all P < 0.05). The effective rate of stiletto needle therapy was 89.5%. There was apparent regression trend between VAS score and tenderness score with Y (VAS) = 7.841-1.569 X (tenderness score) as its regressive equation. CONCLUSION: The stiletto needle therapy is an effective method to relieve the pain of knee osteoarthritis, and its clinical efficacy evaluation could be more objective and digital with tenderness measurement instrument. PMID- 23819245 TI - [Sixty-three cases of pediatric asthma treated with Zhuang medicine herb line moxibustion with point application]. PMID- 23819246 TI - [Research on current situation of standardization of Chinese medicine and acupuncture in Oceania]. AB - The development status of standardization of Chinese medicine and acupuncture in Australia and New Zealand is respectively introduced from 3 levels-national standard, regional standard and association standard. A national registration standard for Chinese medicine has been implemented since July 1, 2012 in Australia. The Oceania Federation of Chinese Medicine and Acupuncture Societies was also founded in capital of New Zealand. Four characteristics are revealed from researches and analyses: people's needs and the relevant system are the foundations of national standards of Chinese medicine; legislation on Chinese medicine is the guarantee for setting and implementing national standards, where necessity, scientificity, vitality, diversity and breakthroughs are embodied; registration standards are the key in international standardization of Chinese medicine; and international organizations are major force in promoting standardization of Chinese medicine and acupunc ture. PMID- 23819247 TI - [Acupuncture and moxibustion in Tunisia]. AB - The development status of acupuncture and moxibustion in Tunisia is introduced in this article. Although acupuncture and moxibustion only has a history of more than 30 years in Tunisia, it is very popular among the local people. Until now, there is one acupuncture and moxibustion center aided and built with the help of the Chinese government. Acupuncture and moxibustion clinical department has been set in some of the hospitals, and acupuncture and moxibustion clinical practice is also carried out in some private clinics. Cost of acupuncture and moxibustion in public hospitals has already been covered by medical insurance. As for education of acupuncture and moxibustion, training courses were set up in medical colleges of Tunisia by Tunisian government which is lectured by Chinese acupuncture experts. Acupuncture and moxibustion has been used to treat many diseases in Tunisia and is warmly welcomed by Tunisian. PMID- 23819248 TI - [Case of crainal polyneuritis]. PMID- 23819249 TI - [Application of acupoint anatomy localization method with colorful tube in education of acupoint anatomy]. AB - To seek a precise and simple method for localization of acupoint in anatomical experiment teaching. Medical bone needles were inserted into acupoints. Then, self-mode copper probe needles were thrust along the center of the bone needles to open the inner structures of acuppoints. And probe needles were replaced by colored plastic tubes. Finally, bone needles were withdrawn so as to fix the plastic tubes into the acupoints to facilitate the later cutting. This method for acupoint anatomic positioning is of low cost with accurate positioning and simple manipulation, which has advantages in strong experimental and innovative values. PMID- 23819250 TI - [Rasch analysis on stroke-specific quality of life (SS-QOL) scale of acupuncture intervention on stroke]. AB - OBJECTIVE: To optimize the evaluation level of active motor threshold and the functional domain of upper limbs of stroke-specific quality of life (SS-QOL) scale with Rasch analysis. METHODS: Sixty patients with acute ischemic stroke that were in accord with research criterid were randomly divided into a test group (30 cases) and a control group (30 cases). Acupuncture treatment and routine western medicine were applied on the test group, and single treatment of routine western medicine was applied on the control group. Selected acupoints were MS 5, Fengchi (GB 20), Hegu (LI 4), etc. Active motor threshold and the functional domain of upper limbs of SS-QOL were self-tested by patients after one treating course. The characteristics of the above mentioned items were tested with Rasch model. RESULTS: The statistical result on fitness of active motor threshold and the functional domain of upper limbs of SS-QOL showed that every reference of samples and items wosin accord with the Rasch model and has well inner reliability and validity. The Infit and Outfit MnSq values of active motor threshold and the functional domain of upper limbs of SS-QOL are basically between 0.5 and 1.5. CONCLUSION: The application of Rasch analysis on the assessment of patient reported outcome (PRO) has optimized the PRO scale (the activity and upper limb function domain of SS-QOL scale) and enhanced evaluation level of active motor threshold and the functional domain of upper limbs of SS QOL scale. PMID- 23819251 TI - [Thinking on controlled setting of plarebo acupuncture in clinical trial of acupuncture and moxibustion]. AB - Differences and relations between effects of acupuncture therapy and sham acupuncture are systematically analyzed in this article through the influential factors of acupuncture effect. And it is held that sham acupuncture effect is not exactly equal to placebo effect. The effects of both acupuncture and sham acupuncture are composed by specific effects and non-specific effects, and the differences of non-specific effects between acupunc ture and sham acupuncture can be minimized furthest with blinding and randomized method. Therefore, the difference of acupuncture and sham acupuncture treatment rests with the degree of differences of the specific effects. Only when both of the specific effect of acupuncture and the effect of acupuncture are minimized, can it be applied as the ideal placebo control. Consequently when placebo acupunture are setted up, factors such as the body condition, site of stimulation and stimulation parameters which can influence the specific effect of acupuncture should be taken into consideration to produce the relatively minimum specific effect. PMID- 23819252 TI - [Three cases on clinical application of "nourishing mother-organ and purging child-organ"]. PMID- 23819253 TI - [Case of senile white hair]. PMID- 23819254 TI - [Chengjiang school descendant Mr. Huang Zong-Xu's academic characteristics of acupuncture and moxibustion]. AB - HUANG Zong-xu, who studied from Mr. Cheng Dan-an, the founder of Chengjiang acupuncture school, is a famous acupuncturist of Fujian Province. Through collecting and sorting of Mr. Huang's theses and medical records, his academic characteristics of acupuncture and moxibustion were summarized as follows. Paying attention to meridians and collaterals and treatment based on syndrome differentiation; valuing the needling sensation as well as being good at reinforcing and reducing methods; thinking highly of taking care of spleen and stomach, ombination of needles and herbal medicine to treat difficult miscellaneous diseases; being adept in externd therapy and penetration needling and diet prescriptions, as well as attaching importance on health preserving. PMID- 23819255 TI - [Discussion on the influence of factors related organic on Deqi in acupuncture treatment]. AB - OBJECTIVE: To discuss the influence of factors related organic on deqi in acupuncture treatment and provide scientific evidence for further research on the influencing factors of deqi sensation. METHODS: China National Knowledge Infrastructure (CNKI) database, VIP-Chinese scientific and technological journal database, Chinese biological medical (CBM) database and PubMed database were retrieved. There were 30 articles about the organic influencing factors of deqi and they were analyzed. RESULTS: The organic related factors which includes individual constitution, syndrome classification, physical condition, specificity of acupoint function, tolerance and psychological factors play an important part in deqi in acupancture treatment, which should be brought to the forefront for acupuncture practitioners and researchers. CONCLUSION: The organic factors are influencing the deqi sensation in many ways but most of the present studies are resting on the affirmation of the phenomenon. Further studies about organic related influencing factors on deqi should be carried out and scientific, objective indices of deqi sensation should be explored which may improve the clinical and research level of acupuncture. PMID- 23819256 TI - [Analysis on scraping therapy literatures in Chinese national knowledge infrastructure (CNKI) from 2002 to 2012]. AB - In order to figure out the current situation and development of scraping therapy, and provide references for further researches. With "scroping therapy" as key word, the inclusive literatures in CNKI from 2002 to 2012 were retrieved and they were analyzed with the bibliometric method. Totaly 420 valid articles were acquined. The article number was increasing yearly and clinical trial was the main researching type. The articles were published in 147 different journals, of which 36.7% were source journals. The articles were mainly from areas with dominating TCM cultural atmosphere, specific folk medicine and prosperous economy. In recent 10 years, although the development of scraping therapy can be seen, the researching depth and width is not enough. In the future, the key point and direction of the research should focus on basic research of action mechanism and standardization of clinical trials in scraping therapy. PMID- 23819257 TI - A bottom-up algorithm of vertical assembling concept lattices. AB - One of the challenges in microarray data analysis is to interpret observed changes in terms of biological properties and relationships from massive amounts of gene expression data. As a powerful clustering tool, formal concept analysis has been used for making associations of gene expression clusters. The method of formal concept analysis constructs a concept lattice from the experimental data together with additional biological information. However, the time taken for constructing a concept lattice will rise sharply when the numbers of both gene clusters and properties are very large. In this article, we present an algorithm for assembling concept lattices for the parallel constructing concept lattice. The process of assembling two lattices is as follows. By traversing the diagram graph in a bottom-up fashion, all concepts in one lattice are added incremental into another sub-lattice one by one. In the process of adding a concept, the algorithm uses the diagram graph to find the generator concepts. It works only with the new and updated concepts of the concept which is added in the last time. The test results show that this algorithm outperforms other similar algorithms found in related literatures. PMID- 23819258 TI - Clinical and molecular models of glioblastoma multiforme survival. AB - Glioblastoma multiforme (GBM), a highly aggressive form of brain cancer, results in a median survival of 12-15 months. For decades, researchers have explored the effects of clinical and molecular factors on this disease and have identified several candidate prognostic markers. In this study, we evaluated the use of multivariate classification models for differentiating between subsets of patients who survive a relatively long or short time. Data for this study came from The Cancer Genome Atlas (TCGA), a public repository containing clinical, treatment, histological and biomolecular variables for hundreds of patients. We applied variable-selection and classification algorithms in a cross-validated design and observed that predictive performance of the resulting models varied substantially across the algorithms and categories of data. The best-performing models were based on age, treatments and global DNA methylation. In this paper, we summarise our findings, discuss lessons learned in analysing TCGA data and offer recommendations for performing such analyses. PMID- 23819259 TI - SQL based cardiovascular ultrasound image classification. AB - This paper proposes a novel method to analyze and classify the cardiovascular ultrasound echocardiographic images using Naive-Bayesian model via database OLAP SQL. Efficient data mining algorithms based on tightly-coupled model is used to extract features. Three algorithms are proposed for classification namely Naive Bayesian Classifier for Discrete variables (NBCD) with SQL, NBCD with OLAP-SQL, and Naive-Bayesian Classifier for Continuous variables (NBCC) using OLAP-SQL. The proposed model is trained with 207 patient images containing normal and abnormal categories. Out of the three proposed algorithms, a high classification accuracy of 96.59% was achieved from NBCC which is better than the earlier methods. PMID- 23819261 TI - Enhancing biomedical concept extraction using semantic relationship weights. AB - Scientific publications are often associated with a set of keywords to describe their content. Automating the process of keyword extraction and assignment could be useful in indexing electronic documents and building digital libraries. In this paper we propose a new approach to biomedical Concept Extraction (CE) using semantic features of concept graphs. We represent full-text documents by graphs and map biomedical terms to predefined ontology concepts. We adopt concept relation weights to improve the ranking process of potential key concepts. We perform both objective and human-based subjective evaluations. The results show that using relation weights significantly improves the performance of CE. The results also highlight the subjectivity of the CE procedure as well as of its evaluation. PMID- 23819260 TI - Module-based breast cancer classification. AB - The reliability and reproducibility of gene biomarkers for classification of cancer patients has been challenged due to measurement noise and biological heterogeneity among patients. In this paper, we propose a novel module-based feature selection framework, which integrates biological network information and gene expression data to identify biomarkers not as individual genes but as functional modules. Results from four breast cancer studies demonstrate that the identified module biomarkers. achieve higher classification accuracy in independent validation datasets. Are more reproducible than individual gene markers. Improve the biological interpretability of results. Are enriched in cancer 'disease drivers'. PMID- 23819262 TI - Finding optimal control policy in probabilistic Boolean Networks with hard constraints by using integer programming and dynamic programming. AB - Boolean Networks (BNs) and Probabilistic Boolean Networks (PBNs) are studied in this paper from the viewpoint of control problems. For BN CONTROL, by applying external control, we propose to derive the network to the desired state within a few time steps. For PBN CONTROL, we propose to find a control sequence such that the network will terminate in the desired state with a maximum probability. Also, we propose to minimise the maximum cost of the terminal state to which the network will enter. We also present a hardness result suggesting that PBN CONTROL is harder than BN CONTROL. PMID- 23819263 TI - Native Australian species are effective in extracting multiple heavy metals from biosolids. AB - Selecting native plant species with characteristics suitable for extraction of heavy metals may have multiple advantages over non-native plants. Six Australian perennial woody plant species and one willow were grown in a pot trial in heavy metal-contaminated biosolids and a potting mix. The plants were harvested after fourteen months and above-ground parts were analysed for heavy metal concentrations and total metal contents. All native species were capable of growing in biosolids and extracted heavy metals to varying degrees. No single species was able to accumulate heavy metals at particularly high levels and metal extraction depended upon the bioavailability of the metal in the substrate. Metal extraction efficiency was driven by biomass accumulation, with the species extracting the most metals also having the greatest biomass yield. The study demonstrated that Grevillea robusta, Acacia mearnsii, Eucalyptus polybractea, and E. cladocalyx have the greatest potential as phytoextractor species in the remediation of heavy metal-contaminated biosolids. Species survival and growth were the main determinants of metal extraction efficiency and these traits will be important for future screening of native species. PMID- 23819264 TI - Phosphorus improves arsenic phytoremediation by Anadenanthera peregrina by alleviating induced oxidative stress. AB - Due to similarities in their chemical behaviors, studies examining interactions between arsenic (As)--in special arsenate--and phosphorus (P) are important for better understanding arsenate uptake, toxicity, and accumulation in plants. We evaluated the effects of phosphate addition on plant biomass and on arsenate and phosphate uptake by Anadenanthera peregrina, an important Brazilian savanna legume. Plants were grown for 35 days in substrates that received combinations of 0, 10, 50, and 100 mg kg(-1) arsenate and 0, 200, and 400 mg kg(-1) phosphate. The addition of P increased the arsenic-phytoremediation capacity of A. peregrina by increasing As accumulation, while also alleviating As-induced oxidative stress. Arsenate phytotoxicity in A. peregrina is due to lipid peroxidation, but not hydrogen peroxide accumulation. Added P also increased the activity of important reactive oxygen species-scavenging enzymes (catalase and ascorbate peroxidase) that help prevent lipid peroxidation in leaves. Our findings suggest that applying P represents a feasible strategy for more efficient As phytoremediation using A. peregrina. PMID- 23819265 TI - Micropropagation of Myriophyllum alterniflorum (Haloragaceae) for stream rehabilitation: first in vitro culture and reintroduction assays of a heavy-metal hyperaccumulator immersed macrophyte. AB - Nowadays, submersed aquatic macrophytes play a key role in stream ecology and they are often used as biomonitors of freshwater quality. So, these plants appear as natural candidates to stream rehabilitation experiments. Among them, the stream macrophyte Myriophyllum alterniflorum is used recently as biomonitor and is potentially useful for the restoration of heavy-metal contaminated localities. The best way to obtain a mass production of watermilfoil plants is micropropagation. We developed in vitro culture of M. alterniflorum and the effects of five media on the plant development were assessed. Five morphological and four physiological endpoints were examined leading to the recommendation of the Murashige and Skoog medium for ecotoxicological studies on chlorophyllous parts, and of the Gaudet medium for root cytotoxicity and phytoremediation studies. Micropropagated clones were acclimatized in a synthetic medium and in situ reintroduction was performed efficiently. This is the first report of micropropagated plants transplantation in streams. The successful establishment of watermilfoil beds even in polluted areas strongly suggested that ecological restoration using micropropagated watermilfoil is a promising biotechnology for phytoremediation and rehabilitation of degraded areas. Moreover, high bioconcentration factors evidenced that watermilfoil hyperaccumulates Cd and Cu, and could be potentially used in phytoremediation studies. PMID- 23819266 TI - Phytoremediation of wastewater containing lead (Pb) in pilot reed bed using Scirpus grossus. AB - Phytoremediation is a technology to clean the environment from heavy metals contamination. The objectives of this study are to threat Pb contaminated wastewater by using phytoremediation technology and to determine if the plant can be mention as hyperaccumulator. Fifty plants of Scirpus grossus were grown in sand medium and 600 L spiked water in various Pb concentration (10, 30 and 50 mg/L) was exposed. The experiment was conducted with single exposure method, sampling time on day-1, day-14, day-28, day-42, day-70, and day-98. The analysis of Pb concentration in water, sand medium and inside the plant tissue was conducted by ICP-OES. Water samples were filtered and Pb concentration were directly analyzed, Pb in sand samples were extracted by EDTA method before analyzed, and Pb in plant tissues were extracted by wet digestion method and analyzed. The results showed that on day-28, Pb concentration in water decreased 100%, 99.9%, 99.7%, and the highest Pb uptake by plant were 1343, 4909, 3236 mg/kg for the treatment of 10, 30, and 50 mg/L respectively. The highest BC and TF were 485,261 on day-42 and 2.5295 on day-70 of treatment 30 mg/L, it can be mentioned that Scirpus grossus is a hyperaccumulator. PMID- 23819267 TI - Field evaluation of willow under short rotation coppice for phytomanagement of metal-polluted agricultural soils. AB - Short rotation coppice (SRC) of willow and poplar might be a promising phytoremediation option since it uses fast growing, high biomass producing tree species with often a sufficient metal uptake. This study evaluates growth, metal uptake and extraction potentials of eight willow clones (Belders, Belgisch Rood, Christina, Inger, Jorr, Loden, Tora and Zwarte Driebast) on a metal-contaminated agricultural soil, with total cadmium (Cd) and zinc (Zn) concentrations of 6.5 +/ 0.8 and 377 +/- 69 mg kg(-1) soil, respectively. Although, during the first cycle, on average generally low productivity levels (3.7 ton DM (dry matter) ha( 1) y(-1)) were obtained on this sandy soil, certain clones exhibited quite acceptable productivity levels (e.g. Zwarte Driebast 12.5 ton DM ha(-1) y(-1)). Even at low biomass productivity levels, SRC of willow showed promising removal potentials of 72 g Cd and 2.0 kg Zn ha(-1) y(-1), which is much higher than e.g. energy maize or rapeseed grown on the same soil Cd and Zn removal can be increased by 40% if leaves are harvested as well. Nevertheless, nowadays the wood price remains the most critical factor in order to implement SRC as an acceptable, economically feasible alternative crop on metal-contaminated agricultural soils. PMID- 23819268 TI - Dynamics of three organic acids (malic, acetic and succinic acid) in sunflower exposed to cadmium and lead. AB - Sunflower (Helianthus annuus L.) has been considered as a good candidate for bioaccumulation of heavy metals. In the present study, sunflower was used to enrich the cadmium and lead in sand culture during 90 days. Biomass, Cd and Pb uptake, three organic acids and pH in cultures were investigated. Results showed that the existence of Cd and Pb showed different interactions on the organic acids exudation. In single Cd treatments, malic and acetic acids in Cd10 showed an incremental tendency with time. In the mixed treatments of Cd and Pb, malic acids increased when 10 and 40 mg x L(-1) Cd were added into Pb50, but acetic acids in Pb50 were inhibited by Cd addition. The Cd10 supplied in Pb10 stimulated the secretion of malic and succinic acids. Moreover, the Cd or Pb uptake in sunflower showed various correlations with pH and some organic acids, which might be due to the fact that the Cd and Pb interfere with the organic acids secretion in rhizosphere of sunflower, and the changes of organic acids altered the form and bioavailability of Cd and Pb in cultures conversely. PMID- 23819269 TI - Phytoremediation potential of maize (Zea mays L.) in co-contaminated soils with pentachlorophenol and cadmium. AB - The ubiquitous coexistence of heavy metals and organic contaminants was increased in the polluted soil and phytoremediation as a remedial technology and management option is recommended to solve the problems of co-contamination. Growth of Zea mays L and pollutant removal ability may be influenced by interactions among mixed pollutants. Pot-culture experiments were conduced to investigate the single and interactive effect of cadmium (Cd) and pentachlorophenol (PCP) on growth of Zea mays L, PCP, and Cd removal from soil. Growth response of Zea mays L is considerably influenced by interaction of Cd and PCP, significantly declining with either Cd or PCP additions. The dissipation of PCP in soils was notably affected by interactions of Cd, PCP, and plant presence or absence. At the Pentachlorophenol in both planted and non-planted soil was greatly decreased at the end of the 10-week culture, accounting for 16-20% of initial extractable concentrations in non-planted soil and 9-14% in planted soil. With the increment of Cd level, residual pentachlorophenol in the planted soil tended to increase. The pentachlorophenol residual in the presence of high concentration of Cd was even higher in the planted soil than that in the non-planted soil. PMID- 23819270 TI - Influence of different salt marsh plants on hydrocarbon degrading microorganisms abundance throughout a phenological cycle. AB - The influence of Juncus maritimus, Phragmites australis, and Triglochin striata on hydrocarbon degrading microorganisms (HD) in Lima River estuary (NW Portugal) was investigated through a year-long plant life cycle. Sediments un-colonized and colonized (rhizosediments) by those salt marsh plants were sampled for HD, total cell counts (TCC), and total petroleum hydrocarbons (TPHs) assessment. Generally, TCC seemed to be markedly thriving by the presence of roots, but without significant (p > 0.05) differences among rhizosediments. Nevertheless, plants seemed to have a distinct influence on HD abundance, particularly during the flowering season, with higher HD abundance in the rhizosediments of the fibrous roots plants (J. maritimus < P. australis < T. striata). Our data suggest that different plants have distinct influence on the dynamics of HD populations within its own rhizosphere, particularly during the flowering season, suggesting a period of higher rhizoremediation activity. Additionally, during the vegetative period, plants with fibrous and dense root system tend to retain hydrocarbons around their belowground tissues more efficiently than plants with adventitious root system. Overall results indicate that fibrous root plants have a higher potential to promote hydrocarbons degradation, and that seasonality should be taken into account when designing long-term rhizoremediation strategies in estuarine areas. PMID- 23819272 TI - Effect of metal tolerant plant growth promoting bacteria on growth and metal accumulation in Zea mays plants grown in fly ash amended soil. AB - The present study was undertaken to examine the effect of the application of fly ash (FA) into Garden soil (GS), with and without inoculation of plant growth promoting bacteria (PGPB), on the growth and metal uptake by Zea mays plants. Three FA tolerant PGPB strains, Pseudomonas sp. PS5, PS14, and Bacillus sp. BC29 were isolated from FA contaminated soils and assessed for their plant growth promoting features on the Z. mays plants. All three strains were also examined for their ability to solubilize phosphate and to produce Indole Acetic Acid (IAA), siderophores, and hydrogencynide acid (HCN) production. Although inoculation of all strains significantly enhanced the growth of plants at both the concentration of FA but maximum growth was observed in plants inoculated with BC29 and PS14 at low level (25%) of FA concentration. The experimental results explored the plant growth promoting features of selected strains which not only enhanced growth and biomass of plants but also protected them from toxicity of FA. PMID- 23819271 TI - Potential of the aquatic fern Azolla filiculoides in biodegradation of an azo dye: modeling of experimental results by artificial neural networks. AB - The potential of an aquatic fern, Azolla filiculoides, in phytoremediation of a mono azo dye solution, C.I. Acid Blue 92 (AB92), was studied. The effects of operational parameters such as reaction time, initial dye concentration, fern fresh weight, pH, temperature and reusability of the fern on biodegradation efficiency were investigated. The intermediate compounds produced by biodegradation process were analyzed using GC-MS analysis. An artificial neural network (ANN) model was developed to predict the biodegradation efficiency. The findings indicated that ANN provides reasonable predictive performance (R2 = 0.961). The effects of AB92 solutions (10 and 20 mg L(-1)) on growth, chlorophylls and carotenoids content, activity of antioxidant enzymes such as superoxide dismutase, peroxidase and catalase and formation of malondialdehyde were analyzed. AB92 generally showed inhibitory effects on the growth. Moreover, photosynthetic pigments in the fronds significantly decreased in the treatments. An increase was detected for lipid peroxidation and antioxidant enzymes activity, suggesting that AB92 caused reactive oxygen species production in Azolla fronds, which were scavenged by induced activities of antioxidant enzymes. PMID- 23819273 TI - Potential use of leaf biomass, Araucaria heterophylla for removal of Pb+2. AB - The present investigation attempt to analyze the biosorption behavior of novel biosorbent, Araucaria heterophylla (green plant) biomass, for removal of Pb(+2) from solution as the function of initial metal ion concentration, pH, temperature, sorbent dosage and biomass particle size. The maximum biosorption was found to be 95.12% at pH 5 and biosorption capacity (q(e)) of Cd(+2) is 9.643 mg/g. The Langmuir and Freundlich equilibrium adsorption isotherms were studied and observed that Freundlich model is best fit than the Langmuir model with correlation coefficient of 0.9927. Kinetic studies indicated that the biosorption process of Cd(+2) followed well pseudo second order model with R2 0.999. The process is exothermic and, spontaneous. The chemical functional groups -OH, CH2 stretching vibrations, C=O of alcohol, C=O of amide, P=O stretching vibrations, CH, were involved in the process. The XRD pattern of the A. heterophylla was found to be mostly amorphous in nature. The SEM studies showed Pb(+2) biosorption on selective grains of the biosorbent. It was concluded that A. heterophylla leaf powder can be used as an effective, low cost, and environmentally friendly biosorbent for the removal of Pb(+2) from aqueous solution. PMID- 23819274 TI - Photobiotreatment: influence of nitrogen and phosphorus ratio in wastewater on growth kinetics of Scenedesmus obliquus. AB - Nitrogen and phosphorus concentration in the effluent of a wastewater treatment plant can vary significantly, which could affect the growth kinetic and chemical composition of microalgae when cultivated in this medium. The aim of this work was to study the rate of growth, nutrient removal and carbon dioxide biofixation as well as biomass composition of Scenedesmus obliquus (S. obliquus) when it is cultivated in wastewater at different nitrogen and phosphorus ratio, from 1:1 to 35:1. A more homogeneous method for calculating productivities in batch reactors was proposed. The proper N:P ratio for achieving optimum batch biomass productivity ranged between 9 and 13 (263 and 322 mg L(-1) d(-1) respectively). This was also the ratio range for achieving a total N and P removal. Above and below this range (9-13) the maximum biomass concentration changed, instead of the specific growth rate.The maximum carbon dioxide biofixation rate was achieved at N:P ratio between 13 and 22 (553 and 557 mg CO2 L(-1) d(-1) respectively). Lipid and crude protein content, both depend on the aging culture, reaching the maximum lipid content (34%) at the lowest N:P (1:1) and the maximum crude protein content (34.2%) at the highest N:P (35:1). PMID- 23819275 TI - Nutrient sequestration, biomass production by microalgae and phytoremediation of sewage water. AB - The present work was aimed at analysing the role of inoculated microalgae in nutrient dynamics, bioremediation and biomass production of sewage water. Preliminary microscopic analyses of sewage water revealed the presence of different algal groups, with predominance of Cyanophyta. Among the inoculated strains, Calothrix showed highest dry cell weight (916.67 mg L(-1)), chlorophyll and carotenoid content in tap water + sewage water (1:1) treatment. Significant removal of NO3-N ranging from 57-78% and PO4-P (44-91%) was recorded in microalgae inoculated tap water + sewage water. The total dissolved solids and electrical conductivity of tap water + sewage water after incubation with Calothrix sp. decreased by 28.5 and 28.0%, accompanied by an increase in dissolved oxygen from 4.4 to 6.4 mg L(-1) on the 20th day. Our investigation revealed the robustness of Calothrix sp. in sequestering nutrients (N and P), improving water quality and proliferating in sewage water. PMID- 23819276 TI - Phycoremediation of lead and cadmium by employing Nostoc muscorum as biosorbent and optimization of its biosorption potential. AB - The present study reports the influence of different factors on the sorption of Pb and Cd by Nostoc muscorum. The results showed that extent of Pb and Cd removal by N. muscorum cells increased with increasing biosorbent dose, but exhibited decline in the adsorption capacity. The maximum sorption of Cd (85.2%) and Pb (93.3%) was achieved at 60 and 80 microg/ml concentrations of respective metal, within 30 and 15 min, respectively. The result revealed that optimum biosorption of Pb and Cd occurred at pH 5 and 6, respectively, at 40 degrees C temperature. Presence of binary metals (both Pb and Cd) in a solution showed that the presence of one metal ion resulted into decreased sorption of other metal ion. The presence of Ca and EDTA showed significant decrease in the sorption of Pb and Cd, while other anions and cations did not show significant effect on the biosorption of both the metals. Maximum desorption of Pb and Cd was achieved in the presence of EDTA and HNO3, respectively. Results also showed that the test biosorbent could be repeatedly used up to six biosorption/desorption cycles without significant loss of its initial metal adsorption capacity. PMID- 23819277 TI - Phytotoxicity of wastewater containing lead (Pb) effects Scirpus grossus. AB - Phytoremediation is an environment-friendly and cost-effective method to clean the environment of heavy metal contamination. A prolonged phytotoxicity test was conducted in a single exposure. Scirpus grossus plants were grown in sand to which the diluted Pb (NO3)2 was added, with the variation of concentration were 0, 100, 200, 400, 600, and 800 mg/L. It was found that Scirpus grossus plants can tolerate Pb at concentrations of up to 400 mg/L. The withering was observed on day-7 for Pb concentrations of 400 mg/L and above. 100% of the plants withered with a Pb concentration of 600 mg/L on day 65. The Pb concentration in water medium decreased while in plant tissues increased. Adsorption of Pb solution ranged between 2 to 6% for concentrations of 100 to 800 mg/L. The Bioaccumulation Coefficient and Translocation Factor of Scirpus grossus were found greater than 1, indicating that this species is a hyperaccumulator plant. PMID- 23819278 TI - 8th Annual Conference, International Phytotechnology Society, putting plants to work, where we live, labor, breathe, and play, September 13-16, 2011, Portland, Oregon, USA. PMID- 23819279 TI - Diversity of the chlorite dismutase gene in low and high organic carbon rhizosphere soil colonized by perchlorate-reducing bacteria. AB - Chlorite dismutase (cld) is an essential enzyme in the biodegradation of perchlorate. The objective of this study was to determine the change in sequence diversity of the cld gene, and universal bacterial 16S rRNA genes, in soil samples under varying conditions of organic carbon, bioaugmentation, and plant influence. The cld gene diversity was not different between high organic carbon (HOC) and low organic carbon (LOC) soil. Combining results from HOC and LOC soil, diversity of the cld gene was decreased in soil that had been bioaugmented or planted. However, with both bioaugmentation and planting the cld diversity was not decreased. These observations were repeated when focusing on LOC soil. However, in HOC soil the cld diversity was not affected by reactor treatment. General bacterial diversity as measured with 16S rRNA was significantly greater in HOC soil than in LOC soil, but no significant difference was observed between reference soil and planted or bioaugmented soil. Different sequences of the cld gene occur in different species of microorganisms. In LOC soil, combining bioaugmentation and planting results in a highly diverse population of perchlorate degraders. This diverse population will be more resilient and is desirable where perchlorate reduction is a critical remediation process. Supplemental materials are available for this article. Go to the publisher's online edition of International Journal of Phytoremediation to view the supplemental file. PMID- 23819280 TI - Comparison of trees and grasses for rhizoremediation of petroleum hydrocarbons. AB - Rhizoremediation of petroleum contaminants is a phytoremediation process that depends on interactions among plants, microbes, and soils. Trees and grasses are commonly used for phytoremediation, with trees typically being chosen for remediation of BTEX while grasses are more commonly used for remediation of PAHs and total petroleum hydrocarbons. The objective of this review was to compare the effectiveness of trees and grasses for rhizoremediation of hydrocarbons and address the advantages of each vegetation type. Grasses were more heavily represented in the literature and therefore demonstrated a wider range of effectiveness. However, the greater biomass and depth of tree roots may have greater potential for promoting environmental conditions that can improve rhizoremediation, such as increased metabolizable organic carbon, oxygen, and water. Overall, we found little difference between grasses and trees with respect to average reduction of hydrocarbons for studies that compared planted treatments with a control. Additional detailed investigations into plant attributes that most influence hydrocarbon degradation rates should provide data needed to determine the potential for rhizoremediation with trees or grasses for a given site and identify which plant characteristics are most important. PMID- 23819281 TI - Inheritance profile of weathered chlordane and p,p'-DDTs accumulation by Cucurbita pepo hybrids. AB - Cucurbita pepo ssp pepo (zucchini) accumulates significant levels of persistent organic pollutants in its roots, followed by unexpectedly high contaminant translocation to the stems. Most other plant species, including the closely related C. pepo ssp ovifera (squash), do not have this ability. To investigate the mechanism of contaminant accumulation, two cultivars each of parental zucchini and squash, as well as previously created first filial (F1) hybrids and F1 backcrosses (BC) of those parental cultivars, were grown under field conditions in a soil contaminated with weathered chlordane (2.29 microg/g) and DDX residues (0.30 microg/g; sum of DDT, DDE, DDD). The parental zucchini had stem-to-soil bioconcentration factors (BCF, contaminant ratio of stem to soil) for chlordane and DDX of 6.23 and 3.10; these values were 2.2 and 3.7 times greater than the squash, respectively. Chlordane and DDX translocation factors, the ratio of contaminant content in the stems to that in the root, were 2.1 and 3.2 times greater for zucchini than for squash. The parental zucchini and squash also differed significantly in chlordane component ratios (relative amounts of trans-nonachlor [TN], cis-chlordane [CC], trans-chlordane [TC]) and enantiomer fractions for the chiral CC and TC. Hybridization of the parental squash and zucchini resulted in significant differences in contaminant uptake. For both the three separate component ratios (CR) and two sets of enantiomer fraction (EF) values, subspecies specific differences in the parental generation became statistically equivalent in the F1 hybrid zucchini and squash. When backcrossed (BC) with the original parental plants, the zucchini and squash F1 BC cultivars reverted to the statistically distinct CR and EF patterns. This pattern of trait segregation upon hybridization suggests either single gene or single locus control for persistent organic pollutant (POP) uptake ability by C. pepo ssp pepo. PMID- 23819282 TI - Field note: phytoremediation of petroleum sludge contaminated field using sedge species, Cyperus rotundus (Linn.) and Cyperus brevifolius (Rottb.) Hassk. AB - The aim of this study was to degrade total petroleum hydrocarbon (TPH) in a petroleum sludge contaminated site (initial TPH concentration of 65,000-75,000 mg kg(-1)) with two native sedge species namely Cyperus rotundus (Linn.) and Cyperus brevifolius (Rottb.) Hassk. Fertilized and unfertilized treatments were maintained separately to record the influence of fertilizer in TPH degradation. The average biomass production (twenty plants from each treatment) of C. rotundus was 345.5 g and that of C. brevifolius was 250.6 g in fertilized soil during 360 days. Decrease in soil TPH concentration was higher in fertilized soil (75% for C. rotundus and 64% for C. brevifolius) than in unfertilized soil (36% for C. rotundus and 32% for C. brevifolius). In unvegetated treatments, decrease in soil TPH concentration in fertilized (12%) and unfertilized soil (8%) can be attributed to natural attenuation and microbial degradation. TPH accumulation in roots and shoots was significantly higher in fertilized soil in comparison to unfertilized soils (p < 0.05). Most probable number (MPN) in planted treatments was significantly higher than in unplanted treatments (p < 0.05). PMID- 23819283 TI - Phytotechnologies--preventing exposures, improving public health. AB - Phytotechnologies have potential to reduce the amount or toxicity of deleterious chemicals and agents, and thereby, can reduce human exposures to hazardous substances. As such, phytotechnologies are tools for primary prevention in public health. Recent research demonstrates phytotechnologies can be uniquely tailored for effective exposure prevention in a variety of applications. In addition to exposure prevention, plants can be used as sensors to identify environmental contamination and potential exposures. In this paper, we have presented applications and research developments in a framework to illustrate how phytotechnologies can meet basic public health needs for access to clean water, air, and food. Because communities can often integrate plant-based technologies at minimal cost and with low infrastructure needs, the use of these technologies can be applied broadly to minimize potential contaminant exposure and improve environmental quality. These natural treatment systems also provide valuable ecosystem services to communities and society. In the future, integrating and coordinating phytotechnology activities with public health research will allow technology development focused on prevention of environmental exposures to toxic compounds. Hence, phytotechnologies may provide sustainable solutions to environmental exposure challenges, improving public health and potentially reducing the burden of disease. PMID- 23819284 TI - Plants as bio-indicators of subsurface conditions: impact of groundwater level on BTEX concentrations in trees. AB - Numerous studies have demonstrated trees' ability to extract and translocate moderately hydrophobic contaminants, and sampling trees for compounds such as BTEX can help delineate plumes in the field. However, when BTEX is detected in the groundwater, detection in nearby trees is not as reliable an indicator of subsurface contamination as other compounds such as chlorinated solvents. Aerobic rhizospheric and bulk soil degradation is a potential explanation for the observed variability of BTEX in trees as compared to groundwater concentrations. The goal of this study was to determine the effect of groundwater level on BTEX concentrations in tree tissue. The central hypothesis was increased vadose zone thickness promotes biodegradation of BTEX leading to lower BTEX concentrations in overlying trees. Storage methods for tree core samples were also investigated as a possible reason for tree cores revealing lower than expected BTEX levels in some sampling efforts. The water level hypothesis was supported in a greenhouse study, where water table level was found to significantly affect tree BTEX concentrations, indicating that the influx of oxygen coupled with the presence of the tree facilitates aerobic biodegradation of BTEX in the vadose zone. PMID- 23819285 TI - Phytoremediation of 1,4-dioxane-containing recovered groundwater. AB - The results of a pilot-scale phytoremediation study are reported in this paper. Small plots of trees established on a closed municipal waste landfill site were irrigated with recovered groundwater containing 1,4-dioxane (dioxane) and other volatile organic compounds (VOCs). The plots were managed to minimize the leaching of irrigation water, and leaching was quantified by the use of bromide tracer. Results indicated that the dioxane (2.5 microg/L) was effectively removed, probably via phytovolatilization, and that a full-scale phytoremediation system could be used. A system is now in place at the site in which the recovered groundwater can be treated using two different approaches. A physical treatment system (PTS) will be used during the winter months, and a 12 ha phytoremediation system (stands of coniferous trees) will be used during the growing season. The PTS removes VOCs using an air-stripper, and destroys dioxane using a photo catalytic oxidation process. Treated water will be routed to the local sewer system. The phytoremediation system, located on the landfill, will be irrigated with effluent from the PTS air-stripper containing dioxane. Seasonal use of the phytoremediation system will reduce reliance on the photo-catalytic oxidation process that is extremely energy consumptive and expensive to operate. PMID- 23819287 TI - Assessing genotypic diversity and symbiotic efficiency of five rhizobial legume interactions under cadmium stress for soil phytoremediation. AB - In the framework of soil phytoremediation using local legume plants coupled with their native root-nodulating bacteria to increase forage yields and preserve contaminated soils in arid regions of Tunisia, we investigated the diversity of bacteria from root nodules of Lathyrus sativus, Lens culinaris, Medicago marina, M. truncatula, and M. minima and the symbiotic efficiency of these five legume symbiosis under Cadmium stress. Fifty bacterial strains were characterized using physiological and biochemical features such heavy metals resistant, and PCR-RFLP of 16S rDNA. Taxonomically, the isolates nodulating L. sativus, and L. culinaris are species within the genera Rhizobium and the ones associated to Medicago sp, within the genera Sinorhizobium. The results revealed also that the cadmium tolerance of the different legumes-rhizobia interaction was as follows: M. minima < M. truncatula < M. marina < L. sativus < L. culinaris indicating that the effect of Cadmium on root nodulation and biomass production is more deleterious on M. minima-S. meliloti and M. truncatula-S. meliloti than in other symbiosis. Knowledge on genetic and functional diversity of M. marina, L. sativus and L. culinaris microsymbiotes is very useful for inoculant strain selection and can be selected to develop inoculants for soil phytoremediation. PMID- 23819286 TI - Behavior of native species Arrhenatherum elatius (Poaceae) and Sonchus transcaspicus (Asteraceae) exposed to a heavy metal-polluted field: plant metal concentration, phytotoxicity, and detoxification responses. AB - The application of vegetation cover for the phytomanagement of heavy metal polluted soils needs prior investigation on the suitability of plant species. In this study, behaviors of Arrhenatherum elatius and Sonchus transcaspicus, two native perennial grasses that currently grow in a mine tailing, were investigated through plant metal concentration, phytotoxicity and their detoxification responses. Both of the species accumulated Ni, Cu, Cd, Co, Mn, Pb, Cr, and Zn in shoots far below criterion concentration as a hyperaccumulators; thus, neither of them were found to be hyperaccumulators. A. elatius accumulated metals in roots and then in shoots, on the contrary, in S. transcaspicus metals were preferentially accumulated in shoots. Plants exposure to such metals resulted in oxidative stress in the considered organs as indicated by the changes in chlorophyll fluorescence, chlorophyll contents, malondialdehyde (MDA) levels and antioxidative enzyme activities. A. elatius seemed to be more affected by metal induced oxidative stress than S. transcaspicus. Correspondingly, S. transcaspicus showed a greater capacity to adapt to metal-induced oxidative stress, depending on more effective antioxidative defense mechanisms to protect itself from oxidative damage. These findings allowed us to conclude that both of these plant species could be suitable for the phytostabilization of metal-polluted soils. PMID- 23819288 TI - A compound containing substituted indole ligand from a hyperaccumulator Sedum alfredii Hance under Zn exposure. AB - Sedum alfredii Hance is a fast-growing and high-biomass zinc (Zn) hyperaccumulator native to China. A compound containing substituted indole ligand was isolated from this Zn hyperaccumulator plants by sonication/ethanol extraction, macroporous resin column as well as preparative HPLC (P-HPLC). Hydroponic experiment showed that the concentrations of both Zn and the compound containing substituted indole ligand were remarkably increased in stems and leaves of both hyperaccumulator and non-hyperaccumulator as Zn rising from 0.5 to 50 micromol L(-1), with much more in the stems of hyperaccumulator than non hyperaccumulator. At 50 micromol L(-1) Zn, hyperaccumulator grew normally but its non-hyperaccumulator suffered from strongly Zn-induced toxicity. This suggested that there was a positive correlation between the compound containing substituted indole ligand and Zn concentration in shoots of hyperaccumulator S. alfredii. PMID- 23819289 TI - Cadmium accumulation retard activity of functional components of photo assimilation and growth of rice cultivars amended with vermicompost. AB - Cadmium (Cd) uptake mediated alterations in functional components of photo assimilation during conversion of cow dung and poultry cast to vermicompost were studied in two Indian rice cultivars; MO 16 and MTU 7029. It was found that higher amount of Cd accumulate in plants grown in soil amended with vermicompost which in turn damaged functional components in photo assimilation. Enhancement of root growth was recognized as reason for Cd accumulation. Metabolic alterations noticed among plants were not taken place during application of raw materials used for vermicomposting such as cow dung and poultry cast amendment. Rice varieties accumulated Cd differentially where MTU 7029 accumulated more Cd compare to MO 16. It was also noticed that existence of negative correlation between zinc status of the plant and Cd accumulation. PMID- 23819290 TI - Studies on cadmium accumulation by some selected floating macrophytes. AB - The results of investigation of the process of cadmium accumulation by floating plants of Eichhornia crassipes and Pistia stratiotes are discussed. The main specialty of this study is that it puts more emphasis on the mechanism of penetration of pollutant within the plant and its fate during accumulation act. As a result it was shown that at the first stage of cadmium uptake the sorption of the metal on the surface of the roots due to the presence of carboxylic groups takes place. At the root of the plant cadmium mainly localized in the cortex and rhizodermis, then the pollutant penetrates into the tissues of the stem according to its translocation factor. It has been also assumed that flavonoids perform an intermediate role in the accumulation of cadmium by the plant, taking part in the transport and combat an oxidative stress. PMID- 23819291 TI - Characterization of plant-growth-promoting effects and concurrent promotion of heavy metal accumulation in the tissues of the plants grown in the polluted soil by Burkholderia strain LD-11. AB - Plant-growth-promoting (PGP) bacteria especially with the resistance to multiple heavy metals are helpful to phytoremediation. Further development of PGP bacteria is very necessary because of the extreme diversity of plants, soils, and heavy metal pollution. A Burkholderia sp. strain, numbered LD-11, was isolated, which showed resistances to multiple heavy metals and antibiotics. It can produce indole-3-acetic acid, 1-aminocyclopropane-1-carboxylic acid deaminase and siderophores. Inoculation with the LD-11 improved germination of seeds of the investigated vegetable plants in the presence of Cu, promoted elongation of roots and hypocotyledonary axes, enhanced the dry weights of the plants grown in the soils polluted with Cu and/or Pb, and increased activity of the soil urease and the rhizobacteria diversity. Inoculation with the LD-11 significantly enhanced Cu and/or Pb accumulation especially in the roots of the plants grown in the polluted soils. Notably, LD-11 could produce siderophores in the presence of Cu. Conclusively, the PGP effects and concurrent heavy metal accumulation in the plant tissues results from combined effects of the above-mentioned multiple factors. Cu is an important element that represses production of the siderophore by the bacteria. Phytoremediation by synergistic use of the investigated plants and the bacterial strain LD-11 is a phytoextraction process. PMID- 23819292 TI - Phytofiltration of arsenic and cadmium from the water environment using Micranthemum umbrosum (J.F. Gmel) S.F Blake as a hyperaccumulator. AB - Arsenic (As) and cadmium (Cd) pollution in water is an important global issue. Phytofiltration is an eco-friendly technology that helps clean up pollutants using ornamental plants, such as Micranthemum umbrosum (J.F. Gmel) S.F. Blake. After a seven-day hydroponic experiment, M. umbrosum removed 79.3-89.5% As and 60 73.1% Cd from 0 to 1.0 microg As mL(-1) and 0.3 to 30.0 microg Cd mL(-1) solutions, respectively. For As treatment, root to stem and stem to leaf translocation factors greater than 1.0 indicated that accumulation of As in leaves was large compared to that in stem and roots. However, the accumulation of Cd in roots was higher than that in the leaves and stem. In addition, M. umbrosum completely removed Cd within three days from 0.38 to around 0 microg mL(-1) Cd in the solution when the plant was exchanged daily. Bio-concentration factors (2350 for As and 3027 for Cd) for M. umbrosum were higher than for other As and Cd phytoremediators. The results show that M. umbrosum can be an effective accumulator of Cd and a hyper-accumulator of As, as it can lower As toxicity to a level close to the limit recommended by the World Health Organization (0.01 microg As mL(-1)). PMID- 23819293 TI - Effects of cadmium on enzymatic and non-enzymatic antioxidative defences of rice (Oryza sativa L.). AB - The effects of 60-d cadmium (Cd) exposure on enzymatic and non-enzymatic antioxidative system of Oryza sativa L. seedlings at tillering stage were studied using soil culture experiment. Research findings showed that chlorophyll content of Oryza sativa L. declined with the increase in soil metal concentration. Cd pollution induced the antioxidant stress by inducing O2(-1) and H2O2, which increased in plants; at the same time, MDA as the final product of peroxidation of membrane lipids, accumulated in plant. The antioxidant enzyme system was initiated under the Cd exposure, i.e. almost all the activities of superoxide dismutase (SOD), peroxidase, catalase, glutathione peroxidase, and ascorbate peroxidase were elevated both in leaves and roots. The non-protein thiols including phytochelatins and glutathione to scavenge toxic free radicals caused by Cd stress was also studied. The contents of phytochelatins and glutathione were about 3.12-6.65-fold and 3.27-10.73-fold in leaves, against control; and the corresponding values were about 3.53-9.37-fold and 1.41-5.11-fold in roots, accordingly. PMID- 23819294 TI - Seasonal variations and aeration effects on water quality improvements and physiological responses of Nymphaea tetragona Georgi. AB - Seasonal variations and aeration effects on water quality improvements and the physiological responses of Nymphaea tetragona Georgi were investigated with mesocosm experiments. Plants were hydroponically cultivated in six purifying tanks (aerated, non-aerated) and the characteristics of the plants were measured. Water quality improvements in purifying tanks were evaluated by comparing to the control tanks. The results showed that continuous aeration affected the plant morphology and physiology. The lengths of the roots, petioles and leaf limbs in aeration conditions were shorter than in non-aeration conditions. Chlorophyll and soluble protein contents of the leaf limbs in aerated tanks decreased, while peroxidase and catalase activities of roots tissues increased. In spring and summer, effects of aeration on the plants were less than in autumn. Total nitrogen (TN) and ammonia nitrogen (NH4(+)-N) in aerated tanks were lower than in non-aerated tanks, while total phosphorus (TP) and dissolved phosphorus (DP) increased in spring and summer. In autumn, effects of aeration on the plants became more significant. TN, NH4(+)-N, TP and DP became higher in aerated tanks than in non-aerated tanks in autumn. This work provided evidences for regulating aeration techniques based on seasonal variations of the plant physiology in restoring polluted stagnant water. PMID- 23819295 TI - Enhancing degradation of total petroleum hydrocarbons and uptake of heavy metals in a wetland microcosm planted with Phragmites communis by humic acids addition. AB - The effects of humic acid (HA) on heavy-metal uptake by plants and degradation of total petroleum hydrocarbons (TPHs) in a wetland microcosm planted with Phragmites communis were evaluated by comparing waterlogged soils and water drained upland soils. Experiments were conducted on soils artificially contaminated with heavy metals (Pb, Cu, Cd, Ni) and diesel fuel. HA showed a positive influence on biomass increase for all conditions, but more for belowground than aboveground biomass, and lower in contaminated than uncontaminated soil. The bioavailability and leachability factor (BLF) for all heavy metals except Ni increased with HA addition in both the control and the P. communis planted microcosms, suggesting that more heavy metals could be potentially phytoavailable for plant uptake. Microbial activities were not affected by both heavy metals and TPH contamination, and HA effects on stimulating microbial activities were much greater in the contaminated soil than under uncontaminated conditions. HA addition enhanced the degradation of TPH and n-alkane in waterlogged conditions. The results show that HA can increase the remedial performance in P. communis dominated wetlands simultaneously contaminated with heavy metals and petroleum hydrocarbons and thus prevent contamination of groundwater or other adjacent ecosystems. PMID- 23819296 TI - Variation characteristics of chlorpyrifos in nonsterile wetland plant hydroponic system. AB - Six wetland plants were investigated for their effect on the degradation characteristics of chlorpyrifos in nonsterile hydroponic system at constant temperature of 28 degrees C. The results showed that the removal rates of chlorpyrifos in the water of plant systems were 1.26-5.56% higher than that in the control without plants. Scirpus validus and Typha angustifolia were better than other hygrophytes in elimination of chlorpyrifos. The removal rates of the two systems were up to 88%. Plants of acaulescent group had an advantage over caulescent group in removing chlorpyrifos. Phytoaccumulation of chlorpyrifos was observed, and the order of chlorpyrifos concentration in different plant tissues was root > stem > leaf. It was also found that chlorpyrifos and its metabolite TCP decreased rapidly at the initial step of the experiment. PMID- 23819297 TI - Irrigation of three wetland species and a hyperaccumlating fern with arsenic laden solutions: observations of growth, arsenic uptake, nutrient status, and chlorophyll content. AB - Engineered wetlands can be an integral part of a treatment strategy for remediating arsenic-contaminated wastewater, wherein, As is removed by adsorption to soil particles, chemical transformation, precipitation, or accumulation by plants. The remediation process could be optimized by choosing plant species that take up As throughout the seasonal growing period. This report details experiments that utilize wetland plant species native to Ohio (Carex stricta, Pycnanthemum virginianum, and Spartina pectinata) that exhibit seasonally related maximal growth rates, plus one hyperaccumulating fern (Pteris vittata) that was used to compare arsenic tolerance. All plants were irrigated with control or As laden nutrient solutions (either 0, 1.5, or 25 mg As L(-1)) for 52 d. Biomass, nutrient content, and chlorophyll content were compared between plants treated and control plants (n = 5). At the higher concentration of arsenic (25 mg L(-1)), plant biomass, leaf area, and total chlorophyll were all lower than values in control plants. A tolerance index, based on total plant biomass at the end of the experiment, indicated C. stricta (0.99) and S. pectinata (0.84) were more tolerant than the other plant species when irrigated with 1.5 mg As L(-1). These plant species can be considered as candidates for engineered wetlands. PMID- 23819298 TI - Copper-resistant bacteria enhance plant growth and copper phytoextraction. AB - In this study, we investigated the role of rhizospheric bacteria in solubilizing soil copper (Cu) and promoting plant growth. The Cu-resistant bacterium DGS6 was isolated from a natural Cu-contaminated soil and was identified as Pseudomonas sp. DGS6. This isolate solubilized Cu in Cu-contaminated soil and stimulated root elongation of maize and sunflower. Maize was more sensitive to inoculation with DGS6 than was sunflower and exhibited greater root elongation. In pot experiment, inoculation with DGS6 increased the shoot dry weight of maize by 49% and sunflower by 34%, and increased the root dry weight of maize by 85% and sunflower by 45%. Although the concentrations of Cu in inoculated and non-inoculated seedlings did not differ significantly, the total accumulation of Cu in the plants increased after inoculation. DGS6 showed a high ability to solubilize P and produce iron-chelating siderophores, as well as significantly improved the accumulation of P and Fe in both maize and sunflower shoots. In addition, DGS6 produced indole-3-acetic acid (IAA) and ACC deaminase, which suggests that it may modulate ethylene levels in plants. The bacterial strain DGS6 could be a good candidate for re-vegetation of Cu-contaminated sites. Supplemental materials are available for this article. Go to the publisher's online edition of International Journal of Phytoremediation to view the supplemental file. PMID- 23819299 TI - Uptake of cadmium by hydroponically grown, mature Eucalyptus camaldulensis saplings and the effect of organic ligands. AB - The potential suitability of Eucalyptus camaldulensis for Cd phytoextraction was tested in a hydroponic study. Saplings were exposed to 4.5 and 89 microM Cd for one month, with and without EDTA and s,s-EDDS at 0.1, 1, and 5 mM. The saplings' growth was not affected at the 4.5 microM Cd concentration, yet it decreased 3 fold at 89 microM, and almost all the Cd taken up was immobilized in the roots, reaching 360 and 5300 mg Cd kg(-1), respectively (approximately 75% of which was non-washable in acid). The respective Cd root-to-shoot translocation factors were 0.14 and approximately 5*10(-4). At 0.1 mM concentration, EDTA and EDDS had no effect or even a positive effect on the saplings growth. This was reversed at 1 mM, and the chelants became lethal at the 5 mM concentration. At 89 microM Cd in the growth medium, 0.1 mM EDTA increased Cd translocation into the shoots by almost 10-fold, however it strongly reduced Cd content inside the roots. This hydroponic study indicates the feasibility of E. camaldulensis use for cleanup Cd contaminated soils at environmental concentrations, both for site stabilization (phytostabilization) and gradual remediation (phytoextraction). EDTA was shown to be much more efficient in enhancing Cd translocation than s,s-EDDS. PMID- 23819301 TI - Synthesis and antifungal activities of 2-(N-arylsulfonylindol-3-yl)-3-aryl-1,3 thiazinan-4-ones. AB - A series of 2-(N-arylsulfonylindol-3-yl)-3-aryl-1,3-thiazinan-4-one derivatives were synthesized and evaluated in vitro against seven phytopathogenic fungi, namely Fusarium graminearum, Alternaria solani, Fusarium oxysporium f. sp. vasinfectum, Alternaria brassicae, Valsa mali, Alternaria alternata, and Pyricularia oryzae. Among all derivatives, especially compound 4j exhibited a potential antifungal activity against four phytopathogenic fungi. PMID- 23819300 TI - Long-term biomonitoring of soil contamination using poplar trees: accumulation of trace elements in leaves and fruits. AB - Phytostabilization aims to immobilize soil contaminants using higher plants. The accumulation of trace elements in Populus alba leaves was monitored for 12 years after a mine spill. Concentrations of As and Pb significantly decreased, while concentrations of Cd and Zn did not significantly over time. Soil concentrations extracted by CaCl2 were measured by ICP-OES and results of As and Pb were below the detection limit. Long-term biomonitoring of soil contamination using poplar leaves was proven to be better suited for the study of trace elements. Plants suitable for phytostabilization must also be able to survive and reproduce in contaminated soils. Concentrations of trace elements were also measured in P. alba fruiting catkins to determine the effect on its reproduction potential. Cadmium and Zn were found to accumulate in fruiting catkins, with the transfer coefficient for Cd significantly greater than Zn. It is possible for trace elements to translocate to seed, which presents a concern for seed germination, establishment and colonization. We conclude that white poplar is a suitable tree for long-term monitoring of soil contaminated with Cd and Zn, and for phytostabilization in riparian habitats, although some caution should be taken with the possible effects on the food web. Supplemental materials are available for this article. Go to the publisher's online edition of International Journal of Phytoremediation to view the supplemental file. PMID- 23819302 TI - Chemical constituents from the leaves of Aglaia odorata. AB - A new dammarane triterpene, 3-acetoxy aglinin C (1), and a new aglain, 10-oxo aglaxiflorin D (2), along with five known compounds, 3-7, were isolated from the leaves of Aglaia odorata using chromatographic methods. The structures of 1 and 2 were determined on the basis of spectroscopic analyses. Bioactivities of 1-7 against AGZY 83-a (human lung cancer cell line) and SMMC-7721 (human liver cancer cell line) cells were determined. PMID- 23819303 TI - Flavonoids from Pseudotsuga menziesii. AB - Four O-acylated flavonol glycosides, new in the plant kingdom, were isolated from the needles of Pseudotsuga menziesii. Their structures were established by 1D and 2D NMR and MS data as: daglesioside I [kaempferol 3-O-[2",5"-O-(4''',4(IV) dihydroxy)-beta-truxinoyl]-alpha-L-arabinofuranoside] (1), daglesioside II [kaempferol 3-O-[2",5"-O-(4"'-hydroxy)-beta-truxinoyl]-alpha-L-arabinofuranoside] (2), daglesioside III [kaempferol 3-O-[2",5"-di-O-(E)-p-coumaroyl]-alpha-L arabinofuranoside] (3), and daglesioside IV [kaempferol 3-O-[3",6"-di-O-(E) cinnamoyl]-beta-D-glucopyranoside] (4). In addition, the known flavonoids (E) tiliroside, (E)-ditiliroside, astragalin (kaempferol 3-O-beta-D-glucopyranoside), isorhamnetin, kaempferol, and quercetin were identified. The cytotoxic activity of compounds 1 and 3 was evaluated towards the HL-60, HeLa, and MDA-MB468 cell lines. PMID- 23819304 TI - Gastroprotective effect of an ethanolic extract from Neoglaziovia variegata (Arruda) Mez (Bromeliaceae) in rats and mice. AB - This study investigates the gastroprotective effect of a crude ethanolic extract of Neoglaziovia variegata (Arruda) Mez (Bromeliaceae), designated Nv-EtOH, in experimental models of gastric ulcer. In the ethanol-induced gastric ulcer model, Nv-EtOH showed gastroprotection at doses of 200 and 400 mg/kg body weight (BW) (57.0% and 79.7%, respectively). Nv-EtOH also significantly reduced the formation of gastric lesions induced by ethanol/HCl (31.6% and 63.5%), ibuprofen (70.0% and 74.3%), or ischemia/reperfusion in rats (65.0% and 87.0%) at 200 and 400 mg/kg BW when compared with the vehicle group. In the antioxidant activity assessment, Nv EtOH (400 mg/kg BW) increased the catalase activity and sulfhydryl groups (SH) levels, respectively. Moreover, gastroprotection against ethanol damage was decreased after ibuprofen pretreatment. Nv-EtOH (400 mg/kg BW) promoted a significant increase in the content of gastric wall mucus. The Nv-EtOH effect was significantly reduced in mice pretreated with N(G)-nitro-L-arginine (L-NOARG) or glibenclamide, inhibitors of nitric oxide synthase and K(ATP) channel activation, respectively, suggesting the involvement of these mechanisms in the Nv-EtOH induced gastroprotective effect. Nv-EtOH decreased the total acidity, but did not modify other gastric juice parameters. Nv-EtOH was also effective in promoting the healing process in chronic gastric ulcer induced by acetic acid in rats. PMID- 23819305 TI - Cytotoxic activity and apoptosis induction by gaillardin. AB - Cytotoxic activity of gaillardin, a sesquiterpene lactone isolated from Inula oculus-christi L. (Asteraceae), was assessed in the human breast adenocarcinoma cell line MCF-7, human hepatocellular carcinoma cell line HepG-2, human non-small cell lung carcinoma cell line A-549, and human colon adenocarcinoma cell line HT 29, resulting in IC50 values of 6.37, 6.20, 4.76, and 1.81 microg/mL, respectively, in the microculture tetrazolium-formazan MTT assay. In vitro apoptosis-inducing properties of gaillardin were also evaluated in MCF-7 cells with the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay. The results suggest gaillardin as a candidate for further studies in cancer therapy PMID- 23819306 TI - Calcium sensitizers isolated from the edible pine mushroom, Tricholoma matsutake (S. Ito & Imai) Sing. AB - Three lactam compounds were isolated from the fruiting body of Tricholoma matsutake (S. Ito & Imai) Sing., an edible mushroom, and their structures were identified as cyclo-S-proline-R-leucine (1), hexahydro-2H-azepin-2-one (2), and butyl 5-oxo-2-pyrrolidine carboxylate (3) by chemical, physicochemical, and spectral evidence. In in vitro screening tests, compounds 1 and 2 acted as calcium sensitizers in ventricular cells from rat. Further studies on compounds 1 and 2 in ex vivo isolated right atria showed positive inotropic effects without disturbing the spontaneous beating rate. The inotropic effect of compounds 1 and 2 could be greatly abolished by pretreating the myocardium in Ca(2+)-free solution. These findings indicate that compounds 1 and 2 can significantly increase the calcium ion concentration ([Ca2+]i) in myocytes, which is greatly dependent on the influx of extracellular Ca2+. PMID- 23819307 TI - GC-MS investigation and acetylcholinesterase inhibitory activity of Galanthus rizehensis. AB - GC-MS (gas chromatography-mass spectrometry) analyses of alkaloids in the aerial parts and bulbs of Galanthus rizehensis Stern (Amaryllidaceae), collected during two different vegetation periods, was performed. Twenty three alkaloids were identified in four different alkaloid extracts. Acetylcholinesterase (AChE) inhibitory activities of the alkaloid extracts were tested. Both the highest alkaloid diversity and the most potent inhibitory activity (IC50 12.94 microg/ml) were obtained in extracts from the bulbs of G. rizehensis collected during the fruiting period. PMID- 23819308 TI - Anticholinesterase activity of phenolic acids and their derivatives. AB - The ability of 36 phenolic acids and their derivatives to inhibit acetyl- and butyrylcholinesterase was studied. The most efficient acetylcholine inhibitors were: carnosic acid = gentisic acid > 3-hydroxy-4-methoxycinnamic acid = ethyl ferulate = ethyl vanillate = nordihydroguaiaretic acid > ethyl 4-hydroxybenzoate = methyl ferulate. The order of effectiveness towards butyrylcholinesterase was: carnosic acid > nordihydroguaiaretic acid = ethyl ferulate > salicylic acid > gentisic acid > rosmarinic acid = caftaric acid > homogentisic acid. The inhibitory activity was dependent on the number/position of OH or/and OCH3 groups attached to a phenol ring. It can be speculated that OCH3 substitution in the phenol ring can promote a higher antibutyrylcholinesterase activity (although not statistically confirmed at p < 0.05). The presence of a CH=CH-COOH group had a highly favourable effect on the antiacetylcholinesterase activity compared with a CH2-CH2-COOH or a COOH group. Methyl and ethyl esters were more potent inhibitors than the corresponding free acids. The molecular weight of the compounds (in the range of M = 154.12 - 474 g/mol) played a minor role in this context. PMID- 23819309 TI - New method for the determination of the half inhibition concentration (IC50) of cholinesterase inhibitors. AB - A new and simple analytical method is described for the determination of the IC50 values of the inhibitors of the hydrolysis of acetylcholine (ACh) or acetylthiocholine (ATCh) by cholinesterases. The method is based on monitoring the time course of the pH value during the uninhibited and inhibited reaction. It requires only a pH meter with a suitable pH measuring cell and a small thermostated stirred batch reactor. The method has been validated for twelve different types of cholinesterase inhibitors. The determined IC50 values are comparable to those obtained by independent, more complicated, and expensive methods (Ellman's and pH-stat). PMID- 23819310 TI - UV-B exposure of indoor-grown Picea abies seedlings causes an epigenetic effect and selective emission of terpenes. AB - Terpenoids are involved in various defensive functions in plants, especially conifers. Epigenetic mechanisms, for example DNA methylation, can influence plant defence systems. The purpose of the present study was to investigate the influence of UV-B exposure on the release of terpenoids from spruce seedlings and on needle DNA methylation. Ten-week-old seedlings grown indoors were exposed to UV-B radiation during 4 h, and the volatile compounds emitted from the seedlings were analysed. Analysis of the volatiles 1, 3, and 22 d after this UV-B exposure showed that bornyl acetate, borneol, myrcene, and limonene contents increased during the first 3 days, while at day 22 the level of emission had returned to the control level. UV-B exposure decreased the level of DNA methylation in needles of young seedlings, reflected in methylation changes in CCGG sequences. Exposure of young seedlings to UV-B radiation might be a way to potentiate the general defensive capacity, improving their ability to survive in outdoor conditions. UV-B-induced defence is discussed in the light of epigenetic mechanisms. PMID- 23819311 TI - Diverse responses are involved in the defence of Arabidopsis thaliana against Turnip crinkle virus. AB - Plant hormones play pivotal roles as signals of plant-pathogen interactions. Here, we report that exogenous application of salicylic acid (SA), jasmonic acid (JA), ethephon (ETH), and abscisic acid (ABA) can reduce Turnip crinkle virus (TCV) accumulation in systemic leaves of Arabidopsis thaliana during early infection. SA and ABA are more efficient and confer a longer-lasting resistance against TCV than JA and ETH, and the plant hormones interact in effecting the plant defence. Synergistic actions of SA and JA, and SA and ET, and an antagonistic action of SA and ABA have been observed in the Arabidopsis-TCV interaction. ABA can down-regulate the expression of the pathogenesis-related genes PR1 and PDF1.2, and compared to the wild type, it drastically reduces TCV accumulation in NahG transgenic plants and the eds5-p1 mutant, both of which do not accumulate SA. This indicates that SA signaling negatively regulates the ABA mediated defence. ABA-induced resistance against TCV is independent of SA. We also found that mitogen-activated protein kinase 5 (MPK5) may be involved in ABA mediated defence. These results indicate that Arabidopsis can activate distinct signals to inhibit virus accumulation. Cooperative or antagonistic crosstalk between them is pivotal for establishing disease resistance. These results show potential to enhance the plant defence against viruses by manipulating diverse hormones. PMID- 23819312 TI - Postnatal development of spinal cord and liver antioxidant status in the young of retinol-overdosed female rats. AB - The metabolic form of vitamin A, retinol, has a pivotal role in the nervous system development and neuronal differentiation, both during embryogenesis through maternal-fetal support and in the early postnatal life. Retinoic acid was administered orally at a dose of 10 mg/kg body weight to pregnant female rats through days 8-10 of gestation. Spinal cord sections were processed for histochemical visualization one day after birth and on day 21, when weaning is expected. NADPH-diaphorase (NADPH-d)-positive neurons were found in the dorsal horn, around the central canal, and at the intermediolateral cell column on postnatal days 1 and 21 in both control and experimental groups. There were no NADPHd-positive structures in the ventral horn. The results suggest that prenatal administration of high doses of retinoic acid is not associated with postnatal morphological changes in NADPH-d-positive neurons in the rat spinal cord. Levels of antioxidants and related enzymes in retinoid storage organs were measured to estimate possible side effects. The activities of enzymes detoxifying superoxide radicals and peroxides were supressed after birth. A decrease in the level of reduced glutathione was observed on postnatal day 21, indicating an unbalanced redox environment. PMID- 23819313 TI - Skin secretion and shedding is a good source for non-destructive genetic sampling in the Chinese giant salamander (Andrias davidianus). AB - A non-destructive method of collecting samples for DNA analysis of the Chinese giant salamander is described and validated. DNA was extracted from the skin secretion and shedding using a Chelex-based method, and partial 12S rRNA gene sequences were amplified and sequenced. Sequences from skin secretion and shedding were cross-checked against the reported sequences from liver and were found to be identical. This method provides a non-destructive way of carrying out larger studies of the genetics of rare amphibians and may be of general use for genetic-based field studies of amphibians. PMID- 23819314 TI - [Clustering analysis of Mycobacterium tuberculosis using the JATA(12)-VNTR system for molecular epidemiological surveillance in broad areas of Japan]. AB - OBJECTIVES: Japan Anti-Tuberculosis Association (JATA) (12)-variable numbers of tandem repeats (VNTR) is a standard method for genotyping of clinical isolates of Mycobacterium tuberculosis in Japan. As a model study for nationwide surveillance, this study aimed to describe the tendency and frequency of genotypes of M. tuberculosis in a large number of clinical samples. METHODS: Clinical isolates of M. tuberculosis (n = 1,778) were obtained from patients with tuberculosis in 3 areas, i.e., Osaka City, Osaka Prefecture, and Kobe City, during 2007 and 2008. The samples were analyzed using JATA (12)-VNTR. All genotypes were subjected to clustering analysis. RESULTS AND DISCUSSION: In total, 1,086 (61.1%) isolates showed clustering. The most common clusters were composed of 3 members. Such clusters were considered to reflect either actual transmission or low discriminatory power of JATA (12)-VNTR. Several prevalent JATA(12)-VNTR genotypes formed large clusters and were discussed in relation with epidemiological findings of other studies. The findings of this study will aid in the construction of an effective genotyping-based surveillance system of M. tuberculosis, through improvement of interpretation of VNTR types, observation of certain particular strains in an area, and efficient detection of unidentified outbreaks. PMID- 23819315 TI - [Evaluation of JATA(12)-variable number of tandem repeats as a marker of the source of tuberculosis outbreaks in Osaka]. AB - OBJECTIVES: To evaluate the usefulness of the JATA (12)-variable number of tandem repeats (VNTR) system for identifying the source of Mycobacterium tuberculosis outbreaks. DESIGN; JATA(12)-VNTR genotyping was performed on M. tuberculosis isolates from a total of 206 patients in whom group infection was confirmed by epidemiological studies ("group infection"), as well as from 64 patient clusters in whom group infection was suspected but not confirmed ("non-group infection"). The patients were diagnosed in Osaka Prefecture from April 1999 to December 2011. RESULTS: All isolates from the "non-group infection" patients showed a unique VNTR pattern, whereas isolates from 185 (89.9%) "group infection" patients showed a common and group-specific JATA (12)-VNTR pattern. However, single-locus variants were observed in 1 (1.6%) "non-group infection" case and in 21 (10.2%) "group infection" cases. CONCLUSION: Tuberculosis in 248 (91.9%) of the 270 study patients could be correctly identified based on the genotyping of the isolates by using the JATA (12)-VNTR. If proper attention is paid to the single-locus variant, the JATA (12)-VNTR system would be a useful tool for identification of sources of tuberculosis outbreaks. PMID- 23819316 TI - [Estimating the prevalence of tuberculosis infection among healthcare workers in our hospital by repeat QFT-G testing]. AB - OBJECTIVE: The QuantiFERON-TB (QFT) blood test is the major tool for the diagnosis of Mycobacterium tuberculosis (TB) infection among healthcare workers (HCWs). We used QFT tests to estimate the prevalence of TB infection among HCWs in our hospital. MATERIAL AND METHODS: Between 2003 and 2010, a total of 733 HCWs were enrolled in this study, and the prevalence of TB infection was analyzed according to the HCWs' jobs and work place. RESULTS: Among the 152 men and 581 women who were evaluated, 3 female HCWs had a history of TB. Fifty-eight HCWs (8 men and 50 women with a mean age of 56.3 years and 48.4 years, respectively) demonstrated positive QFT tests. The positive rate was 7.9% for all staff members throughout the study period. The QFT test was positive for 1 HCW who was treated for TB in 1998, and negative and inconclusive for 2 other HCWs treated for TB in 2002. The positive rate for QFT was 16.0% in the TB ward (12/75, 95% confidence interval [CI]: 7.7-24.3%), 9.9% in the other wards (22/222, 95% CI: 7.9-11.9), and 1.1% in the outpatient department (1/91, 95% CI: 0-2.2). According to the job category, the QFT positive rates were as follows: doctors, 4.3% (3/70, 95% CI: 1.9-6.7); nurses, 10.3 (4/35, 95% CI: 6.0-16.8). The positive rate among doctors working in the TB ward was 10.0%, and that for nurses was 24.3%. This indicates that the prevalence of infection among HCWs in the TB ward was significantly higher than that in other work places. A comparison of the results from 2003 through 2007 revealed that for a total of 307 workers, 90.6% and 5.2% remained negative and positive, respectively, while 1.6% converted from negative to positive, and 2.6% from positive to negative. CONCLUSION: The positive rate among HCWs in the TB ward was higher than that in other wards. This is especially remarkable for doctors and nurses working in the TB ward. PMID- 23819317 TI - [Contact investigation using QuantiFERON-TB Gold test to evaluate TB exposure in 61 subjects in a hospital setting--(2) Change in QuantiFERON response during one year after exposure]. AB - OBJECTIVES & SUBJECTS: The change in IGRA (interferon-gamma release assay, with QuantiFERON-TB Gold, QFT) responses was followed up for one year in a group of contacts of healthcare workers who had been exposed to tuberculosis (TB) infection for a relatively short period in a hospital. The observation was made of a total of 59 close contacts of the index case, where 16 showed positive QFT conversion and 7 showed the intermediate response ranging 0.1 to 0.35 IU/mL. Three of the conversion cases developed active TB. RESULTS: 67% of the QFT conversions occurred within 2 months of exposure and the others between 2 to 9 months. Those having converted later than 2 months after the exposure showed generally weaker QFT responses than the earlier converters. In response to the treatment to converters (either to latent TB infection or to active TB), 80% of the cases reversed to negative or intermediate. The geometric means of the response values for ESAT-6 and CFP-10 also showed significant decline over the treatment time. DISCUSSIONS: The time profile of responses in the intermediate responders revealed an obviously distinct pattern from that of the negative responders with the values remaining uniformly at very low level throughout, which suggests that this group includes somehow exceptional responders either with or without infection. PMID- 23819318 TI - [Impact of introducing rifampicin for the treatment of tuberculosis during the 1970's in Japan]. AB - SETTING: The average duration of tuberculosis chemotherapy in Japan increased year by year throughout the 1960's and reached 49 months by 1973. It then began decreasing slowly in the 1970's and more rapidly after the 1980's. PURPOSE: To clarify the significant factors contributing to the prefectural variation of changes in the average duration of chemotherapy that occurred from 1973 to 1979. METHOD: Multiple regression analysis was conducted with the slopes of the average duration of chemotherapy of tuberculosis in prefectures throughout Japan from 1973 through 1979 as the dependent variable and with parameters related to treatment and patient characteristics of the prefectures as independent variables. RESULTS: The variables, including uses of rifampicin, proportion of bacteriologically confirmed patients among newly registered cases, and average duration of chemotherapy as of 1973, contributed significantly to the slope of change in chemotherapy duration of the prefectures; the duration decreased faster in prefectures where there were more bacteriologically confirmed patients, and where the duration had been shorter at the beginning of the study period. DISCUSSION: Short-course chemotherapy had not been established in the study period, but confidence in the potency of antibacterial activity of the new drug seems to have facilitated the departure from unnecessarily long treatment. The recognition of the importance of bacteriology in the clinical practice of tuberculosis worked in the same way against dependence on X-ray findings causing long-term treatment. Also, the prefectures that had been less affected by the long-term treatment could depart faster from it. PMID- 23819319 TI - [Case of tuberculous pleurisy distinguished from pleurisy caused by Mycoplasma infection]. AB - We report a case of tuberculous pleurisy that required differentiation from pleurisy caused by Mycoplasma infection. A 28-year-old woman presented to a clinic with fever and pain on the left side of her chest. A chest radiograph revealed pleural effusion in the left thorax, and the condition was diagnosed as bacterial pleurisy. The patient was referred to our hospital because of an increase in the pleural effusion despite antibiotic treatment. Mycoplasma infection was suspected because the patient was young, the white blood cell count was not elevated, and the result of the ImmunoCard Mycoplasma test (IC) for Mycoplasma pneumoniae-specific IgM antibodies was positive. However, the fever persisted even after treatment with azithromycin and pazufloxacin. The left pleural effusion was exudative, with lymphocytosis and high adenosine deaminase (ADA) levels. The results of the QuantiFERON test were positive. Therefore, tuberculous pleurisy was diagnosed, and the effusion subsided after treatment with standard anti-tuberculosis chemotherapy. Although detection of Mycoplasma infection using the IC is rapid and simple, the accuracy of this test is poor. The patient was first diagnosed with pleurisy of Mycoplasma origin because of a single high-particle agglutination titer of 1: 320 and because of the presence of exudative pleural effusion with lymphocytosis and elevated ADA levels, which has been reported in patients with Mycoplasma infection. The results of the IC test and the ADA level of the pleural effusion might not be reliable when distinguishing between tuberculous pleurisy and pleurisy caused by Mycoplasma infection. PMID- 23819320 TI - [On-the-street DOTS for a homeless tuberculosis patient--case report of a patient who had difficulties with TB treatment adherence]. AB - PURPOSE: A homeless patient with tuberculosis (TB), who had often quit his TB treatment in mid-course and then gone homeless again, succeeded in completing his treatment for over 10 months through on-the-street DOTS ("Bluesky DOTS" is another expression). Based on the analysis of this case, we have discussed how to provide effective countermeasures to non-compliant TB patients. METHOD: An episode of a successful on-the-street DOTS for a 70-year-old homeless man with sputum smear positive pulmonary TB was qualitatively analyzed, with a view toward patient's empowerment. RESULT: The patient had had human-relations problems in his life, and trouble with medical and welfare service staff. During his hospital admissions, he repeatedly self-discharged or was forced to discharge due to violent behavior against staff. Public health nurses at Shinjuku public health center visited the patient frequently at the hospital, and tried to build a good relationship with the patient from the beginning of the treatment. Following a two and half month interruption of the TB treatment after he disappeared from the hospital, he was discovered staying outside at a canal side in the area, and on the-street TB treatment was carried out, with good cooperation with the hospital and social welfare office. Directly observed TB medication was given to him by a public health nurse and another health center staff member for 293 days, at the park near his living place. The patient often rejected the medication, particularly when he was hungry, but offering lunch to him was a very effective incentive. Through comprehensive supports to the patient, he gradually changed his attitude, and on his own came to consider his health and his future. DISCUSSION: We have analyzed a successfully treated case of a homeless TB patient who had difficulties in maintaining a social life and had not been cooperative in complying with the medication. The level of independence improved during the course of on-the-street DOTS with incentive and other supports. He became receptive to TB treatment and became self-supportive during the course of DOTS, with food as an incentive. This indicates that on-the-street DOTS was successful not only for the treatment completion but also contributed to empowering the TB patient. This approach of adjusting the service to the patient's needs fostered a positive relationship with all stakeholders. PMID- 23819321 TI - [Tuberculosis annual report 2010--(9) Treatment of tuberculosis-2]. AB - The standard treatment for tuberculosis (TB) is the key to its control. Here we report statistics relating to treatment status and the duration of hospitalization and treatment in Japan. Among the newly noted TB patients in 2010, sputum-smear positive pulmonary TB patients were the most likely to receive hospital treatment (91.4%); 2.5% of these patients were primarily hospitalized for other diseases. The median duration of hospitalization in newly notified TB cases in 2009 was 73 days for new sputum-smear positive pulmonary TB cases, 75 days for sputum-smear positive pulmonary TB cases undergoing further treatment, 42 days for other bacillary positive pulmonary TB cases, 40.5 days for bacillary negative pulmonary TB cases, and 44 days for extra-pulmonary TB cases. The duration of TB treatment among newly notified cases in 2009 was assessed at the end of 2010. The median treatment duration for all forms of TB was 270 days. The longest median treatment duration was 285 days for retreatment of sputum-smear positive pulmonary TB cases, and the shortest duration was 196 days for bacillary negative pulmonary TB cases. PMID- 23819322 TI - [Results of the Federal (National) Project for prevention and treatment essential hypertension patients in Russia from 2002-2012 years]. AB - The analysis of measures efficiency for prevention by essential hypertension (EH) in Russian Federation within the space of 2002-2012 years was realized. Those measures were carrying out Federal (National) Project and primary activity of the medical and scientific institutions under the leadership Russian Cardiology Research and Production Complex. The basic result was decrease in cardiovascular disease death rate starting with 2004 year The most pronounced significant changes were found in death rate from the cerebrovascular diseases. From 2003 to 2012, the annual cerebrovascular disease death rate decreased in 1,5 times (in 2003 - 339,9 by 100 thousands, to compare with 2012 - 224,1 by 100 thousands). Moreover, in 2012 thefatal stroke death rate was decreased on 114,8 thousands (to compare with 2004). Decrease of cardiovascular disease death rate is achieved from: early revealing of essential hypertension pts; development and introduction in practical public health of new methods of prevention ("Schools of Health"), adequate diagnostic and treatment of essential hypertension patients; increase of an educational level by cardiology in polyclinics, also use by the government of special purposes for Cardiovascular disease death rate decrease. PMID- 23819323 TI - [Quantitative estimation of the health status dynamics of persons occupationally exposed to mercury vapor: a remote period of intoxication]. AB - The article presents the results of the dynamic clinical observation for persons suffered from occupational chronic mercury intoxication in the remote post exposure period of the disease. The estimation of the dynamics of syndrome manifestations of chronic mercury intoxication and co-morbidity are presented. The important role of mercury exposure load as a predictor of deterioration of actual health of the patients in the remote period of intoxication is demonstrated. PMID- 23819324 TI - [Effect of nanodispersed manganese oxide (III, IV) on morphological properties of various tissues and body systems]. AB - The study of morphological features of tissue organs of experimental animals after a single intragastric administration of an aqueous suspension nanodis dispersed manganese (III, IV) at doses of 2000, 3500 and 5000 mg/kg showed complex of morphological changes in the form of circulatory disorders up to hemostasis and bleeding which lead to changes in the structure of organs, enhanced apoptosis, activation of macrophage system by proliferation and macrophage phagocytosis of degradation products of cells, hypertrophy of lymphoid tissue of immune system; development of histiocytic infiltrates in parenchymal organs and central nervous system. With the introduction of microsized analogues in the same doses of the morphological changes in the circulatory system, macrophage system and immune organsfound predominantly in a dose of 5000 mg/kg. Changes were less significant and were presented as activation of macrophages in the liver in the form of activation of Kupffer cells, proliferation of lymphoid tissue in the spleen, lymph histiocytic infiltrates in the liver, kidney, medium size. PMID- 23819325 TI - [Prevention of cardiovascular complications in patients undergoing aortic-iliac reconstructions by correction of inflammation and endotoxemia]. AB - There were presented the results of examination and treatment of 130 patients with atherosclerosis. Objective is to study the role of atorvastatin in correction of inflammation, endotoxemia and prevention of cardiovascular complications in patients with atherosclerosis undergoing aorto-iliac reconstruction. There were observed initial and postoperative activation of inflammation, endotoxemia in patients with multifocal atherosclerosis. We found that short-term therapy with atorvastatin 60 mg per day had a significant advantage over low-dose in correction of pre- and postoperative endogenous inflammation, endotoxemia and prevention of cardiac events after aorto-iliac reconstruction. PMID- 23819326 TI - [Hormonal-metabolic pattern of postmenopausal females with new onset of diabetes mellitus type 2: the role of cancer and hereditary predisposition to diabetes]. AB - 85 females were studied, 35 females had new onset of diabetes (DM2) and in 50 women DM2 was associated with recently diagnosed cancer (C+DM2). Group C+DM2 was characterized by higher levels ofbody mass index, insulinemia, estradiolemia, interleukin 6 in serum, and glyoxalase I activity in mononuclears. At the same time patients in C+DM2 group who had familial predisposition to DM2 were characterized by lower body mass index, body fat content, waist circumference, insulinemia, serum interleukin 6, viscosity of erythrocyte membranes and percent of comets in mononuclears in comparison with patients without familial predisposition to DM2. These trends were mostly opposite to the data of subgroups comparison (with or without relatives with DM2) in females with DM2 without cancer. The conclusion is made that the hereditary load with DM2 is differently realized in diabetics with higher or lower predisprosition to cancer that deserves further study. PMID- 23819327 TI - [Role of circulating angiogenic factors in diabetic kidney disease]. AB - This original article contains the authors own data on homeostasis of angiogenic growth factors (vascular endothelial growth factor - VEGF, angiopoietin 1 and 2 - Ang-1, Ang-2) in diabetic kidney disease. The aims of study were evaluation of alteration on serum concentration of circulating VEGF, Ang-l and Ang-2, and of their association with markers of renal damage (albuminuria, glomerular filtration rate) and anemia in patients with diabetes mellitus. We studied 78 patients type I diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Among this group 37patients had chronic kidney disease. The serum level of VEGF was elevated in T1DM patients and was associated with degree of proteinuria. The serum concentration of Ang-2 was higher in patients with chronic kidney disease (T1DM and T2DM), renal failure (T1DM), proteinuria and anemia (T2DM). Ang-2 strongly associated with albuminuria (T1DM and T2DM), glomerular filtration rate (T1DM) and hemoglobin (T2DM). Obtained results demonstrate that levels of VEGF and Ang-2 (but not Ang-1) are raised in patients with diabetic kidney disease and associated with markers of renal damage and anemia. These data indicate the presence of the disturbance of angiogenic growth factors (VEGF, Ang-2) homeostasis and activity in diabetic patients with chronic kidney disease. PMID- 23819328 TI - [Fundamental bases of search of medicines for therapy of a diabetes mellitus type 2]. AB - In the presented review the data on searching for new drugs for diabetes mellitus treantment are analyzed. These drugs are used for metabolic disorder correction leading to hyperglycemia: beta-cells dysfunction, peripheral insulin resistance, increased hepatic glucose output. PMID- 23819329 TI - [Intraorganic and intratissue mechanisms of protective action of activated Kupffer cells on hepatocytes]. AB - Endotoxine activated Kupfer cells release into the intercellular space several mediators which act directly on hepatocytes as well as via stellet cells. In both cases Kupfer cells downregulate hepatocytes as a part of paracrine system. However, downregulated part of liver parenchyma might be extended by several mechanisms. The first one is release of vasoconstrictors from activated Kupfer cells which stimulate stellet cells contraction. This effect may also be achieved by formation of hypermetabolicfocuses by Kupffer cells mediators with further activation of hepatocyte-hepatocyte interactions based on the principle of cell competition for oxygen in the intercellular space. Regulatory influence of activated Kupfer cells may be spread in liver parenchyma with participation of the mechanism of intratissue hepatocyte-hepatocyte interactions which also realize tissue stress reaction. PMID- 23819330 TI - [Autochthonous probiotics in prevention of infectious and inflammatory diseases of a human in the altered habitats]. AB - Dysbiotic shifts in intestinal and pharyngeal microflora were studied in 22 normal volunteers in 9-, 14-, 105- and 520-d chamber experiments simulating some of the spaceflight factors. Two preparations were administered to prevent pharyngeal and intestinal dysbiosis: oral dry probiotic based on indigenous intestinal Enterococci and topical collagen-immobilized Lactobacterin based on indigenous intestinal Lactobacilli. Topical autopmrobiotic lactobacterin reduced the growth of opportunistic pathogens in the throat during the experiments. Oral autoprobiotic based on Enterococci reduced the content of intestinal opportunistic pathogens, supporting the high level of protecting microflora. Most of autostrains are free from pathogenicity factors, nevertheless, implementation of genetic testing of indigenous strains are reasonable. PMID- 23819331 TI - [Carcinogenicity of acrylonitrile and evaluation of approaches to pathogenetic correction of acrylate toxicity and antitumorigenic anthracycline doxorubicin toxicity during chemotherapy]. AB - Statistical analysis within the 20-year period showed that approximately 49% of workers who were exposed to widespread industrial poison acrylonitrile subsequently died from malignancy of different localization. The conducted experimental investigations demonstrated that acrylonitrile with the subacute intoxication of animals, the anti-tumor antibiotic doxorubicin, their combination, interwoven tumor and tumor developed against the background the introduction of acrylate and subsequent treatment doxorubicin led to onset of free-radical reactions. These reactions by themselves might stimulate development of malignancy. This fact confirms the need for antioxidant tracking of chemotherapy of tumors in the similar clinical cases. PMID- 23819332 TI - [Rheumatology in Russia in the early 21st century]. AB - Rheumatoid arthritis (RA) is the most common immune inflammatory rheumatic disease. The paper gives the current data of Russian investigations into the early diagnosis of RA and into innovative approaches to its therapy. PMID- 23819333 TI - [The magnitude of fatigue and its association with depression, pain, and inflammatory activity in rheumatoid arthritis]. AB - AIM: To analyze the rate of clinically significant fatigue and to search for its predictors in patients with rheumatoid arthritis (RA). SUBJECTS AND METHODS: The investigation included 95 patients with a valid RA diagnosis. The majority of the patients were women (87.4%); mean age was 46.7 +/- 1.2 years; mean disease duration was 135.5 +/- 11.6 months. The authors evaluated RA activity by the Disease Activity Score (DAS28), magnitude of fatigue by the Fatigue Severity Scale (FSS), that of pain by the Brief Pain Inventory, and functional status and quality of life by the Health Assessment Questionnaire and EQ-5D. A psychiatrist diagnosed mental disorders in accordance with ICD-10 and using the psychiatric and psychological scales and procedures. RESULTS: 80% of the patients felt clinically significant fatigue (FSS scores of > or = 4). Multivariate analysis yielded a prognostic model that made it possible to state that clinically significant fatigue was primarily associated with the magnitude of depression by the Hospital Anxiety and Depression Scale, the presence of a depressive episode, the duration of anxiety and depressive spectrum, the magnitude of pain (Ritchie index), DAS28, and the presence of osteoporosis. CONCLUSION: The presence and magnitude of depression along with the magnitude of pain are an important factor that influences the formation of fatigue in RA, which gives rise to evident functional failure and a low quality of life. Combination therapy for RA may be effective when mental disorders, mainly the anxiety and depressive spectrum, are timely diagnosed. PMID- 23819334 TI - [Genetic factors of angiogenic dysregulation in women with rheumatoid arthritis]. AB - AIM: To study genotype distribution in the MMP and VEGF genes, angiogenesis regulators, and their combinations with genotypes in other cytokines genes with proangiogenic activity in female patients with rheumatoid arthritis (RA) and healthy individuals. SUBJECTS AND METHODS: 509 Europeoid women from the eastern regions of Russia, including 374 healthy women aged 23-68 years and 135 female patients aged 27-66 years with RA, were examined. TNF-alpha gene promoter single nucleotide polymorphisms (SNP) -863 C --> A, TNFA -308 G --> A, TNFA -238 G --> A; IL 1beta-31 C --> T, IL4 -590 C --> T, IL6 -174 G --> C, IL10 -1082 G --> A and IL10 -592 A --> C; VEGF -2578 C --> A, VEGF +936 C --> T; MMP 2 -1306 C --> T, MMP 9 -1562 C --> T were investigated by the restriction analysis of amplification products. RESULTS: The patients with RA show a preponderance of the combinations of genotypes in vascular endothelial growth factor (VEGF) synthesis inducers, which are related to the high-level production of this factor, and those of genotypes in the degradation of the extracellular matrix of MMP2 and MMP9, which characterize the low baseline elaboration of matrix metalloproteinases (MMP) with a high capability for their induced synthesis, which is specific to the dysregulated states of the angiogenesis control system. Along with MMP and VEGF genotypes, the combinations most commonly contain IL1beta, IL4, IL10, IL6, and TNF-alpha genotypes. CONCLUSION: The study of the pathogenesis of RA must comprehensively investigate the role of the genes of the factors involved in the regulation of angiogenesis and inflammation, with particular emphasis on molecular genetic mechanisms for monitoring the baseline level of production of these regulatory factors. PMID- 23819335 TI - [Relationship of the clinical efficiency of tocilizumab therapy to the serum level of matrix metalloproteinase-3 in patients with rheumatoid arthritis]. AB - AIM: To evaluate the impact of tocilizumab (TCZ) therapy on the level of matrix metalloproteinase-3 (MMP-3) 4, 24, and 48 weeks after treatment initiation in relation to the clinical efficiency of TCZ therapy by the Disease Activity Score (DAS28), the Clinical Disease Activity Index (CDAI), and the Simplified Disease Activity Index (SDAI). SUBJECTS AND METHODS: Forty-two rheumatoid arthritis (RA) patients who had received 6 intravenous infusions of TCZ 8 mg/kg at a 4-week interval during permanent therapy with disease-modifying anti-rheumatic drugs (DMARD) and glucocorticosteroids (GCS) were examined. Then TCZ was discontinued and the patients continued to receive the previous therapy with DMARD and GCS. The European League Against Rheumatism (EULAR) classification criteria, as well as SDAI and CDAI were used to evaluate the efficiency of TCZ therapy. The serum concentration of MMP-3 was measured by enzyme immunoassay using the test systems (Invitrogen, USA). RESULTS: After 24 weeks of TCZ therapy (at 48 weeks following trial initiation), DAS28 was 4.69 (3.86; 5.44); the SDAI of 17.8 (10.7; 29.5) and the CDAI of 17.1 (7.2; 26.2) corresponded to moderate disease activity. At 48 weeks, DAS28 remission (< 2.6 scores) remained in 5 (11.90%) patients; SDAI (< or = 3.3 scores) and CDAI (< or = 2.8 scores) remissions did in 3 (7.1%) and 4 (9.5%) patients, respectively. There was a significant reduction in MMP-3 concentrations at 4, 24, and 48 weeks of the therapy, which was 61, 73, and 49.40% of the baseline level. ROC analysis indicated that the normalization of MMP-3 levels in RA patients at 24 weeks of TCZ therapy (a cut-off < or =16.5 ng/ml) was associated with the maintenance of remission/low disease activity from SDAI and CDAI 24 weeks after the drug use (the area under the receiver operating curve was 0.762; 95% confidence interval: 0.548-0.976). CONCLUSION: Analysis of the results of 48-week TCZ therapy suggests its ability to reduce the levels of markers of bone and cartilage destruction in patients with RA. Serum MMP-3 determination at 24 weeks of therapy may be useful in predicting the maintenance of remission/low activity from SDAI and CDAI after discontinuation of the drug. PMID- 23819336 TI - [Evaluation of the efficacy and tolerance of ibandronic acid in patients with osteoarthrosis in the knee joints concurrent with osteoporosis: a pilot study]. AB - AIM: To evaluate the efficacy and tolerance of ibandronic acid (bonviva) in patients with osteoporosis (OP) concurrent with osteoarthrosis (OA) in the knee joints (KJ). SUBJECTS AND METHODS: Twenty female outpatients aged 56 to 77 years with postmonopausal OP and primary KJ OA were examined. All the patients took bonviva in a dose of 150 mg monthly during a year. RESULTS: During the treatment, the patients showed a significant reduction in the values of all components of the Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) (pain intensity from 51.7 +/- 11.6 to 34.6 +/- 20.7 mm, stiffness from 96.0 +/- 55.6 to 78.5 +/- 46.6 mm, and functional failure from 783.6 +/- 333.2 to 657.8 +/- 360.9 mm according to a visual analogue scale), the Oswestry disability index, as well as in the concentration of markers for bone resorption and cartilage degradation. The need for nonsteroidal anti-inflammatory drugs was stated to decrease. CONCLUSION: Bonviva therapy results in a significant reduction in pain, KJ stiffness, and locomotor functional failure in patients with gonoarthrosis. PMID- 23819337 TI - [Severe adverse events from treatment with genetically engineered biological agents in patients with rheumatic diseases]. AB - AIM: To assess the risk of severe adverse events (AEs) within 6 months after treatment with biological agents in patients with rheumatic diseases (RD). SUBJECTS AND METHODS: The 6-month open-label trial included 107 patients with rheumatoid arthritis, antineutrophil cytoplasmic antibody-associated vasculitides, systemic lupus erythematosus, and other RDs who received genetically engineered biological agents (GEBAs), primarily rituximab (n = 66) and infliximab (n = 31). RESULTS: The majority of patients were noted to have improvements, including complete and partial remission in 62 (57.9%) and 42 (39.3%), respectively. There were mild or moderate AEs in 22 (20.6%) of the 107 patients, severe AEs in 6 (5.6%): grade IV neutropenia in 2 patients (after the use of rituximab), severe infusion reactions in 2 (after the administration of infliximab and rituximab), and systemic infections in 2 (fatal nocardial sepsis after rituximab treatment and unspecified sepsis after infliximab treatment). CONCLUSION: The rate of serious AEs, mainly infusion AEs and infections during treatment with infliximab, rituximab, and other GEBAs proved to be relatively low in patients with different RDs. At the same time, the use of biological agents could lower RD activity in the presence of severe visceral injuries refractory to conventional immunosuppressive therapy. PMID- 23819338 TI - [Osteoarthrosis in patients with type 2 diabetes mellitus]. AB - AIM: To estimate the frequency of a comorbidity of type 2 diabetes mellitus (DM) and osteoarthrosis (OA) in relation to patient age and to identify risk factors for degenerative and dystrophic changes in the joints. SUBJECTS AND METHODS: 160 patients with type 2 diabetes (23 men and 137 women at the age of 44 to 82 years; body mass index 33 +/- 5 kg/m2 were examined. A control group consisted of 112 age- and gender-matched subjects without type 2 DM. RESULTS: Degenerative and dystrophic changes in the joints were found in 60% of the patients with type 2 DM, which exceeded the similar values in the control subjects (42.9%; p < 0.05). Moreover, OA developed earlier in the patients with DM than in the general population, but the difference became leveled after the age 60 years. The development of OA was found to be associated with lipid metabolic disturbances: the incidence of obesity, hypercholesterolemia, and triglyceridemia was higher in the group of type 2 DM patients with OA (p < 0.05). CONCLUSION: The patients with type 2 DM showed the higher incidence of OA, the age of disease manifestation is less than in the general population. DM and overweight are risk factors for OA. PMID- 23819339 TI - [Behcet's disease: clinical and demographic associations]. AB - AIM: To comparatively study the clinical manifestations, sexual and HLA-B51 associations in patients with Behcet's disease (BD) in two ethnic groups. SUBJECTS AND METHODS: The authors examined 143 patients with the valid diagnosis of BED who were divided into 2 groups: 1) 85 patients, the dwellers of Dagestan (a multiethnic cohort), 63 men and 22 women (mean age 29 +/- 7.4 years); 2) 58 Russian men and women (mean age 33 +/- 11.7 years). RESULTS: Two major criteria for BD, such as aphthous stomatitis and external genital ulcers, were found with the same frequency. Panuveitis and angiitis of the retina were diagnosed more frequently in the Dagestani population with BD than in the Russians. Out of the minor criteria for BD, the incidence of lower limb deep venous thrombosis was 23% for the Dagestanis versus 3% for the Russians. Arterial thromboses and pulmonary artery aneurysms became causes of death in 4 in 5 men aged 19-23 years from their Dagestani ancestry. HLA B51 (B marker) was found in the dwellers of Dagestan: in 70% of the men and 40% of the women who had BD. CONCLUSION: BD runs a more severe course in male patients and is characterized by severe eye diseases and the systematic pattern of the process at young age. Gender-specific and genetic aspects call for further comparative investigations on large ethnic patient cohorts of other ancestries. PMID- 23819340 TI - [Anti-C1q antibodies in patients with systemic lupus erythematosus treated by rituximab]. AB - AIM: To determine the time course of changes in the blood levels of antibodies (Ab) to complement component C1q (a-C1q) in patients with systemic lupus erythematosus (SLE) during rituximab (RTM) therapy and the association with organ injuries in SLE. SUBJECTS AND METHODS: The study involved 41 patients (3 men and 38 women; their median age was 27.5 (range 22-36) years) with definite SLE. Their blood a-C1q levels were determined by enzyme immunoassay. The levels and detection rates of a-C1q were estimated in relation to organ injuries, the time course of RTM therapy-induced changes in a-C1q levels were determined. High positive (> 30 U/ml), low-positive (10-30 U/ml), and negative (< or = 10 U/ml) a C1q levels were found. RESULTS: A-C1q was detected in 19 (46.3%) patients with different clinical manifestations of SLE. The patients with renal diseases had high-positive levels of a-C1q statistically significantly more frequently than those without renal involvement (p = 0.04). Low-positive and negative a-C1q levels were found in 15 of 16 without nephritis. There was a statistically significant positive correlation of the concentration of a-C1q with Ab to double stranded DNA (a-dsDNA), Ab to nucleosomes, the SLE Disease Activity Index 2000 (SLEDAI-2K), erythrocyturia, hematuria and a negative correlation between a-C1q and complement components C3 and C4. Just after one month of RTM therapy, the patients with nephritis were observed to have a statistically significant decrease in the levels of a-C1q (p = 0.002), which persisted 1 year after the treatment (p = 0.006). Nineteen patients with the higher baseline concentrations of a-C1q after RTM treatment showed a statistically significant decrease in the levels of a-C1q at 1-, 3-, 6-, and 12-month follow-up (p = 0.016, 0.02, 0.035, and 0.04, respectively) which was accompanied by the decreased SLEDAI-2K (p < 0.00004 at 1-, 3-, 6-, and 12-month follow-up). CONCLUSION: The high levels of a C1q were found statistically significantly more often in the patients with lupus nephritis than in those with SLE without renal involvement. The level of a-C1q statistically significantly reduced after RTM therapy and remained within the normal range during a year. PMID- 23819341 TI - [Efficacy and safety of sildenafil in patients with systemic scleroderma]. AB - AIM: To retrospectively analyze the efficacy and safety of sildenafil (Sf) in patients with systemic sclerosis (SS). SUBJECTS AND RESULTS: Sf was used in 16 patients (including 14 women) aged 20-66 years (mean 48.6 +/- 14.6 years; median 51.5 years) with SS of a duration of 2 months to 27 years (mean 8.8 +/- 7.3 years; median 6.5 years). The indications for Sf treatment were significant Raynaud's phenomenon (RP) in 3 patients, digital ulcers (DU) and/or necroses (N) in 9, pulmonary hypertension (PH) in 5 (2 patients had PH concurrent with DU/N), and critical ischemia of the left fingers in 1 patient. RP was seen in all the patients and so the effect of Sf on the course of RP was evaluated in the whole patient group. RESULTS: There was a significant decrease in the frequency and intensity of Raynaud's attacks in 11 (73%) of the 15 patients treated with Sf. This effect was obvious just in the first days of Sf treatment and remained stable throughout the treatment. No RP changes were seen in 3 patients. All 7 patients with DUs showed a decrease in their sizes just within the first two weeks of treatment. Complete DU healing was observed within 4-12 weeks of treatment. During a month, the necrotic area reduced and the signs of reparation appeared in 4 of the 6 patients. Pain ceased just within the first 5-7 days of treatment. Sf resulted in a rapid reduction in systolic pulmonary artery pressure (sPAP); in one case the latter diminished from 60 to 40 mm Hg just 90 min after the first intake of Sf 50 mg and remained unchanged during all 6 months during which the female patient was taking the drug. Doppler echocardiography showed that sPAP decreased from 103 to 85 mm Hg in another female taking Sf 100 mg for a month. The two cases showed clinical improvement as alleviated dyspnea and increased physical activity. In another case, Sf was discontinued because of dizziness after its first intake in a dose of 12.5 mg. The initial drug intake of the drug was not followed by adverse reactions in 12 (75%) of the 16 patients. Four patients had Sf-induced complaints, including headache (1), dizziness (2), and more severe angina pectoris (1). In different periods after treatment initiation, four more patients developed complications, such as fatal myocardial infarction after 6-week treatment, atrial fibrillation at 8 weeks, more severe angina at 6 months, and congestive heart failure after 5-year treatment. These complications were observed in patients with severe ECG changes, such as myocardial focal fibrosis or blood supply impairment. CONCLUSION: Sf is an effective drug to treat the manifestations of scleroderma vasculopathy, such as RP, DU/N, and PH. Sf is well tolerated in most cases. The SS patients with pronounced ECG changes have an increased risk of severe cardiac events and they need careful ECG monitoring. PMID- 23819342 TI - [Comparative evaluation of the impact of four-week therapy with amlodipine and atenolol on quality of life and blood lipid composition in patients with coronary heart disease associated with metabolic syndrome]. AB - AIM: To comparatively estimate the time course of changes in key metabolic parameters and quality of life (QL) in patients with coronary heart disease during 4-week therapy with atenolol and amlodipine. SUBJECTS AND METHODS: The 4 week randomized open-label trial included 60 patients with functional classes II III stable angina pectoris on exertion associated with metabolic syndrome (all male patients aged 29 to 62 years (mean age 48.1 +/- 0.9 years)). Along with the traditional studies accepted in specialized cardiology practice, QL was assessed using the EORTC QLO CORE 30 questionnaire prior to treatment and on the last day of the trial. RESULTS: Four-week therapy with the individually adjusted dosages of atenolol (68.7 +/- 4.17 mg/day) or amlodipine (5.5 +/- 0.34 mg/ day) ensured comparable positive changes in the subjective assessment of QL. CONCLUSION: The positive changes in exercise tolerance that was considered to be an objective indicator for physical improvement in the treatment with amlodipine were more pronounced than those in that with atenolol. Therapy with amlodipine caused no change in blood lipid parameters while that with atenolol was associated with a 9.7% increase in blood triglyceride concentrations. PMID- 23819343 TI - [Epidemiological parameters in the evaluation of endemic goiter in the Republic of North Ossetia-Alania]. AB - AIM: To study the incidence of endemic goiter among urban and rural schoolchildren in the Republic of North Ossetia-Alania (RNO-Alania). SUBJECTS AND METHODS: 1198 urban (637 girls and 561 boys) and 227 rural (137 girls and 90 boys) adolescents aged 13-16 years were examined. All the adolescents underwent thyroid palpation. Thyroid ultrasound study (USS) was performed using an ALOKA SSD-500 scanner (Japan) with a 7.5-mHz transducer. Ioduria levels were measured by the cerium-arsenite method. Thyroid function was evaluated from the content of circulating hormones, such as total triiodothyronine (T3), free thyroxin (free T4), and thyrotrophic hormone (TTH), by using the Alkor-Bio enzyme immunoassay kits. RESULTS: Varying degrees of iodine deficiency were found in the RNO-Alania. Median urban and rural ioduria was 52.1 and 60.7 microg/l, respectively; which corresponded to mild iodine deficiency. Analysis of the gender-specific findings revealed that moderate ioduria was identified in a larger number of girls and mild iodine excretion was detected in most boys. The rate of increased thyroid dimensions was also higher in the boys than in the girls in both the urban and rural areas. Examining the hormone profile revealed a euthyroid state in virtually all schoolchildren. The levels of TTH, free T4, and T3 did not exceed the normal range. The families consuming iodized salt were 46.2 and 47.7% in the urban and rural areas, respectively. CONCLUSION: The findings allow one to give an additional insight into the specific features of formation of a goitrous endemic in the RNO-Alania and may serve as the basis for further investigations and development of pathogenetically sound approaches to treating and preventing iodine deficiency states. PMID- 23819344 TI - [Effect of a fixed-dose perindopril and amlodipine combination on intrarenal hemodynamic and kidney functional parameters in patients with essential hypertension]. AB - AIM: To evaluate the effect of prestans on intrarenal hemodynamic and kidney functional parameters and to study their correlations during 24-week therapy in patients with grade I-II essential hypertension (EH). SUBJECTS AND METHODS: Eighty-two patients (44 men and 38 women) with EH were examined and allocated to 3 groups according to glomerular filtration rate (GFR): 1) 31 patients with a GFR of > 90 ml/min/1.73 m2; 2) 28 with a GFR of 60-89 ml/min/1.73 m2; 3) 23 with a GFR of 59-30 ml/min/1.73 ml. RESULTS: Group 3 patients were found to show a preponderance of metabolic disturbances, such as dyslipidemia, obesity, as well as intrarenal arterial lesions and diminished kidney function. In addition, the most pronounced therapy-induced changes in the parameters under study were also observed in Group 3. In particular, resistive index, pulsatility index of interlobar arteries of the kidneys, and serum creatinine levels increased, the frequency of microalbuminuria episodes reduced, and GFR, endothelium-dependent dilation of the brachial artery, and systolic index rose statistically significantly. Group 3 also displayed statistically significant correlations of the resistive index of the interlobar arteries with GFR, urinary albumin excretion, endothelium-dependent vasodilation, and cardiac index. CONCLUSION: The fixed-dose perindopril and amlodipine combination in patients with EH and hypertensive nephropathy improves intrarenal hemodynamics and exerts marked nephroprotective and antihypertensive effects. PMID- 23819345 TI - [Diagnosis and problems in therapy of interstitial lung disease associated with rheumatoid arthritis]. AB - Rheumatoid arthritis (RA) is an inflammatory rheumatic disease of unknown etiology, which is characterized by symmetric, chronic, and erosive arthritis (synovitis) of the peripheral joints and systemic inflammatory involvement of the viscera. Lung pathology, including interstitial lung disease (ILD), is one of the common extra-articular manifestations in RA. ILD is considered to be present in almost 25% of the RA patients. To study a prognosis in RA patients with ILD was the objective of some investigations in the past decade, the majority of which concluded that the mean survival after the diagnosis was about 3 years. These indicators may reflect the predominance of usual interstitial pneumonia (UIP) in patients in specific trials as this type of lung disease is associated with a poorer prognosis. In addition, there are discrepant results on survival differences between RA patients with ILD and those with idiopathic ILD. However, the data were limited by a small number of cases in both medical centers and daily clinical practice. ILD is the only extra-articular manifestation of RA, the rate of which is increasing. ILD is considered to be a cause of death in nearly 6% of all the patients with RA. The pattern of ILD may be determined by high resolution computed tomography and may be a major prognostic marker; the development of UIP is worst. The material is dedicated to the successes recently achieved in the diagnosis and therapy of RA-associated ILD. The state-of-the-art of investigations in this area is discussed. PMID- 23819346 TI - [Strategy for the use of chondroprotectors in osteoarthrosis]. AB - Symptomatic slow-acting drugs (chondroprotectors) as different dosage forms have widespread application in the treatment of osteoarthrosis (OA) at different locations. The literature review considers their possible effect on carbohydrate metabolism, which is particularly important due to the high prevalence of diabetes mellitus in patients with OA. Current clinical recommendations for the use of chondroprotectors in the therapy of OA are given. PMID- 23819347 TI - [Aspirin resistance candidate genes and their association with the risk of fatal cardiovascular events]. AB - The review presents the current data available in the world literature on the most likely gene polymorphisms, such as cyclooxygenase, glycoproteins (GP) Ib/IIIa, GP Iba, GP VI, adenosine diphosphate receptor P2Y1 and P2Y12 polymorphisms that may lead to aspirin resistance. The frequency of these polymorphisms in laboratory aspirin resistance and their association with the development of adverse cardiovascular events from the use of aspirin are considered. PMID- 23819348 TI - [Problem of a comorbidity of arterial hypertension and acid-dependent diseases]. AB - The paper presents a concise literature review on the concomitant course of the most common nosological entities in the population, such as arterial hypertension (AH) and acid-dependent diseases (ADD). Data on the prevalence, commonness of etiological and pathogenetic factors, the specific features of a clinical course, and diagnostic difficulties are analyzed in persons with AH associated with ulcerative and gastrointestinal reflux diseases. The causes and consequences of these nosological entities are shown; their clinical, morphological, and hemodynamic features are covered. The results of investigations characterizing the specific features of autonomic regulation, diurnal blood pressure variations, and the central hemodynamics in the comorbidity of the diseases in question are given. The rational antihypertensive therapy of AH concurrent with ADD is presented in terms of their impact on gastrointestinal tract disease. PMID- 23819349 TI - [Results of a questionnaire survey on the use of gentamicin sulfate injection]. AB - Unlike what has been approved overseas, only a low dose is approved in Japan for the use of Gentamicin Sulfate Injection (hereinafter referred to as GM Injection). A change in dose and administration was requested to the Evaluation Committee on Unapproved or Off-labeled Drugs with High Medical Needs. As a consequence, high-dose GM Injection began to be developed in Japan. In order to assess the current use of GM Injection, a questionnaire survey was conducted among infectious disease specialists certified by the Japanese Association for Infectious Diseases, and physicians certified as specialists/instructors of antibiotic chemical treatment by the Japanese Society of Chemotherapy. Valid responses were obtained from as many as 38.0% of questionnaire recipients (719/1891 physicians). About 30% of the respondents used GM Injection in the year 2011. Major indications for adult patients included sepsis and infective endocarditis, and bacterial strains mainly included Pseudomonas aeruginosa, Staphylococcus, Enterococcus and Streptococcus species. Some diseases and bacterial strains domestically unapproved as indications were also treated with GM Injection. GM Injection is administered mainly as an intravenous infusion, usually once daily, which is not approved in Japan. Some physicians administered a fixed dose of GM (120 mg/day or less), not more than the upper limit approved in Japan. The majority of physicians, however, adopted a dosage of 3-5 mg/kgy/day, the standard dosage approved overseas. Physicians who implemented TDM outnumbered those who did not. The target blood level when administering 2-3 times a day was mostly 2 microg/mL or less as the trough level, and 4-10 microg/mL as the peak level. In particular, GM Injection was concurrently administered with other injectable antimicrobial agents to treat sepsis or infective endocarditis mainly in the following combinations: with penicillins or carbapenems for sepsis: with penicillins for infective endocarditis. Renal impairment was the most common adverse reaction requiring special care to be reported by the respondents. The survey revealed the current status of use, which is that GM Injection is used at the dose and administration approved in Japan, and that high-dose GM Injection, equivalent to the dosage approved overseas, is also used by quite a few physicians. The current use supports the request submitted to the Evaluation Committee on Unapproved or Off-labeled Drugs with High Medical Needs. Therefore, the same dosage that is approved overseas is recommended to be approved as soon as possible in Japan. PMID- 23819350 TI - [Review of a community-based laboratory diagnosis of pandemic influenza A (H1N1) 2009]. AB - We performed a community-based laboratory diagnosis of pandemic influenza A (H1N1) 2009 with the RT-PCR technique using originally constructed primers. Of 30 patients who were suspected to be infected with the influenza virus from May 2009 until January 2010, the A (H1N1) 2009 virus was detected in 13 patients (43.3%). Three cases were immunologically confirmed to be infected with the A (H1N1) 2009 virus, because significant increases in the HI titer were observed in the convalescent sera. We also measured the antibody titers to the A (H1N1) 2009 virus in 13 healthy individuals with the HI assay using originally isolated virus. In most cases, the HI antibody titers were less than 10, except two cases with titers of 40 and 20. Our inspection system organized in the early phase of the A (H1N1) 2009 pandemic contributed to disease control in an outpatient clinic and a hospital in a small city. The process which we used to construct the system would be a good reference for a treatment protocol in the case of a future literal pandemic. PMID- 23819351 TI - [A case of severe Legionella pneumonia in which survival was achieved without sequelae with the use of extracorporeal membrane oxygenation (ECMO)]. AB - A 54-year-old man presented with fever and dyspnea about a week before his admission. We diagnosed Legionella pneumonia from his chest X-ray imaging which showed bilateral lobe consolidation excluding the left upper lobe, and his sputum culture yielded Legionella pneumophilla serogroup 1. Combination therapy with levofloxacin and rifampin was started on admission. However, the patient developed severe acute respiratory distress syndrome (ARDS) and then extracorporeal membrane oxygenation (ECMO) was initiated on the 2nd day. His respiratory status gradually improved after that and he was weaned from ECMO on the 7th day. He was discharged without sequelae on the 36th day. The outcome suggests that use of ECMO should be considered for patients with severe Legionella pneumonia. PMID- 23819352 TI - [Staphylococcal scalded skin syndrome associated with long-term catherter related infection in an adult]. AB - Staphylococcal scalded skin syndrome (SSSS) is an extensive desquamative erythmatous condition caused by the Staphylococcus aureus exfoliative toxin. Although adult cases of SSSS are rare, the mortality rate is high. We report herein on a case of SSSS due to long-term catheter-related bloodstream infection caused by exfoliative toxin B, which produced methicillin-resistant Staphylococcus aureus. A 64-year-old man was admitted to our hospital with a high fever and generalized exfoliative dermatitis. He had an implanted port vascular access device in his left arm. The port was removed because it was thought to be the focus of infection. A Gram stain of the pus from the incision site revealed Gram positive coccus in clusters, and we administered intravenous vancomycin. MRSA was isolated from blood cultures and the pus, and histiology of a skin biopsy specimen from the exfoliation dermatitis showed epidermal detachment in the uppermost layer, which was consistent with SSSS. Although the patient developed infective endocarditis and septic embolisms, he eventually recovered. PCR of the MRSA was positive for exfoliative toxin B, and we finally diagnosed an adult case of SSSS due to exfoliative toxin B producing MRSA. PMID- 23819353 TI - [A case of tetanus originating from ulcerated breast cancer]. AB - We report herein on a rare case of tetanus originating from ulcerated breast cancer. A 60-year-old homeless woman was admitted to our hospital because of lockjaw. On admission, a physical examination revealed tachypnea, trismus, opisthotonus and an ulcerated right breast. There was no other skin soft tissue damage. A diagnosis of tetanus was entertained from the lockjaw and opisthotonus. Tetanus globulin, tetanus toxoid, penicillin and respiratory support were initiated. Later, a right total mastectomy was performed, and the diagnosis of breast cancer was made, however, gram positive bacilli were not detected and Clostridiuum tetani (C. tetani) was not cultured. It is conceivable that the ulcerated breast was contaminated with C. tetani due to the patients living conditions. PMID- 23819354 TI - [A case of Legionella pneumophila pneumonia accompanied by acute respiratory distress syndrome and epilepsy]. AB - A 32-year-old female with epilepsy presented at our hospital with high-grade fever, seizures, and unconsciousness. She was initially treated for aspiration pneumonia with ampicillin/sulbactam. Despite antibiotic therapy, her chest X-ray findings dramatically worsened, showing extension to the bilateral lung field. Her PaO2/FiO2 ratio decreased to 70.6. Rapid progression of hypoxia, unconsciousness, and hyponatremia led to the suspicion of Legionella pneumonia; however, it was difficult to make a definitive diagnosis because she had denied using a whirlpool spa and the initial urinary Legionella antigen test results were negative. Therefore, we repeated the Legionella urinary antigen test, which was positive. On the basis of these results, sputum polymerase chain reaction findings, and the four-fold elevation of paired antibodies, the patient was diagnosed as having Legionella pneumonia accompanied by acute respiratory distress syndrome. We considered administering fluoroquinolone antibiotics, that are recommended for severe Legionella pneumonia, although quinolones have a potential risk for causing convulsions. In this case, we carefully administered ciprofloxacin. The patient recovered consciousness after treatment without any relapse of epileptic seizures. We also administered a corticosteroid for severe pneumonia with the expectation of clinical improvement and to avoid intubation. We emphasize the importance of aggressive workup and empirical therapy for patients with Legionella pneumonia with rapidly worsening symptoms and clinical features such as unconsciousness, epilepsy, and hyponatremia and in whom fluoroquinolone and corticosteroid therapy are effective despite the presence of epilepsy. PMID- 23819355 TI - [An outbreak of sapovirus gastroenteritis at a special nursing home for the elderly]. PMID- 23819356 TI - [A clinical study on 8 cases of sarcoidosis with a cervical mass as a symptom]. AB - Sarcoidosis is a multiorgan granulomatous disease of unknown origin, which frequently involves the lung and the eyes. It is rare that sarcoidosis causes cervical lymphadenopathy and a chronic continuous salivary gland swelling. In the present study, we examined how to diagnose sarcoidosis in patients complaining of a cervical mass and its clinical presentation according to 8 cases which we experienced. We undertook biopsy of the cervical lymph nodes in 7 cases, and biopsy of the parotid gland in 1 case. In cases non-caseating epithelioid cell granuloma was proved, diagnosed as sarcoidosis histopathlogically. In 6 patients, the sarcoidal lesion was in other organs, whereas in 2 patients the sarcoidal lesion was confined in the head and neck. Bilateral hilar lymphadenopathy and an elevated level of angiotensin-converting enzyme which are typical in sarcoidosis were confirmed in only one of our patients. Therefore, the diagnostic value of these tests is low for the diagnosis of sarcoidosis in the patients whose chief complaint is a cervical mass. Because 4 out of 7 cases were positive for the tuberculin test, it is imperative to distinguish between sarcoidosis and cervical tuberculous lymphadenitis by combining the culture of acid-bacilli and TB-PCR with histopathological evaluation of the biopsy specimen. We experienced one patient in whom the sarcoidal lesion developed in the skin and the eyes 20 years after the onset of cervical lymphadenopathy. It is important to follow the patients carefully, even if we diagnose the disease as sarcoidosis confined in the head and neck. PMID- 23819357 TI - [Migraine-associated vertigo with hearing loss and recurrent vertigo attack]. AB - The clinical features of Meniere's disease and migraine-associated vertigo are quite similar. Both disorders are characterized by repeated vertigo spells. Several diagnostic criteria are used to diagnose migraine-associated vertigo. None of these criteria has been internationally defined, although the criteria proposed by Neuhauser are wieldy accepted. Hearing impairment is believed to be a key factor for diagnosing Meniere's disease. We report herein on a case of repeated vertigo spells with sensorineural hearing loss in the right ear. Initially, the condition was diagnosed as Meniere's disease. Treatment for improving endolymphatic hydrops did not have an effect on the vertigo spells. On careful questioning, we noted the coexistence of migraines without any aura. Treatment with Ca antagonists to prevent the migraine attacks successfully stopped the patient's vertigo spells. On the basis of this clinical course, it is safe to assume that the patient had migraine-associated vertigo with sensorineural hearing loss rather than Meniere's disease. For a patient experiencing migraines together with sensorineural hearing loss, an accurate diagnosis requires careful evaluation. The coexistence of migraines should be carefully ruled out, even if Meniere's disease with hearing loss is strongly suspected. PMID- 23819358 TI - [Rupture of an internal carotid artery pseudoaneurysm after irradiation for a nasopharyngeal carcinoma--case report]. AB - The primary treatment of nasopharyngeal carcinoma (NPC) has been external radiotherapy. Rupture of an internal carotid artery (ICA) pseudoaneurysm is a rare complication of irradiation therapy for a nasopharyngeal carcinoma. A 78 years old man had a history of NPC treated with radiotherapy in 1993. He was admitted to the hospital because of epistaxis. Angiography showed an ICA pseudoaneurysm pointing medially to the nasopharynx. Coil embolization of the ICA was performed, but cerebral infarction occurred. Internal carotid artery (ICA) pseudoaneurysms are an uncommon but potentially lethal condition. Angiography is the mainstay of diagnosis of the aneurysm and planning the embolization of the ICA. We should be more aware of this complication in NPC patients. PMID- 23819359 TI - [Assessment of treatment effect for acromegaly with sleep disordered breathing]. AB - Acromegaly is caused by excessive secretion of growth hormone (GH) and presents with a variety of clinical manifestations, including facial disfigurement and abnormally large hands and feet, as well as diabetes mellitus, hypertension, and sleep-disordered breathing (SDB). Although SDB is known to be associated with serious symptoms, there have been few study reports, and no clear consensus has been reached regarding the method of assessment of individual treatments. We report herein on the results of surgical intervention with transsphenoidal surgery (TSS) for acromegaly and assessment of the treatment effect after the intervention. We studied 6 patients who received a diagnosis of acromegaly complicated with SDB and underwent TSS at our hospital. Polysomnography (PSG) was performed before and after TSS, and the polysomnograms were analyzed. We also examined changes in the levels of GH and insulin-like growth factor-1 (IGF-1) on blood biochemistry. In 6 cases of acromegaly with SDB, we were able to confirm endocrinologic improvement of TSS with blood biochemistry. However there was no meaningful improvement in the PSG index for SDB. PMID- 23819360 TI - [Diffusion-weighted imaging for prostate cancer localization: comparison of apparent diffusion coefficient values in cancerous and non-cancerous tissues, and the Gleason score of the radical prostatectomy specimens]. AB - PURPOSE: We compared magnetic resonance imaging (MRI) with radical prostatectomy specimens to evaluate the diagnostic performance of diffusion-weighted imaging (DWI) and the apparent diffusion coefficient (ADC) value for prostate cancer localization. MATERIALS AND METHODS: We performed a retrospective study of 44 patients who underwent radical prostatectomy. We compared MRI with pathological specimens (74 tumors) to evaluate their diagnostic performance of cancer localization. The ADC value was measured in cancerous and non-cancerous prostate tissues. RESULTS: Of 74 tumors, digital rectal examination, transrectal ultrasonography, T2-weighted imaging (T2WI), DWI, T2WI and DWI detected 9 (12.2%), 9 (12.2%), 26 (35.1%), 30 (40.5%), and 48 (64.9%) tumors, respectively. The mean ADC value was lower in cancerous tissues than in non-cancerous tissues (0.86 +/- 0.15 versus 1.24 +/- 0.16 x 10(-3) mm2/s). The mean ADC values of cancerous and non-cancerous tissues were: 0.85 +/- 0.15 versus 1.28 +/- 0.17 x 10(-3) mm2/s in the peripheral zone; and 0.87 +/- 0.15 versus 1.19 +/- 0.14 x 10( 3) mm2/s in the transition zone. The mean ADC value in patients with a Gleason score of 8 or 9 (0.76 +/- 0.12 x 10(-3) mm2/s) was lower than that in patients with a Gleason score of 6 or 7 (0.86 +/- 0.15 x 10(-3) mm2/s). CONCLUSION: DWI and ADC value were considered to be useful for the diagnosis of prostate cancer localization. PMID- 23819361 TI - [Outcome after radical prostatectomy with extended pelvic lymphadenectomy for untreated high-risk clinically localized prostate cancer]. AB - PURPOSE: We assessed the outcome after radical prostatectomy and extended pelvic lymphadenectomy in patients with untreated high-risk clinically localized prostate cancer, retrospectively. MATERIALS AND METHODS: Between 2001 and 2010, 89 patients for untreated high-risk clinically localized prostate cancer on the risk classification as defined by D'Amico, underwent retropubic radical prostatectomy and extended pelvic lymphadenectomy. Boundaries of the pelvic lymph node dissection field divided into external iliac vessels, obturator fossa, and internal iliac vessels. We investigated mainly the postoperative outcome of 84 patients without any adjuvant therapies. PSA recurrence-free survival among the pretreatment variables was estimated using Kaplan-Meier plots, and the statistical significance was determined by log rank test. RESULTS: In 89 high risk patients, 32.7% had pT3-pT4 tumors, 16.9% positive surgical margin, 6.7% positive lymph node metastases and 30.3% Gleason score 8-10 at the pathological examination. A median of 13 nodes (mean 14.0, range 9-25 nodes) were removed per patient. In 96.6% cases, postoperative PSA values decreased less than 0.2 ng/ml. The median observation period after operation was 1,819 days. Median PSA recurrence-free survival rates, overall survival and cancer cause-specific survival rates at 5 year, in 84 high-risk patients without any adjuvant therapies, were 73.8%, 100% and 100%, respectively. Median PSA recurrence-free survival rates according to pathological T stage and surgical margin status were statistically significant, but that according to preoperative 3 factors (clinical T stage, Gleason score at biopsy, preoperative PSA values) were statistically insignificant. Moreover, that according to both the number of positive preoperative 3 factors (1 vs. 2 positive factors) and the number of removed lymph nodes (< or =13 vs. > or = 14), were statistically insignificant. The median PSA recurrence-free survival rates at 5 year for positive margin cases were 0%. CONCLUSION: Radical prostatectomy and extended pelvic lymphadenectomy is feasible in patients with high-risk clinically localized prostate cancer. We suggest that both wide resection and extended pelvic lymphadenectomy may improve the postoperative outcome for high-risk clinically localized prostate cancer. PMID- 23819363 TI - [Comparison of pneumatic lithotripter and Holmium YAG laser in transureteral lithotripsy (TUL)]. AB - OBJECTIVE: We retrospectively compared the clinical outcomes of Lithoclast assisted lithotripsy (L group) with those of Holmium YAG laser assisted lithotripsy (H group). PATIENTS AND METHODS: We analyzed records for operation time, duration of ureteral stenting, complication and stone-free rates in the L group (388 patients) and the H group (368 patients) for the primary procedure. RESULTS: The stone locations (L group/H group) were U1 in 141/181, U2 in 69/57, and U3 in 178/130. Respective median stone sizes (L group/H group) were: U1,: 10.0/10.0 mm; U2,: 7.0/10.0 mm;, and U3,: 6.0/7.0 mm. Secondary procedures were performed in 79 L group patients and 35 H group patients. The median operation times (L group/H group) were 29.5/25.0 minutes. The median durations of ureteral stenting (L group/H group) were 4.0/4.0 days. The stone-free rates (L group/H group) according to the locations of the stones were 69.3/82.0% in U1, 85.5/87.0% in U2, and 92.0/98.4% in U3. Complications (L group/H group) were ureter perforation in 8/5 cases, pyelonephritis in 7/2 cases, ureteral stricture in 2/6 cases, and stone push up in 27/13 cases. CONCLUSION: The operation time for holmium YAG laser assisted lithotripsy was significantly shorter than that of the Litoclast assisted procedure, and the stone-free rate with holmium YAG laser assisted lithotripsy was better than that with Lithoclast assisted lithotripsy for U1 and U3 stones. PMID- 23819362 TI - [Prospective multi-institutional analysis according to the "Japanese guidelines for prevention of perioperative infections in urological field"]. AB - OBJECTIVE: The "Japanese guidelines for prevention of perioperative infections in urological field" was edited by the Japanese Urological Association in 2007. They are the first Japanese guidelines for antimicrobial prophylaxis specifically to prevent perioperative infections in the urological field. We report here the results of a multicenter prospective study conducted to examine the validity and usefulness of these guidelines. PATIENTS AND METHODS: The subjects were 513 patients who had undergone urological surgeries between July and September 2008 at 10 nationwide university institutions in the Japanese Society of UTI Cooperative Study Group. These surgeries were transurethral resection of bladder (TURBT), transurethral resection of prostate (TURP), adrenalectomy, nephrectomy, nephroureterectomy, radical prostatectomy and total cystectomy. Analysis was performed on patient information, surgical procedures, types and durations of administration of prophylactic antibiotic agents, and the presence of surgical site infections (SSI) and remote infections (RI). RESULTS: Of 513 patients, 387 (75.4%) were administered prophylactic antibiotic agents according to the guidelines. In these patients, the incidences of SSI and RI were 5.9% and 4.1%, respectively. Multivariate analysis showed that significant factors for SSI were the surgical risk (according to the ASA physical status classification system), diabetes, and operation time, and that the only significant factor for RI was the operation time. CONCLUSIONS: More large-scale study and evidences are necessary in order to demonstrate the validity and usefulness of these guidelines. PMID- 23819364 TI - [Surgery without blood transfusion for pheocromocytoma in a Jehovah's Witness patient: a case report]. AB - A 59-year-old woman who identified as a Jehovah's Witness was diagnosed with pheochromocytoma in the left adrenal gland, measuring 11 cm in diameter, during treatment for hypertension. Given her desire to undergo transfusion-less surgery for religious reasons, we obtained fully informed consent and had the patient sign both a transfusion refusal and exemption-from-responsibility certificate and received consent to instead use plasma derivatives, preoperative diluted autologous transfusion and intraoperative salvaged autologous transfusion. To manage anemia and maintain total blood volume, we preoperatively administered erythropoiesis-stimulating agents and alpha 1 blocker, respectively. During the left adrenalectomy, the patient underwent a transfusion of 400 mL of preoperative diluted autologous blood, ultimately receiving no intraoperative salvaged autologous blood. The operation took 4 hours 42 minutes, and the total volume of blood lost was 335 mL. In conclusion, to complete transfusion-less surgery for pheochromocytoma, it is necessary to have the patient sign a generic refusal form for transfusion and exemption-from-responsibility certificate as well as outline via another consent form exactly what sort of transfusion is permitted on a more specific basis. And doctors should become skilled in perioperative management and operative technique for pheochromocytoma and make the best effort by all alternative medical treatment in order to build trust confidence with a patient. PMID- 23819365 TI - [Case of primary retroperitoneal GIST (gastrointestinal stromal tumor) with rapid progression]. AB - A 69-year-old man complaining of left abdominal pain was referred from a private clinic for retroperitoneal masses that were discovered on abdominal ultrasound in November 2010. CT scan showed retroperitoneal masses, located above the left kidney, measuring 10 cm. Para-aortic lymph nodes were swelling. We performed open biopsy to make the diagnosis in December 2010. The diagnosis was primary retroperitoneal GIST (gastrointestinal stromal tumor). We started imatinib 400 mg/day according to the Japan GIST guideline in January 2011. However the tumor pogressed rapidly, after 1 month the patient died. PMID- 23819366 TI - [Case of multiple lung metastases of renal cell carcinoma failing to respond to Interferon-alpha (IFN-alpha) and sunitinib but markedly responding to everolimus]. AB - The case pertains to a 47-year-old male. He consulted our institute regarding a tumor in his right kidney. Endoscopic retroperitoneal nephrectomy of the right kidney was conducted to remove the tumor. The postoperative pathology was Renal Cell Carcinoma (Clear cell carcinoma, pT1b, pNx, V (+), Fuhrman grade 4). Multiple lung metastases were observed upon CT scan the following year. Sunitinib was administered following Interferon alpha (IFN-alpha) therapy; however, the lung metastases became larger, so administration of everolimus at 10 mg/day was commenced. The lung metastatic lesion became smaller upon CT scan from 6 weeks following administration, and it was determined that the therapeutic effect was PR. The PR was still maintained upon CT scan 31 weeks following administration but the lung metastatic lesion still remained; therefore, right lower lobe resection and lymph node biopsy were conducted upon obtaining informed consent. The administration of everolimus at 10 mg/day is still subsequently being continued due to viable tumor cells being observed in the lung metastatic lesion and the lymph node. At present, 43 weeks have past since the start of everolimus administration, but no new metastatic lesions have been observed. PMID- 23819367 TI - [Case of infected renal cyst in polycystic kidney disease]. AB - A 56-year-old woman with polycystic kidney disease (PKD) presented with high fever and left back pain. Abdominal computed tomography (CT) scan showed multiple renal cysts, left hydronephrosis and a left ureteral stone. Her condition could not be managed with antibiotic therapy and indwelling left ureteral stent. Infected of left renal cysts was suspected, we performed diffusion-weighted magnetic resonance imaging (MRI). Diffusion-weighted MRI showed higher signal intensity in one renal cyst than in other renal cysts. CT-guided percutaneous puncture of an infected cyst was performed. Her symptoms and fever resolved following the procedure. Identification of an infected renal cyst in PKD is often difficult on either ultrasonography or CT. Diffusion-weighted MRI allowed exact localization of the infected cyst among many cysts in PKD. PMID- 23819368 TI - [Metastatic micropapillary variant of urothelial carcinoma of the urinary bladder responding to gemcitabine and cisplatin chemotherapy]. AB - A 69-year-old man was admitted to our hospital with a chief complaint of lymphatic edema of left arm. He had a past history of transurethral resection of the bladder tumor 5 years ago, and pathological diagnosis was urothelial carcinoma with micropapillary variant, G3 = G2, pT1. CT scan revealed bladder tumor with invasion of the rectum, and multiple lymph nodes swelling in the axilla, retroperitoneum and pelvis (cT4bN3M1). The patient underwent biopsies of the bladder wall and the left axillary lymph nodes, and pathologic examination revealed micropapillary carcinoma. Five courses of gemcitabine plus cisplatin (GC therapy) were perfomed, and bladder tumor and lymph node metastases reduced remarkably, with serum CA19-9 level decreasing from 172,000 U/ml to 106 U/ml. However, the patient died from recurrence 23 months after the start of GC therapy. PMID- 23819369 TI - [Case of inflammatory lesion in urinary bladder showing high signal intensity on diffusion-weighted MRI: correlation with histopathological finding]. AB - A 66-year-old woman was referred to our department for thickening bladder wall incidentally found during postoperative follow-up of transverse colon cancer. Cystoscopy showed edematous tumor with a diameter of 5 cm on the right wall. Deep portion of the tumor showed high intensity on diffusion-weighted magnetic resonance imaging (DW-MRI). Transurethral resection and transvaginal needle biopsy was performed, and pathological examination revealed granulation tissues mainly consisted of inflammatory cells and fibrosis. DW-MRI is a functional imaging constructed by quantifying the diffusion of water molecules. Recently, the feasibility of this imaging in the diagnosis of bladder cancer has been reported. However, we should keep in mind that granulation tissues consisted of inflammatory cells and fibrosis is also possible to be positive for DW-MRI. PMID- 23819370 TI - [Long-term survival of metastatic clear cell adenocarcinoma of the female urethra by multidisciplinary treatment: a case report]. AB - We report a case of clear cell adenocarcinoma of the female urethra. A 57-year old woman presented with complaint of gross hematuria. Abdominal ultrasonography, cystourethroscopy, computed tomography (CT) and magnetic resonance imaging (MRI) revealed the urethral tumor was invasive to bladder neck. Clinical stage was determined as cT3N1M0, then anterior pelvic exenteration and ileal conduit formation were performed. The pathological diagnosis was clear cell adenocarcinoma of urethra and the stage was pT3N1. The patient received TS-1 and cisplatin for postoperative recurrence, but she died from multiple lung metastasis 54 months after the operation. Clear cell adenocarcinoma of the female urethra is rare case in the Japanese literatures. Pathogenesis and management of this rare condition are discussed. PMID- 23819371 TI - [Computer simulation of dialysis efficacy for various modalities of hemodialysis]. PMID- 23819372 TI - [The present status and perspective of home hemodialysis therapy in Japan]. PMID- 23819373 TI - [The progression and change of the vascular access]. PMID- 23819374 TI - [Evolution of CAPD and PD + HD combination therapy]. PMID- 23819375 TI - [Current topics of purification and composition of dialysis fluid]. PMID- 23819377 TI - [The past, the present, and the future of dialyzer]. PMID- 23819376 TI - [Auto regulation system and monitoring in hemodialysis therapy]. PMID- 23819378 TI - [On-line hemodiafiltration (HDF)]. PMID- 23819379 TI - [Continuous renal replacement therapy in acute kidney injury]. PMID- 23819380 TI - [Dialysis medicine and risk management in disaster]. PMID- 23819381 TI - [Transcatheter renal arterial embolization therapy on patients with polycystic kidney disease]. PMID- 23819382 TI - [Transcatheter arterial embolization with ethanol for symptomatic polycystic kidney disease]. PMID- 23819383 TI - [NBCA embolization for polycystic kidney disease]. PMID- 23819384 TI - [Intravascular embolization therapy in patients with enlarged polycystic liver]. PMID- 23819385 TI - [Preliminary experience of transcatheter hepatic artery embolization using microspheres for polycystic liver disease]. PMID- 23819386 TI - [Validity of the assessment of urinary protein excretion by spot urine in patients with chronic kidney disease]. AB - AIM: We investigate the validity of the assessment of urinary protein excretion by spot urine samples collected by different methods in outpatients with chronic kidney disease (CKD). SUBJECTS AND METHODS We obtained 24-hour urine and two spot urine samples, including the first morning urine and daytime urine in 159 CKD patients. Urinary protein excretion was assessed by the protein/creatinine ratio from spot urine samples (morning: m-UP (g/gCr), daytime: d-UP (g/gCr) ]. We examined the correlations and the differences among m-UP, d-UP and the actual urinary protein excretion obtained by 24-hour urine (a-UP(g/day) . RESULTS: Significant correlations were found between m-UP and a-UP, and between d-UP and a UP (r = 0.88, 0.85; p < 0.001). Correlations between m-UP and a-UP were greater relative to those between d-UP and a-UP in patients with less than 3.5 g/day of a UP and in patients with CKD stages 1 to approximately 3. The percent difference between m-UP and a-UP was--16.0 +/- 40.5%, and that between d-UP and a-UP was 27.1 +/- 72.9%. The absolute value of the percent difference between d-UP and a UP tended to be greater than that between m-UP and a-UP (34.9 +/- 25.9% vs. 49.9 +/- 59.9%, p = 0.06). CONCLUSION: Urinary protein/creatinie ratio of the first morning urine is better approximate the urinary protein excretion obtained by 24 hour urine compared with that of spot urine in the daytime. PMID- 23819387 TI - [A case of crescentic poststreptococcal acute glomerulonephritis (PSAGN) accompanied by membranous nephropathy]. AB - In 2010, a 71-year-old man was referred to our hospital because of mild proteinuria and hematuria. At that time, he had been asymptomatic. Three months later he noticed macroscopic hematuria, followed by general malaise, and then anorexia. He was admitted for acute kidney injury (serum creatinine 2.7 mg/dL), marked proteinuria (4.35 g/gCr), and elevated C-reactive protein (7.21 mg/dL). Some vesicles were noted on the soft palate, and a throat culture yielded a growth of group A beta-hemolytic streptococci. Antistreptolysin O and antistreptokinase titers were elevated, but serum complement levels were within normal limits. Antineutrophil cytoplasmic antibodies (ANCA) directed against elastase and bactericidal permeability increasing protein (BPI)were positive. The renal function and inflammation did not improve despite oral antibiotic therapy. Pathological examination of a renal biopsy specimen revealed diffuse crescent formation, numerous subepithelial dome-shaped deposits (humps), and prominent endocapillary proliferation. Furthermore, a focal and segmental spike appearance was seen, with deposits smaller than humps. There was a striking clinical improvement after steroid pulse therapy followed by oral prednisolone. The features of this case strongly suggest crescentic PSAGN accompanied by pre existing membranous nephropathy. PMID- 23819388 TI - [Successful maintenance hemodialysis therapy with supplemented growth hormone in a diabetic patient with growth hormone insufficiency]. AB - Growth hormone (GH) insufficiency is difficult to identify especially in adults, because its clinical manifestations overlap with metabolic syndrome and diabetes mellitus. We experienced a case of a 38-year-old woman who abruptly gained weight from the age of five, and was diagnosed as type 2 diabetes mellitus (DM) during her 20s. When the patient visited JA Toride Medical Center at age 38, her renal function had been severely damaged, and caused congestive heart failure. Hemodialysis (HD) therapy was introduced, and GH insufficiency was identified, based on her obesity profile since her childhood and hormone surveillance. GH supplementation was initially avoided, because of her concurrent problems of DM and advanced renal failure. However, because of her restricted activities in daily living (ADL) and frequent hypotension episodes, a decision was taken to start supplementary administration of GH, which consequently succeeded in stabilizing blood pressure and extended her ADL. Although GH supplementation has recently been reported to be effective in improving protein energy malnutrition in dialysis patients without GH insufficiency, there is no report concerning GH insufficiency in dialysis patients. This is the first case report of GH insufficiency, in which GH supplementation enabled the patient to continue HD. PMID- 23819389 TI - [A primer for learning: thyroid hormone is a determining factor to start the sensitive period of filial imprinting of domestic chicks]. PMID- 23819390 TI - [Novel mechanism of neural circuit formation in the mammalian central nervous system: discovery of LOTUS serving for axon tract formation]. PMID- 23819391 TI - [Mitochondria and antiviral immunity]. PMID- 23819392 TI - [Serine-type integrases as tools for genome engineering]. PMID- 23819393 TI - [Cell wall shaping during bacterial morphogenesis]. PMID- 23819394 TI - [Interaction between Asp-hemolysin-related synthetic peptides and oxidized LDL/lysophospholipids]. PMID- 23819395 TI - [Mechanisms for maternal inheritance of mitochondrial DNA]. PMID- 23819396 TI - [Physiological significance of phosphatidylinositol 4-phosphate 5-kinase in mammals]. PMID- 23819397 TI - Most of the patients with suburethral sling failure have tapes located outside the high-pressure zone of the urethra. AB - OBJECTIVES: The high-pressure zone of the urethra (HPZ), which is crucial for the continence mechanism, extends between the point of the maximum urethral closure pressure and the urethral knee, and has been calculated to lie between 53% and 72% of the functional urethral length. According to recent studies the best results of suburethral slings are achieved when tapes are positioned under this zone. The aim of the study was to determine the location of tapes relative to the urethral length in patients seeking help due to recurrent stress urinary incontinence (SUI) following sling procedures. MATERIAL AND METHODS: The study group comprised 61 patients suffering from recurrent SUI following suburethral slings performed from 6 months to 5 years earlier Forty-nine (80.3%) women were initially treated with a transobturator sling and 12 (19.7%) with a retropubic procedure. Twenty patients had the original sling performed at our department whereas, the other 41 in other institutions. The position of the tapes was determined at the sagittal plane by 3-D transvaginal ultrasound using a linear transducer The length of the urethra was measured from the bladder neck to the external urethral meatus following the urethral lumen, taking into account its curve. The position of the tapes relative to the percentage of the urethral length was calculated assuming the bladder neck as the proximal end of the urethra. The reference point was set at the midpoint on the tape. RESULTS: Only 13 (21.3%) patients had tapes positioned at 50%-75% of the urethral length. In 45 (73.8%) of women examined the tapes were found under proximal half of the urethra and in 3 (4.9%) distally to the 75% of the urethral length. CONCLUSIONS: In most patients in whom slings procedures proved unsuccessful the tapes are located under the proximal half of the urethra, that is outside the HPZ The position of a.tape outside the HPZ may be considered as a cause of suburethral sling failure. PMID- 23819398 TI - [The use of venous ports in oncological patients]. AB - INTRODUCTION: Venous ports provide a permanent, long-lasting and easy access to the central veins. These subcutaneously inserted systems have found application in the therapy of patients with oncological and chronic illnesses, and in treatment of children with hemophilia. During a planned continuous infusion of chemotherapy they increase patient comfort, reducing the risk of local inflammatory states and moderating the risk of spilling the cytostatic agent to the perivesical compartment. MATERIAL AND METHODS: 83 patients with venous subcutaneous ports implanted between July 2006 and November 2011 were included into the study The methods of implantation and usage were presented. Length of time the port is in situ and occurrence of early and late complications was evaluated. RESULTS: The longest indwelling time for port was 1484 days, while the shortest was 70 days. In 89.9% of cases, the correct position of the port's tip was noted during a control X-ray performed after the implantation. Early complications were not observed, while late ones concerned 16.86% of patients and included: generalized bacteriemia (8.43%), local inflammation of the skin and of the subcutaneous tissue (1.2%), venous thrombosis (2.41%), migration of the catheter (1.2%), necrosis of the skin over the port's chamber (2.41%). CONCLUSION: Venous ports play an important role in the treatment of cancer patients. The placement of venous ports is a safe procedure that has a low rate of early complications. The frequency of late complications correlates with that described in the literature. PMID- 23819399 TI - Immunoexpression of the PTEN protein and matrix metalloproteinase-2 in endometrial cysts, endometrioid and clear cell ovarian cancer. AB - OBJECTIVES: Endometrioid and clear cell ovarian adenocarcinomas are suspected to derive from ectopic endometrial foci. The aim of the study was to determine PTEN and MMP-2 immunoexpression in endometrial ovarian cysts, endometrioid and clear cell ovarian carcinomas and to assess the relationship between the abovementioned values and clinical data of patients in order to find the marker of increased risk of malignant proliferation based on ovarian endometriotic lesions. Detailed analysis of the collected data was conducted to investigate the correlation between immunohistochemical expression of the examined antigens, histopathological diagnosis and clinical condition of patients. MATERIAL AND METHODS: 20 endometrial adenocarcinomas, 21 clear cell ovarian cancers and 26 endometrial cysts were included in the study The control group consisted of 29 specimens of physiological endometrium: 16 samples of the proliferative phase and 13 samples of the secretory phase. Protein expression of PTEN and MMP-2 was evaluated by immunohistochemistry Protein immunoexpression in the collected specimens was estimated with the use of light microscope and MultiScan software. Immunoreactivity of the PTEN antigen was assessed by the quantitative method, whereas MMP-2 immunoexpression was evaluated by the semi-quantitative method. Two sided tests were used for statistical inference. Generalized linear models were used to compare the studied groups. Error distributions were selected using the Akaike criterion (AIC). Statistical analysis was conducted with the use of the R Statistical Package. RESULTS: MMP-2 immunoreactivity differed significantly between the study groups and controls (p<0.001). PTEN immunoexpression was the strongest in endometrial cysts (53.7 %), lower in clear cell cancers (50.2%) and the lowest in endometrioid adenocarcinomas (43.88%), but the differences were not statistically significant (p=0.17). PTEN reactivity in the group of endometrioid carcinomas was significantly higher (p=0.02), while MMP-2 expression had a falling tendency (p=0.076) in obese women. CONCLUSIONS: Increased MMP-2 expression in the successive groups may imply a rising invasive potential of the epithelial cells in endometrial cysts, endometrioid and clear cell adenocarcinomas. Strong immunoreactivity for PTEN in proliferative endometrium implies its role in the regulation of endometrial proliferation. PTEN activity may reduce MMP-2 expression in insulin resistant women suffering from endometrial ovarian cancer Simultaneous evaluation of PTEN and MMP-2 immunoexpression in ectopic endometrial foci cannot be used to identify women with an increased risk of neoplastic transformation. PMID- 23819400 TI - Bacterial infections of the lower genital tract in fertile and infertile women from the southeastern Poland. AB - OBJECTIVES: The objective of the study was to investigate the detection rates of Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma urealyticum, Gardnerella vaginalis, Escherichia coli, Streptococcus agalactiae and Enterococcus faecalis, showing no clinical signs of an ongoing, acute inflammatory state of the vagina and/or the cenrvix, in fertile and infertile women. MATERIAL AND METHODS: The study encompassed 161 women, including 101 women treated for infertility and 60 fertile women who had already given birth to healthy children. The material for the presence of C. trachomatis, N. gonorrhoeae, M. genitalium, M. hominis and U. urealyticum was collected from the cervical canal and analyzed by PCR. Furthermore, BD ProbeTec ET system was used to detect C. trachomatis infection. Vaginal swabs were collected for classification of bacterial vaginosis and aerobic vaginitis and assessed according to the Nugent score, as well as by traditional culture methods. RESULTS: U. urealyticum was identified in 9% of the infertile women and in 8% of controls. Presence of M. hominis was demonstrated only in the former (4%) and C. trachomatis only in latter (3%). N. gonorrhoeae and M. genitalium were not found in any of the examined women. The frequency of aerobic vaginitis in both groups was estimated at 12%. There were 7% bacterial vaginosis cases in the study group, and none in the control group (p=0.0096). CONCLUSIONS: Despite having no symptoms of an ongoing acute inflammation of the reproductive tract, many women may experience permanent or periodic shifts of equilibrium of the vaginal and/or cervical microflora. BV develops more frequently in infertile patients when compared to the fertile women. PMID- 23819401 TI - Risk factors for cesarean section after using the Foley catheter for labor induction. AB - OBJECTIVE: The aim of the study was to investigate the value of the Bishop score and ultrasound examination of the cervix in predicting the success of labor induction with the use of the Foley catheter determined by the mode of delivery MATERIAL AND METHODS: Foley catheter induction of labor was performed in 135 pregnancies between 38 to 42 weeks gestation. The study group was divided into two groups, depending of the mode of delivery: vaginal vs. cesarean. RESULTS: The Bishop score was significantly higher in the vaginal delivery group when compared to the caesarean section group (5.2; 95%CI: 4.4 - 6.2 vs. 3.9; 95%CI: 2.8-4.9). Cervical length was not statistically significantly different between the two groups. Multivariate logistic regression showed that patient-specific risk for caesarean section decreases with increasing maternal age and the Bishop score (Detection Rate [DR] of 52% at fixed False Positive Rate [FPR] of 10%). CONCLUSIONS: Failure of labor induction with the use of the Foley catheter can be predicted by maternal age and pre-induction Bishop score. PMID- 23819402 TI - Vitamin D insufficiency in healthy pregnant women living in Warsaw. AB - BACKGROUND/OBJECTIVES: Ensuring the optimal level of 25-hydroxy-vitamin D (250HD) in serum (concentration above 30 ng/ml) is essential for protecting the health of the mother and the developing fetus. Vitamin D plays an important role in maintaining proper bone structure, preventing infections, reducing the risk of premature birth and gestational diabetes. The aim of the study was to verify whether healthy pregnant residents of Warsaw were deficient in vitamin D. MATERIAL AND METHODS: The material consisted of 150 serum samples of 50 healthy women in 1st, 2nd and 3rd trimester of pregnancy 72.7% of the sera were from women who reported taking multivitamin supplements containing vitamin D3 (71% out of that group was taking 400 IU daily). The concentration of 250HD was measured using the vitamin D total assay on Elecsys 2010 automatic analyzer (Roche Diagnostics). RESULTS: The average serum 250HD concentrations of 50 women in 1st, 2nd and 3rd trimester of pregnancy were respectively: 23.1 ng/ml, 24.8 ng/ml, and 25.1 ng/ml, with no statistically significant differences. The optimal levels of 250HD (30-80 ng/ml) were found in 30.0% of samples, hypovitaminosis (20-30 ng/ml) occurred in 38.7%, deficiency (10-20 ng/ml) in 24.0% and severe deficiency (less than 10 ng/ml) in 7.3% of cases. Mean concentration of 250HD in winter season (October 1 - March 31) was 23.6 ng/ml and in summer season (April 1 - September 30) was 25.5 ng/ml, with no statistically significant difference. On the basis of the BMI in 1st trimester two subgroups were distinguished from the studied subjects: BMI <21 (13 patients, 39 samples) and BMI >25 (14 patients, 42 samples). Mean 250HD concentration in these groups were 27.3 and 23.5 ng/ml respectively (p<0.05). High statistical significance (p<0.001) was found among the total number of samples with 250HD deficiency and severe deficiency (<20 ng/ml) and samples with hypovitaminosis and optimal 250HD level (>20 ng/ml) in these groups. CONCLUSIONS: Regardless of trimester and season, vitamin D below the optimal level is a common occurrence during pregnancy and the current level of supplementation among Polish pregnant women appears to be insufficient. Our data suggest that special attention should be paid to the problem of vitamin D insufficiency in overweight pregnant women. PMID- 23819403 TI - Maternal serum interleukin-6 level in preterm labor. AB - OBJECTIVE: The aim of this study was to measure interleukin-6 (IL-6) levels in maternal serum of women undergoing preterm labor without a clear infection. MATERIALS AND METHODS: Twenty two pregnant women with diagnosis of preterm labor who presented to the outpatient clinic of 19 Mayis University Faculty of Medicine from July 2011 through December 2011 were enrolled in the study group. Twenty two healthy pregnant women who were at the same gestational age as the study group were selected as the control group. RESULTS: Gestational age in the study and control groups varied from 24 weeks and 4 days to 34 weeks and 6 days. In the study group, 11 patients (50%) underwent preterm birth. Pregnant women in preterm labor were compared to healthy pregnant women with regards to serum IL-6 levels. No significant difference was found in the IL-6 levels of maternal serum between the 2 groups. CONCLUSION: In this study we have shown that there is no increase in lL-6 levels in patients undergoing preterm labor without clinical or biochemical infection signs. PMID- 23819404 TI - [Molecular basis of gynecological oncology - TopBP1 protein as the guardian of genome integrity]. AB - Breast cancer is the most common malignancy in women. Its estimated annual incidence is about one million cases worldwide. A number of risk factor have been identified, among them early menarche, late menopause, nulliparity and positive family history Moreover a number of highly penetrant breast and ovarian cancer susceptibility genes, such as BRCA 1 and BRCA2, have been identified. Recent findings suggest TopBP1 to be a breast and ovarian cancer susceptibility gene. Moreover; TopBPI protein may be an important prognostic marker of breast cancer TopBP1 protein is involved in DNA replication, mitosis and meiosis, as well as DNA repair Deregulation of these processes may have pathological implications in cancer PMID- 23819405 TI - [The significance of folate metabolism in complications of pregnant women]. AB - Proper metabolism of folates has a crucial role for body homeostasis. Folate metabolism regulates changing of amino acids (homocysteine and methionine), purine and pyrimidine synthesis and DNA methylation. These whole biochemical processes have significant influence on hematopoietic, cardiovascular and nervous system functions. The disturbances of folate cycle could result in chronic hypertension, coronary artery disease, higher risk of heart infarction, could promote cancers development, and psychic and neurodegenerative diseases. No less important is the connection with complications appearing in pregnant woman (recurrent miscarriages, preeclampsia, fetus hypotrophy intrauterine death, preterm placenta ablation, preterm delivery) and fetus defects (Down syndrome, spina bifida, encephalomeningocele, myelomeningocele). The complex process of folate metabolism requires adequate activity of many enzymes and presence of co enzymes. A key enzyme in folate metabolism is methylenetetrahydrofolate reductase (MTHFR - methylenetetrahydrofolate reductase), and 677C>T polymorphism of MTHFR gene is connected with lower enzymatic activity In several researches it was indicated that 677C>T MTHFR polymorphism is an independent factor influencing homocysteine concentration in serum, and also folate concentration in serum and red blood cells. Nevertheless, it was also observed the correlation of 677C>T MTHFR polymorphism with Down syndrome, and neural tube defects appearance in fetus. In European populations frequency of mutated 677TT genotype ranges from a few to several percent. Women carriers of 677TT or 677CT MTHFR genotypes are exposed on folate metabolism disturbances and on the consequences of incorrect folate process during pregnancy Nowadays in this group of women folic acid supplementation is widely recommended. In the light of modern knowledge the attention was also focused on the importance of metafolin administration that omitted pathways of folic acid transformation after administration, and in pregnant women certainly is valuable complement of supplementation in this respect. PMID- 23819406 TI - [Merkel cell carcinoma of the vulva - case report and the literature review]. AB - Merkel cell carcinoma (MCC) is a rare malignant neoplasm, mostly affecting the skin (97% of cases). It is usually found in elderly people, in the sun-exposed areas of the skin. About 50-60% of MCC cases are located on the head and the neck, less often on the extremities and the torso, and extremely rarely in the genital area. Ultraviolet radiation may be the main factor responsible for the development of the tumors but viral etiology is also debated. Due to extremely rare incidence of MCC in the area of the vulva, proper management remains a challenging task. AIM: To present a case of an aggressive MCC of the vulva and a review of the literature. MATERIAL AND METHODS: A previously healthy 72-year-old patient presented at the Oncology Center of the Maria Sklodowska-Curie Institute, Warsaw, in June 2010. Four months previously the patient noticed a painless lump in the vestibular region of the vagina. She received anti-inflammatory treatment at her local gynecological clinic, with no success. In February the patient underwent removal of the vulvar tumor Histopathological examination confirmed anaplastic carcinoma. Microscopic evaluation revealed the tumor diameter to be 15mm. Surgical margins were free of neoplastic infiltration. The patient did not receive adjuvant therapy due to the results from the histopathological protocol. The disease recurred after three months. Radical vulvectomy and bilateral inguinal femoral lymphadenectomy were performed in May 2010. Histopathological examination confirmed microcellular carcinoma with no metastases to the lymph nodes and complete resection of the tumor (RO). The disease recurred in the next two months: a 50-mm tumor was found in the right inguinal lymph nodes. The decision to verify all histopathological material obtained during all procedures performed so far was made. Immunohistochemical evaluation confirmed MCC. Adjuvant radiotherapy was recommended. The area of the vulva, pelvic and inguinal lymph nodes were irradiated. One month after therapy completion the patient complained of pain in the lumbar area. An ultrasound examination of the abdomen revealed a tumor (9 cm in diameter) in the para-aortic region but it was not histopathologically verified due to extremely poor overall condition of the patient. As the condition of the woman deteriorated systematically the patient was referred to a hospice facility where she died 9 months since the primary diagnosis. CONCLUSIONS: MCC of the vulva is a rare neoplasm with an aggressive course. Clinical and histopathological diagnostic difficulties and consequently lack of standardized management, result in low survival rates. PMID- 23819407 TI - [Intrauterine fetal therapy of NIHF with massive pleural effusion - a case study]. AB - Hydrops fetalis (fetal hydrops) is a serious fetal condition defined as abnormal accumulation of fluid in two or more extravascular compartments, including ascites, pleural effusion, pericardial effusion, and skin edema. Edema is classified as immune or non-immune. Today more than 90% of fetal edema has non immune cause. This paper presents a case of a pregnant woman who was admitted to the Obstetrics and Gynecology Department because of fetal hydrops with massive pleural effusion and polyhydramnios at 34 weeks gestation. The intrauterine therapy consisted of two treatments. During the first surgery amnioreduction, evacuation of fluid from the pleural cavity of the fetus, and shunts to both pleural cavities were performed. During the second surgery amnioreduction, cordocentesis with albumin administration and pleural shunt were performed. Intrauterine therapy led to a reduction of swelling of the fetus from 7mm up to 1 2 mm and the total evacuation of fluid from the pleural cavity and the fetal lung expansion. We also present the condition of the neonate after birth and after 12 months of life. PMID- 23819408 TI - [Guidelines for application of molecular tests identyfying HR HPV DNA in the prevention of cervical cancer. Statement of experts from PGS (PTG) and NCLD (KIDL)]. AB - DNA from high risk types of human papillomavirus (HPV-HR) is detected in virtually all cervical cancer samples. Most of HPV infections are transient, some persist and lead to development of neoplastics or even cervical cancer lesions. Cervical cancer screening programs are designed to detect early precancerous changes, which should decrease the cancer morbidity and mortality and reduce the costs of diagnosis and treatment. The most effective are screening programs that use cytological and HPV testing. Screening with this method are proven to reduce both the incidence and mortality from cervical cancer WOMEN AGED 21-29 YEARS: HPV testing should not be used to screen women aged 21-29 years, either as a stand alone test or as a cotest with cytology DNA HPV HR testing in this group of women is recommended in diagnostics ofASCUS. Women DNA HPV positive with ASCUS should be referred to colposcopy WOMEN AGED 30-65 YEARS: Screening by HPV testing alone is not recommended. Women should be screened with cytology and HPV testing every 5 years or cytology alone every 3 years (acceptable). DNA HPV HR /+/, PAP /-/: Two options are recommended. Option 1: 12-months follow-up with contesting (PAP and DNA HPV HR tests). Option 2: Test for HPV16 or HPV16/18 genotypes. If HPV16 or HPV16/18 positive: refer to colposcopy If HPV16 or HPV16/18 negative:12-months follow-up with cotesting. DNA HPV HR /-/, ASC-US: Repetition of cytology in 12 moths is recommended. WOMEN AGED >65 YEARS: No screening is recommended following adequate negative prior to screening. Women with a history of CIN2 or a more severe diagnosis should continue routine screening for at least 20 years. WOMEN HPV VACCINATED: Follow age-specific recommendations (same as unvaccinated women). REQUIREMENTS OF DNA HPV HR TESTS IN CERVICAL SCREENING: The DNA HPV tests used in cervical screening should detect as much as possible of 14 HPV HR types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 i 68) and genotyping HPV 16/18. Candidates' tests should have control of DNA HPV purification and amplification processes and be preserved against contaminations. Clinical sensitivity for CIN 2 + should be no less than 90%. HPV tests and specimen collection system should fulfill the requirements of the act on medical devices. PMID- 23819409 TI - [Physiopharmacotherapy as an approach to the treatment, prophylaxis, and rehabilitation]. AB - The necessity of and prospects for the development of physiopharmacotherapy as a new direction of physical therapy are substantiated. The article provides information about physiopharmacological and photochemotherapeutical methods and the influence of physical factors on pharmacokinetics and pharmacodynamics of pharmaceutical products. The possibility of preventing (or relieving) side effects and overcoming drug resistance as well as improving the pharmacotherapeutic potential of various agents by applying therapeutic physical factors is demonstrated. PMID- 23819410 TI - [The application of physical factors for the rehabilitative treatment of vertebrogenic cerebral dyscirculation]. AB - The present study included 65 patients presenting with vertebrogenic cerebral dyscirculation and degenerative change within the cervical spine in the absence of hemodynamically and/or morphologically significant lesions in brachiocephalic arteries. During the first phase of the study, 39 randomly selected patients underwent traction of the cervical spine following collar zone massage. Moreover, they were instructed to simultaneously wear a soft cervical collar. The analysis of the results of this treatment showed that a combination of physiotherapeutic procedures produces the beneficial effect in the patients with the early manifestation of degenerative processes in the form of cerebral instability. Those suffering more severe anatomical changes in the vertebral column (spondylosis, spondyloarthrosis, spinal disk dislocation) are much less likely to benefit from the proposed treatment. The patients for the second group (n=26) were selected based on the results X-ray examination; they presented with vertebral instability requiring combined physiotherapeutic treatment including collar zone massage, orthotraction therapy, and simultaneous wearing a soft cervical collar. The results of the treatment were assessed from dynamics of clinical manifestations and the results of radioisotope studies of cerebral blood flow. No complications of combined physiotherapy were documented. The effectiveness of orthotraction therapy after preliminary collar zone massage in the patients of group 2 was estimated at 88.5%. Moreover, arterial pressure in the patients with concomitant arterial hypertension was reduced in conjunction with the improvement of venous outflow characteristics. PMID- 23819411 TI - [The use of siliceous baths for the treatment of the patients presenting with arterial hypertension]. AB - This article is focused on the benefits of drug-free therapeutic technologies, such as the use of artificial general siliceous baths for the treatment of patients with arterial hypertension. This approach results in the anti hypertensive effect simultaneous with the correction of lipid metabolism and lipid peroxidation. The positive changes due to the specific action of silicic acid were much more pronounced than those induced by the hydrostatic water pressure or water temperature known to be the main factors producing the therapeutic effect in fresh-water baths. General siliceous baths with the silicic acid concentration of 50-100 mg/I are recommended for the treatment of patients presenting with grade I-II arterial hypertension (stage II-III) and high risk of development of cardiovascular complications associated with coronary heart disease. One of the advantages of the proposed modality is it does not only produce the hypotensive effect but also exerts specific influence on lipid metabolism. PMID- 23819412 TI - [The heart rate variability during the balneotherapeutic treatment of tension type headache based at the "Ust-Kachka" health resort]. AB - A total of 94 patients suffering tension-type headache were admitted for the treatment at the "Ust-Kachka" health resort. They were divided into three depending on the chosen therapeutic modality. The patients of group 1 were offered bromide-iodine baths in combination with transcranial electric brain stimulation. In the second group, balneotherapy was combined with endonasal electrophoresis of mildronate. The patients of the control group were managed with the use of balneotherapeutic procedures alone. Evaluation of the heart rate variability revealed a significant decrease of the overall spectrum power. The very low frequency (VLF) component proved to be predominant spectral constituent. The results of the orthostatic test reflected the different degree of disturbances of vegetative reactivity in all the three groups; it varied from the excessive sympathetic supply to the paradoxical reaction. The post-treatment period was characterized by well-apparent positive dynamics in the vegetative sphere of the patients in terms of overall power spectrum with evident priority of its parameters in the first group. PMID- 23819413 TI - [The influence of general magnetic therapy on the psychological status of the patients presenting with osteoarthrosis]. AB - The present study was designed to estimate the influence of general magnetic therapy on the psychical conditions of 151 patients presenting with degenerative joint diseases including osteoarthritis (OA). It was shown that the application of general magnetic therapy for the rehabilitative treatment of osteoarthrosis promotes the improvement of the psycho-emotional state of the patients. It is concluded that prescription of general magnetic therapy to the patients with OA suffering from serious psycho-emotional disorders brings about beneficial changes in their anxiety- and depression-related personality traits. PMID- 23819414 TI - [The influence of classical back and neck massage on the functional state of the cardiovascular system and the frequency-time characteristics of its variability in the adolescents]. AB - The present study was designed to study the influence of classical back and neck massage on the functional state of the cardiovascular system and its regulation under conditions of short-term physical loading in the healthy adolescents. It was shown that a course of classical massage promoted the reduction of arterial pressure in all children and the heart rate frequency in the boys. This effect was apparent as a reaction of blood circulation to the dosed physical exercises manifested as a rise in the heart rate frequency and stroke volume. The effects of classical massage were shown to be mediated through the alteration of the levels and mechanisms of regulation of the blood circulatory system and the enhancement of humoral and metabolic segmental sympathetic influences associated with the adaptation to the impact of massage therapy. PMID- 23819415 TI - [Estimation of the efficacy of inertialess exercise machines used for the rehabilitation of adolescents presenting with pediatric cerebral palsy]. AB - The objective of the present study was to estimate the role of the heyvus training machine as a tool for enhancing the effectiveness of combined rehabilitation of the adolescent patients suffering from spastic diplegia cerebral paralysis. The mechanisms of action of this treatment on the clinical manifestations of compromised statics and voluntary movements have been elucidated. PMID- 23819416 TI - [The effectiveness of sulfate magnesium-calcium mineral water for the treatment of the patients presenting with chronic acalculous cholecystitis]. AB - This paper was designed to report the results of investigations into the therapeutic effectiveness of "Kluchi" sulfate magnesiumcalcium mineral water used to treat 194 patients presenting with chronic acalculous cholecystitis and different types of biliary tract dysfunction. The control group was comprised of 92 patients who took a diet. It was shown, that mineral water "Kluchi" exerted well apparent beneficial action on the motor function of the gallbladder and the sphincter apparatus. Moreover, drinking the mineral water improved colloidal stability of bile. It is concluded that the therapeutic application of "Kluchi" sulfate magnesium-calcium mineral water results in the reduction of bile lihogenicity, produces anti-inflammatory and choleretic effects, and promotes normalization of the motor and tonic condition of the biliary tract. PMID- 23819417 TI - [Combined laser therapy of the reactivated form of cytomegalovirus infection of the urogenital tract in the women of reproductive age]. AB - The prevalence of cytomegalovirus infection (CMVI) dictates the necessity of its in-depth investigation in the patients presenting with the signs of chronic inflammatory diseases of sexual organs. The objective of the present study was to estimate the effectiveness of combined laser therapy of inflammatory diseases of the urogenital tract accompanied by the reactivation of CMVI concomitant with other infections. The examination of 158 women presenting with cytomegalovirus infection revealed clinical and laboratory characteristics of the microbiocenosis. These data may be used to improve the effectiveness of diagnostic and therapeutic strategies for such patients. The combined treatment of the patients with the reactivated form of CMVI using josamycin and doxycycline monohydrate in combination with panavir and low-intensity laser irradiation based at the "Matrix-Urolog" laser complex resulted in the favourable outcome of therapy in the majority of the patients. PMID- 23819418 TI - [The use of endonasal electrophoresis for the conservative rehabilitation of the patients presenting with septal perforation]. AB - The treatment of perforation of the nasal septum (PNS) is one of the challenging problems currently facing otorhinolaryngology. The enhancement of the effectiveness of the conservative treatment of PNS was achieved through the three stage development of the methodology including septal fixation in combination with targeted long-term drug application to the affected tissues. At the first stage of the study, characteristic features of the septal defects in patients with PNS were studied. At the second stage, we have developed the method for the conservative treatment of PNS based on the stenting of the nasal septum with the use of original heptangular splinters. At the third stage, the comprehensive comparative analysis was undertaken to estimate the effectiveness of the application of the original method of conservative treatment of the patients with PNS and traditional symptomatic therapy. It is concluded that the proposed original method for the treatment of patients with PNS based on the preventive stenting of the nasal septum original heptangular splinters one of which is equipped with a magnetic manipulation channel is an efficacious method for the conservative treatment of septal perforations. The method provides the basis for the new algorithm of management for the management of the patients suffering from PNS. PMID- 23819419 TI - [Thermal therapy for the management of cardiovascular pathology]. AB - This paper reports the results of analysis of the study on the effect of thermal therapy in the patients presenting with cardiovascular diseases including coronary heart disease, chronic heart failure, and myocardial infarction. It is shown that the correct application of the "Finnish" and infrared sauna taking into consideration specific clinical characteristics of the disease in question and with strict compliance to the relevant methodological recommendations can produce beneficial effects in the form of the improved endothelial function, reduced heart rate variability and oxidative stress as well as enhanced physical performance. It is concluded that full-scale studies in accordance with the principles of evidence-based medicine are needed to further improve the effectiveness of the thermal treatment of cardiovascular diseases and the reliability of the data obtained. PMID- 23819420 TI - [Cryotherapy in stomatology: state-of-the-art]. AB - Increasingly more attention has recently been given by practicing clinicians to the physiotherapeutic methods that influence the human body in a variety of ways. Specifically, they affect the dentofacial system. Cryotherapy is an efficacious physiotherapeutic modality characterized by the high therapeutic effectiveness and allowing the use of pharmaceutical products to be reduced to a minimum. PMID- 23819421 TI - [S.A. Burshtein, the founder of Russian physioytherapy (on the occasion of his 140th birthday anniversary)]. PMID- 23819422 TI - [Fetal diagnosis and prognosis of Ebstein's anomaly]. AB - BACKGROUND: Currently fetal echocardiography may confirm the diagnosis in utero of Ebstein anomaly, as well as determine the perinatal outcome with high certainty. OBJECTIVE: To review 16 cases diagnosed with Ebstein anomaly, by fetal echocardiography, analyzing prognostic echocardiographic parameters set by Pavlova and colleagues. MATERIAL AND METHOD: A descriptive, observational, retrospective study was done in patients with fetal diagnosis of Ebstein anomaly, during January 2001 to December 2011. Echocardiographic parameters are analyzed and its correlation to perinatal evolution of 16 cases of Ebstein anomaly. RESULTS: Maternal age was of 27.94 + 5.7 years, gestational age was 31.3 +/- 3.6 weeks. In utero mortality represented 37.5% (n = 6), and neonatal mortality 50% (n = 8), two patients (12.5%) survived. Cardiothoracic index was of 0.61 +/- 0.074, ratio foramen ovale-atrial septal was of 0.6 +/- 0.015, obstruction of the outflow tract of the right ventricle was seen in 14 (87.5%) patients; 81% of the deceased had a degree of displacement valve > 2.5; ratio right ventricle-left ventricle 2.24 +/- 0.37. The umbilical vein was throbbing in 64% of the deceased, the tricuspid insufficiency was severe in 15 cases (94%, 21.62 +/- 2.82 mmHg), hydrops affected 18.7% of patients. CONCLUSIONS: The following factors are of bad prognosis in fetal stage of Ebstein anomaly: cardiothoracic index > 0.55, relative foramen ovale-atrial septal <0.3, the obstruction to the outflow tract, a degree of valve displacement > 2.5, absence of reverse flow in the duct arteriosus, ratio right ventricle-left ventricle > 2. The Ebstein anomaly diagnosed in utero has a perinatal mortality of 87.5%. PMID- 23819423 TI - [Clinical efficacy of fluconazole, tinidazole and clindamycin vs fluconazole, tinidazole and azithromycin in the treatment of mixed cervical-vaginal infections, included those caused by Mycoplasma and Chlamydia trachomatis]. AB - BACKGROUND: In the United States 19 million people acquire a sexually transmitted disease every year. Sexually transmitted diseases impact in gynecological terms because they may cause sterility, infertility and ectopic pregnancy. OBJECTIVE: To compare the effectiveness of two combinations of three oral antimicrobial drugs in the treatment of mixed cervical-vaginal infections, included those caused by Mycoplasma and Chlamydia trachomatis. MATERIAL AND METHOD: Aclinical, random, comparative, double-blind study included 50 patients assisting to infectology consult with diagnosis of mixed cervical-vaginal infection. Patients were divided into two groups: Group A (n = 25): fluconazole 37.5 mg, tinidazole 500 mg and azithromycin 250 mg; group B (n = 25): fluconazole 37.5 mg, tinidazole 500 mg and clindamycin 312.5 mg. Patients of both groups received two tablets twice p.o. for one day. Cultures were performed to corroborate the diagnosis and then to demonstrate effectiveness of the schemes studied. For the analysis of the data we used measures of central tendency, dispersion and inferential statistics for comparison of proportions by c2 and Fisher's exact tests with a significance level of p < 0.05. RESULTS: All patient got clinical cure; however, regarding the microbiologic eradication a positive case was identified in group A, requiring rescue treatment. The compliance in both groups was of 100%. In both groups, statistical analysis did not show significant differences. Three patients in group A had mild adverse effects. Patients mean age was 33.4 +/- 5.3 years. CONCLUSIONS: Both treatments showed similar effectiveness against mixed cervical vaginal infections. Microbiological efficacy was of 96% and 100% in group A and B, respectively, besides, scheme of group B was better tolerated. PMID- 23819424 TI - [Factors related to hemorrhage during cesarean section]. AB - BACKGROUND: Cesarean section is the most frequent surgery done at health sector hospitals and its most frequent complications include hemorrhage. OBJECTIVES: To determine if risk factors known for this complication are really a risk and to determine the reliability of the measurement of hematocrit and hemoglobin as parameters to quantify the hemorrhage. MATERIAL AND METHODS: A prospective study involving 412 patients was done analyzing the following variables: age, previous cesarean section, occupation, body mass index, hours of labor, weight of the newborn, surgical time, bleeding estimated by the anesthesiologist, hemoglobin and hematocrit. RESULTS: By measuring hemoglobin a significant difference was obtained in favor of minor bleeding in the groups of 21 to 30 years, with normal weight and moderate obesity, with two prior cesarean sections, weight of the newborns of 3 to 4 kg, with less than two hours of labor, when the surgery took less than 50 minutes and when the bleeding was estimated at less than 500 mL. By measuring hematocrit the difference was significant in favor of more bleeding in the following groups: from 31 to 40 years, with mild obesity, without none or one cesarean section, with weight of newborns from 3 to 4 kg, with three to six hours of labor, when the cesarean section took 41 to 50 minutes and when the bleeding was estimated at less than 500 mL. CONCLUSIONS: There are significant differences with the measurement of hemoglobin and hematocrit among the risk factors analyzed. PMID- 23819425 TI - [Genetic variants associated to male infertility in Mexican patients]. AB - Recently Mexican Federation of Obstetrics and Gynecology Colleges (Federacion Mexicana de Colegios de Obstetricia y Ginecologia, FEMECOG) published the Mexican guideline forthe management of male infertility, which suggests performing genetic laboratory tests as part of diagnosis and management of infertile patients and states that these should receive genetic counseling. This paper reviews the genetic approach proposed by Mexican guideline. A systematic review of medical literature was performed in Pubmed and Web of Knowledge from 1980 to 2012 in order to find reports of genetic variants associated to male infertility in Mexican patients. Also it is discussed the current knowledge of these variants, their clinical implications and finally the guidelines and recommendations for their molecular diagnosis. Most genetic variants in Mexican infertile patients are chromosome abnormalities. In relation to other variants there is only a report of Y chromosome microdeletions, repeated CAG in androgen receptor and more common mutations in CFTR, and other article reporting mutations in CFTR in patients with congenital absence of vas deferens. Little is known about the genetics of Mexican infertile patients apart from chromosome abnormalities. However, the contribution of genetics as etiology of male infertility is taking more relevance and currently the consensual management of infertile male should include the screening of genetic background. This review pretends to be a quick guide for clinicians who want to know about reports of genetic variants related to male infertility in Mexican population and how to approach their diagnosis. PMID- 23819426 TI - [Antenatal diagnosis of placental acretism-percretism]. AB - Placental acretism is an adherencial pathology associated with a high maternal morbidity and mortality rates. Antepartum diagnosis is essential to plan a proper management and reduce serious complications. Risk factors in these patients include prior cesarean sections, uterine scars and placenta previa. Second level ultrasonography may detect placental acretism with high sensitivity and specificity; magnetic resonance imaging may play a complimentary role in the diagnosis of placental acretism when ultrasonographic findings are non conclusive, specially when determining miometrium invasion in placental acretism (incretism, percretism). This paper reports the case of a patient treated at the ABC Medical Center of Santa Fe, in her second gestation with the diagnosis of an arcuate uterus, previous cesarean section and placenta previa who presented a vaginal bleeding during pregnancy; ultrasound evaluation, in the second trimester, identified a probable placental acretism, in the third trimester, the same technology suggested placenta percreta, complimentary magnetic resonance imaging supported this diagnosis, with probable invasion to bladder, bowel and abdominal wall muscles. Imaging studies were performed at the Hospital Angeles Lomas (Maternal Fetal Clinic). A diagnosis of placenta acreta-percreta, called for a multidisciplinary surgical team, availability of blood products and other resources to face probable complications associated to the obstetrical resolution. Maternal results were optimal since histopathological evaluation reported miometrial incretism, with placental invasion millimeters away from the uterine serosa. Most ultrasonographic studies evaluating the invasion degree of the placenta have small sample sizes, generating a greater degree of false positive or false negative observations. Therefore, we agree with other authors that in all acretism cases (independent of their invasion degree), a multidisciplinary surgical team should be assembled in order to increase patient's safety. Risk factor identification, precise prenatal diagnosis, and multidisciplinary management diminish maternal morbidity and mortality rates during obstetric resolution procedures. PMID- 23819427 TI - [Adnexal torsion: three cases]. AB - Adnexal torsion is a gynecological emergency caused by the torsion of the ovary over its pedicle producing lymphatic and venous stasis, later it develops into ischemia and necrosis, when is not treated. Until recently, the treatment for adnexal torsion has been adnexectomy. This paper report three cases treated successfully with conservative treatment. It is essential to establish a protocol for adnexal torsion management where radical treatments are abandoned and conservative surgeries, such as detorsion and plication, are performed. We suggest as a first choice management adnexal detorsion, in case malignity is suspected to have intraoperative pathologic analysis, and based on the results to decide to preserve the adnexal or remove it for definitive cure. PMID- 23819428 TI - [Positive result of human chorionic gonadotropin. Diagnostic considerations]. AB - Positive serum beta-human chorionic gonadotropin (beta-HCG) in reproductive-age women generally indicates a pregnancy in healthy women. Nevertheless, this result can also be associated to other different etiologies that every gynecologist must know. A case report of a 41-year-old woman who had an elevated beta-HCG serum level without pregnancy is presented, which turned out to be the first sign of lung cancer. PMID- 23819429 TI - [Gender-based violence: a too high price]. PMID- 23819430 TI - [Endometriosis: certain infrequent aspects. 1958]. PMID- 23819431 TI - [About gyneco-obstetrics and subspecialties]. PMID- 23819433 TI - Impact of Metformin and compound C on NIS expression and iodine uptake in vitro and in vivo: a role for CRE in AMPK modulation of thyroid function. AB - BACKGROUND: Although adenosine monophosphate activated protein kinase (AMPK) plays a crucial role in energy metabolism, a direct effect of AMPK modulation on thyroid function has only recently been reported, and much of its function in the thyroid is currently unknown. The aim of this study was to investigate the mechanism of AMPK modulation in iodide uptake. Furthermore, we wanted to investigate the potential of the AMPK inhibitor compound C as an enhancer of iodide uptake by thyrocytes. METHODS: The in vitro and in vivo effects of AMPK modulation on sodium-iodide symporter (NIS) protein levels and iodide uptake were examined in follicular rat thyroid cell-line cells and C57Bl6/J mice. Activation of AMPK by metformin resulted in a strong reduction of iodide uptake (up to sixfold with 5 mM metformin after 96 h) and NIS protein levels in vitro, whereas AMPK inhibition by compound C not only stimulated iodide uptake but also enhanced NIS protein levels both in vitro (up to sevenfold with 1 MUM compound C after 96 h) and in vivo (1.5-fold after daily injections with 20 mg/kg for 4 days). We investigated the regulation of NIS expression by AMPK using a range of promoter constructs consisting of either the NIS promoter or isolated CRE (cAMP response element) and NF-kappaB elements, which are present within the NIS promoter. RESULTS: Metformin reduced NIS promoter activity (0.6-fold of control), whereas compound C stimulated its activity (3.4-fold) after 4 days. This largely coincides with CRE activation (0.6- and 3.0-fold). These experiments show that AMPK exerts its effects on iodide uptake, at least partly, through the CRE element in the NIS promoter. Furthermore, we have used AMPK-alpha1 knockout mice to determine the long-term effects of AMPK inhibition without chemical compounds. These mice have a less active thyroid, as shown by reduced colloid volume and reduced responsiveness to thyrotropin. CONCLUSION: NIS expression and iodine uptake in thyrocytes can be modulated by metformin and compound C. These compounds exert their effect by modulation of AMPK, which, in turn, regulates the activation of the CRE element in the NIS promoter. Overall, this suggests that the use of AMPK modulating compounds may be useful for the enhancement of iodide uptake by thyrocytes, which could be useful for the treatment of thyroid cancer patients with radioactive iodine. PMID- 23819434 TI - Ultrathin BaTiO3 nanowires with high aspect ratio: a simple one-step hydrothermal synthesis and their strong microwave absorption. AB - In this paper, we report the facile synthesis of ultrathin barium titanate (BaTiO3) nanowires with gram-level yield via a simple one-step hydrothermal treatment. Our BaTiO3 nanowires have unique features: single crystalline, uniform size distribution and ultra high aspect ratio. The synergistic effects including both Ostwald ripening and cation exchange reaction are responsible for the growth of the ultrathin BaTiO3 nanowires. The microwave absorption capability of the ultrathin BaTiO3 nanowires is improved compared to that of BaTiO3 nanotorus,1 with a maximum reflection loss as high as -24.6 dB at 9.04 GHz and an absorption bandwidth of 2.4 GHz (<-10 dB). Our method has some novel advantages: simple, facile, low cost and high synthesis yield, which might be developed to prepare other ferroelectric nanostructures. The strong microwave absorption property of the ultrathin BaTiO3 nanowires indicates that these nanowires could be used as promising materials for microwave-absorption and stealth camouflage techniques. PMID- 23819435 TI - Diplotyper: diplotype-based association analysis. AB - BACKGROUND: It was previously reported that an association analysis based on haplotype clusters increased power over single-locus tests, and that another association test based on diplotype trend regression analysis outperformed other, more common association approaches. We suggest a novel algorithm to combine haplotype cluster- and diplotype-based analyses. METHODS: Diplotyper combines a novel algorithm designed to cluster haplotypes of interest from a given set of haplotypes with two existing tools: Haploview, for analyses of linkage disequilibrium blocks and haplotypes, and PLINK, to generate all possible diplotypes from given genotypes of samples and calculate linear or logistic regression. In addition, procedures for generating all possible diplotypes from the haplotype clusters and transforming these diplotypes into PLINK formats were implemented. RESULTS: Diplotyper is a fully automated tool for performing association analysis based on diplotypes in a population. Diplotyper was tested through association analysis of hepatic lipase (LIPC) gene polymorphisms or diplotypes and levels of high-density lipoprotein (HDL) cholesterol. CONCLUSIONS: Diplotyper is useful for identifying more precise and distinct signals over single-locus tests. PMID- 23819436 TI - Dextran-lipase conjugates as tools for low molecular weight ligand immobilization in microarray development. AB - The development of effective array biosensors relies heavily on careful control of the density of surface-immobilized ligands on the transducing platform. In this paper we describe the synthesis of new dextran-lipase conjugates for use in immobilizing low molecular weight haptens onto glass planar waveguides for immunosensor development. The conjugates were synthesized by immobilizing bacterial thermoalkalophilic lipases (Geobacillus thermocatenulatus lipase 2, BTL2) on agarose macroporous beads, followed by covalent coupling to dextran networks of variable molecular weight (1500-40000). The chimeras were immobilized via nonspecific hydrophobic interactions onto glass planar waveguides modified with 1,1,1,3,3,3-hexamethyldisilazane to obtain highly ordered and homogeneous molecular architectures as confirmed by atomic force microscopy. Microcystin LR (MCLR) was covalently bound to the dextran-BTL2 conjugates. The usefulness of this approach in immunosensor development was demonstrated by determining amounts of MCLR down to a few picograms per liter with an automated array biosensor and evanescent wave excitation for fluorescence measurements of attached DyLight649 labeled secondary antibody. Modifying BTL2 with dextrans of an increased molecular weight (>6000) provided surfaces with an increased loading capacity that was ascribed to the production of three-dimensional surfaces by the effect of analyte binding deep in the volume, leading to expanded dynamic ranges (0.09 136.56 ng L(-1)), lower limits of detection (0.007 +/- 0.001 ng L(-1)), and lower IC50 values (4.4 +/- 0.7 ng L(-1)). These results confirm the effectiveness of our approach for the development of high-performance biosensing platforms. PMID- 23819437 TI - Asthma diagnosis and treatment - 1012. The efficacy of budesonide in the treatmetn of acute asthma in children: a double-blind, randomized, controlled trial. PMID- 23819438 TI - Contemporary carbocation chemistry: applications in organic synthesis. PMID- 23819439 TI - Changes of gait pattern in children with Charcot-Marie-Tooth disease type 1A: a 18 months follow-up study. AB - BACKGROUND: In a previous study we identified 3 different gait patterns in a group of children with CMT1A disease: Normal-like (NL), Foot-drop (FD), Foot-drop and Push-off Deficit (FD&POD). Goal of the present study was to perform a follow up evaluation of the same group of patients to analyze possible changes of gait features in relation to disease progression or specific therapy. METHODS: Nineteen children with CMT1A were evaluated clinically (CMT-Examination Score and Overall Neuropathy Limitation Scale) and through gait analysis 18.2+/-1.5 months after a baseline evaluation. Meanwhile, 3 of them had foot surgery. RESULTS: Fifteen out of the 16 non-operated patients significantly changed at least one of the two parameters associated to primary signs (FD and/or POD). Eleven participants worsened at least one parameter and 9 improved one parameter. CMTES significantly worsened for the group of non-operated patients. However, there was no change in CMTES score in 4 patients and in ONLS score in 11. At subgroup level, participants originally belonging to NL group showed a trend towards a foot-drop deficit (-15%, ns); FD and FD&POD subgroups did not change their primary signs, although significant changes were identified individually. All 3 patients operated have improved push-off and proximal joint patterns during walking. Clinical scores did not change within any sub-group. CONCLUSIONS: Subtle changes occurring in 1.5 year in gait features of CMT1A children can be instrumentally identified. Such changes show a large inter-subject variability, with some patients even improving their walking pattern. There is anecdotal evidence that foot surgery may improve the push-off phase of gait. PMID- 23819440 TI - Platelet-derived growth factor-A regulates lung fibroblast S-phase entry through p27(kip1) and FoxO3a. AB - BACKGROUND: Secondary pulmonary alveolar septal formation requires platelet derived growth factor (PDGF-A) and platelet derived growth factor receptor-alpha (PDGFRalpha), and their regulation influences alveolar septal areal density and thickness. Insufficient PDGFRalpha expression in lung fibroblasts (LF) results in failed septation. METHODS: Mice in which the endogenous PDGFRalpha-gene regulates expression of the green fluorescent protein were used to temporally and spatially track PDGFRalpha-signaling. Transition from the G1/G0 to the S-phase of the cell cycle was compared in PDGFRalpha-expressing and non-expressing LF using flow cytometry. Laser scanning confocal microscopy was used to quantify p27(kip1) and forkhead box "other" 3a (FoxO3a) in the nuclei of alveolar cells from mice bearing the PDGFRalpha-GFP knock-in, and p27(kip1) in mice with a conditional deletion of PDGFRalpha-gene function. The effects of PDGF-A on the phosphorylation and the intracellular location of FoxO3a were examined using Western immuoblotting and immunocytochemistry. RESULTS: In neonatal mouse lungs, entry of the PDGFRalpha-expressing LF subpopulation into the S-phase of the cell cycle diminished sooner than in their non-expressing LF counterparts. This preferential diminution was influenced by PDGFRalpha-mediated signaling, which phosphorylates and promotes cytoplasmic localization of FoxO3a. Comparative observations of LF at different ages during secondary septation and in mice that lack PDGFRalpha in alveolar LF demonstrated that nuclear localization of the G1 cyclin-dependent kinase inhibitor p27(kip1) correlated with reduced LF entry into S-phase. CONCLUSIONS: Nuclear localization of FoxO3a, an important regulator of p27(kip1) gene-expression, correlates with diminished proliferation of the PDGFRalpha-expressing LF subpopulation. These mechanisms for diminishing the effects of PDGFRalpha-mediated signaling likely regulate secondary septal formation and their derangement may contribute to imbalanced fibroblast cell kinetics in parenchymal lung diseases. PMID- 23819442 TI - Formation of new non-oxido vanadium(IV) species in aqueous solution and in the solid state by tridentate (O, N, O) ligands and rationalization of their EPR behavior. AB - The systems formed by the V(IV)O(2+) ion with tridentate ligands provided with the (O, N(imine), O) donor set were described. The ligands studied were 2,2' dihydroxyazobenzene (Hdhab), alpha-(2-hydroxy-5-methylphenylimino)-o-cresol (Hhmpic), calmagite (H2calm), anthracene chrome red A (H3anth), calcon (H2calc), and calconcarboxylic acid (H3calc(C)). They can bind vanadium with the two deprotonated phenol groups and the imine nitrogen to give (5,6)-membered chelate rings. The systems were studied with EPR, UV-vis and IR spectroscopy, pH potentiometry, and DFT methods. The ligands form unusual non-oxido V(IV) compounds both in aqueous solution and in the solid state. [V(anthH(-1))2](4-) and [V(calmH(-1))2](2-) (formed in water at the physiological pH) and [V(dhabH( 1))2] and [V(hmpicH(-1))2] (formed in the solid state in MeOH) are hexa coordinated with geometry intermediate between the octahedron and the trigonal prism and an unsymmetric facial arrangement of the two ligand molecules. DFT calculations were used to predict the structure and (51)V hyperfine coupling tensor A of the non-oxido species. The EPR behavior of 13 non-oxido V(IV) species was put into relationship with the relevant geometrical parameters and was rationalized in terms of the spin density on the d(xy) orbital. Depending on the geometric isomer formed (meridional or facial), d(z)(2) mixes with the d(xy) orbital, and this effect causes the lowering of the highest (51)V A value. PMID- 23819441 TI - Effects of Neurally Adjusted Ventilatory Assist (NAVA) levels in non-invasive ventilated patients: titrating NAVA levels with electric diaphragmatic activity and tidal volume matching. AB - BACKGROUND: Neurally adjusted ventilatory assist (NAVA) delivers pressure in proportion to diaphragm electrical activity (Eadi). However, each patient responds differently to NAVA levels. This study aims to examine the matching between tidal volume (Vt) and patients' inspiratory demand (Eadi), and to investigate patient-specific response to various NAVA levels in non-invasively ventilated patients. METHODS: 12 patients were ventilated non-invasively with NAVA using three different NAVA levels. NAVA100 was set according to the manufacturer's recommendation to have similar peak airway pressure as during pressure support. NAVA level was then adjusted +/-50% (NAVA50, NAVA150). Airway pressure, flow and Eadi were recorded for 15 minutes at each NAVA level. The matching of Vt and integral of Eadi (?Eadi) were assessed at the different NAVA levels. A metric, Range90, was defined as the 5-95% range of Vt/?Eadi ratio to assess matching for each NAVA level. Smaller Range90 values indicated better matching of supply to demand. RESULTS: Patients ventilated at NAVA50 had the lowest Range90 with median 25.6 uVs/ml [Interquartile range (IQR): 15.4-70.4], suggesting that, globally, NAVA50 provided better matching between ?Eadi and Vt than NAVA100 and NAVA150. However, on a per-patient basis, 4 patients had the lowest Range90 values in NAVA100, 1 patient at NAVA150 and 7 patients at NAVA50. Robust coefficient of variation for ?Eadi and Vt were not different between NAVA levels. CONCLUSIONS: The patient-specific matching between ?Eadi and Vt was variable, indicating that to obtain the best possible matching, NAVA level setting should be patient specific. The Range90 concept presented to evaluate Vt/?Eadi is a physiologic metric that could help in individual titration of NAVA level. PMID- 23819443 TI - Efficient preparation of 4-hydroxyquinolin-2(1H)-one derivatives with silver catalyzed carbon dioxide incorporation and intramolecular rearrangement. AB - Although 4-hydroxyquinolin-2(1H)-one derivatives have attracted much attention due to their biological benefits, conventional reactions under harsh heat conditions must be employed to provide these key compounds. In the presence of a catalytic amount of silver salt, various o-alkynylanilines were treated with carbon dioxide and a base under mild reaction conditions to afford the corresponding 4-hydroxyquinolin-2(1H)-one derivatives in high yield. PMID- 23819444 TI - Editorial comment to Preservation of the smooth muscular internal (vesical) sphincter and of the proximal urethra for the early recovery of urinary continence after retropubic radical prostatectomy: a prospective case-control study. PMID- 23819445 TI - Reciprocity among maternal distress, child behavior, and parenting: transactional processes and early childhood risk. AB - Transactional theories support that parent-child processes are best studied in conjunction with one another, addressing their reciprocal influence and change across time. This study tested a longitudinal, autoregressive model exploring bidirectional relations among maternal symptomatology, child internalizing/externalizing symptoms, and maternal sensitivity during the preschool period (child ages 3 to 5 years), comparing relations among families of typically developing children and children with developmental risk. This study included 250 families, 110 of which had a child with early developmental delay. Analyses utilized data from maternal report, father report, and observational methods. The results indicated significant stability in maternal symptomatology, child internalizing/externalizing symptoms, and maternal sensitivity over time. Support for bidirectional effects between maternal symptomatology and child internalizing symptoms was found specifically for mothers of children with developmental risk. Maternal symptomatology was found to mediate the influence of child internalizing and externalizing symptoms on maternal sensitivity. The findings underscore critical transactional processes within families of children with early developmental risk that connect increased maternal symptomatology to emerging child internalizing symptoms during the preschool period. PMID- 23819446 TI - Anti-VCAM-1 and anti-E-selectin SAINT-O-Somes for selective delivery of siRNA into inflammation-activated primary endothelial cells. AB - Activated endothelial cells play a pivotal role in the pathology of inflammatory diseases and present a rational target for therapeutic intervention by endothelial specific delivery of short interfering RNAs (siRNA). This study demonstrates the potential of the recently developed new generation of liposomes based on cationic amphiphile SAINT-C18 (1-methyl-4-(cis-9-dioleyl)methyl pyridinium-chloride) for functional and selective delivery of siRNA into inflamed primary endothelial cells. To create specificity for inflamed endothelial cells, these so-called SAINT-O-Somes were harnessed with antibodies against vascular cell adhesion protein 1 (VCAM-1) or respectively E-selectin and tested in TNF alpha activated primary endothelial cells from venous and aortic vascular beds. Both targeted SAINT-O-Somes carrying siRNA against the endothelial gene VE cadherin specifically downregulated its target mRNA and protein without exerting cellular toxicity. SAINT-O-Somes formulated with siRNA formed small particles (106 nm) with a 71% siRNA encapsulation efficiency. SAINT-O-Somes were stable in the presence of serum at 37 degrees C, protected siRNA from degradation by serum RNases, and after i.v. injection displayed pharmacokinetic comparable to conventional long circulating liposomes. These anti-VCAM-1 and anti-E-selectin SAINT-O-Somes are thus a novel drug delivery system that can achieve specific and effective delivery of siRNA into inflamed primary endothelial cells and have physicochemical features that comply with in vivo application demands. PMID- 23819447 TI - Injury-induced expression of glial androgen receptor in the zebra finch brain. AB - Astrogliosis occurs following injury to the zebra finch brain. To date, only estrogen synthase (aromatase) has been identified in injury-induced astrocytes. The expression of other steroidogenic enzymes or their receptors remains unknown in the avian brain. However, in mammals, an upregulation of androgen receptors has been identified in glial cells. The aim of this study was to determine if the androgen receptor is upregulated following injury in adult zebra finches. Finches were given a single penetrating injury and brain tissue was collected 24 or 72 h later. Expression of androgen receptor was examined using immunohistochemistry and quantified using quantitative polymerase chain reaction (qPCR) analysis. Androgen receptors were localized to astrocytes versus neurons, further solidifying the role for astrocytes in neural recovery. PMID- 23819448 TI - C-terminus of the Sgf73 subunit of SAGA and SLIK is important for retention in the larger complex and for heterochromatin boundary function. AB - The budding yeast Saccharomyces cerevisiae contains active and inactive chromatin separated by boundary domains. Previously, we used genome-wide screening to identify 55 boundary-related genes. Here, we focus on Sgf73, a boundary protein that is a component of the Spt-Ada-Gcn5 acetyltransferase (SAGA) and SLIK (SAGA like) complexes. These complexes have histone acetyltransferase (HAT) and histone deubiquitinase activity, and Sgf73 is one of the factors necessary to anchor the deubiquitination module. Domain analysis of Sgf73 was carried out, and the minimum region (373-402 aa) essential for boundary function was identified. This minimum region does not include the domain involved in anchoring the deubiquitination module, suggesting that the histone deubiquitinase activity of Sgf73 is not important for its boundary function. Next, Sgf73-mediated boundary function was analyzed in disruption strains in which different protein subunits of the SAGA/SLIK/ADA complexes were deleted. Deletion of ada2, ada3 or gcn5 (a HAT module component) caused complete loss of the boundary function of Sgf73. The importance of SAGA or SLIK complex binding to the boundary function of Sgf73 was also analyzed. Western blot analysis detected both the full-length and truncated forms of Spt7, suggesting that SAGA and SLIK complex formation is important for the boundary function of Sgf73. PMID- 23819449 TI - An infant with an alopecic plaque on the scalp and ocular choristomas: case presentation. Diagnosis: Encephalocraniocutaneous lipomatosis (ECCL). PMID- 23819450 TI - Figurate erythema, lymphadenopathy and Fever in a 19 month old child. Diagnosis: Kawasaki disease mimicking a figurate inflammatory dermatosis of infancy. PMID- 23819451 TI - Multiple axillary papules in an infant. Diagnosis: Multiple congenital apocrine hidrocystomas. PMID- 23819452 TI - Neonatal lupus erythematosus mimicking extensive capillary malformation. AB - Neonatal lupus erythematosus is an uncommon transplacentally acquired autoimmune disorder. We report a 7-month-old boy with cutaneous involvement of neonatal lupus erythematosus mimicking an extensive capillary malformation. PMID- 23819453 TI - Inpatient consultative pediatric dermatology: an emerging need in an era of increasing inpatient acuity and complexity. PMID- 23819454 TI - Pili annulati masquerading as hypotrichosis. PMID- 23819455 TI - Postoperative differences between colonization and infection after pediatric cardiac surgery-a propensity matched analysis. AB - BACKGROUND: The objective of this study was to identify the postoperative risk factors associated with the conversion of colonization to postoperative infection in pediatric patients undergoing cardiac surgery. METHODS: Following approval from the Institutional Review Board, patient demographics, co-morbidities, surgery details, transfusion requirements, inotropic infusions, laboratory parameters and positive microbial results were recorded during the hospital stay, and the patients were divided into two groups: patients with clinical signs of infection and patients with only positive cultures but without infection during the postoperative period. Using propensity scores, 141 patients with infection were matched to 141 patients with positive microbial cultures but without signs of infection. Our database consisted of 1665 consecutive pediatric patients who underwent cardiac surgery between January 2004 and December 2008 at a single center. The association between the patient group with infection and the group with colonization was analyzed after propensity score matching of the perioperative variables. RESULTS: 179 patients (9.3%) had infection, and 253 patients (15.2%) had colonization. The occurrence of Gram-positive species was significantly greater in the colonization group (p=0.004). The C-reactive protein levels on the first and second postoperative days were significantly greater in the infection group (p=0.02 and p=0.05, respectively). The sum of all the positive cultures obtained during the postoperative period was greater in the infection group compared to the colonization group (p=0.02). The length of the intensive care unit stay (p<0.001) was significantly longer in the infection group compared to the control group. CONCLUSIONS: Based on our results, we uncovered independent relationships between the conversion of colonization to infection regarding positive S. aureus and bloodstream results, as well as significant differences between the two groups regarding postoperative C-reactive protein levels and white blood cell counts. PMID- 23819457 TI - African leadership for sustainable health policy and systems research. PMID- 23819456 TI - A protein domain-centric approach for the comparative analysis of human and yeast phenotypically relevant mutations. AB - BACKGROUND: The body of disease mutations with known phenotypic relevance continues to increase and is expected to do so even faster with the advent of new experimental techniques such as whole-genome sequencing coupled with disease association studies. However, genomic association studies are limited by the molecular complexity of the phenotype being studied and the population size needed to have adequate statistical power. One way to circumvent this problem, which is critical for the study of rare diseases, is to study the molecular patterns emerging from functional studies of existing disease mutations. Current gene-centric analyses to study mutations in coding regions are limited by their inability to account for the functional modularity of the protein. Previous studies of the functional patterns of known human disease mutations have shown a significant tendency to cluster at protein domain positions, namely position based domain hotspots of disease mutations. However, the limited number of known disease mutations remains the main factor hindering the advancement of mutation studies at a functional level. In this paper, we address this problem by incorporating mutations known to be disruptive of phenotypes in other species. Focusing on two evolutionarily distant organisms, human and yeast, we describe the first inter-species analysis of mutations of phenotypic relevance at the protein domain level. RESULTS: The results of this analysis reveal that phenotypic mutations from yeast cluster at specific positions on protein domains, a characteristic previously revealed to be displayed by human disease mutations. We found over one hundred domain hotspots in yeast with approximately 50% in the exact same domain position as known human disease mutations. CONCLUSIONS: We describe an analysis using protein domains as a framework for transferring functional information by studying domain hotspots in human and yeast and relating phenotypic changes in yeast to diseases in human. This first-of-a-kind study of phenotypically relevant yeast mutations in relation to human disease mutations demonstrates the utility of a multi-species analysis for advancing the understanding of the relationship between genetic mutations and phenotypic changes at the organismal level. PMID- 23819458 TI - Electrochemistry, surface plasmon resonance, and quartz crystal microbalance: an associative study on cytochrome c adsorption on pyridine tail-group monolayers on gold. AB - Quartz crystal microbalance (QCM), surface plasmon resonance (SPR), and electrochemistry techniques were used to study the electron-transfer (ET) reaction of cytochrome c (Cyt c) on gold surfaces modified with thionicotinamide, thioisonicotinamide, 4-mercaptopyridine, 5-(4-pyridyl)-1,3,4-oxadiazole-2-thiol, 5-phenyl-1,3,4-oxadiazole-2-thiol, 4,4'-bipyridine, and 4,4'-dithiopyridine. The electrochemical results showed that the ET process is complex, being chiefly diffusional with steps depending on the orientation of the pyridine or phenyl tail group of the modifiers. The correlation between the electrochemical results and those acquired by SPR and QCM indicated the presence of an adlayer of Cyt c adsorbed on the thiolate SAMs. This adlayer, although being not electroactive, is essential to assess the ET reaction of Cyt c in solution. The results presented in this work are consistent with the statement (Feng, Z. Q.; Imabayashi, S.; Kakiuchi, T.; Niki, K. J. Electroanal. Chem. 1995, 394, 149-154) that the ET reaction of Cyt c can be explained in terms of the through-bond tunneling mechanism. PMID- 23819459 TI - Antioxidant and anti-dermatophytic properties leaf and stem bark of Xylosma longifolium clos. AB - BACKGROUND: The present study was carried out to assess the phytochemical and anti-dermatophytic effect of the leaf and bark extracts of Xylosma longifolium Clos. The leaf and stem bark are used by the indigenous people of Manipur, India for treatment of skin diseases. METHODS: The leaves and stem barks of Xylosma longifolium were extracted using petroleum ether, chloroform and methanol respectively. The different extracts of each plant parts were tested for antioxidant activity using DPPH assay. The phenolic content was assayed using Folin-Ciocalteu colorimetric method. Each extracts was further analysed by RP HPLC to quantify some individual flavonoid components. The anti-dermatophytic activity was evaluated both by agar diffusion method and micro wells dilution method against the Microsporum boullardii MTCC 6059, M. canis (MTCC 2820 and MTCC 32700), M. gypseum MTCC 2819, Trichophyton ajelloi MTCC 4878, T. rubrum (MTCC 296 and MTCC 3272). RESULTS: The free radical scavenging activity values were ranged from 0.7 to 1.41 mg/ml and 0.6 to 1.23 mg/ml, respectively for leaf and stem bark extracts. The amount of total phenolic contents of the extracts occurred in both leaf and bark in the range of 12 to 56.6 mg GAE/100 g and 16 to 58 mg GAE/100 g respectively. RP-HPLC analysis for flavonoids revealed the presence of two major flavonoid compounds, rutin and catechin. Kaempferol was in trace or absent. Methanol leaf extract showed significant low inhibitory effect against tested fungus Trichophyton ajelloi MTCC 4878 (0.140625 mg/ml) as the most sensitive. These finding suggest that the methanol leaf extract tested contain compounds with antimicrobial properties. CONCLUSION: The results of our study may partially justify the folkloric uses on the plant studied and further provide an evidence that the leaf extract of Xylosma longifolium might be indeed a potential sources of antimicrobial agents. PMID- 23819461 TI - Measuring the surgical 'learning curve': methods, variables and competency. AB - OBJECTIVES: To describe how learning curves are measured and what procedural variables are used to establish a 'learning curve' (LC). To assess whether LCs are a valuable measure of competency. PATIENTS AND METHODS: A review of the surgical literature pertaining to LCs was conducted using the Medline and OVID databases. RESULTS: Variables should be fully defined and when possible, patient specific variables should be used. Trainee's prior experience and level of supervision should be quantified; the case mix and complexity should ideally be constant. Logistic regression may be used to control for confounding variables. Ideally, a learning plateau should reach a predefined/expert-derived competency level, which should be fully defined. When the group splitting method is used, smaller cohorts should be used in order to narrow the range of the LC. Simulation technology and competence-based objective assessments may be used in training and assessment in LC studies. CONCLUSIONS: Measuring the surgical LC has potential benefits for patient safety and surgical education. However, standardisation in the methods and variables used to measure LCs is required. Confounding variables, such as participant's prior experience, case mix, difficulty of procedures and level of supervision, should be controlled. Competency and expert performance should be fully defined. PMID- 23819460 TI - Activation of AMPK inhibits cervical cancer cell growth through AKT/FOXO3a/FOXM1 signaling cascade. AB - BACKGROUND: Although advanced-stage cervical cancer can benefit from current treatments, approximately 30% patients may fail after definitive treatment eventually. Therefore, exploring alternative molecular therapeutic approaches is imperatively needed for this disease. We have recently shown that activation of AMP-activated protein kinase (AMPK), a metabolic sensor, hampers cervical cancer cell growth through blocking the Wnt/beta-catenin signaling activity. Here, we report that activated AMPK (p-AMPK) also inhibits cervical cancer cell growth by counteracting FOXM1 function. METHODS: Effect of the activation of AMPK on FOXM1 expression was examined by hypoxia and glucose deprivation, as well as pharmacological AMPK activators such as A23187, AICAR and metformin. RT Q-PCR and Western blot analysis were employed to investigate the activities of AMPK, FOXM1 and AKT/FOXO3a signaling. RESULTS: Consistent with our previous findings, the activation of AMPK by either AMPK activators such as AICAR, A23187, metformin, glucose deprivation or hypoxia significantly inhibited the cervical cancer cell growth. Importantly, we found that activated AMPK activity was concomitantly associated with the reduction of both the mRNA and protein levels of FOXM1. Mechanistically, we showed that activated AMPK was able to reduce AKT mediated phosphorylation of p-FOXO3a (Ser253). Interestingly, activated AMPK could not cause any significant changes in FOXM1 in cervical cancer cells in which endogenous FOXO3a levels were knocked down using siRNAs, suggesting that FOXO3a is involved in the suppression of FOXM1. CONCLUSION: Taken together, our results suggest the activated AMPK impedes cervical cancer cell growth through reducing the expression of FOXM1. PMID- 23819462 TI - Thyroid cancers detected by imaging are not necessarily small or early stage. AB - BACKGROUND: The incidence of well-differentiated thyroid cancer (WDTC) in the United States is increasing rapidly. Much of this increase is due to the detection by imaging of small, nonpalpable tumors. The incidence of advanced WDTC is also increasing, suggesting a true increase in the incidence of WDTC. This study was performed to determine how WDTCs of all sizes and stages are initially detected. METHODS: A retrospective chart review of 519 patients who underwent surgery for WDTC from January 1, 2007, through August 31, 2010, was performed. A total of 473 patients suitable for inclusion in this study were divided into three groups based upon the method by which the tumor was initially detected: tumors detected by an imaging study (184 patients-39%), those detected because a mass was felt in the neck (218 patients-46%), and those detected incidentally on pathological study of the surgical specimen (71 patients-15%). Method of detection was correlated with age and sex of the patient, and size, stage, and nodal status of the tumor. RESULTS: Patients in the Palpation group were more likely to be female (79% vs. 67% vs. 74%), younger (46 vs. 51 vs. 52), and to have larger tumors than those in the Imaging or Incidental groups. In the Imaging group, the tumor was detected on thyroid sonogram in 98 (53%), computed tomography in 38 (21%), magnetic resonance imaging in 19 (10%), carotid duplex scan in 14 (8%), and positron-emission tomography or other imaging studies in 15 (8%). Thirty-three percent of tumors <1 cm, 51% 1-2 cm, 29% 2-4 cm, and 38% >4 cm were first detected on an imaging study. Forty-seven percent of Stage III and IV cancers in patients aged >=45 years and 39% of patients with positive central nodes were in the Imaging group. CONCLUSION: This study demonstrates that while most tumors discovered by imaging were small and early stage, almost half of advanced (Stage III and IV) WDTCs were initially discovered by imaging studies. These findings are consistent with the hypothesis that the frequent use of imaging studies may explain not only the increasing incidence of early WDTC, but more advanced thyroid cancers as well. PMID- 23819463 TI - Occipital cortex activation by long-term repetitive tactile stimulation is necessary for object recognition in blinds: a case report. AB - Tactile vision has been approached from a variety of angles using different techniques. So far, a certain kind of object (and text) recognition has been shown, though seeing as such has not been achieved yet, and it remains unclear. Trough repetitive passive tactile stimulation perceptual processing is transferred from temporo-parietal to occipital areas, which affects object recognition. We report the results of passive tactile stimulation, as well as rTMS, applied to a 50 year old left handed blind male with over 97% loss of vision, who suffers from Peter's anomaly and microphthalmia. After 15 weeks of passive tactile stimulation, the subject showed increased activity in occipital areas associated with the development of visual-like perception which remained unchanged after three months without passive tactile stimulation. Inhibitory rTMS over the visual cortex led to noticeable reduction of spatial recognition performance and visual sensations in this subject. Stable changes in occipital cortical activity can be associated with subjective sensations of seeing. Once occipital activation has been achieved, it is necessary for spatial object recognition. Both facts highlight the implication of occipital areas in tactile vision and the cortical plasticity of passive tactile long-term stimulation in people with blindness. PMID- 23819464 TI - Three-dimensional telomere dynamics in follicular thyroid cancer. AB - BACKGROUND: Over the last decade, annual incidence rates for thyroid cancer have been among the highest of all cancers in the Western world. However, the genomic mechanisms impacting thyroid carcinogenesis remain elusive. METHODS: We employed an established mouse model of follicular thyroid cancer (FTC) with a homozygous proline to valine mutation (Thrb(PV/PV)) in the thyroid receptor beta1 (TRbeta1) and applied quantitative three-dimensional (3D) telomere analysis to determine 3D telomeric profiles in Thrb(PV)(/PV), Thrb(PV/)(+), and Thrb(+/+) mouse thyrocytes before and after histological presentation of FTC. RESULTS: Using quantitative fluorescent in situ hybridization (Q-FISH) and TeloViewTM image analysis, we found altered telomeric signatures specifically in mutant mouse thyrocytes. As early as 1 month of age, Thrb(PV/PV) mouse thyrocytes showed more telomeres than normal and heterozygous age-matched counterparts. Importantly, at the very early age of 1 month, 3D telomeric profiles of Thrb(PV/PV) thyrocyte nuclei reveal genetic heterogeneity with several nuclei populations exhibiting different telomere numbers, suggestive of various degrees of aneuploidy within the same animal. This was detected exclusively in Thrb(PV/PV) mice well before the presentation of histological signs of thyroid carcinoma. CONCLUSIONS: We identified quantitative 3D telomere analysis as a novel tool for early detection and monitoring of thyrocyte chromosomal (in)stability. This technique has the potential to identify human patients at risk for developing thyroid carcinoma. PMID- 23819465 TI - Marginal structural models for comparing alternative treatment strategies in ophthalmology using observational data. PMID- 23819466 TI - Shaped magnetic field pulses by multi-coil repetitive transcranial magnetic stimulation (rTMS) differentially modulate anterior cingulate cortex responses and pain in volunteers and fibromyalgia patients. AB - BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has shown promise in the alleviation of acute and chronic pain by altering the activity of cortical areas involved in pain sensation. However, current single-coil rTMS technology only allows for effects in surface cortical structures. The ability to affect activity in certain deep brain structures may however, allow for a better efficacy, safety, and tolerability. This study used PET imaging to determine whether a novel multi-coil rTMS would allow for preferential targeting of the dorsal anterior cingulate cortex (dACC), an area always activated with pain, and to provide preliminary evidence as to whether this targeted approach would allow for efficacious, safe, and tolerable analgesia both in a volunteer/acute pain model as well as in fibromyalgia chronic pain patients. METHODS: Part 1: Different coil configurations were tested in a placebo-controlled crossover design in volunteers (N = 16). Tonic pain was induced using a capsaicin/thermal pain model and functional brain imaging was performed by means of H2(15)O positron emission tomography - computed tomography (PET/CT) scans. Differences in NRS pain ratings between TMS and sham treatment (NRS(TMS)-NRS(placebo)) which were recorded each minute during the 10 minute PET scans. Part 2: 16 fibromyalgia patients were subjected to 20 multi-coil rTMS treatments over 4 weeks and effects on standard pain scales (Brief Pain Inventory, item 5, i.e. average pain NRS over the last 24 hours) were recorded. RESULTS: A single 30 minute session using one of 3 tested rTMS coil configurations operated at 1 Hz consistently produced robust reduction (mean 70% on NRS scale) in evoked pain in volunteers. In fibromyalgia patients, the 20 rTMS sessions also produced a significant pain inhibition (43% reduction in NRS pain over last 24 hours), but only when operated at 10 Hz. This degree of pain control was maintained for at least 4 weeks after the final session. CONCLUSION: Multi-coil rTMS may be a safe and effective treatment option for acute as well as for chronic pain, such as that accompanying fibromyalgia. Further studies are necessary to optimize configurations and settings as well as to elucidate the mechanisms that lead to the long-lasting pain control produced by these treatments. PMID- 23819468 TI - Flexible palladium-based H2 sensor with fast response and low leakage detection by nanoimprint lithography. AB - Flexible palladium-based H2 sensors have a great potential in advanced sensing applications, as they offer advantages such as light weight, space conservation, and mechanical durability. Despite these advantages, the paucity of such sensors is due to the fact that they are difficult to fabricate while maintaining excellent sensing performance. Here, we demonstrate, using direct nanoimprint lithography of palladium, the fabrication of a flexible, durable, and fast responsive H2 sensor that is capable of detecting H2 gas concentration as low as 50 ppm. High resolution and high throughput patterning of palladium gratings over a 2 cm * 1 cm area on a rigid substrate was achieved by heat-treating nanoimprinted palladium benzyl mercaptide at 250 degrees C for 1 h. The flexible and robust H2 sensing device was fabricated by subsequent transfer nanoimprinting of these gratings into a polycarbonate film at its glass transition temperature. This technique produces flexible H2 sensors with improved durability, sensitivity, and response time in comparison to palladium thin films. At ambient pressure and temperature, the device showed a fast response time of 18 s at a H2 concentration of 3500 ppm. At 50 ppm concentration, the response time was found to be 57 s. The flexibility of the sensor does not appear to compromise its performance. PMID- 23819467 TI - BioBin: a bioinformatics tool for automating the binning of rare variants using publicly available biological knowledge. AB - BACKGROUND: With the recent decreasing cost of genome sequence data, there has been increasing interest in rare variants and methods to detect their association to disease. We developed BioBin, a flexible collapsing method inspired by biological knowledge that can be used to automate the binning of low frequency variants for association testing. We also built the Library of Knowledge Integration (LOKI), a repository of data assembled from public databases, which contains resources such as: dbSNP and gene Entrez database information from the National Center for Biotechnology (NCBI), pathway information from Gene Ontology (GO), Protein families database (Pfam), Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome, NetPath - signal transduction pathways, Open Regulatory Annotation Database (ORegAnno), Biological General Repository for Interaction Datasets (BioGrid), Pharmacogenomics Knowledge Base (PharmGKB), Molecular INTeraction database (MINT), and evolutionary conserved regions (ECRs) from UCSC Genome Browser. The novelty of BioBin is access to comprehensive knowledge-guided multi-level binning. For example, bin boundaries can be formed using genomic locations from: functional regions, evolutionary conserved regions, genes, and/or pathways. METHODS: We tested BioBin using simulated data and 1000 Genomes Project low coverage data to test our method with simulated causative variants and a pairwise comparison of rare variant (MAF < 0.03) burden differences between Yoruba individuals (YRI) and individuals of European descent (CEU). Lastly, we analyzed the NHLBI GO Exome Sequencing Project Kabuki dataset, a congenital disorder affecting multiple organs and often intellectual disability, contrasted with Complete Genomics data as controls. RESULTS: The results from our simulation studies indicate type I error rate is controlled, however, power falls quickly for small sample sizes using variants with modest effect sizes. Using BioBin, we were able to find simulated variants in genes with less than 20 loci, but found the sensitivity to be much less in large bins. We also highlighted the scale of population stratification between two 1000 Genomes Project data, CEU and YRI populations. Lastly, we were able to apply BioBin to natural biological data from dbGaP and identify an interesting candidate gene for further study. CONCLUSIONS: We have established that BioBin will be a very practical and flexible tool to analyze sequence data and potentially uncover novel associations between low frequency variants and complex disease. PMID- 23819469 TI - Asthma diagnosis and treatment - 1013. Six month follow up on pediatric patients with severe persistent allergic asthma after on eyear of omalizumb therapy. PMID- 23819470 TI - Reversal of polarity in masked o-benzoquinones: rapid access to unsymmetrical oxygenated biaryls. AB - An unprecedented diacetoxyiodobenzene induced direct arylation of guaiacol derivatives and electron-rich arenes using a Lewis acid as an activator furnishes unsymmetrical biaryls without prefunctionalization of both coupling partners. The addition of electron-rich arenes on the alpha-position of electrophilic masked o benzoquinones in an anti-Michael addition fashion affords the highly oxygenated unsymmetrical biaryls in good to excellent yields. PMID- 23819471 TI - Synthesis, antibacterial activities, and 3D-QSAR of sulfone derivatives containing 1, 3, 4-oxadiazole moiety. AB - A series of sulfone derivatives containing 1, 3, 4-oxadiazole moiety were prepared and evaluated for their antibacterial activities by the turbidimeter test. Most compounds inhibited growth of Ralstonia solanacearum (R. solanacearum) from tomato and tobacco bacterial wilt with high potency, among which compounds 5a and 5b exhibited the most potent inhibition against R. solanacearum from tomato and tobacco bacterial wilts with EC50 values of 19.77 and 8.29 MUg/mL, respectively. Our results also demonstrated that 5a, 5b, and a number of other compounds were more potent than commercial bactericides Kocide 3000 and Thiodiazole Copper, which inhibited R. solanacearum from tomato bacterial wilt with EC50 values of 93.59 and 99.80 MUg/mL and tobacco bacterial wilt with EC50 values of 45.91 and 216.70 MUg/mL, respectively. The structure-activity relationship (SAR) of compounds was studied using three-dimensional quantitative structure-activity relationship (3D-QSAR) models created by comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) based on compound bioactivities against tomato and tobacco bacterial wilts. The 3D-QSAR models effectively predicted the correlation between inhibitory activity and steric-electrostatic properties of compounds. PMID- 23819473 TI - High-throughput microfluidic single-cell digital polymerase chain reaction. AB - Here we present an integrated microfluidic device for the high-throughput digital polymerase chain reaction (dPCR) analysis of single cells. This device allows for the parallel processing of single cells and executes all steps of analysis, including cell capture, washing, lysis, reverse transcription, and dPCR analysis. The cDNA from each single cell is distributed into a dedicated dPCR array consisting of 1020 chambers, each having a volume of 25 pL, using surface-tension based sample partitioning. The high density of this dPCR format (118,900 chambers/cm(2)) allows the analysis of 200 single cells per run, for a total of 204,000 PCR reactions using a device footprint of 10 cm(2). Experiments using RNA dilutions show this device achieves shot-noise-limited performance in quantifying single molecules, with a dynamic range of 10(4). We performed over 1200 single cell measurements, demonstrating the use of this platform in the absolute quantification of both high- and low-abundance mRNA transcripts, as well as micro RNAs that are not easily measured using alternative hybridization methods. We further apply the specificity and sensitivity of single-cell dPCR to performing measurements of RNA editing events in single cells. High-throughput dPCR provides a new tool in the arsenal of single-cell analysis methods, with a unique combination of speed, precision, sensitivity, and specificity. We anticipate this approach will enable new studies where high-performance single-cell measurements are essential, including the analysis of transcriptional noise, allelic imbalance, and RNA processing. PMID- 23819474 TI - The relationship between self-reported and registry-based data on use of psychoactive medications in postmenopausal women. AB - BACKGROUND: Self-report is commonly used as a source of information on the use of medicine. The aim of this study was to investigate the relationship between self reported and register-based information on the use of psychoactive medication, especially in respect to antidepressants, and reasons of non-reporting. METHODS: Study subjects (n = 11,031) originated from a population-based cohort of postmenopausal women born in 1932-41 from Eastern Finland who responded to a postal enquiry in 1999. Self-reported currently used prescribed medications were compared to the National prescription register data. Diuretics served as a reference for psychoactive medications. RESULTS: Only 44% out of 1,638 women reported their use of psychoactive medication when compared to the prescription register within a 4-month time window preceding their response to enquiry. Altogether, 55% out of 777 women reported their use of antidepressants and 29% out of 861 reported their use of other psychoactive medications. In comparison 83% reported their use of diuretics. After excluding the occasional use, an increase in sensitivity by approximately 10 percentage points was seen regardless of the group of psychoactive medication. High use and history of work disability pension due to psychiatric cause were associated with a much higher likelihood of reporting psychoactive medication use (for antidepressants 70% and 81%, respectively). CONCLUSIONS: For research purposes, self-reported current use of psychoactive medication seems to be a sufficient indicator for regular use of antidepressants or in respect of use of any psychoactive medication, for subjects with severe psychiatric disease. PMID- 23819475 TI - Cataract surgical outcomes from a large-scale micro-surgical campaign in China. AB - PURPOSE: To assess cataract surgical outcomes during the Jiangxi Provincial Government's "Brightness and Smile Initiative" (BSI) in South East China during May 2009 to July 2010. METHOD: This cross sectional combined with retrospective study included 1157 cataract surgical patients (1254 eyes) recruited from six counties in Jiangxi during the initiative. Patient information before surgery and at discharge was obtained from hospitals' case records. Patient follow-up eye examinations were conducted during field visits in the autumn of 2010. Fifteen months after the initiative started, study subjects were examined by provincial ophthalmologists using a Snellen visual chart, portable slit lamp, torch and ophthalmoscope. The World Health Organization (WHO) cataract surgical outcome monitoring tally sheet and the outcome categories good (visual acuity, VA, >= 0.3 (6/18)), borderline (VA <0.3 but >= 0.1 (6/60)) and poor (VA < 0.1) were used for data collection and analysis. RESULTS: A total of 99.7% of operated patients had intraocular lenses implanted. The percentage of eyes with good outcomes (presenting VA) at follow-up was low (49.6%), while the borderline and poor outcome rates were high (34.1% and 16.3%, respectively), in comparison to WHO recommendations. There was a significant outcome difference at follow-up (p < 0.01) between eyes operated by county surgeons trained by an International Non Government Organization and those operated on by other visiting surgeons. CONCLUSIONS: This study documented a low rate of good cataract surgical outcomes from the BSI in Jiangxi. The quality of cataract surgery should be improved further in the province. PMID- 23819477 TI - Revisiting smectic E structure through swollen smectic E phase in binary system of 4-nonyl-4'-isothiocyanatobiphenyl (9TCB) and n-nonane. AB - Thermodynamic and diffraction analyses were performed to establish the phase diagram for a binary system between 4-n-nonyl-4'-isothiocyanatobiphenyl (9TCB) and n-nonane. The swollen SmE structure is identified in the binary system. Upon swelling, a characteristic two-dimensional herringbone array is maintained whereas the layer spacing of SmE structure increases with the content of n nonane. Considering the difficulties in explaining the experimental findings based on the traditional model of SmE structure, a new model, lamellar with two types of sublayers consisting of aromatic core and alkyl chain moieties, is proposed. PMID- 23819476 TI - RApid Primary care Initiation of Drug treatment for Transient Ischaemic Attack (RAPID-TIA): study protocol for a pilot randomised controlled trial. AB - BACKGROUND: People who have a transient ischaemic attack (TIA) or minor stroke are at high risk of a recurrent stroke, particularly in the first week after the event. Early initiation of secondary prevention drugs is associated with an 80% reduction in risk of stroke recurrence. This raises the question as to whether these drugs should be given before being seen by a specialist--that is, in primary care or in the emergency department. The aims of the RAPID-TIA pilot trial are to determine the feasibility of a randomised controlled trial, to analyse cost effectiveness and to ask: Should general practitioners and emergency doctors (primary care physicians) initiate secondary preventative measures in addition to aspirin in people they see with suspected TIA or minor stroke at the time of referral to a specialist? METHODS/DESIGN: This is a pilot randomised controlled trial with a sub-study of accuracy of primary care physician diagnosis of TIA. In the pilot trial, we aim to recruit 100 patients from 30 general practices (including out-of-hours general practice centres) and 1 emergency department whom the primary care physician diagnoses with TIA or minor stroke and randomly assign them to usual care (that is, initiation of aspirin and referral to a TIA clinic) or usual care plus additional early initiation of secondary prevention drugs (a blood-pressure lowering protocol, simvastatin 40 mg and dipyridamole 200 mg m/r bd). The primary outcome of the main study will be the number of strokes at 90 days. The diagnostic accuracy sub-study will include these 100 patients and an additional 70 patients in whom the primary care physician thinks the diagnosis of TIA is possible, rather than probable. For the pilot trial, we will report recruitment rate, follow-up rate, a preliminary estimate of the primary event rate and occurrence of any adverse events. For the diagnostic study, we will calculate sensitivity and specificity of primary care physician diagnosis using the final TIA clinic diagnosis as the reference standard. DISCUSSION: This pilot study will be used to estimate key parameters that are needed to design the main study and to estimate the accuracy of primary care diagnosis of TIA. The planned follow-on trial will have important implications for the initial management of people with suspected TIA. TRIAL REGISTRATION: ISRCTN62019087. PMID- 23819478 TI - Felinine excretion in domestic cat breeds: a preliminary investigation. AB - The aim of this study was to determine possible differences in felinine excretion between domesticated cat breeds. For this purpose, urine was collected from a total of 83 privately owned entire male cats from eight different breeds in the Netherlands during the period of November 2010 till November 2011. In the collected samples, free felinine and creatinine concentrations were measured. Free felinine concentrations were expressed relative to the urinary creatinine concentration to compensate for possible variations in renal output. The mean (+/ SD) felinine:creatinine (Fel:Cr) ratio as measured over all cats was 0.702 (+/ 0.265). Both the Abyssinian and Sphynx breeds showed the highest Fel:Cr ratio (0.878 +/- 0.162 and 0.878 +/- 0.341 respectively) which significantly differed from the ratios of the British Shorthairs (0.584 +/- 0.220), Birmans (0.614 +/- 0.266), Norwegian Forest cats (0.566 +/- 0.296) and Siberian cats (0.627 +/- 0.124). The Fel:Cr ratios of the Persians (0.792 +/- 0.284) and Ragdolls (0.673 +/- 0.256) showed no statistical difference with either of the other breeds. A significant proportion of the observed variation between the different feline breeds could be explained by hair growth, as both hair growth and felinine production compete for available cysteine. Shorthaired and hairless cat breeds generally showed a higher Fel:Cr ratio compared to longhaired cat breeds, with the exception of Persian cats. Further research is warranted to more closely study the effect of hair growth on felinine production. PMID- 23819479 TI - From the ground up: strengthening health systems at district level. PMID- 23819480 TI - PFClust: a novel parameter free clustering algorithm. AB - BACKGROUND: We present the algorithm PFClust (Parameter Free Clustering), which is able automatically to cluster data and identify a suitable number of clusters to group them into without requiring any parameters to be specified by the user. The algorithm partitions a dataset into a number of clusters that share some common attributes, such as their minimum expectation value and variance of intra cluster similarity. A set of n objects can be clustered into any number of clusters from one to n, and there are many different hierarchical and partitional, agglomerative and divisive, clustering methodologies available that can be used to do this. Nonetheless, automatically determining the number of clusters present in a dataset constitutes a significant challenge for clustering algorithms. Identifying a putative optimum number of clusters to group the objects into involves computing and evaluating a range of clusterings with different numbers of clusters. However, there is no agreed or unique definition of optimum in this context. Thus, we test PFClust on datasets for which an external gold standard of 'correct' cluster definitions exists, noting that this division into clusters may be suboptimal according to other reasonable criteria. PFClust is heuristic in the sense that it cannot be described in terms of optimising any single simply-expressed metric over the space of possible clusterings. RESULTS: We validate PFClust firstly with reference to a number of synthetic datasets consisting of 2D vectors, showing that its clustering performance is at least equal to that of six other leading methodologies - even though five of the other methods are told in advance how many clusters to use. We also demonstrate the ability of PFClust to classify the three dimensional structures of protein domains, using a set of folds taken from the structural bioinformatics database CATH. CONCLUSIONS: We show that PFClust is able to cluster the test datasets a little better, on average, than any of the other algorithms, and furthermore is able to do this without the need to specify any external parameters. Results on the synthetic datasets demonstrate that PFClust generates meaningful clusters, while our algorithm also shows excellent agreement with the correct assignments for a dataset extracted from the CATH part-manually curated classification of protein domain structures. PMID- 23819481 TI - The Portuguese formal social support for autonomy and dependence in pain inventory (FSSADI_PAIN): a preliminary validation study. AB - OBJECTIVES: Development and preliminary validation of a Portuguese measure of perceived Formal Social Support for Autonomy and Dependence in Pain (FSSADI_PAIN). METHODS: One hundred and fifty-one older adults (88.1% women), between 56 and 94 years of age (M = 75.41; SD = 9.11), who attended one of the following institutions--day care centre (33.1%), nursing home (36.4%) and senior university (30.5%)--were recruited for this study. Along with the FSSADI_PAIN, participants filled out the Portuguese versions of the Brief Pain Inventory (Azevedo et al., 2007, Dor, 15, 6) and the Social Support Scale of Medical Outcomes Survey (Pais-Ribeiro & Ponte, 2009, Psicologia, Saude & Doenca, 10, 163). RESULTS: The factorial structure reflected the functions of perceived promotion of (1) dependence and (2) autonomy, showing good internal consistency (alpha > .70) and sensitivity indices. The FSSADI_PAIN showed good content, discriminant and criterion validity; it differentiated the perceptions of promotion of dependence/autonomy according to individual's pain severity and disability, as well as the type of institution. CONCLUSIONS: These preliminary findings suggest that the FSSADI_PAIN is an innovative and promising measure of perceived formal social support adapted to pain-related contexts. PMID- 23819482 TI - WS-SNPs&GO: a web server for predicting the deleterious effect of human protein variants using functional annotation. AB - BACKGROUND: SNPs&GO is a method for the prediction of deleterious Single Amino acid Polymorphisms (SAPs) using protein functional annotation. In this work, we present the web server implementation of SNPs&GO (WS-SNPs&GO). The server is based on Support Vector Machines (SVM) and for a given protein, its input comprises: the sequence and/or its three-dimensional structure (when available), a set of target variations and its functional Gene Ontology (GO) terms. The output of the server provides, for each protein variation, the probabilities to be associated to human diseases. RESULTS: The server consists of two main components, including updated versions of the sequence-based SNPs&GO (recently scored as one of the best algorithms for predicting deleterious SAPs) and of the structure-based SNPs&GO(3d) programs. Sequence and structure based algorithms are extensively tested on a large set of annotated variations extracted from the SwissVar database. Selecting a balanced dataset with more than 38,000 SAPs, the sequence-based approach achieves 81% overall accuracy, 0.61 correlation coefficient and an Area Under the Curve (AUC) of the Receiver Operating Characteristic (ROC) curve of 0.88. For the subset of ~6,600 variations mapped on protein structures available at the Protein Data Bank (PDB), the structure-based method scores with 84% overall accuracy, 0.68 correlation coefficient, and 0.91 AUC. When tested on a new blind set of variations, the results of the server are 79% and 83% overall accuracy for the sequence-based and structure-based inputs, respectively. CONCLUSIONS: WS-SNPs&GO is a valuable tool that includes in a unique framework information derived from protein sequence, structure, evolutionary profile, and protein function. WS-SNPs&GO is freely available at http://snps.biofold.org/snps-and-go. PMID- 23819483 TI - Immediate surgical coronary revascularisation in patients presenting with acute myocardial infarction. AB - BACKGROUND: The number of patients presenting with acute myocardial infarction (AMI) and being untreatable by interventional cardiologists increased during the last years. Previous experience in emergency coronary artery bypass grafting (CABG) in these patients spurred us towards a more liberal acceptance for surgery. Following a prospective protocol, patients were operated on and further analysed. METHODS: Within a two year interval, 127 patients (38 female, age 68+/ 12 years, EuroScore (ES) II 6.7+/-7.2%) presenting with AMI (86 non-ST-elevated myocardial infarction (NSTEMI), 41 STEMI) were immediately accepted for emergency CABG and operated on within six hours after cardiac catheterisation (77% three vessel-disease, 47% left main stem stenosis, 11% cardiogenic shock, 21% preoperative intraaortic balloon pump (IABP), left ventricular ejection fraction 48+/-15%). RESULTS: 30-day-mortality was 6% (8 patients, 2 NSTEMI (2%) 6 STEMI (15%), p=0.014). Complete revascularisation could be achieved in 80% of the patients using 2+/-1 grafts and 3+/-1 distal anastomoses. In total, 66% were supported by IABP, extracorporal life support (ECLS) systems were implanted in two patients. Logistic regression analysis revealed the ES II as an independent risk factor for mortality (p<0.001, HR 1.216, 95%-CI-Intervall 1.082-1.366). CONCLUSIONS: Quo ad vitam, results of emergency CABG for patients presenting with NSTEMI can be compared with those of elective revascularisation. Complete revascularisation obviously offers a clear benefit for the patients. Mortality in patients presenting with STEMI and cardiogenic shock is substantially high. For these patients, other concepts regarding timing of surgical revascularisation and bridging until surgery need to be taken into consideration. PMID- 23819485 TI - Energy evaluation of beta-strand packing in a fibril-forming SH3 domain. AB - We examine the energetics of beta-strand packing in a fibril-forming SH3 domain using a simple sequence-based energy model. First, we describe this packing energy function and then apply it to three model systems: Abeta, HET-s prion, and SH3 domain. The packing results of Abeta and HET-s are compared to and are consistent with available experimental and computational results. Moreover, our results show that a native beta-strand in SH3 is strongly disfavored to pack with any other strand, in accord with recent NMR data. Finally, based on packing energy calculations, several SH3 models of beta-strand packing are proposed that fit well with known electron microscopy maps. PMID- 23819484 TI - Design of an acid-activated antimicrobial peptide for tumor therapy. AB - Antimicrobial peptides have received increasing attention as potential antitumor drugs due to their new mode of action. However, the systemic toxicity at high concentration always hampers their successful utilization for tumor therapy. Here, we designed a new type of acid-activated antimicrobial peptide AMitP by conjugating antimicrobial peptide MitP to its anionic binding partner MitPE via a disulfide linker. Compared with MitP, AMitP displayed significant antitumor activity at acidic pH and low cytotoxicity at normal pH. The results of MD simulations demonstrate that the changes of structure and membrane binding tendency of AMitP at different pH values played an important role in its pH dependent antitumor activity. In addition, AMitP showed significant enzymatic stability compared with MitP, suggesting a potential for in vivo application. In short, our work opens a new avenue to develop antimicrobial peptides as potential antitumor drugs with high selectivity. PMID- 23819486 TI - Outpatient laser ablation of non-muscle-invasive bladder cancer: is it safe, tolerable and cost-effective? AB - OBJECTIVES: To evaluate the safety, tolerability and effectiveness of outpatient (office-based) laser ablation (OLA), with local anaesthetic, for non-muscle invasive bladder cancer (NMIBC) in an elderly population with and without photodynamic diagnosis (PDD). To compare the cost-effectiveness of OLA of NMIBC with that of inpatient cystodiathermy (IC). PATIENTS AND METHODS: We conducted a prospective cohort study of patients with NMIBC treated with OLA by one consultant surgeon between March 2008 and July 2011 A subgroup of patients had PDD before undergoing OLA. Safety and effectiveness were determined by complications (In the immediate post operative period, at three days and at three months), patient tolerability (visual analogue score) and recurrence rates. The long-term costs and cost-effectiveness of OLA and IC of NMIBC were evaluated using Markov modeling. RESULTS: A total of 74 OLA procedures (44 white-light, 30 PDD) were carried out in 54 patients. The mean (range) patient age was 77 (52-95) years. More than half of the patients had more than three comorbidities. Previous tumour histology ranged from G1pTa to T3. One patient had haematuria for 1 week which settled spontaneously and did not require hospital admission. There were no other complications. The procedure was well tolerated with pain scores of 0-2/10. Additional lesions were found in 21% of patients using PDD that were not found using white light. At 3 months, the percentage of patients who had recurrence after OLA with white light and OLA with PDD were 10.6 and 4.3%, respectively. At 1 year, 65.1% and 46.9% of patients had recurrence. The cost of OLA was found to be much lower than that of IC (L538 vs L1474), even with the addition of PDD (L912 vs L1844). Over the course of a patient's lifetime, OLA was more clinically effective, measured in quality-adjusted life-years (QALY), than IC (0.147 [sd 0.059]) and less costly (L2576.42 [sd L7293.07]). At a cost-effectiveness threshold of L30,000/QALY, as set by the National Institute for Health and Care Excellence, there was an 82% probability that OLA was cost-effective. CONCLUSIONS: This is the first study to demonstrate the long-term cost effectiveness of OLA of NMIBC. The results support the use of OLA for the treatment of NMIBC, especially in the elderly. PMID- 23819487 TI - Screening intervals for diabetic retinopathy and incidence of visual loss: a systematic review. AB - Screening for diabetic retinopathy can help to prevent this complication, but evidence regarding frequency of screening is uncertain. This paper systematically reviews the published literature on the relationship between screening intervals for diabetic retinopathy and the incidence of visual loss. The PubMed and EMBASE databases were searched until December 2012. Twenty five studies fulfilled the inclusion criteria, as these assessed the incidence/prevalence of sight threatening diabetic retinopathy in relation to screening frequency. The included studies comprised 15 evaluations of real-world screening programmes, three studies modelling the natural history of diabetic retinopathy and seven cost effectiveness studies. In evaluations of diabetic retinopathy screening programmes, the appropriate screening interval ranged from one to four years, in people with no retinopathy at baseline. Despite study heterogeneity, the overall tendency observed in these programmes was that 2-year screening intervals among people with no diabetic retinopathy at diagnosis were not associated with high incidence of sight-threatening diabetic retinopathy. The modelling studies (non economic and economic) assessed a range of screening intervals (1-5 years). The aggregated evidence from both the natural history and cost-effectiveness models favors a screening interval >1 year, but <=2 years. Such an interval would be appropriate, safe and cost-effective for people with no diabetic retinopathy at diagnosis, while screening intervals <=1 year would be preferable for people with pre-existing diabetic retinopathy. A 2-year screening interval for people with no sight threatening diabetic retinopathy at diagnosis may be safely adopted. For patients with pre-existing diabetic retinopathy, a shorter interval <=1 year is warranted. PMID- 23819488 TI - The role of natural health products (NHPs) in dietetic practice: results from a survey of Canadian dietitians. AB - BACKGROUND: Registered dietitians (RDs) play a key role in disseminating information about nutrition and intervening in nutrition-related disorders in the Canadian context. Natural health products (NHPs) are increasingly associated with nutrition in patient and health professional discussions. For this study, NHPs were divided into three categories: nutritional supplements (NS); functional foods/nutraceuticals (FF/N); and herbal preparations (HP). The objective was to explore RDs' perceptions about their professional roles and responsibilities with respect to three categories of natural health products (NHPs). METHODS: This research consisted of an on-line survey of registered dietitians (RDs) in Ontario.Surveys were distributed electronically to all practicing RDs in Ontario by the College of Dietitians of Ontario. There were 558 survey respondents, a response rate of 20%. RESULTS: The vast majority of RDs reported being consulted by clients about all product categories (98% for NS; 94% for FF/N; 91% for HP), with RDs receiving the most frequent questions about NS and the least frequent about HP. 74% of RDs believed that NS are included within the current scope of practice, compared to 59% for FF/N and 14% for HP. Even higher numbers believed that these products should be included: 97% for NS, 91% for FF/N and 47% for HP. RDs who report personally ingesting FF/N and HP were significantly more likely to report that these products should be in the dietetic scope of practice. In contrast, RDs who provide one-on-one counselling services or group-level counselling/workshops were significantly less likely to believe HP should be in the dietetic scope of practice. CONCLUSIONS: Opinions of RDs indicated that NS and FF/N (and possibly HP) fall within, or should fall within, RDs' scope of practice. Opportunity exists for RDs to undertake a professional role with respect to NHPs. Policy clarification regarding RD roles is needed. PMID- 23819489 TI - Biodegradable magnesium-based screw clinically equivalent to titanium screw in hallux valgus surgery: short term results of the first prospective, randomized, controlled clinical pilot study. AB - PURPOSE: Nondegradable steel-and titanium-based implants are commonly used in orthopedic surgery. Although they provide maximal stability, they are also associated with interference on imaging modalities, may induce stress shielding, and additional explantation procedures may be necessary. Alternatively, degradable polymer implants are mechanically weaker and induce foreign body reactions. Degradable magnesium-based stents are currently being investigated in clinical trials for use in cardiovascular medicine. The magnesium alloy MgYREZr demonstrates good biocompatibility and osteoconductive properties. The aim of this prospective, randomized, clinical pilot trial was to determine if magnesium based MgYREZr screws are equivalent to standard titanium screws for fixation during chevron osteotomy in patients with a mild hallux valgus. METHODS: Patients (n=26) were randomly assigned to undergo osteosynthesis using either titanium or degradable magnesium-based implants of the same design. The 6 month follow-up period included clinical, laboratory, and radiographic assessments. RESULTS: No significant differences were found in terms of the American Orthopaedic Foot and Ankle Society (AOFAS) score for hallux, visual analog scale for pain assessment, or range of motion (ROM) of the first metatarsophalangeal joint (MTPJ). No foreign body reactions, osteolysis, or systemic inflammatory reactions were detected. The groups were not significantly different in terms of radiographic or laboratory results. CONCLUSION: The radiographic and clinical results of this prospective controlled study demonstrate that degradable magnesium-based screws are equivalent to titanium screws for the treatment of mild hallux valgus deformities. PMID- 23819492 TI - Patient specific pre-treatment QA verification using an EPID approach. AB - A software program [MU-EPID], has been developed to perform patient specific pre treatment quality assurance (QA) verification for intensity modulated radiation therapy (IMRT) using fluence maps measured with an electronic portal imaging device (EPID). The software converts the EPID acquired images of each IMRT beam, to fluence maps that are equivalent to those calculated by the treatment planning system (TPS). The software has the capability to process Varian, Elekta and Siemens EPID DICOM images. In the present investigation, several IMRT plans for different treatment sites were used to validate the software using the Varian a Si 1000 EPID with the Pinnacle TPS. A total of 20 IMRT plans of different treatment sites were analyzed. Isodose distributions, dose profiles, dose volume histograms (DVH's) and gamma analysis comparisons were performed to evaluate the accuracy of our method. A gamma index analysis of the isocenter coronal plane was done for each plan and showed an average of 97.44% of gamma passing rate using a 3% and 3 mm gamma criterion. Isodose, DVH and dose profile comparisons were conducted between the original calculated plan and the measured reconstructed plan from the EPID images processed through the MU-EPID software. The results suggest that MU-EPID can be used clinically for patient specific IMRT QA, providing a comprehensive 3D dosimetric evaluation through DVH comparison as well as an option for a 2D gamma analysis. PMID- 23819490 TI - Toxicity of valproic acid in isolated rat liver mitochondria. AB - Valproic acid (VPA), an anticonvulsant and mood-stabilizing drug, is widely used for the treatment of different types of seizures and myoclonic epilepsy. Several mechanisms have been suggested for VPA hepatotoxicity, and most of them are associated with oxidative stress. It seems that oxidative stress by VPA treatment has been associated with mitochondrial dysfunction. Therefore, this study investigated the mitochondrial toxicity mechanisms of VPA on freshly isolated rat mitochondria for better understanding pathogenesis of VPA in mitochondrial toxicity. Rat liver mitochondria were obtained by differential ultracentrifugation and were then incubated with different concentrations of VPA (25-200 uM). Our results showed that VPA could induce oxidative stress via rising in mitochondrial reactive oxygen species formation, lipid peroxidation, mitochondrial membrane potential collapse, mitochondrial swelling and finally release of cytochrome c. These effects were well inhibited by pretreatment of isolated mitochondria with cyclosporin A and butylated hydroxytoluene. Based on these results, it is clear that VPA exerts mitochondrial toxicity by impairing mitochondrial functions leading to oxidative stress and cytochrome c expulsion, which start cell death signaling. PMID- 23819493 TI - Quantitative evaluation of the benefit of fiducial image-guidance for prostate cancer intensity modulated radiation therapy using daily dose volume histogram analysis. AB - To quantitatively evaluate the extent to which fiducial-based image-guidance improves dose coverage of the target volume and sparing of critical organs for prostate cancer patients treated with intensity modulated radiotherapy (IMRT) and determination of planning margins by original approach of detailed daily dose volume histogram (DVH) and patient's position correction analysis. Sixty-two patients divided in two groups (clinical target volume (CTV) -> planning target volume (PTV) margin 10 and 7 mm) were treated with IMRT using implanted fiducial markers. Each patient's treatment fraction was recalculated as it would have been treated without fiducial-guided positioning. For both plans (IGRT and non-IGRT), equivalent uniform doses (EUD), maximal and minimal doses for target volumes, normal tissue complication probability (NTCP), maximum and mean doses for organs at risk and the whole DVH differences were assessed. In the group with 10 mm margins, the only significant difference was worse rectal NTCP by 4.5%, but the CTV dose coverage remained at the same level. Recalculated plans with 7 mm margin could not achieve the prescribed target volume coverage, and the EUD decreased by 3.7 and 0.6 Gy for PTV and CTV, respectively. Desired CTV -> PTV margin for non IGRT plans should be no lower than 12 mm to guarantee 95% instances when delivered dose to CTV maintain as planned, for IGRT plans decrease this requirement to 2 mm. Prostate IMRT strategies involving margin reduction below 7 mm require image-guidance to maintain the planned dose coverage. Using fiducial based image-guidance and large margins seems to be superfluous. PMID- 23819494 TI - Using a novel dose QA tool to quantify the impact of systematic errors otherwise undetected by conventional QA methods: clinical head and neck case studies. AB - Recent studies have demonstrated that per-beam planar intensity-modulated radiation therapy (IMRT) quality assurance (QA) passing rates may not predict clinically relevant patient dose errors. This work is to evaluate the effect of dose variations introduced in dynamic multi-leaf collimator (DMLC) modeling and delivery processes on clinically relevant metrics for IMRT. Ten head and neck (HN) IMRT plans were randomly selected for this study. The conventional per-beam IMRT QA was performed for each plan by 2 different methods: (1) with gantry angle of 0 (gantry pointing downward) for all IMRT fields and (2) with gantry at specific angles as designed in the IMRT plan. For each patient, a batch analysis was done for each scenario and then imported to the 3DVH (Sun Nuclear Corp.) for processing. A "corrected DVH" was generated and compared to the DVH from the treatment plan. Their differences represented errors introduced from the combination of the treatment planning system (TPS) dose calculation algorithm and beam-delivery. The dose metrics from the two scenarios were compared with the corresponding calculated doses, and then their differences were analyzed. Although all per-beam planar IMRT QA had high Gamma passing rates 99.3 +/- 1.3% (92.3-100%) for "2%/3 mm" criteria, there were significant errors in some of the calculated clinical dose metrics. Such as, for all the plans studied, there were as much as 3.2%, 5.7%, 5.6%, 2.3%, 4.1%, and 23.8% errors found in max cord dose, max brainstem dose, mean parotid dose, larynx dose, oral cavity dose, and PTV(D95) dose, respectively. The differences in errors for clinical metrics obtained between the two scenarios (zero gantry angle vs. true gantry angles) can also be significant: max cord dose (2.9% vs. 0.2%), max brainstem dose (3.8% vs. 0.4%), mean parotid dose (2.3% vs. 4.5%), mean larynx dose (3.9% vs. 2.0%), mean oral cavity dose (1.6% vs. 3.9%), and PTV(D95) dose (-0.4% vs. -2.6%). However, in the two scenarios, a strong and clear correlation between the dose differences for each of the organ structures was observed. This study confirms that conventional IMRT QA performance metrics are not predictive of dose errors in PTV and organs-at-risk. The clinically-relevant-dose QA has allowed us to predict the patient dose-volume relationships. PMID- 23819496 TI - Outcomes of single fraction stereotactic ablative radiotherapy for lung metastases. AB - Stereotactic Ablative Radiotherapy (SABR) has been previously investigated as an alternative to thoracic surgery in patients with a limited number of pulmonary nodules from different primary tumors. We here report the clinical outcomes of a series of consecutive patients homogeneously selected and treated with single dose SABR in our Institution. Eligibility criteria were: 1-5 lung metastases, maximum tumor diameter <50 mm, absent or controlled extra-thoracic disease, adequate pulmonary function, no prior radiotherapy, performance status ECOG 0-1. All patients were treated with a single dose of 26 Gy prescribed to the 80% isodose, by 3D-CRT or by IGRT-VMAT. Follow-up consisted of clinical evaluation and periodic CT scans. Primary endpoints were Local Control (LC), toxicity and Progression-Free Survival (PFS). Secondary endpoints were Cancer-Specific Survival (CSS) and Overall Survival (OS). Out of 102 patients treated with SABR between october 2003 and october 2011, we selected 67 patients for a total of 90 lesions. Main primary tumor sites were lung and colon-rectum (37.3% and 43.3% of lesions, respectively). Median follow up time was 24 months. Treated metastasis progression at SABR site was observed in 10 lesions (11.1%), and actuarial LC rates at 1 and 2 years were respectively 93.4% and 88.1%. Systemic failure occurred in 37 patients (55.2%) at a median interval of 8 months after SABR. PFS rates were 72% and 55.4% at 1 and 2 year. Seven patients had grade 1 (10.4%) and 8 grade 2-3 late radiological toxicity (11.9%), while 6 experienced late chest wall toxicity (2 rib fractures, 4 chronic chest pain, 8.9%). CSS rates at 1 and 2 years were 90% and 76%, while OS rates were 85.1% and 70.5%, respectively. Median survival time was 40 months. On multivariate analysis, a disease-free interval longer than 24 months was close to significance for a benefit in CSS (p = 0.07; HR 0.34 [95% CI 0.1-1.12]). The study includes a cohort of patients treated with single fraction 26 Gy SABR followed for a prolonged time interval. Single fraction SABR appears to be an effective treatment option, with little observed acute toxicity and limited late toxicity (<15%); its advantages also include a high patients' compliance, a short overall treatment time and an easy combination with systemic therapies. These results might provide supportive evidence to the use of single fraction SABR as a valid and acceptable alternative to surgery for pulmonary metastases from different primary tumors. PMID- 23819495 TI - Fractionated stereotactic radiosurgery treatment results for skull base chordomas. AB - Chordomas are uncommon neoplasms and there is still controversy regarding establishment of diagnosis and management. The aim of this study was to evaluate efficacy and toxicity of fractionated stereotactic radiosurgery (FSRS) in skull base chordomas. There were 4 female (36%) and 7 male (64%) patients. FSRS was delivered with CyberKnife (Accuray Inc., Sunnyvale, CA). The median tumor volume was 14.7 cc (range, 3.9-40.5 cc). The median marginal tumor dose was 30 Gy (range, 20-36 Gy) in a median 5 fractions (range, 3-5 fractions). The median follow-up time was 42 months (range, 17-63 months). At the time of analysis, 10 (91%) patients were alive and 1 (9%) had died due to tumor progression. Of 10 patients, 8 (73%) had stable disease and the remaining 2 (18%) had progressive disease. The actuarial overall survival (OS) after FSRS was 91% at two-years. Two patients developed radiation-induced brain necrosis as a complication in the 8th and 28th months of follow-up, respectively. Our results with robotic FSRS in skull base chordomas are promising for selected patients. However, due to the slow growth pattern of skull base chordomas, a longer follow-up is required to determine exact treatment results and late morbidity. PMID- 23819497 TI - Recombinant Newcastle disease virus Anhinga strain (NDV/Anh-EGFP) for hepatoma therapy. AB - Hepatocellular carcinoma remains one of the most common malignant tumors in the world. Newcastle disease virus (NDV) has been proved to be an efficient oncolytic agent. NDV tumor killing efficacy is not only dependening on the NDV strain but the type of tumor targeted. It is significant to discover more effective and safe oncolytic strains. We investigated the effectiveness of genetically engineered NDV Anhinga strain in hepatoma treatment. The modified virus containing an insertion of enhanced green fluorescent protein (EGFP), named NDV/Anh-EGFP. The antitumor efficacy of the recombinant virus on hepatoma was examined both in vivo and in vitro. NDV Anhinga strain, which could be classified as a lytic strain, is an effective oncolytic agent on hepatoma. There was no significant difference in the TCID50 and growth capability between the recombinant NDV and the parental. NDV/Anh-EGFP can obviously inhibit hepatocarcinoma development in vitro and in vivo. We demonstrate Anhinga strain could become a potent candidate for clinical carcinoma therapy especially for hepatocarcinoma. PMID- 23819498 TI - Ion radiography as a tool for patient set-up and image guided particle therapy: a Monte Carlo study. AB - This study investigate the use of ion radiography as a tool for patient set-up and tumor tracking capabilities for image guided particle therapy (IGPT) using Monte Carlo simulations. One pediatric, two lung and one liver cancer patients were considered in this study. For each patient, 230 and 330 MeV proton, and 500 MeV/nucleon carbon ion pencil beams were simulated through their computed tomography (CT) data set using GEANT4.9.0. Energy, position and direction cosines of each particle were recorded in front and behind the patient. Ion radiographs were subsequently reconstructed using a dedicated in-house software. The image quality was assessed by evaluating the contrast-to-noise ratio of the tumor and its surrounding tissue. In the lung and liver cases, each CT phase of the breathing cycle was treated individually and dynamic sequences were later produced to appreciate tumor motion. Reconstructed radiographs show high spatial resolution. This allows for excellent imaging capabilities in pediatric patients, comparable to X-ray imaging at a fraction of the imaging dose. There is clear visualization of the tumor edges in the lung due to the great contrast-to-noise ratio between the tumor and its surrounding tissues; tumor motion is observed and comparable to 4D CT data thus allowing for on-line tumor tracking during ion radiotherapy. Conversely, tumor edge detection is difficult in liver, and fiducial markers are required to attempt indirect tumor tracking for IGPT. Ion radiographs with high spatial resolution can be generated using the PR-creator software resulting in pediatric patient set-up capabilities at a fraction of the current imaging dose, as well as the capacity to track moving targets in order to achieve IGPT. PMID- 23819500 TI - Pruning the ALS-associated protein SOD1 for in-cell NMR. AB - To efficiently deliver isotope-labeled proteins into mammalian cells poses a main challenge for structural and functional analysis by in-cell NMR. In this study we have employed cell-penetrating peptides (CPPs) to deliver the ALS-associated protein superoxide dismutase (SOD1) into HeLa cells. Our results show that, although full-length SOD1 cannot be efficiently internalized, a variant in which the active-site loops IV and VII have been truncated (SOD1(DeltaIVDeltaVII)) yields high cytosolic delivery. The reason for the enhanced delivery of SOD1(DeltaIVDeltaVII) seems to be the elimination of negatively charged side chains, which alters the net charge of the CPP-SOD1 complex from neutral to +4. The internalized SOD1(DeltaIVDeltaVII) protein displays high-resolution in-cell NMR spectra similar to, but not identical to, those of the lysate of the cells. Spectral differences are found mainly in the dynamic beta strands 4, 5, and 7, triggered by partial protonation of the His moieties of the Cu-binding site. Accordingly, SOD1(DeltaIVDeltaVII) doubles here as an internal pH probe, revealing cytosolic acidification under the experimental treatment. Taken together, these observations show that CPP delivery, albeit inefficient at first trials, can be tuned by protein engineering to allow atomic-resolution NMR studies of specific protein structures that have evaded other in-cell NMR approaches: in this case, the structurally elusive apoSOD1 barrel implicated as precursor for misfolding in ALS. PMID- 23819501 TI - Asthma diagnosis and treatment - 1014. Single center experience of 4 cases of diffuse panbronchiolitis clinically presented as treatment resistant ashtma. PMID- 23819499 TI - Inhibitors of difficult protein-protein interactions identified by high throughput screening of multiprotein complexes. AB - Protein-protein interactions (PPIs) are important in all aspects of cellular function, and there is interest in finding inhibitors of these contacts. However, PPIs with weak affinities and/or large interfaces have traditionally been more resistant to the discovery of inhibitors, partly because it is more challenging to develop high-throughput screening (HTS) methods that permit direct measurements of these physical interactions. Here, we explored whether the functional consequences of a weak PPI might be used as a surrogate for binding. As a model, we used the bacterial ATPase DnaK and its partners DnaJ and GrpE. Both DnaJ and GrpE bind DnaK and catalytically accelerate its ATP cycling, so we used stimulated nucleotide turnover to indirectly report on these PPIs. In pilot screens, we identified compounds that block activation of DnaK by either DnaJ or GrpE. Interestingly, at least one of these molecules blocked binding of DnaK to DnaJ, while another compound disrupted allostery between DnaK and GrpE without altering the physical interaction. These findings suggest that the activity of a reconstituted multiprotein complex might be used in some cases to identify allosteric inhibitors of challenging PPIs. PMID- 23819502 TI - Emerging application of a structural and chemical analyzer for the complete characterization of metal-rich particulate matter. AB - Clean air is considered to be a basic requirement of human health and well-being. An increasing range of adverse health effects has been linked to air pollution, at ever-lower concentrations. This research shows the newly developed Structural and Chemical Analyzer (SCA) to be a successful combination of Raman spectroscopy and scanning electron microscope-energy dispersive X-rays that opens up new insight into the composition of particulate matter (PM). The results obtained with soil and lichen samples demonstrate the capability of the technique to obtain elemental and molecular information of every single atmospheric PM focused at the micrometer and submicrometer levels. The SCA approach permitted the individual PM analysis, allowing the identification of the molecular (most commonly as sulphides, sulphates, carbonates, or oxides) form in which several hazardous metals (Zn, Pb, Cu, etc.) are evolved into potentially inhalable PM. During the present research, the synchronization of both techniques at a time revealed the morphological, elemental, and molecular forms of metal-rich PM, avoiding some analysis precautions and making the sample preparation and measurement steps more dynamic. In addition, the thermodynamic simulations carried out with the information obtained were helpful to differentiate whether the PM may be retained in the alveoli (i.e., galena) or if it may be dissolved and pass into the bloodstream (i.e., plattnerite). PMID- 23819503 TI - Altering physiological networks using drugs: steps towards personalized physiology. AB - BACKGROUND: The rise of personalized medicine has reminded us that each patient must be treated as an individual. One factor in making treatment decisions is the physiological state of each patient, but definitions of relevant states and methods to visualize state-related physiologic changes are scarce. We constructed correlation networks from physiologic data to demonstrate changes associated with pressor use in the intensive care unit. METHODS: We collected 29 physiological variables at one-minute intervals from nineteen trauma patients in the intensive care unit of an academic hospital and grouped each minute of data as receiving or not receiving pressors. For each group we constructed Spearman correlation networks of pairs of physiologic variables. To visualize drug-associated changes we split the networks into three components: an unchanging network, a network of connections with changing correlation sign, and a network of connections only present in one group. RESULTS: Out of a possible 406 connections between the 29 physiological measures, 64, 39, and 48 were present in each of the three component networks. The static network confirms expected physiological relationships while the network of associations with changed correlation sign suggests putative changes due to the drugs. The network of associations present only with pressors suggests new relationships that could be worthy of study. CONCLUSIONS: We demonstrated that visualizing physiological relationships using correlation networks provides insight into underlying physiologic states while also showing that many of these relationships change when the state is defined by the presence of drugs. This method applied to targeted experiments could change the way critical care patients are monitored and treated. PMID- 23819504 TI - Optical coherence tomography as an auxiliary tool for the screening of radiation related caries. AB - OBJECTIVE: The aim of this study was to evaluate the morphological alterations of radiation-related caries using optical coherence tomography. METHODS: Thirty-six extracted teeth from 11 patients who had undergone radiotherapy were sectioned in the sagittal axis in the center of the carious lesion, and 100 MUm thick sections were obtained from each specimen. One sample from each tooth was investigated by an optical coherence tomography (OCT) system, and the results were compared with histological images from polarized light microscopy. RESULTS: In OCT dentin caries images, the demineralized area appeared as a white region, whereas the translucent zone appeared as a dark area, a similar pattern also seen in coronal caries. In noncavitated enamel lesions clinically observed as brown discoloration, the area of high porosity, and also the dark color, absorbs part of the light, resulting in a dark pattern. Finally, the involvement of dentin enamel junction (DEJ) or cement-enamel junction (CEJ) could be clearly observed, when present and marked alterations along the CEJ could be noted, as junction continuity loss, gap formation, and mineral loss tissue. CONCLUSIONS: The OCT technique was able to characterize radiation-related caries, from a morphological point of view. Also demonstrated was its potential benefit for use in the clinical monitoring of radiation-related carious process. PMID- 23819505 TI - Thermography applied during exercises with or without infrared light-emitting diode irradiation: individual and comparative analysis. AB - OBJECTIVE: The aim of our study was to evaluate the cutaneous temperature during an exercise on a treadmill with or without infrared light-emitting diode (LED) irradiation in postmenopausal women. BACKGROUND DATA: Thermography is an imaging technique in which radiation emitted by a body in the middle and far infrared spectrum is detected and associated with the temperature of the body's surface. MATERIALS AND METHODS: Eighteen postmenopausal women were randomly divided into two groups: (1) the LED group, which performed the exercises on a treadmill associated with phototherapy (n=9) and; (2) the exercise group, which performed the exercises on a treadmill without additional phototherapy (n=9). The irradiation parameters for each women's thigh were: array of 2000 infrared LEDs (850 nm) with an area of 1,110 cm(2), 100 mW, 39 mW/cm(2), and 108 J/cm(2) for 45 min. The submaximal constant-speed exercise on the treadmill at intensities between 85% and 90% maximal heart rate (HRmax) with or without phototherapy were performed during 45 min, to perform the thermographic analysis. Thermography images were captured before the exercise (t=0), after 10, 35, and 45 min of exercising (t=10, t=35, and t=45) and at 5 min post-exercising (t=50). RESULTS: The LED group showed an increased cutaneous thigh temperature during the exercise (from 33.5+/-0.8 degrees C to 34.6+/-0.9 degrees C, p=0.03), whereas the exercise group showed a reduced cutaneous temperature (from 33.5+/-0.6 to 32.7+/-0.7 degrees C, p=0.02). The difference between the groups was significant (p<0.05) at t=35, t=45, and t=50. CONCLUSIONS: These data indicate an improved microcirculation, and can explain one possible mechanism of action of phototherapy associated with physical exercises. PMID- 23819506 TI - Systematic study of non-natural short cationic lipopeptides as novel broad spectrum antimicrobial agents. AB - We describe the design and synthesis of a new series of non-natural short cationic lipopeptides (MW = 700) as antimicrobial agents. All of the synthesized lipopeptides were tested against a range of microbes such as Gram-positive, Gram negative bacteria, fungi including methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE). By systematic study of design template, we found that three ornithine residues conjugated with myristic acid are minimum requirement for a compound to be an antimicrobial agent. The most potent lipopeptide LP16 possesses broad-spectrum antimicrobial activity and has MICs in the range of 1.5-6.25 MUg/mL against Escherichia coli, S. aureus, Pseudomonas aeruginosa, Bacillus subtilis, and MRSE. All lipopeptides showed high selectivity toward microbial strains as compared to human red blood cells (HC50 > 250 MUg/mL). Moreover, most potent lipopeptides (LP16 and LP23) did not induce drug resistance in S. aureus even after 15 rounds of passaging. In addition, a representative lipopeptide (LP16) showed tryptic stability for 24 h. These results suggest the potential of short cationic lipopeptides to boost the discovery of future antimicrobial therapeutics. PMID- 23819507 TI - Thyroid-like follicular carcinoma of the kidney in a patient with nephrolithiasis and polycystic kidney disease: a case report. AB - Thyroid-like follicular carcinoma of the kidney (TLFC), a rare neoplasm with low malignant potential, is histologically similar to primary thyroid follicular carcinoma, but characteristically lacks thyroid immunohistochemical markers. We report a case of 34-year old patient with nephrolithiasis. Ultrasound revealed hepatorenal cysts consistent with adult type polycystic kidney disease (ATPKD) and a cytologically confirmed left kidney tumor. Nephrectomy specimen contained sharply demarcated lesion of unusual morphology. Tubular and cystic structures lined by mostly cuboidal cells and filled with amorphous eosinophillic material, reminiscent of follicular carcinoma of the thyroid gland, were diagnostic for TLFC. Thyroid markers were negative. To our knowledge this is the first report of TFLC associated to ATPKD. Brief review of previously published TFLCs, possible relationship between entities and differential diagnosis are discussed. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/8067946569612694. PMID- 23819508 TI - Outcomes and survival analysis of old-to-old simultaneous pancreas and kidney transplantation. AB - Outcomes of old-donor simultaneous pancreas-kidney transplantation (SPKT) have not been thoroughly studied. Scientific Registry of Transplant Recipients data reported for SPKT candidates receiving dialysis wait-listed between 1993 and 2008 (n = 7937) were analyzed for outcomes among those who remained listed (n = 3301) and of SPKT recipients (n = 4636) using multivariable time-dependent regression models. Recipients were stratified by donor/recipient age (cutoff 40 years) into: young-to-young (n = 2099), young-to-old (n = 1873), old-to-young (n = 293), and old-to-old (n = 371). The overall mortality was 12%, 14%, 20%, and 24%, respectively, for those transplanted, and 50% for those remaining on the waiting list. On multivariable analysis, old-donor SPKT was associated with significantly higher overall risks of patient death, death-censored pancreas, and kidney graft failure in both young (73%, 53%, and 63% increased risk, respectively) and old (91%, 124%, and 85% increased risk, respectively) recipients. The adjusted relative mortality risk was similar for recipients of old-donor SPKT compared with wait-listed patients including those who subsequently received young-donor transplants (aHR 0.95; 95% CI 0.78, 1.12) except for candidates in OPOs with waiting times >=604 days (aHR 0.65, 95% CI 0.45-0.94). Old-donor SPKT results in significantly worse graft survival and patient mortality without any waiting-time benefit as compared to young-donor SPKT, except for candidates with expected long waiting times. PMID- 23819509 TI - Depression in the elderly in Karachi, Pakistan: a cross sectional study. AB - BACKGROUND: Depression in elderly is a major global public health concern. There has been no population-based study of depression in the elderly in Pakistan. The aim of the study was to estimate the prevalence of depression and its association with family support of elderly (age 60 years and above) in Karachi, Pakistan. METHODS: A population based cross-sectional study was carried out in Karachi from July-September 2008. Questionnaire based interviews were conducted with individuals (n = 953) recruited through multi-stage cluster sampling technique, using the 15- item Geriatric Depression Scale (GDS). RESULTS: Prevalence of depression was found to be 40.6%, with a higher preponderance in women than men (50% vs. 32%). Elderly currently not living with their spouses were 60% more depressed than those living with their spouses (Adjusted OR = 1.6, 95% CI = 1.3 2.1). Elderly who did not consider their children as future support were twice as likely to be depressed as those considering their children to be old age security (Adjusted OR = 2.1, 95% CI = 1.4-3.1). An increase in one male adult child showed 10% decrease in depression after adjusting for other variables (Adjusted OR = 0.9, 95% CI = 0.8-0.9). CONCLUSION: A relatively high prevalence of depression was found in the elderly in Karachi. There appeared to be a strong association between depression and family support variables such as living with spouse, considering children as future security and number of male adult children in the sample studied. Mental wellbeing of the elderly in Pakistan needs to be given consideration in the health policy of the country. In collectivistic societies like Pakistan family support plays an important part in mental health of the elderly that needs to be recognized and supported through various governmental and non-governmental initiatives. KEYPOINTS: Assessment of depression in elderly, Cross-sectional study in Karachi-Pakistan. PMID- 23819510 TI - AAOHN position statements. PMID- 23819511 TI - All-hazard preparedness: the occupational and environmental health nurse role. PMID- 23819512 TI - Global occupational health and safety responsibilities of occupational health nurses based in the United States. AB - The health and safety of workers is the primary concern of occupational health nurses. The purpose of this study was to identify the global occupational health and safety responsibilities of occupational health nurses based in the United States and factors contributing to these global responsibilities. A total of 2,123 American Association of Occupational Health Nurses, Inc. members completed a web-based survey and were included in the study. Approximately 12% (n = 256) of the respondents worked globally. Occupational health nurses with three or four national certifications, OR (odds ratio) = 2.07, 95% confidence interval (CI) [1.08, 3.98], more than 15 years of occupational health nursing experience, OR = 1.23, 95% CI [1.08, 1.39], and a doctoral degree, OR = 2.89, 95% CI [1.40, 5.99], were most likely to work globally. Advanced practice nurses, OR = 1.55, 95% CI [1.12, 2.15], occupational health nurses who worked for large employers, OR = 1.74, 95% CI [1.29, 2.33], and those who supervised other nurses, OR = 1.74, 95% CI [1.29, 2.34], were also more likely to work globally. In contrast, occupational health nurses who personally provided direct care to workers were less likely to work globally, OR = 0.60, 95% CI [0.44, 0.81]. The findings of this study provide direction for future education, practice, and research to increase global responsibilities among occupational health nurses in the United States. PMID- 23819513 TI - Reverse malingering-staying on the job at any cost. AB - Reverse malingering in the workplace is not as common as malingering. Despite their injuries, some workers will stay at work for various reasons regardless of the potential for further injury. Employers must be aware of reverse malingering and should consider alternative work assignments that will satisfy themselves and employees. [Workplace Health Saf 2013;61(7):297-298.]. PMID- 23819515 TI - Hepatitis C testing guidelines-accurately identifying current infection. AB - Accurate testing to identify current infection assists clinicians in correctly identifying those infected with hepatitis C virus. PMID- 23819516 TI - Highly selective luminescent sensing of fluoride and organic small-molecule pollutants based on novel lanthanide metal-organic frameworks. AB - Two novel isostructural lanthanide metal-organic frameworks (Ln-MOFs), [Ln2(BPDC)(BDC)2(H2O)2]n (Ln = Eu (1) and Tb (2)), have been successfully synthesized via a mixed ligand approach using 2,2'-bipyridine-3,3'-dicarboxylic acid (H2BPDC) and 1,4-benzenedicarboxylic acid (H2BDC) under hydrothermal conditions. Structural analysis shows that two lanthanide ions are 4-fold linked by two kappa(1)-kappa(1)-MU2 carboxylates from BDC(2-) and the other two kappa(2) kappa(1)-MU2 carboxylates from BPDC(2-) to form a binuclear core. The binuclear units are further connected by BDC(2-) and BPDC(2-) to build a three-dimensional framework possessing tfz-d topology with the short (Schlafli) vertex symbol {4(3)}2{4(6).6(18).8(4)}. Moreover, isostructural doped Ln-MOFs [Eu(2x)Tb2(1 x)(BPDC)(BDC)2(H2O)2]n (x = 0.1 (1a), 0.3 (1b), 0.5 (1c), 0.7 (1d), and 0.9 (1e)) were also successfully synthesized. Thermal gravimetric analyses (TGA) reveal high thermal stability of these Ln-MOFs. Luminescent measurements indicate that the characteristic sharp emission bands of Eu(3+) and Tb(3+) ions are simultaneously observed in 1a-e. Further luminescent studies reveal that 1, 2, and 1a not only display a high-sensitivity sensing function with respect to fluoride but also exhibit significant solvent-dependent luminescent response to small-molecule pollutants, such as formaldehyde, acetonitrile, and acetone. PMID- 23819517 TI - Serum albumin level is a notable profiling factor for non-B, non-C hepatitis virus-related hepatocellular carcinoma: A data-mining analysis. AB - AIM: Various factors are underlying for the onset of non-B, non-C hepatitis virus related hepatocellular carcinoma (NBNC-HCC). We aimed to investigate the independent risk factors and profiles associated with NBNC-HCC using a data mining technique. METHODS: We conducted a case-control study and enrolled 223 NBNC-HCC patients and 669 controls from a health checkup database (n = 176 886). Multivariate analysis, random forest analysis and a decision-tree algorithm were employed to examine the independent risk factors, factors distinguishing between the case and control groups, and to identify profiles for the incidence of NBNC HCC, respectively. RESULTS: In multivariate analysis, besides gamma glutamyltransferase (GGT) levels and the Brinkman index, albumin level was an independent negative risk factor for the incidence of NBNC-HCC (odds ratio = 0.67; 95% confidence interval = 0.60-0.70; P < 0.0001). In random forest analysis, serum albumin level was the highest-ranked variable for distinguishing between the case and control groups (98 variable importance). A decision-tree algorithm was created for albumin and GGT levels, the aspartate aminotransferase to-platelet ratio index (APRI) and the Brinkman index. The serum albumin level was selected as the initial split variable, and 82.5% of the subjects with albumin levels of less than 4.01 g/dL were found to have NBNC-HCC. CONCLUSION: Data-mining analysis revealed that serum albumin level is an independent risk factor and the most distinguishable factor associated with the incidence of NBNC HCC. Furthermore, we created an NBNC-HCC profile consisting of albumin and GGT levels, the APRI and the Brinkman index. This profile could be used in the screening strategy for NBNC-HCC. PMID- 23819518 TI - The Ghana essential health interventions program: a plausibility trial of the impact of health systems strengthening on maternal & child survival. AB - BACKGROUND: During the 1990s, researchers at the Navrongo Health Research Centre in northern Ghana developed a highly successful community health program. The keystone of the Navrongo approach was the deployment of nurses termed community health officers to village locations. A trial showed that, compared to areas relying on existing services alone, the approach reduced child mortality by half, maternal mortality by 40%, and fertility by nearly a birth - from a total fertility rate of 5.5 in only five years. In 2000, the government of Ghana launched a national program called Community-based Health Planning and Services (CHPS) to scale up the Navrongo model. However, CHPS scale-up has been slow in districts located outside of the Upper East Region, where the "Navrongo Experiment" was first carried out. This paper describes the Ghana Essential Health Intervention Project (GEHIP), a plausibility trial of strategies for strengthening CHPS, especially in the areas of maternal and newborn health, and generating the political will to scale up the program with strategies that are faithful to the original design. DESCRIPTION OF THE INTERVENTION: GEHIP improves the CHPS model by 1) extending the range and quality of services for newborns; 2) training community volunteers to conduct the World Health Organization service regimen known as integrated management of childhood illness (IMCI); 3) simplifying the collection of health management information and ensuring its use for decision making; 4) enabling community health nurses to manage emergencies, particularly obstetric complications and refer cases without delay; 5) adding $0.85 per capita annually to district budgets and marshalling grassroots political commitment to financing CHPS implementation; and 6) strengthening CHPS leadership at all levels of the system. EVALUATION DESIGN: GEHIP impact is assessed by conducting baseline and endline survey research and computing the Heckman "difference in difference" test for under-5 mortality in three intervention districts relative to four comparison districts for core indicators of health status and survival rates. To elucidate results, hierarchical child survival hazard models will be estimated that incorporate measures of health system strength as survival determinants, adjusting for the potentially confounding effects of parental and household characteristics. Qualitative systems appraisal procedures will be used to monitor and explain GEHIP implementation innovations, constraints, and progress. DISCUSSION: By demonstrating practical means of strengthening a real-world health system while monitoring costs and assessing maternal and child survival impact, GEHIP is expected to contribute to national health policy, planning, and resource allocation that will be needed to accelerate progress with the Millennium Development Goals. PMID- 23819520 TI - On the mechanism of solvation dynamics in imidazolium-based ionic liquids. AB - Experimental studies of solvation dynamics in imidazolium-based ionic liquids (ILs) have revealed complex kinetics over a broad range of time scales from femtoseconds to tens of nanoseconds. Microsecond-length molecular dynamics (MD) simulations of coumarin 153 (C153) in 1-ethyl-3-methyl imidazolium tetrafluoroborate, [emim][BF4], were performed to reveal the molecular-level mechanism for solvation dynamics in imidazolium-based ILs over the full range of time scales accessed in the experiments. The solvation response of C153 in [emim][BF4] compared favorably with experiment. An analysis of the structure of the IL in the vicinity of the C153 dye revealed preferential solvation by the [emim] cations. Despite this observation, decomposition of the solvation response into components from the anions and cations and also from translational and rotational motions shows that translations of the [BF4] anions are the dominant contributor to solvation dynamics. The kinetics for the translation of the [BF4] anions into and out of the first solvation shell of the dye were found to mimic the kinetic profile of the solvation dynamics response. This mechanism for solvation dynamics contrasts dramatically with conventional polar liquids in which solvent rotations are generally responsible for the response. PMID- 23819519 TI - Evolution of Hox gene clusters in deuterostomes. AB - Hox genes, with their similar roles in animals as evolutionarily distant as humans and flies, have fascinated biologists since their discovery nearly 30 years ago. During the last two decades, reports on Hox genes from a still growing number of eumetazoan species have increased our knowledge on the Hox gene contents of a wide range of animal groups. In this review, we summarize the current Hox inventory among deuterostomes, not only in the well-known teleosts and tetrapods, but also in the earlier vertebrate and invertebrate groups. We draw an updated picture of the ancestral repertoires of the different lineages, a sort of "genome Hox bar-code" for most clades. This scenario allows us to infer differential gene or cluster losses and gains that occurred during deuterostome evolution, which might be causally linked to the morphological changes that led to these widely diverse animal taxa. Finally, we focus on the challenging family of posterior Hox genes, which probably originated through independent tandem duplication events at the origin of each of the ambulacrarian, cephalochordate and vertebrate/urochordate lineages. PMID- 23819521 TI - Assessment of computational methods for predicting the effects of missense mutations in human cancers. AB - BACKGROUND: Recent advances in sequencing technologies have greatly increased the identification of mutations in cancer genomes. However, it remains a significant challenge to identify cancer-driving mutations, since most observed missense changes are neutral passenger mutations. Various computational methods have been developed to predict the effects of amino acid substitutions on protein function and classify mutations as deleterious or benign. These include approaches that rely on evolutionary conservation, structural constraints, or physicochemical attributes of amino acid substitutions. Here we review existing methods and further examine eight tools: SIFT, PolyPhen2, Condel, CHASM, mCluster, logRE, SNAP, and MutationAssessor, with respect to their coverage, accuracy, availability and dependence on other tools. RESULTS: Single nucleotide polymorphisms with high minor allele frequencies were used as a negative (neutral) set for testing, and recurrent mutations from the COSMIC database as well as novel recurrent somatic mutations identified in very recent cancer studies were used as positive (non-neutral) sets. Conservation-based methods generally had moderately high accuracy in distinguishing neutral from deleterious mutations, whereas the performance of machine learning based predictors with comprehensive feature spaces varied between assessments using different positive sets. MutationAssessor consistently provided the highest accuracies. For certain combinations metapredictors slightly improved the performance of included individual methods, but did not outperform MutationAssessor as stand-alone tool. CONCLUSIONS: Our independent assessment of existing tools reveals various performance disparities. Cancer-trained methods did not improve upon more general predictors. No method or combination of methods exceeds 81% accuracy, indicating there is still significant room for improvement for driver mutation prediction, and perhaps more sophisticated feature integration is needed to develop a more robust tool. PMID- 23819522 TI - Learning styles and preferences for live and distance education: an example of a specialisation course in epidemiology. AB - BACKGROUND: Distance learning through the internet is increasingly popular in higher education. However, it is unknown how participants in epidemiology courses value live vs. distance education. METHODS: All participants of a 5-day specialisation course in epidemiology were asked to keep a diary on the number of hours they spent on course activities (both live and distance education). Attendance was not compulsory during the course and participants were therefore also asked for the reasons to attend live education (lectures and practicals). In addition, the relation between participants' learning styles (Index of Learning Styles) and their participation in live and distance education was studied. RESULTS: All 54 (100%) participants in the course completed the questionnaire on attendance and 46 (85%) completed the questionnaire on learning styles. The number of hours attending live education was negatively correlated with the number of hours going studying distance learning materials (Pearson correlation 0.5; p < 0.001). The most important reasons to attend live education was to stay focused during lectures (50%), and to ask questions during practicals (50%). A lack of time was the most important reason not to attend lectures (52%) or practicals (61%). Learning styles were not association with the number of hours spent on live or distance education. CONCLUSION: Distance learning may play an important role in epidemiology courses, since it allows participants to study whenever and wherever they prefer, which provides the opportunity to combine courses with clinical duties. An important requirement for distance learning education appears to be the possibility to ask questions and to interact with instructors. PMID- 23819523 TI - Comparison 30-day clinical complications between transfemoral versus transapical aortic valve replacement for aortic stenosis: a meta-analysis review. AB - BACKGROUND: Since 2002, transapical aortic valve replacement has been developed as a clinical pathway for transcatheter aortic valve implantation (TAVI). However the appropriate role of TA in the AS population versus TF remains unclear. We performed a meta-analysis to assess if TF has any benefit in reduction of 30-day clinical complications in AS. METHODS: We conducted a comprehensive search on pub med and web of knowledge from 2002 through September 2012 using following terms: aortic stenosis, aortic valve replacement, transcatheter aortic valve implantation, TAVI, trans-artery, transfemoral, trans-apical. Studies in the original research or review articles were also considered. Included studies must meet the preconditioned criterias. Two investigators independently browsed the studies by title and abstract, finally making decision according to full-text. Disagreements were discussed in group. RESULTS: A total of 20 studies met inclusion criteria's and were included in the analysis (including 4267 patients in TF group, 2242 in TA group). No random clinical trial, one was a retrospective study, others were prospective trials. Our meta-analysis found that TF had the low incidence of 30-day mortality compared with TA procedure (7.5% versus 11.3%). The incidence of stroke at <= 30 days was relatively low (3.8% in TF versus 4.0% in TA). Although the incidence of post-operative heart block was high (8.5% versus 7.5%), but no differences were indicated [1.06,95% CI(0.85,1.33)]. CONCLUSIONS: The result of our meta-analysis suggested that TF may have a low risk for 30-day mortality against TA procedure. No difference was found in the incidence of post-operative stroke and heart block. PMID- 23819524 TI - Comparative analysis of folate derived PET imaging agents with [(18)F]-2-fluoro-2 deoxy-d-glucose using a rodent inflammatory paw model. AB - Activated macrophages play a significant role in initiation and progression of inflammatory diseases and may serve as the basis for the development of targeted diagnostic methods for imaging sites of inflammation. Folate receptor beta (FR beta) is differentially expressed on activated macrophages associated with inflammatory disease states yet is absent in either quiescent or resting macrophages. Because folate binds with high affinity to FR-beta, development of folate directed imaging agents has proceeded rapidly in the past decade. However, reports of PET based imaging agents for use in inflammatory conditions remain limited. To investigate whether FR-beta expressing macrophages could be exploited for PET based inflammatory imaging, two separate folate-targeted PET imaging agents were developed, 4-[(18)F]-fluorophenylfolate and [(68)Ga]-DOTA-folate, and their ability to target activated macrophages were examined in a rodent inflammatory paw model. We further compared inflamed tissue uptake with 2 [(18)F]fluoro-2-deoxy-d-glucose ([(18)F]-FDG). microPET analysis demonstrated that both folate-targeted PET tracers had higher uptake in the inflamed paw compared to the control paw. When these radiotracers were compared to [(18)F] FDG, both folate PET tracers had a higher signal-to-noise ratio (SNR) than [(18)F]-FDG, suggesting that folate tracers may be superior to [(18)F]-FDG in detecting diseases with an inflammatory component. Moreover, both folate-PET imaging agents also bind to FR-alpha which is overexpressed on multiple human cancers. Therefore, these folate derived PET tracers may also find use for localizing and staging FR(+) cancers, monitoring response to therapy, and for selecting patients for tandem folate-targeted therapies. PMID- 23819525 TI - Image-directed, tissue-preserving focal therapy of prostate cancer: a feasibility study of a novel deformable magnetic resonance-ultrasound (MR-US) registration system. AB - OBJECTIVE: To evaluate the feasibility of using computer-assisted, deformable image registration software to enable three-dimensional (3D), multi-parametric (mp) magnetic resonance imaging (MRI)-derived information on tumour location and extent, to inform the planning and conduct of focal high-intensity focused ultrasound (HIFU) therapy. PATIENTS AND METHODS: A nested pilot study of 26 consecutive men with a visible discrete focus on mpMRI, correlating with positive histology on transperineal template mapping biopsy, who underwent focal HIFU (Sonablate 500(r)) within a prospective, Ethics Committee-approved multicentre trial ('INDEX'). Non-rigid image registration software developed in our institution was used to transfer data on the location and limits of the index lesion as defined by mpMRI. Manual contouring of the prostate capsule and histologically confirmed MR-visible lesion was performed preoperatively by a urologist and uro-radiologist. A deformable patient-specific computer model, which captures the location of the target lesion, was automatically generated for each patient and registered to a 3D transrectal ultrasonography (US) volume using a small number (10-20) of manually defined capsule points. During the focal HIFU, the urologist could add additional sonications after image-registration if it was felt that the original treatment plan did not cover the lesion sufficiently with a margin. RESULTS: Prostate capsule and lesion contouring was achieved in <5 min preoperatively. The mean (range) time taken to register images was 6 (3-16) min. Additional treatment sonications were added in 13 of 26 cases leading to a mean (range) additional treatment time of 45 (9-90) s. CONCLUSION: Non-rigid MR-US registration is feasible, efficient and can locate lesions on US. The process has potential for improved accuracy of focal treatments, and improved diagnostic sampling strategies for prostate cancer. Further work on whether deformable MR-US registration impacts on efficacy is required. PMID- 23819526 TI - Influence of chlorine substitution on the hydrolytic stability of biaryl ether nucleoside adducts produced by phenolic toxins. AB - A kinetic study is reported for the acid-catalyzed hydrolysis of oxygen (O) linked biaryl ether 8-2'-deoxyguanosine (dG) adducts produced by phenolic toxins following metabolism into phenoxyl radical intermediates. Strikingly, the reaction rate of hydrolysis at pH 1 decreases as electron-withdrawing chlorine (Cl) substituents are added to the phenoxyl ring. The Hammett plot for hydrolysis at pH 1 shows a linear negative slope with rhoX = -0.65, implying that increased Cl-substitution diminishes the rate of hydrolysis by lowering N(7) basicity. Spectrophotometric titration provided an N(7)H(+) pKa value of 1.1 for the unsubstituted adduct 8-phenoxy-dG (Ph-O-dG). Model pyridine compounds suggest N(7)H(+) pKa values of 0.92 and 0.37 for 4-Cl-Ph-O-dG and 2,6-dichloro-Ph-O-dG (DCP-O-dG), respectively. Density functional theory (DFT) calculations also highlight the ability of the 8-phenoxy substituent to lower N(7) basicity and predict a preference for N(3)-protonation for highly chlorinated O-linked 8-dG adducts in water. The calculations also provide a rationale for the hydrolytic reactivity of O-linked 8-dG adducts in the gas-phase, as determined using electrospray mass spectrometry (ESI-MS). The inclusion of our data now establishes that the order of hydrolytic reactivity at neutral pH for bulky 8-dG adducts is N-linked > C-linked > O-linked, which correlates with their relative ease of N(7)-protonation. PMID- 23819527 TI - Bicycle helmet use and bicycling-related injury among young Canadians: an equity analysis. AB - INTRODUCTION: Cycling is a major activity for adolescents in Canada and potential differences exist in bicycling-related risk and experience of injury by population subgroup. The overall aim of this study was to inform health equity interventions by profiling stratified analytic methods and identifying potential inequities associated with bicycle-related injury and the use of bicycle helmets among Canadian youth. The two objectives of this study were: (1) To examine national patterns in bicycle ridership and also bicycle helmet use among Canadian youth in a stratified analysis by potentially vulnerable population subgroups, and (2) To examine bicycling-related injury in the same population subgroups of Canadian youth in order to identify possible health inequities. METHODS: Data for this study were obtained from the 6th cycle (2009/10) of the Health Behaviour in School-aged Children (HBSC) study, which is a general health survey that was completed by 26,078 students in grades 6-10 from 436 Canadian schools. Based on survey responses, we determined point prevalence for bicycle ridership, bicycle helmet use and relative risks for bicycling-related injury. RESULTS: Three quarters of all respondents were bicycle riders (n=19,410). Independent factors associated with bicycle ridership among students include being male, being a younger student, being more affluent, and being a resident of a small town. Among bicycle riders, 43% (95%CI +/- 0.6%) reported never wearing and 32% (+/- 0.6%) inconsistently wearing a helmet. Only 26% (+/- 0.5%) of students reported always wearing a bicycle helmet. Helmets were less frequently used among older students and there were also important patterns by sex, geographic location and socioeconomic status. Adjusting for all other demographic characteristics, boys reported 2.02-fold increase (95% CI: 1.61 to 1.90) and new immigrants a 1.35-fold increase (95%CI: 1.00 to1.82) in the relative risk of bicycling-related injury in the past 12 months, as compared to girls and students born in Canada. The relative risk of injury did not vary significantly by levels of socioeconomic status. CONCLUSIONS: Troubling disparities exist in bicycle use, bicycle helmet use and bicycling-related injuries across specific population subgroups. Bicycle safety and injury prevention initiatives should be informed by disaggregated analyses and the context of bicycle-related health differences should be further examined. PMID- 23819528 TI - Protective effects of vescalagin from pink wax apple [Syzygium samarangense (Blume) Merrill and Perry] fruit against methylglyoxal-induced inflammation and carbohydrate metabolic disorder in rats. AB - The unbalance of glucose metabolism in humans may cause the excessive formation of methylglyoxal (MG), which can react with various biomolecules to form the precursor of advanced glycation end products (AGEs). Vescalagin (VES) is an ellagitannin that alleviates insulin resistance in cell study. Results showed that VES reduced the value of oral glucose tolerance test, cardiovascular risk index, AGEs, and tumor necrosis factor-alpha contents while increasing C-peptide and d-lactate contents significantly in rats orally administered MG and VES together. The preventive effect of VES on MG-induced inflammation and carbohydrate metabolic disorder in rats was thus proved. On the basis of the experiment data, a mechanism, which involves the increase in d-lactate to retard AGE formation and the decrease in cytokine release to prevent beta-cell damage, is proposed to explain the bioactivities of VES in antiglycation and in the alleviation of MG-induced carbohydrate metabolic disorder in rats. PMID- 23819529 TI - What is so tough about self-monitoring of blood glucose? Perceived obstacles among patients with Type 2 diabetes. AB - AIMS: To identify patient-reported obstacles to self-monitoring of blood glucose among those with Type 2, both insulin users and non-insulin users, and to investigate how obstacles are associated with frequency of self-monitoring and use of self-monitoring data. METHODS: Patients with Type 2 diabetes (n = 886, 65% insulin users) who attended a 1-day diabetes education conference in cities across the USA completed a survey on current and recommended self-monitoring of blood glucose frequency, how they used self-monitoring results and perceived obstacles to self-monitoring use. Exploratory factor analysis examined 12 obstacle items to identify underlying factors. Regression analyses examined associations between self-monitoring of blood glucose use and the key obstacle factors identified in the exploratory factor analysis. RESULTS: Three obstacle factors emerged: Avoidance, Pointlessness and Burden. Avoidance was the only significant independent predictor of self-monitoring frequency (beta = -0.23, P < 0.001). Avoidance (beta = -0.12, P < 0.01) and Pointlessness (beta = -0.15, P < 0.001) independently predicted how often self-monitoring data were shared with healthcare professionals and whether or not data were used to make management adjustments (Avoidance: odds ratio = 0.74, P < 0.001; Pointlessness: odds ratio = 0.75, P < 0.01). Burden was not associated with any of the self-monitoring behavioural measures. Few differences between insulin users and non-insulin users were noted. CONCLUSIONS: Obstacles to self-monitoring of blood glucose use, both practical and emotional, were common. Higher levels of Avoidance and Pointlessness, but not Burden, were associated with less frequent self-monitoring use. Addressing patients' self-monitoring-related emotional concerns (Avoidance and Pointlessness) may be more beneficial in enhancing interest and engagement with self-monitoring of blood glucose than focusing on day-to-day, behavioural issues (Burden). PMID- 23819530 TI - Access to sexual and reproductive health care services: young men's perspectives. AB - This study aimed to identify health issues that affect young men and the barriers they experience in accessing care. Participants were 48 minority men 18-28 years old, distributed among 9 focus groups. Four main themes emerged in the study. First, the authors identified sexually transmitted infections, mental health problems, and drug use as major health issues. Second, participants identified attitudinal and institutional barriers to accessing care. This included denial; fear; embarrassment; perception that it is not considered manly to seek help; cost; and accessibility. Third, focus group participants felt that services have to be augmented in order to address the specific needs of men. Last, participants suggested strategies to attract men to family planning clinics that are consistent with a youth culture. Focus groups are effective in obtaining input in order to augment services for men. PMID- 23819531 TI - Opening up openness: a theoretical sort following critical incidents methodology and a meta-analytic investigation of the trait family measures. AB - Existing taxonomies of Openness's facet structure have produced widely divergent results, and there is limited comprehensive empirical evidence about how Openness related scales on existing personality inventories align within the 5-factor framework. In Study 1, we used a critical incidents sorting methodology to identify 11 categories of Openness measures; in Study 2, we meta-analyzed the relationships of these categories with global markers of the Big Five traits (utilizing data from 106 samples with a total sample size of N = 35,886). Our results identified 4 true facets of Openness: aestheticism, openness to sensations, nontraditionalism, and introspection. Measures of these facets were unadulterated by variance from other Big Five traits. Many traits frequently conceptualized as facets of Openness (e.g., innovation/creativity, variety seeking, and tolerance) emerged as trait compounds that, although related to Openness, are also dependent on other Big Five traits. We discuss how Openness should be conceptualized, measured, and studied in light of the empirically based, refined taxonomy emerging from this research. PMID- 23819532 TI - Designed synthesis, structure, and properties of a family of ferecrystalline compounds [(PbSe)(1.00)](m)(MoSe2)(n). AB - The targeted synthesis of multiple compounds with specific controlled nanostructures and identical composition is a grand challenge in materials chemistry. We report the synthesis of the new metastable compounds [(PbSe)1.00]m(MoSe2)n using precursors each designed to self-assemble into a specific compound. To form a compound with specific values for m and n, the number of atoms within each deposited elemental layer was carefully controlled to provide the correct absolute number of atoms to form complete layers of each component structural unit. On low-temperature annealing, these structures self assemble with a specific crystallographic orientation between the component structural units with atomically abrupt interfaces. There is rotational disorder between the component structural units and between MoSe2 basal plane units within the MoSe2 layers themselves. The lead selenide constituent has a distorted rock salt structure exactly m bilayers thick leading to peaks in the off-axis diffraction pattern as a result of the finite size of and rotational disorder between the crystallites. The in-plane lattice parameters of the PbSe and MoSe2 components are independent of the value of m and n, suggesting little or no strain caused by the interface between them. These compounds are small band gap semiconductors with carrier properties dominated by defects and exhibit extremely low thermal conductivity as a result of the rotational disorder. The thermal conductivity can be tuned by varying the ratio of the number of ordered PbSe rock salt layers relative to the number of rotationally disordered MoSe2 layers. This approach, based on controlling the local composition of the precursor and low temperature to limit diffusion rates, provides a general route to the synthesis of new compounds containing alternating layers of constituents with designed nanoarchitecture. PMID- 23819533 TI - In search of the chemical basis of the hemolytic potential of silicas. AB - The membranolytic activity of silica particles toward red blood cells (RBCs) has been known for a long time and is sometimes associated with silica pathogenicity. However, the molecular mechanism and the reasons why hemolysis differs according to the silica form are still obscure. A panel of 15 crystalline (pure and commercial) and amorphous (pyrogenic, precipitated from aqueous solutions, vitreous) silica samples differing in size, origin, morphology, and surface chemical composition were selected and specifically prepared. Silica particles were grouped into six groups to compare their potential in disrupting RBC membranes so that one single property differed in each group, while other features were constant. Free radical production and crystallinity were not strict determinants of hemolytic activity. Particle curvature and morphology modulated the hemolytic effect, but silanols and siloxane bridges at the surface were the main actors. Hemolysis was unrelated to the overall concentration of silanols as fully rehydrated surfaces (such as those obtained from aqueous solution) were inert, and one pyrogenic silica also lost its membranolytic potential upon progressive dehydration. Overall results are consistent with a model whereby hemolysis is determined by a defined surface distribution of dissociated/undissociated silanols and siloxane groups strongly interacting with specific epitopes on the RBC membrane. PMID- 23819534 TI - Medical evacuations from Afghanistan during Operation Enduring Freedom, active and reserve components, U.S. Armed Forces, 7 October 2001-31 December 2012. AB - From October 7, 2001 to 31 December 2012, over 20,000 service members were medically evacuated from the Operation Enduring Freedom (OEF) theater of combat operations to a medical treatment facility outside of theater. During the period the number, rates, and underlying causes of medical evacuations sharply varied in relation to the natures of ongoing military operations. During every month of the period, medical evacuations for disease and non-battle injuries exceeded those for battle-related injuries. The majority of evacuations (88.7%) occurred among males; however, the rate of medical evacuations was 22 percent higher among females. The major causes of medical evacuations differed among male and female deployers; however, rates of battle injuries and mental health disorders increased in both sexes during the period. Rates of medical evacuations were highest among white, non-Hispanics, soldiers, and in service members in the reserve component, junior enlisted, and in combat-specific occupations. Most service members were discharged back to duty after medical evacuation. The findings enforce the need to tailor force health protection policies and practices to the characteristics of the deployed force and the nature of the military operation. PMID- 23819535 TI - Incident diagnoses of common symptoms ("sequelae") following traumatic brain injury, active component, U.S. Armed Forces, 2000-2012. AB - Many individuals who suffer traumatic brain injuries (TBI) experience subsequent physical, neurocognitive, or psychological symptoms. This analysis examined the occurrence of 14 such symptoms in service members stratified by severity into three groups of TBI and also in two comparison groups (controls) of service members who had no documented TBI diagnosis. For members of each of the five groups, the proportion who had experienced the 14 symptoms of interest was captured for the first 3 month and 12 month periods after the relevant diagnosis. Service members in the group "TBI, non-current injury" differed considerably from the four other groups by demographic characteristics and by previous history of deployment. In general, individuals with diagnoses indicative of TBI, regardless of severity, had higher proportions of the post-TBI diagnoses than either control group. The most common post-TBI diagnoses were headache disorders, alcohol and substance abuse, post-traumatic stress disorder, and sleep disorders. Proportions with diagnosed symptoms increased from the earliest (2000-2002) to the most recent part (2007-2012) of the surveillance period. Probable reasons for this observation are discussed. PMID- 23819536 TI - Outbreak of Group A beta hemolytic Streptococcus pharyngitis in a Peruvian military facility, April 2012. AB - Group A Streptococcus (GAS), or Streptococcus pyogenes, is a common cause of acute pharyngitis as well as other diseases. Closed populations such as those living on military bases, nursing homes, and prisons are particularly vulnerable to GAS outbreaks due to crowding that facilitates person-to-person transmission. This report details a large outbreak of GAS pharyngitis at a Peruvian military training facility near Lima, Peru, in April 2012. Initial findings showed 145 cases. However, as the investigation continued it was revealed that some trainees may have concealed their illness to avoid real or perceived negative consequences of seeking medical care. A subsequent anonymous survey of all trainees revealed at least 383 cases of pharyngitis among the facility's 1,549 trainees and an attack rate of 34 percent among the 1,137 respondents. The epidemic curve revealed a pattern consistent with routine person-to-person transmission, although a point-source initiating event could not be excluded. Laboratory results showed GAS emm type 80.1 to be the culprit pathogen, an organism not commonly implicated in outbreaks of GAS in the Americas. Barious unique and illustrative features of outbreak investigation in military facilities and populations are discussed. PMID- 23819537 TI - Arm and shoulder conditions, active component, U.S. Armed Forces, 2003-2012. AB - This analysis estimated the incidence and health care burden of acute and chronic conditions of the arm and shoulder among active component service members of the Armed Forces from 1 January 2003 through 31 December 2012. There were 196,789 diagnosed incident cases of acute arm and shoulder conditions for a rate of 13.7 cases per 1,000 person-years. The annual incidence rates of sprains, the most common acute condition, nearly doubled during the period. Diagnoses of chronic conditions (overall rate of 28.8 per 1,000 person-years) increased 25 percent during the period, mainly associated with a doubling of the incidence of diagnoses of joint pain. Incidence rates of chronic disorders were progressively higher among successively older age groups of service members. The health care burden of all arm and shoulder conditions together steadily increased during the period, as indicated by numbers of health care encounters, individuals affected, and lost work time. The most commonly documented causes associated with acute and chronic conditions are described. PMID- 23819538 TI - The Reportable Events Monthly Report (REMR). PMID- 23819539 TI - Synthesis of 1,4-anthracene-9,10-dione derivatives and their regulation of nitric oxide, IL-1beta and TNF-alpha in activated RAW264.7 cells. AB - Mitoxantrone is an anthracenedione antineoplastic and immunosuppressive agent approved for multiple sclerosis treatment. Novel mono- and disubstituted anthraquinone derivatives, analogues of mitoxantrone, were synthesized through the addition of lipophilic amino alcohols and evaluated for their effect on IL 1beta, TNF-alpha and nitric oxide production by LPS/IFN-gamma-stimulated RAW264.7 cells. The disubstituted 1,4-anthracene-9,10-dione 10 showed significant inhibition of nitric oxide, TNF-alpha and IL-1beta production at the concentration of 5 MUg/mL, with a much lower cytotoxicity than mitoxantrone. The monosubstituted 3, 4, 11, 12 and 13 also displayed a moderate to good inhibitory capacity on IL-1beta production. However, the methylated compounds 11, 12 and 13 failed to inhibit the TNF-alpha production, and compound 13 was the only one to decrease the production of nitric oxide. None of these derivatives was toxic at the tested concentrations. Compounds 10 and 13 had better inhibitory capacity of the inflammatory mediators analyzed, with reliable viability of the cells. PMID- 23819540 TI - Detecting early-warning signals of type 1 diabetes and its leading biomolecular networks by dynamical network biomarkers. AB - BACKGROUND: Type 1 diabetes (T1D) is a complex disease and harmful to human health, and most of the existing biomarkers are mainly to measure the disease phenotype after the disease onset (or drastic deterioration). Until now, there is no effective biomarker which can predict the upcoming disease (or pre-disease state) before disease onset or disease deterioration. Further, the detail molecular mechanism for such deterioration of the disease, e.g., driver genes or causal network of the disease, is still unclear. METHODS: In this study, we detected early-warning signals of T1D and its leading biomolecular networks based on serial gene expression profiles of NOD (non-obese diabetic) mice by identifying a new type of biomarker, i.e., dynamical network biomarker (DNB) which forms a specific module for marking the time period just before the drastic deterioration of T1D. RESULTS: Two dynamical network biomarkers were obtained to signal the emergence of two critical deteriorations for the disease, and could be used to predict the upcoming sudden changes during the disease progression. We found that the two critical transitions led to peri-insulitis and hyperglycemia in NOD mice, which are consistent with other independent experimental results from literature. CONCLUSIONS: The identified dynamical network biomarkers can be used to detect the early-warning signals of T1D and predict upcoming disease onset before the drastic deterioration. In addition, we also demonstrated that the leading biomolecular networks are causally related to the initiation and progression of T1D, and provided the biological insight into the molecular mechanism of T1D. Experimental data from literature and functional analysis on DNBs validated the computational results. PMID- 23819541 TI - High-throughput screening of one-bead-one-compound peptide libraries using intact cells. AB - Screening approaches based on one-bead-one-compound (OBOC) combinatorial libraries have facilitated the discovery of novel peptide ligands for cellular targeting in cancer and other diseases. Recognition of cell surface proteins is optimally achieved using live cells, yet screening intact cell populations is time-consuming and inefficient. Here, we evaluate the Complex Object Parametric Analyzer and Sorter (COPAS) large particle biosorter for high-throughput sorting of bead-bound human cell populations. When a library of RGD-containing peptides was screened against human cancer cells that express alphavbeta3 integrin, it was found that bead-associated cells are rapidly dissociated when sorted through the COPAS instrument. When the bound cells were reversibly cross-linked onto the beads, however, we demonstrated that cell/bead mixtures can be sorted quickly and accurately. This reversible cross-linking approach is compatible with matrix assisted laser desorption ionization time-of-flight mass spectrometry-based peptide sequence deconvolution. This approach should allow one to rapidly screen an OBOC library and identify novel peptide ligands against cell surface targets in their native conformation. PMID- 23819542 TI - Podocalyxin-like protein expression in primary colorectal cancer and synchronous lymph node metastases. AB - AIMS: Previous studies have shown that membranous expression of podocalyxin-like protein (PODXL) is associated with poor prognosis in colorectal cancer (CRC). In this study, we compared PODXL expression in primary CRC and synchronous lymph node metastases. We further analyzed whether its expression changed in rectal tumours after neoadjuvant radiation therapy. METHODS AND RESULTS: The studied cohort consists of 73 consecutive patients from the South-Swedish Colorectal Cancer Biobank. Immunohistochemical PODXL expression was examined on full-face sections from all primary tumours and all 140 available lymph node metastases from 31 cases. Membranous PODXL expression was denoted in 18/73 (24,7%) primary tumours, with a high concordance between primary and metastatic lesions. While all negative primary tumours had negative metastases, some PODXL positive primaries had a varying proportion of positive and negative metastatic lymph nodes. PODXL expression was also found to be mainly unaltered in pre- and post irradiation surgically resected tumour specimens in rectal cancer patients (n=16). CONCLUSIONS: The findings in this study suggest that analysis of PODXL expression in the primary tumour is sufficient for its use as a prognostic and treatment predictive biomarker in CRC, also in patients with metastatic disease. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9014177329634352. PMID- 23819544 TI - Asthma diagnosis and treatment - 1015. Improvements in lung function in an indian population with IgE mediated asthma receiving omalizumab in a real-world setting. PMID- 23819543 TI - Trauma and posttraumatic stress disorder in South Africa: analysis from the South African Stress and Health Study. AB - BACKGROUND: South Africa's unique history, characterised by apartheid, a form of constitutional racial segregation and exploitation, and a long period of political violence and state-sponsored oppression ending only in 1994, suggests a high level of trauma exposure in the general population. The aim of this study was to document the epidemiology of trauma and posttraumatic stress disorder (PTSD) in the South African general population. METHODS: The South African Stress and Health Study is a nationally representative survey of South African adults using the WHO's Composite International Diagnostic Interview (CIDI) to assess exposure to trauma and presence of DSM-IV mental disorders. RESULTS: The most common traumatic events were the unexpected death of a loved one and witnessing trauma occurring to others. Lifetime and 12-month prevalence rates of PTSD were 2.3% and 0.7% respectively, while the conditional prevalence of PTSD after trauma exposure was 3.5%. PTSD conditional risk after trauma exposure and probability of chronicity after PTSD onset were both highest for witnessing trauma. Socio demographic factors such as sex, age and education were largely unrelated to PTSD risk. CONCLUSIONS: The occurrence of trauma and PTSD in South Africa is not distributed according to the socio-demographic factors or trauma types observed in other countries. The dominant role of witnessing in contributing to PTSD may reflect the public settings of trauma exposure in South Africa and highlight the importance of political and social context in shaping the epidemiology of PTSD. PMID- 23819545 TI - Impact of intrauterine and post-natal nutritional determinants on blood pressure at 4 years of age. AB - BACKGROUND: To prospectively study how the early nutritional environment can programme blood pressure in a well-nourished population of children. METHODS: By means of multivariate modelling, we assessed whether gestational and post-natal dietary intakes and growth influence childhood blood pressure programming in a cohort of 109 healthy mother-child pairs. They had been followed from early pregnancy until the children reached 4 years of age. Dietary intakes were evaluated using 3-day food diaries. Blood pressure levels in the children were measured using an automated oscillometric DINAMAP ProCare 100 (Criticon, Tampa, FL, USA) at the age of 4 years. RESULTS: In the final multivariate model, the predictor variables of childhood systolic blood pressure were maternal dietary carbohydrate and fat intake during pregnancy, as well as childhood weight and dietary fat intake at 4 years of age. Systolic blood pressure levels in the children were found to be positively associated with the maternal carbohydrate intake (P = 0.003), whereas blood pressure levels were lowest in children exposed to the middle tertile of maternal dietary fat intake during pregnancy (P = 0.003) and whose own dietary fat intake was in the middle tertile at the age of 4 years (P = 0.013). The model also showed that heavier children have a higher systolic blood pressure (P < 0.001). None of the maternal clinical characteristics fulfilled the criterion to be included in the model. The only determinant underlying childhood diastolic blood pressure was childhood weight at 4 years of age (r = 0.289, P = 0.026). CONCLUSIONS: Interventions focusing on cardiovascular health in young women during pregnancy and their children should be considered to reduce cardiovascular diseases risk factors in these children. PMID- 23819548 TI - Percolation-based risk index for pathogen invasion: application to soilborne disease in propagation systems. AB - Propagation systems for seedling growth play a major role in agriculture, and in notable cases (such as organic systems), are under constant threat from soil and seedborne fungal plant pathogens such as Rhizoctonia solani or Pythium spp. Yet, to date little is known that links the risk of disease invasion to the host density, which is an agronomic characteristic that can be readily controlled. We introduce here, for the first time in an agronomic system, a percolation framework to analyze the link. We set up an experiment to study the spread of the ubiquitous fungus R. solani in replicated propagation systems with different planting densities, and fit a percolation-based epidemiological model to the data using Bayesian inference methods. The estimated probability of pathogen transmission between infected and susceptible plants is used to calculate the risk of invasion. By comparing the transmission probability and the risk values obtained for different planting densities, we are able to give evidence of a nonlinear relationship between disease invasion and the inter-plant spacing, hence to demonstrate the existence of a spatial threshold for epidemic invasion. The implications and potential use of our methods for the evaluation of disease control strategies are discussed. PMID- 23819546 TI - Real-time metabolomics on living microorganisms using ambient electrospray ionization flow-probe. AB - Microorganisms such as bacteria and fungi produce a variety of specialized metabolites that are invaluable for agriculture, biological research, and drug discovery. However, the screening of microbial metabolic output is usually a time intensive task. Here, we utilize a liquid microjunction surface sampling probe for electrospray ionization-mass spectrometry to extract and ionize metabolite mixtures directly from living microbial colonies grown on soft nutrient agar in Petri-dishes without any sample pretreatment. To demonstrate the robustness of the method, this technique was applied to observe the metabolic output of more than 30 microorganisms, including yeast, filamentous fungi, pathogens, and marine derived bacteria, that were collected worldwide. Diverse natural products produced from different microbes, including Streptomyces coelicolor , Bacillus subtilis , and Pseudomonas aeruginosa are further characterized. PMID- 23819549 TI - Hyperparasites influence population structure of the chestnut blight pathogen, Cryphonectria parasitica. AB - Vegetative compatibility (VC) is commonly used to characterize structure and diversity in fungal populations. In the chestnut blight fungus, Cryphonectria parasitica, high VC diversity is hypothesized to be responsible for the failure of hyperparasitic mycoviruses to spread through pathogen populations in North America. To test this hypothesis, we assessed VC diversity at three recovering sites in Michigan where mycoviruses had invaded and compared them with four epidemic population sites where mycoviruses were absent. VC diversity was assessed for samples collected in 1996 and 2009, which allowed us to determine how C. parasitica populations changed with time. Twelve VC types were found in 1996 while 29 were found in 2009; 75% of types overlapped between the sample dates. Sites where mycoviruses were present had unique VC structures with the exception of the recovering population site at County Line where the main VC group was also detected at two epidemic sites. With one exception, epidemic sites contained more VC groups and displayed higher population level diversity than recovering sites. Mating-type analyses of blight populations revealed that two of three recovering populations were significantly skewed for MAT2 suggesting asexual reproduction, while epidemic sites with a long history of blight infection had ratios near 50:50 suggesting sexual reproduction. We propose that selection in the largely asexual C. parasitica populations at two recovering sites favors the most-fit fungal genotype by mycovirus combination and results in reduced diversity relative to the sexually reproducing pathogen populations at epidemic sites. PMID- 23819550 TI - Sexual dimorphism dominates divergent host plant use in stick insect trophic morphology. AB - BACKGROUND: Clear examples of ecological speciation exist, often involving divergence in trophic morphology. However, substantial variation also exists in how far the ecological speciation process proceeds, potentially linked to the number of ecological axes, traits, or genes subject to divergent selection. In addition, recent studies highlight how differentiation might occur between the sexes, rather than between populations. We examine variation in trophic morphology in two host-plant ecotypes of walking-stick insects (Timema cristinae), known to have diverged in morphological traits related to crypsis and predator avoidance, and to have reached an intermediate point in the ecological speciation process. Here we test how host plant use, sex, and rearing environment affect variation in trophic morphology in this species using traditional multivariate, novel kernel density based and Bayesian morphometric analyses. RESULTS: Contrary to expectations, we find limited host-associated divergence in mandible shape. Instead, the main predictor of shape variation is sex, with secondary roles of population of origin and rearing environment. CONCLUSION: Our results show that trophic morphology does not strongly contribute to host-adapted ecotype divergence in T. cristinae and that traits can respond to complex selection regimes by diverging along different intraspecific lines, thereby impeding progress toward speciation. PMID- 23819551 TI - Genetic polymorphisms in matrix metalloproteinases (MMPs) and tissue inhibitors of MPs (TIMPs), and bladder cancer susceptibility. AB - OBJECTIVES: To elucidate genetic polymorphisms of the matrix metalloproteinases (MMPs) MMP1 (rs1799750), MMP2 (rs243865), MMP9 (rs3918242), MMP12 (rs2276109) and tissue inhibitors of MMPs (TIMPs) TIMP1 (rs2070584) and TIMP3 (rs9619311) genes that may be involved in susceptibility to bladder cancer (BC). PATIENTS AND METHODS: We enrolled 241 patients with BC and 199 controls. Genomic DNA samples were extracted from peripheral blood and polymorphisms were analysed by high resolution melting analysis and by real-time polymerase chain reaction using TaqMan fluorescent probes. RESULTS: Of the six evaluated polymorphisms of MMPs and TIMPs, only one was found to be associated with BC risk. There was a significant difference for MMP1 (rs1799750) 2G/1G+1G/1G genotype (odds ratio [OR] 0.62, 95% confidence interval [CI] 0.39-0.98; P = 0.042). Additionally, there was a joint effect of this genotype on BC risk among 'ever smokers' (OR 0.51, 95% CI 0.28-0.89; P = 0.019), but not in 'never smokers'. The combined genotype MMP2 1306C/T (rs243865) allele T with MMP9 -1562C/T (rs3918242) allele T was found to increase BC risk (OR 2.00, 95% CI 1.10-3.62; P = 0.022). CONCLUSIONS: Our results suggest that genetic variations in five polymorphisms of MMPs and TIMPs are not associated with a high risk of BC. Only MMP1 polymorphism may be related to the risk of BC, notably in 'ever smokers'. Our study suggests that the effects of polymorphisms of MMPs and TIMPs on BC risk deserve further investigation. PMID- 23819552 TI - Strengthening integrated primary health care in Sofala, Mozambique. AB - BACKGROUND: Large increases in health sector investment and policies favoring upgrading and expanding the public sector health network have prioritized maternal and child health in Mozambique and, over the past decade, Mozambique has achieved substantial improvements in maternal and child health indicators. Over this same period, the government of Mozambique has continued to decentralize the management of public sector resources to the district level, including in the health sector, with the aim of bringing decision-making and resources closer to service beneficiaries. Weak district level management capacity has hindered the decentralization process, and building this capacity is an important link to ensure that resources translate to improved service delivery and further improvements in population health. A consortium of the Ministry of Health, Health Alliance International, Eduardo Mondlane University, and the University of Washington are implementing a health systems strengthening model in Sofala Province, central Mozambique. DESCRIPTION OF IMPLEMENTATION: The Mozambique Population Health Implementation and Training (PHIT) Partnership focuses on improving the quality of routine data and its use through appropriate tools to facilitate decision making by health system managers; strengthening management and planning capacity and funding district health plans; and building capacity for operations research to guide system-strengthening efforts. This seven-year effort covers all 13 districts and 146 health facilities in Sofala Province. EVALUATION DESIGN: A quasi-experimental controlled time-series design will be used to assess the overall impact of the partnership strategy on under-5 mortality by examining changes in mortality pre- and post-implementation in Sofala Province compared with neighboring Manica Province. The evaluation will compare a broad range of input, process, output, and outcome variables to strengthen the plausibility that the partnership strategy led to health system improvements and subsequent population health impact. DISCUSSION: The Mozambique PHIT Partnership expects to provide evidence on the effect of efforts to improve data quality coupled with the introduction of tools, training, and supervision to improve evidence-based decision making. This contribution to the knowledge base on what works to enhance health systems is highly replicable for rapid scale-up to other provinces in Mozambique, as well as other sub-Saharan African countries with limited resources and a commitment to comprehensive primary health care. PMID- 23819553 TI - FeCl3-catalyzed cascade cyclization in one pot: synthesis of ring-fused tetrahydroquinoline derivatives from arylamines and N-substituted lactams. AB - Multiple cross-dehydrogenative-coupling reactions catalyzed by FeCl3 in one pot were developed. Arylamines and N-substituted lactams were reacted, and ring-fused tetrahydroquinoline derivatives were formed by two C-C bonds and one C-N bond formation as well as one C-N bond cleavage. The lactams were also used as solvent. PMID- 23819554 TI - Hetero- and adaptive resistance to polymyxin B in OXA-23-producing carbapenem resistant Acinetobacter baumannii isolates. AB - BACKGROUND: Resistance rates to polymyxin B in surveillance studies have been very low despite its increasing use worldwide as the last resort therapy for multidrug-resistant Gram-negative bacilli. However, two other resistance phenotypes, hetero- and adaptive resistance, have been reported to polymyxin. We aimed to investigate the presence of polymyxin B hetero- and adaptive resistance and evaluate its stability in carbapenem-resistant Acinetobacter baumannii (CRAB) clinical isolates. METHODS: CRAB isolates were recovered from hospitalized patients at three Brazilian hospitals. Hetero-resistance was determined by population analysis profile (PAP). Adaptive resistance was evaluated after serial daily passages of isolates in Luria-Bertani broth containing increasing polymyxin B concentrations. MICs of polymyxin B of colonies growing at the highest polymyxin B concentration were further determined after daily sub-cultured in antibiotic-free medium and after storage at -80 degrees C, in some selected isolates. RESULTS: Eighty OXA-23-producing CRAB isolates were typed resulting in 15 distinct clones. Twenty-nine randomly selected isolates (at least one from each clone) were selected for hetero- resistance evaluation: 26 (90%) presented growth of subpopulations with higher polymyxin B MIC than the original one in PAP. No isolate has grown at polymyxin B concentrations higher than 2 mg/L. Polymyxin B MICs of subpopulations remained higher than the original population after daily passages on antibiotic-free medium but returned to the same or similar levels after storage. Twenty-two of the 29 isolates (at least one from each clone) were evaluated for adaptive resistance: 12 (55%) presented growth in plates containing 64 mg/L of polymyxin B. Polymyxin B MICs decreased after daily passages on antibiotic-free medium and returned to the same levels after storage. CONCLUSIONS: The presence of subpopulations with higher polymyxin B MIC was extremely common and high-level adaptive resistance was very frequent in CRAB isolates. PMID- 23819555 TI - Ethical aspects of directly observed treatment for tuberculosis: a cross-cultural comparison. AB - BACKGROUND: Tuberculosis is a major global public health challenge, and a majority of countries have adopted a version of the global strategy to fight Tuberculosis, Directly Observed Treatment, Short Course (DOTS). Drawing on results from research in Ethiopia and Norway, the aim of this paper is to highlight and discuss ethical aspects of the practice of Directly Observed Treatment (DOT) in a cross-cultural perspective. DISCUSSION: Research from Ethiopia and Norway demonstrates that the rigid enforcement of directly observed treatment conflicts with patient autonomy, dignity and integrity. The treatment practices, especially when imposed in its strictest forms, expose those who have Tuberculosis to extra burdens and costs. Socially disadvantaged groups, such as the homeless, those employed as day labourers and those lacking rights as employees, face the highest burdens. SUMMARY: From an ethical standpoint, we argue that a rigid practice of directly observed treatment is difficult to justify, and that responsiveness to social determinants of Tuberculosis should become an integral part of the management of Tuberculosis. PMID- 23819556 TI - Revealing selection in cancer using the predicted functional impact of cancer mutations. Application to nomination of cancer drivers. AB - Every malignant tumor has a unique spectrum of genomic alterations including numerous protein mutations. There are also hundreds of personal germline variants to be taken into account. The combinatorial diversity of potential cancer-driving events limits the applicability of statistical methods to determine tumor specific "driver" alterations among an overwhelming majority of "passengers". An alternative approach to determining driver mutations is to assess the functional impact of mutations in a given tumor and predict drivers based on a numerical value of the mutation impact in a particular context of genomic alterations.Recently, we introduced a functional impact score, which assesses the mutation impact by the value of entropic disordering of the evolutionary conservation patterns in proteins. The functional impact score separates disease associated variants from benign polymorphisms with an accuracy of ~80%. Can the score be used to identify functionally important non-recurrent cancer-driver mutations? Assuming that cancer-drivers are positively selected in tumor evolution, we investigated how the functional impact score correlates with key features of natural selection in cancer, such as the non-uniformity of distribution of mutations, the frequency of affected tumor suppressors and oncogenes, the frequency of concurrent alterations in regions of heterozygous deletions and copy gain; as a control, we used presumably non-selected silent mutations. Using mutations of six cancers studied in TCGA projects, we found that predicted high-scoring functional mutations as well as truncating mutations tend to be evolutionarily selected as compared to low-scoring and silent mutations. This result justifies prediction of mutations-drivers using a shorter list of predicted high-scoring functional mutations, rather than the "long tail" of all mutations. PMID- 23819557 TI - Impact of continuous glucose monitoring on diabetes management and marital relationships of adults with Type 1 diabetes and their spouses: a qualitative study. AB - AIMS: To examine the impact of continuous glucose monitoring on diabetes management and marital relationships of adults with Type 1 diabetes and their spouses. METHODS: Nine younger (30-49 years) and 11 older (50-70 years) patients with Type 1 diabetes and 14 spouses participated in eight focus groups specific to age and role (patient or spouse). Audio-recorded data were transcribed, coded and analysed using thematic analysis and aided by NVivo software. RESULTS: Qualitative analysis revealed participants perceived continuous glucose monitoring as positively influencing hypoglycaemia management by decreasing spouses' anxiety, vigilance and negative experiences. Participants also described continuous glucose monitoring as promoting collaborative diabetes management and increasing spousal understanding of diabetes, especially when planning and managing pregnancy. Couples' conflicts occurred when (1) patients assumed sole responsibility for continuous glucose monitoring and/or did not respond to night time glucose alarms and (2) spouses did not understand alarms and felt frustrated and helpless to assist patients. CONCLUSIONS: Our findings suggest that continuous glucose monitoring may positively impact collaborative diabetes management and marital relationships of patients with Type 1 diabetes and their spouses. However, reluctance to collaborate and lack of understanding may contribute to couples' conflicts around continuous glucose monitoring. Our findings have important implications for clinical care and point to the need for interventions that include spouses in continuous glucose monitoring training to increase their understanding of continuous glucose monitoring, minimize risk for spousal conflict and enhance collaborative diabetes management. Further studies are needed to explore these issues in more detail and depth with larger and more diverse populations. PMID- 23819558 TI - Ischemic preconditioning versus intermittent clamping of portal triad in liver resection: A meta-analysis of randomized controlled trials. AB - AIM: To compare the clinical outcome of patients undergoing liver resection under ischemic preconditioning (IP) versus intermittent clamping (IC). METHODS: A systematic published work search was conducted to detect randomized controlled trials (RCT) comparing IP and intermittent clamping of the portal triad. A meta analysis was conducted to estimate postoperative morbidity and mortality, blood loss, transfusion requirement, and liver injury based on the levels of bilirubin, aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Meta analysis was performed using either the fixed-effects model or random-effects model. RESULTS: Five RCT published between 2006 and 2012 containing a total of 403 patients were eligible for final analysis. Meta-analysis of operative time showed it was lower in the IP group than the IC group with weighted mean difference (WMD) of -18.23 (95% confidence interval (CI), -28.58 to -7.87; P = 0.0006). Meta-analysis of ALT levels indicated lower levels in the IP group on postoperative days 3 and 7 (WMD on day 3: -45.27, 95% CI, -49.92 to -40.62; P < 0.00001; I(2) = 0%; WMD on day 7: -24.33, 95% CI, -28.04 to -20.62; P < 0.00001; I(2) = 0%). Meta-analyses revealed no significant difference in blood loss, transfusion requirement, mortality, morbidity, ischemic duration, hospital stay, AST and bilirubin levels on postoperative days 1, 3 and 7, and ALT levels on postoperative day 1 between IP and IC groups. CONCLUSION: On currently available evidence, IP does not offer a satisfying benefit to patients undergoing hepatic resection. However, they have lower operative time and less liver injury after liver resections. PMID- 23819559 TI - Reactivity of TEMPO toward 16- and 17-electron organometallic reaction intermediates: a time-resolved IR study. AB - The (2,2,6,6-tetramethylpiperidin-1-yl)oxyl radical (TEMPO) has been employed for an extensive range of chemical applications, ranging from organometallic catalysis to serving as a structural probe in biological systems. As a ligand in an organometallic complex, TEMPO can exhibit several distinct coordination modes. Here we use ultrafast time-resolved infrared spectroscopy to study the reactivity of TEMPO toward coordinatively unsaturated 16- and 17-electron organometallic reaction intermediates. TEMPO coordinates to the metal centers of the 16-electron species CpCo(CO) and Fe(CO)4, and to the 17-electron species CpFe(CO)2 and Mn(CO)5, via an associative mechanism with concomitant oxidation of the metal center. In these adducts, TEMPO thus behaves as an anionic ligand, characterized by a pyramidal geometry about the nitrogen center. Density functional theory calculations are used to facilitate interpretation of the spectra and to further explore the structures of the TEMPO adducts. To our knowledge, this study represents the first direct characterization of the mechanism of the reaction of TEMPO with coordinatively unsaturated organometallic complexes, providing valuable insight into its reactions with commonly encountered reaction intermediates. The similar reactivity of TEMPO toward each of the species studied suggests that these results can be considered representative of TEMPO's reactivity toward all low-valent transition metal complexes. PMID- 23819560 TI - Marital functioning and psychological distress among older couples over an 18 month period. AB - Many authors have underlined the existence of a negative association between marital functioning and psychological distress. However, little is known about the direction of this association over time among older couples. This study examined the relation over time between psychological distress and marital functioning among 394 community-dwelling couples. The authors conducted dyadic data analyses to determine whether marital functioning at baseline (T1) predicted psychological distress 18 months later (T2), and inversely. The results for women suggested that marital and psychological functioning may each predict the other. The results for men showed that marital problems lead to more psychological distress. The authors found some significant partner effects: In both genders, the marital functioning of one spouse influenced the marital functioning of the other. Men's marital functioning at baseline significantly predicted women's psychological distress at T2. The authors conducted analyses also to determine how 6 patterns of change in marital functioning between times were associated with changes in psychological distress, and inversely. Changes characterized by an increase in psychological distress over time in at least 1 spouse were associated with a decrease in marital functioning. These findings underlined the importance for clinicians and researchers to pay closer attention to the association between these variables. PMID- 23819561 TI - Clinical care for sexual assault survivors multimedia training: a mixed-methods study of effect on healthcare providers' attitudes, knowledge, confidence, and practice in humanitarian settings. AB - BACKGROUND: Sexual assault is a threat to public health in refugee and conflict affected settings, placing survivors at risk for unintended pregnancy, unsafe abortion, STIs, HIV, psychological trauma, and social stigma. In response, the International Rescue Committee developed a multimedia training tool to encourage competent, compassionate, and confidential clinical care for sexual assault survivors in low-resource settings. This study evaluated the effect of the training on healthcare providers' attitudes, knowledge, confidence, and practices in four countries. METHODS: Using a mixed-methods approach, we surveyed a purposive sample of 106 healthcare providers before and 3 months after training to measure attitudes, knowledge, and confidence. In-depth interviews with 40 providers elaborated on survey findings. Medical record audits were conducted in 35 health facilities before and 3 months after the intervention to measure healthcare providers' practice. Quantitative and qualitative data underwent statistical and thematic analysis. RESULTS: While negative attitudes, including blaming and disbelieving women who report sexual assault, did not significantly decrease among healthcare providers after training, respect for patient rights to self-determination and non-discrimination increased from 76% to 91% (p < .01) and 74% to 81% (p < .05) respectively. Healthcare providers' knowledge and confidence in clinical care for sexual assault survivors increased from 49% to 62% (p < .001) and 58% to 73% (p < .001) respectively following training. Provider practice improved following training as demonstrated by a documented increase in eligible survivors receiving emergency contraception from 50% to 82% (p < .01), HIV post-exposure prophylaxis from 42% to 92% (p < .001), and STI prophylaxis and treatment from 45% to 96% (p < .01). CONCLUSIONS: Although beliefs about sexual assault are hard to change, training can improve healthcare providers' respect for patient rights and knowledge and confidence in direct patient care, resulting in more competent and compassionate clinical care for sexual assault survivors. PMID- 23819562 TI - Inhibition of Pseudomonas aeruginosa and Escherichia coli O157:H7 biofilm formation by plant metabolite epsilon-viniferin. AB - Pathogenic biofilms are associated with persistent infection due to their high resistances to diverse antibiotics. Pseudomonas aeruginosa infects plants, animals, and humans and is a major cause of nosocomial diseases in patients with cystic fibrosis. In the present study, the antibiofilm abilities of 522 plant extracts against P. aeruginosa PA14 were examined. Three Carex plant extracts at a concentration of 200 MUg/mL inhibited P. aeruginosa biofilm formation by >80% without affecting planktonic cell growth. In the most active extract of Carex pumila , resveratrol dimer epsilon-viniferin was one of the main antibiofilm compounds against P. aeruginosa. Interestingly, epsilon-viniferin at 10 MUg/mL inhibited biofilm formation of enterohemorrhagic Escherichia coli O157:H7 by 98%. Although Carex extracts and trans-resveratrol are known to possess antimicrobial activity, this study is the first to report that C. pumila extract and epsilon viniferin have antibiofilm activity against P. aeruginosa and E. coli O157:H7. PMID- 23819563 TI - Ayurvedic constitution (prakruti) identifies risk factor of developing Parkinson's disease. AB - OBJECTIVE: The ancient Indian medical system, Ayurveda, is the oldest scientifically based system of medicine in the world. According to Ayurvedic concepts, there are 3 humors or Doshas: Vata, Pitta, and Kapha. The combination of these Doshas in varying degrees leads to one's constitution, referred to as Prakruti. Prakruti determines one's physical, physiologic, and mental character and disease vulnerability. This clinical study was undertaken to determine the constitutional typing of individuals with known idiopathic Parkinson's disease (PD) compared with that of nonparkinsonian controls. This study sought to validate the ancient observation that persons of Vata Prakruti are at risk for nervous system diseases. PD was used as a test case because the exact cause is not known. METHODS: Patients with established PD (n=75) and closely related controls with no known neurologic disease (n=73) were assessed for their Ayurvedic constitution (Prakruti). An Ayurvedic constitutional assessment form and an independent Ayurvedic clinical assessment were used in the patients and controls. RESULTS: The total mean score (+/-standard deviation) for Vata was 11.0+/-3.9 in patients with PD and 6.9+/-3.0 in controls. This finding was significant (p<0.0001), indicating that the incidence of PD is highest in those with Vata Prakruti. The incidence of PD was higher in men than in women. CONCLUSIONS: Knowledge gained from this study may be helpful in identifying the vulnerable population, delaying the onset of symptoms, or slowing disease progression or development of treatment-related complications by keeping Vata in balance through anti-Vata diet and lifestyle changes as prescribed in Ayurveda. PMID- 23819567 TI - Factors associated with age at first sexual initiation among youths in Gamo Gofa, south west Ethiopia: a cross sectional study. AB - BACKGROUND: Early sexual initiation increases the risk of HIV infection and other sexually transmitted diseases. This study aimed to determine age at first sexual initiation and associated factors among youths in south west Ethiopia. METHODS: Cross-sectional study was conducted in South west Ethiopia from January 15 - March 20, 2012. A sample of youths aged 15-24 years was taken from six health centers and three hospitals using systematic sampling technique. Cox proportional hazard regression model was used to assess the association between the outcome and explanatory variables. RESULT: A total of 405 youths participated in the study and the mean ( +/-SD ) age of sexual initiation was 17.07 years (+/-2.12). Age at first sexual initiation was positively associated with lack of employment [Adj. HR & (95% CI) = 7.372 (1.455, 37.357)], lack of comprehensive knowledge on HIV [Adj. HR & (95% CI) = 8.247 (2.121, 32.067)], alcohol use [Adj. HR & (95% CI) = 3.815 (1.315, 11.070)] and khat use [Adj. HR & (95% CI) = 7.241 (1.871, 28.016)]. CONCLUSION: Majority of the study participants experienced sexual initiation. Strategies should be designed to control the use of substances like alcohol and khat which were found to be responsible for first sexual initiation. PMID- 23819566 TI - Promoter methylation and expression of TIMP3 gene in gastric cancer. AB - BACKGROUND: Gastric carcinoma development is a multi-stage process that involves more than one gene. Aberrant changes in DNA methylation are considered as the third mechanism that leads to anti-oncogene inactivation, which plays an essential role in tumor development. In this study, we assessed the relationship among the aberrant methylation of the promoter CpG islands of tissue inhibitor of metalloproteinase 3 (TIMP3) gene, its protein expression, and the clinicopathological features of gastric adenocarcinoma. METHODS: The methylation status of the promoter CpG islands and the protein expression of TIMP3 gene in tumors and adjacent normal mucosal tissues of 78 patients with gastric adenocarcinoma were detected by methylation-specific PCR (MSP) and immunohistochemistry. RESULTS: The CpG island methylation of TIMP3 was detected in tumor tissues, cancer-adjacent tissues, and lymph nodes with metastasis. In increasing order, the hypermethylation frequency of these tissues were 35.9% (28 of 78 non-neoplastic tissues), 85% (17 of 20 early-stage cases), 89.7% (52 of 58 progressive-stage cases), and 100% (78 of 78 metastatic lymph node). A marked difference was found between tumors and non-neoplastic tissues (P<0.05), but no difference existed among the subgroups of tumors (P>0.05). Immunohistochemistry analysis confirmed TIMP3 down-regulation in tumor tissues. The rate of TIMP3 gene expression was 100% in non-neoplastic tissues but apparently decreased to various extents at different stages, i.e., decreased to 30% (6/20) at the early stage, to 3.4% (2/58) at the progressive stage, and to 0% (0/78) in metastatic lymph nodes. Among the 70 tumor tissues with negative TIMP3 expression, 64 (91.4%) were hypermethylated and 6 were unmethylated (8.6%), indicating a significant association between hypermethylation and reduced or negative TIMP3 expression (P<0.01). CONCLUSION: The hypermethylation of the promoter region in CpG islands is the main mechanism of TIMP3 gene expression and may provide evidence for the molecular diagnosis and stage evaluation of gastric cancer. VIRTUAL SLIDES: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1756134016954958. PMID- 23819568 TI - Openness as a predictor of political orientation and conventional and unconventional political activism in Western and Eastern Europe. AB - This study provides a comprehensive investigation of the relationship between Openness and political orientation and activism in Europe. Analyses were conducted on the 4 waves of the European Social Survey, including large representative samples in up to 26 European countries (total N > 175,000). In line with previous studies, a robust, positive relationship between Openness and left-wing political orientation was obtained in Western Europe. However, in Eastern Europe, the relationship between Openness and political orientation was weaker, and reversed in 3 out of 4 waves. Moreover, Openness yielded significant positive relationships with unconventional activism and to a lesser degree with conventional activism. The magnitude of the relationship between Openness and activism was dependent on political orientation and region. Stronger associations between Openness and activism were found for those having a left-wing orientation in Western Europe, whereas in Eastern Europe, Openness was somewhat stronger related to activism for those having a right-wing orientation. In the discussion we elaborate on the role of the geopolitical context in the relationship between Openness and political variables. PMID- 23819569 TI - Asthma diagnosis and treatment - 1016. Is atopy in people aged 40 and over related to fixed airflow obstruction? PMID- 23819570 TI - Brief intervention content matters. PMID- 23819571 TI - Co5/Co8-cluster-based coordination polymers showing high-connected self penetrating networks: syntheses, crystal structures, and magnetic properties. AB - Two novel Co(II)-cluster-based coordination polymers--namely, [Co5(MU3-OH)2(1,4 ndc)4(bix)2]n (1) and {[Co8(MU3-OH)4(1,4-ndc)6(btp)(H2O)6].H2O}n (2)--were prepared by hydrothermal reactions of Co(II) perchlorate with 1,4 naphthalenedicarboxylic acid (1,4-H2ndc) and different N-donor coligands (bix = 1,4-bis(imidazol-1-ylmethyl)benzene and btp = 4,4'-bis(triazol-1 ylmethyl)biphenyl). In 1, 10-connected [Co5(MU3-OH)2(COO)8] clusters are extended by the MU4-1,4-ndc(2-) and trans-bix ligands to construct a rare, self penetrating ile framework that can interestingly be regarded as the cross-link of two interpenetrating 6-connected pcu networks. While for 2, [Co8(MU3-OH)4(COO)12] clusters serve as the 8-connected nodes, which are bridged by the MU4/MU5-1,4 ndc(2-) and trans-btp ligands to afford the highest-connected uninodal self penetrating (4(20).6(8)) network based on octacobalt clusters. A synthetic and structural comparison of 1 and 2 demonstrates that the features of auxiliary N donor ligands play a key role in governing the in situ formed clusters and the final 3-D coordination frameworks. Magnetic susceptibility measurements indicate that complex 1 shows an antiferromagnetic interaction between the adjacent Co(II) ions, whereas 2 displays the dominant antiferromagnetic exchanges in 300-50 K and a ferrimagnetic-like behavior at lower temperatures. PMID- 23819572 TI - Identification of multiple gene-gene interactions for ordinal phenotypes. AB - BACKGROUND: Multifactor dimensionality reduction (MDR) is a powerful method for analysis of gene-gene interactions and has been successfully applied to many genetic studies of complex diseases. However, the main application of MDR has been limited to binary traits, while traits having ordinal features are commonly observed in many genetic studies (e.g., obesity classification - normal, pre obese, mild obese and severe obese). METHODS: We propose ordinal MDR (OMDR) to facilitate gene-gene interaction analysis for ordinal traits. As an alternative to balanced accuracy, the use of tau-b, a common ordinal association measure, was suggested to evaluate interactions. Also, we generalized cross-validation consistency (GCVC) to identify multiple best interactions. GCVC can be practically useful for analyzing complex traits, especially in large-scale genetic studies. RESULTS AND CONCLUSIONS: In simulations, OMDR showed fairly good performance in terms of power, predictability and selection stability and outperformed MDR. For demonstration, we used a real data of body mass index (BMI) and scanned 1~4-way interactions of obesity ordinal and binary traits of BMI via OMDR and MDR, respectively. In real data analysis, more interactions were identified for ordinal trait than binary traits. On average, the commonly identified interactions showed higher predictability for ordinal trait than binary traits. The proposed OMDR and GCVC were implemented in a C/C++ program, executables of which are freely available for Linux, Windows and MacOS upon request for non-commercial research institutions. PMID- 23819573 TI - Comprehensive and integrated district health systems strengthening: the Rwanda Population Health Implementation and Training (PHIT) Partnership. AB - BACKGROUND: Nationally, health in Rwanda has been improving since 2000, with considerable improvement since 2005. Despite improvements, rural areas continue to lag behind urban sectors with regard to key health outcomes. Partners In Health (PIH) has been supporting the Rwanda Ministry of Health (MOH) in two rural districts in Rwanda since 2005. Since 2009, the MOH and PIH have spearheaded a health systems strengthening (HSS) intervention in these districts as part of the Rwanda Population Health Implementation and Training (PHIT) Partnership. The partnership is guided by the belief that HSS interventions should be comprehensive, integrated, responsive to local conditions, and address health care access, cost, and quality. The PHIT Partnership represents a collaboration between the MOH and PIH, with support from the National University of Rwanda School of Public Health, the National Institute of Statistics, Harvard Medical School, and Brigham and Women's Hospital. DESCRIPTION OF INTERVENTION: The PHIT Partnership's health systems support aligns with the World Health Organization's six health systems building blocks. HSS activities focus across all levels of the health system - community, health center, hospital, and district leadership - to improve health care access, quality, delivery, and health outcomes. Interventions are concentrated on three main areas: targeted support for health facilities, quality improvement initiatives, and a strengthened network of community health workers. EVALUATION DESIGN: The impact of activities will be assessed using population-level outcomes data collected through oversampling of the demographic and health survey (DHS) in the intervention districts. The overall impact evaluation is complemented by an analysis of trends in facility health care utilization. A comprehensive costing project captures the total expenditures and financial inputs of the health care system to determine the cost of systems improvement. Targeted evaluations and operational research pieces focus on specific programmatic components, supported by partnership-supported work to build in-country research capacity. DISCUSSION: Building on early successes, the work of the Rwanda PHIT Partnership approach to HSS has already seen noticeable increases in facility capacity and quality of care. The rigorous planned evaluation of the Partnership's HSS activities will contribute to global knowledge about intervention methodology, cost, and population health impact. PMID- 23819574 TI - Chromosomal diversification and karyotype evolution of diploids in the cytologically diverse genus Prospero (Hyacinthaceae). AB - BACKGROUND: Prospero (Hyacinthaceae) provides a unique system to assess the impact of genome rearrangements on plant diversification and evolution. The genus exhibits remarkable chromosomal variation but very little morphological differentiation. Basic numbers of x = 4, 5, 6 and 7, extensive polyploidy, and numerous polymorphic chromosome variants were described, but only three species are commonly recognized: P. obtusifolium, P. hanburyi, and P. autumnale s.l., the latter comprising four diploid cytotypes. The relationship between evolutionary patterns and chromosomal variation in diploids, the basic modules of the extensive cytological diversity, is presented. RESULTS: Evolutionary inferences were derived from fluorescence in situ hybridization (FISH) with 5S and 35S rDNA, genome size estimations, and phylogenetic analyses of internal transcribed spacer (ITS) of 35S rDNA of 49 diploids in the three species and all cytotypes of P. autumnale s.l. All species and cytotypes possess a single 35S rDNA locus, interstitial except in P. hanburyi where it is sub-terminal, and one or two 5S rDNA loci (occasionally a third in P. obtusifolium) at fixed locations. The localization of the two rDNA types is unique for each species and cytotype. Phylogenetic data in the P. autumnale complex enable tracing of the evolution of rDNA loci, genome size, and direction of chromosomal fusions: mixed descending dysploidy of x = 7 to x = 6 and independently to x = 5, rather than successive descending dysploidy, is proposed. CONCLUSIONS: All diploid cytotypes are recovered as well-defined evolutionary lineages. The cytogenetic and phylogenetic approaches have provided excellent phylogenetic markers to infer the direction of chromosomal change in Prospero. Evolution in Prospero, especially in the P. autumnale complex, has been driven by differentiation of an ancestral karyotype largely unaccompanied by morphological change. These new results provide a framework for detailed analyses of various types of chromosomal rearrangements and karyotypic variation in polyploids. PMID- 23819575 TI - Cutting edge proteomics: benchmarking of six commercial trypsins. AB - Tryptic digestion is an important component of most proteomics experiments, and trypsin is available from many sources with a cost that varies by more than 1000 fold. This high-mass-accuracy LC-MS study benchmarks six commercially available trypsins with respect to autolytic species and sequence specificity. The analysis of autolysis products led to the identification of a number of contaminating proteins and the generation of a list of peptide species that will be present in tryptic digests. Intriguingly, many of the autolysis products were nontryptic peptides, specifically peptides generated by C-terminal cleavage at asparagine residues. Both porcine and bovine trypsins were demonstrated to be tyrosine O sulfated. Using both a label-free and a tandem mass tag (TMT) labeling approach, a comparison of the digestion of a standard protein mixture using the six trypsins demonstrated that, apart from the least expensive bovine trypsin, the trypsins were equally specific. The semitryptic activity led to a better sequence coverage for abundant substrates at the expense of low-abundance species. The label-free analysis was shown to be more sensitive to unique features from the individual digests that were lost in the TMT-multiplexing study. PMID- 23819577 TI - A clinical study of serum lipid disturbance in Chinese patients with sudden deafness. AB - BACKGROUND: Pathological levels of blood lipids could be one of the causes of sudden sensorineural hearing loss (SSNHL). The objective of this manuscript is therefore to evaluate the relationship between blood lipid content and sudden sensorineural hearing loss (SSNHL). METHODS: The correlation between serum lipid parameters, including total cholesterol (TC), triglycerides, high-density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apolipoprotein AI (apo AI), apolipoprotein B (apo B), and lipoprotein A (Lp(a)), and the onset of SSNHL was analyzed from a data set of 250 patients and an age, gender and weight matched control group of 250 subjects. RESULTS: The result of single factor logistic regression shows that TC (p<0.01), LDL-C (p<0.01), and apo B (p=0.03) of SSNHL group were significantly higher than those of the control group. The odds ratio of TC, LDL, and apo B are higher than 1, while the confidence intervals of the odds rations do not include 1. No significant difference was found with the prevalence of hypertension (P=0.818), diabetes (P=0.869) and smoking habits (P=0.653) between SSNHL group and control group. CONCLUSION: Total cholesterol, low density lipoprotein cholesterol and apolipoprotein B concentrations may be important factors in the pathogenesis of sudden sensorineural hearing loss, and should be assessed during the investigation of patients with this condition. PMID- 23819576 TI - Common prescription medication use and erectile dysfunction: results from the Boston Area Community Health (BACH) survey. AB - OBJECTIVE: To investigate the association of erectile dysfunction (ED) with commonly used medications including antihypertensive treatment (AHT), psychoactive medication and pain and anti-inflammatory medication. SUBJECTS AND METHODS: The Boston Area Community Health (BACH) survey used a multistage stratified design to recruit a random sample of 2301 men aged 30-79 years. ED was assessed using the five-item International Index of Erectile Function (IIEF-5). Prescription medications, captured using a combination of drug inventory and self report with a prompt by indication, included in this analysis comprised AHT, psychoactive medication, and pain and anti-inflammatory medication. Logistic regression was used to estimate the odds ratios (ORs) of the association of medication use with ED and to adjust for potential confounders including age, comorbid conditions and sociodemographic and lifestyle factors. RESULTS: Multivariable analyses showed benzodiazepines (adjusted OR = 2.34, 95% confidence interval [CI]: 1.03, 5.31) and tricyclic antidepressants (adjusted OR = 3.35, 95% CI: 1.09, 10.27) were associated with ED, while no association was observed for serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors and atypical antipsychotics. The use of AHT, whether in monotherapy or in conjunction with other AHTs, and pain or anti-inflammatory medications were not associated with ED after accounting for confounding factors. CONCLUSIONS: Results of the BACH survey suggest adverse effects of some psychoactive medications (benzodiazepines and tricyclic antidepressants). No evidence of an association of AHT or pain and anti-inflammatory medication with ED was observed. PMID- 23819578 TI - "A manager in the minds of doctors:" a comparison of new modes of control in European hospitals. AB - BACKGROUND: Hospital governance increasingly combines management and professional self-governance. This article maps the new emergent modes of control in a comparative perspective and aims to better understand the relationship between medicine and management as hybrid and context-dependent. Theoretically, we critically review approaches into the managerialism-professionalism relationship; methodologically, we expand cross-country comparison towards the meso-level of organisations; and empirically, the focus is on processes and actors in a range of European hospitals. METHODS: The research is explorative and was carried out as part of the FP7 COST action IS0903 Medicine and Management, Working Group 2. Comprising seven European countries, the focus is on doctors and public hospitals. We use a comparative case study design that primarily draws on expert information and document analysis as well as other secondary sources. RESULTS: The findings reveal that managerial control is not simply an external force but increasingly integrated in medical professionalism. These processes of change are relevant in all countries but shaped by organisational settings, and therefore create different patterns of control: (1) 'integrated' control with high levels of coordination and coherent patterns for cost and quality controls; (2) 'partly integrated' control with diversity of coordination on hospital and department level and between cost and quality controls; and (3) 'fragmented' control with limited coordination and gaps between quality control more strongly dominated by medicine, and cost control by management. CONCLUSIONS: Our comparison highlights how organisations matter and brings the crucial relevance of 'coordination' of medicine and management across the levels (hospital/department) and the substance (cost/quality-safety) of control into perspective. Consequently, coordination may serve as a taxonomy of emergent modes of control, thus bringing new directions for cost-efficient and quality-effective hospital governance into perspective. PMID- 23819579 TI - Nucleophilic halogenations of diazo compounds, a complementary principle for the synthesis of halodiazo compounds: experimental and theoretical studies. AB - Three new protocols for the nucleophilic halogenations of diazoesters, diazophosphonates, and diazopiperidinylamides as complementary methods to our previously reported electrophilic halogenations are presented for the first time. On the basis of hypervalent alpha-aryliodonio diazo triflate salts 1A, 2A, and 3A, the corresponding halodiazo compounds are generated via nucleophilic halogenations with tetrabutylammonium halides or potassium halides. The products from subsequent catalytic intermolecular cyclopropanations of the halodiazoesters and halodiazophosphonates and thermal intramolecular C-H insertion of the brominated diazopiperidinylamide are obtained in moderate to good yields after two steps. DFT calculations are presented for the diazoesters to give insight into the mechanism and transition states of the nucleophilic substitutions with the neutral nucleophiles dimethyl sulfide and triethylamine and the bromination with Br(-). PMID- 23819580 TI - Oxygen "getter" effects on microstructure and carrier transport in low temperature combustion-processed a-InXZnO (X = Ga, Sc, Y, La) transistors. AB - In oxide semiconductors, such as those based on indium zinc oxide (IXZO), a strong oxygen binding metal ion ("oxygen getter"), X, functions to control O vacancies and enhance lattice formation, hence tune carrier concentration and transport properties. Here we systematically study, in the IXZO series, the role of X = Ga(3+) versus the progression X = Sc(3+) -> Y(3+) -> La(3+), having similar chemical characteristics but increasing ionic radii. IXZO films are prepared from solution over broad composition ranges for the first time via low temperature combustion synthesis. The films are characterized via thermal analysis of the precursor solutions, grazing incidence angle X-ray diffraction (GIAXRD), atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS), and scanning transmission electron microscopy (STEM) with high angle annular dark field (HAADF) imaging. Excellent thin-film transistor (TFT) performance is achieved for all X, with optimal compositions after 300 degrees C processing exhibiting electron mobilities of 5.4, 2.6, 2.4, and 1.8 cm(2) V(-1) s(-1) for Ga(3+), Sc(3+), Y(3+), and La(3+), respectively, and with I(on)/I(off) = 10(7) 10(8). Analysis of the IXZO TFT positive bias stress response shows X = Ga(3+) to be superior with mobilities (MU) retaining >95% of the prestress values and threshold voltage shifts (DeltaV(T)) of <1.6 V, versus <85% MU retention and DeltaV(T) ~ 20 V for the other trivalent ions. Detailed microstructural analysis indicates that Ga(3+) most effectively promotes oxide lattice formation. We conclude that the metal oxide lattice formation enthalpy (DeltaH(L)) and metal ionic radius are the best predictors of IXZO oxygen getter efficacy. PMID- 23819582 TI - Clinical significance of therapy using branched-chain amino acid granules in patients with liver cirrhosis and hepatocellular carcinoma. AB - The liver is the major organ for the metabolism of protein, fat and carbohydrate. A nutritional approach is required in the treatment of cirrhosis, which is frequently complicated with protein-energy malnutrition. Several advanced treatment approaches for hepatocellular carcinoma (HCC) have been established in the past decade. HCC is often complicated by cirrhosis, so treatment of the underlying liver diseases is also necessary to improve the prognosis. Branched chain amino acid (BCAA) granules were developed originally for the treatment of hypoalbuminemia associated with decompensated cirrhosis. However, subsequent studies found various other pharmacological actions of this agent. We review the clinical significance of therapy using BCAA granules in patients receiving different treatment approaches for cirrhosis and HCC based on the published work as well as our own data. PMID- 23819581 TI - Multiscale modeling of the causal functional roles of nsSNPs in a genome-wide association study: application to hypoxia. AB - BACKGROUND: It is a great challenge of modern biology to determine the functional roles of non-synonymous Single Nucleotide Polymorphisms (nsSNPs) on complex phenotypes. Statistical and machine learning techniques establish correlations between genotype and phenotype, but may fail to infer the biologically relevant mechanisms. The emerging paradigm of Network-based Association Studies aims to address this problem of statistical analysis. However, a mechanistic understanding of how individual molecular components work together in a system requires knowledge of molecular structures, and their interactions. RESULTS: To address the challenge of understanding the genetic, molecular, and cellular basis of complex phenotypes, we have, for the first time, developed a structural systems biology approach for genome-wide multiscale modeling of nsSNPs--from the atomic details of molecular interactions to the emergent properties of biological networks. We apply our approach to determine the functional roles of nsSNPs associated with hypoxia tolerance in Drosophila melanogaster. The integrated view of the functional roles of nsSNP at both molecular and network levels allows us to identify driver mutations and their interactions (epistasis) in H, Rad51D, Ulp1, Wnt5, HDAC4, Sol, Dys, GalNAc-T2, and CG33714 genes, all of which are involved in the up-regulation of Notch and Gurken/EGFR signaling pathways. Moreover, we find that a large fraction of the driver mutations are neither located in conserved functional sites, nor responsible for structural stability, but rather regulate protein activity through allosteric transitions, protein protein interactions, or protein-nucleic acid interactions. This finding should impact future Genome-Wide Association Studies. CONCLUSIONS: Our studies demonstrate that the consolidation of statistical, structural, and network views of biomolecules and their interactions can provide new insight into the functional role of nsSNPs in Genome-Wide Association Studies, in a way that neither the knowledge of molecular structures nor biological networks alone could achieve. Thus, multiscale modeling of nsSNPs may prove to be a powerful tool for establishing the functional roles of sequence variants in a wide array of applications. PMID- 23819584 TI - The National Pregnancy in Diabetes Audit: measuring the quality of diabetes pregnancy care. PMID- 23819583 TI - Interleukin-17A: a unique pathway in immune-mediated diseases: psoriasis, psoriatic arthritis and rheumatoid arthritis. AB - Experimental evidence points to the importance of the cytokine interleukin-17A (IL-17A) in the pathogenesis of several immunoinflammatory diseases including psoriasis, psoriatic arthritis and rheumatoid arthritis. Although a principal effector of T helper type 17 cells, IL-17A is produced by many other cell types including CD8(+) T cells and gammadelta T cells, and is found at high levels associated with mast cells and neutrophils at sites of skin and joint disease in humans. IL-17A up-regulates expression of numerous inflammation-related genes in target cells such as keratinocytes and fibroblasts, leading to increased production of chemokines, cytokines, antimicrobial peptides and other mediators that contribute to clinical disease features. Importantly, IL-17A must be considered within the context of the local microenvironment, because it acts synergistically or additively with other pro-inflammatory cytokines, including tumour necrosis factor. Several direct IL-17A inhibitors have shown promising activity in proof of concept and phase 2 clinical studies, thereby providing confirmation of experimental data supporting IL-17A in disease pathogenesis, although levels of response are not predicted by pre-clinical findings. IL-17A inhibitors produced rapid down-regulation of the psoriasis gene signature and high clinical response rates in patients with moderate-to-severe plaque psoriasis, consistent with an important role for IL-17A in psoriasis pathogenesis. Clinical response rates with IL-17A inhibitors in psoriatic arthritis and rheumatoid arthritis, however, were improved to a lesser degree compared with placebo, suggesting that IL-17A is either important in a subset of patients or plays a relatively minor role in inflammatory joint disease. Ongoing phase 3 clinical trials should provide further information on the role of IL-17A in these diseases. PMID- 23819585 TI - Stability of monacolin K and citrinin and biochemical characterization of red koji vinegar during fermentation. AB - Red-koji vinegar is a Monascus -involved and acetic acid fermentation-derived traditional product, in which the presence of monacolin K and citrinin has attracted public attention. In this study, red-koji wine was prepared as the substrate and artificially supplemented with monacolin K and citrinin and subjected to vinegar fermentation with Acetobacter starter. After 30 days of fermentation, 43.0 and 98.1% of the initial supplements of monacolin K and citrinin were decreased, respectively. During fermentation, acetic acid contents increased, accompanied by decreases of ethanol and lactic acid contents and pH values. The contents of free amino acids increased while the contents of other organic acids, including fumaric acid, citric acid, succinic acid, and tartaric acid, changed limitedly. Besides, increased levels of total phenolics in accordance with increased antioxidative potency, alpha,alpha-diphenyl-beta picrylhydrazyl scavenging, and xanthine oxidase inhibitory (XOI) activities were detected. It is of merit that most citrinin was eliminated and >50% of the monacolin K was retained; contents of free amino acids and total phenolics along with antioxidant and XOI activities of the red-koji vinegar were increased after fermentation. PMID- 23819586 TI - New dicoumarol sodium compound: crystal structure, theoretical study and tumoricidal activity against osteoblast cancer cells. AB - BACKGROUND: Enormous interest had been paid to the coordination chemistry of alkali and alkaline metal ions because of their role inside body viz; their Li(+)/Na(+) exchange inside the cell lead to different diseases like neuropathy, hypertension, microalbuminuria, cardiac and vascular hypertrophy, obesity, and insulin resistance. It has been presumed that alkali metal ions (whether Na(+) or K(+)) coordinated to chelating ligands can cross the hydrophobic cell membrane easily and can function effectively for depolarizing the ion difference. This unique function was utilized for bacterial cell death in which K(+) has been found coordinated valinomycin (antibiotic). RESULTS: Distinct sodium adduct (1) with dicoumarol ligand, 4-Hydroxy-3-[(4-hydroxy-2-oxo-4a,8a-dihydro-2H-chromen-3 yl)-phenyl-methyl]-chromen-2-one (L) is isolated from the saturated solution of sodium methoxide. Single crystal X-ray diffraction studies of the adduct reveals that sodium is in the form of cation attached to a methoxide, methanol and a dicoumarol ligand where carbonyl functional groups of the coumarin derivative are acting as bridges. The sodium compound (1) is also characterized by IR, (1)H-NMR, and (13)C{(1)H}-NMR spectroscopic techniques. The composition is confirmed by elemental analysis. DFT study for 1 has been carried out using B3LYP/6-13G calculations which shown the theoretical confirmation of the various bond lengths and bond angles. Both the compounds were studied subsequently for the U2OS tumoricidal activity and it was found that L has LD50 value of 200 MUM whereas the sodium analog cytotoxicity did not drop down below 60%. CONCLUSION: A sodium analogue (1) with medicinally important dicoumarol ligand (L) has been reported. The crystal structure and DFT study confirm the formation of cationic sodium compound with dicoumarol. The ligand was found more active than the sodium analog attributed to the instability of 1 in solution state. Coumarin compound with sodium was observed to be less cytotoxic than the ligand, its LD50 value never dropped below 60%. PMID- 23819588 TI - Bandgap engineering of strained monolayer and bilayer MoS2. AB - We report the influence of uniaxial tensile mechanical strain in the range 0-2.2% on the phonon spectra and bandstructures of monolayer and bilayer molybdenum disulfide (MoS2) two-dimensional crystals. First, we employ Raman spectroscopy to observe phonon softening with increased strain, breaking the degeneracy in the E' Raman mode of MoS2, and extract a Gruneisen parameter of ~1.06. Second, using photoluminescence spectroscopy we measure a decrease in the optical band gap of MoS2 that is approximately linear with strain, ~45 meV/% strain for monolayer MoS2 and ~120 meV/% strain for bilayer MoS2. Third, we observe a pronounced strain-induced decrease in the photoluminescence intensity of monolayer MoS2 that is indicative of the direct-to-indirect transition of the character of the optical band gap of this material at applied strain of ~1%. These observations constitute a demonstration of strain engineering the band structure in the emergent class of two-dimensional crystals, transition-metal dichalcogenides. PMID- 23819587 TI - The Tanzania Connect Project: a cluster-randomized trial of the child survival impact of adding paid community health workers to an existing facility-focused health system. AB - BACKGROUND: Tanzania has been a pioneer in establishing community-level services, yet challenges remain in sustaining these systems and ensuring adequate human resource strategies. In particular, the added value of a cadre of professional community health workers is under debate. While Tanzania has the highest density of primary health care facilities in Africa, equitable access and quality of care remain a challenge. Utilization for many services proven to reduce child and maternal mortality is unacceptably low. Tanzanian policy initiatives have sought to address these problems by proposing expansion of community-based providers, but the Ministry of Health and Social Welfare (MoHSW ) lacks evidence that this merits national implementation. The Tanzania Connect Project is a randomized cluster trial located in three rural districts with a population of roughly 360,000 ( Kilombero, Rufiji, and Ulanga). DESCRIPTION OF INTERVENTION: Connect aims to test whether introducing a community health worker into a general program of health systems strengthening and referral improvement will reduce child mortality, improve access to services, expand utilization, and alter reproductive, maternal, newborn and child health seeking behavior; thereby accelerating progress towards Millennium Development Goals 4 and 5. Connect has introduced a new cadre - Community Health Agents (CHA) - who were recruited from and work in their communities. To support the CHA, Connect developed supervisory systems, launched information and monitoring operations, and implemented logistics support for integration with existing district and village operations. In addition, Connect's district-wide emergency referral strengthening intervention includes clinical and operational improvements. EVALUATION DESIGN: Designed as a community-based cluster-randomized trial, CHA were randomly assigned to 50 of the 101 villages within the Health and Demographic Surveillance System (HDSS) in the three study districts. To garner detailed information on household characteristics, behaviors, and service exposure, a random sub-sample survey of 3,300 women of reproductive age will be conducted at the baseline and endline. The referral system intervention will use baseline, midline, and endline facility-based data to assess systemic changes. Implementation and impact research of Connect will assess whether and how the presence of the CHA at village level provides added life-saving value to the health system. DISCUSSION: Global commitment to launching community-based primary health care has accelerated in recent years, with much of the implementation focused on Africa. Despite extensive investment, no program has been guided by a truly experimental study. Connect will not only address Tanzania's need for policy and operational research, it will bridge a critical international knowledge gap concerning the added value of salaried professional community health workers in the context of a high density of fixed facilities. TRIAL REGISTRATION: ISRCTN96819844. PMID- 23819589 TI - Evolution and homoplasy at the Bem6 microsatellite locus in three sweetpotato whitefly (Bemisia tabaci) cryptic species. AB - BACKGROUND: The evolution of individual microsatellite loci is often complex and homoplasy is common but often goes undetected. Sequencing alleles at a microsatellite locus can provide a more complete picture of the common evolutionary mechanisms occurring at that locus and can reveal cases of homoplasy. Within species homoplasy can lead to an underestimate of differentiation among populations and among species homoplasy can produce a misleading interpretation regarding shared alleles and hybridization. This is especially problematic with cryptic species. RESULTS: By sequencing alleles from three cryptic species of the sweetpotato whitefly (Bemisia tabaci), designated MEAM1, MED, and NW, the evolution of the putatively dinucleotide Bem6 (CA8)imp microsatellite locus is inferred as one of primarily stepwise mutation occurring at four distinct heptaucleotide tandem repeats. In two of the species this pattern yields a compound tandem repeat. Homoplasy was detected both among species and within species. CONCLUSIONS: In the absence of sequencing, size homoplasious alleles at the Bem6 locus lead to an overestimate of alleles shared and hybridization among cryptic species of Bemisia tabaci. Furthermore, the compound heptanucleotide motif structure of a putative dinucleotide microsatellite has implications for the nomenclature of heptanucleotide tandem repeats with step-wise evolution. PMID- 23819590 TI - How do men and women define sexual desire and sexual arousal? AB - The purpose of this study was to understand how men and women define sexual desire and sexual arousal and how they distinguish between the two. The authors conducted 32 semi-structured interviews with individuals in South East England, using a purposive sampling strategy to maximize the variation in experience of sexual function across the group. The authors identified three criteria that participants used to define and distinguish between desire and arousal: the sequence in which they occurred; whether the mind or the body (or both) were engaged; and the extent to which feelings of desire or arousal were responsive (in response to person or stimulus) and motivational (oriented toward a goal). Most participants attempted to distinguish between desire and arousal when prompted, but often with difficulty. Participants commonly felt that desire preceded arousal; some felt that desire was "mind" and arousal "body"; and many felt that both desire and arousal were responsive and motivational. However, the authors identified numerous times when these distinctions were reversed or the differences between terms were blurred. The results support recent proposals to merge the two diagnostic categories of female sexual arousal disorder and hyposexual desire disorder into a single diagnostic category. PMID- 23819591 TI - Cellular toxicity induced by the photorelease of a caged bioactive molecule: design of a potential dual-action Ru(II) complex. AB - The series [Ru(tpy)(CH3CN)3](2+) (1), cis-[Ru(tpy)(CH3CN)2Cl](+) (2), and [Ru(tpy)(5CNU)3](2+) (3), where tpy = 2,2':6',2"-terpyridine and 5CNU = 5 cyanouracil, was synthesized, and their photochemical properties were investigated for use as potential photodynamic therapy (PDT) agents. When irradiated with visible light, 1-3 exhibit efficient exchange of the axial CH3CN or 5CNU ligand with H2O solvent molecules. Complexes 1-3 also exhibit photoinitiated binding to DNA when irradiated with lambdairr >= 395 nm light, and DNA binding can be accessed for 2 with lambdairr > 645 nm, well within the PDT window. Since 3 binds DNA and simultaneously releases biologically active 5CNU, it has the potential to be a dual-action therapeutic agent. Indeed, 3 is cytotoxic upon irradiation with visible light, whereas 1 is not under similar experimental conditions. The lack of toxicity imparted by 1 is explained by the exchange of only one CH3CN ligand in the complex under the irradiation conditions used for the cellular studies. Strategies are being sought to increase the quantum yields of ligand exchange and the cellular penetration of these compounds. PMID- 23819592 TI - Changes in visual acuity and intra-ocular pressure following bleb-related infection: the Japan Glaucoma Society Survey of Bleb-related Infection Report 2. AB - PURPOSE: To identify changes in visual acuity and intra-ocular pressure (IOP) 12 months after the development of bleb-related infection. METHODS: Data obtained from 146 eyes of 146 patients with bleb-related infection were analyzed as a part of the Japan Glaucoma Society Survey of Bleb-related Infection. Multiple logistic regression analysis was conducted to identify factors associated with poor prognosis in visual acuity and increased IOP and for being stage III. RESULTS: The logMAR increased by a mean of 0.140, 0.440, 1.099 and 1.122 at 12 months postinfection for stage I, II, IIIa and IIIb infections, respectively. The logMAR was significantly worse at 6 and 12 months postinfection in stage IIIb (p = 0.002 and p = 0.003, respectively; Wilcoxon signed-rank test) and at 6 months postinfection in stage IIIa (p = 0.036). The IOP was significantly elevated following infection in both stage IIIa and stage IIIb (p = 0.028 and p = 0.008 at 6 and 12 months, respectively, for stage IIIa; p = 0.002 and p = 0.005 for stage IIIb). The multiple logistic regression analysis revealed that being stage III and positive culture were significant risk factors for poor outcome for visual acuity (Odds ratio: 9.26 and 6.29, respectively) and that being stage III was a prognostic factor for increased IOP (Odds ratio: 8.33). Pseudophakia or aphakia was significantly associated with stage III and stage IIIb infections (Odds ratio: 2.85 and 6.30). CONCLUSIONS: Stage III bleb-related infection causes significant visual loss and IOP elevation within 12 months after development. Therefore, preventative measures should be taken, especially in cases that are pseudophakic or aphakic. PMID- 23819593 TI - Clinical bond failure rates of adhesive precoated self-ligating brackets using a self-etching primer. AB - OBJECTIVE: To comparatively assess the failure rate of adhesive precoated (APC) self-ligating metal brackets bonded with two different enamel surface preparation techniques: self-etching primer (SEP) and conventional two-step etch and primer method (CM). MATERIALS AND METHODS: Fifty-seven patients with complete permanent dentition were included in this study. A total of 1140 APC self-ligating brackets (3M Unitek, Monrovia, Calif) were bonded using a split-mouth design. For each patient, SEP (Transbond Plus SEP, 3M Unitek) and CM (37% phosphoric acid) were used in alternate quadrants. All brackets were bonded by the same investigator after pumicing and rinsing of all of the teeth. The number, site, and date of first-time bracket failures were monitored throughout orthodontic treatment (mean, 22 months). The survival rates of the brackets were estimated by Kaplan Meier and log-rank tests (P < .05). The adhesive remnant index was used to determine the bond failure interface. RESULTS: The bond failure rates were 2.97% and 2.18% for the CM and SEP, respectively. No statistically significant difference in failure rates was found between the groups. The bond failure sites were predominantly at the enamel-adhesive interface in both groups. CONCLUSION: This long-term in vivo study showed that the combined use of SEP and the APC bracket system can be used effectively for bonding brackets after pumicing the enamel surfaces in clinical orthodontics. PMID- 23819595 TI - Do variations in mast cell hyperplasia account for differences in radiation induced lung injury among different mouse strains, rats and nonhuman primates? AB - The role of mast cell infiltrates in the pathology of radiation damage to the lung has been a subject of continuing investigation over the past four decades. This has been accompanied by a number of proposals as to how mast cells and the secretory products thereof participate in the generation of acute inflammation (pneumonitis) and the chronic process of collagen deposition (fibrosis). An additional pathophysiology examines the possible connection between mast cell hyperplasia and pulmonary hypertension through the release of vasoactive mediators. The timing and magnitude of pneumonitis and fibrosis are known to vary tremendously among different genetic mouse strains and animal species. Therefore, we have systematically compared mast cell numbers in lung sections from nine mouse strains, two rat strains and nonhuman primates (NHP) after whole thorax irradiation (WTI) at doses ranging from 10-15 Gy and at the time of entering respiratory distress. Mice of the BALB/c strain had a dramatic increase in interstitial mast cell numbers, similar to WAG/Rij and August rats, while relatively low levels of mast cell infiltrate were observed in other mouse strains (CBA, C3H, B6, C57L, WHT and TO mice). Enumeration of mast cell number in five NHPs (rhesus macaque), exhibiting severe pneumonitis at 17 weeks after 10 Gy WTI, also indicated a low response shared by the majority of mouse strains. There appeared to be no relationship between the mast cell response and the strain dependent susceptibility towards pneumonitis or fibrosis. Further investigations are required to explore the possible participation of mast cells in mediating specific vascular responses and whether a genetically diverse mast cell response occurs in humans. PMID- 23819596 TI - Quercetin inhibits radiation-induced skin fibrosis. AB - Radiation induced fibrosis of the skin is a late toxicity that may result in loss of function due to reduced range of motion and pain. The current study sought to determine if oral delivery of quercetin mitigates radiation-induced cutaneous injury. Female C3H/HeN mice were fed control chow or quercetin-formulated chow (1% by weight). The right hind leg was exposed to 35 Gy of X rays and the mice were followed serially to assess acute toxicity and hind leg extension. Tissue samples were collected for assessment of soluble collagen and tissue cytokines. Human and murine fibroblasts were subjected to clonogenic assays to determine the effects of quercetin on radiation response. Contractility of fibroblasts was assessed with a collagen contraction assay in the presence or absence of quercetin and transforming growth factor-beta (TGF-beta). Western blotting of proteins involved in fibroblast contractility and TGF-beta signaling were performed. Quercetin treatment significantly reduced hind limb contracture, collagen accumulation and expression of TGF-beta in irradiated skin. Quercetin had no effect on the radioresponse of fibroblasts or murine tumors, but was capable of reducing the contractility of fibroblasts in response to TGF-beta, an effect that correlated with partial stabilization of phosphorylated cofilin. Quercetin is capable of mitigating radiation induced skin fibrosis and should be further explored as a therapy for radiation fibrosis. PMID- 23819598 TI - Decision maker perceptions of resource allocation processes in Canadian health care organizations: a national survey. AB - BACKGROUND: Resource allocation is a key challenge for healthcare decision makers. While several case studies of organizational practice exist, there have been few large-scale cross-organization comparisons. METHODS: Between January and April 2011, we conducted an on-line survey of senior decision makers within regional health authorities (and closely equivalent organizations) across all Canadian provinces and territories. We received returns from 92 individual managers, from 60 out of 89 organizations in total. The survey inquired about structures, process features, and behaviours related to organization-wide resource allocation decisions. We focus here on three main aspects: type of process, perceived fairness, and overall rating. RESULTS: About one-half of respondents indicated that their organization used a formal process for resource allocation, while the others reported that political or historical factors were predominant. Seventy percent (70%) of respondents self-reported that their resource allocation process was fair and just over one-half assessed their process as 'good' or 'very good'. This paper explores these findings in greater detail and assesses them in context of the larger literature. CONCLUSION: Data from this large-scale cross-jurisdictional survey helps to illustrate common challenges and areas of positive performance among Canada's health system leadership teams. PMID- 23819597 TI - Low-dose radiation-induced enhancement of thymic lymphomagenesis in Lck-Bax mice is dependent on LET and gender. AB - The hypothesis that mitochondrial dysfunction and increased superoxide levels in thymocytes over expressing Bax (Lck-Bax1 and Lck-Bax38&1) contributes to lymphomagenesis after low-dose radiation was tested. Lck-Bax1 single-transgenic and Lck-Bax38&1 double-transgenic mice were exposed to single whole-body doses of 10 or 100 cGy of (137)Cs or iron ions (1,000 MeV/n, 150 keV/MUm) or silicon ions (300 MeV/n, 67 keV/MUm). A 10 cGy dose of (137)Cs significantly increased the incidence and onset of thymic lymphomas in female Lck-Bax1 mice. In Lck-Bax38&1 mice, a 100 cGy dose of high-LET iron ions caused a significant dose dependent acceleration of lymphomagenesis in both males and females that was not seen with silicon ions. To determine the contribution of mitochondrial oxidative metabolism, Lck-Bax38&1 over expressing mice were crossed with knockouts of the mitochondrial protein deacetylase, Sirtuin 3 (Sirt3), which regulates superoxide metabolism. Sirt3(-/-)/Lck-Bax38&1 mice demonstrated significant increases in thymocyte superoxide levels and acceleration of lymphomagenesis (P < 0.001). These results show that lymphomagenesis in Bax over expressing animals is enhanced by radiation exposure in both an LET and gender dependent fashion. These findings support the hypothesis that mitochondrial dysfunction leads to increased superoxide levels and accelerates lymphomagenesis in Lck-Bax transgenic mice. PMID- 23819599 TI - Deciphering the response of Mycobacterium smegmatis to nitrogen stress using bipartite active modules. AB - BACKGROUND: The ability to adapt to environments with fluctuating nutrient availability is vital for bacterial survival. Although essential for growth, few nitrogen metabolism genes have been identified or fully characterised in mycobacteria and nitrogen stress survival mechanisms are unknown. RESULTS: A global transcriptional analysis of the mycobacterial response to nitrogen stress, showed a significant change in the differential expression of 16% of the Mycobacterium smegmatis genome. Gene expression changes were mapped onto the metabolic network using Active Modules for Bipartite Networks (AMBIENT) to identify metabolic pathways showing coordinated transcriptional responses to the stress. AMBIENT revealed several key features of the metabolic response not identified by KEGG enrichment alone. Down regulated reactions were associated with the general reduction in cellular metabolism as a consequence of reduced growth rate. Up-regulated modules highlighted metabolic changes in nitrogen assimilation and scavenging, as well as reactions involved in hydrogen peroxide metabolism, carbon scavenging and energy generation. CONCLUSIONS: Application of an Active Modules algorithm to transcriptomic data identified key metabolic reactions and pathways altered in response to nitrogen stress, which are central to survival under nitrogen limiting environments. PMID- 23819601 TI - Editorial for the virtual issue on models of metalloenzymes. PMID- 23819602 TI - On recognizing 'shades-of-gray' (self-nonself discrimination) or 'colour' (Integrity model) by the immune system. AB - The aim is to discuss Cohn's T-cell receptor (TCR) Tritope model of recognition, propose a novel suggestion for prior-to-positive selection of thymocytes contributing to inherent major histocompatibility complex (MHC) reactivity of a T cell repertoire and clarify the Integrity model about the function of the immune system. If we compare the perception of light with the recognition of nonself, we could imagine that the opacity might be a measure of docking interaction between specific receptors for antigen on T or B cells (TCR/peptide-MHC or BCR/antigen). From this viewpoint, the self-nonself discrimination (S-NS) metaphor would be perception of black (self) versus white (nonself). However, whereas detection of shades-of-gray suffices to describe S-NS discrimination principle, colour vision of the antigenic world portrays best the Integrity model. In concert with recognition of opacity, the Integrity model proposes detection of at least three colours (signals): red (harmful), blue (useful) and yellow (the rest, including homoeostatic ones). As a result, recognition of nonself is transferred into communication within self while deciding on type of the immune response. Hence, the S-NS discrimination model seems to be an oversimplification, because it fails to see colours and consequently lacks the need for suppressor/regulatory function. Similarly, the Danger model stops short of detecting being useful signals that confer immune asylum to helpful micro-organisms like commensals. I suggest that the immune system's repertoire for recognition, in general, has evolved by a novel drive called 'natural integrity' alongside natural selection, thus facilitating communication between cells of the immune system. PMID- 23819600 TI - Evaluating an implementation strategy in cardiovascular prevention to improve prescribing of statins in Germany: an intention to treat analysis. AB - BACKGROUND: The prescription of statins is an evidence-based treatment to reduce the risk of cardiovascular events in patients with elevated cardiovascular risk or with a cardiovascular disorder (CVD). In spite of this, many of these patients do not receive statins. METHODS: We evaluated the impact of a brief educational intervention in cardiovascular prevention in primary care physicians' prescribing behaviour regarding statins beyond their participation in a randomised controlled trial (RCT). For this, prescribing data of all patients > 35 years who were counselled before and after the study period were analysed (each n > 75,000). Outcome measure was prescription of Hydroxymethylglutaryl-CoA Reductase Inhibitors (statins) corresponding to patients' overall risk for CVD. Appropriateness of prescribing was examined according to different risk groups based on the Anatomical Therapeutic Chemical Classification System (ATC codes). RESULTS: There was no consistent association between group allocation and statin prescription controlling for risk status in each risk group before and after study participation. However, we found a change to more significant drug configurations predicting the prescription of statins in the intervention group, which can be regarded as a small intervention effect. CONCLUSION: Our results suggest that an active implementation of a brief evidence-based educational intervention does not lead to prescription modifications in everyday practice. Physician's prescribing behaviour is affected by an established health care system, which is not easy to change. TRIAL REGISTRATION: ISRCTN71348772. PMID- 23819603 TI - Postnatal changes in the growth dynamics of the human face revealed from bone modelling patterns. AB - Human skull morphology results from complex processes that involve the coordinated growth and interaction of its skeletal components to keep a functional and structural balance. Previous histological works have studied the growth of different craniofacial regions and their relationship to functional spaces in humans up to 14 years old. Nevertheless, how the growth dynamics of the facial skeleton and the mandible are related and how this relationship changes through the late ontogeny remain poorly understood. To approach these two questions, we have compared the bone modelling activities of the craniofacial skeleton from a sample of subadult and adult humans. In this study, we have established for the first time the bone modelling pattern of the face and the mandible from adult humans. Our analyses reveal a patchy distribution of the bone modelling fields (overemphasized by the presence of surface islands with no histological information) reflecting the complex growth dynamics associated to the individual morphology. Subadult and adult specimens show important differences in the bone modelling patterns of the anterior region of the facial skeleton and the posterior region of the mandible. These differences indicate developmental changes in the growth directions of the whole craniofacial complex, from a predominantly downward growth in subadults that turns to a forward growth observed in the adult craniofacial skeleton. We hypothesize that these ontogenetic changes would respond to the physiological and physical requirements to enlarge the oral and nasal cavities once maturation of the brain and the closure of the cranial sutures have taken place during craniofacial development. PMID- 23819606 TI - Asthma diagnosis and treatment - 1017. Prevalence and determinants of allergy and asthma amongst Indian children. PMID- 23819605 TI - Immunohistochemical analysis of chromatin remodeler DAXX in high grade urothelial carcinoma. AB - BACKGROUND/AIMS: The chromatin remodeler DAXX, a predominantly nuclear protein, regulates the status of chromatin organization. The aim of this exploratory immunohistochemical study was to evaluate DAXX protein expression in high grade invasive urothelial carcinoma (UC) of the bladder as a biological regulator of aggressiveness. METHODS: Quantitative analysis was made on DAXX immunostained nuclei in tissue sections from 5 cases of bladder normal urothelium (NU) and 5 cases of bladder pT1 UC. Carcinoma in situ (CIS) and high grade papillary carcinoma (HGPCa) were identified in 2 out of 5 UC cases. RESULTS: The nuclei in UC show an open configuration of the chromatin composed of granules varying in size and distribution and a mean nuclear area 1.7 times greater than that in NU (UC: mean and SD 24.4 +/- 11.4 square microns; NU: 14.8 6.5 square microns. The differences are statistically significant). 70% of the NU nuclei are immunostained, whereas 90% of UC nuclei are positive. The mean gray level value in UC, related to the intensity of nuclear immunostaining, is lower than in NU by a factor of 0.94 (UC: mean and SD 100 +/- 15; NU: 106 +/- 15. The differences are statistically significant). In particular, the value in the nuclei adjacent to the stroma in UC is slightly lower than in the intermediate cell layers by factor of 0.98, whereas in NU it is slightly greater by a factor 1.02 and 1.04 compared to the intermediate and superficial cell layers. The values in CIS and HGPCa are similar to those in UC. CONCLUSIONS: The quantitative immunohistochemical analysis shows an altered protein expression of chromatin remodeler DAXX in UC and in its preinvasive phases, when compared to NU. DAXX evaluation, if associated with markers related to global DNA methylation and histone acetylation, could be used in clinical practice as a marker of aggressiveness. VIRTUAL SLIDES: The virtual slides for this article can be found here:http://www.diagnosticpathology.diagnomx.eu/vs/1398457297102379. PMID- 23819607 TI - Predictive factors for improvement of ascites after transjugular intrahepatic portosystemic shunt in patients with refractory ascites. AB - AIM: The aim of this study was to investigate the predictive factors for the response of ascites to a transjugular intrahepatic portosystemic shunt (TIPS) and the impact of improvement of ascites on the overall prognosis of patients with cirrhosis and refractory ascites. METHODS: Forty-seven consecutive patients with liver cirrhosis who underwent TIPS for refractory ascites were studied retrospectively. The mean follow-up period was 615 +/- 566 days. RESULTS: Thirty six of the patients (77%) were responders at 4 weeks after TIPS (early responders) and 37 (79%) were responders at 8 weeks after TIPS. Of the 11 non responders at 4 weeks, four showed an improvement of ascites at 8 weeks. Multivariate analysis showed that only the serum creatinine level before TIPS was an independent predictor of an early response. The cumulative survival rate of early responders was significantly higher than that of non-responders. The survival of patients grouped according to creatinine level was better in patients with serum creatinine of 1.9 mg/dL or less than in those with serum creatinine of more than 1.9 mg/dL. CONCLUSION: A low serum creatinine level in patients with refractory ascites is associated with an early response to TIPS. An early response of ascites to TIPS provides better survival. A serum creatinine level below 1.9 mg/dL is required for a good response to TIPS. PMID- 23819608 TI - Lr67 and Lr34 rust resistance genes have much in common--they confer broad spectrum resistance to multiple pathogens in wheat. AB - BACKGROUND: Adult plant rust resistance genes Lr67 and Lr34 confer race non specific resistance to multiple fungal pathogens of wheat. Induced, susceptible mutants were characterised for both genes. RESULTS: Three categories of Lr34 mutants were identified that were either partial susceptible, fully susceptible or hyper-susceptible to stripe rust and leaf rust. The likely impact of the mutational change on the predicted Lr34 protein correlated with differences in response to rust infection. Four independent Lr67 mutants were recovered that were susceptible to stripe rust, leaf rust and stem rust pathogens, including one possible hyper-susceptible Lr67 mutant. CONCLUSIONS: Detailed study of Lr34 mutants revealed that subtle changes in resistance response to multiple pathogens were correlated with mutational changes in the predicted protein. Recovery of independent Lr67 mutants indicates that as for Lr34, a single gene at the Lr67 locus is likely to confer resistance to multiple pathogens. The infection phenotypes of Lr67 mutants closely resembled that of Lr34 mutants. PMID- 23819609 TI - Photo- and radiation-chemistry of halide anions in ionic liquids. AB - One- and two- photon excitation of halide anions (X(-)) in polar molecular solvents results in electron detachment from the dissociative charge-transfer-to solvent state; this reaction yields a solvated halide atom and a solvated electron. How do such photoreactions proceed in ionic liquid (IL) solvents? Matrix isolation electron paramagnetic resonance (EPR) spectroscopy has been used to answer this question for photoreactions of bromide in aliphatic (1-butyl-1 methylpyrrolidinium) and aromatic (1-alkyl-3-methyl-imidazolium) ionic liquids. In both classes of ILs, the photoreaction (both 1- and 2-photon) yields bromine atoms that promptly abstract hydrogen from the alkyl chains of the IL cation; only in concentrated bromide solutions (containing >5-10 mol % bromide) does Br2( *) formation compete with this reaction. In two-photon excitation, the 2 imidazolyl radical generated via the charge transfer promptly eliminates the alkyl arm. These photolytic reactions can be contrasted with radiolysis of the same ILs, in which large yield of BrA(-*) radicals was observed (where A(-) is a matrix anion), suggesting that solvated Br(*) atoms do not occur in the ILs, as such a species would form three-electron sigma(2)sigma(*1) bonds with anions present in the IL. It is suggested that chlorine and bromine atoms abstract hydrogen faster than they form such radicals, even at cryogenic temperatures, whereas iodine mainly forms such bound radicals. These XA(-*) radicals convert to X2(*-) radicals in a reaction with the parent halide anion. Ramifications of these observations for photodegradation of ionic liquids are discussed. PMID- 23819610 TI - Cytosolic phosphorylated EGFR is predictive of recurrence in early stage penile cancer patients: a retropective study. AB - BACKGROUND: Penile cancer (PC) is a rare tumor, and therapeutic options are limited for this disease, with an overall 5-year overall survival around 65-70%. Adjuvant therapy is not recommended for patients with N0-1 disease, despite up to 60% of these patients will die within 5 years from diagnosis. METHODS: Medical records of all patients who underwent radical surgery at University Federico II of Naples and at National Tumor Institute "Pascale" of Naples for early squamous cell carcinoma of the penis from January, 2000 to December, 2011 were retrieved. Paraffin wax embedded tissue specimens were retrieved from the pathology archives of the participating Institutions for all patients. Expression of p-EGFR, EGFR and positivity to HPV were evaluated along with other histological variables of interest. Demographic data of eligible patients were retrieved along with clinical characteristics such as type of surgical operation, time of follow up, time of recurrence, overall survival. A multivariable model was constructed using a forward stepwise selection procedure. RESULTS: Thirty eligible patients were identified. All patients were positive for EGFR by immunohistochemistry, while 13 and 16 were respectively positive for nuclear and cytosolic p-EGFR. No EGFR amplification was detected by FISH. Eight patients were positive for high-risk HPV by ISH. On univariable analysis, corpora cavernosa infiltration (OR 7.8; 95% CI=0,8 to 75,6; P=0,039) and positivity for cytosolic p-EGFR (OR 7.6; 95% CI =1.49 to 50; P = 0.009) were predictive for recurrence, while only positivity for cytosolic p-EGFR (HR =9.0; 95% CI 1.0-100; P=0,0116) was prognostic for poor survival. CONCLUSION: It is of primary importance to identify patients with N0-1 disease who are at increased risk of recurrence, as they do not normally receive any adjuvant therapy. Expression of p-EGFR was found in this series to be strongly related to increase risk of recurrence and shorter overall survival. This finding is consistent with the role of p-EGFR in other solid malignancies. Integration of p-EGFR with classic prognostic factors and other histology markers should be pursued to establish optimal adjuvant therapy for N0-1 PC patients. PMID- 23819611 TI - Report of the Post Kala-azar Dermal Leishmaniasis (PKDL) Consortium Meeting, New Delhi, India, 27-29 June 2012. AB - Post kala-azar dermal leishmaniasis (PKDL) is a neglected complication of visceral leishmaniasis (VL)-a deadly, infectious disease that claims approximately 20,000 to 40,000 lives every year. PKDL is thought to be a reservoir for transmission of VL, thus, adequate control of PKDL plays a key role in the ongoing effort to eliminate VL. Over the past few years, several expert meetings have recommended that a greater focus on PKDL was needed, especially in South Asia. This report summarizes the Post Kala-Azar Dermal Leishmaniasis Consortium Meeting held in New Delhi, India, 27-29 June 2012. The PKDL Consortium is committed to promote and facilitate activities that lead to better understanding of all aspects of PKDL that are needed for improved clinical management and to achieve control of PKDL and VL. Fifty clinicians, scientists, policy makers, and advocates came together to discuss issues relating to PKDL epidemiology, diagnosis, pathogenesis, clinical presentation, treatment, and control. Colleagues who were unable to attend participated during drafting of the consortium meeting report. PMID- 23819612 TI - In vitro and in vivo protective effects of three mycotoxin adsorbents against ochratoxin A in broiler chickens. AB - 1. The objective of this study was to investigate in vitro and in vivo (in broiler chickens) ochratoxin A (OTA) adsorption efficiency of three different adsorbents: inorganic (modified zeolite); organic (esterified glucomannans) and mixed (inorganic and organic components plus enzymes). 2. The aim of the study was to investigate which of these adsorbents provided the best protection against the presence of residues of OTA in the pectoral muscle and liver of broilers given an OTA-contaminated diet. In addition, it was important to test and compare the results of adsorbent efficiency using two different in vitro methods. 3. The results from classical in vitro investigations carried out in the artificial intestinal fluid, showed that the inorganic adsorbent (Mz), exhibited the highest adsorption, having adsorbed 80.86 +/- 1.85% of OTA, whereas average in vitro adsorption abilities of organic (30.52 +/- 3.50%) and mixed (32.00 +/- 2.60%) adsorbents were significantly lower. 4. In the investigation of absorption in everted sacs of broiler duodenal segments (Everted Duodenal Sacs Procedure), higher OTA adsorption in gut was exhibited by organic adsorbent, 74.26 +/- 4.48%. Furthermore, the mean adsorption efficiency of mixed and inorganic adsorbent was 65.26 +/- 4.76% and 45.75 +/- 7.14%, respectively. 5. In the in vivo investigation, broilers were fed for 21 d on diets containing 2 mg/kg of OTA and supplemented with inorganic (Mz), organic (Ms) or mixed adsorbent (Mf) at the recommended concentration of 2 g/kg of feed. All three adsorbents significantly decreased OTA residue concentrations in the pectoral muscle and livers, but the order of effectiveness was mixed > organic > inorganic. The most efficient was the mixed adsorbent which decreased residue concentration by 72.50% in pectoral muscle and 94.47% in livers. 6. The Everted Duodenal Sac in vitro method provided results similar to those obtained in the in vivo study. However, further studies are required to investigate the efficiencies of adsorbents against various mycotoxins using this method. PMID- 23819613 TI - Atherogenic dyslipidaemic profiles associated with the development of Type 2 diabetes: a 3.1-year longitudinal study. AB - AIMS: While there is thought to be an association between glucose and lipid metabolism, it is largely unknown whether apolipoprotein B and non-high density lipoprotein (HDL) cholesterol are associated with the development of Type 2 diabetes. It is also unknown whether these atherogenic dyslipidaemic profiles have a stronger association with diabetes risk compared with conventional lipid measurements. METHODS: A total of 118 429 subjects without diabetes (70 980 men and 47 449 women), aged 17-90 years (mean age 39.6 years), were enrolled in this study and followed for a mean duration of 3.1 years. RESULTS: Apolipoprotein B and non-HDL cholesterol levels showed a strong association with the development of Type 2 diabetes compared with conventional lipid measurements and their ratios [hazard ratio per 1 sd; 1.39 (95% CI 1.37-1.42) and 1.38 (95% CI 1.35-1.40), respectively; both P < 0.001]. The Kaplan-Meier survival curve demonstrated that Type 2 diabetes developed more frequently as apolipoprotein B or non-HDL cholesterol levels increased across quartiles (both P < 0.001). In multivariate Cox regression analyses, both apolipoprotein B and non-HDL cholesterol were associated with the development of Type 2 diabetes, independent of other risk factor including age, sex, waist circumference, family history of diabetes, fasting serum glucose and insulin levels, HbA1c , systolic blood pressure and other conventional lipid measurements [hazard ratio per 1 sd; 1.14 (95% CI 1.11 1.18) and 1.13 (95% CI 1.10-1.16), respectively; both P < 0.001]. CONCLUSIONS: Atherogenic dyslipidaemia was more strongly associated with the development of Type 2 diabetes than conventional lipid measurements, and this effect was independent of other well-established risk factor for diabetes. PMID- 23819614 TI - Protocol-driven primary care and community linkages to improve population health in rural Zambia: the Better Health Outcomes through Mentoring and Assessment (BHOMA) project. AB - INTRODUCTION: Zambia's under-resourced public health system will not be able to deliver on its health-related Millennium Development Goals without a substantial acceleration in mortality reduction. Reducing mortality will depend not only upon increasing access to health care but also upon improving the quality of care that is delivered. Our project proposes to improve the quality of clinical care and to improve utilization of that care, through a targeted quality improvement (QI) intervention delivered at the facility and community level. DESCRIPTION OF IMPLEMENTATION: The project is being carried out 42 primary health care facilities that serve a largely rural population of more than 450,000 in Zambia's Lusaka Province. We have deployed six QI teams to implement consensus clinical protocols, forms, and systems at each site. The QI teams define new clinical quality expectations and provide tools needed to deliver on those expectations. They also monitor the care that is provided and mentor facility staff to improve care quality. We also engage community health workers to actively refer and follow up patients. EVALUATION DESIGN: Project implementation occurs over a period of four years in a stepped expansion to six randomly selected new facilities every three months. Three annual household surveys will determine population estimates of age-standardized mortality and under-5 mortality in each community before, during, and after implementation. Surveys will also provide measures of childhood vaccine coverage, pregnancy care utilization, and general adult health. Health facility surveys will assess coverage of primary health interventions and measures of health system effectiveness. DISCUSSION: The patient-provider interaction is an important interface where the community and the health system meet. Our project aims to reduce population mortality by substantially improving this interaction. Our success will hinge upon the ability of mentoring and continuous QI to improve clinical service delivery. It will also be critical that once the quality of services improves, increasing proportions of the population will recognize their value and begin to utilize them. PMID- 23819615 TI - GFP variants with alternative beta-strands and their application as light-driven protease sensors: a tale of two tails. AB - Green fluorescent protein (GFP) variants that carry one extra strand 10 (s10) were created and characterized, and their possible applications were explored. These proteins can fold with either one or the other s10, and the ratio of the two folded forms, unambiguously distinguished by their resulting colors, can be systematically modulated by mutating the residues on s10 or by changing the lengths of the two inserted linker sequences that connect each s10 to the rest of the protein. We have discovered robust empirical rules that accurately predict the product ratios of any given construct in both bacterial and mammalian expressions. Exploiting earlier studies on photodissociation of cut s10 from GFP (Do and Boxer, 2011), ratiometric protease sensors were designed from the construct by engineering a specific protease cleavage site into one of the inserted loops, where the bound s10 is replaced by the other strand upon protease cleavage and irradiation with light to switch its color. Since the conversion involves a large spectral shift, these genetically encoded sensors display a very high dynamic range. Further engineering of this class of proteins guided by mechanistic understanding of the light-driven process will enable interesting and useful application of the protein. PMID- 23819616 TI - Development of a subjective loudness rating scale. AB - OBJECTIVE: In an earlier study ( Beach et al, 2012 ), detailed noise exposure measurements were obtained through individual dosimetry. In this further analysis of the data we ask the question "Can the effort required to converse in noise be used to estimate the experienced A-weighted noise level?" DESIGN: The noise levels experienced during specific activities were obtained from the analysis of dosimetry results from personal noise exposure meters worn by study participants. The measured noise levels from particular events were compared to a subjectively judged 'loudness rating' reported by the person wearing the dosimeter during the measured event. STUDY SAMPLE: Volunteers (females = 20, males = 22) between 18 and 35 years (average age = 26.8) willing to wear dosimeters and keep a simple activity log. RESULTS: The relation between the objectively measured and the subjectively judged levels was consistent for the group over a large number of events. CONCLUSIONS: The subjective loudness rating index was shown to be a convenient tool that can be utilized for the retrospective estimation of noise levels from individual activities. PMID- 23819617 TI - Ipsi- and contralateral interaction in the 40 Hz auditory steady state responses (ASSRs) with two carriers at 60 dB SPL. AB - OBJECTIVE: Auditory steady state responses have been suggested for simultaneous threshold assessment using the multiple ASSR (MASSR) technique. However, at least at high stimulation levels, strong interactions reduce response amplitudes. The present study investigates ASSR interaction at a moderate stimulus level. DESIGN: Sinusoidal carriers modulated at rates near 40 Hz were used as probe. Unmodulated and modulated interferers were presented ipsi- or contralaterally. STUDY SAMPLE: Twenty normal-hearing subjects participated. RESULTS: Unmodulated interferers did not significantly change ASSR amplitudes. Modulated interferers, presented ipsilaterally or contralaterally, both significantly reduced the ASSR SNR by 13% and 8%, respectively. CONCLUSIONS: To compensate for the average SNR reduction would require a 32% and 18% longer measurement time for ipsi- and contralateral interferers, respectively, far less than the doubling of measurement time for two single measurements, emphasizing the MASSR technique advantage. However, the largest reduction for a single subject was 22% for the amplitude and 28% for the SNR, almost completely undoing the benefit in measurement time in MASSR. The individually varying interaction effects even at 60 dB SPL clearly limits the advantage of using the MASSR for modulation rates near 40 Hz over corresponding single ASSR measurements, at least for two simultaneous carriers. PMID- 23819619 TI - Speech-in-noise screening tests by internet, part 3: test sensitivity for uncontrolled parameters in domestic usage. AB - OBJECTIVE: The online speech-in-noise test 'Earcheck' is sensitive for noise induced hearing loss (NIHL). This study investigates effects of uncontrollable parameters in domestic self-screening, such as presentation level and transducer type, on speech reception thresholds (SRTs) obtained with Earcheck. DESIGN: Subjects performed 26 Earchecks that differed regarding presentation level (65, 71, and 77 dBA), presentation mode (monotic or diotic), and masking noise (two different low-pass filtered noises) in the lab. To investigate effects of test environment, participants conducted eight additional Earchecks at home using different transducer types (headphones or loudspeakers). STUDY SAMPLE: Thirty noise-exposed workers, either normal-hearing (n = 10), or with different degrees of NIHL (n = 20), participated. RESULTS: There was a minor effect of presentation levels exceeding 65 dBA in severely impaired listeners. Diotic presentation mode yielded lower SRTs compared to monotic presentation mode. Normal-hearing test results at home were poorer than in the laboratory, whereas hearing-impaired subjects performed better in domestic testing. Using loudspeakers deteriorated SRTs significantly in comparison to headphones, but only in hearing-impaired subjects. CONCLUSIONS: A monotic presentation mode using headphones is recommended for domestic screening. Since domestic testing affects SRT results, a follow up study using a large study population should assess Earcheck's validity when performed at home. PMID- 23819618 TI - Central auditory maturation and behavioral outcome in children with auditory neuropathy spectrum disorder who use cochlear implants. AB - OBJECTIVE: We examined cortical auditory development and behavioral outcomes in children with ANSD fitted with cochlear implants (CI). DESIGN: Cortical maturation, measured by P1 cortical auditory evoked potential (CAEP) latency, was regressed against scores on the infant toddler meaningful auditory integration scale (IT-MAIS). Implantation age was also considered in relation to CAEP findings. STUDY SAMPLE: Cross-sectional and longitudinal samples of 24 and 11 children, respectively, with ANSD fitted with CIs. RESULTS: P1 CAEP responses were present in all children after implantation, though previous findings suggest that only 50-75% of ANSD children with hearing aids show CAEP responses. P1 CAEP latency was significantly correlated with participants' IT-MAIS scores. Furthermore, more children implanted before age two years showed normal P1 latencies, while those implanted later mainly showed delayed latencies. Longitudinal analysis revealed that most children showed normal or improved cortical maturation after implantation. CONCLUSION: Cochlear implantation resulted in measureable cortical auditory development for all children with ANSD. Children fitted with CIs under age two years were more likely to show age appropriate CAEP responses within six months after implantation, suggesting a possible sensitive period for cortical auditory development in ANSD. That CAEP responses were correlated with behavioral outcome highlights their clinical decision-making utility. PMID- 23819620 TI - Skin tattoos and the development of uveitis. PMID- 23819621 TI - Dual organism design cycle reveals small subunit substitutions that improve [NiFe] hydrogenase hydrogen evolution. AB - BACKGROUND: Photosynthetic microorganisms that directly channel solar energy to the production of molecular hydrogen are a potential future biofuel system. Building such a system requires installation of a hydrogenase in the photosynthetic organism that is both tolerant to oxygen and capable of hydrogen production. Toward this end, we have identified the [NiFe] hydrogenase from the marine bacterium Alteromonas macleodii "Deep ecotype" that is able to be heterologously expressed in cyanobacteria and has tolerance to partial oxygen. The A. macleodii enzyme shares sequence similarity with the uptake hydrogenases that favor hydrogen uptake activity over hydrogen evolution. To improve hydrogen evolution from the A. macleodii hydrogenase, we examined the three Fe-S clusters found in the small subunit of many [NiFe] uptake hydrogenases that presumably act as a molecular wire to guide electrons to or from the active site of the enzyme. Studies by others altering the medial cluster of a Desulfovibrio fructosovorans hydrogenase from 3Fe-4S to 4Fe-4S resulted in two-fold improved hydrogen evolution activity. RESULTS: We adopted a strategy of screening for improved hydrogenase constructs using an Escherichia coli expression system before testing in slower growing cyanobacteria. From the A. macleodii enzyme, we created a mutation in the gene encoding the hydrogenase small subunit that in other systems is known to convert the 3Fe-4S medial cluster to 4Fe-4S. The medial cluster substitution did not improve the hydrogen evolution activity of our hydrogenase. However, modifying both the medial cluster and the ligation of the distal Fe-S cluster improved in vitro hydrogen evolution activity relative to the wild type hydrogenase by three- to four-fold. Other properties of the enzyme including thermostability and tolerance to partial oxygen did not appear to be affected by the substitutions. CONCLUSIONS: Our results show that substitution of amino acids altering the ligation of Fe-S clusters in the A. macleodii [NiFe] uptake hydrogenase resulted in increased hydrogen evolution activity. This activity can be recapitulated in multiple host systems and with purified protein. These results validate the approach of using an E. coli-cyanobacteria shuttle system for enzyme expression and improvement. PMID- 23819622 TI - Healthcare use and costs before and after parathyroidectomy in patients on dialysis. AB - BACKGROUND: Parathyroidectomy (PTX) is often performed in dialysis patients when medical treatment fails to control secondary hyperparathyroidism (SHPT). PTX is viewed by many as a cost-containing measure for patients who have been treated with vitamin D analogs and calcimimetics. Yet, information about health resource utilization and costs before and after PTX is limited. METHODS: This retrospective cohort study used professional service and pharmacy claims to identify subjects on dialysis undergoing PTX from 1/1/2008-12/31/2010. Only subjects with at least six months of information before and after PTX were considered. Subjects with primary hyperparathyroidism or kidney transplant were excluded. Prescription use, physician encounters, and surgical complications were compared during the six months immediately before and after PTX. RESULTS: The mean (SD) age of the 181 study subjects was 51 (15) years; 59% female; and 80% insured by Medicare. Overall, the percentage of patients receiving medications to manage altered mineral metabolism increased from 67% before to 79% after PTX. Specifically, oral vitamin D use increased, while the utilization of cinacalcet decreased resulting in mean (SD) monthly medication charges decreasing from $486 (507) to $226 (288) (p < 0.01). The mean (SD) number of physician encounters rose from 15 (14) before to 21 (22) per 6 months after PTX (p < 0.01) resulting in the corresponding increase in mean (SD) monthly charges from $1531 (2150) to $1965 (3317) (p = 0.08). Hypocalcemia was the predominant diagnosis recorded for post surgical physician encounters occurring in 31% of all subjects; 84% of hypocalcemic episodes were managed in acute care facilities. CONCLUSIONS: The cost of medications to manage SHPT decreased after PTX largely due to reduction in cinacalcet use, whereas vitamin D use increased likely to manage hypocalcemia. The frequency and cost of physician encounters, especially in acute care settings, were higher in the 6 months after PTX attributable largely to episodes of severe hypocalcemia. Overall, the reduction in prescription costs during the 6 months after PTX is outweighed by the higher costs associated with physician care. PMID- 23819623 TI - Serum metabolic signatures of four types of human arthritis. AB - Similar symptoms of the different types of arthritis have continued to confound the clinical diagnosis and represent a clinical dilemma making treatment choices with a more personalized or generalized approach. Here we report a mass spectrometry-based metabolic phenotyping study to identify the global metabolic defects associated with arthritis as well as metabolic signatures of four major types of arthritis--rheumatoid arthritis (n = 27), osteoarthritis (n = 27), ankylosing spondylitis (n = 27), and gout (n = 33)--compared with healthy control subjects (n = 60). A total of 196 metabolites were identified from serum samples using a combined gas chromatography coupled with time-of-flight mass spectrometry (GC-TOF MS) and ultraperformance liquid chromatography quadrupole-time-of-flight mass spectrometry (UPLC-QTOF MS). A global metabolic profile is identified from all arthritic patients, suggesting that there are common metabolic defects resulting from joint inflammation and lesion. Meanwhile, differentially expressed serum metabolites are identified constituting an unique metabolic signature of each type of arthritis that can be used as biomarkers for diagnosis and patient stratification. The results highlight the applicability of metabonomic phenotyping as a novel diagnostic tool for arthritis complementary to existing clinical modalities. PMID- 23819624 TI - A DArT marker genetic map of perennial ryegrass (Lolium perenne L.) integrated with detailed comparative mapping information; comparison with existing DArT marker genetic maps of Lolium perenne, L. multiflorum and Festuca pratensis. AB - BACKGROUND: Ryegrasses and fescues (genera, Lolium and Festuca) are species of forage and turf grasses which are used widely in agricultural and amenity situations. They are classified within the sub-family Pooideae and so are closely related to Brachypodium distachyon, wheat, barley, rye and oats. Recently, a DArT array has been developed which can be used in generating marker and mapping information for ryegrasses and fescues. This represents a potential common marker set for ryegrass and fescue researchers which can be linked through to comparative genomic information for the grasses. RESULTS: A F2 perennial ryegrass genetic map was developed consisting of 7 linkage groups defined by 1316 markers and deriving a total map length of 683 cM. The marker set included 866 DArT and 315 gene sequence-based markers. Comparison with previous DArT mapping studies in perennial and Italian ryegrass (L. multiflorum) identified 87 and 105 DArT markers in common, respectively, of which 94% and 87% mapped to homoeologous linkage groups. A similar comparison with meadow fescue (F. pratensis) identified only 28 DArT markers in common, of which c. 50% mapped to non-homoelogous linkage groups. In L. perenne, the genetic distance spanned by the DArT markers encompassed the majority of the regions that could be described in terms of comparative genomic relationships with rice, Brachypodium distachyon, and Sorghum bicolor. CONCLUSIONS: DArT markers are likely to be a useful common marker resource for ryegrasses and fescues, though the success in aligning different populations through the mapping of common markers will be influenced by degrees of population interrelatedness. The detailed mapping of DArT and gene-based markers in this study potentially allows comparative relationships to be derived in future mapping populations characterised using solely DArT markers. PMID- 23819625 TI - Disentangling steric and electrostatic factors in nanoscale transport through confined space. AB - The voltage-driven passage of biological polymers through nanoscale pores is an analytically, technologically, and biologically relevant process. Despite various studies on homopolymer translocation there are still several open questions on the fundamental aspects of pore transport. One of the most important unresolved issues revolves around the passage of biopolymers which vary in charge and volume along their sequence. Here we exploit an experimentally tunable system to disentangle and quantify electrostatic and steric factors. This new, fundamental framework facilitates the understanding of how complex biopolymers are transported through confined space and indicates how their translocation can be slowed down to enable future sensing methods. PMID- 23819626 TI - Binding of curcumin with bovine serum albumin in the presence of iota-carrageenan and implications on the stability and antioxidant activity of curcumin. AB - This work studied the influences of formation of BSA/iota-carrageenan complexes on the binding, stability, and antioxidant activity of curcumin. In the presence of BSA and iota-carrageenan, curcumin gives higher intensities of absorption and fluorescence than free curcumin and curcumin only combined with BSA. The added iota-carrageenan is observed to promote curcumin for quenching the instrinsic fluorescence of BSA. These results are explained in terms of the formation of BSA/iota-carrageenan complexes, which help to stabilize the folded structure of BSA for providing curcumin with a more hydrophobic microenvironment. The small difference in anisotropy values of curcumin with BSA alone and of BSA/iota carrageenan complexes suggests that iota-carrageenan acts as outer stretch conformation in BSA/iota-carrageenan complexes but does not directly disturb the hydrophobic pockets inside BSA, where curcumin is hydrophobically located. The determined values of the binding constant are higher for curcumin with BSA/iota carrageenan complexes than with BSA alone. Moreover, BSA/iota-carrageenan complexes are found to be superior to single BSA for enhancing the stability and DPPH radical-scavenging ability of curcumin. PMID- 23819627 TI - The relationship between neutrophil-to-lymphocyte ratio and vascular calcification in end-stage renal disease patients. AB - Chronic inflammation was found to be correlated with coronary (CAC) and thoracic peri-aortic calcification (TAC) in end-stage renal disease (ESRD) patients. Neutrophil-to-lymphocyte ratio (NLR) was introduced as a potential marker to determine inflammation in cardiac and noncardiac disorders. Data regarding NLR and its association with TAC and CAC are lacking. We aimed to determine the relationship between NLR and vascular calcification in ESRD patients. This was a cross-sectional study involving 56 ESRD patients (22 females, 34 males; mean age, 49.9 +/- 14.2 years) receiving peritoneal dialysis or hemodialysis for >=6 months in the Dialysis Unit of Necmettin Erbakan University. TAC and CAC scores were measured by using an electrocardiogram-gated 64-multidetector computed tomography. NLR was calculated as the ratio of the neutrophils and lymphocytes. There was a statistically significant correlation between NLR, TACS and CACS in ESRD patients (r = 0.43, P = 0.001 and r = 0.30, P = 0.02, respectively). The stepwise linear regression analysis revealed that age, as well as NLR were independent predictors of TACS. However, increased age was the only independent predictor of CACS according to linear regression analysis. Simple calculation of NLR can predict vascular calcification in ESRD patients. PMID- 23819628 TI - Role of CIP4 in high glucose induced epithelial--mesenchymal transition of rat peritoneal mesothelial cells. AB - BACKGROUND: Peritoneal mesothelial cell (PMC) plays a key role in the process of peritoneal fibrosis. Epithelial-mesenchymal transition (EMT) of PMCs is an important mechanism of peritoneal fibrosis. Prolonged exposure to peritoneal dialysis fluid containing a high concentration of glucose may lead to EMT of PMCs. Cdc42-interacting protein-4 (CIP4) is a critical regulator of cell skeleton and downstream effector of Cdc42 and participates in EMT of tubular epithelial cells. In the present study, we investigate the possible role of CIP4 in EMT of PMC under high glucose (HG) condition in vitro and further explore the potential therapeutic point for peritoneal fibrosis. METHODS: Rat peritoneal mesothelial cells (RPMCs) were isolated from the peritonea of rats by enzymatic digestion. Under HG conditions (1.5%, 2.5% and 4.25%), E-cadherin, alpha-SMA and CIP4 expression were assessed by Western blot. Effect of CIP4-siRNA and pcDNA3.1-CIP4 transfection on E-cadherin, alpha-SMA and CIP4 expression were also assessed respectively under 2.5% HG concentration. Cells were pretreated for 24 h with PI3K/Akt signaling inhibitor perifosine and effect of perifosine on CIP4 expression were detected by Western blot. RESULTS: EMT induction by HG was confirmed by the prevalence of morphological changes, loss of E-cadherin, increase in alpha-SMA expression. CIP4-siRNA transfection can reverse EMT of RPMCs. Over-expression of CIP4 promoted characteristics similar to those commonly observed in EMT. Furthermore, the increased CIP4 in response to HG was efficiently inhibited by perifosine. CONCLUSION: This study shows that CIP4 promotes high glucose-induced EMT through PI3K-Akt signaling pathway in RPMCs. PMID- 23819629 TI - Subjective quality of life in war-affected populations. AB - BACKGROUND: Exposure to traumatic war events may lead to a reduction in quality of life for many years. Research suggests that these impairments may be associated with posttraumatic stress symptoms; however, wars also have a profound impact on social conditions. Systematic studies utilising subjective quality of life (SQOL) measures are particularly rare and research in post-conflict settings is scarce. Whether social factors independently affect SQOL after war in addition to symptoms has not been explored in large scale studies. METHOD: War-affected community samples were recruited through a random-walk technique in five Balkan countries and through registers and networking in three Western European countries. The interviews were carried out on average 8 years after the war in the Balkans. SQOL was assessed on Manchester Short Assessment of Quality of Life- MANSA. We explored the impact of war events, posttraumatic stress symptoms and post-war environment on SQOL. RESULTS: We interviewed 3313 Balkan residents and 854 refugees in Western Europe. The MANSA mean score was 4.8 (SD = 0.9) for the Balkan sample and 4.7 (SD = 0.9) for refugees. In both samples participants were explicitly dissatisfied with their employment and financial situation. Posttraumatic stress symptoms had a strong negative impact on SQOL. Traumatic war events were directly linked with lower SQOL in Balkan residents. The post-war environment influenced SQOL in both groups: unemployment was associated with lower SQOL and recent contacts with friends with higher SQOL. Experiencing more migration-related stressors was linked to poorer SQOL in refugees. CONCLUSION: Both posttraumatic stress symptoms and aspects of the post-war environment independently influence SQOL in war-affected populations. Aid programmes to improve wellbeing following the traumatic war events should include both treatment of posttraumatic symptoms and social interventions. PMID- 23819630 TI - Effect of phosphorus availability on the selection of species with different ploidy levels and genome sizes in a long-term grassland fertilization experiment. AB - Polyploidy and increased genome size are hypothesized to increase organismal nutrient demands, namely of phosphorus (P), which is an essential and abundant component of nucleic acids. Therefore, polyploids and plants with larger genomes are expected to be selectively disadvantaged in P-limited environments. However, this hypothesis has yet to be experimentally tested. We measured the somatic DNA content and ploidy level in 74 vascular plant species in a long-term fertilization experiment. The differences between the fertilizer treatments regarding the DNA content and ploidy level of the established species were tested using phylogeny-based statistics. The percentage and biomass of polyploid species clearly increased with soil P in particular fertilizer treatments, and a similar but weaker trend was observed for the DNA content. These increases were associated with the dominance of competitive life strategy (particularly advantageous in the P-treated plots) in polyploids and the enhanced competitive ability of dominant polyploid grasses at high soil P concentrations, indicating their increased P limitation. Our results verify the hypothesized effect of P availability on the selection of polyploids and plants with increased genome sizes, although the relative contribution of increased P demands vs increased competitiveness as causes of the observed pattern requires further evaluation. PMID- 23819632 TI - Computational evidence for heavy-atom tunneling in the bergman cyclization of a 10-membered-ring enediyne. AB - DFT and CASSCF calculations for the cyclization of (3Z)-cyclodec-3-en-1,5-diyne were carried out to investigate heavy-atom tunneling. At 37 degrees C, tunneling was computed to enhance the rate by 38-40% over the transition-state theory rate. Intramolecular (12)C/(13)C kinetic isotope effects were predicted to be substantial, with a steep temperature dependence. These results are discussed in relation to recent experimental findings that show heavy-atom tunneling at moderate temperatures. The calculations point to the possibility of a simple computational test for the likelihood of heavy-atom tunneling using standard quantum-chemical information. PMID- 23819631 TI - EARLY Treatment with azilsartan compared to ACE-inhibitors in anti-hypertensive therapy--rationale and design of the EARLY hypertension registry. AB - BACKGROUND: Arterial hypertension is highly prevalent but poorly controlled. Blood pressure (BP) reduction substantially reduces cardiovascular morbidity and mortality. Recent randomized, double-blind clinical trials demonstrated that azilsartan medoxomil (AZM) is more effective in reducing BP than the ubiquitary ACE inhibitor ramipril. Therefore, we aimed to test whether these can be verified under clinical practice conditions. METHODS/DESIGN: The "Treatment with Azilsartan Compared to ACE-Inhibitors in Anti-Hypertensive Therapy" (EARLY) registry is a prospective, observational, national, multicenter registry with a follow-up of up to 12 months. It will include up to 5000 patients on AZM or ACE inhibitor monotherapy in a ratio of 7 to 3. A subgroup of patients will undergo 24-hour BP monitoring. EARLY has two co-primary objectives: 1) Description of the safety profile of azilsartan and 2) achievement of BP targets based on recent national and international guidelines for patients treated with azilsartan in comparison to those treated with ACE-inhibitors. The most important secondary endpoints are the determination of persistence with treatment and the documentation of cardiovascular and renal events. Recruitment commenced in January 2012 and will be completed by February 2013. CONCLUSIONS: The data obtained will supplement previous results from randomized controlled trials to document the potential value of utilizing azilsartan medoxomil in comparison to ACE-inhibitor treatment for target BP achievement in clinical practice. PMID- 23819633 TI - Actinobaculum schaalii recurrent urinary infection in a centenarian patient. PMID- 23819634 TI - Efficacy of white noise therapy for dementia patients with schizophrenia. PMID- 23819635 TI - Newly developed comprehensive geriatric assessment initiative "Dr. SUPERMAN" as a convenient screening test. PMID- 23819636 TI - Listeriosis among elderly patients in Taiwan. PMID- 23819637 TI - Estimation of glomerular filtration rate among elderly patients. PMID- 23819638 TI - On the finding of Taenia saginata in a geriatric patient. PMID- 23819639 TI - The association between XPC Lys939Gln gene polymorphism and urinary bladder cancer susceptibility: a systematic review and meta-analysis. AB - BACKGROUND: Numerous epidemiological studies have been conducted to explore the association between the Lys939Gln polymorphism of Xeroderma pigmentosum group C (XPC) gene and urinary bladder cancer susceptibility. However, the results remain inconclusive. In order to derive a more precise estimation of this relationship, a large and update meta-analysis was performed in this study. METHODS: A comprehensive search was conducted through researching MEDLINE, EMBASE, PubMed, Web of Science, China Biomedical Literature database (CBM) and China National Knowledge Infrastructure (CNKI) databases before June 2013. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the strength of the association. RESULTS: A total of 12 studies with 4828 cases and 4890 controls for evaluating the XPC Lys939Gln polymorphism and urinary bladder cancer were included. Overall, there was significant associations between the XPC Lys939Gln polymorphism and urinary bladder cancer risk were found for homozygous model (OR = 1.352, 95% CL = 1.088-1.681), heterozygous model (OR = 1.354, 95% CL = 1.085-1.688), and allele comparison (OR = 1.109, 95% CL = 1.013-1.214). In subgroup analysis by ethnicity and source of controls, there were still significant associations detected in some genetic models. CONCLUSION: Our meta analysis suggested that the XPC Lys939Gln polymorphism contributed to the risk of urinary bladder cancer. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1001118393101798. PMID- 23819640 TI - Smchd1 regulates a subset of autosomal genes subject to monoallelic expression in addition to being critical for X inactivation. AB - BACKGROUND: Smchd1 is an epigenetic modifier essential for X chromosome inactivation: female embryos lacking Smchd1 fail during midgestational development. Male mice are less affected by Smchd1-loss, with some (but not all) surviving to become fertile adults on the FVB/n genetic background. On other genetic backgrounds, all males lacking Smchd1 die perinatally. This suggests that, in addition to being critical for X inactivation, Smchd1 functions to control the expression of essential autosomal genes. RESULTS: Using genome-wide microarray expression profiling and RNA-seq, we have identified additional genes that fail X inactivation in female Smchd1 mutants and have identified autosomal genes in male mice where the normal expression pattern depends upon Smchd1. A subset of genes in the Snrpn imprinted gene cluster show an epigenetic signature and biallelic expression consistent with loss of imprinting in the absence of Smchd1. In addition, single nucleotide polymorphism analysis of expressed genes in the placenta shows that the Igf2r imprinted gene cluster is also disrupted, with Slc22a3 showing biallelic expression in the absence of Smchd1. In both cases, the disruption was not due to loss of the differential methylation that marks the imprint control region, but affected genes remote from this primary imprint controlling element. The clustered protocadherins (Pcdhalpha, Pcdhbeta, and Pcdhgamma) also show altered expression levels, suggesting that their unique pattern of random combinatorial monoallelic expression might also be disrupted. CONCLUSIONS: Smchd1 has a role in the expression of several autosomal gene clusters that are subject to monoallelic expression, rather than being restricted to functioning uniquely in X inactivation. Our findings, combined with the recent report implicating heterozygous mutations of SMCHD1 as a causal factor in the digenically inherited muscular weakness syndrome facioscapulohumeral muscular dystrophy-2, highlight the potential importance of Smchd1 in the etiology of diverse human diseases. PMID- 23819642 TI - Antiproliferative activities of lesser galangal (Alpinia officinarum Hance Jam1), turmeric (Curcuma longa L.), and ginger (Zingiber officinale Rosc.) against acute monocytic leukemia. AB - Acute monocytic leukemia (AML M5 or AMoL) is one of the several types of leukemia that are still awaiting cures. The use of chemotherapy for cancer management can be harmful to normal cells in the vicinity of the target leukemia cells. This study assessed the potency of the extracts from lesser galangal, turmeric, and ginger against AML M5 to use the suitable fractions in neutraceuticals. Aqueous and organic solvent extracts from the leaves and rhizomes of lesser galangal and turmeric, and from the rhizomes only of ginger were examined for their antiproliferative activities against THP-1 AMoL cells in vitro. Lesser galangal leaf extracts in organic solvents of methanol, chloroform, and dichloromethane maintained distinctive antiproliferative activities over a 48-h period. The turmeric leaf and rhizome extracts and ginger rhizome extracts in methanol also showed distinctive anticancer activities. The lesser galangal leaf methanol extract was subsequently separated into 13, and then 18 fractions using reversed phase high-performance liquid chromatography. Fractions 9 and 16, respectively, showed the greatest antiproliferative activities. These results indicate that the use of plant extracts might be a safer approach to finding a lasting cure for AMoL. Further investigations will be required to establish the discriminatory tolerance of normal cells to these extracts, and to identify the compounds in these extracts that possess the antiproliferative activities. PMID- 23819641 TI - Enhancement of the antifungal activity of antimicrobial drugs by Eugenia uniflora L. AB - Candidiasis is the most frequent infection by opportunistic fungi such as Candida albicans, Candida tropicalis, and Candida krusei. Ethanol extract from Eugenia uniflora was assayed, for its antifungal activity, either alone or combined with four selected chemotherapeutic antimicrobial agents, including anphotericin B, mebendazole, nistatin, and metronidazole against these strains. The obtained results indicated that the association of the extract of E. uniflora to metronidazole showed a potential antifungal activity against C. tropicalis. However, no synergistic activity against the other strains was observed, as observed when the extract was associated with the other, not enhancing their antifungal activity. PMID- 23819643 TI - Vitamin B6 in plasma - sample stability and the reference limits. AB - Quantitatively, the most important B6 vitamer in plasma is pyridoxal-5'-phosphate (p-PLP). The prerequisite for the use of p-PLP measurements in patients with poor nutritional status is an appropriate reference interval, together with knowledge of the stability of vitamin B6 in plasma samples. We used blood samples from healthy blood donors to derive the reference limits for p-PLP, and to examine its stability for 24 hours at room temperature and at 4-8 degrees C. P-PLP was measured using high performance liquid chromatography (HPLC). The reference interval in adults was 23-223 nmol/L. P-PLP was stable for 24 h at room temperature and at 4-8 degrees C, allowing time for normal specimen transport. PMID- 23819644 TI - Activity of neutrophil elastase reflects the progression of acute pancreatitis. AB - OBJECTIVE: Neutrophil elastase (NE) concentration is associated with progression of acute pancreatitis (AP), but measuring total NE concentration includes biologically inactive NE. This study aims to investigate the relationship between NE activity and the aetiology and severity of AP and associated organ failure. METHODS: Seventy-five patients admitted to our surgery department with a first episode of AP during 2004-2005 were age- and sex-matched to 20 healthy volunteers (controls). NE activity was assessed using venous blood samples obtained on patient admission and after 1, 2 and 14 days. One sample was also taken from each control. ANOVA was used for statistical comparison between groups. RESULTS: Baseline NE activity (geometric mean; 95% confidence intervals) differed between patients (58.6 nM of substrate 7-amino-4-methylcoumarin [AMC]/hour; 48.52-70.72) and controls (31.5 nM AMC/hour; 25.5-39.0) (p = 0.0003), and did not correlate with time between symptom onset and admission. Patients with alcohol-induced AP demonstrated higher mean activity (59.1 nM AMC/h; 44.7-78.2) than those with gallstone-induced AP (41.7 nM AMC/h; 33.9-51.4) (p = 0.0496). NE activity was higher overall in patients with predicted severe AP (60.9 nM AMC/h; 48.0-77.2) than in those with predicted mild AP (42.1 nM AMC/h; 34.9-50.8) (p = 0.027). Patients with respiratory failure had higher NE activity (82.5 nM AMC/h; 57.5 118.4) than those without (43.9 nM AMC/h; 37.6-51.3) (p = 0.0024). CONCLUSIONS: NE activity was associated with predicted severity of AP and AP-associated respiratory failure. Specific NE inhibitors may have therapeutic potential in acute pancreatitis. PMID- 23819646 TI - Asthma diagnosis and treatment - 1018. Effect of inhaled corticosteroids with long-acting beta2 agonists vs. inhaled corticosteroids alone on asthma control in children: results from national ashtma survey. PMID- 23819645 TI - Inter- and intra-observer reproducibility of quantitative renographic parameters of differential function and renal drainage in children. AB - PURPOSE: To evaluate inter- and intra-observer reproducibility of renographic quantitative parameters of input and output in children. METHODS: 100 children with unilateral or bilateral uropathy were selected, aiming to cover the entire range of ages, overall glomerular filtration rate (GFR), differential renal function (DRF) and quality of drainage. Renograms were acquired and processed according to the EANM guidelines, using a non-commercial software. Following parameters were tested: DRF using integral and Patlak methods, normalized residual activity (NORA) and output efficiency (OE) at 20 min and on the late post-erect post-micturition acquisition. Three observers from the same department and one from Santiago (Chile) processed independently the 100 renograms using the same renal software. Two observers reprocessed the 100 renograms again two months later in order to evaluate the intra-observer reproducibility. RESULTS AND CONCLUSION: No significant difference was observed between the four observers, whatever the considered parameter of input function or output. For left DRF (Integral and Patlak methods), 95% of the individual differences were between -5% and +5 %. They were between -0.5 and +0.5 units for both NORA 20 and NORA PM, and between -10% and +10% for OE 20 and OE PM. Inter-and intra- observer reproducibility were comparable. Outliers tended to be more frequent for Patlak than for Integral. Very low GFR (< 20 mL/min/1.73 m(2)), very young age (first days of life), huge megaureters, NORA values higher than 2.0, OE values below 60% and bladder in the renal background area (ectopic kidney) were the main characteristics of extreme differences. PMID- 23819647 TI - Cardiovascular and metabolic side effects associated with hydrocortisone and dexamethasone use in VLBW infants: a single-centre experience. PMID- 23819648 TI - Synthesis and vaccine evaluation of the tumor-associated carbohydrate antigen RM2 from prostate cancer. AB - We have successfully developed a [1+2+3] one-pot strategy to synthesize the RM2 antigen hexasaccharide that was proposed to be a prostate tumor antigen. The structure of the synthetic product was verified by NMR analysis and antibody binding assay using a glycan microarray. In addition, the synthetic antigen was conjugated to a mutated diphtheria toxin (DT, CRM197) with different copy numbers and adjuvant combinations to form the vaccine candidates. After vaccination in mice, we used glycan microarrays to monitor their immune response, and the results indicated that, when one molecule of DT was incorporated with 4.7 molecules of RM2 on average (DT-RM4.7) and adjuvanted with the glycolipid C34, the combination exhibited the strongest anti-RM2 IgG titer. Moreover, the induced mouse antibodies mediated effective complement-dependent cytotoxicity (CDC) against the prostate cancer cell line LNCap. PMID- 23819649 TI - Temporal coupling is more robust than spatial coupling: an investigation of interlimb coordination after stroke. AB - Interlimb coordination obtained through temporal and spatial coupling is a significant feature of human motor control. To understand the robustness of this capability the authors introduced a method to quantify interlimb coordination strength and compare individuals with asymmetric effector ability poststroke to nondisabled controls. Quantitative analyses determined the relative strength of interlimb coupling with an asymmetric obstacle avoidance task. Participants performed bimanual discrete, multijoint aiming movements in the frontal plane with a vertical barrier positioned midway to the target for one limb. To quantify coupling strength between limbs and groups, we regressed individual participant nonbarrier limb movement time or maximum vertical displacement separately, on barrier limb performance. Temporal and spatial interlimb coupling strength varied across participants in both groups. Barrier limb performance predicted nonbarrier limb behavior; however, interlimb coupling was significantly stronger for the nondisabled compared to the stroke group. In the stroke group, deficits in interlimb coordination affected spatial coupling more than temporal coupling. The decreased coupling strength detected, even in the presence of mild hemiparesis, demonstrates the measure's sensitivity. The authors propose this metric as a powerful assessment of the effectiveness of rehabilitation interventions and to monitor the recovery of bimanual coordination poststroke. PMID- 23819650 TI - Gravity affects the vertical curvature in human grasping movements. AB - When humans make grasping movements their digits' paths are curved vertically. In a previous study the authors found that this curvature is largely caused by the local constraints at the start and end of the movement. Here the authors examined the contribution of gravity to the part of the curvature that was not explained by the local constraints. Subjects had to grasp a tealight (small cylinder) while sitting on a chair. The authors could rotate the whole setup, including the subject, relative to gravity, whereby the positions of the starting point and of the tealight relative to the subject did not change. They found differences between the paths that are consistent with a direct effect of gravity pulling the arm downward. PMID- 23819651 TI - Exploring what lies behind public preferences for avoiding health losses caused by lapses in healthcare safety and patient lifestyle choices. AB - BACKGROUND: Although many studies have identified public preferences for prioritising health care interventions based on characteristics of recipient or care, very few of them have examined the reasons for the stated preferences. We conducted an on-line person trade-off (PTO) study (N=1030) to investigate whether the public attach a premium to the avoidance of ill health associated with alternative types of responsibilities: lapses in healthcare safety, those caused by individual action or lifestyle choice; or genetic conditions. We found that the public gave higher priority to prevention of harm in a hospital setting such as preventing hospital associated infections than genetic disorder but drug administration errors were valued similar to genetic disorders. Prevention of staff injuries, lifestyle diseases and sports injuries, were given lower priority. In this paper we aim to understand the reasoning behind the responses by analysing comments provided by respondents to the PTO questions. METHOD: A majority of the respondents who participated in the survey provided brief comments explaining preferences in free text responses following PTO questions. This qualitative data was transformed into explicit codes conveying similar meanings. An overall coding framework was developed and a reliability test was carried out. Recurrent patterns were identified in each preference group. Comments which challenged the assumptions of hypothetical scenarios were also investigated. RESULTS: NHS causation of illness and a duty of care were the most cited reasons to prioritise lapses in healthcare safety. Personal responsibility dominated responses for lifestyle related contexts, and many respondents mentioned that health loss was the result of the individual's choice to engage in risky behaviour. A small proportion of responses questioned the assumptions underlying the PTO questions. However excluding these from the main analysis did not affect the conclusions. CONCLUSION: Although some responses indicated misunderstanding or rejection of assumptions we put forward, the results were still robust. The reasons put forward for responses differed between comparisons but responsibility was the most frequently cited. Most preference elicitation studies only focus on eliciting numerical valuations but allowing for qualitative data can augment understanding of preferences as well as verifying results. PMID- 23819652 TI - Secretoglobin expression in ovarian carcinoma: lipophilin B gene upregulation as an independent marker of better prognosis. AB - BACKGROUND: The aim of the present study was to investigate within ovarian carcinoma and normal ovarian biopsies the gene expression of multiple secretoglobin family members relative to mammaglobin B, which we previously reported as a promising novel ovarian carcinoma prognostic marker. METHODS: Using quantitative real-time Reverse Transcription PCR we tested 53 ovarian carcinoma and 30 normal ovaries for the expression of 8 genes belonging to the secretoglobin family: mammaglobin A, lipophilin A, lipophilin B, uteroglobin, HIN 1, UGRP-1, RYD5 and IIS. Next, we decided to expand the LipB gene expression analysis to a further 48 ovarian carcinoma samples, for a total of 101 tumor tissues of various histologies and to study its protein expression by immunohistochemistry in formalin-fixed paraffin-embedded tumors and normal ovaries. Finally, we correlated lipophilin B gene and protein expression to conventional patient clinico-pathological features and outcome. RESULTS: We found significant mammaglobin A, lipophilin A, lipophilin B and RYD5 gene overexpression in ovarian carcinomas compared to normal ovaries. Lipophilin B mRNA showed a higher presence in tumors (75.4%) compared to normal ovaries (16.6%) and the most significant correlation with mammaglobin B mRNA (rs =0.77, p < 0.001). By immunohistochemical analysis, we showed higher lipophilin B expression in the cytoplasm of tumor cells compared to normal ovaries (p < 0.001). Moreover, lipophilin B gene overexpression was significantly associated with serous histology (serous vs clear cell p = 0.027; serous vs undifferentiated p = 0.007) and lower tumor grade (p = 0.02). Lower LipB mRNA levels (low versus high tertiles) were associated to a shorter progression-free (p = 0.03, HR = 2.2) and disease-free survival (p = 0.02, HR = 2.5) by univariate survival analysis and, importantly, they remain an independent prognostic marker for decreased disease-free (p = 0.001, HR = 3.9) and progression-free survival (p = 0.004, HR = 2.8) in multivariate Cox regression analysis. CONCLUSIONS: The present study represents the first quantitative evaluation of secretoglobin gene expression in normal and neoplastic ovarian tissues. Our results demonstrate lipophilin B gene and protein upregulation in ovarian carcinoma compared to normal ovary. Moreover, lipophilin B gene overexpression correlates with a less aggressive tumor phenotype and represents a novel ovarian carcinoma prognostic factor. PMID- 23819653 TI - Fine-tuning of microRNA-mediated repression of mRNA by splicing-regulated and highly repressive microRNA recognition element. AB - BACKGROUND: MicroRNAs are very small non-coding RNAs that interact with microRNA recognition elements (MREs) on their target messenger RNAs. Varying the concentration of a given microRNA may influence the expression of many target proteins. Yet, the expression of a specific target protein can be fine-tuned by alternative cleavage and polyadenylation to the corresponding mRNA. RESULTS: This study showed that alternative splicing of mRNA is a fine-tuning mechanism in the cellular regulatory network. The splicing-regulated MREs are often highly repressive MREs. This phenomenon was observed not only in the hsa-miR-148a regulated DNMT3B gene, but also in many target genes regulated by hsa-miR-124, hsa-miR-1, and hsa-miR-181a. When a gene contains multiple MREs in transcripts, such as the VEGF gene, the splicing-regulated MREs are again the highly repressive MREs. Approximately one-third of the analysable human MREs in MiRTarBase and TarBase can potentially perform the splicing-regulated fine tuning. Interestingly, the high (+30%) repression ratios observed in most of these splicing-regulated MREs indicate associations with functions. For example, the MRE-free transcripts of many oncogenes, such as N-RAS and others may escape microRNA-mediated suppression in cancer tissues. CONCLUSIONS: This fine-tuning mechanism revealed associations with highly repressive MRE. Since high-repression MREs are involved in many important biological phenomena, the described association implies that splicing-regulated MREs are functional. A possible application of this observed association is in distinguishing functionally relevant MREs from predicted MREs. PMID- 23819654 TI - An increase in primary care prescriptions of stop-smoking medication as a result of health insurance coverage in the Netherlands: population based study. AB - AIMS: To examine the impact of two national tobacco control interventions in the past decade on (dispensed) prescriptions of stop-smoking medication. DESIGN: Ecological study with interrupted time-series analyses of quarterly data points of three nation-wide representative databases. SETTING: The Netherlands 2001 2012, with the introduction of the guideline for smoking cessation care for general practitioners (GP) in 2007 and full insurance coverage for smoking cessation treatment in 2011. PARTICIPANTS: GPs, pharmacists and people in the general population aged 15 years and older. MEASUREMENTS: Time-series plots were inspected visually and segmented regression analyses were performed to estimate the change in level and slope of (dispensed) prescriptions of stop-smoking medication and smoking prevalence in the years preceding and after the tobacco control interventions. FINDINGS: No measurable effects of the GP guideline on (dispensed) prescriptions were observed. Shortly after the start of health insurance coverage, an estimated increase in primary care prescriptions of 6.3 per 1000 smokers [95% confidence interval (CI) = 2.9-9.8; P = 0.001] and 17.3 dispensed items per 1000 smokers (95% CI = 12.5-22.0; P < 0.000) was accompanied by a sudden drop in smoking prevalence of 2.9% (95% CI = 4.6-1.1; P = 0.002) in the first quarter of 2011. Immediately after the coverage abolition, smoking prevalence increased by 1.2% (95% CI = 0.5-2.8; P = 0.156) and dispensed prescription rates decreased with 21.6 per 1000 smokers (95% CI = 26.0-17.2; P < 0.000). CONCLUSIONS: Full health insurance coverage for smoking cessation treatment in the Netherlands was accompanied by a significant increase in the number of (dispensed) prescriptions of stop-smoking medication and a decrease in smoking prevalence. PMID- 23819655 TI - Open globe injuries by rotating wire brushes. PMID- 23819656 TI - Endothelial cells derived from embryonic stem cells respond to cues from topographical surface patterns. AB - The generation of micro- and nano-topography similar to those found in the extra cellular matrix of three-dimensional tissues is one technique used to recapitulate the cell-tissue physiology found in the native tissues. Despite the fact that ample studies have been conducted on the physiological significance of endothelial cells alignment parallel to shear stress, as this is the normal physiologic arrangement for healthy arterial EC, very few studies have examined the use of topographical signals to initiate endothelial cell alignment. Here, we have examined the ability for our mouse embryonic stem cell-derived endothelial cells (ESC-EC) to align on various microchip topographical systems. Briefly, we generated metal molds with 'wrinkled' topography using 1) 15 nm and 2) 30 nm of gold coating on the pre-strained polystryene (PS) sheets. After thermal-induced shrinkage of the PS sheets, polydimethylsiloxane (PDMS) microchips were then generated from the wrinkled molds. Using similar ShrinkTM-based technology, 3) larger selectively crazed acetone-etched lines in the PS sheets, and 4) fully crazed acetone-treated PS sheets of stochastic topographical morphology were also generated. The 15 nm and 30 nm gold coating generated 'wrinkles' of uniaxial anisotropic channels at nano-scaled widths while the crazing generated micron sized channels. The ESC-EC were able to respond and align on the 320 nm, 510 nm, and the acetone-etched 10.5 MUm channels, but not on the fully 'crazed' topographies. Moreover, the ESC-EC aligned most robustly on the wrinkles, and preferentially to ridge edges on the 10.5 MUm-sized channels. The ability to robustly align EC on topographical surfaces enables a variety of controlled physiological studies of EC-EC and EC-ECM contact guidance, as well as having potential applications for the rapid endothelialization of stents and vascular grafts. PMID- 23819657 TI - Passive equilibrium sampler for in situ measurements of freely dissolved concentrations of hydrophobic organic chemicals in sediments. AB - In this study, an equilibrium passive sampling device is introduced that facilitates the in situ measurement of hydrophobic organic chemicals bioavailability in sediments in terms of freely dissolved concentrations. The new field sampler allows SPME fibers and silicone hollow fibers to be immersed and equilibrated in situ, whereas an automated liner exchanger (ALEX) facilitates the quantitative transfer of analytes to the GC without the use of extraction solvents. The sampler was developed for environmental monitoring as follows: (1) It is of very solid construction and can be reused practically ad infinitum. (2) Fibers with varying surface to volume ratios can be exposed in parallel in order to confirm that equilibrium was reached between sampler and sediment. (3) The equilibrium times allow a temporal resolution that is suited for monitoring of both long-term trends and seasonal effects. The automated thermal desorption reduced sample treatment to a minimum and ensured cost- and time-efficient measurements while minimizing potential error sources after the sampling. The sampler is applicable in a multitude of aquatic environments, especially where currents are low and sediments are muddy and well-mixed, e.g. by bioturbation. Examples for such environments are mud flats, harbor basins, river banks, and lakes. PMID- 23819658 TI - OvidSP Medline-to-PubMed search filter translation: a methodology for extending search filter range to include PubMed's unique content. AB - BACKGROUND: PubMed translations of OvidSP Medline search filters offer searchers improved ease of access. They may also facilitate access to PubMed's unique content, including citations for the most recently published biomedical evidence. Retrieving this content requires a search strategy comprising natural language terms ('textwords'), rather than Medical Subject Headings (MeSH). We describe a reproducible methodology that uses a validated PubMed search filter translation to create a textword-only strategy to extend retrieval to PubMed's unique heart failure literature. METHODS: We translated an OvidSP Medline heart failure search filter for PubMed and established version equivalence in terms of indexed literature retrieval. The PubMed version was then run within PubMed to identify citations retrieved by the filter's MeSH terms (Heart failure, Left ventricular dysfunction, and Cardiomyopathy). It was then rerun with the same MeSH terms restricted to searching on title and abstract fields (i.e. as 'textwords'). Citations retrieved by the MeSH search but not the textword search were isolated. Frequency analysis of their titles/abstracts identified natural language alternatives for those MeSH terms that performed less effectively as textwords. These terms were tested in combination to determine the best performing search string for reclaiming this 'lost set'. This string, restricted to searching on PubMed's unique content, was then combined with the validated PubMed translation to extend the filter's performance in this database. RESULTS: The PubMed heart failure filter retrieved 6829 citations. Of these, 834 (12%) failed to be retrieved when MeSH terms were converted to textwords. Frequency analysis of the 834 citations identified five high frequency natural language alternatives that could improve retrieval of this set (cardiac failure, cardiac resynchronization, left ventricular systolic dysfunction, left ventricular diastolic dysfunction, and LV dysfunction). Together these terms reclaimed 157/834 (18.8%) of lost citations. CONCLUSIONS: MeSH terms facilitate precise searching in PubMed's indexed subset. They may, however, work less effectively as search terms prior to subject indexing. A validated PubMed search filter can be used to develop a supplementary textword-only search strategy to extend retrieval to PubMed's unique content. A PubMed heart failure search filter is available on the CareSearch website (http://www.caresearch.com.au) providing access to both indexed and non-indexed heart failure evidence. PMID- 23819659 TI - Evaluation of low back pain: comparative study between psychophysical methods. AB - OBJECTIVE: The aims of this study were to validate the measurement of low back pain by different psychophysical methods and to compare different methods of pain measurement. METHODS: This double-blind, randomized experimental study was realized in Brazil. The sample was 60 patients with low back pain, divided into two groups: group I (methylprednisolone 80 mg + 8 mL of 0.9% saline solution) and group II (methylprednisolone 80 mg + 5 mL of levobupivacaine without epinephrine + 3 mL of 0.9% saline solution), both using 10-mL syringes. The methods were the serial exploration and psychophysical (magnitude estimation, category estimation, and cross-modality matching). RESULTS: Pain evaluation was carried out before the block and 30 minutes, 6, 12, and 24 hours after it. After 30 minutes of epidural block, the levobupivacaine group presented more significant reaction of reduction pain than the saline group. The magnitude and line-length scales were evaluated every period of time, showing no significant differences, except in 12 and 24 hours after the first block. The exponential function to every evaluation ranged from 0.87 to 1.00. CONCLUSION: This research tries to bring to health care an original method for measuring low back pain. It is noteworthy that in the future, more research is needed to apply this method in clinical and scientific fields. PMID- 23819661 TI - Directional transport by nonprocessive motor proteins on fascin-cross-linked actin arrays. AB - In this study, the unidirectional transport of heavy meromyosin (HMM)-coated beads is demonstrated on fascin-cross-linked actin arrays. The streptavidin coated surface was properly blocked to prevent nonspecific binding of F-actin and, as a result, a high population of long gelsolin-actin complexes was suspended in the medium for subsequent processes. A flow field was utilized to lay down F-actin aligned along the direction of the flow and fascin cross-linked laid F-actin to prevent F-actin resuspension. When HMM-coated beads came into contact with the fascin-cross-linked actin arrays, they started to move in the same direction over long distances. Because of the nonprocessive nature of myosin II motor protein, the bead size limited the number of HMM heads on the area in contact with F-actin arrays, which resulted in beads traveling at different velocities according to their sizes. Furthermore, this study demonstrates the patterning of actin arrays, which could serve as a basis for the development of applications. PMID- 23819660 TI - A systematic review of HIV interventions for black men who have sex with men (MSM). AB - BACKGROUND: Black men who have sex with men (MSM) are disproportionately burdened by HIV/AIDS. Despite this burden there has been a shortage of research on HIV interventions for black MSM. This article provides a comprehensive review of the literature on interventions for black MSM to identify effective HIV prevention intervention strategies for black MSM. METHODS: We searched 3 databases: Pubmed, Scopus, and Google Scholar to identify peer-reviewed articles and used the following search terms: African American or black; MSM or men who have sex with men and women (MSMW); HIV; program or intervention; and evaluation or intervention science or implementation research. We included research articles that assessed interventions for black men who have sex with men. We included studies that used an experimental, quasi-experimental, or pre-post test design as well as formative research studies. We also searched the CDC and NIH websites to identify planned and on-going intervention studies. We identified a total of 23 studies to include in the review. RESULTS: We identified 12 completed studies of interventions for black MSM. Eight of these 12 interventions aimed to reduce HIV risk behaviors and 5 found a significant reduction in HIV risk behavior over time. We identified 4 health service intervention studies for young black MSM. CONCLUSIONS: Behavior change interventions are effective at reducing HIV risk behaviors among black MSM. However, relying only on behavioral interventions that aim to reduce HIV risk behavior will most likely not have a population-level effect on HIV infection among black MSM. There is a compelling and urgent need to develop and test comprehensive HIV testing, linkage to care, retention in care and adherence interventions for black MSM. PMID- 23819663 TI - The process of a peer-reviewed journal. PMID- 23819662 TI - Approaches to ensuring and improving quality in the context of health system strengthening: a cross-site analysis of the five African Health Initiative Partnership programs. AB - BACKGROUND: Integrated into the work in health systems strengthening (HSS) is a growing focus on the importance of ensuring quality of the services delivered and systems which support them. Understanding how to define and measure quality in the different key World Health Organization building blocks is critical to providing the information needed to address gaps and identify models for replication. DESCRIPTION OF APPROACHES: We describe the approaches to defining and improving quality across the five country programs funded through the Doris Duke Charitable Foundation African Health Initiative. While each program has independently developed and implemented country-specific approaches to strengthening health systems, they all included quality of services and systems as a core principle. We describe the differences and similarities across the programs in defining and improving quality as an embedded process essential for HSS to achieve the goal of improved population health. The programs measured quality across most or all of the six WHO building blocks, with specific areas of overlap in improving quality falling into four main categories: 1) defining and measuring quality; 2) ensuring data quality, and building capacity for data use for decision making and response to quality measurements; 3) strengthened supportive supervision and/or mentoring; and 4) operational research to understand the factors associated with observed variation in quality. CONCLUSIONS: Learning the value and challenges of these approaches to measuring and improving quality across the key components of HSS as the projects continue their work will help inform similar efforts both now and in the future to ensure quality across the critical components of a health system and the impact on population health. PMID- 23819664 TI - Biological perspectives: akathisia: ants in your pants. PMID- 23819665 TI - Addressing psychosocial care using an interactive Web site for combat-wounded patients. AB - PURPOSE: The aims were to examine military nurses and combat-wounded patients' evaluation of a cognitive behavioral intervention Web site called Stress Gym. DESIGN AND METHODS: The use of the intervention was a proof-of-concept design with 129 military nurses and combat-wounded patients in military medical treatment facilities (MTFs). The nurses and patients logged on to Stress Gym, reviewed the nine modules available, and completed a short evaluation of the Web site. FINDINGS: The evaluation of the military nurses and patients was high. There were no significant differences in the evaluation based on military services, sex, deployment, and education levels. PRACTICE IMPLICATIONS: The strength of Stress Gym is that it enables all military members to learn about and get help with problems such as stress, anxiety, anger, and depressive symptoms anonymously and in private. CLINICAL RELEVANCE: Stress Gym is a versatile tool that can help nurses address the psychosocial needs of their patients by encouraging its use and including it in treatment protocols. PMID- 23819666 TI - A social-cognitive sexual counseling intervention post-MI-development and pilot testing. AB - PURPOSE: Individuals experiencing myocardial infarction (MI) report anxiety, depression, diminished quality of life (QOL), and reduced sexual activity. DESIGN AND METHODS: We examined return to sexual activity post-MI, and pilot tested a comprehensive sexual counseling intervention based on social-cognitive theory. The intervention in this pretest/posttest preexperimental study used an informational video, newsletters, and telephone counseling, with cardiac patients (N = 10) and partners (N = 3). Measures included QOL; knowledge; sexual anxiety, depression, self-efficacy, and satisfaction. FINDINGS: At 8 weeks, only 60% had returned to sexual activity, with low QOL and sexual satisfaction for patients and partners. PRACTICE IMPLICATIONS: Supportive interventions by nurses are needed to assist MI patients and partners return to sexual activity. PMID- 23819667 TI - Impact of personalized in-home nursing care plans on dependence in ADLs/IADLs and on family burden among adults diagnosed with schizophrenia: a randomized controlled study. AB - PURPOSE: The study aims to assess the impact of personalized in-home nursing care plans on the degree of dependence among adult patients with schizophrenia, and on family burden. DESIGN AND METHODS: This is a randomized controlled study with 94 participants: The experimental group received a personalized in-home nursing care plan. The comparison group got a standard care at its mental health center. FINDINGS: The pretest-posttest multivariate analysis of covariance revealed statistically significant group differences (p = .003). The help received the positive activity and the degree of independence in the experimental group improved mainly due to intervention. PRACTICE IMPLICATIONS: A personalized in home nursing care plan improves the degree of independence of people diagnosed with schizophrenia living in the community and reduces the burden perceived by the family. PMID- 23819668 TI - Improving cardiovascular disease screening in community mental health centers. AB - PURPOSE: Increased mortality among the seriously mentally ill is largely due to cardiovascular disease (CVD). This applied research project examined a process of CVD screening at a community mental health center, then implemented and evaluated an improved process of identifying and managing CVD risk factors. DESIGN AND METHODS: Patient records (n = 130) were reviewed at baseline and 6 months posteducational intervention and implementation of new monitoring tools. FINDINGS: Statistical analysis showed significant process improvement (p < .001). PRACTICE IMPLICATIONS: Advanced practice registered nurses can design and implement improved CVD screening to mitigate morbidity and mortality in the seriously mentally ill. PMID- 23819669 TI - Childhood experiences of perpetrators of child sexual abuse. AB - PURPOSE: This study explored the childhood experiences of perpetrators of child sexual abuse. DESIGN AND METHODS: A blend of narrative inquiry and phenomenology was employed. Interviews were conducted with 23 community-dwelling perpetrators (21 males, 2 females). The education of participants ranged from GED to PhD. FINDINGS: There were four types of narratives: There Was No Love; Love Left; Love Was Conflated With Sex; and a Pretty Good Childhood. Chronic sorrow for a painful childhood was evident in most participants. PRACTICE IMPLICATIONS: Cognitive behavioral treatment may not be optimal for all perpetrators because it is not designed to facilitate recovery from early trauma and loss. PMID- 23819670 TI - Using short-term group psychotherapy as an evidence-based intervention for first time mothers at risk for postpartum depression. AB - PURPOSE: The purposes were to (a) provide an 8-week, short-term, psychotherapy group as a nonpharmacologic, evidence-based intervention for first-time mothers at risk for postpartum depression (PPD) and (b) determine if women's scores in the Edinburgh Postnatal Depression Scale changed after participation in the intervention. CONCLUSION: The women who participated in the short-term group psychotherapy intervention experienced a decrease in their Edinburgh Postnatal Depression Scale scores, reducing their risk for PPD. PRACTICE IMPLICATIONS: Group psychotherapy is an effective, evidence-based intervention to reduce the risk for PPD and should remain a current competency of psychiatric advanced practice nurses. PMID- 23819671 TI - Nurses' views on training needs to increase provision of primary care for consumers with serious mental illness. AB - PURPOSE: The study aims to ascertain nurses' views on their preparedness to provide physical health care, and their identified training needs. DESIGN AND METHODS: The study used a qualitative exploratory design. Thirty-eight nurses working in a regional mental health setting participated in focus groups. FINDINGS: Three main themes were identified: (a) the need for physical healthcare training, (b) modes of training, (c) access to training, and (d) organizational commitment. PRACTICE IMPLICATIONS: The philosophy and design of training must reflect workplace context, and take into account individual learning styles. Organizational support is crucial. PMID- 23819673 TI - Asthma diagnosis and treatment - 1019. Churg Strauss Syndrome - missed diagnosis and consequences. PMID- 23819672 TI - The Treatment Action Campaign and the three dimensions of lawyering: reflections from the rainbow nation. AB - The spread and perpetuation of the HIV/AIDS epidemic in South Africa has hindered the country's social and economic growth after apartheid. This paper documents my experiences while working with the Projects Abroad Human Rights Office and specifically my interactions with the Treatment Action Campaign (TAC), an organization which has taken a multi-dimensional approach in order to educate people about HIV/AIDS and attempt to provide access to medicines for millions of South Africans afflicted with the disease. I discuss how TAC has used both traditional and non-traditional methods of advocacy to combat the epidemic and equate access to health care to a social justice issue by empowering marginalized communities. The paper's dual purpose is to applaud TAC's continuous success in combating HIV/AIDS with such a multi-dimensional approach and illustrate how other organizations can utilize such an approach in order to affect social change. To illustrate TAC's approach, I utilize Lucie White's three dimensions of lawyering and equate TAC to a single cause lawyer, signifying that White's characterization of multi-dimensional activism is not limited to individuals, but can rather be applied at the firm level. White's three dimensions include: (a) advocacy through litigation, (b) advocacy in stimulating progressive change, and (c) advocacy as a pedagogic process. From this analysis, I conclude that TAC's multi-dimensional approach and specifically its inherent practice of White's three dimensions has been the root of its success in educating millions about the virus and advocating for access to medicines for those who have contracted HIV. TAC's innovative advocacy has also mobilized a new generation of South African activists who have helped TAC grow into a vibrant and integral organization within the country's post-apartheid culture. Such an example can serve as a framework for future organizations who wish to tackle other challenges that face the country. PMID- 23819674 TI - Spoken expository discourse of children and adolescents: retelling versus generation. AB - This cross-sectional study investigated the spoken expository discourse skills of children and adolescents elicited in generation and retelling conditions. There were three groups of participants: young school-age children (M = 7.0 years; n = 64); intermediate-school-age children (M = 11.3 years; n = 18) and high-school age students (M = 17.6 years; n = 18). Participants were asked to generate expository discourse using the favourite game or sport (FGS) task and to retell an expository passage about the game of curling. All samples were transcribed and analysed on measures of verbal productivity (number of utterances), syntactic complexity (mean length of utterance in T-units [MLU] and clausal density) and verbal fluency (percent maze words). Results indicated that although all age groups produced longer samples in the generation condition, MLU was significantly longer in the retelling condition. The results suggest that the expository retelling task may be a clinically useful addition to a language assessment battery for children and adolescents. PMID- 23819676 TI - Effect of word accent on the difficulty of transition from core vowels in first syllables to the following segments in Japanese children who stutter. AB - Matsumoto-Shimamori, Ito, Fukuda, and Fukuda (2011) proposed the hypothesis that the transition from the core vowel (i.e. syllable nucleus) in the first syllable of a word to the following segment significantly affects the occurrence of stuttering in Japanese. The purpose of this study was to investigate whether word accent (i.e. an abrupt pitch fall in Japanese) affects the production difficulty of the transition from the core vowel in the first syllable of a word to the following segment in Japanese. The participants were 25 Japanese children who stuttered, ranging in age from 6;4 to 12;5. A two- and three-syllable word naming task was used. The frequency of stuttering was not significantly different between the words with and without an abrupt pitch fall, and among those whose positions of an abrupt pitch fall were different. These results suggest that word accent does not have a significant effect on the difficulty of the transition from the core vowel in the first syllable of a word in Japanese. PMID- 23819675 TI - Grammatical treatment and specific language impairment: neighbourhood density & third person singular -s. AB - The purpose of this study was to test the effect of manipulating verb neighbourhood density in treatment targeting the third person singular lexical affix. Using a single-subject experimental design, six pre-schoolers with Specific Language Impairment (SLI) were randomly assigned to one of two conditions: (1) treatment with sparse verbs or (2) treatment with dense verbs in 12 sessions. The third person singular lexical affix was targeted for 12 sessions of treatment in both conditions. Treatment gain and generalization were measured as the dependent variables. Third person singular % correct change from pre treatment to post-treatment was measured using sentence production tasks with comparisons across the two treatment conditions. Treatment gain and generalization were greater for children enrolled in the sparse condition. Preliminary clinical recommendations are made and theoretical implications are discussed relative to neighbourhood density effects on lexical activation and storage in children with SLI. PMID- 23819677 TI - Prosodic constraints on inflected words: an area of difficulty for German speaking children with specific language impairment? AB - Recent studies suggest that morphosyntactic difficulties may result from prosodic problems. We therefore address the interface between inflectional morphology and prosody in typically developing children (TD) and children with SLI by testing whether these groups are sensitive to prosodic constraints that guide plural formation in German. A plural elicitation task was designed consisting of 60 words and 20 pseudowords. The performance of 14 German-speaking children with SLI (mean age 7.5) was compared to age-matched controls and to younger children matched for productive vocabulary. TD children performed significantly better than children with SLI. Error analyses revealed that children with SLI produced more forms that did not meet the optimal shape of a noun plural. Beyond the fact that children with SLI have deficits in plural marking, the findings suggest that they also show reduced sensitivity to prosodic requirements. In other words, the prosodic structure of inflected words seems to be vulnerable in children with SLI. PMID- 23819678 TI - Maternal recasts and activity variations: a comparison of mother-child dyads involving children with and without SLI. AB - This study investigated maternal recast and the children's responses comparing dyads made up of a mother and a child with typical language development (TD) or a child with specific language impairment (SLI). More specifically, this article deals with the influence of the type of activity being carried out on the number and types of maternal recasts. A sample of 17 French-speaking children with SLI (age 5 to 7 years) matched with 17 TD same-age peers was observed in interaction with their mother during four different activities (joint reading, symbolic play, question guessing game and clue guessing game). The results showed that group and activity had an impact on the number and type of recasts. Mothers of children with SLI offered more recasts than mothers of TD children. The former preferred phonological recasts whereas the latter preferred lexical ones. Moreover, recasts were more frequently used in joint reading than in other activities. Regarding the children's responses, no significant difference was observed between the two groups. Children with SLI took up the maternal proposition more frequently after a lexical recast than after a recast of another type. The findings provide evidence for considering the features of the activities in clinical settings. PMID- 23819679 TI - Salivary adenoid cystic carcinoma with an early phase of high-grade transformation: case report with an immunohistochemical analysis. AB - BACKGROUND: The early phase of salivary gland carcinomas with high-grade transformation (HGT) is extremely rare. We reported one case of adenoid cystic carcinoma (AdCC) with early HGT, herein. CASE PRESENTATION: The patient was a 27 year-old Japanese woman who suffered from swelling of the left parotid region. Most of this tumor consisted of typical AdCC histology, whereas the central area of this tumor was composed of solid growth component by atypical cells with clear cytoplasm and marked nuclear atypia. Immunohistochemically, this area was strongly and diffusely positive for epithelial membrane antigen, p53, p16, Her-2, cyclin A and cyclin B1. The Ki-67 labeling index of this area was high, entirely different from that of AdCC area. CONCLUSION: Overall, this area was an early phase of AdCC-HGT. This case is the second case of early AdCC-HGT. We discuss the development of salivary gland carcinoma with HGT. VIRTUAL SLIDES: http://www.diagnosticpatology.diagnomx.eu/vx/1598278104895730. PMID- 23819680 TI - Molecular hydrogen formation from photocatalysis of methanol on TiO2(110). AB - It is well established that adding methanol to water could significantly enhance H2 production by TiO2. Recently, we have found that methanol can be photocatalytically dissociated on TiO2(110) at 400 nm via a stepwise mechanism. However, how molecular hydrogen can be formed from the photocatalyzed methanol/TiO2(110) surface is still not clear. In this work, we have investigated deuterium formation from photocatalysis of the fully deuterated methanol (CD3OD) on TiO2(110) at 400 nm using a temperature programmed desorption (TPD) technique. Photocatalytic dissociation products formaldehyde (CD2O) and D-atoms on BBO sites (via D2O TPD product) have been detected. In addition to D2O formation by heating the photocatalyzed methanol/TiO2(110) surface, we have also observed D2 product formation. D2 is clearly formed via thermal recombination of the D-atoms on the BBO sites from photocatalysis of methanol. Experimental results indicate that D2O formation is more important than D2 formation and that D2 formation is clearly affected by the D2O formation process. PMID- 23819682 TI - Perinatal systemic inflammatory responses of growth-restricted preterm newborns. AB - AIM: To compare the early post-natal pattern of systemic inflammation in growth restricted infants born before the 28th week of gestation to that of appropriately grown peers. METHODS: We measured the concentrations of 25 inflammation-related proteins in blood spots collected from 939 newborns during the first 2 post-natal weeks. We calculated the odds ratios (99% confidence intervals) that concentrations would be in the highest quartile. RESULTS: Severely growth-restricted infants (birth weight Z-score <-2) were not at increased risk of systemic inflammation shortly after birth. On post-natal day 14, however, they were significantly more likely than their peers to have a CRP, IL-1beta, IL-6, TNF-alpha, IL-8, MCP-4, ICAM-1, ICAM-3, E-SEL, MMP-9, VEGF-R2 and/or IGFBP-1 concentration in the highest quartile. These increased risks could not be attributed to delivery indication, bacteremia or duration of ventilation. CONCLUSION: Growth-restricted preterm newborns appear to be at increased risk of elevated concentrations of inflammation-associated proteins by post-natal day 14. PMID- 23819684 TI - Body masses, functional responses and predator-prey stability. AB - The stability of ecological communities depends strongly on quantitative characteristics of population interactions (type-II vs. type-III functional responses) and the distribution of body masses across species. Until now, these two aspects have almost exclusively been treated separately leaving a substantial gap in our general understanding of food webs. We analysed a large data set of arthropod feeding rates and found that all functional-response parameters depend on the body masses of predator and prey. Thus, we propose generalised functional responses which predict gradual shifts from type-II predation of small predators on equally sized prey to type-III functional-responses of large predators on small prey. Models including these generalised functional responses predict population dynamics and persistence only depending on predator and prey body masses, and we show that these predictions are strongly supported by empirical data on forest soil food webs. These results help unravelling systematic relationships between quantitative population interactions and large-scale community patterns. PMID- 23819683 TI - Coffee, caffeine, and risk of completed suicide: results from three prospective cohorts of American adults. AB - OBJECTIVE: To evaluate the association between coffee and caffeine consumption and suicide risk in three large-scale cohorts of US men and women. METHODS: We accessed data of 43,599 men enrolled in the Health Professionals Follow-up Study (HPFS, 1988-2008), 73,820 women in the Nurses' Health Study (NHS, 1992-2008), and 91,005 women in the NHS II (1993-2007). Consumption of caffeine, coffee, and decaffeinated coffee, was assessed every 4 years by validated food-frequency questionnaires. Deaths from suicide were determined by physician review of death certificates. Multivariate adjusted relative risks (RRs) were estimated with Cox proportional hazard models. Cohort specific RRs were pooled using random-effect models. RESULTS: We documented 277 deaths from suicide. Compared to those consuming <= 1 cup/week of caffeinated coffee (< 8 oz/237 ml), the pooled multivariate RR (95% confidence interval [CI]) of suicide was 0.55 (0.38-0.78) for those consuming 2-3 cups/day and 0.47 (0.27-0.81) for those consuming >= 4 cups/day (P trend < 0.001). The pooled multivariate RR (95% CI) for suicide was 0.75 (0.63-0.90) for each increment of 2 cups/day of caffeinated coffee and 0.77 (0.63-0.93) for each increment of 300 mg/day of caffeine. CONCLUSIONS: These results from three large cohorts support an association between caffeine consumption and lower risk of suicide. PMID- 23819685 TI - In utero exposure and endometriosis. AB - Adverse living and nutritional conditions in utero and in early infancy may influence the risk of diseases in adult life, because fetal growth seems determined by interactions between the environment and the fetal genome and these interactions may determine the risk of postnatal disease and the capacity to react to and cope with the postnatal environment. It has been proven that massive fetal exposure to toxic agents causes an increased incidence of negative outcomes in pregnant women; of particular interest is the association between in utero exposure to toxic agents and the occurrence of endometriosis. There is evidence that exposure to dioxins can facilitate short-term survival of endometrial implants in non-human primates, but there is no solid evidence that it may lead to endometriosis in humans. In the case of diethylstilbestrol, an increased risk of developing endometriosis seems well established, although the mechanisms through which diethylstilbestrol can modify endometrial physiology remain uncertain. Finally, evidence that environmental and specific dietary factors may play a role in increasing the incidence of endometriosis and other pathologic conditions has accumulated over the years. Although the hypothesis may be valid, the most recent investigations have failed to find specific, significant correlations. PMID- 23819686 TI - Addition of a carbohydrate-binding module enhances cellulase penetration into cellulose substrates. AB - INTRODUCTION: Cellulases are of great interest for application in biomass degradation, yet the molecular details of the mode of action of glycoside hydrolases during degradation of insoluble cellulose remain elusive. To further improve these enzymes for application at industrial conditions, it is critical to gain a better understanding of not only the details of the degradation process, but also the function of accessory modules. METHOD: We fused a carbohydrate binding module (CBM) from family 2a to two thermophilic endoglucanases. We then applied neutron reflectometry to determine the mechanism of the resulting enhancements. RESULTS: Catalytic activity of the chimeric enzymes was enhanced up to three fold on insoluble cellulose substrates as compared to wild type. Importantly, we demonstrate that the wild type enzymes affect primarily the surface properties of an amorphous cellulose film, while the chimeras containing a CBM alter the bulk properties of the amorphous film. CONCLUSION: Our findings suggest that the CBM improves the efficiency of these cellulases by enabling digestion within the bulk of the film. PMID- 23819687 TI - Adherence to management guidelines for growth faltering and anaemia in remote dwelling Australian Aboriginal infants and barriers to health service delivery. AB - BACKGROUND: Remote dwelling Aboriginal infants from northern Australia have a high burden of disease and frequently use health services. Little is known about the quality of infant care provided by remote health services. This study describes the adherence to infant guidelines for anaemia and growth faltering by remote health staff and barriers to effective service delivery in remote settings. METHODS: A mixed method study drew data from 24 semi-structured interviews with clinicians working in two remote communities in northern Australia and a retrospective cohort study of Aboriginal infants from these communities, born 2004-2006 (n = 398). Medical records from remote health centres were audited. The main outcome measures were the period prevalence of infants with anaemia and growth faltering and management of these conditions according to local guidelines. Qualitative data assessed clinicians' perspectives on barriers to effective remote health service delivery. RESULTS: Data from 398 health centre records were analysed. Sixty eight percent of infants were anaemic between six and twelve months of age and 42% had documented growth faltering by one year. Analysis of the growth data by the authors however found 86% of infants experienced growth faltering over 12 months. Clinical management and treatment completion was poor for both conditions. High staff turnover, fragmented models of care and staff poorly prepared for their role were barriers perceived by clinicians' to impact upon the quality of service delivery. CONCLUSION: Among Aboriginal infants in northern Australia, malnutrition and anaemia are common and occur early. Diagnosis of growth faltering and clinicians' adherence to management guidelines for both conditions was poor. Antiquated service delivery models, organisation of staff and rapid staff turnover contributed to poor quality of care. Service redesign, education and staff stability must be a priority to redress serious deficits in quality of care provided for these infants. PMID- 23819688 TI - Optical visualization of ultrathin mica flakes on semitransparent gold substrates. AB - We show that optical visualization of ultrathin mica flakes on metallic substrates is viable using semitransparent gold as substrates. This enables to easily localize mica flakes and rapidly estimate their thickness directly on gold substrates by conventional optical reflection microscopy. We experimentally demonstrate it by comparing optical images with atomic force microscopy images of mica flakes on semitransparent gold. Present results open the possibility for simple and rapid characterization of thin mica flakes as well as other thin sheets directly on metallic substrates. PMID- 23819689 TI - Mercury mobilization in a flooded soil by incorporation into metallic copper and metal sulfide nanoparticles. AB - Mercury is a highly toxic priority pollutant that can be released from wetlands as a result of biogeochemical redox processes. To investigate the temperature dependent release of colloidal and dissolved Hg induced by flooding of a contaminated riparian soil, we performed laboratory microcosm experiments at 5, 14, and 23 degrees C. Our results demonstrate substantial colloidal Hg mobilization concomitant with Cu prior to the main period of sulfate reduction. For Cu, we previously showed that this mobilization was due to biomineralization of metallic Cu nanoparticles associated with suspended bacteria. X-ray absorption spectroscopy at the Hg LIII-edge showed that colloidal Hg corresponded to Hg substituting for Cu in the metallic Cu nanoparticles. Over the course of microbial sulfate reduction, colloidal Hg concentrations decreased but continued to dominate total Hg in the pore water for up to 5 weeks of flooding at all temperatures. Transmission electron microscopy (TEM) suggested that Hg became associated with Cu-rich mixed metal sulfide nanoparticles. The formation of Hg containing metallic Cu and metal sulfide nanoparticles in contaminated riparian soils may influence the availability of Hg for methylation or volatilization processes and has substantial potential to drive Hg release into adjacent water bodies. PMID- 23819690 TI - Neonatal self-inflating bags: achieving titrated oxygen delivery using low flows: an experimental study. AB - AIM: To determine delivered O2 concentration (dFiO2) during manual inflations using neonatal self-inflating resuscitation bags (SIBs) at oxygen (O2) flow rates <1 L/min. METHODS: This experimental study, determined dFiO2 during 216 sets of manual inflations at different O2 flow rate (L/min; 0.2, 0.4, 0.6, 0.8, 1.0 and 5.0), controlling peak inspiratory pressures (PIP; cm of H2O; 10-15, 15-20 and 20 25), inflation rates (per min; 30, 40 and 60), with and without O2 reservoir using two SIBs--the Laerdal infant resuscitator (240 mL) and Ambu Mark IV resuscitator (300 mL). A leak proof circuit connecting the SIB in series with pressure transducer, O2 analyzer and test lung was used. All possible combinations were tested four times each. The dFiO2 with each possible combination was compared using generalised estimating equation. RESULTS: The mean dFiO2 with SIB even without reservoirs varied with rates and PIP from 75 to 93% at O2 flow rate of 5 L/min. At 1 L/min flow itself, 65-85% O2 is delivered. The dFiO2 was reduced to approximately 40% with flow of 0.2 L/min, PIP 20-25 cmH2O and inflations 40-60 per min. CONCLUSION: During manual breaths using neonatal SIBs, the delivered O2 concentration of nearly 40% is attained at clinically used inflation pressures and rates by using lower flows. A graded increase in O2 delivery from 40 to 99% was obtained with flow varying from 0.2 to 5 L/min and addition of reservoir. However, even at such low flows, reduction in O2 concentration below 40% was unattained. PMID- 23819691 TI - Fish scales and SNP chips: SNP genotyping and allele frequency estimation in individual and pooled DNA from historical samples of Atlantic salmon (Salmo salar). AB - BACKGROUND: DNA extracted from historical samples is an important resource for understanding genetic consequences of anthropogenic influences and long-term environmental change. However, such samples generally yield DNA of a lower amount and quality, and the extent to which DNA degradation affects SNP genotyping success and allele frequency estimation is not well understood. We conducted high density SNP genotyping and allele frequency estimation in both individual DNA samples and pooled DNA samples extracted from dried Atlantic salmon (Salmo salar) scales stored at room temperature for up to 35 years, and assessed genotyping success, repeatability and accuracy of allele frequency estimation using a high density SNP genotyping array. RESULTS: In individual DNA samples, genotyping success and repeatability was very high (> 0.973 and > 0.998, respectively) in samples stored for up to 35 years; both increased with the proportion of DNA of fragment size > 1000 bp. In pooled DNA samples, allele frequency estimation was highly repeatable (Repeatability = 0.986) and highly correlated with empirical allele frequency measures (Mean Adjusted R2 = 0.991); allele frequency could be accurately estimated in > 95% of pooled DNA samples with a reference group of at least 30 individuals. SNPs located in polyploid regions of the genome were more sensitive to DNA degradation: older samples had lower genotyping success at these loci, and a larger reference panel of individuals was required to accurately estimate allele frequencies. CONCLUSIONS: SNP genotyping was highly successful in degraded DNA samples, paving the way for the use of degraded samples in SNP genotyping projects. DNA pooling provides the potential for large scale population genetic studies with fewer assays, provided enough reference individuals are also genotyped and DNA quality is properly assessed beforehand. We provide recommendations for future studies intending to conduct high throughput SNP genotyping and allele frequency estimation in historical samples. PMID- 23819692 TI - Size-resolved sea spray aerosol particles studied by vibrational sum frequency generation. AB - We present vibrational sum frequency generation (SFG) spectra of the external surfaces and the internal interfaces of size-selected sea spray aerosol (SSA) particles generated at the wave flume of the Scripps Hydraulics Laboratory. Our findings support SSA particle models that invoke the presence of surfactants in the topmost particle layer and indicate that the alkyl chains of surfactant-rich SSA particles are likely to be disordered. Specifically, the SFG spectra suggest that across the range of sizes studied, surfactant-rich SSA particles contain CH oscillators that are subject to molecular orientation distributions that are broader than the narrow molecular distribution functions associated with well ordered and well-aligned alkyl chains. This result is consistent with the interpretation that the permeability of organic layers at SSA particle surfaces to small reactive and nonreactive molecules may be substantial, allowing for much more exchange between reactive and nonreactive species in the gas or the condensed phase than previously thought. The SFG data also suggest that a one component model is likely to be insufficient for describing the SFG responses of the SSA particles. Finally, the similarity of the SFG spectra obtained from the wave flume microlayer and 150 nm-sized SSA particles suggests that the SFG active CH oscillators in the topmost layer of the wave flume and the particle accumulation mode may be in similar chemical environments. Needs for additional research activities are discussed in the context of the results presented. PMID- 23819693 TI - A call to arms: the credibility gap in interventional pain medicine and recommendations for future research. PMID- 23819695 TI - Screened selection design for randomised phase II oncology trials: an example in chronic lymphocytic leukaemia. AB - BACKGROUND: As there are limited patients for chronic lymphocytic leukaemia trials, it is important that statistical methodologies in Phase II efficiently select regimens for subsequent evaluation in larger-scale Phase III trials. METHODS: We propose the screened selection design (SSD), which is a practical multi-stage, randomised Phase II design for two experimental arms. Activity is first evaluated by applying Simon's two-stage design (1989) on each arm. If both are active, the play-the-winner selection strategy proposed by Simon, Wittes and Ellenberg (SWE) (1985) is applied to select the superior arm. A variant of the design, Modified SSD, also allows the arm with the higher response rates to be recommended only if its activity rate is greater by a clinically-relevant value. The operating characteristics are explored via a simulation study and compared to a Bayesian Selection approach. RESULTS: Simulations showed that with the proposed SSD, it is possible to retain the sample size as required in SWE and obtain similar probabilities of selecting the correct superior arm of at least 90%; with the additional attractive benefit of reducing the probability of selecting ineffective arms. This approach is comparable to a Bayesian Selection Strategy. The Modified SSD performs substantially better than the other designs in selecting neither arm if the underlying rates for both arms are desirable but equivalent, allowing for other factors to be considered in the decision making process. Though its probability of correctly selecting a superior arm might be reduced, it still performs reasonably well. It also reduces the probability of selecting an inferior arm. CONCLUSIONS: SSD provides an easy to implement randomised Phase II design that selects the most promising treatment that has shown sufficient evidence of activity, with available R codes to evaluate its operating characteristics. PMID- 23819696 TI - Supplementation of the maternal diet during pregnancy with chocolate and fructose interacts with the high-fat diet of the young to facilitate the onset of metabolic disorders in rat offspring. AB - Obesity and non-alcoholic fatty liver disease are the most common metabolic disorders in society today. Previously, we found that supplementing the maternal diet during pregnancy with chocolate and fructose has negative effects on the well-being of the offspring that were ameliorated if the offspring were fed a normal diet during postnatal life. In the present study, we investigated whether feeding offspring a high-fat diet would augment the maternal programming effects and whether extra protein supply can correct the low birth weight resulting from the chocolate-supplemented maternal diet. Pregnant Sprague-Dawley rats were divided into three groups and fed either standard chow (normal nutrition; NN), chocolate- and fructose-supplemented standard chow with casein sodium (overnutrition; ON) or the supplemented standard chow without casein sodium (malnutrition; MN) throughout pregnancy. Male offspring were weaned on either standard or high-fat chow. Dams in the MN group exhibited moderate weight gain, consumed 50% less protein (P < 0.001) but more carbohydrates during gestation and delivered pups with a 12% lower birth weight (P < 0.05) than pups in the NN group, results that are consistent with previous findings. When fed on a high-fat diet after birth, pups from dams in the MN group (MNHD) had 30% more body fat (P = 0.023) and liver triglyceride (TG) levels that were double (P < 0.01) those in offspring in the other groups, leading to fatty livers in these offspring at 14 weeks of age. Hepatic expression of the PPARalpha, ApoB100, MTTP, CPT1 and SREBP1c genes was significantly downregulated in the MNHD group (P < 0.05 for all), indicating changes in lipid metabolism. Although dams in the ON group exhibited marked gestational weight gain (P < 0.01), they gave birth to normal weight pups that only manifested mild increases in body fat and liver TG content (P < 0.05), without significant changes in the expression of most genes when fed with the high-fat diet. The results suggest that the extra protein supply in the form of casein sodium was able to correct some negative programming effects of the chocolate and fructose supplementation of the maternal diet, which, in conjunction with a high-fat diet in the offspring, may facilitate the onset of metabolic disorders, with impaired liver gene expression possibly a key contributor. PMID- 23819697 TI - Treatment paradigm after uncomplicated cataract surgery: a prospective evaluation. PMID- 23819698 TI - Efficacy and safety of aclidinium bromide compared with placebo and tiotropium in patients with moderate-to-severe chronic obstructive pulmonary disease: results from a 6-week, randomized, controlled Phase IIIb study. AB - BACKGROUND: This randomized, double-blind, Phase IIIb study evaluated the 24-hour bronchodilatory efficacy of aclidinium bromide versus placebo and tiotropium in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). METHODS: Patients received aclidinium 400 MUg twice daily (morning and evening), tiotropium 18 MUg once daily (morning), or placebo for 6 weeks. The primary endpoint was change from baseline in forced expiratory volume in 1 second area under the curve for the 24-hour period post-morning dose (FEV1 AUC0-24) at week 6. Secondary and additional endpoints included FEV1 AUC12-24, COPD symptoms (EXAcerbations of chronic pulmonary disease Tool-Respiratory Symptoms [E-RS] total score and additional symptoms questionnaire), and safety. RESULTS: Overall, 414 patients were randomized and treated (FEV1 1.63 L [55.8% predicted]). Compared with placebo, FEV1 AUC0-24 and FEV1 AUC12-24 were significantly increased from baseline with aclidinium (? = 150 mL and 160 mL, respectively; p < 0.0001) and tiotropium (? = 140 mL and 123 mL, respectively; p < 0.0001) at week 6. Significant improvements in E-RS total scores over 6 weeks were numerically greater with aclidinium (p < 0.0001) than tiotropium (p < 0.05) versus placebo. Only aclidinium significantly reduced the severity of early-morning cough, wheeze, shortness of breath, and phlegm, and of nighttime symptoms versus placebo (p < 0.05). Adverse-event (AE) incidence (28%) was similar between treatments. Few anticholinergic AEs (<1.5%) or serious AEs (<3%) occurred in any group. CONCLUSIONS: Aclidinium provided significant 24-hour bronchodilation versus placebo from day 1 with comparable efficacy to tiotropium after 6 weeks. Improvements in COPD symptoms were consistently numerically greater with aclidinium versus tiotropium. Aclidinium was generally well tolerated. PMID- 23819700 TI - Partial and radical nephrectomy provide comparable long-term cancer control for T1b renal cell carcinoma. AB - OBJECTIVES: To examine utilization rates of partial nephrectomy relative to radical nephrectomy for T1b renal cell carcinoma in contemporary years, to identify sociodemographic and disease characteristics associated with partial nephrectomy use, and to compare effectiveness of partial versus radical nephrectomy with respect to cancer control. METHODS: Using the Surveillance, Epidemiology, and End Results database, 16,333 patients treated with partial or radical nephrectomy for T1bN0M0 renal cell carcinoma between 1988 and 2008 were identified. Logistic regression models were carried out to identify determinants of partial nephrectomy. Subsequently, cumulative incidence rates of cancer specific and other-cause mortality between partial and radical nephrectomy were assessed, within the matched cohort. Furthermore, competing-risks regression analyses were used for prediction of cancer-specific mortality, after adjusting for other-cause mortality, and vice versa. RESULTS: The utilization rate of partial nephrectomy increased from 1.2% in 1988 to 15.9% in 2008 (P < 0.001). Younger individuals, smaller tumors, persons of black race, as well as men, were more likely to be treated with partial nephrectomy in the current cohort (all P <= 0.002). In the post-propensity cohort, the 5- and 10-year cancer-specific mortality rates were 4.4 and 6.1% for partial versus 6.0 and 10.4% for radical nephrectomy, respectively (P = 0.03). Competing-risks regression analyses showed that nephrectomy type was not statistically significantly associated with cancer specific mortality, even after adjusting for other-cause mortality (hazard ratio 0.89, P = 0.5). CONCLUSIONS: Despite providing a comparable cancer control, the use of partial over radical nephrectomy for T1b renal cell carcinoma in USA has remained limited in recent years. PMID- 23819699 TI - Improving health information systems for decision making across five sub-Saharan African countries: Implementation strategies from the African Health Initiative. AB - BACKGROUND: Weak health information systems (HIS) are a critical challenge to reaching the health-related Millennium Development Goals because health systems performance cannot be adequately assessed or monitored where HIS data are incomplete, inaccurate, or untimely. The Population Health Implementation and Training (PHIT) Partnerships were established in five sub-Saharan African countries (Ghana, Mozambique, Rwanda, Tanzania, and Zambia) to catalyze advances in strengthening district health systems. Interventions were tailored to the setting in which activities were planned. COMPARISONS ACROSS STRATEGIES: All five PHIT Partnerships share a common feature in their goal of enhancing HIS and linking data with improved decision-making, specific strategies varied. Mozambique, Ghana, and Tanzania all focus on improving the quality and use of the existing Ministry of Health HIS, while the Zambia and Rwanda partnerships have introduced new information and communication technology systems or tools. All partnerships have adopted a flexible, iterative approach in designing and refining the development of new tools and approaches for HIS enhancement (such as routine data quality audits and automated troubleshooting), as well as improving decision making through timely feedback on health system performance (such as through summary data dashboards or routine data review meetings). The most striking differences between partnership approaches can be found in the level of emphasis of data collection (patient versus health facility), and consequently the level of decision making enhancement (community, facility, district, or provincial leadership). DISCUSSION: Design differences across PHIT Partnerships reflect differing theories of change, particularly regarding what information is needed, who will use the information to affect change, and how this change is expected to manifest. The iterative process of data use to monitor and assess the health system has been heavily communication dependent, with challenges due to poor feedback loops. Implementation to date has highlighted the importance of engaging frontline staff and managers in improving data collection and its use for informing system improvement. Through rigorous process and impact evaluation, the experience of the PHIT teams hope to contribute to the evidence base in the areas of HIS strengthening, linking HIS with decision making, and its impact on measures of health system outputs and impact. PMID- 23819702 TI - Being a woman researcher in an Anatolian village. AB - This essay represents the first editorial of the series "Recollections, Reflections, and Revelations: Ethnobiologists and their First Time in the Field". In this memoir, the author details the evolvement and intellectual progression of her research focusing on wild food plant consumption within a remote community in the high steppes of Central Anatolia during the early Nineties. The author conveys a human learning journey as a woman and an ethnobiologist, reflecting on the methodological bottlenecks and solutions during her first ethnographic experience in the field. PMID- 23819703 TI - Photochemistry and Photobiology. Editorial. PMID- 23819701 TI - Promoting healthy weight in primary school children through physical activity and nutrition education: a pragmatic evaluation of the CHANGE! randomised intervention study. AB - BACKGROUND: This pragmatic evaluation investigated the effectiveness of the Children's Health, Activity and Nutrition: Get Educated! (CHANGE!) Project, a cluster randomised intervention to promote healthy weight using an educational focus on physical activity and healthy eating. METHODS: Participants (n = 318, aged 10-11 years) from 6 Intervention and 6 Comparison schools took part in the 20 weeks intervention between November 2010 and March/April 2011. This consisted of a teacher-led curriculum, learning resources, and homework tasks. Primary outcome measures were waist circumference, body mass index (BMI), and BMI z scores. Secondary outcomes were objectively-assessed physical activity and sedentary time, and food intake. Outcomes were assessed at baseline, at post intervention (20 weeks), and at follow-up (30 weeks). Data were analysed using 2 level multi-level modelling (levels: school, student) and adjusted for baseline values of the outcomes and potential confounders. Differences in intervention effect by subgroup (sex, weight status, socio-economic status) were explored using statistical interaction. RESULTS: Significant between-group effects were observed for waist circumference at post-intervention (beta for intervention effect =-1.63 (95% CI = -2.20, -1.07) cm, p<0.001) and for BMI z-score at follow up (beta=-0.24 (95% CI = -0.48, -0.003), p=0.04). At follow-up there was also a significant intervention effect for light intensity physical activity (beta=25.97 (95% CI = 8.04, 43.89) min, p=0.01). Interaction analyses revealed that the intervention was most effective for overweight/obese participants (waist circumference: beta=-2.82 (95% CI = -4.06, -1.58) cm, p<0.001), girls (BMI: beta= 0.39 (95% CI = -0.81, 0.03) kg/m2, p=0.07), and participants with higher family socioeconomic status (breakfast consumption: beta=8.82 (95% CI = 6.47, 11.16), p=0.07). CONCLUSIONS: The CHANGE! intervention positively influenced body size outcomes and light physical activity, and most effectively influenced body size outcomes among overweight and obese children and girls. The findings add support for the effectiveness of combined school-based physical activity and nutrition interventions. Additional work is required to test intervention fidelity and the sustained effectiveness of this intervention in the medium and long term. TRIAL REGISTRATION: Current Controlled Trials ISRCTN03863885. PMID- 23819704 TI - Multiple pathways for the primary step of the spiropyran photochromic reaction: a CASPT2//CASSCF study. AB - CASSCF and CASPT2 studies on the reaction mechanism of the photochromic ring opening process of a spiropyran (SP) (1',3',3'-trimethylspiro-[2H-1-benzopyran 2,2'-indoline], also known as BIPS) have been performed and possible excited state C-O (and C-N) bond cleavage pathways and S1-to-S0 nonadiabatic transition channels have been explored. (1) The C-O bond dissociation in SP does not follow a conical-intersection mechanism that has been proposed in a model study with a simplified benzopyran. The CASSCF-optimized crossing points are actually avoided crossings with a large S1-S0 energy gap at the CASPT2 level; thus, they could not act as efficient S1-to-S0 funnels. (2) C-O bond cleavage paths on S1 leading to both the CCC (cis-cis-cis with respect to the configuration around alpha, beta, gamma) and TCC (trans-cis-cis) intermediates of merocyanine (MC) are barrierless, in line with the experimentally observed ultrafast formation of MC. (3) An unexpected low-energy hydrogen-out-of-plane (HOOP) valley on the (pi->sigma*) surface was located not far from the C-O bond cleavage path and was suggested to be an efficient S1-to-S0 nonadiabatic decay channel. Triggered by the active HOOP mode, the molecule can easily access the S1-HOOP valley and then make a transition to the S0 surface through the narrow S1-S0 gap that exists in an extended region. Nonadiabatic decay through a conical intersection on C-N dissociation path as well as the HOOP funnel is responsible for high internal conversion yields of SP. These findings shedding light on the complex mechanism of SP-MC interconversion provide fundamental information for design spiropyran based photochromic devices. PMID- 23819705 TI - Development and application of a high throughput carbohydrate profiling technique for analyzing plant cell wall polysaccharides and carbohydrate active enzymes. AB - BACKGROUND: Plant cell wall polysaccharide composition varies substantially between species, organs and genotypes. Knowledge of the structure and composition of these polysaccharides, accompanied by a suite of well characterised glycosyl hydrolases will be important for the success of lignocellulosic biofuels. Current methods used to characterise enzymatically released plant oligosaccharides are relatively slow. RESULTS: A method and software was developed allowing the use of a DNA sequencer to profile oligosaccharides derived from plant cell wall polysaccharides (DNA sequencer-Assisted Saccharide analysis in High throughput, DASH). An ABI 3730xl, which can analyse 96 samples simultaneously by capillary electrophoresis, was used to separate fluorophore derivatised reducing mono- and oligo-saccharides from plant cell walls. Using electrophoresis mobility markers, oligosaccharide mobilities were standardised between experiments to enable reproducible oligosaccharide identification. These mobility markers can be flexibly designed to span the mobilities of oligosaccharides under investigation, and they have a fluorescence emission that is distinct from that of the saccharide labelling. Methods for relative and absolute quantitation of oligosaccharides are described. Analysis of a large number of samples is facilitated by the DASHboard software which was developed in parallel. Use of this method was exemplified by comparing xylan structure and content in Arabidopsis thaliana mutants affected in xylan synthesis. The product profiles of specific xylanases were also compared in order to identify enzymes with unusual oligosaccharide products. CONCLUSIONS: The DASH method and DASHboard software can be used to carry out large-scale analyses of the compositional variation of plant cell walls and biomass, to compare plants with mutations in plant cell wall synthesis pathways, and to characterise novel carbohydrate active enzymes. PMID- 23819706 TI - Asthma diagnosis and treatment - 1002. FEF25-75%: a more sensitive indicator in the early detection of asthma. PMID- 23819707 TI - The plasma concentration of VEGF, HE4 and CA125 as a new biomarkers panel in different stages and sub-types of epithelial ovarian tumors. AB - BACKGROUND: VEGF may play a role in the pathogenesis of cancer disease, for example in cell growth, proliferation and angiogenesis. In this study, we investigated plasma levels of this cytokine in comparison to plasma levels of a new biomarker - HE4 and the established tumor marker CA125 in ovarian cancer patients (100) as compared to control groups: patients with a benign ovarian tumor (80) and healthy subjects (50). METHODS: Plasma levels of VEGF were determined by ELISA, HE4 and CA125 by CMIA method. RESULTS: The results showed that levels of VEGF, CA125 and HE4 were significantly higher in ovarian cancer (OC) patients as compared to the both control groups. VEGF has demonstrated as high as comparative markers values of the diagnostic sensitivity (SE), specificity (SP), the predictive values of positive and negative test results (PV PR, PV-NR), and the area under the ROC curve (AUC) in early stages of cancer tested groups. The combined use of parameters studied resulted in the increase in the diagnostic criteria values and the AUC. CONCLUSIONS: These findings suggest the usefulness of VEGF in the early diagnostics of ovarian cancer, especially in combination with CA125 and HE4, as a new biomarkers panel. Additionally, VEGF is the most useful tool in the diagnostics of locally advanced ovarian cancer without metastases. Investigated cytokine presented similar to HE4 usefulness in differentiation of OC according to its histopathlogical sub-type, and could be used especially in the diagnostics of endometrioid epithelial OC. PMID- 23819709 TI - Fabrication of inverted zinc oxide photonic crystal using sol-gel solution by spin coating method. AB - Inverted zinc oxide photonic crystal structures were fabricated from polystyrene sphere (PSS) template using the sol-gel solution of ZnO by spin-coating method. It is easily able to control and fabricate the photonic crystal structures using the self-organized PSS with a size of 193 nm. The inverted ZnO photonic crystal structures observed show the (111) tendency of the hexagonal compact arrangement formation. The resulting structures possess the photonic band gaps in the near ultraviolet range and exhibit an enhanced photoluminescence spectrum. The technology can effectively increase the light output intensity or efficiency for the applications of optoelectronic devices. PMID- 23819708 TI - The first engagement of partners in the Euprymna scolopes-Vibrio fischeri symbiosis is a two-step process initiated by a few environmental symbiont cells. AB - We studied the Euprymna scolopes-Vibrio fischeri symbiosis to characterize, in vivo and in real time, the transition between the bacterial partner's free-living and symbiotic life styles. Previous studies using high inocula demonstrated that environmental V. fischeri cells aggregate during a 3 h period in host-shed mucus along the light organ's superficial ciliated epithelia. Under lower inoculum conditions, similar to the levels of symbiont cells in the environment, this interaction induces haemocyte trafficking into these tissues. Here, in experiments simulating natural conditions, microscopy revealed that at 3 h following first exposure, only ~ 5 V. fischeri cells aggregated on the organ surface. These cells associated with host cilia and induced haemocyte trafficking. Symbiont viability was essential and mutants defective in symbiosis initiation and/or production of certain surface features, including the Mam7 protein, which is implicated in host cell attachment of V. cholerae, associated normally with host cilia. Studies with exopolysaccharide mutants, which are defective in aggregation, suggest a two-step process of V. fischeri cell engagement: association with host cilia followed by aggregation, i.e. host cell symbiont interaction with subsequent symbiont-symbiont cell interaction. Taken together, these data provide a new model of early partner engagement, a complex model of host-symbiont interaction with exquisite sensitivity. PMID- 23819710 TI - Nucleation dynamics of active particles. AB - We present a model of a collection of active and adhesive Brownian particles that are capable of aggregation. Besides the mechanical interaction between particles, a simple active dynamics term (motility) is included to provide an active movement. At a given instant, each particle is either in an active (swim) or unanimated (stop) state, which is controlled by a random process. The model includes important features that are inspired by the phenomenon of biological cell-cell association. One feature is the mean motility that is related to the percentage of the particle being active and the maximum swimming speed. Another feature is the stochastic nature of switching between the swim and stop state. We explored how these key features affect the nucleation dynamics and the stability of the aggregates using simulations. Interestingly, particles can change their collective behavior by solely altering the frequency of switching between the swim and stop state while keeping the mean motility unchanged. These results provide insight into how motor-driven forces can be utilized by active biological systems to modulate the single-to-cluster transition efficiently. A dimensionless parameter is also proposed to measure the overall strength of the nonequilibrium effect on active particles. PMID- 23819711 TI - Total synthesis and biological activity of natural product Urukthapelstatin A. AB - Herein we report the first total synthesis of the natural product Urkuthaplestatin A (Ustat A) utilizing a convergent synthetic strategy. The characterization and biological activity match those of the previously published natural product. Interestingly, several intermediates, including the linear and serine cyclized precursors, show a 100-fold decrease in cytotoxicity, with IC50's in the low micromolar range. These data indicate that the rigidity and the consecutive aromatic heterocyclic system are responsible for the biological activity. PMID- 23819713 TI - Harmonized guidance for disseminated intravascular coagulation from the International Society on Thrombosis and Haemostasis and the current status of anticoagulant therapy in Japan. PMID- 23819714 TI - Using a squat toilet: aging in a developing country. PMID- 23819717 TI - Assessing heart failure in long-term care facilities. PMID- 23819719 TI - Vibrational spectroscopy of picolinamide and water: from dimers to condensed phase. AB - Because of the presence of polar groups in picolinamide, its aqueous solvation is characterized by formation of multiple hydrogen bonds, which are responsible for differences in vibrational spectra of picolinamide in the gas phase and its aqueous solution. In this contribution, we try to identify dominant interactions between the solute and the solvent molecules that are the origin of the observed spectral changes. For this purpose, we analyzed the vibrational properties of picolinamide (a single molecule and also embedded in the environment described with an implicit solvent model) and picolinamide-water dimers: by comparing their vibrational frequencies with experimentally observed values of picolinamides' aqueous solution and by analyzing the computed anharmonic force constants, it is possible to recognize whether and in which way the solvent causes changes in the vibrational properties of the title compound. Calculations performed on the picolinamide three-hydrate confirm conclusions obtained by analyzing monohydrates. PMID- 23819721 TI - A patient-centred approach to health service delivery: improving health outcomes for people with chronic illness. AB - BACKGROUND: The Wagner Model provides a framework that can help to facilitate health system transition towards a chronic care oriented model. Drawing on elements of this framework as well as health policy related to patient centred care, we describe the health needs of patients with chronic illness and compare these with services which should ideally be provided by a patient-centred health system. This paper aims to increase understanding of the challenges faced by chronically ill patients and family carers in relation to their experiences with the health care system and health service providers. METHOD: We interviewed patients, carers and health care professionals (HCPs) about the challenges faced by people living with complicated diabetes, chronic heart failure or chronic obstructive pulmonary disease. RESULTS: Patients indicated that they had a range of concerns related to the quality of health care encounters with health care professionals (HCPs), with these concerns being expressed as needs or wants. These included: 1) the need for improved communication and information delivery on the part of HCPs; 2) well organised health services and reduced waiting times to see HCPs; 3) help with self care; 4) greater recognition among professionals of the need for holistic and continuing care; and 5) inclusion of patients and carers in the decision making processes. CONCLUSIONS: In order to address the challenges faced by people with chronic illness, health policy must be more closely aligned with the identified needs and wants of people affected by chronic illness than is currently the case. PMID- 23819720 TI - Comparative study of immune regulatory properties of stem cells derived from different tissues. AB - Allogeneic stem cell (SC)-based therapy is a promising tool for the treatment of a range of human degenerative and inflammatory diseases. Many reports highlighted the immune modulatory properties of some SC types, such as mesenchymal stromal cells (MSCs), but a comparative study with SCs of different origin, to assess whether immune regulation is a general SC property, is still lacking. To this aim, we applied highly standardized methods employed for MSC characterization to compare the immunological properties of bone marrow-MSCs, olfactory ectomesenchymal SCs, leptomeningeal SCs, and three different c-Kit-positive SC types, that is, amniotic fluid SCs, cardiac SCs, and lung SCs. We found that all the analyzed human SCs share a common pattern of immunological features, in terms of expression of activation markers ICAM-1, VCAM-1, HLA-ABC, and HLA-DR, modulatory activity toward purified T, B, and NK cells, lower immunogenicity of inflammatory-primed SCs as compared to resting SCs, and indoleamine-2,3 dioxygenase-activation as molecular inhibitory pathways, with some SC type related peculiarities. Moreover, the SC types analyzed exert an anti-apoptotic effect toward not-activated immune effector cells (IECs). In addition, we found that the inhibitory behavior is not a constitutive property of SCs, but is acquired as a consequence of IEC activation, as previously described for MSCs. Thus, immune regulation is a general property of SCs and the characterization of this phenomenon may be useful for a proper therapeutic use of SCs. PMID- 23819722 TI - Serum amyloid A stimulates cultured endothelial cells to migrate and proliferate: inhibition by the multikinase inhibitor BIBF1120. AB - In the present study, we tested whether serum amyloid A (SAA) protein, an established biomarker of inflammation, also plays a role in stimulating neovascularization. To evaluate this possibility, human carotid artery endothelial (HCtAE) cells were cultured and cellular migration and the proinflammatory and/or thrombotic activity of SAA (0, 1 or 10 MUg/mL) on vascular endothelial cells was verified by determining gene regulation relative to control (in the absence of SAA). Exposure of HCtAE cells to SAA increased expression of the transcription factor nuclear factor-kappaB (NFKB), tumour necrosis factor (TNF) and pro-coagulative tissue factor (F3), and stimulated phosphorylation of the P65 subunit of the NFKB complex. Enhanced production of TNF and NFKB was paralleled by increased vascular endothelial growth factor (VEGF) mRNA and protein expression, as demonstrated by quantitative polymerase chain reaction, western blotting and ELISA. Administration of 10 MUg/mL SAA enhanced endothelial cell migration (1.6-fold vs control), stimulated regrowth of HCtAE cells after mechanical injury (~1.2-fold vs control) and increased endothelial tube formation relative to control after 6 h. The SAA-mediated enhancement of endothelial cell migration, proliferation and tube formation were markedly inhibited by pretreatment of HCtAE cells with the multi-angiokinase receptor inhibitor BIBF1120 (100 nmol/L), although SAA-stimulated gene responses for F3 and NFKB were unaffected by 100 nmol/L BIBF1120 pretreatment. Overall, BIBF1120 inhibited the pro-angiogenic activity of SAA on vascular endothelial cells in this experimental model of inflammation. PMID- 23819723 TI - Effectiveness of the ACA (Availability, Current issues and Anticipation) training programme on GP-patient communication in palliative care; a controlled trial. AB - BACKGROUND: Communicating effectively with palliative care patients has been acknowledged to be somewhat difficult, but little is known about the effect that training general practitioners (GPs) in specific elements of communication in palliative care might have. We hypothesized that GPs exposed to a new training programme in GP-patient communication in palliative care focusing on availability of the GP for the patient, current issues the GP should discuss with the patient and anticipation by the GP of various scenarios (ACA), would discuss more issues and become more skilled in their communication with palliative care patients. METHODS: In this controlled trial among GPs who attended a two-year Palliative Care Peer Group Training Course in the Netherlands only intervention GPs received the ACA training programme. To evaluate the effect of the programme a content analysis (Roter Interaction Analysis System) was performed of one videotaped 15 minute consultation of each GP with a simulated palliative care patient conducted at baseline, and one at 12 months follow-up. Both how the GP communicated with the patient ('availability') and the number of current and anticipated issues the GP discussed with the patient were measured quantitatively. We used linear mixed models and logistic regression models to evaluate between-group differences over time. RESULTS: Sixty-two GPs were assigned to the intervention and 64 to the control group. We found no effect of the ACA training programme on how the GPs communicated with the patient or on the number of issues discussed by GPs with the patient. The total number of issues discussed by the GPs was eight out of 13 before and after the training in both groups. CONCLUSION: The ACA training programme did not influence how the GPs communicated with the simulated palliative care patient or the number of issues discussed by the GPs in this trial. Further research should evaluate whether this training programme is effective for GPs who do not have a special interest in palliative care and whether studies using outcomes at patient level can provide more insight into the effectiveness of the ACA training programme. TRIAL REGISTRATION: Current Controlled Trials ISRCTN56722368. PMID- 23819724 TI - Discontinuation rates and inter-injection interval for repeated intravesical botulinum toxin type A injections for detrusor overactivity. AB - OBJECTIVE: To report discontinuation rates, inter-injection interval and complication rates after repeated intravesical botulinum toxin type A for the treatment of detrusor overactivity. METHOD: Patients with urodyamically proven detrusor overactivity who had two or more botulinum toxin type A injections in the period 2004-2011 at Freeman Hospital, Newcastle Upon Tyne, UK, were considered for the present study. Discontinuation rates, complication rates and interval between botulinum toxin type A treatments were retrospectively analyzed. RESULTS: Overall, 125 patients (median age 53 years, range 19-83 years) were included in the analysis. The female-to-male ratio was 2.4:1 and median follow up was 38 months. A total of 96 patients had idiopathic detrusor overactivity, whereas 29 had neurogenic detrusor overactivity. A total of 667 injections were carried out, with 125 patients receiving two injections, 60 receiving three injections, 28 receiving four injections, 14 receiving five injections, three receiving six injections, three receiving seven injections and two receiving eight injections. The mean interval (+/-standard deviation) between the first and second injection (n = 125) was 17.6 months (+/-10.4), between the second and third (n = 60) was 15.7 +/- 7.4 months, between the third and fourth (n = 28) was 15.4 +/- 8.6 months, and between the fourth and subsequent injections (n = 22) was 11.6 +/- 4.5 months. A total of 26% required intermittent catheterization, and 18% developed recurrent urinary tract infections. There was a discontinuation rate of 25% at 60 months. CONCLUSION: Repeated botulinum toxin type A injections represent a safe and effective method for managing patients with idiopathic detrusor overactivity and neurogenic detrusor overactivity. We have shown that the inter-injection interval remains unchanged up to five injections. PMID- 23819725 TI - Causes of blindness and visual impairment in the interior Maroon population in the Republic of Suriname. PMID- 23819726 TI - Pd-catalyzed cascade crossover annulation of o-alkynylarylhalides and diarylacetylenes leading to dibenzo[a,e]pentalenes. AB - A novel and selective Pd-catalyzed cascade crossover-annulation of o alkynylarylhalides and diarylacetylenes for the synthesis of dibenzo[a,e]pentalenes has been reported. Various arylacetylenes with a wide range of functional groups were tolerated, producing the corresponding multisubstituted dibenzopentalenes with the different substituents on the aromatic rings in good to high yields under the optimized reaction conditions. The reaction proceeds through a Pd-catalyzed cascade carbopalladation and C-H activation. The use of the combined DBU and CsOPiv bases is crucial for the successful implementation of the present cross-annulation. PMID- 23819727 TI - Statins in cardiometabolic disease: what makes pitavastatin different? AB - The term cardiometabolic disease encompasses a range of lifestyle-related conditions, including Metabolic syndrome (MetS) and type 2 diabetes (T2D), that are characterized by different combinations of cardiovascular (CV) risk factors, including dyslipidemia, abdominal obesity, hypertension, hyperglycemia/insulin resistance, and vascular inflammation. These risk factors individually and interdependently increase the risk of CV and cerebrovascular events, and represent one of the biggest health challenges worldwide today. CV diseases account for almost 50% of all deaths in Europe and around 30% of all deaths worldwide. Furthermore, the risk of CV death is increased twofold to fourfold in people with T2D. Whilst the clinical management of CV disease has improved in Western Europe, the pandemic of obesity and T2D reduces the impact of these gains. This, together with the growing, aging population, means the number of CV deaths is predicted to increase from 17.1 million worldwide in 2004 to 23.6 million in 2030. The recommended treatment for MetS is lifestyle change followed by treatment for the individual risk factors. Numerous studies have shown that lowering low-density lipoprotein-cholesterol (LDL-C) levels using statins can significantly reduce CV risk in people with and without T2D or MetS. However, the risk of major vascular events in those attaining the maximum levels of LDL-C reduction is only reduced by around one-third, which leaves substantial residual risk. Recent studies suggest that low high-density lipoprotein-cholesterol (HDL C) (<1 .0 mmol/l; 40 mg/dl) and high triglyceride levels (>=1.7 mmol/l; 150 mg/dl) are independent risk factors for CV disease and that the relationship between HDL-C and CV risk persists even when on-treatment LDL-C levels are low (<1.7 mmol/l; 70 mg/dl). European guidelines highlight the importance of reducing residual risk by targeting these risk factors in addition to LDL-C. This is particularly important in patients with T2D and MetS because obesity and high levels of glycated hemoglobin are directly related to low levels of HDL-C and high triglyceride. Although most statins have a similar low-density lipoprotein lowering efficacy, differences in chemical structure and pharmacokinetic profile can lead to variations in pleiotropic effects (for example, high-density lipoprotein-elevating efficacy), adverse event profiles, and drug-drug interactions. The choice of statin should therefore depend on the needs of the individual patient. The following reviews will discuss the potential benefits of pitavastatin versus other statins in the treatment of patients with dyslipidemia and MetS or T2D, focusing on its effects on HDL-C quantity and quality, its potential impact on atherosclerosis and CV risk, and its metabolic characteristics that reduce the risk of drug interactions. Recent controversies surrounding the potentially diabetogenic effects of statins will also be discussed. PMID- 23819729 TI - The role of traditional medicine practice in primary health care within Aboriginal Australia: a review of the literature. AB - The practice of traditional Aboriginal medicine within Australia is at risk of being lost due to the impact of colonisation. Displacement of people from traditional lands as well as changes in family structures affecting passing on of cultural knowledge are two major examples of this impact. Prior to colonisation traditional forms of healing, such as the use of traditional healers, healing songs and bush medicines were the only source of primary health care. It is unclear to what extent traditional medical practice remains in Australia in 2013 within the primary health care setting, and how this practice sits alongside the current biomedical health care model. An extensive literature search was performed from a wide range of literature sources in attempt to identify and examine both qualitatively and quantitatively traditional medicine practices within Aboriginal Australia today. Whilst there is a lack of academic literature and research on this subject the literature found suggests that traditional medicine practice in Aboriginal Australia still remains and the extent to which it is practiced varies widely amongst communities across Australia. This variation was found to depend on association with culture and beliefs about disease causation, type of illness presenting, success of biomedical treatment, and accessibility to traditional healers and bush medicines. Traditional medicine practices were found to be used sequentially, compartmentally and concurrently with biomedical healthcare. Understanding more clearly the role of traditional medicine practice, as well as looking to improve and support integrative and governance models for traditional medicine practice, could have a positive impact on primary health care outcomes for Aboriginal Australia. PMID- 23819730 TI - Percutaneous cervical cordotomy for the management of pain from cancer: a prospective review of 45 cases. AB - BACKGROUND: Percutaneous cervical cordotomy (PCC) is a well recognized but infrequently performed procedure for the relief of unilateral intractable pain from malignancy. There is a paucity of data regarding efficacy and safety of PCC. OBJECTIVES: The study's objectives were to demonstrate the efficacy and safety of PCC in cancer pain. DESIGN: The study was a prospective review of 45 cases undergoing PCC at a tertiary referral center over a three-year period. SETTINGS/SUBJECTS: All patients were suffering from severe, refractory unilateral pain secondary to malignancy with poor pain relief or intolerable side effects of conventional analgesics including opioids and adjuvants. MEASUREMENTS: Variables recorded preprocedure, at 2 days, and at 28 days postprocedure were numerical rating scale for maximum and average pain, oral morphine equivalent dose, and global impression of change. Adverse events and survival postprocedure were recorded. RESULTS: Prospective data was obtained in 45 patients. Survival postprocedure ranged from 7 days to 33 months. There was a significant reduction from baseline in pain scores at 2 days and at 28 days postprocedure. Thirty-two patients experienced significant pain relief--average numerical rating scale (NRS) of zero--on day 2. Improvement in pain scores was sustained at 28 days. There were no serious adverse events observed such as respiratory failure. CONCLUSIONS: PCC is a safe and highly effective procedure to treat intractable unilateral cancer pain. It offers significant advantages over other pain control methods. Patient selection and attention to detail is paramount for a successful outcome. PMID- 23819728 TI - Effects of respiratory and non-respiratory factors on disability among older adults with airway obstruction: the Cardiovascular Health Study. AB - BACKGROUND: High rates of disability associated with chronic airway obstruction may be caused by impaired pulmonary function, pulmonary symptoms, other chronic diseases, or systemic inflammation. METHODS: We analyzed data from the Cardiovascular Health Study, a longitudinal cohort of 5888 older adults. Categories of lung function (normal; restricted; borderline, mild-moderate, and severe obstruction) were delineated by baseline spirometry (without bronchodilator). Disability-free years were calculated as total years alive and without self-report of difficulty performing &gammatau;1 Instrumental Activities of Daily Living over 6 years of follow-up. Using linear regression, we compared disability-free years by lung disease category, adjusting for demographic factors, body mass index, smoking, cognition, and other chronic co-morbidities. Among participants with airflow obstruction, we examined the association of respiratory factors (FEV1 and dyspnea) and non-respiratory factors (ischemic heart disease, congestive heart failure, diabetes, muscle weakness, osteoporosis, depression and cognitive impairment) on disability-free years. RESULTS: The average disability free years were 4.0 out of a possible 6 years. Severe obstruction was associated with 1 fewer disability-free year compared to normal spirometry in the adjusted model. For the 1,048 participants with airway obstruction, both respiratory factors (FEV1 and dyspnea) and non-respiratory factors (heart disease, coronary artery disease, diabetes, depression, osteoporosis, cognitive function, and weakness) were associated with decreased disability-free years. CONCLUSIONS: Severe obstruction is associated with greater disability compared to patients with normal spirometery. Both respiratory and non respiratory factors contribute to disability in older adults with abnormal spirometry. PMID- 23819731 TI - Factors influencing health related quality of life in cancer patients with bone metastases. AB - OBJECTIVE: Health related quality of life (HRQOL) is a multidimensional concept that is especially important for cancer patients with bone metastases, as maintaining and improving HRQOL is often the main focus of treatment. This study aims to determine factors that may influence HRQOL, which may in turn influence treatment and care of patients. METHODS: Patients (n=396) completed the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Bone Metastases module (BM22) at baseline. The EORTC QLQ-BM22 consists of four scales: painful site (PS), pain characteristics (PC), functional interference (FI), and psychosocial aspect (PA) scales. EORTC QLQ-BM22 data, together with sociodemographic and medical factors were analyzed by univariate analysis of variance (ANOVA). Items of significance were determined through backward selection, which were then put through multivariate analysis to determine further significance. RESULTS: Through ANOVA analysis, KPS>80 and breast primary histology were predictive of better HRQOL in the PS scale, while KPS>80, female gender, and breast primary histology were predictive of better HRQOL in the PC and FI scales. KPS>80 and prostate primary histology were predictive of better HRQOL in the PA scale. KPS>80 and primary cancer site were confirmed as significant predictive factors in multivariate analysis. RECOMMENDATIONS: This study identified baseline factors of gender, performance status, and primary histology as determinants of HRQOL in patients with bone metastases. Further study focusing on current treatment (chemotherapy, bisphosphonates, and radiotherapy) and spiritual well-being may identify additional factors affecting HRQOL. Understanding the influence of these factors will allow health care professionals to provide more effective palliative care. PMID- 23819732 TI - Catalytic asymmetric hydrophosphonylation of ketimines. AB - Catalytic asymmetric hydrophosphonylation of aromatic and aliphatic N thiophosphinoyl ketimines with dialkyl phosphite was efficiently promoted by as little as 0.5 mol% of catalyst loading at ambient temperature. The catalyst can be recovered for repeated use, and facile removal of the thiophosphinoyl group allowed for ready access to the phosphonic acid analogue of enantioenriched alpha,alpha-disubstituted alpha-amino acids. PMID- 23819733 TI - A tandem organocatalytic alpha-chlorination-aldol reaction that proceeds with dynamic kinetic resolution: a powerful tool for carbohydrate synthesis. AB - A tandem, proline-catalyzed alpha-chlorination/aldol reaction is described that involves a dynamic kinetic resolution of alpha-chloroaldehyde intermediates. The resulting syn-chlorohydrins are produced with good to excellent diastereoselectivity in high enantiopurity and provide new opportunities for the synthesis of carbohydrates. PMID- 23819734 TI - Replacing manual sphygmomanometers with automated blood pressure measurement in routine clinical practice. AB - 1. Conventional manual measurement of blood pressure (BP) in clinical practice is no longer considered to be the best method for evaluating a patient's BP status. Home BP and 24 h ambulatory BP monitoring are now recommended for the diagnosis and management of hypertension. 2. Recent studies provide an alternative to conventional office BP, namely automated office (AO) BP, which involves multiple BP readings taken with a fully automated device with the patient resting quietly alone. Automated office BP is preferable to routine manual office BP in that it exhibits improved accuracy and a stronger relationship to both ambulatory BP and target organ damage. 3. Having the patient alone eliminates conversation between the patient and the observer, a cause of 'white coat hypertension'. The use of an automated device improves accuracy, reduces digit preference, minimizes observer bias and facilitates the recording of multiple BP readings. 4. Comparative BP data obtained in clinical studies in both research settings and routine community practice support the use of a cut-off point of 135/85 mmHg for defining hypertension using AOBP, which is the same cut-off point currently recommended for awake ambulatory BP and home BP. 5. Reduction of the white coat response using AOBP should reduce the need to monitor patients with ambulatory BP and home BP after initiation of antihypertensive therapy. There is now sufficient evidence to consider replacing manual office BP with AOBP in routine clinical practice. PMID- 23819736 TI - Using Internet Snapshot Surveys to Enhance Our Understanding of the Availability of the Novel Psychoactive Substance Alpha-methyltryptamine (AMT). AB - Alpha-methyltryptamine (AMT) is a novel psychoactive substance available over the Internet. This study used European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) Internet snapshot methodology to investigate the availability and cost of AMT in March/October 2012. From March to October 2012, there was a decrease in the number of Internet sites selling AMT (44 to 31). AMT powder was cheaper in "bulk" (100 g) than in "recreational-user" (100 mg) quantities, and there was a decrease in price. Data from Internet snapshot surveys complement and allow triangulation of data from other sources to build a more detailed picture on availability and use of novel psychoactive substances. PMID- 23819735 TI - Impact of risk factors, activities and psychological disorders on the health of patients with chronic obstructive pulmonary disease in China: a cross-sectional study. AB - BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) often have organ dysfunction and resulting poor quality of life; however, in China little information is available regarding factors that affect their health. Here, the relationship between risk factors, activities and psychological disorders and health of patients with COPD in rural areas of Xuzhou, China was assessed. METHODS: A cross-sectional study of 7597 COPD patients randomly selected by place of residence from 24,641 COPD patients who had been identified by screening of the 1.10 million health records of all residents of the target area was carried out to evaluate the relationships between risk factors, activities, psychological disorders and the ADO index (age, dyspnea, and airflow obstruction). The participants were assessed by spirometry and by administering a newly designed face-to-face questionnaire, which included items on general factors, risk factors, activities and psychological disorders. Correlations between the ADO index and the items addressed by the questionnaire were calculated. RESULTS: The mean score of the ADO index was 3.7 +/- 1.6. The ADO indices of current smokers, ex-smokers, and non-smokers were 3.9 +/- 2.1, 3.7 +/- 1.9, and 3.2 +/- 1.5, respectively (P < 0.001). The ADO indices of cooks and non-cooks were 4.0 +/- 2.2 and 3.5 +/- 1.7, respectively (P < 0.001). The correlation coefficient between self-assessment of health status and ADO index was 0.976 (P < 0.001). Only 5.7% of patients reported no limitation of their daily living activities. The correlation coefficient between daily living activities and ADO index was 0.981 (P < 0.001). Only 5.5% of patients reported no limitation of social activities. The correlation coefficient between social activities and ADO index was 0.989 (P < 0.001), between the assessed anxiety score and ADO index 0.972 (P < 0.001), and between the assessed depression score and ADO index 0.989 (P < 0.001). CONCLUSIONS: COPD severity was significantly correlated with behavior (especially regarding smoking and cooking with biofuel in confined spaces), physical strength, daily living activities, social activities, anxiety and depression. Comprehensive approaches are required for the prevention and treatment of COPD. PMID- 23819737 TI - A qualitative study of treatment needs among pregnant and postpartum women with substance use and depression. AB - Little is known about treatment for pregnant and postpartum women with co occurring substance use and depression. Funded by the National Institute of Drug Abuse, we conducted three focus groups with 18 pregnant and postpartum women in 2011 at an urban substance use treatment clinic. A semi-structured discussion guide probed for factors impacting treatment outcomes and needs. Data were analyzed using grounded theory. Women identified motivational, family, friend, romantic, and agency characteristics as facilitative or challenging to their recoveries, and desired structure (group treatment, a safe environment, and transportation) and content (attention to mental health, family, and gender specific issues) of treatment. PMID- 23819738 TI - Studying alcohol use prior to sexual intercourse among female sex workers in eastern Indonesia. AB - Researching female sex workers (FSWs) in Indonesia, where commercial sex tends to be hidden or undercover, is challenging but possible. This is even more challenging when it involves investigation of sensitive behaviors, such as their alcohol use, a known disinhibitor to risk behavior. The adoption of effective strategies is needed to increase response rates and improve data quality. This article describes procedures used to research FSWs' alcohol use during commercial sex in the Eastern part of Indonesia. Challenges, lessons learned, and recommendations for best practices are discussed. PMID- 23819739 TI - Current frequent cigarette smoking among U.S. middle and high school students, 2000-2011. AB - This study assessed trends in current frequent smoking among United States middle and high school students. METHODS: Data were obtained from the National Youth Tobacco Survey (2000-2011). Current frequent smoking was defined as smoking cigarettes on >=20 days during the past 30 days. Trends were assessed using linear coefficients in a binary logistic regression (p < 0.05). RESULTS: Current frequent cigarette smoking among all students declined between 2000 (6.4%) and 2011 (3.6%) (p < 0.001 for linear trend). Significant declines were observed by age, sex, race/ethnicity, school and grade level. CONCLUSION: Sustained efforts are needed to further reduce youth use of all tobacco products. PMID- 23819741 TI - Promoting abstinence from alcohol during pregnancy: implications from formative research. AB - This research developed messages to promote abstinence from alcohol during pregnancy and identified elements that enhance message persuasiveness. An exploratory phase was conducted in 2009 that comprised four focus groups with 23 women in Western Australia and elicited beliefs and attitudes on alcohol use during pregnancy and motivations for behavior change. Four television concepts were subsequently developed and appraised in five focus groups with 31 participants using standard advertising pretesting questions. The implications for campaigns addressing prenatal alcohol exposure and further research are noted and limitations discussed. Funding was received from Healthway and the National Health and Medical Research Council. PMID- 23819740 TI - A reexamination of connectivity trends via exponential random graph modeling in two IDU risk networks. AB - Patterns of risk in injecting drug user (IDU) networks have been a key focus of network approaches to HIV transmission histories. New network modeling techniques allow for a reexamination of these patterns with greater statistical accuracy and the comparative weighting of model elements. This paper describes the results of a reexamination of network data from the SFHR and P90 data sets using Exponential Random Graph Modeling. The results show that "transitive closure" is an important feature of IDU network topologies, and provides relative importance measures for race/ethnicity, age, gender, and number of risk partners in predicting risk relationships. PMID- 23819742 TI - 1021- Asthma diagnosis and treatment - 1021. Prevalance of wheezing and risk factor of asthma in preschool children, South Korea. PMID- 23819743 TI - Automated quality measurement in Department of the Veterans Affairs discharge instructions for patients with congestive heart failure. AB - Quality measurement is an important issue for the United States Department of Veterans Affairs (VA). In this study, we piloted the use of an informatics tool, the Multithreaded Clinical Vocabulary Server (MCVS), which extracted automatically whether the VA Office of Quality and Performance measures of quality of care were met for the completion of discharge instructions for inpatients with congestive heart failure. We used a single document, the discharge instructions, from one section of the medical records for 152 patients and developed a reference standard using two independent reviewers to assess performance. When evaluated against the reference standard, MCVS achieved a sensitivity of 0.87, a specificity of 0.86, and a positive predictive value of 0.90. The automated process using the discharge instruction document worked effectively. The use of the MCVS tool for concept-based indexing resulted in mostly accurate data capture regarding quality measurement, but improvements are needed to further increase the accuracy of data extraction. PMID- 23819744 TI - Implementation of a training and structured skills assessment program for medical assistants in a primary care setting. AB - As part of ongoing efforts to improve quality of care through clinical education of our medical assisting staff, we developed a competency-based training and assessment program. At the time of program implementation, we assessed clinical skills of 111 certified medical assistants and found that 10% were unable to accurately measure blood pressure, 9% were unable to correctly perform an intradermal injection, and 48% were unable to correctly draw specified volumes into syringes. More than 10 years after program implementation, we continue to detect and remediate clinical skills in newly hired employees. This case study report describes the evolution of the program and assessment findings. PMID- 23819745 TI - Tunable insulator-quantum Hall transition in a weakly interacting two-dimensional electron system. AB - We have performed low-temperature measurements on a gated two-dimensional electron system in which electron-electron (e-e) interactions are insignificant. At low magnetic fields, disorder-driven movement of the crossing of longitudinal and Hall resistivities (rhoxx and rhoxy) can be observed. Interestingly, by applying different gate voltages, we demonstrate that such a crossing at rhoxx ~ rhoxy can occur at a magnetic field higher, lower, or equal to the temperature independent point in rhoxx which corresponds to the direct insulator-quantum Hall transition. We explicitly show that rhoxx ~ rhoxy occurs at the inverse of the classical Drude mobility 1/MUD rather than the crossing field corresponding to the insulator-quantum Hall transition. Moreover, we show that the background magnetoresistance can affect the transport properties of our device significantly. Thus, we suggest that great care must be taken when calculating the renormalized mobility caused by e-e interactions. PMID- 23819746 TI - Neutrophil activation by Campylobacter concisus. AB - BACKGROUND: Campylobacter concisus is an emerging enteric pathogen associated with prolonged diarrhoea and possibly inflammatory bowel disease in children as well as adults, but the interaction with cells of the innate immune system is unclear. The magnitude of systemic immunoglobulin response in acute infection is unknown. METHODS: Neutrophils from healthy volunteers were activated with five faecal isolates of C. concisus from patients with gastroenteritis as well as the oral reference strain C. concisus ATCC33237. Neutrophils were tested for the expression of adherence molecule CD11b by immunoflourescence and for oxidative burst response by chemiluminescence. The opsonic activity in a chemiluminescence assay was assessed with heat treated serum from patients with C. concisus infection. RESULTS: A strong and dose-dependent activation of neutrophil adherence molecule CD11b and oxidative burst response was demonstrated with all six C. concisus isolates. Bacteria opsonised in heat treated serum induced an increased chemiluminescence response. Heat treated serum from patients with C. concisus infection did not have a higher opsonic activity than heat treated serum from healthy volunteers. CONCLUSION: C. concisus has the capability to activate the innate immune system by stimulating neutrophil cells to increased adherence molecule expression and oxidative burst response, both crucial for acute inflammation. In a chemiluminescence assay the opsonic activity of heat treated serum from patients was not increased compared to heat treated control serum suggesting a weak systemic IgG response to infection. PMID- 23819747 TI - Luminescent hybrid ionogels functionalized with rare earth fluoride up-conversion nanocrystals dispersing in ionic liquid. AB - Rare earth doped fluorides (BaMgF4, aYF4 and BaYF5/BaLuF5) have been synthesized and dispersed in an ionic liquid compound, (3-triethoxysilyl) propyl-3 methylimidazolium chloride (denoted as IM(+)Cl(-)). Through the cohydrolysis and copolycondensatoin reaction between the alkoxy group (3-triethoxysilyl) of IM(+) and tetraethoxysilane in the presence of carboxylic acids (formic acid) as catalyst and water source, luminescent hybrid ionogels form subsequently. (1)H NMR spectroscopy, X-ray diffraction, transmission electron microscopy, scanning electron microscopy and especially up-conversion (UC) luminescence spectroscopy are used to characterize the precursors and the resulted hybrid ionogels. These hybrid ionogels exhibit the UC luminescence properties of immobilized rare earth fluoride nanocrystals (BaMgF4, NaYF4 and BaYF5/BaLuF5) doped Er(3+)/Tm(3+), Yb(3+). PMID- 23819748 TI - Index of circulating anticoagulant cut-off value establishment in activated partial thromboplastin time mixing test for lupus anticoagulant diagnosis. PMID- 23819749 TI - Structure and dynamics of spin-labeled insulin entrapped in a silica matrix by the sol-gel method. AB - The structure and conformational dynamics of insulin entrapped into a silica matrix was monitored during the sol to maturated-gel transition by electron paramagnetic resonance (EPR) spectroscopy. Insulin was successfully spin-labeled with iodoacetamide and the bifunctional nitroxide reagent HO-1944. Room temperature continuous wave (cw) EPR spectra of insulin were recorded to assess the mobility of the attached spin labels. Insulin conformation and its distribution within the silica matrix were studied using double electron-electron resonance (DEER) and low-temperature cw-EPR. A porous oxide matrix seems to form around insulin molecules with pore diameters in the order of a few nanometers. Secondary structure of the encapsulated insulin investigated by Fourier transform infrared spectroscopy proved a high structural integrity of insulin even in the dried silica matrix. The results show that silica encapsulation can be used as a powerful tool to effectively isolate and functionally preserve biomolecules during preparation, storage, and release. PMID- 23819750 TI - The triggering of myocardial infarction by fine particles is enhanced when particles are enriched in secondary species. AB - Previous studies have reported an increased risk of myocardial infarction (MI) associated with acute increases in PM concentration. Recently, we reported that MI/fine particle (PM2.5) associations may be limited to transmural infarctions. In this study, we retained data on hospital discharges with a primary diagnosis of acute myocardial infarction (using International Classification of Diseases ninth Revision [ICD-9] codes), for those admitted January 1, 2004 to December 31, 2006, who were >= 18 years of age, and were residents of New Jersey at the time of their MI. We excluded MI with a diagnosis of a previous MI and MI coded as a subendocardial infarction, leaving n = 1563 transmural infarctions available for analysis. We coupled these health data with PM2.5 species concentrations predicted by the Community Multiscale Air Quality chemical transport model, ambient PM2.5 concentrations, and used the same case-crossover methods to evaluate whether the relative odds of transmural MI associated with increased PM2.5 concentration is modified by the PM2.5 composition/mixture (i.e., mass fractions of sulfate, nitrate, elemental carbon, organic carbon, and ammonium). We found the largest relative odds estimates on the days with the highest tertile of sulfate mass fraction (OR = 1.13; 95% CI = 1.00, 1.27), nitrate mass fraction (OR = 1.18; 95% CI = 0.98, 1.35), and ammonium mass fraction (OR = 1.13; 95% CI = 1.00 1.28), and the lowest tertile of EC mass fraction (OR = 1.17; 95% CI = 1.03, 1.34). Air pollution mixtures on these days were enhanced in pollutants formed through atmospheric chemistry (i.e., secondary PM2.5) and depleted in primary pollutants (e.g., EC). When mixtures were laden with secondary PM species (sulfate, nitrate, and/or organics), we observed larger relative odds of myocardial infarction associated with increased PM2.5 concentrations. Further work is needed to confirm these findings and examine which secondary PM2.5 component(s) is/are responsible for an acute MI response. PMID- 23819751 TI - Thoughts from SNP-SIG 2012: future challenges in the annotation of genetic variations. PMID- 23819752 TI - Pitavastatin in cardiometabolic disease: therapeutic profile. AB - Statins effectively lower low-density lipoprotein-cholesterol (LDL-C) and reduce cardiovascular risk in people with dyslipidemia and cardiometabolic diseases such as Metabolic syndrome (MetS) or type 2 diabetes (T2D). In addition to elevated levels of LDL-C, people with these conditions often have other lipid-related risk factors, such as high levels of triglycerides, low levels of high-density lipoprotein-cholesterol (HDL-C), and a preponderance of highly atherogenic, small, dense low-density lipoprotein particles. The optimal management of dyslipidemia in people with MetS or T2D should therefore address each of these risk factors in addition to LDL-C. Although statins typically have similar effects on LDL-C levels, differences in chemical structure and pharmacokinetic profile can lead to variations in pleiotropic effects, adverse event profiles and drug-drug interactions. The choice of statin should therefore depend on the characteristics and needs of the individual patient. Compared with other statins, pitavastatin has distinct pharmacological features that translate into a broad range of actions on both apolipoprotein-B-containing and apolipoprotein-A containing lipoproteins. Studies show that pitavastatin 1 to 4 mg is well tolerated and significantly improves LDL-C and triglyceride levels to a similar or greater degree than comparable doses of atorvastatin, simvastatin or pravastatin, irrespective of diabetic status. Moreover, whereas most statins show inconsistent effects on HDL-C levels, pitavastatin-treated patients routinely experience clinically significant elevations in HDL-C that are maintained and even increased over the long term. In addition to increasing high-density lipoprotein quantity, pitavastatin appears to improve high-density lipoprotein function and to slow the progression of atherosclerotic plaques by modifying high density lipoprotein-related inflammation and oxidation, both of which are common in patients with MetS and T2D. When choosing a statin, it is important to note that patients with MetS have an increased risk of developing T2D and that some statins can exacerbate this risk via adverse effects on glucose regulation. Unlike many statins, pitavastatin appears to have a neutral and even beneficial effect on glucose regulation, making it a useful treatment option in this high risk group of patients. Together with pitavastatin's beneficial effects on the cardiometabolic lipid profile and its low potential for drug-drug interactions, this suggests that pitavastatin might be a useful lipid-lowering option for people with cardiometabolic disease. PMID- 23819753 TI - Predicting chronic obstructive pulmonary disease hospitalizations based on concurrent influenza activity. AB - Although influenza has been associated with chronic obstructive pulmonary disease (COPD) exacerbations, it is not clear the extent to which this association affects healthcare use in the United States. The first goal of this project was to determine to what extent the incidence of COPD hospitalizations is associated with seasonal influenza. Second, as a natural experiment, we used influenza activity to help predict COPD admissions during the 2009 H1N1 influenza pandemic. To do this, we identified all hospitalizations between 1998 and 2010 in the Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project (HCUP) during which a primary diagnosis of COPD was recorded. Separately, we identified all hospitalizations during which a diagnosis of influenza was recorded. We formulated time series regression models to investigate the association of monthly COPD admissions with influenza incidence. Finally, we applied these models, fit using 1998-2008 data, to forecast monthly COPD admissions during the 2009 pandemic. Based on time series regression models, a strong, significant association exists between concurrent influenza activity and incidence of COPD hospitalizations (p-value < 0.0001). The association is especially strong among older patients requiring mechanical ventilation. Use of influenza data to predict COPD admissions during the 2009 H1N1 pandemic reduced the mean-squared prediction error by 29.9%. We conclude that influenza activity is significantly associated with COPD hospitalizations in the United States and influenza activity can be exploited to more accurately forecast COPD admissions. Our results suggest that improvements in influenza surveillance, prevention, and treatment may decrease hospitalizations of patients diagnosed with COPD. PMID- 23819754 TI - Indication for surgical treatment in patients with adolescent idiopathic scoliosis - a critical appraisal and counter-point. AB - In a recent letter to the editor (Patient Saf. Surg. 2013, 7:17), Weiss and Moramarco made the claim that surgical correction of idiopathic scoliosis is not supported based on the available literature citing no medical indication and high complication rates as compared to non-operative management. In this letter we show that there is a role for surgical treatment as the only predictable option to obtain correction of a curve and that the risk of complications with newer instrumentation does not approach 50% as cited by Weiss and Moramarco. We share the opinion with Weiss and Moramarco that a decision for surgery is not one to be made lightly, and should include options of purely observation, bracing, as well as surgery depending on the potential progression profile and conversations with the child and parents. PMID- 23819756 TI - Photoexcitation and charge-transfer-to-solvent relaxation dynamics of the I( )(CH3CN) complex. AB - Photoexcitation of iodide-acetonitrile clusters, I(-)(CH3CN)n, to the charge transfer-to-solvent (CTTS) state and subsequent cluster relaxation could result in the possible formation of cluster analogues of the bulk solvated electron. In this work, the relaxation process of the CTTS excited iodide-acetonitrile binary complex, [I(-)(CH3CN)]*, is investigated using rigorous ab initio quantum chemistry calculations and direct-dynamics simulations to gain insight into the role and motion of iodine and acetonitrile in the relaxation of CTTS excited I( )(CH3CN)n. Computed potential energy curves and profiles of the excited electron vertical detachment energy for [I(-)(CH3CN)]* along the iodine-acetonitrile distance coordinate reveal for the first time significant dispersion effects between iodine and the excited electron, which can have a significant stabilizing effect on the latter. Results of direct-dynamics simulations demonstrate that [I( )(CH3CN)]* undergoes dissociation to iodine and acetonitrile fragments, resulting in decreased stability of the excited electron. The present work provides strong evidence of solvent translational motion and iodine ejection as key aspects of the early time relaxation of CTTS excited I(-)(CH3CN)n that can also have a substantial impact on the subsequent electron solvation processes and further demonstrates that intricate details of the relaxation process of CTTS excited iodide-polar solvent molecule clusters make it heavily solvent-dependent. PMID- 23819755 TI - Performing isoelectric focusing and simultaneous fractionation of proteins on a rotary valve followed by sodium dodecyl-polyacrylamide gel electrophoresis. AB - In this technical note, we design and fabricate a novel rotary valve and demonstrate its feasibility for performing isoelectric focusing and simultaneous fractionation of proteins, followed by sodium dodecyl-polyacrylamide gel electrophoresis. The valve has two positions. In one position, the valve routes a series of capillary loops together into a single capillary tube where capillary isoelectric focusing (CIEF) is performed. By switching the valve to another position, the CIEF-resolved proteins in all capillary loops are isolated simultaneously, and samples in the loops are removed and collected in vials. After the collected samples are briefly processed, they are separated via sodium dodecyl-polyacrylamide gel electrophoresis (SDS-PAGE, the second-D separation) on either a capillary gel electrophoresis instrument or a slab-gel system. The detailed valve configuration is illustrated, and the experimental conditions and operation protocols are discussed. PMID- 23819757 TI - Controlled, blinded force platform analysis of the effect of intraarticular injection of autologous adipose-derived mesenchymal stem cells associated to PRGF Endoret in osteoarthritic dogs. AB - BACKGROUND: Adipose-derived mesenchymal stem cell (ADMSC) therapy in regenerative medicine is a rapidly growing area of research and is currently also being used to treat osteoarthritis (OA). Force platform analysis has been consistently used to verify the efficacy of different therapeutic strategies for the treatment of OA in dogs, but never with AD-MSC.The aim of this study was to use a force platform to measure the efficacy of intraarticular ADMSC administration for limb function improvement in dogs with severe OA. RESULTS: Eight lame dogs with severe hip OA and a control group of 5 sound dogs were used for this study. Results were statistically analyzed to detect a significant increase in peak vertical force (PVF) and vertical impulse (VI) in treated dogs. Mean values of PVF and VI were significantly improved after treatment of the OA groups, reaching 53.02% and 14.84% of body weight, respectively, at day 180, compared with only 43.56% and 12.16% at day 0. CONCLUSION: This study objectively demonstrated that intraarticular ADMSC therapy resulted in reduced lameness due to OA. PMID- 23819758 TI - Genomics of corneal wound healing: a review of the literature. AB - Corneal wound healing is a complex process: its mechanisms and the underlying genetic control are not fully understood. It involves the integrated actions of multiple growth factors, cytokines and proteases produced by epithelial cells, stromal keratocytes, inflammatory cells and lacrimal gland cells. Following an epithelial insult, multiple cytokines are released triggering a cascade of events that leads to repair the epithelial defect and remodelling of the stroma to minimize the loss of transparency and function. In this review, we examine the literature surrounding the genomics of corneal wound healing with respect to the following topics: epithelial and stromal wound healing (including inhibition); corneal neovascularisation; the role of corneal nerves in wound healing; the endothelium; the role of aquaporins and aptamers. We also examine the effect of ectasia on corneal wound healing with regard to keratoconus and following corneal surgery. A better understanding of the cellular and molecular changes that occur during repair of corneal wounds will provide the opportunity to design treatments that selectively modulate key phases of the healing process resulting in scars that more closely resemble normal corneal architecture. PMID- 23819759 TI - Inhibition of androgen induces autophagy in benign prostate epithelial cells. AB - OBJECTIVE: 5-alpha Reductase inhibitor can reduce the volume of benign prostatic hyperplasia by lowering benign prostatic hyperplasia level and consequently inducing epithelial cells apoptosis. The present study investigated whether autophagy and apoptosis of benign prostatic hyperplasia epithelial cells are influenced by low benign prostatic hyperplasia levels. METHODS: PWR-1E prostate epithelial cells transfected with GFP-LC3 plasmid were subjected to androgen deprivation conditions. Then the autophagic puncta were evaluated by fluorescence microscopy, and the cellular apoptosis rate was detected by 4, 6-diamidino-2 phenylindole staining after blocking of autophagic process by 3-methyladenine. Furthermore, autophagy status was also determined in hyperplasia prostate tissues from 5-alpha reductase inhibitor-treated patients by immunohistochemistry. RESULTS: In the androgen deprivation medium, autophagic punta increased markedly in PWR-1E cells, and blockage of autophagy by 3-methyladenine significantly promoted PWR-1E cells' apoptosis rate. In vivo, the expression of LC3 protein (an important autophagic marker) in hyperplasia prostate tissue significantly increased after 5-alpha reductase inhibitor treatment. Meanwhile, the prostate specific antigen, as an inner control, decreased. CONCLUSION: 5-alpha Reductase inhibitor treatment increases autophagy and possibly decreases the apoptosis of prostate epithelial cells. PMID- 23819761 TI - Implementation research to catalyze advances in health systems strengthening in sub-Saharan Africa: the African Health Initiative. PMID- 23819760 TI - Pre-arrest predictors of survival after resuscitation from out-of-hospital cardiac arrest in the elderly a systematic review. AB - BACKGROUND: To enable older people to make decisions about the appropriateness of cardiopulmonary resuscitation (CPR), information is needed about the predictive value of pre-arrest factors such as comorbidity, functional and cognitive status on survival and quality of life of survivors. We systematically reviewed the literature to identify pre-arrest predictors for survival, quality of life and functional outcomes after out-of-hospital (OHC) CPR in the elderly. METHODS: We searched MEDLINE (through May 2011) and included studies that described adults aged 70 years and over needing CPR after OHC cardiac arrest. Prognostic factors associated with survival to discharge and quality of life of survivors were extracted. Two authors independently appraised the quality of each of the included studies. When possible a meta-analysis of odd's ratios was performed. RESULTS: Twenty-three studies were included (n = 44,582). There was substantial clinical and statistical heterogeneity and reporting was often inadequate. The pooled survival to discharge in patients >70 years was 4.1% (95% CI 3.0-5.6%). Several studies showed that increasing age was significantly associated with worse survival, but the predictive value of comorbidity was investigated in only one study. In another study, nursing home residency was independently associated with decreased chances of survival. Only a few small studies showed that age is negatively associated with a good quality of life of survivors. We were unable to perform a meta-analysis of possible predictors due to a wide variety in reporting and statistical methods. CONCLUSIONS: Although older patients have a lower chance of survival after CPR in univariate analysis (i.e. 4.1%), older age alone does not seem to be a good criterion for denying patients CPR. Evidence for the predictive value of comorbidities and for the predictive value of age on quality of life of survivors is scarce. Future studies should use uniform methods for reporting data and pre-arrest factors to increase the available evidence about pre arrest factors on the chance of survival. Furthermore, patient-specific outcomes such as quality of life and post-arrest cognitive function should be investigated too. PMID- 23819762 TI - Gwen's crazy little green clowns. PMID- 23819763 TI - Reaction products and the X-ray structure of AmpDh2, a virulence determinant of Pseudomonas aeruginosa. AB - The zinc protease AmpDh2 is a virulence determinant of Pseudomonas aeruginosa, a problematic human pathogen. The mechanism of how the protease manifests virulence is not known, but it is known that it turns over the bacterial cell wall. The reaction of AmpDh2 with the cell wall was investigated, and nine distinct turnover products were characterized by LC/MS/MS. The enzyme turns over both the cross-linked and noncross-linked cell wall. Three high-resolution X-ray structures, the apo enzyme and two complexes with turnover products, were solved. The X-ray structures show how the dimeric protein interacts with the inner leaflet of the bacterial outer membrane and that the two monomers provide a more expansive surface for recognition of the cell wall. This binding surface can accommodate the 3D solution structure of the cross-linked cell wall. PMID- 23819765 TI - Asthma diagnosis and treatment - 1003. Severe asthma: a comparison of clinical severity and lung function. PMID- 23819764 TI - The presence of ultralow densities of nanocrystallites in amorphous poly(lactic acid) microspheres. AB - Ultralow densities of crystalline nanospheres have been detected in amorphous polymer microspheres by utilizing the unique sensitivity of second-order nonlinear optical techniques to anisotropy. Vibrational sum frequency scattering (SFS) and X-ray diffraction (XRD) are used to quantify the crystallinity of amorphous poly(d,l-lactic acid) microspheres. While XRD does not display any crystallinity for the microspheres, SFS spectra and patterns are reminiscent of a heterogeneous microsphere that contains small crystalline domains. Nonlinear light scattering theory was used to model the data, and an average domain radius of 147 +/- 65 nm was obtained. The degree of crystallinity (0.2%) was estimated by comparing XRD and SFS data obtained from the amorphous microspheres to similar data obtained from crystalline microspheres. We estimate a detection limit of 0.002% for SFS. PMID- 23819766 TI - Biocompatibility evaluation of emulsion electrospun nanofibers using osteoblasts for bone tissue engineering. AB - Emulsion electrospinning is an advanced technique to fabricate core-shell structured nanofibrous scaffolds, with great potential for drug encapsulation. Incorporation of dual factors hydroxyapatite (HA) and laminin, respectively, within the shell and core of nanofibers through emulsion electrospinning might be of advantageous in supporting the adhesion, proliferation, and maturation of cells instead of single factor-encapsulated nanofibers. We fabricated poly(L lactic acid-co-epsilon-caprolactone) (PLCL)/hydroxyapaptite (PLCL/HA), PLCL/laminin (PLCL/Lam), and PLCL/hydroxyapatite/laminin (PLCL/HA/Lam) scaffolds with fiber diameter of 388 +/- 35, 388 +/- 81, and 379 +/- 57 nm, respectively, by emulsion electrospinning. The elastic modulus of the prepared scaffolds ranged from 22.7-37.0 MPa. The osteoblast proliferation on PLCL/HA/Lam scaffolds, determined on day 21, was found 10.4% and 12.0% higher than the cell proliferation on PLCL/Lam or PLCL/HA scaffold, respectively. Cell maturation determined on day 14, by alkaline phosphatase (ALP) activity, was significantly higher on PLCL/HA/Lam scaffolds than the ALP activity on PLCL/HA and PLCL/Lam scaffolds (p <= 0.05). Results of the energy dispersive X-ray studies carried out on day 28 also showed higher calcium deposition by cells seeded on PLCL/HA/Lam scaffolds. Osteoblasts were found to adhere, proliferate, and mature actively on PLCL/HA/Lam nanofibers with enhanced cell proliferation, ALP activity, bone protein expression, and mineral deposition. Based on the results, we can conclude that laminin and HA individually played roles in osteoblast proliferation and maturation, and the synergistic function of both factors within the novel emulsion electrospun PLCL/HA/Lam nanofibers enhanced the functionality of osteoblasts, confirming their potential application in bone tissue regeneration. PMID- 23819767 TI - The type 2B p.R1306W natural mutation of von Willebrand factor dramatically enhances the multimer sensitivity to shear stress. AB - BACKGROUND: Shear stress triggers conformational stretching of von Willebrand factor (VWF), which is responsible for its self-association and binding to the platelet receptor glycoprotein (GP)Ibalpha. This phenomenon supports primary hemostasis under flow. Type 2B VWF natural mutants are considered to have increased affinity for platelet GPIbalpha. OBJECTIVES: To assess the mechanism responsible for the enhanced interaction of the p.R1306W VWF mutant with the platelet receptor. METHODS: The interaction of GPIbalpha with wild-type (WT) and p.R1306W VWF multimers and A1-A2-A3 constructs was investigated with surface plasmon resonance spectroscopy. Analysis of the static VWF conformation in solution was performed with dynamic light scattering spectroscopy. The shear stress-induced self-association of VWF multimers was investigated with atomic force microscopy (AFM) over a 0-60 dyn cm(-2) range. RESULTS: WT VWF did not interact with GPIbalpha under static conditions, whereas the mutant at ~ 2 MUg mL(-1) already bound to the receptor. By contrast, the WT and p.R1306W-A1-A2-A3 constructs showed comparable affinities for GPIbalpha (Kd ~ 20 nm). The hydrodynamic diameter of resting R1306W VWF multimers was significantly greater than that of the wild type (210 +/- 60 nm vs. 87 +/- 22 nm). At shear forces of < 14 dyn cm(-2) , the p.R1306W multimers rapidly changed conformation, entering a regime of self-aggregation, which, in contrast, was induced for WT VWF by shear forces of > 30 dyn cm(-2) . Mechanical stretching AFM experiments showed that p.R1306W multimers needed less energy per length unit (~ 10 pN) to be stretched than the WT protein. CONCLUSIONS: The increased affinity of p.R1306W VWF for GPIbalpha arises mostly from higher sensitivity to shear stress, which facilitates exposure of GPIbalpha binding sites. PMID- 23819768 TI - Renal sympathetic nerve ablation for treatment-resistant hypertension. AB - Hypertension is a major risk factor for increased cardiovascular events with accelerated sympathetic nerve activity implicated in the pathogenesis and progression of disease. Blood pressure is not adequately controlled in many patients, despite the availability of effective pharmacotherapy. Novel procedure- as well as device-based strategies, such as percutaneous renal sympathetic nerve denervation, have been developed to improve blood pressure in these refractory patients. Renal sympathetic denervation not only reduces blood pressure but also renal as well as systemic sympathetic nerve activity in such patients. The reduction in blood pressure appears to be sustained over 3 years after the procedure, which suggests absence of re-innervation of renal sympathetic nerves. Safety appears to be adequate. This approach may also have potential in other disorders associated with enhanced sympathetic nerve activity such as congestive heart failure, chronic kidney disease and metabolic syndrome. This review will focus on the current status of percutaneous renal sympathetic nerve denervation, clinical efficacy and safety outcomes and prospects beyond refractory hypertension. PMID- 23819769 TI - Association of arterial blood pressure and CPR quality in a child using three different compression techniques, a case report. AB - A 2-year-old boy found in cardiac arrest secondary to drowning received standard CPR for 35 minutes and was transported to a tertiary hospital for rewarming from hypothermia. Chest compressions in hospital were started using two-thumb encircling hands technique. Subsequently two-thumbs direct sternal compression technique and after sternal force/depth sensor placement, chest compression with classic one-hand technique were done. By using CPR recording/feedback defibrillator, quantitative CPR quality data and invasive arterial pressures were available for analyses for 5 hours and 35 minutes. 316 compressions with the two thumb encircling hands technique provided a mean (SD) systolic arterial pressure (SAP) of 24 (4) mmHg, mean arterial pressure (MAP) 18 (3) and diastolic arterial pressure (DAP) of 15 (3) mmHg. ~6000 compressions with the two thumbs direct compression technique created a mean SAP of 45 (7) mmHg, MAP 35 (4) mmHg and DAP of 30 (3) mmHg. ~20,000 compressions with the sternal accelerometer in place produced SAP 50 (10) mmHg, MAP 32 (5) mmHg and DAP 24 (4) mmHg. Restoration of spontaneous circulation (ROSC) was achieved at the point when the child achieved normothermia by using peritoneal dialysis. Unfortunately, the child died ten hours after ROSC without any signs of neurological recovery. This case demonstrates improved hemodynamic parameters with classic one-handed technique with real-time quantitative quality of CPR feedback compared to either the two thumbs encircling hands or two-thumbs direct sternal compression techniques. We speculate that the improved arterial pressures were related to improved chest compression depth when a real-time CPR recording/feedback device was deployed. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00951704. PMID- 23819770 TI - Synthesis of calothrixins and its analogs using FeCl3-mediated domino reaction protocol. AB - A novel one pot synthesis of calothrixin B and its analogs is achieved involving an FeCl3-mediated domino reaction of enamines in dry DMF at reflux. Alternatively, the enamines upon interaction with CuBr2 in DMF at reflux led to the formation of 1-phenylsulfony-2-(2'-nitroaryl)-4-hydroxycarbazole-3 carbaldehydes in excellent yields. PMID- 23819771 TI - Vascular endothelial cells as targets for photochemical internalization (PCI). AB - Cancer treatment can be exerted by targeting both cancer cells and the vasculature supplying solid tumors. Photochemical internalization (PCI) is a modality for cytosolic drug delivery, but recent data on contrast-enhanced MRI have indicated that the method also reduces blood perfusion in HT1080 fibrosarcoma xenografts. The present report aims to investigate if PCI may exert direct cytotoxic effects on endothelial cells. PCI of saporin was performed on endothelial human umbilical vein endothelial cell (HUVEC) and fibrosarcoma cells (HT1080) using two PCI-relevant photosensitizers, TPPS2a and AlPcS2a. A 22- and 13-fold higher photosensitizer uptake was detected in the endothelial cells compared with the HT1080 cells for AlPcS2a and TPPS2a, respectively. PCI of saporin was, however, found more effective in HT1080 cells. For HT1080 cells, PCI with saporin increased cell killing 1.9-fold over photodynamic therapy alone, but under the same conditions, only increased HUVEC cell killing by 1.6- and 1.3-fold with AlPcS2a and TPPS2a , respectively. Saporin uptake was higher in HUVECs than in the HT1080 cells, hence did not reflect the cell line differences in PCI efficacy. This is the first report on PCI-mediated kill of endothelial cells and lays the foundation for further preclinical evaluation of the PCI technology as an antivascular strategy to ablate tumors. PMID- 23819772 TI - Intramolecular triplet energy transfer in anthracene-based platinum acetylide oligomers. AB - Platinum acetylide oligomers that contain an anthracene moiety have been synthesized and subjected to photophysical characterization. Spectroscopic measurement and DFT calculations reveal that both the singlet and triplet energy levels of the anthracene segment are lower than those of the platinum acetylide segment. Thus, the platinum acetylide segment acts as a sensitizer to populate the triplet state of the anthrancene segment via intramolecular triplet-triplet energy transfer. The objective of this work is to understand the mechanisms of energy-transfer dynamics in these systems. Fluorescence quenching and the dominant triplet absorption that arises from the anthracene segment in the transient absorption spectrum of Pt4An give clear evidence that energy transfer adopts an indirect mechanism, which begins with singlet-triplet energy transfer from the anthracene segment to the platinum acetylide segment followed by triplet triplet energy transfer to the anthracene segment. PMID- 23819773 TI - Translational bioinformatics has now come of age: TBC 2012 collection. PMID- 23819774 TI - Hydroalkoxylation of unactivated olefins with carbon radicals and carbocation species as key intermediates. AB - A unique Markovnikov hydroalkoxylation of unactivated olefins with a cobalt complex, silane, and N-fluoropyridinium salt is reported. Further optimization of reaction conditions yielded high functional group tolerance and versatility of alcoholic solvent employed, including methanol, i-propanol, and t-butanol. Use of trifluorotoluene as a solvent made the use of alcohol in stoichiometric amount possible. Mechanistic insight into this novel catalytic system is also discussed. Experimental results suggest that catalysis involves both carbon radical and carbocation intermediates. PMID- 23819777 TI - Dynamics of small, ultraviolet-excited ICN- cluster anions. AB - The ultraviolet (UV) photodissociation of mass-selected ICN(-)Ar(n) and ICN( )(CO2)n clusters (n = 0-5) is studied using a secondary reflectron mass spectrometer. Relative photodissociation cross sections of bare ICN(-) show the dominance of the I(-) photoproduct from 270 to 355 nm, the entire wavelength range studied. UV excitation populates both the (2)Sigma(+) state that produces I* + CN(-) and the (2)Pi states that produce I(-) + CN*. While the excited (2)Pi states directly produce I(-), excitation to the (2)Sigma(+) state also produces some I(-) product via nonadiabatic transitions to the (2)Pi(1/2) state, which produces I(-) + CN. Partial solvation of the anion by Ar atoms or CO2 molecules alters the UV-branching percentages between the various dissociation channels: I* + CN(-) and I(-) + CN or I(-) + CN*. In addition, solvation by two or more Ar atoms or three or more CO2 molecules results in recombination, reforming ICN(-). Examination of the potential surfaces and transition moments in combination with the results of quantum dynamics calculations performed on the relevant excited states assist in the analysis of the experimental results. PMID- 23819776 TI - Statin diabetogenicity: guidance for clinicians. AB - Type 2 diabetes (T2D) is a strong, independent risk factor for cardiovascular (CV) and cerebrovascular outcomes. Meta-analysis of five randomised clinical trials (n = 33,040) showed that, although intensive versus standard glycaemic control significantly reduced CV events in people with T2D, the reduction was less than that achieved with lipid-lowering or antihypertensive treatment. Furthermore, fasting plasma glucose (FPG) concentrations were a modest predictor for CV risk in people without T2D. Thus, although effective glycaemic control is important for the prevention/management of T2D, other risk factors must be addressed to effectively reduce CV risk. Reducing low-density lipoprotein cholesterol levels using statins significantly reduces CV risk in people with and without T2D. Although statins are generally safe and well tolerated, conflicting data exist regarding the diabetogenic effects of some statins. Based on recent clinical trial data, the US Food and Drug Administration have changed the labelling of all statins to include 'an effect of statins on incident diabetes and increases in haemoglobin A1c and/or FPG'. However, the literature suggests that the beneficial effects of most statins on CV risk continue to outweigh their diabetogenic risks and that statins should remain as first-line therapy for the majority of people with dyslipidaemia and metabolic syndrome or T2D. Mechanisms explaining the potentially higher incidence of T2D with statin therapy have not been confirmed. However, independent predictors for statin-associated T2D appear to include elevated levels of baseline FPG, BMI, blood pressure and fasting triglycerides. Moreover, although some statins (for example, atorvastatin) are associated with increased haemoglobin A1c levels in patients receiving intensive but not moderate therapy, other statins (for example, pitavastatin) have demonstrated neutral or favourable effects on glucose control in patients with and without T2D or metabolic syndrome. The potential diabetogenic effects of statins may therefore differ between drugs. In conclusion, conflicting data exist regarding the diabetogenic effects of statins. Further studies are required to understand whether all statins have the same effect and whether some patient groups are at higher risk than others. Meanwhile, results suggest that the net CV benefit favours the use of statin therapy in patients with dyslipidaemia, irrespective of T2D risk. PMID- 23819775 TI - Prevalence and gender patterns of mental health problems in German youth with experience of violence: the KiGGS study. AB - BACKGROUND: Research examining mental health in violence-affected youth in representative samples is rare. Using data from the nationally representative German Health Interview and Examination Survey for Children and Adolescents (KiGGS) this study reports on gender-specific prevalence rates and associations of a broad range of internalizing and externalizing mental health problems: emotional problems, conduct problems, ADHD, disordered eating, somatic pain and substance use in youth variously affected by violence. While internalizing is generally more common in girls and externalizing in boys, observations of prior non-normative studies suggest reverse associations once an individual is affected by violence. The occurrence of such "gender cross-over effects" is therefore examined in a representative sample. METHODS: The sample consisted of 6,813 adolescents aged 11 to 17 from the German Health Interview and Examination Survey for Children and Adolescents (KiGGS): Applying multivariate logistic regression analyses, associations between each type of violence history and mental health indicator were determined for perpetrators, victims, and perpetrating victims of youth violence. Moderating effects of gender were examined by using product term interaction. RESULTS: Victim status was associated primarily with internalizing problems, while perpetrators were more prone to externalizing problems. Perpetrating victims stood out with respect to the number and strength of risk associations with all investigated mental health indicators. However, the risk profiles of all violence-affected youth included both internalizing and externalizing mental health problems. Gender cross-over effects were found for girls and boys: despite lower overall prevalence, girls affected by violence were at far higher risk for conduct problems and illicit drug use; by contrast, somatic pain, although generally lower in males, was positively associated with perpetrator status and perpetrating victim status in boys. All violence-affected youth exhibited significantly higher rates of cumulative mental health problems. CONCLUSIONS: The results highlight the importance of violence for the mental health of youth. They reveal a particular vulnerability as a function of gender. Implications for policy making, clinical practice and research are discussed. PMID- 23819778 TI - A common evaluation framework for the African Health Initiative. AB - BACKGROUND: The African Health Initiative includes highly diverse partnerships in five countries (Ghana, Mozambique, Rwanda, Tanzania, and Zambia), each of which is working to improve population health by strengthening health systems and to evaluate the results. One aim of the Initiative is to generate cross-site learning that can inform implementation in the five partnerships during the project period and identify lessons that may be generalizable to other countries in the region. Collaborators in the Initiative developed a common evaluation framework as a basis for this cross-site learning. METHODS: This paper describes the components of the framework; this includes the conceptual model, core metrics to be measured in all sites, and standard guidelines for reporting on the implementation of partnership activities and contextual factors that may affect implementation, or the results it produces. We also describe the systems that have been put in place for data management, data quality assessments, and cross site analysis of results. RESULTS AND CONCLUSIONS: The conceptual model for the Initiative highlights points in the causal chain between health system strengthening activities and health impact where evidence produced by the partnerships can contribute to learning. This model represents an important advance over its predecessors by including contextual factors and implementation strength as potential determinants, and explicitly including equity as a component of both outcomes and impact. Specific measurement challenges include the prospective documentation of program implementation and contextual factors. Methodological issues addressed in the development of the framework include the aggregation of data collected using different methods and the challenge of evaluating a complex set of interventions being improved over time based on continuous monitoring and intermediate results. PMID- 23819779 TI - GWIS--model-free, fast and exhaustive search for epistatic interactions in case control GWAS. AB - BACKGROUND: It has been hypothesized that multivariate analysis and systematic detection of epistatic interactions between explanatory genotyping variables may help resolve the problem of "missing heritability" currently observed in genome wide association studies (GWAS). However, even the simplest bivariate analysis is still held back by significant statistical and computational challenges that are often addressed by reducing the set of analysed markers. Theoretically, it has been shown that combinations of loci may exist that show weak or no effects individually, but show significant (even complete) explanatory power over phenotype when combined. Reducing the set of analysed SNPs before bivariate analysis could easily omit such critical loci. RESULTS: We have developed an exhaustive bivariate GWAS analysis methodology that yields a manageable subset of candidate marker pairs for subsequent analysis using other, often more computationally expensive techniques. Our model-free filtering approach is based on classification using ROC curve analysis, an alternative to much slower regression-based modelling techniques. Exhaustive analysis of studies containing approximately 450,000 SNPs and 5,000 samples requires only 2 hours using a desktop CPU or 13 minutes using a GPU (Graphics Processing Unit). We validate our methodology with analysis of simulated datasets as well as the seven Wellcome Trust Case-Control Consortium datasets that represent a wide range of real life GWAS challenges. We have identified SNP pairs that have considerably stronger association with disease than their individual component SNPs that often show negligible effect univariately. When compared against previously reported results in the literature, our methods re-detect most significant SNP-pairs and additionally detect many pairs absent from the literature that show strong association with disease. The high overlap suggests that our fast analysis could substitute for some slower alternatives. CONCLUSIONS: We demonstrate that the proposed methodology is robust, fast and capable of exhaustive search for epistatic interactions using a standard desktop computer. First, our implementation is significantly faster than timings for comparable algorithms reported in the literature, especially as our method allows simultaneous use of multiple statistical filters with low computing time overhead. Second, for some diseases, we have identified hundreds of SNP pairs that pass formal multiple test (Bonferroni) correction and could form a rich source of hypotheses for follow-up analysis. AVAILABILITY: A web-based version of the software used for this analysis is available at http://bioinformatics.research.nicta.com.au/gwis. PMID- 23819780 TI - Human factors research applied: the development of a personal touch screen insulin pump and users' perceptions of actual use. AB - BACKGROUND: A brief history of the field of human factors research is covered, along with how this discipline is leveraged within medical device companies, to eliminate design flaws in products, in order to make them safe and effective for human use. The way in which human factors research was used to develop the t:slim((r)) insulin delivery system (Tandem Diabetes Care((r)) Inc., San Diego, CA) is also discussed. Following the development of the t:slim pump, a product evaluation study was conducted to assess users' perceptions of the t:slim pump under actual use conditions versus their current pump system. SUBJECTS AND METHODS: A 30-day, within-subjects study with a total of 74 participants was conducted at four different investigator sites across the United States. Study participants used the t:slim insulin pump in their normal environment for 30 days. Participants were given the Insulin Delivery System Rating Questionnaire during their first visit to assess their current insulin pump and then at the end of the study to measure their perceptions of the t:slim pump. A paired-samples t test was completed to analyze the data. RESULTS: The results indicated that 16 of the questionnaire variables showed statistically significant differences in scores. CONCLUSIONS: It was found that the utilization of a systematic human factors process resulted in an insulin pump that was proved to be safe and effective for human use and was cleared by the Food and Drug Administration for use in the United States. In addition, the results of the product evaluation study showed that, after use of the t:slim pump for 30 days, participants' perceptions of several variables improved. PMID- 23819781 TI - Eurasian dipper eggs indicate elevated organohalogenated contaminants in urban rivers. AB - Many urban European streams are recovering from industrial, mining, and sewage pollution during the 20th century. However, associated recolonization by clean water organisms can potentially result in exposure to legacy or novel toxic pollutants that persist in the environment. Between 2008 and 2010, we sampled eggs of a river passerine, the Eurasian dipper (Cinclus cinclus), from 33 rivers in South Wales and the English borders (UK) which varied in catchment land use from rural to highly urbanized. Dipper egg delta(15)N and delta(13)C stable isotopes were enriched from urban rivers while delta(34)S was strongly depleted, effectively discriminating their urban or rural origins at thresholds of 10% urban land cover or 1000 people/km(2). Concentrations of total polychlorinated biphenyls (PCBs) and polybrominated biphenyl ethers (PBDEs) were positively related to urban land cover and human population density while legacy organochlorine pesticides such as p,p'-DDE, lindane, and hexachlorobenzene were found in higher concentrations at rural sites. Levels of PBDEs in urban dipper eggs (range of 136-9299 ng/g lw) were among the highest ever reported in passerines, and some egg contaminants were at or approaching levels sufficient for adverse effects on avian development. With the exception of dieldrin, our data shows PCBs and other organochlorine pesticides have remained stable or increased in the past 20 years in dipper eggs, despite discontinued use. PMID- 23819782 TI - Hypoxia and P1 receptor activation regulate the high-affinity concentrative adenosine transporter CNT2 in differentiated neuronal PC12 cells. AB - Under several adverse conditions, such as hypoxia or ischaemia, extracellular levels of adenosine are elevated because of increased energy demands and ATP metabolism. Because extracellular adenosine affects metabolism through G-protein coupled receptors, its regulation is of high adaptive importance. CNT2 (concentrative nucleoside transporter 2) may play physiological roles beyond nucleoside salvage in brain as it does in other tissues. Even though nucleoside transport in brain has mostly been seen as being of equilibrative-type, in the present study, we prove that the rat phaeochromocytoma cell line PC12 shows a concentrative adenosine transport of CNT2-type when cells are differentiated to a neuronal phenotype by treatment with NGF (nerve growth factor). Differentiation of PC12 cells was also associated with the up-regulation of adenosine A1 receptors. Addition of adenosine receptor agonists to cell cultures increased CNT2-related activity by a mechanism consistent with A1 and A2A receptor activation. The addition of adenosine to the culture medium also induced the phosphorylation of the intracellular regulatory kinase AMPK (AMP-activated protein kinase), with this effect being dependent upon adenosine transport. CNT2 related activity of differentiated PC12 cells was also dramatically down regulated under hypoxic conditions. Interestingly, the analysis of nucleoside transporter expression after experimental focal ischaemia in rat brain showed that CNT2 expression was down-regulated in the infarcted tissue, with this effect somehow being restricted to other adenosine transporter proteins such as CNT3 and ENT1 (equilibrative nucleoside transporter 1). In summary, CNT2 is likely to modulate extracellular adenosine and cell energy balance in neuronal tissue. PMID- 23819784 TI - Asthma diagnosis and treatment - 1004. The utility of mannitol challenge in the assessment of asthma. PMID- 23819785 TI - Genetic relatedness, antimicrobial and biocide susceptibility comparative analysis of methicillin-resistant and -susceptible Staphylococcus pseudintermedius from Portugal. AB - Forty methicillin-resistant and -susceptible Staphylococcus pseudintermedius (MRSP and MSSP, respectively) from colonization and infection in dogs and cats were characterized for clonality, antimicrobial, and biocide susceptibility. MSSP were genetically more diverse than MRSP by multi-locus sequence typing and pulsed field gel electrophoresis. Three different spa types (t06, t02, t05) and two SCCmec types (II-III and V) were detected in the MRSP isolates. All MRSP and two MSSP strains were multidrug-resistant. Several antibiotic resistance genes (mecA, blaZ, tet(M), tet(K), aac(6')-Ie-aph(2')-Ia, aph(3')-III, ant(6)-Ia, sat4, erm(B), lnu(A), dfr(G), and catp(C221)) were identified by microarray and double mutations in the gyrA and grlA genes and a single mutation in the rpoB gene were detected by sequence analysis. No differences were detected between MSSP and MRSP in the chlorhexidine acetate (CHA) minimum inhibitory concentrations (MICs). However, two MSSP had elevated MIC to triclosan (TCL) and one to benzalkonium chloride and ethidium bromide. One MSSP isolate harboured a qacA gene, while in another a qacB gene was detected. None of the isolates harboured the sh-fabI gene. Three of the biocide products studied had high bactericidal activity (Otodine((r)), Clorexyderm Spot Gel((r)), Dermocanis Piocure-M((r))), while Skingel((r)) failed to achieve a five log reduction in the bacterial counting. S. pseudintermedius have become a serious therapeutic challenge in particular if methicillin- resistance and/or multidrug-resistance are involved. Biocides, like CHA and TCL, seem to be clinically effective and safe topical therapeutic options. PMID- 23819786 TI - Epigenetic switches in clag3 genes mediate blasticidin S resistance in malaria parasites. AB - Malaria parasites induce changes in the permeability of the infected erythrocyte membrane to numerous solutes, including toxic compounds. In Plasmodium falciparum, this is mainly mediated by PSAC, a broad-selectivity channel that requires the product of parasite clag3 genes for its activity. The two paralogous clag3 genes, clag3.1 and clag3.2, can be silenced by epigenetic mechanisms and show mutually exclusive expression. Here we show that resistance to the antibiotic blasticidin S (BSD) is associated with switches in the expression of these genes that result in altered solute uptake. Low concentrations of the drug selected parasites that switched from clag3.2 to clag3.1 expression, implying that expression of one or the other clag3 gene confers different transport efficiency to PSAC for some solutes. Selection with higher BSD concentrations resulted in simultaneous silencing of both clag3 genes, which severely compromises PSAC formation as demonstrated by blocked uptake of other PSAC substrates. Changes in the expression of clag3 genes were not accompanied by large genetic rearrangements or mutations at the clag3 loci or elsewhere in the genome. These results demonstrate that malaria parasites can become resistant to toxic compounds such as drugs by epigenetic switches in the expression of genes necessary for the formation of solute channels. PMID- 23819788 TI - Fatty acid esters of fumonisins: first evidence of their presence in maize. AB - Fumonisin derivatives obtained by esterification of fumonisin B1 (FB1) with palmitic, oleic and linoleic fatty acids have been recently described, but never reported in raw maize so far. In this study, the presence of oleoyl-EFB1 (EFB1OA) and linoleoyl-EFB1 (EFB1LA) in raw maize is reported by means of a suitable LC ESI-MS/MS method. In addition, the production of EFB1 derivatives by three Fusarium verticillioides strains is described on malt extract-based media and on corn meal-based growth media. EFB1OA and EFB1LA were produced by all considered strains in corn meal medium, with EFB1LA > EFB1OA. On the contrary, EFB1OA and EFB1LA were never observed in Fusarium cultures grown on a malt extract medium, suggesting that the esterification of FB1 can occur only in a complex matrix such as maize. PMID- 23819787 TI - Molecular epidemiology of canine GM1 gangliosidosis in the Shiba Inu breed in Japan: relationship between regional prevalence and carrier frequency. AB - BACKGROUND: Canine GM1 gangliosidosis is a fatal disease in the Shiba Inu breed, which is one of the most popular traditional breeds in Japan and is maintained as a standard breed in many countries. Therefore, it is important to control and reduce the prevalence of GM1 gangliosidosis for maintaining the quality of this breed and to ensure supply of healthy dogs to prospective breeders and owners. This molecular epidemiological survey was performed to formulate an effective strategy for the control and prevention of this disease. RESULTS: The survey was carried out among 590 clinically unaffected Shiba Inu dogs from the 8 districts of Japan, and a genotyping test was used to determine nation-wide and regional carrier frequencies. The number and native district of affected dogs identified in 16 years from 1997 to June 2013 were also surveyed retrospectively. Of the 590 dogs examined, 6 dogs (1.02%, 6/590) were carriers: 3 dogs (2.27%, 3/132) from the Kinki district and the other 3 dogs from the Hokkaido, Kanto, and Shikoku districts. The retrospective survey revealed 23 affected dogs, among which, 19 dogs (82.6%) were born within the last 7 years. Of the 23 affected dogs, 12 dogs (52.2%) were from the Kinki district. Pedigree analysis demonstrated that all the affected dogs and carriers with the pedigree information have a close blood relationship. CONCLUSIONS: Our results showed that the current carrier frequency for GM1 gangliosidosis is on the average 1.02% in Japan and rather high in the Kinki district, which may be related to the high prevalence observed over the past 16 years in this region. This observation suggests that carrier dogs are distributed all over Japan; however, kennels in the Kinki district may face an increased risk of GM1 gangliosidosis. Therefore, for effective control and prevention of this disease, it is necessary to examine as many breeding dogs as possible from all regions of Japan, especially from kennels located in areas with high prevalence and carrier frequency. PMID- 23819789 TI - The epidemiological and economic impact of a quadrivalent human papillomavirus (hpv) vaccine in Estonia. AB - BACKGROUND: This analysis assessed the epidemiological and economic impact of quadrivalent human papillomavirus (HPV4: 6/11/16/18) vaccination in Estonia. METHODS: A dynamic transmission model was used to assess the epidemiological and economic impact of the routine vaccination of 12-year-old girls with a HPV4 vaccine in preventing cervical cancer, cervical intraepithelial neoplasia (CIN) grades 1, 2 and 3 and genital warts. RESULTS: The model projected that at year 100, HPV4 vaccination would lead to a reduction of HPV 16/18 related cervical cancer incidence and deaths by over 97% and the incidence of HPV 6/11 related genital warts among Estonian women and men by over 94% and 81%, respectively. The incremental cost-effectiveness ratio of the HPV4 vaccination strategy was ? 4,889 per QALY gained over a time horizon of 100 years. CONCLUSIONS: Routine vaccination of 12-year-old girls with HPV4 vaccine appears to be cost-effective in Estonia, in addition to providing both short term and long term health gains. PMID- 23819790 TI - Evaluation of grafted patients with donor corneas that today are more than 100 years old. AB - PURPOSE: Life expectancy is increasing. When corneal donors become older and corneal-grafted patients live longer with their graft, the need for good-quality donor tissue becomes more crucial. The aim of the present investigation is to study grafted recipients with a donor cornea with a total tissue age of more than 100 years. METHODS: One thousand consecutive donor records from the Danish Cornea Bank were initially reviewed. After applying different inclusion criteria, 35 recipients with corneal donor tissue of more than 100 years of age were invited for a follow-up visit. Visual acuity, corneal transparency and thickness, and intraocular pressure were measured. Corneal topography and endothelial photos were taken. RESULTS: Seventeen of the invited patients attended the examination. The average age of the grafts at examination was 107 years old; the oldest being 118 years. Most grafts were still clear 23-35 years after transplantation, and almost one-fourth had best spectacle-corrected visual acuity (BSCVA) >= 0.50. Cell morphology showed irregularity in size and shape for both grafted and healthy corneas, but the alterations were more extensive in the grafted corneas. The average endothelial cell density (ECD) was 1360 mm(2) in the grafted corneas. Sixty per cent had ECD > 1000 cells/mm(2). No signs of decompensation were observed for those with <1000 cells. The average central corneal thickness of the grafts was 0.582 mm (SD = 0.067) compared with 0.494 mm (SD = 0.043) in the fellow cornea. CONCLUSION: This study shows a trend of moderate long-term survival and quality for very old grafts despite low ECD. Most recipients had a clear transplant, and one-fifth had BSCVA of 0.80. PMID- 23819791 TI - Mannitol has no impact on renal function after open partial nephrectomy in solitary kidneys. AB - Mannitol has been administered during partial nephrectomy as a renal protective agent for ischemic damage. However, we do not have any high-level clinical evidence of its effectiveness. The aim of the present study was to evaluate the effect of mannitol during open partial nephrectomy by comparing the postoperative renal function of patients who received it and those who did not. We retrospectively reviewed the records of 55 patients who underwent open partial nephrectomy for renal cancer in a solitary kidney from January 1990 to December 2012, and who were followed up postoperatively for at least 6 months. Of the 55 patients, mannitol was given to 20 patients (group M+) and not to the other 35 patients (group M-). We compared not only the postoperative estimated glomerular filtration rate, but also its decrease rate and the incidence of acute kidney injury requiring dialysis in the two groups. There were no significant differences in perioperative patient characteristics between the two groups. Mannitol made no significant difference in both the postoperative estimated glomerular filtration rate and its decrease rate at any point within 6 months of the postoperative period. The incidence of acute kidney injury requiring dialysis was one (5.0%) in group M+ and two (5.7%) in group M-. These findings suggest that there might be no advantage from the administration of mannitol during open partial nephrectomy. PMID- 23819792 TI - Mammalian target of rapamycin (mTOR) inhibition does not prevent lung adenocarcinoma-induced malignant pleural effusion. AB - The impact of temsirolimus was investigated in a murine model of malignant pleural effusion (MPE) created with intrapleural injection of Lewis Lung Cancer (LLC) cells. Temsirolimus (1 or 20 mg/kg) did not affect the pleural fluid volume or the number of pleural tumour foci. In addition, temsirolimus did not affect vascular endothelial growth factor expression by LLC cells in vitro. In conclusion, temsirolimus did not curtail experimental lung-adenocarcinoma-induced MPE. PMID- 23819793 TI - Recommendations for prophylaxis of pregnancy-related venous thromboembolism in carriers of inherited thrombophilia. Comment on the 2012 ACCP guidelines: a rebuttal. PMID- 23819794 TI - Analysis of hairpin RNA transgene-induced gene silencing in Fusarium oxysporum. AB - BACKGROUND: Hairpin RNA (hpRNA) transgenes can be effective at inducing RNA silencing and have been exploited as a powerful tool for gene function analysis in many organisms. However, in fungi, expression of hairpin RNA transcripts can induce post-transcriptional gene silencing, but in some species can also lead to transcriptional gene silencing, suggesting a more complex interplay of the two pathways at least in some fungi. Because many fungal species are important pathogens, RNA silencing is a powerful technique to understand gene function, particularly when gene knockouts are difficult to obtain. We investigated whether the plant pathogenic fungus Fusarium oxysporum possesses a functional gene silencing machinery and whether hairpin RNA transcripts can be employed to effectively induce gene silencing. RESULTS: Here we show that, in the phytopathogenic fungus F. oxysporum, hpRNA transgenes targeting either a beta glucuronidase (Gus) reporter transgene (hpGus) or the endogenous gene Frp1 (hpFrp) did not induce significant silencing of the target genes. Expression analysis suggested that the hpRNA transgenes are prone to transcriptional inactivation, resulting in low levels of hpRNA and siRNA production. However, the hpGus RNA can be efficiently transcribed by promoters acquired either by recombination with a pre-existing, actively transcribed Gus transgene or by fortuitous integration near an endogenous gene promoter allowing siRNA production. These siRNAs effectively induced silencing of a target Gus transgene, which in turn appeared to also induce secondary siRNA production. Furthermore, our results suggested that hpRNA transcripts without poly(A) tails are efficiently processed into siRNAs to induce gene silencing. A convergent promoter transgene, designed to express poly(A)-minus sense and antisense Gus RNAs, without an inverted-repeat DNA structure, induced consistent Gus silencing in F. oxysporum. CONCLUSIONS: These results indicate that F. oxysporum possesses functional RNA silencing machineries for siRNA production and target mRNA cleavage, but hpRNA transgenes may induce transcriptional self-silencing due to its inverted-repeat structure. Our results suggest that F. oxysporum possesses a similar gene silencing pathway to other fungi like fission yeast, and indicate a need for developing more effective RNA silencing technology for gene function studies in this fungal pathogen. PMID- 23819795 TI - Growth of single-crystalline cobalt silicide nanowires and their field emission property. AB - In this work, cobalt silicide nanowires were synthesized by chemical vapor deposition processes on Si (100) substrates with anhydrous cobalt chloride (CoCl2) as precursors. Processing parameters, including the temperature of Si (100) substrates, the gas flow rate, and the pressure of reactions were varied and studied; additionally, the physical properties of the cobalt silicide nanowires were measured. It was found that single-crystal CoSi nanowires were grown at 850 degrees C ~ 880 degrees C and at a lower gas flow rate, while single crystal Co2Si nanowires were grown at 880 degrees C ~ 900 degrees C. The crystal structure and growth direction were identified, and the growth mechanism was proposed as well. This study with field emission measurements demonstrates that CoSi nanowires are attractive choices for future applications in field emitters. PMID- 23819796 TI - Are women more susceptible than men to drug-induced QT prolongation? Concentration-QTc modelling in a phase 1 study with oral rac-sotalol. AB - AIM: To study the differences in QTc interval on ECG in response to a single oral dose of rac-sotalol in men and women. METHODS: Continuous 12-lead ECGs were recorded in 28 men and 11 women on a separate baseline day and following a single oral dose of 160 mg rac-sotalol on the following day. ECGs were extracted at prespecified time points and upsampled to 1000 Hz and analyzed manually in a central ECG laboratory on the superimposed median beat. Concentration-QTc analyses were performed using a linear mixed effects model. RESULTS: Rac-sotalol produced a significant reduction in heart rate in men and in women. An individual correction method (QTc I) most effectively removed the heart rate dependency of the QTc interval. Mean QTc I was 10 to 15 ms longer in women at all time points on the baseline day. Rac-sotalol significantly prolonged QTc I in both genders. The largest mean change in QTc I (DeltaQTc I) was greater in females (68 ms (95% confidence interval (CI) 59, 76 ms) vs. 27 ms (95% CI 22, 32 ms) in males). Peak rac-sotalol plasma concentration was higher in women than in men (mean Cmax 1.8 MUg ml(-1) (range 1.1-2.8) vs. 1.4 MUg ml(-1) (range 0.9-1.9), P = 0.0009). The slope of the concentration-DeltaQTc I relationship was steeper in women (30 ms per MUg ml(-1) vs. 23 ms per MUg ml(-1) in men; P = 0.0135). CONCLUSIONS: The study provides evidence for a greater intrinsic sensitivity to rac-sotalol in women than in men for drug-induced delay in cardiac repolarization. PMID- 23819797 TI - Protoporphyrin IX-beta-cyclodextrin bimodal conjugate: nanosized drug transporter and potent phototoxin. AB - Topical or systemic administration of 5-aminolevulinic acid (ALA) and its esters results in increased production and accumulation of protoporphyrin IX (PpIX) in cancerous lesions allowing effective application of photodynamic therapy (PDT). The large concentrations of exogenous ALA practically required to bypass the negative feedback control exerted by heme on enzymatic ALA synthesis and the strong dimerization propensity of ALA are shortcomings of the otherwise attractive PpIX biosynthesis. To circumvent these limitations and possibly enhance the phototoxicity of PpIX by adjuvant chemotherapy, covalent bonding of PpIX with a drug carrier, beta-cyclodextrin (betaCD) was implemented. The resulting PpIX + betaCD product had both carboxylic termini of PpIX connected to the CD. PpIX + betaCD was water soluble, was found to preferentially localize in mitochondria rather than in lysosomes both in MCF7 and DU145 cell lines while its phototoxiciy was comparable to that of PpIX. Moreover, PpIX + betaCD effectively solubilized the breast cancer drug tamoxifen metabolite N-desmethyltamoxifen (NDMTAM) in water. The PpIX + betaCD/NDMTAM complex was readily internalized by both cell lines employed. Furthermore, the multimodal action of PpIX + betaCD was demonstrated in MCF7 cells: while it retains the phototoxic profile of PpIX and its fluorescence for imaging purposes, PpIX + betaCD can efficiently transport tamoxifen citrate intracellularly and confer cell death through a synergy of photo- and chemotoxicity. PMID- 23819798 TI - Taking health systems research to the district level: a new approach to accelerate progress in global health. PMID- 23819799 TI - Asthma diagnosis and treatment - 1005. Optimization for the withdrawal of inhaled corticosteroid treatment by monitoring fractional exhaled nitric oxide (feno) and lung functions. PMID- 23819800 TI - Low-fouling, biospecific films prepared by the continuous assembly of polymers. AB - We report that the continuous assembly of polymers (CAP) approach, mediated by ring-opening metathesis polymerization (ROMP), is a facile and versatile technology to prepare engineered nanocoatings for various biomedical applications. Low-fouling coatings on particles were obtained by the formation of multicompositional, layered films via simple and efficient tandem CAP(ROMP) processes that are analogous to chain extension reactions. In addition, the CAP(ROMP) approach allows for the efficient postfunctionalization of the CAP films with bioactive moieties via cross-metathesis reactions between the surface immobilized catalysts and symmetrical alkene derivatives. The combined features of the CAP(ROMP) approach (i.e., versatile polymer selection and facile functionalization) allow for the fabrication and surface modification of various types of polymer films, including those with intrinsic protein-repellent properties and selective protein recognition capabilities. This study highlights the various types of advanced coatings and materials that the CAP approach can be used to generate, which may be useful for biomedical applications. PMID- 23819801 TI - Effects of geometry and electronic structure on the molecular self-assembly of naphthyl-based dimers. AB - Three new series of symmetric dimers containing a naphthoyloxybenzyl (NB), benzoyloxynaphthyl (BN), and naphthoyloxysalicyl (NS) mesogenic core linked to an alkylene spacer via an imino group were synthesized. The effects of the variant spacer parity as well as the variant core structure on the mesomorphic properties have been studied. The dimers having NB and BN mesogenic units display intercalated smectic structures regardless of the spacer parity. In contrast, bilayer smectic and Colrec structures are observed for the NS core compounds with even and odd spacers, respectively. The influence of geometric and electronic factors on the mesomorphic behavior, in particular on the molecular packing within the smectic phase, is discussed based on conformational and dipolar considerations following DFT calculations using model molecules. The difference in self-organization of symmetric naphthyl-based dimers appears to be governed by the competition between geometric factors and dipole-dipole interactions between identical mesogenic units. PMID- 23819802 TI - Trimethoxy-benzaldehyde levofloxacin hydrazone inducing the growth arrest and apoptosis of human hepatocarcinoma cells. AB - BACKGROUND: In order to search for new structural modification strategies on fluoroquinolones, we have designed and synthesized a series of fluoroquinolone derivatives by linking various hydrazine compounds to the C-3 carboxyl group of levofloxacin and assessed their anticancer activities. Several novel levofloxacin derivatives displayed potent cytotoxicity against the tested cancer cell lines in vitro. In the present study, we investigated the effect of 1-Cyclopropyl-6-fluoro 4-oxo-7- piperazin-1, 4-dihydro- quinoline- 3-carboxylic acid benzo [1,3] dioxol 5- ylmethylene- hydrazide (QNT11) on the apoptosis of human hepatocarcinoma cells in vitro. METHODS: The inhibition effects of QNT11 on cell proliferation were examined by MTT assay. Cell apoptosis was determined by TUNEL and DNA agarose gel electrophoresis method. The topoisomerase IotaIota activity was measured by agarose gel electrophoresis using Plasmid pBR322 DNA as the substrate. Cell cycle progression was analyzed using flow cytometry in conjunction with ethanol fixation and propidium iodide staining. Mitochondrial membrane potential (?psim) was measured by high content screening image system. The caspase-9, caspase-8, caspase-3, Bcl-2, Bax, CDK1, Cyclin B1and cytochrome c protein expressions were detected by Western blot analysis. RESULTS: QNT11 showed selective cytotoxicity against Hep3B, SMMC-7721, MCF-7 and HCT-8 cell lines with IC50 values of 2.21 MUM, 2.38 MUM, 3.17 MUM and 2.79 MUM, respectively. In contrast, QNT11 had weak cytotoxicity against mouse bone marrow mesenchymal stem cells (BMSCs) with IC50 value of 7.46 MUM. Treatment of Hep3B cells with different concentrations of QNT11 increased the percentage of the apoptosis cells significantly, and agarose gel electrophoresis revealed the ladder DNA bands typical of apoptotic cells, with a decrease in the mitochondrial membrane potential. Compared to the control group, QNT11 could influence the DNA topoisomerase IIactivity and inhibit the religation of DNA strands, thus keeping the DNA in fragments. There was a significant increase of cytochrome c in the cytosol after 24 h of treatment with QNT11 and a decrease in the mitochondrial compartment. Observed changes in cell cycle distribution by QNT11 treated might be caused by insufficient preparation for G2/M transition. In addition, QNT11 increased the protein expression of Bax, caspase-9, caspase-8, caspase-3, as well as the cleaved activated forms of caspase-9, caspase-8 and caspase-3 significantly, whereas the expression of Bcl-2 decreased. CONCLUSIONS: Our results showed that QNT11 as a fluoroquinolone derivative exerted potent and selectively anticancer activity through the mechanism of eukaryotic topoisomerase II poisoning. The growth inhibition was in large part mediated via apoptosis-associated mitochondrial dysfunction and regulation of Bcl-2 signaling pathways. PMID- 23819803 TI - DXR inhibition by potent mono- and disubstituted fosmidomycin analogues. AB - The antimalarial compound fosmidomycin targets DXR, the enzyme that catalyzes the first committed step in the MEP pathway, producing the essential isoprenoid precursors, isopentenyl diphosphate and dimethylallyl diphosphate. The MEP pathway is used by a number of pathogens, including Mycobacterium tuberculosis and apicomplexan parasites, and differs from the classical mevalonate pathway that is essential in humans. Using a structure-based approach, we designed a number of analogues of fosmidomycin, including a series that are substituted in both the Calpha and the hydroxamate positions. The latter proved to be a stable framework for the design of inhibitors that extend from the polar and cramped (and so not easily druggable) substrate-binding site and can, for the first time, bridge the substrate and cofactor binding sites. A number of these compounds are more potent than fosmidomycin in terms of killing Plasmodium falciparum in an in vitro assay; the best has an IC50 of 40 nM. PMID- 23819804 TI - Combined spectroelectrochemical and theoretical study of electron-rich dendritic 2,5-diaminothiophene derivatives: N,N,N',N'-tetrakis-(4-diphenylamino-phenyl) thiophene-2,5-diamine. AB - The in situ spectroelectrochemical and electron spin resonance (ESR) behavior of the recently prepared N,N,N',N'-tetrakis-(4-diphenylamino-phenyl)-thiophene-2,5 diamine 11 is presented. The results are compared to the ones of the parent 2,5 bis-diphenylamino-thiophene 41 as well as to the corresponding high-molar third dendrimer generation 8 containing the same thiophene-2,5-diamine core. The dendritic compound 11 can be reversibly oxidized in three separated steps to yield the corresponding stable monocation 11(*+), dication 11(2+), and tetracation 11(4+). A well resolved ESR spectrum of the corresponding cation radical 11(*+) with dominating splittings from two nitrogen atoms and two hydrogen atoms was observed at the first oxidation peak similar to 41(*+). The shape of the SOMOs orbitals very well correlates with the proposed distribution of the unpaired electron mainly on the thiophene center and neighboring nitrogen atoms. The spin delocalization on the central thiophene moiety in the monocations for all three model compounds 41(*+), 11(*+), and 8(*+) was confirmed. The computed single occupied molecular orbital (SOMO) for trication 11(*3+) is completely different compared to the SOMO of the corresponding monocation 11(*+), and it confirms a largely delocalized unpaired spin density. Dominating diamagnetic product was determined at the third oxidation peak, confirming the formation of a tetracation by a two electron oxidation of ESR silent dication. The positive charge is fully delocalized over the lateral parts of the molecule leading to the high stability of tetracation 11(4+). The estimated theoretical limit energy of the lowest optical transition S0 -> S1 is 2.90 eV, and it can be achieved for the 3D dendrimer generation. PMID- 23819805 TI - Proteomics analysis of the regulatory role of Rpf/DSF cell-to-cell signaling system in the virulence of Xanthomonas campestris. AB - The black rot pathogen Xanthomonas campestris utilizes molecules of the diffusible signal factor (DSF) family as signals to regulate diverse processes contributing to virulence. DSF signal synthesis and transduction requires proteins encoded by the rpf gene cluster. RpfF catalyzes DSF synthesis, whereas the RpfCG two-component system links the perception of DSF to alteration in the level of the second messenger cyclic di-GMP. As this nucleotide can exert a regulatory influence at the post-transcriptional and post-translational levels, we have used comparative proteomics to identify Rpf-regulated processes in X. campestris that may not be revealed by transcriptomics. The abundance of a number of proteins was altered in rpfF, rpfC, or rpfG mutants compared with the wild type. These proteins belonged to several functional categories, including biosynthesis and intermediary metabolism, regulation, oxidative stress or antibiotic resistance, and DNA replication. For many of these proteins, the alteration in abundance was not associated with alteration in transcript level. A directed mutational analysis allowed us to describe a number of new virulence factors among these proteins, including elongation factor P and a putative outer membrane protein, which are both widely conserved in bacteria. PMID- 23819806 TI - Host cell entry of powdery mildew is correlated with endosomal transport of antagonistically acting VvPEN1 and VvMLO to the papilla. AB - Challenge by a nonadapted powdery mildew fungal pathogen leads to the formation of a local cell-wall apposition (papilla) beneath the point of attempted penetration. Several plasma membrane (PM) proteins with opposing roles in powdery mildew infection, including Arabidopsis thaliana PENETRATION1 (PEN1) and barley (Hordeum vulgare) MILDEW RESISTANCE LOCUS O (MLO), are localized to the site of powdery mildew attack. PEN1 contributes to penetration resistance to nonadapted powdery mildews, whereas MLO is a susceptibility factor required by adapted powdery mildew pathogens for host cell entry. Our previous studies have demonstrated that the vesicle and endosomal trafficking inhibitors, brefeldin A and wortmannin, have opposite effects on the penetration rates of adapted and nonadapted powdery mildews on grapevine. These findings prompted us to study the pathogen-induced intracellular trafficking of grapevine variants of MLO and PEN1. We first identified grapevine (Vitis vinifera) VvPEN1 and VvMLO orthologs that rescue Arabidopsis Atpen1 and Atmlo2 mlo6 mlo12 null mutants, respectively. By using endomembrane trafficking inhibitors in combination with fluorescence microscopy, we demonstrate that VvMLO3/VvMLO4 and VvPEN1 are co-trafficked together from the PM to the site of powdery mildew challenge. This focal accumulation of VvMLO3/VvMLO4 and VvPEN1 to the site of attack seems to be required for their opposing functions during powdery mildew attack, because their subcellular localization is correlated with the outcome of attempted powdery mildew penetration. PMID- 23819807 TI - Analysis of small-sample clinical genomics studies using multi-parameter shrinkage: application to high-throughput RNA interference screening. AB - High-throughput (HT) RNA interference (RNAi) screens are increasingly used for reverse genetics and drug discovery. These experiments are laborious and costly, hence sample sizes are often very small. Powerful statistical techniques to detect siRNAs that potentially enhance treatment are currently lacking, because they do not optimally use the amount of data in the other dimension, the feature dimension. We introduce ShrinkHT, a Bayesian method for shrinking multiple parameters in a statistical model, where 'shrinkage' refers to borrowing information across features. ShrinkHT is very flexible in fitting the effect size distribution for the main parameter of interest, thereby accommodating skewness that naturally occurs when siRNAs are compared with controls. In addition, it naturally down-weights the impact of nuisance parameters (e.g. assay-specific effects) when these tend to have little effects across siRNAs. We show that these properties lead to better ROC-curves than with the popular limma software. Moreover, in a 3 + 3 treatment vs control experiment with 'assay' as an additional nuisance factor, ShrinkHT is able to detect three (out of 960) significant siRNAs with stronger enhancement effects than the positive control. These were not detected by limma. In the context of gene-targeted (conjugate) treatment, these are interesting candidates for further research. PMID- 23819808 TI - The utility of fat mass index vs. body mass index and percentage of body fat in the screening of metabolic syndrome. AB - BACKGROUND: It has been well documented that obesity is closely associated with metabolic syndrome (MetS). Although body mass index (BMI) is the most frequently used method to assess overweightness and obesity, this method has been criticized because BMI does not always reflect true body fatness, which may be better evaluated by assessment of body fat and fat-free mass. The objective of this study was to investigate the best indicator to predict the presence of MetS among fat mass index, BMI and percentage of body fat (BF %) and determine its optimal cut-off value in the screening of MetS in practice. METHODS: A cross-sectional study of 1698 subjects (aged 20-79 years) who participated in the annual health check-ups was employed. Body composition was measured by bioelectrical impedance analysis (BIA). Fat mass index (FMI) was calculated. Sex-specific FMI quartiles were defined as follows: Q1: <4.39, Q2:4.39- < 5.65, Q3:5.65- < 7.03, Q4:>=7.03,in men; and Q1:<5.25, Q2:5.25- < 6.33, Q3:6.33- < 7.93,Q4:>=7.93, in women. MetS was defined by National Cholesterol Education Program/Adult Treatment Panel III criteria. The association between FMI quartiles and MetS was assessed using Binary logistic regression. Receiver operating curve (ROC) analysis was used to determine optimal cutoff points for BMI,BF% and FMI in relation to the area under the curve (AUC), sensitivity and specificity in men and women. RESULTS: The adjusted odds ratios (95% CI) for the presence of MetS in the highest FMI quartile versus lowest quartile were 79.143(21.243-294.852) for men (P < 0.01) and 52.039(4.144-653.436) for women (P < 0.01) after adjusting age, BMI, BF%, TC, LDL, CRP, smoking status and exercise status, and the odds ratios were 9.166(2.157-38.952) for men (P < 0.01) and 25.574(1.945-336.228) for women (P < 0.05) when WC was also added into the adjustment. It was determined that BMI values of 27.45 and 23.85 kg/m2, BF% of 23.95% and 31.35% and FMI of 7.00 and 7.90 kg/m2 were the optimal cutoff values to predict the presence of MetS among men and women according to the ROC curve analysis. Among the indicators used to predict MetS, FMI was the index that showed the greatest area under the ROC curve in both sexes. CONCLUSIONS: Higher FMI levels appear to be independently and positively associated with the presence of MetS regardless of BMI and BF%. FMI seems to be a better screening tool in prediction of the presence of metabolic syndrome than BMI and percentage of body fat in men and women. PMID- 23819809 TI - Flow patterns on spectral-domain optical coherence tomography reveal flow directions at retinal vessel bifurcations. AB - PURPOSE: To study intravascular characteristics of flowing blood in retinal vessels using spectral-domain optical coherence tomography (SD-OCT). METHODS: Examination of selected arterial bifurcations and venous sites of confluence in 25 healthy 11-year-old children recruited as an ad hoc subsample from the population-based, observational Copenhagen Child Cohort 2000 study. RESULTS: The blood stream in retinal arteries maintains a figure-of-8 SD-OCT profile consistent with a laminar flow in concentric sheets and a parabolic velocity distribution up to the point of divergence at arterial bifurcations. In contrast, the blood stream at the site of confluence of two retinal veins remains divided into two parallel sets of sheets with separate velocity distribution for a downstream distance of at least four trunk vessel diameters. Consequently, retinal trunk vessels near bifurcations/confluences have distinctly different internal SD-OCT profiles, a figure-of-8 pattern in arteries and a figure figure of-88 in veins that can be used to distinguish between the two vessel types. CONCLUSION: This study verified the hypothesis that directions of blood flow at dichotomous vascular branchings can be determined using SD-OCT. This feature may assist the identification of flow reversal near sites of vascular occlusion, the analysis of blood flow near vascular malformations and the segmentation of retinal SD-OCT images. PMID- 23819810 TI - Digital ureteroscopic visualization of lesions responsible for chronic unilateral hematuria, so-called idiopathic renal bleeding. PMID- 23819811 TI - Mathematical modeling of the transport and dissolution of citrate-stabilized silver nanoparticles in porous media. AB - A one-dimensional mathematical model is developed and implemented to describe the coupled transport of citrate-stabilized silver nanoparticles (nAg) and dissolved silver ions in porous media. This hybrid numerical simulator employs an Eulerian finite difference (FD) method to model the reactive transport of dissolved constituents and a Lagrangian (random-walk particle-tracking (RWPT)) approach to capture the transport and differential aging of nanoparticles. Model performance is demonstrated by comparison of simulations with data obtained from a series of nAg transport and dissolution column experiments. A three pore volume pulse of a citrate-stabilized nAg suspension (ca. 3 mg/L) was introduced into a 12 or 16 cm long column packed with water-saturated quartz sand at a pore-water velocity of ca. 7.6 m/day and pH 4 or 7. While low retention levels (ca.17%) and no dissolution were observed for the pH 7 column, analysis of column effluent samples for pH 4 conditions indicated that ca. 88% of the injected silver mass was retained in the column, while 6% was eluted as particles (nAg) and 6% as dissolved ions (Ag(+)). Hybrid model simulations, employing a lumped nAg dissolution coefficient of (3.45 +/- 0.35) * 10(-2)/h, are shown to accurately capture measured nAg transport and Ag(+) release behavior. A model sensitivity analysis explores the influence of flow velocity and particle size on nAg transport and fate, indicating that as velocity and particle size decrease, nAg dissolution and Ag(+) transport processes increasingly dominate silver mobility. PMID- 23819812 TI - Circulating miRNA-20a and miRNA-203 for screening lymph node metastasis in early stage cervical cancer. AB - BACKGROUND: MicroRNAs (miRNAs) are small, noncoding RNAs that are critical regulators of various diseases, including cancer, which may represent a novel class of cancer biomarkers. AIMS: We hypothesized that microRNA-20a (miR-20a) and microRNA-203 (miR-203), which were altered in lymphatic metastatic tissues, could be directly assayed in the serum and used to detect the lymph node status of cervical cancer patients. METHODS: We analyzed serum levels of miR-20a and miR 203 in 80 patients with stage I-IIA of cervical cancer by quantitative real-time polymerase chain reaction assay. Blood samples were collected before surgery and therapy. Logistic regression was used to measure the influence of different variables. Receiver operating characteristic analysis could evaluate the sensitivity and specificity in separating lymph node metastasis (LNM) (+) patients from LNM (-) patients by serum miR-20a and miR-203. RESULTS: We found that the expression level of miR-20a was significantly higher in cervical cancer patients compared to healthy controls (p=0.004), patients with LNM tended to have overexpression of miR-20a (p=0.000), the odds ratio was 1.552. The expression level of miR-203 in cervical cancer patients was also significantly increased in comparison to the healthy patients (p=0.000), while downregulated miR-203 was correlated with LNM (p=0.001), the odds ratio was 0.849. When miR-20a was used for differentiation of LNM (+) patients from LNM (-) patients, the value of the area under the receiver-operating curve (AUC) was 0.734+/-0.058, the sensitivity and specificity of serum miR-20a were 75% and 72.5%, respectively, the cut-off point was 3.0. But the AUC of miR-203 was only 0.658+/-0.061, which showed low accuracy, the sensitivity and specificity were 65% and 62.5%, respectively, the cut-off point was 0.13. CONCLUSION: Our results suggested that the circulating miR-20a may be a potential biomarker for detecting the lymph node status of cervical cancer patients. PMID- 23819813 TI - Study on key genes and regulatory networks associated with osteoporosis by microarray technology. AB - OBJECTIVE: DNA microarray data of patients with osteoporosis were compared with that of healthy people to identify key genes and thus disclose the underlying regulatory network. METHODS: Microarray dataset GSE35958 was downloaded from the Gene Expression Omnibus database, including five gene chips from patients with primary osteoporosis and four from age-matching nonosteoporosis controls. Raw data were preprocessed and differentially expressed genes (DEGs) were identified by the t-test. Then, function and pathway annotations were given by gene ontology (GO) and KEGG. The regulatory network for the DEGs was established from the aspects of transcription factors and microRNAs (miRNAs). The regulators of the miRNAs were also predicted by the MATCH algorithm. RESULTS: A total of 274 DEGs were obtained with 47 significantly over-represented GO terms and 2 KEGG pathways. Transcriptional and post-transcriptional regulatory networks were established for the DEGs. Moreover, upstream regulators of the miRNAs were also obtained. CONCLUSION: A range of genes, which might be implicated in the development of osteoporosis were obtained in the present study. Our findings are of possible benefit for the understanding of the unsolved regulatory mechanisms, and future clinical diagnosis as well as treatment. PMID- 23819814 TI - Association of genetic polymorphisms in matrix metalloproteinase-9 and coronary artery disease in the Chinese Han population: a case-control study. AB - OBJECTIVE: Matrix metalloproteinase-9 (MMP-9) plays an important role in inflammation and matrix degradation involved in atherosclerosis and plaque rupture. The T allele of rs3918242 has been reported to lead to a high promoter activity and associate with the extent of coronary artery disease (CAD). And some studies have reported that the G allele of rs17576 might be associated with CAD. The aim of this study was to assess the association between the polymorphisms of the MMP-9 gene and CAD in the Chinese Han population. METHODS: This case-control study comprised 258 CAD cases and 153 controls from the Chinese Han Population. The genomic DNA of MMP-9 was isolated from whole blood. Polymerase chain reaction based restriction fragment length polymorphism was used to determine the rs3918242 and rs17576 genotypes in the MMP-9 gene and the total serum levels of MMP-9 were measured using enzyme-linked immunosorbent assay in both case and control groups. RESULTS: Analysis of MMP-9 gene polymorphisms showed that the frequencies of the T allele and CT+TT genotypes of rs3918242 were significantly higher in the case group than in the control group (p<0.05). However, the distribution of variant genotypes of rs17576 did not differ between the case and control groups (p>0.05). The total serum level of MMP-9 was significantly higher in the case group than in the control group (p<0.05). The subjects carrying T alleles in the CAD group had higher average serum MMP-9 levels compared with CC genotypes (p<0.05). CONCLUSIONS: Our results suggest that the single-nucleotide polymorphism of rs3918242 in the MMP-9 gene is associated with CAD and high serum levels of MMP-9 are also associated with CAD in the Chinese Han population. Therefore, genetic variation of rs3918242 may participate in the development of CAD through influencing MMP-9 expression. PMID- 23819815 TI - Mercury increases water permeability of a plant aquaporin through a non-cysteine related mechanism. AB - Water transport across cellular membranes is mediated by a family of membrane proteins known as AQPs (aquaporins). AQPs were first discovered on the basis of their ability to be inhibited by mercurial compounds, an experiment which has followed the AQP field ever since. Although mercury inhibition is most common, many AQPs are mercury insensitive. In plants, regulation of AQPs is important in order to cope with environmental changes. Plant plasma membrane AQPs are known to be gated by phosphorylation, pH and Ca2+. We have previously solved the structure of the spinach AQP SoPIP2;1 (Spinacia oleracea plasma membrane intrinsic protein 2;1) in closed and open conformations and proposed a mechanism for how this gating can be achieved. To study the effect of mercury on SoPIP2;1 we solved the structure of the SoPIP2;1-mercury complex and characterized the water transport ability using proteoliposomes. The structure revealed mercury binding to three out of four cysteine residues. In contrast to what is normally seen for AQPs, mercury increased the water transport rate of SoPIP2;1, an effect which could not be attributed to any of the cysteine residues. This indicates that other factors might influence the effect of mercury on SoPIP2;1, one of which could be the properties of the lipid bilayer. PMID- 23819816 TI - Improving implementation of evidence-based practice in mental health service delivery: protocol for a cluster randomised quasi-experimental investigation of staff-focused values interventions. AB - BACKGROUND: There is growing acceptance that optimal service provision for individuals with severe and recurrent mental illness requires a complementary focus on medical recovery (i.e., symptom management and general functioning) and personal recovery (i.e., having a 'life worth living'). Despite significant research attention and policy-level support, the translation of this vision of healthcare into changed workplace practice continues to elude. Over the past decade, evidence-based training interventions that seek to enhance the knowledge, attitudes, and skills of staff working in the mental health field have been implemented as a primary redress strategy. However, a large body of multi disciplinary research indicates disappointing rates of training transfer. There is an absence of empirical research that investigates the importance of worker motivation in the uptake of desired workplace change initiatives. 'Autonomy' is acknowledged as important to human effectiveness and as a correlate of workplace variables like productivity, and wellbeing. To our knowledge, there have been no studies that investigate purposeful and structured use of values-based interventions to facilitate increased autonomy as a means of promoting enhanced implementation of workplace change. METHODS: This study involves 200 mental health workers across 22 worksites within five community-managed organisations in three Australian states. It involves cluster-randomisation of participants within organisation, by work site, to the experimental (values) condition, or the control (implementation). Both conditions receive two days of training focusing on an evidence-based framework of mental health service delivery. The experimental group receives a third day of values-focused intervention and 12 months of values-focused coaching. Well-validated self-report measures are used to explore variables related to values concordance, autonomy, and self-reported implementation success. Audits of work files and staff work samples are reviewed for each condition to determine the impact of implementation. Self-determination theory and theories of organisational change are used to interpret the data. DISCUSSION: The research adds to the current knowledge base related to worker motivation and uptake of workplace practice. It describes a structured protocol that aims to enhance worker autonomy for imposed workplace practices. The research will inform how best to measure and conceptualise transfer. These findings will apply particularly to contexts where individuals are not 'volunteers' in requisite change processes. TRIAL REGISTRATION ACTRN: ACTRN12613000353796. PMID- 23819818 TI - Live anatomy of the perineal body in patients with third-degree rectocele. AB - AIM: In many pelvic floor disorders, the perineal body is damaged or destroyed. There is still a considerable variation in anatomical descriptions of the perineal body and even more debate with regard to its attachments and relationships. Cadaveric dissections do not always reflect the functional behaviour of structures in the pelvis and description of live anatomy on imaging studies is not always reliable. This study aimed to define the anatomy of the perineal body in patients with rectocele during the live dissection required for minimally invasive surgical repair. METHOD: From January 2007 to December 2009 consecutive patients requiring surgery for third-degree rectocele and symptoms of obstructed defaecation were recruited. Participants underwent dissection of the perineal body, rectum and vagina preliminary to a tissue fixation system, an operation which inserts a tensioned tape to repair the perineal body. RESULTS: Thirty Caucasian female patients, mean age 61 (range 47-87) years, mean parity 2.6 (range 1-5), were included. Live dissection demonstrated that the perineal body was divided into two parts, joined by a stretched central part, anchored laterally by the deep transverse perineii muscle to the descending ramus of the pubic bone. The mean longitudinal length of the perineal body was 4.5 (3.5-5.5) cm, accounting for 50% of the posterior vaginal support. CONCLUSION: In women with low rectocele, the perineal body appears to be divided into two parts, severely displaced behind the ischial tuberosities. PMID- 23819817 TI - Pathway analysis of genome-wide data improves warfarin dose prediction. AB - BACKGROUND: Many genome-wide association studies focus on associating single loci with target phenotypes. However, in the setting of rare variation, accumulating sufficient samples to assess these associations can be difficult. Moreover, multiple variations in a gene or a set of genes within a pathway may all contribute to the phenotype, suggesting that the aggregation of variations found over the gene or pathway may be useful for improving the power to detect associations. RESULTS: Here, we present a method for aggregating single nucleotide polymorphisms (SNPs) along biologically relevant pathways in order to seek genetic associations with phenotypes. Our method uses all available genetic variants and does not remove those in linkage disequilibrium (LD). Instead, it uses a novel SNP weighting scheme to down-weight the contributions of correlated SNPs. We apply our method to three cohorts of patients taking warfarin: two European descent cohorts and an African American cohort. Although the clinical covariates and key pharmacogenetic loci for warfarin have been characterized, our association metric identifies a significant association with mutations distributed throughout the pathway of warfarin metabolism. We improve dose prediction after using all known clinical covariates and pharmacogenetic variants in VKORC1 and CYP2C9. In particular, we find that at least 1% of the missing heritability in warfarin dose may be due to the aggregated effects of variations in the warfarin metabolic pathway, even though the SNPs do not individually show a significant association. CONCLUSIONS: Our method allows researchers to study aggregative SNP effects in an unbiased manner by not preselecting SNPs. It retains all the available information by accounting for LD-structure through weighting, which eliminates the need for LD pruning. PMID- 23819819 TI - Professional killer cell deficiencies and decreased survival in pulmonary arterial hypertension. AB - BACKGROUND AND OBJECTIVE: Increasing evidence implicates lymphocytes in pulmonary arterial hypertension (PAH) pathogenesis. Rats deficient in T-lymphocytes show increased propensity to develop PAH but when injected with endothelial progenitor cells are protected from PAH (a mechanism dependent on natural killer (NK) cells). A decreased quantity of circulating cytotoxic CD8+ T-lymphocytes and NK cells are now reported in PAH patients; however, the effect of lymphocyte depletion on disease outcome is unknown. METHODS: This prospective study analysed the lymphocyte profile and plasma brain natriuretic peptide (BNP) levels of patients with idiopathic PAH (IPAH), connective tissue disease-associated PAH (CTD-APAH) and matched healthy controls. Lymphocyte surface markers studied include: CD4+ (helper T-cell marker), CD8+ (cytotoxic T-cell marker), CD56/CD16 (NK cell marker) and CD19+ (mature B-cell marker). Lymphocyte deficiencies and plasma BNP levels were then correlated with clinical outcome. RESULTS: Fourteen patients with PAH (9 IPAH, 5CTD) were recruited. Three patients were deceased at 1-year follow-up; all had elevated CD4 : CD8 ratios and deficiencies of NK cells and cytotoxic CD8+ T-lymphocytes at recruitment. Patients with normal lymphocyte profiles at recruitment were all alive a year later, and none were on the active transplant list. As univariate markers, cytotoxic CD8+ T-cell and NK cell counts were linked to short-term survival. CONCLUSIONS: Deficiencies in NK cells and cytotoxic CD8+ T-cells may be associated with an increased risk of death in PAH patients. Further research is required in larger numbers of patients and to elucidate the mechanism of these findings. PMID- 23819820 TI - In situ preparation of monodispersed Ag/polyaniline/Fe3O4 nanoparticles via heterogeneous nucleation. AB - Acrylic acid and styrene were polymerized onto monodispersed Fe3O4 nanoparticles using a grafting copolymerization method. Aniline molecules were then bonded onto the Fe3O4 nanoparticles by electrostatic self-assembly and further polymerized to obtain uniform polyaniline/Fe3O4 (PANI/Fe3O4) nanoparticles (approximately 35 nm). Finally, monodispersed Ag/PANI/Fe3O4 nanoparticles were prepared by an in situ reduction reaction between emeraldine PANI and silver nitrate. Fourier transform infrared and UV-visible spectrometers and a transmission electron microscope were used to characterize both the chemical structure and the morphology of the resulting nanoparticles. PMID- 23819821 TI - Occurrence of bound 3-monochloropropan-1,2-diol content in commonly consumed foods in Hong Kong analysed by enzymatic hydrolysis and GC-MS detection. AB - The aim of this study was to determine the level of bound 3-monochloropropan-1,2 diol in foodstuffs commonly consumed in Hong Kong, China, by an enzymatic hydrolysis indirect method which proved to be free from interferences. A total of 290 samples were picked up randomly from the local market and analysed. About 73% of these samples were found to contain detectable amounts of bound 3-MCPD. Amongst the 73 food items, bound 3-MCPD was not detected in 13 food items, including extra virgin olive oil, beef ball/salami, beef flank, ham/Chinese ham, nuts, seeds, soy sauce, oyster sauce, butter, yoghurt, cream, cheese and milk. For those found to contain detectable bound 3-MCPD, the content ranged up to 2500 ug kg(-1). The highest mean bound 3-MCPD content among the 14 food groups was in biscuits (440 [50-860] ug kg(-1)), followed by fats and oils (390 [n.d.-2500] ug kg(-1)), snacks (270 [9-1000] ug kg(-1)), and Chinese pastry (270 [n.d.-1200] ug kg(-1)). Among the samples, the highest bound 3-MCPD content was in a grape seed oil (2500 ug kg(-1)), followed by a walnut flaky pastry (1200 ug kg(-1)) and a grilled corn (1000 ug kg(-1)). Basically, the results of this study agreed well with other published results in peer-reviewed journals, except for cheese, cream, ham, nuts and seeds. PMID- 23819822 TI - Asthma diagnosis and treatment - 1001. Identification of prevalent sensitizing allergens in India. PMID- 23819823 TI - Estimating large numbers. AB - Despite their importance in public discourse, numbers in the range of 1 million to 1 trillion are notoriously difficult to understand. We examine magnitude estimation by adult Americans when placing large numbers on a number line and when qualitatively evaluating descriptions of imaginary geopolitical scenarios. Prior theoretical conceptions predict a log-to-linear shift: People will either place numbers linearly or will place numbers according to a compressive logarithmic or power-shaped function (Barth & Paladino, ; Siegler & Opfer, ). While about half of people did estimate numbers linearly over this range, nearly all the remaining participants placed 1 million approximately halfway between 1 thousand and 1 billion, but placed numbers linearly across each half, as though they believed that the number words "thousand, million, billion, trillion" constitute a uniformly spaced count list. Participants in this group also tended to be optimistic in evaluations of largely ineffective political strategies, relative to linear number-line placers. The results indicate that the surface structure of number words can heavily influence processes for dealing with numbers in this range, and it can amplify the possibility that analogous surface regularities are partially responsible for parallel phenomena in children. In addition, these results have direct implications for lawmakers and scientists hoping to communicate effectively with the public. PMID- 23819824 TI - Ecology and geography of hemorrhagic fever with renal syndrome in Changsha, China. AB - BACKGROUND: Hemorrhagic fever with renal syndrome (HFRS) is an important public health problem in mainland China. HFRS is particularly endemic in Changsha, the capital city of Hunan Province, with one of the highest incidences in China. The occurrence of HFRS is influenced by environmental factors. However, few studies have examined the relationship between environmental variation (such as land use changes and climate variations), rodents and HFRS occurrence. The purpose of this study is to predict the distribution of HFRS and identify the risk factors and relationship between HFRS occurrence and rodent hosts, combining ecological modeling with the Markov chain Monte Carlo approach. METHODS: Ecological niche models (ENMs) were used to evaluate potential geographic distributions of rodent species by reconstructing details of their ecological niches in ecological dimensions, and projecting the results onto geography. The Genetic Algorithm for Rule-set Production was used to produce ENMs. Data were collected on HFRS cases in Changsha from 2005 to 2009, as well as national land survey data, surveillance data of rodents, meteorological data and normalized difference vegetation index (NDVI). RESULTS: The highest occurrence of HFRS was in districts with strong temperature seasonality, where elevation is below 200 m, mean annual temperature is around 17.5 degrees C, and annual precipitation is below 1600 mm. Cultivated and urban lands in particular are associated with HFRS occurrence. Monthly NDVI values of areas predicted present is lower than areas predicted absent, with high seasonal variation. The number of HFRS cases was correlated with rodent density, and the incidence of HFRS cases in urban and forest areas was mainly associated with the density of Rattus norvegicus and Apodemus agrarius, respectively. CONCLUSIONS: Heterogeneity between different areas shows that HFRS occurrence is affected by the intensity of human activity, climate conditions, and landscape elements. Rodent density and species composition have significant impacts on the number of HFRS cases and their distribution. PMID- 23819825 TI - Chitosan-based nanocarriers with pH and light dual response for anticancer drug delivery. AB - Currently, the major challenge for cancer treatment is to develop new types of smart nanocarriers that can efficiently retain the encapsulated drug during blood circulation and quickly release the drug in tumor cells under stimulation. In this study, the dual pH-/light-responsive cross-linked polymeric micelles (CPM) were successfully prepared by the self-assembly of amphiphilic glycol chitosan-o nitrobenzyl succinate conjugates (GC-NBSCs) and then cross-linking with glutaraldehyde (GA), which was synthesized by grafting hydrophobic light sensitive o-nitrobenzyl succinate (NBS) onto the main chain of hydrophilic glycol chitosan (GC). The GC-NBSC CPMs exhibited good biocompatibility according to the MTT assay against NIH/3T3 cells. The cell viability was maintained higher than 75% after 24 h incubation with CPMs even at a high concentration of 1.0 mg mL( 1). The hydrophobic anticancer drug camptothecin (CPT) was selected as a model drug and loaded into GC-NBSC CPMs. The results of in vitro evaluation showed that the encapsulated CPT could be quickly released at low pH with the light irradiation. Meanwhile, the CPT-loaded CPMs displayed a better cytotoxicity against MCF-7 cancer cells under UV irradiation, and IC50 of the loaded CPT was as low as 2.3 MUg mL(-1), which was close to that of the free CPT (1.5 MUg mL( 1)). Furthermore, the flow cytometry and confocal laser scanning microscopy (CLSM) measurements confirmed that the CPT-loaded CPMs could be internalized by MCF-7 cells efficiently and release CPT inside the tumor cells to enhance the inhibition of cell proliferation. Thereby, such excellent GC-NBSC CPMs provide a favorable platform to construct smart drug delivery systems (DDS) for cancer therapy. PMID- 23819826 TI - Cyclopeptide alkaloids: stereochemistry and synthesis of the precursors of discarines C and D and myrianthine A. AB - The stereochemistry of discarines C (1) and D (2) and myrianthine A (3), three cyclopeptide alkaloids isolated from Discaria febrifuga, was determined by a combination of NMR studies of 1-3, enantioselective gas chromatography, and comparison of NMR data with those of synthetic tripeptides. For the synthesis of peptides, the nonproteinogenic amino acid 3-phenylserine was also obtained in its four diastereoisomeric forms (l and d threo, obtained by recrystallization of the diastereoisomeric tripeptide, and l and d erythro, obtained by a Mitsunobu reaction with the threo-tripeptides). The general synthetic strategy described in this paper allows the tripeptide to be obtained with the free N-terminal extremity protected or dimethylated. This strategy also allows the synthesis of the corresponding peptide with an imidazolidinone ring. PMID- 23819827 TI - Improving outcomes of renal transplant recipients with behavioral adherence contracts: a randomized controlled trial. AB - The objective of this randomized controlled trial was to assess the effects of a 1-year behavioral contract intervention on immunosuppressant therapy (IST) adherence and healthcare utilizations and costs among adult renal transplant recipients (RTRs). The sample included adult RTRs who were at least 1 year posttransplant, taking tacrolimus or cyclosporine and served by a specialty pharmacy. Pharmacy refill records were used to measure adherence and monthly questionnaires were used to measure healthcare utilizations. Direct medical costs were estimated using the 2009 Medicare Expenditure Panel Survey. Adherence was analyzed using the GLM procedure and the MIXED procedure of SAS. Rate ratios and 95% confidence intervals were estimated to quantify the rate of utilizing healthcare services relative to treatment assignment. One hundred fifty RTRs were enrolled in the study. Intervention group RTRs (n = 76) had higher adherence than control group RTRs (n = 74) over the study period (p < 0.01). And 76.1% of the intervention group compared with 42.7% of the control group was not hospitalized during the 1-year study period (RR = 1.785; 95% CI: 1.314, 2.425), resulting in cost savings. Thus, evidence supports using behavioral contracts as an effective adherence intervention that may improve healthcare outcomes and lower costs. PMID- 23819829 TI - Control of crystal morphology in monodisperse polyfluorenes by solvent and molecular weight. AB - Different crystalline forms are obtained by simply manipulating the good/poor solvent ratio in mixed solvents of toluene/ethanol. Depending on different solvent ratios, poly(9,9-dioctylfluorene)s (PFOs) can generate a large palette of morphologies including lenticular crystals, fibrous crystals and rod-like crystals. In the crystallization process, polymer chains experience different kinetic pathways, yielding lenticular crystals in the toluene solution, rod-like crystals at a low toluene/ethanol ratio (1:1), and fibrous crystals at a high toluene/ethanol ratio (3:1). A combination of atomic force microscopy (AFM) and transmission electron microscopy (TEM) provides an opportunity to elucidate the distinctive molecular arrangements in these different crystals. Moreover, the influence of molecular weights on the crystallization of polymers has also been investigated in different crystals. PMID- 23819828 TI - Biosynthetic origin of alchivemycin A, a new polyketide from Streptomyces and absolute configuration of alchivemycin B. AB - Biosynthetic origin of 2H-tetrahydro-4,6-dioxo-1,2-oxazine, an unprecedented structural unit first discovered in alchivemycin A (1), was investigated by feeding (13)C-labeled precursors. Incorporations of both [1-(13)C]glycine and [1 (13)C]-N-hydroxyglycine into the carbon at the 4-position of this six-membered ring indicate that the hydrooxazine ring is assembled through a PKS-NRPS hybrid pathway. Additionally, alchivemycin B (2), a deoxygenated analog of 1, was isolated and its relative and absolute configurations were determined by spectroscopic analysis including NMR and CD and X-ray crystallography. PMID- 23819830 TI - Interaction of retinoic acid radical cation with lysozyme and antioxidants: laser flash photolysis study in microemulsion. AB - All-trans retinoic acid (ATRA) plays essential roles in the normal biological processes and the treatment of cancer and skin diseases. Considering its photosensitive property, many studies have been focused on the photochemistry of ATRA. In this study, we investigated the transient phenomena in the laser flash photolysis (LFP) of ATRA in microemulsion to further understand the photochemistry of ATRA. Results show that 355 nm LFP of ATRA in both acidic and alkaline conditions leads to the generation of retinoic acid cation radicals (ATRA(*+)) via biphotonic processes. The employment of microemulsion system allows us to investigate the reaction of hydrophobic ATRA(*+) with molecules of different polarity. Therefore, we studied the reaction activity of ATRA(*+) to many hydrophobic and hydrophilic molecules. Results show that ATRA(*+) can efficiently interact with lysozyme, tyrosine, tryptophan and many antioxidants, such as curcumin (Cur), vitamin C (VC) and gallic acid (GA). The apparent rate constants of these reactions were measured and compared. These findings suggest that ATRA(*+) is a reactive transient product which may pose damage to lysozyme, and antioxidants, such as Cur, VC and GA, may inactivate ATRA(*+) by efficient quenching reactions. PMID- 23819831 TI - Evaluation of a real-time quantitative PCR to measure the wild Plasmodium falciparum infectivity rate in salivary glands of Anopheles gambiae. AB - BACKGROUND: Evaluation of malaria sporozoite rates in the salivary glands of Anopheles gambiae is essential for estimating the number of infective mosquitoes, and consequently, the entomological inoculation rate (EIR). EIR is a key indicator for evaluating the risk of malaria transmission. Although the enzyme linked immunosorbent assay specific for detecting the circumsporozoite protein (CSP-ELISA) is routinely used in the field, it presents several limitations. A multiplex PCR can also be used to detect the four species of Plasmodium in salivary glands. The aim of this study was to evaluate the efficacy of a real time quantitative PCR in detecting and quantifying wild Plasmodium falciparum in the salivary glands of An. gambiae. METHODS: Anopheles gambiae (n=364) were experimentally infected with blood from P. falciparum gametocyte carriers, and P. falciparum in the sporozoite stage were detected in salivary glands by using a real-time quantitative PCR (qPCR) assay. The sensitivity and specificity of this qPCR were compared with the multiplex PCR applied from the Padley method. CSP ELISA was also performed on carcasses of the same mosquitoes. RESULTS: The prevalence of P. falciparum and the intensity of infection were evaluated using qPCR. This method had a limit of detection of six sporozoites per MUL based on standard curves. The number of P. falciparum genomes in the salivary gland samples reached 9,262 parasites/MUL (mean: 254.5; 95% CI: 163.5-345.6). The qPCR showed a similar sensitivity (100%) and a high specificity (60%) compared to the multiplex PCR. The agreement between the two methods was "substantial" (kappa = 0.63, P <0.05). The number of P. falciparum-positive mosquitoes evaluated with the qPCR (76%), multiplex PCR (59%), and CSP-ELISA (83%) was significantly different (P <0.005). CONCLUSIONS: The qPCR assay can be used to detect P. falciparum in salivary glands of An. gambiae. The qPCR is highly sensitive and is more specific than multiplex PCR, allowing an accurate measure of infective An. gambiae. The results also showed that the CSP-ELISA overestimates the sporozoite rate, detecting sporozoites in the haemolymph in addition to the salivary glands. PMID- 23819833 TI - Measuring interactions between polydimethylsiloxane and serum proteins at the air water interface. AB - The interaction between synthetic polymers and proteins at interfaces is relevant to basic science as well as a wide range of applications in biotechnology and medicine. One particularly common and important interface is the air-water interface (AWI). Due to the special energetics and dynamics of molecules at the AWI, the interplay between synthetic polymer and protein can be very different from that in bulk solution. In this paper, we applied the Langmuir-Blodgett technique and fluorescence microscopy to investigate how the compression state of polydimethylsiloxane (PDMS) film at the AWI affects the subsequent adsorption of serum protein [e.g., human serum albumin (HSA) or immunoglobulin G (IgG)] and the interaction between PDMS and protein. Of particular note is our observation of circular PDMS domains with micrometer diameters that form at the AWI in the highly compressed state of the surface film: proteins were shown to adsorb preferentially to the surface of these circular PDMS domains, accompanied by a greater than 4-fold increase in protein found in the interfacial film. The PDMS only film and the PDMS-IgG composite film were transferred to cover glass, and platinum-carbon replicas of the transferred films were further characterized by scanning electron microscopy and atomic force microscopy. We conclude that the structure of the PDMS film greatly affects the amount and distribution of protein at the interface. PMID- 23819832 TI - Integrative analysis of congenital muscular torticollis: from gene expression to clinical significance. AB - BACKGROUND: Congenital muscular torticollis (CMT) is characterized by thickening and/or tightness of the unilateral sternocleidomastoid muscle (SCM), ending up with torticollis. Our aim was to identify differentially expressed genes (DEGs) and novel protein interaction network modules of CMT, and to discover the relationship between gene expressions and clinical severity of CMT. RESULTS: Twenty-eight sternocleidomastoid muscles (SCMs) from 23 subjects with CMT and 5 SCMs without CMT were allocated for microarray, MRI, or immunohistochemical studies. We first identified 269 genes as the DEGs in CMT. Gene ontology enrichment analysis revealed that the main function of the DEGs is for extracellular region part during developmental processes. Five CMT-related protein network modules were identified, which showed that the important pathway is fibrosis related with collagen and elastin fibrillogenesis with an evidence of DNA repair mechanism. Interestingly, the expression levels of the 8 DEGs called CMT signature genes whose mRNA expression was double-confirmed by quantitative real time PCR showed good correlation with the severity of CMT which was measured with the pre-operational MRI images (R2 ranging from 0.82 to 0.21). Moreover, the protein expressions of ELN, ASPN and CHD3 which were identified from the CMT related protein network modules demonstrated the differential expression between the CMT and normal SCM. CONCLUSIONS: We here provided an integrative analysis of CMT from gene expression to clinical significance, which showed good correlation with clinical severity of CMT. Furthermore, the CMT-related protein network modules were identified, which provided more in-depth understanding of pathophysiology of CMT. PMID- 23819834 TI - Asthma diagnosis and treatment - 1006. Perillae semen abolished allergic asthmatic response in murine model. PMID- 23819835 TI - Correlation between spasticity and quality of life in patients with multiple sclerosis: the CANDLE study. AB - BACKGROUND: Spasticity is a common symptom in multiple sclerosis (MS) that increases the burden of disease. This study investigated the relationship between the degree of spasticity and patients' health-related quality of life (QoL). METHODS: Epidemiological, multicentre, cross-sectional study in patients with MS spasticity. The SF-12 questionnaire was used to assess QoL. The modified Ashworth scale and a 0-10 Numerical Rating Scale (NRS) were used to assess spasticity severity. RESULTS: Data were analysed for 409 MS patients with spasticity from 53 neurology clinics in Spain. Mean age was 46.4 (+/-11.0) years; 62.4% were women. Most patients had relapsing-remitting MS (42.1%) or secondary progressive MS (43.9%). Mean time since MS diagnosis was 12.5 (+/-7.4) years and mean time since first spasticity symptoms was 6.1 (+/-4.8) years. A total of 71.3% of patients were being treated pharmacologically for spasticity. Moderate to severe spasticity was measured in 59.2% of patients according to the modified Ashworth scale and in 83.4% according to the NRS. Mean scores for the 0-100 Physical Component Summary and Mental Component Summary subscales of the SF-12 questionnaire were 31.0 (+/-9.3) and 45.4 (+/-12.0), respectively. Scores on the SF-12 correlated significantly with scores on both spasticity scales ( p <= 0.002) but the correlation was stronger with the NRS across all domains. CONCLUSIONS: The results confirm an association between spasticity severity and QoL in patients with MS. The correlation between 0-10 NRS scores and QoL was stronger than that between modified Ashworth scale scores and QoL. PMID- 23819837 TI - Effects of the cage unit size and number of cage units as well as bridge unit on the second order nonlinear optical response in multicage electride molecules. AB - Interesting effects of the cage unit size and number of cage units as well as bridge unit on the static first hyperpolarizabilities (beta0) for novel multicage electrides are revealed. (1) The small cage unit C8 systems have larger beta0 for cage unit size effect. (2) The beta0 increases with increasing cage unit number. (3) The effect of the bridge between cage units on beta0 is O > NH > CH2. Specially, a novel relationship between the excess electron cloud and beta0 is revealed. Assembling the three effects, the constructed multicage electride structure with three small C8 cage units connected by the O-bridge (K...3C8(O)) is a electride salt K(+)[e@3C8(O)](-) and has the considerable beta0 value of 7.1 * 10(5) au, which is about 55 times larger than the 13 000 au of the single-cage electride molecule Na3O(+)(e@C20F20)(-). The novel multicage strategy is effective to enhance nonlinear optical (NLO) response. PMID- 23819836 TI - The health economic impact of disease management programs for COPD: a systematic literature review and meta-analysis. AB - BACKGROUND: There is insufficient evidence of the cost-effectiveness of Chronic Obstructive Pulmonary Disease (COPD) Disease Management (COPD-DM) programs. The aim of this review is to evaluate the economic impact of COPD-DM programs and investigate the relation between the impact on healthcare costs and health outcomes. We also investigated the impact of patient-, intervention, and study characteristics. METHODS: We conducted a systematic literature review to identify cost-effectiveness studies of COPD-DM. Where feasible, results were pooled using random-effects meta-analysis and explorative subgroup analyses were performed. RESULTS: Sixteen papers describing 11 studies were included (7 randomized control trials (RCT), 2 pre-post, 2 case-control). Meta-analysis showed that COPD-DM led to hospitalization savings of ?1060 (95% CI: ?2040 to ?80) per patient per year and savings in total healthcare utilization of ?898 (95% CI: ?1566 to ?231) (excl. operating costs). In these health economic studies small but positive results on health outcomes were found, such as the St Georges Respiratory Questionnaire (SGRQ) score, which decreased with 1.7 points (95% CI: 0.5-2.9). There was great variability in DM interventions-, study- and patient characteristics. There were indications that DM showed greater savings in studies with: severe COPD patients, patients with a history of exacerbations, RCT study design, high methodological quality, few different professions involved in the program, and study setting outside Europe. CONCLUSIONS: COPD-DM programs were found to have favourable effects on both health outcomes and costs, but there is considerable heterogeneity depending on patient-, intervention-, and study characteristics. PMID- 23819838 TI - RPLC of intact proteins using sub-0.5 MUm particles and commercial instrumentation. AB - This paper addresses whether one can gain an improvement in speed or resolution with a silica colloidal crystal (SCC) of nonporous 470 nm particles when using a commercial nano-UHPLC. Compared to a capillary packed with nonporous 1.3 MUm particles and the same C4 bonded phase, the peak width for BSA is decreased by a factor of 6.8 for the SCC. Some of this improvement is attributable to slip flow since the ratio of particle diameters is only 2.8. Resolution in protein separations was compared for a 2-cm capillary of SCC vs a 5-cm column of porous 1.7 MUm particles. Both used a C4 bonded phase, and on-column fluorescence detection was used for the SCC. Split flow (5:1) before the SCC decreased the gradient delay time to 0.4 min and the injected volume to 0.4 nL. For variants from the labeling of BSA, the SCC had a 5-fold higher speed and 2-fold higher resolution than did the commercial column. For a monoclonal antibody and its aggregates, the SCC had a 3-fold higher speed and a 3-fold higher resolution compared to the commercial column. The SCC gave baseline resolution of the monomer, dimer and trimer in 5 min. The results show that a significant advantage can be gained using a commercial instrument with the SCC, despite the instrument not being designed for use with such small particles. PMID- 23819839 TI - Prediction of retinal pigment epithelial tear in serous vascularized pigment epithelium detachment. AB - PURPOSE: The aim of the study was to identify predictive factors for detection of impending retinal pigment epithelium (RPE) tears in patients under anti-VEGF therapy for treatment of retinal pigment epithelial detachment (PED) due to exudative age-related macular degeneration (AMD) using near-infrared reflectance imaging (NIR), spectral-domain optical coherence tomography (SD-OCT) and fluorescein angiography (FLA). METHODS: We retrospectively evaluated NIR, SD-OCT and FLA images, number of intravitreal injections as well as demographical data of 103 eyes of 98 patients with vascularized PED [48.5% fibrovascular PED (fPED), 51.5% serous vascularized PED (svPED)] secondary to AMD. RESULTS: Fifteen eyes with svPED of 103 included eyes (14.6%) developed an RPE tear under anti-VEGF therapy. Prior to RPE tear formation, we could identify radial hyperreflective lines spreading in a funnel-like pattern across the PED lesion in NIR images in 11 eyes correlating with folds in the RPE on corresponding SD-OCT scans (mean observation period: 115.4 +/- 66.6 days; mean number of injections: 3.2 +/- 1.5; mean PED height 828.2 +/- 356.5 MUm). In nine RPE tears (81.8%), the edge of the tear could be clearly localized on the opposite side of the PED lesion in relation to the origin of hyperreflective lines. None of the fPED patients showed the described signal. CONCLUSIONS: Patients under anti-VEGF therapy for treatment of svPED due to AMD frequently show radial hyperreflective lines in NIR images prior to RPE tear development that correspond to wrinkled changes in the RPE. Hyperreflective lines may serve as an indicator for an impending RPE tear in svPED patients. PMID- 23819840 TI - Increased prevalence of cigarette smoking in Japanese patients with sarcoidosis. AB - BACKGROUND AND OBJECTIVE: Several studies have shown that individuals with sarcoidosis in Western populations are less likely to have smoked before diagnosis. Epidemiological characteristics of sarcoidosis are known to differ between Japanese and Westerners. Therefore, the relationship between cigarette smoking and sarcoidosis in a Japanese population was investigated. METHODS: Three hundred eighty-eight patients newly diagnosed with sarcoidosis between 2000 and 2008 were retrospectively identified. The results of two large surveys of smoking prevalence in Japan provided reference data. Specific clinical manifestations of sarcoidosis were compared between current smokers and never-smokers, after excluding former smokers. RESULTS: The prevalence of current smokers at the time of the diagnosis of sarcoidosis was 59.6% in men and 27.9% in women. With the exception of men in their 30s, the prevalence was higher in all age groups compared with the general Japanese population. The prevalence of lung parenchymal involvement tended to be higher in current smokers than in never-smokers (odds ratio = 1.33 (0.99-1.77), P = 0.054). CONCLUSIONS: This retrospective cohort study suggests that smoking prevalence is higher in Japanese sarcoidosis patients than that reported in Western sarcoidosis patients and that there could be different relationships between smoking and the development of sarcoidosis in these populations. PMID- 23819841 TI - Non-UV light influences the degradation rate of crop protection products. AB - Crop protection products (CPPs) are subject to strict regulatory evaluation, including laboratory and field trials, prior to approval for commercial use. Laboratory tests lack environmental realism, while field trials are difficult to control. Addition of environmental complexity to laboratory systems is therefore desirable to mimic a field environment more effectively. We investigated the effect of non-UV light on the degradation of eight CPPs (chlorotoluron, prometryn, cinosulfuron, imidacloprid, lufenuron, propiconazole, fludioxonil, and benzovindiflupyr) by addition of non-UV light to standard OECD 307 guidelines. Time taken for 50% degradation of benzovindiflupyr was halved from 373 to 183 days with the inclusion of light. Similarly, time taken for 90% degradation of chlorotoluron decreased from 79 to 35 days under light conditions. Significant reductions in extractable parent compound occurred under light conditions for prometryn (4%), imidacloprid (8%), and fludioxonil (24%) compared to dark controls. However, a significantly slower rate of cinosulfuron (14%) transformation was observed under light compared to dark conditions. Under light conditions, nonextractable residues were significantly higher for seven of the CPPs. Soil biological and chemical analyses suggest that light stimulates phototroph growth, which may directly and/or indirectly impact CPP degradation rates. The results of this study strongly suggest that light is an important parameter affecting CPP degradation, and inclusion of light into regulatory studies may enhance their environmental realism. PMID- 23819842 TI - Public health information needs in districts. PMID- 23819843 TI - Monocopper doping in Cd-In-S supertetrahedral nanocluster via two-step strategy and enhanced photoelectric response. AB - We apply a two-step strategy to realize ordered distribution of multiple components in one nanocluster (NC) with a crystallographically ordered core/shell structure. A coreless supertetrahedral chalcogenide Cd-In-S cluster is prepared, and then a copper ion is inserted at its void core site through a diffusion process to form a Cu-Cd-In-S quaternary NC. This intriguing molecular cluster with mono-copper core and Cd-In shell exhibits enhanced visible-light-responsive optical and photoelectric properties compared to the parent NC. PMID- 23819845 TI - Let's try it: me for you. PMID- 23819844 TI - ICU personnel have inaccurate perceptions of their patients' experiences. AB - BACKGROUND: Intensive care unit (ICU) patient care bases - among others - upon the staff's assumptions about each patient's subjective preferences and experiences. However, these assumptions may be skewed and thus result in client professional gaps (cp-gaps), which occur in two subtypes, hyperattention and blind spots to certain burdens. cp-gaps typically reduce quality of care. We investigated whether cp-gaps of either subtype exist in a 36-bed ICU of a university hospital. METHODS: Observational study on 82 consecutive patients of a 36-bed university ICU, who voluntarily answered a psychometric questionnaire focusing on patients' experiences during an ICU stay. The questionnaire was reliable and valid (Cronbach's alpha, factor analysis). It consisted of 31 Likert scaled items, which represented three scales of perception (communicative, intrapersonal, somatic) supplemented by 55 binary items for more specific information. Details of the questionnaire are given in the text. Demographic, educational, and medical data were registered too. Patients reported their subjective ICU experience 2-7 days after ICU discharge. Analogously, 60 staff members (physicians and nurses) reported their assumptions about patients' experiences. After correction for a general bias, group differences indicated cp gaps. RESULTS: Twelve cp-gaps were found. Hyperattention was found in four communicative and three intrapersonal items. Blind spots appeared in two communicative, two intrapersonal, and one somatic item. The pattern of cp-gap subtypes (hyperattention/blind spots) goes well with self-attributional bias - a model of social interaction. CONCLUSIONS: cp-gaps in ICUs can be identified using analogue questionnaires for patients and staff. Both subtypes of cp-gap occur. cp gaps are substantially influenced by self-attributional bias. PMID- 23819846 TI - Collective judgment predicts disease-associated single nucleotide variants. AB - BACKGROUND: In recent years the number of human genetic variants deposited into the publicly available databases has been increasing exponentially. The latest version of dbSNP, for example, contains ~50 million validated Single Nucleotide Variants (SNVs). SNVs make up most of human variation and are often the primary causes of disease. The non-synonymous SNVs (nsSNVs) result in single amino acid substitutions and may affect protein function, often causing disease. Although several methods for the detection of nsSNV effects have already been developed, the consistent increase in annotated data is offering the opportunity to improve prediction accuracy. RESULTS: Here we present a new approach for the detection of disease-associated nsSNVs (Meta-SNP) that integrates four existing methods: PANTHER, PhD-SNP, SIFT and SNAP. We first tested the accuracy of each method using a dataset of 35,766 disease-annotated mutations from 8,667 proteins extracted from the SwissVar database. The four methods reached overall accuracies of 64%-76% with a Matthew's correlation coefficient (MCC) of 0.38-0.53. We then used the outputs of these methods to develop a machine learning based approach that discriminates between disease-associated and polymorphic variants (Meta SNP). In testing, the combined method reached 79% overall accuracy and 0.59 MCC, ~3% higher accuracy and ~0.05 higher correlation with respect to the best performing method. Moreover, for the hardest-to-define subset of nsSNVs, i.e. variants for which half of the predictors disagreed with the other half, Meta-SNP attained 8% higher accuracy than the best predictor. CONCLUSIONS: Here we find that the Meta-SNP algorithm achieves better performance than the best single predictor. This result suggests that the methods used for the prediction of variant-disease associations are orthogonal, encoding different biologically relevant relationships. Careful combination of predictions from various resources is therefore a good strategy for the selection of high reliability predictions. Indeed, for the subset of nsSNVs where all predictors were in agreement (46% of all nsSNVs in the set), our method reached 87% overall accuracy and 0.73 MCC. Meta-SNP server is freely accessible at http://snps.biofold.org/meta-snp. PMID- 23819847 TI - Factors associated with patient, and diagnostic delays in Chinese TB patients: a systematic review and meta-analysis. AB - BACKGROUND: Delay in seeking care is a major impediment to effective management of tuberculosis (TB) in China. To elucidate factors that underpin patient and diagnostic delays in TB management, we conducted a systematic review and meta analysis of factors that are associated with delays in TB care-seeking and diagnosis in the country. METHODS: This review was prepared following standard procedures of the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and checklist. Relevant studies published up to November 2012 were identified from three major international and Chinese literature databases: Medline/PubMed, EMBASE and CNKI (China National Knowledge Infrastructure). RESULTS: We included 29 studies involving 38,947 patients from 17 provinces in China. Qualitative analysis showed that key individual level determinants of delays included socio-demographic and economic factors, mostly poverty, rural residence, lack of health insurance, lower educational attainment, stigma and poor knowledge of TB. Health facility determinants included limited availability of resources to perform prompt diagnosis, lack of qualified health workers and geographical barriers.Quantitative meta-analysis indicated that living in rural areas was a risk factor for patient delays (pooled odds ratio (OR) (95% confidence interval (CI)): 1.79 (1.62, 1.98)) and diagnostic delays (pooled OR (95% CI): 1.40 (1.23, 1.59)). Female patients had higher risk of patient delay (pooled OR (95% CI): 1.94 (1.13, 3.33)). Low educational attainment (primary school and below) was also a risk factor for patient delay (pooled OR (95% CI): 2.14 (1.03, 4.47)). The practice of seeking care first from Traditional Chinese Medicine (TMC) providers was also identified as a risk factor for diagnostic delay (pooled OR (95% CI): 5.75 (3.03, 10.94)). CONCLUSION: Patient and diagnostic delays in TB care are mediated by individual and health facility factors. Population-based interventions that seek to reduce TB stigma and raise awareness about the benefits of early diagnosis and prompt treatment are needed. Policies that remove patients' financial barriers in access to TB care, and integration of the informal care sector into TB control in urban and rural settings are central factors in TB control. PMID- 23819848 TI - Enterocutaneous fistulae in familial adenomatous polyposis patients with abdominal desmoid disease. AB - AIM: Enterocutaneous fistula is a severe complication of intra-abdominal desmoid disease. It is hard to repair because of the presence of the desmoid itself, the possibility of distal obstruction and the complexity of multiple laparotomies. Here we report the outcome of a series of patients presenting with abdominal desmoid disease and associated enterocutaneous fistula. METHOD: This is a retrospective, descriptive study of patients presenting to a hereditary colorectal cancer registry with familial adenomatous polyposis-related intra abdominal desmoid disease and associated enterocutaneous fistulae. Patients were identified through the registry database and aspects of their treatment and outcome were abstracted. RESULTS: Sixteen patients (11 women, five men) were treated. The mean age at index surgery was 25.2 years and mean time to first fistula was 115.6 (+/- 92.7 standard deviation) months from index surgery. Index surgery included restorative proctocolectomy with ileal pouch (n = 9), colectomy with ileorectal anastomosis (n = 4) and proctocolectomy with end ileostomy (n = 1). One patient had only a small bowel bypass and another did not have any index surgery. Ten patients underwent laparotomy for the enterocutaneous fistula; eight had a repair +/- resection, one had a diversion and one a bypass. All eight patients who had a repair healed, and the bypassed fistula was successfully palliated. Three fistulae recurred and two were successfully repaired at a second procedure. One patient was explored but nothing could be done for the fistula. Two surgery patients died of causes unrelated to the fistula. Six patients received medical treatment, four of whom died. CONCLUSION: Selected desmoid related enterocutaneous fistulae can be repaired successfully. PMID- 23819849 TI - Concurrent occurrence of three renal cell carcinomas with different histological subtypes in the same kidney. PMID- 23819850 TI - Asthma diagnosis and treatment - 1010. Lung function tests in exercise-induced asthma among pediatric population. PMID- 23819851 TI - The effect of exercise on plasma concentrations of inflammatory markers in normal and previously laminitic ponies. AB - REASONS FOR PERFORMING STUDY: The mechanisms underlying predisposition to pasture associated laminitis remain unclear; chronic inflammation is implicated, and this may be exacerbated by physical inactivity. OBJECTIVES: To determine whether exercise affects the inflammatory profile of normal and previously laminitic ponies. STUDY DESIGN: Prospective case-control study. METHODS: The short (1 day) and longer term (14 days) effects of low intensity (10 min walking and 5 min trotting) exercise on plasma inflammatory marker concentrations in normal (NL) and previously laminitic (PL) nonobese ponies (n = 6/group) was determined. Plasma concentrations of TNF-alpha, serum amyloid A (SAA), haptoglobin, insulin, adiponectin and fibrinogen were assayed by validated/standard methods. Data were analysed using a linear mixed effects model. RESULTS: Before exercise, plasma [adiponectin] was significantly (P = 0.0001) lower in PL (mean +/- s.d. 2.4 +/- 0.1 ng/l) than in NL (4.03 +/- 0.2 ng/l), but exercise had no effect. Previous laminitis and exercise had no effect on plasma [TNF-alpha] or [fibrinogen]. Serum amyloid A concentrations in all ponies were significantly (P = 0.00001) reduced after longer term exercise compared to Day 1 values. Plasma [haptoglobin] was significantly (P = 0.00001) higher in PL compared to NL on Day 1. This difference was no longer apparent after longer term exercise, such that [haptoglobin] in PL had decreased to concentrations similar to NL. Following short-term exercise, all ponies had an initial decrease in serum [insulin] immediately after exercise, followed by an increase peaking 10 min after exercise cessation, before returning to pre-exercise values. On Day 14 these fluctuations were significantly (P = 0.001) reduced in all ponies. CONCLUSIONS: Fourteen days of low intensity exercise significantly decreased [SAA] in all ponies and plasma [haptoglobin] in PL such that it was no longer increased compared to NL. Regular low intensity exercise appears to have an anti-inflammatory effect, which is possibly greater in PL and so may be beneficial in reducing this putative risk factor in pasture associated laminitis. PMID- 23819852 TI - A comparison approach to explain risks related to X-ray imaging for scoliosis, 2012 SOSORT award winner. AB - BACKGROUND: X-ray imaging is frequently used as diagnostic approach for scoliosis in children and adolescents. X-ray procedures are considered as justified only when expected benefits exceed related risks. While benefits are well known to physicians, radiological risk awareness can be vague, impeding an optimal communication with patients' parents and possibly leading to discomfort and anxiety. Objective of the study is the suggestion of a risk comparison approach for better communicating the radiological risks related to X-ray investigation of scoliosis. METHODS: Starting point of the analysis is the Linear Non-Threshold (LNT) assumption for radiation stochastic effect, which states that for effective doses (E, Sievert - Sv) below 100 mSv, the probability of future stochastic damage is linearly related to E: absorbing two E's in separate moments results in the addition of the risks related to each E. This allows to add E from different sources to calculate a cumulative risk of health detriment. Medline (Pubmed) was systematically searched in order to determine the average E delivered during X ray investigation of scoliosis. Subsequently, the major natural sources of radiation were considered. The average yearly E due to natural sources was compared with E due to the imaging of the vertebral column. RESULTS: E's due to X ray scoliosis examinations show a large variability: under 7 years of age, 0.03 0.54 mSv; 7-12 years, 0.11-0.80 mSv; 13-18 years, 0.17-1.09 mSv. Overall, 65% of the world population is expected to be exposed to an annual E between 1 and 3 mSv. More in detail, worldwide the total annual average E due to natural sources is 2.4 mSv (range 1-10), of which half originates from Radon exposure. Other sources are cosmic rays and ingestion and inhalation of radionuclides. For example, one flight between Europe and America accounts for 0.030-0.045 mSv because of exposure to cosmic rays. CONCLUSIONS: X-rays are carcinogenic and exposures to them always need to be justified and optimized in order to minimize the risks of health effects. However, the human body is continuously struck by radiations coming from natural sources. A useful element of comparison to evaluate E due to medical exposures in scoliosis can be then provided by the amount of E coming from natural sources. This comparison approach can play a role in the relationship between physicians and patients' parents and lead to an improved awareness in patients' parents. PMID- 23819853 TI - Total synthesis of rugulovasine A. AB - A concise total synthesis of rugulovasine A is achieved by using Uhle's ketone derivative as the key intermediate, which was synthesized by intramolecular cyclization via metal-halogen exchange. Two different routes to construct a spirocyclic butyrolactone subunit involving a Ru-catalyzed cyclocarbonylation and a special Ru-catalyzed double bond rearrangement were studied. PMID- 23819854 TI - Clinical, radiographic characteristics and immunomodulating changes in neuromyelitis optica with extensive brain lesions. AB - BACKGROUND: Neuromyelitis optica (NMO) shows various brain magnetic resonance imaging (MRI) abnormalities with recurrent central nervous system (CNS) attacks, although predominantly affecting the spinal cord and optic nerve. However, NMO with extensive involvement of the brain has infrequently been studied. We investigated the clinical, radiographic features and immunomodulating changes of NMO patients with extensive brain lesions (EBLs) in China. METHODS: NMO patients (including 16 NMO patients with EBLs and 53 NMO patients without EBLs) hospitalized during January 2006 and February 2010 were recruited and analyzed retrospectively. Data of clinical characteristics, magnetic resonance imaging (MRI) features, laboratory abnormalities, treatment details and outcomes were analyzed. All the patients received the follow-up visits for two years. RESULTS: EBLs in NMO were classified into four categories according to their respective MRI characteristics: 1) Tumefactive-like lesions (n=4, 25%); 2) Acute disseminated encephalomyelitis (ADEM)-like lesions (n=6, 37.5%); 3) Multiple sclerosis (MS)-like lesions (n=5, 31.25%); 4) Posterior reversible encephalopathy syndrome (PRES)-like lesions (n=1, 6.25%). NMO patients with EBLs had higher rates of encephalopathy symptoms (37.5% vs. 5.6%, p = 0.004), homonymous hemianopia (18.8% vs. 0%, p = 0.011) and AQP4 seropositivity (100% vs. 69.8%, p = 0.008) than NMO patients without EBLs (NEBLs). Immunomodulating changes (including the levels of C3, C4, ESR and CRP) were significantly higher in patients with EBLs than those without EBLs. The relapse times in EBLs during the follow-up period were more frequent than those happened in NEBLs (1.88 +/- 0.30 vs. 1.23 +/- 0.14, p = 0.04). The EDSS scores in EBLs patients were also much higher than those in NEBLs throughout all the whole visits of follow-up. CONCLUSIONS: The presence of EBLs in NMO may indicate a higher diseases activity and portend a worse prognosis. CRP is a useful marker in monitoring diseases activity. Systemic inflammation may be crucial to the formation of EBLs in NMO. PMID- 23819855 TI - Genetic variation in dopamine-related gene expression influences motor skill learning in mice. AB - Several neurodevelopmental disorders with a strong genetic basis, including attention-deficit/hyperactivity disorder, autism spectrum disorders and developmental coordination disorder, involve deficits in fine motor skills. This phenotype may depend on heritable variation in components of the dopamine (DA) system, which is known to play a critical role in motor skill learning. In this study, we took advantage of two inbred strains of mice (BALB/c and C57BL/6) that differ markedly in the number of midbrain DA neurons in order to investigate the influence of such naturally occurring genetic variation on the acquisition and performance of fine motor skills. Gene expression analysis of midbrain, frontal cortex and striatum showed significant differences in the expression of presynaptic and postsynaptic dopaminergic (DAergic) markers (e.g. tyrosine hydroxylase, DA transporter, DA D4 receptor, DA D5 receptor and DARPP-32) between these two strains. BALB/c mice had lower learning rate and performance scores in a complex skilled reaching task when compared with C57BL/6 mice. A negative correlation was found between the motor learning rate and level of DARPP-32 mRNA expression in the frontal cortex contralateral to the trained forelimb. The rate of motor learning was also negatively correlated with the levels of DARPP-32 and DA D1 receptor mRNAs in the striatum. Our results suggest that genetically driven variation in frontostriatal DAergic neurotransmission is a major contributor to individual differences in motor skill learning. Moreover, these findings implicate the D1R/cAMP/DARPP-32 signaling pathway in those neurodevelopmental disorders that are associated with fine motor skill deficits. PMID- 23819856 TI - Finding new superconductors: the spin-fluctuation gateway to high Tc and possible room temperature superconductivity. AB - We propose an experiment-based strategy for finding new high transition temperature superconductors that is based on the well-established spin fluctuation magnetic gateway to superconductivity in which the attractive quasiparticle interaction needed for superconductivity comes from their coupling to dynamical spin fluctuations originating in the proximity of the material to an antiferromagnetic state. We show how lessons learned by combining the results of almost three decades of intensive experimental and theoretical study of the cuprates with those found in the decade-long study of a strikingly similar family of unconventional heavy electron superconductors, the 115 materials, can prove helpful in carrying out that search. We conclude that, since Tc in these materials scales approximately with the strength of the interaction, J, between the nearest neighbor local moments in their parent antiferromagnetic state, there may not be a magnetic ceiling that would prevent one from discovering a room temperature superconductor. PMID- 23819857 TI - Asthma diagnosis and treatment - 1009. A clinical study of NE-C900 (OMRON) nebulizer. PMID- 23819858 TI - Bone augmentation for cancellous bone- development of a new animal model. AB - BACKGROUND: Reproducible and suitable animal models are required for in vivo experiments to investigate new biodegradable and osteoinductive biomaterials for augmentation of bones at risk for osteoporotic fractures. Sheep have especially been used as a model for the human spine due to their size and similar bone metabolism. However, although sheep and human vertebral bodies have similar biomechanical characteristics, the shape of the vertebral bodies, the size of the transverse processes, and the different orientation of the facet joints of sheep are quite different from those of humans making the surgical approach complicated and unpredictable. Therefore, an adequate and safe animal model for bone augmentation was developed using a standardized femoral and tibia augmentation site in sheep. METHODS: The cancellous bone of the distal femur and proximal tibia were chosen as injection sites with the surgical approach via the medial aspects of the femoral condyle and proximal tibia metaphysis (n = 4 injection sites). For reproducible drilling and injection in a given direction and length, a custom-made c-shaped aiming device was designed. Exact positioning of the aiming device and needle positioning within the intertrabecular space of the intact bone could be validated in a predictable and standardized fashion using fluoroscopy. After sacrifice, bone cylinders (O 32 mm) were harvested throughout the tibia and femur by means of a diamond-coated core drill, which was especially developed to harvest the injected bone area exactly. Thereafter, the extracted bone cylinders were processed as non-decalcified specimens for MUCT analysis, histomorphometry, histology, and fluorescence evaluation. RESULTS: The aiming device could be easily placed in 63 sheep and assured a reproducible, standardized injection area. In four sheep, cardiovascular complications occurred during surgery and pulmonary embolism was detected by computed tomography post surgery in all of these animals. The harvesting and evaluative methods assured a standardized analysis of all samples. CONCLUSIONS: This experimental animal model provides an excellent basis for testing new biomaterials for their suitability as bone augmentation materials. Concomitantly, similar cardiovascular changes occur during vertebroplasties as in humans, thus making it a suitable animal model for studies related to vertebroplasty. PMID- 23819859 TI - Asthma diagnosis and treatment - 1007. Clinical application of forced oscillation technique for children with asthma. PMID- 23819860 TI - Key genes for modulating information flow play a temporal role as breast tumor coexpression networks are dynamically rewired by letrozole. AB - BACKGROUND: Genes do not act in isolation but instead as part of complex regulatory networks. To understand how breast tumors adapt to the presence of the drug letrozole, at the molecular level, it is necessary to consider how the expression levels of genes in these networks change relative to one another. METHODS: Using transcriptomic data generated from sequential tumor biopsy samples, taken at diagnosis, following 10-14 days and following 90 days of letrozole treatment, and a pairwise partial correlation statistic, we build temporal gene coexpression networks. We characterize the structure of each network and identify genes that hold prominent positions for maintaining network integrity and controlling information-flow. RESULTS: Letrozole treatment leads to extensive rewiring of the breast tumor coexpression network. Approximately 20% of gene-gene relationships are conserved over time in the presence of letrozole while 80% of relationships are condition dependent. The positions of influence within the networks are transiently held with few genes stably maintaining high centrality scores across the three time points. CONCLUSIONS: Genes integral for maintaining network integrity and controlling information flow are dynamically changing as the breast tumor coexpression network adapts to perturbation by the drug letrozole. PMID- 23819861 TI - Diffuse large B-cell lymphoma in immunoprivileged sites: association of vitreoretinal, testicular and central nervous system lymphoma. PMID- 23819862 TI - Limitations in the application of the Gibbs equation to anionic surfactants at the air/water surface: sodium dodecylsulfate and sodium dodecylmonooxyethylenesulfate above and below the CMC. AB - This is a second paper responding to recent papers by Menger et al. and the ensuing discussion about the application of the Gibbs equation to surface tension (ST) data. Using new neutron reflection (NR) measurements on sodium dodecylsulfate (SDS) and sodium dodecylmonooxyethylene sulfate (SLES) above and below their CMCs and with and without added NaCl, in conjunction with the previous ST measurements on SDS by Elworthy and Mysels (EM), we conclude that (i) ST measurements are often seriously compromised by traces of divalent ions, (ii) adsorption does not generally reach saturation at the CMC, making it difficult to obtain the limiting Gibbs slope, and (iii) the significant width of micellization may make it impossible to apply the Gibbs equation in a significant range of concentration below the CMC. Menger et al. proposed ii as a reason for the difficulty of applying the Gibbs equation to ST data. Conclusions i and iii now further emphasize the failings of the ST-Gibbs analysis for determining the limiting coverage at the CMC, especially for SDS. For SDS, adsorption increases above the CMC to a value of 10 * CMC, which is about 25% greater than at the CMC and about the same as at the CMC in the presence of 0.1 M NaCl. In contrast, the adsorption of SLES reaches a limit at the CMC with no further increase up to 10 * CMC, but the addition of 0.1 M NaCl increases the surface excess by 20-25%. The results for SDS are combined with earlier NR results to generate an adsorption isotherm from 2 to 100 mM. The NR results for SDS are compared to the definitive surface tension (ST) measurements of EM, and the surface excesses agree over the range where they can safely be compared, from 2 to 6 mM. This confirms that the anomalous decrease in the slope of EM's sigma - ln c curve between 6 mM and the CMC at 8.2 mM results from changes in activity associated with a significant width of micellization. This anomaly shows that it is impossible to apply the Gibbs equation usefully from 6 to 8.2 mM (i.e., the lack of knowledge of the activity in this range is the same as above the CMC (8.2 mM)). It was found that a mislabeling of the original data in EM may have prevented the use of this excellent ST data as a standard by other authors. Although NR and ST results for SDS in the absence of added electrolyte show that the discrepancies can be rationalized, ST is generally shown to be less accurate and more vulnerable to impurities, especially divalent ions, than NR. The radiotracer technique is shown to be less accurate than ST-Gibbs in that the four radiotracer measurements of the surface excess are consistent neither with each other nor with ST and NR. It is also shown that radiotracer results on aerosol-OT are likely to be incorrect. Application of the mass action (MA) model of micellization to the ST curves of SDS and SLES through and above the CMC shows that they can be explained by this model and that they depend on the degree of dissociation of the micelle, which leads to a larger change in the mean activity, and hence the adsorption, for the more highly dissociated SDS micelles than for SLES. Previous measurements of the activity of SDS above the CMC were found to be semiquantitatively consistent with the change in mean activity predicted by the MA model but inconsistent with the combined ST, NR, and Gibbs equation results. PMID- 23819863 TI - In situ forming hydrogels via catalyst-free and bioorthogonal "tetrazole-alkene" photo-click chemistry. AB - In situ forming hydrogels were developed from 4-arm poly(ethylene glycol) methacrylate (PEG-4-MA) and -tetrazole (PEG-4-Tet) derivatives through catalyst free and bioorthogonal "tetrazole-alkene" photo-click chemistry. PEG-4-MA and PEG 4-Tet (Mn = 10 kg/mol) were soluble at 37 degrees C in phosphate buffer (PB, pH 7.4, 10 mM) at total polymer concentrations ranging from 20 to 60 wt % but formed fluorescent hydrogels upon 365 nm UV irradiation at an intensity of 20.6, 30.7, or 60 mW/cm(2). The gelation times ranged from ca. 50 s to 5 min, and storage moduli varied from 0.65 to 25.2 kPa depending on polymer concentrations and degrees of Tet substitution in PEG-4-Tet conjugates. The cell experiments via an indirect contact assay demonstrated that these "tetrazole-alkene" photo-click PEG hydrogels were noncytotoxic. The high specificity of photo-click reaction renders thus obtained PEG hydrogels particularly interesting for controlled protein release. Notably, in vitro release studies showed that cytochrome c (CC), gamma globulins (Ig), and recombinant human interleukin-2 (rhIL-2) all were released from PEG hydrogels in a sustained and quantitative manner over a period of 14-20 days. Importantly, released CC and rhIL-2 exhibited comparable biological activities to native CC and rhIL-2, respectively. These results confirm that "tetrazole-alkene" photo-click reaction is highly compatible with these loaded proteins. This photo-controlled, specific, efficient, and catalyst-free click chemistry provides a new and versatile strategy to in situ forming hydrogels that hold tremendous potentials for protein delivery and tissue engineering. PMID- 23819864 TI - Moving forward: dispersal and species interactions determine biotic responses to climate change. AB - We need accurate predictions about how climate change will alter species distributions and abundances around the world. Most predictions assume simplistic dispersal scenarios and ignore biotic interactions. We argue for incorporating the complexities of dispersal and species interactions. Range expansions depend not just on mean dispersal, but also on the shape of the dispersal kernel and the population's growth rate. We show how models using species-specific dispersal can produce more accurate predictions than models applying all-or-nothing dispersal scenarios. Models that additionally include species interactions can generate distinct outcomes. For example, species interactions can slow climate tracking and produce more extinctions than models assuming no interactions. We conclude that (1) just knowing mean dispersal is insufficient to predict biotic responses to climate change, and (2) considering interspecific dispersal variation and species interactions jointly will be necessary to anticipate future changes to biological diversity. We advocate for collecting key information on interspecific dispersal differences and strong biotic interactions so that we can build the more robust predictive models that will be necessary to inform conservation efforts as climates continue to change. PMID- 23819865 TI - Smoking-related emphysema is associated with idiopathic pulmonary fibrosis and rheumatoid lung. AB - BACKGROUND AND OBJECTIVE: A combined pulmonary fibrosis/emphysema syndrome has been proposed, but the basis for this syndrome is currently uncertain. The aim was to evaluate the prevalence of emphysema in idiopathic pulmonary fibrosis (IPF) and rheumatoid lung (rheumatoid arthritis-interstitial lung disease (RA ILD)), and to compare the morphological features of lung fibrosis between smokers and non-smokers. METHODS: Using high-resolution computed tomography, the prevalence of emphysema and the pack-year smoking histories associated with emphysema were compared between current/ex-smokers with IPF (n = 186) or RA-ILD (n = 46), and non-chronic obstructive pulmonary disease (COPD) controls (n = 103) and COPD controls (n = 34). The coarseness of fibrosis was compared between smokers and non-smokers. RESULTS: Emphysema, present in 66/186 (35%) patients with IPF and 22/46 (48%) smokers with RA-ILD, was associated with lower pack-year smoking histories than in control groups (P < 0.05 for all comparisons). The presence of emphysema in IPF was positively linked to the pack-year smoking history (odds ratio 1.04, 95% confidence interval (CI) 1.02-1.06, P < 0.0005). In IPF, fibrosis was coarser in smokers than in non-smokers on univariate and multivariate analysis (P < 0.01 for all comparisons). In RA-ILD, fibrosis was coarser in patients with emphysema but did not differ significantly between smokers and non-smokers. CONCLUSIONS: In IPF and RA-ILD, a high prevalence of concurrent emphysema, in association with low pack-year smoking histories, and an association between coarser pulmonary fibrosis and a history of smoking in IPF together provide support for possible pathogenetic linkage to smoking in both diseases. PMID- 23819867 TI - Hypoelectronic dimetallaheteroboranes of group 6 transition metals containing heavier chalcogen elements. AB - We have synthesized and structurally characterized several dimetallaheteroborane clusters, namely, nido-[(Cp*Mo)2B4SH6], 1; nido-[(Cp*Mo)2B4SeH6], 2; nido [(Cp*Mo)2B4TeClH5], 3; [(Cp*Mo)2B5SeH7], 4; [(Cp*Mo)2B6SeH8], 5; and [(CpW)2B5Te2H5], 6 (Cp* = eta(5)-C5Me5, Cp = eta(5)-C5H5). In parallel to the formation of 1-6, known [(CpM)2B5H9], [(Cp*M)2B5H9], (M = Mo, W) and nido [(Cp*M)2B4E2H4] compounds (when M = Mo; E = S, Se, Te; M = W, E = S) were isolated as major products. Cluster 6 is the first example of tungstaborane containing a heavier chalcogen (Te) atom. A combined theoretical and experimental study shows that clusters 1-3 with their open face are excellent precursors for cluster growth reactions. As a result, the reaction of 1 and 2 with [Co2(CO)8] yielded clusters [(Cp*Mo)2B4H4E(MU3-CO)Co2(CO)4], 7-8 (7: E = S, 8: E = Se) and [(Cp*Mo)2B3H3E(MU-CO)3Co2(CO)3], 9-10 (9: E = S, 10: E = Se). In contrast, compound 3 under the similar reaction conditions yielded a novel 24-valence electron triple-decker sandwich complex, [(Cp*Mo)2{MU-eta(6):eta(6) B3H3TeCo2(CO)5}], 11. Cluster 11 represents an unprecedented metal sandwich cluster in which the middle deck is composed of B, Co, and Te. All the new compounds have been characterized by elemental analysis, IR, (1)H, (11)B, (13)C NMR spectroscopy, and the geometric structures were unequivocally established by X-ray diffraction analysis of 1, 2, 4-7, and 9-11. Furthermore, geometries obtained from the electronic structure calculations employing density functional theory (DFT) are in close agreement with the solid state structure determinations. We have analyzed the discrepancy in reactivity of the chalcogenato metallaborane clusters in comparison to their parent metallaboranes with the help of a density functional theory (DFT) study. PMID- 23819868 TI - A microreactor and imaging platform for studying chemical oscillators. AB - We present a laser scanning confocal microscopy (LSCM) and continuous flow microreactor (CFMR)-based platform to study the Belousov-Zhabotinsky (BZ) oscillators. We demonstrated that the scanning laser light below a certain power had no detectable influence on the BZ reaction. The CFMR consisted of the poly(methyl methacrylate) (PMMA) microwell and the polydimethylsiloxane (PDMS) microchannel and maintained the oscillation with a continuous supply of the catalyst-free BZ mixture. The synchronization of the two nonidentical oscillators was studied by the platform. The coupling intensity was controlled by changing the distance between the two oscillators. Results showed that the synchronization occurred as the oscillators were closer than a critical distance. The transition from desynchronization to synchronization was observed when the distance between the oscillators was near a critical value. The results of the numerical simulation by COMSOL agreed qualitatively with the experimental observation. PMID- 23819866 TI - A preliminary investigation of the relationship between water quality and Anopheles gambiae larval habitats in Western Cameroon. AB - BACKGROUND: Water quality and anopheline habitat have received increasing attention due to the possibility that challenges during larval life may translate into adult susceptibility to malaria parasite infection and/or insecticide resistance. METHODS: A preliminary study of Anopheles gambiae s.s. larval habitats in the north-west and south-west regions of Cameroon was conducted in order to detect associations between An. gambiae s.s. molecular form and 2La inversion distributions with basic water quality parameters. Water quality was measured by temperature, pH, conductivity, total dissolved solids (TDS) at seven sites in Cameroon and one site in Selinkenyi, Mali. RESULTS: Principal components and correlation analyses indicated a complex relationship between 2La polymorphism, temperature, conductivity and TDS. Cooler water sites at more inland locations yielded more S form larvae with higher 2La inversion polymorphism while warmer water sites yielded more M form larvae with rare observations of the 2La inversion. DISCUSSION: More detailed studies that take into account the population genetics but also multiple life stages, environmental data relative to these life stages and interactions with both humans and the malaria parasite may help us to understand more about how and why this successful mosquito is able to adapt and diverge, and how it can be successfully managed. PMID- 23819869 TI - Engineering youth service system infrastructure: Hawaii's continued efforts at large-scale implementation through knowledge management strategies. AB - Hawaii's Child and Adolescent Mental Health Division provides a unique illustration of a youth public mental health system with a long and successful history of large-scale quality improvement initiatives. Many advances are linked to flexibly organizing and applying knowledge gained from the scientific literature and move beyond installing a limited number of brand-named treatment approaches that might be directly relevant only to a small handful of system youth. This article takes a knowledge-to-action perspective and outlines five knowledge management strategies currently under way in Hawaii. Each strategy represents one component of a larger coordinated effort at engineering a service system focused on delivering both brand-named treatment approaches and complimentary strategies informed by the evidence base. The five knowledge management examples are (a) a set of modular-based professional training activities for currently practicing therapists, (b) an outreach initiative for supporting youth evidence-based practices training at Hawaii's mental health related professional programs, (c) an effort to increase consumer knowledge of and demand for youth evidence-based practices, (d) a practice and progress agency performance feedback system, and (e) a sampling of system-level research studies focused on understanding treatment as usual. We end by outlining a small set of lessons learned and a longer term vision for embedding these efforts into the system's infrastructure. PMID- 23819870 TI - Identifying Mendelian disease genes with the variant effect scoring tool. AB - BACKGROUND: Whole exome sequencing studies identify hundreds to thousands of rare protein coding variants of ambiguous significance for human health. Computational tools are needed to accelerate the identification of specific variants and genes that contribute to human disease. RESULTS: We have developed the Variant Effect Scoring Tool (VEST), a supervised machine learning-based classifier, to prioritize rare missense variants with likely involvement in human disease. The VEST classifier training set comprised ~ 45,000 disease mutations from the latest Human Gene Mutation Database release and another ~45,000 high frequency (allele frequency >1%) putatively neutral missense variants from the Exome Sequencing Project. VEST outperforms some of the most popular methods for prioritizing missense variants in carefully designed holdout benchmarking experiments (VEST ROC AUC = 0.91, PolyPhen2 ROC AUC = 0.86, SIFT4.0 ROC AUC = 0.84). VEST estimates variant score p-values against a null distribution of VEST scores for neutral variants not included in the VEST training set. These p-values can be aggregated at the gene level across multiple disease exomes to rank genes for probable disease involvement. We tested the ability of an aggregate VEST gene score to identify candidate Mendelian disease genes, based on whole-exome sequencing of a small number of disease cases. We used whole-exome data for two Mendelian disorders for which the causal gene is known. Considering only genes that contained variants in all cases, the VEST gene score ranked dihydroorotate dehydrogenase (DHODH) number 2 of 2253 genes in four cases of Miller syndrome, and myosin-3 (MYH3) number 2 of 2313 genes in three cases of Freeman Sheldon syndrome. CONCLUSIONS: Our results demonstrate the potential power gain of aggregating bioinformatics variant scores into gene-level scores and the general utility of bioinformatics in assisting the search for disease genes in large scale exome sequencing studies. VEST is available as a stand-alone software package at http://wiki.chasmsoftware.org and is hosted by the CRAVAT web server at http://www.cravat.us. PMID- 23819871 TI - Bioactive ent-kaurane diterpenoids from Isodon rosthornii. AB - Isorosthin A (1), the first 20-nor-enmein-type diterpenoid, and 15 new ent kauranoids, isorosthins B-P (2-16), along with 22 known analogues were isolated from the aerial parts of Isodon rosthornii. The structures of 1-16 were elucidated by means of spectroscopic analysis. The relative configuration of 2 and the absolute configuration of 3 were determined by single-crystal X-ray diffraction. Cytotoxicity evaluation against five human tumor lines showed inhibitory effects by several of the compounds tested. Furthermore, 12 of the isolates exhibited inhibitory activity against nitric oxide production in LPS activated RAW264.7 macrophages. PMID- 23819873 TI - Linguistic validation of the English version of the Overactive Bladder Symptom Score. PMID- 23819872 TI - Diet patterns are associated with demographic factors and nutritional status in South Indian children. AB - The burden of non-communicable chronic disease (NCD) in India is increasing. Diet and body composition 'track' from childhood into adult life and contribute to the development of risk factors for NCD. Little is known about the diet patterns of Indian children. We aimed to identify diet patterns and study associations with body composition and socio-demographic factors in the Mysore Parthenon Study cohort. We collected anthropometric and demographic data from children aged 9.5 years (n = 538). We also administered a food frequency questionnaire and measured fasting blood concentrations of folate and vitamin B12. Using principal component analysis, we identified two diet patterns. The 'snack and fruit' pattern was characterised by frequent intakes of snacks, fruit, sweetened drinks, rice and meat dishes and leavened breads. The 'lacto-vegetarian' pattern was characterised by frequent intakes of finger millet, vegetarian rice dishes, yoghurt, vegetable dishes and infrequent meat consumption. Adherence to the 'snack and fruit' pattern was associated with season, being Muslim and urban dwelling. Adherence to the lacto-vegetarian pattern was associated with being Hindu, rural dwelling and a lower maternal body mass index. The 'snack and fruit' pattern was negatively associated with the child's adiposity. The lacto-vegetarian pattern was positively associated with blood folate concentration and negatively with vitamin B12 concentration. This study provides new information on correlates of diet patterns in Indian children and how diet relates to nutritional status. Follow-up of these children will be important to determine the role of these differences in diet in the development of risk factors for NCD including body composition. PMID- 23819874 TI - Addressing health systems strengthening through an health equity lens. PMID- 23819875 TI - Age at onset of amyotrophic lateral sclerosis in China. AB - BACKGROUND: For patients with amyotrophic lateral sclerosis (ALS), age at onset is not only a key factor for diagnosis and prognosis, but also a clue for exploring pathogenesis. Reports based on results from a single medical center suggested that the mean age at onset of ALS in China was earlier than in other developed countries. A larger, multicenter-based study is needed to confirm this finding. METHODS: A registry-based study of ALS was conducted at 10 ALS centers of the Chinese ALS Association from March 1, 2009 to August 31, 2009. The demographical and clinical features of patients with ALS were collected. RESULTS: Data from a total of 455 patients with ALS were available for analysis. The mean age at onset for the entire cohort was 52.4 +/- 12.1 years. The peak age at onset was in the 45- to 49-year-old age group for women and the 55- to 59-year-old age group for men. The age at onset for patients from Guangzhou (a southern region) was significantly earlier than it was for patients from Shanghai (an eastern region) (t = 2.270, P = 0.025). CONCLUSIONS: This investigation confirmed the earlier age at onset of ALS in China as compared with other countries. Further population-based case-control investigations of genetic and environmental factors are needed to identify the potential risk factors for Chinese ALS patients. PMID- 23819876 TI - T-shaped donor-acceptor molecules for low-loss red-emission optical waveguide. AB - A series of T-shaped polycyclic molecules with high fluorescence were developed as optical waveguide materials. Their emissions covered almost the whole visible range from 450 to 800 nm. Compound 3-1 showed an optical loss coefficient about 0.29 dB/MUm in red-emission waveguide. Our investigations demonstrated that these molecules held great potential for organic optical waveguide due to the high fluorescence quantum efficiency and large Stokes' shift. PMID- 23819877 TI - Examining the safety of colon anastomosis on a rat model of ischemia-reperfusion injury. AB - INTRODUCTION: Intestinal ischemia and reperfusion can impair anastomotic strength. The purpose of this study was to evaluate the safety of delayed colon anastomosis following remote ischemia-reperfusion (IR) injury. METHODS: Rats divided into two groups underwent bilateral groin incisions, however only the study group had femoral artery clamping to inflict IR injury. Twenty-four hours following this insult, the animals underwent laparotomy, incision of the transverse colon and reanastomosis. End points included anastomotic leakage, strength and histopathological features. RESULTS: Anastomotic leak among IR animals (22.2%) was not statistically different in comparison to the controls [10.5% (p = 0.40)]. Anastomotic mean burst pressures showed no statistically significant difference [150.6 +/- 15.57 mmHg in the control group vs. 159.9 +/- 9.88 mmHg in the IR group (p = 0.64)]. The acute inflammatory process in the IR group was similar to controls (p = 0.26), as was the chronic repair process (p = 0.88). There was no significant difference between the inflammation:repair ratios amongst the two groups (p = 0.67). CONCLUSION: Primary colon repair is safe when performed 24 hours following systemic IR injury. PMID- 23819878 TI - Bonding of histidine to cerium oxide. AB - Adsorption of histidine on cerium oxide model surfaces was investigated by synchrotron radiation photoemission, resonant photoemission, and near edge X-ray absorption fine structure spectroscopies. Histidine was evaporated in a vacuum onto ordered stoichiometric CeO2(111) and partially reduced CeO1.9 thin films grown on Cu(111). Histidine binds to CeO2 in anionic form via the carboxylate group and all three nitrogen atoms, with the imidazole ring parallel to the surface. The amino nitrogen atom of the imidazole ring (IM) is deprotonated, and both IM nitrogen atoms form strong bonds via pi orbitals, while the alpha-amino nitrogen interacts with the oxide via its hydrogen atoms. In the case of CeO1.9, the deprotonation of the amino nitrogen of the imidazole ring is less pronounced and N K-edge spectra do not show a clear orientation of the ring with respect to the surface. A minor reduction of the cerium surface on adsorption of histidine was observed and explained by charge exchange as a result of hybridization of the pi orbitals of the IM ring with the f and d orbitals of ceria. Knowledge of histidine adsorption on the cerium oxide surface can be used for design of mediator-less biosensors where the histidine-containing proteins can be strongly bound to the oxide surface via the imidazole side chain of this residue. PMID- 23819879 TI - Memantine-induced speech problems in two patients with autistic disorder. AB - Stuttering is a complex speech disorder. There are two forms of stuttering: developmental stuttering and acquired stuttering. Developmental stuttering is a disorder of early childhood but acquired stuttering can develop at any age. Some medications can induce or deteriorate stuttering as an adverse effect. There are several reports of stuttering due to psychotropic drugs. Memantine, a glutamate antagonist used in the treatment of Alzheimer's disease, has also been studied for the treatment of autism spectrum disorders. This report presents deterioration of stuttering and speech problem in two children with autistic disorder who were receiving memantine. Based on our knowledge, this is the first time these adverse drug reactions have been attributed to memantine. In conclusion clinicians should consider that speech problems including stuttering may be due to the consumption of memantine, especially, in children may be a side effect of memantine especially in children. PMID- 23819880 TI - Optimization of pentadentate bispidines as bifunctional chelators for 64Cu positron emission tomography (PET). AB - Pentadentate bispidine ligands (3,7-diazabicyclo[3.3.1]nonanes) are optimized for maximum complex stability and facile functionalization with respect to their coupling to biological vector molecules and/or fluorescence markers for PET (positron emission tomography) and multimodal imaging (i.e., PET and optical imaging). The pentadentate ligand with two tertiary amine donors, two p-methoxy substituted pyridines, and one unsubsituted pyridine group is shown to best fulfill important conditions for PET applications, i.e., fast complexation with Cu(II) and high in vivo stability, and this was predicted from the solution chemistry, in particular the Cu(II/I) redox potentials. Also, solvent partition experiments to model the lipophilicity of the Cu(II) complexes indicate that the bis p-methoxy substituted ligand leads to cationic complexes with an appreciable lipophilicity. This is supported by the biodistribution experiments that show that the complex with the p-methoxy substituted ligand is excreted very quickly and primarily via the renal route and therefore is ideally suited for the development of PET tracers with ligands of this type coupled to biomolecules. PMID- 23819881 TI - Asthma diagnosis and treatment - 1008. Is small airways disease a widely prevalent yet underdiagnosed phenotype of asthma and COPD in India? PMID- 23819882 TI - Does continuity of care impact decision making in the next birth after a caesarean section (VBAC)? a randomised controlled trial. AB - BACKGROUND: Caesarean section (CS) has short and long-term health effects for both the woman and her baby. One of the greatest contributors to the CS rate is elective repeat CS. Vaginal birth after caesarean (VBAC) is an option for many women; despite this the proportion of women attempting VBAC remains low. Potentially the relationship that women have with their healthcare professional may have a major influence on the uptake of VBAC. Models of service delivery, which enable an individual approach to care, may make a difference to the uptake of VBAC. Midwifery continuity of care could be an effective model to encourage and support women to choose VBAC. METHODS/DESIGN: A randomised, controlled trial will be undertaken. Eligible pregnant women, whose most recent previous birth was by lower-segment CS, will be randomly allocated 1:1 to an intervention group or control group. The intervention provides midwifery continuity of care to women through pregnancy, labour, birth and early postnatal care. The control group will receive standard hospital care from different midwives through pregnancy, labour, birth and early postnatal care. Both groups will receive an obstetric consultation during pregnancy and at any other time if required. Clinical care will follow the same guidelines in both groups. DISCUSSION: This study will determine whether midwifery continuity of care influences the decision to attempt a VBAC and impacts on mode of birth, maternal experiences with care and the health of the neonate. Outcomes from this study might influence the way maternity care is provided to this group of women and thus impact on the CS rate. This information will provide high level evidence to policy makers, health service managers and practitioners who are working towards addressing the increased rate of CS. TRIAL REGISTRATION: This trial is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12611001214921. PMID- 23819883 TI - Asthma diagnosis and treatment - 1011. OZAC- a herbal medicine for bronchial asthma. PMID- 23819886 TI - Management of malignant left colonic obstruction: is an initial temporary colostomy followed by surgical resection a better option? AB - AIM: The surgical management of obstructed left colorectal cancer (OLCC) is still a matter of debate, and current guidelines recommend Hartmann's procedure (HP). The study evaluated the results of the surgical management with a focus on a strategy of initial colostomy (IC) followed by elective resection. METHOD: All patients operated on for OLCC were reviewed. Clinical, surgical, histological, morbidity and long-term results were noted. RESULTS: From 2000-11, 83 patients (48 men) with a mean age of 70.3 +/- 15.1 years underwent surgery for OLCC. Eleven (13.3%) had a subtotal colectomy owing to a laceration of the caecal wall. Eleven had a HP for tumour perforation (n = 6) or as palliation in a severely ill patient (n = 5). The remaining 61 (73.5%) patients had an IC, with the intention of performing an elective resection shortly after recovery. Postoperative complications occurred in six (9.8%) and there were two (3.3%) deaths. Fifty-nine operation survivors had a colonoscopy shortly afterwards which showed a synchronous cancer in two (3.4%). Twelve of the 59 patients had synchronous metastases. The subsequent elective resection including the colostomy site could be performed in 45 (74%) patients during the same admission at a median interval of 11 (7-17) days. The overall median length of hospital stay was 20 days and the 30-day mortality was 3/61 (5%). CONCLUSION: IC followed by surgical resection is a technically simple strategy, allowing initial abdominal exploration with a short period of having a colostomy, and permitting elective surgery with a low morbidity and full oncological lymphadenectomy. PMID- 23819885 TI - Web-based interventions to promote physical activity by older adults: promising perspectives for a public health challenge. AB - Regular physical activity is associated with a wide range of health benefits. As population age, promotion of physical activity should specifically target older adults, an expanding group involving potential higher health care costs in the near future. Innovative interventions focusing on physical activity behaviors of senior adults exposed promising results, most recently through the use of the Internet. If seniors and Internet are generally considered as two opposite concepts, arguments in favour of bringing them together in a public health perspective have been identified by the recent literature. Older adults are the fastest growing group of Internet users and are more prone than younger to use it for health-related subjects. Web-based interventions are effective in many health promotion sectors, including physical activity. This is particularly true when interventions target the environmental determinants of each senior citizen and are specifically designed for this population. Those early research findings must clearly be extended, particularly regarding to the long term effects of Web-based physical activity interventions. Solutions that will reduce the high dropout rate recorded in the existing literature must also be considered as a priority in order to ensure the development of this forward-looking field of research. PMID- 23819884 TI - In vitro chloroquine resistance for Plasmodium vivax isolates from the Western Brazilian Amazon. AB - BACKGROUND: Chloroquine (CQ) and primaquine (PQ) are still the drugs of choice to treat Plasmodium vivax malaria in many endemic areas, Brazil included. There is in vivo evidence for the P. vivax resistance to CQ in the Brazilian Amazon, where the increase in the proportion of P. vivax malaria parallels the increase of unusual clinical complications related to this species. In this study, in vitro CQ and mefloquine (MQ)-susceptibility of P. vivax isolates from the Western Brazilian Amazon was tested using the double-site enzyme-linked lactate dehydrogenase immunodetection (DELI) assay. METHODS: A total of 112 P. vivax isolates were tested in vitro for CQ-susceptibility and out of these 47 were also tested for MQ-susceptibility. The DELI assay was used to detect P. vivax growth at 48-hour short-term culture in isolates with ring stages ranging from 50 to %. Each isolate was tested in triplicate and geometric means of IC50's was obtained. Nineteen isolates were genetically characterized for pvdhfr, pvmrp1, pvmdr1 and pvdhps candidate genes likely related to CQ resistance (10 with IC50<40 nM and 9 with IC50 >100 nM). RESULTS: Twelve out of 112 isolates were considered resistant to CQ, resulting in 10.7% (IC95% 5.0-16.4), while 3 out of 47 (6.4%; IC95% 0.0 12.8) were resistant to MQ. A discrete correlation was observed between IC50's of CQ and MQ (Spearman=0.294; p=0.045). For pvdhps gene, a non-synonymous mutation was found at codon 382 (S->C) in 5/8 CQ-sensitive samples and 1/9 CQ-resistant samples (p=0.027). The other molecular markers were not associated to CQ susceptibility. CONCLUSIONS: In vitro CQ-resistance estimated in this study, estimated by the DELI test, was very similar to that observed in clinical trials, suggesting that in vitro procedures developed by capable local laboratories are useful in the surveillance of CQ-resistance in the Amazon; concurrent Amazon P. vivax strains with both CQ and MQ resistance may be common; and a non-synonymous mutation at pvdhps codon 382 (S->C) was associated to in vitro susceptibility to CQ, needing further studies to be confirmed. PMID- 23819887 TI - Compensating for literature annotation bias when predicting novel drug-disease relationships through Medical Subject Heading Over-representation Profile (MeSHOP) similarity. AB - BACKGROUND: Using annotations to the articles in MEDLINE(r)/PubMed(r), over six thousand chemical compounds with pharmacological actions have been tracked since 1996. Medical Subject Heading Over-representation Profiles (MeSHOPs) quantitatively leverage the literature associated with biological entities such as diseases or drugs, providing the opportunity to reposition known compounds towards novel disease applications. METHODS: A MeSHOP is constructed by counting the number of times each medical subject term is assigned to an entity-related research publication in the MEDLINE database and calculating the significance of the count by comparing against the count of the term in a background set of publications. Based on the expectation that drugs suitable for treatment of a disease (or disease symptom) will have similar annotation properties to the disease, we successfully predict drug-disease associations by comparing MeSHOPs of diseases and drugs. RESULTS: The MeSHOP comparison approach delivers an 11% improvement over bibliometric baselines. However, novel drug-disease associations are observed to be biased towards drugs and diseases with more publications. To account for the annotation biases, a correction procedure is introduced and evaluated. CONCLUSIONS: By explicitly accounting for the annotation bias, unexpectedly similar drug-disease pairs are highlighted as candidates for drug repositioning research. MeSHOPs are shown to provide a literature-supported perspective for discovery of new links between drugs and diseases based on pre existing knowledge. PMID- 23819888 TI - Diabetic retinopathy in sub-Saharan Africa: meeting the challenges of an emerging epidemic. AB - BACKGROUND: Sub-Saharan Africa faces an epidemic of diabetes. Diabetes causes significant morbidity including visual loss from diabetic retinopathy, which is largely preventable. In this resource-poor setting, health systems are poorly organized to deliver chronic care with multiple system involvement. The specific skills and resources needed to manage diabetic retinopathy are scarce. The costs of inaction for individuals, communities and countries are likely to be high. DISCUSSION: Screening for and treatment of diabetic retinopathy have been shown to be effective, and cost-effective, in resource-rich settings. In sub-Saharan Africa, clinical services for diabetes need to be expanded with the provision of effective, integrated care, including case-finding and management of diabetic retinopathy. This should be underpinned by a high quality evidence base accounting for differences in diabetes types, resources, patients and society in Africa. Research must address the epidemiology of diabetic retinopathy in Africa, strategies for disease detection and management with laser treatment, and include health economic analyses. Models of care tailored to the local geographic and social context are most likely to be cost effective, and should draw on experience and expertise from other continents. Research into diabetic retinopathy in Africa can drive the political agenda for service development and enable informed prioritization of available health funding at a national level. Effective interventions need to be implemented in the near future to avert a large burden of visual loss from diabetic retinopathy in the continent. SUMMARY: An increase in visual loss from diabetic retinopathy is inevitable as the diabetes epidemic emerges in sub-Saharan Africa. This could be minimized by the provision of case-finding and laser treatment, but how to do this most effectively in the regional context is not known. Research into the epidemiology, case-finding and laser treatment of diabetic retinopathy in sub-Saharan Africa will highlight a poorly met need, as well as guide the development of services for that need as it expands. PMID- 23819889 TI - Domain separation and characterization of PriC, a replication restart primosome factor in Escherichia coli. AB - In Escherichia coli the oriC-independent primosome plays an essential role in replication restart after dissociation of the replication DNA-protein complex by DNA damage. Primosome is thought to form via two pathways: one PriA dependent and the other PriA independent. PriC is a key protein in the replication restart of the PriA-independent pathway. In this study, we determined that PriC was divided into two domains. Then, we obtained information that: (i) the C-terminal domain preferentially binds to single-stranded DNA (ssDNA); (ii) the binding of PriC to ssDNA depends on salt concentration; and (iii) the binding site size of PriC is approximately 7-9 nucleotides. The protease digestion of PriC suggested that a possible DNA-binding site is the N-terminus of the C-terminal domain where basic amino acid residues are concentrated. Interestingly, alpha-helical induction of the C-terminal domain of PriC occurred after the addition of DNAs. Also, we examined the role of heptad repeat of leucine or valine residues in the C terminal domain and PriC oligomerization. This study describes the structure and function analysis of PriC which forms the primosome complex in replication restart. PMID- 23819890 TI - Factors affecting the perception of recovery quality in horses after anaesthesia. AB - REASONS FOR PERFORMING STUDY: A significant effect of gender, experience and background, i.e. an evaluator's relationship with horses as equine anaesthetists, orthopaedic surgeons, practitioners or owners, on perceptions of recovery quality after anaesthesia would reduce the validity of recovery quality scoring systems. OBJECTIVES: To determine the effects of evaluator background, experience and gender on their perceptions of recovery quality; and questionnaire response rate as a function of background. STUDY DESIGN: Cross-sectional survey. METHODS: A total of 440 potential evaluators were invited to evaluate the video-recorded recoveries of 24 horses using a visual analogue scale (VAS) in which 0 = worst, 100 = best possible recovery. A mean score was generated for each of the 1-24 recoveries within each background group. These were compared using Spearman's rank correlation. The effect of gender and experience on VAS scores were analysed using an ordinal logistic regression after scores were categorised into 'intermediate, 'worst' and 'best' recovery categories based on median, 25th and 75th percentile VAS scores, respectively. RESULTS: The overall response rate was 35%. The greatest was from the anaesthetists (78%) followed by surgeons (43%). The response rate among owners and practitioners was 26%. Correlation among VAS scores across all background groups was high (Spearman rank > 0.90; P < 0.001). Among the combined veterinarians, there was no significant gender (P = 0.551) or experience (P = 0.103) effect. Among horse owners, the effect of experience was not significant (P = 0.116) although gender was (P = 0.027). Male horse owners awarded significantly greater scores than females. CONCLUSIONS: When VAS are used to grade recovery quality, neither the background nor the gender of veterinary evaluators affects quality perception. Male owners awarded greater scores than female owners, implying that they are less critical of recovery quality and a gender effect among horse owners must be considered when VAS are used to score recovery quality. PMID- 23819891 TI - On their best behavior: how animal behavior can help determine the combined effects of species interactions and climate change. AB - The increasingly appreciated link between climate change and species interactions has the potential to help us understand and predict how organisms respond to a changing environment. As this connection grows, it becomes even more important to appreciate the mechanisms that create and control the combined effect of these factors. However, we believe one such important set of mechanisms comes from species' behavior and the subsequent trait-mediated interactions, as opposed to the more often studied density-mediated effects. Behavioral mechanisms are already well appreciated for mitigating the separate effects of the environment and species interactions. Thus, they could be at the forefront for understanding the combined effects. In this review, we (1) show some of the known behaviors that influence the individual and combined effects of climate change and species interactions; (2) conceptualize general ways behavior may mediate these combined effects; and (3) illustrate the potential importance of including behavior in our current tools for predicting climate change effects. In doing so, we hope to promote more research on behavior and other mechanistic factors that may increase our ability to accurately predict climate change effects. PMID- 23819892 TI - Pancreato-jejunostomy versus hand-sewn closure of the pancreatic stump to prevent pancreatic fistula after distal pancreatectomy: a retrospective analysis. AB - BACKGROUND: Different methods of pancreatic stump closure after distal pancreatectomy (DP) have been described to decrease the incidence of pancreatic fistula (PF) which still represents one of the most common complications in pancreatic surgery. We retrospectively compared the pancreato-jejunostomy technique with the hand-sewn closure of the pancreatic stump after DP, and analyzed clinical outcomes between the two groups, focusing on PF rate. METHODS: Thirty-six patients undergoing open DP at our institution between May 2005 and December 2011 were included. They were divided in two groups depending on pancreatic remnant management: in 24 cases the stump was closed by hand-sewn suture (Group A), while in 12 earlier cases a pancreato-jejunostomy was performed (Group B). We analyzed postoperative data in terms of mortality, morbidity and length of hospital stay between the two groups. RESULTS: PF occurred in 7 of 24 (29.1%) cases of group A (control group) compared to zero fistula rate in group B (anastomosis group) (p=0.005). Operative time was significantly higher in the anastomosis group (p=0.024). Mortality rate was 0% in both groups. Other postoperative outcomes such as hemorrhages, infections, medical complications and length of hospital stay were not significant between the two groups. CONCLUSION: Despite a higher operative time, the pancreato-jejunostomy after DP seems to be related to a lower incidence of PF compared to the hand-sewn closure of the pancreatic remnant. PMID- 23819893 TI - Zebrafish: a multifaceted tool for chemical biologists. PMID- 23819894 TI - Detection of Neospora caninum DNA in semen of experimental infected rams with no evidence of horizontal transmission in ewes. AB - Recent reports from New Zealand indicate Neospora caninum has a possible role in causing abortions in sheep. Transmission of N. caninum via semen has been documented in cattle. This study aimed to investigate if horizontal transmission through semen was also possible in sheep. Initially, 6-month old crossbred ram lambs (n=32), seronegative to N. caninum, were divided into 4 equal groups. Group 1 remained uninoculated whilst the remainder were inoculated with N. caninum tachyzoites intravenously as follows: Group 2 - 50 tachyzoites; Group 3 - 10(3) tachyzoites; Group 4 - 10(7) tachyzoites. Semen samples were collected weekly for 8 weeks for the detection of N. caninum DNA and quantified using quantitative PCR (qPCR). Plasma collected 1 month post-inoculation was subjected to ELISA (IDEXX Chekit) and Western blot. At 2 weeks post-infection, three rams from Group 1 (uninoculated) and three rams from Group 4 (10(7)tachyzoites/ml) were mated with two groups of 16 ewes over two oestrus cycles. Ewe sera collected 1 and 2 months post-mating were tested for seroconversion by ELISA and Western blot. All experimentally infected rams seroconverted by 1 month with ELISA S/P% values ranging from 11% to 36.5% in Group 2, 12-39.5% in Group 3 and 40-81% in Group 4. However, none of the ewes mated with the experimentally infected rams seroconverted. For the Western blot, responses towards immunodominant antigens (IDAs) were observed in ram sera directed against proteins at 10, 17, 21, 25-29, 30, 31, 33 and 37 kDa. Rams in Group 2, 3 and 4 were noted to have at least 3 IDAs present. None of the ewes showed any of the 8 prominent IDAs except for the one at 21 kDa which was seen in 30 out of 32 ewes in both groups. N. caninum DNA was detected intermittently in the ram's semen up to 5 weeks post-inoculation with the concentrations ranging from that equivalent to 1-889 tachyzoites per ml of semen. Low concentrations of N. caninum DNA were also detected in the brain tissue of two rams (Groups 1 and 4). These results suggest that although N. caninum DNA can be found in the semen of experimentally infected rams, the transmission of N. caninum via natural mating is an unlikely event. PMID- 23819895 TI - Self-reflection and positive schizotypy in the adolescent brain. AB - Clinical and phenomenological accounts of schizophrenia suggest that impairments in self-reflective processes significantly contribute to psychopathological expression. Recent imaging studies observe atypical cerebral activation patterns during self-reflection, especially around the cortical midline structures, both in psychosis-prone adults and individuals with schizophrenia. Given that self reflection processes consolidate during adolescence, and that early transient expression of psychosis (positive schizotypy) also arises during this period, the present study sought to examine whether atypical cerebral activation during self reflection task could be associated with early schizotypic expression during adolescence. Forty-two neurotypical adolescent participants (19 females) aged from 12 to 19 (15.92+/-1.9) underwent a self-reflection task using functional neuroimaging (fMRI), where they had to evaluate trait adjectives (1 to 4 ratings) about themselves or their same sex best friend. The Schizotypal Personality Questionnaire (SPQ) was employed to assess positive schizotypic expression. Results showed that positive schizotypy in adolescents significantly correlated with cortical midline activation patterns in the dorsomedial prefrontal cortex (dmPFC) and the posterior cingulate cortex (PCC), as well as the dorsolateral PFC and the lingual gyrus. The results are consistent with previous imaging literature on self-reflection and schizophrenia. They further highlight that the relationship between self-reflection processes and positive schizotypy operates at the trait level of expression and can be observed as early as adolescence. PMID- 23819896 TI - Integrated medical school ultrasound: development of an ultrasound vertical curriculum. AB - BACKGROUND: Physician-performed focused ultrasonography is a rapidly growing field with numerous clinical applications. Focused ultrasound is a clinically useful tool with relevant applications across most specialties. Ultrasound technology has outpaced the education, necessitating an early introduction to the technology within the medical education system. There are many challenges to integrating ultrasound into medical education including identifying appropriately trained faculty, access to adequate resources, and appropriate integration into existing medical education curricula. As focused ultrasonography increasingly penetrates academic and community practices, access to ultrasound equipment and trained faculty is improving. However, there has remained the major challenge of determining at which level is integrating ultrasound training within the medical training paradigm most appropriate. METHODS: The Ohio State University College of Medicine has developed a novel vertical curriculum for focused ultrasonography which is concordant with the 4-year medical school curriculum. Given current evidenced-based practices, a curriculum was developed which provides medical students an exposure in focused ultrasonography. The curriculum utilizes focused ultrasonography as a teaching aid for students to gain a more thorough understanding of basic and clinical science within the medical school curriculum. The objectives of the course are to develop student understanding in indications for use, acquisition of images, interpretation of an ultrasound examination, and appropriate decision-making of ultrasound findings. RESULTS: Preliminary data indicate that a vertical ultrasound curriculum is a feasible and effective means of teaching focused ultrasonography. The foreseeable limitations include faculty skill level and training, initial cost of equipment, and incorporating additional information into an already saturated medical school curriculum. CONCLUSIONS: Focused ultrasonography is an evolving concept in medicine. It has been shown to improve education and patient care. The indications for and implementation of focused ultrasound is rapidly expanding in all levels of medicine. The ideal method for teaching ultrasound has yet to be established. The vertical curriculum in ultrasound at The Ohio State University College of Medicine is a novel evidenced-based training regimen at the medical school level which integrates ultrasound training into medical education and serves as a model for future integrated ultrasound curricula. PMID- 23819897 TI - Implementing health system change: what are the lessons from the African Health Initiative? PMID- 23819898 TI - Editorial comment to Partial and radical nephrectomy provide comparable long-term cancer control for T1b renal cell carcinoma. PMID- 23819899 TI - Thaixylomolins A-C: limonoids featuring two new motifs from the Thai Xylocarpus moluccensis. AB - Three limonoids named thaixylomolins A-C (1-3), featuring two new motifs, were isolated from the seeds of a Thai mangrove, Xylocarpus moluccensis. The absolute configurations of these limonoids were determined by extensive NMR investigations, single-crystal X-ray diffraction analysis, and circular-dichroism spectroscopy in combination with quantum-chemical calculations. Thaixylomolin B exhibited inhibitory activity against nitric oxide production in lipopolysaccharide and IFN-gamma-induced RAW264.7 murine macrophages with an IC50 value of 84.3 MUM. PMID- 23819900 TI - Disrupted white matter in language and motor tracts in developmental stuttering. AB - White matter tracts connecting areas involved in speech and motor control were examined using diffusion-tensor imaging in a sample of people who stutter (n=29) who were heterogeneous with respect to age, sex, handedness and stuttering severity. The goals were to replicate previous findings in developmental stuttering and to extend our knowledge by evaluating the relationship between white matter differences in people who stutter and factors such as age, sex, handedness and stuttering severity. We replicated previous findings that showed reduced integrity in white matter underlying ventral premotor cortex, cerebral peduncles and posterior corpus callosum in people who stutter relative to controls. Tractography analysis additionally revealed significantly reduced white matter integrity in the arcuate fasciculus bilaterally and the left corticospinal tract and significantly reduced connectivity within the left corticobulbar tract in people who stutter. Region-of-interest analyses revealed reduced white matter integrity in people who stutter in the three pairs of cerebellar peduncles that carry the afferent and efferent fibers of the cerebellum. Within the group of people who stutter, the higher the stuttering severity index, the lower the white matter integrity in the left angular gyrus, but the greater the white matter connectivity in the left corticobulbar tract. Also, in people who stutter, handedness and age predicted the integrity of the corticospinal tract and peduncles, respectively. Further studies are needed to determine which of these white matter differences relate to the neural basis of stuttering and which reflect experience-dependent plasticity. PMID- 23819901 TI - Age of language learning shapes brain structure: a cortical thickness study of bilingual and monolingual individuals. AB - We examined the effects of learning a second language (L2) on brain structure. Cortical thickness was measured in the MRI datasets of 22 monolinguals and 66 bilinguals. Some bilingual subjects had learned both languages simultaneously (0 3 years) while some had learned their L2 after achieving proficiency in their first language during either early (4-7 years) or late childhood (8-13 years). Later acquisition of L2 was associated with significantly thicker cortex in the left inferior frontal gyrus (IFG) and thinner cortex in the right IFG. These effects were seen in the group comparisons of monolinguals, simultaneous bilinguals and early and late bilinguals. Within the bilingual group, significant correlations between age of acquisition of L2 and cortical thickness were seen in the same regions: cortical thickness correlated with age of acquisition positively in the left IFG and negatively in the right IFG. Interestingly, the monolinguals and simultaneous bilinguals did not differ in cortical thickness in any region. Our results show that learning a second language after gaining proficiency in the first language modifies brain structure in an age-dependent manner whereas simultaneous acquisition of two languages has no additional effect on brain development. PMID- 23819902 TI - Primary blast injury-induced lesions in the retina of adult rats. AB - BACKGROUND: The effect of primary blast exposure on the brain is widely reported but its effects on the eye remains unclear. Here, we aim to examine the effects of primary blast exposure on the retina. METHODS: Adult male Sprague-Dawley rats were exposed to primary blast high and low injury and sacrificed at 24 h, 72 h, and 2 weeks post injury. The retina was subjected to western analysis for vascular endothelial growth factor (VEGF), aquaporin-4 (AQP4), glutamine synthethase (GS), inducible nitric oxide synthase (NOS), endothelial NOS, neuronal NOS and nestin expression; ELISA analysis for cytokines and chemokines; and immunofluorescence for glial fibrillary acidic protein (GFAP)/VEGF, GFAP/AQP4, GFAP/nestin, GS/AQP4, lectin/iNOS, and TUNEL. RESULTS: The retina showed a blast severity-dependent increase in VEGF, iNOS, eNOS, nNOS, and nestin expression with corresponding increases in inflammatory cytokines and chemokines. There was also increased AQP4 expression and retinal thickness after primary blast exposure that was severity-dependent. Finally, a significant increase in TUNEL+ and Caspase-3+ cells was observed. These changes were observed at 24 h post-injury and sustained up to 2 weeks post injury. CONCLUSIONS: Primary blast resulted in severity-dependent pathological changes in the retina, manifested by the increased expression of a variety of proteins involved in inflammation, edema, and apoptosis. These changes were observed immediately after blast exposure and sustained up to 2 weeks suggesting acute and chronic injury mechanisms. These changes were most obvious in the astrocytes and Muller cells and suggest important roles for these cells in retina pathophysiology after blast. PMID- 23819903 TI - Comprehensive behavioral-motivational nutrition education improves depressive symptoms following bariatric surgery: a randomized, controlled trial of obese Hispanic Americans. AB - OBJECTIVE: To evaluate the effect of 2 post-bariatric support interventions on depressive symptoms of Hispanic Americans treated with gastric bypass for morbid or severe obesity. DESIGN/SETTING: Prospective randomized, controlled trial conducted in a laparoscopic institution. PARTICIPANTS/INTERVENTIONS: During the Phase 1 clinical trial (from preoperative evaluation to 6 months after surgery), all participants received standard care. During Phase 2 (6-12 months after surgery), participants were randomly assigned to receive either standard care (n = 72) or comprehensive support (n = 72). Comprehensive group participants received 6 educational sessions focused on behavior change strategies and motivation with nutrition counseling. MAIN OUTCOME MEASURES: Depression scores and weight change over time. ANALYSIS: Independent samples t tests and regression analysis assessed relationships among depression scores and excess weight loss. RESULTS: Participants receiving behavioral-motivational intervention scored significantly lower on Beck's Depression Inventory questionnaire scores than those receiving standard care. For those with depressive symptoms at randomization, 24% of participants who received the comprehensive intervention reported no depressive symptoms at 12 months after surgery, compared with 6% of those who received standard care (P < .001). Patients' depressive mood improvement was significantly and positively associated with excess weight loss and attendance at educational sessions (P < .001). CONCLUSIONS AND IMPLICATIONS: Findings support the importance of post-bariatric comprehensive behavioral motivational nutrition education for decreasing risk for depression and improving weight loss. PMID- 23819904 TI - Classroom parties in US elementary schools: the potential for policies to reduce student exposure to sugary foods and beverages. AB - OBJECTIVE: To examine associations among school, district, and state policies regarding classroom birthday and holiday parties. DESIGN: School-level policies assessed by survey during the 2009-2011 school years, with collection of corresponding district policies and state laws. SETTING: United States public elementary schools. PARTICIPANTS: Surveys from 1,204 schools (response rate, 60.9%). VARIABLES MEASURED: Prevalence of school-wide restrictions on sugary items served during parties. Predictor variables included district policy and state law. ANALYSIS: Multivariate logistic regressions to examine associations between school-level restrictions (outcome) and district policies and state laws, controlling for demographics and school year. RESULTS: Approximately one half of schools discouraged or prohibited sugary items during parties, or did not allow parties. Schools with a district policy and state law were 2.5 times more likely to restrict sweet items at parties than were schools with no corresponding policy or law. School-level limits were more common where policy and law addressed specific nutritional aspects of foods and beverages served in classroom parties (odds ratios, > 2.0; P < .001). CONCLUSIONS AND IMPLICATIONS: Prohibitions on sugary party fare were uncommon at all levels. Even though most policies were framed as recommendations rather than requirements, policy and law were associated with increased school-level restrictions, which demonstrates the value of policy. PMID- 23819905 TI - Interrogating differences in expression of targeted gene sets to predict breast cancer outcome. AB - BACKGROUND: Genomics provides opportunities to develop precise tests for diagnostics, therapy selection and monitoring. From analyses of our studies and those of published results, 32 candidate genes were identified, whose expression appears related to clinical outcome of breast cancer. Expression of these genes was validated by qPCR and correlated with clinical follow-up to identify a gene subset for development of a prognostic test. METHODS: RNA was isolated from 225 frozen invasive ductal carcinomas,and qRT-PCR was performed. Univariate hazard ratios and 95% confidence intervals for breast cancer mortality and recurrence were calculated for each of the 32 candidate genes. A multivariable gene expression model for predicting each outcome was determined using the LASSO, with 1000 splits of the data into training and testing sets to determine predictive accuracy based on the C-index. Models with gene expression data were compared to models with standard clinical covariates and models with both gene expression and clinical covariates. RESULTS: Univariate analyses revealed over-expression of RABEP1, PGR, NAT1, PTP4A2, SLC39A6, ESR1, EVL, TBC1D9, FUT8, and SCUBE2 were all associated with reduced time to disease-related mortality (HR between 0.8 and 0.91, adjusted p < 0.05), while RABEP1, PGR, SLC39A6, and FUT8 were also associated with reduced recurrence times. Multivariable analyses using the LASSO revealed PGR, ESR1, NAT1, GABRP, TBC1D9, SLC39A6, and LRBA to be the most important predictors for both disease mortality and recurrence. Median C-indexes on test data sets for the gene expression, clinical, and combined models were 0.65, 0.63, and 0.65 for disease mortality and 0.64, 0.63, and 0.66 for disease recurrence, respectively. CONCLUSIONS: Molecular signatures consisting of five genes (PGR, GABRP, TBC1D9, SLC39A6 and LRBA) for disease mortality and of six genes (PGR, ESR1, GABRP, TBC1D9, SLC39A6 and LRBA) for disease recurrence were identified. These signatures were as effective as standard clinical parameters in predicting recurrence/mortality, and when combined, offered some improvement relative to clinical information alone for disease recurrence (median difference in C-values of 0.03, 95% CI of -0.08 to 0.13). Collectively, results suggest that these genes form the basis for a clinical laboratory test to predict clinical outcome of breast cancer. PMID- 23819906 TI - Antifibrotic role of chemokine CXCL9 in experimental chronic pancreatitis induced by trinitrobenzene sulfonic acid in rats. AB - Chemokines have been shown to play an important role in the pathogenesis of pancreatitis, but the role of chemokine CXCL9 in pancreatitis is poorly understood. The aim of this study was to investigate whether CXCL9 was a modulating factor in chronic pancreatitis. Chronic pancreatitis was induced in Sprague-Dawley rats by intraductal infusion of trinitrobenzene sulfonic acid (TNBS) and CXCL9 expression was assessed by immunohistochemistry, Western blot analysis and enzyme linked immunosorbent assay (ELISA). Recombinant human CXCL9 protein (rCXCL9), neutralizing antibody and normal saline (NS) were administered to rats with chronic pancreatitis by subcutaneous injection. The severity of fibrosis was determined by measuring hydroxyproline in pancreatic tissues and histological grading. The effect of rCXCL9 on activated pancreatic stellate cells (PSCs) in vitro was examined and collagen 1alpha1, TGF-beta1 and CXCR3 expression was assessed by Western blot analysis in isolated rat PSCs. Chronic pancreatic injury in rats was induced after TNBS treatment and CXCL9 protein was markedly upregulated during TNBS-induced chronic pancreatitis. Although parenchymal injury in the pancreas was not obviously affected after rCXCL9 and neutralizing antibody administration, rCXCL9 could attenuate fibrogenesis in TNBS-induced chronic pancreatitis in vivo and exerted antifibrotic effects in vitro, suppressing collagen production in activated PSCs. In conclusion, CXCL9 is involved in the modulation of pancreatic fibrogenesis in TNBS-induced chronic pancreatitis in rats, and may be a therapeutic target in pancreatic fibrosis. PMID- 23819907 TI - Dormancy Associated Translation Inhibitor (DATIN/Rv0079) of Mycobacterium tuberculosis interacts with TLR2 and induces proinflammatory cytokine expression. AB - Mycobacterium tuberculosis, the cause of tuberculosis in humans, is present approximately in one third of the world's population, mostly in a dormant state. The proteins encoded by the dormancy survival regulon (DosR regulon) are mainly responsible for survival of the bacilli in a latent form. To maintain latency, mycobacteria orchestrate a balanced interplay of different cytokines secreted by immune cells during the granulomatous stage. The function of most of the DosR regulon proteins of M. tuberculosis is unknown. In this study, we have shown that one of the DosR regulon proteins, DATIN, encoded by the gene Rv0079, can stimulate macrophages and peripheral blood mononuclear cells (PBMC) to secrete important cytokines that may be significant in granuloma formation and its maintenance. The expression level of DATIN in Mycobacterium bovis BCG was found to be upregulated in pH stress and microaerobic conditions. Computational modeling, docking and simulation study suggested that DATIN might interact with TLR2. This was further confirmed through the interaction of recombinant DATIN with TLR2 expressed by HEK293 cells. When in vitro differentiated THP-1 cells were treated with recombinant DATIN, increased secretion of TNF-alpha, IL-1beta and IL-8 was observed in a dose dependent manner. When differentiated THP-1 cells were infected with a modified BCG strain that overexpressed DATIN, augmented secretions of TNF-alpha, IL-1beta and IL-8 were observed as compared to a reference BCG strain containing empty vector. Similarly, human PBMCs when infected with M. bovis BCG that overexpressed DATIN, upregulated secretion of proinflammatory cytokines IFN-gamma, TNF-alpha, IL-1beta and IL-8. The cytokine profiles dissected herein point to a possible role of DATIN in maintenance of latency with the help of the proinflammatory responses. PMID- 23819908 TI - The next generation of the World Health Organization's global antiretroviral guidance. AB - The 2013 World Health Organization's (WHO) Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection provide more than 50 new recommendations across the continuum of HIV care, including recommendations on HIV testing, using antiretroviral drugs for prevention, linking individuals to HIV care and treatment services, initiating and maintaining antiretroviral therapy (ART) and monitoring treatment. Guidance is provided across all age groups and populations of adults, pregnant and breastfeeding women, adolescents and key populations. The guidelines are based on a public health approach to expanding the use of ARV drugs for HIV treatment and prevention, with a particular focus on resource-limited settings. The most important new clinical recommendations include: treating adults, adolescents and older children earlier - starting ART in all individuals with a CD4 cell count of 500 cells/mm(3) or less (but giving priority to those with advanced clinical disease or a CD4 cell count less than 350 cells/mm(3)); starting ART at any CD4 cell count in certain populations, including those with active TB (existing recommendation), Hepatitis B infection and severe chronic liver disease, HIV positive partners in serodiscordant couples (existing recommendation), pregnant and breastfeeding women, and children younger than 5 years of age; a preferred first-line ART regimen of Tenofovir+3TC or FTC+ Efavirenz as a once-daily fixed dose combination for adults, pregnant women, and children aged 3 years and older; and the use of viral load testing as the preferred approach to monitoring the response to ART and to diagnose treatment failure. Guidance is also provided on enhancing the efficiency and effectiveness of HIV services, including strategies to improve retention in care, and adherence to ART; task-shifting to address human resource gaps; decentralizing delivery of ART to primary health care, and integrating ART services within maternal and child health, TB or drug dependency clinics. There is additional guidance for programme managers on how to plan HIV programmes and use resources most efficiently. PMID- 23819909 TI - Cool water vs warm water immersion for minimal sedation colonoscopy: a double blind randomized trial. AB - AIM: Water-aided insertion as an alternative colonoscopy technique reduces patient discomfort. Warm water has been used in most published trials, but the use of cool water is easier and, if equally effective, could support the use of the water-aided technique in routine practice. METHOD: A double-blind, randomized, single-centre study was performed in which 201 patients were randomized to either cool (20-24 degrees C) or warm (37 degrees C) water immersion insertion. The primary outcome was caecal intubation time. The success rate of minimal sedation and patient discomfort were also assessed. RESULTS: The caecal intubation time for cool and warm water was similar (6.9 +/- 3.5 vs 7.0 +/ 3.4 min, P = 0.64). The respective success rates of minimal sedation colonoscopy (89.1% vs 90%, P = 1.00) and discomfort (P = 0.51) were no different. All other outcomes except a greater need for abdominal compression in the cool water arm (P = 0.04) were similar including the total procedure time, terminal ileum intubation rate, adenoma detection, length of the inserted scope, water volume, non-standard position rate, difficulty of the procedure and the patient's temperature sensation. CONCLUSION: The use of cool water did not modify the caecal intubation time compared with warm water. Exception for abdominal compression, all other end-points were no different. Cool water immersion is an alternative to the technically more demanding warm water immersion colonoscopy. PMID- 23819910 TI - Insulin resistance as estimated by the homeostatic method at diagnosis of gestational diabetes: estimation of disease severity and therapeutic needs in a population-based study. AB - BACKGROUND: Chronic insulin resistance, exacerbated in the course of pregnancy, is an important pathophysiologic mechanism of gestational diabetes mellitus (GDM). We hypothesise that the degree of insulin resistance, assessed at diagnosis of GDM, is a parameter of its pathophysiologic heterogeneity and/or severity. Thus, it offers potential to open new avenues for the personalization of therapy in affected women. METHODS: 1254 Polish Caucasian women with GDM were recruited into the study. The following parameters were assessed in the course of the study: body mass index (BMI), parity, weight gain during pregnancy, glycated haemoglobin, glucose level during an oral glucose tolerance test (OGTT), insulin, insulin resistance and insulin secretion. The severity of GDM was assessed based on insulin use and daily insulin dose during gestation. In order to evaluate insulin secretion and insulin resistance the homeostatic method was used (HOMA-B and HOMA-IR, respectively). We compared all the metabolic parameters and methods of treatment of GDM in women subdivided by quartiles of insulin resistance. RESULTS: The HOMA-IR in the whole population ranged from 0.34 to 20.39. The BMI, fasting insulin, fasting glucose and insulin dose per day increased along with increasing quartiles (HOMA-IR > 1.29). We observed a decrease of HOMA-B in the third quartile (1.92-2.89) compared with the first quartile (0.34-1.29). Insulin treatment was associated with HOMA-IR (<1.29 vs. >2.89), OR: 3.37, fasting glucose (<=6.11 vs. >6.11 mmol/dl), OR: 2.61, age (<=30 vs. >30 y. o.), OR: 1.54, and BMI (<25 vs. >=25 kg/m2), OR: 1.45. Maximum insulin dose was associated with HOMA-IR, OR: 2.00, after adjustment for family history of diabetes, and 2-h OGTT glucose. CONCLUSION: Insulin resistance assessed by the HOMA index at diagnosis is associated with the severity and pathophysiological heterogeneity of GDM. A HOMA-IR >1.29 points to the major role of insulin resistance, indicating the need for a treatment aimed at improving tissue sensitivity to insulin. A HOMA-IR 1.29 2.89 suggests reduced insulin secretion, which is an indication for the introduction of insulin therapy. A HOMA-IR >2.89 indicates insufficient compensation for insulin resistance, which suggests the need for a treatment aimed at improving susceptibility of tissues to insulin combined with insulin therapy. PMID- 23819911 TI - Applying science and mathematics to big data for smarter buildings. AB - Many buildings are now collecting a large amount of data on operations, energy consumption, and activities through systems such as a building management system (BMS), sensors, and meters (e.g., submeters and smart meters). However, the majority of data are not utilized and are thrown away. Science and mathematics can play an important role in utilizing these big data and accurately assessing how energy is consumed in buildings and what can be done to save energy, make buildings energy efficient, and reduce greenhouse gas (GHG) emissions. This paper discusses an analytical tool that has been developed to assist building owners, facility managers, operators, and tenants of buildings in assessing, benchmarking, diagnosing, tracking, forecasting, and simulating energy consumption in building portfolios. PMID- 23819912 TI - Effects of cordycepin on Y-maze learning task in mice. AB - Cordycepin (3'-deoxyadenosine) is the major bioactive component of Cordyceps militaris that has been widely used in oriental countries as a Traditional Chinese Medicine and healthy food for preventing early aging, improving physical performance and increasing lifespan. Cordyceps militaris extracts other than cordycepin have been reported to improve cognitive function. Although cordycepin is one of the most utilized Cordyceps militaris components, it remains unknown whether cordycepin could improve learning and memory. Here we investigated effects of cordycepin on learning and memory in healthy and ischemic mice using Y maze test. We found that oral cordycepin administration at dose of 10 mg/kg significantly improved Y-maze learning performance both in healthy and ischemic mice. However, cordycepin at dose of 5 mg/kg enhanced Y-maze learning only in ischemic mice but not healthy mice. In this study, simultaneously, we found that orally administrated cordycepin significantly decreased the neuronal loss induced by ischemia in hippocampal CA1 and CA3 regions. Collectively, our results can provide valuable evidence that cordycepin may act as a nootropic product or potential clinical application in improving cognitive function of patients with ischemic stroke in the future. PMID- 23819913 TI - Molecular approaches towards development of purified natural products and their structurally known derivatives as efficient anti-cancer drugs: current trends. AB - Several natural products and their derivatives, either in purified or structurally identified form, exhibit immense pharmacological and biological properties, some of them showing considerable anticancer potential. Although the molecular mechanisms of action of some of these products are yet to be elucidated, extensive research in this area continues to generate new data that are clinically exploitable. Recent advancement in molecular biology, high throughput screening, biomarker identifications, target selection and genomic approaches have enabled us to understand salient interactions of natural products and their derivatives with cancer cells vis-a-vis normal cells. In this review we highlight the recent approaches and application of innovative technologies made to improve quality as well as efficiency of structurally identified natural products and their derivatives, particularly in small molecular forms capable of being used in "targeted therapies" in oncology. These products preferentially involve multiple mechanistic pathways and overcome chemo-resistance in tumor types with cumulative action. We also mention briefly a few physico-chemical features that compare natural products with drugs in recent natural product discovery approaches. We further report here a few purified natural products as examples that provide molecular interventions in cancer therapeutics to give the reader a glimpse of the current trends of approach for discovering useful anticancer drugs. PMID- 23819914 TI - Antigen and lymphopenia-driven donor T cells are differentially diminished by post-transplantation administration of cyclophosphamide after hematopoietic cell transplantation. AB - Administration of cyclophosphamide after transplantation (post-transplantation cyclophosphamide, PTC) has shown promise in the clinic as a prophylactic agent against graft-versus-host disease (GVHD). An important issue with regard to recipient immune function and reconstitution after PTC is the extent to which, in addition to diminution of antihost allo-reactive donor T cells, the remainder of the nonhost allo-reactive donor T cell pool may be affected. To investigate PTC's effects on nonhost reactive donor CD8 T cells, ova-specific (OT-I) and gp100 specific Pmel-1 T cells were labeled with proliferation dyes and transplanted into syngeneic and allogeneic recipients. Notably, an intermediate dose (66 mg/kg) of PTC, which abrogated GVHD after allogeneic HSCT, did not significantly diminish these peptide-specific donor T cell populations. Analysis of the rate of proliferation after transplantation illustrated that lymphopenic-driven, donor nonhost reactive TCR Tg T cells in syngeneic recipients underwent slow division, resulting in significant sparing of these donor populations. In contrast, after exposure to specific antigens at the time of transplantation, these same T cells were significantly depleted by PTC, demonstrating the global susceptibility of rapidly dividing T cells after an encounter with cognate antigen. In total, our results, employing both syngeneic and allogeneic minor antigen-mismatched T cell replete models of transplantation, demonstrate a concentration of PTC that abrogates GVHD can preserve most cells that are dividing because of the accompanying lymphopenia after exposure. These findings have important implications with regard to immune function and reconstitution in recipients after allogeneic hematopoietic stem cell transplantation. PMID- 23819915 TI - Sub-acute toxicity profile of a modified resveratrol supplement. AB - Longevinex, a nutraceutical formulation containing Resveratrol as the main component along with other polyphenolics exhibits diverse health benefits but systemic safety studies are lacking. Hence, to test the safety of Longevinex use for therapeutic purposes, 50 Sprague Dawley rats were randomly divided into five groups (n=10; 5M, 5F) wherein group I as vehicle treated control, group II and group III received 50 mg and 100 mg of plain Resveratrol respectively and group IV and group V received 50 mg and 100 mg of Longevinex respectively for a period of 28 days. All toxicological parameters were analyzed as per OECD-407 guidelines. Results showed treatment with Resveratrol and Longevinex did not result in any mortality of rats neither did they exhibit any clinical signs of toxicity. Hematological and biochemical analysis of serum enzymes and metabolites were not significantly altered between Longevinex and control rats. Likewise, histopathological analysis for various organs did not reveal significant changes in the vital organs of the treated rats. The study revealed that there were no significant treatment related adverse effects in rats exposed to Longevinex for 28 days and considered safe at the given dose where compared to plain Resveratrol. PMID- 23819916 TI - Studies on meso-zeaxanthin for potential toxicity and mutagenicity. AB - The purpose of these studies was to examine the potential toxicity and genotoxicity of meso-zeaxanthin (MZ). Toxicity was assessed by administering MZ daily to rats for 13 weeks followed by a 4-week recovery period. Potential genotoxicity was assessed in separate experiments using the Ames test method. Rats were randomly assigned to four groups to receive corn oil (control) or MZ at dose levels of 2, 20 and 200 mg/kg/day by oral gavage (10/sex/group). Additional rats (five of each sex) in the control and the 200 mg/kg/day groups were retained for the recovery period. No compound-related clinical, biochemical or pathological signs or symptoms were noted and the no-observed-adverse-effect level (NOAEL) of MZ was >200 mg/kg/day. To investigate genotoxicity, MZ was tested for its ability to induce reverse mutations (+/-microsomal enzymes) at 2 genomic loci; the histidine locus of 4 strains of Salmonella typhimurium and the tryptophan locus of Escherichia coli strain WP2uvrA. Six doses of MZ ranging from 10 to 5000 MUg/plate were tested twice with vehicle and positive controls using 3 plates/dose. MZ did not cause any increase in the mean number of revertants/plate with any bacterial strain, with or without microsomal enzymes, and was therefore unlikely to be mutagenic. PMID- 23819917 TI - Curation-free biomodules mechanisms in prostate cancer predict recurrent disease. AB - MOTIVATION: Gene expression-based prostate cancer gene signatures of poor prognosis are hampered by lack of gene feature reproducibility and a lack of understandability of their function. Molecular pathway-level mechanisms are intrinsically more stable and more robust than an individual gene. The Functional Analysis of Individual Microarray Expression (FAIME) we developed allows distinctive sample-level pathway measurements with utility for correlation with continuous phenotypes (e.g. survival). Further, we and others have previously demonstrated that pathway-level classifiers can be as accurate as gene-level classifiers using curated genesets that may implicitly comprise ascertainment biases (e.g. KEGG, GO). Here, we hypothesized that transformation of individual prostate cancer patient gene expression to pathway-level mechanisms derived from automated high throughput analyses of genomic datasets may also permit personalized pathway analysis and improve prognosis of recurrent disease. RESULTS: Via FAIME, three independent prostate gene expression arrays with both normal and tumor samples were transformed into two distinct types of molecular pathway mechanisms: (i) the curated Gene Ontology (GO) and (ii) dynamic expression activity networks of cancer (Cancer Modules). FAIME-derived mechanisms for tumorigenesis were then identified and compared. Curated GO and computationally generated "Cancer Module" mechanisms overlap significantly and are enriched for known oncogenic deregulations and highlight potential areas of investigation. We further show in two independent datasets that these pathway level tumorigenesis mechanisms can identify men who are more likely to develop recurrent prostate cancer (log-rank_p = 0.019). CONCLUSION: Curation-free biomodules classification derived from congruent gene expression activation breaks from the paradigm of recapitulating the known curated pathway mechanism universe. PMID- 23819918 TI - Crocodylians evolved scattered multi-sensory micro-organs. AB - BACKGROUND: During their evolution towards a complete life cycle on land, stem reptiles developed both an impermeable multi-layered keratinized epidermis and skin appendages (scales) providing mechanical, thermal, and chemical protection. Previous studies have demonstrated that, despite the presence of a particularly armored skin, crocodylians have exquisite mechanosensory abilities thanks to the presence of small integumentary sensory organs (ISOs) distributed on postcranial and/or cranial scales. RESULTS: Here, we analyze and compare the structure, innervation, embryonic morphogenesis and sensory functions of postcranial, cranial, and lingual sensory organs of the Nile crocodile (Crocodylus niloticus) and the spectacled caiman (Caiman crocodilus). Our molecular analyses indicate that sensory neurons of crocodylian ISOs express a large repertoire of transduction channels involved in mechano-, thermo-, and chemosensory functions, and our electrophysiological analyses confirm that each ISO exhibits a combined sensitivity to mechanical, thermal and pH stimuli (but not hyper-osmotic salinity), making them remarkable multi-sensorial micro-organs with no equivalent in the sensory systems of other vertebrate lineages. We also show that ISOs all exhibit similar morphologies and modes of development, despite forming at different stages of scale morphogenesis across the body. CONCLUSIONS: The ancestral vertebrate diffused sensory system of the skin was transformed in the crocodylian lineages into an array of discrete multi-sensory micro-organs innervated by multiple pools of sensory neurons. This discretization of skin sensory expression sites is unique among vertebrates and allowed crocodylians to develop a highly-armored, but very sensitive, skin. PMID- 23819920 TI - A tipping point in interprofessional education. PMID- 23819919 TI - The SAAP pipeline and database: tools to analyze the impact and predict the pathogenicity of mutations. AB - BACKGROUND: Understanding and predicting the effects of mutations on protein structure and phenotype is an increasingly important area. Genes for many genetically linked diseases are now routinely sequenced in the clinic. Previously we focused on understanding the structural effects of mutations, creating the SAAPdb resource. RESULTS: We have updated SAAPdb to include 41% more SNPs and 36% more PDs. Introducing a hydrophobic residue on the surface, or a hydrophilic residue in the core, no longer shows significant differences between SNPs and PDs. We have improved some of the analyses significantly enhancing the analysis of clashes and of mutations to-proline and from-glycine. A new web interface has been developed allowing users to analyze their own mutations. Finally we have developed a machine learning method which gives a cross-validated accuracy of 0.846, considerably out-performing well known methods including SIFT and PolyPhen2 which give accuracies between 0.690 and 0.785. CONCLUSIONS: We have updated SAAPdb and improved its analyses, but with the increasing rate with which mutation data are generated, we have created a new analysis pipeline and web interface. Results of machine learning using the structural analysis results to predict pathogenicity considerably outperform other methods. PMID- 23819921 TI - Curricular innovation to integrate the art and science of nursing. PMID- 23819922 TI - Nanochannel pH gradient electrofocusing of proteins. AB - We demonstrate matrix-free pH gradient electrofocusing of proteins within an 85 nm deep nanochannel. In contrast to conventional isoelectric focusing where the fluid does not move, this pH gradient method traps protein molecules flowing through a channel by balancing electric forces due to pH-dependent protein charge and viscous drag forces caused by electro-osmosis. The nanoscale depth of the device and the low voltage used limit convection relative to diffusion, thus producing a stable focused band of protein. R-Phycoerythrin (RPE) and Dylight labeled streptavidin (Dyl-Strep) were focused within a nanochannel using applied voltages between 0.4 and 1.6 V. Concentration enhancement factors of over 380 have been achieved within 5 min. Varying the buffer pH (between 2.7 and 7.2) at the boundaries of the nanochannel affected the shape of the focused bands. For RPE, a pH span of 4.5 (pH 2.7 to 7.2) yielded the narrowest peak while a span of 2.4 (pH 2.7 to 5.1) produced a significantly wider peak. Such matrix-free nanofluidic devices with pH gradient electrofocusing may enable on-chip integration of orthogonal separation techniques with mass spectrometry offering labor savings and enhanced performance. PMID- 23819923 TI - Human beta-defensin 2 may inhibit internalisation of bacillus Calmette-Guerin (BCG) in bladder cancer cells. AB - OBJECTIVE: To investigate whether secretion of human beta-defensin 2 (HBD-2) is induced by bacillus Calmette-Guerin (BCG) and to determine whether HBD-2 affects BCG internalisation in bladder cancer cells. MATERIALS AND METHODS: Reverse transcription-polymerase chain reaction analysis was used to determine whether HBD-2 mRNA increases after incubation with BCG. HBD-2 proteins in 5637 and T24 human bladder cancer cell lines were assayed by enzyme-linked immunosorbent assay. The internalisation rate was evaluated by double immunofluorescence assay and confocal microscopy to test the optimal dose of HBD-2 for BCG internalisation. We also investigated the difference in internalisation rates and cell viability between recombinant HBD-2 protein, anti-HBD-2 antibody, and HBD-2 plus anti-HBD-2 antibody pretreatments. RESULTS: BCG induced HBD-2 mRNA expression and HBD-2 production dose and time-dependently in bladder cancer cells and affected BCG internalisation. Pretreatment with recombinant HBD-2 protein lowered internalisation of BCG dose-dependently. Moreover, anti-HBD-2 antibody prevented the effect of HBD-2 on BCG internalisation in bladder cancer cells. The internalisation rate of BCG pretreated with anti-HBD-2 antibody was higher than that in the control in 5637 (P < 0.01) and T24 cells (P < 0.05). The BCG internalisation rate in cells pretreated with anti-HBD-2 antibody plus recombinant HBD-2 protein was higher than that in the control in 5637 (P < 0.01) and T24 cells (P < 0.05). Mycobacterium bovis BCG decreased bladder cancer cell viability, and anti-HBD-2 antibody prevented the inhibitory role of HBD-2 on the anti-proliferative effects of M. bovis BCG in bladder cancer cells CONCLUSION: Bladder cancer cells produce HBD-2 when they are infected by BCG to defend themselves against BCG internalisation, which plays an important role during the initiation and propagation of the immunotherapeutic response in bladder cancer cells. PMID- 23819924 TI - 5-HT2A receptors in the feline brain: 123I-5-I-R91150 kinetics and the influence of ketamine measured with micro-SPECT. AB - Subanesthetic doses of ketamine can be used as a rapid-acting antidepressant in patients with treatment-resistant depression. Therefore, the brain kinetics of (123)I-5-I-R91150 (4-amino-N-[1-[3-(4-fluorophenyl)propyl]-4-methylpiperidin-4 yl]-5-iodo-2-methoxybenzamide) and the influence of ketamine on the postsynaptic serotonin-2A receptor (5-hydroxytryptamine-2A, or 5-HT2A) status were investigated in cats using micro-SPECT. METHODS: This study was conducted on 6 cats using the radioligand (123)I-5-I-R91150, a 5-HT2A receptor antagonist, as the imaging probe. Anesthesia was induced and maintained with a continuous-rate infusion of propofol (8.4 +/- 1.2 mg kg(-1) followed by 0.22 mg kg(-1) min(-1)) 75 min after tracer administration, and acquisition of the first image began 15 min after induction of anesthesia. After this first acquisition, propofol (0.22 mg kg(-1) min(-1)) was combined with ketamine (5 mg kg(-1) followed by 0.023 mg kg(-1) min(-1)), and the second acquisition began 15 min later. Semiquantification, with the cerebellum as a reference region, was performed to calculate the 5-HT2A receptor binding indices (parameter for available receptor density) in the frontal and temporal cortices. The binding indices were analyzed with Wilcoxon signed ranks statistics. RESULTS: The addition of ketamine to the propofol continuous-rate infusion resulted in decreased binding indices in the right frontal cortex (1.25 +/- 0.22 vs. 1.45 +/- 0.16; P = 0.028), left frontal cortex (1.34 +/- 0.15 vs. 1.49 +/- 0.10; P = 0.028), right temporal cortex (1.30 +/- 0.17 vs. 1.45 +/- 0.09; P = 0.046), and left temporal cortex (1.41 +/- 0.20 vs. 1.52 +/- 0.20; P = 0.046). CONCLUSION: This study showed that cats can be used as an animal model for studying alterations of the 5-HT2A receptor status with (123)I-5-I-R91150 micro-SPECT. Furthermore, an interaction between ketamine and the 5-HT2A receptors resulting in decreased binding of (123)I-5-I-R91150 in the frontal and temporal cortices was demonstrated. Whether the decreased radioligand binding resulted from a direct competition between ketamine and (123)I-5-I-R91150 or from a decreased affinity of the 5-HT2A receptor caused by ketamine remains to be elucidated. PMID- 23819926 TI - Aspirin and its related non-steroidal anti-inflammatory drugs. PMID- 23819925 TI - An inducible CiliaGFP mouse model for in vivo visualization and analysis of cilia in live tissue. AB - BACKGROUND: Cilia are found on nearly every cell type in the mammalian body, and have been historically classified as either motile or immotile. Motile cilia are important for fluid and cellular movement; however, the roles of non-motile or primary cilia in most tissues remain unknown. Several genetic syndromes, called the ciliopathies, are associated with defects in cilia structure or function and have a wide range of clinical presentations. Much of what we know about the formation and maintenance of cilia comes from model systems like C. elegans and Chalmydomonas. Studies of mammalian cilia in live tissues have been hampered by difficulty visualizing them. RESULTS: To facilitate analyses of mammalian cilia function we generated an inducible CiliaGFP mouse by targeting mouse cDNA encoding a cilia-localized protein somatostatin receptor 3 fused to GFP (Sstr3::GFP) into the ROSA26 locus. In this system, Sstr3::GFP is expressed from the ubiquitous ROSA26 promoter after Cre mediated deletion of an upstream Neo cassette flanked by lox P sites. Fluorescent cilia labeling was observed in a variety of live tissues and after fixation. Both cell-type specific and temporally regulated cilia labeling were obtained using multiple Cre lines. The analysis of renal cilia in anesthetized live mice demonstrates that cilia commonly lay nearly parallel to the apical surface of the tubule. In contrast, in more deeply anesthetized mice the cilia display a synchronized, repetitive oscillation that ceases upon death, suggesting a relationship to heart beat, blood pressure or glomerular filtration. CONCLUSIONS: The ability to visualize cilia in live samples within the CiliaGFP mouse will greatly aid studies of ciliary function. This mouse will be useful for in vivo genetic and pharmacological screens to assess pathways regulating cilia motility, signaling, assembly, trafficking, resorption and length control and to study cilia regulated physiology in relation to ciliopathy phenotypes. PMID- 23819927 TI - Mutagenicity and DNA damage of bisphenol A and its structural analogues in HepG2 cells. AB - Environmental oestrogen bisphenol A (BPA) and its analogues are widespread in our living environment. Because their production and use are increasing, exposure of humans to bisphenols is becoming a significant issue. We evaluated the mutagenic and genotoxic potential of eight BPA structural analogues (BPF, BPAF, BPZ, BPS, DMBPA, DMBPS, BP-1, and BP-2) using the Ames and comet assay, respectively. None of the tested bisphenols showed a mutagenic effect in Salmonella typhimurium strains TA98 and TA100 in either the presence or absence of external S9-mediated metabolic activation (Aroclor 1254-induced male rat liver). Potential genotoxicity of bisphenols was determined in the human hepatoma cell line (HepG2) at non-cytotoxic concentrations (0.1 MUmol L(-1) to 10 MUmol L(-1)) after 4-hour and 24-hour exposure. In the comet assay, BPA and its analogue BPS induced significant DNA damage only after the 24-hour exposure, while analogues DMBPS, BP 1, and BP-2 induced a transient increase in DNA strand breaks. PMID- 23819928 TI - Cytoprotective effects of taurine against toxicity induced by isoniazid and hydrazine in isolated rat hepatocytes. AB - Isoniazid is one of the most commonly used drugs to treat tuberculosis. Its administration is associated with a high incidence of hepatotoxicity. The aim of this study was to establish the protective effects of taurine against cytotoxicity induced by isoniazid and its suspected toxic metabolite hydrazine in isolated rat hepatocytes by measuring reactive oxygen species (ROS) formation, lipid peroxidation, mitochondrial depolarisation, reduced glutathione (GSH), and oxidised glutathione (GSSG). Isoniazid caused no significant ROS formation in normal hepatocytes, but in glutathione-depleted cells it was considerable. Hydrazine caused ROS formation and lipid peroxidation in both intact and glutathione-depleted cells. Both isoniazid and hydrazine caused mitochondrial membrane depolarisation. Hydrazine lowered cellular GSH reserve and increased GSSG. Taurine (200 MUmol L(-1)) and N-acetylcysteine (200 MUmol L(-1)) effectively countered the toxic effects of isoniazid and/or hydrazine by decreasing ROS formation, lipid peroxidation, and mitochondrial damage. Taurine prevented depletion of GSH and lowered GSSG levels in hydrazine-treated cells. This study suggests that the protective effects of taurine against isoniazid and its intermediary metabolite hydrazine cytotoxicity in rat hepatocytes could be attributed to antioxidative action. PMID- 23819929 TI - Percutaneous toxicity and decontamination of soman, VX, and paraoxon in rats using detergents. AB - Highly toxic organophosphorus compounds (OPs) were originally developed for warfare or as agricultural pesticides. Today, OPs represent a serious threat to military personnel and civilians. This study investigates the in vivo decontamination of male Wistar rats percutaneously exposed to paraoxon and two potent nerve agents--soman (GD) and VX. Four commercial detergents were tested as decontaminants--Neodekont(TM), Argos(TM), Dermogel(TM), and FloraFree(TM). Decontamination performed 2 min after exposure resulted in a higher survival rate in comparison with non-decontaminated controls. The decontamination effectiveness was expressed as protective ratio (PR, median lethal dose of agent in decontaminated animals divided by the median lethal dose of agent in untreated animals). The highest decontamination effectiveness was consistently achieved with Argos(TM) (PR=2.3 to 64.8), followed by Dermogel(TM) (PR=2.4 to 46.1). Neodekont(TM) and FloraFree(TM) provided the lowest decontamination effectiveness, equivalent to distilled water (PR=1.0 to 43.2). PMID- 23819931 TI - Protective effect of aerobic exercise against L-NAME-induced kidney damage in rats. AB - Exercise, alone or combined with changes in lifestyle, can prevent or reduce the need for pharmacotherapy in patients with compromised endothelium-dependent function. The aim of this study was to examine the protective effect of aerobic exercise against (L-NAME)-kidney damage in male rats induced by Nomega-nitro-L arginine methyl ester (L-NAME). L-NAME was administered to rats intraperitoneally in doses of 10 mg kg(-1) six days a week over eight weeks. Rats exercised by running on a treadmill at the speed of (15 to 22) m min(-1), 25 min to 64 min per day, five days a week over eight weeks. The rats were killed 48 h after the last dose, and their kidneys removed and homogenised to measure the levels of heat shock protein70 (HSP70), superoxide dismutase activity (SOD), and thiobarbituric acid reactive substances (TBARS). We also measured serum nitrite/nitrate. Chronic administration of L-NAME significantly increased renal HSP70 and TBARS levels and decreased renal SOD activity and serum nitrites/nitrates. Training modified abnormal renal HSP70, lowered TBARS, and increased SOD and serum nitrite/nitrate. Our results have confirmed that regular aerobic exercise protects against nitric oxide deficiency-induced kidney damage by modifying HSP70, up-regulating SOD activity, and depleting TBARS. PMID- 23819930 TI - Melatonin improves liver function in benzene-treated rats. AB - In this study, we investigated the beneficial effects of melatonin against benzene-induced liver function impairments in Wistar rats. After 30 days of treatment, it significantly lowered hepatosomatic indices, bilirubin, and hydroxyproline in male and female benzene-treated rats. Even though it did not influence aspartate aminotransferase, melatonin had beneficial effects on alanine aminotransferase and alkaline phosphatase. Our results suggest that melatonin is an effective modulator of liver function in benzene-treated rats thanks to its antioxidative properties. PMID- 23819932 TI - CYP2E1 testis expression and alcohol-mediated changes of rat spermatogenesis indices and type I collagen. AB - This study is a complex investigation of alcohol-mediated changes in CYP2E1 mRNA and protein expression in the testes, as well as spermatogenesis indices and type I collagen amino acid contents, in male rats. Wistar albino male rats were divided into two groups: I--control (intact animals), II--experimental (chronic alcoholism, exposure to a 15% ethanol aqueous solution during 150 days). The destructive changes in the spermatogenic epithelium were accompanied by a decrease in sperm number and motility time. CYP2E1 mRNA and protein expression were elevated in the testes 3 and 1.4 times, respectively. Also, significantly lower contents of lysine, glutamic acid, serine, proline, alanine, valine, and phenylalanine residues accompanied by an increase of hydroxyproline, glycine, and threonine residue contents were detected in the skin type I collagen of the experimental group. Chronic ethanol consumption caused testicular failure along with an overexpression of CYP2E1 mRNA and protein in the testes as well as quantitative changes in type I collagen amino acid contents. The profound alcohol mediated changes in collagen type I amino acid contents may have affected the spermatogenic epithelium state. The modulation of testicular cytochrome P450 2E1 mRNA and protein expression could change the functioning of this isozyme in target organs and take part in the mechanism of ethanol gonadotoxicity. PMID- 23819933 TI - Association between glutathione S-transferase omega 1 A140D polymorphism in the Turkish population and susceptibility to non-small cell lung cancer. AB - Recent years have seen a growing evidence of ethnic differences in the frequency of glutathione S-transferase omega 1 (GSTO1) A140D gene polymorphism, which is associated with various cancers such as breast and liver. Until now however, no association has been investigated between the GSTO1 A140D polymorphism and lung cancer. The aim of our study was to see if there was one in the Turkish population. To do that, we identified GSTO1 A140D polymorphism in 214 unrelated healthy individuals and 172 patients with non-small cell lung cancer (NSCLC) using the polymerase chain reaction-restriction fragment length polymorphism (PCR RFLP) method. The frequencies of A/A (wild type), A/D (heterozygous mutant), and D/D (homozygous mutant) GSTO1 A140D genotypes in healthy subjects were 48%, 41%, and 11%, respectively. In NSCLC patients they were 48%, 45%, and 7%, respectively. We found no significant association between the GSTO1 A140D gene polymorphism and NSCLC or its histological subtypes, namely squamous cell carcinoma or adenocarcinoma. Furthermore, this polymorphism did not correlate with smoking. Our study is the first to show that the frequency of GSTO1 A140D gene polymorphism in the Turkish population is similar to other Caucasian populations and that this polymorphism is not associated with susceptibility to NSCLC. PMID- 23819934 TI - Is burnout in family physicians in Croatia related to interpersonal quality of care? AB - The impact of physician burnout on the quality of patient care is unclear. This cross-sectional study aimed to investigate the prevalence of burnout in family physicians in Croatia and its association with physician and practice characteristics, and patient enablement as a consultation outcome measure. Hundred and twenty-five out of 350 family physicians responded to our invitation to participate in the study. They were asked to collect data from 50 consecutive consultations with their adult patients who had to provide information on patient enablement (Patient Enablement Instrument). Physicians themselves provided their demographic and professional data, including workload, job satisfaction, consultation length, and burnout [Maslach Burnout Inventory-Human Services Survey (MBI-HSS)]. MBI-HSS scores were analysed in three dimensions: emotional exhaustion (EE), depersonalisation (DP), and personal accomplishment (PA). Of the responding physicians, 42.4% scored high for EE burnout, 16.0% for DP, and 15.2% for PA. Multiple regression analysis showed that low job satisfaction and more patients per day predicted high EE scores. Low job satisfaction, working more years at a current workplace, and younger age predicted high DP scores. Lack of engagement in education and academic work, shorter consultations, and working more years at current workplace predicted low PA scores, respectively (P<0.05 for each). Burnout is common among family physicians in Croatia yet burnout in our physicians was not associated with patient enablement, suggesting that it did not affect the quality of interpersonal care. Job satisfaction, participation in educational or academic activities and sufficient consultation time seem to reduce the likelihood of burnout. PMID- 23819935 TI - Electrocardiographic manifestations in acute methanol poisoning cannot predict mortality. AB - The aim of this retrospective observational case series was to determine electrocardiographic (ECG) manifestations in patients poisoned with methanol and see whether they could predict mortality. We also wanted to see whether there was an association between ECG changes and time elapsed between ingestion and treatment, age, sex, seizure, coma (Glasgow Coma Scale <=8), arterial blood gas (ABG) parameters, and serum potassium levels on hospital admission. The study included 42 patients aged 31.14+/-12.5 years. Twenty-five survived and 17 died. Almost all patients had one or more abnormal ECG findings, including heart rate, rhythm, and conduction abnormalities. However, we found no significant difference between survivors and non-survivors. QTc interval did not correlate with time elapsed between ingestion and treatment, age, sex, seizure and coma, HCO3(-), or serum potassium level. Similarly, T waves showed no correlation with serum potassium. ECG abnormalities did not correlate with coma or seizure. Even though cardiotoxicity in methanol poisoning is high, none of the ECG abnormalities found in our study predicted mortality. This however does not rule out the need to routinely run ECG for cardiotoxicity in every single patient poisoned by methanol. PMID- 23819936 TI - Fresh frozen plasma as a successful antidotal supplement in acute organophosphate poisoning. AB - Despite improvements to intensive care management and specific pharmacological treatments (atropine, oxime, diazepam), the mortality associated with organophosphate (OP) poisoning has not substantially decreased. The objective of this examination was to describe the role of fresh frozen plasma (FFP) in acute OP poisoning. After a deliberate ingestion of malathion, a 55-year-old male suffering from miosis, somnolence, bradycardia, muscular fasciculations, rales on auscultation, respiratory insufficiency, as well as from an inhibition of red blood cell acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BuChE), was admitted to hospital. Malathion was confirmed in a concentration of 18.01 mg L(-1). Apart from supportive measures (including mechanical ventilation for four days), antidotal treatment with atropine, oxime-pralidoxime methylsulphate (Contrathion(R)), and diazepam was administered, along with FFP. The potentially beneficial effects of FFP therapy included a prompt increase of BuChE activity (from 926 IU L(-1) to 3277 IU L(-1); reference range from 7000 IU L(-1) to 19000 IU L(-1)) and a reduction in the malathion concentration, followed by clinical recovery. Due to BuChE replacement, albumin content, and volume restitution, FFP treatment may be used as an alternative approach in patients with acute OP poisoning, especially when oximes are not available. PMID- 23819937 TI - Antifungal and antipatulin activity of Gluconobacter oxydans isolated from apple surface. AB - Fungicides are the most common agents used in postharvest treatment of fruit and are the most effective against blue mould, primarily caused by Penicillium expansum. Alternatively, blue mould can be treated with antagonistic microorganisms naturally occurring on fruit, such as the bacterium Gluconobacter oxydans. The aim of this study was to establish the antifungal potential of the G. oxydans 1J strain isolated from apple surface against Penicillium expansum in culture and apple juice and to compare it with the efficiency of a reference strain G. oxydans ATCC 621H. The highest antifungal activity of G. oxydans 1J was observed between days 3 and 9 with no colony growth, while on day 12, P. expansum colony diameter was reduced to 42.3% of the control diameter. Although G. oxydans 1J did not fully inhibit mould growth, it showed a high level of efficiency and completely prevented patulin accumulation in apple juice. PMID- 23819938 TI - Attitude towards personal protective equipment in the French nuclear fuel industry. AB - This descriptive cross-sectional study examines the compliance of workers from the European Gaseous Diffusion Uranium Enrichment Consortium (EURODIF) with personal protection equipment (PPE) in view of the various hazards in the nuclear fuel industry. The PPE inventory was drawn up by an industrial hygienist in charge of the PPE at EURODIF. Two hundred and twenty seven (10%) randomly selected, active and retired, EURODIF workers filled in a questionnaire on their attitudes towards PPE. Exposure data from the EURODIF job exposure matrix were used to examine whether PPE usage varies according to exposure level. The study suggests a PPE usage profile that varies depending on the hazards present and PPE available. Anti-uranium PPE and gloves were among the best rated, while anti spray goggles were the least used. We found that, for most hazards known to cause cancer or irreversible health damage, PPE usage varied according to exposure (homogeneity test, p<0.05; trend test, p<0.05). The continuous use of PPE among workers should be encouraged through improvements to the PPE management system. A precise model of individual exposure can only be designed if the use and efficiency of PPE are taken into consideration. PMID- 23819939 TI - [Skin protection at work in Croatian hairdressers (results of the EvaHair questionnaire developed within the EU project "SafeHair")]. AB - Hairdressers are under a high occupational risk of developing various health disorders, particularly regarding the skin. The "SafeHair" project was implemented from 2010 to 2012, with the aim to develop health and safety standards for the prevention of occupational skin diseases in hairdressing. Croatian hairdressers participated in the project. The aim of this work was to establish the actual status of skin protection in Croatian hairdressers. Data were collected by the EvaHair questionnaire developed within the "SafeHair" project. A total of 213 questionnaires were analysed. The sample comprised 133 (64%) salon owners, 46 (22%) employees, and 31 (14%) trainees. Thirty-six (17%) subjects confirmed the presence of skin disorders in their salons in the last 3 years, and almost all of the subjects (98%) considered the prevention of occupational skin diseases important. We found a high proportion (from 40% to 50%) of non-answered questions about risk assessment. Protective gloves were mostly used when exposed to chemicals (88%), but rarely for hair washing (13%). They were available to the majority of subjects (95%), but 32% of subjects had trouble wearing them. Hairdressers with over 30 years of working experience used gloves for washing and cutting hair more frequently than those with less than 30 years of experience (p<0.05). Education on skin protection was more often provided (39%) than education on the protection of the respiratory (15%) and musculosceletal (18%) systems. A high proportion of subjects needed assistance with interpreting laws, regulations, and information about products (57%), as well as in the implementation of risk assessment methods (49%). The results indicate a need for further education on the health risks and the implementation of protective measures. This should be carried out during vocational education and later in the form of permanent education. PMID- 23819940 TI - Human exposure to cyanotoxins and their effects on health. AB - Cyanotoxins are secondary metabolites produced by cyanobacteria. They pose a threat to human health and the environment. This review summarises the existing data on human exposure to cyanotoxins through drinking water, recreational activities (e.g., swimming, canoeing or bathing), the aquatic food web, terrestrial plants, food supplements, and haemodialysis. Furthermore, it discusses the tolerable daily intake and guideline values for cyanotoxins (especially microcystins) as well as the need to implement risk management measures via national and international legislation. PMID- 23819942 TI - [Earthquakes--a historical review, environmental and health effects, and health care measures]. AB - Earthquakes are natural disasters that can occur at any time, regardless of the location. Their frequency is higher in the Circum-Pacific and Mediterranean/Trans Asian seismic belt. A number of sophisticated methods define their magnitude using the Richter scale and intensity using the Mercani-Cancani-Sieberg scale. Recorded data show a number of devastating earthquakes that have killed many people and changed the environment dramatically. Croatia is located in a seismically active area, which has endured a series of historical earthquakes, among which several occurred in the Zagreb area. The consequences of an earthquake depend mostly on the population density and seismic resistance of buildings in the affected area. Environmental consequences often include air, water, and soil pollution. The effects of this kind of pollution can have long term health effects. The most dramatic health consequences result from the demolition of buildings. Therefore, quick and efficient aid depends on well organized health professionals as well as on the readiness of the civil defence, fire department, and Mountain Rescue Service members. Good coordination among these services can save many lives Public health interventions must include effective control measures in the environment as secondary prevention methods for health problems caused by unfavourable environmental factors. The identification and control of long-term hazards can reduce chronic health effects. The reduction of earthquake-induced damages includes setting priorities in building seismically safe buildings. PMID- 23819941 TI - [Exposure to phtalates and their presence in alcoholic beverages]. AB - Phthalates are phthalic acid and aliphatic alcohol esters used as additives to plastic in order to improve its softness, flexibility, and elongation. Phthalates are highly mobile and migrate easily from plastic products into the environment due to their physical and chemical properties. This study briefly describes the characteristics and distribution of phthalates in the environment, their toxic effects on human health, the legislation regarding the maximum allowed concentration of phthalates in drinking water and products intended for infants, as well as the tolerable daily intake. Special attention is given to the methods of determining phthalates and their levels in alcoholic beverages, with an overview of phthalate occurrences and concentrations in plum brandy made in Croatia. A segment on denatured alcohol and illegally marketed alcohol is also included, as well as guidelines for the effective monitoring of the routes of human exposure to phthalates. PMID- 23819943 TI - Highlight: protein states with cell biological and medicinal relevance. PMID- 23819945 TI - Context-based strategies for engaging consumers with public reports about health care providers. AB - Efforts to engage consumers in the use of public reports on health care provider performance have met with limited success. Fostering greater engagement will require new approaches that provide consumers with relevant content at the time and in the context they need to make a decision of consequence. To this end, we identify three key factors influencing consumer engagement and show how they manifest in different ways and combinations for four particular choice contexts that appear to offer realistic opportunities for engagement. We analyze how these engagement factors play out differently in each choice context and suggest specific strategies that sponsors of public reports can use in each context. Cross-cutting lessons for report sponsors and policy makers include new media strategies such as a commitment to adaptive web-based reporting, new metrics with richer emotional content, and the use of navigators or advocates to assist consumers with interpreting reports. PMID- 23819944 TI - The importance of a single primary cilium. AB - The centrosome is the main microtubule-organizing center in animal cells, and helps to influence the morphology of the microtubule cytoskeleton in interphase and mitosis. The centrosome also templates the assembly of the primary cilium, and together they serve as a nexus of cell signaling that provide cells with diverse organization, motility, and sensory functions. The majority of cells in the human body contain a solitary centrosome and cilium, and cells have evolved regulatory mechanisms to precisely control the numbers of these essential organelles. Defects in the structure and function of cilia lead to a variety of complex disease phenotypes termed ciliopathies, while dysregulation of centrosome number has long been proposed to induce genome instability and tumor formation. Here, we review recent findings that link centrosome amplification to changes in cilium number and signaling capacity, and discuss how supernumerary centrosomes may be an important aspect of a set of cilia-related disease phenotypes. PMID- 23819946 TI - Cytometric profiling in various clinical forms of multiple sclerosis with respect to CD21+, CD32+, and CD35+ B and T cells. AB - BACKGROUND: We aimed to evaluate the frequency of various types of B and T cells expressing CD21, CD32, and CD35 in multiple sclerosis (MS) clinical courses. METHODS: Peripheral blood mononuclear cell from 30 MS patients (17 relapsing remitting [RRMS], six secondary progressive [SPMS], and seven primary progressive MS [PPMS]) and 18 healthy subjects were analyzed. All patients were in acute attack. Healthy controls were matched for age and gender ratio. The frequencies of various subsets of B and T cells were determined using flow cytometry. RESULTS: The frequency of CD4+T cells was lower in MS patients compared to control subjects (41.14 +/- 9.45% vs. 46.88 +/- 6.98%, respectively, P < 0.05). The CD32+ fraction of CD4+T cells and the CD21+ fraction of CD8+T cells were higher in MS patients (2.85 +/- 3.72% vs. 1.06 +/- 0.62% for CD32+CD4+T cells, 2.71 +/- 1.86% vs. 1.16 +/- 0.99% for CD21+CD8+T cells in MS patients and control subjects, respectively, P < 0.05). After dividing subjects by type of MS course, higher values of these two T cell subsets were found in SPMS patients compared to control subjects (P < 0.05). Further, RRMS patients had lower levels of CD32+CD4+T cells than SPMS patients and also they had lower levels of CD32+CD8+T cells than PPMS patients (P < 0.05). However, neither the expression of CD35 on T cells nor the various B cell subsets were statistically different between the compared groups. CONCLUSIONS: Our findings demonstrate that T cell subsets expressing CD21 and CD32 may differ with respect to the presence or clinical forms of MS disease. By contrast, CD35+T cells and different subsets of B cells are not altered in various MS clinical courses. PMID- 23819947 TI - Towards the goal of personalized medicine in gastric cancer--time to move beyond HER2 inhibition. Part I: Targeting receptor tyrosine kinase gene amplification. AB - Gastric cancer is the second leading cancer cause of death globally. Apart from the successful targeting of HER2 over-expression in gastric cancer (GC) with trastuzumab, other targeted therapies in GC have fallen short or still in early clinical development. While HER2 over-expression accounts for up to 20% of GC, other potential actionable driver mutations occur a much lower frequency in GC. In this review we describe some of the more interesting genetic aberrations including driver mutations in gastric cancer that have very potent inhibitors against them already in clinical development. Part I of this review will focus on the receptor tyrosine kinase (RTK) gene amplification (HER2, FGFR2, MET, EGFR). Part II will devoted to gene mutations (HER2, KRAS, PIK3CA, BRAF) and gene rearrangement (ROS1, BRAF, HER2). Because of the low frequency of these potential driver mutations, perseverance in screening for these mutations will be needed in order to enroll enough of each uniquely molecularly defined subset of GC in order to demonstrate significant clinical benefit in a unique molecularly targeted therapy trial. This approach has been successfully employed in the clinical approval of crizotinib for the treatment of ALK-rearranged non-small cell lung cancer. PMID- 23819948 TI - Current therapeutic approaches in neovascular age-related macular degeneration. AB - Age-related macular degeneration (AMD) is the leading eye disease to cause visual impairment in the elderly. Neovascular AMD is a type of advanced AMD that is characterized by pathologic proliferation and leakage of abnormal blood vessels in the eye. While the pathogenesis of neovascular AMD is not completely known, one of the important milestones in neovascular AMD research was the identification of vascular endothelial growth factor (VEGF) as a major stimulus of abnormal angiogenesis that can be targeted for intravitreal treatment. Anti VEGF therapies that neutralize or block the induction of angiogenesis by VEGF have recently revolutionized the therapeutic approach to neovascular AMD. The scientific literature regarding the efficacy and safety of anti-VEGF treatment has been hugely enriched with results from various recent randomized clinical trials involving the three most commonly utilized anti-VEGF pharmacologic agents- ranibizumab, bevacizumab, and aflibercept. The potential to stop and reverse the progressive loss of vision due to neovascular AMD is evident. Continued investigation into inhibiting VEGF as well as targeting other crucial factors that contribute to neovascular AMD is an active field of research that is expected to accelerate the progress of neovascular AMD therapy. PMID- 23819950 TI - Nanotechnologies for stimulating and recording excitable events in neurons and cardiomyocytes. AB - Nanotechnologies are engineered materials and devices that have a functional organization in at least one dimension on the nanometer scale, ranging from a few to about 100 nanometers. Functionally, nanotechnologies can display physical, chemical, and engineering properties that go beyond the component building block molecules or structures that make them up. Given such properties and the physical scale involved, these technologies are capable of interacting and interfacing with target cells and tissues in unique ways. One particular emerging application of wide spread interest is the development of nanotechnologies for stimulating and recording excitable cells such as neurons and cardiomyocytes. Such approaches offer the possibility of achieving high density stimulation and recording at sub cellular resolutions in large populations of cells. This would provide a scale of electrophysiological interactions with excitable cells beyond anything achievable by current existing methods. In this review we introduce the reader to the key concepts and methods associated with nanotechnology and nanoengineering, and discuss the work of some of the key groups developing nanoscale stimulation and recording technologies. PMID- 23819951 TI - Novel targeted therapies in peripheral T cell lymphoma. AB - Peripheral T cell lymphomas (PTCL), non-Hodgkin lymphomas characterized by having features of T cells that have matured in the thymus, are a heterogeneous group of clinical entities. Compared with B cell lymphomas, they are less common, more difficult to diagnose and classify, more aggressive, and have inferior outcomes with current treatment paradigms. They are also less completely understood in terms of how different PTCL types correspond to normal T cell development, and in identifying cell signaling pathways as targets for new therapies. Recent studies with novel targeted therapies as single agents or in combination with other drugs have illustrated promising outcomes both for relapsed and frontline PTCL. We first briefly review classification, prognostic indices, and results of initial therapy of various T cell lymphomas. We then review recent studies of chemotherapy, monoclonal antibody-based therapy directed at cell surface targets, small molecule inhibitors of intracellular targets such as histone deacetylases and the proteasome, and agents that disrupt stromal interactions. Investigations that enhance our knowledge of T cell molecular biology and integrate novel targeted agents into the treatment algorithm for PTCL will be keys to improved outcomes for patients with PTCL. PMID- 23819949 TI - Marching towards regenerative cardiac therapy with human pluripotent stem cells. AB - Damage in cardiac tissues from ischemia or other pathological conditions leads to heart failure; and cell loss or dysfunction in pacemaker tissues due to congenital heart defects, aging, and acquired diseases can cause severe arrhythmias. The promise of successful therapies with stem cells to treat these conditions has remained elusive to the scientific community. However, recent advances in this field have opened new opportunities for regenerative cardiac therapy. Transplantation of cardiomyocytes derived from human pluripotent stem cells has the potential to alleviate heart disease. Since the initial derivation of human embryonic stem cells, significant progress has been made in the generation and characterization of enriched cardiomyocytes and the demonstration of the ability of these cardiomyocytes to survive, integrate, and function in animal models. The scope of therapeutic potential from pluripotent stem cell derived cardiomyocytes has been further expanded with the invention of induced pluripotent stem cells, which can be induced to generate functional cardiomyocytes for regenerative cardiac therapy in a patient specific manner. The reprogramming technology has also inspired the recent discovery of direct conversion of fibroblasts into cardiomyocyte-like cells, which may allow endogenous cardiac repair. Regenerative cardiac therapy with human pluripotent stem cells is now moving closer to clinic testing. PMID- 23819952 TI - Humoral immunity to AAV vectors in gene therapy: challenges and potential solutions. AB - Gene transfer trials with adeno-associated virus (AAV) vectors have initiated to unveil the therapeutic potential of this approach, with some of the most exciting results coming from clinical studies of gene transfer for hemophilia B, congenital blindness, and the recent market approval of the first AAV-based gene therapy in Europe. With clinical development, however, some of the limitations of in vivo gene transfer have emerged; in particular the host immune system represents an important obstacle to be overcome in terms of both safety and efficacy of gene transfer in vivo with AAV vectors. Results in humans undergoing gene transfer indicate that capsid-specific T cell responses directed against transduced cells may limit the duration of transgene expression following AAV gene transfer, and similarly anti-AAV neutralizing antibodies can completely prevent transduction of a target tissue, resulting in lack of efficacy. Anti-AAV neutralizing antibodies are highly prevalent in humans, and the frequency of subjects with detectable titers can reach up to two thirds of the population. The approach to the problem of preexisting humoral immunity to AAV so far has been the exclusion of seropositive subjects, but this solution is far from being optimal. Several additional strategies have been proposed and tested in a variety of preclinical animal models. Future studies will help defining the optimal strategy, or combination of strategies, to successfully treat subjects with preexisting antibodies to AAV due to natural infection or to prior administration of AAV vectors. These advancements will likely have a significant impact on the field of gene transfer with AAV vectors. PMID- 23819953 TI - Macular hard exudates and scar formation after laser photocoagulation in retinopathy of prematurity. AB - The authors report the formation of hard exudates and macular scarring after laser photocoagulation therapy in patients with retinopathy of prematurity (ROP). Two premature neonates, the first born at 24 weeks and the second at 25 weeks gestational age, were diagnosed as having ROP that necessitated laser photocoagulation treatment at 32 and 36 weeks, respectively. Subretinal fluid and macular hard exudation developed in both patients that eventually caused bilateral macular scarring. Subretinal macular fluid with hard exudation could lead to macular scar formation in neonates with ROP after laser photocoagulation that could significantly affect the visual prognosis in preterm infants. PMID- 23819954 TI - Five year follow-up of two sisters with type II sialidosis: systemic and ophthalmic findings including OCT analysis. AB - The authors report a 5-year follow-up examination of two sisters diagnosed as having a juvenile form of type II sialidosis. Diagnosis occurred during a routine ophthalmic examination when the girls were 5 and 3 years old after bilateral macular cherry-red spots were revealed. Main clinical findings were hypotonia, hepatosplenomegaly, hearing loss, dysostosis, and respiratory distress. Ophthalmic symptoms were low visual acuity and nystagmus. Spectral-domain optical coherence tomography examination showed increased reflectivity of the retinal ganglion cells. Sialidosis may present as a mild form with slow progression. The cherry-red spots may be the first clue for proper diagnosis of storage disease. Spectral-domain optical coherence tomography examination unveiled the accumulation of sialic acid in the retinal ganglion cells and could potentially be used to monitor the progression of storage diseases. PMID- 23819955 TI - A multicenter, randomized trial of a nurse-led, home-based intervention for optimal secondary cardiac prevention suggests some benefits for men but not for women: the Young at Heart study. AB - BACKGROUND: We examined the impact of a prolonged secondary prevention program on recurrent hospitalization in cardiac patients with private health insurance. METHODS AND RESULTS: The Young at Heart multicenter, randomized, controlled trial compared usual postdischarge care (UC) with nurse-led, home-based intervention (HBI). The primary end point was rate of all-cause hospital stay (31.5+/-7.5 months follow-up). In total, 602 patients (aged 70+/-10 years, 72% men) were randomized to UC (n=296) or HBI (n=306, 96% received >=1 home visit). Overall, 42 patients (7.0%) died, and 492 patients (82%) accumulated 2397 all-cause hospitalizations associated with 10,258 hospital days costing >$17 million. There were minimal group differences (HBI versus UC) in the primary end point of all cause hospital stay (5405 versus 4853 days; median [interquartile range], 0.08 [0.03-0.17] versus 0.07 [0.03-0.13]/patient per month). There were similar trends with respect to all hospitalizations (1197 versus 1200; P=0.802) and associated costs ($8.66 versus $8.58 million; P=0.375). At 2 years, however, more HBI versus UC (39% versus 27%; odds ratio, 1.67; 95% confidence interval, 1.15-2.41; P=0.007) patients were assessed as stable and optimally managed. For women, HBI outcomes were predominantly worse than UC outcomes. In men, HBI was associated with reduced risk of cardiovascular hospitalization (adjusted hazard ratio, 0.68; 95% confidence interval, 0.46-0.99; P=0.044) with less cardiovascular hospitalizations (192 versus 269; P=0.054) and costs ($2.49 versus $3.53 million; P=0.046). CONCLUSIONS: HBI did not reduce recurrent all-cause hospitalization compared with UC in privately insured cardiac patients overall. However, it did convey some benefits in cardiac outcomes for men. CLINICAL TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry Unique Identifier: 12608000014358. URL: http://www.anzctr.org.au/trial_view.aspx?id=82509. PMID- 23819956 TI - ICD9 codes cannot reliably identify hemorrhagic transformation of ischemic stroke. PMID- 23819957 TI - A prediction model to identify patients at high risk for 30-day readmission after percutaneous coronary intervention. AB - BACKGROUND: The Affordable Care Act creates financial incentives for hospitals to minimize readmissions shortly after discharge for several conditions, with percutaneous coronary intervention (PCI) to be a target in 2015. We aimed to develop and validate prediction models to assist clinicians and hospitals in identifying patients at highest risk for 30-day readmission after PCI. METHODS AND RESULTS: We identified all readmissions within 30 days of discharge after PCI in nonfederal hospitals in Massachusetts between October 1, 2005, and September 30, 2008. Within a two-thirds random sample (Developmental cohort), we developed 2 parsimonious multivariable models to predict all-cause 30-day readmission, the first incorporating only variables known before cardiac catheterization (pre-PCI model), and the second incorporating variables known at discharge (Discharge model). Models were validated within the remaining one-third sample (Validation cohort), and model discrimination and calibration were assessed. Of 36,060 PCI patients surviving to discharge, 3760 (10.4%) patients were readmitted within 30 days. Significant pre-PCI predictors of readmission included age, female sex, Medicare or State insurance, congestive heart failure, and chronic kidney disease. Post-PCI predictors of readmission included lack of beta-blocker prescription at discharge, post-PCI vascular or bleeding complications, and extended length of stay. Discrimination of the pre-PCI model (C-statistic=0.68) was modestly improved by the addition of post-PCI variables in the Discharge model (C-statistic=0.69; integrated discrimination improvement, 0.009; P<0.001). CONCLUSIONS: These prediction models can be used to identify patients at high risk for readmission after PCI and to target high-risk patients for interventions to prevent readmission. PMID- 23819958 TI - Characteristics of electrode impedance and stimulation efficacy of a chronic cortical implant using novel annulus electrodes in rat motor cortex. AB - OBJECTIVE: Cortical neural prostheses with implanted electrode arrays have been used to restore compromised brain functions but concerns remain regarding their long-term stability and functional performance. APPROACH: Here we report changes in electrode impedance and stimulation thresholds for a custom-designed electrode array implanted in rat motor cortex for up to three months. MAIN RESULTS: The array comprises four 2000 um long electrodes with a large annular stimulating surface (7860-15700 um(2)) displaced from the penetrating insulated tip. Compared to pre-implantation in vitro values there were three phases of impedance change: (1) an immediate large increase of impedance by an average of two-fold on implantation; (2) a period of continued impedance increase, albeit with considerable variability, which reached a peak at approximately four weeks post implantation and remained high over the next two weeks; (3) finally, a period of 5-6 weeks when impedance stabilized at levels close to those seen immediately post-implantation. Impedance could often be temporarily decreased by applying brief trains of current stimulation, used to evoke motor output. The stimulation threshold to induce observable motor behaviour was generally between 75-100 uA, with charge density varying from 48-128 uC cm(-2), consistent with the lower current density generated by electrodes with larger stimulating surface area. No systematic change in thresholds occurred over time, suggesting that device functionality was not compromised by the factors that caused changes in electrode impedance. SIGNIFICANCE: The present results provide support for the use of annulus electrodes in future applications in cortical neural prostheses. PMID- 23819959 TI - Long-term doctor-patient relationships: patient perspective from online reviews. AB - BACKGROUND: Continuity of patient care is one of the cornerstones of primary care. OBJECTIVE: To examine publicly available, Internet-based reviews of adult primary care physicians, specifically written by patients who report long-term relationships with their physicians. METHODS: This substudy was nested within a larger qualitative content analysis of online physician ratings. We focused on reviews reflecting an established patient-physician relationship, that is, those seeing their physicians for at least 1 year. RESULTS: Of the 712 Internet reviews of primary care physicians, 93 reviews (13.1%) were from patients that self identified as having a long-term relationship with their physician, 11 reviews (1.5%) commented on a first-time visit to a physician, and the remainder of reviews (85.4%) did not specify the amount of time with their physician. Analysis revealed six overarching domains: (1) personality traits or descriptors of the physician, (2) technical competence, (3) communication, (4) access to physician, (5) office staff/environment, and (6) coordination of care. CONCLUSIONS: Our analysis shows that patients who have been with their physician for at least 1 year write positive reviews on public websites and focus on physician attributes. PMID- 23819960 TI - Correlation of serum homocysteine and previous history of gestational diabetes mellitus. AB - BACKGROUND: Gestational diabetes mellitus (GDM) is a common pregnancy condition. In this study, the risk of having a history of previous GDM (pGDM) on serum homocysteine level was assessed. METHODS: Biomedical parameters, serum homocysteine, Insulin, homeostatic model assessment (HOMA) in women with (n = 52) and without pGDM (n = 51) were assessed. According to their current status of Oral Glucose Tolerance Test (GTT), the participants in each group were divided into two subgroups of normal or impaired GTT. RESULTS: Mean serum homocysteine in normal women was 8.56 +/- 3.19 vs 11.44 +/- 7.34 MUmol/L (p < 0.01) in women with pGDM. Two groups had significant differences in respect to serum insulin levels (8.35 +/- 5.12 vs 12.48 +/- 5.44, p < 0.002), and HOMA-IR (1.90 +/- 1.30 vs 2.91 +/- 1.30, p < 0.002). In women without pGDM, serum homocysteine in normal and impaired GTT were 7.60 +/- 1.69 and 10.52 +/- 3.65 MUmol/L (p = 0.03), respectively, while in women with pGDM, the figures were 8.38 +/- 2.52 and 14.00 +/- 10.17 (p < 0.01), respectively. In multi regression analysis an association between history of GDM and homocysteine levels was presented (OR: 7.71, 95% CI: 1.67-35.42, p < 0.001). CONCLUSION: A trend of elevation of homocysteine is presented in women with pGDM, that is more prominent in women with impaired GTT, and shows a significant correlation with history of GDM. Further studies with larger sample size are suggested. PMID- 23819961 TI - Bibliography--editors' selection of current world literature. PMID- 23819962 TI - A genetic model with specifically impaired autophagosome-lysosome fusion. AB - Yeast studies identified the evolutionarily conserved core ATG genes responsible for autophagosome formation. However, the SNARE-dependent machinery involved in autophagosome fusion with the vacuole in yeast is not conserved. We recently reported that the SNARE complex consisting of Syx17 (Syntaxin 17), ubisnap (SNAP 29) and Vamp7 is required for the fusion of autophagosomes with late endosomes and lysosomes in Drosophila. Syx17 mutant flies are viable but exhibit neuronal dysfunction, locomotion defects and premature death. These data point to the critical role of autophagosome clearance in organismal homeodynamics. PMID- 23819963 TI - Patients' attitudes about the use of placebo treatments: telephone survey. AB - OBJECTIVE: To examine the attitudes of US patients about the use of placebo treatments in medical care. DESIGN: One time telephone surveys. SETTING: Northern California. PARTICIPANTS: 853 members of Kaiser Permanente Northern California, aged 18-75, who had been seen by a primary care provider for a chronic health problem at least once in the prior six months. RESULTS: The response rate was 53.4% (853/1598) of all members who were eligible to participate, and 73.2% (853/1165) of all who could be reached by telephone. Most respondents (50-84%) judged it acceptable for doctors to recommend placebo treatments under conditions that varied according to doctors' level of certainty about the benefits and safety of the treatment, the purpose of the treatment, and the transparency with which the treatment was described to patients. Only 21.9% of respondents judged that it was never acceptable for doctors to recommend placebo treatments. Respondents valued honesty by physicians regarding the use of placebos and believed that non-transparent use could undermine the relationship between patients and physicians. CONCLUSIONS: Most patients in this survey seemed favorable to the idea of placebo treatments and valued honesty and transparency in this context, suggesting that physicians should consider engaging with patients to discuss their values and attitudes about the appropriateness of using treatments aimed at promoting placebo responses in the context of clinical decision making. PMID- 23819965 TI - International health is a misnomer. PMID- 23819964 TI - Care in specialist medical and mental health unit compared with standard care for older people with cognitive impairment admitted to general hospital: randomised controlled trial (NIHR TEAM trial). AB - OBJECTIVE: To develop and evaluate a best practice model of general hospital acute medical care for older people with cognitive impairment. DESIGN: Randomised controlled trial, adapted to take account of constraints imposed by a busy acute medical admission system. SETTING: Large acute general hospital in the United Kingdom. PARTICIPANTS: 600 patients aged over 65 admitted for acute medical care, identified as "confused" on admission. INTERVENTIONS: Participants were randomised to a specialist medical and mental health unit, designed to deliver best practice care for people with delirium or dementia, or to standard care (acute geriatric or general medical wards). Features of the specialist unit included joint staffing by medical and mental health professionals; enhanced staff training in delirium, dementia, and person centred dementia care; provision of organised purposeful activity; environmental modification to meet the needs of those with cognitive impairment; delirium prevention; and a proactive and inclusive approach to family carers. MAIN OUTCOME MEASURES: PRIMARY OUTCOME: number of days spent at home over the 90 days after randomisation. SECONDARY OUTCOMES: structured non-participant observations to ascertain patients' experiences; satisfaction of family carers with hospital care. When possible, outcome assessment was blind to allocation. RESULTS: There was no significant difference in days spent at home between the specialist unit and standard care groups (median 51 v 45 days, 95% confidence interval for difference -12 to 24; P=0.3). Median index hospital stay was 11 versus 11 days, mortality 22% versus 25% (-9% to 4%), readmission 32% versus 35% (-10% to 5%), and new admission to care home 20% versus 28% (-16% to 0) for the specialist unit and standard care groups, respectively. Patients returning home spent a median of 70.5 versus 71.0 days at home (-6.0 to 6.5). Patients on the specialist unit spent significantly more time with positive mood or engagement (79% v 68%, 2% to 20%; P=0.03) and experienced more staff interactions that met emotional and psychological needs (median 4 v 1 per observation; P<0.001). More family carers were satisfied with care (overall 91% v 83%, 2% to 15%; P=0.004), and severe dissatisfaction was reduced (5% v 10%, -10% to 0%; P=0.05). CONCLUSIONS: Specialist care for people with delirium and dementia improved the experience of patients and satisfaction of carers, but there were no convincing benefits in health status or service use. Patients' experience and carers' satisfaction might be more appropriate measures of success for frail older people approaching the end of life. TRIAL REGISTRATION: Clinical Trials NCT01136148. PMID- 23819966 TI - YODA and truth seeking in medicine. PMID- 23819967 TI - Large rise in consultants' pay has not improved productivity, say MPs. PMID- 23819968 TI - Diclofenac shouldn't be prescribed to people with heart problems, drug agency says. PMID- 23819969 TI - Dealing with cough-related laryngeal sensations for a substantial reduction in chronic cough. PMID- 23819970 TI - Comparison of select polarizable and non-polarizable water models in predicting solvation dynamics of water confined between MgO slabs. AB - We present a molecular dynamics simulation study in which we compare and contrast the performance of a polarizable shell water potential model and non-polarizable water force field-extended simple point charge (SPC/EF) model in predicting the solvation dynamics of confined water molecules sandwiched between MgO(100) slabs. Structural features based on radial distribution functions, atomic density profiles, adsorption patterns, orientational ordering and dynamical correlations such as diffusional characteristics, hydrogen bonding lifetimes and residence probabilities are used as metrics for comparison. The simulations yield significant ordering of water molecules in the two layers adjacent to the oxide interface and the extent of ordering decreases with increasing distance from the oxide-water interface. These results elucidate that the dependence of local ordering and solvation dynamics on the molecular geometry and charge distribution, observed for typical three- and four-site water models, is generally lost for confined water if polarization is explicitly included. While the interfacial water structure predicted by the polarizable and non-polarizable models are similar, the confinement and interface proximity effects on the solvation dynamics are seen to be more pronounced for polarizable water models in comparison to non-polarizable ones. The study also shows that the polarizable water model over predicts the orientational order and under predicts the transport properties of confined water. In addition, analysis of the orientational preferences and hydrogen bonding characteristics of water near oxide interfaces suggests a higher degree of tetrahedral disorder in the polarizable shell compared to the non-polarizable SPC/E flexible model. The origin of the differences in solvation behavior of confined water between oxide slabs is analyzed based on the energetic contributions of the dispersive and electrostatic terms in the two force fields. Our findings suggest some new considerations regarding the role of polarization terms in predicting confinement and interface proximity effects that may guide future development of reliable polarizable water models for confined liquids. PMID- 23819971 TI - Sagittal spinal profile and spinopelvic balance in parents of scoliotic children. AB - BACKGROUND CONTEXT: It is well known that spinal biomechanics and familial predisposition play an important role in the onset and evolution of idiopathic scoliosis. The relationship between the sagittal profile of the spine and spinal biomechanics has also been established in a number of studies. It has been suggested previously that a certain sagittal spinal configuration with implications for spinal rotational stiffness is inherited, thus providing a possible explanation for the well-known hereditary component in adolescent idiopathic scoliosis (AIS). PURPOSE: To test the hypothesis that the familial trend in AIS may be partially explained by the inheritance of a sagittal spinal profile, which has been shown to make the spine less resistant to rotatory decompensation. STUDY DESIGN: A prospective case controlled radiographic analysis of the sagittal profile of the spine and spinopelvic alignment. PATIENT SAMPLE: One hundred two parents of scoliotic children, compared with 102 age-matched controls (parents of nonscoliotic children). OUTCOME MEASURES: Physiologic measures: sagittal profile of the spine and spinopelvic alignment. METHODS: Freestanding lateral radiographs of 51 parent couples of girls with severe (Cobb angle >30 degrees ) progressive AIS (AIS group) and 102 age-matched controls (control group) were taken. Parents with manifest spinal deformities or spinal pathology of any kind were excluded based on history or spinal X-ray to avoid distorted sagittal images with unreliable measurements. Values were calculated for thoracic kyphosis (T4-T12), lumbar lordosis (L1-L5), spinal balance (sagittal plumb line of C7 and T4, T1-L5 sagittal spinal inclination, T9 sagittal offset), curvature parameters (expressed in the area under the curve [AUC]), and pelvic parameters (pelvic tilt, pelvic incidence, and sacral slope). In addition, the height, offset, and length of the posteriorly inclined spinal segment, inclination of each vertebra, and normalized sagittal spinal profile were calculated. Differences in spinopelvic alignment between fathers and mothers of both groups were analyzed. RESULTS: In the fathers of the AIS group, the plumb line of T4 was significantly less posteriorly positioned relative to the hip axis (79 mm vs. 92 mm; p=.009); the overall AUC and the lumbar AUC were significantly smaller (p=.002 and p=.008, respectively) as compared with the fathers in the control group. Vertebrae T11-L2 were significantly less backwardly inclined in the fathers of the AIS group (T11, L2: p<.05 and T12-L1: p<.01). An analysis of sagittal spinal profile showed a significantly flatter spine in the fathers of the AIS group (p=.01). No significant differences were observed in height, offset, and length of the backwardly inclined spinal segment. In the mothers of the AIS group, no statistically significant differences were observed in the spinopelvic parameters, spinal curvature, inclination of the vertebrae, and declive spinal segment parameters or sagittal spinal profile as compared with the mothers in the control group. CONCLUSIONS: The sagittal spinal profile of the fathers of scoliotic children was significantly flatter than the sagittal spinal profile of fathers of nonscoliotic children. No difference was found in the sagittal spinal profile of the mothers of scoliotic children as compared with mothers of nonscoliotic children. Although it is well known that scoliotic mothers have an increased risk of having a scoliotic offspring, this study indicates that fathers may possibly contribute as well through their sagittal spinal profile to the inheritance of idiopathic scoliosis. PMID- 23819972 TI - Modeling of breakthrough curves of single and quaternary mixtures of ethanol, glucose, glycerol and acetic acid adsorption onto a microporous hyper-cross linked resin. AB - The adsorption of quaternary mixtures of ethanol/glycerol/glucose/acetic acid onto a microporous hyper-cross-linked resin HD-01 was studied in fixed beds. A mass transport model based on film solid linear driving force and the competitive Langmuir isotherm equation for the equilibrium relationship was used to develop theoretical fixed bed breakthrough curves. It was observed that the outlet concentration of glucose and glycerol exceeded the inlet concentration (c/c0>1), which is an evidence of competitive adsorption. This phenomenon can be explained by the displacement of glucose and glycerol by ethanol molecules, owing to more intensive interactions with the resin surface. The model proposed was validated using experimental data and can be capable of foresee reasonably the breakthrough curve of specific component under different operating conditions. The results show that HD-01 is a promising adsorbent for recovery of ethanol from the fermentation broth due to its large capacity, high selectivity, and rapid adsorption rate. PMID- 23819973 TI - Degradation mechanism of monosaccharides and xylan under pyrolytic conditions with theoretic modeling on the energy profiles. AB - Xylan and three monosaccharides (mannose, galactose, and arabinose) were selected as model compounds to investigate the mechanism of hemicellulose pyrolysis. The evolution of several typical pyrolysis products were observed by thermogravimetric analysis coupled to Fourier transform infrared spectroscopy. Monosaccharides underwent similar pyrolysis routes involving ring opening and secondary decomposition. Breakage of the O-acetyl groups and 4-O-methylglucuronic acid units in xylan branches resulted in its different pyrolysis behavior for the formation of acetic acid, CO2, and CO. The detailed reaction pathways of the monosaccharides were studied using density functional theory calculations. Furfural formation was more favorable than the formation of 1-hydroxy-2-propanone and 4-hydroxydihydrofuran-2(3H)-one during xylose degradation. However, in the pyrolysis of mannose and galactose, formation of 5-hydroxymethyl-2-furaldehyde was preferred because of the high energy barrier of the dissociation of the hydroxymethyl group. Meanwhile, the breakage of O-acetyl groups leading to acetic acid formation easily occurred because of its lower energy barrier. PMID- 23819974 TI - Direct conversion of chitin biomass to 5-hydroxymethylfurfural in concentrated ZnCl2 aqueous solution. AB - The direct conversion of chitin biomass to 5-hydroxymethylfurfural (5-HMF) in ZnCl2 aqueous solution was studied systemically. D-Glucosamine (GlcNH2) was chosen as the model compound to investigate the reaction, and 5-HMF could be obtained in 21.9% yield with 99% conversion of GlcNH2. Optimization of the reaction parameters including the screening of 8 co-catalysts was carried out. Among them, AlCl3 and B(OH)3 improved 5-HMF yield, whereas CdCl2, CuCl2 and NH4Cl had no effect. CrCl3, SnCl4 and SnCl2 showed negative effects, i.e. lower yields. Consequently, the optimal reaction conditions were found to be 67 wt.% ZnCl2 aqueous solution, at 120 degrees C without co-catalyst. The reactions were further studied by in situ NMR, and no intermediate or other byproducts, except humins, were observed. Finally, the substrate scope was expanded from GlcNH2 to N acetyl-D-glucosamine and various chitosan polymers with different molecular weights, 5-HMF yield from polymers were generally lower than that from GlcNH2. PMID- 23819975 TI - Enhancement of enzymatic saccharification of sugarcane bagasse by liquid hot water pretreatment. AB - Lignocellulosic biomass can be utilized to produce promising biofuels. In this study, liquid hot water pretreatments were performed to break the intricate structure of sugarcane bagasse, which resists the enzyme accessibility to cellulose. The effects of temperatures and times on the hemicellulose degradation (including the yields of pentoses and hexoses, the proportion of monomers and oligosaccharides, as well as limited inhibitors) and cellulose enzymatic digestibility were evaluated. The results indicated that the maximum xylose yields (combined 3.85 g xylose and 13.21 g xylo-oligosaccharides per 100 g raw material) in prehydrolyzate liquid were obtained at 180 degrees C and 30 min. Due to the effective removal of hemicellulose, the maximum glucose yield in enzyme hydrolyzate reached 37.27 g per 100 g raw material, representing 90.13% of glucose in the sugarcane bagasse. The maximal total sugars yield (combined prehydrolyzate and enzymatic hydrolyzate) were 53.65 g based on 100 g raw material. PMID- 23819976 TI - Enhanced butanol production by coculture of Clostridium beijerinckii and Clostridium tyrobutyricum. AB - Cocultures of Clostridium beijerinckii and Clostridium tyrobutyricum in free-cell and immobilized-cell fermentation modes were investigated as a means of enhancing butanol production. The immobilized fermentation was performed in a fibrous-bed bioreactor (FBB). The results demonstrated that two-strain coculture significantly enhanced butanol production, yield and volumetric productivity compared with those in pure culture with or without butyric acid. Further, continuous immobilized-cell cocultures in two FBBs using glucose, cassava starch, or cane molasses were conducted at a dilution rate of 0.144 h(-1). The butanol production (6.66 g/L), yield (0.18 g/g), and productivity (0.96 g/L/h) were obtained with cassava starch as the substrate. Meanwhile, the acetone-butanol ethanol (ABE) yield (0.36 g/g) was the highest among all processes investigated, suggesting that this continuous coculture mode may be suitable for industrial ABE production with no need for repeated sterilization and inoculation. PMID- 23819977 TI - Repetitive succinic acid production from lignocellulose hydrolysates by enhancement of ATP supply in metabolically engineered Escherichia coli. AB - In this study, repetitive production of succinic acid from lignocellulose hydrolysates by enhancement of ATP supply in metabolically engineered E. coli is reported. Escherichia coli BA305, a pflB, ldhA, ppc, and ptsG deletion strain overexpressing ATP-forming phosphoenolpyruvate (PEP) carboxykinase (PEPCK), produced a final succinic acid concentration of 83 g L(-1) with a high yield of 0.87 g g(-1) total sugar in 36 h of three repetitive fermentations of sugarcane bagasse hydrolysate. Furthermore, simultaneous consumption of glucose and xylose was achieved, and the specific productivity and yield of succinic acid were almost maintained constant during the repetitive fermentations. PMID- 23819978 TI - Characteristics of free endoglucanase and glycosidases multienzyme complex from Fusarium verticillioides. AB - A novel multienzyme complex, E1C, and a free endoglucanase, E2 (GH5), from Fusarium verticillioides were purified. The E1C contained two endoglucanases (GH6 and GH10), one cellobiohydrolase (GH7) and one xylanase (GH10). Maximum activity was observed at 80 degrees C for both enzymes and they were thermostable at 50 and 60 degrees C. The activation energies for E1C and E2 were 21.3 and 27.5 kJ/mol, respectively. The KM for E1C was 10.25 g/L while for E2 was 6.58 g/L. Both E1C and E2 were activated by Mn(2+) and CoCl2 while they were inhibited by SDS, CuSO4, FeCl3, AgNO4, ZnSO4 and HgCl2. E1C and E2 presented endo-beta-1,3-1,4 glucanase activity. E1C presented crescent activity towards cellopentaose, cellotetraose and cellotriose. E2 hydrolyzed the substrates cellopentaose, cellotetraose and cellotriose with the same efficiency. E1C showed a higher stability and a better hydrolysis performance than E2, suggesting advantages resulting from the physical interaction between proteins. PMID- 23819979 TI - Capability of Thai Mission grass (Pennisetum polystachyon) as a new weedy lignocellulosic feedstock for production of monomeric sugar. AB - Mission grass (Pennisetum polystachyon) grown in Pakchong District, Nakornratchasima Province, Thailand, with high cellulose and hemicellulose contents were harvested to determine the fermentable monomeric sugars for bioethanol production by two-stage microwave/chemical pretreatment process. Microwave-assisted NaOH pretreatment effectively removed approximately 85% lignin content in Mission grass, using 3% (w/v) NaOH, 15:1 liquid-to-solid ratio (LSR) at 120 degrees C temperatures for 10 min. As a result, in the second stage, microwave-assisted H2SO4 pretreatment of an alkaline-pretreated Mission grass solid releasedan impressively high fermentable sugar content (34.3+/-1.3 g per 100 g of dried biomass), consisting mainly of 31.1+/-0.8 g of glucose per 100 g of dried biomass, using 1% (w/v) H2SO4, 15:1 LSR at 200 degrees C temperature for a very short pretreatment time (5 min). The total monomeric sugar yield obtained via two-stage microwave/chemical process was 40.9 g per 100 g of dried biomass. PMID- 23819980 TI - Evaluation of system performances and microbial communities of two temperature phased anaerobic digestion systems treating dairy manure. AB - Two temperature-phased anaerobic digestion (TPAD) systems, with the thermophilic digesters acidified by acidogenesis products (AT-TPAD) or operated at neutral pH and balanced hydrolysis/acidogenesis and methanogenesis (NT-TPAD), were evaluated to treat high-strength dairy cattle manure. Despite similar methane productions (about 0.22 L/g VS fed), the NT-TPAD system removed significantly more VS (36%) than the AT-TPAD system (31%) and needed no pH adjustments. The thermophilic digester of the NT-TPAD system dominated the system performance and performed significantly better than that of the AT-TPAD system. The opposite held true for the mesophilic digesters. Differences of the thermophilic digesters between two TPAD systems affected the microbial communities of both local and downstream digesters. Each digester harbored distinctive microbial populations, some of which were significantly correlated with system performance. Methanosarcina was the most important methanogenic genus in both TPAD systems, while Methanosaeta only in the NT-TPAD system. Their populations were inversely related to VFA concentrations. PMID- 23819981 TI - The inhibition of cocaine-induced locomotor activity by CART 55-102 is lost after repeated cocaine administration. AB - CART peptide is known for having an inhibitory effect on cocaine- and dopamine mediated actions after acute administration of cocaine and dopamine. In this regard, it is postulated to be a homeostatic, regulatory factor on dopaminergic activity in the nucleus accumbens (NAc). However, there is no data on the effect of CART peptide after chronic administration of cocaine, and this study addresses this. It was found that CART peptide blunted cocaine-induced locomotion (LMA) after acute administration of cocaine, as expected, but it did not affect cocaine mediated LMA after chronic administration of cocaine. The loss of CART peptide's inhibitory effect did not return for up to 9 weeks after stopping the repeated cocaine administration. It may not be surprising that homeostatic regulatory mechanisms in the NAc are lost after repeated cocaine administration, and that this may be a mechanism in the development of addiction. PMID- 23819982 TI - The roles of MMP-9/TIMP-1 in cerebral edema following experimental acute cerebral infarction in rats. AB - Matrix metalloproteinases 9 (MMP-9) and its endogenous inhibitor, tissue inhibitor of metalloproteinases 1 (TIMP-1), regulate homeostasis and turnover of the extra cellular matrix (ECM). They play important roles in acute cerebral infarction (ACI). The contributions of MMP-9 and TIMP-1 to the early stages of ACI are not completely understood. This study investigates the time course of MMP 9 and TIMP-1 and their relations to edema after ACI in rats. Serum concentrations of MMP-9 and TIMP-1 protein were measured using ELISA and mRNA level were measured using real-time PCR. Brain samples were harvested and the brain water content (BWC) was measured. Results revealed that MMP-9 concentration increased fast during the first 12 h after ACI, while after 12 h the increase was much slower. The MMP-9 protein concentration was elevated earlier than the mRNA level. BWC increased starting at 6 h after ACI to reach a peak at 12 h and decreased back to normal levels at 72 h. Both the MMP-9 protein and its mRNA were positively correlated with BWC, however no correlation was found between TIMP-1 levels and BWC. The MMP-9/TIMP-1 protein ratio was more closely correlated with BWC than the MMP-9 concentration. These results indicate that brain edema induced by ACI is associated with increased MMP-9 levels and MMP-9/TIMP-1 ratio in serum. PMID- 23819983 TI - Males and females are just different: sexually dimorphic responses to chronic ethanol exposure in hippocampal slice cultures. PMID- 23819984 TI - Management of undescended testis: a decision analysis. AB - BACKGROUND: Undescended testis (UDT) or cryptorchidism is the most common genital anomaly seen in boys and can be treated surgically by orchidopexy. The age at which orchidopexy should be performed is controversial for both congenital and acquired UDT. METHODS: A decision analysis is performed in which all available knowledge is combined to assess the outcomes of orchidopexy at different ages. RESULTS: Without surgery, unilateral congenital UDT and bilateral congenital UDT are associated with average losses in quality-adjusted life-years (QALYs) of 1.53 QALYs (3% discounting 0.66 QALYs) and 5.23 QALYs (1.91 QALYs), respectively. Surgery reduces this QALY loss to on average 0.84 QALYs (0.21 QALYs) for unilateral UDT and 1.66 QALYs (0.40 QALYs) for bilateral UDT. Surgery at detection will lead to the lowest QALY loss of 0.91 (0.34) and 1.73 (0.60) QALYs, respectively, for unilateral and bilateral acquired UDT compared with surgery during puberty and no surgery. No sensitivity analysis is able to change the preferences for these strategies. CONCLUSIONS: Based on our decision analytic model using societal valuations of health outcomes, surgery for unilateral UDT (both congenital and acquired) yielded the lowest loss in QALYs. Given the modest differences in outcomes, there is room for patient (or parent) preference with respect to the performance and timing of surgery in case of unilateral UDT. For bilateral UDT (both congenital and acquired), orchidopexy at any age provides considerable benefit, in particular through improved fertility. As there is no strong effect of timing, the age at which orchidopexy is performed should be discussed with the parents and the patient. More clinical evidence on issues related to timing may in the future modify these results and hence this advice. PMID- 23819985 TI - Recent advances in the epidermal growth factor receptor/ligand system biology on skin homeostasis and keratinocyte stem cell regulation. AB - The epidermal growth factor (EGF) receptor/ligand system stimulates multiple pathways of signal transduction, and is activated by various extracellular stimuli and inter-receptor crosstalk signaling. Aberrant activation of EGF receptor (EGFR) signaling is found in many tumor cells, and humanized neutralizing antibodies and synthetic small compounds against EGFR are in clinical use today. However, these drugs are known to cause a variety of skin toxicities such as inflammatory rash, skin dryness, and hair abnormalities. These side effects demonstrate the multiple EGFR-dependent homeostatic functions in human skin. The epidermis and hair follicles are self-renewing tissues, and keratinocyte stem cells are crucial for maintaining these homeostasis. A variety of molecules associated with the EGF receptor/ligand system are involved in epidermal homeostasis and hair follicle development, and the modulation of EGFR signaling impacts the behavior of keratinocyte stem cells. Understanding the roles of the EGF receptor/ligand system in skin homeostasis is an emerging issue in dermatology to improve the current therapy for skin disorders, and the EGFR inhibitor-associated skin toxicities. Besides, controlling of keratinocyte stem cells by modulating the EGF receptor/ligand system assures advances in regenerative medicine of the skin. We present an overview of the recent progress in the field of the EGF receptor/ligand system on skin homeostasis and regulation of keratinocyte stem cells. PMID- 23819986 TI - Decrease of reactive oxygen species and reciprocal increase of nitric oxide in human dermal endothelial cells by Bidens pilosa extract: a possible explanation of its beneficial effect on livedo vasculopathy. PMID- 23819987 TI - The rate of wound healing is increased in psoriasis. AB - BACKGROUND: Psoriasis shares many features with wound healing, a process that involves switching keratinocytes from growth to differentiation. Ca2+ is known to regulate this process. The N-methyl-d-aspartate receptor (NMDAR), an ionotropic glutamate receptor found on keratinocytes, is expressed abnormally in psoriasis in vivo. OBJECTIVES: The goals of this study are to determine whether the rate of healing in the skin of psoriatic individuals differs from that observed in normal skin and whether the keratinocyte hyperproliferation found in psoriasis correlates with expression of specific NMDAR subunits. METHODS: Three mm punch biopsies were performed on the skin of normal, as well as, involved and uninvolved skin of subjects with psoriasis. On day 0, as well as, on day 6 after the biopsy, photographs were taken and the size of the wounds determined using ImageJ. Using immunohistochemistry, the biopsy material was stained for NMDAR and its subunits. RESULTS: Involved and uninvolved skin of individuals with psoriasis shows significantly more rapid healing than normal. The NR2C subunit of NMDAR is down-regulated in the basal cell layer of involved and uninvolved epidermis of psoriatic subjects compared to controls. By contrast, cells in the basal cell layer of the uninvolved epidermis showed a significantly greater percent strong staining for NR2D compared to those cells in normal epidermis. CONCLUSIONS: Wound healing is significantly accelerated in psoriasis compared to normal. Immunohistochemistry showed that the relative intensity of strong immunostaining for subunits of the NMDAR is altered in the basal cell layer in psoriatic skin compared to normal controls. We suggest that these alterations may contribute to the increased rate of wound healing in psoriasis. PMID- 23819989 TI - Unique monoclonal antibodies specifically bind surface structures on human fetal erythroid blood cells. AB - BACKGROUND: Continuing efforts in development of non-invasive prenatal genetic tests have focused on the isolation of fetal nucleated red blood cells (NRBCs) from maternal blood for decades. Because no fetal cell-specific antibody has been described so far, the present study focused on the development of monoclonal antibodies (mAbs) to antigens that are expressed exclusively on fetal NRBCs. METHODS: Mice were immunized with fetal erythroid cell membranes and hybridomas screened for Abs using a multi-parameter fluorescence-activated cell sorting (FACS). Selected mAbs were evaluated by comparative FACS analysis involving Abs known to bind erythroid cell surface markers (CD71, CD36, CD34), antigen-i, galactose, or glycophorin-A (GPA). Specificity was further confirmed by extensive immunohistological and immunocytological analyses of NRBCs from umbilical cord blood and fetal and adult cells from liver, bone marrow, peripheral blood, and lymphoid tissues. RESULTS: Screening of 690 hybridomas yielded three clones of which Abs from 4B8 and 4B9 clones demonstrated the desired specificity for a novel antigenic structure expressed on fetal erythroblast cell membranes. The antigenic structure identified is different from known surface markers (CD36, CD71, GPA, antigen-i, and galactose), and is not present on circulating adult erythroid cells, except for occasional detectability in adult bone marrow cells. CONCLUSIONS: The new mAbs specifically bind the same or highly overlapping epitopes of a surface antigen that is almost exclusively expressed on fetal erythroid cells. The high specificity of the mAbs should facilitate development of simple methods for reliable isolation of fetal NRBCs and their use in non invasive prenatal diagnosis of fetal genetic status. PMID- 23819988 TI - Techniques for assessing 3-D cell-matrix mechanical interactions in vitro and in vivo. AB - Cellular interactions with extracellular matrices (ECM) through the application of mechanical forces mediate numerous biological processes including developmental morphogenesis, wound healing and cancer metastasis. They also play a key role in the cellular repopulation and/or remodeling of engineered tissues and organs. While 2-D studies can provide important insights into many aspects of cellular mechanobiology, cells reside within 3-D ECMs in vivo, and matrix structure and dimensionality have been shown to impact cell morphology, protein organization and mechanical behavior. Global measurements of cell-induced compaction of 3-D collagen matrices can provide important insights into the regulation of overall cell contractility by various cytokines and signaling pathways. However, to understand how the mechanics of cell spreading, migration, contraction and matrix remodeling are regulated at the molecular level, these processes must also be studied in individual cells. Here we review the evolution and application of techniques for imaging and assessing local cell-matrix mechanical interactions in 3-D culture models, tissue explants and living animals. PMID- 23819991 TI - Test-retest reliability of four computerized neurocognitive assessment tools in an active duty military population. AB - Computerized neurocognitive assessment tools (NCATs) are increasingly used for baseline and post-concussion assessments. To date, NCATs have not demonstrated strong test-retest reliabilities. Most studies have used non-military populations and different methodologies, complicating the determination of the utility of NCATs in military populations. The test-retest reliability of four NCATs (Automated Neuropsychological Assessment Metrics 4 [ANAM4], CNS-Vital Signs, CogState, and Immediate Post-Concussion Assessment and Cognitive Test [ImPACT]) was investigated in a healthy active duty military sample. Four hundred and nineteen Service Members were randomly assigned to take one NCAT and 215 returned after approximately 30 days for retest. Participants deemed to have inadequate effort during one or both testing sessions, according to the NCATs scoring algorithms, were removed from analyses. Each NCAT had at least one reliability score (intraclass correlation) in the "adequate" range (.70-.79), only ImPACT had one score considered "high" (.80-.89), and no scores met "very high" criteria (.90-.99). However, overall test-retest reliabilities in four NCATs in a military sample are consistent with reliabilities reported in the literature and are lower than desired for clinical decision-making. PMID- 23819990 TI - Uncoupling protein 2 impacts endothelial phenotype via p53-mediated control of mitochondrial dynamics. AB - RATIONALE: Mitochondria, although required for cellular ATP production, are also known to have other important functions that may include modulating cellular responses to environmental stimuli. However, the mechanisms whereby mitochondria impact cellular phenotype are not yet clear. OBJECTIVE: To determine how mitochondria impact endothelial cell function. METHODS AND RESULTS: We report here that stimuli for endothelial cell proliferation evoke strong upregulation of mitochondrial uncoupling protein 2 (UCP2). Analysis in silico indicated increased UCP2 expression is common in highly proliferative cell types, including cancer cells. Upregulation of UCP2 was critical for controlling mitochondrial membrane potential (Deltapsi) and superoxide production. In the absence of UCP2, endothelial growth stimulation provoked mitochondrial network fragmentation and premature senescence via a mechanism involving superoxide-mediated p53 activation. Mitochondrial network fragmentation was both necessary and sufficient for the impact of UCP2 on endothelial cell phenotype. CONCLUSIONS: These data identify a novel mechanism whereby mitochondria preserve normal network integrity and impact cell phenotype via dynamic regulation of UCP2. PMID- 23819993 TI - A TDPAC study of static and dynamic magnetic behaviour. AB - The a-FexHf100-x system is used to explore the application of TDPAC (the time differential perturbed gamma-gamma angular correlation technique) to non-trivial anisotropic magnetic relaxation. The effect of fluctuations in this system is primarily to cause a decay of the zero-frequency component, which is characterized by the phenomenological decay rate lambda. The zero-field magnetic phase diagram, constructed from both static and dynamic features of the data, and the temperature dependence of lambda are both fully consistent with the physics of partial bond frustration. The results demonstrate that the magnetic fluctuations are meaningfully characterized by simple spectrum features, and are not obscured by large static fields or severe disorder. PMID- 23819992 TI - Epistasis with HLA DR3 implicates the P2X7 receptor in the pathogenesis of primary Sjogren's syndrome. AB - INTRODUCTION: The aim of this study was to examine the association between functional polymorphisms in the pro-inflammatory P2X7 receptor and the Ro/La autoantibody response in primary Sjogren's syndrome (pSS). METHODS: Twelve functional P2RX7 polymorphisms were genotyped in 114 pSS patients fulfilling the Revised American-European Consensus Criteria for pSS, and 136 controls. Genotyping of the A1405G (rs2230912) polymorphism was performed on a replication cohort consisting of 281 pSS patients and 534 controls. P2X7 receptor function in lymphocytes and monocytes was assessed by measurement of ATP-induced ethidium+ uptake. Serum IL-18 levels were determined by ELISA. RESULTS: The minor allele of P2RX7 A1405G is a tag for a common haplotype associated with gain in receptor function, as assessed by ATP-induced ethidium+ uptake. A positive association between 1405G and anti-Ro+/-La seropositive pSS patients was observed in Cohort 1. Although not replicated in Cohort 2, there was a consistent, significant, negative epistatic interaction effect with HLA-DR3 in seropositive pSS patients from both cohorts, thereby implicating this gain of function variant in the pathogenesis of pSS. Serum IL-18 was elevated in seropositive pSS patients, but was not influenced by P2RX7 A1405G. CONCLUSIONS: The P2RX7 1405G gain-of-function haplotype may be a risk factor for seropositive pSS in a subset of subjects who do not carry HLA risk alleles, but has no effect in subjects who do (epistasis). Potential mechanisms relate to autoantigen exposure and inflammatory cytokine expression. The observed elevation of IL-18 levels is consistent with P2X7 receptor activation in seropositive pSS patients. Collectively these findings implicate P2X7 receptor function in the pathogenesis of pSS. PMID- 23819994 TI - Unraveling the complexity of hepatitis B virus: from molecular understanding to therapeutic strategy in 50 years. AB - Hepatitis B virus (HBV) is a well-known hepadnavirus with a double-stranded circular DNA genome. Although HBV was first described approximately 50 years ago, the precise mechanisms of HBV infection and effective therapeutic strategies remain unclear. Here, we focus on summarizing the complicated mechanisms of HBV replication and infection, as well as genomic factors and epigenetic regulation. Additionally, we discuss in vivo models of HBV, as well as diagnosis, prevention and therapeutic drugs for HBV. Together, the data in this 50-year review may provide new clues to elucidate molecular mechanisms of HBV pathogenesis and shed new light on the future HBV therapies. PMID- 23819995 TI - Clinical outcomes related to muscle mass in humans with cancer and catabolic illnesses. AB - It is generally accepted that excessive loss of skeletal muscle mass is detrimental. Depletion of muscle mass is associated with poor prognosis in diabetes, trauma, sepsis, lung disease, renal failure and heart failure. In this review we discuss the emergence of muscle mass measurement using diagnostic imaging and the relationship between muscle mass and clinical outcome. The pursuit of specific biochemical targets for reversal of muscle wasting, has spawned a host of investigator initiated research on muscle wasting as well as investigational new drug programs in pharmaceutical companies. Research on therapeutics targeting muscle is to a large extent done in animal models, with relatively few investigations done using human muscle or reporting upon muscle mass or muscle-related outcomes in humans. Since ~1990, a quantitative approach, as opposed to a purely functional approach, to muscle atrophy and hypertrophy has become accessible with the advent of image-based assessments (dual energy X-ray absorptiometry, computed tomography and magnetic resonance imaging). These methods have high specificity and precision. In conclusion, current imaging techniques allow us to quantify the degree of muscularity of different individuals, to relate muscle mass to disease-specific outcomes, to define sarcopenia [severe muscle depletion] in quantitative terms, to detect the prevalence and rates of catabolic loss of muscle, the behavior of specific individual muscles and to define the efficacy of different therapies developed for the treatment of muscle wasting. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. PMID- 23819997 TI - Reply to "the five paradoxes of vitamin D and the importance of sunscreen protection". PMID- 23819998 TI - Is bigger really better? Obesity among high school football players, player position, and team success. AB - OBJECTIVE: American football is one of the most common high school sports in the United States. We examine obesity among high school football players, and variations based on positions, team division, and team success. PATIENTS AND METHODS: We used 2 data sets from the North Carolina High School Athletic Association (n = 2026) and MaxPreps (n = 6417). We examined body mass index, calculated using coach-reported height and weight, by player position, division, and success based on win-loss percentage. RESULTS: Most players (62%) were skill players, with 35% linemen and 3% punters/kickers. Most skill players (62%) were healthy weight and 4% obese or morbidly obese. In contrast, only 8% of linemen were healthy weight, with 21% morbidly obese. Team success was correlated with size only for skill players. CONCLUSIONS: Obesity is a significant problem for high school football players. Pediatricians should consider the context of football playing in assessing long-term health risks for these young men. PMID- 23819996 TI - Drosophila Fip200 is an essential regulator of autophagy that attenuates both growth and aging. AB - Autophagy-related 1 (Atg1)/Unc-51-like protein kinases (ULKs) are evolutionarily conserved proteins that play critical physiological roles in controlling autophagy, cell growth and neurodevelopment. RB1-inducible coiled-coil 1 (RB1CC1), also known as PTK2/FAK family-interacting protein of 200 kDa (FIP200) is a recently discovered binding partner of ULK1. Here we isolated the Drosophila RB1CC1/FIP200 homolog (Fip200/CG1347) and showed that it mediates Atg1-induced autophagy as a genetically downstream component in diverse physiological contexts. Fip200 loss-of-function mutants experienced severe mobility loss associated with neuronal autophagy defects and neurodegeneration. The Fip200 mutants were also devoid of both developmental and starvation-induced autophagy in salivary gland and fat body, while having no defects in axonal transport and projection in developing neurons. Interestingly, moderate downregulation of Fip200 accelerated both developmental growth and aging, accompanied by target of rapamycin (Tor) signaling upregulation. These results suggest that Fip200 is a critical downstream component of Atg1 and specifically mediates Atg1's autophagy , aging- and growth-regulating functions. PMID- 23819999 TI - Play and video effects on mood and procedure behaviors in school-aged children visiting the pediatrician. AB - This study examines how different types of activities, including medical play, typical play, and videos, affect the mood and behaviors of children visiting a pediatric office. Seventy-two school-aged children visiting a pediatrician's office were randomly assigned to 1 of 4 groups: medical play, medical information video, typical play, and nonmedical information video control. Children completed a mood self-report measure and their behaviors were recorded during triage by nurses. The medical information video improved the school-aged children's mood. Children in the medical information video displayed less difficult behaviors during procedures than the medical play group. The findings suggest that providing information about medical equipment through a video of a child engaging in medical play may benefit children visiting the pediatrician. PMID- 23820000 TI - Growth of healthy term infants fed an extensively hydrolyzed casein-based or free amino acid-based infant formula: a randomized, double-blind, controlled trial. AB - A masked, randomized, parallel growth study was conducted in infants fed an amino acid-based formula (AF) or an extensively hydrolyzed casein-based formula (HF). Infants were enrolled between 0 and 9 days and studied to 112 days of age. Growth, formula intake, stool patterns, and serum albumin concentrations were assessed. There were no significant differences between groups in weight, length, or head circumference, gains in weight or length, or study formula intake. The number of stools parents rated as being formed, and the mean daily number of stools were greater in the HF than in the AF group at 14 and 28 days of age. Mean serum albumin concentrations were not significantly different between groups and were within the normal range. This study demonstrates that AF supports normal growth of infants comparable to that of infants fed HF during the critical first 4 months of life. PMID- 23820001 TI - Intravenous dihydroergotamine therapy for pediatric abdominal migraines. AB - Abdominal migraines present with debilitating symptoms in adolescence. At our institution, the gastroenterology, neurology, and autonomic departments collaborated in treating patients with such presentations. This case series describes 6 patients who were given intravenous dihydroergotamine (DHE) for presumed abdominal migraines. DHE was only used when other agents like amitriptyline, verapamil, topiramate, or depakote had proved ineffective. DHE was started at 0.5 mg dose and on average 7 to 9 mg were given on each hospitalization. Patient ages ranged from 13 to 19 years with the majority being female. One patient did not respond to treatment. One patient was admitted 4 times for symptoms of abdominal migraines resolving with DHE. The average time between symptom relapse was about 5 to 12 months. Five of our 6 patients responded to the infusion without significant side effects. Based on these case series, DHE may be a treatment option in children with intractable abdominal migraine. PMID- 23820002 TI - Trends in revision circumcision at pediatric hospitals. AB - BACKGROUND: We sought to determine the incidence of revision circumcision at freestanding children's hospitals, and examine trends over time. METHODS: We searched the Pediatric Health Information Systems database to identify boys undergoing revision circumcision (RC), primary non-newborn circumcision (PC), or lysis of penile adhesions (LPA) from 2004 to 2009. Rates of RC procedures were calculated by dividing the incidence of procedures by the total male ambulatory surgical volume. RESULTS: We identified 34,568 patients of whom 5632 underwent RC, 25,768 PC, and 3168 LPA. The rate of RC increased 119%, which was significantly more than PC (19%; P<.001) or LPA (37%; P<.001). Urologists performed 76% of RC and 12% were performed with other genitourinary procedures. Boys undergoing RC were predominately white (60%) and publicly insured (61%). CONCLUSIONS: There was a disproportionate increased rate of RC performed at Pediatric Health Information Systems hospitals compared with PC or LPA. Wide variation exists in rate increases among hospitals. PMID- 23820003 TI - Association of screen time use and language development in Hispanic toddlers: a cross-sectional and longitudinal study. AB - This study examined the association between screen media use, media content, and language development among 119 Hispanic infants and toddlers. Children and their caregivers were recruited through an urban, Early Head Start program. Duration and content of screen media exposure was measured through a 24-hour recall questionnaire, and language development was measured at baseline and at 1-year follow up. Children in the sample spent an average of 3.29 hours engaged with screen media (median 2.5 hours per day). In both cross-sectional and longitudinal analyses, children who watched over 2 hours of television per day had increased odds of low communication scores. Whereas child-directed media was associated with low language scores, adult-directed media was not. Our findings support the mounting literature on the deleterious impacts of screen media in toddler's language development. Guidance and alternatives to screen media use should be available to families in pediatric practices and early childhood centers. PMID- 23820005 TI - Activation-induced cytidine deaminase auto-activates and triggers aberrant gene expression. AB - DNA methylation is a well-characterized epigenetic landmark involved in transcriptional regulation; however, mechanisms underlying its regulation remain poorly characterized. Recent studies demonstrate that activation-induced cytidine deaminase (AID) is involved in active DNA demethylation. AID is aberrantly expressed in inflammation-associated cancers and generates point mutations; however, cellular disorders attributed to its demethylation function are largely unexplored. Here we demonstrate that ectopic AID expression perturbs tumor related gene expression. AID (with Gadd45) activated a methylated paired box gene 5 (Pax5) reporter construct, and induced expression and association of endogenous Pax5 with the AID promoter, suggesting that aberrant AID expression triggers an auto-activation circuit to consolidate self-expression. PMID- 23820006 TI - Competitive sorption between 1,2,4-trichlorobenzene/tetrachloroethene and 1,2,4,5 tetrachlorobenzene by soils/sediments from South China. AB - 1,2,4-Trichlorobenzene (1,2,4-TCB) and tetrachloroethene (PCE) were chosen to study their competitive effect on 1,2,4,5-tetrachlorobenzene (1,2,4,5-TeCB) sorption by three soils/sediments from South China with different fractions of natural organic matter (NOM) employing a batch technique. Results showed that cosolutes 1,2,4-trichlorobenzene and tetrachloroethene exhibited apparent competition against 1,2,4,5-tetrachlorobenzene in all of the three sediments. 1,2,4-Trichlorobenzene was more effective competitor than tetrachloroethene because the structure of 1,2,4-TCB is very close to that of 1,2,4,5-TeCB. Furthermore, the extent of competition depended on the rigidity of sediment NOM matrixes. The more reduced and condensed the matrixes are, the larger extent of competitive effect would the corresponding sediment show at a given sorbed volume of competitor. PMID- 23820004 TI - TRPM8 is the principal mediator of menthol-induced analgesia of acute and inflammatory pain. AB - Menthol, the cooling natural product of peppermint, is widely used in medicinal preparations for the relief of acute and inflammatory pain in sports injuries, arthritis, and other painful conditions. Menthol induces the sensation of cooling by activating TRPM8, an ion channel in cold-sensitive peripheral sensory neurons. Recent studies identified additional targets of menthol, including the irritant receptor, TRPA1, voltage-gated ion channels and neurotransmitter receptors. It remains unclear which of these targets contribute to menthol-induced analgesia, or to the irritating side effects associated with menthol therapy. Here, we use genetic and pharmacological approaches in mice to probe the role of TRPM8 in analgesia induced by L-menthol, the predominant analgesic menthol isomer in medicinal preparations. L-menthol effectively diminished pain behavior elicited by chemical stimuli (capsaicin, acrolein, acetic acid), noxious heat, and inflammation (complete Freund's adjuvant). Genetic deletion of TRPM8 completely abolished analgesia by L-menthol in all these models, although other analgesics (acetaminophen) remained effective. Loss of L-menthol-induced analgesia was recapitulated in mice treated with a selective TRPM8 inhibitor, AMG2850. Selective activation of TRPM8 with WS-12, a menthol derivative that we characterized as a specific TRPM8 agonist in cultured sensory neurons and in vivo, also induced TRPM8-dependent analgesia of acute and inflammatory pain. L menthol- and WS-12-induced analgesia was blocked by naloxone, suggesting activation of endogenous opioid-dependent analgesic pathways. Our data show that TRPM8 is the principal mediator of menthol-induced analgesia of acute and inflammatory pain. In contrast to menthol, selective TRPM8 agonists may produce analgesia more effectively, with diminished side effects. PMID- 23820008 TI - Nitrate source apportionment in a subtropical watershed using Bayesian model. AB - Nitrate (NO3-) pollution in aquatic system is a worldwide problem. The temporal distribution pattern and sources of nitrate are of great concern for water quality. The nitrogen (N) cycling processes in a subtropical watershed located in Changxing County, Zhejiang Province, China were greatly influenced by the temporal variations of precipitation and temperature during the study period (September 2011 to July 2012). The highest NO3- concentration in water was in May (wet season, mean+/-SD=17.45+/-9.50 mg L(-1)) and the lowest concentration occurred in December (dry season, mean+/-SD=10.54+/-6.28 mg L(-1)). Nevertheless, no water sample in the study area exceeds the WHO drinking water limit of 50 mg L(-1) NO3-. Four sources of NO3(-) (atmospheric deposition, AD; soil N, SN; synthetic fertilizer, SF; manure & sewage, M&S) were identified using both hydrochemical characteristics [Cl-, NO3-, HCO3-, SO42-, Ca2+, K+, Mg2+, Na+, dissolved oxygen (DO)] and dual isotope approach (delta15N-NO3- and delta(18)O NO3-). Both chemical and isotopic characteristics indicated that denitrification was not the main N cycling process in the study area. Using a Bayesian model (stable isotope analysis in R, SIAR), the contribution of each source was apportioned. Source apportionment results showed that source contributions differed significantly between the dry and wet season, AD and M&S contributed more in December than in May. In contrast, SN and SF contributed more NO3- to water in May than that in December. M&S and SF were the major contributors in December and May, respectively. Moreover, the shortcomings and uncertainties of SIAR were discussed to provide implications for future works. With the assessment of temporal variation and sources of NO3-, better agricultural management practices and sewage disposal programs can be implemented to sustain water quality in subtropical watersheds. PMID- 23820007 TI - Dietary exposure to DDTs in two coastal cities and an inland city in China. AB - Dietary intakes of dichloro-diphenyl-trichloroethanes (DDTs) of residents from two coastal cities: Guiyu (GY) and Taizhou (TZ) and one inland city: Lin'an (HZ) were investigated by collecting 73 food items (divided into 9 food groups). The oriental weatherfish and white crab (both from TZ) contained higher DDTs (112+/ 1.81 and 70.1+/-1.81 ng/g wet wt, respectively) than the maximum admissible concentration (50 ng/g wet wt) set by the European Union for human consumption. Furthermore, 40% of TZ seafood, 56% of GY and 30% of HZ freshwater fish exceeded the guideline for subsistence fish eaters for DDTs (14.4 ng/g wet wt) defined by the United States Environmental Protection Agency (US EPA). The estimated daily intakes of DDTs for TZ (52.1 ng/kg bw/day) and GZ (31.5 ng/kg bw/day) were significantly higher than for HZ (13.0 ng/g wet wt, p<0.05), these values were below the US EPA oral reference dose (500 ng/kg bw/day) and the Food and Agriculture Organization of the United Nations and the World Health Organization provisional tolerable daily intake (10,000 ng/kg bw/day). PMID- 23820009 TI - Differential in vitro bioaccessibility of residual As in a field-aged former smelter site and its implication for potential risk. AB - Chemical forms of arsenic (As) present in a former smelter site were determined. A five-step sequential extraction showed that about 94.8 to 99.2% of total As concentration was found to be present as residual form, and interestingly some of the residual As seemed to be still bioaccessible, when determined with an in vitro bioaccessibility test. However, the extents of bioaccessible As greatly varied among the three soils tested. Soil B showed the highest bioaccessibility being 17.18 mg-As/kg (11.9%) followed by 12.71 (2.02%) and 14.03 mg-As/kg (0.64%) in soils C and A, respectively. When the residual As was treated with hydrofluoric acid (i.e., HF) 65.3 to 80.9 mg-As/kg was extracted and only 4.17 to 7.25% of the HF-extractable As was found to be bioaccessible. In contrast, when the residual As was treated with hydroperchloric acid (i.e., HClO4) only 5.64 to 8.01 mg-As/kg was recovered but 64.5 to 92.5% of the HClO4-extractable As was bioaccessible. The results suggest the presence of differential bioaccessibility of residual As, which apparently depends on the solid phase that As is associated with (i.e., organic matter or clay minerals). Of the As present as residual fraction, the As mainly bound to silicate mineral showed extremely low bioaccessibility and the As associated with refractory organic matter was highly bioaccessible. PMID- 23820010 TI - Sildenafil and tadalafil in simulated chlorination conditions: ecotoxicity of drugs and their derivatives. AB - Chlorination experiments on two drugs (sildenafil and tadalafil) were performed mimicking the conditions of a typical wastewater treatment process. The main transformation products were isolated by chromatographic techniques (Thin Layer Chromatography (TLC), Column Chromatography (CC), High Performance Liquid Chromatography (HPLC)) and fully characterized employing Nuclear Magnetic Resonance (NMR) and Mass Spectrometry (MS) analyses. The environmental effects of the parent compounds and transformation products were evaluated using an overall toxicity approach that considered aquatic acute and chronic toxicity on Brachionus calyciflorus and Ceriodaphnia dubia as well as mutagenesis and genotoxicity on bacterial strains. The results revealed that both parent drugs did not show high acute and chronic toxicity for the organisms utilized in the bioassays while, chronic exposure to chlorine derivatives caused inhibition of growth population on rotifers and crustaceans. A mutagenic potential was found for all the compounds investigated. PMID- 23820011 TI - Residential characteristics and household risk factors and respiratory diseases in Chinese women: the Seven Northeast Cities (SNEC) study. AB - BACKGROUND: Few studies have assessed the impact of residential home characteristics and home environmental risk factors on respiratory diseases in Chinese women. Therefore, this study sought to determine the association between residential home features, domestic pets, home renovation and other indoor environmental risk factors with respiratory health outcomes of Chinese women. METHODS: This cross-sectional study included a study sample of 30,780 Chinese women aged 23 to 49 from 25 districts of seven cities in Liaoning Province, Northeast China. Information on respiratory health, residential characteristics, and indoor air pollution sources was obtained by a standard questionnaire from the American Thoracic Society. Multivariable logistic regression was used to estimate prevalence odds ratios (POR) and 95% confidence interval (95%CI). RESULTS: The odds of respiratory diseases were higher for those who lived near the main road, or near ambient air pollution sources. Pet-keeping was associated with increased odds of chronic bronchitis (POR=1.40; 95%CI: 1.09-1.81) and doctor diagnosed asthma (POR=2.07; 95%CI: 1.18-3.64). Additionally, humidifier use was associated with increased odds of chronic bronchitis (POR=1.44; 95%CI: 1.07 1.94). Home renovation in recent 2 years was associated with increased likelihood of allergic rhinitis (POR=1.39; 95%CI 1.17-1.64). CONCLUSION: Home renovation and residential home environmental risk factors were associated with an increased likelihood of respiratory morbidity among Chinese women. PMID- 23820012 TI - Three-channel fluorescent sensing via organic white light-emitting dyes for detection of hydrogen sulfide in living cells. AB - To demonstrate the feasibility of development of three-channel based fluorescent sensors based on organic white light-emitting dyes, in this work, for proof-of principle, we initially judiciously designed an organic white light-emitting dye, which was further used as a robust platform to engineer a new fluorescent sensor for monitoring H2S with turn-on fluorescence signals in blue, green, and red emission channels in both solution and living cells. This work should open a new avenue for design of three- and multiple-channel based fluorescent sensors for various analytes. PMID- 23820014 TI - Development of a gene/drug dual delivery system for brain tumor therapy: potent inhibition via RNA interference and synergistic effects. AB - Malignant brain tumors are characterized by three major physiological processes: proliferation, angiogenesis, and invasion. Traditional cytotoxic chemotherapies (e.g. Paclitaxel) control the tumor by blocking growth and proliferation mechanisms, but leave angiogenesis and invasion unchecked. We identified Matrix metalloproteinase-2 (MMP-2), an essential proteinase regulating brain tumor invasion and angiogenesis, as one of the therapeutic target. A designer RNAi plasmid was developed, and complexed with the gene carrier polyethylenimine (PEI), in an effort to specifically suppress MMP-2 expression in tumor cells. The gene and a cytotoxic drug Paclitaxel were then dual-encapsulated in PLGA based submicron implants to achieve a sustained release of both agents. Potent inhibition effects on MMP-2 mRNA and protein expression, in vitro cell angiogenesis and invasion were demonstrated both on the PEI/DNA nanoparticles alone, and on the PEI/DNA nanoparticles embedded in microfibers. Most importantly, through in vivo test on intracranial xenograft tumor model in BALB/c nude mice, it was proved that the gene/drug dual delivery microfibers are able to impose significant tumor regression compared with single drug delivery microfibers and commercial drug treatment, showing evidence for synergistic therapeutic efficacy. PMID- 23820013 TI - Mannosylated bioreducible nanoparticle-mediated macrophage-specific TNF-alpha RNA interference for IBD therapy. AB - The application of RNA interference (RNAi) for inflammatory bowel disease (IBD) therapy has been limited by the lack of non-cytotoxic, efficient and targetable small interfering RNA (siRNA) carriers. TNF-alpha is the major pro-inflammatory cytokine mainly secreted by macrophages during IBD. Here, a mannosylated bioreducible cationic polymer (PPM) was synthesized and further spontaneously assembled nanoparticles (NPs) assisted by sodium triphosphate (TPP). The TPP PPM/siRNA NPs exhibited high uniformity (polydispersity index = 0.004), a small particle size (211-275 nm), excellent bioreducibility, and enhanced cellular uptake. Additionally, the generated NPs had negative cytotoxicity compared to control NPs fabricated by branched polyethylenimine (bPEI, 25 kDa) or Oligofectamine (OF) and siRNA. In vitro gene silencing experiments revealed that TPP-PPM/TNF-alpha siRNA NPs with a weight ratio of 40:1 showed the most efficient inhibition of the expression and secretion of TNF-alpha (approximately 69.9%, which was comparable to the 71.4% obtained using OF/siRNA NPs), and its RNAi efficiency was highly inhibited in the presence of mannose (20 mm). Finally, TPP PPM/siRNA NPs showed potential therapeutic effects on colitis tissues, remarkably reducing TNF-alpha level. Collectively, these results suggest that non-toxic TPP PPM/siRNA NPs can be exploited as efficient, macrophage-targeted carriers for IBD therapy. PMID- 23820015 TI - Management of herpesvirus infections. AB - Management of human herpesviruses remains a considerable clinical challenge, in part due to their ability to cause both lytic and latent disease. Infection with the Herpesviridae results in lifelong infection, which can reactivate at any time. Control of herpesviruses is by the innate and adaptive immune systems. Herpesviruses must evade the host innate immune system to establish infection. Once infected, the adaptive immune response, primarily CD8(+) T-cells, is crucial in establishing and maintaining latency. Latent herpesviruses are characterised by the presence of viral DNA in infected cells and limited or no viral replication. These characteristics provide a challenge to clinicians and those developing antiviral agents. The scope of this review is two-fold. First, to provide an overview of all antivirals used against herpesviruses, including their mechanism of action, pharmacokinetics, side effects, resistance and clinical uses. And second, to address the management of each of the eight herpesviruses both in the immunocompetent and immunocompromised host, providing evidence for clinical management and therapeutic options, which is important to the clinician engaged in the management of these infections. PMID- 23820016 TI - Defining and measuring completeness of electronic health records for secondary use. AB - We demonstrate the importance of explicit definitions of electronic health record (EHR) data completeness and how different conceptualizations of completeness may impact findings from EHR-derived datasets. This study has important repercussions for researchers and clinicians engaged in the secondary use of EHR data. We describe four prototypical definitions of EHR completeness: documentation, breadth, density, and predictive completeness. Each definition dictates a different approach to the measurement of completeness. These measures were applied to representative data from NewYork-Presbyterian Hospital's clinical data warehouse. We found that according to any definition, the number of complete records in our clinical database is far lower than the nominal total. The proportion that meets criteria for completeness is heavily dependent on the definition of completeness used, and the different definitions generate different subsets of records. We conclude that the concept of completeness in EHR is contextual. We urge data consumers to be explicit in how they define a complete record and transparent about the limitations of their data. PMID- 23820018 TI - Undignified care: violation of patient dignity in involuntary psychiatric hospital care from a nurse's perspective. AB - Patient dignity in involuntary psychiatric hospital care is a complex yet central phenomenon. Research is needed on the concept of dignity's specific contextual attributes since nurses are responsible for providing dignified care in psychiatric care. The aim was to describe nurses' experiences of violation of patient dignity in clinical caring situations in involuntary psychiatric hospital care. A qualitative design with a hermeneutic approach was used to analyze and interpret data collected from group interviews. Findings reveal seven tentative themes of nurses' experiences of violations of patient dignity: patients not taken seriously, patients ignored, patients uncovered and exposed, patients physically violated, patients becoming the victims of others' superiority, patients being betrayed, and patients being predefined. Understanding the contextual experiences of nurses can shed light on the care of patients in involuntary psychiatric hospital care. PMID- 23820017 TI - BreastMark: an integrated approach to mining publicly available transcriptomic datasets relating to breast cancer outcome. AB - INTRODUCTION: Breast cancer is a complex heterogeneous disease for which a substantial resource of transcriptomic data is available. Gene expression data have facilitated the division of breast cancer into, at least, five molecular subtypes, namely luminal A, luminal B, HER2, normal-like and basal. Once identified, breast cancer subtypes can inform clinical decisions surrounding patient treatment and prognosis. Indeed, it is important to identify patients at risk of developing aggressive disease so as to tailor the level of clinical intervention. METHODS: We have developed a user-friendly, web-based system to allow the evaluation of genes/microRNAs (miRNAs) that are significantly associated with survival in breast cancer and its molecular subtypes. The algorithm combines gene expression data from multiple microarray experiments which frequently also contain miRNA expression information, and detailed clinical data to correlate outcome with gene/miRNA expression levels. This algorithm integrates gene expression and survival data from 26 datasets on 12 different microarray platforms corresponding to approximately 17,000 genes in up to 4,738 samples. In addition, the prognostic potential of 341 miRNAs can be analysed. RESULTS: We demonstrated the robustness of our approach in comparison to two commercially available prognostic tests, oncotype DX and MammaPrint. Our algorithm complements these prognostic tests and is consistent with their findings. In addition, BreastMark can act as a powerful reductionist approach to these more complex gene signatures, eliminating superfluous genes, potentially reducing the cost and complexity of these multi-index assays. Known miRNA prognostic markers, mir-205 and mir-93, were used to confirm the prognostic value of this tool in a miRNA setting. We also applied the algorithm to examine expression of 58 receptor tyrosine kinases in the basal-like subtype, identifying six receptor tyrosine kinases associated with poor disease-free survival and/or overall survival (EPHA5, FGFR1, FGFR3, VEGFR1, PDGFRbeta, and TIE1). A web application for using this algorithm is currently available. CONCLUSIONS: BreastMark is a powerful tool for examining putative gene/miRNA prognostic markers in breast cancer. The value of this tool will be in the preliminary assessment of putative biomarkers in breast cancer. It will be of particular use to research groups with limited bioinformatics facilities. PMID- 23820019 TI - The self-assembly of particles with isotropic interactions. AB - A generic field-theoretic model for the self-assembly of particles with isotropic interactions, motivated by ideas in DNA-mediated colloidal assembly, is presented. A simplest possible system of colloids in explicit solvent is examined to determine the ability of non-connected particles to form complex nanometre or micron scale equilibrium structures in the absence of confounding kinetic effects. It is found that non-trivial morphologies are possible and that, for this effectively one component system, these parallel the phases of diblock copolymer melts for certain parameter choices, despite the absence of connectivity or packing frustration in the model. An explanation for the morphological similarity between these architecturally disparate systems is given. For other parameter choices, it is found that meta-stable and defected phases become more common, and that similarity with block copolymer morphologies decreases. PMID- 23820020 TI - Association of total marine fatty acids, eicosapentaenoic and docosahexaenoic acids, with aortic stiffness in Koreans, whites, and Japanese Americans. AB - BACKGROUND: Few previous studies have reported the association of aortic stiffness with marine n-3 fatty acids (Fas) in the general population. The aim of this study was to determine the combined and independent associations of 2 major marine n-3 FAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), with aortic stiffness evaluated using carotid-femoral pulse wave velocity (cfPWV) in Korean, white, and Japanese American men. METHODS: A population-based sample of 851 middle-aged men (299 Koreans, 266 whites, and 286 Japanese Americans) was examined for cfPWV during 2002-2006. Serum FAs, including EPA and DHA, were measured as a percentage of total FAs using gas chromatography. Multiple regression analysis was used to examine the association of EPA and DHA with cfPWV after adjusting for blood pressure and other confounders. RESULTS: Mean EPA and DHA levels were 1.9 (SD = 1.0) and 4.8 (SD = 1.4) for Koreans, 0.8 (SD = 0.6) and 2.4 (SD = 1.2) for whites, and 1.0 (SD = 1.0) and 3.2 (SD = 1.4) for Japanese Americans. Both EPA and DHA were significantly higher in Koreans than in the other 2 groups (P < 0.01). Multiple regression analyses in Koreans showed that cfPWV had a significant inverse association with total marine n-3 FAs and with EPA alone after adjusting for blood pressure and other potential confounders. In contrast, there was no significant association of cfPWV with DHA. Whites and Japanese Americans did not show any significant associations of cfPWV with total marine n-3 FAs, EPA, or DHA. CONCLUSIONS: High levels of EPA observed in Koreans have an inverse association with aortic stiffness. PMID- 23820022 TI - Too much medicine; too little care. PMID- 23820021 TI - When a test is too good: how CT pulmonary angiograms find pulmonary emboli that do not need to be found. PMID- 23820023 TI - The luminal connection: from animal development to lumopathies. AB - Interconnection of epithelial tubules is a crucial process during organogenesis. Organisms have evolved sets of molecular and cellular strategies to generate an interconnected tubular network during animal development. Spatiotemporal control of common cellular strategies includes dissolution of the basement membrane, apoptosis, rearrangements of cell adhesion junctions, and mesenchymal-like invasive cellular behaviors prior to tubular interconnection. Different model systems exhibit varying degrees of active invasive-like behaviors that precede tubular interconnection, which may reflect changes in cell polarity or differential adhesive cell states. Studies in this newly-emerging field of tubular interconnections will provide a greater understanding of pediatric diseases and cancer metastasis, as well as generate fundamentally new insights into lumen formation pathology, or lumopathies. PMID- 23820024 TI - Contrast gain-control in stereo depth and cyclopean contrast perception. AB - Although human observers can perceive depth from stereograms with considerable contrast difference between the images presented to the two eyes (Legge & Gu, 1989), how contrast gain control functions in stereo depth perception has not been systematically investigated. Recently, we developed a multipathway contrast gain-control model (MCM) for binocular phase and contrast perception (Huang, Zhou, Lu, & Zhou, 2011; Huang, Zhou, Zhou, & Lu, 2010) based on a contrast gain control model of binocular phase combination (Ding & Sperling, 2006). To extend the MCM to simultaneously account for stereo depth and cyclopean contrast perception, we manipulated the contrasts (ranging from 0.08 to 0.4) of the dynamic random dot stereograms (RDS) presented to the left and right eyes independently and measured both disparity thresholds for depth perception and perceived contrasts of the cyclopean images. We found that both disparity threshold and perceived contrast depended strongly on the signal contrasts in the two eyes, exhibiting characteristic binocular contrast gain-control properties. The results were well accounted for by an extended MCM model, in which each eye exerts gain control on the other eye's signal in proportion to its own signal contrast energy and also gain control over the other eye's gain control; stereo strength is proportional to the product of the signal strengths in the two eyes after contrast gain control, and perceived contrast is computed by combining contrast energy from the two eyes. The new model provided an excellent account of our data (r(2) = 0.945), as well as some challenging results in the literature. PMID- 23820025 TI - Intrasaccadic suppression is dominated by reduced detector gain. AB - Human vision requires fast eye movements (saccades). Each saccade causes a self induced motion signal, but we are not aware of this potentially jarring visual input. Among the theorized causes of this phenomenon is a decrease in visual sensitivity before (presaccadic suppression) and during (intrasaccadic suppression) saccades. We investigated intrasaccadic suppression using a perceptual template model (PTM) relating visual detection to different signal processing stages. One stage changes the gain on the detector's input; another increases uncertainty about the stimulus, allowing more noise into the detector; and other stages inject noise into the detector in a stimulus-dependent or independent manner. By quantifying intrasaccadic suppression of flashed horizontal gratings at varying external noise levels, we obtained threshold versus-noise (TVN) data, allowing us to fit the PTM. We tested if any of the PTM parameters changed significantly between the fixation and saccade models and could therefore account for intrasaccadic suppression. We found that the dominant contribution to intrasaccadic suppression was a reduction in the gain of the visual detector. We discuss how our study differs from previous ones that have pointed to uncertainty as an underlying cause of intrasaccadic suppression and how the equivalent noise approach provides a framework for comparing the disparate neural correlates of saccadic suppression. PMID- 23820026 TI - Numerosity underestimation with item similarity in dynamic visual display. AB - The estimation of numerosity of a large number of objects in a static visual display is possible even at short durations. Such coarse approximations of numerosity are distinct from subitizing, in which the number of objects can be reported with high precision when a small number of objects are presented simultaneously. The present study examined numerosity estimation of visual objects in dynamic displays and the effect of object similarity on numerosity estimation. In the basic paradigm (Experiment 1), two streams of dots were presented and observers were asked to indicate which of the two streams contained more dots. Streams consisting of dots that were identical in color were judged as containing fewer dots than streams where the dots were different colors. This underestimation effect for identical visual items disappeared when the presentation rate was slower (Experiment 1) or the visual display was static (Experiment 2). In Experiments 3 and 4, in addition to the numerosity judgment task, observers performed an attention-demanding task at fixation. Task difficulty influenced observers' precision in the numerosity judgment task, but the underestimation effect remained evident irrespective of task difficulty. These results suggest that identical or similar visual objects presented in succession might induce substitution among themselves, leading to an illusion that there are few items overall and that exploiting attentional resources does not eliminate the underestimation effect. PMID- 23820027 TI - Collateral ligament strains during knee joint laxity evaluation before and after TKA. AB - BACKGROUND: Passive knee stability is provided by the soft tissue envelope. There is consensus among orthopedic surgeons that good outcome in Total Knee Arthroplasty requires equal tension in the medial/lateral compartment of the knee joint, as well as equal tension in the flexion/extension gap. The purpose of this study was to quantify the ligament laxity in the normal non-arthritic knee before and after Posterior-Stabilized Total Knee Arthroplasty. We hypothesized that the Medial/Lateral Collateral Ligament shows minimal changes in length when measured directly by extensometers in the native human knee during varus/valgus laxity testing. We also hypothesized that due to differences in material properties and surface geometry, native laxity is difficult to reconstruct using a Posterior Stabilized Total Knee. METHODS: Six specimens were used to perform this in vitro cadaver test using extensometers to provide numerical values for laxity and varus valgus tilting in the frontal plane. FINDINGS: This study enabled a precise measurement of varus-valgus laxity as compared with the clinical assessment. The strains in both ligaments in the replaced knee were different from those in the native knee. Both ligaments were stretched in extension, in flexion the Medial Collateral Ligament tends to relax and the Lateral Collateral Ligament remains tight. INTERPRETATION: As material properties and surface geometry of the replaced knee add stiffness to the joint, we recommend to avoid overstuffing the joint, when using this type of Posterior-Stabilized Total Knee Arthroplasty, in order to obtain varus/valgus laxity close to the native joint. PMID- 23820028 TI - Progress of snow mould infection in crowns of winter rye (Secale cereale L.) is related to photosynthetic activity during cold acclimation. AB - Resistance to snow mould is a feature determined by multiple genes. Therefore, determining the phenotype of resistant plants is difficult as it requires an investigation over a long period of time from cold acclimation through pathogenesis. The aim of the present study was (i) to determine the characteristics of the resistant genotype and (ii) to clarify the connections between photosynthesis during cold acclimation and then pathogenesis caused by Microdochium nivale. Two inbred lines of winter rye (Secale cereale L.) differing in their susceptibility to snow mould were used in the study. After cold acclimation snow mould resistant (SMR) line was characterised by higher values of CO2 assimilation and electron transport efficiency but did not differ from snow mould susceptible (SMS) line in carboxylation rate of RuBisCO (Vcmax). Higher soluble carbohydrate accumulation, due to higher photosynthesis intensity, as well as an ABA increase at 5 days post infection (DPI) in leaves and crowns were found in SMR line during the pathogenesis period. Callose deposition was found around non-infected bundle sheets and in cortex cells at 5 DPI (at the same time point as ABA peak) only in SMR line, which probably prevented the infection of leaf initials. Early leaf initials infection in SMS line may be responsible for inhibiting leaf growth and plant regeneration after stress cessation. The results show different physiological and biochemical characteristics of the investigated lines, which can be applied in the selection of resistant genotypes and identifying genomic regions responsible for metabolic pathways increasing pathogen resistance. PMID- 23820029 TI - Strengthening the organizational capacity of health professional associations: the FIGO LOGIC Toolkit. AB - Health professional associations, including national associations of obstetrics and gynecology, can have a leading role in influencing and developing health policy and practice. However, in low- and middle-resource countries, the organizational capacity to facilitate this role is often insufficient. The International Federation of Gynecology and Obstetrics LOGIC (Leadership in Obstetrics and Gynaecology for Impact and Change) Initiative has been developing the capacity of national associations in Africa and Asia. Through this work, an electronic resource of materials (http://figo-toolkit.org/) has been brought together to support organizational capacity development, addressing domains such as culture, strategic planning, human resources, project and financial management, performance, external relations, membership services, and the development and revision of clinical guidelines. PMID- 23820030 TI - Physician and patient use of and attitudes toward complementary and alternative medicine in the treatment of infertility. AB - OBJECTIVE: To determine use of and attitudes toward complementary and alternative medicine (CAM) among infertility patients and subspecialty physicians. METHODS: Infertility patients were asked to complete anonymous written surveys at an academic infertility practice; members of the Society for Reproductive Endocrinology and Infertility were electronically surveyed. Both groups were assessed regarding their use of and attitudes toward CAM. RESULTS: The response rate was 32.1% (115/358) among patients and 22.6% (225/995) among physicians (P<0.05). In total, 105 (91.3%; 95% confidence interval [CI], 85.8-96.2) patients used CAM, and 84 (73.0%; 95% CI, 64.9-81.1) regarded it as beneficial to their fertility treatment. However, only 30 (26.1%; 95% CI, 18.0-34.0) patients reported CAM use to physicians, with the most common reason being that they were "never asked." Overall, 202 (89.8%; 95% CI, 85.9-93.8) physicians reported inquiring about CAM. CONCLUSION: Significant discrepancies exist between subfertile patients and physicians in attitudes toward the use of CAM. The current prevalence of CAM use among infertility patients requires greater physician attention and justifies further study on the risks and benefits of integrating CAM into the biomedical treatment of infertility. PMID- 23820031 TI - Time-specific effect of prenatal stressful life events on gestational weight gain. AB - OBJECTIVE: To investigate the time-specific effect of maternal exposure to prenatal stressful life events (SLEs) on gestational weight gain (GWG) and to determine whether pre-pregnancy body mass index (BMI) modifies the effect. METHODS: Between March and November 2008, data were collected from 1800 pregnant women who received prenatal check-ups in Hefei, China, after 32 completed weeks of gestation. Participants completed a structured interview on demographic characteristics and a checklist of SLEs during different stages of pregnancy. GWG during pregnancy was determined by self-reported pre-pregnancy weight and measured weight at delivery. RESULTS: There was a significant dose-response relationship between prenatal SLEs in the first, but not the second or third, trimester and GWG. For each 1-unit increase in SLEs during the first trimester, there was a reduction in GWG of approximately 0.497 kg (95% confidence interval, 0.176-0.817 kg). After stratification by pre-pregnancy BMI, a significant negative association between SLEs in the first trimester and GWG was observed among women with pre-pregnancy normal (beta=-0.796; 95% CI, -1.291 to -0.301) and low (beta=-1.066; 95% CI, -2.180 to -0.048) weight. CONCLUSION: The effect of prenatal SLEs on GWG depends on the timing of maternal exposure to stress and varies according to pre-pregnancy BMI. PMID- 23820032 TI - Inhibiting toxic aggregation of amyloidogenic proteins: a therapeutic strategy for protein misfolding diseases. AB - BACKGROUND: The deposition of self-assembled amyloidogenic proteins is associated with multiple diseases, including Alzheimer's disease, Parkinson's disease and type 2 diabetes mellitus. The toxic misfolding and self-assembling of amyloidogenic proteins are believed to underlie protein misfolding diseases. Novel drug candidates targeting self-assembled amyloidogenic proteins represent a potential therapeutic approach for protein misfolding diseases. SCOPE OF REVIEW: In this perspective review, we provide an overview of the recent progress in identifying inhibitors that block the aggregation of amyloidogenic proteins and the clinical applications thereof. MAJOR CONCLUSIONS: Compounds such as polyphenols, certain short peptides, and monomer- or oligomer-specific antibodies, can interfere with the self-assembly of amyloidogenic proteins, prevent the formation of oligomers, amyloid fibrils and the consequent cytotoxicity. GENERAL SIGNIFICANCE: Some inhibitors have been tested in clinical trials for treating protein misfolding diseases. Inhibitors that target the aggregation of amyloidogenic proteins bring new hope to therapy for protein misfolding diseases. PMID- 23820033 TI - Responsive systems for cell sheet detachment. AB - Cell sheet engineering has been progressing rapidly during the past few years and has emerged as a novel approach for cell based therapy. Cell sheet harvest technology enables fabrication of viable, transplantable cell sheets for various tissue engineering applications. Currently, the majority of cell sheet studies use thermo-responsive systems for cell sheet detachment. However, other responsive systems began showing their potentials for cell sheet harvest. This review provides an overview of current techniques in creating cell sheets using different types of responsive systems including thermo-responsive, electro responsive, photo-responsive, pH-responsive and magnetic systems. Their mechanism, approach, as well as applications for cell detachment have been introduced. Further development of these responsive systems will allow efficient cell sheet harvesting and patterning of cells to reconstruct complex tissue for broad clinical applications. PMID- 23820034 TI - A 3D electro-mechanical continuum model for simulating skeletal muscle contraction. AB - A thermodynamically consistent three-dimensional electro-mechanical continuum model for simulating skeletal muscle contraction is presented. Active and passive responses are accounted for by means of a decoupled strain energy function into passive and active contributions. The active force is obtained as the maximum tetanic force penalized by two functions that consider the external stimulus frequency and the overlap between actin and myosin filaments. Passive response is modelled by a transversely isotropic strain energy function. The robustness of the model is analyzed by means of finite element simulations that reproduce the one-dimensional isometric, concentric and eccentric contractions in a simplified model of a muscle. The model has also been implemented to reproduce isometric and concentric contractions on a three-dimensional finite element model of the rat tibialis anterior (TA) muscle. The finite element model was obtained from magnetic resonance imaging and the preferential directions associated with the collagen and muscular fibres were considered. The proposed model was able to reproduce the observed experimental response of the active force generated by the isolated rat TA muscle during isometric and concentric contractions. In addition, the predicted force-velocity relationship is in good agreement with experimental data reported for the fast-twitch extensor digitorum longus (e.d.l) muscle of male rats. PMID- 23820035 TI - Simulations show that a small part of variable chlorophyll a fluorescence originates in photosystem I and contributes to overall fluorescence rise. AB - Photosystem I (PSI) is generally assumed not to emit variable chlorophyll (Chl) fluorescence during light-induced Chl fluorescence rise (FLR), which occurs in a time window upto 1s under high intensity of excitation light. Therefore, the measured FLR and its changes caused by any treatment are usually interpreted by changes only in photosystem II (PSII) fluorescence. But examples can be found in the literature indicating that PSI can emit variable Chl fluorescence at least under certain conditions. As it is impossible to determine the PSI variable Chl fluorescence in vivo solely based on experiments, a way to explore a possible existence of PSI variable Chl fluorescence is to construct a mathematical model of reactions occurring inside and around PSI and to simulate a hypothetical FLR. Based on our present knowledge about the function of PSI, a detailed model describing reactions occurring inside and around PSI was constructed and used for the simulation of FLR originating exclusively in PSI. These simulations show that PSI, in principle, can emit variable Chl fluorescence. Several in silico experiments are performed showing the effect of particular reactions on the FLR. The theoretical PSI variable Chl fluorescence is also compared with theoretical variable fluorescence originating in PSII simulated on the basis of an improved model of PSII showing that variable fluorescence originating in PSI can be as high as 8-17% of overall maximal fluorescence signal originating in both photosystems. The overall FLR obtained as a sum of the simulated FLRs originating in PSI and PSII shows a peak which is similar to an H-peak measured with certain type of samples. We suggest that new experiments be planned to prove the new concept of variable PSI fluorescence. PMID- 23820036 TI - A dynamic network population model with strategic link formation governed by individual preferences. AB - Historically most evolutionary models have considered infinite populations with no structure. Recently more realistic evolutionary models have been developed using evolutionary graph theory, which considered the evolution of structured populations. The structures involved in these populations are typically fixed, however, and real populations change their structure over both long and short time periods. In this paper we consider the dynamics of such a population structure. The timescales involved are sufficiently short that no individuals are born or die, but the links between individuals are in a constant state of flux, being actively governed by the preferences of the members of the population. The process is modelled using a Markov chain over the possible structures. We find that under the specified process the population evolves to a closed class of structures, and we show a method to find the stationary distribution on this class. We also consider some special cases of interest. PMID- 23820037 TI - On the effect of circadian oscillations on biochemical cell signaling by NF kappaB. AB - We report the results of a numerical investigation of a mathematical model for NF kappaB oscillations, described by a set of ordinary nonlinear differential equations, when perturbed by a circadian oscillation. The main result is that a circadian rhythm, even when it represents a weak perturbation, enhances the signaling capabilities of NF-kappaB oscillations. This is done by turning rest states into periodic oscillations, and periodic oscillations into quasiperiodic oscillations. Strong perturbations result in complex periodic oscillations and even in chaos. Circadian rhythms would then result in a NF-kappaB dynamics that is more complex than the simple oscillations and rest states, initially reported for this model. This renders it more amenable for information coding. PMID- 23820038 TI - Assessing the prediction ability of different mathematical models for the growth of Lactobacillus plantarum under non-isothermal conditions. AB - Mathematical models taking temperature variations into account are useful in predicting microbial growth in foods, like meat products, for which Lactobacillus plantarum is a mesophilic and one of the main spoiling bacterium. The current study assessed the ability of the main primary models and their non-isothermal versions to predict L. plantarum growth under constant and variable temperature. Experimental data of microbial growth were obtained in MRS medium under isothermal conditions (4, 8, 12, 16, 20, and 30 degrees C) which were used to obtain the secondary models. The experimental data under non-isothermal conditions (periodically oscillating temperature between the plateaus 4-12, 5-15, and 20-30 degrees C) were used to validate the non-isothermal models. The bias factors indicated that all assessed models provided safe predictions of the microorganism growth at the non-isothermal conditions. Overall, despite the very good performance of the primary models (isothermal), none of the models was able to predict with accuracy the L. plantarum growth under temperature variations, mainly when the temperature range was close to refrigeration temperature. Incorporating the complex microbial adaptation mechanisms into the predictive models is a challenge to be overcome. PMID- 23820039 TI - Spatial instabilities untie the exclusion-principle constraint on species coexistence. AB - Using a spatially explicit mathematical model for water-limited vegetation we show that spatial instabilities of uniform states can lead to species coexistence under conditions where uniformly distributed species competitively exclude one another. Coexistence is made possible when water-rich patches formed by a pattern forming species provide habitats for a highly dispersive species that is a better competitor in uniform settings. PMID- 23820040 TI - Myiasis of the foot and leg caused by Chrysomya bezziana. AB - Myiasis is the infestation of the skin and mucous membranes by fly larvae. Myiasis of the lower extremity caused by Chrysomya bezziana is rarely fatal, but it can be associated with considerable morbidity. Proper wound exploration and en masse removal of all the larvae using thorough wound debridement can eradicate the infestation and promote wound healing. In the present report, the management of 4 separate cases of lower extremity infestation with fly larvae is described. PMID- 23820041 TI - The association between silica exposure and development of ANCA-associated vasculitis: systematic review and meta-analysis. AB - BACKGROUND: Crystalline silica is among the environmental exposures associated with increased risk of autoimmune diseases, including rheumatoid arthritis, systemic sclerosis and systemic lupus erythematosus. Silica exposure has also been related to the development of ANCA-associated vasculitides (AAV), but past studies appear to conflict as to the presence and magnitude of the associated risks of disease. We aimed to conduct a systematic review of the existing studies and meta-analysis of their results. METHODS: We searched EMBASE, MEDLINE and international scientific conference abstract databases for studies examining the association of silica exposure with AAV. Studies in English, French, or Spanish were included and those examining the association of silica with ANCA-positivity alone were excluded. We assessed study quality using the Newcastle-Ottawa Scale. We meta-analyzed the results using random effects models and tested for heterogeneity. We performed sensitivity and subgroup analyses, examining studies that adjusted for smoking and occupational risk factors as well as studies that analyzed by subtypes of AAV. RESULTS: We identified 158 potential manuscripts and 3 abstracts related to silica exposure and risk of AAV. 147 were excluded after abstract review and 14 underwent detailed evaluation of full manuscript/abstract. After further application of exclusion criteria, 6 studies (all cases-controls) remained. The studies had moderate heterogeneity in selection of cases and controls, exposure assessment, disease definition and controlling for potential confounders. We found an overall significant summary effect estimate of silica "ever exposure" with development of AAV (summary OR 2.56, 95% CI 1.51-4.36), with moderate heterogeneity (I(2)=48.40%). ORs were similar for studies examining only MPA (OR 3.95, CI 95% 1.89-8.24), compared to those only studying GPA (OR 3.56, CI 95% 1.85-6.82). CONCLUSION: Despite moderate heterogeneity among studies, the totality of the evidence after meta-analysis points to an association between silica exposure and risk for developing AAV. PMID- 23820042 TI - Tocilizumab in refractory Takayasu arteritis: a case series and updated literature review. AB - BACKGROUND/PURPOSE: The aim of this study is to analyze the efficacy and tolerance of tocilizumab in patients with Takayasu arteritis (TA). METHODS: We retrospectively studied patients with TA (ACR and/or Ishikawa's criteria): 5 French multicenter cases and 39 from the literature. Clinical, biological, radiological disease activity and treatment were analyzed before tocilizumab, during the follow-up and at the last available visit. RESULTS: Forty-four patients (median age 26years [3-65];) were included in the present study: 5 patients from the 3 French university hospitals and 39 cases from the literature review. Median follow-up after initiation of tocilizumab was 15months [8-33]. Clinical and biological activities significantly decreased within 3months, similarly to steroid amount (from 15mg/day [5-75] at baseline to 10mg/day [2-30] at 6months; p<0.05) and steroid-dependence rate. Even radiological activity did not significantly decrease at 6months, significant decrease of arterial FDG uptake was noted at 6months. Median duration of tocilizumab treatment was 9months [3-180]. At the last visit, tocilizumab was continued in 17/32 patients (53%), and was discontinued in the 15 remaining cases because of the remission (n=5), relapse (n=3), persistent radiological activity (n=3), cutaneous rash (n=2), severe infection (n=1) and lacking of care welfare system (n=1). No death related to tocilizumab treatment was noted. CONCLUSION: This study show the efficacy of tocilizumab in terms of clinical, biological and radiological response, as well as steroid-sparing agent. Only well-designed studies could definitely address the efficacy of tocilizumab in TA. PMID- 23820044 TI - Pitpnm1 is expressed in hair cells during development but is not required for hearing. AB - Deafness is a genetically complex disorder with many contributing genes still unknown. Here we describe the expression of Pitpnm1 in the inner ear. It is expressed in the inner hair cells of the organ of Corti from late embryonic stages until adulthood, and transiently in the outer hair cells during early postnatal stages. Despite this specific expression, Pitpnm1 null mice showed no hearing defects, possibly due to redundancy with the paralogous genes Pitpnm2 and Pitpnm3. PMID- 23820043 TI - Regulation of conduction time along axons. AB - Timely delivery of information is essential for proper functioning of the nervous system. Precise regulation of nerve conduction velocity is needed for correct exertion of motor skills, sensory integration and cognitive functions. In vertebrates, the rapid transmission of signals along nerve fibers is made possible by the myelination of axons and the resulting saltatory conduction in between nodes of Ranvier. Myelin is a specialization of glia cells and is provided by oligodendrocytes in the central nervous system. Myelination not only maximizes conduction velocity, but also provides a means to systematically regulate conduction times in the nervous system. Systematic regulation of conduction velocity along axons, and thus systematic regulation of conduction time in between neural areas, is a common occurrence in the nervous system. To date, little is understood about the mechanism that underlies systematic conduction velocity regulation and conduction time synchrony. Node assembly, internode distance (node spacing) and axon diameter - all parameters determining the speed of signal propagation along axons - are controlled by myelinating glia. Therefore, an interaction between glial cells and neurons has been suggested. This review summarizes examples of neural systems in which conduction velocity is regulated by anatomical variations along axons. While functional implications in these systems are not always clear, recent studies on the auditory system of birds and mammals present examples of conduction velocity regulation in systems with high temporal precision and a defined biological function. Together these findings suggest an active process that shapes the interaction between axons and myelinating glia to control conduction velocity along axons. Future studies involving these systems may provide further insight into how specific conduction times in the brain are established and maintained in development. Throughout the text, conduction velocity is used for the speed of signal propagation, i.e. the speed at which an action potential travels. Conduction time refers to the time it takes for a specific signal to travel from its origin to its target, i.e. neuronal cell body to axonal terminal. PMID- 23820045 TI - Future-proofing the pharmacy profession in a hypercompetitive market. AB - This paper highlights the hypercompetitive nature of the current pharmacy landscape in Australia and to suggest either a superior level of differentiation strategy or a focused differentiation strategy targeting a niche market as two viable, alternative business models to cost leadership for small, independent community pharmacies. A description of the Australian health care system is provided as well as background information on the current community pharmacy environment in Australia. The authors propose a differentiation or focused differentiation strategy based on cognitive professional services (CPS) which must be executed well and of a superior quality to competitors' services. Market research to determine the services valued by target customers and that they are willing to pay for is vital. To achieve the superior level of quality that will engender high patient satisfaction levels and loyalty, pharmacy owners and managers need to develop, maintain and clearly communicate service quality specifications to the staff delivering these services. Otherwise, there will be a proliferation of pharmacies offering the same professional services with no evident service differential. However, to sustain competitive advantage over the long-term, these smaller, independent community pharmacies will need to exploit a broad core competency base in order to be able to continuously introduce new sources of competitive advantage. With the right expertise, the authors argue that smaller, independent community pharmacies can successfully deliver CPS and sustain profitability in a hypercompetitive market. PMID- 23820046 TI - The use of a novel cardiac bioreactor system in investigating fibroblast physiology and its perspectives. AB - The physical environment of myocardium, featuring excitation-contraction coupling, constant and efficient provision of nutrient/oxygen and delicate integration of cardiomyocytes and supporting cell population (fibroblasts, endothelial cells), is one of the most complex systems in human body. Numerous studies have demonstrated the significance of physical stimulation in cardiac cell physiology, including the maintenance of contractile function in cardiomyocytes, ( 1) cell alignment and extracellular matrix secretion in fibroblasts and endothelial cells. ( 2) (,) ( 3) In effort to reconstruct the physical environment found in the cardiac niche for routine cell culture use, we have devised a bioreactor system to account for three major forms of physical stimuli, namely, cyclic stretch, electrical stimulation and fluid perfusion. ( 4). PMID- 23820047 TI - Small bowel feeding and risk of pneumonia in adult critically ill patients: a systematic review and meta-analysis of randomized trials. AB - INTRODUCTION: This systematic review and meta-analysis aimed to evaluate the effect of small bowel feeding compared with gastric feeding on the frequency of pneumonia and other patient-important outcomes in critically ill patients. METHODS: We searched EMBASE, MEDLINE, clinicaltrials.gov and personal files from 1980 to Dec 2012, and conferences and proceedings from 1993 to Dec 2012 for randomized trials of adult critically ill patients in the intensive care unit (ICU) comparing small bowel feeding to gastric feeding, and evaluating risk of pneumonia, mortality, length of ICU stay, achievement of caloric requirements, duration of mechanical ventilation, vomiting, and aspiration. Independently, in duplicate, we abstracted trial characteristics, outcomes and risk of bias. RESULTS: We included 19 trials with 1394 patients. Small bowel feeding compared to gastric feeding was associated with reduced risk of pneumonia (risk ratio [RR] 0.70; 95% CI, 0.55, 0.90; P = 0.004; I2 = 0%) and ventilator-associated pneumonia (RR 0.68; 95% CI 0.53, 0.89; P = 0.005; I2 = 0%), with no difference in mortality (RR 1.08; 95% CI 0.90, 1.29; P = 0.43; I2 = 0%), length of ICU stay (WMD -0.57; 95%CI -1.79, 0.66; P = 0.37; I2 = 0%), duration of mechanical ventilation (WMD 1.01; 95%CI -3.37, 1.35; P = 0.40; I2 = 17%), gastrointestinal bleeding (RR 0.89; 95% CI 0.56, 1.42; P = 0.64; I2 = 0%), aspiration (RR 0.92; 95% CI 0.52, 1.65; P = 0.79; I2 = 0%), and vomiting (RR 0.91; 95% CI 0.53, 1.54; P = 0.72; I2 = 57%). The overall quality of evidence was low for pneumonia outcome. CONCLUSIONS: Small bowel feeding, in comparison with gastric feeding, reduces the risk of pneumonia in critically ill patients without affecting mortality, length of ICU stay or duration of mechanical ventilation. These observations are limited by variation in pneumonia definition, imprecision, risk of bias and small sample size of individual trials. PMID- 23820048 TI - Complete sequence of a reovirus associated with necrotic focus formation in the liver and spleen of Muscovy ducklings. AB - The complete sequence of a reovirus, strain 815-12 associated with necrotic focus formation in the liver and spleen of Muscovy ducklings in China, was determined and compared with sequences of other duck-, goose-, and chicken-origin reoviruses. The 815-12 genome comprised 22,969 bp with 10 dsRNA segments ranging from 1125 bp (S4) to 3958 bp (L1), all of which (except S4) were almost identical in length to the cognate segments of other waterfowl and chicken isolates. Detailed analyses revealed that 815-12 and other waterfowl isolates contained the conserved 3'-terminal pentanucleotide sequence (UCAUC-3') of the orthoreoviruses and 5'-terminal hexanucleotide sequence (5'-GCUUUU) of avian orthoreoviruses (ARVs), and conserved functional motifs previously identified in ARV proteins. Several notable differences, including organization of the polycistronic genome segments and genomic coding assignments of the S segments, existed between viruses represented by 815-12 and the waterfowl reoviruses emerging in China in recent years; the latter was somewhat similar to chicken isolates. Pairwise sequence comparisons demonstrated extensive sequence diversity among the various waterfowl isolates and between waterfowl and chicken isolates. Phylogenetic analyses identified two genetic groups for waterfowl reoviruses, and potential genetic reassortment of segment M2 between waterfowl and chicken reoviruses and segments encoding for lambdaA, lambdaB, MUA, MUNS and sigmaA between waterfowl reoviruses. Taken together, it was suggested that common designation ARV-Wa should be used to represent ARV isolates from different waterfowl species and that the two ARV-Wa genotypes should be considered as two separate groups distinct from chicken isolates within the species Avian orthoreovirus. PMID- 23820049 TI - Equine picornaviruses: well known but poorly understood. AB - Of the many members that comprise the family Picornaviridae, only two species are known to infect horses: equine rhinitis A virus (ERAV) and equine rhinitis B virus (ERBV). Each species now occupies a distinct phylogenetic branch within the family, with the single serotype of ERAV grouping with the aphthoviruses, such as foot-and-mouth disease virus (FMDV), and the three serotypes of ERBV as the sole members of the genus Erbovirus. The high seroprevalence of equine picornaviruses in horse populations worldwide contrasts with the relatively few reports of detection of these viruses and poor understanding of their contribution to disease. This review examines the current knowledge regarding the distribution and pathogenesis of these viruses and discusses recent advances in diagnostic methods that may lead to a better understanding of the role of these viruses as contributors to equine respiratory disease. PMID- 23820050 TI - Reaction schemes, escape times and geminate recombinations in particle-based spatial simulations of biochemical reactions. AB - Modeling the spatiotemporal dynamics of biochemical reaction systems at single molecule resolution has become feasible with the increase of computing power and is applied especially to cellular signal transduction. For an association reaction the two molecules have to be in contact. Hence, a physically faithful model of the molecular interaction assumes non-overlapping molecules that interact at their surfaces (boundary scheme). For performance reasons, this model can be replaced by particles that can overlap and react when they are closer than a certain distance with a reaction probability (volume scheme). Here we present an analytical approximation for the reaction probability in the volume scheme and compare the volume- with the boundary scheme. A dissociation reaction, in contrast, creates two molecules next to each other. If the reaction is reversible, these two products can directly re-bind again, leading to an overestimation of the dimerized state in the simulation. We show how the correct recombination rate can be achieved if the products of the dissociation are placed at identical positions, but cannot react for a certain timespan. This refractory time corresponds to the completion of the diffusion-controlled dissociation of the two molecules to their contact distance r(i)+r(j) at t = tau *(r(i)+r(j))2/(D(i)+D(j) with tau = 1/10 for molecules with radii r(i) and r(j) and diffusion coefficients D(i) and D(j), respectively. PMID- 23820051 TI - The efficacy of agomelatine in previously-treated depressed patients. AB - OBJECTIVE: Post-hoc analysis of two randomized controlled trials with agomelatine was undertaken to compare data on pretreated versus untreated patients with major depressive disorder. METHOD: Selected trials were Olie and Kasper (2007), a placebo-controlled trial, and Kasper et al. (2010), a randomized, double-blind comparison with sertraline. RESULTS: A total of 40% and 57.7% of patients had been pretreated with antidepressants in the placebo-controlled trial and sertraline-controlled trial, respectively. In the previously-treated patients in the placebo-controlled study, the mean decrease in the total score on the HAM-D17 over 6 weeks was significantly greater with agomelatine than placebo (delta=4.43, P=0.005) and 67.5% of patients were responders. In the previously-treated patients of the sertraline-controlled study, the improvement on the HAM-D17 total score remained numerically higher with agomelatine (delta=1.63, P=0.124), with 55.2% responders. In both studies, agomelatine was well tolerated. CONCLUSION: Data from the subset of previously treated depressed patients, who can be considered more difficult to treat, indicate that agomelatine, due to its different mode of action, demonstrated antidepressant efficacy, and favorable side effect profile-with proven benefits in first-line treatment-is also an effective candidate for patients with major depressive disorder previously treated with other antidepressants. PMID- 23820052 TI - Comparable seizure characteristics in magnetic seizure therapy and electroconvulsive therapy for major depression. AB - Electroconvulsive therapy (ECT) is highly effective for treatment-resistant depression (TRD); however, its use for less severe forms of depression is somewhat limited by a lack of control over current spreading to medial temporal lobe memory structures, resulting in various cognitive side effects. In contrast, magnetic seizure therapy (MST), which uses high frequency repetitive transcranial magnetic stimulation (rTMS) for local seizure induction, has been associated with reduced cognitive side effects. To assess whether different characteristics of seizures induced by both methods are responsible for the differences in neuropsychological side-effect profile, we studied seven TRD-patients undergoing both MST and ECT in an open-label, within subject, controlled crossover pilot study. Comparison parameters included seizure-related ictal characteristics, including motor activity, electromyogram (EMG), electroencephalogram (EEG), and postictal recovery and reorientation times.Our results showed no differences in motor activity or EMG and EEG characteristics, thus implicating similar electrophysiological processes in seizure induction with MST and ECT. In line with previous studies, we observed shorter postictal recovery and reorientation times following MST.The ictal characteristics of induced seizures were found similar with ECT and MST suggesting that the more focal seizure induction associated with MST may account for the more beneficial neuropsychological side effect profile of MST. PMID- 23820053 TI - Difference between urethral circumference and artificial urinary sphincter cuff size, and its effect on postoperative incontinence. AB - PURPOSE: We assessed whether a difference between intraoperative urethral circumference and artificial urinary sphincter cuff size affects postoperative outcomes. MATERIALS AND METHODS: We evaluated the medical records of 87 males who underwent implantation of an artificial urinary sphincter between January 2006 and May 2010. A validated questionnaire was completed by 59 patients for long term followup. The difference between urethral circumference and artificial urinary sphincter cuff size was calculated. Incontinence was recorded as daily pad use. The primary outcome variable was the postoperative decrease in incontinence. Multivariable linear regression was used to model the effect on postoperative incontinence of the difference between urethral circumference and cuff size. RESULTS: Mean long-term followup was 4.2 years. Median preoperative incontinence was 8 pads per day and median abdominal leak point pressure was 50 cm H2O. Median urethral circumference was 38 mm and the median difference between urethral circumference and artificial urinary sphincter cuff size was 2.5 mm. Median postoperative incontinence was 1 pad per day. A 1 mm increase in the difference between urethral circumference and cuff size resulted in a 1.6% increase in incontinence by 4.5 months postoperatively (95% CI -3.1-6.2, p = 0.487). Paradoxically, each 1 mm increase improved postoperative continence at long-term followup by 29% (95% CI -15-56, p = 0.162). CONCLUSIONS: At 4.5-month followup there was no statistical difference in pad use or patient satisfaction when the difference between urethral circumference and artificial urinary sphincter cuff size was less than 4 mm vs 4 mm or greater. However, at long-term followup the 4 mm or greater group reported statistically significantly better continence and satisfaction than the less than 4 mm group. This study does not support efforts to improve continence by minimizing cuff size but rather suggests that modestly up-sizing the cuff may produce improved long-term outcomes. PMID- 23820054 TI - Are patients at nutritional risk more prone to complications after major urological surgery? AB - PURPOSE: The nutritional risk score is a recommended screening tool for malnutrition. While a nutritional risk score of 3 or greater predicts adverse outcomes after digestive surgery, to our knowledge its predictive value for morbidity after urological interventions is unknown. We determined whether urological patients at nutritional risk are at higher risk for complications after major surgery than patients not at nutritional risk. MATERIALS AND METHODS: We performed a prospective observational study in consecutive patients undergoing major surgery. A priori sample calculation resulted in a study cohort of 220 patients. Interim analysis was planned after 110 patients. The nutritional risk score was assessed preoperatively by a specialized study nurse. Nutritional care was standardized in all patients. Postoperative complications were defined previously using the standardized Dindo-Clavien classification. The primary end point was 30-day morbidity. Univariate and multivariate analysis was performed to identify predictors of complications. RESULTS: The study was discontinued due to significant results after interim analysis. A total of 125 patients were included in analysis from June 2011 to June 2012 and 15 were excluded because of incomplete data. Of 51 patients at nutritional risk 38 (74%) presented with at least 1 complication compared to 28 of 59 controls (47%). Patients at nutritional risk were at threefold risk for complications on univariate and multivariate analysis (OR 3.3, 95% CI 1.3-8.0). Cystectomy was the only other predictor of morbidity (OR 10, 95% CI 2-48). CONCLUSIONS: Patients at nutritional risk are more prone to complications after major urological procedures. Whether this increased morbidity can be reversed by perioperative nutritional support should be studied. PMID- 23820055 TI - Extraprostatic extension into periprostatic fat is a more important determinant of prostate cancer recurrence than an invasive phenotype. AB - PURPOSE: Although micrometastasis development correlates closely with the depth of invasion of many tumor types, it is unclear whether invasion into but not through the prostatic pseudocapsule has a negative impact on prognosis, similar to extraprostatic extension. We defined the impact of pseudocapsular invasion on the risk of post-prostatectomy biochemical recurrence. MATERIALS AND METHODS: Patients with pT2-3a prostate cancer were identified from a prospectively recorded database. Those with pT2 disease were categorized according to pseudocapsular invasion presence or absence. The impact of pseudocapsular invasion on biochemical recurrence was determined by univariable and multivariable Cox regression analysis. RESULTS: In a cohort of 1,338 patients we identified 595 with organ confined cancer positive for pseudocapsular invasion. Compared to tumors without evidence of invasion, pseudocapsular invasion was positively associated with higher Gleason grade and tumor volume (1.2 vs 1.9 cc, each p<0.001). On univariable analysis there was no difference in biochemical recurrence-free survival between patients with vs without pseudocapsular invasion, although those with extraprostatic extension had significantly lower biochemical recurrence-free survival (p<0.001). This was confirmed on multivariable analysis, which revealed that extraprostatic extension was a significant independent predictor of biochemical recurrence (HR 1.53, p=0.018). The presence of pseudocapsular invasion had no effect (HR 0.81, p=0.33). CONCLUSIONS: Pseudocapsular invasion is not a pathological feature associated with an adverse outcome after prostatectomy. Thus, the depth of tumor invasion is not a continuum of risk and access to periprostatic adipose tissue is a more important determinant of disease behavior than an invasive phenotype. PMID- 23820056 TI - HDAC dependent transcriptional repression of Bmp-7 potentiates TGF-beta mediated renal fibrosis in obstructive uropathy. AB - PURPOSE: Recombinant BMP-7 inhibits the pathogenesis of renal injury in response to various stimuli. However, little is known about the molecular regulation of endogenous BMP-7 and its renal protective functions. We examined transcriptional regulation of Bmp-7 and its role in the pathogenesis of renal injury resulting from urinary tract dysfunction. MATERIALS AND METHODS: Obstruction induced renal injury was modeled in vivo in mice by unilateral ureteral obstruction and in vitro in primary kidney cells by treatment with transforming growth factor-beta, a profibrotic cytokine that is increased in the obstructed kidney. RESULTS: Unilateral ureteral obstruction resulted in the loss of BMP-7 expression in conjunction with histone deacetylation and transcriptional repression of the Bmp 7 promoter. The histone deacetylase inhibitor trichostatin A stimulated Bmp-7 expression in primary kidney cells. Trichostatin A also inhibited the expression of transforming growth factor-beta dependent profibrotic genes in a manner that depended on BMP receptor signaling. These findings extended to the obstructed kidney in vivo, in which trichostatin A treatment restored the expression of Bmp 7 along with BMP-7 mediated suppression of transforming growth factor-beta dependent signaling pathways. Finally, trichostatin A stimulated activation of the BMP-7 pathway the ameliorated obstruction induced renal injury by preventing disruption of the renal architecture and the development of renal fibrosis. CONCLUSIONS: These findings show that histone deacetylase dependent repression of Bmp-7 transcription is a critical event during the pathogenesis of renal injury in obstructive uropathy. Accordingly, treatment with histone deacetylase inhibitors represents a potentially effective strategy to restore BMP-7 expression and its renal protective functions during treatment of obstructive uropathy. PMID- 23820057 TI - Poor quality of life in patients with urethral stricture treated with intermittent self-dilation. AB - PURPOSE: We assessed patient perceptions of regular intermittent self-dilation in men with urethral stricture. MATERIALS AND METHODS: We constructed and distributed a visual analog questionnaire to evaluate intermittent self-dilation via catheterization by men referred for urethral stricture management at a total of 4 institutions. Items assessed included patient duration, frequency, difficulty and pain associated with intermittent self-dilation as well as interference of intermittent self-dilation with daily activity. The primary outcome was patient perceived quality of life. Multivariate analysis was performed to assess factors that affected this outcome. RESULTS: Included in the study were 85 patients with a median age of 68 years, a median of 3.0 years on intermittent self-dilation and a median frequency of 1 dilation per day. On a 1 to 10 scale the median intermittent self-dilation difficulty was 5.0 +/- 2.7, the median pain score was 3.0 +/- 2.7 and median interference with daily life was 2.0 +/- 1.3. Overall quality of life in patients with stricture was poor (median score 7.0 +/- 2.6 with poor quality of life defined as 7 or greater). On univariate analysis younger age (p <0.01), interference (p = 0.03), pain (p <0.01) and difficulty performing intermittent self-dilation (p = 0.03) correlated with poor quality of life in a statistically significant manner. On multivariate analysis only difficulty catheterizing (p <0.01) and younger age (p = 0.05) were statistically significant predictors. Patients with stricture involving the posterior urethra had a statistically significant increase in difficulty and decrease in quality of life (each p = 0.04). CONCLUSIONS: Most patients with urethral stricture who are on intermittent self-dilation rate difficulty and pain as moderate, and inconvenience as low but report poor quality of life. PMID- 23820058 TI - Development and characteristics of preclinical experimental models for the research of rare neuroendocrine bladder cancer. AB - PURPOSE: For rare cancers such as neuroendocrine bladder cancer treatment options are limited due partly to the lack of preclinical models. Techniques to amplify rare primary neuroendocrine bladder cancer cells could provide novel tools for the discovery of drug and diagnostic targets. We developed preclinical experimental models for neuroendocrine bladder cancer. MATERIALS AND METHODS: Fresh tumor tissue from 2 patients with neuroendocrine bladder cancer was used to establish in vitro and in vivo models. We analyzed additional archived tissues in the National Center of Tumor Diseases tissue bank from patients with neuroendocrine bladder cancer. Primary tumor samples were collected during radical cystectomy. PHA-665752 was used to inhibit MET in animal models and cell cultures. The expression of markers and drug targets in neuroendocrine bladder cancer was determined by flow cytometry. The growth of neuroendocrine bladder cancer in vitro was determined by counting live cells. Tumor growth in mice was assessed by measuring tumor volume. Groups were compared using the nonparametric Kruskal-Wallis test. RESULTS: Xenograft models and serum-free cultures of neuroendocrine bladder cancer cells allowed screening for cell surface markers and drug targets. We found expression of the HGF receptor MET in neuroendocrine bladder cancer cultures, xenograft models and primary patient sections. The growth of neuroendocrine bladder cancer spheroids in vitro depended critically on HGF. Treatment of neuroendocrine bladder cancer bearing mice with a MET inhibitor significantly decreased tumor growth compared to that in control treated mice. CONCLUSIONS: Neuroendocrine bladder cancer xenografts and serum-free cultures provided suitable models in which to identify diagnostic markers and therapeutic targets. Using the models, we noted HGF dependent growth of human neuroendocrine bladder cancer and identified MET as a new treatment target for neuroendocrine bladder cancer. PMID- 23820059 TI - Predictors of pathological progression among men with localized prostate cancer undergoing active surveillance: a sub-analysis of the REDEEM study. AB - PURPOSE: We identify risk factors for pathological progression among men on active surveillance in the REDEEM (REduction by Dutasteride of clinical progression Events in Expectant Management trial). MATERIALS AND METHODS: REDEEM was a 3-year, randomized, double-blind study of patients in 65 North American academic centers. Eligible men were 48 to 82 years old, with low risk prostate cancer (T1c-T2a), Gleason score 6 or less, 3 or fewer cores positive, tumor less than 50% of any 1 core, serum prostate specific antigen 11 ng/ml or less, life expectancy greater than 5 years and undergoing active surveillance. Entry biopsies (10 cores or more) were required. The analysis included 276 patients with 1 biopsy or more after the start of study treatment. Patients received dutasteride 0.5 mg per day or placebo for 3 years. Time to pathological progression (volume [4 or more cores positive or 50% or greater of 1 core] or grade progression [Gleason score 7 or greater]) in a post-baseline biopsy (not preceded by therapeutic intervention), and baseline variables were analyzed using a Cox proportional hazard model. RESULTS: In total 94 of 276 patients with a post baseline biopsy (34.1%) had pathological progression, 54 (19.6%) had volume progression only, 19 (6.9%) had grade progression only and 21 (7.6%) had both types of progression. Older age (HR 1.05, 95% CI 1.01-1.08, p=0.009) and higher prostate specific antigen density (HR 1.06, 95% CI 1.04-1.09, p<0.001) were associated with pathological progression. Post-baseline prostate specific antigen identified grade, but not volume progression in patients treated with placebo and dutasteride. CONCLUSIONS: Older age and higher prostate specific antigen density were independent predictors of pathological progression. Post-baseline measurements as predictors of pathological progression could not be established. Further studies are needed to evaluate the role of dutasteride and establish better markers of pathological progression in active surveillance. PMID- 23820060 TI - Urinary phytoestrogen levels related to idiopathic male infertility in Chinese men. AB - Phytoestrogens (PEs) are naturally occurring chemical constituents of certain plants. The internal PE exposures, mainly from diet, vary among different populations and in different regions due to various eating habits. To investigate the potential relationship between urinary PE levels and idiopathic male infertility and semen quality in Chinese adult males, 608 idiopathic infertile men and 469 fertile controls were recruited by eligibility screening procedures. Individual exposure to PEs was measured using UPLC-MS/MS as spot urinary concentrations of 6 PEs (daidzein, DAI; equol, EQU; genistein, GEN; naringenin, NAR; coumestrol, COU; and secoisolariciresinol, SEC), which were adjusted with urinary creatinine (CR). Semen quality was assessed by sperm concentration, number per ejaculum and motility. We found that exposures to DAI, GEN and SEC were significantly associated with idiopathic male infertility (P-value for trend=0.036; 0.002; and 0.0001, respectively), while these exposures had stronger association with infertile subjects with at least one abnormal semen parameter than those with all normal semen parameters. Exposures to DAI, GEN and SEC were also related to idiopathic male infertility with abnormal sperm concentration, number per ejaculum and motility (P-value for trend<0.05), while these exposures had stronger association with the infertile men with abnormal sperm number per ejaculum. These findings provide the evidence that PE exposures are related to male reproductive function and raise a public health concern because that exposure to PEs is ubiquitous in China. PMID- 23820061 TI - Modeling of experts' divergent prior beliefs for a sequential phase III clinical trial. AB - BACKGROUND: There have been few Bayesian analyses of phase III sequential clinical trials that model divergent expert opinions in a single distribution. PURPOSE: We used modeling of experts' opinions to perform additional Bayesian analyses of a randomized clinical trial (designed as a sequential trial), particularly when a bimodal shape is observed. We provide an illustrative example based on a randomized trial conducted in patients aged between 65 and 75 years with multiple myeloma as the case study. METHODS: The main endpoint of the trial was overall survival (OS). Prior distribution of the log hazard ratio of death in the experimental versus the control arm ( $$?theta $$ ) was constructed based on elicitation of experts using a mixture of normal distributions estimated by the Expectation-Maximisation (EM) algorithm. At each interim and terminal analysis, the posterior probability of $$?theta $$ and the resulting increases in median OS in the experimental arm compared to the control were computed. The results were compared to results obtained using either skeptical, enthusiastic, or a mixture of those priors. Finally, we discuss our results in light of the frequentist approach originally designed for the trial. RESULTS: A total of 39 experts reported their opinion on the median OS in the experimental arm compared to the median control survival of 30 months. The resulting pooled distribution of the log hazard ratios exhibited a bimodal profile. When the prior mixture of the normal distribution was fitted to the data sets from the experts, 44% of the experts' opinions were optimistic and 56% were doubtful. At the final analysis, the percentage of doubting experts dropped to 18%. This corresponded to a posterior probability of an improved OS in the experimental arm compared to the control arm of at least 0.98, regardless of the prior. These findings are in agreement with the original conclusion of the trial regarding the beneficial effect of the experimental treatment in this population. LIMITATIONS: Only 39 experts among the 120 questioned physicians responded to the inquiry. Our approach was hybrid because the prior mixture was estimated using the EM algorithm, and a full Bayesian approach may have been used. CONCLUSIONS: Bayesian inference allows the quantification of increased survival in terms of probability distributions and provides investigators with an additional tool in the analysis of a randomized phase III clinical trial. Using a mixture of densities appears to be a promising strategy for incorporating the bimodal profile of prior opinion, with actualization of the two components along the trial as an illustration of the evolution of opinions as data are accumulated. PMID- 23820062 TI - Implication of minimal extrathyroidal extension as a prognostic factor in papillary thyroid carcinoma. AB - PURPOSE: Extrathyroidal extension (ETE) of papillary thyroid carcinoma (PTC) is a risk factor for tumor recurrence. By TNM Classification (7th edition), differentiated thyroid carcinoma with ETE is designated T3 (minimal invasion), T4a (extended invasion), or T4b (more extensive unresectable invasion), according to the degree of tumor involvement. We subsequently focused our investigation on minimal ETE (MEE), analyzing the clinicopathologic characteristics, recurrence rate, and recurrence-free survival (RFS) in this setting. METHODS: A retrospective study was conducted, based on 332 patients undergoing thyroidectomy for PTC between January 2005 and December 2006. RESULTS: The study population was stratified into two groups: PTC with MEE (103/332; 31.0%) and PTC without MEE (229/332; 69.0%). In patients with PTC, MEE correlated with gender, tumor size, multifocality, lymph node (LN) metastasis, underlying Hashimoto's thyroiditis, and the nature of the surgery. However, no significant intergroup differences were evident with respect to age, recurrence rate, and LN metastasis. In multivariate analysis, LN metastasis (odds ratio = 2.273; 95% confidence interval, 1.280-4.037) was recognized as an independent correlate of mETE (p = 0.005). However, recurrence-free survival did not differ significantly between the groups (p = 0.153), even when further stratified by the presence or absence of LN metastasis. CONCLUSION: In patients with PTC, MEE does not impact RFS. Thus, appropriate surgical intervention and postoperative follow up are mandatory in PTC, regardless of its extent. PMID- 23820063 TI - Prognostic effect of sarcomatoid dedifferentiation in patients with surgically treated renal cell carcinoma: a matched-pair analysis. AB - BACKGROUND: The aim of this study was to assess the prognostic relevance of SD in patients with RCC. PATIENTS AND METHODS: Among 8126 RCC patients surgically treated at 12 academic centers (members of the Collaborative Research on Renal Neoplasms Association [CORONA] project), 316 patients (3.9%) had SD with sarcomatoid areas comprising at least 10% of the tumor tissue. After propensity score-based matched-pair analysis, 281 with and 281 matched RCC patients without SD remained available for direct comparison of cancer-specific survival (CSS). Median follow-up was 36.5 months (interquartile range, 15-82). Uni- and multivariable Cox proportional hazards regression analyses were performed to assess the prognostic value of parameters. RESULTS: In univariable analysis, there was no difference in CSS between patients with or without SD (1 and 5 years CSS, 79% vs. 83% and 59% vs. 64%, respectively; hazard ratio, 1.21; P = .16). Multivariable analysis in patients with SD identified metastatic dissemination at the time of surgery, pT-stage, nodal status, and tumor size as independent predictors of CSS. This study was limited by its retrospective multicenter design and lack of central histopathological review. CONCLUSION: Sarcomatoid dedifferentiation was not an independent predictor of CSS in surgically treated RCC patients in the present matched-pair series. Because pathology reports form the basis on which study specimens are selected for further studies, which are clearly needed to advance our understanding of the prognostic value of SD in RCC, it is imperative that pathologists reliably report on absence or presence and the estimated percentage of a coexisting sarcomatoid component. PMID- 23820065 TI - A better understanding of lymphatic drainage of the prostate with modern imaging and surgical techniques. AB - PURPOSE: In prostate cancer, the spread of cancer to the lymph nodes is often determined by sampling lymph nodes from the obturator region. Historical findings from this area are often used as the basis for calculating the risk of lymph node metastasis in patients with prostate cancer. Therefore, it is of utmost importance to determine whether this sampling is a realistic representation of actual risk of lymphatic spread. This is important for risk assessment as well as for targeting lymphatics in treatment. MATERIALS AND METHODS: We attempted to reconcile historical anatomic descriptions with contemporary imaging and surgical experience to try to obtain an accurate description of the lymphatic drainage of the prostate. RESULTS AND CONCLUSIONS: Although obturator lymph nodes are clearly one of the possible sites of spread of prostate cancer, their sampling was never intended to be a definitive description of the routes of lymphatic cancer or the absolute incidence of lymph node metastasis. There are multiple other lymphatic areas at risk, with drainage primarily from the periprostatic area to the deep branches of the internal iliac lymphatics. The subsequent spread is to the perirectal and lower sacral vessel lymphatics, the proximal external iliac, the obturator, the upper sacral, common iliacs, and, ultimately, the para-aortic lymphatics. Describing the risk of lymphatic spread of prostate cancer based on obturator lymph node dissection alone is not totally accurate and probably underestimates the actual risk by 50% or more. A better understanding of the routes of drainage should make therapy that targets the lymphatics more effective. PMID- 23820064 TI - Paraneoplastic palmar fasciitis and polyarthritis syndrome in a patient with advanced prostate cancer. PMID- 23820067 TI - Electronic communication and text messaging among nephrology providers. PMID- 23820066 TI - Evaluation of the Oxford Classification of IgA nephropathy: a systematic review and meta-analysis. AB - BACKGROUND: The Oxford Classification of the pathology of immunoglobulin A (IgA) nephropathy, developed in 2009, is highly predictive of renal prognosis. It has been validated in different populations, but the results remain inconsistent. STUDY DESIGN: Systematic review and meta-analysis. SETTING & POPULATION: Patients with biopsy-proven primary IgA nephropathy. SELECTION CRITERIA FOR STUDIES: Studies assessing the Oxford Classification of IgA nephropathy published between January 2009 and December 2012 were included following systematic searching of the MEDLINE and EMBASE databases. PREDICTOR: 4 pathologic lesions of the Oxford Classification: mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T). OUTCOME: Kidney failure defined as doubled serum creatinine level, 50% decline in estimated glomerular filtration rate, or end-stage kidney disease. RESULTS: 16 retrospective cohort studies with 3,893 patients and 570 kidney failure events were included. In a multivariate model, HRs for kidney failure were 0.6 (95% CI, 0.5-0.8; P < 0.001), 1.8 (95% CI, 1.4-2.4; P < 0.001), and 3.2 (95% CI, 1.8-5.6; P < 0.001) for scores of M0 (mesangial hypercellularity score <=0.5), S1 (presence of segmental glomerulosclerosis), and T1/2 (>25% tubular atrophy/interstitial fibrosis), respectively, without evidence of heterogeneity. Pooled results showed that E lesions were not associated with kidney failure (HR, 1.4; 95% CI, 0.9-2.0; P = 0.1), with evidence of heterogeneity (I(2) = 54.1%; P = 0.01). Crescent (C) lesions were associated with kidney failure (HR, 2.3; 95% CI, 1.6-3.4; P < 0.001), with no evidence of heterogeneity (I(2) = 14.7%; P = 0.3). LIMITATIONS: All studies were retrospective. This was not an individual-patient data meta-analysis. CONCLUSIONS: This study suggests that M, S, T, and C lesions, but not E lesions, are associated strongly with progression to kidney failure and thus should be included in the Oxford Classification system. PMID- 23820068 TI - The neurobiology of X-linked intellectual disability. AB - X-linked intellectual disability (XLID) affects 1% to 3% of the population. XLID subsumes several heterogeneous conditions, all of which are marked by cognitive impairment and reduced adaptive skills. XLID arises from mutations on the X chromosome; to date, 102 XLID genes have been identified. The proteins encoded by XLID genes are involved in higher brain functions, such as cognition, learning and memory, and their molecular role is the subject of intense investigation. Here, we review recent findings concerning a representative group of XLID proteins: the fragile X mental retardation protein; methyl-CpG-binding protein 2 and cyclin-dependent kinase-like 5 proteins, which are involved in Rett syndrome; the intracellular signaling molecules of the Rho guanosine triphosphatases family; and the class of cell adhesion molecules. We discuss how XLID gene mutations affect the structure and function of synapses. PMID- 23820069 TI - Morphology, morphometry and ultrastructure of captive six-banded armadillo (Euphractus sexcinctus) sperm. AB - We analyzed the sperm characteristics of captive six-banded armadillos (Euphractus sexcinctus), by the assessment of sperm morphology, morphometry, and ultrastructure. In general, armadillo's ejaculates present more than 80% of sperm within the range considered normal for sperm morphology currently accepted for other mammals. Coiled tails (3.9%) and detached heads (2.8%) were the defects most frequently verified. The morphometric analysis revealed that the total length of six-banded armadillo sperm is 77.6+/-1.2MUm, and the length of the tail is 64.7+/-1.1MUm on average. They also present a big head that corresponds to 16.6% of the entire sperm. Through transmission electron microscopy, we identified the presence of electron lucent points into the nucleus and the presence of about 45 mitochondria spirals in the mitochondrial sheath midpiece as a peculiarity of the six-banded armadillo sperm. PMID- 23820070 TI - Associations of TCF12, CTNNAL1 and WNT10B gene polymorphisms with litter size in pigs. AB - In previous research, several WNT signaling pathway genes including transcription factor 12 (TCF12), catenin alpha-like protein 1 (CTNNAL1) and wingless-type MMTV integration site family, member 10B (WNT10B) were differentially expressed in PMSG-hCG stimulated preovulatory ovarian follicles of Large White and Chinese Taihu sows. In the present research, these three genes were selected as the candidate genes for litter size traits in pigs. Four mutations (TCF12 c.-201+65 G>A, TCF12 c.-200-300 G>A, CTNNAL1 c.1878 G>C and WNT10B c.*12 C>T) were detected in eleven pig populations, and results indicated CTNNAL1 c.1878 G and WNT10B c.*12 C were the major alleles in all tested pig populations, while TCF12 c. 201+65 A and TCF12 c.-200-300 A were the major alleles in several Chinese native pig breeds. Association analysis of four mutations with litter size in Large White and DIV pigs showed that both the signficant differences of total number born (TNB) and number born alive (NBA) among three genotypes and the significance of additive effects appeared at TCF12 c.-200-300 G>A and CTNNAL1 c.1878 G>C loci, suggesting these two mutations might be reliable markers for pig selection and breeding. PMID- 23820071 TI - Quantitative determination of optical trapping strength and viscoelastic moduli inside living cells. AB - With the success of in vitro single-molecule force measurements obtained in recent years, the next step is to perform quantitative force measurements inside a living cell. Optical traps have proven excellent tools for manipulation, also in vivo, where they can be essentially non-invasive under correct wavelength and exposure conditions. It is a pre-requisite for in vivo quantitative force measurements that a precise and reliable force calibration of the tweezers is performed. There are well-established calibration protocols in purely viscous environments; however, as the cellular cytoplasm is viscoelastic, it would be incorrect to use a calibration procedure relying on a viscous environment. Here we demonstrate a method to perform a correct force calibration inside a living cell. This method (theoretically proposed in Fischer and Berg-Sorensen (2007 J. Opt. A: Pure Appl. Opt. 9 S239)) takes into account the viscoelastic properties of the cytoplasm and relies on a combination of active and passive recordings of the motion of the cytoplasmic object of interest. The calibration procedure allows us to extract absolute values for the viscoelastic moduli of the living cell cytoplasm as well as the force constant describing the optical trap, thus paving the way for quantitative force measurements inside the living cell. Here, we determine both the spring constant of the optical trap and the elastic contribution from the cytoplasm, influencing the motion of naturally occurring tracer particles. The viscoelastic moduli that we find are of the same order of magnitude as moduli found in other cell types by alternative methods. PMID- 23820072 TI - Stable colloidal dispersion of functionalized reduced graphene oxide in aqueous medium for transparent conductive film. AB - We prepared stable colloidal suspension graphene in aqueous medium by surface modification of graphene with 4-benzenediazonium sulfonate. The sulfonate group on graphene surface interacts with water, exhibits well dispersibility and which prevents the aggregation even at neutral pH. This dispersion shows stability for three months and facile to produce films. Using such a modified graphene dispersion, transparent conductive film (TCF) has been fabricated on glass substrate by spin coating method. At appropriate concentration, the film exhibits an excellent optoelectrical property with resistivity of 1.1 kOmega with the transparency of 89% at the wavelength of 550 nm. Further, we also demonstrated the mechanical, thermal, and optoelectrical properties of prepared films. PMID- 23820073 TI - Analysis of developed transition road safety barrier systems. AB - Road safety barriers protect vehicles from roadside hazards by redirecting errant vehicles in a safe manner as well as providing high levels of safety during and after impact. This paper focused on transition safety barrier systems which were located at the point of attachment between a bridge and roadside barriers. The aim of this study was to provide an overview of the behavior of transition systems located at upstream bridge rail with different designs and performance levels. Design factors such as occupant risk and vehicle trajectory for different systems were collected and compared. To achieve this aim a comprehensive database was developed using previous studies. The comparison showed that Test 3-21, which is conducted by impacting a pickup truck with speed of 100 km/h and angle of 25 degrees to transition system, was the most severe test. Occupant impact velocity and ridedown acceleration for heavy vehicles were lower than the amounts for passenger cars and pickup trucks, and in most cases higher occupant lateral impact ridedown acceleration was observed on vehicles subjected to higher levels of damage. The best transition system was selected to give optimum performance which reduced occupant risk factors using the similar crashes in accordance with Test 3-21. PMID- 23820074 TI - Biodistribution of the GATA-3-specific DNAzyme hgd40 after inhalative exposure in mice, rats and dogs. AB - The DNAzyme hgd40 was shown to effectively reduce expression of the transcription factor GATA-3 RNA which plays an important role in the regulation of Th2-mediated immune mechanisms such as in allergic bronchial asthma. However, uptake, biodistribution and pharmacokinetics of hgd40 have not been investigated yet. We examined local and systemic distribution of hgd40 in naive mice and mice suffering from experimental asthma. Furthermore, we evaluated the pharmacokinetics as a function of dose following single and repeated administration in rats and dogs. Using intranasal administration of fluorescently labeled hgd40 we demonstrated that the DNAzyme was evenly distributed in inflamed asthmatic mouse lungs within minutes after single dose application. Systemic distribution was investigated in mice using radioactive labeled hgd40. After intratracheal application, highest amounts of hgd40 were detected in the lungs. High amounts were also detected in the bladder indicating urinary excretion as a major elimination pathway. In serum, low systemic hgd40 levels were detected already at 5 min post application (p.a.), subsequently decreasing over time to non-detectable levels at 2h p.a. As revealed by Single Photon Emission Computed Tomography, trace amounts of hgd40 were detectable in lungs up to 7 days p.a. Also in the toxicologically relevant rats and dogs, hgd40 was detectable in blood only shortly after inhalative application. The plasma pharmacokinetic profile was dose and time dependent. Repeated administration did not lead to drug accumulation in plasma of dogs and rats. These pharmacokinetic of hgd40 provide guidance for clinical development, and support an infrequent and convenient dose administration regimen. PMID- 23820075 TI - Sublethal effects of the flame retardant intermediate hexachlorocyclopentadiene (HCCPD) on the gene transcription and protein activity of Daphnia magna. AB - Hexachlorocyclopentadiene (HCCPD) is a chlorinated chemical of high production volume used as an intermediate in the production of flame retardants. HCCPD may be released to the environment during production, use, and as a result of product degradation. The objectives of this study were to evaluate sublethal effects of HCCPD exposure to Daphnia magna at environmentally relevant concentrations (0.0138-13.8 MUg/L) using genomic tools (microarray and qPCR), enzyme activities, and life-history endpoints (survival, reproduction, and growth). In chronic exposures, no differences were observed in life-history endpoints (survival, time of first brood, time of first molt, molt frequency, number of neonates, and body length) between exposed organisms and controls. Microarray analyses indicated significant differential genomic transcription for 46 genes (p-value <= 0.05 and fold-change>2). Five identified genes were related to metabolic functions. Enzyme activities of alpha-amylase and trypsin, selected based on transcriptional responses, were evaluated in D. magna. Although trypsin activity was similar between treatments and controls, the activity of alpha-amylase significantly decreased with increasing HCCPD concentrations. On the chemical level, instability of HCCPD was observed in spiked culture media, most probably due to photolysis and biodegradation. HCCPD was not detected in surface water samples collected upstream and at the point of discharge of a major wastewater treatment plant effluent. Environmentally, rapid degradation of HCCPD could be outdone by its continuous release into aquatic ecosystems in specific areas of concern (e.g., vicinity of industries and hazardous sites). Toxicity results from this study highlight the use of genomics in the identification of biomarkers and help advance the science, and potential use, of multi-level biological approaches for environmental risk assessment. PMID- 23820076 TI - Vascular injury involves the overoxidation of peroxiredoxin type II and is recovered by the peroxiredoxin activity mimetic that induces reendothelialization. AB - BACKGROUND: Typical 2-Cys peroxiredoxin (Prx) is inactivated by overoxidation of the peroxidatic cysteine residue under oxidative stress. However, the significance in the context of vascular disease is unknown. METHODS AND RESULTS: Immunohistochemical analyses revealed that 2-Cys Prxs, particularly Prx type II, are heavily overoxidized in balloon-injured rodent carotid vessels and in human atherosclerotic lesions. Consistent with this observation, the selective depletion of Prx II exacerbated neointimal hyperplasia in injured carotid vessels. We also found that the epipolythiodioxopiperazine class of fungal metabolites exhibited an enzyme-like activity mimicking 2-Cys Prx peroxidase and manifestly eliminated the intracellular H2O2 in the vascular cells. Functionally, the epipolythiodioxopiperazines reciprocally regulated the platelet-derived growth factor receptor-beta- and vascular endothelial growth factor receptor mediated signaling in these vascular cells by replacing Prx II. As a consequence, the epipolythiodioxopiperazines inhibited the proliferative and migratory activities of smooth muscle cells but promoted those of endothelial cells in vitro. Moreover, administration of the epipolythiodioxopiperazines to the injured carotid vessels resulted in a successful recovery by inhibiting neointimal hyperplasia without causing cytotoxicity and simultaneously inducing reendothelialization. CONCLUSIONS: This study reveals for the first time the involvement of the 2-Cys Prx overoxidation and thus the therapeutic use of their activity mimetic in vascular injuries like stenting. PMID- 23820078 TI - Fibrin glue for closure of conjunctival incision in strabismus surgery: a report by the american academy of ophthalmology. AB - OBJECTIVE: To evaluate the severity of postoperative inflammation, degree of patient discomfort, adequacy of wound closure, and length of operating time when using fibrin glue compared with sutures to close limbal conjunctival incisions after strabismus surgery. METHODS: Literature searches of the PubMed and Cochrane Library databases were last conducted on January 24, 2013, and resulted in 24 citations, including 2 not in the English language. All citations were reviewed in full text. Five studies compared fibrin glue (68 eyes) with sutures (74 eyes) for closure of limbal conjunctival incisions in patients undergoing strabismus surgery and were included in this assessment; no studies were found that evaluated fornix incisions. A quality rating was assigned to each study using criteria specifically developed for this assessment. RESULTS: No level I studies were found, and 5 level II studies were identified. There was significantly less postoperative inflammation and patient discomfort for 1 to 3 weeks after strabismus surgery for eyes treated with fibrin glue compared with sutures. In 3 studies that evaluated wound apposition, 2 of 50 eyes (4%) with conjunctival incisions that were initially closed using fibrin glue subsequently developed a wound gap that required suture repair. In the 2 studies that compared surgical time, fibrin glue required 1 to 5 minutes less time than suturing in 1 study and 55% less time (3.8 vs. 8.4 minutes) in a second study. These 5 studies did not evaluate the cost-effectiveness or risk of viral transmission from fibrin glue. CONCLUSIONS: Studies in the literature suggest that the off-label use of fibrin glue to close limbal conjunctival incisions in strabismus surgery resulted in less postoperative inflammation and required shorter operating time compared with sutures, but it increased the percentage of wounds requiring subsequent repair with sutures. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23820077 TI - Magnetic resonance T1 relaxation time of venous thrombus is determined by iron processing and predicts susceptibility to lysis. AB - BACKGROUND: The magnetic resonance longitudinal relaxation time (T1) changes with thrombus age in humans. In this study, we investigate the possible mechanisms that give rise to the T1 signal in venous thrombi and whether changes in T1 relaxation time are informative of the susceptibility to lysis. METHODS AND RESULTS: Venous thrombosis was induced in the vena cava of BALB/C mice, and temporal changes in T1 relaxation time correlated with thrombus composition. The mean T1 relaxation time of thrombus was shortest at 7 days following thrombus induction and returned to that of blood as the thrombus resolved. T1 relaxation time was related to thrombus methemoglobin formation and further processing. Studies in inducible nitric oxide synthase (iNOS(-/-))-deficient mice revealed that inducible nitric oxide synthase mediates oxidation of erythrocyte lysis derived iron to paramagnetic Fe3+, which causes thrombus T1 relaxation time shortening. Studies using chemokine receptor-2-deficient mice (Ccr2(-/-)) revealed that the return of the T1 signal to that of blood is regulated by removal of Fe3+ by macrophages that accumulate in the thrombus during its resolution. Quantification of T1 relaxation time was a good predictor of successful thrombolysis with a cutoff point of <747 ms having a sensitivity and specificity to predict successful lysis of 83% and 94%, respectively. CONCLUSIONS: The source of the T1 signal in the thrombus results from the oxidation of iron (released from the lysis of trapped erythrocytes in the thrombus) to its paramagnetic Fe3+ form. Quantification of T1 relaxation time appears to be a good predictor of the success of thrombolysis. PMID- 23820079 TI - Inactivated West Nile Virus (WNV) vaccine, Duvaxyn WNV, protects against a highly neuroinvasive lineage 2 WNV strain in mice. AB - BACKGROUND: Lineage 2 West Nile Virus (WNV) is endemic to southern Africa and Madagascar, and has recently been associated with encephalitis outbreaks in humans and horses in South Africa, central Europe, Italy and Greece. Commercial vaccines have mostly been evaluated against WNV lineage 1 strains and their efficacy against lineage 2 strains rarely reported. METHODS: To evaluate protection of Duvaxyn WNV vaccine against lineage 2 strains associated with encephalitis in South Africa, mice were vaccinated twice intramuscularly three weeks apart, and challenged four weeks later with highly neuroinvasive lineage 1 strain NY385/99 or lineage 2 strain SPU93/01. Neutralising antibody titres were measured at the time of challenge and three weeks later. Immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR) were conducted on brains of mice that succumbed during the trial, on controls and on vaccinated mice that survived. RESULTS: Serum neutralising antibodies in vaccinated mice were detected but low three weeks after primovaccination. Three weeks post-challenge, vaccinated mice had significantly higher serum neutralising antibody titres against both lineages than unvaccinated controls. After challenge, all vaccinated mice remained healthy but all unvaccinated mice demonstrated severe neurological signs with 75% mortality rate. WNV was not detected in brains of vaccinated mice whereas virus replicated in most unvaccinated mice challenged with either lineage. Gross and microscopic lesions were found only in unvaccinated mice challenged with both lineages. CONCLUSION: Duvaxyn WNV vaccine provided complete protection against challenge with lineage 2 WNV and stimulated significant cross protective neutralising antibodies in mice against lineage 2. PMID- 23820080 TI - Estimates of the timing of reductions in genital warts and high grade cervical intraepithelial neoplasia after onset of human papillomavirus (HPV) vaccination in the United States. AB - BACKGROUND: The objective of this study was to estimate the number of years after onset of a quadrivalent HPV vaccination program before notable reductions in genital warts and cervical intraepithelial neoplasia (CIN) will occur in teenagers and young adults in the United States. METHODS: We applied a previously published model of HPV vaccination in the United States and focused on the timing of reductions in genital warts among both sexes and reductions in CIN 2/3 among females. Using different coverage scenarios, the lowest being consistent with current 3-dose coverage in the United States, we estimated the number of years before reductions of 10%, 25%, and 50% would be observed after onset of an HPV vaccination program for ages 12-26 years. RESULTS: The model suggested female only HPV vaccination in the intermediate coverage scenario will result in a 10% reduction in genital warts within 2-4 years for females aged 15-19 years and a 10% reduction in CIN 2/3 among females aged 20-29 years within 7-11 years. Coverage had a major impact on when reductions would be observed. For example, in the higher coverage scenario a 25% reduction in CIN2/3 would be observed with 8 years compared with 15 years in the lower coverage scenario. CONCLUSIONS: Our model provides estimates of the potential timing and magnitude of the impact of HPV vaccination on genital warts and CIN 2/3 at the population level in the United States. Notable, population-level impacts of HPV vaccination on genital warts and CIN 2/3 can occur within a few years after onset of vaccination, particularly among younger age groups. Our results are generally consistent with early reports of declines in genital warts among youth. PMID- 23820082 TI - Secretoglobin 1A member 1 (SCGB1A1) +38A/G polymorphism is associated with asthma risk: a meta-analysis. AB - BACKGROUND: Epidemiological studies have evaluated the association between Secretoglobin 1A member 1 (SCGB1A1) +38A/G polymorphism and asthma, but the results remain inconclusive. The aim of this study was to perform a meta-analysis to investigate a more authentic association between SCGB1A1 +38A/G polymorphism and asthma. METHODS: Published literature from PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), and Embase databases were searched for eligible publications. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using random or fixed-effect model according the between study heterogeneity. RESULTS: A total of 19 case-control studies in 18 articles were included in the meta-analysis, including 3191 cases and 5182 controls. We found that SCGB1A1 +38A/G polymorphism was associated with a significantly increased risk of asthma risk when all studies were pooled in a dominant model (OR=1.29; 95% CI 1.08-1.54; P=0.005). The cumulative meta-analysis and sensitivity analysis further strengthened the stability of the result. Furthermore, publication bias was not detected. CONCLUSIONS: This study suggested that SCGB1A1 +38A/G polymorphism was a risk factor for asthma. Further large and well-designed studies are needed to confirm this association. PMID- 23820081 TI - Expression of antimicrobial peptides thanatin(S) in transgenic Arabidopsis enhanced resistance to phytopathogenic fungi and bacteria. AB - Thanatin(S) is an analog of thanatin, an insect antimicrobial peptide possessing strong and broad spectrum of antimicrobial activity. In order to investigate if the thanatin could be used in engineering transgenic plants for increased resistance against phytopathogens, the synthetic thanatin(S) was introduced into Arabidopsis thaliana plants. To increase the expression level of thanatin(S) in plants, the coding sequence was optimized by plant-preference codon. To avoid cellular protease degradation, signal peptide of rice Cht1 was fused to N terminal of thanatin(S) for secreting the expressed thanatin(S) into intercellular spaces. To evaluate the application value of thanatin(S) in plant disease control, the synthesized coding sequence of Cht1 signal peptide (Cht1SP) thanatin(S) was ligated to plant gateway destination binary vectors pGWB11 (with FLAG tag). Meanwhile, in order to observe the subcellular localization of Cht1SP thanatin(S)-GFP and thanatin(S)-GFP, the sequences of Cht1SP-thanatin(S) and thanatin(S) were respectively linked to pGWB5 (with GFP tag). The constructs were transformed into Arabidopsis ecotype Col-0 and mutant pad4-1 via Agrobacterium mediated transformation. The transformants with Cht1SP-thanatin(S)-FLAG fusion gene were analyzed by genomic PCR, real-time PCR, and western blots and the transgenic Arabidopsis plants introduced respectively Cht1SP-thanatin(S)-GFP and thanatin(S)-GFP were observed by confocal microscopy. Transgenic plants expressing Cht1SP-thanatin(S)-FLAG fusion protein showed antifungal activity against Botrytis cinerea and powdery mildew, as well as antibacterial activity against Pseudomonas syringae pv. tomato. And the results from confocal observation showed that the GFP signal from Cht1SP-thanatin(S)-GFP transgenic Arabidopsis plants occurred mainly in intercellular space, while that from thanatin(S)-GFP transgenic plants was mainly detected in the cytoplasm and that from empty vector transgenic plants was distributed uniformly throughout the cell, demonstrating that Cht1 signal peptide functioned. In addition, thanatin(S) and thanatin(S)-FLAG chemically synthesized have both in vitro antimicrobial activities against P. syringae pv. tomato and B. cinerea. So, thanatin(S) is an ideal candidate AMPs for the construction of transgenic crops endowed with a broad-spectrum resistance to phytopathogens and the strategy is feasible to link a signal peptide to the target gene. PMID- 23820083 TI - Posterior microphthalmia and nanophthalmia in Tunisia caused by a founder c.1059_1066insC mutation of the PRSS56 gene. AB - Congenital microphthalmia (CMIC) is a common developmental ocular disorder characterized by a small, and sometimes malformed, eye. Posterior microphthalmia (PM) and nanophthalmia are two rare subtypes of isolated CMIC characterized by extreme hyperopia due to short axial length and elevated lens/eye volume ratio. While nanophthalmia is associated with a reduced size in both anterior and posterior segments, PM involves a normal-size anterior chamber but a small posterior segment. Several genes encoding transcription and non-transcription regulators have been identified in different forms of CMIC. MFRP gene mutations have, for instance, been associated with nanophthalmia, and mutations in the recently identified PRSS56 gene have been linked to PM. So far, these two forms of CMIC have been associated with 9 mutations in PRSS56. Of particular interest, a c.1059_1066insC mutation has recently been reported in four Tunisian families with isolated PM and one Tunisian family with nanophthalmia. Here, we performed a genome-wide scan using a high density single nucleotide polymorphism (SNP) array 50 K in a large consanguineous Tunisian family (PM7) affected with PM and identified the same causative disease mutation. A total of 24 polymorphic markers spanning the PRSS56 gene in 6 families originating from different regions of Tunisia were analyzed to investigate the origin of the c.1059_1066insC mutation and to determine whether it arose in a common ancestor. A highly significant disease-associated haplotype, spanning across the 146 kb of the 2q37.1 chromosome, was conserved in those families, suggesting that c.1059_1066insC arose from a common founder. The age of the mutation in this haplotype was estimated to be around 1,850 years. The identification of such 'founder effects' may greatly simplify diagnostic genetic screening and lead to better prognostic counseling. PMID- 23820084 TI - Late onset GM2 gangliosidosis mimicking spinal muscular atrophy. AB - A case of late onset GM2 gangliosidodis with spinal muscular atrophy phenotype followed by cerebellar and extrapyramidal symptoms is presented. Genetic analysis revealed compound heterozygous mutation in exon 10 of the HEXA gene. Patient has normal intelligence and emotional reactivity. Neuroimaging tests of the brain showed only cerebellar atrophy consistent with MR spectroscopy (MRS) abnormalities. (18)F-fluorodeoxyglucose positron emission tomography (18)F-FDG PET/CT of the brain revealed glucose hypometabolism in cerebellum and in temporal and occipital lobes bilaterally. PMID- 23820085 TI - A case of acute reversible pure adrenergic failure. AB - A 14-year-old man presented 2 weeks after a viral pharyngitis with acute onset orthostasis and a pattern of pure adrenergic failure with neurogenic orthostatic hypotension that responded to intravenous immunoglobulin. The patient returned to his normal daily activities with resolution of his orthostatic hypotension and return of cardiac adrenergic responses as demonstrated by the Valsalva maneuver. Here we discuss the clinical and laboratory features of pure adrenergic failure, the more common etiologies, and the potential treatment options, with a focus on those presentations presumed to be autoimmune or inflammatory. PMID- 23820086 TI - Neural network-based classification of anesthesia/awareness using Granger causality features. AB - This article investigates the signal processing part of a future system for monitoring awareness during surgery. The system uses features from the patients' electrical brain activity (EEG) to discriminate between "anesthesia" and "awareness." We investigate the use of a neural network classifier and Granger causality (GC) features for this purpose. GC captures anesthetic-induced changes in the causal relationships between pairs of signals from different brain areas. The differences in the pairwise causality estimated from the EEG activity are used as features for subsequent classification between "awake" and "anesthetized" states. EEG data from 31 subjects obtained during surgery and maintenance of anesthesia with propofol, sevoflurane, or desflurane, are classified using a neural network with one layer of hidden units. An average accuracy of 96% is obtained. PMID- 23820088 TI - A mathematical model and quantitative comparison of the small RNA circuit in the Vibrio harveyi and Vibrio cholerae quorum sensing systems. AB - Quorum sensing is the process by which bacteria regulate their gene expression based on the local cell-population density. The quorum sensing systems of Vibrio harveyi and Vibrio cholerae are comprised of a phosphorelay cascade coupled to a small RNA (sRNA) circuit. The sRNA circuit contains multiple quorum regulated small RNA (Qrr) that regulate expression of the homologous master transcriptional regulators LuxR (in V. harveyi) and HapR (in V. cholerae). Their quorum sensing systems are topologically similar and homologous thereby making it difficult to understand why repression of HapR is more robust than LuxR to changes in Qrr. In this work we formulate and parameterize a novel mathematical model of the V. harveyi and V. cholerae sRNA circuit. We parameterize the model by fitting it to a variety of empirical data from both species. We show that we can distinguish all of the parameters and that the parameterizations (one for each species) are robust to errors in the data. We then use our model to propose some experiments to identify and explain kinetic differences between the species. We find that V. cholerae Qrr are more abundant and more sensitive to changes in LuxO than V. harveyi Qrr and argue that this is why expression of HapR is more robust than LuxR to changes in Qrr. PMID- 23820089 TI - Multi-frequency EDMR applied to microcrystalline thin-film silicon solar cells. AB - Pulsed multi-frequency electrically detected magnetic resonance (EDMR) at X-, Q- and W-Band (9.7, 34, and 94GHz) was applied to investigate paramagnetic centers in microcrystalline silicon thin-film solar cells under illumination. The EDMR spectra are decomposed into resonances of conduction band tail states (e states) and phosphorus donor states (P states) from the amorphous layer and localized states near the conduction band (CE states) in the microcrystalline layer. The e resonance has a symmetric profile at all three frequencies, whereas the CE resonance reveals an asymmetry especially at W-band. This is suggested to be due to a size distribution of Si crystallites in the microcrystalline material. A gain in spectral resolution for the e and CE resonances at high fields and frequencies demonstrates the advantages of high-field EDMR for investigating devices of disordered Si. The microwave frequency independence of the EDMR spectra indicates that a spin-dependent process independent of thermal spin polarization is responsible for the EDMR signals observed at X-, Q- and W-band. PMID- 23820087 TI - Sensitivity to numerosity is not a unique visuospatial psychophysical predictor of mathematical ability. AB - Sensitivity to visual numerosity has previously been shown to predict human mathematical performance. However, it is not clear whether it is discrimination of numerosity per se that is predictive of mathematical ability, or whether the association is driven by more general task demands. To test this notion we had over 300 participants (ranging in age from 6 to 73 years) perform a symbolic mathematics test and 4 different visuospatial matching tasks. The visual tasks involved matching 2 clusters of Gabor elements for their numerosity, density, size or orientation by a method of adjustment. Partial correlation and regression analyses showed that sensitivity to visual numerosity, sensitivity to visual orientation and mathematical education level predict a significant proportion of shared as well as unique variance in mathematics scores. These findings suggest that sensitivity to visual numerosity is not a unique visual psychophysical predictor of mathematical ability. Instead, the data are consistent with mathematics representing a multi-factorial process that shares resources with a number of visuospatial tasks. PMID- 23820090 TI - Expression of inhibitory markers is increased on effector memory T cells during hepatitis C virus/HIV coinfection as compared to hepatitis C virus or HIV monoinfection. AB - OBJECTIVE: Hepatitis C virus (HCV)/HIV coinfection is associated with rapid progression of hepatic fibrosis and liver disease. T-cell response has been implicated in the pathophysiological outcome of the disease. DESIGN: This study sought to evaluate the role of memory T-cell exhaustion in enhancing immune dysfunction during coinfection. METHODS: Sixty-four patients were included in the study; HCV monoinfected (n = 21), HIV monoinfected (n = 23), HCV/HIV coinfected (n = 20), and healthy controls (n = 20). Peripheral blood mononuclear cells (PBMCs) were isolated; immunophenotyped and functional assays were performed. RESULTS: A significant increase in the naive T cells and central memory T cells and a marked reduction in effector memory T cells (TEM) were observed with coinfection as compared to monoinfection. Inhibitory markers programmed death 1 (PD-1) and T-cell immunoglobulin and mucin domain containing molecule 3 (TIM3) were highly upregulated on TEM in coinfection and functionally, these TEM cells displayed lowered proliferation. Increased expression of PD-1 and TIM3 correlated with decreased levels of CD8+CD107a+ TEM cells in coinfection. Pro-inflammatory cytokines interferon-gamma and interleukin-2 (IL-2) secretion by TEM cells were also reduced during chronic viral infection. Secretion of IL-10, a human cytokine synthesis inhibitory factor, was significantly upregulated in CD4 TEM with HCV/HIV coinfection in comparison to HCV monoinfection. CONCLUSION: TEM cells play an important role during viral infection and enhanced expression of inhibitory markers is associated with decreased proliferation and cytotoxicity and increased IL-10 production, which was pronounced in HCV/HIV coinfection. Thus, decreased TEM functionality contributes to diminished host immune responses during HCV/HIV coinfection as compared to HCV or HIV monoinfection. PMID- 23820091 TI - Robotic-assisted laparoscopic prostatectomy in men with metabolic syndrome. AB - OBJECTIVES: Metabolic syndrome (MetS), the constellation of obesity and related risk factors for cardiovascular disease, is an expanding epidemiologic concern in the United States and the developed world. However, the relationship between MetS and prostate cancer remains to be definitively assessed. We evaluated the association between obesity and MetS with prostate cancer pathology and surgical and functional outcomes. MATERIALS AND METHODS: A total of 2,639 patients underwent robotic-assisted laparoscopic prostatectomy (RALP) for localized prostate cancer between March 2003 and July 2012. Of them, 186 patients met the criteria for MetS as defined by the presence of obesity (body mass index [BMI] >= 30 kg/m(2)) in conjunction with 2 or more of the following: hypertension (HTN), dyslipidemia (D), and diabetes (DM). Additionally, reference cohorts of (1) 663 nonobese men without HTN, D, or DM; (2) 184 obese patients without HTN, D, or DM; and (3) 211 obese men with solitary risk factors were identified for comparison. Demographic, histopathologic, and perioperative clinical parameters were compared. RESULTS: In comparison with patients without MetS, patients with MetS had larger prostates (Odds Ratio (OR) = 1.609, 95% Confidence Interval (CI) = 1.04-2.49, P = 0.03), increased blood loss (OR = 1.592, 95% CI = 1.15-2.21, P = 0.01), and surgical complexity (OR = 4.940, 95% CI = 2.29-10.69, P<0.001). There was no statistical difference observed between these groups in regard to complication rates, pathologic grade, stage, and postoperative continence or erectile function. With the exception of larger prostates found among men with MetS, men with obesity alone and obesity with 1 additional risk factor appeared similar to those with MetS. CONCLUSIONS: Patients with MetS had similar perioperative, histopathologic, and functional outcomes compared with reference cohorts undergoing RALP. RALP is safe, feasible, and efficacious in men with MetS. PMID- 23820092 TI - Nuclear magnetic resonance study of superprotonic conductor Rb4LiH3(SO4)4 single crystals. AB - To investigate the molecular dynamics of a Rb4LiH3(SO4)4 crystal below superionic phase transitions, we examined the temperature dependences of the NMR spectra and the spin-lattice relaxation time, T1, of the (1)H, (7)Li, and (87)Rb nuclei. The symmetry of (1)H signals resembles the Pake doublet containing a pair of dipolar coupled protons. From the temperature dependence of T1, the activation energy of proton at high temperature is twice of those of (7)Li and (87)Rb. A striking feature was the formation of the weak hydrogen bond creating a significant influence of proton at high temperatures due to the mobility of the hydrogen-bond protons. And, we compared these data with (1)H and (7)Li results for (NH4)4LiH3(SO4)4 and K4LiH3(SO4)4 crystals, which have similar structures. PMID- 23820093 TI - Big Five personality and depression diagnosis, severity and age of onset in older adults. AB - BACKGROUND: Personality may play an important role in late-life depression. The aim of this study is to examine the association between the Big Five personality domains and the diagnosis, severity and age of onset of late-life depression. METHODS: The NEO-Five Factor Inventory (NEO-FFI) was cross-sectionally used in 352 depressed and 125 non-depressed older adults participating in the Netherlands Study of Depression in Older Persons (NESDO). Depression diagnosis was determined by the Composite International Diagnostic Interview (CIDI). Severity of depression was assessed by the Inventory of Depressive Symptomatology (IDS). Logistic and linear regression analyses were applied. Adjustments were made for sociodemographic, cognitive, health and psychosocial variables. RESULTS: Both the presence of a depression diagnosis and severity of depression were significantly associated with higher Neuroticism (OR=1.35, 95% CI=1.28-1.43 and B=1.06, p<.001, respectively) and lower Extraversion (OR=.79, 95% CI=.75-.83; B=-.85, p<.001) and Conscientiousness (OR=.86, 95% CI=.81.-.90; B=-.86, p<.001). Earlier onset of depression was significantly associated with higher Openness (B=-.49, p=.026). LIMITATIONS: Due to the cross-sectional design, no causal inferences can be drawn. Further, current depression may have influenced personality measures. CONCLUSIONS: This study confirms an association between personality and late-life depression. Remarkable is the association found between high Openness and earlier age of depression onset. PMID- 23820094 TI - Incidental treatment effects of CBT on suicidal ideation and hopelessness. AB - BACKGROUND: Depression and alcohol misuse are among the most prevalent diagnoses in suicide fatalities. The risk posed by these disorders is exacerbated when they co-occur. Limited research has evaluated the effectiveness of common depression and alcohol treatments for the reduction of suicide vulnerability in individuals experiencing comorbidity. METHODS: Participants with depressive symptoms and hazardous alcohol use were selected from two randomised controlled trials. They had received either a brief (1 session) intervention, or depression-focused cognitive behaviour therapy (CBT), alcohol-focused CBT, therapist-delivered integrated CBT, computer-delivered integrated CBT or person-centred therapy (PCT) over a 10-week period. Suicidal ideation, hopelessness, depression severity and alcohol consumption were assessed at baseline and 12-month follow-up. RESULTS: Three hundred three participants were assessed at baseline and 12 months. Both suicidal ideation and hopelessness were associated with higher severity of depressive symptoms, but not with alcohol consumption. Suicidal ideation did not improve significantly at follow-up, with no differences between treatment conditions. Improvements in hopelessness differed between treatment conditions; hopelessness improved more in the CBT conditions compared to PCT and in single focused CBT compared to integrated CBT. LIMITATIONS: Low retention rates may have impacted on the reliability of our findings. Combining data from two studies may have resulted in heterogeneity of samples between conditions. CONCLUSIONS: CBT appears to be associated with reductions in hopelessness in people with co occurring depression and alcohol misuse, even when it is not the focus of treatment. Less consistent results were observed for suicidal ideation. Establishing specific procedures or therapeutic content for clinicians to monitor these outcomes may result in better management of individuals with higher vulnerability for suicide. PMID- 23820095 TI - Ethnic differences in seasonal affective disorder and associated factors among five immigrant groups in Norway. AB - BACKGROUND: Research studies on seasonal affective disorder (SAD) among immigrant populations are scarce. The objective of this article was to explore the associated risk and protective factors on prevalence of winter SAD (W-SAD), sub syndromal SAD (S-SAD) and Summer-SAD among five immigrant groups living in Oslo, Norway. METHODS: The Oslo Immigrants Health study (innvandrer HUBRO, 2002), is a large cross sectional epidemiological survey conducted among five of the largest immigrant groups living in Oslo. 1047 subjects were included in the analysis out of 3019 who participated in the survey. Mailed questionnaire which included selected items of the seasonal pattern assessment questionnaire (SPAQ), Hopkins symptom check list (HSCL) and other variables were used in the analysis. RESULTS: The lowest levels of W-SAD were found among Sri Lankan men and women and the highest among Iranians. W-SAD was significantly associated with country of birth, younger age, smoking, presence of mental distress, frequent visits to general practitioner or psychiatrist, self reported poor health and presence of chronic disorders. S-SAD was significantly associated with country of birth, smoking and higher levels of alcohol consumption. LIMITATIONS: SPAQ was not culturally validated. Poor response rate (39.7%) can also be considered as a limitation. CONCLUSIONS: Ethnic differences in W-SAD and S-SAD were observed. Sri Lankans had the lowest levels of W-SAD. However, there is a need for culturally validated instruments and further research must focus on exploring protective factors for SAD. PMID- 23820096 TI - No evidence for association between bipolar disorder risk gene variants and brain structural phenotypes. AB - BACKGROUND: While recent genome-wide association studies have identified several new bipolar disorder (BD) risk variants, structural imaging studies have reported enlarged ventricles and volumetric reductions among the most consistent findings. We investigated whether these genetic risk variants could explain some of the structural brain abnormalities in BD. METHODS: In a sample of 517 individuals (N=121 BD cases, 116 SZ cases, 61 other psychosis cases and 219 healthy controls), we tested the potential association between nine SNPs in the genes CACNA1C, ANK3, ODZ4 and SYNE1 and eight brain structural measures found to be altered in BD, and if these were specifically affecting the BD sample. We also assessed the polygenic effect of all these 9 SNPs on the brain phenotypes. RESULTS: Our most significant result was an association between the risk allele A in CACNA1C SNP rs4775913 and decreased cerebellar volume (pnom.=0.0075) in the total sample, which did not remain significant after multiple testing correction (pthreshold<0.0064). There was no evidence for diagnostic specificity for this association in the BD group. Further, no polygenic effect of these 9 SNPs was observed. LIMITATIONS: Low statistical power might increase our type II error rate. CONCLUSIONS: The present findings indicate that these risk SNPs do not explain a large proportion of the structural brain alterations in BD. Thus, these genes which are all related to neuronal functions must be involved in other pathophysiological aspects of BD development. PMID- 23820097 TI - Parental affectionless control and suicidality. AB - OBJECTIVE: Although poor parental bonding is a known risk factor for suicidality, current literature is inconsistent about the relative role of low parental care and parental overprotection, as well as the combination of the two, termed "affectionless control". This review presents the current state of knowledge of the relationship between suicidality and these two aspects of parental bonding. METHOD: The computerized databases Medline, PubMed, PsychINFO, PsychLit, and Google Scholar were searched using combinations of the following keywords: suicidality, suicide, suicide attempt, suicidal behavior, parental bonding, and parental bonding instrument. Using the results, we reviewed the reports on the relationship between suicidality and parental bonding as measured by validated parental bonding instruments. RESULTS: Twelve papers were analyzed. All of them used the parental bonding instrument (PBI) and one used both the PBI and the object representation inventory (ORI). Most reports agreed that, in mothers, either lack of maternal care and/or overprotection was associated with an increase in suicidal behavior, while in fathers only low care was consistently associated with suicidality. This lack of constancy with regard to the effect of paternal overprotection appears to be due to cultural differences in fathers' role in child rearing. With these differences acknowledged, affectionless control in both parents emerges as the parenting style most strongly associated with suicidal behavior. Common methodological problems included low numbers of subjects, inconsistent control groups, and the lack of a uniform definition of suicidality. CONCLUSION: Despite methodological limitations, current literature consistently indicates that parental affectionless control is associated with suicidal behavior. Recognizing affectionless control as a risk factor for suicide and developing early interventions aimed at modifying affectionless and overprotective parenting style in families with a history of affective disorders may be effective in reducing suicidal risk. PMID- 23820098 TI - Alpha absolute power measurement in panic disorder with agoraphobia patients. AB - BACKGROUND: Panic attacks are thought to be a result from a dysfunctional coordination of cortical and brainstem sensory information leading to heightened amygdala activity with subsequent neuroendocrine, autonomic and behavioral activation. Prefrontal areas may be responsible for inhibitory top-down control processes and alpha synchronization seems to reflect this modulation. The objective of this study was to measure frontal absolute alpha-power with qEEG in 24 subjects with panic disorder and agoraphobia (PDA) compared to 21 healthy controls. METHODS: qEEG data were acquired while participants watched a computer simulation, consisting of moments classified as "high anxiety"(HAM) and "low anxiety" (LAM). qEEG data were also acquired during two rest conditions, before and after the computer simulation display. RESULTS: We observed a higher absolute alpha-power in controls when compared to the PDA patients while watching the computer simulation. The main finding was an interaction between the moment and group factors on frontal cortex. Our findings suggest that the decreased alpha power in the frontal cortex for the PDA group may reflect a state of high excitability. CONCLUSIONS: Our results suggest a possible deficiency in top-down control processes of anxiety reflected by a low absolute alpha-power in the PDA group while watching the computer simulation and they highlight that prefrontal regions and frontal region nearby the temporal area are recruited during the exposure to anxiogenic stimuli. PMID- 23820099 TI - Effects of imitating gestures during encoding or during retrieval of novel verbs on children's test performance. AB - Research has shown that observing and imitating gestures can foster word learning and that imitation might be more beneficial than observation, which is in line with theories of Embodied Cognition. This study investigated when imitation of gestures is most effective, using a 2*2*2*3 mixed design with between-subjects factors Imitation during Encoding (IE; Yes/No) and Imitation during Retrieval (IR; Yes/No), and within-subjects factors Time of Testing (Immediate/Delayed) and Verb Type (Object manipulation/Locomotion/Abstract). Primary school children (N=115) learned 15 novel verbs (five of each type). They were provided with a verbal definition and a video of the gesture. Depending on assigned condition, they additionally received no imitation instructions, instructions to imitate the gesture immediately (i.e., during encoding; IE), instructions to imitate (from memory) during the first posttest (i.e., during retrieval; IR), or both (IE-IR). Based on the literature, all three imitation conditions could be predicted to be more effective than no imitation. On an immediate and delayed posttest, only the object-manipulation verbs were differentially affected by instructional method, with IE and IR being more effective than no imitation on the immediate test; IE IR and no imitation did not differ significantly. After a one week delay, only IR was more effective than no imitation, suggesting that imitation during retrieval is most effective for learning object-manipulation words. PMID- 23820100 TI - Drugs in anesthesia: current developments on the horizon. PMID- 23820101 TI - Hypnotic and sedative drugs--anything new on the horizon? AB - PURPOSE OF REVIEW: Many studies of new intravenous sedative drugs have been published last year, including several phase I trials. This review provides a brief summary of these studies, with recommendations for selected reading. RECENT FINDINGS: Remimazolam is a rapidly metabolized benzodiazepine. Early clinical trials confirm more rapid recovery compared with midazolam. Etomidate analogues can be designed with rapid metabolism and without adrenocortical suppression, but research is only at the preclinical stage. MR04A3 and AZD3043 are gamma aminobutyric acid A agonists with phase I data, but the outlook for further development is uncertain. Pioneers of intravenous emulsions of volatile anesthetics continue their work. SUMMARY: Many of the new sedative drugs were designed to undergo rapid metabolism. Remimazolam has great potential to enter clinical practice because of its rapid offset of action. PMID- 23820102 TI - The aging brain and anesthesia. AB - PURPOSE OF REVIEW: To review the neurophysiology and neuroanatomy of normal aging and the recent recommendations for the clinical management of general anesthesia and sedation in the elderly. RECENT FINDINGS: As the population ages, the number of elderly patients having surgery is likewise increasing and with it, the prevalence of postoperative cognitive disorders. Postoperative cognitive disorders including delirium and postoperative cognitive dysfunction are common postanesthesia complications in elderly patients. Several risk factors for postoperative disorders have been identified, and anesthesiologists commonly adapt their practice habits when taking care of elderly patients to try to mitigate the effects of the anesthetics on postoperative cognitive function. These practices are reasonable and prudent; yet, they are not well supported by an understanding of the aging brain and specifics of how the anesthetic effects on the brain change with age. Through functional imaging and electrophysiological studies, much is being learned about the neurophysiology and the neuroanatomy of normal aging. SUMMARY: Our analysis suggests that understanding the neurophysiology and neuroanatomy should be part of the standard working knowledge of anesthesiologists and that this knowledge can guide their use of the electroencephalogram to track more accurately the brain states of elderly patients receiving anesthesia care. PMID- 23820103 TI - Peripheral nerve blocks for outpatient surgery: evidence-based indications. AB - PURPOSE OF REVIEW: There has been an increasing use of peripheral nerve blocks (PNBs) in ambulatory surgery. Several recent reports have contributed to our understanding of the optimal PNB technique for specific surgical procedures in this setting. In this review, we have summarized the available literature on indications of PNBs for outpatient surgery of the upper extremity. RECENT FINDINGS: Although many of the recent studies focus on technical aspects of PNBs, few center on evidence-based indications or their utility in the ambulatory setting. The available literature suggests that although multiple techniques have been reported for outpatient shoulder surgery, interscalene brachial plexus block (ISBPB) is currently the most preferred technique. Supraclavicular, infraclavicular, and axillary brachial plexus blocks, however, are all commonly used and effective PNBs for outpatient surgery and analgesia of the arm, forearm, and hand. SUMMARY: ISBPB is currently the most beneficial PNB for outpatient shoulder surgery. Supraclavicular block functionally can be considered an alternative to the traditional ISBPB; however, additional studies are required before routine use can be recommended. Although the review identified several reports with benefits of one PNB technique over the others, the existing literature suggests that many of these techniques may be interchangeable with regards to procedures of the distal upper extremity. Future studies are indicated to help standardize the techniques, selection, and postoperative management of PNBs for specific surgical indications. PMID- 23820105 TI - Current world literature. Drugs in anesthesia. PMID- 23820104 TI - Management of the anticipated and unanticipated difficult airway in anesthesia outside the operating room. AB - PURPOSE OF REVIEW: The number of diagnostic and interventional procedures outside the operating room has dramatically increased over the last years. However, providing well tolerated anesthesia with the same standard of care in these locations is often challenging to the anesthesiologist. The remote locations include different organizational aspects and hazards. Airway management in general is still confronted with scenarios of difficult intubation and ventilation and often leads to significant morbidity and mortality. Continuous awareness of the potential complications is urged when providing anesthesia for remote procedures. RECENT FINDINGS: Recent studies have poorly addressed the issue of airway management by trained anesthesiologists outside the operating room. The majority of evidence is provided in the field of emergency medicine and intensive care settings. However, when dealing with difficult airway management in the remote setting, careful assessment and preparation is even more important than in the operating room. New evidence concerning prediction of ventilation and intubation must be incorporated in algorithms of airway management. Different anesthetic regimens using remifentanil and avoiding the use of neuromuscular blockers have to be carefully considered since they might change the scenario of intubation conditions. The new era of video laryngoscopes offers important potential to increase the tools for airway management. These new devices have the perfect design to be incorporated in remote settings. However, studies mainly focus on the emergency department and ICU. Also, there is currently a lack of consensus among professionals about their use and the large number of different devices seems to avoid careful comparisons. SUMMARY: Airway management outside the operating room is challenging and needs the implementation of algorithms including the new airway devices. The recent update of the practice guidelines about difficult airway management of the American Society of Anesthesiologists remains the standard reference guide. PMID- 23820107 TI - Second cancer incidence, risk factor, and specific mortality in head and neck squamous cell carcinoma. AB - OBJECTIVE: Second primary malignancies (SPMs) are common in patients with head and neck squamous cell carcinoma (HNSCC) and have a negative impact on their survival. This study aimed to evaluate risk factors for SPM occurrence and cause specific mortality in Asian HNSCC patients. STUDY DESIGN: A retrospective cohort study. SETTING: University teaching hospital. SUBJECTS: Nine hundred and thirty seven patients without previous cancer history who were treated between 2000 and 2009 and followed for at least 2 years. METHODS: Confirmation of SPMs was performed by histopathology. The cumulative probability of a SPM among survivors of index HNSCC was calculated using a competing risk model. Univariate and multivariate analyses were utilized to determine factors predictive of SPM occurrence and cause-specific mortality. RESULTS: Of 937 patients, cumulative incidence of SPMs was 7.2% at 0 to 6 months (synchronous), 17.9% at 5 years, and 23.1% at 10 years after index tumor diagnosis. In multivariate analyses, old age (>60 years) (P = .002), hypopharyngeal index tumor site (P = .001), and heavy drinker (P = .001) were independently associated with the development of SPMs, and hypopharyngeal index tumor site were independent variables for SPM-specific survival (P < .001). Cumulative incidence function of SPM-specific mortality according to index tumor sites was significantly higher in the hypopharynx than other sites (P = .011). CONCLUSION: Elderly patients, hypopharyngeal index cancer patients, or heavy drinkers may require careful surveillance for the development of SPMs. Our results may help identify and properly manage Asian patients at high risk of SPMs. PMID- 23820109 TI - Physical activity and onset of depression in adolescents: a prospective study in the general population cohort TRAILS. AB - Although it has often been suggested that physical activity and depression are intertwined, only few studies have investigated whether specific aspects of physical activity predict the incidence of major depression in adolescents from the general population. Therefore the aim of this study was to investigate the effects of nature, frequency, duration and intensity of physical activity during early adolescence on the onset of a major depressive episode in early adulthood. In a population sample of adolescents (N = 1396), various aspects of physical activity were assessed at early adolescence (mean age 13.02, SD = 0.61). Major depressive episode onset was assessed using the Composite International Diagnostic Interview. A Cox regression model was performed to investigate whether physical activity characteristics and their interactions with gender predicted a major depressive episode onset up until mean age 18.5 (SD = 0.61). The individual characteristics of physical activity (nature, frequency, duration and intensity) or their interactions with gender did not predict a major depressive episode onset (p values >0.05). So far, there is no prospective evidence that physical activity protects against the development of adolescent depressive episodes in either boys or girls. PMID- 23820108 TI - A 26-gene hypoxia signature predicts benefit from hypoxia-modifying therapy in laryngeal cancer but not bladder cancer. AB - PURPOSE: Tumor hypoxia is associated with a poor prognosis, hypoxia modification improves outcome, and hypoxic status predicts benefit from treatment. Yet, there is no universal measure of clinical hypoxia. The aim of this study was to investigate whether a 26-gene hypoxia signature predicted benefit from hypoxia modifying treatment in both cancer types. EXPERIMENTAL DESIGN: Samples were available from 157 T2-T4 laryngeal cancer and 185 T1-T4a bladder cancer patients enrolled on the accelerated radiotherapy with carbogen and nicotinamide (ARCON) and bladder carbogen nicotinamide (BCON) phase III randomized trials of radiotherapy alone or with carbogen and nicotinamide (CON) respectively. Customized TaqMan low density arrays (TLDA) were used to assess expression of the 26-gene signature using quantitative real-time PCR. The median expression of the 26 genes was used to derive a hypoxia score (HS). Patients were categorized as TLDA-HS low (<=median) or TLDA-HS high (>median). The primary outcome measures were regional control (RC; ARCON) and overall survival (BCON). RESULTS: Laryngeal tumors categorized as TLDA-HS high showed greater benefit from ARCON than TLDA-HS low tumors. Five-year RC was 81% (radiotherapy alone) versus 100% (CON) for TLDA HS high (P=0.009). For TLDA-HS low, 5-year RC was 91% (radiotherapy alone) versus 90% (CON; P=0.90). TLDA-HS did not predict benefit from CON in bladder cancer. CONCLUSION: The 26-gene hypoxia signature predicts benefit from hypoxia-modifying treatment in laryngeal cancer. These findings will be evaluated in a prospective clinical trial. PMID- 23820110 TI - Severity of pre-existing psychiatric illness and response to the Great East Japan Earthquake. AB - Reports have described how psychiatric patients respond to disasters. However, previous reports on the response depending on diagnostic categories have provided no clear consensus. Here we analyzed response to the Great East Japan Earthquake of March 11, 2011, among psychiatric patients in light of severity of pre existing psychiatric illness. We studied psychiatric change among a population of psychiatric outpatients in Tochigi prefecture, located ~160 km (~100 miles) southeast of the Fukushima nuclear power plant, in an area that suffered moderate damage from the earthquake and radiation. A total of 294 psychiatric outpatients was assessed using the Global Assessment of Functioning (GAF-F). A change of >=10 points in the GAF-F score was counted as a change in symptoms. The data were stratified by disease category, gender, and GAF-F score and analyzed using the Fisher's exact test. In the 2 months after the earthquake, 5.4% of patients showed evidence of a change in symptoms, with 4.1% worsening and 1.4% improving. Compared with patients having a GAF-F score <=50, significantly more patients with a score >50 showed evidence of worsening symptoms. No significant difference was found with respect to gender or diagnostic category for patients with worsened or improved symptoms. Our findings reveal that a relatively small percent of patients with pre-existing psychiatric diseases showed evidence of a change in symptoms and that patients with mild-to-moderate psychiatric illness are potentially vulnerable to the impacts of a natural disaster. PMID- 23820112 TI - Pre-operative imaging with CA125 is a poor predictor for granulosa cell tumors. AB - OBJECTIVE: To determine the radiographic characteristics of ovarian granulosa cell tumors (GCTs) and to evaluate the use of CA125 levels >35 in combination with imaging as an algorithm for preoperative diagnosis. METHODS: A retrospective analysis of women from two academic medical centers who were diagnosed with ovarian GCT between January 1998 and August 2012 was conducted. Clinical data included tumor appearance on pre-operative imaging and CA125 levels. Ovarian cysts were defined as complex if imaging exhibited multicystic areas, hemorrhagic, solid, or cystic and solid components. A CA125 level >35 was abnormal. RESULTS: One hundred and fifteen women were diagnosed with GCTs, of whom 63 underwent pre-operative imaging. Median age at surgery was 46 years (12 87). Forty women had preoperative ultrasounds, 43 had CT scans and 20 underwent both modalities. GCTs were almost exclusively classified as complex cysts in 62 (98%) cases. The most common morphology was solid and cystic (n=44 (70%)). Forty four (70%) patients had tumors >10 cm. Forty-two patients had a pre-operative CA125 performed. Eighteen (43%) patients had complex masses and CA125 >35. Twenty three (55%) had CA125 <35 with a complex mass, and one (2%) had a unilocular cyst with a CA125 >35. CONCLUSIONS: In this study, there was a near equal distribution of patients with complex masses and CA125 levels > or <35. If established strategies to predict malignancy are applied to GCTs, we will frequently fail to make the diagnosis pre-operatively. Additional research is necessary to generate an appropriate algorithm to guide pre-operative referral to a gynecologic oncologist. PMID- 23820111 TI - Benign nocturnal alternating hemiplegia of childhood: a new case with unusual findings. AB - It has been described a neuro developmental disorder labelled "Benign nocturnal alternating hemiplegia of childhood" (BNAHC) characterized by recurrent attacks of nocturnal hemiplegia without progression to neurological or intellectual impairment. We report a female patient who at 11months revealed a motionless left arm, unusual crying without impairment of consciousness and obvious precipitating factors. The attacks occur during sleep in the early morning with lack of ictal and interictal electroencephalographic abnormalities, progressive neurological deficit, and cognitive impairment. Unlike previous reports of BNAHC our patient come from a family with a history of both migraine, hemiplegic migraine, and sleep disorders. Our study remarks on the typical features described in previous studies and stresses the uncommon aspects that could help to identify the disorder which is likely to have been underestimated. Despite some clinical similarities between BNAHC and familiar hemiplegic migraine and alternating hemiplegia of childhood, the genetic analyses of our patient did not reveal genetic mutations found in both disorders. PMID- 23820113 TI - Overexpression of c-Abl predicts unfavorable outcome in epithelial ovarian cancer. AB - OBJECTIVES: Abelson tyrosine kinase (c-Abl) has been shown to promote solid tumor invasion and metastasis. However, little is known regarding whether c-Abl contributes to the development or progression of epithelial ovarian cancer (EOC). The aims of this study are to determine the expression of c-Abl and investigate a possible relationship between c-Abl and prognosis in EOC. METHODS: c-Abl protein level was evaluated in 137 EOC specimens by immunohistochemical staining and 32 EOC specimens by Western blot analysis. Expression of c-Abl in ovarian cancer cell lines was measured by Western blot analysis and immunofluorescence. Survival analysis was performed to assess the correlation between c-Abl expression and survival. RESULTS: Immunohistochemical staining and Western blot analysis revealed that c-Abl was overexpressed in EOC compared with samples from a non invasive ovarian tumor and normal ovaries (P<0.05). Furthermore, expression of c Abl was significantly associated with advanced FIGO stage, poor grade, serum Ca 125 and residual tumor size (P<0.05). By Western blot analysis, c-Abl expression was examined in four ovarian cancer cell lines. Meanwhile, immunofluorescence was performed to show c-Abl expression in SKOV3 and 3AO cell lines. Survival analysis demonstrated that patients with low c-Abl staining had a significantly better survival compared to patients with high c-Abl staining (P<0.05). In multivariate analysis, c-Abl overexpression, poor grade, advanced stage and suboptimal surgical debulking were independent prognostic factors of poor survival. CONCLUSIONS: Our present study finds that c-Abl overexpression is associated with an unfavorable outcome. c-Abl may be a crucial predictor for EOC metastasis. PMID- 23820114 TI - Transcutaneous auricular vagus nerve stimulation as a complementary therapy for pediatric epilepsy: a pilot trial. AB - OBJECTIVE: We investigated the safety and efficacy of transcutaneous auricular vagus nerve stimulation (ta-VNS) for the treatment of pediatric epilepsy. METHODS: Fourteen pediatric patients with intractable epilepsy were treated by ta VNS of the bilateral auricular concha using an ear vagus nerve stimulator. The baseline seizure frequency was compared with that after 8weeks, from week 9 to 16 and from week 17 to the end of week 24, according to the seizure diaries of the patients. RESULTS: One patient dropped out after 8weeks of treatment due to lack of efficacy, while the remaining 13 patients completed the 24-week study without any change in medication regimen. The mean reduction in seizure frequency relative to baseline was 31.83% after week 8, 54.13% from week 9 to 16 and 54.21% from week 17 to the end of week 24. The responder rate was 28.57% after 8weeks, 53.85% from week 9 to 16 and 53.85% from week 17 to the end of week 24. No severe adverse events were reported during treatment. CONCLUSION: Transcutaneous auricular VNS may be a complementary treatment option for reducing seizure frequency in pediatric patients with intractable epilepsy and should be further studied. PMID- 23820115 TI - Small proline-rich repeat protein 3 enhances the sensitivity of esophageal cancer cells in response to DNA damage-induced apoptosis. AB - Small proline-rich repeat protein 3 (SPRR3) has been linked with the altered chemoradiosensitivity, however the underlying molecular mechanisms remain elusive. Here, we report that ectopic overexpression of SPRR3 enhanced the sensitivity of cells in response to DNA damage-induced apoptosis via loss of mitochondrial membrane potential (MMP), and increasing activation of caspase 3 in human esophageal cancer cell lines. Conversely, siRNA knockdown of SPRR3 reduced apoptosis. We found that SPRR3 was localized in mitochondria and interacted with Bcl-2 in vivo, thus facilitating Bax mitochondrial translocation and the subsequent release of cytochrome c, and thereby enhancing cell sensitivity to DNA damage stimuli. In clinical samples, expression of SPRR3 was associated with the pathologic response (P = 0.007 in radiotherapy group, P = 0.035 in preoperative radiotherapy group) and good survival of patients with locally advanced esophageal squamous cell carcinoma (ESCC, P = 0.008). Taken together, our results implicate that SPRR3 might serve as a radiation-sensitive predictor of ESCC. PMID- 23820116 TI - Disparate effects of LPS infusion and carbohydrate overload on inflammatory gene expression in equine laminae. AB - Although clinical evidence of endotoxemia has been associated with the development of acute laminitis in hospitalized horses with gastrointestinal diseases and endotoxins have been detected in the circulation of horses with experimentally-induced laminitis, it is unclear what role, if any, endotoxins have play the pathogenesis of the disease. Therefore, in the present study we compared the effects of endotoxin infusion to that of intra-gastric administration of mixed carbohydrate (CHO) on clinical signs of laminitis, plasma concentrations of TNF-alpha and IL-10, and laminar tissue expression of 20 genes associated with inflammation. Horses were divided into 4 groups: Control (water placebo, n=7), endotoxin infusion (LPS, n=6), CHO/Developmental (30% decrease in central venous pressure, n=6) and CHO/Lame (Obel grade I laminitis, n=7). Horses in the LPS group developed clinical signs consistent with systemic inflammation, had rapid increases in plasma concentrations of both TNF-alpha and IL-10, and leukopenia, but did not have any changes in laminar tissue expression of the genes associated with inflammation. In contrast, horses administered CHO developed clinical signs consistent with systemic inflammation, had more delayed increases in TNF-alpha, IL-10 and total leukocyte counts, and had marked increases in laminar tissue expression of the genes associated with inflammation. Only the horses administered CHO developed clinical signs of laminitis, providing additional credence to the concept that factors other than endotoxin are responsible for the changes in laminar tissue gene expression that occur during the development of acute equine laminitis. PMID- 23820117 TI - Mechanochemical ablation in patients with chronic venous disease: a prospective multicenter report. AB - BACKGROUND: There are several endovenous methods to ablate the saphenous vein, all of which require tumescent anesthesia. This report was designed to evaluate the efficacy of a tumescent-free technique using mechanochemical ablation (MOCA). METHODS: This was a prospective observational multicenter report on the efficacy of MOCA in selected patients with lower extremity chronic venous disease. Demographic information, clinical and procedural data were collected on a customized database. The distribution and extent of venous reflux and the closure rate of the treated veins were assessed with duplex ultrasound. Pain was evaluated during the procedure and postoperatively using an analog scale. The presence and severity of complications were recorded. Patient improvement was assessed by clinical-etiology-anatomy-pathophysiology (CEAP) class and venous clinical severity score (VCSS). RESULTS: There were 126 patients that were included at baseline, 81% females, with a mean age of 65.5 +/- 14 years. The average BMI was 30.5 +/- 6. The mean diameter of the great saphenous vein in the upper thigh was 7.3 mm and the mean treatment length was 38 cm. Adjunctive treatment of the varicosities was performed in 11% of patients during the procedure. Closure rates were 100% at one week, 98% at three months, and 94% at six months. Post-procedure complications included hematoma 1%, ecchymosis 9%, and thrombophlebitis 10%. There were no cases of venous thromboembolism. There was significant improvement in VCSS (p < 0.001) for all time intervals. CONCLUSION: MOCA of the saphenous veins has the advantage of endovenous ablation without tumescent anesthesia, making it an almost pain-free procedure. High occlusion rates with significant clinical improvement can be achieved with this method at short term. PMID- 23820118 TI - Leukemia stem cells: Old concepts and new perspectives. AB - Myeloid leukemias are heterogeneous malignancies in morphology, immunophenotype, genetic and epigenetic alterations, and response to therapy. This heterogeneity is thought to depend on the accumulation of secondary mutations enhancing proliferation/survival and/or blocking differentiation in a small subset of leukemia-initiating cells capable of self-renewal. This model of clonal evolution is based on xenotransplantation studies demonstrating that leukemia can be initiated and maintained in immunodeficient mice by a small subset of purified leukemic cells immunophenotypically similar to normal hematopoietic stem cells and is known as the leukemia stem cell model. Since its original formulation, many studies have validated the main conclusion of this model. However, recent data from xenotransplantation studies in more severely immunodeficient mice suggest that imunophenotype and behavior of leukemic stem cells is more heterogeneous and "plastic" than originally thought. We will discuss here the evolution of the leukemia stem cell model and its impact for the therapy of patients with myeloid malignancies. PMID- 23820119 TI - Development and programming of the hypothalamus-pituitary-adrenal axis. AB - The fetal hypothalamus-pituitary-adrenal (HPA) axis plays a critical role in fetal development and physiology in utero: appropriate function of the fetal HPA axis is critical for preparation of the fetus for birth and survival in postnatal life. Because of the critical importance of appropriate physiological regulation of HPA activity in postnatal life, there has been intense interest in the possibility that fetal or neonatal stressors can permanently "program" the axis to hyperrespond or hyporespond to stimuli. This is a review of the literature relevant to normal development and "programming" of the HPA axis. PMID- 23820120 TI - Prenatal programming of insulin secretion in intrauterine growth restriction. AB - Intrauterine growth restriction (IUGR) impairs insulin secretion in humans and in animal models of IUGR. Several underlying mechanisms have been implicated, including decreased expression of molecular regulators of beta-cell mass and function, in some cases shown to be due to epigenetic changes initiated by an adverse fetal environment. Alterations in cell cycle progression contribute to loss of beta-cell mass, whereas decreased islet vascularity and mitochondrial dysfunction impair beta-cell function in IUGR rodents. Animal models of IUGR sharing similar insulin secretion outcomes as the IUGR human are allowing underlying mechanisms to be identified. This review will focus on models of uteroplacental insufficiency. PMID- 23820121 TI - Gestational diabetes, maternal obesity, and the NCD burden. AB - A greater proportion of women of reproductive age are now overweight or obese. Gestational diabetes mellitus and maternal obesity are associated with long-term adverse consequences in the offspring and subsequent generations, and are important drivers of the escalating global burden of diabetes and cardiovascular disease. We review the evidence linking gestational diabetes mellitus and maternal obesity with a greater risk of metabolic compromise in the offspring. We use an evolutionary perspective to elucidate the origins of gestational diabetes. Focusing efforts on maternal health is an important approach to combating the growing burden of diabetes and other noncommunicable diseases. PMID- 23820123 TI - Epidemic of obesity and metabolic syndrome. Foreword. PMID- 23820122 TI - Maturation and differentiation of the fetal vasculature. AB - Rapid postnatal growth and differentiation of fetal arterial smooth muscle is coordinated by a cacophony of growth factors, one of the most important of which is vascular endothelial growth factor (VEGF). In fetal arterial smooth muscle, VEGF influences both the expression and intracellular organization of contractile proteins and helps mediate hypoxic vascular remodeling. Numerous factors influence the expression of VEGF and its receptors, including chronic hypoxia, maternal food restriction, glucocorticoids, and miRNA. Continued study of the coupling between VEGF and transcription factors such as myocardin that govern smooth muscle differentiation, offers great promise for better clinical management of neonates at risk for cardiovascular dysregulation. PMID- 23820124 TI - Gender differences in manifestations of psychogenic non-epileptic seizures in Iran. AB - PURPOSE: Psychogenic non-epileptic seizures (PNES) are more prevalent among women. We investigated the potential differences in demographic and clinical characteristics of PNES between women and men. METHODS: In this prospective study, all patients with a clinical diagnosis of PNES (based on ictal recordings) were recruited at the outpatient epilepsy clinic at Shiraz University of Medical Sciences, from 2008 through 2012. The epileptologist interviewed all the patients. We compared the demographic and clinical characteristics and seizure semiology of PNES between women and men. RESULTS: Two hundred and twenty-two patients were diagnosed as having PNES. One hundred and eighty-eight patients had video-EEG recordings available and included in the study. One hundred and twenty nine (69%) were female and 59 (31%) were male. There were no significant differences between women and men with PNES with regard to demographic, clinical and semiological characteristics. CONCLUSION: We did not observe any significant demographic differences between women and men with PNES. Likewise, seizure characteristics and semiology were very similar in both genders. It appears that an Islamic lifestyle (in Iran) has little influence on the sex ratio and clinical manifestations of PNES compared with the Western studies. PMID- 23820126 TI - Stronger antinociceptive efficacy of opioids at the injured nerve trunk than at its peripheral terminals in neuropathic pain. AB - Activation of opioid receptors on peripheral sensory neurons has the potential for safe pain control, as it lacks centrally mediated side effects. While this approach often only partially suppressed neuropathic pain in animal models, opioids were mostly applied to animal paws although neuropathy was induced at the nerve trunk. Here we aimed to identify the most relevant peripheral site of opioid action for efficient antinociception in neuropathy. On days 2 and 14 following a chronic constriction injury (CCI) of the sciatic nerve in mice, we evaluated dose and time relationships of the effects of MU-, delta-, and kappa opioid receptor agonists injected either at the CCI site or intraplantarly (i.pl.) into the lesioned nerve-innervated paw, on spontaneous paw lifting and heat and mechanical hypersensitivity (using Hargreaves and von Frey tests, respectively). We found that neither agonist diminished spontaneous paw lifting, despite the application site. Heat hypersensitivity was partially attenuated by i.pl. MU-receptor agonist only, while it was improved by all three agonists applied at the CCI site. Mechanical hypersensitivity was slightly diminished by all agonists administered i.pl., whereas it was completely blocked by all opioids injected at the CCI site. These antinociceptive effects were opioid receptor type selective and site-specific. Thus, opioids might not be effective against spontaneous pain, but they improve heat and mechanical hypersensitivity in neuropathy. Importantly, efficient alleviation of hypersensitivity is governed by peripheral opioid receptors at the injured nerve trunk rather than at its peripheral terminals. Identifying the primary action site of analgesics is important for the development of adequate pain therapies. PMID- 23820125 TI - The novel anticancer agent JNJ-26854165 induces cell death through inhibition of cholesterol transport and degradation of ABCA1. AB - JNJ-26854165 (serdemetan) has previously been reported to inhibit the function of the E3 ligase human double minute 2, and we initially sought to characterize its activity in models of mantle cell lymphoma (MCL) and multiple myeloma (MM). Serdemetan induced a dose-dependent inhibition of proliferation in both wild-type (wt) and mutant (mut) p53 cell lines, with IC50 values from 0.25 to 3 MUM/l, in association with an S phase cell cycle arrest. Caspase-3 activation was primarily seen in wtp53-bearing cells but also occurred in mutp53-bearing cells, albeit to a lesser extent. 293T cells treated with JNJ-26854165 and serdemetan-resistant fibroblasts displayed accumulation of cholesterol within endosomes, a phenotype reminiscent of that seen in the ATP-binding cassette subfamily A member-1 (ABCA1) cholesterol transport disorder, Tangiers disease. MM and MCL cells had decreased cholesterol efflux and electron microscopy demonstrated the accumulation of lipid whorls, confirming the lysosomal storage disease phenotype. JNJ-26854165 induced induction of cholesterol regulatory genes, sterol regulatory element-binding transcription factor-1 and -2, liver X receptors alpha and beta, along with increased expression of Niemann-Pick disease type-C1 and -C2. However, JNJ 26854165 induced enhanced ABCA1 turnover despite enhancing transcription. Finally, ABCA1 depletion resulted in enhanced sensitivity to JNJ-26854165. Overall, these findings support the hypothesis that serdemetan functions in part by inhibiting cholesterol transport and that this pathway is a potential new target for the treatment of MCL and MM. PMID- 23820127 TI - Concurrent agonism of adenosine A2B and glucocorticoid receptors in human airway epithelial cells cooperatively induces genes with anti-inflammatory potential: a novel approach to treat chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is a neutrophilic inflammatory disorder that is weakly responsive to glucocorticoids. Identification of ways to enhance the anti-inflammatory activity of glucocorticoids is, therefore, a major research objective. Adenosine receptor agonists that target the A2B-receptor subtype are efficacious in several cell-based assays and preclinical models of inflammation. Accordingly, the present study was designed to determine if a selective A2B-receptor agonist, 2-[6-amino-3,5-dicyano-4-[4 (cyclopropylmethoxy)phenyl]pyridin-2-ylsulphanyl]acetamide (Bay 60-6583), and a glucocorticoid, dexamethasone, in combination display putative anti-inflammatory activity that is superior to either drug alone. In BEAS-2B human airway epithelial cells stably transfected with cAMP-response element (CRE) and glucocorticoid response element (GRE) reporter constructs, Bay 60-6583 promoted CRE-dependent transcription and enhanced GRE-dependent transcription by an adenosine A2B-receptor-mediated mechanism that was associated with cAMP formation and abolished by an inhibitor of cAMP-dependent protein kinase. Analysis of the concentration-response relationship that described the enhancement of GRE dependent transcription showed that Bay 60-6583 increased the magnitude of response without affecting the potency of dexamethasone. Bay 60-6583 and dexamethasone also induced a panel of genes that, collectively, could have benefit in COPD. These were categorized into genes that were induced in a positive cooperative manner (RGS2, p57(kip2)), an additive manner (TTP, BRL-1), or by Bay 60-6583 (CD200, CRISPLD2, SOCS3) or dexamethasone (GILZ) only. Thus, the gene induction "fingerprints" produced by Bay 60-6583 and dexamethasone, alone and in combination, were distinct. Collectively, through their actions on gene expression, an adenosine A2B-receptor agonist and a glucocorticoid administered together may have utility in the treatment of inflammatory disorders that respond suboptimally to glucocorticoids as a monotherapy. PMID- 23820128 TI - Synthesis and bioevaluation of a series of alpha-pyrone derivatives as potent activators of Nrf2/ARE pathway (part I). AB - When exposed to electrophiles, human colorectal cancer cells (HCT116) counteract oxidative stress through activating NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway. To identify new activators, luciferase reporter gene assay was used to screen in-house database of our laboratory, leading to a novel alpha-pyrone compound 1 as a hit. 2 with 2-fluoro phenyl group exhibited the strongest ARE inductive activity in the first round structure-activity relationship (SAR) study. Biological studies showed the compound induced nuclear translocation of Nrf2 preceded by phosphorylation of ERK1/2. The data encouraged us to use 2 as lead and 20 derivatives were synthesized to discuss a more detailed SAR, leading to a more potent compound 9, which can be the starting compound for further modification. PMID- 23820129 TI - Probiotics: a new way to fight bacterial pulmonary infections? AB - Antibiotics, of which Fleming has identified the first representative, penicillin, in 1928, allowed dramatical improvement of the treatment of patients presenting with infectious diseases. However, once an antibiotic is used, resistance may develop more or less rapidly in some bacteria. It is thus necessary to develop therapeutic alternatives, such as the use of probiotics, defined by the World Health Organization (WHO) as "micro-organisms which, administered live and in adequate amounts, confer a benefit to the health of the host". The scope of these micro-organisms is broad, concerning many areas including that of infectious diseases, especially respiratory infections. We describe the rational use of probiotics in respiratory tract infections and detail the results of various clinical studies describing the use of probiotics in the management of respiratory infections such as nosocomial or community acquired pneumonia, or on specific grounds such as cystic fibrosis. The results are sometimes contradictory, but the therapeutic potential of probiotics seems promising. Implementing research to understand their mechanisms of action is critical to conduct therapeutic tests based on a specific rational for the strains to be used, the dose, as well as the chosen mode and rhythm of administration. PMID- 23820130 TI - Circulating fragments of N-terminal pro-B-type natriuretic peptides in plasma of heart failure patients. AB - BACKGROUND: The use of nonstandardized N-terminal pro-B-type natriuretic peptide (NT-proBNP) assays can contribute to the misdiagnosis of heart failure (HF). Moreover, there is yet to be established a common consensus regarding the circulating forms of NT-proBNP being used in current assays. We aimed to characterize and quantify the various forms of NT-proBNP in the circulation of HF patients. METHODS: Plasma samples were collected from HF patients (n = 20) at rest and stored at -80 degrees C. NT-proBNP was enriched from HF patient plasma by use of immunoprecipitation followed by mass spectrometric analysis. Customized homogeneous sandwich AlphaLISA(r) immunoassays were developed and validated to quantify 6 fragments of NT-proBNP. RESULTS: Mass spectrometry identified the presence of several N- and C-terminally processed forms of circulating NT-proBNP, with physiological proteolysis between Pro2-Leu3, Leu3-Gly4, Pro6-Gly7, and Pro75 Arg76. Consistent with this result, AlphaLISA immunoassays demonstrated that antibodies targeting the extreme N or C termini measured a low apparent concentration of circulating NT-proBNP. The apparent circulating NT-proBNP concentration was increased with antibodies targeting nonglycosylated and nonterminal epitopes (P < 0.05). CONCLUSIONS: In plasma collected from HF patients, immunoreactive NT-proBNP was present as multiple N- and C-terminally truncated fragments of the full length NT-proBNP molecule. Immunodetection of NT proBNP was significantly improved with the use of antibodies that did not target these terminal regions. These findings support the development of a next generation NT-proBNP assay targeting nonterminal epitopes as well as avoiding the central glycosylated region of this molecule. PMID- 23820131 TI - Advanced spray-dried design, physicochemical characterization, and aerosol dispersion performance of vancomycin and clarithromycin multifunctional controlled release particles for targeted respiratory delivery as dry powder inhalation aerosols. AB - Respirable microparticles/nanoparticles of the antibiotics vancomycin (VCM) and clarithromycin (CLM) were successfully designed and developed by novel organic solution advanced spray drying from methanol solution. Formulation optimization was achieved through statistical experimental design of pump feeding rates of 25% (Low P), 50% (Medium P) and 75% (High P). Systematic and comprehensive physicochemical characterization and imaging were carried out using scanning electron microscopy (SEM), hot-stage microscopy (HSM), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Karl Fischer titration (KFT), laser size diffraction (LSD), gravimetric vapor sorption (GVS), confocal Raman microscopy (CRM) and spectroscopy for chemical imaging mapping. These novel spray dried (SD) microparticulate/nanoparticulate dry powders displayed excellent aerosol dispersion performance as dry powder inhalers (DPIs) with high values in emitted dose (ED), respirable fraction (RF), and fine particle fraction (FPF). VCM DPIs displayed better aerosol dispersion performance compared to CLM DPIs which was related to differences in the physicochemical and particle properties of VCM and CLM. In addition, organic solution advanced co-spray drying particle engineering design was employed to successfully produce co-spray-dried (co-SD) multifunctional microparticulate/nanoparticulate aerosol powder formulations of VCM and CLM with the essential lung surfactant phospholipid, dipalmitoylphosphatidylcholine (DPPC), for controlled release pulmonary nanomedicine delivery as inhalable dry powder aerosols. Formulation optimization was achieved through statistical experimental design of molar ratios of co-SD VCM:DPPC and co-SD CLM:DPPC. XRPD and DSC confirmed that the phospholipid bilayer structure in the solid-state was preserved following spray drying. Co-SD VCM:DPPC and co-SD CLM:DPPC dry powder aerosols demonstrated controlled release of antibiotic drug that was fitted to various controlled release mathematical fitting models. The Korsmeyer-Peppas model described the best data fit for all powders suggesting super case-II transport mechanism of controlled release. Excellent aerosol dispersion performance for all co-SD microparticulate/nanoparticulate DPIs was higher than the SD antibiotic drugs suggesting that DPPC acts as an aerosol performance enhancer for these antibiotic aerosol dry powders. Co-SD VCM:DPPC DPIs had higher aerosol dispersion parameters compared to co-SD CLM:DPPC which was related to differences in the physicochemical properties of VCM and CLM. PMID- 23820132 TI - Ultrasonic approach for viscoelastic and microstructure characterization of granular pharmaceutical tablets. AB - The mechanical properties of a solid dosage, defined by its granular micro structure and geometry, play a key role in its dissolution profile and performance. An ultrasonic method for extracting the viscoelastic material properties and granular structure of drug tablet compacts is introduced and its utility is demonstrated for tablet compacts made of microcrystalline cellulose (MCC), lactose monohydrate, and sodium starch glycolate as well as magnesium stearate as lubricant. The approach is based on the effect of viscoelasticity and internal micro-structures on the frequency-dependent attenuation of an ultrasonic wave propagating in a granular medium. The models for viscoelastic (a two parameter Zener model) and scattering attenuation (Rayleigh model) mechanisms are employed. The material parameters including viscoelastic and scattering parameters (average Young's modulus, stress and strain relaxation time constants, and the Rayleigh scattering material parameter) and grain size distribution with a known distribution profile are extracted by an optimization algorithm based on the least square method. The results also indicate good agreement between experimentally and computationally determined phase and group velocities in compacted samples. It is found that the effects of both attenuation mechanisms are present and the extracted grain size distribution parameters are in good agreement with the optically determined values. PMID- 23820133 TI - Facile synthesis of camptothecin intercalated layered double hydroxide nanohybrids via a coassembly route. AB - A method has been developed for the synthesis of intercalated layered double hydroxide (LDH) nanohybrids of the charge-neutral and poorly water-soluble anticancer drug camptothecin (CPT) using a coassembly route. For this route, CPT molecules were initially incorporated into the micelles of a biocompatible surfactant, such as sodium cholate (SCh) or sodium deoxycholate (SDC). The resulting negatively charged CPT-loaded micelles and the positively charged LDH nanosheets were then coassembled together into the CPT intercalated LDH nanohybrids. The resulting nanohybrids were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), Fourier transform infrared (FT-IR) and elemental analyses. The results revealed that the loading of CPT in the nanohybrids could reach as high as 13%, indicating that this route could be used to achieve the effective intercalation of charge-neutral and poorly water-soluble drugs into the LDH gallery. The in vitro release of CPT from the nanohybrids was examined, and the results showed that the release was a diffusion-controlled process and that the diffusion process through the LDH particles was the rate limiting step. The parabolic diffusion equation effectively described the kinetic process associated with the release of CPT from the nanohybrids. PMID- 23820134 TI - Imatinib-associated tumour response in a dog with a non-resectable gastrointestinal stromal tumour harbouring a c-kit exon 11 deletion mutation. AB - A 10-year-old female Miniature Dachshund with a non-resectable gastrointestinal stromal tumour was treated with imatinib. The neoplastic cells had a deletion mutation (c.1667_1672del) within exon 11 of the c-kit gene, which resulted in deletion of three amino acids and insertion of one amino acid (p.Trp556_Val558delinsPhe) in the juxtamembrane domain of KIT. Following treatment with imatinib, the dog achieved partial remission on Day 21 with a continuous decrease in tumour size until Day 67 of treatment. Although no additional decrease in size was observed after Day 67 of treatment, the tumour remained stable in size as of Day 140 of treatment. The c-kit mutation found in the tumour cells appears to be a mutation driving oncogenesis, as evidenced by the partial remission elicited by imatinib in this dog. PMID- 23820135 TI - A protocol for the management of canine cerebrospinal fluid for the proteomic assessment of putative biomarkers. AB - Cerebrospinal fluid (CSF) is a potential source for disease-specific biomarkers that may assist in the staging and determining the prognosis of neurodegenerative conditions in animals. However, the validity of such putative biomarkers may be influenced by pre-analytical variables, including the procedures adopted to collect and store the CSF. This study assessed the effect of three handling practices on the stability of a panel of CSF proteins: clusterin (also known as apolipoprotein J), haptoglobin, cystatin C, and transthyretin (TTR). The three handling procedures for canine CSF were mimicked in the laboratory as follows: (1) storage in a refrigerator overnight (4 degrees C for 18 h); (2) carrying a sample in the pocket of a clinician (37 degrees C for 4h); and (3) mailing a sample to a remote laboratory for analysis (room temp for 48 h). The impact of these three scenarios on the concentrations of the selected proteins was assessed using Western blotting and compared to an aliquot of CSF that had been kept frozen. The level of clusterin was significantly reduced following 48 h at room temperature (P<0.05), while the concentration of the dimeric form of TTR increased following this handling procedure and also when held at 37 degrees C for 4h. A reducing agent prevented this increase at 37 degrees C. In conclusion, exposing CSF samples to various environmental conditions can significantly alter their protein content, a factor that must be considered in studies assessing potential biomarkers in canine CSF. PMID- 23820136 TI - Immunocompromised patients and their pets: still best friends? AB - The emergence of immunosuppressive human diseases and therapies in the last decades has raised the question of the risks and benefits for this group of patients deriving from their interaction with pets and the necessity to balance them in the best interest of the pet owner. Risks are related to the possibility of contracting zoonotic infections that are more severe and occasionally lethal in immunocompromised patients. To mitigate the risks and allow the owner to keep the pet, guidelines have been devised. The cooperation and communication between the owner, the physician and the veterinarian are fundamental for a rational approach in evaluating of the potential health risks associated with pets as sources of zoonotic diseases. The final decision should, however, be made by the owner, who alone will enjoy the benefits of the relationship but also be the one to bear the consequences. PMID- 23820137 TI - Dr Robert Proust: a gynaecologist's contribution to world literature. AB - Dr Robert Proust, though overshadowed in history by his more famous brother, the novelist Marcel Proust, was an eminent and innovative French surgeon who achieved recognition largely as a gynaecologist, but also was an accomplished urologist and general surgeon. He was the author of a textbook, The surgery of the female genital tract, that was very successful in his lifetime and ran to six editions. He was always very supportive of his brother's writing, and after Marcel's premature death Robert edited and arranged for publication of the final three volumes of his novel A la recherche du temps perdu, which has been called the greatest novel of the twentieth century. PMID- 23820138 TI - White blood cell differential counts in patients with polycystic ovary syndrome: a pilot study on Chinese women. AB - OBJECTIVE: A state of systemic chronic low grade inflammation has been observed in polycystic ovary syndrome (PCOS). It has been suggested that inflammation is a potential mechanism influencing the ovaries or endocrine system and might therefore contribute to the pathophysiology of PCOS. The aim of this study was to compare the total white blood cell (WBC), neutrophil granulocyte and lymphocyte differential counts between women with PCOS and controls. In addition, we estimated if the WBC differential counts had a relationship with body mass index (BMI), total testosterone levels, estradiol levels and luteinizing hormone levels of women with PCOS. STUDY DESIGN: 1016 subjects with PCOS and 1016 age-matched healthy women from a Han Chinese population were enrolled in this case-control study. Blood samples were taken from all the patients and controls to test total WBC counts, lymphocyte counts, neutrophil counts and related serum hormones. RESULTS: Total WBC counts and lymphocyte counts were elevated in PCOS subjects (t test P<0.01). Higher lymphocyte counts which contributed to higher total WBC counts in PCOS women were compared to age-matched controls. When the data were adjusted by BMI, the difference of WBC counts and lymphocyte counts between patients and controls remained significant. CONCLUSIONS: The state of chronic low grade inflammation in patients with PCOS might be associated with immunological factors. Obesity and hyperandrogenism may be due to the underlying low grade inflammation. PMID- 23820139 TI - Vaginal cuff closure with absorbable bidirectional barbed suture during total laparoscopic hysterectomy. AB - OBJECTIVE: Hysterectomy represents one of the most performed procedures in gynecological surgery. The minimally invasive approach increases patients' benefits and reduces hospitalization costs. The aim of this study was to demonstrate the efficacy and safety of double barbed suture in vaginal cuff closure during total laparoscopic hysterectomy. STUDY DESIGN: A retrospective cohort study of 88 consecutive patients treated with total laparoscopic hysterectomy for benign or precancerous conditions was undertaken from January 2010 to December 2011. Vaginal cuff suture was performed with traditional interrupted suture with polycolic acid (VicrylTM) in 40 patients and with bidirectional barbed device, Quill SRSTM, in 48 patients. RESULTS: No difference in vaginal cuff dehiscence, major vaginal bleeding or spotting, and infection was evident between the two groups, with significant reduction in operative times for the bidirectional barbed suture group. CONCLUSION: Vaginal cuff suture performed with bidirectional barbed QUILL SRSTM is a safe and well-tolerated procedure that reduces operative times. PMID- 23820140 TI - The importance of cystoscopy and bladder biopsy in women with refractory overactive bladder: the urogynaecologist's point of view? AB - OBJECTIVES: To assess the sensitivity, specificity, positive and negative predictive value of cystoscopy and the clinical value of bladder biopsy in women with refractory overactive bladder (OAB) symptoms. STUDY DESIGN: Prospective observational study carried out in a tertiary referral urogynaecology unit in London. Consecutive women with OAB resistant to pharmacotherapy who underwent cystoscopy, hydrodistention and bladder biopsy were studied. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of cystoscopy as well as histological findings for chronic cystitis were evaluated. RESULTS: 106 women aged 22-91 years were studied. Histopathology showed chronic cystitis in 94 women, follicular cystitis 3, acute and chronic cystitis in 2, transitional cell carcinoma in 6 and no abnormality in 1 woman. Trabeculations and increased vascularity were the most common cystoscopic findings, seen in 71% and 72% of women respectively. Haemorrhages on first filling and haemorrhages on refilling had specificities of 86.6% and 80% respectively for chronic cystitis. Their sensitivities were 9.8% and 13.1% respectively. Trabeculations and increased vascularity had sensitivities of 68.1% and 68.1% and their specificities were 11.6% and 4.5% respectively. Trabeculations, increased vascularity, haemorrhages on first filling and haemorrhages on refilling all had a PPV over 80% for chronic cystitis. CONCLUSIONS: More than 90% of women with refractory OAB symptoms have chronic cystitis on histopathology. Cystoscopy alone is useful, but not always adequate to diagnose chronic cystitis. Antibiotic therapy in those women might be beneficial before starting anticholinergics. Larger randomised controlled trials are mandatory to confirm our hypothesis. PMID- 23820141 TI - Technology, trends, and the future for people with spinal cord injury. PMID- 23820143 TI - Functional assessment and performance evaluation for assistive robotic manipulators: Literature review. AB - CONTEXT: The user interface development of assistive robotic manipulators can be traced back to the 1960s. Studies include kinematic designs, cost-efficiency, user experience involvements, and performance evaluation. This paper is to review studies conducted with clinical trials using activities of daily living (ADLs) tasks to evaluate performance categorized using the International Classification of Functioning, Disability, and Health (ICF) frameworks, in order to give the scope of current research and provide suggestions for future studies. METHODS: We conducted a literature search of assistive robotic manipulators from 1970 to 2012 in PubMed, Google Scholar, and University of Pittsburgh Library System - PITTCat. RESULTS: Twenty relevant studies were identified. CONCLUSION: Studies were separated into two broad categories: user task preferences and user-interface performance measurements of commercialized and developing assistive robotic manipulators. The outcome measures and ICF codes associated with the performance evaluations are reported. Suggestions for the future studies include (1) standardized ADL tasks for the quantitative and qualitative evaluation of task efficiency and performance to build comparable measures between research groups, (2) studies relevant to the tasks from user priority lists and ICF codes, and (3) appropriate clinical functional assessment tests with consideration of constraints in assistive robotic manipulator user interfaces. In addition, these outcome measures will help physicians and therapists build standardized tools while prescribing and assessing assistive robotic manipulators. PMID- 23820144 TI - Evacuation preparedness in full-time wheelchair users with spinal cord injury. AB - OBJECTIVE: To analyze and evaluate the efficacy of evacuation plans described by individuals with spinal cord injury (SCI). DESIGN: Descriptive study from a convenience sample. SETTING: Outpatient population center in Pittsburgh, PA, USA. METHODS: Twenty-one individuals with SCI who previously indicated that they had a plan of evacuation from either their homes, places of work, or towns/cities were contacted via telephone and asked to describe their evacuation plans. The number of critical elements (scale of 0-10 with 10 indicating a more thorough plan) and assistive technology (AT) devices were recorded. OUTCOME MEASURES: The number of critical elements (scale of 0-10 with 10 indicating a more thorough plan) and AT devices were recorded. RESULTS: Median home and town/city evacuation scores were both 3.00 (ranges: 1.0-4.0 and 0.0-8.0, respectively). Median evacuation scores of individuals with paraplegia were higher in home (P = 0.05, r = 0.44) and town/city (P = 0.045, r = 0.63) than individuals with tetraplegia. Median evacuation scores of subjects who were employed were higher in home (P = 0.036, r = 0.47) and town/city (P = 0.064, r = 0.59) than unemployed. CONCLUSION: Low scores indicate that individuals with SCI who believe that they have plans are not adequately prepared for an emergency evacuation. Interventions are needed to improve evacuation readiness and lack of preparedness in a catastrophe should be considered by emergency personnel when responding. PMID- 23820142 TI - Neuroprosthetic technology for individuals with spinal cord injury. AB - CONTEXT: Spinal cord injury (SCI) results in a loss of function and sensation below the level of the lesion. Neuroprosthetic technology has been developed to help restore motor and autonomic functions as well as to provide sensory feedback. FINDINGS: This paper provides an overview of neuroprosthetic technology that aims to address the priorities for functional restoration as defined by individuals with SCI. We describe neuroprostheses that are in various stages of preclinical development, clinical testing, and commercialization including functional electrical stimulators, epidural and intraspinal microstimulation, bladder neuroprosthesis, and cortical stimulation for restoring sensation. We also discuss neural recording technologies that may provide command or feedback signals for neuroprosthetic devices. CONCLUSION/CLINICAL RELEVANCE: Neuroprostheses have begun to address the priorities of individuals with SCI, although there remains room for improvement. In addition to continued technological improvements, closing the loop between the technology and the user may help provide intuitive device control with high levels of performance. PMID- 23820145 TI - The use of a computer-assisted rehabilitation environment (CAREN) for enhancing wounded warrior rehabilitation regimens. AB - PURPOSE: This paper seeks to describe how novel technologies such as the computer assisted research environment (CAREN) may improve physical and cognitive rehabilitation for wounded warfighters. DESIGN/METHODOLOGY/APPROACH: The CAREN system is a dynamic platform which may assist service members who have sustained improvised explosive device injuries during Operation Enduring Freedom, Operation Iraqi Freedom, and Operation New Dawn. The complex nature of warfighter injuries present unique rehabilitation challenges that demand new tools for quick return to active duty or the civilian community. FINDINGS: Virtual reality-based gait training programs may directly influence physiological and biomechanical performance for those who have endured combat injuries. The CAREN system provides a safe, interactive environment for the user while capturing kinematic and kinetic data capture to improve rehabilitation regimens. CONCLUSIONS: This paper provides an overview of the CAREN system and describes how this dynamic rehabilitation aid may be a translational tool for collecting biomechanical and physiological data during prosthetic training. The CAREN platform allows users to be fully immersed in a virtual environment while healthcare providers use these simulations to improve gait and stability, obstacle avoidance, or improved weight shifting. As such, rehabilitation regimens may be patient specific. PMID- 23820146 TI - Software wizards to adjust keyboard and mouse settings for people with physical impairments. AB - CONTEXT/OBJECTIVE: This study describes research behind two software wizards that help users with physical impairments adjust their keyboard and mouse settings to meet their specific needs. The Keyboard Wizard and Pointing Wizard programs help ensure that keyboard and pointing devices are properly configured for an individual, and reconfigured as the user's needs change. We summarize four effectiveness studies and six usability studies. METHODS: Studies involved participants whose physical impairments affect their ability to use a keyboard and mouse. Effectiveness studies used an A-B-A design, with condition A using default Windows settings and condition B using wizard-recommended settings. Primary data were performance metrics for text entry and target acquisition. Usability studies asked participants to run through each wizard, with no outside guidance. Primary data were completion time, errors made, and user feedback. RESULTS: The wizards were effective at recommending new settings for users who needed them and not recommending them for users who did not. Sensitivity for StickyKeys, pointer speed, and object size algorithms was 100%. Specificity for StickyKeys and pointer speed was over 80%, and 50% for object size. For those who needed settings changes, the recommendations improved performance, with speed increases ranging from 9 to 59%. Accuracy improved significantly with the wizard recommendations, eliminating up to 100% of errors. Users ran through the current wizard software in less than 6 minutes. Ease-of-use rating averaged over 4.5 on a scale of 1 to 5. CONCLUSION: The wizards are a simple yet effective way of adjusting Windows to accommodate physical impairments. PMID- 23820147 TI - Vertical ground reaction force-based analysis of powered exoskeleton-assisted walking in persons with motor-complete paraplegia. AB - OBJECTIVE: To use vertical ground reaction force (vGRF) to show the magnitude and pattern of mechanical loading in persons with spinal cord injury (SCI) during powered exoskeleton-assisted walking. RESEARCH DESIGN: A cross-sectional study was performed to analyze vGRF during powered exoskeleton-assisted walking (ReWalkTM: Argo Medical Technologies, Inc, Marlborough, MA, USA) compared with vGRF of able-bodied gait. SETTING: Veterans Affairs Medical Center. PARTICIPANTS: Six persons with thoracic motor-complete SCI (T1-T11 AIS A/B) and three age-, height-, weight- and gender-matched able-bodied volunteers participated. INTERVENTIONS: SCI participants were trained to ambulate over ground using a ReWalkTM. vGRF was recorded using the F-ScanTM system (TekScan, Boston, MA, USA). OUTCOME MEASURES: Peak stance average (PSA) was computed from vGRF and normalized across all participants by percent body weight. Peak vGRF was determined for heel strike, mid-stance, and toe-off. Relative linear impulse and harmonic analysis provided quantitative support for analysis of powered exoskeletal gait. RESULTS: Participants with motor-complete SCI, ambulating independently with a ReWalkTM, demonstrated mechanical loading magnitudes and patterns similar to able-bodied gait. Harmonic analysis of PSA profile by Fourier transform contrasted frequency of stance phase gait components between able-bodied and powered exoskeleton assisted walking. CONCLUSION: Powered exoskeleton-assisted walking in persons with motor-complete SCI generated vGRF similar in magnitude and pattern to that of able-bodied walking. This suggests the potential for powered exoskeleton assisted walking to provide a mechanism for mechanical loading to the lower extremities. vGRF profile can be used to examine both magnitude of loading and gait mechanics of powered exoskeleton-assisted walking among participants of different weight, gait speed, and level of assist. PMID- 23820148 TI - Assessment of wheelchair driving performance in a virtual reality-based simulator. AB - OBJECTIVE: To develop a virtual reality (VR)-based simulator that can assist clinicians in performing standardized wheelchair driving assessments. DESIGN: A completely within-subjects repeated measures design. METHODS: Participants drove their wheelchairs along a virtual driving circuit modeled after the Power Mobility Road Test (PMRT) and in a hallway with decreasing width. The virtual simulator was displayed on computer screen and VR screens and participants interacted with it using a set of instrumented rollers and a wheelchair joystick. Driving performances of participants were estimated and compared using quantitative metrics from the simulator. Qualitative ratings from two experienced clinicians were used to estimate intra- and inter-rater reliability. RESULTS: Ten regular wheelchair users (seven men, three women; mean age +/- SD, 39.5 +/- 15.39 years) participated. The virtual PMRT scores from the two clinicians show high inter-rater reliability (78-90%) and high intra-rater reliability (71-90%) for all test conditions. More research is required to explore user preferences and effectiveness of the two control methods (rollers and mathematical model) and the display screens. CONCLUSIONS: The virtual driving simulator seems to be a promising tool for wheelchair driving assessment that clinicians can use to supplement their real-world evaluations. PMID- 23820149 TI - Development of an advanced mobile base for personal mobility and manipulation appliance generation II robotic wheelchair. AB - BACKGROUND: This paper describes the development of a mobile base for the Personal Mobility and Manipulation Appliance Generation II (PerMMA Gen II robotic wheelchair), an obstacle-climbing wheelchair able to move in structured and unstructured environments, and to climb over curbs as high as 8 inches. The mechanical, electrical, and software systems of the mobile base are presented in detail, and similar devices such as the iBOT mobility system, TopChair, and 6X6 Explorer are described. FINDINGS: The mobile base of PerMMA Gen II has two operating modes: "advanced driving mode" on flat and uneven terrain, and "automatic climbing mode" during stair climbing. The different operating modes are triggered either by local and dynamic conditions or by external commands from users. A step-climbing sequence, up to 0.2 m, is under development and to be evaluated via simulation. The mathematical model of the mobile base is introduced. A feedback and a feed-forward controller have been developed to maintain the posture of the passenger when driving over uneven surfaces or slopes. The effectiveness of the controller has been evaluated by simulation using the open dynamics engine tool. CONCLUSION: Future work for PerMMA Gen II mobile base is implementation of the simulation and control on a real system and evaluation of the system via further experimental tests. PMID- 23820150 TI - Development and evaluation of a gyroscope-based wheel rotation monitor for manual wheelchair users. AB - OBJECTIVE: To develop and evaluate a wireless gyroscope-based wheel rotation monitor (G-WRM) that can estimate speeds and distances traveled by wheelchair users during regular wheelchair propulsion as well as wheelchair sports such as handcycling, and provide users with real-time feedback through a smartphone application. METHODS: The speeds and the distances estimated by the G-WRM were compared with the criterion measures by calculating absolute difference, mean difference, and percentage errors during a series of laboratory-based tests. Intraclass correlations (ICC) and the Bland-Altman plots were also used to assess the agreements between the G-WRM and the criterion measures. In addition, battery life and wireless data transmission tests under a number of usage conditions were performed. RESULTS: The percentage errors for the angular velocities, speeds, and distances obtained from three prototype G-WRMs were less than 3% for all the test trials. The high ICC values (ICC (3,1) > 0.94) and the Bland-Altman plots indicate excellent agreement between the estimated speeds and distances by the G WRMs and the criterion measures. The battery life tests showed that the device could last for 35 hours in wireless mode and 139 hours in secure digital card mode. The wireless data transmission tests indicated less than 0.3% of data loss. CONCLUSION: The results indicate that the G-WRM is an appropriate tool for tracking a spectrum of wheelchair-related activities from regular wheelchair propulsion to wheelchair sports such as handcycling. The real-time feedback provided by the G-WRM can help wheelchair users self-monitor their everyday activities. PMID- 23820151 TI - Effectiveness of local cooling for enhancing tissue ischemia tolerance in people with spinal cord injury. AB - OBJECTIVE: To investigate the effects of localized cooling and cooling rate on pressure-induced ischemia for people with and without neurological deficits. DESIGN: A 2 * 3 mixed factorial design with two groups: (1) people with spinal cord injury (SCI) and (2) people without neurological deficits (control), and three test conditions: (1) pressure only, (2) pressure with fast cooling (-4 degrees C/min), and (3) pressure with slow cooling (-0.33 degrees C/min). SETTING: University laboratory. PARTICIPANTS: Fourteen controls and 14 individuals with SCI. INTERVENTIONS: Pressure on the sacrum was 0.4 kPa for 5 minutes, then 8 kPa for 20 minutes, and finally 0.4 kPa for 15 minutes. Fast and slow cooling to 25 degrees C applied during 8 kPa of pressure. OUTCOME MEASURES: Reactive hyperemia and its spectral densities in the metabolic, neurogenic, and myogenic frequency ranges. RESULTS: In controls, reactive hyperemia was greater in pressure only as compared with both cooling conditions. No change was noted in all spectral densities in both cooling conditions, and only neurogenic spectral density increased without cooling. In subjects with SCI, no difference was noted in reactive hyperemia among conditions. However, metabolic and myogenic spectral densities increased without cooling and all spectral densities increased with slow cooling. No change was noted in all spectral densities with fast cooling. CONCLUSION: Local cooling reduced the severity of ischemia in controls. This protective effect may be masked in subjects with SCI due to chronic microvascular changes; however, spectral analysis suggested local cooling may reduce metabolic vasodilation. These findings provide evidence towards the development of support surfaces with temperature control for weight-bearing soft tissues. PMID- 23820152 TI - Health risks of vibration exposure to wheelchair users in the community. AB - OBJECTIVE: The purpose of this study was to evaluate whole-body vibration (WBV) exposure to wheelchair (WC) users in their communities and to determine the effect of WC frame type (folding, rigid, and suspension) in reducing WBV transmitted to the person. DESIGN: An observational case-control study of the WBV exposure levels among WC users. PARTICIPANTS: Thirty-seven WC users, with no pressure sores, 18 years old or older and able to perform independent transfers. MAIN OUTCOME MEASURES: WC users were monitored for 2 weeks to collect WBV exposure, as well as activity levels, by using custom vibration and activity data loggers. Vibration levels were evaluated using ISO 2631-1 methods. RESULTS: All WC users who participated in this study were continuously exposed to WBV levels at the seat that were within and above the health caution zone specified by ISO 2631-1 during their day-to-day activities (0.83 +/- 0.17 m/second(2), weighted root-mean-squared acceleration, for 13.07 +/- 3.85 hours duration of exposure). WCs with suspension did not attenuate vibration transmitted to WC users (V = 0.180, F(8, 56) = 0.692, P = 0.697). Conclusions WBV exposure to WC users exceeds international standards. Suspension systems need to be improved to reduce vibrations transmitted to the users. PMID- 23820153 TI - Physical strain of handcycling: an evaluation using training guidelines for a healthy lifestyle as defined by the American College of Sports Medicine. AB - OBJECTIVE: Developments in assistive technology such as handcycling provide attractive possibilities to pursue a healthy lifestyle for patients with spinal cord injury. The objective of the study is to evaluate physical stress and strain of handcycling against training guidelines as defined by the American College of Sports Medicine (ACSM). DESIGN: Seven able-bodied males conducted an incremental peak exercise handcycling test on a treadmill. In addition, two indoor treadmill (1.3 m/second with an inclination of 0.7% and 1.0 m/second with an inclination of 4.8%) and three outdoor over ground exercise bouts were performed (1.7, 3.3, and 5.0 m/second). One individual handcycled a representative 8-km-distance outdoors. OUTCOME MEASURES: Physical stress and strain were described in terms of absolute and relative power output, oxygen uptake (VO2), gross efficiency (GE), and heart rate (HR). Also, local perceived discomfort (LPD) was determined. RESULTS: Relative handcycling exercise intensities varied between 23.3 +/- 4.2 (below the ACSM lower limit of 46%VO2peak) and 72.5 +/- 15.1%VO2peak (well above the ACSM lower limit), with GE ranging from 6.0 +/- 1.5% at the lower to 13.0 +/- 2.6% at the higher exercise intensities. Exercise intensities were performed at 49.8 +/- 4.2 to 80.1 +/- 10.5%HRpeak. LPD scores were low to moderate (<27 +/- 7). CONCLUSION: Handcycling is relatively efficient and exercise intensities > 46%VO2peak were elicited. However, exercise load seems to be underestimated using %HRpeak. LPD was not perceived as limiting. Physiological stress and strain in able-bodied individuals appear to be comparable to individuals with a paraplegia. To understand individualize and optimize upper-body training, different training programs must be evaluated. PMID- 23820154 TI - Criterion validity and accuracy of global positioning satellite and data logging devices for wheelchair tennis court movement. AB - PURPOSE: To compare the criterion validity and accuracy of a 1 Hz non differential global positioning system (GPS) and data logger device (DL) for the measurement of wheelchair tennis court movement variables. METHODS: Initial validation of the DL device was performed. GPS and DL were fitted to the wheelchair and used to record distance (m) and speed (m/second) during (a) tennis field (b) linear track, and (c) match-play test scenarios. Fifteen participants were monitored at the Wheelchair British Tennis Open. RESULTS: Data logging validation showed underestimations for distance in right (DLR) and left (DLL) logging devices at speeds >2.5 m/second. In tennis-field tests, GPS underestimated distance in five drills. DLL was lower than both (a) criterion and (b) DLR in drills moving forward. Reversing drill direction showed that DLR was lower than (a) criterion and (b) DLL. GPS values for distance and average speed for match play were significantly lower than equivalent values obtained by DL (distance: 2816 (844) vs. 3952 (1109) m, P = 0.0001; average speed: 0.7 (0.2) vs. 1.0 (0.2) m/second, P = 0.0001). Higher peak speeds were observed in DL (3.4 (0.4) vs. 3.1 (0.5) m/second, P = 0.004) during tennis match play. CONCLUSIONS: Sampling frequencies of 1 Hz are too low to accurately measure distance and speed during wheelchair tennis. GPS units with a higher sampling rate should be advocated in further studies. Modifications to existing DL devices may be required to increase measurement precision. Further research into the validity of movement devices during match play will further inform the demands and movement patterns associated with wheelchair tennis. PMID- 23820155 TI - Spinal cord injury facts and figures at a glance. PMID- 23820156 TI - Food for thought: a pilot study of the pros and cons of changing eating patterns within cognitive-behavioural therapy for the eating disorders. AB - Evidence-based cognitive-behavioural therapy (CBT) for the eating disorders has an early focus on behavioural changes around food intake. However, patients' anxiety around such change might account for why they often seem unmotivated in treatment. In order to determine the impact of changing intake, this pilot study of patients with bulimic disorders (N = 19) or anorexia nervosa (N = 9) used a mixed quantitative and qualitative design to retrospectively examine their perspectives of the short- and long-term pros and cons of such change. As expected, change was seen negatively in the short-term (with particularly high numbers reporting anxiety), but there were few reports of long-term negative outcomes. In contrast, there were both short- and long-term benefits of changing eating. The patients described what was helpful in making changes and what they had learned as a result. In both cases, their descriptions mapped closely onto the content and process of evidence-based CBT for the eating disorders. Although there is a need for more extensive research, these findings suggest that patients (and therapists) might benefit from being aware of the contrast between the short and the long-term pros and cons of changing eating within CBT for the eating disorders. PMID- 23820158 TI - WITHDRAWN: Computed tomography-assisted diagnosis and therapy of elbow cysts in two horses. AB - Ahead of Print article withdrawn by publisher. PMID- 23820157 TI - Predicting group cognitive-behavioral therapy outcome of binge eating disorder using empirical classification. AB - The purpose of this study was to use empirical classification based on Latent Profile Analysis to identify subgroups of binge eating disorder (BED) and to evaluate the extent to which these subgroups were predictive of treatment outcome in group cognitive-behavioral therapy (CBT). The Eating Disorder Examination (EDE), Structured Clinical Interview for DSM-IV, and Inventory of Depressive Symptomatology-Self-Report were administered to 259 participants at baseline in a 15-session CBT trial (190 of whom received active treatment). The best fitting model included three profiles: dietary restraint only (DRO; n = 96; 51%); low dietary restraint (LDR; n = 52; 27%); and dietary restraint plus psychopathology (DRP; n = 42; 22%). Regression analyses revealed that after controlling for baseline score and treatment condition, EDE Global scores were lower for the DRO compared to the LDR profile at one year follow-up (p = .047). Class assignment was not predictive of EDE binge eating frequency or abstinence at end of treatment or follow-up. These results suggest that meaningful empirical classes based on eating disorder symptoms, psychopathology, dietary restraint, and BMI can be identified in BED and that these classes may be useful in predicting long term group CBT outcome. PMID- 23820159 TI - Improved rat spinal cord injury model using spinal cord compression by percutaneous method. AB - Here, percutaneous spinal cord injury (SCI) methods using a balloon catheter in adult rats are described. A balloon catheter was inserted into the epidural space through the lumbosacral junction and then inflated between T9-T10 for 10 min under fluoroscopic guidance. Animals were divided into three groups with respect to inflation volume: 20 MUL (n = 18), 50 MUL (n = 18) and control (Fogarty catheter inserted but not inflated; n = 10). Neurological assessments were then made based on BBB score, magnetic resonance imaging and histopathology. Both inflation volumes produced complete paralysis. Gradual recovery of motor function occurred when 20 MUL was used, but not after 50 MUL was applied. In the 50 MUL group, all gray and white matter was lost from the center of the lesion. In addition, supramaximal damage was noted, which likely prevented spontaneous recovery. This percutaneous spinal cord compression injury model is simple, rapid with high reproducibility and the potential to serve as a useful tool for investigation of pathophysiology and possible protective treatments of SCI in vivo. PMID- 23820160 TI - Percutaneous transplantation of human umbilical cord-derived mesenchymal stem cells in a dog suspected to have fibrocartilaginous embolic myelopathy. AB - The use of human umbilical cord blood-derived mesenchymal stem cells for cell transplantation therapy holds great promise for repairing spinal cord injury. Here we report the first clinical trial transplantation of human umbilical cord (hUCB)-derived mesenchymal stem cells (MSCs) into the spinal cord of a dog suspected to have fibrocartilaginous embolic myelopathy (FCEM) and that experienced a loss of deep pain sensation. Locomotor functions improved following transplantation in a dog. Based on our findings, we suggest that transplantation of hUCB-derived MSCs will have beneficial therapeutic effects on FCEM patients lacking deep pain sensation. PMID- 23820161 TI - Prevalence and risk factors for carriage of multi-drug resistant Staphylococci in healthy cats and dogs. AB - We investigated the distribution of commensal staphylococcal species and determined the prevalence of multi-drug resistance in healthy cats and dogs. Risk factors associated with the carriage of multi-drug resistant strains were explored. Isolates from 256 dogs and 277 cats were identified at the species level using matrix-assisted laser desorption ionisation-time of flight mass spectrometry. The diversity of coagulase-negative Staphylococci (CNS) was high, with 22 species in dogs and 24 in cats. Multi-drug resistance was frequent (17%) and not always associated with the presence of the mecA gene. A stay in a veterinary clinic in the last year was associated with an increased risk of colonisation by multi-drug resistant Staphylococci (OR = 2.4, 95% CI: 1.1~5.2, p value LRT = 0.04). When identifying efficient control strategies against antibiotic resistance, the presence of mechanisms other than methicillin resistance and the possible role of CNS in the spread of resistance determinants should be considered. PMID- 23820162 TI - Evaluation of bone healing in canine tibial defects filled with cortical autograft, commercial-DBM, calf fetal DBM, omentum and omentum-calf fetal DBM. AB - The present study was conducted to compare the effects of xenogenic bovine fetal demineralized bone matrix (DBM), commercial DBM, omentum, omentum-calf fetal DBM, cortical autograft and xenogenic cartilage powder on the healing of tibial defects in a dog model to determine the best material for bone healing. Seven male adult mongrel dogs, weighing 26.2 +/- 2.5 kg, were used in this study. Seven holes with a diameter of 4-mm were created and then filled with several biomaterials. Radiographs were taken postoperatively on day 1 and weeks 2, 4, 6, 8. The operated tibias were removed on the 56th postoperative day and histopathologically evaluated. On postoperative days 14, 42 and 56, the lesions of the control group were significantly inferior to those in the other group (p < 0.05). On the 28th postoperative day, the autograft group was significantly superior to the control and omentum groups (p < 0.05). Moreover, calf fetal DBM was significantly superior to the control group. There was no significant difference between the histopathological sections of all groups. Overall, the omentum and omentum-DBM groups were superior to the control group, but inferior to the autograft, commercial-DBM, calf fetal DBM and calf fetal cartilage groups. PMID- 23820163 TI - Expression of verocytotoxic Escherichia coli antigens in tobacco seeds and evaluation of gut immunity after oral administration in mouse model. AB - Verocytotoxic Escherichia (E.) coli strains are responsible for swine oedema disease, which is an enterotoxaemia that causes economic losses in the pig industry. The production of a vaccine for oral administration in transgenic seeds could be an efficient system to stimulate local immunity. This study was conducted to transform tobacco plants for the seed-specific expression of antigenic proteins from a porcine verocytotoxic E. coli strain. Parameters related to an immunological response and possible adverse effects on the oral administration of obtained tobacco seeds were evaluated in a mouse model. Tobacco was transformed via Agrobacteium tumefaciens with chimeric constructs containing structural parts of the major subunit FedA of the F18 adhesive fimbriae and VT2e B-subunit genes under control of a seed specific GLOB promoter. We showed that the foreign Vt2e-B and F18 genes were stably accumulated in storage tissue by the immunostaining method. In addition, Balb-C mice receiving transgenic tobacco seeds via the oral route showed a significant increase in IgA-positive plasma cell presence in tunica propria when compared to the control group with no observed adverse effects. Our findings encourage future studies focusing on swine for evaluation of the protective effects of transformed tobacco seeds against E. coli infection. PMID- 23820165 TI - Differential expression of thymic DNA repair genes in low-dose-rate irradiated AKR/J mice. AB - We previously determined that AKR/J mice housed in a low-dose-rate (LDR) ((137)Cs, 0.7 mGy/h, 2.1 Gy) gamma-irradiation facility developed less spontaneous thymic lymphoma and survived longer than those receiving sham or high dose-rate (HDR) ((137)Cs, 0.8 Gy/min, 4.5 Gy) radiation. Interestingly, histopathological analysis showed a mild lymphomagenesis in the thymus of LDR irradiated mice. Therefore, in this study, we investigated whether LDR irradiation could trigger the expression of thymic genes involved in the DNA repair process of AKR/J mice. The enrichment analysis of Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways showed immune response, nucleosome organization, and the peroxisome proliferator-activated receptors signaling pathway in LDR-irradiated mice. Our microarray analysis and quantitative polymerase chain reaction data demonstrated that mRNA levels of Lig4 and RRM2 were specifically elevated in AKR/J mice at 130 days after the start of LDR irradiation. Furthermore, transcriptional levels of H2AX and ATM, proteins known to recruit DNA repair factors, were also shown to be upregulated. These data suggest that LDR irradiation could trigger specific induction of DNA repair associated genes in an attempt to repair damaged DNA during tumor progression, which in turn contributed to the decreased incidence of lymphoma and increased survival. Overall, we identified specific DNA repair genes in LDR-irradiated AKR/J mice. PMID- 23820164 TI - Preparation and diagnostic utility of a hemagglutination inhibition test antigen derived from the baculovirus-expressed hemagglutinin-neuraminidase protein gene of Newcastle disease virus. AB - A recombinant hemagglutinin-neuraminidase (rHN) protein from Newcastle disease virus (NDV) with hemagglutination (HA) activity was expressed in Spodoptera frugiperda cells using a baculovirus expression system. The rHN protein extracted from infected cells was used as an antigen in a hemagglutination inhibition (HI) test for the detection and titration of NDV-specific antibodies present in chicken sera. The rHN antigen produced high HA titers of 2(13) per 25 MUL, which were similar to those of the NDV antigen produced using chicken eggs, and it remained stable without significant loss of the HA activity for at least 12 weeks at 4 degrees C. The rHN-based HI assay specifically detected NDV antibodies, but not the sera of other avian pathogens, with a specificity and sensitivity of 100% and 98.0%, respectively, in known positive and negative chicken sera (n = 430). Compared with an NDV-based HI assay, the rHN-based HI assay had a relative sensitivity and specificity of 96.1% and 95.5%, respectively, when applied to field chicken sera. The HI titers of the rHN-based HI assay were highly correlated with those in an NDV-based HI assay (r = 0.927). Overall, these results indicate that rHN protein provides a useful alternative to NDV antigen in HI assays. PMID- 23820166 TI - Characterization and clinical application of mesenchymal stem cells from equine umbilical cord blood. AB - Tendinitis of the superficial digital flexor tendon (SDFT) is a significant cause of lameness in horses; however, recent studies have shown that stem cells could be useful in veterinary regenerative medicine. Therefore, we isolated and characterized equine umbilical cord blood mesenchymal stem cells (eUCB-MSCs) from equine umbilical cord blood obtained from thoroughbred mares during the foaling period. Horses that had tendinitis of the SDFT were treated with eUCB-MSCs to confirm the therapeutic effect. After eUCB-MSCs transplantation, the core lesion in the SDFT was found to decrease. These results suggest that transplantation using eUCB-MSCs could be another source of cell treatment. PMID- 23820167 TI - Transrectal Doppler sonography of uterine blood flow during the first two weeks after parturition in Simmenthal heifers. AB - Transrectal Doppler sonography was used to evaluate uterine blood flow during the first two weeks after parturition in six primiparous Simmental cows. The uterine blood flow was evaluated on the day of parturition (Day 0), once daily from Days 1 to 8 and then every other day until Day 14. Blood flow was quantified by determining the diameter (D), the time-averaged maximum velocity (TAMV), the pulsatility index (PI) and the blood flow volume (BFV) of the uterine arteries ipsilateral and contralateral to the formerly pregnant uterine horn. During the first four days after calving D, TAMV and BFV declined (ipsilateral: TAMV 70%, BFV 87%, contralateral: D 47%, BFV 84%; p < 0.05), while PI increased (ipsilateral 158%, contralateral 100%; p < 0.05) distinctly. Between Days 4 and 14 only the ipsilateral D (12%) and the BFV of both arteries (ipsilateral 5%, contralateral 8%) decreased (p < 0.05). Blood flow variables were very strongly correlated with each other (r > +/-0.75, p < 0.05), with negative correlations with PI and positive correlations with all other investigated factors. Overall, this study revealed characteristic changes in uterine perfusion during the first two weeks after parturition in cows that were pronounced during the first four days postpartum. PMID- 23820169 TI - Retraction: Exercise-induced alterations in serum myeloperoxidase in Standardbreds. PMID- 23820168 TI - Pathology of non-thermal irreversible electroporation (N-TIRE)-induced ablation of the canine brain. AB - This study describes the neuropathologic features of normal canine brain ablated with non-thermal irreversible electroporation (N-TIRE). The parietal cerebral cortices of four dogs were treated with N-TIRE using a dose-escalation protocol with an additional dog receiving sham treatment. Animals were allowed to recover following N-TIRE ablation and the effects of treatment were monitored with clinical and magnetic resonance imaging examinations. Brains were subjected to histopathologic and ultrastructural assessment along with Bcl-2, caspase-3, and caspase-9 immunohistochemical staining following sacrifice 72 h post-treatment. Adverse clinical effects of N-TIRE were only observed in the dog treated at the upper energy tier. MRI and neuropathologic examinations indicated that N-TIRE ablation resulted in focal regions of severe cytoarchitectural and blood-brain barrier disruption. Lesion size correlated to the intensity of the applied electrical field. N-TIRE-induced lesions were characterized by parenchymal necrosis and hemorrhage; however, large blood vessels were preserved. A transition zone containing parenchymal edema, perivascular inflammatory cuffs, and reactive gliosis was interspersed between the necrotic focus and normal neuropil. Apoptotic labeling indices were not different between the N-TIRE treated and control brains. This study identified N-TIRE pulse parameters that can be used to safely create circumscribed foci of brain necrosis while selectively preserving major vascular structures. PMID- 23820170 TI - Mitochondrial and DNA damage in bovine somatic cell nuclear transfer embryos. AB - The generation of reactive oxygen species (ROS) and subsequent mitochondrial and DNA damage in bovine somatic cell nuclear transfer (SCNT) embryos were examined. Bovine enucleated oocytes were electrofused with donor cells and then activated by a combination of Ca-ionophore and 6-dimethylaminopurine culture. The H2O2 and OH radical levels, mitochondrial morphology and membrane potential (DeltaPsi), and DNA fragmentation of SCNT and in vitro fertilized (IVF) embryos at the zygote stage were analyzed. The H2O2 (35.6 +/- 1.1 pixels/embryo) and OH radical levels (44.6 +/- 1.2 pixels/embryo) of SCNT embryos were significantly higher than those of IVF embryos (19.2 +/- 1.5 and 23.8 +/- 1.8 pixels/embryo, respectively, p < 0.05). The mitochondria morphology of SCNT embryos was diffused within the cytoplasm. The DeltaPsi of SCNT embryos was significantly lower (p < 0.05) than that of IVF embryos (0.95 +/- 0.04 vs. 1.21 +/- 0.06, red/green). Moreover, the comet tail length of SCNT embryos was longer than that of IVF embryos (515.5 +/- 26.4 MUm vs. 425.6 +/- 25.0 MUm, p < 0.05). These results indicate that mitochondrial and DNA damage increased in bovine SCNT embryos, which may have been induced by increased ROS levels. PMID- 23820172 TI - Spontaneous aortic arch thrombosis in a neonate. PMID- 23820171 TI - Black rice anthocyanidins prevent retinal photochemical damage via involvement of the AP-1/NF-kappaB/Caspase-1 pathway in Sprague-Dawley rats. AB - The effects of black rice anthocyanidins (BRACs) on retinal damage induced by photochemical stress are not well known. In the present study, Sprague-Dawley rats were fed AIN-93M for 1 week, after which 80 rats were randomly divided into two groups and treated with (n = 40) or without BRACs (n = 40) for 15 days, respectively. After treatment, both groups were exposed to fluorescent light (3,000 +/- 200 lux; 25 degrees C), and the protective effect of dietary BRACs were evaluated afterwards. Our results showed that dietary BRACs effectively prevented retinal photochemical damage and inhibited the retinal cells apoptosis induced by fluorescent light (p < 0.05). Moreover, dietary BRACs inhibited expression of AP-1 (c-fos/c-jun subunits), up-regulated NF-kappaB (p65) expression and phosphorylation of IkappaB-alpha, and decreased Caspase-1 expression (p < 0.05). These results suggest that BRACs improve retinal damage produced by photochemical stress in rats via AP-1/NF-kappaB/Caspase-1 apoptotic mechanisms. PMID- 23820173 TI - Comparative study of bronchial artery revascularization in lung transplantation. AB - OBJECTIVE: Restoring dual blood supply to transplanted lungs by bronchial artery revascularization (BAR) remains controversial. We compared outcomes after lung transplantation performed with and without BAR. METHODS: From December 2007 to July 2010, 283 patients underwent transplantation; 187 were 18 years or older, without previous or concomitant cardiac surgery. Of these patients, 27 underwent BAR in a pilot study to test success, safety, effectiveness, and teachability. A propensity score was generated to match BAR patients and 54 routine non-BAR patients. Follow-up was 1.3 +/- 0.68 years. RESULTS: BAR was angiographically successful in 26 (96%) of 27 patients. BAR and non-BAR patients had similar skin to-skin time (P = .07) and postoperative hospital stays (P = .2), but more reoperations for bleeding (P = .002). Tracheostomy was performed in 9 (33%) of 27 BAR and 10 (19%) of 54 non-BAR patients (P = .2, log-rank). One BAR (3.7%) and 4 non-BAR (7.4%) patients required extracorporeal membrane oxygenation (P = .7). Airway ischemia was observed in 1 BAR (3.7%) versus 12 non-BAR (22%) patients (P = .03); anastomotic intervention was required in no BAR versus 8 non-BAR (15%) patients (P = .04). Hospital mortality was 1 of 27 versus 2 of 54 (P = .9). BAR patients had lower early biopsy tissue rejection grades (P = .008) and fewer pulmonary (P < .04) and bloodstream (P < .02) infections. Forced 1-second expiratory volume was similar (P > .2); 3 BAR versus 9 non-BAR patients developed bronchiolitis obliterans syndrome (BOS) (P = .14, log-rank). During follow-up, 4 BAR and 8 non-BAR patients died (P = .6, log-rank). CONCLUSIONS: BAR is safe, with comparable early outcomes. Benefits of BAR include reduced airway ischemia and complications, lower biopsy tissue grades, fewer infections, and delay of BOS. A multicenter study is needed to establish these benefits. PMID- 23820174 TI - Efficacy and safety of recombinant factor XIII on reducing blood transfusions in cardiac surgery: a randomized, placebo-controlled, multicenter clinical trial. AB - OBJECTIVES: Cardiac surgery with cardiopulmonary bypass frequently leads to excessive bleeding, obligating blood product transfusions. Because low factor XIII (FXIII) levels have been associated with bleeding after cardiac surgery, we investigated whether administering recombinant FXIII after cardiopulmonary bypass would reduce transfusions. METHODS: In this double-blinded, placebo-controlled, multicenter trial, 409 cardiac surgical patients at moderate risk for transfusion were randomized to receive an intravenous dose of recombinant FXIII, 17.5 IU/kg (n = 143), 35 IU/kg (n = 138), or placebo (n = 128) after cardiopulmonary bypass. Transfusion guidelines were standardized. The primary efficacy outcome was avoidance of allogeneic blood products for 7 days postsurgery. Secondary outcomes included amount of blood products transfused and reoperation rate. Serious adverse events were measured for 7 weeks. RESULTS: Study groups had comparable baseline characteristics and an approximately 40% decrease in FXIII levels after cardiopulmonary bypass. Thirty minutes postdose, FXIII levels were restored to higher than the lower 2.5th percentile of preoperative activity in 49% of the placebo group, and 85% and 95% of the 17.5- and 35-IU/kg recombinant FXIII groups, respectively (P < .05 for both treatments vs placebo). Transfusion avoidance rates were 64.8%, 64.3%, and 65.9% with placebo, 17.5 IU/kg, and 35 IU/kg recombinant FXIII (respective odds ratios against placebo, 1.05 [95% confidence interval, 0.61-1.80] and 0.99 [95% confidence interval, 0.57-1.72]). Groups had comparable adverse event rates. CONCLUSIONS: Replenishment of FXIII levels after cardiopulmonary bypass had no effect on transfusion avoidance, transfusion requirements, or reoperation in moderate-risk cardiac surgery patients (ClinicalTrials.gov identifier: NCT00914589). PMID- 23820175 TI - Additional value of dual-energy CT to differentiate between benign and malignant mediastinal tumors: an initial experience. AB - OBJECTIVES: To investigate the feasibility of dual-energy computed tomography (DECT) in differentiating malignant from benign mediastinal tumors. MATERIALS AND METHODS: We prospectively enrolled 25 patients (14 males; mean age: 56.7 years) who had suspected mediastinal tumors on chest radiography or non-contrast chest computed tomography (CT). All patients underwent a two-phase DECT using gemstone spectral imaging (GSI) mode (GE HD750). For the quantitative analysis, two investigators measured the following parameters of the tumors in the early and the delayed phases: CT attenuation value in Hounsfield units (HU) and iodine concentration (mg/ml). Pathological results were used for a final diagnosis. Statistical analyses were performed using the Fisher's exact test and the Mann Whitney t-test. RESULTS: 10 patients (40%) had benign pathology, while 15 (60%) had malignant pathology. The iodine concentration measurements were significantly different between benign and malignant tumors both in the early phase (1.38 mg/ml vs. 2.41 mg/ml, p=0.001) and in the delayed phase (1.52 mg/ml vs. 2.84 mg/ml, p=0.001), while mean attenuation values were not significantly different in both phases (57.8 HU vs. 69.1 HU, p=0.067 and 67.4 HU vs. 78.4 HU, p=0.086, respectively). CONCLUSIONS: Dual-energy CT using a quantitative analytic methodology can be used to differentiate between benign and malignant mediastinal tumors. PMID- 23820176 TI - Initial experience of acoustic radiation force impulse ultrasound imaging of cervical lymph nodes. AB - The aim of this study was to evaluate acoustic radiation force impulse imaging for cervical lymphadenopathy in routine clinical practice and to correlate the acoustic radiation force impulse values with the morphological signs and the pathological results, which were used as the reference standard. The virtual touch tissue quantification values were analyzed in 123 patients (mean age 40.8 years, range 1-81 years) with 181 cervical lymph nodes (87 benign, 94 malignant). The diagnostic performance of acoustic radiation force impulse values were evaluated with respect to sensitivity, specificity, and area under the curve using a receiver operating characteristic curve analysis. The mean virtual touch tissue quantification values of the benign lesions (2.01 +/- 0.95 m/s) differed from that of the malignant lesions (4.61 +/- 2.56 m/s; P<0.001). The cutoff level for virtual touch tissue quantification value for malignancy was estimated to be 2.595 m/s. Using the receiver operating characteristic curve curves with the cutoff value, the virtual touch tissue quantification value predicted malignancy with a sensitivity of 82.9%, specificity of 93.1% and gave an areas under the curve of 0.906 (95% CI 0.857-0.954). Acoustic radiation force impulse is feasible for cervical lymph nodes and provides quantitative elasticity measurements, which may complement B-mode ultrasound and potentially improve the characterization of cervical lymph nodes. PMID- 23820177 TI - Is myocardial stress perfusion MR-imaging suitable to predict the long term clinical outcome after revascularization? AB - INTRODUCTION: Aim of our study was to evaluate, whether myocardial ischemia or myocardial infarction (MI) depicted by myocardial stress perfusion MR imaging (SP CMR) can predict the clinical outcome in patients with coronary artery disease (CAD). MATERIALS AND METHOD: 220 patients were included. Myocardial perfusion was assessed at stress and at rest, using a 2D saturation recovery gradient echo sequence (SR GRE) and myocardial viability by late gadolinium enhancement magnetic resonance images (LGE CMR). MR-images were assessed in regard of presence and extent of MI and ischemia. Patients were monitored for major adverse cardiac events (MACE) (monitoring period: 5-7 years). MACE were correlated with the initial results of SP CMR. RESULTS: Ischemia was found in 143 patients, MI in 107 patients. Number of MACE was in patients with normal SP CMR 0 (51 patients), with ischemia 21 (62 patients), with MI 14 (26 patients), with ischemia and MI 52 (81 patients). In all patients with severe MACE (MI, death) and in 63 of those with recurring symptoms LGE CMR revealed MI at baseline. CONCLUSION: Negative SP CMR indicates low risk for MACE. In patients with stress induced ischemia, MACE might occur even after myocardial revascularization. The presence of MI proved by LGE CMR is associated with a significantly increased risk for MACE. PMID- 23820178 TI - Carbodiimide crosslinked collagen from porcine dermal matrix for high-strength tissue engineering scaffold. AB - Naturally-derived collagens for tissue engineering are limited by low mechanical strength and rapid degradation. In this study, carbodiimide is used to chemically modify the collagen derived from porcine acellular dermal matrix (PADM). The results show that the strength and resistance of PADM to enzymatic digestion can be adjusted by the reconnection of free amino and carboxyl groups of the collagen fibers. The cytocompatibility of the crosslinked PADM was evaluated by cell adhesion and proliferation assays. The cell culture studies on crosslinked and uncrosslinked PADM showed that the modification does not affect the scaffold's biocompatibility. These results demonstrate that the PADM collagen materials can be strengthened through a low-cost, non-toxic crosslinking method for potential use in biomedical applications. PMID- 23820179 TI - Comparative study of physico-mechanical and antioxidant properties of edible gelatin films from the skin of cuttlefish. AB - Physicochemical properties of edible films based on cuttlefish skin gelatin extracted without (G0) or with different concentrations of pepsins (5 (G5), 10 (G10) and 15 (G15) U/g of skin) were investigated. Edible films prepared with partially hydrolyzed gelatins had lower tensile strength (TS) and elongation at break (EAB), but higher water vapour permeability (WVP) and water solubility than the control film. FTIR spectra of obtained gelatin films revealed a significant loss of molecular order of the triple helix. In addition, differential scanning calorimetric (DSC) analysis indicated that partially hydrolyzed gelatine films exhibited lower transition temperature and enthalpy compared with those of control film. The properties of the films were related to their microstructure, which was observed by scanning electron microscopy. Films with G0 and G5 had a smooth surface and a more compact structure, while films prepared with G10 and G15 had coarser surface. Thus, the chain length of extracted gelatin directly affected the properties of corresponding films. PMID- 23820180 TI - Learning to navigate: experience versus maps. AB - People use "route knowledge" to navigate to targets along familiar routes and "survey knowledge" to determine (by pointing, for example) a target's metric location. We show that both root in separate memories of the same environment: participants navigating through their home city relied on representations and reference frames different from those they used when doing a matched survey task. Tubingen residents recalled their way along a familiar route to a distant target while located in a photorealistic virtual 3D model of Tubingen, indicating their route decisions on a keyboard. Participants had previously done a survey task (pointing) using the same start points and targets. Errors and response latencies observed in route recall were completely unrelated to errors and latencies in pointing. This suggests participants employed different and independent representations for each task. Further, participants made fewer routing errors when asked to respond from a horizontal walking perspective rather than a constant aerial perspective. This suggests that instead of the single reference, north-up frame (similar to a conventional map) they used in the survey task, participants employed different, and most probably multiple, reference frames learned from "on the ground" navigating experience. The implication is that, within their everyday environment, people use map or navigation-based knowledge according to which best suits the task. PMID- 23820181 TI - Percutaneous removal of a Bard Simon nitinol permanent inferior vena cava filter. AB - Inferior vena cava (IVC) filters are used to treat thromboembolic disease when there is a contraindication to anticoagulation or failure of therapeutic anticoagulation therapy. Although there are retrievable IVC filters available, permanent IVC filters remain the most commonly placed IVC filters worldwide. Permanent IVC filters have been associated with long-term complications such as IVC thrombosis and obstruction, migration, and erosion into surrounding structures. Such complications may require removal of permanent IVC filters, which has been previously described with open surgery involving venotomy of the IVC. We report a case of a Bard Simon Nitinol permanent IVC filter that was removed by using percutaneous endovascular techniques. PMID- 23820182 TI - Objective scoring of transformed foci in BALB/c 3T3 cell transformation assay by statistical image descriptors. AB - In vitro cell transformation assays (CTAs) have been shown to model important stages of in vivo carcinogenesis and have the potential to predict carcinogenicity in humans. Advantages of CTAs are their ability of revealing both genotoxic and non-genotoxic carcinogens while reducing both experimental costs and the number of animals used. The endpoint of the CTA is foci formation, and requires classification under light microscopy based on morphology. Thus current limitations for the wide adoption of the assay partially depend on a fair degree of subjectivity in foci scoring. An objective evaluation may be obtained after separating foci from background monolayer in the digital image, and quantifying values of statistical descriptors which are selected to capture eye-scored morphological features. The aim of this study was to develop statistical descriptors to be applied to transformed foci of BALB/c 3T3, which cover foci size, multilayering and invasive cell growth into the background monolayer. Proposed descriptors were applied to a database of 407 foci images to explore the numerical features, and to illustrate open problems and potential solutions. PMID- 23820183 TI - Characterization of hepatic markers in human Wharton's Jelly-derived mesenchymal stem cells. AB - Stem cell technology could offer a unique tool to develop human-based in vitro liver models that are applicable for testing of potential liver toxicity early during drug development. In this context, recent research has indicated that human Wharton's Jelly-derived mesenchymal stem cells (hWJs) represent an interesting stem cell population to develop human hepatocyte-like cells. Here, an in-depth analysis of the expression of liver-specific transcription factors and other key hepatic markers in hWJs is evaluated at both the mRNA and protein level. Our results reveal that transcription factors that are mandatory to acquire and maintain an adult hepatic phenotype (HNF4A and HNF1A), as well as adult hepatic markers (ALB, CX32, CYP1A1, CYP1A2, CYP2B6 and CYP3A4) are not expressed in hWJs with the exception of K18. On the contrary, transcription factors involved in liver development (GATA4, GATA6, SOX9 and SOX17) and liver progenitor markers (DKK1, DPP4, DSG2, CX43 and K19) were found to be highly expressed in hWJs. These findings provide additional indication that hWJs could be a promising stem cell source to generate hepatocyte-like cells necessary for the development of a functional human-based in vitro liver model. PMID- 23820184 TI - Establishment of an in vitro photoassay using THP-1 cells and IL-8 to discriminate photoirritants from photoallergens. AB - At present, there are no in vivo or in vitro methods developed which has been adopted by regulatory authorities to assess photosensitization induced by chemicals. Recently, we have proposed the use of THP-1 cells and IL-8 release to identify the potential of chemicals to induce skin sensitization. Based on the assumption that sensitization and photosensitization share common mechanisms, the aim of this work was to explore the THP-1 model as an in vitro model to identify photoallergenic chemicals. THP-1 cells were exposed to 7 photoallergens and 3 photoirritants and irradiated with UVA light or kept in dark. Non phototoxic allergens or irritants were also included as negative compounds. Following 24h of incubation, cytotoxicity and IL-8 release were measured. At subtoxic concentrations, photoallergens produced a dose-related increase in IL-8 release after irradiation. Some photoirritants also produced a slight increase in IL-8 release. However, when the overall stimulation indexes of IL-8 were calculated for each chemical, 6 out of 7 photoallergens tested reached a stimulation index above 2, while the entire set of negative compounds had stimulation indexes below 2. Our data suggest that this assay may become a useful cell-based in vitro test for evaluating the photosensitizing potential of chemicals. PMID- 23820185 TI - Impaired inhibition of prepotent motor actions in patients with Tourette syndrome. AB - BACKGROUND: Evidence that tic behaviour in individuals with Tourette syndrome reflects difficulties inhibiting prepotent motor actions is mixed. Response conflict tasks produce sensitive measures of response interference from prepotent motor impulses and the proficiency of inhibiting these impulses as an act of cognitive control. We tested the hypothesis that individuals with Tourette syndrome show a deficit in inhibiting prepotent motor actions. METHODS: Healthy controls and older adolescents/adults with persistent Tourette syndrome without a history of obsessive-compulsive disorder or attention-deficit/hyperactivity disorder and presenting with stable mood functioning (i.e., no history of well treated anxiety or depression) participated in this study. They performed a Simon task that induced conflict between prepotent actions and goal-directed actions. A novel theoretical framework distinguished group differences in acting impulsively (i.e., fast motor errors) from the proficiency of inhibiting interference by prepotent actions (i.e., slope of interference reduction). RESULTS: We included 27 controls and 28 individuals with Tourette syndrome in our study. Both groups showed similar susceptibility to making fast, impulsive motor errors (Tourette syndrome 26% v. control 23%; p = 0.10). The slope (m) reduction of the interference effect was significantly less pronounced among participants with Tourette syndrome than controls (Tourette syndrome: m = -0.07 v. control: m = 0.23; p = 0.022), consistent with deficient inhibitory control over prepotent actions in Tourette syndrome. LIMITATIONS: This study does not address directly the role of psychiatric comorbidities and medication effects on inhibitory control over impulsive actions in individuals with Tourette syndrome. CONCLUSION: The results offer empirical evidence for deficient inhibitory control over prepotent motor actions in individuals with persistent Tourette syndrome with minimal to absent psychiatric comorbidities. These findings also suggest that the frontal-basal ganglia circuits involved in suppressing unwanted motor actions may underlie deficient inhibitory control abilities in individuals with Tourette syndrome. PMID- 23820186 TI - Accuracy of plateau pressure and stress index to identify injurious ventilation in patients with acute respiratory distress syndrome. AB - BACKGROUND: Guidelines suggest a plateau pressure (PPLAT) of 30 cm H(2)O or less for patients with acute respiratory distress syndrome, but ventilation may still be injurious despite adhering to this guideline. The shape of the curve plotting airway pressure versus time (STRESS INDEX) may identify injurious ventilation. The authors assessed accuracy of PPLAT and STRESS INDEX to identify morphological indexes of injurious ventilation. METHODS: Indexes of lung aeration (computerized tomography) associated with injurious ventilation were used as a "reference standard." Threshold values of PPLAT and STRESS INDEX were determined assessing the receiver-operating characteristics ("training set," N = 30). Accuracy of these values was assessed in a second group of patients ("validation set," N = 20). PPLAT and STRESS INDEX were partitioned between respiratory system (Pplat,Rs and STRESS INDEX,RS) and lung (PPLAT,L and STRESS INDEX,L; esophageal pressure; "physiological set," N = 50). RESULTS: Sensitivity and specificity of PPLAT of greater than 30 cm H(2)O were 0.06 (95% CI, 0.002-0.30) and 1.0 (95% CI, 0.87 1.00). PPLAT of greater than 25 cm H(2)O and a STRESS INDEX of greater than 1.05 best identified morphological markers of injurious ventilation. Sensitivity and specificity of these values were 0.75 (95% CI, 0.35-0.97) and 0.75 (95% CI, 0.43 0.95) for PPLAT greater than 25 cm H(2)O versus 0.88 (95% CI, 0.47-1.00) and 0.50 (95% CI, 0.21-0.79) for STRESS INDEX greater than 1.05. Pplat,Rs did not correlate with PPLAT,L (R(2) = 0.0099); STRESS INDEX,RS and STRESS INDEX,L were correlated (R(2) = 0.762). CONCLUSIONS: The best threshold values for discriminating morphological indexes associated with injurious ventilation were Pplat,Rs greater than 25 cm H(2)O and STRESS INDEX,RS greater than 1.05. Although a substantial discrepancy between Pplat,Rs and PPLAT,L occurs, STRESS INDEX,RS reflects STRESS INDEX,L. PMID- 23820187 TI - Selective beta1-antagonism with bisoprolol is associated with fewer postoperative strokes than atenolol or metoprolol: a single-center cohort study of 44,092 consecutive patients. AB - BACKGROUND: Perioperative metoprolol increases postoperative stroke. Animal studies indicate that the mechanism may be related to attenuated beta(2) adrenoreceptor-mediated cerebral vasodilatation. The authors therefore conducted a cohort to study whether the highly beta(1)-specific beta-blocker (bisoprolol) was associated with a reduced risk of postoperative stroke compared with less selective beta-blockers (metoprolol or atenolol). METHODS: The authors conducted a single-center study on 44,092 consecutive patients with age 50 yr or more having noncardiac, nonneurologic surgery. The primary outcome was stroke within 7 days of surgery. The secondary outcome was a composite of all-cause mortality, postoperative myocardial injury, and stroke. A propensity score-matched cohort was created to assess the independent association between bisoprolol and less beta(1)-selective agents metoprolol or atenolol. A secondary analysis using logistic regression, based on previously identified confounders, also compared selective beta(1)-antagonism. RESULTS: Twenty-four percent (10,756) of patients were exposed to in-hospital beta-blockers. A total of 88 patients (0.2%) suffered a stroke within 7 days of surgery. The matched cohort consisted of 2,462 patients, and the pairs were well matched for all variables. Bisoprolol was associated with fewer postoperative strokes than the less selective agents (odds ratio = 0.20; 95% CI, 0.04-0.91). Multivariable risk-adjustment in the beta blockers-exposed patients comparing bisoprolol with the less selective agents was associated with a similarly reduced stroke rate. CONCLUSIONS: The use of metoprolol and atenolol is associated with increased risks of postoperative stroke, compared with bisoprolol. These findings warrant confirmation in a pragmatic randomized trial. PMID- 23820188 TI - Effects of dietary habits and risk factors on allergic rhinitis prevalence among Turkish adolescents. AB - BACKGROUND: Allergic rhinitis (AR) is a global health problem affecting many people from childhood to adulthood. The aim of this study was to evaluate the prevalence of AR and related symptoms, and to assess the risk factors, dietary habits and the Mediterranean diet affecting AR. METHODS: In a cross-sectional study design, 9991 children, aged 13-14 years in 61 primary schools in 32 districts of Istanbul were evaluated. The prevalence of AR symptoms among the children was evaluated using the ISAAC protocol. RESULTS: In our study, total of 10,984 questionnaires were distributed to 13-14yr-old schoolchildren to 61 schools in 32 district of Istanbul and 9991 questionnaires were suitable for analysis with an overall response of 91.7%. The rates of lifetime rhinitis, rhinitis in last 12 months and lifetime doctor diagnosed AR prevalence were 53.5%, 38.3% and 4.5%, respectively. The variation among districts in the prevalence of doctor diagnosed AR was very high. The highest prevalence was about 10 times higher than in the district with the lowest prevalence (range: 1.4-14.5) of Istanbul. A family history of atopy, mother with a university degree, presence of cat at home during last 12 months and adenoidectomy were significant for increased doctor diagnosed AR risk. Additionally, although fish and other sea foods, fermented drinks made from millets and various seeds, animal fats and butter were independent risk factors for doctor diagnosed AR, fish oil and hamburger were protective foods for doctor diagnosed AR. The MD was not associated with the prevalence of doctor diagnosed AR. CONCLUSIONS: This study shows that that there are wide variations for the prevalence of AR related symptoms in 13-14yr-old schoolchildren among districts of Istanbul in Turkey. Socio-economical, environmental factors, some dietary habits, but not Mediterranean diet may affect the prevalence of AR. PMID- 23820189 TI - Titanium distribution in swimming pool water is dominated by dissolved species. AB - The increased use of titanium dioxide nanoparticles (nano-TiO2) in consumer products such as sunscreen has raised concerns about their possible risk to human and environmental health. In this work, we report the occurrence, size fractionation and behavior of titanium (Ti) in a children's swimming pool. Size fractionated samples were analyzed for Ti using ICP-MS. Total titanium concentrations ([Ti]) in the pool water ranged between 21 MUg/L and 60 MUg/L and increased throughout the 101-day sampling period while [Ti] in tap water remained relatively constant. The majority of [Ti] was found in the dissolved phase (<1 kDa), with only a minor fraction of total [Ti] being considered either particulate or microparticulate. Simple models suggest that evaporation may account for the observed variation in [Ti], while sunscreen may be a relevant source of particulate and microparticule Ti. Compared to diet, incidental ingestion of nano-Ti from swimming pool water is minimal. PMID- 23820191 TI - Evaluating legacy contaminants and emerging chemicals in marine environments using adverse outcome pathways and biological effects-directed analysis. AB - Natural and synthetic chemicals are essential to our daily lives, food supplies, health care, industries and safe sanitation. At the same time protecting marine ecosystems and seafood resources from the adverse effects of chemical contaminants remains an important issue. Since the 1970s, monitoring of persistent, bioaccumulative and toxic (PBT) chemicals using analytical chemistry has provided important spatial and temporal trend data in three important contexts; relating to human health protection from seafood contamination, addressing threats to marine top predators and finally providing essential evidence to better protect the biodiversity of commercial and non-commercial marine species. A number of regional conventions have led to controls on certain PBT chemicals over several years (termed 'legacy contaminants'; e.g. cadmium, lindane, polycyclic aromatic hydrocarbons [PAHs] and polychlorinated biphenyls [PCBs]). Analytical chemistry plays a key role in evaluating to what extent such regulatory steps have been effective in leading to reduced emissions of these legacy contaminants into marine environments. In parallel, the application of biomarkers (e.g. DNA adducts, CYP1A-EROD, vitellogenin) and bioassays integrated with analytical chemistry has strengthened the evidence base to support an ecosystem approach to manage marine pollution problems. In recent years, however,the increased sensitivity of analytical chemistry, toxicity alerts and wider environmental awareness has led to a focus on emerging chemical contaminants (defined as chemicals that have been detected in the environment, but which are currently not included in regulatory monitoring programmes and whose fate and biological impacts are poorly understood). It is also known that natural chemicals (e.g. algal biotoxins) may also pose a threat to marine species and seafood quality. Hence complex mixtures of legacy contaminants, emerging chemicals and natural biotoxins in marine ecosystems represent important scientific, economic and health challenges. In order to meet these challenges and pursue cost-effective scientific approaches that can provide evidence necessary to support policy needs (e.g. the European Marine Strategy Framework Directive), it is widely recognised that there is a need to (i) provide marine exposure assessments for priority contaminants using a range of validated models, passive samplers and biomarkers; (ii) integrate chemical monitoring data with biological effects data across spatial and temporal scales (including quality controls); and (iii) strengthen the evidence base to understand the relationship between exposure to complex chemical mixtures, biological and ecological impacts through integrated approaches and molecular data (e.g. genomics, proteomics and metabolomics). Additionally, we support the widely held view that (iv) that rather than increasing the analytical chemistry monitoring of large number of emerging contaminants, it will be important to target analytical chemistry towards key groups of chemicals of concern using effects-directed analysis. It is also important to evaluate to what extent existing biomarkers and bioassays can address various classes of emerging chemicals using the adverse outcome pathway (AOP) approach now being developed by the Organization for Economic Cooperation and Development (OECD) with respect to human toxicology and ecotoxicology. PMID- 23820190 TI - Delayed spontaneous pneumocephalus in ventriculoperitoneal shunting: two case reports and literature review. AB - Spontaneous pneumocephalus following cerebrospinal fluid shunt is a rare complication. In most cases, the air enters in the intracranial cavity via a skull base defect. We report 2 cases of delayed tension pneumocephalus, secondary to ventriculoperitoneal shunt, and review the etiopathogenesis, prevention and treatment of this condition. PMID- 23820192 TI - Levels of 210Po and 210Pb in mussel and sediments in Candarli Gulf and the related dose assessment to the coastal population. AB - (210)Po and (210)Pb in mussel (Mytilus galloprovincialis) and sediment samples collected at Candarli Gulf during the period of 2010-2012 are presented and discussed. The activity concentrations of (210)Po and (210)Pb were measured by means of alpha spectrometry. Activity concentrations of (210)Po and (210)Pb in mussels are in the ranged of 332+/-17-776+/-23 Bq kg(-1)dw and 14+/-1-40+/-5 Bq kg(-1) dw, for sediments the ranges for 52+/-5-109+/-8 Bq kg(-1)dw and 38+/-5 92+/-9 Bq kg(-1) dw, respectively. The estimated consequent annual effective ingestion dose due to (210)Po and (210)Pb from mussel consumption in Candarli Gulf coastal region were calculated. The highest dose due to (210)Po and (210)Po were calculated to be 4232+/-126 MUSv and 126+/-16 MUSv, respectively. PMID- 23820193 TI - Effects of elevated pCO2 on reproductive properties of the benthic copepod Tigriopus japonicus and gastropod Babylonia japonica. AB - We investigated the effects of elevated pCO2 in seawater both on the acute mortality and the reproductive properties of the benthic copepod Tigriopus japonicus and gastropod Babylonia japonica with the purpose of accumulating basic data for assessing potential environmental impacts of sub-sea geological storage of anthropogenic CO2 in Japan. Acute tests showed that nauplii of T. japonicus have a high tolerance to elevated pCO2 environments. Full life cycle tests on T. japonicus indicated NOEC=5800MUatm and LOEC=37,000MUatm. Adult B. japonica showed remarkable resistance to elevated pCO2 in the acute tests. Embryonic development of B. japonica showed a NOEC=1500MUatm and LOEC=5400MUatm. T. japonicus showed high resistance to elevated pCO2 throughout the life cycle and B. japonica are rather sensitive during the veliger stage when they started to form their shells. PMID- 23820194 TI - Environmental recovery in Sydney Harbour, Nova Scotia: evidence of natural and anthropogenic sediment capping. AB - Contaminants were assessed in Sydney Harbour during baseline and three years of remediation of a former coking and steel facility. Concentrations of PAHs; PCBs; and lead measured in surface sediments indicate overall spatial distribution patterns of historical contaminants remains unchanged, although at much lower concentrations than previously reported due to natural sediment recovery. Recovery rates were in broad agreement with predicted concentrations; or in some cases lower, despite remediation at the Sydney Tar Ponds (STP) site. Contaminants showed little temporal variability, except for detection of significant increases in PAH concentrations during onset of remediation compared to baseline which represented a short term interruption in the overall long term natural recovery of sediments in Sydney Harbour. Recovery (via "capping") was enhanced following recent harbour dredging activities where less contaminated outer harbour sediments were discharged into a confined disposal facility (CDF) required for a new container in the inner harbour. PMID- 23820195 TI - Heavy metal pollution and assessment in the tidal flat sediments of Haizhou Bay, China. AB - The heavy metal inventory and the ecological risk of the tidal flat sediments in Haizhou Bay were investigated. Results show that the average concentrations of heavy metals in the surface sediments exceeded the environment background values of Jiangsu Province coastal soil, suggesting that the surface sediments were mainly polluted by heavy metals (Cd, Cr, Cu, Mn, Pb and Zn). In addition, the profiles of heavy metals fluxes can reflect the socio-economic development of Lianyungang City, and heavy metals inputs were attributed to anthropogenic activities. Cr, Cu, Pb and Zn were mainly present in the non-bioavailable residual form in surface sediments, whereas Cd and Mn were predominantly in the highly mobile acid soluble and reducible fractions. The ecological risk of the polluted sediments stemmed mainly from Cd and Pb. According to the Sediment quality guidelines (SQGs), however, the adverse biological effects caused by the heavy metals occasionally occurred in tidal flat. PMID- 23820196 TI - Do videos improve website satisfaction and recall of online cancer-related information in older lung cancer patients? AB - OBJECTIVE: This study investigated the effects of personalized audiovisual information in addition to text on website satisfaction and recall of cancer related online information in older lung cancer patients. METHODS: An experiment using a 3 (condition: text only vs. text with nonpersonalized video vs. text with personalized video) by 2 (age patient: younger [<65 yrs] vs. older [>=65 yrs]) between-subjects factorial design was conducted. Patients were randomly assigned to one of the three information conditions stratified by age group. RESULTS: Patients were more satisfied with the comprehensibility, attractiveness, and the emotional support from the website when information was presented as text with personalized video compared to text only. Text with personalized video also outperformed text with nonpersonalized video regarding emotional support from the website. Furthermore, text with video improved patients' recall of cancer-related information as compared to text only. Older patients recalled less information correctly than younger patients, except when we controlled for Internet use. CONCLUSION: Text with personalized audiovisual information can enhance website satisfaction and information recall. Internet use plays an important role in explaining recall of information. PRACTICE IMPLICATIONS: The results of this study can be used to develop effective health communication materials for cancer patients. PMID- 23820197 TI - Echocardiographic assessment of coronary artery flow in normal canines and model dogs with myocardial infarction. AB - This study was conducted to evaluate the usefulness of coronary arterial profiles from normal dogs (11 animals) and canines (six dogs) with experimental myocardial infarction (MI) induced by ligation of the left coronary artery (LCA). Blood velocity of the LCA and right coronary artery (RCA) were evaluated following transthoracic pulsed-wave Doppler echocardiography. The LCA was observed as an infundibular shape, located adjacent to the sinus of Valsalva. The RCA appeared as a tubular structure located 12 o'clock relative to the aorta. In normal dogs, the LCA and RCA mean peak diastolic velocities were 20.84 +/- 3.24 and 19.47 +/- 2.67 cm/sec, respectively. The LCA and RCA mean diastolic deceleration times were 0.91 +/- 0.14 sec and 1.13 +/- 0.20 sec, respectively. In dogs with MI, the LCA had significantly (p < 0.01) lower peak velocities (14.82 +/- 1.61 cm/sec) than the RCA (31.61 +/- 2.34 cm/sec). The RCA had a significantly (p < 0.01) rapid diastolic deceleration time (0.71 +/- 0.06 sec) than that found in the LCA (1.02 +/- 0.22 sec) of MI dogs. In conclusion, these profiles may serve as a differential factor for evaluating cardiomyopathy in dogs. PMID- 23820198 TI - GC/MS analysis of high-performance liquid chromatography fractions from Sophora flavescens and Torilis japonica extracts and their in vitro anti-neosporal effects on Neospora caninum. AB - We analyzed alcoholic extracts of herbs possessing anti-neosporal activity against Neospora (N.) caninum. To identify the chemical components of Sophora (S.) flavescens and Torilis (T.) japonica associated with anti-neosporal activity, specific fractions were isolated by high-performance liquid chromatography (HPLC). In vitro activity of the fractions against N. caninum was then assessed. Gas chromatography/ mass spectrometry (GC/MS) was used to identify and quantify specific anti-neosporal molecules in the herbal extracts. Almost all HPLC fractions of S. flavescens and T. japonica had higher levels of anti neosporal activity compared to the not treated control. Active constituents of the extracts were sophoridane, furosardonin A, and tetraisopropylidene cyclobutane in S. flavescens; 5,17-beta-dihydroxy-de-A-estra-5,7,9,14-tetraene, furanodiene, and 9,12-octadecadienoic acid (Z,Z)-(CAS,1) in T. japonica. PMID- 23820199 TI - Dissimilarity of ccrAB gene sequences between methicillin-resistant Staphylococcus epidermidis and methicillin-resistant Staphylococcus aureus among bovine isolates in Korea. AB - The sequences of the ccrAB genes from bovine-, canine- and chicken-originating methicillin-resistant Staphylococcus (S.) epidermidis (MRSE) and bovine methicillin-resistant Staphylococcus (S.) aureus (MRSA) were compared to investigate the frequency of intra-species horizontal transfer of the staphylococcal cassette chromosome mec (SCCmec) complex. Nineteen MRSE strains were isolated from bovine milk, chickens, and dogs, and their genetic characteristics were investigated by multilocus sequence typing and SCCmec typing. Among the animal MRSE strains, the most frequent SCCmec type was type IV, which consisted of the type B mec complex and ccrAB type 2. The ccrA2 and ccrB2 genes were sequenced from the bovine, chicken and canine MRSE strains and compared with those of the bovine MRSA strains. The sequences generally clustered as MRSA and MRSE groups, regardless of the animal source. Additionally, no bovine MRSE sequence was associated with the bovine MRSA groups. Although most of the bovine MRSE and MRSA isolates possessed SCCmec type IV sequences, our results suggest that the intra-species gene transfer of the SCCmec complex between bovine S. aureus and bovine S. epidermidis strains is not a frequent event. PMID- 23820200 TI - Effects of administration of IH901, a ginsenoside intestinal metabolite, on muscular and pulmonary antioxidant functions after eccentric exercise. AB - This study was conducted to investigate whether administration of IH901, a ginseng intestinal metabolite, ameliorates exercise-induced oxidative stress while preserving antioxidant defense capability in rat skeletal muscles and lung. Eight adult male Sprague-Dawley rats per group were randomly assigned to the resting control, exercise control, resting with IH901 (25, 50, and 100 mg/kg) consumption (R/IH901), or exercise with IH901 (25, 50, and 100 mg/kg) consumption (E/IH901) group. The trained groups ran 35 min 2 days/week for 8 weeks. To analyze the IH901-training interaction, serum biochemical analysis, lipid peroxidation, citrate synthase, protein oxidation, antioxidant and superoxide dismutase in skeletal muscles and lung tissue were measured. Compared to the exercise control group, animals that consumed IH901 had significantly increased exercise endurance times (p < 0.05) and decreased plasma creatine kinase and lactate dehydrogenase levels (p < 0.05), while those in the E/IH901 groups had increased citrate synthase and anti-oxidant enzymes and decreased lipid peroxidation and protein oxidation (p < 0.05). In conclusion, IH901 consumption in aging rats after eccentric exercise has beneficial effects on anti inflammatory and anti-oxidant activities through down-regulation of pro inflammatory mediators, lipid peroxidation, and protein oxidation and up regulation of anti-oxidant enzymes. PMID- 23820201 TI - Vitamin D3 up-regulated protein 1 controls the priming phase of liver regeneration. AB - Vitamin D3 up-regulated protein 1 (VDUP1) is a potent growth suppressor that inhibits tumor cell proliferation and cell cycle progression when overexpressed. In a previous study, we showed that VDUP1 knockout (KO) mice exhibited accelerated liver regeneration because such animals could effectively control the expression of cell cycle regulators that drive the G1-to-S phase progression. In the present study, we further investigated the role played by VDUP1 in initial priming of liver regeneration. To accomplish this, VDUP1 KO and wild-type (WT) mice were subjected to 70% partial hepatectomy (PH) and sacrificed at different times after surgery. The hepatic levels of TNF-alpha and IL-6 increased after PH, but there were no significant differences between VDUP1 KO and WT mice. Nuclear factor-kappaB (NF-kappaB), c-Jun-N-terminal kinase (JNK), and signal transducer and activator of transcription 3 (STAT-3) were activated much earlier and to a greater extent in VDUP1 KO mice after PH. A single injection of TNF-alpha or IL-6 caused rapid activation of JNK and STAT-3 expression in both mice, but the responses were stronger and more sustained in VDUP1 KO mice. In conclusion, our findings provide evidence that VDUP1 plays a role in initiation of liver regeneration. PMID- 23820202 TI - Evaluation of changes in left ventricular myocardial function observed in canine myocardial dysfunction model using a two-dimensional tissue tracking technique. AB - This study was conducted to assess the ability of two-dimensional tissue tracking (2DTT) to evaluate changes in left ventricular (LV) myocardial function associated with sustained high electrical pacing. Pacemakers were implanted at the right ventricular (RV) apex of five female Beagles, and sustained high electrical pacing of 250 beats per minute (bpm) was performed for three consecutive weeks. Conventional echocardiography and 2DTT were performed at baseline, and at every week for three weeks with pacing. The baseline parameters were then compared to those of weeks 1, 2, and 3. Three weeks of pacing resulted in significant reduction of radial and circumferential global strains (p < 0.001). Regional analysis revealed reduction of segmental strains in both radial and circumferential directions, as well as increased dyssynchrony after three weeks of pacing in the radial direction (p = 0.0007). The results of this study revealed the ability of 2DTT to measure radial and circumferential strains in dogs with sustained high-electrical pacing, and allowed assessment of global and regional myocardial function and the degree of dyssynchrony. PMID- 23820203 TI - Gossypol acetic acid induces apoptosis in RAW264.7 cells via a caspase-dependent mitochondrial signaling pathway. AB - To investigate the effects of gossypol acetic acid (GA) on proliferation and apoptosis of the macrophage cell line RAW264.7 and further understand the possible underlying mechanism responsible for GA-induced cell apoptosis, RAW264.7 cells were treated with GA (25~35 MUmol/L) for 24 h and the cytotoxicity was determined by MTT assay, while apoptotic cells were identified by TUNEL assay, acridine orange/ethidium bromide staining and flow cytometry. Moreover, mitochondrial membrane potential (DeltaPsim) with Rhodamine 123 and reactive oxygen species (ROS) with DCFH-DA were analyzed by fluorescence spectrofluorometry. In addition, the expression of caspase-3 and caspase-9 was assessed by Western Blot assay. Finally, the GA-induced cell apoptosis was evaluated by flow cytometry in the present of caspase inhibitors Z-VAD-FMK and Ac LEHD-FMK, respectively. GA significantly inhibited the proliferation of RAW264.7 cells in a dose-dependent manner, and caused obvious cell apoptosis and a loss of DeltaPsim in RAW264.7 cells. Moreover, the ROS production in cells was elevated, and the levels of activated caspase-3 and caspase-9 were up-regulated in a dose dependent manner. Notably, GA-induced cell apoptosis was markedly inhibited by caspase inhibitors. These results suggest that GA-induced RAW264.7 cell apoptosis may be mediated via a caspase-dependent mitochondrial signaling pathway. PMID- 23820204 TI - Development of in vitro produced porcine embryos according to serum types as macromolecule. AB - This study was conducted to establish an in vitro maturation (IVM) system by selection of efficient porcine serum during porcine in vitro production. To investigate the efficient porcine serum (PS), different types of PS [newborn pig serum, prepubertal gilt serum (PGS), estrus sow serum, and pregnancy sow serum] were used to supplement IVM media with or without gonadotrophin (GTH) and development rates of parthenogenetic activation (PA) and in vitro fertilization (IVF) embryos were then compared. The maturation rates of the PGS group was significantly higher when GTH was not added. Additionally, during development of PA embryos without GTH, the PGS group showed significantly higher cleavage and blastocyst formation rates. Moreover, the cleavage rates of IVF embryos were significantly higher in the PGS group, with no significant differences in the blastocyst formation. However, when GTH was supplemented into the IVM media, there were no significant differences among the four groups in the cleavage rates, development rates of the blastocyst, and cell number of the blastocyst after PA and IVF. In conclusion, PGS is an efficient macromolecule in porcine IVM, and GTH supplementation of the IVM media is beneficial when PS is used as macromolecule, regardless of its origin. PMID- 23820205 TI - Prevalence and characteristics of Shiga toxin-producing Escherichia coli (STEC) from cattle in Korea between 2010 and 2011. AB - A total of 156 Shiga-like toxin producing Escherichia coli (STEC) were isolated from fecal samples of Korean native (100/568, 18%) and Holstein dairy cattle (56/524, 11%) in Korea between September 2010 and July 2011. Fifty-two STEC isolates (33%) harbored both of shiga toxin1 (stx1) and shiga toxin2 (stx2) genes encoding enterohemolysin (EhxA) and autoagglutinating adhesion (Saa) were detected by PCR in 83 (53%) and 65 (42%) isolates, respectively. By serotyping, six STEC from native cattle and four STEC from dairy cattle were identified as O serotypes (O26, O111, O104, and O157) that can cause human disease. Multilocus sequence typing and pulsed-field gel electrophoresis patterns highlighted the genetic diversity of the STEC strains and difference between strains collected during different years. Antimicrobial susceptibility tests showed that the multidrug resistance rate increased from 12% in 2010 to 42% in 2011. Differences between isolates collected in 2010 and 2011 may have resulted from seasonal variations or large-scale slaughtering in Korea performed to control a foot and mouth disease outbreak that occurred in early 2011. However, continuous epidemiologic studies will be needed to understand mechanisms. More public health efforts are required to minimize STEC infection transmitted via dairy products and the prevalence of these bacteria in dairy cattle. PMID- 23820206 TI - Clinical signs, MRI features, and outcomes of two cats with thiamine deficiency secondary to diet change. AB - Two cats were presented with vestibular signs and seizures. Both cats were diagnosed with thiamine deficiency. The transverse and dorsal T2-weighted magnetic resonance (MR) images revealed the presence of bilateral hyperintense lesions at specific nuclei of the midbrain, cerebellum, and brainstem. After thiamine supplementation, the clinical signs gradually improved. Repeated MR images taken 3 weeks after thiamine supplementation had started showed that the lesions were nearly resolved. This case report describes the clinical and MR findings associated with thiamine deficiency in two cats. PMID- 23820207 TI - Emergence of virulent pseudorabies virus infection in northern China. AB - Our investigation was conducted in order to verify a recent severe epidemic at several swine farms in northern China that indicated a newly emerging disease. Evidence confirmed that the epidemic was caused by a virulent Pseudorabies virus infection in swine herds. PMID- 23820208 TI - The signal sequence of type II porcine reproductive and respiratory syndrome virus glycoprotein 3 is sufficient for endoplasmic reticulum retention. AB - The glycoprotein 3 (GP3) of type II porcine reproductive and respiratory syndrome virus has the characteristic domains of a membrane protein. However, this protein has been reported to be retained in the endoplasmic reticulum (ER) rather than transported to the plasma membrane of the cell. In this study, we performed confocal laser scanning microscopy analysis of variants of GP3 and found that the signal sequence of the GP3 led to confinement of GP3 in the ER, while the functional ortransmembrane domain did not affect its localization. Based on these results, we concluded that the signal sequence of GP3 contains the ER retention signal, which might play an important role in assembly of viral proteins. PMID- 23820209 TI - Effect of chronic lead intoxication on the distribution and elimination of amoxicillin in goats. AB - A study of amoxicillin pharmacokinetics was conducted in healthy goats and goats with chronic lead intoxication. The intoxicated goats had increased serum concentrations of liver enzymes (alanine aminotransferase and gamma-glutamyl transferase), blood urea nitrogen, and reactivated delta-aminolevulinic acid dehydratase compared to the controls. Following intravenous amoxicillin (10 mg/kg bw) in control and lead-intoxicated goats, elimination half-lives were 4.14 and 1.26 h, respectively. The volumes of distribution based on the terminal phase were 1.19 and 0.38 L/kg, respectively, and those at steady-state were 0.54 and 0.18 L/kg, respectively. After intramuscular (IM) amoxicillin (10 mg/kg bw) in lead-intoxicated goats and control animals, the absorption, distribution, and elimination of the drug were more rapid in lead-intoxicated goats than the controls. Peak serum concentrations of 21.89 and 12.19 MUg/mL were achieved at 1 h and 2 h, respectively, in lead-intoxicated and control goats. Amoxicillin bioavailability in the lead-intoxicated goats decreased 20% compared to the controls. After amoxicillin, more of the drug was excreted in the urine from lead intoxicated goats than the controls. Our results suggested that lead intoxication in goats increases the rate of amoxicillin absorption after IM administration and distribution and elimination. Thus, lead intoxication may impair the therapeutic effectiveness of amoxicillin. PMID- 23820210 TI - Genetic diversity of Korean Bacillus anthracis isolates from soil evaluated with a single nucleotide repeat analysis. AB - Bacillus (B.) anthracis, the etiological agent of anthrax, is one of the most genetically monomorphic bacteria species in the world. Due to the very limited genetic diversity of this species, classification of isolates of this bacterium requires methods with high discriminatory power. Single nucleotide repeat (SNR) analysis is a type of variable-number tandem repeat assay that evaluates regions with very high mutation rates. To subtype a collection of 21 isolates that were obtained during a B. anthracis outbreak in Korea, we analyzed four SNR marker loci using nucleotide sequencing analysis. These isolates were obtained from soil samples and the Korean Center for Disease Control and Prevention. The SNR analysis was able to detect 13 subgenotypes, which allowed a detailed evaluation of the Korean isolates. Our study demonstrated that the SNR analysis was able to discriminate between strains with the same multiple-locus variable-number tandem repeat analysis genotypes. In summary, we obtained SNR results for four SNR marker loci of newly acquired strains from Korea. Our findings will be helpful for creating marker systems and help identify markers that could be used for future forensic studies. PMID- 23820211 TI - Development and standardization of a monoclonal antibody-based rapid flow-through immunoassay for the detection of Aphanomyces invadans in the field. AB - A monoclonal antibody-based flow-through immunoassay (FTA) was developed using a nitrocellulose membrane placed on the top of adsorbent pads enclosed in a plastic cassette with a test zone at the center. The FTA could be completed within 10 min. Clear purple dots against a white background indicated the presence of Aphanomyces (A.) invadans. The FTA limit of detection was 7 MUg/mL for A. invadans compared to 56 MUg/mL for the immunodot. FTA and polymerase chain reaction (PCR) could detect A. invadans in fish tissue homogenates at a 10(-11) dilution compared to a 10(-8) dilution by immunodot. In fish suffering from natural cases of epizootic ulcerative syndrome (EUS) collected from Mangalore, India, FTA and PCR could detect A. invadans in 100% of the samples compared to 89.04% detected by immunodot. FTA reagents were stable and produced expected results for 4 months when stored at 4~8 degrees C. This rapid test could serve as simple and cost-effective on-site screening tool to detect A. invadans in fish from EUS outbreak areas and in ports during the shipment of live or frozen fish. PMID- 23820212 TI - Prolonged excretion of a low-pathogenicity H5N2 avian influenza virus strain in the Pekin duck. AB - H5N2 strains of low-pathogenicity avian influenza virus (LPAIV) have been circulating for at least 17 years in some Mexican chicken farms. We measured the rate and duration of viral excretion from Pekin ducks that were experimentally inoculated with an H5N2 LPAIV that causes death in embryonated chicken eggs (A/chicken/Mexico/2007). Leghorn chickens were used as susceptible host controls. The degree of viral excretion was evaluated with real-time reverse transcriptase polymerase chain reaction (RRT-PCR) using samples from oropharyngeal and cloacal swabs. We observed prolonged excretion from both species of birds lasting for at least 21 days. Prolonged excretion of LPAIV A/chicken/ Mexico/2007 is atypical. PMID- 23820214 TI - Inhibitory effects of osteoprotegerin on osteoclast formation and function under serum-free conditions. AB - The purpose of this study was to determine whether osteoprotegerin (OPG) could affect osteoclat differentiation and activation under serum-free conditions. Both duck embryo bone marrow cells and RAW264.7 cells were incubated with macrophage colony stimulatory factor (M-CSF) and receptor activator for nuclear factor kB ligand (RANKL) in serum-free medium to promote osteoclastogenesis. During cultivation, 0, 10, 20, 50, and 100 ng/mL OPG were added to various groups of cells. Osteoclast differentiation and activation were monitored via tartrate resistant acid phosphatase (TRAP) staining, filamentous-actin rings analysis, and a bone resorption assay. Furthermore, the expression osteoclast-related genes, such as TRAP and receptor activator for nuclear factor kappaB (RANK), that was influenced by OPG in RAW264.7 cells was examined using real-time polymerase chain reaction. In summary, findings from the present study suggested that M-CSF with RANKL can promote osteoclast differentiation and activation, and enhance the expression of TRAP and RANK mRNA in osteoclasts. In contrast, OPG inhibited these activities under serum-free conditions. PMID- 23820216 TI - Morphology and histology of the adult Paramphistomum gracile Fischoeder, 1901. AB - In the present study, we evaluated the histological morphology of the adult Paramphistomum (P.) gracile. Adult flukes with bodies 5~15 mm in length and 2~7 mm in width were subjected to histological analysis. Longitudinal and transversal serial-sections were stained with hematoxylin and eosin, and examined. The body surface and longitudinal section of P. gracile were also assessed using scanning electron microscopy. In this species, the anterior sucker and posterior sucker (acetabulum) were present on an anterior and posterior part of the body, respectively. The major folds were located in the areas of the anterior sucker, genital canal, and posterior sucker. The fluke membrane was spineless at the tegument surface and in the tegument tissue. Histological data showed structural systematic characteristics of the digestive tract, reproductive tract, excretory tract, copulatory organs, connective tissues, and muscle tissues. We attempted to elucidate the histological characteristics of P. gracile that might increase the knowledge and understanding of rumen fluke morphology. PMID- 23820215 TI - Codon optimization of the rabbit hemorrhagic disease virus (RHDV) capsid gene leads to increased gene expression in Spodoptera frugiperda 9 (Sf9) cells. AB - Rabbit hemorrhagic disease (RHD) is contagious and highly lethal. Commercial vaccines against RHD are produced from the livers of experimentally infected rabbits. Although several groups have reported that recombinant subunit vaccines against rabbit hemorrhagic disease virus (RHDV) are promising, application of the vaccines has been restricted due to high production costs or low yield. In the present study, we performed codon optimization of the capsid gene to increase the number of preference codons and eliminate rare codons in Spodoptera frugiperda 9 (Sf9) cells. The capsid gene was then subcloned into the pFastBac plasmid, and the recombinant baculoviruses were identified with a plaque assay. As expected, expression of the optimized capsid protein was markedly increased in the Sf9 cells, and the recombinant capsid proteins self-assembled into virus-like particles (VLPs) that were released into the cell supernatant. Rabbits inoculated with the supernatant and the purified VLPs were protected against RHDV challenge. A rapid, specific antibody response against RHDV was detected by an ELISA in all of the experimental groups. In conclusion, this strategy of producing a recombinant subunit vaccine antigen can be used to develop a low-cost, insect cell-derived recombinant subunit vaccine against RHDV. PMID- 23820217 TI - Sequential alterations of glucocorticoid receptors in the hippocampus of STZ treated type 1 diabetic rats. AB - Type 1 diabetes is a common metabolic disorder accompanied by increased blood glucose levels along with glucocorticoid and cognitive deficits. The disease is also thought to be associated with environmental changes in brain and constantly induces oxidative stress in patients. Therefore, glucocorticoid-mediated negative feedback mechanisms involving the glucocorticoid receptor (GR) binding site are very important to understand the development of this disease. Many researchers have used streptozotocin (STZ)-treated diabetic animals to study changes in GR expression in the brain. However, few scientists have evaluated the hyperglycemic period following STZ exposure. In the present study, we found GR expression in the hippocampus varied based on the period after STZ administration for up to 4 weeks. We performed immunohistochemistry and Western blotting to validate the sequential alterations of GR expression in the hippocampus of STZ-treated type 1 diabetic rats. GR protein expression increased significantly until week 3 but decreased at week 4 following STZ administration. GR expression after 70 mg/kg STZ administration was highest at 3 weeks post-treatment and decreased thereafter. Although STZ-induced increase in GR expression in diabetic animals has been described, our data indicate that researchers should consider the sequential GR expression changes during the hyperglycemic period following STZ exposure. PMID- 23820218 TI - Elucidating the role of ApxI in hemolysis and cellular damage by using a novel apxIA mutant of Actinobacillus pleuropneumoniae serotype 10. AB - Exotoxins produced by Actinobacillus (A.) pleuropneumoniae (Apx) play major roles in the pathogenesis of pleuropneumonia in swine. This study investigated the role of ApxI in hemolysis and cellular damage using a novel apxIA mutant, ApxIA336, which was developed from the parental strain A. pleuropneumoniae serotype 10 that produces only ApxI in vitro. The genotype of ApxIA336 was confirmed by PCR, Southern blotting, and gene sequencing. Exotoxin preparation derived from ApxIA336 was analyzed for its bioactivity towards porcine erythrocytes and alveolar macrophages. Analysis results indicated that ApxIA336 contained a kanamycin- resistant cassette inserted immediately after 1005 bp of the apxIA gene. Phenotype analysis of ApxIA336 revealed no difference in the growth rate as compared to the parental strain. Meanwhile, ApxI production was abolished in the bacterial culture supernatant, i.e. exotoxin preparation. The inability of ApxIA336 to produce ApxI corresponded to the loss of hemolytic and cytotoxic bioactivity in exotoxin preparation, as demonstrated by hemolysis, lactate dehydrogenase release, mitochondrial activity, and apoptosis assays. Additionally, the virulence of ApxIA336 appeared to be attenuated by 15-fold in BALB/c mice. Collectively, ApxI, but not other components in the exotoxin preparation of A. pleuropneumoniae serotype 10, was responsible for the hemolytic and cytotoxic effects on porcine erythrocytes and alveolar macrophages. PMID- 23820219 TI - Evaluation of a side population of canine lymphoma cells using Hoechst 33342 dye. AB - Cancer stem cell (CSC) research has increased exponentially to gain further insight into the mechanisms underlying both carcinogenesis and chemotherapy resistance. The present study was performed to explore the potential value of a side population (SP) assay for identifying and characterizing putative CSCs among canine lymphoma cells. Canine lymphoma cells from cell lines and clinical samples were subjected to the SP assay consisting of Hoechst 33342 staining and subsequent flow cytometric analysis. The SP assay revealed various amounts of a SP fraction among the canine lymphoma cells. The percentages of SP were not affected by inhibitors of membrane transporters, verapamil hydrochloride, or fumitremorgin C. Most of the canine lymphoma cells expressed high levels of Bmi-1 and membrane transporter proteins such as ABCG2 and phosphorylated (p) glycoprotein. This investigation lays the groundwork for further studies of the biological behaviors and molecular characteristics of CSCs in cases of canine lymphoma. PMID- 23820220 TI - Hypodectes propus (Acarina: Hypoderatidae) in a rufous turtle dove, Streptopelia orientalis (Aves: Columbiformes), in Japan. AB - An adult male rufous turtle dove, Streptopelia (S.) orientalis (Aves: Columbiformes), was found dead in Yorii-machi Town, Osato District 369-1217, Saitama Prefecture, Japan, and subjected to necropsy. A large number of immobile hypopi (deutonymphs) of the hypoderatid mite, Hypodectes (H.) propus (Acarina: Hypoderatidae), were found individually encapsulated subcutaneously primarily in the adipose tissue. The mites were 1.43 mm in length and 0.44 mm in width on average, and had provoked mild inflammatory reactions that predominantly manifested as foamy macrophages and lymphoplasmocytes. PCR analysis using ribosomal DNA extracted from paraffin-blocked tissues produced a 240 bp band specific for hypoderatids. Based on the morphological features (distinct coxal apodemes, especially in the anterior portion) and PCR-based findings, the hypopi were identified as H. propus. To the best of our knowledge, this is the first case describing the subcutaneous mite H. propus in a rufous turtle dove, S. orientalis, in Japan. This study also highlights the use of paraffin blocks as a source of tissue DNA for molecular evaluation. PMID- 23820221 TI - Development of a real-time SYBR Green PCR assay for the rapid detection of Dermatophilus congolensis. AB - Methods such as real time (RT)-PCR have not been developed for the rapid detection and diagnosis of Dermatophilus (D.) congolensis infection. In the present study, a D. congolensis-specific SYBR Green RT-PCR assay was evaluated. The detection limit of the RT-PCR assay was 1 pg of DNA per PCR reaction. No cross-reaction with nucleic acids extracted from Pseudomonas aeruginosa, Mycobacterium tuberculosis, Staphylococcus aureus, or Austwickia chelonae was observed. Finally, the RT-PCR assay was used to evaluate clinical samples collected from naturally infected animals with D. congolensis. The results showed that this assay is a fast and reliable method for diagnosing dermatophilosis. PMID- 23820222 TI - Chemopreventive and metabolic effects of inulin on colon cancer development. AB - Prebiotics modulate microbial composition and ensure a healthy gastrointestinal tract environment that can prevent colon cancer development. These natural dietary compounds are therefore potential chemopreventive agents. Thirty Sprague Dawley rats (4 months old) were experimentally treated with procarcinogen dimethylhydrazine to induce colon cancer development. The rats were randomly assigned to three groups: a control group (CG), a group treated with dimethylhydrazine (DMH), and a group given DMH and inulin, a prebiotic (DMH+PRE). The effects of inulin on the activities of bacterial glycolytic enzymes, short chain fatty acids, coliform and lactobacilli counts, cytokine levels, and cyclooxygenase-2 (COX-2) and transcription nuclear factor kappa beta (NFkappaB) immunoreactivity were measured. Inulin significantly decreased coliform counts (p < 0.01), increased lactobacilli counts (p < 0.001), and decreased the activity of beta-glucuronidase (p < 0.01). Butyric and propionic concentrations were decreased in the DMH group. Inulin increased its concentration that had been reduced by DMH. Inulin decreased the numbers of COX-2- and NFkappaB-positive cells in the tunica mucosae and tela submucosae of the colon. The expression of IL-2, TNFalpha, and IL-10 was also diminished. This 28-week study showed that dietary intake of inulin prevents preneoplastic changes and inflammation that promote colon cancer development. PMID- 23820223 TI - A simplified one-step nuclear transfer procedure alters the gene expression patterns and developmental potential of cloned porcine embryos. AB - Various somatic cell nuclear transfer (SCNT) techniques for mammalian species have been developed to adjust species-specific procedures to oocyte-associated differences among species. Species-specific SCNT protocols may result in different expression levels of developmentally important genes that may affect embryonic development and pregnancy. In the present study, porcine oocytes were treated with demecolcine that facilitated enucleation with protruding genetic material. Enucleation and donor cell injection were performed either simultaneously with a single pipette (simplified one-step SCNT; SONT) or separately with different pipettes (conventional two-step SCNT; CTNT) as the control procedure. After blastocysts from both groups were cultured in vitro, the expression levels of developmentally important genes (OCT4, NANOG, EOMES, CDX2, GLUT-1, PolyA, and HSP70) were analyzed by real-time quantitative polymerase chain reaction. Both the developmental rate according to blastocyst stage as well as the expression levels CDX2, EOMES, and HSP70 were elevated with SONT compared to CTNT. The genes with elevated expression are known to influence trophectoderm formation and heat stress-induced arrest. These results showed that our SONT technique improved the development of SCNT porcine embryos, and increased the expression of genes that are important for placental formation and stress-induced arrest. PMID- 23820225 TI - Visian toric ICL implantation for residual refractive errors after ICRS implantation and corneal collagen cross-linking in keratoconus. PMID- 23820224 TI - Effect of Harderian adenectomy on the statistical analyses of mouse brain imaging using positron emission tomography. AB - Positron emission tomography (PET) using 2-deoxy-2-[(18)F] fluoro-D-glucose (FDG) as a radioactive tracer is a useful technique for in vivo brain imaging. However, the anatomical and physiological features of the Harderian gland limit the use of FDG-PET imaging in the mouse brain. The gland shows strong FDG uptake, which in turn results in distorted PET images of the frontal brain region. The purpose of this study was to determine if a simple surgical procedure to remove the Harderian gland prior to PET imaging of mouse brains could reduce or eliminate FDG uptake. Measurement of FDG uptake in unilaterally adenectomized mice showed that the radioactive signal emitted from the intact Harderian gland distorts frontal brain region images. Spatial parametric measurement analysis demonstrated that the presence of the Harderian gland could prevent accurate assessment of brain PET imaging. Bilateral Harderian adenectomy efficiently eliminated unwanted radioactive signal spillover into the frontal brain region beginning on postoperative Day 10. Harderian adenectomy did not cause any post-operative complications during the experimental period. These findings demonstrate the benefits of performing a Harderian adenectomy prior to PET imaging of mouse brains. PMID- 23820226 TI - ICL versus Veriflex phakic IOL for treatment of moderately high myopia: randomized paired-eye comparison. AB - PURPOSE: To compare the objective and subjective outcome of implantable collamer lenses (ICLs; Staar Surgical, Monrovia, CA) versus Veriflex lenses (AMO, Santa Ana, CA) for the correction of moderately high myopia. METHODS: A prospective randomized comparative eye study was performed on 24 patients with bilateral myopia that ranged from -6 to -14.5 diopters (D). One eye was implanted with an ICL and the other eye was implanted with a Veriflex phakic intraocular lens (PIOL). Uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), higher-order aberrations (HOAs), contrast sensitivity, patient satisfaction, central endothelial cell count, and PIOL centration were determined 6 months after surgery RESULTS: The logMAR UDVA and CDVA improved significantly in both groups (P < .001). There was no statistically significant difference in postoperative logMAR UDVA (P = .41) or logMAR CDVA (P = .36) between the two groups. Postoperative deviation from target refraction was -0.06 +/- 0.41 D in the ICL group and -0.07 +/- 0.49 D in the Veriflex group (P = .15). The difference in both induced and absolute postoperative HOAs between groups was not statistically significant. The area under the log contrast sensitivity function increased significantly in both groups postoperatively. The difference in patient satisfaction between both PIOLs was not statistically significant. A higher but statistically insignificant central endothelial cell count loss occurred in the Veriflex group (P = .11). CONCLUSION: Both ICL and Veriflex PIOLs have equally satisfactory objective and subjective visual outcomes after surgery. PMID- 23820227 TI - Mathematical model to compare the relative tensile strength of the cornea after PRK, LASIK, and small incision lenticule extraction. AB - PURPOSE: To develop a mathematical model to estimate the relative differences in postoperative stromal tensile strength following photorefractive keratectomy (PRK), LASIK, and small incision lenticule extraction (SMILE). METHODS: Using previously published data where in vitro corneal stromal tensile strength was determined as a function of depth, a mathematical model was built to calculate the relative remaining tensile strength by fitting the data with a fourth order polynomial function yielding a high correlation coefficient (R(2) = 0.930). Calculating the area under this function provided a measure of total stromal tensile strength (TTS), based only on the residual stromal layer for PRK or LASIK and the residual stromal layers above and below the lenticule interface for SMILE. RESULTS: Postoperative TTS was greatest after SMILE, followed by PRK, then LASIK; for example, in a 550-MUm cornea after 100-MUm tissue removal, postoperative TTS was 75% for SMILE (130-MUm cap), 68% for PRK, and 54% for LASIK (110-MUm flap). The postoperative TTS decreased for thinner corneal pachymetry for all treatment types. In LASIK, the postoperative TTS decreased with increasing flap thickness by 0.22%/MUm, but increased by 0.08%/MUm for greater cap thickness in SMILE. The model predicted that SMILE lenticule thickness could be approximately 100 MUm greater than the LASIK ablation depth and still have equivalent corneal strength (equivalent to approximately 7.75 diopters). CONCLUSIONS: This mathematical model predicts that the postoperative TTS is considerably higher after SMILE than both PRK and LASIK, as expected given that the strongest anterior lamellae remain intact. Consequently, SMILE should be able to correct higher levels of myopia. PMID- 23820228 TI - Prospective contralateral eye study to compare 80- and 120-MUm flap LASIK using the VisuMax femtosecond laser. AB - PURPOSE: To compare visual outcomes and flap stability of LASIK with ultrathin 80 and 120-MUm flaps created with a VisuMax femtosecond laser (Carl Zeiss Meditec, Jena, Germany) for moderate to high myopia and to evaluate the effect of corneal flap thickness on outcomes. METHODS: In a prospective contralateral eye study, 36 consecutive patients (72 eyes) underwent bilateral LASIK for myopia ranging from 2.00 to -10.00 diopters using the VisuMax femtosecond laser and MEL-80 excimer laser (Carl Zeiss Meditec). One eye of each patient was randomized to have the 80 MUm flap and the other to the 120-MUm flap created with 200-kHz VisuMax femtosecond laser. Preoperative and postoperative tests included visual acuity, manifest refraction, contrast sensitivity, and flap thickness measured by anterior segment optical coherence tomography. Main outcomes and complications were checked at postoperative 1 week and 1, 3, and 6 months. RESULTS: There were no differences in visual outcome, residual refractive error, or contrast sensitivity between groups during follow-up, except for better uncorrected visual acuity at postoperative 1 day in the 120-MUm group. Mean standard deviations of measured flap thickness during follow-up ranged from 3.16 to 3.80 MUm in both groups. Opaque bubble layer, a unique complication in femtosecond LASIK, was more frequent in the 80-MUm group (7 of 36: 19%) than in the 120-MUm flap group (3 of 36: 8%) without a statistically significant difference (P = .301) and was related to thicker central cornea and steeper keratometric value, although it did not influence clinical results. Comparison of the intended versus achieved correction showed no significant differences between groups. CONCLUSIONS: LASIK using the VisuMax femtosecond laser supplied good clinical results and flap reproducibility in both the 80- and 120-MUm flap groups. Patients with relatively thin cornea may benefit from 80-MUm flap LASIK. PMID- 23820229 TI - Dilute brimonidine to improve patient comfort and subconjunctival hemorrhage after LASIK. AB - PURPOSE: To investigate whether dilute brimonidine (0.025%) reduces patient discomfort, subconjunctival hemorrhage, and injection after LASIK without a significant increase in the rate of flap complications or surgical enhancements. METHODS: This randomized, double-blind, prospective study enrolled 180 patients (360 eyes) in a contralateral eye comparison of topical dilute brimonidine, naphazoline/pheniramine, or Systane Ultra (Alcon Laboratories, Inc., Fort Worth, TX) administered shortly before LASIK for any indication. Patients were evaluated for subconjunctival hemorrhage, injection, and flap dislocation 1 hour and 1 day postoperatively. Patient questionnaires measuring patient comfort and ocular symptoms were administered at these same follow-up visits. Patients were examined for 3 months to determine similar outcomes for standard indices of safety, predictability, efficacy, and enhancement rates. RESULTS: Scores of patient discomfort, subconjunctival hemorrhage, and injection were significantly lower in eyes treated with dilute brimonidine at the 1 hour and 1 day postoperative examinations. Refloats for mild-flap edge wrinkling were required in 3 brimonidine eyes (2.5%), 1 naphazoline/pheniramine eye (0.8%), and no control eyes, but this difference did not reach statistical significance (P = .18). There was no significant difference between eyes at 3 months in terms of visual acuity, refractive error, corrected distance visual acuity, or rate of enhancement. CONCLUSIONS: Use of dilute brimonidine before LASIK reduces subconjunctival hemorrhage and injection and improves patient comfort after surgery. Flap edge wrinkling requiring refloat may still be a complication with dilute brimonidine. PMID- 23820230 TI - Astigmatism correction with toric IOL: analysis of visual performance, position, and wavefront error. AB - PURPOSE: To evaluate astigmatism correction, visual performance, intraocular lens (IOL) position, and wavefront error after implantation of toric IOLs in patients with cataract. METHODS: This prospective study comprised 30 eyes of 30 patients with cataract who were candidates for phacoemulsification and implantation of the AcrySof toric IOL (Alcon Laboratories, Inc., Fort Worth, TX). Mean preoperative corneal keratometric and subjective refractive cylinder were 2.10 +/- 0.47 and 2.17 +/- 0.41 diopters (D), respectively. RESULTS: The refractive cylinder decreased significantly from 2.17 +/- 0.41 to 0.73 +/- 0.45 D (P = .001) at 180 days postoperatively. The difference between preoperative corneal astigmatism and postoperative refractive astigmatism was statistically significant (P < .05). At 180 days postoperatively, the uncorrected distance visual acuity was 0.20 logMAR (Snellen 20/32) in 100% of patients and 0.0 logMAR (Snellen 20/20) in 64% of patients. The root mean square of internal coma and trefoil aberrations showed a trend toward reduction; internal spherical aberration significantly decreased, whereas corneal trefoil aberration significantly increased (P < .05). A low amount of IOL decentration and tilt were detected at 30 and 180 days postoperatively, respectively. CONCLUSIONS: Toric IOL implantation is an effective procedure for correction of preexisting corneal astigmatism, improving visual performance, and inducing a low amount of higher-order aberrations. Moreover, the toric IOLs is well positioned early after surgery and stable over time. PMID- 23820231 TI - Comparison of IOL power calculation methods and intraoperative wavefront aberrometer in eyes after refractive surgery. AB - PURPOSE: To compare preoperative methods for calculating intraocular lens (IOL) power versus the intraoperative wavefront aberrometer in eyes with a history of refractive surgery. METHODS: A retrospective study of 46 eyes (33 patients) with previous refractive surgery that underwent subsequent cataract surgery was conducted. Suggested IOL power predicted by ORange intraoperative wavefront aberrometer (WaveTec Vision Systems, Inc., Aliso Viejo, CA) was compared to power predicted by the (1) SRK-T formula using keratometry and axial length measurements from the IOLMaster (Carl Zeiss Meditec, Dublin, CA), (2) average central keratometry (Avg K) from corneal topography, and (3) average IOL power predicted by the American Society of Cataract and Refractive Surgery (ASCRS) web site. No historical information was used for the calculations. IOL power required for emmetropia was back-calculated using manifest refraction and implanted IOL power after cataract surgery. RESULTS: Mean age was 60 +/- 7.9 years. Fifteen percent had a history of myopic photorefractive keratectomy (n = 7), 57% myopic LASIK (n = 26), 13% hyperopic LASIK (n = 6), and 22% radial keratectomy (RK) (n = 10). In 37% of cases, ORange predicted IOL power to within +/-0.50 diopters (D) of emmetropia, compared to 30% for IOLMaster keratometry, 26% for Avg K, and 17% for ASCRS web site. In eyes after myopic treatment, ORange, IOLMaster, Avg K, and ASCRS web site predicted within +/-0.50 D of emmetropia in 39%, 27%, 24%, and 18%, respectively, and within +/-1.0 D in 60%, 39%, 39%, and 51%, respectively. In eyes after RK, ORange, Avg K, and ASCRS web site predicted to within +/-0.50 D of emmetropia in 14% and the IOLMaster in 43% cases. CONCLUSIONS: Although the ORange most often predicted to within +/-0.5 D of emmetropia, no method was able to achieve this accuracy more than 50% of the time. Predictions for eyes after RK were worse than for other types of refractive procedures. PMID- 23820232 TI - Effect of hydration state and storage media on corneal biomechanical response from in vitro inflation tests. AB - PURPOSE: To evaluate corneal deformation with varying intraocular pressure and the dependency of the biomechanical response on the corneal hydration state, modulated by the storage solutions or postmortem period. METHODS: Thirty fresh enucleated porcine eyes were used for in vitro whole eye globe inflation experiments. The eyes were separated into five groups and treated with different solutions: 20% dextran, 8% dextran, 0.125% riboflavin-20% dextran, Optisol-GS (Bausch & Lomb, Rochester, NY), and one control group of virgin (untreated) eyes. Intraocular pressure was increased (from 15 to 55 mm Hg) and decreased (to 15 mm Hg) in 5-mm Hg steps and Scheimpflug images were taken at each step. Measurements were repeated after 24 hours. Thickness and curvature changes were analyzed as a function of intraocular pressure. RESULTS: Corneal deformation differed across conditions and hydration states. Dehydration by any dextran solution increased the hysteresis after the inflation/deflation cycle (14.29 vs 22.07 to 41.75 MUm), whereas overnight hydration did not lead to a significant difference. Compared to control corneas, corneas treated with Optisol-GS showed the most similar behavior. Corneas treated with 0.125% riboflavin-20% dextran deformed most (Deltathickness(max) = 38.27 MUm), indicating a softening of the corneal tissue compared to control corneas (23.18 MUm) and corneas treated with 8% dextran (21.01 MUm) and 20% dextran (29.07 MUm). Dextran instillation decreased corneal thickness on average to 56.5% at 0 hours and 72.7% at 24 hours. CONCLUSIONS: Corneal hydration and tissue preservation changed corneal biomechanics, in particular its relaxation over a period of 24 hours. PMID- 23820233 TI - Implications and management of suction loss during refractive lenticule extraction (ReLEx). AB - PURPOSE: To describe a case in which the ReLEx procedure was abandoned following suction loss on two occasions due to an uncooperative patient. METHODS: Case report with anterior segment optical coherence tomography and aberrometry changes before and after surgery. RESULTS: Lamellar haze was present but diminished in the early postoperative period. The patient successfully underwent a femtosecond LASIK procedure in the same eye 2 months later. CONCLUSIONS: This case demonstrates the possibility of performing femtosecond LASIK after failed ReLEx, with good visual outcomes. PMID- 23820234 TI - Very high fluence collagen cross-linking as a refractive enhancement of a regressed previous astigmatic keratotomy. AB - PURPOSE: To report a novel application of collagen cross-linking (CXL) in refractive astigmatic enhancement of previously performed astigmatic keratotomy. METHODS: A 28-year-old woman with prior history of bioptics correction of high myopic astigmatism with femtosecond laser-assisted astigmatic keratotomy followed by topography-guided LASIK showed long-term regression of the astigmatism 4 years later. A novel CXL application was employed in an attempt to reverse the regression of the astigmatic keratotomy. RESULTS: The high fluence CXL intervention resulted in correction of 2 diopters of topographic and refractive cylinder. Uncorrected distance visual acuity changed from 20/50 to 20/20 and refraction from -0.50 -2.00 @ 90 to +0.25 -0.25 @ 90 at the 7-month follow-up. CONCLUSIONS: A possible novel application of high fluence CXL with refractive cornea effect is introduced. It may offer rapid and simple rehabilitation and its effect may be tapered. PMID- 23820235 TI - Rotationally asymmetric multifocal IOL implantation in acquired nystagmus with spectacle and contact lens intolerance. AB - PURPOSE: To describe a case of refractive lens exchange with multifocal intraocular lens implantation in a 52-year-old woman with emmetropic presbyopia who had near glasses and contact lens intolerance after acquired nystagmus. METHODS: Preoperative corrected distance visual acuity was 20/25 in the right eye, 20/20 in the left eye, and 20/20 binocularly. Corrected near visual acuity was 20/30 in the right eye and 20/20 in the left eye, reaching 20/20 binocularly but showing unsatisfactory binocular vision with asthenopia and intolerance to prolonged reading. The surgical plan entailed bilateral implantation of multifocal intraocular lens. RESULTS: Three months postoperatively, uncorrected distance visual acuity was 20/20 in the right eye and 20/20 in the left eye, reaching 20/20 binocularly. Monocular and binocular uncorrected near visual acuity of 20/20 was achieved without symptoms of asthenopia in prolonged reading. There were no changes in nystagmus characteristics after surgery. CONCLUSIONS: Multifocal intraocular lens implantation to manage a case of clinically significant acquired nystagmus may be a safe alternative, especially if others options have failed. PMID- 23820236 TI - The amyloid-cell membrane system. The interplay between the biophysical features of oligomers/fibrils and cell membrane defines amyloid toxicity. AB - Amyloid cytotoxicity, structure and polymorphisms are themes of increasing importance. Present knowledge considers any peptide/protein able to undergo misfolding and aggregation generating intrinsically cytotoxic amyloids. It also describes growth and structure of amyloid fibrils and their possible disassembly, whereas reduced information is available on oligomer structure. Recent research has highlighted the importance of the environmental conditions as determinants of the amyloid polymorphisms and cytotoxicity. Another body of evidence describes chemical or biological surfaces as key sites of protein misfolding and aggregation or of interaction with amyloids and the resulting biochemical modifications inducing cell functional/viability impairment. In particular, the membrane lipid composition appears to modulate cell response to toxic amyloids, thus contributing to explain the variable vulnerability to the same amyloids of different cell types. Finally, a recent view describes amyloid toxicity as an emerging property dependent on a complex interplay between the biophysical features of early aggregates and the interacting cell membranes taken as a whole system. PMID- 23820237 TI - Endoscopic features of colorectal serrated lesions using image-enhanced endoscopy with pathological analysis. AB - OBJECTIVE: To clarify of the features of sessile serrated adenoma/polyp (SSA/P) observed with image-enhanced endoscopy using immunohistochemical staining. MATERIALS AND METHODS: Twenty-five hyperplastic polyps (HP) and 46 SSA/P were studied with autofluorescence imaging (AFI) and magnifying endoscopy with narrow band imaging (ME-NBI). AFI color change, capillary dilatation, existence of a mucous layer on the tumor surface, and pit dilatation under ME-NBI were examined retrospectively. Immunohistochemical staining was performed with the proliferation-associated antigen MIB-1 (Ki-67). RESULTS: Using AFI, a magenta color was observed in 32% of HP and 44% of SSA/P. With NBI observation, capillary dilatation was observed in 4% of HP and 11% of SSA/P, a mucous cap was observed in 60% of HP and 94% of SSA/P, and pit dilatation was observed in 28% of HP and 80% of SSA/P. When magenta color, capillary dilatation, mucous cap, and pit dilatation were used for the differential diagnosis of SSA/P from HP, the sensitivity, specificity, and accuracy were 43, 68, and 52% for AFI, respectively, 10, 96, and, 41% for capillary dilatation, respectively, 94, 40, and 75% for mucous cap, respectively, and 80, 72, and 78% for pit dilatation, respectively. Compared with HP, MIB-1-positive cells were more frequently distributed in the gland's intermediate zone in SSA/P. CONCLUSION: The biological malignant potential of SSA/P could be higher compared with HP as suggested by the MIB-1 stain. Therefore, endoscopic differentiation of SSA/P from HP is important, and the findings of a mucous cap and dilatated pit might be helpful for the differentiation of SSA/P from HP. PMID- 23820238 TI - Cycling probe technology to quantify and discriminate between wild-type varicella zoster virus and Oka vaccine strains. AB - Rapid differentiation between wild-type varicella zoster virus (VZV) and Oka vaccine (vOka) strains is important for monitoring side reactions of varicella vaccination. To develop a high-throughput molecular diagnostic method for the differentiation of wild-type VZV and vOka strains based on cycling probe technology. The primers were designed to amplify common sequences spanning a single nucleotide polymorphism (SNP) in gene 62 of VZV. DNA-RNA chimeric probes (cycling probes) were designed to detect the SNP at nucleotide 105705. The cycling probe real-time PCR assays for VZV wild-type and vOka strains specifically amplified plasmids containing target sequences that ranged between 10 and 1*10(6) copies per reaction. The inter- and intra-assay coefficients of variation were less than 5%. After initial validation studies, the clinical reliability of this method was evaluated using 38 swab samples that were collected from patients suspected of being zoster. Compared to the loop mediated isothermal amplification method, which is defined as the gold standard, cycling probe real-time PCR was highly sensitive and specific. The cycling probe real time PCR technology is a reliable tool for differentiating between wild-type VZV and vOka strains in clinical samples. PMID- 23820239 TI - Subjective health perception in healthy young men changes in response to experimentally restricted sleep and subsequent recovery sleep. AB - Sleep and subjective health are both prospectively related to objective indices of health and health care use. Here, we tested whether five days with restricted sleep and subsequent recovery days affect subjective health and is related to increased levels of circulating IL-6 and TNF-alpha and fatigue. Nine healthy men (23-28 ears) went through a 6-week sleep protocol with subjects as their own controls in a repeated measures design with a total of 11 nights in a sleep laboratory. The experimental part of the protocol included three baseline days (sleep 23-07 h), five days with sleep restriction (03-07 h) and three recovery days (23-07 h) in the sleep laboratory. Subjective health and fatigue was recorded daily. Eight blood samples were drawn each day (every third hour) on 8 days of the protocol and analyzed with respect to IL-6 and TNF-alpha. Subjective health deteriorated gradually during restricted sleep (p=.002) and returned to baseline levels after three days of recovery. IL-6 and TNF-alpha did not change significantly. Fatigue increased gradually during sleep restriction (p=.001), which significantly contributed to the association between restricted sleep and subjective health. The study is the first to show that subjective health is directly responsive to changes in sleep length and related to increased fatigue. Thus, subjective health is differently appraised after manipulation of one of its presumed determinants. Larger experimental studies would be beneficial to further distinguish causation from association regarding the underpinnings of subjective health. PMID- 23820240 TI - Sonoelectrochemical synthesis of water-soluble CdTe quantum dots. AB - A facile and fast one-pot method has been developed for the synthesis of CdTe quantum dots (QDs) in aqueous phase by a sonoelectrochemical route without the protection of N2. The morphology, structure and composition of the as-prepared products were investigated by high resolution transmission electron microscopy (HRTEM), X-ray diffraction (XRD) and energy dispersive X-ray spectrometer (EDS). The influences of current intensity, current pulse width, and reaction temperature on the photoluminescence (PL) and quantum yield (QY) of the products were studied. The experimental results showed that the water-soluble CdTe QDs with high PL qualities can be conveniently synthesized without precursor preparation and N2 protection, and the PL emission wavelength and QY can be effectively controlled by adjusting some parameters. This method can be expected to prepare other QDs as promising building blocks in solar cell, photocatalysis and sensors. PMID- 23820241 TI - 'Krokodil' and what a long strange trip it's been. PMID- 23820243 TI - Novel polymorphisms of the IGF1R gene and their association with average daily gain in Egyptian buffalo (Bubalus bubalis). AB - The objective of this study was to detect insulin-like growth factor 1 receptor (IGF1R) polymorphisms, their allele, and genotype frequencies and to determine associations between these polymorphisms and growth traits in Egyptian water buffalo. Three loci of the IGF1R coding region were amplified by RT-PCR and, subsequently, subjected to sequence analysis, followed by single-strand conformation polymorphism to identify different allelic patterns. A total of 11 novel polymorphisms were detected; 6 SNPs among Egyptian water buffaloes and 5 polymorphisms compared with Indian buffalo (Y12700). Three of those polymorphisms; GAG Indel polymorphism, C261G, and G263C SNPs, were nonsynonymous mutations. The GAG Indel polymorphism led to deletion of E (glutamic) amino acid (aa) in the IGF1R of Egyptian water buffaloes compared with Indian buffalo. However, C261G SNP, which replaced A (alanine) by G (glycine) aa, and G263C SNP, which changed A (alanine) to P (proline) aa, were detected among Egyptian water buffaloes. Three different single-strand conformation polymorphism patterns were observed in exon 21: CC/CC, GG/GG, and CG/GC with frequencies of 0.291, 0.253, and 0.556, respectively. The heterozygous animals (CG/GC) had a higher ADG than homozygous animals (CC/CC and GG/GG) from birth to 6 mo of age. We conclude that the heterozygous haplotype, C261G/G263C, in exon 21 of the IGF1R gene is associated with the ADG during the early stages of life (from birth to 6 mo of age) and could be used as a genetic marker for selection of growth traits in Egyptian buffalo. PMID- 23820242 TI - Effects of nesfatin-1 on food intake and LH secretion in prepubertal gilts and genomic association of the porcine NUCB2 gene with growth traits. AB - Nesfatin-1, a product of the nucleobindin 2 (NUCB2) gene, purportedly plays important roles in whole-body energy homeostasis. Experiments were conducted to determine how NUCB2 expression in fat depots may be controlled in the pig and to test the hypothesis that nesfatin-1 regulates appetite and LH secretion in the gilt. Prepubertal gilts were used to study expression of NUCB2 in fat and the effects of intracerebroventricular (i.c.v.) injection of nesfatin-1 on food intake and pituitary hormone secretion. Growing pigs (gilts and barrows at 22 wk of age, n = 1,145) or sexually mature gilts (n = 439) were used to test association of SNP in the NUCB2 gene with growth traits. The expression of NUCB2 was similar for subcutaneous fat compared with perirenal fat. An i.c.v. injection of the melanocortin-4 receptor agonist [Nle4, d-Phe7]-alpha-melanocyte stimulating hormone did not alter expression of NUCB2 mRNA in the hypothalamus but reduced (P = 0.056) NUCB2 mRNA expression in subcutaneous fat. Short-term (7 d) submaintenance feeding reduced (P < 0.05) BW and did not alter expression of mRNA for NUCB2, visfatin, or leptin but increased (P < 0.05) expression of adiponectin mRNA in fat. Central injection of nesfatin-1 suppressed (P < 0.001) feed intake. Secretion of LH was greater (P < 0.01) after i.c.v. injection of nesfatin-1 than after saline. Single nucleotide polymorphisms in the porcine NUCB2 gene were not associated with adiposity of growing pigs or age at puberty in gilts but were associated (P < 0.05) with BW at puberty. These data indicate that NUCB2 is expressed in fat depots of the pig and that the level of expression is sensitive to stimulation of appetite-regulating pathways in the hypothalamus. It is confirmed herein that nesfatin-1 can regulate appetite in the pig and affect the gonadotropic axis of the prepubertal pig. Association of SNP in the porcine NUCB2 gene with BW at puberty suggests that regulation of appetite by nesfatin-1 in the pig affects growth, which may have important consequences for adult phenotypes. PMID- 23820244 TI - Shear mechanical properties of the porcine pancreas: experiment and analytical modelling. AB - We provide the first account of the shear mechanical properties of porcine pancreas using a rheometer both in linear oscillatory tests and in constant strain-rate tests reaching the non-linear sub-failure regime. Our results show that pancreas has a low and weakly frequency-dependent dynamic modulus and experiences a noticeable strain-hardening beyond 20% strain. In both linear and non-linear regime, the viscoelastic behaviour of porcine pancreas follows a four parameter bi-power model that has been validated on kidney, liver and spleen. Among the four solid organs of the abdomen, pancreas proves to be the most compliant and the most viscous one. PMID- 23820245 TI - The relationship of Helicobacter pylori infection and colon neoplasia, on the basis of meta-analysis. AB - BACKGROUND: Helicobacter pylori is an important causative factor in gastric carcinogenesis. However, its role in extragastric gastrointestinal malignancies, such as colon neoplasia, is controversial. AIM: The aim of this study was to explore the relationship of H. pylori infection with colon neoplasia by meta analysis of all relevant studies. MATERIALS AND METHODS: Pooled estimates were obtained using fixed or random-effects models as appropriate. Heterogeneity between studies was evaluated using the Cochran Q-test, whereas the likelihood of publication bias was assessed by constructing funnel plots. RESULTS: Among 238 potentially relevant studies, 210 were rejected as unsuitable and 28 studies were finally eligible for meta-analysis, including a total of 33 sets of data (17 on colon cancer and 16 on colon polyps). There was evidence of heterogeneity (I=57.37%); thus, the random-effects model of meta-analysis was chosen, showing pooled odds ratio (OR) equal to 1.41 [95% confidence interval 1.24-1.60, P=0.000]. The subgroup meta-analyses showed a significant relationship between H. pylori and colon cancer as well as colon polyps [OR 1.3 (1.07-1.59), P=0.01 and OR 1.5 (1.26-1.79), P=0.000, respectively]. CONCLUSION: The results of this meta analysis showed a modest statistically significant relationship of H. pylori infection with both colon cancer and polyps. PMID- 23820246 TI - Modulation of gut barrier function in patients with obstructive jaundice using probiotic LP299v. AB - OBJECTIVES: This study aimed to determine the effect of LP229v on intestinal permeability and tumour necrosis factor (TNF) p55 receptor concentrations in patients with obstructive jaundice undergoing biliary drainage. PATIENTS AND METHODS: Patients undergoing biliary drainage were recruited and randomized into three groups to receive Lactobacillus plantarum 299v (LP299v), inactivated LP299v (placebo) or water. These were administered daily at noon until 7 days after biliary drainage. Intestinal permeability was measured using the lactulose/mannitol (L/M) dual sugar absorption test on admission, the day before biliary drainage and on days 1 and 7 after biliary drainage. Blood and urine were collected to determine the L/M ratio and the TNF p55 receptor levels at each time point. RESULTS: A total of 25 patients were recruited; 12 had choledocholithiasis and nine had a periampullary tumour. Open surgical biliary drainage was performed in nine patients, endoscopic retrograde cholangiopancreatography in 12 and percutaneous transhepatic cholangiography in two. Five patients received LP299v, five received placebo and seven, water. The median L/M ratio was 0.035 (0.018 0.065) at baseline. No difference existed between the groups on admission, before drainage and on day 7 after drainage (P=0.59, 0.175 and 0.61, respectively). The L/M ratio was lower in the LP299v group on day 1 after drainage [0.01 (0.01) vs. 0.18 (0.03-0.3) and 0.11 (0.07-0.14); P=0.37]. Although the TNF p55 receptor levels were lower on day 1 after drainage in the LP299v group (15.3 vs. 30.9 vs. 82.7 ng/ml; P=0.43), the concentration at the four time points was similar (P=0.24, 0.96, 0.43 and 0.68). CONCLUSION: Pretreatment with probiotic LP299v improves intestinal permeability after biliary drainage and attenuates the inflammatory response. However, a larger multicentre trial is required to determine the effect on clinical outcome. PMID- 23820248 TI - Design and characterization of a close-proximity thermoacoustic sensor. AB - Although the radiation force balance is the gold standard for measuring ultrasound intensity, it cannot be used for real-time monitoring in certain settings, for example, bioreactors or in the clinic to measure ultrasound intensities during treatment. Foreseeing these needs, we propose a close proximity thermoacoustic sensor. In this article, we describe the design, characterization, testing and implementation of such a sensor. We designed a 20 mm-diameter plexiglass sensor with a 2-mm-long absorber and tested it against low intensity pulsed ultrasound generated at a 1.5-MHz frequency, 20% duty cycle, 1 kHz pulse repetition frequency and intensities between 30 and 120 mW/cm(2). The sensor captures the beam, converts the ultrasound power into heat and indirectly measures the spatial-average time-average ultrasound intensity (Isata) by dividing the calculated power by the beam cross section (or the nominal area of the transducers). A thin copper sheet was attached to the back face of the sensor with thermal paste to increase heat diffusivity 1000-fold, resulting in uniform temperature distribution across the back face. An embedded system design was implemented using an Atmel microcontroller programmed with a least-squares algorithm to fit measured temperature-versus-time data to a model describing the temperature rise averaged across the back side of the sensor in relation to the applied ultrasound intensity. After it was calibrated to the transducer being measured, the thermoacoustic sensor was able to measure ultrasound intensity with an average error of 5.46% compared with readings taken using a radiation force balance. PMID- 23820247 TI - Expression of E-cadherin in pig kidney. AB - E-cadherin is a cell adhesion molecule that plays an important role in maintaining renal epithelial polarity and integrity. The purpose of this study was to determine the exact cellular localization of E-cadherin in pig kidney. Kidney tissues from pigs were processed for light and electron microscopy immunocytochemistry, and immunoblot analysis. E-cadhedrin bands of the same size were detected by immunoblot of samples from rat and pig kidneys. In pig kidney, strong E-cadherin expression was observed in the basolateral plasma membrane of the tubular epithelial cells. E-cadherin immunolabeling was not detected in glomeruli or blood vessels of pig kidney. Double-labeling results demonstrated that E-cadherin was expressed in the calbindin D28k-positive distal convoluted tubule and H(+)-ATPase- positive collecting duct, but not in the aquaporin 1 positive, N-cadherin-positive proximal tubule. In contrast to rat, E-cadherin immunoreactivity was not expressed at detectable levels in the Tamm-Horsfall protein-positive thick ascending limb of pig kidney. Immunoelectron microscopy confirmed that E-cadherin was localized in both the lateral membranes and basal infoldings of the collecting duct. These results suggest that E-cadherin may be a critical adhesion molecule in the distal convoluted tubule and collecting duct cells of pig kidney. PMID- 23820249 TI - Effect of phonophoresis on skin permeation of commercial anti-inflammatory gels: sodium diclofenac and ketoprofen. AB - This study evaluated the use of ultrasound in combination with the commercial anti-inflammatory drugs ketoprofen and sodium diclofenac, according to the parameters used in physiotherapy. Ketoprofen and sodium diclofenac were used in the Franz diffusion cell model adapted to an ultrasound transducer in three conditions: no ultrasound, one application of ultrasound and two applications of ultrasound. High-performance liquid chromatography was used to quantify the total amount of drug permeating skin per unit area, as well as flux and latency. The results showed that for ketoprofen, the amount of drug permeating skin and flux increased with two ultrasound applications. Permeation of sodium diclofenac decreased in the presence of ultrasound. Ultrasound parameters and drug properties must be considered in the use of phonophoresis. PMID- 23820250 TI - Experimental methods for improved spatial control of thermal lesions in magnetic resonance-guided focused ultrasound ablation. AB - Magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU, or MRgFUS) is a hybrid technology that was developed to provide efficient and tolerable thermal ablation of targeted tumors or other pathologic tissues, while preserving the normal surrounding structures. Fast 3-D ablation strategies are feasible with the newly available phased-array HIFU transducers. However, unlike fixed heating sources for interstitial ablation (radiofrequency electrode, microwave applicator, infra-red laser applicator), HIFU uses propagating waves. Therefore, the main challenge is to avoid thermo-acoustical adverse effects, such as energy deposition at reflecting interfaces and thermal drift of the focal lesion toward the near field. We report here our investigations on some novel experimental solutions to solve, or at least to alleviate, these generally known tolerability problems in HIFU-based therapy. Online multiplanar MR thermometry was the main investigational tool extensively used in this study to identify the problems and to assess the efficacy of the tested solutions. We present an improved method to cancel the beam reflection at the exit window (i.e., tissue-to-air interface) by creating a multilayer protection, to dissipate the residual HIFU beam by bulk scattering. This study evaluates selective de-activation of transducer elements to reduce the collateral heating at bone surfaces in the far field, mainly during automatically controlled volumetric ablation. We also explore, using hybrid US/MR simultaneous imaging, the feasibility of using disruptive boiling at the focus, both as a far-field self-shielding technique and as an enhanced ablation strategy (i.e., boiling core controlled HIFU ablation). PMID- 23820251 TI - Diagnostic value of transthoracic echocardiography for patent foramen ovale: a meta-analysis. AB - As a non-invasive and convenient modality, transthoracic echocardiography (TTE) has been widely recommended for the diagnosis of patent foramen ovale (PFO). In this study our aim was to systematically review the diagnostic accuracy of TTE in detection of PFO. We conducted comprehensive searches in PubMed, Embase and the Cochrane Library to the end of September 1, 2012. Sixteen studies comprising 1831 patients were included in the meta-analysis. The quality of reported studies was modest. The summary sensitivity and specificity of TTE in diagnosis of PFO were 88% (95% confidence interval [CI], 79-94) and 97% (95% CI, 92-99), respectively. The positive likelihood ratio was 27.1 (95% CI, 11.2-65.1), and the negative likelihood ratio was 0.12 (95% CI, 0.07-0.22). The summary diagnostic odds ratio was 221 (95% CI, 95-518). Subgroup analyses suggested that age and initial disease may affect the accuracy of TTE in detection of PFO. The meta-analysis suggested that TTE is a test with high sensitivity and specificity in detection of PFO, but it may not be appropriate for screening for PFO in all patients, especially patients with a small right-left shunt. PMID- 23820252 TI - A derived neutrophil to lymphocyte ratio predicts clinical outcome in stage II and III colon cancer patients. AB - BACKGROUND: Inflammation has a critical role in the pathogenesis and progression of cancer. Recently, the derived neutrophil to lymphocyte ratio (absolute count of neutrophils divided by the absolute white cell count minus the absolute count of neutrophils; dNLR) has been shown to influence clinical outcome in various cancer entities. In this study, we analysed the dNLR with clinical outcome in stage II and III colon cancer patients. METHODS: Three-hundred and seventy-two patients with stage II and III colon cancer were included in this retrospective study. Kaplan-Meier curves and multivariate Cox proportion analyses were calculated for time to recurrence (TTR) and overall survival (OS). RESULTS: In univariate analysis, the elevated preoperative dNLR was significantly associated with decreased TTR (hazard ratio (HR) 2.38, 95% confidence interval (CI) 1.57 3.6, P<0.001) and remained significant in multivariate analysis. Patients with dNLR >3 had a median TTR of 83 months, and patients with dNLR <= 3 showed a median TTR of 132 months. In OS analysis, a dNLR >2.2 was significantly associated with decreased OS in univariate (HR 1.85, 95% CI 1.11-3.08, P=0.018) and multivariate analysis. Patients with dNLR >2.2 showed a median OS of 121 months, and patients with dNLR <= 2.2 had a median OS of 147 months. CONCLUSION: The dNLR may be an independent prognostic marker for TTR and OS in patients with stage II and III colon cancer. Independent validation of our findings is warranted. PMID- 23820253 TI - Statin use in primary inflammatory breast cancer: a cohort study. AB - BACKGROUND: Some studies have suggested that statins, which have cholesterol lowering and anti-inflammatory properties, may have antitumor effects. Effects of statins on inflammatory breast cancer (IBC) have never been studied. METHODS: We reviewed 723 patients diagnosed with primary IBC in 1995-2011 and treated at The University of Texas MD Anderson Cancer Center. Statin users were defined as being on statins at the initial evaluation. Based on Ahern et al's statin classification (JNCI, 2011), clinical outcomes were compared by statin use and type (weakly lipophilic to hydrophilic (H-statin) vs lipophilic statins (L statin)). We used the Kaplan-Meier method to estimate the median progression-free survival (PFS), overall survival (OS) and disease-specific survival (DSS), and a Cox proportional hazards regression model to test the statistical significance of potential prognostic factors. RESULTS: In the multivariable Cox model, H-statins were associated with significantly improved PFS compared with no statin (hazard ratio=0.49; 95% confidence interval=0.28-0.84; P<0.01); OS and DSS P-values were 0.80 and 0.85, respectively. For L-statins vs no statin, P-values for PFS, DSS, and OS were 0.81, 0.4, and 0.74, respectively. CONCLUSION: H-statins were associated with significantly improved PFS. A prospective randomised study evaluating the survival benefits of statins in primary IBC is warranted. PMID- 23820254 TI - STAT3 upregulates miR-92a to inhibit RECK expression and to promote invasiveness of lung cancer cells. AB - BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) activation is frequently found in human lung cancer and is associated with increased metastasis and reduced survival. How STAT3 enhances invasiveness is unclear. METHODS: The expression of microRNAs and target genes was measured by real-time RT-PCR. Protein level was studied by western blotting. Luciferase reporter assay was used to confirm the direct targeting of microRNAs. Gelatin zymography was used to study matrix metalloproteinase (MMP) activity. Transwell assay was used to investigate cell migration and invasion. RESULTS: Enforced expression of STAT3 decreases the endogenous MMP inhibitor RECK protein but not mRNA level in H460 cells. Conversely, STAT3 inhibitor S3I-201 increases RECK protein in STAT3 activating H1299 cells. We demonstrate that STAT3 upregulates miR-92a to repress RECK via post-transcriptional inhibition. The RECK 3'-untranslated region (3'UTR) reporter activity assay suggests that RECK is a direct repression target of miR 92a. Delivery of pre-miR-92a reduces RECK protein level whereas transfection of anti-miR-92a restores STAT3-induced downregulation of RECK. Anti-miR-92a attenuates MMP activity, migration and invasion of H1299 cells and STAT3 overexpressing H460 cells, suggesting miR-92a is critical for STAT3-induced invasiveness. CONCLUSION: The STAT3-induced miR-92a promotes cancer invasion by suppressing RECK and targeting of the STAT3/miR-92a axis may be helpful for cancer treatment. PMID- 23820255 TI - Hormonal risk factors and invasive epithelial ovarian cancer risk by parity. AB - BACKGROUND: Recent studies have suggested that several ovarian cancer risk factors differ by parity status, but these findings have not been confirmed. We evaluated whether known risk factors of ovarian cancer differ between nulliparous and parous women using data from two large prospective cohorts. METHODS: Data from the National Institutes of Health-AARP Diet and Health Study and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial were combined for this analysis. Cox regression models were used to estimate associations with ovarian cancer risk. Risk heterogeneity by parity status was assessed using likelihood-ratio tests. RESULTS: Among the 125 437 women included in the analysis, there were 16 589 (13%) nulliparous women and 108 848 (87%) parous women. Of the 623 women diagnosed with invasive epithelial ovarian cancer, 102 (16%) were nulliparous and 521 (84%) were parous. While parity reduced ovarian cancer risk, no differences were found for other risk factors by parity. Among ever users of hormone therapy, body mass index suggestively increased the risk of ovarian cancer by 1.5-fold in nulliparous but not parous women (P heterogeneity=0.08). CONCLUSION: While nulliparous women have higher ovarian cancer risk than parous women, our findings suggest that the relative effects of most other risk factors do not differ by parity. PMID- 23820256 TI - Combination of platelet count and neutrophil to lymphocyte ratio is a useful predictor of postoperative survival in patients with colorectal cancer. AB - BACKGROUND: This study investigated the usefulness of a novel inflammation-based prognostic system, named the COP-NLR (COmbination of Platelet count and Neutrophil to Lymphocyte Ratio), for predicting the postoperative survival of patients with colorectal cancer (CRC). METHODS: The COP-NLR was calculated on the basis of data obtained on the day of admission: patients with both an elevated platelet count (>30 * 10(4) mm(-3)) and an elevated NLR (>3) were allocated a score of 2, and patients showing one or neither were allocated a score of 1 or 0, respectively. RESULTS: Four-hundred and eighty patients were enrolled. Multivariate analysis of clinical characteristics selected by univariate analysis showed that the COP-NLR (1, 2/0) (odds ratio, 0.464; 95% confidence interval, 0.267-0.807; P=0.007) had an association with cancer-specific survival, along with pathology, lymph node metastasis, the serum levels of carcinoembryonic antigen, C-reactive protein and albumin, and the Glasgow Prognostic Score. Kaplan Meier analysis and log-rank test revealed that the COP-NLR was able to divide such patients into three independent groups (P<0.001). CONCLUSION: The COP-NLR is considered to be a useful predictor of postoperative survival in patients with CRC. PMID- 23820257 TI - Characteristics and screening history of women diagnosed with cervical cancer aged 20-29 years. AB - BACKGROUND: There was concern that failure to screen women aged 20-24 years would increase the number of cancers or advanced cancers in women aged 20-29 years. We describe the characteristics of women diagnosed with cervical cancer in England aged 20-29 years and examine the association between the period of diagnosis, screening history and FIGO stage. METHODS: We used data on 1800 women diagnosed with cervical cancer between April 2007 and March 2012 at age 20-29 from the National Audit of Invasive Cervical Cancers. RESULTS: The majority of cancers (995, or 62% of those with known stage) were stage 1A. Cancer at age 20-24 years was rare (12% of those aged 20-29 years), when compared with age 25 (24%) and age 26-29 years (63%); however, cancers in women aged 20-24 years tended to be more advanced and were more often of a rare histological type. For 59% of women under age 30, the cervical cancer was screen detected, most of them (61%) as a result of their first screening test. A three-fold increase in the number of cancers diagnosed at age 25 years was seen since the start of the study period. CONCLUSION: Cervical cancer at age 20-24 years is rare. Most cancers in women under age 30 years are screen detected as microinvasive cancer. PMID- 23820258 TI - Downregulation of miR-302c and miR-520c by 1,25(OH)2D3 treatment enhances the susceptibility of tumour cells to natural killer cell-mediated cytotoxicity. AB - BACKGROUND: NKG2D recognises several ligands, including polymorphic major histocompatibility complex class I chain-related chain-related proteins A and B (MICA/B) and unique long 16-binding proteins (ULBPs). These ligands are present on cancer cells and are recognised by NKG2D in a cell-structure-sensing manner, triggering natural killer (NK) cell cytotoxicity. However, the mechanisms that control the expression of NKG2D ligands in malignant cells are poorly understood. 1-alpha,25-Dihydroxyvitamin D3 (1,25(OH)2D3) was recently shown to enhance the susceptibility of melanoma cells to the cytotoxicity of NK cells. However, the function of 1,25(OH)2D3 in other cancers and its potential mechanisms of action remain unknown. METHODS: The expression levels of miR-302c and miR-520c in Kasumi 1, K562, MCF7 and MDA-MB-231 cells were evaluated using quantitative real-time PCR. The targets of miR-302c and miR-520c were confirmed by luciferase reporter assay. The killing effects of NK92 cells against Kasumi-1, K562, MCF7 and MDA-MB 231 cells were examined using the CytoTox 96 Non-Radioactive Cytotoxicity Assay. The levels of cytokines IFN-gamma and granzyme B, which indicate the activation of NK cells, were also measured by enzyme-linked immunosorbent assay. RESULTS: Treatment with 1,25(OH)2D3 enhanced the susceptibility of both the haematological tumour cell line Kasumi-1 and solid tumour cell line MDA-MB-231 to NK92 cells. miR-302c and miR-520c expression was induced, and their levels inversely correlated with the levels of NKG2D ligands MICA/B and ULBP2 upon 1,25(OH)2D3 treatment. A luciferase reporter assay revealed that miR-302c and miR-520c directly targeted the 3'-UTRs of MICA/B and ULBP2 and negatively regulated the expression of MIA/B and ULBP2. Moreover, upregulation of miR-302c or miR-520c by transfection of their mimics remarkably reduced the viability of Kasumi-1 cells upon NK cell co-incubation. By contrast, the suppression of the activity of miR 302c or miR-520c by their respective antisense oligonucleotides improved the resistance of Kasumi-1 cells to NK cells. CONCLUSION: 1,25(OH)2D3 facilitates the immuno-attack of NK cells against malignant cells partly through downregulation of miR-302c and miR-520c and hence upregulation of the NKG2D ligands MICA/B and ULBP2. PMID- 23820259 TI - Revision arthroscopic Bankart repair. AB - PURPOSE: Failed anterior shoulder stabilization procedures have traditionally been treated with open procedures. Recent advances in arthroscopic techniques have allowed for certain failed stabilization procedures to be treated by arthroscopic surgery. The aim of this systematic review was to determine the outcomes of revision arthroscopic Bankart repair. METHODS: We searched Medline, Embase, and CINAHL (Cumulative Index to Nursing and Allied Health Literature) for articles on revision arthroscopic Bankart repairs. Key words included shoulder dislocation, anterior shoulder instability, revision surgery, and arthroscopic Bankart repair. Two reviewers selected studies for inclusion, assessed methodologic quality, and extracted data. RESULTS: We included 16 studies comprising 349 patients. All studies were retrospective (1 Level II study and 15 Level IV studies). The mean incidence of recurrent instability after revision arthroscopic Bankart repair was 12.7%, and the mean follow-up period was 35.4 months. The most common cause for failure of the primary surgeries was a traumatic injury (62.1%), and 85.1% of patients returned to playing sports. The reasons for failure of revision cases included glenohumeral bone loss, hyperlaxity, and return to contact sports. CONCLUSIONS: With proper patient selection, the outcomes of revision arthroscopic Bankart repair appear similar to those of revision open Bankart repair. Prospective, randomized clinical trials are required to confirm these findings. LEVEL OF EVIDENCE: Level IV, systematic review of Level II and Level IV studies. PMID- 23820260 TI - Long-term failure of anterior cruciate ligament reconstruction. AB - PURPOSE: The aim of this study was to review and describe the cumulative incidence of anterior cruciate ligament (ACL) graft rupture and/or clinical objective failures at greater than 10 years after ACL reconstruction. METHODS: A PubMed search was performed to identify and systematically evaluate all studies performed between 1980 and 2012 with clinical outcomes after intra-articular, non artificial ACL reconstruction and minimum 10-year follow-up. Studies reporting standardized surgical technique, ACL graft rupture, and objective International Knee Documentation Committee (IKDC) grade or ligament stability examination were included for analysis. After we first identified patients with graft rupture, clinical failure was further identified as 1 or more of the following: overall IKDC objective score of C or D, IKDC grade C or D pivot shift (i.e., >2+ or pivot shift), IKDC grade C or D Lachman examination, and/or abnormal KT arthrometer (MEDmetric, San Diego, CA) measurement (i.e., >5 mm). For this study, cumulative ACL failure rates were defined as the sum of both clinical failures and ACL graft ruptures. RESULTS: After review and exclusion of 625 references, 14 studies were identified for subsequent review. At longer than 10 years' clinical follow-up, the reported ACL graft rupture rate was 6.2% (173 of 2,782) (range, 0% to 13.4%) and clinical failure occurred in approximately 10.3% (158 of 1,532) (range, 1.9% to 25.6%). The overall cumulative ACL failure rate was 11.9% (range, 3.2% to 27%). CONCLUSIONS: At least 1 in 9 patients undergoing ACL reconstruction will have rerupture or clinical failure at long-term follow-up. LEVEL OF EVIDENCE: Level IV, systematic review of Level II and IV studies. PMID- 23820261 TI - Arthroscopy-assisted reduction of posteromedial tibial plateau fractures with buttress plate and cannulated screw construct. AB - PURPOSE: To present the radiologic and clinical results of posteromedial fractures treated with arthroscopy-assisted reduction and buttress plate and cannulated screw fixation. METHODS: Twenty-five patients with posteromedial tibial plateau fractures treated by the described technique were included in this study. According to the Schatzker classification, there were 5 type IV fractures (20%), 2 type V fractures (8%), and 18 type VI fractures (72%). The mean age at operation was 46 years (range, 21 to 79 years). The mean follow-up period was 86 months (range, 60 to 108 months). Clinical and radiologic outcomes were scored by the Rasmussen system. Subjective data were collected to assess swelling, difficulty climbing stairs, joint stability, ability to work and participate in sports, and overall patient satisfaction with recovery. Secondary osteoarthritis was diagnosed when radiographs showed a narrowed joint space in the injured knee at follow-up in comparison with the films taken at the time of injury. RESULTS: The mean postoperative Rasmussen clinical score was 25.9 (range, 18 to 29), and the mean radiologic score was 15.8 (range, 10 to 18). All 25 fractures achieved successful union, and 92% had good or excellent clinical and radiologic results. The 3 fracture types did not significantly differ in Rasmussen scores or rates of satisfactory results (P > .05). Secondary osteoarthritis was noted in 6 injured knees (24%). CONCLUSIONS: Arthroscopy-assisted reduction with buttress plate and cannulated screw fixation can restore posteromedial tibial plateau fractures of the knee with well-documented radiographic healing, good clinical outcomes, and low complication rates. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 23820262 TI - Molecular cloning, characterization and functional analysis of a novel juvenile specific cathepsin L of Fasciola gigantica. AB - Cathepsin L proteases are a major class of endopeptidases expressed at a high level in Fasciola parasites. Several isoforms of cathepsin L were detected and they may perform different functions during the parasite development. In this study, a complete cDNA encoding a cathepsin L protease was cloned from a newly excysted juvenile (NEJ) cDNA library of Fasciola gigantica and named FgCatL1H. It encoded a 326 amino acid preproenzyme which shared 62.8-83.1% and 39.5-42.9% identity to Fasciola spp. and mammalian cathepsins L, respectively. All functionally important residues previously described for cathepsin L were conserved in FgCatL1H. Phylogenetic analysis demonstrated that FgCatL1H belonged to a distinct group, clade 4, with respect to adult and other juvenile Fasciola cathepsin L genes. FgCatL1H expression was detected by RT-PCR, using gene specific primers, in metacercariae and NEJ, and the expression gradually decreased in advanced developmental stages. A recombinant proFgCatL1H (rproFgCatL1H) was expressed in the yeast Pichia pastoris, affinity purified, and found to migrate in SDS-PAGE at approximately 47.6 and 38.3kDa in glycosylated and deglycosylated forms, respectively. The molecular mass of the activated mature rFgCatL1H in glycosylated form was approximately 40.7kDa. Immunoblotting and immunohistochemistry using rabbit antibodies against rproFgCatL1H showed that FgCatL1H was predominantly expressed in epithelial cells of the digestive tract of metacercariae, NEJs and juveniles of F. gigantica. FgCatL1H could cleave the synthetic fluorogenic substrate Z-Phe-Arg-MCA preferentially over Z-Gly-Pro-Arg MCA at an optimum pH of 6.5. It also showed hydrolytic activity against native substrates, including type I collagen, laminin, and immunoglobulin G (IgG) in vitro, suggesting possible roles in host tissue migration and immune evasion. Therefore, the FgCatL1H is a possible target for vaccine and chemotherapy for controlling F. gigantica infection. PMID- 23820263 TI - Three-dimensional culture may promote cell reprogramming. AB - Stem cells reside in stem cells niches, which maintain the balance of self renewal and differentiation of stem cells. In stem cell niches, cell-cell, cell extracellular matrix interactions and diffusible signals are important elements. However, another pivotal element is that localized and diffusible signals are all organized as three-dimensional (3-D) structures, which is easily neglected by in vitro cell biology research. Under 3-D culture conditions, the morphology of cells exhibited differently from cultured in traditional two-dimensional (2-D) conditions. Under 3-D culture conditions, the self-renewal and pluripotency of neural stem cells (NSCs) and bone marrow mesenchymal stem cells (BMSCs) were enhanced compared with culturing under 2-D conditions. 3-D cultures could change the transcriptional profile of NSCs compared with 2-D cultures. We hypothesized that 3-D cultures could reprogram mature cells such as fibroblasts to an immature state, like the pluripotent stem cells. The primary results indicated that several ES marker genes were upregulated by 3-D cultures. Though further experiments are needed, this work may provide a method of reprogramming mature cells without gene modifications. PMID- 23820264 TI - Can resistin be a new indicator of neonatal sepsis? AB - BACKGROUND: Sepsis is an important cause of neonatal death and perinatal brain damage, particularly in preterm infants. It is thought that activation of the inflammatory cascade triggered by cytokine might play a role in the pathogenesis of sepsis. Recent evidence supports a role for resistin in inflammation. There are no data in the literature on resistin levels of premature newborns with sepsis, which can also cause inflammatory response. The objective of this study was to evaluate whether resistin can be used as an indicator in neonatal sepsis of preterm babies. MATERIALS AND METHODS: Forty-three premature newborns considered to have sepsis were included in the study. Forty-three gestational and postnatal age- and sex-matched premature newborns without premature prolonged rupture of membrane or sepsis served as controls. RESULTS: The median resistin and interleukin-6 (IL-6) levels of the premature babies with sepsis were 85.9 ng/mL and 342.7 pg/mL, respectively, and were higher than those of the control group (29.9 ng/mL and 17.7 pg/mL, respectively). The sensitivity, specificity, positive, and negative predictive values for resistin were 73.7%, 45.8%, 68.3%, and 52.4%, respectively. CONCLUSION: Resistin levels were higher in premature newborns with sepsis and correlated with IL-6 levels, which is an indicator of neonatal sepsis. This suggests that resistin may also be used in the diagnosis of neonatal sepsis. However, it has limited value when compared with the other inflammatory markers including C-reactive protein, procalcitonin, and IL-6. PMID- 23820265 TI - Oncogenic functions of the transcription factor Nrf2. AB - Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor that controls the expression of a large pool of antioxidant and cytoprotective genes regulating the cellular response to oxidative and electrophilic stress. Nrf2 is negatively regulated by Kelch-like ECH-associated protein 1 (Keap1) and, upon stimulation by an oxidative or electrophilic insult, is rapidly activated by protein stabilization. Owing to its cytoprotective functions, Nrf2 has been traditionally studied in the field of chemoprevention; however, there is accumulated evidence that Keap1/Nrf2 mutations or unbalanced regulation that leads to overexpression or hyperactivation of Nrf2 may participate in tumorigenesis and be involved in chemoresistance of a wide number of solid cancers and leukemias. In addition to protecting cells from reactive oxygen species, Nrf2 seems to play a direct role in cell growth control and is related to apoptosis-regulating pathways. Moreover, Nrf2 activity is connected with oncogenic kinase pathways, structural proteins, hormonal regulation, other transcription factors, and epigenetic enzymes involved in the pathogenesis of various types of tumors. The aim of this review is to compile and summarize existing knowledge of the oncogenic functions of Nrf2 to provide a solid basis for its potential use as a molecular marker and pharmacological target in cancer. PMID- 23820266 TI - gamma-Glutamyltransferase catabolism of S-nitrosoglutathione modulates IL-8 expression in cystic fibrosis bronchial epithelial cells. AB - S-nitrosoglutathione (GSNO) is an endogenous nitrosothiol involved in several pathophysiological processes. A role for GSNO has been envisaged in the expression of inflammatory cytokines such as IL-8; however, conflicting results have been reported. gamma-Glutamyltransferase (GGT) enzyme activity can hydrolyze the gamma-glutamyl bond present in the GSNO molecule thus greatly accelerating the release of bioactive nitric oxide. Expression of GGT is induced by oxidative stress, and activated neutrophils contribute to GGT increase in cystic fibrosis (CF) lung exudates by releasing GGT-containing microvesicles. This study was aimed at evaluating the effect of GSNO catabolism mediated by GGT on production of IL-8 in CF transmembrane regulation protein-mutated IB3-1 bronchial cells. The rapid, GGT-catalyzed catabolism of GSNO caused a decrease in both basal and lipopolysaccharide-stimulated IL-8 production in IB3-1 cells, by modulating both NF-kappaB and ERK1/2 pathways, along with a decrease in cell proliferation. In contrast, a slow decomposition of GSNO produced a significant increase in both cell proliferation and expression of IL-8, the latter possibly through p38 mediated stabilization of IL-8 mRNA. Our data suggest that the differential GSNO catabolism mediated by GGT enzyme activity can downregulate the production of IL 8 in CF cells. Hence, the role of GGT activity should be considered when evaluating GSNO for both in vitro and in vivo studies, the more so in the case of GSNO-based therapies for cystic fibrosis. PMID- 23820267 TI - Roundup disrupts male reproductive functions by triggering calcium-mediated cell death in rat testis and Sertoli cells. AB - Glyphosate is the primary active constituent of the commercial pesticide Roundup. The present results show that acute Roundup exposure at low doses (36 ppm, 0.036 g/L) for 30 min induces oxidative stress and activates multiple stress-response pathways leading to Sertoli cell death in prepubertal rat testis. The pesticide increased intracellular Ca(2+) concentration by opening L-type voltage-dependent Ca(2+) channels as well as endoplasmic reticulum IP3 and ryanodine receptors, leading to Ca(2+) overload within the cells, which set off oxidative stress and necrotic cell death. Similarly, 30 min incubation of testis with glyphosate alone (36 ppm) also increased (45)Ca(2+) uptake. These events were prevented by the antioxidants Trolox and ascorbic acid. Activated protein kinase C, phosphatidylinositol 3-kinase, and the mitogen-activated protein kinases such as ERK1/2 and p38MAPK play a role in eliciting Ca(2+) influx and cell death. Roundup decreased the levels of reduced glutathione (GSH) and increased the amounts of thiobarbituric acid-reactive species (TBARS) and protein carbonyls. Also, exposure to glyphosate-Roundup stimulated the activity of glutathione peroxidase, glutathione reductase, glutathione S-transferase, gamma-glutamyltransferase, catalase, superoxide dismutase, and glucose-6-phosphate dehydrogenase, supporting downregulated GSH levels. Glyphosate has been described as an endocrine disruptor affecting the male reproductive system; however, the molecular basis of its toxicity remains to be clarified. We propose that Roundup toxicity, implicated in Ca(2+) overload, cell signaling misregulation, stress response of the endoplasmic reticulum, and/or depleted antioxidant defenses, could contribute to Sertoli cell disruption in spermatogenesis that could have an impact on male fertility. PMID- 23820268 TI - Folic acid reverses nitric oxide synthase uncoupling and prevents cardiac dysfunction in insulin resistance: role of Ca2+/calmodulin-activated protein kinase II. AB - Nitric oxide synthase (NOS) may be uncoupled to produce superoxide rather than nitric oxide (NO) under pathological conditions such as diabetes mellitus and insulin resistance, leading to cardiac contractile anomalies. Nonetheless, the role of NOS uncoupling in insulin resistance-induced cardiac dysfunction remains elusive. Given that folic acid may produce beneficial effects for cardiac insufficiency partially through its NOS recoupling capacity, this study was designed to evaluate the effect of folic acid on insulin resistance-induced cardiac contractile dysfunction in a sucrose-induced insulin resistance model. Mice were fed a sucrose or starch diet for 8 weeks before administration of folic acid in drinking water for an additional 4 weeks. Cardiomyocyte contractile and Ca(2+) transient properties were evaluated and myocardial function was assessed using echocardiography. Our results revealed whole body insulin resistance after sucrose feeding associated with diminished NO production, elevated peroxynitrite (ONOO(-)) levels, and impaired echocardiographic and cardiomyocyte function along with a leaky ryanodine receptor (RYR) and intracellular Ca(2+) handling derangement. Western blot analysis showed that insulin resistance significantly promoted Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) phosphorylation, which might be responsible for the leaky RYR and cardiac mechanical dysfunction. NOS recoupling using folic acid reversed insulin resistance-induced changes in NO and ONOO(-), CaMKII phosphorylation, and cardiac mechanical abnormalities. Taken together, these data demonstrated that treatment with folic acid may reverse cardiac contractile and intracellular Ca(2+) anomalies through ablation of CaMKII phosphorylation and RYR Ca(2+) leak. PMID- 23820269 TI - Inhibitory and combinatorial effect of diphyllin, a v-ATPase blocker, on influenza viruses. AB - An influenza pandemic poses a serious threat to humans and animals. Conventional treatments against influenza include two classes of pathogen-targeting antivirals: M2 ion channel blockers (such as amantadine) and neuraminidase inhibitors (such as oseltamivir). Examination of the mechanism of influenza viral infection has shown that endosomal acidification plays a major role in facilitating the fusion between viral and endosomal membranes. This pathway has led to investigations on vacuolar ATPase (v-ATPase) activity, whose role as a regulating factor on influenza virus replication has been verified in extensive genome-wide screenings. Blocking v-ATPase activity thus presents the opportunity to interfere with influenza viral infection by preventing the pH-dependent membrane fusion between endosomes and virions. This study aims to apply diphyllin, a natural compound shown to be as a novel v-ATPase inhibitor, as a potential antiviral for various influenza virus strains using cell-based assays. The results show that diphyllin alters cellular susceptibility to influenza viruses through the inhibition of endosomal acidification, thus interfering with downstream virus replication, including that of known drug-resistant strains. In addition, combinatorial treatment of the host-targeting diphyllin with pathogen targeting therapeutics (oseltamivir and amantadine) demonstrates enhanced antiviral effects and cell protection in vitro. PMID- 23820270 TI - Colitis and colon cancer in WASP-deficient mice require helicobacter species. AB - BACKGROUND: Wiskott-Aldrich syndrome protein-deficient patients and mice are immunodeficient and can develop inflammatory bowel disease. The intestinal microbiome is critical to the development of colitis in most animal models, in which Helicobacter spp. have been implicated in disease pathogenesis. We sought to determine the role of Helicobacter spp. in colitis development in Wiskott Aldrich syndrome protein-deficient (WKO) mice. METHODS: Feces from WKO mice raised under specific pathogen-free conditions were evaluated for the presence of Helicobacter spp., after which a subset of mice were rederived in Helicobacter spp.-free conditions. Helicobacter spp.-free WKO animals were subsequently infected with Helicobacter bilis. RESULTS: Helicobacter spp. were detected in feces from WKO mice. After rederivation in Helicobacter spp.-free conditions, WKO mice did not develop spontaneous colitis but were susceptible to radiation induced colitis. Moreover, a T-cell transfer model of colitis dependent on Wiskott-Aldrich syndrome protein-deficient innate immune cells also required Helicobacter spp. colonization. Helicobacter bilis infection of rederived WKO mice led to typhlitis and colitis. Most notably, several H. bilis-infected animals developed dysplasia with 10% demonstrating colon carcinoma, which was not observed in uninfected controls. CONCLUSIONS: Spontaneous and T-cell transfer, but not radiation-induced, colitis in WKO mice is dependent on the presence of Helicobacter spp. Furthermore, H. bilis infection is sufficient to induce typhlocolitis and colon cancer in Helicobacter spp.-free WKO mice. This animal model of a human immunodeficiency with chronic colitis and increased risk of colon cancer parallels what is seen in human colitis and implicates specific microbial constituents in promoting immune dysregulation in the intestinal mucosa. PMID- 23820272 TI - Rotary pumps and diminished pulsatility: do we need a pulse? AB - Ventricular assist devices (VADs) have been successfully used as a bridge to heart transplant and destination therapy (DT) for congestive heart failure (HF) patients. Recently, continuous flow VAD (CVAD) has emerged as an attractive clinical option for long-term mechanical support of HF patients, with bridge-to transplant outcomes comparable with pulsatile flow VAD (PVAD). Continuous flow VADs are smaller, more reliable, and less complex than the first-generation PVAD. Despite the widespread clinical use, CVAD support has been associated with gastrointestinal bleeding, hemorrhagic strokes, and aortic valve insufficiency. Speculation that diminished arterial pressure pulsatility associated with continuous flow devices may be contributing to these complications has sparked much debate over CVAD support. Studies comparing pulsatile flow and continuous flow (CF) support have presented conflicting findings, and the relevance to CVAD as DT is uncertain due to variations in device operation, support duration, and the criteria used to quantify pulsatility. Currently, there is interest in developing control algorithms for CVAD to increase the delivered pulsatility as a strategy to mitigate adverse event risks associated with CVAD therapy. There may also be the added benefit of specific control strategies for managing CVAD therapy, potentially improving the rate of myocardial recovery and successful weaning of mechanical circulatory support. PMID- 23820273 TI - Prompt diagnosis of a new clinical entity: membrane oxygenator infection during ECMO. PMID- 23820274 TI - Microbial adhesion on membrane oxygenators in patients requiring extracorporeal life support detected by a universal rDNA PCR test. AB - Extracorporeal membrane oxygenation (ECMO) represents a temporary life-saving therapy for respiratory or circulatory failure, but infections during ECMO support are a life-threatening complication. Surface-related infections of ECMO are mentioned, but rarely described in the literature. A universal rDNA polymerase chain reaction (PCR) test was used to investigate the potential microbiological colonization of membrane oxygenators (MOs) in 20 patients undergoing ECMO. The overall patient-based positivity by PCR was 45%. Gram positive bacteria (71%) represented the most abundant microorganisms on MO surfaces, followed by Gram-negative bacteria (22%) and fungi (7%). The most frequently detected causative pathogens were staphylococci (58%). Bacterial mixed infections represented 56% of all infections. In four PCR-positive cases, the pathogens detected on the MO surfaces were also found by blood culture or by culture of specimens obtained from the infectious focus. In conclusion, hollow fiber membranes of MOs can be colonized by microorganisms and appear to be a potential source of bacterial and fungal infections in ECMO patients. These infections may pose an increased risk for clinical worsening. As a consequence, persistent septic complications have to be discussed as an indication for MO exchange. The initial results suggest that the applied PCR assay is a valuable tool to investigate MOs. PMID- 23820276 TI - Novel thrombosis risk index as predictor of left ventricular assist device thrombosis. AB - Left ventricular assist devices (LVADs) are an effective therapy for patients with advanced heart failure, increasing patient survival and quality of life. Left ventricular assist devices are associated with the risks of bleeding and thrombosis. We used lactate dehydrogenase (LDH) and brain natriuretic peptide (BNP) as biomarkers for developing a thrombosis risk index. Data from a single center was retrospectively queried between January 1, 2008, and 10/15, 2011, to identify LVAD patients and related complications. Of 75 consecutive patients implanted with an LVAD, nine had device thrombosis. Analysis of the relationship among international normalized ratio (INR), BNP, LDH, and device thrombosis was performed. Of nine patients with thrombosis, seven had at least 30% of INR readings below 1.5 and two had at least 22% below the therapeutic range from the time of LVAD implant to date of thrombosis. Timeline variability in INR, BNP, and LDH were used to calculate thrombosis risk index (TRI). The TRI retrospectively was able to accurately predict patients with impending device thrombosis. Indexed rise in BNP and LDH in LVAD patients may be useful to identify early device dysfunction and possible future thrombosis. Fibrinogen and D-dimer assays are currently being evaluated in these patients for their possible inclusion and added value to the TRI. PMID- 23820271 TI - Blood substitutes: evolution from noncarrying to oxygen- and gas-carrying fluids. AB - The development of oxygen (O2)-carrying blood substitutes has evolved from the goal of replicating blood O2 transport properties to that of preserving microvascular and organ function, reducing the inherent or potential toxicity of the material used to carry O2, and treating pathologies initiated by anemia and hypoxia. Furthermore, the emphasis has shifted from blood replacement fluid to "O2 therapeutics" that restore tissue oxygenation to specific tissues regions. This review covers the different alternatives, potential and limitations of hemoglobin-based O2 carriers (HBOCs) and perfluorocarbon-based O2 carriers (PFCOCs), with emphasis on the physiologic conditions disturbed in the situation that they will be used. It describes how concepts learned from plasma expanders without O2-carrying capacity can be applied to maintain O2 delivery and summarizes the microvascular responses due to HBOCs and PFCOCs. This review also presents alternative applications of HBOCs and PFCOCs namely: 1) How HBOC O2 affinity can be engineered to target O2 delivery to hypoxic tissues; and 2) How the high gas solubility of PFCOCs provides new opportunities for carrying, dissolving, and delivering gases with biological activity. It is concluded that the development of current blood substitutes has amplified their applications horizon by devising therapeutic functions for O2 carriers requiring limited O2 delivery capacity restoration. Conversely, full, blood-like O2-carrying capacity reestablishment awaits the control of O2 carrier toxicity. PMID- 23820275 TI - A comparative study of cerebral microcirculation during pulsatile and nonpulsatile selective cerebral perfusion: assessment by synchrotron radiation microangiography. AB - Currently, nonpulsatile selective cerebral perfusion for cerebroprotection against thoracic aortic aneurysm is used in clinical settings. We performed synchrotron radiation microangiography to determine the effects on selective cerebral perfusion modulation by pulsatile flow. We established cerebral perfusion at normothermia and severe hypothermia in anesthetized rats, during which cerebral angiography was performed. NG-nitro-L-arginine-methyl ester hydrochloride (L-NAME) was administered to determine the effect of pulsatile flow with nitric oxide synthesis. In comparison with nonpulsatile flow, the relative diameters of small internal carotid artery were 132.11 +/- 5.49% and 114.96 +/- 4.60% during pulsatile flow at normothermia and severe hypothermia (p < 0.05). The angiographic scores, an indicator of vessel count, for nonpulsatile and pulsatile flow at normothermia were 0.198 +/- 0.013 vs. 0.258 +/- 0.010 (p < 0.001) and those at severe hypothermia were 0.158 +/- 0.017 vs. 0.214 +/- 0.015 (p < 0.01), respectively. In comparison with nonpulsatile flow, the relative internal carotid artery diameters during pulsatile flow with and without L-NAME were 98.50 +/- 1.7% vs. 114.96 +/- 4.6%, respectively, during severe hypothermia. These results show that pulsatile flow is effective in increasing blood vessel diameter, number of vessels, and perfusion distribution range in the rat model and that it was more effective at normothermia during nitric oxide production. PMID- 23820277 TI - An old problem with a new therapy: gastrointestinal bleeding in ventricular assist device patients and deep overtube-assisted enteroscopy. AB - Conventional algorithms for diagnosis and treatment of gastrointestinal bleeding (GIB) in patients with nonpulsatile ventricular assist devices (VADs) may take days to perform while patients require transfusions. We developed a new algorithm based on deep overtube-assisted enteroscopy (DOAE) to facilitate a rapid diagnosis and treatment. From 2004 to 2012, 84 patients who underwent VAD placement in our institution, were evaluated for episodes of GIB. Our new algorithm for the management of GIB using DOAE was evaluated by dividing the episodes into three groups: group A (traditional management without enteroscopy), group B (traditional management with enteroscopy performed >24 hours after presentation), and group C (new management algorithm with enteroscopy performed <24 hours after presentation). Gastrointestinal bleeding was observed in 14 (17%) of our study patients for a total of 45 individual episodes of which 28 met our criteria for subanalysis. Forty-one (84%) lesions were confined to the upper gastrointestinal tract with more than 91% of these lesions being arteriovenous malformations. Average number of transfusions in groups A, B, and C were 4.1, 6.3, and 1.3, respectively (p = 0.001). The number of days to treatment was significantly shorter in group C than group B (0.4 vs. 5.3 days, p = 0.0002). Our new algorithm for the management of GIB using DOAE targets the most common locations of bleeding found in this patient population. When performed early, DOAE has the potential to decrease the need for transfusions and allow for an early diagnosis of GIB in VAD recipients. PMID- 23820279 TI - Biplane angiography for experimental validation of computational fluid dynamic models of blood flow in artificial lungs. AB - This article presents an investigation into the validation of velocity fields obtained from computational fluid dynamic (CFD) models of flow through the membrane oxygenators using x-ray digital subtraction angiography (DSA). Computational fluid dynamic is a useful tool in characterizing artificial lung devices, but numerical results must be experimentally validated. We used DSA to visualize flow through a membrane oxygenator at 2 L/min using 37% glycerin at 22 degrees C. A Siemens Artis Zee system acquired biplane x-ray images at 7.5 frames per second, after infusion of an iodinated contrast agent at a rate of 33 ml/s. A maximum cross-correlation (MCC) method was used to track the contrast perfusion through the fiber bundle. For the CFD simulations, the fiber bundle was treated as a single momentum sink according to the Ergun equation. Blood was modeled as a Newtonian fluid, with constant viscosity (3.3 cP) and density (1050 kg/m3). Although CFD results and experimental pressure measurements were in general agreement, the simulated 2 L/min perfusion did not reproduce the flow behavior seen in vitro. Simulated velocities in the fiber bundle were on average 42% lower than experimental values. These results indicate that it is insufficient to use only pressure measurements for validation of the flow field because pressure validated CFD results can still significantly miscalculate the physical velocity field. We have shown that a clinical x-ray modality, together with a MCC tracking algorithm, can provide a nondestructive technique for acquiring experimental data useful for validation of the velocity field inside membrane oxygenators. PMID- 23820278 TI - Resolution of pulmonary hypertension complication during venovenous perfusion induced systemic hyperthermia application. AB - We are developing a venovenous perfusion-induced systemic hyperthermia (vv-PISH) system for advanced cancer treatment. The vv-PISH system consistently delivered hyperthermia to adult healthy swine, but significant pulmonary hypertension developed during the heating phase. The goal of this study was to develop a method to prevent pulmonary hypertension. We hypothesized that pulmonary hypertension results from decreased priming solution air solubility, which causes pulmonary gas embolism. Healthy adult sheep (n = 3) were used to establish a standard vv-PISH sheep model without priming solution preheating. In subsequent sheep (n = 7), the priming solution was preheated (42-46 degrees C) and the hyperthermia circuit flushed with CO2. All sheep survived the experiment and achieved 2 hours of 42 degrees C hyperthermia. In the group lacking priming solution preheating, significant pulmonary hypertension (35-44 mm Hg) developed. In the sheep with priming solution preheating, pulmonary artery pressure was very stable without pulmonary hypertension. Blood electrolytes were in physiologic range, and complete blood counts were unaffected by hyperthermia. Blood chemistries revealed no significant liver or kidney damage. Our simple strategy of priming solution preheating completely resolved the problem of pulmonary hypertension as a milestone toward developing a safe and easy-to-use vv-PISH system for cancer treatment. PMID- 23820280 TI - Mitral regurgitation and axial flow left ventricular assist device: a computer simulation study. AB - Good right ventricular function is one of the major determinants of long-term outcomes in patients with implanted left ventricular assist devices (LVADs). In the present study, a computer model was developed to assess the impact of mitral regurgitation on right ventricular workload at different levels of LVAD support. Left ventricular assist device was simulated by a model of HeartMate II. The computer model has shown that the regurgitant volume of the mitral valve falls significantly only after the systolic pressure in the left ventricle decreases, which occurs at higher LVAD revolutions per minute (RPM) when there is no ejection through the aortic valve. However, at low LVAD RPM, the pressures in the left atrium and the pulmonary artery decrease significantly, despite a small decrease in regurgitant volume. According to the computer model, LVAD support decreases mitral regurgitation. Furthermore, regurgitant volume has a smaller impact on the right ventricular afterload when compared with a heart without LVAD support. PMID- 23820281 TI - Fault detection in rotary blood pumps using motor speed response. AB - Clinical acceptance of ventricular assist devices (VADs) as long-term heart failure therapy requires safe and effective circulatory support for a minimum of 5 years. Yet, VAD failure beyond 2 years of support is still a concern. Currently, device controllers cannot consistently predict VAD failure modes, and undetected VAD faults may lead to catastrophic device failure. To minimize this risk, a model-based algorithm for reliable VAD fault detection that only requires VAD revolutions per minute (rpm) was developed. The algorithm was tested using computer models of the human cardiovascular system simulating heart failure and axial flow (AF) or centrifugal flow (CF) VADs. Ventricular assist device rpm was monitored after a step down of motor current for normal and simulated fault conditions (>750 faults). The ability to detect fault conditions with 1%, 5%, and 10% rpm measurement noise was evaluated. All failure modes affected the VAD rpm responses to the motor current step down. Fault detection rates were >95% for AF and >89% for CF VADs, even with 10% rpm measurement noise. The VAD rpm responses were significantly altered by blood viscosity (3.5-6.2 cP), which should be accounted for in clinical application. The proposed VAD fault detection algorithm may deliver a convenient and nonintrusive way to minimize catastrophic device failures. PMID- 23820282 TI - Pump flow estimation from pressure head and power uptake for the HeartAssist5, HeartMate II, and HeartWare VADs. AB - The use of long-term mechanical circulatory support (MCS) for heart failure by means of implanted continuous-flow left ventricular assist devices (cf-LVADs) will increase, either to enable recovery or to provide a destination therapy. The effectiveness and user-friendliness of MCS will depend on the development of near physiologic control strategies for which accurate estimation of pump flow is essential. To provide means for the assessment of pump flow, this study presents pump models, estimating pump flow (Q(lvad)) from pump speed (n) and pressure difference across the LVAD (Deltap(lvad)) or power uptake (P). The models are evaluated for the axial-flow LVADs HeartAssist5 (HA5) and HeartMate II (HMII), and for a centrifugal pump, the HeartWare (HW). For all three pumps, models estimating Q(lvad) from Deltap(lvad) only is capable of describing pump behavior under static conditions. For the axial pumps, flow estimation from power uptake alone was not accurate. When assuming an increase in pump flow with increasing power uptake, low pump flows are overestimated in these pumps. Only for the HW, pump flow increased linearly with power uptake, resulting in a power-based pump model that estimates static pump flow accurately. The addition of pressure head measurements improved accuracy in the axial cf-LVAD estimation models. PMID- 23820283 TI - Oxygen consumption during oxygenated hypothermic perfusion as a measure of donor organ viability. AB - Hypothermic machine perfusion (HMP) for the preservation of kidneys, recovered from extended criteria organ donors (ECDs), presents the opportunity for assessing ex vivo parameters that may have value in predicting postimplantation organ viability. Organ perfusion and vascular resistance are the parameters most frequently cited as the basis for the decision to use or discard a donor kidney. The limitation of these measures is emphasized by the observation that a significant percentage of ECD kidneys with poor perfusion parameters can provide life-sustaining function after transplantation. It has been suggested that whole organ oxygen consumption (OC) during oxygenated HMP may better reflect the proportion of viable tissue in the organ and more reliably predict posttransplant organ function. Our study correlates renal OC and renal vascular resistance (RVR) during oxygenated HMP with postpreservation glomerular filtration rates (GFRs) in rodent kidneys after 24 hours of oxygenated HMP. Kidneys from adult rodents were preserved for 24 hours using oxygenated HMP and static cold storage (SCS). During oxygenated HMP preservation, organ OC, renal organ flow rates, and RVR were serially measured. After the preservation period, organs were mounted onto a Langendorff device for warming to normal body temperature and measurement of GFR. Oxygen consumption and RVR during HMP were correlated with postpreservation GFR. Oxygen consumption during oxygenated HMP was significantly correlated (r2 = 0.871; p < 0.05) with postpreservation GFR, suggesting that higher OC predicts better postpreservation GFR. In contrast, RVR was poorly correlated with postpreservation GFR (r2 = 0.258; p = 0.199). Glomerular filtration rate in SCS kidneys was 0.002 +/- 0.003 ml/min/g. We demonstrate that measurement of organ OC during oxygenated HMP may have significant value in predicting postpreservation organ function. PMID- 23820284 TI - Combined pulmonary and renal support in a single extracorporeal device. AB - Combined acute lung injury (ALI) and kidney injury (AKI) is a common problem in critically ill patients. By combining pulmonary (gas exchange) and renal (hemofiltration) support in one extracorporeal device with low-flow resistance, we seek to provide less artificial surfaces maintaining sufficient organ support. Modified Interventional Lung Assist (iLA) Membrane Ventilator (miLA), consisting of polymethylpentene gas exchange membranes and polyethersulfone hemofiltration membranes, was compared in vitro with the original iLA design, consisting only of gas exchange membranes, regarding both delivery volume and loss in pressure versus pump rate. Efficiency tests concerning gas exchange and hemofiltration rate were performed in vitro and in vivo. In vitro analyses showed no differences between both systems, with adequate filtration rates in miLA. Anticoagulation and constant blood pressure allowed 1.2 L/min of blood flow and hemofiltration rates of 70 ml/h through miLA in vivo. No major differences between concentrations of filtered molecules in blood and hemofiltrate were found. A stable gas exchange function was maintained. No signs of hemolysis were detected. Our results confirm the feasibility of single-device support for combined pulmonary and renal injury. Novel devices expanding on this concept may potentially improve therapy of critically ill patients with ALI/AKI. PMID- 23820285 TI - Visualization of thrombotic deposits in extracorporeal membrane oxygenation devices using multidetector computed tomography: a feasibility study. AB - Despite heparin coating and systemic anticoagulation, thrombotic clot formation is a serious complication in extracorporeal membrane oxygenation (ECMO). We describe our first results of visualization of thrombotic deposits in ECMO devices using advanced multidetector computed tomography (MDCT). A bioline-coated polymethylpentene membrane oxygenator (MO) after 8 days of ECMO treatment (device 1) and a factory-sealed MO serving as an internal quality control (device 2) were analyzed with three-dimensional (3D) visualization volume rendering technique (VRT) using a 0.6 mm3 voxel isotropic MDCT dataset. After the computed tomography (CT) scan, device 1 was anatomically dissected for direct visualization of potential deposits and further analyzed by scanning electron microscopy (SEM). The VRT 3D model based on the MDCT dataset of device 1 showed red-coded areas within the gas exchange surface of the device consistent with fibrous and cellular deposits. These deposits could be confirmed by anatomical dissection of the device and by SEM. Device 2 showed no signs of clot formation in MDCT using the same VRT settings. It was demonstrated that MDCT with VRT is able to detect thrombotic deposits in ECMO devices under ex vivo conditions. MDCT allows direct visualization of the actual thrombus load of a used ECMO device as well as the quantification of the thrombus volume and could, therefore, play a significant role in better understanding the oxygenator thrombosis in modern ECMO treatment. PMID- 23820286 TI - Optimal endovascular methods for placement of bicaval dual-lumen cannulae for venovenous extracorporeal membrane oxygenation. AB - Early mobility is associated with improved outcomes in critically ill patients with acute respiratory failure. The Avalon Elite Bicaval Dual-Lumen cannula provides support for extracorporeal membrane oxygenation through a single cannula in the internal jugular position in the neck, avoiding femoral cannulation. This allows the patient to participate in early mobility and strength exercises, facilitating early reconditioning. Placement of the Avalon bicaval cannula poses a potential risk of intracardiac placement and right ventricular rupture as a result of the flexibility of the guidewire. We present our endovascular technique for Avalon bicaval cannula placement with fluoroscopic guidance to prevent inadvertent intracardiac placement. PMID- 23820287 TI - Bivalirudin for treatment of aortic valve thrombosis after left ventricular assist device implantation. AB - Ventricular assist devices are increasingly being used for mechanical support in patients with advanced heart failure. However, thromboembolism remains a leading cause of mortality in this population. We describe the successful treatment of native aortic valve thrombosis with bivalirudin in a patient with factor V Leiden mutation, who had undergone left ventricular assist device implantation, preventing the need for further surgical intervention. PMID- 23820288 TI - Octreotide for left ventricular assist device-related gastrointestinal hemorrhage: can we stop the bleeding? AB - Left ventricular support devices (LVADs) are associated with a propensity toward gastrointestinal bleeding. A postulated mechanism is related to gastrointestinal arteriovenous malformations secondary to nonpulsatile flow. We describe a case of LVAD-related, gastrointestinal bleeding successfully treated with a combination of subcutaneous and intramuscular depot formulations of octreotide. PMID- 23820289 TI - Thromboembolism is linked to intraventricular flow stasis in a patient supported with a left ventricle assist device. AB - A case report is presented of a left ventricular assist device (LVAD) recipient with a pre-existing thrombus that was removed on LVAD implant but quickly reformed and was removed, reformed again, and ultimately embolized, causing death. The thrombus formed proximal to the left ventricular outflow tract, because of the presence and subsequent repair of a calcified left ventricular infarct which had extruded from the septum. This region is vulnerable to flow stasis during LVAD support as predicted by experimental fluid mechanics studies, because of the lack of opening of the aortic valve. The presence of the repair and the altered flow field contributed to blood stasis and thrombus growth in a positive feedback loop. Although LVADs provide tremendous benefits for patients by reducing the symptoms of heart failure, the accompanying changes have some secondary consequences that remain problematic. One of these is an abnormal intraventricular flow field that decreases washout, especially in the region proximal to the left ventricular outflow tract, which is an area of flow stasis. PMID- 23820290 TI - Case series using the ROTAFLOW system as a temporary right ventricular assist device after HeartMate II implantation. AB - The purpose of this study was to investigate the outcomes of using the ROTAFLOW as a temporary right ventricular assist device (RVAD) support in patients who develop right ventricular dysfunction (RVD) at the time of left ventricular assist device (LVAD) implantation with the HeartMate (HM) II. We conducted a retrospective chart review of patients in whom the ROTAFLOW system was used for RV support during HM II implantation from October 2009 to September 2011. Twelve patients received a ROTAFLOW as an RVAD at the time of HM II implantation; 83% had preoperative echocardiography evidence of either moderate or severe RVD. The most common complications in the postoperative period were the need for tracheostomy because of respiratory failure (45%) and mediastinal bleeding requiring exploration (36%). Ninety-one percent of patients survived to discharge, and all were alive at 1 year follow-up. Our results show that temporary RVAD support with the ROTAFLOW system in the setting of RVD at the time of HM II implantation is feasible and effective. PMID- 23820291 TI - Recycling and recovery routes for incinerated sewage sludge ash (ISSA): a review. AB - The drivers for increasing incineration of sewage sludge and the characteristics of the resulting incinerated sewage sludge ash (ISSA) are reviewed. It is estimated that approximately 1.7 milliontonnes of ISSA are produced annually world-wide and is likely to increase in the future. Although most ISSA is currently landfilled, various options have been investigated that allow recycling and beneficial resource recovery. These include the use of ISSA as a substitute for clay in sintered bricks, tiles and pavers, and as a raw material for the manufacture of lightweight aggregate. ISSA has also been used to form high density glass-ceramics. Significant research has investigated the potential use of ISSA in blended cements for use in mortars and concrete, and as a raw material for the production of Portland cement. However, all these applications represent a loss of the valuable phosphate content in ISSA, which is typically comparable to that of a low grade phosphate ore. ISSA has significant potential to be used as a secondary source of phosphate for the production of fertilisers and phosphoric acid. Resource efficient approaches to recycling will increasingly require phosphate recovery from ISSA, with the remaining residual fraction also considered a useful material, and therefore further research is required in this area. PMID- 23820292 TI - ABCB1 gene polymorphisms are associated with suicide in forensic autopsies. AB - BACKGROUND: Polymorphisms in ABCB1 have the ability to affect both the function and the expression of the transporter protein P-glycoprotein and may lead to an altered response for many drugs including some antidepressants and antipsychotics. OBJECTIVE: The aim of this study was to examine the impact of the ABCB1 polymorphisms 1199G>A, 1236C>T, 2677G>T/A, and 3435C>T in deaths by suicide. PATIENTS AND METHODS: A total of 998 consecutive Swedish forensic autopsies performed in 2008 in individuals 18 years of age or older, where femoral blood was available and a toxicological screening had been performed, were investigated. Genotypes were assessed with pyrosequencing and information on the cause and manner of each death was obtained from the forensic pathology and toxicology databases. RESULTS: There was a significantly higher frequency of the T allele at positions 1236, 2677, and 3435 among the suicide cases compared with the nonsuicide cases. CONCLUSION: Our result from forensic cases suggests that ABCB1 polymorphisms are associated with an increased risk for completed suicides. The biological mechanisms involved and the clinical implications for these findings are largely unknown and need to be examined further. PMID- 23820293 TI - Meeting the challenges in freeze-drying of pharmaceuticals and biologicals. PMID- 23820295 TI - Gait training of poststroke patients assisted by the Walkaround (body postural support). AB - Improvement in gait abilities is one of the important goals of stroke rehabilitation. The Walkaround is a new postural assistance device for gait training, which allows an early start for gait training. This device provides body postural support (BPS) and trunk orientation by means of a lumbar belt that is connected to a powered rolling walker. We conducted a randomized, single blinded, 4-week clinical trial of 22 subacute stroke patients with a follow-up period of 6 months. Patients were divided into two identically sized groups: the treatment group (BPS), which was assisted by the Walkaround, and the control (CON) group, which was assisted by conventional means (cane, therapist) during gait training. The objective of the study was to assess whether the Walkaround is more effective than conventional assistance during gait training. The outcome measures were as follows: Barthel index, Fugl-Meyer score for the lower extremities, Berg balance test, and gait speed. Changes in the outcome measures were significant for the Berg balance score after 6 months in both groups and in gait speed among the BPS group at the end of therapy and after 6 months (P<0.05) compared with the same outcome measures at the beginning of the trial. Significant differences were found in gait speed and Berg balance test scores after 4 weeks and in gait speed after 6 months (P<0.05) between the BPS and the CON groups. The results suggest that added postural support by the Walkaround led to limited yet significant changes in gait speed and balance control. PMID- 23820294 TI - Vaccination with Vaxfectin((r)) adjuvanted SIV DNA induces long-lasting humoral immune responses able to reduce SIVmac251 Viremia. AB - We evaluated the immunogenicity and efficacy of Vaxfectin((r)) adjuvanted SIV DNA vaccines in mice and macaques. Vaccination of mice with Vaxfectin((r)) adjuvanted SIV gag DNA induced higher humoral immune responses than administration of unadjuvanted DNA, whereas similar levels of cellular immunity were elicited. Vaxfectin((r)) adjuvanted SIVmac251 gag and env DNA immunization of rhesus macaques was used to examine magnitude, durability, and efficacy of humoral immunity. Vaccinated macaques elicited potent neutralizing antibodies able to cross-neutralize the heterologous SIVsmE660 Env. We found remarkable durability of Gag and Env humoral responses, sustained during ~2 y of follow-up. The Env specific antibody responses induced by Vaxfectin((r)) adjuvanted env DNA vaccination disseminated into mucosal tissues, as demonstrated by their presence in saliva, including responses to the V1-V2 region, and rectal fluids. The efficacy of the immune responses was evaluated upon intrarectal challenge with low repeated dose SIVmac251. Although 2 of the 3 vaccinees became infected, these animals showed significantly lower peak virus loads and lower chronic viremia than non-immunized infected controls. Thus, Vaxfectin((r)) adjuvanted DNA is a promising vaccine approach for inducing potent immune responses able to control the highly pathogenic SIVmac251. PMID- 23820296 TI - Lumbar fusion compared with conservative treatment in patients with chronic low back pain: a meta-analysis. AB - We assess the effect of lumbar fusion (LF) in reducing disability among patients with chronic low back pain (CLBP) compared with conservative treatment and to weigh the clinical significance of this effect. We conducted a random-effect meta analysis on the basis of a systematic review with research quality grading according to Grading of Recommendations Assessment, Development and Evaluation (GRADE). The studies included were retrieved from MEDLINE and Cochrane CENTRAL databases from 1990 till January 2013. Randomized or nonrandomized controlled studies were included if the study participants had a history of CLBP because of degenerative spinal diseases and had been treated with LF. A study was included if it compared LF with conservative treatment. The outcome measure was a change in the Oswestry Disability Index (ODI) score during a follow-up. The meta analysis included data on 666 patients (402 cases) who participated in four randomized-controlled trials. The ODI score reduced in the LF and the control groups. The mean reduction in the ODI score in the follow-up of 1.5 years was 2.91 (95% confidence interval -6.66 to 0.84) in favor of LF. The difference between groups was statistically and clinically insignificant. Test for heterogeneity indicated that study imputation would favor LF but the imputed result would still be clinically insignificant with an estimated corrected reduction of ODI score of -5.51 (95% confidence interval -5.78 to -5.24). There is strong evidence that LF is not more effective than conservative treatment in reducing perceived disability because of CLBP among patients with degenerative spinal diseases. It is unlikely that further research on the subject would considerably affect this conclusion. PMID- 23820297 TI - Autophagy receptor CALCOCO2/NDP52 takes center stage in Crohn disease. AB - To advance understanding of the complex genetics of Crohn disease (CD) we sequenced 42 whole exomes of patients with CD and five healthy control individuals, resulting in identification of a missense mutation in the autophagy receptor calcium binding and coiled-coil domain 2 (CALCOCO2/NDP52) gene. Protein domain modeling and functional studies highlight the potential role of this mutation in controlling NFKB signaling downstream of toll-like receptor (TLR) pathways. We summarize our recent findings and discuss the role of autophagy as a major modulator of proinflammatory signaling in the context of chronic inflammation. PMID- 23820298 TI - Speed and distance requirements for community ambulation: a systematic review. AB - OBJECTIVE: To provide an overview of the research literature on distance and speed requirements for adults to walk outside the home. DATA SOURCES: We conducted a systematic review and searched PubMed, MEDLINE (Ovid), EMBASE, CINAHL, Scopus, PEDro, and The Cochrane Library from 1948 to May 2012, and other sources. Search terms included communities, walk, ambulation, and neighborhood. STUDY SELECTION: Full-text peer-reviewed articles written in English, French, or Spanish reporting distance and/or speed requirements for individuals walking outside the home were considered eligible. Two authors independently screened titles and abstracts. One author reviewed full-text articles to determine inclusion. Of the 3191 titles and abstracts screened, 15 studies (.47%) were selected for detailed review. One author appraised methodological quality. Inadequate description of the reliability of the measurement methods and the population of the town/city assessed was noted. DATA EXTRACTION: One author extracted data from included studies. A second reviewer independently verified extracted data for accuracy. DATA SYNTHESIS: Seven studies examining 24 community sites and crosswalks in the United States, Australia, and Singapore were included. Three sites with the largest mean distance requirements for adults to walk were club warehouses (677m), superstores (183-607m), and hardware stores (566m). Three sites with the lowest mean distance requirements were walking at the front (16m) and back (19m) of the house, and at cemeteries (18m). The average speed required to cross the street in the time of a walk signal varied from .44 to 1.32m/s. CONCLUSIONS: Distance and speed requirements for adults to walk in the community environment vary widely. Findings are relevant to judging capacity for community ambulation to carry out essential activities of daily living, educating patients, and setting rehabilitation goals. PMID- 23820299 TI - The role of inherited TPMT and COMT genetic variation in cisplatin-induced ototoxicity in children with cancer. AB - Ototoxicity is a debilitating side effect of platinating agents with substantial interpatient variability. We sought to evaluate the association of thiopurine S methyltransferase (TPMT) and catechol O-methyltransferase (COMT) genetic variations with cisplatin-related hearing damage in the context of frontline pediatric cancer treatment protocols. In 213 children from the St. Jude Medulloblastoma-96 and -03 protocols, hearing loss was related to younger age (P = 0.013) and craniospinal irradiation (P = 0.001), but did not differ by TPMT or COMT variants. Results were similar in an independent cohort of 41 children from solid-tumor frontline protocols. Functional hearing loss or hair cell damage was not different in TPMT knockout vs. wild-type mice following cisplatin treatment, and neither TPMT nor COMT variant was associated with cisplatin cytotoxicity in lymphoblastoid cell lines. In conclusion, our results indicated that TPMT or COMT genetic variation was not related to cisplatin ototoxicity in children with cancer and did not influence cisplatin-induced hearing damage in laboratory models. PMID- 23820301 TI - Milestones in collaboration between the United States and China including the Hopkins-Nanjing Center. PMID- 23820300 TI - Thymosin beta4-sulfoxide attenuates inflammatory cell infiltration and promotes cardiac wound healing. AB - The downstream consequences of inflammation in the adult mammalian heart are formation of a non-functional scar, pathological remodelling and heart failure. In zebrafish, hydrogen peroxide released from a wound is the initial instructive chemotactic cue for the infiltration of inflammatory cells, however, the identity of a subsequent resolution signal(s), to attenuate chronic inflammation, remains unknown. Here we reveal that thymosin beta4-sulfoxide lies downstream of hydrogen peroxide in the wounded fish and triggers depletion of inflammatory macrophages at the injury site. This function is conserved in the mouse and observed after cardiac injury, where it promotes wound healing and reduced scarring. In human T cell/CD14+ monocyte co-cultures, thymosin beta4-sulfoxide inhibits interferon gamma, and increases monocyte dispersal and cell death, likely by stimulating superoxide production. Thus, thymosin beta4-sulfoxide is a putative target for therapeutic modulation of the immune response, resolution of fibrosis and cardiac repair. PMID- 23820303 TI - Rapid sequential endothelial keratoplasty with and without combined cataract extraction. AB - PURPOSE: To evaluate the outcomes of bilateral Descemet membrane endothelial keratoplasty (DMEK) combined with cataract extraction as indicated within a 1- to 2-week timeframe for treatment of Fuchs endothelial corneal dystrophy. SETTING: Private practice, Indianapolis, Indiana, USA. DESIGN: Case series. METHODS: This retrospective review identified patients who had DMEK in both eyes within 2 weeks. RESULTS: The study comprised 12 patients (median age 61 years). Seven patients had bilateral DMEK 1 week apart and 5 patients, 2 weeks apart. Twelve eyes had triple procedures (cataract extraction, intraocular lens implantation, DMEK), 7 eyes were pseudophakic before DMEK, and 5 eyes had clear lenses and remained phakic after DMEK. Preoperatively, the median corrected distance visual acuity (CDVA) was 20/40 (range 20/15 to 20/70). By 1 month postoperatively, the median CDVA had improved to 20/25 (range 20/15 to 20/70). The median CDVA in the 10 patients examined between 3 months and 6 months postoperatively was 20/20 (range 20/15 to 20/30). All grafts successfully attached and cleared. Four patients had bilateral air reinjection and 1 patient had unilateral air reinjection to treat partial graft detachment. The rate of air reinjection was comparable between single and triple procedures (P=.65). No other complications were noted. CONCLUSIONS: Patients with bilateral visual impairment associated with Fuchs dystrophy can have both eyes treated with DMEK within 1 to 2 weeks. With DMEK, corneal transplantation begins to approach cataract surgery in the speed of visual recovery and the time to full resumption of daily activities. PMID- 23820302 TI - Increasing incidence of cataract surgery: population-based study. AB - PURPOSE: To estimate the incidence of cataract surgery in a defined population and to determine longitudinal cataract surgery patterns. SETTING: Mayo Clinic, Rochester, Minnesota, USA. DESIGN: Cohort study. METHODS: Rochester Epidemiology Project (REP) databases were used to identify all incident cataract surgeries in Olmsted County, Minnesota, between January 1, 2005, and December 31, 2011. Age specific and sex-specific incidence rates were calculated and adjusted to the 2010 United States white population. Data were merged with previous REP data (1980 to 2004) to assess temporal trends in cataract surgery. Change in the incidence over time was assessed by fitting generalized linear models assuming a Poisson error structure. The probability of second-eye cataract surgery was calculated using the Kaplan-Meier method. RESULTS: Included were 8012 cataract surgeries from 2005 through 2011. During this time, incident cataract surgery significantly increased (P<.001), peaking in 2011 with a rate of 1100 per 100 000 (95% confidence interval, 1050-1160). The probability of second-eye surgery 3, 12, and 24 months after first-eye surgery was 60%, 76%, and 86%, respectively, a significant increase compared with the same intervals in the previous 7 years (1998 to 2004) (P<.001). When merged with 1980 to 2004 REP data, incident cataract surgery steadily increased over the past 3 decades (P<.001). CONCLUSION: Incident cataract surgery steadily increased over the past 32 years and has not leveled off, as reported in Swedish population-based series. Second-eye surgery was performed sooner and more frequently, with 60% of residents having second-eye surgery within 3 months of first-eye surgery. PMID- 23820304 TI - Thin-flap laser in situ keratomileusis with femtosecond-laser technology. AB - PURPOSE: To evaluate the results of thin-flap laser in situ keratomileusis (LASIK) using a femtosecond-laser platform for flap creation. SETTING: Institute of Vision and Optics, Faculty of Medicine, University of Crete, Heraklion, Greece. DESIGN: Prospective interventional case series. METHODS: Patients had LASIK with the FS200 femtosecond laser for flap creation and the Allegretto Wave Eye-Q excimer laser. Flap thickness was set at 105 MUm. All eyes were examined 1 month postoperatively. Flap thickness was assessed with anterior segment optical coherence tomography using the manual flap tool at 5 locations on a horizontal B scan. RESULTS: This study comprised 50 eyes of 25 patients (mean age 28 years +/ 5.72 [SD]); 42 eyes completed 6 months of follow-up. Preoperatively, the mean sphere was -3.61 +/- 1.87 diopters (D) and the mean cylinder, -1.08 +/- 1.23 D. Six months postoperatively, no eye lost lines of corrected distance visual acuity (CDVA), 29% gained 1 line, and 7% gained 2 lines. The mean spherical equivalent was -0.03 +/- 0.42 D (range -0.88 to +0.88 D); 86% had an uncorrected distance visual acuity of 20/20 or better. The mean central flap thickness at 1 month was 102.98 +/- 6.33 MUm (range 91 to 114 MUm). There were no intraoperative or postoperative complications. CONCLUSIONS: No significant complications occurred after treatment with this new femtosecond-laser platform in thin-flap LASIK. Clinical (visual and refractive) results were satisfactory in terms of safety, predictability, and stability. PMID- 23820305 TI - Posterior corneal elevation and back difference corneal elevation in diagnosing forme fruste keratoconus in the fellow eyes of unilateral keratoconus patients. AB - PURPOSE: To evaluate posterior corneal elevation and back difference corneal elevation in patients with keratoconus in 1 eye and forme fruste keratoconus in the fellow eye. SETTING: Kudret Eye Hospital, Ankara, Turkey. DESIGN: Case control study. METHODS: This study retrospectively reviewed patients with keratoconus in 1 eye and forme fruste keratoconus in the fellow eye and eyes of normal subjects. All subjects were evaluated with a rotating Scheimpflug imaging system (Pentacam), including sagittal and tangential anterior curve analysis, keratometry, and posterior elevation. The back difference elevation values were extrapolated from the difference maps of the Belin-Ambrosio enhanced ectasia display of the Scheimpflug system. The receiver operating characteristic (ROC) curves were analyzed to evaluate the sensitivity and specificity of the parameters. RESULTS: The corneal power, pachymetric progression index, and posterior corneal elevation (posterior elevation and back difference elevation) measurements were statistically significantly higher in eyes with keratoconus or forme fruste keratoconus than in eyes of normal control subjects (P<.05). Using ROC analysis, the area under the curve values of mean keratometry, steepest point on the tangential curve, minimum corneal thickness, pachymetric progression index, Ambrosio's relational thickness, posterior elevation, and back difference elevation to distinguish forme fruste keratoconus from control subjects were 0.51, 0.84, 0.65, 0.81, 0.72, 0.68, and 0.76, respectively. CONCLUSIONS: Back difference elevation was better than posterior elevation in diagnosing forme fruste keratoconus. However, as sole parameters, both had limited sensitivity and specificity to differentiate between forme fruste keratoconus eyes and normal control eyes. PMID- 23820306 TI - Incidence of endophthalmitis and impact of prophylaxis with cefuroxime on cataract surgery. AB - PURPOSE: To evaluate the clinical and economic impact of prophylactic administration of intracameral cefuroxime on cataract surgery. SETTING: Hospital Universitario Fundacion Alcorcon, Madrid, Spain. DESIGN: Quasi-experimental study with before and after analysis. METHODS: The evolution of the cumulative incidence of endophthalmitis before and after (October 2005) administration of intracameral cefuroxime as endophthalmitis prophylaxis in cataract surgery was studied. The annual incidence adjusting to a Poisson distribution was compared. The effectiveness of the prophylaxis was evaluated with the relative risk (RR). The impact of cefuroxime was evaluated with the attributable risk fraction and the number of patients needed to treat to avoid a case of endophthalmitis. RESULTS: Cataract surgery was performed in 19 463 patients, 6595 patients before and 12 868 patients after October 2005. Endophthalmitis was diagnosed in 44 cases (39 before and 5 after). Positive microbiology cultures were obtained in 29 patients (66%). The overall cumulative incidence was 0.23 cases per 100 patients. Cefuroxime protected against endophthalmitis (RR = 0.06; P<.05; 95% confidence interval [CI], 0.03-0.17); the impact or number needed to treat was 182, and the attributable risk fraction was -0.93% (P<.05; 95% CI, -0.82 to -0.97). The cost of a dose of cefuroxime was ?1, and the cost of a case of endophthalmitis was ?1358. The potential saving with cefuroxime was ?1177 for every 182 patients treated. CONCLUSION: Intracameral cefuroxime reduced the incidence of endophthalmitis in cataract surgery and had a high clinical and economic impact on its prevention. PMID- 23820307 TI - Ectopic expression of ghrelin affects gastric H(+)-K(+)-ATPase activity and expression of GHR/IGF-1 system in weaned mice. AB - OBJECTIVES: Ghrelin has been implicated in the regulation of gastric growth and functional development, but it is yet to be determined whether and how ghrelin over-expression may modify gastric growth, gastric acid secretion and mRNA expression of other gastric endocrine hormones. 25-day-old mice were injected intramuscularly with vacant plasmid (VP) or recombinant plasmid expressing secretory ghrelin at the doses of 50MUg (LG) and 100MUg (HG). RESULTS: Expression of ghrelin mRNA was detected in muscles 15days post-injection, being most abundant in HG mice. In accordance with the ghrelin expression, gastric weight increased (P<0.05) in HG mice, compared with VP control group. Significant increase of gastric mucosa H(+)-K(+)-ATPase mRNA expression was detected in HG mice compared to VP control group (P<0.05). Compared with VP mice, gastric somatostatin (SS) mRNA expression decreased in LG and HG mice (P<0.05), while gastric gastrin expression had no significant difference. CONCLUSIONS: I.M. injection of plasmid encoding ghrelin improved gastric growth and gastric acid secretion with decreased SS mRNA in weaned mice. PMID- 23820308 TI - Desensitization of human CRF2(a) receptor signaling governed by agonist potency and betaarrestin2 recruitment. AB - The primary goal was to determine agonist-specific regulation of CRF2(a) receptor function. Exposure of human retinoblastoma Y79 cells to selective (UCN2, UCN3 or stresscopins) and non-selective (UCN1 or sauvagine) agonists prominently desensitized CRF2(a) receptors in a rapid, concentration-dependent manner. A considerably slower rate and smaller magnitude of desensitization developed in response to the weak agonist CRF. CRF1 receptor desensitization stimulated by CRF, cortagine or stressin1-A had no effect on CRF2(a) receptor cyclic AMP signaling. Conversely, desensitization of CRF2(a) receptors by UCN2 or UCN3 did not cross-desensitize Gs-coupled CRF1 receptor signaling. In transfected HEK293 cells, activation of CRF2(a) receptors by UCN2, UCN3 or CRF resulted in receptor phosphorylation and internalization proportional to agonist potency. Neither protein kinase A nor casein kinases mediated CRF2(a) receptor phosphorylation or desensitization. Exposure of HEK293 or U2OS cells to UCN2 or UCN3 (100nM) produced strong betaarrestin2 translocation and colocalization with membrane CRF2(a) receptors while CRF (1MUM) generated only weak betaarrestin2 recruitment. betaarrestin2 did not internalize with the receptor, however, indicating that transient CRF2(a) receptor-arrestin complexes dissociate at or near the cell membrane. Since deletion of the betaarrestin2 gene upregulated Gs-coupled CRF2(a) receptor signaling in MEF cells, a betaarrestin2 mechanism restrains Gs-coupled CRF2(a) receptor signaling activated by urocortins. We further conclude that the rate and extent of homologous CRF2(a) receptor desensitization are governed by agonist-specific mechanisms affecting GRK phosphorylation, betaarrestin2 recruitment, and internalization thereby producing unique signal transduction profiles that differentially affect the stress response. PMID- 23820309 TI - Dissecting non-coding RNA mechanisms in cellulo by Single-molecule High Resolution Localization and Counting. AB - Non-coding RNAs (ncRNAs) recently were discovered to outnumber their protein coding counterparts, yet their diverse functions are still poorly understood. Here we report on a method for the intracellular Single-molecule High-Resolution Localization and Counting (iSHiRLoC) of microRNAs (miRNAs), a conserved, ubiquitous class of regulatory ncRNAs that controls the expression of over 60% of all mammalian protein coding genes post-transcriptionally, by a mechanism shrouded by seemingly contradictory observations. We present protocols to execute single particle tracking (SPT) and single-molecule counting of functional microinjected, fluorophore-labeled miRNAs and thereby extract diffusion coefficients and molecular stoichiometries of micro-ribonucleoprotein (miRNP) complexes from living and fixed cells, respectively. This probing of miRNAs at the single molecule level sheds new light on the intracellular assembly/disassembly of miRNPs, thus beginning to unravel the dynamic nature of this important gene regulatory pathway and facilitating the development of a parsimonious model for their obscured mechanism of action. PMID- 23820311 TI - Neurofeedback training aimed to improve focused attention and alertness in children with ADHD: a study of relative power of EEG rhythms using custom-made software application. AB - Neurofeedback is a nonpharmacological treatment for attention-deficit hyperactivity disorder (ADHD). We propose that operant conditioning of electroencephalogram (EEG) in neurofeedback training aimed to mitigate inattention and low arousal in ADHD, will be accompanied by changes in EEG bands' relative power. Patients were 18 children diagnosed with ADHD. The neurofeedback protocol ("Focus/Alertness" by Peak Achievement Trainer) has a focused attention and alertness training mode. The neurofeedback protocol provides one for Focus and one for Alertness. This does not allow for collecting information regarding changes in specific EEG bands (delta, theta, alpha, low and high beta, and gamma) power within the 2 to 45 Hz range. Quantitative EEG analysis was completed on each of twelve 25-minute-long sessions using a custom-made MatLab application to determine the relative power of each of the aforementioned EEG bands throughout each session, and from the first session to the last session. Additional statistical analysis determined significant changes in relative power within sessions (from minute 1 to minute 25) and between sessions (from session 1 to session 12). Analysis was of relative power of theta, alpha, low and high beta, theta/alpha, theta/beta, and theta/low beta and theta/high beta ratios. Additional secondary measures of patients' post-neurofeedback outcomes were assessed, using an audiovisual selective attention test (IVA + Plus) and behavioral evaluation scores from the Aberrant Behavior Checklist. Analysis of data computed in the MatLab application, determined that theta/low beta and theta/alpha ratios decreased significantly from session 1 to session 12, and from minute 1 to minute 25 within sessions. The findings regarding EEG changes resulting from brain wave self-regulation training, along with behavioral evaluations, will help elucidate neural mechanisms of neurofeedback aimed to improve focused attention and alertness in ADHD. PMID- 23820310 TI - The Rumsfeld paradox: some of the things we know that we don't know about plant virus infection. AB - Plant-infecting viruses cause significant crop losses around the world and the majority of emerging threats to crop production have a viral etiology. Significant progress has been made and continues to be made in understanding how viruses induce disease and overcome some forms of resistance-particularly resistance based on RNA silencing. However, it is still not clear how other antiviral mechanisms work, how viruses manage to exploit their hosts so successfully, or how viruses affect the interactions of susceptible plants with other organisms and if this is advantageous to the virus, the host, or both. In this article we explore these questions. PMID- 23820312 TI - Non-convulsive status epilepticus associated with glutamic acid decarboxylase antibody. AB - Autoimmune encephalitis associated with glutamic acid decarboxylase antibodies (GAD-Ab) often presents with treatment-resistant partial seizures, as well as other central nervous system symptoms. In contrast to several other well characterized autoantibodies, GAD-Ab has very rarely been associated with status epilepticus. We report a 63-year-old woman initially admitted with somnolence and psychiatric findings. The EEG findings, of generalized and rhythmical slow spike wave activity over the posterior regions of both hemispheres, together with the clinical deterioration in responsiveness, led to the diagnosis of non-convulsive status epilepticus. Investigation of a broad panel of autoantibodies, revealed only increased serum GAD-Ab levels. Following methylprednisolone and intravenous immunoglobulin treatments, the patient's neurological symptoms improved, EEG findings disappeared and GAD-Ab levels significantly decreased. GAD-Ab should be added to the list of anti-neuronal antibodies associated with non-convulsive status epilepticus. Disappearance of clinical findings and seroreversion after immunotherapy suggest that GAD-Ab might be involved in seizure pathogenesis. PMID- 23820313 TI - Disappearance of breach rhythm heralding recurrent tumor progression in a patient with astrocytoma. AB - The breach rhythm is sometimes considered the consequence of reduced resistance between the cortex and the scalp electrode in the region of a skull defect. On the other hand, the electroencephalographic (EEG) changes after craniotomy were attributed to an activation of EEG activity by meningocortical adhesions with admixed gliosis. We report changes of the breach rhythm in a patient with astrocytoma, which give further evidence that the breach rhythm is not merely the result of physical changes in the area of a skull defect. In our patient, the breach rhythm was no longer detectable before a new tumor progression took place, showed up again, and at the end changed into localized slowing before the deterioration of the patient's general medical condition. This case suggests that in patients with brain tumors, the loss or attenuation in frequency of an established breach rhythm might be considered as an indication of a new tumor progression. PMID- 23820314 TI - Phenanthrenes, 9,10-dihydrophenanthrenes, bibenzyls with their derivatives, and malate or tartrate benzyl ester glucosides from tubers of Cremastra appendiculata. AB - Eleven previously unknown compounds and 23 known compounds, including 20 phenanthrene or 9,10-dihydrophenanthrene derivatives, five bibenzyls, seven malate or tartrate benzyl ester glucosides, adenosine and gastrodin were isolated from tubers of Cremastra appendiculata. Among the obtained compounds, two are the first isolated dimers with one phenanthrene or bibenzyl unit connected to C-3 of 2,3,4,5-tetrahydro-phenanthro[2,1-b]furan moiety. In addition, 33 of these compounds were evaluated in vitro for their cytotoxic activity against two cancer cell lines. Among the compounds examined, one compound showed moderate cytotoxic activity, while five showed weak cytotoxic activity against the A549 cell line. PMID- 23820316 TI - A new women's health series. PMID- 23820317 TI - Individual risk factors and complexity associated with congenital heart disease in a pediatric medicaid cohort. AB - OBJECTIVES: To determine the sex and race differences associated with specific congenital heart diseases (CHDs) and the patterns of concomitant conditions associated with eight severe, complex lesions. METHODS: A 15-year Medicaid dataset (1996-2010) from one state was analyzed for 14,496 patients aged 17 years and younger and diagnosed as having a CHD on one or more service visits to a pediatrician or pediatric cardiologist. RESULTS: Controlling for all other diagnosed CHDs, boys were more likely to be diagnosed as having transposition of the great arteries, hypoplastic left heart syndrome, aortic stenosis, and coarctation of the aorta, whereas African Americans were more likely to be diagnosed as having tricuspid regurgitation, atrial septal defect sinus venosus, coronary artery anomaly, and pulmonary stenosis. Ventricular septal defects, atrial septal defects secundum, patent ductus arteriosus, and pulmonary stenosis were the most prevalent isolated CHDs, whereas tetralogy of Fallot, atrioventricular canal/endocardial cushion defect, common/single ventricle, double outlet right ventricle, and transposition of the great arteries were the most prevalent severe, complex lesions. The complexity of some severe cardiac anomalies appears to be increasing over time. CONCLUSIONS: Changes over time in pediatric CHD caseload mix may affect care management and result in prognosis or outcome differences. These changes present important opportunities for pediatricians and pediatric cardiologists to collaborate, especially in the care of the most severe anomalies. PMID- 23820318 TI - Fibrinolytic therapy versus primary percutaneous coronary interventions for ST segment elevation myocardial infarction in Kentucky: time to establish systems of care? AB - BACKGROUND: Fibrinolytic therapy is recommended for ST-segment myocardial infarctions (STEMI) when primary percutaneous coronary intervention (PPCI) is not available or cannot be performed in a timely manner. Despite this recommendation, patients often are transferred to PPCI centers with prolonged transfer times, leading to delayed reperfusion. Regional approaches have been developed with success and we sought to increase guideline compliance in Kentucky. METHODS: A total of 191 consecutive STEMI patients presented to the University of Kentucky (UK) Chandler Medical Center between July 1, 2009 and June 30, 2011. The primary outcome was in-hospital mortality and the secondary outcomes were major adverse cardiovascular events, extent of myocardial injury, bleeding, and 4) length of stay. Patients were analyzed by presenting facility-the UK hospital versus an outside hospital (OSH)-and treatment strategy (PPCI vs fibrinolytic therapy). Further analyses assessed primary and secondary outcomes by treatment strategy within transfer distance and compliance with American Heart Association guidelines. RESULTS: Patients presenting directly to the UK hospital had significantly shorter door-to-balloon times than those presenting to an OSH (83 vs 170 minutes; P < 0.001). This did not affect short-term mortality or secondary outcomes. By comparison, OSH patients treated with fibrinolytic therapy had a numeric reduction in mortality (4.0% vs 12.3%; P = 0.45). Overall, only 20% of OSH patients received timely reperfusion, 13% PPCI, and 42% fibrinolytics. In a multivariable model, delayed reperfusion significantly predicted major adverse cardiovascular events (odds ratio 3.87, 95% confidence interval 1.15-13.0; P = 0.02), whereas the presenting institution did not. CONCLUSIONS: In contemporary treatment of STEMI in Kentucky, ongoing delays to reperfusion therapy remain regardless of treatment strategy. For further improvement in care, acceptance of transfer delays is necessary and institutions should adopt standardized protocols in association with a regional system of care. PMID- 23820319 TI - Providing guidance to patients: physicians' views about the relative responsibilities of doctors and religious communities. AB - OBJECTIVES: Patients' religious communities often influence their medical decisions. To date, no study has examined what physicians think about the responsibilities borne by religious communities to provide guidance to patients in different clinical contexts. METHODS: We mailed a confidential, self administered survey to a stratified random sample of 1504 US primary care physicians (PCPs). Criterion variables were PCPs' assessment of the responsibility that physicians and religious communities bear in providing guidance to patients in four different clinical scenarios. Predictors were physicians' demographic and religious characteristics. RESULTS: The overall response rate was 63%. PCPs indicated that once all medical options have been presented, physicians and religious communities both are responsible for providing guidance to patients about which option to choose (mean responsibility between "some" and "a lot" in all scenarios). Religious communities were believed to have the most responsibility in scenarios in which the patient will die within a few weeks or in which the patient faces a morally complex medical decision. PCPs who were older, Hispanic, or more religious tended to rate religious community responsibility more highly. Compared with physicians of other affiliations, evangelical Protestants tended to rate religious community responsibility highest relative to the responsibility of physicians. CONCLUSIONS: PCPs ascribe more responsibility to religious communities when medicine has less to offer (death is imminent) or the patient faces a decision that science cannot settle (a morally complex decision). Physicians' ideas about the clinical role of religious communities are associated with the religious characteristics of physicians themselves. PMID- 23820320 TI - Commentary on "providing guidance to patients: physicians' views about the relative responsibilities of doctors and religious communities". PMID- 23820321 TI - Outlet constipation 1 year after robotic sacrocolpopexy with and without concomitant posterior repair. AB - OBJECTIVES: The aim of this study was to estimate the rate of outlet constipation at 1 year after robotic sacrocolpopexy (RSCP) with and without a concomitant distal posterior repair (PR). We sought, first, to determine the rate of persistent outlet constipation and second, to determine de novo outlet constipation. METHODS: This was a cohort study of women who underwent RSCP alone versus RSCP + PR, at each surgeon's discretion, between November 2007 and February 2011 at an academic center. Specific questions in the Pelvic Floor Distress Inventory Short Form correlating to outlet constipation and its colorectal-anal subscale scores were compared between and within groups. Rates of posterior compartment reoperation were assessed. RESULTS: Of the 77 women who underwent RSCP, 21 (27%) had a concomitant distal PR. Overall, there was significant improvement in pelvic floor function and quality of life at 1 year after surgery (P = 0.01). Preoperatively, outlet constipation was present in 63.4% of those who underwent RSCP only and in 53.3% of those with concomitant PR. Postoperatively at 1 year, 56% of preoperative outlet constipation resolved and 44% persisted (P = 0.001), with no differences between groups (RSCP vs RSCP + PR). The rate of postoperative de novo outlet constipation was 13.6%. At 1 year after RSCP, 18.2% of patients had symptomatic posterior prolapse, with no difference between both groups (P = 0.746). Overall, 11.7% underwent a subsequent PR, none of whom underwent PR with the initial RSCP (P = 0.104). CONCLUSIONS: At 1 year after RSCP, there was a high rate of persistent outlet constipation and a moderate rate of de novo outlet constipation. Concomitant PR did not significantly affect these bowel symptoms. PMID- 23820322 TI - Academic productivity and its relationship to physician salaries in the University of California Healthcare System. AB - OBJECTIVES: To evaluate whether physicians with higher academic productivity, as measured by the number of publications in Scopus and the Scopus Hirsch index (h index), earn higher salaries. METHODS: This was a cross-sectional study. Participants were ophthalmologists, otolaryngologists, neurosurgeons, and neurologists classified as "top earners" (>$100,000 annually) within the University of California (UC) healthcare system in 2008. Bibliometric searches on Scopus were conducted to retrieve the total number of publications and Hirsch indices (h-index), a measure of academic productivity. The association between the number of publications and h-index on physicians' total compensation was determined with multivariate regression models after controlling for the four specialties (ophthalmology, otolaryngology, neurosurgery, and neurology), the five institutions (UC San Francisco, UC Los Angeles, UC San Diego, UC Irvine, and UC Davis), and academic rank (assistant professor, associate professor, and professor). RESULTS: The UC healthcare system departments reported 433 faculty physicians among the four specialties, with 71.6% (n = 310) earning more than $100,000 in 2008 and classifying as top earners. After controlling for the specialty, institution, and ranking, there was a significant association between the number of publications on salary (P < 0.000001). Scopus number of publications and h-index were correlated (P < 0.001). Scopus h-index was of borderline significance in predicting physician salary (P = 0.12). Physicians with higher Scopus publications had higher total salaries across all four specialties. Every 10 publications were associated with a 2.40% increase in total salary after controlling for specialty, institution, rank, and chair. CONCLUSIONS: Ophthalmologists, otolaryngologists, neurosurgeons, and neurologists in the UC healthcare system who are more academically productive receive greater remuneration. PMID- 23820323 TI - Women with chronic hepatitis C virus infection: recommendations for clinical practice. AB - The natural history of hepatitis C virus infection differs between women and men. Women demonstrate a slow rate of disease progression until menopause. Older women are more likely to develop fibrosis and are less responsive than younger women to pegylated interferon and ribavirin. Women of childbearing age have higher rates of sustained virologic response, but current therapies are contraindicated during pregnancy. Vertical transmission of hepatitis C virus occurs, but data supporting recommendations for prevention of mother-to-infant transmission are limited. PMID- 23820324 TI - Ischemic heart disease in women. AB - Cardiovascular disease is the leading cause of death in women. Although overall mortality from coronary heart disease (CHD) has decreased, there are subsets of patients, particularly young women, in whom the mortality rate has increased. Underlying sex differences in CHD may be an explanation. Women have more frequent symptoms, more ischemia, and higher mortality than men, but less obstructive coronary artery disease (CAD). Despite this, traditional risk factor assessment has been ineffective in risk stratifying women, prompting the emergence of novel markers and prediction scores to identify a population at risk. Sex differences in manifestations and the pathophysiology of CHD also have led to differences in the selection of diagnostic testing and treatment options for women, having profound effects on outcomes. The frequent finding of nonobstructive CAD in women with ischemia suggests microvascular dysfunction as an underlying cause; therefore, coronary reactivity and endothelial function testing may add to diagnostic accuracy in female patients. In spite of evidence that women benefit from the same therapies as men, they continue to receive less-aggressive therapy, which is reflected in higher healthcare resource utilization and adverse outcomes. More sex-specific research is needed in the area of symptomatic nonobstructive CAD to define the optimal therapeutic approach. PMID- 23820325 TI - Considerations in women with hypertension. AB - Cardiovascular disease is the most common cause of death in women in the United States, and hypertension is a major contributor to cardiovascular mortality. The incidence of hypertension in women is steadily increasing, paralleling the epidemics of obesity and diabetes. Blood pressure control rates among women are suboptimal, even when secondary causes are identified and treated. There are few high-quality data describing specific hypertension-related outcomes in women. Some data comparing hypertensive women to age-matched men suggest advantages to sex-specific strategies, but further study is needed to determine optimal regimens for women throughout their lives. Pregnancy and menopause present unique, complex challenges in hypertension management. PMID- 23820326 TI - Laboratory diagnosis of antiphospholipid syndrome. AB - Antiphospholipid syndrome is an intriguing clinical entity encountered by all physicians because of the wide range of clinical manifestations involving every organ system. Ordering a single test under the name "antiphospholipid antibody" does not rule out this entity. There are overlapping but distinct autoantibodies, and a positive result in one assay is conclusive despite a negative result in another. Laboratories continue to conduct several nonstandard tests as part of integrated kits and physicians should be familiar with them for proper interpretation of the results. Lupus anticoagulant testing is an integral part of every thrombophilia workup and should be performed regardless of the screening activated partial thromboplastin time or mixing study. PMID- 23820327 TI - Principles of assessment of abuse liability: US legal framework and regulatory environment. AB - Identifying the abuse potential of drug products in the premarketing and postmarketing environment has been a critical component in the implementation of drug abuse control laws worldwide. In the US, the Controlled Substances Act of 1970 (CSA) is a comprehensive federal law enacted to prevent the abuse or diversion of substances with abuse liability or addiction potential (for present purposes, these terms are used interchangeably). Under the jurisdiction of the Drug Enforcement Administration, the law applies to the manufacture and distribution of narcotics and other drug substances with potential of abuse. The CSA classifies substances with abuse potential into schedules I-V based on the substance's risk of diversion or abuse, and thus provides a legal framework for the assessment of abuse liability of New Molecular Entities. When the Food and Drug Administration reviews the safety and efficacy of a New Drug Application it also determines whether the drug has potential for abuse, and if so, will begin the process to schedule the drug under the CSA. As the assessment of abuse potential is a critical component of a marketing application, pharmaceutical companies (sponsors) bear the responsibility of generating a comprehensive preclinical and clinical data package for regulators to review and make decisions on labeling and the corresponding postmarketing surveillance. Recent regulatory guidelines adopted in the European Union (EU) (2006), Canada (2007), and USA (2010) provide recommendations to sponsors on preclinical and clinical methodologies for the assessment of abuse potential. This paper reviews the legal framework of the assessment of abuse liability and scheduling of controlled substances in the USA and describes the current global regulatory environment and the challenges that sponsors and regulators face when assessing abuse liability of New Molecular Entities, from the early stages of development through the late stages, review, and approval. PMID- 23820328 TI - Epilepsy surgery outcome in temporal lobe cavernoma and multiple sclerosis. PMID- 23820329 TI - Giant vertebral artery aneurysm presenting with 'hemiplegia cruciata'. PMID- 23820330 TI - Primary diffuse leptomeningeal atypical teratoid/rhabdoid tumour in an adolescent. PMID- 23820331 TI - Carotid artery stenting in patients with near occlusion: a single-center experience and comparison with recent studies. AB - OBJECTIVE: The optimal management strategy for carotid artery near occlusion is still controversial. Nevertheless, prior studies about carotid artery stenting in patients with near occlusion reported both technically and clinically inspiring results. To define the effectiveness, safety, and clinical outcomes of carotid artery stenting in patients with near occlusion, we analyzed our experiences and compared with recent studies. METHODS: We performed 24 carotid artery stenting procedures in 24 patients with near occlusion between January 2010 and July 2012. The patient group comprised 20 men (83.3%) and four women (16.7%) with a mean age of 69.5 years (range, 53-85 years). Eighteen patients had prior stroke or transient ischemic attack (75%), and six patients were asymptomatic (25%). RESULTS: Successful stent insertion was achieved in 23 of 24 patients (95.8%). Cerebral hyperperfusion syndrome and post-procedural vascular events occurred in four patients, and all of these developed within 24h after the procedure (17.4%; two: hyperperfusion syndrome, two: acute myocardial infarction). The mean follow up period after carotid artery stenting was 16.7+/-9.2 months (range, 6-32 months). No stroke related to carotid artery stenting or significant restenosis of the inserted stent developed during the follow-up period. CONCLUSIONS: Carotid artery stenting in patients with near occlusion seems to be a technically feasible and effective method to prevent stroke recurrence. But hyperperfusion syndrome and post-procedural vascular event rates may be high, as shown in this study. PMID- 23820332 TI - A DNA tweezer-actuated enzyme nanoreactor. AB - The functions of regulatory enzymes are essential to modulating cellular pathways. Here we report a tweezer-like DNA nanodevice to actuate the activity of an enzyme/cofactor pair. A dehydrogenase and NAD(+) cofactor are attached to different arms of the DNA tweezer structure and actuation of enzymatic function is achieved by switching the tweezers between open and closed states. The enzyme/cofactor pair is spatially separated in the open state with inhibited enzyme function, whereas in the closed state, enzyme is activated by the close proximity of the two molecules. The conformational state of the DNA tweezer is controlled by the addition of specific oligonucleotides that serve as the thermodynamic driver (fuel) to trigger the change. Using this approach, several cycles of externally controlled enzyme inhibition and activation are successfully demonstrated. This principle of responsive enzyme nanodevices may be used to regulate other types of enzymes and to introduce feedback or feed-forward control loops. PMID- 23820333 TI - An early improvement in depressive symptoms predicts symptomatic remission of schizophrenia treated with quetiapine: a multicenter, 4-week case-control study. AB - The aim of this study was to determine whether an early improvement in depressive symptoms is a predictor of symptomatic remission in schizophrenia. Patients with DSM-IV schizophrenia diagnosis who received antipsychotic treatment but did not fulfill Andreasen's symptomatic remission criteria were recruited. Each patient received quetiapine with a flexible dose strategy of 300-800 mg daily for 4 weeks after a 1-week washout period of previous antipsychotics. Remission was defined by Andreasen's criteria, which includes eight items of the Positive and Negative Symptom Scale with scores of less than three in each item. Seventy-five patients completed the study. Of these, 27 (36%) achieved symptomatic remission after treatment with quetiapine. A significant improvement in depressive symptoms was found in both the remission and the nonremission groups, although the improvement was less pronounced in the nonremission group at the endpoint. Binary logistic regression analysis showed that age (beta=-0.07, P=0.02) and early improvement in depressive symptoms within the first 3 days were predictive of symptomatic remission (beta=-0.27, P=0.01) for the treatment of schizophrenia. Our data suggest that an early improvement in depressive symptoms in the treatment of schizophrenia is crucial for symptomatic remission. PMID- 23820334 TI - Ten year outcomes of outpatients with schizophrenia on conventional depot antipsychotics: a systematic chart review. AB - Long-term follow-up data of patients with schizophrenia on depot antipsychotics have been few and the longest follow-up period has been up to 7 years. We carried out a systematic chart review to examine 10-year outcomes for outpatients with schizophrenia who were receiving a conventional depot antipsychotic. Maintenance of outpatient status for 10 years was considered as a favorable outcome. From the initial sample of 1587 outpatients, 90 patients who were receiving a depot antipsychotic were included in this study (mean+/-SD, age 44.0+/-13.0 years; men, N=54). Haloperidol decanoate, fluphenazine decanoate, fluphenazine enanthate, and haloperidol decanoate plus fluphenazine enanthate were used in 53 (58.9%), 29 (32.2%), seven (7.8%), and one (1.1%) patients, respectively. These depot antipsychotics accounted for 36.9% of the total antipsychotic dosage on average. Seventeen patients (18.9%) successfully maintained outpatient status for 10 years. The most frequent reason for dropout was 'hospitalization' (N=49, 54.4%), followed by 'referral to another clinic/hospital' (N=9, 10.0%) and 'side effects' (N=7, 7.8%). As only 36.9% of the chlorpromazine equivalents were administered through depot antipsychotics, it is difficult to draw any firm conclusion. Still, the data suggest that even depot antipsychotics may not sufficiently prevent relapse in the treatment of schizophrenia. PMID- 23820335 TI - Psychopharmacological treatment and course in paranoid personality disorder: a case series. AB - Little is known about the role of psychopharmacological treatment and course of illness in patients diagnosed with a paranoid personality disorder. This short communication provides a naturalistic study of a psychiatric hospital case series. Fifteen consecutive patients were retrospectively studied. The Clinical Global Impression was rated at first admission, at last psychiatric contact, and after a 6-week observation period with or without antipsychotic treatment. During psychiatric admissions, three patients improved markedly, eight showed only minor changes, and four worsened. In total, seven patients had been administered any antipsychotic medication. The median duration of treatment was 15 weeks (range 4 days-328 weeks). No major adverse effects were noted. Among patients with sixth week observations available, four had received antipsychotics; they appeared to improve considerably compared with six patients who had not received antipsychotics. Although the findings should be interpreted with caution, they support the notion of the disorder being a relatively chronic condition, although antipsychotics appeared to be safe and possibly had an effect in the short term. PMID- 23820336 TI - Completion of biosynthetic pathways for bacteriochlorophyll g in Heliobacterium modesticaldum: The C8-ethylidene group formation. AB - Heliobacteria have the simplest photosynthetic apparatus, i.e., a type-I reaction center lacking a peripheral light-harvesting complex. Bacteriochlorophyll (BChl) g molecules are bound to the reaction center complex and work both as special pair and antenna pigments. The C8-ethylidene group formation for BChl g is the last missing link in biosynthetic pathways for bacterial special-pair pigments, which include BChls a and b as well. Here, we report that chlorophyllide a oxidoreductase (COR) of Heliobacterium modesticaldum catalyzes the C8-ethylidene formation from 8-vinyl-chlorophyllide a, producing bacteriochlorophyllide g, the direct precursor for BChl g without the farnesyl tail. The finding led to plausible biosynthetic pathways for 8(1)-hydroxy-chlorophyll a, a primary electron acceptor from the special pair in heliobacterial reaction centers. Proposed catalytic mechanisms on hydrogenation reaction of the ethylidene synthase-type CORs are also discussed. PMID- 23820337 TI - Status of iodine deficiency in district Kangra, Himachal Pradesh after 60 years of salt iodization. AB - BACKGROUND/OBJECTIVES: District Kangra, Himachal Pradesh(HP), India is a known endemic area for iodine deficiency disorders (IDD) since 1956. The present study was conducted in district Kangra, Himachal Pradesh with the objective to assess the prevalence of iodine deficiency in school-age children. SUBJECTS/METHODS: A total of 1864 children in the age group of 6-12 years were included. Clinical examination of thyroid of all children was undertaken. 'On the spot' urine samples were collected from 463 children. The salt samples were collected from 327 children. RESULTS: The total goiter prevalence of 15.8% was found. The proportion of children with urinary iodine excretion (UIE) levels <50.0, 50.0 99.9 and >= 100 MUg/l was 2.2, 14.3 and 83.5%, respectively. The median UIE level was 200 MUg/l. About 82.3% of the families were consuming salt with iodine content >= 15 ppm. CONCLUSION: The population in district Kangra is possibly in a transition phase from iodine deficient (as revealed by total goiter rate of 15.8%) to iodine sufficiency (as revealed by median UIE levels of 200 MUg/l). PMID- 23820338 TI - Influence of additional criteria from a definition of cachexia on its prevalence- good or bad thing? AB - BACKGROUND/OBJECTIVES: Cachexia is a state of involuntary weight loss. The latest generic definition states that aside from weight loss, patient needs to fulfill additional criteria to be diagnosed with cachexia. New, condition-specific definitions also take the weight loss as a principal criterion, and additional criteria are not mandatory but are a part of further assessment. The aim of this study was to reveal the influence of additional criteria on the prevalence of cachexia in patients with various diseases linked to cachexia. Owing to this, we used the last generic definition. Possible differences in clinical presentations of patients with documented weight loss, with the respect of fulfillment of additional criteria were sought. SUBJECTS/METHODS: Clinical and anthropometric data on 137 consecutive patients with malignant diseases and chronic heart failure from a single institution were collected. RESULTS: Fourty-two (30.6%) patients had >5% weight loss in the last 12 months. Only 30 (21.8%) of them were found to meet additional three out of five criteria proposed by the new definition. This observed difference in the prevalence of cachexia diagnosed with or without using additional criteria was found to be significant (P=0.0006). Comparison of clinical/laboratory data showed significantly higher levels of C reactive protein and lower levels of albumin, as well as lower measurements of mid-arm circumference, triceps and suprailiac skinfolds in patients that fulfilled additional criteria. Survival analysis did not show reduced survival of patients fulfilling additional criteria. CONCLUSIONS: Additional criteria 'reduce' the prevalence of cachexia. They are indicative of differences in laboratory and clinical features of cachectic patients but do not influence their survival. PMID- 23820339 TI - The effect of a meal on measures of impedance and percent body fat estimated using contact-electrode bioelectrical impedance technology. AB - BACKGROUND/OBJECTIVES: To determine the effect of a meal on impedance and percent body fat (%BF) determined using contact-electrode bioelectrical impedance analysis (BIA) technology. SUBJECTS/METHODS: Forty-three adults (23 women and 20 men) volunteered to participate in this study (age=20.5+/-1.1 years; body mass index=24.1+/-3.8 kg/m(2)). Body composition was assessed using three BIA analyzers: leg-to-leg (LBIA), segmental (SBIA) and multi-frequency (MFBIA), on two separate occasions. After a baseline measurement, subjects consumed a meal or received nothing, which served as the control (CON). Subjects were reassessed 20, 40 and 60 min following (POST) the baseline measure in each condition. RESULTS: Twenty minutes after eating (3847+/-900 kJ), body mass (LBIA=0.8 kg, SBIA=0.8 kg, MFBIA=0.7 kg, P<0.05), impedance (LBIA=6.0 Omega, SBIA=17.9 Omega, MFBIA=27.1 Omega, P<0.05) and %BF (LBIA=0.9%, SBIA=1.7%, MFBIA=0.8%, P<0.05) increased significantly and remained elevated at 60 min POST. During the CON trial, a consistent body mass reduction (60-80 g) and impedance increase (4-9 Omega) was observed over time resulting in a small increase in %BF (0.3-0.7%) 60 min POST (P<0.05). CONCLUSIONS: Twenty minutes after eating, %BF increased due to elevations in impedance and body mass. As such, when precision is critical, we recommend adhering to the pretest fasting guidelines to avoid meal-induced alterations in %BF estimates. In addition, use of a consistent testing schedule may minimize normal %BF variation over time. PMID- 23820340 TI - Dietary intakes of HIV-infected adults in urban UK. AB - Maintaining a good nutritional status is important for immune health and for managing metabolic comorbidities in adults with HIV infection. Little is known about the dietary habits of adults living with HIV infection in the United Kingdom. The aims of this study were to characterise their dietary intakes, and to identify subgroups of patients who may require nutritional counselling and/or food support services. An observational study of adults attending a London HIV out-patient clinic who completed a demographics questionnaire and a structured 24 h diet recall interview was conducted. In all, 196 (162 men, 34 women) adults participated. Forty-three percent (n=66) of men and thirty-six percent (n=11) of women did not consume enough energy to meet their basal metabolic requirements and activity factor. The majority of both men (64%) and women (56%) consumed more than the recommended amount of saturated fat. Self-report of lipodystrophy (B coefficient -2.27 (95% CI -3.92 to -0.61), P=0.008) was associated with lower dietary fibre intake/1000 kcal per day, and a more recent diagnosis of HIV (B coefficient -0.11 (95% CI -0.20 to -0.02), P=0.013) was associated with a higher dietary fibre/1000 kcal intake per day. Recreational drug use was associated with a higher overall calorie (P=0.003) and protein (P=0.001) intake than non-usage after adjusting for basal metabolic requirements and weight, respectively. Our data describe the dietary intakes of a diverse group of adults with HIV infection in the United Kingdom. These dietary habits may have an impact on their overall health and development of other metabolic comorbidities common in people with HIV. PMID- 23820341 TI - War Related Illness and Injury Study Center (WRIISC): a multidisciplinary translational approach to the care of Veterans with chronic multisymptom illness. PMID- 23820342 TI - Military occupation and deployment: descriptive epidemiology of active duty U.S. Army men evaluated for a disability discharge. AB - OBJECTIVE: Physically demanding jobs and history of deployment put Soldiers at increased risk for injury, hospitalizations, and disability. Characterizing differences in disability outcomes by occupation and deployment history may identify specific military populations for targeted prevention and intervention programs as well as potential areas of future research. METHODS: A cross sectional analysis was conducted on U.S. Army enlisted men evaluated in the Department of Defense's Disability Evaluation System (DES) between fiscal years 2005 and 2011, comparing those assigned a Combat Arms military occupational specialty (MOS) to individuals with any other MOS (Other). RESULTS: Among deployed Soldiers, those with Combat Arms MOS were substantially and significantly more likely to receive medical disability retirement than Other MOS and were more likely to be evaluated for conditions compatible with combat exposures, including post-traumatic stress disorder, residuals of traumatic brain injury, and paralysis. Among nondeployed Soldiers, Combat Arms MOS were only slightly more likely to receive medical disability than Other MOS, and no substantial differences in medical conditions were noted between the two MOS groups. CONCLUSIONS: Combat Arms MOS is a significant risk factor for disability retirement primarily among deployed men. Further research is needed to identify specific military occupations most at risk for disability retirement. PMID- 23820343 TI - The effectiveness of Soldier Medical Readiness Councils in reducing and shaping the population of soldiers not medically deployable. AB - The population of Soldiers not medically fit for deployment has created readiness problems for the U.S. Army in recent years. To address this issue, the 3rd Infantry Division created councils of experts to address the size of its medically nondeployable population. Our results demonstrate success in effectively reducing the subpopulation of Soldiers who have been medically nondeployable for long periods of time by enforcing their return to duty or medical retirement. This study also demonstrates that council-based management affects the composition of the medically-not-ready population. Traditional approaches allow a minority subpopulation of Soldiers with poor prognoses to dwell within the nondeployable population for long periods of time (6-18+ months), whereas the healthier majority recovers within the first 6 months. This creates a dynamic in which remaining in the population for longer time periods increases the probability of being medically retired. Our study demonstrates that councils consistently and actively shape the character of the group such that those remaining in the medically-not-ready population for longer periods of time do not have an increased risk of medical retirement. Soldier Medical Readiness Councils have already been adopted by the Army. This article provides evidence to support their efficacy. PMID- 23820344 TI - Perceived demands during modern military operations. AB - Using a cross-sectional design, this study explored operational demands during the International Security Assistance Force for Afghanistan (2009-2010) across distinct military units. A total of 1,413 Dutch soldiers, nested within four types of units (i.e., combat, combat support, service support, and command support units) filled out a 23-item self-survey in which they were asked to evaluate the extent to which they experienced operational characteristics as demanding. Exploratory factor analysis identified six underlying dimensions of demands. Multivariate analysis of variance revealed that distinct units are characterized by their own unique constellation of perceived demands, even after controlling for previous deployment experience. Most notable findings were found when comparing combat units to other types of units. These insights can be used to better prepare different types of military units for deployment, and support them in the specific demands they face during deployment. PMID- 23820345 TI - Deployment of military mothers: supportive and nonsupportive military programs, processes, and policies. AB - Military mothers and their children cope with unique issues when mothers are deployed. In this article, we present mothers' perspectives on how military resources affected them, their children, and their caregivers during deployment. Mothers described beneficial features of military programs such as family readiness groups and behavioral health care, processes such as unit support, and policies on length and timing of deployments. Aspects that were not supportive included inflexibility in family care plans, using personal leave time and funds for transporting children, denial of release to resolve caretaker issues, and limited time for reintegration. We offer recommendations for enhanced support to these families that the military could provide. PMID- 23820346 TI - Injury and illness incidence in a Sergeants Major Academy class. AB - PURPOSE: This study examined the incidence and risk factors for training injuries and illnesses for 149 male and 6 female U.S. Army Sergeants Major Academy students. METHODS: This was a retrospective report based on injuries and illnesses that occurred during 9.5 months of physical fitness training including running, marching, and calisthenics. During this time, 49.7% (74/149) students were injured at least once. The crude incidence rate was 5.2 injuries (68.9%), and accounted for 1749 limited duty days (LDD). The most common overuse injuries were pain, muscle strain, and tendinitis/bursitis involving primarily the lower extremities and lower back. For illnesses, 63.1% (94/149) of the students had one or more illness visits to a medical facility. The crude incidence rate was 6.6 illnesses per 100 soldiers per month. Infectious illnesses were the most frequent illness reported (48.3%), and 94 students had a total of 311 days of illness associated LDD. CONCLUSIONS: Medical record reviews revealed that musculoskeletal injuries were the major cause of LDD during physical fitness training. Overuse lower extremity and lower back injuries were the most commonly reported injuries. Respiratory bacterial and viral infectious illnesses were the most commonly reported illnesses. Alcohol consumption was a risk factor for developing infectious illnesses. Cigarette smoking was associated with slower 2-mile run times when compared with history of nonsmoking. PMID- 23820347 TI - Hybrid simulation during military medical student field training--a novel curriculum. AB - OBJECTIVES: Implement a new hybrid simulation curriculum into the Uniformed Services University of the Health Sciences Bushmaster Field Training Exercise for fourth-year medical students. The principal goal was to determine if high fidelity hybrid simulation could be successfully implemented in a field environment. The secondary goals were to enhance the medical realism of training, allow students to practice crucial combat emergency medical skills and management in stressful field conditions, and develop medical team leadership. METHODS: Low , mid- and high-fidelity simulators were used in combination with standardized patients in a variety of field clinical settings. Students were given multiple opportunities to interact with the hybrid simulations. Student feedback about the simulation training was sought as part of their normal after-course critiques. RESULTS: High-fidelity simulation can be successfully implemented in combat simulated field conditions, and QA feedback indicated very positive perceptions from students. CONCLUSIONS: Multiple modality hybrid simulation can be successfully implemented into large-scale military medical field exercises, and appears beneficial for multiple educational goals. PMID- 23820348 TI - VINSIA: visual navigator for surgical information access. AB - Information access at the point of care presents a different set of requirements than those for traditional search engines. Critical care in remote (e.g., battle field) and rural settings not only requires access to clinical guidelines and medical libraries with surgical precision but also with minimal user effort and time. Our development of a graphical, anatomy-driven navigator called Visual Navigator for Surgical Information Access (VINSIA) fulfills the goal for providing evidence-based clinical decision support, specifically in perioperative and critical care settings, to allow rapid and precise information access through a portable stand-alone system. It comes with a set of unique characteristics: (a) a high precision, interactive visual interface driven by human anatomy; (b) direct linkage of anatomical structures to associated content such as clinical guidelines, literature, and medical libraries; and (c) an administrative content management interface allowing only an accredited, expert-level curator to edit and update the clinical content to ensure accuracy and currency. We believe that the deployment of VINSIA will improve quality, safety, and evidence-based standardization of patient care. PMID- 23820349 TI - Validation of one-mile walk equations for the estimation of aerobic fitness in British military personnel under the age of 40 years. AB - OBJECTIVE: To provide an accurate estimate of peak oxygen uptake (VO2 peak) for British Royal Navy Personnel aged between 18 and 39, comparing a gold standard treadmill based maximal exercise test with a submaximal one-mile walk test. METHODS: Two hundred military personnel consented to perform a treadmill-based VO2 peak test and two one-mile walk tests round an athletics track. The estimated VO2 peak values from three different one-mile walk equations were compared to directly measured VO2 peak values from the treadmill-based test. One hundred participants formed a validation group from which a new equation was derived and the other 100 participants formed the cross-validation group. RESULTS: Existing equations underestimated the VO2 peak values of the fittest personnel and overestimated the VO2 peak of the least aerobically fit by between 2% and 18%. The new equation derived from the validation group has less bias, the highest correlation with the measured values (r = 0.83), and classified the most people correctly according to the Royal Navy's Fitness Test standards, producing the fewest false positives and false negatives combined (9%). CONCLUSION: The new equation will provide a more accurate estimate of VO2 peak for a British military population aged 18 to 39. PMID- 23820350 TI - NATO survey of mental health training in army recruits. AB - To-date, there has been no international review of mental health resilience training during Basic Training nor an assessment of what service members perceive as useful from their perspective. In response to this knowledge gap, the North Atlantic Treaty Organization (NATO) Human Factors & Medicine Research & Technology Task Group "Mental Health Training" initiated a survey and interview with seven to twenty recruits from nine nations to inform the development of such training (N = 121). All nations provided data from soldiers joining the military as volunteers, whereas two nations also provided data from conscripts. Results from the volunteer data showed relatively consistent ranking in terms of perceived demands, coping strategies, and preferences for resilience skill training across the nations. Analysis of data from conscripts identified a select number of differences compared to volunteers. Subjects also provided examples of coping with stress during Basic Training that can be used in future training; themes are presented here. Results are designed to show the kinds of demands facing new recruits and coping methods used to overcome these demands to develop relevant resilience training for NATO nations. PMID- 23820351 TI - ANAM4 TBI reaction time-based tests have prognostic utility for acute concussion. AB - The Concussion Restoration Care Center has used the Automated Neuropsychological Assessment Metrics version 4 Traumatic Brain Injury (ANAM4 TBI) battery in clinical assessment of concussion. The study's aim is to evaluate the prognostic utility of the ANAM4 TBI. In 165 concussed active duty personnel (all ultimately returned to duty) seen and tested on the ANAM4 TBI on days 3 and 5 (median times) from their injury, Spearman's rho statistics showed that all performance subtests (at day 5) were associated with fewer days return-to-duty (RTD) time, whereas concussion history or age did not. Kruskal-Wallis statistics showed that ANAM4 TBI, loss of consciousness, and post-traumatic amnesia were associated with increased RTD time; ANAM4 TBI reaction time-based subtests, collectively, showed the largest effect sizes. A survival analysis using a Kaplan-Meier plot showed that the lowest 25% on the reaction time-based subtests had a median RTD time of 19 days, whereas those in the upper 25% had a median RTD time of approximately 7 days. Results indicate that until validated neurocognitive testing is introduced, the ANAM4 TBI battery, especially reaction time-based tests, has prognostic utility. PMID- 23820352 TI - Gender differences in combat medic mental health services utilization, barriers, and stigma. AB - Military health care providers experience considerable stressors related to their exposure to death and traumatic injuries in others. This study used survey data from 799 active duty U.S. Army Combat Medics deployed to Operation Iraqi Freedom/Operation Enduring Freedom. Military experiences, combat exposures, and mental health care seeking of active duty Combat Medics were explored and compared across both genders. Barriers to care were also assessed. Male and female Combat Medics reported surprisingly similar experiences, exposures, and health issues. Overall, results indicate no striking differences in barriers for females compared to their male counterparts, suggesting the barriers to utilization of mental health services may be consistent across gender. Although medics endorsed barriers and stigma related to mental health counseling services, they still sought these health services. Female and male medics who endorsed barriers were more likely to report seeking services than those who did not endorse barriers. This study provides an initial description of utilization of mental health counseling services for U.S. Army Combat Medics, the majority of whom were involved in combat operations in Afghanistan or Iraq. Our findings indicate that comprehensive assessment of the military experiences and combat exposures is needed to appreciate their potential influence on military health care providers. PMID- 23820353 TI - Prehospital blood product transfusion by U.S. army MEDEVAC during combat operations in Afghanistan: a process improvement initiative. AB - U.S. Army flight medics performed a process improvement initiative of 15 blood product transfusions on select Category A (Urgent) helicopter evacuation casualties meeting approved clinical indications for transfusion. These transfusions were initiated from point of injury locations aboard MEDEVAC aircraft originating from one of two locations in southern Afghanistan. All flight medics executing the transfusions were qualified through a standardized and approved program of instruction, which included day and night skills validation, and a 90% or higher written examination score. There was no adverse reaction or out-of-standard blood product temperature despite hazardous conditions and elevated cabin temperatures. All casualties within a 10-minute flight time who met clinical indications were transfused. Utilization of a standard operating procedure with strict handling and administration parameters, a rigorous training and qualification program, an elaborate cold chain system, and redundant documentation of blood product units ensured that flight medic initiated transfusions were safe and effective. Research study is needed to refine the indications for prehospital blood transfusion and to determine the effect on outcomes in severely injured trauma patients. PMID- 23820355 TI - Prehospital emergency inguinal clamp controls hemorrhage in cadaver model. AB - BACKGROUND: The Combat Ready Clamp is indicated to stop difficult inguinal bleeding on the battlefield, the most common type of junctional bleeding and now the most common cause of preventable battlefield death. The purpose of the present study is to report the data of clamp development to help appliers use it correctly. METHODS: Wake Forest University investigators used a cadaver model to test the clamp's ability to control hemorrhage. Ten fresh cadavers were made to simulate inguinal and popliteal wound bleeding. Blood simulant was pumped to quantify device effectiveness in testing. Points of application included proximal pressure point control of popliteal, inguinal, and bilateral bleeding. RESULTS: Clamp use promptly controlled pulsing arterial hemorrhages from inguinal, popliteal, and bilateral wounds. The device, when placed on the common iliac artery, stopped all ipsilateral distal bleeding. CONCLUSIONS: The evidence of how the clamp works in the cadaver model showed that clamp use can plausibly be tailored to control inguinal hemorrhage from one wound, control two ipsilateral wounds with hemorrhage from one artery (e.g., common iliac artery), and control bilateral inguinal wounds (compression of the origins of bilateral common iliac arteries). PMID- 23820354 TI - Effects of hydration on cognitive function of pilots. AB - The objective of this study was to examine the effect of fluid intake and possible dehydration on cognitive flight performance of pilots. A repeated measures, counterbalanced, mixed study design was used to examine differences in working memory, spatial orientation, and cognitive flight performance of 40 randomly selected healthy pilots after having high and low fluid intakes. Serial weights were also analyzed to determine differences in cognitive flight performance of the dehydrated (1-3% weight loss) and hydrated study participants. Results showed flight performance and spatial cognition test scores were significantly (p < 0.05) poorer for pilots who had low fluid intakes and experienced dehydration in comparison to the hydrated pilots. These findings indicate fluid intake differences resulting in dehydration may have safety implications because peak cognitive performance among pilots is critical for flight safety. PMID- 23820356 TI - Analysis of recovered tourniquets from casualties of Operation Enduring Freedom and Operation New Dawn. AB - BACKGROUND: Tourniquet use recently became common in war, but knowledge gaps remain regarding analysis of recovered devices. The purpose of this study was to analyze tourniquets to identify opportunities for improved training. METHODS: We analyzed tourniquets recovered from deceased service members serving in support of recent combat operations by a team at Dover Air Force Base from 2010 to 2012. Device makes and models, breakage, deformation, band routing, and windlass turn numbers were counted. RESULTS: We recovered 824 tourniquets; 390 were used in care and 434 were carried unused. Most tourniquets were recommended by the Committee on Tactical Combat Casualty Care (Combat Application Tourniquet [CAT] or Special Operations Forces Tactical Tourniquet). The band was routed once through the buckle in 37% of used CATs, twice in 62%, and 1% had none. For tourniquets with data, the windlass turn number averaged 3.2 (range, 0-9). The CAT windlass turn number was associated positively with tourniquet deformation as moderate or severe deformation began at 2 turns, increased in likelihood stepwise with each turn, and became omnipresent at 7 or more. CONCLUSIONS: Tourniquet counts, band routings, windlass turn numbers, and deformation rates are candidate topics for instructors to refine training. PMID- 23820357 TI - Veteran eye disease after eligibility reform: prevalence and characteristics. AB - PURPOSE: To determine the prevalence of eye disease in new "routine" eye patients at the Atlanta Veteran Affairs Medical Center. DESIGN: Retrospective chart review of all new eye patients seen in the Atlanta Veteran Affairs Medical Center Comprehensive Eye Clinic over a 2-month period (January 1, 2008-February 28, 2008). PARTICIPANTS: 691 charts met inclusion criteria, with 33 charts excluded for insufficient documentation in the medical record. This left a total of 658 charts for the study. METHODS: Charts were reviewed for the following information: demographic data, vision, ocular diagnoses (International Classification of Diseases, 9th Revision, Clinical Modification codes), and planned minor/laser/incisional surgical procedures. Additional data collected included whether glasses were prescribed and legal blindness. MAIN OUTCOME MEASURES: Vision-threatening ocular diagnoses and need for minor/laser/incision surgery were tabulated. RESULTS: There was a very high prevalence of potentially blinding disease in this population of new "routine" eye patients. About 63.4% of veterans were diagnosed with at least one ocular diagnosis other than refractive error; 25% had glaucoma or were suspects, 6% had cataracts, 5% had age-related macular degeneration, and 8% required a surgical procedure. CONCLUSION: The rate of ocular pathology is high in the veteran population. PMID- 23820358 TI - Children's utilization of the U.S. military dental insurance. AB - OBJECTIVES: The objectives of this study were to determine the dental utilization of children enrolled in a military dental insurance program and to assess if utilization differs by socioeconomic status. METHODS: Claims data for children enrolled in the Department of Defense TRICARE Dental Program for the period of February 1, 2010 through January 31, 2011 were used to identify children who had a dental visit during that benefit year. RESULTS: Of the 376,681 continuously enrolled children, 266,862 (71%) had at least one dental visit during the benefit year. 82.7% of children of officers had a dental visit, as compared to 66.4% of children from enlisted families. There was a difference in dental utilization based on the military rank of the sponsors (chi(2) = 8,939.39, df = 1, p < 0.0001). Children of officers were 2.5 times (95% confidence intervals = 2.44 2.61), and children of warrant officers were 1.6 times (95% confidence intervals = 1.51-1.74) more likely to have a dental visit than children from enlisted families. The results also show utilization trends within the enlisted and officer categories with higher utilization among more senior personnel. CONCLUSIONS: Socioeconomic status does play a role in dental care-seeking behavior of military families. Even when families voluntarily enroll in a program and there are no cost shares for services such as preventive services, there may be other barriers to accessing care that need to be addressed so that all groups can maximize their oral health. PMID- 23820359 TI - Laparoendoscopic single-site (LESS) renal cyst decortication during Pacific Partnership humanitarian assistance mission. AB - We describe the first laparoendoscopic single-site surgery (LESS) performed during a U.S. Navy humanitarian assistance mission. In conjunction with host nation surgeons, we performed a LESS renal cyst decortication in a 72-year-old woman during Pacific Partnership aboard the USNS Mercy (T-AH19). LESS procedures during humanitarian assistance missions offer advantages of rapid recovery and minimal convalescence. This case illustrates an innovative way to transfer technology and techniques between mission personnel and host nation providers during missions designed to build stronger relationships and disaster response capabilities in the Asia-Pacific region. PMID- 23820360 TI - Physiological, biochemical, and psychological responses to environmental survival training in the Royal Australian Air Force. AB - Military environmental survival training (EST) is designed and considered to evoke significant stressors to military personnel in preparation for combat-like scenarios. The aim of this study was to observe and report selected physiological, biochemical, psychological, and performance responses to this intense 15-day program of Royal Australian Air Force (RAAF) EST. Fourteen RAAF participants undertook the EST course. Physiological and psychological responses were collected across the 15 days across outcomes: (1) biochemical markers (blood lactate, interlukin-6, and creatine kinase), (2) performance and anthropometric indices (vertical jump, body mass), and (3) psychological questionnaires profile of mood states, depression anxiety stress scale, Kessler-10 etc.). Creatine kinase concentration increased significantly from baseline to day 5 (p < 0.05) and thereafter remained elevated for the remaining 10 days of EST (128%; p < 0.01). Vertical jump (-10%; p < 0.01) and body mass (-8%; p < 0.01) both decreased across 15 days of EST, while there were no significant change in interlukin-6. Negative psychological responses were observed for mood (p < 0.01), depression (p < 0.05), anxiety (p < 0.01), and stress (p < 0.01) following the EST course. This case study showed the RAAF EST course imposed significant physiological and psychological stress as observed from markers of muscle damage, deterioration in physical performance, substantial weight loss, negative mood, and psychological distress. PMID- 23820361 TI - Clinical case series: treatment of PTSD with transcendental meditation in active duty military personnel. AB - Active duty U.S. Army Service Members previously diagnosed with post-traumatic stress disorder (PTSD) were selected from review of patient records in the Traumatic Brain Injury Clinic at the Department of Defense Eisenhower Army Medical Center at Fort Gordon in Augusta, Georgia. Patients agreed to practice the Transcendental Meditation (TM) technique for 20 minutes twice a day for the duration of a 2-month follow-up period. Three cases are presented with results that show the feasibility of providing TM training to active duty soldiers with PTSD in a Department of Defense medical facility. Further investigation is suggested to determine if a TM program could be used as an adjunct for treatment of PTSD. Impact of this report is expected to expand the complementary and alternative evidence base for clinical care of PTSD. PMID- 23820362 TI - Skin temperature and heart rate can be used to estimate physiological strain during exercise in the heat in a cohort of fit and unfit males. AB - OBJECTIVE: To evaluate the previously developed physiological strain index (PSI) model using heart rate and skin temperature to provide further insight into the detection and estimation of thermal and physiological heat strain indices. A secondary aim was to characterize individuals who excel in their performance in the heat. METHODS: 56 male participants completed 2 walking trials (3.5 miles per hour, 5% grade) in controlled environments of 43.3 degrees C and 15.5 degrees C (40% humidity). Core and skin temperature, along with heart rate and PSI, were continually monitored during exercise. Participants completed a physical fitness test. RESULTS: The logistic regression model exhibited 4 false positives and 1 false negative at the 40% decision boundary. The "Not at Risk" group (N = 33) had higher body weight (84 +/- 13 vs. 77 +/- 10 kg, respectively) compared to the "At Risk" (N = 23) group, p < 0.05. The "Not at Risk" group had a faster 3-mile run time compared to the "At Risk" group (21:53 +/- 3:13 vs. 25:16 +/- 2:37, respectively), p < 0.05. During the Heat Trial, the "At Risk" group had a higher rating of perceived exertion at 60 and 90 minutes compared to the "Not at Risk" group (13.5 +/- 2.8 vs. 11.5 +/- 1.8 and 14.8 +/- 3.2 vs. 12.2 +/- 2.0 for "At Risk" vs. "Not at Risk" at 60 and 90 minutes, respectively), p < 0.05. CONCLUSIONS: The previously developed model relating heart rate and skin temperature to PSI is highly accurate at assessing heat risk status. Participants classified as "At Risk" had lower physical performance scores and different body weights compared to the "Not at Risk" group and perceived themselves as working harder during exercise in the heat. PMID- 23820363 TI - Case report: Military subcultural competency. AB - The military is comprised of numerous subcultures. These subcultures can dramatically impact perceptions of illness and care. Although efforts are currently underway to improve the military cultural competence of all health care providers, efforts to improve the subcultural competence of military providers require attention. Military providers, although part of the military culture, may not appreciate their patients' military subculture or be aware of the impact their own subculture plays on the encounter. To illustrate potential difficulties, a case is described where limited military subcultural competence disrupted care. As the military medical corps continues to integrate across service lines, this case underscores the importance of training military physicians to assess the influence of a service member's specific military subculture. PMID- 23820364 TI - A pain in the neck: carotid artery dissection presenting as vasculitis. AB - Spontaneous cervical artery dissection is increasingly recognized as a common cause of ischemic stroke in the young and middle-aged. Noninvasive imaging techniques such as magnetic resonance imaging and magnetic resonance angiography have widely replaced conventional angiography as the initial diagnostic study of extracranial dissections, allowing greater numbers of patients to be screened and thus leading to increased frequency of the diagnosis. We present a case of spontaneous carotid artery dissection in a previously healthy 48-year-old woman who presented with neck pain and elevated inflammatory markers. Marked gadolinium enhancement of the right extracranial internal carotid artery on magnetic resonance imaging led to an initial diagnosis of vasculitis. This case shows that the vessel injury associated with spontaneous carotid artery dissection is associated with an inflammatory response that can mimic vasculitis on highly sensitive imaging techniques, a phenomenon not well described previously. In this report, we review the nonvasculitic conditions that can mimic vasculitis and present clinicians complex diagnostic challenges. Recognition of these pseudovasculitic syndromes is important to avoid overdiagnosis resulting in unnecessary and potentially harmful immunosuppressive and cytotoxic treatments. PMID- 23820365 TI - Atypical presentation of ascending aortic dissection diagnosed via transthoracic echocardiogram. AB - A 62-year-old female presented to the emergency department after sudden onset of epigastric pain. She had no previous medical history to include no history of hypertension or vascular disease. She was admitted to the hospital and her workup revealed an ascending aortic dissection. Here, we present an atypical presentation of a patient with an aortic dissection diagnosed on transthoracic echocardiogram. PMID- 23820366 TI - Buprenorphine/naloxone therapy for opioid refractory neuropathic pain following traumatic amputation: a case series. AB - Phantom limb pain is a common consequence of limb amputation and is prevalent among the service members sustaining traumatic battlefield limb injuries during the conflicts in Iraq and Afghanistan. Current treatment to relieve phantom limb pain consists of physical, behavioral, and medical modalities including opioids and adjunct medications. Treatment failure resulting in persistent pain and disability may result. This case series describes four previously healthy service members who developed phantom limb pain following traumatic amputation successfully treated with buprenorphine/naloxone after failing traditional treatment. This is the first reported case series of patients expressing improved pain control with decreased frequency of phantom limb pain with the use of buprenorphine/naloxone instead of traditional opioid agonists. PMID- 23820367 TI - Decrease corneal hysteresis in steroid-induced ocular hypertension: a case report. AB - PURPOSE: To describe a case of steroid-induced ocular hypertension in which a clinical significant increase in intraocular pressure resulted with a corresponding corneal hysteresis decreased response. METHOD: A case report is presented in which a 62-year-old white male who was diagnosed with rosacea meibomitis and treated with topical antibiotic steroid combination ointment responded such. CONCLUSION: This case report illustrates a reverse model of the topical antiglaucoma medication studies recently described of decrease in intraocular pressure with an increase in corneal hysteresis with the application of topical prostaglandins and beta-blocker compounds. This may provide additional insight into how the biomechanical properties of the cornea and tunics of the eye respond to local applications of different ocular medications. PMID- 23820368 TI - Pericarditis, thymic hyperplasia, and Graves' thyrotoxicosis: case report and review of the literature. AB - Graves' thyrotoxicosis with thymic hyperplasia and pericarditis has never been described in the literature. In this case report, we present the clinical, laboratory, and radiographic findings of a 24-year-old active duty male who was admitted for management of nonexertional, positional, pleuritic chest pain. Electrocardiography confirmed pericarditis as the presenting diagnosis. Laboratory findings revealed an undetectable serum thyrotropin level and further evaluation with a contrast chest computed tomography confirmed the presence of a goiter and an anterior mediastinal mass. The patient's pericarditis and thymic hyperplasia resolved with treatment of his Graves' disease. PMID- 23820369 TI - Long-term outcomes of a dynamic ankle-foot orthosis on gait characteristics of a service member with incomplete nerve injury to the lower extremity: a case report. AB - This case study reports a 5-year follow-up of a 32-year-old male service member who suffered polytrauma in 2007 following a Humvee rollover in Afghanistan. The service member's injured left lower extremity was salvaged, but severe damage to the lumbosacral plexus and significant injuries to the pelvis, hip, and femur resulted in near total paralysis and foot drop of the left lower limb. Two years of multiple substandard ankle-foot orthotic devices pushed him to investigate a dynamic ankle-foot orthotic (DAFO) with energy storing capability, which allowed him to remain on active duty and deploy for a second tour while wearing the device. The anecdotal improvements described by this service member prompted a biomechanical analysis of walking and running gait, comparing a shoes only condition to the DAFO. Results of gait analysis demonstrated an improvement in spatial-temporal parameters in both walking and running, improved sagittal angles and moments at the ankle, knee, and hip, greater ankle stability through decreased dorsiflexion excursion, and a marked increase in ankle power while running. Most notably, the service member credits this device for substantial improvement in quality of life including total cessation of pain medication and return to regular vigorous activity. PMID- 23820370 TI - Curious marks on an Iraqi man with respiratory complaints. AB - A 26-year-old suspected Iraqi insurgent is brought to a Troop Medical Clinic in Baghdad, Iraq, with curious marks on his body. On questioning, he describes productive cough, subjective fever, drenching night sweats, and unintentional weight loss. This case shows a condition with which Western physicians are generally unfamiliar but one which quite possibly could be encountered by the deploying provider. PMID- 23820371 TI - Rehabilitation of a U.S. Army soldier diagnosed with cerebellar atrophy with an ataxic gait. AB - BACKGROUND AND PURPOSE: Balance impairments can disrupt the careers of U.S. Army soldiers and put themselves and their mates in danger. The purpose of this case report is to review the rehabilitation process and outcome of a U.S. Army soldier diagnosed with gait ataxia secondary to cerebellar atrophy. CASE DESCRIPTION: The patient is a 35-year-old active duty U.S. Army male who presented with an ataxic gait pattern and had magnetic resonance image evidence of cerebellar atrophy. OUTCOMES: Over the course of 7 months of rehabilitation, the patient showed improvement in ambulation and balance as evidenced by improved dynamic gait index and Propriotest dynamic motion analysis scores. DISCUSSION: This relatively young, active duty soldier was able to improve with physical therapy intervention. However, even in this young, highly motivated patient, it took several months of rehabilitation to achieve his goals. PMID- 23820372 TI - Eating disorder in a young active duty male. AB - Eating disorders can have atypical presentations, be challenging to diagnose, and often result in treatment delay, as illustrated here. Bulimia nervosa is characterized by binge eating and inappropriate compensatory behaviors, and is ten times more common in females. Studies show increased prevalence over the past decade, with similar prevalence in young military members and civilians. Risk factors include dieting, gender preference, life-altering events, and history of a psychiatric condition. Relatively little research has focused on eating disorders among military males, but factors unique to this group include rigid weight standards, mandatory semiannual personal fitness assessments, and extended deployments. Bulimia and other eating disorders can have subtle or atypical presentations and are often overlooked in males. Other diagnostic obstacles include career concerns and stigma avoidance, along with provider time constraints, inexperience, or discomfort with the issue. Serious medical complications of bulimia are uncommon, but delayed diagnosis can lead to hospitalization and significant morbidity. This case emphasizes the importance of a thorough history and wide differential when faced with an unusual presentation. Recognizing risk factors and incorporating simple screening tools can aid the timely identification and treatment of service members with disordered eating before unit and mission effectiveness are compromised. PMID- 23820373 TI - A case report of acute idiopathic scrotal edema. AB - Acute Idiopathic Scrotal Edema (AISE) is an uncommon cause of bilateral scrotal swelling encountered in primary care. AISE is usually seen in children; however, several case reports have shown that AISE can occur in adult males. We present an active duty adult male who presented with AISE while deployed in Afghanistan. The clinical course of AISE is usually benign with labs and ultrasound being unremarkable. Besides swelling, the most common symptom tends to be intense scrotal puritis. Treatment for AISE is watchful waiting and conservative therapy. Full symptom resolution usually occurs within 24 hours. PMID- 23820374 TI - Cristalius: a case in designer drugs. AB - INTRODUCTION: Among recreational drug users, there is a new wave of designer drugs being marketed as "bath salts" and "plant food," which mimic the effects of cocaine/amphetamines and ecstasy (MDMA [3,4-methylenedioxy-N-methamphetamine]). Presented is the case of a patient who snorted a bath salt called Cristalius. CASE PRESENTATION: A 22-year-old male Soldier was seen in an emergency department for syncope, agitation, confusion, and tachycardia. He reported snorting 1 g of Cristalius the night before. Significant labs included a creatine kinase of 668 U/L, serum creatinine of 1.35 mg/dL, and troponin of 0.516 ng/mL. His abnormal labs trended to normal and a computed tomography coronary angiogram was unremarkable. DISCUSSION: The main ingredients postulated in these products are mephedrone and a synthetic cathinone derivatives of the khat plant. The intended effects include euphoria, empathic connection, mood enhancement, increased sensory perception, with decreased inhibition. Unwanted sympathomimetic side effects include hypertension, tachycardia, chest pain, diaphoresis, dilated pupils, seizures, bruxism, and headaches. Neuropsychiatric symptoms include agitation, anxiety, paranoia, tremors, and insomnia. CONCLUSION: No treatment guidelines currently exist for mephedrone or MDPV (3,4 methylenedioxypyrovalerone) toxicity. If suspected, ensure adequate cardiac evaluation is completed regardless of age. Appropriate supportive care and addressing any complications is the primary treatment. PMID- 23820376 TI - E3 ubiquitin ligase Fbw7 negatively regulates granulocytic differentiation by targeting G-CSFR for degradation. AB - Tight control between activation and attenuation of granulocyte colony stimulating factor receptor (G-CSFR) signaling is essential to regulate survival, proliferation and differentiation of myeloid progenitor cells. Previous studies demonstrated negative regulation of G-CSFR through endosomal-lysosomal routing and ubiquitin-proteasome mediated degradation. However, very few E3 ubiquitin ligases are known to target G-CSFR for ubiquitin-proteasome pathway. Here we identified F-box and WD repeat domain-containing 7 (Fbw7), a substrate recognizing component of Skp-Cullin-F box (SCF) E3 ubiquitin Ligase physically associates with G-CSFR and promotes its ubiquitin-mediated proteasomal degradation. Our data shows that Fbw7 also interacts with and degrades G-CSFR T718 (a truncated mutant of G-CSFR found in severe congenital neutropenia/acute myeloid leukemia (SCN/AML patients)) though at a quite slower rate compared to G CSFR. We further show that glycogen synthase kinase 3 beta (GSK3beta), like Fbw7 also targets G-CSFR and G-CSFR-T718 for degradation; however, Fbw7 and GSK3beta are interdependent in targeting G-CSFR/G-CSFR-T718 for degradation because they are unable to degrade G-CSFR individually when either of them is knocked down. We further show that Fbw7 mediated downregulation of G-CSFR inhibits signal transducer and activator of transcription 3 (STAT3) phosphorylation which is required for G-CSF dependent granulocytic differentiation. In addition, our data also shows that inhibition of Fbw7 restores G-CSFR signaling leading to enhanced STAT3 activity resulting in massive granulocytic differentiation. These data indicate that Fbw7 together with GSK3beta negatively regulates G-CSFR expression and its downstream signaling. PMID- 23820378 TI - Asymmetric selection and the evolution of extraordinary defences. AB - Evolutionary biologists typically predict future evolutionary responses to natural selection by analysing evolution on an adaptive landscape. Much theory assumes symmetric fitness surfaces even though many stabilizing selection gradients deviate from symmetry. Here we revisit Lande's adaptive landscape and introduce novel analytical theory that includes asymmetric selection. Asymmetric selection and the resulting skewed trait distributions bias equilibrium mean phenotypes away from fitness peaks, usually toward the flatter shoulder of the individual fitness surface. We apply this theory to explain a longstanding paradox in biology and medicine: the evolution of excessive defences against enemies. These so-called extraordinary defences can evolve in response to asymmetrical selection when marginal risks of insufficient defence exceed marginal costs of excessive defence. Eco-evolutionary feedbacks between population abundances and asymmetric selection further exaggerate these defences. Recognizing the effect of asymmetrical selection on evolutionary trajectories will improve the accuracy of predictions and suggest novel explanations for apparent sub-optimality. PMID- 23820377 TI - Molecular epidemiology of influenza A (H5N1) viruses, Bangladesh, 2007-2011. AB - To investigate the origins, evolution and patterns of spread of HPAI H5N1 outbreaks in Bangladesh, we performed a phylogenetic reconstruction analysis using Bayesian methods. The analysis was conducted using 81 hemagglutinin (HA) gene sequences from the H5N1 viruses isolated in Bangladesh from 2007 to 2011, together with 264 publicly available HA sequences of clade 2.2, 2.3.2 and 2.3.4 retrieved from GenBank. Our study provides evidence that clade 2.2.2 viruses that caused outbreaks in Bangladesh were lineages independent from the viruses introduced earlier into India. Furthermore, the Bangladesh clade 2.2.2 descendents subsequently spread to India and Bhutan. This has implications for avian influenza control in southern Asia suggesting multiple routes of entry of the virus including one pathway that spread to neighboring countries via Bangladesh. PMID- 23820379 TI - Health related guide values for drinking-water since 1993 as guidance to assess presence of new analytes in drinking-water. AB - Regulatory toxicologists, when going into assessment of a new analyte in drinking water, very often miss the occasion to revert to scientifically consensual virtually safe lifetime exposure reference doses and corresponding health-related guide values (HRGV) for drinking-water, be those derived either to avoid concern over "threshold effects" or concern over exceedance of an unacceptable non threshold cancer risk level. They then need a more restrictive precautionary yet science-compatible approach to directly avoid concern over the presence (measured concentration) of a new analyte in drinking-water. Therefore, the German Environment Agency (UBA, Umweltbundesamt) decided in 2003 to extrapolate international toxicological expertise collected since 1993 from assessing "old" analytes in drinking-water on new ones in form of five HRIV=health related indication values. They indicate the reasonable lowest maximal concentration from which on tiered or stepwise human toxicological evaluation of a new analyte might be necessary and meaningful. Their regulatory-toxicological function is that of placeholders as long as a possibly higher scientific HRGV or a surrogate value based on a threshold of toxicological concern (TTC) was not broadly agreed by science. The five-step HRIV scale between 0.01 and 3.0 MUg/l combines international toxicological experience gained from "old" analytes since 1993 with the concepts of safety factors (SF(D)) to assess database deficiency and science related extrapolation factors (EF) to extrapolate experimental data on humans. Each HRIV is valid and safe for a 2 l/day drinking-water exposure scenario either counting for 10% relative source contribution (compounds with threshold effects) or for a lifetime non-threshold cancer risk of up to 10(-6) and is the higher the more positive information exists regarding possible effects at critical toxic endpoints and for length of possible exposure. Past (historical) and present evaluations of "old" analytes were available in form of hundreds of HRGVs to count in 2 liters per day and person for 10% RSC or a 10(-6) non-threshold risk. These HRGVs were calculated by the present author either from ADI-, TDI- or RfD values derived since 1993 by six large health authorities or they were identified directly at their websites or in the literature, always looking for confirmed or assumed worldwide relevance for drinking-water (resources). 36 of these up to 200 "old" analytes were ascribed since 1993 at least once an HRGV at or below 1 MUg/l for (confirmed or provisionally assumed) "high" or "very high" threshold chronic toxicity. None but one of the corresponding 113 scientific HRGVs fell distinctly short of 0.3 MUg/l. Only 14 carcinogens turned out as being relevant for drinking water due to confirmed occurrence and coincident toxicological significance there. 13 of these exhibited a structural alert for genotoxicity. Ten of these 13 were "high-potency" genotoxic carcinogens with presently calculated non-threshold 10(-6) risk minimal HRGVs between 0.06 MUg/l and 0.005 MUg/l (9 compounds) or possibly down to 0.0007 MUg/l (1 compound). This motivated UBA to propose a precautionary range between a minimal HRIV0=0.01 and a HRIV1=0.1 MUg/l to assess new analytes bearing a structural alert for genotoxicity. The HRGVs for the remaining three (from 13) carcinogens with alerts for genotoxicity were at best similar for both genotoxic and non-genotoxic effects and higher or equal to 0.3 MUg/l. Therefore, a minimal HRIV of 0.01 MUg/l (HRIV0) or even 0.1 MUg/l (HRIV1) would have appeared too low for assessing the presence in drinking-water of new analytes with no other human toxicity data than proven absence of both genotoxicity and of structural alerts for such. Instead, UBA proposes to provisionally assess such compounds by its next higher precautionary of HRIV3=0.3 MUg/l. Any value once set is open for falsification upwards to either 1.0 MUg/l (HRIV4) or 3.0 MUg/l (HRIV5) or even for being replaced by an HRGV>3.0 MUg/l if pertinent high toxicity effect potentials different from genotoxicity are similarly ruled out by either mechanistic and TTC-based arguments or a tiered experimental (in vitro and/or in vivo) approach. CONCLUSION: Regulatory toxicological expertise gained since 1993 with "old" analytes in drinking-water (resources) and its extrapolation by analogy on new analytes with patchy human toxicological database allows for provisional assessment of their presence in drinking-water in form of five precautionary HRIVs. Selecting a HRIV, instead referring to a TTC or a virtually safe reference dose, just asks an expert judgment on the degree of formal completeness and informational potential of a new analyte's human toxicity database. Exceedance of a HRIV indicates need for supplementary toxicological data to improve assessment, their nature and comprehensiveness depending on degree and expected length of exceedance. The regulatory function of a HRIV is that of a placeholder for a possibly higher TTC based surrogate HRGVTTC or a highest possible science-based HRGV. PMID- 23820380 TI - Verapamil for the treatment of clozapine-induced persistent sinus tachycardia in a patient with schizophrenia: a case report and literature review. PMID- 23820382 TI - Atomic structure and edge magnetism in MoS(2+x) parallelogram shaped platelets. AB - The structural, electronic, and magnetic properties of MoS(2+x) parallelogram shaped platelets having m and n Mo atoms on the adjoining edges have been studied using first principles calculations and by varying m and n from 1 to 6. These platelets have 100% S coverage on two adjoining edges while 50% S coverage on the other two edges. The structural stability of the platelets increases with size but the highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) energy gap in general decreases. There is a triangular metallic corner at the intersection of 100% S covered edges of the platelets when m = n. On the other hand magnetism is observed on the 50% S covered edges of the platelets for the sizes greater than that of the (3,4) platelet. The magnetic moments mainly arise from the undercoordinated S(2c) atoms at the 50% S covered edges rather than from Mo atoms. The criteria for the existence of the magnetic moments on S(2c) atoms are suggested and the electronic structure of the platelets on the edges as well as inside is discussed. PMID- 23820381 TI - A dodecameric ring-like structure of the N0 domain of the type II secretin from enterotoxigenic Escherichia coli. AB - In many bacteria, secretins from the type II secretion system (T2SS) function as outer membrane gated channels that enable passage of folded proteins from the periplasm into the extracellular milieu. Cryo-electron microscopy of the T2SS secretin GspD revealed previously the dodecameric cylindrical architecture of secretins, and crystal structures of periplasmic secretin domains showed a modular domain organization. However, no high-resolution experimental data has as yet been provided about how the entire T2SS secretin or its domains are organized in a cylindrical fashion. Here we present a crystal structure of the N0 domain of the T2SS secretin GspD from enterotoxigenic Escherichia coli containing a helix with 12 subunits per turn. The helix has an outer diameter of ~125A and a pitch of only 24A which suggests a model of a cylindrical dodecameric N0 ring whose dimensions correspond with the cryo-electron microscopy map of Vibrio cholerae GspD. The N0 domain is known to interact with the HR domain of the inner membrane T2SS protein GspC. When the new N0 ring model is combined with the known N0.HR crystal structure, a dodecameric double-ring of twelve N0-HR heterodimers is obtained. In contrast, the previously observed compact N0-N1 GspD module is not compatible with the N0 ring. Interestingly, a N0-N1 T3SS homolog is compatible with forming a N0-N1 dodecameric ring, due to a different N0-vs-N1 orientation. This suggests that the dodecameric N0 ring is an important feature of T2SS secretins with periplasmic domains undergoing considerable motions during exoprotein translocation. PMID- 23820383 TI - Lasting inhibition of receptor-mediated calcium oscillations in pancreatic acini by neutrophil respiratory burst--a novel mechanism for secretory blockade in acute pancreatitis? AB - Although overwhelming evidence indicates that neutrophil infiltration is an early event in acute pancreatitis, the effect of neutrophil respiratory burst on pancreatic acini has not been investigated. In the present work, effect of fMLP induced neutrophil respiratory burst on pancreatic acini was examined. It was found that neutrophil respiratory burst blocked calcium oscillations induced by cholecystokinin or by acetylcholine. Such lasting inhibition was dependent on the density of bursting neutrophils and could be overcome by increased agonist concentration. Inhibition of cholecystokinin stimulation was also observed in AR4 2J cells. In sharp contrast, neutrophil respiratory burst had no effect on calcium oscillations induced by phenylephrine (PE), vasopressin, or by ATP in rat hepatocytes. These data together suggest that inhibition of receptor-mediated calcium oscillations in pancreatic acini by neutrophil respiratory burst would lead to secretory blockade, which is a hallmark of acute pancreatitis. The present work has important implications for clinical treatment and management of acute pancreatitis. PMID- 23820385 TI - Nonconjugated anionic polyelectrolyte as an interfacial layer for the organic optoelectronic devices. AB - A nonconjugated anionic polyelectrolyte, poly(sodium 4-styrenesulfonate) (PSS Na), was applied to the optoelectronic devices as an interfacial layer (IFL) at the semiconducting layer/cathode interface. The ultraviolet photoelectron spectroscopy and the Kelvin probe microscopy studies support the formation of a favorable interface dipole at the organic/cathode interface. For polymer light emitting diodes (PLEDs), the maximum luminance efficiency (LEmax) and the turn-on voltage (Von) of the device with a layer of PSS-Na spin-coated from the concentration of 0.5 mg/mL were 3.00 cd/A and 5.5 V, which are dramatically improved than those of the device without an IFL (LEmax = 0.316 cd/A, Von = 9.5 V). This suggests that the PSS-Na film at the emissive layer/cathode interface improves the electron injection ability. As for polymer solar cells (PSCs), the power conversion efficiency (PCE) of the device with a layer of PSS-Na spin coated from the concentration of 0.5 mg/mL was 2.83%, which is a 16% increase compared to that of the PSC without PSS-Na. The PCE improvement is mainly due to the enhancement of the short-circuit current (12% increase). The results support that the electron collection and transporting increase by the introduction of the PSS-Na film at the photoactive layer/cathode interface. The improvement of the efficiency of the PLED and PSC is due to the reduction of the Schottky barrier by the formation of a favorable interface as well as the better Ohmic contact at the cathode interface. PMID- 23820384 TI - Ten-eleven translocation (Tet) and thymine DNA glycosylase (TDG), components of the demethylation pathway, are direct targets of miRNA-29a. AB - The ten-eleven translocation family of proteins (Tet1/2/3, Tets) converts 5 methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which can be further oxidized and repaired by thymine DNA glycosylase (TDG), to influence gene transcription in embryonic and adult tissues. However the mechanisms of how Tets and TDG levels are regulated are unknown. We show that miR-29 can directly regulate Tet1-3 and TDG mRNA levels through binding to their 3'UTRs. miR-29 mimic decreases global 5hmC levels, a hallmark of Tet activity. Moreover, the mRNA levels for Tet3 and TDG are inversely correlated with the levels of miR-29 in aged mouse aorta implying that aging may affect methylation patterns via miRNA. In summary, our data show that Tets and TDG are direct targets of miR-29 and unravel a novel regulatory role for this miRNA in epigenetic DNA demethylation pathways. PMID- 23820386 TI - Structure guided optimization of a fragment hit to imidazopyridine inhibitors of PI3K. AB - PI3 kinases are a family of lipid kinases mediating numerous cell processes such as proliferation, migration and differentiation. The PI3 Kinase pathway is often de-regulated in cancer through PI3Kalpha overexpression, gene amplification, mutations and PTEN phosphatase deletion. PI3K inhibitors represent therefore an attractive therapeutic modality for cancer treatment. Herein we describe how the potency of a benzothiazole fragment hit was quickly improved based on structural information and how this early chemotype was further optimized through scaffold hopping. This effort led to the identification of a series of 2-acetamido-5 heteroaryl imidazopyridines showing potent in vitro activity against all class I PI3Ks and attractive pharmacokinetic properties. PMID- 23820387 TI - Synthesis and the 5-HT6 receptor antagonistic effect of 3-arylsulfonylamino-5,6 dihydro-6-substituted pyrazolo[3,4]pyridinones for neuropathic pain treatment. AB - A novel series of 3-arylsulfonylamino-5,6-dihydro-6-substituted-1H-pyrazolo[3,4 c]pyridine-7-ones was designed and synthesized as 5-HT6 ligands. Among the derivatives synthesized, the lead compound, 12b, having piperidine functionality at the 6-position and (1-naphthyl)sulfonamino at the 3-position of the core structure showed the most potent 5-HT6 inhibitory activity in vitro, good stability without CYP liability, and good neuropathic pain alleviation activity in a rat animal model. PMID- 23820388 TI - Isolated nanographene crystals for nano-floating gate in charge trapping memory. AB - Graphene exhibits unique electronic properties, and its low dimensionality, structural robustness, and high work-function make it very promising as the charge storage media for memory applications. Along with the development of miniaturized and scaled up devices, nanostructured graphene emerges as an ideal material candidate. Here we proposed a novel non-volatile charge trapping memory utilizing isolate and uniformly distributed nanographene crystals as nano floating gate with controllable capacity and excellent uniformity. Nanographene charge trapping memory shows large memory window (4.5 V) at low operation voltage (+/-8 V), good retention (>10 years), chemical and thermal stability (1000 degrees C), as well as tunable memory performance employing with different tunneling layers. The fabrication of such memory structure is compatible with existing semiconductor processing thus has promise on low-cost integrated nanoscale memory applications. PMID- 23820390 TI - Brain symmetry plane detection based on fractal analysis. AB - In neuroimage analysis, the automatic identification of symmetry plane has various applications. Despite the considerable amount of research, this remains an open problem. Most of the existing work based on image intensity is either sensitive to strong noise or not applicable to different imaging modalities. This paper presents a novel approach for identifying symmetry plane in three dimensional brain magnetic resonance (MR) images based on the concepts of fractal dimension and lacunarity analysis which characterizes the complexity and homogeneity of an object. Experimental results, evaluation, and comparison with two other state-of-the-art techniques show the accuracy and the robustness of our method. PMID- 23820391 TI - Using sequence data to infer the antigenicity of influenza virus. AB - The efficacy of current influenza vaccines requires a close antigenic match between circulating and vaccine strains. As such, timely identification of emerging influenza virus antigenic variants is central to the success of influenza vaccination programs. Empirical methods to determine influenza virus antigenic properties are time-consuming and mid-throughput and require live viruses. Here, we present a novel, experimentally validated, computational method for determining influenza virus antigenicity on the basis of hemagglutinin (HA) sequence. This method integrates a bootstrapped ridge regression with antigenic mapping to quantify antigenic distances by using influenza HA1 sequences. Our method was applied to H3N2 seasonal influenza viruses and identified the 13 previously recognized H3N2 antigenic clusters and the antigenic drift event of 2009 that led to a change of the H3N2 vaccine strain. IMPORTANCE: This report supplies a novel method for quantifying antigenic distance and identifying antigenic variants using sequences alone. This method will be useful in influenza vaccine strain selection by significantly reducing the human labor efforts for serological characterization and will increase the likelihood of correct influenza vaccine candidate selection. PMID- 23820392 TI - X-linked immunodeficient mice exhibit enhanced susceptibility to Cryptococcus neoformans Infection. AB - ABSTRACT Bruton's tyrosine kinase (Btk) is a signaling molecule that plays important roles in B-1 B cell development and innate myeloid cell functions and has recently been identified as a target for therapy of B cell lymphomas. We examined the contribution of B-1 B cells to resistance to Cryptococcus neoformans infection by utilizing X-linked immunodeficient (XID) mice (CBA-CaHN-XID), which possess a mutation in Btk. XID mice had significantly higher brain fungal burdens than the controls 6 weeks after infection with C. neoformans strain 52D (CN52D); however, consistent with the propensity for greater virulence of C. neoformans strain H99 (CNH99), CNH99-infected XID mice had higher lung and brain fungal burdens than the controls 3 weeks after infection. Further studies in a chronic CN52D model revealed markedly lower levels of total and C. neoformans-specific serum IgM in XID mice than in the control mice 1 and 6 weeks after infection. Alveolar macrophage phagocytosis was markedly impaired in CN52D-infected XID mice compared to the controls, with XID mice exhibiting a disorganized lung inflammatory pattern in which Gomori silver staining revealed significantly more enlarged, extracellular C. neoformans cells than the controls. Adoptive transfer of B-1 B cells to XID mice restored peritoneal B-1 B cells but did not restore IgM levels to those of the controls and had no effect on the brain fungal burden at 6 weeks. Taken together, our data support the hypothesis that IgM promotes fungal containment in the lungs by enhancing C. neoformans phagocytosis and restricting C. neoformans enlargement. However, peritoneal B-1 B cells are insufficient to reconstitute a protective effect in the lungs. IMPORTANCE Cryptococcus neoformans is a fungal pathogen that causes an estimated 600,000 deaths per year. Most infections occur in individuals who are immunocompromised, with the majority of cases occurring in those with HIV/AIDS, but healthy individuals also develop disease. Immunoglobulin M (IgM) has been linked to resistance to disease in humans and mice. In this article, we found that X-linked immunodeficient (XID) mice, which have markedly reduced levels of IgM, were unable to contain Cryptococcus in the lungs. This was associated with reduced yeast uptake by macrophages, an aberrant tissue inflammatory response, an enlargement of the yeast cells in the lungs, and fungal dissemination to the brain. Since XID mice have a mutation in the Bruton's tyrosine kinase (Btk) gene, our data suggest that treatments aimed at blocking the function of Btk could pose a higher risk for cryptococcosis. PMID- 23820393 TI - Pathogenicity of the novel A/H7N9 influenza virus in mice. AB - A novel avian-origin influenza A/H7N9 virus infecting humans was first identified in March 2013 and, as of 30 May 2013, has caused 132 human infections leading to 33 deaths. Phylogenetic studies suggest that this virus is a reassortant, with the surface hemagglutinin (HA) and neuraminidase (NA) genes being derived from duck and wild-bird viruses, respectively, while the six "internal gene segments" were derived from poultry H9N2 viruses. Here we determine the pathogenicity of a human A/Shanghai/2/2013 (Sh2/H7N9) virus in healthy adult mice in comparison with that of A/chicken/Hong Kong/HH8/2010 (ck/H9N2) virus, highly pathogenic avian influenza (HPAI) A/Hong Kong/483/1997 (483/H5N1) virus, and a duck influenza A H7N9 virus of different genetic derivation, A/duck/Jiangxi/3286/2009 (dk/H7N9). Intranasal infection of mice with Sh2/H7N9 virus doses of 10(3), 10(4), and 10(5) PFU led to significant weight loss without fatality. This virus was more pathogenic than dk/H7N9 and ck/H9N2 virus, which has six internal gene segments that are genetically similar to Sh2/H7N9. Sh2/H7N9 replicated well in the nasal cavity and lung, but there was no evidence of virus dissemination beyond the respiratory tract. Mice infected with Sh2/H7N9 produced higher levels of proinflammatory cytokines in the lung and serum than did ck/H9N2 and dk/H7N9 but lower levels than 483/H5N1. Cytokine induction was positively correlated with virus load in the lung at early stages of infection. Our results suggest that Sh2/H7N9 virus is able to replicate and cause disease in mice without prior adaptation but is less pathogenic than 483/H5N1 virus. IMPORTANCE: An H7N9 virus isolate causing fatal human disease was found to be more pathogenic for mice than other avian H9N2 or H7N9 viruses but less pathogenic than the highly pathogenic avian influenza virus (HPAI) H5N1. Similarly, the ability of Sh2/H7N9 to elicit proinflammatory cytokines in the lung and serum of mice was intermediate to ck/H9N2 and dk/H7N9 on the one hand and HPAI H5N1 on the other. These findings accord with the observed epidemiology in humans, in whom, as with seasonal influenza viruses, H7N9 viruses cause severe disease predominantly in older persons while HPAI H5N1 can cause severe respiratory disease and death in children and young adults. PMID- 23820394 TI - Evolutionary dynamics of Vibrio cholerae O1 following a single-source introduction to Haiti. AB - Prior to the epidemic that emerged in Haiti in October of 2010, cholera had not been documented in this country. After its introduction, a strain of Vibrio cholerae O1 spread rapidly throughout Haiti, where it caused over 600,000 cases of disease and >7,500 deaths in the first two years of the epidemic. We applied whole-genome sequencing to a temporal series of V. cholerae isolates from Haiti to gain insight into the mode and tempo of evolution in this isolated population of V. cholerae O1. Phylogenetic and Bayesian analyses supported the hypothesis that all isolates in the sample set diverged from a common ancestor within a time frame that is consistent with epidemiological observations. A pangenome analysis showed nearly homogeneous genomic content, with no evidence of gene acquisition among Haiti isolates. Nine nearly closed genomes assembled from continuous-long read data showed evidence of genome rearrangements and supported the observation of no gene acquisition among isolates. Thus, intrinsic mutational processes can account for virtually all of the observed genetic polymorphism, with no demonstrable contribution from horizontal gene transfer (HGT). Consistent with this, the 12 Haiti isolates tested by laboratory HGT assays were severely impaired for transformation, although unlike previously characterized noncompetent V. cholerae isolates, each expressed hapR and possessed a functional quorum-sensing system. Continued monitoring of V. cholerae in Haiti will illuminate the processes influencing the origin and fate of genome variants, which will facilitate interpretation of genetic variation in future epidemics. IMPORTANCE: Vibrio cholerae is the cause of substantial morbidity and mortality worldwide, with over three million cases of disease each year. An understanding of the mode and rate of evolutionary change is critical for proper interpretation of genome sequence data and attribution of outbreak sources. The Haiti epidemic provides an unprecedented opportunity to study an isolated, single-source outbreak of Vibrio cholerae O1 over an established time frame. By using multiple approaches to assay genetic variation, we found no evidence that the Haiti strain has acquired any genes by horizontal gene transfer, an observation that led us to discover that it is also poorly transformable. We have found no evidence that environmental strains have played a role in the evolution of the outbreak strain. PMID- 23820395 TI - Reovirus cell entry requires functional microtubules. AB - Mammalian reovirus binds to cell-surface glycans and junctional adhesion molecule A and enters cells by receptor-mediated endocytosis in a process dependent on beta1 integrin. Within the endocytic compartment, reovirus undergoes stepwise disassembly, allowing release of the transcriptionally active viral core into the cytoplasm. To identify cellular mediators of reovirus infectivity, we screened a library of small-molecule inhibitors for the capacity to block virus-induced cytotoxicity. In this screen, reovirus-induced cell killing was dampened by several compounds known to impair microtubule dynamics. Microtubule inhibitors were assessed for blockade of various stages of the reovirus life cycle. While these drugs did not alter reovirus cell attachment or internalization, microtubule inhibitors diminished viral disassembly kinetics with a concomitant decrease in infectivity. Reovirus virions colocalize with microtubules and microtubule motor dynein 1 during cell entry, and depolymerization of microtubules results in intracellular aggregation of viral particles. These data indicate that functional microtubules are required for proper sorting of reovirus virions following internalization and point to a new drug target for pathogens that use the endocytic pathway to invade host cells. IMPORTANCE: Screening libraries of well-characterized drugs for antiviral activity enables the rapid characterization of host processes required for viral infectivity and provides new therapeutic applications for established pharmaceuticals. Our finding that microtubule-inhibiting drugs impair reovirus infection identifies a new cell based antiviral target. PMID- 23820398 TI - Prospective study of the effect on gait of a two-component total ankle replacement. AB - BACKGROUND: The purpose of this study was to evaluate the functional outcome as measured by prospective gait analysis of patients undergoing total ankle arthroplasty using a 2-component Salto Talaris total ankle prostheses with a fixed polyethylene bearing. METHODS: Twenty-one patients with severe ankle arthritis who underwent unilateral total ankle arthroplasty using a 2-component Salto Talaris device with a fixed polyethylene bearing were studied prospectively. Mean age was 69 years in 16 female and 5 male patients, and mean follow-up was 37.2 (range, 24-50) months. Three-dimensional gait analysis was performed using a 12-camera digital-motion capture system preoperatively and repeated at a minimum of 2 years postoperatively. Temporospatial measurements included velocity, cadence, step length, and support times. Measured kinematic parameters included sagittal plane range of motion of the ankle, knee, and hip. Kinetic parameters included sagittal plane ankle power and ankle plantarflexion moment. RESULTS: There was significant improvement in temporospatial parameters, including step length (P = .014) and walking velocity, which increased from 0.9 to 1 m/s (P = .01). Kinematic results showed sagittal plane range of motion of the ankle increased significantly from a mean of 15.8 degrees preoperatively to 20.6 degrees (P = .00005) postoperatively with the increase occurring primarily in dorsiflexion. Kinetic results showed ankle peak power increased from a mean of 0.7 Nm/kg to 1.1 Nm/kg (P = .004). CONCLUSIONS: A prospective study of gait in patients undergoing total ankle arthroplasty using a 2-component Salto Talaris device with a fixed polyethylene bearing showed, at midterm follow-up, significant improvements in multiple parameters of gait when compared to the patients' own preoperative function. LEVEL OF EVIDENCE: Level IV, prospective case series. PMID- 23820396 TI - Envelope protein dynamics in paramyxovirus entry. AB - Paramyxoviruses include major pathogens with significant global health and economic impact. This large family of enveloped RNA viruses infects cells by employing two surface glycoproteins that tightly cooperate to fuse their lipid envelopes with the target cell plasma membrane, an attachment and a fusion (F) protein. Membrane fusion is believed to depend on receptor-induced conformational changes within the attachment protein that lead to the activation and subsequent refolding of F. While structural and mechanistic studies have considerably advanced our insight into paramyxovirus cell adhesion and the structural basis of F refolding, how precisely the attachment protein links receptor engagement to F triggering remained poorly understood. Recent reports based on work with several paramyxovirus family members have transformed our understanding of the triggering mechanism of the membrane fusion machinery. Here, we review these recent findings, which (i) offer a broader mechanistic understanding of the paramyxovirus cell entry system, (ii) illuminate key similarities and differences between entry strategies of different paramyxovirus family members, and (iii) suggest new strategies for the development of novel therapeutics. PMID- 23820397 TI - Streptomycin-induced inflammation enhances Escherichia coli gut colonization through nitrate respiration. AB - Treatment with streptomycin enhances the growth of human commensal Escherichia coli isolates in the mouse intestine, suggesting that the resident microbial community (microbiota) can inhibit the growth of invading microbes, a phenomenon known as "colonization resistance." However, the precise mechanisms by which streptomycin treatment lowers colonization resistance remain obscure. Here we show that streptomycin treatment rendered mice more susceptible to the development of chemically induced colitis, raising the possibility that the antibiotic might lower colonization resistance by changing mucosal immune responses rather than by preventing microbe-microbe interactions. Investigation of the underlying mechanism revealed a mild inflammatory infiltrate in the cecal mucosa of streptomycin-treated mice, which was accompanied by elevated expression of Nos2, the gene that encodes inducible nitric oxide synthase. In turn, this inflammatory response enhanced the luminal growth of E. coli by nitrate respiration in a Nos2-dependent fashion. These data identify low-level intestinal inflammation as one of the factors responsible for the loss of resistance to E. coli colonization after streptomycin treatment. IMPORTANCE: Our intestine is host to a complex microbial community that confers benefits by educating the immune system and providing niche protection. Perturbation of intestinal communities by streptomycin treatment lowers "colonization resistance" through unknown mechanisms. Here we show that streptomycin increases the inflammatory tone of the intestinal mucosa, thereby making the bowel more susceptible to dextran sulfate sodium treatment and boosting the Nos2-dependent growth of commensal Escherichia coli by nitrate respiration. These data point to the generation of alternative electron acceptors as a by-product of the inflammatory host response as an important factor responsible for lowering resistance to colonization by facultative anaerobic bacteria such as E. coli. PMID- 23820399 TI - Incidence, Paris classification, and follow-up in a nationwide incident cohort of pediatric patients with inflammatory bowel disease. AB - OBJECTIVES: The aim of the study was to evaluate the incidence, baseline disease characteristics, and disease location based on the Paris classification in pediatric inflammatory bowel disease (IBD) in the Hungarian nationwide inception cohort. In addition, 1-year follow-up with therapy was analyzed. METHODS: From January 1, 2007 to December 31, 2009, newly diagnosed pediatric patients with IBD were prospectively registered. Twenty-seven pediatric gastroenterology centers participated in the data collection ensuring the data from the whole country. Newly diagnosed patients with IBD younger than 18 years were reported. Disease location was classified according to the Paris classification. RESULTS: A total of 420 patients were identified. The incidence rate of pediatric IBD was 7.48/105 (95% confidence interval [CI] 6.34/105-8.83/105). The incidence for Crohn disease (CD) was 4.72/105 (95% CI 3.82-5.79), for ulcerative colitis (UC) 2.32/105 (95% CI 1.71-3.09), and for IBD-unclassified 0.45/105 (95% CI 0.22-0.84). Most common location in CD was L3 (58.7%); typical upper gastrointestinal abnormalities (ulcer, erosion and aphthous lesion) were observed in 29.9%. Extensive colitis in patients with UC (E4, proximal to hepatic flexure) was the most common disease phenotype (57%), whereas only 5% of children had proctitis. A total of 18.6% of patients had ever severe disease (S1). Frequency of azathioprine administration at diagnosis was 29.5% in patients with CD, and this rate increased to 54.6% (130/238) at 1-year follow-up. In UC, only 3.3% received azathioprine initially, and this rate elevated to 22.5% (25/111). Use of corticosteroid decreased from 50% to 15.3% in patients with UC. Rate of bowel resection in patients with CD during the first year of follow-up was 5%. CONCLUSIONS: The incidence of pediatric IBD in Hungary was among the higher range reported. This is the first large, nationwide incident cohort analyzed according to the Paris classification, which is a useful tool to determine the characteristic pediatric CD phenotype. PMID- 23820400 TI - Management of portal hypertension in children with portal vein thrombosis. AB - Portal vein thrombosis (PVT) is a common cause of portal hypertension in children. Predisposing conditions for PVT are obscure in more than half of the cases. Variceal bleeding and splenomegaly are the most frequent initial manifestations. Radiologic imaging studies are the mainstay for diagnosis. Treatment includes pharmacologic, endoscopic, and surgical modalities. beta Adrenergic blockers are not routinely used in children because of unproven efficacy and significant adverse effects. Endoscopic methods, such as sclerotherapy and endoscopic variceal ligation (EVL), are highly effective in the treatment of acute variceal bleeding and eradication of varices. EVL is the treatment of choice because of minimal complications and the need for few endoscopic sessions. EVL facilitates portal decompression either by the formation of collateral vessels or by surgical portosystemic shunting, when vessels grow to the proper diameter for anastomosis. Surgical portosystemic shunts are reserved for refractory cases because of significant complications and technical difficulties. Transjugular portosystemic shunts have an emerging role in the management of portal hypertension caused by PVT. PVT may occur in the posttransplant setting, but optimal management is not defined yet. PMID- 23820401 TI - Can we really skip the biopsy in diagnosing symptomatic children with celiac disease. PMID- 23820402 TI - Authors' response. PMID- 23820403 TI - Emergency department revisits in children with gastroenteritis. AB - OBJECTIVES: The aim of the study was to determine whether intravenous fluid administration is independently associated with a reduction in unscheduled emergency department (ED) revisits within 7 days. METHODS: We conducted a single center, retrospective observational cohort study in a pediatric ED in Toronto, Canada. Participants were younger than 18 years, diagnosed as having gastroenteritis, and discharged home between July 2003 and June 2008. Multivariable regression models were used to determine the associations between the exposures (intravenous rehydration, triage severity score, age) and ED revisits and revisits with intravenous rehydration. Accuracy was assessed using bootstrap analysis. RESULTS: There were 22,125 potentially eligible visits; 3346 were included in our final cohort. A total of 497 children (15%) received intravenous rehydration and 543 (16%) had an unscheduled revisit. Regression analysis included 2874 children with complete data, and identified 5 independent predictors of an ED revisit: intravenous rehydration (odds ratio [OR] 1.76; 95% confidence interval [CI] 1.36-2.26); number of vomiting episodes (1.20; 95% CI 1.04-1.28/5 episode increase); days of diarrhea (OR 0.92; 95% CI 0.88-0.97/day increase); frequency of diarrhea (1.19; 95% CI 1.03-1.38/5 episode increase); and age (OR 0.94; 95% CI 0.91-0.98/year). Bootstrap methodology identified intravenous rehydration, age, number of vomiting episodes, days of diarrhea, and number of diarrheal stools a minimum of 500 of 1000 iterations. CONCLUSIONS: Intravenous rehydration is associated with unscheduled ED revisits after adjustment for clinical findings. Although children experiencing revisits were likely more unwell, our data do not support the provision of intravenous fluids to prevent unscheduled ED revisits in children with mild-to-moderate dehydration. PMID- 23820404 TI - Clinical features and treatment responses in pediatric lymphocytic and collagenous colitis. AB - OBJECTIVE: Microscopic colitis (MC) is prevalent in adults investigated for chronic watery diarrhea, yet characterization of pediatric MC is limited. METHODS: Our pathology database was searched from 1995 to 2011 for pediatric cases of lymphocytic colitis (LC) or collagenous colitis (CC). Those with diarrhea persisting for >2 weeks and visually normal colonoscopy were accepted as cases. Demographics, laboratory results, medication use within 3 months of presentation, medical and family history of autoimmune disease, and response to treatment were abstracted. RESULTS: A total of 27 cases were histologically consistent with MC on biopsy; 5 with concomitant enteric infection or isolated abdominal pain were excluded. Twenty-two cases of MC (female patients, 59%; median age at diagnosis, 15.3 years) were included (19 LC and 3 CC). Two had type 1 diabetes mellitus, 2 were anti-nuclear antibody positive, and 2 had common variable immunodeficiency. Of 20 patients who underwent an esophagogastroduodenoscopy, 1 had collagenous sprue and 4 had celiac disease. One presented after the clearance of recurrent Clostridium difficile infection. Previous drug exposures included nonsteroidal anti-inflammatory drugs (n = 7), proton pump inhibitors (n = 6), and selective serotonin reuptake inhibitors (n = 3). Common symptoms in addition to diarrhea included abdominal pain (77.3%) and weight loss (27.3%). Of 17 patients with follow-up, all of the 8 treated with steroids had some response: 57.1% (4/7) responded to mesalamine and 42.9% (3/7) responded to bismuth subsalicylate. CONCLUSIONS: In this cohort of pediatric patients, LC was much more common than CC. As described in adults, we observed associations with celiac disease, type 1 diabetes mellitus, and medications; we additionally saw an association with immunodeficiency. Our patients showed greater response to steroids than mesalamine or bismuth. PMID- 23820406 TI - Authors' response. PMID- 23820407 TI - Antitumor necrosis factor, infliximab, and adalimumab: use with caution in eosinophilic bowel disease. PMID- 23820408 TI - Hypothermic oxygenated perfusion (HOPE) protects from biliary injury in a rodent model of DCD liver transplantation. AB - BACKGROUND & AIMS: The use of livers from donors after cardiac arrest (DCD) is increasing in many countries to overcome organ shortage. Due to additional warm ischemia before preservation, those grafts are at higher risk of failure and bile duct injury. Several competing rescue strategies by machine perfusion techniques have been developed with, however, unclear effects on biliary injury. We analyze the impact of an end-ischemic Hypothermic Oxygenated PErfusion (HOPE) approach applied only through the portal vein for 1h before graft implantation. METHODS: Rat livers were subjected to 30-min in situ warm ischemia, followed by subsequent 4-h cold storage, mimicking DCD-organ procurement and conventional organ transport. Livers in the HOPE group underwent also passive cold storage for 4h, but were subsequently machine perfused for 1h before implantation. Outcome was tested by liver transplantation (LT) at 12h after implantation (n=10 each group) and after 4 weeks (n=10 each group), focusing on early reperfusion injury, immune response, and later intrahepatic biliary injury. RESULTS: All animals survived after LT. However, reperfusion injury was significantly decreased by HOPE treatment as tested by hepatocyte injury, Kupffer cell activation, and endothelial cell activation. Recipients receiving non-perfused DCD livers disclosed less body weight gain, increased bilirubin, and severe intrahepatic biliary fibrosis. In contrast, HOPE treated DCD livers were protected from biliary injury, as detected by cholestasis parameter and histology. CONCLUSIONS: We demonstrate in a DCD liver transplant model that end-ischemic hypothermic oxygenated perfusion is a powerful strategy for protection against biliary injury. PMID- 23820410 TI - POEM: way to go! PMID- 23820411 TI - EUS-guided biliary drainage: is it ready for prime time? Yes! PMID- 23820412 TI - Listen carefully. PMID- 23820413 TI - Differential diagnosis of focal pancreatic masses by semiquantitative EUS elastography: between strain ratios and strain histograms. PMID- 23820414 TI - Response. PMID- 23820415 TI - Postablative stricture formation in ultra-long-segment Barrett's esophagus. PMID- 23820416 TI - Response. PMID- 23820417 TI - Response. PMID- 23820418 TI - Removing in situ esophageal stents. PMID- 23820419 TI - Targeting adenoviral vectors for enhanced gene therapy of uterine leiomyomas. AB - STUDY QUESTION: Is targeted adenovirus vector, Ad-SSTR-RGD-TK (Adenovirus -human somatostatin receptor subtype 2- arginine, glycine and aspartate-thymidine kinase), given in combination with ganciclovir (GCV) against immortalized human leiomyoma cells (HuLM) a potential therapy for uterine fibroids? SUMMARY ANSWER: Ad-SSTR-RGD-TK/GCV, a targeted adenovirus, effectively reduces cell growth in HuLM cells and to a significantly greater extent than in human uterine smooth muscle cells (UtSM). WHAT IS KNOWN ALREADY: Uterine fibroids (leiomyomas), a major cause of morbidity and the most common indication for hysterectomy in premenopausal women, are well-defined tumors, making gene therapy a suitable and potentially effective non-surgical approach for treatment. Transduction of uterine fibroid cells with adenoviral vectors such as Ad-TK/GCV (herpes simplex virus thymidine kinase gene) decreases cell proliferation. STUDY DESIGN, SIZE, DURATION: An in vitro cell culture method was set up to compare and test the efficacy of a modified adenovirus vector with different multiplicities of infection in two human immortalized cell lines for 5 days. PARTICIPANTS/MATERIALS, SETTING, METHODS: Immortalized human leiomyoma cells and human uterine smooth muscle cells were infected with different multiplicities of infection (MOI) (5-100 plaque-forming units (pfu)/cell) of a modified Ad-SSTR-RGD TK vector and subsequently treated with GCV. For comparison, HuLM and UtSM cells were transfected with Ad-TK/GCV and Ad-LacZ/GCV. Cell proliferation was measured using the CyQuant assay in both cell types. Additionally, western blotting was used to assess the expression of proteins responsible for regulating proliferation and apoptosis in the cells. MAIN RESULTS AND THE ROLE OF CHANCE: Transduction of HuLM cells with Ad-SSTR-RGD-TK/GCV at 5, 10, 50 and 100 pfu/cell decreased cell proliferation by 28, 33, 45, and 84%, respectively (P < 0.05) compared with untransfected cells, whereas cell proliferation in UtSM cells transfected with the same four MOIs of Ad-SSTR-RGD-TK/GCV compared with that of untransfected cells was decreased only by 8, 23, 25, and 28%, respectively (P < 0.01). Western blot analysis showed that, in comparison with the untargeted vector Ad-TK, Ad-SSTR-RGD-TK/GCV more effectively reduced expression of proteins that regulate the cell cycle (Cyclin D1) and proliferation (PCNA, Proliferating Cell Nuclear Antigen), and it induced expression of the apoptotic protein BAX, in HuLM cells. LIMITATIONS, REASONS FOR CAUTION: Results from this study need to be replicated in an appropriate animal model before testing this adenoviral vector in a human trial. WIDER IMPLICATIONS OF THE FINDINGS: Effective targeting of gene therapy to leiomyoma cells enhances its potential as a non-invasive treatment of uterine fibroids. PMID- 23820420 TI - The history of Belgian assisted reproduction technology cycle registration and control: a case study in reducing the incidence of multiple pregnancy. AB - STUDY QUESTION: What is the effect of a legal limitation of the number of embryos that can be transferred in an assisted reproductive technology (ART) cycle on the multiple delivery rate? SUMMARY ANSWER: The Belgian national register shows that the introduction of reimbursement of ART laboratory costs in July 2003, and the imposition of a legal limitation of the number of embryos transferred in the same year, were associated with a >50% reduction of the multiple pregnancy rate from 27 to 11% between 2003 and the last assessment in 2010, without any reduction of the pregnancy rate per cycle. WHAT IS KNOWN ALREADY: Individual Belgian IVF centres have published their results since the implementation of the law, and these show a decrease in the multiple pregnancy rate on a centre by centre basis. However, the overall national picture remains unpublished. STUDY DESIGN, SIZE, DURATION: Cohort study from 1990 to 2010 of all ART cycles in Belgium (2685 cycles in 1990 evolving to 19 110 cycles in 2010), with a retrospective analysis from 1990 to 2000 and prospective online data collection since 2001. PARTICIPANTS/MATERIALS, SETTING, METHODS: Registration evolved from paper written reports per centre to a compulsory online registration of all ART cycles. From 2001 up to mid-2009, data were collected from Excel spread sheets or MS Access files into an MS Access database. Since mid-2009, data collection is done via a remote and secured web-based system (www.belrap.be) where centres can upload their data and get immediate feedback about missing data, errors and inconsistencies. MAIN RESULTS AND THE ROLE OF CHANCE: National Belgian registration data show that reimbursement of IVF laboratory costs in July 2003, coupled to a legal limitation in the number of embryos transferred in utero, were associated with a 50% reduction of the multiple pregnancy rate from 27 to 11% without reduction of the pregnancy rate per cycle, and with an increase in the number of fresh and frozen ART cycles due to improved access to treatment. LIMITATIONS, REASONS FOR CAUTION: There is potential underreporting of complications of ART treatment, pregnancy outcome and neonatal health. WIDER IMPLICATIONS OF THE FINDINGS: Over the 20 years of registration, the pregnancy rate has remained constant, despite the reduction in the number of embryos transferred, optimization of laboratory procedures and stimulation protocols, introduction of quality systems and implementation of the EU Tissue Directive over the period 2004-2010. STUDY FUNDING/COMPETING INTEREST(S): No external funding was sought for this study. None of the authors has any conflict of interest to declare. PMID- 23820421 TI - Positive experiences of patient-centred care are associated with intentions to comply with fertility treatment: findings from the validation of the Portuguese version of the PCQ-Infertility tool. AB - STUDY QUESTION: Are positive experiences of different aspects of patient-centred care (PCC) associated with higher intentions to comply with fertility treatment? SUMMARY ANSWER: Positive experiences regarding information received, respect from staff about values and preferences, continuity in treatment and competence of staff are directly associated with higher compliance intentions, while positive experiences regarding accessibility to and involvement in the treatment and communication with staff are indirectly associated, via associations with less concerns about treatment. WHAT IS KNOWN ALREADY: The quality of infertility services can influence patients' intentions to comply with treatment. Patients cite negative care experiences as one of the main reasons why they discontinue treatment prematurely. Delivering PCC in routine infertility care is associated with higher quality of life and lower distress during treatment. STUDY DESIGN, SIZE, DURATION: In this cross-sectional study of 265 women and 83 men, we investigated first, the psychometric properties of the Portuguese version of the Patient-Centredness Questionnaire (PCQ)-Infertility tool, which assesses infertility PCC, and secondly, the associations between PCC and intentions to comply with treatment. PARTICIPANTS/MATERIALS, SETTING, METHODS: Men and women undergoing fertility diagnostic investigation or treatment at Portuguese fertility clinics were recruited online and in clinical setting. Participants filled out a socio-demographic and fertility data file and other questionnaires to assess PCC (PCQ-Infertility), intentions to comply with treatment (FertiQoL Persistence Scale), wellbeing (Anxiety and Depression subscales of the BSI and FertiQoL), concerns about treatment (CART Scale) and treatment tolerability (FertiQoL Tolerability Domain). MAIN RESULTS AND THE ROLE OF CHANCE: There were 265 women and 83 men who completed the questionnaires. The confirmatory factor analysis for the PCQ-Infertility indicated a good fit [X2 = 479.097; P < 0.001; comparative fit index = 0.929; root mean square error of approximation = 0.058 (0.051-0.065)]. All PCQ-Infertility dimensions showed good internal consistency (alpha >= 0.70, excepting for organization: alpha = 0.57). Information provision, respect for patients' values, continuity of care and competence of the team were directly associated with higher intentions to comply with treatment (r from 0.13 to 0.23). Greater accessibility, patient involvement and good communication were negatively associated with concerns about treatment (r from -0.14 to -0.16) and less concerns were associated with higher intentions to comply with treatment (r from -0.14 to -0.15). LIMITATIONS, REASONS FOR CAUTION: Of the sample, 49% were recruited online. Patients recruited online had higher education and were more likely to be undergoing assisted reproduction treatment and this could have influenced the ratings of PCC reported. We did not account for treatment prognosis factors and/or doctor censuring and this may have resulted in underestimation of the strength of associations reported involving compliance intentions. The cross-sectional design of the study does not allow for cause and effect analysis between the study variables. WIDER IMPLICATIONS OF THE FINDINGS: To promote treatment compliance, clinics should allow patients to establish stable relationships with a reference doctor who is competent and respectful of their interests and values and who provides them with the information they need. Clinics can also alleviate their patients' concerns regarding medical procedures by ensuring that these professionals are easily accessible, have good communication skills, and involve patients in the treatment process and associated decision-making. The Portuguese version of the PCQ-Infertility tool is valid and reliable. PMID- 23820422 TI - Expression of neuronal markers in the endometrium of women with and those without endometriosis. AB - STUDY QUESTION: How do the expression patterns of neuronal markers differ in the endometrium of women with and without endometriosis? SUMMARY ANSWER: The neuronal markers, PGP9.5, NGFp75 and VR1, are expressed in the endometrium at levels that do not differ between women with and without endometriosis. WHAT IS KNOWN ALREADY: Aberrant neuronal growth within the uterus may contribute to abnormal fertility and uterine dysfunction. However, controversy still exists as to whether aberrant innervation in the endometrium is associated with gynaecological pathology such as endometriosis. This may reflect the use of subjective methods such as histology to assess the innervation of the endometrium. We, therefore, employed a quantitative method, western blotting, to study markers of endometrial innervation in the presence and absence of endometriosis. STUDY DESIGN, SIZE, DURATION: This study included 45 women undergoing laparoscopic examination for the diagnosis of endometriosis. Endometrial samples were analysed by western blot for the expression of neuronal and neurotrophic markers, PGP9.5, VR1 and NGFp75. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Endometrial pipelle biopsies were obtained from patients with (n = 20, study group) and without (n = 25, control group) endometriosis. Tissue was analysed by immunohistochemistry and western blot analysis for the expression of pan-neuronal marker, PGP9.5, sensory nociceptive marker, TPVR1, and low-affinity neurotrophic growth factor receptor, NGFRp75. MAIN RESULTS AND THE ROLE OF CHANCE: PGP9.5, NGFp75 and VR1 were expressed in the endometrium of women, independent of the presence of endometriosis. Furthermore, the expression level of PGP9.5, VR1 and NGFp75 did not alter between the two cohorts of women. LIMITATIONS, REASONS FOR CAUTION: Studies of this nature are subject to the heterogeneous nature of patient population and tissue samples despite attempts to standardize these parameters. Hence, further studies using similar methodology will be required to confirm our results. WIDER IMPLICATIONS OF THE FINDINGS: Our results highlight that sensory neuronal markers are present in women with and without endometriosis. Future work will assess what the targets of the endometrial nerves are and investigate their function, their impact on endometrial biology and, in particular, whether aberrant neuronal function, rather than the mere presence of neuronal function, could be the root cause of subfertility and/or pain affecting many endometriosis sufferers. Our results do not, however, confirm the previous paradigm of increased innervation in the endometrium of women with endometriosis, nor the use of nerve cell detection from pipelle biopsies to diagnose endometriosis. PMID- 23820423 TI - Does unilateral laparoscopic diathermy adjusted to ovarian volume increase the chances of ovulation in women with polycystic ovary syndrome? AB - STUDY QUESTION: Does unilateral volume-adjusted laparoscopic diathermy increase the chances of ovulation in women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Although unilateral laparoscopic ovarian drilling (ULOD) using adjusted thermal doses was more efficient than bilateral laparoscopic ovarian drilling (BLOD) using fixed doses, the chances of ovulation were improved in patients irrespective of the technique used. WHAT IS KNOWN ALREADY: The adjustment of the thermal dose to ovarian volume in BLOD increases ovulation and pregnancy rates compared with fixed-dose treatment, but BLOD causes the formation of adhesions, particularly on the left ovary, and increases the risk of damage to ovarian tissue. In contrast, ULOD with a fixed thermal dose minimizes the risk of ovarian tissue damage, and can increase the activity in both right and left ovaries, although this varies in humans and in other species. STUDY DESIGN, SIZE, DURATION: This prospective, longitudinal, study, between September 2009 and January 2013, included 96 infertile women with PCOS who were unresponsive to clomiphene citrate treatment and had underwent either ULOD or BLOD. After surgery, the groups were followed up for 6 months to assess ovulatory response. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients were assigned to two groups; one group underwent laparoscopic ovarian drilling of the right ovary alone, while both ovaries were treated in the second group. The ULOD group (n = 49) received thermal doses adjusted to the volume of the right ovary (60 J/cm3). The BLOD group (n = 47) received fixed doses of 600 J per ovary, regardless of its volume. The two treatment groups were matched by the number of participants, age and baseline parameters. MAIN RESULTS AND THE ROLE OF CHANCE: The ovulation rate during the first menstrual cycle after LOD was significantly higher in the ULOD group than in the BLOD group [73 versus 49%; absolute risk reduction (ARR), 0.25; 95% confidence interval (CI), -0.44 to -0.03; P = 0.014]. Treatment with ULOD on the right ovary significantly increased the chances of ovulation in patients with a larger right ovary compared with those who had a smaller right ovary (100 versus 36%; ARR, -0.64; 95% CI, -0.84 to -0.37; P = 0.004). Interestingly, the chances of ovulation were also significantly higher in patients in the BLOD group who had a larger right ovary compared with those who had a smaller right ovary (88 versus 33%; ARR, -0.55; 95% CI, -0.73 to -0.28; P = 0.002). The pregnancy rate was also significantly higher in patients with a larger right ovary compared with those with a smaller right ovary, regardless of the treatment group. LIMITATIONS, REASONS FOR CAUTION: The 6-month follow-up was too short to demonstrate any long-term differences in the ovulation rates. Future research should therefore extend the follow-up beyond 6 months. Another limitation is that ULOD was used to treat only the right ovary. Future studies should investigate whether ULOD treatment of the larger ovary, whether left or right, would significantly increase the ovulation rate. WIDER IMPLICATIONS OF THE FINDINGS: This study represents an advance in the determination of the optimal laparoscopic treatment for women with PCOS, as it was shown that improved results can be achieved using less thermal energy in volume-adjusted ULOD. PMID- 23820424 TI - Sensorimotor control of vocal pitch production in Parkinson's disease. AB - The present study was designed to investigate the sensorimotor control of voice fundamental frequency (F0) in individuals with Parkinson's diseases (PD). Fifteen Cantonese individuals with PD, and fifteen age- and sex-matched healthy Cantonese individuals participated in the experiment. Participants were asked to vocalize a vowel sound while hearing their voice auditory feedback unexpectedly pitch shifted upwards or downwards through headphones. The size of pitch shifts varied from 50, 100, to 200 cents. One novel averaging method was used to categorize the individual trials such that only those trials that opposed the perturbation direction were averaged to generate an overall response. The results showed that Cantonese individuals with PD produced significantly larger magnitudes of vocal compensation for pitch perturbations than healthy participants. Both groups showed systematic changes in compensation magnitude as a function of perturbation size and direction: larger perturbation size or upward direction elicited greater compensation magnitude. Moreover, pitch variability indexed by the standard deviations of the baseline F0 was significantly correlated with the magnitude of vocal compensation in individuals with PD, whereas this correlation failed to reach significance for healthy participants. This study presents the first data demonstrating the abnormal processing of auditory feedback in the sensorimotor control of voice F0 for Cantonese individuals with PD. It is suggested that the abnormal sensorimotor integration of voice F0 control in PD may be caused by the increased weighting of auditory feedback control resulting from dysfunction of feedforward control and somatosensory feedback caused by the impairment of the basal ganglia. PMID- 23820425 TI - Early neurophysiological correlates of vocal versus non-vocal sound processing in adults. AB - Electrophysiological correlates of voice processing were studied in twenty adults by comparing auditory evoked potentials in response to voice and environmental sounds in passive condition. Both categories of stimuli elicited similar cortical auditory responses (i.e. N1, P2, N2 peaks); however these peaks were overlapped by two components specifically elicited by voice. The first component was evidenced as a positive deflection recorded over the fronto-temporal sites, and lateralized on the right hemiscalp. This fronto-temporal positivity to voice (FTPV) may constitute the electrophysiological counterpart of the activation of the temporal voice areas previously described in neuroimaging studies. The second component was recorded at occipito-temporo-parietal sites. This occipito-temporo parietal negativity to voice might correspond to visual mental imagery of the vocal sounds or to some form of mental simulation of the action sounds (e.g. coughing). Both components began as early as 70 ms post-stimulus onset indicating a rapid discrimination of voice in our auditory environment, which might be the basis of communication functions in humans. PMID- 23820426 TI - Ultrastructural and electrophysiological analysis of Area X in the untutored and deafened Bengalese finch in relation to normally reared birds. AB - Birdsong learning bears many similarities to human speech acquisition. Although the anterior forebrain pathway (AFP) is believed to be involved in birdsong learning, the underlying neural mechanisms are unclear. We produced two types of abnormal song learning: young birds untutored from adult "song tutors", or birds deafened by bilateral cochlear removal before the onset of sensory learning. We then studied how ultrastructure and electrophysiological activity changed in an AFP nucleus, Area X, among these birds at adulthood. Our results showed that, although the size of Area X did not change significantly, the numbers of synapses per unit area and compound synapses and the percent of concave synapses increased significantly in the untutored or deafened birds. The percent of perforated synapses or axo-spinous synapses decreased compared to the normally reared birds, suggesting a decreased efficiency of synaptic transmission in the untutored or deafened birds. We then identified several types of spontaneously firing cells in Area X. Cells with fast and slow firing rates did not show significant electrophysiological differences among the groups, but cells with moderate firing rates, most likely DLM-projecting neurons, fired at significantly lower rates in the untutored and deafened birds. In addition, cells firing irregularly were only found in the deafened birds. Thus, the decreased or irregular electrophysiological activity in the untutored or deafened birds, together with the corresponding ultrastructural findings, could be implicated in the abnormal song production in these two types of birds. PMID- 23820427 TI - Presence of Fe3+ and Zn2+ promoted biotransformation of Cd-citrate complex and removal of metals from solutions. AB - The promotion to Cd-citrate complex biotransformation via addition of Fe(3+) and Zn(2+) was investigated. Single Fe(III)- or Zn-citrate complex was completely degraded by Pseudomonas sp. MBR, Cd-citrate complex was not. In the Cd-citrate media with molar ratio of 1:2 and 1:3, pH increase obtained from the metabolism of excess citrate slightly promoted the biotransformation of Cd-citrate complex, Cd remained in solutions. The presence of Fe(3+) and Zn(2+) resulted in complete biotransformation of Cd-citrate complex in the 1:1:2 Fe:Cd:citrate and Zn:Cd:citrate and 1:1:1:3 Fe:Zn:Cd:citrate media. Alkaline pH obtained from biotransformation of metal-citrate complexes caused almost complete removal of metals (>98%) through precipitation and co-precipitation. Pseudomonas sp. MBR potentially could be used to treat wastewater containing mixed citrate complexes of Fe(III), Zn and Cd. PMID- 23820428 TI - CRISPR-Cas and restriction-modification systems are compatible and increase phage resistance. AB - Bacteria have developed a set of barriers to protect themselves against invaders such as phage and plasmid nucleic acids. Different prokaryotic defence systems exist and at least two of them directly target the incoming DNA: restriction modification (R-M) and CRISPR-Cas systems. On their own, they are imperfect barriers to invasion by foreign DNA. Here, we show that R-M and CRISPR-Cas systems are compatible and act together to increase the overall phage resistance of a bacterial cell by cleaving their respective target sites. Furthermore, we show that the specific methylation of phage DNA does not impair CRISPR-Cas acquisition or interference activities. Taken altogether, both mechanisms can be leveraged to decrease phage contaminations in processes relying on bacterial growth and/or fermentation. PMID- 23820429 TI - Effect of Mirasol pathogen reduction technology system on in vitro quality of MCS+ apheresis platelets. AB - Reducing the risk of pathogen transmission to transfusion recipients is one of the great concerns in transfusion medicine. Important among the measures suggested to minimise pathogen transmission is pathogen reduction technology (PRT) systems. The present study examined the effects of Mirasol PRT system on MCS+ apheresis platelets in vitro quality measures during a seven-day storage period at 22 degrees C. Statistical analysis indicated no significant difference in platelet concentrations between the control and treated platelet concentrates (PCs) during the storage period. Glucose and lactate levels were measured to determine metabolic activities of control and treated platelets. In both control and treated platelets, the amount of glucose consumed and lactate produced increased significantly with storage time, but glucose consumption and lactate production rates were significantly higher in treated platelets compared with control platelets. The mean pH of treated PCs was decreased at all time points relative to control PCs but remained within acceptable limits. The expression of P-selectin was also higher in Mirasol PRT treated platelets throughout the storage period, but differences were not statistically significant on Days 1 and 4. Finally, visual inspection of swirling indicated that Mirasol PRT treatment of platelets is associated with platelet shape change. Overall, our results show that MCS+ apheresis platelets treated with Mirasol PRT can preserve adequate in vitro properties for at least 5 days of storage. PMID- 23820430 TI - Plasma constituent integrity in pre-storage vs. post-storage riboflavin and UV light treatment--a comparative study. AB - Treatment of fresh frozen plasma (FFP) by riboflavin (RB) and ultraviolet (UV) light inhibits nucleic acid replication, leading to inactivation of white blood cells (WBCs) and pathogens. The goal of this study was to compare the effects of pathogen reduction technology (PRT) treatment on the plasma protein content based on biochemical, immune and hemostatic characteristics in "typical" pre-storage vs. post-storage PRT-treatment setting. Following whole blood centrifugation, separated plasma units were: (a) inactivated and frozen (pre-storage setting or control group [CG]) or (b) immediately frozen (post-storage setting or study group [SG]) afterward thawed, inactivated and stored at -40 +/- 5 degrees C (cryostorage). Plasma units were inactivated by the Mirasol PRT system (TerumoBCT, USA). Using multi-laboratory techniques and equipments, biochemistry (Advia 1800; Siemens, Germany), IgM, IgG and IgA, complement components C3 and C4 (BNA II nefelometer analyzer; Siemens, Germany), as well as CH50 activity (Behring coagulation timer; Siemens, Germany) were investigated. Procoagulant and inhibitor factors, such as antithrombin-III (AT-III), and protein C (PC) were determined by BCS XP Coagulation system (Siemens, Germany). There were neither significant changes in final protein levels, nor any differences in plasma immunoglobulin levels investigated. In the final samples CH50 activity was reduced in both investigated groups. The plasma concentration of the complement C3 following post-storage treatment was significantly (p<0.05) higher than in pre storage setting. There was a trend of depletion of procoagulant activities in both, pre-storage and post-storage PRT-treatment (initial vs. final values), but there were no significant differences between two groups. Results confirmed that AT-III was significantly higher after post-storage inactivation. In conclusion, this study confirmed that there were not clinically relevant intergroup (pre storage vs. post-storage PRT-treatment) differences in plasma constituent levels. Post-storage treated FFP remains, protein quantity, and activity well, and therefore can be used in clinical practice. Previously cryostored or quarantine FFP units (despite the reduced quarantine period after NAT/PCR testing) could be safely and effectively inactivated, directly prior to clinical application. PMID- 23820431 TI - Therapeutic plasma exchange in treatment of neuroimmunologic disorders: review of 92 cases. AB - Therapeutic plasma exchange (TPE) is a procedure that reduces amount of circulating antibodies in patients through filtration for the treatment of neurologic diseases in which autoimmunity plays a major role. We reviewed the medical records of 92 neurologic patients who had been consecutively treated by TPE between June 2000 and April 2011 at Ankara University School of Medicine, Neurology Department and The Apaheresis Center. Neurological indications included myastehia gravis (MG, 16 patients), Guillain-Barre syndrome (GBS, 37 patients) and miscellaneous diseases (39 patients). The median TPE session number was 5 with a range of 1-8; total number of TPE procedures in all cases was 454. All MG patients improved with TPE during their hospitalization time. Regarding GBS, nearly 67% of the patients improved early, during their hospitalization time, either. In our series, 25% of GBS cases died because of dysautonomia. TPE was not effective in the treatment of the patients with Lambert-Eaton myasthenic syndrome, paraneoplastic polineuropathy, toxic polineuropathy, mononeuropathy multiplex in the case series. During the TPE procedures, 4 patients had hypotension and total number of the procedures was 21 in those patients. One patient had urticaria in only one session of total 5 TPE procedures. Two patients had septicemia; the first one had 3 and the second had 5 TPE procedures; both septic cases died. In conclusion, TPE is an effective treatment in neurologic diseases that autoimmunity plays an important role in the pathogenesis. PMID- 23820432 TI - Safety improving by complementary serological and molecular testing combined with pathogen reduction of the donated blood in window period. PMID- 23820433 TI - Minneapolis bridges falling down: emergency transfusion preparedness. AB - The 7/1/2007 bridge collapse into the Mississippi River was instructional from both a disaster response and a mass casualty transfusion response perspective. It is a well cited example of how community disaster response coordination can work well, especially following systematic preparation of an integrated response network. The blood center is and should be an integral part of this disaster response and should be included in drills where appropriate. We give personal perspectives on both the hospital and transfusion service response to this particularly dramatic event. PMID- 23820434 TI - Beliefs underlying the intention to donate again among first-time blood donors who experience a mild adverse event. AB - Using the belief basis of the theory of planned behavior (TPB), the current study explored the rate of mild reactions reported by donors in relation to their first donation and the intention and beliefs of those donors with regard to returning to donate again. A high proportion of first-time donors indicated that they had experienced a reaction to blood donation. Further, donors who reacted were less likely to intend to return to donate. Regression analyses suggested that targeting different beliefs for those donors who had and had not reacted would yield most benefit in bolstering donors' intentions to remain donating. The findings provide insight into those messages that could be communicated via the mass media or in targeted communications to retain first-time donors who have experienced a mild vasovagal reaction. PMID- 23820435 TI - Molecular characterization of the Fy(a-b-) phenotype in a Polish family. AB - The Fy(a-b-) phenotype, very rare in Caucasians and defined by the homozygous FY(*)B-33 allele, is associated with the -33T>C mutation in the promoter region of the FY gene. The allele FY(*)X is correlated with weak expression of Fy(b) antigen due to 265C>T and 298G>A mutations in FY(*)B allele. The purpose of this study was molecular characterization of Fy blood group antigens in Fy(a-b-) members of a Polish family. High-resolution melting analysis was performed to detect single nucleotide polymorphisms in amplified fragments of the FY gene. The Fy(a-b-) phenotype in three siblings of the Polish family was caused by the FY(*)X/FY(*)B-33 genotype. PMID- 23820436 TI - In vivo visualization of the PICA perfusion territory with super-selective pseudo continuous arterial spin labeling MRI. AB - In this work a method is described to discern the perfusion territories in the cerebellum that are exclusively supplied by either or both vertebral arteries. In normal vascular anatomy the posterior inferior cerebellar artery (PICA) is supplied exclusively by its ipsilateral vertebral artery. The perfusion territories of the vertebral arteries were determined in 14 healthy subjects by means of a super-selective pseudo-continuous ASL sequence on a 3T MRI scanner. Data is presented to show the feasibility of determining the PICA perfusion territory. In 10 subjects it was possible to accurately determine both PICA perfusion territories. In two subjects it was possible to determine the perfusion territory of one PICA. Examples in which it was not possible to accurately determine the PICA territory are also given. Additionally, the high variability of the extent of the PICA territory is illustrated using a statistical map. The posterior surface of the cerebellum is entirely supplied by the PICA in six subjects. The most posterior part of the superior surface is supplied by the PICA in eight subjects, and the inferior half of the anterior surface in six subjects. The inferior part of the vermis is supplied by the PICA in all subjects. Two subjects were found with interhemispheric blood flow to both tonsils from one PICA without contribution from the contralateral PICA. With the method as presented, clinicians may in the future accurately classify cerebellar infarcts according to affected perfusion territories, which might be helpful in the decision whether a stenosis should be considered symptomatic. PMID- 23820437 TI - Philippines brain drain: fact or fiction? PMID- 23820438 TI - Glioblastoma in a former Chernobyl resident 24 years later. PMID- 23820439 TI - Unprepared. PMID- 23820440 TI - Legislation ignores benefits of safe injection sites, say doctors. PMID- 23820441 TI - Deployment-related mental disorders among Canadian Forces personnel deployed in support of the mission in Afghanistan, 2001-2008. AB - BACKGROUND: The conflict in Afghanistan has exposed more Canadian Forces personnel to a greater degree of adversity than at any time in recent memory. We determined the incidence of Afghanistan deployment-related mental disorders and associated risk factors among personnel previously deployed in support of this mission. METHODS: The study population consisted of 30,513 Canadian Forces personnel who began a deployment in support of the mission in Afghanistan before Jan. 1, 2009. The primary outcome was a mental disorder perceived by a Canadian Forces clinician to be related to the Afghanistan deployment. Data on diagnoses and perceptions were abstracted from medical records of a stratified random sample of 2014 personnel. Sample design weights were used in all analyses to generate descriptive statistics for the entire study population. RESULTS: Over a median follow-up of 1364 days, 13.5% (95% confidence interval [CI] 12.1%-14.8%) of the study population had a mental disorder that was attributed to the Afghanistan deployment. Posttraumatic stress disorder was the most common diagnosis (in 8.0%, 95% CI 7.0%-9.0%, of personnel). Deployment to higher-threat locations, service in the Canadian Army and lower rank were independent risk factors associated with an Afghanistan-related diagnosis (e.g., hazard ratio for deployment to Kandahar Province 5.6, 95% CI 2.6-12.5, relative to deployment to the United Arab Emirates). In contrast, sex, Reserve Forces status, multiple deployments and deployment length were not independent risk factors. INTERPRETATION: An important minority of Canadian Forces personnel deployed in support of the Afghanistan mission had a diagnosis of a mental disorder perceived to be related to the deployment. Determining long-term outcomes is an important next step. PMID- 23820442 TI - Report criticized federal drug-control policies. PMID- 23820443 TI - Dual-energy x-ray absorptiometry in obesity. PMID- 23820444 TI - Reproductive health experts warn women not to abandon birth control. PMID- 23820445 TI - New medical marijuana regulations shift onus to doctors to prescribe. PMID- 23820446 TI - Silencing of PrP C (prion protein) expression does not affect Brucella melitensis infection in human derived microglia cells. AB - Cellular prion proteins (PrP(C)) are mainly expressed in the central nervous system where they have antioxidant effects and a role in the endocytosis of bacteria within cells. These proteins also have some crucial biological functions including roles in neurotransmission, signal transduction and programmed cell death. However, the role of prion proteins in neuronal Brucella infection, specifically in the interaction of the pathogen and the host cell is controversial. In the present study, the silencing of PrP(C) mRNA by small interfering RNA (siRNA) transfection was investigated in human microglia cells infected with Brucella melitensis. More than 70% of prion proteins were down regulated in microglia by siRNA transfection and this caused a slight decrease in the cellular viability of the control cells. Silencing of PrP(C) suppressed the antioxidant systems, though it led to an up-regulation of pro-inflammatory cytokines such as IL-12 and TNF-alpha as demonstrated by qRT-PCR analysis. B. melitensis infection of prion protein-silenced cells led to increase host viability, but had no effect on bacterial phagocytosis. According to the present study, there is no significant effect of prion proteins on phagocytosis and intracellular killing of B. melitensis in microglia cells. PMID- 23820447 TI - Polymorphism in PGLYRP-1 gene by PCR-RFLP and its association with somatic cell score in Chinese Holstein. AB - Bovine peptidoglycan recognition protein 1 (PGLYRP-1), an important pattern recognition molecule (PRM) of the innate immune system, is an effector molecule in killing different microorganisms directly. To investigate whether the PGLYRP-1 gene was associated with mastitis and milk production traits in dairy cattle, the polymorphism of this gene was analyzed by PCR-RFLP in a population of 524 Chinese Holstein. A total of ten single nucleotide polymorphism (SNP) loci were identified. The association analysis of single SNP locus showed that T-35A, T-12G and G+102C were significantly associated (P<0.05) with somatic cell score (SCS), while G+102C and G+649C were significantly associated (P<0.05) with 305-day milk yield. Association analysis between combined haplotypes and SCS, milk production traits indicated that H3H3 was associated with the lower SCS (P<0.01), and H2H2 was associated with the lower 305-day milk yield (P<0.01). These findings demonstrated that polymorphisms in PGLYRP-1 gene associated with mastitis resistance and 305-day milk yield, and the H3H3 would provide a useful genetic marker of combined haplotypes for mastitis resistance selection and breeding in Chinese Holstein. PMID- 23820448 TI - Can we predict a favourable response to Ketogenic Diet Therapies for drug resistant epilepsy? AB - Ketogenic Dietary Therapies (KDT) are an effective treatment option for some people with drug-resistant epilepsy. They are, however, resource-intensive and can cause adverse side effects. Predictors of response would improve the selection process and perhaps further our understanding of the mechanisms behind dietary treatments for epilepsy. We conducted a literature review to identify factors that may influence response to KDT. We found no strong evidence that there are any specific factors that affect response. Gender and intellectual status do not seem to affect response; evidence is inconsistent for all other factors. Experimental studies may point us in the right direction for future work. PMID- 23820449 TI - Relationships between frontal-plane angular momentum and clinical balance measures during post-stroke hemiparetic walking. AB - Stroke has significant impact on dynamic balance during locomotion, with a 73% incidence rate for falls post-stroke. Current clinical assessments often rely on tasks and/or questionnaires that relate to the statistical probability of falls and provide little insight into the mechanisms that impair dynamic balance. Current quantitative measures that assess medial-lateral balance performance do not consider the angular motion of the body, which can be particularly impaired after stroke. Current control methods in bipedal robotics rely on the regulation of angular momentum (H) to maintain dynamic balance during locomotion. This study tests whether frontal-plane H is significantly correlated to clinical balance tests that could be used to provide a detailed assessment of medial-lateral balance impairments in hemiparetic gait. H was measured in post-stroke (n=48) and control (n=20) subjects. Post-stroke there were significant negative relationships between the change in frontal-plane H during paretic single-leg stance and two clinical tests: the Dynamic Gait Index (DGI) (r=-0.57, p<0.001) and the Berg Balance Scale (BBS) (r=-0.54, p<0.001). Control subjects showed timely regulation of frontal-plane H during the first half of single-leg stance, with the level of regulation depending on the initial magnitude. In contrast, the post-stroke subjects who made poorer adjustments to frontal-plane H during initial paretic leg single stance exhibited lower DGI and BBS scores (r=0.45, p=0.003). We conclude that H is a promising balance indicator during steady-state hemiparetic walking and that paretic single-leg stance is a period with higher instability for stroke patients. PMID- 23820450 TI - Neostigmine product for NMBA reversal approved by FDA. PMID- 23820451 TI - FDA advisers favor easing rosiglitazone restrictions. PMID- 23820453 TI - Synchronized prescription fills improve patients' medication adherence. PMID- 23820454 TI - Oklahoma community recovers through pharmacists' help. PMID- 23820455 TI - Fenugreek use in patients with diabetes mellitus. PMID- 23820456 TI - Vemurafenib and ipilimumab: new agents for metastatic melanoma. AB - PURPOSE: The development and place in therapy of vemurafenib and ipilimumab for the treatment of metastatic melanoma are reviewed. SUMMARY: Vemurafenib is an adenosine triphosphate-competitive, reversible, and highly selective BRAF kinase inhibitor targeted at BRAF-V600E and is a first-line option for patients with BRAF-mutation-positive disease. Vemurafenib has clinically significant antitumor activity in metastatic melanoma, and response rates and overall and progression free survival rates are improved when compared with dacarbazine. Responses also occur quickly, often within days to weeks of starting treatment. Disadvantages of vemurafenib include the short duration of response; significant skin toxicities, including skin cancers and severe photosensitivity; the need for long-term daily administration; and the potential for drug interactions. Ipilimumab is a fully human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen 4 to enhance and prolong T-cell responses to elicit antitumor activity. Clinical trials have demonstrated the superiority of ipilimumab in terms of overall survival when compared with an immune stimulator and placebo. While the rate of response to ipilimumab is low, responses tended to be more durable than those achieved with vemurafenib. A disadvantage of ipilimumab is that a response may require months, making ipilimumab inappropriate as monotherapy for patients with symptomatic disease. Additional disadvantages are the adverse-effect profile and the requirement of enrollment in the risk evaluation and mitigation strategy program. CONCLUSION: Vemurafenib and ipilimumab are important advances in the treatment of metastatic melanoma. Benefit is typically short lived for vemurafenib and uncommon for ipilimumab. Neither agent is curative, and clinical trials remain an alternative first-line treatment option. PMID- 23820457 TI - An integrated approach to research and manuscript development. AB - PURPOSE: A stepwise process for planning, writing, and submitting a research manuscript to a peer-reviewed journal is described. SUMMARY: The research project and writing-related activities should be conducted concurrently along a clear timeline developed with input from all members of the writing team. Issues of conformance to standards of scholarly publishing (e.g., ordering of the author list, contributor acknowledgments, disclosure statements) should be resolved and agreed on by all authors before manuscript development begins. After deciding on an appropriate hypothesis or research question, members of the writing team should meet to craft a detailed manuscript outline and identify a target journal. In addition to writing or coordinating the writing of the various manuscript sections, one designated team member (typically the lead, or primary, author) should be responsible for ensuring consistency of data presentation and overall article cohesion. Before submitting the manuscript to a journal, the writing team should solicit internal and external review and feedback from colleagues with expertise in statistical analysis and the research topic. Once an article is accepted by a journal, the corresponding author has primary responsibility for communicating with editors and coordinating the team's response to peer reviewer concerns and requests for revisions. CONCLUSION: The process of writing and securing journal acceptance of manuscripts should proceed along a well-defined pathway integrating all research and writing tasks. Close adherence to the target journal's instructions for authors and prompt response to reviewer comments help avoid delays in the publication of accepted articles. PMID- 23820458 TI - Fenofibrate-associated nephrotoxicity: a review of current evidence. AB - PURPOSE: The literature describing fenofibrate-associated nephrotoxicity was reviewed. SUMMARY: Fenofibrate-associated nephrotoxicity is an underrecognized adverse effect that is being reported with increasing frequency in the medical literature. A MEDLINE search identified articles describing fenofibrate associated nephrotoxicity. Two retrospective chart reviews reported this adverse reaction in transplant recipients and patients with renal insufficiency. A case series of six patients noted that the adverse reaction also occurred in patients without a predisposition to renal injury. Two small prospective studies have examined fenofibrate-associated nephrotoxicity, with conflicting findings regarding the mechanism. Finally, a large retrospective review and a population based cohort study found that patients with preexisting renal disease or taking high-dosage fenofibrate have a higher risk of developing fenofibrate-associated nephrotoxicity. Fenofibrate-associated nephrotoxicity was shown to be reversible with both discontinuation and continued use of fenofibrate, though one study found that the elevations in serum creatinine (SCr) levels were permanent in study participants. Some argue that SCr elevations described in these articles were not due to renal toxicity but may be attributed to reversible mechanisms. While several mechanisms may be biologically plausible, none of the theories have been tested in clinical trials. A possible mechanism for the increase in SCr levels may include changes in renal hemodynamics causing volume depletion and the impairment of generation of vasodilatory prostaglandins, leading to renal vasoconstriction. CONCLUSION: Fenofibrate-associated nephrotoxicity is an underrecognized adverse drug reaction. Several published reports have detailed possible etiologies; however, data detailing the true incidence of fenofibrate associated nephrotoxicity and its associated risk factors are limited. PMID- 23820459 TI - Apparent lisinopril overdose requiring hemodialysis. AB - PURPOSE: A case of apparent overdose of angiotensin-converting-enzyme inhibitors requiring hemodialysis is reported. SUMMARY: A 51-year-old white man (weight, 85 kg; height, 178 cm; body mass index, 28) with a history of hypertension, low back pain, and anxiety apparently took 27 lisinopril 10-mg tablets (3.18 mg/kg body weight) over a period of 3 or fewer days. The friend who brought him to the emergency department reported that the patient was hard to rouse and was speaking incoherently on the day of admission. Over the previous few days, the patient reportedly had visual hallucinations, incoherence, and inarticulate speech. Laboratory tests, electrocardiography, and computed tomography were performed. The patient was judged to have high-anion-gap metabolic acidosis, acute kidney injury, severe hyperkalemia, and rhabdomyolysis. He was given three doses of albuterol via a nebulizer, three doses of calcium gluconate 1 g i.v., two doses of sodium bicarbonate 100 meq i.v., two doses of sodium polystyrene sulfonate 30 g orally, three doses of insulin 10 units i.v., and three doses of dextrose 25 g (as 50% dextrose injection) i.v. He then underwent emergent hemodialysis and was admitted to the intensive care unit. The patient's confusion abated, kidney function improved, and acid-base and electrolyte imbalances resolved. The patient was discharged after 15 days. CONCLUSION: A man who had evidently taken an overdose of lisinopril had multiorgan dysfunction in the absence of hypotension. The abnormalities resolved after he was treated for acidosis and hyperkalemia and received hemodialysis to remove the lisinopril. PMID- 23820460 TI - Relative bioavailability of tolvaptan administered via nasogastric tube and tolvaptan tablets swallowed intact. AB - PURPOSE: The bioavailability of a crushed tolvaptan tablet suspended in water and administered by nasogastric (NG) tube was compared to the bioavailability from the tablet administered whole. METHODS: In a randomized crossover study, 28 healthy adults received a single 15-mg dose of tolvaptan on two occasions (one dose given as an intact tablet swallowed whole and the other as a crushed tablet in suspension given by NG tube), with a washout interval of >=7 days. During each administration period, blood samples were collected at 15 time points over 36 hours. A validated liquid chromatography-tandem mass spectrometry assay was used to obtain plasma tolvaptan concentrations. Plasma tolvaptan time-concentration data were analyzed using noncompartmental methods, and pharmacokinetic data including maximum concentration (Cmax), time to Cmax (tmax), area under the concentration-time curve (AUC) from time zero to the time of the last measurable concentration (AUCt), and AUC extrapolated to infinity (AUCinfinity) resulting from oral and NG tube tolvaptan delivery were compared via repeated-measures, mixed-effects analysis of variance. Due to differences in total drug exposure seen, an in vitro experiment was conducted on three dose levels to quantify drug sequestration. RESULTS: The ratios of geometric mean Cmax, AUCt, and AUCinfinity values (expressed as a percentage) with NG tube versus oral tolvaptan administration were 88.9%, 74.3%, and 74.2%, respectively; the latter two values were not within the specified bioequivalence tolerance limits (80-125%). In vitro analysis showed that approximately 11% of all tolvaptan doses evaluated was sequestered by the NG tube. CONCLUSION: In healthy adults, a single 15-mg dose of tolvaptan administered as a crushed tablet suspended in water by NG tube resulted in AUCt and AUCinfinity values that were approximately 25% lower than those observed after oral administration of a 15-mg tolvaptan tablet swallowed intact. PMID- 23820461 TI - Economic impact of ambulatory care formulary restrictions at a large county health system. AB - PURPOSE: Study results documenting substantial cost savings achieved by an outpatient indigent-care pharmacy program through formulary modifications and optimized purchasing practices are presented. METHODS: Wholesale purchasing data were retrospectively evaluated to compare drug expenditures before and after a large Florida hospital's adoption of a tiered formulary system for three ambulatory care facilities serving mostly uninsured patients. The outcomes assessed included the average cost per prescription and total medication purchases before and after implementation of the tiered formulary, which was phased in over several months and accompanied by intensive educational programs targeting physicians and pharmacy staff. Other outcomes included cost avoidance resulting from an increased emphasis on patient assistance program (PAP) enrollment and the use of "bulk replacement" arrangements for prescription replenishment. RESULTS: During a designated nine-month postimplementation period, the average cost per prescription declined by 4.7% (from $19.86 to $18.92) relative to the baseline value. Six-month spending decreases of 36-58% from prior year levels were achieved in 7 of the 10 most-purchased drug classes, with an overall 25% decline in medication purchases. Cost avoidance due to more aggressive use of PAPs and bulk replacement programs also yielded substantial program savings. CONCLUSION: Formulary streamlining and other cost-control initiatives at an outpatient pharmacy program were associated with a decrease in the average cost per prescription of $0.94 over a nine-month period. The primary endpoint showed a potential annualized savings of approximately $1 million. PMID- 23820462 TI - Biological contamination of insulin pens in a hospital setting. AB - PURPOSE: Biological contamination of insulin pens in a hospital setting was studied. METHODS: This prospective study, conducted at two hospitals within a multihospital system, examined 125 insulin pens that had been returned to the inpatient pharmacies after patient discharge and were refrigerated for up to 48 hours before laboratory testing. Insulin was removed from the 125 pens and examined microscopically for the presence of nucleated cells and red blood cells (RBCs). Positive samples were examined by a pathologist to determine the cell types present. An immunochromatographic assay was used to determine the presence of free hemoglobin in the insulin. The 10 control samples were negative on microscopic examination. RESULTS: Out of 125 insulin pens, 7 (5.6%) tested positive for cells or hemoglobin. Microscopic examination revealed six positive samples containing a total of nine cells, including macrophages, squamous cells, and an RBC. The sample containing the RBC was not the same sample that tested positive for hemoglobin. Based on findings of intact cells and hemoglobin in insulin pens after administration, the potential exists for transmission of infectious agents from patient to patient if a single pen cartridge is used to administer insulin to multiple patients, even if a new needle is used for each individual. CONCLUSION: Examination of 125 insulin pens used in hospitals revealed hemoglobin in 1 pen and at least one cell in another 6 pens. The nine detected cells consisted of four squamous epithelial cells, four macrophages, and one RBC. PMID- 23820463 TI - Preapproval and postapproval availability of published comparative efficacy research on biological agents. AB - PURPOSE: Preapproval and postapproval availability of published comparative efficacy studies on biological agents approved between 2000 and 2010 was investigated. METHODS: Approval packages published on the Food and Drug Administration (FDA) website were examined for all biological agents approved between 2000 and 2010 to determine if comparative efficacy studies were available at the time of FDA approval. The availability of comparative efficacy studies published subsequent to approval was determined by searching PubMed for randomized, active-controlled experimental or observational study designs that measured efficacy as the primary endpoint and were relevant to the original FDA approved indication. RESULTS: From 2000 to 2010, 107 biological agents were approved by FDA. Of the biological agents with alternative treatments, 54.6% had comparative efficacy data available at the time of approval. Although standard reviewed biological agents were more likely to have comparative efficacy trials included in the FDA approval packages than priority-reviewed biological agents, statistically significant differences are unlikely. Subsequent to approval, 58.1% of biological agents had at least one published comparative efficacy trial, representing a 3.5% absolute increase in the availability of comparative efficacy studies since the time of approval. Vaccines and biological agents in the hematologic diseases, oncology, and miscellaneous diseases classes had fewer published postapproval comparative efficacy studies per agent compared with the overall group of biological agents. CONCLUSION: Nearly half of all biological agents approved for marketing between 2000 and 2010 lacked publicly accessible, active-controlled efficacy studies at the time of drug approval; a slightly greater proportion of biological agents had comparative efficacy data published subsequent to their approval. PMID- 23820464 TI - Cannabis use is associated with increased CCL11 plasma levels in young healthy volunteers. AB - Cannabis is a widely used recreational drug. Its effect on human health and psychosis remains controversial. In this study, we aimed to explore the possibility that cannabis use influenced CCL11 plasma levels. Increased CCL11 chemokine has been reported in schizophrenia and cannabis is a known trigger of schizophrenia. Additionally, plasma levels of the chemokine CCL11 have recently been shown to increase with age and with cognitive deficits and hippocampal neurogenesis. For this study, a total of 87 healthy volunteers (68% men, age range 18-35 years) completed the Cannabis Experience Questionnaire that included information on sociodemographic and morphometric data and provided a blood sample for CCL11 measurement. 'Current users' of cannabis (n=18) had significantly higher CCL11 plasma levels compared to 'past users' (n=33) and 'never users' (n=36) [F(3,84)=3.649; p=0.030]. The latter two groups had similar CCL11 levels. Higher CCL11 plasma levels could not be attributed to gender, age, body mass index, physical activity or use of other legal/illegal drugs. These results suggest that cannabis use increases CCL11 plasma levels and the effects are reversible when cannabis use ceases. PMID- 23820465 TI - Promising operational stability of high-efficiency organic light-emitting diodes based on thermally activated delayed fluorescence. AB - Organic light-emitting diodes (OLEDs) are attractive for next-generation displays and lighting applications because of their potential for high electroluminescence (EL) efficiency, flexibility and low-cost manufacture. Although phosphorescent emitters containing rare metals such as iridium or platinum produce devices with high EL efficiency, these metals are expensive and their blue emission remains unreliable for practical applications. Recently, a new route to high EL efficiency using materials that emit through thermally activated delayed fluorescence (TADF) was demonstrated. However, it is unclear whether devices that emit through TADF, which originates from the contributions of triplet excitons, are reliable. Here we demonstrate highly efficient, stable OLEDs that emit via TADF by controlling the position of the carrier recombination zone, resulting in projected lifetimes comparable to those of tris(2-phenylpyridinato)iridium(III) based reference OLEDs. Our results indicate that TADF is intrinsically stable under electrical excitation and optimization of the surrounding materials will enhance device reliability. PMID- 23820466 TI - Context for practice: evolving evidence and the desire to be told what to do. PMID- 23820467 TI - Looking back: a review of classic ostomy literature in the WOCN society's official publication. AB - In recognition of the 40-year anniversary of the Journal of Wound, Ostomy and Continence Nursing, a review of ostomy-related articles in the Society's official publications was done. The goal was to find what were considered classic ostomy articles, articles that contributed to the practice of ostomy care nursing, and articles that as clinicians practicing in the late 70s we felt helped to shape the future of ostomy care nursing. The review began with the 1975 ET Journal and continued forward ending in 1990. A classic article was defined as one that described a new or unique use of an ostomy product, a new procedure that impacted ostomy practice, the evolution of evidence-based ostomy practice, concepts that would drive our future practice, and management of stoma complications. These articles are a glimpse into the unique, creative, and evolving practice that makes our ostomy specialty distinctive. PMID- 23820468 TI - Urinary incontinence severity and quality-of-life instruments. PMID- 23820469 TI - WOC nursing practice in the home care setting: a view from here. PMID- 23820470 TI - The economic impact of complex wound care on home health agencies. AB - The cost of care for home health clients with complicated wounds frequently exceeds reimbursement received from Medicare and other payer sources. As a result, home health agencies may be reluctant to accept this type of referral. Many of the costs associated with complex wound care can be substantially reduced by appropriate use of expensive therapies and dressings and establishment of a cost-effective wound care formulary. Costs can also be reduced by collaboration with prescribing providers to ensure that orders are written generically, and avoid unnecessary nursing visits. Knowledgeable WOC nurses can play a critical role in coordinating care that is both clinically and fiscally effective. This article reviews common challenges in caring for complex wounds in the home care setting with a focus on strategies the prescribing provider and wound care clinician can use to optimize outcomes. PMID- 23820471 TI - Knowledge deficits and information-seeking behavior in leg ulcer patients: an exploratory qualitative study. AB - PURPOSE: The aim of this study was to explore knowledge deficits and underlying processes in information-seeking behavior in patients with leg ulcers. METHOD: A qualitative approach based on grounded theory methods with constant comparison was used. Semistructured interviews were held with 15 patients with venous leg ulcers in community care settings and wound care clinics between October 2008 and June 2009. Data processing and data analysis occurred via a cyclic process. RESULTS: Patients did not express a clear understanding of the causes of ulcers or their own contribution to enhance leg ulcer healing. They often lacked knowledge about relevant lifestyle advice and its relationship to healing or recurrence. During the leg ulcer trajectory, different leg ulcer perceptions were present: the ulcer as a trifle, the ulcer as a wound not healing on its own and making everyday life impossible, the ulcer as a skin problem, and the ulcer as a chronic condition. These perceptions defined patients' actions in leg ulcer care. CONCLUSION: Leg ulcer patients often have inadequate knowledge of their condition and related lifestyle advice. Patients require greater knowledge about their condition before they can understand their treatment and recognize their role in promoting healing. PMID- 23820472 TI - The incidence of stoma and peristomal complications during the first 3 months after ostomy creation. AB - PURPOSE: The purpose of this study was to examine stoma and peristomal complications and related variables among adults with ostomies. The primary study aim was to determine the incidence of peristomal and stoma complications during the first 3 months after stoma creation. DESIGN: Data were collected using a prospective, repeated-measures descriptive study design. SUBJECTS AND SETTING: Data were collected at 2 university-based hospitals with outpatient ostomy clinics in the Midwestern United States. The sample included 43 adults with newly created colostomy, ileostomy, or urostomy stomas. METHODS: Participants were examined for the presence of complications up to 4 times during a 3-month period: within 7 days of surgery. Patients were also evaluated at 2, 6, and 12 weeks after stoma creation. Data were collected using a validated instrument with acceptable interrater reliability. RESULTS: Peristomal skin complications developed in 27 participants, comprising 63% of the sample. The onset of peristomal skin complications occurred most frequently during the 21- to 40-day time period. The most common skin conditions at nearly all time intervals were irritation (peristomal moisture-associated skin damage) and infection. Of the 18 participants observed 70 days or longer, just 7 (38%) remained free of peristomal skin complications throughout the study. Six participants developed 1 or more stoma complications, all of which occurred 20 or more days after surgery. No demographic or clinical factors were found to be associated with the development of complications. CONCLUSIONS: Although the participants were evaluated at regular intervals by a specialized nurse, the majority experienced peristomal skin complications. These results underscore the importance of further work in interventions to prevent and treat peristomal skin complications and to provide ongoing outpatient follow-up to individuals with stomas. PMID- 23820473 TI - Learning to live with a permanent intestinal ostomy: impact on everyday life and educational needs. AB - PURPOSE: The aim of the study was to explore the impact of a permanent stoma on patients' everyday lives and to gain further insight into their need for ostomy related education. SUBJECTS AND SETTING: The sample population comprised 15 persons with permanent ostomies. Stomas were created to manage colorectal cancer or inflammatory bowel disease. The research setting was the surgical department at a hospital in the Capitol Region of Denmark associated with the University of Copenhagen. METHODS: Focus group interviews were conducted using a phenomenological hermeneutic approach. Data were collected and analyzed using qualitative content analysis. RESULTS: Stoma creation led to feelings of stigma, worries about disclosure, a need for control and self-imposed limits. Furthermore, patients experienced difficulties identifying their new lives with their lives before surgery. Participants stated they need to be seen as a whole person, to have close contact with health care professionals, and receive trustworthy information about life with an ostomy. Respondents proposed group sessions conducted after hospital discharge. They further recommended that sessions be delivered by lay teachers who had a stoma themselves. CONCLUSIONS: Self-imposed isolation was often selected as a strategy for avoiding disclosing the presence of a stoma. Patient education, using health promotional methods, should take the settings into account and patients' possibility of effective knowledge transfer. Respondents recommend involvement of lay teachers, who have a stoma, and group-based learning processes are proposed, when planning and conducting patient education. PMID- 23820474 TI - Tied to the toilet: lived experiences of altered bowel function (anterior resection syndrome) after temporary stoma reversal. AB - PURPOSE: The purpose of this study was to explore the lived experiences of patients with anterior resection syndrome, defined as altered bowel function as a consequence of rectal cancer treatment. Interviews were completed 4 to 6 weeks post-temporary stoma reversal. SUBJECTS AND SETTING: Eight rectal cancer patients, who had completed their primary treatment, and were now up to 6 weeks poststoma closure and reported altered bowel function, were recruited. The sample was drawn from St. Mark's Hospital, which is an NHS Trust situated in Greater London, England. METHODS: Data were collected via semistructured in-depth interviews. A Husserlian phenomenological approach was used in order to explore the lived experiences of respondents. Interviews were transcribed and analyzed using framework analysis. RESULTS: Participants reported significant alteration in bowel function following stoma reversal that impacted or dictated daily routines. A lack of certainty over when and how bowel movements occurred caused distress and feelings of vulnerability. Consequently respondents stated they often felt as if they were tied to the toilet. Coping strategies included conservative measures such as the use of prescribed drugs, dietary modification, and incontinence pads. These strategies did not always prove effective and most individuals perceived they were not self-managing their symptoms satisfactorily. CONCLUSIONS: Rectal cancer patients should be made aware of the potential for altered bowel function post stoma closure and encouraged to report bothersome bowel elimination symptoms. Treatment should promote a proactive strategy to reduce distress and the risk of symptom chronicity. PMID- 23820475 TI - Critical Thinking WOCNCB APN Examination. AB - EDITOR'S NOTE: This feature from the WOCNCB is linked to supplemental digital content (Supplemental Digital content 1, http://links.lww.com/JWOCN/A21) discussing the use of critical thinking when taking a WOCNCB examination. PMID- 23820476 TI - Cardboard tube technique for ostomy wafer placement and management of peristomal skin with persistent output. AB - BACKGROUND: Managing a stoma with persistent output presents challenges for both the WOC nurse and the patient. Traditional approaches are not always effective. Presenting a new and different way to assist people with pouching in such circumstances or when they have dexterity or visual problems, increases the options at our disposal and may improve the quality of life for those able to use this technique. CASE: The study of a 72-year-old man experiencing difficulties managing his ileostomy due to persistent output and a new onset of tremors is described. The cardboard tube technique provided a simple, cost-effective method of applying an ostomy pouch and treating peristomal skin breakdown in the presence of persistent output from the ostomy. CONCLUSION: Use of a simple cardboard tube was effective in maintaining this patient's independence in care. PMID- 23820479 TI - THEMIS and PTPRK in celiac intestinal mucosa: coexpression in disease and after in vitro gliadin challenge. AB - Celiac disease (CD) is an immune mediated, polygenic disorder, where HLA-DQ2/DQ8 alleles contribute around 35% to genetic risk, but several other genes are also involved. Genome-wide association studies (GWASs) and the more recent immunochip genotyping projects have fine-mapped 39 regions of genetic susceptibility to the disease, most of which harbor candidate genes that could participate in this disease process. We focused our attention to the GWAS peak on chr6: 127.99-128.38 Mb, a region including two genes, thymocyte-expressed molecule involved in selection (THEMIS) and protein tyrosine phosphatase, receptor type, kappa (PTPRK), both of which have immune-related functions. The aim of this work was to evaluate the expression levels of these two genes in duodenal mucosa of active and treated CD patients and in controls, and to determine whether SNPs (rs802734, rs55743914, rs72975916, rs10484718 and rs9491896) associated with CD have any influence on gene expression. THEMIS showed higher expression in active CD compared with treated patients and controls, whereas PTPRK showed lower expression. Our study confirmed the association of this region with CD in our population, but only the genotype of rs802734 showed some influence in the expression of THEMIS. On the other hand, we found a significant positive correlation between THEMIS and PTPRK mRNA levels in CD patients but not in controls. Our results suggest a possible role for both candidate genes in CD pathogenesis and the existence of complex, regulatory relationships that reside in the vast non-coding, functional intergenic regions of the genome. Further investigation is needed to clarify the impact of the disease-associated SNPs on gene function. PMID- 23820481 TI - Valgus slipped capital femoral epiphysis: subcapital growth plate orientation analysis. AB - The aim of the study was to determine the risk factors of unusual, lateral direction of epiphyseal displacement in primarily unilateral slipped capital femoral epiphysis (SCFE) patients with a special focus on radiological parameters of an unaffected hip. A total of 115 patients (75 boys, 40 girls), mean age 13.2 years (8.4-18.6), were analyzed. The mean follow-up time was 11 years (2-29). The proportion of valgus slip among SCFE patients was 11 of 115 cases (9.6%). The patients with valgus slip compared with the classic ones were predominantly females (55 vs. 33%), were younger (11.1 vs. 13.4 years), had a greater epiphyseal-shaft angle (67.4 vs. 59.1 degrees ), smaller displacement in the frontal plane (absolute value 6.7 vs. 15 degrees ), and a lower risk of contralateral slip (27 vs. 65%). There was no difference in the neck-shaft angle and epiphyseal-neck angle value. A more horizontal orientation of the subcapital growth plate, assessed by epiphyseal-shaft angle, can be considered a conducive factor in the valgus direction of epiphyseal slip in SCFE. In valgus SCFE cases, there is a smaller degree of epiphyseal displacement in both the sagittal and the coronal plane and a lower risk of consecutive contralateral slip. PMID- 23820480 TI - Clinical utility gene card for: Beckwith-Wiedemann Syndrome. PMID- 23820482 TI - Rib osteoblastoma as an incidental finding in a patient with adolescent idiopathic scoliosis: a case report. AB - The purpose of this article is to present an unreported case of rib osteoblastoma associated with progressive adolescent idiopathic scoliosis and to discuss thoracogenic scoliosis as a potential cause of curve progression after tumor resection. An 11-year and 8-month-old girl with adolescent idiopathic scoliosis was referred with an incidental finding of an expansile lesion in the posterior left seventh rib. A computed tomography-guided needle biopsy established the diagnosis of benign osteoblastoma. Transarterial embolization was performed followed by wide resection. Sixteen months after surgery the patient underwent posterior spinal fusion to address her scoliosis progression during the growth spurt. Forty-one and 25 months after rib resection and spinal fusion, respectively, the patient remains asymptomatic, without local tumor recurrence, and with excellent correction of her spinal deformity. Although scoliosis secondary to rib osteoblastoma has been described in the literature, rib osteoblastoma may coexist with idiopathic scoliosis. In such a case, surgical management of osteoblastoma should not interfere with treatment of idiopathic scoliosis. PMID- 23820483 TI - A novel cobalt tetranitrophthalocyanine/graphene composite assembled by an in situ solvothermal synthesis method as a highly efficient electrocatalyst for the oxygen reduction reaction in alkaline medium. AB - A novel micro/nano-composite, based on cobalt(II) tetranitrophthalocyanine (CoTNPc) grown on poly(sodium-p-styrenesulfonate) modified graphene (PGr), as a non-noble-metal catalyst for the oxygen reduction reaction (ORR), is fabricated by an in situ solvothermal synthesis method. The CoTNPc/PGr is characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), ultraviolet-visible (UV-vis) absorption spectroscopy, Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS), respectively. The electrocatalytic activity of the CoTNPc/PGr composite toward the ORR is evaluated using cyclic voltammetry and linear sweep voltammetry methods. The CoTNPc/PGr composite exhibits an unexpected, surprisingly high ORR activity compared to CoTNPc or PGr. The onset potential for ORR on CoTNPc/PGr is found to be around 0.10 V vs. SCE in 0.1 M NaOH solution, which is 30 mV and 70 mV more positive than that on PGr and CoTNPc, respectively. The peak current density on CoTNPc/PGr is about 2 times than that on PGr and CoTNPc, respectively. Rotating disk electrode (RDE) measurements reveal that the ORR mechanism is nearly via a four electron pathway on CoTNPc/PGr. The current density for ORR on CoTNPc/PGr still remains 69.9% of its initial value after chronoamperometric measurements for 24 h. Pt/C catalyst, on the other hand, only retains 13.3% of its initial current. The peak potential shifts slightly and current barely changes when 3 M methanol is added. The fabricated composite catalyst for ORR displays high activity, good stability and excellent tolerance to the crossover effect, which may be used as a promising Pt-free catalyst in alkaline direct methanol fuel cells (DMFCs). PMID- 23820484 TI - Insights into the role of DNA methylation in diatoms by genome-wide profiling in Phaeodactylum tricornutum. AB - DNA cytosine methylation is a widely conserved epigenetic mark in eukaryotes that appears to have critical roles in the regulation of genome structure and transcription. Genome-wide methylation maps have so far only been established from the supergroups Archaeplastida and Unikont. Here we report the first whole genome methylome from a stramenopile, the marine model diatom Phaeodactylum tricornutum. Around 6% of the genome is intermittently methylated in a mosaic pattern. We find extensive methylation in transposable elements. We also detect methylation in over 320 genes. Extensive gene methylation correlates strongly with transcriptional silencing and differential expression under specific conditions. By contrast, we find that genes with partial methylation tend to be constitutively expressed. These patterns contrast with those found previously in other eukaryotes. By going beyond plants, animals and fungi, this stramenopile methylome adds significantly to our understanding of the evolution of DNA methylation in eukaryotes. PMID- 23820485 TI - Predictors of outcome in hypoglycemic encephalopathy. AB - AIMS: The aim of this study was to investigate factors predicting poor prognosis in patients with hypoglycemic encephalopathy. METHODS: We retrospectively analyzed data on 165 consecutive patients with hypoglycemic encephalopathy. We evaluated their outcome 1 week after hypoglycemia onset using the Glasgow outcome scale (GOS) and compared the clinical features of patients with good outcomes (GOS = 5) and poor outcomes (GOS <= 4). RESULTS: The poor-outcome group included 38 patients (23%). The initial blood glucose level in the poor-outcome group was lower than that in the good-outcome group (p = 0.002). The duration of hypoglycemia in the poor-outcome group was longer than that in the good-outcome group (p < 0.001). Body temperature during hypoglycemia in the poor-outcome group was higher than that in the good-outcome group (p < 0.001). Furthermore, lactic acid level in the poor-outcome group was lower than in the good-outcome group (p = 0.032). There was no significant difference in the frequency of posttreatment hyperglycemia between the good-outcome and poor-outcome groups (p = 0.984). CONCLUSION: Profound and prolonged hypoglycemia, normal or higher body temperature, and a low lactic acid level during hypoglycemia may be predictors of a poor outcome in patients with hypoglycemic encephalopathy. PMID- 23820486 TI - The incidence of severe hypoglycaemia in pregnant women with type 1 diabetes mellitus can be reduced with unchanged HbA1c levels and pregnancy outcomes in a routine care setting. AB - AIMS: To investigate whether the incidence of severe hypoglycaemia in pregnant women with type 1 diabetes can be reduced without deteriorating HbA1c levels or pregnancy outcomes in a routine care setting. METHODS: Two cohorts (2004-2006; n=108 and 2009-2011; n=104) were compared. In between the cohorts a focused intervention including education of caregivers and patients in preventing hypoglycaemia was implemented. Women were included at median 8 (range 5-13) weeks. Severe hypoglycaemia (requiring assistance from others) was prospectively reported in structured interviews. RESULTS: In the first vs. second cohort, severe hypoglycaemia during pregnancy occurred in 45% vs. 23%, p=0.0006, corresponding to incidences of 2.5 vs. 1.6 events/patient-year, p=0.04. Unconsciousness and/or convulsions occurred at 24% vs. 8% of events. Glucagon and/or glucose injections were given at 15% vs. 5% of events. At inclusion HbA1c was comparable between the cohorts while in the second cohort fewer women reported impaired hypoglycaemia awareness (56% vs. 36%, p=0.0006), insulin dose in women on multiple daily injections was lower (0.77 IU/kg (0.4-1.7) vs. 0.65 (0.2-1.4), p=0.0006) and more women were on insulin analogues (rapid-acting 44% vs. 97%, p<0.0001; long-acting 6% vs. 76%, p<0.0001) and insulin pumps (5% vs. 23%, p<0.0001). Pregnancy outcomes were similar in the two cohorts. CONCLUSIONS: A 36% reduction in the incidence of severe hypoglycaemia in pregnancy with unchanged HbA1c levels and pregnancy outcomes was observed after implementation of focused intervention against severe hypoglycaemia in a routine care setting. Improved insulin treatment, increased health professional education and fewer women with impaired hypoglycaemia awareness may contribute. PMID- 23820487 TI - Reflections on thermoelectrics. PMID- 23820488 TI - Dissipative feedback does not improve the optimal resolution of incoherent force detection. PMID- 23820489 TI - Nanobots today. PMID- 23820491 TI - Plasmonic lasers: A sense of direction. PMID- 23820492 TI - Nanomechanics: Sensing from the bottom up. PMID- 23820493 TI - Sensors: Good vibrations for bad bacteria. PMID- 23820494 TI - Spintronics: Chiral domain walls move faster. PMID- 23820495 TI - Comments on ''Effect of the surface free energy on the behaviour of surface and guided waves", by V. Vlasie Belloncle, M. Rousseau, Ultrasonics, 45 (2006) 188 195. AB - In this short communication, it is demonstrated that the main results obtained by the authors of the commented paper, ''Effect of the surface free energy on the behaviour of surface and guided waves", by V. Vlasie Belloncle, M. Rousseau Ultrasonics, 45 (2006) 188-195, have been well-established long before publication of this paper. Therefore, the claim to novelty asserted by the authors is incorrect. PMID- 23820496 TI - Spatial memory impairment and changes in hippocampal morphology are triggered by high-fat diets in adolescent mice. Is there a role of leptin? AB - Recent evidence has established that consumption of high-fat diets (HFD) is associated with deficits in hippocampus-dependent memory. Adolescence is an important period for shaping learning and memory acquisition that could be particularly sensitive to the detrimental effects of HFD. In the current study we have administered this kind of diets to both adolescent (5-week old) and young adult (8-week old) male C57BL mice during 8 weeks and we have evaluated its effect on (i) spatial memory performance in the novel location recognition (NLR) paradigm, and (ii) spine density and neural cell adhesion molecule (NCAM) expression in hippocampal CA1 pyramidal neurons. In order to characterize the eventual involvement of central leptin receptors we have also investigated the functionality of leptin receptors within the hippocampus. Here we report that animals that started to consume HFD during the adolescence were less efficient than their control counterparts in performing spatial memory tasks. In contrast to that, mice that were submitted to HFD during the young adult period displayed intact performance in the NLR test. In mice receiving HFD from the adolescence, the behavioral impairment was accompanied by an increase of dendritic spine density in CA1 pyramidal neurons that correlated with the up-regulation of neural cell adhesion molecule (NCAM) in this area. Deficits in spatial memory occurred concomitantly with a desensitization of the proteinkinase B (Akt) pathway coupled to hippocampal leptin receptors. In contrast, the STAT3 pathway remained unaffected by HFD. All effects of HFD were long-lasting because they remained intact even after 5 weeks of food restriction. Our results provide further evidence of the susceptibility of the hippocampus to HFD in adolescent individuals and suggest that leptin signaling integrity in this brain area is pivotal for memory performance. PMID- 23820497 TI - Impacts of fullerene derivatives on regulating the structure and assembly of collagen molecules. AB - During cancer development, the fibrous layers surrounding the tumor surface get thin and stiff which facilitates the tumor metastasis. After the treatment of metallofullerene derivatives Gd@C82(OH)22, the fibrous layers become thicker and softer, the metastasis of tumor is then largely suppressed. The effect of Gd@C82(OH)22 was found to be related to their direct interaction with collagen and the resulting impact on the structure of collagen fibrils, the major component of extracellular matrices. In this work we study the interaction of Gd@C82(OH)22 with collagen by molecular dynamics simulations. We find that Gd@C82(OH)22 can enhance the rigidity of the native structure of collagen molecules and promote the formation of an oligomer or a microfibril. The interaction with Gd@C82(OH)22 may regulate further the assembly of collagen fibrils and change the biophysical properties of collagen. The control run with fullerene derivatives C60(OH)24 also indicates that C60(OH)24 can influence the structure and assembly of collagen molecules as well, but to a lesser degree. Both fullerene derivatives can form hydrogen bonds with multiple collagen molecules acting as a "fullerenol-mediated bridge" that enhance the interaction within or among collagen molecules. Compared to C60(OH)24, the interaction of Gd@C82(OH)22 with collagen is stronger, resulting in particular biomedical effects for regulating the biophysical properties of collagen fibrils. PMID- 23820498 TI - Hepatitis B virus in the Arab world: where do we stand? AB - The epidemiology of viral hepatitis is of great importance for planning and managing health provision for all the countries in the Arab world. However, data on viral hepatitis are not readily available in a large percentage of Arab countries. Hepatitis B virus (HBV) is considered to be one of the most important causes of chronic hepatitis, cirrhosis and hepatocellular carcinoma. A systematic electronic search of published literature was conducted to extract data on epidemiology and risk factors for the analysis of HBV infection among the countries in the Arab world. The prevalence of chronic HBV infection was found to be decreasing in some Arab countries although it was still unacceptably high. This was particularly evident in the Arabian Gulf region, in Lebanon, Egypt and Libya. The age-specific prevalence varied from country to country with decline in prevalence being noted among children in the Gulf States and among Libyan women. These declines in prevalence are most likely to be related to the Expanded Immunization Programme. The alarmingly high prevalence of chronically infected patients in some areas and the widespread differences in HBV prevalence between Arab nations may be explained by the variation in risk factors involved. This situation calls for targeted approaches to tackle HBV-related mortality and morbidity. Precise HBV infection prevalence data are needed at the national and the sub-national level to estimate the disease burden, guide health intervention programmes and evaluate vaccine efficiency. PMID- 23820499 TI - Role of fibroscan and APRI in detection of liver fibrosis: a systematic review and meta-analysis. AB - BACKGROUND AND STUDY AIMS: Fibroscan and APRI are promising noninvasive alternatives to liver biopsy for detecting hepatic fibrosis. However, their overall test performance in various settings remains questionable. The aim of our study was to perform a systematic review and meta-analysis of diagnostic accuracy studies comparing fibroscan and APRI with liver biopsy for hepatic fibrosis. PATIENTS AND METHODS: Electronic and manual bibliographic searches to identify potential studies were performed. Selection of studies was based on reported accuracy of fibroscan and APRI compared with liver biopsy. Data extraction was performed independently by two reviewers. Meta-analysis combined the sensitivities, specificities, and likelihood ratios of individual studies. Extent and reasons for heterogeneity were assessed. RESULTS: 23 studies for fibroscan and 20 studies for APRI in full publication were identified. For patients with stage IV fibrosis (cirrhosis), the pooled estimates for sensitivity of fibroscan were 83.4% (95% confidence interval [CI], 71.7-95.0%) and specificity 92.4% (95% CI, 85.6-99.2%). For patients with stage IV fibrosis (cirrhosis), the pooled estimates for sensitivity of APRI at cutoff point of 1.5 were 66.5% (95% CI, 25.0 100%) and specificity 71.7% (95% CI, 35.0-100%). Diagnostic threshold bias was identified as an important cause of heterogeneity for pooled results in both patient groups. CONCLUSIONS: Fibroscan and APRI appear to be clinically useful tests for detecting cirrhosis however not useful tools in early stages of fibrosis. PMID- 23820500 TI - Screening for Barrett's oesophagus with oesophageal capsule endoscopy in first degree relatives of patients affected by Barrett's oesophagus: results of a pilot study. AB - BACKGROUND AND STUDY AIMS: Barrett's oesophagus (BE) is one of the complications of gastro-oesophageal reflux disease (GERD). Oesophageal capsule endoscopy (ECE) has been proposed as a non-invasive investigation of oesophageal pathology. The aims were to evaluate the diagnostic yield of ECE in first-degree relatives of patients with BE and reflux symptoms and to assess prospectively the prevalence of BE in these conditions. PATIENTS AND METHODS: Inclusion criteria were familial history of at least one first-degree relative with BE and typical reflux syndrome. Patients underwent ECE followed by oesophagogastroduodenoscopy (EGD). The ECE findings were compared with those during EGD. RESULTS: Between February and October 2009, 18 patients were enrolled. Oesophagitis and endoscopically suspected oesophageal metaplasia (ESEM) were present, at ECE, in 7 and 11 patients, respectively. Intestinal metaplasia was histologically confirmed in eight patients. Sensitivity and specificity of ECE were, respectively, 86% and 91%, for oesophagitis, and 100% and 70% for ESEM; positive predictive value (PPV) and negative predictive value (NPV) were 86% and 91%, respectively, for oesophagitis and 73% and 100%, respectively, for ESEM. Prevalence of BE was 44%. CONCLUSION: ECE showed an optimal NPV for BE detection. Pending confirmation of these results, ECE could be proposed as a screening test in symptomatic relatives of patients with BE. PMID- 23820501 TI - Effect of Helicobacter pylori eradication on glycaemia control in patients with type 2 diabetes mellitus and comparison of two therapeutic regimens. AB - BACKGROUND AND STUDY AIMS: The eradication rate of Helicobacter pylori (H. pylori) has been reported as being lower in patients with type 2 diabetes mellitus (DM) than in those without DM. The aim of the study was to assess the efficacy of the two H. pylori eradication regimens in patients without and with type 2 DM and to study the effect of H. pylori treatment on glycaemia control. PATIENTS AND METHODS: A total of 93 consecutive type 2 DM (non-insulin users) and 98 non-diabetic age- and sex-matched patients were enrolled. Patients were randomly assigned to one of the two treatment protocols all given twice daily: (a) a 14-day quadruple therapy comprising of omeprazole 20mg, metronidazole 500mg, amoxicillin 1g and bismuth subcitrate 240mg (OMAB) and (b) a 14-day triple regimen comprising of omeprazole 20mg plus clarithromycin 500mg and amoxicillin 1g (OCA). Cure was defined as a negative (13)C-urea breath test at least 6weeks after treatment. RESULTS: The H. pylori eradication rate with the OCA regimen was 63% in patients with type 2 DM (non-insulin users) and 87.7% in the control group (p=0.017). The H. pylori eradication rate with the OMAB regimen was 38.2% in patients with type 2 DM and 55.1% in the control group (p<0.001). Mean decrease of fasting plasma glucose and HbA1c level shows no statistically significant difference after H. pylori eradication. CONCLUSION: This study suggests that the eradication rate of H. pylori with OCA or OMAB treatment is lower in patients with type 2 diabetes than in non-diabetics and H. pylori treatment in patients with type 2 DM has no role in the control of the glycaemia. The triple therapy (OCA) is superior to the quadruple protocol (OMAB) in H. pylori eradication of both DM and non-DM cases. PMID- 23820502 TI - Serotonin transporter gene polymorphisms in Southwestern Iranian patients with irritable bowel syndrome. AB - BACKGROUND AND STUDY AIMS: Irritable bowel syndrome is a common chronic functional gastrointestinal disorder of unknown etiology. Serotonin is an important factor in sensory signaling in the brain-gut axis, which plays a key role in intestinal motility and secretion. Serotonin clearance is mediated by a specific protein called the serotonin reuptake transporter. Transcription activity of the serotonin transporter gene is affected by some polymorphisms in this gene. The aim of this study was to investigate the relationship between serotonin transporter gene polymorphisms and irritable bowel syndrome. PATIENTS/MATERIAL AND METHODS: The 5-HTTLPR, rs25531 and STin2VNTR polymorphisms of the serotonin transporter gene were analyzed by PCR-based methods in 50 patients with irritable bowel syndrome and 100 healthy controls. RESULTS: Serotonin transporter polymorphisms were similar in patients and healthy controls. There were no significant differences in allele or genotype frequencies between the two groups. CONCLUSION: Our findings suggest that polymorphisms in the gene encoding for the serotonin transporter are not associated with irritable bowel syndrome. Interactions between environmental factors and predisposing genetic factors are important in the pathophysiology of irritable bowel syndrome, and further genetic and epigenetic research may provide novel insights into the mechanisms contributing to this disease. PMID- 23820503 TI - Predictors of early re-bleeding and mortality after acute variceal haemorrhage. AB - BACKGROUND AND STUDY AIMS: Oesophageal variceal haemorrhage is a devastating complication of portal hypertension (PHT). This study was done to determine the risk factors for re-bleeding within 5 days and mortality up to 6 weeks in patients with cirrhosis and acute variceal haemorrhage (AVH). PATIENTS AND METHODS: The study included 100 patients presenting with haematemesis and/or melena due to bleeding varices. All patients were subjected to full clinical assessment, routine laboratory investigations, calculation of the Child-Turcotte Pugh (CTP) and model for end stage liver disease (MELD) scores, abdominal ultrasound and emergency upper gastrointestinal endoscopy. The patients were followed up since admission and up to 6 weeks for the occurrence of rebleeding (in the first 5days) and mortality (up to 6weeks) after the acute attack. RESULTS: The patients were grouped into three groups: Group I: patients who survived more than 6 weeks following endoscopic management and did not rebleed during this period (75 patients). Group II: patients who died within 6 weeks of AVH (10 patients). Group III: patients who rebled or died within 5 days of AVH (15 patients). The mean MELD score was significantly higher in group II (18.29+/ 0.66) and group III (18.73+/-0.89) as compared to group I (12.8+/-2.1) (p=0.001). Active bleeding at time of endoscopy was present in 8% of group I, 70% of group II and 53.3% of group III and the difference was statistically significant (p=0.003), while white nipple sign was present in 10.6% of group I, 90% of group II and 73.3% of group III and the difference was statistically significant (p=0.05). In conclusion high MELD score (>18), presence of active bleeding or white nipple sign at time of endoscopy are significant predictors for early rebleeding and mortality after AVH. PMID- 23820504 TI - Evaluation of the diagnostic value of serum and tissue apoptotic cytokeratin-18 in patients with chronic hepatitis C. AB - BACKGROUND AND STUDY AIMS: Hepatitis C virus (HCV) is considered the most common aetiology of chronic liver disease (CLD) in Egypt. The disease severity ranges from mild illness to cirrhosis and hepatocellular carcinoma. A role for apoptosis in liver damage caused by HCV chronic infection has been suggested. Cytokeratin 18 (CK-18) is the major intermediate filament protein in the liver and is a known caspase substrate in hepatocyte apoptosis. Therefore, we analysed the serum and tissue levels of CK-18 in patients with chronic HCV infection to evaluate its role in hepatocyte apoptosis. We also correlated CK-18 expression with the severity of hepatic pathology. PATIENTS AND METHODS: This study examined 80 Egyptian patients with liver disease. There were 69 patients with chronic hepatitis C and 11 patients with hepatitis C-induced cirrhotic changes. Fifteen healthy controls were also included in the study. The levels of CK-18 fragment were quantified in paired serum and liver biopsy samples. RESULTS: The serum and tissue CK-18 levels were reduced in chronic HCV patients compared to early cirrhosis patients. This result indicates that serum levels of CK-18 and the hepatic expression of CK-18 might play an important role in disease progression. The serum and tissue levels of CK-18 were significantly increased and directly correlated with inflammation severity, stage of fibrosis, and ALT levels in the chronic HCV group and the cirrhotic liver group. There was no significant difference in viral load between patient cohorts. CONCLUSION: The serum level and the hepatic expression of CK-18 are related to disease activity and are directly correlated with METAVIR scoring. This result suggests that serum CK-18 levels may be useful for monitoring disease activity in chronic HCV and liver cirrhosis patients. PMID- 23820505 TI - Response and seroconversion rates among HBeAg-positive chronic HBV Egyptian patients treated with peginterferon alpha 2a (Pegasys), a single-centre experience. AB - BACKGROUND AND STUDY AIMS: We aimed to evaluate the therapeutic efficacy of pegylated interferon alpha-2a 180MUg as a treatment for hepatitis B 'e' antigen (HBeAg)-positive genotype D chronic hepatitis B patients. PATIENTS AND METHODS: Thirty patients attending the outpatient clinic at the National Hepatology and Tropical Medicine Research Institute were treated with peg.interferon alpha-2a (180MUg) weekly for a period of 48 weeks. Pre-enrolment assessment was performed through biochemical, serological and quantitative HBV DNA testing. Liver biopsy was performed in all patients. Evaluation was done at weeks 12, 24 and 48 of treatment by liver enzymes, complete blood count (CBC), HBeAg/HBeAb and quantitative HBV DNA testing. RESULTS: At the end of 48 weeks of treatment only three cases (10%) of the study population showed HBeAg seroconversion and an undetectable HBV DNA level. None of responders exhibited hepatitis B surface antigen (HbsAg) loss. There were five (16.7%) primary non-responders, four (13.3%) relapsers, four (13.3%) cases flared at week 12, and 14 (46.6%) cases who were non-responders. No specific predictors of response could be identified among patients. CONCLUSION: One year of peg. interferon alpha-2a 180MUg weekly led to HBeAg seroconversion and an undetectable HBV DNA level in 10% of cases. Considering the privilege of a finite duration of treatment, tailoring of treatment and proper patient selection is of great importance in considering this therapy as a first line of treatment among HBeAg-positive chronic HBV Egyptian patients. PMID- 23820506 TI - Serological markers of inflammatory bowel disease in children from the Western region of Saudi Arabia. AB - BACKGROUND AND STUDY AIMS: Serological markers including peri-nuclear anti neutrophil cytoplasmic antibodies (pANCA) and anti-Saccharomyces cerevisiae antibodies (ASCA) have been reported in relation to inflammatory bowel disease (IBD). The aim of this study was to ascertain the prevalence and diagnostic accuracy of pANCA and ASCA antibodies in Saudi children with IBD. PATIENTS AND METHODS: A retrospective case-control study of children with IBD seen at King Abdulaziz University Hospital, Jeddah, between September 2002 and February 2012. RESULTS: The study included 131 patients with IBD (86 Crohn's disease (CD) and 45 ulcerative colitis (UC)) and 67 non-IBD control subjects. Females comprised 51% of CD, 60% of UC and 52% of non-IBD controls. The mean age was 10.7+/-5.2years for CD, 8.9+/-5years for UC, and 11.2+/-6.8years for the non-IBD controls. Positive ASCA-IgA and ASCA-IgG were detected in 35.8% and 35% of CD patients and in 5.8% and 3.7% of the non-IBD controls, respectively. The pANCA was detected in 28.9% of UC patients and in none of the non-IBD controls. The pANCA recognised the myeloperoxidase (MPO) antibody in 36.4% of the patients with UC. No significant difference in the frequency of pANCA between extensive disease and disease limited to the rectosigmoid colon (p=0.48), and no significant difference in the ASCAs antibodies in patients with or without involvement of the terminal ileum (p=0.81). CONCLUSION: The prevalence of ASCA and pANCA antibodies was low in Saudi children with IBD. Therefore, it may not be useful as a screening tool for IBD but it may be employed to aid the diagnosis in clinically suspected cases. PMID- 23820507 TI - Shedding light on a painful rash. AB - We present a case of a rare inherited disorder--erythropoietic protoporphyria- with typical clinical manifestations. The diagnosis was suspected on the basis of a history of a light-sensitive rash and characteristic liver biopsy, and confirmed with genetic testing. The patient was followed up for more than 20 years, and ultimately developed the uncommon associated complication of liver cirrhosis. The clinical features, pathogenesis and management of erythropoietic protoporphyria are discussed herein. PMID- 23820508 TI - Portal vein thrombosis resulting from tubercular lymphadenitis: an unusual scenario. PMID- 23820509 TI - Severe respiratory syndromes: travel history matters. AB - History of travel or contact is an important clue to emerging infections. Common and novel respiratory viruses can occasionally cause epidemics of viral pneumonitis with severe acute respiratory symptoms (sars). In 2003, World Health Organisation (WHO) coined the word SARS for Severe Acute Respiratory Syndrome in patients with a relevant travel/contact history and sars. The WHO case definition of suspected SARS was fever, respiratory symptoms and close contact with SARS patients or travel history to an epidemic area. The clinical features are essentially the same as for any respiratory viral infections or pneumonitis. Since 2003, many new surveillance guidelines and confusing abbreviations appeared in the city of Hong Kong. In 2012, another outbreak of coronavirus pneumonitis occurred in the Middle-East. More case definitions such as MERS (Middle East Respiratory Syndrome) and SARI (Severe Acute Respiratory Infections) were coined for the viral pneumonitis. In medicine, a definition or syndrome representing "a constellation of symptomatology seen in association" should stand the trial of time after it is coined. Health organisations should provide consistent definitions for index surveillance, epidemiological and prognostication studies. Travel or contact history is pivotal in formulating management protocol during any outbreak when the pathogen is not initially clear. PMID- 23820510 TI - The task force that rescues stalled ribosomes in bacteria. AB - In bacteria, the main quality control mechanism for rescuing ribosomes that have arrested during translation is trans-translation, performed by transfer-mRNA (tmRNA) associated with small protein B (SmpB). Intriguingly, this very elegant mechanism is not always necessary to maintain cell viability, suggesting the existence of alternatives. Other rescue systems have recently been discovered, revealing a far more complicated story than expected. These include the alternative ribosome rescue factors ArfA and ArfB, the elongation factors EF4 and EF-P, the peptidyl-tRNA hydrolase Pth, and several protein synthesis factors. These discoveries make it possible to describe a large network of factors dedicated to ribosome rescue, thus ensuring cell survival during stresses that induce ribosome stalling. PMID- 23820511 TI - Hollow microporous organic capsules. AB - Fabrication of hollow microporous organic capsules (HMOCs) could be very useful because of their hollow and porous morphology, which combines the advantages of both microporous organic polymers and non-porous nanocapsules. They can be used as storage materials or reaction chambers while supplying the necessary path for the design of controlled uptake/release systems. Herein, the synthesis of HMOCs with high surface area through facile emulsion polymerization and hypercrosslinking reactions, is described. Due to their tailored porous structure, these capsules possessed high drug loading efficiency, zero-order drug release kinetics and are also demonstrated to be used as nanoscale reactors for the prepareation of nanoparticles (NPs) without any external stabilizer. Moreover, owing to their intrinsic biocompatibility and fluorescence, these capsules exhibit promising prospect for biomedical applications. PMID- 23820512 TI - The GlycoFilter: a simple and comprehensive sample preparation platform for proteomics, N-glycomics and glycosylation site assignment. AB - Current strategies to study N-glycoproteins in complex samples are often discrete, focusing on either N-glycans or N-glycosites enriched by sugar-based techniques. In this study we report a simple and rapid sample preparation platform, the GlycoFilter, which allows a comprehensive characterization of N glycans, N-glycosites, and proteins in a single workflow. Both PNGase F catalyzed de-N-glycosylation and trypsin digestions are accelerated by microwave irradiation and performed sequentially in a single spin filter. Both N-glycans and peptides (including de-N-glycosylated peptides) are separately collected by filtration. The condition to effectively collect complex and heterogeneous N glycans was established on model glycoproteins, bovine ribonuclease B, bovine fetuin, and human serum IgG. With this platform, the N-glycome, N-glycoproteome and proteome of human urine and plasma were characterized. Overall, a total of 865 and 295 N-glycosites were identified from three pairs of urine and plasma samples, respectively. Many sites were defined unambiguously as partially occupied by the detection of their nonsugar-modified peptides (128 from urine and 61 from plasma), demonstrating that partial occupancy of N-glycosylation occurs frequently. Given the likely high prevalence and variability of partial occupancy, glycoprotein quantification based exclusively on deglycosylated peptides may lead to inaccurate quantification. PMID- 23820513 TI - Maximizing peptide identification events in proteomic workflows using data dependent acquisition (DDA). AB - Current analytical strategies for collecting proteomic data using data-dependent acquisition (DDA) are limited by the low analytical reproducibility of the method. Proteomic discovery efforts that exploit the benefits of DDA, such as providing peptide sequence information, but that enable improved analytical reproducibility, represent an ideal scenario for maximizing measureable peptide identifications in "shotgun"-type proteomic studies. Therefore, we propose an analytical workflow combining DDA with retention time aligned extracted ion chromatogram (XIC) areas obtained from high mass accuracy MS1 data acquired in parallel. We applied this workflow to the analyses of sample matrixes prepared from mouse blood plasma and brain tissues and observed increases in peptide detection of up to 30.5% due to the comparison of peptide MS1 XIC areas following retention time alignment of co-identified peptides. Furthermore, we show that the approach is quantitative using peptide standards diluted into a complex matrix. These data revealed that peptide MS1 XIC areas provide linear response of over three orders of magnitude down to low femtomole (fmol) levels. These findings argue that augmenting "shotgun" proteomic workflows with retention time alignment of peptide identifications and comparative analyses of corresponding peptide MS1 XIC areas improve the analytical performance of global proteomic discovery methods using DDA. PMID- 23820514 TI - Socioeconomic deprivation increases the effect of winter on admissions to hospital with COPD: retrospective analysis of 10 years of national hospitalisation data. AB - BACKGROUND: Admission to hospital with chronic obstructive pulmonary disease (COPD) is associated with deprivation and season. However, it is not known whether deprivation and seasonality act synergistically to influence the risk of hospital admission with COPD. AIMS: To investigate whether the relationship between season/temperature and admission to hospital with COPD differs with deprivation. METHODS: All COPD admissions (ICD10 codes J40-J44 and J47) were obtained for the decade 2001-2010 for all Scottish residents by month of admission and 2009 Scottish Index of Multiple Deprivation (SIMD) quintile. Confidence intervals for rates and absolute differences in rates were calculated and the proportion of risk during winter attributable to main effects and interactions were estimated. Monthly rates of admission by average daily minimum temperatures were plotted for each quintile of SIMD. RESULTS: Absolute differences in admission rates between winter and summer increased with greater deprivation. In the most deprived quintile, in winter 19.4% (95% CI 17.3% to 21.4%) of admissions were attributable to season/deprivation interaction, 61.2% (95% CI 59.5% to 63.0%) to deprivation alone, and 5.2% (95% CI 4.3% to 6.0%) to winter alone. Lower average daily minimum temperatures over a month were associated with higher admission rates, with stronger associations evident in the more deprived quintiles. CONCLUSIONS: Winter and socioeconomic deprivation related factors appear to act synergistically, increasing the rate of COPD admissions to hospital more among deprived people than among affluent people in winter than in the summer months. Similar associations were observed for admission rates and temperatures. Interventions effective at reducing winter admissions for COPD may have potential for greater benefit if delivered to more deprived groups. PMID- 23820515 TI - What is the optimal means of preparing the endometrium in frozen-thawed embryo transfer cycles? A systematic review and meta-analysis. AB - BACKGROUND Frozen-thawed embryo transfer (FET) enables surplus embryos derived from IVF or IVF-ICSI treatment to be stored and transferred at a later date. In recent years the number of FET cycles performed has increased due to transferring fewer embryos per transfer and improved laboratory techniques. Currently, there is little consensus on the most effective method of endometrium preparation prior to FET. METHODS Using both MEDLINE and EMBASE database a systematic review and meta-analysis of literature was performed. Case-series, case-control studies and articles in languages other than English, Dutch or Spanish were excluded. Those studies comparing clinical and ongoing pregnancy rates as well as live birth rates in (i) true natural cycle FET (NC-FET) versus modified NC-FET, (ii) NC-FET versus artificial cycle FET (AC-FET), (iii) AC-FET versus artificial with GnRH agonist cycle FET and (iv) NC-FET versus artificial with GnRH agonist cycle FET were included. Forest plots were constructed and relative risks or odds ratios were calculated. RESULTS A total of 43 publications were selected for critical appraisal and 20 articles were included in the final review. For all comparisons, no differences in the clinical pregnancy rate, ongoing pregnancy rate or live birth rate could be found. Based on information provided in the articles no conclusions could be drawn with regard to cancellation rates. CONCLUSIONS Based on the current literature it is not possible to identify one method of endometrium preparation in FET as being more effective than another. Therefore, all of the current methods of endometrial preparation appear to be equally successful in terms of ongoing pregnancy rate. However, in some comparisons predominantly retrospective studies were included leaving these comparisons subject to selection and publication bias. Also patients' preferences as well as cost-efficiency were not addressed in any of the included studies. Therefore, prospective randomized studies addressing these issues are needed. PMID- 23820516 TI - The spinal control of ejaculation revisited: a systematic review and meta analysis of anejaculation in spinal cord injured patients. AB - BACKGROUND After spinal cord injury (SCI), most men cannot ejaculate without medical assistance. A major advance in the knowledge of the spinal control of ejaculation has been achieved with the discovery of a spinal generator of ejaculation (SGE) in the rat. The aim of this report was to review studies about ejaculation after SCI in order to revisit the spinal control of ejaculation and especially to assess the existence of an SGE in man. METHODS Studies were identified from Embase, PubMed, EBSCOhost and Cochrane Library. Studies were eligible when they specify the occurrence of antegrade ejaculation as a function of the neurological characterization of SCI. Studies were excluded when ejaculation was elicited by rectal electrical stimulation or when ejaculation could not be discriminated from climax. Meta-analyses were performed to assess the reference ejaculation rates for each procedure used to elicit ejaculation, i.e. masturbation or coitus, penile vibratory stimulation (PVS) or acetylcholine esterase (AchE) inhibitors prior to masturbation. Subgroup analyses were performed according to the procedure used to elicit ejaculation on (i) the completeness of the SCI and (ii) the upper and lower limits of the SCI. To assess the existence of an SGE, the effect of concurrent lesions of different spinal segments was assessed by means of a stratified bivariate analysis. RESULTS From 523 studies, 45 were selected (n = 3851). Ejaculation occurred in response to masturbation or coitus, PVS or AchE inhibitors followed by masturbation in, respectively, 11.8% (n = 1161), 47.4% (n = 597) and 54.7% (n = 309) of patients with complete SCI and in, respectively, 33.2% (n = 343), 52.8% (n = 305) and 78.1% (n = 32) of patients with incomplete SCI. Ejaculation, in the case of complete lesion of the sympathetic centres (T12 to L2), of the parasympathetic and somatic centres (S2-S4) or of all spinal ejaculation centres (T12 to S5) occurred in response to PVS in none of the patients (respectively, n = 5, n = 4 and n = 21) and in response to AchE inhibitors followed by masturbation in 4.9% (n = 61), 30.8% (n = 26) and 0% (n = 16) of the patients, respectively. Ejaculation in response to PVS or AchE inhibitors prior to masturbation was rhythmic forceful in 97.9% (n = 48) of the patients with complete lesion strictly above Onuf's nucleus (segments S2-S4). Complete lesion of the S2-S4 segments precluded the occurrence of rhythmic forceful ejaculation (n = 5). Controlling for the number of the injured segments between T12 and L2, the ejaculation rate sharply decreased when the lesion extended to the L3 segment and below. CONCLUSIONS The results reinforce the crucial roles of the spinal sympathetic and parasympathetic centres for emission and the somatic centre for expulsion. The spinal segments between L2 and S2 is more than a pathway to connect the ejaculation centres and likely harbours an SGE in man located in the L3, L4 and L5 segments. PMID- 23820517 TI - Cost of switching inhalers is high in carbon trading terms. PMID- 23820518 TI - Authors' reply to Reynolds. PMID- 23820519 TI - Risk of diabetes with statins must be monitored in each patient. PMID- 23820520 TI - Statins and the quality and outcomes framework. PMID- 23820521 TI - Don't ignore non-pharmacological aspects of analgesia while pursuing analgesic success. PMID- 23820522 TI - All opportunities should now be taken to meet the needs of patients with learning difficulties. PMID- 23820523 TI - Austerity measures hit the sickest hardest. PMID- 23820524 TI - Time to focus on positive health indicators to reduce health inequalities. PMID- 23820525 TI - Don't forget that central corneal thickness affects intraocular pressure. PMID- 23820526 TI - Authors' reply to Georgalas and colleagues. PMID- 23820527 TI - Hypothermia and the assessment of sick children. PMID- 23820528 TI - Time for a putsch of the l'oreal consultants? PMID- 23820529 TI - The few who abuse their position bring all consultants into disrepute. PMID- 23820530 TI - Five patients benefit from India's first "domino" kidney swap. PMID- 23820531 TI - Hunt promises crackdown on foreigners who misuse NHS, despite GPs' objections to checking entitlement. PMID- 23820532 TI - Another US health system adopts "tobacco-free" hiring policy. PMID- 23820533 TI - Surgeon condemns crude data on outcomes for causing "debacle". PMID- 23820534 TI - Comments on Rithidech, K.N.; et al. Lack of genomic instability in bone marrow cells of SCID mice exposed whole-body to low-dose radiation. Int. J. Environ. Res. Public Health 2013, 10, 1356-1377. AB - I would like to take issue with Rithidech et al., authors of the paper entitled "Lack of genomic instability in mice at low doses" [1] who claim to have shown that their results on the measurement of late occurring chromosome aberrations after irradiation of SCID mice with X-rays show that lower doses (0.05 Gy) do not induce genomic instability. Their earlier work at higher doses (0.1 and 1.0 Gy) on the same strain of mouse indicated that de novo chromosome aberrations were detected at 6 months post-irradiation. This was taken, almost certainly correctly, to be an indication of the presence of genomic instability: late appearing chromosome damage, as the authors note, seems to be a reliable indicator of the process. The lack of de novo chromosome aberrations at 6 months post-irradiation, however, cannot be taken as evidence of the absence of genomic instability. In drawing their conclusion of a "lack of genomic instability ...." the authors have committed two category errors. PMID- 23820535 TI - Response to Baverstock, K. Comments on Rithidech, K.N.; et al. Lack of Genomic Instability in Bone Marrow Cells of SCID Mice Exposed Whole-Body to Low-Dose Radiation. Int. J. Environ. Res. Public Health 2013, 10, 1356-1377. AB - We thank Dr. Baverstock [1] for his interest in reading our article and his time in writing his comments for our work [2]. We, however, respectfully disagree with his statement that we made "two category errors" associated with the assessment of the occurrence of "genomic instability" by determining the frequencies of delayed- or late-occurring chromosomal damage. Our disagreement is based upon the well-known fact that radiation-induced genomic instability (or delayed/late occurring damage) can be manifested in many ways. These include late-occurring chromosomal damage, or mutations, or gene expression, or gene amplifications, or transformation, or microsatellite instability, or cell killing [3-9]. Such phenomena have been detected many cell generations after irradiation. We agree that genomic instability may well be the consequence of epigenetic changes. Another mechanism mentioned by Dr. Bavertock as being probably unlikely is the reversibility of damage. This potential may not be discarded off-hand, as Dr. Baverstock prefers to do. There is much reproducible evidence of adaptive protection that depending on absorbed dose precisely may reverse early damage, and damage appearing late may be due to some form of residual damage letting the cell become genetically unstable. In other words, the argument by Dr. Baverstock regarding upward or downward causation appears to be rather speculative and far from being settled. PMID- 23820536 TI - Effects of various reaction parameters on solvolytical depolymerization of lignin in sub- and supercritical ethanol. AB - Organosolv lignin was treated with ethanol at sub/supercritical temperatures (200, 275, and 350 degrees C) for conversion to low molecular phenols under different reaction times (20, 40, and 60 min), solvent-to-lignin ratios (50, 100, and 150 mL g(-1)), and initial hydrogen gas pressures (2 and 3 MPa). Essential lignin-degraded products, oil (liquid), char (solid), and gas were obtained, and their yields were directly influenced by reaction conditions. In particular, concurrent reactions involving depolymerization and recondensation as well as further (secondary) decomposition were significantly accelerated with increasing temperature, leading to both lignin-derived phenols in the oil fraction and undesirable products (char and gas). As the main components in the oil fraction, oxygenated phenols, guaiacol, and syringol as well as their alkylated forms were detected. The yield of alkylated phenols showed a drastic increase at 350 degrees C in the presence of initial hydrogen gas due to prevailing hydrodeoxygenation and hydrogenation reactions of the vinyl/allyl/oxygenated phenols. These reactions were also demonstrated indirectly from the results of atomic H/C and O/C of the oils. The highest amount of monomeric phenols released from lignin (1.0 g) was measured as ca. 96.7 mg at 350 degrees C, 40 min, 100 mL g(-1), and 3 MPa of H2. In addition, GPC analysis suggested a possibility of condensation between lignin-degraded fragments during the solvolysis reaction. PMID- 23820537 TI - Assessment of cytotoxicity and toxicity for phosphonium-based deep eutectic solvents. AB - In this work, the cytotoxicity and toxicity of phosphonium-based deep eutectic solvents (DESs) with three hydrogen bond donors, namely glycerine, ethylene glycol, and triethylene glycol were investigated. The cytotoxicity effect was tested using brine shrimp (Artemia salina). The toxicity was investigated using the two Gram positive bacteria Bacillus subtilis and Staphylococcus aureus, and two Gram negative bacteria Escherichia coli and Pseudomonas aeruginosa. The cytotoxicity of tested DESs was much higher than that of their individual components, indicating their toxicological behavior was different. It was also found that there was toxic effect on the studied bacteria, indicating their potential application as anti-bacterial agents. To the best of our knowledge, this is the first time the cytotoxicity and toxicity of phosphonium-based DESs were studied. PMID- 23820538 TI - Potential of BAC combined with UVC/H2O2 for reducing organic matter from highly saline reverse osmosis concentrate produced from municipal wastewater reclamation. AB - The organic matter present in the concentrate streams generated from reverse osmosis (RO) based municipal wastewater reclamation processes poses environmental and health risks on its disposal to the receiving environment (e.g., estuaries, bays). The potential of a biological activated carbon (BAC) process combined with pre-oxidation using a UVC/H2O2 advanced oxidation process for treating a high salinity (TDS~10000 mg L(-1)) municipal wastewater RO concentrate (ROC) was evaluated at lab scale during 90 d of operation. The combined treatment reduced the UVA254 and colour of the ROC to below those for the influent of the RO process (i.e., biologically treated secondary effluent), and the reductions in DOC and COD were approximately 60% and 50%, respectively. UVC/H2O2 was demonstrated to be an effective means of converting the recalcitrant organic compounds in the ROC into biodegradable substances which were readily removed by the BAC process, leading to a synergistic effect of the combined treatment in degrading the organic matter. The tests using various BAC feed concentrations suggested that the biological treatment was robust and consistent for treating the high salinity ROC. Using Microtox analysis no toxicity was detected for the ROC after the combined treatment, and the trihalomethane formation potential was reduced from 3.5 to 2.8 mg L(-1). PMID- 23820539 TI - PILL series. Prescribing health: exercise. AB - The healthcare challenges in developed countries centre around the rise of chronic conditions and obesity. There is a call to shift the focus toward the primary prevention of these conditions. Clinicians will need to move beyond the comfort of prescribing pharmaceuticals and expand the scope to prescribing health, i.e. exercise. We discuss an easy-to-follow exercise prescription to highlight some essential principles and useful tools that can help busy family practices achieve this. PMID- 23820540 TI - Psychometric properties of the Iranian version of the Pediatric Quality of Life InventoryTM Short Form 15 Generic Core Scales. AB - INTRODUCTION: The objective of this study was to assess the feasibility, reliability and validity of the Iranian version of the Pediatric Quality of Life InventoryTM 4.0 Short Form 15 Generic Core Scales (PedsQLTM 4.0 SF15) in a sample of Iranian schoolchildren and children with chronic health conditions. METHODS: A total of 1236 schoolchildren and 1183 parents of schoolchildren participated, and 52 children with chronic health conditions and their parents were recruited from an outpatient clinic. Feasibility, internal consistency reliability, test-retest reliability, known-groups discriminant validity and construct validity of the PedsQLTM 4.0 SF15 were determined. RESULTS: The Iranian version of PedsQLTM 4.0 SF15 evidenced minimal missing responses for child self-report and parent proxy report (0.4% and 0.6%, respectively), generally demonstrated no significant floor or ceiling effects, and achieved acceptable internal consistency reliability for the Total Scale Score (alpha = 0.82 child self-report, 0.84 parent proxy-report) and acceptable test-retest reliability. Schoolchildren and their parents reported significantly higher PedsQLTM 4.0 SF15 scores than paediatric patients with chronic health conditions. Child self-report and parent proxy-report showed poor to good agreement. A four-factor model was confirmed among child self-report and parent proxy-report in the confirmatory factor analyses. CONCLUSION: This study supports the feasibility, reliability and validity of the Iranian version of the PedsQLTM 4.0 SF15 among Iranian children and their parents. PMID- 23820541 TI - Effect of testosterone propionate on hippocampal pyramidal neuron number in female rats. AB - INTRODUCTION: The hippocampus is an important region of the brain that regulates cognitive and emotional functions. In this study, we examined the impact of perinatal administration of testosterone propionate (TP) on the number of pyramidal neurons in the CA1 and CA3 regions of the hippocampi of female rats. METHODS: Five groups of rats were used in this study. Three groups of female rats were administered TP in either both the prenatal and the postnatal periods (Group 1), only the prenatal period (Group 2) or only the postnatal period (Group 3). The other two groups of rats included control females (Group 4) and control males (Group 5). The rats were sacrificed on postnatal Day 120 and their brains were analysed for hippocampal pyramidal neuron number using stereological methods. RESULTS: Control male rats (Group 5; p = 0.043) and TP-treated female rats in Groups 1 (p = 0.012) and 2 (p = 0.037), but not Group 3 (p > 0.05), had a significantly higher number of pyramidal neurons than control female rats (Group 4). The rats in Group 1 had the highest number of pyramidal neurons among the female rats. CONCLUSION: Perinatal TP treatment has an augmenting effect on the number of pyramidal neurons in the hippocampi of female rats. We also found gender-based differences in the hippocampi of male and female rats, with a higher number of pyramidal neurons seen in male rats. Continuous TP administration during the prenatal and postnatal periods is more effective than administration only in the prenatal or postnatal period. PMID- 23820542 TI - The modified Medical Research Council dyspnoea scale is a good indicator of health-related quality of life in patients with chronic obstructive pulmonary disease. AB - INTRODUCTION: Health-related quality of life (HRQoL) is an important patient centred outcome in chronic obstructive pulmonary disease (COPD). The aim of the current study is to compare the discriminative capacity of the modified Medical Research Council (mMRC) dyspnoea scale and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) spirometric classification of COPD on HRQoL, as well as determine other factors that are simple and determinative of HRQoL. METHODS: In this cross-sectional observational study, a total of 328 patients with COPD were enrolled from the pulmonology outpatient clinic. HRQoL was measured using the St George's Respiratory Questionnaire (SGRQ) and the World Health Organization Quality of Life-BREF (WHOQOL-BREF). HRQoL scores were compared between the four GOLD stages and the five grades of the mMRC scale. Significant differences were determined using analysis of variance with Scheffe post-hoc test. Multiple linear regression was applied to explore the major determinants of HRQoL and exclude confounding factors. RESULTS: Significant differences were found in many more domains of the two questionnaires between mMRC grades than between GOLD stages. In the multiple linear regression model, the mMRC scale was the only factor that remained determinative of all the domains of SGRQ and WHOQOL-BREF. Patients with chronic productive cough, sleep disorders and frequent exacerbations had poorer HRQoL, as reflected by higher scores in SGRQ or lower scores in WHOQOL-BREF. CONCLUSION: The mMRC dyspnoea scale is a concise and practical tool to assess the HRQoL of patients with COPD in daily clinical practice. PMID- 23820543 TI - Is semen polymorphonuclear leucocytes count a good predictor of male genital tract infection? AB - INTRODUCTION: This study aims to evaluate whether an increased polymorphonuclear leucocyte (PMN) count in semen is a good predictor of male genital tract infection, which is detected by semen culture. METHODS: A retrospective cross sectional study examining the semen of 388 men was conducted at the in vitro fertilisation centre of a tertiary hospital. We compared the culture results of 109 men with increased semen PMN count against those of 279 men with normal semen PMN count. RESULTS: There was no significant difference in the percentage of positive cultures between men with increased PMN count in their semen and those without PMN count elevation (original sensitivity 20.8%, specificity 70.3%; p = 0.1289). The overall percentage of positive semen cultures among all 388 patients was 18.6%. CONCLUSION: Based on the positive cultures of significant organisms in the semen of our cohort, an increased semen PMN count is not a good predictor of genital tract infection in men. PMID- 23820544 TI - Management of ruptured intracranial aneurysms in the post-ISAT era: outcome of surgical clipping versus endovascular coiling in a Singapore tertiary institution. AB - INTRODUCTION: The results of the International Subarachnoid Aneurysm Trial (ISAT) in 2002 have significantly influenced the management of ruptured intracranial aneurysms. There is now an established shift worldwide toward endovascular coiling as the initial treatment of choice. We assessed the outcomes of patients admitted to our institution for aneurysmal subarachnoid haemorrhage (SAH), comparing the outcomes of patients (World Federation of Neurosurgical Societies [WFNS] grades 1-3) who underwent surgical clipping versus those who underwent endovascular coiling. METHODS: We retrospectively reviewed patients admitted to the National University Hospital for SAH secondary to ruptured intracranial aneurysm in 2005-2009. Patients were divided into two groups - clipping and coiling. Data on individual demographics, comorbidities, Fisher grading and Glasgow Outcome Scale scores were collected for the two groups and subjected to relevant statistical analyses. RESULTS: Of the 133 patients admitted for nontraumatic SAH, 89 had ruptured aneurysms. Among the 56 patients classified as WFNS grades 1-3, 23 underwent coiling while the remaining 33 underwent clipping. A significant association was found between Fisher grade and the likelihood of developing hydrocephalus in these patients. CONCLUSION: Although we acknowledge the presence of management bias in our institution, our findings were similar to those of the ISAT trial. Upon correlation between our results and current evidence-based findings, our findings show that clipping provides similar long term outcomes as endovascular coiling. In the event that an aneurysm is deemed unsuitable for coiling, clipping remains an effective option. PMID- 23820545 TI - Pattern of psychiatric morbidity among theft offenders remanded or referred for psychiatric evaluation and factors associated with reoffence. AB - INTRODUCTION: In Singapore, theft and related crimes constitute more than 50% of all reported crime, and are the most common offences committed by accused persons remanded to the Institute of Mental Health (IMH), Singapore. There is a need for better understanding of the forensic psychiatric aspects of such offenders. This study aimed to determine the prevalence of psychiatric disorders among theft offenders remanded or referred for forensic assessment in 2010, compare the differences between first-time and repeat theft offenders, and identify the factors associated with reoffence. METHODS: Forensic evaluations of inpatient and outpatient theft offenders that were conducted at IMH in the year 2010 were retrieved and reviewed. The sociodemographic and clinical data of first-time and repeat theft offenders were collected and compared using Student's t-test and chi square test for continuous and categorical variables, respectively. Multivariate regression was used to identify the factors that were predictive of repeat offence. RESULTS: Overall, 10% of offenders had no mental illness. Substance use disorders, mood disorders and psychotic disorders were the most common diagnoses. Psychotic disorders were significantly less common in repeat offenders. Repeat offenders also tended to have a history of conduct problems in childhood. Noncompliance with psychiatric treatment was positively associated with repeat offence, while psychotic disorders were negatively associated. CONCLUSION: The pattern of psychiatric morbidity among theft offenders in Singapore has changed over the last ten years. Kleptomania remains rare. Significant differences between first-time and repeat offenders have implications on the treatment, follow-up and rehabilitation of theft offenders in Singapore. PMID- 23820546 TI - Enteric duplication in children: clinical presentation and outcome. AB - INTRODUCTION: Enteric duplication (ED) is an anomaly with varied presentations and possible involvement of the alimentary tract. Once diagnosed, resection of the lesion and the involved part of the gut is usually required. The aim of this study was to evaluate the clinical presentations, diagnostic investigations, management and outcomes of patients with ED. METHODS: This was a descriptive case study conducted at the Department of Paediatric Surgery, Military Hospital, Rawalpindi, Pakistan, from January 2005 to January 2011. The medical records of all patients diagnosed with ED were retrospectively analysed with respect to age, presentation, investigations, site and type of lesion, surgical procedures, histological findings and complications. RESULTS: A total of nine patients were managed during the study period. The patients' ages ranged from three months to five years. Four out of nine EDs were rectal duplications. Three EDs were of the cystic type, five were of the tubular type and one was a complex mixed anomaly. Patients presented with varied symptoms, with the two most common being the presence of an abdominal mass and bleeding per rectum. Diagnosis was mainly achieved based on magnetic resonance imaging and computed tomography, although Meckel's scan provided accurate diagnosis in three of the nine patients. All the cysts were resected without any major complications, and patients were event-free during the five-year follow-up. CONCLUSION: EDs should be kept in mind when examining patients with an abdominal mass and bleeding per rectum. Meckel's scan can provide accurate diagnosis of EDs with bleeding. Prompt diagnosis and management results in satisfactory outcomes. PMID- 23820547 TI - Clinics in diagnostic imaging (147). Male breast carcinoma. AB - A 51-year-old man with no significant medical history was referred to our institution for further management of a palpable, painless right breast lump that had been gradually increasing in size for a period of six months. Physical examination revealed a firm right breast lump and bloody right nipple discharge, but no skin involvement or axillary lymphadenopathy was observed. Subsequent mammography and breast ultrasonography demonstrated a discrete, heterogeneous and vascular right breast mass with spiculated and angulated margins. The breast mass was found to be an invasive ductal carcinoma on ultrasonography-guided core needle biopsy. This case illustrates that a combination of detailed clinical history, careful physical examination and radiological assessment using mammography and breast ultrasonography may be used to identify cases suspicious for male breast carcinoma that warrant biopsy. PMID- 23820548 TI - Dr Sun Yat-sen (1866-1925): medical doctor and China's founding president. PMID- 23820549 TI - Optimisation of cholesterol management. PMID- 23820550 TI - Author's reply: To PMID 23338914. PMID- 23820551 TI - Docetaxel (Taxotere(r))-induced cavitary change of pulmonary metastatic lesions complicated by bilateral spontaneous pneumothoraces in a patient with primary adenocarcinoma of the lung. AB - Pneumothorax is a complication that rarely occurs after chemotherapy for lung cancer. We report the chest computed tomography findings of a case of spontaneous pneumothorax complicating docetaxel (Taxotere(r)) treatment for pulmonary metastasis in a 70-year-old woman with pulmonary adenocarcinoma. The patient developed bilateral pneumothoraces, which was induced by changes in the cavitary pulmonary metastatic lesions, after systemic chemotherapy with docetaxel. The chest computed tomography findings and possible mechanisms of this unusual complication are discussed in this report. PMID- 23820552 TI - Efficient solar water oxidation using photovoltaic devices functionalized with earth-abundant oxygen evolving catalysts. AB - Indium tin oxide (ITO) surfaces of triple junction photovoltaic cells were functionalized with oxygen evolving catalysts (OECs) based on amorphous hydrous earth-abundant metal oxides (metal = Fe, Ni, Co), obtained by straightforward Successive Ionic Layer Adsorption and Reaction (SILAR) in an aqueous environment. Functionalization with Fe(iii) oxides gave the best results, leading to photoanodes capable of efficiently splitting water, with photocurrent densities up to 6 +/- 1 mA cm(-2) at 0 V vs. the reversible hydrogen electrode (RHE) under AM 1.5 G simulated sunlight illumination. The resulting Solar To Hydrogen (STH) conversion efficiencies, measured in two electrodes configuration, were in the range 3.7-5%, depending on the counter electrode that was employed. Investigations on the stability showed that these photoanodes were able to sustain 120 minutes of continuous illumination with a < 10% photocurrent loss at 0 V vs. RHE. Pristine photoanodic response of the cells could be fully restored by an additional SILAR cycle, evidencing that the observed loss is due to the detachment of the more weakly surface bound catalyst. PMID- 23820553 TI - The photoconvertible water-soluble chlorophyll-binding protein of Chenopodium album is a member of DUF538, a superfamily that distributes in Embryophyta. AB - Various plants possess hydrophilic chlorophyll (Chl) proteins known as water soluble Chl-binding proteins (WSCPs). WSCPs exist in two forms: Class I and Class II, of which Class I alone exhibits unique photoconvertibility. Although numerous genes encoding Class II WSCPs have been identified and the molecular properties of their recombinant proteins have been well characterized, no Class I WSCP gene has been identified to date. In this study, we cloned the cDNA and a gene encoding the Class I WSCP of Chenopodium album (CaWSCP). Sequence analyses revealed that CaWSCP comprises a single exon corresponding to 585bp of an open reading frame encoding 195 amino acid residues. The CaWSCP protein sequence possesses a signature of DUF538, a protein superfamily of unknown function found almost exclusively in Embryophyta. The recombinant CaWSCP was expressed in Escherichia coli as a hexa-histidine fusion protein (CaWSCP-His) that removes Chls from the thylakoid. Under visible light illumination, the reconstituted CaWSCP-His was successfully photoconverted into a different pigment with an absorption spectrum identical to that of native CaWSCP. Interestingly, while CaWSCP-His could bind both Chl a and Chl b, photoconversion occurred only in CaWSCP-His reconstituted with Chl a. PMID- 23820554 TI - The saccus vasculosus of fish is a sensor of seasonal changes in day length. AB - The pars tuberalis of the pituitary gland is the regulatory hub for seasonal reproduction in birds and mammals. Although fish also exhibit robust seasonal responses, they do not possess an anatomically distinct pars tuberalis. Here we report that the saccus vasculosus of fish is a seasonal sensor. We observe expression of key genes regulating seasonal reproduction and rhodopsin family genes in the saccus vasculosus of masu salmon. Immunohistochemical studies demonstrate that all of these genes are expressed in the coronet cells of the saccus vasculosus, suggesting the existence of a photoperiodic signalling pathway from light input to neuroendocrine output. In addition, isolated saccus vasculosus has the capacity to respond to photoperiodic signals, and its removal abolishes photoperiodic response of the gonad. Although the physiological role of the saccus vasculosus has been a mystery for several centuries, our findings indicate that the saccus vasculosus acts as a sensor of seasonal changes in day length in fish. PMID- 23820555 TI - New dye-decolorizing peroxidases from Bacillus subtilis and Pseudomonas putida MET94: towards biotechnological applications. AB - This work provides spectroscopic, catalytic, and stability fingerprints of two new bacterial dye-decolorizing peroxidases (DyPs) from Bacillus subtilis (BsDyP) and Pseudomonas putida MET94 (PpDyP). DyPs are a family of microbial heme containing peroxidases with wide substrate specificity, including high redox potential aromatic compounds such as synthetic dyes or phenolic and nonphenolic lignin units. The genes encoding BsDyP and PpDyP, belonging to subfamilies A and B, respectively, were cloned and heterologously expressed in Escherichia coli. The recombinant PpDyP is a 120-kDa homotetramer while BsDyP enzyme consists of a single 48-kDa monomer. The optimal pH of both enzymes is in the acidic range (pH 4-5). BsDyP has a bell-shape profile with optimum between 20 and 30 degrees C whereas PpDyP shows a peculiar flat and broad (10-30 degrees C) temperature profile. Anthraquinonic or azo dyes, phenolics, methoxylated aromatics, and also manganese and ferrous ions are substrates used by the enzymes. In general, PpDyP exhibits higher activities and accepts a wider scope of substrates than BsDyP; the spectroscopic data suggest distinct heme microenvironments in the two enzymes that might account for the distinctive catalytic behavior. However, the Bs enzyme with activity lasting for up to 53 h at 40 degrees C is more stable towards temperature or chemical denaturation than the PpDyP. The results of this work will guide future optimization of the biocatalytis towards their utilization in the fields of environmental or industrial biotechnology. PMID- 23820556 TI - Encapsulation in a natural, preformed, multi-component and complex capsule: yeast cells. AB - From the first observation about 40 years ago that yeast cells were interesting protective structures that could be used in several industrial applications, processes have been developed enabling technologists to incorporate several compounds possessing different physico-chemical (hydrophobic/hydrophilic) properties. Technologists screened yeast diversity to choose strains possessing the best potential and modified their physiological state to increase the uptake capability and the envelope plasticity, for instance by increasing the amount of lipids. Physico-chemical treatments were also used to improve the uptake and decrease the yeast natural material impact on the final products. For example, yeast cells could be "emptied" of their plasmic material. Yeast cells can also be coated with an additional polymeric material to increase resistance to heat treatment or decrease material liberation.These capsules can be used for several applications including carbonless paper, perfuming tissues and drug targeting, but the main industrial application deals currently with flavour encapsulation, although encapsulation in yeast is also interesting for the global food industry trend for health products.This paper proposes to review the use of yeast as an encapsulation structure focusing particularly on the properties of the yeast capsule and their impact on loading, protection, targeting and release. PMID- 23820557 TI - Secretory production of ricinoleic acid in fission yeast Schizosaccharomyces pombe. AB - We have succeeded to produce a high content of ricinoleic acid (RA), a hydroxylated fatty acid with great values as a petrochemical replacement, in fission yeast Schizosaccharomyces pombe by introducing Claviceps purpurea oleate Delta12-hydroxylase gene (CpFAH12). Although the production was toxic to S. pombe cells, we solved the problem by identifying plg7, encoding phospholipase A2, as a multicopy suppressor. Characterization of the RA-tolerant strains suggested that the removal of RA moieties from phospholipids would be the suppression mechanism by plg7. In this study, we extended our analysis and report our new discovery that the overexpression of plg7 enabled cells to secrete free RA into culture media. When the FAH12 integrant in the absence of the overexpressed plg7 was grown at 20 degrees C for 11 days, the amount of intracellular RA reached 200.1 MUg/ml of culture and only 69.3 MUg/ml of RA was detected in culture media. On the other hand, the FAH12 integrant harboring the plg7 multicopy plasmid secreted RA in the media (184.5 MUg/ml) without decreasing the amount in the cells, i.e., a significantly higher total secretion and a lead to making RA by its secretory production in S. pombe. PMID- 23820558 TI - Global transcriptome analysis of Escherichia coli exposed to immobilized anthraquinone-2-sulfonate and azo dye under anaerobic conditions. AB - The immobilization of quinone compounds is regarded as a promising strategy to accelerate anaerobic decolorization of xenobiotic compounds azo dyes in the presence of quinone-reducing microorganisms. However, little is known about the basic response of these microorganisms to immobilized quinones in the presence of azo dyes. In the present study, whole-genome DNA microarrays were used to investigate a quinone-reducing bacterium Escherichia coli K-12 transcription response to immobilized anthraquinone-2-sulfonate (AQSim) reduction and azo dye acid red 18 (AR 18) decolorization. Transcriptome analysis showed that AQSim was more accessible for the cells of E. coli K-12 than AR 18. Despite there being some differences between AQSim and soluble AQS mediated decolorization of AR 18, AQSim reduction and AR 18 decolorization, more similarity could be observed in the four processes. Among over 60 % shared genes, several groups of genes exhibited high expression levels, including those genes encoding terminal reductases, menaquinone biosynthesis, formate dehydrogenases and outer membrane proteins. Especially, nrfABCD, frdBCD and dsmABC encoding terminal reductases were significantly upregulated. Further gene deletion experiments demonstrated that the above three groups of genes were involved in AQSim-mediated AR 18 decolorization. In addition, significant upregulation of stress response genes was observed, which indicated the adaptation of E. coli K-12 to AQSim and AR 18 exposures. PMID- 23820559 TI - Oxidized glutathione fermentation using Saccharomyces cerevisiae engineered for glutathione metabolism. AB - Glutathione is a valuable tripeptide that is widely used in the pharmaceutical, food, and cosmetic industries. Intracellular glutathione exists in two forms, reduced glutathione (GSH) and oxidized glutathione (GSSG). Most of the glutathione produced by fermentation using yeast is in the GSH form because intracellular GSH concentration is higher than GSSG concentration. However, the stability of GSSG is higher than GSH, which makes GSSG more advantageous for industrial production and storage after extraction. In this study, an oxidized glutathione fermentation method using Saccharomyces cerevisiae was developed by following three metabolic engineering steps. First, over-expression of the glutathione peroxidase 3 (GPX3) gene increased the GSSG content better than over expression of other identified peroxidase (GPX1 or GPX2) genes. Second, the increase in GSSG brought about by GPX3 over-expression was enhanced by the over expression of the GSH1/GSH2 genes because of an increase in the total glutathione (GSH + GSSG) content. Finally, after deleting the glutathione reductase (GLR1) gene, the resulting GPX3/GSH1/GSH2 over-expressing DeltaGLR1 strain yielded 7.3 fold more GSSG compared with the parental strain without a decrease in cell growth. Furthermore, use of this strain also resulted in an enhancement of up to 1.6-fold of the total glutathione content compared with the GSH1/GSH2 over expressing strain. These results indicate that the increase in the oxidized glutathione content helps to improve the stability and total productivity of glutathione. PMID- 23820560 TI - Jump-landing differences between varsity, club, and intramural athletes: the Jump ACL Study. AB - Abnormal movement patterns have been identified as important prospective risk factors for lower extremity injury, including anterior cruciate ligament injury. Specifically, poor neuromuscular control during the early landing phase has been associated with increased injury risk. Although it is commonly assumed that higher division collegiate athletes generally exhibit better movement patterns than lower division athletes, few studies compare the biomechanical differences on basic tasks such as jump landing between various levels of athletic groups. The objective of this study was to evaluate jump-landing and fitness differences among college-aged Intramural, Competitive Club, and National Collegiate Athletic Association (NCAA) Division I level athletes. Two hundred seventy-seven student athletes (222 men, 55 women; age 19.3 +/- 0.8 years) categorized as NCAA Division I, Competitive Club, or Intramural level athletes were evaluated during a jump landing task using the Landing Error Scoring System (LESS), a validated qualitative movement assessment. Fitness was measured using the Army Physical Fitness Test (APFT). Results showed no significant differences in landing errors between the levels of athletic group (F(2,267) = 0.36, p = 0.70). There was a significant difference in landing errors between genders (F(1,268) = 3.99, p = 0.05). Significant differences in APFT scores were observed between level of athletic group (F(2,267) = 11.14, p < 0.001) and gender (F(1,268) = 9.27, p = 0.003). There was no significant correlation between the APFT and LESS scores (p = 0.26). In conclusion, higher level athletes had better physical fitness as measured by the APFT but did not as a group exhibit better landing technique. The implications of this research suggest that "high-risk" movement patterns are prevalent in all levels of athletes. PMID- 23820561 TI - The interactive effects of recovery mode and duration on subsequent repeated sprint performance. AB - The aim of this study was to examine the interactive effects of recovery mode and duration on subsequent repeated short sprint (RSS) performance. Ten male recreational athletes (age, 27.9 +/- 5.0 years; height, 1.80 +/- 0.07 m; mass, 81.6 +/- 13.5 kg) performed 4 randomized trials consisting of a 30-second cycle sprint, followed by a specified recovery period (45 or 180 seconds), and a subsequent set of RSS (7 * 5 seconds, 20-second passive rest periods). Recovery mode was either active (AR; 70% of the power output at lactate threshold) or passive (PR). Mean heart rate and V[Combining Dot Above]O2 were significantly higher (p <= 0.05) in AR than in PR over both recovery durations. Although the difference in V[Combining Dot Above]O2 reached significance after 10-15 seconds, a significant (p <= 0.05) difference in heart rate was observed only after 26 seconds (45-second trials) - 75 seconds (180-second trials). Blood lactate was significantly (p <= 0.05) lower in AR than in PR only after 135 seconds (mean difference, 2.16 mmol.L; 95% likely range, 0.77-3.55 mmol.L). Mean peak power output in the RSS test was significantly (p <= 0.05) higher following PR45 than AR45 (12.0 +/- 1.4 vs. 11.4 +/- 1.4 W.kg) and following AR180 than PR180 (12.7 +/ 1.2 vs. 12.0 +/- 1.2 W.kg). In conclusion, when rest periods are short, a PR strategy appears to optimize subsequent RSS performance. However, as the recovery duration increases subsequent RSS performance appears to benefit from an AR strategy. PMID- 23820562 TI - Relationships Between Reactive Agility Movement Time and Unilateral Vertical, Horizontal, and Lateral Jumps. AB - Henry, GJ, Dawson, B, Lay, BS, and Young, WB. Relationships between reactive agility movement time and unilateral vertical, horizontal, and lateral jumps. J Strength Cond Res 30(9): 2514-2521, 2016-This study compared reactive agility movement time and unilateral (vertical, horizontal, and lateral) jump performance and kinetics between dominant and nondominant legs in Australian rules footballers (n = 31) to investigate the role of leg strength characteristics in reactive agility performance. Jumps involved jumping forward on 1 leg, then for maximum height or horizontal or lateral distance. Agility and movement time components of reactive agility were assessed using a video-based test. Correlations between each of the jumps were strong (r = -0.62 to -0.77), but between the jumps and agility movement time the relationships were weak (r = 0.25 to -0.33). Dominant leg performance was superior in reactive agility movement time (4.5%; p = 0.04), lateral jump distance (3%; p = 0.008), and lateral reactive strength index (4.4%; p = 0.03) compared with the nondominant leg. However, when the subjects were divided into faster and slower performers (based on their agility movement times) the movement time was significantly quicker in the faster group (n = 15; 12%; p < 0.001), but no differences in jump performance or kinetics were observed. Therefore, although the capacity for jumps to predict agility performance seems limited, factors involved in producing superior lateral jump performance in the dominant leg may also be associated with advantages in agility performance in that leg. However, because reactive strength as measured by unilateral jumps seems to play a limited role in reactive agility performance and other factors such as skill, balance, and coordination, and also cognitive and decision-making factors, are likely to be more important. PMID- 23820563 TI - Monitoring internal load parameters during competitive synchronized swimming duet routines in elite athletes. AB - The aim of the study is to compare the heart rate (HR) and rate of perceived exertion (RPE) responses as internal load indicators while performing duet routines during training and competition, both in the technical and free programs of synchronized swimming (SS). Participants were 10 SS Olympic medalists (age, 17.4 +/- 3.0 years; height, 164.0 +/- 6.1 cm; body mass, 52.0 +/- 6.4 kg; training, 36.3 +/- 6.2 h.wk; experience, 9.2 +/- 2.6 years). They were monitored while performing the same technical duet or free duet, during a training session (T) and during an official competition (C). Heart rate was continuously monitored. Rate of perceived exertion was assessed using the Borg CR10 scale. Heart rate responses during T and C were almost identical: pre-exercise mean HR (b.min) was 130.5 +/- 13.9 (T) and 133.6 +/- 7.7 (C) and quickly increased yielding mean peak values of 184.8 +/- 5.8 (T) and 184.8 +/- 6.6 (C), with interspersed bradycardic events down to 86.6 +/- 4 (T) and 86.3 +/- 5 (C). Routines were perceived as "hard" to "extremely hard" by the swimmers in both conditions, and mean RPE scores (0-10+) were equally high during C (7.9 +/- 1.2) and T (7.5 +/- 1.2) (p = 0.223). Rate of perceived exertion inversely correlated with minimum (R = -0.545; p = 0.008) and mean HR (R = -0.452; p = 0.026) and positively correlated with HRrange (R = 0.520; p = 0.011). The internal load imposed by SS duets performed during training is virtually identical to that elicited in a real competitive situation. Therefore, practicing competitive routines is suitable for developing and maintaining the cardiovascular fitness that is needed for specific conditioning in elite synchronized swimmers, with the added value of favoring exercise automaticity, interindividual coordination, and artistic expression simultaneously. PMID- 23820564 TI - Isokinetic concentric quadriceps and hamstring normative data for elite collegiate American football players participating in the NFL Scouting Combine. AB - Isokinetic concentric quadriceps and hamstring strength data using a Cybex dynamometer are collected for elite collegiate American football players invited to the annual National Football League Scouting Combine. We constructed a normative (reference) database of the Cybex strength data for the purpose of allowing comparison of an individual's values to his peers. Data reduction was performed to construct frequency distributions of hamstring/quadriceps (H/Q) ratios and side-to-side strength differences. For the cohort (n = 1,252 players), a statistically significant but very small (1.9%) mean quadriceps strength preference existed for dominant side vs. nondominant side. Peak torque (Newton meters, best repetition) for quadriceps and hamstrings was significantly correlated to player body mass (weight) (the same relationship was found for other variables using peak torque in the calculation). Peak torque varied by player position, being greatest for offensive linemen and lowest for kickers (p < 0.0001). Adjusting for body weight overcorrected these differences. The H/Q ratios and frequency distributions were similar across positions, with a mean of 0.6837 +/- 0.137 for the cohort dominant side vs. 0.6940 +/- 0.145 for the nondominant side (p = 0.021, n = 1,252). Considerable variation was seen for dominant-to-nondominant side difference for peak torque. For quadriceps, 47.2% of players had differences between -10% and +10%, 21.0% had a peak torque dominant side deficit of 10% or greater compared to nondominant side, and for 31.8% of players, dominant-side peak torque was greater than 10% compared to nondominant side. For hamstrings, 57.0% of players had differences between -10% and +10%, 19.6% had a peak torque dominant-side deficit of 10% or greater compared to nondominant side, and 23.4% of players, dominant-side peak torque was greater than 10% compared to nondominant side. We observed that isokinetic absolute strength variables are dependent on body weight and vary across player position. The H/Q ratios vary only within a relatively narrow range. Side-to-side differences in strength variables >10% are common, not the exception. PMID- 23820565 TI - Effects of Vibration on Leg Blood Flow After Intense Exercise and Its Influence on Subsequent Exercise Performance. AB - This study aimed to determine the effects of vibration on leg blood flow after intense exercise and find out whether or not these effects can influence subsequent maximal exercise performance. Twenty-three participants performed an exercise test-to-exhaustion followed by a recovery period using six 1-minute sets of whole-body vibration (WBV; 25 Hz-4 mm) or a passive control (noWBV; 0 Hz-0 mm) in the seated position on separate days in random order. Blood flow was assessed at baseline and during each 1-minute interset rest periods post-WBV and noWBV. Thereafter, participants performed a cycle-ergometer test, and time to exhaustion and total distance covered (TDC) were recorded. During recovery, a similar trend was observed in both systolic and diastolic peak frequency dynamics in both conditions. The pulsatility index decreased (p < 0.01) from baseline during postbout 1 in both trials and during post-4 and post-5 in the WBV trial. Significant between-group differences were observed during post-4 (p <= 0.05) with greater decreases in pulsatility index after WBV compared with noWBV. Time to exhaustion and TDC were higher after WBV compared with noWBV. In conclusion, WBV decreased pulsatility index in the popliteal artery after maximal exercise and was effective to increase performance in a later exercise test-to-exhaustion. PMID- 23820566 TI - Effect of one- vs. two-stair climb training on sprint power. AB - Although running stairs is often used in sport conditioning programs, at present, little research has examined the effect of stair climb training on sprint power. The purpose of this study was to investigate the effects of running stairs either 1 stair (1S) or 2 stairs (2S) at a time on power. Fourteen male college track and field athletes were randomized into 3 groups; 1S, 2S, or control (C). All groups were pre- and posttested for 1S, 2S, and 40-m sprint split times. The 1S and 2S groups trained twice per week, for 4 weeks, performing 10 sets of climbing 68 total stairs with 2.5-minute rest between trials. The greatest power values (W) from pre- and poststairs and sprint splits were used for statistical analyses. There was a significant (p < 0.05) interaction of group * time for stair climb. The 1S group increased power for the 1S test (pre-1,492.89 +/- 123.76; post 1,647.41 +/- 73.65) with no change in the 2S test (pre-2,428.80 +/- 414.81; post 2,430.32 +/- 154.90), whereas the 2S group increased power for the 2S test (pre 2,343.73 +/- 317.50; post-2,646.17 +/- 305.43) with no change in the 1S test (pre 1,516.69 +/- 210.64; post-1,529.38 +/- 236.69). The C group showed no change in either stair test (1S: pre-1,403.35 +/- 238.67, post-1,384.38 +/- 153.32; 2S: pre 2,285.93 +/- 345.03, post-2,261.85 +/- 356.88). There were no significant interactions or main effects for any sprint split power (40 m: pre-5,337.13 +/- 611.86, post-5,318.68 +/- 586.24).Therefore, stair climb training either 1 or 2 at a time did not affect 40-m sprint split power but increased power for the specific stair training type. Coaches should choose the number of stairs that are similar in time and power output to sprint training. PMID- 23820567 TI - [Schoolchild with bronchitis and surprising diagnosis: or what an X-ray image can still contribute]. PMID- 23820568 TI - [Hans Holfelder and the Waffen SS Roentgensturmbann]. PMID- 23820569 TI - Electrofluorescence switching of tetrazine-modified TiO2 nanoparticles. AB - Highly fluorescent tetrazine-modified TiO2 nanoparticles were prepared by the reaction of triethoxysilane-appended chloroalkoxy tetrazine (ESTZ) with TiO2 nanoparticles through a condensation reaction between the surface hydroxyl groups of an electrode and the silane anchor group of ESTZ. The prepared electrodes were used as robust fluorescent layers for electrochemical fluorescence switching (electrofluorochromism) applications in the presence of 2,2,6,6-tetramethyl-1 piperidinyloxy (TEMPO) as a charge balancing mediator. The stable charge balancing mediator, TEMPO, in the electrolyte was found to be essential to reduce the intrinsic electron transport resistance of TiO2 in order to achieve reversible electrofluorescence switching. Furthermore it facilitated a fully reversible electrochemical reaction and provided a sufficient charge balance, which allowed us to realize semiconductor-based electrofluorescence switching with an on/off ratio of 4.0 and cyclability greater than 100 cycles. PMID- 23820570 TI - QTc interval screening in an opioid treatment program. AB - Methadone is highly effective for opioid dependency, but it is associated with Torsade de pointes. Although electrocardiography (ECG) has been proposed, its utility is uncertain, because an ECG-based intervention has not been described. An ECG-based cardiac safety program in methadone maintenance patients was evaluated in a single opioid treatment program from September 1, 2009, to August 31, 2011, in the United States. Time from pretreatment to repeat ECG in new entrants was assessed. The proportion with marked rate-corrected QT (QTc) interval prolongation (>500 ms) and the effect of the intervention on the QTc interval in this group were evaluated. Multivariate predictors of QTc interval change were assessed using a mixed-effects model. Of 531 new entrants, 436 (82%) underwent >=1 electrocardiographic assessment, and 186 (35%) underwent pretreatment ECG. Median time to follow-up ECG was 43 days but decreased over time (p <0.0001). In 21 patients with QTc intervals >500 ms, the mean QTc interval from peak to final ECG decreased significantly (-55.5 ms, 95% confidence interval -77.0 to -33.9, p = 0.001), and 12 of 21 (57.1%) decreased to lower than the 500-ms threshold. In new entrants with serial ECG, only methadone dose (p = 0.009) and pretreatment QTc interval (p <0.0001) were associated with the magnitude of QTc interval change. In conclusion, this study suggests that the implementation of an ECG-based intervention in methadone maintenance can decrease the QTc interval in high-risk patients; clinical characteristics alone were inadequate to identify patients in need of electrocardiographic screening. PMID- 23820571 TI - Incremental prognostic power of novel biomarkers (growth-differentiation factor 15, high-sensitivity C-reactive protein, galectin-3, and high-sensitivity troponin-T) in patients with advanced chronic heart failure. AB - Elevated natriuretic peptides provide strong prognostic information in patients with heart failure (HF). The role of novel biomarkers in HF needs to be established. Our objective was to evaluate the prognostic power of novel biomarkers, incremental to the N-terminal portion of the natriuretic peptide (NT proBNP) in chronic HF. Concentrations of circulating NT-proBNP, growth differentiation factor 15 (GDF-15), high-sensitivity C-reactive protein (hs-CRP), galectin-3 (Gal-3), and high-sensitivity troponin T (hs-TnT) were measured and related to all-cause long-term mortality. Of 209 patients (age 71 +/- 10 years, 73% male patients, 97% New York Heart Association class III), 151 (72%) died during a median follow-up of 8.7 +/- 1 year. The calculated area under the curve for NT-proBNP was 0.63, GDF-15 0.78, hs-CRP 0.66, Gal-3 0.68, and hs-TnT 0.68 (all p <0.01). Each marker was predictive for mortality in univariate analysis. In multivariate analysis, elevated concentrations of GDF-15 (hazard ratio [HR] 1.41, confidence interval [CI] 1.1 to 178, p = 0.005), hs-CRP (HR 1.38, CI 1.15 to 1.67, p = 0.001), and hs-TnT (HR 1.27, CI 1.06 to 1.53, p = 0.008) were independently related to mortality. All novel markers had an incremental value to NT-proBNP, using the integrated discrimination improvement. In conclusion, in chronic HF, GDF-15, hs-CRP, and hs-TnT are independent prognostic markers, incremental to NT-proBNP, in predicting long-term mortality. In this study, GDF 15 is the most predictive marker, even stronger than NT-proBNP. PMID- 23820572 TI - Synthesis and in vitro cytostatic activity of 1,2- and 1,3 diacylglycerophosphates of clofarabine. AB - The conjugates of anticancer nucleoside clofarabine [2-chloro-9-(2-deoxy-2-fluoro beta-d-arabinofuranosyl)adenine] with 1,2- and 1,3-diacylglycerophosphates have been prepared by the phosphoramidite method using a combination of 1,1,3,3 tetraisopropyldisiloxane-1,3-diyl protecting group for the sugar moiety of the nucleoside and 2-cyanoethyl protection for the phosphate fragment. Some of the synthesized conjugates exhibited cytostatic activity against HL-60, A-549, MCF-7, and HeLa tumor cell lines. PMID- 23820573 TI - Lipophilic derivatives of natural chlorins: synthesis, mixed micelles with phospholipids, and uptake by cultured cells. AB - The chemical synthesis of six lipophilic conjugates of chlorins was carried out, in which lipophilic fragment (either hexadecyl- or cholest-5-en-3beta-yloxyethyl ) bound to 13(1)-, 15(2)-, 17(3)-positions of macrocycle by formation of related carboxamides. Structure of synthesized conjugates was studied by spectral methods and molecular modeling. Lipophilic conjugates of chlorins, being mixed with egg yolk phosphatidyl choline, formed mixed micelles stable in aqueous media under physiological conditions. Mixed micelles of conjugates with phosphatidyl choline differing in stoichiometric compositions were prepared and characterized by absorption spectra, electron microscopy and laser scattering. These micelles were found to bind and internalized by human breast carcinoma MCF-7 cells. The presented data reveal that modification of macrocycle with lipophilic substituents, solubilization of obtained conjugates in aqueous medium as mixed micelles with phospholipids, and transfer of mixed micelles to cells is simple approach for targeting of chlorin derivatives, which apparently may be used in photodynamic therapy. PMID- 23820574 TI - Novel N-hydroxyfurylacrylamide-based histone deacetylase (HDAC) inhibitors with branched CAP group (Part 2). AB - Histone deacetylases (HDACs) are significant enzymes involved in tumor genesis and development. Herein, we report a series of novel N-hydroxyfurylacryl-amide based HDAC inhibitors, which are marked by introducing branched hydrophobic groups as the capping group. The inhibitory activity of the synthesized compounds against HDACs and several tumor cell lines are firstly determined. Fifteen compounds with promising activities are selected for further evaluation of target selectivity profile against recombinant human HDAC1, HDAC4 and HDAC6. Compounds 10a, 10b, 10d and 16a exhibit outstanding selectivity against HDAC6. Analysis of HDAC4 X-ray structure and HDAC1, HDAC6 homology model indicates that these enzyme differ significantly in the rim near the surface of the active site. Although TSA has been known as a pan-HDAC inhibitor, it exhibits outstanding selectivity for HDAC6 over HDAC4. For further physicochemical properties study, six compounds are chosen for determination of their physicochemical properties including logD7.4 and aqueous solubility. The results suggest that compounds with a smaller framework and with hydrophilicgroups are likely to have better aqueous solubility. PMID- 23820575 TI - [Transition of care from the perspective of adult rheumatology]. PMID- 23820576 TI - Effect of riparian vegetation on diatom assemblages in headwater streams under different land uses. AB - Differences in the structure of diatom assemblages in headwaters with contrasting shading conditions and different land use in the buffer zone and upper catchment were studied in order to evaluate the influence of the lack of riparian vegetation on the biofilm. The objective was to ascertain whether a riparian buffer can mitigate the negative influence of human induced disturbance and pollution on diatom assemblages in headwaters. Four streams were selected in order to maximize the differences in the land cover and minimize other environmental gradients. Multivariate statistics, different comparative and permutation tests and correlations were applied to compare the diatom assemblages, the Specific Polluosensitivity Index (IPS) and the diatom ecological guilds (low profile, high profile and motile) among the sites studied and to evaluate their responses to disturbances. The analysis showed that low profile diatoms typically dominated in forested headwaters with limited resources, whilst assemblages at impacted sites showed a wider range of growth forms. In unimpacted streams, the diatom assemblages were influenced by temperature, pH, conductivity and calcium, as usually reported for oligotrophic streams with high natural disturbance due to fast current and shading. In both shaded and unshaded impacted streams, the importance of nutrients and land use disturbance, especially urbanization, prevailed. This trend was also reflected by the IPS index that showed consistently lower values at impacted sites, correlating most significantly with nutrients. The diatom species composition as well as diatom guilds at impacted sites were similar, regardless of the presence or absence of riparian vegetation, and were significantly influenced by seasonal changes. Our results indicate that diatoms react sensitively to alterations of the water environment in headwaters, induced by anthropogenic activities, and these impacts are not buffered by an intact riparian zone. Diatoms closely reflected land use practices in the upper catchment regardless of the buffer zone status. PMID- 23820577 TI - Rapid and accurate identification of in vivo-induced haploid seeds based on oil content in maize. AB - The needs of a growing human population require rapid and efficient development of improved cultivars by plant breeders. The doubled haploid (DH) technology enables generating completely homozygous lines in a single step and, thus, is central to modern genetics and breeding approaches. Rapid and reliable identification of seeds with a haploid embryo after in vivo haploid induction is elementary in the method utilized in maize but current systems have severe shortcomings preventing their use in many germplasm types. Here, we describe an alternative method for discrimination of haploid from diploid seeds based on differences in their oil content stemming from pollination with high oil inducers. After presenting some fundamental theory, we provide a proof-of-concept with experimental results, demonstrating acceptable error rates across different germplasm. Our approach represents a breakthrough in DH technology in maize, because it is amenable to automated high-throughput screening and applicable to any maize germplasm worldwide. PMID- 23820578 TI - Cysteamine-modified silver nanoparticle aggregates for quantitative SERS sensing of pentachlorophenol with a portable Raman spectrometer. AB - Cysteamine-modified silver nanoparticle aggregates has been fabricated for pentachlorophenol (PCP) sensing by surface-enhanced Raman spectroscopy (SERS) using a portable Raman spectrometer. The cysteamine monolayers could preconcentrate PCP close to the substrate surface through the electrostatic interaction, which makes the SERS detection of PCP possible. Moreover, the Raman bands of cysteamine could be used as the internal spectral reference in the quantitative analysis. Qualitative detection of PCP was carried out by SERS without any sample pretreatment. Quantitative analysis of PCP was further realized based on the prepared substrate, as the log-log plot of normalized SERS intensity of PCP versus its concentrations exhibits a good linear relationship. The SERS signals collected on 20 randomly selected points show that the relative standard deviation of the normalized Raman intensity is 5.8%, which indicates the substrate had good uniformity. The PCP sensor also shows good long-term stability in the analyte solution. The substrate was cyclic immersed into PCP and methanol solution; after several cycles, the sensor still had good adsorption to PCP, which revealed the sensor has good reusability. Coupling with a portable Raman spectrometer, the cysteamine-modified silver nanoparticle aggregates have the potential to be used for in situ and routine SERS analysis of PCP in environmental samples. PMID- 23820579 TI - Homoeologous chromosomes of Xenopus laevis are highly conserved after whole genome duplication. AB - It has been suggested that whole-genome duplication (WGD) occurred twice during the evolutionary process of vertebrates around 450 and 500 million years ago, which contributed to an increase in the genomic and phenotypic complexities of vertebrates. However, little is still known about the evolutionary process of homoeologous chromosomes after WGD because many duplicate genes have been lost. Therefore, Xenopus laevis (2n=36) and Xenopus (Silurana) tropicalis (2n=20) are good animal models for studying the process of genomic and chromosomal reorganization after WGD because X. laevis is an allotetraploid species that resulted from WGD after the interspecific hybridization of diploid species closely related to X. tropicalis. We constructed a comparative cytogenetic map of X. laevis using 60 complimentary DNA clones that covered the entire chromosomal regions of 10 pairs of X. tropicalis chromosomes. We consequently identified all nine homoeologous chromosome groups of X. laevis. Hybridization signals on two pairs of X. laevis homoeologous chromosomes were detected for 50 of 60 (83%) genes, and the genetic linkage is highly conserved between X. tropicalis and X. laevis chromosomes except for one fusion and one inversion and also between X. laevis homoeologous chromosomes except for two inversions. These results indicate that the loss of duplicated genes and inter- and/or intrachromosomal rearrangements occurred much less frequently in this lineage, suggesting that these events were not essential for diploidization of the allotetraploid genome in X. laevis after WGD. PMID- 23820580 TI - Testing the consistency of connectivity patterns for a widely dispersing marine species. AB - Connectivity is widely recognized as an important component in developing effective management and conservation strategies. Although managers are generally most interested in demographic, rather than genetic connectivity, new analytic approaches are able to provide estimates of both demographic and genetic connectivity measures from genetic data. Combining such genetic data with mathematical models represents a powerful approach for accurately determining patterns of population connectivity. Here, we use microsatellite markers to investigate the genetic population structure of the New Zealand Rock Lobster, Jasus edwardsii, which has one of the longest known larval durations of all marine species (>2 years), a very large geographic range (>5500 km), and has been the subject of extensive dispersal modeling. Despite earlier mitochondrial DNA studies finding homogeneous genetic structure, the mathematical model suggests that there are source-sink dynamics for this species. We found evidence of genetic structure in J. edwardsii populations with three distinct genetic groups across New Zealand and a further Australian group; these groups and patterns of gene flow were generally congruent with the earlier mathematical model. Of particular interest was the consistent identification of a self-recruiting population/region from both modeling and genetic approaches. Although there is the potential for selection and harvesting to influence the patterns we observed, we believe oceanographic processes are most likely responsible for the genetic structure observed in J. edwardsii. Our results, using a species at the extreme end of the dispersal spectrum, demonstrate that source-sink population dynamics may still exist for such species. PMID- 23820582 TI - Rapid range expansion increases genetic differentiation while causing limited reduction in genetic diversity in a damselfly. AB - Many ectothermic species are currently expanding their geographic range due to global warming. This can modify the population genetic diversity and structure of these species because of genetic drift during the colonization of new areas. Although the genetic signatures of historical range expansions have been investigated in an array of species, the genetic consequences of natural, contemporary range expansions have received little attention, with the only studies available focusing on range expansions along a narrow front. We investigate the genetic consequences of a natural range expansion in the Mediterranean damselfly Coenagrion scitulum, which is currently rapidly expanding along a broad front in different directions. We assessed genetic diversity and genetic structure using 12 microsatellite markers in five centrally located populations and five recently established populations at the edge of the geographic distribution. Our results suggest that, although a marginal significant decrease in the allelic richness was found in the edge populations, genetic diversity has been preserved during the range expansion of this species. Nevertheless, edge populations were genetically more differentiated compared with core populations, suggesting genetic drift during the range expansion. The smaller effective population sizes of the edge populations compared with central populations also suggest a contribution of genetic drift after colonization. We argue and document that range expansion along multiple axes of a broad expansion front generates little reduction in genetic diversity, yet stronger differentiation of the edge populations. PMID- 23820583 TI - The organization of the quorum sensing luxI/R family genes in Burkholderia. AB - Members of the Burkholderia genus of Proteobacteria are capable of living freely in the environment and can also colonize human, animal and plant hosts. Certain members are considered to be clinically important from both medical and veterinary perspectives and furthermore may be important modulators of the rhizosphere. Quorum sensing via N-acyl homoserine lactone signals (AHL QS) is present in almost all Burkholderia species and is thought to play important roles in lifestyle changes such as colonization and niche invasion. Here we present a census of AHL QS genes retrieved from public databases and indicate that the local arrangement (topology) of QS genes, their location within chromosomes and their gene neighborhoods show characteristic patterns that differ between the known Burkholderia clades. In sequence phylogenies, AHL QS genes seem to cluster according to the local gene topology rather than according to the species, which suggests that the basic topology types were present prior to the appearance of current Burkholderia species. The data are available at http://net.icgeb.org/burkholderia/. PMID- 23820581 TI - Evolutionary and dispersal history of Eurasian house mice Mus musculus clarified by more extensive geographic sampling of mitochondrial DNA. AB - We examined the sequence variation of mitochondrial DNA control region and cytochrome b gene of the house mouse (Mus musculus sensu lato) drawn from ca. 200 localities, with 286 new samples drawn primarily from previously unsampled portions of their Eurasian distribution and with the objective of further clarifying evolutionary episodes of this species before and after the onset of human-mediated long-distance dispersals. Phylogenetic analysis of the expanded data detected five equally distinct clades, with geographic ranges of northern Eurasia (musculus, MUS), India and Southeast Asia (castaneus, CAS), Nepal (unspecified, NEP), western Europe (domesticus, DOM) and Yemen (gentilulus). Our results confirm previous suggestions of Southwestern Asia as the likely place of origin of M. musculus and the region of Iran, Afghanistan, Pakistan, and northern India, specifically as the ancestral homeland of CAS. The divergence of the subspecies lineages and of internal sublineage differentiation within CAS were estimated to be 0.37-0.47 and 0.14-0.23 million years ago (mya), respectively, assuming a split of M. musculus and Mus spretus at 1.7 mya. Of the four CAS sublineages detected, only one extends to eastern parts of India, Southeast Asia, Indonesia, Philippines, South China, Northeast China, Primorye, Sakhalin and Japan, implying a dramatic range expansion of CAS out of its homeland during an evolutionary short time, perhaps associated with the spread of agricultural practices. Multiple and non-coincident eastward dispersal events of MUS sublineages to distant geographic areas, such as northern China, Russia and Korea, are inferred, with the possibility of several different routes. PMID- 23820584 TI - KRAS and MAPK1 gene amplification in type II ovarian carcinomas. AB - In this study, we examined the clinical significance of KRAS and MAPK1 amplification and assessed whether these amplified genes were potential therapeutic targets in type II ovarian carcinoma. Using fluorescence in situ hybridization, immunohistochemistry, and retrospectively collected clinical data, KRAS and MAPK1 amplifications were identified in 9 (13.2%) and 5 (7.4%) of 68 type II ovarian carcinoma tissue samples, respectively. Interestingly, co amplification of KRAS and MAPK1 seemed to be absent in the type II ovarian carcinomas tested, except one case. Active phospho-ERK1/2 was identified in 26 (38.2%) out of 68 type II ovarian carcinomas and did not correlate with KRAS or MAPK1 amplification. There was no significant relationship between KRAS amplification and overall or progression-free survival in patients with type II ovarian carcinoma. However, patients with MAPK1 amplification had significantly poorer progression-free survival than patients without MAPK1 amplification. Moreover, type II ovarian carcinoma cells with concomitant KRAS amplification and mutation exhibited dramatic growth reduction following treatment with the MEK inhibitor PD0325901. These findings indicate that KRAS/MAPK1 amplification is critical for the growth of a subset of type II ovarian carcinomas. Additionally, RAS/RAF/MEK/ERK pathway-targeted therapy may benefit selected patients with type II ovarian carcinoma harboring KRAS/MAPK1 amplifications. PMID- 23820585 TI - Biosynthetic pathway and health benefits of fucoxanthin, an algae-specific xanthophyll in brown seaweeds. AB - Fucoxanthin is the main carotenoid produced in brown algae as a component of the light-harvesting complex for photosynthesis and photoprotection. In contrast to the complete elucidation of the carotenoid biosynthetic pathways in red and green algae, the biosynthetic pathway of fucoxanthin in brown algae is not fully understood. Recently, two models for the fucoxanthin biosynthetic pathway have been proposed in unicellular diatoms; however, there is no such information for the pathway in brown seaweeds to date. Here, we propose a biosynthetic pathway for fucoxanthin in the brown seaweed, Ectocarpus siliculosus, derived from comparison of carotenogenic genes in its sequenced genome with those in the genomes of two diatoms, Thalassiosira pseudonana and Phaeodactylum tricornutum. Currently, fucoxanthin is receiving attention, due to its potential benefits for human health. Therefore, new knowledge regarding the medical and nutraceutical properties of fucoxanthin from brown seaweeds is also summarized here. PMID- 23820586 TI - PAS-induced potentiation of cortical-evoked activity in the dorsolateral prefrontal cortex. AB - Neuroplasticity and long-term potentiation (LTP) in the dorsolateral prefrontal cortex (DLPFC) are considered important mechanisms in learning and memory, and their disruption may be related to the pathophysiology of several neuropsychiatric disorders. Paired associative stimulation (PAS) is a brain stimulation paradigm that produces enhanced activity in the human motor cortex that may be related to LTP. In a group of 15 healthy participants, we report on the potentiation of cortical-evoked activity in the human DLPFC using the combination of PAS and electroencephalography. In contrast, a PAS control condition did not result in potentiation in another group of nine healthy participants. We also demonstrate that PAS-induced potentiation of cortical evoked activity is characterized by anatomical specificity that is largely confined to the site of stimulation. Finally, we show that PAS results in potentiation of theta- and gamma-activity and theta-phase-gamma-amplitude coupling. These neurophysiological indices may be related to working memory, an important function of the DLPFC. To our knowledge, this is the first report of potentiation of cortical-evoked activity in the DLPFC. As this potentiation may be related to LTP, our findings provide a model through which neuroplasticity in health and disease states in the frontal cortex can be studied. PMID- 23820587 TI - Alzheimer's disease and Parkinson's disease genome-wide association study top hits and risk of Parkinson's disease in Korean population. AB - Alzheimer's disease (AD) and Parkinson's disease (PD) have overlapping clinical and pathological features, suggesting a common pathway for these 2 neurodegenerative disorders. Here we investigated the association of both AD and PD GWAS top hits with PD susceptibility. We selected 25 single nucleotide polymorphisms (SNPs) in 9 genes (ABCA7, APOE, BST1, CLU, CR1, LRRK2, PARK16, PICALM, and SNCA) that were genotyped in 1036 PD case patients and 1208 controls. Case patients and controls were all ethnic Koreans. Logistic regression analysis was performed to calculate age- and sex-adjusted odds ratios. None of the AD susceptibility loci (ABCA7, APOE, CLU, CR1, and PICALM) showed statistically significant association with PD susceptibility. In contrast, we replicated associations of SNCA, LRRK2, BST1, and PARK16 with PD susceptibility in Koreans. Of those, the SNCA SNP rs11931074 showed the most significant association with PD susceptibility (adjusted odds ratio = 1.48; 95% confidence interval = 1.31-1.67; p = 2.20E-10). In a logistic regression analysis with SNPs coded under an additive model, there was no significant genetic interaction between the LRRK2 and the PARK16 locus gene RAB7L1 in PD risk. Our results confirm the associations of SNCA, LRRK2, BST1, and PARK16 with PD susceptibility and fail to show significant associations of AD genome-wide association study (GWAS) top hits with PD susceptibility in a Korean population. PMID- 23820588 TI - Striatal shape in Parkinson's disease. AB - Parkinson's disease (PD) is marked pathologically by nigrostriatal dopaminergic terminal loss. Histopathological and in vivo labeling studies demonstrate that this loss occurs most extensively in the caudal putamen and caudate head. Previous structural studies have suggested reduced striatal volume and atrophy of the caudate head in PD subjects. The spatial distribution of atrophy in the putamen, however, has not been characterized. We aimed to delineate the specific locations of atrophy in both of these striatal structures. T1- and T2-weighted brain MR (3T) images were obtained from 40 PD and 40 control subjects having no dementia and similar age and gender distributions. Shape analysis was performed using doubly segmented regions of interest. Compared to controls, PD subjects had lower putamen (p = 0.0003) and caudate (p = 0.0003) volumes. Surface contraction magnitudes were greatest on the caudal putamen (p <= 0.005) and head and dorsal body of the caudate (p <= 0.005). This spatial distribution of striatal atrophy is consistent with the known pattern of dopamine depletion in PD and may reflect global consequences of known cellular remodeling phenomena. PMID- 23820589 TI - Cholinergic activity correlates with reserve proxies in Alzheimer's disease. AB - The clinical expression of Alzheimer's disease (AD) occurs as neuropathology exceeds the brain "reserve capacity." A possible association between the cholinergic system and reserve is suggested by preclinical observations that the cholinergic system allows cortical plasticity and by clinical observations of variable responses to cholinergic treatments depending on the patient's educational level. The aim of this study was to investigate the association of reserve proxies, that is, education and occupation, with acetylcholinesterase (AChE) activity, measured voxelwise by [(11)C]-MP4A and positron emission tomography (PET), in 9 healthy controls (HC), 7 patients with early probable AD, and 9 subjects with mild cognitive impairment (MCI) at the time of PET imaging, who progressed to AD at follow-up (prodromal AD). The analysis of prodromal and early AD showed positive correlations between education and AChE activity in the hippocampus, bilaterally, and between occupation and AChE activity in the right posterior cingulate gyrus. The significant correlation between AChE activity in structures belonging to the memory network and reserve proxies suggests that the brain reserve in AD is associated with a preserved/stimulated cholinergic neurotransmission. PMID- 23820590 TI - Strengthening effect of single-atomic-layer graphene in metal-graphene nanolayered composites. AB - Graphene is a single-atomic-layer material with excellent mechanical properties and has the potential to enhance the strength of composites. Its two-dimensional geometry, high intrinsic strength and modulus can effectively constrain dislocation motion, resulting in the significant strengthening of metals. Here we demonstrate a new material design in the form of a nanolayered composite consisting of alternating layers of metal (copper or nickel) and monolayer graphene that has ultra-high strengths of 1.5 and 4.0 GPa for copper-graphene with 70-nm repeat layer spacing and nickel-graphene with 100-nm repeat layer spacing, respectively. The ultra-high strengths of these metal-graphene nanolayered structures indicate the effectiveness of graphene in blocking dislocation propagation across the metal-graphene interface. Ex situ and in situ transmission electron microscopy compression tests and molecular dynamics simulations confirm a build-up of dislocations at the graphene interface. PMID- 23820591 TI - Activation of RAW264.7 mouse macrophage cells in vitro through treatment with recombinant ricin toxin-binding subunit B: involvement of protein tyrosine, NF kappaB and JAK-STAT kinase signaling pathways. AB - Ricin toxin-binding subunit B (RTB) is a galactose-binding lectin protein. In the present study, we investigated the effects of RTB on inducible nitric oxide (NO) synthase (iNOS), interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha, as well as the signal transduction mechanisms involved in recombinant RTB-induced macrophage activation. RAW264.7 macrophages were treated with RTB. The results revealed that the mRNA and protein expression of iNOS was increased in the recombinant RTB-treated macrophages. TNF-alpha production was observed to peak at 20 h, whereas the production of IL-6 peaked at 24 h. In another set of cultures, the cells were co-incubated with RTB and the tyrosine kinase inhibitor, genistein, the phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, the p42/44 inhibitor, PD98059, the p38 inhibitor, SB203580, the JNK inhibitor, SP600125, the protein kinase C (PKC) inhibitor, staurosporine, the JAK2 inhibitor, tyrphostin (AG490), or the NOS inhibitor, L-NMMA. The recombinant RTB induced production of NO, TNF-alpha and IL-6 was inhibited in the macrophages treated with the pharmacological inhibitors genistein, LY294002, staurosporine, AG490, SB203580 and BAY 11-7082, indicating the possible involvement of protein tyrosine kinases, PI3K, PKC, JAK2, p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-kappaB in the above processes. A phosphoprotein analysis identified tyrosine phosphorylation targets that were uniquely induced by recombinant RTB and inhibited following treatment with genistein; some of these proteins are associated with the downstream cascades of activated JAK-STAT and NF kappaB receptors. Our data may help to identify the most important target molecules for the development of novel drug therapies. PMID- 23820592 TI - Measures of personal recovery: a systematic review. AB - OBJECTIVE Mental health systems internationally have adopted a goal of supporting recovery. Measurement of the experience of recovery is, therefore, a priority. The aim of this review was to identify and analyze recovery measures in relation to their fit with recovery and their psychometric adequacy. METHODS A systematic search of six data sources for articles, Web-based material, and conference presentations related to measurement of recovery was conducted by using a defined search strategy. Results were filtered by title and by abstract (by two raters in the case of abstracts), and the remaining papers were reviewed to identify any suitable measures of recovery. Measures were then evaluated for their fit with the recovery processes identified in the CHIME framework (connectedness, hope, identity, meaning, and empowerment) and for demonstration of nine predefined psychometric properties. RESULTS Thirteen measures of personal recovery were identified from 336 abstracts and 35 articles. The Recovery Assessment Scale (RAS) was published most, and the Questionnaire About the Process of Recovery (QPR) was the only measure to have all items map to the CHIME framework. No measure demonstrated all nine psychometric properties. The Stages of Recovery Instrument demonstrated the most psychometric properties (N=6), followed by the Maryland Assessment of Recovery (N=5), and the QPR and the RAS (N=4). Criterion validity, responsiveness, and feasibility were particularly underinvestigated properties. CONCLUSIONS No recovery measure can currently be unequivocally recommended, although the QPR most closely maps to the CHIME framework of recovery and the RAS is most widely published. PMID- 23820593 TI - The use of STEM imaging to analyze thickness variations due to electromigration induced mass transport in thin polycrystalline nanobridges. AB - Scanning transmission electron microscopy (STEM) imaging is applied to analyze the electromigration-induced thickness variations of thin polycrystalline films. It is shown that a high angle annular dark field (HAADF) detector is required to minimize the effect of diffraction contact. A further reduction of the diffraction contrast can be obtained using a tilt series. A correlation between the intensity of the STEM signal obtained with the HAADF detector and the real thickness value was found by comparing corresponding STEM and AFM images. STEM in combination with a tilt series can determine the material distribution in polycrystalline films and can accurately analyze 1-3 nm gaps of nanoelectrodes formed by electromigration. PMID- 23820594 TI - Estimation of unknown structure parameters from high-resolution (S)TEM images: what are the limits? AB - Statistical parameter estimation theory is proposed as a quantitative method to measure unknown structure parameters from electron microscopy images. Images are then purely considered as data planes from which structure parameters have to be determined as accurately and precisely as possible using a parametric statistical model of the observations. For this purpose, an efficient algorithm is proposed for the estimation of atomic column positions and intensities from high angle annular dark field (HAADF) scanning transmission electron microscopy (STEM) images. Furthermore, the so-called Cramer-Rao lower bound (CRLB) is reviewed to determine the limits to the precision with which continuous parameters such as atomic column positions and intensities can be estimated. Since this lower bound can only be derived for continuous parameters, alternative measures using the principles of detection theory are introduced for problems concerning the estimation of discrete parameters such as atomic numbers. An experimental case study is presented to show the practical use of these measures for the optimization of the experiment design if the purpose is to decide between the presence of specific atom types using STEM images. PMID- 23820596 TI - Legacies of the Gerchberg-Saxton algorithm. AB - To celebrate W. Owen Saxton's 65th birthday, this paper presents some of the impact that the Gerchberg-Saxton algorithm has had over the last 40 years. We explore some of the fundamental concepts underlying the success of the Gerchberg Saxton algorithm, in the context of how it stimulated many related methods for estimating fields and deepening the understanding of the relationships between complex objects, images and their Fourier transforms. PMID- 23820598 TI - Continuously manufactured magnetic polymersomes--a versatile tool (not only) for targeted cancer therapy. AB - Micromixer technology was used to prepare polymeric vesicles (Pluronic(r) L-121) dual loaded with the anti-cancer drug camptothecin and magnetic nanoparticles. Successful incorporation of the magnetic nanoparticles was confirmed by transmission electron microscopy. Dynamic light scattering measurements showed a relatively narrow size distribution of the hybrid polymersomes. Camptothecin polymersomes reduced the cell viability of prostate cancer cells (PC-3) measured after 72 h significantly, while drug-free polymersomes showed no cytotoxic effects. Covalent attachment of a cancer targeting peptide (bombesin) as well as a fluorescent label (Alexa Fluor(r) 647) to the hybrid polymersomes was performed and specific cell binding and internalization were shown by flow cytometry and confocal microscopy. Relaxometry measurements clearly demonstrated the capacity of magnetic polymersomes to generate significant T2-weighted MRI contrast and potentially allow for direct monitoring of the biodistribution of the polymersomes. Micromixer technology as an easy, fast and efficient way to manufacture hybrid polymersomes as theranostic drug delivery devices is a further step from basic research to personalized medicine. PMID- 23820597 TI - A novel frontal pathway underlies verbal fluency in primary progressive aphasia. AB - The frontal aslant tract is a direct pathway connecting Broca's region with the anterior cingulate and pre-supplementary motor area. This tract is left lateralized in right-handed subjects, suggesting a possible role in language. However, there are no previous studies that have reported an involvement of this tract in language disorders. In this study we used diffusion tractography to define the anatomy of the frontal aslant tract in relation to verbal fluency and grammar impairment in primary progressive aphasia. Thirty-five patients with primary progressive aphasia and 29 control subjects were recruited. Tractography was used to obtain indirect indices of microstructural organization of the frontal aslant tract. In addition, tractography analysis of the uncinate fasciculus, a tract associated with semantic processing deficits, was performed. Damage to the frontal aslant tract correlated with performance in verbal fluency as assessed by the Cinderella story test. Conversely, damage to the uncinate fasciculus correlated with deficits in semantic processing as assessed by the Peabody Picture Vocabulary Test. Neither tract correlated with grammatical or repetition deficits. Significant group differences were found in the frontal aslant tract of patients with the non-fluent/agrammatic variant and in the uncinate fasciculus of patients with the semantic variant. These findings indicate that degeneration of the frontal aslant tract underlies verbal fluency deficits in primary progressive aphasia and further confirm the role of the uncinate fasciculus in semantic processing. The lack of correlation between damage to the frontal aslant tract and grammar deficits suggests that verbal fluency and grammar processing rely on distinct anatomical networks. PMID- 23820599 TI - Is mindfulness associated with insomnia after menopause? AB - OBJECTIVE: Mindfulness has been defined as being intentionally aware of internal and external experiences that occur at the present moment, without judgment. Techniques that develop mindfulness, such as meditation, have positive effects on reducing insomnia, a sleep disorder that is common both during and after menopause. Our aim was to establish whether postmenopausal women with insomnia are less mindful than postmenopausal women without sleep disorders. METHODS: Postmenopausal women aged 50 to 65 years who did not use hormone therapy were recruited for the study. The sample included 14 women with insomnia and 12 women without insomnia or any other sleep disorder. The groups were comparable in age, schooling, and anxiety level. To assess mindfulness, we used the validated Mindful Attention Awareness Scale and the attentiveness domain of the Positive and Negative Affect Schedule-Expanded Form. RESULTS: Participants with insomnia were less mindful than healthy women. The level of mindfulness was able to discriminate the group with insomnia from the healthy group, with 71.4% accuracy. CONCLUSIONS: Postmenopausal women with insomnia are less mindful than women without insomnia. Mindfulness-based interventions, such as meditation, may be beneficial for postmenopausal insomnia. PMID- 23820600 TI - Increased hot flash severity and related interference in perimenopausal human immunodeficiency virus-infected women. AB - OBJECTIVE: As women with human immunodeficiency virus (HIV) are living longer, more are entering perimenopause. Prior studies suggest that HIV-infected women are more likely to have hot flashes than non-HIV-infected women. However, little is known regarding hot flash severity and hot flash-related interference with daily function, mood, and quality of life in this population. METHODS: Perimenopausal HIV-infected and non-HIV-infected women matched by age, race, and menstrual patterns completed the Menopause Rating Scale (to assess hot flash severity) and the Hot Flash Related Daily Interference Scale (HFRDIS). Menopause Rating Scale and HFRDIS scores and subscores were compared between the groups. RESULTS: Thirty-three HIV-infected women and 33 non-HIV-infected women who were similar in age (median [interquartile range], 47 [45-48] vs 47 [46-49] y), race (64% vs 52% nonwhite, P = 0.32), and menstrual patterns (number of periods in the past year; 5 [4-9] vs 6 [4-10], P = 0.53) were studied. Perimenopausal HIV infected women reported greater hot flash severity (HIV vs non-HIV: 2 [1-3] vs 1 [0-3], P = 0.03) and hot flash-related interference (HFRDIS total score, 37 [10 60] vs 6 [0-20], P = 0.001). CONCLUSIONS: Perimenopausal HIV-infected women experience greater hot flash severity and related interference compared with non HIV-infected perimenopausal women. Increased distress secondary to hot flashes may reduce quality of life and negatively impact important health-promoting behaviors, including adherence to antiretroviral therapy, in HIV-infected women. PMID- 23820601 TI - Associations between dietary and lifestyle risk factors and colorectal cancer in the Scottish population. AB - Colorectal cancer (CRC) accounts for 9.7% of all cancer cases and for 8% of all cancer-related deaths. Established risk factors include personal or family history of CRC as well as lifestyle and dietary factors. We investigated the relationship between CRC and demographic, lifestyle, food and nutrient risk factors through a case-control study that included 2062 patients and 2776 controls from Scotland. Forward and backward stepwise regression was applied and the stability of the models was assessed in 1000 bootstrap samples. The variables that were automatically selected to be included by the forward or backward stepwise regression and whose selection was verified by bootstrap sampling in the current study were family history, dietary energy, 'high-energy snack foods', eggs, juice, sugar-sweetened beverages and white fish (associated with an increased CRC risk) and NSAIDs, coffee and magnesium (associated with a decreased CRC risk). Application of forward and backward stepwise regression in this CRC study identified some already established as well as some novel potential risk factors. Bootstrap findings suggest that examination of the stability of regression models by bootstrap sampling is useful in the interpretation of study findings. 'High-energy snack foods' and high-energy drinks (including sugar sweetened beverages and fruit juices) as risk factors for CRC have not been reported previously and merit further investigation as such snacks and beverages are important contributors in European and North American diets. PMID- 23820602 TI - Morphological and molecular characterization of Lecithochirium grandiporum (Digenea: Hemiuridae) infecting the European eel Anguilla anguilla as a new host record in Egypt. AB - In the present study, the morphological and molecular characterization of Lecithochirium grandiporum, a digenetic trematode infecting the European eel Anguilla anguilla (Family (F): Anguillidae), were described for the first time from Burullus Lake, Kafr El-Sheikh Governorate, Egypt. Twenty-five out of 60 specimens (infection rate of 41.66%) were found to be naturally infected. Infection was recorded as small worms attached to the inner wall of the intestine of host fish. Adult worms measured 1.59 +/- 0.20 (1.3-1.85) mm long and 0.3 +/- 0.02 (0.29-0.48) mm wide for everted specimens with a smaller oral sucker measuring 0.15 +/- 0.02 (0.13-0.18) mm, and a larger ventral sucker which was 0.16 +/- 0.02 (0.14-0.25) mm. Our results recorded morphological differences as smaller dimensions of different body parts and the smaller oral/ventral sucker ratio between Lecithochirium fusiforme and L. grandiporum. Also, the phylogenetic position of the worm was determined by molecular characterization of their 18 SSU rDNA. Results were compared with those of previously recorded species on the Gene Bank. It was found that the present species coincide with those belonging to genus Lecithochirium. Comparison of the nucleotide sequences and divergence showed that the SSU rDNA gene of this Lecithochirium species revealed 92 % sequence identity with L. fusiforme (accession no. DQ413192) differing in 26 nucleotides with lower divergence value. According to these results, this study indicated that the present species is recorded as L. grandiporum with accession no. KC166146 as a parasite with new host and locality records in Egypt. PMID- 23820603 TI - Development of a facile system for mass production of Brugia malayi in a small space laboratory. AB - Brugia malayi is one of the important lymphatic filarial nematodes that cause elephantiasis and disability in humans in the Asian region. Mass production at any stage of this nematode in both small laboratory animal hosts and mosquito vectors is still necessary in order to continue various research aspects. This study elucidated on the use of nonblood feeding or the autogenous Ochlerotatus togoi (Thailand strain) and male Mongolian jird (Meriones unguiculatus) system. This has brought about a low-cost and highly-effective procedure for the mass production of blood containing microfilariae, infective (L3) larvae, and adults of B. malayi under nonanimal-blood-feeding insectary and small-space animal-house conditions. The highly-infective rates (human-heparinized blood, 86.67-93.33; swine-heparinized blood, 83.33-96.67; bovine-heparinized blood, 76.67-80; chicken heparinized blood, 73.33-76.67) and parasite loads (human-heparinized blood, 10.58-12.36; swine-heparinized blood, 8.40-10.38; bovine-heparinized blood, 9.75 9.91; chicken-heparinized blood, 3.41-4.65) of autogenous O. togoi to B. malayi and high numbers of adults recovered from ten B. malayi-infected male jirds (total = 327, 16-52) are good supportive evidence. In addition, all special techniques required for succeeding in the establishment of a facile system regarding these matters are detailed. PMID- 23820604 TI - Alteration in Bacillus thuringiensis toxicity by curing gut flora: novel approach for mosquito resistance management. AB - Mosquitoes are known for acquiring resistance against insecticides in many ways, namely target side mutation, enzyme modification, sequestration, quick elimination, etc. But, the role of microflora present in abundance in the larval midgut is less explored with respect to their role in insecticide resistance. During the course of their development, mosquitoes are continuously exposed to microbes and have naturally acquired midgut microbial flora. This midgut flora can modulate the mosquito's susceptibility to Bacillus thuringiensis (Bt) infection by degrading toxic Bt protein forms through an unknown mechanism. In this study, we show that microbe-free aseptic mosquito larvae displayed an increased susceptibility to Bt toxicity compared to larvae harboring natural microbial flora. Fourth instar larvae of Anopheles stephensi were treated separately with penicillin, streptomycin, erythromycin (100 MUg/ml), and mixtures of all three antibiotics and then analyzed for Bt toxicity. We have also examined the influence of the mosquito's midgut microbial flora under microaerophilic condition on the Bt protein degradation through plate, broth, TLC, and UV-vis spectrophotometric assay. A better understanding of the roles of microbiota in preventing Bt toxicity to mosquitoes could potentially lead to the development of new sustainable mosquito control strategies. PMID- 23820605 TI - Intra-phylum and inter-phyla associations among gastrointestinal parasites in two wild mammal species. AB - A growing body of literature reveals that the interactions among the parasite community may be strong and significant for parasite dynamics. There may be inter specific antagonistic interactions as a result of competition and cross-effective immune response, or synergistic interactions where infection by one parasite is facilitated by another one, either by an impoverishment of the host's defenses, parasite-induced selective immunosuppression, or trade-offs within the immune system. The nature of these interactions may depend on how related are the parasite species involved. Here we explored the presence of associations among gastrointestinal parasites (coccidia and helminths) in natural populations of two wild mammal species, the capybara (Hydrochoerus hydrochaeris) and the guanaco (Lama guanicoe). The associations explored were between the oocyst outputs of a selected Eimeria species and the other coccidia of that parasite community, and between Eimeria spp. and the predominant nematodes. The statistical analysis included adjustment for potential confounders or effect modifiers. In guanacos, the prevailing interactions were synergistic among the coccidia and between coccidia and nematodes (Nematodirus spp.). However, in capybaras, the interaction between nematodes (Viannaiidae) and Eimeria spp. depended on environmental and host factors. The relationship was positive in some circumstances (depending on season, year, sex, or animal size), but it appeared to become antagonistic under different scenarios. These antagonist interactions did not follow a particular seasonal pattern (they occurred in autumn, spring, and summer), but they were predominantly found in females (when they depended on sex) or in 2010 and 2011 (when they depended on the sampling year). These results suggest that the relationship between coccidia and nematodes in capybaras may be context dependent. We propose that the context-dependent immune investment documented in capybaras may be the cause of these varying interactions. PMID- 23820606 TI - Comparative analysis of macrophage migration inhibitory factors (MIFs) from the parasitic nematode Onchocerca volvulus and the free-living nematode Caenorhabditis elegans. AB - The macrophage migration inhibitory factors (MIFs) from the filarial parasite Onchocerca volvulus (OvMIF) were compared to the MIFs from the free-living nematode Caenorhabditis elegans (CeMIF) with respect to molecular, biochemical and immunological properties. Except for CeMIF-4, all other MIFs demonstrated tautomerase activity. Surprisingly, OvMIF-1 displayed oxidoreductase activity. The strongest immunostaining for OvMIF-1 was observed in the outer cellular covering of the adult worm body, the syncytial hypodermis; moderate immunostaining was observed in the uterine wall. The generation of a strong humoral immune response towards OvMIF-1 and reduced reactivity to OvMIF-2 was indicated by high IgG levels in patients infected with O. volvulus and cows infected with the closely related Onchocerca ochengi, both MIFs revealing identical amino acid sequences. Using Litomosoides sigmodontis-infected mice, a laboratory model for filarial infection, MIFs derived from the tissue-dwelling O. volvulus, the rodent gut-dwelling Strongyloides ratti and from free-living C. elegans were recognized, suggesting that L. sigmodontis MIF-specific IgM and IgG1 were produced during L. sigmodontis infection of mice and cross-reacted with all MIF proteins tested. Thus, MIF apparently functions as a target of B cell response during nematode infection, but in the natural Onchocerca-specific human and bovine infection, the induced antibodies can discriminate between MIFs derived from parasitic or free-living nematodes. PMID- 23820607 TI - Expression, immunolocalization and serodiagnostic value of Tc38630 protein from Trypanosoma congolense. AB - Animal African trypanosomosis is a serious constraint to livestock sector development in sub-Saharan Africa. The disease, mainly caused by Trypanosoma congolense, has a limitation in its diagnosis and treatment. There is urgent need for a simple, rapid detection technique to replace the few available serological tests that are of variable sensitivity and specificity. Currently, there is a promising use of recombinant proteins to improve on the trypanosome lysate to detect antibodies. In this respect, we have identified a stage-specific gene that is relatively highly expressed in metacyclic and blood trypomastigotes of T. congolense. According to previously obtained differential protein expression data, the gene TcIL3000.0.38630 (1,236 bp) is by 8.5 times more expressed in metacyclic and blood trypomastigotes than in procyclic trypomastigotes and epimastigotes. The same stage specific expression pattern was shown in Western blot analysis. In addition, in confocal laser scanning microscopy the Tc38630 protein was present in the cytosol and on the cell surface of metacyclic and blood trypomastigotes. Through bioinformatics, the Tc38630 had N-terminal signal sequence, hydrophilic extracellular domain, single transmembrane alpha-helix and short cytoplasmic domain, which is characteristic of the Trypanosoma brucei invariant surface glycoprotein. However, unlike T. brucei invariant surface glycoprotein, the Tc38630 existed as a single copy gene with a probable allelic polymorphism at the Nar I restriction site. The recombinant Tc38630-based ELISA detected antibodies against Tc38630 as early as 7 days post infection in experimentally infected mouse model. Taken together, our results suggest that the Tc38630 is a novel potential diagnostic antigen of Animal African trypanosomosis. PMID- 23820608 TI - Characterization and localization of an Eimeria-specific protein in Eimeria maxima. AB - A recently completed analysis of Eimeria maxima transcriptome identified a gene with homology to sequences expressed by E. tenella and E. acervulina but lacking homology with other organisms including other apicomplexans. This gene, designated Eimeria-specific protein (ESP), codes for a protein with a predicted molecular weight of 19 kDa. The ESP gene was cloned and the recombinant protein expressed in bacteria and purified for preparation of specific antisera. Quantitative RT-PCR showed transcription of ESP was low in unsporulated oocysts and after 24 h of sporulation. However, transcription nearly doubled after 48 h of sporulation and reached its highest levels in sporozoites (SZ) and merozoites (MZ). The protein was detectable by Western blot in both sporulated oocysts and in SZ and MZ. Immuno-localization by light microscopy identified ESP in paired structures in the anterior of SZ and MZ. Immuno-localization by electron microscopy identified ESP in MZ rhoptries but no specific staining of any SZ structures was detected. In addition, localization studies on intestinal sections recovered from birds 120-h post-infection indicates that oocysts do not stain with anti-ESP but staining of microgametocytes and developing oocysts was observed. The results indicate that ESP is associated with the rhoptry of E. maxima and that the protein may have functions in other developmental stages. PMID- 23820609 TI - Molecular characterization of Cryptosporidium isolates from high-excreting young dairy calves in dairy cattle herds in Western France. AB - Ninety-two Cryptosporidium sp.-positive fecal samples of dairy diarrheic or non diarrheic calves from 30 cattle herds in Normandy (France) were selected. Here, the aim was to investigate the species of Cryptosporidium excreted as well as the subtypes of Cryptosporidium parvum found in 7-17-day-old dairy calves. Excretion levels were comprised between 2 * 10(4) and 4 * 10(7) oocysts per gram of feces. Here, a nested 18S SSU rRNA PCR associated with sequencing was performed for identification of Cryptosporidium species and revealed the presence of C. parvum in most cases (80/82), except for two animals which were infected with Cryptosporidium bovis. Then, C. parvum samples were submitted to gp60 PCR. For 39 samples from 24 different herds, a multilocus analysis based on four mini microsatellites loci (MM19, MM5, MSF, and MS9-Mallon) were conducted. These results were combined with sequence analysis of the gp60 to obtain multilocus types (MLTs). Here, C. parvum gp60 genotyping identified three subtypes in the IIa zoonotic allele family: IIaA15G2R1 (88%), IIaA16G3R1 (10%), and IIaA19G2R1 (2%), and we identified 12 MLTs. The MS9-Mallon locus was reported as the most polymorphic (five alleles). The most common MLT was MLT 1 with 15 samples in 10 farms: (MS9-M: 298, MSF: 165, MM5: 264, MM19: 462, and gp60 subtype: IIaA15G2R1). When comparing diarrheic and non-diarrheic fecal samples, no difference was seen for distribution of Cryptosporidium species, C. parvum gp60 subtypes, and MLTs. Here, in a range of oocyst excretion of 10(4)-10(7) opg, both in diarrheic and non-diarrheic calves, infection was mainly due to C. parvum and to the zoonotic subtype: IIaA15G2R1. PMID- 23820611 TI - Real-time observation of the charge transfer to solvent dynamics. AB - Intermolecular electron-transfer reactions have a crucial role in biology, solution chemistry and electrochemistry. The first step of such reactions is the expulsion of the electron to the solvent, whose mechanism is determined by the structure and dynamical response of the latter. Here we visualize the electron transfer to water using ultrafast fluorescence spectroscopy with polychromatic detection from the ultraviolet to the visible region, upon photo-excitation of the so-called charge transfer to solvent states of aqueous iodide. The initial emission is short lived (~60 fs) and it relaxes to a broad distribution of lower energy charge transfer to solvent states upon rearrangement of the solvent cage. This distribution reflects the inhomogeneous character of the solvent cage around iodide. Electron ejection occurs from the relaxed charge transfer to solvent states with lifetimes of 100-400 fs that increase with decreasing emission energy. PMID- 23820610 TI - Alcohol-induced metabolomic differences in humans. AB - Alcohol consumption is one of the world's major risk factors for disease development. But underlying mechanisms by which moderate-to-heavy alcohol intake causes damage are poorly understood and biomarkers are sub-optimal. Here, we investigated metabolite concentration differences in relation to alcohol intake in 2090 individuals of the KORA F4 and replicated results in 261 KORA F3 and up to 629 females of the TwinsUK adult bioresource. Using logistic regression analysis adjusted for age, body mass index, smoking, high-density lipoproteins and triglycerides, we identified 40/18 significant metabolites in males/females with P-values <3.8E-04 (Bonferroni corrected) that differed in concentrations between moderate-to-heavy drinkers (MHD) and light drinkers (LD) in the KORA F4 study. We further identified specific profiles of the 10/5 metabolites in males/females that clearly separated LD from MHD in the KORA F4 cohort. For those metabolites, the respective area under the receiver operating characteristic curves were 0.812/0.679, respectively, thus providing moderate-to-high sensitivity and specificity for the discrimination of LD to MHD. A number of alcohol-related metabolites could be replicated in the KORA F3 and TwinsUK studies. Our data suggests that metabolomic profiles based on diacylphosphatidylcholines, lysophosphatidylcholines, ether lipids and sphingolipids form a new class of biomarkers for excess alcohol intake and have potential for future epidemiological and clinical studies. PMID- 23820612 TI - Linfuranone A, a new polyketide from plant-derived Microbispora sp. GMKU 363. PMID- 23820613 TI - Structure-activity relationship study of novel iminothiadiazolo-pyrimidinone antimicrobial agents. AB - An iminothiadiazolo-pyrimidinone derivative, 0002-04-KK, harboring a furan moiety, acts as an antimicrobial agent with a minimum inhibitory concentration (MIC) against Staphylococcus aureus of 25 MUg ml(-1). Several derivatives of 0002 04-KK were synthesized and among them 0026-59-KK, harboring a nitrofuran moiety, had the most potent antimicrobial activity with an MIC of 6 MUg ml(-1). Both 0002 04-KK and 0026-59-KK inhibited the biosynthesis of DNA, RNA and proteins. Peptidoglycan biosynthesis was inhibited by 0026-59-KK, and slightly inhibited by 0002-04-KK. Derivative 0002-04-KK showed bactericidal activity in contrast to the bacteriostatic activity of 0002-04-KK. Derivative 0002-04-KK had less toxicity in silkworms (lethal dose fifty (LD50): >230 MUg g(-1)) than 0002-04-KK (LD50: 100 MUg g(-1)). The bactericidal activity against S. aureus was because of the nitrofuran moiety. These findings suggest that iminothiadiazolo-pyrimidinone compounds could be used as lead molecules to develop antimicrobial agents. PMID- 23820614 TI - Langkocyclines: novel angucycline antibiotics from Streptomyces sp. Acta 3034(*). AB - Langkocyclines A1-A3 and B1 and B2, five new angucycline antibiotics produced by Streptomyces sp. Acta 3034, were detected in the course of our HPLC-diode array screening. The producing strain was isolated from the rhizospheric soil of a Clitorea sp. collected from Burau Bay, Langkawi, Malaysia, and was characterized by morphological, physiological and chemotaxonomic features in addition to 16S ribosomal RNA gene sequence information. Strain Acta 3034 is closely related to Streptomyces psammoticus NBRC 13971(T) and Streptomyces lanatus NBRC 12787(T). Langkocyclines consist of an angular tetracyclic benz[a]anthracene skeleton and hydrolyzable O-glycosidic sugar moieties. The yellow-colored A-type langkocyclines differ in their aglycon from the blue-lilac-colored B-type langkocyclines. The A-type langkocycline aglycon is identical to that of aquayamycin and urdamycin A. The chemical structures of the langkocyclines were elucidated by HR-MS, 1D and 2D NMR experiments. They are biologically active against Gram-positive bacteria and exhibit a moderate antiproliferative activity against various human tumor cell lines. PMID- 23820615 TI - Exploring quality and its potential effects of multi-components antibiotic: consistency evaluation between matrix components ratio and microbiological potency of teicoplanin. AB - The production process, such as fermentation and purification etc., can significantly affect the relative ratio of matrix components in a multi-component antibiotic. The ratio of components can be varied in different products. This status causes a difficulty to assure the homogeneity and consistency between reference standards and test samples in potency determination, which hinders the results judgment and accuracy of a routine microbiological assay. In the current study, a multi-component antibiotic, teicoplanin, was selected as a model to explore the relationship between the ratio of matrix component and antibiotics potency. Single-component samples, TA3-1, TA2-1, and mixed-component samples, TA2 2.3, TA2-4.5, of teicoplanin were prepared and purified. Dose-response relationship of each sample has been determined by HPLC and microbiological assay, respectively. The accuracy of the potency result was guaranteed by choosing a test organism with the same sensitivity to each component of teicoplanin when there were differences existing in the ratio of components between the reference standard and the test sample. The experimental methods in current specifications can be replaced with the new potency determination method, which can provide a more realistic reflection of the biological activity of the product. PMID- 23820616 TI - Side chain length is more important than stereochemistry in the antibacterial activity of enantiomerically pure 4-aminoalcohol quinoline derivatives. PMID- 23820618 TI - Cell proliferation, potassium channels, polyamines and their interactions: a mini review. AB - Polyamines, which are obligatory molecules involved in cell cycling and proliferation, are subject to a change in their free intracellular concentrations during the cell cycle. Potassium (K(+)) channels are also considered, but less well recognized, to be necessary for cell proliferation by either hyperpolarizing or depolarizing cells during the cell cycle. A block of polyamine synthesis as well as block or knockout of K(+) channels can halt cell proliferation. K(+) channels like BK (maxi calcium (Ca(2+))-activated K(+)), Kir (inward rectifier), M-type K(+)-and TASK (two-pore domain K(+)) channels or the delayed rectifier K(+) channels are modulated in their electrical properties by polyamines. Polyamines are most effective in blocking these channels when applied to the intracellular face of these channels except for TASK channels where they act only from the extracellular side. Quinidine, a general K(+) channel blocker, was found to reduce putrescine concentrations, to block the ornithine decarboxylase and halt cell proliferation. From these results, the question arises if there is an interaction between polyamines, K(+) channels and proliferation. It might be speculated that a decrease of intracellular polyamines allows more K(+) channels to be active, thus inducing hyperpolarization, while an increase of the polyamine concentration may block K(+) channel activity leading to depolarization of the membrane potential. On the other hand, a block or a deletion of K(+) channels may cause a decrease of the polyamine concentration in cells. More research is needed to test these hypotheses. PMID- 23820617 TI - Spermine oxidase is a regulator of macrophage host response to Helicobacter pylori: enhancement of antimicrobial nitric oxide generation by depletion of spermine. AB - The gastric pathogen Helicobacter pylori causes peptic ulcer disease and gastric cancer. We have reported that in H. pylori-activated macrophages, nitric oxide (NO) derived from inducible NO synthase (iNOS) can kill the bacterium, iNOS protein expression is dependent on uptake of its substrate L-arginine (L-Arg), the polyamine spermine can inhibit iNOS translation by inhibiting L-Arg uptake, and inhibition of polyamine synthesis enhances NO-mediated bacterial killing. Because spermine oxidase (SMO), which back-converts spermine to spermidine, is induced in macrophages by H. pylori, we determined its role in iNOS-dependent host defense. SMO shRNA knockdown in RAW 264.7 murine macrophages resulted in a marked decrease in H. pylori-stimulated iNOS protein, but not mRNA expression, and a 90% reduction in NO levels; NO production was also inhibited in primary murine peritoneal macrophages with SMO knockdown. There was an increase in spermine levels after H. pylori stimulation that rapidly decreased, while SMO knockdown caused a greater increase in spermine that was sustained. With SMO knockdown, L-Arg uptake and killing of H. pylori by macrophages was prevented. The overexpression of SMO by transfection of an expression plasmid prevented the H. pylori-stimulated increase in spermine levels, and led to increased L-Arg uptake, iNOS protein expression and NO production, and H. pylori killing. In two human monocytic cell lines, U937 and THP-1, overexpression of SMO caused a significant enhancement of NO production with H. pylori stimulation. By depleting spermine, SMO can abrogate the inhibitory effect of polyamines on innate immune responses to H. pylori by enhancing antimicrobial NO production. PMID- 23820619 TI - Straightforward synthesis of non-natural L-chalcogen and L-diselenide N-Boc protected-gamma-amino acid derivatives. AB - The synthesis of new chiral seleno-, telluro-, and thio-N-Boc-gamma-amino acids is described herein. These new compounds were prepared through a simple and short synthetic route, from the inexpensive and commercially-available amino acid L glutamic acid. The products, with a highly modular character, were obtained in good to excellent yields, via hydrolysis of chalcogen pyroglutamic derivatives with overall retention of the L-glutamic acid stereochemistry. Also, an L diselenide-N-Boc-gamma-amino acid was prepared in good yield. This new synthetic route represents an efficient method for preparing new L-chalcogen- and L diselenide-gamma-amino acids with biological potential. PMID- 23820620 TI - Distinct metabolic and vascular effects of dietary triglycerides and cholesterol in atherosclerotic and diabetic mouse models. AB - Cholesterol and triglyceride-rich Western diets are typically associated with an increased occurrence of type 2 diabetes and vascular diseases. This study aimed to assess the relative impact of dietary cholesterol and triglycerides on glucose tolerance, insulin sensitivity, atherosclerotic plaque formation, and endothelial function. C57BL6 wild-type (C57) mice were compared with atherosclerotic LDLr(-/ ) ApoB(100/100) (LRKOB100) and atherosclerotic/diabetic IGF-II * LDLr(-/-) ApoB(100/100) (LRKOB100/IGF) mice. Each group was fed either a standard chow diet, a 0.2% cholesterol diet, a high-fat diet (HFD), or a high-fat 0.2% cholesterol diet for 6 mo. The triglyceride-rich HFD increased body weight, glucose intolerance, and insulin resistance but did not alter endothelial function or atherosclerotic plaque formation. Dietary cholesterol, however, increased plaque formation in LRKOB100 and LRKOB100/IGF animals and decreased endothelial function regardless of genotype. However, cholesterol was not associated with an increase of insulin resistance in LRKOB100 and LRKOB100/IGF mice and, unexpectedly, was even found to reduce the insulin-resistant effect of dietary triglycerides in these animals. Our data indicate that dietary triglycerides and cholesterol have distinct metabolic and vascular effects in obese atherogenic mouse models resulting in dissociation between the impairment of glucose homeostasis and the development of atherosclerosis. PMID- 23820621 TI - Postprandial glucose fluxes and insulin sensitivity during exercise: a study in healthy individuals. AB - Quantifying the effect size of acute exercise on insulin sensitivity (SI(exercise)) and simultaneous measurement of glucose disappearance (R(d)), endogenous glucose production (EGP), and meal glucose appearance in the postprandial state has not been developed in humans. To do so, we studied 12 healthy subjects [5 men, age 37.1 +/- 3.1 yr, body mass index 24.1 +/- 1.1 kg/m2, fat-free mass (FFM) 50.9 +/- 3.9 kg] during moderate exercise at 50% V(O2max) for 75 min, 120-195 min after a triple-tracer mixed meal consumed at time 0. Tracer infusion rates were adjusted to achieve constant tracer-to-tracee ratio and minimize non-steady-state errors. Glucose turnover was estimated by accounting for the nonstationary kinetics introduced by exercise. Insulin sensitivity index was calculated in each subject both in the absence [time (t) = 0-120 min, SI(rest)] and presence (t = 0-360 min, SI(exercise)) of physical activity. EGP at t = 0 min (13.4 +/- 1.1 MUM.kg FFM-1.min-1) fell at t = 120 min (2.4 +/- 0.4 MUM.kg FFM-1.min-1) and then rapidly rose almost eightfold at t = 180 min (18.2 +/- 2.6 MUM.kg FFM-1.min-1) before gradually falling at t = 360 min (10.6 +/- 0.9 MUM.kg FFM-1.min-1). R(d) rapidly peaked at t = 120 min at the start of exercise (89.5 +/- 11.6 MUM.kg FFM-1.min-1) and then gradually declined at t = 195 min (26.4 +/- 3.3 MUM.kg FFM-1.min-1) before returning to baseline at t = 360 min. SI(exercise) was significantly higher than SI(rest) (21.6 +/- 3.7 vs. 12.5 +/- 2.0 10-4 dl.kg-1.min-1 per MUU/ml, P < 0.0005). Glucose turnover was estimated for the first time during exercise with the triple-tracer technique. Our results, applying state-of-the-art techniques, show that moderate exercise almost doubles postprandial insulin sensitivity index in healthy subjects. PMID- 23820622 TI - Hyperinsulinemia and skeletal muscle fatty acid trafficking. AB - We hypothesized that insulin alters plasma free fatty acid (FFA) trafficking into intramyocellular (im) long-chain acylcarnitines (imLCAC) and triglycerides (imTG). Overnight-fasted adults (n = 41) received intravenous infusions of [U 13C]palmitate (0400-0900 h) and [U-13C]oleate (0800-1400 h) to label imTG and imLCAC. A euglycemic-hyperinsulinemic (1.0 mU.kg fat-free mass-1.min-1) clamp (0800-1400 h) and two muscle biopsies (0900 h, 1400 h) were performed. The patterns of [U-13C]palmitate incorporation into imTG-palmitate and palmitoylcarnitine were similar to those we reported in overnight postabsorptive adults (saline control); the intramyocellular palmitoylcarnitine enrichment was not different from and correlated with imTG-palmitate enrichment for both the morning (r = 0.38, P = 0.02) and afternoon (r = 0.44, P = 0.006) biopsy samples. Plasma FFA concentrations, flux, and the incorporation of plasma oleate into imTG oleate during hyperinsulinemia were ~1/10th of that observed in the previous saline control studies (P < 0.001). At the time of the second biopsy, the enrichment in oleoylcarnitine was <25% of that in imTG-oleate and was not correlated with imTG-oleate enrichment. The intramyocellular nonesterified fatty acid-palmitate-to-imTG-palmitate enrichment ratio was greater (P < 0.05) in women than men, suggesting that sex differences in intramyocellular palmitate trafficking may occur under hyperinsulinemic conditions. We conclude that plasma FFA trafficking into imTG during hyperinsulinemia is markedly suppressed, and these newly incorporated FFA fatty acids do not readily enter the LCAC preoxidative pools. Hyperinsulinemia does not seem to inhibit the entry of fatty acids from imTG pools that were labeled under fasting conditions, possibly reflecting the presence of two distinct imTG pools that are differentially regulated by insulin. PMID- 23820623 TI - Dysfunctional mitochondrial bioenergetics and oxidative stress in Akita(+/Ins2) derived beta-cells. AB - Insulin release from pancreatic beta-cells plays a critical role in blood glucose homeostasis, and beta-cell dysfunction leads to the development of diabetes mellitus. In cases of monogenic type 1 diabetes mellitus (T1DM) that involve mutations in the insulin gene, we hypothesized that misfolding of insulin could result in endoplasmic reticulum (ER) stress, oxidant production, and mitochondrial damage. To address this, we used the Akita(+/Ins2) T1DM model in which misfolding of the insulin 2 gene leads to ER stress-mediated beta-cell death and thapsigargin to induce ER stress in two different beta-cell lines and in intact mouse islets. Using transformed pancreatic beta-cell lines generated from wild-type Ins2(+/+) (WT) and Akita(+/Ins2) mice, we evaluated cellular bioenergetics, oxidative stress, mitochondrial protein levels, and autophagic flux to determine whether changes in these processes contribute to beta-cell dysfunction. In addition, we induced ER stress pharmacologically using thapsigargin in WT beta-cells, INS-1 cells, and intact mouse islets to examine the effects of ER stress on mitochondrial function. Our data reveal that Akita(+/Ins2)-derived beta-cells have increased mitochondrial dysfunction, oxidant production, mtDNA damage, and alterations in mitochondrial protein levels that are not corrected by autophagy. Together, these findings suggest that deterioration in mitochondrial function due to an oxidative environment and ER stress contributes to beta-cell dysfunction and could contribute to T1DM in which mutations in insulin occur. PMID- 23820625 TI - Costs of diabetes and its complications in Poland. AB - OBJECTIVE: Diabetes mellitus (DM) is a major health problem with severe complications and a significant impact on quality of life. It constitutes an enormous burden of disease due to high prevalence, severe co-morbidities and high costs for society. This study is the first comprehensive study on the direct and indirect costs of DM (type 1 and type 2) and associated complications in Poland. METHODS: In order to estimate the direct medical costs of DM and its complications, including the costs of medical consultation, hospitalisation, rehabilitation, drugs and medical equipment, data from the National Health Fund were used. Indirect costs on loss of productivity due to diabetes and its complications were based on data obtained from the ZUS (Social Insurance Institution) and from GUS (Poland's Central Statistical Office). Attributable risk methodology was used to assess the burden of DM complications. RESULTS: A continuous increase of the direct costs of diabetes has been observed since the year 2005. In the analysed time period (2005-2009) the direct costs of medical services for both types of DM doubled. DM is a cause of significant sickness absence and incapacity for work and therefore is associated with a growing productivity decline in Poland. The highest direct costs and indirect costs are associated with treatment of diabetes-related complications. Direct costs of hospital complication treatment were EUR 332 million, which exceeded by more than five times the direct costs of hospital treatment of diabetes per se, which in the same year amounted to EUR 58.5 million. The indirect costs of diabetes related complications were higher by 41% compared with indirect costs related to DM itself. Total costs of health care services for DM and its complications amounted to EUR 654 million, which constitutes a 2.8% of total health care costs in Poland. Total DM cost in Poland in 2009 amounted EURO 1.5 billion. CONCLUSIONS: DM is causing a growing economic burden on the health care system and on Polish society in terms of health care and productivity losses. Most of the total cost of diabetes are indirect costs caused by productivity losses. Both direct and indirect costs are driven by the cost of diabetes complications. PMID- 23820624 TI - The membrane estrogen receptor ligand STX rapidly enhances GABAergic signaling in NPY/AgRP neurons: role in mediating the anorexigenic effects of 17beta-estradiol. AB - Besides its quintessential role in reproduction, 17beta-estradiol (E2) is a potent anorexigenic hormone. E2 and the selective Gq-coupled membrane estrogen receptor (Gq-mER) ligand STX rapidly increase membrane excitability in proopiomelanocortin (POMC) neurons by desensitizing the coupling of GABAB receptors to G protein-coupled inwardly rectifying K(+) channels (GIRKs), which upon activation elicit a hyperpolarizing outward current. However, it is unknown whether E2 and STX can modulate GABAB signaling in neuropeptide Y (NPY)/agouti related peptide (AgRP) neurons. We used single-cell RT-PCR and whole cell patch clamping with selective pharmacological reagents to show that NPY/AgRP cells of mice express the GABAB-R1 and -R2 receptors and are hyperpolarized by the GABAB agonist baclofen in an E2-dependent manner. In males, E2 rapidly attenuated the coupling of GABAB receptors to GIRKs, which was blocked by the general PI3K inhibitors wortmannin and LY-294002 or the selective p110beta subunit inhibitor TGX-221. The ERalpha-selective agonist propyl pyrazole triol mimicked the effects of E2. STX, in contrast, enhanced the GABAB response in males, which was abrogated by the estrogen receptor (ER) antagonist ICI 182,780. In gonadectomized mice of both sexes, E2 enhanced or attenuated the GABAB response in different NPY/AgRP cells. Coperfusing wortmannin with E2 or simply applying STX always enhanced the GABAB response. Thus, in NPY/AgRP neurons, activation of the Gq-mER by E2 or STX enhances the GABAergic postsynaptic response, whereas activation of ERalpha by E2 attenuates it. These findings demonstrate a clear functional dichotomy of rapid E2 membrane-initiated signaling via ERalpha vs. Gq-mER in a CNS neuron vital for regulating energy homeostasis. PMID- 23820626 TI - Neurologic outcomes after cardiac operations. PMID- 23820627 TI - Impact of age and duration of banding on left ventricular preparation before anatomic repair for congenitally corrected transposition of the great arteries. AB - BACKGROUND: The optimal age and duration of left ventricular (LV) training in congenitally corrected transposition (ccTGA) with an unprepared LV is unknown. The objective of this study was to review the effect of age at pulmonary artery banding (PAB) and duration of ventricular training on LV function and aortic regurgitation (AR) after anatomic repair. METHODS: The medical records of all patients who underwent PA banding for LV training between 1998 and 2011 were retrospectively reviewed. The primary end points were moderate or more LV dysfunction and moderate or more AR after anatomic repair. RESULTS: During the study period, 25 patients with ccTGA underwent PAB for LV preparation. There was 1 early death. Eighteen patients underwent anatomic repair at a median of 10 months (range, 2 weeks to 11 years) from PAB. At the most recent follow-up after anatomic repair, moderate AR developed in 1 patient, and moderate or more LV dysfunction developed in 4. LV dysfunction developed in 4 of 6 patients banded after 2 years of age, compared with 0 of 12 patients banded before 2 years (p = 0.005). After anatomic repair, LV dysfunction developed in 4 of 7 patients repaired after age 3 years compared with 0 of 11 repaired before 3 years (p = 0.01). CONCLUSIONS: Early PAB strategy is associated with favorable LV and neoaortic valve function after anatomic repair for ccTGA with an unprepared LV. Candidates for anatomic repair who require LV training should be referred early in infancy for consideration of appropriate timing of PAB. PMID- 23820628 TI - Selective identification of macrophages and cancer cells based on thermal transport through surface-imprinted polymer layers. AB - In this article, we describe a novel straightforward method for the specific identification of viable cells (macrophages and cancer cell lines MCF-7 and Jurkat) in a buffer solution. The detection of the various cell types is based on changes of the heat transfer resistance at the solid-liquid interface of a thermal sensor device induced by binding of the cells to a surface-imprinted polymer layer covering an aluminum chip. We observed that the binding of cells to the polymer layer results in a measurable increase of heat transfer resistance, meaning that the cells act as a thermally insulating layer. The detection limit was found to be on the order of 10(4) cells/mL, and mutual cross-selectivity effects between the cells and different types of imprints were carefully characterized. Finally, a rinsing method was applied, allowing for the specific detection of cancer cells with their respective imprints while the cross selectivity toward peripheral blood mononuclear cells was negligible. The concept of the sensor platform is fast and low-cost while allowing also for repetitive measurements. PMID- 23820629 TI - Oxygenated polyketides from Plakinastrella mamillaris as a new chemotype of PXR agonists. AB - Further purification of the apolar extracts of the sponge Plakinastrella mamillaris, afforded a new oxygenated polyketide named gracilioether K, together with the previously isolated gracilioethers E-G and gracilioethers I and J. The structure of the new compound has been elucidated by extensive NMR (1H and 13C, COSY, HSQC, HMBC, and ROESY) and ESI-MS analysis. With the exception of gracilioether F, all compounds are endowed with potent pregnane-X-receptor (PXR) agonistic activity and therefore represent a new chemotype of potential anti inflammatory leads. Docking calculations suggested theoretical binding modes of the identified compounds, compatible with an agonistic activity on hPXR, and clarified the molecular basis of their biological activities. PMID- 23820631 TI - Bumps over cheeks. PMID- 23820630 TI - Correlation of morphologic and pathologic features of the various tendon groups around the ankle: MR imaging investigation. AB - OBJECTIVE: To determine if a statistical association exists between abnormalities in one ankle tendon group (i.e., peroneal, medial flexor, or Achilles) and those in another. MATERIALS AND METHODS: A retrospective analysis of 1.5-T and 3-T MR ankle examinations in 100 patients conducted between November 1, 2011 and April 1, 2012 was performed. The cross-sectional areas and diameters of the ankle tendons-Achilles (ACH), peroneus brevis (PB) and longus (PL), tibialis posterior (TP), flexor digitorum longus (FDL), and flexor hallux longus (FHL)-were measured, and the results were correlated to determine any association with the presence of qualitative abnormalities (tenosynovitis, tendinosis, and tendon tearing). RESULTS: Subjects with larger diameters of the ACH tendon also revealed larger PL, TP, FDL, and FHL tendon diameters and sectional areas. Furthermore, subjects with larger PL tendons generally revealed larger flexor tendons and the same was also true when medial compartment tendons were individually assessed and measurements compared among the three of them. There was a statistically significant association with regard to the presence of tendon abnormalities (tendinosis, tenosynovitis, and tearing) in both the peroneal and medial flexor tendons. The presence of an abnormality in the ACH tendon correlated strongly with increasing diameters and areas of all the other ankle tendons except for the PB tendon. CONCLUSIONS: There is an association between quantitative and qualitative abnormalities of one group of tendons when compared with the others with respect to the ACH, medial flexor, and peroneal tendons of the ankle, which is perhaps explained by a retinacular and fascial complex that anatomically connects the three groups. PMID- 23820632 TI - Association between mRNA levels of DNMT1, DNMT3A, DNMT3B, MBD2 and LINE-1 methylation status in infants with tetralogy of Fallot. AB - DNA methylation is catalyzed and maintained by DNA methyltransferases (DNMTs: DNMT1, DNMT3A and DNMT3B) and methyl-CpG-binding domain protein 2 (MBD2). However, little is known about the biological and clinical significance of the expression changes of DNMTs and MBD2 and their association with the methylation levels of long interspersed nuclear element-1 (LINE-1) in patients with tetralogy of Fallot (TOF). In this study, quantitative RT-PCR (qRT-PCR) was applied to analyze the mRNA levels of DNMTs and MBD2. The methylation status of LINE-1 was measured using the sequenom MassARRAY platform. The mRNA levels of the DNMTs and MBD2 showed a statistically significant decrease in the patients with TOF (P<0.001). The results also showed that patients with TOF had significantly lower global DNA methylation levels with a median of 61.50% [interquartile range (IQR), 59.78-63.77] compared with 63.54% (IQR, 62.49-64.88) among the controls (P=0.0099). In the controls, only DNMT1 showed a significant positive correlation with the DNMT3A mRNA levels (r=0.718, P=0.002). Of note, the DNMT1, DNMT3A, DNMT3B and MBD2 mRNA levels positively correlated with each other; this was statistically significant (P<0.05). A significant positive correlation with the global DNA methylation status was observed only for MBD2 (r=-0.579, P=0.005) in patients with TOF. In conclusion, lower LINE-1 methylation levels significantly correlate with aberrant MBD2 mRNA levels. The lower expression of DNMT1 and DNMT3B may play an important role in the pathogenesis of TOF. PMID- 23820633 TI - Fatty acids differentially regulate insulin resistance through endoplasm reticulum stress-mediated induction of tribbles homologue 3: a potential link between dietary fat composition and the pathophysiological outcomes of obesity. AB - AIMS/HYPOTHESIS: Previous studies have shown that saturated fatty acids cause insulin resistance (IR) that is prevented by unsaturated fatty acids. Tribbles homologue 3 (TRIB3) is a putative endogenous inhibitor of insulin signalling, but its role in insulin signalling is controversial. This study aimed to determine whether fatty acids regulate IR via TRIB3. METHODS: We treated HepG2 cells with saturated and unsaturated fatty acids and evaluated TRIB3 expression. We then tested whether regulation of TRIB3 occurred through endoplasmic reticulum (ER) stress, and whether modulating TRIB3 and ER stress marker genes was necessary and/or sufficient for regulation of insulin signalling. To test the in vivo significance of this mechanism, we fed mice obesogenic diets with different fatty acid profiles and assessed physiological variables of diabetes, ER stress markers and Trib3 expression in the liver. RESULTS: Our data show that fatty acids differentially regulate IR through ER stress-mediated induction of TRIB3. Intriguingly, a standard and widely used obesogenic diet high in unsaturated fats failed to induce ER stress, TRIB3 or IR. However, an alternative obesogenic diet with lower unsaturated fat recapitulated the cell studies by causing ER stress, TRIB3 induction and IR. CONCLUSIONS/INTERPRETATION: This study revealed a novel mechanism linking dietary fat composition to IR. Given the emerging roles for ER stress in non-alcoholic liver disease, we conclude that dietary fat composition rather than total amount may mediate hepatic pathology associated with obesity. PMID- 23820634 TI - Differences in cardiovascular risk factors and socioeconomic status do not explain the increased risk of death after a first stroke in diabetic patients: results from the Swedish Stroke Register. AB - AIMS/HYPOTHESIS: This study compared survival rates and causes of death after stroke in diabetic and non-diabetic patients in Sweden. We hypothesised that differences in cardiovascular risk factors, acute stroke management or socioeconomic status (SES) could explain the higher risk of death after stroke in diabetic patients. METHODS: The study included 155,806 first-ever stroke patients from the Swedish Stroke Register between 2001 and 2009. Individual patient information on SES was retrieved from Statistics Sweden. Survival was followed until 2010 (532,140 person-years) with a median follow-up time of 35 months. Multiple Cox regression was used to analyse survival adjusting for differences in background characteristics, in-hospital treatment, SES and year of stroke. Causes of death were analysed using cause-specific proportional hazard models. RESULTS: The risk of death after stroke increased in diabetic patients (HR 1.28, 95% CI 1.25, 1.31), and this risk was greater in younger patients and in women. Differences in background characteristics, cardiovascular risk factors, in hospital treatment and SES did not explain the increased risk of death after stroke (HR 1.35, 95% CI 1.32, 1.37) after adjustments. Diabetic patients had an increased probability of dying from cerebrovascular disease and even higher probabilities of dying from other circulatory causes and all other causes except cancer. CONCLUSIONS/INTERPRETATION: Differences in cardiovascular risk factors, acute stroke management and SES do not explain the lower survival after stroke in diabetic compared with non-diabetic patients. Diabetic patients are at higher risk of dying from cardiovascular causes and all other causes of death, other than cancer. PMID- 23820635 TI - Pancreatic safety of GLP-1-based therapeutic agents: further insights from rodent studies? PMID- 23820636 TI - Up-regulation of SGTB is associated with neuronal apoptosis after neuroinflammation induced by lipopolysaccharide. AB - SGTB (Small glutamine-rich tetratricopeptide repeat (TPR)-containing, beta) plays a critical role in protein-protein interactions. The interaction between SGTB and heat shock cognate protein (Hsc70)/heat shock protein (Hsp70) has aroused much attention in recent years. The present study was designed to elucidate dynamic changes in SGTB expression and distribution in the cerebral cortex in a lipopolysaccharide (LPS)-induced neuroinflammation rat model. It was found that SGTB expression was increased significantly in apoptotic neurons after LPS injection. The result of our in vitro study suggested that SGTB up-regulation might be associated with neuronal apoptosis after H2O2 challenge. In addition, silencing of SGTB in cultured PC12 (Pheochromocytoma) by siRNA indicated that SGTB was required for neuronal apoptosis induced by oxidative stress. Our finding about the cellular signal pathway may provide a new strategy against neuronal apoptosis in neuroinflammation in CNS. PMID- 23820637 TI - Haematological cancer: Prophylactic platelet transfusion is frequently not necessary. PMID- 23820638 TI - Urological cancer: Poorer prostate cancer outcomes in African American men. PMID- 23820643 TI - Supporting the adolescent mother-infant relationship: preliminary trial of a brief perinatal attachment intervention. AB - The purpose of this study is to test a brief, attachment intervention added to routine maternity care that aims to improve the adolescent mother-infant relationship during transition to motherhood. A pre-test, post-test, peer-control group trial was set in a large tertiary maternity hospital in Melbourne, Australia. Participants were multi-cultural, pregnant adolescents (n = 97). The two-session 'AMPLE' intervention was provided in late pregnancy and neonatally. The main outcome measure was mother-infant interaction quality at age 4 months, blind-coded using the Emotional Availability Scales (EAS) (fourth edition). Study acceptability was high: participation rate 82.9 % and completion rate 75.3 %. Thirty-five participants received the intervention plus usual care (intervention group) and 38 received usual care (control group). There were no pre-test between group differences across demographic, psychosocial or obstetric domains. At post test, mother-infant interaction was significantly better in the intervention group. MANOVA analyses showed an overall intervention effect on emotional availability in 20 min of free play (n = 73), F (6,65) = 5.05, p < .01, partial eta (2) = .32, and in 25 min of play plus brief separation-reunion (n = 55), F (6,48) = 2.72, p = .02, partial eta (2) = .25. T tests showed significant between group differences in specific EAS subscales. All effect sizes were medium-large. This promising intervention appears to exert a clinically meaningful effect on the adolescent mother-infant relationship. Further research is warranted to replicate the findings and confirm causality. The study suggests a brief attachment focus, incorporated into routine maternity care, could influence the developmental trajectory of infants of young mothers from birth. PMID- 23820644 TI - Influence of health information levels on postpartum depression. AB - While extensive research has been conducted on postpartum depression (PPD), the majority has been focused on psychological risk factors and treatments. There is limited research on the explicit relationship between the degree to which individuals are informed about relevant prenatal and postnatal health topics and whether this level of knowledge influences psychological outcome. This study assesses health information levels of new mothers and their influence on PPD as measured by Edinburgh Postnatal Depression Scale (EPDS) scores. Data from the 2006 Maternity Experiences Survey developed by the Canadian Perinatal Surveillance System (N = 6,421) were used. The study population included mothers >=15 years of age at the time of the birth, who had a singleton live birth in Canada during a 3-month period preceding the 2006 Census and who lived with their infants at the time of the survey. Pre- and postnatal health information components were measured using latent variables constructed by structural equation modeling. EPDS score was added to the model, adjusting for known covariates to assess the effects of information levels on EPDS score. Pre- and postnatal health information levels are associated with decreased EPDS scores. More specifically, information on topics such as postnatal concerns and negative feelings was associated with the largest decrease in score for primiparous and multiparous women, respectively (p < 0.0001 for both). The pre-established predictors of PPD were confirmed for both samples, with life stress associated with the largest change in EPDS score for both samples (p < 0.0001 for both). This study demonstrates a distinct role for pre- and postnatal health information in influencing EPDS scores, supplementing previous literature. Primiparous and multiparous women benefited from different information content, with information on postnatal concerns had the largest effect on the primiparous group while information on negative feelings had the largest effect on the multiparous group. Therefore, information provision should be tailored to these two groups. PMID- 23820645 TI - Functional deterioration of endothelial nitric oxide synthase after focal cerebral ischemia. AB - Endothelial nitric oxide synthase (eNOS) dysfunction is related to secondary injury and lesion expansion after cerebral ischemia. To date, there are few reports about postischemic alterations in the eNOS regulatory system. The purpose of the present study was to clarify eNOS expression, Ser1177 phosphorylation, and monomer formation after cerebral ischemia. Male Wistar rats were subjected to transient focal cerebral ischemia. Endothelial nitric oxide synthase messenger RNA (mRNA) and protein expression increased ~ 8-fold in the ischemic lesion. In the middle cerebral artery core, eNOS-Ser1177 phosphorylation increased 6 hours after ischemia; however, there was an approximately 90% decrease in eNOS-Ser1177 phosphorylation observed 24 hours after ischemia that continued until at least 7 days after ischemia. Endothelial nitric oxide synthase monomer formation also increased 24 and 48 hours after ischemia (P<0.05), and protein nitration progressed in parallel with monomerization. To assess the effect of a neuroprotective agent on eNOS dysfunction, we evaluated the effect of fasudil, a Rho-kinase inhibitor, on eNOS phosphorylation and dimerization. Postischemic treatment with fasudil suppressed lesion expansion and dephosphorylation and monomer formation of eNOS. In conclusion, functional deterioration of eNOS progressed after cerebral ischemia. Rho-kinase inhibitors can reduce ischemic lesion expansion as well as eNOS dysfunction in the ischemic brain. PMID- 23820646 TI - Regenerative glutamate release by presynaptic NMDA receptors contributes to spreading depression. AB - Spreading depression (SD) is a slowly propagating neuronal depolarization that underlies certain neurologic conditions. The wave-like pattern of its propagation suggests that SD arises from an unusual form of neuronal communication. We used enzyme-based glutamate electrodes to show that during SD induced by transiently raising extracellular K(+) concentrations ([K(+)]o) in rat brain slices, there was a rapid increase in the extracellular glutamate concentration that required vesicular exocytosis but unlike fast synaptic transmission, still occurred when voltage-gated sodium and calcium channels (VGSC and VGCC) were blocked. Instead, presynaptic N-methyl-D-aspartate (NMDA) receptors (NMDARs) were activated during SD and could generate substantial glutamate release to support regenerative glutamate release and propagating waves when VGSCs and VGCCs were blocked. In calcium-free solutions, high [K(+)]o still triggered SD-like waves and glutamate efflux. Under such a condition, glutamate release was blocked by mitochondrial Na(+)/Ca(2+) exchanger inhibitors that likely blocked calcium release from mitochondria secondary to NMDA-induced Na(+) influx. Therefore presynaptic NMDA receptor activation is sufficient for triggering vesicular glutamate release during SD via both calcium entry and release from mitochondria by mitochondrial Na(+)/Ca(2+) exchanger. Our observations suggest that presynaptic NMDARs contribute to a cycle of glutamate-induced glutamate release that mediate high [K(+)]o-triggered SD. PMID- 23820647 TI - Inhibition of soluble epoxide hydrolase after cardiac arrest/cardiopulmonary resuscitation induces a neuroprotective phenotype in activated microglia and improves neuronal survival. AB - Cardiac arrest (CA) causes hippocampal neuronal death that frequently leads to severe loss of memory function in survivors. No specific treatment is available to reduce neuronal death and improve functional outcome. The brain's inflammatory response to ischemia can exacerbate injury and provides a potential treatment target. We hypothesized that microglia are activated by CA and contribute to neuronal loss. We used a mouse model to determine whether pharmacologic inhibition of the proinflammatory microglial enzyme soluble epoxide hydrolase (sEH) after CA alters microglial activation and neuronal death. The sEH inhibitor 4-phenylchalcone oxide (4-PCO) was administered after successful cardiopulmonary resuscitation (CPR). The 4-PCO treatment significantly reduced neuronal death and improved memory function after CA/CPR. We found early activation of microglia and increased expression of inflammatory tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta in the hippocampus after CA/CPR, which was unchanged after 4-PCO treatment, while expression of antiinflammatory IL-10 increased significantly. We conclude that sEH inhibition after CA/CPR can alter the transcription profile in activated microglia to selectively induce antiinflammatory and neuroprotective IL-10 and reduce subsequent neuronal death. Switching microglial gene expression toward a neuroprotective phenotype is a promising new therapeutic approach for ischemic brain injury. PMID- 23820648 TI - Direct measurement and modulation of single-molecule coordinative bonding forces in a transition metal complex. AB - Coordination chemistry has been a consistently active branch of chemistry since Werner's seminal theory of coordination compounds inaugurated in 1893, with the central focus on transition metal complexes. However, control and measurement of metal-ligand interactions at the single-molecule level remain a daunting challenge. Here we demonstrate an interdisciplinary and systematic approach that enables measurement and modulation of the coordinative bonding forces in a transition metal complex. Terpyridine is derived with a thiol linker, facilitating covalent attachment of this ligand on both gold substrate surfaces and gold-coated atomic force microscopy tips. The coordination and bond breaking between terpyridine and osmium are followed in situ by electrochemically controlled atomic force microscopy at the single-molecule level. The redox state of the central metal atom is found to have a significant impact on the metal ligand interactions. The present approach represents a major advancement in unravelling the nature of metal-ligand interactions and could have broad implications in coordination chemistry. PMID- 23820650 TI - Widespread high grade prostatic intraepithelial neoplasia on biopsy predicts the risk of prostate cancer: a 12 months analysis after three consecutive prostate biopsies. AB - PURPOSE: To evaluate the risk of prostate cancer (PCa) on a third prostate biopsy in a group of patients with two consecutive diagnoses of high grade intraepithelial neoplasia (HGPIN). MATERIALS AND METHODS: From November 2004 to December 2007, patients referred to our clinic with a PSA ! 4 ng/ml or an abnormal digital rectal examination (DRE) were scheduled for trans-rectal ultrasound (TRUS) guided 12-core prostate biopsy. Patients with HGPIN underwent a second prostate biopsy, and if the results of such procedure yielded a second diagnosis of HGPIN, we proposed a third 12-core needle biopsy regardless of PSA value. Crude and adjusted logistic regressions were used to assess predictors of PCa on the third biopsy. RESULTS: A total of 650 patients underwent 12 cores transrectal ultrasound prostatic biopsy in the study period. Of 147 (22%) men with a diagnosis of HGPIN, 117 underwent a second prostatic biopsy after six months and 43 a third biopsy after other six months. After the third biopsy, 19 patients (34%) still showed HGPIN, 15 (35%) were diagnosed with PCa and 9 (21%) presented with chronic prostatitis. Widespread HGPIN on a second biopsy was significantly associated with PCa on further biopsy (!2 = 4.04, p = 0.04). Moreover, the presence of widespread HGPIN significantly predicted the risk of PCa on crude and adjusted logistic regressions. CONCLUSIONS: Widespread HGPIN on second biopsy is associated with the presence of PCa on a third biopsy. Nonetheless, the relationship between HGPIN and PCa remains complex and further studies are needed to confirm our findings. PMID- 23820651 TI - Does prolonged anti-inflammatory therapy reduce number of unnecessary repeat saturation prostate biopsy? AB - INTRODUCTION: The effect of a prolonged oral anti-inflammatory therapy on PSA values in patients with persistent abnormal PSA values after negative prostate biopsy (PBx) was evaluated. MATERIAL AND METHODS: From September 2011 to September 2012, 70 patients (medi- an age 62 years), with persistent abnormal PSA values after negative extended PBx, were given an herbal extract with anti inflammatory activity for 3 months (Lenidase(r); 1 tablet daily constituted of baicalina, bromelina and escina). All patients were submitted to prostate biopsy for: abnormal DRE; PSA > 10 ng/mL, PSA values between 4.1-10 or 2.6-4 ng/mL with free/total PSA < 25% and < 20%, respectively. Three months after the end of anti inflammato- ry therapy all patients were revaluated; indication for repeat saturation biopsy (SPBx) and detection rate for PCa were compared with those previously recorded in our Department using the same inclusions criteria for biopsy. RESULTS: Oral administration of Lenidase(r) was well tolerated and no side effects were observed; PSA values decreased in 54 (77.8%) out 70 patients with a median PSA reduction of 20.5% (from 8.8 to 7 ng/mL) and remained unchanged in 16 patients (22.2%); the repeat SPBx rate resulted significantly lower (22.8% vs 35.5%; p < 0.05) showing a superimposable detection rate for PCa (3 cases) in comparison with our previous data (18.7% vs 22%). CONCLUSIONS: In our preliminary data a prolonged oral anti-inflammatory therapy reduced PSA levels in patients with negative PBx and persistent suspicious for PCa decreasing the indication to perform repeat SPBx (about 30% of the cases). PMID- 23820652 TI - The effectivity of periprostatic nerve blockade for the pain control during transrectal ultrasound guided prostate biopsy. AB - AIM: Transrectal ultrasound (TRUS) guided prostete biopsy is accepted as a standard procedure in the diagnosis of prostate cancer. Many different protocoles are applied to reduce the pain during the process. In this study we aimed to the comparison of two procedure with intrarectal lidocaine gel and periprostatice nerve blockade respective- ly in addition to perianal intrarectal lidocaine gel on the pain control in prostate biop- sy by TRUS. METHODS: 473 patients who underwent prostate biopsy guided TRUS between 2008-2012 were included in the study. 10-point linear visual analog pain scale(VAS) was used to evaluate the pain during biopsy. The patients were divided into two groups according to anesthesia procedure. In Group 1, there were 159 patients who had perianal intrarectal lidocaine gel, in Group 2 there were 314 patients who had periprostatic nerve blockade in addition to intrarectal lidocain gel. The pain about probe manipulation was aseesed by VAS-1 and during the biopsy needle entries was evalu- ated by VAS-2. Results were compared with Mann-Whitney U and Pearson chi-square test. RESULTS: Mean VAS-2 scores in Group 1 and Group 2 were 4.54 +/- 1.02 and 2.06 +/- 0.79 respectively. The pain score was determined significantly lower in the Group 2 (p = 0.001). In both groups there was no significant difference in VAS-1 scores, patient's age, prostate volume, complication rate and PSA level. CONCLUSION: The combination of periprostatic nerve blockade and intrarectal lidocain gel provides a more meaningful pain relief compared to group of patients undergoing intrarectal lidocaine gel. PMID- 23820653 TI - HER-2 immunohistochemical expression as prognostic marker in high-grade T1 bladder cancer (T1G3). AB - OBJECTIVES: To evaluate if the Human epidermal growth factor receptor 2 (HER-2) expression levels may be used as potential prognostic marker in high grade T1 blad- der cancer (T1G3) METHODS: Specimens from transurethral resection of bladder tumour (TURBT) of 103 patients with high-grade T1 bladder cancer were collected. This pathologic database was reviewed. Four-year follow-up data were matched with pathologic data. Eighty-three patients entered the study. HER-2 staining was performed. Patients were grouped for HER-2 status. Statistical analysis included Kaplan Meier survival analysis and Log-rank test. RESULTS: Pathological review of TURBT specimens confirmed high-grade T1 transitional cell bladder cancer in all patients. Median follow-up was 12 months (mean 23,5; range 3-48). Twenty-one patients (25.4%) present strong HER-2 expression (3+), 28 (33.7%) moderate expression (2+), 26 (33.7%) weak staining (1+) and 8 (9.6%) negative expression (0). Thirty- one patients of 83 (37.4%) had not evidence of disease, 41 (49.4%) recurred, 11 (13.2%) had a progression of disease. Forty-one patients had high grade T1 recurrence. Patients with HER-2 status 0 did not showed progression of disease. Patients with HER-2 status 3+, undergoing cys- tectomy because progression of disease, had a pathological stage > pT2 and a nodal involve- ment. Median Disease-Free Survival (DFS) for all patients was 12 months (DFS probability (pDFS) = 49.3%; 95% CI, -11.1/+10.1). Median DFS in HER-2 groups was 8 (pDFS 37.5%; 95% CI,-28.8/+29.9), 24 (pDFS 46.1%; 95% CI, 19.5/+17.5), 20 (pDFS 46.4%; 95% CI,-18.8/+16.9) and 10 months (pDFS 47.6%; 95% CI,-21.9/+19.1) respectively in HER-2 status 0,1+,2+,3+. Log-Rank test is not statistically significant (p = 0,39). CONCLUSIONS: This study showed that HER-2 expression does not represent a prognostic mark- er of recurrence/progression of disease in high-grade T1 bladder cancer. PMID- 23820654 TI - Resident training in urology: bipolar transurethral resection of the prostate - a safe method in learning endoscopic surgical procedure. AB - INTRODUCTION: Modern medicine uses increasingly innovative techniques that require more and more capabilities for acquisition. In the urological department is increasing the presence of patients with lower urinary tract symptoms (LUTS) and transurethral resection of the prostate (TURP) is the standard of care in their surgical treatment. We report our surgical experience and learning curve of using bipolar plasmakinetic devices in the training of urological residents to benign prostatic hyperplasia (BPH) treatment. MATERIALS AND METHODS: 80 patients with benign prostatic enlargement due to BPH were enrolled in the study. TURP has been performed by three urological residents and by an expe- rienced urologist. Patients were evaluated before and 6 months after the endoscopic bipolar plasmakinetic resection using the International Prostate Symptom Score (IPSS), maximum uri- nary flow rate (Qmax), postvoid residual urine (PVR) and prostate specific antigen (PSA). RESULTS: Overall 60 procedures were performed, 18 PlasmaKinetic (PK)-TURP procedures were completed by the three residents. In the other 42 cases the procedures were completed by the experienced urologist. In eight cases there was a capsular perforation and the experienced urol- ogist replaced the resident to complete the resection. No complications have been reported in the procedures completed by the senior urologist. All complications caused by the residents were man- aged intraoperatively without changing the course of the procedure. Statistical differences were observed regarding IPSS, quality of life (QoL), and PVR at 6-month follow-up when procedures completed by urological residents were compared to those completed by the senior urologist. CONCLUSION: Bipolar device represents appropriate tools to acquire endoscopic skills. It is safe and it can be used at the first experience of BPH treatment by a resident who has not previ- ously approached this endoscopic surgical procedure. PMID- 23820655 TI - Split-leg percutaneous nephrolithotomy: a safe and versatile technique. AB - OBJECTIVES: Percutaneos nephrolithotomy (PCNL) is the gold standard for treatment of urinary stones larger than 2 cm and refractory to ESWL. Nowadays most debate about surgical technique is related to the positioning of patients. We report our expe- rience on prone PCNL with split-leg variant (SL-PCNL) MATERIALS AND METHODS: 30 consecutive patients underwent prone SL-PCNL. Preoperative stone size was deter- mined by measuring stones longest diameter on CT scan. In cases with multiple stones, stone size was determined by the sum of each stone diameter on CT scan. Patients evaluated con- sisted of 20 females and 10 males and median age was 55 (20-72). The average BMI was 27 (24-35). 15 patients had multiple stones, 10 pyelocalicial, 10 pelvic larger than 2 cm, 2 in horseshoe kidneys and 3 staghorn stones. RESULTS: Stone free rate was 87% after first look and 97% after second look. In 2 cases, we used a flexible ureteroscopy 7.5 Fr (Flex 2 - Storz) to treat a calculus in ureter or for a contemporary double access (Endoscopic combined Retrograde Intrarenal Surgery ECIRS). In 28 cases we placed a 20 fr nephrostomy while in two cases procedure was tubeless. In 20 cases we placed a double-J catheter. In 2 cases we performed two tract and in 2 horseshoe kidneys access was close to spine. The average surgical time was about 90 minutes (range 30-120 minutes). Hemoglobin drop was about 1.5 mg/dl (range 1-3 .4 mg/dl) and no major complications were reported. CONCLUSIONS: In our experience PCNL in prone with spread-legs variant is a versatile technique and allows to match the advantages you have with same technique in supine, providing at the same time benefits in cases of anatomical abnormalities, challenging cases, or when multi tract accesses are required. PMID- 23820656 TI - Comparative randomized study on the efficaciousness of endoscopic bipolar prostate resection versus monopolar resection technique. 3 year follow-up. AB - OBJECTIVE: Transurethral resection of the prostate (TURP) is the current optimal thera- py for the relief of bladder outflow obstruction, with subjective and objective success rate of 85 to 90%. Aim of this study was to evaluate efficacy and safety of Plasmakinetic ener- gy (Gyrus electro surgical system), which produces vaporization of tissue immersed in isotonic saline against standard monopolar transurethral resection of the prostate. METHODS: From January 2002 to April 2002, 160 consecutive patients, who had low urinary tract symptoms (LUTS) of benign prostatic hyperplasia (BPH) were enrolled in this study. Patients were randomised to undergo bipolar TURP (80 patients) or monopolar TURP (80 patients). Preoperative work-up was assessed by administering IPSS, IIEF-5 and Qol questionnaires. All patients were submitted to uroflowmetry, transrectal ultrasound (TRUS), post-voidal residual urine measurement and PSA determination. In the two groups, IPSS, IIEF-5 and Qol, uroflowme- try, TRUS, post-voidal residual urine measurement, PSA determination and number of reopera- tions were evaluated at 1, 3, 6, 12, 18, 24, 30 and 36 months follow up, and then every year. Furthermore, in both groups operative time, resected tissue weight and perioperative complica- tions were analysed. Total postoperative catheter time, total post-operative hospital stay, haemo- globin loss were also recorded in the two groups. RESULTS: Comparative data on IPSS symptom score, IIEF-5, Qol, PSA, peak urinary flow rate and post-void residual urine volume were similar in the two groups but showed a significant improve- ment respect to baseline values. The postoperative haemoglobin levels, postoperative catheteri- zation time, hospital stay and 3-year overall surgical re-treatment-free rate were significantly better in the bipolar group. CONCLUSIONS: Bipolar TURP has a comparable outcome to standard monopolar TURP at short and medium term regard to subjective and objective outcome measurements. Its impact on blad- der outlet function is also similar to that of monopolar TURP. Improvement in IPSS, Qol index, IIEF-5, Qmax and post-void residual urine volume were comparable in both group denoting sim- ilar efficacy of the techniques. PMID- 23820657 TI - Continence and complications rates after male slings as primary surgery for post prostatectomy incontinence: a systematic review. AB - OBJECTIVES: to analyze continence and complications rates after male slings as first line surgical treatment, in order to improve patient counseling for the management of SUI postprostatectomy. METHOD: A MedLine search using specified search terms was done on January 23, 2012. This research rendered 160 records. RESULTS: No controlled trial was available for analysis. The majority of papers dealing with out- come and complications came from a few centres. At a median follow-up of 15 months the pooled cure rates for all kinds of slings was 77.4; in the AdVance group the pooled cure rates was 72.5%; in the InVance group it was 74.2% while in the Remeex group it was 84.3%. CONCLUSIONS: Only a few number observational studies addressed review selection criteria. The pooled overall cure rates is high but there are no data concerning reliable pre- and postoperative prognostic factors affecting treatment failure and complications rates, thus it is not possible to have suitable criteria for a better patient selection. The statistically pooled results obtained should be interpreted with caution because of several limitations due to several study selection limitations: observational study design, few number of analysed studies, heterogeneity, lack of outcome definition and standardisation, between-study variability, high risk of bias. PMID- 23820658 TI - Massive hematuria due to ruptured iatrogenic aortic pseudoaneurysm: a case report. AB - We report an interesting case of massive haematuria secondary to a rupture of a pseudoa- neurysm of the abdominal aorta below the renal vessels. A 65-year-old woman present- ed at our institution with a painful massive haematuria and anaemia. Two months before, she undergone a pelvic surgery complicated by an accidental injury of the right ureter sutured with a end-to-end anastomosis. An abdominal computed tomography (CT) scan with intravenous contrast showed a right sided hydronephrosis with clots in the lumen of the right pelvis with a massive retroperitoneal hematoma due to a rupture of a iatrogenic pseudoaneurysm of the abdominal aorta below the origin of the renal arteries. PMID- 23820659 TI - A case of eosinophilic cystitis in patients with abdominal pain, dysuria, genital skin hyperemia and slight toxocariasis. AB - Eosinophilic cystitis is a rare inflammatory disease with controversial aetiology and treatment. We report the case of a 61-year-old man presented with lower quadrant abdominal pain and lower urinary tract symptoms, non responsive to antibiotics and nonsteroidal antiinflammatory drugs. Physical examination was substantially negative, such as laboratory parameters, microscopic, bacteriological and serological evaluations. Cystoscopy revealed red areas involving the mucosa of the bladder and transurethral biopsies revealed infiltrating eosinophils. The patient was treated with corticosteroids and montelukast sodium with improving of the symptoms, and at 5 weeks postoperative pain score was reduced. After discontinuing corticosteroids dysuria recurred with the development of hyperemia at the genital skin; the specific enzyme-linked immunosorbent assay (ELISA) to detect antibodies against several parasites was slightly positive for Toxocara species. Montelukast sodium was discontinued and corticosteroid therapy was started together with albendazole, with improving of patient’s symptoms and pain decreasing after one week. PMID- 23820661 TI - Vaginocutaneous fistula and inguinal abcess presented 6 years after tension-free vaginal tape sling. AB - Surgical treatment of female stress urinary incontinence (SUI) has become very pop- ular after respectable success with minimal invasive surgeries. This is the first report of long term vaginocutaneous fistula (VCF) plus inguinal abcess after tension-free vaginal tape (TVT). A 67 year-old woman with vaginal discharge lasting more than 3 years complained with a painful swelling in the left inguinal area for the last three months. She had a medical history of TVT sling procedure for SUI six years ago. She had no history of pelvic surgery, cancer treatment or pelvic irradiation before or after TVT sling. No urethrovaginal or vesicovaginal fistula was found in physical examination and cystocopy. MRI showed a vaginocutenaous fistula and inguinal abcess. This case highlights the need for a high index of suspicion for VCF after TVT. PMID- 23820660 TI - Iatrogenic direct rectal injury: an unusual complication during suprapubic cystostomy (SPC) insertion and its laparoscopic management. AB - Suprapubic cystostomy (SPC) is commonly used, instead of indwelling urethral catheter- ization, as indicated in many pathological conditions. Although considered to be a safe procedure that can be easily performed in an outpatient basis several complications have been reported in international literature. Bowel injury can be a serious complication with the small intestine affected in the majority of cases. We present a case of an acci- dental rectal injury by a suprapubic catheter misplacement, in a 76 year old demented patient with prostatic hyperplasia and chronic urinary retention. The injury was confirmed by cystogra- phy and injection of contrast meterial through the suprapubic catheter, and successfully treated laparoscopically by an extraperitoneal approach. The patient was discharged after 10 days with- out any complications. The above method, in experienced hands, can be an effective primary treatment option for such rare but devastating complications. The case and management is unique as, to our knowledge, as no similar cases have been presented. PMID- 23820662 TI - Renal angiomyolipoma with renal vein invasion. AB - Renal angiomyolipoma is a uncommon benign tumor, considered an hamartoma. The lesion, usually benign, can be single or multiple and well-circumscribed. In letterature only few cases of infiltrating angiomyolipomas have been described. The aim of the paper is to describe a paradigmatic case of a giant kidney angiomyolipoma, not associ- ated with tuberous sclerosis, invading the pelvis and the renal vein. The lesion have been discovered incidentally during abdominal ultrasound for other pathology. Owing to the extent of the lesion and the appreciable risk of bleeding, we opted for surgical treatment. PMID- 23820664 TI - Imidafenacin on bladder and cognitive function in neurologic OAB patients. AB - OBJECTIVE: To explore imidafenacin's effects on bladder and cognitive function in neurologic overactive bladder (OAB) patients. METHODS: Sixty-two subjects (25 men, 37 women; mean age 70 years (25-86) with OAB due to neurologic diseases) were enrolled in the study. We conducted a urinary symptom survey and cognitive tests (MMSE, FAB, ADAS-cog) in all patients. We performed urodynamics in 35 patients and measured real-time near-infrared spectroscopy (NIRS)-urodynamics in eight patients before and after the administration of imidafenacin, an anticholinergic agent, for 3 months at 0.2 mg/day. RESULTS: Imidafenacin significantly ameliorated urinary urgency, nighttime urinary frequency, and quality of life index (p < 0.05). Three cognitive measures did not change significantly. Urodynamics showed increased bladder capacity (p < 0.05) but detrusor overactivity did not change significantly. NIRS showed that the subtraction of oxyhemoglobin between the start of filling and the first sensation increased in the bilateral prefrontal area but without statistical significance. CONCLUSIONS: Imidafenacin ameliorated bladder sensation without cognitive worsening, with a trend of prefrontal activation. Regarding cognitive function, imidafenacin is safely used in OAB patients due to neurologic diseases. SYNOPSIS: In order to explore imidafenacin (anticholinergic agent)'s effects on bladder and brain function, we performed urinary questionnaire, cognitive tests, urodynamics and near-infrared spectroscopy (selected cases) in 62 overactive bladder (OAB) patients due to various neurologic diseases. As a result, imidafenacin ameliorated bladder sensation without cognitive worsening, with a trend of prefrontal activation. Imidafenacin seems safe in treating OAB patients due to neurologic diseases. PMID- 23820665 TI - The impact of IT over five decades - towards the Ambient organization. AB - This contribution to the Ken D. Eason special issue is an illustration of the value of socio-technical analysis applied at an organizational level. We provide a brief historical overview of socio-technical IS research and review studies investigating the impact of IT on organizational structures in the last five decades, identifying a dominating (new) research theme in each decade. A key overall impact of IT in all decades has been a dramatic decrease in transaction costs making it increasingly easier for organizations to source from external providers. A five level taxonomy of sourcing arrangement is developed together with a framework of organizational activities, and a number of significant cases are offered of how organizations are sourcing practically all types of business processes, including innovation. We argue that future IT will further accelerate the movement towards more sourcing, eventually leading to a new type of organization that we call the Ambient organization. PMID- 23820666 TI - Synthesis of highly branched gold nanodendrites with a narrow size distribution and tunable NIR and SERS using a multiamine surfactant. AB - Gold nanodendrites with a long and densely branched morphology were fabricated by a seed-mediated method in a solution containing gold nanoparticles (AuNPs), bis(amidoethyl-carbamoylethyl)octadecylamine (C18N3), HAuCl4, and the reducing agent ascorbic acid (AA). The length and density of the branches could be mediated by changing the AuNP seed and AA concentrations. The amphiphilic C18N3 molecules function as a template and induce the unique morphology of the AuNPs/C18N3 structures. The localized surface plasmon resonance (LSPR) peaks of the gold nanodendrites can be modulated from the visible (~530 nm) to the near infrared region (~1100 nm) of the electromagnetic spectrum. Surface-enhanced Raman scattering (SERS) signals using rhodamine can also be mediated by changing the seed and AA concentrations. These unique highly branched gold nanodendrites with a narrow size distribution and tunable NIR and SERS spectra should have great potential in sensing applications. PMID- 23820667 TI - Adjustable tricuspid annuloplasty. AB - The methods for repairing functional tricuspid regurgitation (TR) are still controversial. A novel concept of tricuspid annuloplasty for functional TR was developed. A flexible annuloplasty band, through which an expanded polytetrafluoroethylene (ePTFE) thread (CV3) was passed inside the cover cloth, was secured to the tricuspid annulus. Both ends of the ePTFE thread were passed through the right atrial wall. The thread was snared from outside the ejecting heart under observation by a transoesophageal echocardiogram after weaning off the cardiopulmonary bypass. We used this technique in 11 patients with functional TR (mean TR grade: 3.4 +/- 0.8). The mean circumference of the annulus after snaring was 86.5 +/- 4.6 mm (diameter 27.6 +/- 1.5 mm). The postoperative TR at discharge was trivial or 0 in 9 patients and Grade 1 in 2. We concluded that this method has the potential to minimize residual regurgitation. PMID- 23820668 TI - Intra-abdominal hypertension in cardiac surgery. AB - OBJECTIVES: The occurrence of intra-abdominal hypertension (IAH), as well as its promoting factors in cardiac surgery, has been poorly explored. The aim of the present study was to characterize intra-abdominal pressure (IAP) variations in patients undergoing cardiac surgical procedures, and to identify the risk factors for IAH in this setting. METHODS: All consecutive adult patients requiring postoperative intensive care unit admission for >24 h were enrolled. Demographic data, pre-existing comorbidities, type and duration of surgery, cardiopulmonary bypass (CPB) use and duration, perioperative IAP, organ function and fluid balance were recorded. IAH was defined as a sustained increase in IAP >12 mmHg. Multivariate logistic regression and stepwise analyses identified the baseline and perioperative variables associated with IAH. RESULTS: Of 69 patients, 22 (31.8%) developed IAH. In the logistic model, baseline IAP, high central venous pressure, vasoactive drugs administration, positive fluid balance, AKI, CPB, total sequential organ failure assessment score and age were all promoting factors for IAH (Hosmer-Lemeshow chi(2) = 7.23; P = 0.843). Baseline IAP, high central venous pressure and positive fluid balance were independent risk factors for IAH in the stepwise analysis. The ROC curve analysis, obtained by plotting the occurrence of IAH vs the IAP baseline value, showed an AUC of 0.75 (SE 0.064; 99% CI 0.62-0.87; P < 0.0001). The best IAP cut-off value was at 8 mmHg (sensitivity 63% and specificity 76%). Considering on- and off-pump surgery groups, fluid balance and vasoactive drugs use were significantly higher in the on-pump group. Linear regression analysis showed a positive correlation (P = 0.0001) between IAP changes and fluid balance only in the on-pump group. CONCLUSIONS: IAH develops in one-third of cardiac surgery patients and is strongly associated with higher baseline IAP values, higher central venous pressure, positive fluid balance, extracorporeal circulation, use of vasoactive drugs and AKI. Determinants of IAH should be accurately assessed before and after surgery, and patients presenting risk factors must be monitored properly during the perioperative period. In this context, the baseline value of IAP may be a valuable and early warning parameter for IAH occurrence. PMID- 23820649 TI - Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease. AB - Some individuals with a particular disease-causing mutation or genotype fail to express most if not all features of the disease in question, a phenomenon that is known as 'reduced (or incomplete) penetrance'. Reduced penetrance is not uncommon; indeed, there are many known examples of 'disease-causing mutations' that fail to cause disease in at least a proportion of the individuals who carry them. Reduced penetrance may therefore explain not only why genetic diseases are occasionally transmitted through unaffected parents, but also why healthy individuals can harbour quite large numbers of potentially disadvantageous variants in their genomes without suffering any obvious ill effects. Reduced penetrance can be a function of the specific mutation(s) involved or of allele dosage. It may also result from differential allelic expression, copy number variation or the modulating influence of additional genetic variants in cis or in trans. The penetrance of some pathogenic genotypes is known to be age- and/or sex dependent. Variable penetrance may also reflect the action of unlinked modifier genes, epigenetic changes or environmental factors. At least in some cases, complete penetrance appears to require the presence of one or more genetic variants at other loci. In this review, we summarize the evidence for reduced penetrance being a widespread phenomenon in human genetics and explore some of the molecular mechanisms that may help to explain this enigmatic characteristic of human inherited disease. PMID- 23820670 TI - An RCT with three-year follow-up of peer support groups for Chinese families of persons with schizophrenia. AB - OBJECTIVE: This study was conducted to test the effects of a nine-month family led peer support group for Chinese people with schizophrenia in Hong Kong over a three-year follow-up and to compare outcomes with those of psychoeducation and standard psychiatric outpatient care. METHODS: A randomized controlled trial of 106 Chinese families of patients with schizophrenia was conducted between August 2007 and January 2011 in three psychiatric outpatient clinics. Families were randomly assigned to peer support (N=35), psychoeducation (N=35), or standard care (N=36). In addition to standard care received, peer support and psychoeducation consisted of 14 two-hour group sessions, with patients participating in six to 14 sessions. Multiple patient and family outcomes- including families' support service utilization and functioning and patients' functioning mental state and rehospitalization rate--were measured at recruitment and one week, 18 months, and 36 months after completion of the interventions. RESULTS: Patients and families in the peer support group reported consistently greater improvements over three years in overall functioning (family p<.005; patient p<.001) and reductions in duration and number of hospitalizations (p<.01 for both), without any increase in service utilization. CONCLUSIONS: Family-led peer support groups were an effective intervention for Chinese people with schizophrenia, resulting in long-term effects of improving patient and family functioning and reducing rehospitalizations. PMID- 23820669 TI - Thyroid hormone signalling is altered in response to physical training in patients with end-stage heart failure and mechanical assist devices: potential physiological consequences? AB - OBJECTIVES: The present study investigated the potential of the failing myocardium of patients with ventricular assist devices (VAD) to respond to physiological growth stimuli, such as exercise, by activating growth signalling pathways. This may be of therapeutic relevance in identifying novel pharmacological targets for therapies that could facilitate recovery after VAD implantation. METHODS: Twenty-two patients bridged to heart transplantation (HTx) with VAD were included in the study. A group of patients underwent moderate intensity aerobic exercise (GT), while another group of patients did not receive exercise training (CG). Thyroid hormone receptor alpha1 (TRalpha1) protein and total (t) and phosphorylated (p) protein kinase B (Akt) and c-Jun N-terminal kinase (JNK) kinase signalling were measured in myocardial tissue by western blotting at pre-VAD and pre-HTx period. In addition, Thyroid hormone (TH) levels were measured in plasma. RESULTS: Peak oxygen consumption (VO2) at pre-HTx period was higher in patients subjected to training protocol [18.0 (0.8) for GT when compared with 13.7 (0.7) for CG group, P = 0.002]. N-terminal-prohormone of brain natriuretic peptide (NT-proBNP) levels were 1068 (148) for CG vs 626 (115) for GT group, P = 0.035. A switch towards up-regulation of physiological growth signalling was observed: the ratio of p-Akt/t-Akt was 2-fold higher in GT vs CG, P < 0.05 while p-JNK/t-JNK was 2.5-fold lower (P < 0.05) in GT vs CG, in pre-HTx samples. This response was accompanied by a 2.0-fold increase in TRalpha1 expression in pre-HTx samples with concomitant increase in circulating T3 in GT vs CG, P < 0.05. No differences in peak VO2, NT-proBNP, T3, TRalpha1, p/t-AKT and p/t-JNK were found between groups in the pre-VAD period. CONCLUSIONS: The unloaded failing myocardium responded to physical training by enhancing thyroid hormone signalling. This response was associated with an up-regulation of Akt and suppression of JNK activation. PMID- 23820671 TI - Preschool motor skills following physical and occupational therapy services among non-disabled very low birth weight children. AB - Children born very low birth weight (VLBW) are at an increased risk of delayed development of motor skills. Physical and occupational therapy services may reduce this risk. Among VLBW children, we evaluated whether receipt of physical or occupational therapy services between 9 months and 2 years of age is associated with improved preschool age motor ability. Using data from the Early Childhood Longitudinal Study Birth Cohort we estimated the association between receipt of therapy and the following preschool motor milestones: skipping eight consecutive steps, hopping five times, standing on one leg for 10 seconds, walking backwards six steps on a line, and jumping distance. We used propensity score methods to adjust for differences in baseline characteristics between children who did and did not receive physical or occupational therapy, since children receiving therapy may be at higher risk of impairment. We applied propensity score weights and modeled the estimated effect of therapy on the distance that the child jumped using linear regression. We modeled all other end points using logistic regression. Treated VLBW children were 1.70 times as likely to skip eight steps (RR 1.70, 95 % CI 0.84, 3.44) compared to the untreated group and 30 % more likely to walk six steps backwards (RR 1.30, 95 % CI 0.63, 2.71), although these differences were not statistically significant. We found little effect of therapy on other endpoints. Providing therapy to VLBW children during early childhood may improve select preschool motor skills involving complex motor planning. PMID- 23820672 TI - Bringing life course home: a pilot to reduce pregnancy risk through housing access and family support. AB - Proponents of life course comment that while the theory is persuasive, translating theory to practice is daunting. This paper speaks to the challenges and possibilities of intervention based on life course theory. It describes Healthy Start in Housing (HSiH), a partnership between the Boston Public Health Commission (BPHC) and the Boston Housing Authority (BHA) to reduce stress due to housing insecurity among low-income, pregnant women. HSiH seeks improved birth outcomes and long term health of mothers and infants. BHA goals are improved quality of life for participants, greater public housing stability and enhanced impact of housing on community well-being. HSiH is a 1 year pilot offering 75 housing units to pregnant women at risk of adverse birth outcomes and homelessness. BHA provides housing and expedites processing of HSiH applications; BPHC staff oversee enrollment, guide women through the application process, and provide enhanced, long-term case management. Of 130 women referred to HSiH to date, 53 were ineligible, 59 have submitted applications, 13 are preparing applications and 5 dropped out. Nineteen women have been housed. Among eligible women, 58 % had medical conditions, 56 % mental health conditions, and 14 % prior adverse outcomes; 30 % had multiple risks. Standardized assessments reflected high levels of depressive symptoms; 41 % had symptoms consistent with post traumatic stress disorder. Life course theory provides both the framework and the rationale for HSiH. HSiH experience confirms the salience of daily social experience to women's health and the importance of addressing stressors and stress in women's lives. PMID- 23820673 TI - From the waters of the empire to the tanks of Paris: the creation and early years of the Aquarium Tropical, Palais de la Porte Doree. AB - From May to November 1931, the Exposition coloniale internationale was held in Paris. Publicized as a trip around the world in a single day, it was designed to stimulate investments and general enthusiasm for the colonies. Along with exotic temporary pavilions representing the various colonies, model villages inhabited by colonial natives, and pavilions representing commercial product brands and other colonial powers, the exposition included a zoo and an aquarium featuring animals from the colonies. Installing a large aquarium had been a costly and difficult process, and construction was plagued by many delays and problems. But when the aquarium finally opened a few months into the exposition, it quickly became a favorite of the public. With the double mission to provide a living synthesis of the products of the warm waters of the French empire and give visitors a sense of the diversity, beauty, and economic resources of their colonial possessions, the aquarium functioned as a panorama that presented a striking visual metaphor for the empire. This article follows the aquarium during the exposition and in the years that followed. We explore its place in the history of aquaria in general and pay particular attention to its role in the exposition and within the French colonial context of the 1930s and onward. Here, both the scientists in charge of the site and the aquatic animals living in its tanks and terrariums provide a window into the relationship of marine biology, public education, consumerism, and colonialism at mid-twentieth century. PMID- 23820674 TI - Molecular basis for the expression of major vault protein induced by hyperosmotic stress in SW620 human colon cancer cells. AB - Major vault protein (MVP) is identical to lung resistance-related protein (LRP), which is the major component of vaults. Vaults are considered to play a protective role against xenobiotics and other types of stress. In a previous study, we reported that the expression levels of MVP in SW620 human colon cancer cells were increased in hypertonic culture medium with sucrose. However, the molecular mechanism behind the induction of MVP expression by osmotic stress has not yet been elucidated. Therefore, in the present study, we investigated the mechanism behind the induction of MVP expression by osmotic stress. Under hyperosmotic stress conditions, the ubiquitination of specificity protein 1 (Sp1) decreased, Sp1 protein levels increased, its binding to the MVP promoter was enhanced, and small interfering RNA (siRNA) for Sp1 suppressed the induction of MVP expression. The inhibition of c-jun N-terminal kinase (JNK) by SP600125, a specific JNK inhibitor, decreased the expression of MVP and Sp1 under hyperosmotic conditions. Our data indicate that the stabilization and upregulation of Sp1 protein expression by JNK participate in the inhibition of the ubiquitination and degradation of Sp1, and thus in the induction of MVP expression under hyperosmotic conditions. PMID- 23820676 TI - What is acceptable delay in emergency abdominal surgery? PMID- 23820677 TI - Hyperbilirubinemia as a predictor for appendiceal perforation: a systematic review. AB - BACKGROUND AND AIMS: Delayed or wrong diagnosis in patients with appendicitis can result in perforation and consequently increased morbidity and mortality. Serum bilirubin may be a useful marker for appendiceal perforation. The purpose of this systematic review was to evaluate studies investigating elevated serum bilirubin as a predictor for appendiceal perforation. MATERIAL AND METHODS: Medline, Embase, and Cochrane databases were searched for studies evaluating elevated bilirubin in the diagnosis of perforated appendicitis. Study selection criteria included English language papers evaluating serum bilirubin as a marker of appendiceal perforation in humans. A total of 189 abstracts were screened for eligibility, of which five clinical studies were included in this study. RESULTS: Bilirubin was significantly higher in patients with appendiceal perforation compared with patients with appendicitis without perforation. Elevated serum bilirubin had a sensitivity ranging from 0.38 to 0.77 and a specificity ranging from 0.70 to 0.87 in predicting appendiceal perforation. CONCLUSIONS: Elevated serum bilirubin for determining the risk of perforation in appendicitis has low sensitivity but higher specificity. This measure can therefore be used as a supplement in the diagnostic process. PMID- 23820675 TI - Morphine stimulates platelet-derived growth factor receptor-beta signalling in mesangial cells in vitro and transgenic sickle mouse kidney in vivo. AB - BACKGROUND: Pain and renal dysfunction occur in sickle cell disease. Morphine used to treat pain also co-activates platelet-derived growth factor receptor-beta (PDGFR-beta), which can adversely affect renal disease. We examined the influence of morphine in mesangial cells in vitro and in mouse kidneys in vivo. METHODS: > Mouse mesangial cells treated with 1 MUM morphine in vitro or kidneys of transgenic homozygous or hemizygous sickle or control mice (n=3 for each), treated with morphine (0.75, 1.4, 2.14, 2.8, 3.6, and 4.3 mg kg(-1) day(-1) in two divided doses during the first, second, third, fourth, fifth, and sixth weeks, respectively), were used. Western blotting, bromylated deoxy uridine incorporation-based cell proliferation assay, reverse transcriptase-polymerase chain reaction, immunofluorescent microscopy, and blood/urine chemistry were used to analyse signalling, cell proliferation, opioid receptor (OP) expression, and renal function. RESULTS: Morphine stimulated phosphorylation of PDGFR-beta and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) to the same extent as induced by platelet-derived growth factor-BB (PDGF-BB) and promoted a two-fold increase in mesangial cell proliferation. The PDGFR-beta inhibitor, AG1296, OP antagonists, and silencing of MU- and kappa-OP abrogated morphine-induced MAPK/ERK phosphorylation and proliferation by ~100%. Morphine treatment of transgenic mice resulted in phosphorylation of PDGFR-beta, MAPK/ERK, and signal transducer and activator of transcription 3 (Stat3) in the kidneys. Morphine inhibited micturition and blood urea nitrogen (BUN) clearance and increased BUN and urinary protein in sickle mice. CONCLUSION: Morphine stimulates mitogenic signalling leading to mesangial cell proliferation and promotes renal dysfunction in sickle mice. PMID- 23820678 TI - "Enteroatmospheric fistulae"--gastrointestinal openings in the open abdomen: a review and recent proposal of a surgical technique. AB - The occurrence of an enteric fistula in the middle of an open abdomen is called an enteroatmospheric fistula, which is the most challenging and feared complication for a surgeon to deal with. It is in fact not a true fistula because it neither has a fistula tract nor is covered by a well-vascularized tissue. The mortality of enteroatmospheric fistulae was as high as 70% in past decades but is currently approximately 40% due to advanced modern intensive care and improved surgical techniques. Management of patients with an open abdomen and an enteroatmospheric fistula is very challenging. Intensive care support of organs and systems is vital in order to manage the severely septic patient and the associated multiple organ failure syndrome. Many of the principles applied to classic enterocutaneous fistulae are used as well. Control of enteric spillage, attempts to seal the fistula, and techniques of peritoneal access for excision of the involved loop are reviewed in this report. Additionally, we describe our recent proposal of a lateral surgical approach via the circumference of the open abdomen in order to avoid the hostile and granulated surface of the abdominal trauma, which is adhered to the intraperitoneal organs. PMID- 23820679 TI - A meta-analysis of operative versus nonoperative treatment in 463 scapular neck fractures. AB - BACKGROUND AND AIMS: Treatment of scapular neck fractures remains controversial. Advantages of surgical treatments, such as anatomical restoration of fracture displacement, are counterbalanced by approach morbidity. We conducted a meta analysis of 463 scapular neck fractures and compared clinical, functional, and radiographical outcomes in operatively and nonoperatively treated scapular neck fractures. MATERIAL AND METHODS: A literature search was conducted, including the databases PubMed/MEDLINE, Embase, and the Cochrane Database of Systematic Reviews. Manuscripts were included if they reported a precise description of treatment, complications, functional outcomes, and/or radiographic evaluation. Data about day-to-day activities, level of pain-freeness, range of motion, functional grading, and radiographical assessment were pooled and compared using fixed effects models. RESULTS AND CONCLUSIONS: A total of 22 manuscripts were relevant, including 1 prospective cohort study and 21 retrospective studies. The studies showed a high heterogeneity in the result assessment. Most patients had concomitant injuries. In total, 234 out of the 463 fractures were treated operatively. Pain-freeness and radiographic outcome measurements were significantly better in the operatively treated group, whereas range of motion was significantly improved in the nonoperative treated patients. Complication rate for surgical treatment was about 10%. From the achievable data, there was no bias detected when comparing the two treatment groups. However, those data could not be analyzed for all included studies. For the same reason, the role of additional surgical treatment for concomitant injuries to the shoulder girdle could not be cleared completely. Caution should be exercised, and individual injury patterns have to be taken into consideration when considering the best treatment options. PMID- 23820680 TI - Comparison of the health-related quality of life in patients with narrow gastric tube and whole stomach reconstruction after oncologic esophagectomy: a prospective randomized study. AB - BACKGROUND AND AIMS: To compare the health-related quality of life in patients with narrow gastric tube and whole stomach reconstructions after oncologic esophagectomy. MATERIAL AND METHODS: In a prospective randomized single-center study from 2007 to 2008, 104 patients underwent esophagectomy for cancer. To assess health-related quality of life, the questionnaire (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and the Oesophagus-Specific Quality of Life Questionnaire 18) was administered at 3 weeks, 6 months, 1 year, and 2 years after surgery. RESULTS: The perioperative complication rate was 26.9% in narrow gastric tube group and 48.1% in whole stomach group (P = 0.31). At the time of 3 weeks after surgery, the reflux and dyspnea scores were higher in whole stomach group than in narrow gastric tube group, which meant that the patients in whole stomach group suffered more severe problem. At the time of 6 months and 1 year after surgery, the reflux scores were lower in narrow gastric tube group than in whole stomach group, which revealed that there were less problems of reflux in the patients of narrow gastric tube group; meanwhile, the score of physical function scale in narrow gastric tube group was higher conversely, which suggested that the patients gain a better status in physical function. Nausea and vomiting is the only notable symptom that was worse in whole stomach group at the time of 2 years after surgery, which suggested that patients in whole stomach group suffered more severe nausea and vomiting. CONCLUSIONS: Narrow gastric tube reconstruction may be a good alternative choice for patients undergoing oncologic esophagectomy in view of better health-related quality of life after the surgery. PMID- 23820681 TI - Large-diameter (30-35 mm) pneumatic balloon dilatation of the pylorus in patients with gastric outlet obstruction symptoms after esophagectomy. AB - BACKGROUND AND AIMS: Functional gastric outlet obstruction is a common problem after esophagectomy. The aim of this study was to evaluate the safety and efficacy of treating this group of patients with pneumatic dilatation of the pyloric sphincter region using a large-diameter (30-35 mm) balloon. MATERIAL AND METHODS: A review of all patients who had undergone pneumatic dilatation of the pylorus sphincter because of gastric outlet obstruction symptoms after esophagectomy at the Karolinska University Hospital from 2006-2011 was completed. Main outcomes were recordings of nausea, regurgitation and bloating. RESULTS: A total of 13 patients received pneumatic dilatation after an esophagectomy. The median time between esophagectomy and the first dilatation was 100 days, and the patients underwent a total of 21 dilatations (1-3 per patient) to a final median diameter of 30 mm. No procedure-related complications occurred. The median follow up time was 205 days, and nausea and regurgitation improved significantly (p < 0.001, Fisher's test). CONCLUSIONS: Pneumatic dilatation of the pylorus using a large-diameter pneumatic balloon seems to be a safe and effective method for treating symptoms suggestive of gastric outlet obstruction after esophagectomy. To document its true effectiveness, a randomized and sham-controlled study is needed. PMID- 23820682 TI - The prophylactic use of a ureteral stent in laparoscopic colorectal surgery. AB - BACKGROUND AND AIMS: The insertion of prophylactic ureteral stents in traditional colorectal surgery has been debated for a long time. The aim of this study is to investigate the results of ureteric stent insertion in elective laparoscopic colorectal surgery in terms of complications and costs. MATERIAL AND METHODS: From June 2009 to June 2011 one or two prophylactic ureteral stents were placed in all patients undergoing elective laparoscopic resection of their colon or rectum. RESULTS: A total of 89 patients took part in this study, 61% had a benign disease and 39% malignant. The mean time for ureteral stent insertion was 16 min if one-sided and 21 min if bilateral. Incidental findings were found in the bladder in four (4.5%) patients. In all, 13 (26%) male patients had a benign prostatic adenoma, and 3 (6%) male patients had a significant stenosis of the urethral meatus and required bouginage. Complications due to ureteral stent insertion were transient hematuria in 11 (12.3%) cases, postoperative urinary tract infections in 2 (2.2%) cases, and hydronephrosis in 2 (2.2%) cases. One patient suffered an accidental damage of the right ureter despite the presence of a stent; this was recognized intraoperatively. The total cost for a one-sided ureteral stent insertion is calculated at around ?360, and for a bilateral ureteral stent insertion, it is around ?410. CONCLUSIONS: The prophylactic use of a ureteral stent in laparoscopic colorectal surgery leads to minor complications and may be cost-effective. PMID- 23820683 TI - Adenomas with adenocarcinoma: a study evaluating the risk of residual cancer and lymph node metastasis. AB - BACKGROUND AND AIMS: The increasing number of cases with colorectal adenomas with adenocarcinoma necessitates renewed evaluation of classification systems and risk factors. The aim for this retrospective study was to evaluate the potential risk of residual cancer and lymph node metastasis in patients with colorectal adenomas with adenocarcinoma. MATERIAL AND METHODS: An investigation of adenomas with adenocarcinoma in 74 patients was performed on histological slides and compared with clinical characteristics. A total of 44 of the samples were from macroscopically and microscopically completely resected lesions, and cancer at extended surgery was compared with pathology reports, classifications, and histopathological features. RESULTS: In all, 26 cases of adenomas with adenocarcinoma in the rectum and rectosigmoid were among women and 11 in men while 22 men as opposed to 15 women had primary lesions in colon, giving a significant association between gender and localization (p = 0.01). For macroscopically and microscopically fully resected lesions, Haggitt classification or submucosal invasion did not correlate with cancer at extended surgery. The lack of information on resection margins in the primary pathology reports was found to correlate significantly with residual cancer at extended surgery (p < 0.001) with residual cancer in 3 out of the 10 cases with no information, 1 out of the 5 where the resection margins were uncertain, 1 out of the 4 where the resection margins were not free, and none of the 25 cases when the resection margins were reported as free. In colon, 1 case out of the 6 with extended surgery (16.7%) was diagnosed with residual cancer compared with 4 out of the 10 (40%) from rectum. CONCLUSIONS: Haggitt or submucosal classifications were not found to be predictors for residual cancer in the remaining bowel tissue or lymph node metastasis. The only significant factor indicating increased risk of residual cancer was the lack of information on resection margins in the pathology report. Surgeons should therefore be alert when adenomas with adenocarcinomas are not confirmed as microscopically free in the pathology report. PMID- 23820684 TI - Clinical and proctoscopic evaluation of topical formalin application in the treatment of chronic radiation proctitis. AB - BACKGROUND AND AIMS: Chronic radiation proctitis is a disease associated with radiotherapy of cancer in the pelvic region. The main symptom is rectal bleeding. Several treatment modalities have been attempted, but few have demonstrated satisfactory effects. We present our experience with formalin applied locally to the rectal mucosa in the treatment of chronic radiation proctitis. Furthermore, we assess possible complications, the gravest suggested being cancer. Previous studies on the subject have reported good results, but often with a somewhat vaguely defined follow-up. Our evaluation of the treatment was based on both subjective symptoms and proctoscopic findings. MATERIAL AND METHODS: A small study (N = 11) was conducted retrospectively. All patients treated for chronic radiation proctitis with formalin in our clinic were identified, and data concerning effect and complications were collected by studying the patients' records, with a questionnaire and a follow-up interview and proctoscopy. RESULTS: The study showed a marked decrease in bleeding and objective signs of proctitis in all patients. Complete cessation of bleeding was achieved in five patients. Possible complications to the treatment detected in our study were the following: anorectal pain, tenesmus, incontinence, diarrhea, and mucous rectal discharge. No signs of neoplasia were found. CONCLUSIONS: The formalin treatment had a very good effect on chronic radiation proctitis. Possible complications were detected. Except in the case of anorectal pain, these are all of a questionable nature and can possibly be attributed to chronic radiation proctitis itself rather than the formalin treatment. Further study is warranted to confirm long-term effects of the formalin and to exclude possible complications, especially secondary anorectal cancer. PMID- 23820686 TI - Should we abandon wire-guided localization for nonpalpable breast cancer? A plea for wire-guided localization. AB - BACKGROUND AND AIMS: To evaluate wire-guided localization for nonpalpable breast cancer regarding procedure and surgery-related outcome in a nonteaching community hospital in the Netherlands. MATERIAL AND METHODS: A consecutive series of 117 patients who were treated with breast-conserving surgery after wire-guided localization for nonpalpable breast cancer between January 2006 and December 2010 was retrospectively analyzed. The patients' digital records were reviewed for patient, radiological, histological, and surgical characteristics. In order to quantify the excess resected tissue, a calculated resection ratio was determined by dividing the total resection volume by the optimal resection volume. The optimal resection volume was defined as a spherical tumor volume with an added 1.0 cm margin. The total resection volume was defined as the corresponding ellipsoid. RESULTS: There were no procedure-related complications. There were two postoperative hemorrhages. Margins were clear in 92.3% of the cases after the first surgical procedure. Eight (6.8%) patients required two operations and one (0.9%) patient required three operations in order to obtain negative margins. Breast conservation was possible in 113 (96.6%) patients. The median calculated resection ratio was 1.87 (range 0.47-14.92). CONCLUSIONS: This study proves that it is possible to obtain excellent results performing breast-conserving surgery for nonpalpable breast cancer regarding margin status, total amount of operations, and the ratio between tumor and resected tissue volume using wire guided localization as a localization tool. PMID- 23820685 TI - Human early liver regeneration after hepatectomy in patients with hepatocellular carcinoma: special reference to age. AB - BACKGROUND AND AIMS: This study was conducted to clarify the effects of age on human liver regeneration. PATIENTS AND METHODS: Thirty major hepatectomies, equal to or more than two segmentectomies for hepatocellular carcinoma, were performed. Ages ranged from 37 to 85 years and five octogenarians were included. The early regenerative index was defined: (liver volume after 7 days after hepatectomy - estimated remnant liver volume before hepatectomy)/estimated remnant liver volume, using three-dimensional computed tomographic volumetry. Farnesoid X receptor and forkhead box m1 expression in the liver, which has been reported to age-related decrease of liver regeneration in animal model, were examined using real-time polymerase chain reaction. The patients were divided into two groups: low early regenerative index (n = 15), early regenerative index less than 55% and high early regenerative index (n = 15), early regenerative index equal to or more than 55%. RESULTS: The mean early regenerative index was 57%. Age (R (2) = 0.274, P = 0.003) and estimated blood loss (R (2) = 0.134, P = 0.0466) were inversely correlated with the early regenerative index, and the expression of farnesoid X receptor and forkhead box m1 was not. The incidence of post-hepatectomy liver failure in the low early regenerative index group was higher than that in the high early regenerative index group (P = 0.0421). CONCLUSIONS: Age and intraoperative blood loss are inversely correlated with early liver regeneration in humans. In elderly patients, massive blood loss should be avoided in view of liver regeneration. PMID- 23820687 TI - Does blood transfusion affect intermediate survival after coronary artery bypass surgery? AB - BACKGROUND: The aim of this study was to investigate the impact of transfusion of blood products on intermediate outcome after coronary artery bypass surgery. PATIENTS: Complete data on perioperative blood transfusion in patients undergoing coronary artery bypass surgery were available from 2001 patients who were operated at our institution. RESULTS: Transfusion of any blood product (relative risk = 1.678, 95% confidence interval = 1.087-2.590) was an independent predictor of all-cause mortality. The additive effect of each blood product on all-cause mortality (relative risk = 1.401, 95% confidence interval = 1.203-1.630) and cardiac mortality (relative risk = 1.553, 95% confidence interval = 1.273-1.895) was evident when the sum of each blood product was included in the regression models. However, when single blood products were included in the regression model, transfusion of fresh frozen plasma/Octaplas(r) was the only blood product associated with increased risk of all-cause mortality (relative risk = 1.692, 95% confidence interval = 1.222-2.344) and cardiac mortality (relative risk = 2.125, 95% confidence interval = 1.414-3.194). The effect of blood product transfusion was particularly evident during the first three postoperative months. Since follow-up was truncated at 3 months, transfusion of any blood product was a significant predictor of all-cause mortality (relative risk = 2.998, 95% confidence interval = 1.053-0.537). Analysis of patients who survived or had at least 3 months of potential follow-up showed that transfusion of any blood product was not associated with a significantly increased risk of intermediate all-cause mortality (relative risk = 1.430, 95% confidence interval = 0.880 2.323). CONCLUSIONS: Transfusion of any blood product is associated with a significant risk of all-cause and cardiac mortality after coronary artery bypass surgery. Such a risk seems to be limited to the early postoperative period and diminishes later on. Among blood products, perioperative use of fresh frozen plasma or Octaplas seems to be the main determinant of mortality. PMID- 23820688 TI - Cementless total hip arthroplasty with large diameter metal-on-metal heads: short term survivorship of 8059 hips from the Finnish Arthroplasty Register. AB - BACKGROUND AND AIMS: Population-based register data from the National Joint Register of Australia and England and Wales have revealed that the mid-term outcome of cementless large diameter head metal-on-metal total hip arthroplasty is inferior to that of conventional cemented metal-on-polyethylene total hip arthroplasty. The aim of this study was to compare the results of cementless large diameter head metal-on-metal total hip arthroplasty with conventional cemented arthroplasty in Finland. The second aim of this study was to compare the cementless large diameter head metal-on-metal models with each other. MATERIAL AND METHODS: Based on the data extracted from the Finnish Arthroplasty Register, the risk of revision of 8059 cementless large diameter head metal-on-metal total hip arthroplasties performed during 2002-2009 was analyzed using Cox regression model. The revision risk of these hips was compared to that of 16,978 cemented metal-on-polyethylene total hip arthroplasties performed during the same time period. RESULTS: In the Cox regression analysis, there was no difference in revision risks between cementless large diameter head metal-on-metal total hip arthroplasty and cemented metal-on-polyethylene total hip arthroplasty (relative risk = 0.90, confidence interval = 0.74-1.10, p = 0.3). However, in female patients aged 55 years or above, cementless large diameter head metal-on-metal total hip replacements showed a significantly increased risk of revision as compared to cemented total hip replacements (relative risk = 1.33, confidence interval = 1.04-1.70). Compared to the reference implant in this study (cementless Synergy stem combined with Birmingham Hip Resurfacing [BHR] cup), the CementLess Spotorno (CLS) stem combined with Durom cup had a 2.9-fold (95% confidence interval = 1.17-6.90) increased risk of revision. CONCLUSIONS: We found that cementless large diameter head metal-on-metal total hip arthroplasty had short-term survivorship compared with cemented total hip arthroplasty at a nation-wide level. However, in female patients aged 55 years or above, cementless large diameter head metal-on-metal total hip arthroplasty showed inferior results. Furthermore, implant design had an influence on revision rates. Longer follow-up time is needed to assess the success of large diameter head metal-on metal total hip arthroplasty. PMID- 23820689 TI - Perioperative complications after cemented or uncemented hemiarthroplasty in hip fracture patients. AB - BACKGROUND AND AIMS: Both cemented and uncemented hemiarthroplasties are acceptable methods for treating displaced femoral neck fractures. Cemented hemiarthroplasty has traditionally been recommended as being more safe and reliable. However, the cementing process carries a risk of fat embolism and cardiovascular problems. This study attempted to determine whether these complications can be avoided when using a modern uncemented stem. MATERIAL AND METHODS: We retrospectively compared 222 hip fracture patients treated with hemiarthroplasty in our hospital. A total of 100 of these patients were treated with a hydroxyapatite-coated uncemented hemiendoprosthesis (Bi-Metric BFx) and 122 patients with a cemented hemiendoprosthesis (Lubinus SPII). Information on mortality and complications during the first 18.7 months was retrieved from patient files. RESULTS AND CONCLUSIONS: Nine perioperative fat-embolic events were found in the cemented group and none in the uncemented group. During the initial hospital treatment, there were five deaths (4.1%) in the cemented group and one death (1%) in the uncemented group. There were significantly more perioperative fractures in the uncemented versus cemented group (7% versus 0.8%). We conclude that uncemented hemiarthroplasty is associated with more perioperative fractures than cemented hemiarthroplasty. However, perioperative cardiovascular disturbances may be less frequent with uncemented hemiarthroplasty, and early mortality may be lower with uncemented hemiarthroplasty. PMID- 23820690 TI - Epiphrenic diverticula mini-invasive surgery: a challenge for expert surgeons- personal experience and review of the literature. AB - BACKGROUND AND AIMS: While in the past, thoracotomy represented the traditional surgical approach for the treatment of epiphrenic diverticula, actually mini invasive approach seems to be the preferred treatment as many series have been published in the recent years. This article describes the authors' experience with the laparoscopic approach for performing diverticulectomy, myotomy, and Nissen-Rossetti fundoplication. MATERIAL AND METHODS: From 1994 to 2010, 21 patients (10 men and 11 women), mean age 58.5 years (range 45-74 years), with symptomatic epiphrenic diverticulum underwent laparoscopic diverticulectomy, myotomy and Nissen-Rossetti fundoplication. RESULTS: The mean operative time was 135 min (range = 105-190 min). Mean hospital stay was 14.2 days (range = 7-25 days). In 5 patients (23.8%), a partial suture staple line leak was observed. Conservative treatment achieved leak resolution in all the cases. One patient (4.8%) died of a myocardial infarction in the postoperative period. After a mean clinical follow-up period of 78 months (range = 6-192 months), excellent or good outcome was referred with no dysphagia in 16 patients (80%) and only mild occasional dysphagia in 4 patients (20%). CONCLUSIONS: Surgical treatment of epiphrenic diverticula remains a challenging procedure also by mini-invasive approach, with major morbidity and mortality rates. For this reason, indications must be restricted only to selected and symptomatic patients in specialized centers. PMID- 23820691 TI - In vitro investigation of the bioaccessibility of carotenoids from raw, frozen and boiled red chili peppers (Capsicum annuum). AB - BACKGROUND: Carotenoid-rich foods are associated with antioxidant activity and the ability to alleviate chronic diseases. PURPOSE: The present study investigated the effect of processing on the content and bioaccessibility of carotenoids from 13 cultivars of red chili pepper (Capsicum annuum). METHODS: Carotenoids in chili peppers were analyzed before an in vitro digestion process. The portion of carotenoid transferred to the micelle fraction (bioaccessibility) was also quantified. RESULTS: beta-Carotene, beta-cryptoxanthin, capsanthin and antheraxanthin were the most abundant carotenoids. Zeaxanthin, violaxanthin, neoxanthin and lutein were detected at lower concentrations. In general, freezing and boiling reduced carotenoid contents. Capsanthin and zeaxanthin had the highest bioaccessibility at an average value from 36 to 40%, followed by antheraxanthin (26%). Bioaccessibility of beta-cryptoxanthin, violaxanthin and beta-carotene was lower, averaging 6.1, 4.8 and 4.0%, respectively. Neoxanthin and lutein were not detected in micelles. Freezing increased the bioaccessibility of capsanthin, zeaxanthin, antheraxanthin, beta-cryptoxanthin and violaxanthin; beta-cryptoxanthin bioaccessibility increased and capsanthin and zeaxanthin bioaccessibility decreased following boiling. CONCLUSIONS: Differences in the contents and bioaccessibility of carotenoids in 13 C. annuum cultivars and between the processed methods were herein evidenced. PMID- 23820692 TI - Percutaneous biopsy of focal lesions of the gastrointestinal tract. AB - PURPOSE: To evaluate the technical success and diagnostic accuracy of image guided percutaneous biopsy of the gastrointestinal (GI) tract. MATERIALS AND METHODS: An interventional radiology database was used to retrospectively identify patients who underwent image-guided percutaneous biopsy of the GI tract. The medical and imaging records were reviewed to assess biopsy results and complications. RESULTS: Twenty-nine patients (M:F = 19:10, mean age 65 years) were identified who underwent image-guided (CT/US) percutaneous biopsies of the GI tract. All biopsies were performed using coaxial technique with 18 g core and 22 g FNA needles. Twenty-two biopsies (76 %) were for circumferential or segmental wall thickening; the remaining were wall thickening with exophytic mass. Mean tumor diameter was 7.4 cm (SD = 3.4 cm), average wall thickening was 2.1 cm (SD 7.2), and exophytic mass was 10.0 cm (SD = 4.2). Tumor locations included stomach (n = 5), small bowel (n = 8), and colon (n = 16). Malignancy was confirmed in 22 patients, 12 of whom underwent excision, with 3 false positive samples. Benign disease was diagnosed in 7 patients, including 3 with pathology confirmation, with one false negative sample. The overall sensitivity was 83 % and accuracy was 84 %. There was one complication presenting as bleeding at the biopsy site, treated conservatively. CONCLUSION: Percutaneous biopsy of the GI tract is an uncommon procedure. The results of this study suggest that it is a safe and sensitive procedure that may be considered for small bowel lesions in which endoscopy is not feasible, for submucosal lesions, or in the setting of patients with previously negative endoscopic biopsies. PMID- 23820693 TI - Biliary-enteric anastomoses: spectrum of findings on Gd-EOB-DTPA-enhanced MR cholangiography. AB - Biliary-enteric anastomosis is a common surgical procedure performed for the management of a variety of benign and malignant diseases. This procedure presents a high risk of developing complications such as anastomotic leak, hemorrhage, cholangitis, stones, stricture formation, that have been reported as ranging from 3 % to 43 %. Because the endoscopic approach of the biliary tract is generally precluded in this setting, there is clearly a role for a non-invasive imaging technique to follow up these patients and to detect the possible complications. T2-weighted MR cholangiography has been shown to be effective in the evaluation of patients with biliary-enteric anastomosis. Some of these patients may have mild duct dilatation in spite of a patent anastomosis, and stenosis should be considered only when duct dilatation is associated with narrowing of the anastomotic site. T2-weighted MRC depicts the site of biliary-enteric anastomosis, the cause of obstruction, and the status of the biliary ducts upstream. However, the disadvantages of conventional MRC are that it lacks functional information and so, differentiation between obstructive and non obstructive dilatation of the bile ducts is often extremely difficult. T1 weighted contrast-enhanced MR cholangiography using Gd-EOB-DTPA is a recently emerging technique that is useful for delineating the anatomy of biliary-enteric anastomoses and detecting complications such as strictures, intraductal stones, and biliary leaks; besides, this technique can provide functional information that are extremely promising in the grading of biliary obstruction. We present the spectrum of findings of biliary-enteric anastomoses on Gd-EOB-DTPA-enhanced MR cholangiography focusing on the main clinical applications. PMID- 23820694 TI - Engineering p-wave interactions in ultracold atoms using nanoplasmonic traps. AB - Engineering strong p-wave interactions between fermions is one of the challenges in modern quantum physics. Such interactions are responsible for a plethora of fascinating quantum phenomena, such as topological quantum liquids and exotic superconductors. Here we propose a method to generate these fermionic interactions by combining recent developments in nanoplasmonics with progress in realizing laser-induced gauge fields. Nanoplasmonics allows for strong confinement, leading to a geometric resonance in the atom-atom scattering. In combination with the laser coupling of the atomic states, this is shown to result in the desired interaction. We illustrate how this scheme can be used for the stabilization of strongly correlated fractional quantum Hall states in ultracold fermionic gases. PMID- 23820695 TI - Establishing reference values of spectral reflectance indices in transplants of Pseudoscleropodium purum for potential use in atmospheric biomonitoring. AB - We studied the spatiotemporal variation of the photochemical reflectance index (PRI) and the chlorophyll content index (CHL index) in a terrestrial moss, using self-watering transplants distributed in 8 sampling sites that were sampled periodically during up to 4 years. We did not detect any seasonal patterns or difference between the studied sites, and therefore the variation across the sites reflected the influence of environmental variables in the area. We established the reference thresholds associated with physiological stress as 0.212 for PRI and 1.195 for CHL index. Our findings could be applied for biomonitoring atmospheric contamination on the basis of the physiological stress shown by the moss used. PMID- 23820696 TI - Sub-acute deltamethrin and fluoride toxicity induced hepatic oxidative stress and biochemical alterations in rats. AB - The current study investigated the effects of deltamethrin, fluoride (F(-)) and their combination on the hepatic oxidative stress and consequent alterations in blood biochemical markers of hepatic damage in rats. Significant hepatic oxidative stress and hepatic damage were observed in the toxicant exposed groups. These changes were higher in the deltamethrin-F(-) co-exposure treatment group, depicting a positive interaction between the two chemicals. PMID- 23820697 TI - Current and future aspects of the Japanese medical system in the treatment of musculoskeletal tumors. PMID- 23820698 TI - Response to "On crestal/marginal bone loss around dental implants". PMID- 23820699 TI - Changes in soft tissue dimensions following three different techniques of stage two surgery: a case series report. AB - The aim of this case series report is to compare the results of the increase in keratinized mucosa using three different techniques of stage-two surgery. Thirty two patients with one to eight dental implants who received prosthetic rehabilitation of the maxilla were included. Patients were divided into three groups based on preoperative anatomical considerations. Stage-two surgery was performed using either the apically repositioned flap (ARF; n = 14), the roll flap (RF; n = 10), or an apically repositioned flap combined with a connective tissue graft (ARFCT; n = 8). The height of the keratinized mucosa and relative tissue thickness were measured preoperatively and postoperatively at 2 weeks and 3, 6, and 12 months after surgery. The mean gains of keratinized mucosa and tissue thickness were calculated from these measurements. After 1 year, the mean gains in tissue thickness and keratinized tissue were 1.37 and 4.63 mm in the ARF group, 2.41 and 1.35 mm in the RF group, and 3.10 and 4.10 mm in the ARFCT group, respectively. There was no significant statistical difference between the 12 month and postoperative measurements (P > .05). In patients with deficient tissue thickness, a roll flap or an apically repositioned flap should be performed, while a lack of keratinized mucosa indicates the use of an apically repositioned flap with or without a connective tissue graft. When an increase in both keratinized mucosa and tissue thickness is necessary, an apically repositioned flap combined with a free connective tissue graft can be recommended. After a 12 month healing period, the obtained results showed excellent stability. PMID- 23820700 TI - What do we do after an implant fails? A review of treatment alternatives for failed implants. AB - The problem of failed implants cannot be overlooked. The purpose of this paper is to explore treatment alternatives for failed implants and their strengths and shortcomings. A comprehensive literature search was performed using PubMed and a manual search. Only five studies were identified that explored treatment in sites where implants had failed. In all five studies, the treatment alternative tested was the placement of a new implant in the failed site. The overall survival rate for such implants ranged from 71% to 92.3%. Four other alternatives are also discussed in light of data derived from other studies on the survival of various treatment strategies. These include: a continuation of the original plan using the remaining implants, modification of treatment to a tooth-supported fixed partial denture (FPD) or to a hybrid tooth-implant? supported FPD, or modification to a removable prosthesis. The selection of an appropriate alternative for failed implants is complex and involves biologic, mechanical, and psychologic considerations along with financial aspects. This should be a team decision with the patient's opinion included. PMID- 23820701 TI - A novel combined surgical approach to vertical alveolar ridge augmentation with titanium mesh, resorbable membrane, and rhPDGF-BB: a retrospective consecutive case series. AB - The purpose of this case series was to report the clinical outcomes and histologic findings of vertical ridge augmentation using a combination of titanium mesh, resorbable collagen membrane, and recombinant human platelet derived growth factor BB (rhPDGF-BB). Nineteen patients were included, and autogenous bone and anorganic bovine bone particles were used. The bone graft was mixed with rhPDGF-BB and loaded onto the bony defect up to the level of the adjacent alveolar crest. A pre-adapted titanium mesh was placed over the grafted region and covered with a resorbable collagen membrane, leaving no areas of the grafted region exposed. Seventeen patients exhibited good soft tissue healing. Postoperative flap dehiscence occurred relatively early in the healing period in one patient, whereas the covering collagen membrane was exposed during the later phase of the healing period in another. During reentry surgery for removal of the titanium mesh, three patients with favorable soft and hard tissue healing underwent bone biopsies for histologic evaluation of the augmented tissue just below the titanium mesh. The mean vertical height of augmented bone was 8.6 +/- 4.0 mm. This report demonstrates the remarkable efficacy of guided bone regeneration using a combination of titanium mesh, resorbable collagen membrane, and rhPDGF for vertical ridge augmentation, thus expanding the indications for implant therapy and allowing recovery of the three-dimensional esthetic architecture in a severely absorbed alveolar ridge. PMID- 23820702 TI - Horizontal guided bone regeneration in the posterior maxilla using recombinant human platelet-derived growth factor: a case report. AB - This clinical case report describes and demonstrates the successful use of purified recombinant human platelet-derived growth factor in conjunction with autogenous bone, an organic bovine bone-derived mineral, and a barrier membrane to reconstruct severe alveolar bone defects. Significant horizontal bone regeneration was achieved in the posterior maxillary region. Three implants were placed into the newly formed ridge and demonstrated stable crestal bone after 36 months of loading. PMID- 23820703 TI - In vivo measurements of human gingival translucency parameters. AB - The aim of this study was to evaluate the relationship between gingival translucency and peri-implant mucosa. A total of 22 peri-implant sites in 16 patients who required tooth replacement in the esthetic zone were included. Color measurements were obtained using a spectrophotometer and customized colored abutments. Mucosal thickness measurements were taken incrementally 0.5 mm from the facial gingival margin on sectioned casts. A statistically significant difference in gingival translucency was observed beginning at 1.5 mm. A negative correlation was observed between the thickness and translucency parameter (TP) (r = -0.64), with TP values decreasing as the gingival thickness increased. The gingival translucency was correlated with the thickness of the peri-implant mucosa and distance from the facial gingival margin. PMID- 23820704 TI - Peri-implant soft tissue conditioning with provisional restorations in the esthetic zone: the dynamic compression technique. AB - An optimal esthetic implant restoration is a combination of a visually pleasing prosthesis and surrounding peri-implant soft tissue architecture. This article introduces a clinical method, the dynamic compression technique, of conditioning soft tissues around bone-level implants with provisional restorations in the esthetic zone. The technique has several goals: to establish an adequate emergence profile; to recreate a balanced mucosa course and level in harmony with the gingiva of the adjacent teeth, including papilla height/width, localization of the mucosal zenith and the tissue profile's triangular shape; as well as to establish an accurate proximal contact area with the adjacent tooth/implant crown. PMID- 23820705 TI - Short dental implants: what works and what doesn't? A literature interpretation. AB - Dental implants with lengths <= 8 mm have been used with success in posterior arch regions where significant alveolar ridge resorption has occurred. Nevertheless, many clinicians are reluctant to use them regularly, if at all. Key factors for success include implant surface roughness, surgical placement methods, and, possibly, implant diameter, all of which are discussed here. PMID- 23820706 TI - Effect of xenograft (ABBM) particle size on vital bone formation following maxillary sinus augmentation: a multicenter, randomized, controlled, clinical histomorphometric trial. AB - The purpose of this study was a histomorphometric comparison of vital bone formation following maxillary sinus augmentation with two different particle sizes of anorganic bovine bone matrix (ABBM). Bilateral sinus floor augmentations were performed in 13 patients. Trephine bone cores were taken from the lateral window areas of 11 patients 6 to 8 months after augmentation for histologic and histomorphometric analysis. Bone samples from both the large and small particle size groups showed evidence of vital bone formation similar to that seen in previous studies, confirming the osteoconductivity of ABBM. Significant bone bridging was seen creating new trabeculae composed of the newly formed bone and residual ABBM particles. Histologic evaluation revealed the newly formed bone to be mostly woven bone with some remodeling to lamellar bone. Osteocytes were seen within the newly formed bone as well as osteoblast seams with recently formed osteoid. Isolated osteoclasts were observed on the ABBM surfaces. Vital bone formation (primary outcome measure) was more extensive in the large particle grafts compared with the small particle grafts (26.77% +/- 9.63% vs 18.77% +/- 4.74%, respectively). The histologic results reaffirm the osteoconductive ability of ABBM when used as the sole grafting material in maxillary sinus augmentation. The histomorphometric results at 6 to 8 months revealed a statistically significant increase (P = .02) in vital bone formation when the larger particle size was used. Additional studies should be performed to confirm these results. PMID- 23820707 TI - Use of the piezosurgery technique for cutting bones in the autotransplantation of unerupted third molars. AB - Autotransplantation is a well-known method used in oral surgery. However, risk of failure, most commonly resulting from root resorption of the transplanted tooth or ankylosis, is quite high. Piezosurgery with specific device tip vibration frequencies enables selective tissue cutting, and therefore, tooth buds or teeth can easily be removed from bones with little injury to periodontal fibers or bud follicles. PMID- 23820708 TI - Equine-derived bone mineral matrix for maxillary sinus floor augmentation: a clinical, radiographic, histologic, and histomorphometric case series. AB - The objective of this proof-of-principle multicenter case series was to examine the bone regenerative potential of a newly introduced equine-derived bone mineral matrix (Equimatrix) to provide human sinus augmentation for the purpose of implant placement in the posterior maxilla. There were 10 patients requiring 12 maxillary sinus augmentations enrolled in this study. Histologic results at 6 months demonstrated abundant amounts of vital new bone in intimate contact with residual graft particles. Active bridging between residual graft particles with newly regenerated bone was routinely observed in intact core specimens. A mean value of 23.4% vital bone formation was observed at 6 months. This compared favorably with previous results using xenografts to produce bone in the maxillary sinus for the purpose of dental implant placement. Both the qualitative and quantitative results of this case series suggest comparable bone regenerative results at 6 months to bovine-derived xenografts. PMID- 23820709 TI - The bone lamina technique: a novel approach for lateral ridge augmentation--a case series. AB - The goal of this case series is to present a novel treatment approach for lateral ridge augmentation. Four systemically healthy patients (aged 48 to 59 years) with inadequate dental alveolar ridge widths were selected for inclusion. All ridge defects were augmented using a xenogeneic cortical bone shield in combination with particulated bone substitutes and a thin collagen barrier. At baseline and after 6 months, digital cone beam computed tomography scans were performed. Biopsy specimens were harvested at reentry surgery and processed for histologic analysis. The results revealed a sufficient amount of bone structure for implant placement without additional augmentation procedures. The histologic analysis demonstrated that new bone formation had taken place and the bone shield had resorbed entirely. This case series indicates that the bone lamina technique has the biologic and mechanical properties to successfully achieve hard tissue augmentation of deficient ridges. PMID- 23820710 TI - A prospective, multicenter study of bovine pericardium membrane with cancellous particulate allograft for localized alveolar ridge augmentation. AB - Resorption of the alveolar ridge may lead to ridge deformities that make dental implant placement difficult or impossible. Augmentation of the alveolar ridge may restore appropriate ridge form to allow implant placement. Forty-four patients with edentulous spaces completed this multicenter prospective trial to clinically and radiographically evaluate the efficacy of a bovine pericardium membrane and a particulate mineralized cancellous bone allograft in promoting lateral ridge augmentation. Overall, 38 of 44 patients (86.4%) were able to receive dental implants in the appropriate restoratively driven position 6 months after ridge augmentation. The mean gain in clinical ridge width after augmentation was 2.61 mm, while radiographically the mean gain in ridge width was 1.65 mm at a level 3 mm apical to the bony crest and 1.93 mm at a level 6 mm apical to the crest. On average, approximately 50% of the graft material added horizontally during surgery was displaced or resorbed during healing. Histomorphometric evaluation of cores taken from the augmented ridge at 6 months revealed that approximately 58% of the tissue volume was vital bone, with 12% residual allograft particles and 30% nonmineralized tissue. PMID- 23820711 TI - Classification and management of antral septa for maxillary sinus augmentation. AB - The antral septum, a commonly found anatomical variation, has been related to the occurrence of membrane perforation during sinus augmentation. The aims of this study were to review features of antral septa and to propose a classification system and options for managing antral septa during sinus augmentation. A literature search of the PubMed database was performed to identify articles investigating antral septa. Manuscripts using three-dimensional computed tomography, providing direct measurements of human subjects or cadavers, and reporting features of antral septa besides the prevalence were included. Antral septa presented in approximately 20% to 35% of maxillary sinuses. Single septum was much more common than multiple septa. Mediolaterally (transversely) oriented septa were more frequently found than anteroposteriorly (sagittally) oriented septa. Their size varies and commonly increases from the lateral to medial segment within one septum. The proposed classification consists of three categories--easy (E), moderate (M), and difficult (D)--based on the location, number, orientation, and size of antral septa. Corresponding treatment approaches were suggested for each category. Sinus augmentation is complicated by the presence of antral septa, the features of which determine the degree of surgical difficulty. Based on the results of the included studies and clinical experiences, a classification system and treatment strategies of antral septa were proposed and may assist surgeons in managing antral septa during sinus augmentation. PMID- 23820712 TI - The role of hypoxia in the regulation of osteogenesis and angiogenesis coupling in intraoral regenerative procedures: a review of the literature. AB - Intraoral bone grafting is routinely employed for implant site development. Bone graft consolidation is a complex biologic process depending on the formation of blood vessels into the augmented area. Hypoxia-inducible factors (HIFs) and hypoxia-mimicking agents (HMAs) are key stimulators of blood vessel formation. Hypoxia prevents HIFs from degradation, thus signaling angiogenesis. Under normoxia, HMAs prevent degradation of HIFs. The cellular and molecular mechanisms responsible for angiogenic-osteogenic coupling and the therapeutic manipulation of HIFs and HMAs in intraoral bone repair and regeneration are discussed. Such discoveries suggest promising approaches for the development of novel therapies to improve intraoral bone repair and regeneration procedures. PMID- 23820713 TI - Recreating an esthetically and functionally acceptable dentition: a multidisciplinary approach. AB - Patients today demand a youthful, attractive smile with comfortable functional acceptance. The complete oral rehabilitation of patients with a functionally compromised dentition frequently involves a multidisciplinary approach and presents a considerable clinical challenge. To a great extent, proper patient selection and careful interdisciplinary treatment planning, including acknowledgment of the patient's perceived needs, reasons for seeking services, financial ability, and socioeconomic profile, can govern the predictability of successful restorations. This clinical report describes a successful interdisciplinary approach for the management of a severely worn dentition with reduced vertical dimension of occlusion. Treatment modalities included periodontal crown lengthening procedures, endodontic treatment followed by post and core restorations, and prosthetic rehabilitation for severe tooth surface loss and reduced vertical dimension of occlusion comprising metal-ceramic restorations in esthetic zones and full-metal restorations in posterior regions. PMID- 23820714 TI - Long-term bony integration and resorption kinetics of a xenogeneic bone substitute after sinus floor augmentation: histomorphometric analyses of human biopsy specimens. AB - In this case series, a systematic histomorphometric analysis of two human bone biopsy specimens was conducted 1 and 5 years after grafting with a xenogeneic bovine bone substitute material (BSM). While the 1-year specimen still showed extensive signs of an active desmal ossification, the specimen after 5 years mainly showed mature lamellar bone without bone turnover or remodeling. A completed bony integration without extensive resorption of the BSM particles could be detected. Altogether, a good integration in the bone with osteoconduction and a high biocompatibility was seen. PMID- 23820715 TI - Effect of various surface treatments on the bond strength of porcelain repair. AB - This study evaluated the effect of surface treatments on the repair strength of composite resin on a feldspathic ceramic. Ninety ceramic specimens were divided into six groups. In the experimental groups, 4% hydrofluoric acid etching, Er:YAG laser irradiation, CO2 laser irradiation, airborne-particle abrasion, and silica coating were used as surface treatments. After the application of a porcelain repair kit, composite resin was placed on the treated surfaces. After a shear bond strength test, data were statistically analyzed (alpha = .05). Surface treatments increased the repair bond strength values (P < .05). Airborne particle abrasion and silica coating were found to be the most effective. CO2 laser showed higher repair strength values than Er:YAG laser. PMID- 23820716 TI - A retrospective case report series of clinical outcomes with moderately rough, wide-diameter 8-mm implants in the posterior maxilla. AB - Patients with insufficient residual alveolar bone height are often treated using short implants. Historically, short implants are associated with higher failure rates. However, recent research has shown short implants with modified surfaces to have success rates similar to those of longer implants. This retrospective report aimed to evaluate clinical outcomes of 8-mm-wide diameter, moderately rough threaded implants in the posterior maxilla. From June 2008 through May 2010, 16 patients were identified who had been treated with short implants. The mean age of the patients was 50.4 years, the mean primary stability of the implants was 66 ISQ, the mean secondary stability was 75.6, and the mean loading time was 16.2 months. There were no failed implants. The mean marginal bone loss at final follow-up was 0.04 mm. This study exhibited excellent short-term clinical outcomes. PMID- 23820717 TI - Introduction to milestones in photobiology. PMID- 23820718 TI - Epidemiology and UV exposure. PMID- 23820719 TI - Milestones in photocarcinogenesis. PMID- 23820720 TI - Phototherapy. PMID- 23820721 TI - Photoaging. PMID- 23820722 TI - Lasers for dermatology and skin biology. PMID- 23820723 TI - Milestones in photoimmunology. PMID- 23820724 TI - Exploring and enhancing relaxation-based sodium MRI contrast. AB - OBJECT: Sodium MRI is typically concerned with measuring tissue sodium concentration. This requires the minimization of relaxation weighting. However, (23)Na relaxation may itself be interesting to explore, given an underlying mechanism (i.e. the electric-quadrupole-moment-electric-field-gradient interaction) that differs from (1)H. A new sodium sequence was developed to enhance (23)Na relaxation contrast without decreasing signal-to-noise ratio. MATERIALS AND METHODS: The new sequence, labeled Projection Acquisition in the steady-state with Coherent MAgNetization (PACMAN), uses gradient refocusing of transverse magnetization following readout, a short repetition time, and a long radiofrequency excitation pulse. It was developed using simulation, verified in model environments (saline and agar), and evaluated in the brain of three healthy adult volunteers. RESULTS: Projection Acquisition in the steady-state with Coherent MAgNetization generates a large positive contrast-to-noise ratio (CNR) between saline and agar, matching simulation-based design. In addition to enhanced CNR between cerebral spinal fluid and brain tissue in vivo, PACMAN develops substantial contrast between gray and white matter. Further simulation shows that PACMAN has a ln(T 2f/T 1) contrast dependence (where T 2f is the fast component of (23)Na T 2), as well as residual quadrupole interaction dependence. CONCLUSION: The relaxation dependence of PACMAN sodium MRI may provide contrast related to macromolecular tissue structure. PMID- 23820725 TI - Lifetime treatment contact and delay in treatment seeking after first onset of a mental disorder. AB - OBJECTIVE: This study examined lifetime treatment contact and delays in treatment seeking, including rates for receipt of helpful treatment, after the onset of specific mental disorders and evaluated factors that predicted treatment seeking and delays in treatment seeking. METHODS: Data were from the Netherlands Mental Health Survey and Incidence Study-2, a nationally representative, face-to-face survey of the general population aged 18-64 (N=6,646). DSM-IV diagnoses, treatment contact, and respondents' perception of treatment helpfulness were assessed with the Composite International Diagnostic Interview 3.0. RESULTS: The proportion of respondents with lifetime mental disorders who made lifetime treatment contact ranged from 6.5% to 56.5% for substance use disorders and from 75.3% to 91.4% for mood disorders. Delays in initial treatment contact varied among persons with mood disorders (median=0 years), substance use disorders (0-4 years), impulse-control disorders (4-8 years), and anxiety disorders (0-19 years). The proportion of respondents who received helpful treatment ranged from 33.5% for substance use disorders to 69.5% for mood disorders. Men, older cohorts, and respondents with younger age at onset of the disorder generally were more likely to have no lifetime treatment contact, to have longer treatment delay, and to have not received helpful treatment. CONCLUSIONS: There was substantial variation in lifetime treatment contact and delays in initial treatment contact by mental disorder. Lifetime treatment contact, delays in treatment seeking, and receipt of helpful treatment did not vary by educational level. PMID- 23820726 TI - Meniscal tear film fluid dynamics near Marx's line. AB - Extensive studies have explored the dynamics of the ocular surface fluid, though theoretical investigations are typically limited to the use of the lubrication approximation, which is not guaranteed to be uniformly valid a-priori throughout the tear meniscus. However, resolving tear film behaviour within the meniscus and especially its apices is required to characterise the flow dynamics where the tear film is especially thin, and thus most susceptible to evaporatively induced hyperosmolarity and subsequent epithelial damage. Hence, we have explored the accuracy of the standard lubrication approximation for the tear film by explicit comparisons with the 2D Navier-Stokes model, considering both stationary and moving eyelids. Our results demonstrate that the lubrication model is qualitatively accurate except in the vicinity of the eyelids. In particular, and in contrast to lubrication theory, the solution of the full Navier-Stokes equations predict a distinct absence of fluid flow, and thus convective mixing in the region adjacent to the tear film contact line. These observations not only support emergent hypotheses concerning the formation of Marx's line, a region of epithelial cell staining adjacent to the contact line on the eyelid, but also enhance our understanding of the pathophysiological consequences of the flow profile near the tear film contact line. PMID- 23820727 TI - Diminishing risk for age-related macular degeneration with nutrition: a current view. AB - Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. Clinical hallmarks of AMD are observed in one third of the elderly in industrialized countries. Preventative interventions through dietary modification are attractive strategies, because they are more affordable than clinical therapies, do not require specialists for administration and many studies suggest a benefit of micro- and macro-nutrients with respect to AMD with few, if any, adverse effects. The goal of this review is to provide information from recent literature on the value of various nutrients, particularly omega-3 fatty acids, lower glycemic index diets and, perhaps, some carotenoids, with regard to diminishing risk for onset or progression of AMD. Results from the upcoming Age Related Eye Disease Study (AREDS) II intervention trial should be particularly informative. PMID- 23820729 TI - Sucrose-induced receptor kinase SIRK1 regulates a plasma membrane aquaporin in Arabidopsis. AB - The transmembrane receptor kinase family is the largest protein kinase family in Arabidopsis, and it contains the highest fraction of proteins with yet uncharacterized functions. Here, we present functions of SIRK1, a receptor kinase that was previously identified with rapid transient phosphorylation after sucrose resupply to sucrose-starved seedlings. SIRK1 was found to be an active kinase with increasing activity in the presence of an external sucrose supply. In sirk1 T-DNA insertional mutants, the sucrose-induced phosphorylation patterns of several membrane proteins were strongly reduced; in particular, pore-gating phosphorylation sites in aquaporins were affected. SIRK1-GFP fusions were found to directly interact with aquaporins in affinity pull-down experiments on microsomal membrane vesicles. Furthermore, protoplast swelling assays of sirk1 mutants and SIRK1-GFP expressing lines confirmed a direct functional interaction of receptor kinase SIRK1 and aquaporins as substrates for phosphorylation. A lack of SIRK1 expression resulted in the failure of mutant protoplasts to control water channel activity upon changes in external sucrose concentrations. We propose that SIRK1 is involved in the regulation of sucrose-specific osmotic responses through direct interaction with and activation of an aquaporin via phosphorylation and that the duration of this response is controlled by phosphorylation-dependent receptor internalization. PMID- 23820730 TI - Proteomic analysis of the SH2 domain-containing leukocyte protein of 76 kDa (SLP76) interactome in resting and activated primary mast cells [corrected]. AB - We report the first proteomic analysis of the SLP76 interactome in resting and activated primary mouse mast cells. This was made possible by a novel genetic approach used for the first time here. It consists in generating knock-in mice that express signaling molecules bearing a C-terminal tag that has a high affinity for a streptavidin analog. Tagged molecules can be used as molecular baits to affinity-purify the molecular complex in which they are engaged, which can then be studied by mass spectrometry. We examined first SLP76 because, although this cytosolic adapter is critical for both T cell and mast cell activation, its role is well known in T cells but not in mast cells. Tagged SLP76 was expressed in physiological amounts and fully functional in mast cells. We unexpectedly found that SLP76 is exquisitely sensitive to mast cell granular proteases, that Zn(2+)-dependent metalloproteases are especially abundant in mast cells and that they were responsible for SLP76 degradation. Adding a Zn(2+) chelator fully protected SLP76 in mast cell lysates, thereby enabling an efficient affinity-purification of this adapter with its partners. Label-free quantitative mass spectrometry analysis of affinity-purified SLP76 interactomes uncovered both partners already described in T cells and novel partners seen in mast cells only. Noticeably, molecules inducibly recruited in both cell types primarily concur to activation signals, whereas molecules recruited in activated mast cells only are mostly associated with inhibition signals. The transmembrane adapter LAT2, and the serine/threonine kinase with an exchange factor activity Bcr were the most recruited molecules. Biochemical and functional validations established the unexpected finding that Bcr is recruited by SLP76 and positively regulates antigen-induced mast cell activation. Knock-in mice expressing tagged molecules with a normal tissue distribution and expression therefore provide potent novel tools to investigate signalosomes and to uncover novel signaling molecules in mast cells. PMID- 23820728 TI - The metabolic status drives acclimation of iron deficiency responses in Chlamydomonas reinhardtii as revealed by proteomics based hierarchical clustering and reverse genetics. AB - Iron is a crucial cofactor in numerous redox-active proteins operating in bioenergetic pathways including respiration and photosynthesis. Cellular iron management is essential to sustain sufficient energy production and minimize oxidative stress. To produce energy for cell growth, the green alga Chlamydomonas reinhardtii possesses the metabolic flexibility to use light and/or carbon sources such as acetate. To investigate the interplay between the iron-deficiency response and growth requirements under distinct trophic conditions, we took a quantitative proteomics approach coupled to innovative hierarchical clustering using different "distance-linkage combinations" and random noise injection. Protein co-expression analyses of the combined data sets revealed insights into cellular responses governing acclimation to iron deprivation and regulation associated with photosynthesis dependent growth. Photoautotrophic growth requirements as well as the iron deficiency induced specific metabolic enzymes and stress related proteins, and yet differences in the set of induced enzymes, proteases, and redox-related polypeptides were evident, implying the establishment of distinct response networks under the different conditions. Moreover, our data clearly support the notion that the iron deficiency response includes a hierarchy for iron allocation within organelles in C. reinhardtii. Importantly, deletion of a bifunctional alcohol and acetaldehyde dehydrogenase (ADH1), which is induced under low iron based on the proteomic data, attenuates the remodeling of the photosynthetic machinery in response to iron deficiency, and at the same time stimulates expression of stress-related proteins such as NDA2, LHCSR3, and PGRL1. This finding provides evidence that the coordinated regulation of bioenergetics pathways and iron deficiency response is sensitive to the cellular and chloroplast metabolic and/or redox status, consistent with systems approach data. PMID- 23820731 TI - A new model to evaluate Raf signaling in hematopoietic cells. AB - The Raf/MEK/ERK pathway is thought to be critical in mediating cell survival and proliferation by cytokine receptors. However, the exact contribution of Raf is complex and not well understood. A better understanding of Raf signaling is important because of the recent observation that B-Raf is frequently mutated in various human cancers. We have generated a new model system that activates Raf directly by linking the extracytoplasmic and transmembrane domains of the erythropoietin receptor (EPOR) with the catalytic domain of Raf (CR3). This synthetic oncogene in which dimerization can be controlled by an exogenous ligand, is fixed at the cellular membrane, while the endogenous Raf is normally activated by binding with Ras. The chimeric receptor EPOR/CR3 was stably expressed in Ba/F3 cells which lack EPO receptors. Although the lines remained dependent on IL-3 for proliferation, EPO treatment reduced the rate of cell death in the absence of IL-3. Also, EPO was synergistic with sub-optimal concentrations of IL-3 in inducing long-term cell proliferation, but did not augment proliferation of cells cultured with full concentrations of IL-3. EPO induced a rapid activation of ERK and also phosphorylation of endogenous Raf. It also induced tyrosine phosphorylation of several cellular proteins. The MEK1 inhibitor PD98059 reduced EPO-induced tyrosine phosphorylation, suggesting these substrates are downstream of MEK kinase. Interestingly, PD98059 also reduced the phosphorylation of endogenous Raf, indicating there is a positive feedback mechanism in Raf activation. We conclude that Raf can be activated by a mechanism that induces clustering at the cell membrane, and that this leads directly to activation of MEK and ERK. This EPOR/CR3 system may serve as a useful model to evaluate the unknown Raf kinase pathway and the effects of signal transduction inhibitors for Raf as a target. PMID- 23820732 TI - The relationship between sluggish cognitive tempo and impairment in children with and without ADHD. AB - This study examined impairment in multiple domains of functioning in children with and without ADHD who present with high or low levels of sluggish cognitive tempo (SCT) while taking into account the total symptom ratings of ADHD. Participants were 584 children in kindergarten through eighth grade (55.7 % male, 91.7 % Caucasian), drawn from five archival datasets. Two, 2 (SCT groups: high and low) x 3 (ADHD Status: ADHD-I, ADHD-C, and non-ADHD) MANCOVAs were conducted with the total ADHD symptom ratings and child age as covariates. One MANCOVA was conducted on scores on the teacher Impairment Rating Scale (IRS; Fabiano et al. Journal of Clinical Child and Adolescent Psychology 35:369-385, 2006) and the other on the 6 scores on the parent IRS. The results indicated that the presence of SCT symptoms was associated with greater functional impairment at home according to parent report while it was associated with less functional impairment at school according to teacher report. Thus, the relationship between SCT symptoms and impairment differs depending on the informant and the context in which impairment is evaluated. PMID- 23820733 TI - Knockdown BMI1 expression inhibits proliferation and invasion in human bladder cancer T24 cells. AB - B cell-specific moloney murine leukemia virus integration site 1 (BMI1) is a transcriptional repressor of polycomb repressive complex 1, which is involved in the proliferation, senescence, migration, and tumorigenesis of cancer. Experimental researchers have convincingly linked BMI1 to tumorigenesis. However, there is no study about the issue on the role of BMI1 in the proliferation, apoptosis, and migration of bladder cancer. To address this question, we examined the expression of BMI1 in bladder cancer tissues and used siRNA to knockdown BMI1 expression in bladder cancer T24 cells. Then we tested the cell proliferation by CCK8 assay and soft agar colony formation assay, apoptosis by flow cytometry assay, and cell invasiveness by transwell migration assay. Our results revealed that BMI1 promoted proliferation, migration, invasion, and progression in bladder cancer. Over-expression of BMI1 was correlated with tumor clinic-pathological features. BMI1 siRNA effectively inhibited bladder cancer cell proliferation and migration in vitro, and it promoted bladder cancer invasion, maybe by causing epithelial-to-mesenchymal transition. Our findings suggested that BMI1 may represent a novel diagnostic marker and a therapeutic target for bladder cancer, and deserves further investigation. PMID- 23820735 TI - Regulation of tight junctions by sex hormones in normal human endometrial epithelial cells and uterus cancer cell line Sawano. AB - The number of patients with uterine endometrial carcinoma, the cause of which involves sex hormones, has recently been growing rapidly because of increases in life expectancy and obesity. Tight junction proteins claudin-3 and -4 are receptors of Clostridium perfringens enterotoxin (CPE) and increase during endometrial carcinogenesis. In the present study of normal human endometrial epithelial (HEE) cells and the uterus cancer cell line Sawano, we investigate changes in the expression of tight junction proteins including claudin-3 and -4, the fence and barrier functions of the tight junction and the cytotoxic effects of CPE by sex hormones. In primary cultured HEE cells, treatment with progesterone (P4) but not estradiol (E2), induced claudin-1, -3, -4 and -7 and occludin, together with the downregulation of the barrier function but not the fence function. In Sawano cells, claudin-3 and -4 were upregulated by E2 but not by P4, together with a disruption of both the barrier and fence function. In primary cultured HEE cells, claudin-3 and -4 were localized at the apicalmost regions (tight junction areas) and no cytotoxicity of CPE was observed. In Sawano cells, claudin-3 and -4 were found not only in the apicalmost regions but also at the basolateral membrane and the cytotoxicity of CPE was enhanced by E2. Thus, tight junctions are physiological regulated by sex hormones in normal HEE cells during the menstrual cycle suggesting that safer and more effective therapeutic methods targeting claudins in uterine cancer can be developed. PMID- 23820734 TI - Intestinal stem cells remain viable after prolonged tissue storage. AB - Intestinal stem cells (ISCs) are responsible for renewal of the epithelium both during normal homeostasis and following injury. As such, they have significant therapeutic potential. However, whether ISCs can survive tissue storage is unknown. We hypothesize that, although the majority of epithelial cells might die, ISCs would remain viable for at least 24 h at 4 degrees C. To explore this hypothesis, jejuna of C57Bl6/J or Lgr5-LacZ mice were removed and either processed immediately or placed in phosphate-buffered saline at 4 degrees C. Delayed isolation of epithelium was performed after 24, 30, or 48 h storage. At the light microscope level, despite extensive apoptosis of villus epithelial cells, small intestinal crypts remained morphologically intact for 30 h and ISCs were identifiable via Lgr5-LacZ positivity. Electron microscopy showed that ISCs retained high integrity for 24 h. When assessed by flow cytometry, ISCs were more resistant to degeneration than the rest of the epithelium, including neighboring Paneth cells, with higher viability across all time points. Cultured isolated crypts showed no loss of capacity to form complex enteroids after 24 h tissue storage, with efficiencies after 7 days of culture remaining above 80 %. By 30 h storage, efficiencies declined but budding capability was retained. We conclude that, with delay in isolation, ISCs remain viable and retain their proliferative capacity. In contrast, the remainder of the epithelium, including the Paneth cells, exhibits degeneration and programmed cell death. If these findings are recapitulated in human tissue, storage at 4 degrees C might offer a valuable temporal window for the harvesting of crypts or ISCs for therapeutic application. PMID- 23820736 TI - Isolation, characterization and differentiation of cells expressing pluripotent/multipotent markers from adult human ovaries. AB - Pluripotent stem cells are still generally accepted not to exist in adult human ovaries, although increasing studies confirm the presence of pluripotent/multipotent stem cells in adult mammalian ovaries, including those of humans. The aim of this study is to isolate, characterize and differentiate in vitro stem cells that originate from the adult human ovarian cortex and that express markers of pluripotency/multipotency. After enzymatic degradation of small ovarian cortex biopsies retrieved from 18 women, ovarian cell cultures were successfully established from 17 and the formation of cell colonies was observed. The presence of cells/colonies expressing some markers of pluripotency (alkaline phosphatase, surface antigen SSEA-4, OCT4, SOX-2, NANOG, LIN28, STELLA), germinal lineage (DDX4/VASA) and multipotency (M-CAM/CD146, Thy-1/CD90, STRO-1) was confirmed by various methods. Stem cells from the cultures, including small round SSEA-4-positive cells with diameters of up to 4 MUm, showed a relatively high degree of plasticity. We were able to differentiate them in vitro into various types of somatic cells of all three germ layers. However, these cells did not form teratoma when injected into immunodeficient mice. Our results thus show that ovarian tissue is a potential source of stem cells with a pluripotent/multipotent character for safe application in regenerative medicine. PMID- 23820737 TI - Monitoring long-term effects of mild traumatic brain injury with magnetic resonance spectroscopy: a pilot study. AB - This pilot study explores the metabolic changes associated with persistent postconcussion syndrome (PCS) after mild traumatic brain injury (mTBI; >12 months after injury) using magnetic resonance spectroscopy. We hypothesized that those mTBI participants with PCS will have larger metabolic differences than those without. Data were collected from mTBI participants with PCS, mTBI participants without PCS and non-head-injured participants (all groups: n=8). Magnetic resonance spectroscopy metabolite profiles within the dorsolateral prefrontal cortex showed a reduced creatine/choline ratio in mTBI patients compared with control participants. This data provides initial evidence for residual metabolic changes in chronic mTBI patients, but there was no conclusive relationship between these metabolic changes and PCS symptom report. Creatine is involved in maintaining energy levels in cells with high or fluctuating energy demand, suggesting that there may be some residual energy impairment in chronic mTBI. PMID- 23820738 TI - Impairments of tight junctions are involved in D-galactose-induced brain aging. AB - Impairments of tight junctions are implicated in the course of various age related neurodegenerative disorders. Chronic injection of D-galactose can cause a progressive deterioration in learning and memory capacity and serve as an animal model of aging. To investigate the involvement of tight junctions in this model, oxidative stress biomarkers, expression and ultrastructure of tight junctions, and the permeability of blood-brain barrier were examined in the hippocampus of the mice, which received an injection of D-galactose for 6 weeks. D-Galactose injected mice showed impaired antioxidant systems, decreased levels of tight junction proteins, and ultrastructural pathological changes of tight junctions, accompanied by increased blood-brain barrier permeability in the hippocampus. These results show that impairments in tight junctions are involved in D galactose-induced brain aging. PMID- 23820739 TI - N-methyl-D-aspartate receptors and protein synthesis are necessary for reinstatement of conditioned fear. AB - Conditioned fear is extinguished if a conditioned animal receives the conditioned stimulus without an unconditioned stimulus. The extinguished fear response can be reinstated after the animal experiences a mild unconditioned stimulus. Although extensive studies on the neuronal circuitry and neurochemical mechanisms leading to fear acquisition and extinction have been carried out, few studies have focused on reinstatement. In this study, we investigated the effects of N-methyl D-aspartic acid receptor (NMDAR) antagonists, protein synthesis inhibitors, cannabinoid receptor type 1 (CB1R) antagonists, and benzodiazepine on reinstatement of conditioned fear in mice. An intraperitoneal injection of the NMDAR antagonist MK-801 or the protein synthesis inhibitor anisomycin before the reminder shock attenuated fear reinstatement tested the next day. However, anisomycin had no effect on fear reinstatement tested 2 h after the reminder shock. CB1R antagonists, SR141716, and a benzodiazepine, diazepam, had no effect on fear reinstatement. These results suggested that NMDAR and protein synthesis dependent plasticity contributed toward the reinstatement of conditioned fear and that protein synthesis was involved in consolidation of reinstated fear. PMID- 23820740 TI - N-linked glycosylation of cortical N-methyl-D-aspartate and kainate receptor subunits in schizophrenia. AB - Dysfunctional glutamate neurotransmission has been implicated in the pathophysiology of schizophrenia. Abnormal expressions in schizophrenia of ionotropic glutamate receptors (iGluRs) and the proteins that regulate their trafficking have been found to be region and subunit specific in brain, suggesting that abnormal trafficking of iGluRs may contribute toward altered glutamatergic neurotransmission. The post-translational modification N glycosylation of iGluR subunits can be used as a proxy for their intracellular localization. Receptor complexes assemble in the lumen of the endoplasmic reticulum, where N-glycosylation begins with the addition of N-linked oligomannose glycans, and is subsequently trimmed and replaced by more elaborate glycans while trafficking through the Golgi apparatus. Previously, we found abnormalities in N-glycosylation of the GluR2 AMPA receptor subunit in schizophrenia. Here, we investigated N-glycosylation of N-methyl-D-aspartate and kainate (KA) receptor subunits in the dorsolateral prefrontal cortex from patients with schizophrenia and a comparison group. We used enzymatic deglycosylation with two glycosidases: endoglycosidase H (Endo H), which removes immature high mannose-containing sugars, and peptide-N-glycosidase F (PNGase F), which removes all N-linked sugars. The NR1, NR2A, NR2B, GluR6, and KA2 subunits were all sensitive to treatment with Endo H and PNGase F. The GluR6 KA receptor subunit was significantly more sensitive to Endo H-mediated deglycosylation in schizophrenia, suggesting a larger molecular mass of N-linked high mannose and/or hybrid sugars on GluR6. This finding, taken with our previous work, suggests that a cellular mechanism underlying abnormal glutamate neurotransmission in schizophrenia may involve abnormal trafficking of both AMPA and KA receptors. PMID- 23820741 TI - Cell migration: Collective cell courtship. PMID- 23820742 TI - Stem cells: Tailored splicing patterns. PMID- 23820743 TI - A rare case of ovarian and pelvic filariasis. AB - Lymphatic filariasis is an important tropic disease associated with significant morbidity. The patients in endemic areas mostly experience problems related to lymphatic obstruction. Physicians practicing in non- endemic areas rarely consider filariasis, especially if it is an uncommon presentation. We present a young woman who posed a significant problem in the diagnosis of ovarian filariasis. PMID- 23820744 TI - Novel RF interrogation of a fiber Bragg grating sensor using bidirectional modulation of a Mach-Zehnder electro-optical modulator. AB - We propose and experimentally demonstrate the novel radio-frequency (RF) interrogation of a fiber Bragg grating (FBG) sensor using bidirectional modulation of a Mach-Zehnder electro-optical modulator (MZ-EOM). Based on the microwave photonic technique and active detection, the transfer function of the proposed system was obtained, and the time delay was calculated from the change in the free spectral range (FSR) at different wavelengths over the optimal measuring range. The results show that the time delay and the wavelength variation have a good linear relationship, with a gradient of 9.31 ps/nm. An actual measurement taken with a sensing FBG for temperature variation shows the relationship with a gradient of 0.93 ps/10 degrees C. The developed system could be used for FBG temperature or strain sensing and other multiplexed sensor applications. PMID- 23820745 TI - Measurement of the robot motor capability of a robot motor system: a Fitts's-law inspired approach. AB - Robot motor capability is a crucial factor for a robot, because it affects how accurately and rapidly a robot can perform a motion to accomplish a task constrained by spatial and temporal conditions. In this paper, we propose and derive a pseudo-index of motor performance (pIp) to characterize robot motor capability with robot kinematics, dynamics and control taken into consideration. The proposed pIp provides a quantitative measure for a robot with revolute joints, which is inspired from an index of performance in Fitts's law of human skills. Computer simulations and experiments on a PUMA 560 industrial robot were conducted to validate the proposed pIp for performing a motion accurately and rapidly. PMID- 23820746 TI - Active pneumatic vibration control by using pressure and velocity measurements and adaptive fuzzy sliding-mode controller. AB - This paper presents an intelligent control strategy to overcome nonlinear and time-varying characteristics of a diaphragm-type pneumatic vibration isolator (PVI) system. By combining an adaptive rule with fuzzy and sliding-mode control, the method has online learning ability when it faces the system's nonlinear and time-varying behaviors during an active vibration control process. Since the proposed scheme has a simple structure, it is easy to implement. To validate the proposed scheme, a composite control which adopts both chamber pressure and payload velocity as feedback signal is implemented. During experimental investigations, sinusoidal excitation at resonance and random-like signal are input on a floor base to simulate ground vibration. Performances obtained from the proposed scheme are compared with those obtained from passive system and PID scheme to illustrate the effectiveness of the proposed intelligent control. PMID- 23820747 TI - Self-assembled 3D ZnO porous structures with exposed reactive {0001} facets and their enhanced gas sensitivity. AB - Complex three-dimensional structures comprised of porous ZnO plates were synthesized in a controlled fashion by hydrothermal methods. Through subtle changes to reaction conditions, the ZnO structures could be self-assembled from 20 nm thick nanosheets into grass-like and flower-like structures which led to the exposure of high proportions of ZnO {0001} crystal facets for both these materials. The measured surface area of the flower-like and the grass, or platelet-like ZnO samples were 72.8 and 52.4 m2?g-1, respectively. Gas sensing results demonstrated that the porous, flower-like ZnO structures exhibited enhanced sensing performance towards NO2 gas compared with either grass-like ZnO or commercially sourced ZnO nanoparticle samples. The porous, flower-like ZnO structures provided a high surface area which enhanced the ZnO gas sensor response. X-ray photoelectron spectroscopy characterization revealed that flower like ZnO samples possessed a higher percentage of oxygen vacancies than the other ZnO sample-types, which also contributed to their excellent gas sensing performance. PMID- 23820748 TI - Connection between Bell nonlocality and Bayesian game theory. AB - In 1964, Bell discovered that quantum mechanics is a nonlocal theory. Three years later, in a seemingly unconnected development, Harsanyi introduced the concept of Bayesian games. Here we show that, in fact, there is a deep connection between Bell nonlocality and Bayesian games, and that the same concepts appear in both fields. This link offers interesting possibilities for Bayesian games, namely of allowing the players to receive advice in the form of nonlocal correlations, for instance using entangled quantum particles or more general no-signalling boxes. This will lead to novel joint strategies, impossible to achieve classically. We characterize games for which nonlocal resources offer a genuine advantage over classical ones. Moreover, some of these strategies represent equilibrium points, leading to the notion of quantum/no-signalling Nash equilibrium. Finally, we describe new types of question in the study of nonlocality, namely the consideration of nonlocal advantage given a set of Bell expressions. PMID- 23820749 TI - Pneumococcal IgA1 protease subverts specific protection by human IgA1. AB - Bacterial immunoglobulin A1 (IgA1) proteases may sabotage the protective effects of IgA. In vitro, both exogenous and endogenously produced IgA1 protease inhibited phagocytic killing of Streptococcus pneumoniae by capsule-specific IgA1 human monoclonal antibodies (hMAbs) but not IgA2. These IgA1 proteases cleaved and reduced binding of the the effector Fcalpha1 heavy chain but not the antigen binding F(ab)/light chain to pneumococcal surfaces. In vivo, IgA1 protease resistant IgA2, but not IgA1 protease-sensitive IgA1, supported 60% survival in mice infected with wild-type S. pneumoniae. IgA1 hMAbs protected mice against IgA1 protease-deficient but not -producing pneumococci. Parallel mouse sera with human IgA2 showed more efficient complement-mediated reductions in pneumococci with neutrophils than did IgA1, particularly with protease-producing organisms. After natural human pneumococcal bacteremia, purified serum IgG inhibited IgA1 protease activity in 7 of 11 patients (64%). These observations provide the first evidence in vivo that IgA1 protease can circumvent killing of S. pneumoniae by human IgA. Acquisition of IgA1 protease-neutralizing IgG after infection directs attention to IgA1 protease both as a determinant of successful colonization and infection and as a potential vaccine candidate. PMID- 23820750 TI - Imaging murine NALT following intranasal immunization with flagellin-modified circumsporozoite protein malaria vaccines. AB - Intranasal (IN) immunization with a Plasmodium circumsporozoite (CS) protein conjugated to flagellin, a Toll-like receptor 5 agonist, was found to elicit antibody-mediated protective immunity in our previous murine studies. To better understand IN-elicited immune responses, we examined the nasopharynx-associated lymphoid tissue (NALT) in immunized mice and the interaction of flagellin modified CS with murine dendritic cells (DCs) in vitro. NALT of immunized mice contained a predominance of germinal center (GC) B cells and increased numbers of CD11c+ DCs localized beneath the epithelium and within the GC T-cell area. We detected microfold cells distributed throughout the NALT epithelial cell layer and DC dendrites extending into the nasal cavity, which could potentially function in luminal CS antigen uptake. Flagellin-modified CS taken up by DCs in vitro was initially localized within intracellular vesicles followed by a cytosolic distribution. Vaccine modifications to enhance delivery to the NALT and specifically target NALT antigen-presenting cell populations will advance development of an efficacious needle-free vaccine for the 40% of the world's population at risk of malaria. PMID- 23820752 TI - Let-7g and miR-21 expression in non-small cell lung cancer: correlation with clinicopathological and molecular features. AB - MicroRNAs (miRNAs) play a key role in cancer pathogenesis and are involved in several human cancers, including non-small cell lung cancer (NSCLC). This study evaluated Let-7g and miR-21 expression by quantitative real-time PCR in 80 NSCLC patients and correlated the results with their main clinicopathological and molecular features. MiR-21 expression was significantly higher in NSCLC tissues compared to non-cancer lung tissues (p<0.0001), while no significant changes in Let-7g expression were observed between the tumor and normal lung tissues. Target prediction analysis led to the identification of 26 miR-21 and 24 Let-7g putative target genes that play important roles in cancer pathogenesis and progression. No significant association was observed between the analysed miRNAs and the main clinicopathological or molecular characteristics of the NSCLC patients, although both miRNAs were downregulated in squamous cell carcinomas compared to adenocarcinomas. Noteworthy, we observed a significant association between low Let-7g expression and metastatic lymph nodes at diagnosis (p=0.046), as well as between high miR-21 expression and K-Ras mutations (p=0.0003). Survival analysis did not show any significant correlation between prognosis and the analysed miRNAs, although the patients with a high Let-7g and miR-21 expression showed a significantly lower short-term progression-free survival (p=0.01 and p=0.0003, respectively) and overall survival (p=0.023 and p=0.0045, respectively). In conclusion, we showed that Let-7g and miR-21 expression was deregulated in NSCLC and we demonstrated a strong relationship between miR-21 overexpression and K-Ras mutations. Our data indicate that Let-7g and miR-21 profiling combined with the determination of K-Ras mutational status may be considered a useful biomarker for a more effective molecular characterization and clinical management of NSCLC patients. PMID- 23820751 TI - CMRF35-like molecule 1 (CLM-1) regulates eosinophil homeostasis by suppressing cellular chemotaxis. AB - Eosinophil accumulation in health and disease is a hallmark characteristic of mucosal immunity and type 2 helper T cell (Th2) inflammation. Eotaxin-induced CCR3 (chemokine (C-C motif) receptor 3) signaling has a critical role in eosinophil chemotactic responses. Nevertheless, the expressions of immunoreceptor tyrosine-based inhibitory motif-bearing receptors such as CMRF35-like molecule-1 (CLM-1) and their ability to govern eosinophil migration are largely unknown. We now report that CLM-1 (but not CLM-8) is highly and distinctly expressed by colonic and adipose tissue eosinophils. Furthermore, Clm1-/- mice display elevated baseline tissue eosinophilia. CLM-1 negatively regulated eotaxin-induced eosinophil responses including eosinophil chemotaxis, actin polymerization, calcium influx, and extracellular signal-regulated kinase (ERK)-1/2, but not p38 phosphorylation. Addition of CLM-1 ligand (e.g., phosphatidylserine) rendered wild-type eosinophils hypochemotactic in vitro and blockade of CLM-1/ligand interactions rendered wild-type eosinophils hyperchemotactic in vitro and in vivo in a model of allergic airway disease. Interestingly, suppression of cellular recruitment via CLM-1 was specific to eosinophils and eotaxin, as leukotriene B4 (LTB4)- and macrophage inflammatory protein-1alpha (MIP-1alpha)-induced eosinophil and neutrophil migration were not negatively regulated by CLM-1. Finally, peripheral blood eosinophils obtained from allergic rhinitis patients displayed elevated CLM-1/CD300f levels. These data highlight CLM-1 as a novel regulator of eosinophil homeostasis and demonstrate that eosinophil accumulation is constantly governed by CLM-1, which negatively regulates eotaxin-induced eosinophil responses. PMID- 23820753 TI - A comparison of assertive community treatment fidelity measures and patient centered medical home standards. AB - OBJECTIVE This study compared program measures of assertive community treatment (ACT) with standards of accreditation for the patient-centered medical home (PCMH) to determine whether there were similarities in the infrastructure of the two methods of service delivery and whether high-fidelity ACT teams would qualify for medical home accreditation. METHODS The authors compared National Committee for Quality Assurance PCMH standards with two ACT fidelity measures (the Dartmouth Assertive Community Treatment Scale and the Tool for Measurement of Assertive Community Treatment [TMACT]) and with national ACT program standards. RESULTS PCMH standards pertaining to enhanced access and continuity, management of care, and self-care support demonstrated strong overlap across ACT measures. Standards for identification and management of populations, care coordination and follow-up, and quality improvement demonstrated less overlap. The TMACT and the program standards had sufficient overlap to score in the range of a level 1 PCMH, but no ACT measure sufficiently detailed methods of population-based screening and tracking of referrals to satisfy "must-pass" elements of the standards. CONCLUSIONS ACT measures and medical home standards had significant overlap in innate infrastructure. ACT teams following the program standards or undergoing TMACT fidelity review could have the necessary infrastructure to serve as medical homes if they were properly equipped to supervise general medical care and administer activities to improve management of chronic diseases. PMID- 23820755 TI - The other side of medicalization: self-medicalization and self-medication. AB - The concept of medicalization has given rise to considerable discussion in the social sciences, focusing especially on the extension of medicine's jurisdiction and its hold over our bodies through the reduction of social phenomena to individual biological pathologies. However, the process leading to medical treatment may start when individuals engage in self-medication and thus practice "self-medicalization." But, can we apply to this concept the same type of analysis as the first and see merely the individual's replication of the social control mechanisms to which he/she usually falls victim? This article aims to demonstrate that the medicalization individuals practice on themselves takes on a completely different meaning to that practiced by the medical profession. Empirical data collected in France show that self-medicalization, which may involve treating a problem medically when doctors believe it to be of a non medical nature, can be an attempt by individuals to furnish a social explanation for their somatic problems and experiences. In this article, I examine the social and political significance of this phenomenon. PMID- 23820756 TI - Distal soft tissue procedure in hallux valgus surgery: biomechanical background and technique. AB - The distal soft tissue procedure has evolved into an indispensable additional surgical procedure to increase the corrective effect in hallux valgus surgery. Considering the biomechanical development of hallux valgus deformity, degenerative changes of the soft tissues around the first metatarsophalangeal joint contribute much more to the deformity than changes in the bony structures which can rather be seen as degenerative changes secondary to the deformity. Thus the principles in hallux valgus correction should aim to reverse all pathogenetic steps leading to deformity: release of the contracted lateral soft tissue structures, tightening of the torn-out medial structures and reduction and rebalancing the first metatarsal head onto the sesamoid complex. The scientific discussion over the last decades has clarified the impact of different surgical steps and methods on the efficacy of the lateral release, the risk of creating overcorrection or instability of the joint and the risk of avascular necrosis of the first metatarsal head. According to anatomical and clinical data, a lateral soft tissue release can be combined with a distal metatarsal osteotomy, provided that the osteotomy is performed in a defined safe zone without increasing the risk for avascular necrosis of the first metatarsal head. Transecting the lateral metatarsosesamoid suspensory ligament is the key to a successful lateral release in hallux valgus surgery. Release of the deep transverse metatarsal ligament and the adductor hallucis muscle does not contribute to hallux valgus correction. The lateral short sesamophalangeal ligament and the plantar attachment of the articular capsule should be preserved to avoid possible joint instability. Thus today, the distal soft tissue procedure cannot be seen only as a supplementary surgical procedure in cases where the bony procedure needs additional correction, but rather is an indispensable procedure to restore the physiological situation and function of the first metatarsophalangeal joint. PMID- 23820758 TI - Comment on Zhang et al.: Modified posterior soft tissue repair for the prevention of early postoperative dislocation in total hip arthroplasty. PMID- 23820757 TI - A minimally invasive technique for surgical treatment of hallux valgus: simple, effective, rapid, inexpensive (SERI). AB - PURPOSE: Several bony and soft tissue procedures have been described for the treatment of hallux valgus, and currently mini-invasive surgical techniques are preferred in order to reduce surgical trauma, complications, time of surgery and to allow an earlier recovery. The aim of this study is to analyse a series of 1,000 consecutive cases of hallux valgus, surgically treated by the minimally invasive SERI technique, reporting results at mid-term follow-up. METHODS: We prospectively studied 641 patients (1,000 feet) with symptomatic hallux valgus surgically treated by SERI osteotomy. Inclusion criteria were: age between 20 and 65 years, reducible mild or moderate hallux valgus, HVA <= 40 degrees , IMA <= 20 degrees , and arthritis of the first metatarsophalangeal joint up to grade 2 according to the Regnauld classification. RESULTS: The American Orthopaedic Foot and Ankle Society (AOFAS) score rose from 46.8 +/- 6.7 preoperatively to 89 +/- 10.3 at last follow-up. Radiographic control at follow-up showed a complete healing of the osteotomy and remodelling of the metatarsal bone. Low rate of complication has been reported. CONCLUSIONS: This study demonstrated that the SERI technique is effective in treating mild to moderate hallux valgus in terms of relief from symptoms and functional improvement. This technique allowed correction of the main parameters of the deformity, with durable clinical and radiographic results at a mid-term follow-up. PMID- 23820760 TI - Biomechanical properties of femoral posterior cruciate ligament fixations. AB - PURPOSE: The success of reconstructions of the posterior cruciate ligament (PCL) mainly depends on the fixation strength of the tendon-bone interface. Reliable data about the mechanical characteristics of PCL fixation techniques are sparse. The aim of this study was to investigate the biomechanical properties of different femoral PCL fixation techniques. METHODS: Fresh human cadaver quadriceps (Q) and hamstring (H) tendons were harvested and fixed into porcine femora with a press-fit fixation suturing the tendon over a bone bridge (group A), a novel implant post-fixation (group B) or an interference screw fixation (group C). Each group consisted of 10 specimens. The constructs were cyclically stretched and eventually loaded until failure. Elongation during cyclic loading, stiffness, failure mode and maximum failure load was evaluated. RESULTS: Elongation during cyclical loading was significantly larger between the 1st and the 20th cycle than between the 20th and the 500th cycle in all groups (p < 0.05). Maximum failure load was 409 +/- 71 (336-517) N in group QA, 456 +/- 58 (347-510) N in group QB, 548 +/- 116 (400-798) N in group QC, 472 +/- 114 N (316 676 N) in group HA, 494 +/- 98 N (371-668 N) in group HB and 498 +/- 87 N (391 687 N) in group HC (significantly higher for QB compared to QA, p < 0.05). CONCLUSION: This is the first study investigating the biomechanical properties of femoral PCL fixations. Implant-free fixation techniques like press-fit or post fixations are able to withstand equal biomechanical forces compared to interference screw fixation. The novel fixations described in this study can be considered as a reliable alternative for the reconstruction of PCL using either hamstring or quadriceps tendons. PMID- 23820759 TI - Afferent sensory mechanisms involved in jaw gape-related muscle activation in unilateral biting. AB - OBJECTIVES: In unilateral biting or chewing, the working/balancing-side ratio (W/B-ratio) of masseter activities is inversely proportional to the jaw gape which was interpreted as a neuromuscular strategy to protect occlusion. This suggests that jaw separation is afferently perceived, raising the question how this perception might work. In related studies, isometric biting was exerted on rubber pieces that slightly yielded similar to compressed food in chewing. We hypothesized that minor jaw movements associated with this yielding are necessary to elicit a jaw gape-related control of relative activation in isometric biting. MATERIALS AND METHODS: Surface electromyograms of masseter muscles were recorded bilaterally in 20 males during (a) unilateral chewing, (b) isometric biting on rubber pieces inducing jaw gapes of 5, 3, 2, 1, and 0.5 mm, and (c) isometric biting with teeth embedded in rigid splints causing gapes of 5 and 1 mm. RESULTS: With rubber, the masseter W/B-ratio increased from 100 % (5 mm) to 166 % (1 mm) (p = 0.0003) whereas with the splint it increased just slightly to 112 % (p = 0.005). With 1 mm gape, W/B-ratios in splint biting were significantly smaller than in rubber biting or in chewing (p = 0.01). CONCLUSIONS: We conclude that minor jaw motion preceding peak force in unilateral biting is necessary to create afferent sensory information that could elicit jaw gape-related activation of masseter muscles. CLINICAL RELEVANCE: Demonstrating a condition under which jaw gape-related activation can lose its occlusion protecting effect, these findings might contribute to disclose the causes of craniomandibular disorders. PMID- 23820761 TI - Minimization of target registration error for vertebra in image-guided spine surgery. AB - PURPOSE: The accuracy of pedicle screw placement during image-guided spine surgery (IGSS) can be characterized by estimating the target registration error (TRE). The major factors that influence TRE were identified, minimized, and verified with in vitro experiments. MATERIALS AND METHODS: Computed-tomography compatible markers are placed over anatomical landmarks of lumbar vertebral segments in locations that are feasible and routinely used in surgical procedures. TRE was determined directly for markers placed on the pedicles of vertebra segments. First, optimum selections of landmarks are proposed for different landmarks according to the minimum achievable TRE values in different configurations. These anatomical landmarks are feasible and accessible to overcome constraints that may be imposed during surgical procedures. Second, the effect of fiducial weighting on corresponding points to overcome anisotropic localization error based on maximum likelihood approach is evaluated. Third, an experimental model for fiducial localization error (FLE) is derived to obtain the weights. At the end, an error zone was obtained for each marker to indicate the possible acceptable deviation from the marker's exact location in practice. This study was performed in vitro on a spine phantom. RESULTS: Optimal landmark selection led to a 30% reduction in TRE. In addition, optimum weighting of the fiducials in an FLE model that incorporates anisotropic localization error in the registration algorithm led to a 28% reduction in the TRE. CONCLUSION: Landmark configuration, transformation parameters, and fiducial localization error are factors that significantly affect the total TRE. These factors should be optimized to minimize the TRE. Both the optimum configuration of landmarks and the anisotropic weighing of fiducials have significant impact on the registration accuracy for IGSS. PMID- 23820762 TI - C-arm angle measurement with accelerometer for brachytherapy: an accuracy study. AB - PURPOSE: X-ray fluoroscopy guidance is frequently used in medical interventions. Image-guided interventional procedures that employ localization for registration require accurate information about the C-arm's rotation angle that provides the data externally in real time. Optical, electromagnetic, and image-based pose tracking systems have limited convenience and accuracy. An alternative method to recover C-arm orientation was developed using an accelerometer as tilt sensor. METHODS: The fluoroscopic C-arm's orientation was estimated using a tri-axial acceleration sensor mounted on the X-ray detector as a tilt sensor. When the C arm is stationary, the measured acceleration direction corresponds to the gravitational force direction. The accelerometer was calibrated with respect to the C-arm's rotation along its two axes, using a high-accuracy optical tracker as a reference. The scaling and offset error of the sensor was compensated using polynomial fitting. The system was evaluated on a GE OEC 9800 C-arm. Results obtained by accelerometer, built-in sensor, and image-based tracking were compared, using optical tracking as ground truth data. RESULTS: The accelerometer based orientation measurement error for primary angle rotation was -0.1 +/- 0.0 degrees and for secondary angle rotation it was 0.1 +/- 0.0 degrees . The built in sensor orientation measurement error for primary angle rotation was -0.1 +/- 0.2 degrees , and for secondary angle rotation it was 0.1 +/- 0.2 degrees . The image-based orientation measurement error for primary angle rotation was -0.1 +/- 1.3 degrees , and for secondary angle rotation it was -1.3 +/- 0.3 degrees . CONCLUSION: The accelerometer provided better results than the built-in sensor and image-based tracking. The accelerometer sensor is small, inexpensive, covers the full rotation range of the C-arm, does not require line of sight, and can be easily installed to any mobile X-ray machine. Therefore, accelerometer tilt sensing is a very promising applicant for orientation angle tracking of C-arm fluoroscopes. PMID- 23820763 TI - Determining the appropriate time of execution of an I-131 post-therapy whole-body scan: comparison between early and late imaging. AB - OBJECTIVE: The aim of this study was to investigate the appropriate time for performing an iodine-131 post-therapy whole-body scan (TxWBS) through a qualitative and semiquantitative analysis of early and late scans. MATERIALS AND METHODS: This study evaluated pairs of scans of 134 patients who underwent TxWBS on the third and seventh day. The scans were analyzed to evaluate sites, intensity of uptake, concordance or discordance between the scans, relationship with risk factors, and serum thyroglobulin (Tg) levels. To evaluate early and late radioiodine kinetics in thyroid remnants and metastases, 65/134 pairs of scans (48.5%) were subjected to a semiquantitative analysis. RESULTS: The early and late scans furnished concordant images in 108/134 patients (80.5%). In 10/134 patients (7.5%), early scans provided more information compared with late scans, showing lymph node and distant metastases in seven and three patients, respectively. In 16/134 patients (12%), late scans provided more data compared with early scans, with thyroid remnants and lymph node and distant metastases demonstrated in four, seven, and five patients, respectively. Negative early/positive late TxWBS results in patients were found to be significantly correlated (P=0.007) with elevated serum levels of Tg and a high-risk for recurrence (P=0.003). CONCLUSION: This study suggests that in about 20% of patients early or late TxWBS can miss the visualization of thyroid remnants or lymph node or distant metastases, which can be achieved performing both studies. High-risk patients with elevated serum Tg levels should be considered for a late TxWBS, which can demonstrate a possible metastatic involvement that was not diagnosed or that was downstaged by early TxWBS. PMID- 23820764 TI - SPECT/CT in patients with lower back pain after lumbar fusion surgery. AB - OBJECTIVE: The aim of the study was to investigate the incremental diagnostic value of skeletal hybrid imaging with single-photon emission computed tomography and X-ray computed tomography (SPECT/CT) over conventional nuclear medical imaging in patients with lower back pain after lumbar fusion surgery (LFS). PATIENTS AND METHODS: This retrospective study comprised 37 patients suffering from lower back pain after LFS in whom three-phase planar bone scintigraphies of the lumbar spine including SPECT/CT of that region had been performed. The findings visible on these imaging data sets were classified into the following five diagnostic categories: (a) metal loosening; (b) insufficient stabilizing function of the metal implants indicated by metabolically active facet joint arthritis and/or intervertebral osteochondrosis in the instrumented region; (c) adjacent instability defined as metabolically active degenerative disease in the segments adjacent to the instrumented region; (d) indeterminate; and (e) normal. RESULTS: In the case of eight patients no lesions were visible on their planar scintigraphy and SPECT (planar/SPECT) or SPECT/CT images. In the remaining 29 patients, planar/SPECT disclosed 62 pathological foci of uptake within the graft region and SPECT/CT revealed 55. The rate of reclassification by SPECT/CT compared with planar/SPECT was 5/12 for lesions categorized as metal loosening by planar/SPECT, 16/29 for foci with a planar/SPECT diagnosis of insufficient stabilizing function, 7/20 when the planar/SPECT diagnosis had been adjacent instability, and 1/1 for the lesions indeterminate on planar/SPECT. Two lesions had been detected on SPECT/CT only. The overall rate of reclassification was 45.2% (28/62) (95% confidence interval, 33.4-57.5%). CONCLUSION: Because of its significantly higher accuracy compared with planar/SPECT, SPECT/CT should be the conventional nuclear medical procedure of choice for patients with lower back pain after LFS. PMID- 23820766 TI - Demonstration of the spin solar cell and spin photodiode effect. AB - Spin injection and extraction are at the core of semiconductor spintronics. Electrical injection is one method of choice for the creation of a sizeable spin polarization in a semiconductor, requiring especially tailored tunnel or Schottky barriers. Alternatively, optical orientation can be used to generate spins in semiconductors with significant spin-orbit interaction, if optical selection rules are obeyed, typically by using circularly polarized light at a well-defined wavelength. Here we introduce a novel concept for spin injection/extraction that combines the principle of a solar cell with the creation of spin accumulation. We demonstrate that efficient optical spin injection can be achieved with unpolarized light by illuminating a p-n junction where the p-type region consists of a ferromagnet. The discovered mechanism opens the window for the optical generation of a sizeable spin accumulation also in semiconductors without direct band gap such as Si or Ge. PMID- 23820765 TI - Parent-reported temperament trajectories among infant siblings of children with autism. AB - Temperament atypicalities have been documented in infancy and early development in children who develop autism spectrum disorders (ASD). The current study investigates whether there are differences in developmental trajectories of temperament between infants and toddlers with and without ASD. Parents of infant siblings of children with autism completed the Carey Temperament Scales about their child at 6, 12, 18, 24, and 36 months of age. Temperament trajectories of children with ASD reflected increases over time in activity level, and decreasing adaptability and approach behaviors relative to high-risk typically developing (TD) children. This study is the first to compare temperament trajectories between high-risk TD infants and infants subsequently diagnosed with ASD in the developmental window when overt symptoms of ASD first emerge. PMID- 23820767 TI - Organocatalysis in the three-component Povarov reaction and investigation by mass spectrometry. AB - A diastereoselective three-component cascade reaction, catalyzed by p-sulfonic acid calix[4]arene, provides a unique method to access diverse julolidine derivatives in high yields. Additionally, the reaction was also monitored by mass spectrometry and the mechanistic pathway uncovered. PMID- 23820769 TI - Cellular function and adhesion mechanisms of human bone marrow mesenchymal stem cells on multi-walled carbon nanotubes. AB - Multiwalled carbon nanotubes (MWCNTs) are considered to be excellent reinforcements for biorelated applications, but, before being incorporated into biomedical devices, their biocompatibility need to be investigated thoroughly. We investigated the ability of films of pristine MWCNTs to influence human mesenchymal stem cells' proliferation, morphology, and differentiation into osteoblasts. Moreover, the selective integrin subunit expression and the adhesion mechanism to the substrate were evaluated on the basis of adherent cell number and adhesion strength, following the treatment of cells with blocking antibodies to a series of integrin subunits. Results indicated that MWCNTs accelerated cell differentiation to a higher extent than tissue culture plastic, even in the absence of additional biochemical inducing agents. The pre-treatment with anti integrin antibodies decreased number of adherent cells and adhesion strength at 4 60%, depending on integrin subunit. These findings suggest that pristine MWCNTs represent a suitable reinforcement for bone tissue engineering scaffolds. PMID- 23820768 TI - Biomaterials for tissue engineering. AB - Biomaterials serve as an integral component of tissue engineering. They are designed to provide architectural framework reminiscent of native extracellular matrix in order to encourage cell growth and eventual tissue regeneration. Bone and cartilage represent two distinct tissues with varying compositional and mechanical properties. Despite these differences, both meet at the osteochondral interface. This article presents an overview of current biomaterials employed in bone and cartilage applications, discusses some design considerations, and alludes to future prospects within this field of research. PMID- 23820772 TI - Misuse of power: in defence of small-scale science. PMID- 23820775 TI - Small sample size is not the real problem. PMID- 23820777 TI - Experimental power comes from powerful theories - the real problem in null hypothesis testing. PMID- 23820773 TI - Iron metabolism in the CNS: implications for neurodegenerative diseases. AB - Abnormal accumulation of brain iron has been detected in various neurodegenerative diseases, but the contribution of iron overload to pathology remains unclear. In a group of distinctive brain iron overload diseases known as 'neurodegeneration with brain iron accumulation' (NBIA) diseases, nine disease genes have been identified. Brain iron accumulation is observed in the globus pallidus and other brain regions in NBIA diseases, which are often associated with severe dystonia and gait abnormalities. Only two of these diseases, aceruloplasminaemia and neuroferritinopathy, are directly caused by abnormalities in iron metabolism, mainly in astrocytes and neurons, respectively. Understanding the early molecular pathophysiology of these diseases should aid insights into the role of iron and the design of specific therapeutic approaches. PMID- 23820778 TI - Confidence and precision increase with high statistical power. PMID- 23820779 TI - Synaptic transmission: short-term consequences for calyces. PMID- 23820780 TI - Reproductive timing and reliance on hoarded capital resources by lactating red squirrels. AB - Successful reproduction in a seasonal environment can be accomplished with resources that are stored before use ("capital resources") or resources that are used immediately ("income resources"). Research examining capital versus income resource usage during reproduction has primarily focused on assigning species to positions along a capital-income gradient. Here, we examine the causes and reproductive consequences of among and within-year variation in hoarded capital versus income resource usage by female North American red squirrels (Tamiasciurus hudsonicus) during mid-lactation in a highly seasonal environment. Among years, the proportion of feeding events that were on capital resources (PROPCAP) averaged 39 % during the yearly median mid-lactation periods, but ranged widely between 2 and 100 %. In years with earlier parturition dates, females primarily used hoarded capital resources during mid-lactation, whereas in years with later parturition dates, females primarily used income resources during mid-lactation. Within years, PROPCAP during mid-lactation tended to be greater in early-breeding females than in late-breeding females. Rates of water flux in females during mid lactation provided further evidence that late-breeding females used more water rich income resources. The proportion of litters that were partially or completely lost, and the litter mass that lactating females supported, was not influenced by the large among-year differences in hoarded capital resource usage. Red squirrels appear to delay reproduction following years with low cone production to time peak reproductive demands to be late enough to be supported by income resources that only become available later in the season. In conclusion, our results offer a rare example of the capacity of a food-hoarding mammal to support reproduction exploiting a wide range of capital and income resources. PMID- 23820783 TI - Effects of dietary guidance on the symptoms, quality of life and habitual dietary intake of patients with irritable bowel syndrome. AB - Diet is important in triggering the symptoms of irritable bowel syndrome (IBS). This study investigated the impact of dietary guidance on the symptoms, quality of life and habitual diet of patients with IBS. Forty-six patients who fulfilled the Rome III criteria for the diagnosis of IBS were included. Of these patients, 17 completed the entire study. Each patient attended three sessions (~45 min in duration) and received individual guidance on their dietary management. The patients were asked to complete the following questionnaires prior to receiving the dietary guidance, and at least 3 months subsequently: The Birmingham IBS symptom score questionnaire, the IBS Quality of Life (IBS-QOL) questionnaire, the Short-Form Nepean and Dyspepsia Index (SF-NDI) and the MoBa Food Frequency Questionnaire (MoBa FFQ). The time at which patients completed the questionnaires following dietary guidance ranged from 3-9 months (median, 4 months). The total IBS symptom scores were reduced once the patients had received dietary guidance (P=0.001). The total score for the quality of life, as assessed by the IBS-QOL and the SF-NDI, increased significantly following the dietary guidance sessions (P=0.003 and P=0.002, respectively). There were no statistical differences in the intake of calories, carbohydrate, fiber, protein, fat or alcohol in the patients with IBS following dietary guidance. There were increases in the consumption of dairy products, beta-carotene, retinol equivalents, riboflavin, vitamin B12 and calcium, although only the increase in vitamin B12 consumption was statistically significant. There was a significant reduction in the consumption of certain fruits and vegetables that were rich in highly fermentable short-chain carbohydrates, disaccharides, monosaccharides and polyols, as well as insoluble fibers. In conclusion, three 45-min dietary guidance sessions, administered by a nurse, reduced the symptoms and improved the quality of life of patients with IBS, and resulted in an adequate intake of vitamins and minerals. Individual dietary guidance is a cost-effective option for the management of IBS. PMID- 23820781 TI - Insulin/IGF-1-mediated longevity is marked by reduced protein metabolism. AB - Mutations in the daf-2 gene of the conserved Insulin/Insulin-like Growth Factor (IGF-1) pathway double the lifespan of the nematode Caenorhabditis elegans. This phenotype is completely suppressed by deletion of Forkhead transcription factor daf-16. To uncover regulatory mechanisms coordinating this extension of life, we employed a quantitative proteomics strategy with daf-2 mutants in comparison with N2 and daf-16; daf-2 double mutants. This revealed a remarkable longevity specific decrease in proteins involved in mRNA processing and transport, the translational machinery, and protein metabolism. Correspondingly, the daf-2 mutants display lower amounts of mRNA and 20S proteasome activity, despite maintaining total protein levels equal to that observed in wild types. Polyribosome profiling in the daf-2 and daf-16;daf-2 double mutants confirmed a daf-16-dependent reduction in overall translation, a phenotype reminiscent of Dietary Restriction-mediated longevity, which was independent of germline activity. RNA interference (RNAi)-mediated knockdown of proteins identified by our approach resulted in modified C. elegans lifespan confirming the importance of these processes in Insulin/IGF-1-mediated longevity. Together, the results demonstrate a role for the metabolism of proteins in the Insulin/IGF-1-mediated extension of life. PMID- 23820784 TI - Mental illness and domestic homicide: a population-based descriptive study. AB - OBJECTIVE: Approximately 10% of convicted homicide perpetrators in England and Wales have symptoms of mental illness at the time of homicide. The prevalence among perpetrators of adult domestic homicide is unclear. METHODS: The study was a consecutive case series of all convicted adult domestic homicide perpetrators in England and Wales between 1997 and 2008. Sociodemographic, clinical, and offense characteristics were gathered from the United Kingdom Home Office, the Police National Computer, psychiatric court reports, and, for psychiatric patients, questionnaires completed by supervising clinicians. RESULTS: A total of 1,180 perpetrators were convicted of intimate partner homicide, and 251 were convicted of homicide of an adult family member. Fourteen percent of perpetrators of intimate partner homicide and 23% of perpetrators of adult family homicide had been in contact with mental health services in the year before the offense; 20% of intimate partner homicide perpetrators and 34% of adult family homicide perpetrators had symptoms of mental illness at the time of offense. Perpetrators with symptoms of mental illness at the time of offense were less likely than perpetrators without symptoms to have previous violence convictions or history of alcohol abuse. CONCLUSIONS: A significant minority of adult domestic homicide perpetrators had symptoms of mental illness at the time of the homicide. Most perpetrators, including those with mental illnesses, were not in contact with mental health services in the year before the offense. Risk reduction could be achieved through initiatives that encourage individuals with mental health problems to access mental health services and that develop closer interagency working, including between mental health services, police, social services, and domestic violence services. PMID- 23820786 TI - The impact of long-term body mass index patterns on health-related quality of life: the Doetinchem Cohort Study. AB - Overweight is associated with a reduced health-related quality of life (QOL), but less is known about the impact of long-term body mass index (BMI, calculated as weight (kg)/height (m)(2)) patterns on QOL in adults. In the Dutch Doetinchem Cohort Study (1989-2009) that included 1,677 men and 1,731 women aged 20-66 years, 6 BMI patterns were defined by using 4 measurements over a 15-year period: 1) persistent healthy weight (18.5-24.9, reference pattern); 2) persistent overweight (25.0-29.9); 3) persistent obesity (>=30.0); 4) developing overweight; 5) developing obesity; and 6) switching between BMI categories. For each BMI pattern, adjusted QOL (measured on a 0-100 scale) was estimated at the end of this period. The lowest QOL was observed for persistent obesity of all BMI patterns. It was 5.0 points (P = 0.02) lower for 1 mental dimension in men and 6.2-11.6 points (P < 0.05) lower for 5 (mainly physical) dimensions in women. Developing overweight or obesity scored 1.8-6.3 points (P < 0.05) lower on 2-5 (mainly physical) dimensions. Persistent overweight hardly differed from a persistent healthy weight. In women, switching between BMI categories resulted in a lower QOL on the mental dimensions. Studying long-term BMI patterns over a 15 year period showed that persistent obesity, developing overweight, and developing obesity resulted in a lower QOL-particularly on the physical dimensions-compared with a persistent healthy weight. PMID- 23820785 TI - Allergies and risk of pancreatic cancer: a pooled analysis from the Pancreatic Cancer Case-Control Consortium. AB - In order to quantify the risk of pancreatic cancer associated with history of any allergy and specific allergies, to investigate differences in the association with risk according to age, gender, smoking status, or body mass index, and to study the influence of age at onset, we pooled data from 10 case-control studies. In total, there were 3,567 cases and 9,145 controls. Study-specific odds ratios and 95% confidence intervals were calculated by using unconditional logistic regression adjusted for age, gender, smoking status, and body mass index. Between study heterogeneity was assessed by using the Cochran Q statistic. Study-specific odds ratios were pooled by using a random-effects model. The odds ratio for any allergy was 0.79 (95% confidence interval (CI): 0.62, 1.00) with heterogeneity among studies (P < 0.001). Heterogeneity was attributable to one study; with that study excluded, the pooled odds ratio was 0.73 (95% CI: 0.64, 0.84) (Pheterogeneity = 0.23). Hay fever (odds ratio = 0.74, 95% CI: 0.56, 0.96) and allergy to animals (odds ratio = 0.62, 95% CI: 0.41, 0.94) were related to lower risk, while there was no statistically significant association with other allergies or asthma. There were no major differences among subgroups defined by age, gender, smoking status, or body mass index. Older age at onset of allergies was slightly more protective than earlier age. PMID- 23820788 TI - Re: "longevity in male and female joggers: the Copenhagen City Heart Study". PMID- 23820789 TI - Discussion for oncologic surveillance of breast cancer patients after lipofilling. PMID- 23820787 TI - Association of the FTO obesity risk variant rs8050136 with percentage of energy intake from fat in multiple racial/ethnic populations: the PAGE study. AB - Common obesity risk variants have been associated with macronutrient intake; however, these associations' generalizability across populations has not been demonstrated. We investigated the associations between 6 obesity risk variants in (or near) the NEGR1, TMEM18, BDNF, FTO, MC4R, and KCTD15 genes and macronutrient intake (carbohydrate, protein, ethanol, and fat) in 3 Population Architecture using Genomics and Epidemiology (PAGE) studies: the Multiethnic Cohort Study (1993-2006) (n = 19,529), the Atherosclerosis Risk in Communities Study (1987 1989) (n = 11,114), and the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) Study, which accesses data from the Third National Health and Nutrition Examination Survey (1991-1994) (n = 6,347). We used linear regression, with adjustment for age, sex, and ethnicity, to estimate the associations between obesity risk genotypes and macronutrient intake. A fixed-effects meta-analysis model showed that the FTO rs8050136 A allele (n = 36,973) was positively associated with percentage of calories derived from fat (betameta = 0.2244 (standard error, 0.0548); P = 4 * 10(-5)) and inversely associated with percentage of calories derived from carbohydrate (betameta = -0.2796 (standard error, 0.0709); P = 8 * 10(-5)). In the Multiethnic Cohort Study, percentage of calories from fat assessed at baseline was a partial mediator of the rs8050136 effect on body mass index (weight (kg)/height (m)(2)) obtained at 10 years of follow-up (mediation of effect = 0.0823 kg/m(2), 95% confidence interval: 0.0559, 0.1128). Our data provide additional evidence that the association of FTO with obesity is partially mediated by dietary intake. PMID- 23820790 TI - Extended spreader graft placement before lateral nasal osteotomy. AB - The extended spreader graft technique in septorhinoplasty is presented. The procedure involves applying spreader grafts before lateral osteotomies to support the whole osteocartilaginous vault. This study enrolled 51 patients who had undergone open septorhinoplasty between January 2010 and March 2012. The dorsal width ratio (DWR) was calculated for each patient by dividing the keystone width score by the intercanthal width score. The preoperative DWR scores classified 32 of the 51 noses as normal, six noses as narrow, and 13 noses as wide. All the patients with a nose classified as narrow preoperatively had a nose with a normal width postoperatively. All but one patient who had a normal preoperative DWR score also had a normal DWR score postoperatively. Of the 13 patients who had a wide nose preoperatively, seven were classified in the normal-width group postoperatively. Although the remaining six patients had a positive DWR score change (DWR closer to 0.50), they still were in the wide-nose group postoperatively. All but three patients were satisfied with their cosmetic and aesthetic results. Inverted-V or open-roof deformities were not observed. For all 18 patients in the normal nasal width group preoperatively (18/32), the nasal dorsum seemed wide after lateral osteotomies due to the spacing effect of the graft. As a result of medializing the bones, the caudal end of the graft became palpable. Although the graft position was checked perioperatively, at the postoperative 6-month follow-up assessment, three patients had palpable cartilages in the keystone area, one of which needed a surgical revision. Extended spreader grafts applied before lateral nasal osteotomies can support the entire nasal dorsum, including the bony vault. This spacing effect could be highly advantageous for both narrow and wide noses. In narrow noses, these grafts prevent further narrowing of the osteocartilaginous vault and support the dorsal aesthetic lines. In wide noses, extended spreader grafts fill the bone gap before lateral osteotomy and help to prevent open-roof deformity. In addition, fixing the upper lateral cartilages before lateral osteotomies might further prevent bone collapses, even after premature fractures. In normal-width noses, after completion of the lateral osteotomies, the bone gap usually does not persist, and nasal bones push the cranial end of the spreader graft dorsally. Therefore, in normal-width noses, extending the graft along the bony gap is not necessary, and the use of extended spreader grafts is not preferred. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23820791 TI - Mesh pullout force: comparative study of different deployment techniques in a sheep model. AB - INTRODUCTION AND HYPOTHESIS: Pullout force of mesh from tissue is one of the important mechanical properties of an implanted mesh to repair pelvic organ prolapse (POP). The EndoFast ReliantTM system kit allows mesh attachment with soft-tissue fasteners. The aim of this study was to compare the pullout force that developed in mesh that was attached by EndoFast Reliant fasteners to mesh that was attached by trocar-based methods (tunnel, pocket) in a sheep model. METHODS: Six sheep underwent mesh attachment with three methods (EndoFast Reliant, tissue pocket, tissue tunnel), and each method was repeated five times in both thighs of the same sheep. The pullout force was measured at different time intervals from surgery: 0, 3, 7, 15, 30, and 45 days. Statistical analysis was performed by using the appropriate one-way analysis of variance (ANOVA) for each time interval and a general linear model for repeated measures using IBM(r) SPSS(r) software version 20.0.0. RESULTS: During the immediate postoperative period (0-3 days), pullout force was significantly higher with EndoFast Reliant than with tissue pocket or tissue tunnel. At day 7, this trend continues without statistical significance. Pullout force increased progressively until day 15, when the force caused the mesh to tear; it was similar in all three groups. ANOVA showed significant effect of time and study group. CONCLUSIONS: The EndoFast Reliant system provides significantly stronger attachment in the immediate postoperative period (0-3 days) compared with trocar-based techniques, and this difference disappeared at day 15 postsurgery. PMID- 23820792 TI - Norovirus contamination levels in ground water treatment systems used for food catering facilities in South Korea. AB - This study aimed to inspect norovirus contamination of groundwater treatment systems used in food-catering facilities located in South Korea. A nationwide study was performed in 2010. Water samples were collected and, for the analysis of water quality, the temperature, pH, turbidity, and residual chlorine content were assessed. To detect norovirus genotypes GI and GII, RT-PCR and semi-nested PCR were performed with specific NV-GI and NV-GII primer sets, respectively. The PCR products amplified from the detected strains were then subjected to sequence analyses. Of 1,090 samples collected in 2010, seven (0.64%) were found to be norovirus-positive. Specifically, one norovirus strain was identified to have the GI-6 genotype, and six GII strains had the GII, GII-3, GII-4, and GII-17 genotypes. The very low detection rate of norovirus most likely reflects the preventative measures used. However, this virus can spread rapidly from person to person in crowded, enclosed places such as the schools investigated in this study. To promote better public health and sanitary conditions, it is necessary to periodically monitor noroviruses that frequently cause epidemic food poisoning in South Korea. PMID- 23820793 TI - An artificial temporal bone as a training tool for cochlear implantation. AB - OBJECTIVE: Description and evaluation of a newly developed artificial temporal bone (TB) model suitable for surgical training for cochlear implantation. SUBJECT: Based on micro-computed tomographic images, a TB model was designed with material properties as similar to bone as possible. The bony anatomic details were rebuilt as closely as possible with preservation of the endocochlear lumen. INTERVENTION: The TB model was compared with a human cadaveric TB by 8 otologists experienced in cochlear implantation. MAIN OUTCOME MEASURE: The otologists were asked to respond to a semiquantitative questionnaire with scales from 1 (strongly disagree) to 5 (strongly agree). Anatomic details were compared macroscopically and microscopically. The surgical steps of mastoidectomy, posterior tympanotomy, cochleostomy, and insertion of a cochlear electrode were assessed. RESULTS: The material properties and anatomic details of the TB model were generally comparable to the human TB. One exception was the round window membrane, which was not modeled appropriately. The surgical steps, including the insertion of the electrode, were rated as comparable. CONCLUSION: The TB model is suitable for surgical training for interventions such as cochlear implantation. It cannot replace cadaveric human temporal bones completely, but it provides an easily available alternative to train and develop surgical skills. A wider variety of anatomic models, such as an infant's TB or malformations, will increase the value of TB models. PMID- 23820794 TI - The possible associations of septal deviation on mastoid pneumatization and chronic otitis. AB - OBJECTIVES: The purpose of this study was to determine the role of nasal septal deviation on volume of mastoid air cells and possible relationship to chronic otitis. MATERIALS AND METHODS: Between May 2010 and September 2012, paranasal sinus computed tomographic findings of 825 patients (470 male and 355 female subjects) who were treated in Ear Nose and Throat Department of Bozok University Medical Faculty were retrospectively analyzed. By excluding the other coexistent sinonasal pathologies, 100 patients (45 male and 55 female subjects; mean age, 37.7 +/- 10.4 yr; range, 18-70 yr) with nasal septal deviations were recruited for the study. The convex side of the septal curvature was accepted as the direction of deviation. The findings were grouped according to the radiologically measured angle of nasal septal deviations. The deviation angle of the nasal septum was described as follows: mild (<9 degrees), moderate (9-15 degrees), or severe (>= 15 degrees). The volume of each mastoid air cells was also calculated using the computer program. Chronic otitis was defined a abnormality criteria of the normal temporal scan. Criteria for a normal temporal bone were as follows: 1) absence of bony destruction or sclerosis; 2) absence of fluid or mass in any of the temporal bone air spaces; and 3) the presence of "normal" air cells. RESULTS: There were 45 male and 55 female subjects (mean age, 37.7 +/- 10.4 yr; range, 18 70 yr). Nasal septal deviation angles were found to range between 5 and 28.1 degrees (mean, 14 +/- 1.2 degrees). The left-sided deviations included 16 mild (<9 degrees, Group I), 15 moderate (9-15 degrees, Group II), and 17 severe (>= 15 degrees, Group III) subjects. The right-sided deviations included 18 mild (<9 degrees, Group I), 16 moderate (9-15 degrees, Group II), and 18 severe (>= 15 degrees, Group III) cases. We could not demonstrate a statistically significant difference between the right mastoid cell volumes of the Group I and Group II in left-sided deviation cases (p = 0.51). In the same side comparison of Group I to Group III and Group II to Group III, the mastoid cell volume differences were found to be significantly meaningful (p = 0.00 and p = 0.00, respectively). Identical results were yielded in the right-sided septal deviation group related to the mastoid cell volumes of Group I and Group II and Group I to Group III and Group II to Group III comparisons (p = 0.55, p = 0.00, and p = 0.011, respectively). In both right and left deviation groups, ipsilateral and contralateral mastoid cell volume comparisons produced statistically significant results (p = 0.04 and p = 0.003, respectively). The presence of chronic otitis findings were significantly increased in both groups (p = 0.00). Statistical significance was set at p < 0.05. CONCLUSION: Our findings suggest that mastoid cell volumes tend to be larger at the contralateral side of the severe septum deviations. PMID- 23820795 TI - Randomized prospective trial of hyperbaric oxygen therapy and intratympanic steroid injection as salvage treatment of sudden sensorineural hearing loss. AB - OBJECTIVE: To compare the effects of hyperbaric oxygen (HBO) and intratympanic (IT) steroid injection on hearing after the failure of primary treatment in patients with idiopathic sudden sensorineural hearing loss (ISSHL). STUDY DESIGN: A prospective randomized trial. SETTING: Tertiary referral center. PATIENTS: Fifty patients with failure of primary therapy for ISSHL. INTERVENTION(S): After primary treatment with systemic steroids and failure of therapy, defined as less than 10-dB hearing gain, 50 patients were enrolled in the study and received either hyperbaric oxygen or intratympanic steroid treatment. The patients were not matched and not similar. MAIN OUTCOME MEASURE(S): Hearing gain at 0.25, 0.5, 1, 2, and 4 kHz after treatment. RESULTS: There were significant differences between hearing thresholds at all frequencies before and after the HBO treatment. Similarly, there were significant differences between hearing thresholds at most frequencies (except 2 kHz) before and after the treatment in the IT group. The subgroups of patients with pure tone average less than 81 dB and were younger than 60 years had better response to HBO treatment than those with profound deafness and in the elderly. CONCLUSION: HBO and IT steroid therapy could be successfully used as salvage therapies in patients with sudden deafness. Further study is needed to demonstrate superiority of one of the treatments. PMID- 23820796 TI - Vibroplasty for mixed and conductive hearing loss. AB - OBJECTIVE: To summarize new application methods of an active middle ear implant (Vibrant Soundbridge) in patients with conductive or mixed hearing loss. DATA SOURCES: Publications listed in the Medline/PubMed database. STUDY SELECTION: All publications published in English language; search term Vibrant Soundbridge AND floating mass transducer in all fields. DATA EXTRACTION: Structured analysis of all publications. DATA SYNTHESIS: Extraction of significant findings and conclusions and audiometric data. CONCLUSION: Modern application methods of an active middle ear implant (VSB) open new therapeutic options for patients with various outer and middle ear diseases resulting in conductive or mixed hearing loss. Titanium couplers can help to couple the active middle ear implant in a standardized way to remnants of the ossicular chain or to the round window. Thus, the active middle ear implant has been established as an alternative treatment option for patients with mixed and conductive hearing. However, the heterogeneity of the studies published so far complicates the analysis of the audiometric results, and thus, the functional hearing gain after VSB implantation varies a lot. PMID- 23820797 TI - Evaluation of preoperative hearing-in-noise protocol for osseointegrated hearing implants. AB - OBJECTIVE: Evaluate the clinical use of a preoperative protocol using hearing-in noise improvement as measured by Adaptive HINT and Quick SIN in patients undergoing ossseointegrated hearing implantation for single-sided deafness (SSD). STUDY DESIGN: Prospective cohort. SETTING: Tertiary academic hospital and clinic. PATIENTS: All consecutive English-speaking patients with SSD undergoing osseointegrated hearing implantation whom we have preoperative and postoperative Quick SIN and Adaptive HINT measurements. INTERVENTIONS: Measure preoperative unaided and aided (headband simulator) hearing-in-noise ratio improvement and compare with postoperative results. MAIN OUTCOME MEASURES: The improvement in hearing-in-noise in preoperative unaided to aided and then correlate to postoperative hearing-in-noise results. RESULTS: Total of 12 patients participated in the study. There was a statistically significant improvement from preoperative unaided Quick SIN and Adaptive HINT scores to preoperative aided scores (p = 0.001 and p = 0.004). There was statistically significant improvement from preoperative unaided Quick SIN and adaptive HINT to postoperative implant scores (p = 0.002 and p = 0.003). Comparing preoperative aided with postoperative implant aided, there demonstrated a significant improvement in QuickSIN with -2.7 SNR (p = 0.045) and in HINT with -2.35 dB (p = 0.05). CONCLUSION: This is the first study evaluating a preoperative protocol using both Quick SIN and Adaptive HINT testing for osseointegrated hearing implantation. Postoperatively, there was a statistically significant improvement in both of the hearing-in-noise measures. There was significant correlation between the preoperative simulator and postoperative hearing-in-noise measures signifying the benefit of using Quick SIN and HINT as a predictive preoperative tool to evaluate surgical candidacy and improve patient education and expectations. PMID- 23820798 TI - Relation between head impulse tests, rotating chair tests, and stance and gait posturography after an acute unilateral peripheral vestibular deficit. AB - BACKGROUND: Vestibulo-ocular reflex (VOR) deficits and balance instability during stance and gait are typical for an acute unilateral peripheral vestibular deficit (AUPVD). The relation between different VOR measures with recovery is unknown, as is the relation of VOR measures to balance control. To answer these questions, we examined changes over time in caloric canal paresis (CP), head impulse tests (HIT), whole body rotation (ROT) tests of the horizontal VOR, and changes in trunk sway during stance and gait tests, for cases of presumed vestibular neuritis. METHODS: HIT was performed with short ca. 200 degrees per second head turns, ROT with triangular 24-second velocity profiles (peak 120 degrees per second, acceleration 20 degrees per second squared). To measure balance control, body-worn gyroscopes measured pitch (anterior-posterior) and roll (lateral) sway angles and angular velocities at lumbar 1 to 3. RESULTS: Changes during recover in ROT and HIT responses to the deficit side were equally well related (R = 0.8, p < 0.001) to changes in caloric CP values. ROT but not HIT responses to the normal side were also related to CP responses (R = 0.53, p = 0.02). Spontaneous nystagmus levels were related to changes instance balance control (R = 0.52, p = 0.001). Balance during gait improved over time but was not well correlated with changes in VOR measures (R = 0.26 max., p > 0.05). CONCLUSION: Both HIT and ROT track VOR recovery on the deficit side due to central compensation and peripheral recovery. However, only ROT track changes in the central compensation of normal side responses. The weak correlations between VOR and stance and gait tests suggest that the latter should also be tested to judge the effect of an AUPVD on balance control. PMID- 23820799 TI - Short-term storage of tripronucleated human embryos. AB - PURPOSE: To determine the survival and subsequent in vitro development of human cleavage stage embryos and hatched blastocysts following varying periods of short term storage at 4 degrees C, using tripronucleated human embryos (TPN) as a model. METHODS: TPN cleavage embryos and hatched blastocysts short-term stored at 4 degrees C for 0 h (control), 24 h and 48 h. The main outcome measures were: survival rates (SR) and in vitro developmental ability (blastocyst rate and blastocyst-re-expansion rate) in each of the groups after storage. RESULTS: Cleavage-stage TPN survived at comparable rates to controls, regardless of storage time (average: 97.3 %). The in vitro development of cleavage-stage TPN stored for 24 h was comparable to that of controls (average 64.7 %), but was significantly impaired when storage lasted 48-h (20.8 %). After artificial shrinkage, SR was comparable in 24-h-stored and non-stored hatched blastocysts (85.7 %; p > 0.05), but was significantly impaired in the 48-h-stored group (20.0 %). Following 24-h storage, the re-expansion rate of hatched blastocysts was similar to that of controls (average: 57.1 %; p > 0.05), but was higher than that of the 48-h-stored group (15.0 %; p < 0.05). CONCLUSIONS: TPN human cleavage embryos and blastocysts can be successfully stored short-term for up to 24 h at 4 degrees C without using cryoprotectants without any significant negative impact on survival or subsequent in vitro development. PMID- 23820800 TI - Bacterial composition of soils of the Lake Wellman area, Darwin Mountains, Antarctica. AB - The aim of this study was to examine the bacterial composition of high latitude soils from the Darwin-Hatherton glacier region of Antarctica. Four soil pits on each of four glacial drift sheets were sampled for chemical and microbial analyses. The four drifts-Hatherton, Britannia, Danum, and Isca-ranged, respectively, from early Holocene (10 ky) to mid-Quaternary (ca 900 ky). Numbers of culturable bacteria were low, with highest levels detected in soils from the younger Hatherton drift. DNA was extracted and 16S rRNA gene clone libraries prepared from samples below the desert pavement for each of the four drift sheets. Between 31 and 262 clones were analysed from each of the Hatherton, Britannia, and Danum drifts. Bacterial sequences were dominated by members of the phyla Deinococcus-Thermus, Actinobacteria, and Bacteroidetes. Culturable bacteria, including some that clustered with soil clones (e.g., members of the genera Arthrobacter, Adhaeribacter, and Pontibacter), belonged to Actinobacteria and Bacteroidetes. The isolated bacteria are ideal model organisms for genomic and phenotypic investigations of those attributes that allow bacteria to survive and/or grow in Antarctic soils because they have close relatives that are not tolerant of these conditions. PMID- 23820801 TI - Surgical versus nonsurgical treatment of infected pancreatic necrosis: more arguments to change the paradigm. AB - OBJECTIVES: This study aimed to compare primary surgical versus nonsurgical treatment in a series of patients with infected pancreatic necrosis (IPN) and to investigate whether the success of nonsurgical approach is related to a less severe disease. METHODS: Thirty-nine consecutive patients with IPN have been included and further subdivided into two groups: primary surgical (n = 21) versus nonsurgical (n = 18). Outcome measures were the differences in mortality, morbidity, and pancreatic function. Comorbidity, organ failure, and other severity indexes were compared between the two groups. RESULTS: Mortality occurred in 16.7% of cases in the nonsurgical group versus 42.9% in the surgical group. In the primary nonsurgical group, seven were operated on due to failure of initial conservative treatment. In this latter group, mortality was 28.6% and was performed significantly later than in the primary surgical group. The group of primary surgical treatment was associated with a significant higher rate of multiple organ failure (MOF) at IPN diagnosis, new onset or worsening of organ failure, and MOF and nosocomial infection after surgery. CONCLUSIONS: Initial nonsurgical approach in IPN is associated with better results both in cases which respond to this treatment as well as in those who, failing this conservative approach, have to be operated on after a delayed period. Primary surgically treated patients had a more severe disease at the time of IPN. PMID- 23820802 TI - An interview with Bernie Auchter. Interview by Walter S DeKeseredy. AB - Since the creation of the 1994 Violence Against Women Act (VAWA), Bernie Auchter and his colleagues affiliated with the National Institute of Justice's (NIJ) Violence Against Women Research and Evaluation Program have done much to assist the efforts of progressive researchers, practitioners, activists, and policy makers. Their work also helped enhance the health and well-being of countless women victimized by violence. This article is based on an interview with Bernie and chronicles some of his key contributions to the field. PMID- 23820807 TI - Neuropathological review of 138 cases genetically tested for X-linked hydrocephalus: evidence for closely related clinical entities of unknown molecular bases. AB - L1 syndrome results from mutations in the L1CAM gene located at Xq28. It encompasses a wide spectrum of diseases, X-linked hydrocephalus being the most severe phenotype detected in utero, and whose pathophysiology is incompletely understood. The aim of this study was to report detailed neuropathological data from patients with mutations, to delineate the neuropathological criteria required for L1CAM gene screening in foetuses by characterizing the sensitivity, specificity and positive predictive value of the cardinal signs, and to discuss the main differential diagnoses in non-mutated foetuses in order to delineate closely related conditions without L1CAM mutations. Neuropathological data from 138 cases referred to our genetic laboratory for screening of the L1CAM gene were retrospectively reviewed. Fifty-seven cases had deleterious L1CAM mutations. Of these, 100 % had hydrocephalus, 88 % adducted thumbs, 98 % pyramidal tract agenesis/hypoplasia, 90 % stenosis of the aqueduct of Sylvius and 68 % agenesis/hypoplasia of the corpus callosum. Two foetuses had L1CAM mutations of unknown significance. Seventy-nine cases had no L1CAM mutations; these were subdivided into four groups: (1) hydrocephalus sometimes associated with corpus callosum agenesis (44 %); (2) atresia/forking of the aqueduct of Sylvius/rhombencephalosynapsis spectrum (27 %); (3) syndromic hydrocephalus (9 %), and (4) phenocopies with no mutations in the L1CAM gene (20 %) and in whom family history strongly suggested an autosomal recessive mode of transmission. These data underline the existence of closely related clinical entities whose molecular bases are currently unknown. The identification of the causative genes would greatly improve our knowledge of the defective pathways involved in these cerebral malformations. PMID- 23820810 TI - Dialysis: Effect of cinacalcet on survival--the saga continues. PMID- 23820809 TI - Gliomas of the pineal region. AB - Although several series of pineal region tumors are available, the issue of pineal gliomas has been scarcely faced in the literature. Gliomas are usually included in largest series of pineal neoplasms. Therefore, whether pineal gliomas share the biological behavior of either hemispheric gliomas or other midline lesions is not yet defined. The aim of this retrospective study is to analyze long-term morbidity and mortality of these lesions. In English published literature gliomas account for about 14-22 % of all pineal region tumors. Most of these tumors are pilocytic astrocytomas, while glioblastoma multiforme is rare. We retrospectively analyzed all pineal region tumors operated on in our department in the last 28 years, and identified eight pineal astrocytomas, accounting for 14.03 % of all pineal tumors. The series includes four pilocytic astrocytomas, two grade II diffuse astrocytomas, and two anaplastic astrocytomas. A comprehensive review of the available literature data shows that the mean survival time of WHO grade II gliomas is shorter when tumor grows in the pineal region than for hemispheric locations, although the limited amount of available data prevents a rigorous statistical analysis. This difference might be due to the peculiar infiltrating behavior of pineal tumors, which often can't be satisfactorily resected from vital structures. PMID- 23820813 TI - Vasculitis: Validating the new classification system for ANCA-associated GN. PMID- 23820808 TI - The Alzheimer's beta-secretase BACE1 localizes to normal presynaptic terminals and to dystrophic presynaptic terminals surrounding amyloid plaques. AB - beta-Site amyloid precursor protein (APP) cleaving enzyme-1 (BACE1) is the beta secretase that initiates Abeta production in Alzheimer's disease (AD). BACE1 levels are increased in AD, which could contribute to pathogenesis, yet the mechanism of BACE1 elevation is unclear. Furthermore, the normal function of BACE1 is poorly understood. We localized BACE1 in the brain at both the light and electron microscopic levels to gain insight into normal and pathophysiologic roles of BACE1 in health and AD, respectively. Our findings provide the first ultrastructural evidence that BACE1 localizes to vesicles (likely endosomes) in normal hippocampal mossy fiber terminals of both non-transgenic and APP transgenic (5XFAD) mouse brains. In some instances, BACE1-positive vesicles were located near active zones, implying a function for BACE1 at the synapse. In addition, BACE1 accumulated in swollen dystrophic autophagosome-poor presynaptic terminals surrounding amyloid plaques in 5XFAD cortex and hippocampus. Importantly, accumulations of BACE1 and APP co-localized in presynaptic dystrophies, implying increased BACE1 processing of APP in peri-plaque regions. In primary cortical neuron cultures, treatment with the lysosomal protease inhibitor leupeptin caused BACE1 levels to increase; however, exposure of neurons to the autophagy inducer trehalose did not reduce BACE1 levels. This suggests that BACE1 is degraded by lysosomes but not by autophagy. Our results imply that BACE1 elevation in AD could be linked to decreased lysosomal degradation of BACE1 within dystrophic presynaptic terminals. Elevated BACE1 and APP levels in plaque associated presynaptic dystrophies could increase local peri-plaque Abeta generation and accelerate amyloid plaque growth in AD. PMID- 23820817 TI - Chronic kidney disease: Does serum phosphate predict death and ESRD in CKD patients? PMID- 23820815 TI - Treatment of idiopathic membranous nephropathy. AB - Immunosuppressive treatment of patients with idiopathic membranous nephropathy (iMN) is heavily debated. The controversy is mainly related to the toxicity of the therapy and the variable natural course of the disease-spontaneous remission occurs in 40-50% of patients. The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Glomerulonephritis provides guidance for the treatment of iMN. The guideline suggests that immunosuppressive therapy should be restricted to patients with nephrotic syndrome and persistent proteinuria, deteriorating renal function or severe symptoms. Alkylating agents are the preferred therapy because of their proven efficacy in preventing end stage renal disease. Calcineurin inhibitors can be used as an alternative although efficacy data on hard renal end points are limited. In this Review, we summarize the KDIGO guideline and address remaining areas of uncertainty. Better risk prediction is needed to identify patients who will benefit from immunosuppressive therapy, and the optimal timing and duration of this therapy is unknown because most of the randomized controlled trials were performed in low risk or medium-risk patients. Alternative therapies, directed at B cells, are under study. The discovery of anti-M type phospholipase A2 receptor-antibodies is a major breakthrough and we envisage that in the near future, antibody-driven therapy will enable more individualized treatment of patients with iMN. PMID- 23820818 TI - Perceptual judgements and chronic imaging of altered odour maps indicate comprehensive stimulus template matching in olfaction. AB - Lesion experiments suggest that odour input to the olfactory bulb contains significant redundant signal such that rodents can discern odours using minimal stimulus-related information. Here we investigate the dependence of odour-quality perception on the integrity of glomerular activity by comparing odour-evoked activity maps before and after epithelial lesions. Lesions prevent mice from recognizing previously experienced odours and differentially delay discrimination learning of unrecognized and novel odour pairs. Poor recognition results not from mice experiencing an altered concentration of an odour but from perception of apparent novel qualities. Consistent with this, relative intensity of glomerular activity following lesions is altered compared with maps recorded in shams and by varying odour concentration. Together, these data show that odour recognition relies on comprehensively matching input patterns to a previously generated stimulus template. When encountering novel odours, access to all glomerular activity ensures rapid generation of new templates to perform accurate perceptual judgements. PMID- 23820819 TI - Relationship between respiratory sinus arrhythmia, heart period, and caregiver reported language and cognitive delays in children with autism spectrum disorders. AB - The present study examines the relationship between autonomic activity and cognitive/language delays in children with autism spectrum disorder (ASD). Baseline levels of respiratory sinus arrhythmia (RSA) and heart period (HP) were assessed in 23 4-7-year old children diagnosed with ASD. The relationship between RSA, HP, and ASD behavioral symptoms was examined. Similar to prior studies on typically developing children, lower basal RSA was related to more caregiver reported language and cognitive delays, and to the lack of language. PMID- 23820820 TI - Silencing mutant ATXN3 expression resolves molecular phenotypes in SCA3 transgenic mice. AB - Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease caused by a polyglutamine expansion in the deubiquitinating enzyme, Ataxin-3. Currently, there are no effective treatments for this fatal disorder but studies support the hypothesis that reducing mutant Ataxin-3 protein levels might reverse or halt the progression of disease in SCA3. Here, we sought to modulate ATXN3 expression in vivo using RNA interference. We developed artificial microRNA mimics targeting the 3'-untranslated region (3'UTR) of human ATXN3 and then used recombinant adeno associated virus to deliver them to the cerebellum of transgenic mice expressing the full human disease gene (SCA3/MJD84.2 mice). Anti-ATXN3 microRNA mimics effectively suppressed human ATXN3 expression in SCA3/MJD84.2 mice. Short-term treatment cleared the abnormal nuclear accumulation of mutant Ataxin-3 throughout the transduced SCA3/MJD84.2 cerebellum. Analysis also revealed changes in the steady-state levels of specific microRNAs in the cerebellum of SCA3/MJD84.2 mice, a previously uncharacterized molecular phenotype of SCA3 that appears to be dependent on mutant Ataxin-3 expression. Our findings support the preclinical development of molecular therapies aimed at halting the expression of ATXN3 as a viable approach to SCA3 and point to microRNA deregulation as a potential surrogate marker of SCA3 pathogenesis. PMID- 23820822 TI - Dopaminergic function in cannabis users and its relationship to cannabis-induced psychotic symptoms. AB - BACKGROUND: Cannabis is the most widely used illicit drug globally, and users are at increased risk of mental illnesses including psychotic disorders such as schizophrenia. Substance dependence and schizophrenia are both associated with dopaminergic dysfunction. It has been proposed, although never directly tested, that the link between cannabis use and schizophrenia is mediated by altered dopaminergic function. METHODS: We compared dopamine synthesis capacity in 19 regular cannabis users who experienced psychotic-like symptoms when they consumed cannabis with 19 nonuser sex- and age-matched control subjects. Dopamine synthesis capacity (indexed as the influx rate constant [Formula: see text] ) was measured with positron emission tomography and 3,4-dihydroxy-6-[(18)F]-fluoro-l phenylalanine ([(18)F]-DOPA). RESULTS: Cannabis users had reduced dopamine synthesis capacity in the striatum (effect size: .85; t36 = 2.54, p = .016) and its associative (effect size: .85; t36 = 2.54, p = .015) and limbic subdivisions (effect size: .74; t36 = 2.23, p = .032) compared with control subjects. The group difference in dopamine synthesis capacity in cannabis users compared with control subjects was driven by those users meeting cannabis abuse or dependence criteria. Dopamine synthesis capacity was negatively associated with higher levels of cannabis use (r = -.77, p < .001) and positively associated with age of onset of cannabis use (r = .51, p = .027) but was not associated with cannabis induced psychotic-like symptoms (r = .32, p = .19). CONCLUSIONS: These findings indicate that chronic cannabis use is associated with reduced dopamine synthesis capacity and question the hypothesis that cannabis increases the risk of psychotic disorders by inducing the same dopaminergic alterations seen in schizophrenia. PMID- 23820823 TI - Batch anaerobic co-digestion of cow manure and waste milk in two-stage process for hydrogen and methane productions. AB - Anaerobic co-digestion of cow manure (CM) and waste milk (WM), produced by sick cows during treatment with antibiotics, was evaluated in two-stage process under thermophilic condition (55 degrees C) to determine the effect of WM addition on hydrogen (H2) and methane (CH4) production potentials, volatile solids (VS) removal, and energy recovery. Six CM to WM VS ratios of 100:0, 90:10, 70:30, 50:50, 30:70, and 10:90 were examined using 1-L batch digesters. The WM VS ratio of 30 % was found to be the minimum limit for significant increases in specific H2 and CH4 yields, and VS removal as compared to digestion of manure alone (P < 0.05). The highest specific H2 and CH4 yields, VS removal and energy yield were 38.2 mL/g VS, 627.6 mL/g VS, 78.4 % and 25,459.8 kJ/kg VS, respectively, in CM:WM 30:70. Lag phases to H2 and CH4 productions were observed in CM-WM mixtures, increased with increasing the amount of WM in the feedstock and were greater than 72 h in CM:WM 50:50 and 30:70. The digestion system failed in CM:WM 10:90. The results suggest that CM:WM 30:70 was optimum, however, due to limited amount of WM usually generated and long lag phase at this ratio which may make the process uneconomical, CM:WM 70:30 is recommended in practice. PMID- 23820821 TI - Regulation of fear responses by striatal and extrastriatal adenosine A2A receptors in forebrain. AB - BACKGROUND: Adenosine A2A receptors (A2ARs) are enriched in the striatum but are also present at lower levels in the extrastriatal forebrain (i.e., hippocampus, cortex), integrating dopamine, glutamate, and brain-derived neurotrophic factor (BDNF) signaling, and are thus essential for striatal neuroplasticity and fear and anxiety behavior. METHODS: We tested two brain region-specific A2AR knockout lines with A2ARs selectively deleted either in the striatum (st-A2AR KO) or the entire forebrain (striatum, hippocampus, and cortex [fb-A2AR KO]) on fear and anxiety-related responses. We also examined the effect of hippocampus-specific A2AR deletion by local injection of adeno-associated virus type 5 (AAV5)-Cre into floxed-A2AR knockout mice. RESULTS: Selectively deleting A2ARs in the striatum increased Pavlovian fear conditioning (both context and tone) in st-A2AR KO mice, but extending the deletion to the rest of the forebrain apparently spared context fear conditioning and attenuated tone fear conditioning in fb-A2AR KO mice. Moreover, focal deletion of hippocampal A2ARs by AAV5-Cre injection selectively attenuated context (but not tone) fear conditioning. Deletion of A2ARs in the entire forebrain in fb-A2AR KO mice also produced an anxiolytic phenotype in both the elevated plus maze and open field tests, and increased the startle response. These extrastriatal forebrain A2AR behavioral effects were associated with reduced BDNF levels in the fb-A2AR KO hippocampus. CONCLUSIONS: This study provides evidence that inactivation of striatal A2ARs facilitates Pavlovian fear conditioning, while inactivation of extrastriatal A2ARs in the forebrain inhibits fear conditioning and also affects anxiety-related behavior. PMID- 23820824 TI - Metabolic engineering of Escherichia coli for biosynthesis of D-galactonate. AB - D-galactose is an attractive substrate for bioconversion. Herein, Escherichia coli was metabolically engineered to convert D-galactose into D-galactonate, a valuable compound in the polymer and cosmetic industries. D-galactonate productions by engineered E. coli strains were observed in shake flask cultivations containing 2 g L(-1) D-galactose. Engineered E. coli expressing gld coding for galactose dehydrogenase from Pseudomonas syringae was able to produce 0.17 g L(-1) D-galactonate. Inherent metabolic pathways for assimilating both D galactose and D-galactonate were blocked to enhance the production of D galactonate. This approach finally led to a 7.3-fold increase with D-galactonate concentration of 1.24 g L(-1) and yield of 62.0 %. Batch fermentation in 20 g L( 1) D-galactose of E. coli ?galK?dgoK mutant expressing the gld resulted in 17.6 g L(-1) of D-galactonate accumulation and highest yield of 88.1 %. Metabolic engineering strategy developed in this study could be useful for industrial production of D-galactonate. PMID- 23820825 TI - Extracellular recombinant protein production under continuous culture conditions with Escherichia coli using an alternative plasmid selection mechanism. AB - The secretion of recombinant proteins into the extracellular space by Escherichia coli presents advantages like easier purification and protection from proteolytic degradation. The controlled co-expression of a bacteriocin release protein aids in moving periplasmic proteins through the outer membrane. Since such systems have rarely been applied in continuous culture it seemed to be attractive to study the interplay between growth-phase regulated promoters controlling release protein genes and the productivity of a chemostat process. To avoid the use of antibiotics and render this process more sustainable, alternative plasmid selection mechanisms were required. In the current study, the strain E. coli JM109 harboring plasmid p582 was shown to stably express and secrete recombinant beta-glucanase in continuous culture using a minimal medium. The segregational instability of the plasmid in the absence of antibiotic selection pressure was demonstrated. The leuB gene, crucial in the leucine biosynthetic pathway, was cloned onto plasmid p582 and the new construct transformed into an E. coli Keio (DeltaleuB) knockout strain. The ability of the construct to complement the leucine auxotrophy was initially tested in shake-flasks and batch cultivation. Later, this strain was successfully grown for more than 200 h in a chemostat and was found to be able to express the recombinant protein. Significantly, it showed a stable maintenance of the recombinant plasmid in the absence of any antibiotics. The plasmid stability in a continuously cultivated E. coli fermentation, in the absence of antibiotics, with extracellular secretion of recombinant protein provides an interesting model for further improvements. PMID- 23820826 TI - Enhancing the usefulness of cross dehydrogenative coupling reactions with a removable protecting group. AB - A removable protecting group has been identified that allows the products of widely-used cross dehydrogenative couplings to be synthetically elaborated. The method can be used with enantiopure amines with no loss of enantiomeric excess. The methodology is exemplified by a new synthesis of enantiopure praziquantel, the drug used in the treatment of millions of people suffering from the neglected tropical disease, schistosomiasis. PMID- 23820827 TI - The dynamics of subthreshold psychopathology: implications for diagnosis and treatment. PMID- 23820828 TI - Harnessing N-methyl-d-aspartate receptors for new treatment development in psychiatry: positive lessons from negative studies. PMID- 23820829 TI - Psychotherapy: a paradox. PMID- 23820831 TI - Iphis and Anaxarete in Ovid's Metamorphoses: poem of the shut-out lover. PMID- 23820830 TI - Behavioral treatment of insomnia in bipolar disorder. AB - Sleep disturbance is common in bipolar disorder. Stimulus control and sleep restriction are powerful, clinically useful behavioral interventions for insomnia, typically delivered as part of cognitive-behavioral therapy for insomnia (CBT-I). Both involve short-term sleep deprivation. The potential for manic or hypomanic symptoms to emerge after sleep deprivation in bipolar disorder raises questions about the appropriateness of these methods for treating insomnia. In a series of patients with bipolar disorder who underwent behavioral treatment for insomnia, the authors found that regularizing bedtimes and rise times was often sufficient to bring about improvements in sleep. Two patients in a total group of 15 patients reported mild increases in hypomanic symptoms the week following instruction on stimulus control. Total sleep time did not change for these individuals. Two of five patients who underwent sleep restriction reported mild hypomania that was unrelated to weekly sleep duration. Sleep restriction and stimulus control appear to be safe and efficacious procedures for treating insomnia in patients with bipolar disorder. Practitioners should encourage regularity in bedtimes and rise times as a first step in treatment, and carefully monitor changes in mood and daytime sleepiness throughout the intervention. PMID- 23820832 TI - Late-onset agoraphobia: general population incidence and evidence for a clinical subtype. AB - OBJECTIVE: The purpose of this study was to estimate the general population incidence of late-life agoraphobia and to define its clinical characteristics and risk factors. METHOD: A total of 1,968 persons >=65 years old were randomly recruited from the electoral rolls of the district of Montpellier, France. Prevalent and incident agoraphobia diagnosed with a standardized psychiatric examination and validated by a clinical panel were assessed at baseline and over a 4-year follow-up. RESULTS: The 1-month baseline prevalence of agoraphobia was estimated to be 10.4%. Among persons with agoraphobia, 10.9% reported having their first episode at age 65 or above. During the 4-year follow-up, 11.2% of participants without agoraphobia at baseline had a first episode, resulting in an incidence rate of 32 per 1,000 person-years. These 132 incident late-onset cases were associated with higher incidence rates of anxiety disorders and suicidal ideation. Of the incident cases, only two were characterized by past or concurrent panic attacks, a rate that was not significantly different from that of the noncase group. The principal baseline risk factors for incident cases, derived from a multivariate model incorporating all significant risk factors, were younger age at onset (odds ratio=0.94, 95% CI=0.90-0.99), poorer visuospatial memory performance (odds ratio=1.60, 95% CI=1.02-2.49), severe depression (odds ratio=2.62, 95% CI=1.34-5.10), and trait anxiety (odds ratio=1.73, 95% CI=1.03-2.90). No significant association was found with cardiac pathologies. CONCLUSIONS: Agoraphobia has a high prevalence in the elderly, and unlike cases in younger populations, late-onset cases are not more common in women and are not associated with panic attacks, suggesting a late-life subtype. Severe depression, trait anxiety, and poor visuospatial memory are the principal risk factors for late-onset agoraphobia. PMID- 23820833 TI - Key issues relevant to the efficacy of behavioral treatment for ADHD. PMID- 23820834 TI - Response to Chronis-Tuscano et al. and Arns and Strehl. PMID- 23820835 TI - Whole-body hyperthermia for the treatment of major depression: associations with thermoregulatory cooling. PMID- 23820836 TI - Suspected dronabinol withdrawal in an elderly cannabis-naive medically ill patient. PMID- 23820837 TI - SLC6A15 rs1545843 and depression: implications from brain imaging data. PMID- 23820843 TI - Evidence for efficacy of neurofeedback in ADHD? PMID- 23820845 TI - An insight into the hepatocellular death induced by amphetamines, individually and in combination: the involvement of necrosis and apoptosis. AB - The liver is a vulnerable target for amphetamine toxicity, but the mechanisms involved in the drug's hepatotoxicity remain poorly understood. The purpose of the current research was to characterize the mode of death elicited by four amphetamines and to evaluate whether their combination triggered similar mechanisms in immortalized human HepG2 cells. The obtained data revealed a time- and temperature-dependent mortality of HepG2 cells exposed to 3,4 methylenedioxymethamphetamine (MDMA, ecstasy; 1.3 mM), methamphetamine (3 mM), 4 methylthioamphetamine (0.5 mM) and D-amphetamine (1.7 mM), alone or combined (1.6 mM mixture). At physiological temperature (37 degrees C), 24-h exposures caused HepG2 death preferentially by apoptosis, while a rise to 40.5 degrees C favoured necrosis. ATP levels remained unaltered when the drugs where tested at normothermia, but incubation at 40.5 degrees C provoked marked ATP depletion for all treatments. Further investigations on the apoptotic mechanisms triggered by the drugs (alone or combined) showed a decline in BCL-2 and BCL- XL mRNA levels, with concurrent upregulation of BAX, BIM, PUMA and BID genes. Elevation of Bax, cleaved Bid, Puma, Bak and Bim protein levels was also seen. To the best of our knowledge, Puma, Bim and Bak have never been linked with the toxicity induced by amphetamines. Time-dependent caspase-3/-7 activation, but not mitochondrial membrane potential (?psim) disruption, also mediated amphetamine-induced apoptosis. The cell dismantling was confirmed by poly(ADP-ribose)polymerase proteolysis. Overall, for all evaluated parameters, no relevant differences were detected between individual amphetamines and the mixture (all tested at equieffective cytotoxic concentrations), suggesting that the mode of action of the amphetamines in combination does not deviate from the mode of action of the drugs individually, when eliciting HepG2 cell death. PMID- 23820846 TI - Human skin in vitro permeation of bentazon and isoproturon formulations with or without protective clothing suit. AB - Skin exposures to chemicals may lead, through percutaneous permeation, to a significant increase in systemic circulation. Skin is the primary route of entry during some occupational activities, especially in agriculture. To reduce skin exposures, the use of personal protective equipment (PPE) is recommended. PPE efficiency is characterized as the time until products permeate through material (lag time, Tlag). Both skin and PPE permeations are assessed using similar in vitro methods; the diffusion cell system. Flow-through diffusion cells were used in this study to assess the permeation of two herbicides, bentazon and isoproturon, as well as four related commercial formulations (Basagran((r)), Basamais((r)), Arelon((r)) and Matara((r))). Permeation was measured through fresh excised human skin, protective clothing suits (suits) (Microchem((r)) 3000, AgriSafe Pro((r)), Proshield((r)) and Microgard((r)) 2000 Plus Green), and a combination of skin and suits. Both herbicides, tested by itself or as an active ingredient in formulations, permeated readily through human skin and tested suits (Tlag < 2 h). High permeation coefficients were obtained regardless of formulations or tested membranes, except for Microchem((r)) 3000. Short Tlag, were observed even when skin was covered with suits, except for Microchem((r)) 3000. Kp values tended to decrease when suits covered the skin (except when Arelon((r)) was applied to skin covered with AgriSafe Pro and Microgard((r)) 2000), suggesting that Tlag alone is insufficient in characterizing suits. To better estimate human skin permeations, in vitro experiments should not only use human skin but also consider the intended use of the suit, i.e., the active ingredient concentrations and type of formulations, which significantly affect skin permeation. PMID- 23820847 TI - Ecological status of a Margaritifera margaritifera (Linnaeus, 1758) population at the southern edge of its distribution (River Paiva, Portugal). AB - An important population of the critically endangered pearl mussel Margaritifera margaritifera (Linnaeus, 1758) was surveyed at the edge of its southern distribution (River Paiva, Portugal). Although an earlier study suggested that this population had a very low number of individuals (<500), a narrow distribution, and was mainly comprised by old specimens our data contradict these findings. Our assessment estimated a population with probably more than 5,000 individuals distributed across 80 km of the river length. From the 32 sites surveyed, 19 contained M. margaritifera with higher abundances verified in the middle and upper parts of the river (a maximum of 78 ind. per 100 m of river stretch was recorded). The pearl mussels showed a clear preference for areas near the banks, in shallow water, sandier and gravel sediments, and a high degree of riparian vegetation cover. The population structure was skewed with a very high percentage of large (and old) animals but 3.7 % of the individuals collected were juveniles (<60 mm in length); therefore, this population can be considered functional. Environmental characterization indicated that this river is still in excellent or good condition although some areas showed deterioration due to discharge of domestic effluents. The main conservation requirements of M. margaritifera in the River Paiva include maintaining the water quality (and if possible stopping the discharge of domestic effluents), increasing riparian vegetation cover, removing several weirs to increase connectivity, and increasing trout density. PMID- 23820850 TI - Theoretical study of photophysical properties of 1,4-dihydropyrrolo[3,2-b]pyrrole cored branched molecules with thienylenevinylene arms toward broad absorption spectra for solar cells. AB - A series of oligo(thienylenevinylene) derivatives with 1,4-dihydropyrrolo[3,2 b]pyrrole as core has been investigated at the PBE0/6-31G(d) and the TD-PBE0/6 31+G(d,p) levels to design materials with high performances such as broad absorption spectra and higher balance transfer property. The results show that position and amount of arm affect the electronic density contours of frontier molecular orbitals significantly. The molecule with four arms owns the narrowest energy gap and the largest maximum absorption wavelength, and the molecule with two arms in positions a and c has the broadest absorption region among the designed molecules. Calculated reorganization energies of the designed molecules indicate that the molecules with two arms can be good potential ambipolar transport materials under proper operating conditions. PMID- 23820851 TI - Medial femoral condyle fracture as a complication of antegrade intramedullary nailing. AB - A 49-year-old man suffered a closed oblique fracture of the middle third of his left femur. Closed reduction and internal fixation by intramedullary (IM) nailing were performed. Per-operative fluoroscopic imaging and initial postoperative X rays were judged normal and the patient followed the usual rehabilitation protocol. At 3-month follow-up the patient still demonstrated poor knee function and pain. A plain X-ray and a CT scan of the left knee revealed a displaced fracture of the medial femoral condyle. Analysis of the postoperative imaging suggests that the fracture occurred during the insertion of the IM nail. The nail possibly hit the Steinmann traction pin in the distal femur causing the medial condyle fracture. The patient was reoperated; open reduction and internal plate and screw fixation were performed with satisfactory clinical progress postoperatively. The description and illustration of this case is intended to make trauma surgeons aware of this rare but serious complication of IM femoral nailing. PMID- 23820848 TI - Long-term exposure to black carbon and carotid intima-media thickness: the normative aging study. AB - BACKGROUND: Evidence suggests that air pollution is associated with atherosclerosis and that traffic-related particles are a particularly important contributor to the association. OBJECTIVES: We investigated the association between long-term exposure to black carbon, a correlate of traffic particles, and intima-media thickness of the common carotid artery (CIMT) in elderly men residing in the greater Boston, Massachusetts, area. METHODS: We estimated 1-year average exposures to black carbon at the home addresses of Normative Aging Study participants before their first CIMT measurement. The association between estimated black carbon levels and CIMT was estimated using mixed effects models to account for repeated outcome measures. In secondary analyses, we examined whether living close to a major road or average daily traffic within 100 m of residence was associated with CIMT. RESULTS: There were 380 participants (97% self-reported white race) with an initial visit between 2004 and 2008. Two or three follow-up CIMT measurements 1.5 years apart were available for 340 (89%) and 260 (68%) men, respectively. At first examination, the average +/- SD age was 76 +/- 6.4 years and the mean +/- SD CIMT was 0.99 +/- 0.18 mm. A one interquartile range increase in 1-year average black carbon (0.26 ug/m3) was associated with a 1.1% higher CIMT (95% CI: 0.4, 1.7%) based on a fully adjusted model. CONCLUSIONS: Annual mean black carbon concentration based on spatially resolved exposure estimates was associated with CIMT in a population of elderly men. These findings support an association between long-term air pollution exposure and atherosclerosis. PMID- 23820852 TI - Operative versus non-operative treatment for two-part surgical neck fractures of the proximal humerus. AB - INTRODUCTION: Aim of this study was to evaluate outcomes of operative as compared to conserveative treatment for two-part humerus fractures at the surgical neck. METHODS: Data from a prospective multi-centre cohort study on four treatment options (conservative treatment and three implants, i.e. LPHP, PHILOS and PHN) for proximal humerus fractures were evaluated in this post hoc analysis. All patients with two-part fractures of the surgical neck (AO types A2, n = 54 and A3, n = 110) were identified and included for the analysis. All operatively treated patients were gathered and compared to those receiving conservative treatment. Primary outcome parameters were pain, range of motion and absolute and relative Constant scores at 3, 6 and 12 months following injury and coronal plane alignment at 12 months. RESULTS: Operative (n = 133) and non-operative (n = 31) groups were comparable with regard to all parameters assessed including mean age (62.9 vs. 65.6, P = 0.479), gender (27 vs. 29 % male, P = 0.826) and fracture distribution (65 vs. 77 % A3 type, P = 0.207). 26 of the 31 conservatively treated and 103 of the 133 operatively treated patients (84 and 77 %, respectively) were available for final follow-up. There was a continuous improvement for all outcome parameters in both treatment groups (P < 0.001). Operative treatment resulted in a more effective reduction of pain at 3 months (51 vs. 76 % reporting pain at fracture site, P = 0.03) and a reduction of coronal plane malalignment. Both range of motion and Constant scores were, however, comparable in both groups at all follow-up visits. Relative and absolute Constant scores were generally excellent at final follow-up (74 vs. 74, P = 0.528 and 89 vs. 91, P = 0.494, respectively). CONCLUSIONS: Both non-operative treatment and operative treatment using modern implants (LPHP, PHILOS and PHN) can be considered safe and effective treatment options for two-part fractures of the proximal humerus. Operative treatment may result in better range of motion and reduced pain in the early postoperative course of treatment. PMID- 23820854 TI - Sclerostin, an osteocytes-derived bone-forming inhibitor. AB - Sclerostin is a recently identified glycoprotein expressed and synthesized by osteocytes. It is a powerful inhibitor of osteoblasts proliferation and differentiation. Sclerostin inhibits the Wnt signaling, the main trigger of osteoblasts activity. Osteocytes on response to a mechanical loading decrease the synthesis of sclerostin enabling in osteoblasts the Wnt signaling and promote their bone-forming activity. This explains why mechanical loading induces bone formation. Monoclonal antibodies directed against sclerostin reverses sclerostin induced bone catabolic effect and are promising tool in prevention and treatment of osteoporosis in human. PMID- 23820853 TI - Preoperative radiographic and histopathologic evaluation of central chondrosarcoma. AB - BACKGROUND: Distinguishing grade 1 chondrosarcoma from grade 2 chondrosarcoma is critical both for planning the surgical procedure and for predicting the outcome. We aimed to review the preoperative radiographic and histologic findings, and to evaluate the reliability of preoperative grading. METHODS: We retrospectively reviewed the medical records of 17 patients diagnosed with central chondrosarcoma at our institution between 1996 and 2011. In these cases, we compared the preoperative and postoperative histologic grades, and evaluated the reliability of the preoperative histologic grading. We also assessed the preoperative radiographic findings obtained using plain radiography, computed tomography (CT), and magnetic resonance imaging (MRI). RESULTS: Preoperative histologic grade was 1 in 12 patients, 2 in 4 patients, and 3 in 1 patient. However, 6 of the 12 cases classified as grade 1 before surgery were re-classified as grade 2 postoperatively. In the radiographic evaluation, grade 1 was suspected by the presence of a ring-and-arc pattern of calcification on plain radiography and CT and entrapped fat and ring-and-arc enhancement on MRI. Grades 2 and 3 were suspected by the absence of calcification and the presence of cortical penetration and endosteal scalloping on plain radiography and CT, as well as soft tissue mass formation on MRI. CONCLUSION: Although the combination of radiographic interpretation and histologic findings may improve the accuracy of preoperative grading in chondrosarcoma, the establishment of a standard evaluation system with the histologic and radiographic findings and/or the development of new biologic markers are necessary for preoperative discrimination of low-grade chondrosarcoma from high-grade chondrosarcoma. PMID- 23820855 TI - Expression of DNMTs and genomic DNA methylation in gastric signet ring cell carcinoma. AB - The aim of the present study was to investigate the protein expression of DNA methyltransferases (DNMTs) and genomic DNA methylation status of genomes in gastric signet ring cell carcinoma (SRC). Immunohistochemistry was performed to analyze DNMT expression and methylated DNA immunoprecipitation microarray (MeDIP chip) and MeDIP quantitative real-time PCR (MeDIP-qPCR) were performed to analyze the genomic DNA methylation status in gastric SRC tissue. An increase in DNMT1 and decrease in DNMT3A expression in SRC tissue was observed compared with matched non-cancerous tissue. However, expression of other DNMTs, DNMT2, DNMT3B and DNMT3L, was not found to differ significantly between carcinoma and control. The MeDIP-chip assay revealed that methylation of gene promoters and CpG islands in SRC was higher than those in matched control tissue. However, MeDIP-qPCR analysis demonstrated that specific tumor-related genes, including ABL2, FGF18, TRAF2, EGFL7 and RAB33A were aberrantly hypomethylated in SRC tissue. Results of the current study indicate that gastric SRC may produce complex patterns of aberrant DNA methylation and DNMT expression. PMID- 23820856 TI - Synergy, redundancy, and multivariate information measures: an experimentalist's perspective. AB - Information theory has long been used to quantify interactions between two variables. With the rise of complex systems research, multivariate information measures have been increasingly used to investigate interactions between groups of three or more variables, often with an emphasis on so called synergistic and redundant interactions. While bivariate information measures are commonly agreed upon, the multivariate information measures in use today have been developed by many different groups, and differ in subtle, yet significant ways. Here, we will review these multivariate information measures with special emphasis paid to their relationship to synergy and redundancy, as well as examine the differences between these measures by applying them to several simple model systems. In addition to these systems, we will illustrate the usefulness of the information measures by analyzing neural spiking data from a dissociated culture through early stages of its development. Our aim is that this work will aid other researchers as they seek the best multivariate information measure for their specific research goals and system. Finally, we have made software available online which allows the user to calculate all of the information measures discussed within this paper. PMID- 23820857 TI - Switching mechanisms and bout times in a pair of reciprocally inhibitory neurons. AB - Within the appropriate parameter regime, a deterministic model of a pair of mutually inhibitory neurons receiving excitatory driving currents exhibits bistability-each of the two stable states corresponds to one neuron being active and the other being quiescent. The presence of noise in the driving currents results in a system that randomly switches back and forth between these two states, causing alternating bouts of spiking activity. In this work, we examine the random bout durations of the two neurons and dependence on system parameters. We find that bout durations of each neuron are exponentially distributed, with changes in system parameters altering only the mean of the distribution. Synaptic inhibition independently controls the bout durations of the two neurons-the mean bout time of a neuron is a function of efferent (or outgoing) inhibition, and is independent of afferent (or incoming) inhibition. Furthermore, we find that the mean bout time of a neuron exhibits a critical dependence on the time course (rather than amplitude) of efferent inhibition-mean bout time of a neuron grows exponentially with the time course of efferent inhibition, and the growth rate of this exponential function depends only on the excitatory driving current to that neuron (and not on any other system parameters). We discuss the relevance of our results to the regulation of sleep-wake cycling by medullary and pontine structures within the brain. PMID- 23820858 TI - A geometric understanding of how fast activating potassium channels promote bursting in pituitary cells. AB - The electrical activity of endocrine pituitary cells is mediated by a plethora of ionic currents and establishing the role of a single channel type is difficult. Experimental observations have shown however that fast-activating voltage- and calcium-dependent potassium (BK) current tends to promote bursting in pituitary cells. This burst promoting effect requires fast activation of the BK current, otherwise it is inhibitory to bursting. In this work, we analyze a pituitary cell model in order to answer the question of why the BK activation must be fast to promote bursting. We also examine how the interplay between the activation rate and conductance of the BK current shapes the bursting activity. We use the multiple timescale structure of the model to our advantage and employ geometric singular perturbation theory to demonstrate the origin of the bursting behaviour. In particular, we show that the bursting can arise from either canard dynamics or slow passage through a dynamic Hopf bifurcation. We then compare our theoretical predictions with experimental data using the dynamic clamp technique and find that the data is consistent with a burst mechanism due to a slow passage through a Hopf. PMID- 23820859 TI - Paediatric rheumatology: Juvenile idiopathic arthritis--are biologic agents effective for pain? AB - Biologic medications are highly efficacious in juvenile idiopathic arthritis. However, a recent study found that a subgroup of children treated with anti-TNF agents had persistent pain despite good disease control. This finding highlights the importance of monitoring pain symptoms during treatment with modern DMARDs. PMID- 23820861 TI - Therapy: Ustekinumab therapeutic effects--more than skin deep. PMID- 23820860 TI - Vaccinations in juvenile chronic inflammatory diseases: an update. AB - Vaccination is a powerful tool to reduce the burden of infectious diseases in paediatric patients with chronic rheumatic diseases. Live attenuated vaccines are not recommended for profoundly immunosuppressed patients, but nonlive vaccines have adequate safety and efficacy profiles in the few (admittedly underpowered) studies published to date. No severe vaccine-specific or disease-specific adverse events have been observed in patients with juvenile idiopathic arthritis (JIA) or childhood-onset systemic lupus erythematosus (SLE) who have been vaccinated with live or nonlive agents. The immune response to live vaccines is variable in these patients but generally adequate, despite concomitant use of immunosuppressive and biologic agents. The proposal that onset of autoimmune rheumatic diseases could be induced by vaccination is controversial and primarily based on case reports; however, patients with mevalonate kinase deficiency can experience febrile attacks after immunizations. Adequately powered studies of live and nonlive vaccination in patients with paediatric rheumatic diseases are necessary to clarify safety and efficacy issues. This narrative Review discusses vaccination in patients with JIA, childhood-onset SLE, juvenile dermatomyositis, juvenile systemic sclerosis, primary vasculitis and autoinflammatory syndromes. Vaccine safety, short-term and long-term changes in disease parameters, and the immunogenicity and influence of immunosuppressive agents are outlined for each combination of disease and vaccine. PMID- 23820862 TI - Culture, science and the changing nature of fibromyalgia. AB - Fibromyalgia is a common but contested illness. Its definition and content have changed repeatedly in the 110 years of its existence. The most important change was the requirement for multiple tender points and extensive pain that arose in the 1980s, features that were not required previously. By 2010, a second shift occurred that excluded tender points, allowed less extensive pain, and placed reliance on patient-reported somatic symptoms and cognitive difficulties ('fibro fog') that had never been part of past definitions or content. Fibromyalgia is closely allied with and often indistinguishable from neurasthenia, a disorder of the late 19th and early 20th centuries that lost favour when it was perceived as being a psychological illness. Fibromyalgia's status as a 'real disease', rather than a psychocultural illness, is buttressed by social forces that include support from official criteria, patient and professional organizations, pharmaceutical companies, disability access, and the legal and academic communities. PMID- 23820863 TI - Oral contraceptives and women's sexuality: Commentary on Roberts, Cobey, Klapilova, and Havlicek (2013). PMID- 23820864 TI - Redesigning fraternal birth order studies from top to bottom. PMID- 23820865 TI - Realistic loophole-free Bell test with atom-photon entanglement. AB - The establishment of nonlocal correlations, guaranteed through the violation of a Bell inequality, is not only important from a fundamental point of view but constitutes the basis for device-independent quantum information technologies. Although several nonlocality tests have been conducted so far, all of them suffered from either locality or detection loopholes. Among the proposals for overcoming these problems are the use of atom-photon entanglement and hybrid photonic measurements (for example, photodetection and homodyning). Recent studies have suggested that the use of atom-photon entanglement can lead to Bell inequality violations with moderate transmission and detection efficiencies. Here we combine these ideas and propose an experimental setup realizing a simple atom photon entangled state that can be used to obtain nonlocality when considering realistic experimental parameters including detection efficiencies and losses due to required propagation distances. PMID- 23820866 TI - Characterization of damaged skin by impedance spectroscopy: chemical damage by dimethyl sulfoxide. AB - PURPOSE: To relate changes in the electrochemical impedance spectra to the progression and mechanism of skin damage arising from exposure to dimethyl sulfoxide (DMSO). METHODS: Electrochemical impedance spectra measured before and after human cadaver skin was treated with neat DMSO or phosphate buffered saline (control) for 1 h or less were compared with electrical circuit models representing two contrasting theories describing the progression of DMSO damage. Flux of a model lipophilic compound (p-chloronitrobenzene) was also measured. RESULTS: The impedance spectra collected before and after 1 h treatment with DMSO were consistent with a single circuit model; whereas, the spectra collected after DMSO exposure for 0.25 h were consistent with the model circuits observed before and after DMSO treatment for 1 h combined in series. DMSO treatments did not significantly change the flux of p-chloronitrobenzene compared to control. CONCLUSIONS: Impedance measurements of human skin exposed to DMSO for less than about 0.5 h were consistent with the presence of two layers: one damaged irreversibly and one unchanged. The thickness of the damaged layer increased proportional to the square-root of treatment time until about 0.5 h, when DMSO affected the entire stratum corneum. Irreversible DMSO damage altered the lipophilic permeation pathway minimally. PMID- 23820867 TI - Commentary on "Uttley L, Campbell F, Rhodes M et al. Minimally invasive esophagectomy versus open surgery: is there an advantage? Surg Endosc 2013;27(3):724-731". PMID- 23820869 TI - Re-TEVAR for complications after blunt aortic traumatic injury stenting. AB - We report an endovascular approach that was used to treat two patients with previous thoracic aortic repair or endovascular repair (TEVAR) for blunt thoracic aortic injury. The first patient was a 38-year-old man who presented with distal intragraft thrombosis 24 months after TEVAR. The second patient, a 32-year-old man, developed a symptomatic distal device collapse at 39th month follow-up, associated with buttock claudication. Both patients were offered an endograft relining, complicated in the first case by distal embolization. PMID- 23820868 TI - Improved air quality and attenuated lung function decline: modification by obesity in the SAPALDIA cohort. AB - BACKGROUND: Air pollution and obesity are hypothesized to contribute to accelerated decline in lung function with age through their inflammatory properties. OBJECTIVE: We investigated whether the previously reported association between improved air quality and lung health in the population-based SAPALDIA cohort is modified by obesity. METHODS: We used adjusted mixed-model analyses to estimate the association of average body mass index (BMI) and changes in particulate matter with aerodynamic diameter <= 10 um (PM10; DeltaPM10) with lung function decline over a 10-year follow-up period. RESULTS: Lung function data and complete information were available for 4,664 participants. Age-related declines in lung function among participants with high average BMI were more rapid for FVC (forced vital capacity), but slower for FEV1/FVC (forced expiratory volume in 1 sec/FVC) and FEF25-75 (forced expiratory flow at 25-75%) than declines among those with low or normal average BMI. Improved air quality was associated with attenuated reductions in FEV1/FVC, FEF25-75, and FEF25-75/FVC over time among low- and normal-BMI participants, but not overweight or obese participants. The attenuation was most pronounced for DeltaFEF25-75/FVC (30% and 22% attenuation in association with a 10-MUg/m3 decrease in PM10 among low- and normal-weight participants, respectively.) CONCLUSION: Our results point to the importance of considering health effects of air pollution exposure and obesity in parallel. Further research must address the mechanisms underlying the observed interaction. PMID- 23820870 TI - Loop snare removal of pigtail catheter fragment from the pleural space. PMID- 23820872 TI - PNA-NLS conjugates as single-molecular activators of target sites in double stranded DNA for site-selective scission. AB - Artificial DNA cutters have been developed by us in our previous studies by combining two strands of pseudo-complementary peptide nucleic acid (pcPNA) with Ce(IV)-EDTA-promoted hydrolysis. The pcPNAs have two modified nucleobases (2,6 diaminopurine and 2-thiouracil) instead of conventional A and T, and can invade double-stranded DNA to activate the target site for the scission. This system has been applied to site-selective scissions of plasmid, lambda-phage, E. coli genomic DNA, and human genomic DNA. Here, we have reported a still simpler and more convenient DNA cutter obtained by conjugating peptide nucleic acid (PNA) with a nuclear localization signal (NLS) peptide. This new DNA cutter requires only one PNA strand (instead of two) bearing conventional (non-pseudo complementary) nucleobases. This PNA-NLS conjugate effectively activated the target site in double-stranded DNA and induced site-selective scission by Ce(IV) EDTA. The complex formation between the conjugate and DNA was concretely evidenced by spectroscopic results based on time-resolved fluorescence. The target scission site of this new system was straightforwardly determined by the Watson-Crick base pairing rule, and mismatched sequences were clearly discriminated. Importantly, even highly GC-rich regions, which are difficult to be targeted by a previous strategy using pcPNA, were successfully targeted. All these features of the present DNA cutter make it promising for various future applications. PMID- 23820871 TI - Combined gemcitabine and CHK1 inhibitor treatment induces apoptosis resistance in cancer stem cell-like cells enriched with tumor spheroids from a non-small cell lung cancer cell line. AB - Evaluating the effects of novel drugs on appropriate tumor models has become crucial for developing more effective therapies that target highly tumorigenic and drug-resistant cancer stem cell (CSC) populations. In this study, we demonstrate that a subset of cancer cells with CSC properties may be enriched into tumor spheroids under stem cell conditions from a non-small cell lung cancer cell line. Treating these CSC-like cells with gemcitabine alone and a combination of gemcitabine and the novel CHK1 inhibitor PF-00477736 revealed that PF-00477736 enhances the anti-proliferative effect of gemcitabine against both the parental and the CSC-like cell populations. However, the CSC-like cells exhibited resistance to gemcitabine-induced apoptosis. Collectively, the spheroid-forming CSC-like cells may serve as a model system for understanding the mechanism underlying the drug resistance of CSCs and for guiding the development of better therapies that can inhibit tumor growth and eradicate CSCs. PMID- 23820873 TI - The dual H3/4R antagonist thioperamide does not fully mimic the effects of the 'standard' H4R antagonist JNJ 7777120 in experimental murine asthma. AB - Histamine is detected in high concentrations in the airways during an allergic asthma response. In a murine model of allergic asthma, the histamine H4 receptor (H4R)-selective ligand JNJ 7777120 reduces asthma-like symptoms. A sole antagonistic function of JNJ 7777120 at the murine H4R has, however, been questioned in the literature. Therefore, in the present study, we aimed at analyzing the effects of JNJ 7777120 in comparison to that of the H3/4R-selective antagonist thioperamide. Experimental murine asthma was induced by sensitization and provocation of BALB/c mice with ovalbumine (OVA). JNJ 7777120, thioperamide, or JNJ 5207852, an H3R-selective antagonist which was used to dissect H3R- and H4R-mediated activities of thioperamide, were injected subcutaneously during sensitization and effects were analyzed after provocation. Pharmacokinetic analyses revealed shortest t1/2 values in both plasma and lung tissue and lowest maximal concentration in lung tissue for JNJ 7777120 in comparison to thioperamide and JNJ 5207852. Nevertheless, JNJ 7777120 reduced serum titers of allergen-specific (anti-OVA) IgE, inflammatory infiltrations in lung tissue, and eosinophilia in bronchoalveolar lavage fluid. In contrast, thioperamide reduced only eosinophilia in bronchoalveolar lavage fluid, while anti-OVA IgE concentrations and lung infiltrations remained unaffected. JNJ 5207852 had no effect on these parameters. JNJ 7777120 provides beneficial effects in experimental murine asthma, which, however, could only partially be mimicked by thioperamide, despite more favorable pharmacokinetics. Thus, whether these effects of JNJ 7777120 are entirely attributable to an antagonistic activity at the murine H4R or whether an agonistic activity is also involved has to be reconsidered. PMID- 23820874 TI - Young women's experiences with complementary therapies during cancer described through illness blogs. AB - Many young women with cancer have a high symptom burden and negative psychosocial consequences as a result of their disease. To offset some of these experiences, a growing number of young women with cancer are writing about their experience with complementary therapies through online illness blogs. The purpose of this qualitative study was to examine descriptions of complementary therapy use among young women (diagnosed between 20 and 39 years of age) who maintained an online cancer blog. Women's narratives describe several themes of the experience of using complementary therapies including awakening, new identities (that incorporate loss), the good stuff, and release. Online illness blogs allow researchers to understand the complete experience of the patient through personal accounts and substantially contributes to the body of knowledge surrounding cancer in young adulthood and complementary therapy use. PMID- 23820875 TI - Correlation among lesion level, muscle strength and hand function in cervical spinal cord injury. AB - BACKGROUND: Few epidemiological data are available regarding distribution of cervical spinal cord injury with respect to level of lesion and the relationship between the neurological level of lesion and residual hand function. Such data are important to evaluate the relevance of innovative therapeutic approaches, and to plan prospective clinical trials. AIM: To examine the frequency distribution of neurological level of lesion and to investigate the correlation among level, active muscles in the arm and the relation to hand function. DESIGN: Cross sectional study. SETTING: Two spinal units in the Lombardy region of Italy. POPULATION: Patients with cervical spinal cord lesion. METHODS: Consecutive records, taken from an 8-year interval of admission to either spinal unit, of patients with a cervical spinal cord lesion were examined, and individuals with a C5 to C7 neurological level of lesion were called in for clinical examination. The arm muscles were evaluated according to the International Classification for Surgery of the Hand in Tetraplegia (ICSHT), and hand function was tested with the Action Research Arm Test (ARAT). A correlation analysis was made of the ICSHT, ARAT and neurological level of lesion. RESULTS: In 253 clinical records we found the most frequent lesions to be C5 (21%), C6 (31%) and C7 (21%); 76 of these patients were enrolled for a clinical evaluation. Both ICSHT (Spearmans' rho=0.6; P<0.001) and ARAT (rho=0.2; P<0.05) were poorly correlated with the neurological level of lesion. ARAT was also poorly correlated with the ICSHT group (rho=0.5; P<0.001). CONCLUSION: Our study suggests that 73% of tetraplegic subjects have a neurological level of lesion between C5 and C7, and that it is not possible to accurately predict residual hand function from the level of lesion obtained from the clinical records, or from an ICSHT evaluation. CLINICAL REHABILITATION IMPACT: The results of our work show that a large number of patients with cervical spinal cord lesion have impaired hand function. Residual hand function must be assessed with specific functional tests; it cannot be derived simply from a lesion's neurological level. PMID- 23820876 TI - Abnormal lactate levels in patients with polymyositis and dermatomyositis: the benefits of a specific rehabilitative program. AB - BACKGROUND: Polymyositis (PM) and Dermatomyositis (DM) are chronic, inflammatory and autoimmune skeletal muscle disorders characterized by reduced muscle strength, fatigue and myalgia. While inflammation causes muscle damage in the early phase, metabolic alterations such as an impairment of oxidative metabolism seem to be responsible for the disability in the chronic phase of the disease. AIM: To assess muscle oxidative efficiency and to test the effect of aerobic training in a group of PM/DM patients. DESIGN: A case-control study and a within group comparison. SETTING. Outpatients of the Unit of Neurorehabilitation of the University Hospital of Pisa. POPULATION: 20 patients with myositis (15 PM and 5 DM) and 15 healthy subjects as a control group. METHODS: The test consisted of an incremental, sub-maximal aerobic exercise on a treadmill; haematic lactate was assessed at rest and after 1', 5', 10' and 30' minutes from the end of the exercise. A within-group comparison was conducted on four of the PM patients (P group). They were subjected to six weeks aerobic training. Lactate curve and functional tests were assessed before and after the treatment. RESULTS: A precocious fatigability and significantly higher values of lactate at rest and after the exercise were observed in patients. In the P group mean lactate levels were significantly decreased after the treatment and an improvement of muscle performance was observed. CONCLUSION: Abnormal blood lactate levels suggested an impaired muscle oxidative efficiency in PM/DM patients. A specific aerobic training program reduced lactate levels and relieved fatigue symptoms in a within group of four of the PM patients. CLINICAL REHABILITATION IMPACT: Such a specific aerobic training program could be introduced in everyday practice for the rehabilitative treatment of PM/DM patients. PMID- 23820877 TI - Effect of Cheneau brace on postural balance in adolescent idiopathic scoliosis: a pilot study. AB - BACKGROUND: Adolescents with idiopathic scoliosis show a postural instability compared with healthy subjects. DESIGN TYPE. Case control study. SETTING: Outpatient clinic of the Complex Operative Unit of Physical Medicine and Rehabilitation of Policlinico Umberto I Hospital. POPULATION: Thirteen patients (11 females and 2 males, mean age 13.3+/-1.7 years, mean Cobb angle 32+/-9, median Risser sign 2) and thirteen healthy adolescents (8 females and 5 males, mean age: 13.0+/-1.6 years) as age-matched control group were enrolled. METHODS: Postural ability of the participants was assessed with stabilometry (under open eyes and closed eyes conditions), computing sway length, sway ellipse area, and sway velocities. Static and dynamic baropodometry (open eyes only) was used to measure the limb load, and to compute: walking speed, step length, step cadence and step width. The symmetry of left and right limb values was also investigated. RESULTS: Patient's group was characterized by significantly higher postural instability than control group (P<0.05) that decreased with brace in terms of limb load symmetry (-12% in eyes open condition), sway length (-12%), velocity in anteroposterior (-16%) and latero-lateral directions (-10%). Significant correlations were found between the changes occurred when wearing Cheneau brace on load symmetry during standing and those on symmetry of gait (R>0.5, P<0.05). CONCLUSION AND CLINICAL REHABILITATION IMPACT: Our results show slight changes in terms of posture when wearing Cheneau brace according with the severity of pathology and significantly affecting gait parameters. For these reasons, use of postural balance evaluation should be objectively used to verify the efficacy of Cheneau brace on body functioning of adolescents with idiopathic scoliosis. PMID- 23820878 TI - Developing comprehensive and Brief ICF core sets for morbid obesity for disability assessment in Taiwan: a preliminary study. AB - BACKGROUND: The International Classification of Functioning, Disability, and Health (ICF) provides a framework for measuring functioning and disability based on a biopsychosocial model. AIM: The aim of this study was to develop comprehensive and brief ICF core sets for morbid obesity for disability assessment in Taiwan. DESIGN: Observational SETTING: Other POPULATION: Twenty nine multidisciplinary experts of ICF METHODS: The questionnaire contained 112 obesity-relevant and second-level ICF categories. Using a 5-point Likert scale, the participants rated the significance of the effects of each category on the heath status of people with obesity. Correlation between an individual's score and the average score of the group indicated consensus. The categories were selected for the comprehensive core set for obesity if more than 50% of the experts rated them as "important" in the third round of the Delphi exercise, and for the brief core set if more than 80% of the experts rated them "very important." RESULTS: Twenty-nine experts participated in the study. These included 18 physicians, 4 dieticians, 3 physical therapists, 2 nurses, and 2 ICF experts. The comprehensive core set for morbid obesity contained 61 categories. Of these, 26 categories were from the component body function, 8 were from body structure, 18 were from activities and participation, and 9 were from environmental factors. The brief core set for obesity disability contained 29 categories. Of these, 19 categories were from the component body function, 3 were from body structure, 6 were from activities and participation, and one was from environmental factors. The comprehensive and brief ICF core sets provide comprehensive information on the health effects of morbid obesity and concise information for clinical practice. CONCLUSION: Comprehensive and brief core sets were created after three rounds of Delphi technique. Further validation study of these core sets by applying to patients with morbid obesity is needed. CLINICAL REHABILITAITON IMPACT: The comprehensive ICF core set for morbid obesity provides comprehensive information on the health effects of morbid obesity; the brief core set can provide concise information for clinical practice. PMID- 23820879 TI - Effects of a multimodal exercise program on balance, functional mobility and fall risk in older adults with cognitive impairment: a randomized controlled single blind study. AB - BACKGROUND: Exercise programs have important role in prevention of falls, but to date, there are conflicting findings about the effects of exercise programs on balance, functional performance and fall risk among cognitively impaired older adults. AIM. To investigate the effects of a multimodal exercise program on static and dynamic balance, and risk of falls in older adults with mild or moderate cognitive impairment. DESIGN: A randomized controlled study. SETTING: A long-term care institute. POPULATION: Cognitively impaired individuals aged over 60 years. METHODS: Eighty-six participants were randomized to an exercise group providing multimodal exercise program for 12 months or a control group which did not participate in any exercise program. The Performance Oriented Mobility Assessment scale, Timed Up and Go test, and incidence of falls were measured at baseline, at 6 months and at 12 months. RESULTS: There was a significant improvement in balance-related items of Performance Oriented Mobility Assessment scale in the exercise group both at 6 month and 12 month (P<0.0001, P=0.002; respectively). There was no statistically significant increase in gait-related items of Performance Oriented Mobility Assessment scale after the first 6-month treatment period (P=0.210), but in the second 6-month treatment period the POMA-G score improved significantly (P=0.001). There was no significant difference between groups regarding falls. CONCLUSION: Our results confirmed that a 12-month multimodal exercise program can improve the balance in cognitively impaired older adults. CLINICAL REHABILITATION IMPACT: Based on our results, the multimodal exercise program may be a promising fall prevention exercise program for older adults with mild or moderate cognitive impairment improving static balance but it is supposed that more emphasis should be put on walking component of exercise program and environmental fall risk assessment. PMID- 23820880 TI - Closed kinetic chain exercises with or without additional hip strengthening exercises in management of patellofemoral pain syndrome: a randomized controlled trial. AB - BACKGROUND: Patellofemoral pain syndrome (PFPS) is a common musculoskeletal pain condition, especially in females. Decreased hip muscle strength has been implicated as a contributing factor. Isolated open kinetic chain hip abductors and lateral rotators exercises were added by many authors to the rehabilitation program. However, Closed Kinetic Chain (CKC) exercises focusing on hip and knee muscles were not investigated if they can produce similar effect of hip strengthening and decreasing pain without the need of isolated exercises for hip musculature. AIM: The aim of the present study was to determine the effect of a CKC exercises program with or without additional hip strengthening exercises on pain and hip abductors and lateral rotators peak torque. DESIGN: Prospective randomized clinical trial. SETTING: Patients with patellofemoral pain syndrome referred to the outpatient physical therapy clinic of the faculty of physical therapy, cairo university. POPULATION: Thirty two patients who had patellofemoral pain syndrome with age ranged from eighteen to thirty years. METHODS: Patients were randomly assigned into two groups: CKC group and CKC with hip muscles strengthening exercises as a control (CO) group. Treatment was given 3 times/week, for 6 weeks. Patients were evaluated pre- and post-treatment for their pain severity using VAS, function of knee joint using Kujala questionnaire, hip abductors and external rotators concentric/eccentric peak torque. RESULTS: There were significant improvements in pain, function and hip muscles peak torque in both groups (P<0.05). However, there was no statistically significant difference between groups in hip muscles torque (P<0.05) but pain and function improvements were significantly greater in the CO group (P<0.05). CONCLUSION: Six weeks CKC program focusing on knee and hip strengthening has similar effect in improving hip muscles torque in patients with PFPS as a CKC exercises with additional hip strengthening exercises. However, adding isolated hip strengthening exercises has the advantage of more pain relief. CLINICAL REHABILITATION IMPACT: CKC exercises with additional hip strengthening could be more beneficial in decreasing pain in PFPS than CKC exercises alone. PMID- 23820881 TI - Characteristics of flexed knee gait and functional outcome of a patient who underwent knee reconstruction with a hingeless prosthesis for bone tumor resection: a case report with gait analysis and comparison with healthy subjects. AB - We report on a patient after knee reconstruction for osteosarcoma in the distal femur using a hingeless prosthesis K-MAX KNEE system K-5 who walked without ipsilateral knee extension in the latter half of the stance phase (flexed knee gait). We evaluated the patient using three-dimensional gait analysis and isokinetic knee strength measurement, and compared the patient with five healthy subjects. The Musculoskeletal Tumor Society (MSTS) score was also used for evaluation. The patient kept his operated knee flexed during mid stance. The maximal ankle plantarflexion internal moment was lower on the ipsilateral side than on the contralateral side, and lower than in the healthy subjects. The negative ankle power during the stance phase was generally stronger on the ipsilateral side than on the contralateral side, and also in the healthy subjects. Unusual contralateral hip flexion occurred after the initial contact, indicating increased joint load on the ipsilateral ankle and the contralateral hip. The ratios of the peak knee extension/flexion torque were 0.7 on the ipsilateral side, 1.9 on the contralateral side, and 1.7 in the healthy subjects. The MSTS score of the patient was 23/30 (76.6%). Flexed knee gait might account for the reduction of ipsilateral hip flexion and ankle plantarflexion moment during the late stance phase. These results suggest the importance of focusing more on the ipsilateral ankle joint and the contralateral hip joint to maintain the function of the entire limb joints of the patients with flexed knee gait. PMID- 23820882 TI - First clinical experience with the new four-pole standard connector for high voltage ICD leads. Early results of a multicenter comparison with conventional implant outcomes. AB - PURPOSE: A new four-pole connector system (DF-4) for transvenous high-voltage implantable cardioverter defibrillators (ICD) is currently available in clinical practice. However, no clinical data demonstrating the safety and effectiveness of this complex electromechanical design is available. This study aims to test the safety and effectiveness of this newly designed system compared to the conventional DF-1 leads. METHODS: During a 3-year period, 351 consecutive patients were implanted with DF-4 leads as part of an ICD or ICD-cardiac resynchronization therapy system. Patients were matched for age, sex, and follow up with 154 patients implanted with a standard DF-1 lead. The primary outcome of the study was defibrillation lead failure, defined as the need for lead removal or capping. Operative, electrical, and safety data were obtained at implant and during postoperative follow-up. RESULTS: Implantation success rate in both groups was 100 %. A trend towards shorter procedure time was observed in the DF-4 group but the difference did not reach statistical significance. Handling characteristics of the DF-4 leads were graded better than those of DF-1 models. During a total follow-up of 8,130.5 lead-months, there were nine ICD-lead failures (four system erosion/infections and five electrical lead dysfunctions). The overall incidence of electrical lead failure was 0.64 vs. 0.97 per 100 lead years, for DF-4 and DF-1 leads, respectively (P = 0.2). CONCLUSIONS: This multi center experience provides strong evidence that the feasibility and safety of this novel technology compare favorably with those of the conventional DF-1 leads. PMID- 23820883 TI - Oxidative stress in the kidney of reproductive female rats during aging. AB - Reproduction is a costly life process, and the reproductive investment by females appears to be greater than males in many species. We have analyzed the effects of reproductive investment during aging with respect to oxidative stress parameters in female Wistar rats. We measured the activity glutathione peroxidase, glutathione S-transferase, superoxide dismutase, consumption of hydrogen peroxide, protein carbonylation, lipid peroxidation, nitrite and nitrate levels, and Vitamin C (Vit. C) and E levels. We traced oxidative profiles at ages 3, 6, 12, and 24 months. Animals were grouped according to reproductive experience: experienced or naive with respect to reproductive activity. We measured aconitase activity and sex hormone levels. The naive animals exhibited an increase with respect to experienced in most parameters studied at 6 and 24 months, whereas experienced animals exhibited a similar increase at 3 and 12 months. At 6 months of age, during the period that would represent peak reproductive activity, naive animals showed higher levels of MDA, Vit. C, consumption of hydrogen peroxide and GPx, aconitase, and SOD activities. In naive elderly rats, we observed an increase in oxidative damage markers and an increase in enzymatic and non enzymatic antioxidants, with the exception of consumption of hydrogen peroxide and Vit. C. In the long term, the reproductive investment was not sufficient to interfere with antioxidant capacity, and did not contribute to oxidative damage in kidneys of female Wistar rats. PMID- 23820884 TI - Bacterial colonization dampens influenza-mediated acute lung injury via induction of M2 alveolar macrophages. AB - While the presence of airway bacteria is known to be associated with improved immunity against influenza virus, the mechanism by which endogenous microbiota influence antiviral immunity remains unclear. Here we show that specific pathogen free mice are more sensitive to influenza-mediated death than mice living in a natural environment. Priming with Toll-like receptor 2-ligand(+) Staphylococcus aureus, which commonly colonizes the upper respiratory mucosa, significantly attenuates influenza-mediated lung immune injury. Toll-like receptor 2 deficiency or alveolar macrophage depletion abolishes this protection. S. aureus priming recruits peripheral CCR2(+)CD11b(+) monocytes into the alveoli that polarize to M2 alveolar macrophages in an environment created by Toll-like receptor 2 signalling. M2 alveolar macrophages inhibit influenza-mediated lethal inflammation via anti-inflammatory cytokines and inhibitory ligands. Our results suggest a previously undescribed mechanism by which the airway microbiota may protect against influenza-mediated lethal inflammation. PMID- 23820885 TI - Structure of the catalytic domain of protein tyrosine phosphatase sigma in the sulfenic acid form. AB - Protein tyrosine phosphatase sigma (PTPsigma) plays a vital role in neural development. The extracellular domain of PTPsigma binds to various proteoglycans, which control the activity of 2 intracellular PTP domains (D1 and D2). To understand the regulatory mechanism of PTPsigma, we carried out structural and biochemical analyses of PTPsigma D1D2. In the crystal structure analysis of a mutant form of D1D2 of PTPsigma, we unexpectedly found that the catalytic cysteine of D1 is oxidized to cysteine sulfenic acid, while that of D2 remained in its reduced form, suggesting that D1 is more sensitive to oxidation than D2. This finding contrasts previous observations on PTPalpha. The cysteine sulfenic acid of D1 was further confirmed by immunoblot and mass spectrometric analyses. The stabilization of the cysteine sulfenic acid in the active site of PTP suggests that the formation of cysteine sulfenic acid may function as a stable intermediate during the redox-regulation of PTPs. PMID- 23820886 TI - MicroRNA-409-3p inhibits migration and invasion of bladder cancer cells via targeting c-Met. AB - There is increasing evidence suggesting that dysregulation of certain microRNAs (miRNAs) may contribute to tumor progression and metastasis. Previous studies have shown that miR-409-3p is dysregulated in some malignancies, but its role in bladder cancer is still unknown. Here, we find that miR-409-3p is down-regulated in human bladder cancer tissues and cell lines. Enforced expression of miR-409-3p in bladder cancer cells significantly reduced their migration and invasion without affecting cell viability. Bioinformatics analysis identified the pro metastatic gene c-Met as a potential miR-409-3p target. Further studies indicated that miR-409-3p suppressed the expression of c-Met by binding to its 3' untranslated region. Silencing of c-Met by small interfering RNAs phenocopied the effects of miR-409-3p overexpression, whereas restoration of c-Met in bladder cancer cells bladder cancer cells overexpressing miR-409-3p, partially reversed the suppressive effects of miR-409-3p. We further showed that MMP2 and MMP9 may be downstream effector proteins of miR-409-3p. These findings indicate that miR 409-3p could be a potential tumor suppressor in bladder cancer. PMID- 23820887 TI - Perspective: Opportunities in recalcitrant, rare and neglected tumors. AB - The 'Recalcitrant Cancer Research Act of 2012' defines recalcitrant cancers as having a 5-year survival rate of <20% and estimated to cause the death of at least 30,000 individuals in the US each year. Cancers specifically mentioned in the act are lung and pancreatic cancers. In addition to recalcitrant tumors, rare tumors are often neglected in the drug discovery arena. Sarcomas are ~1% of cancers. The NCI Specialized Programs of Research Excellence (SPOREs) provide disease-focused cancer center grants specifically to accelerate the impact of laboratory research on the treatment of patients. There are 3 SPOREs focused on pancreatic cancer, 7 SPOREs focused on lung cancer and 1 SPORE focused on sarcoma. Through the Developmental Therapeutics Program (DTP), NCI maintains the infrastructure and expertise for the operation of cell-free and cell-based high-, medium- and low-throughput assays. The current effort is on sarcoma, SCLC and pancreatic lines. The DTP functional genomics laboratory provides molecular analyses including gene expression microarrays, exon arrays, microRNA arrays, multiplexing gene assays, plus others as tools to identify potential drug targets and to determine the role of selected genes in the mechanism(s) of drug action and cellular responses to stressors. The DTP tumor microenvironment laboratory focuses on the discovery of targets and the development of therapeutic strategies targeting the tumor microenvironment and physiological abnormalities of tumors resulting from environmental factors or alterations in metabolic enzymes. The DTP maintains a group focused on determining the mechanism(s) of action and identifying potential surrogate markers of activity for select compounds integrating proteomics, transcriptomics and molecular biology platforms. In conclusion, the NCI has active SPORE programs and an internal effort focused on recalcitrant, rare and neglected cancers which are generating data toward improving treatment of these difficult diseases. PMID- 23820888 TI - Is rituximab effective in childhood nephrotic syndrome? Yes and no. AB - The idiopathic nephrotic syndrome (i.e. MCNS and FSGS) in children has been regarded as a disorder of T-cell function. Recent studies, however, also describe abnormalities of B-cell function. This supports the use of B-cell modulating treatment for idiopathic nephrotic syndrome (INS), especially rituximab, which has been used in other glomerular disorders as well. Many studies indicate that rituximab is effective in steroid-sensitive and -dependent nephrotic syndrome, by either inducing long-term remission or reducing relapses. In most series, children with primary (and recurrent) focal segmental glomerulosclerosis (FSGS) do not respond as well. The exact mechanisms of action of rituximab (as well as those of the other treatment options) in INS are as yet unclear. In addition to hosting mechanisms a direct stabilizing effect on the podocyte may also be of relevance, especially in FSGS. Although results are encouraging especially in steroid-sensitive patients, further studies on the clinical use of rituximab and the short- and long-term immunological effects and side-effects are necessary. PMID- 23820889 TI - CD8+ T cell granzyme B activates keratinocyte endogenous IL-18. AB - IL-18 is a pro-inflammatory cytokine of the IL-1 family involved in Th1/Th2 polarization. IL-18 is produced and stored as an inactive precursor (proIL-18) in several cells including keratinocytes, and thus appropriate processing is required to release its active form. In a previous study using recombinant protein, we demonstrated that granzyme B (GrB) cleaves proIL-18 into its active forms in a similar fashion as caspase-1 and human mast cell chymase. GrB released from cytotoxic T lymphocyte (CTL) and NK cells has roles in apoptosis and cytotoxic activity. In certain inflammatory skin diseases with epidermal cell death, the epidermal keratinocytes are targets of CTL and NK cells. However, IL 18 activation during the direct interaction of CTL/NK with keratinocytes has not been described so far. We investigated the interaction between CTL and keratinocytes, and IL-18 processing by CTL-derived GrB using cultured CD8+ T cells and keratinocyte cell line HaCaT. GrB(+)/caspase-1(-) CD8+ T cells cultivated from healthy human PBMC were co-cultured with interferon(IFN)-gamma treated HaCaT cells. The expression of GrB and caspase-1 in HaCaT cells was analyzed by flow cytometry and PCR. The IL-18 concentration in the culture supernatant was measured by specific ELISA. The interaction between HaCaT cells and CTL co-culture increased the number of cytoplasmic GrB-positive HaCaT cells with limited endogenous GrB mRNA expression. The concentration of mature IL-18 levels increased in the co-culture supernatant. GrB from CTLs acts double roles to keratinocytes: a IL-18 converting enzyme and pro-apoptotic factor in the skin inflammatory diseases. PMID- 23820890 TI - Repair of Mybpc3 mRNA by 5'-trans-splicing in a Mouse Model of Hypertrophic Cardiomyopathy. AB - RNA trans-splicing has been explored as a therapeutic option for a variety of genetic diseases, but not for cardiac genetic disease. Hypertrophic cardiomyopathy (HCM) is an autosomal-dominant disease, characterized by left ventricular hypertrophy (LVH) and diastolic dysfunction. MYBPC3, encoding cardiac myosin-binding protein C (cMyBP-C) is frequently mutated. We evaluated the 5' trans-splicing strategy in a mouse model of HCM carrying a Mybpc3 mutation. 5' trans-splicing was induced between two independently transcribed molecules, the mutant endogenous Mypbc3 pre-mRNA and an engineered pre-trans-splicing molecule (PTM) carrying a FLAG-tagged wild-type (WT) Mybpc3 cDNA sequence. PTMs were packaged into adeno-associated virus (AAV) for transduction of cultured cardiac myocytes and the heart in vivo. Full-length repaired Mybpc3 mRNA represented up to 66% of total Mybpc3 transcripts in cardiac myocytes and 0.14% in the heart. Repaired cMyBP-C protein was detected by immunoprecipitation in cells and in vivo and exhibited correct incorporation into the sarcomere in cardiac myocytes. This study provides (i) the first evidence of successful 5'-trans-splicing in vivo and (ii) proof-of-concept of mRNA repair in the most prevalent cardiac genetic disease. Since current therapeutic options for HCM only alleviate symptoms, these findings open new horizons for causal therapy of the severe forms of the disease.Molecular Therapy-Nucleic Acids (2013) 2, e102; doi:10.1038/mtna.2013.31; published online 2 July 2013. PMID- 23820891 TI - 5' Unlocked Nucleic Acid Modification Improves siRNA Targeting. AB - Optimization of small interfering RNAs (siRNAs) is important in RNA interference (RNAi)-based therapeutic development. Some specific chemical modifications can control which siRNA strand is selected by the RNA-induced silencing complex (RISC) for gene silencing. Intended strand selection will increase potency and reduce off-target effects from the unintended strand. Sometimes, blocking RISC loading of the unintended strand leads to improved intended strand-silencing potency, but the generality of this phenomenon is unclear. Specifically, unlocked nucleic acid (UNA) modification of the 5' end of canonical (i.e., 19+2) siRNAs abrogates gene silencing of the modified strand, but the fate and potency of the unmodified strand has not been investigated. Here, we show that 5' UNA-modified siRNAs show improved silencing potency of the unmodified strand. We harness this advantageous property in a therapeutic context, where a limited target region in a conserved HIV 5' long terminal repeat U5 region would otherwise yield siRNAs with undesired strand selection properties and poor silencing. Applying 5' UNA modification to the unintended sense (S) strand of these otherwise poorly targeted siRNAs dramatically improves on-target silencing by the intended antisense (AS) strand in pNL4-3.luciferase studies. This study highlights the utility of 5' UNA siRNA modification in therapeutic contexts where siRNA sequence selection is constrained.Molecular Therapy-Nucleic Acids (2013) 2, e103; doi:10.1038/mtna.2013.36; published online 2 July 2013. PMID- 23820892 TI - Successful surgical resection in non-lesional operculo-insular epilepsy without intracranial monitoring. AB - Pre-operative assessment and surgical management of patients with non-lesional extratemporal epilepsy remain challenging due to a lack of precise localisation of the epileptic zone. In most cases, invasive recording with depth or subdural electrodes is required. Here, we describe the case of 6.5-year-old girl who underwent comprehensive non-invasive phase I video-EEG investigation for drug resistant epilepsy, including electric source and nuclear imaging. Left operculo insular epilepsy was diagnosed. Post-operatively, she developed aphasia which resolved within one year, corroborating the notion of enhanced language plasticity in children. The patient remained seizure-free for more than three years. PMID- 23820893 TI - Connectivity within the primary motor cortex: a DTI tractography study. AB - PURPOSE: Because of the motor function of the precentral area, the connections of the primary motor cortex by white matter fiber bundles have been widely studied in diffusion tensor imaging (DTI). Nevertheless, the connections within the primary motor cortex have yet to be explored. We have studied the connectivity between the different regions of the precentral gyrus in a population of subjects. METHODS: Based on T1 magnetic resonance imaging (MRI) and on individual sulco-gyral anatomy, we defined a parcellation of the right and the left precentral gyri in 20 healthy subjects (10 right-handers; 10 left-handers). This parcellation gave us the opportunity to study MRI tracks reconstructed by tractography within the precentral gyrus and to compare these connections across subjects. We also performed a classical dissection of post-mortem brain tissue to isolate this pattern of connectivity. RESULTS: We showed MRI tracks connecting the different parts of the same precentral gyrus. This result was reproducible and was found in the left and right hemispheres of the 20 subjects. A quantitative description of the bilateral distribution of the MRI tracks was performed, based on statistical analysis and asymmetry indices, to compare asymmetry and handedness. CONCLUSIONS: To the best of our knowledge, this pattern of connectivity has never before been detailed in the literature. Its functional meaning remains to be determined, which requires further study. PMID- 23820894 TI - Filgrastim therapy in a child with neutropenia induced by linezolid. AB - We describe the case of a young child with multidrug-resistant tuberculosis, treated with linezolid. The child developed severe neutropenia after 5 months of treatment. Filgrastim was used, a drug that officially is not indicated for non cytostatic drug-induced neutropenia. This allowed the fast recovery of the patient's neutrophil-count. However, more experience with the off-label use of filgrastrim is needed in the pediatric population. PMID- 23820895 TI - Consumers' attitude towards the use and safety of herbal medicines and herbal dietary supplements in Serbia. AB - BACKGROUND: The use of herbal medicines and herbal dietary supplements in Serbia is very common and many patients consume herbal preparations with conventional drug therapy. OBJECTIVE: The aim of this survey was to evaluate the consumers' awareness of herbal remedies and the safety of herbal dietary supplements, their attitude towards combining herbals and drugs, and the source of recommendations for their use. SETTING: The study included all consumers who bought herbal remedies and herbal dietary supplements in 15 pharmacies on the territory of Novi Sad during 2011 and who accepted to be interviewed. METHODS: Structured interviews using questionnaire, conducted by pharmacists. The questionnaire included 4 parts: socio-demographic characteristics of consumers, source of recommendations for the use of herbal products, attitude towards safety of herbal remedies and herbal dietary supplements use and their combination with regular drugs, as well as the question of purchased herbal products. MAIN OUTCOME MEASURE: Consumers' attitude towards the safety and use of herbal medicines and herbal dietary supplements measured by 9 items. RESULTS: The majority of interviewed participants were highly educated, aged 41-60 and they consumed herbal remedies on their own initiative or on recommendation of nonmedically educated person, without previous consultation with medical doctor or pharmacist. Out of all participants: 88.9 % did not consider it important to inform their physician or pharmacist about use of herbal remedies and herbal dietary supplements; 73.3 % found the use of herbal remedies harmless (where 9.4 % did not have any attitude towards that issue), while 40.3 % of participants regarded the combining of herbal and regular drugs unsafe. CONCLUSION: There is a need for consumers' education on reliable use of herbal medicines and herbal dietary supplements, in order to improve their awareness of the limits of herbal remedies safety and potential risks of their combination with drugs. PMID- 23820896 TI - Ethnicity influences weight loss 1 year after bariatric surgery: a study in Turkish, Moroccan, South Asian, African and ethnic Dutch patients. AB - Several studies conducted in the USA have demonstrated that the effectiveness of bariatric surgery differs between patients from African and European origin. However, little is known on differences in outcomes after bariatric surgery between individuals from other ethnic backgrounds. In this retrospective study, we found that, in terms of weight loss, gastric bypass surgery is less effective in African, South Asian, Turkish and Moroccan patients than in their ethnic Dutch counterparts. Our results underscore that ethnic differences in the effectiveness of bariatric surgery are not limited to those between patients of African and European origin, but extend to other minority groups as well. Therefore, it is important that prospective studies both determine ethnic differences in weight loss-related improvement of co-morbidities and elucidate the exact reasons for these ethnic disparities. PMID- 23820897 TI - [French translation, validation and adaptation of the Stigma Scale]. AB - AIM: People suffering from mental illness are exposed to stigma. However, only few tools are available to assess stigmatization as perceived from the patient's perspective. The aim of this study is to adapt and validate a French version of the Stigma Scale (King et al., 2007 [8]). This self-report questionnaire has a three-factor structure: discrimination, disclosure and positive aspects of mental illness. Discrimination subscale refers to perceived negative reactions of others. Disclosure subscale refers mainly to managing disclosure to avoid discrimination and finally positive aspects subscale taps into how patients are becoming more accepting, more understanding toward their illness. METHOD: In the first step, internal consistency, convergent validity and test-retest reliability of the French adaptation of the 28-item scale were assessed in a sample of 183 patients. Results of confirmatory factor analyses (CFA) did not confirm the hypothesized structure. In the light of the failed attempts to validate the original version, an alternative 9-item short-form version of the Stigma Scale, maintaining the integrity of the original model, was developed based on results of exploratory factor analyses in the first sample and cross-validated in a new sample of 234 patients. RESULTS: Results of CFA did not confirm that the data fitted well to the three-factor model of the 28-item Stigma Scale (chi(2)/df=2.02, GFI=0.77, AGFI=0.73, RMSEA=0.07, CFI=0.77 and NNFI=0.75). Cronbach's alpha was excellent for discrimination (0.84) and disclosure (0.83) subscales but poor for potential positive aspects (0.46). External validity was satisfactory. Overall Stigma Scale total score was negatively correlated with the score on Rosenberg's Self-Esteem Scale (r=-0.49), and each subscale was significantly correlated with a visual analogue scale that referred to the specific aspect of stigma (0.43<=|r|<=0.60). Intraclass correlation coefficients between 0.68 and 0.89 indicated good test-retest reliability. The results of the CFA demonstrated that the items chosen for the short version of the Stigma Scale have the expected fit properties (chi(2)/df=1.02, GFI=0.98, AGFI=0.98, RMSEA=0.01, CFI=1.0 and NNFI=1.0). Considering the small number (three) of items in each subscale of the short version of the Stigma Scale, alpha coefficients for discrimination (0.57), disclosure (0.80) and potential positive aspects subscales (0.62) are considered as good. CONCLUSION: Our results suggest that the 9-item French short version of the Stigma Scale is a useful, reliable and valid self report questionnaire to assess perceived stigmatization in people suffering from mental illness. The time of completion is really short and questions are well understood and accepted by the patients. PMID- 23820898 TI - Uterine-specific loss of Tsc2 leads to myometrial tumors in both the uterus and lungs. AB - Lymphangioleiomyomatosis (LAM) is a rare disease characterized by proliferation of abnormal smooth-muscle cells in the lungs, leading to functional loss and sometimes lung transplantation. Although the origin of LAM cells is unknown, several features of LAM provide clues. First, LAM cells contain inactivating mutations in genes encoding Tsc1 or Tsc2, proteins that limit mTORC1 activity. Second, LAM tumors recur after lung transplantation, suggesting a metastatic pathogenesis. Third, LAM is found almost exclusively in women. Finally, LAM shares features with uterine leiomyomas, benign tumors of myometrial cells. From these observations, we proposed that LAM cells might originate from uterine leiomyomas containing Tsc mutations. To test our hypothesis, and to develop mouse models for leiomyoma and LAM, we targeted Tsc2 deletion primarily in uterine cells. In fact, nearly 100% of uteri from uterine-specific Tsc2 knockout mice developed myometrial proliferation and uterine leiomyomas by 12 and 24 weeks, respectively. Myometrial proliferation and mTORC1/S6 activity were abrogated by the mTORC1 inhibitor rapamycin or by elimination of sex steroid production through ovariectomy or aromatase inhibition. In ovariectomized Tsc2 null mice, mTORC1/S6 activity and myometrial growth were restored by estrogen but not progesterone. Thus, even without Tsc2, estrogen appears to be required for myometrial mTORC1/S6 signaling and proliferation. Finally, we found Tsc2 null myometrial tumors in lungs of older Tsc2 uterine-specific knockout females, suggesting that lung LAM-like myometrial lesions may indeed originate from the uterus. This mouse model may improve our understanding of LAM and leiomyomas and might lead to novel therapeutic strategies for both diseases. PMID- 23820899 TI - Minireview: Nutrient sensing by G protein-coupled receptors. AB - G protein-coupled receptors (GPCRs) are membrane proteins that recognize molecules in the extracellular milieu and transmit signals inside cells to regulate their behaviors. Ligands for many GPCRs are hormones or neurotransmitters that direct coordinated, stereotyped adaptive responses. Ligands for other GPCRs provide information to cells about the extracellular environment. Such information facilitates context-specific decision making that may be cell autonomous. Among ligands that are important for cellular decisions are amino acids, required for continued protein synthesis, as metabolic starting materials and energy sources. Amino acids are detected by a number of class C GPCRs. One cluster of amino acid-sensing class C GPCRs includes umami and sweet taste receptors, GPRC6A, and the calcium-sensing receptor. We have recently found that the umami taste receptor heterodimer T1R1/T1R3 is a sensor of amino acid availability that regulates the activity of the mammalian target of rapamycin. This review focuses on an array of findings on sensing amino acids and sweet molecules outside of neurons by this cluster of class C GPCRs and some of the physiologic processes regulated by them. PMID- 23820900 TI - Minireview: Novel aspects of M3 muscarinic receptor signaling in pancreatic beta cells. AB - The release of insulin from pancreatic beta-cells is regulated by a considerable number of G protein-coupled receptors. During the past several years, we have focused on the physiological importance of beta-cell M3 muscarinic acetylcholine receptors (M3Rs). At the molecular level, the M3R selectively activates G proteins of the G(q) family. Phenotypic analysis of several M3R mutant mouse models, including a mouse strain that lacks M3Rs only in pancreatic beta-cells, indicated that beta-cell M3Rs play a key role in maintaining blood glucose levels within a normal range. Additional studies with transgenic M3R mouse models strongly suggest that strategies aimed to enhance signaling through beta-cell M3Rs may prove useful in the treatment of type 2 diabetes. More recently, we analyzed transgenic mice that expressed an M3R-based designer receptor in a beta cell-specific fashion, which enabled us to chronically activate a beta-cell G(q) coupled receptor by a drug that is otherwise pharmacologically inert. Drug dependent activation of this designer receptor stimulated the sequential activation of G(q), phospholipase C, ERK1/2, and insulin receptor substrate 2 signaling, thus triggering a series of events that greatly improved beta-cell function. Most importantly, chronic stimulation of this pathway protected mice against experimentally induced diabetes and glucose intolerance, induced either by streptozotocin or by the consumption of an energy-rich, high-fat diet. Because beta-cells are endowed with numerous receptors that mediate their cellular effects via activation of G(q)-type G proteins, these findings provide a rational basis for the development of novel antidiabetic drugs targeting this class of receptors. PMID- 23820901 TI - RIG-I-like receptors mediate innate antiviral response in mouse testis. AB - The testis is an immune privileged organ in which the tissue-specific cells have adopted effective innate immune functions against microbial pathogens. Toll-like receptors (TLRs) mediate innate immune response in the testis. The current study demonstrates that melanoma differentiation-associated protein 5 (MDA5) and retinoic acid-inducible gene I (RIG-I) initiate the testicular innate antiviral response. Both MDA5 and RIG-I are expressed in Leydig cells, and MDA5 is also expressed in spermatids. Polyinosinic-polycytidylic acid [poly(I:C)], a common agonist of MDA5 and RIG-I, significantly induces the expression of type I interferons (IFN-alpha/beta) and antiviral proteins, including IFN-stimulated gene 15, 2'5'-oligoadenylate synthetase 1, and Mx GTPase 1, in primary TLR3 deficient (TLR3(-/-)) Leydig and germ cells. Moreover, major proinflammatory cytokines, including TNF-alpha and IL-6, are significantly up-regulated by poly(I:C) in these testicular cells. The poly(I:C)-induced innate antiviral response in the testicular cells is significantly reduced by knockdown of individual MDA5 and RIG-I using specific small interfering RNA. We also provide evidence that local injection of poly(I:C) induces antiviral response in the testis of TLR3(-/-) mice. These data provide novel insights into the mechanisms underlying testicular antiviral response. PMID- 23820902 TI - Phosphoinositide 3-kinase p110delta mediates estrogen- and FSH-stimulated ovarian follicle growth. AB - In the mammalian ovary, primordial follicles are generated early in life and remain dormant for prolonged periods. Their growth resumes via primordial follicle activation, and they continue to grow until the preovulatory stage under the regulation of hormones and growth factors, such as estrogen, FSH, and IGF-1. Both FSH and IGF-1 activate the phosphatidylinositol-3 kinase (PI3K)/Akt (acute transforming retrovirus thymoma protein kinase) signaling pathway in granulosa cells (GCs), yet it remains inconclusive whether the PI3K pathway is crucial for follicle growth. In this study, we investigated the p110delta isoform (encoded by the Pik3cd gene) of PI3K catalytic subunit expression in the mouse ovary and its function in fertility. Pik3cd-null females were subfertile, exhibited fewer growing follicles and more atretic antral follicles in the ovary, and responded poorly to exogenous gonadotropins compared with controls. Ovary transplantation showed that Pik3cd-null ovaries responded poorly to FSH stimulation in vitro; this confirmed that the follicle growth defect was intrinsically ovarian. In addition, estradiol (E2)-stimulated follicle growth and GC proliferation in preantral follicles was impaired in Pik3cd-null ovaries. FSH and E2 substantially activated the PI3K/Akt pathway in GCs of control mice but not in those of Pik3cd null mice. However, primordial follicle activation and oocyte meiotic maturation were not affected by Pik3cd knockout. Taken together, our findings indicate that the p110delta isoform of the PI3K catalytic subunit is a key component of the PI3K pathway for both FSH and E2-stimulated follicle growth in ovarian GCs; however, it is not required for primordial follicle activation and oocyte development. PMID- 23820904 TI - How to get help with starting your research project: ADMSEP task force on research and scholarship. PMID- 23820903 TI - Determinants of the heightened activity of glucocorticoid receptor translational isoforms. AB - Translational isoforms of the glucocorticoid receptor alpha (GR-A, -B, -C1, -C2, C3, -D1, -D2, and -D3) have distinct tissue distribution patterns and unique gene targets. The GR-C3 isoform-expressing cells are more sensitive to glucocorticoid killing than cells expressing other GRalpha isoforms and the GR-D isoform expressing cells are resistant to glucocorticoid killing. Whereas a lack of activation function 1 (AF1) may underlie the reduced activity of the GR-D isoforms, it is not clear how the GR-C3 isoform has heightened activity. Mutation analyses and N-terminal tagging demonstrated that steric hindrance is probably the mechanism for the GR-A, -B, -C1, and -C2 isoforms to have lower activity than the GR-C3 isoform. In addition, truncation scanning analyses revealed that residues 98 to 115 are critical in the hyperactivity of the human GR-C3 isoform. Chimera constructs linking this critical fragment with the GAL4 DNA-binding domain showed that GR residues 98 to 115 do not contain any independent transactivation activity. Mutations at residues Asp101 or Gln106 and Gln107 all reduced the activity of the GR-C3 isoform. In addition, functional studies indicated that Asp101 is crucial for the GR-C3 isoform to recruit coregulators and to mediate glucocorticoid-induced apoptosis. Thus, charged and polar residues are essential components of an N-terminal motif that enhances the activity of AF1 and the GR-C3 isoform. These studies, together with the observations that GR isoforms have cell-specific expression patterns, provide a molecular basis for the tissue-specific functions of GR translational isoforms. PMID- 23820905 TI - Changes in residency training over the past quarter-century: reflections of a longtime program director. PMID- 23820906 TI - The future of psychiatric education: an international perspective. PMID- 23820907 TI - Psychiatry residency education in Canada: past, present and future. AB - OBJECTIVE This article provides a brief overview of the history of psychiatry residency training in Canada, and outlines the rationale for the current training requirements, changes to the final certification examination, and factors influencing future trends in psychiatry education and training. METHOD The author compiled findings and reports on residency education in Canada from current and historical sources. RESULTS Residency training in psychiatry in Canada has undergone significant change in the past 5 years, moving from an "apprenticeship" model to a competency-based curriculum with explicit expectations for the acquisition of key, defined competencies. CONCLUSION Continuous evaluation of teaching methodologies, increasing use of innovative and creative medical education techniques, flexible curricula, and increasingly rigorous standards of accreditation are some of the factors likely to continue to shape the future. PMID- 23820908 TI - Education and training in psychiatry in the U.K. AB - BACKGROUND/OBJECTIVE: Recent training and education changes have raised important issues in delivery of psychiatric education at all levels. In this article, the authors describe the current status of mental health education in the training of all doctors and postgraduate training and education in psychiatry in the U.K. METHOD: The authors explore and describe some of the initiatives that are being used in order to increase exposure to mental health placements in the Foundation Program, and they then describe the existing specific mental health opportunities within general practice and other specialist training programs. DESCRIPTION: After graduation from medical school, a two-year Foundation training program is a must, and, at the end of the first year, trainees become eligible for full registration with the "regulator," the General Medical Council; after finishing the second year, they become eligible to undertake specialist training. Psychiatry training takes up to 6 years, and six specialties are recognized as leading to certificates for completion of training before independent practice. These six specialties are 1) general and community; 2) child and adolescent; 3) medical psychotherapy; 4) forensic psychiatry; 5) psychiatry of old age; and 6) psychiatry of learning disability. Also, three subspecialties-liaison psychiatry, addictions, and rehabilitation-form a part of the training in general and community psychiatry. CONCLUSIONS: The authors discuss advantages and disadvantages of such an approach and raise key issues related to ongoing work to improve recruitment, progression, and retention of trainee psychiatrists. PMID- 23820910 TI - Advanced psychotherapy training: psychotherapy scholars' track, and the apprenticeship model. AB - BACKGROUND/OBJECTIVE: Guided by ACGME's requirements, psychiatric residency training in psychotherapy currently focuses on teaching school-specific forms of psychotherapy (i.e., cognitive-behavioral, supportive, and psychodynamic psychotherapy). On the basis of a literature review of common factors affecting psychotherapy outcomes and experience with empirically supported and traditional psychotherapies, the authors aimed to develop an advanced contemporary and pragmatic approach to psychotherapy training for eight residents (two per PGY year) enrolled in a specialized Psychotherapy Scholars' Track within an adult general-residency program. METHOD: The authors developed core principles and clinical practices, and drafted year-by-year educational goals and objectives to teach the psychotherapy scholars. Based on experiential learning principles, we also developed an individualized form of psychotherapy training, which we call "The Apprenticeship Model." RESULTS: The Psychotherapy Scholars' Track, and "Apprenticeship Model" of training are now in their third year. To date, authors report that scholars are highly satisfied with the structure and curriculum in the track. Trainees appreciate the protected time for self-directed study, mentored scholarship, and psychotherapy rotations. Patients and the Psychotherapy Scholars experience the "Apprenticeship Model" of psychotherapy training as authentic and compatible with their needs and resources. CONCLUSION: The Psychotherapy Scholars' Track developed and piloted in our general psychiatry residency is based on common factors, empirically-supported treatments, and use of experiential learning principles. Whether the Psychotherapy Scholars' Track and "Apprenticeship Model" will ultimately increase residents' psychotherapy skills and positively affect their ability to sustain postgraduate psychotherapy practice in varied settings requires long-term evaluation. The developers welcome empirical testing of the comparative effectiveness of this psychotherapy teaching approach relative to others. PMID- 23820911 TI - Leadership considerations for executive vice chairs, new chairs, and chairs in the 21st century. PMID- 23820912 TI - The Horse Boy--attending to the stories our patients tell us. AB - In the summer of 2007, Rupert Isaacson and Kirsten Neff set off to Mongolia on an extraordinary journey to heal their 7-year old autistic son. Their story was captured on film by a small crew, and both the resulting documentary, The Horse Boy, and the associated book have reached a wide audience. For those involved in psychiatric education, the film represents a valuable opportunity to explore a range of relevant clinical and ethical issues with their learners, including an introduction to the world of complementary and alternative medicine and the emerging discipline of narrative medicine. Perhaps most importantly, The Horse Boy is an impetus for health professionals to consider their own responsibilities when determined patients in their care undertake such remarkable quests to heal themselves or their loved ones. PMID- 23820914 TI - Impact of a global mental health program on a residency training program. PMID- 23820916 TI - The focus group: a method for curricular review. PMID- 23820917 TI - Medical student healthcare barriers and solutions: perspectives of students. PMID- 23820918 TI - Compassion cultivation: a missing piece in medical education. PMID- 23820919 TI - Resident didactic education in borderline personality disorder: is it sufficient? PMID- 23820920 TI - Mentorship of clinical-track junior faculty: impact of a facilitated peer mentoring program to promote scholarly productivity. PMID- 23820921 TI - How the British Mental Health Service and University collaborated to develop a master's degree program in psychiatry for residents and other health professionals. PMID- 23820926 TI - Comparatively preserved impulse control in late-onset opiate users. AB - RATIONALE: A substantial literature indicates that in alcohol addiction aspects of impulsive decision-making are typical of individuals with an early onset of addictive behaviour problems. It is not known whether the same applies to opiate addiction, and this insight has important theoretical and clinical implications. OBJECTIVES: This study aims to examine the relationship between age at onset of addictive behaviour problems and decision-making in opiate addiction. METHODS: Ninety-three opiate-dependent, treatment-seeking individuals were divided in three groups, early, late and intermediate onset of problems, and completed impulsivity questionnaires and delay discounting and gambling tasks. RESULTS: Individuals with a late onset of opiate problems (25 years or above) had lower delay discounting rates than individuals with early (18 years or less) or intermediate onset. There were no differences in performance on the gambling tasks. Late-onset individuals were older and had shorter drug histories, but there was no relationship between either age or length of exposure to opiates and delay discounting rates. CONCLUSIONS: In keeping with previous studies in alcohol addiction, these findings support the notion of at least two distinct subgroups of opiate-dependent individuals, characterised by a different onset of problems, different propensity to impulsive behaviour and perhaps distinct mechanisms leading to addiction. PMID- 23820927 TI - Early markers of cognitive enhancement: developing an implicit measure of cognitive performance. AB - There is intense interest in the development of effective cognitive enhancing drugs which would have therapeutic application across a number of neurological and psychological disorders including dementia, schizophrenia and depression. However, development in this area has been limited by the absence of sensitive biomarkers which can be used to detect and refine therapeutic-like action in phase 1 clinical studies. The aim of the present study was therefore to develop a measure of cognition relevant to the action of candidate cognitive enhancers which might be sensitive to pharmacological manipulation in healthy volunteers. Healthy volunteers (n = 34) were randomised to receive a single dose of modafinil (100 mg) or placebo. Five hours post dose, attentional flexibility in learning was assessed using a novel implicit learning task. Volunteers also completed an auditory digit span task and visual analogue scales (VAS). Modafinil increased alertness as measured by the VAS. In the implicit learning task, modafinil enhanced learning rates in terms of both accuracy and reaction time, suggesting an increase in implicit rule learning. These results suggest that the novel learning task should be explored as a biomarker of early cognitive improvement which could be more sensitive than conventional measures. PMID- 23820928 TI - Netrin-1 receptor-deficient mice show age-specific impairment in drug-induced locomotor hyperactivity but still self-administer methamphetamine. AB - RATIONALE: The mesocorticolimbic dopamine system undergoes significant reorganization of neuronal connectivity and functional refinement during adolescence. Deleted in colorectal cancer (DCC), a receptor for the guidance cue netrin-1, is involved in this reorganization. Previous studies have shown that adult mice with a heterozygous (het) loss-of-function mutation in DCC exhibit impairments in sensitization and conditioned place preference (CPP) to psychostimulants. However, the commonly abused psychostimulant methamphetamine (METH) has not been assessed, and the role of DCC in drug self-administration remains to be established. OBJECTIVES: Using dcc het mice and wildtype (WT) littermates, we extended previous findings on dcc haplodeficiency by examining self-administration of METH in adult mice, including cue-induced drug seeking following abstinence. We also examined hyperactivity, sensitization, and CPP to a METH-paired context in adult and adolescent mice. RESULTS: While adult dcc het mice expressed largely similar METH self-administration and cue-induced drug seeking as WT littermates, they failed to modulate responding according to dose of METH. Compared to WT, both adult and adolescent dcc het mice expressed impaired locomotor hyperactivity to acute METH but nevertheless showed comparable behavioral sensitization. Conditioned hyperactivity increased with age in WT but not in dcc het mice. CONCLUSIONS: Impaired METH-induced hyperactivity and dose related responding in adult dcc het mice suggest that reduced DCC alters METH related behaviors. Adolescence is identified as a vulnerable period during which impairment in hyperactivity due to reduced DCC can be overcome with repeated METH injections. Nevertheless, DCC appears to have a somewhat limited role in METH consumption and seeking following abstinence. PMID- 23820929 TI - Patrinia scabiosaefolia inhibits colorectal cancer growth through suppression of tumor angiogenesis. AB - Angiogenesis is an essential process for tumor development and metastasis, therefore inhibition of tumor angiogenesis has become a promising strategy for anticancer treatments. Patrinia scabiosaefolia, a well-known Oriental folk medicine, has been shown to be effective in the clinical treatment of gastrointestinal cancers. However, the precise mechanism of its tumoricidal activity remains largely unknown. Using a colorectal cancer (CRC) mouse xenograft model, the human colon carcinoma cell line HT-29 and human umbilical vein endothelial cells (HUVECs), in the present study we evaluated the effects of an ethanol extract of Patrinia scabiosaefolia (EEPS) on tumor angiogenesis in vivo and in vitro, and investigated the underlying molecular mechanisms. We found that EEPS treatment significantly reduced the tumor volume in CRC mice and decreased the intratumoral microvessel density in tumor tissues. In addition, EEPS inhibited several key processes of angiogenesis, including the proliferation, migration and tube formation of HUVECs. Moreover, EEPS treatment suppressed the expression of VEGF-A in CRC tumors and HT-29 cells. Collectively, our data suggest that Patrinia scabiosaefolia inhibits CRC growth likely via suppression of tumor angiogenesis. PMID- 23820930 TI - Case-control analysis on metformin and cancer of the esophagus. AB - PURPOSE: Metformin use has been associated with decreased cancer risks, though data on esophageal cancer are scarce. We explored the relation between use of metformin or other anti-diabetic drugs and the risk of esophageal cancer. METHODS: We conducted a case-control analysis in the UK-based general practice research database (GPRD, now clinical practice research datalink, CPRD). Cases were individuals with an incident diagnosis of esophageal cancer between 1994 and 2010 at age 40-89 years. Ten controls per case were matched on age, sex, calendar time, general practice, and number of years of active history in the GPRD prior to the index date. Various potential confounders including diabetes mellitus, gastro-esophageal reflux, and use of proton-pump inhibitors were evaluated in univariate models, and the final results were adjusted for BMI and smoking. Results are presented as odds ratios (ORs) with 95 % confidence intervals (CI). RESULTS: Long-term use (>=30 prescriptions) of metformin was not associated with a materially altered risk of esophageal cancer (adj. OR 1.23, 95 % CI 0.92-1.65), nor was long-term use of sulfonylureas (adj. OR 0.93, 95 % CI 0.70-1.23), insulin (adj. OR 0.87, 95 % CI 0.60-1.25), or of thiazolidinediones (adj. OR 0.71, 95 % CI 0.37-1.36). CONCLUSION: In our population-based study, use of metformin was not associated with an altered risk of esophageal cancer. PMID- 23820931 TI - Emergence of charge order from the vortex state of a high-temperature superconductor. AB - Evidence is mounting that charge order competes with superconductivity in high Tc cuprates. Whether this has any relationship to the pairing mechanism is unknown as neither the universality of the competition nor its microscopic nature has been established. Here, we show using nuclear magnetic resonance that charge order in YBa2Cu3Oy has maximum strength inside the superconducting dome, similar to compounds of the La2-x(Sr,Ba)xCuO4 family. In YBa2Cu3Oy, this occurs at doping levels of p=0.11-0.12. We further show that the overlap of halos of incipient charge order around vortex cores, similar to those visualised in Bi2Sr2CaCu2O8+delta, can explain the threshold magnetic field at which long-range charge order emerges. These results reveal universal features of a competition in which charge order and superconductivity appear as joint instabilities of the same normal state, whose relative balance can be field-tuned in the vortex state. PMID- 23820932 TI - A retrospective analysis of clinicopathological characteristics, treatment, and outcome of 27 patients of primary intestinal lymphomas. AB - PURPOSE: Primary intestinal lymphomas comprise of a wide variety of histological subtypes with varied presentation. The objective of this study was to determine the presentation, histological type, treatment, and outcome of patients of primary intestinal lymphoma. METHODS: A retrospective analysis of 27 patients of primary intestinal lymphoma treated at our institute from 2004 to 2010 was carried out. Patients were staged according to Musshoff's modification of Ann Arbor classification. RESULTS: The median age was 51 years (range, 7-76 years). Abdominal pain was the most common presenting symptom followed by mass abdomen, loss of appetite, constipation, and vomiting. The most common site of disease presentation was ileocecal region and jejunum. Diffuse large B cell lymphoma was the predominant histological type observed in 55.6%. Eighteen patients underwent surgery with or without chemotherapy. Chemotherapy, either alone or with radiotherapy, was given to nine patients. The median follow-up was 48.3 months (range 5-94 months). The 5-year overall survival (OS) and event-free survival were 53.5 and 53%, respectively. The 5-year OS for patients who underwent both surgery and chemotherapy was 79.5% and for those without surgery was 13.9%, respectively. CONCLUSION: Primary intestinal lymphomas are heterogenous diseases. Patients who underwent surgery had better survival and outcome than those without surgery. Chemotherapy is necessary for improving the survival of these patients. Optimal management is still uncertain due to the rarity of this disease. PMID- 23820933 TI - A rare case of primary pancreatic Hodgkin lymphoma. PMID- 23820934 TI - Summary of Notifiable Diseases - United States, 2011. AB - The Summary of Notifiable Diseases - United States, 2011 contains the official statistics, in tabular and graphic form, for the reported occurrence of nationally notifiable infectious diseases in the United States for 2011. Unless otherwise noted, the data are final totals for 2011 reported as of June 30, 2012. These statistics are collected and compiled from reports sent by state health departments and territories to the National Notifiable Diseases Surveillance System (NNDSS), which is operated by CDC in collaboration with the Council of State and Territorial Epidemiologists (CSTE). PMID- 23820935 TI - What limits tool use in nonhuman primates? Insights from tufted capuchin monkeys (Sapajus spp.) and chimpanzees (Pan troglodytes) aligning three-dimensional objects to a surface. AB - Perceptuomotor functions that support using hand tools can be examined in other manipulation tasks, such as alignment of objects to surfaces. We examined tufted capuchin monkeys' and chimpanzees' performance at aligning objects to surfaces while managing one or two spatial relations to do so. We presented six subjects of each species with a single stick to place into a groove, two sticks of equal length to place into two grooves, or two sticks joined as a T to place into a T shaped groove. Tufted capuchins and chimpanzees performed equivalently on these tasks, aligning the straight stick to within 22.5 degrees of parallel to the groove in approximately half of their attempts to place it, and taking more attempts to place the T stick than two straight sticks. The findings provide strong evidence that tufted capuchins and chimpanzees do not reliably align even one prominent axial feature of an object to a surface, and that managing two concurrent allocentric spatial relations in an alignment problem is significantly more challenging to them than managing two sequential relations. In contrast, humans from 2 years of age display very different perceptuomotor abilities in a similar task: they align sticks to a groove reliably on each attempt, and they readily manage two allocentric spatial relations concurrently. Limitations in aligning objects and in managing two or more relations at a time significantly constrain how nonhuman primates can use hand tools. PMID- 23820936 TI - Influence of the carboxymethyl chitosan anti-adhesion solution on the TGF-beta1 in a postoperative peritoneal adhesion rat. AB - The aim of this paper was to investigate the effect of carboxymethyl chitosan anti-adhesion solution on prevention of postsurgical adhesion. Forty adult male Wistar rats were randomly divided into three groups: 0.9% normal saline solution (group A), hyaluronic acid gels (group B) and carboxymethyl chitosan anti adhesion solution (group C). The animals were treated with normal saline, hyaluronic acid gels or carboxymethyl chitosan anti-adhesion solution at the time of surgery. After 2 or 3 weeks, the degree of adhesions and histological effects were determined. The adhesions in groups B and C were significantly decreased, and the levels of TGF-beta1 and hydroxyproline in group C were significantly lower than that in group A (P < 0.05). The histopathology in group C showed fewer inflammatory cells and fibroblasts. Carboxymethyl chitosan anti-adhesion solution can effectively prevent postoperative adhesion which is a promising drug delivery system in the context of postsurgical anti-adhesion. PMID- 23820937 TI - In vitro bioactivity, cytocompatibility, and antibiotic release profile of gentamicin sulfate-loaded borate bioactive glass/chitosan composites. AB - Borate bioactive glass-based composites have been attracting interest recently as an osteoconductive carrier material for local antibiotic delivery. In the present study, composites composed of borate bioactive glass particles bonded with a chitosan matrix were prepared and evaluated in vitro as a carrier for gentamicin sulfate. The bioactivity, degradation, drug release profile, and compressive strength of the composite carrier system were studied as a function of immersion time in phosphate-buffered saline at 37 degrees C. The cytocompatibility of the gentamicin sulfate-loaded composite carrier was evaluated using assays of cell proliferation and alkaline phosphatase activity of osteogenic MC3T3-E1 cells. Sustained release of gentamicin sulfate occurred over ~28 days in PBS, while the bioactive glass converted continuously to hydroxyapatite. The compressive strength of the composite loaded with gentamicin sulfate decreased from the as fabricated value of 24 +/- 3 MPa to ~8 MPa after immersion for 14 days in PBS. Extracts of the soluble ionic products of the borate glass/chitosan composites enhanced the proliferation and alkaline phosphatase activity of MC3T3-E1 cells. These results indicate that the gentamicin sulfate-loaded composite composed of chitosan-bonded borate bioactive glass particles could be useful clinically as an osteoconductive carrier material for treating bone infection. PMID- 23820938 TI - Changing air mass frequencies in Canada: potential links and implications for human health. AB - Many individual variables have been studied to understand climate change, yet an overall weather situation involves the consideration of many meteorological variables simultaneously at various times diurnally, seasonally, and yearly. The current study identifies a full weather situation as an air mass type using synoptic scale classification, in 30 population centres throughout Canada. Investigative analysis of long-term air mass frequency trends was completed, drawing comparisons between seasons and climate zones. We find that the changing air mass trends are highly dependent on the season and climate zone being studied, with an overall increase of moderate ('warm') air masses and decrease of polar ('cold') air masses. In the summertime, general increased moisture content is present throughout Canada, consistent with the warming air masses. The moist tropical air mass, containing the most hot and humid air, is found to increase in a statistically significant fashion in the summertime in 46% of the areas studied, which encompass six of Canada's ten largest population centres. This emphasises the need for heat adaptation and acclimatisation for a large proportion of the Canadian population. In addition, strong and significant decreases of transition/frontal passage days were found throughout Canada. This result is one of the most remarkable transition frequency results published to date due to its consistency in identifying declining trends, coinciding with research completed in the United States (US). We discuss relative results and implications to similar US air mass trend analyses, and draw upon research studies involving large-scale upper-level air flow and vortex connections to air mass changes, to small-scale meteorological and air pollution interactions. Further research is warranted to better understand such connections, and how these air masses relate to the overall and city-specific health of Canadians. PMID- 23820939 TI - Mean surface temperature prediction models for broiler chickens-a study of sensible heat flow. AB - Body surface temperature can be used to evaluate thermal equilibrium in animals. The bodies of broiler chickens, like those of all birds, are partially covered by feathers. Thus, the heat flow at the boundary layer between broilers' bodies and the environment differs between feathered and featherless areas. The aim of this investigation was to use linear regression models incorporating environmental parameters and age to predict the surface temperatures of the feathered and featherless areas of broiler chickens. The trial was conducted in a climate chamber, and 576 broilers were distributed in two groups. In the first trial, 288 broilers were monitored after exposure to comfortable or stressful conditions during a 6-week rearing period. Another 288 broilers were measured under the same conditions to test the predictive power of the models. Sensible heat flow was calculated, and for the regions covered by feathers, sensible heat flow was predicted based on the estimated surface temperatures. The surface temperatures of the feathered and featherless areas can be predicted based on air, black globe or operative temperatures. According to the sensible heat flow model, the broilers' ability to maintain thermal equilibrium by convection and radiation decreased during the rearing period. Sensible heat flow estimated based on estimated surface temperatures can be used to predict animal responses to comfortable and stressful conditions. PMID- 23820940 TI - Global coagulation in myeloproliferative neoplasms. AB - In spite of their recognized risk of thrombosis, patients with myeloproliferative neoplasms (MPN) show little or no abnormalities of traditional coagulation tests, perhaps because these are unable to represent the balance between pro- and anticoagulants nor the effect of platelets and blood cells. We investigated whether global tests such as thrombin generation in platelet-rich plasma (PRP) or thromboelastometry in whole blood were able to detect signs of procoagulant imbalance in MPN. The endogenous thrombin potential (ETP) of 111 patients and 89 controls was measured in PRP with platelet count adjusted to the original patient or control-count. Testing was performed with and without thrombomodulin (the physiological protein C activator) and results were expressed as ETP ratios (with/without thrombomodulin). High ETP ratios reflect resistance to thrombomodulin and were taken as indexes of procoagulant imbalance. Patients were also investigated by thromboelastometry that provides such parameters as the clot formation time (CFT) and maximal clot firmness (MCF). Short CFT or high MCF were taken as indexes of procoagulant imbalance. ETP ratios were higher in patients than in controls and were directly correlated with platelet counts and inversely with the plasma levels of free protein S, protein C and antithrombin. Patients on hydroxyurea had lower ETP ratios than those on other treatments. CFT was shorter and MCF was greater in patients than controls; CFT and MCF were correlated with platelet counts. In conclusion, patients with MPN display a procoagulant imbalance detectable by thrombin generation and thromboelastometry. These tests might be useful in the frame of clinical trials to assess their association with the occurrence of thrombosis and with the effect of therapeutic strategies in MPN. PMID- 23820941 TI - Testicular invading refractory multiple myeloma during bortezomib treatment successfully treated with lenalidomide: a case report. PMID- 23820942 TI - Use of rasburicase in a pregnant woman with acute lymphoblastic leukaemia and imminent tumour lysis syndrome. PMID- 23820943 TI - Mechanisms underlying transfer of task-defined rules across feature dimensions. AB - The Simon effect can be reversed, favoring spatially noncorresponding responses, when people respond to stimulus colors (e.g., green) by pressing a key labeled with the alternative color (i.e., red). This Hedge and Marsh reversal is most often attributed to transfer of logical recoding rules from the color dimension to the location dimension. A recent study showed that this transfer of logical recoding rules can occur not only within a single task but also across two separate tasks that are intermixed. The present study investigated the conditions that determine the transfer of logical recoding rules across tasks. Experiment 1 examined whether it occurs in a transfer paradigm, that is when the two tasks are performed separately, but provided little support for this possibility. Experiment 2 investigated the role of task-set readiness, using a mixed-task paradigm with a predictable trials sequence, which indicated that there is no transfer of task-defined rules across tasks even when they are highly active during the Simon task. Finally, Experiments 3 and 4 used a mixed-task paradigm, where trials of the two tasks were mixed randomly and unpredictably, and manipulated the amount of feature overlap between tasks. Results indicated that task similarity is a determining factor for transfer of task-defined rules to occur. Overall, the study provides evidence that transfer of logical recoding rules tends to occur across two tasks when tasks are unpredictably intermixed and use stimuli that are highly similar and confusable. PMID- 23820944 TI - Different response patterns between auditory spectral and spatial temporal order judgment (TOJ). AB - Temporal order judgment (TOJ) thresholds have been widely reported as valid estimates of the temporal disparity necessary for correctly identifying the order of two stimuli. Data for two auditory TOJ paradigms are often reported in the literature: (1) spatially-based TOJ in which the order of presentation of the same stimulus to the right and left ear differs; and (2) spectrally-based TOJ in which the order of two stimuli differing in frequency is presented to one ear or to both ears simultaneously. Since the thresholds reported using the two paradigms differ, the aim of the current study was to compare their response patterns. The results from three different experiments showed that: (1) while almost none of the participants were able to perform the spatial TOJ task when ISI = 5 ms, with the spectral task, 50% reached an accuracy level of 75% when ISI = 5 ms; (2) temporal separation was only a partial predictor for performance in the spectral task, while it fully predicted performance in the spatial task; and (3) training improved performance markedly in the spectral TOJ task, but had no effect on spatial TOJ. These results suggest that the two paradigms may reflect different perceptual mechanisms. PMID- 23820945 TI - Moving to solution: effects of movement priming on problem solving. AB - Embodied cognition theories suggest a link between bodily movements and cognitive functions. Given such a link, it is assumed that movement influences the two main stages of problem solving: creating a problem space and creating solutions. This study explores how specific the link between bodily movements and the problem solving process is. Seventy-two participants were tested with variations of the two-string problem (Experiment 1) and the water-jar problem (Experiment 2), allowing for two possible solutions. In Experiment 1 participants were primed with arm-swing movements (swing group) and step movements on a chair (step group). In Experiment 2 participants sat in front of three jars with glass marbles and had to sort these marbles from the outer jars to the middle one (plus group) or vice versa (minus group). Results showed more swing-like solutions in the swing group and more step-like solutions in the step group, and more addition solutions in the plus group and more subtraction solutions in the minus group. This specificity of the connection between movement and problem-solving task will allow further experiments to investigate how bodily movements influence the stages of problem solving. PMID- 23820946 TI - Inhibition of return in the visual field: the eccentricity effect is independent of cortical magnification. AB - Inhibition of return (IOR) as an indicator of attentional control is characterized by an eccentricity effect, that is, the more peripheral visual field shows a stronger IOR magnitude relative to the perifoveal visual field. However, it could be argued that this eccentricity effect may not be an attention effect, but due to cortical magnification. To test this possibility, we examined this eccentricity effect in two conditions: the same-size condition in which identical stimuli were used at different eccentricities, and the size-scaling condition in which stimuli were scaled according to the cortical magnification factor (M-scaling), thus stimuli being larger at the more peripheral locations. The results showed that the magnitude of IOR was significantly stronger in the peripheral relative to the perifoveal visual field, and this eccentricity effect was independent of the manipulation of stimulus size (same-size or size-scaling). These results suggest a robust eccentricity effect of IOR which cannot be eliminated by M-scaling. Underlying neural mechanisms of the eccentricity effect of IOR are discussed with respect to both cortical and subcortical structures mediating attentional control in the perifoveal and peripheral visual field. PMID- 23820947 TI - Irrelevant speech disrupts item-context binding. AB - The present study examines the effects of irrelevant speech on immediate memory. Previous research led to the suggestion that auditory distractors particularly impair memory for serial order. These findings were explained by assuming that irrelevant speech disrupts the formation and maintenance of links between adjacent items in a to-be-remembered sequence, resulting in a loss of order information. Here we propose a more general explanation of these findings by claiming that the capacity to form and maintain item-context bindings is generally impaired by the presence of auditory distractors. The results of Experiment 1 show that memory for the association between an item and its background color is drastically impaired by irrelevant speech, just as memory for the association between an item and its serial position. In Experiment 2 it was examined whether the disrupting effects of irrelevant sound are limited to memory for item-context associations or whether item memory is also affected by the auditory distractors. The results revealed that irrelevant speech disrupts both item memory and item-context binding. The results suggest that the effects of irrelevant sound on immediate memory are more general than previously assumed, which has important theoretical and applied implications. PMID- 23820948 TI - Visualizing size-dependent deformation mechanism transition in Sn. AB - Displacive deformation via dislocation slip and deformation twinning usually plays a dominant role in the plasticity of crystalline solids at room temperature. Here we report in situ quantitative transmission electron microscope deformation tests of single crystal Sn samples. We found that when the sample size was reduced from 450 nm down to 130 nm, diffusional deformation replaces displacive plasticity as the dominant deformation mechanism at room temperature. At the same time, the strength-size relationship changed from "smaller is stronger" to "smaller is much weaker". The effective surface diffusivity calculated based on our experimental data matches well with that reported in literature for boundary diffusion. The observed change in the deformation mode arises from the sample size-dependent competition between the Hall-Petch-like strengthening of displacive processes and Coble diffusion softening processes. Our findings have important implications for the stability and reliability of nanoscale devices such as metallic nanogaps. PMID- 23820949 TI - An inter-laboratory validation of a multiplex dipstick assay for four classes of antibiotics in honey. AB - In this paper, we report the inter-laboratory validation (ILV) of a recently developed indirect competitive multiplex dipstick (Bee4sensor(r)) which is capable of the simultaneous detection of residues of some of the most frequently detected antibiotic residues in honey: sulfonamides, tylosin, fluoroquinolones and chloramphenicol. The multi-sensor dipstick can be interpreted via visual observation or by an instrumental measurement of four test lines. Statistical analysis of the ILV data demonstrated that the multi-sensor can reliably detect the presence of sulfathiazole at 25 MUg kg(-1) and tylosin at 10 MUg kg(-1), which fully meet the 'recommended concentrations' of the EU. Ciprofloxacin and chloramphenicol can be detected at 25 and 5 MUg kg(-1) in honey, respectively. Whilst the concentration for chloramphenicol is above the EU minimum required performance limit of 0.3 MUg kg(-1), this part of the multiplex test may still be of use to both the industry and enforcement authorities, to provide an early warning of contaminated honey. The estimated false-negative and false-positive rates for this easy-to-use and robust assay were less than 5%. PMID- 23820950 TI - Innovative detection methods for aquatic algal toxins and their presence in the food chain. AB - Detection of aquatic algal toxins has become critical for the protection of human health. During the last 5 years, techniques such as optical, electrochemical, and piezoelectric biosensors or fluorescent-microsphere-based assays have been developed for the detection of aquatic algal toxins, in addition to optimization of existing techniques, to achieve higher sensitivities, specificity, and speed or multidetection. New toxins have also been incorporated in the array of analytical and biological methods. The impact of the former innovation on this field is highlighted by recent changes in legal regulations, with liquid chromatography-mass spectrometry becoming the official reference method for marine lipophilic toxins and replacing the mouse bioassay in many countries. This review summarizes the large international effort to provide routine testing laboratories with fast, sensitive, high-throughput, multitoxin, validated methods for the screening of seafood, algae, and water samples. PMID- 23820951 TI - Ultrasound-assisted emulsification-microextraction for the sensitive determination of ethyl carbamate in alcoholic beverages. AB - A method based on ultrasound-assisted emulsification-microextraction (USAEME) was proposed in this contribution for the determination of ethyl carbamate (EC) in alcoholic beverages using gas chromatography coupled to triple quadrupole mass spectrometry. To achieve the determination of EC in alcoholic beverages, the influences on the extraction efficiency of type and volume of extraction solvent, temperature, ionic strength, alcohol content, and extraction time were studied, once the extraction solvent had been selected. The optimized conditions were 200.0 MUL of chloroform at 30 degrees C during 5 min with 15% (m/v) sodium chloride addition. The detection limit, relative standard deviations, linear range, and recoveries under the optimized conditions were 0.03 MUg L(-1), 4.2 6.1%, 0.1-50.0 MUg L(-1), and 80.5-87.9%, respectively. Moreover, the feasibility of the present method was also validated by real samples. To the best of our knowledge, this is the first time that USAEME has been applied to determine a strongly hydrophilic compound in alcoholic beverages. PMID- 23820952 TI - Development and validation method for the determination of selected tetracyclines in animal medicated feedingstuffs with the use of micellar liquid chromatography. AB - A chromatographic procedure for the determination of oxytetracycline (OTC), tetracycline (TC), chlorotetracycline (CTC), and doxycycline (DC) in medicated feedingstuffs was developed. Samples were extracted with 0.01 M citric buffer/acetonitrile (pH 3.0) and further purified with 0.45 MUm syringe filters. The purified extract was separated on Thermo column C18, 150 * 4 mm, 5 MUm and detection was carried out at 360 nm for OTC, and TC, 370 nm for CTC, and 350 nm for DC. TCs were eluted with a mobile phase of 0.03 M SDS/7% 1-butanol/0.02 M oxalic acid/NaOH at pH 2.5. This method provided average recoveries of 80.4% to 100.2%, with CVs of 0.5% to 6.6% in the range of 50 to 1500 mg/kg OTC, TC, CTC, and DC in feeds. The linearity for the four TCs was determined by high performance liquid chromatography-diode array detector (HPLC-DAD) in the range 10 300 MUg/mL (50-1500 mg/kg), with a linear correlation coefficient (R) > 0.99. The LOD and LOQ for TCs in pig and poultry feeds ranged from 4.0 to 10.7 and 4.7 to 12.6 mg/kg, respectively. The methodology was applied to the analysis of animal feedingstuffs collected from poultry and pig farms. PMID- 23820953 TI - Simultaneous electrochemical determination of two analytes based on nuclease assisted target recycling amplification. AB - In the present study, a method for simultaneous determination of two different DNAs is developed based on nuclease-assisted target recycling and nanoparticle amplification. The target recycling process is accomplished by taking advantage of the cleavage property of nicking endonuclease (NEase) for specific nucleotide sequences in duplex. In the presence of target DNA, the linker DNA in our detection system can hybridize with the target and be cleaved to form short fragments. Thus the target DNA is released and recognized by another linker DNA, activating the next round of cleavage reaction. On the other hand, two bio barcode probes, a PbS nanoparticles (NPs)-DNA probe and a CdS NPs-DNA probe, are used for tracing two target DNAs to further amplify the detection signals. Based on a sensitive differential pulse anodic stripping voltammetry (DPASV) method for the simultaneous detection of Pb(2+) and Cd(2+) obtained by dissolving two probes, two different target DNAs are determined with high sensitivity and single base mismatch selectivity. PMID- 23820954 TI - Profiling of the calcitonin-calcitonin receptor axis in primary prostate cancer: clinical implications and molecular correlates. AB - Expression of the neuroendocrine peptide calcitonin (CT) and its receptor (CTR) is frequently elevated in prostate cancers (PCs), and activation of the CT-CTR axis in non-invasive PC cells induces an invasive phenotype. We aimed to link CT/CTR expression in prostate specimens to clinicopathological parameters of PC. We analyzed CT and CTR expression in cohorts of benign prostates and primary PCs with/without metastatic disease by immunohistochemistry. Furthermore, we correlated CT/CTR expression with several clinicopathological parameters. CT/CTR immunostaining in benign prostate acini was predominantly localized to basal epithelium. However, this spatial specificity was lost in malignant prostates. PC sections displayed a remarkable increase in cell populations expressing CT/CTR and their staining intensity. Tumors with higher CT/CTR expression consistently displayed metastatic disease and poor clinical outcome. High CT/CTR expression in primary prostate tumors may serve as a prognostic indicator of disease aggressiveness and poor clinical outcome. PMID- 23820955 TI - Upregulated ZO-1 correlates with favorable survival of gastrointestinal stromal tumor. AB - Zonula occludens-1 (ZO-1) is a membrane-scaffolding protein that plays an important role in maintaining tight-junction integrity, which is disrupted in many invasive cancers and intestinal diseases. However, the expression of ZO-1 in gastrointestinal stromal tumor (GIST) and its relationship with clinical characteristics of this disease remain poorly understood. In this study, immunohistochemical analysis using tissue microarray was employed to evaluate the expression of ZO-1 in GIST and to investigate the relationship between its expression and GIST prognosis. High ZO-1 expression was displayed in 71.8 % of GIST patients, which was related to tumor diameter (p < 0.05). The Kaplan-Meier method and log-rank test indicated that high ZO-1 expression, small tumor diameter, tumor position in the esophagus, and a borderline-to-intermediate tumor grade displayed significant correlations with longer survival of GIST patients. The data suggest that ZO-1 expression is correlated with malignant phenotypes of GIST and it may serve as a favorable prognostic factor for GIST. These results also support a role for ZO-1 as a tumor-suppressor gene in GIST. PMID- 23820956 TI - Detection of perioperative cancer antigen 72-4 in gastric juice pre- and post distal gastrectomy and its significances. AB - Gastric carcinoma is one of the most common malignancies nowadays, and caner antigen 72-4 (CA 72-4) in gastric juice has been rarely studied. To compare CA 72 4 in gastric juice pre- and post-distal gastrectomy (DG) and analyze its possible significances, we selected 64 patients diagnosed with gastric carcinoma who underwent DG and collected their perioperative gastric juice samples whose contents of CA 72-4 were detected. We found that CA 72-4 in gastric juice pre gastrectomy is significantly higher among patients in advanced stages and correlated with tumor TNM classification (P < 0.01), within which tumor size, levels of gastric wall invaded, and number of metastatic lymph nodes are significant influencing factors (P < 0.05); CA 72-4 in gastric juice post gastrectomy is significantly higher than that pre-surgery (P < 0.01), and it is significantly correlated with tumor TNM classification and radical degree (P < 0.01), and regards the sum of distances from tumor to two cutting edges and the classification of cutting edge as significant impact factors (P < 0.05); nine patients whose CA 72-4 in gastric juice rose post-DG show features indicating poor prognosis; the difference of CA 72-4 in gastric juice between pre- and post gastrectomy is significantly correlated with tumor TNM classification and radical degree (P < 0.05), and regards tumor size, levels of gastric walls invaded, the sum of distances from tumor to two cutting edges and the classification of cutting edge as significant influential factors (P < 0.05). We conclude that CA 72-4 in gastric juice pre- and post-gastrectomy can provide us with much information about tumor and radical gastrectomy and that CA 72-4 in gastric juice post-gastrectomy and the difference of CA 72-4 in gastric juice between pre- and post-gastrectomy may indicate prognosis. PMID- 23820957 TI - An optimal cardiothoracic ratio cut-off to predict clinical outcomes in patients with acute myocardial infarction. AB - The traditional cut-off for the cardiothoracic ratio (CTR) by chest X-ray was not originally proposed as a prognostic variable. We investigated an optimal CTR cut off that could predict clinical outcomes in patients with acute myocardial infarction (AMI). A total of 3,083 AMI patients (65.2 +/- 12.0 years, 2,091 males) who underwent successful percutaneous coronary intervention were divided into two groups by use of a CTR of 0.42 as determined by receiver-operating characteristic curve analysis (group I: CTR <= 0.42, group II: CTR > 0.42). We compared the incidences of in-hospital death and major adverse cardiac events (MACEs), including cardiac death, reinfarction, coronary artery bypass grafting, and target lesion revascularization, during 12 months between the groups. The patients in group II were older than those in group I and included more women. The patients in group II were more likely to have hypertension and multivessel disease and had a higher Killip class, higher troponin, higher N-terminal pro brain natriuretic peptide, and lower ejection fraction than did those in group I. The in-hospital death rate was higher in group II (1.9 vs. 4.8%, p < 0.001). The incidences of cardiac death and composite of MACEs during 12 months of follow-up were significantly higher in group II than in group I (2.4 vs. 5.7%, p < 0.001, and 16.0 vs. 19.8%, p = 0.007, respectively). Multivariable logistic regression analysis revealed that CTR greater than 0.42 was an independent predictor of MACEs (relative risk: 1.361, 95% CI 1.014-1.827, p = 0.040). A CTR greater than 0.42, although within the traditional normal range, was associated with worse in hospital and long-term clinical outcome in AMI patients. PMID- 23820958 TI - Longitudinal systolic ventricular interaction in pediatric and young adult patients with TOF: a cardiac magnetic resonance and M-mode echocardiographic study. AB - Aim of this prospective study was to evaluate longitudinal systolic left ventricular (LV)-right ventricular (RV) interaction using M-mode compared to magnetic resonance imaging (MRI) data in 146 pediatric and adults with operated tetralogy of Fallot (TOF). We determined biventricular measures of longitudinal M mode echocardiography [i.e., tricuspid annular plane systolic excursion (TAPSE); the mitral annular plane systolic excursion (MAPSE)] compared to longitudinal function parameters using MRI. M-mode data were compared to established normal z score values. We found a good correlation between MAPSE and LVEF values (r = 0.788; p < 0.001). Correlations between MRI derived MAPSE and M-mode guided MAPSE (r = 0.879, p < 0.001), and between MRI derived TAPSE and M-mode guided TAPSE were significant (r = 0.780, p < 0.001). While the LVEF was normal in patients with a normal RVEF, the LVEF was decreased in patients with significantly reduced RVEF. Patients with a significantly dilated RV (RVEDVi > 150 ml/m(2)) showed a significantly reduced mean MAPSE of 1.30 +/- 0.26 cm. LV longitudinal function decreases below -2 SD of normal MAPSE z-score values after a mean of 22 postoperative years. Our data confirm progressive adverse RV-LV interaction in the long-term follow-up of TOF. We show that simple M-mode measurement of the longitudinal LV function (i.e. MAPSE) is a sufficient surrogate for estimation of LVEF. Therefore determination of the MAPSE is a helpful additional tool for LV systolic function assessment late after TOF repair. PMID- 23820959 TI - Neurophysiological and immunohistochemical studies of IgG anti-GM1 monoclonal antibody on neuromuscular transmission: effects in rat neuromuscular junctions. AB - Guillain-Barre syndrome, which is a variant of acute inflammatory neuropathy, is associated with anti-GM1 antibodies and causes ataxia. We investigated the effects of IgG anti-GM1 monoclonal antibody (IgG anti-GM1 mAb) on spontaneous muscle action potentials in a rat spinal cord-muscle co-culture system and the localization of IgG anti-GM1 mAb binding in the rat hemi-diaphragm. The frequency of spontaneous muscle action potentials in innervated muscle cells was acutely inhibited by IgG anti-GM1 mAb. When cultures were pretreated with GM2 synthase antisense oligodeoxynucleotide, IgG anti-GM1 mAb failed to inhibit spontaneous muscle action potentials, demonstrating the importance of the GM1 epitope in the action of IgG anti-GM1 mAb. Immunohistochemistry of rat hemi-diaphragm showed that IgG anti-GM1 mAb binding overlapped with neurofilament 200 (NF200) antibodies staining, but not alpha-bungarotoxin (alpha-BuTx) staining, demonstrating that IgG anti-GM1 mAb was localized at the presynaptic nerve terminal. IgG anti-GM1 mAb binding overlapped with syntaxin antibody and S-100 antibody in the nerve terminal. After collagenase treatment, IgG anti-GM1 mAb and NF200 antibodies did not show staining, but alpha-BuTx selectively stained the hemi-diaphragm. IgG anti-GM1 mAb binds to the presynaptic nerve terminal of neuromuscular junctions. Therefore, we suggest that the inhibitory effect of IgG anti-GM1 mAb on spontaneous muscle action potentials is related to the GM1 epitope in presynaptic motor nerve terminals at the NMJs. PMID- 23820960 TI - Acute brachial neuritis with central pontine and extrapontine myelinolysis in a renal transplant recipient. PMID- 23820961 TI - Can taxanes provide benefit in patients with CNS tumors and in pediatric patients with tumors? An update on the preclinical development of cabazitaxel. AB - PURPOSE: While first-generation taxanes are valuable treatment options for many solid tumors, they are limited by an inability to cross the blood-brain barrier (BBB) and by limited efficacy in pediatric patients. Following promising preclinical data for the next-generation taxane cabazitaxel, including activity in tumor models fully sensitive, poorly sensitive or insensitive to docetaxel, and its ability to cross the BBB, further preclinical studies of cabazitaxel relevant to these two clinical indications were performed. METHODS: Cabazitaxel brain distribution was assessed in mice, rats and dogs. Cabazitaxel antitumor activity was assessed in mice bearing intracranial human glioblastoma (SF295; U251) xenografts, and subcutaneous cell line-derived human pediatric sarcoma (rhabdomyosarcoma RH-30; Ewing's sarcoma TC-71 and SK-ES-1) or patient-derived pediatric sarcoma (osteosarcoma DM77 and DM113; Ewing's sarcoma DM101) xenografts. The activity of cabazitaxel-cisplatin combination was evaluated in BALB/C mice bearing the syngeneic murine colon adenocarcinoma, C51. RESULTS: Cabazitaxel penetrated rapidly in the brain, with a similar brain-blood radioactivity exposure relationship across different animal species. In intracranial human glioblastoma models, cabazitaxel demonstrated superior activity to docetaxel both at early (before BBB disruption) and at advanced stages, consistent with enhanced brain penetration. Compared with similar dose levels of docetaxel, cabazitaxel induced significantly greater tumor growth inhibition across six pediatric tumor models and more tumor regressions in five of the six models. Therapeutic synergism was observed between cisplatin and cabazitaxel, regardless of administration sequence. CONCLUSIONS: These preclinical data suggest that cabazitaxel could be an effective therapy in CNS and pediatric tumors, supporting ongoing clinical evaluation in these indications. PMID- 23820962 TI - Clinical pharmacology profile of vorinostat, a histone deacetylase inhibitor. AB - PURPOSE: Vorinostat is a histone deacetylase inhibitor that has demonstrated preclinical activity in numerous cancer models. Clinical activity has been demonstrated in patients with a variety of malignancies. Vorinostat is presently indicated for the treatment of patients with advanced cutaneous T cell lymphoma (CTCL). Clinical investigation is ongoing for therapy of other solid tumors and hematological malignancies either as monotherapy or in combination with other chemotherapeutic agents. This review summarizes the pharmacokinetic properties of vorinostat. METHODS: Monotherapy pharmacokinetic data across a number of pharmacokinetic studies were reviewed, and data are presented. In addition, literature review was performed to obtain published Phase I and II pharmacokinetic combination therapy data to identify and characterize potential drug interactions with vorinostat. Pharmacokinetic data in special populations were also reviewed. RESULTS: The clinical pharmacology profile of vorinostat is favorable, exhibiting dose-proportional pharmacokinetics and modest food effect. There appear to be no major differences in the pharmacokinetics of vorinostat in special populations, including varying demographics and hepatic dysfunction. Combination therapy pharmacokinetic data indicate that vorinostat has a low propensity for drug interactions. CONCLUSIONS: Vorinostat's favorable clinical pharmacology and drug interaction profile aid in the ease of administration of vorinostat for the treatment of advanced CTCL and will be beneficial in continued assessment for other oncologic indications. Although a number of studies have been conducted to elucidate the detailed pharmacokinetic profile of vorinostat, more rigorous assessment of vorinostat pharmacokinetics, including clinical drug interaction studies, will be informative. PMID- 23820963 TI - A phase 2 study of intravenous panobinostat in patients with castration-resistant prostate cancer. AB - PURPOSE: Panobinostat, a pan-deacetylase inhibitor, increases acetylation of proteins associated with growth and survival of malignant cells. This phase 2 study evaluated the efficacy of intravenous (IV) panobinostat in patients with castration-resistant prostate cancer (CRPC) who had previously received chemotherapy. The primary end point was 24-week progression-free survival. Secondary end points included safety, tolerability, and the proportion of patients with a prostate-specific antigen (PSA) decline. METHODS: IV panobinostat (20 mg/m(2)) was administered to patients on days 1 and 8 of a 21-day cycle. Tumor response was assessed by imaging every 12 weeks (4 cycles) according to modified response evaluation criteria in solid tumors (Scher et al. in Clin Cancer Res 11:5223-5232, 23), and PSA response was defined as a 50 % decrease from baseline maintained for >=4 weeks. Safety monitoring was routinely performed and included electrocardiogram monitoring. RESULTS: Of 35 enrolled patients, four (11.4 %) were alive without progression of disease at 24 weeks. PSA was evaluated in 34 (97.1 %) patients: five (14.3 %) patients demonstrated a decrease in PSA but none >=50 %; one patient (2.9 %) had carcinoembryonic antigen as a marker of his prostate cancer, which declined by 43 %. Toxicities regardless of relationship to panobinostat included fatigue (62.9 %), thrombocytopenia (45.7 %), nausea (51.4 %), and decreased appetite (37.1 %). CONCLUSIONS: Despite promising preclinical data and scientific rationale, treatment with IV panobinostat did not show a sufficient level of clinical activity to pursue further investigation as a single agent in CRPC. PMID- 23820964 TI - Central nervous system hemangiopericytoma with bone and lung metastases: a case report. PMID- 23820965 TI - Botulism associated with home-fermented tofu in two Chinese immigrants--New York City, March-April 2012. AB - In March 2012, the New York City Department of Health and Mental Hygiene (DOHMH) received two reports of recent immigrants from China admitted to the same hospital 23 days apart for suspected foodborne botulism. Patient 1 had a laboratory-confirmed case of foodborne botulism, and patient 2 had a probable case; patient 1's case was definitively associated with home-fermented tofu, and patient 2's case might have been associated with home-fermented tofu. Both patients had purchased fresh tofu from the same Chinese grocery in Queens, a New York City borough, in January 2012, and each had prepared home-fermented tofu using similar recipes. Similar fermentation practices at the two homes might have facilitated toxin production. Testing confirmed botulinum toxin type B in home fermented tofu consumed by patient 1. Bulk tofu at the grocery in Queens was found to be sold in unrefrigerated, uncovered, water-filled bins. Traceback revealed that the grocery's fresh bulk tofu supplier at the time of the patients' purchases had gone out of business. DOHMH advised the grocery's manager of the need to properly store bulk tofu. Public health responders and clinicians should be aware of the association between botulism and fermented tofu. PMID- 23820966 TI - Suicide and suicidal ideation among Bhutanese refugees--United States, 2009-2012. AB - During the period February 2009-February 2012, the Office of Refugee Resettlement of the U.S. Department of Health and Human Services reported 16 suicides among the approximately 57,000 Bhutanese refugees who had resettled in the United States since 2008. In 2012, the office requested assistance from CDC and the Massachusetts Department of Public Health's Refugee Health Technical Assistance Center to identify risk factors that might be associated with suicidal ideation among Bhutanese refugees. In collaboration with the Massachusetts refugee health center, CDC conducted a survey of randomly selected Bhutanese refugees in four U.S. states with large populations of resettled refugees. The results indicated significant associations between ever having expressed suicidal ideation and current self-reported symptoms of mental health disorder (e.g., anxiety, depression, or posttraumatic stress disorder) and postmigration difficulties (e.g., family conflict or inability to find work). The findings highlight the need for development of culturally appropriate community-based interventions for suicide prevention and standard procedures for monitoring and reporting suicides and suicide attempts in the Bhutanese refugee population. PMID- 23820967 TI - Vital signs: overdoses of prescription opioid pain relievers and other drugs among women--United States, 1999-2010. AB - BACKGROUND: Overdose deaths have increased steadily over the past decade. This report describes drug-related deaths and emergency department (ED) visits among women. METHODS: CDC analyzed rates of fatal drug overdoses and drug misuse- or abuse-related ED visits among women using data from the National Vital Statistics System (1999-2010) and the Drug Abuse Warning Network (2004-2010). RESULTS: In 2010, a total of 15,323 deaths among women were attributed to drug overdose, a rate of 9.8 per 100,000 population. Deaths from opioid pain relievers (OPRs) increased fivefold between 1999 and 2010 for women; OPR deaths among men increased 3.6 times. In 2010, there were 943,365 ED visits by women for drug misuse or abuse. The highest ED visit rates were for cocaine or heroin (147.2 per 100,000 population), benzodiazepines (134.6), and OPR (129.6). ED visits related to misuse or abuse of OPR among women more than doubled between 2004 and 2010. CONCLUSIONS: Although more men die from drug overdoses than women, the percentage increase in deaths since 1999 is greater among women. More women have died each year from drug overdoses than from motor vehicle-related injuries since 2007. Deaths and ED visits related to OPR continue to increase among women. The prominent involvement of psychotherapeutic drugs, such as benzodiazepines, among overdoses provides insight for prevention opportunities. IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: Health-care providers should follow guidelines for responsible prescribing, including screening and monitoring for substance abuse and mental health problems, when prescribing OPR. Health-care providers who treat women for pain should use their state's prescription drug monitoring program and regularly screen patients for psychological disorders and use of psychotherapeutic drugs, with or without a prescription. PMID- 23820968 TI - Ultrasound-guided adductor canal block for arthroscopic medial meniscectomy: a randomized, double-blind trial. AB - PURPOSE: The saphenous nerve block using a landmark-based approach has shown promise in reducing postoperative pain in patients undergoing arthroscopic medial meniscectomy. We hypothesized that performing an ultrasound-guided adductor canal saphenous block as part of a multimodal analgesic regimen would result in improved analgesia after arthroscopic medial meniscectomy. METHODS: Fifty patients presenting for ambulatory arthroscopic medial meniscectomy under general anesthesia were prospectively randomized to receive an ultrasound-guided adductor canal block with 0.5% ropivacaine or a sham subcutaneous injection of sterile saline. Our primary outcome was resting pain scores (numerical rating scale; NRS) upon arrival to the postanesthesia care unit (PACU). Secondary outcomes included NRS at six hours, 12 hr, 18 hr, and 24 hr; postoperative nausea; and postoperative opioid consumption. RESULTS: There was a statistically significant difference in mean NRS pain scores upon arrival to the PACU (P = 0.03): block group NRS = 1.71 (95% confidence interval [CI] 0.73 to 2.68) vs sham group NRS = 3.25 (95% CI 2.27 to 4.23). Cumulative opioid consumption (represented in oral morphine equivalents) over 24 hr was 71.8 mg (95% CI 56.5 to 87.2) in the sham group vs 44.9 mg (95% CI 29.5 to 60.2) in the block group (P = 0.016). CONCLUSIONS: An ultrasound-guided block at the adductor canal as part of a combined multimodal analgesic regimen significantly reduces resting pain scores in the PACU following arthroscopic medial meniscectomy. Furthermore, 24-hr postoperative opioid consumption and pain scores were also reduced. PMID- 23820969 TI - Role of the anesthesiologist in the wider governance of healthcare and health economics. AB - PURPOSE: Healthcare resources will always be limited, and as a result, difficult decisions must be made about how to allocate limited resources across unlimited demands in order to maximize health gains per resource expended. Governments and hospitals now in severe financial deficits recognize that reengagement of physicians is central to their ability to contain the runaway healthcare costs. Health economic analysis provides tools and techniques to assess which investments in healthcare provide good value for money vs which options should be forgone. Robust decision-making in healthcare requires objective consideration of evidence in order to balance clinical and economic benefits vs risks. PRINCIPAL FINDINGS: Surveys of the literature reveal very few economic analyses related to anesthesia and perioperative medicine despite increasing recognition of the need. Now is an opportune time for anesthesiologists to become familiar with the tools and methodologies of health economics in order to facilitate and lead robust decision-making in quality-based procedures. For most technologies used in anesthesia and perioperative medicine, the responsibility to determine cost effectiveness falls to those tasked with the governance and stewardship of limited resources for unlimited demands using best evidence plus economics at the local, regional, and national levels. Applicable cost-effectiveness, cost utility, and cost-benefits in health economics are reviewed in this article with clinical examples in anesthesia. CONCLUSIONS: Anesthesiologists can make a difference in the wider governance of healthcare and health economics if we advance our knowledge and skills beyond the technical to address the "other" dimensions of decision-making--most notably, the economic aspects in a value based healthcare system. PMID- 23820970 TI - Rapid changes in the electrical state of the 1999 Izmit earthquake rupture zone. AB - Crustal fluids exist near fault zones, but their relation to the processes that generate earthquakes, including slow-slip events, is unclear. Fault-zone fluids are characterized by low electrical resistivity. Here we investigate the time dependent crustal resistivity in the rupture area of the 1999 Mw 7.6 Izmit earthquake using electromagnetic data acquired at four sites before and after the earthquake. Most estimates of apparent resistivity in the frequency range of 0.05 to 2.0 Hz show abrupt co-seismic decreases on the order of tens of per cent. Data acquired at two sites 1 month after the Izmit earthquake indicate that the resistivity had already returned to pre-seismic levels. We interpret such changes as the pressure-induced transition between isolated and interconnected fluids. Some data show pre-seismic changes and this suggests that the transition is associated with foreshocks and slow-slip events before large earthquakes. PMID- 23820971 TI - Allele frequencies for 11 X chromosomal short tandem repeats in a population from Turkey. AB - X chromosomal STRs are nowadays an important part of forensic genetic analysis, especially in complex kinship cases. In this study, allele frequencies and forensic efficiency parameters of the 11 X chromosomal STRs DXS6807, DXS8378, DXS7132, DXS6800, DXS9898, DXS7424, DXS101, DXS7133, HPRTB, DXS8377 and DXS7423 in an admixed population from Turkey are presented. PMID- 23820972 TI - Morphology as a cause for different classification of the ossification stage of the medial clavicular epiphysis by ultrasound, computed tomography, and macroscopy. AB - The assessment of the ossification status of the medial clavicular epiphysis plays a decisive role in forensic age diagnostics to determine whether a person has completed his or her 18th or, respectively, 21st year of life. Currently, computed tomography is the gold standard method for age diagnostics of this kind. However, efforts are being made to establish non-ionizing methods, such as ultrasonography, predominantly, in an attempt to reduce the radiation exposure load of living persons. The present study is the first to score and to compare the ossification status of both medial clavicular epiphyses of the same subjects by sonography, computed tomography, and, in some of the cases, by macroscopy. Our study was conducted on five male corpses, ranging in age from 15.8-28.8 years. In the comparison of high-resolution sonography (frequency, 12-15 MHz) and thin slice computed tomography (slice thickness, 0.6 mm), performed separately for left and right clavicles, the results from these two methods differed in seven of ten cases. In six cases, the ossification stage of the medial clavicle, determined by sonography and classified according to Schulz et al. (2008), was scored higher than with computed tomography. In one case, it was rated lower. There was only one subject for whom both the sonographic and computed tomography findings agreed for both body sides. PMID- 23820973 TI - Lossless hybridization between photovoltaic and thermoelectric devices. AB - The optimal hybridization of photovoltaic (PV) and thermoelectric (TE) devices has long been considered ideal for the efficient harnessing solar energy. Our hybrid approach uses full spectrum solar energy via lossless coupling between PV and TE devices while collecting waste energy from thermalization and transmission losses from PV devices. Achieving lossless coupling makes the power output from the hybrid device equal to the sum of the maximum power outputs produced separately from individual PV and TE devices. TE devices need to have low internal resistances enough to convey photo-generated currents without sacrificing the PV fill factor. Concomitantly, a large number of p-n legs are preferred to drive a high Seebeck voltage in TE. Our simple method of attaching a TE device to a PV device has greatly improved the conversion efficiency and power output of the PV device (~30% at a 15 degrees C temperature gradient across a TE device). PMID- 23820974 TI - Short-term therapeutic effects of 890-nanometer light therapy for chronic low back pain: a double-blind randomized placebo-controlled study. AB - We conducted a double-blind randomized placebo-controlled study to investigate the effects of short-term 890-nm light therapy in patients with chronic low back pain in a rehabilitation clinic. Thirty-eight women and 22 men with chronic low back pain (mean age, 60.3 years; range, 32-80 years) received 40-min sessions of hot-pack therapy combined with active or placebo 890-nm light therapy (wavelength = 890 nm, radiant power output = 6.24 W, power density = 34.7 mW/cm(2) for 40 min, total energy = 83.2 J/cm(2)) over the lower back three times weekly for 2 weeks. Participants were assessed before and after treatment by using a range of motion measurements, a visual analog scale evaluation of pain, the Multidimensional Fatigue Inventory, the Biodex Stability System, the Fear Avoidance Beliefs Questionnaire, repeated chair-rising times, the Frenchay Activity Index, the Oswestry Disability Questionnaire (ODQ), and the Osteoarthritis Quality of Life Questionnaire. The severity of disability based on the ODQ score was used as the primary clinical outcome measurement. Compared to the baseline measurements, participants in the treatment group reported significant reductions in fear-avoidance beliefs regarding physical activity (P = 0.040) and work (P = 0.007) and in the severity of disability (P = 0.021). Treatment with hot-pack therapy and 890-nm light therapy was associated with reductions in the severity of disability and fear avoidance beliefs in patients with chronic low back pain. PMID- 23820975 TI - The role of transforming growth factor beta1 in fractional laser resurfacing with a carbon dioxide laser. AB - The aim of this study was to investigate the role of transforming growth factor beta1 in mechanisms of cutaneous remodeling induced by fractional carbon dioxide laser treatment. The dorsal skin of Kunming mice was exposed to a single-pass fractional CO2 laser treatment. Biopsies were taken at 1 h and at 1, 3, 7, 14, 21, 28, and 56 days after treatment. Transforming growth factor (TGF) beta1 expression in skin samples was evaluated by ELISA, dermal thickness by hematoxylin-eosin staining, collagen and elastic fibers by Ponceau S and Victoria blue double staining, and types I and III collagens by ELISA. The level of TGF beta1 in the laser-treated areas of skin was significantly increased compared with that in the control areas on days 1 (p < 0.05), 3 (p < 0.01), and 7 (p < 0.05) and then decreased by day 14 after treatment, at which time it had returned to the baseline level. Dermal thickness and the amount of type I collagen of the skin of the laser-treated areas had increased significantly (p < 0.05) compared with that in control areas on days 28 and 56. Fibroblast proliferation showed a positive correlation with TGF beta1 expression during the early stages (r = 0.789, p < 0.01), and there was a negative correlation between the level of TGF beta1 and type I collagen in the late stages, after laser treatment (r = -0.546, p < 0.05). TGF beta1 appears to be an important factor in fractional laser resurfacing. PMID- 23820977 TI - Visual and linguistic cues to graspable objects. AB - Two experiments investigated (1) how activation of manual affordances is triggered by visual and linguistic cues to manipulable objects and (2) whether graspable object parts play a special role in this process. Participants pressed a key to categorize manipulable target objects copresented with manipulable distractor objects on a computer screen. Three factors were varied in Experiment 1: (1) the target's and (2) the distractor's handles' orientation congruency with the lateral manual response and (3) the Visual Focus on one of the objects. In Experiment 2, a linguistic cue factor was added to these three factors participants heard the name of one of the two objects prior to the target display onset. Analysis of participants' motor and oculomotor behaviour confirmed that perceptual and linguistic cues potentiated activation of grasp affordances. Both target- and distractor-related affordance effects were modulated by the presence of visual and linguistic cues. However, a differential visual attention mechanism subserved activation of compatibility effects associated with target and distractor objects. We also registered an independent implicit attention attraction effect from objects' handles, suggesting that graspable parts automatically attract attention during object viewing. This effect was further amplified by visual but not linguistic cues, thus providing initial evidence for a recent hypothesis about differential roles of visual and linguistic information in potentiating stable and variable affordances (Borghi in Language and action in cognitive neuroscience. Psychology Press, London, 2012). PMID- 23820976 TI - Abnormal auditory sensory gating-out in first-episode and never-medicated paranoid schizophrenia patients: an fMRI study. AB - Numerous electrophysiological studies have showed auditory sensory gating-out abnormalities in chronic schizophrenia with antipsychotic medication. Previous research has used functional magnetic resonance imaging (fMRI) with excellent spatial resolution to identify the neural substrates of sensory gating-out deficits revealing increased hemodynamic response in the hippocampus, thalamus and prefrontal cortex. However, such results obtained from medicated patients may be confounded by antipsychotic medication. The present study scanned 15 first episode schizophrenia patients not yet receiving any medical treatment and 15 healthy controls matched in gender, age and education when they performed a sensory gating-out task adapted for fMRI. The symptoms of the patients were assessed with the positive and negative syndrome scale. Different from previous findings, the schizophrenia patients showed decreased activation in hippocampus and thalamus during sensory gating-out, compared with the normal controls. The results support the theory attributing abnormal sensory gating-out in schizophrenia patients to the dysfunction of hippocampus and thalamus. PMID- 23820978 TI - Inhibition of histone deacetylation alters Arabidopsis root growth in response to auxin via PIN1 degradation. AB - KEY MESSAGE: Our results showed the histone deacetylase inhibitors (HDIs) control root development in Arabidopsis via regulation of PIN1 degradation. Epigenetic regulation plays a crucial role in the expression of many genes in response to exogenous or endogenous signals in plants as well as other organisms. One of epigenetic mechanisms is modifications of histone, such as acetylation and deacetylation, are catalyzed by histone acetyltransferase (HAT) and histone deacetylase (HDAC), respectively. The Arabidopsis HDACs, HDA6, and HDA19, were reported to function in physiological processes, including embryo development, abiotic stress response, and flowering. In this study, we demonstrated that histone deacetylase inhibitors (HDIs) inhibit primary root elongation and lateral root emergence. In response to HDIs treatment, the PIN1 protein was almost abolished in the root tip. However, the PIN1 gene did not show decreased expression in the presence of HDIs, whereas IAA genes exhibited increases in transcript levels. In contrast, we observed a stable level of gene expression of stress markers (KIN1 and COR15A) and a cell division marker (CYCB1). Taken together, these results suggest that epigenetic regulation may control auxin mediated root development through the 26S proteasome-mediated degradation of PIN1 protein. PMID- 23820979 TI - Transgenic tobacco lines expressing defective CMV replicase-derived dsRNA are resistant to CMV-O and CMV-Y. AB - Cucumber mosaic virus (CMV) is a tripartite, positive sense RNA virus causing infections and yield losses to many plant species. Here, we generated a construct containing inverted repeat of 1,793 bp fragment of defective CMV replicase gene derived from RNA2 of cucumber mosaic virus strain O (CMV-O). The replicase gene was modified by deleting a 9 bp region between nucleotides 1909-1918. This caused a deletion in the active centre motif of polymerases, producing defective translated product 9 nucleotides shorter than the full length protein. The RNAi construct containing inverted repeat of the defective gene was used to produce transgenic tobacco lines expressing CMV-derived double-stranded RNA via Agrobacterium-mediated transformation. Of the four transgenic lines inoculated with CMV-O or CMV-Y in vitro and ex vivo, three lines (T1, T4 and T5) showed immunity to both strains of CMV as no symptoms were detected, whereas one line (T7) exhibited high resistance with mild symptoms limited to inoculation portions. No virus could be detected in uninoculated new leaves of the transgenic lines after RT-PCR and Dot-immunobinding assay analyses. Small interfering RNAs present in transgenic lines before and after virus challenge indicates that the resistance was acquired through RNA silencing. PMID- 23820980 TI - Analysis of HOX gene expression patterns in human breast cancer. AB - HOX genes are highly conserved transcription factors that determine the identity of cells and tissues along the anterior-posterior body axis in developing embryos. Aberrations in HOX gene expression have been shown in various tumors. However, the correlation of HOX gene expression patterns with tumorigenesis and cancer progression has not been fully characterized. Here, to analyze putative candidate HOX genes involved in breast cancer tumorigenesis and progression, the expression patterns of 39 HOX genes were analyzed using breast cancer cell lines and patient-derived breast tissues. In vitro analysis revealed that HOXA and HOXB gene expression occurred in a subtype-specific manner in breast cancer cell lines, whereas most HOXC genes were strongly expressed in most cell lines. Among the 39 HOX genes analyzed, 25 were chosen for further analysis in malignant and non-malignant tissues. Fourteen genes, encoding HOXA6, A13, B2, B4, B5, B6, B7, B8, B9, C5, C9, C13, D1, and D8, out of 25 showed statistically significant differential expression patterns between non-malignant and malignant breast tissues and are putative candidates associated with the development and malignant progression of breast cancer. Our data provide a valuable resource for furthering our understanding of HOX gene expression in breast cancer and the possible involvement of HOX genes in tumor progression. PMID- 23820981 TI - The consequences of long-term glycogen synthase kinase-3 inhibition on normal and insulin resistant rat hearts. AB - BACKGROUND: Glycogen synthase kinase-3 (GSK-3) is a serine-threonine protein kinase, discovered as a regulator of glycogen synthase. GSK-3 may regulate the expression of SERCA-2a potentially affecting myocardial contractility. It is known to phosphorylate and inhibit IRS-1, thus disrupting insulin signalling. This study aimed to determine whether myocardial GSK-3 protein and its substrate proteins are dysregulated in obesity and insulin resistance, and whether chronic GSK-3 inhibition can prevent or reverse this. METHODS: Weight matched male Wistar rats were rendered obese by hyperphagia using a special diet (DIO) for 16 weeks and compared to chow fed controls. Half of each group was treated with the GSK-3 inhibitor CHIR118637 (30 mg/kg/day) from week 12 to16 of the diet period. Biometric and biochemical parameters were measured and protein expression determined by Western blotting and specific antibodies. Ca(2+)ATPase activity was determined spectrophotometrically. Cardiomyocytes were prepared by collagenase perfusion and insulin stimulated 2-deoxy-glucose uptake determined. RESULTS: DIO rats were significantly heavier than controls, associated with increased intra peritoneal fat and insulin resistance. GSK-3 inhibition did not affect weight but improved insulin resistance, also on cellular level. It had no effect on GSK-3 expression but elevated its phospho/total ratio and elevated IRS-2 expression. Obesity lowered SERCA-2a expression and activity while GSK-3 inhibition alleviated this. The phospho/total ratio of phospholamban underscored inhibition of SERCA-2a in obesity. In addition, signs of myocardial hypertrophy were observed in treated control rats. CONCLUSION: GSK-3 inhibition could not reverse all the detrimental effects of obesity but may be harmful in normal rat hearts. It regulates IRS-2, SERCA-2a and phospholamban expression but not IRS-1. PMID- 23820982 TI - Gold nanoparticle-composite nanofibers for enzymatic electrochemical sensing of hydrogen peroxide. AB - Robust composite nanofibers (NFs) are prerequisite for highly efficient electrochemical sensors. We report the electrochemical application of gold nanoparticle (Au NP)-composite Nafion NFs using a facile electrospinning technique. Owing to the uniform distribution and large surface area of the Au NPs in the NFs, the Au NP-composite electrodes gave rise to greatly improved electrochemical properties, compared to AuNP-free composite electrodes. When they were employed as reservoirs for immobilizing horseradish peroxidase (HRP), reliable and sensitive electrochemical detection by the enzyme reaction was achieved. The detection sensitivity for H2O2 was determined to be as low as 38 nM, which was one order higher than that of previous electrochemical sensors. In addition, there was no change in the enzyme stability over three weeks. In this regard, the developed NP/NF-based electrochemical sensors are anticipated to be very suitable for monitoring other enzyme reactions with high sensitivity and stability. PMID- 23820983 TI - Characteristics, processes, management and outcome of accesses to accident and emergency departments by citizenship. AB - OBJECTIVES: The aim of this study was to analyze the characteristics of accident and emergency department (A and E) access, process management and outcome after grouping patients by their citizenship. METHODS: The study was conducted using the recorded linkage database at a local public health agency in north-east Italy. We investigated 35,541 adult patients (18-65 years) accessing the A and E. RESULTS: An underutilization of primary care services and the use of A and E for nonurgent conditions is a problem affecting all nationalities, natives included. The length of the stay in A and E and the consistency between level of urgency and priority of the visits at entry and exit triage were similar for all citizenship groups. Illegal migrants were more frequently hospitalized after A and E visits than other groups. CONCLUSIONS: The potentially inappropriate use of A and E for non-urgent conditions was common among all the patient groups considered and barriers to primary care may enhance this behavior among migrants. This situation could also explain the higher odds ratio for migrants' hospitalization and discharge to ambulatory services after A and E visits. PMID- 23820985 TI - Intranasal and subcutaneous administration of dopamine D3 receptor agonists functionally restores nigrostriatal dopamine in MPTP-treated mice. AB - Parkinson's disease (PD) is a neurodegenerative disease with a hallmark motor defect caused by the death of dopaminergic neurons in the substantia nigra. Intranasal drug administration may be useful for Parkinson's treatment because this route avoids first-pass metabolism and increases bioavailability in the brain. In this study, we investigated the neuroprotection/neurorestoration effect of dopamine D3 receptor (D3R) agonists administered via both intranasal and subcutaneous routes in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced PD mouse model. Furthermore, we employed D3R knock-out mice to validate the dependence on D3R signaling. We found that in wild-type mice, but not D3 receptor knockout mice, both intranasal and subcutaneous administration of D3R agonists rescue dopamine (DA) depletion in the striatum as well as DA neuronal death in the substantia nigra after MPTP treatment. Moreover, subcutaneous 7-OH DPAT administration significantly improved gait performance (stride length and overall running speed) of MPTP-lesioned mice after 7 and 14 days of recovery. In addition, the distribution of D3 agonist 7-OH-DPAT was measured in designated brain areas by mass spectrometry analysis after subcutaneous and intranasal administration. Our data suggest that intranasal administration of D3R agonist would be a practical approach to treat PD. PMID- 23820987 TI - Problem alcohol use among problem drug users: development and content of clinical guidelines for general practice. AB - BACKGROUND: Problem alcohol use is common and associated with considerable adverse outcomes among patients who attend primary care in Ireland and other European countries for opiate substitution treatment. AIMS: This paper aims to describe the development and content of clinical guidelines for the management of problem alcohol use among this population. METHODS: The guidelines were developed in three stages: (1) identification of key stakeholders, (2) development of evidence-based draft guidelines, and (3) determination of a modified 'Delphi facilitated' consensus among the group members. RESULTS: The guidelines incorporate advice for physicians on all aspects of care, including (1) definition of problem alcohol use among problem drug users, (2) alcohol screening, (3) brief intervention, and (4) subsequent management of patients with alcohol dependence. CONCLUSIONS: Primary care has an important role to play in the care of problem alcohol use among problem drug users, especially opiate substitution patients. Further research on strategies to inform the implementation of these guidelines is a priority. PMID- 23820989 TI - Hospital readmissions in patients with inflammatory bowel disease. AB - OBJECTIVES: We aimed to identify the frequency and costs of, and the disease predictors and inpatient process issues that may predispose to, 30-day readmission for an inflammatory bowel disease (IBD) patient. METHODS: IBD patients admitted to an inpatient gastroenterology service were followed for a time-to-readmission analysis assessing factors associated with readmission within 30 days. RESULTS: Index admissions were more costly among those readmitted than among those not readmitted. Patients admitted with evidence of increased inflammation, infection, or obstruction or for dehydration or pain control had a higher risk of readmission. Patients treated with opioid analgesia during index admission were no less likely to be readmitted, and there was a 2.2-fold increase in readmissions when patients were discharged with no opioid analgesia. Scheduling variability and outpatient follow-up compliance were associated with readmission. CONCLUSIONS: Predicting readmission is complex. A predictive model developed to be used at discharge yielded an area under the curve of 0.757. PMID- 23820986 TI - Chronic alcohol alters dendritic spine development in neurons in primary culture. AB - Dendritic spines are specialised membrane protrusions of neuronal dendrites that receive the majority of excitatory synaptic inputs. Abnormal changes in their density, size and morphology have been associated with various neurological and psychiatric disorders, including those deriving from drug addiction. Dendritic spine formation, morphology and synaptic functions are governed by the actin cytoskeleton. Previous in vivo studies have shown that ethanol alters the number and morphology of spines, although the mechanisms underlying these alterations remain unknown. It has also been described how chronic ethanol exposure affects the levels, assembly and cellular organisation of the actin cytoskeleton in hippocampal neurons in primary culture. Therefore, we hypothesised that the ethanol-induced alterations in the number and shape of dendritic spines are due to alterations in the mechanisms regulating actin cytoskeleton integrity. The results presented herein show that chronic exposure to moderate levels of alcohol (30 mM) during the first 2 weeks of culture reduces dendritic spine density and alters the proportion of the different morphologies of these structures in hippocampal neurons, which affects the formation of mature spines. Apparently, these effects are associated with an increase in the G-actin/F-actin ratio due to a reduction of the F-actin fraction, leading to changes in the levels of the different factors regulating the organisation of this cytoskeletal component. The data presented herein indicate that these effects occur between weeks 1 and 2 of culture, an important period in dendritic spines development. These changes may be related to the dysfunction in the memory and learning processes present in children prenatally exposed to ethanol. PMID- 23820990 TI - A nationwide survey of gastroenterologists and their acquisition of knowledge. AB - OBJECTIVES: The Gastroenterology (GI) Core Curriculum is a culmination of efforts from the American Association for the Study of Liver Diseases, the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy to develop a review of knowledge and skills for those training in a gastrointestinal subspecialty. Fellows are expected to conduct scholarly activity, attend seminars, and read textbooks and syllabus materials. While efforts to standardize education across the nation are welcomed, we sought to ascertain the learning preferences of GI fellows and attending physicians. METHODS: A national online survey was e-mailed to directors of US adult GI programs, who were also asked to invite their colleagues and fellows to participate. RESULTS: While majorities of both fellows and attendings affirmed regular attendance at national conferences, more attendings affirmed that their knowledge was improved by their participation. Asked how they acquire knowledge best, 45 fellows and 67 attendings responded; 42% of attendings favored journal articles, and 40% of fellows favored conferences. More attendings than fellows felt that writing a manuscript and belonging to a GI society improved knowledge. CONCLUSIONS: We believe the Gastroenterology Core Curriculum provides trainees with essential tools for becoming an autonomous gastroenterologist who can appreciate various learning modalities. PMID- 23820991 TI - The next generation of endoscopic simulation. AB - Over the past decade, the capabilities and use of endoscopic simulators have steadily expanded. Nevertheless, simulator use has yet to become fully integrated into standard endoscopic training programs. There are two obstacles. First, we lack adequate knowledge about how competency should be defined and how people become proficient in various specific techniques. Second, there has not been an affordable and convenient model to effectively assist in training and assessment. This paper explores the barriers to incorporation of simulators in training programs, and discusses currently available mechanical, computer, and ex vivo tissue models for assessment. PMID- 23820997 TI - Adequate interval for hepatocellular carcinoma surveillance. PMID- 23820998 TI - Response to Giannini et al. PMID- 23820999 TI - Growth of ambulatory surgical centers, surgery volume, and savings to medicare. PMID- 23821000 TI - Anesthesia service costs and savings to medicare from the growth of ASCs. PMID- 23821001 TI - Optimizing ribavirin exposure by therapeutic drug monitoring improves treatment response in patients with chronic hepatitis C genotype 1. PMID- 23821002 TI - BAG3 is a novel serum biomarker for pancreatic adenocarcinomas. PMID- 23821003 TI - Reactivation of latent tuberculosis in a Crohn's patient after TB prophylaxis treated with adalimumab. PMID- 23821004 TI - Helicobacter-negative gastritis: the pediatric perspective. PMID- 23821008 TI - Synthesis, characterization and reactivity of single-site aluminium amides bearing benzotriazole phenoxide ligands: catalysis for ring-opening polymerization of lactide and carbon dioxide/propylene oxide coupling. AB - New aluminium complexes containing bis-BTP ligands (BTP = N,O-bidentate benzotriazole phenoxide) were synthesized and structurally characterized. Amine elimination of Al(NMe2)3 with (R)BTP-H ligands ((CMe2Ph)BTP-H = 2-(2H benzotriazol-2-yl)-4,6-bis(1-methyl-1-phenylethyl)phenol, (t-Bu)BTP-H = 2-(2H benzotriazol-2-yl)-4,6-di-tert-butylphenol and (TMCl)BTP-H = 2-tert-butyl-6-(5 chloro-2H-benzotriazol-2-yl)-4-methylphenol) (2.0 mol equiv.) in toluene or hexane afforded the penta-coordinated single-site amidoaluminium complexes [((R)BTP)2Al(NMe2)] (R = CMe2Ph for 1; R = t-Bu for 2; R = TMCl for 3) in satisfactory yields. With the addition of H2O (0.5 molar equiv.), the hydrolysis of Al amides 2 and 3 in a mixed solvent of THF/toluene at 25 degrees C produced oxo-bridged bimetallic aluminium complexes [{((R)BTP)2Al}2(MU-O)] (R = t-Bu for 4 and R = TMCl for 5) in >=70% yield. According to single crystal X-ray diffraction studies, complex 2 shows a monomeric Al(iii) amide with bis((t-Bu)BTP) ligands and one -NMe2 group, whereas alumoxane 4 is a dinuclear species, in which the bonding mode of the Al-O-Al moiety from MU2-oxo assumes a linear type. Catalysis for ring-opening polymerization of lactide (LA) and CO2/propylene oxide (PO) coupling was systematically studied. Single-site Al amide 3 is an efficient initiator for LA polymerizations with a living character; the polymerization displays a first-order dependence on the concentration of l-LA. Bimetallic BTP ligated alumoxane 5 is an active catalyst (TOF: 120 h(-1)) for the coupling of CO2 with PO in the presence of n-Bu4NBr to give propylene carbonate under mild conditions. PMID- 23821009 TI - The mediator role of emotion regulation processes on infertility-related stress. AB - The objective of this study is to investigate gender differences regarding the mediator role of self-compassion and self-judgment on the effects of external shame, internal shame, dyadic adjustment, on infertility-related stress. One hundred and sixty-two women and 147 men with a primary infertility diagnosis completed the following set of self-report measures: Others as Shamer, Experience of Shame Scale, Dyadic Adjustment Scale, Self-Compassion Scale, and Fertility Problem Inventory. Path analyses results revealed that in women self-compassion fully mediated the effect of internal shame on infertility-related stress and partially mediated the effect of dyadic adjustment on this variable, while external shame had only a direct effect. In men self-judgment fully mediated the effect of external and internal shame on infertility-related stress. Dyadic adjustment had only a direct effect on infertility-related stress. In conclusion, there is a distinct role of self-compassion and self-judgment on the relationship between shame and infertility-related stress in men and women. Such differences should be taken into account in psychological interventions with these patients. Future research is warranted to further support our results. PMID- 23821010 TI - Factors associated with non-reimbursable activity on an inpatient pediatric consultation-liaison service. AB - The aim of this study was to identify factors contributing to clinician time spent in non-reimbursable activity on an inpatient pediatric consultation-liaison (C-L) service. A retrospective study was conducted using inpatient C-L service data on 1,246 consecutive referrals. For this patient population, the strongest predictor of level of non-reimbursable clinical activity was illness chronicity and the number of contacts with C-L service clinicians during their hospital stay. Patients with acute life-threatening illnesses required the highest mean amount of non-reimbursable service activity. On average, 28 % of total clinician time in completing a hospital consultation was spent in non-reimbursable activity. Effective C-L services require a proportion of time spent in non reimbursable clinical activity, such as liaison and coordinating care with other providers. Identifying referral and systemic factors contributing to non reimbursable activity can provide insight into budgeting/negotiating for institutional support for essential clinical and non-clinical functions in providing competent quality patient care. PMID- 23820984 TI - Neurotoxic saboteurs: straws that break the hippo's (hippocampus) back drive cognitive impairment and Alzheimer's Disease. AB - Late onset Alzheimer's disease (AD) is the most common cause of progressive cognitive dysfunction and dementia. Despite considerable progress in elucidating the molecular pathology of this disease, we are not yet close to unraveling its etiopathogenesis. The hippocampus is at the epicenter of cognition being associated with learning and memory. A battery of neurotoxic modifiers has been delineated that may unleash deleterious heterogeneous pathologic impacts. Synergistically they target hippocampus causing its neuronal degeneration, gray matter volume atrophy, and progressive cognitive decline. The neurotoxic factors include aging, stress, depression, hypoxia/hypoxemia, hypertension, diabetes, obesity, alcohol abuse, smoking, malnutrition, and polypharmacy-to name a few. Addressing "upstream pathologies" due to these multiple and heterogeneous neurotoxic modifiers vis-a-vis hippocampal dysfunction is of paramount importance. The downstream-generated inflammatory cytokines, mitochondrial dysfunction, oxidative stress, hypoperfusion, excitotoxicity, amyloid beta, and neurofibrillary tangles may then trigger and sustain neurocognitive pathology. The failure of clinical trials in AD is due in part to this complex multifactorial neurotoxic-pathophysiological labyrinth. The key is to employ appropriate preventive and treatment strategies prior to significant hippocampus damage and its dysfunction. Prevention/reversal of the diverse neurotoxic impacts, delineated here, should be an integral part of therapeutic armamentarium, in order to ameliorate hippocampus dysfunction and to enhance memory in aging, mild cognitive impairment, and AD. Throughout, the paper highlights both the challenges presented by the ever present neurotoxic onslaught, and the opportunities to overcome them. Hence, arresting AD pathogenesis is achievable through early intervention. A targeted approach may ameliorate neurocognitive pathology and attenuate memory deterioration. PMID- 23821011 TI - A clinical and radiographic comparison of two hardware systems used to treat jones fracture of the fifth metatarsal. AB - BACKGROUND: There is a broad variation in the type and size of screws used for Jones fractures. Therefore, a screw implant specifically designed for the operative treatment of a Jones fracture has been developed. The purpose of this retrospective study was to compare the clinical and radiographic results of patients treated with a screw specifically designed for this fracture to a group treated with a traditional screw. METHODS: Forty-seven patients underwent surgery (47 feet) for a Jones fracture between 1999 and 2007, performed by 4 foot and ankle fellowship-trained orthopaedic surgeons at one institution. Twenty-six patients (26 feet) were treated with the indication-specific screw (group I), while 21 patients (21 feet) were operated on with the traditional screw (group II). All patients were retrospectively reviewed for either radiographic signs of union or an adverse event. Radiographic parameters were evaluated by 2 independent observers, which included Torg's classification system (intramedullary sclerosis, cortical hypertrophy, periosteal reaction), hardware failure, with an endpoint of healing or nonunion. Of 47 patients, 40 were available for clinical follow-up, and functional outcomes with VAS pain scores at final follow-up visit were compared. Additional procedures (bone grafting), complications, and adverse events were recorded. The results were analyzed using Fisher's exact tests and independent t test with a significance level of .05. The average age of the patients was 43.8 years, with a mean clinical follow-up of 37 months (range of 6 to 105 months). RESULTS: Preoperative films were classified according to the Torg classification system and did not demonstrate any difference between group I and group II, with respect to the type of Jones fracture. There was no significant difference found between the 2 groups as related to fracture union, but there was a higher number of adverse events in group II as compared with group I (P = .03). The adverse events included 2 implant failures, 1 intraoperative fracture, and 1 symptomatic hardware, all requiring further surgical interventions. All adverse events occurred within an average of 2 months after surgery. Clinically, there were no statistically significant differences between the 2 systems in regard to limitations in activity, shoe-wear modifications, recovery time, satisfaction, and willingness to repeat the surgery. The VAS pain scales (0-100) were equivalent; average VAS pain of group II was reported as 9 (range, 0-33), as compared to the VAS pain of patients in group I averaging 11 (range, 0-47). CONCLUSIONS: In our retrospective series, comparing 2 differing instrumentation systems in treating Jones fractures, both groups were found to progress to radiographic union above 95%. Although there was a statistically greater number of adverse events in the traditional hardware system (group II), clinically both groups had similar outcomes with good results. LEVEL OF EVIDENCE: Level III, retrospective comparative series. PMID- 23821012 TI - Joint preservation procedures for ankle arthritis. PMID- 23821013 TI - Hospital-based employment for orthopaedic surgeons. PMID- 23821015 TI - Dual energy CT in patients with acute abdomen; is it possible for virtual non enhanced images to replace true non-enhanced images? AB - This study aims to determine whether virtual non-enhanced images derived from dual-energy computed tomography (CT) can replace true non-enhanced images in patients with acute abdomen. Patients with acute abdomen (n = 202) underwent multidetector CT including non-enhanced and contrast-enhanced images obtained at the portal phase using the dual-energy technique. CT attenuation values were measured in abdominal organs. Image quality, noise, artifacts, and acceptability for virtual non-enhanced images compared to true non-enhanced images were rated. Mean sizes of clinically significant stones and mean attenuation values of intraabdominal hemorrhages were compared by means of five-point scales. Effective radiation doses were calculated. Mean CT attenuation values of virtual non enhanced and true non-enhanced images were similar. Virtual non-enhanced images showed good image quality, mild noise, mild artifacts, and good acceptability compared to true non-enhanced images. A total of 71 clinically significant stones (11 appendicoliths, 33 gallbladder stones, 11 bile duct stones, and 16 urinary stones) and 15 intraabdominal hemorrhages were included in the study. Small stones were detected better on true non-enhanced images than on virtual non enhanced images. Hemorrhage was similarly detected on both virtual non-enhanced and true non-enhanced images. Mean radiation dose reductions by omitting true non enhanced images were 33 % in the virtual triple protocol and 47 % in the virtual dual protocol. Image qualities of virtual non-enhanced images are comparable to those of true non-enhanced images. Small stones can be obscured on virtual non enhanced images. Therefore, tailored application of dual-energy CT is needed for evaluation of patients with acute abdomen. PMID- 23821016 TI - First-principles prediction and experimental verification of glass-forming ability in Zr-Cu binary metallic glasses. AB - In the field of metallic materials with amorphous structures, it is vitally important to understand the glass formation and to predict glass-forming ability (GFA) in terms of constituent elements and alloy compositions. In this study, an expression has been formulated from first-principles calculations to predict the trend of GFA by hybridizing both internal energies and atomic-scale defect structures. The prediction of GFA from compositions has been verified successfully by available experimental data in the model Zr-Cu alloy system. The physical scenario revealed here has extensive implications for the design of bulk metallic glasses with superior GFA. PMID- 23821017 TI - The prognostic significance of peroxisome proliferator-activated receptor beta expression in the vascular endothelial cells of colorectal cancer. AB - OBJECTIVE: Currently, little is known regarding the role of peroxisome proliferator-activated receptor-beta (PPAR beta) in the vascular endothelial cells (VECs) of colorectal cancers (CRCs). The aim of this study was to investigate the relationship of PPAR beta expression in the VECs of CRCs in terms of the prognosis and clinicopathological features of CRC patients. DESIGN: The expression and localization of PPAR beta in the primary cancers and the matched normal mucosal samples of 141 Swedish CRC patients were analyzed in terms of its correlation with clinicopathological features and the expression of angiogenesis related genes. This study also included 92 Chinese CRC patients. RESULTS: PPAR beta was predominantly localized in the cytoplasm and was significantly downregulated in the VECs of CRC compared to that of the normal mucosa. The low expression levels of PPAR beta in the VECs of CRC were statistically correlated with enhanced differentiation, early staging and favorable overall survival and were associated with the increased expression of VEGF and D2-40. The patients exhibiting elevated expression of PPAR beta in CRC cells but reduced expression in VECs exhibited more favorable survival compared with the other patients, whereas the patients with reduced expression of PPAR beta in CRC cells but increased expression in VECs exhibited less favorable prognosis. CONCLUSIONS: PPAR beta might play a tumor suppressor role in CRC cells in contrast to a tumor promoter role in the VECs of CRCs. PMID- 23821019 TI - Towards a single VOICE for European clinical pharmacology: proposals for future developments. PMID- 23821018 TI - Prognostic significance of the modified Glasgow prognostic score in elderly patients with gastric cancer. AB - BACKGROUND: The Glasgow prognostic score (GPS) is a preoperatively determined inflammation-based score. Reports suggest a significant correlation between the GPS and prognosis in several cancer types. We aimed to clarify the prognostic significance of the modified GPS (mGPS) in patients undergoing gastrectomy for gastric cancer. METHODS: Two hundred and ninety-four patients with gastric cancer, 195 aged < 75 years (group NE) and 99 aged > 75 years (group E), who underwent gastrectomy from March 2005 to March 2011 were enrolled. Patients with an elevated C-reactive protein level (> 0.5 mg/dL) and hypoalbuminemia (< 3.8 g/dL) were assigned a mGPS of 2, those with either 1 abnormality were assigned a mGPS of 1, and those with neither abnormality were assigned a mGPS of 0. Cox proportional hazard models and Kaplan-Meier analysis were used to evaluate the usefulness of mGPS as a prognostic indicator. RESULTS: In the NE group, the prognosis of the 3 groups stratified by mGPS did not differ significantly. In multivariate Cox regression analysis, the type of gastrectomy, peritoneal metastasis, and stage were independently associated with poor prognosis. However, group E patients with a mGPS of 2 had significantly poorer prognosis than those with a mGPS of 0 or 1. In this age group, stage and mGPS were independently associated with poor prognosis. CONCLUSIONS: In patients aged > 75 years undergoing potentially curative gastrectomy, the preoperative mGPS was an independent predictor of survival. Therefore, mGPS can be a useful prognostic indicator in elderly patients with gastric cancer. PMID- 23821020 TI - Detection of left atrial thrombus in patients with mitral stenosis and atrial fibrillation: retrospective comparison of two-phase computed tomography, transoesophageal echocardiography and surgical findings. AB - OBJECTIVE: This retrospective study aims to assess the accuracy of two-phase computed tomography (CT) and transoesophageal echocardiography (TEE) for the detection of left atrial (LA) thrombus in patients with mitral stenosis (MS) and atrial fibrillation (AF), by using intraoperative findings as the reference standard. METHODS: Preoperative two-phase CT and intraoperative TEE were performed in 106 patients with MS and AF. The ratio (LAA/AAL) of Hounsfield units (HU) in the LA appendage (LAA) to the ascending aorta (AA) was calculated on the late-phase CT image. RESULTS: LA echodense masses on TEE and LA filling defects on two-phase CT were observed in 29 and 39 patients, respectively. Thirty-five LA thrombi were identified at surgery in 27 patients. Compared with the intraoperative findings, per-patient sensitivity, specificity, positive and negative predictive values of two-phase CT were 100 %, 85 %, 69 % and 100 %, and those by using TEE were 93 %, 95 %, 86 % and 97 % in detecting LAA thrombus. After adopting the cut-off value of 0.5 for the LAA/AAL HU ratio, the specificity and positive predictive value of two-phase CT were increased to 96 % and 90 %, respectively. CONCLUSION: Two-phase CT with a cut-off value of LAA/AAL HU ratio of 0.5 provides high performance for the detection of LAA thrombus. KEY POINTS: * Accurate detection of left atrial appendage (LAA) thrombus is extremely important. * However artefacts from flow effects influence both CT and ultrasound findings. * Two-phase ECG-gated CT offers new insight into thrombus detection. * Analysis of aortic/atrial opacification helps differentiate LAA thrombus from artefact at CT. PMID- 23821021 TI - Appendiceal length as an independent risk factor for acute appendicitis. AB - OBJECTIVES: To determine if appendiceal lengths differ between adults with acute appendicitis and asymptomatic controls. METHODS: In vivo appendiceal length at computed tomography (CT) in 321 adults with surgically proven appendicitis was compared with that in 321 consecutive asymptomatic adult controls. CT length was derived using curved multiplanar reformats along the long axis. Gross pathological length provided external validation for appendectomy cases. RESULTS: Appendiceal length at CT correlated well with appendicitis specimens (mean length, 6.8 cm vs 6.6 cm; 79 % within 1.5 cm). For asymptomatic controls, mean CT appendiceal length was 7.9 cm, longer in men (8.4 +/- 3.8 vs 7.4 +/- 3.1 cm; P = 0.02), matching closely historical normative post-mortem data. The mean and standard deviation of appendiceal length at CT were significantly greater among negative controls than in the positive appendicitis group (7.9 +/- 3.5 vs 6.8 +/- 1.9 cm; P = 0.03). Of appendicitis cases, 90 % (288/321) fell within the range 4.0-10.0 cm, compared with 59 % (189/321) of negative controls (P < 0.001). Among controls, a fivefold increase in appendixes >10 cm and a twofold increase in appendixes <4 cm were observed. Half (9/18) of long appendicitis cases showed tip appendicitis at CT. CONCLUSIONS: "Intermediate" appendiceal lengths (4-10 cm) are more frequently complicated by acute appendicitis, whereas both "long" (>10 cm) and "short" (<4 cm) lengths are more frequently observed in unaffected adults. PMID- 23821023 TI - Correlation of contrast-enhanced ultrasound kinetics with prognostic factors in invasive breast cancer. AB - OBJECTIVES: To correlate contrast-enhanced ultrasound (CEUS) kinetic parameters with traditional and molecular prognostic factors in invasive breast cancer. METHODS: Seventy-five invasive breast cancers were evaluated with contrast harmonic imaging after the injection of a bolus dose of 2.4 ml sulphur hexafluoride microbubble contrast agent. The lognormal function was used for quantitative analysis of kinetic data. These parameters correlated with traditional prognostic factors (tumour size, histological type, tumour grade, axillary lymph node status) and immunohistochemical biomarkers (ER, PR and HER2 status). RESULTS: Statistically significant correlation was found between time-to peak and tumour grade (P value = 0.023), PR status (P value = 0.042) and axillary node status (P value = 0.025). Wash-out ratio, measured at 21 s was significantly associated with ER status (P value = 0.042) and PR status (P value = 0.026). CONCLUSIONS: Invasive breast carcinomas exhibiting earlier peak enhancement and faster elimination of microbubble contrast agent at CEUS are found to be associated with established predictors of poor prognosis. PMID- 23821022 TI - Diffusion-weighted MR imaging in primary rectal cancer staging demonstrates but does not characterise lymph nodes. AB - OBJECTIVES: To evaluate the performance of diffusion-weighted MRI (DWI) for the detection of lymph nodes and for differentiating between benign and metastatic nodes during primary rectal cancer staging. METHODS: Twenty-one patients underwent 1.5-T MRI followed by surgery (+/- preoperative 5 * 5 Gy). Imaging consisted of T2-weighted MRI, DWI (b0, 500, 1000), and 3DT1-weighted MRI with 1 mm isotropic voxels. The latter was used for accurate detection and per lesion histological validation of nodes. Two independent readers analysed the signal intensity on DWI and measured the mean apparent diffusion coefficient (ADC) for each node (ADCnode) and the ADC of each node relative to the mean tumour ADC (ADCrel). RESULTS: DWI detected 6 % more nodes than T2W-MRI. The signal on DWI was not accurate for the differentiation of metastatic nodes (AUC 0.45-0.50). Interobserver reproducibility for the nodal ADC measurements was excellent (ICC 0.93). Mean ADCnode was higher for benign than for malignant nodes (1.15 +/- 0.24 vs. 1.04 +/- 0.22 *10(-3) mm(2)/s), though not statistically significant (P = 0.10). Area under the ROC curve/sensitivity/specificity for the assessment of metastatic nodes were 0.64/67 %/60 % for ADCnode and 0.67/75 %/61 % for ADCrel. CONCLUSIONS: DWI can facilitate lymph node detection, but alone it is not reliable for differentiating between benign and malignant lymph nodes. PMID- 23821025 TI - Epidemiological aspects of Guillain-Barre syndrome. PMID- 23821024 TI - Impact of aortic valve calcification severity and impaired left ventricular function on 3-year results of patients undergoing transcatheter aortic valve replacement. AB - OBJECTIVES: To evaluate clinical pre-interventional predictors of 3-year outcome and mortality in high-risk patients with severe aortic valve stenosis treated with transcatheter aortic valve implantation (TAVI). METHODS: Among 367 patients included in the Aachen TAVI registry, 76 patients with baseline dual-source computed tomography (DSCT) for the quantification of aortic valve calcification (AVC) and a 3-year follow-up were identified. RESULTS: Survival at 30 days was 91 %, and it was 75 %, 66 % and 64 % at 1, 2 years and 3 years, respectively. Non survivors at 3 years showed a significantly higher Agatston AVC score (2,854 +/- 1,651) than survivors (1,854 +/- 961, P = 0.007). Multivariate analysis including age, logistic EuroScore, glomerular filtration rate, Agatston AVC score, ejection fraction < 40 %, NYHA class, baseline medication, chronic lung disease and aortic regurgitation revealed that only the Agatston AVC score (P = 0.03) and impaired left ventricular function (P = 0.001) was significantly associated with mortality. Patients with Agatston AVC scores >2,000 had a significantly lower 3 year survival rate compared with patients with scores <2,000 (47 % vs 79 %, P = 0.004). CONCLUSIONS: In patients referred for TAVI, aortic valve calcification severity and impaired left ventricular function may serve as a predictor of long term mortality. Therefore, AVC scores easily determined from pre-procedural CT datasets may be used for patient risk stratification. PMID- 23821026 TI - Hemiplegic migraine with reversible cerebral vasoconstriction caused by ATP1A2 mutations. PMID- 23821027 TI - Drivers with Parkinson's disease: are the symptoms of PD associated with restricted driving practices? AB - This study examined whether symptoms (motor, cognitive, vision, sleepiness, depression) of Parkinson's disease (PD) were associated with restricted driving practices. To quantify driving practices, electronic devices were installed in the vehicles of 27 drivers with PD (78 % men; M = 71.6, SD = 6.6; Unified Parkinson's Disease Rating Scale (UPDRS) motor score M = 30.1, SD = 8.6; disease duration M = 3.9, SD = 2.8 years) and 20 controls (80 % men; M = 70.6, SD = 7.9) for 2 weeks. Participants completed measures of sleepiness, depression, quality of life, and assessments of motor, cognitive and visual functions. The PD group had significantly slower brake response times (p < 0.05), poorer cognitive and quality of life scores (p < 0.01) and greater depression (p < 0.05) compared to controls. Slower reaction time was significantly related to reduced driving; specifically, fewer trips (r = -0.46; p < 0.05), distance (r = -0.54, p < 0.01) and duration at night (r = -0.58, p < 0.01). Better cognitive scores were associated with driving less often in difficult situations such as bad weather and rush hour (p < 0.05), as well as reduced speed on city streets, but only for the control group. While most drivers with PD rated their overall health as good or excellent, the five PD drivers who rated their health more poorly had significantly worse clinical symptoms (UPDRS motor scores, contrast sensitivity, depression, brake response time) and more restricted driving patterns. These findings show that drivers with PD who perceive their health poorly have greater symptomatology and were more likely to restrict their driving, possibly due to noticeable declines in multiple driving-related abilities. PMID- 23821028 TI - Ultrasonographic nerve enlargement of the median and ulnar nerves and the cervical nerve roots in patients with demyelinating Charcot-Marie-Tooth disease: distinction from patients with chronic inflammatory demyelinating polyneuropathy. AB - Demyelinating Charcot-Marie-Tooth disease (CMT) and chronic inflammatory demyelinating polyneuropathy (CIDP) are both demyelinating polyneuropathies. The differences in nerve enlargement degree and pattern at multiple evaluation sites/levels are not well known. We investigated the differences in nerve enlargement degree and the distribution pattern of nerve enlargement in patients with demyelinating CMT and CIDP, and verified the appropriate combination of sites/levels to differentiate between these diseases. Ten patients (aged 23-84 years, three females) with demyelinating CMT and 16 patients (aged 30-85 years, five females) with CIDP were evaluated in this study. The nerve sizes were measured at 24 predetermined sites/levels from the median and ulnar nerves and the cervical nerve roots (CNR) using ultrasonography. The evaluation sites/levels were classified into three regions: distal, intermediate and cervical. The number of sites/levels that exhibited nerve enlargement (enlargement site number, ESN) in each region was determined from the 24 sites/levels and from the selected eight screening sites/levels, respectively. The cross-sectional areas of the peripheral nerves were markedly larger at all evaluation sites in patients with demyelinating CMT than in patients with CIDP (p < 0.01). However, the nerve sizes of CNR were not significantly different between patients with either disease. When we evaluated ESN of four selected sites for screening from the intermediate region, the sensitivity and specificity to distinguish between demyelinating CMT and CIDP were 0.90 and 0.94, respectively, with the cut-off value set at four. Nerve ultrasonography is useful to detect nerve enlargement and can clarify morphological differences in nerves between patients with demyelinating CMT and CIDP. PMID- 23821029 TI - Functional implications of an early exposure to general anesthesia: are we changing the behavior of our children? AB - There is a rapidly growing body of animal and clinical evidence suggesting that the exposure to anesthetics and sedatives during the critical stages of brain development results in long-lasting (perhaps permanent) impairment in cognitive development in a variety of mammalian species. With improved understanding of the mechanisms responsible for behavioral outcomes of anesthesia-induced developmental neurotoxicity, there is hope for development of protective strategies that will enable safe use of anesthesia in the youngest members of our society. Here, I review presently available evidence regarding anesthesia-induced neurocognitive and social behavioral impairments and possible strategies for preventing them. I also review limited and somewhat controversial evidence that examines the effects of nociception and surgical stimulation on anesthesia- induced developmental neurotoxicity. PMID- 23821030 TI - Statins, Bcl-2, and apoptosis: cell death or cell protection? AB - Statins have proven their effectiveness in the treatment of cardiovascular disease. This class of drugs has also attracted attention as a potential treatment for dissimilar diseases such as certain types of cancers and neurodegenerative diseases. What appears to be a contradiction is that, in the case of cancer, it has been suggested that statins increase apoptosis and alter levels of Bcl-2 family members (e.g., reduce Bcl-2 and increase Bax), whereas studies mainly using noncancerous cells report opposite effects. This review examined studies reporting on the effects of statins on Bcl-2 family members, apoptosis, cell death, and cell protection. Much, but not all, of the evidence supporting the pro-apoptotic effects of statins is based on data in cancer cell lines and the use of relatively high drug concentrations. Studies indicating an anti-apoptotic effect of statins are fewer in number and generally used much lower drug concentrations and normal cells. Those conclusions are not definitive, and certainly, there is a need for additional research to determine if statin repositioning is justified for noncardiovascular diseases. PMID- 23821031 TI - Size- and age-dependent neurotoxicity of engineered metal nanoparticles in rats. AB - Earlier we showed that chronic administration of engineered nanoparticles (NPs) from metals, e.g., Cu, Ag, or Al (50-60 nm, 50 mg/kg, i.p. daily for 1 week) alter blood-brain barrier (BBB) disruption and induce brain pathology in adult rats (age 18 to 22 weeks). However, effects of size-dependent neurotoxicity of NPs in vivo are still largely unknown. In present investigation, we examined the effects of different size ranges of the above-engineered NPs on brain pathology in rats. Furthermore, the fact that age is also an important factor in brain pathology was also investigated in our rat model. Our results showed that small sized NPs induced the most pronounced BBB breakdown (EBA +480 to 680 %; radioiodine +850 to 1025 %), brain edema formation (+4 to 6 %) and neuronal injuries (+30 to 40 %), glial fibrillary acidic protein upregulation (+40 to 56 % increase), and myelin vesiculation (+30 to 35 % damage) in young animals as compared to controls. Interestingly, the oldest animals (30 to 35 weeks of age) also showed massive brain pathology as compared to young adults (18 to 20 weeks old). The Ag and Cu exhibited greater brain damage compared with Al NPs in all age groups regardless of their size. This suggests that apart from the size, the composition of NPs is also important in neurotoxicity. The very young and elderly age groups exhibited greater neurotoxicity to NPs suggests that children and elderly are more vulnerable to NPs-induced brain damage. The NPs-induced brain damage correlated well with the upregulation of neuronal nitric oxide synthase activity in the brain indicating that NPs-induced neurotoxicity may be mediated via increased production of nitric oxide, not reported earlier. PMID- 23821032 TI - Tubulogenesis. AB - Metazoans require epithelial and endothelial tubes to transport liquids and gasses throughout their bodies. Although biological tubes may look relatively similar at first glance, there are multiple and distinct mechanisms by which tubes form and even more regulatory events driving the cell shape changes that produce tubes of specific dimensions. An overview of the current understanding of the molecular processes and physical forces involved in tubulogenesis is presented in this review and the accompanying poster. PMID- 23821033 TI - Oct transcription factors in development and stem cells: insights and mechanisms. AB - The POU domain family of transcription factors regulates developmental processes ranging from specification of the early embryo to terminal differentiation. About half of these factors display substantial affinity for an 8 bp DNA site termed the octamer motif, and are hence known as Oct proteins. Oct4 (Pou5f1) is a well known Oct factor, but there are other Oct proteins with varied and essential roles in development. This Primer outlines our current understanding of Oct proteins and the regulatory mechanisms that govern their role in developmental processes and concludes with the assertion that more investigation into their developmental functions is needed. PMID- 23821034 TI - The miR-310/13 cluster antagonizes beta-catenin function in the regulation of germ and somatic cell differentiation in the Drosophila testis. AB - MicroRNAs (miRNAs) are regulators of global gene expression and function in a broad range of biological processes. Recent studies have suggested that miRNAs can function as tumor suppressors or oncogenes by modulating the activities of evolutionarily conserved signaling pathways that are commonly dysregulated in cancer. We report the identification of the miR-310 to miR-313 (miR-310/13) cluster as a novel antagonist of Wingless (Drosophila Wnt) pathway activity in a functional screen for Drosophila miRNAs. We demonstrate that miR-310/13 can modulate Armadillo (Arm; Drosophila beta-catenin) expression and activity by directly targeting the 3'-UTRs of arm and pangolin (Drosophila TCF) in vivo. Notably, the miR-310/13-deficient flies exhibit abnormal germ and somatic cell differentiation in the male gonad, which can be rescued by reducing Arm protein levels or activity. Our results implicate a previously unrecognized function for miR-310/13 in dampening the activity of Arm in early somatic and germline progenitor cells, whereby inappropriate/sustained activation of Arm-mediated signaling or cell adhesion may impact normal differentiation in the Drosophila male gonad. PMID- 23821035 TI - Dpp signaling inhibits proliferation in the Drosophila wing by Omb-dependent regional control of bantam. AB - The control of organ growth is a fundamental aspect of animal development but remains poorly understood. The morphogen Dpp has long been considered as a general promoter of cell proliferation during Drosophila wing development. It is an ongoing debate whether the Dpp gradient is required for the uniform cell proliferation observed in the wing imaginal disc. Here, we investigated how the Dpp signaling pathway regulates proliferation during wing development. By systematic manipulation of Dpp signaling we observed that it controls proliferation in a region-specific manner: Dpp, via omb, promoted proliferation in the lateral and repressed proliferation in the medial wing disc. Omb controlled the regional proliferation rate by oppositely regulating transcription of the microRNA gene bantam in medial versus lateral wing disc. However, neither the Dpp nor Omb gradient was essential for uniform proliferation along the anteroposterior axis. PMID- 23821036 TI - Iridophores and their interactions with other chromatophores are required for stripe formation in zebrafish. AB - Colour patterns of adult fish are produced by several types of pigment cells that distribute in the dermis during juvenile development. The zebrafish, Danio rerio, displays a striking pattern of dark stripes of melanophores interspersed by light stripes of xanthophores. Mutants lacking either cell type do not form proper stripes, indicating that interactions between these two chromatophore types are required for stripe formation. A third cell type, silvery iridophores, participates to render a shiny appearance to the pattern, but its role in stripe formation has been unclear. Mutations in rose (rse) or shady (shd) cause a lack or strong reduction of iridophores in adult fish; in addition, the melanophore number is drastically reduced and stripes are broken up into spots. We show that rse and shd are autonomously required in iridophores, as mutant melanophores form normal sized stripes when confronted with wild-type iridophores in chimeric animals. We describe stripe formation in mutants missing one or two of the three chromatophore types. None of the chromatophore types alone is able to create a pattern but residual stripe formation occurs with two cell types. Our analysis shows that iridophores promote and sustain melanophores. Furthermore, iridophores attract xanthophores, whereas xanthophores repel melanophores. We present a model for the interactions between the three chromatophore types underlying stripe formation. Stripe formation is initiated by iridophores appearing at the horizontal myoseptum, which serves as a morphological landmark for stripe orientation, but is subsequently a self-organising process. PMID- 23821037 TI - Gpr125 modulates Dishevelled distribution and planar cell polarity signaling. AB - During vertebrate gastrulation, Wnt/planar cell polarity (PCP) signaling orchestrates polarized cell behaviors underlying convergence and extension (C&E) movements to narrow embryonic tissues mediolaterally and lengthen them anteroposteriorly. Here, we have identified Gpr125, an adhesion G protein-coupled receptor, as a novel modulator of the Wnt/PCP signaling system. Excess Gpr125 impaired C&E movements and the underlying cell and molecular polarities. Reduced Gpr125 function exacerbated the C&E and facial branchiomotor neuron (FBMN) migration defects of embryos with reduced Wnt/PCP signaling. At the molecular level, Gpr125 recruited Dishevelled to the cell membrane, a prerequisite for Wnt/PCP activation. Moreover, Gpr125 and Dvl mutually clustered one another to form discrete membrane subdomains, and the Gpr125 intracellular domain directly interacted with Dvl in pull-down assays. Intriguingly, Dvl and Gpr125 were able to recruit a subset of PCP components into membrane subdomains, suggesting that Gpr125 may modulate the composition of Wnt/PCP membrane complexes. Our study reveals a role for Gpr125 in PCP-mediated processes and provides mechanistic insight into Wnt/PCP signaling. PMID- 23821038 TI - Zebrafish rhabdomyosarcoma reflects the developmental stage of oncogene expression during myogenesis. AB - Rhabdomyosarcoma is a pediatric malignancy thought to arise from the uncontrolled proliferation of myogenic cells. Here, we have generated models of rhabdomyosarcoma in the zebrafish by inducing oncogenic KRAS(G12D) expression at different stages during muscle development. Several zebrafish promoters were used, including the cdh15 and rag2 promoters, which drive gene expression in early muscle progenitors, and the mylz2 promoter, which is expressed in differentiating myoblasts. The tumors that developed differed in their ability to recapitulate normal myogenesis. cdh15:KRAS(G12D) and rag2:KRAS(G12D) fish developed tumors that displayed an inability to complete muscle differentiation as determined by histological appearance and gene expression analyses. By contrast, mylz2:KRAS(G12D) tumors more closely resembled mature skeletal muscle and were most similar to well-differentiated human rhabdomyosarcoma in terms of gene expression. mylz2:KRAS(G12D) fish showed significantly improved survival compared with cdh15:KRAS(G12D) and rag2:KRAS(G12D) fish. Tumor-propagating activity was enriched in myf5-expressing cell populations within all of the tumor types. Our results demonstrate that oncogenic KRAS(G12D) expression at different stages during muscle development has profound effects on the ability of tumor cells to recapitulate normal myogenesis, altering the tumorigenic capability of these cells. PMID- 23821041 TI - Asymmetric syntheses of enantiopure C(5)-substituted transpentacins via diastereoselective Ireland-Claisen rearrangements. AB - Asymmetric syntheses of (S,S,S)-2-amino-5-methylcyclopentanecarboxylic acid and (S,S,S)-2-amino-5-phenylcyclopentanecarboxylic acid were achieved in 9 steps from commercially available starting materials via the Ireland-Claisen rearrangement of two enantiopure beta-amino allyl esters, followed by ring-closing metathesis, reduction and deprotection. PMID- 23821042 TI - Genetic services and testing in the Sultanate of Oman. Sultanate of Oman steps into modern genetics. AB - The Sultanate of Oman is a rapidly developing Muslim country with well-organised government-funded health care services, including primary, secondary and tertiary, and rapidly expanding medical genetic facilities. At the present time, the Omani population is characterised by a rapid rate of growth, large family size, consanguineous marriages, and the presence of genetic isolates. The preservation of a tribal structure in the community coupled with traditional isolation has produced unique and favourable circumstances for building genealogical records and the study of genetic disease. Genetic services developed in the Sultanate of Oman in the past decade have become an important component of health care. The recently constructed Genetic Centre in Muscat expects to meet the needs of the Omani population in provision of genetic services and research, in a manner deferential to the cultural and religious traditions of the country. PMID- 23821040 TI - Prospects for improving brain function in individuals with Down syndrome. AB - Down syndrome (DS), which results from an extra copy of chromosome 21 (trisomy 21), is the most common genetically defined cause of intellectual disability. Although no pharmacotherapy aimed at counteracting the cognitive and adaptive deficits associated with this genetic disorder has been approved at present, there have been several new promising studies on pharmacological agents capable of rescuing learning/memory deficits seen in mouse models of DS. Here, we will review the available mouse models for DS and provide a comprehensive, albeit not exhaustive review of the following preclinical research strategies: (1) SOD1 and antioxidant agents; (2) APP and gamma-secretase inhibitors; (3) DYRK1A and the polyphenol epigallocatechin gallate (EGCG); (4) GIRK2 and fluoxetine; (5) adrenergic receptor agonists; (6) modulation of GABAA and GABAB receptors; (7) agonism of the hedgehog signaling pathway; (8) nerve growth factor (NGF) and other neurotrophic factors; (9) anticholinesterase (AChE) agents; and (10) antagonism of NMDA receptors. Finally, we will review briefly five different strategies in DS that have led to clinical studies that either have been concluded or are currently underway: (1) antioxidant therapy; (2) AChE therapy; (3) green tea extract therapy; (4) RG1662 therapy; and (5) memantine therapy. These are exciting times in DS research. Within a decade or so, it is well into the realm of possibility that new forms of pharmacotherapies might become valuable tools in the armamentarium of developmental clinicians, as adjutants to more traditional and proven forms of habilitative interventions aimed at improving the quality of life of individuals with DS. PMID- 23821043 TI - In vitro comparison of the novel, dual-acting FIIa/FXa-inhibitor EP217609C101, unfractionated heparin, enoxaparin, and fondaparinux in preventing cardiac catheter thrombosis. AB - Efficient and safe anticoagulation is crucial in patients requiring percutaneous coronary intervention (PCI) or extracorporeal circulation during cardiac surgery. Although new anticoagulant strategies have emerged for PCI as alternatives to the established treatment with heparins, the development of new anticoagulants with an improved efficacy/safety ratio is still necessary. Our study compared the efficacy of the novel, dual-acting, neutralizable FIIa/FXa-inhibitor EP217609C101 (EP) at 2, 1.2, 0.9, and 0.6 MUg/ml to unfractionated heparin (UFH), enoxaparin, and fondaparinux in preventing cardiac catheter thrombosis under in vitro conditions. Blood drawn by venepunction from healthy male volunteers (n = 10) pretreated with 500 mg aspirin orally was treated with the anticoagulant to test and continuously circulated through a cardiac catheter for 60 min or until the catheter became blocked by thrombotic debris. Anticoagulant efficacy was assessed by thrombus weight, electron microscopic features of the developing thrombi, and laboratory parameters. Whereas UFH, enoxaparin, EP 2, and EP 1.2 MUg/ml secured maximum circulation times, statistically significant premature catheter occlusions were observed for EP 0.9, EP 0.6 MUg/ml, and fondaparinux. The UFH group and both high-dose concentrations of EP showed significantly lower thrombus weights than the low-dose concentrations of EP and fondaparinux, (p <= 0.05). On electron microscopic analysis of the thrombotic debris no differences were observed in erythrocyte deposition between UFH, enoxaparin, and all EP concentrations tested. A significant reduction in fibrin deposition was achieved by UFH and EP 2 MUg/ml but no significant differences in platelet deposition were found, except for a significant reduction for EP 0.6 MUg/ml. Our in vitro study showed that EP217609C101 is a promising new drug that is dose-dependently superior to classical (UFH, enoxaparin) and newer (fondaparinux) drugs in preventing heart catheter thrombosis. PMID- 23821044 TI - Elevated levels of RDW is associated with non-valvular atrial fibrillation. AB - Red cell distribution width (RDW) and neutrophil/lymphocyte ratio (NLR) have been found to be associated with cardiovascular diseases. Only a few trials have investigated the correlation of these parameters with postoperative atrial fibrillation (AF). However, the correlation of these parameters in non-valvular AF is still unclear. We retrospectively analyzed consecutive AF patients from medical records and included 117 non-valvular AF patients (103 paroxysmal and 14 chronic AF). All subjects underwent physical examination and echocardiographic imaging. Complete blood counts (CBCs) were analyzed for hemoglobin, RDW, neutrophil and lymphocyte counts as well as mean corpuscular volume. Results of CBC tests within the previous year were also included and the averages were used. The demographic and echocardiographic properties of non-valvular AF group were comparable to the control group except for left atrial volumes which were increased in AF (median 33.1, IQR 26.3-41.1 cm(3) vs. median 26.4, IQR 24.2-28.9 cm(3); p = 0.01). RDW levels were significantly higher in the AF group (median 13.4 %, IQR 12.9-14.1 %) compared to the control (median 12.6 %, IQR 12.0-13.1 %; p = 0.01). NLR was not statistically different in the AF group and the controls (2.04 +/- 0.94 vs. 1.93 +/- 0.64, respectively; p = 0.32). Hs-CRP levels were higher in the AF group compared to the controls (median 0.84, IQR 0.30-1.43 mg/L vs. median 0.29, IQR 0.18-0.50 mg/L, respectively; p = 0.01). Multivariate logistic regression analysis revealed RDW (OR 4.18, 95 % CI 2.15-8.15; p = 0.01), hs-CRP (OR 3.76, 95 % CI 1.43-9.89; p = 0.01) and left atrial volume (OR 1.31, 95 % CI 1.06-1.21; p = 0.01) as the independent markers of non-valvular AF. Multivariate linear regression analysis revealed that hemoglobin levels (standardized beta coefficient = -0.252; p = 0.01) and the presence of AF (standardized beta coefficient = 0.336; p = 0.01) were the independent correlates of RDW levels. Elevated RDW levels, not NLR, may be an independent risk marker for non-valvular AF. PMID- 23821039 TI - Withdrawal symptoms and rebound syndromes associated with switching and discontinuing atypical antipsychotics: theoretical background and practical recommendations. AB - With the widespread use of atypical or second-generation antipsychotics, switching treatment has become current practice and more complicated, as the pharmacological profiles of these agents differ substantially despite their similarity in being 'atypical'. All share the ability to block dopamine D2 receptors, and most of them also block serotonin 5-HT2A receptors. Apart from these common features, some atypical antipsychotics are also able to block or stimulate other dopamine or serotonin receptors, as well as histaminergic, muscarinergic or adrenergic receptors. As a result of the varying receptor affinities, in switching or discontinuing compounds several possible pitfalls have to be considered, including the occurrence of withdrawal and rebound syndromes. This article reviews the pharmacological background of functional blockade or stimulation of receptors of interest in regard to atypical antipsychotics and the implicated potential withdrawal and rebound phenomena. A MEDLINE search was carried out to identify information on withdrawal or rebound syndromes occurring after discontinuation of atypical antipsychotics. Using the resulting literature, we first discuss the theoretical background to the functional consequences of atypical antipsychotic-induced blockade or stimulation of neurotransmitter receptors and, secondly, we highlight the clinical consequences of this. We then review the available clinical literature on switching between atypical antipsychotics, with respect to the occurrence of withdrawal or rebound symptoms. Finally, we offer practical recommendations based on the reviewed findings. The systematic evaluation of withdrawal or rebound phenomena using randomized controlled trials is still understudied. Knowledge of pharmacological receptor-binding profiles may help clinicians in choosing adequate switching or discontinuation strategies for each agent. Results from large switching trials indicate that switching atypical antipsychotics can be performed in a safe manner. Treatment-emergent adverse events during or after switching are not always considered to be, at least in part, associated with the pre-switch antipsychotic. Further studies are needed to substantiate the evidence gained so far on different switching strategies. The use of concomitant medication, e.g., benzodiazepines or anticholinergic drugs, may help to minimize symptoms arising from the discontinuation or switching of antipsychotic treatment. PMID- 23821045 TI - The amount and composition of monkey parietal cortex neurons that are active during functionally different behaviors. PMID- 23821046 TI - Sodium nitrite influences metabolic conversions of nitric oxide in tissues of the right and left ventricles of the rat heart. PMID- 23821047 TI - Epidermal growth factor modulates voltage sensitivity of slow sodium channels. PMID- 23821048 TI - Semax corrects brain dysfunction caused by prenatal introduction of valproic acid. PMID- 23821049 TI - The opioid system is involved in the analgesic effects of Tactivin. PMID- 23821050 TI - Effect of tonic pain on the corticosterone level in rat pups of various ages subjected to prenatal stress and opportunities for correction of stress-induced impairments. PMID- 23821051 TI - Embryogenic cell lines and somatic embryogenesis in an vitro culture of Siberian larch. PMID- 23821052 TI - Life history strategy diversity in the Kamchatkan Dolly Varden char Salvelinus malma (Walbaum) (Salmonidae, Salmoniformes): ontogenetic reconstructions based on the data of X-ray fluorescence analysis of the microchemistry of recording structures. PMID- 23821053 TI - Study of proteolysis of Semax analogues with different N-terminal amino acids by carboxypeptidases. PMID- 23821054 TI - Cancer and environmental factors. PMID- 23821055 TI - Comparative analysis of hemoglobin content in four species of anurans from the Ural uplands. PMID- 23821056 TI - Stability of the structural and functional characteristics of carbon diagnostic preparations. PMID- 23821057 TI - Water resistance of soils and structural transition in the humus matrix of soil gels. PMID- 23821058 TI - Tobacco cell cultures transformed by the hsp101 gene exhibit an increased resistance to Clavibacter michiganensis ssp. sepedonicus. PMID- 23821059 TI - Three strategies of cold tolerance in click beetles (Coleoptera, Elateridae). PMID- 23821060 TI - CO2 and H2O exchange in the forest ecosystems of southern taiga under climate changes. PMID- 23821061 TI - The nature of organic substance from soil gel films. PMID- 23821062 TI - The uncoupling of synaptic protein homer 1c from target proteins activates store operated calcium entry in a neurotransmitter-like manner in human neuroblastoma cells. PMID- 23821063 TI - Effects of photodynamic treatment on mesenchymal stromal cells. PMID- 23821064 TI - T cell apoptosis in HIV-infected patients with incomplete immune recovery after antiretroviral therapy. PMID- 23821065 TI - A pyrene-based highly selective turn-on fluorescent chemosensor for iron(III) ions and its application in living cell imaging. AB - A new pyrene-based chemosensor (1) exhibits excellent selectivity for Fe(3+) ions over a wide range of tested metal ions Ag(+), Ca(2+), Cd(2+), Co(2+), Cu(2+), Fe(2+), Hg(2+), K(+), Mg(2+), Mn(2+), Ni(2+), Pb(2+), and Zn(2+). The binding of Fe(3+) to chemosensor 1 produces an emission band at 507 nm due to the formation of a Py-Py* excimer that is induced by Fe(3+)-binding. The binding ratio of 1 Fe(3+) was determined to be 1:1 from a Job plot. The association constant of 1 Fe(3+) complexes was found to be 1.27 * 10(4) M(-1) from a Benesi-Hildebrand plot. In addition, fluorescence microscopy experiments show that 1 can be used as a fluorescent probe for detecting Fe(3+) in living cells. PMID- 23821066 TI - The role of normal versus twisted intramolecular charge transfer fluorescence in predicting the forms of inclusion complexes of ethyl-4-dialkylaminobenzoate with alpha-cyclodextrin in aqueous solution. AB - An evidence is introduced through the b- and the twisted intramolecular charge transfer (TICT) fluorescence of ethyl-4-(N,N-dimethylamino)benzoate (EDMAB) and ethyl-4-(N,N-diethylamino)benzoate (EDEAB), confirming the role of donor size on the formation and emission of various inclusion complexes formed between these probes and alpha-CD in aqueous solution. A large variation in the b-fluorescence band of EDEAB as compared to that of EDMAB and a large variation in the TICT fluorescence band of EDMAB as compared to that EDEAB, as the concentration of alpha-CD is increased in their aqueous solutions are observed. These variations are supported by time resolved fluorescence (TRF) spectra, fluorescence decay lifetimes and red edge effect (REE) results. PMID- 23821069 TI - Untitled: Xenia Kamlookhine. PMID- 23821070 TI - Preparedness key to combating potential pandemic resulting from any new influenza strain. PMID- 23821071 TI - Scientists celebrate successes, new tools in fight against human parasitic worms. PMID- 23821072 TI - IOM details an ambitious agenda for US gun violence research. PMID- 23821082 TI - The convenience revolution for treatment of low-acuity conditions. PMID- 23821083 TI - A piece of my mind. Pay it forward. PMID- 23821085 TI - Home blood pressure monitoring: take it to the bank. PMID- 23821086 TI - In vitro fertilization and risk of autistic disorder and mental retardation. PMID- 23821087 TI - Preventing heart failure. PMID- 23821088 TI - Effect of home blood pressure telemonitoring and pharmacist management on blood pressure control: a cluster randomized clinical trial. AB - IMPORTANCE: Only about half of patients with high blood pressure (BP) in the United States have their BP controlled. Practical, robust, and sustainable models are needed to improve BP control in patients with uncontrolled hypertension. OBJECTIVES: To determine whether an intervention combining home BP telemonitoring with pharmacist case management improves BP control compared with usual care and to determine whether BP control is maintained after the intervention is stopped. DESIGN, SETTING, AND PATIENTS: A cluster randomized clinical trial of 450 adults with uncontrolled BP recruited from 14,692 patients with electronic medical records across 16 primary care clinics in an integrated health system in Minneapolis-St Paul, Minnesota, with 12 months of intervention and 6 months of postintervention follow-up. INTERVENTIONS: Eight clinics were randomized to provide usual care to patients (n = 222) and 8 clinics were randomized to provide a telemonitoring intervention (n = 228). Intervention patients received home BP telemonitors and transmitted BP data to pharmacists who adjusted antihypertensive therapy accordingly. MAIN OUTCOMES AND MEASURES: Control of systolic BP to less than 140 mm Hg and diastolic BP to less than 90 mm Hg (<130/80 mm Hg in patients with diabetes or chronic kidney disease) at 6 and 12 months. Secondary outcomes were change in BP, patient satisfaction, and BP control at 18 months (6 months after intervention stopped). RESULTS: At baseline, enrollees were 45% women, 82% white, mean (SD) age was 61.1 (12.0) years, and mean systolic BP was 148 mm Hg and diastolic BP was 85 mm Hg. Blood pressure was controlled at both 6 and 12 months in 57.2% (95% CI, 44.8% to 68.7%) of patients in the telemonitoring intervention group vs 30.0% (95% CI, 23.2% to 37.8%) of patients in the usual care group (P = .001). At 18 months (6 months of postintervention follow-up), BP was controlled in 71.8% (95% CI, 65.0% to 77.8%) of patients in the telemonitoring intervention group vs 57.1% (95% CI, 51.5% to 62.6%) of patients in the usual care group (P = .003). Compared with the usual care group, systolic BP decreased more from baseline among patients in the telemonitoring intervention group at 6 months (-10.7 mm Hg [95% CI, -14.3 to -7.3 mm Hg]; P<.001), at 12 months (-9.7 mm Hg [95% CI, -13.4 to -6.0 mm Hg]; P<.001), and at 18 months (-6.6 mm Hg [95% CI, -10.7 to -2.5 mm Hg]; P = .004). Compared with the usual care group, diastolic BP decreased more from baseline among patients in the telemonitoring intervention group at 6 months (-6.0 mm Hg [95% CI, -8.6 to -3.4 mm Hg]; P<.001), at 12 months (-5.1 mm Hg [95% CI, -7.4 to -2.8 mm Hg]; P<.001), and at 18 months (-3.0 mm Hg [95% CI, -6.3 to 0.3 mm Hg]; P = .07). CONCLUSIONS AND RELEVANCE: Home BP telemonitoring and pharmacist case management achieved better BP control compared with usual care during 12 months of intervention that persisted during 6 months of postintervention follow-up. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00781365. PMID- 23821089 TI - Home-based walking exercise intervention in peripheral artery disease: a randomized clinical trial. AB - IMPORTANCE: Clinical practice guidelines state there is insufficient evidence to support advising patients with peripheral artery disease (PAD) to participate in a home-based walking exercise program. OBJECTIVE: To determine whether a home based walking exercise program that uses a group-mediated cognitive behavioral intervention, incorporating both group support and self-regulatory skills, can improve functional performance compared with a health education control group in patients with PAD with and without intermittent claudication. DESIGN, SETTING, AND PATIENTS: Randomized controlled clinical trial of 194 patients with PAD, including 72.2% without classic symptoms of intermittent claudication, performed in Chicago, Illinois between July 22, 2008, and December 14, 2012. INTERVENTIONS: Participants were randomized to 1 of 2 parallel groups: a home-based group mediated cognitive behavioral walking intervention or an attention control condition. MAIN OUTCOMES AND MEASURES: The primary outcome was 6-month change in 6-minute walk performance. Secondary outcomes included 6-month change in treadmill walking, physical activity, the Walking Impairment Questionnaire (WIQ), and Physical and Mental Health Composite Scores from the 12-item Short-Form Health Survey. RESULTS: Participants randomized to the intervention group significantly increased their 6-minute walk distance ([reported in meters] 357.4 to 399.8 vs 353.3 to 342.2 for those in the control group; mean difference, 53.5 [95% CI, 33.2 to 73.8]; P < .001), maximal treadmill walking time (intervention, 7.91 to 9.44 minutes vs control, 7.56 to 8.09; mean difference, 1.01 minutes [95% CI, 0.07 to 1.95]; P = .04), accelerometer-measured physical activity over 7 days (intervention, 778.0 to 866.1 vs control, 671.6 to 645.0; mean difference, 114.7 activity units [95% CI, 12.82 to 216.5]; P = .03), WIQ distance score (intervention, 35.3 to 47.4 vs control, 33.3 to 34.4; mean difference, 11.1 [95% CI, 3.9 to 18.1]; P = .003), and WIQ speed score (intervention, 36.1 to 47.7 vs control, 35.3-36.6; mean difference, 10.4 [95% CI, 3.4 to 17.4]; P = .004). CONCLUSION AND RELEVANCE: A home-based walking exercise program significantly improved walking endurance, physical activity, and patient-perceived walking endurance and speed in PAD participants with and without classic claudication symptoms. These findings have implications for the large number of patients with PAD who are unable or unwilling to participate in supervised exercise programs. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00693940. PMID- 23821090 TI - Natriuretic peptide-based screening and collaborative care for heart failure: the STOP-HF randomized trial. AB - IMPORTANCE: Prevention strategies for heart failure are needed. OBJECTIVE: To determine the efficacy of a screening program using brain-type natriuretic peptide (BNP) and collaborative care in an at-risk population in reducing newly diagnosed heart failure and prevalence of significant left ventricular (LV) systolic and/or diastolic dysfunction. DESIGN, SETTING, AND PARTICIPANTS: The St Vincent's Screening to Prevent Heart Failure Study, a parallel-group randomized trial involving 1374 participants with cardiovascular risk factors (mean age, 64.8 [SD, 10.2] years) recruited from 39 primary care practices in Ireland between January 2005 and December 2009 and followed up until December 2011 (mean follow-up, 4.2 [SD, 1.2] years). INTERVENTION: Patients were randomly assigned to receive usual primary care (control condition; n=677) or screening with BNP testing (n=697). Intervention-group participants with BNP levels of 50 pg/mL or higher underwent echocardiography and collaborative care between their primary care physician and specialist cardiovascular service. MAIN OUTCOMES AND MEASURES: The primary end point was prevalence of asymptomatic LV dysfunction with or without newly diagnosed heart failure. Secondary end points included emergency hospitalization for arrhythmia, transient ischemic attack, stroke, myocardial infarction, peripheral or pulmonary thrombosis/embolus, or heart failure. RESULTS: A total of 263 patients (41.6%) in the intervention group had at least 1 BNP reading of 50 pg/mL or higher. The intervention group underwent more cardiovascular investigations (control, 496 per 1000 patient-years vs intervention, 850 per 1000 patient-years; incidence rate ratio, 1.71; 95% CI, 1.61-1.83; P<.001) and received more renin-angiotensin-aldosterone system-based therapy at follow-up (control, 49.6%; intervention, 56.5%; P=.01). The primary end point of LV dysfunction with or without heart failure was met in 59 (8.7%) of 677 in the control group and 37 (5.3%) of 697 in the intervention group (odds ratio [OR], 0.55; 95% CI, 0.37-0.82; P = .003). Asymptomatic LV dysfunction was found in 45 (6.6%) of 677 control-group patients and 30 (4.3%) of 697 intervention-group patients (OR, 0.57; 95% CI, 0.37-0.88; P = .01). Heart failure occurred in 14 (2.1%) of 677 control-group patients and 7 (1.0%) of 697 intervention-group patients (OR, 0.48; 95% CI, 0.20-1.20; P = .12). The incidence rates of emergency hospitalization for major cardiovascular events were 40.4 per 1000 patient-years in the control group vs 22.3 per 1000 patient-years in the intervention group (incidence rate ratio, 0.60; 95% CI, 0.45-0.81; P = .002). CONCLUSION AND RELEVANCE: Among patients at risk of heart failure, BNP-based screening and collaborative care reduced the combined rates of LV systolic dysfunction, diastolic dysfunction, and heart failure. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00921960. PMID- 23821091 TI - Autism and mental retardation among offspring born after in vitro fertilization. AB - IMPORTANCE: Between 1978 and 2010, approximately 5 million infants were born after in vitro fertilization (IVF) treatments. Yet limited information on neurodevelopment after IVF exists, especially after the first year of life. OBJECTIVE: To examine the association between use of any IVF and different IVF procedures and the risk of autistic disorder and mental retardation in the offspring. DESIGN, SETTING, AND PARTICIPANTS: A population-based, prospective cohort study using Swedish national health registers. Offspring born between 1982 and 2007 were followed up for a clinical diagnosis of autistic disorder or mental retardation until December 31, 2009. The exposure of interest was IVF, categorized according to whether intracytoplasmic sperm injection (ICSI) for male infertility was used and whether embryos were fresh or frozen. For ICSI, whether sperm were ejaculated or surgically extracted was also considered. MAIN OUTCOMES AND MEASURES: Relative risks (RRs) for autistic disorder and mental retardation and rates per 100,000 person-years, comparing spontaneously conceived offspring with those born after an IVF procedure and comparing 5 IVF procedures used in Sweden vs IVF without ICSI with fresh embryo transfer, the most common treatment. We also analyzed the subgroup restricted to singletons. RESULTS: Of the more than 2.5 million infants born, 30,959 (1.2%) were conceived by IVF and were followed up for a mean 10 (SD, 6) years. Overall, 103 of 6959 children (1.5%) with autistic disorder and 180 of 15,830 (1.1%) with mental retardation were conceived by IVF. The RR for autistic disorder after any procedure compared with spontaneous conception was 1.14 (95% CI, 0.94-1.39; 19.0 vs 15.6 per 100,000 person-years). The RR for mental retardation was 1.18 (95% CI, 1.01-1.36; 46.3 vs 39.8 per 100,000 person-years). For both outcomes, there was no statistically significant association when restricting analysis to singletons. Compared with IVF without ICSI with fresh embryo transfer, there were statistically significantly increased risks of autistic disorder following ICSI using surgically extracted sperm and fresh embryos (RR, 4.60 [95% CI, 2.14-9.88]; 135.7 vs 29.3 per 100,000 person-years); for mental retardation following ICSI using surgically extracted sperm and fresh embryos (RR, 2.35 [95% CI, 1.01-5.45]; 144.1 vs 60.8 per 100,000 person-years); and following ICSI using ejaculated sperm and fresh embryos (RR, 1.47 [95% CI, 1.03-2.09]; 90.6 vs 60.8 per 100,000 person years). When restricting the analysis to singletons, the risks of autistic disorder associated with ICSI using surgically extracted sperm were not statistically significant, but the risks associated with ICSI using frozen embryos were significant for mental retardation (with frozen embryos, RR, 2.36 [95% CI, 1.04-5.36], 118.4 vs 50.6 per 100,000 person-years]; with fresh embryos, RR, 1.60 [95% CI, 1.00-2.57], 80.0 vs 50.6 per 100,000 person-years). CONCLUSIONS AND RELEVANCE: Compared with spontaneous conception, IVF treatment overall was not associated with autistic disorder but was associated with a small but statistically significantly increased risk of mental retardation. For specific procedures, IVF with ICSI for paternal infertility was associated with a small increase in the RR for autistic disorder and mental retardation compared with IVF without ICSI. The prevalence of these disorders was low, and the increase in absolute risk associated with IVF was small. PMID- 23821092 TI - The paradox of disease prevention: celebrated in principle, resisted in practice. AB - Prevention of disease is often difficult to put into practice. Among the obstacles: the success of prevention is invisible, lacks drama, often requires persistent behavior change, and may be long delayed; statistical lives have little emotional effect, and benefits often do not accrue to the payer; avoidable harm is accepted as normal, preventive advice may be inconsistent, and bias against errors of commission may deter action; prevention is expected to produce a net financial return, whereas treatment is expected only to be worth its cost; and commercial interests as well as personal, religious, or cultural beliefs may conflict with disease prevention. Six strategies can help overcome these obstacles: (1) Pay for preventive services. (2) Make prevention financially rewarding for individuals and families. (3) Involve employers to promote health in the workplace and provide incentives to employees to maintain healthy practices. (4) Reengineer products and systems to make prevention simpler, lower in cost, and less dependent on individual action. (5) Use policy to reinforce choices that favor prevention. (6) Use multiple media channels to educate, elicit health-promoting behavior, and strengthen healthy habits. Prevention of disease will succeed over time insofar as it can be embedded in a culture of health. PMID- 23821093 TI - Gradual reduction vs abrupt cessation as a smoking cessation strategy in smokers who want to quit. AB - CLINICAL QUESTION: Is gradual smoking cessation associated with poorer success rates than abrupt cessation in smokers who want to quit? BOTTOM LINE: Gradual reduction may not be associated with a clinically significant difference in smoking cessation rates compared with abrupt cessation. PMID- 23821094 TI - Smoking cessation, weight change, and coronary heart disease among postmenopausal women with and without diabetes. PMID- 23821095 TI - Management setting of obstructive sleep apnea. PMID- 23821096 TI - Management setting of obstructive sleep apnea. PMID- 23821097 TI - Mental illness and gun control. PMID- 23821098 TI - Management setting of obstructive sleep apnea--reply. PMID- 23821099 TI - Mental illness and gun control--reply. PMID- 23821104 TI - Expectation of life. PMID- 23821105 TI - JAMA patient page. Insect bites and stings. PMID- 23821106 TI - Urticaria and autoimmunity: where are we now? AB - There is considerable debate whether chronic urticaria is an autoimmune disease or whether its features suggestive of autoimmunity are epiphenomena. A plethora of circumstantial evidence suggests that chronic urticaria is an autoimmune disease, but criteria to establish autoimmunity require direct proof and indirect evidence, and these are lacking in chronic urticaria. Current approaches to assessing for autoimmunity in vivo via the autologous serum skin test, and in vitro via either basophil histamine release or the basophil activation test are widely utilized, but the results of these tests have limited impact on prediction of the clinical course and efficacy of treatments. Recent guidelines for diagnosing autoimmune urticaria have been proposed, but further investigation is needed. PMID- 23821107 TI - High-density three-dimension graphene macroscopic objects for high-capacity removal of heavy metal ions. AB - The chemical vapor deposition (CVD) fabrication of high-density three-dimension graphene macroscopic objects (3D-GMOs) with a relatively low porosity has not yet been realized, although they are desirable for applications in which high mechanical and electrical properties are required. Here, we explore a method to rapidly prepare the high-density 3D-GMOs using nickel chloride hexahydrate (NiCl2.6H2O) as a catalyst precursor by CVD process at atmospheric pressure. Further, the free-standing 3D-GMOs are employed as electrolytic electrodes to remove various heavy metal ions. The robust 3D structure, high conductivity (~12 S/cm) and large specific surface area (~560 m2/g) enable ultra-high electrical adsorption capacities (Cd2+ ~ 434 mg/g, Pb2+~ 882 mg/g, Ni2+ ~ 1,683 mg/g, Cu2+ ~ 3,820 mg/g) from aqueous solutions and fast desorption. The current work has significance in the studies of both the fabrication of high-density 3D-GMOs and the removal of heavy metal ions. PMID- 23821118 TI - Ischemic optic neuropathies - where are we now? AB - Ischemic optic neuropathy is of two types: anterior and posterior. Non-arteritic anterior ischemic optic neuropathy (NA-AION) is the most common type of ischemic optic neuropathy. There are three major misconceptions about NA-AION: (1) that its pathogenesis is not known, (2) that NA-AION and ischemic cerebral stroke are similar in nature, pathogenetically and in management, and (3) that there is no treatment. All these misconceptions are based on lack of in-depth knowledge of the subject. They are discussed in the light of our current scientific knowledge. The pathogenesis of NA-AION is known but is highly complex. NA-AION and ischemic cerebral stroke are very different clinical entities, pathogenetically and in management. Aspirin has no beneficial effect. Corticosteroid therapy during the initial stages can be beneficial. To reduce the risk of development of NA-AION in the other eye or of further visual loss in the same eye, it is essential to reduce as many risk factors as possible. Management of arteritic anterior ischemic optic neuropathy and of posterior ischemic optic neuropathy is discussed. PMID- 23821119 TI - Conjunctival hamartoma with eosinophilia--a novel lesion in a child with PTEN hamartoma syndrome. PMID- 23821120 TI - Effect of suppression during tropia and phoria on phoria maintenance in intermittent exotropia. AB - BACKGROUND: Treatment for intermittent exotropia X(T) aims to keep the eye in a phoric position and to maintain the phoria. However, maintenance of phoria is difficult even after treatment, and the cause is unclear. The aim of this study was to investigate the presence of suppression during tropia and/or phoria in X(T), and to determine how the suppression affected patient's ability to maintain phoria. METHODS: Medical records of 89 children with X(T) (mean age, 9.8 +/- 2.7 years) were reviewed retrospectively. According to their previous treatment for X(T), the patients were divided into four groups and compared: untreated and under observation only (28 patients), surgical treatment (32 patients), orthoptic training (eight patients) and a combined treatment of surgery and orthoptic training (21 patients). Suppression during phoria was evaluated by a physiologic diplopia test, and suppression during tropia was evaluated by a convergence test or a cover test when fusion broke. Phoria maintenance was achieved if a phoric condition was maintained even when the fusion broke at both near and far. Furthermore, the Bagolini's red filter bar was used to quantitatively assess patient's ability to maintain phoria at near and far distances. RESULTS: No subject only suppressed during phoria. Patients who suppressed under both conditions could not maintain phoria. Suppression under both conditions significantly correlated with phoria maintenance and the ability to maintain phoria (P < 0.01, Fisher's exact probability test). All the patients with a strong ability to maintain phoria did not suppress under either condition. As compared to the surgical treatment group, the combined treatment group had a higher percentage of patients who did not suppress under either condition and could maintain the phoria. Suppression under both conditions also significantly correlated the treatment methods (P < 0.01, Chi-square for the independence test). CONCLUSIONS: Suppression under both tropic and phoric conditions significantly relates to the outcome of patients' phoria maintenance and their ability to maintain a phoric position. Suppression under both conditions is an important indication of whether X(T) shifts to constant exotropia. PMID- 23821122 TI - Combined semirigid and flexible ureterorenoscopy via a large ureteral access sheath for kidney stones >2 cm: a bicentric prospective assessment. AB - PURPOSE: The international guidelines on urolithiasis state that the percutaneous approach is superior for kidney stones >=20 mm. Nevertheless, several groups have reported high stone-free rates (SFRs) with low morbidity for ureteroscopic treatment of calculi >15 mm. We hereby describe a new technique including the combined use of semirigid and flexible ureteroscopy via a large ureteral access sheath (UAS). METHODS: The proposed technique includes (a) preoperative ureteral stenting, (b) use of a large lumen UAS (14/16F, 35 cm), (c) use of a semirigid ureteroscope, (d) holmium laser lithotripsy, (e) passive and (f) active fragment extraction, and finally, the removal of caliceal stones (g) using a flexible scope. We conducted a prospective outcome analysis for 38 patients treated at two tertiary university centers. RESULTS: Perioperative data were as follows: median cumulative stone size 24.5 mm (20-60), median operating time 95 min (50-205), post-operative ureteral stenting (2-35 days) in 33 patients (86.8 %), Clavien complications 2 and 3 in 7.9 %, primary SFR 63.2 %, and overall computed tomography (CT) controlled SFR after 3 months 81.8 % (including staged procedures). No late complications were observed. CONCLUSIONS: The combined use of semirigid ureteroscopy and an UAS further develops the endoscopic treatment of kidney stones. This is the first series of this kind that confirms high SFRs by CT. The approach has significant advantages: Superior irrigation and outflow enhance both vision and stone clearance, and multiple ureteral passages without putting the ureter at injury risk. These encouraging results make this modality an appealing alternative to percutaneous nephrolithotomy. PMID- 23821121 TI - Perioperative complications and clinical outcomes of intraocular lens exchange in patients with opacified lenses. AB - BACKGROUND: To evaluate the perioperative complications and the outcomes of intraocular lens (IOL) exchange in patients with opacified lenses. METHODS: Retrospective multicentrical consecutive series of cases that comprised 22 eyes from 21 patients who had previous phacoemulsification with implantation of an IOL in the capsular bag and developed severe late opacification of the IOL. All patients had loss of vision and reported light disturbances. The IOLs were explanted and replaced with new IOLs. The perioperative complications were evaluated. The best spectacle-corrected visual acuity (BSCVA) before and after the surgery was compared. RESULTS: The mean time lapsed between the original cataract surgery and the IOL exchange surgery was 89.1 +/- 33.6 [48-216] months. The IOL exchange was uneventful in 14 eyes (63.6 %). Anterior vitrectomy was needed in seven cases (31.8 %). Other complications included zonular dehiscence in one case (4.5 %). In most of the cases, 14 eyes (63.6 %), the IOL was implanted in the sulcus. The most explanted IOL was the Hydroview H60M (Bausch & Lomb). The mean BSCVA (LogMAR) before and after the surgery were 0.57 +/- 0.69 (0.10-3) and 0.18 +/- 0.22 (0.0-1.10) respectively (t paired test, p < 0.001). After the operation, 20 eyes (90.9 %) achieved a BSCVA <= 0.3. No eye lost 1 or more lines of corrected vision after the surgery. CONCLUSIONS: IOL exchange surgery, although associated with a high incidence of complications, restores and significantly improves the visual acuity of patients with opacified IOLs. PMID- 23821123 TI - Thin-film ratiometric fluorescent chemosensors with tunable performance characteristics. AB - A simple method for tuning the performance characteristics of fluorescent ratiometric sensors based on surface-immobilized monolayers of pi-conjugated molecules enabled gradual adjustment of the sensitivity and the analyte detection range of the sensor. This approach has been applied to fine-tune the sensing performance of a prototype ratiometric chemosensor for fluoride ions. PMID- 23821124 TI - Novel 3D-CT evaluation of carotid stent volume: greater chronological expansion of stents in patients with vulnerable plaques. AB - INTRODUCTION: Although self-expanding carotid stents may dilate gradually, the degrees of residual stenosis have been quantified by the NASCET criteria, which is too simple to reflect the configuration of the stented artery. We measured the volumes of the stent lumens chronologically by 3D-CT in patients after carotid artery stenting (CAS), and analyzed the correlations between the volume change and medical factors. METHODS: Fourteen patients with carotid artery stenosis were treated using self-expanding, open-cell stents. All patients underwent preoperative plaque MRI (magnetization-prepared rapid acquisition gradient-echo, MPRAGE) and chronological 3D-CT examinations of their stents immediately after their placement and 1 day, 1 week, and 1 month after the procedure. The volume of the stent lumen was measured using a 3D workstation. The correlations between stent volume and various factors including the presence of underlying diseases, plaque characteristics, and the results of the CAS procedure were analyzed. RESULTS: Stent volume gradually increased in each case and had increased by 1.04 1.55 (mean, 1.25)-fold at 1 postoperative month. The presence of underlying medical diseases, plaque length, the degree of residual stenosis immediately after CAS, and plaque calcification did not have an impact on the change in stent volume. On the other hand, the stent volume increase was significantly larger in the patients with vulnerable plaques that demonstrated high MPRAGE signal intensity (P < 0.05). CONCLUSIONS: A 3D-CT examination is useful for precisely measuring stent volume. Self-expanding stents in carotid arteries containing vulnerable plaques expand significantly more than those without such plaques in a follow-up period. PMID- 23821125 TI - In response to Goyal R, et al. J Anesth, Dec. 9 (2012). PMID- 23821127 TI - Microbicidal and anti-inflammatory effects of Actinomadura spadix (EHA-2) active metabolites from Himalayan soils, India. AB - Actinomycetes play an essential role in producing several bioactive compounds. In the present study, microbicidal and anti-inflammatory effects of metabolites from actinomycetes were investigated. Actinomycetes were isolated from north eastern Himalayan soil samples, India. The actinomycetes were investigated for their microbicidal property by conventional method and the active actinomycetes were identified by 16s rDNA sequence analyses. Further the metabolites were extracted and fractionated to evaluate the antimicrobial potency; they were subjected to GC MS analysis. The active fraction was evaluated for selective toxicity and anti inflammatory potential. Among isolated actinomycetes, EHA-2 showed potent antimicrobial activity and was identified as Actinomadura spadix. Fraction-8 from ethyl acetate extract of EHA-2 showed 100% inhibition against Candida sp. (MIC-80 MUg/mL) and Enterococcus faecalis (MIC-80 MUg/mL). The expression of GAPDH in primary cells and 16s rRNA levels on E. faecalis treated with fraction-8 revealed no toxicity to the primary cells. Fraction-8 also suppressed the paw thickness on carrageenan induced animals and also controlled the release of NO, TNFalpha and IL-1beta levels on LPS induced RAW 264.7 cell lines. GC-MS profile of fraction-8 showed the presence of an antimicrobial agent 3,6 di-isobutyl 2,5 piperazinedione, which is the first report in A. spadix. The actinomycetes isolate EHA-2 can be proceed further to produce antibiotics. PMID- 23821128 TI - Growth, antioxidant capacity and total carotene of Dunaliella salina DCCBC15 in a low cost enriched natural seawater medium. AB - Dunaliella is currently drawing worldwide attention as an alternative source of nutraceuticals. Commercially, beta-carotene making up over 10% of Dunaliella biomass is generating the most interest. These compounds, because of their non toxic properties, have found applications in the food, drug and cosmetic industry. The beta-carotene content of Dunaliella cells, however, depends heavily on the growth conditions and especially on the availability of nutrients, salinity, irradiance and temperature in the growth medium. A chemically well defined medium is usually required, which significantly contributes to the cost of pigment production; hence a desire for low cost marine media. The present study aimed at evaluating the suitability of six different media, especially exploiting local potential resources, for the mass production of Dunaliella salina DCCBC15 as functional food and medicine. The efficacy of a new selected low-cost enriched natural seawater medium (MD4), supplemented with industrial N-P K fertilizer, was investigated with respect to biomass production, chlorophyll, antioxidant capacity, and total carotene by Dunaliella though culture conditions were not optimized yet. This new medium (MD4) appears extremely promising, since it affords a higher production of Dunaliella biomass and pigments compared with the control, a common artificial medium (MD1), while allowing a substantial reduction in the production costs. The medium is also recommended for culturing other marine algae. PMID- 23821126 TI - Rapid phenotypic changes in Caenorhabditis elegans under uranium exposure. AB - Pollutants can induce selection pressures on populations, and the effects may be concentration-dependant. The main ways to respond to the stress are acclimation (i.e. plastic changes) and adaptation (i.e. genetic changes). Acclimation provides a short-term response to environmental changes and adaptation can have longer-term implications on the future of the population. One way of studying these responses is to conduct studies on the phenotypic changes occurring across generations in populations experimentally subjected to a selective factor (i.e. multigenerational test). To our knowledge, such studies have not been performed with uranium (U). Here, the phenotypic changes were explored across three generations in experimental Caenorhabditis elegans populations exposed to different U-concentrations. Significant negative effects of U were detected on survival, generation time, brood size, body length and body bend. At lower U concentrations, the negative effects were reduced in the second or the third generation, indicating an improvement by acclimation. In contrast, at higher U concentrations, the negative effects on brood size were amplified across generations. Consequently, under high U-concentrations acclimation may not be sufficient, and adaptation of individuals would be required, to permit the population to avoid extinction. The results highlight the need to consider changes across generations to enhance environmental risk assessment related to U pollution. PMID- 23821129 TI - High-throughput ultra-performance liquid chromatography-mass spectrometry characterization of metabolites guided by a bioinformatics program. AB - Metabolite profiling in biomarker discovery research requires new data preprocessing approaches to correlate specific metabolites to their biological origin. Mass spectrometry-based metabolomics often results in the observation of hundreds to thousands of features that are differentially regulated in biosamples. Extracting biomedical information from large metabolomic datasets by multivariate data analysis is of considerable complexity. Therefore, more efficient and optimized metabolomics data processing technologies are needed to improve MS applications in biomarker discovery. Here we use a sensitive ultra performance LC-ESI/quadrupole-TOF high-definition mass spectrometry (UPLC-ESI-Q TOF-MS) approach, in negative ion mode, to characterize metabolites. XCMS online analysis was used which incorporates novel nonlinear retention time alignment, matched filtration, peak detection, and peak matching. XCMS software can facilitate prioritization of the data and greatly increases the probability of identifying metabolites causally related to the phenotype of interest. 26 urinary differential metabolites contributing to the complete separation of HCC patients from matched healthy controls were identified involving the key metabolic pathways including tyrosine metabolism, glutathione metabolism, phenylalanine metabolism, ascorbate and aldarate metabolism, and arginine and proline metabolism. It demonstrates that high-throughput UPLC-ESI-Q-TOF-MS metabonomics combined with the proposed bioinformatic approach (based on XCMS) are pivotal to elucidate the developing biomarkers and physiological mechanism of disease in a clinical setting. PMID- 23821130 TI - Backbone NMR assignments of a topologically knotted protein in urea-denatured state. AB - YbeA is a 3-methylpseudoridine methyltransferase from Escherichia coli that forms a stable homodimer in solution. It is one of the deeply trefoil 31 knotted proteins, of which the knot encompasses the C-terminal helix that threads through a long loop. Recent studies on the knotted protein folding pathways using YbeA have suggested that the protein knot remains present under chemically denaturing conditions. Here, we report (1)H, (13)C and (15)N chemical shift assignments for urea-denatured YbeA, which will serve as the basis for further structural characterisations using solution state NMR spectroscopy with paramagnetic spin labeled and partial alignment media. PMID- 23821132 TI - Emergency EC-IC bypass for symptomatic atherosclerotic ischemic stroke. AB - Previous studies have shown that extracranial-intracranial (EC-IC) bypass surgery has no preventive effect on subsequent ipsilateral ischemic stroke in patients with symptomatic atherosclerotic internal carotid occlusion and hemodynamic cerebral ischemia. A few studies have assessed whether an urgent EC-IC bypass surgery is an effective treatment for main trunk stenosis or occlusion in acute stage. The authors retrospectively reviewed 58 consecutive patients who underwent urgent EC-IC bypass for symptomatic internal carotid artery or the middle cerebral artery stenosis or occlusion between January 2003 and December 2011. Clinical characteristics and neuroimagings were evaluated and analyzed. Based on preoperative angiogram, responsible lesions were the internal carotid artery in 19 (32.8%) patients and the middle cerebral artery in 39 (67.2%). No hemorrhagic complication occurred. Sixty-nine percent of patients showed improvement of neurological function after surgery, and 74.1% of patients had favorable outcome. Unfavorable outcome was associated with insufficient collateral flow and new infarction after bypass surgery. PMID- 23821131 TI - The safety and effectiveness of low field intraoperative MRI guidance in frameless stereotactic biopsies of brain tumours-design and interim analysis of a prospective randomized trial. AB - The aim of the study was to assess the safety and effectiveness of stereotactic brain tumour biopsy (STx biopsy) guided by low-field intraoperative magnetic resonance imaging (iMRI) in comparison with its frameless classic analogue based on a prospective randomized trial. A pilot group of 42 brain tumour patients was prospectively randomized into a low-field iMRI group and a control group that underwent a frameless STx biopsy. The primary endpoints of the analysis were postoperative complication rate and diagnostic yield, and the secondary endpoints were length of hospital stay and duration of operation. The iMRI group (21 patients) and the control group (21 patients) did not differ significantly according to demographic and epidemiological data. No major postoperative complications were noted in either group. In addition, no significant differences in the diagnostic yield (p = 1.00) and length of hospital stay (p = 0.16) were observed. The mean total OR time was 111 +/- 24 min in iMRI and 78 +/- 29 min in the control group (p = 0.0001). Usage of iMRI may prolong the time of the procedure but seems to be comparable in safety and effectiveness to the standard frameless STx biopsy. PMID- 23821133 TI - Men's experience with sexual dysfunction post-rectal cancer treatment: a qualitative study. AB - In an effort to address reports from men that their sex life is worse after treatment for rectal cancer, this qualitative study was designed to better understand their experience with sexual dysfunction following rectal cancer treatment, thus providing information on the adaptation of a psycho-educational sexual health intervention for male rectal cancer survivors and simultaneously investigating barriers and promoters that would influence their participation in a psycho-educational sexual health intervention. Thirteen male rectal cancer survivors who were treated at Memorial Sloan-Kettering Cancer Center (MSKCC) for rectal cancer participated (median time post-treatment was 6.4 years). Six survivors participated in individual semi-structured phone interviews, and seven others took part in focus groups. We performed standard procedures of qualitative thematic text analysis, which involved independent review of interview and focus group transcripts by several analysts followed by consensus meetings to identify key themes. Participants reported bowel dysfunction (N = 13, or 100%) and erectile dysfunction (N = 12, or 92%) as chief complaints. The participants thought a psychoeducational sexual health intervention post-surgery would be helpful because it would provide educational information regarding the etiology of their problems and treatments to improve their sexual health (N = 8, or 62%). Most participants' primary concern immediately after treatment was surviving their disease; improving sexual functioning seemed to become more important over time. Barriers to potentially participating in a psycho-educational sexual health intervention included geographical distance from MSKCC (N = 3, or 3/13) and the risk of embarrassment when discussing sexual issues (N = 5, or 5/13). Men reported that a psycho-educational sexual health intervention would be helpful to improve their sexual functioning post-treatment. Discussion of bowel issues and logistical concerns gave information on the psycho-educational sexual health intervention. PMID- 23821134 TI - Colorectal cancer screening brochure for Latinos: focus group evaluation. AB - Colorectal cancer (CRC) can be effectively prevented via screening colonoscopy, yet adherence rates remain low among Latinos. Interventions targeting individual and cultural barriers to screening are needed. We developed an educational brochure to target these barriers faced by a diverse Latino population. The objective was to evaluate the responses of the target population to the culturally and theoretically informed brochure through community member focus groups. Facilitators conducted six focus groups, stratified by gender, language, and prior colonoscopy experience. Topics included: brochure content and layout, cancer knowledge, and CRC screening determinants. Focus groups documented community members' responses to the brochure's overall message and its informational and visual components. Changes to wording, visual aids, and content were suggested to make the brochure culturally more acceptable. Results indicated relevance of the theoretically and culturally guided approach to the development of the brochure leading to refinement of its content and design. PMID- 23821135 TI - What do patients want? A survey on information needs of Indian patients diagnosed with cancer. PMID- 23821137 TI - Notice of redundant publication. PMID- 23821136 TI - Conditional survival is greater than overall survival at diagnosis in patients with osteosarcoma and Ewing's sarcoma. AB - BACKGROUND: Conditional survival is a measure of the risk of mortality given that a patient has survived a defined period of time. These estimates are clinically helpful, but have not been reported previously for osteosarcoma or Ewing's sarcoma. QUESTIONS/PURPOSES: We determined the conditional survival of patients with osteosarcoma and Ewing's sarcoma given survival of 1 or more years. METHODS: We used the Surveillance, Epidemiology, and End Results (SEER) Program database to investigate cases of osteosarcoma and Ewing's sarcoma in patients younger than 40 years from 1973 to 2009. The SEER Program is managed by the National Cancer Institute and provides survival data gathered from population-based cancer registries. We used an actuarial life table analysis to determine any cancer cause-specific 5-year survival estimates conditional on 1 to 5 years of survival after diagnosis. We performed a similar analysis to determine 20-year survival from the time of diagnosis. RESULTS: The estimated 5-year survival improved each year after diagnosis. For local/regional osteosarcoma, the 5-year survival improved from 74.8% at baseline to 91.4% at 5 years-meaning that if a patient with localized osteosarcoma lives for 5 years, the chance of living for another 5 years is 91.4%. Similarly, the 5-year survivals for local/regional Ewing's sarcoma improved from 72.9% at baseline to 92.5% at 5 years, for metastatic osteosarcoma 35.5% at baseline to 85.4% at 5 years, and for metastatic Ewing's sarcoma 31.7% at baseline to 83.6% at 5 years. The likelihood of 20-year cause specific survival from the time of diagnosis in osteosarcoma and Ewing's sarcoma was almost 90% or greater after 10 years of survival, suggesting that while most patients will remain disease-free indefinitely, some experience cancer-related complications years after presumed eradication. CONCLUSIONS: The 5-year survival estimates of osteosarcoma and Ewing's sarcoma improve with each additional year of patient survival. Knowledge of a changing risk profile is useful in counseling patients with time. The presence of cause-specific mortality decades after treatment supports lifelong monitoring in this population. LEVEL OF EVIDENCE: Level II, prognostic study. See the Instructions for Authors for a complete description of levels of evidence. PMID- 23821139 TI - Reply to the letter of Junginger et al. Strahlenther Onkol 2013 DOI 10.1007/s00066-013-0353-y. PMID- 23821138 TI - Taxane-containing induction chemotherapy followed by definitive chemoradiotherapy. Outcome in patients with locally advanced head and neck cancer. AB - BACKGROUND: Induction chemotherapy followed by definitive chemoradiotherapy is an intensified treatment approach for locally advanced squamous cell carcinoma of the head and neck (HNSCC) that might be associated with high rates of toxicity. MATERIALS AND METHODS: The data of 40 consecutive patients who underwent induction chemotherapy with docetaxel-containing regimens followed by intensity modulated radiotherapy (IMRT) and concomitant systemic therapy for unresectable locally advanced HNSCC were retrospectively analyzed. Primary objectives were RT related acute and late toxicity. Secondary objectives were response to induction chemotherapy, locoregional recurrence-free survival (LRRFS), overall survival (OS), and influencing factors for LRRFS and OS. RESULTS: The median follow-up for surviving patients was 21 months (range, 2-53 months). Patients received a median of three cycles of induction chemotherapy followed by IMRT to 72 Gy. Three patients died during induction chemotherapy and one during chemoradiotherapy. Acute RT-related toxicity was of grade 3 and 4 in 72 and 3 % of patients, respectively, mainly dysphagia and dermatitis. Late RT-related toxicity was mainly xerostomia and bone/cartilage necrosis and was of grade 3 and 4 in 15 % of patients. One- and 2-year LRRFS and OS were 72 and 49 % and 77 and 71 %, respectively. CONCLUSION: Induction chemotherapy followed by chemoradiotherapy using IMRT was associated with a high rate of severe acute and late RT-related toxicities in this selected patient cohort. Four patients were lost because of fatal complications. Induction chemotherapy did not compromise the delivery of full-dose RT; however, the use of three cycles of concomitant cisplatin was impaired. PMID- 23821140 TI - Peroxisome interactions and cross-talk with other subcellular compartments in animal cells. AB - Peroxisomes are remarkably plastic and dynamic organelles, which fulfil important functions in hydrogen peroxide and lipid metabolism rendering them essential for human health and development. Despite great advances in the identification and characterization of essential components and molecular mechanisms associated with the biogenesis and function of peroxisomes, our understanding of how peroxisomes are incorporated into metabolic pathways and cellular communication networks is just beginning to emerge. Here we address the interaction of peroxisomes with other subcellular compartments including the relationship with the endoplasmic reticulum, the peroxisome-mitochondria connection and the association with lipid droplets. We highlight metabolic cooperations and potential cross-talk and summarize recent findings on peroxisome-peroxisome interactions and the interaction of peroxisomes with microtubules in mammalian cells. PMID- 23821141 TI - Peroxisomes in human health and disease: metabolic pathways, metabolite transport, interplay with other organelles and signal transduction. AB - Peroxisomes play a key role in human physiology as exemplified by the devastating consequences of a defect in peroxisome biogenesis as observed in patients affected by Zellweger syndrome. The main metabolic functions of peroxisomes in humans include: (1) fatty acid beta-oxidation; (2) etherphospholipid synthesis; (3) bile acid synthesis; (4) fatty acid alpha-oxidation, and (5) glyoxylate detoxification. Since peroxisomes lack a citric acid cycle and respiratory chain like mitochondria do, metabolism in peroxisomes requires continued cross-talk with other organelles, notably mitochondria and the endoplasmic reticulum in order to allow continued metabolism of the products generated by peroxisomes. Many of the metabolites which require peroxisomes for homeostasis, are involved in signal transduction pathways. These include the primary bile acids; platelet activating factor; plasmalogens, N-acylglycines and N-acyltaurines; docosahexaenoic acid as well as multiple prostanoids. The current state of knowledge in this area will be discussed in this review. PMID- 23821142 TI - Aging, age-related diseases and peroxisomes. AB - Human aging is considered as one of the biggest risk factors for the development of multiple diseases such as cancer, type-2 diabetes, and neurodegeneration. In addition, it is widely accepted that these age-related diseases result from a combination of various genetic, lifestyle, and environmental factors. As biological aging is a complex and multifactorial phenomenon, the molecular mechanisms underlying disease initiation and progression are not yet fully understood. However, a significant amount of evidence supports the theory that oxidative stress may act as a primary etiologic factor. Indeed, many signaling components like kinases, phosphatases, and transcription factors are exquisitely sensitive to the cellular redox status, and a chronic or severe disturbance in redox homeostasis can promote cell proliferation or trigger cell death. Now, almost 50 years after their discovery, there is a wealth of evidence that peroxisomes can function as a subcellular source, sink, or target of reactive oxygen and nitrogen molecules. Yet, the possibility that these organelles may act as a signaling platform for a variety of age-related processes has so far been underestimated and largely neglected. In this review, we will critically discuss the possible role of peroxisomes in the human aging process in light of the available data. PMID- 23821144 TI - Peroxisome proliferator-activated receptor-alpha signaling in hepatocarcinogenesis. AB - Peroxisomes are subcellular organelles that are found in the cytoplasm of most animal cells. They perform diverse metabolic functions, including H2O2-derived respiration, beta-oxidation of fatty acids, and cholesterol metabolism. Peroxisome proliferators are a large class of structurally dissimilar industrial and pharmaceutical chemicals that were originally identified as inducers of both the size and the number of peroxisomes in rat and mouse livers or hepatocytes in vitro. Exposure to peroxisome proliferators leads to a stereotypical orchestration of adaptations consisting of hepatocellular hypertrophy and hyperplasia, and transcriptional induction of fatty acid metabolizing enzymes regulated in parallel with peroxisome proliferation. Chronic exposure to peroxisome proliferators causes liver tumors in both male and female mice and rats. Evidence indicates a pivotal role for a subset of nuclear receptor superfamily members, called peroxisome proliferator-activated receptors (PPARs), in mediating energy metabolism. Upon activation, PPARs regulate the expression of genes involved in lipid metabolism and peroxisome proliferation, as well as genes involved in cell growth. In this review, we describe the molecular mode of action of PPAR transcription factors, including ligand binding, interaction with specific DNA response elements, transcriptional activation, and cross talk with other signaling pathways. We discuss the evidence that suggests that PPARalpha and transcriptional coactivator Med1/PBP, a key subunit of the Mediator complex play a central role in mediating hepatic steatosis to hepatocarcinogenesis. Disproportionate increases in H2O2-generating enzymes generates excess reactive oxygen species resulting in sustained oxidative stress and progressive endoplasmic reticulum (ER) stress with activation of unfolded protein response signaling. Thus, these major contributors coupled with hepatocellular proliferation are the key players of peroxisome proliferators-induced hepatocarcinogenesis. PMID- 23821143 TI - Peroxisomes and the antiviral responses of mammalian cells. AB - Cell biology and microbiology are some of the oldest areas of scientific inquiry. Despite the depth of knowledge we now have in these respective fields, much remains unclear about how microorganisms interact with host intracellular organelles. Perhaps nowhere is this statement more accurate than in the role of peroxisomes in microbial infections. Peroxisomes were one of the first organelles discovered by Christian De Duve over 50 years ago (de Duve Ann N Y Acad Sci 386:1 4, 1982). These organelles are ubiquitously found in eukaryotic cells, where they serve several well-defined functions in lipid and oxygen homeostasis (Waterham and Wanders Biochim Biophys Acta 1822:1325, 2012). This chapter will discuss the emerging evidence that indicates that in addition to their functions in cellular metabolism, peroxisomes play an important role in viral infections. PMID- 23821145 TI - Involvement of human peroxisomes in biosynthesis and signaling of steroid and peptide hormones. AB - Although peroxisomes exert essential biological functions, cell type-specific features of this important organelle are still only superficially characterized. An intriguing new aspect of peroxisomal function was recently uncovered by the observation that the peptide hormones beta-lipotropin (beta-LPH) and beta endorphin are localized to peroxisomes in various human tissues. This suggests a functional link between peptide hormone metabolism and peroxisomes. In addition, because endocrine manifestations that affect steroid hormones are often found in patients suffering from inherited peroxisomal disorders, the question has been raised whether peroxisomes are also involved in steroidogenesis. With this chapter, we will review several crucial aspects concerning peroxisomes and hormone metabolism. PMID- 23821146 TI - Peroxisome Ca(2+) homeostasis in animal and plant cells. AB - Ca(2+) homeostasis in peroxisomes has been an unsolved problem for many years. Recently novel probes to monitor Ca(2+) levels in the lumen of peroxisomes in living cells of both animal and plant cells have been developed. Here we discuss the contrasting results obtained in mammalian cells with chemiluminecsent (aequorin) and fluorescent (cameleon) probes targeted to peroxisomes. We briefly discuss the different characteristics of these probes and the possible pitfalls of the two approaches. We conclude that the contrasting results obtained with the two probes may reflect a heterogeneity among peroxisomes in mammalian cells. We also discuss the results obtained in plant peroxisomes. In particular we demonstrate that Ca(2+) increases in the cytoplasm are mirrored by similar rises of Ca(2+) concentration the lumen of peroxisomes. The increases in peroxisome Ca(2+) level results in the activation of a catalase isoform, CAT3. Other functional roles of peroxisomal Ca(2+) changes in plant physiology are briefly discussed. PMID- 23821147 TI - The versatility of peroxisome function in filamentous fungi. AB - Peroxisomes are ubiquitous and versatile cell organelles. They consist of a single membrane that encloses a proteinaceous matrix. Conserved functions are fatty acid beta-oxidation and hydrogen peroxide metabolism. In filamentous fungi, many other metabolic functions have been identified. Also, they contain highly specialized peroxisome-derived structures termed Woronin bodies, which have a structural function in plugging septal pores in order to prevent cytoplasmic bleeding of damaged hyphae.In filamentous fungi peroxisomes play key roles in the production of a range of secondary metabolites such as antibiotics. Most likely the atlas of fungal peroxisomal metabolic pathways is still far from complete. Relative recently discovered functions include their role in biotin biosynthesis as well as in the production of several toxins, among which polyketides. Finally, in filamentous fungi peroxisomes are important for development and pathogenesis.In this contribution we present an overview of our current knowledge on fungal peroxisome formation as well as on their functional diversity. PMID- 23821148 TI - Essential roles of peroxisomally produced and metabolized biomolecules in regulating yeast longevity. AB - The essential role of the peroxisome in oxidizing fatty acids, maintaining reactive oxygen species homeostasis and replenishing tricarboxylic acid cycle intermediates is well known. Recent findings have broadened a spectrum of biomolecules that are synthesized and metabolized in peroxisomes. Emergent evidence supports the view that, by releasing various biomolecules known to modulate essential cellular processes, the peroxisome not only operates as an organizing platform for several developmental and differentiation programs but is also actively involved in defining the replicative and chronological age of a eukaryotic cell. The scope of this chapter is to summarize the evidence that the peroxisome defines yeast longevity by operating as a system controller that: (1) modulates levels of non-esterified fatty acids and diacylglycerol; (2) replenishes tricarboxylic acid cycle intermediates destined for mitochondria; and (3) contributes to the synthesis of polyamines. We critically evaluate molecular mechanisms underlying the essential role of peroxisomally produced and metabolized biomolecules in governing cellular aging in yeast. PMID- 23821149 TI - Metabolite transporters of the plant peroxisomal membrane: known and unknown. AB - Tremendous progress in plant peroxisome research has revealed unexpected metabolic functions for plant peroxisomes. Besides photorespiration and lipid metabolism, plant peroxisomes play a key role in many metabolic and signaling pathways, such as biosynthesis of phytohormones, pathogen defense, senescence associated processes, biosynthesis of biotin and isoprenoids, and metabolism of urate, polyamines, sulfite, phylloquinone, volatile benzenoids, and branched chain amino acids. These peroxisomal pathways require an interplay with other cellular compartments, including plastids, mitochondria, and the cytosol. Consequently, a considerable number of substrates, intermediates, end products, and cofactors have to shuttle across peroxisome membranes. However, our knowledge of their membrane passage is still quite limited. This review describes the solute transport processes required to connect peroxisomes with other cell compartments. Furthermore, we discuss the known and yet-to-be-defined transport proteins that mediate these metabolic exchanges across the peroxisomal bilayer. PMID- 23821150 TI - Peroxisomes and photomorphogenesis. AB - In higher plants, light-grown seedlings exhibit photomorphogenesis, a developmental program controlled by a complex web of interactions between photoreceptors, central repressors, and downstream effectors that leads to changes in gene expression and physiological changes. Light induces peroxisomal proliferation through a phytochrome A-mediated pathway, in which the transcription factor HYH activates the peroxisomal proliferation factor gene PEX11b. Microarray analysis revealed that light activates the expression of a number of peroxisomal genes, especially those involved in photorespiration, a process intimately associated with photosynthesis. In contrast, light represses the expression of genes involved in beta-oxidation and the glyoxylate cycle, peroxisomal pathways essential for seedling establishment before photosynthesis begins. Furthermore, the peroxisome is a source of signaling molecules, notably nitric oxide, which promotes photomorphogenesis. Lastly, a gain-of-function mutant of the peroxisomal membrane-tethered RING-type E3 ubiquitin ligase PEX2 partially suppresses the phenotype of the photomorphogenic mutant det1. Possible mechanisms underlying this phenomenon are discussed. PMID- 23821151 TI - Biosynthesis of vitamin K1 (phylloquinone) by plant peroxisomes and its integration into signaling molecule synthesis pathways. AB - Vitamin K1 (phylloquinone) is a substituted membrane-anchored naphthoquinone that functions as an essential electron carrier in photosystem I in photosynthetic organisms. While plants can synthesize phylloquinone de novo, humans rely on vitamin K1 uptake from green leafy vegetables as a precursor for the synthesis of its structural derivative, menaquinone-4 (vitamin K2). In vertebrates, menaquinone-4 serves as an enzymatic co-factor that is required for posttranslational protein modification, i.e. the gamma-carboxylation of glutamate residues in specific proteins involved in blood coagulation, bone metabolism and vascular biology. Comprehensive knowledge of the subcellular compartmentalization of vitamin K biosynthesis in plants, pathway regulation and its integration in cellular metabolic networks is important to design functional food with elevated vitamin levels and health benefits to human consumers. It had long been assumed that plants obtained all enzymes for phylloquinone biosynthesis from the ancient cyanobacterial endosymbiont and that, upon gene transfer to the nucleus, all biosynthetic enzymes were re-directed to the plastid. This view, however, has been recently challenged by the exclusive localization of the 6th pathway enzyme (MenB/NS) to peroxisomes in Arabidopsis. Soon afterwards, not only the preceding enzyme, acyl-activating enzyme 14 (MenE/AAE14), but also the succeeding thioesterase (DHNAT) were also shown to be peroxisomal. Phylogenetic analysis revealed a heterogeneous evolutionary origin of the peroxisomal enzymes. Phylloquinone biosynthesis reveals several branching points leading to the synthesis of important defence signalling molecules, such as salicylic acid and benzoic acid derivatives. Recent research data demonstrate that, of the two phenylalanine-dependent pathways for benzoic and salicylic acid biosynthesis, the CoA-dependent beta-oxidative pathway, which is peroxisomal, is the major route. Hence, peroxisomes emerge as an important cell compartment for the interconnected networks of phylloquinone, benzoic and salicylic acid biosynthesis. Numerous mechanisms to regulate intermediate flux and the fine-tuned inducible production of secondary metabolites, including signalling molecules, await their characterization at the molecular level. PMID- 23821152 TI - Role of peroxisomes as a source of reactive oxygen species (ROS) signaling molecules. AB - Peroxisomes are very dynamic and metabolically active organelles and are a very important source of reactive oxygen species (ROS), H2O2, O2 (.-) and . OH, which are mainly produced in different metabolic pathways, including fatty acid beta oxidation, photorespiration, nucleic acid and polyamine catabolism, ureide metabolism, etc. ROS were originally associated to oxygen toxicity; however, these reactive species also play a central role in the signaling network regulating essential processes in the cell. Peroxisomes have the capacity to rapidly produce and scavenge H2O2 and O2 (.-) which allows to regulate dynamic changes in ROS levels. This fact and the plasticity of these organelles, which allows adjusting their metabolism depending on different developmental and environmental cues, makes these organelles play a central role in cellular signal transduction. The use of catalase and glycolate oxidase loss-of-function mutants has allowed to study the consequences of changes in the levels of endogenous H2O2 in peroxisomes and has improved our knowledge of the transcriptomic profile of genes regulated by peroxisomal ROS. It is now known that peroxisomal ROS participate in more complex signaling networks involving calcium, hormones, and redox homeostasis which finally determine the response of plants to their environment. PMID- 23821153 TI - Peroxisomes as a source of auxin signaling molecules. AB - Peroxisomes house many metabolic processes that allow organisms to safely sequester reactions with potentially damaging byproducts. Peroxisomes also produce signaling molecules; in plants, these include the hormones indole-3 acetic acid (IAA) and jasmonic acid (JA). Indole-3-butyric acid (IBA) is a chain elongated form of the active auxin IAA and is a key tool for horticulturists and plant breeders for inducing rooting in plant cultures and callus. IBA is both made from and converted to IAA, providing a mechanism to maintain optimal IAA levels. Based on genetic analysis and studies of IBA metabolism, IBA conversion to IAA occurs in peroxisomes, and the timing and activity of peroxisomal import and metabolism thereby contribute to the IAA pool in a plant. Four enzymes have been hypothesized to act specifically in peroxisomal IBA conversion to IAA. Loss of these enzymes results in decreased IAA levels, a reduction in auxin-induced gene expression, and strong disruptions in cell elongation resulting in developmental abnormalities. Additional activity by known fatty acid beta oxidation enzymes also may contribute to IBA beta-oxidation via direct activity or indirect effects. This review will discuss the peroxisomal enzymes that have been implicated in auxin homeostasis and the importance of IBA-derived IAA in plant growth and development. PMID- 23821154 TI - Peroxisomes as cell generators of reactive nitrogen species (RNS) signal molecules. AB - Nitric oxide is a gaseous free radical with a wide range of direct and indirect actions in plant cells. However, the enzymatic sources of NO and its subcellular localization in plants are still under debate. Among the different subcellular compartments where NO has been found to be produced, peroxisomes are the best characterized since in these organelles it has been demonstrated the presence of NO and it has been biochemically characterized a L-arginine-dependent nitric oxide synthase activity. This chapter summarizes the present knowledge of the NO metabolism and its derived reactive nitrogen species (RNS) in plant peroxisomes and how this gaseous free radical is involved in natural senescence, and is released to the cytosol under salinity stress conditions acting as a signal molecule. PMID- 23821155 TI - Role of plant peroxisomes in the production of jasmonic acid-based signals. AB - Jasmonates are a family of oxylipins derived from linolenic acid that control plant responses to biotic and abiotic stress factors and also regulate plant growth and development. Jasmonic acid (JA) is synthesized through the octadecanoid pathway that involves the translocation of lipid intermediates from the chloroplast membranes to the cytoplasm and later on into peroxisomes. The peroxisomal steps of the pathway involve the reduction of cis-(+)-12 oxophytodienoic acid (12-OPDA) and dinor-OPDA, which are the final products of the choroplastic phase of the biosynthetic pathway acting on 18:3 and 16:3 fatty acids, respectively. Further shortening of the carbon side-chain by successive rounds of beta-oxidation reactions are required to complete JA biosynthesis. After peroxisomal reactions are completed, (+)-7-iso-JA is synthesized and then transported to the cytoplasm where is conjugated to the amino acid isoleucine to form the bioactive form of the hormone (+)-7-iso-JA-Ile (JA-Ile). Further regulatory activity of JA-Ile triggering gene activation in the jasmonate dependent signaling cascades is exerted through a process mediated by the perception via the E3 ubiquitin ligase COI1 and further ligand-activated interaction with the family of JAZ repressor proteins. Upon interaction, JAZ are ubiquitinated and degraded by the proteasome, thus releasing transcription factors such as MYC2 from repression and allowing the activation of JA-responsive genes. PMID- 23821156 TI - Role of plant peroxisomes in protection against herbivores. AB - Peroxisomes are subcellular organelles of vital importance. They are ubiquitous, have a single membrane and execute numerous metabolic reactions in plants. Plant peroxisomes are multifaceted and have diverse functions including, but not limited to, photomorphogenesis, lipid metabolism, photorespiration, nitrogen metabolism, detoxification and plant biotic interactions. Plants have evolved a variety of defence barriers against herbivory. These barriers are unique and loaded with various metabolites. Peroxisomes play an important role in cells, maintaining the compartmentation of certain specific reactions. They serve as a first line of defence, as peroxisomes generate primary signals such as reactive oxygen species (ROS) and reactive nitrogen species (RNS). Both ROS and RNS sense the invasion by herbivores and dramatically reshape the plant transcriptomes, proteomes, and metabolomes, so indicating the importance of signals generated by peroxisomes. Peroxisomes also store a plethora of important enzymes, which have a key role in producing defence molecules. Some of the main enzymes in the biosynthesis of isoprenoids are present in peroxisomes. These enzymes generate plant volatiles, which have numerous functions and important roles in plant herbivore communication.Although disputed, the enzyme myrosinase has also been reported to be present in peroxisomes, and myrosinases are well known for their role in the mustard bomb, a powerful defence against herbivores. This chapter focuses on the diverse roles of peroxisomes in the generation of direct and indirect defenses against herbivores. PMID- 23821157 TI - Function of peroxisomes in plant-pathogen interactions. AB - Peroxisomes are ubiquitous organelles of eukaryotic cells that accomplish a variety of biochemical functions, including beta-oxidation of fatty acids, glyoxylate cycle, etc. Many reports have been accumulating that indicate peroxisome related metabolic functions are essential for pathogenic development of plant pathogenic fungi. They include peroxisome biogenesis proteins, peroxins and preferential destruction of peroxisomes, pexophagy. Gene disrupted mutants of anthracnose disease pathogen Colletotrichum orbiculare or rice blast pathogen Magnaporthe oryzae defective in peroxins or pexophagy showed deficiency in pathogenesis. Woronin body, a peroxisome related cellular organelle that is related to endurance of fungal cells against environmental damage has essential roles in pathogenesis of M. oryzae. Also, peroxisome related metabolisms such as beta-oxidation and glyoxylate cycle are essential for pathogenesis in several plant pathogenic fungi. In addition, secondary metabolisms including polyketide melanin biosynthesis of C. orbiculare and M. oryzae, and host selective toxins produced by necrotrophic pathogen Alternaria alternata have pivotal roles in fungal pathogenesis. Every such factor was listed and their functions for pathogenesis were demonstrated (Table 18.1 and Fig. 18.1). PMID- 23821158 TI - Adjustable versus non-adjustable sutures for strabismus. AB - BACKGROUND: Strabismus, or squint, can be defined as a deviation from perfect ocular alignment and can be classified in many ways according to its aetiology and presentation. Treatment can be broadly divided into medical and surgical options, with a variety of surgical techniques being available, including the use of adjustable or non-adjustable sutures for the extraocular muscles. There exists an uncertainty as to which of these techniques produces a better surgical outcome, and also an opinion that the adjustable suture technique may be of greater benefit in certain situations. OBJECTIVES: To examine whether adjustable or non-adjustable sutures are associated with a more accurate long-term ocular alignment following strabismus surgery and to identify any specific situations in which it would be of benefit to use a particular method. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 12), Ovid MEDLINE, Ovid MEDLINE In Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE, (January 1950 to January 2013), EMBASE (January 1980 to January 2013), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to January 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled trials.com), ClinicalTrials.gov (http://clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 17 January 2013. We also contacted experts in the field for further information. SELECTION CRITERIA: We planned to include only randomised controlled trials (RCTs) comparing adjustable to non-adjustable sutures for strabismus surgery. DATA COLLECTION AND ANALYSIS: We did not find any studies that met the inclusion criteria for this review. MAIN RESULTS: We did not find any studies that met the inclusion criteria for this review, therefore none were included for analysis. Results of non-randomised studies that compared these techniques are reported. AUTHORS' CONCLUSIONS: No reliable conclusions could be reached regarding which technique (adjustable or non-adjustable sutures) produces a more accurate long-term ocular alignment following strabismus surgery or in which specific situations one technique is of greater benefit than the other. High quality RCTs are needed to obtain clinically valid results and to clarify these issues. Such trials should ideally a) recruit participants with any type of strabismus or specify the subgroup of participants to be studied, for example, thyroid, paralytic, non-paralytic, paediatric; b) randomise all consenting participants to have either adjustable or non-adjustable surgery prospectively; c) have at least six months of follow-up data; and d) include re-operation rates as a primary outcome measure. PMID- 23821159 TI - Development of a novel regulatory pharmacovigilance prioritisation system: an evaluation of its performance at the UK Medicines and Healthcare products Regulatory Agency. AB - BACKGROUND: The prioritisation of drug safety issues for further evaluation or regulatory action is critical to ensure that acceptable timelines and appropriate resource allocation are defined to meet public health and regulatory obligations. OBJECTIVE: Our objective was to develop, pilot and implement a novel tool for prioritising pharmacovigilance issues within the Medicines and Healthcare products Regulatory Agency (MHRA). METHODS: An initial system was developed empirically and then piloted over a 10-month period in the pharmacovigilance signal management meeting at the MHRA that discusses potential pharmacovigilance issues, and determines, through consensus, their priority and a timescale for action. The priority assigned by the tool was compared with the priority decided by collective judgement at the meeting. Once an acceptable level of concordance between the tool and the meeting had been achieved, the finalised tool was implemented into routine use at the MHRA, with an evaluation of its performance conducted after the first year. RESULTS: The Regulatory Pharmacovigilance Prioritisation System (RPPS) tool prioritises pharmacovigilance issues according to the following four broad categories, each with four inputs: strength of evidence, public health implications, agency regulatory obligations and public perceptions. A weighted scoring system links the inputs to a pre-defined number of points where if a threshold is reached then the points are awarded. The overall priority is determined by the sum of all points obtained from each of the inputs. The pilot study included a total of 73 pharmacovigilance issues during the 10-month study period, with an overall exact agreement between the RPPS priority and the collective judgement of the meeting of 60.3 %. Where exact agreement was not obtained, the RPPS generally prioritised the issues slightly higher than the meeting. Over the first year following implementation, the RPPS achieved an overall exact agreement of 82.2 %. CONCLUSION: Following the pilot study and implementation at the UK MHRA, the RPPS has provided a systematic approach to drug safety issue prioritisation that should help to reduce the subjectivity of reliance on individual judgement. PMID- 23821160 TI - Expression of orphan nuclear receptor NR4A2 in gastric cancer cells confers chemoresistance and predicts an unfavorable postoperative survival of gastric cancer patients with chemotherapy. AB - BACKGROUND: NR4A2, an orphan nuclear receptor essential in the generation of dopaminergic neurons, has been recently linked to inflammation and cancer. This study sought to identify the role of NR4A2 on chemoresistance and postoperative prognosis of gastric cancer (GC). METHODS: NR4A2 was transfected into GC cells to investigate its effects on chemoresistance to 5-fluorouracil and the tumorigenicity in nude mice. This study also investigated prostaglandin E2 (PGE2 )-induced NR4A2 expression and its effect on chemoresistance. Surgical specimens from patients with stage I through III GC were examined immunohistochemically for NR4A2 expression. Median follow-up time was 76 months for 245 patients. RESULTS: Ectopic expression of NR4A2 significantly increased the chemoresistance and attenuated 5-fluorouracil-induced apoptosis. Transient treatment of GC cells with PGE2 significantly upregulated NR4A2 expression via the protein kinase A pathway and increased the chemoresistance. Ectopic expression of NR4A2 significantly increased the tumorigenicity. In clinical samples, NR4A2 was preferentially expressed in lymphocytes and epithelial cytoplasm in adjacent mucosa. High expression of NR4A2 (immunoreactive score >= 3) in cancer cells significantly predicted an unfavorable postoperative disease-specific survival of patients with stage I to III GC (P = .011), especially for those who received 5-fluorouracil based chemotherapy (P = .016). This effect was not found in those without the chemotherapy. In multivariate Cox analyses, age, TNM (tumor/node/metastasis) stage, and high NR4A2 expression significantly predicted an unfavorable postoperative survival. CONCLUSIONS: High NR4A2 expression in GC cells confers chemoresistance, attenuates 5-fluorouracil-induced apoptosis, and predicts an unfavorable survival, especially for those who received chemotherapy. NR4A2 might serve as a prognostic and predictive factor and therapeutic target for patients with GC. Cancer 2013;119:3436-3445.. (c) 2013 American Cancer Society. PMID- 23821161 TI - Regulation of traffic and organelle architecture of the ER-Golgi interface by signal transduction. AB - The components that control trafficking between organelles of the secretory pathway as well as their architecture were uncovered to a reasonable extent in the past decades. However, only recently did we begin to explore the regulation of the secretory pathway by cellular signaling. In the current review, we focus on trafficking between the endoplasmic reticulum and the Golgi apparatus. We highlight recent advances that have been made toward a better understanding of how the secretory pathway is regulated by signaling and discuss how this knowledge is important to obtain an integrative view of secretion in the context of other homeostatic processes such as growth and proliferation. PMID- 23821162 TI - Golgi as an MTOC: making microtubules for its own good. AB - In cells, microtubules (MTs) are nucleated at MT-organizing centers (MTOCs). The centrosome-based MTOCs organize radial MT arrays, which are often not optimal for polarized trafficking. A recently discovered subset of non-centrosomal MTs nucleated at the Golgi has proven to be indispensable for the Golgi organization, post-Golgi trafficking and cell polarity. Here, we summarize the history of this discovery, known molecular prerequisites of MT nucleation at the Golgi and unique functions of Golgi-derived MTs. PMID- 23821164 TI - Homelessness and premature mortality among veterans. PMID- 23821163 TI - Accommodation of large cargo within Golgi cisternae. AB - In mammalian cells, the Golgi complex has an elaborate structure consisting of stacked, flattened cisternal membranes collected into a ribbon in the center of the cell. Amazingly, the flattened cisternae can rapidly dilate to accommodate large cargo as it traffics through the organelle. The mechanism by which this occurs is unknown. Exocytosis of large cargo is essential for many physiological processes, including collagen and lipoprotein secretion, and defects in the process lead to disease. In addition, enveloped viruses that bud into the endoplasmic reticulum or Golgi complex must also be transported through Golgi cisternae for secretion from the infected cell. This review summarizes our understanding of intra-Golgi transport of large cargo, and outlines current questions open for experimentation. PMID- 23821166 TI - Datapoints: trends in mortality among homeless VA patients with severe mental illness. PMID- 23821167 TI - Law & psychiatry: the evolution of laws regulating psychiatric commitment in France. AB - This column reviews the evolution of French laws governing psychiatric commitment, culminating in the July 2011 Act, which was opposed by most professional organizations. The 2011 Act has maintained the two traditional French approaches to involuntary treatment: at the request of a third person and upon a decision by a prefect representing the government. However, the 2011 Act introduced major innovations into French practices: systematic review by a judge, a 72-hour observation period, and the possibility of compulsory community treatment. PMID- 23821168 TI - Mental health care reforms in Asia: the urgency of now: building a recovery oriented, community mental health service in china. AB - For the first time in history, China has a mental health legal framework. People in China can now expect a better life and more accessible, better-quality health care services for their loved ones. Development of a community mental health service (CMHS) is at a crossroads. In this new column on mental health reforms in Asia, the authors review the current state of the CMHS in China and propose four strategic directions for future development: building on the strengths of the "686 Project," the 2004 initiative that launched China's mental health reform; improving professional skills of the mental health workforce, especially for a recovery approach; empowering families and caregivers to support individuals with severe mental illness; and using information and communications technology to promote self-help and reduce the stigma associated with psychiatric disorders. PMID- 23821169 TI - Mental health care reforms in Asia: the regional health care strategic plan: the growing impact of mental disorders in Japan. AB - In April 2013 Japan designated mental disorders as the fifth "priority disease" for national medical services, after cancer, stroke, acute myocardial infarction, and diabetes. All prefectures will be required to assess local mental health needs and develop necessary service components. This column provides an overview of the Regional Health Care Strategic Plan in the context of mental health and welfare reforms. The goals of the plan are to alter the balance between institutional and community-based care for patients with severe and persistent mental disorders, integrate general medical and mental health care, and support greater independence for people with mental disorders. It is a political challenge for Japan to reallocate resources to rebalance care services while maintaining free access to care. PMID- 23821170 TI - Sustaining practice change one year after completion of the national depression management leadership initiative. AB - OBJECTIVE: This report describes the sustainability of quality improvement interventions for depression care in psychiatric practice one year after the completion of the National Depression Management Leadership Initiative (NDMLI) in 2006. The main intervention involved continued use of the nine-item depression scale of the Patient Health Questionnaire (PHQ-9) for routine care of patients with depressive disorders. METHODS: One year after project completion, lead psychiatrists from the 17 participating practices were surveyed about the sustainability of key practice interventions and dissemination of the interventions. RESULTS: All 14 practices that provided baseline and follow-up data reported sustained use of the PHQ-9 for screening, diagnosis, or monitoring purposes. Moreover, practices reported dissemination of this approach to clinicians within and outside their practices. CONCLUSIONS: Psychiatrists reported sustainability and dissemination of PHQ-9 use one year after the conclusion of the NDMLI. The model has potential as a depression care improvement strategy and is worthy of additional study. PMID- 23821171 TI - Smoking cessation care provision and support procedures in Australian community mental health centers. AB - OBJECTIVE: The study assessed the association of supportive clinical systems and procedures with smoking cessation care at community mental health centers. METHODS: Managers (N=84) of community mental health centers in New South Wales, Australia, were asked to complete a survey during 2009 about smoking cessation care. RESULTS: Of the 79 managers who responded, 56% reported that the centers assessed smoking for over 60% of clients, and 34% reported that more than 60% of clients received minimum acceptable smoking cessation care. They reported the use of guidelines and protocols (34%), the use of forms to record smoking status (65%), and the practice of always enforcing smoking bans (52%). Minimum acceptable smoking cessation care was associated with encouraging nicotine replacement therapy for staff who smoke (odds ratio [OR]=9.42), using forms for recording smoking status (OR=5.80), and always enforcing smoking bans (OR=3.82). CONCLUSIONS: Smoking cessation care was suboptimal, and additional supportive systems and procedures are required to increase its delivery. PMID- 23821172 TI - Web-based intensive therapeutic contact for eating disorders. PMID- 23821173 TI - Pop-up treatment plans for the urban psychiatric emergency room. PMID- 23821174 TI - Did microinsults and microaggressions play a role? PMID- 23821175 TI - Did microinsults and microaggressions play a role?: in reply. PMID- 23821176 TI - Age and suicide among veterans with a history of homelessness. PMID- 23821177 TI - Responses of health care institutions to staff suicides. PMID- 23821178 TI - Case management for frequent emergency department users. PMID- 23821179 TI - IOM identifies research priorities on firearm-related violence. PMID- 23821180 TI - CDC's First Surveillance Report on Children's Mental Health. PMID- 23821182 TI - Minimally invasive endoscope-assisted surgery for bilateral branchial cleft fistula. PMID- 23821183 TI - The trigger-maintenance model of persistent mild to moderate hyperoxaluria induces oxalate accumulation in non-renal tissues. AB - Persistent mild to moderate hyperoxaluria (PMMH) is a common side effect of bariatric surgery. However, PMMH's role in the progression to calcium oxalate (CaOx) urolithiasis and its potential effects on non-renal tissues are unknown. To address these points, a trigger + maintenance (T + Mt) model of PMMH was developed in rats (Experiment 1). The trigger was an i.p. injection of PBS (TPBS) or 288 MUmol sodium oxalate (T288). Maintenance (Mt) was given via minipumps dispensing PBS or 7.5-30 MUmol potassium oxalate/day for 28 days. Urinary oxalate ranged from 7.7 +/- 0.8 MUmol/day for TPBS + MtPBS to 18.2 +/- 1.5 MUmol/day for T288 + Mt30 (p <= 0.0005). All rats receiving T288 developed CaOx nephrocalcinosis, and many developed 'stones'. This was also true for Mt doses that did not elevate urinary oxalate above that of TPBS + MtPBS (p > 0.1) and for rats that did not have a detectable surge in urinary oxalate post T288. When TPBS was administered, CaOx nephrocalcinosis did not develop regardless of the Mt dose even if urinary oxalate was elevated compared to TPBS + MtPBS (p <= 0.0005). One of the risks associated with PMMH is oxalate accumulation within tissues. Hence, in a second set of experiments (Experiment 2) different doses of oxalate (Mt0.05, Mt15, Mt30) labeled with (14)C-oxalate ((14)C-Ox) were administered by minipump for 13 days. Tissues were harvested and (14)C-Ox accumulation assessed by scintillation counting. (14)C-Ox accumulated in a dose dependent manner (p <= 0.004) in bone, kidney, muscle, liver, heart, kidney, lungs, spleen, and testis. All these tissues exhibited (14)C-Ox concentrations higher (p <= 0.05) than the plasma. Extrapolation of our results to patients suggests that PMMH patients should take extra care to avoid dietary-induced spikes in oxalate excretion to help prevent CaOx nephrocalcinosis or stone development. Monitoring for oxalate accumulation within tissues susceptible to damage by oxalate or CaOx crystals may also be required. PMID- 23821184 TI - Impact of official technical training for urologists on the efficacy of shock wave lithotripsy. AB - To evaluate the efficacy of company-initiated training of urologists on shock wave lithotripsy (SWL) treatment results, we retrospectively assessed 602 patients who underwent SWL in Nagoya City University Hospital between January 2004 and June 2011 using Lithotripter S (Dornier MedTech, Japan). Training provided by a training specialist of the company in June 2010-focused on the targeting of renal and proximal ureter stones with a combination of radiography and ultrasonography (US). The stretcher wedges were positioned in the semi-prone position or the semi-supine position for middle and distal ureter stones, respectively. Success rates between 519 pre-training treatments and 83 post training treatments were compared. Patient age and stone location, burden, number, and composition did not significantly differ between pre- and post training. Training improved the overall success rate from 66.3 to 87.2 % (P < 0.0001). The mean number of SWL treatments decreased from 1.8 +/- 1.8 to 1.4 +/- 1.3 (P = 0.01). The first SWL treatment success rate increased from 67.1 to 83.7 % (P = 0.002), and the need for multiple treatments decreased. The frequency of detection of renal and proximal ureter stones by both radiography and US increased from 10.5 % before training to 58.2 % after training (P < 0.0001). Significant factors for successful SWL were determined to be training and prone position for distal ureter stones by multivariate analysis and ultrasonic detection for renal and proximal ureter stones by univariate analysis. Skills in targeting stones using ultrasonography and selecting the proper therapeutic position are essential for improving the success rate of stone removal. PMID- 23821185 TI - Biotransformation of a novel positive allosteric modulator of metabotropic glutamate receptor subtype 5 contributes to seizure-like adverse events in rats involving a receptor agonism-dependent mechanism. AB - Activation of metabotropic glutamate receptor subtype 5 (mGlu5) represents a novel strategy for therapeutic intervention into multiple central nervous system disorders, including schizophrenia. Recently, a number of positive allosteric modulators (PAMs) of mGlu5 were discovered to exhibit in vivo efficacy in rodent models of psychosis, including PAMs possessing varying degrees of agonist activity (ago-PAMs), as well as PAMs devoid of agonist activity. However, previous studies revealed that ago-PAMs can induce seizure activity and behavioral convulsions, whereas pure mGlu5 PAMs do not induce these adverse effects. We recently identified a potent and selective mGlu5 PAM, VU0403602, that was efficacious in reversing amphetamine-induced hyperlocomotion in rats. The compound also induced time-dependent seizure activity that was blocked by coadministration of the mGlu5 antagonist, 2-methyl-6-(phenylethynyl) pyridine. Consistent with potential adverse effects induced by ago-PAMs, we found that VU0403602 had significant allosteric agonist activity. Interestingly, inhibition of VU0403602 metabolism in vivo by a pan cytochrome P450 (P450) inactivator completely protected rats from induction of seizures. P450-mediated biotransformation of VU0403602 was discovered to produce another potent ago-PAM metabolite-ligand (M1) of mGlu5. Electrophysiological studies in rat hippocampal slices confirmed agonist activity of both M1 and VU0403602 and revealed that M1 can induce epileptiform activity in a manner consistent with its proconvulsant behavioral effects. Furthermore, unbound brain exposure of M1 was similar to that of the parent compound, VU0403602. These findings indicate that biotransformation of mGlu5 PAMs to active metabolite-ligands may contribute to the epileptogenesis observed after in vivo administration of this class of allosteric receptor modulators. PMID- 23821186 TI - Intestinal first-pass metabolism by cytochrome p450 and not p-glycoprotein is the major barrier to amprenavir absorption. AB - Recent studies showed that P-glycoprotein (P-gp) increases the portal bioavailability (FG) of loperamide by sparing its intestinal first-pass metabolism. Loperamide is a drug whose oral absorption is strongly attenuated by intestinal P-gp-mediated efflux and first-pass metabolism by cytochrome P450 3A (CYP3A). Here the effect of the interplay of P-gp and Cyp3a in modulating intestinal first-pass metabolism and absorption was investigated for another Cyp3a/P-gp dual substrate amprenavir, which is less efficiently effluxed by P-gp than loperamide. After oral administration of amprenavir, the portal concentrations and FG of amprenavir were approximately equal in P-gp competent and P-gp deficient mice. Mechanistic studies on the effect of P-gp on Cyp3a mediated metabolism of amprenavir using intestinal tissue from P-gp competent and P-gp deficient mice (Ussing-type diffusion chamber) revealed that P-gp-mediated efflux caused only a slight reduction of oxidative metabolism of amprenavir. Studies in which portal concentrations and FG were measured in P-gp competent and P-gp deficient mice whose cytochrome P450 (P450) enzymes were either intact or inactivated showed that intestinal first-pass metabolism attenuates the oral absorption of amprenavir by approximately 10-fold, whereas P-gp efflux has a relatively small effect (approximately 2-fold) in attenuating the intestinal absorption. Cumulatively, these studies demonstrate that P-gp has little influence on the intestinal first-pass metabolism and FG of amprenavir and that intestinal P450-mediated metabolism plays the dominant role in attenuating the oral absorption of this drug. PMID- 23821187 TI - Imaging the intact mouse cornea using coherent anti-stokes Raman scattering (CARS). AB - PURPOSE: The aim of this study was to image the cellular and noncellular structures of the cornea and limbus in an intact mouse eye using the vibrational oscillation of the carbon-hydrogen bond in lipid membranes and autofluorescence as label-free contrast agents. METHODS: Freshly enucleated mouse eyes were imaged using two nonlinear optical techniques: coherent anti-Stokes Raman scattering (CARS) and two-photon autofluorescence (TPAF). Sequential images were collected through the full thickness of the cornea and limbal regions. Line scans along the transverse/sagittal axes were also performed. RESULTS: Analysis of multiple CARS/TPAF images revealed that corneal epithelial and endothelial cells could be identified by the lipid-rich plasma membrane CARS signal. The fluorescent signal from the collagen fibers of the corneal stroma was evident in the TPAF channel. The transition from the cornea to sclera at the limbus was marked by a change in collagen pattern (TPAF channel) and thickness of surface cells (CARS channel). Regions within the corneal stroma that lack collagen autofluorescence coincided with CARS signal, indicating the presence of stromal fibroblasts or nerve fibers. CONCLUSIONS: The CARS technique was successful in imaging cells in the intact mouse eye, both at the surface and within corneal tissue. Multiphoton images were comparable to histologic sections. The methods described here represent a new avenue for molecular specific imaging of the mouse eye. The lack of need for tissue fixation is unique compared with traditional histology imaging techniques. PMID- 23821189 TI - Genomic profile of 320 uveal melanoma cases: chromosome 8p-loss and metastatic outcome. AB - PURPOSE: Uveal melanoma (UM) was a fatal malignancy in 40% to 50% of cases. The aim of this study is to evaluate the independent contributions of chromosome 1, 3, 6, and 8 abnormalities for prognostication of metastasis, and to define multichromosome copy number aberration (CNA) signatures that can be used to evaluate risk. METHODS: A series of 320 UM were analyzed for chromosome 1, 3, 6, and 8 abnormalities using whole genome single-nucleotide polymorphism arrays. Results for changes in six chromosomal regions were analyzed using univariate and multivariate Cox proportional hazard modeling to identify significant predictors of metastasis and CNA signatures. RESULTS: Univariate Cox analysis indicated that losses of chromosome 3, 1p, 6q, and 8p and gain of 8q, as well as sex, source of tumor tissue (fine-needle aspiration biopsy [FNAB] compared with tumor from an enucleated eye), tumor basal diameter and height, and ciliary body involvement were all significant predictors of poor metastatic outcome. In the multivariate analysis, loss of chromosome 3 and 8p remained significant after adjusting for the effects of all other variables, as did sex, tissue source, and basal diameter. Multivariate analysis of the joint effects of changes in the six chromosomal regions showed that six signatures, including chromosome 3-loss, 1p loss, 8p-loss, and/or 8q-gain had hazard ratios (HR) ranging from 7.90 to 37.25. CONCLUSIONS: In UM, tumor size and location, tissue source, and sex were all significantly associated with increased metastasis. In addition, chromosome 3 loss and 8p-loss were found to be independent predictors of poor metastatic outcome and CNA signatures were identified that can add a specific HR value for classification of risk categories. PMID- 23821188 TI - Age-dependent changes in FasL (CD95L) modulate macrophage function in a model of age-related macular degeneration. AB - PURPOSE: We examined the effect of aging on Fas ligand (FasL) function in a mouse model of choroidal neovascularization (CNV). METHODS: Young and aged mice were laser treated to induce CNV. Bone marrow chimeras were performed between young and aged mice. FasL protein expression was examined in the eye and soluble FasL (sFasL) was measured in the blood. Young and aged mice were treated with a matrix metalloprotease (MMP) inhibitor and systemic sFasL was neutralized by antibody treatment. Macrophages from young and aged mice were tested for sFasL-mediated cytokine production and migration. RESULTS: The elevated CNV response observed with aging was dependent on bone marrow-derived cells. FasL expression in the eye was increased with age, but decreased following laser treatment. Aged mice had higher levels of sFasL in the blood compared to young mice. Systemic treatment with an MMP inhibitor decreased bloodborne sFasL, and reduced CNV in young and aged mice. Systemic neutralization of sFasL reduced CNV only in aged mice. sFasL increased cytokine production in aged macrophages and proangiogenic M2 macrophages. Aged M2 macrophages had elevated Fas (CD95) expression and displayed increased migration in response to sFasL compared to M1 macrophages derived from young animals. CONCLUSIONS: Age modulates FasL function where increased MMP cleavage leads to a loss of function in the eye. The released form of FasL (sFasL) preferentially induces the migration of proangiogenic M2 macrophages into the laser lesions and increases proangiogenic cytokines promoting CNV. FasL may be a viable target for therapeutic intervention in aged-related neovascular disease. PMID- 23821191 TI - A prototype hyperspectral system with a tunable laser source for retinal vessel imaging. AB - PURPOSE: To describe the technology and determine the within-session repeatability of manual retinal reflectance measurements of arterioles and venules using a prototype hyperspectral retinal camera. METHODS: Six healthy young volunteers (three males, average age 26 +/- 4 years) had five repeated sets of retinal images captured between 500 and 600 nm at 5-nm intervals using a newly developed hyperspectral retinal camera. Optical densities were manually extracted for first-degree arterioles and venules and the repeatability of retinal reflectance was compared sequentially. The SDs of the differences between sequential mean values were used as an indication of the variance, while the coefficient of repeatability (COR) and intraclass correlation coefficient (ICC) were used to assess repeatability. RESULTS: The mean difference between each sequential measure was calculated using 21 images from each of the five spectral cubes. The SDs of these values ranged from 0.01 to 0.06 OD units and from 0.01 to 0.07 OD units for first-degree arterioles and venules, respectively. The COR ranged from 0.02 to 0.11 OD units (relative to a mean OD of 0.15 [0.06-0.23] OD units) for arterioles and 0.03 to 0.14 OD units (relative to a mean OD of 0.25 [0.17-0.31] OD units) for venules. Good reliability (P < 0.001) was found for arterioles (ICC: 78.8%-94.4% with a Cronbach's alpha of 89.6%-97.6%) and for venules (ICC: 63.7%-92.1% with a Cronbach's alpha of 86.2%-98.1%). CONCLUSIONS: Manual optical density determination with this novel hyperspectral camera showed very good intrasession (and intraobserver) repeatability with a small degree of variance that should form the basis of reliable retinal oxygen saturation values in future imaging research studies. Future automation of retinal vessel reflectance image analyses will likely further improve this repeatability. PMID- 23821190 TI - Postocclusive reactive hyperemia occurs in the rat retinal circulation but not in the choroid. AB - PURPOSE: We tested the hypothesis that retinal blood flow has a postocclusive reactive hyperemia response modulated by occlusion duration and metabolic activity, and that choroidal blood flow does not. METHODS: Anesthetized and paralyzed rats (n = 34) were studied. Retinal and choroidal blood flow was measured by laser speckle imaging and laser Doppler flowmetry, respectively. Blood oxygenation level-dependent functional magnetic resonance imaging (BOLD fMRI) was used to measure changes in relative blood oxygenation of the retinal and choroidal circulations. Transient carotid occlusion was elicited with a hydraulic occluder on the common carotid artery. Several occlusion durations were tested during dark, constant light, and flicker light conditions to modulate metabolic demand. The hyperemia response magnitude was quantified by integrating the area above the blood flow baseline for the 3 minutes after release of the occlusion. RESULTS: Systemic arterial pressure (108.2 +/- 1.4 mm Hg) was unaffected by the carotid occlusions, and was similar among animals and conditions. Retinal blood flow had a reactive hyperemia, but choroidal blood flow did not (e.g., 14 +/- 2%.sec versus 0.5 +/- 4%. sec after 60-second occlusion). The hyperemia magnitude increased as a nonlinear function of occlusion duration and reached a plateau at occlusion durations < 60 second. The hyperemia magnitude was not altered by different lighting conditions at occlusion durations of 15 and 60 seconds. BOLD fMRI results were similar to the laser-based blood flow measurements. CONCLUSIONS: The results indicate that metabolic local control has a negligible role in choroidal blood flow regulation and only partially accounts for the blood flow behavior in the retinal circulation. PMID- 23821192 TI - Serine protease inhibitor A3K protects rabbit corneal endothelium from barrier function disruption induced by TNF-alpha. AB - PURPOSE: To determine if a serine protease inhibitor A3K (SA3K) reduces TNF-alpha induced declines in rabbit corneal endothelial junctional barrier integrity. METHODS: New Zealand rabbit corneas were incubated ex vivo for 24 hours in Dulbecco's modified Eagle's medium (DMEM) containing 10% FBS with or without TNF alpha, in the presence or absence of SA3K at different concentrations. Corneal endothelial barrier function permeability was determined based on measurements of FITC-dextran tissue accumulation. Apical junctional complex (AJC) integrity was evaluated of zonula occludens-1 (ZO-1), vascular endothelial (VE)-cadherin, and filamentous actin (F-actin) and associated microtubules, as well as myosin light chain (MLC) by immunofluorescent staining, Western blot analysis, and/or RT-PCR. RESULTS: TNF-alpha (20 ng/mL) increased corneal endothelial FITC-dextran permeability by 1.8-fold compared with the untreated control. SA3K (100-200 nM) dose dependently suppressed TNF-alpha-induced increases in permeability. SA3K nearly completely reversed TNF-alpha-induced disruptions of tight junctional ZO-1 and subjacent adherens junctions VE-cadherin integrity. Interestingly, SA3K reversed TNF-alpha-induced disruption of AJC linkage to the cytoskeletal F-actin array by restoring F-actin double-band structures. SA3K also attenuated TNF-alpha induced microtubule disassembly. Furthermore, SA3K blocked increases in MLC phosphorylation status elicited by TNF-alpha. CONCLUSIONS: SA3K exposure markedly reduced TNF-alpha-induced disruption of barrier structure and function in the rabbit corneal endothelium by maintaining AJC integrity. These protective effects are due to suppression of MLC activation. SA3K may have, in vivo, a therapeutic potential to offset TNF-alpha-induced declines in endothelial barrier structural integrity and function. PMID- 23821193 TI - The role of LOX and LOXL2 in scar formation after glaucoma surgery. AB - PURPOSE: The aim of this study was to elucidate the role of lysyl oxidase (LOX) and lysyl oxidase like (LOXL) 2 in pathologic wound healing after glaucoma surgery. We therefore investigated the expression of LOX and LOXL2 and evaluated the therapeutic potential of anti-LOX (GS-639556, formerly M64) and anti-LOXL2 (GS-607601, formerly AB0023) antibodies in a rabbit model of glaucoma trabeculectomy. METHODS: Ocular expression of LOX and LOXL2 was investigated by immunohistologic staining at different time points after trabeculectomy. Treatment with GS-639556 or GS-607601 was initiated in rabbits immediately after trabeculectomy by giving both intracameral and subconjunctival injections. Thereafter, the antibodies were given twice a week subconjunctivally until day 30 after surgery (day of euthanization). Treatment outcome was studied by clinical investigation of the bleb and by immunohistochemical analysis of angiogenesis, inflammation, and collagen deposition. RESULTS: LOX and LOXL2 were both upregulated in Tenon's capsule and the conjunctiva after glaucoma surgery. Repeated administration of LOX- or LOXL2-targeting monoclonal antibodies increased bleb area and bleb survival. Analyses of immunohistologic stainings showed that both antibodies significantly decreased fibrosis, whereas the anti LOXL2 antibody also significantly reduced blood vessel density and inflammation. CONCLUSIONS: Targeting LOXL2 with an inhibitory monoclonal antibody (GS-607601) reduced pathologic angiogenesis, inflammation, and fibrosis. These results suggest that LOXL2 could be an appealing target for treatment of scar formation after glaucoma surgery, and point to the potential therapeutic benefits of simtuzumab, a humanized monoclonal antibody derived from GS-607601. PMID- 23821194 TI - Intraocular pressure change over a habitual 24-hour period after changing posture or drinking water and related factors in normal tension glaucoma. AB - PURPOSE: We investigated the correlation between 24-hour IOP in the habitual (sitting during day and supine during night) position (H24h-IOP) and IOP after a postural-change test (PCT-IOP) and a water-drinking test (WDT-IOP). We also investigated ocular and systemic factors related with them in patients with normal tension glaucoma (NTG). METHODS: Japanese NTG patients underwent H24h-IOP, PCT-IOP, and WDT-IOP measurements during a 24-hour period. Correlations among H24h-IOP, PCT-IOP, and WDT-IOP, and contributing ocular/systemic factors were investigated using regression analysis. RESULTS: There were 33 patients included. Peak H24h-IOP correlated positively with peak PCT-IOP and peak WDT-IOP (estimate = 0.422 and 0.419, P <= 0.010), and peak PCT-IOP with WDT-IOP (0.44, P = 0.002). Peak H24h-IOP correlated with refraction (0.36, P = 0.048) and negatively with the mean deviation (MD, -0.066, P = 0.031). MD and baseline IOP (the mean of H24h IOP) correlated negatively with the H24h-IOP fluctuation (-0.058 and -0.58, P <= 0.050). Refraction, baseline IOP, mean blood pressure (mBP), and body mass index (BMI) correlated with peak PCT-IOP (0.23, 0.52, 0.097, and 0.32, respectively, P <= 0.038). PCT-IOP difference correlated with refraction and mBP (0.31 and 0.093, P <= 0.016) and negatively with age (-0.069, P = 0.003). Central corneal thickness, baseline IOP, age, and BMI correlated with peak WDT-IOP (0.030, 0.40, 0.088, and 0.26, P <= 0.050). Age and BMI correlated with WDT-IOP difference (0.086 and 0.20, P < 0.032). CONCLUSIONS: Positive correlation was found among the peaks of H24h-, PCT-, and WDT-IOP. A worse visual field was associated with higher peak and greater fluctuation of H24h-IOP in NTG. Several ocular/systemic factors were important in interpreting H24h-, PCT-, and WDT-IOP. PMID- 23821195 TI - Subjects with unilateral neovascular AMD have bilateral delays in rod-mediated phototransduction activation kinetics and in dark adaptation recovery. AB - PURPOSE: To assess the impact of early (dry) and late (wet/neovascular and/or atrophic) forms of AMD on panretinal function. METHODS: Light- and dark-adapted full-field ERG recordings were obtained over a 5-log-unit intensity range from both eyes of 25 patients with unilateral wet AMD. Fellow eyes showed various signs of dry AMD ranging from multiple medium-sized drusen to noncentral geographic atrophy. The leading edges of rod-isolated ERG a-waves were fitted to a quantitative model of phototransduction. ERG a- and b-wave amplitudes and implicit times were compared between wet and dry AMD eyes and from non-AMD eyes of age-matched subjects. A quantitative and objective assessment of dark adaptation was achieved by recording the recovery of the pure rod b-wave (postsynaptic depolarization of rod bipolar cells); b-wave amplitudes were measured at 120-second intervals for 20 minutes and normalized to the amplitude recorded at t = 20 minutes. RESULTS: Delays in mixed a- and b-wave implicit times were recorded in both wet and dry AMD eyes. Time required to reach 50% of fully recovered responses was delayed in all wet and dry AMD eyes independently of dry AMD severity in the fellow eye. Generalized cone dysfunction and slower activation of the rod phototransduction cascade was noted in a subgroup of patients with advanced features of dry AMD in the fellow eye. CONCLUSIONS: Patients with unilateral wet AMD display rod dysfunction in both their wet and dry AMD eyes. A subset of these patients display, in addition, bilateral cone dysfunction and delayed rod phototransduction activation, which may either reflect extensive morphologic change in advanced stages of AMD and/or represent a distinct phenotypic manifestation within the heterogeneous context of AMD as a disease. PMID- 23821197 TI - Quantitative changes in perifoveal capillary networks in patients with vascular comorbidities. AB - PURPOSE: To determine if patients with cardiovascular comorbidities but no clinically detectable retinal disease demonstrate quantitative alterations to perifoveal capillary networks. METHODS: Comparisons were made between 10 eyes from patients with vascular comorbidities and 17 control eyes. All eyes were absent of clinically evident ocular disease. Microcannulation techniques were used to label the retinal microvasculature. Retinae were flat mounted, and the peripapillary region 2 mm nasal to the fovea was imaged using confocal laser scanning microscopy. Two- and three-dimensional image reconstructions were used to perform quantitative measurements of individual capillary networks within the perifovea. Parameters measured included capillary diameter, capillary loop area, capillary loop length, capillary density, and capillary surface area. RESULTS: Capillary diameter was increased in the retinal ganglion cell and superficial inner plexiform layer capillary network in patients with vascular comorbidities. Capillary loop area and capillary loop length were reduced in all capillary networks in patients with vascular comorbidities except the deep capillary network of the inner nuclear layer. Capillary density was reduced in the nerve fiber layer capillary network in patients with vascular comorbidities. There was no difference in the relative occupied capillary surface area between control and diseased eyes. CONCLUSIONS: The results in this study suggest that the quantitative characteristics of perifoveal capillary networks are nonuniformly altered in patients with vascular comorbidities, before the onset of clinically identifiable eye diseases. These findings may be important for understanding pathophysiological mechanisms involved in retinal vascular diseases. PMID- 23821196 TI - Activated alphavbeta3 integrin regulates alphavbeta5 integrin-mediated phagocytosis in trabecular meshwork cells. AB - PURPOSE: To investigate the roles of alphavbeta3 and alphavbeta5 integrins in phagocytosis in human trabecular meshwork (HTM) cells. METHODS: Immunofluorescence microscopy and FACS analysis were used to determine levels of alphavbeta3 and alphavbeta5 integrins in TM tissue and cultures of normal and immortalized TM cells. Phagocytosis was measured using pHrodo-labeled S. aureus bioparticles followed by FACS analysis. The role of alphavbeta5 integrin in phagocytosis was evaluated by knocking down alphavbeta5 integrin expression with siRNA against the human beta5 gene. Signaling from focal adhesion kinase (FAK) was blocked using FAK inhibitor 14. The role of alphavbeta3 integrins in phagocytosis was determined by treating HTM cells with dexamethasone (DEX) or ethanol (EtOH) and by generating stable cell lines that overexpressed either wild type (WT) or constitutively active (CA) beta3 integrin subunit. RESULTS: Both TM tissue and cell lines expressed alphavbeta3 and alphavbeta5 integrins. Knockdown of alphavbeta5 integrin reduced phagocytosis by ~60% and FAK inhibition significantly reduced phagocytosis up to 84%, in a dose-dependent manner. DEX treatment increased alphavbeta3 integrin expression in HTM cells but reduced phagocytosis by ~50% compared with untreated and EtOH-treated cells. The CA beta3 integrin-expressing cell line showed increased alphavbeta3 integrin levels and decreased phagocytosis by ~50% compared with the control. CONCLUSIONS: The alphavbeta5 integrin-FAK-mediated pathway regulates phagocytosis in TM cells and this pathway is inhibited by activation of alphavbeta3 integrins. This suggests that changes in integrin expression and activity may be responsible for alterations in phagocytosis observed in steroid induced glaucoma. PMID- 23821198 TI - SIRT1 promotes RGC survival and delays loss of function following optic nerve crush. AB - PURPOSE: Activation of SIRT1 deacetylase prevents retinal ganglion cell (RGC) loss in experimental optic neuritis, an inflammatory optic neuropathy. While mechanisms of this effect are not known, evidence suggests it involves reduction of oxidative stress. We hypothesized that SIRT1 reduces RGC loss due to oxidative stress in noninflammatory optic neuropathies, and examined effects following traumatic injury. METHODS: Optic nerve crush injury was induced in wild-type C57BL/6 mice, mice overexpressing SIRT1, and mice with conditional deletion of SIRT1 in neurons. Wild-type mice were treated daily with vehicle or 250 mg/kg resveratrol, a naturally occurring polyphenol that activates SIRT1. RGC function was assessed by pupillometry and optokinetic responses (OKR), and RGC survival was measured. Superoxide levels were measured to assess oxidative stress. RESULTS: Significant decreases in pupillary light responses, OKR and RGC survival occurred 1 week after optic nerve crush, with progressive worsening at 2 to 4 weeks. Resveratrol treatment and SIRT1 overexpression delayed RGC loss and loss of pupillary light responses following optic nerve crush, although no change in RGC loss occurred in neuronal SIRT1-deficient mice. A significant accumulation of superoxide was detected in wild-type optic nerves following crush, and was reduced in mice overexpressing SIRT1 or treated with resveratrol. CONCLUSIONS: SIRT1 delays RGC loss following traumatic injury. Effects are associated with reduced oxidative stress. Results suggest SIRT1-activating drugs may have a specific role in preventing traumatic optic nerve damage, and suggest a broader role for this strategy in treating a variety of optic neuropathies that may include a component of oxidative stress. PMID- 23821200 TI - Contributing factors to corneal deformation in air puff measurements. AB - PURPOSE: Air puff systems have been presented recently to measure corneal biomechanical properties in vivo. In our study we tested the influence of several factors on corneal deformation to an air puff: IOP, corneal rigidity, dehydration, presence of sclera, and in vivo versus in vitro conditions. METHODS: We used 14 freshly enucleated porcine eyes and five human donor eyes for in vitro experiments; nine human eyes were used for in vivo experiments. Corneal deformation was studied as a function of: IOP ranging from 15 to 45 mm Hg (in vitro); dehydration after riboflavin-dextran instillation (in vitro); corneal rigidity after standard ultraviolet (UV) corneal crosslinking (CXL, in vitro); boundary conditions, that is effect of the presence of the sclera (comparing corneal buttons and whole globes in vitro in pigs); and effect of ocular muscles (comparing human whole globes in vitro and in vivo). The temporal corneal deformation was characterized by the apex indentation across time, the maximal indentation depth, and the temporal symmetry (comparing inward versus outward deformation). The spatial corneal profile was characterized by the peak distance at maximal deformation. RESULTS: Temporal and spatial deformation profiles were very sensitive to the IOP (P < 0.001). The sclera slightly affected the temporal symmetry, while the ocular muscles drastically changed the amount of corneal recovery. CXL produced a significant (P = 0.001) reduction of the cornea indentation (by a factor of 1.41), and a change in the temporal symmetry of the corneal deformation profile (by a factor of 1.65), indicating a change in the viscoelastic properties with treatment. CONCLUSIONS: Corneal deformation following an air puff allows the measurement of dynamic properties, which are essential for the characterization of corneal biomechanics. PMID- 23821199 TI - Development of a model of elevated intraocular pressure in rats by gene transfer of bone morphogenetic protein 2. AB - PURPOSE: To determine whether inducing calcification in the trabecular meshwork results in elevated IOP in living rats. To use this property to create an elevated IOP animal model by gene transfer of bone morphogenetic protein 2 (BMP2). METHODS: Calcification was assessed by alizarin red staining in primary human trabecular meshwork (HTM) cells and alkaline phosphatase (ALP) activity in the angle tissue. Brown Norway (BN) and Wistar rats were intracamerally injected with Ad5BMP2 (OS) and control Ad5.CMV-Null (OD). IOPs were taken twice a week and expressed as mean integral pressures. Morphology was assessed on fixed, paraffin embedded anterior segments. Retinal ganglion cells (RGCs) were quantified on retrograde and Brn-3a-labeled flat mounts using MetaMorph software. RESULTS: BMP2 treated cells displayed marked increase in calcification. Trabecular meshwork tissue showed moderate ALP activity at 13 days postinjection. Fifty-four of 55 BN and 15 of 19 Wistar rats displayed significantly elevated IOP. In a representative 29-day experiment, the integral IOP difference between treated and control eyes was 367.7 +/- 83 mm Hg-days (P = 0.007). Morphological evaluation revealed a well-organized trabecular meshwork tissue, exhibiting denser matrix in the treated eyes. The Ad5BMP2-treated eye showed 34.4% +/- 4.8% (P = 0.00002) loss of peripheral RGC over controls. CONCLUSIONS: Gene transfer of the calcification inducer BMP2 gene to the trabecular meshwork induces elevated IOP in living rats without altering the basic structure of the tissue. This strategy generates an elevated IOP model in rats that would be useful for evaluation of glaucoma drugs targeting the outflow pathway. PMID- 23821201 TI - Prospective audit of exudative age-related macular degeneration: 12-month outcomes in treatment-naive eyes. AB - PURPOSE: We report the 12-month outcomes of 1140 treatment-naive eyes with exudative age-related macular degeneration (wet AMD) who were treated for 12 months with intravitreal anti-VEGF drugs in routine clinical practice. METHODS: Index visit characteristics, such as lesion type and size, visual acuity (VA, in Logarithm of the Minimal Angle of Resolution [logMAR] letters), as well as treatments, outcomes (VA, lesion activity status) and ocular adverse events were recorded in a prospectively designed electronic database. Index visit characteristics associated with the 12-month VA outcome were identified using mixed effects linear regression. RESULTS: Mean change in VA in the cohort after 12 months was +4.7 logMAR letters (95% confidence interval [CI], 3.4-6.1) with a mean of 7.0 injections. No significant difference was found in change in VA, or number of injections by type or size of the lesion. Median time to inactivation of lesions was 194 days. VA at the index visit was the strongest predictor for the 12-month outcomes. Infectious endophthalmitis occurred in 2 cases, and retinal detachment occurred in 1 case from a total of 9162 injections. CONCLUSIONS: These findings indicate that VEGF inhibitors can achieve reasonably good outcomes for wet AMD when used in routine clinical practice. PMID- 23821202 TI - MicroRNA profiling in ocular adnexal lymphoma: a role for MYC and NFKB1 mediated dysregulation of microRNA expression in aggressive disease. AB - PURPOSE: Ocular adnexal lymphoma (i.e., lymphoma with involvement of the orbit, eyelids, conjunctiva, lacrimal gland, and lacrimal sac), although rare, is common among malignant tumors involving the ocular adnexal region. The main subtypes are low-grade extranodal marginal zone lymphoma (EMZL) and aggressive diffuse large B cell lymphoma (DLBCL). In rare cases, low-grade EMZL are reported to transform to DLBCL. It is unclear, however, which genetic events distinguish low-grade disease from aggressive, potentially fatal disease. METHODS: Using LNA-based arrays from Exiqon, we performed global microRNA (miRNA) expression profiling of 18 EMZLs and 25 DLBCLs involving ocular adnexal sites to investigate changes in the miRNA expression in low- versus high-grade disease. Findings were confirmed by real time quantitative PCR (RTq-PCR). RESULTS: Our analysis revealed 43 miRNAs with altered expression profiles in DLBCL compared to EMZL. Seven of the miRNAs down regulated in DLBCL relative to EMZL showed enrichment for a direct transcriptional repression by the oncoprotein MYC. We also report a possible loss of-regulation of NFKB1 and its downstream miRNAs. In addition, our analysis identified a group of DLBCLs whose expression profiles resembled that of EMZL. Although transformation of EMZL to DLBCL in the ocular adnexal region is rare, we hypothesize that the intermediate group potentially may derive from transformation of EMZL that was not recognized by histology. CONCLUSIONS: We conclude that fundamental differences in miRNA expression exist between ocular adnexal EMZL and DLBCL, mainly due to differences in MYC and NF-KB regulatory pathways. PMID- 23821203 TI - Inner retinal oxygen delivery and metabolism under normoxia and hypoxia in rat. AB - PURPOSE: Retinal hypoxia is a common pathological condition usually caused by ischemia that may result in alterations in oxidative energy metabolism. We report measurements of oxygen delivery by the retinal circulation (DO2_IR) and inner retinal oxygen metabolism (MO2_IR) under systemic normoxia and hypoxia in rat. METHODS: Rats were ventilated with fractions of inspired oxygen (FiO2) to induce either normoxia (n = 10), moderate hypoxia (n = 14), or severe hypoxia (n = 10). Oxygen tension was measured in retinal vessels using phosphorescence lifetime imaging and converted to arterial (O2A) and venous (O2V) oxygen contents. Total retinal blood flow (F) was assessed by red-free and fluorescent microsphere imaging. DO2_IR and MO2_IR were calculated as the products of F and O2A, and F and the arteriovenous oxygen content difference (O2A-V), respectively. RESULTS: Measurements of O2A, O2V, and O2A-V were significantly reduced with decreased FiO2 (P < 0.001). In response to reduced oxygen availability, F increased under moderate hypoxia (P < 0.001) but did not increase further under severe hypoxia (P = 0.5). DO2_IR was similar under normoxia and moderate hypoxia (P = 0.7), but significantly lower under severe hypoxia (P < 0.001). Likewise, MO2_IR under normoxia and moderate hypoxia was similar (P = 0.1), but significantly reduced under severe hypoxia (P <= 0.02). CONCLUSIONS: DO2_IR and MO2_IR were maintained during moderate hypoxia, but reduced under severe hypoxia, indicating blood flow compensation became insufficient for the reduced oxygen availability. Future studies may aid our understanding of retinal metabolic function in ischemic conditions. PMID- 23821204 TI - Associations with retinal nerve fiber layer measures in the EPIC-Norfolk Eye Study. AB - PURPOSE: To describe GDxVCC retinal nerve fiber layer (RNFL) measures and associations in a predominantly white British population. METHODS: The EPIC Norfolk Eye Study is nested within a large multicenter cohort study, the European Prospective Investigation of Cancer. RNFL measurements were taken using the GDxVCC. Generalized estimating equation models were used to assess associations of RNFL measures with age, sex, body mass index (BMI), height, blood pressure, social class, education level, alcohol intake, smoking status, axial length, intraocular pressure, and lens status. Models were linearly adjusted for typical scan score to handle scans with atypical retardation. RESULTS: There were complete data from 11,030 eyes of 6309 participants with mean age 68 years (48-90 years). Older age (-1.53 MUm/decade [95% confidence interval {CI} -1.73, -1.33], P < 0.001), male sex (-0.44 MUm [95% CI -0.04, -0.84], P = 0.031), shorter axial length (-0.15 MUm/mm [95% CI -0.02, -0.28], P = 0.024), and pseudophakia (-0.49 MUm [95% CI -0.94, -0.04], P = 0.033) were associated with thinner RNFL after adjustment for possible confounders. Higher BMI was associated with a thinner RNFL in men only (-0.30 MUm/5 kg/m(2) [95% CI -0.58, -0.02], P = 0.039). CONCLUSIONS: This analysis of associations with RNFL thickness in a largely healthy population may provide insight into the determinants of glaucoma, suggesting higher risk in those who are older, in men, and in men with a higher BMI. PMID- 23821205 TI - Survey on amacrine cells coupling to retrograde-identified ganglion cells in the mouse retina. AB - PURPOSE: Retinal amacrine cells (ACs) may make inhibitory chemical synapses and potentially excitatory gap junctions on ganglion cells (GCs). The total number and subtypes of ACs coupled to the entire GC population were investigated in wild type and three lines of transgenic mice. METHODS: GCs and GC-coupled ACs were identified by the previously established LY-NB (Lucifer yellow-Neurobiotin) retrograde double-labeling technique, in conjunction with specific antibodies and confocal microscopy. RESULTS: GC-coupled ACs (NB-positive and LY-negative) comprised nearly 11% of displaced ACs and 4% of conventional ACs in wild-type mice, and were 9% and 4% of displaced ACs in Cx45(-/-) and Cx36/45(-/-) mice, respectively. Their somas were small in Cx36/45(-/-) mice, but variable in other strains. They were mostly gamma-aminobutyric acid (GABA)-immunoreactive (IR) and located in the GC layer. They comprised only a small portion in the AC subpopulations, including GABA-IR, glycine-IR, calretinin-IR, 5-HT-accumulating, and ON-type choline acetyltransferase (ChAT) ACs in wild-type and ChAT transgenic mice (ChAT- tdTomato). In the distal 80% of the inner plexiform layer (IPL), dense GC dendrites coexisted with rich glycine-IR and GABA-IR. In the inner 20% of the IPL, sparse GC dendrites presented with a major GABA band and sparse glycine-IR. CONCLUSIONS: Various subtypes of ACs may couple to GCs. ACs of the same immunoreactivity may either couple or not couple to GCs. Cx36 and Cx45 dominate GC-AC coupling except for small ACs. The overall potency of GC-AC coupling is moderate, especially in the proximal 20% of the IPL, where inhibitory chemical signals are dominated by GABA ACs. PMID- 23821206 TI - Carcinoma ex pleomorphic adenoma, with particular emphasis on early lesions. AB - Carcinoma ex pleomorphic adenoma (CXPA) is a broad category of carcinomas of the salivary glands which includes at least 2 clinically relevant categories; one is referred here as early CXPA (ECXPA), the other as widely invasive CXPA. The former includes several histological patterns ranging from non-invasive/in situ/intraductal/intratubular, early invasive/extratubular/intracapsular and extracapsular (up to 6 mm). The latter includes any CXPA with invasion of >6 mm. The clinical behaviour of ECXPA is not aggressive and tends to overlap that of a pleomorphic adenoma (PA) which makes the histological report of carcinoma contradictory. These early malignant changes in PA are known since the 1970s but it has been the use of immunohistochemical and molecular genetic analysis for HER 2 and TP53 gene in the last decade that has clarified the genuine malignant nature of the cells. HER-2 and TP53 gene and protein are involved in the early stages of malignant transformation of PA. Moreover the immunohistochemical over expression HER-2, p53 protein and Mib-1 proliferation marker may be useful markers to identify malignant areas in PA. PMID- 23821207 TI - Mammary analogue secretory carcinoma of salivary gland origin: an update and expanded morphologic and immunohistochemical spectrum of recently described entity. AB - Mammary analogue secretory carcinoma of salivary gland origin (MASC) is a recently described tumor with ETV6 translocation. Akin to secretory breast cancer, MASC expresses S-100 protein, mammaglobin, vimentin, and harbors a t(12;15) (p13;q25) translocation which leads to ETV6-NTRK3 fusion product. Histologically, MASC displays a lobulated growth pattern and is often composed of microcystic, tubular, and solid structures with abundant eosinophilic homogeneous or bubbly secretions. Colloid-like secretory material stains positive for periodic acid-Schiff (PAS) with and without diastase and for Alcian blue. The cells of MASC are devoid of PAS-positive secretory zymogen granules. These features help to exclude the most important differential diagnostic considerations, namely acinic cell carcinoma, low-grade cribriform cystadenocarcinoma, cystadenocarcinoma (not otherwise specified), and low-grade mucoepidermoid carcinoma. To date the presence of the ETV6-NTRK3 fusion gene has not been demonstrated in any other salivary gland tumor than MASC. It is likely that MASC is more common than currently recognized and with further studies, the clinical need for molecular studies of the ETV6-NTRK3 fusion may diminish. However, molecular testing is recommended at this time to arrive at the diagnosis of MASC. PMID- 23821208 TI - Salivary duct carcinoma: new developments--morphological variants including pure in situ high grade lesions; proposed molecular classification. AB - Salivary duct carcinoma (SDC) is an aggressive primary salivary malignancy which microscopically resembles high-grade ductal carcinoma of the breast, with both in situ and invasive patterns. It is typically found in older men, most often in the parotid. It can arise de novo or as the malignant component of carcinoma ex pleomorphic adenoma. SDC is generally a hematoxylin and eosin stain-based diagnosis, with special stains and immunohistochemistry acting mainly in a confirmatory role. Other than epithelial markers, SDC expresses androgen receptors in most cases, with true HER2 positivity seen in about 15 %. Based on these data and analogous to similar schemes in the breast, it is suggested that SDCs can be classified into three main groups: luminal androgen receptor positive, HER2+ and basal phenotype. This may form the basis for prognostic information and new therapeutic possibilities. In addition to the usual type of SDC, a few less common morphological variants have been reported: papillary, micropapillary, mucin-rich, sarcomatoid and oncocytic, as well as pure in situ cases. PMID- 23821209 TI - Cribriform adenocarcinoma of the tongue and minor salivary glands: a review. AB - Cribriform adenocarcinoma of the tongue and minor salivary glands (CATMSG) is a tumor occurring mostly, but not exclusively, in the base of the tongue. Other locations are minor salivary glands of the oral cavity. Histopathologically, CATMSG resembles papillary carcinoma of the thyroid gland. It usually reveals a solid growth devoid of colloid, and eosinophilic material present in follicular areas is rather pale in contrast to metastatic foci seen in papillary thyroid carcinoma that shows typical deeply eosinophilic colloid with "moth-eaten peripheries" and cystic configuration. In addition, giant multinucleated cells are not observed in CATMSG and psammoma bodies are found only exceptionally. Unlike papillary thyroid carcinoma, CATMSG is composed of hybrid secretory myoepithelial cells. Most importantly, CATMSG is consistently negative with both thyroglobulin and TTF-1. CATMSG is a distinct tumor entity that also differs from polymorphous low-grade adenocarcinoma by location, cytology, histological architecture, and behavior, with frequent metastases at the time of presentation. Paradoxically, early metastatic disease seen in most cases of CATMSG is associated with an indolent behavior. It makes CATMSG a unique neoplasm among all low-grade salivary gland tumors. PMID- 23821210 TI - "Dedifferentiation" and high-grade transformation in salivary gland carcinomas. AB - "Dedifferentiation" and/or high-grade transformation (HGT) has been described in a variety of salivary gland carcinomas, including acinic cell carcinoma, adenoid cystic carcinoma, epithelial-myoepithelial carcinoma, polymorphous low-grade adenocarcinoma, myoepithelial carcinoma, low-grade mucoepidermoid carcinoma and hyalinizing clear cell carcinoma, although the phenomenon is a rare event. Recent authors tend to preferably use the term HGT instead of "dedifferentiation" in these cases. HGT-tumors are composed of conventional carcinomas juxtaposed with areas of HG morphology, usually either poorly differentiated adenocarcinoma or "undifferentiated" carcinoma, in which the original line of differentiation is no longer evident. The HG component is generally composed of solid nests, sometimes occurring in cribriform pattern of anaplastic cells with large vesicular pleomorphic nuclei, prominent nucleoli and abundant cytoplasm. Frequent mitoses and extensive necrosis is evident. The Ki-67 labeling index is consistently higher in the HG component. p53 abnormalities have been demonstrated in the transformed component in a few examples, but the frequency varies by the histologic type. HER-2/neu overexpression and/or gene amplification is considerably exceptional. The molecular-genetic mechanisms responsible for the pathway of HGT in salivary gland carcinomas largely still remain to be elucidated. Salivary gland carcinomas with HGT have been shown to be more aggressive than conventional carcinomas with a poorer prognosis, accompanied by higher local recurrence rate and propensity for cervical lymph node metastasis, suggesting the need for wider resection and neck dissection. PMID- 23821211 TI - Fat-containing salivary gland tumors: a review. AB - Fat-containing tumors of the salivary glands are uncommon. Their wide histological spectrum varies from pure lipomatous neoplasms similar to their cutaneous and soft tissue counterparts to mixed lipoepithelial lesions specific to the salivary glands. With few exceptions, these uncommon lesions affect mainly the elderly, with a mean age at presentation of >= 50 years and show a predilection for males. A few cases occur in childhood; some of them represent congenital lesions. In decreasing order of frequency, ordinary (soft-tissue type) lipoma, oncocytic lipoadenoma, non-oncocytic sialolipoma, and pleomorphic adenoma/myoepithelioma with extensive lipometaplasia are the main variants of fat containing tumors encountered in the salivary glands. While pleomorphic adenoma/myoepithelioma with lipometaplasia behave in the same way as their non fat-containing counterparts, other lipomatous salivary gland tumors listed above are cured with simple excision and do not carry a risk of recurrence. Other lipoma variants (spindle cell lipoma, osteolipoma, fibrolipoma, angiolipoma, pleomorphic lipoma, lipoblastoma and hibernoma) are exceptionally rare in the salivary gland. Atypical lipomatous tumors/liposarcoma have been only rarely reported in the salivary gland and they behave in a similar fashion to their soft tissue counterparts. Diffuse lipomatosis and lobular fatty atrophy are the two tumor-like lesions that might closely mimic sialolipoma, particularly in limited biopsy material without knowledge of the gross findings. This review summarizes the clinicopathological features of the main types of salivary fat-containing lesions and discusses their differential diagnoses. PMID- 23821212 TI - Low-grade salivary duct carcinoma or low-grade intraductal carcinoma? Review of the literature. AB - Low-grade salivary duct carcinoma (LG-SDC) is a rare neoplasm characterized by predominant intraductal growth, luminal ductal phenotype, bland microscopic features, and favorable clinical behavior with an appearance reminiscent of florid to atypical ductal hyperplasia to low grade intraductal breast carcinoma. LG-SDC is composed of multiple cysts, cribriform architecture with "Roman Bridges", "pseudocribriform" proliferations with floppy fenestrations or irregular slits, micropapillae with epithelial tufts, fibrovascular cores, and solid areas. Most of the tumor cells are small to medium sized with pale eosinophilic cytoplasm, and round to oval nuclei, which may contain finely dispersed or dark condensed chromatin. Foci of intermediate to high grade atypia, and invasive carcinoma or micro-invasion have been reported in up to 23 % of cases. The neoplastic cells have a ductal phenotype with coexpression of keratins and S100 protein and are surrounded by a layer of myoepithelial cells in non invasive cases. The main differential diagnosis of LG-SDC includes cystadenoma, cystadenocarcinoma, sclerosing polycystic adenosis, salivary duct carcinoma in situ/high-grade intraductal carcinoma, and papillary-cystic variant of acinic cell carcinoma. There is no published data supporting the continuous classification of LG-SDC as a variant of cystadenocarcinoma. Given that most LG SDC are non-invasive neoplasms; the terms "cribriform cystadenocarcinoma" and LG SDC should be replaced by "low-grade intraductal carcinoma" (LG-IDC) of salivary gland or "low-grade intraductal carcinoma with areas of invasive carcinoma" in those cases with evidence of invasive carcinoma. PMID- 23821213 TI - Oncocytic and apocrine epithelial myoepithelial carcinoma: novel variants of a challenging tumor. AB - Epithelial myoepithelial carcinoma (EMCa) is a rare but well characterized biphasic salivary gland malignancy with several variant morphologies. Oncocytic and apocrine EMCa are uncommon variants that constitute up to 8 % of all EMCa. Both variants invoke an eosinophilic or oncocytic differential diagnosis and challenge the traditional requirement of clear myoepithelial cells for EMCa. Oncocytic EMCa occurs in patients a decade older than conventional EMCa. This variant is often papillary with calcification and associated with sebaceous components and occurs in older individuals. Apocrine EMCa is named for its apocrine ductal component, which may be mistaken for salivary duct carcinoma. In this variant, the epithelial component often shows overgrowth in a cribriform or even solid pattern and is immunophenotypically defined by androgen receptor and gross cystic disease fluid protein 15 positivity. The most important aspect of differentiating both oncocytic and apocrine EMCa from other salivary oncocytic tumors is recognition of the biphasic nature of these variants and confirmation that the abluminal outer layer consists of plump, 'activated' myoepithelial cells, regardless of tinctorial characteristics. Both oncocytic and apocrine EMCa behave very indolently in the limited literature to date. PMID- 23821215 TI - An update on salivary gland pathology. PMID- 23821214 TI - Fusion oncogenes in salivary gland tumors: molecular and clinical consequences. AB - Salivary gland tumors constitute a heterogeneous group of uncommon diseases that pose significant diagnostic and therapeutic challenges. However, the recent discovery of a translocation-generated gene fusion network in salivary gland carcinomas as well in benign salivary gland tumors opens up new avenues for improved diagnosis, prognostication, and development of specific targeted therapies. The gene fusions encode novel fusion oncoproteins or ectopically expressed normal or truncated oncoproteins. The major targets of the translocations are transcriptional coactivators, tyrosine kinase receptors, and transcription factors involved in growth factor signaling and cell cycle regulation. Notably, several of these targets or pathways activated by these targets are druggable. Examples of clinically significant gene fusions in salivary gland cancers are the MYB-NFIB fusion specific for adenoid cystic carcinoma, the CRTC1-MAML2 fusion typical of low/intermediate-grade mucoepidermoid carcinoma, and the recently identified ETV6-NTRK3 fusion in mammary analogue secretory carcinoma. Similarly, gene fusions involving the PLAG1 and HMGA2 oncogenes are specific for benign pleomorphic adenomas. Continued studies of the molecular consequences of these fusion oncoproteins and their down stream targets will ultimately lead to the identification of novel driver genes in salivary gland neoplasms and will also form the basis for the development of new therapeutic strategies for salivary gland cancers and, perhaps, other neoplasms. PMID- 23821216 TI - Mucinous myoepithelioma, a recently described new myoepithelioma variant. AB - Myoepithelial neoplasms are tumors composed almost exclusively of cells with myoepithelial differentiation. They frequently contain spindle, plasmacytoid or epithelioid shaped cells and may have oncocytic or clear cytoplasmic features. They are uncommon, accounting for 1.5 % of all salivary gland tumors and for 2.2 5.7 % of major and minor salivary gland tumors, respectively. Recently this author, together with several colleagues, have described three unusual myoepithelial tumors, two benign and one malignant that contained abundant intracellular mucin material, which they termed the mucinous variant of myoepithelioma. This represents a unique, previously undescribed subtype that does not fit in the current classification system. A literature review revealed several similar cases reported as "signet ring-cell" adenocarcinomas of salivary gland, which stained for myoepithelial markers, in addition to containing intracellular mucin material, that are more accurately classified as mucinous myoepithelioma. To date, there are 17 reported mucinous myoepitheliomas; four were classified as benign and 13 as malignant. Thirteen arose in minor salivary glands and four in the parotid gland. One patient presented with a lymph node metastasis. With minimal follow-up currently available, this appears to be a benign to low-grade malignancy. PMID- 23821217 TI - Sclerosing polycystic adenosis of salivary glands: a review with some emphasis on intraductal epithelial proliferations. AB - Sclerosing polycystic adenosis (SPA) is a rare condition of salivary glands. The most common site is the parotid gland (80 % of cases). SPA shows no gender predilection and occurs over a wide age spectrum (9-84 years). SPA is mostly unifocal, but may rarely be multifocal. Histologically, SPA are sharply circumscribed mostly unencapsulated lesions composed of acinar and ductal components with variable cytomorphological characteristics, including foamy, vacuolated, apocrine, mucous, clear/ballooned, squamous, columnar and oncocyte like cells. Characteristic for SPA is the presence of large acinar cells with abundant eosinophilic cytoplasmic granules. The stroma is densely collagenized, frequently harbouring a variably intense chronic inflammatory infiltrate and may contain fat. Rarely the stroma is myxoid. Some degree of intraductal epithelial proliferations have been reported in at least 50 % of cases. The proportion of cases with epithelial proliferations that fulfill criteria for high-grade ductal carcinoma in-situ is <10 %. Immunohistochemically, both ductal and acinar cells are positive for broad spectrum cytokeratins. There is variable immunoreactivity for epithelial membrane antigen and S-100 protein. CEA, p53 and HER2 is reportedly negative. Gross cystic disease fluid protein-15 is strongly expressed in the acinar component. There is consistent but variable expression of estrogen and progesterone receptors. The proliferative index (Ki-67) is low (1-2 %) in the benign (acinar and ductal) components. Using HUMARA methodology (non-random inactivation of X-chromosomes), six cases with atypical epithelial proliferations have been shown to be clonal processes. Recurrences have been reported in up to 19 % of cases. PMID- 23821218 TI - Hyalinizing clear cell carcinoma of salivary gland: a review and update. AB - Hyalinizing clear cell carcinoma (HCCC) is a rare minor salivary gland tumor made up of clear cells and forming cords and nests in a hyalinized stroma. The overall outcome is excellent with only occasional metastatic spread. HCCC has a wide differential diagnosis including other clear cell-containing tumors, such as epithelial-myoepithelial carcinoma, mucoepidermoid carcinoma, and myoepithelial carcinoma. HCCC is currently classified as a "clear cell adenocarcinoma" by the AFIP and as "clear cell carcinoma, not otherwise specified (NOS)" by the World Health Organization (WHO). It is considered by the WHO to be a diagnosis of exclusion. Since the original description in 1994, there have been few new insights into HCCC, until recently. Dardick re-examined the features of HCCC, including the original electron microscopic images, and concluded that HCCC is a squamous lesion, at odds with the above nomenclature. Bilodeau et al. recently showed that this tumor essentially cannot be separated reliably from clear cell odontogenic carcinoma (CCOC) except by location. Antonescu et al. recently identified a consistent EWSR1-ATF1 fusion in HCCC. Bilodeau et al. subsequently argued a link between these two entities, with evidence of similar EWSR1 and ATF1 rearrangements in CCOC. This molecular signature is not present in other clear cell mimics. Cases with recurrence, metastasis, high-grade features and other alternative morphologies or presentations have also been seen and proven by molecular analysis to be HCCC. In the molecular era, HCCC can no longer be seen as a diagnosis of exclusion. It is neither an adenocarcinoma nor a "not otherwise specified" tumor, as the AFIP and WHO currently classify it. This review provides an in-depth look at the current state of knowledge of HCCC from morphology to molecular features. New developments and personal insights are provided that help identify and properly classify this lesion. PMID- 23821219 TI - Salivary gland lymphoproliferative disorders: a Canadian tertiary center experience. AB - Salivary gland lymphoproliferative disorders (SGLD) are very rare tumors and clinicopathological data is sparse. In a Canadian series of 30 cases, extracted from the surgical pathology files of The Ottawa Hospital between 1990 and 2010, a clinical, histopathological, and immunophenotypic analysis was conducted. Tumors were staged using the Ann Arbor staging and classified using the World Health Organization 2008 classification. There were 15 salivary gland (SG) primary lymphomas with localized disease, predominantly mucosa associated lymphoid tissue type marginal zone lymphoma (MALT-L), but with a significant incidence of low grade follicular lymphoma (FL) and diffuse large B cell phenotype as well. There were 7 systemic SG lymphomas and 5 patients were diagnosed with lymphoproliferative disorders originating from intra-parotid lymph nodes. Finally, the remaining 3 cases represented reactive sialadenitis. A literature review was conducted and our primary lymphoma group was compared to those from other countries. SGLDs are predominantly B cell lymphomas that develop in older adults. Primary tumors, which have MALT-L and low grade FL characteristics, have a favorable survival, however MALT-L have a high rate of relapse. A minority of SG lesions are excised secondary to lymphomas that definitely arose from intra parotid lymph nodes. PMID- 23821220 TI - The impact of sound in modern multiline video slot machine play. AB - Slot machine wins and losses have distinctive, measurable, physiological effects on players. The contributing factors to these effects remain under-explored. We believe that sound is one of these key contributing factors. Sound plays an important role in reinforcement, and thus on arousal level and stress response of players. It is the use of sound for positive reinforcement in particular that we believe influences the player. In the current study, we investigate the role that sound plays in psychophysical responses to slot machine play. A total of 96 gamblers played a slot machine simulator with and without sound being paired with reinforcement. Skin conductance responses and heart rate, as well as subjective judgments about the gambling experience were examined. The results showed that the sound influenced the arousal of participants both psychophysically and psychologically. The sound also influenced players' preferences, with the majority of players preferring to play slot machines that were accompanied by winning sounds. The sounds also caused players to significantly overestimate the number of times they won while playing the slot machine. PMID- 23821221 TI - Evaluation of biomechanical properties of anterior atlantoaxial transarticular locking plate system using three-dimensional finite element analysis. AB - PURPOSE: To evaluate a new anterior atlantoaxial transarticular locking plate system using finite element analysis. METHODS: Thin-section spiral computed tomography was performed from occiput to C2 region. A finite element model of an unstable atlantoaxial joint, treated with an anterior atlantoaxial transarticular locking plate system, was compared with the simple anterior atlantoaxial transarticular screw system. Flexion, extension, lateral bending, and axial rotation were imposed on the model. Displacement of the atlantoaxial transarticular screw and stress at the screw-bone interface were observed for the two internal fixation systems. RESULTS: Screw displacement was less using the anterior atlantoaxial transarticular locking plate system compared to simple anterior atlantoaxial transarticular screw fixation under various conditions, and stability increased especially during flexion and extension. CONCLUSIONS: The anterior atlantoaxial transarticular locking plate system not only provided stronger fixation, but also decreased screw-bearing stress and screw-bone interface stress compared to simple anterior atlantoaxial transarticular screw fixation. PMID- 23821222 TI - The importance of solid-phase distribution on the oral bioaccessibility of Ni and Cr in soils overlying Palaeogene basalt lavas, Northern Ireland. AB - Potentially toxic elements (PTEs) including nickel and chromium are often present in soils overlying basalt at concentrations above regulatory guidance values due to the presence of these elements in underlying geology. Oral bioaccessibility testing allows the risk posed by PTEs to human health to be assessed; however, bioaccessibility is controlled by factors including mineralogy, particle size, solid-phase speciation and encapsulation. X-ray diffraction was used to characterise the mineralogy of 12 soil samples overlying Palaeogene basalt lavas in Northern Ireland, and non-specific sequential extraction coupled with chemometric analysis was used to determine the distribution of elements amongst soil components in 3 of these samples. The data obtained were related to total concentration and oral bioaccessible concentration to determine whether a relationship exists between the overall concentrations of PTEs, their bioaccessibility and the soils mineralogy and geochemistry. Gastric phase bioaccessible fraction (BAF %) ranged from 0.4 to 5.4 % for chromium in soils overlying basalt and bioaccessible and total chromium concentrations are positively correlated. In contrast, the range of gastric phase BAF for nickel was greater (1.4-43.8 %), while no significant correlation was observed between bioaccessible and total nickel concentrations. However, nickel BAF was inversely correlated with total concentration. Solid-phase fractionation information showed that bioaccessible nickel was associated with calcium carbonate, aluminium oxide, iron oxide and clay-related components, while bioaccessible chromium was associated with clay-related components. This suggests that weathering significantly affects nickel bioaccessibility, but does not have the same effect on the bioaccessibility of chromium. PMID- 23821223 TI - Research review trends of food analysis in Latvia: major and trace element content. AB - The current paper involves overview of several studies concerning quantitative major and trace element analysis of different food samples, such as products of plant origin, e.g., locally grown vegetables (carrots, onions, potatoes) and products of animal origin derived with or without processing (cottage cheese, eggs, honey). Food samples were collected over the territory of Latvia in the time period 2009-2012. Sample pre-treatment was chosen according to the product specifics but mostly wet mineralization with concentrated nitric acid was applied. Analysis of major elements (e.g., Ca, Fe, K, Mg, Na) and trace elements (e.g., As, Cd, Co, Cr, Cu, Ni, Pb, Se, Zn) was performed by appropriate quantitative analytical technique: atomic absorption spectrometry, inductively coupled plasma mass spectrometry or total reflection X-ray fluorescence spectrometry. Not only the influence of environmental factors (e.g., geographical or seasonal impact) was detected in element dissemination in food, also botanical origin (if applicable) and applied agricultural praxis, product processing and storage specifics were found to be important. Possible food contamination by potentially toxic elements can be associated mostly with the consequences of anthropogenic activities. The studies revealed the significance of food research in the context of environmental science. PMID- 23821224 TI - Research priority setting: a summary of the 2012 NINDS Stroke Planning Meeting Report. PMID- 23821225 TI - Regulatory T cells in ischemic stroke: helpful or hazardous? PMID- 23821226 TI - Satisfaction with palliative care after stroke: a prospective cohort study. AB - BACKGROUND AND PURPOSE: The determinants of satisfaction for families of acute stroke patients receiving palliative care have not been extensively studied. We surveyed families to determine how they perceived palliative care after stroke. METHODS: Families of patients palliated after ischemic stroke, intracerebral, or subarachnoid hemorrhage were approached. Four weeks after the patient's death, families were administered the After-Death Bereaved Family Member Interview to determine satisfaction with the care provided. RESULTS: Fifteen families participated. Families were most satisfied with participation in decision making and least satisfied with attention to emotional needs. In stroke-specific domains, families had less satisfaction with artificial feeding, hydration, and communication. Overall satisfaction was high (9.04 out of 10). CONCLUSIONS: Families of patients receiving palliative care at our institution showed generally high satisfaction with palliation after stroke; specific domains were identified for improvement. Further study in larger populations is required. PMID- 23821227 TI - Con: Regulatory T cells are protective in ischemic stroke. PMID- 23821228 TI - Monocyte chemoattractant protein-1-deficiency results in altered blood-brain barrier breakdown after experimental stroke. AB - BACKGROUND AND PURPOSE: Stroke-induced blood-brain barrier (BBB)-disruption can contribute to further progression of cerebral damage. There is rising evidence for a strong involvement of chemokines in postischemic BBB-breakdown. In a previous study, we showed that monocyte chemoattractant protein-1 (MCP-1) deficiency results in a markedly reduced inflammatory reaction with decreased levels of interleukin-6, interleukin-1beta, and granulocyte colony-stimulating factor after experimental stroke. With MCP-1 as one of the key players in stroke induced inflammation, in this study, we investigated the influence of MCP-1 on poststroke BBB-disruption as well as transcription/translation of BBB-related genes/proteins after cerebral ischemia. METHODS: Sixteen wild-type and 16 MCP-1( /-) mice were subjected to 30 minutes of middle cerebral artery occlusion. By injecting high molecular-tracer, we compared the degree of BBB-disruption after middle cerebral artery occlusion. Real-time polymerase chain reactions and Western blot technique were used to compare tight-junction gene expression, protein secretion, and BBB-leakage. RESULTS: Here, we report that MCP-1 deficiency results in a reduced BBB-leakage and a diminished expression of BBB related genes occludin, zonula occludens-1, and zonula occludens-2. Real-time polymerase chain reactions and Western blot analysis revealed elevated claudin-5 levels in MCP-1(-/-) animals. MCP-1-deficiency resulted in reduced infarct sizes and an increased vascular accumulation of fluorescein-isothiocyanate-albumin. CONCLUSIONS: The results of the study provide further insights into the molecular mechanisms of BBB-opening and may help to better understand the mechanisms of infarct development after cerebral ischemia. PMID- 23821229 TI - Comparison of the sex-specific associations between systolic blood pressure and the risk of cardiovascular disease: a systematic review and meta-analysis of 124 cohort studies, including 1.2 million individuals. AB - BACKGROUND AND PURPOSE: Conflicting results have been reported on whether the association between increments in systolic blood pressure (SBP) and cardiovascular disease differs between men and women. We performed a systematic review with meta-analysis to compare reliably sex-specific associations between SBP and cardiovascular risk. METHODS: PubMed MEDLINE was systematically searched for prospective population-based cohort studies published between January 1, 1966, and March 31, 2012. Studies were selected if they presented sex-specific estimates, with associated variability, of the relative risk for either ischemic heart disease or stroke according to SBP. The data were pooled using random effects models with inverse variance weighting, and estimates of the ratio of the relative risks per 10 mm Hg increment in SBP, comparing women with men, were derived. RESULTS: Data from 124 prospective cohort studies, including information on 1197 472 individuals (44% women) and 26 176 stroke and 24 434 ischemic heart disease events, were included. Overall, there was no evidence to suggest a sex difference in the relationship between SBP and either the risk of stroke (pooled ratio of relative risks, 0.98 [95% confidence interval, 0.96; 1.01]; P=0.13) or ischemic heart disease (pooled ratio of relative risks, 1.00 [95% confidence interval, 0.97; 1.04]; P=0.85). CONCLUSIONS: Elevated levels of SBP are a major risk factor for stroke and ischemic heart diseases in both women and men. This study unequivocally demonstrates the broadly similar impact of SBP increments on cardiovascular outcomes in both sexes. PMID- 23821230 TI - The NINDS Stroke Progress Review Group final analysis and recommendations. PMID- 23821231 TI - Pro: Regulatory T cells are protective in ischemic stroke. PMID- 23821232 TI - The Feinberg Award Lecture 2013: treatment of intracranial atherosclerosis: learning from the past and planning for the future. PMID- 23821233 TI - [Pathophysiology of fibrotic encapsulation of episcleral glaucoma drainage implants: modification for improvement of clinical results]. AB - Episcleral glaucoma drainage implants (GDI) are being used increasingly more as a surgical option for lowering intraocular pressure (IOP). One of the main reasons for failure to control IOP is the formation of water-impervious fibrotic tissue around the base plate of GDIs that prevents effective resorption of the drained aqueous humor and thus leads to an increase in IOP. Surgical removal of the fibrotic tissue can often rescue implant function; however, repeated encapsulation can often not be prevented and necessitates additional interventions up to the removal of the implant itself. The reasons for the fibrotic reaction are not fully understood. Apart from patient-dependent mechanisms that are also involved in bleb scarring after trabeculectomy, implant properties, such as size, shape, surface properties and biomaterial probably contribute to the encapsulation process. Based on the literature on this topic this article looks at possible ways of improving the design of currently used drainage implants including the potential use of GDIs as a carrier for antifibrotic medication released at low doses over an extended period of time. PMID- 23821234 TI - Influence of body mass index on clinicopathological factors including estrogen receptor, progesterone receptor, and Ki67 expression levels in breast cancers. AB - BACKGROUND: High body mass index (BMI) is associated not only with a higher incidence of breast cancers but also with poorer prognosis. It is speculated that both enhanced production of estrogens and other factors associated with obesity are involved in these associations, but the biological characteristics associated with high BMI have yet to be thoroughly identified. METHODS: We studied 525 breast cancers, focusing on biological differences between tumors associated with high and low BMI and by immunohistochemically defined intrinsic subtype. Ki67 expression levels were used to differentiate luminal A from luminal B estrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)-breast cancers. RESULTS: Premenopausal patients with high BMI showed a significantly higher frequency of lymph node metastasis (46.4 % vs. 22.9 %, P = 0.005) and tended to have a larger tumor size (P = 0.05) and higher nuclear grade (P = 0.07) than those with low BMI. These differences were not observed among postmenopausal patients. BMI was not associated with distribution of breast cancer subtypes, and ER, progesterone receptor (PR), and Ki67 expression levels of each subtype showed no differences between high and low BMI among premenopausal patients. CONCLUSION: Higher BMI might influence aggressive tumor characteristics among premenopausal patients, but its influence on ER, PR, and Ki67 expression levels seems to be limited. PMID- 23821235 TI - Hypersalinity toxicity thresholds for nine California ocean plan toxicity test protocols. AB - Currently, several desalination facilities have been proposed to operate or are actually operating in California. These facilities' use of reverse osmosis (RO) may discharge hypersaline reject brine into the marine environment. The risks, if any, this brine would pose to coastal receiving waters are unknown. To test the toxicity of hypersaline brine in the absence of any additional toxic constituents, we prepared brine and tested it with the seven toxicity test organisms listed in the 2009 California Ocean Plan. The most sensitive protocols were the marine larval development tests, whereas the most tolerant to increased salinities were the euryhaline topsmelt, mysid shrimp, and giant kelp tests. Reject brines from the Monterey Bay Aquarium's RO desalination facility were also tested with three species. The effects of the aquarium's brine effluent on topsmelt, mussels, and giant kelp were consistent with those observed in the salinity tolerance experiments. This information will be used by regulators to establish receiving water limitations for hypersaline discharges. PMID- 23821236 TI - [Venous malformation of the cheek]. AB - Venous malformations as a cause of space-occupying lesions in the head and neck region are rare, especially at an advanced age. We report on a 74-year-old female patient with a venous malformation of the cheek and its successful surgical treatment. PMID- 23821237 TI - Immobilized silver nanoparticles enhance contact killing and show highest efficacy: elucidation of the mechanism of bactericidal action of silver. AB - Antimicrobial materials with immobilized/entrapped silver nanoparticles (AgNPs) are of considerable interest. There is significant debate on the mode of bactericidal action of AgNPs, and both contact killing and/or ion mediated killing have been proposed. In this study, AgNPs were immobilized on an amine functionalized silica surface and their bactericidal activity was studied concurrently with the silver release profile over time. This was compared with similar studies performed using colloidal AgNPs and AgCl surfaces that released Ag ions. We conclude that contact killing is the predominant bactericidal mechanism and surface immobilized nanoparticles show greater efficacy than colloidal AgNPs, as well as a higher concentration of silver ions in solution. In addition, the AgNP immobilized substrate was used multiple times with good efficacy, indicating this immobilization protocol is effective for retaining AgNPs while maintaining their disinfection potential. The antibacterial surface was found to be extremely stable in aqueous medium and no significant leaching (~1.15% of total silver deposited) of the AgNPs was observed. Thus, immobilization of AgNPs on a surface may promote reuse, reduce environmental risks associated with leaching of AgNPs and enhance cost effectiveness. PMID- 23821238 TI - Acute effects of sex-specific sex hormones on heat shock proteins in fast muscle of male and female rats. AB - Heat shock protein (HSP) expression and sex hormone levels have been shown to influence several aspects of skeletal muscle physiology (e.g., hypertrophy, resistance to oxidative stress), suggesting that sex hormone levels can effect HSP expression. This study evaluated the effects of differing levels of sex specific sex hormones (i.e., testosterone in males and estrogen in females) on the expression of 4: HSP70, HSC70, HSP25, and alphaB-crystallin in the quadriceps muscles of male and female rats. Animals were assigned to 1 of 3 groups (n = 5 M and F/group). The first group (Ctl) consisted of typically cage-housed animals that served as controls. The second group (H) was gonadectomized and received either testosterone (males) or estradiol (females) via injection for 12 consecutive days. The third group (Gx) was gonadectomized and injected as above, but with vehicle only, rather than hormones. Significant sex by condition interactions (P < 0.05 by two-way MANOVA) were found for all 4 proteins studied, except for HSP70, which exhibited a significant effect of condition only. The expression of all HSPs was greater (1.9-2.5-fold) in males vs. females in the Ctl group, except for HSP70, which was no different. Generally, gonadectomy appeared to have greater effects in males than females, but administration of the exogenous sex hormones tended to produce more robust relative changes in females than males. There were no differences in myosin composition in any of the groups, suggesting that changes in fiber type were not a factor in the differential protein expression. These data may have implications for sex-related differences in muscular responses to exercise, disuse, and injury. PMID- 23821239 TI - Jump training with different loads: effects on jumping performance and power output. AB - PURPOSE: To investigate the selective effects of different types of external loads applied in vertical jump training on both the performance and muscle power output of the squat (SJ) and countermovement jump (CMJ). METHODS: Physically active males practiced maximum unconstrained vertical jumps over an 8-week period with no load, with either a negative or positive load exerted by a nearly constant external force that altered their body weight, and with a loaded vest that increased both the body weight and inertia. The magnitude of all applied loads corresponded to 30 % of body weight. RESULTS: A similar training-associated increase in jump height was observed in all experimental groups in both CMJ (7.4 11.8 %) and SJ (6.4-14.1 %). The relative increase in power output was comparable to the increase in jump height in SJ (7.4-11.5 %), while the power increase in CMJ was relatively small and load-specific (0.5-9.5 %). The observed differences could originate from the changes in the CMJ pattern, reflected through the depth of the counter movement that particularly increased after the training with negative load (42 %) and no load (21 %). The same participants also revealed increased CMJ duration, reduced ground reaction forces, as well as reduced maximum and average power output when compared with other training groups. CONCLUSION: Jump training with the applied loads could lead to a comparable improvement in jumping performance. However, the observed load-specific adaptations of CMJ pattern could decouple the training-associated increase in jump height from the increase in muscle power output. PMID- 23821240 TI - Hemodynamic adjustments during breath-holding in trained divers. AB - PURPOSE: Voluntary breath-holding (BH) elicits several hemodynamic changes, but little is known about maximal static immersed-body BH. We hypothesized that the diving reflex would be strengthened with body immersion and would spare more oxygen than maximal dry static BH, resulting in a longer BH duration. METHODS: Eleven trained breath-hold divers (BHDs) performed a maximal dry-body BH and a maximal immersed-body BH. Cardiac output (CO), stroke volume (SV), heart rate (HR), left ventricular end-diastolic volume (LVEDV), contractility index (CTI), and ventricular ejection time (VET) were continuously recorded by bio impedancemetry (PhysioFlow PF-05). Arterial oxygen saturation (SaO2) was assessed with a finger probe oximeter. RESULTS: In both conditions, BHDs presented a bi phasic kinetic for CO and a tri-phasic kinetic for SV and HR. In the first phase of immersed-body BH and dry-body BH, results (mean +/- SD) expressed as percentage changes from starting values showed decreased CO (55.9 +/- 10.4 vs. 39.3 +/- 16.8 %, respectively; p < 0.01 between conditions), due to drops in both SV (24.9 +/- 16.2 vs. 9.0 +/- 8.5 %, respectively; p < 0.05 between conditions) and HR (39.7 +/- 16.7 vs. 33.6 +/- 17.0 %, respectively; p < 0.01 between conditions). The second phase was marked by an overall stabilization of hemodynamic variables. In the third one, CO kept stabilizing due to increased SV (17.0 +/- 20.2 vs. 10.9 +/- 13.8 %, respectively; p < 0.05 between conditions) associated with a second HR drop (14.0 +/- 10.0 vs. 12.7 +/- 8.9 %, respectively; p < 0.01 between conditions). CONCLUSION: This study highlights similar time course patterns for cardiodynamic variables during dry-body and immersed-body BH, although the phenomenon was more pronounced in the latter condition. PMID- 23821241 TI - Constrained diffusion kurtosis imaging using ternary quartics & MLE. AB - PURPOSE: Diffusion kurtosis imaging (DKI) is a recent improvement over diffusion tensor imaging that characterizes tissue by quantifying non-gaussian diffusion using a 3D fourth-order kurtosis tensor. DKI needs to consider three constraints to be physically relevant. Further, it can be improved by considering the Rician signal noise model. A DKI estimation method is proposed that considers all three constraints correctly, accounts for the signal noise and incorporates efficient gradient-based optimization to improve over existing methods. METHODS: The ternary quartic parameterization is utilized to elegantly impose the positivity of the kurtosis tensor implicitly. Sequential quadratic programming with analytical gradients is employed to solve nonlinear constrained optimization efficiently. Finally, a maximum likelihood estimator based on Rician distribution is considered to account for signal noise. RESULTS: Extensive experiments conducted on synthetic data verify a MATLAB implementation by showing dramatically improved performance in terms of estimation time and quality. Experiments on in vivo cerebral data confirm that in practice the proposed method can obtain improved results. CONCLUSION: The proposed ternary quartic-based approach with a gradient-based optimization scheme and maximum likelihood estimator for constrained DKI estimation improves considerably on existing DKI methods. PMID- 23821243 TI - Circulating 25-hydroxyvitamin D levels and hypertension risk. PMID- 23821246 TI - Does the magnetic-guided intramedullary nailing technique shorten operation time and radiation exposure? AB - AIM: The aim of this study is to show whether a new magnetic-guided locking technique is superior to a standard freehand technique in terms of operation time and radiation exposure. This treatment will be used for distal locking of the tibia during intramedullary nailing. METHODS: This randomized trial is done through 80 patients having tibial fractures with a mean age of 25 years (range 16 67 years). In the magnetic locking group, there were 20 fractures of the distal third, 16 of the shaft, and 4 of the proximal tibia; in the freehand group, these numbers were 15, 20, and 5, respectively. The parameters like operation time, distal locking time, radiation exposure duration, and dose were compared. RESULTS: We placed 100 distal locking screws in the magnetic locking group and 95 in the freehand group. Fluoroscopy was necessary only in the freehand group. All screws were correctly positioned the first time in both groups. The magnetic locking group had a shorter mean surgical time (52 +/- 6.2 vs 70 +/- 10.9 min; P < 0.01), a shorter mean distal locking time (5 +/- 1.1 vs 16 +/- 2.0 min; P < 0.01), and a shorter mean placement time for each screw (2 +/- 0.5 vs 7 +/- 1.2 min; P < 0.01). The magnetic locking group had lower mean radiation exposures (8 +/- 4.5 vs 40 +/- 7.6 s; P < 0.01) and mean radiation exposure (5.4 +/- 2.5 vs 25 +/- 6.8 mGy range; P < 0.01). CONCLUSIONS: For distal locking during tibial intramedullary nailing, the magnetic locking system is as accurate as the standard freehand technique, but it has lower operative times and radiation exposures compared to the standard freehand technique. Therefore, the magnetic locking system should be preferred to current standard freehand techniques. PMID- 23821247 TI - A case of intrauterine diagnosed posterior fossa dermoid presenting in childhood. AB - Intrauterine intracranial brain tumor is a rare entity. Traditionally, the outcome of this tumor had been dismal. In a large series of congenital brain tumor, the commonest have been teratoma followed by astrocytoma and craniopharyngioma. We report a case of intracranial dermoid in post-fossa diagnosed at 8 months of intrauterine life during routine prenatal ultrasonography. The child's clinical picture, the surgery performed and the final outcome have been discussed. As far as our knowledge goes, this is perhaps the first reported case of intrauterine-diagnosed intracranial dermoid. PMID- 23821245 TI - Mid-term efficacy of percutaneous laser disc decompression for treatment of cervical vertigo. AB - OBJECTIVE: To observe and analyze the mid-term efficacy of percutaneous laser disc decompression (PLDD) for the treatment of cervical vertigo. METHODS: Thirty five patients with cervical vertigo were admitted from September 2002 to December 2006, including 14 males and 21 females, aged between 35 and 79 years with an average of 59.1 years. All patients were treated with PLDD by the Nd:YAG laser therapy (wavelength: 1,064 nm) and were followed up. The improvement of vertigo and associated symptoms was evaluated by numerical rating scale (NRS) assessment, while fineness rate and efficient rate were evaluated using modified MacNab assessment criteria. RESULTS: No intraoperative and postoperative complication was reported. The patients were followed up for 24-66 months. At the end of the follow-up, the average NRS scores of the dizziness and complications are significantly smaller. The overall efficacy was evaluated based on modified MacNab criteria: excellent, 18 cases; good, 7 cases; acceptable, 5 cases; and poor, 5 cases. No statistical difference existed between age groups (P > 0.05) and also between gender groups (P > 0.05). CONCLUSION: PLDD treatment of cervical vertigo trauma has many advantages, such as minimal trauma, high safety, and satisfactory mid-term efficacy with no significant difference in clinical efficacy between different age and gender groups. PMID- 23821248 TI - Myxopapillary ependymoma of the conus medullaris presenting with intratumoral hemorrhage during weight lifting in a teenager. AB - Intratumoral hemorrhage within a myxopapillary ependymoma of the conus medullaris and cauda equina is rare. Most patients with myxopapillary ependymoma present insidiously, but they may present with hemorrhage or cauda equina syndrome. Limited number of case reports available has described this condition only in adult patients. We report our experience with intratumoral hemorrhage of myxopapillary ependymoma of the conus medullaris during weight lifting in a 15 year-old boy. PMID- 23821244 TI - Seventeen year risk of all-cause and cause-specific mortality associated with C reactive protein, fibrinogen and leukocyte count in men and women: the EPIC Norfolk study. AB - There is strong evidence from observational studies suggesting serum C-reactive protein (CRP) is associated with cardiovascular and all-cause mortality. However, less is known about whether there are differences in the association of CRP with all-cause or cause specific mortality by sex, smoking, body mass index (BMI), or physical activity. We aimed to investigate these interactions and also investigate and compare the association of CRP and other inflammation markers (i.e., fibrinogen and leukocyte count) with all-cause and cause-specific mortality. Men and women aged 40-79 were recruited in 1993-1997 in the EPIC Norfolk cohort study. A total of 16,850 participants with high-sensitivity assayed CRP data who had no known cancer, myocardial infarction and stroke at baseline were entered in the analysis to test the association of CRP, fibrinogen and leukocyte count with risk of all-cause and cause specific mortality. A total of, 2,603 all-cause deaths (1,452 in men) including 823 cardiovascular and 1,035 cancer deaths, were observed after 231,000 person-years of follow-up (median 14.3 years). CRP was positively associated with risk of all-cause, cardiovascular, and non-cancer non-cardiovascular mortality independent of established risk factors. The hazard ratio of all-cause mortality (95 % CI) for participants with CRP in the range of 3-10 and >10 mg/l (vs. <0.5 mg/l) was 1.56 (1.26-1.93) and 1.87 (1.43-2.43) respectively in men and 1.34 (1.07-1.68) and 1.98 (1.50-2.63) in women. The association was less positively graded in women with the increased risk being significant only at higher levels of the CRP distribution. The association persisted in never smokers and did not vary by levels of BMI or physical activity. Although fibrinogen and leukocyte count were also positively associated with mortality risk, only CRP remained a significant predictor of mortality when the inflammation markers were adjusted for one another in multivariable models. Serum CRP levels were a long-term predictor of risk of cardiovascular and non-cardiovascular mortality independent of known risk factors, fibrinogen, and leukocyte count. PMID- 23821249 TI - Molecular tools for monitoring harmful algal blooms.